PMID- 24337285 TI - Epidemiology. Coming to an airport near you. PMID- 24337286 TI - Chemistry. Improving biologic drugs via total chemical synthesis. PMID- 24337287 TI - Molecular biology. Finding the right partner in a 3D genome. PMID- 24337288 TI - Retrospective. Michael Neuberger (1953-2013). PMID- 24337289 TI - The hidden geometry of complex, network-driven contagion phenomena. AB - The global spread of epidemics, rumors, opinions, and innovations are complex, network-driven dynamic processes. The combined multiscale nature and intrinsic heterogeneity of the underlying networks make it difficult to develop an intuitive understanding of these processes, to distinguish relevant from peripheral factors, to predict their time course, and to locate their origin. However, we show that complex spatiotemporal patterns can be reduced to surprisingly simple, homogeneous wave propagation patterns, if conventional geographic distance is replaced by a probabilistically motivated effective distance. In the context of global, air-traffic-mediated epidemics, we show that effective distance reliably predicts disease arrival times. Even if epidemiological parameters are unknown, the method can still deliver relative arrival times. The approach can also identify the spatial origin of spreading processes and successfully be applied to data of the worldwide 2009 H1N1 influenza pandemic and 2003 SARS epidemic. PMID- 24337290 TI - Detection of a noble gas molecular ion, 36ArH+, in the Crab Nebula. AB - Noble gas molecules have not hitherto been detected in space. From spectra obtained with the Herschel Space Observatory, we report the detection of emission in the 617.5- and 1234.6-gigahertz J = 1-0 and 2-1 rotational lines of (36)ArH(+) at several positions in the Crab Nebula, a supernova remnant known to contain both molecular hydrogen and regions of enhanced ionized argon emission. Argon-36 is believed to have originated from explosive nucleosynthesis in massive stars during core-collapse supernova events. Its detection in the Crab Nebula, the product of such a supernova event, confirms this expectation. The likely excitation mechanism for the observed (36)ArH(+) emission lines is electron collisions in partially ionized regions with electron densities of a few hundred per centimeter cubed. PMID- 24337291 TI - Phosphorus in the young supernova remnant Cassiopeia A. AB - Phosphorus ((31)P), which is essential for life, is thought to be synthesized in massive stars and dispersed into interstellar space when these stars explode as supernovae (SNe). Here, we report on near-infrared spectroscopic observations of the young SN remnant Cassiopeia A, which show that the abundance ratio of phosphorus to the major nucleosynthetic product iron ((56)Fe) in SN material is up to 100 times the average ratio of the Milky Way, confirming that phosphorus is produced in SNe. The observed range is compatible with predictions from SN nucleosynthetic models but not with the scenario in which the chemical elements in the inner SN layers are completely mixed by hydrodynamic instabilities during the explosion. PMID- 24337292 TI - Effect of collective molecular reorientations on Brownian motion of colloids in nematic liquid crystal. AB - In the simplest realization of Brownian motion, a colloidal sphere moves randomly in an isotropic fluid; its mean squared displacement (MSD) grows linearly with time tau. Brownian motion in an orientationally ordered fluid--a nematic--is anisotropic, with the MSD being larger along the axis of molecular orientation, called the director. We found that at short time scales, the anisotropic diffusion in a nematic becomes anomalous, with the MSD growing slower or faster than tau; these states are respectively termed subdiffusion and superdiffusion. The anomalous diffusion occurs at time scales that correspond to the relaxation times of director deformations around the sphere. Once the nematic melts, the diffusion becomes normal and isotropic. Our experiment shows that the deformations and fluctuations of long-range orientational order profoundly influence diffusive regimes. PMID- 24337293 TI - Detection and structure of HOON: microwave spectroscopy reveals an O-O bond exceeding 1.9 A. AB - Nitric oxide (NO) reacts with hydroxyl radicals (OH) in the gas phase to produce nitrous acid, HONO, but essentially nothing is known about the isomeric nitrosyl O-hydroxide (HOON), owing to its perceived instability. We report the detection of gas-phase HOON in a supersonic molecular beam by Fourier transform microwave spectroscopy and a precise determination of its molecular structure by further spectroscopic analysis of its (2)H, (15)N, and (18)O isotopologs. HOON contains the longest O-O bond in any known molecule (1.9149 +/- 0.0005 A) and appears surprisingly stable, with an abundance roughly 3% that of HONO in our experiments. PMID- 24337294 TI - Erythropoietin derived by chemical synthesis. AB - Erythropoietin is a signaling glycoprotein that controls the fundamental process of erythropoiesis, orchestrating the production and maintenance of red blood cells. As administrated clinically, erythropoietin has a polypeptide backbone with complex dishomogeneity in its carbohydrate domains. Here we describe the total synthesis of homogeneous erythropoietin with consensus carbohydrate domains incorporated at all of the native glycosylation sites. The oligosaccharide sectors were built by total synthesis and attached stereospecifically to peptidyl fragments of the wild-type primary sequence, themselves obtained by solid-phase peptide synthesis. The glycopeptidyl constructs were joined by chemical ligation, followed by metal-free dethiylation, and subsequently folded. This homogeneous erythropoietin glycosylated at the three wild-type aspartates with N-linked high mannose sialic acid-containing oligosaccharides and O-linked glycophorin exhibits Procrit-level in vivo activity in mice. PMID- 24337295 TI - Exonic transcription factor binding directs codon choice and affects protein evolution. AB - Genomes contain both a genetic code specifying amino acids and a regulatory code specifying transcription factor (TF) recognition sequences. We used genomic deoxyribonuclease I footprinting to map nucleotide resolution TF occupancy across the human exome in 81 diverse cell types. We found that ~15% of human codons are dual-use codons ("duons") that simultaneously specify both amino acids and TF recognition sites. Duons are highly conserved and have shaped protein evolution, and TF-imposed constraint appears to be a major driver of codon usage bias. Conversely, the regulatory code has been selectively depleted of TFs that recognize stop codons. More than 17% of single-nucleotide variants within duons directly alter TF binding. Pervasive dual encoding of amino acid and regulatory information appears to be a fundamental feature of genome evolution. PMID- 24337296 TI - Cryptic variation in morphological evolution: HSP90 as a capacitor for loss of eyes in cavefish. AB - In the process of morphological evolution, the extent to which cryptic, preexisting variation provides a substrate for natural selection has been controversial. We provide evidence that heat shock protein 90 (HSP90) phenotypically masks standing eye-size variation in surface populations of the cavefish Astyanax mexicanus. This variation is exposed by HSP90 inhibition and can be selected for, ultimately yielding a reduced-eye phenotype even in the presence of full HSP90 activity. Raising surface fish under conditions found in caves taxes the HSP90 system, unmasking the same phenotypic variation as does direct inhibition of HSP90. These results suggest that cryptic variation played a role in the evolution of eye loss in cavefish and provide the first evidence for HSP90 as a capacitor for morphological evolution in a natural setting. PMID- 24337297 TI - Progressive specification rather than intercalation of segments during limb regeneration. AB - An amputated salamander limb regenerates the correct number of segments. Models explaining limb regeneration were largely distinct from those for limb development, despite the presence of common patterning molecules. Intercalation has been an important concept to explain salamander limb regeneration, but clear evidence supporting or refuting this model was lacking. In the intercalation model, the first blastema cells acquire fingertip identity, creating a gap in positional identity that triggers regeneration of the intervening region from the stump. We used HOXA protein analysis and transplantation assays to show that axolotl limb blastema cells acquire positional identity in a proximal-to-distal sequence. Therefore, intercalation is not the primary mechanism for segment formation during limb regeneration in this animal. Patterning in development and regeneration uses similar mechanisms. PMID- 24337298 TI - Direct and reversible hydrogenation of CO2 to formate by a bacterial carbon dioxide reductase. AB - Storage and transportation of hydrogen is a major obstacle for its use as a fuel. An increasingly considered alternative for the direct handling of hydrogen is to use carbon dioxide (CO2) as an intermediate storage material. However, CO2 is thermodynamically stable, and developed chemical catalysts often require high temperatures, pressures, and/or additives for high catalytic rates. Here, we present the discovery of a bacterial hydrogen-dependent carbon dioxide reductase from Acetobacterium woodii directly catalyzing the hydrogenation of CO2. We also demonstrate a whole-cell system able to produce formate as the sole end product from dihydrogen (H2) and CO2 as well as syngas. This discovery opens biotechnological alternatives for efficient CO2 hydrogenation either by using the isolated enzyme or by employing whole-cell catalysis. PMID- 24337299 TI - Fear learning enhances neural responses to threat-predictive sensory stimuli. AB - The central nervous system rapidly learns that particular stimuli predict imminent danger. This learning is thought to involve associations between neutral and harmful stimuli in cortical and limbic brain regions, though associative neuroplasticity in sensory structures is increasingly appreciated. We observed the synaptic output of olfactory sensory neurons (OSNs) in individual mice before and after they learned that a particular odor indicated an impending foot shock. OSNs are the first cells in the olfactory system, physically contacting the odor molecules in the nose and projecting their axons to the brain's olfactory bulb. OSN output evoked by the shock-predictive odor was selectively facilitated after fear conditioning. These results indicate that affective information about a stimulus can be encoded in its very earliest representation in the nervous system. PMID- 24337300 TI - The genome of the ctenophore Mnemiopsis leidyi and its implications for cell type evolution. AB - An understanding of ctenophore biology is critical for reconstructing events that occurred early in animal evolution. Toward this goal, we have sequenced, assembled, and annotated the genome of the ctenophore Mnemiopsis leidyi. Our phylogenomic analyses of both amino acid positions and gene content suggest that ctenophores rather than sponges are the sister lineage to all other animals. Mnemiopsis lacks many of the genes found in bilaterian mesodermal cell types, suggesting that these cell types evolved independently. The set of neural genes in Mnemiopsis is similar to that of sponges, indicating that sponges may have lost a nervous system. These results present a newly supported view of early animal evolution that accounts for major losses and/or gains of sophisticated cell types, including nerve and muscle cells. PMID- 24337301 TI - (-)-Epigallocatechin-3-gallate suppresses liver metastasis of human colorectal cancer. AB - (-)-Epigallocatechin-3-gallate (EGCG), the major constituent of green tea, has been shown to inhibit cell proliferation and induce apoptosis in several types of human tumors. The most common site of distant metastases in colorectal cancer is the liver. However, no previous studies have reported the ability of EGCG to suppress liver metastases of human colorectal cancer. The aim of the present study was to elucidate the potential use of EGCG as chemotherapy targeting liver metastases of human colorectal cancer. To assess the effect of EGCG on human colorectal cancer cell lines, RKO and HCT116, cell viability, cell proliferation and apoptosis were measured by cell counting kit-8, BrdU assay and TUNEL staining, respectively. Protein and gene expression were measured by western blot analysis and RT-PCR analysis, respectively. EGCG inhibited cell proliferation and induced apoptosis. EGCG dephosphorylated constitutively activated Akt and increased the activation of p38. EGCG also decreased the expression of vascular endothelial growth factor receptor 2. Additionally, the ability of EGCG to prevent the development of liver metastases of RKO tumors was evaluated in SCID mice. EGCG suppressed angiogenesis and induced apoptosis in liver metastases without associated body weight loss or hepatotoxicity. Furthermore, the liver metastatic area was significantly reduced by EGCG administration. Our findings indicate that EGCG may be useful in the treatment of liver metastases of human colorectal cancer. PMID- 24337302 TI - [Anaphylaxis to PR-10 proteins (Bet v1 homologues)]. AB - Secondary food allergies to PR-10 proteins (Bet v1 homologues) are the most common food allergies in Germany. Clinically they present with an oral allergy syndrome (intraoral pruritus and perhaps swelling). When drinks containing PR-10 proteins are rapidly consumed, for example after sporting activities, large concentrations of allergen can be reached without any intraoral symptoms and then lead to anaphylaxis. This phenomenon has often been described for soja milk and occurred in our case with an apple drink with 60% fruit concentration. It seems likely that such cases of anaphylaxis are not adequately represented in the anaphylaxis registry. PMID- 24337303 TI - [Cutaneous radiation damage]. PMID- 24337304 TI - [Cutaneous radiation syndrome after accidental skin exposure to ionizing radiation]. AB - Accidental exposure of the human skin to single doses of ionizing radiation greater than 3 Gy results in a distinct clinical picture, which is characterized by a transient and faint erythema after a few hours, then followed by severe erythema, blistering and necrosis. Depending on severity of damage, the latter generally occurs 10-30 days after exposure, but in severe cases may appear within 48 hrs. Between three and 24 months after exposure, epidermal atrophy combined with progressive dermal and subcutaneous fibrosis is the predominant clinical feature. Even years and decades after exposure, atrophy of epidermis, sweat and sebaceous glands; telangiectases; and dermal and subcutaneous fibrosis may be found and even continue to progress. For this distinct pattern of deterministic effects following cutaneous accidental radiation exposure the term "cutaneous radiation syndrome (CRS)" was coined in 1993 and has been accepted by all international authorities including IAEA and WHO since 2000. In contrast to the classical concept that inhibition of epidermal stem cell proliferation accounts for the clinical symptomatology, research of the last three decades has demonstrated the additional crucial role of inflammatory processes in the etiology of both acute and chronic sequelae of the CRS. Therefore, therapeutic approaches should include topical and systemic anti-inflammatory measures at the earliest conceivable point, and should be maintained throughout the acute and subacute stages, as this reduces the need for surgical intervention, once necrosis has occurred. If surgical intervention is planned, it should be executed with a conservative approach; no safety margins are needed. Antifibrotic measures in the chronic stage should address the chronic inflammatory nature of this process, in which over-expression TGF beta-1 may be a target for therapeutic intervention. Life-long follow-up often is required for management of delayed effects and for early detection of secondary malignancies, which must be searched for especially in the borderline areas between clinically symptomatic and asymptomatic skin. PMID- 24337305 TI - [Cutaneous damage after acute exposure to ionizing radiation: decisive for the prognosis of radiation accident victims]. AB - The cutaneous radiation syndrome includes all deterministic effects on the skin and visible parts of the mucosa from ionizing radiation. The Intensity and duration of radiation-induced skin symptoms depend on the kind and quality of ionizing radiation. The aim of this study was the investigation of the importance of the time of the development of radiation induced-skin effects on the prognosis of radiation accident victims. Clinical data about radiation accident victims from the database SEARCH were used. 211 cases with good documentation regarding radiation-induced skin effects were selected. From these 211 patients, 166 survived the acute phase of the acute radiation syndrome, while 45 died during the acute phase. Among those patients who did not survive the acute phase, 82.2 % showed their first documented radiation-induced skin symptoms during the first 3 days after radiation exposure. Of those patients whose first documented radiation induced skin symptoms appeared on or after day four, 94.2 % survived the acute phase. The time to the occurrence of the first radiation-induced skin effects is diagnostically significant. The skin plays an important role in the clinical course of radiation syndromes and in the development of radiation-induced multi organ failure. In a retrospective data analysis like this, the quality of data might be a limitation. PMID- 24337307 TI - [Giant squamous cell carcinoma of the scalp: successful excision with use of bovine dermal substitute]. AB - A 68-year-old woman presented with an enormous exophytic tumor on her forehead extending to the scalp. After complete resection of the tumor, the resulting defect was closed successfully using a bovine dermal substitute followed by a split-thickness skin graft. PMID- 24337306 TI - [Stem cell derived therapy for cutaneous radiation exposure]. AB - Radiation injury to skin results in a variety of deterministic effects including inflammatory reactions and cell depletion leading to distinct clinical symptoms following a defined time pattern. Therapeutic approaches are still limited, a complete restitution of affected areas is so far impossible. In the last few years increasing experimental knowledge about acquisition and administration of autologous stem cells also in the field of radiation injuries has been obtained. Evidence reviewed in this article shows that the beneficial effects of stem cell transplantation are not necessarily due to the replacement of damaged cells by transplanted cells but most probably due in the most part to a paracrine effect. Transplanted cells secrete bioactive factors that initiate the stimulation of the host stem cells to regenerate the damaged tissues. Transplanted stem cells produce trophic factors which aid the systemic healing of the victims. Furthermore, administration of stem cell secretomes in the form of conditioned media containing microvesicles or exosomes can be as effective as administering the stem cells. This hypothesis is supported by findings that cell-free derivatives from hMSCs were useful for wound healing purposes and could circumvent the need for intact cells. Furthermore, the beneficial effect of MSC injection on reperfusion and tissue damage in a mouse model of hind limb ischemia could be attributed to paracrine mechanisms with local release of arteriogenic cytokines. Further evaluation of the paracrine potential of autologous stem cells may open new means for treatment of acute as well as chronic sequelae of cutaneous radiation injuries. PMID- 24337309 TI - [Brown macule with parallel ridge pattern on the palm of a 58-year-old woman]. PMID- 24337308 TI - [Bullous pemphigoid]. AB - Pemphigoid diseases are a group of autoimmune disorders characterized by subepidermal blistering and autoantibodies against structural proteins of the dermal-epidermal junction. In bullous pemphigoid, the most common subepidermal blistering autoimmune disease, antibodies are directed against the hemidesmosomal antigens BP180 (collagen type XVII) and BP230. Bullous pemphigoid typically presents with severe pruritus and tense blisters accompanied by erosions and crusts in elderly patients. Diagnostic landmarks are the detection of linear IgG and/or C3 deposits at the dermo-epidermal junction by direct immunofluorescence microscopy of a perilesional biopsy and the detection of serum autoantibodies by indirect immunofluorescence microscopy on human salt-split skin and ELISA employing recombinant immunodominant fragments of BP180 and BP230. Treatment options include topical (class IV) and/or systemic corticosteroids, frequently combined with immunomodulatory agents like dapsone and tetracyclines or immunosuppressants such as methotrexate and azathioprine. PMID- 24337310 TI - Anticoagulation during and after acute coronary syndrome. AB - Current antithrombotic therapy in patients with acute coronary syndrome (ACS) comprises antiplatelet and anticoagulant therapy. Dual antiplatelet therapy composed of aspirin plus a third generation P2Y12 inhibitor (prasugrel or ticagrelor) represents the gold standard, while aspirin plus second generation P2Y12 inhibitor (clopidogrel) may be used as an alternative in the presence of contraindications for third generation P2Y12 inhibitors and/or a high risk of bleeding. Unfractionated heparin (UFH) has been the unchallenged mainstay in anticoagulation for ACS for many decades and is still widely used in patients with ACS treated interventionally. Novel alternative parenteral anticoagulant strategies include the low molecular weight heparin enoxaparin and the synthetic pentasaccharide fondaparinux. Both of these agents share advantages over UFH particularly in medically treated patients with ACS not scheduled for PCI. The direct parenteral factor IIa (thrombin) inhibitor bivalirudin, when used as sole anticoagulant in patients with ACS undergoing PCI, is as effective as the regimen of UFH plus GPIIb/IIIa inhibitor in NSTEMI and superior to the latter regimen in patients with STEMI. The novel approach of a long-term low dose factor Xa inhibition with rivaroxaban in the post ACS phase even further reduced cardiovascular mortality in a clinical trial but has yet to be established in daily clinical practice in the setting of third generation P2Y12 inhibitors. This review discusses currently clinically established anticoagulants for the treatment of ACS alongside with novel approaches such as rivaroxaban. PMID- 24337311 TI - ESCAP online: integrating alignment and internet technology in our vision on international CAP relations. PMID- 24337312 TI - Implications of new insurance coverage for access to care, cost-sharing, and reimbursement. PMID- 24337313 TI - Dynamics of vitellogenin and vitellogenesis-inhibiting hormone levels in adult and subadult whiteleg shrimp, Litopenaeus vannamei: relation to molting and eyestalk ablation. AB - Levels of vitellogenin (VG) and vitellogenesis-inhibiting hormone (VIH) in the whiteleg shrimp, Litopenaeus vannamei, were measured by time-resolved fluoroimmunoassay in relation to the molting cycle and ovarian maturation induced by eyestalk ablation. During the molt cycle, VG mRNA expression levels and VG concentrations showed similar patterns of fluctuation. VG levels increased significantly at early intermolt (stage C0) in adults, but not in subadults. Unilateral and bilateral eyestalk ablation increased VG levels in adults, whereas only bilateral eyestalk ablation affected subadults. VIH levels showed contrasting patterns between adults and subadults. In adults, levels were high in late postmolt adults (stage B) and then low thereafter, whereas they increased from postmolt (stage A) to intermolt (stage C0) in subadults and remained high. Unilateral eyestalk ablation increased VIH levels 10 days following ablation in adults, after which levels decreased at 20 days. VIH levels decreased from 10 to 20 days after bilateral ablation. Both unilateral and bilateral ablation led to increased VIH levels in subadults. Eyestalk ablation induced ovarian maturation, but did not reduce VIH concentrations in the hemolymph. This phenomenon was perhaps due to other crustacean hyperglycemic hormone peptides having cross reactivity with VIH antibodies. This is the first report to quantify concentrations of VG and VIH together in L. vannamei hemolymph, and to examine their relative dynamics. PMID- 24337314 TI - The naturally occurring luteinizing hormone surge is diminished in mice lacking estrogen receptor Beta in the ovary. AB - Female ESR2-null mice (betaERKO) display defects in ovarian function and are subfertile. Follicular maturation is impaired and explains smaller litters, but betaERKO also produce fewer litters, which may be partially due to inadequate ovulatory signals. To test this, the amplitude and timing of the naturally occurring luteinizing hormone (LH) surge was measured in individual intact betaERKO and wild-type (WT) mice. Vaginal cytology was evaluated daily, and blood samples were taken from mice in proestrus. The amplitude of the LH surge was severely blunted in betaERKO mice compared to WT, but pituitary LH levels revealed no differences. The betaERKO mice did not produce a preovulatory estradiol surge. To determine if the smaller LH surges and the reduced number of litters in betaERKO were due to the lack of ESR2 in the hypothalamic-pituitary axis or due to the absence of ESR2 in the ovary, ovaries were transplanted from WT into betaERKO mice and vice versa. The size of the LH surge was reduced only in mice lacking ESR2 within the ovary, and these mice had fewer litters. Fertility and size of the LH surge were rescued in betaERKO mice receiving a WT ovary. These data provide the first experimental evidence that the LH surge is impaired in betaERKO females and may contribute to their reduced fertility. ESR2 is not necessary within the pituitary and hypothalamus for the generation of a normal LH surge and for normal fertility, but ESR2 is essential within the ovary to provide proper signals. PMID- 24337315 TI - In vitro culture increases the frequency of stochastic epigenetic errors at imprinted genes in placental tissues from mouse concepti produced through assisted reproductive technologies. AB - Assisted reproductive technologies (ART) have enabled millions of couples with compromised fertility to conceive children. Nevertheless, there is a growing concern regarding the safety of these procedures due to an increased incidence of imprinting disorders, premature birth, and low birth weight in ART-conceived offspring. An integral aspect of ART is the oxygen concentration used during in vitro development of mammalian embryos, which is typically either atmospheric (~20%) or reduced (5%). Both oxygen tension levels have been widely used, but 5% oxygen improves preimplantation development in several mammalian species, including that of humans. To determine whether a high oxygen tension increases the frequency of epigenetic abnormalities in mouse embryos subjected to ART, we measured DNA methylation and expression of several imprinted genes in both embryonic and placental tissues from concepti generated by in vitro fertilization (IVF) and exposed to 5% or 20% oxygen during culture. We found that placentae from IVF embryos exhibit an increased frequency of abnormal methylation and expression profiles of several imprinted genes, compared to embryonic tissues. Moreover, IVF-derived placentae exhibit a variety of epigenetic profiles at the assayed imprinted genes, suggesting that these epigenetic defects arise by a stochastic process. Although culturing embryos in both of the oxygen concentrations resulted in a significant increase of epigenetic defects in placental tissues compared to naturally conceived controls, we did not detect significant differences between embryos cultured in 5% and those cultured in 20% oxygen. Thus, further optimization of ART should be considered to minimize the occurrence of epigenetic errors in the placenta. PMID- 24337316 TI - Ureaplasma parvum undergoes selection in utero resulting in genetically diverse isolates colonizing the chorioamnion of fetal sheep. AB - Ureaplasmas are the microorganisms most frequently isolated from the amniotic fluid of pregnant women and can cause chronic intrauterine infections. These tiny bacteria are thought to undergo rapid evolution and exhibit a hypermutatable phenotype; however, little is known about how ureaplasmas respond to selective pressures in utero. Using an ovine model of chronic intraamniotic infection, we investigated if exposure of ureaplasmas to subinhibitory concentrations of erythromycin could induce phenotypic or genetic indicators of macrolide resistance. At 55 days gestation, 12 pregnant ewes received an intraamniotic injection of a nonclonal, clinical Ureaplasma parvum strain followed by (i) erythromycin treatment (intramuscularly, 30 mg/kg/day, n = 6) or (ii) saline (intramuscularly, n = 6) at 100 days gestation. Fetuses were then delivered surgically at 125 days gestation. Despite injecting the same inoculum into all the ewes, significant differences between amniotic fluid and chorioamnion ureaplasmas were detected following chronic intraamniotic infection. Numerous polymorphisms were observed in domain V of the 23S rRNA gene of ureaplasmas isolated from the chorioamnion (but not the amniotic fluid), resulting in a mosaiclike sequence. Chorioamnion isolates also harbored the macrolide resistance genes erm(B) and msr(D) and were associated with variable roxithromycin minimum inhibitory concentrations. Remarkably, this variability occurred independently of exposure of ureaplasmas to erythromycin, suggesting that low-level erythromycin exposure does not induce ureaplasmal macrolide resistance in utero. Rather, the significant differences observed between amniotic fluid and chorioamnion ureaplasmas suggest that different anatomical sites may select for ureaplasma subtypes within nonclonal, clinical strains. This may have implications for the treatment of intrauterine ureaplasma infections. PMID- 24337317 TI - Characteristics of long-term cultures of avian primordial germ cells and gonocytes. AB - Avian cell lines derived from germinal crescent primordial germ cells and gonadal gonocytes with long-term proliferative capacity in vitro and their subsequent rates of colonization and germline transmission are described. In general, male cultures proliferate more rapidly than female cultures although both can be developed into cell lines of >2 * 10(6) cells, at which time, they can be grown indefinitely and a cell bank can be established. All the cell lines injected into embryos transmitted through the germline with the percentage of germline transmission of both male and female cell lines varying from single digits to the high 90s. The derivation of these primordial germ cell and gonadal cell lines and the subsequent robustness of germline transmission validates these cells as suitable for establishment of lines of chickens bearing novel genetic modifications. PMID- 24337318 TI - Advanced age remains an achilles heel for liver resections. AB - BACKGROUND: As the general population is aging, surgery in elderly patients has become a major public health issue. This basic question is especially true for liver resection (LR). The aim of this study was to evaluate the operative risks of LR in the elderly. METHODS: Retrospective analysis of a large recent and monocentric database of LR was performed between January 1, 2005 and May 31, 2011. Patients were categorized into three groups (<60, 60-74, and >=75 years old) to analyze postoperative outcomes and 1-year mortality. Clinicopathologic factors likely to influence outcomes were assessed by univariate and multivariate analysis. RESULTS: Altogether, 1,001 consecutive LRs were performed in 912 patients (mean age 62 +/- 13 years). The distribution of the LR by age was 372 (37.2 %), 477 (47.6 %), and 152 (15.2 %) in patients <60, 60-74, and >=75 years, respectively. The overall morbidity and mortality rates were 33.3 and 2.5 %, respectively. Age >=75 years was independently associated with postoperative mortality [odds ratio (OR) 4.75, 95 % confidence interval (CI) 1.5-15.1; p = 0.008] and 1-year mortality (OR 2.8, 95 % CI 1.2-6.6; p = 0.015). The postoperative complication rate (p = 0.216) was not increased, even for major complications (p = 0.09). The other independent risk factors for mortality were a cirrhotic liver (p = 0.017), preoperative arterial chemoembolization (p = 0.001), caval vein clamping (p = 0.001), and intraoperative blood transfusion (p = 0.044). CONCLUSIONS: Age beyond 75 years represent a risk factor of death after LR and should be avoided after chemoembolization or in cirrhotic patients. A specific assessment using geriatric indexes might be the key to success in this population. PMID- 24337319 TI - Citrate anticoagulation for continuous renal replacement therapy in small children. AB - BACKGROUND: Regional citrate anticoagulation (RCA) is one of the methods used to prevent clotting in continuous renal replacement therapy (CRRT). The aim of this study was to describe the outcomes and complications of RCA-CRRT in comparison to heparin anticoagulation (HA)-CRRT in critically ill children. METHODS: This study was a retrospective review of 30 critically ill children (16 on RCA- and 14 on HA CRRT) who underwent at least 24 h of CRRT. The mean body weight of the children was 8.69 +/- 5.63 kg. RCA-CRRT was performed with a commercially available pre dilution citrate solution (Prismocitrate 18/0). RESULTS: The mean time on RCA CRRT and HA-CRRT was 148.73 +/- 131.58 and 110.24 +/- 105.38 h, respectively. Circuit lifetime was significantly higher in RCA-CRRT than in HA-CRRT (58.04 +/- 51.18 h vs. 37.64 +/- 32.51 h, respectively; p = 0.030). Circuit clotting was observed in 11.63 % of children receiving RCA-CRRT and 34.15 % of those receiving HA-CRRT. Episodic electrolyte and metabolic disturbances were more common in children receiving RCA-CRRT. The survival at discharge from the hospital was 37.5 and 14.3 % among children receiving RCA-CRRT and HA-CRRT, respectively. CONCLUSIONS: In critically ill children with a low body weight, RCA appeared to be safe and easy to used. Among our patient cohort, RCA was more effective in preventing circuit clotting and provided a better circuit lifetime than HA. PMID- 24337320 TI - microRNA-202 suppresses MYCN expression under the control of E2F1 in the neuroblastoma cell line LAN-5. AB - microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by binding to the untranslated regions (UTRs) of target mRNAs. Bioinformatic software predicted that MYCN, a gene overexpressed in aggressive neuroblastoma cells, is a target gene of miRNA-202 (miR-202) and that the promoter region of miR-202 contains binding sites for the transcription factor E2F1. The aims of this study were to explore the regulation of MYCN expression by miR-202 in the LAN-5 human neuroblastoma cell line and to confirm the presence of binding sites for E2F1 in the miR-202 promoter region. LAN-5 cells were transfected with a synthetic miR-202 mimic, an miRNA inhibitor or appropriate control miRNAs. miR 202 expression levels prior to and following transfection were measured by quantitative polymerase chain reaction (PCR) and MYCN protein expression was measured by western blot analysis. The interaction between miR-202 and MYCN was examined using a luciferase reporter assay. The transcription start site of miR 202 was determined by the rapid amplification of 5'cDNA ends (5'RACE) test and a chromatin immunoprecipitation (ChIP) assay was used to confirm binding sites for E2F1 in the miR-202 promoter region. Overexpression of miR-202 in LAN-5 cells specifically inhibited MYCN protein expression. The 5'RACE test showed that the transcription start site of miR-202 was at a thymidine, 312 bp upstream of the stem-loop sequence. A ChIP assay demonstrated that E2F1 binds directly to the miR 202 promoter region. miR-202 is activated by E2F1 and in turn downregulates MYCN protein expression in the neuroblastoma cell line LAN-5. Upregulation of miR-202 may therefore be a novel strategy for neuroblastoma treatment. PMID- 24337321 TI - On the exact distribution of the numbers of alleles in DNA mixtures. AB - When more than one individual contributes biological material to a forensic stain, the resulting DNA type is termed a DNA mixture. DNA mixtures occur frequently in forensic genetic casework, and in recent years, much research has been devoted to this subject. This paper presents a derivation of the exact distribution of the number of alleles for any number of profiles and investigated loci. The per locus number of observed alleles is of interest as it indicates the plausible range on the number of contributors. Hence, by specifying a prior distribution on the number of contributors, the locus distribution may be used to assess the number of contributors. Furthermore, the total number of alleles across all loci is used by some forensic geneticists to estimate the probability that an allele has failed to be detected (allelic drop-out). PMID- 24337322 TI - The Michel Benoist and Robert Mulholland Yearly European Spine Journal Review: a survey of the "medical" articles in the European Spine Journal, 2013. PMID- 24337323 TI - Adjacent-level failures after occipito-thoracic fusion for rheumatoid cervical disorders. AB - INTRODUCTION: The natural history of cervical spine lesions in rheumatoid arthritis (RA) is variable. We have actively performed occipito-thoracic fusion for severe destructive rheumatoid cervical disorders and reported its clinical results and complications. In our previous study, the most frequent complication was the adjacent-level failures caused by the fragile spine. The objective of this study was to determine risk factors for adjacent-level failures after occipito-thoracic fusion. MATERIALS AND METHODS: Subjects were 35 RA patients (31 females and 4 males) who underwent occipito-thoracic fusion using RRS Loop Spinal System((r)) (Robert Reid Inc. Tokyo, Japan), and the incidence and characteristics of adjacent-level failures were investigated. Furthermore, the adjacent-level failures were divided into two types according to their levels, fracture at the lowest level of the fusion area and that at the level inferior to the fusion area, and the characteristics of each type were evaluated. RESULTS AND CONCLUSION: Nine (26%) of 35 patients suffered adjacent-level failures (10 vertebral fractures). Adjacent-level failures occurred when the distance of fixation was "O-T4" or longer. The long fusion might cause adjacent-level failures due to greater mechanical stress. Seven fractures occurred at the lowest level of the fusion area, and all of them were cured without symptoms by conservative treatment. Three fractures occurred at the level inferior to the fusion area, and one of them needed additional surgery due to sudden paraplegia resulting from collapse of the adjacent vertebra. After occipito-thoracic fusion, burst fractures at the level inferior to the fusion area might cause sudden paraplegia, and therefore a careful observation should be required for patients with these fractures. PMID- 24337325 TI - A novel compound heterozygous mutation in the GJB2 gene causing non-syndromic hearing loss in a family. AB - Mutations in the GJB2 gene are responsible for up to 50% of cases of non syndromic recessive hearing loss, with c.35delG, c.167delT and c.235delC being the predominant mutations in many world populations. However, a large number of rare mutations in this gene may also contribute to hearing loss. The aim of the present study was to conduct a clinical and molecular characterization of a Chinese family with non-syndromic hearing loss. Sequence analysis of the GJB2 gene led to the identification of a novel compound heterozygous mutation c.257C>G (p.T86R)/c.605ins46 in two profoundly deaf siblings whose hearing parents were each heterozygous, either for the c.257C>G (paternal) or for the c.605ins46 (maternal) mutations. Both c.257C>G and c.605ins46 are rare GJB2 mutations that have previously been reported to segregate with autosomal recessive hearing loss exclusively in East Asian populations. To study the pathogenic effect of the compound heterozygous mutation, a three-dimensional model was constructed and Anolea mean force potential energy was predicted for a bioinformatic structural analysis. HEK293 cells were used to study the pathogenic effect of mutant connexin 26 proteins. The results suggested that the c.257C>G (p.T86R)/c.605ins46 mutations in the GJB2 gene provides a novel molecular explanation for the role of the GJB2 gene in hearing loss. PMID- 24337326 TI - How to coordinate care for people with dementia? A case study of a region in the Netherlands. AB - The greying of the population and trends that will change the future institutional context have implications for the social care for people with dementia and their caregivers. Based on the data of services provided by 50 organisations in a region in the South of the Netherlands, an organisational analysis revealed that better coordinated care is needed to fit the changing needs of clients in different phases of the disease process. PMID- 24337327 TI - Introducing a Latin ballroom dance class to people with dementia living in care homes, benefits and concerns: a pilot study. AB - The objective of the study was to investigate the effect of introducing a dance based psychomotor intervention using Danzon (Latin ballroom) for people with dementia in care homes. This was a grounded theory qualitative study. Thirteen of the 22 participants had dementia and were care-home residents. The remaining participants were care staff and facilitators of the dance sessions. Interviews were undertaken with seven people with dementia and nine staff, resulting in two separate sets of grounded theory methodologies. Two conceptual models, outlining positive outcomes and negative concerns of the use of Danzon were developed, depicting the experiences of people with dementia and care staff respectively. Danzon psychomotor intervention was found to enhance positive emotional states and general levels of satisfaction for both people with dementia and care staff. The details of these findings have been used to design a quantitative study. PMID- 24337328 TI - The implementation of integrated emotion-oriented care: did it actually change the attitude, skills and time spent of trained caregivers? AB - BACKGROUND: Successful implementation is a vital precondition for investigating the outcome of care innovation. This study concerned the evaluation of the implementation of integrated emotion-oriented care (IEOC) in psychogeriatric nursing home wards. The main question was whether the trained caregivers actually applied the knowledge and techniques of IEOC during their daily work. METHODS: The study was conducted within the framework of a randomized clinical trial into the effectiveness of IEOC in 16 wards. Preceding the experimental period, staff from 16 wards were educated and trained to work with a standardized care plan, resulting in a similar level of quality of care at the start of the trial. On the experimental wards IEOC was then implemented by training on the job in addition to training courses for personnel. To examine the implementation effectiveness, a self-report questionnaire, 'Emotion-oriented Skills in the Interaction with Elderly People with Dementia', was administered at baseline and after 7 months to a sample of caregivers from the experimental and the control wards. In addition, participant observation was conducted on four experimental and four control wards, and time spent by care personnel on different type of care tasks was registered. RESULTS: The implementation of IEOC resulted in increased emotion oriented skills and more knowledge of the residents among the caregivers. Providing IEOC was not more time consuming for the caregivers than providing usual care. CONCLUSION: This study shows that the implementation of IEOC was effective. It is recommended that in intervention studies the correct application of a new intervention or care approach is examined before jumping to conclusions about the effectiveness of the intervention or care approach itself. PMID- 24337329 TI - Why do dementia patients become unable to lead a daily life with decreasing cognitive function? AB - In order to understand the words and deeds of dementia patients that we find very hard to explain or understand, we have paid attention to the self-awareness ability of dementia patients, the intellectual subject that integrates their own intellectual functions, and created 'a model for interpreting puzzling words and deeds of dementia patients from the viewpoint of self-awareness'. The purpose of this study is to explain the reasons why dementia patients become unable to successfully perform activities of daily living (ADL) with advancement of dementia, using our model to present viewpoints understandable to caregivers. We classified dementia inpatients of a geriatric health services facility into four stages, using the model of self-awareness ability (consisting of 'theory of mind', 'self-evaluation' and 'self-consciousness') that was constructed by combining 'theory of mind' and Lewis's developmental model of cognition and emotion. Furthermore, we observed and documented scenes from daily life, and we interpreted the reasons why patients become unable to seek assistance from others for ADL, based on the model. We came to understand why the patients could not seek assistance from others, because the patients who failed in the task of 'theory of mind' were unable to self-assess their own mind and the minds of others, and those having failed in the task of 'self-evaluation' could not evaluate their own situation. PMID- 24337330 TI - Evaluating proFamilies-dementia: adopting photovoice to capture clinical significance. AB - Dementia is a challenging chronic illness that affects the patients and their families. Families often perform a full-time, specialised role, which requires expert knowledge and skills. This paper describes the evaluation of proFamilies dementia (a programme developed to support families that care for a relative with dementia) using an innovative participatory methodology: photovoice, a qualitative method of research that uses photography and voice to access people's experiences. The programme was evaluated in order to identify the positive and negative impacts of the intervention on individuals and families; the advantages and disadvantages of photovoice as a participatory tool were also captured. The sample consisted of six people from five families. Participants identified only positive impacts of the programme, including better emotional management, normalisation of feelings and increased focus on self-care. Photovoice facilitated access to the process of change initiated by proFamilies-dementia, described by a process of going beyond illness, negativity and loneliness. PMID- 24337331 TI - Negotiating the balance: the triadic relationship between spousal caregivers, people with dementia and Admiral Nurses. AB - Informal caregiving for a person with dementia often takes place within a health care triad, whose members include the caregiver, the care-recipient and the health care-professional. The aim of the current study was to explore how the members work together with this triadic context. Six spousal caregiving dyads and the three Admiral Nurses who worked with the couples were interviewed. Transcripts of these interviews were analysed to form six case studies, each containing the perspectives of the three members of the triad. The processes emerging in these case studies were encompassed under an overarching dynamic process of 'negotiating the balance'. This describes the ongoing struggle of the members to balance the views of the other members against their own needs. Coalitions could occur as members worked together to tackle problems. The findings of this study highlight the importance of exploring the perspectives of all members of the triad. This should help health care professionals to improve the quality of the support they provide to caregivers and care-recipients. PMID- 24337332 TI - Attitudes to shared care for patients with dementia: a survey of general practitioners. AB - Early diagnosis of dementia is important, but implications for care shared between primary and secondary care remain uncertain. We explored attitudes and expectations of Edinburgh's general practitioners (GPs) regarding current sharing of care for dementia. Surveys were distributed to all 335 Edinburgh GPs; 79.7% were returned. Attitudes and expectations were examined, specifically whether dementia care was currently appropriately shared. Two-thirds of GPs were sure of their role and a similar number felt that care was appropriately shared. The latter opinion was not associated with individual GP factors, such as gender or length of time since qualification, or local levels of deprivation. However, there was a significant association with sector consultant psychiatrist (F = 2.79, df = 6, p = 0.012) and with the proportion of the practice list diagnosed with dementia (rho = -0.13, p = 0.038). The endangered relationship between GP and specialist could be a key target to improve shared care and early diagnosis of dementia. PMID- 24337333 TI - An overview of the use of music therapy in the context of Alzheimer's disease: a report of a French expert group. AB - OBJECTIVES: The aim of this overview is to present the developments of music therapy in France, its techniques, mechanisms and principal indications, mainly in the context of Alzheimer's disease. METHODS: An international review of the literature on music therapy applied to Alzheimer's disease was conducted using the principal scientific search engines. A work group of experts in music therapy and psychosocial techniques then considered the different points highlighted in the review of literature and discussed them. RESULTS AND DISCUSSION: Clinical and neurophysiological studies have enlightened some positive benefits of music in providing support for people with Alzheimer's disease or related disorders. Music therapy acts mainly through emotional and psycho-physiological pathways. It includes a series of techniques that can respond to targeted therapeutic objectives. Some studies have shown that music therapy reduces anxiety, alleviates periods of depression and aggressive behaviour and thus significantly improves mood, communication and autonomy of patients. CONCLUSION: Psychosocial interventions, such as music therapy, can contribute to maintain or rehabilitate functional cognitive and sensory abilities, as well as emotional and social skills and to reduce the severity of some behavioural disorders. PMID- 24337334 TI - The experience of caring for a partner with young onset dementia: how younger carers cope. AB - A growing body of literature suggests that the social context of experiencing dementia at a younger age may influence carers' and particularly partners' subjective experience and coping strategies. The current paper aims to explore the coping strategies adopted by six carers in order to adapt to changes in their relationship with their partner with young onset dementia. All were recruited from the north west of England and interpretative phenomenological analysis was used to analyse the data. Four major themes were evident: (1) 'this is not happening': the use of denial as a coping strategy; (2) 'let's not have anymore of this demeaning [treatment]': stigma in young onset dementia; (3) 'I've had to fight every inch': struggling to maintain control of events and emotions; (4) 'what will become of me?': carers' adaptation to loss. Comparisons with existing literature are made and implications for clinical practice are considered. PMID- 24337335 TI - Innovative practice. Editorial. PMID- 24337336 TI - The Special Needs Program for Inmate-Patients with Dementia (SNPID): a psychosocial program provided in the prison system. AB - This article discusses a comprehensive psychosocial program developed for a prison in California--the Special Needs Program for Inmate-Patients with Dementia (SNPID). It describes the individual steps of the program, their content and their application in a system that has safety and security as its highest priority. An important and innovatory aspect of SNIPD is the role of other inmates in supporting inmates with dementia. The article concludes that psychosocial interventions can be appropriately applied in prison settings and make a difference in the quality of life for inmate-patients with dementia. PMID- 24337337 TI - Evaluating a dementia focused performance management programme. AB - This article describes a Dementia Focused Performance Management Programme run for care home managers in the north-west of England. The programme highlighted the challenges faced by managers in terms of complying with policy changes and providing adequate supervision and training for care staff in dementia care. It proposes 'turn around simulations' as a way of engaging more participatory approaches to raising standards but recognises the barriers to achieving this created by the limited amount of time that managers have to attend outside meetings and the need to recognise that there is a competitive marketplace among providers. PMID- 24337338 TI - Side by Side: a workplace engagement program for people with younger onset dementia. AB - This paper describes an innovative demonstration program called Side by Side that was initiated to assess the feasibility of supported workplace engagement for people with younger onset dementia. Seven people with mild dementia work one day per week beside a work-buddy in a large metropolitan hardware store. Work-buddies are store employees who have undergone dementia training. Work duties are negotiated at the start of each shift and include restocking, plant care, assembling display stock and serving customers. All participants have been able to adapt to the workplace environment and some now talk about 'their customers'. Family carers have reported a positive impact on self-esteem and life satisfaction as a result of the workplace experience. This evaluation of feasibility has exceeded all expectations and has demonstrated that it is possible to offer meaningful activities for people with mild dementia if an appropriate framework of support is provided. PMID- 24337339 TI - A randomized controlled trial of a peer-run antistigma photovoice intervention. AB - OBJECTIVE: Psychiatric stigma is a major barrier to the recovery of persons with serious mental illnesses. This study tested the efficacy of an innovative peer run photography-based intervention, called antistigma photovoice, which targets self-stigma and promotes proactive coping with public stigma. METHODS: A total of 82 individuals with serious mental illnesses enrolled at a university-based recovery center were randomly assigned to the antistigma photovoice program or to a wait-list control group. Mixed-effects regression models were used to examine the impact of photovoice on self-stigma, coping with stigma, empowerment, perceived recovery, self-efficacy, and depression. RESULTS: Participation in the photovoice intervention was associated with significantly reduced self-stigma, greater use of proactive coping with societal stigma, greater increase in a sense of community activism, and perceived recovery and growth. CONCLUSIONS: The photovoice intervention demonstrated promise for reducing self-stigma and enhancing proactive coping with prejudice and discrimination. PMID- 24337340 TI - Myosin II regulates actin rearrangement-related structural synaptic plasticity during conditioned taste aversion memory extinction. AB - Similar to memory formation, memory extinction is also a new learning process that requires synaptic plasticity. Actin rearrangement is fundamental for synaptic plasticity, however, whether actin rearrangement in the infralimbic cortex (IL) plays a role in memory extinction, as well as the mechanisms underlying it, remains unclear. Here, using a conditioned taste aversion (CTA) paradigm, we demonstrated increased synaptic density and actin rearrangement in the IL during the extinction of CTA. Targeted infusion of an actin rearrangement inhibitor, cytochalasin D, into the IL impaired memory extinction and de novo synapse formation. Notably, we also found increased myosin II phosphorylation in the IL during the extinction of CTA. Microinfusion of a specific inhibitor of the myosin II ATPase, blebbistatin (Blebb), into the IL impaired memory extinction as well as the related actin rearrangement and changes in synaptic density. Moreover, the extinction deficit and the reduction of synaptic density induced by Blebb could be rescued by the actin polymerization stabilizer jasplakinolide (Jasp), suggesting that myosin II acts via actin filament polymerization to stabilize synaptic plasticity during the extinction of CTA. Taken together, we conclude that myosin II may regulate the plasticity of actin-related synaptic structure during memory extinction. Our studies provide a molecular mechanism for understanding the plasticity of actin rearrangement-associated synaptic structure during memory extinction. PMID- 24337341 TI - [Implantation of intraocular lenses in the ciliary sulcus]. AB - Implantation of an intraocular lens (IOL) into the ciliary sulcus is the second most common implantation site after the regular capsular bag (in the bag) placement of an IOL. Although mainly not primarily intended, it is very often used in both complicated cataract surgery and secondary implantation due to IOL dislocation or aphakia. In most cases stable positioning is possible, especially when using optic capture techniques. A variety of difficulties can occur with sulcus implantation depending on the anatomical and surgical conditions present at the time of implantation. The most anterior position of the sulcus lense has to be considered for calculation of the refractive power of the IOL. PMID- 24337342 TI - [Pharmacokinetics of the anterior eye]. AB - The pharmacokinetics of the anterior eye comprises the application, resorption, bioavailability, metabolization and elimination of topically administered drugs. In addition to the necessity of the penetration of the substance through the naturally occurring barriers of the eye in the form of the tear film, cornea, conjunctiva and sclera, the correct technique for administration is necessary for an optimal effect of the drug. Several new application devices have been described in the literature but most are still in an experimental phase. The main aims are to increase drug exposure time to the anterior surface of the eye and decrease problems in administration. Furthermore, new preservative agents are in use in order to produce less toxic side effects. PMID- 24337343 TI - [Pharmacokinetics of systemic, regional and topical drugs for therapy of intraocular inflammation]. AB - A broad spectrum of anti-inflammatory drugs with different mechanisms is available for the treatment of intraocular inflammation. Corticosteroids are the mainstay of therapy. Mechanisms of action are quite well understood for most drugs in particular taken from animal research studies. However, pharmacokinetic evidence for treatment of ocular disease is generally limited for the human eye and especially for ocular inflammation. The bioavailability of a particular drug in an inflamed eye is expected to be faster due to a barrier breakdown. Therefore, intraocular level of effective substances should be lowered more rapidly than in a non-inflamed eye due to improved drainage. This article reviews current knowledge firstly about local, regional and systemic anti-inflammatory therapy of uveitis and finally on immuosuppressive systemic therapy. PMID- 24337345 TI - An effective method for the detoxification of cyanide-rich wastewater by Bacillus sp. CN-22. AB - The biodetoxification of cyanide-rich wastewater has become increasingly popular because of its cost-effectiveness and environmental friendliness. Therefore, we have developed an effective method, optimised by response surface methodology, for detoxifying cyanide-rich wastewater using Bacillus sp. CN-22, which was newly isolated from a cyanide-contaminated electroplating sludge and could tolerate a CN- concentration of 700 mg L-1. The concentration of CN- in the treated wastewater decreased from 200 to 6.62 mg L-1 after cultivation with 2.38 % inocula for 72 h on the medium, consisting of 0.05 % KH2PO4, 0.15 % K2HPO4, 1.0 mM MgCl2, 1.0 mM FeCl3, 0.1 % NH4Cl, and 0.1 % glycerol. The CN- degradability of 96.69 % is similar to the predicted value of 96.82 %. The optimal cultivation conditions were controlled as follows: initial pH, 10.3; temperature, 31 degrees C; and rotary speed, 193 rpm. The maintenance of higher pH in the overall treatment procedures may avoid the production of volatile HCN and the risk associated with cyanide detoxification. Additionally, the bacterial strain Bacillus sp. CN-22, with its potent cyanide-degrading activity at the initial CN- concentration of 200 mg L-1, may be employed to effectively treat cyanide-rich wastewater, especially electroplating effluent. PMID- 24337344 TI - Sequential-digital image correlation for mapping human posterior sclera and optic nerve head deformation. AB - Optic nerve head (ONH) deformations may be involved in the onset or further development of glaucoma, including in patients with relatively normal intraocular pressures (IOPs). Characterizing posterior scleral deformations over physiological pressures may provide a better understanding of how changes in IOP lead to changes in the mechanical environment of the ONH and possibly retinal ganglion cell death. Pressure inflation measurement test protocols are commonly used to measure deformation of the peripapillary sclera with full-field noncontact optical methods. The purpose of this work was to develop and validate a new sequential 3D digital image correlation (S-DIC) approach for quantification of posterior scleral pressure induced deformation that improves z (in-depth) resolution of the DIC measurement without losing in-plane sensitivity, while also being able to contour and map deformations of the complex-shaped ONH. Our approach combines two orthogonal axes of parallax with standard 3D DIC methods using a single high-resolution camera. The enhanced capabilities of S-DIC with respect to standard 3D DIC has been demonstrated by carrying out a complete benchmark for shape, deformation, and strain measurement on an object of known complex geometry. Our S-DIC method provided a reconstruction accuracy of 0.17% and an uncertainty in z-position measurement of 8 MUm. The developed methodology has also been applied to a human posterior scleral shell, including the full peripapillary sclera and optic nerve. The relatively inexpensive S-DIC approach may provide new information on the biomechanical deformations of the optic nerve head and, thus, the death of retinal ganglion cells in primary open angle glaucoma. PMID- 24337346 TI - Tunable recombinant protein expression with E. coli in a mixed-feed environment. AB - Controlling the recombinant protein production rate in Escherichia coli is of utmost importance to ensure product quality and quantity. Up to now, only the genetic construct, introduced into E. coli, and the specific growth rate of the culture were used to influence and stir the productivity. However, bioprocess technological means to control or even tune the productivity of E. coli are scarce. Here, we present a novel method for the process-technological control over the recombinant protein expression rate in E. coli. A mixed-feed fed-batch bioprocess based on the araBAD promoter expression system using both D-glucose and L-arabinose as assimilable C-sources was designed. Using the model product green fluorescent protein, we show that the specific product formation rate can be efficiently tuned even on the cellular level only via the uptake rate of L arabinose. This novel approach introduces an additional degree of freedom for the design of recombinant bioprocesses with E. coli. We anticipate that the presented method will result in significant quality and robustness improvement as well as cost and process time reduction for recombinant bacterial bioprocesses in the future. PMID- 24337347 TI - Investigating commercial cellulase performances toward specific biomass recalcitrance factors using reference substrates. AB - Three commercial cellulase preparations, Novozymes Cellic((r)) Ctec2, Dupont Accellerase((r)) 1500, and DSM Cytolase CL, were evaluated for their hydrolytic activity using a set of reference biomass substrates with controlled substrate characteristics. It was found that lignin remains a significant recalcitrance factor to all the preparations, although different enzyme preparations respond to the inhibitory effect of lignin differently. Also, different types of biomass lignin can inhibit cellulase enzymes in different manners. Enhancing enzyme activity toward biomass fiber swelling is an area significantly contributing to potential improvement in cellulase performance. While the degree of polymerization of cellulose in the reference substrates did not present a major recalcitrance factor to Novozymes Cellic((r)) Ctec2, cellulose crystallite has been shown to have a significant lower reactivity toward all enzyme mixtures. The presence of polysaccharide monooxygenases (PMOs) in Novozymes Ctec2 appears to enhance enzyme activity toward decrystallization of cellulose. This study demonstrated that reference substrates with controlled chemical and physical characteristics of structural features can be applied as an effective and practical strategy to identify cellulosic enzyme activities toward specific biomass recalcitrance factor(s) and provide specific targets for enzyme improvement. PMID- 24337348 TI - T1a as the sole selection criterion for RFA of renal masses: randomized controlled trials versus surgery should not be postponed. AB - PURPOSE: To evaluate the long-term effects of radiofrequency ablation (RFA) of renal masses (RM) and compare them with surgery. METHODS: A total of 203 RM (193 malignant; mean size 30 mm) in 137 patients (95 male subjects; average age 64 years) underwent RFA. Complications and technique effectiveness were evaluated. Overall survival, cancer-specific survival, and disease-free survival were calculated (mean follow-up time 39 months). Predictors for complications, technique effectiveness, and survival were investigated. RESULTS: Seventeen (8.4 %) adverse events were recorded (2 % major complications). Exophytic development and smaller size were protective against adverse events. Complete ablation was obtained in 87 % RM (93 % <=3 cm, 89 % <=4 cm). T1a threshold was a positive predictor for complete ablation and central location a negative one. Three- and 5 year overall survival were 84 and 75 %; cancer-specific survival 96 and 91 %; and disease-free survival 80 and 75 %. Considering only the 79 patients with newly diagnosed renal cell carcinoma, T1a disease stage resulted a positive predictor for both overall survival (87 and 83 % at 3 and 5 years) and cancer-specific survival (100 % at 5 years). CONCLUSION: RFA of noncentral small RM is safe and effective, and it provides favorable long-term oncological outcomes. Selection criteria for RFA can also include T1a renal cell carcinoma in patients without surgical contraindications, even though randomized controlled trials are needed to establish the best treatment. PMID- 24337349 TI - Osteoid osteoma treated by percutaneous thermal ablation: when do we fail? A systematic review and guidelines for future reporting. AB - PURPOSE: Osteoid osteoma (OO) is a painful benign bone tumor of the young that is widely treated by percutaneous thermal ablation (PTA) with success rates close to 100%. Nevertheless, some patients have recurrences. We reviewed the literature to understand whether these are true recurrences or incomplete treatments; to analyze safety and efficacy during long-term follow-up in a extremely large cohort of patients; to detail best-practice suggestions from the largest clinical trials as well as report their complications; and to recommend standards for future reporting. MATERIALS AND METHODS: This study followed the Cochrane's guidelines for Systematic Reviews of Interventions. Inclusion criteria were as follows: (1) prospective or retrospective cohort study for PTA of OO under computed tomography (CT) guidance; (2) CT or magnetic resonance diagnosis; (3) radiofrequency ablation or interstitial laser ablation technique; (4) English language; (5) population <10 patients; (6) follow-up >=12 months; and (7) original research. Risk of bias was assessed with a modified Newcastle-Ottawa Scale. RESULTS: Two hundred fourteen articles were initially found. After applying the criteria mentioned previously, 27 PTA articles concerning 1,772 patients were chosen for inclusion. No exclusions were made due to risk of bias. CONCLUSION: The investigators proved the long-term efficacy and superiority of PTA for OO compared with other techniques. In 5% of patients, however, the technique failed, and the researchers did not offer detailed exhaustive explanations. Future clinical trials for OO ablation should consider reporting essential procedure details and follow-up findings to allow for a meta-analysis. We provide both recommended standards for future reporting and suggestions for the prevention of recurrence. PMID- 24337350 TI - The effects of LED emissions on sternotomy incision repair after myocardial revascularization: a randomized double-blind study with follow-up. AB - This study aimed to analyze the effects of light-emitting diode (LED) therapy on sternotomy pain and healing in patients who underwent coronary artery bypass grafting (CABG). The patients were followed for 6 months after the surgery to determine their dehiscence. This study was conducted with 90 volunteers who electively submitted to CABG. The volunteers were randomly allocated into three different groups of equal size: LED (lambda of 640 +/- 20 nm and spatial average energy fluency of 1.2 J/cm(2) during hospitalization), placebo, or control. The outcomes assessed were pain when coughing by a visual analog scale (VAS) and the McGill questionnaire and sternotomy healing by clinical assessment and photographical register end interpretation. The LED group had better pain reduction, as indicated by both the VAS and the McGill questionnaire (number of words chosen and pain index) (p <= 0.05), on days 6 and 8 after hospital discharge compared to the placebo and control groups. One month after surgery, almost no individual mentioned pain when coughing. Three researchers blindly analyzed the incision photographs to determine hyperemia and wound closure, and they found that the LED group had both less hyperemia and less incision bleeding or dehiscence. The LED therapy (640 nm) had an analgesic effect on the sternotomies of patients who underwent CABG, increasing their incision healing and preventing dehiscence. PMID- 24337351 TI - Dissociating affordance and spatial compatibility effects using a pantomimed reaching action. AB - Previous research has demonstrated faster reaction times in response to appropriately oriented action-inducing stimuli (affordance effect, e.g. Tucker and Ellis in J Exp Psychol Hum Percept Perform 24:830-846, 1998). However, it has been argued that faster responses may be due to a spatial compatibility effect. In the current investigation, we aimed to dissociate the affordance and spatial compatibility effects. Moreover, we explored these effects beyond button-press responses by measuring detailed kinematics of the arms and hands during a naturalistic reach response. Participants were presented with images of a door handle (affording) or an abstract (non-affording) stimulus and made a pantomimed reach response with either hand depending on a colour change of the stimulus (i.e. Blue = left, Green = right). Stimuli could be aligned as spatially compatible or incompatible with the responding hand. The colour change occurred after a delay of 0, 500 or 1,000 ms. Only spatially compatible affordance stimuli facilitated reach onset compared to other stimuli and compatibility combinations, replicating previous reaction time studies. Therefore, in the absence of graspable stimuli, spatial compatibility alone was not sufficient to facilitate reach onset. There was also a larger outwards deviation of reach trajectory for spatially incompatible abstract stimuli compared to spatially compatible abstract stimuli, which waned with stimulus onset delay. However, no such affect was observed for the affording stimuli. Accordingly, later kinematics of the reaching action was influenced by the spatial compatibility of the stimulus alone. Overall, the dissociation of affordance and spatial compatibility effects suggests that these effects are driven by visuomotor priming and the inhibition of the incompatible spatial location, respectively. PMID- 24337352 TI - How posture affects macaques' reach-to-grasp movements. AB - Although there is a wealth of behavioral data regarding grasping movements in non human primates, how posture influences the kinematics of prehensile behavior is not yet clearly understood. The purpose of this study was to examine and compare kinematic descriptions of grip behaviors while primates (macaque monkeys) were in a sitting posture or when stopping after quadrupedal locomotion (i.e., tripedal stance). Video footage taken while macaques grasped objects was analyzed frame-by frame using digitalization techniques. Each of the two grip types considered (power and precision grips) was found to be characterized by specific, distinct kinematic signatures for both the reaching and the grasping components when those actions were performed in a sitting position. The grasping component did not differentiate in relation to the type of grip that was needed when, instead, the prehensile action took place in a tripedal stance. Quadrupedal locomotion affected the concomitant organization of prehensile activities determining in fact a similar kinematic patterning for the two grips regardless of the size of the object to be grasped. It is suggested that using a single kinematic grip patterning for all prehensile activities might be both the by-product of planning a grasping action while walking and a way to simplify motor programming during unstable tripedal stance. PMID- 24337354 TI - Fulminant myelitis with NMO IgG antibody following treatment with interferon alpha. PMID- 24337353 TI - Quercetin reduces oxidative stress and inhibits activation of c-Jun N-terminal kinase/activator protein-1 signaling in an experimental mouse model of abdominal aortic aneurysm. AB - Oxidative stress is becoming increasingly linked to the pathogenesis of abdominal aortic aneurysms (AAAs). The antioxidant activity of flavonoids has attracted attention for their possible role in the prevention of cardiovascular diseases. The purpose of this study was to determine whether an antioxidant mechanism is involved in the aneurysm formation inhibitory effect afforded by quercetin. Male C57/BL6 mice received quercetin continuously from 2 weeks prior to and 6 weeks following the AAA induction with extraluminal CaCl2. Quercetin treatment decreased AAA incidence and inhibited the reactive oxygen species generation, nitrotyrosine formation and lipid peroxidation production in the aortic tissue during AAA development. In addition, quercetin-treated mice exhibited significantly lower expression of the p47phox subunit of nicotinamide adenine dinucleotide phosphate oxidase and inducible nitric oxide synthase, as well as coordinated downregulation of manganese-superoxide dismutase activities and glutathione peroxidase (GPx)-1 and GPx-3 expression. Quercetin also blunted the expression of c-Jun N-terminal kinase (JNK) and phospho-JNK and, in addition, diminished activation of the activator protein (AP)-1 transcription factor. Gelatin zymography showed that quercetin eliminated matrix metalloproteinase (MMP)-2 and MMP-9 activation during AAA formation. In conclusion, the inhibitory effects of quercetin on oxidative stress and MMP activation, through modulation of JNK/AP-1 signaling, may partly account for its benefit in CaCl2-induced AAA. PMID- 24337355 TI - Modelling psychosocial influences on the distress and impairment caused by psychotic-like experiences in children and adolescents. AB - Psychological understanding of psychotic-like experiences (PLEs) occurring in childhood is limited, with no recognised conceptual framework to guide appropriate intervention. We examined the contribution to PLE severity of emotional, cognitive and socio-environmental mechanisms thought to influence the development and maintenance of psychosis. Forty 8-14 year olds referred to a community Child and Adolescent Mental Health Service completed a battery of questionnaires and assessments measuring severity of PLEs, emotional problems, cognitive biases, and negative life events. 85% of children assessed reported having experienced a PLE over the previous year; and 55% reported more than one. 60% had experienced at least one in the previous fortnight. Multiple linear regression demonstrated that each of the variables made a significant and independent contribution to PLE severity, after adjusting for verbal ability and age, accounting together for more than half of the variance (reasoning B = 6.324, p = .049; emotion B = 1.807, p = .005; life events B = 4.039, p = .001). PLEs were common in this clinical sample of children. Psychological factors implicated in the development and maintenance of psychosis in adults were also associated with PLE severity in these children. PLE severity may be reduced by targeting each of these factors in cognitive therapy, at this very early stage. Any improvements in emotional wellbeing and functioning may then increase future resilience. PMID- 24337356 TI - Alkoxyamines: a new family of pro-drugs against cancer. Concept for theranostics. AB - Development of anti-cancerous theranostic agents is a vivid field. This article describes a theranostic approach that relies on the triggering of cancer cell death by generation of alkyl radicals at the right place and at the right time using the presence of active proteases in the tumour environment. Alkoxyamines (R(1)R(2)NOR(3)) are labile molecules that homolyze into nitroxides (R(1)R(2)NO) and reactive alkyl radicals (R(3)). They are used as a source of active alkyl radicals for curing and nitroxides for monitoring by Overhauser-enhanced magnetic resonance imaging (OMRI). Herein, the requirements needed for applying alkoxyamines are described: (i) highly selective activation of the alkoxyamine by specific proteases; (ii) fast homolysis of the alkoxyamine C-ON bond at physiological temperature; (iii) activation of cell death processes through an increase of the local oxidative stress or potential re-activation of the immune system due to short-lived alkyl radicals; and (iv) imaging of the tumor and the drug release by sensing the nitroxide by OMRI. PMID- 24337357 TI - [Epithelioid sarcoma of the orbit]. AB - BACKGROUND: Sarcomas count among the very rare malignancies of the orbit. Epithelioid sarcomas typically occur in the subcutaneous tissue of younger patients; an affected orbit constitutes a rarity. OBJECTIVES: Only three cases of this extremely rare disease of the orbit, which is associated with marked aggressiveness and a very poor prognosis, have been analysed in the worldwide current literature. PATIENT AND METHODS: We present a case report together with a literature review. A rapidly progressing painful proptosis with visual loss occurred in a 30-year-old patient. Imaging and invasive diagnostic procedures were initiated as a consequence of this. RESULTS: Diagnostic imaging revealed an infiltrative process of the right orbit. Following endonasal decompression of the orbit and probe acquisition, histological and immunohistochemical tests showed the presence of a proximal type epithelioid sarcoma. Therapy consisted of orbit exenteration together with implantation of titanium miniplates for orbital prosthesis. During the course of disease, osseous metastases developed. The patient died during palliative chemotherapy, 14 months after the initial diagnosis. CONCLUSION: Epithelioid sarcomas are extremely rare, difficult to treat tumours in the head and neck region. The associated mortality rates are high. Aggressive surgical therapy with intensive follow-up is recommended. The prognosis depends upon the resection status. PMID- 24337358 TI - Biological explanations of generalized anxiety disorder: effects on beliefs about prognosis and responsibility. AB - OBJECTIVE: Biological explanations of psychopathology can reduce the extent to which people with mental disorders are blamed for their symptoms but can also yield prognostic pessimism--the belief that psychiatric conditions are relatively immutable. However, few studies have examined whether these effects occur among persons who actually have psychiatric symptoms. This study sought to address this question. METHODS: Adults living in the United States (N=351) were recruited online in January and February 2012 and assessed for symptoms of generalized anxiety disorder. The participants were randomly assigned to two groups: a biological condition, in which participants (N=176) were provided a description of generalized anxiety disorder and a biological explanation of the etiology of the disorder, and a control condition, in which participants (N=175) were provided the same description without any explanation of etiology. Dependent measures of treatability, duration of symptoms, and responsibility for symptoms were used to gauge beliefs regarding the prognosis and personal responsibility of a typical person with generalized anxiety disorder. RESULTS: Among participants with and without symptoms of generalized anxiety disorder, the biological condition was associated with decreased ascriptions of personal responsibility for anxiety (p=.02) and expectations of increased duration of symptoms of generalized anxiety disorder (p=.01). CONCLUSIONS: This finding has important social and clinical implications, especially because biological conceptualizations of psychopathology are increasingly prevalent. By causing prognostic pessimism about generalized anxiety disorder, including among those with symptoms of the disorder, biological explanations could negatively affect treatment seeking and outcomes. Efforts to dispel the link between biological explanations and prognostic pessimism are needed. PMID- 24337359 TI - Long-term surgical outcomes of cervical myelopathy with athetoid cerebral palsy. AB - PURPOSE: To understand the long-term surgical outcomes and prognostic factors for the operative treatment of cervical myelopathy (CM) in patients with athetoid cerebral palsy (ACP). METHODS: We retrospectively reviewed 24 patients with ACP who underwent surgery for CM at our hospital between March 2002 and June 2008. All patients had more than 5 years follow-up. Anterior fusion (11 patients), posterior fusion (1 patient), or combined anterior and posterior (AP) fusion (7 patients) and C1-2 fusion (5 patients) surgeries were performed. Surgical outcomes (average follow-up 102 months), as assessed using modified JOA (mJOA) scores, the Neck Disability Index (NDI), and a visual analog scale (VAS) were compared between the preoperative and postoperative states. RESULTS: Preoperatvie cervical kyphosis decreased mJOA scores significantly. Long-term follow-up clinical outcomes demonstrated that 10 patients showed favorable (excellent and good) outcomes and 11 patients had non-favorable (fair and worse) outcomes. According to the mJOA scores, patients showed postoperative improvement (7.10 10.45). NDI decreased from 68.46 to 31.66. A second operation was done in seven cases due to instrument failure, progressive kyphotic deformities and adjacent segment degeneration. A preoperative botulinum toxin injection significantly decreased (p < 0.05) the incidence of a second operation. CONCLUSIONS: Patients with ACP have high incidence of instrument failure. Strong surgical fixation, bone fusion and perioperative immobilizations using botulinum toxin injection should be carefully planned preoperatively. PMID- 24337360 TI - Risk factors for wound infection in surgery for spinal metastasis. AB - Wound infection rates are generally higher in patients undergoing surgery for spinal metastasis. Risk factors of wound infection in these patients are poorly understood. PURPOSE: To identify demographic and clinical variables that may be associated with patients experiencing a higher wound infection rate. STUDY DESIGN: Retrospective study with prospectively collected data of spinal metastasis patients operated consecutively at a University Teaching Hospital, adult spine division which is a tertiary referral centre for complex spinal surgery. PATIENT SAMPLE: Ninety-eight patients were all surgically treated, consecutively from January 2009 to September 2011. Three patients had to be excluded due to inadequate data. OUTCOME MEASURES: Physiological measures, with presence or absence of microbiologically proven infection. METHODS: Various demographic and clinical data were recorded, including age, serum albumin level, blood total lymphocyte count, corticosteroid intake, Malnutrition Universal Screening Tool (MUST) score, neurological disability, skin closure material used, levels of surgery and administration of peri-operative corticosteroids. No funding was received from any sources for this study and as far as we are aware, there are no potential conflict of interest-associated biases in this study. RESULTS: Higher probabilities of infection were associated with low albumin level, seven or more levels of surgery, use of delayed/non-absorbable skin closure material and presence of neurological disability. Of these factors, levels of surgery were found to be statistically significant at the 5 % significance level. CONCLUSION: Risk of infection is high (17.9 %) in patients undergoing surgery for spinal metastasis. Seven or more vertebral levels of surgery increase the risk of infection significantly (p < 0.05). Low albumin level and presence of neurological disability appear to show a trend towards increased risk of infection. Use of absorbable skin closure material, age, low lymphocyte count, peri-operative administration of corticosteroids and MUST score do not appear to influence the risk of infection. PMID- 24337361 TI - [Prof. Dr. Reinhard Graf : retirement from the editorial board of Der Orthopade]. PMID- 24337363 TI - [Simulation of teleangiectactic osteosarcoma by aneurysmatic bone cyst]. AB - Aneurysmatic bone cysts are usually diagnosed by the combination of x-ray imaging and magnetic resonance imaging (MRI) with a sensitivity of 77.8% and specificity of 66.7%. We present an unusual case of an aneurysmatic bone cyst which initially mimicked an osteosarcoma on imaging and later developed the characteristic features of an aneurysmatic bone cyst which was confirmed by histology. PMID- 24337364 TI - Pre- and post-treatment urinary tract findings in children with nephrogenic diabetes insipidus. AB - BACKGROUND: Nephrogenic diabetes insipidus (NDI) is characterized by the kidney's inability to concentrate urine, which causes intense polyuria that may lead to urinary tract dilation. We report the morphological findings of the urinary tract in ten boys with NDI specifically addressing the presence and changes of urinary tract dilation during treatment. DIAGNOSIS/TREATMENT: Patients were diagnosed at a median age of 1.6 years (range, 0.16-6.33 years) and treated with a low osmotic diet, hydrochlorothiazide-amiloride and indomethacin, which decreased the diuresis from a median of 10.5 ml/kg/h to 4.4 ml/kg/h (p < 0.001). Three patients showed normal renal ultrasound before treatment until last control, while the remaining seven showed urinary tract dilation. In this second group, dilation was reduced with treatment in four patients and disappeared in the remaining three. Children without dilation or in whom the dilation disappeared were diagnosed and treated earlier than those with persistent dilation (median 1.66 versus 4.45 years, respectively). After a median of 10.4 (range, 2.3-20.3) years of follow up, no patients showed urological complications. CONCLUSIONS: Medical treatment of the disease improved the dilation in all cases, preventing its potential complications. Regardless of the good outcome of our patients, periodic urologic follow-up is recommended in NDI patients. PMID- 24337365 TI - Aliskiren, the first direct renin inhibitor: assessing a role in pediatric hypertension and kidney diseases. AB - This article provides a review of the role of aliskiren, a direct renin inhibitor, in pediatric hypertension and kidney diseases. Among the many mechanisms involved in regulating blood pressure, the renin-angiotensin aldosterone system (RAAS) plays a major role. Additionally, the RAAS has been identified as a contributing factor to cardiovascular and renal diseases for more than three decades. The potential benefits of inhibiting the RAAS by aliskiren alone or in combination with other RAAS blockers (ACEIs, ARBs) seem to be theoretically promising. However, caution should be exercised in treating children, especially in those with significant chronic kidney disease until there is more evidence regarding the safety and efficacy of this new drug in the pediatric population from ongoing clinical trials. PMID- 24337366 TI - Combination of immunoglobulins and natural killer cells in the context of CMV and EBV infection. AB - Cytomegalovirus (CMV)-specific hyperimmunoglobulin (CMV-HIG) is used to treat and prevent CMV infection in immunocompromised patients, and anti-CD20 monoclonal antibody is successfully used in the treatment for post-transplant lymphoproliferative disease caused by Epstein-Barr virus (EBV). Two immunological approaches have been suggested to further improve the control of viral reproduction in patients with active disease: first, the use of monoclonal antibodies with specificity against viral epitopes and second, coadministration of cells with the capacity to promote antibody-dependent cell-mediated cytotoxicity. Here, we have evaluated the effectiveness of these strategies in vitro (alone and in combination) with neutralization and cytotoxicity assays. Our results indicate that monoclonal antibodies (in particular SM5-1) can be as effective as CMV-HIG in neutralizing-cell-free CMV. Moreover, our data indicate that antibody-mediated elimination (either by moAb or by HIG) of EBV-infected cells can be significantly enhanced by NK cells. Using human NK cells that have been purified, cultured and expanded under GMP conditions, we were able to demonstrate that the combination of NK cells and antibodies could represent a feasible and highly effective clinical approach to achieve control of EBV infections. Especially in leukopenic patients with low numbers of ADCC-promoting cells, the combination of adoptively transferred NK cells and antiviral antibodies offers a promising strategy that should be tested in clinical trials. PMID- 24337367 TI - Haemodialysis impairs clopidogrel but not aspirin responsiveness in patients with end-stage renal disease. Results of a pilot study. AB - Dual antiplatelet therapy (DAPT) with aspirin (ASA) and clopidogrel (Clp) is the standard treatment to reduce ischaemic coronary events, but in patients with end stage renal disease (ESRD) the efficacy of Clp remains unclear. Patients with ESRD are at higher risk for coronary artery disease (CAD) and also their post interventional outcome is worse compared to patients with normal renal function. Little is known about the influence of haemodialysis (HD) on ASA and Clp responsiveness. To assess the effect of HD on ASA- and Clp-responsiveness in patients with documented CAD and ESRD, 31 patients with ESRD (mean age 66.5 +/- 1.8 years, 23 male) on DAPT were evaluated for their ASA and Clp responsiveness with the Verify Now System (Accumetrics Inc.) We measured the antiplatelet effect in all ESRD patients at three time points: T1: just before HD; T2: directly after HD; T3: steady state on a HD free day one week after T1. In our study at baseline 10 (32.3%) patients were ASA-low responder (ASA-LR) and 14 (45.2%) patients Clp low responder (Clp-LR). There was a significant difference in the PRU values before (T1) and immediately after HD (T2) [PRU T1=234 (169; 274) vs PRUT2= 247 (199; 278); pT1,2=0.036; ]. Results were shown as median ARU T1 (25th, 75th percentile) or median PRU T1 (25th, 75th percentile). Hence HD seems to impair responsiveness to Clp, resulting in an increase of 6.5 % Clp-LR. No significant differences in the ARU values at the different time-points were found. PMID- 24337369 TI - Suppression of collagen synthesis by Dicer gene silencing in hepatic stellate cells. AB - MicroRNAs (miRNAs) have emerged as important mediators of hepatic stellate cells (HSCs) and are pivotal in the pathogenesis of liver fibrosis. Dicer, the key enzyme in the RNA interference (RNAi) pathway, is involved in cutting precursor miRNAs to functionally mature forms. Emerging evidence has demonstrated that Dicer expression is dysregulated in embryo development and tumors. In the present study, we aimed to address whether Dicer expression was correlated with the activity of HSCs. We used a recombinant lentivirus to generate short hairpin RNAs (shRNAs) targeting Dicer. The mRNA and protein expression of Dicer was effectively inhibited by three pairs of Dicer shRNA vectors, of which the shRNA1 vector exhibited the strongest inhibitory effect. The shRNA1 vector demonstrated a marked inhibitory effect on the activity of HSCs, resulting in the reduction of cell proliferation and the decrease of fibrosis-related genes, including type I collagen (Col1A1), alpha-smooth muscle actin (alpha-SMA) and tissue inhibitor of metalloproteinases (TIMP). The mRNA expression of Col1A1, alpha-SMA and TIMP were decreased by 60, 56 and 49%, respectively. The protein expression was reduced by 56, 52 and 42%, respectively. Additionally, the inhibition of Dicer resulted in a decrease of miR-138, -143, -140 and -122 levels, of which miR-138 exhibited the strongest decline. The firefly luciferase reporter experiments and RT-PCR indicated that phosphatase and tension homolog deleted on chromosome 10 (PTEN), Ras GTPase activating-like protein 1 (RASAL1), acyl-CoA synthetase long-chain family member 1 (ACSL1) and p27 3' untranslated region sequences were targeted by miR-138, -143, -140 and -122, respectively. Taken together, the present study contributes important new findings for the role of Dicer-mediated miRNA processing in collagen synthesis of HSCs, which may serve as a foundation for RNAi study of liver fibrosis in vivo. PMID- 24337368 TI - Comparison of gene expression profiles and related pathways in chronic thromboembolic pulmonary hypertension. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the main causes of severe pulmonary hypertension. However, despite treatment (pulmonary endarterectomy), in approximately 15-20% of patients, pulmonary vascular resistance and pulmonary arterial pressure continue to increase. To date, little is known about the changes that occur in gene expression in CTEPH. The identification of genes associated with CTEPH may provide insight into the pathogenesis of CTEPH and may aid in diagnosis and treatment. In this study, we analyzed the gene expresion profiles of pulmonary artery endothelial cells from 5 patients with CTEPH and 5 healthy controls using oligonucleotide microarrays. Bioinformatics analyses using the Gene Ontology (GO) and KEGG databases were carried out to identify the genes and pathways specifically associated with CTEPH. Signal transduction networks were established to identify the core genes regulating the progression of CTEPH. A number of genes were found to be differentially expressed in the pulmonary artery endothelial cells from patients with CTEPH. In total, 412 GO terms and 113 pathways were found to be associated with our list of genes. All differential gene interactions in the Signal-Net network were analyzed. JAK3, GNA15, MAPK13, ARRB2 and F2R were the most significantly altered. Bioinformatics analysis may help gather and analyze large amounts of data in microarrays by means of rigorous experimental planning, scientific statistical analysis and the collection of complete data. In this study, a novel differential gene expression pattern was constructed. However, further studies are required to identify novel targets for the diagnosis and treatment of CTEPH. PMID- 24337371 TI - Polymorphisms of the pri-miR-34b/c promoter and TP53 codon 72 are associated with risk of colorectal cancer. AB - The microRNA (miR)-34 family is a direct transcriptional target of tumor suppressor TP53 and loss of miR-34 function may impair TP53-mediated cell cycle arrest and apoptosis. In the present study, we investigated whether the single nucleotide polymorphisms (SNPs) rs4938723 (T>C) in the promoter region of miR 34b/c and Arg72Pro (G>C) in codon 72 of TP53 are independently or complementarily associated with the risks and clinical outcomes of colorectal cancer (CRC) and whether the combined effect of these SNPs and metabolic risk factors are related to CRC. We evaluated the SNPs in 545 CRC patients and 428 healthy controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequence analysis. We found that the GC and GC/CC genotypes of TP53 Arg72Pro were associated with decreased risk of CRC (adjusted OR = 0.727 for GC; OR = 0.735 for GC/CC). The combined genotypes of TT-GC and CC-GG were significantly associated with reduced CRC risk (adjusted OR = 0.628 for TT-GC; OR = 0.381 for CC-GG, respectively). The SNP rs4938723 and diabetes mellitus (DM) together were associated with an increased CRC risk, but the SNP TP53 Arg72Pro CC with DM showed a protective effect against CRC. These findings indicate that rs4938723 in the promoter region of pri-miR-34b/c and the SNP in TP53 codon 72 were related to decreased risk of CRC in the population studied and those metabolic diseases and genetic variants influence each other with regard to CRC susceptibility. PMID- 24337372 TI - Electroencephalographic signals synchronize with behaviors and are sexually dimorphic during the light-dark cycle in reproductive frogs. AB - Male frogs behave differently from females during the breeding season, particularly with respect to courtship displays and in response to mating signals. In search of physiological correlates of these differences, the present study measured changes in baseline electroencephalogram (EEG) power output within four frequency bands in the telencephalon and mesencephalon, together with changes in locomotor activity as a function of the light-dark cycle in male and female Emei music frogs (Babina daunchina) at the reproductive stage. Previous studies have shown that male vocal activity varies both seasonally and daily in this species and that females use male advertisement calls to locate and select mates. The present results show that both EEG and locomotor activity exhibit highly correlated circadian patterns with peaks around light onset and offset. Importantly, during the reproductive stage, statistically significant sex differences in EEG output across brain regions during the light and dark phases were found indicating that sexual dimorphism exists for EEG activity which may underlie sexually specific information processing and behavioral activities. PMID- 24337373 TI - Identification of a unique hybrid macrophage-polarization state following recovery from lipopolysaccharide tolerance. AB - LPS tolerance is an essential immune-homeostatic response to repeated exposure to LPS that prevents excessive inflammatory responses. LPS tolerance induces a state of altered responsiveness in macrophages, resulting in repression of proinflammatory gene expression and increased expression of factors that mediate the resolution of inflammation. In this study, we analyzed the transcriptional plasticity of macrophages following LPS tolerance using genome-wide transcriptional profiling. We demonstrate that LPS tolerance is a transient state and that the expression of proinflammatory genes is restored to levels comparable to the acute response to LPS. However, following recovery from LPS tolerance a number of genes remained locked in a tolerizable state, including IL-33, CD86, IL 10, and NFIL3. Furthermore, we identified of a number of genes uniquely induced following recovery from LPS tolerance. Thus, macrophages adopt a unique transcriptional profile following recovery from LPS tolerance and have a distinct expression pattern of regulators of Ag presentation, antiviral responses, and transcription factors. Our data suggest that recovery from LPS tolerance leads to a hybrid macrophage activation state that is proinflammatory and microbicidal in nature but that possesses a regulatory anti-inflammatory profile distinct from that of LPS-tolerant and LPS-activated macrophages. PMID- 24337374 TI - Killer Ig-like receptor 2DL4 does not mediate NK cell IFN-gamma responses to soluble HLA-G preparations. AB - The MHC class Ib molecule HLA-G has previously been reported to be the ligand for the NK cell receptor killer Ig-like receptor (KIR)2DL4, but this remains controversial. In this study, we investigated IFN-gamma production by freshly isolated NK cells in response to both soluble and solid-phase ligands, including anti-KIR2DL4 mAbs and rHLA-G. Although freshly isolated CD56(bright) NK cells produced IFN-gamma in response to soluble HLA-G preparations, the response was found to be absolutely dependent on the presence of small numbers of contaminating CD56(-), CD14(-), CD11c(+) myeloid dendritic cells (mDCs). HLA-G tetramers bound only to the contaminating mDCs in the NK preparations, and Abs to KIR2DL4 and HLA-G did not block NK cell IFN-gamma production. NK cells did not respond to plate-bound HLA-G. Freshly isolated NK cells also produced IFN-gamma in response to unpurified soluble anti-KIR2DL4 mAb but not to low endotoxin affinity-purified Ab. The data suggest that previous reports of functional interactions between KIR2DL4 and HLA-G may have resulted from the use of purified NK cells that were contaminated with mDCs and HLA-G preparations that were contaminated with material capable of stimulating mDCs to produce cytokines that stimulate NK cells to produce IFN-gamma. PMID- 24337375 TI - Oral Escherichia coli colonization factor antigen I fimbriae ameliorate arthritis via IL-35, not IL-27. AB - A Salmonella therapeutic expressing enterotoxigenic Escherichia coli colonization factor Ag I (CFA/I) fimbriae protects against collagen-induced arthritis (CIA) by eliciting two regulatory T cell (Treg) subsets: TGF-beta-producing Foxp3( )CD39(+)CD4(+) T cells and IL-10-producing Foxp3(+)CD39(+)CD4(+) T cells. However, it is unclear whether CFA/I fimbriae alone are protective and whether other regulatory cytokines are involved, especially in the context for the EBI3 sharing cytokines, Treg-derived IL-35 and APC-derived IL-27, both capable of suppressing Th17 cells and regulating autoimmune diseases. Subsequent evaluation revealed that a single oral dose of purified, soluble CFA/I fimbriae protected against CIA as effectively as did Salmonella-CFA/I and found that Foxp3(+)CD39(+)CD4(+) T cells were the source of secreted IL-35, whereas IL-27 production by CD11c(+) cells was inhibited. Inquiring into their relevance, CFA/I fimbriae-treated IL-27R-deficient (WSX-1(-/-)) mice were equally protected against CIA as were wild-type mice, suggesting a limited role for IL-27. In contrast, CFA/I fimbriae-mediated protection was abated in EBI3(-/-) mice, accompanied by the loss of TGF-beta- and IL-10-producing Tregs. Adoptive transfer of C57BL/6 CD39(+)CD4(+) T cells to EBI3(-/-) mice with concurrent CFA/I plus IL 35 treatment effectively stimulated Tregs suppressing proinflammatory collagen II specific Th cells. In contrast, recipients cotransferred with C57BL/6 and EBI3(-/ ) CD39(+)CD4(+) T cells and treated with CFA/I plus IL-35 were not protected, implicating the importance of endogenous IL-35 for conferring CFA/I-mediated protection. Thus, CFA/I fimbriae stimulate IL-35 required for the coinduction of TGF-beta and IL-10. PMID- 24337376 TI - Effects of aging, cytomegalovirus infection, and EBV infection on human B cell repertoires. AB - Elderly humans show decreased humoral immunity to pathogens and vaccines, yet the effects of aging on B cells are not fully known. Chronic viral infection by CMV is implicated as a driver of clonal T cell proliferations in some aging humans, but whether CMV or EBV infection contributes to alterations in the B cell repertoire with age is unclear. We have used high-throughput DNA sequencing of IGH gene rearrangements to study the BCR repertoires over two successive years in 27 individuals ranging in age from 20 to 89 y. Some features of the B cell repertoire remain stable with age, but elderly subjects show increased numbers of B cells with long CDR3 regions, a trend toward accumulation of more highly mutated IgM and IgG Ig genes, and persistent clonal B cell populations in the blood. Seropositivity for CMV or EBV infection alters B cell repertoires, regardless of the individual's age: EBV infection correlates with the presence of persistent clonal B cell expansions, whereas CMV infection correlates with the proportion of highly mutated Ab genes. These findings isolate effects of aging from those of chronic viral infection on B cell repertoires and provide a baseline for understanding human B cell responses to vaccination or infectious stimuli. PMID- 24337377 TI - Membrane transfer from tumor cells overcomes deficient phagocytic ability of plasmacytoid dendritic cells for the acquisition and presentation of tumor antigens. AB - The potential contribution of plasmacytoid dendritic cells (pDCs) in the presentation of tumor cell Ags remains unclear, and some controversies exist with regard to the ability of pDCs to phagocytose cell-derived particulate Ags and cross-present them to MHC class I-restricted T lymphocytes. In this study, we show that human pDCs, although inefficient in the internalization of cell membrane fragments by phagocytosis, can efficiently acquire membrane patches and associated molecules from cancer cells of different histotypes. The transfer of membrane patches to pDCs occurred in a very short time and required cell-to-cell contact. Membrane transfer also included intact HLA complexes, and the acquired Ags could be efficiently recognized on pDCs by tumor-specific CD8(+) T cells. Remarkably, pDCs isolated from human colon cancer tissues displayed a strong surface expression of epithelial cell adhesion molecule, indicating that the exchange of exogenous Ags between pDCs and tumor cells also can occur in vivo. These data demonstrate that pDCs are well suited to acquire membrane patches from contiguous tumor cells by a cell-to-cell contact-dependent mechanism that closely resembles "trogocytosis." This phenomenon may allow pDCs to proficiently present tumor cell-derived Ags, despite limited properties of endophagocytosis. PMID- 24337378 TI - Regulatory T cells shape the resident memory T cell response to virus infection in the tissues. AB - Regulatory T cells (Tregs) are well known for their role in dampening the immune responses to self-Ags and, thereby, limiting autoimmunity. However, they also must permit immune responses to occur against foreign infectious agents. Using a mouse model of West Nile virus infection, we examined the role of Tregs in the generation of effector and memory T cell responses in the secondary lymphoid organs, as well as the infected tissues. We found that Treg numbers and activation increased in both the secondary lymphoid organs and CNS postinfection. Using Foxp3(DTR) knock-in mice, we found that Treg-deficient mice had increased Ag-driven production of IFN-gamma from both CD4(+) and CD8(+) T cells in the spleen and CNS during the effector phase. In mice lacking Tregs, there were greater numbers of short-lived effector CD8(+) T cells in the spleen during the peak of the immune response, but the memory CD8(+) T cell response was impaired. Specifically, we demonstrate that Treg-dependent production of TGF-beta results in increased expression of CD103 on CD8(+) T cells, thereby allowing for a large pool of resident memory T cells to be maintained in the brain postinfection. PMID- 24337379 TI - CCL-21 conditioned regulatory T cells induce allotolerance through enhanced homing to lymphoid tissue. AB - Regulatory T cells (Tregs) are instrumental in the induction and maintenance of tolerance, including in transplantation. Tregs induce allotolerance by interacting with APCs and T cells, interactions that require their proper homing to the lymphoid tissues. Using a well-characterized model of corneal allotransplantation, we demonstrate in this study that Tregs in the draining lymph nodes (LN) of allograft acceptors, but not rejectors, colocalize with APCs in the paracortical areas and express high levels of CCR7. In addition, we show that Treg expression of CCR7 is important not only for Treg homing to the draining LN, but also for optimal Treg suppressive function. Finally, we show that Tregs augmented for CCR7 expression by their ex vivo stimulation with the CCR7 ligand CCL21 show enhanced homing to the draining LN of allograft recipients and promote transplant survival. Together, these findings suggest that CCR7 expression is critical for Treg function and migration and that conditioning of Treg for maximal CCR7 expression may be a viable strategy for promoting allograft survival. PMID- 24337380 TI - Effector-memory T cells develop in islets and report islet pathology in type 1 diabetes. AB - CD8(+) T cells are critical in human type 1 diabetes and in the NOD mouse. In this study, we elucidated the natural history of islet-specific glucose-6 phosphatase catalytic subunit-related protein (IGRP)-specific CD8(+) T cells in NOD diabetes using MHC-tetramer technology. IGRP206-214-specific T cells in the peripheral lymphoid tissue increased with age, and their numbers correlated with insulitis progression. IGRP206-214-specific T cells in the peripheral lymphoid tissue expressed markers of chronic Ag stimulation, and their numbers were stable after diagnosis of diabetes, consistent with their memory phenotype. IGRP206-214 specific T cells in NOD mice expand, acquire the phenotype of effector-memory T cells in the islets, and emigrate to the peripheral lymphoid tissue. Our observations suggest that enumeration of effector-memory T cells of multiple autoantigen specificities in the periphery of type 1 diabetic subjects could be a reliable reporter for progression of islet pathology. PMID- 24337381 TI - Novel mechanisms underlying the immediate and transient global tolerization of splenic dendritic cells after vaccination with a self-antigen. AB - Dendritic cells (DCs) are important orchestrators of the immune response, ensuring that immunity against pathogens is generated, whereas immunity against healthy tissues is prevented. Using the tumor Ag MUC1, we previously showed that i.v. immunization of MUC1 transgenic mice, but not wild-type, with a MUC1 peptide resulted in transient tolerization of all splenic DCs. These DCs did not upregulate costimulatory molecules and induced regulatory T cells rather than effector T cells. They were characterized by suppressed expression of a cohort of pancreatic enzymes not previously reported in DCs, which were upregulated in DCs presenting the same MUC1 peptide as a foreign Ag. In this article, we examined the self-antigen-tolerized DC phenotype, function, and mechanisms responsible for inducing or maintaining their tolerized state. Tolerized DCs share some characteristics with immature DCs, such as a less inflammatory cytokine/chemokine profile, deficient activation of NF-kappaB, and sustained expression of zDC and CCR2. However, tolerized DCs demonstrated a novel inducible expression of aldehyde dehydrogenase 1/2 and phospho-STAT3. Suppressed expression of one of the pancreatic enzymes, trypsin, in these DC impeded their ability to degrade extracellular matrix, thus affecting their motility. Suppressed metallopeptidases, reflected in low expression of carboxypeptidase B1, prevented optimal Ag-specific CD4(+) T cell proliferation suggesting their role in Ag processing. Tolerized DCs were not refractory to maturation after stimulation with a TLR3 agonist, demonstrating that this tolerized state is not terminally differentiated and that tolerized DCs can recover their ability to induce immunity to foreign Ags. PMID- 24337383 TI - GM-CSF modulates autoantibody production and skin blistering in experimental epidermolysis bullosa acquisita. AB - GM-CSF activates hematopoietic cells and recruits neutrophils and macrophages to sites of inflammation. Inhibition of GM-CSF attenuates disease activity in models of chronic inflammatory disease. Effects of GM-CSF blockade were linked to modulation of the effector phase, whereas effects on early pathogenic events, for example, Ab production, have not been identified. To evaluate yet uncharacterized effects of GM-CSF on early pathogenic events in chronic inflammation, we employed immunization-induced epidermolysis bullosa acquisita (EBA), an autoimmune bullous disease caused by autoantibodies to type VII collagen. Compared to wild-type mice, upon immunization, GM-CSF(-/-) mice produced lower serum autoantibody titers, which were associated with reduced neutrophil numbers in draining lymph nodes. The same effect was observed in neutrophil-depleted wild-type mice. Neutrophil depletion in GM-CSF(-/-) mice led to a stronger inhibition, indicating that GM-CSF and neutrophils have additive functions. To characterize the contribution of GM-CSF specifically in the effector phase of EBA, disease was induced by transfer of anti-type VII collagen IgG into mice. We observed an increased GM-CSF expression, and GM-CSF blockade reduced skin blistering. Additionally, GM-CSF enhanced reactive oxygen species release and neutrophil migration in vitro. In immunization-induced murine EBA, treatment with anti-GM CSF had a beneficial effect on established disease. We demonstrate that GM-CSF modulates both autoantibody production and skin blistering in a prototypical organ-specific autoimmune disease. PMID- 24337382 TI - IL-27, a cytokine, and IFN-lambda1, a type III IFN, are coordinated to regulate virus replication through type I IFN. AB - IL-27, a member of the IL-12 family, plays a critical role in the control of innate and adaptive immune responses. IFN-lambda1, a member of the type III IFN family, shows antiviral abilities. In this study, we investigated the effects of IL-27 and IFN-lambda1 on the replication of hepatitis B virus (HBV), a major pathogen associated with a high risk for cirrhosis, liver failure, and hepatocellular carcinoma. We revealed that HBV infection activates IL-27 expression and IFN-lambda1 production and demonstrated that viral-activated IL-27 and IFN-lambda1 are coordinated to inhibit HBV replication. Initially, HBV infection upregulates IL-27 expression, which, in turn, stimulates IFN-lambda1 production through regulating ERK1/2 signaling and by enhancing NF-kappaB nuclear translocation to bind to the IFN-lambda1 promoter. Moreover, IL-27-activated IFN lambda1 upregulates IFN-lambda1 receptor (IL-28R1 and IL-10Rbeta) activity, resulting in the activation of the STAT1/2 pathway, which, in turn, induces the expression of IFN-stimulated genes, including IFN-inducible dsRNA-activated protein kinase, oligoadenylate synthetase 1, and IFN-induced GTP-binding protein 1 and, finally, inhibits HBV protein expression and viral capsid-associated DNA replication. More interestingly, we also revealed that type I IFN (IFN-alpha) is also involved in the downregulation of HBV replication mediated by IL-27. Thus, we identified a previously unknown mechanism by which IL-27 and IFN-lambda1 are coordinated to regulate virus replication through type I IFN. PMID- 24337384 TI - TNFR-associated factor 6 and TGF-beta-activated kinase 1 control signals for a senescence response by an endosomal NK cell receptor. AB - The endosomal innate receptor CD158d (killer cell Ig-like receptor 2DL4) induces cellular senescence in human NK cells in response to soluble ligand (HLA-G or agonist Ab). These senescent NK cells display a senescence-associated secretory phenotype, and their secretome promotes vascular remodeling and angiogenesis. To understand how CD158d initiates signaling for a senescence response, we mapped the region in its cytoplasmic tail that controls signaling. We identified a conserved TNFR-associated factor 6 (TRAF6) binding motif, which was required for CD158d-induced NF-kappaB activation and IL-8 secretion, TRAF6 association with CD158d, and TRAF6 recruitment to CD158d(+) endosomes in transfected cells. The adaptor TRAF6 is known to couple proximal signals from receptors such as endosomal TLRs and CD40 through the kinase TGF-beta-activated kinase 1 (TAK1) for NF-kappaB-dependent proinflammatory responses. Small interfering RNA-mediated silencing of TRAF6 and TAK1, and inhibition of TAK1 blocked CD158d-dependent IL-8 secretion. Stimulation of primary, resting NK cells with soluble Ab to CD158d induced TRAF6 association with CD158d, induced TAK1 phosphorylation, and inhibition of TAK1 blocked the CD158d-dependent reprogramming of NK cells that produces the senescence-associated secretory phenotype signature. Our results reveal that a prototypic TLR and TNFR signaling pathway is used by a killer cell Ig-like receptor that promotes secretion of proinflammatory and proangiogenic mediators as part of a unique senescence phenotype in NK cells. PMID- 24337385 TI - IL-32 promotes angiogenesis. AB - IL-32 is a multifaceted cytokine with a role in infections, autoimmune diseases, and cancer, and it exerts diverse functions, including aggravation of inflammation and inhibition of virus propagation. We previously identified IL-32 as a critical regulator of endothelial cell (EC) functions, and we now reveal that IL-32 also possesses angiogenic properties. The hyperproliferative ECs of human pulmonary arterial hypertension and glioblastoma multiforme exhibited a markedly increased abundance of IL-32, and, significantly, the cytokine colocalized with integrin alphaVbeta3. Vascular endothelial growth factor (VEGF) receptor blockade, which resulted in EC hyperproliferation, increased IL-32 three fold. Small interfering RNA-mediated silencing of IL-32 negated the 58% proliferation of ECs that occurred within 24 h in scrambled-transfected controls. Reduction of IL-32 neither affected apoptosis (insignificant changes in Bak-1, Bcl-2, Bcl-xL, lactate dehydrogenase, annexin V, and propidium iodide) nor VEGF or TGF-beta levels, but siIL-32-transfected adult and neonatal ECs produced up to 61% less NO, IL-8, and matrix metalloproteinase-9, and up to 3-fold more activin A and endostatin. In coculture-based angiogenesis assays, IL-32gamma dose dependently increased tube formation up to 3-fold; an alphaVbeta3 inhibitor prevented this activity and reduced IL-32gamma-induced IL-8 by 85%. In matrigel plugs loaded with IL-32gamma, VEGF, or vehicle and injected into live mice, we observed the anticipated VEGF-induced increase in neocapillarization (8-fold versus vehicle), but unexpectedly, IL-32gamma was equally angiogenic. A second signal such as IFN-gamma was required to render cells responsive to exogenous IL 32gamma; importantly, this was confirmed using a completely synthetic preparation of IL-32gamma. In summary, we add angiogenic properties that are mediated by integrin alphaVbeta3 but VEGF-independent to the portfolio of IL-32, implicating a role for this versatile cytokine in pulmonary arterial hypertension and neoplastic diseases. PMID- 24337386 TI - Role of IL-6 in Mycobacterium avium--associated immune reconstitution inflammatory syndrome. AB - Immune reconstitution inflammatory syndrome (IRIS) is a major adverse event of antiretroviral therapy in HIV infection, and paradoxically occurs as HIV viremia is suppressed and CD4 T cell numbers recover. IRIS reflects pathogenic immune responses against opportunistic infections acquired during the period of immunodeficiency, but little is understood about the mechanisms of inflammatory pathology. In this study, we show that IL-6 and C-reactive protein levels transiently rise at the time of the IRIS event in HIV-infected patients, unmasking Mycobacterium avium complex infection after starting antiretroviral therapy. To directly test the role of IL-6 in IRIS pathology, we used a model of experimentally inducible IRIS in which M. avium-infected T cell-deficient mice undergo a fatal inflammatory disease after reconstitution with CD4 T cells. We find that IL-6 neutralization reduces C-reactive protein levels, alleviates wasting disease, and extends host survival during experimental IRIS. Moreover, we show that combined blockade of IL-6 and IFN-gamma further reduces IRIS pathology, even after the onset of wasting disease. The combination of these clinical and experimental-model data show that the IL-6 pathway is not only a biomarker of mycobacterial IRIS but also a major mediator of pathology distinct from IFN-gamma and may be a useful target for therapeutic intervention. PMID- 24337388 TI - The quadriceps gastrocnemius muscle. AB - The gastrocnemius muscle forms the belly of calf muscles in the posterior compartment of the leg. This paper reports a four-headed gastrocnemius (named quadriceps gastrocnemius) muscle as a new variant and when present can alter the anatomy and/or the boundaries of the popliteal fossa. The four heads are named as medial, intermedio-medial, intermedio-lateral and medial. The newly identified heads, intermedio-medial and intermedio-lateral heads form the inferior boundaries of the popliteal fossa. Clinical conditions like popliteal entrapment syndrome may arise because of distal fossa congestion created by the intermedio medial and intermedio-lateral heads. This supernumerary heads may also be useful for grafting and they also provide bulkier mass for gastrocnemius proximal attachment. The knowledge of anatomical variants presented is useful to surgeons, prosectors and radiologists. PMID- 24337387 TI - Anatomic variations and lesions of the mandibular canal detected by cone beam computed tomography. AB - PURPOSE: The mandibular canal is a significant anatomical structure in implant dentistry, and cone beam computed tomography (CBCT) is an important diagnostic image modality in this field of dentistry. The aim of this study was to evaluate the frequencies of anatomic variations and lesions affecting the mandibular canal in CBCT images of the mandible produced for dental implant planning. METHODS: This cross-sectional study evaluated a sample of 250 CBCT examinations (500 mandibular canals). The inclusion criterion was CBCT examinations of the mandible requested for dental implant planning. The presence of anatomic variations and lesions affecting the mandibular canal was evaluated in the CBCT examinations. Moreover, the buccolingual position of the mandibular canal was evaluated in the molar region and in the ramus region. The CBCT exams were evaluated by one observer. The data were analyzed using descriptive and analytical statistics. The one-way ANOVA test was employed to compare the age between the anatomic variations. A paired t test was used to compare the buccolingual position between the molar region and the ramus region. Differences were considered significant when p values were lower than 0.05. RESULTS: The anatomic variations detected were large-diameter mandibular incisive canal (51.6 %), ramification (12 %), and accessory mental foramen (3.2 %). No difference was observed in the age of the patients between the anatomic variations (p > 0.05). The identified lesions included hypomineralization of the canal walls (20.8 %), idiopathic osteosclerosis (8.8 %), osteolytic lesions (3.2 %), iatrogenic perforation of the mandibular canal (2.8 %), and fibro-osseous lesions (1.6 %). The distance between the mandibular canal and the vestibular cortical bone was higher in the molar region than in the ramus region (p < 0.05). CONCLUSIONS: Anatomic variations and lesions affecting the mandibular canal were common findings in the CBCT images of the mandible produced for dental implant planning. An awareness of these alterations is important for dentistry because some of them might require treatment, change oral surgery planning and difficult inferior alveolar nerve anesthetic block. PMID- 24337389 TI - The influence of weight status on radial bone mineral density in Lebanese women. AB - The aim of this study was to investigate the influence of the weight-status (obese, overweight and normal-weight) on bone mineral density of the forearm in Lebanese women. 3,989 Lebanese women (1,138 obese, 1,570 overweight and 1,281 normal weight) aged from 19 to 92 years old participated in this study. Weight and height were measured, and body mass index (BMI) was calculated. BMD of the ultra-distal (UD) radius, the 1/3 radius and the total radius was measured by DXA (GE Healthcare Lunar Prodigy). In the whole population, body weight was positively correlated to UD Radius BMD (r = 0.41; P < 0.001), 1/3 radius BMD (r = 0.35; P < 0.001) and total radius BMD (r = 0.48; P < 0.001) while age was negatively correlated to UD BMD (r = -0.42; P < 0.001), 1/3 Radius BMD (r = 0.52; P < 0.001) and total radius BMD (r = -0.42; P < 0.001). Using multiple linear regression analysis models, age and weight explained 36 %, 41 % and 42 of the UD radius BMD, 1/3 radius BMD and total radius BMD variances respectively. UD radius BMD, 1/3 radius BMD and total radius BMD values were significantly different among the three groups (P < 0.001). UD Radius BMD, 1/3 radius BMD and total radius BMD values were higher in obese and overweight women compared to normal-weight women (P < 0.001) and in obese women compared to overweight women (P < 0.001). These differences among the three groups remained significant after adjusting for age and height (P < 0.001). This study suggests that obesity is associated with higher UD radius, 1/3 radius and total radius BMD values in Lebanese women. Thus, obesity seems to be protective against forearm osteopenia in Lebanese women. PMID- 24337390 TI - A ChIP-seq-defined genome-wide map of MEF2C binding reveals inflammatory pathways associated with its role in bone density determination. AB - Genome-wide association studies (GWAS) have demonstrated that genetic variation at the MADS box transcription enhancer factor 2, polypeptide C (MEF2C) locus is robustly associated with bone mineral density, primarily at the femoral neck. MEF2C is a transcription factor known to operate via the Wnt signaling pathway. Our hypothesis was that MEF2C regulates the expression of a set of molecular pathways critical to skeletal function. Drawing on our laboratory and bioinformatic experience with ChIP-seq, we analyzed ChIP-seq data for MEF2C available via the ENCODE project to gain insight in to its global genomic binding pattern. We aligned the ChIP-seq data generated for GM12878 (an established lymphoblastoid cell line) and, using the analysis package HOMER, a total of 17,611 binding sites corresponding to 8,118 known genes were observed. We then performed a pathway analysis of the gene list using Ingenuity. At 5 kb, the gene list yielded 'EIF2 Signaling' as the most significant annotation, with a P value of 5.01 * 10(-26). Moving further out, this category remained the top pathway at 50 and 100 kb, then dropped to just second place at 500 kb and beyond by 'Molecular Mechanisms of Cancer'. In addition, at 50 kb and beyond 'RANK Signaling in Osteoclasts' was a consistent feature and resonates with the main general finding from GWAS of bone density. We also observed that MEF2C binding sites were significantly enriched primarily near inflammation associated genes identified from GWAS; indeed, a similar enrichment for inflammation genes has been reported previously using a similar approach for the vitamin D receptor, an established key regulator of bone turnover. Our analyses point to known connective tissue and skeletal processes but also provide novel insights in to networks involved in skeletal regulation. The fact that a specific GWAS category is enriched points to a possible role of inflammation through which it impacts bone mineral density. PMID- 24337391 TI - [Aerosinusitis: part 1: Fundamentals, pathophysiology and prophylaxis]. AB - The relevance of aerosinusitis stems from the high number of flight passengers and the impaired fitness for work of the flight personnel. The frontal sinus is more frequently affected than the maxillary sinus and the condition generally occurs during descent. Sinonasal diseases and anatomic variations leading to obstruction of paranasal sinus ventilation favor the development of aerosinusitis. This Continuing Medical Education (CME) article is based on selective literature searches of the PubMed database (search terms: "aerosinusitis", "barosinusitis", "barotrauma" AND "sinus", "barotrauma" AND "sinusitis", "sinusitis" AND "flying" OR "aviator"). Additionally, currently available monographs and further articles that could be identified based on the publication reviews were also included. Part 1 presents the pathophysiology, symptoms, risk factors, epidemiology and prophylaxis of aerosinusitis. In part 2, diagnosis, conservative and surgical treatment will be discussed. PMID- 24337392 TI - Characterizing cerebral oxygen metabolism employing oxygen-17 MRI/MRS at high fields. AB - This article provides a comprehensive overview of oxygen ((17)O) magnetic resonance spectroscopy and imaging, including the advantages and challenges offered by the different methods developed thus far. The physiological role and relevance of oxygen, and its participation in aerobic metabolism, are addressed to emphasize the importance of the investigations and the efforts related to these developments. Furthermore, a number of methods employed in the determination of the cerebral metabolic rate of oxygen in neural cells will be presented, focusing primarily on methodologies enabling absolute quantification. PMID- 24337393 TI - ViP MRI: virtual phantom magnetic resonance imaging. AB - OBJECT: The ability to generate reference signals is of great benefit for quantitation of the magnetic resonance (MR) signal. The aim of the present study was to implement a dedicated experimental set-up to generate MR images of virtual phantoms. MATERIALS AND METHODS: Virtual phantoms of a given shape and signal intensity were designed and the k-space representation was generated. A waveform generator converted the k-space lines into a radiofrequency (RF) signal that was transmitted to the MR scanner bore by a dedicated RF coil. The k-space lines of the virtual phantom were played line-by-line in synchronization with the magnetic resonance imaging data acquisition. RESULTS: Virtual phantoms of complex patterns were reproduced well in MR images without the presence of artifacts. Time-series measurements showed a coefficient of variation below 1% for the signal intensity of the virtual phantoms. An excellent linearity (coefficient of determination r (2) = 0.997 as assessed by linear regression) was observed in the signal intensity of virtual phantoms. CONCLUSION: Virtual phantoms represent an attractive alternative to physical phantoms for providing a reference signal. MR images of virtual phantoms were here generated using a stand-alone, independent unit that can be employed with MR scanners from different vendors. PMID- 24337394 TI - Low-level laser therapy and light-emitting diode effects in the secretion of neuropeptides SP and CGRP in rat skin. AB - The phototherapy effects in the skin are related to biomodulation, usually to accelerate wound healing. However, there is no direct proof of the interrelation between the effects of low-level laser therapy (LLLT) and light-emitting diode (LED) in neuropeptide secretion, these substances being prematurely involved in the neurogenic inflammation phase of wound healing. This study therefore focused on investigating LLLT and LED in Calcitonin gene-related peptide (CGRP) and substance P (SP) secretion in healthy rat skin. Forty rats were randomly distributed into five groups with eight rats each: Control Group, Blue LED Group (470 nm, 350 mW power), Red LED Group (660 nm, 350 mW power), Red Laser Group (660 nm, 100 mW power), and Infrared Laser Group (808 nm, 100 mW power) (DMC(r) Equipamentos Ltda., Sao Carlos, Sao Paulo, Brazil). The skin of the animals in the experimental groups was irradiated using the punctual contact technique, with a total energy of 40 J, single dose, standardized at one point in the dorsal region. After 14 min of irradiation, the skin samples were collected for CGRP and SP quantification using western blot analysis. SP was released in Infrared Laser Group (p = 0.01); there was no difference in the CGRP secretion among groups. Infrared (808 nm) LLLT enhances neuropeptide SP secretion in healthy rat skin. PMID- 24337395 TI - Progress in engineering acid stress resistance of lactic acid bacteria. AB - Lactic acid bacteria (LAB) are widely used for the production of a variety of fermented foods, and are considered as probiotic due to their health-promoting effect. However, LAB encounter various environmental stresses both in industrial fermentation and application, among which acid stress is one of the most important survival challenges. Improving the acid stress resistance may contribute to the application and function of probiotic action to the host. Recently, the advent of genomics, functional genomics and high-throughput technologies have allowed for the understanding of acid tolerance mechanisms at a systems level, and many method to improve acid tolerance have been developed. This review describes the current progress in engineering acid stress resistance of LAB. Special emphasis is placed on engineering cellular microenvironment (engineering amino acid metabolism, introduction of exogenous biosynthetic capacity, and overproduction of stress response proteins) and maintaining cell membrane functionality. Moreover, strategies to improve acid tolerance and the related physiological mechanisms are also discussed. PMID- 24337396 TI - A novel third chromosomal locus controls susceptibility to Autographa californica multiple nucleopolyhedrovirus in the silkworm, Bombyx mori. AB - Baculovirus demonstrates specific infection spectrums and thus one certain host exhibits particular response to single baculovirus isolate. Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is considered to be not an innate pathogen to Bombyx mori, but some silkworm strains have been identified to be permissive to AcMNPV, indicating the positive or negative involvement of certain host factors in baculovirus replications in vivo. To provide a fundamental knowledge of this process, we performed large-scale screening to investigate the responses of 448 silkworm strains against recombinant AcMNPV inoculation. By genetic analysis between permissive and resistant strains identified, we further confirmed that a potential corresponding locus on chromosome 3 regulates host responses to AcMNPV in silkworm. Additionally, we found that it is available for AcMNPV-silkworm baculovirus expression vector system to produce proteins of interest. PMID- 24337397 TI - Genome rearrangements of Streptomyces albus J1074 lead to the carotenoid gene cluster activation. AB - Streptomyces albus J1074 is a derivative of the S. albus G1 strain defective in SalG1 restriction-modification system. Genome sequencing of S. albus J1074 revealed that the size of its chromosome is 6.8 Mb with unusually short terminal arms of only 0.3 and 0.4 Mb. Here we present our attempts to evaluate the dispensability of subtelomeric regions of the S. albus J1074 chromosome. A number of large site-directed genomic deletions led to circularization of the S. albus J1074 chromosome and to the overall genome reduction by 307 kb. Two spontaneous mutants with an activated carotenoid cluster were obtained. Genome sequencing and transcriptome analysis indicated that phenotypes of these mutants resulted from the right terminal 0.42 Mb chromosomal region deletion, followed by the carotenoid cluster amplification. Our results indicate that the right terminal 0.42 Mb fragment is dispensable under laboratory conditions. In contrast, the left terminal arm of the S. albus J1074 chromosome contains essential genes and only 42 kb terminal region is proved to be dispensable. We identified overexpressed carotenoid compounds and determined fitness costs of the large genomic rearrangements. PMID- 24337398 TI - Influence of genes and the environment in familial congenital heart defects. AB - The present study aimed to investigate genetic and environmental factors involved in the pathogenesis of congenital heart disease (CHD). A total of 61 familial pedigrees with CHD were analyzed, and 134 patients out of 761 family members had a diagnosis of CHD confirmed. The present study revealed that the prevalence of CHD in first-degree relatives (55/249, 22.0%) was significantly higher than that in second-degree relatives (18/526, 3.4%). Additionally, the recurrence rate of CHD in families in which the patient's mother (12/61) or sister (15/61) had CHD were significantly higher than in cases with the father (6/61) or brother (4/61) having CHD. The subtypes of CHD with increased risk of recurrence were ventricle septal defect (VSD) and atrial septal defect (ASD), followed by patent ductus arteriosus and tetralogy of fallot (TOF). In the 21 sets of twins among the 61 familial pedigrees analyzed, the concordance of both twins affected by CHD in identical and dizygotic twins was 94.4% (17/18) and 33.3% (1/3), respectively. Identical subtypes of CHD were identified in 10 out of 21 sets of twins. Of note, the following pattern was identified in three sets of the twins: One twin had TOF, while the other one had VSD. A risk factor survey revealed that threatened abortion in early pregnancy was associated with familial CHD. In conclusion, genetic factors may have important roles in the development of CHD, and TOF and VSD may have similar molecular mechanisms. Threatened abortion in early pregnancy is a novel environmental factor that may be specific in Chinese females with CHD. PMID- 24337399 TI - Evaluation of patients' attitudes towards stroke prevention and bleeding risk in atrial fibrillation. AB - Patient's values and preferences regarding the relative importance of preventing strokes and avoiding bleeding are now recognised to be of great importance in deciding on therapy for the prevention of stroke due to atrial fibrillation (SPAF). We used an iPad questionnaire to determine the minimal clinically important difference (Treatment Threshold) and the maximum number of major bleeding events that a patient would be willing to endure in order to prevent one stroke (Bleeding Ratio) for the initiation of antithrombotic therapy in 172 hospital in-patients with documented non-valvular atrial fibrillation in whom anticoagulant therapy was being considered. Patients expressed strong opinions regarding SPAF. We found that 12% of patients were "medication averse" and were not willing to consider antithrombotic therapy; even if it was 100% effective in preventing strokes. Of those patients who were willing to consider antithrombotic therapy, 42% were identified as "risk averse" and 15% were "risk tolerant". Patients required at least a 0.8% (NNT=125) annual absolute risk reduction and 15% relative risk reduction in the risk of stroke in order to agree to initiate antithrombotic therapy, and patients were willing to endure 4.4 major bleeds in order to prevent one stroke. In conclusion, there was a substantial amount of inter-patient variability, and often extreme differences in opinion regarding tolerance of bleeding risk in the context of stroke prevention in atrial fibrillation. These findings highlight the importance of considering patient preferences when deciding on SPAF therapy. PMID- 24337400 TI - Police encounters involving citizens with mental illness: use of resources and outcomes. AB - OBJECTIVE: Few studies have addressed use of resources in police interventions involving individuals with mental illness. The time police officers spend on interventions is a straightforward measure with significant administrative weight, given that it addresses human resource allocation. This study compared the characteristics of police interventions involving individuals with mental illness and a control sample of individuals without mental illness. METHODS: A total of 6,128 police interventions in Montreal, Quebec, were analyzed by using a retrospective analysis of police intervention logs from three days in 2006. Interventions involving citizens with (N=272) and without (N=5,856) mental illness were compared by reason for the intervention, the use of arrest, and the use of police resources. RESULTS: Police interventions involving individuals with mental illness were less likely than those involving individuals without mental illness to be related to more severe offenses. However, interventions for minor offenses were more likely to lead to arrest when they involved citizens with mental illness. Interventions for reasons of equal severity were twice as likely to lead to arrest if the citizen involved had a mental illness. After controlling for the use of arrest and the severity of the situation, the analysis showed that police interventions involving individuals with mental illness used 87% more resources than interventions involving individuals without mental illness. CONCLUSIONS: Future studies using administrative police data sets could investigate the use of resources and division of costs involved in new programs or partnerships to better address the interface of criminal justice and mental health care. PMID- 24337401 TI - Access to urban acute care services in high- vs. middle-income countries: an analysis of seven cities. AB - PURPOSE: Cities are expanding rapidly in middle-income countries, but their supply of acute care services is unknown. We measured acute care services supply in seven cities of diverse economic background. METHODS: In a cross-sectional study, we compared cities from two high-income (Boston, USA and Paris, France), three upper-middle-income (Bogota, Colombia; Recife, Brazil; and Liaocheng, China), and two lower-middle-income (Chennai, India and Kumasi, Ghana) countries. We collected standardized data on hospital beds, intensive care unit beds, and ambulances. Where possible, information was collected from local authorities. We expressed results per population (from United Nations) and per acute illness deaths (from Global Burden of Disease project). RESULTS: Supply of hospital beds where intravenous fluids could be delivered varied fourfold from 72.4/100,000 population in Kumasi to 241.5/100,000 in Boston. Intensive care unit (ICU) bed supply varied more than 45-fold from 0.4/100,000 population in Kumasi to 18.8/100,000 in Boston. Ambulance supply varied more than 70-fold. The variation widened when supply was estimated relative to disease burden (e.g., ICU beds varied more than 65-fold from 0.06/100 deaths due to acute illnesses in Kumasi to 4.11/100 in Bogota; ambulance services varied more than 100-fold). Hospital bed per disease burden was associated with gross domestic product (GDP) (R (2) = 0.88, p = 0.01), but ICU supply was not (R (2) = 0.33, p = 0.18). No city provided all requested data, and only two had ICU data. CONCLUSIONS: Urban acute care services vary substantially across economic regions, only partially due to differences in GDP. Cities were poor sources of information, which may hinder their future planning. PMID- 24337402 TI - Year in review in Intensive Care Medicine 2013: I. Acute kidney injury, ultrasound, hemodynamics, cardiac arrest, transfusion, neurocritical care, and nutrition. PMID- 24337403 TI - Concomitant treatment with pertussis toxin plus temozolomide increases the survival of rats bearing intracerebral RG2 glioma. AB - PURPOSE: Glioblastoma multiforme is the most frequent primary brain tumor, it has poor prognosis, and it remains refractory to current treatment. The success of temozolomide (TMZ) appears to be limited by the occurrence of chemoresistance. Recently, we report the use of pertussis toxin as adjuvant immunotherapy in a C6 glioma model; showing a decrease in tumoral size, it induced selective cell death in Treg cells, and it elicited less infiltration of tumoral macrophages. Here, we evaluated the cytotoxic effect of pertussis toxin in combination with TMZ for glioma treatment, both in vitro and in vivo RG2 glioma model. METHODS: We determined cell viability, cell cycle, apoptosis, and autophagy on treated RG2 cells through flow cytometry, immunofluorescence, and Western blot assays. Twenty eight rats were divided in four groups (n = 7) for each treatment. After intracranial implantation of RG2 cells, animals were treated with TMZ (10 mg/Kg/200 MUl of apple juice), PTx (2 MUg/200 MUl of saline solution), and TMZ + PTx. Animals without treatment were considered as control. RESULTS: We found an induction of apoptosis in around 20 % of RG2 cells, in both single treatments and in their combination. Also, we determined the presence of autophagy vesicles, without any modifications in the cell cycle in the TMZ - PTx-treated groups. The survival analyses showed an increase due to individual treatments; while in the group treated with the combination TMZ - PTx, this effect was enhanced. CONCLUSION: We show that the concomitant use of pertussis toxin plus TMZ could represent an advantage to improve the glioma treatment. PMID- 24337404 TI - Enhancement of DEN-induced liver tumourigenesis in hepatocyte-specific Lass2 knockout mice coincident with upregulation of the TGF-beta1-Smad4-PAI-1 axis. AB - Longevity assurance homolog 2 of yeast LAG1 (Lass2) gene is capable of suppressing the proliferation and metastasis of several types of tumours including liver cancer. In the present study, hepatocyte-specific Lass2-knockout (Lass2 KO) and wild-type (WT) mice were exposed to the carcinogen, diethylnitrosamine (DEN), to induced liver tumours. At week 23 following DEN injection, tumours were produced in 100% of the Lass2 KO mice and 21.4% of the WT mice. At week 40, 100% of the Lass2 KO mice and 78.6% of the WT mice developed tumours, with no distinct significant difference in tumour occurrences between the two genotypes; yet, tumours in the Lass2 KO mouse livers were more numerous and larger in size. Hepatocellular carcinoma (HCC) was confirmed by alpha fetoprotein (AFP). PCNA and EdU assays indicated more active proliferation whereas TUNEL assay revealed decreased apoptosis in Lass2 KO livers, when compared with the WT control. The expression of plasminogen activator inhibitor type-1 (PAI-1), a tumour-promoting gene, in the liver tissues of the 2 genotypes was detected using qPCR and western blotting, showing that PAI-1 levels were significantly elevated in Lass2 KO livers at week 40 following DEN introduction. Moreover, the expression of PAI-1-related TGF-beta1, Smad-4 and -7 was detected, displaying an elevation in TGF-beta1 and Smad-4 (not including Smad-7) in the Lass2 KO livers. Our data demonstrates that i) Lass2 is a protective gene against DEN-induced liver tumourigenesis; and ii) upregulation of the TGF-beta1-Smad4-PAI 1 axis may contribute to the vulnerability of Lass2-knockout mice to DEN. PMID- 24337405 TI - Precise and rapid costal cartilage graft sectioning using a novel device: clinical application. AB - IMPORTANCE The use of costal cartilage as a graft in facial reconstructive surgery requires sectioning the cartilage into a suitable shape. OBJECTIVE To evaluate the accuracy of a novel mechanical device for producing uniform slices of costal cartilage and to illustrate the use of the device during nasal surgery. DESIGN Basic and clinical study using 100 porcine ex vivo costal cartilage slices and 9 operative cases. METHODS This instrument departs from antecedent devices in that it uses compression to secure and stabilize the specimen during sectioning. A total of 75 porcine costal cartilage ribs were clamped with minimal compression just sufficient to secure and stabilize the specimen while cutting. Slices having a length of 4 cm and width of 1 cm were obtained using the cartilage cutter at 3 thicknesses: 1 mm (n = 25), 2 mm (n = 25), and 3 mm (n = 25). The procedure was repeated for the 2-mm thick samples; however, the ribs in this group (n = 25) were clamped using the maximum amount of compression attainable by the device. Thickness was measured using a digital micrometer. Case presentations illustrate the use of the device in secondary and reconstructive rhinoplasty surgery. RESULTS All specimens were highly uniform in thickness on visual inspection and appeared to be adequate for clinical application. Sectioning was completed in several seconds without complication. In the porcine specimens sectioned using minimal compression, the percentage difference in thickness for each individual sample averaged 18%, 10%, and 11% for the 1-mm-, 2-mm-, and 3-mm-thick slices, respectively. Within the specimens sectioned using maximum compression, the percentage difference in thickness for each individual sample averaged 35% for the 2-mm-thick slices. In the setting of nasal reconstructive surgery, slices having a thickness from 1 to 2 mm were found to be well suited for all necessary graft types. CONCLUSIONS AND RELEVANCE The simple mechanical device described produces costal cartilage graft slices with highly uniform thickness. Securing the rib by clamping during cutting reduces uniformity of the slices; however, the imperfections are minimal, and all sectioned grafts are adequate for clinical application. The device can be adjusted to produce slices of appropriate thickness for all nasal cartilage grafts. This device is valuable for reconstructive procedures owing to its ease of use, rapid operation, and reproducible results. PMID- 24337406 TI - Long-term prehypertension treatment with losartan effectively prevents brain damage and stroke in stroke-prone spontaneously hypertensive rats. AB - Prehypertension has been associated with adverse cerebrovascular events and brain damage. The aims of this study were to investigate i) whether short- and long term treatments with losartan or amlodipine for prehypertension were able to prevent blood pressure (BP)-linked brain damage, and ii) whether there is a difference in the effectiveness of treatment with losartan and amlodipine in protecting BP-linked brain damage. In the present study, prehypertensive treatment with losartan and amlodipine (6 and 16 weeks treatment with each drug) was performed on 4-week-old stroke-prone spontaneously hypertensive rats (SHRSP). The results showed that long-term (16 weeks) treatment with losartan is the most effective in lowering systolic blood pressure in the long term (up to 40 weeks follow-up). Additionally, compared with the amlodipine treatment groups, the short- and long-term losartan treatments protected SHRSP from stroke and improved their brains structurally and functionally more effectively, with the long-term treatment having more benefits. Mechanistically, the short- and long-term treatments with losartan reduced the activity of the local renin-angiotensin aldosterone system (RAAS) in a time-dependent manner and more effectively than their respective counterpart amlodipine treatment group mainly by decreasing AT1R levels and increasing AT2R levels in the cerebral cortex. By contrast, the amlodipine treatment groups inhibited brain cell apoptosis more effectively as compared with the losartan treatment groups mainly through the suppression of local oxidative stress. Taken together, the results suggest that long-term losartan treatment for prehypertension effectively protects SHRSP from stroke induced brain damage, and this protection is associated with reduced local RAAS activity than with brain cell apoptosis. Thus, the AT1R receptor blocker losartan is a good candidate drug that may be used in the clinic for long-term treatment on prehypertensive populations in order to prevent BP-linked brain damage. PMID- 24337407 TI - Fate and plasticity of renin precursors in development and disease. AB - Renin-expressing cells appear early in the embryo and are distributed broadly throughout the body as organogenesis ensues. Their appearance in the metanephric kidney is a relatively late event in comparison with other organs such as the fetal adrenal gland. The functions of renin cells in extra renal tissues remain to be investigated. In the kidney, they participate locally in the assembly and branching of the renal arterial tree and later in the endocrine control of blood pressure and fluid-electrolyte homeostasis. Interestingly, this endocrine function is accomplished by the remarkable plasticity of renin cell descendants along the kidney arterioles and glomeruli which are capable of reacquiring the renin phenotype in response to physiological demands, increasing circulating renin and maintaining homeostasis. Given that renin cells are sensors of the status of the extracellular fluid and perfusion pressure, several signaling mechanisms (beta-adrenergic receptors, Notch pathway, gap junctions and the renal baroreceptor) must be coordinated to ensure the maintenance of renin phenotype- and ultimately the availability of renin--during basal conditions and in response to homeostatic threats. Notably, key transcriptional (Creb/CBP/p300, RBP-J) and posttranscriptional (miR-330, miR125b-5p) effectors of those signaling pathways are prominent in the regulation of renin cell identity. The next challenge, it seems, would be to understand how those factors coordinate their efforts to control the endocrine and contractile phenotypes of the myoepithelioid granulated renin-expressing cell. PMID- 24337408 TI - Left ventricular mass and cardiac function in a population of children with chronic kidney disease. AB - BACKGROUND: Cardiovascular disease (CVD) is a common cause of morbidity and mortality in children with chronic kidney disease (CKD). Left ventricular hypertrophy (LVH) and diastolic dysfunction (LVDD) are early markers. The aims of this study were to evaluate (1) LVH and LVDD, using both conventional echocardiographic evaluation and Tissue Doppler Imaging (TDI), and (2) the correlation between cardiac disease and possible risk factors, in children with CKD. METHODS: The study cohort comprised 34 paediatric patients with CKD and 34 healthy children (mean +/- standard deviation: age 9 +/- 4.6 and 8.2 +/- 4.3 years, respectively). Thirteen (38 %) patients were in CKD stage 2, 15 (44 %) in stage 3 and six (18 %) in stage 4-5. LVH was defined as a left ventricular mass index (LVMI) of >95th percentile (38 g/h(2.7)). RESULTS: Left ventricular hypertrophy was present in 13 patients (38 %). Diastolic function evaluated with TDI (E'/A' = early/late diastolic myocardial velocity) worsened with the reduction of glomerular filtration rate (p = 0.020). There was a positive correlation between LVMI and body mass index-standard deviation score (p = 0.020) and a negative correlation between E'/A' and serum phosphorus and calcium levels and their respective product (p = 0.004, p = 0.017, p < 0.001). The relaxation index E' was reduced in 68 % of patients. CONCLUSION: Based on our results, TDI is a simple procedure and would appear to be a more accurate diagnostic tool than conventional echocardiography in the early diagnosis of LVDD. PMID- 24337409 TI - Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis. AB - Complicated hereditary spastic paraplegias (HSP) are a heterogeneous group of HSP characterized by spasticity associated with a variable combination of neurologic and extra-neurologic signs and symptoms. Among them, HSP with thin corpus callosum and intellectual disability is a frequent subtype, often inherited as a recessive trait (ARHSP-TCC). Within this heterogeneous subgroup, SPG11 and SPG15 represent the most frequent subtypes. We analyzed the mutation frequency of three genes associated with early-onset forms of ARHSP with and without TCC, CYP2U1/SPG56, DDHD2/SPG54 and GBA2/SPG46, in a large population of selected complicated HSP patients by using a combined approach of traditional-based and amplicon-based high-throughput pooled-sequencing. Three families with mutations were identified, one for each of the genes analyzed. Novel homozygous mutations were identified in CYP2U1 (c.1A>C/p.Met1?) and in GBA2 (c.2048G>C/p.Gly683Arg), while the homozygous mutation found in DDHD2 (c.1978G>C/p.Asp660His) had been previously reported in a compound heterozygous state. The phenotypes associated with the CYP2U1 and DDHD2 mutations overlap the SPG56 and the SPG54 subtypes, respectively, with few differences. By contrast, the GBA2 mutated patients show phenotypes combining typical features of both the SPG46 subtype and the recessive ataxia form, with marked intrafamilial variability thereby expanding the spectrum of clinical entities associated with GBA2 mutations. Overall, each of three genes analyzed shows a low mutation frequency in a general population of complicated HSP (<1 % for either CYP2U1 or DDHD2 and approximately 2 % for GBA2). These findings underline once again the genetic heterogeneity of ARHSP-TCC and the clinical overlap between complicated HSP and the recessive ataxia syndromes. PMID- 24337410 TI - Elevated transferrin saturation, health-related quality of life and telomere length. AB - We sought to examine the relationship between elevated transferrin saturation (TS) and measures of health status (telomere length and patient-reported health related quality of life) to assess whether elevated TS is associated with negative patient outcomes beyond increased risk for morbidity and mortality, using a cross-sectional analysis of the Hemochromatosis and Iron Overload Screening Study supplemented with assays for leukocyte telomere length in adults >=25 years old (n = 669). Among individuals with elevated TS (>=45 % for women and >=50 % for men), who also had a usual source of care, only 5.2 % reported ever being told by a doctor that they had an elevated iron condition. In a fully adjusted general linear regression model controlling for demographic characteristics as well as health conditions associated with iron overload, elevated TS versus non-elevated TS was associated with worse general health status (60.4 vs. 63.8, P < 0.05), mental health status (76.5 vs. 82.2, P < 0.0001) and shorter telomere length (241.4 vs. 261.3, P < 0.05). Increased surveillance of elevated TS may be in order as elevated TS is associated with decreased health status and very few patients with elevated TS are aware of their condition. PMID- 24337411 TI - Validation of nucleolar protein 4 as a novel methylated tumor suppressor gene in head and neck cancer. AB - Methylation of CpG islands in the promoter region of genes acts as a significant mechanism of epigenetic gene silencing in head and neck cancer. In the present study, we assessed the association of epigenetic alterations of a panel of 12 genes [nucleolar protein 4 (NOL4), iroquois homeobox 1 (IRX1), SLC5A8, LRRC3B, FUSSEL18, EBF3, GBX2, HMX2, SEPT9, ALX3, SOCS3 and LHX6] with head and neck squamous cell carcinoma (HNSCC) via a candidate gene approach. After the initial screening of methylated CpG islands on the promoter regions by bisulfite sequencing using salivary rinse samples, only two genes had methylated CpG dinucleotides on their promoter regions in tumor samples and absence of methylated CpGs were found in normal salivary rinse samples after bisulfite modification and bisulfite sequencing. We then performed real-time quantitative methylation-specific PCR (QMSP) on 16 salivary rinse and 14 normal mucosal samples from healthy subjects and 33 HNSCC tumor samples for the two genes selected. After validation with QMSP, one gene, NOL4, was highly methylated (91%) in tumor samples and unmethylated in normal salivary rinses and minimally methylated in normal mucosal samples demonstrating cancer-specific methylation in HNSCC tissues. Although the IRX1 gene was observed as methylated in normal mucosal and salivary rinse samples, the methylation values of these normal samples were very low (<10%). In conclusion, we identified NOL4 as a highly specific promoter methylated gene associated with HNSCC. IRX1 may have potential as a biomarker for HNSCC and should be assessed in a larger cohort. PMID- 24337412 TI - Development of ICF Core Sets to standardize assessment of functioning and impairment in ADHD: the path ahead. AB - In the study of health and quality of life in attention deficit/hyperactivity disorder (ADHD), it is of paramount importance to include assessment of functioning. The International Classification of Functioning, Disability and Health (ICF) provides a comprehensive, universally accepted framework for the description of functioning in relation to health conditions. In this paper, the authors outline the process to develop ICF Core Sets for ADHD. ICF Core Sets are subgroups of ICF categories selected to capture the aspects of functioning that are most likely to be affected in specific disorders. The ICF categories that will be included in the ICF Core Sets for ADHD will be determined at an ICF Core Set Consensus Conference, wherein evidence from four preliminary studies (a systematic review, an expert survey, a patient and caregiver qualitative study, and a clinical cross-sectional study) will be integrated. Comprehensive and Brief ICF Core Sets for ADHD will be developed with the goal of providing useful standards for research and clinical practice, and to generate a common language for the description of functioning in ADHD in different areas of life and across the lifespan. PMID- 24337413 TI - Mutant DNMT3A clone evading chemotherapy and infiltrating central nervous system in a patient with molecularly good-risk acute myeloid leukemia. PMID- 24337414 TI - The distribution of urate deposition within the extremities in gout: a review of 148 dual-energy CT cases. AB - OBJECTIVE: Clinical detection of gout can be difficult due to co-existent and mimicking arthropathies and asymptomatic disease. Understanding of the distribution of urate within the body can aid clinical diagnosis and further understanding of the resulting pathology. Our aim was to determine this distribution of urate within the extremities in patients with gout. MATERIALS AND METHODS: All patients who underwent a four-limb dual-energy computed tomography (DECT) scan for suspected gout over a 2-year period were identified (n = 148, 121 male, 27 female, age range, 16-92 years, mean = 61.3 years, median = 63 years). The reports of the positive cases were retrospectively analyzed and the locations of all urate deposition recorded and classified by anatomical location. RESULTS: A total of 241 cases met the inclusion criteria, of which 148 cases were positive. Of these, 101 (68.2 %) patients had gout in the foot, 81 (56.1 %) in the knee, 79 (53.4 %) in the ankle, 41 (27.7 %) in the elbow, 25 (16.9 %) in the hand, and 25 (16.9 %) in the wrist. The distribution was further subcategorized for each body part into specific bone and soft tissue structures. CONCLUSIONS: In this observational study, we provide for the first time a detailed analysis of extremity urate distribution in gout, which both supports and augments to the current understanding based on clinical and microscopic findings. PMID- 24337415 TI - The representation of conceptual knowledge: visual, auditory, and olfactory imagery compared with semantic processing. AB - Two experiments comparing imaginative processing in different modalities and semantic processing were carried out to investigate the issue of whether conceptual knowledge can be represented in different format. Participants were asked to judge the similarity between visual images, auditory images, and olfactory images in the imaginative block, if two items belonged to the same category in the semantic block. Items were verbally cued in both experiments. The degree of similarity between the imaginative and semantic items was changed across experiments. Experiment 1 showed that the semantic processing was faster than the visual and the auditory imaginative processing, whereas no differentiation was possible between the semantic processing and the olfactory imaginative processing. Experiment 2 revealed that only the visual imaginative processing could be differentiated from the semantic processing in terms of accuracy. These results showed that the visual and auditory imaginative processing can be differentiated from the semantic processing, although both visual and auditory images strongly rely on semantic representations. On the contrary, no differentiation is possible within the olfactory domain. Results are discussed in the frame of the imagery debate. PMID- 24337416 TI - Interactions of the polarization and the sun compass in path integration of desert ants. AB - Desert ants, Cataglyphis fortis, perform large-scale foraging trips in their featureless habitat using path integration as their main navigation tool. To determine their walking direction they use primarily celestial cues, the sky's polarization pattern and the sun position. To examine the relative importance of these two celestial cues, we performed cue conflict experiments. We manipulated the polarization pattern experienced by the ants during their outbound foraging excursions, reducing it to a single electric field (e-)vector direction with a linear polarization filter. The simultaneous view of the sun created situations in which the directional information of the sun and the polarization compass disagreed. The heading directions of the homebound runs recorded on a test field with full view of the natural sky demonstrate that none of both compasses completely dominated over the other. Rather the ants seemed to compute an intermediate homing direction to which both compass systems contributed roughly equally. Direct sunlight and polarized light are detected in different regions of the ant's compound eye, suggesting two separate pathways for obtaining directional information. In the experimental paradigm applied here, these two pathways seem to feed into the path integrator with similar weights. PMID- 24337417 TI - Effect of withdrawal from long-term use of temazepam, zopiclone or zolpidem as hypnotic agents on cognition in older adults. AB - PURPOSE: The aim of this study was to assess the effect of withdrawal from the long-term use of temazepam, zopiclone or zolpidem as hypnotics drugs (here referred to as BZD) on cognitive performance. METHODS: Ninety-two adults (age >=55 years) with primary insomnia and who were long-term daily users of BZD volunteered to participate in a 1-month medically supported withdrawal attempt from BZD use, with a subsequent 5-month follow-up. Withdrawal was based on plasma BZD measurements at baseline, at 1 month and during subsequent regular clinical appointments. Attention and psychomotor performance were measured using the CogniSpeed(r) at baseline and at 1, 2 and 6 months. Reaction times were determined in the Simple Reaction Time (SRT), Two-Choice Reaction Time (2-CRT) and Vigilance tests, and errors were measured by the 2-CRT and Vigilance tests. The cognition data of the withdrawal group were also compared with a cohort of BZD non-users. RESULTS: Eighty-nine (97 %) participants (59 women, 30 men) were followed-up for a maximum of 6 months. During the follow-up period, changes in reaction times and errors did not differ between short-term withdrawers (no residual BZD at 1 month; N = 69), non-withdrawers (residual BZD at 1 month; N = 20) or long-term withdrawers (N = 34). Compared to the reaction times of the BZD free cohort, those of BZD users were slower at baseline. The reaction times of BZD withdrawers based on the results of the SRT or 2-CRT tests during follow-up did not reach those of the BZD-free cohort, but there was no difference between these groups in the Vigilance test. CONCLUSIONS: Long-term use of BDZ as hypnotic drugs by older adults is related to prolonged impairment of attentional and psychomotor cognitive functioning that persists for at least 6 months after withdrawal. PMID- 24337418 TI - Characterisation of the p.A1461D mutation causing von Willebrand disease type 2B with severe thrombocytopenia, circulating giant platelets, and defective alpha granule secretion. PMID- 24337419 TI - How to determine bortezomib-based regimen for elderly patients with multiple myeloma: PAD versus CBd, an observational study. AB - BACKGROUND: This was an open-label, observational, prospective assessment. We conducted an analysis of the impact of bortezomib-based therapy (PAD: bortezomib, doxorubicin, high-dose dexamethasone vs. CBd: cyclophosphamide bortezomib, low dose dexamethasone) on the survival rates and adverse events in elderly patients with newly diagnosed multiple myeloma (MM). METHODS: Out of 303 patients, 128 received the PAD regimen and the other 175 patients received the CBd induction therapy (age 65-89 years). Baseline patient characteristics between the two cohorts were balanced in age (P = 0.69), international staging system (ISS) prognostic stages (P = 0.90), serum calcium (P = 0.70), and serum creatinine (P = 0.52). RESULTS: Overall response (OS) after the induction chemotherapy was achieved in 214 of 303 patients (70.6 %), with no significant differences observed between the two treatment groups (71.9 vs. 69.7 %, P = 0.68). Patients with ISS stage 2 reached the same 5-year OS advantages compared to patients with ISS stage 1, because they received bortezomib-based PAD or CBd treatments. Patients receiving CBd protocol gained similar satisfactory progression-free survival (PFS) results when compared to the PAD regimen group: PFS at 5 years reached 58.2 versus 58.9 % (P = 0.85). Five-year OS in the CBd arm had significant advantages compared to the PAD group, 79.9 versus 49.9 % (P < 0.05). The overall safety profiles showed that 26 of 128 (20.3 %) patients died in the PAD arm, while 13 of 175 patients died (7.4 %) in the CBd group (P < 0.01). Similarly, the PAD arm had a higher serious infection rate than that of the CBd arm (39.2 vs. 13.1 %, P < 0.01). CONCLUSIONS: Bortezomib benefits elderly patients with newly diagnosed MM; they achieve satisfactory treatment responses and survival advantages. Further, patients treated with CBd have superior treatment advantages, with a predictable safety profile, when compared to the PAD regimen. PMID- 24337420 TI - Correlates of competitive versus noncompetitive employment among adults with psychotic disorders. AB - OBJECTIVE: Studies of the demographic and clinical correlates of employment activity have proven useful for identifying employment assistance needs among people with severe and persistent mental illness. However, the results of prior studies remain unclear, and most reviews of prior studies have not differentiated competitive from noncompetitive employment. This study attempted to clarify the relative strength and consistency of correlates of competitive versus noncompetitive employment. METHODS: Data were drawn from a population-based survey of Australian adults with psychotic disorders between March and December 2010. Demographic, clinical, and employment assistance correlates of competitive and noncompetitive employment were compared. The sample comprised 1,825 participants who agreed to face-to-face interviews. RESULTS: A total of 408 (22.3%) participants were employed in the previous four weeks, 330 (18.1%) in competitive employment and 78 (4.3%) in noncompetitive employment. Those in competitive employment were more likely to be female and aged 18-34, to have a partner, to have received formal vocational training or education after high school, and to have no literacy difficulties. Better global functioning, shorter illness duration, less severe course of illness, and affective versus nonaffective psychosis were associated with a greater likelihood of competitive employment. Those using Australian government employment services were less likely to be in competitive employment, suggesting a service provider preference for noncompetitive employment. CONCLUSIONS: Four times as many employees were in competitive employment than in noncompetitive employment. The negative relationship between employment assistance and competitive employment highlights the urgent need to improve the effectiveness of Australian employment services for people with severe mental illnesses. PMID- 24337421 TI - [J.J. Bonica would have been pleased]. PMID- 24337422 TI - [Requirements for the organization of pain therapy in hospitals: interdepartmental comparison for pain management from the employees' perspective]. AB - BACKGROUND: In recent decades, the focus of pain management in hospitals was the organization and quality of control of postoperative pain, although there is a similar demand in nonsurgical departments. The aim of this study was to assess the employees' perspective on problems and corresponding solutions in pain management in a university hospital and to further clarify whether the implementation of concepts and tools of pain management across disciplines is feasible. METHODS: Physicians and nursing staff of all inpatient departments of the University Hospital Gottingen were asked about problems in pain management and the importance of various established instruments using a standardized questionnaire. Ratings were recorded on a numeric rating scale (0-10). The analysis was primarily descriptive, the Kruskal-Wallis and Mann-Whitney U test were used when appropriate. RESULTS: In all, 149 medical and 501 nursing employees were included. The quality of pain management was perceived as better in surgical departments than in the conservative and pediatric departments. In all areas, the lack of an adequate order for baseline- and rescue-analgesic, and accordingly the nursing staff's limited ability to act was rated as problematic. In contrast to the conservative and pediatric departments, the predominant problem of surgical departments was the lack of availability of physicians on the ward. As a solution, the advice provided by pain consultation services was rated highly by the staff in all areas. The importance of implementation of standardized analgesic concepts was also supported equally in all areas. The evaluation of the quality of pain management was related to the employee's estimation of their ability to actively treat pain. Physicians rated problems in quality and organization lower compared to nursing stuff. CONCLUSION: The results demonstrate that from the employee's perspective problems in pain management in surgical and nonsurgical departments are very similar. Transferring concepts and structures of surgical pain management, such as standardized concepts and advice and or care through pain services, would meet high levels of acceptance. The results also indicate that the nursing staff's ability to treat should be increased by the provision of adequate rescue-analgesics. To close deficits in the management of care, established concepts of pain management could be extended to all departments of a hospital. Similarities outweigh differences in the employee's assessment. PMID- 24337423 TI - [Effects of interdisciplinary functional restoration treatment with cognitive behavior therapy in patients with chronic back pain: healthcare research in the context of selective contracts]. AB - INTRODUCTION: The efficacy of functional restoration programs for the treatment of chronic back pain is well documented. Nevertheless, there are only a few such centres in Germany and few trials have been conducted in German-speaking regions to demonstrate that implementing such programs in everyday clinical settings with large numbers of patients is just as effective as in a research setting. The present study examined whether the positive effects of such programs can also be observed in the clinically relevant context of a standardized day clinic treatment regimen. MATERIAL AND METHODS: A total of 681 back pain patients in 2 German cities were examined at 4 measurement points (before and immediately after the program, as well as 6 and 12 months after treatment) using a comprehensive questionnaire on perceived pain and symptoms of anxiety and depression, as well as the work situation. RESULTS: In both cities significant and long-term improvements in back pain, pain-related impairment and degree of chronification were observed, as well as a high return-to-work rate after treatment. Hence, the quality of such programs was also confirmed for a large patient population. PMID- 24337424 TI - [Economic effects of chronic pain in childhood and adolescence: self-assessment of health care costs for affected families before and after a multidisciplinary inpatient pain therapy]. AB - BACKGROUND: Chronic pain in children and adolescents causes a high utilization of the health care system and thereby significant costs. The aim of the present study is to describe the economic effects of pediatric chronic pain from the family's perspective. MATERIAL AND METHODS: Six months before and 6 and 12 months after a 3-week inpatient-based intensive interdisciplinary pain treatment, the parents of 101 children with chronic pain filled in a standardized cost questionnaire containing the following parameters: (1) child's utilization of medical and social services, (2) subjective financial burden, and (3) type and extent of direct costs. RESULTS: During the 6 months before inpatient-based intensive interdisciplinary pain treatment, children used a median of four different services. After inpatient pain treatment, service utilization has been reduced significantly (p < 0.001). One fifth of the families report a high or very high financial burden before treatment. Family's direct costs are most often caused by travelling (86 %) and drugs (60 %). After inpatient pain treatment, family's financial burden decreased significantly (p < 0.001). The frequency of additional expenditures is also reduced after treatment: parents report less additional costs due to travelling and drugs (p < 0.001, respectively). CONCLUSION: The present study emphasizes the pronounced utilization of health and social care due to pediatric chronic pain. In the future, the use of appropriate diagnostic and therapeutic standards that contribute to avoiding unnecessary and expensive interventions is preferred. PMID- 24337425 TI - [Evaluation of the German new back school: pain-related and psychological characteristics]. AB - BACKGROUND: Results related to the outcome of the classical back schools are inconsistent. Accordingly, a reformulation of the program integrating psychological and social aspects was performed as a necessary step for the development of the new back school in Germany. The aim of this study was to assess the effectiveness and sustainability of the new back school in subjects with non-specific back pain in the prevention setting. MATERIAL AND METHODS: In a modified waiting design, individuals were investigated with respect to demographical, pain-related and psychological characteristics 3 months before the start, at the start and at the end of the back school and as well as 12 months after completion. In addition, predictors for a successful participation were analyzed. RESULTS: A total of 88 subjects with back pain initially participated in the study. In the short and long-term course, low to moderate effects were detected; however, during follow-up a reduction of pain showed high effects. Depression as assessed by the hospital anxiety and depression scale (HADS) and passive coping strategies assessed using the coping strategies questionnaire (CSQ) were identified as predictors for response to the intervention. CONCLUSION: On the basis of the sample studied, the new back school proved to be an effective treatment for short and long-term reduction of pain-related stress and associated psychological aspects. Maladaptive, passive coping strategies and higher depression scores were associated with a higher probability of success in terms of pain reduction and functional improvement. PMID- 24337426 TI - [Surgical patients with chronic pain or chronic postsurgical pain: a prospective analysis of psychological and social factors]. AB - INTRODUCTION: The interference of biological, social, and psychological factors of the patient, collectively known as the biopsychosocial perspective, plays an important role in the chronification of postsurgical pain. The aim of this pilot study was to detect whether patients suffering from chronic pain without a relationship to a recent operation (CP) differ from chronic pain patients whose pain exists since a recent operation and is related with it (CPSP) in these factors. MATERIALS AND METHODS: A step-by-step analysis of patients with chronic pain was conducted via a questionnaire of 36 questions in which mental state, pain, fear, and depression [Hospital Anxiety and Depression Scale - Deutsche Version (HADS-D), Chronic Pain Grade Questionnaire (CPGQ, von Korff), SF-12, McGill Pain Questionnaire (sensoric/affective)] were surveyed. STATISTICAL ANALYSIS: Fisher's exact test for counts, U test for continuous variables; group comparisons with: chi(2) test; p < 0.05 was considered significant. RESULTS: On average 29 months postoperatively (24-35 +/- 3.5 months), 113 chronic pain patients were analyzed. A group comparison between the CPSP group (n = 73 with chronic postsurgical pain) and the group CP (n = 29 with chronic pain) was conducted. Both groups showed highly significant reductions of SF-12 data compared to a German normal collective (p < 0.001), but normal results regarding depression in the HADS-D and a moderately limiting, highly pain-related limitation in the CPGQ (von Korff III). No differences in the sensoric and affective parameters of the McGill Pain Questionnaire were found. Compared with the CPSP group, the CP group demonstrated higher pain intensities (p = 0.022). CONCLUSION: Regarding these results critically, there were no group differences concerning psychological and social patient factors in chronic pain patients with or without postsurgical pain. PMID- 24337427 TI - [Self-medication to treat pain in attacks of familial Mediterranean fever: aiming to find a new approach to pain management]. AB - BACKGROUND: Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by bouts of fever and serositis. Morbidity caused by bouts as well as self-medication were assessed among patients of Turkish ancestry living in Germany (D) or Turkey (T) in order to evaluate current analgetic concepts from a patient's perspective. MATERIAL AND METHODS: D and T were asked about the 3 months preceding the interview. RESULTS: A total of 40 D and 40 T were included; 35/40 D and 40/40 T were on colchicine. In the last 3 months, 61.3 % had >= 1 bout and suffered from peritonitis (87.8 %), fever (61.2 %), myalgia (45 %), pleuritis (42.8 %), arthralgia (36.7 %), and cephalgia (32.6 %). Of the patients, 65.3 % were bedridden during bouts, 61.2 % sought the attention of a physician, 53.1 % were unable to work or attend school, and 38.8 % were hospitalized. The following drugs were taken: NSAIDs (45.6 %), NSAIDs and paracetamol (42.6 %), and combinations of NSAIDs with other analgesics. NSAIDs (58.6 %) and paracetamol (20.7 %) were considered the most potent substances. CONCLUSION: FMF inflicts substantial morbidity. Patients most commonly rely on NSAIDs and paracetamol to relieve symptoms of FMF bouts. PMID- 24337428 TI - [Depressivity as mediator in the fear-avoidance model: a path analysis investigation of patients with chronic back pain]. AB - INTRODUCTION: The fear-avoidance model (FAM) has gained widespread acceptance as a conceptual framework predicting chronic pain development. However, there is still a high amount of unexplained variance in the prediction of outcome variables. This study aimed to test depression as a mediator of prospective links between the FAM variables pain intensity, pain-related fear, avoidance behavior and disability in order to achieve a better prediction of model variables. MATERIAL AND METHODS: Single mediation analyses were conducted using path analysis of longitudinal data from patients with chronic back pain (n = 243). RESULTS: There was at least partial mediation by depression for all prospective relations of FAM variables analyzed. The mediation effects increased the percentage of explained variance of the predicted model variables. CONCLUSION: The findings provide support for additional consideration of depressive symptoms to obtain a better understanding of prospective associations between FAM variables. The findings indicate that in the treatment of chronic back pain following a multiple target approach to reduce pain, pain-related fear and avoidance behavior and also depressive symptoms should be considered. PMID- 24337429 TI - Oil-water biphasic parallel flow for the precise patterning of metals and cells. AB - Fluidic patterning is a convenient and versatile tool for the patterning of materials, cells and microstructures on surface and in microchannels. However, its performance is usually limited by transverse diffusion between fluid streams. It would blur the boundary and deteriorate the precision of patterns. In this paper, we adopted geometric confinement to generate biphasic parallel flow that is constituted of oil and water. Since there is minimum transverse diffusion in biphasic parallel flow, the performance of fluid patterning is expected to be improved. The results show that the metal (Silver and Chromium) patterns have distinct boundary and well-controlled geometry in comparison with that by conventional laminar flow patterning. Furthermore, the high biocompatibility of oil phase (perfluorodecalin, PFD) enables the precise patterning of viable bacteria inside microchannels. Our work demonstrated a new route of using biphasic parallel flow to patterning, which would serve wide applications in prototyping and research settings. PMID- 24337430 TI - A microdevice for parallelized pulmonary permeability studies. AB - We describe a compartmentalized microdevice specifically designed to perform permeability studies across a model of lung barrier. Epithelial cell barriers were reproduced by culturing Calu-3 cells at the air-liquid interface (AIC) in 1 mm2 microwells made from a perforated glass slide with an embedded porous membrane. We created a single basolateral reservoir for all microwells which eliminated the need to renew the growth medium during the culture growth phase. To perform drug permeability studies on confluent cell layers, the cell culture slide was aligned and joined to a collection platform consisting in 35 MUL collection reservoirs connected at the top and bottom with microchannels. The integrity and functionality of the cell barriers were demonstrated by measurement of trans-epithelial electrical resistance (TEER), confocal imaging and permeability assays of 14C-sucrose. Micro-cell barriers were able to form confluent layers in 1 week, demonstrating a similar bioelectrical evolution as the Transwell systems used as controls. Tight junctions were observed throughout the cell-cell interfaces, and the low permeability coefficients of 14C-sucrose confirmed their functional presence, creating a primary barrier to the diffusion of solutes. This microdevice could facilitate the monitoring of biomolecule transport and the screening of formulations promoting their passage across the pulmonary barrier, in order to select candidates for pulmonary administration to patients. PMID- 24337431 TI - A comparison of false positives in retinal nerve fiber layer, optic nerve head and macular ganglion cell-inner plexiform layer from two spectral-domain optical coherence tomography devices. AB - BACKGROUND: The incidence of false positive (FP) results of optic coherence tomography (OCT) retinal nerve fiber layer (RNFL) color code in healthy subjects can be very high with Cirrus OCT. Recent evidence has shown that OCT parameters derived from macular ganglion cell-inner plexiform layer (GCIPL) have excellent ability to discriminate between normal eyes and eyes with early glaucoma. METHODS: This was a prospective, cross-sectional study. One hundred eyes from 50 healthy volunteers underwent circumpapillary scanning by Cirrus and Spectralis OCT and macular scanning using Cirrus OCT. FP rates for each of the OCT parameters, using predefined criteria for an abnormal test were calculated. Comparative analysis was performed using the McNemar test. A generalized estimating equations model (GEE) was used to compare demographic and clinical factors between the eyes with normal findings and eyes with abnormal results. RESULTS: The overall RNFL color-code FP rate was significantly higher for Cirrus (39 %) than for Spectralis (18 %) (P = 0.000). The Spectralis RNFL FP rate showed no significant difference when compared to the FP rate by Cirrus GCIPL (13 %) and ONH (11 %) analysis. Axial length, mean spherical equivalent, presence of peripapillary atrophy, and tilted disc were significantly related to the RNFL FP occurrence displayed by both devices. CONCLUSIONS: Spectralis might be more specific than Cirrus when evaluating the RNFL thickness for Caucasians and moderate myopic population. GCIPL and ONH analysis might be more useful than RNFL thickness to evaluate this population using Cirrus OCT. PMID- 24337432 TI - Molecular and biochemical expression of TLRs in human amniotic membrane: a comparative study of fresh and cryopreserved specimens. AB - BACKGROUND: To assess the expression of toll-like receptors (TLRs) in human amniotic membrane (AM) specimens and compare this expression with those of AMs undergoing the standard preservation procedure (handling) for ocular surgery. METHODS: Human fresh (n = 10; five spontaneous and five cesarean) or handled (n = 5) AMs were analyzed for TLR gene and protein expression. Two pieces were obtained from each specimen, and subjected to molecular or biochemical analysis. Relative real-time PCR and SDS-PAGE were carried out according to standard procedures. The REST-ANOVA coupled analysis was used to compare the molecular and biochemical data. RESULTS: The fresh membranes expressed all the TLRs (TLR1-10), with different gene expression as detected/evidenced by the Ct values, the intra fresh group analysis showing that there was a variation of TLR expression whichvaried within the fresh membranes. The handled AMs retained the TLR expression after standard processing and preservation, but with a particular pattern which included a high TLR3/TLR4 and low TLR6 expression, when compared to the fresh membranes. The molecular data were confirmed by Western blot analysis. CONCLUSIONS: AM is routinely used in several ophthalmic surgical procedures, and notwithstanding its preservation procedure, AM is reported to favour wound healing and exert anti-angiogenic, anti-inflammatory, anti-scarring as well as anti-bacterial activities. The presence of TLRs in handled AM would imply that TLRs might be preserved in AMs used in ocular surgery. The findings herein described provide additional data concerning the presence of TLRs in cryopreserved AM, and suggest a possible contribution of AM in ocular surgery, via the innate immune response. PMID- 24337433 TI - Integration of microarray profiles associated with cardiomyopathy and the potential role of Ube3a in apoptosis. AB - Cardiomyopathy is the one of the primary causes of mortality. High-throughput genome datasets provide novel information that aids the understanding of the complex mechanisms involved in cardiomyopathy. However, the causative mechanisms underlying cardiomyopathy are yet to be elucidated. In order to improve the use of the high-throughput genome datasets, the present study employed 9 microarray datasets to mine for differentially expressed cardiomyopathy-associated genes using bioinformatic methods. Following validation using quantitative polymerase chain reaction, ubiquitin-protein ligase E3a (Ube3a) was selected as a candidate gene for the disease. Substantial evidence suggests that apoptosis may be involved in the pathophysiology of cardiomyopathies. Therefore, in the present study, H2O2 was utilized to induce apoptosis in H9C2 cells in order to understand the interrelation between Ube3a and the apoptosis-related protein p53. Ube3a and p53 were observed to be significantly increased at the transcriptional and translational levels in response to H2O2 treatment. The results of this study indicate the efficiency of the data integration and the significant interrelation between Ube3a and p53 in myocardial cells during apoptosis. PMID- 24337434 TI - A randomized trial to determine the diagnostic accuracy of conventional vs. jumbo forceps biopsy of gastric epithelial neoplasias before endoscopic submucosal dissection; open-label study. AB - BACKGROUND AND AIMS: Larger biopsy specimens or increasing the number of biopsies may improve the diagnostic accuracy of gastric epithelial neoplasia (GEN). The aims of this study was to compare the diagnostic accuracies between conventional and jumbo forceps biopsy of GEN before endoscopic submucosal dissection (ESD) and to confirm that increasing the number of biopsies is useful for the diagnosis of GEN. RESULTS: The concordance rate between EFB and ESD specimens was not significantly different between the two groups [83.1 % (54/65) in JG vs. 79.1 % (53/67) in CG]. On multivariate analyses, two or four EFBs significantly increased the cumulating concordance rate [coefficients; twice: 5.1 (P = 0.01), four times: 5.9 (P = 0.02)]. But, the concordance rate was decreased in high grade dysplasia (coefficient -40.32, P = 0.006). PATIENTS AND METHODS: One hundred and sixty GENs from 148 patients were randomized into two groups and finally 67 GENs in 61 patients and 65 GENs in 63 patients were allocated to the conventional group (CG) or jumbo group (JG), respectively. Four endoscopic forceps biopsy (EFB) specimens were obtained from each lesion with conventional (6.8 mm) forceps or jumbo (8 mm) forceps. The histological concordance rate between 4 EFB specimens and ESD specimens was investigated in the two groups. CONCLUSIONS: Before ESD, the diagnostic accuracy of GENs was significantly increased not by the use of jumbo forceps biopsy but by increasing the number of biopsies. PMID- 24337435 TI - Deregulation of the cell polarity protein Lethal giant larvae 2 (Lgl2) correlates with gastric cancer progression. AB - BACKGROUND: We investigated the roles of Lethal giant larvae 2 (Lgl2), an epithelial cell polarity protein, during gastric carcinogenesis and gastric cancer (GC) progression and evaluated the correlation of Lgl2 with epithelial mesenchymal transition (EMT) markers. METHODS: Lgl2 protein and mRNA expression were determined by immunohistochemistry and mRNA in situ hybridization in a large series of GC and preneoplastic lesions. Additionally, expression of 7 EMT markers was examined by immunohistochemistry. RESULTS: Loss of membrane Lgl2 staining in GC was observed in 347 of 409 GCs. Lgl2 loss was associated with diffuse histological type (P < 0.001), advanced stage (P = 0.021), and worse prognosis (P = 0.047). Furthermore, Lgl2 loss correlated with reduced E-cadherin expression (P < 0.01) and increased expression of vimentin (P < 0.01). Combined analysis of Lgl2 and the EMT markers, S100A4 and MMP2, improved predictions of patient outcomes. During gastric carcinogenesis, membrane expression of Lgl2 was progressively lost in 4 % of normal mucosa, 75 % of intestinal metaplasia, 58 % of gastric dysplasia, 69 % of intestinal type GC, and 96 % of diffuse type GC. CONCLUSIONS: Our results suggest that Lgl2 loss occurs at an early stage of gastric carcinogenesis and contributes to GC progression. PMID- 24337436 TI - Expression levels of P-glycoprotein in peripheral blood CD8+ T lymphocytes from HIV-1-infected patients on antiretroviral therapy. AB - In this study, we aimed to measure P-glycoprotein (P-gp) expression in CD8(+) T lymphocytes of HIV-1-infected patients, to investigate how P-gp levels are affected by antiretroviral therapy (ART) in HIV-1 infection, and to assess the value of using P-gp expression to predict virologic response to ART. Peripheral blood mononuclear cells (PBMCs) were obtained from a cohort of HIV-1-infected patients in China: 140 patients on ART, and 49 ART-naive patients. We also enrolled 24 healthy blood donors as the controls. The expression levels of P-gp in CD8(+) T cells of HIV-1-infected patients were evaluated by quantitative reverse transcription PCR, ELISA and flow cytometry. A high inter-individual variability was observed in the CD8(+) T cells of both HIV-1-infected patients and healthy donors; however, the expression levels of P-gp were significantly higher in the HIV-1-infected group on ART compared to the ART-naive group. The relative proportion of P-gp(+)CD8(+) T cells inversely correlated with the blood CD4(+) T cell count in the HIV-1-infected patients on ART (r=-0.3343, P=0.0375). Groups of both good and poor responders showed significantly elevated levels of P gp(+)CD8(+) T cells. The percentage of P-gp(+)CD8(+) T cells appeared to provide a sensitive estimate of the virologic response to ART compared to the CD4(+) T cell count. Our results suggest that P-gp expression varies among HIV-1-infected patients, but is significantly higher in HIV-1-infected patients on ART. The overexpression of P-gp is involved in ART initiation during HIV-1 infection, and P-gp(+)CD8(+) T cells may be an additional criterion for the evaluation of the antiretroviral response to ART. PMID- 24337437 TI - Intractable epistaxis due to isolated primary telangiectasias. AB - IMPORTANCE: Epistaxis is the most common otolaryngologic emergency in the United States. Most cases are controlled with first-line measures, but intractable epistaxis can be a challenging clinical problem requiring posterior nasal packing and surgical or endovascular intervention. Bleeding from nasal telangiectasias is well known in hereditary hemorrhagic telangiectasia, but there are no reports in the literature of recurrent epistaxis due to isolated telangiectasias not associated with systemic disease. This report describes a series of cases in which intractable epistaxis due to isolated primary telangiectasias was effectively controlled with bipolar electrosurgery. OBSERVATIONS: We describe a patient with intractable epistaxis that had failed management with posterior packing and embolization. We also report a series of 16 cases of epistaxis, 6 of which were intractable, in adults without hereditary hemorrhagic telangiectasia who received treatment between 2009 and 2012. These cases reveal a common pattern of bleeding from telangiectasias on the anterior septum (8 cases [42%]), nasal sidewall (3 [16%]), inferior meatus (2 [10%]), posterior septum (2 [10%]), nasal floor (2 [10%]), middle turbinate (1 [5%]), and inferior turbinate (1 [5%]). CONCLUSIONS AND RELEVANCE: Telangiectasias not associated with systemic disease are a previously unreported source of significant nasal bleeding that, when identified endoscopically, can be treated successfully with bipolar electrosurgery rather than with more invasive and costly surgical and endovascular measures. PMID- 24337438 TI - A model predicting fluindione dose requirement in elderly inpatients including genotypes, body weight, and amiodarone. AB - Indandione VKAs have been widely used for decades, especially in Eastern Europe and France. Contrary to coumarin VKAs, the relative contribution of individual factors to the indandione-VKA response is poorly known. In the present multicentre study, we sought to develop and validate a model including genetic and non-genetic factors to predict the daily fluindione dose requirement in elderly patients in whom VKA dosing is challenging. We prospectively recorded clinical and therapeutic data in 230 Caucasian inpatients mean aged 85 +/- 6 years, who had reached international normalized ratio stabilisation (range 2.0 3.0) on fluindione. In the derivation cohort (n=156), we analysed 13 polymorphisms in seven genes potentially involved in the pharmacological effect or vitamin-K cycle (VKORC1, CYP4F2, EPHX1) and fluindione metabolism/transport (CYP2C9, CYP2C19, CYP3A5, ABCB1). We built a regression model incorporating non genetic and genetic data and evaluated the model performances in a separate cohort (n=74).Body-weight, amiodarone intake, VKORC1, CYP4F2, ABCB1 genotypes were retained in the final model, accounting for 31.5% of dose variability. None influence of CYP2C9 was observed. Our final model showed good performances: in 83.3% of the validation cohort patients, the dose was accurately predicted within 5 mg, i.e.the usual step used for adjusting fluindione dosage. In conclusion, in addition to body-weight and amiodarone-intake, pharmacogenetic factors (VKORC1, CYP4F2, ABCB1) related to the pharmacodynamic effect and transport of fluindione significantly influenced the dose requirement in elderly patients while CYP2C9 did not. Studies are required to know whether fluindione could be an alternative VKA in carriers of polymorphic CYP2C9 alleles, hypersensitive to coumarins. PMID- 24337439 TI - Wnt1 inducible signalling pathway protein-2 (WISP-2/CCN5): roles and regulation in human cancers (review). AB - Wnt1 inducible signalling pathway protein-2 (WISP-2), also known as CCN5, CT58, CTGF-L, CTGF-3, HICP and Cop1, is one of the 3 WNT1 inducible proteins that belongs to the CCN family. This family of members has been shown to play multiple roles in a number of pathophysiological processes, including cell proliferation, adhesion, wound healing, extracellular matrix regulation, epithelial-mesenchymal transition, angiogenesis, fibrosis, skeletal development and embryo implantation. Recent results suggest that WISP-2 is relevant to tumorigenesis and malignant transformation, particularly in breast cancer, colorectal cancer and hepatocarcinoma. Notably, its roles in cancer appear to vary depending on cell/tumour type and the microenvironment. The striking difference in the structure of WISP-2 in comparison with the other 2 family members may contribute to its difference in functions, which leads to the hypothesis that WISP-2 may act as a dominant-negative regulator of other CCN family members. In the present review, we summarise the roles, regulation and underlying mechanism of WISP-2 in human cancers. PMID- 24337440 TI - Morphological evaluation of the distal interosseous membrane using ultrasound. AB - Evidence from a recent cadaveric study has revealed that the thickness of the distal interosseous membrane (DIOM) of the forearm shows substantial individual variations, and a thick fibrous tissue known as the distal oblique bundle (DOB) was found in 40% specimens in the study. Another cadaveric study revealed that greater stability of the distal radioulnar joint (DRUJ) was obtained in a group with DOB following ulnar shortening than in a group without DOB. Thus, the presence of DOB influences the condition of DIOM and the ability of DIOM to provide stability to the compromised DRUJ. In the present study, we carried out a preoperative morphological evaluation of DIOM using ultrasound (US) and compared the US findings with intraoperative findings in order to investigate the efficacy and the meanings of this US evaluation. A total of 14 patients with various diseases or injuries of the distal forearm requiring corrective surgery were enrolled. The mean values of DIOM thickness as measured by US evaluation correlated well with those measured intraoperatively. The sensitivity of US evaluation in confirming presence of DOB was 80% when the presence of DOB bundle was judged by DIOM thickness. In addition, 4 of 5 patients with chronic DRUJ instability showed no DOB. This study suggested that US can be a useful tool in evaluating DIOM and for detecting the presence of DOB and may provide helpful information regarding DRUJ instability. PMID- 24337441 TI - The effect of inferomedial screw on postoperative shoulder function and mechanical alignment in proximal humerus fractures. AB - AIM: The aim of the study was to evaluate the clinical and radiologic results of locking plate fixation with or without inferomedial screw (IMS) in surgically treated proximal humerus fractures. PATIENTS AND METHODS: Thirty-six patients with displaced proximal humerus fractures from two centers were operated using locking plate. All of the fractures were classified according to the Neer classification. In 18 of the cases, an additional IMS running through the medial curvature of the surgical neck was used. There was no significant difference among both groups in terms of height, gender, weight, and mechanism of injury. The fractures were evaluated according to the radiographic and functional findings during follow-up period of 14 months in average (range 8-32 months). At the end of first year, shoulder radiographs were received and shoulder examinations were performed using ASES scores. Humeral head-shaft angles were measured by true AP projections. Head-shaft angle measurements were categorized as varus if <125, normal if between 125 and 145, and valgus if >145. RESULTS: Mean time for fracture healing was 18 weeks. Complete union was achieved in 35 patients by the end of 6 months. In one of the 18 displaced proximal humerus fractures of IMS (+) group, the head-shaft angle was measured to be <125, whereas six patients had varus deviation in IMS (-) group at follow-up (p < 0.05). Mean ASES scores of IMS (+) group and IMS (-) group were 58.21 +/- 5.82 and 38.61 +/- 3.44, respectively (p < 0.001). CONCLUSION: Use of inferomedial screw running through the medial curvature of surgical neck prevents varus deformity and improves functional outcome after surgical treatment for proximal humerus fractures. PMID- 24337442 TI - TERT promoter mutation and aberrant hypermethylation are associated with elevated expression in medulloblastoma and characterise the majority of non-infant SHH subgroup tumours. PMID- 24337443 TI - On the nature of canopy illumination due to differences in elemental orientation and aggregation for radiative transfer. AB - The nature of canopy radiative transfer mechanism (CRTM) describes the amount of beam penetration through a canopy and governs the nature of canopy illumination, i.e. the abundance of sunlit and shaded portions. Realistic representation of canopy illumination is critical for simulating various canopy biophysical processes associated with vegetated land surfaces. The adequate representation of CRTM can be attributed to the parameterizations of the two main canopy characteristics: the foliage projection (G-function) and the clumping effect (Omega function). Herein, using various types of G and Omega functions developed in a previous study, I tested 15 CRTM scenarios that combine different types of G and Omega functions to predict the dynamics of sunlit fraction (epsilon) of canopies having a wide range of plant area index (Ptotal) at various solar zenith angles (SZAs). It was observed that, for a given Ptotal, epsilon decreases as the SZA increases. However, epsilon significantly changed in accordance with the type of G and Omega functions used. Scenarios that employed random distribution of elements in space (S-4, S-9, and S-14) consistently returned larger epsilon values even at lower SZAs. This means that ignoring the clumping behavior of canopies could result in greater proportion of sunlit elements thereby reducing the beam penetration deeper into the canopy as opposed to those canopies where the elements are more aggregated. Beyond 70 degrees SZA, almost all the scenarios returned similar epsilon values for a given Ptotal, which implied that the methods used is less sensitive at higher SZAs. The values of epsilon calculated by all the scenarios were significantly different from the S-6 (the ideal case). This observation highlights the importance of explicitly describing the G and Omega functions to adequately depict canopy illumination conditions. PMID- 24337444 TI - Effects of Medicare Part D on guideline-concordant pharmacotherapy for bipolar I disorder among dual beneficiaries. AB - OBJECTIVE: In January 2006 insurance coverage for medications shifted from Medicaid to Medicare Part D private drug plans for the six million individuals enrolled in both programs. Dual beneficiaries faced new formularies and utilization management policies. It is unclear whether Part D, compared with Medicaid, relaxed or tightened psychiatric medication management, which could affect receipt of recommended pharmacotherapy, and emergency department use related to treatment discontinuities. This study examined the impact of the transition from Medicaid to Part D on guideline-concordant pharmacotherapy for bipolar I disorder and emergency department use. METHODS: Using interrupted-time series analysis and Medicaid and Medicare administrative data from 2004 to 2007, the authors analyzed the effect of the coverage transition on receipt of guideline-concordant antimanic medication, guideline-discordant antidepressant monotherapy, and emergency department visits for a nationally representative continuous cohort of 1,431 adults with diagnosed bipolar I disorder. RESULTS: Sixteen months after the transition to Part D, the proportion of the population with any recommended use of antimanic drugs was an estimated 3.1 percentage points higher than expected once analyses controlled for baseline trends. The monthly proportion of beneficiaries with seven or more days of antidepressant monotherapy was 2.1 percentage points lower than expected. The number of emergency department visits per month temporarily increased by 19% immediately posttransition. CONCLUSIONS: Increased receipt of guideline-concordant pharmacotherapy for bipolar I disorder may reflect relatively less restrictive management of antimanic medications under Part D. The clinical significance of the change is unclear, given the small effect sizes. However, increased emergency department visits merit attention for the Medicaid beneficiaries who continue to transition to Part D. PMID- 24337445 TI - Source localisation of visual evoked potentials in congenitally deaf individuals. AB - Previous studies have suggested that individuals deprived of auditory input can compensate with specific superior abilities in the remaining sensory modalities. To better understand the neural basis of deafness-induced changes, the present study used electroencephalography to examine visual functions and cross-modal reorganization of the auditory cortex in deaf individuals. Congenitally deaf participants and hearing controls were presented with reversing chequerboard stimuli that were systematically modulated in luminance ratio. The two groups of participants showed similar modulation of visual evoked potential (VEP) amplitudes (N85, P110) and latencies (P110) as a function of luminance ratio. Analysis of VEPs revealed faster neural processing in deaf participants compared with hearing controls at early stages of cortical visual processing (N85). Deaf participants also showed higher amplitudes (P110) than hearing participants. In contrast to our expectations, the results from VEP source analysis revealed no clear evidence for cross-modal reorganization in the auditory cortex of deaf participants. However, deaf participants tended to show higher activation in posterior parietal cortex (PPC). Moreover, modulation of PPC responses as a function of luminance was also stronger in deaf than in hearing participants. Taken together, these findings are an indication of more efficient neural processing of visual information in the deaf, which may relate to functional changes, in particular in multisensory parietal cortex, as a consequence of early auditory deprivation. PMID- 24337446 TI - Intersection syndrome: ultrasound imaging. AB - OBJECTIVE: To evaluate the use of ultrasound for the diagnosis of intersection syndrome. MATERIALS AND METHODS: A total of 1,131 reports from hand and wrist ultrasound examinations performed between 1 January 2008 and 31 December 2012 were re-evaluated. Two hundred and fifteen video clips present in the electronic database were reviewed by two musculoskeletal radiologists with 20 years of experience. RESULTS: Of the 215 video clips reviewed, 21 patients were diagnosed with intersection syndrome. The mean age was 45 years (ranging from 22 to 60); 15 were male (13 with proximal intersection syndrome, 2 with distal intersection syndrome) and 6 female (5 with proximal intersection syndrome, 1 with distal intersection syndrome). CONCLUSION: Intersection syndrome was identified in 1.9 % of all patients evaluated in the setting of a specialized hospital. Ultrasound is a non-invasive, simple, and economical method for the identification of intersection syndrome, tendon sheath anatomy (individual or separate sheaths) and to exclude other pathological conditions. PMID- 24337447 TI - Long-term clinical and molecular remissions in patients with mantle cell lymphoma following high-dose therapy and autologous stem cell transplantation. AB - Long-term clinical and molecular remissions in patients with mantle cell lymphoma (MCL) following high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) have been evaluated in only a few studies. Thirty-six patients with MCL received ASCT in our institution (27 patients undergoing first-line therapy, 8 patients undergoing second-line therapy, and 1 patient undergoing third-line therapy). In the case of long-term remission (>=5 years; n = 8), peripheral blood was tested for minimal residual disease (MRD) by t(11; 14) polymerase chain reaction (PCR) and immunoglobulin heavy-chain (IGH) PCR at the last follow-up. Ten-year overall survival (OS), progression-free survival (PFS), and freedom from progression (FFP) after first-line ASCT were 42 %, 43 %, and 54 %; after second line ASCT, these were all 0 %. Four-year OS, PFS, and FFP for the first-line cohort were 75 %, 48 %, and 61 %, respectively. Four-year OS, PFS, and FFP after second-line ASCT were 55 %, 30 %, and 30 %, respectively. Treatment-related mortality (3 months after ASCT) was 0 %. The only prognostic factor for OS, PFS, and FFP was treatment line (p = 0.011, p = 0.046, and p = 0.023, respectively). No relapses occurred after 5 years following ASCT. So far, eight patients developed sustained long-term clinical and molecular complete remissions of up to 14.6 years following ASCT in the first treatment line. Sustained long-term clinical and molecular remissions can be achieved following ASCT in the first treatment line and apparently less frequent in the second treatment line. PMID- 24337448 TI - Acquired von Willebrand syndrome associated with monoclonal gammopathy of undetermined significance. PMID- 24337449 TI - Paediatric European Risperidone Studies (PERS): context, rationale, objectives, strategy, and challenges. AB - In children and adolescents with conduct disorder (CD), pharmacotherapy is considered when non-pharmacological interventions do not improve symptoms and functional impairment. Risperidone, a second-generation antipsychotic is increasingly prescribed off-label in this indication, but its efficacy and tolerability is poorly studied in CD, especially in young people with normal intelligence. The Paediatric European Risperidone Studies (PERS) include a series of trials to assess short-term efficacy, tolerability and maintenance effects of risperidone in children and adolescents with CD and normal intelligence as well as long-term tolerability in a 2-year pharmacovigilance. In addition to its core studies, secondary PERS analyses will examine moderators of drug effects. As PERS is a large-scale academic project involving a collaborative network of expert centres from different countries, it is expected that results will lead to strengthen the evidence base for the use of risperidone in CD and improve standards of care. Challenging issues faced by the PERS consortium are described to facilitate future developments in paediatric neuropsychopharmacology. PMID- 24337450 TI - Suppression of VEGF expression through interruption of the HIF-1alpha and Akt signaling cascade modulates the anti-angiogenic activity of DAPK in ovarian carcinoma cells. AB - Death-associated protein kinase (DAPK) plays an important role in apoptosis regulation and has been shown to maintain antitumor and metastasis suppressor properties. In the present study, we investigated whether DAPK overexpression may mediate vascular endothelial growth factor (VEGF)/hypoxia-inducible factor-1alpha (HIF-1alpha) expression and angiogenic activity in the human carcinoma cell model system. VEGF plays a pivotal role in tumor angiogenesis and tumorigenesis. We found that DAPK significantly downregulated VEGF-induced endothelial cell proliferation, migration and tube formation as well as VEGF receptor-2 (VEGFR-2) phosphorylation in vitro. In addition, DAPK exhibited potent anti-angiogenic activity and clearly decreased the levels of VEGF and HIF-1alpha expression, a key regulator for angiogenesis. Notably, our results strongly indicated that DAPK can disturb VEGFR-2 transcriptional activity by inhibiting VEGFR-2 phosphorylation through the PI3K/Akt signaling cascade. Collectively, our study identified a novel function of DAPK in regulating cellular VEGF/HIF-1alpha activity during tumorigenesis, which may act together with its anti-angiogenic function to inhibit tumor progression. PMID- 24337451 TI - Patterns of ubiquitylation and SUMOylation associated with exposure to anoxia in embryos of the annual killifish Austrofundulus limnaeus. AB - Embryos of the annual killifish Austrofundulus limnaeus acquire extreme tolerance to anoxia during embryonic development. These embryos can survive environmental and cellular conditions that would likely result in death in the majority of vertebrate cells, despite experiencing a massive loss of ATP. It is highly likely that the initial response to anoxia must quickly alter cellular physiology to reprogram cell signaling and metabolic pathways to support anaerobiosis. Covalent protein modifications are a mechanism that can quickly act to effect large-scale changes in protein structure and function and have been suggested by others to play a key role in mammalian ischemia tolerance. Using Western blot analysis, we explored patterns of protein ubiquitylation and SUMOylation in embryos of A. limnaeus exposed to anoxia and anoxic preconditioning. Surprisingly, we report stage-specific protein ubiquitylation patterns that suggest different mechanisms for altering protein turnover in dormant and actively developing embryos that both survive long-term anoxia. Anoxic preconditioning does not appear to alter levels of ubiquitin conjugates in a unique manner. Global SUMOylation of proteins does not change in response to anoxia, but there are stage-specific changes in SUMOylation of specific protein bands. Contrary to other systems, global changes in protein SUMOylation may not be required to support long-term tolerance to anoxia in embryos of A. limnaeus. These data lead us to conclude that embryos of A. limnaeus respond to anoxia in a unique manner compared to other vertebrate models of anoxia tolerance and may provide novel mechanisms for engineering vertebrate tissues to survive long-term anoxia. PMID- 24337453 TI - Capsaicin induces apoptosis and modulates MAPK signaling in human gastric cancer cells. AB - Capsaicin is known to have tumor suppressive effects. However, the molecular mechanisms and targets of capsaicin involved in exerting anticancer activity are complex and remain to be clarified. The aim of the current study was to investigate the effects of capsaicin on human gastric cancer cells (AGS cells) and demonstrate that capsaicin induced apoptosis in AGS cells. Results of the MTT assay and flow cytometry revealed that capsaicin potentially inhibited the proliferation of AGS cells and induced apoptosis in vitro in a dose-dependent manner. Cleaved caspase-3 was increased and Bcl-2 was reduced by treatment with capsaicin in AGS cells. Capsaicin treatment decreased the expression of phosphorylated ERK 1/2, p38 MAPK or JNK in AGS cells. The results of this study suggest that capsaicin may serve as an anti-tumorigenic agent in human gastric cancer. PMID- 24337452 TI - Biomechanics of cardiac electromechanical coupling and mechanoelectric feedback. AB - Cardiac mechanical contraction is triggered by electrical activation via an intracellular calcium-dependent process known as excitation-contraction coupling. Dysregulation of cardiac myocyte intracellular calcium handling is a common feature of heart failure. At the organ scale, electrical dyssynchrony leads to mechanical alterations and exacerbates pump dysfunction in heart failure. A reverse coupling between cardiac mechanics and electrophysiology is also well established. It is commonly referred as cardiac mechanoelectric feedback and thought to be an important contributor to the increased risk of arrhythmia during pathological conditions that alter regional cardiac wall mechanics, including heart failure. At the cellular scale, most investigations of myocyte mechanoelectric feedback have focused on the roles of stretch-activated ion channels, though mechanisms that are independent of ionic currents have also been described. Here we review excitation-contraction coupling and mechanoelectric feedback at the cellular and organ scales, and we identify the need for new multicellular tissue-scale model systems and experiments that can help us to obtain a better understanding of how interactions between electrophysiological and mechanical processes at the cell scale affect ventricular electromechanical interactions at the organ scale in the normal and diseased heart. PMID- 24337454 TI - Corneal radius of curvature after anterior lamellar versus penetrating keratoplasty. AB - BACKGROUND: Keratoplasty may induce major spherical refractive error related to abnormal corneal radius of curvature (CRC). METHODS: Two hundred and thirty-eight consecutive eyes of 238 patients with clear graft and at least one postoperative Orbscan examination performed after suture removal (average follow-up time, 86 months) were retrospectively analyzed. Anterior lamellar keratoplasties (ALK group, n = 119) and penetrating keratoplasties (PK group, n = 119) were matched for preoperative diagnosis and lens status. RESULTS: The average postoperative, suture-out, Orbscan 3-mm CRC was 7.17 mm with a wide 95 % confidence interval [6.26 mm; 8.37 mm]. It was 7.05 mm in the ALK group and 7.31 mm in the PK group (p < 0.01). In the ALK group, this figure was 7.00 mm for oversized grafts and 7.67 mm for non-oversized grafts (p < 0.001). CRC values were significantly lower for eyes with keratoconus (7.00 mm) or stromal scar after infectious keratitis (7.06 mm) compared with stromal scar after trauma (7.74 mm) or stromal dystrophies (8.17 mm). Values were significantly lower for big-bubble ALKs (6.92 mm) and manual dissection-ALKs (7.14 mm) compared with PKs (7.31 mm) and microkeratome-assisted ALKs (7.45 mm). The average Orbscan 3-mm SimK cylinder, irregularity, and refractive power symmetry index were, respectively, 4.7 D/4.8 D/1.9 D for ALKs and 5.2 D/4.8 D/1.8 D for PKs (p = 0.99). CONCLUSIONS: The CRC is lower after ALK compared with PK, and features important variability. In eyes with ALK, non-oversized grafts result in postoperative CRC close to normal values and corneal diseases associated with stromal thinning and DALK result in lower postoperative CRC. PMID- 24337455 TI - Prognostic factors and efficacy of different chemotherapeutic regimens in patients with mediastinal nonseminomatous germ cell tumors. AB - PURPOSE: Patients (pts) with mediastinal nonseminomatous germ cell tumors (MNGCT) are belonged to poor prognostic group by IGCCCG. We retrospectively studied the prognostic factors and efficacy of different chemotherapeutic regimen in pts with MNGCT. METHODS: We analyzed data on 61 pts with MNGCT. Conditional induction chemotherapy BEP was performed in 38 %, TBEP-in 28 %, CBOP-in 28 %, accelerated (two weekly) version of BEP-in 6 % pts. Based on similar efficacy of CBOP and TBEP regimens, we combines pts with CPOB and TBEP regimen in one group-55.8 % and different variants of BEP regimen in the second group-44.2 %. Multivariate Cox regression analysis was performed to determine independent factors, which influenced on overall survival. RESULTS: We revealed the following independent negative prognostic factors: age >= 24 years (p = 0.07), size of the primary mediastinal tumor >=19 cm (p = 0.03). Median overall survival (OS) has not been reached, and 2-year OS was 66 % in pts with good prognosis (age < 24 years and/or size of mediastinal tumor < 19 cm) versus 15 months and 40 % in pts with poor prognosis (p = 0.03). Objective marker negative response was revealed more often in pts with CPOB/TBEP group: 26/34 (76.5 %) versus 14/27 (52 %), p = 0.08. Median OS was also higher in pts with CPOB/TBEP group: nonreached versus 15 months (p = 0.01). CONCLUSION: CPOB and TBEP regimen were significantly associated with better outcome in pts with MNGCT. Age >= 24 years and size of the primary mediastinal tumor >= 19 cm were found as independent negative prognostic factors. PMID- 24337456 TI - Release kinetics of circulating cardiac myosin binding protein-C following cardiac injury. AB - Diagnosis of myocardial infarction (MI) is based on ST-segment elevation on electrocardiographic evaluation and/or elevated plasma cardiac troponin (cTn) levels. However, troponins lack the sensitivity required to detect the onset of MI at its earliest stages. Therefore, to confirm its viability as an ultra-early biomarker of MI, this study investigates the release kinetics of cardiac myosin binding protein-C (cMyBP-C) in a porcine model of MI and in two human cohorts. Release kinetics of cMyBP-C were determined in a porcine model of MI (n = 6, pigs, either sex) by measuring plasma cMyBP-C level serially from 30 min to 14 days after coronary occlusion, with use of a custom-made immunoassay. cMyBP-C plasma levels were increased from baseline (76 +/- 68 ng/l) at 3 h (767 +/- 211 ng/l) and peaked at 6 h (2,418 +/- 780 ng/l) after coronary ligation. Plasma cTnI, cTnT, and myosin light chain-3 levels were all increased 6 h after ligation. In a cohort of patients (n = 12) with hypertrophic obstructive cardiomyopathy undergoing transcoronary ablation of septal hypertrophy, cMyBP-C was significantly increased from baseline (49 +/- 23 ng/l) in a time-dependent manner, peaking at 4 h (560 +/- 273 ng/l). In a cohort of patients with non-ST segment elevation MI (n = 176) from the SYNERGY trial, cMyBP-C serum levels were significantly higher (7,615 +/- 4,514 ng/l) than those in a control cohort (416 +/- 104 ng/l; n = 153). cMyBP-C is released in the blood rapidly after cardiac damage and therefore has the potential to positively mark the onset of MI. PMID- 24337457 TI - The obligatory role of the actin cytoskeleton on inward remodeling induced by dithiothreitol activation of endogenous transglutaminase in isolated arterioles. AB - Inward remodeling is the most prevalent structural change found in the resistance arteries and arterioles of hypertensive individuals. Separate studies have shown that the inward remodeling process requires transglutaminase activation and the polymerization of actin. Therefore, we hypothesize that inward remodeling induced via endogenous transglutaminase activation requires and depends on actin cytoskeletal structures. To test this hypothesis, isolated and cannulated rat cremaster arterioles were exposed to dithiothreitol (DTT) to activate endogenous transglutaminases. DTT induced concentration-dependent vasoconstriction that was suppressed by coincubation with cystamine or cytochalasin-D to inhibit tranglutaminase activity or actin polymerization, respectively. Prolonged (4 h) exposure to DTT caused arteriolar inward remodeling that was also blocked by the presence of cystamine or cytochalasin-D. DTT inwardly remodeled arterioles had reduced passive diameters, augmented wall thickness-to-lumen ratios and altered elastic characteristics that were reverted upon disruption of the actin cytoskeleton with mycalolide-B. In freshly isolated arterioles, exposure to mycalolide-B caused no changes in their passive diameters or their elastic characteristics. These results suggest that, in arterioles, the early stages of the inward remodeling process induced by prolonged endogenous transglutaminase activation require actin dynamics and depend on changes in actin cytoskeletal structures. PMID- 24337458 TI - Variation of mechanical properties and quantitative proteomics of VSMC along the arterial tree. AB - Vascular smooth muscle cells (VSMCs) are thought to assume a quiescent and homogeneous mechanical behavior after arterial tree development phase. However, VSMCs are known to be molecularly heterogeneous in other aspects and their mechanics may play a role in pathological situations. Our aim was to evaluate VSMCs from different arterial beds in terms of mechanics and proteomics, as well as investigate factors that may influence this phenotype. VSMCs obtained from seven arteries were studied using optical magnetic twisting cytometry (both in static state and after stretching) and shotgun proteomics. VSMC mechanical data were correlated with anatomical parameters and ultrastructural images of their vessels of origin. Femoral, renal, abdominal aorta, carotid, mammary, and thoracic aorta exhibited descending order of stiffness (G, P < 0.001). VSMC mechanical data correlated with the vessel percentage of elastin and amount of surrounding extracellular matrix (ECM), which decreased with the distance from the heart. After 48 h of stretching simulating regional blood flow of elastic arteries, VSMCs exhibited a reduction in basal rigidity. VSMCs from the thoracic aorta expressed a significantly higher amount of proteins related to cytoskeleton structure and organization vs. VSMCs from the femoral artery. VSMCs are heterogeneous in terms of mechanical properties and expression/organization of cytoskeleton proteins along the arterial tree. The mechanical phenotype correlates with the composition of ECM and can be modulated by cyclic stretching imposed on VSMCs by blood flow circumferential stress. PMID- 24337460 TI - Overexpression of VEGF-C attenuates chronic high salt intake-induced left ventricular maladaptive remodeling in spontaneously hypertensive rats. AB - Recent studies have shown that the tonicity-responsive enhancer binding protein (TonEBP)/vascular endothelial growth factor-C (VEGF-C) signaling pathway-induced lymphangiogenesis provides a buffering mechanism for high salt (HS) intake induced elevation of blood pressure (BP). Moreover, blocking of TonEBP/VEGF-C signaling by mononuclear phagocyte depletion can induce salt-sensitive hypertension in rats. We hypothesized that HS intake could have an impact on cardiac lymphangiogenesis, and regulation of VEGF-C bioactivity, which is largely through the main receptor for VEGFR-3, may modulate HS intake-induced left ventricular remodeling. We demonstrated upregulation of TonEBP, increased macrophage infiltration, and enhanced lymphangiogenesis in the left ventricles of spontaneously hypertensive rats (SHR) that were fed a HS diet (8.0% NaCl). Then, retrovirus vectors capable of overexpression (DeltaNDeltaC/VEGF-C/Cys152Ser, used for overexpressing VEGF-C) and blocking (VEGFR-3-Rg, used for trapping of bioactive VEGF-C) of VEGF-C and control vector (pLPCX) were intravenously administered to SHR from week 9 of a 12-wk HS loading period. At the end of the HS challenge, overexpression of VEGF-C led to enhanced cardiac lymphangiogenesis, decreased myocardial fibrosis, and macrophage infiltration, preserved left ventricular functions, as well as decreased blood pressure level compared with the HS group and the control vector-treated HS group. In contrast, systemic blocking of VEGF-C was associated with elevation of blood pressure level and an exacerbation of hypertensive left ventricular remodeling, as indicated by increased fibrosis and macrophage infiltration, and diminished lymphangiogenesis. Hence, our findings highlight that VEGF-C/VEGFR-3 is a promising therapeutic target to attenuate hypertensive left ventricular remodeling induced by HS intake, presumably via blood pressure-dependent and -independent mechanisms. PMID- 24337459 TI - Augmented dilation to nitric oxide in uterine arteries from rats with type 2 diabetes: implications for vascular adaptations to pregnancy. AB - Pre-existing diabetes increases the risk of maternal and fetal complications during pregnancy, which may be due to underlying maternal vascular dysfunction and impaired blood supply to the uteroplacental unit. Endothelial dysfunction and reduced vascular smooth muscle responsiveness to nitric oxide (NO) are common vascular impairments in type 2 diabetes (T2D). We hypothesized that uterine arteries from diabetic rats would have reduced vascular smooth muscle sensitivity to NO compared with nondiabetic rats due to impairment in the NO/soluble guanylate cyclase (sGC)/cGMP signaling pathway. Uterine arteries from pregnant Goto-Kakizaki (GK; model of T2D) and Wistar (nondiabetic) rats were studied in a wire myograph. GK nonpregnant uterine arteries had reduced responses to ACh and sodium nitroprusside (SNP) but increased responses to propylamine propylamine NONOate and greater sensitivity to sildenafil compared with Wistar nonpregnant arteries. In late pregnancy, Wistar rats had reduced uterine vascular smooth muscle responsiveness to SNP, but GK rats failed to show this adaptation and had reduced expression of sGC compared with the nonpregnant state. GK rats had a smaller litter size (13.9 +/- 0.48 vs. 9.8 +/- 0.75; P < 0.05) and a greater number of resorptions compared with Wistar controls (0.8 +/- 0.76% vs. 19.9 +/- 6.06%; P < 0.05). These results suggest that uterine arteries from rats with T2D show reduced sensitivity of uterine vascular smooth muscle sGC to NO. During pregnancy, the GK uterine vascular smooth muscle fails to show relaxation responses similar to those of arteries from nondiabetic rats. PMID- 24337461 TI - Enhanced currents through L-type calcium channels in cardiomyocytes disturb the electrophysiology of the dystrophic heart. AB - Duchenne muscular dystrophy (DMD), induced by mutations in the gene encoding for the cytoskeletal protein dystrophin, is an inherited disease characterized by progressive muscle weakness. Besides the relatively well characterized skeletal muscle degenerative processes, DMD is also associated with cardiac complications. These include cardiomyopathy development and cardiac arrhythmias. The current understanding of the pathomechanisms in the heart is very limited, but recent research indicates that dysfunctional ion channels in dystrophic cardiomyocytes play a role. The aim of the present study was to characterize abnormalities in L type calcium channel function in adult dystrophic ventricular cardiomyocytes. By using the whole cell patch-clamp technique, the properties of currents through calcium channels in ventricular cardiomyocytes isolated from the hearts of normal and dystrophic adult mice were compared. Besides the commonly used dystrophin deficient mdx mouse model for human DMD, we also used mdx-utr mice, which are both dystrophin- and utrophin-deficient. We found that calcium channel currents were significantly increased, and channel inactivation was reduced in dystrophic cardiomyocytes. Both effects enhance the calcium influx during an action potential (AP). Whereas the AP in dystrophic mouse cardiomyocytes was nearly normal, implementation of the enhanced dystrophic calcium conductance in a computer model of a human ventricular cardiomyocyte considerably prolonged the AP. Finally, the described dystrophic calcium channel abnormalities entailed alterations in the electrocardiograms of dystrophic mice. We conclude that gain of function in cardiac L-type calcium channels may disturb the electrophysiology of the dystrophic heart and thereby cause arrhythmias. PMID- 24337462 TI - NADH changes during hypoxia, ischemia, and increased work differ between isolated heart preparations. AB - Langendorff-perfused hearts and working hearts are established isolated heart preparation techniques that are advantageous for studying cardiac physiology and function, especially when fluorescence imaging is a key component. However, oxygen and energy requirements vary widely between isolated heart preparations. When energy supply and demand are not in harmony, such as when oxygen is not adequately available, the imbalance is reflected in NADH fluctuations. As such, NADH imaging can provide insight into the metabolic state of tissue. Hearts from New Zealand white rabbits were prepared as mechanically silenced Langendorff perfused hearts, Langendorff-perfused hearts, or biventricular working hearts and subjected to sudden changes in workload, instantaneous global ischemia, and gradual hypoxia while heart rate, aortic pressure, and epicardial NADH fluorescence were monitored. Fast pacing resulted in a dip in NADH upon initiation and a spike in NADH when pacing was terminated in biventricular working hearts only, with the magnitude of the changes greatest at the fastest pacing rate. Working hearts were also most susceptible to changes in oxygen supply; NADH was at half-maximum value when perfusate oxygen was at 67.8 +/- 13.7%. Langendorff-perfused and mechanically arrested hearts were the least affected by low oxygen supply, with half-maximum NADH occurring at 42.5 +/- 5.0% and 23.7 +/- 4.6% perfusate oxygen, respectively. Although the biventricular working heart preparation can provide a useful representation of mechanical in vivo heart function, it is not without limitations. Understanding the limitations of isolated heart preparations is crucial when studying cardiac function in the context of energy supply and demand. PMID- 24337463 TI - A comprehensive, targeted approach to the clinical care of athletes following sport-related concussion. AB - PURPOSE: The purpose of this paper is to discuss risk and prognostic factors for concussion outcomes, review comprehensive approaches to assessment, and describe a new method for conceptualizing treatment for sport-related concussion using clinical experience. METHODS: Based on the current literature of sport-related concussion and clinical experience, an approach for conceptualizing concussion care using clinical trajectories and targeted treatments was developed. RESULTS: A comprehensive approach to assessment and targeted treatments for sport-related concussion was developed using specific clinical trajectories. CONCLUSION: Sport related concussions are heterogeneous and require an individualized clinical approach. The use of a comprehensive approach for assessing specific clinical trajectories following a sport-related concussion will help clinicians better conceptualize this injury. Clinicians can then match targeted treatment pathways to specific clinical trajectories to accelerate safe return to play for athletes following a sport-related concussion. PMID- 24337464 TI - Internal rotation resistance test at abduction and external rotation: a new clinical test for diagnosing subscapularis lesions. AB - PURPOSE: A new clinical test for evaluating subscapularis (SSC) integrity was described, and its diagnostic value was compared with the present SSC tests (the lift-off, belly-press, IRLS and bear-hug tests). The new test is called internal rotation resistance test at abduction and external rotation (IRRT). The test is performed at maximal 90 degrees of abduction and maximal external rotation. METHODS: Two hundred and thirty-five consecutive patients suffering from rotator cuff injury were evaluated preoperatively. Six tests were performed to assess the function of the SSC: the lift-off, belly-press, IRLS, the bear-hug, IRRT at 0 degrees abduction and 0 degrees external rotation (IRRT0 degrees ) and IRRT at maximal 90 degrees abduction and maximal external rotation (IRRTM). Arthroscopic findings were the reference for diagnosing of SSC lesions. RESULTS: The IRRTM test showed the greatest sensitivity (76.5 %), and IRLS (31.6 %) test had the lowest sensitivity. The IRRTM had the highest accuracy (79.0 %), and lift-off had the lowest accuracy (65.3 %). Positive IRRTM, bear-hug, belly-press, IRRT0 degrees tests indicate that about one-third of the SSC is torn, and a positive lift-off and IRLS tests predict a severe tear at least two-thirds of the SSC. CONCLUSIONS: The IRRTM represents a sensitive diagnostic test for SSC lesions and improves the chance of finding the upper part of the SSC tears. When the IRRTM is positive, the surgeon should pay particular attention to detecting the SSC tendon during arthroscopy. LEVEL OF EVIDENCE: Diagnostic study, Level I. PMID- 24337466 TI - ERalpha on the cell membrane helps the heart. PMID- 24337465 TI - Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance. AB - Alzheimer's disease (AD) is a neurodegenerative disorder associated with amyloid accumulation and autophagic changes. Parkin is an E3 ubiquitin ligase involved in proteasomal and autophagic clearance. We previously demonstrated decreased parkin solubility and interaction with the key autophagy enzyme beclin-1 in AD, but tyrosine kinase inhibition restored parkin-beclin-1 interaction. In the current studies, we determined the mechanisms of nilotinib-induced parkin-beclin-1 interaction, which leads to amyloid clearance. Nilotinib increased endogenous parkin levels and ubiquitination, which may enhance parkin recycling via the proteasome, leading to increased activity and interaction with beclin-1. Parkin solubility was decreased and autophagy was altered in amyloid expressing mice, suggesting that amyloid stress affects parkin stability, leading to failure of protein clearance via the lysosome. Isolation of autophagic vacuoles revealed amyloid and parkin accumulation in autophagic compartments but nilotinib decreased insoluble parkin levels and facilitated amyloid deposition into lysosomes in wild type, but not parkin(-/-) mice, further underscoring an essential role for endogenous parkin in amyloid clearance. These results suggest that nilotinib boosts the autophagic machinery, leading to increased level of endogenous parkin that undergoes ubiquitination and interacts with beclin-1 to facilitate amyloid clearance. These data suggest that nilotinib-mediated autophagic changes may trigger parkin response via increased protein levels, providing a therapeutic strategy to reduce Abeta and Tau in AD. KEY MESSAGE: Parkin solubility (stability) is decreased in AD and APP transgenic mice. Nilotinib-induced autophagic changes increase endogenous parkin level. Increased parkin level leads to ubiquitination and proteasomal recycling. Re-cycling decreases insoluble parkin and increases parkin-beclin-1 interaction. Beclin-1 parkin interaction enhances amyloid clearance. PMID- 24337467 TI - Mechanical and electrokinetic effects of polyamines/phospholipid interactions in model membranes. AB - The mechanical and electrical properties of phospholipids layers influenced by interaction with polyamines were determined by measuring surface pressure and compression modulus of monolayers and zeta potential of liposomes. The saturated derivative of phosphatidic acid (DPPA) formed layers of the organization varying with compression degree. Contact of DPPA layers with polyamines present in the subphase resulted in changing their mechanical properties and the conditions in which the layer reorganization appears. The parameters corresponding to the layer reorganization depended on the size and charge of polyamines' molecules. The values of: area per DPPA molecule, surface pressure at the point of layer structure reorganization, and surface pressure at the point of collapse characterizing of DPPA layers in the studied systems were determined. It was found that polyamines influenced to a much lesser extent the mechanical properties of monolayers formed from unsaturated derivative of phosphatidic acid slightly increasing its mechanical resistance in the range of higher molecular packing. The results of electrokinetic measurements revealed that surface charge of phosphatidic acid liposomes was effectively neutralized in the presence of polyamines. A similar effect was observed for phosphatidyl glycerol and for negatively charged polystyrene latex particles used as a reference. The influence of polyamines on the mechanical properties of DPPA layers was interpreted assuming a possibility of penetration of the lipid layer by polyamines' molecules. Comparison of action of putrescine and calcium ions and effects of polyamines on phosphatidyl glycerol provided additional justification for the proposed interpretation of the observed effects. PMID- 24337468 TI - Mesenteric mycotic pseudoaneurysm: a hidden catastrophe. AB - We present the radiology surgical correlation in emergency radiology for mesenteric mycotic pseudoaneurysm that was easily overlooked on routine CT in a 23-year-old young man with a chronic history of intravenous drug abuse. PMID- 24337469 TI - Unusual clotting dynamics of plasma supplemented with iron(III). AB - Iron salts are used in the treatment of iron deficiency anemia. Diabetic patients are frequently anemic and treatment includes administration of iron. Anemic patients on hemodialysis are at an increased risk of thromboembolic coronary events associated with the formation of dense fibrin clots resistant to fibrinolysis. Moreover, in chronic kidney disease patients, high labile plasma iron levels associated with iron supplementation are involved in complications found in dialyzed patients such as myocardial infarction. The aim of the present study was to investigate whether iron treatment is involved in the formation of the fibrin clots. Clotting of citrated plasma supplemented with Fe(3+) was investigated by thromboelastometry and electron microscopy. The results revealed that iron modifies coagulation in a complex manner. FeCl(3) stock solution underwent gradual chemical modification during storage and altered the coagulation profile over 29 days, suggesting that Fe(3+) interacts with both proteins of the coagulation cascade as well as the hydrolytic Fe(3+) species. Iron extends clotting of plasma by interacting with proteins of the coagulation cascade. Fe(3+) and/or its hydrolytic species interact with fibrinogen and/or fibrin changing their morphology and properties. In general FeCl(3) weakens the fibrin clot while at the same time precipitating plasma proteins immediately after application. Fe(3+) or its derivatives induced the formation of insoluble coagulums in non-enzymatic reactions including albumin and transferrin. Iron plays a role in coagulation and can precipitate plasma proteins. The formation of coagulums resistant to lysis in non-enzymatic reactions can increase the risk of thrombosis, and extending clotting of plasma can prolong bleeding. PMID- 24337470 TI - Indications of reduced prefrontal cortical function in chronically homeless adults. AB - This study investigated why some homeless individuals seem unable to transition towards self-reliance, following traditional supportive services. It was hypothesized that this may be due to some cognitive dysfunction. Chronically homeless adults were compared to controls on three tests of prefrontal competency: the Iowa Gambling Task, Word Fluency (FAS), and the Burglar's Story; they performed significantly worse than controls on all three tests. These results indicate a relationship between chronic homelessness and possible pre frontal deficits. This may explain why some long-term homeless fail to learn from the consequences of unproductive behavior and to develop more constructive behaviors needed to attain stability. PMID- 24337471 TI - School-related and social-emotional outcomes of providing mental health services in schools. AB - This study evaluated student outcomes of an expanded school mental health (ESMH) model that placed community mental health clinicians on-site in schools to identify and treat children with mental health needs. The first aim of this study was to consider school-related outcomes (suspension rates and attendance rates) for those students who received ESMH treatment (n = 159) were compared to a matched high-risk sample that did not receive such services (n = 148). Results demonstrated differences between groups over time on measures of suspensions and attendance but not academic achievement. The second aim of this study was to evaluate change in social-emotional functioning (Strengths and Difficulties Questionnaire Scores) over time for the treatment group. Results indicated significant improvements on several parent and teacher ratings. Despite limitations of the ESMH framework examined in this study, the overall results suggest some promising advantages for students who received ESMH services. PMID- 24337472 TI - Exploring primary care activities in ACT teams. AB - People with serious mental illness often receive inadequate primary and preventive care services. Federal healthcare reform endorses team-based care that provides high quality primary and preventive care to at risk populations. Assertive community treatment (ACT) teams offer a proven, standardized treatment approach effective in improving mental health outcomes for the seriously mentally ill. Much is known about the effectiveness of ACT teams in improving mental health outcomes, but the degree to which medical care needs are addressed is not established. The purpose of this study was to explore the extent to which ACT teams address the physical health of the population they serve. ACT team leaders were invited to complete an anonymous, web-based survey to explore attitudes and activities involving the primary care needs of their clients. Information was collected regarding the use of health screening tools, physical health assessments, provision of medical care and collaboration with primary care systems. Data was analyzed from 127 team leaders across the country, of which 55 completed the entire survey. Nearly every ACT team leader believed ACT teams have a role in identifying and managing the medical co-morbidities of their clientele. ACT teams report participation in many primary care activities. ACT teams are providing a substantial amount of primary and preventive services to their population. The survey suggests standardization of physical health identification, management or referral processes within ACT teams may result in improved quality of medical care. ACT teams are in a unique position to improve physical health care by virtue of having medically trained staff and frequent, close contact with their clients. PMID- 24337473 TI - Effects of a recovery-oriented cognitive therapy training program on inpatient staff attitudes and incidents of seclusion and restraint. AB - We investigated the feasibility of implementing a recovery-oriented cognitive therapy (CT-R) milieu training program in an urban acute psychiatric inpatient unit. Over a 1-month period, 29 staff members learned short-term CT-R strategies and techniques in an 8-h workshop. Trainees' perceptions of CT-R, beliefs about the therapeutic milieu, and attitudes about working with individuals with psychosis were evaluated both before the workshop and 6 months after the workshop had been completed. Incidents of seclusion and restraint on the unit were also tallied prior to and after the training. Results indicate that staff perceptions of CT-R and their beliefs about the therapeutic environment significantly improved, whereas staff attitudes towards individuals with psychosis remained the same. Incidents of seclusion and restraint also decreased after the training. These findings provide evidence that CT-R training is feasible and can improve the therapeutic milieu of an acute psychiatric inpatient unit. PMID- 24337474 TI - The CANSAS self-report for screening of needs in outpatients with schizophrenia and schizoaffective disorders. AB - The importance of needs assessment for service development has been widely recognized. In this study we examined the agreement between the Camberwell Assessment of Need Short Appraisal Schedule self-report version (CANSAS-P) and the Camberwell Assessment of Need interview-based scale in 100 outpatients with schizophrenia and schizoaffective disorders. We found equivalent number of met, unmet, and no needs for most of the domains of the two instruments. Both intraclass correlations and Kappa reliability coefficients were high for most need domains. The high agreement between the two instruments suggests that the CANSAS-P can be used as a screening tool to detect unmet needs in both clinical routine practice and research surveys in mental health outpatient settings. PMID- 24337475 TI - Psychometric properties of the Dutch version of the self-sufficiency matrix (SSM D). AB - Measuring treatment outcomes can be challenging in patients who experience multiple interlinked problems, as is the case in public mental health care (PMHC). This study describes the development and psychometric properties of a Dutch version of the self-sufficiency matrix (SSM-D), an instrument that measures outcomes and originates from the US. In two different settings, clients were rated using the SSM-D in combination with the Health of the Nation Outcome Scales (HoNOS) and the Camberwell assessment of need short appraisal schedule (CANSAS). The results provided support for adequate psychometric properties of the SSM-D. The SSM-D had a solid single factor structure and internal consistency of the scale was excellent. In addition, convergent validity of the SSM-D was indicated by strong correlations between HoNOS and CANSAS, as well as between several subdomains. Further research is needed to establish whether the results presented here can be obtained in other PMHC settings. PMID- 24337476 TI - Humour-related interventions for people with mental illness: a randomized controlled pilot study. AB - This study explored the feasibility and effects of humour-related interventions for mentally ill adults. Twelve, randomly assigned, participated in each of 3 arms--stand up comedy training (the experimental arm), discussing comedy videos (the active control arm), and no humour-related intervention (the passive control arm). Quantitative and qualitative data were collected at baseline, end of interventions (3 months) and follow up (after another 3 months). Scale comparisons were largely negative, although self-esteem marginally increased in the experimental arm. Interview responses indicated benefits for the interventions, including improved self-esteem in the experimental arm. These results, though mixed, justify further study. PMID- 24337477 TI - Stewardship practices of U.S. biobanks. AB - Biobanks require new governance models that address their ethical and regulatory challenges. One model relies on stewardship of specimens throughout their life course. Here, we discuss findings from our survey of 456 U.S. biobank managers that addressed whether and how biobanks steward their specimens. The findings reveal that most biobanks do not create ongoing relationships with contributors but do practice stewardship over storing and sharing of specimens. Biobanks now need guidance to fully articulate stewardship practices that ensure respect for contributors while facilitating research. PMID- 24337478 TI - Comment on "Progesterone/RANKL is a major regulatory axis in the human breast". AB - In vivo menstrual cycle data support the findings by Tanos et al. that progesterone regulates RANKL in an ex vivo microstructure model of the human breast, but dispute the suppression of estradiol on progesterone-stimulated RANKL expression. RANKL responds to progesterone in a three-dimensional organoid culture model under conditions mimicking luteal-phase hormone concentration, suggesting that the microstructure may not be crucial to demonstrate progesterone responsiveness. PMID- 24337479 TI - PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off target immunotherapy responses. AB - T cell therapies have demonstrated long-term efficacy and curative potential for the treatment of some cancers. However, their use is limited by damage to bystander tissues, as seen in graft-versus-host disease after donor lymphocyte infusion, or "on-target, off-tumor" toxicities incurred in some engineered T cell therapies. Nonspecific immunosuppression and irreversible T cell elimination are currently the only means to control such deleterious responses, but at the cost of abrogating therapeutic benefits or causing secondary complications. On the basis of the physiological paradigm of immune inhibitory receptors, we designed antigen-specific inhibitory chimeric antigen receptors (iCARs) to preemptively constrain T cell responses. We demonstrate that CTLA-4- or PD-1-based iCARs can selectively limit cytokine secretion, cytotoxicity, and proliferation induced through the endogenous T cell receptor or an activating chimeric receptor. The initial effect of the iCAR is temporary, thus enabling T cells to function upon a subsequent encounter with the antigen recognized by their activating receptor. iCARs thus provide a dynamic, self-regulating safety switch to prevent, rather than treat, the consequences of inadequate T cell specificity. PMID- 24337480 TI - Dietary therapy mitigates persistent wake deficits caused by mild traumatic brain injury. AB - Sleep disorders are highly prevalent in patients with traumatic brain injury (TBI) and can significantly impair cognitive rehabilitation. No proven therapies exist to mitigate the neurocognitive consequences of TBI. We show that mild brain injury in mice causes a persistent inability to maintain wakefulness and decreases orexin neuron activation during wakefulness. We gave mice a dietary supplement of branched-chain amino acids (BCAAs), precursors for de novo glutamate synthesis in the brain. BCAA therapy reinstated activation of orexin neurons and improved wake deficits in mice with mild brain injury. Our data suggest that dietary BCAA intervention, acting in part through orexin, can ameliorate injury-induced sleep disturbances and may facilitate cognitive rehabilitation after brain injury. PMID- 24337481 TI - CD4+ T cells from IPEX patients convert into functional and stable regulatory T cells by FOXP3 gene transfer. AB - In humans, mutations in the gene encoding for forkhead box P3 (FOXP3), a critically important transcription factor for CD4+CD25+ regulatory T (T(reg)) cell function, lead to a life-threatening systemic poly-autoimmune disease, known as immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Severe autoimmunity results from the inborn dysfunction and instability of FOXP3-mutated T(reg) cells. Hematopoietic stem cell transplantation is the only current curative option for affected patients. We show here that when CD4+ T cells are converted into T(reg) cells after lentivirus-mediated FOXP3 gene transfer, the resulting CD4(FOXP3) T cell population displays stable phenotype and suppressive function, especially when naive T cells are converted. We further demonstrate that CD4(FOXP3) T cells are stable in inflammatory conditions not only in vitro but also in vivo in a model of xenogeneic graft-versus-host disease. We therefore applied this FOXP3 gene transfer strategy for the development of a T(reg) cell-based therapeutic approach to restore tolerance in IPEX syndrome. IPEX-derived CD4(FOXP3) T cells mirrored T(reg) cells from healthy donors in terms of cellular markers, anergic phenotype, cytokine production, and suppressive function. These findings pave the way for the treatment of IPEX patients by adoptive cell therapy with genetically engineered T(reg) cells and are seminal for future potential application in patients with autoimmune disorders of different origin. PMID- 24337483 TI - Quality of life among long-term survivors of head and neck cancer treated by intensity-modulated radiotherapy. AB - IMPORTANCE: Radiation therapy to the head and neck has traditionally been associated with adverse effects that can affect oral health and physical functioning. Although intensity-modulated radiotherapy (IMRT) has been widely adopted as a means of decreasing toxic effects, limited clinical data exist on its potential effect on long-term quality of life. OBJECTIVE: To analyze quality of life among long-term survivors of head and neck cancer treated with IMRT. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional analysis studied 50 consecutive long-term survivors of head and neck cancer from a comprehensive cancer center who had previously undergone IMRT that required bilateral neck irradiation for locally advanced disease. All patients were clinically without evidence of recurrent disease and had at least 5 years of follow-up. MAIN OUTCOMES AND MEASURES: The University of Washington Quality of Life (UW-QOL) scores were reviewed for all study participants. The UW-QOL questionnaire consists of 12 domains that pertain to the degree of quality of life in the categories of pain, appearance, activity, recreation, swallowing, chewing, speech, shoulder function, taste, saliva, mood, and anxiety. RESULTS: Five years after completion of IMRT, 42 patients (84%) reported that their health-related quality of life was "much better" or "somewhat better" than at the time of cancer diagnosis. With respect to recent health-related quality of life during the preceding 7 days at the time of completing the UW-QOL questionnaire, 40 patients (80%) treated with IMRT reported "outstanding" or "very good" levels of functioning. Five years after completion of treatment, 41 (82%) rated their overall quality of life as "outstanding" or "very good." The lowest domain score on the UW-QOL questionnaire at 5 years pertained to salivary dysfunction. However, 42 patients (84%) reported saliva "of normal consistency" or "less saliva than normal but enough" compared with 8 (16%) reporting "too little saliva." No patient reported having "no saliva." CONCLUSIONS AND RELEVANCE: Our findings add to the body of literature that supports the acceptance of IMRT as standard treatment for head and neck cancer. The fact that most 5-year survivors were satisfied with their quality of lives points to the ability of IMRT to preserve long-term functioning. PMID- 24337482 TI - Metabolic rates of ATP transfer through creatine kinase (CK Flux) predict clinical heart failure events and death. AB - Morbidity and mortality from heart failure (HF) are high, and current risk stratification approaches for predicting HF progression are imperfect. Adenosine triphosphate (ATP) is required for normal cardiac contraction, and abnormalities in creatine kinase (CK) energy metabolism, the primary myocardial energy reserve reaction, have been observed in experimental and clinical HF. However, the prognostic value of abnormalities in ATP production rates through CK in human HF has not been investigated. Fifty-eight HF patients with nonischemic cardiomyopathy underwent 31P magnetic resonance spectroscopy (MRS) to quantify cardiac high-energy phosphates and the rate of ATP synthesis through CK (CK flux) and were prospectively followed for a median of 4.7 years. Multiple-event analysis (MEA) was performed for HF-related events including all-cause and cardiac death, HF hospitalization, cardiac transplantation, and ventricular assist device placement. Among baseline demographic, clinical, and metabolic parameters, MEA identified four independent predictors of HF events: New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), African-American race, and CK flux. Reduced myocardial CK flux was a significant predictor of HF outcomes, even after correction for NYHA class, LVEF, and race. For each increase in CK flux of 1 MUmol g-1 s-1, risk of HF-related composite outcomes decreased by 32 to 39%. These findings suggest that reduced CK flux may be a potential HF treatment target. Newer imaging strategies, including noninvasive 31P MRS that detect altered ATP kinetics, could thus complement risk stratification in HF and add value in conditions involving other tissues with high energy demands, including skeletal muscle and brain. PMID- 24337484 TI - Butein induces cell apoptosis and inhibition of cyclooxygenase-2 expression in A549 lung cancer cells. AB - Butein is a flavonoid isolated from the bark of Rhus verniciflua Stokes and the flowers of Butea monosperma, and is known to be a potential therapeutic drug for treating inflammation and cancer. Cyclooxygenase (COX) converts arachidonic acid to prostanoids, and increased expression of its isoform, COX-2, has been observed in lung cancer tissue. The aim of the present study was to investigate expression alteration of COX-2 in A549 lung cancer cells following butein treatment at the mRNA and protein levels by quantitative polymerase chain reaction and western blotting, respectively. It was observed that COX-2 mRNA and protein levels were significantly downregulated in the butein treatment group in comparison with the control group (P<0.05). In addition, the effects of butein on proliferation and apoptosis were evaluated. The data demonstrated that butein induces cell-cycle arrest and apoptosis in human lung cancer cells. These results indicated that butein may be a promising candidate drug for lung cancer treatment. PMID- 24337486 TI - Predicting survival for multiple myeloma patients using baseline neutrophil/lymphocyte ratio. AB - The neutrophil/lymphocyte ratio (NLR) at diagnosis has been shown to be a prognostic factor for survival in solid tumors. The NLR at diagnosis as a prognostic factor for multiple myeloma (MM) has not been studied. Therefore, the focus of the study was the correlation of NLR with the proven prognostic parameters in patients with MM. A total of 151 MM patients who fulfilled the International Myeloma Working Group (IMWG) criteria were enrolled in the study by a retrospective review of the patients' records. One hundred fifty-one age- and gender-matched healthy controls were also included in the study. NLR was calculated using data obtained from the complete blood count (CBC). NLR was significantly higher in MM patients than the control group (2.79 +/- 1.82 vs. 1.9 +/- 0.61, respectively; p < 0.0001). The median follow-up on living patients in this study was 41 months. NLR at the diagnosis was found to be an independent predictor for overall survival (OS) and event-free survival (EFS) by univariate and multivariate analysis. Patients with a NLR <2 at diagnosis experienced superior OS compared with patients with a NLR >=2 (5-year OS rates were 87.5 and 42.4 %, respectively; p < 0.0001). In a similar fashion, superior EFS was observed in patients with a NLR <2 at the diagnosis compared with patients with a NLR >=2 (5-year EFS rates were 88.4 and 41.8 %, respectively, p < 0.0001). This study suggests that NLR at the diagnosis is a simple, inexpensive, possible prognostic factor to assess clinical outcomes in MM patients. PMID- 24337485 TI - Progress in detecting cell-surface protein receptors: the erythropoietin receptor example. AB - Testing for the presence of specific cell-surface receptors (such as EGFR or HER2) on tumor cells is an integral part of cancer care in terms of treatment decisions and prognosis. Understanding the strengths and limitations of these tests is important because inaccurate results may occur if procedures designed to prevent false-negative or false-positive outcomes are not employed. This review discusses tests commonly used to identify and characterize cell-surface receptors, such as the erythropoietin receptor (EpoR). First, a summary is provided on the biology of the Epo/EpoR system, describing how EpoR is expressed on erythrocytic progenitors and precursors in the bone marrow where it mediates red blood cell production in response to Epo. Second, studies are described that investigated whether erythropoiesis-stimulating agents could stimulate tumor progression in cancer patients and whether EpoR is expressed and functional on tumor cells or on endothelial cells. The methods used in these studies included immunohistochemistry, Northern blotting, Western blotting, and binding assays. This review summarizes the strengths and limitations of these methods. Critically analyzing data from tests for cell-surface receptors such as EpoR requires understanding the techniques utilized and demonstrating that results are consistent with current knowledge about receptor biology. PMID- 24337487 TI - Immunosuppressive therapy with horse anti-thymocyte globulin and cyclosporine as treatment for fulminant aplastic anemia in children. AB - Patients with severe aplastic anemia (SAA) and an absolute neutrophil count (ANC) of 0 typically have fatal outcomes. We defined fulminant AA (FAA) as ANC = 0 for at least 2 weeks prior to and after immunosuppressive therapy (IST). We analyzed the outcomes of 35 children with FAA among 288 children who enrolled in a prospective study for AA (AA-97 study). AA was classified as FAA (n = 35), very SAA (vSAA; n = 129), or SAA (n = 124). All of the children received the IST with horse anti-thymocyte globulin (ATG) and cyclosporine (CsA). A significantly lower response rate at 6 months was seen in children with FAA when compared to those with vSAA or SAA (40.0, 63.6, and 63.7 %, respectively; p = 0.027). Of 20 nonresponder patients in the FAA group, 11 were rescued by alternative donor transplantation, and 5 patients showed a late response after 6 months. Consequently, no significant difference was noted in overall survival when comparing the FAA, vSAA, and SAA groups (88.5, 95.8, and 96.8 %). These findings indicate that IST with ATG and CsA is justified as a first-line treatment for children with FAA who lack a human leukocyte antigen-matched sibling donor. PMID- 24337488 TI - Successful vemurafenib salvage treatment in a patient with primary refractory hairy cell leukemia and pulmonary aspergillosis. PMID- 24337489 TI - Prevalence of HAGL lesions and associated abnormalities on shoulder MR examination. AB - OBJECTIVE: Humeral avulsion of the glenohumeral ligament (HAGL) is an uncommon shoulder injury. We report the prevalence of HAGL lesions and other associated shoulder injuries in a large series of shoulder MR examinations. All results were correlated with surgery. MATERIALS AND METHODS: MR reports of 1,000 consecutive conventional shoulder MR exams performed on patients with shoulder pain were reviewed in our information system for the word HAGL. A total of 743 patients went on to surgery. There were 23 HAGL lesions reported at surgery. Those 23 examinations were reviewed retrospectively in consensus by two musculoskeletal radiologists. Scans were assessed for HAGL lesions, full or partial thickness supraspinatus, infraspinatus or subscapularis tendon tears, superior labral anterior posterior (SLAP) tears, anterior or posterior labral tears, and Hill Sachs lesions. RESULTS: All 23 patients had HAGL lesions at surgery. Sixteen HAGL lesions were seen on prospective MR reading and 17 HAGL lesions were seen on retrospective MR consensus reading. Six HAGL lesions were not seen on retrospective consensus reading. Sixteen patients had Hill-Sachs deformities, ten had subscapularis tendon tears, five had supraspinatus tendon tears, six had superior labral tearing, and six had anterior labral tears. The above findings were confirmed on arthroscopy. CONCLUSIONS: In this series, there was a 1.6 % prevalence on all MR examinations, and prevalence of 2.1 % seen on MR examination for those who went to surgery. Common injuries associated with HAGL lesions are Hill-Sachs deformities and subscapularis tendon tears. Anterior labral tears were seen in only six cases despite Hill-Sachs deformities in 16 patients. In patients with Hill-Sachs deformities without anterior labral tears, one must carefully assess for the presence of a HAGL lesion. PMID- 24337490 TI - Comparison of acetabular version angle measurements between prone and reformatted supine computed tomography images. AB - PURPOSE: To compare acetabular version angle measurements of CT scans in the prone and reformatted supine positions. CT acetabular version angle measurements have previously been done in the prone position to correct for pelvic tilt. With the advent of multidetector CT, recent studies have evaluated acetabular version angles measured in the supine position. To our knowledge, a comparison between these two approaches has not been performed. STUDY DESIGN: Case series in which consecutive CT urography studies of 49 adult patients performed in both prone and supine positions were retrospectively reviewed, and acetabular version angles of both hips measured. METHOD: Retrospective review of 49 consecutive CT urography studies performed in both prone and supine positions was done, and acetabular version angles of both hips were measured. Two radiologists measured the acetabular version angles independently. Multiplanar reformation of the supine CT images was performed to compensate for pelvic tilt and rotation prior to angle measurements. RESULTS: There was excellent interobserver agreement between the two readers (ICC = 0.90). Acetabular version angle measurements from the prone CT images were larger compared to reformatted supine images (24.0 and 21.3 degrees , respectively, p < 0.0001), with greater angles found in women. There was strong correlation between supine and prone acetabular version angle measurements with a Pearson correlation coefficient of 0.743. CONCLUSIONS: Acetabular version angles measured from prone and reformatted supine CT images show strong correlation but are significantly different with larger angles obtained from the former and in women; clinical implications of these findings may require further study in other to determine the best method of version angle measurement. CT acetabular version angle measurement is also reliable with excellent interobserver correlation. PMID- 24337491 TI - Case-control study to estimate the performance of dual-energy computed tomography for anterior cruciate ligament tears in patients with history of knee trauma. AB - OBJECTIVE: Computed tomography (CT) is used to assess for fracture after knee trauma, but identification of ligamentous injuries may also be beneficial. Our purpose is to assess the potential of dual-energy computed tomography (DECT) for the detection of complete anterior cruciate ligament (ACL) disruption. METHODS: Sixteen patients with unilateral traumatic ACL disruption (average of 58 days following trauma) confirmed by MRI, and 11 control patients without trauma, underwent DECT of both knees. For each knee, axial, sagittal, and oblique sagittal images (with DECT bone removal, single-energy (SE) bone removal, and DECT tendon-specific color mapping) were reconstructed. Four musculoskeletal radiologists randomly evaluated the 324 DECT reconstructed series (54 knees with 6 displays) separately, to assess for ACL disruption using a five-point scale (1 = definitely not torn, to 5 = definitely torn). ROC analysis was used to compare performance across readers and displays. RESULTS: Sagittal oblique displays (mixed kV soft tissue, SE bone removal, and DECT bone removal) demonstrated higher areas under the curve for ACL disruption (AUC = 0.95, 0.93 and 0.95 respectively) without significant differences in performance between readers (p > 0.23). Inter-reader agreement was also better for these display methods (ICC range 0.62-0.69) compared with other techniques (ICC range 0.41-0.57). Mean sensitivity for ACL disruption was worst for DECT tendon-specific color map and axial images (24 % and 63 % respectively). CONCLUSION: DECT knee images with oblique sagittal reconstructions using either mixed kV or bone removal displays (either DECT or SE) depict ACL disruption in the subacute or chronic setting with reliable identification by musculoskeletal radiologists. PMID- 24337493 TI - The weak effects of climatic change on Plantago pollen concentration: 17 years of monitoring in Northwestern Spain. AB - Plantago L. species are very common in nitrified areas such as roadsides and their pollen is a major cause of pollinosis in temperate regions. In this study, we sampled airborne pollen grains in the city of Leon (NW, Spain) from January 1995 to December 2011, by using a Burkard(r) 7-day-recording trap. The percentage of Plantago pollen compared to the total pollen count ranged from 11% (1997) to 3% (2006) in the period under study. Peak pollen concentrations were recorded in May and June. Our 17-year analysis failed to disclose significant changes in the seasonal trend of plantain pollen concentration. In addition, there were no important changes in the start dates of pollen release and the meteorological parameters analyzed did not show significant variations in their usual trends. We analyzed the influence of several meteorological parameters on Plantago pollen concentration to explain the differences in pollen concentration trends during the study. Our results show that temperature, sun hours, evaporation, and relative humidity are the meteorological parameters best correlated to the behavior of Plantago pollen grains. In general, the years with low pollen concentrations correspond to the years with less precipitation or higher temperatures. We calculated the approximate Plantago flowering dates using the cumulative sum of daily maximum temperatures and compared them with the real bloom dates. The differences obtained were 4 days in 2009, 3 days in 2010, and 1 day in 2011 considering the complete period of pollination. PMID- 24337492 TI - Licochalcone A induces apoptosis in KB human oral cancer cells via a caspase dependent FasL signaling pathway. AB - Licochalcone A (Lico-A) is a natural phenol licorice compound with multiple bioactivities, including anti-inflammatory, anti-microbial, anti-fungal and osteogenesis-inducing properties. In the present study, we investigated the Lico A-induced apoptotic effects and examined the associated apoptosis pathway in KB human oral cancer cells. Lico-A decreased the number of viable KB oral cancer cells. However, Lico-A did not have an effect on primary normal human oral keratinocytes. In addition, the IC50 value of Lico-A was determined to be ~50 uM following dose-dependent stimulation. KB oral cancer cells stimulated with Lico-A for 24 h showed chromatin condensation by DAPI staining, genomic DNA fragmentation by agarose gel electrophoresis and a gradually increased apoptotic cell population by FACS analysis. These data suggest that Lico-A induces apoptosis in KB oral cancer cells. Additionally, Lico-A-induced apoptosis in KB oral cancer cells was mediated by the expression of factor associated suicide ligand (FasL) and activated caspase-8 and -3 and poly(ADP-ribose) polymerase (PARP). Furthermore, in the KB oral cancer cells co-stimulation with a caspase inhibitor (Z-VAD-fmk) and Lico-A significantly abolished the apoptotic phenomena. Our findings demonstrated that Lico-A-induced apoptosis in KB oral cancer cells involves the extrinsic apoptotic signaling pathway, which involves a caspase dependent FasL-mediated death receptor pathway. Our data suggest that Lico-A be developed as a chemotherapeutic agent for the management of oral cancer. PMID- 24337494 TI - Statistical analysis of spectral data: a methodology for designing an intelligent monitoring system for the diabetic foot. AB - Early detection of (pre-)signs of ulceration on a diabetic foot is valuable for clinical practice. Hyperspectral imaging is a promising technique for detection and classification of such (pre-)signs. However, the number of the spectral bands should be limited to avoid overfitting, which is critical for pixel classification with hyperspectral image data. The goal was to design a detector/classifier based on spectral imaging (SI) with a small number of optical bandpass filters. The performance and stability of the design were also investigated. The selection of the bandpass filters boils down to a feature selection problem. A dataset was built, containing reflectance spectra of 227 skin spots from 64 patients, measured with a spectrometer. Each skin spot was annotated manually by clinicians as "healthy" or a specific (pre-)sign of ulceration. Statistical analysis on the data set showed the number of required filters is between 3 and 7, depending on additional constraints on the filter set. The stability analysis revealed that shot noise was the most critical factor affecting the classification performance. It indicated that this impact could be avoided in future SI systems with a camera sensor whose saturation level is higher than 106, or by postimage processing. PMID- 24337495 TI - Effect of 940 nm low-level laser therapy on osteogenesis in vitro. AB - Bone regeneration is essential in medical treatment, such as in surgical bone healing and orthodontics. The aim of this study is to examine the effect of different powers of 940 nm diode low-level laser treatment (LLLT) on osteoblast cells during their proliferation and differentiation stages. A human fetal osteoblast cell line was cultured and treated with LLLT. The cells were divided into experimental groups according to the power delivered and periods of exposure per day for each laser power. The (3-(4,5-dimethylthiazol-2yl)-2,5 diphenyl tetrazolium bromide) (MTT) assay was used to determine cell proliferation. Both alkaline phosphatase and osteocalcin activity assays were assessed for cell differentiation. All treatment groups showed a significant increase in cell proliferation and differentiation compared to the control group. Regarding the exposure time, the subgroups treated with the LLLT for 6 min showed higher proliferation and differentiation rates for the powers delivered, the 300-mW LLLT group significantly increased the amount of cell proliferation. By contrast, the 100 and 200 mW groups showed significantly greater amounts of cell differentiation. These results suggest that the use of LLLT may play an important role in stimulating osteoblast cells for improved bone formation. PMID- 24337496 TI - Influence of different energy densities of laser phototherapy on oral wound healing. AB - The aim of the present prospective study was to evaluate the impact of laser phototherapy (LPT) on the healing of oral ulcers. Different power densities were used on oral wounds in Wistar rats (n=72) randomly divided into three groups: control (0 J/cm2), 4 J/cm2 laser, and 20 J/cm2 laser. Ulcers (3 mm in diameter) were made on the dorsum of the tongue with a punch. Irradiation with an indium gallium-aluminum-phosphide laser (660 nm; output power: 40 mW; spot size: 0.04 cm2) was performed once a day in close contact with the ulcer for 14 consecutive days. A statistically significant acceleration in healing time was found with wounds treated with 4 J/cm2 LPT. Moreover, striking differences were found in the ulcer area, healing percentage, degree of reepithelialization, and collagen deposition. The most significant changes occurred after 5 days of irradiation. Based on the conditions employed in the present study, LPT is capable of accelerating the oral mucosa wound-healing process. Moreover, faster and more organized reepithelialization and tissue healing of the oral mucosa were achieved with an energy density of 4 J/cm2 in comparison to 20 J/cm2. PMID- 24337497 TI - Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity. AB - Three histological variants are known within the family of embryonal rosette forming neuroepithelial brain tumors. These include embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL). In this study, we performed a comprehensive clinical, pathological, and molecular analysis of 97 cases of these rare brain neoplasms, including genome-wide DNA methylation and copy number profiling of 41 tumors. We identified uniform molecular signatures in all tumors irrespective of histological patterns, indicating that ETANTR, EBL, and MEPL comprise a single biological entity. As such, future WHO classification schemes should consider lumping these variants into a single diagnostic category, such as embryonal tumor with multilayered rosettes (ETMR). We recommend combined LIN28A immunohistochemistry and FISH analysis of the 19q13.42 locus for molecular diagnosis of this tumor category. Recognition of this distinct pediatric brain tumor entity based on the fact that the three histological variants are molecularly and clinically uniform will help to distinguish ETMR from other embryonal CNS tumors and to better understand the biology of these highly aggressive and therapy-resistant pediatric CNS malignancies, possibly leading to alternate treatment strategies. PMID- 24337498 TI - Neuropathological characterization of two siblings carrying the MAPT S305S mutation demonstrates features resembling argyrophilic grain disease. PMID- 24337499 TI - Acceptance of insurance by psychiatrists and the implications for access to mental health care. AB - IMPORTANCE: There have been recent calls for increased access to mental health services, but access may be limited owing to psychiatrist refusal to accept insurance. OBJECTIVE: To describe recent trends in acceptance of insurance by psychiatrists compared with physicians in other specialties. DESIGN, SETTING, AND PARTICIPANTS: We used data from a national survey of office-based physicians in the United States to calculate rates of acceptance of private noncapitated insurance, Medicare, and Medicaid by psychiatrists vs physicians in other specialties and to compare characteristics of psychiatrists who accepted insurance and those who did not. MAIN OUTCOMES AND MEASURES: Our main outcome variables were physician acceptance of new patients with private noncapitated insurance, Medicare, or Medicaid. Our main independent variables were physician specialty and year groupings (2005-2006, 2007-2008, and 2009-2010). RESULTS: The percentage of psychiatrists who accepted private noncapitated insurance in 2009 2010 was significantly lower than the percentage of physicians in other specialties (55.3% [95% CI, 46.7%-63.8%] vs 88.7% [86.4%-90.7%]; P < .001) and had declined by 17.0% since 2005-2006. Similarly, the percentage of psychiatrists who accepted Medicare in 2009-2010 was significantly lower than that for other physicians (54.8% [95% CI, 46.6%-62.7%] vs 86.1% [84.4%-87.7%]; P < .001) and had declined by 19.5% since 2005-2006. Psychiatrists' Medicaid acceptance rates in 2009-2010 were also lower than those for other physicians (43.1% [95% CI, 34.9% 51.7%] vs 73.0% [70.3%-75.5%]; P < .001) but had not declined significantly from 2005-2006. Psychiatrists in the Midwest were more likely to accept private noncapitated insurance (85.1%) than those in the Northeast (48.5%), South (43.0%), or West (57.8%) (P = .02). CONCLUSIONS AND RELEVANCE: Acceptance rates for all types of insurance were significantly lower for psychiatrists than for physicians in other specialties. These low rates of acceptance may pose a barrier to access to mental health services. PMID- 24337500 TI - Comparison of the effects of pitavastatin versus pravastatin on coronary artery plaque phenotype assessed by tissue characterization using serial virtual histology intravascular ultrasound. AB - Thin-cap fibroatheroma (TCFA) is the most common type of vulnerable plaque and is the precursor of plaque rupture. However, rupture of a TCFA is not the only mechanism underlying thrombus formation or acute coronary syndrome. Although statin therapy changes the composition of coronary artery plaques, the effects of statins, particularly different types of statins, on plaque phenotype have not been fully examined. This study compared the effects of pitavastatin versus pravastatin on coronary artery plaque phenotype assessed by virtual histology (VH) intravascular ultrasound (IVUS) in patients with angina pectoris (AP). Coronary atherosclerosis in nonculprit lesions was evaluated using VH-IVUS at baseline and 8 months after statin therapy; analyzable IVUS data were obtained from 83 patients with stable AP (39 patients treated with pitavastatin and 44 with pravastatin) and 36 patients with unstable AP (19 patients treated with pitavastatin and 17 with pravastatin). Pitavastatin had a strong effect on reducing pathologic intimal thickening (PIT), especially in patients with unstable AP, but had no impact on VH-TCFA or fibroatheroma (FA). By contrast, pravastatin had weak effects on reducing PIT, VH-TCFA, or FA. Increases in the number of calcified plaques were observed for both statins. In conclusion, pitavastatin and pravastatin changed coronary artery plaque phenotype as assessed by VH-IVUS in patients with AP. However, the effects of these statins on coronary artery plaque phenotype were different. PMID- 24337501 TI - Risk factors for surgical site infection in Japanese patients with ulcerative colitis: a multicenter prospective study. AB - PURPOSE: A prospective, multicenter, observational study was performed to investigate the risk factors of surgical site infection (SSI) in patients with ulcerative colitis (UC). METHODS: From 2009 to 2010, perioperative clinicopathological data were collected from patients who had undergone surgery for UC within the research period, for up to 6 consecutive months in 13 hospitals in Japan. The primary outcome was the development of SSI. RESULTS: A total of 195 patients with UC who underwent colorectal surgery were enrolled. SSI was diagnosed in 38 (19.5 %) patients, in the form of incisional infection in 23 (11.8 %), organ/space infection in 16 (8.2 %), and both in 1 (0.5 %). There were no significant risk factors associated with an increased risk of development of incisional SSI. An American Society of Anesthesiologists physical status of >= 3 was indicated as the only significant risk factor for organ/space SSI (P = 0.02) compared with other factors, such as a neutrophil count of >100 * 10(2)/mm(3), albumin level of <3.5 g/dl, perioperative packed red blood cell transfusion, fair or poor colonic cleanliness, and therapeutic use of antibiotics. CONCLUSION: Poor general physical status was the significant independent risk factor for organ/space SSI in patients with UC in Japan. PMID- 24337502 TI - Analysis of endoloops and endostaples for closing the appendiceal stump during laparoscopic appendectomy. AB - PURPOSE: An inadequate closure of the appendiceal stump can lead to intra abdominal surgical site infections. The aim of this study was to assess the efficiency of different closure techniques by focusing on the intraoperative and postoperative complications versus cost. METHODS: From June 2011 to June 2013, 333 patients from two different hospitals undergoing laparoscopic appendectomy were included in this study. The patients were divided into two groups based on the technique used for appendiceal stump closure: there were 104 patients in the stapler group and 229 in the loop group. RESULTS: Among the 333 patients who underwent laparoscopic appendectomy, there were two (0.6%) intraoperative complications and 22 (6.6%) postoperative complications. There were no significant differences between the groups with respect to the intraoperative and postoperative complications. The length of the operation was 7 min shorter when the endoloop was used (p = 0.014). The mean costs of the operation were significantly lower when the loop was used ( 554.93) compared to the stapler ( 900.70) (p = 0.000). CONCLUSIONS: There is no clinical evidence supporting the routine use of endoscopic staplers. The appendiceal stump can be secured safely with the use of endoloops in the majority of patients. Surgeons have to be more selective when choosing how to perform closure, and an endostapler should be used only in cases where it is clinically indicated. PMID- 24337503 TI - Sparing level Ib lymph nodes by intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma. AB - BACKGROUND: We retrospectively investigated the patterns of locoregional relapse and survival of patients to evaluate whether sparing level Ib lymph nodes by intensity-modulated radiotherapy (IMRT) in the treatment of nasopharyngeal carcinoma was feasible. METHODS: One hundred and twenty nasopharyngeal carcinoma patients received treatment with level Ib lymph nodes spared by IMRT between January 2005 and August 2008 in our center. Before treatment, each patient underwent enhanced magnetic resonance imaging of the nasopharynx and neck. Patients with negative cervical lymph nodes received radiotherapy to the nasopharynx, skull base and upper neck drainage areas, while patients with cervical lymph node involvement received treatment to the whole neck. The prescription doses were 66-70.4 Gy/30-32 fractions to the gross tumor volume of nasopharynx, 66 Gy to the positive neck nodes, 60 Gy to the high-risk clinical target volume and 54 Gy to the low-risk clinical target volume. Patients staged III, IV A/B or II also received chemotherapy. RESULTS: The median follow-up of these 120 patients was 54 months. The 5-year local control, regional control, distant metastasis-free and overall survival rates were 90.7, 96.5, 84.8 and 81.4 %, respectively. Four patients suffered regional recurrence: 2, 1 and 1 experienced regional recurrence in level II, retropharyngeal and parotid lymph nodes, respectively. CONCLUSION: In nasopharyngeal carcinoma patients with negative level Ib lymph nodes who are treated with level Ib-sparing IMRT, regional lymph node recurrence alone is rare. Therefore, sparing level Ib lymph nodes by IMRT is feasible in selected patients. PMID- 24337504 TI - Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. AB - Mesenchymal stem cells (MSCs) have been increasingly tested experimentally and clinically for cardiac repair. However, the underlying mechanisms remain controversial due to the poor viability and considerable death of the engrafted cells in the infracted myocardium. Recent reports have suggested that extracellular vesicles (EVs) released by MSCs have angiogenesis-promoting activity; however, the therapeutic effect of MSC-EVs on an ischemic heart is unclear. In the present study, we reported that MSCs could release a large quantity of EVs around 100 nm in diameter upon hypoxia stimulation though the majority of the cells had not experienced apoptosis. MSC-EVs could be promptly uptaken by human umbilical vein endothelial cells, and the internalization resulted in dose-dependent enhancement of in vitro proliferation, migration, and tube formation of endothelial cells. Using an acute myocardial infarction rat model, we found that intramyocardial injection of MSC-EVs markedly enhanced blood flow recovery, in accordance with reduced infarct size and preserved cardiac systolic and diastolic performance compared to those treated with PBS. These data suggest that like MSCs, MSC-EVs could also protect cardiac tissue from ischemic injury at least by means of promoting blood vessel formation, though further detailed investigations should be performed to define the functionality of MSC EVs. KEY MESSAGES: MSCs released extracellular vesicles (EVs) upon hypoxia stimulation. MSC-EVs were a mixture of microvesicles and exosomes. MSC-EVs could be promptly uptaken by human umbilical vein endothelial cells. MSC-EVs promoted neoangiogenesis in vitro and in vivo. MSC-EVs preserved cardiac performance in an AMI model. PMID- 24337505 TI - Antibiotics and Staphylococcus aureus--more than meets the MIC. PMID- 24337506 TI - Ten years on: generating innovative responses to avian influenza. AB - Since 2006, the number of recorded H5N1 avian influenza outbreaks has declined globally, but at mid-2012 the disease was enzootic in six countries in Asia and Africa, and sporadic outbreaks continue over a wide area. It is now accepted that it will take decades to eliminate the H5N1 virus in poultry and 'unconventional' response approaches have been called for. Drawing on increased understandings of the epizoosis over the last 10 years, this paper investigates what conditions are required if such innovative approaches are to be generated. It argues that addressing the spread and persistence of avian influenza is primarily a political matter, and if approaches appropriate for enzooticity are to be devised, the social, political, and economic dynamics of the disease and responses to it need to be identified and prioritised. A dominant response strategy focused on outbreak events, containment and eradication has obscured these important dynamics. If innovative 'unconventional' responses are to be generated, a wider range of perspectives and expertise needs to be engaged. This will result in political processes of negotiation, which the technically led, development orientated institutions directing and funding the global response are ill equipped to facilitate. PMID- 24337507 TI - Near-infrared fluorescence sentinel lymph node mapping in breast cancer: a multicenter experience. AB - Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) has the potential to improve the sentinel lymph node (SLN) procedure by facilitating percutaneous and intraoperative identification of lymphatic channels and SLNs. Previous studies suggested that a dose of 0.62 mg (1.6 mL of 0.5 mM) ICG is optimal for SLN mapping in breast cancer. The aim of this study was to evaluate the diagnostic accuracy of NIR fluorescence for SLN mapping in breast cancer patients when used in conjunction with conventional techniques. Study subjects were 95 breast cancer patients planning to undergo SLN procedure at either the Dana-Farber/Harvard Cancer Center (Boston, MA, USA) or the Leiden University Medical Center (Leiden, the Netherlands) between July 2010 and January 2013. Subjects underwent the standard-of-care SLN procedure at each institution using (99)Technetium-colloid in all subjects and patent blue in 27 (28 %) of the subjects. NIR fluorescence-guided SLN detection was performed using the Mini FLARE imaging system. SLN identification was successful in 94 of 95 subjects (99 %) using NIR fluorescence imaging or a combination of both NIR fluorescence imaging and radioactive guidance. In 2 of 95 subjects, radioactive guidance was necessary for initial in vivo identification of SLNs. In 1 of 95 subjects, NIR fluorescence was necessary for initial in vivo identification of SLNs. A total of 177 SLNs (mean 1.9, range 1-5) were resected: 100 % NIR fluorescent, 88 % radioactive, and 78 % (of 40 nodes) blue. In 2 of 95 subjects (2.1 %), SLNs containing macrometastases were found only by NIR fluorescence, and in one patient this led to upstaging to N1. This study demonstrates the safe and accurate application of NIR fluorescence imaging for the identification of SLNs in breast cancer patients, but calls into question what technique should be used as the gold standard in future studies. PMID- 24337509 TI - Muscle system of Diplodiscus subclavatus (Trematoda: Paramphistomida) cercariae, pre-ovigerous, and ovigerous adults. AB - The musculature of cercariae, pre-ovigerous, and ovigerous adults of Diplodiscus subclavatus was studied by means of TRITC-conjugated phalloidin staining of filamentous actin and confocal scanning laser microscopy. The body wall appears to include four muscle layers as follows: circular, outer longitudinal, diagonal, and inner longitudinal. Two layers of longitudinal muscle fibers are arranged in different modes due to the secondary transformed paramphistomid body construction. The organization of the acetabulum turned out to be more complex than ever described, with a radial layer, two layers of circular, two layers of meridional, an additional starry layer of muscle fibers, as well as a few separate muscle layers of the accessory sucker. Within the pharynx, I found a group of alar muscle fibers, never described before for any paramphistomids, and some morphological features which were not considered to be characteristic for D. subclavatus (namely--the middle semicircular layer and the transverse muscle fibers in the pre-sphincteric space). No significant reorganizations of the somatic musculature occur throughout the development from the cercaria to the ovigerous adult worm, so the metamorphosis goes in the manner of completion. The cercarial tail includes a layer of circular muscle fibers and a longitudinal muscle layer beneath. The latter consists of two medial longitudinal bundles of smooth muscle fibers and two lateral longitudinal bands of obliquely striated muscle fibers which are partially divided in halves. PMID- 24337508 TI - Inhibition of LINE-1 retrotransposon-encoded reverse transcriptase modulates the expression of cell differentiation genes in breast cancer cells. AB - Long Interspersed Elements (L1 elements) are biologically active retrotransposons that are capable of autonomous replication using their own reverse transcriptase (RT) enzyme. Expression of the normally repressed RT has been implicated in cancer cell growth. However, at present, little is known about the expression of L1-encoded RT activity or the molecular changes that are associated with RT activity in the development of breast cancer. Here, we report that RT activity is widespread in breast cancer cells. The expression of RT protein decreased markedly in breast cancer cells after treatment with the antiretroviral drug, efavirenz. While the majority of cells showed a significant reduction in proliferation, inhibition of RT was also accompanied by cell-specific differences in morphology. MCF7 cells displayed elongated microtubule extensions that adhered tightly to their substrate, while a large fraction of the T47D cells that we studied formed long filopodia projections. These morphological changes were reversible upon cessation of RT inhibition, confirming their dependence on RT activity. We also carried out gene expression profiling with microarrays and determined the genes that were differentially expressed during the process of cellular differentiation. Genes involved in proliferation, cell migration, and invasive activity were repressed in RT-inhibited cells. Concomitantly, genes involved in cell projection, formation of vacuolar membranes, and cell-to-cell junctions were significantly upregulated in RT-inhibited cells. qRT-PCR examination of the mRNA expression of these genes in additional cell lines yielded close correlation between their differential expression and the degree of cellular differentiation. Our study demonstrates that the inhibition of L1 encoded RT can reduce the rate of proliferation and promote differentiation of breast cancer cells. Together, these results provide a direct functional link between the expression of L1 retrotransposons and the development of breast cancer. PMID- 24337510 TI - Effect of root bark extract of Berberis vulgaris L. on Leishmania major on BALB/c mice. AB - Leishmaniasis is one of the most important diseases transmitted by arthropod. This disease is present in 88 countries. Approximately 400 million people are at risk, and 12 million are involved. We aimed to examine the application of ethanolic extract of the root bark of Berberis vulgaris L. for treatment of mice infected with cutaneous leishmaniasis. At first, 40 BALB/c mice were infected to Leishmania major promastigotes and were divided in two groups A and B. Then, each of A and B groups were divided to two subgroups. Mice from subgroup A1 were treated with 10% root bark alcoholic extract, and mice from subgroup A2 were treated with only alcohol (control). Mice from subgroup B1 were treated with 20% root bark alcoholic extract, and mice from subgroup B2 were treated with only alcohol (control). The 90% recovery was found in the mice treated with 20% root bark extract, and 55% recovery was found with 10% root bark extract, but in the control group, 0% recovery was found. The results of our study showed that the lotion of root bark extract has good suppression effects on parasites. Therefore, it might be a pro for developing new antileishmanial drugs. PMID- 24337511 TI - Scanning electron microscopy of Anopheles hyrcanus group (Diptera: Culicidae) eggs in Thailand and an ultrastructural key for species identification. AB - The eggs of Anopheles argyropus, Anopheles crawfordi, Anopheles nigerrimus, Anopheles nitidus, Anopheles paraliae, Anopheles peditaeniatus, Anopheles pursati, and Anopheles sinensis are described with the aid of scanning electron micrographs. Comparisons of the egg structure among the eight species showed that the eggs differed with respect to the following characteristics: the deck complete (An. argyropus, An. nigerrimus, An. paraliae, An. peditaeniatus, and An. sinensis); variable (complete, split and incomplete decks found together within an egg batch/An. crawfordi); and division into an area at each end (An. nitidus and An. pursati). The ratios of the entire length per maximal deck width within the area covered by floats were 3.33-6.86 (An. sinensis), 8.78-18.20 (An. peditaeniatus), 13.67-22 (An. nigerrimus), 26.33-44.25 (An. paraliae), and 26.99 75.94 (An. argyropus). The numbers of float ribs were 21-27 (An. peditaeniatus) and 28-34 (An. nigerrimus), and the total numbers of anterior and posterior tubercles were 6-8 (An. paraliae) and 9-11 (An. argyropus). Exochorionic sculpturing was of reticulum type (An. argyropus, An. crawfordi, An. nigerrimus, An. nitidus, An. paraliae, An. peditaeniatus, and An. sinensis) and pure tubercle type (An. pursati). Attempts are proposed to construct a robust key for species identification based on the morphometrics and ultrastructures of eggs under scanning electron microscopy. PMID- 24337512 TI - Seasonal recovery of Eimeria oocysts from soil on naturally contaminated pastures. AB - Though Eimeria is an important parasite of cattle, research is lacking on how the parasite persist in the pasture soils. In this study, feces samples were collected from three pastures in June and October 2010 and soil samples in April 2011. Coordinates of sampling locations were recorded with Global Positioning System together with information about grass cover, shade, and elevation. All soil samples were collected from the same locations as the fecal samples and used in model evaluating the possible factors influencing the concentration of oocysts in the soil. Feces and soil samples were investigated using a quantitative flotation technique. Eimeria oocysts were found in 95.6% of fecal samples collected in summer and 84.5% of samples in fall. In contrast, the same locations soil samples were positive for Eimeria oocysts in 37.3% (summer) and 44.3% (fall). Despite larger numbers of oocysts in fecal samples shed during summer compared to fall, there was no difference in the concentration of oocysts in soil samples the following spring. The odds of higher numbers of oocysts in soil samples in spring were higher if fecal samples collected in summer were in shade or if containing Eimeria alabamensis during the fall. Factors other than the concentrations of oocysts shed in feces appear to affect whether oocysts persist between grazing seasons. PMID- 24337513 TI - Width of anterior chamber angle determined by OCT, and correlation to refraction and age in a German working population: the MIPH Eye&Health Study. AB - BACKGROUND: Optical coherence tomography (OCT) of the anterior segment allows quantitative analysis of the geometry of the chamber angle. We performed bilateral spectral-domain OCT measurements in healthy, emmetropic, hyperopic, and myopic subjects to establish correlations between the width of the angle, the refraction, and intraocular pressure of the test persons. METHODS: Out of 4,617 eyes (2,309 subjects), those with refractive errors of < -4 or > +3 diopters were identified by objective refraction measurement (KR-8800 Kerato-Refractometer, Topcon Inc., Japan) and examined using the anterior segment mode of a spectral domain 3D OCT-2000 (Topcon Inc., Japan). Non-contact tonometry was performed (CT 80, Topcon Inc., Japan). One hundred and eight eyes of 54 emmetropic subjects (+/ 0.5 dpt) served as reference group. Previous ocular surgery was exclusion criterion in all groups. Width of the chamber angle was determined using semi automated software tools and statistical analysis of the data (Pearson correlation, ANOVA with post-hoc test and Bonferroni correction, regression analysis) was performed using SPSS software (SPSS 19.0, Chicago, IL, USA). RESULTS: Six hundred and sixty-eight eyes of 398 persons (292 male, 96 female) were included in the study. Mean hyperopic refraction was +4.24 (+3 to +7.75) dpt, mean myopic refraction was -5.86 (-4 to -11.75) dpt. Valid chamber angle OCT measurements could be obtained from 50 (69.4 %) hyperopic and 400 (71.4 %) myopic eyes meeting the inclusion criteria. The mean width of the chamber angle was determined as 31.8 degrees (range: 13.5 to 45.6, SD 7.49) in the hyperopic group, 40.8 degrees (range: 19.3 to 66.0, SD 8.1) in the myopic group, and 36.3 degrees (range: 21.1 to 51.8, SD 6.8) in the emmetropic reference group. Correlation was highly significant (p > 0.001) between refractive error and the aperture of the chamber angle as measured from OCT. The association of the intraocular pressure and the refraction was also highly significant (p > 0.001) for the three groups. CONCLUSION: The spectral-domain OCT yielded measurements that could be used for digital analysis of the chamber angle geometry. Our results highlight the correlation between refraction and aperture of the angle in hyperopia and myopia as determined by the 3D OCT-2000: hyperopia is associated with a narrower chamber angle, myopia with a wider aperture of the angle. PMID- 24337514 TI - Hepatoprotective and antioxidant activity of linden (Tilia platyphyllos L.) infusion against ethanol-induced oxidative stress in rats. AB - The present study was carried out to evaluate the hepatoprotective effect and antioxidant role of infusion prepared from linden flowers (LF) against ethanol induced oxidative stress. The hepatoprotective and antioxidant role of the plant's infusion against ethanol-induced oxidative stress was evaluated by measuring liver damage serum biomarkers, aspartate aminotransferase (AST), alanine aminotransferase, lactate dehydrogenase (LDH), total protein, total albumin, and total cholesterol level; ADS such as GSH, GR, SOD, GST, CAT and GPx, and MDA contents in various tissues of rats. Rats were divided into four experimental groups: I (control), II (20 % ethanol), III (2 % LF), and IV (20 % ethanol + 2 % LF). According to the results, the level of serum marker enzymes, AST and LDH, was significantly increased in group alcohol and group LF as compared to control group, whereas decreased in group IV as compared to ethanol group. With regard to MDA content and ADS constituents, MDA contents of alcohol group in all tissues, except for erythrocytes and heart, and in brain, kidney, and spleen of LF group significantly increased compared to control group, whereas LF beverage extract supplementation did not restore the increased MDA towards close the control level. In addition, while ethanol caused fluctuation in antioxidant defense system constituents level as a result of oxidative stress condition in the rats, it could have not been determined the healing effects of the LF against these fluctuations. The results indicated that LF beverage extract could not be as important as diet-derived antioxidants in preventing oxidative damage in the tissues by reducing the lipid oxidation or inhibiting the production of ethanol-induced free radicals in rats. PMID- 24337515 TI - Crocetin induces apoptosis of BGC-823 human gastric cancer cells. AB - Gastric cancer (GC) is one of the most common types of gastrointestinal tumors worldwide, and the side effects of chemotherapeutic drugs and the resistance to chemotherapy remain problematic in its clinical treatment. Therefore, safe and effective novel agents are urgently required. The purpose of the present study was to investigate the crocetin-sensitive treatment of GC and its possible mechanisms. BGC-823 human GC cells were treated with crocetin. The effects of crocetin on the viability of the cells were determined by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Hoechst 33258 dyeing and Rh123 staining were used to detect cell apoptosis. The BGC-823 cells were subjected to western blotting analysis for detection of cytochrome c and cleaved caspase-3 protein expression. Crocetin inhibited the proliferation of the GC cell line in a dose- and time-dependent manner. Apoptotic BGC-823 cells induced by crocetin were stained by Hoechst 33258 and observed under a light microscope for cell membrane staining of dense nuclei, nuclear pyknosis, fragmentation, chromatin condensation and highlighted nuclear membrane staining. This revealed a decline in the mitochondrial membrane potential of the BGC-823 cells. Crocetin also induced caspase-3 activation and cytochrome c translocation into the cytosol from the mitochondria. The results of this study indicate that crocetin induces the apoptosis of BGC-823 cells, and may be used as an effective agent in the treatment of GC. PMID- 24337516 TI - Relationship between the 46/1 haplotype of the JAK2 gene and the JAK2 mutational status and allele burden, the initial findings, and the survival of patients with myelofibrosis. AB - An association has been reported between a specific haplotype of the JAK2 gene, the homozygous 46/1 haplotype, and a predisposition to the development of chromosome Philadelphia-negative myeloproliferative neoplasms. Concerning myelofibrosis (MF), controversy remains on the relationship between the above JAK2 haplotype and the patients' clinicohematological features and survival. Among 132 patients with MF (60 % primary MF, 20 % postpolycythemia vera MF, 20 % post-essential thrombocythemia MF; 59 % JAK2V617F positive) who were analyzed for the JAK2 46/1 haplotype, 29 were found to be homozygous and 53 heterozygous. The homozygous 46/1 haplotype was more often observed in JAK2V617F-positive patients (29.5 versus 11 %, p = 0.012). Moreover, among JAK2V617F-positive patients, those who were homozygous for the 46/1 haplotype had a higher allele burden than the remainder (92 versus 48 %, p = 0.0017). Overall, patients with homozygous 46/1 haplotype showed significantly higher hemoglobin values and higher leukocyte counts, but no association was seen with other clinicohematological features. Finally, no relationship was observed between the JAK2 46/1 haplotype and either the patients' prognostic score or survival. PMID- 24337517 TI - Smouldering systemic mastocytosis with lymph node involvement mimicking malignant lymphoma. PMID- 24337519 TI - Involuntary movement in pediatric moyamoya disease patients: consideration of pathogenetic mechanism using neuroimaging studies. AB - PURPOSE: Involuntary movement is a rare symptom of moyamoya disease (MMD). No consensus has been reached regarding its clinical features and pathogenetic mechanism. Therefore, pediatric MMD patients presenting with involuntary movement were retrospectively analyzed, focusing on the image findings. METHODS: A total of 513 patients who were treated for MMD were reviewed. After exclusion of MMD syndromes and those with accompanying conditions related to involuntary movements, five patients (mean age: 11.6 years, range: 5-13 years) were evaluated. RESULTS: All of the patients improved their symptoms rapidly after the indirect bypass operations to the contralateral hemisphere. All remained symptom free during the long follow-up period. Comprehensive evaluation of the preoperative imaging findings failed to suggest a characteristic feature in common, corresponding to the existing hypotheses or a new hypothesis. Only one patient showed infarction preoperatively, and only one patient showed prominently enhanced collateral vessels in the basal ganglia. Although a decrease in vascular reserve was observed in all patients, the location and laterality were nonspecific. CONCLUSION: There still appears to be confusion regarding the pathogenetic mechanism of involuntary movement in MMD with no repetitive, established imaging features to explain the phenomenon. Nonetheless, with its excellent response to surgical treatment, clinical awareness of this rare symptom of MMD should be emphasized as a differential diagnosis for secondary movement disorder in children. PMID- 24337520 TI - Anxiety, depression and suicidal ideation in Lebanese patients undergoing hemodialysis. AB - Anxiety, depression and suicidal thoughts are highly prevalent comorbidities of end-stage-renal-disease (ESRD). There are no studies in Lebanon on the prevalence of these symptoms in Lebanese end-stage-renal-disease patients. Moreover, the association between ESRD on one hand, and anxiety, depression and suicidal ideation on the other has never been established in Lebanon. Groups of patients at a high-risk of development of these symptoms are not determined. The Hospital Anxiety and Depression Score and M.I.N.I (module C) were used to measure the prevalence of anxiety, depression and suicidal ideation in 51 patients from the dialysis center of Hotel-Dieu de France Hospital in Lebanon. In our sample, 45% of included patients suffered from symptoms of anxiety and 50% presented symptoms of depression.The prevalence of suicidal ideation as detected by the M.I.N.I. is at 37%. No patients presented with a high risk of suicide. There was a statistically significant correlation between the existence of organic comorbidities and the presence of symptoms of depression and suicidal ideation. As for anxiety, the association was marginally significant. The results obtained by our study are consistent with those found in studies performed in other societies. The profile of depression- and suicidal ideation-prone patients has been determined. It consists of patients with at least one medical comorbidity to the ESRD. This, in turn, should lead to increased awareness and better treatment of these psychiatric ailments, considering their impact on morbidity and mortality in ESRD. PMID- 24337521 TI - Persistent disparity in prevalence of current cigarette smoking between US adolescents with vs. without a past-year major depressive episode. AB - Using data from annual (2004-2010) cross-sectional surveys of nationally representative samples, the prevalence rate of current (i.e., past 30 days) cigarette smoking among US adolescents age 12-17 years was twice as high for those with vs. without a past-year major depressive episode (PYMDE) (22 vs. 11% in the 2004 survey and 16 vs. 8% in the 2010 survey). The proportion of all US adolescent current smokers who had a PYMDE was about 24% for females; 70-80% of all smokers with PYMDE were females. The persistently higher smoking rates in US adolescents with vs. without PYMDE emphasizes the need for interventions. PMID- 24337522 TI - Activating people to address their health care needs: learning from people with lived experience of chronic illnesses. AB - One of the primary goals of health care reform is improving the quality and reducing the costs of care for people with co-morbid mental health and physical health conditions. One strategy is to integrate primary and behavioral health care through care coordination and patient activation. This qualitative study using community based participatory research methods informs the development of integrated care by presenting the perspectives of those with lived experience of chronic illnesses and homelessness. Themes presented include the internal and external barriers to addressing health needs and the key role of peer support in overcoming these barriers. PMID- 24337523 TI - Prevalence and correlates of criminal victimization among new admissions to outpatient mental health services in Hawaii. AB - Adults with serious mental illness (SMI) experience criminal victimization at rates higher than the general population whether they reside in the community or correctional settings. This study examines the past-six month prevalence and correlates of criminal victimization among a large community sample (N = 2,209) of consumers with SMI newly admitted to outpatient mental health services during 2005 through 2008. A cross-sectional design was used with self-report and clinical data collected from administrative records. Victimization was determined by responses to direct questions about experiences in the previous 6 months with respect to victimization of a non-violent and/or violent crime. Socio demographic, clinical and criminal correlates of victimization were abstracted from a quality of life survey and clinical assessment interview conducted at admission. Overall, 25.4 % of consumers reported being a victim of any crime (violent or non-violent) in the past 6 months, with 20.3 % reporting non-violent and 12.3 % violent victimization. The risk of victimization was elevated for those who were female, White, not taking atypical psychotropic medication, not feeling safe in their living arrangement, and were arrested or homeless in the six-months prior to engaging in mental health outpatient treatment. Policy and practice implications of these findings are discussed. PMID- 24337524 TI - Explaining homeless youths' criminal justice interactions: childhood trauma or surviving life on the streets? AB - Homeless youth are at increased risk for involvement in the criminal justice system. This study investigated childhood trauma as a risk factor for arrest or jail among a sample of youth seeking services at drop in, shelter, and transitional housing settings, while controlling for more established risk factors including: substance use, peer deviance, and engagement in survival behaviors. Standardized and researcher developed measures collected quantitative data through face-to-face interviews with youth (N = 202). Two sequential logic regression models identified significant predictors of arrest and jail, with a particular interest in the effects of childhood maltreatment. Youth with a history of physical abuse were nearly twice as likely to be arrested and to be jailed compared to non-abused youth, controlling for the significant influence of drug use and survival behaviors. These findings suggest the need for trauma screening and trauma-informed services for homeless youth at risk of illegal behavior. PMID- 24337525 TI - Similar survival between uncemented and cemented fixation prostheses in total knee arthroplasty: a meta-analysis and systematic comparative analysis using registers. AB - PURPOSE: The purpose of this analysis was to determine whether uncemented total knee arthroplasty performs as well as cemented total knee arthroplasty. METHODS: We searched PubMed, MEDLINE, and EMBASE, and major orthopaedic journals. This search was performed for the years from 1980 to the present. Randomised controlled trials and observational studies comparing cemented and uncemented fixation were identified. Effective data were pooled for meta-analysis. A systematic search was carried out using the EFORT website to identify the relevant arthroplasty registers. RESULTS: Nine studies were included in the meta analysis. The combined odds ratio for failure of the implant due to aseptic loosening for the uncemented group over 5 and 10 years were 3.41 (p = 0.0001) and 4.73 (p = 0.0002), respectively. Subgroup analysis of data when design-related failed total knee arthroplasty (TKA)s were excluded showed no difference between the groups for odds of aseptic loosening (n.s.). There was no difference between the groups with respect to infection (n.s.). Pooled outcome of register data revealed that uncemented knees had a higher revision rate than cemented knees. CONCLUSIONS: The important finding from the current study is that there is no evidence to support that fixation techniques alone affect the durability of a total knee arthroplasty when design-related failure in TKAs was excluded. The way of fixation is not relevant to the incidence of infection. LEVEL OF EVIDENCE: IV. PMID- 24337527 TI - [MUW researcher of the month]. PMID- 24337526 TI - Is the clinical outcome after cartilage treatment affected by subchondral bone edema? AB - PURPOSE: Subchondral bone edema is a common finding after cartilage treatment, but its interpretation is still debated. The aim of this study is to analyse the presence of edema after matrix-assisted autologous chondrocyte transplantation (MACT) for knee cartilage lesions at different follow-up times and its correlation with the clinical outcome. METHODS: Two hundred and forty-eight magnetic resonance imagings (MRIs) of patients treated with a hyaluronic acid based MACT for lesions of the knee articular surface were considered. The MRIs belonged to 116 patients (mean age at surgery 28.6 +/- 10.3 years, average defect size 2.4 +/- 1.0 cm(2)), 57 affected by degenerative cartilage lesions, 27 traumatic and 32 were osteochondritis dissecans (OCD). MRI follow-up was performed from 6 to 108 months after treatment. Other than its presence or absence, the subchondral bone edema was evaluated using a 3-level grading considering extension and hyperintensity, and with the WORMS score edema classification. The IKDC subjective score was collected at the time of every MRI. RESULTS: An analysis of the entire MRI group showed that edema is not constantly present through the follow-up, but presents a particular and well-defined trend. Edema was present within the first 2 years and was then markedly reduced or disappeared at 2 and 3 years (p = 0.044). Afterwards the level of edema increased again (p < 0.0005) and remained steadily present at medium/long-term follow-up. Patellar lesions presented significantly lower edema (p = 0.012), whereas OCD lesions presented more edema at all follow-up (p = 0.002) and a different trend, with an increasing level of edema over time. No correlation was found between edema and clinical outcome. CONCLUSIONS: Edema after MACT is present during the first phases of cartilage maturation up to 2 years of follow-up, and then tends to disappear. However, after a few years, it tends to reappear. Less edema was found in the patella, whereas more edema was found in the OCD, where subchondral bone is primarily involved. Interestingly, the presence of edema was not correlated with a poorer clinical outcome. Whether this might be a prognostic factor at longer follow-up remains to be determined, but our results give some indication on what to expect on both MRI edema and clinical outcome after MACT. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 24337529 TI - Value of the serum I-FABP level for diagnosing acute mesenteric ischemia. AB - PURPOSE: This study examined the feasibility of using the serum intestinal fatty acid binding protein (I-FABP) level for the early diagnosis of acute mesenteric ischemia, and investigated whether it contributes to the clinical decision-making process. METHOD: Thirty patients diagnosed with acute mesenteric ischemia, 27 patients with other types of acute abdomen who presented with acute abdomen symptoms but were not diagnosed with acute mesenteric ischemia, and 20 healthy people were included in the study. Mesenteric ischemia was confirmed by a pathological evaluation in patients who underwent intestinal resection due to detection of mesenteric ischemia during surgery. RESULTS: There was no significant difference in the leukocyte counts and D-dimer levels between subjects with mesenteric ischemia and acute abdomen due to other causes (p > 0.05). There was a significant difference in the serum I-FABP level between these groups (p < 0.001). CONCLUSION: The I-FABP level is a more reliable parameter for diagnosing acute mesenteric ischemia compared to leukocytosis and D-dimer elevation. PMID- 24337530 TI - Association between traumatic brain injury and risk of posttraumatic stress disorder in active-duty Marines. AB - IMPORTANCE: Whether traumatic brain injury (TBI) is a risk factor for posttraumatic stress disorder (PTSD) has been difficult to determine because of the prevalence of comorbid conditions, overlapping symptoms, and cross-sectional samples. OBJECTIVE: To examine the extent to which self-reported predeployment and deployment-related TBI confers increased risk of PTSD when accounting for combat intensity and predeployment mental health symptoms. DESIGN, SETTING, AND PARTICIPANTS: As part of the prospective, longitudinal Marine Resiliency Study (June 2008 to May 2012), structured clinical interviews and self-report assessments were administered approximately 1 month before a 7-month deployment to Iraq or Afghanistan and again 3 to 6 months after deployment. The study was conducted at training areas on a Marine Corps base in southern California or at Veterans Affairs San Diego Medical Center. Participants for the final analytic sample were 1648 active-duty Marine and Navy servicemen who completed predeployment and postdeployment assessments. Reasons for exclusions were nondeployment (n = 34), missing data (n = 181), and rank of noncommissioned and commissioned officers (n = 66). MAIN OUTCOMES AND MEASURES: The primary outcome was the total score on the Clinician-Administered PTSD Scale (CAPS) 3 months after deployment. RESULTS: At the predeployment assessment, 56.8% of the participants reported prior TBI; at postdeployment assessment, 19.8% reported sustaining TBI between predeployment and postdeployment assessments (ie, deployment-related TBI). Approximately 87.2% of deployment-related TBIs were mild; 250 of 287 participants (87.1%) who reported posttraumatic amnesia reported less than 24 hours of posttraumatic amnesia (37 reported >= 24 hours), and 111 of 117 of those who lost consciousness (94.9%) reported less than 30 minutes of unconsciousness. Predeployment CAPS score and combat intensity score raised predicted 3-month postdeployment CAPS scores by factors of 1.02 (P < .001; 95% CI, 1.02-1.02) and 1.02 (P < .001; 95% CI, 1.01-1.02) per unit increase, respectively. Deployment-related mild TBI raised predicted CAPS scores by a factor of 1.23 (P < .001; 95% CI, 1.11-1.36), and moderate/severe TBI raised predicted scores by a factor of 1.71 (P < .001; 95% CI, 1.37-2.12). Probability of PTSD was highest for participants with severe predeployment symptoms, high combat intensity, and deployment-related TBI. Traumatic brain injury doubled or nearly doubled the PTSD rates for participants with less severe predeployment PTSD symptoms. CONCLUSIONS AND RELEVANCE: Even when accounting for predeployment symptoms, prior TBI, and combat intensity, TBI during the most recent deployment is the strongest predictor of postdeployment PTSD symptoms. PMID- 24337531 TI - Posterior septal resection: a simple surgical option for management of nasal septal perforation. AB - IMPORTANCE: Large and complex nasal septal perforations may cause considerable patient discomfort and are challenging to repair. Posterior septal resection (PSR) is a simple procedure and can be incorporated into the surgical management algorithm for this patient population. OBJECTIVE: To evaluate PSR for the treatment of symptomatic complex and large nasal septal perforations. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical chart review from 1995 through 2007 of patients who underwent PSR. Medical charts were reviewed, and a follow-up telephone questionnaire was performed. INTERVENTIONS: Posterior septal resection. MAIN OUTCOMES AND MEASURES: Improvement of selected symptoms after PSR. RESULTS: Twenty-one patients were identified, 16 patients had thorough documentation of perioperative information contained in their medical charts, and 12 patients were available for follow-up survey. All patients tolerated the procedure well without long-term sequelae from surgery. Overall nasal discomfort was significantly improved in 12 of 12 patients (P < .001). All nasal symptom scores of obstruction, pain, whistling, drainage, crusting, and epistaxis showed statistically significant (P < .05) improvement from preoperative values. Nasal obstruction and crusting were symptoms that improved with high statistical significance (P < .001). Patients reported on average a 79% improvement (range, 45%-100% improvement) in nasal airway, with only 1 patient reporting no improvement. All patients were satisfied with their surgery and would undergo the procedure again and recommend it to others. CONCLUSIONS AND RELEVANCE: Posterior septal resection provides overall patient satisfaction and improvement in subjective nasal symptom scores when used for large and complex septal perforations. This simple procedure may be included in the treatment algorithm of large and complex symptomatic septal perforations. PMID- 24337532 TI - Preoperative factors associated with red blood cell transfusion in hip fracture patients. AB - INTRODUCTION: Red blood cell (RBC) transfusion is a frequently used treatment in patients admitted with a fractured hip, but the use remains an area of much debate. The aim of this study was to determine preoperative factors associated with the risk of receiving a red blood cell transfusion in hip fracture patients. METHOD: The study included 986 consecutive hip fracture patients (aged 60 years or above). The patients were identified from a database of all hip fracture patients admitted to Bispebjerg University Hospital. Data for the database are collected via chart review and data extraction from the hospitals laboratory system, public registries and from the Capital Region Blood Bank Database. RESULTS: Overall transfusion rate was 58.7 %. The univariate analyses showed that transfusion rate was higher among women (p = 0.004), older patients (p < 0.0001), patients with high ASA scores (p < 0.0001), patients with more severe fractures (p < 0.0001), patients with lower admission haemoglobin levels (p < 0.0001), patients not admitted from own home (p = 0.02) and patients taking aspirin (p = 0.007) or other platelet inhibitors (p = 0.01) on admission. In the multivariate analysis, increasing age, ASA >=3, being admitted from own home, extracapsular fractures, decreasing admission haemoglobin and use of platelet inhibitors were all significantly associated with the risk of receiving a RBC transfusion. CONCLUSION: Several readily available preoperative factors in the form of age, residence, ASA, admission haemoglobin, medication and type of fracture were independently associated with the likelihood of receiving a red blood cell transfusion in patients admitted with a fractured hip. PMID- 24337533 TI - Investigation of the mechanism involved in the As2O3-regulated decrease in MDR1 expression in leukemia cells. AB - Arsenic trioxide (As2O3) inhibits the expression of P-glycoprotein (P-gp) in leukemia cells; however, the mechanism behind this inhibition is unclear. The present study aimed to explore the effect of As2O3 on the expression and regulation of P-gp in leukemia cells, and elucidate the mechanism of the reversal of drug resistance. In the present study, electrophoretic mobility shift assay results indicated that p65 binds to the NF-kappaB binding site of MDR1, specifically in K562/D cells. Expression of p65 and phosphorylated IkappaB was reduced, while the expression of IkappaB was increased in K562/D cells treated with As2O3. The activity of luciferase increased up to 9-fold with 40 ng/ml TNF alpha, and it was suppressed by ~25% following treatment with 1 uM As2O3. These findings suggest that As2O3 reverses the P-gp-induced drug resistance of leukemia cells through the NF-kappaB pathway. As2O3 may inhibit the activity of phosphorylase to inhibit IkappaB phosphorylation, thereby inhibiting NF-kappaB activity and MDR1 gene expression, leading to reversal of drug resistance. PMID- 24337534 TI - Evaluating principal surrogate endpoints with time-to-event data accounting for time-varying treatment efficacy. AB - Principal surrogate (PS) endpoints are relatively inexpensive and easy to measure study outcomes that can be used to reliably predict treatment effects on clinical endpoints of interest. Few statistical methods for assessing the validity of potential PSs utilize time-to-event clinical endpoint information and to our knowledge none allow for the characterization of time-varying treatment effects. We introduce the time-dependent and surrogate-dependent treatment efficacy curve, ${?mathrm {TE}}(t|s)$, and a new augmented trial design for assessing the quality of a biomarker as a PS. We propose a novel Weibull model and an estimated maximum likelihood method for estimation of the ${?mathrm {TE}}(t|s)$ curve. We describe the operating characteristics of our methods via simulations. We analyze data from the Diabetes Control and Complications Trial, in which we find evidence of a biomarker with value as a PS. PMID- 24337535 TI - Respiratory syncytial virus-related encephalitis: magnetic resonance imaging findings with diffusion-weighted study. AB - INTRODUCTION: Respiratory syncytial virus (RSV) is a common pathogen causing acute respiratory infection in children. Herein, we describe the incidence and clinical and magnetic resonance imaging (MRI) findings of RSV-related encephalitis, a major neurological complication of RSV infection. METHODS: We retrospectively reviewed the medical records and imaging findings of the patients over the past 7 years who are admitted to our medical center and are tested positive for RSV-RNA by reverse transcriptase PCR. In total, 3,856 patients were diagnosed with RSV bronchiolitis, and 28 of them underwent brain MRI for the evaluation of neurologic symptoms; 8 of these 28 patients had positive imaging findings. Five of these 8 patients were excluded because of non-RSV-related pathologies, such as subdural hemorrhage, brain volume loss due to status epilepticus, periventricular leukomalacia, preexisting ventriculomegaly, and hypoxic brain injury. RESULTS: The incidence of RSV-related encephalitis was as follows: 3/3,856 (0.08 %) of the patients are positive for RSV RNA, 3/28 (10.7 %) of the patient underwent brain MRI for neurological symptom, and 3/8 (37.5 %) of patients revealed abnormal MR findings. The imaging findings were suggestive of patterns of rhombenmesencephalitis, encephalitis with acute disseminated encephalomyelitis, and limbic encephalitis. They demonstrated no diffusion abnormality on diffusion-weighted image and symptom improvement on the follow-up study. CONCLUSION: Encephalitis with RSV bronchiolitis occurs rarely. However, on brain MRI performed upon suspicion of neurologic involvement, RSV encephalitis is not infrequently observed among the abnormal MR findings and may mimic other viral and limbic encephalitis. Physicians should be aware of this entity to ensure proper diagnosis and neurologic care of RSV-positive patients. PMID- 24337536 TI - Pitfalls of conservative treatments of multiple probable cerebral cavernous malformations (CCMs): clinicopathological features of CCMs coexisting with vasculogenic mimicry in an anaplastic oligodendroglioma. AB - Developments in magnetic resonance imaging (MRI) techniques have dramatically increased the detection of cerebral cavernous malformations (CCMs). Conservative treatment is often recommended for asymptomatic cases. However, CCMs occasionally harbor malignant gliomas. Here, we describe a rare case of multiple probable CCMs and an anaplastic oligodendroglioma (AO) showing vasculogenic mimicry (VM) and discuss the potential pitfalls of conservative treatments. A 42-year-old otherwise healthy woman presented with generalized seizures. Magnetic resonance imaging (MRI) revealed multiple parenchymal hypointensities, particularly in the right frontal lobe, with hyperintensity on fluid-attenuated inversion recovery (FLAIR) images. The patient was diagnosed with multiple probable CCMs, and conservative treatment was administered. However, follow-up MRI showed a slightly enlarged hyperintense area in the right frontal lobe. The patient then underwent surgery; histological diagnosis was CCMs and AO with VM. The patient subsequently underwent radiotherapy and chemotherapy. No neurological deficits or tumor recurrence were evident 21 months after surgery. We present this rare case and emphasize the possibility of the coexistence of malignant gliomas with CCMs. Close observation with MRI is essential in cases of multiple probable CCMs, and a histological confirmation should be considered in cases showing any enlargement of hyperintensity on FLAIR images. PMID- 24337537 TI - Prospective associations of depression with survival: a population-based cohort study in patients with newly diagnosed breast cancer. AB - Psychological factors may influence survival in breast cancer patients but results of previous research are inconclusive. This prospective population-based study tested whether depression predicts mortality in breast cancer patients. Routinely collected depression screening data were merged with electronically archived provincial cancer registry data and censored data from British Columbia Vital Statistics (extracted in December 2012). Cox proportional-hazards regression analyses were conducted to predict all-cause and breast cancer specific mortality as a function of depression after controlling for biomedical confounders. Of 1,646 patients, 1,604 had breast cancer stages I-III and 42 had stage IV breast cancer. 176 (11.0 %) versus 28 (66.7 %) were deceased after a median follow-up of 76 months. In patients with curable breast cancer, depression predicted all-cause (HR = 1.54 (95 % CI 1.06-2.25); p = 0.024), but not breast cancer-specific mortality (HR = 1.51 (95 % CI 0.95-2.41); p = 0.084). No association was shown for metastatic disease. Stage-specific analyses demonstrated a 2-2.5-fold increase in breast cancer-specific and all-cause mortality in patients with stage I and II disease, but not in patients with stage III or IV breast cancer. In stage I breast cancer patients, age moderated effects of depression such that depressed younger patients diagnosed at age 45 (i.e., mean age -1SD) showed a ninefold (HR = 9.82 (95 % CI 2.26-42.68); p = 0.002) increase in all-cause mortality and depressed patients at 57 a 3.7-fold (HR = 3.69 (95 % CI 1.44-9.48); p = 0.007) increase, while no association was evident in older patients at age 69 (mean age +1SD). Depression is strongly associated with mortality in younger patients with early stage breast cancer. PMID- 24337538 TI - The role of genes co-amplified with nicastrin in breast invasive carcinoma. AB - Breast cancer accounts for more than 450,000 deaths per year worldwide. Discovery of novel therapeutic targets that will allow patient-tailored treatment of this disease is an emerging area of scientific interest. Recently, nicastrin has been identified as one such therapeutic target. Its overexpression is indicative of worse overall survival in the estrogen-receptor-negative patient population. In this paper, we analyze data from a large invasive breast carcinoma study and confirm nicastrin amplification. In search for genes that are co-amplified with nicastrin, we identify a potential novel breast cancer-related amplicon located on chromosome 1. Furthermore, we search for "influential interactors," i.e., genes that interact with a statistically significantly high number of genes which are co-amplified with nicastrin, and confirm their involvement in this female neoplasm. Among the influential interactors, we find genes which belong to the core diseasome (a recently identified therapeutically relevant set of genes which is known to drive disease formation) and propose that they might be important for breast cancer onset, and serve as its novel therapeutic targets. Finally, we identify a pathway that may play a role in nicastrin's amplification process and we experimentally confirm downstream signaling mechanism of nicastrin in breast cancer cells. PMID- 24337539 TI - Spinal IFN-gamma-induced protein-10 (CXCL10) mediates metastatic breast cancer induced bone pain by activation of microglia in rat models. AB - Cancer-induced bone pain (CIBP) is a common clinical problem in breast cancer patients with bone metastasis. Recent studies shows chemokines are novel targets for treatment of CIBP. In this study, we intra-tibial inoculated with Walker 256 rat mammary gland carcinoma cells into rat bone to established metastatic breast cancer. Then we measured the expression of CXCL10 in the spinal cord of metastatic bone cancer rats, investigated the role of CXCL10 in the development of CIBP, and the underlying mechanism. Results revealed that after intra-tibial inoculation with Walker 256 cells, rats showed up-regulation of CXCL10 and its receptor CXCR3 in the spinal cord. Interestingly, intrathecally injection of recombinant CXCL10 protein induced mechanical allodynia in naive rats. Blocking the function of CXCL10/CXCR3 pathway via anti-CXCL10 antibody or CXCR3 antagonist prevented the development of CIBP and microglial activation. Moreover, CXCL10 induced mechanical allodynia was rescued by minocycline treatment during the late stage of CIBP, days 10-14. The regulation of CXCL10 expression involved microglial activation in a manner of autocrine positive feedback. These results suggest that CXCL10 may be a necessary algogenic molecule, especially in the development of CIBP. Its function was partly mediated via spinal microglial activation. This study provides a novel insight into the biological function of chemokine CXCL10 in the molecular mechanism underlying cancer pain. It also provides new target for clinical treatment of metastatic breast cancer-induced bone pain in future. PMID- 24337540 TI - CXCL13-CXCR5 co-expression regulates epithelial to mesenchymal transition of breast cancer cells during lymph node metastasis. AB - We investigated the expression of -CXC chemokine ligand 13 (CXCL13) and its receptor -CXC chemokine receptor 5 (CXCR5) in 98 breast cancer (BC) patients with infiltrating duct carcinoma, out of which 56 were found lymph node metastasis (LNM) positive. Interestingly, co-expression of CXCL13 and CXCR5 showed a significant correlation with LNM. Since, epithelial to mesenchymal transition (EMT) is highly associated with metastasis we investigated EMT-inducing potential of CXCL13 in BC cell lines. In CXCL13-stimulated BC cells, expression of various mesenchymal markers (Vimentin, N-cadherin), EMT regulators (Snail, Slug), and matrix metalloproteinase-9 (MMP9) was increased, whereas the expression of epithelial marker E-cadherin was found to be decreased. In addition, expression of receptor activator of nuclear factor kappa-B ligand (RANKL), which is known to regulate MMP9 expression via Src activation, was also significantly increased after CXCL13 stimulation. Using specific protein kinase inhibitors, we confirmed that CXCL13 stimulated EMT and MMP9 expression via RANKL-Src axis in BC cell lines. To further validate this observation, we examined gene expression patterns in primary breast tumors and detected significantly higher expression of various mesenchymal markers and regulators in CXCL13-CXCR5 co-expressing patients. Therefore, this study showed the EMT-inducing potential of CXCL13 as well as demonstrated the prognostic value of CXCL13-CXCR5 co-expression in primary BC. Moreover, CXCL13-CXCR5-RANKL-Src axis may present a therapeutic target in LNM positive BC patients. PMID- 24337542 TI - Risk factors associated with breast lymphedema. AB - BACKGROUND: The development of breast lymphedema (BLE) after breast/axillary surgery is poorly characterized. We prospectively evaluated clinical and surgical factors associated with development of BLE. METHODS: Patients undergoing unilateral breast-conserving surgery were prospectively enrolled preoperatively and followed for development of BLE. To augment the number of patients with BLE for evaluation of risk factors, postoperative patients identified in the clinic with signs and symptoms of BLE were also enrolled. Logistic regression with Firth's penalized likelihood bias-reduction method was used for univariate and multivariate analysis. RESULTS: Of 144 women, 124 were enrolled preoperatively (38 of whom developed BLE), and 20 women with BLE were enrolled postoperatively. Any type of axillary surgery was the strongest factor associated with BLE (odds ratio, 134; 95 % confidence interval, 18 to >1,000). All 58 BLE events occurred in women with axillary surgery as compared with no events in the 46 patients without axillary surgery (p < 0.0001). Among 98 women who underwent axillary surgery, BLE did not occur more often after axillary lymph node dissection versus sentinel lymph node biopsy (p = 0.38) and was not associated with total number of nodes removed (p = 0.52). In multivariate analysis, factors associated with the development of BLE in the axillary surgery subgroup included baseline BMI (p = 0.004), incision location (p = 0.009), and prior surgical biopsy (p = 0.01). CONCLUSIONS: Risk of BLE is primarily related to performance of any axillary surgery but not the extent of axillary surgery or number of lymph nodes removed. Other factors associated with BLE were increased body mass index, incision location, and prior surgical excisional biopsy. PMID- 24337541 TI - Male breast cancer: a population-based comparison with female breast cancer in Hong Kong, Southern China: 1997-2006. AB - BACKGROUND: Male breast cancer (MBC) is uncommon. As a result, there is limited availability of studies and reviews and even fewer reports from Asia. This is the largest population-based study to compare Chinese MBC patients with female patients during a 10-year period in Hong Kong, Southern China. METHODS: A retrospective review of medical records of 132 male and 8,118 female breast cancer patients between year 1997 and 2006 in Hong Kong was performed. Each MBC patient was matched with three female breast cancer patients for further analysis. Different characteristics, overall, breast-cancer specific, and disease free survivals (DFS) were compared. RESULTS: Mean age at diagnosis of male and female patients was 64.5 and 52.7 years respectively. Male patients showed lower histological grade, overall stage, smaller tumor size, and more positive sensitivity in hormone receptors. They were more likely to die of causes other than breast cancer. Matched analysis found that the 5-year overall survival (OS), breast-cancer-specific mortality, and DFS for male and female patients were 78.7, 90.5, 90.5, and 77.9, 86.4, and 81.4 % respectively. Male patients had poorer OS at early overall stage but better breast-cancer-specific mortality rates at any age (p < 0.01). Male patients had a significant risk of dying due to any cause in the presence of distant relapse and had less risk of dying when tumor was ER positive and HER2-positive. CONCLUSIONS: Chinese male breast cancer patients tend to have poorer OS but better breast-cancer-specific survival compared with their female counterparts. PMID- 24337543 TI - Effects of adenoviral vector expressing hIGF-1 on apoptosis in nucleus pulposus cells in vitro. AB - The excessive apoptosis of cells of the nucleus pulposus may plays an important role in intervertebral disc (IVD) degeneration. It has been shown that the pro inflammatory cytokine tumour necrosis factor (TNF)-alpha can induce disc cell apoptosis. Insulin-like growth factor (IGF)-1 can promote nucleus pulposus cell proliferation; however, whether or not IGF-1 inhibits TNF-alpha-induced apoptosis in the nucleus pulposus has not yet been elucidated. In this study, our objective was to create a potentially therapeutic viral vector, which could be used to achieve the enforced expression of IGF-1 in rabbit nucleus pulposus cells. Furthermore, we investigated the ability of IGF-1 to reverse TNF-alpha-induced apoptosis in cells of the nucleus pulposus. Isolated nucleus pulposus cells were cultured to a confluent monolayer, digested with collagenase II and purified using trypsin and differential adhesion methods. Nucleus pulposus cells were positively identified using type II collagen immunohistochemistry. Following transfection with adenoviral vectors engineered to overexpress recombinant human IGF-1 (Ad-hIGF-1) or TNF-alpha, the cells were observed under a light microscope. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) and flow cytometry (FCM) were used to assess the rate of apoptosis. The Ad-hIGF-1 viral vector was effectively transduced into the nucleus pulposus cells and increased IGF-1 expression as confirmed by RT-PCR and western blot analysis. In the TNF-alpha-treated group, a large number of apoptotic cells was observed that exhibited morphological changes associated with this form of cell death. Minimal apoptosis was observed in the Ad-hIGF-1-treated group and the control group showed no obvious signs of apoptosis. TUNEL assay revealed that the rate of apoptosis in the Ad-hIGF-1 group was significantly reduced compared with the TNF-alpha-treated group (P<0.01). This result was confirmed using FCM. The rate of apoptosis was also significantly increased in the TNF-alpha-exposed cells compared with the control group (P<0.01). Our findings strongly suggest that the adenoviral vector expressing hIGF-1 can successfully infect nucleus pulposus cells in vitro and effectively enhance the expression of IGF-1. In addition, IGF 1 reversed the TNF-alpha -induced apoptosis of nucleus pulposus cells. Thus, Ad hIGF-1 may be useful in the development of clinical interventions for disc degeneration. PMID- 24337544 TI - Shedding light on bioactivity of botanical by-products: neem cake compounds deter oviposition of the arbovirus vector Aedes albopictus (Diptera: Culicidae) in the field. AB - Industrial plant-borne by-products can be sources of low-cost chemicals, potentially useful to build eco-friendly control strategies against mosquitoes. Neem cake is a cheap by-product of neem oil extraction obtained by pressing the seeds of Azadirachta indica. Neem products are widely used as insecticides since rarely induce resistance because their multiple mode of action against insect pests and low-toxicity rates have been detected against vertebrates. In this research, we used field bioassays to assess the effective oviposition repellence of neem cake fractions of increasing polarity [n-hexane (A), methanol (B), ethyl acetate (C), n-butanol (D), and aqueous (E) fraction] against Aedes albopictus, currently the most invasive mosquito worldwide. These fractions, already characterized for low nortriterpenoids contents by HPLC analyses, were analyzed for their total content by HPTLC, highlighting striking differences in their chemical composition. Field results showed that B, A, and C tested at 100 ppm exerted higher effective repellence over the control (71.33, 88.59, and 73.49% of ER, respectively), while E and D did not significantly deter A. albopictus oviposition (17.06 and 22.72% of ER, respectively). The highest oviposition activity index was achieved by A (-0.82), followed by C (-0.63), and B (-0.62). Lower OAIs were achieved by D (-0.14) and E (-0.09). On the basis of our results, we believe that A, B, and C are very promising as oviposition deterrents against the arbovirus vector A. albopictus since they are proved as rich in active metabolites, cheap, and really effective at low doses. PMID- 24337545 TI - Haemoproteus infections (Haemosporida, Haemoproteidae) kill bird-biting mosquitoes. AB - Haemoproteus parasites (Haemosporida, Haemoproteidae) are widespread; some species cause severe diseases in avian hosts. Heavy Haemoproteus infections are often lethal for biting midges (Ceratopogonidae), which transmit avian haemoproteids, but there is no information regarding detrimental effect on other blood-sucking insects. We examined effects of Haemoproteus tartakovskyi (lineage hSISKIN1), Haemoproteus lanii (lineages hRB1and hRBS2) and Haemoproteus balmorali (lineage hCOLL3) on the survival of Ochlerotatus cantans, a widespread Eurasian mosquito. Wild-caught females were infected by allowing them to feed on naturally infected birds with light (0.01%) and high (3.0-9.6%) parasitaemia. Mosquitoes fed on uninfected birds were used as controls. Both experimental and control groups were maintained under the same laboratory conditions until 20 days post exposure (dpe). Dead insects were counted daily and used for parasitological examination and PCR-based testing. No difference was discernible in the survival rate of control mosquitoes and those fed on meal with light parasitaemia. There was a highly significant difference in the survival rate between the control group and all groups fed on meals with high parasitaemia, with the greatest mortality reported 1-3 dpe. For 4 dpe, the percentage of survived control mosquitoes (88%) was 2.2-, 3.6- and 4-fold greater than that of groups fed on meals with high parasitaemia of H. balmorali, H. tartakovskyi and H. lanii, respectively. Numerous ookinetes were observed in the gut area and adjacent tissues located in the head, thorax and abdomen of infected insects 0.5-1 dpe. The migrating parasites damage organs throughout the entire body of mosquitoes; that is the main reason of mortality. To the end of this study, 46% of mosquitoes survived in control group, but the survival rates of experimental mosquitoes fed on meals with high parasitaemia were between 2.6- and 5.8-fold lower. This study indicates that widespread Haemoproteus infections are markedly virulent for bird biting mosquitoes, which rapidly die after feeding on heavily infected blood meals. PMID- 24337547 TI - Flat lesions missed at conventional colonoscopy (CC) and visualized by CT colonography (CTC): a pictorial essay. AB - The purpose of this study is to describe our experience with cases of false negative findings at conventional colonoscopy (CC) that were identified by CT colonography (CTC). Conventional colonoscopy (CC) is the universally accepted gold-standard technique for the diagnosis of colonic polyps and cancers, however occasionally this method can generate false negative findings. We present examples of false negatives at CC, correctly identified by CT colonography (CTC), and later confirmed at a second endoscopy, describing the reasons of false negative, when possible. PMID- 24337546 TI - B lymphocyte compartments in the human splenic red pulp: capillary sheaths and periarteriolar regions. AB - The microvasculature of human spleens is still incompletely understood. Two enigmatic types of red pulp microvessels, penicillar arterioles and sheathed capillaries, have already been described in the nineteenth century without gaining much attention afterwards. We performed a detailed analysis of sheathed capillaries to clarify the cellular composition of their sheaths by immunohistological double-staining experiments. Capillary sheaths comprise three different cell types, namely specialized cuboidal CD271(++) inner sheath cells surrounded by CD271(-) macrophages and accumulations of B lymphocytes. The CD271(++) inner sheath cells express the chemokine CXCL13 in a unique single dot pattern. Sheath-associated B lymphocytes consist of IgM(+), IgD(++), and of "switched" cells. T lymphocytes do not accumulate in pericapillary sheaths. The predominant sheath-associated macrophage population is CD163(-)CD68(+) and thus differs from the majority of red pulp macrophages. The sheath-associated macrophages strongly express CD169 only in perifollicular sheaths, but not in sheaths located deeper in the red pulp. IgM(+), IgD(++), and "switched" B cells are also closely associated with red pulp arterioles characterized by the expression of smooth muscle actin in muscle cells and in branched periarteriolar stromal cells. Capillary sheaths are observed in a post-arteriolar position and appear to be of limited length. We suggest to change the term "Vagina periarteriolaris makrophagocytica" of the international histological and embryological terminologies to "Vagina pericapillaris." PMID- 24337548 TI - Rescuing failures: can large data sets provide the answer? PMID- 24337550 TI - [Thoracic and lumbar spinal injuries in children and adolescents]. AB - Spinal injuries are generally very rare in childhood. Fractures of the thoracic and lumbar spine occur mainly in older children and adolescents. Exact knowledge of the anatomy is essential for accurate diagnosis in still incomplete ossification. With increasing age the classification can be performed by using the AO classification over the age of 8 years. Neurological symptoms in the thoracic and lumbar spine occur mainly in adolescence. Conventional radiography is the standard diagnostic tool for thoracic and lumbar spinal injuries. With the appearance of abnormal neurological deficits magnetic resonance imaging (MRI) diagnostics should also be performed and for operative cases computed tomography (CT) scans are mandatory. The most common fractures of the thoracic and lumbar spine are compression fractures (type A) which can generally be treated conservatively due to the stable situation but unstable fractures of the thoracic and lumbar spine (types B and C) are stabilized dorsally (internal fixation). Ventral stabilization with vertebral body replacement is occasionally necessary in adolescents. Spinal injuries in children have a good overall prognosis. PMID- 24337551 TI - [Injuries of the pelvis and apophysis in childhood and adolescence]. AB - BACKGROUND: Pediatric pelvic fractures are rare injuries. Typically they are associated with high-energy trauma, which often leads to life-threatening injuries of other organs. Anatomical differences (e.g., greater elasticity, different stages of maturation, remodeling) account for the different fracture mechanisms, fracture management, and outcome in children. The AO Classification (International Association for Osteosynthesis) is useful and can be used as a basis for the treatment algorithm in pediatric pelvic fractures. AIM: This article provides a review on pediatric pelvic fractures and shows--based on the AO classification--principles of conservative und operative treatment. PMID- 24337552 TI - [Acetabulum injuries in infancy and childhood]. AB - In this article, the anatomical and morphological features of the acetabulum in infancy and childhood are presented. The pathology and treatment of older children and adolescents is deliberately not covered, because the fracture morphology and treatment of patients aged 13 to 15 years is based on the criteria of adult medicine. Especially in the younger child, the anatomical differences are of particular importance. The younger the child is, the more difficult the diagnosis. Therefore today, MRI examinations should be generous used, even if anesthesia is necessary. If the injured child is hemodynamic stable, anesthesia can be electively used for a more complex diagnosis. Acetabular fractures are particularly problematic in infancy because even with optimal treatment and perfect reduction growth disturbances can occur. These manifest as so-called secondary dysplasia. During treatment, care should be taken to ensure that a surgical team having experience with the infant and juvenile skeleton is available and that appropriate implants are available. PMID- 24337553 TI - [Subtrochanteric femoral fractures]. AB - Subtrochanteric femoral fractures are proximal femoral fractures which are located between the trochanter minor and an area of 3 cm below the minor trochanter on the femoral shaft. About 10-15% of all proximal femoral fractures correspond to this fracture site. Elderly or geriatric patients are generally affected and the injury is often the result of a fall in the home, while high energy trauma is the cause in a small group of generally younger patients. Clinical evaluation of the affected extremity shows disability of axial weight bearing and pain during compression and rotation of the hip joint. Basic diagnostics include conventional x-rays of the injured femur in the anterior posterior and lateral planes. These subtrochanteric femoral fractures are almost always treated surgically due to the inherent high degree of instability. The main goals of surgical intervention are to achieve anatomic fracture reduction and primary full weight-bearing stability of the corresponding leg. Intramedullary interlocking nails are used for primary treatment, while extramedullary implants are often used in revision surgery. Early mobilization and intensive respiratory exercises are necessary to prevent early postoperative complications. PMID- 24337554 TI - [Repositioning, reduction and surgical approaches for subtrochanteric femoral fractures]. PMID- 24337557 TI - Ophthalmic surgical simulation: a new era. AB - Simulation has been widely used to great effect in many high-risk industries and well validated in a number of medical disciplines. Different forms of medical simulation exist, from traditional wet laboratories, through immersive scenarios, to modern high-fidelity simulation such as virtual reality. What remains unestablished is the exact when, where, and how this technology should fit within recognized ophthalmic training systems. The International Forum of Ophthalmic Simulation is a multinational, multicenter collaborative established to introduce and evaluate virtual-reality simulation through a global cloud of networked simulators. In this article, we detail the modern evolution of virtual-reality simulation in ophthalmology and present the ultimate goal of the profession and the International Forum of Ophthalmic Simulation, which is to develop a virtual reality program that augments and accelerates surgical training, thereby improving outcomes for trainees, trainers, and patients. PMID- 24337558 TI - Evolution and impact of eye and vision terms in written English. AB - With this article, we aimed to trace the evolution and impact of eye-related terms common in written English during the past 2 centuries by studying digital resources. Eye-related words and phrases (n-grams) occurring in English books at a frequency of 0.00001% for at least 25 years between 1790 and 2008 were identified from the Google n-gram database by searching for 254 strings such as eye or ophth. The first known English use of these n-grams was identified from historical articles and from multiple digital resources. Eye color was not commonly described as brown or green before 1840. Many common bigrams, such as bright eyes, suggested light emanating from the eyes, consistent with the extramission theory of vision. Based on word frequency, the impact of the revolutionary 1850 ophthalmoscope exceeded that of the stethoscope for 60 years. Glaucoma was not commonly written until the ophthalmoscope permitted visualization of the characteristic optic neuropathy. Green spectacles gave way during the early 1900s to dark glasses, subsequently renamed sunglasses. Until the mid-1900s, an eye surgeon was more often described as an oculist than an ophthalmologist, and inflamed eyes were said to experience ophthalmia more often than uveitis. Macular degeneration was rarely written about for more than a century after 1850 because it was labeled choroiditis. Of the 135 n-grams in the dictionary, an earlier written instance was identified in 92 cases (68%). Online databases of the written word reveal the origin and impact of many important vision concepts. PMID- 24337559 TI - Subretinal pneumatic displacement of subretinal hemorrhage. AB - Massive submacular hemorrhage can cause disastrous visual complications. Prompt displacement away from the fovea is desirable in some patients. We describe a novel surgical technique involving subretinal air as a therapeutic adjuvant for massive submacular hemorrhage displacement. PMID- 24337560 TI - Smudge in my vision. PMID- 24337561 TI - Iris microhemangiomatosis with videographically documented active bleeding and vision loss. PMID- 24337562 TI - Clinical and genetic misdiagnosis of autosomal recessive bestrophinopathy. PMID- 24337563 TI - Management of ozurdex in the anterior chamber. PMID- 24337566 TI - Characterization of Golgi scaffold proteins and their roles in compartmentalizing cell signaling. AB - Subcellular compartmentalization has become an important theme in cell signaling. In particular, the Golgi apparatus (GA) plays a prominent role in compartmentalizing signaling cascades that originate at the plasma membrane or other organelles. To precisely regulate this process, cells have evolved a unique class of organizer proteins, termed "scaffold proteins". Sef, PAQR3, PAQR10 and PAQR11 are scaffold proteins that have recently been identified on the GA and are referred to as Golgi scaffolds. The major cell growth signaling pathways, such as Ras/MAPK, PI3K/AKT, insulin and VEGF (vascular endothelial growth factor), are tightly regulated spatially and temporally by these Golgi scaffolds to ensure a physiologically appropriate outcome. Here, we discuss the subcellular localization and characterization of the topology and functional domains of these Golgi scaffolds and summarize their roles in the compartmentalization of cell signaling. We also highlight the physiological and pathological roles of these Golgi scaffolds in tumorigenesis and developmental disorders. PMID- 24337567 TI - Neurodevelopmental and esthetic results in children after surgical correction of metopic suture synostosis: a single institutional experience. AB - INTRODUCTION: Metopic suture synostosis leading to trigonocephaly is considered the second most frequent type of craniosynostosis. Besides esthetic results, we present 25 consecutive pediatric cases operated upon metopic suture synostosis with a focus on the child's motor, speech, and neurocognitive development. METHODS: Twenty-five children (aged 6 to 33 months; median 9.2 months) with trigonocephaly were operated upon between 2002 and 2012 with fronto-orbital advancement including frontal bone cranioplasty and fronto-orbital bandeau remodeling. Neurodevelopmental deficits were evaluated by a standardized questionnaire including gross motor function, manual coordination, speech, and cognitive function performed by independent pediatric/developmental neurologists before surgery and at 6 and 12 months of time interval postoperatively. RESULTS: Twenty-one (84 %) boys and four (16 %) girls were included in this study. Mean follow-up period was 33 +/- 28 months. Outcome analysis for esthetic results showed a high degree of satisfaction by the parents and treating physicians in 23 cases (92 %). Preoperative evaluation revealed neurodevelopmental deficits in 10 children (40 %; six mild, four moderate degree). Twelve children (48 %) were proven to have a normal preoperative neuropediatric development. Mild or moderate developmental restraints were no longer apparent in 6/13, improved but still apparent in 3/13, and stable in 4/13, 6 months after cranial vault reconstruction. At 12 months of follow-up, deficits were no longer present in 9/13 and improved in 4/13. Apart from this cohort, two children were diagnosed with a syndromic form, and one child had a fetal valproate syndrome. In these three children, neurodevelopmental deficits were more pronounced. Neurocognitive progress was obvious, but was comparably slower, and major deficits were still apparent at last follow-up. All children with proven mild/moderate/severe deficits received intensive physiotherapy, logopedic, or neurobehavioral support. CONCLUSIONS: As shown in a single-center observation, surgical correction of metopic suture synostosis not only refines esthetic appearance but also might improve neurodevelopmental outcome if deficits are apparent, even in syndromic forms of the deformity under additional physiotherapy, logopedic, or neurobehavioral support. PMID- 24337568 TI - Organization of the mitochondrial apoptotic BAK pore: oligomerization of the BAK homodimers. AB - The multidomain pro-apoptotic Bcl-2 family proteins BAK and BAX are believed to form large oligomeric pores in the mitochondrial outer membrane during apoptosis. Formation of these pores results in the release of apoptotic factors including cytochrome c from the intermembrane space into the cytoplasm, where they initiate the cascade of events that lead to cell death. Using the site-directed spin labeling method of electron paramagnetic resonance (EPR) spectroscopy, we have determined the conformational changes that occur in BAK when the protein targets to the membrane and forms pores. The data showed that helices alpha1 and alpha6 disengage from the rest of the domain, leaving helices alpha2-alpha5 as a folded unit. Helices alpha2-alpha5 were shown to form a dimeric structure, which is structurally homologous to the recently reported BAX "BH3-in-groove homodimer." Furthermore, the EPR data and a chemical cross-linking study demonstrated the existence of a hitherto unknown interface between BAK BH3-in-groove homodimers in the oligomeric BAK. This novel interface involves the C termini of alpha3 and alpha5 helices. The results provide further insights into the organization of the BAK oligomeric pores by the BAK homodimers during mitochondrial apoptosis, enabling the proposal of a BAK-induced lipidic pore with the topography of a "worm hole." PMID- 24337569 TI - A role for peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) in the regulation of cardiac mitochondrial phospholipid biosynthesis. AB - The energy demands of the adult mammalian heart are met largely by ATP generated via oxidation of fatty acids in a high capacity mitochondrial system. Peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1)-alpha and -beta serve as inducible transcriptional coregulators of genes involved in mitochondrial biogenesis and metabolism. Whether PGC-1 plays a role in the regulation of mitochondrial structure is unknown. In this study, mice with combined deficiency of PGC-1alpha and PGC-1beta (PGC-1alphabeta(-/-)) in adult heart were analyzed. PGC-1alphabeta(-/-) hearts exhibited a distinctive mitochondrial cristae-stacking abnormality suggestive of a phospholipid abnormality as has been described in humans with genetic defects in cardiolipin (CL) synthesis (Barth syndrome). A subset of molecular species, containing n-3 polyunsaturated species in the CL, phosphatidylcholine, and phosphatidylethanolamine profiles, was reduced in PGC 1alphabeta-deficient hearts. Gene expression profiling of PGC-1alphabeta(-/-) hearts revealed reduced expression of the gene encoding CDP-diacylglycerol synthase 1 (Cds1), an enzyme that catalyzes the proximal step in CL biosynthesis. Cds1 gene promoter-reporter cotransfection experiments and chromatin immunoprecipitation studies demonstrated that PGC-1alpha coregulates estrogen related receptors to activate the transcription of the Cds1 gene. We conclude that the PGC-1/estrogen-related receptor axis coordinately regulates metabolic and membrane structural programs relevant to the maintenance of high capacity mitochondrial function in heart. PMID- 24337570 TI - Insig proteins mediate feedback inhibition of cholesterol synthesis in the intestine. AB - Enterocytes are the only cell type that must balance the de novo synthesis and absorption of cholesterol, although the coordinate regulation of these processes is not well understood. Our previous studies demonstrated that enterocytes respond to the pharmacological blockade of cholesterol absorption by ramping up de novo sterol synthesis through activation of sterol regulatory element-binding protein-2 (SREBP-2). Here, we genetically disrupt both Insig1 and Insig2 in the intestine, two closely related proteins that are required for the feedback inhibition of SREBP and HMG-CoA reductase (HMGR). This double knock-out was achieved by generating mice with an intestine-specific deletion of Insig1 using Villin-Cre in combination with a germ line deletion of Insig2. Deficiency of both Insigs in enterocytes resulted in constitutive activation of SREBP and HMGR, leading to an 11-fold increase in sterol synthesis in the small intestine and producing lipidosis of the intestinal crypts. The intestine-derived cholesterol accumulated in plasma and liver, leading to secondary feedback inhibition of hepatic SREBP2 activity. Pharmacological blockade of cholesterol absorption was unable to further induce the already elevated activities of SREBP-2 or HMGR in Insig-deficient enterocytes. These studies confirm the essential role of Insig proteins in the sterol homeostasis of enterocytes. PMID- 24337571 TI - The beta-glucanase ZgLamA from Zobellia galactanivorans evolved a bent active site adapted for efficient degradation of algal laminarin. AB - Laminarinase is commonly used to describe beta-1,3-glucanases widespread throughout Archaea, bacteria, and several eukaryotic lineages. Some beta-1,3 glucanases have already been structurally and biochemically characterized, but very few from organisms that are in contact with genuine laminarin, the storage polysaccharide of brown algae. Here we report the heterologous expression and subsequent biochemical and structural characterization of ZgLamAGH16 from Zobellia galactanivorans, the first GH16 laminarinase from a marine bacterium associated with seaweeds. ZgLamAGH16 contains a unique additional loop, compared with other GH16 laminarinases, which is composed of 17 amino acids and gives a bent shape to the active site cleft of the enzyme. This particular topology is perfectly adapted to the U-shaped conformation of laminarin chains in solution and thus explains the predominant specificity of ZgLamAGH16 for this substrate. The three-dimensional structure of the enzyme and two enzyme-substrate complexes, one with laminaritetraose and the other with a trisaccharide of 1,3-1,4-beta-d glucan, have been determined at 1.5, 1.35, and 1.13 A resolution, respectively. The structural comparison of substrate recognition pattern between these complexes allows the proposition that ZgLamAGH16 likely diverged from an ancestral broad specificity GH16 beta-glucanase and evolved toward a bent active site topology adapted to efficient degradation of algal laminarin. PMID- 24337572 TI - Dynamic structural changes underpin photoconversion of a blue/green cyanobacteriochrome between its dark and photoactivated states. AB - The phytochrome superfamily of photoreceptors exploits reversible light-driven changes in the bilin chromophore to initiate a variety of signaling cascades. The nature of these alterations and how they impact the protein moiety remain poorly resolved and might include several species-specific routes. Here, we provide a detailed picture of photoconversion for the photosensing cGMP phosphodiesterase/adenylyl cyclase/FhlA (GAF) domain from Thermosynechococcus elongatus (Te) PixJ, a member of the cyanobacteriochrome clade. Solution NMR structures of the blue light-absorbing dark state Pb and green light-absorbing photoactivated state Pg, combined with paired crystallographic models, revealed that the bilin and GAF domain dynamically transition via breakage of the C10/Cys 494 thioether bond, opposite rotations of the A and D pyrrole rings, sliding of the bilin in the GAF pocket, and the appearance of an extended region of disorder that includes Cys-494. Changes in GAF domain backbone dynamics were also observed that are likely important for inter-domain signal propagation. Taken together, photoconversion of T. elongatus PixJ from Pb to Pg involves complex structural changes within the GAF domain pocket that transduce light into a mechanical signal, many aspects of which should be relevant to others within the extended phytochrome superfamily. PMID- 24337573 TI - Chondroitin sulfate proteoglycan tenascin-R regulates glutamate uptake by adult brain astrocytes. AB - In our previous study, the CS-56 antibody, which recognizes a chondroitin sulfate moiety, labeled a subset of adult brain astrocytes, yielding a patchy extracellular matrix pattern. To explore the molecular nature of CS-56-labeled glycoproteins, we purified glycoproteins of the adult mouse cerebral cortex using a combination of anion-exchange, charge-transfer, and size-exclusion chromatographies. One of the purified proteins was identified as tenascin-R (TNR) by mass spectrometric analysis. When we compared TNR mRNA expression patterns with the distribution patterns of CS-56-positive cells, TNR mRNA was detected in CS-56-positive astrocytes. To examine the functions of TNR in astrocytes, we first confirmed that cultured astrocytes also expressed TNR protein. TNR knockdown by siRNA expression significantly reduced glutamate uptake in cultured astrocytes. Furthermore, expression of mRNA and protein of excitatory amino acid transporter 1 (GLAST), which is a major component of astrocytic glutamate transporters, was reduced by TNR knockdown. Our results suggest that TNR is expressed in a subset of astrocytes and contributes to glutamate homeostasis by regulating astrocytic GLAST expression. PMID- 24337574 TI - Tumor necrosis factor and transforming growth factor beta regulate clock genes by controlling the expression of the cold inducible RNA-binding protein (CIRBP). AB - The circadian clock drives the rhythmic expression of a broad array of genes that orchestrate metabolism, sleep wake behavior, and the immune response. Clock genes are transcriptional regulators engaged in the generation of circadian rhythms. The cold inducible RNA-binding protein (CIRBP) guarantees high amplitude expression of clock. The cytokines TNF and TGFbeta impair the expression of clock genes, namely the period genes and the proline- and acidic amino acid-rich basic leucine zipper (PAR-bZip) clock-controlled genes. Here, we show that TNF and TGFbeta impair the expression of Cirbp in fibroblasts and neuronal cells. IL 1beta, IL-6, IFNalpha, and IFNgamma do not exert such effects. Depletion of Cirbp is found to increase the susceptibility of cells to the TNF-mediated inhibition of high amplitude expression of clock genes and modulates the TNF-induced cytokine response. Our findings reveal a new mechanism of cytokine-regulated expression of clock genes. PMID- 24337575 TI - Proteasome inhibition increases recruitment of IkappaB kinase beta (IKKbeta), S536P-p65, and transcription factor EGR1 to interleukin-8 (IL-8) promoter, resulting in increased IL-8 production in ovarian cancer cells. AB - Proinflammatory and pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8) contributes to ovarian cancer progression through its induction of tumor cell proliferation, survival, angiogenesis, and metastasis. Proteasome inhibition by bortezomib, which has been used as a frontline therapy in multiple myeloma, has shown only limited effectiveness in ovarian cancer and other solid tumors. However, the responsible mechanisms remain elusive. Here, we show that proteasome inhibition dramatically increases the IL-8 expression and release in ovarian cancer cells. The responsible mechanism involves an increased nuclear accumulation of IkappaB kinase beta (IKKbeta) and an increased recruitment of the nuclear IKKbeta, p65-phosphorylated at Ser-536, and the transcription factor early growth response-1 (EGR-1) to the endogenous IL-8 promoter. Coimmunoprecipitation studies identified the nuclear EGR-1 associated with IKKbeta and with p65, with preferential binding to S536P-p65. Both IKKbeta activity and EGR-1 expression are required for the increased IL-8 expression induced by proteasome inhibition in ovarian cancer cells. Interestingly, in multiple myeloma cells the IL-8 release is not increased by bortezomib. Together, these data indicate that the increased IL-8 release may represent one of the underlying mechanisms responsible for the decreased effectiveness of proteasome inhibition in ovarian cancer treatment and identify IKKbeta and EGR-1 as potential new targets in ovarian cancer combination therapies. PMID- 24337576 TI - Chorismate pyruvate-lyase and 4-hydroxy-3-solanesylbenzoate decarboxylase are required for plastoquinone biosynthesis in the cyanobacterium Synechocystis sp. PCC6803. AB - Plastoquinone is a redox active lipid that serves as electron transporter in the bifunctional photosynthetic-respiratory transport chain of cyanobacteria. To examine the role of genes potentially involved in cyanobacterial plastoquinone biosynthesis, we have focused on three Synechocystis sp. PCC 6803 genes likely encoding a chorismate pyruvate-lyase (sll1797) and two 4-hydroxy-3 solanesylbenzoate decarboxylases (slr1099 and sll0936). The functions of the encoded proteins were investigated by complementation experiments with Escherichia coli mutants, by the in vitro enzyme assays with the recombinant proteins, and by the development of Synechocystis sp. single-gene knock-out mutants. Our results demonstrate that sll1797 encodes a chorismate pyruvate lyase. In the respective knock-out mutant, plastoquinone was hardly detectable, and the mutant required 4-hydroxybenzoate for growth underlining the importance of chorismate pyruvate-lyase to initiate plastoquinone biosynthesis in cyanobacteria. The recombinant Slr1099 protein displayed decarboxylase activity and catalyzed in vitro the decarboxylation of 4-hydroxy-3-prenylbenzoate with different prenyl side chain lengths. In contrast to Slr1099, the recombinant Sll0936 protein did not show decarboxylase activity regardless of the conditions used. Inactivation of the sll0936 gene in Synechocystis sp., however, caused a drastic reduction in the plastoquinone content to levels very similar to those determined in the slr1099 knock-out mutant. This proves that not only slr1099 but also sll0936 is required for plastoquinone synthesis in the cyanobacterium. In summary, our data demonstrate that cyanobacteria produce plastoquinone exclusively via a pathway that is in the first reaction steps almost identical to ubiquinone biosynthesis in E. coli with conversion of chorismate to 4 hydroxybenzoate, which is then prenylated and decarboxylated. PMID- 24337577 TI - Protein interaction screening for the ankyrin repeats and suppressor of cytokine signaling (SOCS) box (ASB) family identify Asb11 as a novel endoplasmic reticulum resident ubiquitin ligase. AB - The ankyrin and SOCS (suppressor of cytokine signaling) box (ASB) family of proteins function as the substrate recognition subunit in a subset of Elongin Cullin-SOCS (ECS) E3 ubiquitin ligases. Despite counting 18 members in humans, the identity of the physiological targets of the Asb proteins remains largely unexplored. To increase our understanding of the function of ASB proteins, we conducted a family-wide SILAC (stable isotope labeling by amino acids in cell culture)-based protein/protein interaction analysis. This investigation led to the identification of novel as well as known ASB-associated proteins like Cullin 5 and Elongins B/C. We observed that several proteins can be bound by more than one Asb protein. The additional exploration of this phenomenon demonstrated that ASB-Cullin 5 complexes can oligomerize and provides evidence that Cullin 5 forms heterodimeric complexes with the Cullin 4a-DDB1 complex. We also demonstrated that ASB11 is a novel endoplasmic reticulum-associated ubiquitin ligase with the ability to interact and promote the ubiquitination of Ribophorin 1, an integral protein of the oligosaccharyltransferase (OST) glycosylation complex. Moreover, expression of ASB11 can increase Ribophorin 1 protein turnover in vivo. In summary, we provide a comprehensive protein/protein interaction data resource that can aid the biological and functional characterization of ASB ubiquitin ligases. PMID- 24337578 TI - Toll-like receptor agonists promote prolonged triglyceride storage in macrophages. AB - Macrophages in infected tissues may sense microbial molecules that significantly alter their metabolism. In a seeming paradox, these critical host defense cells often respond by increasing glucose catabolism while simultaneously storing fatty acids (FA) as triglycerides (TAG) in lipid droplets. We used a load-chase strategy to study the mechanisms that promote long term retention of TAG in murine and human macrophages. Toll-like receptor (TLR)1/2, TLR3, and TLR4 agonists all induced the cells to retain TAG for >=3 days. Prolonged TAG retention was accompanied by the following: (a) enhanced FA uptake and FA incorporation into TAG, with long lasting increases in acyl-CoA synthetase long 1 (ACSL1) and diacylglycerol acyltransferase-2 (DGAT2), and (b) decreases in lipolysis and FA beta-oxidation that paralleled a prolonged drop in adipose triglyceride lipase (ATGL). TLR agonist-induced TAG storage is a multifaceted process that persists long after most early pro-inflammatory responses have subsided and may contribute to the formation of "lipid-laden" macrophages in infected tissues. PMID- 24337580 TI - Amino acids activate mammalian target of rapamycin (mTOR) complex 1 without changing Rag GTPase guanyl nucleotide charging. AB - Activation of mammalian target of rapamycin complex 1 (mTORC1) by amino acids is mediated in part by the Rag GTPases, which bind the raptor subunit of mTORC1 in an amino acid-stimulated manner and promote mTORC1 interaction with Rheb-GTP, the immediate activator. Here we examine whether the ability of amino acids to regulate mTORC1 binding to Rag and mTORC1 activation is due to the regulation of Rag guanyl nucleotide charging. Rag heterodimers in vitro exhibit a very rapid, spontaneous exchange of guanyl nucleotides and an inability to hydrolyze GTP. Mutation of the Rag P-loop corresponding to Ras(Ser-17) abolishes guanyl nucleotide binding. Such a mutation in RagA or RagB inhibits, whereas in RagC or RagD it enhances, Rag heterodimer binding to mTORC1. The binding of wild-type and mutant Rag heterodimers to mTORC1 in vitro parallels that seen with transient expression, but binding to mTORC1 in vitro is entirely independent of Rag guanyl nucleotide charging. HeLa cells stably overexpressing wild-type or P-loop mutant RagC exhibit unaltered amino acid regulation of mTORC1. Despite amino acid independent raptor binding to Rag, mTORC1 is inhibited by amino acid withdrawal as in parental cells. Rag heterodimers extracted from (32)P-labeled whole cells, or just from the pool associated with the lysosomal membrane, exhibit constitutive [(32)P]GTP charging that is unaltered by amino acid withdrawal. Thus, amino acids promote mTORC1 activation without altering Rag GTP charging. Raptor binding to Rag, although necessary, is not sufficient for mTORC1 activation. Additional amino acid-dependent steps couple Rag-mTORC1 to Rheb-GTP. PMID- 24337579 TI - Elevated protein kinase D3 (PKD3) expression supports proliferation of triple negative breast cancer cells and contributes to mTORC1-S6K1 pathway activation. AB - Here, we show that the expression of the Golgi-localized serine-threonine kinase protein kinase D3 (PKD3) is elevated in triple-negative breast cancer (TNBC). Using an antibody array, we identified PKD3 to trigger the activation of S6 kinase 1 (S6K1), a main downstream target of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. Accordingly, PKD3 knockdown in TNBC cells led to reduced S6K1 phosphorylation, which was associated with impaired activation of mTORC1 at endolysosomal membranes, the accumulation of the mannose 6-phosphate receptor in and the recruitment of the autophagy marker light chain 3 to enlarged acidic vesicles. We further show that PKD3 depletion strongly inhibited cell spreading and proliferation of TNBC cells, identifying this kinase as a potential novel molecular therapeutic target in TNBC. Together, our data suggest that PKD3 in TNBC cells provides a molecular connection between the Golgi and endolysosomal compartments to enhance proliferative mTORC1-S6K1 signaling. PMID- 24337581 TI - The nitrogen-regulated response regulator NrrA controls cyanophycin synthesis and glycogen catabolism in the cyanobacterium Synechocystis sp. PCC 6803. AB - The cellular metabolism in cyanobacteria is extensively regulated in response to changes of environmental nitrogen availability. Multiple regulators are involved in this process, including a nitrogen-regulated response regulator NrrA. However, the regulatory role of NrrA in most cyanobacteria remains to be elucidated. In this study, we combined a comparative genomic reconstruction of NrrA regulons in 15 diverse cyanobacterial species with detailed experimental characterization of NrrA-mediated regulation in Synechocystis sp. PCC 6803. The reconstructed NrrA regulons in most species included the genes involved in glycogen catabolism, central carbon metabolism, amino acid biosynthesis, and protein degradation. A predicted NrrA-binding motif consisting of two direct repeats of TG(T/A)CA separated by an 8-bp A/T-rich spacer was verified by in vitro binding assays with purified NrrA protein. The predicted target genes of NrrA in Synechocystis sp. PCC 6803 were experimentally validated by comparing the transcript levels and enzyme activities between the wild-type and nrrA-inactivated mutant strains. The effect of NrrA deficiency on intracellular contents of arginine, cyanophycin, and glycogen was studied. Severe impairments in arginine synthesis and cyanophycin accumulation were observed in the nrrA-inactivated mutant. The nrrA inactivation also resulted in a significantly decreased rate of glycogen degradation. Our results indicate that by directly up-regulating expression of the genes involved in arginine synthesis, glycogen degradation, and glycolysis, NrrA controls cyanophycin accumulation and glycogen catabolism in Synechocystis sp. PCC 6803. It is suggested that NrrA plays a role in coordinating the synthesis and degradation of nitrogen and carbon reserves in cyanobacteria. PMID- 24337582 TI - Increased ribozyme activity in crowded solutions. AB - Noncoding RNAs must function in the crowded environment of the cell. Previous small-angle x-ray scattering experiments showed that molecular crowders stabilize the structure of the Azoarcus group I ribozyme, allowing the ribozyme to fold at low physiological Mg(2+) concentrations. Here, we used an RNA cleavage assay to show that the PEG and Ficoll crowder molecules increased the biochemical activity of the ribozyme, whereas sucrose did not. Crowding lowered the Mg(2+) threshold at which activity was detected and increased total RNA cleavage at high Mg(2+) concentrations sufficient to fold the RNA in crowded or dilute solution. After correcting for solution viscosity, the observed reaction rate was proportional to the fraction of active ribozyme. We conclude that molecular crowders stabilize the native ribozyme and favor the active structure relative to compact inactive folding intermediates. PMID- 24337583 TI - Correlates of secondhand tobacco smoke exposure among individuals with a history of substance use and/or psychiatric disorders participating in a tobacco treatment program in Vancouver, Canada. AB - Individuals with substance use (SUD) and/or psychiatric disorders (PD) are disproportionately affected by tobacco use; yet, little is known about secondhand tobacco smoke (SHS) exposure in these populations. An analysis of existing data examined SHS exposure among 497 smokers in community clinics in Vancouver, Canada. Seventy-percent of the participants reported SHS exposure. In sex stratified multivariate logistic regression analyses correlates of SHS exposure among women were not having a history of using evidence-based smoking cessation treatment and using a single substance (as compared to a polysubstance use history); whereas among men, a history of a respiratory illness and higher nicotine dependence were associated with SHS exposure. Despite limitations about the measures of SHS exposure used in the study, these findings suggest a need to further determine the risks associated with SHS exposure and tobacco use among individuals with SUD and/or PD within mental health and addictions treatment settings. PMID- 24337584 TI - Bone morphogenetic protein 9 regulates tumor growth of osteosarcoma cells through the Wnt/beta-catenin pathway. AB - Bone morphogenetic protein 9 (BMP9) is a member of the transforming growth factor beta (TGF-beta) family, which has been shown to regulate the progression of several tumors. Recent studies indicated that BMP9 affects osteosarcoma (OS) processes, but its specific roles and molecular mechanisms have yet to be fully elucidated. The human OS cell lines 143B and MG63 were used for the present study. We found that BMP9 overexpression suppressed the growth of OS cells, whereas inhibition of BMP9 reversed this effect. Our results also showed that BMP9 overexpression induced G0/G1 phase arrest and apoptosis in OS cells. We further investigated the possible molecular mechanisms mediating the biological role of BMP9. We observed that BMP9 overexpression reduced beta-catenin mRNA and protein levels, and also downregulated its downstream proteins c-Myc and osteoprotegerin (OPG) and inhibited the phosphorylation levels of GSK-3beta (Ser 9) in OS cells, whereas inhibition of BMP9 reversed these effects. Moreover, the suppressive effects of BMP9 overexpression on OS cells was reversed by exogenous beta-catenin expression, but augmented by beta-catenin silencing. In conclusion, our results revealed that BMP9 can regulate tumor growth of OS cells through the Wnt/beta-catenin pathway. Therefore, BMP9 may be a new therapeutic target in OS. PMID- 24337586 TI - Pelvic floor muscle function in women with pelvic floor dysfunction: a retrospective chart review, 1992-2008. AB - INTRODUCTION AND HYPOTHESIS: The objectives of this study were to investigate the level of pelvic floor muscle (PFM) function in women with pelvic floor dysfunction (PFD) referred by gynaecologists and urologists for in-hospital pelvic floor muscle training (PFMT), and to identity associated factors for a low level of PFM function. METHODS: Data of women with PFD referred to a PFMT programme were included in a retrospective chart review. Measurement of PFM function performed by digital vaginal palpation included: voluntary PFM contraction, PFM strength (Modified Oxford Grading Scale) and PFM static endurance. RESULTS: Data of 998 women, mean age 56 (SD 13) years, with PFD (urinary incontinence, n = 757, anal incontinence, n = 36, pelvic organ prolapse, n = 111, other PFD, n = 94) were analysed. In all, 690 women (70%) were, at baseline, unable to perform correct voluntary PFM contraction, mean PFM strength was 1.5 (SD 1.0) points, mean PFM static endurance was 16.7 (SD 16.1) seconds. Age >= 65 years and year of referral > 2000 were significantly (p < 0.01) associated with the ability to perform correct PFM contraction. Likewise, year of referral was significantly associated with high PFM strength (p < 0.01). CONCLUSIONS: The majority of the women were unable to perform correct voluntary PFM contraction and almost all had low PFM strength. The most important factor associated with a low level of PFM function was age. PMID- 24337585 TI - Perineal body length as a risk factor for ultrasound-diagnosed anal sphincter tear at first delivery. AB - INTRODUCTION AND HYPOTHESIS: Shortened perineal body (PB) is associated with an increased risk of ultrasound-detected obstetric anal sphincter tear. The objective was to determine if shortened perineal body length (<3 cm) is a risk factor for ultrasound-detected anal sphincter tear at first delivery. METHODS: Pregnant nulliparous women were recruited over 18 months. At 35-37 weeks' gestation and 6 weeks' postpartum perineal body length (PB) was measured and subjects completed quality of life questionnaires. Primary outcome was ultrasound diagnosed anal sphincter tear at 6 weeks postpartum. Secondary outcomes were also assessed. A priori power analysis determined that 70 subjects were needed to detect a difference in anal sphincter tear based on a PB cut-off of 3 cm. RESULTS: Seventy-three subjects completed the study. Mode of delivery was 69.9% spontaneous vaginal, 15.1% operative vaginal, and 15.1% labored cesarean. There were 25 anal sphincter abnormalities (34.2%) seen on ultrasound: 11 (15.1%) internal or external sphincter tears, 3 (4.1%) internal sphincter atrophy, 6 (8.2%) external sphincter thinning, and 7 (9.6%) external sphincter scarring. Only the 11 sphincter tears qualified as abnormal for the primary outcome. In the vaginal delivery group 16.4% (10 out of 61) had a sphincter tear, compared with 8.3% (1 out of 12) in the labored cesarean group (p = 0.68). Women with PB < 3 had a significantly higher rate of ultrasound-diagnosed anal sphincter tear (40.0% vs 11.1%, p = 0.038). When comparing women with and without sphincter tear, there was a significant difference in mean antepartum PB (3.1 vs 3.7 cm, p = 0.043). CONCLUSIONS: A shortened perineal body length in primiparous women is associated with an increased risk of anal sphincter tear at the time of first delivery. PMID- 24337587 TI - beta-catenin mediates the inflammatory cytokine expression induced by the Der p 1 house dust mite allergen. AB - The modulations of beta-catenin were analyzed during the inflammatory response induced by the Der p 1 house dust mite allergen. Der p 1 induced the dose dependent expression of inflammatory cytokines, including interleukin (IL)-6, IL 8, monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) in THP-1 human monocytic cells. The mRNA expression levels of beta catenin were not altered, however protein levels increased following Der p 1 treatment, demonstrating that beta-catenin was modulated by post-transcriptional processes. It was also revealed that nuclear beta-catenin levels were significantly increased while cytoplasmic beta-catenin levels were reduced, which demonstrated the nuclear translocation of beta-catenin by the Der p 1 allergen. Glycogen synthase kinase 3beta (GSK3beta), a regulator of beta-catenin stability, was demonstrated to be phosphorylated following Der p 1 treatment. When beta catenin was knocked down by the transfection of its small interfering RNA (siRNA), inflammatory cytokine expression as well as nuclear factor-kappaB (NF kappaB) activity, which were induced by Der p 1 treatment, were all significantly reduced. The results demonstrated that Der p 1-induced inflammatory responses were mediated by beta-catenin. PMID- 24337588 TI - Simultaneous avulsion fracture of the posterior medial and posterior lateral meniscus root: a case report and review of the literature. AB - Injuries of the meniscus roots are increasingly recognized as a serious knee joint pathology. An avulsion fracture of the meniscus root is a rare variant of this injury pattern. In this article, a case of a traumatic simultaneous avulsion fracture of both the posterior medial and posterior lateral meniscus root associated with a tear of the anterior cruciate ligament is presented. Both avulsion fractures were treated by indirect arthroscopic transtibial pullout fixation of the bony fragment. Based on the findings of our literature review, root avulsion fractures seem to be more common in young male patients after an acute trauma to the knee joint. PMID- 24337589 TI - Open-label, randomized, single-dose, crossover study to evaluate the pharmacokinetics and safety differences between two docetaxel products, CKD-810 and Taxotere injection, in patients with advanced solid cancer. AB - PURPOSE: The aim of this study was to compare CKD-810 (test docetaxel) with Taxotere((r)) (reference docetaxel) in terms of pharmacokinetics and safety for patients with advanced or metastatic carcinoma. METHODS: A randomized, open label, two-way crossover study was conducted in eligible patients. Patients received with reference or test drugs of 75 mg/m(2) docetaxel by intravenous infusion for 60 min in the first period and the alternative drug in the second period with a washout of 3 weeks. Plasma concentrations of docetaxel were determined by validated high-performance liquid chromatography coupled to tandem mass spectrometry detection. Pharmacokinetic parameters, including the maximum plasma concentration (C(max)) and the area under the concentration-time curve (AUC), were determined by non-compartmental analysis. RESULTS: A total of 44 patients were included in the study, 21 patients received test drug and 23 received reference drug for the first cycle. The C(max) of docetaxel was 2,658.77 ng/mL for test drug and 2,827.60 ng/mL for reference drug, and two drugs showed no difference with a statistical significance. Time to reach C(max) (T(max)) of CKD-810 (0.94 h) versus reference docetaxel (0.97 h) was also not significantly different. Other pharmacokinetic parameters including the plasma AUC, elimination half-life, and total body clearance exhibited similar values without a significant difference. The most common grade 3 or 4 toxicity was neutropenia (CKD-810 19.5 or 29.3 %; reference docetaxel 14.6 or 41.5 %). Febrile neutropenia was experienced by only one patient in each group. Two patients died of progression of disease during the study. CONCLUSION: Docetaxel anhydrous CKD-810 use with patients suffering advanced or metastatic solid malignancies was equivalent to reference docetaxel in terms of pharmacokinetic parameters and safety profile. Additionally, the test and reference drug met the regulatory criteria for pharmacokinetic equivalence. PMID- 24337590 TI - Effects of immune modulation therapy in the first Croatian infant diagnosed with Pompe disease: a 3-year follow-up study. AB - Pompe disease is a storage disorder characterized by deficient or absent activity of the enzyme acid alpha-glucosidase. As a result of ineffective metabolism, glycogen accumulates in muscle tissues. Patients with a classic infantile-onset form present by the first few months of life with hypertrophic cardiomyopathy and muscle weakness. If left untreated, these patients rapidly die of cardiorespiratory failure. A cross-reactive immunological material (CRIM) negative status is predictive of high anti-alglucosidase alpha antibody titers. However, CRIM-positive patients also sometimes develop robust antibody titers. High antibody titers complicate therapeutic management, and those patients have a worse clinical outcome of enzyme replacement therapy (ERT).Four years ago, we successfully used an immune modulation therapy (IMT) protocol in a CRIM-positive infantile-onset patient with Pompe disease in whom ERT had to be discontinued because of severe infusion-associated reactions. She was found to be positive for anti-alglucosidase alpha antibodies. IMT (rituximab, methotrexate, and intravenous gammaglobulin) was started, and ERT was safely reintroduced during the IMT induction phase without any complications. Antibodies disappeared; IMT was tapered and discontinued; and cardiomyopathy steadily improved. During more than 3 years of follow-up, she remained ventilator dependent, and no gains in motor skills were noticed. The antibodies are still undetectable, and no adverse reactions associated with IMT had occurred. The cardiomyopathy is gradually increasing, but there is still ~ 50 % reduction as compared with the highest value measured. Although the reversal of clinical decline in our CRIM-positive and antibody-positive infant cannot be solely attributed to IMT, this protocol proved itself efficient and safe. PMID- 24337591 TI - Almanac 2013: novel non-coronary cardiac interventions. AB - Recent innovations in interventional cardiology have dramatically expanded the therapeutic options for patients with cardiac conditions. Interventional cardiology is no longer limited to the treatment of coronary artery disease but allows also treatment of valvular disease, stroke prevention, hypertension, etc. One of the most important new treatment options is the percutaneous treatment for aortic valve stenosis (transcatheter aortic valve implantation), since aortic valve disease is a rather common problem in elderly patients, with many of them at high risk for surgery. Similarly, mitral regurgitation is often associated with comorbidities which make surgery high risk. The MitraClip is a promising percutaneous alternative to surgical valve repair or replacement. Other procedures discussed in this review are the percutaneous left atrial appendage closure as a non-pharmacologic therapy to prevent strokes, and renal denervation for resistant hypertension. This review explains the basic principles of these procedures, the most important clinical evidence, and also provides additional recent clinical data on each of these them. PMID- 24337593 TI - Mean platelet volume may be confused in many conditions. PMID- 24337594 TI - Endoscopic approaches to the craniovertebral junction. PMID- 24337595 TI - Resection in glioblastoma: maximal or safe. PMID- 24337596 TI - Estrogen receptor (ER) mRNA expression and molecular subtype distribution in ER negative/progesterone receptor-positive breast cancers. AB - We examined estrogen receptor (ER) mRNA expression and molecular subtypes in stage I-III breast cancers that are progesterone receptor (PR) positive but ER and HER2 negative by immunohistochemistry (IHC) or fluorescent in situ hybridization. The ER, PR, and HER2 status was determined by IHC as part of routine clinical assessment (N = 501). Gene expression profiling was done with the Affymetrix U133A gene chip. We compared expressions of ESR1 and MKI67 mRNA, distribution of molecular subtypes by the PAM50 classifier, the sensitivity to endocrine therapy index, and the DLDA30 chemotherapy response predictor signature among ER/PR-positive (n = 223), ER-positive/PR-negative (n = 73), ER-negative/PR positive (n = 20), and triple-negative (n = 185) cancers. All patients received neoadjuvant chemotherapy with an anthracycline and taxane and had adjuvant endocrine therapy only if ER or PR > 10 % positive. ESR1 expression was high in 25 % of ER-negative/PR-positive, in 79 % of ER-positive/PR-negative, in 96 % of ER/PR-positive, and in 12 % of triple-negative cancers by IHC. The average MKI67 expression was significantly higher in the ER-negative/PR-positive and triple negative cohorts. Among the ER-negative/PR-positive patients, 15 % were luminal A, 5 % were Luminal B, and 65 % were basal like. The relapse-free survival rate of ER-negative/PR-positive patients was equivalent to ER-positive cancers and better than the triple-negative cohort. Only 20-25 % of the ER-negative/PR positive tumors show molecular features of ER-positive cancers. In this rare subset of patients (i) a second RNA-based assessment may help identifying the minority of ESR1 mRNA-positive, luminal-type cancers and (ii) the safest clinical approach may be to consider both adjuvant endocrine and chemotherapy. PMID- 24337597 TI - Hyaluronan synthases (HAS1-3) in stromal and malignant cells correlate with breast cancer grade and predict patient survival. AB - Accumulation of hyaluronan (HA) in pericellular stroma and carcinoma cells is predictive of unfavorable patient prognosis in many epithelial cancers. However, it is not known whether the HA originates from carcinoma or stromal cells, or whether increased expression of hyaluronan synthase proteins (HAS1-3) contributes to HA accumulation. In this study, localization and expression of HAS1-3 were evaluated immunohistochemically in 278 cases of human breast cancer, and correlated with prognostic factors and patient outcome. Both carcinoma cells and stromal cells were HAS-positive. In carcinoma cells, HAS1 and HA stainings correlated with each other, and HAS1 associated with estrogen receptor negativity, HER2 positivity, high relapse rate, and short overall survival. In stromal cells, the staining levels of all HAS isoforms correlated with the stromal HA staining, stromal cell CD44, high relapse rate, and short overall survival of the patients. In addition, expression levels of stromal HAS1 and HAS2 were related to obesity, large tumor size, lymph node positivity, and estrogen receptor negativity. Thus, stromal HAS1 and HAS3 were independent prognostic factors in the multivariate analysis. The data suggest that increased levels of HAS enzymes contribute to the accumulation of HA in breast cancer, and that HA is synthesized in carcinoma cells and stromal cells. The study also indicates that HAS enzyme levels are related to tumor aggressiveness and poor patient outcome representing potential targets for therapy. PMID- 24337598 TI - The effects of exercise on cardiovascular outcomes before, during, and after treatment for breast cancer. AB - Asymptomatic cardiotoxicity following breast cancer treatment is a significant issue for many patients, as these patients typically face an increased risk of cardiovascular disease (CVD). Exercise has well established benefits to improve and maintain cardiovascular function across patients with and without CVD. However, there is a dearth of information on the effects of exercise on cardiovascular outcomes in breast cancer patients. While pre-clinical studies support the use of exercise in mitigating cardiotoxicity, only one human study has specifically investigated cardiac function following an exercise intervention during chemotherapy treatment. No significant differences were observed between groups, which highlights the unidentified role of exercise in altering the risk of cardiotoxicity in breast cancer patients. Issues such as establishing the optimal timing, type, and intensity of an exercise program before, during, or after oncologic treatment for breast cancer are unclear. CVD risk and incidence increase in breast cancer survivors post therapy, and CVD is the number one killer of women in the United States. Thus, there is an increasing need to define the efficacy of exercise as a non-pharmacologic intervention in this growing population. PMID- 24337599 TI - Evaluation of sigma-1 receptor radioligand 18F-FTC-146 in rats and squirrel monkeys using PET. AB - The noninvasive imaging of sigma-1 receptors (S1Rs) could provide insight into their role in different diseases and lead to novel diagnostic/treatment strategies. The main objective of this study was to assess the S1R radiotracer (18)F-FTC-146 in rats. Preliminary squirrel monkey imaging and human serum/liver microsome studies were performed to gain information about the potential of (18)F FTC-146 for eventual clinical translation. METHODS: The distribution and stability of (18)F-FTC-146 in rats were assessed via PET/CT, autoradiography, gamma counting, and high-performance liquid chromatography (HPLC). Preliminary PET/MRI of squirrel monkey brain was conducted along with HPLC assessment of (18)F-FTC-146 stability in monkey plasma and human serum. RESULTS: Biodistribution studies showed that (18)F-FTC-146 accumulated in S1R-rich rat organs, including the lungs, pancreas, spleen, and brain. Pretreatment with known S1R compounds, haloperidol, or BD1047, before radioligand administration, significantly attenuated (18)F-FTC-146 accumulation in all rat brain regions by approximately 85% (P < 0.001), suggesting radiotracer specificity for S1Rs. Similarly, PET/CT and autoradiography results demonstrated accumulation of (18)F FTC-146 in rat brain regions known to contain S1Rs and that this uptake could be blocked by BD1047 pretreatment. Ex vivo analysis of (18)F-FTC-146 in the brain showed that only intact radiotracer was present at 15, 30, and 60 min, whereas rapid metabolism of residual (18)F-FTC-146 was observed in rat plasma. Preliminary monkey PET/MRI studies demonstrated specific accumulation of (18)F FTC-146 in the brain (mainly in cortical structures, cerebellum, and vermis) that could be attenuated by pretreatment with haloperidol. HPLC of monkey plasma suggested radioligand metabolism, whereas (18)F-FTC-146 appeared to be stable in human serum. Finally, liver microsome studies revealed that (18)F-FTC-146 has a longer half-life in human microsomes, compared with rodents. CONCLUSION: Together, these results indicate that (18)F-FTC-146 is a promising tool for visualizing S1Rs in preclinical studies and that it has potential for mapping these sites in the human brain. PMID- 24337600 TI - Additional diagnostic value of integrated analysis of cardiac CTA and SPECT MPI using the SMARTVis system in patients with suspected coronary artery disease. AB - CT angiography (CTA) and SPECT myocardial perfusion imaging (MPI) are complementary imaging techniques to assess coronary artery disease (CAD). Spatial integration and combined visualization of SPECT MPI and CTA data may facilitate correlation of myocardial perfusion defects and subtending coronary arteries and thus offer additional diagnostic value over either stand-alone or side-by-side interpretation of the respective datasets from the 2 modalities. In this study, we investigated the additional diagnostic value of a software-based CTA/SPECT MPI image fusion system over conventional side-by-side analysis in patients with suspected CAD. METHODS: Seventeen symptomatic patients who underwent both CTA and SPECT MPI within a 90-d period were included in our study; 7 of them also underwent invasive coronary angiography (ICA). The potential benefits of the synchronized multimodal heart visualization (SMARTVis) system in assessing CAD were investigated through a case study involving 4 experts from 2 medical centers, in which we performed, first, a side-by-side analysis using structured CTA and SPECT reports and, second, an integrated analysis using the SMARTVis system in addition to the reports. RESULTS: The fused interpretation led to a more accurate diagnosis, reflected in an increase in the individual observers' sensitivity and specificity to correctly refer for invasive angiography eventually followed by revascularization. For the first, second, third, and fourth observers, the respective sensitivities improved from 50%, 60%, 80%, and 80% to 70%, 80%, 100%, and 90% and the respective specificities from 100%, 94%, 83%, and 83% to 100%, 100%, 94%, and 83%. Additionally, the interobserver diagnosis agreement increased from 74% to 84%. The improvement was primarily found in patients presenting with CAD in more vessels than the number of reported perfusion defects. CONCLUSION: Integrated analysis of cardiac CTA and SPECT MPI using the SMARTVis system results in an improved diagnostic performance. PMID- 24337601 TI - Cost analysis of PET and comprehensive lifestyle modification for the reversal of atherosclerosis. AB - We present a preliminary cost analysis of a combination intervention using PET and comprehensive lifestyle modification to reverse atherosclerosis. With a sensitivity of 92%-95% and specificity of 85%-95%, PET is an essential tool for high-precision diagnosis of coronary artery disease, accurately guiding optimal treatment for both symptomatic and asymptomatic patients. PET imaging provides a powerful visual and educational aid for helping patients identify and adopt appropriate treatments. However, little is known about the operational cost of using the technology for this purpose. METHODS: The analysis was done in the context of the Century Health Study for Cardiovascular Medicine (Century Trial), a 1,300-patient, randomized study combining PET imaging with lifestyle changes. Our methodology included a microcosting and time study focusing on estimating average direct and indirect costs. RESULTS: The total cost of the Century Trial in present-value terms is $9.2 million, which is equal to $7,058 per patient. Sensitivity analysis indicates that the present value of total costs is likely to range between $8.8 and $9.7 million, which is equivalent to $6,655-$7,606 per patient. CONCLUSION: The clinical relevance of the Century Trial is significant since it is, to our knowledge, the first randomized controlled trial to combine high-precision imaging with lifestyle strategies. The Century Trial is in its second year of a 5-y protocol, and we present preliminary findings. The results of this cost study, however, provide policy makers with an early estimate of the costs of implementing, at large scale, a combined intervention such as the Century Trial. Further, we believe that imaging-guided lifestyle management may have considerable potential for improving outcomes and reducing health-care costs by eliminating unnecessary invasive procedures. PMID- 24337602 TI - Anti-prostate-specific membrane antigen liposomes loaded with 225Ac for potential targeted antivascular alpha-particle therapy of cancer. AB - This study evaluates targeted liposomes loaded with the alpha-particle generator (225)Ac to selectively kill prostate-specific membrane antigen (PSMA)-expressing cells with the aim to assess their potential for targeted antivascular radiotherapy. METHODS: In this study, PEGylated liposomes were loaded with (225)Ac and labeled with the mouse antihuman PSMA J591 antibody or with the A10 PSMA aptamer. The targeting selectivity, extent of internalization, and killing efficacy of liposomes were evaluated on monolayers of prostate cancer cells intrinsically expressing PSMA (human LNCaP and rat Mat-Lu cells) and on monolayers of HUVEC induced to express PSMA (induced HUVEC). RESULTS: The loading efficiency of (225)Ac into preformed liposomes ranged from 58.0% +/- 4.6% to 85.6% +/- 11.7% of introduced radioactivity. The conjugation reactions resulted in approximately 17 +/- 2 J591 antibodies and 9 +/- 2 A10 aptamers per liposome. The average size of liposomes, 107 +/- 2 nm in diameter, was not affected by conjugation or loading. LNCaP cells exhibit 2:1:0.5 relative PSMA expression, compared with MatLu and induced HUVEC, respectively, based on flow cytometry detecting association of the J591 antibody. J591-labeled liposomes display higher levels of total specific binding to all cell lines than A10 aptamer-labeled liposomes. Specific cell association of targeted liposomes increases with incubation time. Cytotoxicity studies demonstrate that radiolabeled J591-labeled liposomes are most cytotoxic, with median lethal dose values, after 24 h of incubation, equal to 1.96 (5.3 * 10(-5)), 2.92 * 10(2) (7.9 * 10(-3)), and 2.33 * 10(1) Bq/mL (6.3 * 10(-4) MUCi/mL) for LNCaP, Mat-Lu, and induced HUVEC, respectively, which are comparable to the values for the radiolabeled J591 antibody. For A10 aptamer-labeled liposomes, the corresponding values are 3.70 * 10(1) (1.0 * 10(-3)), 1.85 * 10(3) (5.0 * 10(-2)), and 4.07 * 10(3) Bq/mL (1.1 * 10(-1) MUCi/mL), respectively. CONCLUSION: Our studies demonstrate that anti-PSMA targeted liposomes loaded with (225)Ac selectively bind, become internalized, and kill PSMA-expressing cells including endothelial cells induced to express PSMA. These findings-combined with the unique ability of liposomes to be easily tuned, in terms of size and surface modification, for optimizing biodistributions suggest the potential of PSMA-targeting liposomes encapsulating alpha-particle emitters for selective antivascular alpha radiotherapy. PMID- 24337603 TI - A comparison of the behavior of (64)Cu-acetate and (64)Cu-ATSM in vitro and in vivo. AB - (64)Cu-diacetyl-bis(N(4)-methylthiosemicarbazonate), (64)Cu-ATSM, continues to be investigated clinically as a PET agent both for delineation of tumor hypoxia and as an effective indicator of patient prognosis, but there are still aspects of the mechanism of action that are not fully understood. METHODS: The retention of radioactivity in tumors after administration of (64)Cu-ATSM in vivo is substantially higher for tumors with a significant hypoxic fraction. This hypoxia dependent retention is believed to involve the reduction of Cu-ATSM, followed by the loss of copper to cellular copper processing. To shed light on a possible role of copper metabolism in hypoxia targeting, we have compared (64)Cu retention in vitro and in vivo in CaNT and EMT6 cells or cancers after the administration of (64)Cu-ATSM or (64)Cu-acetate. RESULTS: In vivo in mice bearing CaNT or EMT6 tumors, biodistributions and dynamic PET data are broadly similar for (64)Cu-ATSM and (64)Cu-acetate. Copper retention in tumors at 15 min is higher after injection of (64)Cu-acetate than (64)Cu-ATSM, but similar values result at 2 and 16 h for both. Colocalization with hypoxia as measured by EF5 immunohistochemistry is evident for both at 16 h after administration but not at 15 min or 2 h. Interestingly, at 2 h tumor retention for (64)Cu-acetate and (64)Cu-ATSM, although not colocalizing with hypoxia, is reduced by similar amounts by increased tumor oxygenation due to inhalation of increased O2. In vitro, substantially less uptake is observed for (64)Cu-acetate, although this uptake had some hypoxia selectivity. Although (64)Cu-ATSM is stable in mouse serum alone, there is rapid disappearance of intact complex from the blood in vivo and comparable amounts of serum bound activity for both (64)Cu-ATSM and (64)Cu-acetate. CONCLUSION: That in vivo, in the EMT6 and CaNT tumors studied, the distribution of radiocopper from (64)Cu-ATSM in tumors essentially mirrors that of (64)Cu-acetate suggests that copper metabolism may also play a role in the mechanism of selectivity of Cu-ATSM. PMID- 24337604 TI - Functional imaging of human epidermal growth factor receptor 2-positive metastatic breast cancer using (64)Cu-DOTA-trastuzumab PET. AB - Women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are candidates for treatment with the anti-HER2 antibody trastuzumab. Assessment of HER2 status in recurrent disease is usually made by core needle biopsy of a single lesion, which may not represent the larger tumor mass or other sites of disease. Our long-range goal is to develop PET of radiolabeled trastuzumab for systemically assessing tumor HER2 expression and identifying appropriate use of anti-HER2 therapies. The purpose of this study was to evaluate PET/CT of (64)Cu DOTA-trastuzumab for detecting and measuring tumor uptake of trastuzumab in patients with HER2-positive metastatic breast cancer. METHODS: Eight women with biopsy-confirmed HER2-positive metastatic breast cancer and no anti-HER2 therapy for 4 mo or longer underwent complete staging, including (18)F-FDG PET/CT. For 6 of the 8 patients, (64)Cu-DOTA-trastuzumab injection (364-512 MBq, 5 mg of trastuzumab) was preceded by trastuzumab infusion (45 mg). PET/CT (PET scan duration 1 h) was performed 21-25 (day 1) and 47-49 (day 2) h after (64)Cu-DOTA trastuzumab injection. Scan fields of view were chosen on the basis of (18)F-FDG PET/CT. Tumor detection sensitivity and uptake analyses were limited to lesions identifiable on CT; lesions visualized relative to adjacent tissue on PET were considered PET-positive. Radiolabel uptake in prominent lesions was measured as maximum single-voxel standardized uptake value (SUVmax). RESULTS: Liver uptake of (64)Cu was reduced approximately 75% with the 45-mg trastuzumab predose, without significant effect on tumor uptake. The study included 89 CT-positive lesions. Detection sensitivity was 77%, 89%, and 93% for day 1, day 2, and (18)F-FDG, respectively. On average, tumor uptake was similar for (64)Cu-DOTA-trastuzumab and (18)F-FDG (SUVmax and range, 8.1 and 3.0-22.5 for day 1 [n = 48]; 8.9 and 0.9 28.9 for day 2 [n = 38]; 9.7 and 3.3-25.4 for (18)F-FDG [n = 56]), but same lesion SUVmax was not correlated between the 2 radiotracers. No toxicities were observed, and estimated radiation dose from (64)Cu-DOTA-trastuzumab was similar to (18)F-FDG. CONCLUSION: (64)Cu-DOTA-trastuzumab visualizes HER2-positive metastatic breast cancer with high sensitivity and is effective in surveying disseminated disease. A 45-mg trastuzumab predose provides a (64)Cu-DOTA trastuzumab biodistribution favorable for tumor imaging. (64)Cu-DOTA-trastuzumab PET/CT warrants further evaluation for assessing tumor HER2 expression and individualizing treatments that include trastuzumab. PMID- 24337605 TI - Development of 111In-labeled liposomes for vulnerable atherosclerotic plaque imaging. AB - Macrophage infiltration is a common characteristic feature of atherosclerotic vulnerable plaques. Macrophages recognize phosphatidylserine (PS) exposed on the surface of apoptotic cells, which triggers the engulfment of the apoptotic cells by macrophages through phagocytosis. In this study, we prepared radiolabeled PS liposomes for detection of vulnerable plaques. METHODS: PS liposomes were prepared by lipid film hydration. Phosphatidylcholine (PC) liposomes were prepared as controls. Liposomes (100 or 200 nm) were generated by an extruder to produce PS100, PS200, PC100, and PC200 liposomes. These were then radiolabeled by encapsulating (111)In-nitrilotriacetic acid using an active-loading method. (111)In liposomes were incubated with cultured macrophages for 2 h, and the uptake level was measured. For biodistribution studies, the (111)In liposomes were injected intravenously into ddY mice. In addition, the (111)In liposomes were injected into apolipoprotein E-deficient (apoE-/-) mice, and the aortas were harvested for autoradiography and oil red O staining. For SPECT imaging, (111)In liposomes were injected intravenously into Watanabe heritable hyperlipidemic rabbits and scanned 48 h after injection. RESULTS: The radiochemical yields were greater than 95% for all the prepared (111)In liposomes. The level of in vitro uptake by macrophages was 60.5, 14.7, 32.0, and 14.4 percentage injected dose per milligram of protein for (111)In-PS100, (111)In-PC100, (111)In-PS200, and (111)In PC200, respectively. In biodistribution studies, high spleen uptake was seen with PC liposomes. Liver uptake was high for all liposomes but was lowest with (111)In PS200. The blood half-lives were 3.2, 22.0, 3.6, and 7.4 min for (111)In-PS100, (111)In-PC100, (111)In-PS200, and (111)In-PC200, respectively. The distribution of (111)In-labeled PS liposomes into atherosclerotic regions determined by autoradiography was well matched with the results of oil red O staining in apoE-/ mice. The target-to-nontarget ratios were 2.62, 2.23, 3.27, and 2.51 for (111)In PS100, (111)In-PC100, (111)In-PS200, and (111)In-PC200, respectively. The aorta was successfully visualized by SPECT at 48 h after (111)In-labeled PS liposome injection; however, high liver uptake was also observed. DISCUSSION: From the in vitro uptake study, it has been demonstrated that macrophage targeting was accomplished by PS modification. Also, an atherosclerotic region was successfully detected by (111)In-PS200 in apoE-/- mice and Watanabe heritable hyperlipidemic rabbits in vivo. Liposome modification to obtain slower blood clearance and lower liver uptake would be required to improve the SPECT images. PMID- 24337606 TI - Tumor imaging in patients with advanced tumors using a new (99m) Tc-radiolabeled vitamin B12 derivative. AB - Targeting cancer cells with vitamin B12 (cobalamin) is hampered by unwanted physiologic tissue uptake mediated by transcobalamin. Adhering to good manufacturing practice, we have developed a new (99m)Tc-cobalamin derivative ((99m)Tc(CO)3-[(4-amido-butyl)-pyridin-2-yl-methyl-amino-acetato] cobalamin, (99m)Tc-PAMA-cobalamin). The derivative shows no binding to transcobalamin but is recognized by haptocorrin, a protein present in the circulation and notably expressed in many tumor cells. In this prospective study, we investigated cancer specific uptake of (99m)Tc-PAMA-cobalamin in 10 patients with various metastatic tumors. METHODS: Ten patients with biopsy-proven metastatic cancer were included. Dynamic imaging was started immediately after injection of 300-500 MBq of (99m)Tc PAMA-cobalamin, and whole-body scintigrams were obtained at 10, 30, 60, 120, and 240 min and after 24 h. The relative tumor activity using SPECT/CT over the tumor region after 4 h was measured in comparison to disease-free lung parenchyma. Patients 3-10 received between 20 and 1,000 MUg of cobalamin intravenously before injection of (99m)Tc-PAMA-cobalamin. The study population comprised 4 patients with adenocarcinomas of the lung, 3 with squamous cell carcinomas of the hypopharyngeal region, 1 with prostate adenocarcinoma, 1 with breast, and 1 with colon adenocarcinoma. RESULTS: The median age of the study group was 61 +/- 11 y. Six of 10 patients showed positive tumor uptake on (99m)Tc-PAMA-cobalamin whole body scintigraphy. The scan was positive in 1 patient with colon adenocarcinoma, in 3 of 4 lung adenocarcinomas, in 1 of 3 hypopharyngeal squamous cell carcinomas, and in 1 breast adenocarcinoma. Renal uptake was between 1% and 3% for the left kidney. Predosing with cobalamin increased the tumor uptake and improved blood-pool clearance. The best image quality was achieved with a predose of 20-100 ug of cold cobalamin. The mean patient dose was 2.7 +/- 0.9 mSv/patient. CONCLUSION: To our knowledge, we report for the first time on (99m)Tc-PAMA-cobalamin imaging in patients with metastatic cancer disease and show that tumor targeting is feasible. PMID- 24337607 TI - On the destiny of (copper) species. PMID- 24337608 TI - Qualitative and quantitative comparison of PET/CT and PET/MR imaging in clinical practice. AB - The aim of this study was to prospectively compare whole-body PET/MR imaging and PET/CT, qualitatively and quantitatively, in oncologic patients and assess the confidence and degree of inter- and intraobserver agreement in anatomic lesion localization. METHODS: Fifty patients referred for staging with known cancers underwent PET/CT with low-dose CT for attenuation correction immediately followed by PET/MR imaging with 2-point Dixon attenuation correction. PET/CT scans were obtained according to standard protocols (56 +/- 20 min after injection of an average 367 MBq of (18)F-FDG, 150 MBq of (68)Ga-DOTATATE, or 333.8 MBq of (18)F fluoro-ethyl-choline; 2.5 min/bed position). PET/MR was performed with 5 min/bed position. Three dual-accredited nuclear medicine physicians/radiologists identified the lesions and assigned each to an exact anatomic location. The image quality, alignment, and confidence in anatomic localization of lesions were scored on a scale of 1-3 for PET/CT and PET/MR imaging. Quantitative analysis was performed by comparing the standardized uptake values. Intraclass correlation coefficients and the Wilcoxon signed-rank test were used to assess intra- and interobserver agreement in image quality, alignment, and confidence in lesion localization for the 2 modalities. RESULTS: Two hundred twenty-seven tracer-avid lesions were identified in 50 patients. Of these, 225 were correctly identified on PET/CT and 227 on PET/MR imaging by all 3 observers. The confidence in anatomic localization improved by 5.1% when using PET/MR imaging, compared with PET/CT. The mean percentage interobserver agreement was 96% for PET/CT and 99% for PET/MR imaging, and intraobserver agreement in lesion localization across the 2 modalities was 93%. There was 10% (5/50 patients) improvement in local staging with PET/MR imaging, compared with PET/CT. CONCLUSION: In this first study, we show the effectiveness of whole-body PET/MR imaging in oncology. There is no statistically significant difference between PET/MR imaging and PET/CT in respect of confidence and degree of inter- and intraobserver agreement in anatomic lesion localization. The PET data on both modalities were similar; however, the observed superior soft-tissue resolution of MR imaging in head and neck, pelvis, and colorectal cancers and of CT in lung and mediastinal nodal disease points to future tailored use in these locations. PMID- 24337609 TI - Multimodal MR imaging model to predict tumor infiltration in patients with gliomas. AB - INTRODUCTION: Gliomas remain difficult to treat, in part, due to our inability to accurately delineate the margins of the tumor. The goal of our study was to evaluate if a combination of advanced MR imaging techniques and a multimodal imaging model could be used to predict tumor infiltration in patients with diffuse gliomas. METHODS: Institutional review board approval and written consent were obtained. This prospective pilot study enrolled patients undergoing stereotactic biopsy for a suspected de novo glioma. Stereotactic biopsy coordinates were coregistered with multiple standard and advanced neuroimaging sequences in 10 patients. Objective imaging values were assigned to the biopsy sites for each of the imaging sequences. A principal component analysis was performed to reduce the dimensionality of the imaging dataset without losing important information. A univariate analysis was performed to identify the statistically relevant principal components. Finally, a multivariate analysis was used to build the final model describing nuclear density. RESULTS: A univariate analysis identified three principal components as being linearly associated with the observed nuclear density (p values 0.021, 0.016, and 0.046, respectively). These three principal component composite scores are predominantly comprised of DTI (mean diffusivity or average diffusion coefficient and fractional anisotropy) and PWI data (rMTT, Ktrans). The p value of the model was <0.001. The correlation between the predicted and observed nuclear density was 0.75. CONCLUSION: A multi input, single output imaging model may predict the extent of glioma invasion with significant correlation with histopathology. PMID- 24337610 TI - The combination of baseline magnetic resonance perfusion-weighted imaging-derived tissue volume with severely prolonged arterial-tissue delay and diffusion weighted imaging lesion volume is predictive of MCA-M1 recanalization in patients treated with endovascular thrombectomy. AB - INTRODUCTION: Indices of collateral flow deficit derived from MR perfusion imaging that are predictive of MCA-M1 recanalization after intravenous thrombolysis have been recently reported. Our objective was to test the performance of such MRI-derived collateral flow indices for prediction of recanalization after endovascular thrombectomy. METHODS: Fifty-seven patients with MCA-M1 occlusion evaluated with multimodal MRI prior to thrombectomy were included. Bayesian processing allowed quantification of collateral perfusion indices like the volume of tissue with severely prolonged arterial-tissue delay (>6 s) (VolATD6). Baseline DWI lesion volume was also measured. Correlations with angiographic collateral flow grading and post-thrombectomy recanalization were assessed. RESULTS: VolATD6 < 27 ml or DWI lesion volume <15 ml provide the most accurate diagnosis of excellent collateral supply (p < 0.0001). The combination of VolATD6 > 27 ml and DWI lesion volume >15 ml significantly discriminates recanalizers versus nonrecanalizers (whole cohort, p = 0.032; MERCI cohort (n = 50), p = 0.024). When both criteria are positive, 76.2 % of the patients treated with the MERCI retriever do not fully recanalize (p = 0.024). In multivariate analysis, the aforementioned combined criterion and the angiographic collateral grade are the only independent predictors of recanalization with the MERCI retriever (p = 0.015 and 0.029, respectively). CONCLUSION: Bayesian arterial tissue delay maps and DWI maps provide a non-invasive assessment of the degree of collateral flow and a combined index that is predictive of MCA-M1 recanalization after endovascular thrombectomy. Further studies are needed to evaluate the accuracy of this index in patients treated with novel stent retriever devices. PMID- 24337611 TI - Purified vitexin compound 1 inhibits growth and angiogenesis through activation of FOXO3a by inactivation of Akt in hepatocellular carcinoma. AB - Vitexins, isolated from the seeds of the Chinese herb Vitex negundo, is known to exert antitumor activity in cancer xenograft models and cell lines. The aim of the current study was to examine whether the Akt/forkhead box protein O3a (FOXO3a) pathway mediates the biological effects of purified vitexin compound 1 (VB-1) in hepatocellular carcinoma (HCC) cells. The effect of VB-1 on the viability of the HCC cell lines HepG2, Hep3B, Huh-7 and the human embryonic liver cells L-02 was investigated using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. Growth inhibition was assessed by clonogenic assay, and cell cycle arrest was investigated using flow cytometry. Inhibition of angiogenesis was evaluated using a matrigel in vitro HUVEC tube formation assay. The effects on the Akt/FOXO3a pathway were detected by western blotting. VB-1 suppressed the proliferation of HepG2, Hep3B, Huh-7 cells, but had little effect on L-02 cells. VB-1 inhibited anchorage-dependent and -independent HepG2 cell growth in a concentration-dependent manner by induction of cell cycle arrest at G1/G0. VB-1 also reduced the secretion of vascular endothelial growth factor (VEGF), resulting in the inhibition of endothelial tube formation. Phosphorylated Akt and its downstream effector FOXO3a were downregulated in VB-1 treated HepG2 cells. Knockdown of Akt1 by small interfering RNA (siRNA) enhanced growth inhibition, and silencing FOXO3a by siRNA attenuated this action. VB-1 inhibited growth and induced cell cycle arrest at G1/G0 by regulating the Akt/FOXO3a pathway. The findings suggested that VB-1 is a potentially promising candidate for the treatment of HCC. PMID- 24337612 TI - National assessment of margin status as a quality indicator after pancreatic cancer surgery. AB - BACKGROUND: Surgical margin involvement is an important outcome after pancreatic cancer surgery; however, variation in pathologic review practices may limit its use as a quality indicator. Our objectives were to assess variation in hospital performance and the reliability of margin involvement after pancreatic cancer surgery. METHODS: From the National Cancer Data Base, patients who underwent pancreatic resection for stage I to III adenocarcinoma were identified. Risk adjusted surgical margin involvement was evaluated using hierarchical regression methods, and variation in hospital performance and reliability was determined. RESULTS: From 1,002 hospitals, 14,889 patients underwent pancreatic resection for adenocarcinoma, and 3,573 (24.0 %) had an involved surgical margin (R1 22.8 %; R2 1.2 %). The strongest predictors associated with margin involvement were T stage [T3: odds ratio (OR) 2.08, 95 % confidence interval (CI) 1.68-2.59; T4: OR 7.26, 95 % CI 5.50-9.60; vs. T1] and tumor size (2-3.9 cm: OR 1.66, 95 % CI 1.39-1.98, >= 4 cm: OR 2.28, 95 % CI 1.90-2.74; vs. <2 cm). Factors associated with a decreased likelihood of margin involvement were the use of neoadjuvant therapy and hospital type (academic and National Cancer Institute-designated comprehensive cancer centers vs. community). At the hospital level, the mean risk adjusted surgical margin involvement rate was 25.9 % and ranged 10.1 to 50.5 %. Twenty-one (2.1 %) hospitals had lower-than-expected and 17 (1.7 %) had higher than-expected margin involvement. A minimum acceptable reliability of 0.4 was met after 13 cases and was achieved by 249 hospitals that performed 79 % of pancreatic resections assessed. CONCLUSIONS: Despite differences in pathologic evaluation practices, hospitals can be feasibly and reliably provided comparative data on surgical margin status after resection for pancreatic cancer. PMID- 24337613 TI - Larvicidal potential of silver nanoparticles synthesized from Leucas aspera leaf extracts against dengue vector Aedes aegypti. AB - Vector-borne diseases caused by mosquitoes are one of the major economic and health problems in many countries. Aedes aegypti mosquito is a vector of several diseases in humans like yellow fever and dengue. Vector control methods involving use of chemical insecticides are becoming less effective due to the development of insecticides resistance, biological magnification of toxic substances through the food chain, and adverse effects on environmental quality and nontarget organisms including human health. Application of active toxic agents from plant extracts as an alternative mosquito control strategy was available from ancient times. These are nontoxic, easily available at affordable prices, biodegradable, and show broad-spectrum target-specific activities against different species of vector mosquitoes. Today, nanotechnology is a promising research domain which has a wide ranging application in vector control programs. The present study investigates the larvicidal potential of solvent leaf extracts of Leucas aspera and synthesized silver nanoparticles using aqueous leaf extract against fourth instar larvae of A. aegypti. Larvae were exposed to varying concentrations of plant extracts and synthesized AgNPs for 24 h. The results were recorded from UV Vis spectra, X-ray diffraction (XRD), Fourier transform infrared (FTIR), and scanning electron microscopy (SEM), and were used to characterize and support the biosynthesis of silver nanoparticles. The formation of the synthesized AgNPs from the XRD spectrum compared with Bragg reflections can be indexed to the (111) orientations, respectively, confirmed the presence of AgNPs. The FTIR spectra of AgNPs exhibited prominent peaks at 3,447.77, 2,923.30, and 1,618.66 cm(-1). The spectra showed sharp and strong absorption band at 1,618.66 cm(-1) assigned to the stretching vibration of (NH) C?O group. The band 1,383 developed for C?C and C?N stretching, respectively, and was commonly found in the proteins. SEM analysis of the synthesized AgNPs clearly showed the clustered and irregular shapes, mostly aggregated and having the size of 25-80 nm. Energy-dispersive X ray spectroscopy (EDX) showed the complete chemical composition of the synthesized AgNPs. In larvicidal activity, the results showed that the maximum efficacy was observed in synthesized AgNP from leaf extracts against the fourth instar larvae of A. aegypti with LC50 values of 8.5632, 10.0361, 14.4689, 13.4579, 17.4108, and 27.4936 mg/l and LC90 values of 21.5685, 93.03928, 39.6485, 42.2029, 31.3009, and 53.2576 mg/l respectively. These results suggest that the synthesized AgNP from leaf extracts have a higher larvicidal potential as compared to crude solvent extracts thus making them an effective combination for controlling A. aegypti. PMID- 24337614 TI - Effect of host species diversity on multiparasite systems in rodent communities. AB - Reduced species diversity has been suggested to increase transmission rates and prevalence of infectious diseases. While this theory has been studied mostly in single pathogen systems, little is known regarding multiple pathogens systems in vertebrates at the community level. The aim of this study was to evaluate the effect of host richness and diversity on multiple parasite systems on a local scale. We captured small rodents and collected feces in three different vegetation types in a natural protected area in Janos, Chihuahua, Mexico. The flotation technique was used to identify parasite eggs or oocysts. Analysis of linear correlations was conducted between parasite prevalence and host and parasite diversity and richness. Negative correlation was detected between parasite prevalence and host diversity (p = 0.02 r(2) =-0.86), but no significant correlations was detected between parasite prevalence and host richness or parasite diversity or richness. Our study shows that at local scale, host diversity could affect multiple parasite systems in the same way that single pathogens do. Further studies should be performed on larger temporal and spatial scales to more thoroughly investigate the correlation observed in our analysis. PMID- 24337615 TI - Interrater reliability of assessing levator ani deficiency with 360 degrees 3D endovaginal ultrasound. AB - INTRODUCTION AND HYPOTHESIS: Three-dimensional endovaginal ultrasound has been used for evaluation of levator ani muscle deficiency. The aim of this study was to assess interrater agreement/reliability of 3D endovaginal ultrasound for scoring levator ani deficiency (LAD). METHODS: This was a cross-sectional study. Women referred to our urogynecology clinic for different pelvic floor dysfunction symptoms during November 2010-November 2012 were recruited. All patients underwent physical examination, including Pelvic Organ Prolapse Quantification (POP-Q) examination and high-resolution 3D endovaginal ultrasound. The levator muscle was divided into three subgroups based on our prior work: the puboperinealis/puboanalis (PA), puborectalis (PR), and iliococcygeus/pubococcygeus (PV). Subgroups were evaluated in their specific axial plane and were scored according to thickness and detachment from the pubic bone. Scoring was conducted by four raters blinded to case status and to one another's scores. RESULTS: Ninety patients were recruited. The median age was 52 (range 24-86). Median body mass index (BMI) was 28.08 (range 17.08-51.39). Fifty percent of patients were menopausal. The range of exact agreement for total LAD score was 77-90 %. All the correlation coefficients at the individual sites as well as the overall scores were positive at above 0.63 and significant at <0.0001 level. CONCLUSIONS: Our study demonstrates excellent agreement between raters assessing levator ani muscle deficiency using 3D endovaginal ultrasound. This level of concordance supports the reliability of the 3D endovaginal ultrasound technique and scoring method among raters [corrected]. PMID- 24337616 TI - Surgical management of chronic traumatic pseudomeningocele of the craniocervical junction: case report. AB - PURPOSE: Chronic traumatic pseudomeningocele (PM) is a rare complication of gunshot injuries of the craniocervical junction in pediatric patients. Impairment of the CSF dynamics may cause severe symptoms and should be treated. METHODS: We report the case of a 6-year-old girl who was accidentally shot in the neck during tribal clashes. On being admitted, she was neurologically intact with cerebrospinal fluid (CSF) leakage through the wounds. She underwent primary closure of the wounds in a rural medical facility. After two episodes of meningitis, CSF leakage resolved spontaneously. Nine months later, the patient was presented with a disfiguring mass growing in the posterior neck, severe headaches, and constitutional symptoms such as loss of appetite and a failure to thrive. RESULTS: Neurosurgical intervention was performed with the patient in the prone position. Occipital pericranium graft was used to repair the defect, and the cavity of the PM was obliterated with muscle layers. The patient's symptoms improved at 1 year follow-up without PM recurrence. CONCLUSION: This is a rare presentation of gunshot injuries in an environment with limited neurosurgical resources. Restoring the normal pattern of CSF circulation should be the aim of any neurosurgical intervention. PMID- 24337617 TI - [Chronic migraine]. AB - The classification of the International Headache Society (IHS) generally differentiates episodic from chronic headache. Chronic migraine is defined as headache on 15 and more days a month over more than 3 months and headache on 8 days or more fulfils the criteria for migraine or were triptan/ergot-responsive when thought to be migrainous in early stages of the attack. The prevalence of chronic migraine is estimated at 2-4 %. The quality of life is highly compromised in this condition and comorbidities are much more frequent compared to episodic migraine. Data from prospective randomized studies are scarce as most patients with chronic migraine were excluded from previous trials and only few studies were conducted for this condition. The efficacy for prophylactic treatment compared with placebo is proven for topiramate and onabotulinum toxin A. PMID- 24337619 TI - [Treatment of asymptomatic carotid artery stenosis: improvement of evidence with new SPACE-2 design necessary]. AB - Asymptomatic carotid artery stenosis may be treated with carotid endarterectomy (CEA), carotid artery stenting (CAS) or with best medical treatment (BMT) only. Definitive and evidence-based treatment recommendations for one of these options are currently not possible. Studies showing an advantage of CEA over BMT alone do not meet current standards from a pharmacological point of view. On the other hand, more recent data point to a further stroke risk reduction using BMT according to current standards. Studies on carotid artery stenting as a third alternative treatment are partially insufficient, especially when comparing CAS with BMT. Initiated in 2009, the randomized, controlled, multicenter SPACE-2 trial is intended to answer the question about the best treatment option of asymptomatic carotid artery stenosis; however, to increase recruitment rates as a condition for the successful completion of this important study, the trial design had to be modified. PMID- 24337620 TI - [Optic nerve neuritis: from an ophthalmological perspective]. AB - Optic nerve neuritis is one of the most important differential diagnoses of visual loss in young and middle aged adults. The prognosis in terms of functional outcome is generally good. The diagnosis of optic neuritis is clinical. Steroids can reduce the recovery time but do not affect the long-term functional outcome. Magnetic resonance imaging (MRI) is the most important investigation for assessing an associated risk of multiple sclerosis. Optical coherence tomography (OCT) contributes additional details on the course and functional outcome of optic neuritis. In the future OCT may additionally contribute to the relationship between optic neuritis and possible associated multiple sclerosis. PMID- 24337621 TI - Safety and efficacy of aprepitant, ramosetron, and dexamethasone for chemotherapy induced nausea and vomiting in patients with ovarian cancer treated with paclitaxel/carboplatin. AB - PURPOSE: Women with ovarian carcinoma that are treated with paclitaxel/carboplatin are particularly susceptible to chemotherapy-induced nausea and vomiting (CINV). The current study evaluated the new combination (aprepitant/ramosetron/dexamethasone, 20 mg) in ovarian cancer patients receiving multiple cycles of paclitaxel/carboplatin. METHODS: This is a prospective non randomized single site study. Patients received the following regimen for the prevention of CINV-day 1, 125 mg aprepitant, 0.6 mg ramosetron, and 20 mg dexamethasone before chemotherapy; and days 2-3, 80 mg aprepitant each day. The primary end point was the proportion of patients with complete response (CR) during the 120 h following the first chemotherapy cycle. Toxicity assessments were conducted using the NCI-CTC investigator guide (version 3.0). RESULTS: Of the 89 patients enrolled, 85 patients were evaluable for efficacy and toxicity, and 68 (80 %) completed all 6 cycles. In cycle 1, the percentage of patients who achieved CR in the acute, delayed, and overall phases was 98.8 %, 89.4 %, and 89.4 %, respectively. Of the 460 cycles, adverse events, drug-related adverse events, and serious adverse events occurred in 179 (38.9 %), 35 (7.6 %), and 10 cycles (2.2 %), respectively. The most common adverse event was constipation (12.4 %) and headache (11.1 %). None of the patients discontinued the study because of adverse events. CONCLUSIONS: The combination of aprepitant, ramosetron, and high-dose dexamethasone demonstrated efficacy for CINV prevention in ovarian cancer patients receiving paclitaxel and carboplatin. PMID- 24337622 TI - Neutrophil gelatinase-associated lipocalin levels associated with cardiovascular disease in chronic kidney disease patients. AB - BACKGROUND: Elevated levels of neutrophil gelatinase-associated lipocalin (NGAL) have been reported in patients with cardiovascular disease (CVD), heart failure, and stroke. We assessed the relationships between serum levels of NGAL and the prevalence of CVD, and clarified the prognostic usefulness of systemic NGAL levels in hemodialysis (HD) patients. METHODS: Eighty-eight HD patients were followed up for 1 year. Logistic regression analyses were used to investigate the relationship between de novo CVD status and NGAL levels as well as other risk factors. RESULTS: During follow-up, CVD events occurred in 20 patients. Initial serum levels of NGAL and brain natriuretic peptide of HD patients with de novo CVD were significantly higher than those of HD patients without de novo CVD. Multivariate logistic regression analyses showed that initial serum levels of NGAL were independent risk factors for de novo CVD in HD patients. When patients were classified on the basis of NGAL quartiles, multiple logistic regression analyses demonstrated that the highest quartile of NGAL level showed an increased odds ratio for the prevalence of CVD. CONCLUSION: These findings suggest that NGAL levels can be used to detect the prevalence of CVD in HD patients with or without diabetes. PMID- 24337623 TI - Accumulation of advanced glycation end products and beta 2-microglobulin in fibrotic thickening of the peritoneum in long-term peritoneal dialysis patients. AB - Characteristics of pathological alterations in long-term peritoneal dialysis (PD) are thickening of submesothelial compact (SMC) zone, small-vessel vasculopathy, and loss of mesothelial cells. Bioincompatible PD fluid plays crucial roles in peritoneal injury. Encapsulating peritoneal sclerosis (EPS), a rare and serious complication, occurred in patients on long-term PD or frequent peritonitis episodes, and ~50 % of EPS developed after PD cessation. We hypothesized that PD related peritoneal injury factors induced by bioincompatible PD fluid accumulated in the peritoneum and might induce EPS. We therefore examined the accumulation of advanced glycation end products (AGE) and beta 2-microglobulin (beta2M) in peritoneum and evaluated the relationship between their accumulation, clinical parameters, and outcome after PD cessation. Forty-five parietal peritoneal specimens were obtained from 28 PD patients, 14 uremic patients, and three patients with normal kidney function. The peritoneal equilibration test was used for peritoneal function. AGE- and beta2M-expressing areas were found in vascular walls, perivascular areas, and the deep layer of the SMC in short-term PD patients and extended over the entire SMC in long-term patients. Peritonitis and prolonged PD treatment aggravated peritoneal thickening and the proportion of AGE expressing areas. The proportion of beta2M-expressing areas was increased in long term PD patients. Thickening of the SMC and the proportions of AGE- and beta2M expressing areas were not related to ascites or EPS after PD withdrawal. It appears that the increased proportion of AGE and beta2M deposition induced by long-term exposure of PD fluid may be a marker of peritoneal injury. PMID- 24337624 TI - The Men's Shed: providing biopsychosocial and spiritual support. AB - Community Men's Sheds (CMS) have been a unique approach within Australia for addressing and promoting men's health and well-being issues by providing biopsychosocial support. Given the decline of traditional religious influence, and the contemporary understanding of 'spirituality', it can be argued that CMS may also develop and demonstrate characteristics of a communal spirituality. This research aimed to explore the individual and community contribution of CMS in terms of men's health and well-being and subsequently whether CMS programmes satisfied the contemporary and consensus understanding of spirituality. A qualitative case study was undertaken combining both participant observation over a 6-month period and semi-structured in-depth interviews with 21 men of varying ages and occupations attending a Melbourne suburban CMS (Victoria, Australia). Thematic analysis indicated that the CMS provided a number of health and well being benefits at individual, family, community and public health levels. These included increased self-esteem and empowerment, respite from families, a sense of belonging in the community and the opportunity to exchange ideas relating to personal, family, communal and public health issues. It is concluded that CMS, through the provision of an appropriate spatial context and organizational activities, encourage intra-personal and inter-personal reflection and interaction that subsequently results in men meaningfully, purposefully and significantly connecting with the moment, to self, to others and to their environment-and thus, CMS not only provides biopsychosocial support but can also deliver spiritual support. PMID- 24337625 TI - A randomized phase II study of autologous cytokine-induced killer cells in treatment of hepatocellular carcinoma. AB - PURPOSE: This prospective study aims to explore the benefit of cytokine-induced killer cell (CIK) treatment in hepatocellular carcinoma patients, which has not yet been thoroughly studied before. METHODS: From January 2004 to May 2009, 132 patients who were initially diagnosed with hepatocellular carcinoma of Barcelona Clinic Liver Cancer (BCLC) stage A, B or C, Child-Pugh scores of A or B and without prior treatment were enrolled in the study. Patients were randomly assigned to either arm 1 (n = 66) to receive CIK treatment plus standard treatment, or arm 2 (n = 66) to receive standard treatment only. The primary end point was overall survival (OS) and the secondary endpoint was progression-free survival as evaluated by Kaplan-Meier analyses and treatment hazard ratios with the Cox proportional hazards model. RESULTS: The 1-year (OS: 74.2% vs. 50.0%, 95% CI: 63.6-84.8% vs. 37.8-62.2, p = 0.002), 2-year (OS: 53.0% vs. 30.3%, 95% CI: 40.8-65.2% vs. 19.1-41.5%, p = 0.002), 3-year (OS: 42.4% vs. 24.2%, 95% CI: 30.4 54.4% vs. 13.8-34.6%, p = 0.005) and median overall and progression-free survivals of arm 1 patients were significantly higher than those of arm 2. Therefore, in patients who are not suitable for surgery, significant benefit is obtained from CIK treatment. The main adverse effects of CIK included fever, allergy and headache pain. CONCLUSIONS: Hepatocellular carcinoma patients who were not suitable for surgery demonstrate prolonged overall and progression-free survival from CIK treatment. PMID- 24337627 TI - Posttraumatic and postoperative osteomyelitis: surgical revision strategy with persisting fistula. AB - INTRODUCTION: Posttraumatic and postoperative osteomyelitis (PPO) with bacteria colonisation during trauma and associated surgery is an increasing clinical problem. This study investigated the treatment of PPO by surgical revision including irrigation, debridement, and temporary hardware maintenance. In addition, a drainage was inserted as persisting fistula to control osteomyelitis until fracture healing was achieved. Trauma- and osteomyelitis-related factors that influenced the study outcome were determined. PATIENTS AND METHODS: 67 consecutive patients with PPO were included. At onset of PPO, patients had incomplete fracture healing. Patients were subdivided by time of PPO occurrence (acute, subacute or chronic), initial soft tissue trauma, anatomical location, and initial fracture type (AO classification). The study outcome measures included radiographic and clinical follow-up. RESULTS: 59 patients could be followed for an average of 23 months after revision surgery. A bone healing was achieved by 89% of patients after 14.7 +/- 13.4 weeks. Fractures of the lower extremity, open fractures and comminuted C-type fractures took significantly longer to achieve bone healing (p < 0.05 each). Time of PPO occurrence did not influence bone healing. After fracture consolidation, no re-infection was found. CONCLUSIONS: This study showed high rates of bone healing, indicating that this strategy with persisting fistula should be considered as alternative treatment option in patients with PPO. PMID- 24337628 TI - Role of prenatal undernutrition in the expression of serotonin, dopamine and leptin receptors in adult mice: implications of food intake. AB - Perturbations in the levels of serotonin expression have a significant impact on behavior and have been implicated in the pathogenesis of several neuropsychiatric disorders including anxiety, mood and appetite. Fetal programming is a risk factor for the development of metabolic diseases during adulthood. Moreover, previous studies have shown that serotonin (5-HT), dopamine and leptin are important in energy balance. In the present study, the impact of maternal malnutrition-induced prenatal undernutrition (UN) was investigated in mice and the expression of 5-HT1A, dopamine (D)1, D2 and Ob-Rb receptors was analyzed in the hypothalamus during adulthood. The UN group showed a low birth weight compared with the control group. With regard to receptor expression, 5-HT1A in the UN group was increased in the hypothalamus and D1 was reduced, whereas D2 showed an increase from postnatal day (P)14 in the arcuate nucleus. Ob-Rb receptor expression was increased in the hypothalamus at P14 and P90. These observations indicated that maternal caloric restriction programs a postnatal body weight gain in offspring with an increased food intake in early postnatal life which continues into adulthood. In addition, UN in mice was found to be affected by Ob-Rb, 5-HT1A and D1/2 receptor expression, indicating that these observations may be associated with hyperphagia and obesity. PMID- 24337629 TI - From embouchure problems to embouchure dystonia? A survey of self-reported embouchure disorders in 585 professional orchestra brass players. AB - OBJECTIVES: Data concerning embouchure problems in professional brass players are scarce. Embouchure problems can potentially lead to focal dystonia. The aim of this study was to investigate the frequency of distinct embouchure problems in professional brass players. Furthermore, the frequency of "cramping", a distinct symptom of embouchure dystonia, was evaluated in the context of established embouchure dystonia risk factors. METHODS: Five hundred and eighty-five professional brass players participated in a cross-sectional study concerning embouchure problems. A self-administered questionnaire was developed to evaluate embouchure fatigue, embouchure disorders and their consequences. To study the association between risk factors and cramping (a symptom of embouchure dystonia), a log-binomial regression analysis was conducted, enabling estimation of prevalence ratios (PR) and 95 % confidence intervals (95 % CI). RESULTS: Thirty percent (95 % CI 25.9-33.3) reported embouchure fatigue. The relative frequency of embouchure disorders was 59 % (95 % CI 54.6-63.6), with 26 % (95 % CI 22.4 29.5) reporting embouchure cramping. Embouchure disorders resulted in sick leave in 16 % (95 % CI 12.7-20.6). Female brass players (PR 2.0, 95 % CI 0.98-3.98) and musicians with a prior change in their embouchure (PR 2.4, 95 % CI 1.38-4.05) or breathing technique (PR 2.2, 95 % CI 1.25-3.72) and musicians with embouchure fatigue (PR 1.9, 95 % CI 1.18-2.93) presented more frequently with embouchure cramping than musicians with other or without risk factors. CONCLUSION: This study shows a high relative frequency of embouchure problems in professional brass players. Given that embouchure dystonia is often preceded by embouchure problems, these findings may assist in gaining further insight into the characteristics of embouchure dystonia and the development of preventive strategies. PMID- 24337626 TI - Neutrophil and monocyte recruitment by PECAM, CD99, and other molecules via the LBRC. AB - The recruitment of specific leukocyte subtypes to the site of tissue injury is the cornerstone of inflammation and disease progression. This process has become an intense area of research because it presents several possible steps against which disease-specific therapies could be targeted. Leukocytes are recruited out of the blood stream by a series of events that include their capture, rolling, activation, and migration along the endothelium. In the last step, the leukocytes squeeze between adjacent endothelial cells to gain access to the inflamed tissue through a process referred to as transendothelial migration (TEM). Although many of the molecules, such as PECAM and CD99, that regulate these sequential steps have been identified, much less is understood regarding how they work together to coordinate the complex intercellular communications and dramatic shape changes that take place between the endothelial cells and leukocytes. Several of the endothelial cell proteins that function in TEM are localized to the lateral border recycling compartment (LBRC), an interconnected reticulum of membrane that recycles selectively to the endothelial borders. The recruitment of the LBRC to surround the migrating leukocyte is required for efficient TEM. This review will focus on the proteins and mechanisms that mediate TEM and specifically how the LBRC functions in the context of these molecular interactions and membrane movements. PMID- 24337630 TI - HTRA2 variations in Taiwanese Parkinson's disease. AB - Mutations in HTRA2 have been reported to associate with Parkinson's disease (PD). This study investigates if the genetic variants in HTRA2 contribute to Taiwanese PD. HTRA2 cDNA fragments from 80 patients with early-onset PD (onset <=50 years) were sequenced. The identified variants were further examined for a cohort of PD and ethnically matched controls. A novel heterozygous R36W was identified in one early-onset and two late-onset PD patients, which was absent in 606 normal controls. The clinical features and 99mTc-TRODAT-1 SPECT image of the early-onset patient carrying R36W were similar to that of idiopathic PD. The R36W mutation of the patient was inherited from his mother whose SPECT revealed asymmetric reduction of 99mTc-TRODAT-1 uptake in the left striatum, suggesting that the defect of the nigrostriatal pathway may be attributable to the R36W in this family. Protein subcellular fractionation further revealed that R36W affected the processing of the proprotein after transport into mitochondria. Although the functional assays are promising, a larger cohort of both cases and controls should be screened to clarify the role of R36W in Taiwanese PD pathogenicity. PMID- 24337631 TI - The antioxidant effects of isorhamnetin contribute to inhibit COX-2 expression in response to inflammation: a potential role of HO-1. AB - Previously, we reported that isorhamnentin, a 3'-O-methylated metabolite of quercetin, reduced inducible nitric oxide synthase (iNOS) expression and NO production. The present study further investigated the underlying mechanism of anti-inflammatory and antioxidant effects of isorhamnentin. Administration of isorhamnetin decreased the number of cyclooxygenase-2 (COX-2) positive cells in rats with carrageenan-induced paw edema. Isorhamnetin also suppressed lipopolysaccharide (LPS)-induced expression of COX-2 in cells. It is well known that LPS-induced reactive oxygen species (ROS) production leads to COX-2 induction. Isorhamnetin decreased LPS-induced ROS production and apoptosis. In addition, the basal expression of heme oxygenase-1 (HO-1) was increased by isorhamnetin treatment in agreement with the increase in nuclear translocation of NF-E2-related factor-2 (Nrf2), an essential transcription factor for the regulation of HO-1 expression. Moreover, pretreatment of tin protoporphyrin IX (SnPP), a chemical inhibitor of HO-1, reversed the ability of isothamnetin to inhibit COX-2 expression. These results demonstrate that induction of HO-1 by isorhamnetin leads to a reduction in ROS production and its antioxidant property might contribute to the inhibition of COX-2 expression in response to inflammation. PMID- 24337633 TI - Embodiment and dementia--dance movement psychotherapists respond. PMID- 24337632 TI - Active form of AKT controls cell proliferation and response to apoptosis in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide. Deregulation of the AKT signaling pathway has been found in HCC. However, the effect of AKT activation on the proliferation and apoptosis in HCC is not clear. Herein, expression of phosphorylated form of AKT (Ser 473) was investigated in HCC tumor (n=73), cirrhosis (n=17), normal liver (n=22) samples and in HCC cell lines (n=8). The results showed that expression of p-AKT was higher in tumor (53%) than in cirrhotic tissues (12%) while it was absent in normal liver (p<0.0001). p-AKT expression was also associated with number of tumor nodules and differentiation status (p<0.05). LY294002 induced cell cycle arrest at G0/G1 in SNU-449 and Mahlavu cells by decreasing expression of CDK2, CDK4, CycD1, CycD3, CycE, CycA and increasing expression of p21 and p27 as well; it also caused a decrease in the E2F1 transcriptional activity through declining phosphorylated Rb. LY294002 did not affect the basal level of apoptosis; however, it amplified cisplatin-induced apoptosis in SNU-449 cells. When the p-AKT level was decreased specifically after transfection with the DN-AKT plasmid, SNU-449 cells became more sensitive to cisplatin-induced apoptosis. HuH-7 cells with no basal p-AKT, were markedly affected by the treatment of doxorubicin. Thus, Akt signaling controls growth and chemical-induced apoptosis in HCC and p-AKT may be a potential target for therapeutic interventions in HCC patients. PMID- 24337634 TI - Developing theoretical understandings of dementia and their application to dementia care policy in the UK. AB - This paper discusses theoretical models for understanding dementia and how these are emerging in the formation and development of dementia care policy across the UK. Dementia attracts multi-disciplinary and multi-professional questions and responses. Three broad theoretical models underpin dementia care policy (as well as practice and research): biomedical, psycho-social and social-gerontological. These are critically assessed and discussed in relation to illustrative examples of dementia policy across three policy regions of the devolved UK. The contribution and implications of theoretical models of dementia policy highlight the importance of recognising how different theoretical understandings of dementia influence dementia policy. The development and improvement of policy and practice in the area of dementia care require an understanding of the often implicit theoretical approaches to dementia. PMID- 24337635 TI - An exploration into the relationships people with dementia have with physical objects: an ethnographic study. AB - In recent years there has been increasing interest in how different aspects of object relations theory might apply to dementia. While attachment theory in dementia has been well studied, there have been no systematic investigations of the way in which transitional objects are used by people with dementia. This study explores the relationship people with dementia have with physical objects using a focussed ethnographic method. Twenty-one residents and the staff of a care home for people with dementia were observed over a two-month period. Observations were recorded and analysed in light of Winnicott's criteria for transitional objects and incorporated the work of other key theorists. The ethnography found evidence that people with dementia have varied relationships with objects and can employ objects in a transitional way. The paper then explores the implications of this research for understanding the function of transitional objects for people with dementia. The findings suggest that that Winnicott's theory of transitional objects can provide a framework for understanding some of the processes of dementia. PMID- 24337636 TI - How people with Alzheimer's disease express their sense of self: analysis using Rom Harre's theory of selfhood. AB - The aim of this study was to use Harre's social constructionist theory of selfhood to describe how people with mild and moderate Alzheimer's disease (AD) express their sense of self. The findings show that Self 1, the embodied sense of being a person, was expressed fluently by participants through the use of first person indexicals. Self 2, the experienced personal attributes and life narrative, had undergone changes. Those changes were not entirely for the worse; participants had also developed new skills in managing life with AD. In a lifetime perspective, those changes were minor and participants perceived themselves to be basically the same people that they were before having AD. When constructing Self 3, the social personae, participants usually described being supported by others, but sometimes described being exposed to malignant positioning. They also feared that they might become more exposed to negative attitudes as their AD progressed. However, participants were understanding towards the offensive behaviours of others. PMID- 24337637 TI - Medication management: the perspectives of people with dementia and family carers. AB - The safe self management of medicines will be affected by the presence of dementia. A qualitative study using grounded theory was undertaken by a community nursing organisation in Melbourne, Australia, in order to develop a strength based and person-centred approach to the assessment of medication ability. The perspectives of the person with dementia and their carers were explored to see if there were any significant differences in their medication management experiences when compared to those of older adults without dementia and their carers. People with dementia are able to sustain self management of their medicines using established routines and strategies. As cognitive changes affect short-term memory, external strategies and task allocation to family members are introduced by the individual to support their continuing independence. The family member assumed the carer role as their concern for medication safety increased, but this role engendered stress and a burden that was unacknowledged by the health professional. PMID- 24337638 TI - The experience of people with dementia in a social care group: case study. AB - In Germany hourly care for people with dementia and relief for family caregivers are often delivered through social care groups. The existing literature describes these groups from the perspective of professionals or family caregivers, with little involvement of people with dementia. This qualitative study is the first step in exploring the experiences of people with dementia in social care groups. Five persons suffering from dementia in one group were interviewed and additionally observed with DCM in three group sessions. The interview transcripts were coded open and axial according to Grounded Theory. The DCM data was analysed descriptive. The main phenomena in the interviews are 'familiar community' and 'personal meaning'. The DCM results show that people with lower cognitive function are excluded from most activities, whereas more staff attention causes better well-being. To create a 'familiar community' in a social care group, staff skills and knowledge are required. PMID- 24337639 TI - Pathways to dementia diagnosis among South Asian Canadians. AB - Urban centers are increasingly ethnically diverse. However, some visible minorities are less likely than their majority counterparts to seek and receive services and treatment for dementia. This study explored experiences of South Asian Canadians, Canada's largest visible minority group, prior to dementia diagnosis. Six persons with dementia and eight of their family carers described their early perceptions of dementia-related changes, actions taken, including help seeking and diagnosis, and affective responses. Early signs were attributed to aging or personality. Even after cognitive enhancers were prescribed, some respondents continued to believe that the dementia symptoms were 'normal'. Family carers' affective responses may be related to their attributions. Before seeking medical attention, family carers modified physical or social environments because of symptoms. Help seeking was delayed up to four years, even with significant dementia symptoms. Recognition of a health problem was influenced by safety concerns, emergence of new symptoms following trauma, and treatment for other health problems. For some, relatives living outside the home or outside Canada were instrumental in recognizing a problem and convincing family carers and persons with dementia to seek medical attention. The pathway to diagnosis might be easier with outreach to help South Asian immigrants differentiate between normal aging and dementia. Symptom recognition by physicians treating other acute conditions was a portal to dementia services for others. Screening and referral in acute care could result in earlier diagnosis and treatment. PMID- 24337640 TI - An examination of the psychometric properties and efficacy of Dementia Care Mapping. AB - This paper offers a critique of Dementia Care Mapping (DCM) as a practice development and research tool by examining the psychometric properties and efficacy of DCM as a method for evaluating and enhancing care quality and quality of life. Based on a review and analysis of the published empirical studies utilizing DCM, it becomes apparent that there is mixed support for the tool's validity and reliability. More importantly, there is a need for additional studies specifically examining the range of related assessments to provide conclusive evidence for DCM's relevance, applicability and reliability as a practice and research tool in dementia care. The paper identifies methodological issues of implementation and use of DCM, i.e., coding practices, mapping duration. Also, a summary of the tool's strengths and limitations in practice and research settings, areas for improvement and future research avenues is provided. PMID- 24337641 TI - Experiences and concerns of family caregivers providing support to people with dementia: a cross-cultural perspective. AB - We examined experiences and concerns among caregivers of community-dwelling people with dementia from two ethnic groups. We conducted a thematic analysis of responses to the question, 'What is your life like as a caregiver?' in nine focus groups (n = 75) with Filipino and non-Hispanic White caregivers. Constant comparison methods identified themes by ethnicity. Experiences and concerns expressed across groups were related to care recipient symptoms commonly associated with dementia, including severe memory loss and behavioral changes. Participants in both ethnic groups described strategies that help them cope, such as receiving help from family and friends, receiving respite support, and participating in support groups. Filipino caregivers more often emphasized positive aspects of caregiving, whereas Whites often expressed that others do not understand the daily experiences of caregiving. Filipinos more commonly described caregivers as a 'good person' or 'saint' and emphasized that caregiving made them stronger. PMID- 24337642 TI - The effectiveness of dyadic interventions for people with dementia and their caregivers. AB - The need for dyadic intervention is enhanced with increasing numbers of older adults with early-stage dementia. The purpose of this paper is to review the effects of dyadic interventions on caregivers (CGs) and care recipients (CRs) at the early stage of dementia. Four databases, AgeLine, Medline, EBSCO, and PyscINFO were searched and relevant literature from 2000 onwards was reviewed. The twelve studies identified used a variety of intervention approaches including support group, counseling, cognitive stimulation, skill training, and notebook keeping. This review suggests that intervention programs for early-stage dementia caregiving dyads were feasible and well accepted by participants. The reviewed studies provided rich evidence of the significance of mutual understanding and communication to partners' well-being and relationship quality within the caregiving process. The findings suggest that these intervention approaches improved cognitive function of the CRs, social relations, and the relationship between the primary CG and the CR, although evidence of long-term effectiveness is lacking. PMID- 24337643 TI - Funny things happen at the Grange: introducing comedy activities in day services to older people with dementia--innovative practice. AB - This paper shares outcomes from the evaluation of a community project where comedy activities were introduced into a day centre for older people with dementia as a result of a partnership between the day centre, a local university and a specialist comedy provider. Four workshops were provided using improvisatory activities and comedy, as a medium to engage older people in reflecting on aspects of their care environment. The main output resulted in a 30 minute 'mockumentary' of the 'Her Majesty the Queen' visiting the day centre, in the form of a digital reusable learning object to be used by social work and mental health professionals. The evaluation demonstrated some additional outcomes for those involved and highlighted the benefits of laughter and fun in promoting a positive climate. PMID- 24337644 TI - The 15-deoxy-delta12,14-prostaglandin J2 inhibits LPS-stimulated inflammation via enhancement of the platelet-activating factor acetylhydrolase activity in human retinal pigment epithelial cells. AB - A well-recognized natural ligand of PPARgamma, 15-deoxy-delta(12,14) prostaglandin J(2) (15d-PGJ(2)) possesses immunomodulatory properties. The aim of this study was to elucidate whether 15d-PGJ(2) was able to attenuate lipopolysaccharide (LPS)-induced inflammatory responses in human retinal pigment epithelial (RPE) cells, which are involved in ocular immune responses. In addition, we examined whether the platelet activating factor (PAF) is associated with the anti-inflammatory activity of 15d-PGJ(2). ARPE19 cells treated with varying concentrations of 15d-PGJ(2) and a PAF antagonist (CV3988) were used in this study. The activity of PAF-acetylhydrolase (PAF-AH) was assayed by treatment with 15d-PGJ(2) and CV3988 in the presence of LPS. 15d-PGJ(2) and CV3988 inhibited the LPS-induced mRNA expression and protein production of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) in ARPE19 cells. These effects resulting from 15d-PGJ(2) were not abrogated by the PPARgamma antagonist, indicating that the actions were PPARgamma-independent. Furthermore, 15d-PGJ(2) and CV3988 enhanced the PAF-AH activity. Additionally, 15d-PGJ(2) inhibited the phosphorylation of the extracellular signal-regulated kinase (ERK) and the activation of nuclear transcription factor-kappaB (NF-kappaB). These results demonstrated that 15d PGJ(2) reduced LPS-stimulated inflammatory responses in ARPE19 cells by enhancing the PAH-AH activity. These results suggest that 15d-PGJ(2) may have potent anti inflammatory activity against ocular inflammation. PMID- 24337645 TI - Comparative genomic analysis of eutherian ribonuclease A genes. AB - The present study attempted to update comprehensive eutherian ribonuclease A gene data sets, using public eutherian genomic sequence data sets and new genomics and molecular evolution tests. Among 448 ribonuclease A potential coding sequences, the present analysis annotated 255 complete coding sequences. The most comprehensive data set of eutherian ribonuclease A genes first characterized 13 major gene clusters, 9 of which showed evidence of differential gene expansions. In addition, the present analysis described common predicted promoter regions of eutherian ribonuclease A genes. The present study also attempted to resolve discrepancies in descriptions of eutherian ribonuclease A genes. Thus, the integrated gene annotations, phylogenetic analysis and protein molecular evolution analysis proposed new classification and nomenclature of eutherian ribonuclease A genes, as new framework of future experiments. PMID- 24337646 TI - Initial experience of micro-percutaneous nephrolithotomy in the treatment of renal calculi in 140 renal units. AB - The aim of this study was to investigate the effectiveness and reliability of the micro-percutaneous nephrolithotomy (PNL) method for the management of kidney stones. We performed a retrospective analysis of 136 patients (140 renal units) who underwent micro-PNL for renal stones between September 2011 and February 2013 in four referral hospitals in Turkey. The selection of treatment modality was primarily based on factors such as stone size and location. In this study, we analyzed patient- and procedure-related factors. The mean age of patients in this study was 28.7 +/- 20.6 (1-69) years, and the mean stone size was 15.1 +/- 5.15 (6-32) mm. Conversion to mini-PNL was required in 12 patients. All interventions were performed with the patient in the prone position, except for the 3-year-old patient with the pelvic kidney who was placed in the supine position. The mean hospital stay was 1.76 +/- 0.65 (1-4) days, and the mean drop in the hemoglobin level was 0.87 +/- 0.84 (0-4.1) mg/dL. One of our patients required transfusion. Ureteral J stent was implanted in nine (6.43 %) patients because of residual stones. Seven (6.43 %) patients complained of postoperative renal colic which was managed conservatively. Abdominal distension related to extravasation of the irrigation fluid was observed in three patients (2.19 %). There were no other postoperative complications. An overall success rate of 82.14 % was achieved. Micro-PNL can be effectively and safely used for small and moderate kidney stones resistant to shock wave lithotripsy or as an alternative to other minimally invasive treatment methods. PMID- 24337647 TI - Yttrium-90 radioembolization for unresectable, chemoresistant breast cancer liver metastases: a large single-center experience of 40 patients. AB - INTRODUCTION: There are a paucity of data on the treatment of unresectable, chemoresistant breast cancer liver metastases (BRCLM) with yttrium-90 (Y90) radioembolization. METHODS: Forty patients underwent resin-based Y90 radioembolization for unresectable, chemoresistant BRCLM between 2006 and 2012 in a single institution. All patients were followed up with imaging studies at regular intervals as clinically indicated until death. Radiologic response was evaluated with the Response Criteria in Solid Tumors criteria. Clinical toxicities were prospectively recorded as per the National Cancer Institute Common Toxicity Criteria. Survival was calculated by the Kaplan-Meier method and potential prognostic variables were identified on univariate and multivariate analysis. RESULTS: Follow-up was complete in all patients. The median follow-up was 11.2 (range 0.6-30.5) months and the median survival after Y90 radioembolization was 13.6 months, with a 24-month survival of 39 %. On imaging follow-up of 38 patients who survived beyond 1 month of treatment, a complete response (CR) to treatment was observed in two patients (5 %), partial response (PR) in 10 patients (26 %), stable disease (SD) in 15 patients (39 %), and progressive disease (PD) in 11 patients (29 %). Two factors were associated with an improved survival on multivariate analysis: CR/PR to treatment (vs. SD vs. PD; p < 0.001) and chemotherapy after radioembolization (vs. no chemotherapy; p = 0.004). Sixteen patients (40 %) developed clinical toxicity after treatment; all complications were minor grade I/II and resolved without active intervention. CONCLUSION: This study provides supportive evidence of the safety and efficacy on Y90 radioembolization for the treatment of unresectable, chemoresistant BRCLM. Further prospective investigation is required to assess the suitability of this treatment in this population. PMID- 24337648 TI - Bevacizumab doubles the early postoperative complication rate after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis of colorectal origin. AB - BACKGROUND: Patients with stage IV colorectal cancer and peritoneal carcinomatosis are increasingly treated with curative intent and perioperative systemic chemotherapy combined with targeted therapy. The aim of this study was to analyze the potential impact of bevacizumab on early morbidity after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal carcinomatosis of colorectal origin. METHODS: From 2004 to 2010, in three referral centers, 182 patients with colorectal carcinomatosis were treated with complete cytoreduction followed by HIPEC after either preoperative systemic chemotherapy alone or in combination with bevacizumab. Because there was no control on treatment allocation, propensity score methods were used to control for this bias. RESULTS: The median time from discontinuation of bevacizumab to HIPEC was 7 weeks (range 6-10 weeks). Major morbidity was greater in the bevacizumab group (34 vs. 19 %, p = 0.020). Nine patients died postoperatively, 5 (6.2 %) in the bevacizumab group (n = 80) and 4 (3.9 %) in the group treated with chemotherapy alone (n = 102) (p = 0.130). The rate of digestive fistulas was greater in the bevacizumab group, although not statistically significant (18 vs. 10 %, p = 0.300). The effect of bevacizumab on major morbidity (including death) was found to be statistically significant (odds ratio 2.28, 95 % confidence interval 1.05-4.95) (p = 0.04). CONCLUSIONS: Administration of bevacizumab before surgery with complete cytoreduction followed by HIPEC for colorectal carcinomatosis is associated with twofold increased morbidity. The oncologic benefit of bevacizumab before HIPEC remains to be evaluated. PMID- 24337649 TI - Measurement of pneumococcal polysaccharide antibodies. PMID- 24337651 TI - [Cervicalgia with increased C-reactive protein levels]. PMID- 24337650 TI - Microbiota and nonalcoholic steatohepatitis. AB - The recent rise in obesity-related diseases, such as nonalcoholic fatty liver disease and its strong association with microbiota, has elicited interest in the underlying mechanisms of these pathologies. Experimental models have highlighted several mechanisms connecting microbiota to the development of liver dysfunction in nonalcoholic steatohepatitis (NASH) such as increased energy harvesting from the diet, small intestine bacterial overgrowth, modulation of the intestinal barrier by glucagon-like peptide-2 secretions, activation of innate immunity through the lipopolysaccharide-CD14 axis caused by obesity-induced leptin, periodontitis, and sterile inflammation. The manipulation of microbiota through probiotics, prebiotics, antibiotics, and periodontitis treatment yields encouraging results for the treatment of obesity, diabetes, and NASH, but data in humans is scarce. PMID- 24337652 TI - The effect of bisphenol A on some oxidative stress parameters and acetylcholinesterase activity in the heart of male albino rats. AB - Bisphenol A (BPA) is an endocrine disrupting chemical used on a wide range in industry. Several studies reported that BPA may cause cardiovascular disorders in humans and animals. The present study aims to investigate the effect of BPA on the heart of adult male rats. The rats received a daily oral administration of BPA (25 mg/kg for 6 weeks and 10 mg/kg for 6 and 10 weeks). It was found that BPA at the two studied doses induced a significant increase in malondialdehyde, and a significant decrease in catalase after 6 weeks. Moreover, a significant decrease in reduced glutathione and acetylcholinesterase (AchE) activity was observed after treatment with the two doses of BPA throughout the studied time intervals. The two doses (25 and 10 mg/kg) resulted in a significant decrease in nitric oxide (NO) levels after 6 and 10 weeks, respectively. A significant increase in body weight gain occurred in all animals after BPA treatment. These results suggest that BPA has cardiotoxic effects which are mediated by the oxidative stress resulting from the overproduction of free radicals, the deficiency of NO and the inhibition of AchE leading to cholinergic activation. The obesity promoting effect of BPA may also participate in the observed cardiovascular disturbances. PMID- 24337653 TI - Genotoxicity of indium tin oxide by Allium and Comet tests. AB - Genotoxic effects of indium tin oxide (ITO) were investigated on root cells of Allium cepa by employing both Allium and Comet assays. A. cepa roots were treated with the aqueous dispersions of ITO at 5 different concentrations (12.5, 25, 50, 75, and 100 ppm) for 4 h. Exposure of ITO significantly increased mitotic index, and total chromosomal aberrations by the Allium test. While chromosome laggards, stickiness, disturbed anaphase-telophase and anaphase bridges were observed in anaphase-telophase cells, c-metaphase and binuclear cells were observed in other cells. A significant increase in DNA damage was also observed at all concentrations of ITO by the Comet assay. These results indicate that ITO exhibits genotoxic activity in A. cepa root meristematic cells. PMID- 24337654 TI - Staged gastroschisis closure using Alexis wound retractor: first experiences. AB - INTRODUCTION: The aim of this study is to analyze the effectiveness of an Alexis wound retractor (AWR) device for staged gastroschisis closures. PATIENTS AND METHODS: AWR device was used to cover unreduced viscera of a gastroschisis when primary abdominal wall closure was not convenient. The eviscerated organs were covered with one of the two spring-loaded rings of the AWR inserted underneath the abdominal wall. Gradual reduction was guaranteed through careful traction on the external ring. We retrospectively analyzed the prenatal, post-natal and operative data of the first patients treated with AWR and report their post operative outcomes. RESULTS: The AWR device was used for staged closure in eight cases. Complete reduction and fascial closure were performed at a median of 3.5 +/- 1.6 days. Ventilatory support was necessary for 4.0 +/- 3 days and full parenteral feeds for 7.5 +/- 6.1 days after fascial closure. Median full enteral feeding was observed at 18 +/- 12.5 days after closure allowing discharge in a median period of 30.5 +/- 15.6 days after closure. CONCLUSION: The AWR device is not only a safe and efficient silo for a progressive reduction of severe gastroschisis, but also an interesting tool for continuous stretching leading to an increase of the peritoneal cavity volume, enhancing the equalizing of the viscero-abdominal disproportion. PMID- 24337655 TI - Improving genetic risk prediction by leveraging pleiotropy. AB - An important task of human genetics studies is to predict accurately disease risks in individuals based on genetic markers, which allows for identifying individuals at high disease risks, and facilitating their disease treatment and prevention. Although hundreds of genome-wide association studies (GWAS) have been conducted on many complex human traits in recent years, there has been only limited success in translating these GWAS data into clinically useful risk prediction models. The predictive capability of GWAS data is largely bottlenecked by the available training sample size due to the presence of numerous variants carrying only small to modest effects. Recent studies have shown that different human traits may share common genetic bases. Therefore, an attractive strategy to increase the training sample size and hence improve the prediction accuracy is to integrate data from genetically correlated phenotypes. Yet, the utility of genetic correlation in risk prediction has not been explored in the literature. In this paper, we analyzed GWAS data for bipolar and related disorders and schizophrenia with a bivariate ridge regression method, and found that jointly predicting the two phenotypes could substantially increase prediction accuracy as measured by the area under the receiver operating characteristic curve. We also found similar prediction accuracy improvements when we jointly analyzed GWAS data for Crohn's disease and ulcerative colitis. The empirical observations were substantiated through our comprehensive simulation studies, suggesting that a gain in prediction accuracy can be obtained by combining phenotypes with relatively high genetic correlations. Through both real data and simulation studies, we demonstrated pleiotropy can be leveraged as a valuable asset that opens up a new opportunity to improve genetic risk prediction in the future. PMID- 24337656 TI - Case-control association study of polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B and epilepsy. AB - High-frequency action potentials are mediated by voltage-gated sodium channels, composed of one large alpha subunit and two small beta subunits, encoded mainly by SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B genes in the brain. These play a key role in epilepsy, with the most commonly mutated gene in epilepsy being SCN1A. We examined whether polymorphisms in the above genes affect epilepsy risk in 1,529 epilepsy patients and 1,935 controls from four ethnicities or locations: Malay, Indian, and Chinese, all from Malaysia, and Chinese from Hong Kong. Of patients, 19 % were idiopathic, 42 % symptomatic, and 40 % cryptogenic. We genotyped 43 polymorphisms: 27 in Hong Kong, 28 in Malaysia, and 12 in both locations. The strongest association with epilepsy was rs3812718, or SCN1A IVS5N+5G>A: odds ratio (OR) = 0.85 for allele G (p = 0.0009) and 0.73 for genotype GG versus AA (p = 0.003). The OR was between 0.76 and 0.87 for all ethnicities. Meta-analysis confirmed the association (OR = 0.81 and p = 0.002 for G, and OR = 0.67 and p = 0.007 for GG versus AA), which appeared particularly strong for Indians and for febrile seizures. Allele G affects splicing and speeds recovery from inactivation. Since SCN1A is preferentially expressed in inhibitory neurons, G may decrease epilepsy risk. SCN1A rs10188577 displayed OR = 1.20 for allele C (p = 0.003); SCN2A rs12467383 had OR = 1.16 for allele A (p = 0.01), and displayed linkage disequilibrium with rs2082366 (r (2) = 0.67), whose genotypes tended toward association with SCN2A brain expression (p = 0.10). SCN1A rs2298771 was associated in Indians (OR = 0.56, p = 0.005) and SCN2B rs602594 with idiopathic epilepsy (OR = 0.62, p = 0.002). Therefore, sodium channel polymorphisms are associated with epilepsy. PMID- 24337657 TI - De novo ACTG2 mutations cause congenital distended bladder, microcolon, and intestinal hypoperistalsis. AB - Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is characterized by prenatal-onset distended urinary bladder with functional intestinal obstruction, requiring extensive surgical intervention for survival. While it is believed to be an autosomal recessive disorder, most cases are sporadic. Through whole-exome sequencing in a child with MMIHS, we identified a de novo mutation, p.R178L, in the gene encoding the smooth muscle gamma-2 actin, ACTG2. We subsequently detected another de novo ACTG2 mutation, p.R178C, in an additional child with MMIHS. Actg2 transcripts were primarily found in murine urinary bladder and intestinal tissues. Structural analysis and functional experiments suggested that both ACTG2 mutants interfere with proper polymerization of ACTG2 into thin filaments, leading to impaired contractility of the smooth muscle. In conclusion, our study suggests a pathogenic mechanism for MMIHS by identifying causative ACTG2 mutations. PMID- 24337658 TI - The role of surgical timing in the treatment of thoracic and lumbar spinal tuberculosis. AB - PURPOSE: To determine the outcome and safety of surgical treatment of thoracic and lumbar spinal tuberculosis in patients without obvious clinical and laboratory improvement after preoperative short-time chemotherapy. METHODS: Data of 86 patients with single-level thoracic and lumbar tuberculosis, treated by one stage posterior instrumentation combined with anterior radical debridement and fusion, were studied retrospectively. Patients were divided into two groups based on the results of erythrocyte sedimentation rate (ESR) after preoperative 2-week chemotherapy. Surgical outcome and prognosis were compared between the two groups. RESULTS: After antituberculous chemotherapy for 2 weeks, the ESR did not decrease or even increase in 57 patients (group A), but decreased in 29 patients (group B). However, the ESR decreased gradually after surgery and returned to a normal level at the final follow-up in both groups. Between group A and B, no significant difference was observed in pain improvement (6.3 +/- 1.4, 6.4 +/- 1.4, respectively, P = 0.805). The corrected angle was 12.4 degrees +/- 5.9 degrees , 13.8 degrees +/- 6.4 degrees , respectively, for group A and group B (P = 0.305). CONCLUSIONS: It is safe and effective to carry out the surgery just after a short-time antituberculous chemotherapy. And it is the postoperative drugs, not the preoperative drugs, that play an important role in reinforcing the surgical outcome. PMID- 24337659 TI - The effect of desflurane versus propofol on regional cerebral oxygenation in the sitting position for shoulder arthroscopy. AB - The sitting position may cause significant hemodynamic instability and cerebral hypoperfusion. We investigated the effects of desflurane and propofol on regional cerebral oxygenation (rSO2) in the sitting position during arthroscopic shoulder surgery. Forty patients undergoing arthroscopic shoulder surgery in the sitting position were randomly allocated to the desflurane group (n = 20) or the propofol group (n = 20). Anesthetic agents were maintained and adjusted with the effect site concentration of propofol (2-3.5 MUg/ml) or desflurane (4-7 vol%) to obtain a bispectral index (BIS) of 40-50. The hemodynamic variables, end-tidal carbon dioxide tension (ETCO2) and rSO2 were measured and evaluated. There were no differences in BIS, hemodynamic variables and ETCO2 between the groups. The rSO2 values in the desflurane group were higher compared to the propofol group at 3, 5, 7 and 9 min after the sitting position (P = 0.031, 0.047, 0.025 and 0.034, respectively). However, it decreased significantly from the baseline values at 3, 5, 7 and 9 min after the sitting position in both groups (P < 0.001). The change in rSO2 across time was not significantly different between the groups (P = 0.183). The incidence of rSO2 <75% of the baseline values after the sitting position was similar between the groups (0 and 10% in the desflurane and propofol group, respectively, P = 0.487). When anesthetized patients were raised to the sitting position, desflurane preserved cerebral oxygenation better than propofol at equipotent concentrations in terms of BIS. However, both anesthetics were associated with significant decrease in the rSO2 values during the sitting position. PMID- 24337660 TI - IL-17A-mediated sRANK ligand elevation involved in postmenopausal osteoporosis. AB - The role of proinflammatory IL-17 cytokine was studied in postmenopausal bone loss between 31 osteopenic and 41 osteoporotic women. The effect of serum IL-17A, soluble receptor activator of NF-kappaB (sRANK) ligand, and osteoprotegerin (OPG) levels on lumbar bone mineral densities was measured. The results demonstrated an increased IL-17A-mediated sRANK ligand elevation in postmenopausal osteoporotic bone loss. INTRODUCTION: IL-17 proinflammatory cytokine is a new inducer of bone loss. Postmenopausal osteoporosis represents a cross talk between estrogen deprivation and increased immune reactivity. The role of IL-17 was studied in the bone loss of postmenopausal osteoporosis. METHODS: Serum IL-17A, sRANK ligand, and OPG levels were investigated on bone mineral densities (BMDs) in the total lumbar (L1-L4) region in 18 pre- and 72 postmenopausal women. IL-17A, sRANK ligand, OPG levels, and BMDs were measured with enzyme-linked immunosorbent assay (ELISA) and dual-energy X-ray absorptiometry (DXA). RESULTS: Increased serum IL 17A, sRANK ligand, and OPG levels were demonstrated in postmenopausal osteoporotic women compared to osteopenic women (3.65 +/- 0.61 vs 3.31 +/- 0.43 ng/ml for IL-17A, P < 0.007; 2.88 +/- 0.84 vs 2.49 +/- 0.61 ng/ml for sRANK ligand, P < 0.027; and 1.43 +/- 0.07 vs 1.39 +/- 0.07 ng/ml for OPG, P < 0.038). In postmenopausal women, IL-17A levels correlated inversely with total lumbar BMDs (P < 0.008, r = -0.279) and positively with sRANK ligand levels (P < 0.0001, r = 0.387) or the ratio of sRANK ligand and OPG (P < 0.013, r = 0.261), but did not with OPG levels alone. CONCLUSION: Increased IL-17A levels are involved in postmenopausal osteoporosis, playing a role in the bone-resorpting processes. PMID- 24337661 TI - Dissecting the relationship between high-sensitivity serum C-reactive protein and increased fracture risk: the Rotterdam Study. AB - Serum high-sensitivity C-reactive protein (CRP) is an inflammatory biomarker. We investigated the relationship between CRP and bone health in the Rotterdam Study. Serum high-sensitivity CRP was associated with fracture risk and lower femoral neck bending strength. Mendelian randomization analyses did not yield evidence for this relationship being causal. INTRODUCTION: Inflammatory diseases are associated with bone pathology, reflected in a higher fracture risk. Serum high sensitivity CRP is an inflammatory biomarker. We investigated the relationship between CRP and bone mineral density (BMD), hip bone geometry, and incident fractures in the Rotterdam Study, a prospective population-based cohort. METHODS: At baseline, serum high-sensitivity CRP was measured. A weighted genetic risk score was compiled for CRP based on published studies (29 polymorphisms; Illumina HumanHap550 Beadchip genotyping and HapMap imputation). Regression models were reported per standard deviation increase in CRP adjusted for sex, age, and BMI. Complete data was available for 6,386 participants, of whom 1,561 persons sustained a fracture (mean follow-up, 11.6 years). RESULTS: CRP was associated with a risk for any type of fracture [hazard ratio (HR) = 1.06; 95 % confidence interval (CI), 1.02-1.11], hip fractures (HR = 1.09; 1.02-1.17) and vertebral fractures [odds ratio (OR) = 1.34; 1.14-1.58]. An inverse relationship between CRP levels and section modulus (-0.011 cm(3); -0.020 to -0.003 cm(3)) was observed. The combined genetic risk score of CRP single nucleotide polymorphisms (SNPs) was associated with serum CRP levels (p = 9 * 10(-56)), but not with fracture risk (HR = 1.00; 0.99-1.00; p = 0.23). CONCLUSIONS: Serum high sensitivity CRP is associated with fracture risk and lower bending strength. Mendelian randomization analyses did not yield evidence for this relationship being causal. Future studies might reveal what factors truly underlie the relationship between CRP and fracture risk. PMID- 24337662 TI - Prescribing with indication: uptake of regulations in current practice and patients opinions in the Netherlands. AB - BACKGROUND: Since January 2012 the Dutch Medicines Act has been changed to enable medication monitoring and counselling for individual patients. Prescribers of medicines are now obliged to record the indication on the prescription of medicines mentioned in this law. OBJECTIVE: To assess patients' opinion about recording of the indication on prescription and to explore the uptake of alterations in the medicines act in clinical practice. METHODS: The study was conducted in a sample of 57 community pharmacies belonging to the Utrecht Pharmacy Practice Network for Education and Research. In total, 528 patients were interviewed in these pharmacies and automated dispensing records were obtained from 22 community pharmacies to check prescriptions for linking of diagnosis codes (indications). RESULTS: For 12.5 % of the prescriptions that required notification of the indication, a diagnosis code was mentioned. For all other medicines, 15.1 % of the prescriptions were provided with diagnosis codes. There was large variation between different drugs. Only 11.7 % of the interviewed patients were familiar with the law. The majority of patients (91.1 %) had no objections with mentioning the indication for use on the prescription. CONCLUSION: Indications are insufficiently mentioned on prescriptions while the majority of patients are generally positive about the law. PMID- 24337663 TI - Short-term prospective effects of homophobic victimization on the mental health of heterosexual adolescents. AB - Many heterosexual youth report homophobic victimization but there is little longitudinal research to examine its mental health consequences for them. In a 7 month study across an academic school year among 572 heterosexual high school students (55% females), we tested the short-term effects of homophobic victimization on anxiety and depressive symptoms with attention to gender differences. Homophobic victimization at the beginning of the school year predicted higher levels of concurrent anxiety over and above levels attributable to general victimization. Further, when controlling for initial anxiety and general victimization, homophobic victimization at the beginning of the school year predicted increased anxiety at the end of the school year for males, but not for females. Homophobic victimization across time points was more strongly associated for males than females, and this accounted for why initial homophobic victimization predicted increased anxiety for males but not females (i.e., it was indicative of mediated moderation). In contrast, homophobic victimization at the beginning of the school year did not predict concurrent depressive symptoms over and above general victimization. Similarly, although it predicted increased depressive symptoms at the end of the school year for males but not for females, the effect was weaker than for anxiety. These findings underscore that the effects of homophobic victimization are not temporary, particularly as they pertain to anxiety, and underscore the need to consider the nature of the victimization that youth experience, including for heterosexual youth. PMID- 24337664 TI - Upregulation of NEK2 is associated with drug resistance in ovarian cancer. AB - NEK2 [NIMA (never in mitosis gene A)-related expressed kinase 2] is associated with various biological behaviors in the development of cancer, while research concerning its association with drug resistance is limited. The association of NEK2 with drug resistance in ovarian cancer has not yet been reported. In the present study, on the basis of microarray results from Oncomine and the GEO Profiles online database, we revealed that NEK2 mRNA expression in ovarian cancer tissues is upregulated. In addition, its expression in drug-resistant ovarian cancer cells was upregulated when compared with expression with their sensitive or parental counterparts. Finally, we performed a comprehensive bioinformatic analysis consisting of protein/gene-protein/gene interaction network, annotation of biological processes and microRNA-mRNA interaction analysis. We observed that NEK2 directly or indirectly interacts with a number of genes, proteins, microRNAs and biological processes associated with drug resistance in ovarian and other types of cancer. These results indicate that NEK2 contributes to drug resistance in ovarian cancer and it may be an important therapeutic target. PMID- 24337665 TI - Preoperative beta-blocker treatment is a key for deciding left ventricular assist device implantation strategy as a bridge to recovery. AB - To date, there have been few reports demonstrating preoperative predictors for left ventricular reverse remodeling (LVRR) after LV assist device (LVAD) implantation, especially among patients with dilated cardiomyopathy (DCM). We retrospectively analyzed 60 patients with stage D heart failure due to DCM who had received LVAD treatment [pulsatile flow (PF) type, 26; continuous flow type, 34]. Data were evaluated at 6 months or just before explantation of the LVAD. We defined "LV reverse remodeling" (LVRR) by the achievement of an LV ejection fraction (LVEF) of >= 35 % after 6 months of LVAD support or explantation of LVAD within 6 months. LVRR occurred in 16 of our patients (26.7 %). Uni/multivariate logistic regression analyses for LVRR demonstrated that of the preoperative variables evaluated, PF LVAD usage and insufficient preoperative beta-blocker treatment were independent predictors for LVRR. Patients who accomplished LVRR had a better clinical course, including lower levels of aortic valve insufficiency and lower levels of plasma B-type natriuretic peptide. Of the six patients (10.0 %) in whom LVADs were eventually explanted, all had an LVEF of >= 35 % before explantation or at 6 months. Based on these results, we conclude that DCM patients with insufficient preoperative beta-blocker treatment have a chance to achieve LVRR under LVAD support as a bridge to recovery. PMID- 24337666 TI - Vascular cognitive impairment, dementia, aging and energy demand. A vicious cycle. AB - To a great extent, cognitive health depends on cerebrovascular health and a deeper understanding of the subtle interactions between cerebrovascular function and cognition is needed to protect humans from one of the most devastating affliction, dementia. However, the underlying biological mechanisms are still not completely clear. Many studies demonstrated that the neurovascular unit is compromised in cerebrovascular diseases and also in other types of dementia. The hemodynamic neurovascular coupling ensures a strong increase of the cerebral blood flow (CBF) and an acute increase in neuronal glucose uptake upon increased neural activity. Dysfunction of cerebral autoregulation with increasing age along with age-related structural and functional alterations in cerebral blood vessels including accumulation of amyloid-beta (Abeta) in the media of cortical arterioles, neurovascular uncoupling due to astrocyte endfeet retraction, impairs the CBF and increases the neuronal degeneration and susceptibility to hypoxia and ischemia. A decreased cerebral glucose metabolism is an early event in Alzheimer's disease (AD) pathology and may precede the neuropathological Abeta deposition associated with AD. Abeta accumulation in turn leads to further decreases in the CBF closing the vicious cycle. Alzheimer, aging and diabetes are also influenced by insulin/insulin-like growth factor-1 signaling, and accumulated evidence indicates sporadic AD is associated with disturbed brain insulin metabolism. Understanding how vascular and metabolic factors interfere with progressive loss of functional neuronal networks becomes essential to develop efficient drugs to prevent cognitive decline in elderly. PMID- 24337667 TI - ERK inhibition with PD184161 mitigates brain damage in a mouse model of stroke. AB - Ischemic stroke is a leading cause of death. It has previously been shown that blocking activation of extracellular signal-regulated kinase (ERK) with the MEK inhibitor U0126 mitigates brain damage in rodent models of ischemic stroke. Here we show that the newer MEK inhibitor PD184161 reduces cell death and altered gene expression in cultured neurons and mice undergoing excitotoxicity, and has similar protective effects in a mouse model of stroke. This further supports ERK inhibition as a potential treatment for stroke. PMID- 24337668 TI - The Gooseneck Barnacle (Pollicipes pollicipes) as a candidate sentinel species for coastal contamination. AB - The assessment of toxic effects caused by complex mixtures of contaminants in the marine environment requires previous validation of toxicological criteria, which may include biomarker end points with distinct biological meanings. This is the case of oxidative stress/phase II detoxification (glutathione-S-transferases activity), oxidative damage (thiobarbituric acid reactive substances), and neurotransmission (cholinesterase activity), which are likely to be affected after toxic insults by common marine pollutants. The main purpose of the present study was to assess potential biological alterations in the mollusk species Pollicipes pollicipes (gooseneck barnacle) caused by human contamination and seasonality, during a period of 1 year, in three different areas of the North Atlantic shore of Portugal. Our results indicate that fluctuations of the mentioned biomarkers were strongly related to seasonality, but they may also suffer influence by the already documented patterns of chemical contamination. Organisms collected in contaminated sampling sites (urban areas and oil refinery) showed greater levels of metabolic enzymes and increased levels of lipid peroxidation. These alterations were more evident during the summer, and, in some cases, spring months, suggesting an association between the presence of chemical stressors and temperature-dependent seasonal physiological fluctuations, which contribute to the modulation of the toxic response. In general terms, P. pollicipes was shown to be a promising organism in coastal biomonitoring programs, with an adequate sensitivity toward contamination and/or seasonal fluctuations. However, it is of the utmost importance to consider seasonal fluctuations in physiological parameters that modulate the toxic response. These factors can ultimately compromise the development and interpretation of data from marine biomonitoring programs if a thorough characterization of biological responses is not previously performed. PMID- 24337669 TI - Is Borg's perceived exertion scale a useful indicator of muscular and cardiovascular load in blue-collar workers with lifting tasks? A cross-sectional workplace study. AB - PURPOSE: To investigate associations between perceived exertion and objectively assessed muscular and cardiovascular load during a full working day among workers with manual lifting tasks. METHODS: A total of 159 men and 41 women from 14 workplaces with manual lifting tasks participated. Participants reported perceived exertion (BORG-CR10) at midday and after work. Surface electromyography of the thigh, lower back and neck muscles were normalized to isometric voluntary contractions (MVC) to express relative muscle load during the day. Cardiovascular load was measured with electrocardiography and calculated as the average percentage of the heart rate reserve capacity (((heart rate during work - resting heart rate) / (maximum heart rate - resting heart rate)) * 100) during the day. RESULTS: Using linear regression, significant but weak associations (beta < 0.23) were observed between perceived exertion and (1) high muscle activity (>60% of MVC) of the neck muscles and (2) inactivity (<1% of MVC) of the thigh muscles and (3) cardiovascular load, respectively. Using logistic regression, perceived exertion >=4 (high exertion), referencing <4 (low-to-moderate exertion), was related to high activity of the trapezius muscle [OR 18 (95% CI 2-143)], i.e., the odds for experiencing high exertion during work increased 18-fold for each percentage increase in time above 60% MVC. CONCLUSIONS: During a full working day among blue-collar workers with lifting tasks, high neck muscle activity increases the odds for experiencing high perceived physical exertion. Perceived exertion of at least 4 on the BORG CR10 scale appears to be a good indicator that high muscular loading occurs. PMID- 24337670 TI - Acute hyperglycaemia does not alter nitric oxide-mediated microvascular function in the skin of adolescents with type 1 diabetes. AB - PURPOSE: We assessed the impact of an acute bout of hyperglycaemia on nitric oxide (NO)-mediated microvascular function in the skin of adolescents with type 1 diabetes (T1DM). METHODS: Twelve subjects (12-18 years) with T1DM were randomised into a control (n = 6) or hyperglycaemia (n = 6) group. Hyperinsulinaemic clamps were used to manipulate blood glucose level (BGL). Following a baseline period, where all subjects were euglycaemic (20 min), the experimental phase began. During the experimental phase, BGL was elevated to 16.7 +/- 0.9 mmol L(-1) in the hyperglyceamic group, while it was maintained at euglycaemia (5.5 +/- 0.1 mmol L( 1)) in the control group. Simultaneously, cutaneous microvascular function (% max cutaneous vascular conductance, CVC%) was assessed using laser Doppler fluxometry following stimulation of skin blood flow using localised heating (42 degrees C). To determine the NO contribution to skin blood flow, two microdialysis sites were assessed, one perfused with Ringers and the other with the NO blocker, NG monomethyl-L-arginine (L-NMMA). RESULTS: In the hyperglycaemic group, acute increase in BGL was not associated with changes in skin blood flow (CVC% 82.4 +/- 8.7% at 5.5 +/- 0.1 mmol L(-1) vs 79.5 +/- 9.1% at 16.7 +/- 0.9 mmol L(-1), unpaired t tests, P = 0.588) or the contribution of NO to vasodilation. CONCLUSIONS: These results suggest that, in our group of adolescents with type 1 diabetes, acute hyperglycaemia did not affect skin microvascular NO-mediated function. PMID- 24337671 TI - Compression stockings do not improve muscular performance during a half-ironman triathlon race. AB - PURPOSE: This study aimed at investigating the effectiveness of compression stockings to prevent muscular damage and preserve muscular performance during a half-ironman triathlon. METHODS: Thirty-six experienced triathletes volunteered for this study. Participants were matched for age, anthropometric data and training status and placed into the experimental group (N = 19; using ankle-to knee graduated compression stockings) or control group (N = 17; using regular socks). Participants competed in a half-ironman triathlon celebrated at 29 +/- 3 degrees C and 73 +/- 8% of relative humidity. Race time was measured by means of chip timing. Pre- and post-race, maximal height and leg muscle power were measured during a countermovement jump. At the same time, blood myoglobin and creatine kinase concentrations were determined and the triathletes were asked for perceived exertion and muscle soreness using validated scales. RESULTS: Total race time was not different between groups (315 +/- 45 for the control group and 310 +/- 32 min for the experimental group; P = 0.46). After the race, jump height (-8.5 +/- 3.0 versus -9.2 +/- 5.3%; P = 0.47) and leg muscle power reductions ( 13 +/- 10 versus -15 +/- 10 %; P = 0.72) were similar between groups. Post-race myoglobin (718 +/- 119 versus 591 +/- 100 MUg/mL; P = 0.42) and creatine kinase concentrations (604 +/- 137 versus 525 +/- 69 U/L; P = 0.60) were not different between groups. Perceived muscle soreness (5.3 +/- 2.1 versus 6.0 +/- 2.0 arbitrary units; P = 0.42) and the rating of perceived effort (17 +/- 2 versus 17 +/- 2 arbitrary units; P = 0.58) were not different between groups after the race. CONCLUSION: Wearing compression stockings did not represent any advantage for maintaining muscle function or reducing blood markers of muscle damage during a triathlon event. PMID- 24337673 TI - [Radiotherapeutic concepts in cancer of unknown primary site]. AB - BACKGROUND: The term cancer of unknown primary (CUP) encompasses a group of entities which differ to a great extent regarding etiology, prognosis and therapeutic management. OBJECTIVES: The aim of the study was an elaboration of the role of radiotherapy in CUP syndrome. MATERIAL AND METHODS: Systematic literature search and specification of the available treatment options. RESULTS: Radiotherapy is an integral part of interdisciplinary management approaches for patients with CUP in both curative and palliative situations. Radio-oncological techniques, such as intensity-modulated radiotherapy and stereotactic body radiotherapy increase the therapeutic window. Modern diagnostic modalities from radiology and nuclear medicine are the cornerstone of radiotherapeutic interventions, especially in terms of target volume definition and pretherapeutic staging. In the interdisciplinary setting radiation oncology offers the possibility of curative and often organ preserving approaches in patients with axillary and cervical CUP. In addition, improvement and preservation of quality of life can be achieved in patients with metastatic disease. CONCLUSION: Radiation oncology is a crucial component of the interdisciplinary management of patients with CUP. Therapeutic decisions in patients with CUP should be made in an interdisciplinary setting. PMID- 24337674 TI - [A cystic lesion in the ulna. A simple one-look diagnosis?]. PMID- 24337675 TI - [Multiple osteosclerotic intraspongiosa focal findings]. PMID- 24337676 TI - Gene expression profiling of lens tumors, liver and spleen in alpha crystallin/SV40 T antigen transgenic mice treated with Juzen-taiho-to. AB - The autogenic lens tumors induced by the Simian vacuolating virus 40 (SV40) T antigen in alpha-crystallin/SV40 T antigen transgenic (TG) mice, provide a tool to screen anti-tumor reagents in vivo and to clarify the underlying mechanisms. Juzen-taiho-to, a Chinese medicine composed of 10 herbs, was frequently used as an alternative medicine for cancer patients by clinicians and occasionally it was demonstrated to have beneficial effects on the prognosis and general condition of cancer patients. However, it was not scientifically verified. In the present study, the anti-tumor effects and underlying mechanisms of Juzen-taiho-to in the TG mice model was examined using cDNA microarray analysis and the results were confirmed by real-time PCR. The TG mice demonstrated a higher cumulative survival rate after treatment with the drug compared with the control group (P<0.05). Gene chip profiles demonstrated that cell functions involving the membrane, glycoprotein, cell membrane, signal and ionic channel for the lens tumor, the cell cycle, DNA replication, homeobox, mitosis and cell division for the spleen and the acetylation, mitochondrion, ribosomal protein, ribonucleoprotein for the liver, were altered by the administration of Juzen-taiho-to. The important canonical pathways were those of the mitogen-activated protein kinase (MAPK), the cell cycle and the ribosome for the altered genes of the lens tumor, spleen and liver after drug administration, respectively. From real-time PCR, in the eyeball, epidermal growth factor receptor (Egfr), Rasgrf1 and heat shock protein 1B (Hspa1b) mRNAs were found to be significantly lower in treated lenses than in those not exposed to the drug, while Rps25 mRNA demonstrated the opposite association in the liver. It was suggested that Juzen-taiho-to may prolong the survival time of SV40 T antigen TG mice by improving their nutritional condition, inhibiting the MAPK pathway and strengthening the immune system without causing hepatic toxicity. PMID- 24337677 TI - The PPARbeta/delta agonist GW501516 attenuates peritonitis in peritoneal fibrosis via inhibition of TAK1-NFkappaB pathway in rats. AB - Peritoneal fibrosis is a common consequence of long-term peritoneal dialysis (PD), and peritonitis is a factor in its onset. Agonist-bound peroxisome proliferator-activated receptors (PPARs) function as key regulators of energy metabolism and inflammation. Here, we examined the effects of PPARbeta/delta agonist GW501516 on peritonitis in a rat peritoneal fibrosis model. Peritoneal fibrosis secondary to inflammation was induced into uremic rats by daily injection of Dianeal 4.25% PD solutions along with six doses of lipopolysaccharide before commencement of GW501516 treatment. Normal non-uremic rats served as control, and all rats were fed with a control diet or a GW501516 containing diet. Compared to control group, exposure to PD fluids caused peritoneal fibrosis that was accompanied by increased mRNA levels of monocyte chemoattractant protein-1, tumor necrotic factor-alpha, and interleukin-6 in the uremic rats, and these effects were prevented by GW501516 treatment. Moreover, GW501516 was found to attenuate glucose-stimulated inflammation in cultured rat peritoneal mesothelial cells via inhibition of transforming growth factor-beta activated kinase 1 (TAK1), and nuclear factor kappa B (NFkappaB) signaling pathway (TAK1-NFkappaB pathway), a main inflammation regulatory pathway. In conclusion, inhibition of TAK1-NFkappaB pathway with GW501516 may represent a novel therapeutic approach to ameliorate peritonitis-induced peritoneal fibrosis for patients on PD. PMID- 24337678 TI - Effects of costimulation on intrahepatic immunopathogenesis in patients with chronic HBV infection. AB - OBJECTIVE: Chronic HBV infection can lead to "immune tolerance" in asymptomatic carriers (ACs), "immune injury" in active chronic hepatitis (ACH) patients or "immune abnormality" in cirrhosis (Cir) and hepatocellular carcinoma (HCC) patients. Previous investigations reported that chronic hepatitis presented abnormal expression of costimulatory molecules. We investigated the costimulation profile in the liver of ACs and patients with ACH, Cir and HCC. METHODS: Patients with ACH, Cir and HCC, ACs and normal controls were recruited into the present study. The costimulation profiles and cytokines in the liver of patients were investigated by Western blotting, immunohistochemistry and real-time quantitative PCR. Correlations between serum alanime aminotransferase (ALT) levels, necroinflammation scores, cytokines and costimulatory proteins were assessed. RESULTS: The ACs presented decreased inflammatory and increased inhibitory costimulation, which was negatively correlated with inflammatory costimulatory proteins and ALT, whereas the ACH patients exhibited increased inflammatory costimulation and decreased inhibitory costimulation, which was correlated with increased ALT. The Cir patients showed both increased inhibitory and inflammatory costimulation. The HCC patients exhibited both decreased inhibitory and inflammatory costimulation. CONCLUSION: Costimulation participates in intrahepatic immune responses, and plays important roles in immune tolerance, immune injury and immune abnormalities in patients with chronic HBV infection. PMID- 24337679 TI - Mathematical analysis of a model for the growth of the bovine corpus luteum. AB - The corpus luteum (CL) is an ovarian tissue that grows in the wound space created by follicular rupture. It produces the progesterone needed in the uterus to maintain pregnancy. Rapid growth of the CL and progesterone transport to the uterus require angiogenesis, the creation of new blood vessels from pre-existing ones, a process which is regulated by proteins that include fibroblast growth factor 2 (FGF2). In this paper we develop a system of time-dependent ordinary differential equations to model CL growth. The dependent variables represent FGF2, endothelial cells (ECs), luteal cells, and stromal cells (like pericytes), by assuming that the CL volume is a continuum of the three cell types. We assume that if the CL volume exceeds that of the ovulated follicle, then growth is inhibited. This threshold volume partitions the system dynamics into two regimes, so that the model may be classified as a Filippov (piecewise smooth) system. We show that normal CL growth requires an appropriate balance between the growth rates of luteal and stromal cells. We investigate how angiogenesis influences CL growth by considering how the system dynamics depend on the dimensionless EC proliferation rate, rho5. We find that weak (low rho5) or strong (high rho5) angiogenesis leads to 'pathological' CL growth, since the loss of CL constituents compromises progesterone production or delivery. However, for intermediate values of rho5, normal CL growth is predicted. The implications of these results for cow fertility are also discussed. For example, inadequate angiogenesis has been linked to infertility in dairy cows. PMID- 24337680 TI - Mathematical models for CFSE labelled lymphocyte dynamics: asymmetry and time-lag in division. AB - Since their invention in 1994, fluorescent dyes such as carboxyfluorescein diacetate succinimidyl ester (CFSE) are used for cell proliferation analysis in flow cytometry. Importantly, the interpretation of such assays relies on the assumption that the label is divided equally between the daughter cells upon cell division. However, recent experimental studies indicate that division of cells is not perfectly symmetric and there is unequal distribution of protein between sister cell pairs. The uneven partition of protein or mass to daughter cells can lead to an overlap in the generations of CFSE-labelled cells with straightforward consequences for the resolution of individual generations. Numerous mathematical models developed so far for the analysis of CFSE proliferation assay incorporate the premise that the CFSE fluorescence intensity is halved in the two daughter cells. Here, we propose a novel modelling approach for the analysis of the CFSE cell proliferation assays which are characterized by poorly resolved peaks of cell generations in flow cytometric histograms. We formulate a mathematical model in the form of a system of delay hyperbolic partial differential equations which provides a good agreement with the CFSE histograms time-series data and allows an analytical treatment. The model is a further generalization of the recently proposed class of division- and label-structured models as it considers an asymmetric cell division. In addition, the basic structure of the cell cycle, i.e. the resting and cycling cell compartments, is taken into account. The model is used to estimate fundamental parameters such as activation rate, duration of the cell cycle, apoptosis rate, CFSE decay rate and asymmetry factor in cell division of monoclonal T cells during cognate interaction with dendritic cells. PMID- 24337681 TI - Impact of kidney function and urinary protein excretion on pulmonary function in Japanese patients with chronic kidney disease. AB - BACKGROUND: Although the cardiorenal relationship in chronic kidney disease has been investigated, information about the lung-kidney relationship is limited. Here, we investigated the impact of kidney function and urinary protein excretion on pulmonary dysfunction. METHODS: The data from pulmonary function tests and kidney function (estimated glomerular filtration rate [eGFR] and urinary protein) between 1 April 2005 and 30 June 2010 were selected from our laboratory database. Data were classified into 4 categories according to eGFR and proteinuria. Category 1, eGFR >=60 ml/min/1.73 m(2) and urinary protein <0.3 g/gCr; category 2, eGFR <60 ml/min/1.73 m(2) and urinary protein <0.3 g/gCr; category 3, eGFR >=60 ml/min/1.73 m(2) and urinary protein >=0.3 g/gCr; and category 4, eGFR <60 ml/min/1.73 m(2) and urinary protein >=0.3 g/gCr. Pulmonary function data were evaluated according to these 4 categories. RESULTS: A total of 133 participants without major respiratory disease, abnormal computed tomography and smoking history were enrolled. Hemoglobin (Hb)-adjusted percentage carbon monoxide diffusing capacity (%DLCO) in category 4 (46.2 +/- 7.5) and category 2 (63.6 +/- 17.8) were significantly lower than in category 1 (75.8 +/- 18.9) (P < 0.05). In addition, Hb-adjusted %DLCO was weakly correlated with eGFR in participants with urinary protein <0.3 g/gCr (R = 0.30, P = 0.001). Hb-adjusted %DLCO was strongly correlated with eGFR in participants with urinary protein >=0.3 g/gCr (R = 0.81, P < 0.001). Other pulmonary function test markers (percentage (%) vital capacity, % forced expiratory volume in one second (FEV1), FEV1/forced vital capacity, % total lung capacity, and % residual volume) were not significantly different between categories. CONCLUSION: This study suggests that decreased eGFR is associated with decreased %DLCO in proteinuric patients. PMID- 24337682 TI - Sorcin silencing inhibits epithelial-to-mesenchymal transition and suppresses breast cancer metastasis in vivo. AB - Sorcin, a 22-kDa calcium-binding protein, renders cancer cells resistant to chemotherapeutic agents, thus playing an important role in multidrug resistance. As there is a clear association between drug resistance and an aggressive phenotype, we asked whether sorcin affects also the motility, invasion, and stem cell characteristics of cancer cells. We have used both RNA interference (transient and stable expression of hairpins) and a lentiviral expression vector to experimentally modulate sorcin expression in a variety of cells. We demonstrate that sorcin depletion in MDA-MB-231 breast cancer cells reduces the pool of CD44(+)/CD24(-) and ALDH1(high) cancer stem cells (CSCs) as well as mammosphere-forming capacity. We also observe that sorcin regulates epithelial mesenchymal transition and CSCs partly through E-cadherin and vascular endothelial growth factor expression. This leads to the acquisition of an epithelial-like phenotype, attenuating epithelial-mesenchymal transition and suppression of metastases in nude mice. The sorcin-depleted phenotype can also be reproduced in lung adenocarcinoma A549 cells and lung fibrosarcoma HT1080 cells. In addition, overexpression of sorcin in MCF7 cells, which have low endogenous sorcin expression levels, increases their migration and invasion in vitro. This offers the rationale for the development of therapeutic strategies down regulating sorcin expression for the treatment of cancer. PMID- 24337683 TI - Correlation of gastric heterotopia and Meckel's diverticular bleeding in children: a unique association. AB - PURPOSE: Meckel's diverticular bleeding is the commonest cause of major gastrointestinal (GI) haemorrhage in children. We hypothesise that gastric heterotopia (GH) is associated with increased risk of bleeding and, therefore, may affect initial management. METHODS: Paediatric patients with histological diagnosis of Meckel's diverticulum (MD) following diverticulectomy from 1995 to 2011 were reviewed retrospectively, focusing on histological correlation to bleeding. GH identified on histology was regarded as GH+, and where GH was not found was regarded as GH-. Two-tailed Chi-square test and Fisher's exact test were used, p < 0.05 was statistically significant. RESULTS: Thirty-nine patients underwent Meckel's diverticulectomy. The number of patients with GH+, GH-, and bowel necrosis were 21, 15, and 3. Eighteen children with MD had GI bleeding. GI bleeding was more commonly associated with GH+ (14/21) than GH- (4/15) (67 vs 27 %, p = 0.02). Further analysis revealed all four GH- bleeding originated from other sources than the MD. GH+ had no significant association with other presentations. GH+ was present in 8/8 (100 %) positive Meckel's scans and 2/5 (40 %) negative scans. Meckel's scan had a sensitivity of 8/10 (80 %), and specificity of 3/3 (100 %). CONCLUSION: This study confirmed that GH positive MD is a unique entity presenting typically with GI bleeding. PMID- 24337684 TI - Symptom prevalence, frequency, severity, and distress during chemotherapy for patients with colorectal cancer. AB - PURPOSE: Early detection and improvements in treatment have increased survival after colorectal cancer (CRC), but studies investigating the multidimensional nature of treatment-related symptoms are rare. The aim of this study was therefore to describe the prevalence, frequency, and severity of symptoms and the distress they cause during the early treatment of patients with CRC undergoing chemotherapy. METHODS: Consecutive outpatients were asked to rate their symptoms during cycle 2 or 3 of chemotherapy, using the Memorial Symptom Assessment Scale. RESULTS: A total of 104 patients, 58 men and 46 women, evaluated their symptoms of the preceding week at one point during the treatment. The mean number of symptoms was 10.3 (SD, 7.7; range, 0-32). Highly prevalent symptoms were numbness/tingling in the hands/feet (64 %), lack of energy (62 %), feeling drowsy (49 %), and nausea (45 %). Symptoms with the highest scores for frequency, severity, and distress were lack of energy followed by difficulty in sleeping and numbness in the hands/feet. Lack of energy was noted as occurring almost constantly by 26 % and was rated as being severe or very severe by 12 % and as quite distressing or very distressing by 15 %. CONCLUSIONS: This study shows that patients with CRC receiving chemotherapy experience several distressing symptoms early in the treatment phase. In order to provide symptom control, oncology staff should consider evaluating the patient's symptoms early during treatment and plan adequate measures to minimize the impact of treatment-induced toxicity. PMID- 24337685 TI - Acute stress, depression, and anxiety symptoms among English and Spanish speaking children with recent trauma exposure. AB - A growing literature suggests the clinical importance of acute stress disorder symptoms in youth following potentially traumatic events. A multisite sample of English and Spanish speaking children and adolescents (N = 479) between the ages of 8-17, along with their caregivers completed interviews and self-report questionnaires between 2 days and 1 month following the event. The results indicate that children with greater total acute stress symptoms reported greater depressive (r = .41, p < .01) and anxiety symptoms (r = .53, p < .01). Examining specific acute stress subscales, reexperiencing was correlated with anxiety (r = .47, p < .01) and arousal was correlated with depression (r = .50, p < .01) and anxiety (r = .55, p < .01). Age was inversely associated with total acute stress symptoms (r = -.24, p < .01), reexperiencing (r = -.17, p < .01), avoidance (r = .27, p < .01), and arousal (r = -.19, p < .01) and gender was related to total anxiety symptoms (Spearman's rho = .17, p < .01). The current study supports the importance of screening acute stress symptoms and other mental health outcomes following a potentially traumatic event in children and adolescents. Early screening may enable clinicians to identify and acutely intervene to support children's psychological and physical recovery. PMID- 24337686 TI - Upregulation of the long non-coding RNA PlncRNA-1 promotes esophageal squamous carcinoma cell proliferation and correlates with advanced clinical stage. AB - BACKGROUND: Recent studies revealed that long noncoding RNAs (lncRNAs) play critical regulatory roles in cancer biology. PlncRNA-1 is one of lncRNAs that is associated with cell apoptosis and proliferation of prostate cancer. AIM: This study aimed to assess the potential role of PlncRNA-1 in the pathogenesis of esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression level of PlncRNA-1 in 73 pairs of ESCC and their matched normal tissues. The correlation of PlncRNA-1 with clinicopathological features and clinical stages was also analyzed. Cancer cell proliferation and apoptosis were assessed following knock-down of PlncRNA-1 by MTT, colony formation assay, and flow cytometry. RESULTS: The expression of PlncRNA-1 was significantly higher in human ESCC compared with the adjacent noncancerous tissues (69.8 %, p < 0.05), and the high level of PlncRNA-1 expression was significantly correlated with advanced clinical stage (p < 0.01) and lymph node metastasis (p < 0.05). Furthermore, knockdown of PlncRNA-1 reduced cell proliferation and increased the apoptosis in vitro. CONCLUSIONS: PlncRNA-1 plays an important role in ESCC cell proliferation. Overexpression of PlncRNA-1 is correlated with advanced tumor stage and lymph node metastasis, and may serve as a potential prognostic marker and therapeutic target for ESCC. PMID- 24337687 TI - Identification of circulating microRNAs as novel potential biomarkers for gastric cancer detection: a systematic review and meta-analysis. AB - BACKGROUND: Recent studies show that microRNAs (miRNAs) in serum or plasma can be stably detected and used as potential biomarkers in cancer diagnosis. OBJECTIVES: To systematically evaluate circulating miRNAs from numerous gastric cancer (GC) expression profiling studies and to determine miRNA biomarkers for GC detection. METHODS: A systematic review and meta-analysis of published studies comparing the circulating miRNA expressions between GC patients and healthy controls were carried out. An miRNA ranking system that considered the number of comparisons in agreement, total number of samples, and average fold change was used. Then the receiver-operating characteristic curve (ROC) results of the top miRNAs were combined to further evaluate their diagnostic value by using Meta-disc 1.4. RESULTS: A total of 35 miRNAs were reported in the 22 included studies, with 7 miRNAs reported in at least 2 studies. MiR-21 is the most consistently reported miRNA with upregulation. In further analysis, the sensitivity, specificity, and area under the curve of summary ROC for miR-21 in GC diagnosis are 0.78 (95 % CI 0.71-0.85), 0.89 (95 % CI 0.82-0.94), and 0.91, respectively. CONCLUSION: Circulating miR-21 can serve as a potential biomarker for detection of GC. PMID- 24337688 TI - Plerixafor induces the rapid and transient release of stromal cell-derived factor 1 alpha from human mesenchymal stromal cells and influences the migration behavior of human hematopoietic progenitor cells. AB - The interaction between the stromal cell-derived factor-1 alpha (SDF-1alpha, CXCL12) and its chemokine receptor CXCR4 has been reported to regulate stem cell migration, mobilization and homing. The CXCR4 antagonist plerixafor is highly efficient in mobilizing hematopoietic progenitor cells (HPCs). However, the precise regulatory mechanisms governing the CXCR4/SDF-1alpha axis between the bone marrow niche and HPCs remain unclear. In this study, we quantify the impact of plerixafor on the interaction between human bone marrow derived mesenchymal stromal cells (MSCs) and human CD34+ HPCs. An assessment of SDF-1alpha levels in the supernatant of MSC cultures revealed that exposure to plerixafor led to a transient increase but had no long-term effect. In Transwell experiments, we observed that the addition of SDF-1alpha significantly stimulated HPC migration; this stimulation was almost completely antagonized by the addition of plerixafor, confirming the direct impact of the CXCR4/SDF-1alpha interaction on the migration capacity of HPCs. We also developed a new microstructural niche model to determine the chemotactic sensitivity of HPCs. Time-lapse microscopy demonstrated that HPCs migrated actively along an SDF-1alpha gradient within the microchannels and the quantitative assessment of the required minimum gradient initiating this chemotaxis revealed a surprisingly high sensitivity of HPCs. These data demonstrate the fine-tuned balance of the CXCR4/SDF-1alpha axis and the synergistic effects of plerixafor on HPCs and MSCs, which most likely represent the key mechanisms for the consecutive mobilization of HPCs from the bone marrow niche into the circulating blood. PMID- 24337689 TI - Rat choroidal pericytes as a target of the autonomic nervous system. AB - Pericytes are contractile cells that surround blood vessels. When contracting, they change the diameter of the vessel and therefore influence blood flow homeostasis; however, mechanisms controlling pericyte action are less well understood. Since blood flow regulation per se is controlled by the autonomic nervous system, the latter might also be involved in pericyte action. Hence, rat choroidal pericytes were analyzed for such a connection by using appropriate markers. Rat choroidal wholemounts and sections were prepared for immunohistochemistry of the pericyte marker chondroitin-sulfate-proteoglycan (NG2) and the pan-neuronal marker PGP9.5 or of tyrosine hydroxylase (TH), vasoactive intestinal polypeptide (VIP) and choline acetyl transferase (ChAT). Additionally, PGP9.5 and TH were analyzed in the choroid of DCX-dsRed2 transgenic rats, displaying red-fluorescent perivascular cells and serving as a putative model for studying pericyte function in vivo. Confocal laser-scanning microscopy revealed NG2-immunoreactive cells and processes surrounding the blood vessels. These NG2-positive cells were not co-localized with PGP9.5 but received close appositions of PGP9.5-, TH-, VIP- and ChAT-immunoreactive boutons and fibers. In the DCX-dsRed2 transgenic rat, PGP9.5 and TH were also densely apposed on the dsRed-positive cells adjacent to blood vessels. These cells were likewise immunoreactive for NG2, suggesting their pericyte identity. In addition to the innervation of vascular smooth muscle cells, the close relationship of PGP9.5 and further sympathetic (TH) and parasympathetic (VIP, ChAT) nerve fibers on NG2 positive pericytes indicated an additional target of the autonomic nervous system for choroidal blood flow regulation. Similar findings in the DCX-dsRed transgenic rat indicate the potential use of this animal model for in vivo experiments revealing the role of pericytes in blood flow regulation. PMID- 24337690 TI - Does mother know best? Adolescent and mother reports of impulsivity and subsequent delinquency. AB - Although impulsivity is one of the strongest psychological predictors of crime, it is unclear how well impulsivity, measured at a specific moment in adolescence, predicts criminal behavior months or years into the future. The present study investigated how far into the future self-reports and parents' reports of a youth's impulsivity predicted whether he engaged in illegal behavior, whether one reporter's assessment was more predictive than the other's, and whether there is value in obtaining multiple reports. Data were obtained from a 6-year longitudinal study of adjudicated juvenile offenders (n = 701 mother-son dyads). Youth (m = 15.93 years old; sd = 1.14) and their mothers independently reported on adolescents' impulsivity at the initial assessment. We examined the prospective correlation of these measures with illegal behavior, assessed by official records of arrests and youths' self-reports of offending across the 72 month study period. Youths' and mothers' reports of the adolescents' impulsivity were weakly, but significantly, correlated with one another. Furthermore, mothers' ratings of their sons' impulsivity predicted arrest up to 6 years into the future, whereas youths' reports did not significantly predict arrest beyond 30 months. With respect to youths' self-reports of offending, mothers' ratings of impulsivity again predicted farther into the future (as late as 6 years later) than did youths' self-reports of impulsivity, which were not predictive beyond 4 years. However, across the first 4 years, youths' self-reports of impulsivity explained more variance in self-reported offending than did mothers' ratings. The results underscore the endurance of the predictive utility of an assessment of impulsivity and the importance (and accuracy) of parents' reports of developmental constructs, even when their children are adolescents. PMID- 24337691 TI - Interrelationships between pain processing, cortisol and cognitive performance in chronic whiplash-associated disorders. AB - The present study aims at studying interactions between cognitive performance and conditioned pain modulation in patients with chronic whiplash-associated disorders (WAD) and healthy controls. In addition, the relation between cortisol concentrations and cognitive performance will be studied in patients with chronic WAD. Thirty-one subjects, 16 healthy subjects and 15 patients with chronic WAD, were enrolled and subjected to several self-report and physiological measures. Self-report measures encompassed pain rating during a procedure evaluating conditioned pain modulation. Afterward, they were subjected to physiological measures, which are cognitive tests (Stroop task, psychomotor vigilance task, and operation span task) preceded and followed by salivary cortisol concentration measurements. Chronic WAD patients performed worse in recall at the operation span task and presented longer reaction times at the psychomotor vigilance task and at the Stroop task when sleep-related words were shown (p < .05). Conditioned pain modulation and cortisol concentrations were not significantly different between patients and controls (p > .05). Only in the healthy subjects, conditioned pain modulation and baseline cortisol concentrations were correlated to cognitive performance (p < .05). This is the first study addressing the relation between pain inhibition and cognitive performance in chronic WAD. We did not reveal impaired pain inhibition but did reveal cognitive dysfunctions in patients with chronic WAD. In healthy subjects, pain inhibition was related to cognitive performance but not in the patient group. PMID- 24337692 TI - Use of rituximab in histologically confirmed idiopathic inflammatory myositis: a case series. AB - The purpose of the study was to undertake an audit of the use of rituximab in refractory idiopathic inflammatory myositis (IIM). Patients with biopsy-proven refractory IIM treated with rituximab, attending the rheumatology clinic at the Royal Adelaide Hospital were identified by searching the electronic database of patient records from 2007 to March 2013. Seven cases (five women, two men), age range 31 to 68 years with histologically confirmed IIM, were identified. All patients had received rituximab following other immunosuppressive agents, including prednisolone. With rituximab, all patients showed improvement in muscle strength and reduction in muscle enzyme levels and required reduced doses of oral corticosteroids. Response continued for at least 5 months from the initial treatment. No serious adverse events were noted, and there were no infections during the study period. This case series supports the use of B cell depletion therapy with rituximab as an effective treatment for patients with refractory IIM. PMID- 24337693 TI - Clinical Rheumatology: building-up on past success. PMID- 24337694 TI - DNA repair mechanisms and Toxoplasma gondii infection. AB - Lately, we can observe significant progress in understanding mechanism of DNA repair owing to fast methods of DNA sequence analysis from different organisms the revealing of structure and function of DNA repair proteins in prokaryota and eukaryota. The protozoan parasites survival depends on DNA repair systems. Better understanding of DNA repair systems can help in new antipathogen drug development. This review is aimed at updating our current knowledge of the various repair pathways by providing an overview of DNA repair genes regarding Toxoplasma gondii infections and the corresponding proteins, participating either directly in DNA repair, or in checkpoint control and signaling of DNA damage. PMID- 24337695 TI - Does prior sepsis alter subsequent circadian and sickness behaviour response to lipopolysaccharide treatment in mice? AB - Previous data has shown that prior history of immune challenge may affect central and behavioural responses to subsequent immune challenge, either leading to exaggerated responses via priming mechanisms or lessened responses via endotoxin tolerance. In this set of experiments we have examined how previously lipopolysaccharide (LPS)-induced sepsis shapes the response to subsequent treatment with lower dose LPS. After treatment with LPS (5 mg/kg) or saline mice were allowed to recover for 3-4 months before being challenged with a lower dose of LPS (100 MUg/kg) for assessment of sickness behaviours. Performance on the open field test and the tail suspension test was assessed, and no evidence was found that prior sepsis altered sickness or depressive-like behaviour following LPS treatment. We then examined the responsiveness of the circadian system of mice to LPS. We found that in control animals, LPS induced a significant phase delay of the behavioural rhythm and that this was not the case in post-septic animals (4-6 weeks after sepsis), indicating that prior sepsis alters the responsivity of the circadian system to subsequent immune challenge. We further assessed the induction of the immediate early genes c-Fos and EGR1 in the hippocampus and the suprachiasmatic nucleus (SCN; the master circadian pacemaker) by LPS in control or post-septic animals, and found that post-septic animals show elevated expression in the hippocampus but not the SCN. These data suggest that previous sepsis has some effect on behavioural and molecular responses to subsequent immune challenge in mice. PMID- 24337697 TI - Franca Buffoni (1924-2011): a pioneer in biochemical pharmacology. PMID- 24337696 TI - Cerebellar and parkinsonian phenotypes in multiple system atrophy: similarities, differences and survival. AB - Multiple system atrophy (MSA) is a neurodegenerative disease with two motor phenotypes: parkinsonian (MSA-P) and cerebellar (MSA-C). To elucidate whether in addition to the motor abnormalities there are other significant differences between these phenotypes, we performed a retrospective review of 100 patients (61 males, 39 females) with a diagnosis of possible (12 %), or probable (88 %) MSA. Four patients eventually had post-mortem confirmation (i.e., definite MSA). Sixty percent were classified as having MSA-P and 40 % as MSA-C. MSA-C and MSA-P patients had similar male prevalence (60 %), age of onset (56 +/- 9 years), and frequency of OH (69 %). Brain MRI abnormalities were more frequent in MSA-C patients (p < 0.001). Mean survival was 8 +/- 3 years for MSA-C and 9 +/- 4 years for MSA-P patients (p = 0.22). Disease onset before 55 years predicted longer survival in both phenotypes. Initial autonomic involvement did not influence survival. We conclude that patients with both motor phenotypes have mostly similar survivals and demographic distributions. The differences here identified could help counseling of patients with MSA. PMID- 24337698 TI - Social contexts of heterosexual transmission of HIV/STI in Liuzhou City, China. AB - In this special issue of AIDS and Behavior, we focus on the social contexts of sexual transmission of HIV/STI in one South China city. Our multiple projects grew from partnerships across the social and biomedical sciences, and with public health experts in Liuzhou City, to address critical gaps in knowledge about how social factors drive heterosexual transmission. The eleven articles that comprise this special issue feature multidisciplinary and mixed method approaches, collecting data in Liuzhou from different populations, environments, and social venues where individuals often find sexual partners. They document heterosexual behaviors and their meanings. They investigate the experiences and behaviors of women and men in social venues, exploring the networks of people within these venues, how they relate to one another, share information, and influence each other. The articles also examine the experiences of people living with HIV, again collecting data from multiple levels and sources, and revealing the ongoing power of stigma to shape these lives. Taken together, the articles demonstrate the critical role of social contexts in shaping behaviors and meanings, which are linked to heterosexual transmission of HIV/STI, and which must be taken into account for the development of appropriate and effective public health interventions. PMID- 24337699 TI - Structural bridging network position is associated with HIV status in a younger Black men who have sex with men epidemic. AB - Younger Black men who have sex with men (BMSM) ages 16-29 have the highest rates of HIV in the United States. Despite increased attention to social and sexual networks as a framework for biomedical intervention, the role of measured network positions, such as bridging and their relationship to HIV risk has received limited attention. A network sample (N = 620) of BMSM respondents (N = 154) and their MSM and transgendered person network members (N = 466) was generated through respondent driven sampling of BMSM and elicitation of their personal networks. Bridging status of each network member was determined by a constraint measure and was used to assess the relationship between this bridging and unprotected anal intercourse (UAI), sex-drug use (SDU), group sex (GS) and HIV status within the network in South Chicago. Low, moderate and high bridging was observed in 411 (66.8 %), 81 (13.2 %) and 123 (20.0 %) of the network. In addition to age and having sex with men only, moderate and high levels of bridging were associated with HIV status (aOR 3.19; 95 % CI 1.58-6.45 and aOR 3.83; 95 % CI 1.23-11.95, respectively). Risk behaviors observed including UAS, GS, and SDU were not associated with HIV status, however, they clustered together in their associations with one another. Bridging network position but not risk behavior was associated with HIV status in this network sample of younger BMSM. Socio-structural features such as position within the network may be important when implementing effective HIV prevention interventions in younger BMSM populations. PMID- 24337700 TI - Palmitate induces COX-2 expression via the sphingolipid pathway-mediated activation of NF-kappaB, p38, and ERK in human dermal fibroblasts. AB - It has been suggested that free fatty acids (FFA) such as palmitate, which are secreted from enlarged adipocytes in the subcutaneous fat of obese subjects, serve as a link between obesity and altered skin functions. Cyclooxygenease-2 (COX-2) and prostanoids participate in the induction of impaired dermal function. In the current study, we investigated the issue of whether palmitate induces COX 2 expression via the sphingolipid pathway-mediated activation of NF-kappaB or mitogen-activated protein kinase (MAPK) pathways in human dermal fibroblasts. Palmitate treatment significantly induced COX-2 expression and prostaglandin E2 (PGE2) release in human dermal fibroblasts. In addition, pre-treatment with triacsin C, an inhibitor of acyl-CoA synthetase in de novo ceramide synthesis, was found to reduce palmitate-induced COX-2 expression and PGE2 release in human dermal fibroblast. The findings also show that palmitate-induced COX-2 expression and PGE2 release are mediated by the NF-kappaB, p38, and extracellular signal regulated kinase (ERK) MAPK pathways. These findings point to a new mechanism for explaining the link between increased FFAs in obesity and impaired dermal function. PMID- 24337701 TI - Gradient compression garments protect against orthostatic intolerance during recovery from bed rest. AB - INTRODUCTION: Abdomen-high, lower body graded compression garments (GCGs) may represent the next-generation of orthostatic intolerance protection with applications for exploration missions and commercial space flight. PURPOSE: To evaluate the efficacy of the GCG to prevent orthostatic intolerance after a 14 day 6 degrees head-down tilt bed rest (BR) and to determine whether wearing thigh-high compression garments impairs recovery from BR. METHODS: Sixteen (12 M, 4 F) subjects participated in a 15-min 80 degrees head-up tilt test 5 day before BR (BR-5), on the last morning of BR (BR+0), and on day 1 (BR+1) and 3 after BR (BR+3). No subjects wore the GCG on BR-5, and all subjects wore the GCG during testing on BR+0. Control subjects (n = 8) wore the GCG only through testing on BR+0. Treatment subjects (n = 8) wore the GCG on BR+0 and thigh-high garments on BR+1 and BR+2. RESULTS: No subjects were presyncopal during tilt on BR+0 while wearing the GCG. Despite lower plasma volume index (BR-5: 1.52 +/- 0.06, BR+0: 1.32 +/- 0.05 l/m(2)), the tilt-induced increase in heart rate (DeltaHR, 17 +/- 2 bpm) and decrease in stroke volume (DeltaSV, -28 +/- 3 ml) on BR+0 were less than on BR-5 (24 +/- 2 bpm, -43 +/- 4 ml). On BR+1 DeltaHR in the control group (33 +/ 4 bpm) was higher than in the treatment group (23 +/- 2 bpm) but there were no group differences on BR+3. CONCLUSIONS: Wearing the GCG prevented the orthostatic intolerance that is normally present after BR. Thigh-high garments provided protection after BR, and wearing these garments did not impair recovery. PMID- 24337702 TI - Prognostic significance of IL-17 mRNA expression in peritoneal lavage in gastric cancer patients who underwent curative resection. AB - Peritoneal dissemination is frequently detected in patients with advanced gastric cancer. The peritoneal cavity is a compartment in which an immunologic host-tumor interaction can occur. There are no reports on the relationship between IL-17 expression in peritoneal lavage and prognosis in gastric cancer patients. Therefore, we investigated the expression of IL-17 mRNA in peritoneal lavage from gastric cancer patients and assessed the association of its expression with clinicopathological parameters and prognosis. Peritoneal lavage was obtained from 114 patients with gastric cancer at initial surgery. Seventy-nine patients underwent curative resection. Among these 79 patients, IL-17 mRNA expression was associated with the depth of tumor invasion (p<0.05). Twelve of the 79 patients who underwent curative resection died, and 9 of those 12 developed peritoneal metastasis. Notably, among the 79 patients who underwent curative resection, those with high expression of IL-17 mRNA in peritoneal lavage had significantly prolonged survival when compared to these patients with low expression of IL-17 mRNA in peritoneal lavage (p<0.05) as evidence by the survival curves. In a multivariate analysis, low expression of IL-17 mRNA in peritoneal lavage and tumor size were found to be independent significant predictive factors for prognosis (HR, 7.91; 95% CI, 1.65-38.03) in the patients who underwent curative resection. IL-17 mRNA expression in peritoneal lavage is a reliable prognostic factor for patients undergoing curative resection for gastric cancer. Low IL-17 expression in the peritoneal cavity may correlate with cancer development in the peritoneal cavity in patients with gastric cancer. PMID- 24337703 TI - Identifying molecular features that distinguish fluvastatin-sensitive breast tumor cells. AB - Statins, routinely used to treat hypercholesterolemia, selectively induce apoptosis in some tumor cells by inhibiting the mevalonate pathway. Recent clinical studies suggest that a subset of breast tumors is particularly susceptible to lipophilic statins, such as fluvastatin. To quickly advance statins as effective anticancer agents for breast cancer treatment, it is critical to identify the molecular features defining this sensitive subset. We have therefore characterized fluvastatin sensitivity by MTT assay in a panel of 19 breast cell lines that reflect the molecular diversity of breast cancer, and have evaluated the association of sensitivity with several clinicopathological and molecular features. A wide range of fluvastatin sensitivity was observed across breast tumor cell lines, with fluvastatin triggering cell death in a subset of sensitive cell lines. Fluvastatin sensitivity was associated with an estrogen receptor alpha (ERalpha)-negative, basal-like tumor subtype, features that can be scored with routine and/or strong preclinical diagnostics. To ascertain additional candidate sensitivity-associated molecular features, we mined publicly available gene expression datasets, identifying genes encoding regulators of mevalonate production, non-sterol lipid homeostasis, and global cellular metabolism, including the oncogene MYC. Further exploration of this data allowed us to generate a 10-gene mRNA abundance signature predictive of fluvastatin sensitivity, which showed preliminary validation in an independent set of breast tumor cell lines. Here, we have therefore identified several candidate predictors of sensitivity to fluvastatin treatment in breast cancer, which warrant further preclinical and clinical evaluation. PMID- 24337704 TI - TLR4-dependant immune response, but not hepatitis B virus reactivation, is important in radiation-induced liver disease of liver cancer radiotherapy. AB - Toll-like receptor 4 (TLR4) is an important trigger of the immune response against hepatitis B virus (HBV) infection and liver injuries. The roles of HBV reactivation versus TLR4-dependant immune response may be critical factors in preventing radiation-induced liver diseases (RILDs) after liver cancer radiotherapy. This study consists of three phases. In the primary phase, livers of mutant TLR4 (TLR4(-)) mice were irradiated with 30 Gy in either the absence or presence of HBV infection. The latter was done by introduction of plasmid pAAV/HBV 1.2. In the advanced phase, RILDs were compared in normal TLR4 (TLR4(+)) versus TLR4(-) mice. In the validation phase, 28 liver cancer patients who had undergone radiotherapy before hepatectomy were enrolled. Liver biopsies near tumors, irradiated with 35-48 Gy, were used to construct tissue microarrays. HBV reactivation, TLR4 expression, and severity of RILDs were studied in both mouse and human. More HBV reactivation, without significant RILD, was observed in irradiated versus unirradiated TLR4(-) mice. RILD scores of TLR4(+) mice were higher than TLR4(-) mice. In humans, serious RILDs tended to develop in patients with high TLR4 expression, but not in patients with low TLR4 or high HBV surface antigen expression. High TLR4 expression was seen in only 2 of 12 HBV-reactive patients, but in HBV-nonreactive patients, it was seen in 6 of 9 (P < 0.03). In summary, RILDs correlated with high TLR4 expression, but not with HBV reactivation, which is inhibited in liver with high TLR4 expression after liver cancer radiotherapy. PMID- 24337705 TI - Mothers' and fathers' autonomy-relevant parenting: longitudinal links with adolescents' externalizing and internalizing behavior. AB - The goal of this study was to advance the understanding of separate and joint effects of mothers' and fathers' autonomy-relevant parenting during early and middle adolescence. In a sample of 518 families, adolescents (49 % female; 83 % European American, 16 % African American, 1 % other ethnic groups) reported on their mothers' and fathers' psychological control and knowledge about adolescents' whereabouts, friends, and activities at ages 13 and 16. Mothers and adolescents reported on adolescents' externalizing and internalizing behaviors at ages 12, 14, 15, and 17. Adolescents perceived their mothers as using more psychological control and having more knowledge than their fathers, but there was moderate concordance between adolescents' perceptions of their mothers and fathers. More parental psychological control predicted increases in boys' and girls' internalizing problems and girls' externalizing problems. More parental knowledge predicted decreases in boys' externalizing and internalizing problems. The perceived levels of behavior of mothers and fathers did not interact with one another in predicting adolescent adjustment. The results generalize across early and late adolescence and across mothers' and adolescents' reports of behavior problems. Autonomy-relevant mothering and fathering predict changes in behavior problems during early and late adolescence, but only autonomy-relevant fathering accounts for unique variance in adolescent behavior problems. PMID- 24337706 TI - Congenital anomalies of coronary arteries in children: the evaluation of 22 patients. AB - Although congenital coronary artery anomalies are seen in 0.6-1 % of adult patients undergoing coronary angiography, the data for the pediatric population are few. This study of 22 children with coronary artery anomalies evaluated them in terms of demographic and clinical features and analyzed their angiographic findings and surgical results. Databases in the Department of Pediatric Cardiology at the University of Uludag were searched for all the patients with a diagnosis of congenital coronary artery anomaly who underwent coronary angiography between 1993 and 2013. Patients with coexistent congenital heart disease were excluded from the study. The study noted 22 patients (0.9 %; 10 boys and 11 girls) with coronary artery anomalies. The mean age of these patients was 58.77 +/- 52.04 months (range, 1 month-16 years). Coronary arteriovenous fistula (50 %) and anomalous left coronary artery from the pulmonary artery (ALCAPA) (36 %) were the most common anomalies. In addition, the study included one patient with diffuse coronary artery hypoplasia, one patient with muscular bridge, and one patient with left main coronary artery originating from the right aortic sinus valsalva. Of the 11 patients who had coronary atrioventricular fistula, 7 were asymptomatic, whereas 75 % of the patients with ALCAPA syndrome were admitted because of heart failure. Although 13 patients had an exact diagnosis by echocardiography, 50 % of the patients with ALCAPA syndrome had their diagnosis determined by catheter angiography performed because of severe mitral regurgitation or dilated cardiomyopathy. The mortality rate for all the patients was found to be 18.1 %. Eight patients with coronary arteriovenous fistula have been followed up without surgery to the present. In contrast, seven patients with ALCAPA syndrome have undergone surgery, and three have died. Two of these patients died during the postoperative period, and the remaining patient died suddenly during the preoperative period at home. Isolated congenital coronary artery anomalies are very rare in the pediatric population. Although most congenital coronary artery anomalies are clinically silent, they may be associated with severe symptoms in children. Recognition of potentially serious anomalies such as ALCAPA syndrome is mandatory so that early surgical treatment can be prescribed. PMID- 24337707 TI - Solubilization of tricalcium phosphate by P(3HB) accumulating Azotobacter chroococcum MAL-201. AB - Cells of Azotobacter chroococcum MAL-201 (MTCC 3853) are capable of accumulating the intracellular poly(3-hydroxybutyric acid) [P(3HB)], accounting for 65-71 % of its cell dry weight and also capable of synthesizing the enzyme alkaline phosphatase (APase), when grown in glucose and tricalcium phosphate containing nitrogen-free modified Stockdale medium. The concentration of insoluble phosphate in broth medium was optimized as 0.25 % (w/v) for growth and biosynthesis of APase. However, the suboptimal concentration of phosphate (0.1 %, w/v) appeared as the best suited for accumulation of P(3HB) by the strain. The significant differences were observed in biosynthesis of polymer and APase enzyme under variable phosphate concentrations. Glucose, 3.0 % (w/v) was recorded as the optimum concentration for all of the three parameters. The continuation of APase biosynthesis was observed during the period of significant decline in the cellular content of the polymer in the late phase of growth. In order to study the role of P(3HB), the rate of autodigestion of biopolymer and phosphate solubilization rate (k, mineralization constant) were determined in carbon-free medium under batch cultivation process and the parameters were found to be positively correlated. The maximum phosphate solubilization rate (k = 0.0154) by the strain MAL-201 timed at the 10th hour of incubation when the rate of polymer degradation concomitantly attained its peak corresponding to 87 mg/l/h and then declined gradually. Only a negligible amount of residual polymer remained undigested. These data strongly support the functional role of P(3HB) in response to multinutritional stress condition. PMID- 24337708 TI - Patent processus vaginalis in a peritoneal dialysis patient. PMID- 24337710 TI - Drought enhances symbiotic dinitrogen fixation and competitive ability of a temperate forest tree. AB - General circulation models project more intense and frequent droughts over the next century, but many questions remain about how terrestrial ecosystems will respond. Of particular importance, is to understand how drought will alter the species composition of regenerating temperate forests wherein symbiotic dinitrogen (N2)-fixing plants play a critical role. In experimental mesocosms we manipulated soil moisture to study the effect of drought on the physiology, growth and competitive interactions of four co-occurring North American tree species, one of which (Robinia pseudoacacia) is a symbiotic N2-fixer. We hypothesized that drought would reduce growth by decreasing stomatal conductance, hydraulic conductance and increasing the water use efficiency of species with larger diameter xylem vessel elements (Quercus rubra, R. pseudoacacia) relative to those with smaller elements (Acer rubrum and Liriodendron tulipifera). We further hypothesized that N2 fixation by R. pseudoacacia would decline with drought, reducing its competitive ability. Under drought, growth declined across all species; but, growth and physiological responses did not correspond to species' hydraulic architecture. Drought triggered an 80% increase in nodule biomass and N accrual for R. pseudoacacia, improving its growth relative to other species. These results suggest that drought intensified soil N deficiency and that R. pseudoacacia's ability to fix N2 facilitated competition with non-fixing species when both water and N were limiting. Under scenarios of moderate drought, N2 fixation may alleviate the N constraints resulting from low soil moisture and improve competitive ability of N2-fixing species, and as a result, supply more new N to the ecosystem. PMID- 24337709 TI - High glucose induces activation of the local renin-angiotensin system in glomerular endothelial cells. AB - Activation of the intrarenal renin-angiotensin system (RAS), which has been identified in podocytes and mesangial cells, is a novel mechanism in the progression of diabetic kidney disease (DKD). The present study aimed to identify the local RAS in glomerular endothelial cells (GEnCs). Rat GEnCs were stimulated by culture medium containing 30 mmol/l glucose for 12, 24, 48 and 72 h. Angiotensin II (Ang II) concentrations in cell lysates and culture media were examined by ELISA and mRNA levels of angiotensinogen and renin in cell lysates were analyzed by quantitative polymerase chain reaction. Ang II type 1 receptor (AT1R), Ang II type 2 receptor (AT2R), renin and angiotensinogen levels in cell lysates were determined by western blot analysis. Localization of intracellular AT1R, AT2R, angiotensinogen and renin was identified by confocal immunofluorescence microscopy. Consequently, high glucose (HG) increased intracellular and extracellular Ang II levels. Captopril and chymostatin (inhibitor of chymase, an enzyme that converts Ang I to Ang II) were able to antagonize HG-induced Ang II generation. Moreover, HG increased angiotensinogen production in GEnCs and reduced renin mRNA expression without altering renin protein production. However, HG decreased AT1R levels and resulted in AT2R shifting from the nuclear to perinuclear region in GEnCs. In conclusion, HG activated the intracellular RAS in rat GEnCs and the underlying mechanism may involve angiotensin-converting enzyme (ACE) and non-ACE pathways. The effects of HG on GEnCs may also involve the substrate and receptors of Ang II. PMID- 24337711 TI - Tree species from different functional groups respond differently to environmental changes during establishment. AB - Savanna plant communities change considerably across time and space. The processes driving savanna plant species diversity, coexistence and turnover along environmental gradients are still unclear. Understanding how species respond differently to varying environmental conditions during the seedling stage, a critical stage for plant population dynamics, is needed to explain the current composition of plant communities and to enable us to predict their responses to future environmental changes. Here we investigate whether seedling response to changes in resource availability, and to competition with grass, varied between two functional groups of African savanna trees: species with small leaves, spines and N-fixing associations (fine-leaved species), and species with broad leaves, no spines, and lacking N-fixing associations (broad-leaved species). We show that while tree species were strongly suppressed by grass, the effect of resource availability on seedling performance varied considerably between the two functional groups. Nutrient inputs increased stem length only of broad-leaved species and only under an even watering treatment. Low light conditions benefited mostly broad-leaved species' growth. Savannas are susceptible to ongoing global environment changes. Our results suggest that an increase in woody cover is only likely to occur in savannas if grass cover is strongly suppressed (e.g. by fire or overgrazing). However, if woody cover does increase, broad-leaved species will benefit most from the resulting shaded environments, potentially leading to an expansion of the distribution of these species. Eutrophication and changes in rainfall patterns may also affect the balance between fine- and broad-leaved species. PMID- 24337712 TI - Variation in anti-parasite behaviour and infection among larval amphibian species. AB - Along with immune defences, many animals exhibit effective anti-parasite behaviours such as parasite avoidance and removal that influence their susceptibility to infection. Host ecology and life history influence investment into comparatively fixed defences such as innate immunity but may affect the strength of anti-parasite behaviours as well. We investigated activity levels in five different species of larval amphibian with varying life histories and ecology in control, novel food stimulus, and trematode parasite (Echinoparyphium sp.) threat conditions. There was a significant interaction of species and treatment given that American toad (Bufo americanus), wood frog (Lithobates sylvaticus), and bullfrog (Lithobates catesbeianus) tadpoles generally increased their activity when parasite infectious stages were present while grey tree frogs (Hyla versicolor) and northern leopard frogs (Lithobates pipiens) did not, even though activity was negatively related to infection. In addition, there was considerable variation among species in their susceptibility to parasitism, with infection prevalence ranging from 17% in bullfrog tadpoles to 70% in wood frogs. However, amphibian life history (larval and adult traits) was not related to parasitism or level of anti-parasite behaviour at the species level. Consequently, we suggest that future investigations include more species with a range of life history traits and also consider host ecology, particularly if conspicuous anti-parasite behaviours are more likely in amphibian species that experience a relatively low risk of predation. PMID- 24337714 TI - Impact of treatment satisfaction on quality of life of patients with acromegaly. AB - PURPOSE: To evaluate satisfaction of acromegalic subjects with their medical treatment and its contribution to their quality of life. METHODS: This cross sectional study included a total of 159 medications used in 133 subjects with acromegaly (controlled n = 84 and uncontrolled n = 49, female/male: 81/52). Subjects were asked to complete questionnaires on symptoms of depression (BDI) and satisfaction with the medical therapy they received for acromegaly (TSQM). Acromegaly cases also completed Acromegaly Quality of Life Questionnaire (AcroQoL). RESULTS: Subjects on pegvisomant therapy scored lower on convenience (p = 0.007). Cases on combination therapy had lower domain scores for effectiveness, convenience and global satisfaction in comparison to the cases on monotherapy (p = 0.01, p = 0.01 and p = 0.01, respectively). The time elapsed since diagnosis and the duration of medical therapy were positively correlated with effectiveness score (r = 0.2, p = 0.007 and r = 0.2, p = 0.04, respectively). The AcroQoL score was positively correlated with all domains of TSQM (for effectiveness r = 0.2, p = 0.01; for side effects r = 0.3, p = 0.001; for convenience r = 0.3, p = 0.004 and for global satisfaction r = 0.2, p = 0.01). In contrast, the BDI score was inversely correlated with all domains of TSQM (for effectiveness r = -0.3, p = 0.001; for side effects r = -0.2, p = 0.006; for convenience r = -0.3, p < 0.001 and for global satisfaction r = -0.3, p = 0.001). CONCLUSION: In acromegaly, quality of life, status of depression and satisfaction of the subjects with their treatment are intercorrelated. PMID- 24337715 TI - Creation of an effective colorectal anastomotic leak early detection tool using an artificial neural network. AB - PURPOSE: Anastomotic leaks greatly increase both morbidity and mortality amongst colorectal patients. Earlier detection of leaks leads to improved patient outcomes; however, diagnosis often proves difficult due to heterogeneous presentation and varied differential diagnosis. The purpose of the study was to create an artificial neural network (ANN) capable of accurately identifying patients at risk of developing a post-operative colorectal anastomotic leak. METHODS: A genetic ANN was trained and validated on a retrospective patient cohort. Two comparative groups were identified: those with anastomotic leaks confirmed at re-operation with a control group of patients with a post-operative delayed recovery, but in whom leak was excluded and no re-operation required. RESULTS: Seventy-six patients were identified: 20 confirmed leaks and 56 controls. No significant difference in the baseline features between leak and control groups in terms of age (leaks 65.9 years [SD 9.29] controls 58.3 years [SD 17.0)], P = 0.054). Utilising backwards variable selection, ANN maintained 19 input variables. Internal validation of the ANN produced a sensitivity of 85.0 %, specificity of 82.1 %, and AUC of 0.89 for correct identification of clinical anastomotic leaks. Of the 20 confirmed leaks, the model correctly identified 17 and misclassified 10 control patients in the clinical leak category. External validation on 12 consecutive pilot prospective patients produced a specificity of 83.3 %. CONCLUSIONS: ANNs can be created to accurately detect clinical anastomotic leaks in the early post-operative period using routinely available clinical data. Further prospective ANN testing is required to confirm generalisability. ANNs may provide useful real-world tools for improving patient safety and outcomes. PMID- 24337713 TI - Clinical and biochemical characteristic features of metastatic cancer to the sella turcica: an analytical review. AB - BACKGROUND AND OBJECTIVES: Sellar metastasis is uncommon and poorly characterized as published data include small series of subjects. This study's goal is to identify unique features that differentiate this entity from other sellar masses such as pituitary macroadenomas. METHODS: Published cases of pathologically confirmed sellar metastasis along with our experience in such patients over a 6 years period were reviewed (total = 129). As a control group, we reviewed similar data on 55 patients with pituitary macroadenomas managed over the same time period. Presenting symptoms, pituitary dysfunction were analyzed using univariate, multivariate and receiver operating characteristic (ROC) analyses. RESULTS: Sellar metastasis has equal gender distribution with a median patient age of 56 years. The most common primary malignancy was breast cancer (29%) in women and lung cancer (30%) in men. Sellar metastasis was the first manifestation of cancer in over 40% of patients. Common presenting symptoms included headaches, visual field deficits, abnormal eye motility and diabetes insipidus. These symptoms were less frequent among patients with pituitary macroadenomas. Univariate regression analyses showed that headaches, abnormal eye motility, visual field deficits and diabetes insipidus were each predictive of metastatic disease. ROC analysis combining all 4 features revealed an AUC of 0.953 with a sensitivity of 0.818 and a specificity of 0.935. Using the multivariate regression, abnormal eye motility and/or diabetes insipidus independently predicted metastatic disease. CONCLUSIONS: Sellar metastasis should be suspected in patients presenting with sellar masses, abnormal eye motility and/or diabetes insipidus even those without known malignancy since pituitary metastasis can often be the first manifestation of cancer. PMID- 24337716 TI - Stochastic amplification of spatial modes in a system with one diffusing species. AB - The problem of pattern formation in a generic two species reaction-diffusion model is studied, under the hypothesis that only one species can diffuse. For such a system, the classical Turing instability cannot take place. At variance, by working in the generalized setting of a stochastic formulation to the inspected problem, spatially organized patterns can develop, seeded by finite size corrections. General conditions are given for the stochastic patterns to occur. The predictions of the theory are tested for a specific case study. PMID- 24337717 TI - Prevention and management of adverse events related to regorafenib. AB - Regorafenib is an oral multikinase inhibitor that has shown antitumor activity in a range of solid tumors. Based on data from phase III clinical trials, regorafenib is indicated for the treatment of adult patients with metastatic colorectal cancer who have previously been treated with, or are not considered candidates for, other available therapies, and in patients with advanced gastrointestinal stromal tumors that cannot be surgically removed and no longer respond to other appropriate treatments. A panel of oncology nurses, research coordinators, and other medical oncology experts, experienced in the care of patients treated with regorafenib, met to discuss the best practice for the management of regorafenib-associated adverse events (AEs). The panel agreed that, in clinical trials and daily practice with regorafenib, AEs are common but mostly manageable. The most common and/or important AEs associated with regorafenib were considered to be hand-foot skin reaction, rash or desquamation, stomatitis, diarrhea, hypertension, liver abnormalities, and fatigue. This manuscript describes the experience and recommendations of the panel for managing these AEs in everyday clinical practice. Appropriate education, monitoring, and management are considered essential for reducing the incidence, duration, and severity of regorafenib-associated AEs. PMID- 24337718 TI - The end-of-life phase of high-grade glioma patients: a systematic review. AB - BACKGROUND: High-grade gliomas (HGG) are rare and incurable; yet, these neoplasms result in a disproportionate share of cancer morbidity and mortality. Treatment of HGG patients is directed not merely towards prolonging life but also towards quality of life, which becomes the major goal in the end of life (EOL). The latter has received increasing attention over the last decade. METHODS: We reviewed the literature related to the EOL phase of HGG patients from 1966 up to April 2012. Articles were retrieved from PubMed, Embase, Cinahl, PsycINFO and Cochrane database. We then selected papers for analysis using pre-determined inclusion criteria and subtracted information on the topics of interest. RESULTS: The search yielded 695 articles, of which 17 were classified eligible for analysis according to pre-defined inclusion criteria. Reviewed topics were symptoms and signs, quality of life and quality of dying, caregiver burden, organization and location of palliative care, supportive treatment, and EOL decision making. Nearly all identified studies were observational, with only two non-randomized intervention studies. Symptom burden is high in the EOL phase and affects the quality of life of both patient and carer. Palliative care services are more intensively used compared to other cancer patients. Cognitive deficits increase as the disease progresses, hampering communication and decision making. CONCLUSION: The EOL phase of HGG is substantially different from other patient groups, and more clinical studies in HGG on supportive medication, advance care planning and decision making are required. The organization of care, development of guidelines and interventions to decrease caregiver burden in the EOL phase are critical as well. PMID- 24337720 TI - Molecular diversity of poleroviruses infecting cucurbit crops in four countries reveals the presence of members of six distinct species. AB - When 66 cucurbit samples with yellowing symptoms from fields in Mali, the Philippines, Thailand and Uzbekistan were screened by RT-PCR using universal polerovirus primers, 21 were identified as harboring polerovirus RNA. When these 21 samples were screened with specific primers for the known cucurbit-infecting poleroviruses, suakwa aphid-borne yellows virus and a recombinant strain of cucurbit aphid-borne yellows virus were detected for the first time in the Philippines and Thailand. However, seven polerovirus-positive samples did not react with any of the known species-specific primers. Sequencing of 1.4-kb universal polerovirus RT-PCR products revealed the presence of two poleroviruses that had not been described previously. These viruses, from Mali and Thailand, were provisionally named pepo aphid-borne yellows virus and luffa aphid-borne yellows virus, respectively. PMID- 24337719 TI - Terpenes tell different tales at different scales: glimpses into the Chemical Ecology of conifer - bark beetle - microbial interactions. AB - Chemical signaling mediates nearly all aspects of species interactions. Our knowledge of these signals has progressed dramatically, and now includes good characterizations of the bioactivities, modes of action, biosynthesis, and genetic programming of numerous compounds affecting a wide range of species. A major challenge now is to integrate this information so as to better understand actual selective pressures under natural conditions, make meaningful predictions about how organisms and ecosystems will respond to a changing environment, and provide useful guidance to managers who must contend with difficult trade-offs among competing socioeconomic values. One approach is to place stronger emphasis on cross-scale interactions, an understanding of which can help us better connect pattern with process, and improve our ability to make mechanistically grounded predictions over large areas and time frames. The opportunity to achieve such progress has been heightened by the rapid development of new scientific and technological tools. There are significant difficulties, however: Attempts to extend arrays of lower-scale processes into higher scale functioning can generate overly diffuse patterns. Conversely, attempts to infer process from pattern can miss critically important lower-scale drivers in systems where their biological and statistical significance is negated after critical thresholds are breached. Chemical signaling in bark beetle - conifer interactions has been explored for several decades, including by the two pioneers after whom this award is named. The strong knowledge base developed by many researchers, the importance of bark beetles in ecosystem functioning, and the socioeconomic challenges they pose, establish these insects as an ideal model for studying chemical signaling within a cross-scale context. This report describes our recent work at three levels of scale: interactions of bacteria with host plant compounds and symbiotic fungi (tree level, biochemical time), relationships among inducible and constitutive defenses, population dynamics, and plastic host-selection behavior (stand level, ecological time), and climate-driven range expansion of a native eruptive species into semi-naive and potentially naive habitats (geographical level, evolutionary time). I approach this problem by focusing primarily on one chemical group, terpenes, by emphasizing the curvilinear and threshold-structured basis of most underlying relationships, and by focusing on the system's feedback structure, which can either buffer or amplify relationships across scales. PMID- 24337721 TI - Circulation of classical swine influenza virus in Europe between the wars? AB - The complete genomes of two swine influenza viruses from England were sequenced. Phylogenetic analysis revealed classical swine H1N1 viruses, one of which, A/swine/London, is closely related to virus strains of the early 1930s. Both strains are also antigenically related to A/swine/Iowa/15/1930, the strain originally isolated by Richard Shope. The source of A/swine/London is unknown, but its relationship to early classical swine influenza viruses suggests that the emergence of these viruses in Europe has to be antedated by 15-20 years. PMID- 24337722 TI - The carcinogen 1-methylpyrene forms benzylic DNA adducts in mouse and rat tissues in vivo via a reactive sulphuric acid ester. AB - The common polycyclic aromatic hydrocarbon 1-methylpyrene is hepatocarcinogenic in the newborn mouse assay. In vitro studies showed that it is metabolically activated via benzylic hydroxylation and sulphation to a reactive ester, which forms benzylic DNA adducts, N(2)-(1-methylpyrenyl)-2'-deoxyguanosine (MPdG) and N(6)-(1-methylpyrenyl)-2'-deoxyadenosine (MPdA). Formation of these adducts was also observed in animals treated with the metabolites, 1-hydroxymethylpyrene and 1-sulphooxymethylpyrene (1-SMP), whereas corresponding data are missing for 1 methylpyrene. In the present study, we treated mice with 1-methylpyrene and subsequently analysed blood serum for the presence of the reactive metabolite 1 SMP and tissue DNA for the presence of MPdG and MPdA adducts. We used wild-type mice and a mouse line transgenic for human sulphotransferases (SULT) 1A1 and 1A2, males and females. All analyses were conducted using ultra-performance liquid chromatography coupled with tandem mass spectrometry, for the adducts with isotope-labelled internal standards. 1-SMP was detected in all treated animals. Its serum level was higher in transgenic mice than in the wild-type (p < 0.001). Likewise, both adducts were detected in liver, kidney and lung DNA of all exposed animals. The transgene significantly enhanced the level of each adduct in each tissue of both sexes (p < 0.01-0.001). Adduct levels were highest in the liver, the target tissue of carcinogenesis, in each animal model used. MPdG and MPdA adducts were also observed in rats treated with 1-methylpyrene. Our findings corroborate the hypothesis that 1-SMP is indeed the ultimate carcinogen of 1 methylpyrene and that human SULT are able to mediate the terminal activation in vivo. PMID- 24337723 TI - Functional and high resolution retinal imaging assessment in a case of ocular siderosis. AB - PURPOSE: To report new findings in a case of ocular siderosis explored by high resolution angiography and adaptive optics (AO). METHODS: We report data on a 40 year-old man with an intraocular foreign body (IOFB) embedded in the sclera after hammering. RESULTS: Nine months after this accident, the patient presented with full-field electroretinogram (FF-ERG) abnormalities. Subsequent IOFB extraction was performed. One month after the surgery, high resolution angiography showed for the first time small iron particles all over the inner retinal surface. Spreading of these deposits was followed by inflammatory prepapillary new vessels and venous retinal vasculatis, which spontaneously resolved within a few months. ERG responses became slightly electronegative at this time. Clearance of the iron particles was followed over a year with AO and ERG recording. AO revealed an arterial tropism with a decrease in the amount of particles overtime, which may be consistent with macrophagic activity. CONCLUSION: High resolution angiography and AO are new tools, combined with electrophysiology, to better understand ocular siderosis pathophysiology. PMID- 24337724 TI - Coping strategies for HIV-related stigma in Liuzhou, China. AB - This study explores the feelings, experiences, and coping strategies of people living with HIV (PLHIV) in Liuzhou, China. In a southwestern Chinese city with high HIV prevalence, we conducted semi-structured in-depth interviews with 47 PLHIV selected to represent individuals who had acquired HIV via different acquisition routes. Many participants felt severely stigmatized; they commonly reported having very low self-esteem and feelings of despair. Based on style of coping and whether it occurred at the interpersonal or intrapersonal level, four types of coping that participants used to deal with HIV-associated stigma were identified: (1) Compassion (Passive/Avoidant-Interpersonal); (2) Hiding HIV status (Passive/Avoidant-Intrapersonal); (3) Social support (Active/Problem focused-Interpersonal; and (4) Self-care (Active/Problem-focused-Intrapersonal). Educational and stigma-reduction interventions targeting potential social support networks for PLHIV (e.g., family, close friends, and peers) could strengthen active interpersonal PLHIV coping strategies. Interventions teaching self-care to PLHIV would encourage active intrapersonal coping, both of which may enhance PLHIV quality of life in Liuzhou, China. PMID- 24337725 TI - Depressive symptoms and antiretroviral therapy (ART) initiation among HIV infected Russian drinkers. AB - The impact of depressive symptoms on ART initiation among Russian HIV-infected heavy drinkers enrolled in a secondary HIV prevention trial (HERMITAGE) was examined. We assessed 133 participants eligible for ART initiation (i.e., CD4 count <350 cells/MUl) who were not on ART at baseline. Depressive symptom severity and ART use were measured at baseline, 6- and 12-months. Association between depressive symptoms and subsequent ART initiation was evaluated using GEE logistic regression adjusting for gender, past ART use, injection drug use and heavy drinking. Depressive symptom severity was not significantly associated with lower odds of initiating ART. Cognitive depression symptoms were not statistically significant (global p = 0.05); however, those with the highest level of severity had an AOR of 0.25 (95 % CI 0.09-0.71) for delayed ART initiation. Although the effect of depression severity was not significant, findings suggest a potential role of cognitive depression symptoms in decisions to initiate ART in this population. PMID- 24337726 TI - The implications of post-coital intravaginal cleansing for the introduction of vaginal microbicides in South Africa. AB - Post-coital intravaginal cleansing (IVC) could counteract the protective effect of a vaginal microbicide. IVC less than 1 h after sex is discouraged in most microbicide trials. During a microbicide trial in KwaZulu-Natal, we collected quantitative data on post-coital IVC. We discussed IVC during in-depth-interviews (IDIs) and focus-group discussions (FGDs) with women enrolled in the trial, and during FGDs with community members. Nearly one-third (336/1,143) of women reported IVC less than an hour after sex. In multivariate analysis, post-coital IVC was associated with younger age, larger household size, greater sexual activity, consistent gel use, and clinic of enrolment. During IDIs and FGDs, respondents described post-coital IVC as a common hygiene practice motivated by the need to remove semen, vaginal fluids and sweat, although this practice may be amenable to change in the context of microbicide use. We need to consider strategies for influencing post-coital IVC practices in future microbicide trials and delivery programmes. PMID- 24337727 TI - Characterization of cognitive dysfunction in Sjogren's syndrome patients. AB - Sjogren's syndrome is an autoimmune disorder primarily affecting women, with decreased saliva and tear production as the principal characteristic. Cognitive, neurological, and psychiatric disorders also are associated with Sjogren's. The present study addressed the hypothesis that patients with Sjogren's syndrome differ significantly from matched controls in the prevalence and impact of a number of neuropsychiatric abnormalities. Sjogren's patients and controls (n = 37 per group) underwent medical and psychiatric evaluation, demographic assessments, quality of life and symptom evaluation, and extensive testing of cognitive function and memory. Patients and controls were closely matched for age, gender distribution, verbal IQ, marital status, educational level, employment status, and current/past medical or psychiatric history. On most subjective self-ratings, Sjogren's patients reported greater fatigue, impaired physical functioning, feeling depressed, and autonomic symptomatology compared to controls. Impaired memory was described mainly as loss of thought continuity in the midst of a task or activity. However, the majority of objective measures of cognition, psychomotor function, and memory showed minimal differences between groups. Sjogren's patients rate themselves as impaired on multiple ratings of emotional, cognitive, and physical function, but objective measures of cognition reveal fewer substantive differences between patients and matched controls. Sjogren's patients perceive deteriorated physical function over time, but they achieve a level of functioning comparable to controls despite the burden of their illness. PMID- 24337728 TI - Polypoid endometriosis of the cervix: a case report and review of the literature. AB - BACKGROUND: Giant and multilobular endocervical polyps are rare and need to be differentiated from cervical neoplastic lesions. CASE REPORT: The authors report a 29-year-old sexually inactive woman presenting with a prolapsed giant endocervical polyp, associated with malodorous discharge and menorrhagia. The wide-based polyp originated in part from the posterior lip of the exocervix and in part from the endocervix. This trilobular pedunculated mass (90 * 50 * 35 mm) had small cysts on the surface and focal areas of haemorrhage. Microscopic examination revealed areas with classic endocervical mucosal polyp histology intimately mixed with expanses of endometrial stroma and occasional endometrial glands. Immunohistochemically the endometrial stroma showed strong CD10 positivity, glands were oestrogen and progesterone receptor positive and Ki-67 proliferation index was low. CONCLUSION: Polypoid endometriosis of the cervix is a distinct form of endometriosis that may be mistaken for a neoplasm. Five earlier reports of this entity have not described a prolapsed polyp assuming gigantic proportions. We conclude that this condition be considered in the differential diagnosis of polypoid lesions of the cervix. PMID- 24337729 TI - High HIV risk in a cohort of male sex workers from Nairobi, Kenya. AB - OBJECTIVES: Men who have sex with men (MSM) are at high risk of HIV-1 acquisition and transmission, yet there remains limited data in the African context, and for men who sell sex to men (MSM SW) in particular. METHODS: We enrolled 507 male sex workers in a Nairobi-based prospective cohort study during 2009-2012. All participants were offered HIV/STI screening, counselling and completed a baseline questionnaire. RESULTS: Baseline HIV prevalence was 40.0% (95% CI 35.8% to 44.3%). Prevalent HIV infection was associated with age, less postsecondary education, marijuana use, fewer female partners and lower rates of prior HIV testing. Most participants (73%) reported at least two of insertive anal, receptive anal and insertive vaginal sex in the past 3 months. Vaginal sex was reported by 37% of participants, and exclusive MSM status was associated with higher HIV rates. Condom use was infrequent, with approximately one-third reporting 100% condom use during anal sex. HIV incidence was 10.9 per 100 person years (95% CI 7.4 to 15.6). Predictors of HIV risk included history of urethral discharge (aHR 0.29, 95% CI 0.08 to 0.98, p=0.046), condom use during receptive anal sex (aHR 0.05, 95% CI 0.01 to 0.41, p=0.006) and frequency of sex with male partners (aHR 1.33/sex act, 95% CI 1.01 to 1.75, p=0.04). CONCLUSIONS: HIV prevalence and incidence were extremely high in Nairobi MSM SW; a combination of interventions including increasing condom use, pre-exposure prophylaxis and access to effective treatment is urgently needed to decrease HIV transmission in this key population. PMID- 24337730 TI - HSV-2 incidence by sex over four age periods to age 38 in a birth cohort. AB - OBJECTIVES: To examine herpes simplex virus type 2 (HSV-2) incidence over four periods to age 38 in a birth cohort, and to compare risks for men and women, taking into account sexual behaviour. METHODS: At ages 21, 26, 32 and 38, participants in the Dunedin Multidisciplinary Health and Development Study were invited to provide serum for HSV-2 serology, and information on sexual behaviour. HSV-2 incidence rates were calculated for four age periods, and comparisons made by sex and period, taking into account number of sexual partners. RESULTS: By age 38, 17.3% of men and 26.8% of women had ever been seropositive for HSV-2. Incidence peaked for women from age 21 to 26 (19.1 per 1000 person-years) and men from age 26 to 32 (14.1 per 1000 person-years); it fell markedly for both from age 32 to 38 (5.1 and 6.8 per 1000 person-years for men and women, respectively). Overall risk was significantly higher for women: adjusted incidence rate ratio 1.9 (95% CI 1.4 to 2.7); the sex difference was most marked from age 21 to 26 (3.4, 95% CI 1.9 to 6.3). CONCLUSIONS: Our findings are consistent with a greater biological susceptibility to HSV-2 among women, and with the increasing risk to the early/mid-20s for women and late 20s/early 30s for men, being driven by an increasing pool of prevalent infection. The reduced risk in the mid-30s is consistent with declining infectivity of long-term prevalent infections. PMID- 24337731 TI - Detection of Chlamydia trachomatis or Neisseria gonorrhoeae in otorhinolaryngology patients with pharyngeal symptoms. PMID- 24337732 TI - Neisseria gonorrhoeae and Chlamydia trachomatis infection in HIV-1-infected women taking antiretroviral therapy: a prospective cohort study from Burkina Faso. AB - OBJECTIVES: Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) are common sexually transmitted infections (STI). We assessed the cumulative risk of NG and CT in a cohort of HIV-1-infected high-risk women taking antiretrovirals over 4 years in Burkina Faso. METHODS: Between March 2007 and February 2011, participants were followed every 3-6 months. At each visit, participants underwent a gynaecological examination with collection of cervical and vaginal swabs. Random-effects logistic regression models were used to analyse associations of NG and CT infection with behavioural and biological factors. RESULTS: 172 women had samples tested for NG and CT during the study period, in a total of 1135 visits. NG was detected in 6.4% of women (11/172, 95% CI 2.7 to 10.1) at a rate of 2.76 cases (95% CI 1.53 to 4.99) per 100 person-years. CT was detected in 1.7% (3/172, 95% CI 0 to 3.7) of women at a rate of 0.75 cases (95% CI 0.24 to 2.34) per 100 person-years. The majority of women were asymptomatic (9/14). In the multivariable model, the presence of NG or CT was associated with tobacco use (aOR=11.85, 95% CI 1.13 to 124.17), and concurrent genital HIV-1 RNA shedding (aOR=4.78, 95% CI 1.17 to 19.46). Higher levels of education (aOR=0.17, 95% CI 0.03 to 0.92), and age greater than 35 years (aOR=0.07, 95% CI 0.01 to 0.92) were associated with lower odds of infection. CONCLUSIONS: The risk of NG or CT infection remains low among high-risk women in Bobo-Dioulasso. This provides some evidence that antiretroviral use does not contribute to behavioural disinhibition. The asymptomatic nature of most infections underscores the need for regular screening and treatment of STIs in core groups. PMID- 24337733 TI - Field evaluation of the CRT and ACON chlamydia point-of-care tests in a tropical, low-resource setting. AB - OBJECTIVE: To evaluate the clinical performance of two chlamydia point-of-care (POC) tests compared with a gold standard nucleic acid amplification testing (NAAT). METHODS: Tests evaluated were the Chlamydia Rapid Test (CRT), Diagnostics for the Real World and the ACON Chlamydia Rapid Test Device, ACON Laboratories (ACON). Overall 226 men and 225 women in Port Vila, Vanuatu, participated in this prospective study in 2010. NAAT and POC testing was performed on samples of male urine and female vaginal swabs for 156 men and 223 women (CRT), and 133 men and 75 women (ACON). RESULTS: The sensitivity and specificity of the CRT in men were 41.4% (95% CI 23.5% to 61.1%) and 89.0% (95% CI 82.2% to 93.8%), respectively, and in women 74.2% (95% CI 61.5% to 84.5%) and 95.7% (95% CI 91.3% to 98.2%), respectively; for ACON, they were 43.8% (95% CI 19.8% to 70.1%) and 98.3% (95% CI 93.9% to 99.8%) in men, and in women 66.7% (95% CI 22.3% to 95.7%) and 91.3% (95% CI 82.0% to 96.7%), respectively. Both tests were (absolutely) insensitive at organism loads less than 1000 (log=3) per mL or per swab; the CRT sensitivity was significantly lower at loads less than, compared with those greater than, 100 000 (log=5) per mL or per swab. CONCLUSIONS: The performance of both CRT and ACON is well below the levels stated by the manufacturers. The evaluated tests are unlikely to be helpful in clinical settings due to the high proportion of false negatives that will go untreated and false-positives that will result in overtreatment and potential adverse social consequences. PMID- 24337734 TI - Fast-track surgery decreases the incidence of postoperative delirium and other complications in elderly patients with colorectal carcinoma. AB - OBJECTIVE: This study aims to investigate the role of fast-track surgery in preventing the development of postoperative delirium and other complications in elderly patients with colorectal carcinoma. METHODS: A total of 240 elderly patients with colorectal carcinoma (aged >=70 years) undergoing open colorectal surgery was randomly assigned into two groups, in which the patients were managed perioperatively either with traditional or fast-track approaches. The length of hospital stay (LOS) and time to pass flatus were compared. The incidence of postoperative delirium and other complications were evaluated. Serum interleukin 6 (IL-6) levels were determined before and after surgery. RESULTS: The LOS was significantly shorter in the fast-track surgery (FTS) group than that in the traditional group. The recovery of bowel movement (as indicated by the time to pass flatus) was faster in the FTS group. The postoperative complications including pulmonary infection, urinary infection and heart failure were significantly less frequent in the FTS group. Notably, the incidence of postoperative delirium was significantly lower in patients with the fast track therapy (4/117, 3.4 %) than with the traditional therapy (15/116, 12.9 %; p = 0.008). The serum IL-6 levels on postoperative days 1, 2, and 3 in patients with the fast-track therapy were significantly lower than those with the traditional therapy (p < 0.001). CONCLUSIONS: Compared to traditional perioperative management, fast-track surgery decreases the LOS, facilitates the recovery of bowel movement, and reduces occurrence of postoperative delirium and other complications in elderly patients with colorectal carcinoma. The lower incidence of delirium is at least partly attributable to the reduced systemic inflammatory response mediated by IL-6. PMID- 24337735 TI - Delineating selection and mediation effects among childhood personality and environmental risk factors in the development of adolescent substance abuse. AB - Utilizing the large, longitudinal Minnesota Twin Family Study (N = 2510; 96 % European American ancestry), we examined the influence of several person environment transactions on adolescent substance abuse. We focused on the two childhood personality traits found to be most predictive of substance abuse in this sample-socialization (willingness to follow rules and endorse conventional values) and boldness (social engagement and assurance, stress resilience, thrill seeking)-and the environmental variables of antisocial and prosocial peers, academic engagement, parent-child relationship quality, and stressful life events. Path analysis revealed that low socialization had a selection effect for each environmental risk factor, that is, socialization at age 11 predicted environmental risk at age 14, after controlling for the stability of the environmental variables from ages 11 to 14. Antisocial peers and academic engagement at age 14 then mediated some of the risk of low socialization on substance abuse at age 17, but the majority of risk for substance abuse was accounted for by the stability of socialization from age 11 to 14. Boldness at age 11 also increased risk for substance abuse, but did so primarily via a direct effect. The findings help to parse the nature of person-environment transactions across multiple personality traits and contextual risk factors that contribute to adolescent substance abuse. PMID- 24337736 TI - Executive functioning and non-verbal intelligence as predictors of bullying in early elementary school. AB - Executive function and intelligence are negatively associated with aggression, yet the role of executive function has rarely been examined in the context of school bullying. We studied whether different domains of executive function and non-verbal intelligence are associated with bullying involvement in early elementary school. The association was examined in a population-based sample of 1,377 children. At age 4 years we assessed problems in inhibition, shifting, emotional control, working memory and planning/organization, using a validated parental questionnaire (the BRIEF-P). Additionally, we determined child non verbal IQ at age 6 years. Bullying involvement as a bully, victim or a bully victim in grades 1-2 of elementary school (mean age 7.7 years) was measured using a peer-nomination procedure. Individual bullying scores were based on the ratings by multiple peers (on average 20 classmates). Analyses were adjusted for various child and maternal socio-demographic and psychosocial covariates. Child score for inhibition problems was associated with the risk of being a bully (OR per SD = 1.35, 95%CI: 1.09-1.66), victim (OR per SD = 1.21, 95%CI: 1.00-1.45) and a bully victim (OR per SD = 1.55, 95%CI: 1.10-2.17). Children with higher non-verbal IQ were less likely to be victims (OR = 0.99, 95%CI: 0.98-1.00) and bully-victims (OR = 95%CI: 0.93-0.98, respectively). In conclusion, our study showed that peer interactions may be to some extent influenced by children's executive function and non-verbal intelligence. Future studies should examine whether training executive function skills can reduce bullying involvement and improve the quality of peer relationships. PMID- 24337737 TI - A general population twin study of conduct problems and the auditory P300 waveform. AB - Reduced amplitude of the P300 event-related potential has been consistently associated with a variety of externalising problems, including conduct disorder. The few available genetically-informative studies of these relationships, however, were conducted among adolescents/adults (i.e., at an age when conduct disorder has typically already become manifest). Among 200 general population twins with a mean age of 9 years (range 6-14 years), we studied the relationship between the P300 waveform elicited by an auditory oddball task and the DSM oriented conduct problems scale of the Child Behavior Checklist 6-18. Conduct problems scores were negatively and significantly correlated (r = -0.19, p = 0.01) with P300 amplitude; correlations between P300 amplitude and the other DSM oriented Child Behavior Checklist scales were non-significant, except for oppositional defiant problems (p = 0.01). We found moderate heritability estimates for both P300 amplitude (0.58, CI:0.37;0.73) and conduct problems (0.52, CI:0.25;0.70). Bivariate twin analyses indicated that the covariation between these two phenotypes can be explained by additive genetic factors only, with a genetic correlation of -0.33. An association between reduced P300 amplitude and conduct problems can be substantiated already in childhood, at an age that precedes the most typical onset of conduct disorder. This relationship appears to be genetic in nature. Reduced P300 amplitude can represent a valuable marker for conduct problems, and can contribute to the early identification of children at high-risk for conduct disorder. PMID- 24337738 TI - EGFR signaling blunts allergen-induced IL-6 production and Th17 responses in the skin and attenuates development and relapse of atopic dermatitis. AB - Despite the important role for epidermal growth factor (EGF) in epithelial homeostasis and wound healing, it has not been investigated in atopic dermatitis (AD). We used AD animal models to explore the role of EGF in AD. In an acute AD model, skin transepidermal water loss was significantly attenuated in EGF-treated mice. Blockade of EGFR signaling genetically or pharmacologically confirms a protective role for EGFR signaling in AD. In a chronic/relapsing AD model, EGF treatment of mice with established AD resulted in an attenuation of AD exacerbation (skin epithelial thickness, cutaneous inflammation, and total and allergen specific IgE) following cutaneous allergen rechallenge. EGF treatment did not alter expression of skin barrier junction proteins or antimicrobial peptides in the AD model. However, EGF treatment attenuated allergen-induced expression of IL-17A, CXCL1, and CXCL2 and neutrophil accumulation in AD skin following cutaneous allergen exposure. IL-17A production was decreased in the in vitro restimulated skin-draining lymph node cells from the EGF-treated mice. Similarly, IL-17A was increased in waved-2 mice skin following allergen exposure. Whereas IL-6 and IL-1beta expression was attenuated in the skin of EGF-treated mice, EGF treatment also suppressed allergen-induced IL-6 production by keratinocytes. Given the central role of IL-6 in priming Th17 differentiation in the skin, this effect of EGF on keratinocytes may contribute to the protective roles for EGFR in AD pathogenesis. In conclusion, our study provides evidence for a previously unrecognized protective role for EGF in AD and a new role for EGF in modulating IL-17 responses in the skin. PMID- 24337740 TI - Cutting edge: DNAX accessory molecule 1-deficient CD8+ T cells display immunological synapse defects that impair antitumor immunity. AB - DNAX accessory molecule 1 (DNAM-1) is expressed on all CD8(+) T cells and promotes their activation and effector function. DNAM-1 interacts with LFA-1, a critical molecule for immunological synapse formation between T cells and APCs, and for cytotoxic killing of target cells. Mice that lack DNAM-1 display abnormal T cell responses and antitumor activity; however, the mechanism involved is unclear. In this article, we show that DNAM-1 deficiency results in reduced proliferation of CD8(+) T cells after Ag presentation and impaired cytotoxic activity. We also demonstrate that DNAM-1-deficient T cells show reduced conjugations with tumor cells and decreased recruitment of both LFA-1 and lipid rafts to the immunological synapse, which correlates with reduced tumor cell killing in vitro. This synapse defect may explain why DNAM-1-deficient mice cannot clear tumors in vivo, and highlights the importance of DNAM-1 and the immunological synapse in T cell-mediated antitumor immunity. PMID- 24337739 TI - Aged mice are unable to mount an effective myeloid response to sepsis. AB - The elderly have increased morbidity and mortality following sepsis; however, the cause(s) remains unclear. We hypothesized that these poor outcomes are due in part to defects in innate immunity, rather than to an exaggerated early inflammatory response. Young (6-12 wk) or aged (20-24 mo) mice underwent polymicrobial sepsis, and subsequently, the aged mice had increased mortality and defective peritoneal bacterial clearance compared with young mice. No differences were found in the magnitude of the plasma cytokine responses. Although septic aged mice displayed equivalent or increased numbers of circulating, splenic, and bone marrow myeloid cells, some of these cells exhibited decreased phagocytosis, reactive oxygen species production, and chemotaxis. Blood leukocyte gene expression was less altered in aged versus young mice 1 d after sepsis. Aged mice had a relative inability to upregulate gene expression of pathways related to neutrophil-mediated protective immunity, chemokine/chemokine receptor binding, and responses to exogenous molecules. Expression of most MHC genes remained more downregulated in aged mice at day 3. Despite their increased myeloid response to sepsis, the increased susceptibility of aged mice to sepsis appears not to be due to an exaggerated inflammatory response, but rather, a failure to mount an effective innate immune response. PMID- 24337742 TI - ADAM17-mediated shedding of FcgammaRIIIA on human NK cells: identification of the cleavage site and relationship with activation. AB - FcgammaRIIIA/CD16A, the low-affinity receptor for the IgG Fc portion expressed on human CD56(dim) NK cells and involved in Ab-dependent cell cytotoxicity, is shed upon NK cell activation. We found that recombinant a disintegrin and metalloprotease (ADAM) 17 cleaved the ectodomain of FcgammaRIIIA/CD16A and a peptide for which the sequence encompasses aa 191-201 of the FcgammaRIIIA/CD16A stalk region but not ADAM10. MALDI-TOF analysis revealed that the peptide was cleaved between Ala(195) and Val(196) (i.e., 1 aa upstream of the expected position). This location of the cleavage site was confirmed by the finding that ADAM17 failed to cleave a peptide in which Ala and Val were reversed. ADAM17 was found to be expressed on NK cells, and stimulation with PMA or N-ethyl-maleimide resulted in the shedding of FcgammaRIIIA/CD16A and CD62L, a specific substrate of ADAM17. Selective inhibition of ADAM17 prevented the shedding of both molecules. Moreover, the shedding of FcgammaRIIIA/CD16A was strongly correlated with degranulation when a wide range of CD56(dim) NK cell activating receptors were stimulated, whereas both ADAM17-dependent shedding and internalization were involved in FcgammaRIIIA/CD16A downmodulation when the latter was engaged. Finally, the shedding of FcgammaRIIIA/CD16A was restricted to activated cells, suggesting that ADAM17 acts mainly, if not exclusively, in cis. Taken together, our results demonstrated for the first time, to our knowledge, at the molecular level that ADAM17 cleaves the stalk region of FcgammaRIIIA/CD16A and identified its cleavage site. The shedding of FcgammaRIIIA/CD16A was at least partially ADAM17 dependent, and it may be considered as a marker of FcgammaRIIIA/CD16A independent NK cell activation highly correlated with degranulation. PMID- 24337741 TI - T cell Ig and mucin domain-containing protein 3 is recruited to the immune synapse, disrupts stable synapse formation, and associates with receptor phosphatases. AB - CD8(+) CTLs are adept at killing virally infected cells and cancer cells and releasing cytokines (e.g., IFN-gamma) to aid this response. However, during cancer and chronic viral infections, such as with HIV, this CTL response is progressively impaired due to a process called T cell exhaustion. Previous work has shown that the glycoprotein T cell Ig and mucin domain-containing protein 3 (Tim-3) plays a functional role in establishing T cell exhaustion. Tim-3 is highly upregulated on virus and tumor Ag-specific CD8(+) T cells, and antagonizing Tim-3 helps restore function of CD8(+) T cells. However, very little is known of how Tim-3 signals in CTLs. In this study, we assessed the role of Tim 3 at the immunological synapse as well as its interaction with proximal TCR signaling molecules in primary human CD8(+) T cells. Tim-3 was found within CD8(+) T cell lipid rafts at the immunological synapse. Blocking Tim-3 resulted in a significantly greater number of stable synapses being formed between Tim 3(hi)CD8(+) T cells and target cells, suggesting that Tim-3 plays a functional role in synapse formation. Further, we confirmed that Tim-3 interacts with Lck, but not the phospho-active form of Lck. Finally, Tim-3 colocalizes with receptor phosphatases CD45 and CD148, an interaction that is enhanced in the presence of the Tim-3 ligand, galectin-9. Thus, Tim-3 interacts with multiple signaling molecules at the immunological synapse, and characterizing these interactions could aid in the development of therapeutics to restore Tim-3-mediated immune dysfunction. PMID- 24337743 TI - Cytosolic group IVA and calcium-independent group VIA phospholipase A2s act on distinct phospholipid pools in zymosan-stimulated mouse peritoneal macrophages. AB - Phospholipase A2s generate lipid mediators that constitute an important component of the integrated response of macrophages to stimuli of the innate immune response. Because these cells contain multiple phospholipase A2 forms, the challenge is to elucidate the roles that each of these forms plays in regulating normal cellular processes and in disease pathogenesis. A major issue is to precisely determine the phospholipid substrates that these enzymes use for generating lipid mediators. There is compelling evidence that group IVA cytosolic phospholipase A2 (cPLA2alpha) targets arachidonic acid-containing phospholipids but the role of the other cytosolic enzyme present in macrophages, the Ca(2+) independent group VIA phospholipase A2 (iPLA2beta) has not been clearly defined. We applied mass spectrometry-based lipid profiling to study the substrate specificities of these two enzymes during inflammatory activation of macrophages with zymosan. Using selective inhibitors, we find that, contrary to cPLA2alpha, iPLA2beta spares arachidonate-containing phospholipids and hydrolyzes only those that do not contain arachidonate. Analyses of the lysophospholipids generated during activation reveal that one of the major species produced, palmitoyl glycerophosphocholine, is generated by iPLA2beta, with minimal or no involvement of cPLA2alpha. The other major species produced, stearoyl-glycerophosphocholine, is generated primarily by cPLA2alpha. Collectively, these findings suggest that cPLA2alpha and iPLA2beta act on different phospholipids during zymosan stimulation of macrophages and that iPLA2beta shows a hitherto unrecognized preference for choline phospholipids containing palmitic acid at the sn-1 position that could be exploited for the design of selective inhibitors of this enzyme with therapeutic potential. PMID- 24337744 TI - Arsenic trioxide and other arsenical compounds inhibit the NLRP1, NLRP3, and NAIP5/NLRC4 inflammasomes. AB - Inflammasomes are large cytoplasmic multiprotein complexes that activate caspase 1 in response to diverse intracellular danger signals. Inflammasome components termed nucleotide-binding oligomerization domain-like receptor (NLR) proteins act as sensors for pathogen-associated molecular patterns, stress, or danger stimuli. We discovered that arsenicals, including arsenic trioxide and sodium arsenite, inhibited activation of the NLRP1, NLRP3, and NAIP5/NLRC4 inflammasomes by their respective activating signals, anthrax lethal toxin, nigericin, and flagellin. These compounds prevented the autoproteolytic activation of caspase-1 and the processing and secretion of IL-1beta from macrophages. Inhibition was independent of protein synthesis induction, proteasome-mediated protein breakdown, or kinase signaling pathways. Arsenic trioxide and sodium arsenite did not directly modify or inhibit the activity of preactivated recombinant caspase-1. Rather, they induced a cellular state inhibitory to both the autoproteolytic and substrate cleavage activities of caspase-1, which was reversed by the reactive oxygen species scavenger N-acetylcysteine but not by reducing agents or NO pathway inhibitors. Arsenicals provided protection against NLRP1-dependent anthrax lethal toxin-mediated cell death and prevented NLRP3-dependent neutrophil recruitment in a monosodium urate crystal inflammatory murine peritonitis model. These findings suggest a novel role in inhibition of the innate immune response for arsenical compounds that have been used as therapeutics for a few hundred years. PMID- 24337746 TI - IL-17A produced by neutrophils protects against pneumonic plague through orchestrating IFN-gamma-activated macrophage programming. AB - Innate immune cells, including neutrophils and macrophages, are critically involved in host antimicrobial defense responses. Intrinsic regulatory mechanisms controlling neutrophil and macrophage activities are poorly defined. In this study, we found that IL-17A, a natural signal factor, could provide protection against early pneumonic plague inflammation by coordinating the functions of neutrophils and programming of macrophages. The IL-17A level is promptly increased during the initial infection. Importantly, abrogation of IL-17A or IL 17AR significantly aggravated the infection, but mIL-17A treatment could significantly alleviate inflammatory injury, revealing that IL-17A is a critical requirement for early protection of infection. We also demonstrated that IL-17A was predominantly produced by CD11b(+)Ly6G(+) neutrophils. Although IL-17A could not significantly affect the antimicrobial responses of neutrophils, it could target the proinflammatory macrophage (M1) programming and potentiate the M1's defense against pneumonic plague. Mechanistically, IFN-gamma treatment or IFN gamma-activated M1 macrophage transfer could significantly mitigate the aggravated infection of IL-17A(-/-) mice. Finally, we showed that IL-17A and IFN gamma could synergistically promote macrophage anti-infection immunity. Thus, our findings identify a previously unrecognized function of IL-17A as an intrinsic regulator in coordinating neutrophil and macrophage antimicrobial activity to provide protection against acute pneumonic plague. PMID- 24337745 TI - Thymic medullary epithelium and thymocyte self-tolerance require cooperation between CD28-CD80/86 and CD40-CD40L costimulatory pathways. AB - A critical process during thymic development of the T cell repertoire is the induction of self-tolerance. Tolerance in developing T cells is highly dependent on medullary thymic epithelial cells (mTEC), and mTEC development in turn requires signals from mature single-positive thymocytes, a bidirectional relationship termed thymus crosstalk. We show that CD28-CD80/86 and CD40-CD40L costimulatory interactions, which mediate negative selection and self-tolerance, upregulate expression of LTalpha, LTbeta, and receptor activator for NF-kappaB in the thymus and are necessary for medullary development. Combined absence of CD28 CD80/86 and CD40-CD40L results in profound deficiency in mTEC development comparable to that observed in the absence of single-positive thymocytes. This requirement for costimulatory signaling is maintained even in a TCR transgenic model of high-affinity TCR-ligand interactions. CD4 thymocytes maturing in the altered thymic epithelial environment of CD40/CD80/86 knockout mice are highly autoreactive in vitro and are lethal in congenic adoptive transfer in vivo, demonstrating a critical role for these costimulatory pathways in self-tolerance as well as thymic epithelial development. These findings demonstrate that cooperativity between CD28-CD80/86 and CD40-CD40L pathways is required for normal medullary epithelium and for maintenance of self-tolerance in thymocyte development. PMID- 24337747 TI - Role for sigma38 in prolonged survival of Escherichia coli in Drosophila melanogaster. AB - Bacteria adapt themselves to host environments by altering the pattern of gene expression. The promoter-recognizing subunit sigma of bacterial RNA polymerase plays a major role in the selection of genes to be transcribed. Among seven sigma factors of Escherichia coli, sigma(38) is responsible for the transcription of genes in the stationary phase and under stressful conditions. We found a transient increase of sigma(38) when E. coli was injected into the hemocoel of Drosophila melanogaster. The loss of sigma(38) made E. coli rapidly eliminated in flies, and flies infected with sigma(38)-lacking E. coli stayed alive longer than those infected with the parental strain. This was also observed in fly lines defective in humoral immune responses, but not in flies in which phagocytosis was impaired. The lack of sigma(38) did not influence the susceptibility of E. coli to phagocytosis, but made them vulnerable to killing after engulfment. The changes caused by the loss of sigma(38) were recovered by the forced expression of sigma(38)-encoding rpoS as well as sigma(38)-regulated katE and katG coding for enzymes that detoxify reactive oxygen species. These results collectively suggested that sigma(38) contributes to the prolonged survival of E. coli in Drosophila by inducing the production of enzymes that protect bacteria from killing in phagocytes. Considering the similarity in the mechanism of innate immunity against invading bacteria between fruit flies and humans, the products of these genes could be new targets for the development of more effective antibacterial remedies. PMID- 24337748 TI - Guanylate binding protein 1-mediated interaction of T cell antigen receptor signaling with the cytoskeleton. AB - GTPases act as important switches in many signaling events in cells. Although small and heterotrimeric G proteins are subjects of intensive studies, little is known about the large IFN-inducible GTPases. In this article, we show that the IFN-gamma-inducible guanylate binding protein 1 (GBP-1) is a regulator of T cell activation. Silencing of GBP-1 leads to enhanced activation of early T cell Ag receptor/CD3 signaling molecules, including Lck, that is translated to higher IL 2 production. Mass spectrometry analyses showed that regulatory cytoskeletal proteins, like plastin-2 that bundles actin fibers and spectrin beta-chain, brain 1 that links the plasma membrane to the actin cytoskeleton, are binding partners of GBP-1. The spectrin cytoskeleton influences cell spreading and surface expression of TCR/CD3 and the leukocyte phosphatase CD45. We found higher cell spreading and enhanced surface expression of TCR/CD3 and CD45 in GBP-1 silenced T cells that explain their enhanced TCR/CD3 signaling. We conclude that GBP-1 is a downstream processor of IFN-gamma via which T cells regulate cytoskeleton dependent cell functions. PMID- 24337750 TI - Lack of galactosylation enhances the pathogenic activity of IgG1 but Not IgG2a anti-erythrocyte autoantibodies. AB - IgG bears asparagine-linked oligosaccharide side chains in the Fc region. Variations in their extent of galactosylation and sialylation could modulate IgG Fc-dependent effector functions, and hence Ab activity. However, it has not yet been clarified whether the pathogenic potential of IgG autoantibodies is consistently enhanced by the absence of galactose residues per se or the lack of terminal sialylation, which is dependent on galactosylation. Moreover, it remains to be defined whether the increased pathogenicity of agalactosylated IgG is related to activation of the complement pathway by mannose-binding lectin, as suggested by in vitro studies. Using a murine model of autoimmune hemolytic anemia, we defined the contribution of galactosylation or sialylation to the pathogenic activity of IgG1 and IgG2a anti-erythrocyte class-switch variants of 34-3C monoclonal autoantibody. We generated their degalactosylated or highly sialylated glycovariants and compared their pathogenic effects with those of highly galactosylated or desialylated counterparts. Our results demonstrated that lack of galactosylation, but not sialylation, enhanced the pathogenic activity of 34-3C IgG1, but not IgG2a autoantibodies. Moreover, analysis of in vivo complement activation and of the pathogenic activity in mice deficient in C3 or IgG FcRs excluded the implication of mannose-binding lectin-mediated complement activation in the enhanced pathogenic effect of agalactosylated IgG1 anti erythrocyte autoantibodies. PMID- 24337749 TI - KLRG1 impairs CD4+ T cell responses via p16ink4a and p27kip1 pathways: role in hepatitis B vaccine failure in individuals with hepatitis C virus infection. AB - Coinfection of hepatitis B virus (HBV) with hepatitis C virus (HCV) is quite common, leading to an increase in morbidity and mortality. As such, HBV vaccination is recommended in HCV-infected individuals. However, HBV vaccine responses in HCV-infected individuals are often blunted compared with uninfected populations. The mechanism for this failure of vaccine response in HCV-infected subjects remains unclear. In this study, we investigated the expression and function of an inhibitory receptor, killer cell lectin-like receptor subfamily G member 1 (KLRG1), in the regulation of CD4(+) T cells and HBV vaccine responses during HCV infection. We demonstrated that KLRG1 was overexpressed on CD4(+) T cells from HCV-infected, HBV vaccine nonresponders compared with HBV vaccine responders. The capacity of CD4(+) T cells to proliferate and secrete IL-2 cytokine was inversely associated with the level of KLRG1 expression. Importantly, blocking KLRG1 signaling resulted in a significant improvement in CD4(+) T cell proliferation and IL-2 production in HCV-infected, HBV vaccine nonresponders in response to TCR stimulation. Moreover, blockade of KLRG1 increased the phosphorylation of Akt (Ser(473)) and decreased the expression of cell cycle inhibitors p16(ink4a) and p27(kip1), which subsequently enhanced the expression of cyclin-dependent kinase 2 and cyclin E. These results suggest that the KLRG1 pathway impairs CD4(+) T cell responses to neoantigen and induces a state of immune senescence in individuals with HCV infection, raising the possibility that blocking this negative-signaling pathway might improve HBV vaccine responses in the setting of chronic viral infection. PMID- 24337751 TI - Implementing a clinical pathway for hip fractures; effects on hospital length of stay and complication rates in five hundred and twenty six patients. AB - PURPOSE: Modern management of the elderly with a hip fracture is complex and costly. The aim of this study was to compare the treatment-related hospital length of stay (HLOS) before and after implementing a clinical pathway for patients undergoing hip fracture surgery. METHODS: This was a retrospective, before-and-after study. The first period ranged from June 21, 2008 to November 1, 2009 (N = 212), and the second was from January 7, 2010 to July 7, 2011 (N = 314). The electronic hospital system and patients records were reviewed for demographics, HLOS, mortality, complications and readmissions. RESULTS: In the first period 53 % had a femoral neck fracture, of which 57 % were treated with hemiarthroplasty. In the second period this was 46 % and 71 %. Pertrochanteric fractures were treated with a Gamma nail in 85 % in the first period, and in 92 % in the second period. The median HLOS decreased from nine to six days (p < 0.001). For the hemiarthroplasty group HLOS decreased from nine to seven days (p < 0.001); for internal fixation there was no significant difference (five versus six days, p = 0.557) and after Gamma nailing it decreased from ten to six days (p < 0.001). For mortality no statistically significant difference was found (6 % versus 5 %, p = 0.698). Complications decreased for the Gamma nail group (44 % versus 31 %, p = 0.049). Readmissions for the total group were not different (16 % versus 17 %, p = 0.720). CONCLUSIONS: Implementing a clinical pathway for hip fractures is a safe way to reduce the HLOS and it improves the quality of care. PMID- 24337752 TI - Bilateral decompression using a unilateral pedicle construct for lumbar stenosis. AB - PURPOSE: To determine the effectiveness of bilateral decompression via a unilateral approach using unilateral pedicle screw fixation for two-level lumbar stenosis with instability. METHODS: Between October 2006 and October 2010, 98 patients (61 men and 37 women) who had reached the three-year follow-up interval were treated with unilateral pedicle screw fixation at the authors' institution. All patients underwent two-level transforaminal lumbar interbody fusion (TLIF), and the mean age was 59.6 years (range, 40-72). Visual analog scale (VAS) scores and Oswestry Disability Index (ODI) were used to assess the pre-operative and postoperative clinical results. Fusion status, the disc space height, and the whole lumbar lordotic angle were analysed for the radiological evaluation. RESULTS: The ODI scores decreased significantly in both early and late follow-up evaluations and the visual analog scale (VAS) score demonstrated significant improvement in late follow-up (P < 0.01). The disc space height (P < 0.05) and the whole lumbar lordotic angle (P < 0.05) were increased at the final follow-up. Successful fusion was achieved in all patients. CONCLUSION: Bilateral decompression via a unilateral approach using unilateral pedicle screw fixation for two-level lumbar stenosis with instability, which can maintain the lumbar lordosis and the disc space height, is an effective and less invasive method than with bilateral constructs. PMID- 24337753 TI - Evaluation of occupational exposure in magnetic resonance sites. AB - PURPOSE: In an attempt to evaluate the exposure level of magnetic resonance imaging (MRI) workers to static magnetic fields, the isotropic magnetic flux density values were integrated over time to produce the cumulative exposure. To protect occupational staff a further precautionary step is proposed by introducing a weighting function incorporating the limits imposed by the Italian legislation. The results obtained should be reported, at the end of each working day, on a special dose card, in order to record each worker's exposure to the static magnetic field. Moreover, this dose card could be an important tool if long-term effects occur because it provides a complete history of the occupational exposure in an MRI site. MATERIALS AND METHODS: To conduct measurements, three Hall-sensor probes were used. The consistency of experimental data, tools and methodologies used was evaluated by performing the Kruskal-Wallis test. Finally, the weighted magnitude of the magnetic flux density was integrated over time to obtain global exposure. RESULTS: Measurements were performed on different MRI scanners ranging from 0.25 up to 3.0 T. The results obtained were compared with the 200 mT.h, which represents the upper limit of the Italian regulation. In no case was the 200 mT.h per day exposure exceeded: however, when the strength of the magnetic field was >200 mT the weighted function overestimated the exposure, so that it represents a highly precautionary measure taking into account possible acute and long-term effects. In addition, from the data recorded during patient positioning operations by MRI staff the dB/dt curve was obtained. CONCLUSIONS: The areas obtained from the integral of the weighted static magnetic field strength over time can be indicative of the global exposure of the occupational staff. These values should be reported on a special dose card that could be considered as an important tool if long-term effects occur because it provides a complete history of the occupational exposure in an MRI site. PMID- 24337754 TI - Head and neck intensity modulated radiotherapy parotid glands: time of re planning. AB - PURPOSE: To investigate the correct time point for re-planning by evaluating dosimetric changes in the parotid glands (PGs) during intensity-modulated radiotherapy (IMRT) in head and neck cancer patients. MATERIALS AND METHODS: Patients with head and neck cancer treated with IMRT were enrolled. During treatment all patients underwent cone-beam computed tomography (CBCT) scans to verify the set-up. CBCT scans at treatment days 10, 15, 20 and 25 were used to transfer the original plan (CBCTplan I, II, III, IV, respectively) using rigid registration between the two. The PGs were retrospectively contoured and evaluated with the dose-volume histogram. The mean dose, the dose to 50 % of volume, and the percentage of volume receiving 30 and 50 Gy were evaluated for each PG. The Wilcoxon sign ranked test was used to evaluate the effects of dosimetric variations and values <0.05 were taken to be significant. RESULTS: From February to June 2011, ten patients were enrolled and five IMRT plans were evaluated for each patient. All the dosimetric parameters increased throughout the treatment course. However, this increase was statistically significant at treatment days 10 and 15 (CBCTplan I, II; p = 0.02, p = 0.03, respectively). CONCLUSION: CBCT is a feasible method to assess the dosimetric changes in the PGs. Our data showed that checking the PG volume and dose could be indicated during the third week of treatment. PMID- 24337755 TI - Occult neural foraminal stenosis caused by association between disc degeneration and facet joint osteoarthritis: demonstration with dedicated upright MRI system. AB - PURPOSE: The aim of our study was to evaluate the presence of dynamic foraminal stenosis using a new low-field dedicated magnetic resonance (MR) unit with a balancing system that allows images to be acquired both in the recumbent and upright position. Imaging of lumbar spine with the patient in a supine, nonweight bearing position is likely to misrepresent the degree and potential risk of spinal stenosis. MATERIALS AND METHODS: In the period between September 2008 and May 2011, we selected 630 symptomatic patients aged 40-65 years (mean age 56) who underwent conventional MR in clinostatic position. The study only included selected patients (total 160) who underwent clinostatic and orthostatic evaluation using a dedicated MR system (G-scan). The biomechanical parameters were also considered. Changes in the dimension of the neural foramina were compared using the presence of disc and facet degeneration by statistical analysis. RESULTS: Stenosis of the intervertebral foramen was never found in the presence of normal intervertebral discs either in the presence or in the absence of facet disease, in either clinostatic or orthostatic position. Sixty-one stenotic levels were detected which were visualised exclusively in scans obtained under weight-bearing conditions. We named this dynamic condition "occult stenosis". In all of these cases, disc disease was associated with facet pathology. CONCLUSION: Our data show that the association between disc pathology and facet osteoarthrosis can cause occult foraminal stenosis. Strategies to image the spine under physiological load conditions may improve the clinical diagnosis of radicular pain. PMID- 24337756 TI - 256-slice CT coronary angiography: in vivo dosimetry and technique optimization. AB - PURPOSE: This study was undertaken to compare the different acquisition protocols available in a last-generation multislice computed tomography scanner used for cardiovascular studies, with particular attention to dosimetric aspects. MATERIALS AND METHODS: Our study compared prospective and retrospective electrocardiographic-gating techniques for cardiac imaging. For each patient, we performed in vivo dose measurements, using Gafchromic film. We compared the effective dose values estimated from the experimental measurements and the dose data reported on the CT console. Image quality was also assessed. RESULTS: Prospective acquisition allows for major dose savings compared to retrospective acquisition (mean effective dose, 4.5 mSv with prospective acquisition versus 27.5 mSv with retrospective acquisition). The agreement between the experimental and software-based dose estimates was excellent and showed below 10% of variation of the measured dose. CONCLUSION: In patients with regular rhythm and a heart rate lower than 75 bpm, the prospective acquisition technique ensures adequate diagnostic results and allows for significant patient dose savings. PMID- 24337757 TI - Effective DQE (eDQE) and dose to optimize radiographic technical parameters: a survey of pediatric chest X-ray examinations in Korea. AB - OBJECTIVE: The purpose of this study was to investigate the effect of various technical parameters for dose optimization in pediatric chest radiological examinations by evaluating effective dose and effective detective quantum efficiency (eDQE). MATERIALS AND METHODS: For tube voltages ranging from 40 to 90 kV in 10 kV increments at the focus-to-detector distance (FDD) of 100, 110, 120, 150, 180 cm, the eDQE was evaluated at same effective dose. RESULTS: The eDQE was considerably higher without the use of the grid on equivalent effective dose. This indicates that the reduction of scatter radiation did not compensate for the loss of absorbed effective photons in the grid. The eDQE increased with increasing FDD because of the greater effective modulation transfer function (eMTF) with lower focal spot blurring. However, most of the major hospitals in Korea employed a short FDD of 100 cm with the grid. The entrance surface air kerma values for the hospitals of this survey exceeded the Korean reference level of 100 MUGy. CONCLUSIONS: The different reference levels might be appropriate for the same examination conducted on children of different ages. Also, it is necessary to refine the technical parameters to perform pediatric chest examinations. PMID- 24337758 TI - Utility of cardiac magnetic resonance (CMR) in the evaluation of right ventricular (RV) involvement in patients with myocardial infarction (MI). AB - PURPOSE: The aim of this work was to compare the prevalence of right ventricle involvement in a population of patients with myocardial infarction as detected by cardiac magnetic resonance (CMR), clinical presentation, electrocardiographic (ECG) and echocardiographic criteria. MATERIALS AND METHODS: A total of 97 consecutive patients, admitted to our institution for acute myocardial infarction, underwent a standard CMR examination within 5 days after the event. The presence of myocardial oedema and late enhancement of the right ventricle were compared to infarct location (anterior vs. inferior), clinical data, ECG, echocardiography results and other CMR findings. The results were analysed statistically using the Student's t test for independent samples and the K statistic. RESULTS: Among the 97 patients included in the study, a diagnosis of right ventricular infarction was established in 12, 14 and 24 cases on the basis of the clinical data, the ECG and echocardiography, respectively. CMR demonstrated myocardial oedema and late enhancement of the right ventricle in 48 and 32 cases, respectively. The right ventricle was involved in 46 % of patients with inferior myocardial infarction (15/32) and in 30 % with anterior myocardial infarction (17/56), correlating to a worsening of both right and left ventricular performance (p = 0.001-0.05). CONCLUSIONS: The right ventricle is frequently involved in myocardial infarction, correlating to a worse functional impairment of both ventricles and a worse prognosis. This finding, which is often underestimated by traditional cardiological tests, is well revealed by CMR, with potential clinical and therapeutic impact. PMID- 24337760 TI - X-ray population exposure from projection radiology and computed tomography in Emilia-Romagna from 2001 to 2010: comparison of ICRP 60 and ICRP 103 weighting factors. AB - PURPOSE: This paper shows the trends from 2001 to 2010 of per caput and collective effective dose (S) to the Emilia-Romagna population due to radiation exposure from projection radiology (PR) and computed tomography (CT), calculated according to both ICRP60 and ICRP103 tissue weighting factors. MATERIALS AND METHODS: The frequency of examinations and dose calculations were based on data provided directly by Emilia-Romagna Health Trusts. In particular, effective doses were evaluated using the tissue weighting (w T) factors reported both in ICRP60 (w T,60) and in ICRP103 (w T,103). RESULTS: A decrease in the frequency of PR skull examinations and an increase in the frequency of mammography, CT of the abdomen, chest, and head-neck were found during the decade. In 2010, the PR/CT procedures contributed 75.4 %/24.6 % to examination frequency and approximately 10 %/90 % to dose; S was 6,169.2 man Sv when w T,60 was used and 5,855.1-6,665.5 man Sv when w T,103 in two different mathematical models was utilised. CONCLUSIONS: Dose estimates pre- and post-ICRP103 must be compared carefully, because changes due to different radiological practices could be confused with changes due to the use of different w T's. In general, dose evaluations with the use of w T,60 until 2007 and w T,103 from 2008 seem to be consistent and coherent. PMID- 24337759 TI - Proton beam radiotherapy: report of the first ten patients treated at the "Centro Nazionale di Adroterapia Oncologica (CNAO)" for skull base and spine tumours. AB - PURPOSE: The Italian National Centre for Oncological Hadrontherapy (Centro Nazionale di Adroterapia Oncologica, CNAO), equipped with a proton and ion synchrotron, started clinical activity in September 2011. The clinical and technical characteristics of the first ten proton beam radiotherapy treatments are reported. MATERIALS AND METHODS: Ten patients, six males and four females (age range 27-73 years, median 55.5), were treated with proton beam radiotherapy. After one to two surgical procedures, seven patients received a histological diagnosis of chordoma (of the skull base in three cases, the cervical spine in one case and the sacrum in three cases) and three of low-grade chondrosarcoma (skull base). Prescribed doses were 74 GyE for chordoma and 70 GyE for chondrosarcoma at 2 GyE/fraction delivered 5 days per week. RESULTS: Treatment was well tolerated without toxicity-related interruptions. The maximal acute toxicity was grade 2, with oropharyngeal mucositis, nausea and vomiting for the skull base tumours, and grade 2 dermatitis for the sacral tumours. After 6-12 months of follow-up, no patient developed tumour progression. CONCLUSIONS: The analysis of the first ten patients treated with proton therapy at CNAO showed that this treatment was feasible and safe. Currently, patient accrual into these as well as other approved protocols is continuing, and a longer follow-up period is needed to assess tumour control and late toxicity. PMID- 24337761 TI - Phase III, randomized, double-blind, placebo-controlled study of modafinil for fatigue in patients treated with docetaxel-based chemotherapy. AB - PURPOSE: Modafinil has been reported to benefit a subgroup of patients suffering severe fatigue while undergoing chemotherapy. Docetaxel is associated with fatigue that may lead to premature therapy withdrawal. We investigated whether modafinil could reduce fatigue during docetaxel chemotherapy. METHODS: This multicenter, randomized, double-blind, placebo-controlled study evaluated the efficacy of modafinil in patients with metastatic prostate or breast cancer undergoing docetaxel chemotherapy (every 21 days; minimum dose 50 mg/m(2)). At the start of their third or subsequent chemotherapy cycle, patients with significant docetaxel-associated fatigue were randomized to receive concurrent modafinil 200 mg/day or placebo for 15 days ("treatment periods" (TP)). Docetaxel was continued for up to four further cycles. Fatigue was evaluated with the fatigue component of the MD Anderson Symptom Inventory (MDASI). The primary endpoint was cumulative MDASI area under the curve (AUC) during the first 7 days of study medication during TP1 and TP2. RESULTS: Evaluable data were available from 83 patients (65 with prostate cancer). There was no statistically significant difference between the two treatment arms for the primary endpoint (MSADI AUC3-10 35.9 vs 39.6; 95 % confidence interval -8.9, 1.4; P=0.15). Overall toxicity was comparable between treatment groups; however, the incidence of grade <= 2 nausea and vomiting was higher in the modafinil arm (45.4 vs 25 %). CONCLUSIONS: Assessing and managing chemotherapy-related fatigue remains a major challenge. There was a lack of difference between the two arms in the planned primary endpoint. However, there was a modest but consistent trend towards improvement of docetaxel-related fatigue in those treated with modafinil. Based on the study findings, modafinil for the treatment of fatigue associated with docetaxel chemotherapy elicits modest improvements. Larger, longer term, randomized, controlled studies are required to clarify the exact role of modafinil in the treatment of docetaxel-related fatigue. PMID- 24337762 TI - Parent perspectives on family-based psychosocial interventions in pediatric cancer: a mixed-methods approach. AB - Family-based interventions in pediatric cancer face challenges associated with integrating psychosocial care into a period of intensive treatment and escalating stress. Little research has sought input from parents on the role of interventions delivered shortly after diagnosis. This mixed-methods study obtained parents' perspectives on the potential role of family-based interventions. Twenty-five parents provided feedback on the structure and timing of psychosocial interventions via focus groups and a questionnaire. Qualitative analyses resulted in three themes that were illustrative of a traumatic stress framework: (1) tension between focusing on child with cancer and addressing other family needs, (2) factors influencing parents' perception of a shared experience with other parents, and (3) the importance of matching interventions to the trajectory of parent adjustment. Quantitative data indicated that parents preferred intervention within 6 months of diagnosis, with almost half favoring within 2 months of diagnosis, and the majority wanted interventions targeted to parents only. Qualitative themes highlight the importance of using a traumatic stress framework to inform the development of family-based interventions for those affected by pediatric cancer. PMID- 24337763 TI - Handling uncertainty. AB - Uncertainty is triggered by many events during the experience of illness - from hearing bad news to meeting a new doctor. Oncology professionals need to recognize the intense feelings associated with uncertainty and respond empathically to patients. This article describes opportunities to strengthen the therapeutic connection and minimize uncertainty. PMID- 24337764 TI - Biologically based therapies are commonly self-prescribed by Brazilian women for the treatment of advanced breast cancer or its symptoms. AB - PURPOSE: Breast cancer (BC) might be associated with loss of function in affected patients, with a direct impact on their quality of life (QOL). Many women with metastatic BC seek relief of symptoms, including the use of complementary and alternative medicine (CAM) to cure cancer. The present study aimed to identify the pattern of CAM used by patients with metastatic BC and to assess the correlation between CAM use and scores on anxiety, depression, and QOL scales. METHODS: A total of 126 women with metastatic BC were interviewed using four instruments: (1) a questionnaire containing socioeconomic, clinical, and demographic data and CAM use; (2) European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ)-C30; (3) EORTC QLQ-BR23; and (4) the Hospital Anxiety and Depression Scale. RESULTS: Fifty percent of the participants reported the use of at least one CAM modality. Biologically based practices were the most frequently used to treat BC and/or its symptoms, the most commonly discussed with the oncologists, and one of the CAM categories in which more patients reported a desire to learn more about. The overall use of CAM was not correlated with the scores on the anxiety, depression, and QOL scales. However, analysis of the association of the QOL scores with specific CAM modalities revealed some potential associations (especially for food supplements, art therapy, psychotherapy, and prayer). CONCLUSIONS: Women with metastatic BC frequently make use of CAM to treat the cancer and/or its symptoms. Biologically based practices seem to be particularly important in Brazil. An association between specific CAM modalities and some QOL domains was suggested, but it needs further confirmation. PMID- 24337765 TI - Patterns and predictors of symptom incongruence in older couples coping with prostate cancer. AB - PURPOSE: Prostate cancer survivors (PCSs) may experience persistent symptoms following treatment. If PCSs and spouses differ in their perceptions of symptoms, that incongruence may cause mismanagement of symptoms and reduced relationship quality. The purpose of this study was to examine symptom incongruence and identify the PCS and spouse characteristics associated with symptom incongruence in older couples coping with prostate cancer. METHODS: Participants in the study were older PCSs (>60 years) and their spouses (N=59 couples). Symptom incongruence was determined by comparing patient and spouse independent ratings of the severity of his cancer-related symptoms. Predictor variables included PCS age, time since diagnosis, PCS comorbidity, PCS and spouse depressive symptoms, and spouse caregiving strain. RESULTS: PCS and spouse ratings of his symptom severity and the amount of incongruence over his symptoms varied significantly across couples. Overall, couples rated a moderate level of PCS symptom severity, but PCSs and their spouses significantly differed in their perceptions of PCS symptom severity with spouses rating severity higher (t=-2.66, df=51, p<0.01). PCS younger age and high spouse caregiver strain accounted for 29 % of incongruence in perceptions of PCS symptom severity. CONCLUSIONS: This study is among the first to show that PCSs and spouses may perceive cancer-related persistent symptoms differently. Among this older sample, younger PCS age and spouse caregiver strain were associated with incongruence in symptoms perceptions in couples. These and other factors may inform future interventions aimed at preserving relationship quality in older couples who have experienced prostate cancer. PMID- 24337766 TI - Response to Letter to the Editor: Risk prediction models for chemotherapy-induced nausea and vomiting: almost ready for prime time? : Dranitsaris and Clemons. PMID- 24337767 TI - Candidate's single-nucleotide polymorphism predictors of treatment nonresponse to the first anti-TNF inhibitor in ankylosing spondylitis. AB - The objective of this study is to identify single-nucleotide polymorphisms (SNPs) predictors of treatment nonresponse to the first anti-TNF-alpha agent in ankylosing spondylitis (AS). Patients were classified as "nonresponders" if they failed to achieve improvement >=50 % of the initial BASDAI. We selected candidate SNPs previously reported, associated with susceptibility or pathogenesis of AS and with other spondylarthropaties (SpAs). The predictors of nonresponse were modeled with multiple logistic regression. The predictive power of the genetic model of nonresponse to treatment was tested with AUC-ROC. One hundred and twenty one (121) AS patients fulfilled the inclusion criteria. Of the candidate SNPs tested for association with treatment effectiveness, five independent predictors were identified: rs917997, rs755622, rs1800896, rs3740691, and rs1061622. The genetic model of nonresponse to treatment had a predictive power of 0.77 (95 % CI 0.68-0.86). Our study identified several polymorphisms which could be the useful genetic biomarkers in predicting nonresponse to anti-TNF-alpha therapy. PMID- 24337768 TI - Phase 1 study of efatutazone, a novel oral peroxisome proliferator-activated receptor gamma agonist, in combination with FOLFIRI as second-line therapy in patients with metastatic colorectal cancer. AB - BACKGROUND: Efatutazone, a novel oral highly-selective peroxisome proliferator activated receptor gamma (PPARgamma) agonist, has demonstrated some inhibitory effects on disease stabilization in patients with metastatic colorectal cancer (mCRC) enrolled in previous phase I studies. Here, we evaluate the safety and pharmacokinetics of efatutazone combined with FOLFIRI (5-fluorouracil, levo leucovorin, and irinotecan) as second-line chemotherapy in Japanese patients with mCRC. METHODS: Dose-limiting toxicities (DLTs) were evaluated at 2 efatutazone dose levels of 0.25 and 0.50 mg (the recommended dose [RD] of efatutazone monotherapy) twice daily in combination with FOLFIRI in a 3-9 patient cohort. Furthermore, tolerability at the RD level was assessed in additional patients, up to 12 in total. Blood samples for pharmacokinetics and biomarkers and tumor samples for archival tissues were collected from all patients. RESULTS: Fifteen patients (0.25 mg, 3; 0.5 mg, 12) were enrolled. No DLTs were observed. Most patients experienced weight increase (100 %) and edema (80.0 %), which were manageable with diuretics. Common grade 3/4 toxicities were neutropenia (93.3 %), leukopenia (46.7 %), and anemia (33.3 %). Stable disease was observed in 8 of the 14 patients evaluable for tumor response. The plasma adiponectin levels increased over time and increased dose. No clear relationship was detected between treatment efficacies and plasma levels of adiponectin as well as the expression levels of PPARgamma and the retinoid X receptor in tumor tissues. CONCLUSIONS: Efatutazone combined with FOLFIRI demonstrates an acceptable safety profile and evidence of disease stabilization in Japanese patients with mCRC. The RD for efatutazone monotherapy can be used in combination with FOLFIRI. PMID- 24337769 TI - A phase II trial of a selective c-Met inhibitor tivantinib (ARQ 197) monotherapy as a second- or third-line therapy in the patients with metastatic gastric cancer. AB - BACKGROUND: Tivantinib is a selective, non-ATP competitive, small-molecule inhibitor of c-Met and is under development in several cancers including non small cell lung and hepatocellular carcinoma. Activation of c-Met has been frequently found in metastatic gastric cancer (MGC) and is associated with poor prognosis. In this single-arm study, we evaluated the efficacy of tivantinib monotherapy in Asian patients with previously treated MGC. This is the first clinical report from the trials evaluating the efficacy of a selective c-Met inhibitor for MGC. PATIENTS AND METHODS: Eligibility criteria included: MGC with at least one measurable lesion; 1 or 2 prior chemotherapy regimens; and ECOG PS 0 or 1. Tivantinib was daily administered orally. The primary endpoint was the disease control rate (DCR). Pre-treatment tumor tissue was collected to evaluate the biomarkers related to efficacy. RESULTS: Thirty patients, including 12 patients with prior gastrectomy, received tivantinib: median age 62.5 years; ECOG PS 0/1 (8/22); 1/2 prior regimen (16/14). No objective response was observed, and DCR was 36.7 %. Median progression-free survival was 43 days (95 % CI: 29.0 92.0). Grade 3 or 4 adverse events occurred in 13 patients (43.3 %), in whom neutropenia (N = 4) and anemia (N = 4) were recognized as drug-related. c-Met gene amplification was observed in 2 patients (6.9 %). No obvious relationship was identified between efficacy and biomarkers including gene amplification of c Met, expression of c-Met, p-Met and HGF. CONCLUSION: Tivantinib as a monotherapy showed a modest efficacy in previously treated MGC, and further studies taking account of predictive biomarkers and/or combination with other chemotherapy may be needed in MGC. PMID- 24337771 TI - Exposure to household painting and floor treatments, and parental occupational paint exposure and risk of childhood brain tumors: results from an Australian case-control study. AB - PURPOSE: Childhood brain tumors (CBT) are the leading cause of cancer death in children, yet their etiology remains largely unknown. This study investigated whether household exposure to paints and floor treatments and parental occupational painting were associated with CBT risk in a population-based case control study conducted between 2005 and 2010. METHODS: Cases were identified through all ten Australian pediatric oncology centers, and controls via nationwide random-digit dialing, frequency matched to cases on age, sex, and state of residence. Data were obtained from parents in mailed questionnaires and telephone interviews. Information on domestic painting and floor treatments, and parental occupational exposure to paint, in key periods relating to the index pregnancy and childhood was obtained for 306 cases and 950 controls. Data were analyzed using unconditional logistic regression, adjusting for frequency matching variables and potential confounders. RESULTS: Overall, we found little evidence that parental, fetal, or childhood exposure to home painting or floor treatments was associated with risk of CBT. There was, though, some evidence of a positive association between childhood exposure to indoor painting and risk of high-grade glioma [odds ratio (OR) 3.31, 95 % confidence interval (CI) 1.29, 8.52] based on very small numbers. The OR for the association between CBT and paternal occupational exposure to paint any time before the pregnancy was 1.32 (95 % CI 0.90, 1.92), which is consistent with the results of other studies. CONCLUSIONS: Overall, we found little evidence of associations between household exposure to paint and the risk of CBT in any of the time periods investigated. PMID- 24337770 TI - Development of FRET biosensors for mammalian and plant systems. AB - Genetically encoded biosensors are increasingly used in visualising signalling processes in different organisms. Sensors based on green fluorescent protein technology are providing a great opportunity for using Forster resonance energy transfer (FRET) as a tool that allows for monitoring dynamic processes in living cells. The development of these FRET biosensors requires careful selection of fluorophores, substrates and recognition domains. In this review, we will discuss recent developments, strategies to create and optimise FRET biosensors and applications of FRET-based biosensors for use in the two major eukaryotic kingdoms and elaborate on different methods for FRET detection. PMID- 24337774 TI - Combined Quenching Mechanism of Anthracene Fluorescence by Cetylpyridinium Chloride in Sodium Dodecyl Sulfate Micelles. AB - The Stern-Volmer quenching constant (KSV) for quenching of anthracene fluorescence in sodium dodecyl sulfate (SDS) micelles by pyridinium chloride has been reported previously to be 520 M(-1) based on steady state fluorescence measurements. However, such measurements cannot distinguish static versus dynamic contributions to the overall quenching. In the work reported here, the quenching dynamics of anthracene in SDS micelles by cetylpyridinium chloride (CPC), an analogue of pyridinium chloride, were investigated using both steady state and time resolved fluorescence quenching. Concurrent measurement of the decrease in fluorescence intensity and lifetime of anthracene provide a quantitative evaluation of collision induced (i.e. dynamic) versus complex formation (i.e. static) quenching of the anthracene fluorophore. The results reveal that a combined quenching mechanism is operative with approximately equal constants of 249 +/- 6 M(-1) and 225 +/- 12 M(-1) for dynamic and static quenching, respectively. PMID- 24337772 TI - The influence of genetic ancestry and ethnicity on breast cancer survival associated with genetic variation in the TGF-beta-signaling pathway: The Breast Cancer Health Disparities Study. AB - The TGF-beta signaling pathway regulates cellular proliferation and differentiation. We evaluated genetic variation in this pathway, its association with breast cancer survival, and survival differences by genetic ancestry and self-reported ethnicity. The Breast Cancer Health Disparities Study includes participants from the 4-Corners Breast Cancer Study (n = 1,391 cases) and the San Francisco Bay Area Breast Cancer Study (n = 946 cases) who have been followed for survival. We evaluated 28 genes in the TGF-beta signaling pathway using a tagSNP approach. Adaptive rank truncated product (ARTP) was used to test the gene and pathway significance by Native American (NA) ancestry and by self-reported ethnicity (non-Hispanic white (NHW) and Hispanic/NA). Genetic variation in the TGF-beta signaling pathway was associated with overall breast cancer survival (P ARTP = 0.05), especially for women with low NA ancestry (P ARTP = 0.007) and NHW women (P ARTP = 0.006). BMP2, BMP4, RUNX1, and TGFBR3 were significantly associated with breast cancer survival overall (P ARTP = 0.04, 0.02, 0.002, and 0.04, respectively). Among women with low NA, ancestry associations were as follows: BMP4 (P ARTP = 0.007), BMP6 (P ARTP = 0.001), GDF10 (P ARTP = 0.05), RUNX1 (P ARTP = 0.002), SMAD1 (P ARTP = 0.05), and TGFBR2 (P ARTP = 0.02). A polygenic risk model showed that women with low NA ancestry and high numbers of at-risk alleles had twice the risk of dying from breast cancer as did women with high NA ancestry. Our data suggest that genetic variation in the TGF-beta signaling pathway influences breast cancer survival. Associations were similar when the analyses were stratified by genetic ancestry or by self-reported ethnicity. PMID- 24337775 TI - Prevalence of metabolic syndrome and associated cardiovascular risk factors in Guatemalan school children. AB - Guatemala is experiencing a nutritional and lifestyle transition. While chronic malnutrition is prevalent, overweight, obesity and chronic diseases have increased substantially in the country. This study was conducted to investigate the prevalence of metabolic syndrome and the associated cardiovascular risk factors in the pre-adolescent Guatemalan population. A cross-sectional study was conducted among 302 Guatemalan children (8-13 years old) attending public and private schools in the Municipality of Chimaltenango. Demographic data and anthropometric and blood pressure measurements were collected. A blood sample was taken after an 8 h overnight fast and analyzed for glucose, triglyceride and high density lipoprotein cholesterol levels. The data were analyzed to identify factors associated with metabolic syndrome and with its components. The prevalence of metabolic syndrome in the study population was 2.0 %. However, approximately 54 % of the children had at least one component of metabolic syndrome, while none had four or five of the components. The three most prevalent risk factors were high triglycerides (43.4 %), low HDL cholesterol (17.2 %) and obesity (12.3 %). Boys were more likely to be obese than girls and rural children were more likely to have higher triglyceride levels than urban children. Although the prevalence of metabolic syndrome is low, the fact that majority of the children already have at least one component of metabolic syndrome is cause for concern since components of metabolic syndrome can continue into adulthood and increase the risk for chronic diseases later in life. Therefore, immediate action should be taken to address the problem. PMID- 24337776 TI - Message framing strategies to increase influenza immunization uptake among pregnant African American women. AB - We explored the attitudes, opinions, and concerns of African American women regarding influenza vaccination during pregnancy. As influenza immunization coverage rates remain suboptimal in the United States among this population, we elicited message framing strategies for multicomponent interventions aimed at decreasing future incident cases of maternal and neonatal influenza. Semi structured in-depth interviews (N = 21) were conducted with pregnant African American women at urban OB/GYN clinics who had not received an influenza vaccine. Interviews were transcribed, subjected to intercoder reliability assessment, and content analyzed to identify common thematic factors related to acceptance of the influenza vaccine and health communication message preferences. Four major themes were identified. These were communication approaches, normal vaccine behavior, pregnancy vaccination, and positive versus negative framing. Two strong themes emerged: positively-framed messages were preferred over negatively-framed messages and those emphasizing the health of the infant. Additionally, previous immunization, message source, and vaccine misperceptions also played important roles in decision-making. The majority of women indicated that positively framed messages focusing on the infant's health would encourage them to receive an influenza vaccine. Messages emphasizing immunization benefits such as protection against preterm birth and low birth weight outcomes have potential to overcome widespread negative community perceptions and cultural beliefs. Additionally, messages transmitted via interpersonal networks and social media strongly influence motivation to obtain vaccination during pregnancy. The findings of this study will assist in developing tailored messages that change pregnant African American women's influenza vaccination decision-making to achieve improved coverage. PMID- 24337777 TI - 3,4-DGE is cytotoxic and decreases HSP27/HSPB1 in podocytes. AB - Hyperglycemia is the key driver of diabetic complications and increased concentrations of glucose degradation products. The study of peritoneal dialysis solution biocompatibility has highlighted the adverse biological effects of glucose degradation products. Recently, 3,4-dideoxyglucosone-3-ene (3,4-DGE) was identified as the most toxic glucose degradation product in peritoneal dialysis fluids. In addition, 3,4-DGE is present in high-fructose corn syrup, and its precursor 3-deoxyglucosone is increased in diabetes. The role of 3,4-DGE in glomerular injury had not been addressed. We studied the effects of 3,4-DGE on cultured human podocytes and in vivo in mice. 3,4-DGE induced apoptosis in podocytes in a dose- and time-dependent manner. 3,4-DGE promoted the release of cytochrome c from mitochondria and activation of caspase-3. While high glucose concentrations increased the levels of the podocyte intracellular antiapoptotic protein HSP27/HSPB1, 3,4-DGE decreased the expression of podocyte HSP27/HSPB1. Apoptosis induced by 3,4-DGE was caspase-dependent and could be prevented by the broad-spectrum caspase inhibitor zVAD-fmk. Antagonism of Bax by a Ku-70-derived peptide also prevented apoptosis. Intravenous administration of 3,4-DGE to healthy mice resulted in a decreased expression of HSP27/HSPB1 and caspase-3 activation in whole kidney and in podocytes in vivo. In conclusion, 3,4-DGE induces apoptotic cell death in cultured human podocytes, suggesting a potential role in glomerular injury resulting from metabolic disorders. PMID- 24337778 TI - Prolactin levels in manganese-exposed male welders. AB - PURPOSE: Early studies on manganese (Mn) exposure have demonstrated that this transition metal affects dopamine neurotransmission. Dopamine serves as a tonic inhibitor of prolactin release in the anterior hypophysis. Our aim was to determine the relation between serum prolactin levels and manganese-exposure. METHODS: Whole blood was collected from 95 non-exposed control subjects and 179 manganese-exposed male welders. Whole blood manganese was analyzed by Inductively Coupled Plasma--Mass Spectrometer on Agilent 7700 (Agilent Technologies, USA). Serum prolactin levels (PRL), aspartate transaminase (AST), alanine transaminase (ALT), urea, creatinine, soduim (Na), potassium (K) were analyzed by immunological and spectrophotometric methods on Roche E170 Modular System (Roche Diagnostics, Mannheim, Germany). RESULTS: The mean ages for control and manganese exposed group were 40.5 +/- 7.8 and 39.5 +/- 8.7, respectively (p = 0.258). The mean working period (years) for control and manganese-exposed group were 17.4 +/- 9.8 and 18.2 +/- 7.7 years, respectively (p = 0.581). Serum AST and potassium levels were significantly higher in control group than manganese-exposed group (p = 0.002 and p = 0.048, respectively) and body-mass index (BMI) was significantly lower in control group than manganese-exposed group (p = 0.033). There was a significantly positive correlation between whole blood manganese levels and serum prolactin (r = 0.860, p < 0.001). Serum ALT levels were positively correlated with serum AST, urea and sodium (r = 0.315, p < 0.001; r = 0.121, p = 0.046; r = 0.130, p = 0.031). CONCLUSIONS: Serum prolactin level is a diagnostic marker for determining the effect of manganese-exposure. PMID- 24337779 TI - A stepwise model of polyreactivity of the T cell antigen-receptor (TCR): its impact on the self-nonself discrimination and on related observations (receptor editing, anergy, dual receptor cells). AB - The existence of antigen-receptors, BCR, and T cell antigen-receptors, that are "polyreactive", necessitates a rethinking of its effect on two problems faced by the "adaptive" immune system: the self (S)-nonself (NS) discrimination and the determination of effector class. Here, we will concentrate on the impact of polyreactivity on the S-NS discrimination. The anti-S cells interacting with S (i.e., responding to Signal 1) are on the pathway to inactivation. Before irreversibility sets in, these cells can be activated by a second signal (Signal 2) from an effector T-helper (eTh). As these polyreactive anti-S cells express anti-NS specificities, they can be activated by recognition of NS-epitopes in the host's normal immunogenic load with the potential to result in autoimmunity. This problem is delineated using a discrete structural model, the corollaries of which are: (1) a two-step pathway for the purging of anti-S cells (i.e., the S-NS discrimination), and (2) defensible contexts within which to view the phenomena of receptor editing, anergy, and dual receptor cells. PMID- 24337780 TI - Predictive factors of hospital length of stay in patients with operatively treated ankle fractures. AB - BACKGROUND: Operative fixation of ankle fractures is common. However, as reimbursement plans evolve with the potential for bundled payments, it is critical that orthopedic surgeons better understand factors influencing the postoperative length of stay (LOS) in patients undergoing these procedures to negotiate appropriate reimbursement. We sought to identify factors influencing the postoperative LOS in patients with operatively treated ankle fractures. MATERIALS AND METHODS: Six hundred twenty-two patients with ankle fractures between January 1st, 2004 and December 31st, 2010 were identified retrospectively. Charts were reviewed for gender, length of operative procedure, method of fixation, American Society of Anesthesiologists (ASA) physical status score, medical comorbidities, and postoperative LOS. Both univariate and multivariate models were developed to determine predictors of patient LOS. Financial data for an average 24-h inpatient stay were obtained from financial services. RESULTS: Six hundred twenty-two patients were included. In a linear regression analysis, a statistically significant relationship was demonstrated between ASA status and LOS (P < 0.001). Multiple regression analysis further characterized the relationship between ASA and LOS: a 1-U increase in ASA classification conferred a 3.42-day increase in LOS on average (P < 0.001). Based on an average per-day inpatient cost of $4,503, each unit increase in ASA status led to a $15,490 increase in cost. CONCLUSIONS: Our study demonstrates that ASA status is a powerful predictor of LOS in patients undergoing operative fixation of ankle fractures. More complete understanding of these factors will lead to better risk adjustment models for measuring outcomes, determining fair reimbursement, and potential improvements to the efficiency of patient care. LEVEL OF EVIDENCE: Level III retrospective comparative study regressing length of stay with many variables, including ASA physical status. PMID- 24337782 TI - Risk of recurrence and long-term outcomes after colonic diverticular bleeding. AB - PURPOSE: Diverticular disease is one of the most common causes of acute lower gastrointestinal bleeding. We aimed to evaluate the natural history, follow-up, and risk factors associated with re-bleeding (recurrence) in patients with colonic diverticular bleeding. METHODS: We reviewed patients with proven colonic diverticular hemorrhage from September 1993 to June 2012 at our institution. Recurrence was the main outcome measure. RESULTS: We identified 78 out of 95 patients with proven diverticular bleed who were treated non-operatively and were followed up for a median of 57.1 months. Thirty-seven (47 %) of these patients with a median age of 67 years developed recurrent diverticular bleed after a median time of 8.1 months. The bleeding originated from the left colon in 78 (83 %) out of 95 patients in the first bleeding episode and 31(84 %) out of 37 patients during the recurrent bleeding episode. Thirty-six patients (97 %) with recurrent diverticular bleed required surgical intervention. Old age at the time of initial bleeding was associated with recurrence (p = 0.001). Patients with diverticulitis (p < 0.0001), peripheral vascular (p = 0.01), and chronic renal diseases (p = 0.047) were found to have an increased risk for recurrent colonic diverticular bleed. We only had one perioperative mortality due to postoperative sepsis. All other mortalities were not directly associated with surgery. CONCLUSION: Patients with a history of colonic diverticular bleed are prone to recur shortly thereafter. Certain risk factors including increased age, documented diverticulitis, history of peripheral vascular disease, and chronic renal failure may predispose to recurrence. PMID- 24337781 TI - Enhanced recovery strategies in colorectal surgery: is the compliance with the whole program required to achieve the target? AB - PURPOSE: The complexity of "fast track" (FT) surgery might decrease its applicability in daily practice and extensive diffusion. The aim of this study was to understand if the positive effect of FT on the outcome might be affected by the number, type, level of evidence of the components, or their possible combinations. METHODS: We performed a Medline, Embase, Pubmed, and Cochrane Library literature search of randomized and non-randomized trials comparing FT to conventional care (CC) in elective colorectal operations. By a meta-analytic approach, the effect of FT was estimated by the risk ratio (RR) with a 95 % confidence interval (CI) for the risk of post-operative complications. RESULTS: The analysis included 53 studies (36 non-RCTs with and 17 RCTs), with 4,100 patients in the FT group and 4,424 patients in the CC group for a total of 8,524 patients. Fifty-six different item combinations were observed. The median rate of strategy implementation was 50 %. The positive effect of FT over CC was observed regardless the number (<10 vs. >=10) of strategies used (RR = 0.80; 95 % CI 0.66 0.98 and RR = 0.75; 95 % CI 0.65-0.87, respectively), the application of items with strong vs. low level evidence (RR = 0.78; 95 % CI 0.67-0.90 and RR = 0.76; 95 % CI 0.63-0.92, respectively), or the frequency (>=80 vs. <80 %) of items implemented (RR = 0.80; 95 % CI 0.69-0.93 and RR = 0.73; 95 % CI 0.61-0.87, respectively). CONCLUSION: The positive effects of FT seem to be achieved regardless the multiplicity and variance of item grouping. PMID- 24337783 TI - Cross-modal transitivity in a California sea lion (Zalophus californianus). AB - The ability of an experimentally experienced female California sea lion to form transitive relations across sensory modalities was tested using a matching-to sample procedure. The subject was trained by trial-and-error, using differential reinforcement, to relate an acoustic sample stimulus to one member from each of two previously established visual classes. Once the two auditory-visual relations were formed, she was tested to determine whether untrained transitive relations would emerge between each of the acoustic stimuli and the remaining stimuli of each 10-member visual class. During testing, the sea lion demonstrated immediate transfer by responding correctly on 89% of the 18 novel transfer trials compared to 88% on familiar baseline trials. We then repeated this training and transfer procedure twice more with new auditory-visual pairings with similar positive results. Finally, the six explicitly trained auditory-visual relations and the 56 derived auditory-visual relations were intermixed in a single session, and the subject's performance remained stable at high levels. This sea lion's transfer performance indicates that a nonhuman animal is capable of forming new associations through cross-modal transitivity. PMID- 24337784 TI - Semi-wild chimpanzees open hard-shelled fruits differently across communities. AB - Researchers investigating the evolutionary roots of human culture have turned to comparing behaviours across nonhuman primate communities, with tool-based foraging in particular receiving much attention. This study examined whether natural extractive foraging behaviours other than tool selection differed across nonhuman primate colonies that had the same foods available. Specifically, the behaviours applied to open the hard-shelled fruits of Strychnos spp. were examined in three socially separate, semi-wild colonies of chimpanzees (Pan troglodytes) that lived under shared ecological conditions at Chimfunshi Wildlife Orphanage, and were comparable in their genetic makeup. The chimpanzees (N=56) consistently applied six techniques to open these fruits. GLMM results revealed differences in the number of combined technique types to open fruits across the colonies. They also showed colony differences in the application of three specific techniques. Two techniques (full biting and fruit cracking) were entirely absent in some colonies. This study provides empirical evidence that natural hard-shelled fruit-opening behaviours are distinct across chimpanzee colonies, differences that most likely have not resulted from ecological and genetic reasons. PMID- 24337785 TI - Rapid rebound of soil respiration following partial stand disturbance by tree girdling in a temperate deciduous forest. AB - Forests serve an essential role in climate change mitigation by removing CO2 from the atmosphere. Within a forest, disturbance events can greatly impact C cycling and subsequently influence the exchange of CO2 between forests and the atmosphere. This connection makes understanding the forest C cycle response to disturbance imperative for climate change research. The goal of this study was to examine the temporal response of soil respiration after differing levels of stand disturbance for 3 years at the Black Rock Forest (southeastern NY, USA; oaks comprise 67% of the stand). Tree girdling was used to mimic pathogen attack and create the following treatments: control, girdling all non-oaks (NOG), girdling half of the oak trees (O50), and girdling all the oaks (OG). Soil respiratory rates on OG plots declined for 2 years following girdling before attaining a full rebound of belowground activity in the third year. Soil respiration on NOG and O50 were statistically similar to the control for the duration of the study although a trend for a stronger decline in respiration on O50 relative to NOG occurred in the first 2 years. Respiratory responses among the various treatments were not proportional to the degree of disturbance and varied over time. The short-lived respiratory response on O50 and OG suggests that belowground activity is resilient to disturbance; however, sources of the recovered respiratory flux on these plots are likely different than they were pre-treatment. The differential taxon response between oaks and non-oaks suggests that after a defoliation or girdling event, the temporal response of the soil respiratory flux may be related to the C allocation pattern of the affected plant group. PMID- 24337786 TI - Neonatal and maternal risk in Hermansky-Pudlak syndrome: peripartum management brief report and review of literature. AB - INTRODUCTION: Challenges of modern medicine are peripartum bleeding complications as one of the most frequent cases of emergency in obstetrics with a prevalence of 0.5-5.0 %, meaning the main cause of maternal morbidity and mortality. In this context, inherited diseases such as Hermansky-Pudlak syndrome (HPS) should be recognized. HPS is a rare disease and belongs to a heterogeneous group of autosomal recessive disorders characterized by the triad of partial oculocutaneous albinism, disorder of "ceroid" metabolism and platelet storage pool deficiency with bleeding disorder. MATERIALS AND METHODS: We report on a 30 year-old primipara, to show the peripartum obstetrical and anaesthesiological management. The patient presented with contractions in our outpatient department in the 39th gestational week. In previous operations there were bleeding complications due to HPS. DISCUSSION: Therefore, to minimize bleeding complications we aimed a vaginal birth, advised against the peridural anesthesia and optimized the coagulation parameters. The subsequent delivery was performed as vacuum extraction without complications. Patient and newborn could be discharged from the hospital without complications. CONCLUSION: In conclusion, decisive factor for patients with bleeding disorders is a close interdisciplinary cooperation between obstetrician and anesthesiologist. PMID- 24337787 TI - Cortical necrosis secondary to trauma in a child: contrast-enhanced ultrasound comparable to magnetic resonance imaging. AB - Cortical necrosis is an uncommon cause of renal impairment and is rarely a consequence of blunt abdominal trauma. We present a case of unilateral traumatic acute cortical necrosis in a child demonstrated on contrast-enhanced US with confirmation on MRI. Contrast-enhanced US provides a rapid, accurate evaluation of renal parenchyma abnormalities in blunt abdominal trauma in children without exposure to ionising radiation or the risk of sedation. PMID- 24337788 TI - PHACES syndrome associated with carcinoid endobronchial tumor. AB - PHACES syndrome consists of the constellation of manifestations including posterior fossa anomalies of the brain (most commonly Dandy-Walker malformations), hemangiomas of the face and scalp, arterial abnormalities, cardiac defects, eye anomalies and sternal defects. We present a case with a possible PHACES syndrome including sternal cleft and supraumbilical raphe, precordial skin tag, persistent left superior vena cava and subtle narrowing of the aorta with an endobronchial carcinoid tumor. All these anomalies were discovered on chest multi-detector CT. This is a unique case of PHACES syndrome associated with carcinoid tumor. Review of the literature revealed 3 cases of PHACES syndrome with glial tumor. The authors tried to find the relationship between PHACES syndrome and carcinoid tumors or gliomas, which all derive from the neural crest cells. PMID- 24337789 TI - Selective ultrasound screening for developmental hip dysplasia: effect on management and late detected cases. A prospective survey during 1991-2006. AB - BACKGROUND: Early treatment is considered essential for developmental dysplasia of the hip (DDH), but the choice of screening strategy is debated. OBJECTIVE: We evaluated the effect of a selective ultrasound (US) screening programme. MATERIALS AND METHODS: All infants born in a defined region during 1991-2006 with increased risk of developmental dysplasia of the hip, i.e. clinical hip instability, breech presentation, congenital foot deformities or a family history of DDH, underwent US screening at age 1-3 days. Severe sonographic dysplasia and dislocatable/dislocated hips were treated with abduction splints. Mild dysplasia and pathological instability, i.e. not dislocatable/dislocated hips were followed clinically and sonographically until spontaneous resolution, or until treatment became necessary. The minimum observation period was 5.5 years. RESULTS: Of 81,564 newborns, 11,539 (14.1%) were identified as at-risk, of whom 11,190 (58% girls) were included for further analyses. Of the 81,564 infants, 2,433 (3.0%) received early treatment; 1,882 (2.3%) from birth and 551 (0.7%) after 6 weeks or more of clinical and sonographic surveillance. An additional 2,700 (3.3%) normalised spontaneously after watchful waiting from birth. Twenty-six infants (0.32 per 1,000, 92% girls, two from the risk group) presented with late subluxated/dislocated hips (after 1 month of age). An additional 126 (1.5 per 1,000, 83% girls, one from the risk group) were treated after isolated late residual dysplasia. Thirty-one children (0.38 per 1,000) had surgical treatment before age 5 years. Avascular necrosis was diagnosed in seven of all children treated (0.27%), four after early and three after late treatment. CONCLUSION: The first 16 years of a standardised selective US screening programme for developmental dysplasia of the hip resulted in acceptable rates of early treatment and US follow-ups and low rates of late subluxated/dislocated hips compared to similar studies. PMID- 24337790 TI - MRI-compatible positioning device for guiding a focused ultrasound system for transrectal treatment of prostate cancer. AB - BACKGROUND: High-intensity focused ultrasound (HIFU) is a promising treatment method for many common cancers, including prostate cancer. Magnetic resonance image (MRI) guidance of HIFU permits targeting and monitoring of therapy. A prototype MRI-compatible positioning device that navigates a HIFU transducer was designed, fabricated and tested. MATERIALS AND METHODS: The positioning device has two PC-controlled and one manually driven stage that allow endorectal access to the prostate. The positioning device was constructed using a 3-D rapid prototype manufacturing device. Software was developed that controls the motion of the positioning device and enables activation of a HIFU transducer. In vitro testing of the system was performed in a 1.5T MRI scanner using ex vivo turkey tissue. Optical encoders were employed to enhance the accuracy of this positioning device. RESULT: The positioning device was successfully tested for MRI compatibility. The movement error of the positioning device is approximately 20 [Formula: see text]m. The robot has the ability to accurately move the transducer for creation of discrete and overlapping lesions. CONCLUSION: An MRI compatible HIFU positioning system was developed that has the ability to create thermal lesions with MRI guidance for endorectal treatment of prostate cancer. PMID- 24337791 TI - Clinical, functional, and radiographic outcomes following total knee arthroplasty with patient-specific instrumentation, computer-assisted surgery, and manual instrumentation: a short-term follow-up study. AB - PURPOSE: The purpose of this study was to evaluate clinical, functional, and radiographic outcomes following total knee arthroplasty (TKA) performed with patient-specific instrumentation (PSI), computer-assisted surgery (CAS), and manual instruments at short-term follow-up. METHODS: 122 TKAs were performed by a single surgeon: 42 with PSI, 38 with CAS, and 40 with manual instrumentation. Preoperative, 1-month, and 6-month clinical and functional outcomes were measured using the Knee Society scoring system (knee score, function score, range of motion, and pain score). Improvements in clinical and functional outcomes from the preoperative to postoperative period were analyzed. Preoperative and postoperative radiographs were measured to evaluate limb and component alignment. RESULTS: Preoperative, 1-month postoperative, and 6-month postoperative knee scores, function scores, range of motion, and pain scores were highest in the PSI group compared to CAS and manual instrumentation. At 6-month follow-up, PSI TKA was associated with a statistically significant improvement in functional score when compared to manual TKA. Otherwise, there were no statistically significant differences in improvements among PSI, CAS, and manual TKA groups. CONCLUSION: The higher preoperative scores in the PSI group limits the ability to draw definitive conclusions from the raw postoperative scores, but analyzing the changes in scores revealed that PSI was associated with a statistically significant improvement in Knee Society Functional score at 6-month post-TKA as compared to CAS or manual TKA. This may be attributable to improvements in component rotation and positioning, improved component size accuracy, or other factors that are not discernible on plain radiograph. PMID- 24337792 TI - Fast-track surgery in gastrectomy for gastric cancer: a systematic review and meta-analysis. AB - PURPOSE: Fast-track surgery aims to attenuate the surgical stress response, reduce complications, and shorten hospital stay. The goal of the present meta analysis is to assess the safety and effectiveness of fast-track surgery in patients undergoing gastrectomy for gastric cancer compared with conventional perioperative care. METHODS: PubMed, Embase, the Cochrane Central Register of Controlled Trials, and reference lists of the identified studies were searched to identify randomized clinical trials that compared fast-track surgery with conventional perioperative care in patients undergoing gastrectomy for gastric cancer. RESULTS: Five studies with a total of 400 patients were included in the meta-analysis. Meta-analysis shows that postoperative hospital stay (weighted mean difference (WMD) -1.87 days, 95 % confidence interval (CI), -2.46 to -1.28 days, P < 0.00001), time to first passage of flatus (WMD -0.71 days, 95 % CI, 1.03 to -0.39 days, P < 0.0001), and hospital costs (WMD -505.87 dollars, 95 % CI, -649.91 to -361.84 dollars, P < 0.00001) were significantly reduced for fast track surgery. No significant differences were found for readmission rates (relative risk (RR), 1.97 95 % CI, 0.37 to 10.64, P = 0.43) and total postoperative complications (RR, 0.99 95 % CI, 0.56 to 1.76, P = 0.97). CONCLUSIONS: Fast-track surgery is safe and effective in gastrectomy for gastric cancer. Further randomized trials are needed to strengthen the conclusions. PMID- 24337793 TI - Age-adjusted glycated albumin: a more robust parameter to establish glycaemic control in neonatal diabetes mellitus. AB - BACKGROUND: We previously reported that glycated albumin (GA) levels increased in an age-dependent manner in infancy. In order to determine whether this phenomenon is true from infancy to adulthood, we investigated the GA levels in non-diabetic subjects of a wide range of age. METHODS: GA levels of 376 non-diabetic subjects [average age, 31.8 +/- 23.8 years (4 days-78 years)] were determined. A relationship between GA and logarithmically transformed age [log(age)] was analysed. RESULTS: GA levels were significantly positively correlated with log(age) [R = 0.865, P < 0.0001, GA = 1.77 * log(day) + 6.55]. Based on a regression line, we established the formula for adjusting GA levels according to age. CONCLUSION: We showed that GA increases with age from infancy to adulthood and that normal GA levels are demonstrated as a simple regression formula with log(age). This formula allowing us to use the adult reference range has the potential for treatment monitoring of diabetic patients regardless of age. PMID- 24337794 TI - Mercury biomagnification in subtropical reservoir fishes of eastern China. AB - Little is known about mercury (Hg) biomagnification in the subtropics, aquatic systems with high species diversity resulting in complex food webs. High atmospheric Hg emissions and ubiquitous reservoir fisheries may lead to elevated Hg bioaccumulation in Chinese freshwater fishes. However, stocking practices using fast-growing species can result in low fish total Hg (THg) concentrations. Here, we describe Hg transfer within the fish food web of a large subtropical reservoir, Qiandao Hu (Xin'anjiang reservoir) situated in eastern China. We measured food web Hg biomagnification and THg concentrations in 33 species of stocked and wild fishes. Mercury concentrations in most fishes were low, though we also found high Hg concentrations in wild top predators. The food web structure, assessed using stable isotopes of carbon (delta(13)C) and nitrogen (delta(15)N), demonstrated a high degree of omnivory and a long food chain. THg concentrations were highly correlated with fish delta(15)N values. The regression of log10THg against delta(15)N revealed the overall Hg biomagnification rate was low. This study shows that where long food chains exist in subtropical reservoirs, elevated Hg accumulation in top predators can occur despite a low Hg biomagnification rate. PMID- 24337796 TI - Maternal immune-mediated conditions, autism spectrum disorders, and developmental delay. AB - The maternal immune system may play a role in offspring neurodevelopment. We examined whether maternal autoimmune disease, asthma, and allergy were associated with child autism spectrum disorder (ASD) and developmental delay without autism (DD) using 560 ASD cases, 391 typically developing controls, and 168 DD cases from the CHildhood Autism Risk from Genetics and the Environment (CHARGE) study. Results from conditional logistic regression demonstrated few significant associations overall. Maternal autoimmune disease was significantly associated with a modest increase in odds of developmental disorders (combined ASD + DD; OR = 1.46, 95% CI 1.01, 2.09) but not of ASD alone. Associations with certain allergens and onset periods were also suggested. These findings suggest maternal autoimmune disease may modestly influence childhood developmental disorders (ASD + DD). PMID- 24337797 TI - Feasibility and safety of performing outpatient unicompartmental knee arthroplasty. AB - PURPOSE: Unicompartmental knee arthroplasty (UKA) has a faster short-term recovery than total knee arthroplasty (TKA). The purpose of this study was to determine the feasibility and safety of performing outpatient UKAs in a consecutive group of patients presenting with unicompartmental knee osteoarthritis. METHODS: A total of 105 consecutive patients underwent unicompartmental arthroplasty before noon with the intention of being discharged as an outpatient. All patients followed an established rapid recovery pathway to facilitate a same-day discharge. Post-operative complications and hospital readmissions were retrospectively recorded for all patients at one week and at three months after surgery. RESULTS: All of the 105 patients (100 %) indicated for outpatient UKA could be discharged home on the same day of surgery. No patients required readmission within the first week post-operatively, while one patient required readmission between week one and week 12. The single patient who required readmission developed a post-operative infection requiring irrigation/debridement with polyethylene liner exchange and intravenous antibiotics. CONCLUSION: Using an established, multidisciplinary, rapid recovery protocol, outpatient UKA is safe and feasible in the vast majority of patients. PMID- 24337798 TI - Reply to comments by Wu et al. regarding our manuscript titled: A minimally invasive technique for surgical treatment of hallux valgus: simple, effective, rapid, inexpensive (SERI). PMID- 24337799 TI - Lateral unicondylar knee arthroplasty (UKA): contemporary indications, surgical technique, and results. AB - Unicompartmental femoro-tibial osteoarthritis usually affects the medial compartment of the knee, but in 10%, the lateral compartment is primarily involved. Femoral osteotomy is attractive to avoid TKA in younger patients with low-grade unicompartmental osteoarthritis and a valgus deformity. However, only limited functional results can be expected for patients with Ahlback grade 2 or greater osteoarthritis. Moreover, because of previous skin incisions and hardware removal, TKA after femoral osteotomy remains a complex procedure with poor functional results. Unicompartmental knee arthroplasty for both the medial and the lateral compartments has been performed since the 1970s. In a patient with involvement of only one compartment, a medial or a lateral UKA can provide a quicker recovery and enhanced function when compared to TKA. In addition, it preserves bone stock and can be "easily" revised by a TKA. Technical improvements, combined with strict patient selection, have resulted in ten year survivorships greater than 90%. However, lateral UKA is technically more challenging than medial UKA due to the lower number of indications, as well as the functional anatomy of the lateral compartment. The goals of this article are to present up-to-date information concerning indications, patients' selection, surgical technique and results of lateral compartment UKA. PMID- 24337800 TI - A novel chloroplast localized Rab GTPase protein CPRabA5e is involved in stress, development, thylakoid biogenesis and vesicle transport in Arabidopsis. AB - A novel Rab GTPase protein in Arabidopsis thaliana, CPRabA5e (CP = chloroplast localized) is located in chloroplasts and has a role in transport. Transient expression of CPRabA5e:EGFP fusion protein in tobacco (Nicotiana tabacum) leaves, and immunoblotting using Arabidopsis showed localization of CPRabA5e in chloroplasts (stroma and thylakoids). Ypt31/32 in the yeast Saccharomyces cerevisiae are involved in regulating vesicle transport, and CPRabA5e a close homolog of Ypt31/32, restores the growth of the ypt31Delta ypt32(ts) mutant at 37 degrees C in yeast complementation. Knockout mutants of CPRabA5e displayed delayed seed germination and growth arrest during oxidative stress. Ultrastructural studies revealed that after preincubation at 4 degrees C mutant chloroplasts contained larger plastoglobules, lower grana, and more vesicles close to the envelopes compared to wild type, and vesicle formation being enhanced under oxidative stress. This indicated altered thylakoid development and organization of the mutants. A yeast-two-hybrid screen with CPRabA5e as bait revealed 13 interacting partner proteins, mainly located in thylakoids and plastoglobules. These proteins are known or predicted to be involved in development, stress responses, and photosynthesis related processes, consistent with the stress phenotypes observed. The results observed suggest a role of CPRabA5e in transport to and from thylakoids, similar to cytosolic Rab proteins involved in vesicle transport. PMID- 24337801 TI - A special member of the rice SRO family, OsSRO1c, mediates responses to multiple abiotic stresses through interaction with various transcription factors. AB - SIMILAR TO RCD ONE (SRO) is a plant-specific gene family involved in development and abiotic stress responses. SRO proteins are characterized by containing poly (ADP-ribose) polymerase catalytic (PARP) and C-terminal RCD1-SRO-TAF4 domains, and can be classified into two groups and five subgroups on the basis of their PARP domain. Expression analysis of rice SRO genes in response to various abiotic stresses showed that OsSRO1c, a rice SRO gene which functions downstream of the stress-responsive transcription factor SNAC1, is the major stress-responsive gene in the rice SRO family. The ossro1c-1 mutant showed resistance not only to chloroplastic oxidative stress, but also to apoplastic oxidative stress. However, the ossro1c-1 mutant and artificial microRNA-OsSRO1c transgenic rice were significantly impaired in cold tolerance. When compared with the well characterized Arabidopsis SRO protein radical-induced cell death 1 (RCD1), OsSRO1c has considerable variation in the protein sequence, and the two genes exhibit different expression profiles under abiotic stresses. Furthermore, ossro1c-1 and rcd1 showed different responses to multiple abiotic stresses. By screening an Arabidopsis transcription factor library, 29 transcription factors interacted with OsSRO1c in yeast, but only two of these transcription factors were reported to interact with RCD1, which may partly explain the different responses of the two mutants under various stresses. The data presented in this report provide important clues for further elucidating the molecular and biochemical mechanisms of OsSRO1c in mediating responses to multiple abiotic stresses. PMID- 24337802 TI - Endoplasmic reticulum-targeted GFP reveals ER remodeling in Mesorhizobium-treated Lotus japonicus root hairs during root hair curling and infection thread formation. AB - The endoplasmic reticulum (ER) of the model legume Lotus japonicus was visualized using green fluorescent protein (GFP) fused with the KDEL sequence to investigate the changes in the root hair cortical ER in the presence or absence of Mesorhizobium loti using live fluorescence imaging. Uninoculated root hairs displayed dynamic forms of ER, ranging from a highly condensed form to an open reticulum. In the presence of M. loti, a highly dynamic condensed form of the ER linked with the nucleus was found in deformed, curled, and infected root hairs, similar to that in uninoculated and inoculated growing zone I and II root hairs. An open reticulum was primarily found in mature inoculated zone III root hairs, similar to that found in inactive deformed/curled root hairs and infected root hairs with aborted infection threads. Co-imaging of GFP-labeled ER with light transmission demonstrated a correlation between the mobility of the ER and other organelles and the directionality of the cytoplasmic streaming in root hairs in the early stages of infection thread formation and growth. ER remodeling in root hair cells is discussed in terms of possible biological significance during root hair growth, deformation/curling, and infection in the Mesorhizobium-L. japonicus symbiosis. PMID- 24337803 TI - Silicon in Imperata cylindrica (L.) P. Beauv: content, distribution, and ultrastructure. AB - Silicon concentration, distribution, and ultrastructure of silicon deposits in the Poaceae Imperata cylindrica (L.) P. Beauv. have been studied. This grass, known for its medicinal uses and also for Fe hyperaccumulation and biomineralization capacities, showed a concentration of silicon of 13,705 +/- 9,607 mg/kg dry weight. Silicon was found as an important constituent of cell walls of the epidermis of the whole plant. Silica deposits were found in silica bodies, endodermis, and different cells with silicon-collapsed lumen as bulliforms, cortical, and sclerenchyma cells. Transmission electron microscope observations of these deposits revealed an amorphous material of an ultrastructure similar to that previously reported in silica bodies of other Poaceae. PMID- 24337804 TI - High-throughput screening of multispecies biofilm formation and quantitative PCR based assessment of individual species proportions, useful for exploring interspecific bacterial interactions. AB - Multispecies biofilms are predominant in almost all natural environments, where myriads of resident microorganisms interact with each other in both synergistic and antagonistic manners. The interspecies interactions among different bacteria are, despite the ubiquity of these communities, still poorly understood. Here, we report a rapid, reproducible and sensitive approach for quantitative screening of biofilm formation by bacteria when cultivated as mono- and multispecies biofilms, based on the Nunc-TSP lid system and crystal violet staining. The relative proportion of the individual species in a four-species biofilm was assessed using quantitative PCR based on SYBR Green I fluorescence with specific primers. The results indicated strong synergistic interactions in a four-species biofilm model community with a more than 3-fold increase in biofilm formation and demonstrated the strong dominance of two strains, Xanthomonas retroflexus and Paenibacillus amylolyticus. The developed approach can be used as a standard procedure for evaluating interspecies interactions in defined microbial communities. This will be of significant value in the quantitative study of the microbial composition of multispecies biofilms both in natural environments and infectious diseases to increase our understanding of the mechanisms that underlie cooperation, competition and fitness of individual species in mixed-species biofilms. PMID- 24337805 TI - Differential activity of autochthonous bacteria in controlling drought stress in native Lavandula and Salvia plants species under drought conditions in natural arid soil. AB - The effectiveness of autochthonous plant growth-promoting rhizobacteria was studied in Lavandula dentata and Salvia officinalis growing in a natural arid Mediterranean soil under drought conditions. These bacteria identified as Bacillus megaterium (Bm), Enterobacter sp. (E), Bacillus thuringiensis (Bt), and Bacillus sp. (Bsp). Each bacteria has different potential to meliorate water limitation and alleviating drought stress in these two plant species. B. thuringiensis promoted growth and drought avoidance in Lavandula by increasing K content, by depressing stomatal conductance, and it controlled shoot proline accumulation. This bacterial effect on increasing drought tolerance was related to the decrease of glutathione reductase (GR) and ascorbate peroxidase (APX) that resulted sensitive indexes of lower cellular oxidative damage involved in the adaptative drought response in B. thuringiensis-inoculated Lavandula plants. In contrast, in Salvia, having intrinsic lower shoot/root ratio, higher stomatal conductance and lower APX and GR activities than Lavandula, the bacterial effects on nutritional, physiological and antioxidant enzymatic systems were lower. The benefit of bacteria depended on intrinsic stress tolerance of plant involved. Lavadula demonstrated a greater benefit than Salvia to control drought stress when inoculated with B. thuringiensis. The bacterial drought tolerance assessed as survival, proline, and indolacetic acid production showed the potential of this bacteria to help plants to grow under drought conditions. B. thuringiensis may be used for Lavandula plant establishment in arid environments. Particular characteristic of the plant species as low shoot/root ratio and high stomatal conductance are important factors controlling the bacterial effectiveness improving nutritional, physiological, and metabolic plant activities. PMID- 24337806 TI - Kinetic modelling and characterization of microbial community present in a full scale UASB reactor treating brewery effluent. AB - The performance of a full-scale upflow anaerobic sludge blanket (UASB) reactor treating brewery wastewater was investigated by microbial analysis and kinetic modelling. The microbial community present in the granular sludge was detected using fluorescent in situ hybridization (FISH) and further confirmed using polymerase chain reaction. A group of 16S rRNA based fluorescent probes and primers targeting Archaea and Eubacteria were selected for microbial analysis. FISH results indicated the presence and dominance of a significant amount of Eubacteria and diverse group of methanogenic Archaea belonging to the order Methanococcales, Methanobacteriales, and Methanomicrobiales within in the UASB reactor. The influent brewery wastewater had a relatively high amount of volatile fatty acids chemical oxygen demand (COD), 2005 mg/l and the final COD concentration of the reactor was 457 mg/l. The biogas analysis showed 60-69% of methane, confirming the presence and activities of methanogens within the reactor. Biokinetics of the degradable organic substrate present in the brewery wastewater was further explored using Stover and Kincannon kinetic model, with the aim of predicting the final effluent quality. The maximum utilization rate constant U max and the saturation constant (K(B)) in the model were estimated as 18.51 and 13.64 g/l/day, respectively. The model showed an excellent fit between the predicted and the observed effluent COD concentrations. Applicability of this model to predict the effluent quality of the UASB reactor treating brewery wastewater was evident from the regression analysis (R(2) = 0.957) which could be used for optimizing the reactor performance. PMID- 24337808 TI - Lysosomal multienzyme complex: pros and cons of working together. AB - The ubiquitous distribution of lysosomes and their heterogeneous protein composition reflects the versatility of these organelles in maintaining cell homeostasis and their importance in tissue differentiation and remodeling. In lysosomes, the degradation of complex, macromolecular substrates requires the synergistic action of multiple hydrolases that usually work in a stepwise fashion. This catalytic machinery explains the existence of lysosomal enzyme complexes that can be dynamically assembled and disassembled to efficiently and quickly adapt to the pool of substrates to be processed or degraded, adding extra tiers to the regulation of the individual protein components. An example of such a complex is the one composed of three hydrolases that are ubiquitously but differentially expressed: the serine carboxypeptidase, protective protein/cathepsin A (PPCA), the sialidase, neuraminidase-1 (NEU1), and the glycosidase beta-galactosidase (beta-GAL). Next to this 'core' complex, the existence of sub-complexes, which may contain additional components, and function at the cell surface or extracellularly, suggests as yet unexplored functions of these enzymes. Here we review how studies of basic biological processes in the mouse models of three lysosomal storage disorders, galactosialidosis, sialidosis, and GM1-gangliosidosis, revealed new and unexpected roles for the three respective affected enzymes, Ppca, Neu1, and beta-Gal, that go beyond their canonical degradative activities. These findings have broadened our perspective on their functions and may pave the way for the development of new therapies for these lysosomal storage disorders. PMID- 24337810 TI - The joint contribution of tumor phenotype and education to breast cancer survival disparity between Hispanic and non-Hispanic white women. AB - Some studies suggest that Hispanic women are more likely to have ER- and triple negative (ER-/PR-/HER2-) tumors and subsequently poorer prognosis than non Hispanic white (NHW) women. In addition, only a handful of studies have examined period-specific effects of tumor phenotype and ethnicity on breast cancer survival, leaving the time-varying effects of hormonal status and ethnicity on breast cancer survival poorly defined. This study describes short and long-term breast cancer survival by ethnicity at 0-5 years and 5+ years post-diagnosis using data from the New Mexico Health, Eating, Activity, and Lifestyle cohort of Hispanic and NHW women ages 29-88 years newly diagnosed with stages I-IIIA breast cancer. The survival rate for Hispanics at 0-5 years was 82.2 % versus 94.3 % for NHW. Hispanics were more likely to have larger tumors, more advanced stage, and ER- phenotypes compared to NHW women. There was a significantly higher risk of breast cancer mortality in Hispanics over 5 years of follow-up compared to NHW (HR = 2.78, 95 % CI 1.39-5.56), adjusting for age, tumor phenotype, stage, and tumor size. This ethnic difference in survival, however, was attenuated and no longer statistically significant when additional adjustment was made for education, although a >1.5-fold increase in mortality was observed. In contrast, there was no difference between ethnic groups for survival after 5 years (HR = 1.08, 95 % CI 0.36-3.24). Our results indicate that the difference in survival between Hispanic and NHW women with breast cancer occurs in the first few years following diagnosis and is jointly associated with tumor phenotype and socio demographic factors related to education. PMID- 24337809 TI - N-linked glycosylation of the bone morphogenetic protein receptor type 2 (BMPR2) enhances ligand binding. AB - The bone morphogenetic protein (BMP) signaling pathway is essential for normal development and tissue homeostasis. BMP signal transduction occurs when ligands interact with a complex of type 1 and type 2 receptors to activate downstream transcription factors. It is well established that a single BMP receptor may bind multiple BMP ligands with varying affinity, and this has been largely attributed to conformation at the amino acid level. However, all three type 2 BMP receptors (BMPR2, ACVR2A/B) contain consensus N-glycosylation sites in their extracellular domains (ECDs), which could play a role in modulating interaction with ligand. Here, we show a differential pattern of N-glycosylation between BMPR2 and ACVR2A/B. Site-directed mutagenesis reveals that BMPR2 is uniquely glycosylated near its ligand binding domain and at a position that is mutated in patients with heritable pulmonary arterial hypertension. We further demonstrate using a cell free pulldown assay that N-glycosylation of the BMPR2-ECD enhances its ability to bind BMP2 ligand but has no impact on binding by the closely-related ACVR2B. Our results illuminate a novel aspect of BMP signaling pathway mechanics and demonstrate a functional difference resulting from post-translational modification of type 2 BMP receptors. Additionally, since BMPR2 is required for several aspects of normal development and defects in its function are strongly implicated in human disease, our findings are likely to be relevant in several biological contexts in normal and abnormal human physiology. PMID- 24337811 TI - Robotic learning of motion using demonstrations and statistical models for surgical simulation. AB - PURPOSE: In robotic-assisted surgical training, the expertise of surgeons in maneuvering surgical instruments may be utilized to provide the motion trajectories for teaching. However, the motion primitives for trajectory planning are not known until the motion trajectory is generalized. We hypothesize that a generic model that encodes surgical skills using demonstrations and statistical models can be used by the surgical training robot to determine the motion primitive base on the motion trajectory. METHODS: The generic model was developed from twenty-two sets of motion trajectories of soft tissue division with laparoscopic scissors collected from a robotic laparoscopic surgical training system. Adaptive mean shift method with initial bandwidth determined by the plug in-rule method was used to identify the primitives in the motion trajectories. Gaussian Mixture Model was applied to model the underlying motion structure. Gaussian Mixture Regression was then applied to reconstruct a generic motion trajectory for the task. RESULTS: The generic model and proposed method were investigated in experiments. Motion trajectory of tissue division was model and reconstructed. The motion model which was trained based on primitives determined by adaptive mean shift method produced RMS error of 3.05 degrees and 3.08 degrees with respect to the demonstrated trajectories of left and right instruments, respectively. The RMS error was smaller than that of k-means method and fixed bandwidth mean shift method. The dexterous features in the demonstrations were also preserved. CONCLUSIONS: Surgical tasks can be modeled using Gaussian Mixture Model and motion primitives identified by adaptive mean shift method with minimum user intervention. Generic motion trajectory has been successfully reconstructed based on the motion model. Investigation on the effectiveness of this method and generic model for surgical training is ongoing. PMID- 24337812 TI - Ankle fusion with centralisation of the fibula after distal tibia bone tumour resection. AB - BACKGROUND: Management of distal tibial tumours with limb salvage surgery poses a challenge for the orthopaedic surgeon. This study was done to evaluate the results of fibular centralisation as a technique to reconstruct defects that occurred after resection at this site. MATERIALS AND METHODS: Nine patients with a mean age of 23.2 years (range 17-34) with diagnosis of osteosarcoma in four patients, Ewing's sarcoma in two, giant cell tumour in two and chondrosarcoma in one patient underwent surgical treatment for tumour in the distal tibia. All patients had wide resection of the tumour and ankle arthrodesis with centralisation of the fibula. Patients were assessed clinico-radiologically for bone union, infection and complications. The final functional outcome was estimated according to Musculoskeletal Tumor Society (MSTS) scores. RESULTS: The mean age at the time of surgery was 23.2 years (17-34). There were five females and four males. The mean follow-up was 37 months (range 28-54 months). One of the patients with osteosarcoma had a recurrence a year after limb salvage surgery, underwent above-knee amputation, and died 18 months later due to metastasis. One patient developed leg length discrepancy. The mean MSTS score was 22.75 (range 17 27). CONCLUSION: Fibular centralisation is a durable reconstruction tool for defects of the distal tibial metaphysis with an acceptable functional outcome. It is an inexpensive and simple procedure, with a low rate of late complications, and reproducible results. LEVEL OF EVIDENCE: IV Retrospective case series. PMID- 24337813 TI - Maternal mortality among migrants in Western Europe: a meta-analysis. AB - To examine whether an excess risk of maternal mortality exists among migrant women in Western Europe. We searched electronic databases for studies published 1970 through 2013 for all observational studies comparing maternal mortality between the host country and a defined migrant population. Results were derived from a random-effects meta-analysis, and statistical heterogeneity assessed by the I (2) statistic. In sub-analyses we also calculated summary estimates stratified by direct and indirect death causes. We included 13 studies with more than 42 million women and 4,995 maternal deaths. Compared with indigenous born women, the pooled risk estimate (RR) was 2.00 with 95 % confidence interval (CI) of 1.72, 2.33. Migrant women had a non-significantly higher risk of dying from direct than indirect death causes; pooled RRs of 2.65 CI 1.88, 3.74 and 1.83 CI 1.37, 2.45. This meta-analysis provides evidence that migrant women in Western European countries have an excess risk of maternal mortality. PMID- 24337814 TI - Validity of prepregnancy weight status estimated from self-reported height and weight. AB - The Institute of Medicine's gestational weight gain guidelines are intended to reduce pregnancy complications, poor birth outcomes and excessive postpartum weight retention. The specific weight gain guidelines vary by prepregnancy weight status. We evaluated the validity of prepregnancy weight status (underweight, normal weight, overweight and obesity) classified from self-reported prepregnancy height and weight in reference to those from measured data during the first trimester of pregnancy and imputed data for both pregnant and age-matched non pregnant women included in the National Health and Nutrition Examination Survey 2003-2006. Self-reported prepregnancy weight status was validated by two ideal references: imputed data with the number of imputations as 10 (n = 5,040) using the data of age-matched non-pregnant women who had both self-reported and measured data, and weight status based on height and weight measured during the first trimester (n = 95). Mean differences, Pearson's correlations (r), and Kappa statistics (kappa) were used to examine the strength of agreement between self reported data and the two reference measures. Mean (standard error of the mean) differences between self-reported versus imputed prepregnancy weight was -1.7 (0.1) kg with an r = 0.98 (p < 0.001), and kappa = 0.78 which indicate substantial agreement for the 504 pregnant women. Mean (SEM) differences between self-reported prepregnancy weight versus measured weight in the first trimester was -2.3 (0.7) kg with r = 0.98 (p < 0.001), and kappa = 0.76, which also showed substantial agreements in 95 pregnant women. Prepregnancy weight status classified based on self-reported prepregnancy height and weight was valid. PMID- 24337815 TI - Novel pyrazoline-based selective fluorescent sensor for Hg2+. AB - This paper presents the preparation of a pyrazoline compound and the properties of its UV-Vis absorption and fluorescence emission. Moreover, this compound can be used to determine Hg(2+) ion with selectivity and sensitivity in the EtOH:H2O =9:1 (v/v) solution. This sensor forms a 1:1 complex with Hg(2+) and shows a fluorescent enhancement with good tolerance of other metal ions. This sensor is very sensitive with fluorometric detection limit of 3.85 * 10(-10) M. In addition, the fluorescent probe has practical application in cells imaging. PMID- 24337816 TI - Laser induced fluorescence of biochemical for UV LIDAR application. AB - Laser induced fluorescence spectroscopy in the ultraviolet regime has been used for the detection of biochemical through a fiber coupled CCD detector from a distance of 2 m. The effect of concentration and laser excitation energy on the fluorescence spectra of nicotinamide adenine dinucleotide (NADH) has been investigated. The signature fluorescence peak of NADH was centred about 460 nm. At lower concentration Raman peak centred at 405 nm was also observed. The origin of this peak has been discussed. Detection limit with the proposed set up is found to be 1 ppm. PMID- 24337817 TI - A fungal protein elicitor PevD1 induces Verticillium wilt resistance in cotton. AB - KEY MESSAGE: We found that the elicitor PevD1 triggered innate immunity in cotton, which plays an important role in future cotton wilt disease control. ABSTRACT: Elicitors can induce defense responses in plants and improve pathogen resistance. PevD1 is a secreted protein from Verticillium dahliae and activates the hypersensitive response and systemic acquired resistance to tobacco mosaic virus in tobacco plants. To investigate the PevD1-induced disease resistance mechanisms in cotton (Gossypium hirsutum), we report that Escherichia coli expressing PevD1 enhanced cotton resistance and the defense response to the fungal pathogen V. dahliae. The results showed that recombinant PevD1 improved cotton resistance when infiltrated at a concentration as low as 4 MUg ml(-1), and the highest disease reduction was 38.16 % on the 15th day post V. dahliae inoculation. This protein was able to systemically induce hydrogen peroxide production, nitric oxide generation, lignin deposition, vessel reinforcement and defense enzymes, including phenylalanine ammonia-lyase, peroxidase, and polyphenol oxidase. PevD1 also enhanced the expression of three pathogenesis related genes, namely, beta-1,3-glucanase, chitinase, and cadinene synthase, and three key genes, PAL, C4H1, and 4CL, from the cotton defense phenylpropanoid metabolism pathway. Our results demonstrated that PevD1 acted as an effector in cotton and V. dahliae interactions and triggered innate immunity in cotton, resulting in the upregulation of defense-related genes, metabolic substance deposition and cell wall modifications. PevD1 is a candidate plant defense activator for cotton wilt disease control. PMID- 24337819 TI - Epigenetic regulation and cancer (review). AB - 'Epigenetics' is defined as the inheritable changes in gene expression with no alterations in DNA sequences. Epigenetics is a rapidly expanding field, and the study of epigenetic regulation in cancer is emerging. Disruption of the epigenome is a fundamental mechanism in cancer, and several epigenetic drugs have been proven to prolong survival and to be less toxic than conventional chemotherapy. Promising results from combination clinical trials with DNA methylation inhibitors and histone deacetylase inhibitors have recently been reported, and data are emerging that describe molecular determinants of clinical responses. Despite significant advances, challenges remain, including a lack of predictive markers, unclear mechanisms of response and resistance, and rare responses in solid tumors. Preclinical studies are ongoing with novel classes of agents that target various components of the epigenetic machinery. In the present review, examples of studies that demonstrate the role of epigenetic regulation in human cancers with the focus on histone modifications and DNA methylation, and the recent clinical and translational data in the epigenetics field that have potential in cancer therapy are discussed. PMID- 24337818 TI - The Gossypium hirsutum WRKY gene GhWRKY39-1 promotes pathogen infection defense responses and mediates salt stress tolerance in transgenic Nicotiana benthamiana. AB - KEY MESSAGE: Our results indicate that overexpression of the GhWRKY39 - 1 gene enhances resistance to pathogen infection and tolerance to high salt and oxidative stress in transgenic Nicotiana benthamiana. ABSTRACT: WRKY transcription factor genes play significant roles in the response to biotic and abiotic stresses. Cotton (Gossypium hirsutum) is an important fiber and oil crop worldwide. We isolated and characterized GhWRKY39-1, which is a group IId WRKY gene that is present as a single copy in the cotton genome. Quantitative PCR analyses indicated that GhWRKY39-1 was induced by pathogen infection, defense related signaling molecules, and abiotic stresses, such as NaCl and methyl viologen. An analysis of the subcellular localization of the GhWRKY39-1 protein indicated that it localized to the nucleus. Furthermore, constitutive overexpression of GhWRKY39-1 in Nicotiana benthamiana conferred a greater resistance to infection by both the bacterial pathogen Ralstonia solanacearum and the fungal pathogen Rhizoctonia solani. The transgenic plants also exhibited elevated mRNA levels of several pathogen-related (PR) genes, including PR1c, PR2 and PR4. Moreover, transgenic plants displayed an enhanced tolerance to salt and oxidative stress and elevated expression of several oxidation-related genes, including APX, CAT, GST and SOD. Overall, these results indicate that GhWRKY39-1 functions as a positive regulator of plant defense against pathogen infection and responses to salt stress and reactive oxygen species. PMID- 24337820 TI - Coenzyme Q10 ameliorates oxidative stress and prevents mitochondrial alteration in ischemic retinal injury. AB - Coenzyme Q10 (CoQ10) acts by scavenging reactive oxygen species for protecting neuronal cells against oxidative stress in neurodegenerative diseases. We tested whether a diet supplemented with CoQ10 ameliorates oxidative stress and mitochondrial alteration, as well as promotes retinal ganglion cell (RGC) survival in ischemic retina induced by intraocular pressure elevation. A CoQ10 significantly promoted RGC survival at 2 weeks after ischemia. Superoxide dismutase 2 (SOD2) and heme oxygenase-1 (HO-1) expression were significantly increased at 12 h after ischemic injury. In contrast, the CoQ10 significantly prevented the upregulation of SOD2 and HO-1 protein expression in ischemic retina. In addition, the CoQ10 significantly blocked activation of astroglial and microglial cells in ischemic retina. Interestingly, the CoQ10 blocked apoptosis by decreasing caspase-3 protein expression in ischemic retina. Bax and phosphorylated Bad (pBad) protein expression were significantly increased in ischemic retina at 12 h. Interestingly, while CoQ10 significantly decreased Bax protein expression in ischemic retina, CoQ10 showed greater increase of pBad protein expression. Of interest, ischemic injury significantly increased mitochondrial transcription factor A (Tfam) protein expression in the retina at 12 h, however, CoQ10 significantly preserved Tfam protein expression in ischemic retina. Interestingly, there were no differences in mitochondrial DNA content among control- or CoQ10-treated groups. Our findings demonstrate that CoQ10 protects RGCs against oxidative stress by modulating the Bax/Bad-mediated mitochondrial apoptotic pathway as well as prevents mitochondrial alteration by preserving Tfam protein expression in ischemic retina. Our results suggest that CoQ10 may provide neuroprotection against oxidative stress-mediated mitochondrial alterations in ischemic retinal injury. PMID- 24337821 TI - Activated sludge model 2d calibration with full-scale WWTP data: comparing model parameter identifiability with influent and operational uncertainty. AB - The present work developed a model for the description of a full-scale wastewater treatment plant (WWTP) (Manresa, Catalonia, Spain) for further plant upgrades based on the systematic parameter calibration of the activated sludge model 2d (ASM2d) using a methodology based on the Fisher information matrix. The influent was characterized for the application of the ASM2d and the confidence interval of the calibrated parameters was also assessed. No expert knowledge was necessary for model calibration and a huge available plant database was converted into more useful information. The effect of the influent and operating variables on the model fit was also studied using these variables as calibrating parameters and keeping the ASM2d kinetic and stoichiometric parameters, which traditionally are the calibration parameters, at their default values. Such an "inversion" of the traditional way of model fitting allowed evaluating the sensitivity of the main model outputs regarding the influent and the operating variables changes. This new approach is able to evaluate the capacity of the operational variables used by the WWTP feedback control loops to overcome external disturbances in the influent and kinetic/stoichiometric model parameters uncertainties. In addition, the study of the influence of operating variables on the model outputs provides useful information to select input and output variables in decentralized control structures. PMID- 24337824 TI - Hierarchical stimulus processing by dogs (Canis familiaris). AB - The purpose of this study was to assess the visual processing of global and local levels of hierarchical stimuli in domestic dogs. Fourteen dogs were trained to recognise a compound stimulus in a simultaneous conditioned discrimination procedure and were then tested for their local/global preference in a discrimination test. As a group, dogs showed a non-significant trend for global precedence, although large inter-individual variability was observed. Choices in the test were not affected by either dogs' sex or the type of stimulus used for training. However, the less time a dog took to complete the discrimination training phase, the higher the probability that it chose the global level of test stimulus. Moreover, dogs that showed a clear preference for the global level in the test were significantly less likely to show positional responses during discrimination training. These differences in the speed of acquisition and response patterns may reflect individual differences in the cognitive requirements during discrimination training. The individual variability in global/local precedence suggests that experience in using visual information may be more important than predisposition in determining global/local processing in dogs. PMID- 24337823 TI - MYBPC3 in hypertrophic cardiomyopathy: from mutation identification to RNA-based correction. AB - Mutations in MYBPC3 gene, encoding cardiac myosin-binding protein C (cMyBP-C), frequently cause hypertrophic cardiomyopathy (HCM), which affects 0.2 % of the general population. This myocardial autosomal-dominant disorder is the leading cause of sudden cardiac death particularly in young athletes. The current pharmacological and surgical treatments of HCM focus on symptoms relief, but do not address the cause of the disease. With the development of novel strategies targeting the endogenous mutation, causal HCM therapy is now possible. This review will discuss the current knowledge on HCM from the identification of MYBPC3 gene mutations to potential RNA-based correction. PMID- 24337822 TI - Traditional and emerging roles for the SLC9 Na+/H+ exchangers. AB - The SLC9 gene family encodes Na(+)/H(+) exchangers (NHEs). These transmembrane proteins transport ions across lipid bilayers in a diverse array of species from prokaryotes to eukaryotes, including plants, fungi, and animals. They utilize the electrochemical gradient of one ion to transport another ion against its electrochemical gradient. Currently, 13 evolutionarily conserved NHE isoforms are known in mammals [22, 46, 128]. The SLC9 gene family (solute carrier classification of transporters: www.bioparadigms.org) is divided into three subgroups [46]. The SLC9A subgroup encompasses plasmalemmal isoforms NHE1-5 (SLC9A1-5) and the predominantly intracellular isoforms NHE6-9 (SLC9A6-9). The SLC9B subgroup consists of two recently cloned isoforms, NHA1 and NHA2 (SLC9B1 and SLC9B2, respectively). The SLC9C subgroup consist of a sperm specific plasmalemmal NHE (SLC9C1) and a putative NHE, SLC9C2, for which there is currently no functional data [46]. NHEs participate in the regulation of cytosolic and organellar pH as well as cell volume. In the intestine and kidney, NHEs are critical for transepithelial movement of Na(+) and HCO3(-) and thus for whole body volume and acid-base homeostasis [46]. Mutations in the NHE6 or NHE9 genes cause neurological disease in humans and are currently the only NHEs directly linked to human disease. However, it is becoming increasingly apparent that members of this gene family contribute to the pathophysiology of multiple human diseases. PMID- 24337825 TI - Effects of oral contraceptives on selected parameters of the homeostatic control system in young women having a sudden disorder of the auditory and/or balance system. AB - The purpose of the paper was to assess the effects of oral contraceptives on selected parameters of the homeostatic control system in women having a sudden disorder of the auditory and/or balance system. The study included 105 young women divided into two groups: Group I--52 women with the disorder of the auditory and/or balance system using hormonal contraceptives for at least 2 months, aged 20-49; and Group II--53 women without any disorder of the auditory and/or balance system using hormonal contraceptives for at least 2 months, aged 18-40. The patients included in the study underwent a full otoneurological evaluation, detailed laryngological diagnostics and an evaluation of selected parameters of the homeostatic control system--fibrinogen level, D-dimer level, evaluation of APTT and PT indicator, plasma estradiol and progesterone with the Roche Cobas analyser by means of chemiluminescence. The vertigo occurring in the study group was most often central (59.6% of cases), mixed with compensation in 36.6% of cases, and peripheral only in 3.8% of cases, indicating labyrinth damage in 40.4% of cases. An analysis of the progesterone level, considering the menstrual cycle phase in the group, showed that its value was abnormal in 51.0% of women in the study group and 47.1% in the control group. In their own studies, the authors observed that the estradiol level in the plasma, considering the menstrual cycle phase in the study group, was abnormal in 41.2% of women and that the differences in its concentration were statistically significant in the study and control groups (p = 0.005), which may have a negative impact on the possibility of a thromboembolic episode. PMID- 24337827 TI - Evaluating pyrene toxicity on Arctic key copepod species Calanus hyperboreus. AB - Calanus hyperboreus is a key species in the Arctic regions because of its abundance and role in the Arctic food web. Exploitation of the off shore oil reserves along Western Greenland is expected in the near future, and it is important to evaluate the acute and chronic effects of oil emissions to the ecosystem. In this study C. hyperboreus females were exposed to concentrations of 0, 0.1, 1, 10 and 100 nM pyrene and saturated concentrations measured to ~300 nM. Daily quantification of egg and faecal pellet production showed significant decreases in the pellet production, while the egg production was unaffected. The hatching success was also unaffected, although the total reproductive output was reduced with increased pyrene concentrations. Accumulation of pyrene in the copepods was higher in feeding than starving females and only trace amounts of the phase I metabolite 1-hydroxypyrene, were found. Lowered reproductive output, reduced grazing, and reduced ability to metabolize pyrene suggest that oil contamination may constitute a risk to C. hyperboreus recruitment, energy transfer in the food web and transfer of pyrene to higher trophic levels. PMID- 24337826 TI - Geraniol-a flavoring agent with multifunctional effects in protecting the gastric and duodenal mucosa. AB - Geraniol is an acyclic monoterpene alcohol commonly used as a flavoring agent. The present study was undertaken to investigate antiulcerogenic effects of geraniol and to determine the possible mechanisms involved in this action. In the model of the ethanol-induced ulcer, treatment of rats with geraniol by oral route significantly inhibited gastric lesions by 70 % (7.50 mg/kg) to 99 % (200 mg/kg). Analysis of the gastric tissue of rats treated with geraniol (7.50 mg/kg) revealed that total glutathione content levels (GSH) increased and levels of myeloperoxidase (MPO) decreased in the gastric mucosa. Oral treatment with geraniol significantly decreased the number of ulcerative lesions induced by ischemia/reperfusion injury by 71 % and the duodenal ulcers induced by cysteamine by 68 %. The action of geraniol was mediated by the activation of defensive mucosa-protective factors such as the nitric oxide (NO) pathway, endogenous prostaglandins, increased mucus production, increased sulfhydryl compounds, antioxidant properties and the stimulation of calcitonin gene-related peptide (CGRP) release through the activation of transient receptor potential vanilloid (TRPV). The multifaceted gastroprotective mechanisms of geraniol represent a promising option for the treatment of gastric and duodenal mucosa injury. PMID- 24337829 TI - Validation of the emotion regulation and social skills questionnaire for young people with autism spectrum disorders. AB - The current study aims to evaluate the psychometric properties of the Emotion Regulation and Social Skills Questionnaire (ERSSQ), a rating scale designed specifically to assess the social skills of young people with Autism Spectrum Disorder (ASD). The participants were 84 children and young adolescents with ASD, aged between 7.97 and 14.16 years with a mean IQ score of 90.21 (SD = 18.82). The results provide evidence for the concurrent and criterion validity of the ERSSQ Parent form, and the concurrent validity of the ERSSQ Teacher form. The clinical and theoretical implications are discussed, including the necessity of ratings across multiple contexts and the potential use of the ERSSQ in identifying individuals most in need of intervention and for planning and assessing the outcomes of social skills interventions. PMID- 24337828 TI - Non-invasive prediction of hepatocellular carcinoma development using serum fibrosis marker in chronic hepatitis C patients. AB - BACKGROUND: The FIB-4 index is a simple formula to predict liver fibrosis. This study aimed to evaluate the utility of the FIB-4 index and associated time-course changes as a predictor of hepatocellular carcinoma (HCC) development. METHODS: A total of 171 chronic hepatitis C patients who underwent paired liver biopsies and 875 patients who underwent a single liver biopsy (validation group) were investigated during mean follow-up periods of 6.4 and 5.9 years, respectively. All patients had received interferon therapy and had not achieved a sustained virological response. Factors associated with HCC development were analyzed in these patients. RESULTS: HCC developed in 30 patients in the paired biopsy group and 89 patients in the validation group. Univariate analysis demonstrated that the FIB-4 index >3.25 and change in the FIB-4 index per year (DeltaFIB-4/year) >= 0.3 were predictive factors for HCC development in both groups. Multivariate analysis in the combined population revealed that these two factors were independent. The hazard ratio (HR) for the FIB-4 index >3.25 was 2.7 (p < 0.001) and DeltaFIB-4/year >= 0.3 was 1.8 (p = 0.003). Patients with a FIB-4 index >3.25 and a DeltaFIB-4/year >= 0.3 were defined as high risk, and those with a FIB-4 index <= 3.25 and a DeltaFIB-4/year <0.3 were defined as low risk. The HR of HCC development in patients at high risk was 7.3 (95% confidence interval 4.3-12.5, p < 0.001). CONCLUSIONS: It was possible to define a group at high risk of developing HCC by intermittently measuring the FIB-4 index and considering time course changes in this index. PMID- 24337830 TI - Brand switching or reduced consumption? A study of how cigarette taxes affect tobacco consumption. AB - We examined the influence of cigarette taxes on tobacco consumption, with an emphasis on smokers' choice between reducing cigarette consumption and switching brands. We constructed three scenario-based models to study the following two subjects: (1) the relationship between deciding whether to reduce one's cigarette consumption and to practice brand switching (simultaneous or sequential); (2) the key determinants that affect smokers' decisions in terms of their consumption and brand switching when facing higher taxes. We applied data collected from a survey in Taiwan, and the results indicated that both independent and two-stage decision making models generated very similar conclusions. We also found that gender difference contributed to reduce cigarette consumption. In addition, this study indicated that high-income smokers were less likely to switch brands, whereas well-educated smokers were more likely to switch brands. Most importantly, we questioned the effectiveness of cigarette tax policy, as our results suggested that higher price did not necessarily reduce consumption. Indeed, data indicated that <24 % of smokers actually reduced their cigarette consumption after the tax on cigarettes increased. PMID- 24337831 TI - Dietary supplementation with L-arginine between days 14 and 25 of gestation enhances embryonic development and survival in gilts. AB - Embryonic loss is a major problem in mammals, but there are few effective ways to prevent it. Using a porcine model, we determined effects of dietary L-arginine supplementation between days 14 and 25 of gestation on embryonic growth and survival. Gilts were checked daily for estrus with boars in the morning and bred at onset of the second estrus and 12 h later (the time of breeding = day 0 of gestation). Between days 14 and 25 of gestation, 15 gilts/treatment were housed individually and fed twice daily 1 kg of a corn- and soybean meal-based diet supplemented with 0.0, 0.4, or 0.8 % L-arginine. All diets were made isonitrogenous by addition of L-alanine. On day 25 of gestation, gilts were hysterectomized to obtain conceptuses. Compared with controls, dietary supplementation with 0.4 or 0.8 % L-arginine increased (P <= 0.05) arginine concentrations in maternal plasma, total volume of amniotic fluid; total amounts of arginine in allantoic and amniotic fluids; total amounts of fructose and most amino acids in amniotic fluid; placental growth; and the number of viable fetuses per litter by 2. The numbers of total fetuses, fetal weight, corpora lutea, volume of allantoic fluid, maternal circulating levels of progesterone and estrogen, or total amounts of hormones in allantoic fluid did not differ among the three treatment groups. Reproductive performance of gilts did not differ between the 0.4 and 0.8 % L-arginine groups. Thus, dietary supplementation with 0.4 or 0.8 % L-arginine between days 14 and 25 of gestation enhances embryonic/fetal survival in swine. PMID- 24337832 TI - Enzymatic production and degradation of cheese-derived non-proteolytic aminoacyl derivatives. AB - Gamma-glutamyl-amino acids, lactoyl-amino acids and pyroglutamyl-amino acids, collectively named Non-Proteolytic Aminoacyl Derivatives (NPADs) are unusual aminoacyl derivatives of non-proteolytic origins found in consistent amount in several cheeses. Although their enzymatic origin arising from lactic acid bacteria has been demonstrated, the exact enzymes originating them, the ones eventually degrading them and also their resistance to digestive enzymes in the human gastrointestinal tract and in the blood serum after eventual absorption are still unknown. In this paper, pure enzymes and biological media were tested on NPAD and their aminoacidic precursors, for identifying the conditions favoring bioproduction and biodegradation of these compounds. Pure gamma-glutamyl phenylalanine and its precursor (glutamic acid and phenylalanine), also in the isotopically labeled forms, were tested with Parmigiano-Reggiano extracts, blood serum and different pure enzymes, including typical digestion enzymes (pepsin, trypsin and chymotrypsin), gamma-glutamyl transpeptidase and carboxypeptidase. The data suggested that their production in cheese, and also their partial degradation, might be due to the action of peptidases and gamma-glutamyl transpeptidase. Anyway, under simulated gastrointestinal digestion and in blood serum these compounds turned out to be perfectly stable, suggesting a potential to be absorbed as such and possibly being transported to the body tissues. PMID- 24337833 TI - Molecular marker for predicting treatment response in advanced renal cell carcinoma: does the promise fulfill clinical need? AB - Renal cell carcinoma (RCC) is largely diagnosed incidentally on imaging taken for unrelated reasons. The management of localized lesions is primarily extirpative with excellent results. Treatment of advanced RCC has evolved over recent years with the use of targeted therapies such as tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and antibody-mediated therapies. The treatment response to these targeted therapies is highly variable, with no clear clinical method of identifying patients who will benefit from or not tolerate therapy. The field of molecular markers has evolved significantly in the last decade, with a multitude of markers identified that predict treatment response and drug toxicity. The following review critically evaluates those molecular markers that have been assessed for their utility in predicting treatment response in patients with advanced/metastatic renal cell carcinoma (mRCC). Identifying the ideal treatment for these patients will improve responses to therapy, minimize morbidity, and save significant healthcare dollars. PMID- 24337834 TI - Post-operative outcomes in adult obstructive sleep apnea patients undergoing non upper airway surgery: a systematic review and meta-analysis. AB - BACKGROUND: With the current obesity epidemic, obstructive sleep apnea (OSA) has become increasingly common. Several studies have reported on the risk of post operative complications in OSA patients undergoing non-upper airway surgeries. The objective of our study was to systematically review the medical literature reporting the incidence of post-operative complications in patients with OSA. METHODS: We conducted a systematic review using the Cochrane Collaboration Methodology. We searched Medline via Ovid, Pubmed, Embase, and Evidence-Based Medicine Reviews databases from 1950 to 2012. We rated the quality of evidence for each outcome using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Meta-analysis was done using Review Manager Version 5.0.20. RESULTS: Our search resulted in 18 eligible studies. OSA was found to be associated with a significantly increased incidence of post-operative hypoxemia (odds ratio [OR] = 3.06; 95% confidence interval [CI] 2.35-3.97), respiratory complications (OR = 2.77, 95% CI 1.73-4.43), cardiac complications (OR = 1.76 95% CI 1.16-2.67), neurological complications (OR = 2.65, 95% CI 1.43 4.92), and unplanned intensive care unit (ICU) transfer (OR = 2.97, 95% CI 1.90 4.64). Re-intubation (OR = 1.37, 95% CI 0.65-2.91) was not significantly increased in patients with OSA. The association between OSA and post-operative outcomes remained unchanged with sub-group analysis including only studies that used polysomnography (PSG) for diagnosis. CONCLUSIONS: OSA patients are at increased risk of post-operative complications from non-upper airway surgeries. Early diagnosis and treatment of OSA might decrease post-operative complications in these patients. There is a need for further studies to assess the benefit of peri-operative treatment of OSA on post-operative outcomes. PMID- 24337835 TI - Fistulectomy with primary sphincter reconstruction in the treatment of high transsphincteric anal fistulas. AB - PURPOSE: The treatment of transsphincteric anal fistulas is a challenge between recurrence rate and incontinence. Many surgical and conservative procedures have been described in the treatment of anal fistulas. Fistulectomy and primary sphincter reconstruction (FPSR) has not gained great popularity in this field due to the risk of sphincter damage. The aim of this study is to evaluate FPSR in the treatment of transsphincteric fistulas. METHODS: We retrospectively analyzed 50 patients with high transsphincteric fistulas of cryptoglandular origin that were treated with FPSR between 2005 and 2008. Preoperative assessment included physical and proctologic examination. Continence and pain scores were evaluated preoperatively and postoperatively. RESULTS: In our 50 patients, 22 patients (44 %) had a previous proctologic operation and 11 patients (22 %) presented with recurrent fistulas. The fistulas existed for an average of 8 months. The operation time was 28 +/- 16 min. Mean follow-up was 22+/- months. The fistula healed in 44 patients (88 %) who developed no recurrence. In five patients (10 %), the fistula healed, but they developed a recurrence in the observation period. In one patient (2 %), the fistula did not heal. Three patients developed low-grade incontinence for flatus, and one patient with 2 degrees incontinence improved. Preoperatively and postoperatively calculated continence and pain scores showed a slight but significant elevation in the Clinical Continence Score, the German Society of Coloproctology Score showed no significant difference, and preexisting pain was reduced significantly by surgery. CONCLUSIONS: FPSR is a safe surgical procedure for the treatment of high transsphincteric anal fistula. The primary healing rate is high with a low risk of recurrence or incontinence. PMID- 24337836 TI - Cementless modular intramedullary nail without bone-on-bone fusion as a salvage procedure in chronically infected total knee prosthesis: long-term results. AB - PURPOSE: Our purpose was to evaluate long-term results of two-stage cementless intramedullary nailing without achieving bone-to-bone fusion for treating chronically infected total knee arthroplasty (TKA). METHODS: Thirty-eight patients treated according to the same protocol were retrospectively evaluated for clinical, functional, laboratory and radiological outcomes. RESULTS: Spacer exchange was necessary for infection persistence in one case. At a minimum two year follow-up, 34 patients (89.5%) showed no infection recurrence; among these 34 patients, 29 (85.3%) reported no or moderate pain [visual analogue scale (VAS) <=3]; mild to moderate handicap (Lequesne Algofunctional Index < 7.5) was observed in 18 patients (52.9%). No patient underwent revision for aseptic loosening, and no nail breakage was observed. CONCLUSIONS: Two-stage cementless intramedullary nailing without achieving bone-to-bone fusion is a viable option for treating chronically infected TKA in selected, complex cases. PMID- 24337837 TI - Expert consensus on laparoscopic hepatectomy (2013 version). AB - BACKGROUND: Laparoscopic hepatectomy has many advantages over open surgery, including minimization of local injury, reduced systemic reactions, and faster postoperative recovery. The aim of this "Consensus" is to provide guidance and reference to surgeons who perform, or are interested in performing laparoscopic liver surgeries. METHODS: The National Hepatic Surgery Group of the Society of Surgery, a professional society of the Chinese Medical Association, gathered 60 expert hepatic surgeons in Wuhan, China in December 2012, and an "Expert Consensus on Laparoscopic Hepatectomy" was developed. RESULTS: The types of hepatectomy, indications and contraindications, preoperative preparation, anesthesia, patient position, insufflation pressure, port position, control of hepatic inflow and outflow, indications for conversion to open surgery, and surgical devices and equipment are reviewed. Techniques and procedures of various laparoscopic hepatectomies are also discussed. PMID- 24337838 TI - Aberrant DNA methylation in human cancers. AB - DNA methylation, one of the best-characterized epigenetic modifications, plays essential roles in diseases, including human cancers. In recent years, our understanding on DNA methylation with human cancers has made significant progress, which was facilitated by stunning development in the analysis of the human methylome of multiple cancer types. In this review, recent developments in the characterization of aberrant DNA methylation involved in human cancers development were discussed with special emphasis on the mechanisms of aberrant DNA methylation in human cancers. We also summarize the recent treatment strategy for human cancers with de-methylation drugs. PMID- 24337839 TI - Variant anatomy of the shoulder on MRI. PMID- 24337840 TI - Protective effect of autophagy inhibition on ischemia-reperfusion-induced injury of N2a cells. AB - Autophagy is a conserved and programmed catabolic process that degrades damaged proteins and organelles. But the underlying mechanism and functions of autophagy in the ischemia-reperfusion (IR)-induced injury are unknown. In this study, we employed simulated IR of N2a cells as an in vitro model of IR injury to the neurons and monitored autophagic processes. It was found that the levels of Beclin-1 (a key molecule of autophay complex, Beclin-1/class III PI3K) and LC-3II (an autophagy marker) were remarkably increased with time during the process of ischemia and the process of reperfusion after 90 min of ischemia, while the protein kinases p70S6K and mTOR which are involved in autophagy regulation showed delayed inactivation after reperfusion. Administration of 3-methyladenine (3MA), an inhibitor of class III PI3K, abolished autophagy during reperfusion, while employment of rapamycin, an inhibitor of mTORC1 (normally inducing autophagy), surprisingly weakened the induction of autophagy during reperfusion. Analyses of mitochondria function by relative cell viability demonstrated that autophagy inhibition by 3-MA attenuated the decline of mitochondria function during reperfusion. Our data demonstrated that there were two distinct dynamic patterns of autophagy during IR-induced N2a injury, Beclin-1/class III PI3K complex dependent and mTORC1-dependent. Inhibition of over-autophagy improved cell survival. These suggest that targeting autophagy therapy will be a novel strategy to control IR-induced neuronal damage. PMID- 24337841 TI - Amplification of functional myeloid-derived suppressor cells during stem cell mobilization induced by granulocyte colony-stimulation-factor. AB - The effects of granulocyte colony-stimulation-factor (G-CSF) on stem cell mobilization and its impact on the amplification of myeloid-derived suppressor cells (MDSCs) of donor mice were examined. A mouse model of stem cell mobilization was established by consecutive subcutaneous injection of 100 MUg/kg G-CSF for 5 days. The blood from the donor mice was routinely examined during mobilization. Stem cells and MDSCs were analyzed by flow cytometry. The immunosuppressive molecules derived from MDSCs in serum and spleen, including hydrogen dioxide (H2O2) and nitric oxide (NO), and the activity of nitric oxide synthase (NOS) were determined during the mobilization. Apoptosis of T lymphocytes was assessed by using Annexin-V/PI. During stem cell mobilization, the number of lymphocytes and white blood cells in the peripheral blood was increased, and peaked on the 4th day. The number of stem cells in G-CSF-treated mice was significantly greater than that in controls (P<0.01). The expansions of MSDCs were also observed after G-CSF mobilization, with a more notable rate of growth in the peripheral blood than in the spleen. The activity of NOS and the production of NO were increased in the donor mice, and the serum H2O2 levels were approximately 4-fold greater than the controls. Consequently, apoptosis of T lymphocytes was increased and showed a positive correlation with the elevated percentage of MDSCs. It was concluded that G-CSF could provide sufficient peripheral blood stem cells for transplantation. Exogenous administration of G CSF caused the accumulation of MDSCs in the peripheral blood and the spleen, which could lead to apoptosis of T lymphocytes and may offer a new strategy for the prevention and treatment of graft versus host disease. PMID- 24337842 TI - Nardosinone protects H9c2 cardiac cells from angiotensin II-induced hypertrophy. AB - Pathological cardiac hypertrophy induced by angiotensin II (AngII) can subsequently give rise to heart failure, a leading cause of mortality. Nardosinone is a pharmacologically active compound extracted from the roots of Nardostachys chinensis, a well-known traditional Chinese medicine. In order to investigate the effects of nardosinone on AngII-induced cardiac cell hypertrophy and the related mechanisms, the myoblast cell line H9c2, derived from embryonic rat heart, was treated with nardosinone (25, 50, 100, and 200 MUmol/L) or AngII (1 MUmol/L). Then cell surface area and mRNA expression of classical markers of hypertrophy were detected. The related protein levels in PI3K/Akt/mTOR and MEK/ERK signaling pathways were examined by Western blotting. It was found that pretreatment with nardosinone could significantly inhibit the enlargement of cell surface area induced by AngII. The mRNA expression of ANP, BNP and beta-MHC was obviously elevated in AngII-treated H9c2 cells, which could be effectively blocked by nardosinone at the concentration of 100 MUmol/L. Further study revealed that the protective effects of nardosinone might be mediated by repressing the phosphorylation of related proteins in PI3K/Akt and MEK/ERK signaling pathways. It was suggested that the inhibitory effect of nardosinone on Ang II-induced hypertrophy in H9c2 cells might be mediated by targeting PI3K/Akt and MEK/ERK signaling pathways. PMID- 24337843 TI - Genotoxicity and reduced heat shock protein 70 in human airway smooth muscle cells exposed to cigarette smoke extract. AB - Cigarette smoke is associated with the development of several diseases, such as chronic obstructive pulmonary disease (COPD). The purpose of this study was to investigate genotoxicity and heat shock protein 70 (Hsp70) in human airway smooth muscle cells (HASMCs) exposed to cigarette smoke extract (CSE). HASMCs was exposed to CSE with different doses for 24 h. The level of 8 hydroxydeoxyguanosine (8-OHdG) was determined by using HPLC-ECD, the DNA damage was analyzed by using comet assay, and apoptosis was examined by using Annexin FITC/PI staining. The production of Hsp70 after CSE stimulation was tested. Results indicated that CSE significantly increased the level of 8-OHdG, DNA damage and cell apoptosis, and reduced the production of Hsp70. In particular, levels of Hsp70 were inversely correlated with 8-OHdG, DNA damage and cell apoptosis. It was concluded that cigarette smoke induced genotoxicity and decreased the production of cell protective protein Hsp70, which may contribute to the development of some airway diseases. PMID- 24337844 TI - MicroRNA-34a regulates high glucose-induced apoptosis in H9c2 cardiomyocytes. AB - Hyperglycemia is an important initiator of cardiovascular disease, contributing to the development of cardiomyocyte death and diabetic complications. The purpose of the present study was to investigate whether high glucose state could induce apoptosis of rat cardiomyocyte cell line H9c2 through microRNA-mediated Bcl-2 signaling pathway. The expression of miR-34a and Bcl-2 mRNA was detected by using real-time PCR. Western blotting was used to examine the changes in apoptosis associated protein Bcl-2. Apoptosis of H9c2 cells was tested by using flow cytometry. The results showed that the expression of miR-34a was significantly elevated and that of Bcl-2 was strongly reduced, and apoptosis of cardiomyocytes was apparently increased in the high-glucose-treated H9c2 cells as compared with normal-glucose-treated controls. In addition, we identified Bcl-2 gene was the target of miR-34a. miR-34a mimics reduced the expression of Bcl-2 and increased glucose-induced apoptosis, but miR-34a inhibitor acted as the opposite mediator. Our data demonstrate that miR-34a contributes to high glucose-induced decreases in Bcl-2 expression and subsequent cardiomyocyte apoptosis. PMID- 24337845 TI - Reversal effect of BM-cyclin 1 on multidrug resistance by down-regulating MRP2 in BALB/C nude mice bearing C-A120 cells. AB - Our previous study demonstrated that BM-cyclin 1, a traditional anti-mycoplasma drug, could effectively reverse the multidrug resistance (MDR) of C-A120 cells. The present study aims to explore the reversal effect of BM-cyclin 1 on MDR and its mechanisms in BALB/C nude mice bearing C-A120 cells. Immunoblotting analysis and reverse transcription-polymerase chain reaction (RT-PCR) were used to study the change in multidrug resistance-associated protein 2 (MRP2) induced by BM cyclin 1. We found that the expression levels of MRP2 protein and mRNA in C-A120 cells treated with BM-cyclin 1 were reduced significantly. Chemical colorimetry revealed no significant change in the level of glutathione (GSH). In the xenograft model, the inhibitory rate of C-A120 cells growth in BM-cyclin 1 plus adriamycin (ADM) group was 52%, which was significantly higher than in control group (P<0.01). The immunoblotting and RT-PCR results conclusively demonstrated that BM-cycin 1 could significantly reduce the expression of MRP2 in transplanted tumor. In conclusion, BM-cyclin 1 could effectively reverse the MDR of C-A120 cells in vivo by suppressing the expression of MRP2. PMID- 24337846 TI - Effects of PI3K inhibitor NVP-BKM120 on acquired resistance to gefitinib of human lung adenocarcinoma H1975 cells. AB - The effects of class I PI3K inhibitor NVP-BKM120 on cell proliferation, cell cycle distribution, cellular apoptosis, phosphorylation of several proteins of the PI3K/AKT signaling pathway and the mRNA expression levels of HIF1-alpha, VEGF and MMP9 in the acquired gefitinib resistant cell line H1975 were investigated, and whether NVP-BKM120 can overcome the acquired resistance caused by the EGFR T790M mutation and the underlying mechanism were explored. MTT assay was performed to detect the effect of gefitinib, NVP-BKM120, NVP-BKM120 plus 1 MUmol/L gefitinib on growth of H1975 cells. The distribution of cell cycle and apoptosis rate of H1975 cells were examined by using flow cytometry. The mRNA expression levels of tumor-related genes such as HIF1-alpha, VEGF and MMP9 were detected by using real-time quantitative PCR. Western blotting was used to detect the expression level of phosphorylated proteins in the PI3K/AKT signaling pathway, such as Ser473-p-AKT, Ser235/236-p-S6 and Thr70-p-4E-BP1, as well as total AKT, S6 and 4E-BP1. The results showed that the NVP-BKM120 could inhibit the growth of H1975 cells in a concentration-dependent manner, and H1975 cells were more sensitive to NVP-BKM120 than gefitinib (IC50:1.385 vs. 15.09 MUmol/L respectively), whereas combination of NVP-BKM120 and gefitinib (1 MUmol/L) did not show more obvious effect than NVP-BKM120 used alone on inhibition of cell growth (P>0.05). NVP-BKM120 (1 MUmol/L) increased the proportion of H1975 cells in G0-G1 phase and the effect was concentration-dependent, and 2 MUmol/L NVP BKM120 promoted apoptosis of H1975 cells. There was no significant difference in the proportion of H1975 cells in G0-G1 phase and apoptosis rate between NVP BKM120-treated alone group and NVP-BKM120 plus genfitinib (1 MUmol/L)-treated group or between DMSO-treated control group and gefitinib (1 MUmol/L)-treated alone group (P>0.05 for all). It was also found that the mRNA expression levels of these genes were down-regulated by NVP-BKM120 (1 MUmol/L), and NVP-BKM120 (1 MUmol/L) or NVP-BKM120 (1 MUmol/L) plus gefitinib (1 MUmol/L) obviously inhibited the activation of Akt, S6 and 4E-BP1 as compared with control group, but single use of gefitinib (1 MUmol/L) exerted no significant effect. These data suggested that NVP-BKM120 can overcome gefitinib resistance in H1975 cells, and the combination of NVP-BKM120 and gefitinib did not have additive or synergistic effects. It was also concluded that NVP-BKM120 could overcome the acquired resistance to gefitinib by down-regulating the phosphorylated protein in PI3K/AKT signal pathways in H1975 cells, but it could not enhance the sensitivity of H1975 cells to gefitinib. PMID- 24337847 TI - Tacolimus postconditioning alleviates apoptotic cell death in rats after spinal cord ischemia-reperfusion injury via up-regulating protein-serine-threonine kinases phosphorylation. AB - The effects of tacrolimus postconditioning on protein-serine-threonine kinases (Akt) phosphorylation and apoptotic cell death in rats after spinal cord ischemia reperfusion injury were investigated. Ninety male SD rats were randomly divided into sham operation group, ischemia-reperfusion group and tacrolimus postconditioning group. The model of spinal cord ischemia was established by means of catheterization through femoral artery and balloon dilatation. The spinal cord was reperfused 20 min after ischemia via removing saline out of balloon. The corresponding spinal cord segments were excised and determined for Akt activity in spinal cord tissue by using Western blotting at 5, 15, and 60 min after reperfusion respectively. Spinal cord tissue sections were stained immunohistochemically for detection of the phosphorylated Akt expression at 15 min after reperfusion. Flow cytometry was applied to assess apoptosis of neural cells, and dry-wet weights method was employed to measure water content in spinal cord tissue at 24 h after reperfusion. The results showed that the activities of Akt in tarcolimus postconditioning group were significantly higher than those in ischemia-reperfusion group at 5, 15, and 60 min after reperfusion (P<0.05, P<0.01). The Akt activities reached the peak at 15 min after reperfusion in ischemia-reperfusion group and tacrolimus postconditioning group. The percentage of apoptotic cells and water content in spinal cord tissue were significantly reduced (P<0.01) in tacrolimus postconditioning group as compared with those in ischemia-reperfusion group at 24 h after reperfusion. It is concluded that tacrolimus post-conditioning can increase Akt activity in spinal cord tissue of rats, inhibit apoptosis of neural cells as well as tissue edema, and thereby alleviate spinal cord ischemia-reperfusion injury. PMID- 24337848 TI - Unsedated versus sedated gastrointestinal endoscopy: a questionnaire investigation in Wuhan, central China. AB - National data show that in China mainland unsedated gastrointestinal (GI) endoscopy has been applied in most hospitals for clinical examination, while sedated GI endoscopy is only performed in some hospitals. The purpose of this study was to compare sedated versus unsedated GI endoscopy regarding cost, safety, degree of comfort, tolerance level and overall satisfaction of patients over a 6-month period investigation. From March to September 2011, a questionnaire survey was performed on 1800 patients and 30 physicians at Zhongnan Hospital of Wuhan University and Wuhan General Hospital of Guangzhou Military Command. The patients fell into two groups according to their own decisions: the unsedated group (n=1000) and the sedated group (n=800). After examination, the patients and the physicians were required to fill in a questionnaire form. All the data were analyzed statistically. The results showed that the main factors the patients took for consideration between sedated and unsedated procedures included economy, comfort and safety. The income levels between the sedated and unsedated groups showed significant difference (P<0.01). Most patients in the unsedated group had lower income and were covered by less medical insurance. The tolerance rate was 92.4% vs. 65.5% between the sedated and unsedated group, respectively. 95.5% patients in the sedated group and 72.1% patients in the unsedated group chose the same endoscopy procedure for repeat examination. The survey data from endoscopists suggested the sedated procedure was more comfortable but less safe than the unsedated procedure (P<0.01). In China, unsedated GI endoscopy is now widely accepted by the majority of patients due to low cost and safety. Compared to unsedated GI endoscopy, sedated GI endoscopy is less painful, but more expensive and less safe. With the rapid improvement of people's living standard and the reliability of sedation technology, we expect sedated GI endoscopy will be gradually accepted by more patients. PMID- 24337849 TI - Holotransferrin enhances selective anticancer activity of artemisinin against human hepatocellular carcinoma cells. AB - Artemisinin, also termed qinghaosu, is extracted from the traditional Chinese medicine artemesia annua L. (the blue-green herb) in the early 1970s, which has been confirmed for effectively treating malaria. Additionally, emerging data prove that artemisinin exhibits anti-cancer effects against many types of cancers such as leukemia, melanoma, etc. Artemisinin becomes cytotoxic in the presence of ferrous iron. Since iron influx is high in cancer cells, artemisinin and its analogs selectively kill cancer cells with increased intracellular iron concentrations. This study is aimed to investigate the selective inhibitory effects of artemisinin on SMMC-7721 cells in vitro and determine the effect of holotransferrin, which increases the concentration of ferrous iron in cancer cells, combined with artemisinin on the anticancer activity. MTT assay was used for assessing the proliferation of SMMC-7721 cells treated with artemisinin. The induction of apoptosis and inhibition of colony formation in SMMC-7721 cells treated with artemisinin were determined by TdT-mediated dUTP nick end labeling (TUNEL) and colony formation assay, respectively. The results showed that artemisinin at various concentrations significantly inhibited growth, colony formation and cell viability of SMMC-7721 cells (P<0.05), likely due to induction of apoptosis of SMMC-7721 cells. Of interest, it was found that incubation of artemisinin combined with holotransferrin sensitized the growth inhibitory effect of artemisinin on SMMC-7721 cells (P<0.01). Our data suggest that treatment with artemisinin leads to inhibition of viability and proliferation, and apoptosis of SMMC-7721 cells. Furthermore, we observed that holotransferrin significantly enhanced the anti-cancer activity of artemisinin. This study may provide a potential therapeutic choice for liver cancer. PMID- 24337850 TI - Surgical selection for late pancreatic head carcinoma without gastric outlet obstruction. AB - The effects of different surgical procedures for late pancreatic head carcinoma without gastric outlet obstruction were explored in order to provide theoretical basis to select a suitable operation for these patients. The clinical data of 441 cases of late pancreatic head carcinoma without gastric outlet obstruction were retrospectively analyzed. All patients were divided into 4 groups based on different surgical procedures: group A (101 cases) subjected to Roux-en-Y cholecystojejunostomy; group B (133 cases) undergoing Roux-en-Y choledochojejunostomy; group C (83 cases) given Roux-en-Y cholecystojejunostomy combined with gastrojejunostomy; group D (124 cases) receiving Roux-en-Y choledochojejunostomy combined with gastrojejunostomy. Therapeutic efficacy in each group was evaluated comparatively. Both groups B and D had a lower rate of postoperative obstructive jaundice than groups A and C separately (P<0.05 for all). The data of mean life span showed that both groups B and D had a lower survival rate than groups A and C separately (P<0.05 for all). The incidence of postoperative gastric outlet obstruction in groups A and B was higher than that in groups C and D separately (P<0.05 for all). The gastrojejunostomy had no impacts on the mean life span, and there was no statistically significant difference in complications, average hospital stay (days) and median survival among four groups (P>0.05). For the late pancreatic head carcinoma without gastric outlet obstruction, Roux-en-Y choledochojejunostomy is effective for the reduction of icteric index and the incidence of recurrent jaundice, also offers an opportunity for prolonged survival. Combined use of prophylactic Roux-en-Y gastrojejunostomy during surgical biliary drainage is safe for advanced pancreatic carcinoma with obstructive jaundice, which can decrease the incidence of postoperative gastric outlet obstruction, and has important implications for improving outcomes. PMID- 24337851 TI - Inhibitory effects of mild hyperthermia plus docetaxel therapy on ER(+/-) breast cancer cells and action mechanisms. AB - The purpose of this study was to verify that a combination of mild hyperthermia and docetaxel chemotherapy produces synergistic antitumor effects and to explore the action mechanisms of this treatment approach. The effects of docetaxel on the proliferation of cells from the estrogen receptor (ER)-positive human breast cancer cell line MCF-7 and the ER-negative human breast cancer cell line MDA-MB 453 were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and effective experimental concentrations of docetaxel were determined. The effects of mild hyperthermia plus docetaxel therapy on apoptosis rate in the MCF-7 and MDA-MB-453 human breast cancer cell lines were analyzed by using flow cytometry with Annexin-V fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. The effects of these combined treatments on cell cycle progression in the MCF-7 and MDA-MB-453 human breast cancer cell lines were examined by using flow cytometry. The effects of these combined treatments on the expression of apoptosis-related proteins and proteins in the mitogen-activated protein kinase (MAPK) pathways were analyzed by using Western blotting. The effects of these combined treatments on the expression of the heat shock protein 70 (HSP70) and the multi-drug resistance (MDR) gene product P-glycoprotein (Pgp) were examined by using Western blotting. The results showed that the half-maximal inhibitory concentration (IC50) of docetaxel for MCF-7 and MDA-MB-453 cells was 19.57+/-1.12 and 21.64+/-2.31 MUmol/L respectively. Mild hyperthermia with docetaxel therapy could increase apoptosis rate in the MCF-7 and MDA-MB-453 cells. Apoptosis rate in MCF-7 and MDA-MB-453 cells was increased from (23.66+/ 3.59)% and (18.51+/-3.17)% in docetaxel treatment group to (47.12+/-6.73)% and (55.16+/-7.42)% in mild hyperthermia plus docetaxel group, indicating that the mild hyperthermia and docetaxel therapeutic approaches exhibited significant synergistic antitumor effects. Treatments of mild hyperthermia plus docetaxel induced G2/M cell cycle arrest in the MCF-7 and MDA-MB-453 cells. Western blotting demonstrated that proteins in the MAPK pathway were expressed at higher levels in docetaxel-treated cells following mild hypothermia than those in cells treated with docetaxel alone. As compared with blank control group, cells from the mild hyperthermia plus docetaxel group exhibited significantly decreased B cell lymphoma 2 (Bcl-2) protein expression but slightly increased Bcl-2 associated X protein (Bax) expression. Western blotting results revealed that HSP70 and Pgp expression levels were significantly increased following mild hypothermia. It was concluded that treatments of mild hyperthermia plus docetaxel inhibited the proliferation of human breast cancer cells, promoted apoptosis of breast cancer cells, and produced synergistic antitumor effects. PMID- 24337852 TI - Effects of Chinese Fructus Mume formula and its separated prescription extract on insulin resistance in type 2 diabetic rats. AB - The effect of Fructus Mume formula and its separated prescription extract on insulin resistance in type 2 diabetic rats was investigated. The rat model of type 2 diabetes was established by feeding on a high-fat diet for 8 weeks and by subsequently intravenous injection of small doses of streptozotocin. Rats in treatment groups, including the Fructus Mume formula treatment group (FM), the cold property herbs of Fructus Mume formula treatment group (CFM), the warm property herbs of Fructus Mume formula treatment group (WFM), were administrated with Fructus Mume formula and its separated prescription extract by gavage, while the rats in diabetic model group (DM) and metformin group (MET) were given by gavage with normal saline and metformin correspondingly. The body weight before and after treatment was measured, and the oral glucose tolerance test (OGTT) and the insulin release test (IRT) were performed. The homeostasis model assessment insulin resistance index (HOMA-IR) was calculated. The protein and mRNA expression levels of Insr, beta-arrestin-2, Irs-1 and Glut-4 in the liver, skeletal muscle and fat tissues were detected by using Western blotting and RT PCR respectively. The results demonstrated that, as compared with DM group, OGTT, IRT (0 h, 1 h) levels and HOMR-IR in treatment groups were all reduced, meanwhile their protein and mRNA expression levels of Insr, Irs-1 and Glut-4 in the liver, skeletal muscle and fat tissues were obviously increased, and their protein and mRNA expression levels of beta-arrestin-2 in the liver and skeletal muscle tissues were also markedly increased. It was suggested that the Fructus Mume formula and its separated prescription extracts could effectively improve insulin resistance in type 2 diabetic rats, which might be related to the up-regulated expression of Insr, Irs-1 and Glut-4 in the liver, skeletal muscle and fat tissues, and beta-arrestin-2 in the liver and skeletal muscle tissues. PMID- 24337853 TI - Clinical effect of Tip-Edge plus appliance in children with angle II(1) malocclusion. AB - The effects of Tip-Edge plus appliance in the treatment of Angle II(1) malocclusion and the mechanism were investigated. Fifty-two Angle II(1) children, aged from 12.3-14.2 years, with mandibular retrusion in permanent dentition were selected and treated with Tip-Edge plus appliance. Lateral cephalometric films taken before and after treatment were analyzed. The arithmetic mean and standard deviation were calculated for each variable. Paired t-test was performed to evaluate the significant treatment change. Results showed that the average treatment time was 16 months. Normal overjet and overbite were established with retroclination of upper incisors and proclination of lower incisors. U1-NA was decreased by 15.4 degrees (P<0.01). ANB and Y axial angle were decreased significantly (P<0.05). Soft tissue measurements showed that FCA and UL-E were decreased dramatically (P<0.05), and LL-E was increased significantly (P<0.05). Remarkable soft tissue change was noted after the treatment and convex facial profile changed to the straight profile. In conclusion, Tip-Edge plus technique can quickly and efficiently correct anterior bite and lateral outlook. PMID- 24337854 TI - Left ventricle geometry remolding after heart transplantation: a two-dimensional ultrasound study. AB - The function of the transplanted heart will be affected by acute allograft rejection, chronic rejection, high blood pressure and so on, which may induce the reconstruction of the left ventricle and the increase of left ventricular mass (LVM), and eventually lead to left ventricular hypertrophy that will significantly affect the prognosis of heart transplantation (HT). The purpose of this study was to dynamically monitor the changes of left ventricular geometric patterns after HT using two-dimensional echocardiography and to understand the remodeling process and its possible influencing factors. The left ventricular internal diameter, interventricular septal wall thickness, posterior wall thickness at end diastole were measured and the relative wall thickness (RWT), left ventricular mass, left ventricular mass index were calculated respectively in 34 HT patients and 34 healthy volunteers by two-dimensional echocardiography. The type of left ventricular geometry was identified based on the echocardiographic determination of LVM index (LVMI) and RWT. The HT patients were divided into three groups according to the time length after surgery: A (3 months postoperatively), B (6 months postoperatively) and C (12 months postoperatively). We compared the parameters of left ventricle between HT group and normal control group, and explored the risk factors causing the increase of LVM. The results showed that 4 patients (16%) in group A had concentric remodeling. Nine patients (34.62%) in group B had reconstruction, including 5 cases of concentric remodeling, 2 cases of concentric hypertrophy and 2 cases of eccentric hypertrophy. The hypertrophy incidence rate was 15.4% in group B. 15 patients (62.5%) had reconstruction in group C, including 9 cases of concentric remodeling, 5 cases of concentric hypertrophy, and 1 case of eccentric hypertrophy. The prevalence of hypertrophy was 25%. Multivariate analysis showed that hypertension and acute rejection history were the risk factors that resulted in left ventricular hypertrophy. It is concluded that the left ventricular remodeling occurs following cardiac transplantation at an early stage and the incidence of left ventricular hypertrophy increases with survival time. In this study, the one-year prevalence of left ventricular hypertrophy was 25% after surgery. Hypertension and acute rejection history are risk factors that can predict the left ventricular hypertrophy. PMID- 24337855 TI - Association between CHRNA3 rs1051730 genotype and lung cancer risk in Chinese Han population: a case-control study. AB - Recent population-based genome wide association studies have revealed potential susceptibility loci of lung cancer at the region of chromosome 15q25.1 containing nicotinic acetylcholine receptor genes. The loci increasing lung cancer risk has been widely identified in Caucasians, but whether this association also exists in Asians and whether this association is a direct role or mediated via tobacco smoking indirectly has not been fully established. We conducted a case-control study comprising of 210 histologically confirmed lung cancer cases and 200 healthy controls to examine rs1051730 genotyping, a single nucleotide polymorphism receiving much attention recently, and its influence on lung cancer risk as well as nicotine dependence in a Chinese Han population. Our results showed that the heterozygous C/T genotype and minor allele T conferred a significant higher risk of lung cancer than the CC homozygotes and allele C (adjusted OR=2.25, 95% CI=1.04-4.89, P=0.040 and OR=2.18, 95% CI=1.02-4.67, P=0.045 respectively). However, no association between the smoking habit and the CHRNA3 rs1051730 polymorphism was observed in this study. The results suggested that the rs1051730 polymorphism may modify susceptibility to lung cancer via a smoking-independent manner among Chinese Han population. Additional studies in vitro and in vivo are warranted to further elucidate the impact of rs1051730 on lung cancer susceptibility. PMID- 24337856 TI - Genetic polymorphism of 17 Y-STR loci in Han Chinese living in Lanzhou. AB - The genetic polymorphism across 17 Y-STR loci in a population of Han Chinese in Lanzhou was investigated. Haplotypes and allele frequencies for the 17 Y chromosomal STRs loci DYS456, DYS389I, DYS390, DYS389II, DYS458, DYS19, DYS385a/b, DYS393, DYS391, DYS439, DYS635, DYS392, Y GATA H4, DYS437, DYS438 and DYS448 were determined in 500 healthy unrelated autochthonous males from Lanzhou. The results showed that no shared haplotypes were observed. Gene diversity values ranged from 0.3987 (DYS391) to 0.9740 (DYS385a,b). It was concluded that these loci will be very useful for human identification in forensic cases and paternity tests within the Han Chinese population inhabiting Lanzhou. PMID- 24337857 TI - Impact evaluation of HIV/AIDS education in rural Henan province of China. AB - Nowadays, there is a trend of HIV prevalence transmitting from high-risk group to average-risk group in China. Rural China is the weak link of HIV prevention, and rural areas of Henan province which is one of the most high-risk regions in China have more than 60% of the AIDS patients in the province. Thus, improving the HIV awareness and implementing health education become the top-priority of HIV/AIDS control and prevention. A multistage sampling was designed to draw 1129 people living with HIV/AIDS (PLWHAs) and 1168 non-PLWHAs in 4 prevalence counties of Henan province. A health promoting and social-psychological support model was constructed to improve the health knowledge of participants. Chi-square tests and unconditional logistic regression were performed to determine the intervention effect and influencing factors. All groups had misunderstandings towards the basic medical knowledge and the AIDS transmission mode. Before the intervention, 59.3% of the HIV/AIDS patients and 74.6% of the healthy people had negative attitudes towards the disease. There was statistically significant difference in the improvement of knowledge, attitude and action with regards to HIV prevention before and after intervention (P<0.05). PLWHAs who were males (OR=1.731) and had higher education level (OR=1.910) were found to have better HIV/AIDS health knowledge, whereas older PLWHAs (OR=0.961) were less likely to have better HIV/AIDS health knowledge. However, the intervention effect was associated with the expertise of doctors and supervisors, the content and methods of education, and participants' education level. It was concluded that health education of HIV/AIDS which positively influences the awareness and attitude of HIV prevention is popular in rural areas, therefore, a systematic and long-term program of HIV control and prevention is urgently needed in rural areas. PMID- 24337858 TI - LC-MS/MS method for determination of megestrol in human plasma and its application in bioequivalence study. AB - A rapid and highly selective liquid chromatography-tandem mass spectrometric (LC MS/MS) method for the determination of megestrol in human plasma was described using medrysone as internal standard (IS). Blood samples were collected from 20 healthy volunteers after oral administration of 160 mg megestrol acetate dispersible tablets. The analytes were extracted by liquid-liquid extraction procedure and separated on a hanbon lichrospher column with the mobile phase of methanol and water containing 0.1% formic acid and 20 mmol/L ammonium acetate (5:1, v/v). Positive ion electrospray ionization with multiple reaction monitoring mode (MRM) was employed by monitoring the transitions m/z 385.5-325.4 and m/z 387.5-327.4 for megestrol and medrysone, respectively. Under the isocratic separation conditions, the chromatographic run time was approximately 2.54 min for megestrol and 2.59 min for medrysone. The calibration curve range was from 0.5 to 200.0 ng/mL. The inter-batch and intra-batch precision and accuracy were less than 5.2% relative standard deviation (RSD) and 6.4% relative error (RE). The proposed method was successfully applied in the bioequivalence study of megestrol acetate dispersible tablets. PMID- 24337859 TI - Morphological and molecular identification of two strains of dermatophytes. AB - In this study, we used traditional morphological and molecular identification methods to preliminarily identify two strains of dermatophytes. The two strains were observed under the microscope. And then the dermatophytes were cultured on Sabouraud's dextrose agar (SDA). The 18S rRNA regions of the two dermatophyte strains were amplified by polymerase chain reaction (PCR), and the PCR products were sequenced and compared with GenBank data. BLAST tools and DNAMAN software were used to analyze the sequences. To further determine highly homologous sequences, a phylogenetic tree was constructed using the Neighbor-Joining method. The two strains of dermatophytes were identified by traditional morphological identification as Epidermophyton floccosum and Microsporum ferrugineum. The 18S rRNA sequence analyses showed high similarities to Cladosporium cladosporioides isolate C115LM-UFPR and Ascomycete sp. LB68A1A2. Epidermophyton and Cladosporium belong to dermatophyte, while Microsporum ferrugineum and Ascomycete belong to microsporum. The two novel strains of dermatophytes were therefore identified as Cladosporium cladosporioides isolate C115LM-UFPR (JN650537, Cladosporium) and Ascomycete sp. LB68A1A2 (AY770409, Ascomycete sp). PMID- 24337860 TI - PAHs in organic film on glass window surfaces from central Shanghai, China: distribution, sources and risk assessment. AB - Polycyclic aromatic hydrocarbons (PAHs) concentrations were analysed in the organic film on the glass surfaces of different functional areas in central Shanghai. Concentration levels of total PAHs in the organic film ranged from 1,348.5 to 4,007.9 ng m(-2). The concentration of PAHs was lowest in parks and green spaces (1,348.5 ng m(-2)) and highest in traffic zones (4,007.9 ng m(-2)). A concentration gradient of total PAHs was observed as follows: traffic zones > commercial areas > cultural and educational areas > parks and green spaces. The distribution of PAHs was characterised by 3-4 ring PAHs in the study areas. The most abundant PAHs were phenanthrene (20.5 %), fluorene (16.7 %), pyrene (12.4 %) and chrysene (Chry) (11.2 %). The mass of the bulk film was composed of organic and inorganic compounds and ranged from 246 to 1,288 mg m(-2). The bulk film thickness varied from 144 to 757 nm in the different functional areas. The ratios of An/178 and Fl/202 and principal component analysis suggested that PAHs came mainly from the mixed sources of fossil fuel, coal and incomplete combustion of biomass. Benzo[a]anthracene (BaA)/Chry is not suitable for use as a tracer for the transmission process of PAHs because of the rapid depletion of BaA in the organic film by photooxidation during daylight hours. The concentration of benzo[a]pyrene equivalent (BaPeq) varied from 21 to 701 ng g(-1), and the major carcinogenic contributors of the 16 PAHs were BaP, DahA, B[b/k]F and InP, accounting for 83 % of BaPeq. PMID- 24337861 TI - Analysis of mandibular condylar and glenoid fossa fractures with computed tomography. AB - OBJECTIVES: The purpose of this study was to investigate the prevalence of glenoid fossa and condylar fractures in patients with mandibular fractures using multidetector computed tomography (MDCT). METHODS: A prospective study was performed in 227 patients with mandibular fractures who underwent 64-MDCT. Mandibular fractures were classified into four types: median, paramedian, angle and condylar. Statistical analysis of the relationship between prevalence of condylar fractures and mandibular fracture locations was performed using chi(2) test with Fisher's exact test. A P value less than 0.05 was considered statistically significant. RESULTS: The prevalence of condylar fracture was 64.8 % of all patients with mandibular fractures, 66.7 % of median type (P = 0.667), 45.5 % of paramedian type (P = 0.001) and 12.3 % of angle type (P = 0.000), respectively. Furthermore, glenoid fossa fracture was seen in 1.4 % of patients with condylar fractures. CONCLUSIONS: The results of the presented study suggest focusing also on incidental findings such as glenoid fossa fractures. KEY POINTS: * The prevalence of condylar fracture was 64.8 % in patients with mandibular fractures. * Glenoid fossa fracture was seen in 1.4 % of patients with condylar fractures. * The study suggests a focus on incidental findings such as glenoid fossa fractures. PMID- 24337862 TI - Grandmothers' smoking in pregnancy and grandchildren's birth weight: comparisons by grandmother birth cohort. AB - This study examined whether grandmothers' smoking behavior during pregnancy was associated with birth weights in their grandchildren, considering possible birth cohort effects in the grandmothers' generation. The birth weights of 935 singleton children were compared by grandmothers' and mothers' smoking status during pregnancy. In 2008, women (n = 397) from the Michigan Bone Health and Metabolism Study were interviewed about their own birth history, including whether their own mother smoked while pregnant with them, and the birth histories of their offspring. While also accounting for family clustering, linear mixed models were used to evaluate whether birth weight differences in the grandchildren were associated with grandmothers' and mothers' smoking behavior during pregnancy. Associations were compared among grandmothers born from 1904 to 1928 versus grandmothers born from 1929 to 1945 to determine potential birth cohort effects. Forty-six (5 %) grandchildren had grandmothers and mothers who smoked while pregnant, while 455 (49 %) had grandmothers and mothers who did not smoke during pregnancy. After adjustment, birth weight was an average of 346 (95 % confidence interval 64-628) grams higher in grandchildren whose grandmother and mother both smoked during pregnancy relative to grandchildren whose grandmother and mother both did not smoke during pregnancy, but only among grandmothers who were born from 1929 to 1945. For grandmothers born from 1904 to 1928, grandchildren birth weights did not differ by grandmother and mother smoking status. Birth weight may be associated with grandmother and mother smoking behaviors during pregnancy, but birth cohort effects should be considered. PMID- 24337863 TI - A qualitative study to understand positive and negative child feeding behaviors of immigrant Asian Indian mothers in the US. AB - To understand current practice of child feeding behaviors, and underlying factors influencing these practices in Asian Indian mothers, qualitative in-depth interviews were conducted with 27 immigrant Asian Indian mothers of children ages 5-10 years. Using the theory of planned behavior as a guiding framework, child feeding behaviors employed, beliefs about the outcomes of feeding behaviors, perceived ease or difficultly in practicing feeding behaviors, and social norms were explored during the interviews. Thematic analysis was conducted using coding and display matrices. Mothers were motivated by nutrition outcomes when practicing positive and negative controlling feeding behaviors. Outcomes related to preservation of Indian culture and values also influenced feeding behaviors. Pressuring to eat was often practiced despite the perception of ineffectiveness. Use of food rewards was found, and use of TV to control children's food intake despite the clear understanding of undesirable nutrition outcomes was a unique finding. Asian Indian mothers need effective child feeding strategies that are culturally appropriate. Integrating cultural beliefs in nutrition education could help support existing motivation and behavior modification. PMID- 24337864 TI - Similarities and differences in the epidemiology of pyloric stenosis and SIDS. AB - Similar temporal declines in infantile hypertrophic pyloric stenosis (IHPS) and sudden infant death syndrome (SIDS) and other common features have led to hypotheses about a shared etiology. We carried out a population-based study to highlight similarities and differences between IHPS and SIDS. We used vital statistics and hospitalization data on all live births in Washington State, USA (1987-2009). Changes in IHPS and SIDS rates over time were quantified using rate ratios with 95 % confidence intervals (CI). The duration between birth and diagnosis of IHPS or SIDS was examined as a function of gestational age at birth. Logistic regression analysis was used to identify risk factors and quantify adjusted temporal trends (2000-2008). Although both IHPS and SIDS rates declined significantly between 1987 and 2008, the patterns and magnitude of the declines (40 and 74 %, respectively) were different. IHPS and SIDS shared risk factors such as maternal smoking and single parent status but other factors showed qualitatively or and quantitatively different associations. Primiparity was a risk factor for IHPS [odds ratio (OR) 1.24, 95 % CI 1.09-1.41], and a protective factor for SIDS (OR 0.44, 95 % CI 0.36-0.55), while male sex had a stronger association with IHPS (OR 4.51, 95 % CI 3.85-5.28 vs 1.36, 95 % CI 1.13-1.64). Both IHPS and SIDS showed significant inverse associations between gestational age at birth and chronologic age at diagnosis/death. IHPS and SIDS share some epidemiologic features and risk factors but other risk factors have qualitatively or quantitatively different effects and recent temporal trends in the two diseases are dissimilar. PMID- 24337865 TI - Maternal Chlamydia trachomatis infections and preterm birth:the impact of early detection and eradication during pregnancy. AB - The risks for preterm birth are heterogeneous and there remains much to elucidate regarding etiology of this adverse perinatal outcome. Antenatal infection with Chlamydia trachomatis, a highly prevalent sexually-transmitted infection, may convey a higher risk of preterm birth. Early detection and eradication of this sexually-transmitted infection without recurrent/persistent infection during pregnancy may serve as an intervention that reduces the risk of preterm birth. The objective of this study was to characterize the association between early antenatal detection and eradication of maternal C. trachomatis infection and the likelihood of preterm birth among pregnant women in an urban county. A retrospective cohort study was conducted in Hamilton County, Ohio (2006-2011) to evaluate the risk of preterm birth among women with maternal C. trachomatis infections detected and eradicated at or before 20 weeks gestation--the intervention group. Infected women whose infections were detected after 20 weeks gestation or persistent during the pregnancy represented the reference group. The study population contained 3,354 pregnant women with documented C. trachomatis infections. The relative risk for moderate to late spontaneous preterm birth (32 36 weeks gestation) was 0.54 (95 % CI 0.37-0.80) for women in the intervention group who were 19 years of age and younger. Pregnant adolescents benefited the most from early detection and eradication of antenatal C. trachomatis infections through a reduction in the risk of PTB at 32-36 weeks gestation. This finding suggests the importance of early antenatal detection and effective treatment of C. trachomatis. PMID- 24337866 TI - Cloning and characterization of a novel dehydrin gene, SiDhn2, from Saussurea involucrata Kar. et Kir. AB - Saussurea involucrata Kar. et Kir. is a hardy dicotyledonous plant capable of tolerating severe abiotic stress conditions. In a previous study, we created a cDNA library to determine what factors are associated with the cold acclimation response in S. involucrata. From this, a full-length cDNA of a dehydrin-like gene (SiDhn2) was obtained by RT-PCR. The SiDhn2 gene was characterized in this study. The full-length SiDhn2 cDNA comprised 693 bp containing an open reading frame of 345 bp specifying a protein of 115 amino acids. An alignment of the deduced amino acid sequence showed that SiDhn2 shared 55 % identity with two Brassica dehydrins. Agrobacterium tumefaciens was used to transform RD29A:SiDhn2 and 35S:SiDhn2 constructs into tobacco to investigate the germination and resistance to freezing and drought stress of transgenic plants. The RD29A:SiDhn2 transgenic plants showed greater resistance to freezing and drought stress than 35S:SiDhn2 transgenic plants or the wild-type. This study demonstrates that SiDhn2 confers cold hardiness and drought resistance, and may be a candidate resistance gene for genetic improvement of crops to increase stress resistance. PMID- 24337867 TI - Chin tuck against resistance (CTAR): new method for enhancing suprahyoid muscle activity using a Shaker-type exercise. AB - For patients with dysphagia resulting from upper esophageal sphincter dysfunction, strengthening the suprahyoid muscles through therapeutic exercise has proved effective in restoring oral feeding. The aim of this study was to compare the maximum and mean surface electromyography (sEMG) activity of the suprahyoid muscles during the Chin Tuck Against Resistance (CTAR) exercise and the Shaker exercise for both isokinetic and isometric tasks. During the CTAR exercises, the participant is seated while tucking the chin to compress an inflatable rubber ball, whereas during the Shaker exercise, the participant is lay supine while lifting the head to look at the feet. Forty healthy participants (20 males, 20 females) aged 21-39 years completed all four tasks in counterbalanced order, with measures of resting activation taken prior to each exercise. Although subjective feedback suggested that the sitting position for CTAR is less strenuous than the supine position for Shaker, the results of separate analyses showed significantly greater maximum sEMG values during the CTAR isokinetic and isometric exercises than during the equivalent Shaker exercises, and significantly greater mean sEMG values were observed for the CTAR isometric exercise than for the Shaker isometric exercise. Clinical trials are now needed, but the CTAR exercises appear effective in exercising the suprahyoid muscles, and they could achieve therapeutic effects comparable to those of Shaker exercises, with the potential for greater compliance by patients. PMID- 24337868 TI - Different routes lead to apoptosis in unfertilized sea urchin eggs. AB - Results obtained in various species, from mammals to invertebrates, show that arrest in the cell cycle of mature oocytes is due to a high ERK activity. Apoptosis is stimulated in these oocytes if fertilization does not occur. Our previous data suggest that apoptosis of unfertilized sea urchin eggs is the consequence of an aberrant short attempt of development that occurs if ERK is inactivated. They contradict those obtained in starfish, another echinoderm, where inactivation of ERK delays apoptosis of aging mature oocytes that are nevertheless arrested at G1 of the cell cycle as in the sea urchin. This suggests that the cell death pathway that can be activated in unfertilized eggs is not the same in sea urchin and in starfish. In the present study, we find that protein synthesis is necessary for the survival of unfertilized sea urchin eggs, contrary to starfish. We also compare the effects induced by Emetine, an inhibitor of protein synthesis, with those triggered by Staurosporine, a non specific inhibitor of protein kinase that is widely used to induce apoptosis in many types of cells. Our results indicate that the unfertilized sea urchin egg contain different mechanisms capable of leading to apoptosis and that rely or not on changes in ERK activity, acidity of intracellular organelles or intracellular Ca and pH. We discuss the validity of some methods to investigate cell death such as measurements of caspase activation with the fluorescent caspase indicator FITC VAD-fmk or acidification of intracellular organelles, methods that may lead to erroneous conclusions at least in the sea urchin model. PMID- 24337869 TI - Synergistic induction of apoptosis in A549 cells by dihydroartemisinin and gemcitabine. AB - This report is designed to study the ability of the combined treatment with gemcitabine (Gem) and dihydroartemisinin (DHA) to induce apoptosis in a non-small cell lung cancer cell line (A549 cells). This combination treatment synergistically inhibited cell growth by inducing apoptosis, and this synergistic action was not associated with reactive oxygen species (ROS). Although either Gem or DHA induced a significant increase in ROS generation, the combination treatment did not further enhance ROS level. Compared with single drugs, the combination treatment significantly potentiated Bak activation, loss of mitochondrial membrane potential, caspase-9 and -3 activation, indicating the important role of the Bak-mediated intrinsic apoptosis pathway in the synergistic action, which was further verified by the significant prevention of the cytotoxicity of the combination treatment by inhibiting one of caspase-9, -3 and Bcl-xL or silencing Bak. In addition, the combination treatment also synergistically activated caspase-8, and inhibition of Fas and caspase-8 presented significant prevention on the cytotoxicity of the combination treatment, indicating that the Fas-caspase-8-mediated extrinsic apoptosis pathway partially participated in the synergistic action. Collectively, the present study demonstrates a strong synergistic action of the combined treatment with Gem and DHA in inducing apoptosis of A549 cells via both the Bak-mediated intrinsic pathway and the Fas-caspase-8-mediated extrinsic pathway. PMID- 24337871 TI - The impact of cancer diagnosis on employment: is there a difference between rural and urban populations? AB - PURPOSE: To determine if living in a rural or urban area influences the impact of cancer diagnosis on employment. METHOD: Surveys that asked about changes in employment status related to a cancer diagnosis or treatment were sent to 2,005 cancer survivors enrolled in the Vermont Cancer Survivor Surveillance Registry. Data on cancers were obtained from hospital cancer registries. Respondents indicating that they were working at the time of diagnosis were included in this study for a total of 1,155 participants. Associations between rural or urban residence and changes in employment were assessed by chi-square tests and logistic regression. RESULTS: There were no statistically significant differences in the proportions of rural and urban survivors working fewer hours, experiencing a career change or unable to work. However, a larger proportion of rural than urban patients retired early after their diagnosis (11.1 vs. 7.2%, p = 0.031). There were also fewer rural patients that reported that they went on paid disability during cancer treatment (12.3 vs. 17.0%, p = 0.030). CONCLUSIONS: While many patients will return to work after treatment for a cancer diagnosis, it appears that rural patients may be less likely to receive paid disability and more likely to retire early. It is possible that rural populations engage in more physically demanding jobs that they are unable to continue after their cancer treatment. Additionally the types of manual labor available in rural areas rarely offer disability benefits, increasing the impact of cancer diagnosis for this population. IMPLICATIONS FOR CANCER SURVIVORS: A cancer diagnosis may have a greater impact on employment among rural residents. Cancer programs should recognize this disparity and enhance return to work and disability counseling in patients from rural areas. PMID- 24337870 TI - Apoptosis repressor with caspase recruitment domain is regulated by MAPK/PI3K and confers drug resistance and survival advantage to AML. AB - The apoptosis repressor with caspase recruitment domain (ARC) protein is known to suppress both intrinsic and extrinsic apoptosis. We previously reported that ARC expression is a strong, independent adverse prognostic factor in acute myeloid leukemia (AML). Here, we investigated the regulation and role of ARC in AML. ARC expression is upregulated in AML cells co-cultured with bone marrow-derived mesenchymal stromal cells (MSCs) and suppressed by inhibition of MAPK and PI3K signaling. AML patient samples with RAS mutations (N = 64) expressed significantly higher levels of ARC than samples without RAS mutations (N = 371) (P = 0.016). ARC overexpression protected and ARC knockdown sensitized AML cells to cytarabine and to agents that selectively induce intrinsic (ABT-737) or extrinsic (TNF-related apoptosis inducing ligand) apoptosis. NOD-SCID mice harboring ARC-overexpressing KG-1 cells had significantly shorter survival than mice injected with control cells (median 84 vs 111 days) and significantly fewer leukemia cells were present when NOD/SCID IL2Rgamma null mice were injected with ARC knockdown as compared to control Molm13 cells (P = 0.005 and 0.03 at 2 and 3 weeks, respectively). Together, these findings demonstrate that MSCs regulate ARC in AML through activation of MAPK and PI3K signaling pathways. ARC confers drug resistance and survival advantage to AML in vitro and in vivo, suggesting ARC as a novel target in AML therapy. PMID- 24337872 TI - Ginsenoside Rg3 induces DNA damage in human osteosarcoma cells and reduces MNNG induced DNA damage and apoptosis in normal human cells. AB - Panax ginseng is a Chinese medicinal herb. Ginsenosides are the main bioactive components of P. ginseng, and ginsenoside Rg3 is the primary ginsenoside. Ginsenosides can potently kill various types of cancer cells. The present study was designed to evaluate the potential genotoxicity of ginsenoside Rg3 in human osteosarcoma cells and the protective effect of ginsenoside Rg3 with respect to N methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced DNA damage and apoptosis in a normal human cell line (human fibroblasts). Four human osteosarcoma cell lines (MG-63, OS732, U-2OS and HOS cells) and a normal human cell line (human fibroblasts) were employed to investigate the cytotoxicity of ginsenosides Rg3 by MTT assay. Alkaline comet assay and gammaH2AX focus staining were used to detect the DNA damage in MG-63 and U-2OS cells. The extent of cell apoptosis was determined by flow cytometry and a DNA ladder assay. Our results demonstrated that the cytotoxicity of ginsenoside Rg3 was dose-dependent in the human osteosarcoma cell lines, and MG-63 and U-2OS cells were the most sensitive to ginsenoside Rg3. As expected, compared to the negative control, ginsenoside Rg3 significantly increased DNA damage in a concentration-dependent manner. In agreement with the comet assay data, the percentage of gammaH2AX-positive MG-63 and U-2OS cells indicated that ginsenoside Rg3 induced DNA double-strand breaks in a concentration-dependent manner. The results also suggest that ginsenoside Rg3 reduces the extent of MNNG-induced DNA damage and apoptosis in human fibroblasts. PMID- 24337873 TI - Analysis of fluorescence quenching of coumarin derivatives by 4-hydroxy-TEMPO in aqueous solution. AB - The fluorescence quenching of different coumarin derivatives (7-hydroxy-4 methylcoumarin, 5,7-dimethoxycoumarin, 7-amino-4-methyl-3-coumarinylacetic acid, 7-ethoxy-4-methylcoumarin, 7-methoxycoumarin, 7-hydroxycoumarin, 7-hydroxy-4 methyl-3-coumarinylacetic acid and 7-amino-4-methylcoumarin) by 4-hydroxy-TEMPO in aqueous solutions at the room temperature was studied with the use of UV-Vis absorption spectroscopy as well as a steady-state and time-resolved fluorescence spectroscopy. In order to understand the mechanism of quenching the absorption and fluorescence emission spectra of all coumarins along with fluorescence decays were recorded under the action of 4-hydroxy-TEMPO. The Stern-Volmer plots (both from time-averaged and time-resolved measurements) displayed no positive (upward) deviation from a linearity. The fluorescence quenching mechanism was found to be entirely dynamic, what was additionally confirmed by the registration of Stern Volmer plots at different temperatures. The Stern-Volmer quenching constants and bimolecular quenching rate constants were obtained for all coumarins studied at the room temperature. The findings demonstrate the possibility of developing an analytical method for the quantitative determination of the free radicals' scavenger, 4-hydroxy-TEMPO. PMID- 24337874 TI - Confinement of 4,4-diaminodiphenyl sulfone by gamma -CD in micellar environment: a spectroscopic investigation. AB - This paper reports the double confinement of 4,4-diaminodiphenyl sulfone (Dapsone) inside gamma-cyclodextrin (CD) in presence of surfactants (cationic, anionic and nonionic) using steady-state and time-resolved fluorescence spectroscopy. Interpretation of fluorescence spectra, fluorescence anisotropy and time resolved fluorescence decay of the gamma-CD * Dapsone*micellar system hints at lesser microviscosity and the partial release of the probe molecule from the supramolecular host-guest complex in ionic micelles, of which greater in cationic micelles, but due to greater restriction and rigidity in presence of non-ionic micelle makes the probe more rigidly inside CD. Changes in computed rotational decay also corroborate the above findings. PMID- 24337876 TI - Reliability and validity of the Spanish Glasgow Benefit Inventory after cochlear implant surgery in adults. AB - In recent years, the outcome assessment of subjects undergoing otorhinolaryngological (ORL) intervention has relied increasingly upon patient reported questionnaires. The English Glasgow Benefit Inventory (GBI) is a reliable, sensitive and validated post-intervention questionnaire that is used to determine health-related quality-of-life (QoL) in patients following ORL intervention. The GBI has been translated into eight languages including Spanish. The present study aimed to determine the internal consistency and validity of the Spanish version of the GBI in patients with a cochlear implant (CI). 121 adult Spanish speaking patients with a CI were questioned retrospectively using the Spanish GBI. Reliability of the questionnaire was determined using Cronbach's alpha coefficient; factor analyses were performed using principal component extraction with orthogonal rotation; and validity was confirmed using Pearson's correlation coefficient. The mean total score (mean +/- standard deviation) of the GBI was 35.1 +/- 23.6, 47.6 +/- 28.9 for General Health, 17.9 +/- 33.2 for Social Benefit and 1.7 +/- 27.9 for Physical Health. The reliability was above 0.70 in all test domains. Using factor analyses a 4-factor solution that explained 63.2% of the variance was reached. The objective measures: bisyllables tested without lip-reading and without masking were correlated with the total score and the General Health subscales. The Spanish GBI is a reliable and practicable instrument for the assessment of health-related QoL in Spanish adult CI users. PMID- 24337877 TI - Direct current stimulation of the ear in tinnitus treatment: a double-blind placebo-controlled study. AB - The objectives of the study are assessment of the influence of direct current electrical stimulations of the ear in tinnitus treatment, comparison of the results with placebo group and evaluation of hearing after electrical stimulations. The study comprised 120 tinnitus and sensorineural hearing loss patients (n = 184 tinnitus ears). In group one (n = 119 tinnitus ears) the authors applied a non-invasive hydrotransmissive electrical stimulation (15) of the ear, in group two (n = 65 tinnitus ears)--placebo electrical stimulation. Direct rectangular, positive polarization current was used. The frequency of stimulation was adjusted according to tinnitus frequency. In group two, the authors used similar procedure, but no current was delivered through the active electrode. Evaluation of tinnitus and hearing was conducted. In groups one and two, directly after the treatment, the number of ears with permanent tinnitus decreased considerably. In group one in 40 ears (33.6%) tinnitus disappeared; in group two, tinnitus disappeared in four ears (6.1%). After 30 days, statistically significant changes were observed in group one (p < 0.05), which were comparable with results returned 90 days later (p > 0.05). Changes in group two (after 30 and 90 days) were not significant (p > 0.05). The authors recognized audiometric improvement of hearing (in pure tone audiometry). The application of direct current electrical stimulation of the hearing organ, with current frequencies similar to tinnitus frequencies (selective electrical stimulation), was an efficient method in severe tinnitus treatment. We did not observe a harmful effect of direct current on hearing organ. PMID- 24337878 TI - Are bovine pericardium underlay xenograft and butterfly inlay autograft efficient for transcanal tympanoplasty? AB - To evaluate the success rate and the surgical procedure of two different transcanal myringoplasty techniques using the Tutopatch((r)) (Tutogen Medical, Inc., Alachua, FL, USA), a xenograft produced from bovine pericardium or the butterfly, an inlay tragal cartilage autograft. This is a retrospective study. We studied all cases of transcanal myringoplasty with Tutopatch and butterfly, performed by the same surgeon between April 2005 and May 2013. Perforations were secondary to chronic otitis media without cholesteatoma, perforation post ventilation tube or trauma. They were not exceeding one-third of the tympanic membrane surface for the Tutopatch and one quarter for the butterfly. We evaluated the anatomical success rate, complications and postoperative hearing results in both techniques. A total of 106 myringoplasties were performed: 66 with Tutopatch and 40 with butterfly with a mean follow-up of 16.5 and 5.2 months, respectively. Successful closure rates of Tutopatch and butterfly were 75.8% (P < 0.0001) and 85.0% (P < 0.0001), respectively. Myringitis controlled with topical antibiotics treatment occurred in 8 (12.1%) and 5 (12.5%) cases. Eighty percent of patients with Tutopatch had a mean residual air-bone gap within 10 dB, compared to 85.0% in patients with butterfly. When anatomically feasible, a transcanal approach myringoplasty with a Tutopatch((r)) graft or butterfly appears to provide good anatomical and functional results. We show that both techniques provide good anatomical and functional results. The butterfly has the advantage to use an autograft, which is surgically easier because it does not require tympanomeatal flap elevation. We recommend the butterfly technique for non-marginal perforation not exceeding one quarter of the tympanic membrane after excision of the perforation edge and Tutopatch for bigger perforation or when standard autografts are not available. Myringitis is the only described complication without specific incidence. PMID- 24337875 TI - 5-HT(1A) [corrected] receptors in mood and anxiety: recent insights into autoreceptor versus heteroreceptor function. AB - RATIONALE: Serotonin (5-HT) neurotransmission is intimately linked to anxiety and depression and a diverse body of evidence supports the involvement of the main inhibitory serotonergic receptor, the serotonin-1A (5-HT(1A)) subtype, in both disorders. OBJECTIVES: In this review, we examine the function of 5-HT(1A) receptor subpopulations and re-interpret our understanding of their role in mental illness in light of new data, separating both spatial (autoreceptor versus heteroreceptor) and the temporal (developmental versus adult) roles of the endogenous 5-HT(1A) receptors, emphasizing their distinct actions in mediating anxiety and depression-like behaviors. RESULTS: It is difficult to unambiguously distinguish the effects of different populations of the 5-HT(1A) receptors with traditional genetic animal models and pharmacological approaches. However, with the advent of novel genetic systems and subpopulation-selective pharmacological agents, direct evidence for the distinct roles of these populations in governing emotion-related behavior is emerging. CONCLUSIONS: There is strong and growing evidence for a functional dissociation between auto- and heteroreceptor populations in mediating anxiety and depressive-like behaviors, respectively. Furthermore, while it is well established that 5-HT(1A) receptors act developmentally to establish normal anxiety-like behaviors, the developmental role of 5-HT(1A) heteroreceptors is less clear, and the specific mechanisms underlying the developmental role of each subpopulation are likely to be key elements determining mood control in adult subjects. PMID- 24337879 TI - Multilevel radiofrequency ablation to the soft palate and tongue base: tips and pitfalls. AB - The objective of the study is to increase awareness and understanding of the techniques and safety measures to minimise complications and improve patient outcomes. Literature review using MedLine and keywords snoring; obstructive sleep apnoea; radiofrequency ablation; electrosurgery; palate; tongue base was conducted. There is no accepted gold standard technique for radiofrequency ablation; to date, there is no published literature regarding common tips and pitfalls in radiofrequency application specifically for superficial applications and second-stage surgery. Surgery for snoring and obstructive sleep apnoea is typically multilevel. Pre-operative patient assessment and selection are critical to ensure good outcomes. Radiofrequency is generally safe and efficacious in this subset of patients. However, as with all surgery, it is operator-dependent. In particular, we emphasise the methodology for second-stage surgery, optimising visualisation and avoiding ulceration/fistulation of the soft palate, which are previously undescribed in the literature. PMID- 24337880 TI - Interleukin-4 receptor alpha-chain polymorphisms and susceptibility to allergic rhinitis: a meta-analysis. AB - Several polymorphisms in interleukin-4 receptor alpha-chain (IL-4RA) have been implicated in susceptibility to allergic rhinitis (AR), but the results are inconclusive. This meta-analysis was aimed to clarify the impact of IL-4RA polymorphisms on AR risk. Pubmed, EMBASE and Cochrane Library were searched until 2 October 2013 for eligible studies on IL-4RA polymorphism. Data were extracted, and pooled odd ratios (ORs) as well as 95 % confidence intervals (95 % CIs) were calculated. Ten studies with 1,552 AR patients and 1,473 controls were included. The results indicated that IL4RA Gln551Arg polymorphism was associated with AR susceptibility in Asian (AG vs. AA OR = 1.63, 95 % CI 1.17-2.28, I (2) = 57 %; GG vs. AA, OR = 1.69, 95 % CI 1.00-2.86, I (2) = 7 %; AG + GG vs. AA, OR = 1.68, 95 % CI 1.18-2.39, I (2) = 64 %; GG vs. AG + AA, OR = 1.47, 95 % CI 0.87-2.49, I (2) = 0 %; G vs. A, OR = 1.54, 95 % CI 1.14-2.10, I (2) = 64 %) but not in Caucasian. IL4RA Ile50 Val as well as Ser478Pro polymorphisms were not associated with AR susceptibility both in Asian and in Caucasian. Gene-gene and gene-environment interactions should be investigated in the future. PMID- 24337882 TI - Sodium-dependent transporters in health and disease--a special issue. PMID- 24337883 TI - The association of vitamin D supplementation with the risk of cancer in postmenopausal women. AB - PURPOSE: There is inconclusive evidence on whether vitamin D therapy reduces cancer risk. We investigated the effect of vitamin D (+/-calcium) supplementation on the risk of breast, ovarian, uterine, colorectal, and lung cancer in women. METHODS: We conducted a case-control study using the UK Clinical Practice Research Datalink (CPRD); cases were women aged >=55 years with a first diagnosis of either breast, colorectal, lung, ovarian, or uterine cancer between 2002 and 2009, with at least 5 years of CPRD follow-up prior to the date of diagnosis, and controls were women without cancer, frequency-matched to cases by year of birth, date of study entry, length of follow-up, and general practice. The association of vitamin D supplementation with the odds of developing each cancer was determined using multivariable logistic regression, controlling for body mass index, smoking, alcohol, and deprivation. RESULTS: Ninety-seven percent of women took vitamin D with a calcium supplement. Exposure to three or more prescriptions of vitamin D was associated with a 17 % reduced odds (95 % CI 0.71-0.97) of breast cancer versus 1-2 prescriptions, but this effect disappeared when omitting women first exposed within a year of diagnosis (OR 1.0, 95 % CI 0.82-1.23). Having more than 10 prescriptions of vitamin D was associated with a 17 % lower odds (95 % CI 0.65-1.06) of colorectal cancer, but the estimates are imprecise. There was little evidence of associations of supplements with lung or gynecological cancers. CONCLUSION: We found little evidence that vitamin D (largely with calcium) supplementation is associated with decreased breast, lung, ovarian, and uterine cancer risk. There is a possible protective association between having more than 10 prescriptions of vitamin D supplements and colorectal cancer, but it requires further investigation. PMID- 24337881 TI - The SLC6 transporters: perspectives on structure, functions, regulation, and models for transporter dysfunction. AB - The human SLC6 family is composed of approximately 20 structurally related symporters (co-transporters) that use the transmembrane electrochemical gradient to actively import their substrates into cells. Approximately half of the substrates of these transporters are amino acids, with others transporting biogenic amines and/or closely related compounds, such as nutrients and compatible osmolytes. In this short review, five leaders in the field discuss a number of currently important research themes that involve SLC6 transporters, highlighting the integrative role they play across a wide spectrum of different functions. The first essay, by Gary Rudnick, describes the molecular mechanism of their coupled transport which is being progressively better understood based on new crystal structures, functional studies, and modeling. Next, the question of multiple levels of transporter regulation is discussed by Reinhard Kramer, in the context of osmoregulation and stress response by the related bacterial betaine transporter BetP. The role of selected members of the human SLC6 family that function as nutrient amino acid transporters is then reviewed by Francois Verrey. He discusses how some of these transporters mediate the active uptake of (essential) amino acids into epithelial cells of the gut and the kidney tubule to support systemic amino acid requirements, whereas others are expressed in specific cells to support their specialized metabolism and/or growth. The most extensively studied members of the human SLC6 family are neurotransmitter reuptake transporters, many of which are important drug targets for the treatment of neuropsychiatric disorders. Randy Blakely discusses the role of posttranscriptional modifications of these proteins in regulating transporter subcellular localization and activity state. Finally, Dennis Murphy reviews how natural gene variants and mouse genetic models display consistent behavioral alterations that relate to altered extracellular neurotransmitter levels. PMID- 24337884 TI - Safety and patient satisfaction of early diet after endoscopic submucosal dissection for gastric epithelial neoplasia: a prospective, randomized study. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is a standard treatment for gastric neoplasia limited to the mucosa without lymph node metastasis. However, there are neither standardized guidelines nor studies on the best time to start oral intake after ESD. The aim of this study was to compare patient satisfaction, safety, length of hospital stay, and economic feasibility between an early post ESD diet and the conventional immediate fasting protocol. METHODS: A total of 130 patients with 156 gastric epithelial neoplasias who underwent ESD by a single expert endoscopist were consecutively and prospectively enrolled. Enrolled patients were randomized to an early diet group or a control group. The early diet group started meals as a clear liquid diet on day 0, and a soft diet and general diet in sequence on day 1. The fasting group was fasted for 2 days. Patients in both groups underwent second-look endoscopy within 2 days following ESD and follow-up endoscopy after 2 months. RESULTS: In the course of the study, ten patients were excluded. The total number of patients in the early diet group and control group was 63 and 57, respectively. Mean age was 62 years (+/-9.4). There were no significant differences in clinicopathologic conditions or endoscopic results such as procedure time or size of lesions between the two groups. There were no significant differences in abdominal pain score, rate of post-ESD bleeding or healing rate of ESD-induced ulcer between the two groups. However, the early diet protocol led to significantly higher patient satisfaction (p = 0.001), lower hospital costs (p < 0.001), and shorter hospital stay (p < 0.001) than the conventional fasting protocol. CONCLUSIONS: An early post-ESD diet protocol provides higher patient satisfaction, is more cost effective, decreases hospital stay, and does not influence complication rates such as post ESD bleeding, abdominal pain, or ulcer healing compared with the conventional fasting protocol. PMID- 24337885 TI - Endoscopic simulator curriculum improves colonoscopy performance in novice surgical interns as demonstrated in a swine model. AB - INTRODUCTION: The purpose of this study was to determine whether independent virtual endoscopic training accelerates the acquisition of endoscopic skill by novice surgical interns. METHODS: Nine novice surgical interns participated in a prospective study comparing colonoscopy performance in a swine model before and after an independent simulator curriculum. An independent observer evaluated each intern for the ability to reach the cecum within 20 min and technical ability as determined by Global Assessment of Gastrointestinal Endoscopic Skills- Colonoscopy (GAGES-C) score and performance compared. In addition, at the conclusion of training, a post test of two basic simulated colonoscopy modules was completed and metrics evaluated. As a control, three attending physicians who routinely perform colonoscopy also completed colonoscopy in the swine model. RESULTS: Prior to endoscopic training, one (11 %) intern successfully intubated the cecum in 19.56 min. Following training, six (67 %) interns reached the cecum with mean time of 9.2 min (p < 0.05). Statistically significant improvement was demonstrated in four out of five GAGES-C criteria. All three experts reached the cecum, with a mean time of 4.40 min. Comparison of expert and post-curriculum intern times demonstrated the experts to be significantly faster (p < 0.05). Comparison of interns who were and were not able to reach the cecum following the simulator curriculum demonstrated significantly improved GI MentorTM performance in the efficiency (79 vs. 67.1 %, p = 0.05) and time to cecum (3.37 vs. 5.59 min, p = 0.01) metrics. No other significant difference was demonstrated in GAGES-C categories or other simulator parameter. CONCLUSION: Simulator training on the GI MentorTM alone significantly improved endoscopic skills in novice surgical interns as demonstrated in a swine model. This study also identified parameters on the GI MentorTM that could indicate 'clinical readiness'. This study supports the role for endoscopic simulator training in surgical resident education as an adjunct to clinical experience. PMID- 24337886 TI - Outcomes of distal humerus diaphyseal injuries fixed with a single-column anatomic plate. AB - PURPOSE: The locking compression extra-articular distal humerus plate (EADHP) is an anatomically shaped, angular stable single-column fixation system for distal third humerus fractures. The purpose of this retrospective study was to evaluate clinical and radiographic outcomes after open reduction and internal fixation of distal humerus fractures with this device. METHODS: Twenty-one consecutive patients with distal humerus fractures were treated with the EADHP system between February 2006 and June 2012. Of these, 19 were clinically and radiographically evaluated after a mean follow-up of 10.4 months. Follow-up assessment included anteroposterior and lateral radiographs, assessment of range of motion (ROM), pain according to a visual analogue scale (VAS) and Disabilities of the Arm, Shoulder and Hand (DASH) score. RESULTS: All fractures demonstrated satisfactory reduction and healing at an average of 7.3 months. One patient showed post operative sensory ulnar neuropathy that recovered completely, and nine patients had a preoperative radial nerve palsy, which recovered spontaneously following exploration and plating. Mean post-operative ROM was as follows: flexion 126 degrees , extension -7 degrees , pronation 82 degrees and supination 83 degrees . The VAS score was zero points in eight patients, while the mean DASH score was 25.8 points. CONCLUSIONS: For extra-articular distal humerus fractures, including high-energy injuries often seen in gunshot wounds or motor vehicle injuries, the anatomically shaped angular stable single-column plate provides satisfactory clinical and radiographic results and serves as a valuable tool in the treatment of these injuries. PMID- 24337887 TI - Hemodynamics and progression of a hypervascular focus in a borderline lesion of hepatocellular carcinoma: analysis by angiography-assisted CT and histopathology. AB - PURPOSE: To investigate the hemodynamics and progression of a hypervascular focus (HF) in a borderline lesion by dual-phase CT during hepatic arteriography (CTHA) and reveal the process of the transformation to hypervascular overt hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This study was performed with the approval of our institutional ethics committee, and informed consent for the retrospective usage of clinical materials was obtained from all the patients. The 121 nodules in 76 consecutive patients with liver cirrhosis and chronic hepatitis showing an HF in a borderline lesion on angiography-assisted CT were analyzed. Hemodynamic changes were observed in 24 patients who underwent repeated angiography-assisted CT. Histopathological analysis was conducted in eight nodules. RESULTS: HF was classifiable into type A (stain disappeared), B (stain prolonged), C (stain was washed out and corona-like drainage into the outer nodule was seen) and D (stain was washed out and corona-like drainage into the whole outer nodule was seen) on the late phase of CTHA and was seen to progress in this order on follow-up observation. Histopathologically, de-differentiated foci showed significantly higher expression of sinusoidal capillarization and unpaired arteries than background nodules and showed pseudocapsule, compressive and replacing growth at the border of the background nodule. CONCLUSION: HF showed multi-step progression and transformation to hypervascular overt HCC. PMID- 24337888 TI - The birth of the photosynthetic reaction center: the story of Lou Duysens. PMID- 24337889 TI - Next gen ARTs: what lies ahead? PMID- 24337890 TI - Sevoflurane induces cardioprotection through reactive oxygen species-mediated upregulation of autophagy in isolated guinea pig hearts. AB - PURPOSE: Sevoflurane increases reactive oxygen species (ROS), which mediate cardioprotection against myocardial ischemia-reperfusion injury. Emerging evidence suggests that autophagy is involved in cardioprotection. We examined whether reactive oxygen species mediate sevoflurane preconditioning through autophagy. METHODS: Isolated guinea pigs hearts were subjected to 30 min ischemia followed by 120 min reperfusion (control). Anesthetic preconditioning was elicited with 2 % sevoflurane for 10 min before ischemia (SEVO). The ROS scavenger, N-(2-mercaptopropionyl) glycine (MPG, 1 mmol/l), was administered starting 30 min before ischemia to sevoflurane-treated (SEVO + MPG) or non sevoflurane-treated (MPG) hearts. Infarct size was determined by triphenyltetrazolium chloride stain. Tissue samples were obtained after reperfusion to determine autophagy-related protein (microtubule-associated protein light chain I and II: LC3-I, -II) and 5' AMP-activated protein kinase (AMPK) expression using Western blot analysis. Electron microscopy was used to detect autophagosomes. RESULTS: Infarct size was significantly reduced and there were more abundant autophagosomes in SEVO compared with control. Western blot analysis revealed that the ratio of LC3-II/I and phosphorylation of AMPK were significantly increased in SEVO. These effects were abolished by MPG. CONCLUSIONS: Sevoflurane induces cardioprotection through ROS-mediated upregulation of autophagy. PMID- 24337891 TI - The human right to water: the importance of domestic and productive water rights. AB - The United Nations (UN) Universal Declaration of Human Rights engenders important state commitments to respect, fulfill, and protect a broad range of socio economic rights. In 2010, a milestone was reached when the UN General Assembly recognized the human right to safe and clean drinking water and sanitation. However, water plays an important role in realizing other human rights such as the right to food and livelihoods, and in realizing the Convention on the Elimination of All Forms of Discrimination against Women. These broader water related rights have been recognized but have not yet been operationalized. This paper unravels these broader water-related rights in a more holistic interpretation of existing international human rights law. By focusing on an emerging approach to water services provision--known as 'domestic-plus' services- the paper argues how this approach operationalizes a comprehensive range of socio economic rights in rural and peri-urban areas. Domestic-plus services provide water for domestic and productive uses around homesteads, which challenges the widespread practice in the public sector of planning and designing water infrastructure for a single-use. Evidence is presented to show that people in rural communities are already using their water supplies planned for domestic uses to support a wide range of productive activities. Domestic-plus services recognize and plan for these multiple-uses, while respecting the priority for clean and safe drinking water. The paper concludes that domestic-plus services operationalize the obligation to progressively fulfill a comprehensive range of indivisible socio-economic rights in rural and peri-urban areas. PMID- 24337892 TI - A scoring system to predict inferior mesenteric artery lymph node metastasis and prognostic value of its involvement in rectal cancer. AB - PURPOSE: The aim of this study is to establish a prediction scoring system for inferior mesenteric artery (IMA) lymph node metastasis and to assess the prognostic impact of dissection of positive IMA node on patients with stage III rectal cancer. METHODS: A retrospective study was performed in 264 patients with stage III rectal cancer undergoing curative surgery. Clinicopathological, survival, and recurrence data were compared between 29 patients with positive IMA nodes and 235 patients with negative IMA nodes. Clinicopathological data which were found to be significantly associated with IMA nodal status were incorporated into a scoring system. RESULTS: In the training samples, tumor differentiation and preoperative serum CEA were significant predictors of IMA node metastasis in multivariate analysis, which were incorporated into a scoring system. Using receiver operating characteristic curve analysis, we determined a cutoff value of 46.5 for scores, at which the system's sensitivity was 86 % and specificity 61 %. When applied to testing sample, the sensitivity was 80 % and specificity 60 %. Survival analysis showed that 5-year disease-free survival rate (5-DFS) and 5 year overall survival (5-OS) in the positive IMA node group (24.4 and 27.6 %, respectively) were significantly lower than in the negative IMA node group (61.8 and 71.3 %, respectively) (P < 0.001). Furthermore, multivariate analysis indicated that IMA lymph node metastasis was an unfavorable independent prognostic factor for 5-DFS and 5-OS. CONCLUSIONS: IMA lymph node metastasis is an independent poor prognostic factor for stage III rectal cancer. The prediction scoring system for IMA node metastasis would be beneficial in determining the appropriate level of IMA ligation. PMID- 24337893 TI - Allograft inflammatory factor-1 is an independent prognostic indicator that regulates beta-catenin in gastric cancer. AB - Previous studies have revealed that expression of allograft inflammatory factor-1 (AIF-1) protein appears to be increased in malignancies and is correlated with a poorer prognosis in cervical cancer, while its role in gastric cancer has not been reported. We analyzed the expression of AIF-1 in 78 cancer lesions and the corresponding non-cancerous tissues by immunohistochemistry. In contrast with other cancers, we found that AIF-1 protein levels were significantly decreased in 53 of the 78 (67.9%) gastric cancer tissues when compared with the matched normal tissues. This was further confirmed using 7 pairs of fresh gastric cancer tissues and matched adjacent normal tissues. Low tumoral AIF-1 expression was significantly correlated with less favorable clinicopathological characteristics, as well as with reduced overall survival (P<0.001) in the gastric cancer patients. Furthermore, knockdown of AIF-1 obviously increased proliferation, migration and beta-catenin expression in BGC-823 and SGC-7901 gastric cancer cells. Taken together, for the first time, we provide evidence that the level of AIF-1 expression may serve as a protective prognostic indicator for gastric cancer. PMID- 24337894 TI - Income-related inequalities and inequities in health care services utilisation in 18 selected OECD countries. AB - A key policy objective in OECD countries is to achieve adequate access to health care for all people on the basis of need. Previous studies have shown that there are inequities in health care services utilisation (HCSU) in the OECD area. In recent years, measures have been taken to enhance health care access. This paper re-examines income-related inequities in doctor visits among 18 selected OECD countries, updating previous results for 12 countries with 2006-2009 data, and including six new countries. Inequalities in preventive care services are also considered for the first time. The indirect standardisation procedure is used to estimate the need-adjusted HCSU and concentration indexes are derived to gauge inequalities and inequities. Overall, inequities in HCSU remain present in OECD countries. In most countries, for the same health care needs, people with higher incomes are more likely to consult a doctor than those with lower incomes. Pro rich inequalities in dental visits and cancer screening uptake are also found in nearly all countries, although the magnitude of these varies among countries. These findings suggest that further monitoring of inequalities is essential in order to assess whether country policy objectives are achieved on a regular basis. PMID- 24337895 TI - Disparities in unmet dental need and dental care received by pregnant women in Maryland. AB - To examine prenatal dental care needs, utilization and oral health counseling among Maryland women who delivered a live infant during 2001-2003 and identify the factors associated with having a dental visit and having an unmet dental need during pregnancy. Pregnancy Risk Assessment Monitoring System is an ongoing population based surveillance system that collects information of women's attitudes and experiences before, during, and shortly after pregnancy. Logistic regression was used to model dental visits and unmet dental need using predictor variables for Maryland 2001-2003 births. Less than half of all women reported having a dental visit and receiving oral health advice during pregnancy. Twenty five percent of women reported a need for dental care, of which 33 % did not receive dental care despite their perceived need. Multivariate modeling revealed that racial minorities, women who were not married and those with annual income <$40,000 were least likely to have a dental visit. Women who were not married, had low annual income, were older than 40 years of age, had an unintended pregnancy and received prenatal care later than desired were most likely to have an unmet dental need during pregnancy. Despite reported needs and existing recommendations to include oral health as a component of prenatal care, less than half of pregnant women have a dental visit during their pregnancy. One-third of women with a dental problem did not have a dental visit highlighting the unmet need for dental care during pregnancy. PMID- 24337896 TI - A pilot randomized controlled trial comparing bismuth iodine paraffin paste external ear pack and no ear pack after middle ear surgery. AB - To pilot a substantive randomized control trial comparing post-operative external ear canal pack with no ear pack after middle ear surgery, 32 adults undergoing primary posterior bony canal wall preserving middle ear surgery were randomized to have either a bismuth iodoform paraffin paste pack or no ear pack post operatively. Outcome measures included clinician- and patient-recorded visual analogue scale scores for ear signs and symptoms at 3 weeks and 3 months and audiometric findings at 3 months post-operatively. There was no statistically significant inter-group difference in 3-week clinician and patient cumulative scores for ear signs and symptoms. There was also no significant difference in graft take rate, appearance of ear canals and audiometric results in either group at 3 months. No difference in ear symptoms, clinician findings or hearing was demonstrated between patients with a post-operative pack compared to those without a pack following middle ear surgery in this pilot study. PMID- 24337897 TI - Safety of transtympanic application of 4 % manuka honey in a chinchilla animal model. AB - The antimicrobial and anti-biofilm properties of manuka honey (MH) are currently being explored in the treatment of chronic recalcitrant rhinosinusitis. Due to similarities between chronic rhinosinusitis and chronic otitis, manuka honey may find applications in the management of challenging cases of chronic otitis media implicating biofilms. The goal of this study was to investigate the safety of topical application of 4 % MH in the middle ear. Eleven adult female chinchillas had one of their ears randomly assigned to receive transtympanic 4 % MH, while the contralateral ear served as control. Auditory brainstem-evoked response (ABR) was performed before and after MH application. The facial nerve function and vestibular system were assessed clinically. The animals were euthanized one month following the last application, and the cochleae samples were processed for light and scanning electron microscopy. There was no statistically significant differences between ABR thresholds in both control and experimental ears before and after the application of MH. No morphological differences were seen in both groups of cochleae. The outer hair cell counts for both groups were comparable. Our results suggest that 4 % MH appears not toxic to the cells of the cochlea after 4 weeks of application. The long-term effects of prolonged contact on the structure and function of the cochlea however need further investigations. PMID- 24337898 TI - Functional outcomes following endoscopic laser cricopharyngeal myotomy with mucosal repair. AB - Endoscopic laser cricopharyngeal myotomy is an effective treatment for cricopharyngeal dysfunction, but concern remains over the risk of serious complications following the procedure. Some authors have therefore considered endoscopic laser cricopharyngeal myotomy with mucosal repair; however, outcome data for the procedure is scanty. This study aims to identify functional outcomes in a series of patients following endoscopic laser cricopharyngeal myotomy with mucosal repair. Endoscopic laser cricopharyngeal myotomy with mucosal repair was performed on 38 subjects in two centres over a period of 33 months. Pre- and post operative outcomes were evaluated in 32 subjects using the Sydney Swallow Questionnaire and Reflux Symptom Index. An improvement in swallowing scores was seen in 30 subjects (94%, p < 0.001). The Reflux Symptom Index improved 28 subjects (88%, p < 0.001). Mean procedure time was 58 min. One subject (2.6%) developed mediastinitis following surgery, and four experienced (12.5%) a recurrence of dysphagic symptoms. Endoscopic laser cricopharyngeal myotomy with mucosal repair is an effective treatment for cricopharyngeal dysfunction. The complication rate observed in this study was comparable or lower than previously reported studies into endoscopic laser cricopharyngeal myotomy without mucosal repair. Larger studies may be required to determine the additional benefit of mucosal repair over endoscopic laser cricopharyngeal myotomy alone. PMID- 24337899 TI - Medium-term results of combined treatment with transcranial magnetic stimulation and antidepressant drug for chronic tinnitus. AB - We compared the effects of repetitive transcranial magnetic stimulation (rTMS) and paroxetine [a selective serotonin reuptake inhibitor (SSRI)] on tinnitus in terms of effectiveness and medium-term results. This is a randomised, double blind, placebo-controlled study. Seventy-five patients with moderate tinnitus were divided into five equal groups. Each group was treated for 1 month as follows: group 1 received rTMS alone at 1 Hz frequency; group 2 received rTMS alone at 10 Hz frequency; group 3 received rTMS at 1 Hz frequency combined with paroxetine; group 4 received paroxetine alone; and group 5 received a placebo (sham rTMS). Participants were tested using the Tinnitus Handicap Inventory (THI), Tinnitus Severity Index (TSI), the Beck Anxiety Scoring (BAS), and Psychiatric Sign Screening (PSS) tests. THI, TSI, BAS, and PSS were measured prior to treatment, and at the first and sixth month post-treatment. The THI and TSI scores improved after treatment in all groups, except the placebo group. The THI scores in groups 1 and 2 showed a statistically significant improvement after the first and sixth month compared to pretreatment scores, whereas a significant improvement in THI scores occurred only after the sixth month in groups 3 and 4. The TSI scores in group 3 showed a significant improvement at the first and sixth month marks after treatment. The rTMS and SSRI play potential roles in the reduction of tinnitus severity, but without cumulative or synergistic effects when a combination of treatment regimens is applied. These positive effects might be due to the relationship between the auditory cortex areas related to emotions and tinnitus. PMID- 24337900 TI - Elective management of cervical and parotid lymph nodes in stage N0 cutaneous squamous cell carcinoma of the head and neck: a decision analysis. AB - There is uncertainty regarding the threshold for recommending elective regional nodal treatment in the management of stage N0 cutaneous squamous cell carcinoma of the head and neck (cSCCHN). Elective treatment in the form of nodal surgery or irradiation is associated with morbidity. However, patients managed with careful observation sometimes present with advanced disease which often require more extensive therapy or may be unsalvageable altogether. We used decision analysis to examine the tradeoffs and benefits of different management approaches in the stage N0 patient. A decision tree comprising the three different treatment strategies was built: surveillance, elective nodal dissection (END) and elective nodal irradiation (ENI). Probabilities of nodal recurrence and likelihood of successful salvage were obtained from the literature. A convenience sample of patients previously treated for metastatic and non-metastatic cSCCHN was interviewed using the standard gamble technique to determine utility for post treatment health states. Sensitivity analysis was performed and the effect on the expected utility was examined. When the probability of occult metastasis was >19 %, ENI resulted in a higher expected utility than observation. When the probability of occult metastasis exceeds 25 %, END has a higher expected utility compared to observation. Given the current available evidence, a wait-and-see approach is justified in patients with a probability of occult metastases <19 %. PMID- 24337901 TI - Insights into cardiovascular effects of proline-rich oligopeptide (Bj-PRO-10c) revealed by structure-activity analyses: dissociation of antihypertensive and bradycardic effects. AB - We have previously reported that the proline-rich decapeptide from Bothrops jararaca (Bj-PRO-10c) causes potent and sustained antihypertensive and bradycardic effects in SHR. These activities are independent of ACE inhibition. In the present study, we used the Ala-scan approach to evaluate the importance of each amino acid within the sequence of Bj-PRO-10c (Pyr(1)-Asn(2)-Trp(3)-Pro(4) His(5)-Pro(6)-Gln(7)-Ile(8)-Pro(9)-Pro(10)). The antihypertensive and bradycardic effects of the analogues Bj-PRO-10c Ala(3), Bj-PRO-10c Ala(7), Bj-PRO-10c Ala(8) were similar to those of Bj-PRO-10c, whereas the analogues Bj-PRO-10c Ala(2), Bj PRO-10c Ala(4), Bj-PRO-10c Ala(5), Bj-PRO-10c Ala(9), and Bj-PRO-10c Ala(10) kept the antihypertensive activity and lost bradycardic activity considerably. In contrast, Bj-PRO-10c Ala(1) and Bj-PRO-10c Ala(6) were unable to provoke any cardiovascular activity. In summary, we demonstrated that (1) the Pyr(1) and Pro(6) residues are essential for both, the antihypertensive and bradycardic effects of Bj-PRO-10c; (2) Ala-scan approach allowed dissociating blood pressure reduction and bradycardic effects. Conformational properties of the peptides were examined by means of circular dichroism (CD) spectroscopy. The different Ala-scan analogues caused either an increase or decrease in the type II polyproline helix content compared to Bj-PRO-10c. The complete loss of activity of the Pro(6) -> Ala(6) mutant is probably due to the fact that in the parent peptide the His(5) Pro(6) bond can exist in the cis configuration, which could correspond to the conformation of this bond in the bound state. Current data support the Bj-PRO-10c as a promising leader prototype to develop new agents to treat cardiovascular diseases and its co-morbidities. PMID- 24337902 TI - The control of hyperhomocysteinemia through thiol exchange mechanisms by mesna. AB - In hyperhomocysteinemic patients, after reaction with homocysteine-albumin mixed disulfides (HSS-ALB), mesna (MSH) forms the mixed disulfide with Hcy (HSSM) which can be removed by renal clearance, thus reducing the plasma concentration of total homocysteine (tHcy). In order to assess the HSS-ALB dethiolation via thiol exchange reactions, the distribution of redox species of cysteine, cysteinylglycine, homocysteine and glutathione was investigated in the plasma of healthy subjects: (i) in vitro, after addition of 35 MUM reduced homocysteine (HSH) to plasma for 72 h, followed by MSH addition (at the concentration range 10 600 MUM) for 25 min; (ii) in vivo, after oral treatment with methionine (methionine, 200 mg/kg body weight, observation time 2-6 h). In both experiments the distribution of redox species, but not the total amount of each thiol, was modified by thiol exchange reactions of albumin and cystine, with changes thermodynamically related to the pKa values of thiols in the corresponding mixed disulfides. MSH provoked a dose-response reversal of the redox state of aged plasma, and the thiol action was confirmed by in vivo experiments. Since it was observed that the dimesna production could be detrimental for the in vivo optimization of HSSM formation, we assume that the best plasma tHcy lowering can be obtained at MSH doses producing the minimum dimesna concentration in each individual. PMID- 24337903 TI - Licochalcone A induces apoptosis through endoplasmic reticulum stress via a phospholipase Cgamma1-, Ca(2+)-, and reactive oxygen species-dependent pathway in HepG2 human hepatocellular carcinoma cells. AB - Licochalcone A (LicA), an estrogenic flavonoid, induces apoptosis in multiple types of cancer cells. In this study, the molecular mechanisms underlying the anti-cancer effects of LicA were investigated in HepG2 human hepatocellular carcinoma cells. LicA induced apoptotic cell death, activation of caspase-4, -9, and -3, and expression of endoplasmic reticulum (ER) stress-associated proteins, including C/EBP homologous protein (CHOP). Inhibition of ER stress by CHOP knockdown or treatment with the ER stress inhibitors, salubrinal and 4 phenylbutyric acid, reduced LicA-induced cell death. LicA also induced reactive oxygen species (ROS) accumulation and the anti-oxidant N-acetylcysteine reduced LicA-induced cell death and CHOP expression. In addition, LicA increased the levels of cytosolic Ca(2+), which was blocked by 2-aminoethoxydiphenyl borate (an antagonist of inositol 1,4,5-trisphosphate receptor) and BAPTA-AM (an intracellular Ca(2+) chelator). 2-Aminoethoxydiphenyl borate and BAPTA-AM inhibited LicA-induced cell death. Interestingly, LicA induced phosphorylation of phospholipase Cgamma1 (PLCgamma1) and inhibition of PLCgamma1 reduced cell death and ER stress. Moreover, the multi-targeted receptor tyrosine kinase inhibitors, sorafenib and sunitinib, reduced LicA-induced cell death, ER stress, and cytosolic Ca(2+) and ROS accumulation. Finally, LicA induced phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) and c-Met receptor and inhibition of both receptors by co-transfection with VEGFR2 and c-Met siRNAs reversed LicA-induced cell death, Ca(2+) increase, and CHOP expression. Taken together, these findings suggest that induction of ER stress via a PLCgamma1-, Ca(2+)-, and ROS-dependent pathway may be an important mechanism by which LicA induces apoptosis in HepG2 hepatocellular carcinoma cells. PMID- 24337904 TI - Chemical accident at Hoechst AG Frankfurt/Main, Germany, 1993: a 15 year follow up analysis of mortality. PMID- 24337905 TI - Internet gambling in problem gambling college students. AB - Internet gambling is popular in college students and associated with problem gambling behaviors. This study evaluated Internet gambling in 117 students participating in study evaluating brief interventions to reduce gambling; the brief interventions consisted of minimal advice, motivational enhancement therapy, and cognitive-behavioral therapy (1-4 sessions). Compared to their counterparts who did not gamble via the Internet (n = 60), those who reported recent Internet gambling (n = 57) wagered in greater frequencies and amounts and reported missing school more often and more problems with family and anxiety due to gambling. Recent Internet gamblers demonstrated similar reductions in gambling over time and in response to the brief interventions as non-Internet gamblers. These data suggest that Internet gambling is common in problem gambling college students, and students who wager over the Internet can benefit from brief interventions. PMID- 24337906 TI - Multifocal fibrosing thyroiditis and its association with papillary thyroid carcinoma using BRAF pyrosequencing. AB - Multifocal fibrosing thyroiditis (MFT) is characterized by numerous foci of fibrosis in a stellate configuration with fibroelastotic and fibroblastic centers entrapping epithelial structures. MFT has been proposed as a risk factor for papillary thyroid carcinoma (PTC) development. We attempted to identify whether MFT showed such molecular changes and could possibly be related to PTC. We identified seven cases of PTC with MFT in our institutional pathology database and personal consult service of one of the authors (VAL) for the years 1999 to 2012. Areas of PTC, MFT, and normal tissue were selected for BRAF analysis. Macro dissection, DNA extraction and PCR amplification, and pyrosequencing were performed to detect BRAF mutations in codon 600. All of the MFT lesions and normal thyroid tissue were negative for BRAF mutations. Of the seven PTCs analyzed, five (71 %) were negative for BRAF mutations, while two cases were positive. In our study, none of the MFT lesions harbored BRAF mutations, whereas 29 % (two of seven) PTCs in the same gland were positive. Hence, in this small study, we found no evidence that the MFT lesion is a direct precursor to PTC. It is likely an incidental bystander in the process and a reflection of the background thyroiditis. PMID- 24337907 TI - The contribution of private and public information in foraging by Australasian gannets. AB - Predators that forage on foods with temporally and spatially patchy distributions may rely on private or public sources of information to enhance their chances of foraging success. Using GPS tracking, field observations, and videography, we examined potential sites and mechanisms of information acquisition in departures for foraging trips by colonially breeding Australasian gannets (Morus serrator). Analyses of the bill-fencing ceremony between mated pairs of breeding gannets did not detect correlations between parameters of this reciprocal behavior and foraging trips, as would have been predicted if gannets used this behavior as a source of private information. Instead, 60% of the departing birds flew directly to join water rafts of other conspecific en route to the feeding grounds. The departure of solitary birds from the water rafts was synchronized (within 60 s) with the arrival of incoming foragers and also among departing birds. Furthermore, solitary departing birds from the rafts left in the same directional quadrant (90o slices) as the prior arriving (67%) and also prior departing forager (79%). When associated plunge dives of conspecific were visible from the colony, providing a public source of information, gannets more often departed from the water rafts in groups. Our study thus provides evidence for the use of water rafts, but not the nest site, as locations of information transfer, and also confirms the use of local enhancement as a strategy for foraging flights by Australasian gannets. PMID- 24337908 TI - Downregulation of uncoupling protein-1 mRNA expression and hypoadiponectinemia in a mouse model of sleep apnea. AB - PURPOSE: The knowledge on the effect of intermittent hypoxia on adipose tissue mediated processes is incipient. The aim of the present study was to assess the effect of a sleep apnea model on a limited set of specific molecular, biochemical, histological, and behavioral parameters of adipose tissue function. METHODS: Mice were exposed to either intermittent hypoxia or sham hypoxia during 8 h a day for 37 days. Uncoupling protein-1 expression in brown adipose tissue was measured by real-time PCR and immunohistochemistry. Digital quantification of adipose cells and immunohistochemistry of uncoupling protein-1 were performed to determine cell dimensions, positive area, and staining intensity. Serum levels of leptin, adiponectin, and cortisol were measured by ELISA. RESULTS: In comparison with the control group, animals in the hypoxia group had significantly lower chow ingestion, weight gain, and smaller white and brown adipocytes on histological examination. Adiponectin levels were also lower in the hypoxia group. Uncoupling protein-1 mRNA was abolished in the mice exposed to hypoxia; accordingly, fewer cells positive for uncoupling protein-1 and lighter staining intensity were observed in brown adipocytes. CONCLUSIONS: An experimental model of sleep apnea produced changes in uncoupling protein-1 expression and adiponectin levels. These results confirm previous findings on the response of brown adipose tissue to intermittent hypoxia and indicate a yet-unknown interference of intermittent hypoxia on energy control, which may participate in the propensity to weight gain observed in patients with sleep apnea. Brown adipose tissue activity in this patient population needs to be further investigated. PMID- 24337910 TI - Editorial by European Radiology's new Editor in Chief, Maximilian F. Reiser. PMID- 24337909 TI - Ins and outs of T-channel structure function. AB - We review the ins and outs of T-channel structure, focusing on the extracellular high-affinity metal-binding site and intracellular loops. The high-affinity metal binding site was localized to repeat I of Cav3.2. Interestingly, a similar binding site was found in the high voltage-activated Cav2.3 channel where it controls the channels' voltage dependence. Histidine at position 191 has a particularly interesting role in the high-affinity binding site, and its modification plays an important role in channel regulation by pharmacological agents that alter redox reactions. The intracellular loop connecting repeats I and II plays two important roles in Cav3.2 properties: one, its gating; and two, its surface expression. These studies have also identified a highly conserved intracellular gating brake that is predicted to form a helix-loop-helix structure. We conclude that the gating brake establishes important contacts with the gating machinery, thereby stabilizing a closed state of T-channels. This interaction is disrupted by depolarization, allowing the S6 segments to open and allowing Ca(2+) ions to flow through. Studies in cultured hippocampal neurons provided novel insights into how mutations found in idiopathic generalized epilepsy patients increase seizure susceptibility by both altering T-current pacemaker currents and by activating Ca-activated transcription factors that regulate dendritic arborization. These studies reveal novel roles for T-channels to control cellular physiology. PMID- 24337911 TI - MRI differentiation of low-grade from high-grade appendicular chondrosarcoma. AB - OBJECTIVES: To identify magnetic resonance imaging (MRI) features which differentiate low-grade chondral lesions (atypical cartilaginous tumours/grade 1 chondrosarcoma) from high-grade chondrosarcomas (grade 2, grade 3 and dedifferentiated chondrosarcoma) of the major long bones. METHODS: We identified all patients treated for central atypical cartilaginous tumours and central chondrosarcoma of major long bones (humerus, femur, tibia) over a 13-year period. The MRI studies were assessed for the following features: bone marrow oedema, soft tissue oedema, bone expansion, cortical thickening, cortical destruction, active periostitis, soft tissue mass and tumour length. The MRI-features were compared with the histopathological tumour grading using univariate, multivariate logistic regression and receiver operating characteristic curve (ROC) analyses. RESULTS: One hundred and seventy-nine tumours were included in this retrospective study. There were 28 atypical cartilaginous tumours, 79 grade 1 chondrosarcomas, 36 grade 2 chondrosarcomas, 13 grade 3 chondrosarcomas and 23 dedifferentiated chondrosarcomas. Multivariate analysis demonstrated that bone expansion (P = 0.001), active periostitis (P = 0.001), soft tissue mass (P < 0.001) and tumour length (P < 0.001) were statistically significant differentiating factors between low-grade and high-grade chondral lesions with an area under the ROC curve of 0.956. CONCLUSIONS: On MRI, bone expansion, active periostitis, soft tissue mass and tumour length can reliably differentiate high-grade chondrosarcomas from low grade chondral lesions of the major long bones. KEY POINTS: * Accurate differentiation of low-grade from high-grade chondrosarcomas is essential before surgery * MRI can reliably differentiate high-grade from low-grade chondrosarcomas of long bone * Differentiating features are bone expansion, periostitis, soft tissue mass and tumour length * Presence of these four MRI features demonstrated a diagnostic accuracy (AUC) of 95.6 % * The findings may result in more accurate diagnosis before definitive surgery. PMID- 24337912 TI - Diffusion-weighted imaging of focal renal lesions: a meta-analysis. AB - OBJECTIVES: Contrast-enhanced MRI can only distinguish to a limited extent between malignant and benign focal renal lesions. The aim of this meta-analysis is to review renal diffusion-weighted imaging (DWI) to compare apparent diffusion coefficient (ADC) values for different renal lesions that can be applied in clinical practice. METHODS: A PubMed search was performed to identify relevant articles published 2004-2011 on renal DWI of focal renal lesions. ADC values were extracted by lesion type to determine whether benign or malignant. The data table was finalised in a consensus read. ADC values were evaluated statistically using meta-regression based on a linear mixed model. Two-sided P value <5 % indicated statistical significance. RESULTS: The meta-analysis is based on 17 studies with 764 patients. Renal cell carcinomas have significant lower ADC values than benign tissue (1.61 +/- 0.08 * 10(-3) mm(2)/s vs 2.10 +/- 0.09 * 10(-3) mm(2)/s; P < 0.0001). Uroepithelial malignancies can be differentiated by lowest ADC values (1.30 +/- 0.11 * 10(-3) mm(2)/s). There is a significant difference between ADC values of renal cell carcinomas and oncocytomas (1.61 +/- 0.08 * 10(-3) mm(2)/s vs 2.00 +/- 0.08 * 10(-3) mm(2)/s; P < 0.0001). CONCLUSIONS: Evaluation of ADC values can help to determine between benign and malignant lesions in general but also seems able to differentiate oncocytomas from malignant tumours, hence potentially reducing the number of unnecessarily performed nephrectomies. KEY POINTS: * This meta-analysis assesses the role of diffusion-weighted MRI in renal lesions. * ADC values obtained by DW MRI have been compared for different renal lesions. * ADC values can help distinguish between benign and malignant tumours. * Differentiating oncocytomas from malignant tumours can potentially reduce inappropriate nephrectomies. PMID- 24337913 TI - Prevalence and clinical significance of incidental F18-FDG breast uptake: a systematic review and meta-analysis. AB - This review aims to analyse the published data on the prevalence and clinical significance of breast incidental F18-FDG uptake detected by PET or PET/CT (BIU). A comprehensive computer literature search of the PubMed/MEDLINE, Scopus and Embase databases for studies on BIU published through July 2013 was performed. Pooled prevalence and malignancy risk of BIU were calculated. The literature search revealed 42 articles, and 17 were selected. One study was excluded because of data overlap but four additional studies were found screening the references. Finally, 20 articles were included in the systematic review and 13 were eligible for a meta-analysis. The pooled prevalence of BIU on all scans was 0.4 % (95 % CI 0.23-0.61 %), the pooled prevalence on scans on female patients only was 0.82 % (95 % CI 0.51-1.2 %), the pooled risk of malignancy of BIU when further analysed was 48 % (95 % CI 38-58 %) and the pooled risk of malignancy of BIU with histological examination was 60 % (95 % CI 53-66 %). The most frequent malignant lesion detected was infiltrating ductal carcinoma. Despite being rare, the identification of BIU frequently signals the presence of an unsuspected subclinical lesion, which differs from the indicated reason for which the patient was initially scanned, and the risk of malignancy is very high. PMID- 24337915 TI - Objective analysis of surgeons' ergonomy during laparoendoscopic single-site surgery through the use of surface electromyography and a motion capture data glove. AB - BACKGROUND: Adding to the ergonomic inconveniences already presented by traditional laparoscopy (LAP), laparoendoscopic single-site (LESS) surgery has been found to entail other more specific problems, including greater reduction in movement freedom, in-line vision with loss of triangulation, and greater proximity of instruments. The objective of this study was to evaluate surgeons' ergonomy during LESS surgery, through the study of muscular activity, wrist angle, and hand movements, and compare it with conventional laparoscopy. METHODS: The study group was composed by 14 experienced laparoscopic surgeons, all right handed. Each one performed dissection tasks on a physical simulator through LAP and LESS approaches. For LAP, straight laparoscopic scissors and dissector were used, whilst for LESS articulating tip scissors and dissector were chosen. During both tasks, muscular activity of biceps brachii, triceps brachii, forearm flexors and extensors, and trapezius muscles was registered through surface electromyography. Simultaneously right-hand movements and wrist angles were obtained through a motion capture data glove (CyberGlove((r))), which allowed for the use of a modified RULA test applied to the recorded angles with subsequent establishment of risk levels for the wrist joint. RESULTS: Muscular activity for trapezius (LAP 6.94 +/- 4.12 vs. LESS 11.32 +/- 4.68; p <= 0.05) and forearm extensor muscles (LAP 9.2 +/- 2.45 vs. LESS 37.07 <= 16.05; p <= 0.001) was significantly lower in conventional laparoscopy compared with LESS approach. No statistical significance was obtained between the different sensors, except in 3 of the 11 analyzed CyberGlove((r)) sensors. The modified RULA test showed a score of 3 for laparoscopy (unacceptable), whereas for LESS a score of 2 was obtained (acceptable), with statistically significant differences between them (p <= 0.05). CONCLUSIONS: The LESS approach entails greater level of muscular activity in the trapezius and forearm extensor muscles, but we have found evidences of a better wrist position during LESS compared with traditional laparoscopy. PMID- 24337914 TI - Endoscopic submucosal dissection for gastric cancer: the influence of hospital volume on complications and length of stay. AB - BACKGROUND: Little information is available about the relationship between hospital volume and the clinical outcome of endoscopic submucosal dissection (ESD) for gastric cancer. The purpose of this study was to investigate the influence of hospital volume on clinical outcomes of ESD using a national administrative database. METHODS: A total of 27,385 patients treated with ESD for gastric cancer were referred to 867 hospitals between 2009 and 2011 in Japan. We collected patients' data from the administrative database to compare ESD-related complications and length of stay (LOS) in relation to hospital volume. Hospital volume was categorized into three groups based on the number of cases treated over the study period: low-volume hospitals (LVHs, <50 cases), medium-volume hospitals (MVHs, 50-100 cases), and high-volume hospitals (HVHs, >100 cases). These analyses were performed for each location of gastric cancer [upper (cardia and fundus), middle (body), and lower third (antrum and pylorus)]. RESULTS: Significant differences in ESD-related complications among the three hospital volume categories were observed for upper gastric cancer (6.5 % in LVHs vs. 5.2 % in MVHs vs. 3.4 % in HVHs; p = 0.017). Multiple logistic regression revealed that HVHs were significantly associated with decreased relative risk of ESD-related complications in upper gastric cancer (odds ratio for HVHs 0.51; 95 % confidence interval, 0.31-0.83, p = 0.007). However, no significant differences for ESD related complications were seen for middle and lower gastric cancers among the different hospital volume categories (p > 0.05). Additionally, hospital volume was significantly associated with a decreasing LOS for all locations of gastric cancers (p < 0.001). CONCLUSIONS: The present study has demonstrated that hospital volume was mainly associated with clinical outcome in patients with ESD for upper gastric cancer. Further studies for successive monitoring of outcomes of ESD should be conducted in the near future. PMID- 24337917 TI - Dynamic behaviour of lactate values during mild hypothermia in patients with cardiac arrest. AB - BACKGROUND AND METHODS: The present investigation was aimed at assessing the dynamic behaviour of lactate values during hypothermia in 33 patients with cardiac arrest. RESULTS: Fifteen patients died during intensive care stay (15/33, 45.5%). When compared to survivors, they were older (survivors 50.7 +/- 14.7 vs. non-survivors 70.1 +/- 10.4 years, p<0.001) and exhibited a significantly higher APACHE score (survivors 21.9 +/- 3.9 vs. non-survivors 27.5 +/- 4.6, p<0.001). A higher incidence of non-shockable rhythms was observed in non-survivors (p=0.026) who showed a longer collapse-recovery of spontaneous circulation time (p=0.01). During hypothermia, lactate values showed a progressive and significant decrease despite no significant change in mean arterial pressure and central venous pressure (i.e. independently of blood pressure values and volaemia). Lactate values when measured during hypothermia were related to in-intensive cardiac care unit (in-ICCU) death. CONCLUSION: In our series, lactate values measured during hypothermia hold a prognostic role in these patients since they are related to in ICCU death. PMID- 24337916 TI - Surgical technique of robotic D3 lymph node dissection around the inferior mesenteric artery with preservation of the left colic artery and autonomic nerves for the treatment of distal rectal cancer. AB - BACKGROUND: Our objective was to evaluate the quality of surgery regarding application of the robotic approach to perform D3 lymph node dissection over the inferior mesenteric artery (IMA) with preservation of the left colic artery (LCA) and autonomic nerves for the treatment of distal rectal cancer, which has not been reported before, although it has been successfully performed by some surgeons laparoscopically. METHODS: Patients with distal rectal cancer posing risk factors for anastomotic leakage were recruited and underwent the present robotic procedure, which was standardized and presented in the attached video file. Patients' surgical outcomes were prospectively evaluated. RESULTS: A total of 26 patients with distal rectal cancer were operated on via the present robotic approach. The number of cleared lymph nodes was 26.1 +/- 7.2 (range 10-44). The operation time was 307.3 +/- 74.1 min (including docking time). The blood loss was 190.5 +/- 225.8 ml. Anastomotic leakage occurred in one (1/16, 6 %) patient without preoperative chemoradiation therapy, and wound infection of port sites was detected in two (2/26, 7.6 %) patients. The patients had quick convalescence, as evaluated by the recovery of flatus passage (48.0 +/- 12.0 h), hospitalization (14.6 +/- 4.8 days), and degree of postoperative pain (2.5 +/- 0.5, visual analog scale). The median duration for indwelling urine Foley catheter was 6.0 days (range 3.0-28). The voiding function after removal of the urine Foley catheter was good (International Prostate Score Symptom [IPSS] 0-7) in 22 (84.6 %) patients, fair (IPSS 8-14) in three (11.5 %), and poor (IPSS 15-35) in one (3.8 %). The median time of return to partial activity, full activity, and work was 2.0, 4.0, and 6.0 weeks, respectively. CONCLUSIONS: By using the three-armed Da Vinci((r)) robotic system in our clinical setting, quality surgery of the D3 lymph node dissection around the IMA with preservation of the LCA and autonomic nerves, in which the adequacy of lymph node harvest and the security of blood supply over distal colon were juggled, can be achieved for patients with distal rectal cancer posing risk factors of anastomotic failure. PMID- 24337918 TI - Relation of plasma adiponectin levels and aortic stiffness after acute ST-segment elevation myocardial infarction. AB - BACKGROUND: Pulse wave velocity is a measure of aortic stiffness and an independent predictor of cardiovascular morbidity and mortality. Adiponectin is involved in atherosclerosis and inflammation. In the present study we aimed to explore the association between plasma adiponectin concentrations and pulse wave velocity in the acute phase after ST-segment elevation myocardial infarction (STEMI). METHODS: Forty-six consecutive STEMI patients (mean age 57 +/- 11 years) treated with primary percutaneous coronary intervention (PCI) were enrolled in this cross-sectional study. Plasma adiponectin was measured 2 days after index event by enzyme-linked immunosorbent assay. Aortic pulse wave velocity (PWV) was calculated by the transit-time method with the use of a velocity-encoded, phase contrast cardiac magnetic resonance protocol. RESULTS: Median plasma adiponectin concentration was 2385 ng/ml (interquartile range 1735-5403). Males had lower plasma adiponectin values than females and current smokers had lower values than non-smokers (all p<0.02). Adiponectin was significantly associated with PWV (r=0.505, p<0.001), age (r=0.437, p=0.002), and total cholesterol (r=0.468, p=0.001). Multiple linear regression analysis revealed adiponectin as a predictor of PWV independently of age, sex, smoking status, total cholesterol, and N terminal pro-B-type natriuretic peptide (p=0.027). CONCLUSIONS: Plasma adiponectin concentrations are strongly associated with aortic stiffness in patients after acute STEMI treated with primary PCI. Our data support a possible role for adiponectin as an independent risk marker for increased aortic stiffness in STEMI patients. PMID- 24337919 TI - Transportation to primary percutaneous coronary intervention, compared with on site fibrinolysis, is a strong independent predictor of functional status after myocardial infarction: 5-year follow-up of the PRAGUE-2 trial. AB - AIMS: Subjective symptoms represent significant criteria of a patient's health condition; therefore, we focused on the long-term prevalence of heart failure symptoms and angina pectoris after myocardial infarction between two groups of patients in which two different therapeutic strategies were used during the acute phase of ST-elevation myocardial infarction (STEMI). METHODS: The PRAGUE-2 study enrolled 850 patients with STEMI. The patients were randomized into two groups - transport to a primary percutaneous coronary intervention (PCI) centre (n=429) vs. fibrinolysis in community hospitals (n=421). The data were collected from either primary hospitals or PCI centres, as well as via questionnaires. RESULTS: The mean follow-up was 58 months. At 5 years, 45.4% of patients were in New York Heart Association class I following primary PCI vs. 31.8% of those treated with fibrinolysis (OR 2.02, 95% CI 1.37-2.97, p<0.002). At 5 years, 83.6% of patients had no symptoms of angina pectoris following invasive therapy vs. 58% of patients treated with fibrinolysis (OR 4.47, 95% CI 2.79-7.18, p<0.001). CONCLUSIONS: The symptoms of angina pectoris and heart failure were significantly lower in patients assigned to primary PCI in the acute stage of myocardial infarction compared with patients treated with fibrinolysis at the 5-year follow up. PMID- 24337920 TI - Plasma osmolality predicts clinical outcome in patients with acute coronary syndrome undergoing percutaneous coronary intervention. AB - AIMS: The impact of plasma osmolality on clinical outcome in acute coronary syndrome (ACS) patients has not been investigated so far. METHODS: In a retrospective analysis, we included 985 patients with ACS undergoing percutaneous coronary intervention (PCI). Plasma osmolality was calculated using concentrations of sodium, plasma glucose, and blood urea nitrogen at admission. Patients were stratified by quartiles (Q) of admission osmolality, clinical outcome was compared between those groups. The primary endpoints were in hospital, 30-day, and 1-year mortality. RESULTS: Univariate analysis in the Cox proportional-hazards model revealed significantly higher rates of in-hospital death for patients with osmolality in Q4, as compared to patients with osmolality in Q1-3 (HR 5.4, 95% CI 3.3-9.0, p<0.01). After adjustment for confounding baseline variables, osmolality in Q4 was associated with 2.8-fold hazard of in hospital death (HR 2.75, 95% CI 1.35-5.61, p=0.005). Upon multivariate analysis, admission osmolality in Q4 vs. Q1-3 was associated with higher mortality rates after 30 days (HR 2.53, 95% CI 1.23-5.21, p=0.012) and 1 year (HR 1.73, 95% CI 1.02-2.91, p=0.04). Moreover, we performed landmark analysis in order to exclude critically ill patients, which revealed similar adjusted rates of death beyond 30 days to 1 year (HR 1.21, 95% CI 0.55-2.66, p=0.642). CONCLUSIONS: Using the 4th quartile of plasma osmolality at admission as a natural cut-off point, osmolality in Q4, as compared to Q1-3, was significantly predictive of short term but not long-term outcome in ACS patients undergoing coronary stenting. Our data suggest osmolality to be an independent, feasible, and cost-effective tool for rapid risk stratification in ACS patients. PMID- 24337921 TI - Photosynthesis and the environment. PMID- 24337922 TI - Medical iPad use in the cardiac catheterization and echo laboratories. AB - The present study aims to describe a dedicated cardiac imaging application on a tablet and to assess the accuracy and reproducibility of this novel application for measurement on angiography and echocardiography data sets. Tablet devices have recently been used in radiological image interpretation and enable transfer of images. It allows the clinician to look up clinical information, search the Internet and communicate with colleagues and family. The study group consisted of 30 patients who had both echocardiographic and angiographic examinations. For each patient, a few measurements (i.e. length, area and angle) were performed using the iPad, and compared to the McKesson workstation, which is routinely used in the hospital. In order to show the equivalence between these two methods, a linear regression was fitted and the distribution of differences between measurements was examined. In addition, the variability of the measurements was compared between two different reviewers (inter-observer test) and between the measurements of the same reviewer at two different time settings (intra-observer test) by calculating the intraclass correlation coefficient (ICC). In all comparisons, the linear regression showed high correlation coefficient (r > 0.9), and the distribution of differences was around zero, implying that the two methods lead to equivalent results. The absolute mean difference between the two different observers demonstrated high agreement between the two observers' repeated measurements. The same conclusions can be deduced from the same observer's repeated measurements. The ICC indicates the resemblance between the two sets, and could be considered almost perfect (ICC > 0.968 for all cases). The newly developed cardiology iPad application offers the opportunity to accurately present the cardiac procedure in a visual, clear and professional manner. PMID- 24337923 TI - Fibroblast engraftment in the decellularized mouse lung occurs via a beta1 integrin-dependent, FAK-dependent pathway that is mediated by ERK and opposed by AKT. AB - Creation of bioartificial organs has been enhanced by the development of strategies involving decellularized mammalian lung. Because fibroblasts critically support lung function through a number of mechanisms, study of these cells in the context of the decellularized lung has the potential to improve the structure and function of tissue-engineered lungs. We characterized the engraftment and survival of a mouse fibroblast cell line in decellularized rat lung slices and found a time-dependent increase in cell numbers assessed by hematoxylin and eosin staining, cell proliferation assessed by Ki67 staining, and minimal cell death assessed by TUNEL staining. We developed a repopulation index to allow quantification of cell survival that accounts for variation in cell density throughout the seeded scaffold. We then applied this method to the study of mouse lung scaffolds and found that decellularization of presliced mouse lungs produced matrices with preserved alveolar architecture and proteinaceous components including fibronectin, collagens I and IV, laminin, and elastin. Treatment with a beta1-integrin-neutralizing antibody significantly reduced the repopulation index after 24 h of culture. Treatment with focal adhesion kinase (FAK) inhibitor and extracellular signal-regulated kinase (ERK) inhibitor further reduced initial repopulation scores while treatment with AKT inhibitor increased initial scores. Rho-associated kinase inhibitor had no discernible effect. These data indicate that initial adhesion and survival of mouse fibroblasts in the decellularized mouse lung occur in a beta1-integrin-dependent, FAK/ERK-dependent manner that is opposed by AKT. PMID- 24337924 TI - Thinking outside the cell: how cell-free hemoglobin can potentiate acute lung injury. PMID- 24337926 TI - The role of simple elbow dislocations in cubitus valgus development in children. AB - PURPOSE: We investigated the functional and radiological outcomes of conservatively treated simple traumatic elbow dislocations and subsequent incidence of cubitus valgus development in children. METHODS: Eleven patients (one female, ten male; mean age 9.8 years, range seven to 12 years) who presented to our hospital with simple elbow dislocations and were conservatively treated between July 2008 and September 2010 were included in the study. All were posterolateral closed dislocations. None of the patients had accompanying elbow fractures. All patients had pre- and postoperative radiographic examinations. The carrying angle of the involved elbow was measured and compared to the contralateral non-injured elbow during follow-up. The incidence and severity of cubitus valgus development was assessed. The functional and clinical outcomes were evaluated using the Mayo Elbow Performance Scale. The mean monitoring period was 24.3 months (range 19-30 months). RESULTS: All patients had satisfactory good and excellent results (85-100 points; mean 96.8 points) according to the Mayo Elbow Performance Scale. The final average elbow flexion was 137 degrees (range, 130-145 degrees ) and average extension was 8.6 degrees (range 0-20 degrees ) with full supination and pronation in traumatic elbow. Four patients (36.4%) had an average increase (cubitus valgus) of 14.5 degrees (10-20 degrees ) in carrying angle compared to the other elbow. CONCLUSIONS: While isolated traumatic dislocation of the elbow is uncommon among children, it can be successfully treated by urgent closed reduction, proper fixation of the elbow and appropriate timely rehabilitation. However, it should be considered that some patients may develop cubitus valgus deformity in a later period. Therefore, each patient with a simple traumatic elbow dislocation should be followed, and the parents should be informed of the potential for any deformity development. PMID- 24337925 TI - Endothelin-1 decreases endothelial PPARgamma signaling and impairs angiogenesis after chronic intrauterine pulmonary hypertension. AB - Increased endothelin-1 (ET-1) disrupts angiogenesis in persistent pulmonary hypertension of the newborn (PPHN), but pathogenic mechanisms are unclear. Peroxisome proliferator activated receptor gamma (PPARgamma) is decreased in adult pulmonary hypertension, but whether ET-1-PPARgamma interactions impair endothelial cell function and angiogenesis in PPHN remains unknown. We hypothesized that increased PPHN pulmonary artery endothelial cell (PAEC) ET-1 production decreases PPARgamma signaling and impairs tube formation in vitro. Proximal PAECs were harvested from fetal sheep after partial ligation of the ductus arteriosus in utero (PPHN) and controls. PPARgamma and phospho-PPARgamma protein were compared between normal and PPHN PAECs +/- ET-1 and bosentan (ETA/ETB receptor blocker). Tube formation was assessed in response to PPARgamma agonists +/- ET-1, N-nitro-l-arginine (LNA) (NOS inhibitor), and PPARgamma siRNA. Endothelial NO synthase (eNOS), phospho-eNOS, and NO production were measured after exposure to PPARgamma agonists and PPARgamma siRNA. At baseline, PPHN PAECs demonstrate decreased tube formation and PPARgamma protein expression and activity. PPARgamma agonists restored PPHN tube formation to normal. ET-1 decreased normal and PPHN PAEC tube formation, which was rescued by PPARgamma agonists. ET-1 decreased PPARgamma protein and activity, which was prevented by bosentan. PPARgamma agonists increased eNOS protein and activity and NO production in normal and PPHN PAECs. LNA inhibited the effect of PPARgamma agonists on tube formation. PPARgamma siRNA decreased eNOS protein and tube formation in normal PAECs. We conclude that ET-1 decreases PPARgamma signaling and contributes to PAEC dysfunction and impaired angiogenesis in PPHN. We speculate that therapies aimed at decreasing ET-1 production will restore PPARgamma signaling, preserve endothelial function, and improve angiogenesis in PPHN. PMID- 24337927 TI - Minimally invasive reduction and fixation of displaced calcaneal fractures: surgical technique and radiographic analysis. AB - PURPOSE: The optimal treatment of calcaneal fractures is controversial. A specific subgroup of healthy patients has good outcomes with open reduction and internal fixation using an extensile lateral approach. However, there are many patients who do not fit into this category. Consequently, they are either denied surgical intervention or put at significant risk of developing complications as a result of open surgical intervention. Minimally invasive reduction and fixation (MIRF) of calcaneal fractures can restore the height, width, length and shape of the hindfoot in addition to restoring the orientation of the posterior facet of the calcaneus (Bohler's angle). METHODS: We present a series of 31 patients treated with minimally invasive reduction and fixation technique using threaded K wires and Steinmann pins as an alternative treatment method in patients who are not suitable for open reduction and internal fixation. RESULTS: The mean time to surgery from injury was six days (range one to ten days). The mean duration of surgery was 35 minutes (range 11-52 minutes). The mean followup was 14.9 months (range of seven to 30 months). The mean change in Bohler's angle and length of the calcaneus from intra-operative fixation to final followup were 18.7 degrees and 4.7 mm, respectively. The complication rate was low and there was one case of a superficial wound infection and no cases of deep infection or peroneal impingement in this series. CONCLUSION: The MIRF technique with the use of threaded K wires has not been previously described in the literature. In our experience, the operative time is short and can be safely performed even in the presence of extensive soft tissue swelling in the immediate period following injury. The infection risk is low and calcaneal morphology was improved and maintained in terms of Bohler's angle. This technique is suitable to be considered in patients who have significant medical co-morbidities (smokers, diabetics, peripheral vascular disease) and in those patients who are not suitable for an extensile lateral approach and internal fixation. PMID- 24337928 TI - [Geriatric health care structures in Germany. The cross-border cooperation in geriatric medicine as a needs-driven further development]. AB - BACKGROUND: To cover future needs of specialised geriatric patient-centred care, existing structures need to be developed further. MATERIALS AND METHODS: Taking into account regional structures of providing care, the Federal Association of Geriatric Medicine in Germany developed the concept of Cross-Border Cooperation in Geriatric Medicine. RESULTS: This concept combines specific geriatric expertise provided by inpatient health care with specialised networking in ambulatory treatment of elderly with a typical geriatric profile. The objective is to provide geriatric patients with a holistic and specific care and case management that overcomes existing limitations. PMID- 24337929 TI - [The care of obese persons from the perspective of executives of inpatient care facilities. Results of qualitative expert interviews]. AB - BACKGROUND: Although nursing home residents are increasingly suffering from obesity, little research has been done on the appropriate care for them. The present study examines how executives of long-term care facilities perceive obese residents, which meaning does obesity have for them, and whether they associate the care of the obese with additional expenditures. MATERIALS AND METHODS: In all, 15 guideline-based interviews were conducted with executive managers of nursing homes in Berlin, Saxony and Bavaria. The analysis of the interviews was based on the method of Meuser and Nagel. RESULTS: The results demonstrate that obese nursing home residents are hardly noticed by executives. This results from the fact that they attribute only minor significance to obesity as a nutritional and health problem. The care of obese residents is associated with additional instrumental and personnel-related expenditures. However, facilities do not have sufficient resources to provide them. Obesity is a serious, but unrecognized problem in long-term care. CONCLUSION: To improve the awareness of obesity, intense professional discussions are required. The provision of additional instrumental and human resources becomes necessary to ensure appropriate care of obese nursing home residents. PMID- 24337930 TI - Enhanced flux of substrates into polyamine biosynthesis but not ethylene in tomato fruit engineered with yeast S-adenosylmethionine decarboxylase gene. AB - S-adenosylmethionine (SAM), a major substrate in 1-C metabolism is a common precursor in the biosynthetic pathways of polyamines and ethylene, two important plant growth regulators, which exhibit opposing developmental effects, especially during fruit ripening. However, the flux of various substrates including SAM into the two competing pathways in plants has not yet been characterized. We used radiolabeled (14)C-Arg, (14)C-Orn, L-[U-(14)C]Met, (14)C-SAM and (14)C-Put to quantify flux through these pathways in tomato fruit and evaluate the effects of perturbing these pathways via transgenic expression of a yeast SAM decarboxylase (ySAMDC) gene using the fruit ripening-specific promoter E8. We show that polyamines in tomato fruit are synthesized both from Arg and Orn; however, the relative contribution of Orn pathway declines in the later stages of ripening. Expression of ySAMDC reversed the ripening associated decline in spermidine (Spd) and spermine (Spm) levels observed in the azygous control fruit. About 2- to 3 fold higher levels of labeled-Spd in transgenic fruit (556HO and 579HO lines) expressing ySAMDC confirmed the enzymatic function of the introduced gene. The incorporation of L-[U-(14)C]Met into Spd, Spm, ethylene and 1-aminocyclopropane-1 carboxylic acid (ACC) was used to determine Met-flux into these metabolites. The incorporation of (14)C-Met into Spd/Spm declined during ripening of the control azygous fruit but this was reversed in fruits expressing ySAMDC. However, incorporation of (14)C-Met into ethylene or ACC during ripening was not altered by the expression of ySAMDC in the fruit. Taken together these results show that: (1) There is an inverse relationship between the production of higher polyamines and ethylene during fruit ripening, (2) the inverse relationship between higher polyamines and ethylene is modulated by ySAMDC expression in that the decline in Spd/Spm during fruit ripening can be reversed without significantly altering ethylene biosynthesis, and (3) cellular flux of SAM in plants is homeostatically regulated based on its demand for competing pathways. PMID- 24337931 TI - Clinical significance of taurine. PMID- 24337932 TI - Standards of scientific conduct: are there any? AB - The practice of research is full of ethical challenges, many of which might be addressed through the teaching of responsible conduct of research (RCR). Although such training is increasingly required, there is no clear consensus about either the goals or content of an RCR curriculum. The present study was designed to assess community standards in three domains of research practice: authorship, collaboration, and data management. A survey, developed through advice from content matter experts, focus groups, and interviews, was distributed in November 2010 to U.S. faculty from 50 graduate programs for each of four different disciplines: microbiology, neuroscience, nursing, and psychology. The survey addressed practices and perceived standards, as well as perceptions about teaching and learning. Over 1,300 responses (response rate of 21 %) yielded statistically significant differences in responses to nearly all questions. However the magnitude of these differences was typically small, leaving little reason to argue for community consensus on standards. For nearly all questions asked, the clear finding was that there was nothing approaching consensus. These results may be useful not so much to teach what the standards are, but to increase student awareness of the diversity of those standards in reported practice. PMID- 24337933 TI - Application of quinidine on rat sciatic nerve decreases the amplitude and increases the latency of evoked responses. AB - PURPOSE: Multi-modality electrophysiological techniques were performed to assess the effects of quinidine on peripheral nerve conduction. METHODS: Twenty-seven rats were treated with 1, 3, and 5 MUmol quinidine in 0.1 ml 5 % glucose. The mixed-nerve somato-sensory evoked potential (M-SSEP), dermatomal-SSEP (D-SSEP), and compound muscle action potentials (CMAP) were evoked and recorded. After positioning Gelfoam strips saturated with quinidine and 5 % glucose around the left and right sciatic nerves, potentials were measured at baseline, immediately after treatment, every 15 min for the 1st hour, and every 30 min for the next 3 h. After 2 weeks, the walking behaviors and potentials were again analyzed and myelinated fibers in the sciatic nerve were counted. RESULTS: Quinidine applied directly to sciatic nerves reduced the amplitude and prolonged the latency in SSEPs and CMAP, compared to baseline and the contralateral right limbs (controls). This persisted for at least 4 h. After 2 weeks, electrophysiological tests and walking behavior showed no significant difference between the controls and experimental limbs. There was also no difference in the number of myelinated fibers in the sciatic nerves. CONCLUSIONS: Quinidine decreases amplitude and prolongs latency in the sciatic nerve in a dose-related manner without local neural toxicity. PMID- 24337934 TI - A computational model coupling mechanics and electrophysiology in spinal cord injury. AB - Traumatic brain injury and spinal cord injury have recently been put under the spotlight as major causes of death and disability in the developed world. Despite the important ongoing experimental and modeling campaigns aimed at understanding the mechanics of tissue and cell damage typically observed in such events, the differentiated roles of strain, stress and their corresponding loading rates on the damage level itself remain unclear. More specifically, the direct relations between brain and spinal cord tissue or cell damage, and electrophysiological functions are still to be unraveled. Whereas mechanical modeling efforts are focusing mainly on stress distribution and mechanistic-based damage criteria, simulated function-based damage criteria are still missing. Here, we propose a new multiscale model of myelinated axon associating electrophysiological impairment to structural damage as a function of strain and strain rate. This multiscale approach provides a new framework for damage evaluation directly relating neuron mechanics and electrophysiological properties, thus providing a link between mechanical trauma and subsequent functional deficits. PMID- 24337935 TI - Moderation analysis using a two-level regression model. AB - Moderation analysis is widely used in social and behavioral research. The most commonly used model for moderation analysis is moderated multiple regression (MMR) in which the explanatory variables of the regression model include product terms, and the model is typically estimated by least squares (LS). This paper argues for a two-level regression model in which the regression coefficients of a criterion variable on predictors are further regressed on moderator variables. An algorithm for estimating the parameters of the two-level model by normal distribution-based maximum likelihood (NML) is developed. Formulas for the standard errors (SEs) of the parameter estimates are provided and studied. Results indicate that, when heteroscedasticity exists, NML with the two-level model gives more efficient and more accurate parameter estimates than the LS analysis of the MMR model. When error variances are homoscedastic, NML with the two-level model leads to essentially the same results as LS with the MMR model. Most importantly, the two-level regression model permits estimating the percentage of variance of each regression coefficient that is due to moderator variables. When applied to data from General Social Surveys 1991, NML with the two-level model identified a significant moderation effect of race on the regression of job prestige on years of education while LS with the MMR model did not. An R package is also developed and documented to facilitate the application of the two-level model. PMID- 24337936 TI - Nonlinear random-effects mixture models for repeated measures. AB - A mixture model for repeated measures based on nonlinear functions with random effects is reviewed. The model can include individual schedules of measurement, data missing at random, nonlinear functions of the random effects, of covariates and of residuals. Individual group membership probabilities and individual random effects are obtained as empirical Bayes predictions. Although this is a complicated model that combines a mixture of populations, nonlinear regression, and hierarchical models, it is straightforward to estimate by maximum likelihood using SAS PROC NLMIXED. Many different models can be studied with this procedure. The model is more general than those that can be estimated with most special purpose computer programs currently available because the response function is essentially any form of nonlinear regression. Examples and sample code are included to illustrate the method. PMID- 24337937 TI - Additive multilevel item structure models with random residuals: item modeling for explanation and item generation. AB - An additive multilevel item structure (AMIS) model with random residuals is proposed. The model includes multilevel latent regressions of item discrimination and item difficulty parameters on covariates at both item and item category levels with random residuals at both levels. The AMIS model is useful for explanation purposes and also for prediction purposes as in an item generation context. The parameters can be estimated with an alternating imputation posterior algorithm that makes use of adaptive quadrature, and the performance of this algorithm is evaluated in a simulation study. PMID- 24337938 TI - Bacterial change in external auditory canal upon antisepsis with povidone-iodine during tympanoplasty. AB - The aim of this single-arm prospective study was to determine the flora of the external auditory canal (EAC) in inactive chronic otitis media and evaluate the alteration of microorganisms of the EAC during tympanoplasty upon povidone-iodine antisepsis. Sixty-three patients with central tympanic membrane perforation were enrolled in the study. Preoperative swab cultures were obtained and the EAC was packed with povidone-iodine absorbed gauze. Type I tympanoplasty via a retroauricular route was performed. Cultures from the EAC were taken at the end of each operation. Isolated organisms were identified based upon microbiological, morphological, and biochemical characteristics. The most commonly isolated organisms from preoperative samples were normal commensal flora, including 73 coagulase-negative staphylococci (CNS) and 18 diphtheroid bacilli (DB). Less commonly cultured pathogenic species included four isolates of Staphylococcus aureus and three isolates of Candida albicans. No bacteria were observed in five patients. Following povidone-iodine antisepsis, 32 of the samples were negative. Eradication was statistically significant for CNS, DB and pathogen microorganism (P < 0.05). Isolated bacteria differed from those in preoperative swab cultures in eight cases. After antisepsis, diverse strains of the CNS were isolated in 13 cases and 10 patients showed no change in microbial flora. Postoperative culture demonstrated that all seven pathogenic isolates were eradicated (100 %); this selective efficacy of povidone-iodine antisepsis against pathogenic isolates was significant when compared with commensal flora (P < 0.05). These results suggest that povidone-iodine antisepsis of the EAC before tympanoplasty is an effective method for the elimination microorganisms, especially pathogenic bacteria. PMID- 24337939 TI - Behavioral analysis of narcoleptic episodes in orexin-deficient mice. AB - Orexin-deficient mice express narcoleptic episodes which mirror some of the main symptoms of human narcolepsy. Therefore, they are often used in narcolepsy research. However, little is known about some behavioral characteristics of narcoleptic episodes, e.g. about episode types, duration, and variability. In the present study, 351 narcoleptic episodes of orexin-deficient mice were behaviorally characterized. Based on this data, we describe different onset and progression episodes types. These episode types affected episode duration, i.e. abrupt onsets and 'shaking'-like movements increased episode duration. Our data suggests that promoting motor activity enhances the frequency of narcoleptic episode. Inter-individual variability of episode frequency and duration was large; however, the intra-individual frequency was relatively stable. Based on these findings we suggest the following to increase the statistical power of experiments in orexin-deficient mice: Using a pre-screen and selecting the mice with decent episode frequency, using an enriched environment as well as using repeated-measure designs. PMID- 24337940 TI - Pien Tze Huang induces apoptosis in multidrug-resistant U2OS/ADM cells via downregulation of Bcl-2, survivin and P-gp and upregulation of Bax. AB - Pien Tze Huang (PZH) is a well-known traditional Chinese formula that was first prescribed by a royal physician in the Ming Dynasty. PZH has been used to treat various types of cancers including osteosarcoma. Previous studies have shown that PZH may effectively inhibit osteosarcoma cell growth in vivo and in vitro via induction of apoptosis and inhibition of migratory and invasive abilities. However, little is known regarding the effects of PZH on osteosarcomas that are resistant to chemotherapy, which has emerged as a major clinical problem. In the present study, the cellular effects of PZH on multidrug-resistant U2OS/ADM human osteosarcoma cells were investigated. Our results showed that PZH reduced cell viability in a dose- and time-dependent manner and arrested cells in the G2/M phase of the cell cycle, suggesting that PZH inhibits the proliferation of U2OS/ADM cells. Hoechst 33258 staining and Annexin V/propidium iodide double staining revealed typical nuclear features of apoptosis, and treatment with PZH increased the proportion of apoptotic Annexin V-positive cells in a dose dependent manner. Further experiments demonstrated that apoptosis induction by PZH was accompanied by downregulation of Bcl-2 and survivin and upregulation of Bax. In addition, following treatment with PZH, intracellular Rhodamine 123 accumulation was increased and the expression of P-gp was significantly suppressed. Taken together, these results provide a possible molecular mechanism for the anticancer effect of PZH on U2OS/ADM cells and suggest that PZH may be a potent therapeutic agent for drug-resistant osteosarcoma. PMID- 24337941 TI - Competitiveness facets and sensation seeking as predictors of problem gambling among a sample of university student gamblers. AB - Understanding the factors that contribute to problem gambling (PG) is imperative. Individual differences in sensation seeking (SS), as measured by the Sensation Seeking Scale Form (SSS-V), have been found to be predictive of PG among university student samples. However, what is less clear, is if the four SSS-V subscales capture unique facets of SS that are particularly predictive of PG. Much less studied than SS, competitiveness has also been found to be predictive of PG. The Competitiveness Orientation Measure (COM) is a newly developed measure of competitiveness, comprising of four facets. The main purpose of the current study was to examine if these four facets of competitiveness predicted variance in PG over and above the variance predicted by the four SSS-V subscales. Participants included 158 university student gamblers. Sequential regression analysis showed that after accounting for gender, age, and the four SSS-V subscales the only facet of the COM found to be a significant predictor of PG severity was Dominant Competitiveness. Dominant Competitiveness predicted an additional 11% of PG severity. These results provide support for the Dominant Competitiveness subscale of the COM as having utility in predicting PG over and above the predictive utility of the SSS-V subscales. Practical implications for the current findings are discussed. PMID- 24337943 TI - Task switching among two or four tasks: effects of a short-term variation of the number of candidate tasks. AB - In two experiments, using a modified task-cueing paradigm, participants switched among a set of four tasks that was on some trials reduced to two by a pre-cue preceding the task cue. A pre-cue temporarily restricting the options to two candidate tasks facilitated performance on switch trials to a much larger extent than on repeat trials. This observation is interpreted as an indication of a short-term restructuring of a global task representation by implementing antagonistic constraints among the representations of the two remaining candidate tasks. PMID- 24337942 TI - Adult height and risk of ischemic heart disease, atrial fibrillation, stroke, venous thromboembolism, and premature death: a population based 36-year follow-up study. AB - Few studies have associated height with cardiovascular diseases other than myocardial infarction. We conducted a population-based 36-year cohort study of 12,859 men born in 1955 or 1965 whose fitness for military service was assessed by Draft Boards in Northern Denmark. Hospital diagnoses for ischemic heart diseases, atrial fibrillation, stroke, and venous thromboembolism were obtained from the Danish National Patient Registry, covering all Danish hospitals since 1977. Mortality data were obtained from the Danish Civil Registration System. We began follow-up on the 22nd birthday of each subject and continued until occurrence of an outcome, emigration, death, or 31 December 2012, whichever came first. We used Cox regression to compute hazard ratios (HRs) with 95 % confidence intervals (CIs). Compared with short stature, the education-adjusted HR among tall men was 0.67 (95 % CI 0.54-0.84) for ischemic heart disease (similar for myocardial infarction, angina pectoris, and heart failure), 1.60 (95 % CI 1.11 2.33) for atrial fibrillation, 1.05 (95 % CI 0.75-1.46) for stroke, 1.04 (95 % CI 0.67-1.64) for venous thromboembolism, and 0.70 (95 % CI 0.58-0.86) for death. In conclusion, short stature was a risk factor for ischemic heart disease and premature death, but a protective factor for atrial fibrillation. Stature was not substantially associated with stroke or venous thromboembolism. PMID- 24337944 TI - Silencing of TBC1D15 promotes RhoA activation and membrane blebbing. AB - Membrane blebs are round-shaped dynamic membrane protrusions that occur under many physiological conditions. Membrane bleb production is primarily controlled by actin cytoskeletal rearrangements mediated by RhoA. Tre2-Bub2-Cdc16 (TBC) domain-containing proteins are negative regulators of the Rab family of small GTPases and contain a highly conserved TBC domain. In this report, we show that the expression of TBC1D15 is associated with the activity of RhoA and the production of membrane blebs. Depletion of TBC1D15 induced activation of RhoA and membrane blebbing, which was abolished by the addition of an inhibitor for RhoA signaling. In addition, we show that TBC1D15 is required for the accumulation of RhoA at the equatorial cortex for the ingression of the cytokinetic furrow during cytokinesis. Our results demonstrate a novel role for TBC1D15 in the regulation of RhoA during membrane blebbing and cytokinesis. PMID- 24337945 TI - Effect of naringenin on brain insulin signaling and cognitive functions in ICV STZ induced dementia model of rats. AB - Recent evidence indicates that severe abnormalities in brain glucose/energy metabolism and insulin signaling have been documented to take a pivotal role in early sporadic Alzheimer's disease pathology. It has been reported that naringenin (NAR), derived from citrus aurantium, exhibits antioxidant potential and protects the brain against neurodegeneration. The current study was designed to further investigate the protective effect of the NAR on neurodegeneration in a rat model of AD induced by an intracerebroventricular (ICV) injection of streptozotocin (STZ), and to determine whether this neuroprotective effect was associated with brain insulin signaling. Rats were injected bilaterally with ICV STZ (3 mg/kg), while sham rats received the same volume of vehicle and then supplemented with NAR (25, 50 mg, 100 mg/kg, respectively) for 3 weeks. The ICV STZ injected rats did not have elevated blood glucose levels. 21 days following ICV-STZ injection, rats treated with NAR had better learning and memory performance in the Morris water maze test compared with rats treated with saline. We demonstrated that NAR increased the mRNA expression of INS and INSR in cerebral cortex and hippocampus. In addition, NAR reversed ICV-STZ induced Tau hyper-phosphorylation in both hippocampus and cerebral cortex through downregulation of glycogen synthase kinase-3beta (GSK-3beta) activity, a key kinase in the insulin signaling. Brain levels of Abeta, which were elevated in ICV-STZ rats, were significantly reduced in NAR-treated rats via upregulation of insulin degrading enzyme. These effects were mediated by increased insulin and insulin receptors expression in the brain, suggesting that insulin sensitizer agents might have therapeutic efficacy in early AD. PMID- 24337946 TI - Substantia nigra in Parkinson's disease: a multimodal MRI comparison between early and advanced stages of the disease. AB - This study focused on the substantia nigra (SN) in Parkinson's disease (PD). We measured its area and volume, mean diffusivity (MD), fractional anisotropy (FA) and iron concentration in early and late PD and correlated the values with clinical scores. Twenty-two early PD (EPD), 20 late PD (LPD) and 20 healthy subjects (age 64.7 +/- 4.9, 60.5 +/- 6.1, and 61 +/- 7.2 years, respectively) underwent 1.5 T MR imaging with double-TI-IR T1-weighted, T2*-weighted and diffusion tensor imaging scans. Relative SN area, MD, FA and R2* were measured in ROIs traced on SN. Correlation with Unified Parkinson Disease Rating Scale (UPDRS) scores was assessed. In LPD, the SN area was significantly reduced with respect to EPD (p = 0.04) and control subjects (p < 0.001). In EPD, the SN area was also significantly smaller than in controls (p = 0.006). Similarly, the SN volume significantly differed between LPD and controls (p = 0.001) and between EPD and LPD (p = 0.049), while no significant differences were found between controls and EPD. Both SN area (r = 0.47, p = 0.004) and volume (r = 0.46, p = 0.005) correlated with UPDRS scores. At 1.5 T, SN morphological measurements were sensitive to early PD changes and able to track the disease progression, while MD and FA measures and relaxometry did not provide significant results. PMID- 24337947 TI - Anterior tarsal tunnel syndrome: a misunderstood and a misleading entrapment neuropathy. AB - Anterior tarsal tunnel syndrome (ATTS) is a rare entrapment neuropathy of the deep peroneal nerve beneath the extensor retinaculum on the top of the ankle. ATTS is often asymptomatic or olygosymptomatic. There are few reports describing the ATTS. We describe the clinical and electrophysiological features of 85 patients with unilateral or bilateral ATTS prospectively collected between January 2000 and December 2010 in our laboratory of Clinical Neurophysiology. This entrapment neuropathy remains poorly diagnosed and it might be misleading when performing a diagnostic EMG-ENG examination for suspected polyneuropathy or lumbosacral radiculopathy. PMID- 24337948 TI - A suspected case of coronary periarteritis due to IgG4-related disease as a cause of ischemic heart disease. AB - IgG4-related disease (IgG4-RD) is a systemic inflammatory disease characterized by marked infiltration of IgG4-positive (+) plasma cells into affected organs, but the concept of this disease has only recently been established. Coronary vasculitis is a rare disease that can cause sudden death, and it has recently been reported that IgG4-RD may be associated with vasculitis, including periarteritis and coronary disease. In this paper we report an autopsy case of sudden death of a man in his thirties, in which coronary periarteritis with features of IgG4-related periarteritis was detected. IgG4-RD was suspected from the presence of the following histopathological features: (1) markedly thickened adventitia and marked infiltration of the adventitia and periarterial fat by lymphocytes and plasma cells; and (2) infiltration of IgG4-positive plasma cells (ratio of IgG4+ cells to IgG4+ cells of >40 %, 50 IgG4+ plasma cells per high power field) on immunostaining. The etiology and pathophysiology of IgG4-RD and IgG4-related periarteritis are still unclear, and further investigation of these conditions and their association with coronary lesions is needed. Careful consideration should be given to the possible presence of IgG4-RD when forensic pathologists encounter cases of sudden death accompanied by coronary periarteritis. PMID- 24337949 TI - Is environment really a function? PMID- 24337950 TI - Pulsed acoustic cellular expression (PACE) reduces capsule formation around silicone implants. AB - Capsular contracture remains a major complication after reconstructive or aesthetic breast augmentation. Formation of capsular fibrosis is a multifactorial process. An initial inflammatory reaction appears to be key to the development of capsular contracture. Recent studies have shown that pulsed acoustic cellular expression (PACE) has significant antiinflammatory effects. Thus, this study aimed to determine the potential of PACE to prevent or attenuate capsular contracture around silicone implants in a rodent model. For this study, 36 Lewis rats were divided into two groups, and a textured silicone implant was placed in a dorsal submuscular pocket. One group received PACE treatment, whereas the other group served as the control group and received no treatment. Follow-up evaluations were performed after 10, 35, and 100 days. Capsule thickness, collagen density, myofibroblasts, vascular density, and a semiquantitative real time polymerase chain reaction that addressed differential gene expression were assessed. The PACE treatment significantly reduced capsule thickness on days 10, 35, and 100 compared with the control group (day 10: 632.9 +/- 164.5 vs 932.6 +/- 160.8, p < 0.05; day 35: 709.5 +/- 175 vs 825.9 +/- 313.3, p < 0.0.5; day 100: 736.3 +/- 198.1 vs 1,062.3 +/- 151.9, p < 0.05). This was accompanied by a significant suppression of proinflammatory genes (cluster of differentiation 68, monocyte chemotactic protein-1, CCL4) and synergistic alterations of pro- and antifibrotic proteins (transforming growth factor-beta 1, matrix metalloproteinase-2). This study showed that the PACE application significantly reduces capsular contracture around silicone implants. A decrease in capsular thickness after PACE treatment seems to be associated with a downregulation of proinflammatory genes and proteins. The study identifies PACE technology as a potential low-cost technique that is easy to use for reduction of capsular contracture after augmentation using silicone implants. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266 . PMID- 24337951 TI - Medial thighplasty after massive weight loss: are there any risk factors for postoperative complications? AB - BACKGROUND: With the increasing incidence of obesity in Western societies, an increasing number of patients undergo bariatric surgery that leads to functional and aesthetic sequelae related to a rapid and massive weight loss, namely, skin and fat excess. The goal of surgical management after massive weight loss is to optimize the functional results obtained from bariatric surgery or diet by removal of the redundant skin folds. The authors report their experience with medial thighplasty after massive weight loss and identify factors predictive of postoperative complications. METHODS: This retrospective study investigated 53 patients who underwent surgery for medial thighplasty after massive weight loss. Data were collected through chart review and submitted to statistical analysis. RESULTS: The average weight loss before thighplasty was 43.5 +/- 14.9 kg, and 39.6 % of the patients experienced at least one complication. The complications were seroma (9.4 %), wound dehiscence (20.8 %), scar migration (17 %), wound infection (5.7 %), and partial skin necrosis (1.9 %). The body mass index (BMI) before massive weight loss and the BMI before medial thighplasty were found to be risk factors for the development of a postoperative complication. CONCLUSION: Few guidelines exist for the optimization of care and safety in this complex patient population. The information from this retrospective study complements the current data from the literature and can help surgeons select patients eligible for medial thighplasty. This report shows that the BMI before medial thighplasty should be taken into consideration for patients willing to undergo a body contouring procedure. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 24337952 TI - Psychosomatic conditions of the children and adolescents exposed to 5.12 Wenchuan earthquake. AB - BACKGROUND: A devastating earthquake registering 8.0 on the Richter Scale struck Wenchuan County in Northwest Sichuan Province in China on May 12, 2008, claiming over 69,200 lives, seriously wounding more than 374,600 people, and rendering more than 18,400 people missing. The epicenter was close to Yingxiu Township in Wenchuan County. PURPOSE: This study aimed to investigate the psychosomatic conditions of the children and adolescents exposed to the devastating earthquake and explore the risk factors for psychosomatic symptoms. METHOD: A total of 1,828 participants aged 6 to 16 years, of whom 842 from the affected area and 986 from non-affected area, were administered a Psychosomatic Conditions Scale. RESULTS: Each factor score, total somatic score, total psychological score, and total psychosomatic score of the experimental group were significantly higher than those of the control group (P < 0.001). Positive correlation was found between the psychological state and somatic symptoms in the experimental group(r = 0.157 ~ 0.489, P < 0.01). Respiratory system, cardiovascular system, nervous system, digestive system, urogenital system, emotion, behavior, and language, combined as a panel, were significantly differentiated between the two groups, accounting for 73.4% of the total difference. In the experimental group, the factor scores of anxiety, behavior, total psychological score, and total psychosomatic score of the girls were obviously higher than those of the boys (P < 0.01 ~ 0.05); most somatic factors and psychological factors, total somatic score, total psychological score, and total psychosomatic score of the elder adolescents were significantly higher than those of the younger children (P < 0.01 ~ 0.05). CONCLUSION: The children and adolescents exposed to 5.12 earthquake greatly suffered from terrible psychosomatic conditions, among whom the elder girls had more severe symptoms, particularly in terms of anxiety and behavior. PMID- 24337953 TI - Adoptive immunotherapy of metastatic breast cancer: present and future. AB - Breast cancer is a systemic disease with a primarily local component. Besides surgical resection and irradiation of the locoregional tumor setting, central therapeutic aim is the elimination of disseminated micrometastatic tumor cells using cytostatic and/or hormonal treatment. Nevertheless, in the course of time a majority of patients suffer from systemic recurrence in the form of distant metastases. Intriguingly, in this connection, intratumoral cytotoxic T lymphocytes might serve as independent predictors of treatment efficacy and clinical outcome. Loss of immune balance (tumor dormancy) during intensive cross talk between T cells and tumor cells in the bone marrow microenvironment is suggested one reason for distant metastatic relapse. In this clinical context, further supportive therapies become increasingly attractive, taking immunological features of breast cancer cells into special account. The present review aims to dissect bone marrow-derived cellular antitumor immune responses and translational immunologic treatment options regarding their actual relevance to patients' clinical benefit and their future directions in breast cancer management. PMID- 24337954 TI - Heterogeneous drug target expression as possible basis for different clinical and radiological response to the treatment of primary and metastatic renal cell carcinoma: suggestions from bench to bedside. AB - Metastatic disease occurs in a significant percentage of patients with renal cell carcinoma (RCC) and is usually associated with an overall poor prognosis. However, not all of the sites of metastases seem to have the same prognostic significance in patients receiving targeted agents. Indeed, patients with lung only metastases seem to present a better survival than patients with other sites, whereas liver and bone metastases are associated with a worst prognosis. Some clinical studies suggest that metastatic sites are more responsive than primary tumors. This event may be due to intratumor heterogeneity in terms of somatic mutations, chromosome aberrations, and tumor gene expression, primarily centered around Von Hippel-Lindau (VHL) pathway, such as VHL mutations, HIF levels, vascular endothelial growth factor (VEGF) isoforms, and VEGF receptor levels. Nevertheless, these data do not completely explain the discordant biological behavior between primary tumor and metastatic sites. Understanding the causes of this discordance will have profound consequences on translational research and clinical trials in RCC. In this review, we overview current data on the differences between primary RCC and metastases in terms of drug target expression and clinical/radiological response to targeted agents, thus describing the prognostic role of different metastatic sites in RCC patients. PMID- 24337955 TI - Replication study of three functional polymorphisms associated with bone mineral density in a cohort of Spanish women. AB - Gene candidate and genome-wide association studies have revealed tens of loci of susceptibility for osteoporosis. Some limitations such as sample size, use of confounding variables, and control for multiple testing and for population stratification, however, represent common problems in these studies that make replication in independent cohorts desirable and even necessary. The main objective of the present study is to replicate previous data on three functional polymorphisms in a cohort of Spanish women. To that end, we performed an association study of three functional polymorphisms previously associated with bone phenotypes in the LRP5, TNFRSF11B, and FGFBP1 genes with low bone mineral density (BMD) in a cohort of 721 Spanish women, most of them postmenopausal. We detected a strong significant association, even when correcting for multiple comparisons, for polymorphism rs312009 in the LRP5 gene with low BMD at the lumbar-spine site. These were women with the CC genotype, which showed the worst bone parameters. Moreover, these women had a higher risk of osteoporosis (adjusted odds ratio 2.82, P = 0.001) than women with the TT/TC genotype. This association seems to be caused because the rs312009 single nucleotide polymorphism (SNP) is located at a binding site for the transcription factor RUNX2 at the 5' region of the LRP5 gene, and the T allele seems to be a better transcriber than the C allele. Regarding the other two SNPs, only the rs4876869 SNP in the TNFRSF11B gene showed a suggestive trend for both skeletal sites. These results underscore the significance of the LRP5 gene in bone metabolism and emphasize the significance of the replication of previous results in independent cohorts. PMID- 24337956 TI - Serum ferritin levels are positively associated with bone mineral density in elderly Korean men: the 2008-2010 Korea National Health and Nutrition Examination Surveys. AB - A possible negative effect of iron overload on bone metabolism has been suggested by the fact that patients with hemochromatosis, thalassemia, and sickle cell anemia have lower bone mineral density than the general population. However, the influence of iron overload on bone health in the general population is uncertain. The aim of this study was to investigate the relationship between serum ferritin levels and bone mineral density (BMD) in elderly Koreans. A total of 2,943 subjects aged 65 years and over who participated in the 2008-2010 Korea National Health and Nutrition Examination Surveys were included in this study. Age, physical activity, current smoking status, alcohol consumption, education level, household income, and dietary assessment were surveyed by a face-to-face interview. BMD was measured at the lumbar spine and femur by dual-energy X-ray absorptiometry, and other biochemical markers, including serum ferritin, 25 hydroxyvitamin D3, serum alkaline phosphatase, and parathyroid hormone, were assayed. After adjusting for age and body mass index, we found an association between BMD of the total lumbar spine, total femur, and femur neck and levels of alkaline phosphatase, parathyroid hormone, vitamin D3, and daily intake of calcium and protein. Serum ferritin levels were positively associated with BMD of the total lumbar spine, total femur, and femur neck after adjusting for all covariates in men, but not in women. This study suggests a positive association between serum ferritin levels and BMD in elderly South Korean men without hematologic disorders. Further study is warranted to verify the effects of iron on bone metabolism. PMID- 24337957 TI - [Work-related medical rehabilitation for patients with rheumatic diseases]. AB - In recent years work-related rehabilitation has been intensified. Several studies have shown the effectiveness of work-related interventions in medical rehabilitation by improving participation in the work force and reducing sick leave. The German pension insurance fund has developed standardized requirements for medical work-related rehabilitation which include diagnostic procedures to identify patients with specific occupational problems and vocation-related interventions. These requirements address patients across different indications and diagnoses. Rehabilitation centers are assigned to different levels of work related interventions depending on the intensity and specificity of the profile. Centers providing the complete range of work-related interventions offer differentiated work-related diagnostics, job training and occupational groups in addition to general social advice. In this article four case studies with different priorities regarding vocational interventions are presented. PMID- 24337958 TI - A Note on Statistical Hypothesis Testing Based on Log Transformation of the Mantel-Haenszel Common Odds Ratio for Differential Item Functioning Classification. AB - When differential item functioning (DIF) is investigated, DIF classification is made using statistical test results and estimated DIF sizes in practice. One of the well-known DIF classifications is that of the Educational Testing Service (ETS) A (negligible DIF), B (medium DIF), and C (large DIF) rules. This article provides a clarifying note on (a) a sketch of the proof of the asymptotic normality of what is known as the Mantel-Haenszel (MH) delta, which provides the basis of a point and an interval null hypothesis test based on the MH delta, and (b) how to conduct an interval null hypothesis test using the MH delta, which is necessary for the C DIF classification. PMID- 24337959 TI - Remarks and a Correction of Ligtvoet's Treatment of the Isotonic Partial Credit Model. AB - This note contains some remarks on Ligtvoet's (Psychometrika, 77:479-494, 2012) treatment of the isotonic partial credit model. The Proposition relating to the observable property MWI is shown to be false. PMID- 24337960 TI - A systems analysis of age-related changes in some cardiac aging traits. AB - Aging process or senescence affects the expression of a wide range of phenotypic traits throughout the life span of organisms. These traits often show modular, synergistic, and even antagonistic relationships, and are also influenced by genomic, developmental, physiological and environmental factors. The cardiovascular system (CVS) in humans represents a major modular system in which the relationships among physiological, anatomical and morphological traits undergo continuous remodeling throughout the life span of an individual. Here we extend the concept of developmental plasticity in order to study the relationships among 14 traits measured on 3,412 individuals from the Framingham Heart Study cohort, relative to age and gender, using exploratory structural equation modeling-a form of systems analysis. Our results reveal differing patterns of association among cardiac traits in younger and older persons in both sexes, indicating that physiological and developmental factors may be channeled differentially in relation to age and gender during the remodeling process. We suggest that systems approaches are necessary in order to understand the coordinated functional relationships among traits of the CVS over the life course of individuals. PMID- 24337961 TI - Korean mistletoe (Viscum album coloratum) extract extends the lifespan of nematodes and fruit flies. AB - Viscum album coloratum (Korean mistletoe) is a semi-parasitic plant that grows on various trees and has a variety of biological functions such as immunomodulation, apoptosis, and anti-tumor activity. In this study, we investigated the effects of Korean mistletoe extract (KME) on lifespan in experimental models using Caenorhabditis elegans and Drosophila melanogaster. Supplementation of KME at 50 MUg/ml extended the mean survival time by 9.61 and 19.86 % in worms and flies, respectively. The longevity benefit of KME was not due to reduced feeding, reproduction, and/or locomotion in flies and worms. The supplementation of KME also did not increase resistance to various stresses including heat shock, oxidative, or starvation stresses. Furthermore, KME did not further extend the lifespan of flies fed a dietary restricted diet but did increase the expression of Sir2, one of the target genes of dietary restriction, suggesting that KME may function as a putative dietary restriction mimetic. These results also suggest that the longevity promoting effects of KME may be an example of mild stress induced hormesis. PMID- 24337962 TI - Cumulative live-birth rate in women with polycystic ovary syndrome or isolated polycystic ovaries undergoing in-vitro fertilisation treatment. AB - PURPOSE: This retrospective cohort study evaluated the cumulative live birth rate in women with polycystic ovary syndrome (PCOS) and isolated polycystic ovaries (PCO) undergoing in-vitro fertilisation (IVF) treatment. METHODS: We studied 104 women with PCOS, 184 with PCO and 576 age-matched controls undergoing the first IVF treatment cycle between 2002 and 2009. The main outcome measure was cumulative live birth in the fresh plus all the frozen embryo transfers combined after the same stimulation cycle. RESULTS: Women in both the PCOS (n = 104) and isolated PCO groups (n = 184) had higher ovarian response parameters compared to age-matched controls (n = 576), and higher rates of withholding fresh embryo transfer for risk of ovarian hyperstimulation syndrome (OHSS). The actual incidence of moderate to severe OHSS was significantly higher in the PCOS (11.5 %) but not the isolated PCO group (8.2%) compared to controls (4.9%). The live birth rates in the fresh cycle were comparable among the 3 groups, but the PCOS group had a significantly higher miscarriage rate compared to the other 2 groups. Cumulative live birth rate was significantly higher in the isolated PCO group (60.3%), but not the PCOS group (50.0%), compared to controls (47.5%). CONCLUSIONS: Women in the isolated PCO group, but not the PCOS group, had a significantly higher cumulative live birth rate compared to controls. This could be explained by the quantitative effect of the higher number of transferable embryos obtained per stimulation cycle, which is uncompromised by the unfavourable embryo competence otherwise observed in PCOS. PMID- 24337963 TI - Sexual dimorphism in Grp78 and Hsp90A heat shock protein expression in the estuarine copepod Eurytemora affinis. AB - Aquatic organisms are constantly exposed to both natural and anthropogenic stressors. Under stress conditions, they elicit a cellular stress response, involving heat shock proteins (HSPs). HSPs are essential to protect proteins against aggregation and to help in the folding of native proteins or refolding of damaged ones. Because of their conservation among taxons and their inducibility after environmental/chemical stress, HSPs are commonly used as ecological and ecotoxicological biomarkers. However, the appropriate use of such molecular tools requires the investigation of the influence of biotic factors on their basal levels. As a first step in biomarker characterization, the present study aims to evaluate the impact of the reproductive cycle on the expression of the two major HSPs, Grp78 and Hsp90A in the estuarine copepod Eurytemora affinis. The constitutive expression of both genes in males was weak when compared to female levels suggesting gender-specific stress tolerance. Transcript levels gradually increased during oogenesis and maximal levels were recorded in ovigerous females. The present data support the view that the reproductive condition of individuals has to be considered as a confounding factor in stress evaluation by HSP quantification. PMID- 24337965 TI - Virus isolate from carp: genetic characterization reveals a novel picornavirus with two aphthovirus 2A-like sequences. AB - Picornaviruses have been isolated from a variety of hosts, mainly mammals and birds. Here, we describe the sequence analysis of carp picornavirus 1 (CPV-1) F37/06 that was isolated from an organ pool (heart, brain, liver) of a common carp (Cyprinus carpio). This carp perished after an accidental discharge of liquid manure into a fish pond and presented without obvious clinical symptoms. Experimental intraperitoneal infection of young carp with CPV-1 revealed no clinical signs, but the virus was re-isolated from various organs. Sequence analysis of almost the complete genome (7632 nt excluding the poly-A tract) revealed a novel picornavirus clade. In phylogenetic trees, the polymerase sequence clusters with parechoviruses, duck hepatitis A virus, eel picornavirus and aquamavirus A. The ORF includes 6807 nt and encodes a polyprotein of 2269 amino acids. CPV-1 has a genome layout like that of picornaviruses except for the presence of two aphthovirus 2A-like NPGP sequence motifs: VPg+5'UTR[1AB-1C-1D 2A1(npgp)/2A2(npgp)-2B-2C(ATPase)/3A-3B(VPg)-3C(pro)-3D(pol)]3'UTR-poly-A. 2A1(npgp) and 2A2(npgp) are separated by 133 amino acids. The proteins 2A2(npgp), 2B, 3A and 3B(VPg) have no significant similarity to the corresponding proteins of other picornaviruses. Amino acid identities of the orthologous proteins P1, 2C, 3C(pro) and 3D(pol) range from 16.4 to 40.8 % in the eel picornavirus/CPV-1 comparison. 3D(pol) shows the closest similarity to eel picornavirus, with an amino acid identity of 40.8 %, followed by human parechovirus (36.5 %), duck hepatitis A virus (32.7 %) and swine pasivirus (29.3 %). Both the unique genome organization and low sequence similarity support the assignment of CPV-1 to a novel picornavirus species within a novel genus. PMID- 24337967 TI - Do features of Mozart's letter-writing style indicate the presence of a neuropsychiatric disorder? Controversies about the Basle letters. AB - In recent decades, several scientific publications have come to the conclusion that Wolfgang Amadeus Mozart might have had a Tourette syndrome. Other papers, however, have questioned this hypothetical diagnosis. The evidence for this diagnosis was mostly based on the so-called Basle letters, letters that Mozart wrote to his cousin when aged around 20 years. The letters have common stylistic characteristics such as frequent mention of erotic topics and, in particular, intensive use of scatological terms. However, these characteristics cannot be interpreted as clearly indicating a Tourette syndrome but may rather be related to psychosocial and cultural aspects of that time. There is little evidence for a Tourette syndrome from other sources, such as reports of behavioural abnormalities, and the evidence is not convincing. PMID- 24337968 TI - Redox regulation of apurinic/apyrimidinic endonuclease 1 activity in Long-Evans Cinnamon rats during spontaneous hepatitis. AB - The Long-Evans Cinnamon (LEC) rat is an animal model for Wilson's disease. This animal is genetically predisposed to copper accumulation in the liver, increased oxidative stress, accumulation of DNA damage, and the spontaneous development of hepatocellular carcinoma. Thus, this animal model is useful for studying the relationship of endogenous DNA damage to spontaneous carcinogenesis. In this study, we have investigated the apurinic/apyrimidinic endonuclease 1 (APE1) mediated excision repair of endogenous DNA damage, apurinic/apyrimidinic (AP) sites, which is highly mutagenic and implicated in human cancer. We found that the activity was reduced in the liver extracts from the acute hepatitis period of LEC rats as compared with extracts from the age-matched Long-Evans Agouti rats. The acute hepatitis period had also a heightened oxidative stress condition as assessed by an increase in oxidized glutathione level and loss of enzyme activity of glyceraldehyde 3-phosphate dehydrogenase, a key redox-sensitive protein in cells. Interestingly, the activity reduction was not due to changes in protein expression but apparently by reversible protein oxidation as the addition of reducing agents to extracts of the liver from acute hepatitis period reactivated APE1 activity and thus, confirmed the oxidation-mediated loss of APE1 activity under increased oxidative stress. These findings show for the first time in an animal model that the repair mechanism of AP-sites is impaired by increased oxidative stress in acute hepatitis via redox regulation which contributed to the increased accumulation of mutagenic AP-sites in liver DNA. PMID- 24337969 TI - Differences in cerebral perfusion according to phenotypes of essential tremor: brain perfusion SPECT study using SPM analysis. AB - Essential tremor (ET) is one of the most common movement disorders. However, few studies regarding the differences of pathophysiology according to phenotypes of ET have been reported. We investigated whether a functional difference occurs between ET with only a limb tremor (L-ET) and ET with only a head tremor (H-ET). We recruited 13 patients with L-ET, 10 patients with H-ET, and 33 healthy subjects. We compared the severity of tremor symptoms using the Fahn-Tolosa-Marin rating scale (FTM) to compare L-ET with H-ET. All subjects underwent magnetic resonance imaging and perfusion SPECT of the brain. The total score of FTM was significantly higher in the L-ET than in the H-ET. However, Part A in FTM did not show significant differences between the two ET groups. A brain perfusion SPECT analysis demonstrated no significant difference between L-ET and H-ET, but a regional perfusion of subjects with ET compared with healthy subjects showed hypoperfusion in the insular, cingulate gyrus, frontal lobe, and cerebellum. In conclusion, we suggested that cerebellar dysfunction might be involved in the pathogenesis of ET. In addition, we assumed that ET has the same pathogenesis in the origin of the disease, regardless of the clinical difference of ET. PMID- 24337970 TI - Guilty bystanders: nurse-like cells as a model of microenvironmental support for leukemic lymphocytes. AB - B-cell chronic lymphocytic leukemia (B-CLL) is one of the most common leukemias among the elderly and, despite many efforts, still stays incurable. Recent studies point to the microenvironment as the critical factor providing leukemic lymphocytes with pro-survival signals. Thus, the neighboring cells appear to be a perfect target for antileukemic therapy. Nurse-like cells (NLCs) largely contribute to CLL microenvironmental support. We developed the CLL lymphocyte/NLC co-culture model for the investigation of microenvironmental interactions. Viability and apoptosis were investigated in CLL lymphocytes treated with dexamethasone (DEX) and chlorambucil (CLB), with and without NLCs' support. For the first time, the capacity of DEX and CLB to affect NLCs viability was also evaluated. Apoptosis-associated gene expression profiles of leukemic lymphocytes ex vivo and cultured with NLCs were assessed by expression arrays. CLL lymphocytes escaped spontaneous apoptosis for several months when cultured with NLCs. The presence of NLCs significantly reduced apoptosis induced with DEX and CLB (p < 0.001; p = 0.012, respectively), and their protective effect was more evident than the effect of recombinant SDF1. Both DEX and CLB also decreased NLCs viability, but to a lesser extent (mean viability in DEX-treated cultures was 37.79% in NLCs compared to 29.24% in lymphocytes). NLCs induced the expression of important anti-apoptotic genes in cultured CLL lymphocytes; median expression of BCL2, SURVIVIN, BCL2A1, and XIAP was significantly higher as compared to ex vivo status. The CLL lymphocyte/NLC co-culture makes up the convenient and close to the natural-state model for studying the relationship between leukemic cells and the microenvironment. Direct cell-to-cell contact with NLCs increases the expression of anti-apoptotic genes in CLL lymphocytes, thus protecting them against induced apoptosis. As the effect of antileukemic drugs is not so apparent in NLCs, the combined therapy targeted at both lymphocytes and the microenvironment should be considered for CLL patients. Simultaneous aiming at the disruption of several different signaling pathways and/or anti-apoptotic proteins may further improve treatment efficiency. PMID- 24337972 TI - Is it really search or just matching? The influence of Goodness, number of stimuli and presentation sequence in same-different tasks. AB - The Goodness of Garner dot patterns has been shown to influence same-different response times in a specific way, which has led to the formulation of a memory search model of pattern comparison. In this model, the space of possible variations of each pattern is searched separately for each pattern in the comparison, resulting in faster response times for patterns that have fewer alternatives. Compared to an alternative explanation based on stimulus encoding plus mental rotation, however, the existing data strongly favor this explanation. To obtain a more constraining set of data to distinguish between the two possible accounts, we extended the original paradigm to a situation in which participants needed to compare three, rather than two patterns and varied the way the stimuli were presented (simultaneously or sequentially). Our findings suggest that neither the memory search nor the encoding plus mental rotation model provides a complete description of the data, and that the effects of Goodness must be understood in a combination of both mechanisms, or in terms of cascades processing. PMID- 24337971 TI - On the time course of attentional focusing in older adults. AB - Many sensory and cognitive changes accompany normal ageing, including changes to visual attention. Several studies have investigated age-related changes in the control of attention to specific locations (spatial orienting), but it is unknown whether control over the distribution or breadth of attention (spatial focus) also changes with age. In the present study, we employed a dual-stream attentional blink task and assessed changes to the spatial distribution of attention through the joint consequences of temporal lag and spatial separation on second-target accuracy. Experiment 1 compared the rate at which attention narrows in younger (mean age 22.6, SD 4.25) and older (mean age 66.8, SD 4.36) adults. The results showed that whereas young adults can narrow attention to one stream within 133 ms, older adults were unable to do the same within this time period. Experiment 2 showed that older adults can narrow their attention to one stream when given more time (266 ms). Experiment 3 confirmed that age-related changes in retinal illuminance did not account for delayed attentional narrowing in older adults. Considered together, these experiments demonstrate that older adults can narrow their attentional focus, but that they are delayed in initiating this process compared to younger adults. This finding adds to previously reported reductions in attentional dynamics, deficits in inhibitory processes, and reductions in posterior parietal cortex function that accompany normal ageing. PMID- 24337973 TI - Tracking the attentional blink profile: a cross-sectional study from childhood to adolescence. AB - This cross-sectional study is the first to examine the developmental trajectory of temporal attention control from childhood to adolescence. We used a rapid serial visual presentation paradigm, calling for the identification of two targets (T1 and T2) embedded in a distractor stream. In adults, manipulating the lag time within the target doublet typically leads to pronounced impairment in report for T2, when it follows T1 after approximately 200 ms, with one intervening distractor (lag 2); this is referred to as the attentional blink (AB). Participants, however, tend to identify T2 more often when the targets have occurred in a row ("lag-1 sparing"), or are separated by larger lag times, resulting in a hook-shaped accuracy profile. Here, we investigated the extent to which this AB profile undergoes systematic developmental changes in 204 students aged between 6 and 16 years (grades 1-10). T1-T2 lags varied from zero up to seven intervening distractors. Behavioral accuracy in younger children (grades 1 2) was found to follow a linear path, having its minimum at the earliest lag. Lag 1 sparing, accompanied by a relative accuracy loss in the AB interval, first appeared in grade 3, and became more robust in grade 4. From grades 5-6, the hook shaped profile remained stable, with steady increases in overall performance up through the highest grades. This suggests that younger children's performance is limited by processing speed, while from preadolescence onwards, children are increasingly able to identify rapid target sequences at the cost of an interference sensitive, higher control system. PMID- 24337974 TI - Pyrosequencing analysis of BRCA1 methylation level in breast cancer cells. AB - BRCA1 and BRCA2 genes are crucial for double-strand break repair by homologous recombination, and mutations in these genes are responsible for most familial breast carcinomas. Cells with inactivating mutations of the BRCA1 or BRCA2 tumor suppressor genes are sensitive to poly (ADP-ribose) polymerase-1 (PARP1) inhibitors. Already in 2010, it has been predicted, that BRCA1 hypermethylation might be sensitive to PARP1 inhibitor. However, till today, a statistically significant proof has been missing, and the effectiveness of PARP1 inhibitors for breast cancer caused by BRCA1 promoter hypermethylation remained elusive. Pyrosequencing has been proposed as an optimal method to investigate the methylation status of the BRCA1 genes. Here, we show for the first time that BRCA1 CpG island hypermethylation is sensitive to PARP1 inhibitors. In clinical settings, this might improve treatment response and provide a more personalized therapy for breast cancer patients. Furthermore, the determination of methylation status of BRCA1 and other genes of the BRCA/homologous recombination (HR) pathway may be an important predictive classifier of response to PARP inhibitor therapy. PMID- 24337975 TI - Association of glutathione S-transferase M1, T1, and P1 polymorphisms with renal cell carcinoma: evidence from 11 studies. AB - The glutathione S-transferases (GSTs) are a gene superfamily of phase II metabolic enzymes that has attracted a considerable attention as a candidate gene for renal cell carcinoma (RCC) based on its enzyme function as a key factor in biotransformation pathways. In the past decade, a number of case-control studies were conducted to investigate the association of GST genetic polymorphisms and RCC risk. However, studies on the association between GST (GSTM1, GSTT1, and GSTP1) polymorphisms and RCC remain to be conflicting. To derive a more precise estimation of the relationship, a meta-analysis of 2,189 cases and 3,817 controls from 11 case-control studies was performed. Overall, the summarized odds ratio for RCC of the GSTM1 null and GSTT1 null polymorphisms was 1.02 (95% confidence interval (CI) 0.91-1.15, P = 0.70) and 1.28 (95% CI 0.96-1.72, P = 0.09), respectively. No significant results were observed in heterozygous and homozygous genotypes when compared with wild-type genotype for GSTP1 I105V polymorphism. However, the GSTM1-GSTT1 interaction analysis showed that the dual null genotype of GSTM1/GSTT1 was significantly associated with an increased RCC risk (odds ratio (OR) = 1.42, 95% CI 1.14-1.76, P = 0.001). In the stratified analyses by ethnicity, significant gene-disease association was obtained among Asians for GSTT1 and GSTP1 polymorphisms. In our meta-analysis, the associations between variations of GSTs and RCC may vary in different ethnic populations, and the interaction between unfavorable GST genotypes may exist. PMID- 24337976 TI - Expanding the study of internet gambling behavior: trends within the Icelandic lottery and sportsbetting platform. AB - As rates of Internet gambling participation increase worldwide, so too does the need to understand how people engage in this form of gambling. This study represents the first examination of actual Internet gambling records within Iceland, a Nordic country with an active Internet lottery market that imposes strict regulations on gambling operator licenses. We summarized electronic betting records of a cohort of subscribers to the Internet betting service provider Islensk Getspa. We observed that the typical subscriber bet approximately 3 days per month and made fewer than two bets per gambling day, each worth approximately the equivalent of $4 US. Subscribers lost the bulk (96%) of the amount they wagered, for a total loss of approximately $40 across the 2 year window of observation. Although these observations do not support the view of Internet gambling as an activity that is inherently risky for the typical subscriber, we did observe discontinuity across the distributions of gambling behavior, with the top 1% of subscribers making more than three bets per day. PMID- 24337977 TI - A method developed for determination of heptachlor and its metabolites from pork. AB - A new method has been developed to determine heptachlor and its metabolites heptachlor-exo-epoxide and heptachlor-endo-epoxide in pork. The pork samples were extracted with acetone-n-hexane (2:8, V:V) and cleaned up by gel permeation chromatography and florisil solid-phase extraction cartridge. The extract was then determined by gas chromatography equipped with electron capture detector (GC ECD), followed by validation using gas chromatography-mass spectrometry (GC-MS) with negative chemical ionization. Linearity of calibration curves ranged from 0.01 to 0.5 mg L(-1), with correlation coefficients of more than 0.9980 for GC ECD and GC-MS, respectively. At spiked concentrations of 0.01, 0.05, and 0.1 mg kg(-1), the average recovery and relative standard deviation values were 87.1 102.2 and 4.0-11.3%, respectively. The limit of quantification for each analyte was 0.01 mg kg(-1), which satisfied the current maximum residue limit permitted in pork. Our results showed that the method developed was successfully used to determine heptachlor and heptachlor epoxide residues in real pork samples. PMID- 24337978 TI - Randomised, double-blind, placebo-controlled, dose-escalating phase I study of QGC001, a centrally acting aminopeptidase a inhibitor prodrug. AB - BACKGROUND AND OBJECTIVES: Inhibition of brain aminopeptidase A (APA), which converts angiotensin II into angiotensin III, has emerged as a novel antihypertensive treatment, as demonstrated in several experimental animal models. QGC001 (originally named RB150) is a prodrug of the specific and selective APA inhibitor EC33, and as such it is the prototype of a new class of centrally acting antihypertensive agents. Given by the oral route in hypertensive rats, it enters the brain and generates EC33, which blocks the brain renin angiotensin system activity and normalises blood pressure. The aim of the present study was to evaluate the safety, pharmacokinetics and pharmacodynamic effects of QGC001 in humans. DESIGN AND METHODS: Fifty-six healthy male volunteers were randomly assigned to receive in double-blind and fasted conditions single oral doses of 10, 50, 125, 250, 500, 750, 1,000 and 1,250 mg of QGC001 (n = 6/dose) or placebo (n = 2/dose). We measured plasma and urine concentrations of both QGC001 and EC33 by liquid chromatography-tandem mass spectrometry, plasma renin concentrations (PRC), plasma and free urine aldosterone (PAldo and UAldo), plasma copeptine (PCop), and plasma and urine cortisol (PCort and UCort) concentrations, and supine systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) at various time points. RESULTS: All doses of QGC001 were clinically and biologically well-tolerated. Peak plasma concentrations (Cmax) of QGC001 and EC33 increased linearly with the dose, with a median time to reach Cmax (tmax) of 1.5 h for QGC001 and 3.0 h for EC33. The median plasma elimination half-life of QGC001 was 1.6 h consistently throughout doses. Urinary excretion of QGC001 and EC33 was below 2% of the administered dose. When compared with placebo, QGC001 did not significantly change PRC, PAldo, UAldo, PCop, PCort or UCort. No significant change was observed for supine HR, SBP and DBP in any treatment group. CONCLUSION: Single oral administration of QGC001 up to 1,250 mg in healthy volunteers was well-tolerated. Following oral administration, QGC001 is absorbed via the gastrointestinal tract and converted partially into its active metabolite EC33 in plasma. As in animal experiments, in normotensive subjects QGC001 had no effect on the systemic renin-angiotensin-aldosterone parameters and on PCop concentrations, a marker of vasopressin release. In normotensive subjects, a single dose of QCG001 had no effect on SBP, DBP or HR. These data support further evaluation of multiple oral doses of QGC001 in human volunteers and its clinical efficacy in hypertensive patients. PMID- 24337979 TI - Understanding proximal-distal economic projections of the benefits of childhood preventive interventions. AB - This paper discusses the steps and decisions involved in proximal-distal economic modeling, in which social, behavioral, and academic outcomes data for children may be used to inform projections of the economic consequences of interventions. Economic projections based on proximal-distal modeling techniques may be used in cost-benefit analyses when information is unavailable for certain long-term outcomes data in adulthood or to build entire cost-benefit analyses. Although examples of proximal-distal economic analyses of preventive interventions exist in policy reports prepared for governmental agencies, such analyses have rarely been completed in conjunction with research trials. The modeling decisions on which these prediction models are based are often opaque to policymakers and other end-users. This paper aims to illuminate some of the key steps and considerations involved in constructing proximal-distal prediction models and to provide examples and suggestions that may help guide future proximal-distal analyses. PMID- 24337980 TI - Do neighborhood attributes moderate the relationship between alcohol establishment density and crime? AB - Although numerous studies have found a positive association between the density of alcohol establishments and various types of crime, few have examined how neighborhood attributes (e.g., schools, parks) could moderate this association. We used data from Minneapolis, MN with neighborhood as the unit of analysis (n = 83). We examined eight types of crime (assault, rape, robbery, vandalism, nuisance crime, public alcohol consumption, driving while intoxicated, underage alcohol possession/consumption) and measured density as the total number of establishments per roadway mile. Neighborhood attributes assessed as potential moderators included non-alcohol businesses, schools, parks, religious institutions, neighborhood activism, neighborhood quality, and number of condemned houses. Using Bayesian techniques, we created a model for each crime outcome (accounting for spatial auto-correlation and controlling for relevant demographics) with an interaction term (moderator * density) to test each potential moderating effect. Few interaction terms were statistically significant. The presence of at least one college was the only neighborhood attribute that consistently moderated the density-crime association, with the presence of a college attenuating the association between the density and three types of crime (assaults, nuisance crime, and public consumption). However, caution should be used when interpreting the moderating effect of college presence because of the small number of colleges in our sample. The lack of moderating effects of neighborhood attributes, except for presence of a college, suggests that the addition of alcohol establishments to any neighborhood, regardless of its other attributes, could result in an increase in a wide range of crime. PMID- 24337981 TI - Orthopaedic triage at a physiotherapist-led 'Musculoskeletal Assessment Clinic': a seven-month service evaluation of outcomes. AB - BACKGROUND: A number of clinical specialist physiotherapist (CSP)-led musculoskeletal triage clinics have been established in the Republic of Ireland as a means of managing patients referred for an outpatient orthopaedic consultation. AIMS: The purpose of this study was to evaluate the outcomes of a recently established 'Musculoskeletal Assessment Clinic' (MAC) in St Vincent's University Hospital (SVUH) Dublin. We identified the (a) number of patients independently managed by the CSPs and (b) conversion rate to orthopaedic intervention as a useful measure of this. METHODS: University College Dublin Research Ethics Committee granted ethical exemption and the Clinical Audit Department of SVUH approved the study. A retrospective service evaluation was carried out on all orthopaedic patients who attended the MAC between January and July 2012. Data were analysed using SPSS v20 using descriptive statistics. RESULTS: Seven-hundred and fourteen patients attended the MAC, 54 % of whom were female; mean age 50 years (range 12-89). The majority of patients were diagnosed with low back pain (35 %) and knee osteoarthritis (16 %). The majority of patients who attended the MAC (76 %) were independently managed by the CSPs without need for orthopaedic consultation; from a valid sample (n = 110), 80 patients required orthopaedic intervention, a conversion rate of 73 %. The most common interventions were arthroplasty (22 %) and arthroscopy (16 %). CONCLUSIONS: The findings of this service evaluation indicate that a significant number of patients referred for an orthopaedic consultation may be managed independently by a CSP and that onward referrals for orthopaedic consultation were highly appropriate. PMID- 24337982 TI - Extensor pollicis et indicis communis with triple slips in a bilateral case of accessory muscles of the hand. AB - The presence and disposition of supernumerary tendons in the fourth extensor compartment of the wrist have been described by several authors. The aim of this communication was to describe a finding in a study of an anatomical dissection of an adult cadaver that presents a rare disposition of extensor tendons in the fourth extensor compartment of both wrists. In the right wrist, we found an extensor pollicis et indicis communis with three slips: two toward the index finger and one toward the thumb. We found no similar reports in a review of the literature. Additionally, we found an extensor indicis radialis in the left wrist. In both hands, the course of accessory slips was modified by fiber derived from intertendinous fascia. Although this represents a small percentage of the distribution of tendons of the dorsal hand, knowledge of these anatomical variations and their relationships to intertendinous fascia is critical for clinical decisions because this area is used frequently in treatments related to tendon graft, transfer, and transplantation. PMID- 24337984 TI - The contribution of Cdc2 in rotenone-induced G2/M arrest and caspase-3-dependent apoptosis. AB - Neuronal cell cycle reentry maintained in a G2-like state before cell death, has been confirmed in dopaminergic neurons of patients with Parkinson's disease (PD). Caspase-3 is a final effector in apoptotic dopaminergic neurons in patients. The association of aberrant G2/M regulation with caspase-3 dependent apoptosis remains to be elucidated. Cell division cycle protein 2 (Cdc2) is a key player in G2/M transition in mitotic cells. Although the deregulation of Cdc2 correlated with the control of apoptosis in neurons, the molecular pathway by which Cdc2 involves in apoptosis is not clear. In a rotenone-based cell model of PD, we demonstrated that rotenone arrested cell cycle at G2/M phase and activated caspase-3 both in cytoplasm and nucleus. The decreased activity of Cdc2 by roscovitine or rotenone enhanced G2/M arrest. The increased cells in G2/M arrest by rotenone upregulated the expression of Cdc2. Suppression of Cdc2 expression downregulated cleaved caspase-3/9 and delayed cell apoptosis. Used together, the upregulation of Cdc2 contributes to rotenone-induced caspase-3/9-dependent apoptosis, which is associated with the enhancement of G2/M arrest. Our results suggest the deregulation of Cdc2 as a transition between cell cycle arrest and cell death. PMID- 24337985 TI - Ischemic postconditioning protects the neurovascular unit after focal cerebral ischemia/reperfusion injury. AB - Recently, cerebral ischemic postconditioning (Postcond) has been shown to reduce infarction volume in cerebral ischemia/reperfusion (I/R) injury. However, it is unclear if ischemic Postcond offers more extensive neuroprotection than current therapies. The aim of this study was to investigate the neuroprotective effects of ischemic Postcond on the neurovascular unit (NVU). A middle cerebral artery occlusion rat model was used; cerebral infarct volumes, neurologic scores, and transmission electron microscopy were evaluated 24 h after reperfusion. We used Evans blue extravasation, immunohistochemistry, and Western blot analyses to evaluate the integrity of the blood brain barrier (BBB) and the distribution and expression of the tight junction (TJ)-associated proteins of claudin-5 and occludin in brain microvessel endothelium. The Postcond group showed significantly reduced infarct volumes and decreased neurologic impairment scores compared to the I/R group. Also, injuries to the cerebral microvascular endothelial cells, astrocytes, and neurons were minimized in the Postcond group. The permeability of the BBB increased in both the I/R and Postcond groups, but the Postcond group showed a significant decrease in permeability than the I/R group. Expression of both claudin-5 and occludin were higher in the Postcond groups compared to the I/R group, but expression of both proteins decreased in the I/R and Postcond groups compared to the sham group. The results of our study suggest that ischemic Postcond is an effective way to reduce injury to neurons, astrocytes, and endothelial cells, to increase protein expressions of TJ associated proteins, and to improve BBB intergrity affected by focal I/R. Ischemic Postcond could protect the NVU from I/R injury. PMID- 24337987 TI - As plant scientists who faced the Fukushima nuclear disaster. PMID- 24337986 TI - Defining incidence and risk factors of venous thromboemolism after hepatectomy. AB - BACKGROUND: The incidence of venous thromboembolism (VTE) among patients undergoing hepatic surgery is poorly defined, leading to varied use of VTE prophylaxis among surgeons. We sought to define the incidence of VTE after liver surgery and identify risk factors associated with VTE. METHODS: Incidence of VTE and associated risk factors within 90 days of hepatic resection between 2006 and 2012 at a major academic center was analyzed. Risk factors for VTE were identified using univariate and multivariate analyses. RESULTS: A total of 599 patients were included in the study cohort; 30 (5.0 %) had a prior history of VTE. The indications for surgery were malignant (90.8 %) and benign lesions (9.2 %). The majority of patients underwent a minor hepatectomy (<3 Couinaud segments; n = 402, 67.1 %) while 195 (32.6 %) patients underwent a major hepatectomy (>=3 Couinaud segments). Three hundred seven (51.3 %) patients were started on VTE chemoprophylaxis preoperatively with 407 (67.8 %) patients receiving VTE chemoprophylaxis within 24 h of surgery. Twenty-eight (4.7 %) patients developed VTE; 20 (3.3 %) had deep venous thrombosis (DVT), 11 (1.8 %) had pulmonary embolism (PE), and three (0.5 %) developed both DVT and PE. Among the VTE patients, 23 (82.1 %) had received VTE chemoprophylaxis. On multivariate analyses, history of VTE (odds ratio [OR] 4.51, 95 % confidence interval [CI] 1.81-17.22, P = 0.03), prolonged operative time (OR 1.17 per additional hour, 95 % CI 1.04-1.32, P = 0.009), and increased length of stay (LOS) (OR 1.07, 95 % CI 1.02-1.12, P = 0.01) were independent risk factors for VTE. CONCLUSION: VTE within 90 days of hepatic resection is common, occurring in nearly one in 20 patients. Most VTE events occurred among patients who received current best practice prophylaxis for VTE. More aggressive strategies to identify and reduce the risk of VTE in patients at highest risk of VTE, including those with a history of VTE, extended operative time, and prolonged LOS, are warranted. PMID- 24337988 TI - Mapping NAD(+) metabolism in the brain of ageing Wistar rats: potential targets for influencing brain senescence. AB - Over the last decade, the importance of NAD(+) has expanded beyond its role as an essential cofactor for energy metabolism. NAD(+) has emerged as a major signalling molecule that serves as the sole substrate for several enzymatic reactions including the DNA repair enzyme, poly(ADP-ribose) polymerase (PARP), NAD-dependent protein deacetylases or CD38, and transcriptional factors by a new class of histone deacetylases known as sirtuins. NAD(+) levels are regulated by the metabolic status and cellular stress caused by oxidative stress and DNA damage. Since a detailed study of NAD(+) metabolism in the healthy ageing mammalian brain is nascent, we examined the effect of ageing on intracellular NAD(+) metabolism in different brain regions in female Wistar rats in young (3 months), middle aged (12 months) and older adults (24 months). Our results are the first to show a significant decline in intracellular NAD(+) levels and NAD:NADH ratio with ageing in the CNS, occurring in parallel to an increase in lipid peroxidation and protein oxidation (o- and m-tyrosine) and a decline in total antioxidant capacity. Hyperphosphorylation of H2AX levels was also observed together with increased PARP-1 and PARP-2 expression, and CD38 activity, concomitantly with reduced NAD(+) and ATP levels and SIRT1 function in the cortex, brainstem, hippocampus and cerebellum. Reduced activity of mitochondrial complex I-IV and impaired maximum mitochondrial respiration rate were also observed in the ageing rat brain. Among the multiple physiological pathways associated with NAD(+) catabolism, our discovery of CD38 as the major regulator of cellular NAD(+) levels in rat neurons indicates that CD38 is a promising therapeutic target for the treatment of age-related neurodegenerative diseases. PMID- 24337989 TI - Antinociceptive effect of matrine on vincristine-induced neuropathic pain model in mice. AB - Chemotherapy drugs treatment causes neuropathic pain, hyperalgesia and allodynia are common components of neuropathic pain, so effectively therapeutic strategy is required. In this study, we evaluated the antinociceptive effects of matrine on vincristine-induced neuropathic pain in mice. Vincristine (100 MUg/kg i.p.) was administered once per day for 7 days (day 0-6) in mice. Matrine (15, 30, 60 mg/kg, i.p.) was repeated administration in early phase (day 0-6) or late phase (day 7-13). Hyperalgesia and allodynia were evaluated by withdrawal response using von Frey filaments, plantar and cold-plate on 7, 14 and 21 day. Injection of vincristine produced mechanical hyperalgesia and cold allodynia. Matrine was found to produce a protective role in both von Frey filaments and cold-plate test. The analysis of the effect supports the hypothesis that matrine is useful in therapy of vincristine-induced neuropathic pain. In conclusion, this study demonstrates that administration of matrine is associated with antinociceptive effect on mechanical and cold stimuli in a mice model of vincristine-induced neuropathy pain. PMID- 24337990 TI - Field performance evaluation during fog-dominated wintertime of a newly developed denuder-equipped PM1 sampler. AB - This study presents the performance evaluation of a novel denuder-equipped PM1 (particles having aerodynamic diameter less than 1 MUm) sampler, tested during fog-dominated wintertime, in the city of Kanpur, India. One PM1 sampler and one denuder-equipped PM1 sampler were co-located to collect ambient PM1 for 25 days. The mean PM1 mass concentration measured on foggy days with the PM1 sampler and the denuder-equipped PM1 sampler was found to be 165.95 and 135.48 MUg/m(3), respectively. The mean PM1 mass concentration measured on clear days with the PM1 sampler and the denuder-equipped PM1 sampler was observed to be 159.66 and 125.14 MUg/m(3), respectively. The mass concentration with denuder-fitted PM1 sampler for both foggy and clear days was always found less than the PM1 sampler. The same drift was observed in the concentrations of water-soluble ions and water soluble organic carbon (WSOC). Moreover, it was observed that the use of denuder leads to a significant reduction in the PM positive artifact. The difference in the concentration of chemical species obtained by two samplers indicates that the PM1 sampler without denuder had overestimated the concentrations of chemical species in a worst-case scenario by almost 40 %. Denuder-fitted PM1 sampler can serve as a useful sampling tool in estimating the true values for nitrate, ammonium, potassium, sodium and WSOC present in the ambient PM. PMID- 24337991 TI - Levels and risks of particulate-bound PAHs in indoor air influenced by tobacco smoke: a field measurement. AB - Considering tobacco smoke as one of the most health-relevant indoor sources, the aim of this work was to further understand its negative impacts on human health. The specific objectives of this work were to evaluate the levels of particulate bound PAHs in smoking and non-smoking homes and to assess the risks associated with inhalation exposure to these compounds. The developed work concerned the application of the toxicity equivalency factors approach (including the estimation of the lifetime lung cancer risks, WHO) and the methodology established by USEPA (considering three different age categories) to 18 PAHs detected in inhalable (PM10) and fine (PM2.5) particles at two homes. The total concentrations of 18 PAHs (SigmaPAHs) was 17.1 and 16.6 ng m(-3) in PM10 and PM2.5 at smoking home and 7.60 and 7.16 ng m(-3) in PM10 and PM2.5 at non-smoking one. Compounds with five and six rings composed the majority of the particulate PAHs content (i.e., 73 and 78 % of SigmaPAHs at the smoking and non-smoking home, respectively). Target carcinogenic risks exceeded USEPA health-based guideline at smoking home for 2 different age categories. Estimated values of lifetime lung cancer risks largely exceeded (68-200 times) the health-based guideline levels at both homes thus demonstrating that long-term exposure to PAHs at the respective levels would eventually cause risk of developing cancer. The high determined values of cancer risks in the absence of smoking were probably caused by contribution of PAHs from outdoor sources. PMID- 24337992 TI - Accumulated sediments in a detention basin: chemical and microbial hazard assessment linked to hydrological processes. AB - Accumulated sediments in a 32,000-m(3) detention basin linked to a separate stormwater system were characterized in order to infer their health hazards. A sampling scheme of 15 points was defined according to the hydrological behaviour of the basin. Physical parameters (particle size and volatile organic matter content) were in the range of those previously reported for stormwater sediments. Chemical analyses on hydrocarbons, PAHs, PCBs and heavy metals showed high pollutant concentrations. Microbiological analyses of these points highlighted the presence of faecal indicator bacteria (Escherichia coli and intestinal enterococci) and actinomycetes of the genus Nocardia. These are indicative of the presence of human pathogens. E. coli and enterococcal numbers in the sediments were higher at the proximity of the low-flow gutter receiving waters from the catchment. These bacteria appeared to persist over time among urban sediments. Samples highly contaminated by hydrocarbons were also shown to be heavily contaminated by these bacteria. These results demonstrated for the first time the presence of Nocardial actinomycetes in such an urban context with concentrations as high as 11,400 cfu g(-1). PMID- 24337993 TI - Evaluating the exchange of DDTs between sediment and water in a major lake in North China. AB - A large-scale sampling program was conducted to simultaneously collect surface water, overlying water, pore water, and sediment samples at monthly intervals between March and December 2010 from Baiyangdian Lake, North China to assess the distribution of DDTs and determine the net direction of sediment-water exchange. Total DDT concentrations ranged 2.36-22.4 ng/L, 0.72-21.9 ng/L, 2.25-33.7 ng/L, and 4.42-7.29 ng/g in surface water, overlying water, pore water, and sediments, respectively, which were at the intermediate levels compared to those of other area around the world. Seasonal variations of DDTs were featured by higher concentration in summer. This was likely associated with (a) the increase of land runoff in the summer and (b) application of dicofol and DDT-containing antifouling paints for ships in summer. Sediment-water fugacity ratios of the DDT isomers were used to predict the direction of the sediment-water exchange of these isomers. The sediment-surface water, sediment-overlying water, and sediment pore water fugacity ratios of DDT isomers averaged 0.34, 0.44, and 0.1, which are significantly lower than the equilibrium status (1.0), suggesting that the net flux direction were from the water to sediment and the sediment acted as a sink for the DDTs. The difference of DDT concentrations between sediment and water samples was found to be an important factor affecting the diffusion of DDT from the water to sediment. PMID- 24337994 TI - Spatial distribution and reduction of PCDD/PCDF toxic equivalents along three shallow lowland reservoirs. AB - Reservoirs situated along a river continuum are ecosystems where rates of transfer of suspended matter and associated micropollutants are reduced due to sedimentation, accumulation, and biological and physical transformation processes. Among the micropollutants, PCDDs and PCDFs are substances that are highly toxic and carcinogenic for humans and animals. They are emitted and dispersed in the environment throughout the whole catchment area and may accumulate in aquatic and terrestrial food chains, creating a risk for human health. A wealth of data exists indicating the increase in the concentrations of pollutants along a river continuum. A comparative analysis of total, individual, and TEQ PCDD/PCDF concentrations in large lowland, shallow reservoirs located in different catchments ("I"-industrial/urban/agricultural, "U"-urban/agricultural, and "A"-agricultural/rural) showed decreases of the TEQ concentrations in bottom sediments along a gradient from the middle sections to the dam walls. Moreover, penta-, hexa-, and heptachlorinated CDD/CDF congeners were reduced from 28.8 up to 93.6 % in all three types of reservoirs. A further analysis of water samples from the inlets and outlets of the "A" reservoir confirmed this tendency. PMID- 24337995 TI - Stability of cocaine and its metabolites in municipal wastewater--the case for using metabolite consolidation to monitor cocaine utilization. AB - Transformations of cocaine and eleven of its metabolites were investigated in untreated municipal sewage at pH ~ 7 and 9, 23, and 31 degrees C. Results indicated that hydrolysis-possibly bacterially mediated-was the principal transformation pathway. Residues possessing alkyl esters were particularly susceptible to hydrolysis, with pseudo-first-order rate constants varying from 0.54 to 1.7 day(-1) at 23 degrees C. Metabolites lacking esters or possessing only a benzoyl ester appeared stable. Residues lacking alkyl esters did accumulate through hydrolysis of precursors, however. As noted previously, this may positively bias cocaine utilization estimates based on benzoylecgonine alone. Reported variability in metabolic excretion was used in conjunction with transformation data to evaluate different approaches for estimating cocaine loading. Results indicate that estimates derived from measurands that capture all major cocaine metabolites, such as COCtot (the sum of all measurable metabolites) and EChyd (the sum of all metabolites that can be hydrolyzed to ecgonine), may reduce uncertainty arising from variability in metabolite transformation and excretion, possibly to ~ 10 % RSD. This is more than a two-fold reduction relative to estimates derived from benzoylecgonine (>26 % RSD), and roughly equivalent to reported uncertainties from sources that are not metabolite specific (e.g., sampling frequency, flow variability). They and other composite measurands merit consideration from the sewage epidemiology community, beginning with efforts to evaluate the stability of the total cocaine load under realistic sewer conditions. PMID- 24337996 TI - Effects of permethrin exposure on antioxidant enzymes and protein status in Mediterranean clams Ruditapes decussatus. AB - The effects of permethrin (PER) on a panel of antoxidant enzymes; superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST) and indices of protein oxidation status (carbonylation and free thiols) were determined in digestive gland and gills of the clam Ruditapes decussatus. Animals were exposed to 100 ppb PER for 2 days. These enzyme activities increased significantly in digestive gland (p<0.05) after PER treatment and oxidative modification of proteins was detected in both gill and digestive gland extracts using redox proteomics. PER exposure significantly reduced the amount of protein free thiol groups in digestive gland rather than in gill, when compared to controls. Conversely, digestive gland showed significantly higher levels of carbonylated proteins than gill after PER exposure. Some proteins were successfully identified by mass spectrometry of tryptic peptides. Our data suggest that digestive gland of R. decussatus can be used as a model tissue for investigating environmental risk of PER contamination. PMID- 24337997 TI - Impact of lime-stabilized biosolid application on Cu, Ni, Pb and Zn mobility in an acidic soil. AB - A soil column leaching study was conducted on an acidic soil in order to assess the impact of lime-stabilized biosolid on the mobility of metallic pollutants (Cu, Ni, Pb and Zn). Column leaching experiments were conducted by injecting successively CaCl2, oxalic acid and ethylenediaminetetraacetic acid (EDTA) solutions through soil and biosolid-amended soil columns. The comparison of leaching curves showed that the transport of metals is mainly related to the dissolved organic carbon, pH and the nature of extractants. Metal mobility in the soil and biosolid-amended soils is higher with EDTA than with CaCl2 and oxalic acid extractions, indicating that metals are strongly bound to solid-phase components. The single application of lime-stabilized biosolid at a rate ranging from 15 to 30 t/ha tends to decrease the mobility of metals, while repeated applications (2 * 15 t/ha) increase metal leaching from soil. This result highlights the importance of monitoring the movement and concentrations of metals, especially in acid and sandy soils with shallow and smaller water bodies. PMID- 24337998 TI - Amendment application in a multi-contaminated mine soil: effects on soil enzymatic activities and ecotoxicological characteristics. AB - Several amendments were tested on soils obtained from an arsenopyrite mine, further planted with Arrhenatherum elatius and Festuca curvifolia, in order to assess their ability to improve soil's ecotoxicological characteristics. The properties used to assess the effects were: soil enzymatic activities (dehydrogenase, beta-glucosidase, acid phosphatase, urease, protease and cellulase), terrestrial bioassays (Eisenia fetida mortality and avoidance behaviour), and aquatic bioassays using a soil leachate (Daphnia magna immobilisation and Vibrio fischeri bioluminescence inhibition). The treatment with FeSO4 1 % w/w was able to reduce extractable As in soil, but increased the extractable Cu, Mn and Zn concentrations, as a consequence of the decrease in soil pH, in relation to the unamended soil, from 5.0 to 3.4, respectively. As a consequence, this treatment had a detrimental effect in some of the soil enzymatic activities (e.g. dehydrogenase, acid phosphatase, urease and cellulase), did not allow plant growth, induced E. fetida mortality in the highest concentration tested (100 % w/w), and its soil leachate was very toxic towards D. magna and V. fischeri. The combined application of FeSO4 1 % w/w with other treatments (e.g. CaCO3 1 % w/w and paper mill 1 % w/w) allowed a decrease in extractable As and metals, and a soil pH value closer to neutrality. As a consequence, dehydrogenase activity, plant growth and some of the bioassays identified those as better soil treatments to this type of multi-contaminated soil. PMID- 24337999 TI - Combined use of DGT and transplanted shrimp (Litopenaeus vannamei) to assess the bioavailable metals of complex contamination: implications for implementing bioavailability-based water quality criteria. AB - The diffusive gradients in thin films (DGT) were field deployed alongside the shrimp Litopenaeus vannamei at seven sites with different levels of contamination to assess the potentially bioavailable and toxic fraction of metal contaminants. After 7 days of exposure, several antioxidant biomarkers were quantified in hepatopancreas of exposed shrimps, and tissue levels as well as the total, dissolved, and DGT-labile concentrations of metal contaminants were determined in the pooled site samples. The results showed that the caged shrimps had high tissue contaminant concentrations and significantly inhibited antioxidant responses at the more contaminated sites. DGT-labile metal concentrations provided better spatial resolution of differences in metal contamination when compared with traditional bottle sampling and transplanted shrimp. The total, dissolved, and DGT-labile metal fractions were used to evaluate the potential bioavailability of metal contaminants, comparing with metal accumulation and further linking to antioxidant biomarker responses in tissues of exposed shrimps. Regression analysis showed the significant correlations between DGT-Cu concentrations and tissue-Cu and activities of some biomarker responses in the shrimp hepatopancreas. This indicated that DGT-labile Cu concentrations provided the better prediction of produced biological effects and of the bioavailability than the total or dissolved concentrations. The study supports the use of methods combining transplanted organisms and passive sampling for assessing the chemical and ecotoxicological status of aqueous environments and demonstrates the capability of the DGT technique as a powerful tool for measuring the bioavailability-based water quality in variable coastal environments. PMID- 24338000 TI - Source identification of inorganic airborne particle fraction (PM10) at ultratrace levels by means of INAA short irradiation. AB - Many studies have focused their attention on the determination of elements of toxicological and environmental interest in atmospheric particulate matter using analytical techniques requiring chemical treatments. The instrumental nuclear activation analysis technique allows achieving high sensitivity, good precision, and excellent limit of detection without pretreatment, also considering the problems related to the radioisotope characteristics (e.g., half-life time, interfering reactions, spectral interferences). In this paper, elements such as Al, As, Br, Cl, Cu, I, La, Mg, Mn, Na, Sb, Si, Ti, and V are studied in atmospheric PM10 sampled in downtown Rome: The relative radionuclides after activation of the sample are characterized by very short (ranging from 2.24 to 37.2 min) and short (ranging from 2.58 h to 2.70 days) half-lives. Furthermore, As, Br, La, Mn, and Sb were also determined for evaluating the aerosol characteristics. The results, elaborated considering the matrix effects and the interfering reaction contribution to the radioisotope formation (e.g., (28)Al generated by both (n,gamma) reaction from (27)Al and (n,p) reaction from (28)Si), show interesting values of As (0.3-6.1 ng m(-3)), Cu (22-313 ng m(-3)), Mn (17 125 ng m(-3)), V (7-63 ng m(-3)), higher than those determined in an area not influenced by autovehicular traffic, and significant levels of I (1-11 ng m(-3)) and Ti (25-659 ng m(-3)) in Rome PM10. The other elements show a pattern similar to the very few data present in the literature. It should be underlined the good correlation (r (2)) of Al vs. Mg (0.915) and Al vs. La (0.726), indicating a same sources for these species as well as Br-Sb showing a little lower correlation (0.623). This last hypothesis is confirmed by the study of the enrichment factors: Sb and Br may be attributed to anthropogenic sources; Cu, Cl, and I show a mixed origin (natural and anthropogenic), whereas Al, Si, Ti, Mn, Na, Mg, and As are of crustal origin. For having more information, a statistical approach based on the principal component analysis and the canonical discriminant analysis has been performed: All the samples (except one) are grouped in a cluster, and elements such as As, Br, Cu, I, La, Mn, Sb, Ti, and V are highly correlated, whereas Na and Cl and Mg and Al assemble in two different clusters. Finally, a comparison with other similar studies is reported showing interesting values for Al, As, Mg, Mn, and Ti. PMID- 24338001 TI - Field application of electrokinetic remediation for multi-metal contaminated paddy soil using two-dimensional electrode configuration. AB - In this study, we evaluated the feasibility of in situ electrokinetic remediation for arsenic (As)-, copper (Cu)-, and lead (Pb)-contaminated soil, in a pilot scale field application with two-dimensional electrode configurations. Square and hexagonal configurations with different electrode spacing, 1 m and 2 m, were investigated under a constant 100 V. A square configuration with electrode spacing of 2 m removed 61.5 % of As, 11.4 % of Cu, and 0.9 % of Pb, respectively, and a hexagonal configuration with the same spacing showed a higher removal efficiency in top (59 % of As, 0-0.5 m) and middle (53 % of As, 0.5-1.0 m) layers, but much lower removal efficiency in the bottom layer (1-1.5 m), which was thought to be due to groundwater flow through periodic rise and fall of tides. Fractionation analysis showed that As bound to Fe-Mn oxyhydroxide was the main form of As removed by the electrokinetic process. The two-dimensional configuration wasted less electrical energy by Joule heating, and required fewer electrode installations, compared to the one-dimensional electrode configuration. PMID- 24338003 TI - Biological insights into effective and antagonistic combinations of targeted agents with chemotherapy in solid tumors. AB - The potential for synergistic interactions between anticancer drugs has been used to justify combinations of agents in clinical trials. However, most combinations of targeted agents and chemotherapies have been tested in the clinic without previous systematic evaluation of their potential benefit. Preclinical studies may help in the identification of synergistic or antagonistic interactions. For antineoplastic therapies, these studies may reveal synergy or antagonism of the drug combinations. Synergy occurs when two agents given together produce higher antitumoral activity than the sum of each individual drug. This represents the ideal setting for the development of combinations of targeted agents and chemotherapies. On the other side, certain drug combinations have shown adverse results, indicative of an antagonistic effect. In this article, we review the preclinical molecular bases that justify approved combinations of targeted agents with chemotherapy including examples of synergistic and antagonistic combinations. We also discuss scenarios for rational associations of targeted agents based on biological data and propose strategies that may improve the success of combinations of anticancer agents. PMID- 24338004 TI - GAP-independent functions of DLC1 in metastasis. AB - Metastases are responsible for most cancer-related deaths. One of the hallmarks of metastatic cells is increased motility and migration through extracellular matrixes. These processes rely on specific small GTPases, in particular those of the Rho family. Deleted in liver cancer-1 (DLC1) is a tumor suppressor that bears a RhoGAP activity. This protein is lost in most cancers, allowing malignant cells to proliferate and disseminate in a Rho-dependent manner. However, DLC1 is also a scaffold protein involved in alternative pathways leading to tumor and metastasis suppressor activities. Recently, substantial information has been gathered on these mechanisms and this review is aiming at describing the potential and known alternative GAP-independent mechanisms allowing DLC1 to impair migration, invasion, and metastasis formation. PMID- 24338002 TI - Why anti-Bcl-2 clinical trials fail: a solution. AB - The alteration in expression of B cell lymphoma-2 (Bcl-2) family of protein members in cancer is involved mainly in the regulation of apoptosis. Bcl-2 family proteins are currently used as major targets in the development of methods to improve treatment outcomes for cancer patients that underwent clinical trials. Although many agents have been developed for targeting Bcl-2 in the past decade, some previous attempts to target Bcl-2 have not resulted in beneficial clinical outcome for reasons unknown. Here, we propose that this was due in part for not considering the cellular level of a different antiapoptotic protein, i.e., galectin-3 (Gal-3). Gal-3 is a member of the beta-galactoside binding protein family and a multifunctional oncogenic protein which regulates cell growth, cell adhesion, cell proliferation, angiogenesis, and apoptosis. Gal-3 is the sole protein that contains the NWGR anti-death motif of the Bcl-2 family and inhibits cell apoptosis induced by chemotherapeutic agents through phosphorylation, translocation and regulation of survival signaling pathways. It is now established that Gal-3 is a candidate target protein to suppress antiapoptotic activity and anticancer drug resistance. In this review, we describe the role and relevance of Gal-3 and Bcl-2 protein family in the regulation of apoptosis and propose a novel combination therapy modality. Combination therapy that targets Gal-3 could be essential for improvement of the efficacy of Bcl-2 targeting therapy in cancers and should be studied in future clinical trials. Otherwise, not considering Gal-3 cellular level could lead to trial failure. PMID- 24338005 TI - Netrin-1 as a potential target for metastatic cancer: focus on colorectal cancer. AB - Despite advanced screening technology and cancer treatments available today, metastasis remains an ongoing major cause of cancer-related deaths worldwide. Typically, colorectal cancer is one of the cancers treatable by surgery in conjunction with chemotherapy when it is detected at an early stage. However, it still ranks as the second highest modality and mortality of cancer types in western countries, and this is mostly due to a recurrence of metastatic colorectal cancer post-resection of the primary malignancy. Colorectal cancer metastases predominantly occur in the liver and lung, and yet the molecular mechanisms that regulate these organ-specific colorectal cancer metastases are largely unknown. Therefore, the identification of any critical molecule, which triggers malignancy in colorectal cancer, would be an excellent target for treatment. Netrin-1 was initially discovered as a chemotropic neuronal guidance molecule, and has been marked as a regulator for many cancers including colorectal cancer. Here, we summarise key findings of the role of netrin-1 intrinsic to colorectal cancer cells, extrinsic to the tumour microenvironment and angiogenesis, and consequently, we evaluate netrin-1 as a potential target molecule for metastasis. PMID- 24338006 TI - Oxygen regulates molecular mechanisms of cancer progression and metastasis. AB - Oxygen is the basic molecule which supports life and it truly is "god's gift to life." Despite its immense importance, research on "oxygen biology" has never received the light of the day and has been limited to physiological and biochemical studies. It seems that in modern day biology, oxygen research is summarized in one word "hypoxia." Scientists have focused on hypoxia-induced transcriptomics and molecular-cellular alterations exclusively in disease models. Interestingly, the potential of oxygen to control the basic principles of biology like homeostatic maintenance, transcription, replication, and protein folding among many others, at the molecular level, has been completely ignored. Here, we present a perspective on the crucial role played by oxygen in regulation of basic biological phenomena. Our conclusion highlights the importance of establishing novel research areas like oxygen biology, as there is great potential in this field for basic science discoveries and clinical benefits to the society. PMID- 24338007 TI - A thermodynamic geography: night-time satellite imagery as a proxy measure of emergy. AB - Night-time satellite imagery enables the measurement, visualization, and mapping of energy consumption in an area. In this paper, an index of the "sum of lights" as observed by night-time satellite imagery within national boundaries is compared with the emergy of the nations. Emergy is a measure of the solar energy equivalent used, directly or indirectly, to support the processes that characterize the economic activity in a country. Emergy has renewable and non renewable components. Our results show that the non-renewable component of national emergy use is positively correlated with night-time satellite imagery. This relationship can be used to produce emergy density maps which enable the incorporation of spatially explicit representations of emergy in geographic information systems. The region of Abruzzo (Italy) is used to demonstrate this relationship as a spatially disaggregate case. PMID- 24338008 TI - The extent of protease resistance of misfolded prion protein is highly dependent on the salt concentration. AB - Transmissible spongiform encephalopathies are neurodegenerative diseases caused by prions in mammals. An aberrantly folded protein (PrP(Sc)) is the main component of these proteinaceous infectious particles. Prions exhibit strong resistance to protease digestion, which is typically exploited for biochemical discrimination from its native cellular form (PrP(C)). This classical feature has been partially challenged by the isolation of sizeable amounts of protease sensitive PrP(Sc) isoforms that self-propagate in vivo. Here, we report that the degree of PrP(Sc) protease resistance is highly dependent on the concentration of salt in the solution. Similar changes were observed in PrP(Sc) obtained from different strains and species. Strikingly, the effect of salt is reversible and is associated with changes on the size of PrP(Sc) particles, but surprisingly, the more protease-sensitive species consists of a larger size. These findings shed light on the mechanistic aspects of prion proteolysis and should be considered when assessing samples of biomedical relevance. PMID- 24338009 TI - The interaction of integrin alphaIIbbeta3 with fibrin occurs through multiple binding sites in the alphaIIb beta-propeller domain. AB - The currently available antithrombotic agents target the interaction of platelet integrin alphaIIbbeta3 (GPIIb-IIIa) with fibrinogen during platelet aggregation. Platelets also bind fibrin formed early during thrombus growth. It was proposed that inhibition of platelet-fibrin interactions may be a necessary and important property of alphaIIbbeta3 antagonists; however, the mechanisms by which alphaIIbbeta3 binds fibrin are uncertain. We have previously identified the gamma370-381 sequence (P3) in the gammaC domain of fibrinogen as the fibrin specific binding site for alphaIIbbeta3 involved in platelet adhesion and platelet-mediated fibrin clot retraction. In the present study, we have demonstrated that P3 can bind to several discontinuous segments within the alphaIIb beta-propeller domain of alphaIIbbeta3 enriched with negatively charged and aromatic residues. By screening peptide libraries spanning the sequence of the alphaIIb beta-propeller, several sequences were identified as candidate contact sites for P3. Synthetic peptides duplicating these segments inhibited platelet adhesion and clot retraction but not platelet aggregation, supporting the role of these regions in fibrin recognition. Mutant alphaIIbbeta3 receptors in which residues identified as critical for P3 binding were substituted for homologous residues in the I-less integrin alphaMbeta2 exhibited reduced cell adhesion and clot retraction. These residues are different from those that are involved in the coordination of the fibrinogen gamma404-411 sequence and from auxiliary sites implicated in binding of soluble fibrinogen. These results map the binding of fibrin to multiple sites in the alphaIIb beta-propeller and further indicate that recognition specificity of alphaIIbbeta3 for fibrin differs from that for soluble fibrinogen. PMID- 24338010 TI - Molecular basis of purinergic signal metabolism by ectonucleotide pyrophosphatase/phosphodiesterases 4 and 1 and implications in stroke. AB - NPP4 is a type I extracellular membrane protein on brain vascular endothelium inducing platelet aggregation via the hydrolysis of Ap3A, whereas NPP1 is a type II extracellular membrane protein principally present on the surface of chondrocytes that regulates tissue mineralization. To understand the metabolism of purinergic signals resulting in the physiologic activities of the two enzymes, we report the high resolution crystal structure of human NPP4 and explore the molecular basis of its substrate specificity with NPP1. Both enzymes cleave Ap3A, but only NPP1 can hydrolyze ATP. Comparative structural analysis reveals a tripartite lysine claw in NPP1 that stabilizes the terminal phosphate of ATP, whereas the corresponding region of NPP4 contains features that hinder this binding orientation, thereby inhibiting ATP hydrolysis. Furthermore, we show that NPP1 is unable to induce platelet aggregation at physiologic concentrations reported in human blood, but it could stimulate platelet aggregation if localized at low nanomolar concentrations on vascular endothelium. The combined studies expand our understanding of NPP1 and NPP4 substrate specificity and range and provide a rational mechanism by which polymorphisms in NPP1 confer stroke resistance. PMID- 24338012 TI - WITHDRAWN: A mutation in the chaperone sigma1-receptor impairs mitochondrial ATP production in amyotrophic lateral sclerosis. AB - This manuscript was withdrawn by the Author. PMID- 24338011 TI - Pannexin 3 inhibits proliferation of osteoprogenitor cells by regulating Wnt and p21 signaling. AB - Canonical Wnt signaling and BMP promote the proliferation and differentiation of osteoprogenitors, respectively. However, the regulatory mechanism involved in the transition from proliferation to differentiation is unclear. Here, we show that Panx3 (pannexin 3) plays a key role in this transition by inhibiting the proliferation and promoting the cell cycle exit. Using primary calvarial cells and explants, C3H10T1/2 cells, and C2C12 cells, we found that Panx3 expression inhibited cell growth, whereas the inhibition of endogenous Panx3 expression increased it. We also found that the Panx3 hemichannel inhibited cell growth by promoting beta-catenin degradation through GSK3beta activation. Additionally, the Panx3 hemichannel inhibited cyclin D1 transcription and Rb phosphorylation through reduced cAMP/PKA/CREB signaling. Furthermore, the Panx3 endoplasmic reticulum Ca(2+) channel induced the transcription and phosphorylation of p21, through the calmodulin/Smad pathway, and resulted in the cell cycle exit. Our results reveal that Panx3 is a new regulator that promotes the switch from proliferation to differentiation of osteoprogenitors via multiple Panx3 signaling pathways. PMID- 24338013 TI - N-terminal acetylation stabilizes N-terminal helicity in lipid- and micelle-bound alpha-synuclein and increases its affinity for physiological membranes. AB - The Parkinson disease protein alpha-synuclein is N-terminally acetylated, but most in vitro studies have been performed using unacetylated alpha-synuclein. Binding to lipid membranes is considered key to the still poorly understood function of alpha-synuclein. We report the effects of N-terminal acetylation on alpha-synuclein binding to lipid vesicles of different composition and curvature and to micelles composed of the detergents beta-octyl-glucoside (BOG) and SDS. In the presence of SDS, N-terminal acetylation results in a slightly increased helicity for the N-terminal ~10 residues of the protein, likely due to the stabilization of N-terminal fraying through the formation of a helix cap motif. In the presence of BOG, a detergent used in previous isolations of helical oligomeric forms of alpha-synuclein, the N-terminally acetylated protein adopts a novel conformation in which the N-terminal ~30 residues bind the detergent micelle in a partly helical conformation, whereas the remainder of the protein remains unbound and disordered. Binding of alpha-synuclein to lipid vesicles with high negative charge content is essentially unaffected by N-terminal acetylation irrespective of curvature, but binding to vesicles of lower negative charge content is increased, with stronger binding observed for vesicles with higher curvature. Thus, the naturally occurring N-terminally acetylated form of alpha synuclein exhibits stabilized helicity at its N terminus and increased affinity for lipid vesicles similar to synaptic vesicles, a binding target of the protein in vivo. Furthermore, the novel BOG-bound state of N-terminally acetylated alpha synuclein may serve as a model of partly helical membrane-bound intermediates with a role in alpha-synuclein function and dysfunction. PMID- 24338014 TI - Characterization of a reduced form of plasma plasminogen as the precursor for angiostatin formation. AB - Plasma plasminogen is the precursor of the tumor angiogenesis inhibitor, angiostatin. Generation of angiostatin in blood involves activation of plasminogen to the serine protease plasmin and facilitated cleavage of two disulfide bonds and up to three peptide bonds in the kringle 5 domain of the protein. The mechanism of reduction of the two allosteric disulfides has been explored in this study. Using thiol-alkylating agents, mass spectrometry, and an assay for angiostatin formation, we show that the Cys(462)-Cys(541) disulfide bond is already cleaved in a fraction of plasma plasminogen and that this reduced plasminogen is the precursor for angiostatin formation. From the crystal structure of plasminogen, we propose that plasmin ligands such as phosphoglycerate kinase induce a conformational change in reduced kringle 5 that leads to attack by the Cys(541) thiolate anion on the Cys(536) sulfur atom of the Cys(512)-Cys(536) disulfide bond, resulting in reduction of the bond by thiol/disulfide exchange. Cleavage of the Cys(512)-Cys(536) allosteric disulfide allows further conformational change and exposure of the peptide backbone to proteolysis and angiostatin release. The Cys(462)-Cys(541) and Cys(512)-Cys(536) disulfides have -/+RHHook and -LHHook configurations, respectively, which are two of the 20 different measures of the geometry of a disulfide bond. Analysis of the structures of the known allosteric disulfide bonds identified six other bonds that have these configurations, and they share some functional similarities with the plasminogen disulfides. This suggests that the -/+RHHook and -LHHook disulfides, along with the -RHStaple bond, are potential allosteric configurations. PMID- 24338015 TI - Conformational stability of mammalian prion protein amyloid fibrils is dictated by a packing polymorphism within the core region. AB - Mammalian prion strains are believed to arise from the propagation of distinct conformations of the misfolded prion protein PrP(Sc). One key operational parameter used to define differences between strains has been conformational stability of PrP(Sc) as defined by resistance to thermal and/or chemical denaturation. However, the structural basis of these stability differences is unknown. To bridge this gap, we have generated two strains of recombinant human prion protein amyloid fibrils that show dramatic differences in conformational stability and have characterized them by a number of biophysical methods. Backbone amide hydrogen/deuterium exchange experiments revealed that, in sharp contrast to previously studied strains of infectious amyloid formed from the yeast prion protein Sup35, differences in beta-sheet core size do not underlie differences in conformational stability between strains of mammalian prion protein amyloid. Instead, these stability differences appear to be dictated by distinct packing arrangements (i.e. steric zipper interfaces) within the amyloid core, as indicated by distinct x-ray fiber diffraction patterns and large strain dependent differences in hydrogen/deuterium exchange kinetics for histidine side chains within the core region. Although this study was limited to synthetic prion protein amyloid fibrils, a similar structural basis for strain-dependent conformational stability may apply to brain-derived PrP(Sc), especially because large strain-specific differences in PrP(Sc) stability are often observed despite a similar size of the PrP(Sc) core region. PMID- 24338016 TI - Mechanisms of allosteric activation and inhibition of the deoxyribonucleoside triphosphate triphosphohydrolase from Enterococcus faecalis. AB - EF1143 from Enterococcus faecalis, a life-threatening pathogen that is resistant to common antibiotics, is a homo-tetrameric deoxyribonucleoside triphosphate (dNTP) triphosphohydrolase (dNTPase), converting dNTPs into the deoxyribonucleosides and triphosphate. The dNTPase activity of EF1143 is regulated by canonical dNTPs, which simultaneously act as substrates and activity modulators. Previous crystal structures of apo-EF1143 and the protein bound to both dGTP and dATP suggested allosteric regulation of its enzymatic activity by dGTP binding at four identical allosteric sites. However, whether and how other canonical dNTPs regulate the enzyme activity was not defined. Here, we present the crystal structure of EF1143 in complex with dGTP and dTTP. The new structure reveals that the tetrameric EF1143 contains four additional secondary allosteric sites adjacent to the previously identified dGTP-binding primary regulatory sites. Structural and enzyme kinetic studies indicate that dGTP binding to the first allosteric site, with nanomolar affinity, is a prerequisite for substrate docking and hydrolysis. Then, the presence of a particular dNTP in the second site either enhances or inhibits the dNTPase activity of EF1143. Our results provide the first mechanistic insight into dNTP-mediated regulation of dNTPase activity. PMID- 24338017 TI - Pyruvate formate-lyase and its activation by pyruvate formate-lyase activating enzyme. AB - The activation of pyruvate formate-lyase (PFL) by pyruvate formate-lyase activating enzyme (PFL-AE) involves formation of a specific glycyl radical on PFL by the PFL-AE in a reaction requiring S-adenosylmethionine (AdoMet). Surface plasmon resonance experiments were performed under anaerobic conditions on the oxygen-sensitive PFL-AE to determine the kinetics and equilibrium constant for its interaction with PFL. These experiments show that the interaction is very slow and rate-limited by large conformational changes. A novel AdoMet binding assay was used to accurately determine the equilibrium constants for AdoMet binding to PFL-AE alone and in complex with PFL. The PFL-AE bound AdoMet with the same affinity (~6 MUM) regardless of the presence or absence of PFL. Activation of PFL in the presence of its substrate pyruvate or the analog oxamate resulted in stoichiometric conversion of the [4Fe-4S](1+) cluster to the glycyl radical on PFL; however, 3.7-fold less activation was achieved in the absence of these small molecules, demonstrating that pyruvate or oxamate are required for optimal activation. Finally, in vivo concentrations of the entire PFL system were calculated to estimate the amount of bound protein in the cell. PFL, PFL-AE, and AdoMet are essentially fully bound in vivo, whereas electron donor proteins are partially bound. PMID- 24338018 TI - Relationship between Ni(II) and Zn(II) coordination and nucleotide binding by the Helicobacter pylori [NiFe]-hydrogenase and urease maturation factor HypB. AB - The pathogen Helicobacter pylori requires two nickel-containing enzymes, urease and [NiFe]-hydrogenase, for efficient colonization of the human gastric mucosa. These enzymes possess complex metallocenters that are assembled by teams of proteins in multistep pathways. One essential accessory protein is the GTPase HypB, which is required for Ni(II) delivery to [NiFe]-hydrogenase and participates in urease maturation. Ni(II) or Zn(II) binding to a site embedded in the GTPase domain of HypB modulates the enzymatic activity, suggesting a mechanism of regulation. In this study, biochemical and structural analyses of H. pylori HypB (HpHypB) revealed an intricate link between nucleotide and metal binding. HpHypB nickel coordination, stoichiometry, and affinity were modulated by GTP and GDP, an effect not observed for zinc, and biochemical evidence suggests that His-107 coordination to nickel toggles on and off in a nucleotide dependent manner. These results are consistent with the crystal structure of HpHypB loaded with Ni(II), GDP, and Pi, which reveals a nickel site distinct from that of zinc-loaded Methanocaldococcus jannaschii HypB as well as subtle changes to the protein structure. Furthermore, Cys-142, a metal ligand from the Switch II GTPase motif, was identified as a key component of the signal transduction between metal binding and the enzymatic activity. Finally, potassium accelerated the enzymatic activity of HpHypB but had no effect on the other biochemical properties of the protein. Altogether, this molecular level information about HpHypB provides insight into its cellular function and illuminates a possible mechanism of metal ion discrimination. PMID- 24338019 TI - Intracellular and extracellular carbonic anhydrases cooperate non-enzymatically to enhance activity of monocarboxylate transporters. AB - Proton-coupled monocarboxylate transporters (MCTs) are carriers of high-energy metabolites such as lactate, pyruvate, and ketone bodies and are expressed in most tissues. It has previously been shown that transport activity of MCT1 and MCT4 is enhanced by the cytosolic carbonic anhydrase II (CAII) independent of its catalytic activity. We have now studied the influence of the extracellular, membrane-bound CAIV on transport activity of MCT1/4, heterologously expressed in Xenopus oocytes. Coexpression of CAIV with MCT1 and MCT4 resulted in a significant increase in MCT transport activity, even in the nominal absence of CO2/HCO3(-). CAIV-mediated augmentation of MCT activity was independent of the CAIV catalytic function, since application of the CA-inhibitor ethoxyzolamide or coexpression of the catalytically inactive mutant CAIV-V165Y did not suppress CAIV-mediated augmentation of MCT transport activity. The interaction required CAIV at the extracellular surface, since injection of CAIV protein into the oocyte cytosol did not augment MCT transport function. The effects of cytosolic CAII (injected as protein) and extracellular CAIV (expressed) on MCT transport activity, were additive. Our results suggest that intra- and extracellular carbonic anhydrases can work in concert to ensure rapid shuttling of metabolites across the cell membrane. PMID- 24338020 TI - The role of prolyl hydroxylase domain protein (PHD) during rosiglitazone-induced adipocyte differentiation. AB - Rosiglitazone, a well known insulin sensitizer, stimulates adipocyte differentiation via the activation of peroxisome proliferator-activated receptor gamma (PPARgamma). Previous two-dimensional proteomics studies using C3H10T1/2 murine mesenchymal pluripotent stem cells revealed that prolyl hydroxylase domain protein (PHD) levels significantly increased during rosiglitazone-induced adipocyte differentiation (RIAD). In this study, we investigated the functional role played by PHD during RIAD. Three PHD isoforms (PHD1, 2, and 3) were found to be up-regulated in C3H10T1/2 cells during RIAD, whereas PHD knockdown and treatment with PHD inhibitors (dimethyloxalyl glycine or ethyl-3,4 dihydroxybenzoate) blocked RIAD. PHD inhibition was found to be associated with increases in the levels of anti-adipogenic proteins such as GATA-3, KLF-2, and transcriptional coactivator with PDZ binding motif (TAZ), with their reduced ubiquitination, suggesting that PHDs evoke the ubiquitination/proteasomal degradation of anti-adipogenic proteins. On the other hand, MG-132 (a proteasomal inhibitor) prevented the degradation of anti-adipogenic proteins and retarded RIAD. PPARgamma antagonists (bisphenol A diglycidyl ether or GW9662) blunted the effects of rosiglitazone on PHD regulation. Furthermore, putative PPARgamma binding sites were identified in the promoter region of PHDs by ChIP-PCR, implying that rosiglitazone may induce PHD up-regulation directly by PPARgamma activation. Consistent with in vitro results, oral administration of rosiglitazone to ob/ob mice for 2 weeks increased adipose PHD levels and decreased anti-adipogenic protein levels by increasing their ubiquitination. These results suggest that rosiglitazone increases PHD expression in a PPARgamma dependent manner and that this leads to the commitment of anti-adipogenic proteins to the ubiquitination-proteasomal pathway and to the subsequent induction of adipocyte differentiation. PMID- 24338021 TI - Nuclear import factor Srp1 and its associated protein Sts1 couple ribosome-bound nascent polypeptides to proteasomes for cotranslational degradation. AB - Cotranslational protein degradation plays an important role in protein quality control and proteostasis. Although ubiquitylation has been suggested to signal cotranslational degradation of nascent polypeptides, cotranslational ubiquitylation occurs at a low level, suggesting the existence of an alternative route for delivery of nascent polypeptides to the proteasome. Here we report that the nuclear import factor Srp1 (also known as importin alpha or karyopherin alpha) is required for ubiquitin-independent cotranslational degradation of the transcription factor Rpn4. We further demonstrate that cotranslational protein degradation is generally impaired in the srp1-49 mutant. Srp1 binds nascent polypeptides emerging from the ribosome. The association of proteasomes with polysomes is weakened in srp1-49. The interaction between Srp1 and the proteasome is mediated by Sts1, a multicopy suppressor of srp1-49. The srp1-49 and sts1-2 mutants are hypersensitive to stressors that promote protein misfolding, underscoring the physiological function of Srp1 and Sts1 in degradation of misfolded nascent polypeptides. This study unveils a previously unknown role for Srp1 and Sts1 in cotranslational protein degradation and suggests a novel model whereby Srp1 and Sts1 cooperate to couple proteasomes to ribosome-bound nascent polypeptides. PMID- 24338022 TI - Naturally occurring variants of the dysglycemic peptide pancreastatin: differential potencies for multiple cellular functions and structure-function correlation. AB - Pancreastatin (PST), a chromogranin A-derived peptide, is a potent physiological inhibitor of glucose-induced insulin secretion. PST also triggers glycogenolysis in liver and reduces glucose uptake in adipocytes and hepatocytes. Here, we probed for genetic variations in PST sequence and identified two variants within its functionally important carboxyl terminus domain: E287K and G297S. To understand functional implications of these amino acid substitutions, we tested the effects of wild-type (PST-WT), PST-287K, and PST-297S peptides on various cellular processes/events. The rank order of efficacy to inhibit insulin stimulated glucose uptake was: PST-297S > PST-287K > PST-WT. The PST peptides also displayed the same order of efficacy for enhancing intracellular nitric oxide and Ca(2+) levels in various cell types. In addition, PST peptides activated gluconeogenic genes in the following order: PST-297S ~ PST-287K > PST WT. Consistent with these in vitro results, the common PST variant allele Ser-297 was associated with significantly higher (by ~17 mg/dl, as compared with the wild type Gly-297 allele) plasma glucose level in our study population (n = 410). Molecular modeling and molecular dynamics simulations predicted the following rank order of alpha-helical content: PST-297S > PST-287K > PST-WT. Corroboratively, circular dichroism analysis of PST peptides revealed significant differences in global structures (e.g. the order of propensity to form alpha helix was: PST-297S ~ PST-287K > PST-WT). This study provides a molecular basis for enhanced potencies/efficacies of human PST variants (likely to occur in ~300 million people worldwide) and has quantitative implications for inter-individual variations in glucose/insulin homeostasis. PMID- 24338023 TI - Novel piperazine-based compounds inhibit microtubule dynamics and sensitize colon cancer cells to tumor necrosis factor-induced apoptosis. AB - We recently identified a series of mitotically acting piperazine-based compounds that potently increase the sensitivity of colon cancer cells to apoptotic ligands. Here we describe a structure-activity relationship study on this compound class and identify a highly active derivative ((4-(3 chlorophenyl)piperazin-1-yl)(2-ethoxyphenyl)methanone), referred to as AK301, the activity of which is governed by the positioning of functional groups on the phenyl and benzoyl rings. AK301 induced mitotic arrest in HT29 human colon cancer cells with an ED50 of ~115 nm. Although AK301 inhibited growth of normal lung fibroblast cells, mitotic arrest was more pronounced in the colon cancer cells (50% versus 10%). Cells arrested by AK301 showed the formation of multiple microtubule organizing centers with Aurora kinase A and gamma-tubulin. Employing in vitro and in vivo assays, tubulin polymerization was found to be slowed (but not abolished) by AK301. In silico molecular docking suggests that AK301 binds to the colchicine-binding domain on beta-tubulin, but in a novel orientation. Cells arrested by AK301 expressed elevated levels of TNFR1 on their surface and more readily activated caspases-8, -9, and -3 in the presence of TNF. Relative to other microtubule destabilizers, AK301 was the most active TNF-sensitizing agent and also stimulated Fas- and TRAIL-induced apoptosis. In summary, we report a new class of mitosis-targeting agents that effectively sensitizes cancer cells to apoptotic ligands. These compounds should help illuminate the role of microtubules in regulating apoptotic ligand sensitivity and may ultimately be useful for developing agents that augment the anti-cancer activities of the immune response. PMID- 24338024 TI - Thioredoxin-mediated denitrosylation regulates cytokine-induced nuclear factor kappaB (NF-kappaB) activation. AB - S-nitrosylation of nuclear factor kappaB (NF-kappaB) on the p65 subunit of the p50/p65 heterodimer inhibits NF-kappaB DNA binding activity. We have recently shown that p65 is constitutively S-nitrosylated in the lung and that LPS-induced injury elicits a decrease in SNO-p65 levels concomitant with NF-kappaB activation in the respiratory epithelium and initiation of the inflammatory response. Here, we demonstrate that TNFalpha-mediated activation of NF-kappaB in the respiratory epithelium similarly induces p65 denitrosylation. This process is mediated by the denitrosylase thioredoxin (Trx), which becomes activated upon cytokine-induced degradation of thioredoxin-interacting protein (Txnip). Similarly, inhibition of Trx activity in the lung attenuates LPS-induced SNO-p65 denitrosylation, NF kappaB activation, and airway inflammation, supporting a pathophysiological role for this mechanism in lung injury. These data thus link stimulus-coupled activation of NF-kappaB to a specific, protein-targeted denitrosylation mechanism and further highlight the importance of S-nitrosylation in the regulation of the immune response. PMID- 24338026 TI - Systematic review of neuroimaging studies in vertically transmitted HIV positive children and adolescents. AB - One of the most serious consequences of vertical HIV-infection is its impact on the central nervous system (CNS). Although much work has been done to elucidate the complex mechanism of HIV associated neurotoxicity, several questions remain unanswered. The purpose of this review is to summarise what is already known in the field of neuroimaging in vertically acquired HIV, addressing three aims and to highlight possible future directions in using neuroimaging and neurocognitive testing to understand the spectrum of neurocognitive disorders in HIV positve children. Here we aim to address several clinically relevant questions in pediatric neuroHIV, using the current evidence base by conducting a systematic review. We aim to investigate what is known about the relationship between cognitive impairment and central nervous system damage in HIV as seen in neuroimaging studies, and to search for any evidence in the current literature which suggests a spectrum of neuocognitive disorders in vertically infected HIV. Secondly, we aim to enquire whether children with a clinical diagnosis of encephalopathy are clearly distinguishable from HIV positive children without encephalopathy on neuroimaging and neurocognitive testing. Finally aim to investigate what is known about the effect on the CNS of antiretroviral therapy in paediatric HIV. Three separate databases were searched and two investigators systematically evaluated the titles, abstracts, and keywords associated with each individual article to determine those that may have met the inclusion and exclusion criteria. Following this process 11 studies were included in the review. Thus there was limited available data to address the 3 questions posed. PMID- 24338025 TI - NF-kappaB and enhancer-binding CREB protein scaffolded by CREB-binding protein (CBP)/p300 proteins regulate CD59 protein expression to protect cells from complement attack. AB - The complement system can be activated spontaneously for immune surveillance or induced to clear invading pathogens, in which the membrane attack complex (MAC, C5b-9) plays a critical role. CD59 is the sole membrane complement regulatory protein (mCRP) that restricts MAC assembly. CD59, therefore, protects innocent host cells from attacks by the complement system, and host cells require the constitutive and inducible expression of CD59 to protect themselves from deleterious destruction by complement. However, the mechanisms that underlie CD59 regulation remain largely unknown. In this study we demonstrate that the widely expressed transcription factor Sp1 may regulate the constitutive expression of CD59, whereas CREB-binding protein (CBP)/p300 bridge NF-kappaB and CREB, which surprisingly functions as an enhancer-binding protein to induce the up-regulation of CD59 during in lipopolysaccharide (LPS)-triggered complement activation, thus conferring host defense against further MAC-mediated destruction. Moreover, individual treatment with LPS, TNF-alpha, and the complement activation products (sublytic MAC (SC5b-9) and C5a) could increase the expression of CD59 mainly by activating NF-kappaB and CREB signaling pathways. Together, our findings identify a novel gene regulation mechanism involving CBP/p300, NF-kappaB, and CREB; this mechanism suggests potential drug targets for controlling various complement related human diseases. PMID- 24338027 TI - Depo-provera effects on Wistar rat performance in the Y-maze. AB - Medroxyprogesterone acetate is the most commonly used progestin component of hormone therapy. The goal of the present study was to determine whether Medroxyprogesterone affects rat behavior using a Y-maze test. Twenty-four female Wistar rats were randomly selected into three groups; control group, a low dose (13 mg/ml MPA) group and a high dose (33 mg/1 ml MPA) group. Doses of Medroxyprogesterone were delivered by intramuscular injection for a period of 3 weeks. Medroxyprogesterone administration resulted in a decrease in memory and locomotion activity of rats (p < 0.05). Despite Medroxyprogesterone being effective in modulating hormonal interaction to prevent conception in actively reproducing females, cognitive impairment could be one of its adverse effects. PMID- 24338028 TI - Changes in behavior and ultrasonic vocalizations during antidepressant treatment in the maternally separated Wistar-Kyoto rat model of depression. AB - Genetic predisposition and stress are major factors in depression. The objective of this study was to establish a robust animal model of depression by selecting the appropriate substrain of the Wistar-Kyoto (WKY) rat, and subjecting these rats to the stress of maternal separation during the early stages of development. The initial experiment identified WKY/NCrl as the appropriate substrain of WKY to use for the study. In the second part of the study, depression-like behavior and ultrasonic vocalizations (USVs) were recorded in WKY/NCrl and maternally separated WKY/NCrl rats during the course of reversal of depression-like behavior. Wistar rats served as the reference strain. In adulthood, non-separated WKY/NCrl, maternally separated WKY/NCrl and Wistar rats were injected intraperitoneally with either saline or desipramine (15 mg/kg/day) for 15 days and their behavior recorded. Desipramine decreased immobility and increased active swimming and struggling behavior of WKY/NCrl in the FST and also decreased their USVs in response to removal of cage mates. The USVs in this study appeared to signal an attempt to re-establish social contact with cage mates and provided a measure of social dependence. Maternally separated WKY/NCrl rats displayed more anxiety than normally reared WKY/NCrl rats and responded to the anxiolytic effects of desipramine. The present findings support the use of WKY/NCrl as an animal model of depression. Maternal separation increased the anxiety-like behavior of the WKY/NCrl, thus providing a robust model to study depression- and anxiety-related behavior. PMID- 24338029 TI - MERRF/MELAS overlap syndrome due to the m.3291T>C mutation. AB - We report the case of a 19-year-old Chinese female harboring the m.3291T>C mutation in the MT-TL1 gene encoding the mitochondrial transfer RNA for leucine. She presented with a complex phenotype characterized by progressive cerebellar ataxia, frequent myoclonus seizures, recurrent stroke-like episodes, migraine like headaches with nausea and vomiting, and elevated resting lactate blood level. It is known that the myoclonus epilepsy with ragged-red fibers (MERRF) is characterized by cerebellar ataxia and myoclonus epilepsy, while that the mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is characterized by recurrent stroke-like episodes, migraine-like headaches, and elevated resting lactate blood level. So the patient's clinical manifestations suggest the presence of a MERRF/MELAS overlap syndrome. Muscle biopsy of the patient showed the presence of numerous scattered ragged-red fibers, some cytochrome c oxidase-deficient fibers, and several strongly succinate dehygrogenase-reactive vessels, suggestive of a mitochondrial disorder. Direct sequencing of the complete mitochondrial genome of the proband revealed no mutations other than the T-to-C transition at nucleotide position 3291. Restriction fragment length polymorphism analysis of the proband and her family revealed maternal inheritance of the mutation in a heteroplasmic manner. The analysis of aerobic respiration and glycolysis demonstrated that the fibroblasts from the patient had mitochondrial dysfunction. Our results suggest that the m.3291T>C is pathogenic. This study is the first to describe the m.3291T>C mutation in association with the MERRF/MELAS overlap syndrome. PMID- 24338030 TI - Pipecolic acid induces oxidative stress in vitro in cerebral cortex of young rats and the protective role of lipoic acid. AB - Pipecolic acid (PA) levels are increased in severe metabolic disorders of the central nervous system such as Zellweger syndrome, infantile Refsum disease, neonatal adrenoleukodystrophy and hyperlysinemia. The affected individuals present progressive neurological dysfunction, hypotonia and growth retardation. The mechanisms of brain damage of these disorders remain poorly understood. Since PA catabolism can produce H2O2 by oxidases, oxidative stress may be a possible mechanism involved in the pathophysiology of these diseases. Lipoic acid (LA) is considered an efficient antioxidant and has been shown to prevent oxidative stress in experimental models of many disorders of the neurologic system. Considering that to our knowledge no study investigated the role of PA on oxidative stress, in the present work we investigated the in vitro effects of PA on some oxidative stress parameters and evaluated the LA efficacy against possible pro-oxidant effects of PA in cerebral cortex of 14-day-old rats. The activities of catalase (CAT), glutathione peroxidase (GPx), glucose 6-phosphate dehydrogenase (G6PD), and glutathione S-transferase (GST) along with reduced glutathione (GSH) content were significantly decreased, while superoxide dismutase (SOD) activity and thiobarbituric acid-reactive substances (TBA-RS) were significantly enhanced by PA. LA was able to prevent these effects by improving the activity of antioxidant enzymes, increasing GSH content and reducing TBA-RS. In contrast, glutathione reductase and 6-phosphogluconate dehydrogenase activities and sulfhydryl content were not affected. Taken together, it may be presumed that PA in vitro elicits oxidative stress and LA is able to prevent these effects. PMID- 24338031 TI - Attentional deficits and emotional bias in bipolar disorders: comparison at different stages of the disease. PMID- 24338032 TI - Elaborate ligand-based modeling coupled with QSAR analysis and in silico screening reveal new potent acetylcholinesterase inhibitors. AB - Inhibition of the enzyme acetylcholinesterase (AChE) has been shown to alleviate neurodegenerative diseases prompting several attempts to discover and optimize new AChE inhibitors. In this direction, we explored the pharmacophoric space of 85 AChE inhibitors to identify high quality pharmacophores. Subsequently, we implemented genetic algorithm-based quantitative structure-activity relationship (QSAR) modeling to select optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of explaining bioactivity variation among training compounds (r2(68)=0.94, F-statistic=125.8, r2 LOO=0.92, r2 PRESS against 17 external test inhibitors = 0.84). Two orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least two binding modes accessible to ligands within AChE binding pocket. The successful pharmacophores were comparable with crystallographically resolved AChE binding pocket. We employed the pharmacophoric models and associated QSAR equation to screen the national cancer institute list of compounds. Twenty-four low micromolar AChE inhibitors were identified. The most potent gave IC50 value of 1.0 MUM. PMID- 24338033 TI - Evaluation of the effectiveness of X-ray protective aprons in experimental and practical fields. AB - Few practical evaluation studies have been conducted on X-ray protective aprons in workplaces. We examined the effects of exchanging the protective apron type with regard to exposure reduction in experimental and practical fields, and discuss the effectiveness of X-ray protective aprons. Experimental field evaluations were performed by the measurement of the X-ray transmission rates of protective aprons. Practical field evaluations were performed by the estimation of the differences in the transit doses before and after the apron exchange. A 0.50-mm lead-equivalent-thick non-lead apron had the lowest transmission rate among the 7 protective aprons, but weighed 10.9 kg and was too heavy. The 0.25 and 0.35-mm lead-equivalent-thick non-lead aprons differed little in the practical field of interventional radiology. The 0.35-mm lead apron had lower X ray transmission rates and transit doses than the 0.25-mm lead-equivalent-thick non-lead apron, and each of these differences exceeded 8% in the experimental field and approximately 0.15 mSv/month in the practical field of computed tomography (p < 0.01). Therefore, we concluded that the 0.25-mm lead-equivalent thick aprons and 0.35-mm lead apron are effective for interventional radiology operators and computed tomography nurses, respectively. PMID- 24338034 TI - A survey-based inventory of clinical decision support systems in computerised provider order entry in Swiss hospitals. AB - QUESTIONS UNDER STUDY: Computerised order entry and clinical decision support systems (CDSSs) are considered to be important strategies to safeguard drug treatment. Although their dissemination is nationally enforced in Switzerland, current implementation rates vary. Moreover, types and implementation modes of CDSSs can differ substantially. This study maps the implementation of computerised order entry and CDSSs in Switzerland. METHODS: In February 2011, a survey exploring the implementation of computerised order entry and types of CDSS was sent via e-mail to all public hospitals (n = 120) and private clinics (n = 165) registered at the Swiss Hospitals Federation (H+). Nonresponders were reminded three times to complete the survey. Data were analysed descriptively. RESULTS: One-third of all hospitals and clinics respon-ded to the survey (n = 92/285; 32.3%), with 73 institutions agreeing to participate. Of these 73 institutions, 29 prescribed electronically and 13 planned to implement electronic prescribing. Implementation of CDSSs was less frequent, with 14 institutions actually using CDSSs (19.1%) and another 18 institutions planning the implementation (24.6%). The type of CDSS most frequently implemented was information on hospital formularies (n = 13) and drug-drug interactions (n = 11), but CDSSs with regard to genotype, drug interactions with laboratory test results, contraindications, specific age groups and necessary drug orders were only rarely implemented. CONCLUSIONS: Although implementation of computerised order entry in Switzerland is increasing, the types and magnitude of CDSSs vary largely and mainly focus on basic decision support. PMID- 24338035 TI - Personal weight status classification and health literacy among Supplemental Nutrition Assistance Program (SNAP) participants. AB - The purpose of this study was to examine the conceptual gap between self perceived weight and body mass index (BMI), and to assess the knowledge gap between perceived importance of following dietary guidelines and health literacy levels. Adults (n = 131) eligible for the Supplemental Nutrition Assistance Program (SNAP) were interviewed at eleven SNAP regional offices in Maryland. Based on BMI calculated from self-reported height and weight, 65.6% of participants were overweight or obese while 40.5% perceived that they were overweight or obese. In sub-group analysis categorized by BMI, only 20.0% in the overweight and 20.0% in the obese group correctly perceived themselves as being overweight or obese. Following dietary guidelines was perceived as important by a majority of participants, but only 43.5% had adequate health literacy. Conceptual and knowledge gaps between self-perception and objective health status existed in the low-income SNAP-eligible sample. Future studies need to address these gaps because misperceived weight status and insufficient health literacy are critical barriers to inducing behavioral change. PMID- 24338036 TI - Individual and community effectiveness of a cervical cancer screening program for semi-urban Mexican women. AB - The effectiveness at the individual and community level of an educational intervention to increase cervical cancer screening self-efficacy among semi-urban Mexican women was evaluated and changes in reported community barriers were measured after the intervention was implemented. The educational intervention was evaluated with a quasi-experimental pre-test/post-test design and a control group, based on the Integrative Model of Behavior Prediction and AMIGAS project materials. For the intervention group, increased self-efficacy increased requests to obtain a Pap (p < 0.05). Barriers to obtaining a Pap were embarrassment and lack of time at the individual level, and lack of time, test conditions and fear of social rejection in the community's cultural domain. At both the individual and community levels, having more information about the test and knowing it would be performed by a woman were primary facilitators. Few women used medically precise information when referring to the Pap and cervical uterine cancer. Although the level of self-efficacy of the participants increased, barriers in the health system affect the women's perceived ability to get a Pap. Better care for users is needed to increase consistent use of the test. The study shows the importance of using culturally adapted, multilevel, comprehensive interventions to achieve successful results in target populations. PMID- 24338037 TI - Childhood-onset dense deposit disease: a rare cause of proteinuria. AB - INTRODUCTION: Dense deposit disease (DDD) is a rare renal disease related to the dysregulation of the alternative pathway of the complement cascade, caused by several factors including the presence of an autoantibody to C3 nephritic factor, mutations in factor H and autoantibodies to this protein. DDD is characterized by C3 accumulation with absent or scanty immunoglobulin deposition. CASE PRESENTATION: Herein we report the case of a child with benign course of DDD, who presented with moderate proteinuria and lack of clinical symptoms without immunosuppressive treatment. Laboratory testing revealed moderate proteinuria, normal serum creatinine, total protein, and albumin levels, but significantly decreased serum C3 level. The results of renal biopsy were consistent with DDD. Genetic analysis revealed that the patient carried one copy of the H402 risk allele of factor H. The level of proteinuria did not change during the follow-up period and no nephrotic syndrome signs occurred. Renal function was stable. CONCLUSION: In conclusion, a program of urine screening for asymptomatic proteinuria and hematuria to detect children with kidney disease before they experience loss of kidney functions should be considered. Children diagnosed with DDD should have the opportunity to get treatment early on and to be followed very closely. PMID- 24338038 TI - Balloon tibioplasty: pearls and pitfalls. AB - Methods of tibial plateau fracture fixation have evolved over the last decades; however the techniques used to reduce these fractures have remained relatively unchanged. Balloon tibioplasty, a minimally invasive novel technique used in the reduction of depressed tibial plateau fractures, has been gaining popularity. This technique offers a slow controlled expansion of the balloon with multidirectional force vectors and a large surface area allowing for more bone to be elevated simultaneously. The technique also creates a well-defined bone void of known volume while theoretically compressing the surrounding bone, potentially limiting the risk of cement extrusion as well as late subsidence of the elevated bone. Although an attractive option, as with all novel techniques there is a learning curve. The purpose of this article is to briefly describe our technique of balloon tibioplasty, potential contraindications, and to illustrate some possible complications, and provide some tips and tricks we have found useful to avoid them. PMID- 24338040 TI - Complications in brief: Quadriceps and patellar tendon tears. AB - Effective treatment of knee extensor mechanism disruptions requires prompt diagnosis and thoughtful decision-making with surgical and nonsurgical approaches. When surgery is chosen, excellent surgical technique can result in excellent outcomes. Complications and failures arise from missed or delayed diagnoses and from technical problems in the operating room. In particular, inappropriate surgical timing (especially late surgery), misplaced patellar drill holes, and failure to address concomitant injuries can result in complications seen when repairing a patellar or quadriceps tendon tear. We review the complications that can occur during treatment of these injuries (Table 1). PMID- 24338041 TI - Not by bread alone: shortcomings of the pay-for-performance approach. PMID- 24338043 TI - Comment on: "EU's new pharmacovigilance legislation: considerations for biosimilars". PMID- 24338042 TI - Can Internet information on vertebroplasty be a reliable means of patient self education? AB - BACKGROUND: Studies of the quality and accuracy of health and medical information available on the Internet have shown that many sources provide inadequate information. However, to our knowledge, there are no published studies analyzing the quality of information available online regarding vertebroplasty. Because this has been a high-volume procedure with highly debated efficacy, it is critical that patients receive complete, accurate, and well-balanced information before deciding a treatment course. Additionally, few studies have evaluated the merit of academic site authorship or site certification on information quality, but some studies have used measurements of quality that are based primarily on subjective criteria or information accuracy rather than information completeness. QUESTIONS/PURPOSES: The purposes of our study were (1) to evaluate and analyze the information on vertebroplasty available to the general public through the Internet; (2) to see if sites sponsored by academic institutions offered a higher quality of information; and (3) to determine whether quality of information varied according to site approval by a certification body. METHODS: Three search engines were used to identify 105 web sites (35 per engine) offering information regarding vertebroplasty. Sites were evaluated for authorship/sponsorship, content, and references cited. Information quality was rated as "excellent," "high," "moderate," "low," or "unacceptable." Sites also were evaluated for contact information to set up an appointment. Data were analyzed as a complete set, then compared between authorship types, and finally evaluated by certification status. Academic sites were compared with other authorship groups and certified sites were compared with noncertified sites using Student's t-test. RESULTS: Appropriate indications were referenced in 74% of sites, whereas only 45% discussed a contraindication to the procedure. Benefits were expressed by 100% of sites, but risks were outlined in only 53% (p < 0.001). Ninety-nine percent of sites provided step-by-step descriptions of the procedure, and 44% of sites also included images. Alternative treatments were mentioned by 51% of sites. Twenty-seven percent of sites referenced peer-reviewed literature, 41% offered experiential or noncited data based on American populations, and 7% offered analogous data from international populations. Thirty percent of sites provided contact information for patient appointment scheduling. Seven percent of sites were classified as excellent quality, 6% as high quality, 11% as moderate quality, 19% as poor quality, and 57% as unacceptable. Sixteen percent of sites were sponsored by academic institutions, 62% by private groups, 8% by biomedical device companies, and 14% were sponsored otherwise. Academic sites reported fewer risks of the procedure than private sites or other sites (p = 0.05 and p = 0.04), but reported more risks than industry sites (p = 0.007). Academic sites were more likely than sites classified as other to offer contact information for patient appointment scheduling (p = 0.004). Nine percent of sites evaluated were Health on the Net Foundation (HONCode) certified. No association with improved information quality was observed in these sites relative to noncertified sites (all p > 0.05). CONCLUSIONS: Internet information regarding vertebroplasty is not only inadequate for proper patient education, but also potentially misleading as sites are more likely to present benefits of the procedure than risks. Although academic sites might be expected to offer higher-quality information than private, industry, or other sites, our data would suggest that they do not. HONCode certification cannot be used reliably as a means of qualifying website information quality. Academic sites should be expected to set a high standard and alter their Internet presence with adequate information distribution. Certification bodies also should alter their standards to necessitate provision of complete information in addition to emphasizing accurate information. Treating physicians may want to counsel their patients regarding the limitations of information present on the Internet and the pitfalls of current certification systems. LEVEL OF EVIDENCE: Level IV, economic and decision analyses. See the Instructions for Authors for a complete description of levels of evidence. PMID- 24338044 TI - Sexual dysfunction associated with second-generation antidepressants in patients with major depressive disorder: results from a systematic review with network meta-analysis. AB - BACKGROUND: Sexual dysfunction (SD) is prevalent in patients with major depressive disorder (MDD) and is also associated with second-generation antidepressants (SGADs) that are commonly used to treat the condition. Evidence indicates under-reporting of SD in efficacy studies. SD associated with antidepressant treatment is a serious side effect that may lead to early termination of treatment and worsening of quality of life. OBJECTIVES: Our objective was to systematically assess the harms of SD associated with SGADs in adult patients with MDD by drug type. METHODS: We retrieved English-language abstracts from PubMed, EMBASE, the Cochrane Library, PsycINFO, and International Pharmaceutical Abstracts from 1980 to October 2012 as well as from reference lists of pertinent review articles and grey literature searches. Two independent reviewers identified randomized controlled trials (RCTs) of at least 6 weeks' duration and observational studies with at least 1,000 participants. STUDY SELECTION: Reviewers abstracted data on study design, conduct, participants, interventions, outcomes and method of SD ascertainment, and rated risk of bias. A senior reviewer checked and confirmed extracted data and risk-of-bias ratings. ANALYSES: Random effects network meta-analysis using Bayesian methods for data from head-to-head trials and placebo-controlled comparisons; descriptive analyses calculating weighted mean rates from individual trials and observational studies. RESULTS/SYNTHESIS: Data from 63 studies of low and moderate risk of bias (58 RCTs, five observational studies) with more than 26,000 patients treated with SGADs were included. Based on network meta-analyses of 66 pairwise comparisons from 37 RCTs, most comparisons showed a similar risk of SD among included SGADs. However, credible intervals were wide and included differences that would be considered clinically relevant. We observed three main patterns: bupropion had a statistically significantly lower risk of SD than some other SGADs, and both escitalopram and paroxetine showed a statistically significantly higher risk of SD than some other SGADs. We found reporting of harms related to SD inconsistent and insufficient in some trials. LIMITATIONS: Most trials were conducted in highly selected populations. Search was restricted to English-language only. CONCLUSION AND IMPLICATIONS: Because of the indirect nature of the comparisons, the often wide credible intervals, and the high variation in magnitude of outcome, we rated the overall strength of evidence with respect to our findings as low. The current degree of evidence does not allow a precise estimate of comparative risk of SD associated with a specific antidepressant. In the absence of such evidence, clinicians need to be aware of SD as a common adverse event and should discuss patients' preferences before initiating antidepressant therapy. PMID- 24338045 TI - Author's reply to Borg et al. Comment on: "EU's new pharmacovigilance legislation: considerations for biosimilars". PMID- 24338046 TI - The influence of phosphorus availability and Laccaria bicolor symbiosis on phosphate acquisition, antioxidant enzyme activity, and rhizospheric carbon flux in Populus tremuloides. AB - Many forest tree species are dependent on their symbiotic interaction with ectomycorrhizal (ECM) fungi for phosphorus (P) uptake from forest soils where P availability is often limited. The ECM fungal association benefits the host plant under P limitation through enhanced soil exploration and increased P acquisition by mycorrhizas. To study the P starvation response (PSR) and its modification by ECM fungi in Populus tremuloides, a comparison was made between nonmycorrhizal (NM) and mycorrhizal with Laccaria bicolor (Myc) seedlings grown under different concentrations of phosphate (Pi) in sand culture. Although differences in growth between NM and Myc plants were small, Myc plants were more effective at acquiring P from low Pi treatments, with significantly lower k m values for root and leaf P accumulation. Pi limitation significantly increased the activity of catalase, ascorbate peroxidase, and guaiacol-dependent peroxidase in leaves and roots to greater extents in NM than Myc P. tremuloides. Phosphoenolpyruvate carboxylase activity also increased in NM plants under P limitation, but was unchanged in Myc plants. Formate, citrate, malonate, lactate, malate, and oxalate and total organic carbon exudation by roots was stimulated by P limitation to a greater extent in NM than Myc plants. Colonization by L. bicolor reduced the solution Pi concentration thresholds where PSR physiological changes occurred, indicating that enhanced Pi acquisition by P. tremuloides colonized by L. bicolor altered host P homeostasis and plant stress responses to P limitation. Understanding these plant-symbiont interactions facilitates the selection of more P-efficient forest trees and strategies for tree plantation production on marginal soils. PMID- 24338047 TI - Nationwide investigation into adverse tissue reactions to metal debris after metal-on-metal total hip arthroplasty in Japan. AB - BACKGROUND: Adverse reactions to metal debris (ARMD) after receiving metal-on metal (MoM) hip implants is a recent concern. However, no epidemiologic study has examined ARMD for MoM hip implants in Japan. The purposes of this study were to research the incidence of ARMD and to identify poorly performing MoM hip implants in Japan. METHODS: From 2000 to 2011, 7 companies provided 23,226 MoM implants in Japan. A questionnaire regarding ARMD was sent to 101 hospitals at which 62% of the 23,226 MoM implants had been used. RESULTS: Replies to the questionnaire were received from 82 hospitals. In these hospitals, surface hip replacement types (SRs) were used in 606 hips and stemmed types were used in 12,961 hips. ARMD were reported in 3 hips (0.5%) with SRs and 160 hips (1.2%) with stemmed types. ARMD in the 3 hips with SRs were asymptomatic and no revisions were performed. Among AMRD with stemmed implants, revision was performed in 83 hips and excision of an ARMD lesion was performed in 3 hips. The remaining 74 hips were asymptomatic and careful follow-up was continued. A significant difference in reoperation rate was evident between SRs (0%) and stemmed types (0.7%). Incidences of ARMD were significantly higher with Ultamet (P = 0.005), Conserve (P < 0.001), and Cormet (P < 0.001) MoM bearing couples than with Metasul bearings. CONCLUSIONS: The incidence of ARMD in large surgical volume hospitals in Japan from 2000 to 2011 was estimated to be 0.5% with SRs and 1.2% with stemmed types. The reoperation rate was significantly higher with stemmed types than with SRs. Three brands of MoM stemmed implants were identified as showing a higher incidence of ARMD. PMID- 24338048 TI - Biomechanical characteristics of the horizontal mattress stitch: implication for double-row and suture-bridge rotator cuff repair. AB - BACKGROUND: We investigated the effects of bite-size horizontal mattress stitch (distance between the limbs passed through the tendon) on the biomechanical properties of the repaired tendon. METHODS: We anchored 20 bovine Achilles tendons to bone using no. 2 high-strength suture and 5-mm titanium suture anchors in a mattress-suture technique. Tendons were allocated randomly into two groups of ten each to receive stitches with a 4- or 10-mm bite. Specimens underwent cyclic loading from 5 to 30 N at 1 mm/s for 30 cycles, followed by tensile testing to failure. Gap formation, tendon strain, hysteresis, stiffness, yield load, ultimate load, energy to yield load, and energy to ultimate load were compared between groups using unpaired t tests. RESULTS: The 4-mm group had less (p < 0.05) gap formation and less (p < 0.05) longitudinal strain than did the 10 mm group. Ultimate load (293.6 vs. 148.9 N) and energy to ultimate load (2,563 vs. 1,472 N-mm) were greater (p < 0.001) for the 10-mm group than the 4-mm group. All tendons repaired with 4-mm suturing failed at the suture-tendon interface, with sutures pulling through the tendon, whereas the suture itself failed before the tendon did in seven of the ten specimens in the 10-mm group. CONCLUSIONS: Whereas a 4-mm bite fixed the tendon more tightly but at the cost of decreased ultimate strength, a 10-mm bite conveyed greater ultimate strength but with increased gap and strain. These results suggest that for the conventional double row repair, small mattress stitches provide a tighter repair, whereas large stitches are beneficial to prevent sutures from pulling through the tendon after surgery. For suture-bridge rotator cuff repair, large stitches are beneficial because the repaired tendon has a higher strength, and the slightly mobile medial knot can be tightened by lateral fixation. PMID- 24338049 TI - Mechanical stress-induced apoptosis of nucleus pulposus cells: an in vitro and in vivo rat model. AB - BACKGROUND: Un-physiological loads play an important role in the degenerative process of inter-vertebral discs (IVD). In this study, we used an in vitro and in vivo rat model to investigate the mechanism of nucleus pulposus (NP) cells apoptosis induced by mechanical stress. METHODS: Static compressive load to IVDs of rat tails was used as the in vivo model. For the in vitro model, NP cells were tested under the physiological and un-physiological loading. For histological examination, apoptotic index study, and apoptotic gene expression, we also selected cytokines [bone morphogenetic protein (BMP)-2/7, insulin-like growth factor (IGF)-1, platelet-derived growth factor (PDGF)] to be analyzed. RESULTS: Under mechanical loading, cellular density was significantly decreased, but there was an increase of TUNEL positive cells and apoptosis index. In a dose-dependent manner; the necrosis became apparent in the un-physiologic strain. The selected cytokines (BMP-2/7, IGF-1, PDGF) can significantly reduce the percentage of apoptotic and necrotic cells. CONCLUSIONS: We conclude that the intrinsic (mitochondrial) apoptotic pathway plays an important role in the compressive load induced apoptosis of NP cells. Combination therapy reducing the mechanical load and selected cytokines (BMP-2/7, IGF-1 and PDGF) may have considerable promise in the treatment of spine disc degeneration. PMID- 24338050 TI - Prevalence of hallux valgus and risk factors among Japanese community dwellers. AB - BACKGROUND: To investigate the prevalence and severity of radiographically detected hallux valgus (HV) as well as associated risk factors among Japanese residents of Miyagawa, a mountain village located in the center of Mie Prefecture. METHODS: The height, weight and body mass index (BMI) of 403 participants (male n = 135, female n = 268) recruited from among the residents of Miyagawa Village, Japan aged >=65 years were measured, and baseline data, including age, sex and medical history were obtained from interviews and questionnaires. Knee osteoarthritis (KOA) was determined from radiographs of the feet and knees, and osteoporosis was determined by measuring bone mineral density. Hallux valgus, defined as angulation of the big toe at the first metatarsophalangeal joint of >20 degrees , was classified as: mild (20 degrees 30 degrees ), moderate (30 degrees -40 degrees ) or severe (>40 degrees ). Risk factors for HV were calculated using multivariate logistic regression analysis that included age, sex, obesity (BMI >=25), KOA, osteoporosis, Heberden's nodes and low back pain as variables. RESULTS: The overall prevalence of definite radiographic HV was 22.8 % (184/806), and mild, moderate and severe HV was found in 66.3, 27.2 and 6.5 % of the participants, respectively. Hallux valgus was found in at least one foot in 120 (29.8 %) of the participants and the prevalence significantly differed between females with and without HV and KOA (odds ratios: 2.54 and 1.71, respectively). CONCLUSIONS: The prevalence of definite radiographic HV was 29.8 %. Female sex and KOA were significantly associated with increased risk for radiographic HV. PMID- 24338051 TI - Acceptable parameters for alignment of distal radius fracture with conservative treatment in elderly patients. AB - BACKGROUND: There is a conflict in the treatment of distal radius fractures in elderly patients, because fracture reduction does not appear to be as strongly associated with functional outcomes as in younger patients. The purpose of this study was to evaluate radiographic findings of acceptable reduction without leading to wrist dysfunction and poor outcomes. METHODS: Fifty-two active and healthy elderly patients with conservatively managed distal radius fractures were included in the study. They consisted of 7 men and 45 women, all 60 years or older. Radiographic assessment included volar tilt, radial inclination and ulnar variance, and outcome evaluation included the Mayo wrist score and DASH score. As a control group, the preoperative radiographic and clinical outcomes were examined as well for 19 patients older than 60 with malunion, for whom corrective osteotomy was performed because of wrist dysfunction. The radiographic parameters and clinical outcomes were compared between the two groups in a statistical manner. Correlation coefficients of the radiographic parameters with Mayo wrist score and DASH score were analyzed by multiple regression. RESULTS: Volar tilt (mean -1.2 degrees ) and ulnar variance (mean 2.5 mm), as well as Mayo wrist score (mean 80.0 points) and DASH score (mean 8.6 points) in the objective group were significantly superior to those in the control group when comparing radiographic parameters and clinical outcomes. There was no significant difference between the two groups in regard to RI (mean 14.9 degrees ). Multiple regression analysis revealed that volar tilt and ulnar variance were significantly correlated with the clinical outcomes in the objective. CONCLUSION: The parameters of volar tilt and ulnar variance had a significant correlation with clinical outcomes. Clinical outcomes significantly worsened when those parameters exceeded a tolerable range. In elderly patients, it is important to determine an appropriate therapeutic modality for a distal radius fracture when considering the acceptable parameters for alignment. PMID- 24338052 TI - Assessment of physico-chemical qualities and heavy metal concentrations of Umgeni and Umdloti Rivers in Durban, South Africa. AB - We assessed the effects of seasonal dynamics on the physico-chemical qualities and heavy metals concentrations of the Umgeni and Umdloti Rivers in Durban, South Africa. Water samples were taken from nine different sampling points and analysed for the following parameters; temperature, pH, turbidity, electrical conductivity (EC), biological oxygen demand (BOD5), chemical oxygen demand (COD), phosphate (PO4(2-)), nitrate (NO3(2-)), ammonium (NH4(+)), sulphate (SO4(2-)), lead (Pb(2+)), mercury (Hg(2+)), cadmium (Cd(2+)), aluminium (Al(3+)), and copper (Cu(2+)) using standard methods. The data showed variations it terms of the seasonal fluctuations and sampling regime as follows: temperature 12-26.5 degrees C; pH 5.96-8.45; turbidity 0.53-18.8 NTU; EC 15.8-5180 mS m(-1); BOD5 0.60-7.32 mg L(-1); COD 10.5-72.9 mg L(-1); PO4 (2-) < 500-2,460 MUg L(-1); NO3 (2-) <0.05-4.21 mg L(-1); NH4 (+) < 0.5-1.22 mg L(-1); SO4 (2-) 3.90-2,762 mg L( 1); Pb(2+) 0.023-0.135 mg L(-1); Hg(2+) 0.0122-0.1231 mg L(-1) Cd(2+) 0.068-0.416 mg L(-1); Al(3+) 0.037-1.875 mg L(-1), and Cu(2+)0.006-0.144 mg L(-1). The concentrations of most of the investigated parameters exceeded the recommended limit of the South African Guidelines and World Health Organization tolerance limits for freshwater quality. We conclude that these water bodies are potentially hazardous to public health and this highlights the need for implementation of improved management strategies of these river catchments for continued sustainability. PMID- 24338053 TI - Characterization of domestic wastewater treatment in Oman from three different regions and current implications of treated effluents. AB - Treated effluents become one of the most significant sources for irrigation and other activities in arid and semi arid countries such as Oman. This study focuses on characterizing the quality of domestic wastewater in chosen three regions: Muscat, Sohar, and Salalah. The knowledge on treatment processes, quality, and proper management of domestic wastewater reuse for various purposes is essential. Wastewater samples were collected from six different sewage treatment plants (STPs) over a period of 1 year in 2009 on a monthly basis. The raw sewage (RS) and treated effluent (TEs) samples were collected from different sampling points in each STP. Both types of samples were analyzed for physicochemical and microbiological assessment. All tests were conducted according to the standard method for the examination of water and wastewater. The results revealed that the TEs electrical conductivity, biological oxygen demand, chemical oxygen demand, heavy metals, sodium, potassium, and total dissolved solids values were found within Omani Standards (OS). The RS in all STPs was categorized as high strength concentration and samples exceeded the acceptable range for ammonia in most of the selected plants except Sohar and Salalah. Nitrate values in RS were also observed in higher concentrations. In general, the produced TEs have met most of regulatory limits stated by OS except for nitrate, Escherichia coli and total suspended solids (TSS). Furthermore, it should be noted that the performance of Salalah and Darsayt STPs can be classified as the best compared to the other four STPs studied in Oman. PMID- 24338054 TI - Analyzing riparian forest cover changes along the Firniz River in the Mediterranean City of Kahramanmaras in Turkey. AB - Riparian forests adjacent to surface water are important transitional zones which maintain and enrich biodiversity and ensure the sustainability in a forest ecosystem. Also, riparian forests maintain water quality, reduce sediment delivery, enhance habitat areas for aquatic life and wildlife, and provide ecological corridors between the upland and the downstream. However, the riparian ecosystems have been degraded mainly due to human development, forest operations, and agricultural activities. In order to evaluate the impacts of these factors on riparian forests, it is necessary to estimate trends in forest cover changes. This study aims to analyze riparian forest cover changes along the Firniz River located in Mediterranean city of Kahramanmaras in Turkey. Changes in riparian forest cover from 1989 to 2010 have been determined by implementing supervised classification method on a series of Landsat TM imagery of the study area. The results indicated that the classification process applied on 1989 and 2010 images provided overall accuracy of 80.08 and 75 %, respectively. It was found that the most common land use class within the riparian zone was productive forest, followed by degraded forest, agricultural areas, and other land use classes. The results also indicated that the areas of degraded forest and forest openings increased, while productive forest and agricultural areas decreased between the years of 1989 and 2010. The amount of agricultural areas decreased due to the reduction in the population of rural people. According to these results, it can be concluded that special forest management and operation techniques should be implemented to restore the forest ecosystem in riparian areas. PMID- 24338055 TI - Simultaneous determination of insecticide fipronil and its metabolites in maize and soil by gas chromatography with electron capture detection. AB - An integrated method for the simultaneous determination of insecticide fipronil and its three metabolites, desulfinyl, sulfide, and sulfone, in maize grain, maize stem, and soil was developed. This three-step method uses liquid-solid extraction with ultrasound or mechanical grinding, followed by liquid-liquid partitioning and florisil solid-phase extraction (SPE) for cleanup. The quantification was conducted by gas chromatography-electron capture detection in triplicate for each sample. The method was validated with five replicates at three fortification concentrations, 0.002, 0.01, and 0.1 mg kg(-1), in each matrix and gave mean recoveries from 83 to 106 % with relative standard deviation <= 8.9 %. The limits of quantification (LOQ) were 0.002 mg kg(-1) for the compounds in all matrixes. In the field study in Beijing and Shandong 2012, fipronil-coated maize seeds were planted and the proposed method was applied for checking the possible existence of four compounds in maize and soil samples, but none of them contained residues higher than the LOQs in both application rates. Moreover, the dissipation of fipronil in soil fits first-order kinetics with half lives 9.90 and 10.34 days in Beijing and Shandong, respectively. Combined with an adequate sample treatment, this technique offers good sensitivity and selectivity in the three complex matrixes. The results could provide guidance for the further research on pesticide distribution and safe use of fipronil as seed coat in cereals. PMID- 24338056 TI - Physicians, politics, and health insurance expansion. PMID- 24338057 TI - miR-124 represses ROCK1 expression to promote neurite elongation through activation of the PI3K/Akt signal pathway. AB - Recent studies have demonstrated an important role for miR-124, the most abundant and well-conserved brain-specific microRNA(miRNA), in promoting neurite outgrowth and elongation during neuronal differentiation. This miRNA's target genes and the mechanisms that execute this role remain unclear. In this study, we identified ROCK1, a small GTPase Rho kinase, as a direct target of miR-124 for regulating neurite elongation. miR-124 significantly inhibited ROCK1 expression in M17 cells. Inhibiting ROCK1 promoted neurite elongation, and the overexpression of ROCK1 strongly repressed the neurite elongation-enhancing effect of miR-124 in M17 cells. We determined that Akt functions as a novel ROCK1 downstream effector in regulating neurite outgrowth and elongation. PMID- 24338058 TI - Neuromuscular electrical stimulation: no enhancement of recovery from maximal exercise. AB - PURPOSE: To investigate the use of neuromuscular electrical stimulation (NMES) during acute recovery between 2 bouts of maximal aerobic exercise. METHODS: On 3 separate days, 19 trained male cyclists (28 +/- 7 y, 76.4 +/- 10.4 kg, power output at maximal aerobic power [pVo2max] 417 +/- 44 W) performed a 3-min maximal cycling bout at 105% PVo2max before a 30-min randomly assigned recovery intervention of passive (PAS: resting), active (ACT: 30% PVo2max), or NMES (5 Hz, 4 pulses at 500 MUs). Immediately afterward, a cycle bout at 95% PVo2max to exhaustion (TLIM) was performed. Heart rate (HR) and blood lactate (BLa) were recorded at designated time points. Data were analyzed using repeated-measures ANOVA with a Tukey honestly significantly different post hoc test. Statistical significance threshold was P < .05. RESULTS: The TLIM was significantly shorter for NMES than for ACT (199.6 +/- 69.4 s vs 250.7 +/- 105.5 s: P = .016) but not PAS recovery (199.6 +/- 69.4 s vs 216.4 +/- 77.5 s: P = .157). The TLIM was not significantly different between ACT and PAS (250.7 +/- 105.5 s vs 216.4 +/- 77.5 s: P = .088). The decline in BLa was significantly greater during ACT than NMES and PAS recovery (P < .001), with no difference between NMES and PAS. In addition, HR was significantly higher during ACT than NMES and PAS recovery (P < .001), with no difference between NMES and PAS. CONCLUSIONS: NMES was less effective than ACT and comparable to PAS recovery when used between 2 bouts of maximal aerobic exercise in trained male cyclists. PMID- 24338059 TI - Measurements of gamma (gamma)-emitting radionuclides with a high-purity germanium detector: the methods and reliability of our environmental assessments on the Fukushima 1 Nuclear Power Plant accident. AB - The severe accident of Fukushima 1 Nuclear Power Plant due to the Tohoku Region Pacific Coast Earthquake in 11 March 2011 caused wide contamination and pollution by radionuclides in Fukushima and surrounding prefectures. In the current JPR symposium, a group of plant scientists attempted to examine the impact of the radioactive contamination on wild and cultivated plants. Measurements of gamma (gamma) radiation from radionuclides in "Fukushima samples", which we called and collected from natural and agricultural areas in Fukushima prefecture were mostly done with a high-purity Ge detector in the Graduate School of Maritime Sciences, Kobe University. In this technical note, we describe the methods of sample preparation and measurements of radioactivity of the samples and discuss the reliability of our data in regards to the International Atomic Energy Agency (IAEA) Interlaboratory comparisons and proficiency test (IAEA proficiency test). PMID- 24338060 TI - (134)Cs and 137Cs levels in a grassland, 32 km northwest of the Fukushima 1 Nuclear Power Plant, measured for two seasons after the fallout. AB - We measured the levels of radioactive caesium (RACs; 134Cs and 137Cs) in plants and soil in a grassland, 32 km northwest of the Fukushima 1 Nuclear Power Plant, from June 2011 to October 2012. In 2011, the highest RACs levels (134Cs + 137Cs) in plants and in the 0-5 cm soil layer were approximately 80 kBq per kg dry weight (DW). Forage grasses and clovers in this grassland showed similar RACs levels. On a DW basis, the levels of RACs in these plants tended to increase with increasing biomass over both years, but the absolute levels decreased in 2012. The RACs levels in the soil decreased sharply with soil depth; the RACs level in the 5-10 cm soil layer was only 3 % of that in the 0-5 cm layer. The transfer factor (ratio of radioactivity in plant parts on DW basis to that in the 0-10 cm soil layer) was 0.5 and 1.0 for the aboveground and belowground plant parts, respectively, in 2011, and these values decreased by approximately 50 % in 2012. We discuss the possible mechanisms underlying these trends, and strategies to decrease the level of RACs in plants to the permissible level for forage. PMID- 24338061 TI - Evaluation of the radioactive Cs concentration in brown rice based on the K nutritional status of shoots. AB - The radioactive cesium ((134,137)Cs) concentration in brown rice is correlated with that in the straw/husk. The distribution of (134,137)Cs, resembles that of potassium (K), a homologous element of Cs, in the rice plant body. The relative isotopic abundance of (40)K is 0.0117 %; thus, 1 g K contains 30.4 Bq 40K, and the mass of 4,000 Bq (40)K is 0.0154 g, indicating that the K concentration can be calculated from (40)K concentration. We examined if the radioactive Cs concentration in brown rice can be estimated from (40)K concentrations in straw, and especially might be predicted from the (40)K:(134,137)Cs ratio in straw. We determined the concentrations of (40)K and radioactive Cs in straw and brown rice, and found a strong correlated-equation (y = 72.922 x(-0.759); r = 0.907) between the radioactive Cs concentration in brown rice and the 40K:(134,137)Cs ratio in straw. The estimated-radioactive Cs concentration in brown rice can be as much as double, depending on the K nutritional status changing the 40K:(134,137)Cs ratio in straw. We herein propose a nutritional diagnosis that radioactive Cs concentrations in brown rice can be predicted from the 40K:(134,137)Cs ratio in shoots. PMID- 24338062 TI - Difference in cesium accumulation among rice cultivars grown in the paddy field in Fukushima Prefecture in 2011 and 2012. AB - After the accident of the Fukushima 1 Nuclear Power Plant in March 2011, radioactive cesium was released and paddy fields in a wide area including Fukushima Prefecture were contaminated. To estimate the levels of radioactive Cs accumulation in rice produced in Fukushima, it is crucial to obtain the actual data of Cs accumulation levels in rice plants grown in the actual paddy field in Fukushima City. We herein conducted a two-year survey in 2011 and 2012 of radioactive and non-radioactive Cs accumulation in rice using a number of rice cultivars grown in the paddy field in Fukushima City. Our study demonstrated a substantial variation in Cs accumulation levels among the cultivars of rice. PMID- 24338063 TI - The effect of fertilization on cesium concentration of rice grown in a paddy field in Fukushima Prefecture in 2011 and 2012. AB - After the accident of the Fukushima 1 nuclear power plant in March 2011, radioactive cesium was released and paddy field in a wide area of Fukushima Prefecture was contaminated. To reduce radioactive Cs uptake by rice, it is important to understand factors that affect Cs uptake in rice. Here we describe our study in 2011 and 2012 to investigate Cs concentration in two rice cultivars, Koshihikari and Hitomebore, the top two cultivars in Fukushima prefecture, grown under different fertilizer conditions in the contaminated paddy field. Our study demonstrated that high nitrogen and low potassium conditions increase Cs concentrations both in straw and brown rice. PMID- 24338064 TI - Brief review: Obstetric care and perioperative analgesic management of the addicted patient. AB - PURPOSE: Addiction to alcohol and illicit drugs occurs in approximately 10% of the Canadian population and thus likely affects numerous perioperative patients. Provision of perioperative analgesia to these patients is challenging for physiological and behavioural reasons. Seven electronic databases were searched to identify papers addressing the perioperative management of analgesia in addicted patients. PRINCIPAL FINDINGS: There are few controlled trials on addiction care in obstetrical management, and controlled trials are lacking in obstetrical analgesia and addiction and in perioperative analgesia and addiction. The focus of the limited number of publications in the obstetrical population is on addiction management during pregnancy and does not address analgesic requirements. There are principle-based discussions on factors affecting analgesic management in patients receiving chronic opioid therapy and multimodal analgesic therapy. This discourse includes consideration of the physiological and affective factors that impact perioperative management. A number of empirically derived protocols available for managing alcohol withdrawal are based on response to the physical manifestations of withdrawal. Protocols for management of patients receiving opioid replacement therapy for opioid addiction are also well described. Nevertheless, evaluations of these protocols are lacking in clinical trials, and the impact of addiction on perioperative outcomes is unknown. CONCLUSION: Perioperative analgesic management of addicted patients remains poorly understood. Most clinical trials specifically exclude addicted patients. Suggestions for management are provided. PMID- 24338066 TI - Direct observation therapy with appropriate treatment regimens was associated with a decline in second-line drug-resistant tuberculosis in Taiwan. AB - The resistance of Mycobacterium tuberculosis (MTB) to second-line drugs (SLDs) is growing worldwide; however, associations between the appropriateness of treatment for tuberculosis (TB) and whether the directly observed treatment, short course (DOTS)/DOTS-plus programs had an impact on the prevalence of SLD-resistant MTB are still uncertain. We performed a retrospective analysis of resistance profiles among MTB isolates obtained from 6,035 consecutive patients from 2004 to 2011 at two TB referral hospitals in Taiwan. There was a significant decrease (all p values <0.01) in the prevalence of MTB isolates that were resistant to fluoroquinolones, injectable SLDs, and orally administered SLDs, and multidrug resistant (MDR) and extensively drug-resistant (XDR) MTB isolates over time. There was a significant increase in the coverage rate of DOTS/DOTS-plus programs and that of administering appropriate first-line and second-line regimens (all p < 0.01). Compared with isoniazid-susceptible isolates, high-level (1.0 mg/L) isoniazid-resistant and MDR isolates showed extensive cross resistance to ofloxacin (5.9%, p < 0.01 and 33.6%, p < 0.01), levofloxacin (9.6%, p < 0.01 and 38.1%, p < 0.01), moxifloxacin (11.1%, p < 0.01 and 26.5%, p < 0.01), kanamycin (6.8 %, p < 0.01 and 16.7 %, p < 0.01), ethionamide (6.4%, p < 0.01 and 16.2%, p < 0.01), and para-aminosalicylic acid (13.1%, p < 0.01 and 20.4%, p < 0.01), but not to capreomycin (2.0%, p = 0.06 and 1.6%, p = 0.08). The decline in prevalence of resistance to SLDs was negatively correlated with the rise in rates of administering appropriate regimens as well as the DOTS/DOTS-plus programs, but not with the increase in usage of second-line regimens. The implementation of DOTS/DOTS-plus programs with appropriate regimens was associated with a decrease in the prevalence of SLD-resistant and XDR TB. PMID- 24338065 TI - Krupple-like factors in the central nervous system: novel mediators in stroke. AB - Transcription factors play an important role in the pathophysiology of many neurological disorders, including stroke. In the past three decades, an increasing number of transcription factors and their related gene signaling networks have been identified, and have become a research focus in the stroke field. Kruppel-like factors (KLFs) are members of the zinc finger family of transcription factors with diverse regulatory functions in cell growth, differentiation, proliferation, migration, apoptosis, metabolism, and inflammation. KLFs are also abundantly expressed in the brain where they serve as critical regulators of neuronal development and regeneration to maintain normal brain function. Dysregulation of KLFs has been linked to various neurological disorders. Recently, there is emerging evidence that suggests KLFs have an important role in the pathogenesis of stroke and provide endogenous vaso-or neuro protection in the brain's response to ischemic stimuli. In this review, we summarize the basic knowledge and advancement of these transcriptional mediators in the central nervous system, highlighting the novel roles of KLFs in stroke. PMID- 24338067 TI - Developmentally sensitive cognitive behavioral therapy for adolescent school refusal: rationale and case illustration. AB - School refusal can be difficult to treat and the poorest treatment response is observed among older school refusers. This poor response may be explained, in part, by the impact of developmental transitions and tasks upon the young person, their family, and the treatment process. This paper describes and illustrates the @school program, a cognitive behavioral therapy (CBT) designed to promote developmental sensitivity when planning and delivering treatment for adolescent school refusal. Treatment is modularized and it incorporates progress reviews, fostering a planned yet flexible approach to CBT. The treatment is illustrated in the case of Allison, a 16-year-old female presenting with major depressive disorder and generalized anxiety disorder. A case formulation guided the selection, sequencing, and pacing of modules targeting predisposing, precipitating, perpetuating, and protective factors. Treatment comprised 16 sessions with Allison (interventions addressing depression, anxiety, and school attendance) and 15 concurrent sessions with her mother (strategies to facilitate an adolescent's school attendance), including two sessions with Allison and mother together (family communication and problem solving to reduce parent adolescent conflict). Two treatment-related consultations were also conducted with Allison's homeroom teacher. Allison's school attendance improved during the course of treatment. By post-treatment, there was a decrease in internalizing behavior, an increase in self-efficacy, and remission of depressive disorder and anxiety disorder. Clinically significant treatment gains were maintained at 2 month follow-up. Factors influencing outcome may include those inherent to the @school program together with less specific factors. Special consideration is given to parents' use of both authoritative and autonomy-granting approaches when helping an adolescent to attend school. PMID- 24338068 TI - Longitudinal change in health-related quality of life after intensity-modulated radiation monotherapy for clinically localized prostate cancer. AB - PURPOSE: The purpose of the study is to assess longitudinal changes in general and disease-specific health-related quality-of-life (HRQOL) indices after intensity-modulated radiotherapy (IMRT) monotherapy for patients with localized prostate cancer (PCA). METHODS: Between 2006 and 2010, 91 patients with localized PCA underwent IMRT monotherapy and were enrolled into this prospective study. At baseline, and at 3, 6, 12, and 24 months after IMRT, the general and prostate specific HRQOL were estimated using physical (PCS) and mental component summaries (MCS) calculated using the Medical Outcomes Study 8-Item Short Form Health Survey and Expanded Prostate Cancer Index Composite (EPIC). RESULTS: For 2 years, there were no significant changes in EPIC scores in all subscales of urinary domain, hormonal function, and bother. Bowel and sexual function scores decreased after IMRT and did not return to those at baseline (p = 0.006 and < 0.001, respectively). PCS began to decrease at 3 months after IMRT and then returned to the baseline score at 24 months. In contrast, the MCS score began to significantly increase after IMRT, and thereafter the score remained constant until 24 months (p < 0.001). On multivariate logistic regression analysis, urinary (p = 0.003) and sexual functions (p = 0.0005) at baseline were identified as significant predictors of EPIC urinary irritative/obstructive score and sexual function at 24 months after IMRT. CONCLUSION: Urinary function, including irritative/obstruction symptoms and hormonal function, was not affected by IMRT. However, bowel and sexual function decreased after IMRT. These findings will provide important information for PCA patients considering IMRT. PMID- 24338069 TI - Spatial variability of metallic and organic contamination of anguilliform fish in New Caledonia. AB - New Caledonia is one of the main hot spots of biodiversity on the planet. Large amounts of contaminants are discharged into the lagoon as a result of increasing anthropogenic activities such as intense mining, urbanization, and industrialization. Concentrations of 14 trace elements and 26 persistent organic pollutants (POPs: PCBs and pesticides) were measured in the muscles of two anguilliform fish species, over a coast to barrier reef gradient in two lagoon areas differently exposed to anthropic disturbances. This study emphasizes the high trace element contamination status of anguilliform fish and also highlights slight but perceptible organic pollution. The contamination extends throughout the lagoon, from coast to barrier reef, even in areas remote from emission points. High levels of trace elements, especially those linked to mining activities (i.e., Co, Cr, Fe, Mn, and Ni), were detected in coastal sites. Furthermore, the large dispersion of most POPs throughout the entire lagoon poses the question of their potential toxicity on marine organisms from numerous habitats. Our results underline the need for long-term monitoring of various contaminants over large spatial and time scales. PMID- 24338070 TI - Biodegradation potential of cyano-based ionic liquid anions in a culture of Cupriavidus spp. and their in vitro enzymatic hydrolysis by nitrile hydratase. AB - Biodegradation tests with bacteria from activated sludge revealed the probable persistence of cyano-based ionic liquid anions when these leave waste water treatment plants. A possible biological treatment using bacteria capable of biodegrading similar compounds, namely cyanide and cyano-complexes, was therefore examined. With these bacteria from the genera Cupriavidus, the ionic liquid anions B(CN)4(-), C(CN)3(-), N(CN)2(-) combined with alkaline cations were tested in different growth media using ion chromatography for the examination of their primary biodegradability. However, no enhanced biodegradability of the tested cyano-based ionic liquids was observed. Therefore, an in vitro enzymatic hydrolysis test was additionally run showing that all tested ionic liquid (IL) anions can be hydrolysed to their corresponding amides by nitrile hydratase, but not by nitrilase under the experimental conditions. The biological stability of the cyano-based anions is an advantage in technological application, but the occurrence of enzymes that are able to hydrolyse the parent compound gives a new perspective on future cyano-based IL anion treatment. PMID- 24338071 TI - Mercury in the Mediterranean, part I: spatial and temporal trends. AB - The present paper provides an overview of mercury studies performed in the Mediterranean Sea region in the framework of several research projects funded by the European Commission and on-going national programmes carried out during the last 15 years. These studies investigated the temporal and spatial distribution of mercury species in air, in the water column and sediments, and the transport mechanisms connecting them. It was found that atmospheric concentrations of Hg compounds, particularly oxidised Hg species observed at five coastal sites in the Mediterranean Sea Basin, are significantly higher compared with those recorded at five coastal sites distributed across N Europe, most probably due to natural emissions. Hg levels in water are comparable to other oceans. Anthropogenic and natural point sources show locally limited enrichments, while natural diffusive sources influence Hg speciation over larger areas. Results and statistic comparison of mercury species concentrations within Mediterranean compartments will be presented and discussed. PMID- 24338072 TI - Probing the distribution and contamination levels of 10 trace metal/metalloids in soils near a Pb/Zn smelter in Middle China. AB - The horizontal and vertical distribution patterns and contamination status of ten trace metal/metalloids (Ag, Bi, Co, Cr, Ge, In, Ni, Sb, Sn, Tl) in soils around one of the largest Chinese Pb-Zn smelter in Zhuzhou City, Central China, were revealed. Different soil samples were collected from 11 areas, including ten agricultural areas and one city park area, with a total of 83 surface soil samples and six soil cores obtained. Trace metal/metalloids were determined by inductively coupled plasma-mass spectrometry after digestion by an acid mixture of HF and HNO3. The results showed that Ag, Bi, In, Sb, Sn, and Tl contents decreased both with the distance to the Pb-Zn smelter as well as the soil depth, hinting that these elements were mainly originated from the Pb-Zn smelting operations and were introduced into soils through atmospheric deposition. Soil Ge was influenced by the smelter at a less extent, while the distributions of Co, Cr, and Ni were roughly even among most sampling sites and soil depths, suggesting that they were primarily derived from natural sources. The contamination status, as revealed by the geo-accumulation index (I geo), indicated that In and Ag were the most enriched elements, followed by Sb, Bi, and Sn. In general, Cr, Tl, Co, Ni, and Ge were of an uncontaminated status. PMID- 24338073 TI - Parallel detection of harmful algae using reverse transcription polymerase chain reaction labeling coupled with membrane-based DNA array. AB - Harmful algal blooms (HABs) are a global problem, which can cause economic loss to aquaculture industry's and pose a potential threat to human health. More attention must be made on the development of effective detection methods for the causative microalgae. The traditional microscopic examination has many disadvantages, such as low efficiency, inaccuracy, and requires specialized skill in identification and especially is incompetent for parallel analysis of several morphologically similar microalgae to species level at one time. This study aimed at exploring the feasibility of using membrane-based DNA array for parallel detection of several microalgae by selecting five microaglae, including Heterosigma akashiwo, Chaetoceros debilis, Skeletonema costatum, Prorocentrum donghaiense, and Nitzschia closterium as test species. Five species-specific (taxonomic) probes were designed from variable regions of the large subunit ribosomal DNA (LSU rDNA) by visualizing the alignment of LSU rDNA of related species. The specificity of the probes was confirmed by dot blot hybridization. The membrane-based DNA array was prepared by spotting the tailed taxonomic probes onto positively charged nylon membrane. Digoxigenin (Dig) labeling of target molecules was performed by multiple PCR/RT-PCR using RNA/DNA mixture of five microalgae as template. The Dig-labeled amplification products were hybridized with the membrane-based DNA array to produce visible hybridization signal indicating the presence of target algae. Detection sensitivity comparison showed that RT-PCR labeling (RPL) coupled with hybridization was tenfold more sensitive than DNA-PCR-labeling-coupled with hybridization. Finally, the effectiveness of RPL coupled with membrane-based DNA array was validated by testing with simulated and natural water samples, respectively. All of these results indicated that RPL coupled with membrane-based DNA array is specific, simple, and sensitive for parallel detection of microalgae which shows promise for monitoring natural samples in the future. PMID- 24338075 TI - Health services use and prescription access among uninsured patients managing chronic diseases. AB - Effective chronic condition management is dependent upon prescription medication access and compliance. Impacted access results in increased pain, worsening of the condition and association of additional health-related problems. Prescription medication costs constitute a significant burden for patients who are uninsured and managing chronic conditions. This burden links to the likelihood of medication non-compliance. The purpose of this research was to test the ability of the Andersen Behavioral Model of Health Services Use to examine health behaviors among adult uninsured patients managing physician-diagnosed chronic conditions. To enhance its chronic disease management model for uninsured patients diagnosed with chronic conditions requiring prescription regimens, a local community health center added a pharmaceutical access component to its health care delivery model. The Andersen Behavioral Model of Health Services Use was employed to gain insight on how the predictors of predisposing, enabling and need factors impact the change in clinical outcomes and the number of non-urgent triage telephone encounters, physician visits, and emergency department visits of each uninsured patient diagnosed with a chronic condition requiring prescription medication treatment and receiving care at this facility. Individual health behavior patterns are based on predisposition to care, factors that impede or enable the use of care and overall need for care. In this study, there was a statistically significant relationship between population characteristics and health behavior; between health behavior and outcomes; and between population characteristics and outcomes. PMID- 24338076 TI - Smoke-free coalition cohesiveness in rural tobacco-growing communities. AB - Promoting tobacco control policies in rural tobacco-growing communities presents unique challenges. The purpose of this study was to assess smoke-free coalition cohesiveness in rural communities and identify coalition members' perceived barriers or divisive issues that impede the development of smoke-free policies. A secondary aim was to evaluate differences in coalition cohesiveness between advocates in communities receiving stage-based, tailored policy advocacy assistance versus those without assistance. Tobacco control advocates from 40 rural Kentucky communities were interviewed by telephone during the final wave of a 5-year longitudinal study of community readiness for smoke-free policy. On average, five health advocates per county participated in the 45-min interview. Participants rated coalition cohesiveness as not at all cohesive, somewhat cohesive, or very cohesive, and answered one open-ended question about potentially divisive issues within their coalitions. The mean age of the 186 participants was 48.1 years (SD = 13.3). The sample was predominantly female (83.6%) and Caucasian (99.5%). Divisive concerns ranged from rights issues, member characteristics, type of law, and whether or not to allow certain exemptions. Three of the divisive concerns were significantly associated with their rankings of coalition cohesiveness: raising tobacco in the community, the belief that smoke-free would adversely affect the economy, and government control. Educating coalition members on the economics of smoke-free laws and the actual economic impact on tobacco-growing may promote smoke-free coalition cohesiveness. More resources are needed to support policy advocacy in rural tobacco-growing communities as well as efforts to reduce the divisive concerns reported in this study. PMID- 24338077 TI - Adverse effects of e-cigarette exposures. AB - In 2007, a new source of nicotine exposure was introduced to the United States market, the electronic cigarette (ECIG) or "e-cigarette". Since then, the USA ECIG market has been doubling annually. Despite their widespread popularity, there is a paucity of existing data regarding ECIG toxicity. We report the experience of a statewide poison system. The database of a statewide poison system was queried for human ECIG exposures from 2010 (when Poisindex code first generated) through 2012. Year, age, manner and route of exposure, estimate exposure amount, product concentration, if evaluated at healthcare facility and symptoms were recorded. A total of 35 cases were identified--4 in 2010, 12 in 2011, 19 in 2012. Age range 8 months-60 years. Reported symptoms were mild and transient. Five patients were evaluated in an emergency department and none were admitted. Product concentrations ranged from 4 to 30 mg of nicotine per ml. Poison centers are likely to see an increase in exposures to ECIG given their growing popularity. Our modest results suggest that adverse effects and accidental exposures to ECIG cartridges are unlikely to result in serious toxicity. PMID- 24338078 TI - Selection of indigenous isolates of entomopathogenic soil fungus Metarhizium anisopliae under laboratory conditions. AB - Eight native isolates of the entomopathogenic fungus Metarhizium anisopliae (Metschnikoff) Sorokin were obtained by monitoring soils cultivated in a conventional manner. These isolates were compared in three areas: (a) conidial germination, (b) radial growth and sporulation and (c) ability of conidia to infect Tenebrio molitor larvae. All bioassays were carried out at constant temperatures of 10, 15, and 20 degrees C. Conidia of individual isolates demonstrated differences in germination after a 24-h long incubation at all evaluated temperatures. At 20 degrees C, the germination ranged from 67 to 100 % and at 15 degrees C from 5.33 to 46.67 %. At 10 degrees C, no germination was observed after 24 h; nevertheless, it was 8.67-44.67 % after 48 h. In terms of radial growth, the culture diameters and the associated production of spores of all isolates increased with increasing temperature. At 10 degrees C, sporulation was observed in three isolates while all remaining cultures appeared sterile. Three weeks post-inoculation, conidia of all assessed isolates caused 100 % cumulative mortality of treated larvae of T. molitor at 15 and 20 degrees C with the exception of isolate 110108 that induced 81.33 % mortality at 15 degrees C. At 10 degrees C, larval cumulative mortality ranged from 6.67 to 85.33 % depending on the isolate. Isolates 110108 and 110111 showed significantly slower outset and a much lower rate of infection at all temperatures compared to other tested isolates of M. anisopliae. The bioassays were carried out with the purpose to sort and select indigenous isolates of M. anisopliae useful as biocontrol agents in their original habitat. PMID- 24338079 TI - DOCSS: doctors on-call smartphone study. AB - INTRODUCTION: Smartphones have revolutionised our demands for constant access to information. The usage of smartphones in the clinical setting is becoming widespread. The aim of our study was to assess smartphone ownership and usage across a cohort of interns. METHODS: A voluntary novel questionnaire was distributed to interns in two university hospitals. Details regarding smartphone ownership and usage were assessed. Likert scales were utilised for analysis. RESULTS: Sixty-one (74.4 %) interns responded to the survey. Sixty (98.4 %) owned a smartphone with iPhone((r)) being the most popular (76.7 %). Fifty-five (91.6 %) interns have downloaded medical applications ('apps'), while 29 (52.3 %) reported paying for them. Regarding smartphone use on-call, 30 (50 %) interns agreed it aids diagnoses, 26 (43 %) agree it helped in interpreting laboratory values, 31 (51.7 %) agreed it helped in dosing of medication and 33 (55 %) agreed it was of assistance in medical emergency protocols. Forty-two (70 %), 42 (70 %) and 46 (76.7 %) interns agreed or strongly agreed smartphones have a positive influence on them in terms of levels of stress, confidence and level of knowledge, respectively. CONCLUSION: Smartphone usage is widespread among our intern cohort. The introduction of hospital applications with local guidelines would be welcomed; however, this may require informed patient consent regarding their use. PMID- 24338080 TI - Evaluation of universal newborn hearing screening in Switzerland 2012 and follow up data for Zurich. AB - BACKGROUND: The European Consensus Statement of Neonatal Hearing recommended universal newborn hearing screening (UNHS) in 1998. UNHS was introduced in Switzerland in 1999 under the auspices of a "Swiss Working Group Hearing Screening in Newborns". The aim of this study was to evaluate the number of newborns being screened and consequently followed-up in Switzerland for the year 2012. METHODS: Postal questionnaires were sent to all registered maternity clinics and birth-centres in Switzerland. To evaluate follow-up of newborns failing the screening process, a retrospective consecutive cohort analysis of newborns failing screening at the University Hospital Zurich between 2005 and 2010 was performed. RESULTS: A total of 102/110 (92.7%) maternity clinics and 1/14 (7.1%) birth-centres routinely performed UNHS. When weighted according to the number of births in the varying locations, 97.9% of all newborn received hearing screening. At the University Hospital of Zurich, 253/12,080 (2.1%) newborns failed the screening test and in 15/253 (6%) a relevant bilateral hearing impairment was found. This makes an overall incidence of congenitally relevant hearing loss of 0.12%. Unfortunately, 33/253 (13%) of newborns with failed screening were lost to follow-up. CONCLUSION: UNHS is well-established in Switzerland and the vast majority of newborns are screened. However, follow-up of failed screens is disappointing. Further measures need to be taken to improve follow up. PMID- 24338082 TI - Relaxant effects of asafoetida extract and its constituent umbelliprenin on guinea-pig tracheal smooth muscle. AB - OBJECTIVE: To investigate the relaxant effects of the asafoetida (Ferula Asafoetida Oleo-Gum-Resin) and its coumarin constituent umbelliprenin on tracheal chains of guinea pigs. METHODS: The relaxant effects of three cumulative concentrations of the aqueous extract (2, 5 and 10 mg/mL), umbelliprenin (0.04, 0.2 and 0.4 mg/mL), theophylline (0.05, 0.1 and 0.15 mg/mL) and saline were examined by their relaxant effects on precontracted tracheal chains of guinea pig by 60 mmol/L KCl (group 1), and 10 MU mol/L methacholine (group 2). RESULTS: In group 1 all concentrations of theophylline and the highest concentration of the extract showed signififi cant relaxant effects compared with that of saline (P<0.01 for theophylline and P<0.05 for extract). In group 2, relaxant effects of all concentrations of theophylline, extract and two higher concentrations of umbelliprenin differed significantly compared with saline [P<0.01 for all cases except low concentration of umbelliprenin (0.04 mg/mL)]. There were no signififi cant differences between relaxant effects of the extract and theophylline in group 2. The relaxant effect of the extract in group 2 was signififi cantly greater than that of group 1 (P<0.01). The relaxant effect of the extract was significantly more potent than umbelliprenin in all groups (P<0.05 or P<0.01). CONCLUSION: These results showed a potent relaxant effect for the asafoetida extract on tracheal smooth muscle which is, at least, in part, due to its constituent umbelliprenin. A muscarinic receptor blockade was also suggested for the extract. PMID- 24338081 TI - Hydrolysis rates of different small interfering RNAs (siRNAs) by the RNA silencing promoter complex, C3PO, determines their regulation by phospholipase Cbeta. AB - C3PO plays a key role in promoting RNA-induced gene silencing. C3PO consists of two subunits of the endonuclease translin-associated factor X (TRAX) and six subunits of the nucleotide-binding protein translin. We have found that TRAX binds strongly to phospholipase Cbeta (PLCbeta), which transmits G protein signals from many hormones and sensory inputs. The association between PLCbeta and TRAX is thought to underlie the ability of PLCbeta to reverse gene silencing by small interfering RNAs. However, this reversal only occurs for some genes (e.g. GAPDH and LDH) but not others (e.g. Hsp90 and cyclophilin A). To understand this specificity, we carried out studies using fluorescence-based methods. In cells, we find that PLCbeta, TRAX, and their complexes are identically distributed through the cytosol suggesting that selectivity is not due to large scale sequestration of either the free or complexed proteins. Using purified proteins, we find that PLCbeta binds ~5-fold more weakly to translin than to TRAX but ~2-fold more strongly to C3PO. PLCbeta does not alter TRAX-translin assembly to C3PO, and brightness studies suggest one PLCbeta binds to one C3PO octamer without a change in the number of TRAX/translin molecules suggesting that PLCbeta binds to an external site. Functionally, we find that C3PO hydrolyzes siRNA(GAPDH) at a faster rate than siRNA(Hsp90). However, when PLCbeta is bound to C3PO, the hydrolysis rate of siRNA(GAPDH) becomes comparable with siRNA(Hsp90). Our results show that the selectivity of PLCbeta toward certain genes lies in the rate at which the RNA is hydrolyzed by C3PO. PMID- 24338083 TI - A multi-component meningococcal serogroup B vaccine (4CMenB): the clinical development program. AB - Recently approved in Europe and Australia, the multi-component meningococcal B vaccine, 4CMenB (Bexsero(r), Novartis Vaccines and Diagnostics), contains three surface-exposed recombinant proteins (fHbp, NadA, and NHBA) and New Zealand strain outer membrane vesicles (NZ OMV) with PorA 1.4 antigenicity. This comprehensive review of the 4CMenB clinical development program covers pivotal phase I/IIb/III studies in over 7,000 adults, adolescents, and infants. The immunological correlate for clinical protection used was human complement mediated serum bactericidal activity titers >=4 or 5 against indicator strains for individual antigens. Based on achievement of protective titers, a four-dose schedule (three primary doses and one booster dose) for infants and a two-dose schedule for adolescents provided the best results. Observed increases in injection site pain/tenderness and fever in infants, and injection site pain, malaise, and headache in adolescents compared with routine vaccines, were mostly mild to moderate; frequencies of rare events (Kawasaki disease, juvenile arthritis) were not significantly different from non-vaccinated individuals. 4CMenB is conservatively estimated to provide 66-91 % coverage against meningococcal serogroup B strains worldwide. PMID- 24338084 TI - Miglustat: a review of its use in Niemann-Pick disease type C. AB - Miglustat (Zavesca(r), Brazaves(r)), a small iminosugar molecule that reversibly inhibits glycosphingolipid synthesis, is the only disease-specific drug approved for the treatment of progressive neurological manifestations of Niemann-Pick disease type C (NP-C) in adult and paediatric patients. NP-C is a rare, autosomal recessive lipid storage disorder characterized by impaired intracellular lipid trafficking and progressive neurological symptoms leading to premature death. In a randomized clinical trial, long-term extension studies and a retrospective observational cohort study, treatment with oral miglustat stabilized key neurological manifestations of NP-C (including horizontal saccadic eye movement peak velocity, ambulation, manipulation, language and swallowing) in paediatric and adult patients with the disease. The therapeutic effects of miglustat in stabilizing or slowing disease progression have been confirmed in other reports in the clinical experience setting. The primary tolerability issues associated with miglustat are mild to moderate gastrointestinal effects (e.g. diarrhoea, flatulence and abdominal pain/discomfort) and weight loss, which usually occur during initial therapy and are generally manageable. In the absence of a cure, miglustat is a valuable agent to reduce the progression of clinically relevant neurological symptoms in paediatric and adult patients with NP-C, which is considered a significant achievement in the treatment of this disease. PMID- 24338085 TI - Techniques and outcomes of minimally invasive trabecular ablation and bypass surgery. AB - Minimally invasive glaucoma surgeries (MIGS) can improve the conventional, pressure-dependent outflow by bypassing or ablating the trabecular meshwork (TM), or creating alternative drainage routes into the suprachoroidal or subconjunctival space. They have a highly favourable risk profile compared to penetrating surgeries, and lower intraocular pressure with variable efficacy that may depend on the extent of outflow segments accessed. Since they are highly standardised procedures that use clear corneal incisions, they can elegantly be combined with cataract and refractive procedures to improve vision in the same session. There is a growing need for surgeons to become proficient in MIGS to address the increasing prevalence of glaucoma and cataracts in a well-informed, aging population. Techniques of visualisation and instrumentation in an anatomically highly confined space with semitransparent tissues are fundamentally different from other anterior segment surgeries, and present even experienced surgeons with a substantial learning curve. Here, we provide practical tips, and review techniques and outcomes of TM bypass and ablation MIGS. PMID- 24338086 TI - Visual acuity, self-reported vision and falls in the EPIC-Norfolk Eye study. AB - PURPOSE: To examine the relationship between visual acuity (VA) and self-reported vision (SRV) in relation to falls in 8317 participants of the European Prospective Investigation into Cancer-Norfolk Eye study. METHODS: All participants completed a health questionnaire that included a question regarding SRV and questions regarding the number of falls in the past year. Distance VA was measured using a logMAR chart for each eye. Poor SRV was defined as those reporting fair or poor distance vision. The relationship between VA and SRV and self-rated falls was analysed by logistic regression, adjusting for age, sex, physical activity, body mass index, chronic disease, medication use and grip strength. RESULTS: Of 8317 participants, 26.7% (95% CI 25.7% to 27.7%) had fallen in the past 12 months. Worse VA and poorer SRV were associated with one or more falls in multivariable analysis (OR for falls=1.31, 95% CI 1.04 to 1.66 and OR=1.32, 95% CI 1.09 to 1.61, respectively). Poorer SRV was significantly associated with falls even after adjusting for VA (OR=1.28, 95% CI 1.05 to 1.57). CONCLUSIONS: SRV was associated with falls independently of VA and could be used as a simple proxy measure for other aspects of visual function to detect people requiring vision-related falls interventions. PMID- 24338087 TI - Outpatient Ultra wide-field intravenous fundus fluorescein angiography in infants using the Optos P200MA scanning laser ophthalmoscope. AB - PURPOSE: To determine the feasibility of Ultra wide-field intravenous fundus fluorescein angiography (UWF-IV-FFA) in infants. METHODS: A retrospective review of infants who underwent UWF-IV-FFA with the Optos P200MA was performed. The ability to capture different phases of the angiogram, the total image acquisition time and the presence of image artefacts were analysed. RESULTS: Twelve infants with a variety of proliferative retinopathies underwent UWF-IV-FFA over a 7-month period. The mean age was 3.4 months (range 2-6 months) and the mean image acquisition time was 4 min (range 3-5). Pseudocolour fundus images and the venous, recirculation and late phases of UWF-IV-FFA were captured successfully in all infants (100%). Choroidal and arterial phases were captured in one (8.3%) and 10 (83.3%) infants, respectively. Image artefacts due to eyelashes and corneal desiccation occurred in nine (75%) and six (50%) infants, respectively. No adverse medical problems were noted. CONCLUSIONS: We have shown that UWF-IV-FFA can be successfully and safely performed in infants using the Optos P200MA system. It is a feasible new alternative to RetCam for obtaining an IV-FFA in the outpatients setting. PMID- 24338089 TI - Thoracoabdominal approach in liver surgery: how, when, and why. AB - Liver resection can be performed with different surgical approaches whether abdominal or combined thoracoabdominal. This work focuses on the surgical technique for the thoracoabdominal approach in liver surgery, describing the technique, the rationale, and making a review of the current literature on such subject. PMID- 24338088 TI - The combination of exercise and respiratory training improves respiratory muscle function in pulmonary hypertension. AB - PURPOSE: Increased dyspnea and reduced exercise capacity in pulmonary arterial hypertension (PAH) can be partly attributed to impaired respiratory muscle function. This prospective study was designed to assess the impact of exercise and respiratory training on respiratory muscle strength and 6-min walking distance (6MWD) in PAH patients. METHODS: Patients with invasively confirmed PAH underwent 3 weeks of in-hospital exercise and respiratory training, which was continued at home for another 12 weeks. Medication remained constant during the study period. Blinded observers assessed efficacy parameters at baseline (I) and after 3 (II) and 15 weeks (III). Respiratory muscle function was assessed by twitch mouth pressure (TwPmo) during nonvolitional supramaximal magnetic phrenic nerve stimulation. RESULTS: Seven PAH patients (4 women; mean pulmonary artery pressure 45 +/- 11 mmHg, median WHO functional class 3.1 +/- 0.4, idiopathic/associated PAH n = 5/2) were included. The training program was feasible and well tolerated by all patients with excellent compliance. TwPmo was I: 0.86 +/- 0.37 kPa, II: 1.04 +/- 0.29 kPa, and III: 1.27 +/- 0.44 kPa, respectively. 6MWD was I: 417 +/- 51 m, II: 509 +/- 39 m, and III: 498 +/- 39 m, respectively. Both TwPmo (+0.41 +/- 0.34 kPa, +56 +/- 39 %) and 6MWD (+81 +/- 30 m, +20 +/- 9 %) increased significantly in the period between baseline and the final assessment (pairwise comparison: p = 0.012/<0.001; RM-ANOVA considering I, II, III: p = 0.037/<0.001). CONCLUSIONS: Exercise and respiratory training as an adjunct to medical therapy may be effective in patients with PAH to improve respiratory muscle strength and exercise capacity. Future, randomized, controlled trials should be carried out to further investigate these findings. PMID- 24338090 TI - Medical image file formats. AB - Image file format is often a confusing aspect for someone wishing to process medical images. This article presents a demystifying overview of the major file formats currently used in medical imaging: Analyze, Neuroimaging Informatics Technology Initiative (Nifti), Minc, and Digital Imaging and Communications in Medicine (Dicom). Concepts common to all file formats, such as pixel depth, photometric interpretation, metadata, and pixel data, are first presented. Then, the characteristics and strengths of the various formats are discussed. The review concludes with some predictive considerations about the future trends in medical image file formats. PMID- 24338091 TI - The association of chronic apical periodontitis and endodontic therapy with atherosclerosis. AB - OBJECTIVES: Chronic apical periodontitis (CAP) appears to be a risk factor for coronary heart disease. The aims of the study were to estimate the significance of AP for the atherosclerotic burden and to examine the potential effect of endodontic treatment. MATERIALS AND METHODS: The whole-body computed tomography (CT) examinations of 531 patients with a mean age of 50 +/- 15.7 years were evaluated retrospectively. The atherosclerotic burden of the abdominal aorta was quantified using a calcium scoring method. The parameters of periodontitis were measured using the CT scan. RESULTS: The patients had a total of 11,191 teeth. The volume of the aortic atherosclerotic burden for patients with at least one CAP lesion was 0.32 +/- 0.92 ml, higher than for patients with no CAP (0.17 +/- 0.51 ml; p < 0.05). The atherosclerotic burden increased with age and number of CAP lesions without root canal treatment, but not with number of CAP lesions with endodontic treatments (p < 0.05 each). In logistic regression models, age (Wald 90.8), CAP without endodontic treatment (Wald 39.9), male gender (Wald 9.8), and caries per tooth (Wald 9.0) correlated positively and the number of fillings (Wald 11) correlated negatively with the atherosclerotic burden (p < 0.05 each). Apical radiolucencies in teeth with endodontic treatment were irrelevant with respect to atherosclerosis. CONCLUSIONS: CAP correlated positively with the aortic atherosclerotic burden. In regression models, CAP without endodontic treatment was found to be an important factor, not however apical radiolucencies in teeth with endodontic treatment. CLINICAL RELEVANCE: Further research is needed to clarify the possible clinical significance of these associations. PMID- 24338092 TI - Heterogeneous glycopeptide intermediate Staphylococcus epidermidis isolated from prosthetic joint infections. AB - Methicillin-resistant Staphylococcus epidermidis (MRSE) poses a major problem in prosthetic joint infections (PJIs). Vancomycin is often considered the drug of choice in the empirical treatment of staphylococcal PJIs. As recent decades have seen reports of heterogeneous glycopeptide intermediate S. aureus (hGISA), our aim was to examine the prevalence of heterogeneous glycopeptide intermediate S. epidermidis (hGISE) in PJIs. S. epidermidis isolates (n = 122) from 119 patients in three Swedish counties between 1993 and 2012 were included. All were isolated from perioperative tissue samples from revision surgery in clinically verified PJIs. Antimicrobial susceptibility testing against staphylococcal antibiotics was performed. The macromethod Etest (MME) and glycopeptide resistance detection (GRD) Etest were used to detect hGISE. Standard minimal inhibitory concentration (MIC) determination revealed no vancomycin-resistant isolates, while teicoplanin resistance was detected in 14 out of 122 isolates (11.5%). hGISE was found in 95 out of 122 isolates (77.9%), 64 out of 67 of isolates with teicoplanin MIC >2 mg/L (95.5%) and 31 out of 55 of isolates with teicoplanin MIC <=2 mg/L (56.4%). Thus, the presence of hGISE cannot be ruled out by teicoplanin MIC <=2 mg/L alone. Multidrug resistance was detected in 86 out of 95 hGISE isolates (90.5%) and in 16 out of 27 isolates (59.3%), where hGISE could not be detected. In conclusion, hGISE detected by MME or GRD was common in this material. However, hGISE is difficult to detect with standard laboratory diagnostic routines. Glycopeptide treatment may not be sufficient in many of these PJIs, even if standard MIC classifies the isolated S. epidermidis as susceptible. PMID- 24338093 TI - Rapid detection of antibiotic resistance based on mass spectrometry and stable isotopes. AB - With the emergence and growing complexity of bacterial drug resistance, rapid and reliable susceptibility testing has become a topical issue. Therefore, new technologies that assist in predicting the effectiveness of empiric antibiotic therapy are of great interest. Although the use of matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) for the rapid detection of antibiotic resistance is an attractive option, the current methods for MALDI-TOF MS susceptibility testing are restricted to very limited conditions. Here, we describe a technique that may allow for rapid susceptibility testing to an extent that is comparable to phenotypic methods. The test was based on a stable isotope labelling by amino acids in cell culture (SILAC)-like approach. This technique was used to visualise the growth of bacteria in the presence of an antibiotic. Pseudomonas aeruginosa was chosen as the model organism, and strains were incubated in normal medium, medium supplemented with (13)C6-(15) N2-labelled lysine and medium supplemented with labelled lysine and antibiotic. Peak shifts occurring due to the incorporation of the labelled amino acids were detected by MALDI-TOF MS. Three antibiotics with different mechanisms of action, meropenem, tobramycin and ciprofloxacin, were tested. A semi-automated algorithm was created to enable rapid and unbiased data evaluation. With the proposed test, a clear distinction between resistant and susceptible isolates was possible for all three antibiotics. The application of SILAC technology for the detection of antibiotic resistance may contribute to accelerated and reliable susceptibility testing. PMID- 24338095 TI - CORR Insights((r)): Subungual exostosis of the toes: a systematic review. PMID- 24338094 TI - Mesenchymal stem cells in synovial fluid increase after meniscus injury. AB - BACKGROUND: Although relatively uncommon, spontaneous healing from a meniscus injury has been observed even within the avascular area. This may be the result of the existence of mesenchymal stem cells in synovial fluid. QUESTIONS/PURPOSES: The purpose of this study was to investigate whether mesenchymal stem cells existed in the synovial fluid of the knee after meniscus injury. METHODS: Synovial fluid was obtained from the knees of 22 patients with meniscus injury just before meniscus surgery and from 8 volunteers who had no history of knee injury. The cellular fraction of the synovial fluid was cultured for 14 days followed by analysis for multilineage potential and presentation of surface antigens characteristic of mesenchymal stem cells. Colony-forming efficiency and proliferation potential were also compared between the two groups. RESULTS: Cells with characteristics of mesenchymal stem cells were observed in the synovial fluid of injured knees to a much greater degree than in uninjured knees. The colony-forming cells derived from the synovial fluid of the knee with meniscus injury had multipotentiality and surface epitopes identical to mesenchymal stem cells. The average number of colony formation, obtained from 1 mL of synovial fluid, in meniscus-injured knees was 250, higher than that from healthy volunteers, which was 0.5 (p < 0.001). Total colony number per synovial fluid volume was positively correlated with the postinjury period (r = 0.77, p < 0.001). CONCLUSIONS: Mesenchymal stem cells were found to exist in synovial fluid from knees after meniscus injury. Mesenchymal stem cells were present in higher numbers in synovial fluid with meniscus injury than in normal knees. Total colony number per synovial fluid volume was positively correlated with the postinjury period. CLINICAL RELEVANCE: Our current human study and previous animal studies suggest the possibility that mesenchymal stem cells in synovial fluid increase after meniscus injury contributing to spontaneous meniscus healing. PMID- 24338097 TI - Investigation of landslide potential parameters on Zonguldak-Eregli Highway and adverse effects of landslides in the region. AB - Landslides are natural phenomena in the same class of natural disasters as earthquakes, floods, hurricanes, erosion, and volcanic eruptions that adversely affect human lives and property. Owing to their widespread occurrence, landslides are easily visible and able to be partially understood by people witnessing them. Nevertheless, to comprehend the detail of their formation and determine their potential, it is necessary to undertake geodetic, geological, and geophysical measurements in regions prone to landslides. By analyzing these measurements, it is possible to better ascertain those regions predisposed to landslides and thus provide the means to prevent loss of life and property. The city of Zonguldak, situated in the Western Black Sea region of Turkey, has a high occurrence of landslides owing to its harsh topography with rugged and steep slopes and rainfall in almost every season. Furthermore, the diurnal temperature ranging up to 10 degrees C in all seasons, especially in winter, plays a crucial role in rock disintegration in this region. Other factors damage ground composition and trigger landslides, such as underground mining operations, road construction that collapses rocky hills using explosives, and excavation works in steep terrain for building construction. This study gives a detailed account of the causes and adverse effects of landslides and their parameters through examples of landslide occurrences in the region, together with the results and analyses of two periods of geodetic measurements conducted on the Zonguldak-Eregli Highway in Iliksu district. PMID- 24338098 TI - An alternative approach for delineating eco-sensitive zones around a wildlife sanctuary applying geospatial techniques. AB - The dynamics, degradation, and conservation of forest ecosystems are matters of prime concerns worldwide at the present. Proper planning and management of a forest area are essentially needed to protect it from the grasp of burgeoning pressure of urban-industrial sprawl. Establishment of eco-sensitive zones (ESZs), which act as buffer areas around the core forests, is one of the key approaches towards achieving this goal. This paper deals with the applicability of geospatial techniques to identify the ESZ around an Indian wildlife sanctuary following the different rules and acts prescribed by the Government of India. Gumti Wildlife Sanctuary, located in the northeastern state of Tripura in India, has been selected here as a case study. Collected pieces of information on the distribution of biodiversity and human population in the area were also used to make the approach more holistic. As inferred from this study, remote sensing and geographical information systems were found to be easily implementable and time as well as cost-effective tools for this purpose with a distinct advantage of spatial as well as temporal accuracy in identifying the existing land use and land cover patterns in pilot assessments. However, the results indicated that only appropriate hybridization of field-based information on the biodiversity and ecological aspects of the forest as well as patterns of human interferences with the remote sensing and GIS-based data could make this approach more relevant in actual implementations. PMID- 24338099 TI - Predicting dissolved oxygen concentration using kernel regression modeling approaches with nonlinear hydro-chemical data. AB - Kernel function-based regression models were constructed and applied to a nonlinear hydro-chemical dataset pertaining to surface water for predicting the dissolved oxygen levels. Initial features were selected using nonlinear approach. Nonlinearity in the data was tested using BDS statistics, which revealed the data with nonlinear structure. Kernel ridge regression, kernel principal component regression, kernel partial least squares regression, and support vector regression models were developed using the Gaussian kernel function and their generalization and predictive abilities were compared in terms of several statistical parameters. Model parameters were optimized using the cross validation procedure. The proposed kernel regression methods successfully captured the nonlinear features of the original data by transforming it to a high dimensional feature space using the kernel function. Performance of all the kernel-based modeling methods used here were comparable both in terms of predictive and generalization abilities. Values of the performance criteria parameters suggested for the adequacy of the constructed models to fit the nonlinear data and their good predictive capabilities. PMID- 24338100 TI - Consistency of commercial devices for measuring elevation gain. AB - PURPOSE: To determine the consistency of commercially available devices used for measuring elevation gain in outdoor activities and sports. METHODS: Two separate observational validation studies were conducted. Garmin (Forerunner 310XT, Edge 500, Edge 750, and Edge 800; with and without elevation correction) and SRM (Power Control 7) devices were used to measure total elevation gain (TEG) over a 15.7-km mountain climb performed on 6 separate occasions (6 devices; study 1) and during a 138-km cycling event (164 devices; study 2). RESULTS: TEG was significantly different between the Garmin and SRM devices (P < .05). The between devices variability in TEG was lower when measured with the SRM than with the Garmin devices (study 1: 0.2% and 1.5%, respectively). The use of the Garmin elevation-correction option resulted in a 5-10% increase in the TEG. CONCLUSIONS: While measurements of TEG were relatively consistent within each brand, the measurements differed between the SRM and Garmin devices by as much as 3%. Caution should be taken when comparing elevation-gain data recorded with different settings or with devices of different brands. PMID- 24338101 TI - The effects of prenatal methylmercury exposure on trace element and antioxidant levels in rats following 6-hydroxydopamine-induced neuronal insult. AB - Methylmercury (MeHg) is a metal toxin found commonly in the environment. Studies have shown severe neurotoxic effects of MeHg poisoning especially during pregnancy where it crosses the foetoplacental and the blood brain barrier of the foetus leading to neurodevelopmental deficits in the offspring. These deficits may predispose offspring to neurodegenerative diseases later in life. In this study we investigated the effects of prenatal methylmercury exposure (2.5 mg/L in drinking water from GND 1-GND 21) on the trace element status in the brain of adolescent offspring (PND 28). Total antioxidant capacity (TAC) was measured in their blood plasma. In a separate group of animals that was also exposed prenatally to MeHg, 6-hydroydopamine (6-OHDA) was administered at PND 60 as a model of neuronal insult. Trace element and TAC levels were compared before and after 6-OHDA exposure. Prenatal MeHg treatment alone resulted in significantly higher concentrations of zinc, copper, manganese and selenium in the brain of offspring at PND 28 (p < 0.05), when compared to controls. In contrast, brain iron levels in MeHg-exposed adolescent offspring were significantly lower than their controls (p < 0.05). Following 6-OHDA exposure, the levels of iron, zinc, copper and manganese were increased compared to sham-lesioned offspring (p < 0.05). Prenatal MeHg exposure further increased these trace element levels thereby promoting toxicity (p < 0.05). Total antioxidant capacity was not significantly different in MeHg and control groups prior to lesion. However, following 6-OHDA administration, MeHg-exposed animals had a significantly lower TAC than that of controls (p < 0.05). Brain TAC levels were higher in adult male rats than in female rats during adolescence however male rats that had been exposed to MeHg in utero failed to show this increase at PND 74. Prenatal MeHg exposure results in trace element dyshomeostasis in the brain of offspring and reduces total antioxidant capacity. This may reflect a mechanism by which methylmercury exerts its neurotoxicity and/or predispose offspring to further neurological insults during adulthood. PMID- 24338102 TI - A population-based association study of casein kinase 1 epsilon loci with heroin dependence in Han Chinese. AB - Pharmacogenetic studies have confirmed that the genetic variant of the casein kinase 1 epsilon (Csnk1epsilon) gene contributes to response variability to amphetamine and methamphetamine in both mice and humans. A polymorphism in the Csnk1epsilon gene has been reported to be associated with heroin dependence. In this study, to identify markers contributing to the genetic susceptibility of the Csnk1epsilon gene to heroin dependence, we examined the potential association between heroin dependence and 14 single nucleotide polymorphisms (SNPs; rs1997644, rs135764, rs867198, rs135763, rs135757, rs6001090, rs5750581, rs1534891, rs1005473, rs3890379, rs2075984, rs2075983, rs135749, and rs135745) of the Csnk1epsilon gene using the MassARRAY system. Participants included 398 heroin-dependent patients and 436 healthy controls from a Han Chinese population. The result revealed a strong association between the rs135745 (3'-untranslated region) genotype distribution and heroin dependence (P = 0.0006). The frequency of the C allele was significantly higher in the heroin-dependent patients than in the healthy controls (chi(2) = 7.172, P = 0.007, OR = 1.426, 95 % CI = 1.099 1.849). Further genotype and clinical phenotype correlation study of the rs135745 carriers showed that the amount of heroin self-injection was higher in patients with the GC + CC genotype compared to the patients with the GG genotypes (P < 0.01). Strong linkage disequilibrium (LD) was observed in block 1, block 2, and block 3 (D' > 0.9), whereas significant evidence of LD was not observed between these SNPs in our sample population. These findings point to a role for Csnk1epsilon polymorphisms in heroin dependence among the Han Chinese population and may be informative for future genetic or neurobiological studies on heroin dependence. PMID- 24338104 TI - Screening for mental disorders in heart failure patients using computer-adaptive tests. AB - PURPOSE: Item response theory is increasingly used in the development of psychometric tests. This paper evaluates whether these modern psychometric methods can improve self-reported screening for depression and anxiety in patients with heart failure. METHODS: The mental health status of 194 patients with heart failure was assessed using six screening tools for depression (Patient Health Questionnaire -9 (9 items), Hospital Anxiety and Depression Scale (HADS) (7 items), PROMIS-Depression Short Form 8a (8 items)) and Anxiety (GAD-7 (7 items), Hospital Anxiety and Depression Scale (HADS) (7 items), PROMIS-Anxiety Short Form 8a (8 items)). An in-person structured clinical interview was used as the current gold standard to identify the presence of a mental disorder. The diagnostic accuracy of all static tools was compared when item response theory (IRT)-based person parameter were estimated instead of sum scores. Furthermore, we compared performance of static instruments with post hoc simulated individual tailored computer-adaptive test (CATs) for both disorders and a common negative affect CAT. RESULTS: In general, screening for depression was highly efficient and showed a better performance than screening for anxiety with only minimal differences among the assessed instruments. IRT-based person parameters yielded the same diagnostic accuracy as sum scores. CATs showed similar screening performance compared to legacy instruments but required significantly fewer items to identify patients without mental conditions. Ideal cutoffs varied between male and female samples. CONCLUSIONS: Overall, the diagnostic performance of all investigated instruments was similar, regardless of the methods being used. However, CATs can individually tailor the test to each patient, thus significantly decreasing the respondent burden for patients with and without mental conditions. Such approach could efficiently increase the acceptability of mental health screening in clinical practice settings. PMID- 24338105 TI - A coarse-grained framework for spiking neuronal networks: between homogeneity and synchrony. AB - Homogeneously structured networks of neurons driven by noise can exhibit a broad range of dynamic behavior. This dynamic behavior can range from homogeneity to synchrony, and often incorporates brief spurts of collaborative activity which we call multiple-firing-events (MFEs). These multiple-firing-events depend on neither structured architecture nor structured input, and are an emergent property of the system. Although these MFEs likely play a major role in the neuronal avalanches observed in culture and in vivo, the mechanisms underlying these MFEs cannot easily be captured using current population-dynamics models. In this work we introduce a coarse-grained framework which illustrates certain dynamics responsible for the generation of MFEs. By using a new kind of ensemble average, this coarse-grained framework can not only address the nucleation of MFEs, but can also faithfully capture a broad range of dynamic regimes ranging from homogeneity to synchrony. PMID- 24338106 TI - Once or twice daily versus three times daily amoxicillin with or without clavulanate for the treatment of acute otitis media. AB - BACKGROUND: Acute otitis media (AOM) is a common problem in children, for which amoxicillin, with or without clavulanate, is frequently prescribed as a treatment of choice. The conventional recommendation is either three or four daily doses. However, nowadays it is frequently prescribed as once or twice daily doses. If once or twice daily amoxicillin, with or without clavulanate, is as effective for acute otitis media as three or four times a day, it may be more convenient to give the medication once or twice a day to children and hence improve compliance. OBJECTIVES: To compare the effectiveness of one or two daily doses with three or four daily doses of amoxicillin, with or without clavulanate, for the treatment of AOM in children; and to compare complication rates and adverse reactions. SEARCH METHODS: We searched CENTRAL 2013, Issue 2, MEDLINE (January 1950 to March week 1, 2013), EMBASE (1974 to March 2013) and the Science Citation Index (2001 to March 2013). SELECTION CRITERIA: We included randomised controlled trials (RCTs) of children aged 12 years or younger with AOM, diagnosed by acute ear pain (otalgia) and inflamed ear drum (confirmed by positive tympanocentesis or tympanogram of type B or C). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data on treatment outcomes from individual trials and assessed trial quality based on selection bias, performance bias and detection bias, attrition bias, reporting bias and other biases. We defined the quality grading as low risk of bias, high risk of bias or unclear risk of bias. We summarised the results as risk ratio (RR) with 95% confidence intervals (CI). MAIN RESULTS: We included five studies with 1601 children in the review. Pooled analysis demonstrated that the following outcomes were comparable between the two groups: clinical cure at the end of therapy (RR 1.03, 95% CI 0.99 to 1.07); during therapy (RR 1.06, 95% CI 0.85 to 1.33) and at follow-up (RR 1.02, 95% CI 0.95 to 1.09); recurrent AOM (RR 1.21, 95% CI 0.52 to 2.81); compliance rate (RR 1.04, 95% CI 0.98 to 1.10) and overall adverse events (RR 0.92, 95% CI 0.52 to 1.63). When we performed subgroup analysis separately for trials with amoxicillin only and amoxicillin/clavulanate only, it showed that all important outcomes were comparable between once or twice daily groups and the three times daily group. The risk of bias amongst the five included studies was as follows: for random sequence generation we graded two studies as low and three unclear risk of bias; for allocation concealment all studies were at unclear risk of bias; for blinding (performance and detection bias) we graded four as high and one as unclear risk of bias; for incomplete outcome data (attrition bias) we graded two low, two high and one as unclear risk of bias; for reporting bias four were at low and one at high risk; and for 'other' bias four were at low and one at unclear risk of bias. AUTHORS' CONCLUSIONS: This review showed that the results of using once or twice daily doses of amoxicillin, with or without clavulanate, were comparable with three doses for the treatment of AOM. PMID- 24338107 TI - Carbon dioxide capturing technologies: a review focusing on metal organic framework materials (MOFs). AB - In this study, a relevant literature has been reviewed focusing on the carbon dioxide capture technologies in general, such as amine-based absorption as conventional carbon dioxide capturing technology, aqueous ammonia-based absorption, membranes, and adsorption material (e.g., zeolites, and activated carbons). In more details, metal organic frameworks (MOFs) as new emerging technologies for carbon dioxide adsorption are discussed. The MOFs section is intended to provide a comprehensive overview of MOFs including material characteristics and synthesis, structural features, CO2 adsorption capacity, heat of adsorption and selectivity of CO2. PMID- 24338108 TI - Changes in pH, dissolved organic matter and Cd species in the rhizosphere soils of Cd phytostabilizer Athyrium wardii (Hook.) Makino involved in Cd tolerance and accumulation. AB - Phytostabilization has great practical significance and flexibility in the ecological restoration of mining tailings and remediation of heavy metals polluted soils. However, potential use of metallophytes in phytostabilization is limited by a lack of knowledge of many basic plant processes. A mining ecotype (ME) Athyrium wardii, Pb/Cd phytostabilizer, and a non-mining ecotype (NME) A. wardii were grown in a pot experiment to investigate the chemical characteristics of the rhizosphere when exposed to the Cd polluted soils. Rhizobags were used to collect rhizosphere and bulk soils, separately. The results indicated that the ME A. wardii was more efficient in Cd accumulation in the root than NME after growing in Cd polluted soils for 50 days in a green house. Soil solution pH and dissolved organic carbon (DOC) concentration in the rhizosphere of ME A. wardii were higher than in the bulk soil and initial values (before planting), whereas the increment in the ME A. wardii were greater than NME. Owing to the increasing of rhizosphere soil pH, exchangeable Cd significantly decreased, whereas the other Cd species were increased with increasing soil DOC values. It is assumed that the ME A. wardii was effective in stabilizing Cd from the mobile fraction to non-mobile fractions. Results from this study suggest that rhizosphere alkalinization and the exudation of high amounts of dissolved organic matter (DOM) to reduce heavy metal mobility might be the two important mechanisms involved in the metal tolerance/accumulation of ME A. wardii. PMID- 24338109 TI - Use of a packed-bed airlift reactor with net draft tube to study kinetics of naphthalene degradation by Ralstonia eutropha. AB - Biodegradation of naphthalene by Ralstonia eutropha (also known as Cupriavidus necator) in a packed-bed airlift reactor with net draft tube (PBALR-nd) was studied; the Kissiris pieces were the packing material. The reactor hydrodynamics has been characterized under abiotic conditions and the dependencies of the superficial gas velocity (U G) on the gas holdup (epsilonG), liquid mixing time, and mass transfer coefficient were determined. The improving role of the net draft tube in this small column reactor (height 42 cm, ID 5 cm) was confirmed. The flow regime was described using the epsilonG alpha U G (n) expression, and bubbly flow was observed in PBALR-nd at U G < 2.83 cm/s. In the second step of the present work, the kinetics of biodegradation was modeled using the Haldane and Aiba equations. The fitting of the experimental results to the models were done according to the nonlinear least square regression technique. The biokinetic constants (q m, K s, and K i) were estimated and q m as the specific biodegradation rate was equaled to 0.415 and 0.24 mgnaph./mgcell h for the Haldane and Aiba equations, respectively. The goodness of fit reported as R (2) and root-mean-square error (RMSE) showed the adequate fitness of the Haldane and Aiba models in predicting naphthalene biodegradation kinetics. On the basis of the HPLC results, a hypothetical pathway for the biodegradation was presented. PMID- 24338110 TI - Macroalgae mitigation potential for fish aquaculture effluents: an approach coupling nitrogen uptake and metabolic pathways using Ulva rigida and Enteromorpha clathrata. AB - Aquaculture effluents are rich in nitrogen compounds that may enhance local primary productivity, leading to the development of algae blooms. The goal of this study was to assess the potential use of naturally occurring green macroalgae (Ulva and Enteromorpha) as bioremediators for nitrogen-rich effluents from a fish aquaculture plant, by evaluating their respective uptake dynamics under controlled conditions. Ulva and Enteromorpha were incubated separately in aquaculture effluent from a local pilot station. Algae tissue and water samples were collected periodically along 4 h. For each sample, nitrate, nitrite, and ammonia concentrations were quantified in the effluent, while internal algae reserve pools and nitrate reductase activity (NRA) were determined within the algae tissues. Both macroalgae absorbed all dissolved inorganic nitrogen compounds in less than 1 h, favoring ammonia over nitrate. Ulva stored nitrate temporarily as an internal reserve and only used it after ammonia availability decreased, whereas Enteromorpha stored and metabolized ammonia and nitrate simultaneously. These distinct dynamics of ammonia and nitrate uptake supported an increase in NRA during the experiment. This study supports the hypothesis that Ulva or Enteromorpha can be used as bioremediators in aquaculture effluents to mitigate excess of dissolved inorganic nitrogen. PMID- 24338111 TI - Intentional misuse of over-the-counter medications, mental health, and polysubstance use in young adults. AB - In recent years, the non-medical use of prescription drugs (without a doctor's prescription) has increased dramatically. Less attention has been paid to the intentional misuse of over-the-counter (OTC) medications. Misuse of OTC medications has negative health consequences similar to those of illicit drugs, including psychosis, tachycardia, seizures and agitation. When mixed with alcohol or other drugs, these medications can also be dangerous: OTC-related emergency room visits increased 70% from 2004 to 2008. This study examined the intentional misuse of OTC medications, the non-medical use of prescription drugs, the use of alcohol and illicit drugs, and psychological factors in two samples of young adults (ages 18-25) from different areas of the United States (Total N = 1,197). Overall, 18.6% of the Colorado sample and 13.0% of the Virginia sample reported lifetime misuse of an OTC medication. Participants who reported misusing OTC medications were also significantly more likely to report using marijuana, ecstasy, cocaine, and non-medical use of prescription analgesics, stimulants, anxiolytics, and sedatives. Participants who reported misusing OTC medications were more than twice as likely to report hazardous alcohol use, relative to individuals who denied misusing OTC medications. Individuals who had misused OTC medications scored significantly higher in sensation seeking and hopelessness and reported more symptoms of depression, anxiety, and somatic distress, relative to those who denied OTC misuse. Results suggest that a considerable minority of young adults are jeopardizing their health with the misuse of OTC medications as part of a pattern of polysubstance use. PMID- 24338112 TI - Use of different parameters and equations for calculation of IC50 values in efflux assays: potential sources of variability in IC50 determination. AB - Drug interactions due to efflux transporters may result in one drug increasing or decreasing the systemic exposure of a second drug. The potential for in vivo drug interactions is estimated through in vitro cell assays. Variability in in vitro parameter determination (e.g., IC50 values) among laboratories may lead to different conclusions in in vivo interaction predictions. The objective of this study was to investigate variability in in vitro inhibition potency determination that may be due to calculation methods. In a Caco-2 cell assay, the absorptive and secretive permeability of digoxin was measured in the presence of spironolactone, itraconazole and vardenafil. From the permeability data, the efflux ratio and net secretory flux where calculated for each inhibitor. IC50 values were then calculated using a variety of equations and software programs. All three drugs decreased the secretory transport of digoxin in a concentration dependent manner while increasing digoxin's absorption to a lesser extent. The resulting IC50 values varied according to the parameter evaluated, whether percent inhibition or percent control was applied, and the computational IC50 equation. This study has shown that multiple methods used to quantitate the inhibition of drug efflux in a cell assay can result in different IC50 values. The variability in the results in this study points to a need to standardize any transporter assay and calculation methods within a laboratory and to validate the assay with a set of known inhibitors and non-inhibitors against a clinically relevant substrate. PMID- 24338113 TI - Obinutuzumab: first global approval. AB - Obinutuzumab (GazyvaTM) is an intravenously administered, humanized and glycoengineered, type II anti-CD20 monoclonal antibody for the treatment of B cell malignancies. It is approved in the US for use in combination with chlorambucil for the first-line treatment of chronic lymphocytic leukaemia (CLL), and has been filed for approval in the EU in this indication. The antibody is based on GlycArt Biotechnology's (later Roche Glycart AG) proprietary GlycoMAb(r) technology, which uses glycoengineered antibodies that specifically increase antibody-dependent cellular cytotoxicity and thereby increase immune-mediated target cell death. Obinutuzumab is a type II anti-CD20 antibody that induces enhanced direct cell death. The monoclonal antibody is in worldwide phase III development with Roche and its subsidiaries, Genentech and Chugai Pharmaceutical, as well as Biogen Idec, for diffuse large B-cell lymphoma and non-Hodgkin's lymphoma generally, and is also in phase III development in countries outside of the US and EU for CLL. PMID- 24338114 TI - Spontaneously conceived pregnancy after 40: influence of age and obesity on outcome. AB - OBJECTIVE: The aim of the study was to examine pregnancy outcomes of healthy nulliparous women aged >= 40 years at delivery. STUDY DESIGN: The study included 53,480 nulliparous women aged 20 to 29 or >= 40 years delivering singleton infants, enrolled in a pregnancy risk assessment program between July 1, 2006, and August 1, 2011. Women reporting medical disorders, tobacco use, or conception with assistive reproductive technology were excluded. Data were grouped by body mass (obese or nonobese) and age (20-29 or >= 40 years). Pregnancy outcomes were compared within each body mass group for women aged 20 to 29 years versus >= 40 years and between obese and nonobese women aged >= 40 years. RESULTS: Within each body mass group, nulliparous women aged >= 40 years delivered at a significantly lower gestational age and had a greater incidence of cesarean delivery, gestational diabetes, preterm birth, and both low and very low birth weight infants, compared with controls aged 20 to 29 years. For women aged >= 40 years, obesity was associated with higher rates of adverse pregnancy outcomes. CONCLUSION: In healthy women, both advanced maternal age and obesity negatively influence pregnancy outcomes. Women who delay pregnancy until age 40+ years may modify their risk for cesarean section, preterm birth, and low-birth-weight infants by reducing their weight to nonobese levels before conception. PMID- 24338115 TI - The impact of noninvasive prenatal testing on the practice of maternal-fetal medicine. AB - OBJECTIVE: Noninvasive prenatal testing (NIPT) via cell-free fetal DNA in the maternal circulation is a highly sensitive and specific new testing option. The objective of this study was to determine the impact of NIPT on the uptake of first trimester screening (FTS) and invasive genetic testing. STUDY DESIGN: Uptake of prenatal testing was investigated in women referred for advanced maternal age or abnormal screening to the University of Texas Health Maternal Fetal Medicine Clinics in Houston. Patients who presented from August to November 2011, before clinical introduction of NIPT, were compared with patients who presented from March to June 2012, after its introduction. RESULTS: In patients referred between 14 and 22 weeks gestational age, invasive genetic testing was significantly reduced following the introduction of NIPT (35.4 vs. 17.9%, p < 0.05). For patients referred at < 14 weeks gestational age, FTS was significantly reduced with NIPT introduction (89.1 vs. 59.1%, p < 0.05); however, invasive genetic testing was not significantly different (20.0 vs. 14.0%, p > 0.05). CONCLUSION: NIPT has made an impact on the practice of maternal-fetal medicine by significantly decreasing the number of second trimester diagnostic tests performed. In addition, patients interested in early screening information appear to prefer the higher sensitivity and specificity of NIPT. PMID- 24338116 TI - Labor progression in teenage women. AB - OBJECTIVE: Compare labor progression in first and second stages in women < 18 years with those >=18 years. STUDY DESIGN: Retrospective cohort study of consecutive women at term that reached the second stage of labor between 2004 and 2008. The first stage in women < 18 years was compared with women >=18 years. Average labor curves were constructed and median time spent to progress 1 cm in dilation and total time from 4 to 10 cm was estimated. Time spent pushing and total duration of second stage were compared between groups. Analyses were then stratified by parity. RESULTS: There was no significant difference in progress of the first stage of labor between women < 18 years and those >=18 years. In the second stage, nulliparous teenage women were less likely to have a duration > 60 or 120 minutes. CONCLUSION: Laboring women < 18 years should be managed with the same expectations of labor as women >=18 years. PMID- 24338117 TI - The effect of neuraxial anesthesia on maternal cerebral hemodynamics. AB - OBJECTIVE: Neuraxial anesthesia is known to reduce sympathetic tone and mean arterial pressure. Effects on cerebral hemodynamics in pregnancy are not well known. We hypothesize that cerebral hemodynamic parameters will change with respect to baseline following regional analgesia/anesthesia. STUDY DESIGN: We performed maternal transcranial Doppler of the middle cerebral artery in 20 women receiving epidural analgesia for labor, and 18 undergoing spinal anesthesia for cesarean section at baseline, 5 and 15 minutes. Systemic blood pressure (BP), systolic/diastolic/mean velocity, resistance and pulsatility index (PI) were recorded. Cerebral perfusion pressure, critical closing pressure (CrCP), resistance area product, and cerebral flow index were calculated. RESULTS: Epidural placement was associated with significant decreases in systolic/diastolic BP/mean velocity/CrCP after 15 minutes, with a corresponding increase in PI. In the spinal group, systolic/diastolic BP/mean velocity uniformly decreased and remained low after 15 minutes, and PI significantly increased and remained constant after 15 minutes. No differences were seen in BP or cerebral hemodynamics between the groups. CONCLUSION: This study demonstrates that both epidural analgesia and spinal anesthesia result in measurable cerebral hemodynamic changes in normotensive term pregnancy that are likely to be clinically insignificant as they do not affect perfusion pressure or flow. PMID- 24338118 TI - Impact of cervical effacement and fetal station on progress during the first stage of labor: a biexponential model. AB - OBJECTIVE: To develop a model that uses cervical effacement, fetal station, and parity to predict progress during the first stage of labor. STUDY DESIGN: This was a secondary analysis of a cohort of 1,128 parturients delivering after 34 weeks. Timed cervical exams from each patient were fit with a biexponential model. Methods for consideration of fetal station, cervical effacement and parity were developed and validated. RESULTS: The biexponential model fit the data in an unbiased manner with a median absolute prediction error of 1.1 cm. Although nulliparous women had slower active labor, they did not differ from multiparous women in their rate of latent labor or the cervical dilation at which they transitioned to active labor. In addition, nulliparous women began laboring with a more effaced cervix (45 vs. 31%) and lower fetal station (-2.8 vs. -3.2). CONCLUSION: We validated a biexponential model for labor progress using a large mixed parity cohort. We demonstrated that parity and initial fetal station add important clinical information that can be used to make a labor model more accurate. As such, parity and fetal station can be utilized in such structural models to predict normal labor progress and potentially identify abnormalities in labor progress. PMID- 24338119 TI - The effects of intermittent pneumatic compression during cesarean delivery on fibrinolysis. AB - OBJECTIVE: Pregnancy is associated with increased risk for thromboembolic events. Intermittent pneumatic compression (IPC) devices are the method of thromboprophylaxis in a nonpregnant population. The aim of this study was to examine the effects of IPC on markers of fibrinolysis during cesarean delivery. STUDY DESIGN: We conducted a randomized controlled trial from April 2009 to March 2010 of women undergoing scheduled elective cesarean delivery. Forty-nine women were randomized to IPCs or usual care. All participants had three blood samples obtained: (1) baseline, (2) 1 hour after randomization, and (3) 30 minutes after cesarean delivery. Tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), thrombin-antithrombin complex (TAT), plasminogen activator inhibitor-1 (PAI-1), and plasminogen activator inhibitor-2 (PAI-2) levels were analyzed in each sample using an enzyme-linked immunosorbent assay. Statistical analysis was performed using repeated measures two-way analysis of variance with alpha = 0.05. RESULTS: There was a time-dependent change in tPA, uPA, and PAI-1 levels following delivery but no difference in TAT and PAI-2 levels with time. There were no differences between women randomized to IPCs or usual care. CONCLUSION: Markers of fibrinolysis were not significantly altered by IPCs in this study of low-risk pregnant women. Further research regarding the mechanism and efficacy of IPCs in pregnant women is warranted. PMID- 24338121 TI - Does tongue size contribute to risk of airway narrowing in preterm infants sitting in a car safety seat? AB - BACKGROUND: Preterm infants are at risk of narrowing of the upper airway while restrained in infant car seats, leading to secondary apnea. However, some infants are able to maintain a normal airway. We hypothesized that this might reflect relatively smaller tongue size. METHODS: We retrospectively analyzed previously reported respiration-timed lateral radiographs of the upper airways of 17 preterm infants ready for discharge (32.6 +/- 1.0 weeks gestation at birth, and 37.8 +/- 9.7 days old at study) taken during sleep, first in a car safety seat with an insert that allowed the head to remain upright, and then without the insert, when the head slumped forward. The presence of air above the tongue was used as an index of relative tongue size. RESULTS: A smaller airspace around the tongue (relatively larger tongue) was associated with greater narrowing of the upper airway when the head was flexed forward in sleep (p < 0.002). In contrast, there was no significant correlation between baseline airway size and change in airway size (r (2) = 0.16, p = 0.11). CONCLUSION: The present study supports the hypothesis that the vulnerability of preterm infants to airways compromise while restrained in a car safety seat may be in part related to relative tongue size. PMID- 24338122 TI - Evaluating the side effects of treatment for preterm labor in a center that uses "high-dose" magnesium sulfate. AB - OBJECTIVE: To evaluate the tolerability and safety of intravenous magnesium sulfate use for tocolysis in a center that uses a "high-dose" regimen. STUDY DESIGN: We conducted a retrospective cohort study of patients treated with magnesium sulfate for preterm labor from December 2006 to June 2010. Data were abstracted from review of individual patient electronic medical records. RESULTS: The cohort consisted of 456 women. Of these, 417 (91.4%) experienced side effects. Severe side effects (pulmonary edema, respiratory arrest, intensive care unit transfer, cardiac arrest, or death) occurred in 24 (5.3%) cases, all but one due to pulmonary edema. No cases of respiratory arrest, cardiac arrest, or death occurred. Those with severe side effects were less likely to have a singleton and more likely to have a higher order multifetal gestation (p < 0.001), received more magnesium, and more often were given multiple concurrent tocolytics (p = 0.04). CONCLUSION: "High-dose" magnesium tocolysis results in side effects for 9 of every 10 patients treated, and severe side effects occur in 1 of every 20 patients. When used for tocolysis, magnesium should be used as a single agent, for less than 48 hours, and with great caution in multifetal gestations. PMID- 24338120 TI - Umbilical cord serum interleukin-6, C-reactive protein, and myeloperoxidase concentrations at birth and association with neonatal morbidities and long-term neurodevelopmental outcomes. AB - OBJECTIVE: The aim of the study is to determine if umbilical cord serum concentrations of interleukin-6 (IL-6), C-reactive protein (CRP), and myeloperoxidase (MPO), in pregnancies at risk for preterm birth (PTB), are associated with neonatal morbidities and/or altered neurodevelopmental outcomes in the children. STUDY DESIGN: Umbilical cord serum samples were collected at birth from 400 newborns delivered within a multicenter randomized controlled trial of repeated versus single course of antenatal corticosteroids (ACs), in women at increased risk for PTB. Newborns were followed through discharge and were evaluated between 36 and 42 months corrected age with neurological examination and Bayley Scales of Infant Development. Umbilical cord serum concentrations of IL-6, CRP, and MPO were determined using enzyme-linked immunoassays. Multivariate logistic regression analyses explored the relationship between umbilical cord serum IL-6, CRP, and MPO levels, adverse newborn outcomes, and PTB < 32 weeks of gestational age (GA). RESULTS: Univariate analysis revealed that umbilical cord IL-6 above the 75th percentile was associated with increased respiratory distress syndrome (RDS) and chronic lung disease (CLD), but not with necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), or neonatal sepsis; however, this association was not significant after adjusting for GA at delivery and treatment group. No significant associations between CRP or MPO and RDS, CLD, NEC, sepsis, or IVH were evident. Regression analysis revealed that CRP above the 75th percentile was associated with a decreased risk of CLD (odds ratio, 0.10; 95% confidence interval, 0.02-0.41). No associations between umbilical cord IL-6, CRP, or MPO and MDI < 70 or PDI < 70 were evident. Umbilical cord serum concentrations of IL-6, CRP, and MPO, above the 75th percentile, were associated with more frequent PTB < 32 weeks of GA. CONCLUSION: Elevated umbilical cord serum concentration of CRP is associated with reduced risk for CLD even after adjusting for GA at delivery. Occurrence of levels > 75th percentile of IL-6, CRP, and MPO in umbilical cord serum was associated with PTB < 32 weeks of GA. Elevated umbilical cord serum concentrations of IL-6, CRP, and MPO at birth were not associated with poor neurodevelopmental outcomes. PMID- 24338123 TI - Unexpected postpartum hemorrhage due to an acquired factor VIII inhibitor. AB - Unexplained postpartum hemorrhage (PPH) refractory to standard hemostatic measures should trigger a heightened clinical suspicion of an acquired bleeding disorder. When hemostatic medical interventions and surgical procedures fail to control the bleeding, then significant postoperative blood loss, debilitating morbidity, loss of fertility, and death may occur. In the setting of an autoantibody inhibitor to factor VIII (FVIII), control of life-threatening PPH and avoidance of subsequent bleeding episodes depends on a timely and accurate diagnosis, prompt hemostatic treatment and eradication of FVIII inhibitors, and appropriate long-term patient care and management. Acquired postpartum hemophilia due to a FVIII inhibitor is a rare cause of PPH; however, delayed treatment can lead to increased maternal morbidity and mortality. Acquired FVIII inhibitors also pose an emerging bleeding threat to the neonate as a result of possible transplacental transfer of FVIII autoantibodies to the fetus during the last trimester of pregnancy. The purpose of this review is to increase awareness among hematologists and obstetricians/gynecologists regarding the occurrence of FVIII neutralizing autoantibodies as a cause of PPH, and emphasize the importance of collaboration between obstetrician/gynecologists and hematology specialists to optimize the diagnostic evaluation, treatment, and long-term management of women who experience PPH due to an acquired FVIII inhibitor. PMID- 24338124 TI - Reconsidering the switch from low-molecular-weight heparin to unfractionated heparin during pregnancy. AB - Venous thromboembolic disease accounts for 9% of all maternal deaths in the United States. In patients at risk for thrombosis, common practice is to start prophylactic doses of low-molecular-weight heparin and transition to unfractionated heparin during the third trimester, with the perception that administration of neuraxial anesthesia will be safer while on unfractionated heparin, as spinal/epidural hematomas have been associated with recent use of low molecular-weight heparin. In patients receiving prophylactic doses of unfractionated heparin, neuraxial anesthesia may be placed, provided the dose used is 5,000 units twice a day. The American Society of Regional Anesthesia and Pain Medicine guidelines recognize that the safety of neuraxial anesthesia in patients receiving more than 10,000 units per day or more than 2 doses per day is unknown, limiting the theoretical benefit of unfractionated heparin at doses higher than 5,000 units twice a day. PMID- 24338125 TI - Induction of meiotic gynogenesis in ship sturgeon Acipenser nudiventris using UV irradiated heterologous sperm. AB - Diploid gynogenesis was induced in ship sturgeon Acipenser nudiventris using UV irradiated sperm from Siberian sturgeon Acipenser baerii. The optimal condition for the retention of the second polar body in ship sturgeon was determined to be 10 min after activation/fertilization in experiments. The temperature of cold shock and its duration were 2.5 degrees C and 30 min, respectively. A total of 30 gynogens of known parentage from experimental treatments were screened using microsatellite DNA analysis, and uniparental transmission in meiogens was confirmed. The results show that heterologous Siberian sturgeon sperm is applicable as UV-irradiated sperm for the induction of gynogenesis in ship sturgeon. This technique may recover the critically endangered sturgeon species that are becoming extinct. PMID- 24338126 TI - Mycophagy among Japanese macaques in Yakushima: fungal species diversity and behavioral patterns. AB - Mycophagy (fungus-feeding) by Japanese macaques (Macaca fuscata yakui) in Yakushima has been observed by many researchers, but no detailed information is available on this behavior, including which fungal species are consumed. To provide a general description of mycophagy and to understand how and whether macaques avoid poisonous fungi, we conducted behavioral observation of wild Japanese macaques in Yakushima and used molecular techniques to identify fungal species. The results indicate that the diet of the macaques contains a large variety of fungal species (67 possible species in 31 genera), although they compose a very small portion of the total diet (2.2% of annual feeding time). Fungi which were eaten by macaques immediately after they were picked up were less likely to be poisonous than those which were examined (sniffed, nibbled, carefully handled) by macaques. However, such examining behaviors did not appear to increase the macaques' abilities to detect poisonous fungi. Fungi that were only partially consumed included more poisonous species than those fully consumed with/without examining behavior, yet this was not significant. Taste, therefore, might also play an important role in discriminating poisonous from non-poisonous. PMID- 24338128 TI - Translational regulation of NeuroD1 expression by FMRP: involvement in glutamatergic neuronal differentiation of cultured rat primary neural progenitor cells. AB - Fragile X mental retardation protein (FMRP) is encoded by Fmr1 gene in which mutation is known to cause fragile X syndrome characterized by mental impairment and other psychiatric symptoms similar to autism spectrum disorders. FMRP plays important roles in cellular mRNA biology such as transport, stability, and translation as an RNA-binding protein. In the present study, we identified potential role of FMRP in the neural differentiation, using cortical neural progenitor cells from Sprague-Dawley rat. We newly found NeuroD1, an essential regulator of glutamatergic neuronal differentiation, as a new mRNA target interacting with FMRP in co-immunoprecipitation experiments. We also identified FMRP as a regulator of neuronal differentiation by modulating NeuroD1 expression. Down-regulation of FMRP by siRNA also increased NeuroD1 expression along with increased pre- and post-synaptic development of glutamatergic neuron, as evidenced by Western blot and immunocytochemistry. On the contrary, cells harboring FMRP over-expression construct showed decreased NeuroD1 expression. Treatment of cultured neural precursor cells with a histone deacetylase inhibitor, valproic acid known as an inducer of hyper-glutamatergic neuronal differentiation, down-regulated the expression of FMRP, and induced NeuroD1 expression. Our study suggests that modulation of FMRP expression regulates neuronal differentiation by interaction with its binding target mRNA, and provides an example of the gene and environmental interaction regulating glutamatergic neuronal differentiation. PMID- 24338129 TI - Late-onset dietary restriction modulates protein carbonylation and catalase in cerebral hemispheres of aged mice. AB - Oxidative stress is an important factor in causing aging and age-related diseases. It is caused by an imbalance between oxidants such as reactive oxygen species (ROS) and antioxidants. Protein oxidation elicited by free radicals may cause protein function disruptions. Protein carbonylation, an irreversible process resulting in loss of function of the modified proteins, is a widely used marker for oxidative stress. In the present study, we have evaluated the levels of protein carbonyls, ROS, and catalase in the cerebral hemispheres of young and aged mice. When aged mice were subjected to a dietary restriction (DR) regimen (alternate days feeding) of 3 months, a significant reduction in the endogenous levels of protein carbonylation as well as ROS and elevation of catalase was observed in their cerebral hemispheres. The present study, thus, demonstrated the antioxidative effects of late-onset DR regimen in the cerebral hemispheres of aged mice which may act as a powerful modulator of age-related neurodegenerative diseases. PMID- 24338130 TI - Risk factors for placenta accreta: a large prospective cohort. AB - OBJECTIVE: Placenta previa and prior cesarean delivery are known risk factors for placenta accreta. However, other risk factors have not been identified. Our objective was to examine risk factors for accreta using data collected prospectively in a large multicenter cohort. STUDY DESIGN: Secondary analysis of women with accreta compared to those without accreta in a large multicenter cesarean delivery cohort. Potential accreta risk factors were examined by univariate and multivariate analyses. RESULTS: In this study, 196 of 73,257 (0.27%) cesarean deliveries were complicated by accreta. As expected, women with increasing numbers of prior cesareans were more likely to have an accreta (p < 0.001), as were women with previa (adjusted odds ratio [OR], 34.9; 95% confidence interval [CI], 22.4-54.3). We also considered only patients with previa and examined the following variables: maternal demographics, prior cesareans, interval between deliveries, parity, body mass index, tobacco use, and coexisting hypertension or diabetes. In this model, patients with previa and two or three prior cesarean deliveries had an adjusted OR for accreta of 4.9 (95% CI, 1.7 14.3) or 7.7 (95% CI, 2.4-24.9), respectively. However, no other variables were significantly associated with accreta. CONCLUSION: Patients with previa have increased risk for accreta that increases with the number of prior cesarean deliveries. However, no other maternal characteristics were associated with accreta. PMID- 24338131 TI - Obstetric and neonatal outcomes for women >= 45 years of age: a cohort study. AB - OBJECTIVE: To evaluate outcomes in women >= 45 years of age in comparison to a group of women aged 40 to 44 years. MATERIALS AND METHODS: A cohort study was conducted including women >= 45 years who delivered at > 24 weeks gestation during the period (1989-2011). Women aged 40 to 44 years formed the comparison group. The maternal demographics, mode of conception, maternal complications, timing and mode of delivery, neonatal features and postpartum complications were included as outcomes. Statistical analyses were performed using the t-test and Chi-square test. RESULTS: There were 67,278 deliveries; 140 occurred in women >= 45 years of age, (2.1/1,000). Compared with the 40 to 44 year age group (n = 139), women >= 45 years had higher body mass index (26.7 +/- 4.7 vs. 24.6 +/- 7.1, p = 0.01), and were more likely to have a previous pregnancy loss at < 24 weeks gestation (57.9 vs. 44.6%, p = 0.03). There was no difference in the incidence of maternal complications, preterm delivery, birthweight, Apgar scores or admission to neonatal intensive care. The presence of pre-existing maternal hypertension was associated with a poor outcome. Women >= 45 years were more likely to be delivered by cesarean section (45 vs. 30.2%, p = 0.01). CONCLUSION: Women aged >= 45 years have comparable outcomes to those aged 40 to 44 years, albeit the presence of pre-existing maternal disease is higher and associated with a poor outcome. PMID- 24338132 TI - Impact of sickle hemoglobinopathies on pregnancy-related venous thromboembolism. AB - OBJECTIVE: The aim of the study is to examine the relationship between sickle cell trait (Hb AS) and other sickle hemoglobinopathies and the risk of thromboembolism during pregnancy or the puerperium. STUDY DESIGN: Retrospective cohort study of African American women receiving prenatal care from 1991 to 2006. Sickle cell status was ascertained by routine hemoglobin electrophoresis. Venous thromboembolism (VTE) was defined as one or more episodes of deep venous and/or pulmonary thromboembolism during pregnancy or the puerperium according to discharge diagnoses based on International Classification of Diseases, Ninth Revision codes. RESULTS: Among 22,140 women with hemoglobin (Hb) AA status, 20 women (0.09%) experienced pregnancy-related VTE compared with 3 women (0.15%) of 2,037 women with Hb AS; relative risk (RR) for the association with AS status = 1.6; 95% confidence interval (CI) 0.5 to 5.5. Of 103 women, 3 women (2.9%) with sickle cell disease conditions (Hb SS, Hb SC, or Hb S,beta-thalassemia) experienced thromboembolism. Compared with women with Hb AA status, the RR = 32.2, 95% CI 9.7 to 107. CONCLUSION: Sickle cell trait may be associated with a modest increase in VTE in the setting of pregnancy; sickle cell disease conditions are strongly associated with this rare but potentially fatal outcome. PMID- 24338133 TI - Commonly used fiber tips in endovenous laser ablation (EVLA): an analysis of technical differences. AB - Many different types of fiber tips have been developed over the last few years to be used in endovenous laser ablation (EVLA) procedures. All these new but different tips claim a certain superiority over the other tips. Evidence for a best tip is however lacking. Four of these fiber tips have been compared in this article: (1) the bare fiber, (2) the Tulip-Tip, (3) the NeverTouchTM tip, and (4) the radially emitting tip. The aim of this paper is to provide information on the technical differences between these fiber tips and differences in their underlying heat transfer mechanisms. Although all tips are effective in the primary goal of EVLA, namely to occlude the incompetent vein, they differ in side effects, they differ in side effects, practicality, and cost. Although these new tips have improved EVLA, the perfect tip is not on the market yet. PMID- 24338134 TI - Photodynamic effects of zinc oxide nanowires in skin cancer and fibroblast. AB - Cytotoxic effects of zinc oxide (ZnO) nanomaterials, individual and conjugated with a photosensitizer (protoporphyrin IX), were studied in the presence and absence of ultraviolet light exposure (240 nm of light wavelength for a very short time exposure) in cell cultures of human normal and cancerous skin models. Zinc Oxide nanowires (ZnO NWs) were grown on the capillary tip and conjugated with protoporphyrin IX (PpIX). This coated tip was used as tool/pointer for intracellular drug delivery protocol in suggested normal as well as carcinogenic cellular models. After true delivery of optimal drug, the labelled biological model was irradiated with UV-A, which led to a loss of mitochondrial membrane potential, as tested by neutral red assay (NRA). PMID- 24338135 TI - Open-irrigated laser catheter ablation: influence of catheter irrigation and of contact and noncontact mode of laser application on lesion formation in bovine myocardium. AB - Lesions achieved by radiofrequency application increase with catheter irrigation and with catheter pressure on the endocardial surface. Purpose of this study was to test the influence of catheter irrigation and of contact vs. noncontact mode of laser application on lesion formation in bovine myocardium. By applying continuous wave 1,064 nm laser light via an open-irrigated catheter lesions were produced at 15 W (9.5 W/mm(2))/30 s (285 J/mm(2)), in stagnant blood (activated clotting time > 350 s) at 18 degrees C, on bovine myocardium. During flow rates of 15, 30, and 50 ml/min radiation was applied with the catheter end hole in contact (n = 10, each) or 2 mm away from the endocardial surface (n = 5, each). Lesions were evaluated morphometrically, and groups of lesions were compared by using the unpaired t test. By augmentation of irrigation flow from 15 to 30 ml/min, contact lesions increased significantly (p = 0.0001). A further increase of flow from 30 to 50 ml/min increased lesions significantly in depth (p = 0.0011) but not in width (p = 0.639) and volume (p = 0.218). Noncontact lesions were significantly smaller than contact lesions (p > 0.05). Lesions of homogenous coagulation necrosis were clear-cut and sharply demarcated from the surrounding normal myocardium. There was no occurrence of steam-pop with intramural cavitation or with tissue vaporization with crater or thrombus formation. It is suggested that by using an open-irrigated laser catheter as described in this study, catheter irrigation at flow rates of 30 to 40 ml/min are optimal for myocardial coagulation, and catheter pressure on the endocardial surface is not needed for lesion formation. Laser lesions can be achieved also without intimate endocardial catheter contact. PMID- 24338137 TI - Neoplasia from genetic point of view. AB - Cancer is a genetic-epigenetic based disease which contains a complex of alterations that cause irreversible transformation of cells with a new anarchic behavior. Tumor suppressor inactivation and/or oncogene activation will lead to tumorigenesis. Based on the genetic alteration in germ or somatic cells, the affected person will have a different fate of cancer incidence or inheritable cancer susceptibility syndrome. Knowing the mechanism of molecular and cytogenetic alterations in cancer will give an advantage in finding more practical approaches to cancer management. In this review, the cancer genetics is discussed from different aspects. PMID- 24338136 TI - Anti-inflammatory effects of botulinum toxin type a in a complete Freund's adjuvant-induced arthritic knee joint of hind leg on rat model. AB - The objective of the study is to verify histopathologically the anti-inflammatory effect of botulinum toxin type A (BoNT-A) in a Complete Freund's Adjuvant (CFA) induced arthritic knee joint of hind leg on rat model using immunofluorescent staining of anti-ionized calcium-binding adaptor molecule 1 (Iba-1) and interleukin-1beta (IL-1beta) antibody. Twenty-eight experimental rats were injected with 0.1 ml of CFA solution in the knee joint of the hind leg bilaterally. Three weeks after CFA injection, the BoNT-A group (N = 14) was injected with 20 IU (0.1 ml) of BoNT-A bilaterally while the saline group (N = 14) was injected with 0.1 ml of saline in the knee joint of the hind leg bilaterally. One and two weeks after BoNT-A or saline injection, joint inflammation was investigated in seven rats from each group using histopathological and immune-fluorescent staining of Iba-1 and IL-1beta antibody. The number of Iba-1 and IL-1beta immune-reactive (IR) cells was counted in the BoNT-A and saline groups for comparison. There was a significant reduction in joint inflammation and destruction in the BoNT-A group at 1 and 2 weeks after BoNT-A injection compared with the saline group. The binding of Iba-1 and IL 1beta antibody was significantly lower in the BoNT-A group than the saline group at 1 and 2 weeks after BoNT-A injection. The number of Iba-1 and IL-1beta-IR cells at 1 and 2 weeks after the injection of BoNT-A were significantly different from the corresponding number of Iba-1 and IL-1beta-IR cells in the saline group. To conclude, BoNT-A had an anti-inflammatory effect in a CFA-induced arthritic rat model, indicating that BoNT-A could potentially be used to treat inflammatory joint pain. PMID- 24338138 TI - Potentiation of indomethacin-induced anti-inflammatory response by montelukast in formalin-induced inflammation in rats. AB - The leukotrienes and prostaglandins are biologically active metabolites derived from arachidonic acid. The leukotrienes have a role in inflammatory diseases such as allergic rhinitis, inflammatory bowel disease and asthma. Montelukast, a cysteinyl leukotriene receptor antagonist, is claimed to be effective in asthma. The present study aimed to assess the role of cysteinyl leukotriene receptor antagonist on peripheral inflammation and whether montelukast treatment enhances the anti-inflammatory effect of indomethacin. Anti-inflammatory response was measured using a plethysmometer. Histopathologic examination for leukocyte accumulation was done. Montelukast (0.5-2mg/kg, i.p.) produced a significant anti inflammatory effect in dose dependent manner against formalin-induced rat paw oedema at 1h but not in 3 and 5 h. When indomethacin (5 mg/kg, i.p) was co administered with montelukast (1 mg/kg, i.p), the anti-inflammatory effects of indomethacin were significantly increased as compared to the per se effect at 3 and 5 hour after formalin challenge. In histopathology it has been found that combination therapy significantly decreased migration of leucocytes into the site of inflammation. These results show that montelukast has anti-inflammatory properties in peripheral tissue and markedly potentiates the anti-inflammatory activity of indomethacin at 3 and 5 h. It is expected that combination of montelukast with cyclooxygenase inhibitor would prove to be a novel approach to manage complex inflammatory conditions. PMID- 24338139 TI - Effect of milrinone on short term outcome of patients with myocardial dysfunction undergoing off-pump coronary artery bypass graft: a randomized clinical trial. AB - Myocardial dysfunction is a major complication in cardiac surgery that needs inotropic support. This study evaluates the effect of milrinone on patients with low ventricular ejection fraction undergoing off- pump coronary artery bypass graft (OPCAB). The present study is designed to evaluate the effect of milrinone on myocardial dysfunction. Eighty patients with low ventricular ejection fraction (<35%), candidate for elective OPCAB, were enrolled in this study. They were randomly assigned to two groups. One group received milrinone (50 MUg/kg) intravenously and another group received a saline as placebo followed by 24 hours infusion of each agent (0.5 MUg/kg/min). Short outcome of patients such as hemodynamic parameters and left ventricular ejection fraction were variables evaluated. Serum levels of creatine phosphokinase, the MB isoenzyme of creatine kinase, occurrence of arrhythmias and mean duration of mechanical ventilation were significantly lower in milrinone group (P<0.05). The mean post operative left ventricular ejection fraction was significantly higher in milrinone group (P=0.031). There were no statistical significant differences between the two groups in terms of intra-aortic balloon pump, inotropic support requirement, myocardial ischemia, myocardial infarction, duration of inotropic support, duration of intensive care unit stay, mortality and morbidity rate. Administration of milrinone in patients undergoing OPCAB with low ventricular ejection fraction is useful and effective. PMID- 24338140 TI - Determination of the accuracy and optimal cut-off point for ELISA test in diagnosis of human brucellosis in Iran. AB - In endemic area the most challenging problem for brucellosis is to find a reliable diagnostic method. In this case-control study, we investigated the accuracy of ELISA test for diagnosis of human brucellosis and determined the optimal cut-off value for ELISA results in Iran. The laboratory diagnosis of brucellosis was performed by blood isolation of Brucella organism with a BACTEC 9240 system and/or detection of Brucella antibodies by standard agglutination test (titer >= 1:160). Serum level of ELISA IgG and ELISA IgM from 56 confirmed cases of brucellosis and 126 controls were compared with each other by Box plot graph and Receiver Operating Characteristic (ROC) curve. Box plot graphs showed the high degree of dispersion for IgG and IgM data in patients compared with all controls. We observed partially overlapping for IgM data (not for IgG) between cases and controls in graphs. The area under ROC curve for distinguishing between cases and controls was larger for IgG compared to IgM. Based on results of this study, ELISA IgG test was more reliable than ELISA IgM test in diagnosis of human brucellosis in Iran. Using a cut-off of 10 IU/ml and 50 IU/ml had most sensitivity (92.9%) and most specificity (100%) for ELISA IgG test, respectively. PMID- 24338141 TI - Comparison of serum progesterone in non-viable pregnancy and ectopic pregnancy. AB - Ectopic pregnancy (EP) and miscarriage are important differential diagnosis of first trimester vaginal bleeding. In first trimester, serum progesterone value can be 5-20 ng/ml in EP and miscarriage. Since delay in diagnosis of EP could have high mortality and morbidity, the aim of this study was comparison of serum progesterone value in EP and miscarriage in order to differentiate these conditions. A total of 60 patients (30 EP and 30 miscarriages) with gestational age of 5-7 weeks by LMP were enrolled in this study. The titer of progesterone and betahCG of serum were measured. The mean of progesterone and betahCG titers were compared in two groups by Student's t-test. The mean progesterone titer for all patients was 6.36+/-5.62 ng/ml, with a minimum value of 0.44 and maximum value of 21.50 ng/ml. Serum progesterone level in 33 patients was lower than 5 ng/ml and in 27 patients was between 5-25 ng/ml. Mean serum progesterone for miscarriage was 6.803+/-5.72 and for EP was 5.915+/-5.45 ng/ml. Difference between two values was not significant statistically (P=0.067). Mean betahCG for miscarriage was 1313.04 IU/l and for EP 1805.56 IU/l. Mean patients age were 27.2 totally that for miscarriage was 25.8 and for EP 28.5 years. This study indicated, the mean value of progesterone could not differentiate EP from miscarriage. PMID- 24338142 TI - Performance of pregnant women on folic acid intake. AB - The cause of neural tube defects (NTDs) is multifactorial and in this case folic acid has an important role. Since the neural tube is closed during 21-28 days of pregnancy, most of women are not informed about their pregnancy at this time, and as a result the golden time of folic acid consumption is missed. The aim of this study was evaluating the performance of pregnant women attending to Tehran Women's Hospital in regard to folic acid intake during pre-conceptional period between 2011 and 2012. This cross-sectional study was conducted in 370 pregnant women attending the prenatal clinic of a hospital affiliate to Tehran University of Medical Sciences between 2011 and 2012. Data were collected through interview using a questionnaire. Although 70% of the pregnancies were planned, but 70.5% of pregnant women had not taken folic acid before conception or in necessary time. There was found a significant relationship between level of education, history of abnormalities in children and the number of abortions and taking folic acid before pregnancy (P=0.005, P=0.000 and P=0.000, respectively). PMID- 24338143 TI - Does aging increase vitamin D serum level in healthy postmenopausal women? AB - Vitamin D deficiency is the most under-diagnosed medical condition in postmenopausal women. There are few epidemiologic studies on vitamin D status of postmenopausal women in Iran. This study aimed to investigate the 25 hydroxyvitamin D levels in postmenopausal women living in Tehran, capital of Iran. In this cross sectional study, 110 women were selected via convenience sampling method from menopause clinic of Tehran Women General Hospital between 2011 and 2012. For each woman, a questionnaire was completed, and 25 hydroxyvitamin D levels were determined by chemiluminescence's immunoassay. Vitamin D deficiency has been considered as a 25(OH)D of less than 20ng/ml. Vitamin D insufficiency has been defined as a 25(OH)D of 21-29ng/ml, and sufficiency as a 25(OH)D of 30-100ng/ml. The data was analyzed by using Pearson correlation test in SPSS version 16. The mean age of women was 52.67+/-5 years. The mean age at natural menopause onset was 47.66+/-4.44 years, and the median menopause age was 49.00. The median 25(OH)D level was 19.28 (Inter Quartile Range=26.08). We found vitamin D deficiency and vitamin D insufficiency 52.7% and17.3% respectively. Serum 25(OH) D concentrations were significantly correlated with age(r=0.21, P=0.024). These findings indicate that 25(OH)D level in postmenopausal women from Tehran is low. There is a statistically significant positive correlation between vitamin D concentration and age in late postmenopausal period. PMID- 24338144 TI - Prevalence of vitamin D deficiency and secondary hyperparathyroidism in nonunion of traumatic fractures. AB - Nonunion is common complication of fracture management. Various factors are involved in its occurring. Metabolic and endocrine factors are often overlooked. So that aim of study was to evaluate the level of vitamin D and PTH in patients with unexplained nonunion and fractures due to low energy trauma. In the case control study, 30 patients with tibial nonunion compared with 32 patients with normal bone healing. There were matched according to, surgical treatment, sex, age and body mass index. In order to measure the serum levels of laboratory parameters, vitamin D and parathyroid hormone, blood samples were taken and were sent to a reference laboratory. A high percentage of vitamin D deficiency was observed in tibial unexplained nonunion (60%) versus 30% in normal union. The level of vitamin D in patients with nonunion was significant difference compared with normal union (25.8+/-20.4 nmol/l versus 49.03+/-26.9 nmol/l, P=0.002). PTH measurement showed that was not meaningful statistical difference between two groups but prevalence of hyperparathyroidism in nonunion was higher than union (33% versus 9.3%). In other laboratory findings were not statistical difference. According to our results, vitamin D deficiency in unexplained tibial nonunion fractures are common. In areas with high prevalence of hypovitaminosis D, that could be one reason of unexplained nonunion. PMID- 24338145 TI - Retinitis due to opportunistic infections in Iranian HIV infected patients. AB - We tried to evaluate prevalence and characteristics of Iranian HIV infected patients with retinitis due to opportunistic infections. In this cross sectional study, we evaluated 106 HIV infected patients via indirect ophthalmoscopy and slit lamp examination by 90 lens to find retinitis cases. General information and results of ophthalmologic examination were analyzed. Prevalence of retinitis due to opportunistic infections was 6.6%: cytomegalovirus (CMV) retinitis 1.88%, toxoplasmosis retinochoroiditis 1.88% and tuberculosis chorioretinitis 2.83%. CD4 count was higher than 50 cell/ulit in both cases with CMV retinitis. Along with increasing survival in the HIV infected patients, the prevalence of complications such as ocular manifestation due to opportunistic infections are increasing and must be more considered. PMID- 24338146 TI - A cross sectional study on prevalence and etiology of syncope in Tehran. AB - Recurrent syncope of obscure etiology, particularly in those with structural heart diseases, is associated with higher mortality rates. There are insufficient and conflicting data on prevalence and etiology of syncope in the urban Middle Eastern population. Evaluating the etiologic basis of syncope can be an effective step in prevention of morbidities and sudden cardiac death in susceptible populations. The aim of our study was to determine the prevalence and etiology of syncope in an outpatient cardiology clinic in Tehran the capital of Iran. In this cross sectional study data was collected from patients' records whose first visits were from March 2006 to September 2007 and had undergone thorough examination for syncope (ECG, Holter monitoring, echocardiography, Tilt table testing, Electrophysiological study). All efforts were done to determine underlying heart diseases, physical exam and test abnormalities, final diagnosis and treatment in all selected patients. Overall prevalence of syncope was estimated to be 9%. The age-specific prevalence rates were 5-14 years: 4.14%, 15 44 years: 44.8%, 45-64 years: 31%, 65 years and Older: 20%. The most frequently identified cause (60%) was neurally-mediated (vasovagal) syncope. Mean age of patients was 44.9 years with a minimum of 5 years and maximum of 85 years. In our study, coronary heart disease had a high prevalence among participants (12.4%). Syncope is a common clinical problem. In this study prevalence rates peaked in 15 44 years age group. Considering that recurrent syncope is often disabling and may cause injury and the fact that heart diseases are more common in people affected by syncope, especial cautions should be taken while evaluating this group of patients. PMID- 24338147 TI - Delayed colonic perforation following stent placement for colorectal obstruction: a description of two cases with stent palliation. AB - Bowel stent insertion has a variety of complications one major of which is colonic perforation. The purpose of this article is to reveal two cases with delayed colonic perforation after stent placement to relieve bowel obstruction caused by rectal cancer. The first patient was a 55 year-old man who was a candidate for stent placement to avoid palliative surgery and relieve his bowel obstruction. Although the procedure resulted in complete relief of patient symptoms, but he returned with signs of peritonitis 10 days after the stent placement. A perforation was found at rectosigmoid junction on laparotomy. The second patient was a 60 year-old man who underwent a successful stent placement and returned 3 months later with a complaint of abdominal pain that showed up to be due to a rectal perforation on investigations. In conclusion, bowel perforation following stent placement can be a major complication, so close follow-up is necessary to detect it as soon as possible and prevent it from becoming an irreparable complication. PMID- 24338148 TI - Amyotrophic lateral sclerosis as a paraneoplastic manifestation in the neuroendocrine tumor of stomach: a case report. AB - Motor neuron diseases have been reported as a rare paraneoplastic syndrome (PNS) of a systemic neoplasm. We present a patient with amyotrophic lateral sclerosis (ALS) in association with neuroendocrine tumor (NET) of stomach, which is the first case of motor neuronopathy with underlying neuroendocrine tumor. A 79-year old woman presented with a two months history of progressive dysphagia, spastic dysarthria and marked fasciculation in her atrophic tongue. Gag reflexes were diminished bilaterally. Other cranial nerves were intact. In muscle testing there was significant atrophy in thenar and hypothenar areas of both hands compatible with diffuse motor neuronopathy with active denervation. Upper GI endoscopic study showed patchy erythematous mucosa with congestion in body of stomach, Histological biopsy of stomach confirmed the neuroendocrine tumor (NET). The importance of considering a paraneoplastic syndrome in a patient with presentation of ALS, which can leads to searching for underlying neoplasm before its apparent signs and symptoms, to initiate tumor treatment so much sooner. In addition even though paraneoplastic motor neuron disease is rare, treating the underlying neoplasm may resolve neurologic signs and symptoms. PMID- 24338149 TI - Pediatric intramedullary schwannoma without neurofibromatosis: case report. AB - Pediatric intramedullary schwannoma without neurofibromatosis is extremely rare with only five cases reported so far. We present this rare finding in an 10-year old boy who presented with a sudden onset of weakness in the lower limbs. An intraoperative diagnosis of schwannoma enabled us to carry out a total excision of the tumor, which resulted in near complete recovery at 10 months follow-up. Although rare, this diagnosis should be considered when a child presents with a solitary intramedullary tumor since its total resection can be achieved improving surgical outcome. PMID- 24338150 TI - Cytomegalovirus retinitis after initiation of antiretroviral therapy. AB - Patients with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART), despite a reduced viral load and improved immune responses, may experience clinical deterioration. This so called "immune reconstitution inflammatory syndrome (IRIS)" is caused by inflammatory response to both intact subclinical pathogens and residual antigens. Cytomegalovirus retinitis is common in HIV-infected patients on ART with a cluster differentiation 4 (CD4+) counts less than 50 cells/mm3. We reported a patient with blurred vision while receiving ART. She had an unmasking classic CMV retinitis after ART. PMID- 24338151 TI - Costochondritis caused by Aspergillus flavus following cardiac surgery. AB - Mediastinitis is an infrequent complication after coronary artery bypass graft (CABG) that is associated with prolonged intensive care unit and hospital stay, and increased early and late morbidity and mortality. Patients with mediastinitis have an osteoporotic, fragile, and broken sternum. All foreign bodies as well as infected tissue should be removed. Osteomyelitis of sternum often perseveres after debridement for mediastinitis. In this report, we describe an unusual case of costochondritis caused by aspergillosis following off pump CABG surgery in a male patient in Yazd-Iran. PMID- 24338152 TI - 5-HT3 receptor antagonists: new promising therapeutic agents in diabetes and its complications. PMID- 24338153 TI - Aquaporin water channels in the mammary gland: from physiology to pathophysiology and neoplasia. AB - Aquaporins are membrane proteins that play fundamental roles in water and small solute transport across epithelial and endothelial barriers. Recent studies suggest that several aquaporin proteins are present in the mammary gland. Immunohistochemical techniques have confirmed the presence of aquaporin 1 (AQP1) and AQP3 water channels in rat, mouse, bovine and human mammary glands. Studies suggest that in addition to AQP1 and AQP3 AQP4, AQP5 and AQP7 proteins are expressed in different locations in the mammary gland. Aquaporins play key roles in tumor biology and are involved in cell growth, migration and formation of ascites via increased water permeability of micro-vessels. Emerging evidence suggests that expression of these proteins is altered in mammary tumors and in breast cancer cell lines although it is not yet clear whether this is a cause or a consequence of neoplastic development. This review analyzes the expression and potential functional roles of aquaporin water channels in the mammary gland. The physiological mechanisms involved in the transport of water and small solutes across mammary endothelial and epithelial barriers are discussed in the context of milk production and lactation. This paper also reviews papers from the recent cancer literature that implicate aquaporins in mammary neoplasia. PMID- 24338155 TI - Effects of cold acclimation and storage temperature on crucian carp (Carassius auratus gibelio) in a waterless preservation. AB - The research aims to explore the impact of cold acclimation and storage temperature on crucian carp in a waterless preservation. It is conducted by studying the influence of cold acclimation on crucian carp in temperatures of 5 and 1 degrees C h(-1), followed by having them preserved under waterless conditions at 4 and 0 degrees C for 24 h to analyze their aerobic and anaerobic capacities. The research findings revealed that the temperature drop at 1 degrees C h(-1) is conducive to preserving the activity of lactate dehydrogenase. The activity of isocitrate dehydrogenase was maintained, and the brain succinate dehydrogenase remained unchanged. With regards to alanine transaminase, its activity, being sensitive to the changes of storage temperatures, was maintained when the temperature was decreased to 0 degrees C and malondialdehyde was accumulated at the same temperature. Stored in cold environment, blood catalase was accumulated; however, obvious changes were not found in the liver. It is likely that cold acclimation contributes to retaining aerobic and anaerobic metabolism under waterless preservation as well as decreasing the damage of blood oxidation. PMID- 24338154 TI - Vagal regulation and internalizing psychopathology among adolescents exposed to childhood adversity. AB - Childhood adversity (CA) is strongly associated with youth psychopathology. Identifying factors that reduce vulnerability following CA is critical for developing preventive interventions. Vagal tone and vagal reactivity following psychosocial stressors might influence psychopathology among youths exposed to CA. We acquired heart period and impedance cardiography data to calculate respiratory sinus arrhythmia (RSA) and preejection period (PEP) from 157 adolescents aged 13-17 years at rest and during the Trier Social Stress Test (TSST). Internalizing and externalizing symptoms and multiple forms of CA were assessed. Resting RSA and RSA reactivity interacted with CA in predicting internalizing but not externalizing psychopathology; CA was unassociated with internalizing problems in adolescents with high resting RSA and RSA reactivity. No interactions were observed with PEP. High resting RSA predicted greater vagal rebound and accelerated heart rate recovery following the TSST, highlighting one potential mechanism underlying low internalizing symptoms following CA among youths with high vagal tone. PMID- 24338156 TI - Mu opioid receptor in spermatozoa, eggs and larvae of gilthead sea bream (Sparus Aurata) and its involvement in stress related to aquaculture. AB - In aquaculture, unfavourable conditions experienced during early development may have strong downstream effects on the adult phenotype and fitness. Sensitivity to stress, leading to disease, reduced growth and mortality, is higher in larvae than in adult fish. In this study, conducted on sea bream (Sparus aurata), we evidenced the presence of the mu opioid receptor in gametes and larvae at different developmental stages. Moreover, we evaluated the possibility of reducing the effects of artificially produced stress, altering temperature, salinity and pH, by naloxone (an opioid antagonist) and calcium. Results evidenced that mu opioid receptor is present in larvae and in gametes of both sexes and that, during larval growth, its expression level changes accordingly; furthermore, naloxone/calcium association is efficacious in increasing the survival period of treated larvae compared to controls. We conclude that in sea bream rearing, the use of naloxone/calcium against stress can improve fish farming techniques by reducing larval mortality and consequently increasing productivity. PMID- 24338158 TI - Human adipose-derived stem cells modified by HIF-1alpha accelerate the recovery of cisplatin-induced acute renal injury in vitro. AB - Human adipose-derived stem cells (hASCs) improve renal function in acute kidney injury. Hypoxia-inducible factor-1alpha (HIF-1alpha) was transfected into hASCs. hASCs modified by lentivirus-mediated empty-vector and HIF-1alpha maintained their stem cell characteristics. The expression of the renal-protective gene, heme oxygenase-1 and vascular endothelial growth factor were significantly increased in hASCs modified by HIF-1alpha, compared to hASCs modified by empty vector. Cellular ultra-structure and TUNEL staining revealed that hASCs modified by HIF-1alpha promoted the recovery of apoptotic morphology in cisplatin-treated human kidney-2 cells (HK-2 cells) when compared to hASCs modified by empty vector. Additionally, hASCs modified by empty-vector inhibited caspase-3 expression and up-regulated Bcl-2 expression in cisplatin-treated HK-2 cells, an effect even more pronounced with hASCs modified by HIF-1alpha. Thus, HIF-1alpha gene-modified ASCs could be an effective way to enhance the renal-protective effect. PMID- 24338159 TI - Expression and characterization of a thermostable penicillin G acylase from an environmental metagenomic library. AB - One clone (ACPGA001) exhibiting penicillin G acylase (PGA) activity was screened from a metagenomic library by using a medium containing penicillin G. A novel PGA gene from the inserted fragment of ACPGA001 was obtained by sequencing. The amino acid sequence of ACPGA001 PGA exhibited <33 % similarity to PGAs retrieved from GenBank. This gene was expressed in Escherichia coli M15 and the recombinant protein was purified and characterized. The ACPGA001 PGA exhibited a maximum activity at 60 degrees C and showed high activity at pH 4-10 with an optimum pH of 8.0. This enzyme was stable at 40 degrees C for 70 min with a half-life of 60 min at 55 degrees C. These beneficial characteristics of ACPGA001 PGA provide some advantages for the potential application of ACPGA001 PGA in industry. PMID- 24338157 TI - The importance of non-uniformities in mechano-electric coupling for ventricular arrhythmias. AB - Cardiac mechanical and electrical activities are tightly linked through an intra cardiac regulatory loop (mechano-electric coupling). This connection is essential for normal heart function and auto-regulation. In diseases associated with altered myocardial mechanical properties or function, however, feedback from the mechanical environment to the origin and spread of excitation can result in deadly cardiac arrhythmias. Ventricular tachyarrhythmias, especially, are encountered in cardiac diseases associated with volume and pressure overload or changes in tissue mechanics. Little is known about the influence of changes in mechano-electric coupling on cardiac rhythm in these settings or the potential therapeutic benefit of its manipulation. Improved understanding may be central to explaining the origin of arrhythmias that occur with these pathologies and to the development of novel mechanics-based therapies. The present review explores the potential role of mechano-electric coupling in ventricular arrhythmogenesis, with a focus on the importance of non-uniformity in mechanical function for the induction and sustenance of ventricular tachyarrhythmias. PMID- 24338160 TI - Residue Val237 is critical for the enantioselectivity of Penicillium expansum lipase. AB - The shape of the hydrophobic tunnel leading to the active site of Penicillium expansum lipase (PEL) was redesigned by single-point mutations, in order to better understand enzyme enantioselectivity towards naproxen. A variant with a valine-to-glycine substitution at residue 237 exhibited almost no enantioselectivity (E = 1.1) compared with that (E = 104) of wild-type PEL. The function of the residue, Val237, in the hydrophobic tunnel was further analyzed by site-directed mutagenesis. For each of these variants a significant decrease of enantioselectivity (E < 7) was observed compared with that of wild-type enzyme. Further docking result showed that Val237 plays the most important role in stabilizing the correct orientation of (R)-naproxen. Overall, these results indicate that the residue Val237 is the key amino acid residue maintaining the enantioselectivity of the lipase. PMID- 24338162 TI - MicroRNA-22 targeting CBP protects against myocardial ischemia-reperfusion injury through anti-apoptosis in rats. AB - MicroRNAs are extensively involved in the pathogenesis of major cardiovascular diseases by suppressing target gene expression. Recent studies have reported that microRNA-22 (miR-22) may be implicated in ischemia-reperfusion (I/R) induced myocardial injury. However, the specific function of miR-22 in myocardial I/R injury is far from clear nowadays. The present study was designed to determine the role of miR-22 in myocardial I/R injury and investigate the underlying cardio protective mechanism. The rat myocardial I/R injury model was induced by occluding the left anterior descending coronary artery for 30 min followed by 12 h reperfusion. As predicted, adenovirus-mediated miR-22 overexpression markedly reduced the release of creatine kinase and lactate dehydrogenase, infarct size and cardiomyocytes apoptosis. Moreover, CREB binding protein (CBP) as a potential miR-22 target by bioinformatics was significantly inhibited after miR-22 transfection. We also found that p53 acetylation activity, pro-apoptotic related genes Bax and p21 levels were all decreased associated with the down-regulation of CBP. In conclusion, our data demonstrate that miR-22 could inhibit apoptosis of cardiomyocytes through one of its targets, CBP. Thus, miR-22 may constitute a new therapeutic target for the prevention of myocardial I/R injury. PMID- 24338161 TI - Using existing data to identify candidate items for a health state classification system in multiple sclerosis. AB - PURPOSE: In multiple sclerosis (MS), the use of preference-based measures is limited to generic measures such as Health Utilities Index Mark 2 and 3, the EQ 5D and the SF-6D. However, the challenge of using such generic preference-based measures in people with MS is that they may not capture all domains of health relevant to the disease. Therefore, the main aim of this paper is to describe the development of a health state classification system for MS patients. The specific objectives are: (1) to identify items best reflecting the domains of quality of life important to people with MS and (2) to provide evidence for the discriminative capacity of the response options by cross-walking onto a visual analog scale of health rating. METHODS: The data come from an epidemiologically sampled population of people with MS diagnosed post-1994. The dataset consisted of 206 items relating to impairments, activity limitations, participation restrictions, health perception and quality of life. Important domains were identified from the responses to the Patient Generated Index, an individualized measure of quality of life. The extent to which the items formed a uni dimensional, linear construct was estimated using Rasch analysis, and the best item was selected using the threshold map. RESULTS: The sample was young (mean age 43) and predominantly female (n = 140/189; 74%). The P-PBMSI classification system consisted of five items, with three response levels per item, producing a total of 243 possible health states. Regression coefficient values consistently decreased between response levels and the linear test for trend were statistically significant for all items. The linear test for trend indicated that for each item the response options provided the same discriminative ability within the magnitude of their capacity. A scoring algorithm was estimated using a simple additive formula. The classification system demonstrated convergent validity against other measures of similar constructs and known-groups validity between different clinical subgroups. CONCLUSION: This study produced a health state classifier system based on items impacted upon by MS, and demonstrated the potential to discriminate the health impact of the disease. PMID- 24338163 TI - Isolation and characterization of a Delta1-pyrroline-5-carboxylate synthetase (NtP5CS) from Nitraria tangutorum Bobr. and functional comparison with its Arabidopsis homologue. AB - Several functional and regulatory proteins play important roles in controlling plant stress tolerance. Proline (Pro) is one of the most accumulated osmolytes correlated with tolerance to stresses. Delta(1)-Pyrroline-5-carboxylate synthetase (P5CS) is a rate-limiting enzyme in Pro biosynthesis. In the present study, we isolated the cDNA for a P5CS gene (NtP5CS) from the halophyte Nitraria tangutorum. Phylogenetic analysis and subcellular localization analysis of NtP5CS GFP protein in onion cells showed that NtP5CS was a new P5CS gene and was involved in Pro synthesis in N. tangutorum. Expression of the NtP5CS gene was induced by salt stress, dehydration, and high and low temperatures. Escherichia coli overexpressing AtP5CS or NtP5CS exhibited better growth in all treatments, including high salinity, high alkalinity, dehydration, osmotic, heat and cold stresses. Additionally, NtP5CS recombinant E. coli cells grew better than did AtP5CS recombinant cells in response to abiotic stresses. Our data demonstrate that the P5CS from a halophytic species functions more efficiently than its homologue from a glycophytic species in improving the stress tolerance of E. coli. PMID- 24338164 TI - Neurochemicals measured by (1)H-MR spectroscopy: putative vulnerability biomarkers for obsessive compulsive disorder. AB - OBJECT: Obsessive compulsive disorder (OCD) is the fourth most common psychiatric disorder characterized by recurrent, intrusive thoughts and repetitive, ritualistic behaviors that are debilitating to the patient. Despite its high prevalence and the attendant morbidity, the pathophysiology of OCD remains unclear. Magnetic resonance spectroscopy (MRS) provides a noninvasive method to characterize the molecular biochemistry that may contribute to the pathophysiology of OCD. This study aimed to identify alterations in neurochemical measures that are specific to OCD using in vivo proton ((1)H) MRS of the caudate nucleus, anterior cingulate cortex, and medial thalamus in these patients, and to identify their role as vulnerability markers by comparing them with the healthy first degree relatives of these patients and healthy controls. MATERIALS AND METHODS: Appropriate psychometric instruments were applied in the study population followed by (1)H- MRS. The absolute neurochemical measures were quantified using a linear combination model. RESULTS: Significant differences in neurochemical measures were demonstrated in two of the three candidate regions (except the medial thalamus) between the three study groups. CONCLUSIONS: Our results lend support to the neurodegenerative hypothesis of OCD, and also raise the possibility of exploring these neurochemical measures (as measured by MRS) as putative vulnerability biomarkers in OCD that may aid in early identification and devising early prevention or management strategies for the population vulnerable to OCD. PMID- 24338165 TI - Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen (Stribild(r)): a review of its use in the management of HIV-1 infection in adults. AB - A new single-tablet, fixed-dose formulation consisting of elvitegravir, an HIV-1 integrase strand transfer inhibitor (INSTI); cobicistat, a pharmacokinetic enhancer; emtricitabine, a nucleoside reverse transcriptase inhibitor; and tenofovir disoproxil fumarate (tenofovir DF), a nucleotide reverse transcriptase inhibitor (elvitegravir/cobicistat/emtricitabine/tenofovir DF 150 mg/150 mg/200 mg/300 mg; Stribild(r)) is available in some countries for the once-daily treatment of HIV-1 infection in antiretroviral therapy-naive adults. Elvitegravir/cobicistat/emtricitabine/tenofovir DF is the first INSTI-based single-tablet regimen available for the complete initial treatment of adults with HIV-1 infection. In two large, randomized, double-blind, phase III trials, once daily treatment with elvitegravir/cobicistat/emtricitabine/tenofovir DF was effective in reducing plasma HIV-1 RNA levels to <50 copies/mL at the week 48 assessment and showed virological efficacy noninferior to that of the efavirenz/emtricitabine/tenofovir DF single-tablet regimen or a once-daily regimen of atazanavir plus ritonavir (ritonavir-boosted atazanavir) plus the fixed-dose combination of emtricitabine/tenofovir DF. Elvitegravir/cobicistat/emtricitabine/tenofovir DF also showed durable efficacy in terms of achieving sustained suppression of HIV-1 RNA levels to <50 copies/mL for up to 144 weeks in both of the phase III trials. Elvitegravir/cobicistat/emtricitabine/tenofovir DF is an important addition to the group of simplified once-daily single-tablet regimens currently available for the effective treatment of HIV-1 infection in antiretroviral therapy-naive patients and is among the preferred regimens recommended for use as initial treatment. It offers advantages over more complex multiple-tablet regimens that may impair treatment adherence, which is fundamental to the successful management of HIV-1 infection. PMID- 24338166 TI - Darunavir: a review of its use in the management of HIV-1 infection. AB - The latest HIV-1 protease inhibitor (PI) darunavir (PrezistaTM) has a high genetic barrier to resistance development and is active against wild-type HIV and HIV strains no longer susceptible to some older PIs. Ritonavir-boosted darunavir, as a component of antiretroviral therapy (ART), is indicated for the treatment of HIV-1 infection in adult and paediatric patients (aged >=3 years), with or without treatment experience (details vary depending on region of approval). Several open-label or partially-blinded trials have evaluated the efficacy of ritonavir-boosted darunavir ART regimens for up to 192 weeks in these settings. In treatment-naive adults, once-daily boosted darunavir was no less effective in establishing virological suppression than once- or twice-daily boosted lopinavir, yet was more effective at maintaining suppression long term. Moreover, treatment experienced adults with no darunavir resistance-associated mutations (RAMs) had no less effective viral load suppression with once-daily than with twice-daily boosted darunavir. In treatment-experienced adults, including some with multiple major PI RAMs, twice-daily boosted darunavir was more effective than twice-daily boosted lopinavir or boosted control PIs in reducing viral load, and provided virological benefit as part of a salvage regimen in those with few remaining treatment options. Boosted darunavir also reduced viral load when administered once-daily in treatment-naive adolescents or twice-daily in treatment-experienced children and adolescents. Boosted darunavir is generally well tolerated, with gastrointestinal disturbances and lipid abnormalities among the most common tolerability issues. It has a lipid profile more favourable than that of boosted lopinavir in terms of total cholesterol and triglyceride changes and, when administered once daily, its lipid effects are generally similar to those of boosted atazanavir. Thus, boosted darunavir is a useful option for the ART regimens of adult and paediatric patients with HIV-1 infection. PMID- 24338167 TI - Clinicopathologic features of breast cancer patients with type 2 diabetes mellitus in southwest of China. AB - The aim of this study was to study the prevalence and clinicopathologic features of breast cancer patients with type 2 diabetes mellitus in southwest of China for providing clinical guidance and prognosis appreciation for these patients. Through a case-control study of 3,381 primary breast cancer patients initially diagnosed from January 2007 to May 2013, one case group (164 female breast cancer patients with type 2 diabetes) and two control groups (first control group consists of 328 randomly selected nondiabetic breast cancer patients and second control group consists of 279 nondiabetic breast cancer patients without diabetes related diseases such as cardiovascular or cerebrovascular diseases) were selected. The clinicopathological features between them were statistically analyzed. (1) Of 3,381 primary breast cancer patients with the average age of 50.5, ranging from 21 to 97 years of age, 164 (4.9 %) cases (with the average age of 60.7) suffered diabetes (previously diagnosed diabetes). (2) The differences of clinicopathologic features between the case group and first control group (with the average age of 61.5) were the ratio of hypertension (41.5 vs 26.1 %, P = 0.001) and axillary lymph node metastasis (51.1 vs 38.1 %, P = 0.046); and the differences of clinicopathologic features between the case group and second control group (with the average age of 64.3) were axillary lymph node metastasis (51.1 vs 35.8 %, P = 0.017), tumor size (>= T2: 62.3 vs 53.1 %, P = 0.019) and p53 expression (51.0 vs 62.7 %, P = 0.018). No statistical significances (P > 0.05) of histological type, histological grade, or the expressions of estrogen receptor (ER), progesterone receptor, human epidermal growth factor 2 (HER2) and Ki67 were found between them. (3) The clinicopathologic features of ER-positive and ER-negative patients in each group were as follows: (1) In the case group, the ER-negative patients have more advanced tumor histological grade (G3, 19.0 vs 2.8 %, P = 0.012), more positive expression of Her-2 (16.9 vs 8.1 %, P = 0.029) and more axillary lymph node metastasis (63.3 vs 44.4 %, P = 0.048). (2) In the first control group, the same results with tumor histological grade (G3, 15.6 vs 6.2 %, P = 0.025) and positive expression of Her-2 (16.7 vs 4.3 %, P = 0.001), and more positive expression of Ki67 (65.1 vs 52.0 %, P < 0.001) were found. (3) In the second control group, the ER-negative patients have more positive expression of Ki67 (70.5 vs 55.7 %, P = 0.009) and fewer family history of malignancy (1.9 vs 10.0 %, P = 0.013). Diabetes has a high incidence in breast cancer patients and is more common with postmenopausal patients. It is suggested that initially diagnosed breast cancer patients should undertake oral glucose tolerance test screening for occult diabetes and prediabetes. More concerns should be put onto diabetic patients with breast cancer. PMID- 24338168 TI - Low-dose versus standard-dose gemcitabine infusion and cisplatin for patients with advanced bladder cancer: a randomized phase II trial-an update. AB - Prolonged infusion of low-dose gemcitabine and cisplatin (GC) proved to be an effective treatment for patients with advanced bladder cancer. One hundred and twenty untreated patients with stage III/IV bladder cancer were randomized to receive either gemcitabine (250 mg/m(2)) 6-h infusion on days 1 and 8, and cisplatin (70 mg/m(2)) on day 2 every 21-day cycle (arm 1) or gemcitabine (1,250 mg/m(2)) 30-min infusion on days 1 and 8, with the same dose of cisplatin (arm 2). The 92 males and 28 females included in the study had a median age of 62 years (range 40-85 years). Among the 120 patient, complete response was achieved in 11.7 % (7/60 patients of arm 1) and 5 % (3/60 patients of arm 2). Eighteen patients in arm 1 (30 %) and 17 patients (28.3 %) in arm 2 had partial response on therapy. Thus, the overall response rate of patients in arm 1 and arm 2 was 41.7 % (25/60 patients) and 33.3 % (20/60 patients), respectively (p = 0.37). No significant difference in median time to disease progression (26 vs. 24 months, p = 0.4), median survival (12 vs. 16 months, p = 0.8), and 1-year survival (49.9 vs. 54.7 %, p = 0.8) was detected between arms 1 and 2, respectively. Main toxicities were similar in both arms with no statistically significant differences. Low-dose, prolonged infusion gemcitabine in combination with cisplatin is not inferior to the standard GC regimen with favorable toxicity profile and less financial costs. PMID- 24338169 TI - The relationship between thyroid volume and malignant thyroid disease. AB - The present retrospective study aimed to investigate the relationship between thyroid volume and prevalence of thyroid cancer. We investigated the data of 3,850 patients who underwent fine-needle aspiration biopsy (FNAB). Biopsy results were evaluated as diagnostic or nondiagnostic, and diagnostic results were classified as benign, malignant, and indeterminate. We included 2,672 patients who underwent FNAB firstly in our hospital and evaluated as diagnostic biopsy except subgroup of indeterminate. We obtained cytologic data, levels of serum thyroid-stimulating hormone (TSH), and thyroid volumes of those patients retrospectively. Among 2,672 patients with thyroid nodule, 2,562 (95.9 %) patients had benign cytology and 110 (%4,1) patients had malignant cytology. There was no correlation between the malignancy and gender (p = 0.935), and patients with malignant cytology were younger (52 vs 59, p < 0.001). Also, TSH levels were higher in patients with malignant than benign cytology (p = 0.017). Median volume of right part, left part, and total thyroid for patients who had malignant cytology was significantly lower than patients who had benign cytology (8.3, 7.1, 15.9 vs 10.8 ml, 9.0 mml, 20.6 ml, respectively, p <= 0.001 for all parameters). The results demonstrated that thyroid cancer prevalence was higher in patients with low thyroid volume. According to our results, thyroid volume should be considered as a risk factor for malignancy in the evaluation of thyroid nodules. PMID- 24338170 TI - Endoscopic retrieval of a distally migrated stent using detachable snares. PMID- 24338171 TI - Perforated gastric diverticulum with bleeding. PMID- 24338172 TI - Transient parotitis after upper gastrointestinal endoscopy. PMID- 24338173 TI - Endoscopic ultrasound-guided placement of fiducial markers using a novel "wet fill technique" without a bone wax seal. PMID- 24338174 TI - Adenocarcinoid tumor of the rectum: a rare finding in a patient with recurrent fistulizing perianal Crohn's disease. PMID- 24338175 TI - Colonic duplication in adulthood presenting with diarrhea. PMID- 24338176 TI - A rare cause of gastric malignancy: Burkitt's lymphoma. PMID- 24338177 TI - Sengstaken-Blakemore tube: an unusual complication. PMID- 24338178 TI - Endoscopic ultrasound-guided retrograde pancreatic stent placement for the treatment of stenotic jejunopancreatic anastomosis after a Whipple procedure. PMID- 24338179 TI - Shiitake mushroom-induced ileus managed using double-balloon enteroscopy. PMID- 24338180 TI - Retraction note. Phylogenetic analysis of the non-structural (NS) gene of influenza A viruses isolated in Kazakhstan in 2002-2009. PMID- 24338181 TI - Size distribution and leaching characteristics of poly brominated diphenyl ethers (PBDEs) in the bottom ashes of municipal solid waste incinerators. AB - The particle size distributions and leaching characteristics of polybrominated diphenyl ethers (PBDEs) in the bottom ashes of two Taiwanese municipal solid waste incinerators (MSWIs A and B) were investigated to evaluate PBDE leaching into the environment through reutilization of bottom ashes. The PBDE contents in the bottom ashes of the MSWIs (29.0-243 ng/g) could be two orders higher than those in rural and urban soils. The PBDE fraction of the bottom ashes was more distributed in larger particles (> 0.25 mm). Similar trends were found for the PBDE contents in the bottom ashes and their PBDE leaching concentrations, revealing that the elevated PBDE contents in the bottom ashes may lead to a higher PBDE leaching mass. The leaching of PBDEs is attributed to diffusion driven by the concentration gradient and effective surface area. The normalized leaching ratios (NLRs) of PBDEs for the bottom ashes of the MSWIs are about four orders greater than those of PBDE-related raw materials and products, and this may be due to their porous structures having much greater effective surface area. The elevated NLRs of PBDEs thus deserve more attention when bottom ashes are recycled and reutilized as construction materials. PMID- 24338182 TI - An attempt to assess the relevance of flood events-biomarker response of rainbow trout exposed to resuspended natural sediments in an annular flume. AB - There is a consensus within the scientific community that sediments act as a long term sink for a variety of organic and inorganic pollutants, which, however, can re-enter the water column upon resuspension of deposited material under certain hydraulic conditions such as flood events. Within the implementation of the European Water Framework Directive, it is important to understand the potential short- and long-term impact of suspended particulate matter (SPM)-associated contaminants on aquatic organisms as well as the related uptake mechanisms for a sound risk assessment. To elucidate the effects of sediment-bound organic pollutants, such as polycyclic aromatic hydrocarbons (PAHs), rainbow trout (Oncorhynchus mykiss) were exposed to three resuspended natural sediments with different contamination levels. Physicochemical parameters including dissolved oxygen concentration, pH and temperature, total PAH concentration in sediments and SPM as well as different biomarkers of exposure in fish (7-ethoxyresorufin O deethylase activity, biliary PAH metabolites, micronuclei, and lipid peroxidation) were measured following seven days of exposure within an annular flume, a device to assess erosion and deposition processes of cohesive sediment. Concentrations of PAHs in SPM remained constant and represented the different contamination levels in the un-suspended sediments. Significant differences in bile metabolite concentrations as well as in 7-ethoxyresorufin O-deethylase induction compared to control experiments (untreated animals and animals that were exposed in the annular flume without sediment) were observed for all exposure scenarios. The ratio between 1-hydroxypyrene in bile from fish exposed to the three different contamination levels was 1.0:3.6:10.7 and correlated well with (1) the ratio of pyrene concentrations in corresponding sediments which was 1.0:3.1:12.7 and (2) with the ratio of particle-bound pyrene in SPM which was 1.0:2.7:11.7. In contrast, hepatic lipid peroxidation and micronuclei formation represented the different contamination levels less conclusive. The results of this study clearly demonstrate that firmly bound PAH from aged sediments can become bioaccessible upon resuspension under flood-like conditions and are readily absorbed by aquatic organisms such as rainbow trout. Associated short term effects were clearly documented and possible adverse long-term impacts due to genotoxicity are likely to follow. PMID- 24338183 TI - Effectiveness of acupuncture for palliative care in cancer patients: a systematic review. AB - OBJECTIVE: To critically evaluate the currently available randomized clinical trials regarding the effectiveness of acupuncture in palliative care for cancer patients, hence, to provide sufficient evidences for the widespread use of acupuncture in cancer treatment. METHODS: Two independent reviewers extracted data from all of the randomized clinical trials (RCTs) that assessed the efficacy of acupuncture in palliative care for cancer patients. Seven databases were searched from their respective inception to December 2010. All eligible trials identified were evaluated by two independent reviewers using the Jadad scale, and data from the articles were validated and extracted. RESULTS: In total, 33 RCTs met the inclusion criteria. The effects of acupuncture on different cancer related aspects were shown, including chemotherapy or radiotherapy-induced side effects (13/33, 39.4%), cancer pain (6/33, 18.2%), post-operative urinary retention (4/33, 12.1%), quality of life (2/33, 6.1%), vasomotor syndrome (2/33, 6.1%), post-operative gastrointestinal dysfunction (2/33, 6.1%), prevention of prolonged postoperative ileus (2/33, 6.1%), joint symptoms (1/33, 3.0%), and immunomodulation (1/33, 3.0%). CONCLUSIONS: The result of our systematic review suggested that the effectiveness of acupuncture in palliative care for cancer patients is promising, especially in reducing chemotherapy or radiotherapyinduced side effects and cancer pain. Acupuncture may be an appropriate adjunctive treatment for palliative care. PMID- 24338184 TI - The Fourier transform infrared spectra of the key organs derived from Kidney (Shen)-yang deficiency syndrome mice. AB - OBJECTIVE: To explore an approach to rapidly and accurately identify the compounds as biomarkers of Chinese medicine (CM) syndromes. METHOD: The Fourier transform infrared (FT-IR) spectrometry was applied to investigate the characteristic components of a mice model of Kidney (Shen)-yang deficiency syndrome (KDS), and the remedial effect of a typical CM formula Shenqi Pill (). Thirty-six females and 18 males of Balb/c mice were randomly divided into KDS, Shenqi or control group. The females and males of the same group freely were mated for 96 h, and the males were taken out and only the female mice were raised. Females of the KDS group were threatened by a ferocious cat every other day for 14 d. After delivery, the KDS, or gestational threatened, offspring were raised at standard condition for 11 weeks. Then 10 male offspring were randomly selected, anaesthetized and their representative organs, i.e. testes, kidneys, lungs and feet were collected, for the FT-IR scan. Mice of the Shenqi group were intragastric administered Shenqi Pill; while mice in the KDS and control groups were given the same volume of saline. RESULTS: The attenuated birth outcomes of the KDS group were displayed. The remarkable FT-IR differences of all organs between KDS mice and healthy control were mainly at 1,735-1,745 cm(-1) (indicating the increased levels of lipids) and at 1,640-1,647 cm(-1) and 1,539 1,544 cm(-1) (displaying the decreased proteins). No statistic FT-IR difference between Shenqi and control mice was observed. CONCLUSION: In accordance with major traits of KDS, prenatal stress extensively impaired the building up of proteins and resulting in the excessive lipid storage, and FT-IR could effectively identify the biomarkers of KDS. PMID- 24338185 TI - A pragmatic observational feasibility study on integrated treatment for musculoskeletal disorders: Design and protocol. AB - BACKGROUND: Musculoskeletal disorders (MSD) comprise a wide range of conditions, associated with an enormous pain and impaired mobility, and are affecting people's lives and work. Management of musculoskeletal disorders typically involves a multidisciplinary team approach. Positive findings have been found in previous studies evaluating the effectiveness of complementary therapies, though little attention has been paid to evaluating of the effectiveness of integrated packages of care combining conventional and complementary approaches for musculoskeletal conditions in a National Health Service (NHS) setting. OBJECTIVE: To determine the feasibility of all aspects of a pragmatic observational study designed: (1) to evaluate the effectiveness and cost effectiveness of integrated treatments for MSDs in an integrated NHS hospital in the UK; (2) to determine the acceptability of the study design and research process to patients; (3) to explore patients' expectation and experience of receiving integrated treatments. METHODS: This is an observational feasibility study, with 1-year recruitment and 1-year follow-up, conducted in Royal London Hospital for Integrated Medicine, University College London Hospital Trust, UK. All eligible patients with MSDs newly referred to the hospital were included in the study. Interventions are integrated packages of care (conventional and complementary) as currently provided in the hospital. SF-36TM Health Survey, short form Brief Pain Inventory, Visual Analogue Scale, and modified Client Service Receipt Inventory will be assessed at 4/5 time points. Semi-structured interview/focus group will be carried out before treatment, and 1 year after commence of treatment. DISCUSSION: We intend to conduct a pragmatic observational study of integrated medical treatment of MSDs at a public sector hospital. It will inform the design of a future trial including recruitment, retention, suitability of the outcome measures and patients experiences. PMID- 24338186 TI - Clinical effect of Maixuekang Capsule (?????) on long-term prognosis in patients with acute coronary syndrome after percutaneous coronary intervention. AB - OBJECTIVE: To study the changes of adenosine diphosphate (ADP)-induced platelet aggregation rate, and evaluate the effects of Maixuekang Capsule (, MKC) on platelet aggregation rate and long-term prognosis of patients with acute coronary syndrome after percutaneous coronary intervention (PCI). METHODS: A total of 236 patients with acute coronary syndrome, who received successful PCI, were randomly assigned to a trial group (116 cases) and a control group (120 cases) according to random numbers; treatment allocation occurred when the participants met the inclusion criteria and signed the informed consent forms. In the trial group, the patients were treated with MKC combined with routine medication, and in the control group the patients were treated with routine medication. The therapeutic course for the two groups was 12 months and the follow-up was 12 months. The levels of ADP-induced platelet aggregation rate and serum high-sensitive C reactive protein (hs-CRP) were determined before PCI, 12 h and 30 days after PCI. In the meantime, the incidence of cardio-/cerebrovascular events was recorded during the 12-month follow-up. RESULTS: Compared with before PCI, the levels of ADP-induced platelet aggregation rate and serum hs-CRP were significantly higher at 12 h after PCI (P<0.05). They were significantly reduced after 30-day treatment of MKC, showing statistical differences when compared with those in the control group (P<0.05). During the 12-month follow-up, the incidence of cardio /cerebrovascular events was significantly lower in the trial group than in the control group (6.9% vs. 12.5%, P<0.01). CONCLUSIONS: ADP-induced platelet aggregation function was significantly elevated after PCI. MKC improved the prognosis of patients with acute coronary syndrome, possibly through inhibiting the platelet aggregation, fighting against inflammation, and protecting the vascular endothelial function. PMID- 24338188 TI - The role of milk thistle extract in breast carcinoma cell line (MCF-7) apoptosis with doxorubicin. AB - Breast cancer is the most commonly diagnosed invasive malignancy and first leading cause of cancer-related deaths in Iranian women. Based on silymarin's unique characteristics, its application in chemotherapy combined with doxorubicin can be effective to enhance the efficacy together with a reduced toxicity on normal tissues. The present study focus on evaluate the efficacy of silymarin in combination with doxorubicin, on viability and apoptosis of estrogen-dependent breast carcinoma cell line (MCF-7). After being cultured, MCF-7 cells were divided into 8 groups and treated as follows: 1st group received 75 MUg silymarin, groups 2, 3, and 4 were treated with 10, 25, and 50 nM doxorubicin, respectively, and groups 5, 6, and 7 respectively received 10, 25, and 50 nM doxorubicin as well as 75 MUg silymarin. Viability percentage and apoptosis of the cells were assessed with Trypan Blue staining after 16, 24, and 48 hours. Silymarin has a synergistic effect on the therapeutic potential of doxorubicin. Use of silymarin in combination with doxorubicin can be more effective on the therapeutic potential of doxorubicin and decreases its dose-limiting side effects. PMID- 24338189 TI - The effect of heart disease differential mortality rate on cholesterol distribution. AB - In a good deal of studies cholesterol distribution, as a risk factor, demonstrates a special treatment towards age so that it shows an upward trend up to an age group and exhibits a downward trend for older age brackets thereafter. To investigate this phenomenon, two general points of view are presented. First, this issue may occur naturally for many subjects and it may be due to natural treatment of cholesterol variable with age. Second, it could be related to differential mortality, i.e. mortality changes in different age groups. In other words, it can be said that higher levels of cholesterol are relevant to younger age mortality rate. Constructing a parametric model based on Weibull distribution, the association of this phenomenon with differential mortality was investigated. This study revealed that the effect of differential mortality on cholesterol distribution in the age groups younger than 65 were insignificant and it could partly be justifiable just in older age groups because it involves 35% changes in the 85-95 age groups. Thus, the differential mortality justifies just a part of cholesterol changes and other parts are due to intrinsic changes of cholesterol variable with time. PMID- 24338190 TI - Effect of inpatient cardiac rehabilitation on QT dispersion in patients with acute myocardial infarction. AB - QT dispersion is an indicator of lack of ventricular repolarization homogeneity and an independent predictor for ventricular arrhythmia and sudden cardiac death. In this study, we evaluated the effect of inpatient cardiac rehabilitation on QT dispersion in patients admitted to Afshar hospital CCU with diagnosis of acute myocardial infarction (AMI), including ST elevation or non-ST elevation MI. Sixty patients with diagnosis of AMI were randomly divided into two 30-subject groups. The subjects in the first group were undergone inpatient cardiac rehabilitation, and the subjects in the control group received only conventional treatments. QT interval dispersion was measured in two occasions: once in the first day of admission and once before discharge from hospital. In this study there was a significant reduction in QT dispersion in patients undergoing inpatient cardiac rehabilitation (48.4 vs. 42.4 ms, P<0.001), but in the control group, QT dispersion was not significantly reduced (49.2 vs. 46.2 ms, P>0.05). The reduction was not significantly different regarding gender. The effectiveness of the rehabilitation on the reduction of QT dispersion was not affected by such variables as age, gender, hypertension, positive family history, hyperlipidemia, type of AMI (with ST-elevation or non-ST-elevation) and left ventricular ejection fraction. Diabetes caused a resistance to the beneficial effects of inpatient cardiac rehabilitation, so as non-diabetic patients showed more reduction in QT dispersion in response to inpatient cardiac rehabilitation comparing non-diabetic patients and the difference was statistically significant. PMID- 24338187 TI - The biology of zinc transport in mammary epithelial cells: implications for mammary gland development, lactation, and involution. AB - Zinc plays a critical role in a vast array of cellular functions including gene transcription, protein translation, cell proliferation, differentiation, bioenergetics, and programmed cell death. The mammary gland depends upon tight coordination of these processes during development and reproduction for optimal expansion, differentiation, and involution. For example, zinc is required for activation of matrix metalloproteinases, intracellular signaling cascades such as MAPK and PKC, and the activation of both mitochondrial-mediated apoptosis and lysosomal-mediated cell death. In addition to functional needs, during lactation the mammary gland must balance providing optimal zinc for cellular requirements with the need to secrete a substantial amount of zinc into milk to meet the requirements of the developing neonate. Finally, the mammary gland exhibits the most profound example of programmed cell death, which is driven by both apoptotic and lysosomal-mediated cell death. Two families of zinc-specific transporters regulate zinc delivery for these diverse functions. Members of the ZIP family of zinc transporters (ZIP1-14) import zinc into the cytoplasm from outside the cell or from subcellular organelles, while members of the ZnT family (ZnT1-10) export zinc from the cytoplasm. Recently, the ion channel transient receptor potential mucolipin 1 (TRPML1) has also been implicated in zinc transport. Herein, we review our current understanding of the molecular mechanisms through which mammary epithelial cells utilize zinc with a focus on the transport of zinc into discrete subcellular organelles for specific cellular functions during mammary gland development, lactation, and involution. PMID- 24338191 TI - Value of ABCD2 in predicting early ischemic stroke in patients diagnosed with transient ischemic attack. AB - As a significant number of patients diagnosed with transient ischemic attack (TIA) at emergency department are at risk to develop TIA or cerebral vascular accident (CVA), several attempts have been made to figure out a predictive method to detect those at higher risk of such attacks. We aimed to evaluate the role of ABCD2 scoring which includes age, blood pressure, clinical symptoms, diabetes mellitus, and duration of symptoms in predicting short term outcome of the patients presenting with TIA. One hundred consecutive patients visited between 2009 and 2010 in Hazrat Rasoul Akram Hospital and diagnosed with TIA were enrolled and their ABCD2 scores were registered. The incidence of death, CVA, or TIA during the first week after the attack was recorded. Eleven patients suffered new TIA/CVA after 1 week. Sensitivity and specificity of ABCD2 score for predicting CVA/TIA at cut-off point of 4 were 72.7% and 52.8%, respectively. At the same cut-off point for ABCD2, positive and negative predictive values were 16% and 94 %, respectively. Our results show that although patients with ABCD2 score greater than 4 were more likely to develop recurrent TIA/CVA in short term, those with lesser score still harbour a considerable risk for TIA/CVA. Though ABCD2 as an easily applicable tool is very helpful in management of TIA patients at emergency department, but it should not be the only measure to rely on in our decision making. PMID- 24338192 TI - Relation between asthma and body mass index in 6-15 years old children. AB - Childhood asthma and obesity are significant public health problems. Most prospective studies suggest that obesity increases the risk of asthma. But, some authors did not found this association. In this study the association between asthma and body mass index (BMI) was investigated. This case-control study was conducted on 200 asthmatic children aged 6-15 years and 200 children without asthma. The criteria for asthma diagnosis and its classification were on the basis of National Asthma Education and Prevention Program (NAEPP). BMI of patients and controls were also measured and BMI grater than 85% and 95% were defined as overweight and obese respectively. The data was analyzed by SPSS software. The BMI among the asthmatic children (17.9 kg/m2) was higher than the BMI among the non-asthmatics (16.5 kg/m2), P=0.0001. This relationship was significant in both males and females. 18% of asthmatic children were classified as overweight and 13.5% of them were obese versus 7.5% and 6% respectively in non asthmatics (P=0.0001). However, there was no significant relationship between severity, duration of asthma, kind of medication and BMI in children with asthma (P>0.05). Result of this study showed that there is an association between asthma symptoms and obesity in children. Therefore, any attempts for weight control in asthmatic children might be beneficial. PMID- 24338193 TI - Correction of high myopia with foldable Artiflex Phakic intraocular lenses: 1 year follow-up results. AB - To assess the one year results of Artiflex Phakic intraocular lens (IOL) implantation in the treatment of high myopia. In this non-random interventional study, myopic patients with spherical equivalent worse than -5.0 diopters (D) who were not eligible for laser surgery were assessed. All patients had refraction, uncorrected and best corrected visual acuity tests (UCVA and BCVA), endothelial cell count (ECC), and measurement of the anterior chamber depth and intraocular pressure before surgery and at 1, 3, 6, and 12 months after surgery. Main outcome measures of this study were refractive stability, refractive predictability, safety, and efficacy after implanting Artiflex IOLs. We studied 53 eyes of 20 female and 8 male patients. The mean preoperative spherical equivalent was 10.22+/-3.02 D which reached -0.69+/-1.08 D one year after surgery (P<0.001). On the last follow-up visit, 75% of the eyes were within +0.5 D of emmetropia, 2 eyes had lost one line of BCVA, 18.75% had gained one line and 31.25% had gained 2 or more lines of BCVA. Others showed no change in BCVA. At one year after surgery, 72.2% of the eyes had 20/25 vision or better. The safety and efficacy indices were 1.16 and 1.05, respectively. ECC showed 3.04% decrease (P=0.176). In cases where laser surgery is not an option for myopic patients, use of Artiflex IOLs can have good results with acceptable safety and efficacy. PMID- 24338194 TI - Skin protective behavior amongst girl students; based on health belief model. AB - Skin cancer is the most prevalent type of cancer in most of the countries and more than 90% of cancer cases are related to ultra violet rays of the sun. Therefore protective behaviors against sunlight are considered the most essential measures for skin cancer prevention. This study has been conducted to determine the frequency of protective behavior against sunlight among female students of Tehran city high schools. The Health Belief Model has been used for this cross sectional study to analyze the factors related to protective behaviors. A multi phase sampling method was used. 941 female student of Tehran city high schools were studied using a probed question form. The data were then analyzed using SPSS software. During the study of protective behaviors against the sunlight, 24.7% of participants mentioned that they always use sunscreen. The behavior of using sunscreen is related to perceived sensitivity, severity and benefit amongst the students (P<0.05). Also 3.8% of the students who participated in our study were always using gloves in summer to protect against sunlight. The behavior of using gloves in summer was also related to perceived sensitivity, severity and benefit (P<0.05). Physicians were the most effective influencing people with 84.9% influence on the appropriate decision making by these students. There is a low frequency of protective behavior against sunlight among the female students of Tehran city high schools. These findings show the necessity of training the students in this regard and promote the protective behaviors amongst them. PMID- 24338195 TI - Clinical nutrition knowledge of gastroenterology fellows: is there anything omitted? AB - Despite the increased emphasis on chronic non-communicable diseases, there are notable deficits about nutrition education in many medicine training programs particularly gastroenterology fellowship programs. In the present cross-sectional study, we examined the nutritional knowledge related to clinical nutrition among Iranian gastroenterology fellows. Thirty-six gastroenterology fellows currently enrolled in a gastroenterology fellowship program completed a questionnaire, including two sections. The first of which assessed the gastroenterology fellows experience about nutrition training, nutrition management of patients with gastrointestinal (GI) disorders and evaluating perceived nutrition education needs. The second section consisted of multiple choice questions that assessed nutritional knowledge. A total of 32 gastroenterology fellows completed the first section. The majority of gastroenterology fellows failed to partake in any nutrition education during their fellowship training particularly for inpatients despite the availability to participate in the nutrition training especially for the purpose of nutrition support. Mean correct response rates for the second section was 38%. The highest mean score was seen in nutrition assessment (48.1%), followed by scores of 40.5% in nutrition support, 37.0% nutrition in GI disease, and 25.0% in micro and macronutrients. Iranian gastroenterology fellows have serious deficits in their nutrition knowledge. This study paves the way for the development of an education program to improve nutritional knowledge of gastroenterology fellows. PMID- 24338196 TI - Clinical features of laryngeal tuberculosis in Iran. AB - Tuberculosis is a major health problem in Iran and its laryngeal involvement is not uncommon. Laryngeal tuberculosis is so infectious and delay in diagnosis and treatment could result spread of disease and causes divesting complications. We reviewed clinical and para-clinical characteristics of patients with laryngeal tuberculosis in Iran. In a cross sectional study, patients with laryngeal tuberculosis were studied and followed. All patients admitted from May 2000 to Dec 2011 in Amir-Alam hospital, a referral center for laryngeal diseases in Tehran. We studied 19 cases of laryngeal tuberculosis with typical histopathology (chronic granulomatous inflammation with caseous necrosis and langhans-type giant cells) and 6 cases of laryngeal tuberculosis with atypical histopathology (chronic granulomatous inflammation or chronic inflammation without necrosis). They had laryngeal symptoms and signs from 2 to 12 months before definitive diagnosis. Macroscopic appearances of laryngeal lesions were exophytic in 11 cases and ulcerative in 14 cases. True vocal cords were involved in 22 cases. The primary clinical diagnosis was malignancy in 17 cases, tuberculosis in 5 cases, and nonspecific inflammation in 3 cases. The chest x-ray findings were compatible with tuberculosis in 14 patients. The response to anti-tuberculosis therapy was desirable in all patients. In endemic area, tuberculosis should be considered as an important diagnosis in patients with laryngeal lesions even when histopathology of laryngeal lesions is not typical. Association with pulmonary tuberculosis helps for diagnosis. PMID- 24338197 TI - Trend of blood cholesterol level in Iran: results of four national surveys during 1991-2008. AB - Trends in cholesterol level of different populations have been investigated in several studies. This study is conducted to determine the trend of cholesterol level of Iranian adults from 1990 to 2007. Data on cholesterol measurements of four national health surveys that have been carried out in Iran used in this study. Cholesterol level of 12728 adults aged 25-64 were measured in 1990-1 survey. Also in 1999, 2005, and 2007 surveys, blood cholesterol level of 18398, 52344 and 19630 have been sampled, respectively. The median of cholesterol were modeled with age for men and women separately for the four surveys using fractional polynomials. Then, trends in the median of cholesterol across these four surveys were studied. The analysis of cholesterol data over four national health surveys showed that the change in males' cholesterol level had a decreasing trend. This decreasing trend was more pronounced in ages younger than 45 years. However, the medians of cholesterol of females during 16 years of four national surveys had a varying trend. It was decreasing in ages younger than 45; but increasing in ages over 45 years. The median of the cholesterol level of males and females in 2005 survey was on average about 10 mg/dl higher in comparison with the other surveys. Our findings showed that the pattern of trend in cholesterol level of Iranian men and women adults have a considerable difference with those of the other developing and developed countries. PMID- 24338198 TI - Endometrial carcinoma metastatic to the clitoris: a case report and review of the literature. AB - Endometrial cancer generally carries a good prognosis. Endometrial carcinoma more frequently metastasizes to the pelvic and para-aortic nodes. Visceral metastases usually occur in the vagina and ovaries. Distant metastases involve lungs and occur as a terminal event. This case report describes vulvalar metastasis of endometrial cancer to the clitoris. Metastatic tumors of the vulva are rare. Moreover, in the presence of metastatic endometrial carcinoma to the vulva, it is necessary to verify if other visceral metastases are present. Endometrial cancer can extend through direct dermatogens and lymphatic spread. We report a clitoral metastasis of an endometrial carcinoma and discuss whether the possible mechanism is vascular spreading or direct seeding. PMID- 24338199 TI - Familial congenital hepatic fibrosis: report of a family with three affected children. AB - Congenital hepatic fibrosis (CHF) is a developmental disorder of the biliary system, characterized by defective remodeling of the ductal plate. Herein a family of three children, from consanguineous parents, with minor thalassemia is presented who suffered from congenital hepatic fibrosis (CHF). Prompt diagnosis and appropriate treatment are necessary to avoid further complications in the affected patients. PMID- 24338200 TI - Bilateral retinal vein occlusion and rubeosis irides: lessons to learn. AB - Uncontrolled hypertension is well- known to give rise to systemic complications involving multiple central organs. Artherosclerosis leads to damage of the retinal vessels wall, contributing to venous stasis, thrombosis and finally, occlusion. Retinal vein occlusions compromise vision through development of ischaemic maculopathy, macular oedema, and rubeotic glaucoma. Laser photocoagulation remains the definitive treatment for ischaemic vein occlusion with secondary neovascularization. Timely treatment with anti- vascular endothelial growth factor prevents development of rubeotic glaucoma. We hereby report an unusual case of bilateral retinal vein occlusion complicated by rubeosis irides, which was successfully managed to improve vision and prevent rubeotic glaucoma. PMID- 24338201 TI - Cranial nerve palsy in tuberculous meningitis versus acute bacterial meningitis. PMID- 24338202 TI - DRG axon elongation and growth cone collapse rate induced by Sema3A are differently dependent on NGF concentration. AB - Regeneration of embryonic and adult dorsal root ganglion (DRG) sensory axons is highly impeded when they encounter neuronal growth cone-collapsing factor semaphorin3A (Sema3A). On the other hand, increasing evidence shows that DRG axon's regeneration can be stimulated by nerve growth factor (NGF). In this study, we aimed to evaluate whether increased NGF concentrations can counterweight Sema3A-induced inhibitory responses in 15-day-old mouse embryo (E15) DRG axons. The DRG explants were grown in Neurobasal-based medium with different NGF concentrations ranging from 0 to 100 ng/mL and then treated with Sema3A at constant 10 ng/mL concentration. To evaluate interplay between NGF and Sema3A number of DRG axons, axon outgrowth distance and collapse rate were measured. We found that the increased NGF concentrations abolish Sema3A-induced inhibitory effect on axon outgrowth, while they have no effect on Sema3A-induced collapse rate. PMID- 24338203 TI - Effects of sesamin on the biosynthesis of chondroitin sulfate proteoglycans in human articular chondrocytes in primary culture. AB - Osteoarthritis (OA) is a degenerative joint disease that progressively causes a loss of joint functions and the impaired quality of life. The most significant event in OA is a high degree of degradation of articular cartilage accompanied by the loss of chondroitin sulfate-proteoglycans (CS-PGs). Recently, the chondroprotective effects of sesamin, the naturally occurring substance found in sesame seeds, have been proved in a rat model of papain-induced osteoarthritis. We hypothesized that sesamin may be associated with possible promotion of the biosynthesis of CS-PGs in human articular chondrocytes. The aim of the study was to investigate the effects of sesamin on the major CS-PG biosynthesis in primary human chondrocyte. The effects of sesamin on the gene expression of the PG core and the CS biosynthetic enzymes as well as on the secretion of glycosaminoglycans (GAGs) in monolayer and pellet culture systems of articular chondrocytes. Sesamin significantly increased the GAGs content both in culture medium and pellet matrix. Real-time-quantitative PCR showed that sesamin promoted the expression of the genes encoding the core protein (ACAN) of the major CS-PG aggrecan and the biosynthetic enzymes (XYLT1, XYLT2, CHSY1 and CHPF) required for the synthesis of CS-GAG side chains. Safranin-O staining of sesamin treated chondrocyte pellet section confirmed the high degree of GAG accumulation. These results were correlated with an increased level of secreted GAGs in the media of cultured articular chondrocytes in both culture systems. Thus, sesamin would provide a potential therapeutic strategy for treating OA patients. PMID- 24338204 TI - Clinical implications of left ventricular assist device implantation in patients with an implantable cardioverter-defibrillator. AB - PURPOSE: This study aims to study the clinical implications of the concomitant use of a left ventricular assist device (LVAD) and an implantable cardioverter defibrillator (ICD). METHODS: In this retrospective study, all patients who underwent LVAD (Heart Mate II) implantation with concomitant ICD therapy at our institution between June 2007 and August 2012 were included. We sought to investigate (1) the electromagnetic interference between LVAD and ICD telemetry, (2) the effect of LVAD implantation on right ventricular (RV) lead parameters and (3) the ventricular tachyarrhythmias (VAs) that occur post-LVAD implantation. RESULTS: Of the 23 patients (53 +/- 9 years, 73 % male, LVEF 19 +/- 9 %) included, ICD telemetry was lost in four patients post-LVAD implantation (Saint Jude-Medical Atlas V-193, V-240, V-243, and Sorin CRT-8750), prompting either use of a metal shield (n = 1), a change in position of the programmer head (n = 1) or ICD replacement (n = 2). LVAD implantation was associated with a decrease in both RV signal amplitude (p = 0.04) and RV impedance (p < 0.01), and a trend towards an increased RV pacing threshold (p = 0.08), without affecting clinical outcome. Eleven patients (47.8 %) experienced VAs after LVAD implantation, which on the whole were well tolerated. Their occurrence was strongly linked to a history of VAs before device implantation (p < 0.01). CONCLUSIONS: Electromagnetic interference between LVADs and ICD telemetry may necessitate ICD replacement. LVAD placement is associated with significant changes in RV lead parameters that have minimal clinical significance. VAs occur in approximately half of LVAD patients seen and their occurrence is strongly related to a history of VAs prior to LVAD implantation. PMID- 24338205 TI - Characterization of a laboratory-scale container for freezing protein solutions with detailed evaluation of a freezing process simulation. AB - A 300-mL stainless steel freeze container was constructed to enable QbD (Quality by Design)-compliant investigations and the optimization of freezing and thawing (F/T) processes of protein pharmaceuticals at moderate volumes. A characterization of the freezing performance was conducted with respect to freezing kinetics, temperature profiling, cryoconcentration, and stability of the frozen protein. Computational fluid dynamic (CFD) simulations of temperature and phase transition were established to facilitate process scaling and process analytics as well as customization of future freeze containers. Protein cryoconcentration was determined from ice-core samples using bovine serum albumin. Activity, aggregation, and structural perturbation were studied in frozen rabbit muscle l-lactic dehydrogenase (LDH) solution. CFD simulations provided good qualitative and quantitative agreement with highly resolved experimental measurements of temperature and phase transition, allowing also the estimation of spatial cryoconcentration patterns. LDH exhibited stability against freezing in the laboratory-scale system, suggesting a protective effect of cryoconcentration at certain conditions. The combination of the laboratory-scale freeze container with accurate CFD modeling will allow deeper investigations of F/T processes at advanced scale and thus represents an important step towards a better process understanding. PMID- 24338206 TI - Considerations for bio-specimen collection among black women residing in the rural Deep South participating in a cancer prevention study. PMID- 24338207 TI - Proteomic identification of Syzygium cumini seed extracts by MALDI-TOF/MS. AB - Syzygium cumini is traditionally used medicinal plant. The different part of the plant such as bark, leaves, seed and fruits are widely used as an alternative medicine in various diseases. Although the scientific community has a strong interest on S. cumini seed biochemistry focusing on metabolite composition, proteins have not yet been investigated. In the present study, we have applied a proteomic approach to study the proteome of the S. cumini seed using phenol extraction method for protein isolation, which were never analysed before. Fifteen brightly silver stained protein spots were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry after resolving on two-dimensional gel electrophoresis. These proteins have been found to involve in various functions such as antifungal, sulphur metabolism, carbohydrate metabolism, fruit ripening and softening, dormancy breaking and seed germination, hormone signalling, secondary metabolite transport, defence and stress response, nitrogen metabolism, synthesis and stabilization. Amongst the identified protein, lactoferrin was a mammalian origin protein with high nutritious and pharmaceutical value, which was purified by different types of chromatographic techniques and confirmed by western blotting. The antibacterial activity of lactoferrin was assessed by disc diffusion assay. We suggest that the protein constituents of S. cumini may have role in various functions required for plant physiology and its dietary values. PMID- 24338208 TI - Purification and applications of a lectin from the mushroom Gymnopilus spectabilis. AB - A lectin was isolated from fruiting bodies of the mushroom Gymnopilus spectabilis (GSL) by ionic exchange chromatography. The lectin agglutinates mouse red cells exhibiting broad specificity towards several monosaccharides including the N acetylneuraminic acid. Agglutination was also inhibited by the glycoproteins: fetuin, lactoferrin, and recombinant erythropoietin. GSL is a glycoprotein possessing 16 % of carbohydrates; the SDS-PAGE showed two bands with molecular mass of 52.1 and 64.4 kDa. Isoelectric focusing displayed microheterogeneity, with two bands at pIs 5.1 and 5.3. The lectin was stable between pH 2 and pH 8 while at pH 10, the agglutination decayed to 50 % of initial activity. Incubation at 40 and 80 degrees C led to 50 and 100 % loss in activity of the lectin, respectively. Synthesized GSL-Sepharose interacts with serum pregnant mare gonadotropin, and at least two subpopulations of this glycoprotein were separated. There was no interaction between transferrin and soluble GSL while a partial recognition was achieved with GSL-Sepharose. The terminal sialic acid seems to play an active role in modifying the interaction with GSL, depending if the lectin is in a soluble or immobilized form. The purified lectin inhibited in vitro the growth of Staphylococcus aureus and Aspergillus niger. PMID- 24338209 TI - Enhanced xylanase performance in the hydrolysis of lignocellulosic materials by surfactants and non-catalytic protein. AB - Addition of additives has been confirmed to increase cellulase performance in the hydrolysis of lignocellulosic materials. In the hydrolysis of xylan-containing lignocellulosic biomass, xylanase can synergistically enhance the performance of cellulase. However, the role of additives in xylan hydrolysis by xylanase is not yet clear. In this work, with the presence of additives (bovine serum albumin, poly(ethylene glycol), and Tween), the hydrolysis of isolated xylan and the xylan in corn stover increased to different extents. Additives increased free xylanase in supernatants in the hydrolysis with xylanase, indicating the reduction of the adsorption of xylanase on corn stover and insoluble xylan. Enhanced hydrolysis of Avicel and corn stover by additives suggested that besides the prevention of unproductive binding of xylanase to lignin by additives, reducing the adsorption of xylanase on substrates was also contributed to enzymatic hydrolysis. The increment of xylanase activity by additives suggests that the additives were activators of xylanase. The results of this work indicate that the supplementation of additives could improve xylanase performance, synergistically enhanced the cellulose hydrolysis, and beneficial for the recycling of xylanase. PMID- 24338210 TI - In vitro and in vivo antioxidant and antimutagenic activities of polyphenols extracted from hops (Humulus lupulus L.). AB - BACKGROUND: Hops (Humulus lupulus L.) contain 40-140 mg g(-1) polyphenols. The objective of this study was to determine the phenolic composition of a high purity (total phenolic content = 887 mg g(-1) ) hop polyphenol extract (HPE) and evaluate its antioxidant activities in vivo and in vitro and its antimutagenic activity. The antioxidant activity of HPE was compared with the activity of green tea polyphenols. RESULTS: The phenolic compositions of HPE were more than 55% proanthocyanidins and more than 28% flavonoid glycosides. In vitro, HPE effectively scavenged alpha,alpha-diphenyl-beta-picrylhydrazyl, hydroxyl and superoxide anion radicals, and inhibited DNA oxidative damage. In vivo, oral HPE at a polyphenol dose of 200-800 mg kg(-1) body weight significantly prevented a bromobenzene-induced decrease in liver superoxide dismutase and glutathione peroxidase activity, and decreased levels of liver thiobarbituric acid reactive substances in bromobenzene-treated mice. An oral dose of 20-80 mg kg(-1) body weight HPE significantly reduced the frequency of bone marrow micronuclei induced by cyclophosphamide. The antioxidant activities of hop polyphenols in vitro and in vivo were higher than green tea polyphenols at the same concentration. CONCLUSION: Hop polyphenols had the same or higher antioxidant activity than tea polyphenols. Hop polyphenols might be useful as natural antioxidants and antimutagens. PMID- 24338211 TI - A rare infectious presentation of a temporal bone meningioma. PMID- 24338212 TI - Intrafamilial phenotypic variability in families with biallelic SLC26A4 mutations. AB - OBJECTIVES/HYPOTHESIS: Enlarged vestibular aqueduct (EVA) and hearing loss are known to be caused by SLC26A4 mutations, but large phenotypic variability exists among patients with biallelic SLC26A4 mutations. Intrafamilial phenotypic variability was analyzed in multiplex EVA families carrying biallelic SLC26A4 mutations to identify the contribution of SLC26A4 mutations and other genetic or environmental factors influencing the clinical manifestations. STUDY DESIGN: Retrospective case series. METHODS: Eleven multiplex Korean families with EVA and hearing loss that carry biallelic mutations of the SLC26A4 gene were included. Genetic analysis for SLC26A4 and other genes including FOXI1, FOXI1-DBD, and KCNJ10 was performed. The auditory and other phenotypes were compared among siblings with the same SLC26A4 mutations. RESULTS: The difference in the auditory phenotypes was identified between siblings in approximately half of the EVA families. Families with SLC26A4 mutations other than H723R homozygous mutations demonstrated more phenotypic variability, especially in those carrying IVS7-2A>G splice site mutation. Cochlear malformation was a consistent finding among siblings with the same SLC26A4 mutations. No mutation was identified in the FOXI1, FOXI1-DBD, and KCNJ10 genes in the tested families. CONCLUSIONS: The possibility of variability concerning auditory phenotype should be considered even within family members carrying the same SLC26A4 mutations when providing genetic counseling to multiplex EVA families. Mutations in the currently known genes associated with EVA other than SLC26A4 were not found to be responsible for the intrafamilial phenotypic variability. Modifier genes or environmental factors other than the currently known genes seem to play a role in the phenotypic expressions of EVA patients. PMID- 24338213 TI - Formation and fragmentation of unsaturated fatty acid [M - 2H + Na]- ions: stabilized carbanions for charge-directed fragmentation. AB - Fatty acids are long-chain carboxylic acids that readily produce [M - H](-) ions upon negative ion electrospray ionization (ESI) and cationic complexes with alkali, alkaline earth, and transition metals in positive ion ESI. In contrast, only one anionic monomeric fatty acid-metal ion complex has been reported in the literature, namely [M - 2H + Fe(II)Cl](-). In this manuscript, we present two methods to form anionic unsaturated fatty acid-sodium ion complexes (i.e., [M - 2H + Na](-)). We find that these ions may be generated efficiently by two distinct methods: (1) negative ion ESI of a methanolic solution containing the fatty acid and sodium fluoride forming an [M - H + NaF](-) ion. Subsequent collision-induced dissociation (CID) results in the desired [M - 2H + Na](-) ion via the neutral loss of HF. (2) Direct formation of the [M - 2H + Na](-) ion by negative ion ESI of a methanolic solution containing the fatty acid and sodium hydroxide or bicarbonate. In addition to deprotonation of the carboxylic acid moiety, formation of [M - 2H + Na](-) ions requires the removal of a proton from the fatty acid acyl chain. We propose that this deprotonation occurs at the bis-allylic position(s) of polyunsaturated fatty acids resulting in the formation of a resonance-stabilized carbanion. This proposal is supported by ab initio calculations, which reveal that removal of a proton from the bis-allylic position, followed by neutral loss of HX (where X = F(-) and (-)OH), is the lowest energy dissociation pathway. PMID- 24338214 TI - Interventions for promoting physical activity in people with cystic fibrosis. AB - BACKGROUND: In individuals with cystic fibrosis there are no established targets for participation in physical activity, nor have any ideal strategies to promote participation in physical activity been identified OBJECTIVES: To evaluate the effect of treatment to increase participation in physical activity in people with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register using the terms 'physiotherapy and exercise'.Date of the most recent search: 05 December 2013.Additionally, we conducted searches of the electronic databases MEDLINE, CINAHL (Ebscohost), PsycINFO (OvidSP) and the Physiotherapy Evidence Database (PEDro). We also searched for potentially relevant, completed but unpublished studies, on several clinical trials registers.Date of the most recent searches: 10 September 2012. SELECTION CRITERIA: All randomised and quasi-randomised controlled studies which investigated strategies designed to promote increased participation in daily physical activity for individuals with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion, assessed the risk of bias and extracted data. Any disagreements were resolved by discussion and consensus, or in arbitration with a third author. MAIN RESULTS: Four studies (199 participants) met the inclusion criteria and were predominantly conducted in children with cystic fibrosis. Only one study had a combined cohort of adult and paediatric participants. The description of study methods was inadequate to assess the risk of bias, particularly with regard to blinding of assessors and selective reporting. One study was conducted in an inpatient setting with follow up in the outpatient setting; while the remaining three studies were conducted in individuals with stable respiratory disease in the outpatient setting. All included studies used exercise training to promote participation in physical activity, with the duration of the intervention period ranging from 18 days to three years. No improvement in physical activity participation was reported with any intervention period less than or equal to six months. Improvements in physical activity participation were only seen where follow up occurred beyond 12 months. There was no significant impact on quality of life from any of the intervention strategies. AUTHORS' CONCLUSIONS: Although participation in physical activity is generally regarded as beneficial for people with cystic fibrosis, there is a lack of evidence regarding strategies to promote the uptake and the continued participation in physical activity for this population. This review provides very limited evidence that activity counselling and exercise advice, undertaken over at least six months, to engage in a home exercise programme may result in improved physical activity participation in people with cystic fibrosis. Further research is needed to determine the effect of strategies such as health coaching or telemedicine applications, in promoting the uptake and adherence to regular participation in physical activity. In addition, establishing the ideal duration of any interventions that promote physical activity, including exercise training programmes, will be important in addressing issues relating to participation in physical activity for people with cystic fibrosis. PMID- 24338215 TI - Frequent epigenetic inactivation of RSK4 by promoter methylation in cancerous and non-cancerous tissues of breast cancer. AB - Breast cancer is one of the most common cancers and is the second leading cause of cancer-related death in women worldwide. Ribosomal s6 kinase4 (RSK4) is a potential tumor suppressor in multiple cancers, while its role in breast cancer is largely unknown. Our study here aimed to explore the relationship between RSK4 expression with the clinicopathologic characteristics and the promoter methylation status of RSK4. Real-time PCR and bisulfite sequencing PCR were, respectively, used to detect the expression difference of RSK4 mRNA and RSK4 methylation in the 49 breast cancer and paired non-cancerous samples. The associations of RSK4 expression and methylation status with the clinicopathologic characteristics were analyzed. In the 49 breast cancer patients' specimens, RSK4 mRNA expression was found to be significantly decreased in most of breast cancer tissues compared with paired non-cancerous tissues (p = 0.002), which was largely due to the promoter hypermethylation (p = 0.005). Frequency of RSK4 promoter methylation in breast cancers was significantly higher than paired non-cancerous tissues (p = 0.009); RSK4 methylation was not associated with all clinicopathological features. The silencing of RSK4 due to promoter hypermethylation is a frequent event in breast cancer. The majority of cancers have a higher level of methylation status when compared with non-cancerous tissues. RSK4 may be a valuable biomarker for the study of breast cancer carcinogenesis and progression. PMID- 24338216 TI - Methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms in chronic myeloid leukemia: an Egyptian study. AB - Methylenetetrahydrofolate reductase (MTHFR) gene plays a pivotal role in folate metabolism. Several genetic variations in MTHFR gene as MTHFR-C677T and MTHFR A1298C result in decreased MTHFR activity, which could influence efficient DNA methylation and explain susceptibility to different cancers. The etiology of chronic myeloid leukemia (CML) is obscure and little is known about individual's susceptibility to CML. In order to assess the influence of these genetic polymorphisms on the susceptibility to CML and its effect on the course of the disease among Egyptians, we performed an age-gender-ethnic matched case-control study. The study included 97 CML patients and 130 healthy controls. Genotyping of MTHFR-C677T and -A1298C was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The results showed no statistical difference in the distribution of MTHFR-C677T and -A1298C polymorphic genotypes between CML patients and controls. The frequency of MTHFR 677-TT homozygous variant was significantly higher in patients with accelerated/blastic transformation phase when compared to those in the chronic phase of the disease. In conclusion, our study revealed that MTHFR-C677T and -A1298C polymorphisms could not be considered as genetic risk factors for CML in Egyptians. However, MTHFR 677-TT homozygous variant might be considered as a molecular predictor for disease progression. PMID- 24338217 TI - Association of single nucleotide polymorphisms in MTHFR and ABCG2 with the different efficacy of first-line chemotherapy in metastatic colorectal cancer. AB - Either oxaliplatin- or irinotecan-containing regimen could receive a good effectiveness in patients with metastatic colorectal cancer as the first-line chemotherapy, but not all patients would benefit from the treatment they have received. This study was to investigate the role of single nucleotide polymorphisms (SNPs) of methylenetetrahydrofolate reductase (MTHFR) and ATP binding cassette sub-family G member 2 (ABCG2) in selecting the most appropriate treatment for individual patients. Ninety-two metastatic colorectal cancer patients treated with first-line 5-fluoropyrimidine (5-FU), leucovorin, and oxaliplatin (FOLFOX), capecitabine, and oxaliplatin (XELOX) and sixty-two patients receiving 5-FU, leucovorin, and irinotecan (FOLFIRI) were reviewed. The SNPs of MTHFR and ABCG2 were detected using gene sequencing method after DNA PCR amplification, which was extracted from peripheral blood karyocytes. Clinical characteristics and gene polymorphisms were evaluated in univariate and multivariate analysis as predictive factors for response rate (RR) and progression-free survival (PFS). In patients bearing 2-4 genotypes of MTHFR 677C/C, MTHFR 1298 A/C or C/C, ABCG2 34G/G, and ABCG2 421C/A or A/A, those who received oxaliplatin-based chemotherapy achieved a higher RR (41.7 vs. 18.8 %, P = 0.027) and longer median PFS (mPFS) than irinotecan-based therapy [8.9 vs. 7.1 m, FOLFIRI: hazard ratio (HR) = 1.722, 95 % confidence interval (CI) 1.026-2.892, P = 0.040, compared with FOLFOX/XELOX]; on the contrary, patients carrying 0 or 1 above genotype exhibited better outcomes after receiving FOLFIRI chemotherapy (mPFS: 9.3 vs. 6.4 m, FOLFIRI: HR = 0.422, 95 % CI 0.205-0.870, P = 0.019, compared with FOLFOX/XELOX). Combination of SNPs with MTHFR and ABCG2 may play a role in helping clinicians to select first-line chemotherapy for patients with metastatic colorectal cancer. PMID- 24338218 TI - Hypoxia-inducible factor-1alpha and its role in the proliferation of retinoblastoma cells. AB - In order to better understand the role of HIF-1alpha in the proliferation of the retinoblastoma cells, a siRNA knockdown of HIF-1alpha followed by a proliferation assay was performed. Further sequencing was then carried out in order to assess knockdown efficiency and expression of HIF-1alpha. Upregulation of HIF-1alpha gene expression in CoCl2-treated retinoblastoma cells was demonstrated via melting curve analysis from PCR tests and was further analyzed using western blot and densitometry analysis. Reduction of HIF-1alpha expression in retinoblastoma, post HIF-1alpha knockdown, was observed after siRNA transfection into Y-79 cells. Knockdown of HIF-1alpha resulted in a significant decrease in proliferation thereby demonstrating that HIF-1alpha is involved in promoting survival and proliferation in retinoblastoma cells. Stabilization of HIF-1alpha in retinoblastoma cells using CoCl2 was unsuccessful. PMID- 24338219 TI - Functional and quality-of-life outcomes after reirradiation for head and neck cancer. AB - OBJECTIVES/HYPOTHESIS: To examine functional and quality-of-life outcomes for patients treated by reirradiation to the head and neck for recurrent or new primary cancers. STUDY DESIGN: Retrospective review. METHODS: The University of Washington Quality of Life Instrument (UW-QOL) scores were reviewed with swallow evaluations for 17 patients with biopsy-proven recurrent or new primary squamous cell carcinoma of the head and neck treated with reirradiation who were clinically without evidence of disease at a minimum follow-up of 1 year. All patients had received their initial radiation therapy to a median dose of 66 Gy (range, 60-72 Gy). The median interval between radiation courses was 30 months (range, 6-132 months). The median reirradiation dose was 60 Gy (range, 54-70 Gy). RESULTS: At 1 year after reirradiation, the mean UW-QOL composite score was 67.0 (range, 22.1-83.5), which did not differ significantly from baseline (P = .57). The proportion of patients who rated their global quality of life as "very good" or "outstanding" at 1 year after reirradiation was 35%. The percentage of patients who reported their global quality of life as "good/fair" and "poor/very poor" were 59% and 6%, respectively. CONCLUSIONS: The majority of survivors in this highly selected series were devoid of new impairment after reirradiation and were satisfied with their functional status. Although nearly all patients had side effects from their prior radiation course prior to reirradiation, no patient reported a decline in global quality of life from before reirradiation to 1 year post-treatment. PMID- 24338220 TI - Adverse effects of clozapine in older patients: epidemiology, prevention and management. AB - Research into the use of clozapine in older people is somewhat scarce. Clozapine is associated with serious adverse effects such as agranulocytosis, seizures, myocarditis and metabolic syndrome. Other common undesirable effects such as sedation, constipation (which can be fatal), urinary incontinence and hypersalivation further limit its use. These adverse effects are particularly important for the use of clozapine in older people, who are generally more susceptible to medication-related adverse effects. Whilst clozapine should be used with caution in elderly people, strict monitoring procedures can help to prevent harmful effects through early detection, and certain management techniques exist to minimise them. This review outlines the epidemiology of clozapine-related adverse effects in older people and discusses potential prevention and management strategies. PMID- 24338222 TI - Listeria monocytogenes protein fraction induces dendritic cells maturation and T helper 1 immune responses. AB - Fully mature dendritic cells (DCs) play pivotal role in inducing immune responses and converting naive T lymphocytes into functional Th1 cells. We aimed to evaluate Listeria Monocytogenes-derived protein fractions to induce DC maturation and stimulating T helper (Th)1 immune responses.In the present study, we fractionated Listeria Monocytogenes-derived proteins by adding of ammonium sulfate in a stepwise manner. DCs were also generated from C57BL/6 mice bone marrow precursor cells. Then, the effects of protein fractions on bone marrow derived DC (BMDC) maturation were evaluated. In addition, we assessed the capacity of activated DCs to induce cytokine production and proliferation of lymphocytes.Listeria-derived protein fractions induced fully mature DCs expressing high costimulatory molecules such as CD80, CD86 and CD40. DCs that were activated by selected F3 fraction had low capacity to uptake exogenous antigens while secreted high levels of Interleukine (IL)-12. Moreover, lymphocytes cultured with activated BMDCs produced high amounts of IFN-gamma and showed higher proliferation than control. Listeria derived protein fractions differently influenced DC maturation.In conclusion, Listeria protein activated BMDCs can be used as a cell based vaccine to induce anti-tumor immune responses. PMID- 24338221 TI - Changes in microglial inflammation-related and brain-enriched MicroRNAs expressions in response to in vitro oxygen-glucose deprivation. AB - Microglia plays important role in central nervous system immune surveillance and has emerged as an essential cellular component for understanding brain diseases. MicroRNAs (miRs) are small, noncoding RNAs that regulate the post-transcriptional expression of protein-coding mRNAs, which may have key roles in microglial activation in response to brain ischemia and other stressors. Primary cultured rat microglial cells were prepared, and then microglial activation model was established by oxygen-glucose deprivation (OGD) method. Morphological observation, CD11b/c immunofluorence, MTT assay and Propidium iodide staining were done to test microglia viability at different OGD time points (0, 5, 10, 15, 30, 60 min). qPCR were performed to detect the dynamic changes in expressions of inflammation-related miRs (146a, 21, 181a, 221, and 222) and brain-enriched miRs (124, 134, 9, 132, and 138) in resting microglia and after challenge with OGD for the same time points. The activation and viability of the microglia was time dependent. Similarly, expressions of different miRs in microglia were significantly upregulated and reached the peak at different time points before reaching the baseline level with extension of OGD. Our data demonstrates for the first time that OGD as a model of an ischemic insult modulates the expressions of some inflammation-related and brain-enriched miRs. These changes may help to explore the molecular basis of microglia activation on the post-transcriptional level in response to different time points of OGD. PMID- 24338223 TI - Rosiglitazone inhibits HMC-1 cell migration and adhesion through a peroxisome proliferator-activated receptor gamma-dependent mechanism. AB - Mast cells play an important role in a variety of inflammatory diseases, particularly asthma and atopy. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the large nuclear hormone receptor transcription factor superfamily, and has been recently implicated in the anti-inflammatory response. To investigate a possible role for PPARgamma in human mast cells, we studied the effects of a PPARgamma ligand, rosiglitazone (RG), on stem cell factor (SCF)-induced migration and fibronectin-induced adhesion in human mast cell-1(HMC-1) cells. It was found that HMC-1 cells expressed PPARgamma mRNA. RG inhibited SCF-induced HMC-1 cell migration and fibronectin-induced HMC-1 cell adhesion, the selective PPARgamma antagonist GW9662 prevented the inhibitory effect of RG on HMC-1 cells. In conclusion, RG inhibits the migration and adhesion of HMC-1 cells by a PPARgamma-dependent mechanism. PMID- 24338224 TI - Lack of association between single nucleotide polymorphism rs10818488 in TRAF1/C5 region and rheumatoid arthritis in iranian population. AB - The association of rs10818488 SNP located in TRAF1/C5 region with Rheumatoid Arthritis (RA), has been picked up by genome-wide association studies. Independent studies in different populations revealed inconsistent results. The aim of this study was to investigate the possible association of this SNP with RA in Iranian population. A total of 362 cases and 422 healthy controls were recruited in this study. Genomic DNA was extracted from whole blood and the genotyping was performed by PCR-RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism). A set of genotypes was confirmed by sequencing. Genotype and allele frequencies were compared between the case and control groups. Analysis indicated a higher frequency of A allele in cases, although the difference was not statistically significant (Chi-square=2.8, p=0.09). Comparison of genotype frequencies, revealed higher frequencies of AA and AG genotypes in case group but statistically the difference was not significant (Chi-square=2.72, p=0.25). These findings suggest that the rs0818488 in TRAF1/C5 region is not associated with rheumatoid arthritis in Iranian population. PMID- 24338225 TI - Comparison of immunomodulating properties of Beta-lactoglobulin and its hydrolysates. AB - Cow's milk allergy is one of the most common food allergies in childhood. Beta lactoglobulin (beta- lg) is a dominant allergen in cow's milk. Hydrolysis is known as an effective method to reduce the allergenicity of proteins. Thus, the objective of this study was to compare the allergenicity of beta-lg and its hydrolysates using an animal model. Twenty four BALB/c mice were divided into three groups and subcutaneously injected with native bovine beta-lg and its hydrolysates on days 0, 7 and 14. During the sensitization period, a number of systemic anaphylactic indicators were observed in mice sensitized by beta-lg compared to those sensitized by hydrolysates of beta-lg. Mice sensitized by hydrolysates of beta-lg showed a significantly lower spleen lymphocyte proliferation level than that sensitized by intact beta-lg. Antibody levels of beta-lg-specific IgE in serum induced by native beta-lg were significantly high. Plasma histamine levels were also evaluated and showed the same trend as IgE. Moreover, the hydrolysates of beta-lg significantly down-regulated IL-4 and IL-5 secretions in serum. These results suggested that enzymatic hydrolysis could reduce the allergenicity of beta-lg. PMID- 24338226 TI - Significant changes of 5-Hydroxytriptamine 3A receptor gene expression in peripheral blood mononuclear cells of allergic asthmatic patients. AB - Asthma is a chronic inflammatory disorder of the airways. The stress is a factor for asthma which indicates a disorder in the function of communicational mediators of nervous and immunological systems such as neurotransmitters. A study indicated that blood serotonin concentration increases in asthmatic patients. Other study indicates that one kind of the serotonin receptors, named 5HT3A, on PBMCs causes secretion of series of pro-inflammatory cytokines which play important roles in allergic asthma disease. Thus, we evaluated the ratio expression level of 5HT3A subtype receptors in asthma. The Peripheral Blood Mononuclear Cells were separated from whole blood of 30 allergic asthmatic patients and 30 normal controls by a gradient density centrifugation technique, then the total cellular RNA was extracted and the cDNA was synthesized. This process was followed by real-time PCR using primer pairs specific for 5 hydroxytryptamine 3A subtype receptor mRNA and beta-actin as internal control. Results revealed that relative gene expression of 5-hydroxytryptamine 3A subtype receptor increased significantly in Peripheral Blood Mononuclear Cells of patients with asthma in comparison with normal individuals. To conclude, considering 5-hydroxytryptamine 3A subtype receptor role in accomplishment of asthma symptoms, this increase in its expression may exacerbate the seriousness of asthma disease. PMID- 24338227 TI - Chronic aspiration of gastric and duodenal contents and their effects on inflammatory cytokine production in respiratory system of rats. AB - Gastroesophageal reflux disease (GERD) is defined with clinical symptoms of heart burning and regurgitation. It may be associated with external esophageal symptoms such as chronic cough, asthma, laryngitis, chronic lung disease, sinusitis and pulmonary fibrosis. In the present study, rats with chronic aspiration of gastroduodenal contents were studied for cellular phenotypes and cytokine concentrations in bronchoalveolar lavage and lung tissue. Thirty-six male Albino N-MRI rats were randomly divided into six groups. After anesthesia and tracheal intubation, the animals received either 0.5ml/kg of normal saline (control), gastric juice, pepsin, hydrochloric acid or bile salts by injection into their lungs twice a week for 8 weeks. In sham group nothing was injected. Thereafter, cellular phenotypes and cytokine concentrations of Interleukine (IL)-1alpha, IL 1beta, Transforming Growth Factor (TGF)-beta, Tumor Necrosis Factor (TNF)-alpha, and IL-6 were assessed in bronchoalveolar lavage and lung tissue homogenates. The numbers of epithelial cells, macrophages, neutrophils and lymphocytes in BAL and levels of cytokines IL-1alpha, IL-6, TNF-alpha and TGF-beta in BAL and lung tissue of test groups were significantly higher than the control group. Aspiration of bile salts caused more cytokine levels and inflammatory cells compared to other reflux components. It can be concluded that GERD with increased cytokines and inflammatory cells in lung could cause or exacerbate asthma and pulmonary fibrosis. PMID- 24338228 TI - The effect of personality disorders on asthma severity and quality of life. AB - Assesment of health related quality of life (HRQL) is increasingly recognized as an important part of the patient care in asthma. We aimed to evaluate the effect of personality disorders (PDs) on HRQL and the severity of disease in asthmatic patients. Ninety seven consecutive patients with asthma and ninety healthy controls were included. All patients completed a Short Form-36 health survey (SF 36) and Structured Clinical Interview Form for DSM-III-R Axis-II Disorders (SCID II). All SF-36 questionnaire scores of asthmatic patients were significantly lower than the controls. There were statistical differences between the asthma severity and the mean scores of vitality and emotional role difficulties of HRQL's subdomains (p=0.03, p=0.014, respectively). There was a weak but statistically significant correlation between the scores of pain and emotional role difficulties, and forced expiratory volume in 1 second (FEV1) (r=0.27, p=0.007; r=0.24, p=0.01, respectively). When compared to healthy controls, patients with asthma had higher prevalence of PDs (p=0.0001). The most common PDs found in asthmatic patients were obsessive-compulsive and avoidant PDs. HRQL values of asthma patients with PDs were significantly lower than patients without PDs except for the physical functioning subscores on HRQL. We conclude that patients with asthma have higher prevalence of PDs, which is associated with their poor quality of life. A psychiatric evaluation may be beneficial in patients with asthma if a concomitant PD is suspected. PMID- 24338229 TI - Assessment of the quality of life in patients with bronchial asthma, before and after yoga: a randomised trial. AB - Yoga which is used as an adjunct treatment for bronchial asthma is gaining popularity throughout the world. The objective of this study was to assess the effect of yoga on quality of life in patients with bronchial asthma. 120 non smoking male and female patients of asthma in the age group of 17-50 years were randomized into two groups i.e. Group A (Yoga group) and Group B (control group). All patients remained on their prescribed medication, but Group A patients practiced yoga breathing exercises for 8 weeks. Asthma Quality of Life Questionnaire (AQLQ) and diary record was used to assess quality of life, number and severity of asthmatic attacks, and the dosage of the medication required at baseline and after 8 weeks. Group A subjects showed a statistically significant improvement in "symptoms", "activities" and "environmental" domains of AQLQ at 8 weeks (p<0.01) and significant reduction in daily number and severity of attacks, and the dosage of medication required at 4 and 8 weeks (p<0.01) compared to the baseline. Yoga breathing exercises used adjunctively with standard pharmacological treatment significantly improved quality of life in patients with bronchial asthma. PMID- 24338230 TI - Prenatal diagnosis of leukocyte adhesion deficiency type-1 (five cases from iran with two new mutations). AB - Leukocyte adhesion deficiency type-1(LAD-1) is one of the immunodeficiency autosomal recessive diseases that results from mutation in integrin, beta 2 (complement component 3 receptor 3 and 4 subunit) ITGB2 gene. The aim of this study was to investigate molecular prenatal diagnosis of LAD-1. Four pregnant women with five fetuses (one pregnancy was twin) with clinical and laboratory diagnosis of LAD-1 in their previous children were studied. The chorionic villus sampling (CVS) was obtained when mothers were in 10-12th weeks of gestation. Mutation analysis of ITGB2 gene for affected children revealed 3 misssense mutations (c.382G>A, a novel mutation, c.2146G>C, and c.715G>A) and one splice site novel mutation (c.1877+2G>A). All of Parents were heterozygous for these mutations. Consideration of affected gene regions for five CVS samples showed two homozygotes and one heterozygote for mutant allele and two homozygotes for normal allele. Interestingly, one of the twin fetuses was affected and another was normal. Briefly, two cases of CVS samples were affected and three cases of remained CVS samples were unaffected.This is the first report of prenatal diagnosis of LAD-1 from Iran with two new mutations that can be used for genetic and prenatal diagnosis for all patients suspected to LAD1 and can be helpful to prevent the birth of affected children with LAD-1. This abstract presented in the second international congress of Immunology, Asthma and Allergy, Tehran, Iran 2013. PMID- 24338231 TI - Disseminated aspergillosis as the herald manifestation of chronic granulomatous disease in an adult patient. AB - Chronic granulomatous disease is an inherited defect in intracellular killing of ingested microorganisms characterized by recurrent life threatening bacterial and fungal infections including invasive aspergillosis in early childhood. We report a disseminated aspergillosis as the representative of adult onset chronic granulomatous disease without previous infection, with dramatic response to combination of antifungal and interferon therapy. PMID- 24338232 TI - Abortion in Iranian legal system: a review. AB - Abortion traditionally means, "to miscarry" and is still known as a problem which societies has been trying to reduce its rate by using legal means. Despite the pregnant women and fetuses have being historically supported; abortion was firstly criminalized in 1926 in Iran, 20 years after establishment of modern legal system. During next 53 years this situation changed dramatically, so in 1979, the time of Islamic Revolution, aborting fetuses before 12 weeks and therapeutic abortion (TA) during all the pregnancy length was legitimate, based on regulations that used medical justification. After 1979 the situation changed into a totally conservative and restrictive approach and new Islamic concepts as "Blood Money" and "Ensoulment" entered the legal debates around abortion. During the next 33 years, again a trend of decriminalization for the act of abortion has been continuing. Reduction of punishments and omitting retaliation for criminal abortions, recognizing fetal and maternal medical indications including some immunologic problems as legitimate reasons for aborting fetuses before 4 months and omitting the fathers' consent as a necessary condition for TA are among these changes. The start point for this decriminalization process was public and professional need, which was responded by religious government, firstly by issuing juristic rulings (Fatwas) as a non-official way, followed by ratification of "Therapeutic Abortion Act" (TAA) and other regulations as an official pathway. Here, we have reviewed this trend of decriminalization, the role of public and professional request in initiating such process and the rule-based language of TAA. PMID- 24338233 TI - Age-related changes in the rate of muscle activation and rapid force characteristics. AB - Declines in muscle size and strength are commonly reported as a consequence of aging; however, few studies have investigated the influence of aging on the rate of muscle activation and rapid force characteristics across the lifespan. This study aims to investigate the effects of aging on the rate of muscle activation and rapid force characteristics of the plantar flexors. Plantar flexion peak force (PF), absolute (peak, 50, and 100-200 ms), and relative (10 %, 30 %, and 50 %) rate of force development (RFD), the rapid to maximal force ratio (RFD/PF), and the rate of electromyography rise (RER) were examined during an isometric maximal voluntary contraction (MVC) in young (age = 22 +/- 2 years), middle-aged (43 +/- 2 years), and old (69 +/- 5 years) men. The old men exhibited lower PF (30.7 % and 27.6 % lower, respectively) and absolute (24.4-55.1 %) and relative (16.4-28.9 %) RFD values compared to the young and middle-aged men (P <= 0.03). RER values were similar between the young and old men (P >= 0.30); however, RER values were greater for the middle-aged men when compared to the young and old men for the soleus (P < 0.01) and the old men for the medial gastrocnemius (P <= 0.02). Likewise, RFD/PF ratios were similar between young and old men (P >= 0.26); however, these ratios were greater for the middle-aged men at early (P <= 0.03), but not later (P >= 0.10), time intervals. The lower PF and absolute and relative RFD values for the old men may contribute to the increased functional limitations often observed in older adults. Interestingly, higher rates of muscle activation and greater early RFD/PF ratios in middle-aged men may be a reflection of physiological alterations in the neuromuscular system occurring in the fifth decade. PMID- 24338234 TI - Lone aspiration thrombectomy without stenting for a patient with ST-segment elevation myocardial infarction associated with coronary ectasia. AB - A 57-year-old male with a previous history of inferior myocardial infarction suffered from chest pain and diagnosed as ST-segment elevation myocardial infarction (STEMI). Coronary angiography revealed a thrombus with delayed filling in the distal right coronary artery. After an aspiration thrombectomy, TIMI 3 flow was restored successfully. An intracoronary ultrasound imaging revealed coronary ectasia. Stenting and ballooning were deferred. A successful lone aspiration thrombectomy was performed for a patient with STEMI associated with coronary ectasia. PMID- 24338235 TI - Exposure to road traffic and railway noise and postmenopausal breast cancer: A cohort study. AB - Exposure to traffic noise may result in stress and sleep disturbances. Studies on self-reported sleep duration and breast cancer risk have found inconsistent results. In a population-based Danish cohort of 29,875 women aged 50-64 years at enrolment in 1993-1997, we identified 1219 incident, postmenopausal breast cancer cases during follow-up through 2010. Mean follow-up time was 12.3 years. Road traffic and railway noise was calculated for all present and historical residential addresses from 1987 to 2010. We used Cox proportional hazard model for analyses and adjusted for hormone replacement therapy use, parity, alcohol consumption and other potential confounders. We found no overall association between residential road traffic or railway noise and breast cancer risk. Among women with estrogen receptor negative breast cancer, a 10-dB higher level of road traffic noise (continuous scale) during the previous 1, 5 and 10 years were associated with 28% (95% CI: 1.04-1.56), 23% (95% CI: 1.00-1.51) and 20% (95% CI: 0.97-1.48) higher risks of estrogen receptor negative breast cancer, respectively, in fully adjusted models. Similarly, a 10-dB increase in railway noise (1-year mean at diagnosis address) increased risk for estrogen receptor negative breast cancer by 38% (95% CI: 1.01-1.89). There was no association between road traffic or railway noise and estrogen receptor positive breast cancer. In conclusion, these results suggest that residential road traffic and railway noise may increase risk of estrogen receptor negative breast cancer. As the first study on traffic noise and breast cancer results should be treated with caution. PMID- 24338236 TI - Comparison of surgical completeness between robotic total thyroidectomy versus open thyroidectomy. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to investigate the surgical completeness of robotic total thyroidectomy compared with conventional open thyroidectomy. STUDY DESIGN: Retrospective, case-control study. METHODS: We studied 245 patients with papillary thyroid carcinoma who underwent total thyroidectomy and postoperative radioactive iodine (RAI) ablation. Of these, 62 patients underwent robotic thyroidectomy by a gasless unilateral axillo-breast (GUAB) or axillary (GUA) approach, and 183 underwent conventional open thyroidectomy. We analyzed serum TSH-stimulated thyroglobulin (Tg) and RAI uptake at the time of RAI remnant ablation to compare surgical completeness in the two groups. RESULTS: Tumor characteristics and complications did not differ between the two groups except TNM stage. The mean TSH-stimulated Tg at the first RAI ablation was significantly higher in the robotic group (10.20 +/- 9.98 ng/ml) than in the open group (3.85 +/- 6.79 ng/ml) (P <0.001). In subgroup analysis of the robotic group by the period in which operations took place, TSH-stimulated Tg was significantly higher than in the open group in the first (13.28 +/- 11.91 ng/ml) and second (10.45 +/- 9.30 ng/ml) periods, but there was no significant difference in the third period (6.00 +/- 6.26 ng/ml, P = 0.141). The RAI uptake rate at the first RAI ablation did not differ between the two groups, and TSH stimulated Tg after RAI ablation was similar. CONCLUSION: The surgical completeness of robotic total thyroidectomy by a GUAB/GUB approach is comparable to that of open thyroidectomy, if performed by experienced robotic thyroid surgeons in properly selected patients. LEVEL OF EVIDENCE: 3b. Laryngoscope, 124:1042-1047, 2014. PMID- 24338237 TI - Cost and technical efficiency of physician practices: a stochastic frontier approach using panel data. AB - This is the first study to use stochastic frontier analysis to estimate both the technical and cost efficiency of physician practices. The analysis is based on panel data from 3,126 physician practices for the years 2006 through 2008. We specified the technical and cost frontiers as translog function, using the one step approach of Battese and Coelli to detect factors that influence the efficiency of general practitioners and specialists. Variables that were not analyzed previously in this context (e.g., the degree of practice specialization) and a range of control variables such as a patients' case-mix were included in the estimation. Our results suggest that it is important to investigate both technical and cost efficiency, as results may depend on the type of efficiency analyzed. For example, the technical efficiency of group practices was significantly higher than that of solo practices, whereas the results for cost efficiency differed. This may be due to indivisibilities in expensive technical equipment, which can lead to different types of health care services being provided by different practice types (i.e., with group practices using more expensive inputs, leading to higher costs per case despite these practices being technically more efficient). Other practice characteristics such as participation in disease management programs show the same impact throughout both cost and technical efficiency: participation in disease management programs led to an increase in both, technical and cost efficiency, and may also have had positive effects on the quality of care. Future studies should take quality-related issues into account. PMID- 24338239 TI - Gastric adenocarcinoma of the fundic gland type (chief cell predominant type). AB - Gastric adenocarcinoma of the fundic gland (chief cell predominant type, GA-FG CCP) was recently proposed as a new, rare variant of gastric adenocarcinoma. The aim of the current study was to evaluate the endoscopic features of GA-FG-CCP. A total of 10 GA-FG-CCPs were included and evaluated retrospectively. The endoscopic and clinicopathological features of the lesions were analyzed to provide information of diagnostic value. The GA-FG-CCPs were classified into two categories: submucosal tumor shape (60 %) and flat or depressed type (40 %). Endoscopically, the most common features were submucosal tumor shape (60 %), whitish color (70 %), dilated vessels with branching architecture (50 %), and background mucosa without atrophic change (90 %). GA-FG-CCP has distinct endoscopic characteristics, especially in terms of shape, color, vessels, and background mucosa and may be classified into two categories macroscopically. To diagnose GA-FG-CCP correctly by pathological examination of biopsy specimens, these endoscopic features should be taken into consideration. PMID- 24338240 TI - High proximal migration rate of a partially covered "big cup" duodenal stent in patients with malignant gastric outlet obstruction. AB - Endoscopic placement of self-expandable metal stents (SEMS) has emerged as a palliative treatment for patients with malignant gastric outlet obstruction (GOO). Recently, a new partially covered "big cup" SEMS has been developed to prevent both stent migration and tissue ingrowth. The aim of the study was to evaluate safety and efficacy of this SEMS in a cohort of patients with incurable malignant GOO. The study was terminated prematurely due to three proximal stent migrations in six patients. Migrations occurred at 2, 4, and 29 days, respectively, and necessitated endoscopic removal and placement of another SEMS. The remaining three patients had a patent SEMS at the end of follow-up. The high proximal migration rate of this new SEMS should be taken into account when considering routine clinical use in malignant GOO. Further research is warranted in order to find an optimal stent design that prevents both stent migration and tumor ingrowth. PMID- 24338241 TI - Jet injection of dyed saline facilitates efficient peroral endoscopic myotomy. AB - BACKGROUND AND STUDY AIMS: Peroral endoscopic myotomy (POEM) is technically challenging and time consuming. Repeated injection of dyed saline during tunneling is performed to enhance the demarcation between the submucosal layer and the muscularis propria. This process requires exchanging the knife for a catheter to spray dyed saline and is time consuming. This study aimed to describe a new method of injecting dyed saline through an integrated water jet channel during POEM. PATIENTS AND METHODS: POEM was performed using a triangular tip knife. Repeated jet injection of saline mixed with indigo carmine was performed whenever the submucosal dissection plane became unclear. RESULTS: The study cohort consisted of nine patients (8 achalasia, 1 Jackhammer esophagus). All procedures were technically feasible and successful without any complications and resulted in the patients' Eckhardt's scores returning to normal. The mean submucosal tunnel length was 13.3 cm and the mean myotomy length was 9.9 cm. The mean procedure time was 127 minutes. CONCLUSION: The modified POEM technique with use of jet injection of dyed saline is simple and may render POEM easier and more efficient than the standard dissection method. PMID- 24338242 TI - Capnographic monitoring of propofol-based sedation during colonoscopy. AB - BACKGROUND AND STUDY AIMS: Capnography enables the measurement of end-tidal CO2 and thereby the early detection of apnea, prompting immediate intervention to restore ventilation. Studies have shown that capnographic monitoring is associated with a reduction of hypoxemia during sedation for endoscopy and early detection of apnea during sedation for colonoscopy. The primary aim of this prospective randomized study was to evaluate whether capnographic monitoring without tracheal intubation reduces hypoxemia during propofol-based sedation in patients undergoing colonoscopy. PATIENTS AND METHODS: A total of 533 patients presenting for colonoscopy at two study sites were randomized to either standard monitoring (n = 266) or to standard monitoring with capnography (n = 267). The incidence of hypoxemia (SO2 < 90 %) and severe hypoxemia (SO2 < 85 %) were compared between the groups. Furthermore, risk factors for hypoxemia were evaluated, and sedation performed by anesthesiologists was compared with nurse administered propofol sedation (NAPS) or endoscopist-directed sedation (EDS). RESULTS: The incidence of hypoxemia was significantly lower in patients with capnography monitoring compared with those receiving standard monitoring (18 % vs. 32 %; P = 0.00091). Independent risk factors for hypoxemia were age (P = 0.00015), high body mass index (P = 0.0044), history of sleep apnea (P = 0.025), standard monitoring group (P = 0.000069), total dose of propofol (P = 0.031), and dose of ketamine (P < 0.000001). Patients receiving anesthesiologist-administered sedation developed hypoxemic events more often than those receiving NAPS or EDS. In patients with anesthesiologist-administered sedation, sedation was deeper, a combination of sedative medication (propofol, midazolam and/or ketamine) was administered significantly more often, and sedative doses were significantly higher compared with patients receiving NAPS or EDS. CONCLUSIONS: In patients undergoing colonoscopy during propofol-based sedation capnography monitoring with a simple and inexpensive device reduced the incidence of hypoxemia. PMID- 24338244 TI - Sensory analysis and consumer acceptance of 140 high-quality extra virgin olive oils. AB - BACKGROUND: Sensory analysis is a crucial tool for evaluating the quality of extra virgin olive oils. One aim of such an investigation is to verify if the sensory attributes themselves - which are strictly related to volatile and phenolic compounds - may permit the discrimination of high-quality products obtained by olives of different cultivars and/or grown in various regions. Moreover, a crucial topic is to investigate the interdependency between relevant parameters determining consumer acceptance and objective sensory characteristics evaluated by the panel test. RESULTS: By statistically analysing the sensory results, a grouping - but not discriminatory - effect was shown for some cultivars and some producing areas. The preference map shows that the most appreciated samples by consumers were situated in the direction of the 'ripe fruity' and 'sweet' axis and opposite to the 'bitter' and 'other attributes' (pungent, green fruity, freshly cut grass, green tomato, harmony, persistency) axis. CONCLUSION: Extra virgin olive oils produced from olives of the same cultivars and grown in the same areas shared similar sensorial attributes. Some differences in terms of expectation and interpretation of sensory characteristics of extra virgin olive oils might be present for consumers and panellists: most of the consumers appear unfamiliar with positive sensorial attributes, such as bitterness and pungency. PMID- 24338243 TI - Anthropometric measures and cognition in middle-aged HIV-infected and uninfected women. The Women's Interagency HIV Study. AB - This study aimed to explore the relationship of body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) with cognition in women with (HIV+) and without HIV (HIV-) infection. One thousand six hundred ninety participants (1,196 HIV+, 494 HIV-) in the Women's Interagency HIV Study (WIHS) with data available on anthropometric measures comprise the analytical sample. Cross-sectional analyses using linear regression models estimated the relationship between anthropometric variables and Trails A, Trails B, Stroop interference time, Stroop word recall, Stroop color naming and reading, and Symbol Digit Modalities Test (SDMT) with consideration for age, HIV infection status, Wide Range Achievement Test score, CD4 count, insulin resistance, drug use, and race/ethnicity. Among HIV+ women, BMI < 18.5 kg/m(2) was associated with poorer cognitive performance evidenced by longer Trails A and Trails B and shorter SDMT completion times. An obese BMI (30 kg/m(2) or higher) was related to better performance on Trails B and worse performance on the Stroop interference test. Among HIV- women, an obese BMI was related to worse performance on the Stroop color naming test. Few and inconsistent associations were observed between WC, WHR, and cognition. Among women at mid-life with chronic (at least 10 years) HIV infection, common anthropometric measures, primarily BMI, were differentially related to cognitive test performance by cognitive domain. Higher levels of BMI were associated with better cognitive function. In this era of antiretroviral therapies, restoration of health evidenced as higher BMI due to effective antiretroviral therapies, may improve cognitive function in middle-aged HIV infected women. PMID- 24338245 TI - Low prevalence of K-RAS, EGF-R and BRAF mutations in sinonasal adenocarcinomas. Implications for anti-EGFR treatments. AB - We have previously shown that a subset of sinonasal intestinal-type adenocarcinomas (ITAC) shows activation of the epidermal growth factor-receptor (EGFR) pathway. In this study we examine the status of the EGFR, KRAS and BRAF genes in a series of sinonasal intestinal (ITAC) and non-intestinal type adenocarcinomas (non-ITAC). Eighteen ITACs and 12 non-ITACs were studied immunohistochemically for EGFR expression. Point mutations were analyzed for EGFR exons 19 and 21, KRAS exon 2 and BRAF exon 15 by direct sequencing. Non-ITACs showed significantly higher expression of EGFR (p = 0.015). Mutation analysis revealed one ITAC with EGFR and one ITAC with KRAS mutation, while two non-ITACs presented mutation of BRAF. We conclude that a subset of sinonasal adenocarcinomas shows overexpression of EGFR, while activating mutations of the signaling cascade downstream of EGFR are rare, suggesting that these tumors could be good candidates for anti-EGFR therapies. PMID- 24338246 TI - In response to simultaneous pericranial and nasoseptal flap reconstruction of anterior skull base defects following endoscopic-assisted craniofacial resection. PMID- 24338247 TI - Global and local brain network reorganization in attention-deficit/hyperactivity disorder. AB - Brain is a complex network with an anatomical and functional organization. The differences in brain organization of those with attention-deficit/hyperactivity disorder (ADHD) are still not well understood. Here, we study brain organization in ADHD subjects using a complex network derived from resting-state functional magnetic resonance imaging (fMRI) data of ADHD and normal subjects. Our results reveal that the brain networks of ADHD subjects are reorganized compared to those without ADHD in global and local brain functional networks. We find that the ADHD subjects show decreasing brain network integration and increasing brain network segregation. More interestingly, we find similarities of brain topology properties between local and global brain networks. Our finding indicates that cognitive dysfunction in ADHD is probably associated with disrupted global and local brain network topological properties. Our results can help us understand the pathophysiological mechanism of ADHD and serve as a sensitive and specific biomarker of ADHD. PMID- 24338248 TI - Downregulation of T-bet/GATA-3 ratio induced by IL-11 treatment is responsible for Th1/Th2 balance restoration in human immune thrombocytopenic purpura (ITP). AB - Abnormal cellular immunity induced by deranged Th1/Th2 profile has been revealed to play a critical role in the pathogenesis of immune thrombocytopenic purpura (ITP). Correction of the shifted Th1/Th2 balance represents a potential therapeutic approach to treat ITP. Here, we investigated the effects of IL-11 on the restoration of Th1/Th2 balance in the peripheral blood mononuclear cells (PBMCs) isolated from adult ITP patients. As shown here, we observed a higher ratio of T-bet/GATA-3 gene expression by quantitative real-time PCR in the PBMCs from ITP patients, consistent with the presence of an abnormally high Th1/Th2 ratio. Remarkably, upon IL-11 treatment, a reversal of T-bet/GATA-3 ratio in ITP was achieved and was shown to be responsible for the restoration of Th1/Th2 balance, with IL-11 at 100 ng/ml demonstrating the highest efficiency. T-bet and GATA-3 are the two transcriptional factors that have been indicated to be the master regulators for Th1 and Th2 lineage commitment, respectively. In the presence of 100 ng/ml IL-11, GATA-3 transcript abundance rose up to ~85-fold of that measured in untreated cells, whereas T-bet transcripts were lowered merely to ~41%, suggesting that GATA-3 was the major contributor for the reversal of T bet/GATA-3 ratio. Thus, our findings may very well encourage the development of novel medicines that specifically target and correct the T-bet/GATA-3 imbalance identified in ITP. PMID- 24338249 TI - Portal vein thrombosis after laparoscopic splenectomy during childhood. AB - Portal vein thrombosis (PVT) is a rare but potentially life-threatening complication of laparoscopic splenectomy (LS) and can lead to bowel ischemia or portal hypertension. In childhood, this complication is reported in 5-10 % of the cases whereas it can be up to 50 % in adult population. Our aim was to evaluate PVT incidence after LS and associated risks factors. A retrospective chart review identified 37 children who underwent elective LS from 2005 to 2013. The main indications were spherocytosis or sickle cell disease. Median age and weight were respectively 7.4 years and 25.1 kg. Thromboembolic prophylaxis was not routinely given. Duration of surgery was 129 min and hospital length of stay 4 days. Doppler ultrasound scan (USS) was performed post-operatively in 26 cases. Post operative course was uneventful in all but one patient. She was a 17 year-old girl previously operated for an ovarian tumor with hyperandrogenism. Histopathology revealed a splenic lymphoma. At day 4, a systematic USS showed a PVT extending in the portal branches. Therapeutic low molecular weight heparin was used and then transitioned to fluindione for 3 months. Follow-up USS performed at 1 and 4 months demonstrated complete resolution of the PVT. PVT after pediatric LS is a rare event in our series. Clinician should be cautious in oncologic cases and if very large spleen or if thrombocythemia >650.10(9)/L is present. If detected early, PVT can be treated efficiently. We therefore recommend a systematic USS during the first postoperative week. PMID- 24338250 TI - Cloning, expression, and characterization of a milk-clotting aspartic protease gene (Po-Asp) from Pleurotus ostreatus. AB - An aspartic protease gene from Pleurotus ostreatus (Po-Asp) had been cloned based on the 3' portion of cDNA in our previous work. The Po-Asp cDNA contained 1,324 nucleotides with an open reading frame (ORF) of 1,212 bp encoding 403 amino acid residues. The putative amino acid sequence included a signal peptide, an activation peptide, two most possible N-glycosylation sites and two conserved catalytic active site. The mature polypeptide with 327 amino acid residues had a calculated molecular mass of 35.3 kDa and a theoretical isoelectric point of 4.57. Basic Local Alignment Search Tool analysis showed 68-80 % amino acid sequence identical to other basidiomycetous aspartic proteases. Sequence comparison and evolutionary analysis revealed that Po-Asp is a member of fungal aspartic protease family. The DNA sequence of Po-Asp is 1,525 bp in length without untranslated region, consisting of seven exons and six introns. The Po Asp cDNA without signal sequence was expressed in Pichia pastoris and sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated the molecular mass of recombinant Po-Asp was about 43 kDa. The crude recombinant aspartic protease had milk-clotting activity. PMID- 24338251 TI - Image analysis technique as a tool to identify morphological changes in Trametes versicolor pellets according to exopolysaccharide or laccase production. AB - Image analysis technique was applied to identify morphological changes of pellets from white-rot fungus Trametes versicolor on agitated submerged cultures during the production of exopolysaccharide (EPS) or ligninolytic enzymes. Batch tests with four different experimental conditions were carried out. Two different culture media were used, namely yeast medium or Trametes defined medium and the addition of lignolytic inducers as xylidine or pulp and paper industrial effluent were evaluated. Laccase activity, EPS production, and final biomass contents were determined for batch assays and the pellets morphology was assessed by image analysis techniques. The obtained data allowed establishing the choice of the metabolic pathways according to the experimental conditions, either for laccase enzymatic production in the Trametes defined medium, or for EPS production in the rich Yeast Medium experiments. Furthermore, the image processing and analysis methodology allowed for a better comprehension of the physiological phenomena with respect to the corresponding pellets morphological stages. PMID- 24338252 TI - Alteration in frequency and function of CD4+CD25+FOXP3+ regulatory T cells in patients with immune thrombocytopenic purpura. AB - Immune thrombocytopenic purpura (ITP) is an autoimmune bleeding disorder characterized by production of auto-antibodies against platelet antigens. It is obvious that regulatory T cells (Tregs) have a major role in controlling immune homeostasis and preventing autoimmunity.To investigate the frequency and functions of Tregs, twenty ITP patients and twenty age- and sex-matched healthy controls were recruited. The peripheral blood mononuclear cells were isolated and the proportion of Tregs was defined by flow cytometry method. The expression of immune-regulatory markers, cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and glucocorticoid induced tumor necrosis factor receptor (GITR) were also assessed by quantitative Real-time PCR TaqMan method. For evaluation of Treg function, Tregs were enriched and their ability to inhibit proliferation of T cells was measured and levels of immune-regulatory cytokines IL-10 and TGF-beta were also measured.Results showed that the frequency of Tregs and the mean fluorescence intensity of FOXP3 protein significantly decreased in ITP patients compared to those in healthy controls. In addition, there was a significant reduction in relative expression of both CTLA-4 and GITR mRNA in ITP patients (P=0.02 and P=0.006, respectively). The suppressive function of Tregs also diminished in ITP patients compared to that in controls. Both IL-10 and TGF-beta cytokines were produced in lower amounts in ITP patients than controls.It could be concluded that alteration in Treg frequency and functional characteristics might be responsible for loss of self-tolerance and subsequently destructive immune responses observed in ITP patients. PMID- 24338253 TI - The effects of vitamin D on allergen-induced expression of interleukin-13 and interleukin-17 in cord blood CD4+T cells. AB - Cytokine production in response to allergens may influence the development of atopy-predisposing immune responses, initializing the early programming of allergy and asthma. Vitamin D intake may be protective due to its immunoregulatory properties, that may contribute to influence the expression of the atopic phenotype initiated in early life. The objective of our study was to investigate the effects of 1,25-(OH)2D3 on allergen-stimulated expression of asthma related cytokines in cord blood T cells. Cord blood samples were collected from the umblilical vein of 24 term deliveries during labor, CD4+T cells derived from cord blood mononuclear cells (CBMCs), were cultured for 72 hours with ovalbumin (OVA), beta-lactoglobulin (beta-LG), respectively, in presence or absence of 1,25-(OH)2D3 to detect the levels of interleukin-13 (IL-13) and interleukin-17 (IL-17) in culture supernatants and the mRNA expressions in CD4+T cells. After allergens stimulation, CD4+T cells showed an increase of IL-13 and IL-17 production, while cultured in the presence of 1,25-(OH)2D3 displayed a statistically significant down-regulation of allergen-induced expression of IL-13 and IL-17 in CD4+T cells. These results indicated that allergens may induce changes in CD4+T cell function to increase inflammatory cytokine production. 1,25 (OH)2D3 modulated the capacity of CD4+T cells in response to allergens, which might be protective for allergy. PMID- 24338254 TI - Vitamin e supplementation, lung functions and clinical manifestations in children with moderate asthma: a randomized double blind placebo- controlled trial. AB - Asthma is the most common chronic inflammatory disorder characterized by cough, wheezing and dyspnea in children. Nutrition is an important factor which influences on induction and exacerbation of asthma. There are controversies to use Vitamin E in asthmatic patients. The aim of this study was to evaluate the effect of vitamin E supplement in children with moderate asthma. This is a randomized double blind placebo-controlled trial performed on children (age 2-17 years old) with moderate asthma (5-17 years old) from March 2010 to March 2012. Case group were treated with fluticasone and vitamin E (50mg/day) and control group received fluticasone plus placebo for 8 weeks. Out of 300 cases, 240 cases completed the study. Female to male ratio was 0.84. Serum level of Vitamin E significantly increased after treatment in intervention group. FEV1 and FEV1/FVC ratio was significantly improved in case group compared to the control group. It can be concluded that vitamin E supplement could improve clinical manifestations and pulmonary function test in children with moderate asthma. PMID- 24338255 TI - Gastroesophagial reflux disease and asthma in pregnant women with dyspnea. AB - Asthma and gastroesophageal reflux disease (GERD) are two common problems in pregnancy and they affect pregnancy in several ways. In this study, we aimed to evaluate GERD and asthma in pregnant women who referred for prenatal care visits. One-hundred and seventy three pregnant women with a complaint of dyspnea were included in the study. A questionnaire was filled and lung function tests were performed. All patients were visited by a respiratory specialist and questionnaires were evaluated by a gastroenterologist. Out of the total number of women studied, 37% were diagnosed to have asthma and 36.4% were non-asthmatics. Twenty six percent of the pregnant women who had symptoms and signs of asthma with normal spirometry were classified as probable to have asthma. GERD was diagnosed in 80.9% of the pregnant women, but it was not significantly higher in asthmatic or probable asthmatic women compared to non-asthmatic ones. However, severity of GERD was significantly higher in asthmatic pregnant women compared to the others. In conclusion, the prevalence of GERD was quite high in pregnant women, irrespective of the fact that they were asthmatic or non-asthmatic. Further studies evaluating women throughout pregnancy will inform us more about this relationship. PMID- 24338256 TI - Evaluation of immunological parameters in diabetic patients: are these patients immunodeficient? AB - It has been widely thought that diabetic patients are prone to infections due to hyperglycemia induced immunodeficiency; the present study was designed to examine this opinion. In diabetic patients and normal control groups T-cell reactivity to hsp-60 molecule, tetanus toxoid recall antigen (TT) and phytohemagglutinin-A (PHA) mitogen were evaluated The number of circulating IFN-gamma, IL-10 and IL-13 cytokine producing cells stimulated with above antigens or mitogen as well as the serum levels of Th1/Th2 type cytokines were determined. Total serum immunoglobulins (IgG, IgA, IgM), C3, C4 and CH50 were also measured. Diabetic patients showed a positive circulating T-cell reactivity to human recombinant hsp60 However, this reactivity was significantly lower in comparison to control group (p<0.001). All other examined factors were not significantly different between diabetic and normal subjects except for the number of IFN-gamma and IL-13 producing cells in response to PHA stimulation, which was higher in control gtroup (p=0.006, 0.018, respectively). The mean serum concentration of IgA in diabetic patients was 245.86 +/- 115.05 mg/dl versus 192.96 +/- 105.33 mg/dl in healthy control group (p<0.018). We were not able to demonstrate any substantial mitigation in cellular arms of immune reaction to some prominent T-cell antigens and mitogens, as well as, in main parameters of humoral immunity of diabetic patients, thus, the common notion of believing that patients with diabetes suffering from immunodeficiency should be revised. It is much more appropriate that "altered immunity" is applied instead of "immunodeficiency" to explain the immunity condition in this group of patients. PMID- 24338257 TI - Mannan-binding lectin serum levels in 593 healthy Iranian children and adults. AB - Mannan-binding lectin (MBL) is a vital protein of innate immune system and has two critical functions: complement activation through the lectin pathway and opsonization. MBL deficiency has been classified as the most common inherited immunodeficiency known in humans (about 30% of the population), and is associated with predisposition to infections and high risk of some autoimmune diseases. The purpose of this study was to determine the profile of MBL serum level in Iranian healthy population in association with sex and age groups for the first time. We studied the serum concentration of MBL in 593 Iranian healthy cases: 340 males and 235 females in 4 different age groups by using enzyme-linked immunosorbent assay. The mean serum levels of MBL were 3.854 +/- 2.77 ug/ml at the age of less than 6 months, 4.147 +/- 3.54 ug/ml at 6 months to 2 years of age, 4.410 +/- 3.09 ug/ml at 2-6 years and 2.207 +/- 1.73 ug/ml in adults. There was significant differences in the mean concentration of MBL among different age groups of children and also between children and adults (p<0.05). No association was observed between sex and MBL concentrations. MBL serum levels of Iranian population seem to be different from some of other populations which may be explained by genetic variations. The MBL values in this study can be used as a normal reference range for future studies in Iranian population. PMID- 24338258 TI - Proinflammatory cytokines in the embolic model of cerebral ischemia in rat. AB - Increased levels of proinflammatory cytokines have been recorded after the onset of transient or permanent brain ischemia and are usually associated with exacerbation of ischemic injury. Embolic stroke model is more relevant to the pathophysiological situation in such patients, because the majority of ischemic injuries in humans are induced by old thrombi that originate from the heart and carotid arteries. Therefore, the aim of the present study was to investigate changes of inflammatory cytokines after embolic stroke. Rats were subjected to embolic stroke, induced by a natural old clot which was injected in Middle Cerebral Artery (MCA), or sham stroke, which the same volume of saline was injected into the MCA. At 48 h after stroke induction, the levels of 5 cytokines (IL-1alpha and beta, IL-6, IFN-gamma and TNF-alpha) were determined in 500 ug of total protein using the Bio-Plex Rat Cytokine Array (BioRad), according to the manufacturer's instructions in ischemic and non-ischemic cortices. While stroke animals showed infarctions and neurological deficits, we did not observe any cerebral infarction and neurological deficits in sham-operated animals. The levels of IL-1alpha (p=0.000) and -beta (p =0.004), IL-6 (p =0.008), TNF-alpha (p =0.000) and IFN-gamma (p =0.044) were significantly increased compared to sham treated animals. The findings of the present study suggest that part of ischemic injury in the embolic stroke may be mediated through the increased levels of inflammatory cytokines. PMID- 24338259 TI - The role of interleukin-23 in stability of in vitro T helper-17 cells. AB - Interleukin (IL)-17-producing T helper (Th)-17 cells have recently been explained as a distinct population of CD4+ T cells which play an important role in immunity against infectious agents. Establishment of persistent phenotype of Th17 cells and recognition of lineage-deviating factors are of most attractive goals in modern researches in immunology. Although IL-6 and TGF-beta are frequently used to differentiate naive T cells to Th17 phenotype in mouse models, the application of IL-23 and its importance in preventing cells from plasticity needs to be more investigated. Our main objective was to evaluate the role of IL-23 in Th17 to Th1 plasticity. In this research project, we generated in vitro Myelin oligodendrocyte glycoprotein (MOG)-specific Th17 cells in the presence of TGF beta, IL-6, IL-23 and peptide MOG35-55. Th17 development was confirmed by assessment of relevant transcription factors and secreted cytokines by flowcytometry and ELISA, respectively. Th17 to Th1 plasticity was monitored by consecutive samplings in different time points without any extra supplementation of IL-23. Cell culture supernatant was evaluated for Interferon (IFN)-gamma secretion and cells were evaluated for intracellular expression of this cytokine. Our results showed that the employed method was relatively convenient in developing antigen-specific Th17 cells. We also showed that IL-23 deprivation which happens by prolongation of culture period, can convert IL-17 producing cells to IFN-gamma secreting Th1 phenotype. IL-23 can be considered as a Th17 phenotype stabilizing factor for in-vitro developed lineages. PMID- 24338260 TI - Pure red cell aplasia as a presenting feature in systemic lupus erythematosus and association with thymoma, hypothyroidism and hypoparathyroidism: a case report and literature review. AB - This paper presents a 54-year-old female with lupus whom severe anaemia due to pure red cell aplasia (PRCA) was the first manifestation. There was seven years interval between PRCA onset and diagnosis of lupus. Thymectomy due to thymoma had been carried out six years before but anaemia sustained. Hypothyroidism and hypoparathyroidism were other associated diseases. Severe anaemia and the need for monthly blood infusions were resolved following treatment with Prednisolone, Hydroxychloroquine and Levothyroxine. PMID- 24338261 TI - Current concepts on anti-phospholipase A2 receptor antibody in idiopathic membranous nephropathy. PMID- 24338262 TI - Wound drainage for caesarean section. AB - BACKGROUND: Subcutaneous and sub rectus sheath wound drains are sometimes used in women who have undergone caesarean section. The indications for using drains vary by clinician. OBJECTIVES: To compare the effects of using a wound drain with not using a wound drain at caesarean section, and of different types of drain, on maternal health and healthcare resource use. SEARCH METHODS: In November 2013, for this second update, we searched the Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid Medline; Ovid Medline - In-Process & Other Non-Indexed Citations; Ovid Embase; and EBSCO CINAHL. No date, language or publication status limits were applied SELECTION CRITERIA: Studies were included if they allocated women to groups at random and they compared any type of wound drain with no wound drainage, or with any other type of drain, in women undergoing caesarean section. DATA COLLECTION AND ANALYSIS: Trials were evaluated for appropriateness for inclusion and methodological quality without consideration of their results. This was done by two reviewers according to pre-stated eligibility criteria. MAIN RESULTS: Ten trials that recruited 5248 women were included in the review. Meta analysis found no evidence of a difference in the risk of wound infection, other wound complications, febrile morbidity or pain in women who had wound drains compared with those who did not. There was some evidence from one trial that a subcutaneous drain may increase wound infection compared to a sub-sheath drain (RR 5.42, 95% CI 1.28 to 22.98). No differences in outcomes were found between subcutaneous drainage and subcutaneous suturing in the three trials that made this comparison. AUTHORS' CONCLUSIONS: Existing evidence suggests that the routine use of wound drains at caesarean section does not confer any substantial benefit to the women involved. However, neither moderate benefit nor harm are excluded. PMID- 24338263 TI - The anti-aging effects of Ludwigia octovalvis on Drosophila melanogaster and SAMP8 mice. AB - We investigated the anti-aging effects of Ludwigia octovalvis (Jacq.) P. H. Raven (Onagraceae), an extract of which is widely consumed as a healthful drink in a number of countries. Using the fruit fly, Drosophila melanogaster, as a model organism, we demonstrated that L. octovalvis extract (LOE) significantly extended fly lifespan on a high, but not a low, calorie diet, indicating that LOE may regulate lifespan through a dietary restriction (DR)-related pathway. LOE also attenuated age-related cognitive decline in both flies and in the senescence accelerated-prone 8 (SAMP8) mouse, without causing any discernable negative trade offs, including water intake, food intake, fecundity, or spontaneous motor activity. LOE contained high levels of polyphenols and flavonoids, which possess strong DPPH radical scavenging activity, and was shown to attenuate paraquat induced oxidative damage and lethality in flies. Gas chromatography-mass spectrometry (GC-MS) analyses identified 17 known molecules, of which beta sitosterol and squalene were the two most abundant. We further demonstrated that beta-sitosterol was capable of extending lifespan, likely through activating AMP activated protein kinase (AMPK) in the fat body of adult flies. Taken together, our data suggest that LOE is a potent anti-aging intervention with potential for treating age-related disorders. PMID- 24338264 TI - The cost effectiveness of dry powder antibiotics for the treatment of Pseudomonas aeruginosa in patients with cystic fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) affects over 9,000 people in the UK and limits life expectancy. CF patients are susceptible to lung infections, most commonly Pseudomonas aeruginosa. Once infection is established, patients require lifetime treatment using nebulised antibiotics. Newer dry powder formulations of antibiotics may reduce treatment burden and improve compliance. OBJECTIVE: Our objective was to evaluate the cost effectiveness of (i) colistimethate sodium dry powder for inhalation (DPI) and (ii) tobramycin DPI versus nebulised tobramycin for the treatment of chronic P. aeruginosa lung infection in patients with CF from the perspective of the National Health Service (NHS) and Personal Social Services (PSS). METHODS: We developed a state transition model based on transitions between three strata of lung function measured in terms of forced expiratory volume in 1 second (FEV1) % predicted. Additional health states representing post-lung transplantation and dead are also modelled. The model structure was informed by systematic reviews of evidence concerning the plausibility of potential relationships between intermediate endpoints and final outcomes. The model assumes that treatment impacts on FEV1 trajectory, which manifest as changes in health-related quality of life. No survival benefit is assumed due to the absence of robust quantifiable evidence. Model parameters were informed by patient-level and aggregate data from two randomised controlled trials together with the best available evidence from the literature. Resource use and costs associated with drug acquisition, the management of exacerbations and reduced nebuliser maintenance were drawn from reference sources and expert opinion. Costs were valued at 2011/2012 prices. Costs and health outcomes were discounted at a rate of 3.5 %. Simple and probabilistic sensitivity analyses were undertaken, including additional analyses of Patient Access Scheme (PAS) price discounts offered by the manufacturers of both DPI products. RESULTS: Colistimethate sodium DPI is expected to produce fewer quality-adjusted life years (QALYs) than nebulised tobramycin. Based on its list price, colistimethate sodium DPI is expected to be dominated by nebulised tobramycin. When the PAS is incorporated, the incremental cost-effectiveness ratio (ICER) for colistimethate sodium DPI versus nebulised tobramycin is expected to be approximately L288,600 saved per QALY lost. Based on its current list price, the ICER for tobramycin DPI versus nebulised tobramycin is expected to be approximately L124,000 per QALY gained. When the proposed PAS is included, tobramycin DPI is expected to dominate nebulised tobramycin. CONCLUSIONS: Under their list prices, neither DPI product is likely to represent good value for money for the NHS given current cost effectiveness thresholds. The PAS discounts have a significant impact upon the economic attractiveness of both DPI products compared against nebulised tobramycin. The clinical effectiveness and cost effectiveness of the DPIs against other nebulised antibiotics, such as aztreonam and inhaled colistimethate sodium, remains unclear. PMID- 24338265 TI - Survival modeling for the estimation of transition probabilities in model-based economic evaluations in the absence of individual patient data: a tutorial. AB - BACKGROUND: Survival modeling techniques are increasingly being used as part of decision modeling for health economic evaluations. As many models are available, it is imperative for interested readers to know about the steps in selecting and using the most suitable ones. The objective of this paper is to propose a tutorial for the application of appropriate survival modeling techniques to estimate transition probabilities, for use in model-based economic evaluations, in the absence of individual patient data (IPD). An illustration of the use of the tutorial is provided based on the final progression-free survival (PFS) analysis of the BOLERO-2 trial in metastatic breast cancer (mBC). METHODS: An algorithm was adopted from Guyot and colleagues, and was then run in the statistical package R to reconstruct IPD, based on the final PFS analysis of the BOLERO-2 trial. It should be emphasized that the reconstructed IPD represent an approximation of the original data. Afterwards, we fitted parametric models to the reconstructed IPD in the statistical package Stata. Both statistical and graphical tests were conducted to verify the relative and absolute validity of the findings. Finally, the equations for transition probabilities were derived using the general equation for transition probabilities used in model-based economic evaluations, and the parameters were estimated from fitted distributions. RESULTS: The results of the application of the tutorial suggest that the log-logistic model best fits the reconstructed data from the latest published Kaplan-Meier (KM) curves of the BOLERO-2 trial. Results from the regression analyses were confirmed graphically. An equation for transition probabilities was obtained for each arm of the BOLERO-2 trial. CONCLUSIONS: In this paper, a tutorial was proposed and used to estimate the transition probabilities for model-based economic evaluation, based on the results of the final PFS analysis of the BOLERO-2 trial in mBC. The results of our study can serve as a basis for any model (Markov) that needs the parameterization of transition probabilities, and only has summary KM plots available. PMID- 24338267 TI - Influence of SrO substitution for CaO on the properties of bioactive glass S53P4. AB - Commercial melt-quenched bioactive glasses consist of the oxides of silicon, phosphorus, calcium and sodium. Doping of the glasses with oxides of some other elements is known to affect their capability to support hydroxyapatite formation and thus bone tissue healing but also to modify their high temperature processing parameters. In the present study, the influence of gradual substitution of SrO for CaO on the properties of the bioactive glass S53P4 was studied. Thermal analysis and hot stage microscopy were utilized to measure the thermal properties of the glasses. The in vitro bioactivity and solubility was measured by immersing the glasses in simulated body fluid for 6 h to 1 week. The formation of silica rich and hydroxyapatite layers was assessed from FTIR spectra analysis and SEM images of the glass surface. Increasing substitution of SrO for CaO decreased all characteristic temperatures and led to a slightly stronger glass network. The initial glass dissolution rate increased with SrO content. Hydroxyapatite layer was formed on all glasses but on the SrO containing glasses the layer was thinner and contained also strontium. The results suggest that substituting SrO for CaO in S53P4 glass retards the bioactivity. However, substitution greater than 10 mol% allow for precipitation of a strontium substituted hydroxyapatite layer. PMID- 24338268 TI - The prevalence and psychosocial correlates of suicide attempts among inpatient adolescent offspring of Croatian PTSD male war veterans. AB - Despite evidence that children of male war veterans with combat-related posttraumatic stress disorder (PTSD) are at particularly high risk for behavior problems, very little is currently known about suicidal behaviors in this population of youth. This study aimed to examine the prevalence and psychosocial correlates of suicide attempts among psychiatrically hospitalized adolescent offspring of Croatian male PTSD veterans. Participants were psychiatric inpatients, ages 12-18 years. Self-report questionnaires assessed demographics, suicide attempts, psychopathology, parenting style, and family functioning. The prevalence of suicide attempts was 61.5% (65.2% for girls and 58.0% for boys). Internalizing symptoms, family dysfunction, lower levels of maternal and paternal care, and paternal overcontrol were significantly associated with suicide attempts. Our findings suggest that suicide attempts are common among inpatient adolescent offspring of male PTSD veterans and that interventions targeting both adolescent psychopathology and family relationships are needed for adolescents who have attempted suicide. PMID- 24338266 TI - Current management of delayed cerebral ischemia: update from results of recent clinical trials. AB - Subarachnoid hemorrhage (SAH) accounts for 5-7% of all strokes worldwide and is associated with high mortality and morbidity. Even after surgical intervention, approximately 30% of patients develop long-term cognitive and neurological deficits that significantly affect their capacity to return to work or daily life unassisted. Much of this stems from a secondary ischemic phenomenon referred to as delayed cerebral ischemia (DCI). While DCI has been historically attributed to the narrowing of the large basal cerebral arteries, it is now recognized that numerous pathways contribute to its pathogenesis, including microcirculatory dysfunction, microthrombosis, cortical spreading depression, and early brain injury. This paper seeks to summarize some of the key pathophysiological events that are associated with poor outcome after SAH, provide a general overview of current methods of treating SAH patients, and review the results of recent clinical trials directed at improving outcome after SAH. The scientific basis of these studies will be discussed, in addition to the available results and recommendations for effective patient management. Therapeutic methods under current clinical investigation will also be addressed. In particular, the mechanisms by which they are expected to elicit improved outcome will be investigated, as well as the specific study designs and anticipated time lines for completion. PMID- 24338269 TI - Insecure attachment attitudes in the onset of problematic Internet use among late adolescents. AB - Studies on the role played by attachment attitudes among late adolescents who show Problematic Internet Use (PIU) are still lacking. Three self-report measures concerning attachment attitudes, childhood experiences of abuse, and Internet addiction were administered to 310 students (49 % males) aged 18-19 attending the last year of high school. Students who screened positive for PIU were more likely to be male and to have suffered childhood experiences of physical and sexual abuse; they also scored higher than the other participants on scales assessing anxious and avoidant attachment attitudes. A logistic regression showed that the classification of participants in the PIU group was predicted by male gender, having suffered from physical and sexual abuse in childhood, and preoccupation with relationships. Keeping constant the effects of gender and childhood experiences of abuse in the equation model, increasing values of preoccupation with relationships were reflected by an exponential growth in the probability curve for PIU classification. Findings of the study support the hypothesis that insecure attachment attitudes (particularly the preoccupation with relationships) are involved in the development of PIU among late adolescents. PMID- 24338271 TI - Mutation abundance affects the efficacy of EGFR tyrosine kinase inhibitor readministration in non-small-cell lung cancer with acquired resistance. AB - There is no consensus in the salvage treatment for non-small-cell lung cancer (NSCLC) with acquired resistance to primary epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Fifty-one consecutive EGFR-mutated NSCLC patients with TKI retreatment after acquired resistance were enrolled in this study. The quantitation of mutation abundance was performed by real-time fluorescent quantitative PCR. The correlation between mutation abundance and outcomes of readministrated TKI was analyzed by survival analysis. Patients with high (H) mutation abundance (24/51) had a significantly (log-rank, P < 0.05) longer (5.27-2.53 months) median progression-free survival (PFS), compared with the low (L) abundance group (27/51), whereas the median overall survival showed no difference (21.00-18.20 months, log-rank P = .403) between the two groups. Objective response and disease control rates in group H and group L regarding the second round TKI treatment were 8.3, 70.8 and 0, 48.1 %, respectively. Groupings with different mutation abundances were significantly associated with PFS under multivariate Cox proportional hazards regression model [hazard ratio (HR) for group H vs. L, 0.527; P = .036]. Mutation abundance affects the efficacy of EGFR TKIs readministration in NSCLC with acquired resistance. The quantitative mutation abundance of EGFR may be a potential predictor for selecting optimal patients to readministrate EGFR-TKIs after acquired resistance to primary TKI. PMID- 24338270 TI - Insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R) signaling systems: novel treatment strategies for cancer. AB - Insulin and insulin-like growth factor (IGF) signaling system, commonly known for fine-tuning numerous biological processes, has lately made its mark as a much sought-after therapeutic targets for diabetes and cancer. These receptors make an attractive anticancer target owing to their overexpression in variety of cancer especially in prostate and breast cancer. Inhibitors of IGF signaling were subjected to clinical cancer trials with the main objective to confirm the effectiveness of these receptors as a therapeutic target. However, the results that these trials produced proved to be disappointing as the role played by the cross talk between IGF and insulin receptor (IR) signaling pathways at the receptor level or at downstream signaling level became more lucid. Therapeutic strategy for IGF-1R and IR inhibition mainly encompasses three main approaches namely receptor blockade with monoclonal antibodies, tyrosine kinase inhibition (ATP antagonist and non-ATP antagonist), and ligand neutralization via monoclonal antibodies targeted to ligand or recombinant IGF-binding proteins. Other drug discovery approaches are employed to target IGF-1R, and IR includes antisense oligonucleotides and recombinant IGF-binding proteins. However, therapies with monoclonal antibodies and tyrosine kinase inhibition targeting the IGF-1R are not evidenced to be satisfactory as expected. Factors that are duly held responsible for the unsuccessfulness of these therapies include (a) the existence of the IR isoform A overexpressed on a variety of cancers, enhancing the mitogenic signals to the nucleus leading to the endorsement of cell growth, (b) IGF-1R and IR that form hybrid receptors sensitive to the stimulation of all three IGF axis ligands, and (c) IGF-1R and IR that also have the potential to form hybrid receptors with other tyrosine kinase to potentiate the cellular transformation, tumorigenesis, and tumor vascularization. This mini review is a concerted effort to explore and fathom the well-recognized roles of the IRA signaling system in human cancer phenotype and the main strategies that have been so far evaluated to target the IR and IGF-1R. PMID- 24338272 TI - Long-lasting complete response of metastatic melanoma to ipilimumab with analysis of the resident immune cells. AB - Even though ipilimumab is a promising antibody used for stage IV melanoma therapy, the response varies and is difficult to predict. We here report on a case of successful treatment with ipilimumab in dacarbazine-resistant metastatic malignant melanoma, including a review of the literature on the long-term treatment results. A 62-year-old patient with a history of a resected lentigo maligna melanoma 5 years earlier and parotideal metastasis 1 year before was admitted with a newly detected 3.5 cm liver metastasis. Atypical liver resection was performed (R1). Immunohistochemically, CD3+ T-lymphocytes and CD68+ macrophages were detected at the tumour margins and within the parotideal and hepatic melanoma metastases. A sub-analysis of the liver metastasis showed scattered FOX-P3+ regulatory T-lymphocytes as well as multiple CD8+ effector T cells. Chemotherapy with dacarbazine 1,000 mg/m(2)/day was administered at 4 weeks intervals for 3 months. A follow-up positron-emission computed tomography and liver biopsy revealed melanoma metastases in the liver, lungs, and mediastinum. Compassionate use of ipilimumab was administered at 3 mg/kg every 3 weeks for a total of four doses. After an initial increase in tumour size, most lesions responded, but progressive axillary and cervical lymphadenopathy was observed before complete remission was achieved. Side effects included fatigue, dyspnoea, cough, upper abdominal pain with diarrhoea, and gingival hyperplasia. Now, 36 months after ipilimumab therapy and 8 years after the initial melanoma diagnosis, the tumour did not recur. It would be challenging to hypothesize that long intervals between diagnosis and need for treatment, clinical side effects, an initial increase in tumour size and the presence of intra-tumoural T-cells and macrophages might predict tumour response. PMID- 24338273 TI - Characteristics and clinical outcome of patients with hypereosinophilia of undetermined significance. AB - The term "hypereosinophilia of undetermined significance" (HEus) previously known as idiopathic, benign eosinophilia relates to patients who have a long-lasting, unexplained and asymptomatic blood HE. These patients have not been studied so far in terms of demographic characteristics and clinical outcome. The aim of this study was to present the clinical characteristics and outcome of HEus patients. This is a retrospective, single-center study of 40 patients with HEus. All patients underwent the basic and specialized evaluations in order to rule out the most common causes of blood HE, but no abnormalities were detected. Twelve patients with at least moderate blood hypereosinophilia (defined as greater than 3.0 * 10(9)/L) for more than 1-year duration were treated with corticosteroids (CS) to avoid end-organ damage. Twenty-one patients (52 %) had an increased leukocyte count at diagnosis. Median blood eosinophilia was 4.2 * 10(9)/L (range 1.5-55.4). HE > 3.0 * 10(9)/L was demonstrated in 17 patients. 65 % of studied population had an increased serum IgE levels, whereas only 2 % demonstrated an increased serum vitamin B12 levels. A median bone marrow infiltration by eosinophils was 30.5 % (range 11-78.2). All treated patients responded promptly to CS and remained in complete remission while receiving low doses of CS (20 mg/day to 5 mg every 2-day). One patient developed hypereosinophilic syndrome (HES) after 11 years of follow-up. Further studies are needed to define risk factors of HES development. The use of CS for HEus patients is controversial and should be individualized. PMID- 24338274 TI - DNA promoter and histone H3 methylation downregulate NGX6 in gastric cancer cells. AB - Nasopharyngeal carcinoma-associated gene 6 (NGX6) is a novel candidate tumor metastasis suppressor gene. Our study was to determine whether DNA hypermethylation and histone modification at the NGX6 gene promoter play important roles in silencing NGX6 expression in gastric cancer. NGX6 expression was downregulated in all gastric cancer cells and 76.19 % tissues. In three GC cell lines, hypermethylated NGX6 loci were characterized by histone H3-K9 hypoacetylation and hypermethylation. Trichostatin A treatment could moderately increase H3-K9 acetylation at the silenced loci; however, it had no effect on DNA and H3-K9 methylation and minimal effects on NGX6 expression. In contrast, 5'aza 2'-deoxycytidine treatment could rapidly decrease DNA and H3-K9 methylation at the silenced loci, leading to the reexpression of NGX6. Combined treatment with 5'aza-2'-deoxycytidine and trichostatin A had synergistic effects on the reexpression of NGX6 at the hypermethylation loci. Our current study shows that NGX6 expression is downregulated in GC cancer cells and tissues due to NGX6 promoter methylation and H3-K9 methylation, but not H3-K9 acetylation. Our findings indicate that the downregulation of NGX6 expression contributes to the development and progression of gastric cancer. More studies are needed to determine the precise mechanism of NGX6 in the progression of gastric cancer. PMID- 24338275 TI - Prognostic value of mutational characteristics in gastrointestinal stromal tumors: a single-center experience in 275 cases. AB - The objective of this study was to investigate the impact of KIT/PDGFRA mutations on the prognosis of gastrointestinal stromal tumors (GISTs). In the present study, genotype analyses were performed based on GIST samples from 275 patients. The relationship between mutation and clinicopathological characteristics were explored. All factors were evaluated for their impacts on relapse-free survival (RFS). Briefly, the results of genotype analyses showed that mutations were identified in 258 (93.8 %) patients, and deletion was the most frequent type of mutation accounting for 47.3 % (122/258) of all mutation cases, followed by substitution (87/258, 33.7 %) and duplication (49/258, 19.0 %). Moreover, for KIT exon 11 mutation, the most frequently involved area was from codon 557 to 560. Deep analyses showed that the mutation types were correlated with tumor location (P = 0.005), tumor size (P = 0.022), mitosis rate (P < 0.001), risk grade (P < 0.001), and relapse (P = 0.004). Furthermore, delW557-K558 correlated with mitosis rate (P = 0.042) and relapse (P = 0.036), and delTyr568/570 correlated with tumor origin (P = 0.018). Most importantly, mitotic rate [HR = 2.901 (95 % CI 1.094-7.695), P = 0.032] and risk grade [HR = 9.629 (95 % CI 1.997-46.416), P = 0.005] would be the representative traditional prognostic factors, and deletion with >3 codons would be an novel independent predictor of poor outcome for RFS in GIST patients with deletion mutation of KIT exon 11 [HR = 7.970 (95 % CI 1.774 35.803), P = 0.007]. All results indicated that mutation determined clinicopathological features and prognosis of GISTs, and more than three codons involvement may be a novel adverse indicator. PMID- 24338276 TI - Decreased expression of myosin light chain MYL9 in stroma predicts malignant progression and poor biochemical recurrence-free survival in prostate cancer. AB - The aim of this study was to investigate the associations of myosin light chain (MYL9) downregulation with tumor progression and prognosis in patients with prostate cancer (PCa). MYL9 protein expression in human PCa and non-cancerous prostate tissues was detected by Western blot and immunohistochemistry analyses, which was validated by microarray-based Taylor data at mRNA level. Then, the associations of MYL9 expression with clinicopathological features and clinical outcome of PCa patients were statistically analyzed. Both Western blot and immunohistochemistry analyses found that MYL9 expression was significantly decreased (both P < 0.001) in PCa tissues compared with those in non-cancerous prostate tissues. In addition, MYL9 was mainly expressed in the cytoplasm of stromal cells of prostate tissues, and the decreased expression of MYL9 in PCa tissues was significantly correlated with the older age of patients (P = 0.011), the higher Gleason score (P < 0.001), the advanced pathological stage (P = 0.002), the presence of metastasis (P < 0.001) and PSA failure (P = 0.001). Furthermore, both univariate and multivariate analyses showed that the downregulation of MYL9 was an independent predictor of shorter overall survival (P = 0.026 and P = 0.009, respectively) and biochemical recurrence-free survival (P = 0.001 and P = 0.002, respectively). Our data strongly confirmed for the first time that the decreased expression of MYL9 may play an important role in tumor progression of PCa. More importantly, the downregulation of MYL9 may efficiently predict both overall and biochemical recurrence-free survivals in PCa patients. PMID- 24338277 TI - Activity of the hypoxia-activated pro-drug TH-302 in hypoxic and perivascular regions of solid tumors and its potential to enhance therapeutic effects of chemotherapy. AB - Many chemotherapy drugs have poor therapeutic activity in regions distant from tumor blood vessels because of poor tissue penetration and low cytotoxic activity against slowly-proliferating cells. The hypoxia-activated pro-drug TH-302 may have selective toxicity for hypoxic and neighboring cells in tumors. Here we characterize the spatial distribution and ability of TH-302 to selectively target hypoxic regions and complement the effect of doxorubicin and docetaxel by modifying biomarker distribution. Athymic nude mice bearing human breast MCF-7 or prostate PC-3 tumors were treated with doxorubicin or docetaxel respectively and TH-302 alone or in combination. Biomarkers of drug effect including gammaH2aX (a marker of DNA damage), cleaved caspase-3 or -6 (markers of apoptosis) and reduction in Ki-67 (a marker of cell proliferation) were quantified in tumor sections in relation to functional blood vessels (recognized by DiOC7) and hypoxia (recognized by EF5) using immunohistochemistry. gammaH2aX expression at 10 min and cleaved caspase-3 or -6 at 24 hr after doxorubicin or docetaxel decreased with increasing distance from tumor blood vessels, with minimal expression in hypoxic regions; maximum reduction in Ki67 levels was observed in regions closest to vasculature at 24 hr. TH-302 induced maximal cell damage in hypoxic and neighboring regions, but was also active in tumor regions closer to blood vessels. TH-302 given 4 hr before doxorubicin or docetaxel increased DNA damage and apoptosis throughout the tumor compared to chemotherapy alone. When given with doxorubicin or docetaxel, TH-302 complements and enhances anticancer effects in both perivascular and hypoxic regions but also increases toxicity. PMID- 24338278 TI - Intraperitoneal chemotherapy from Armstrong to HIPEC: challenges and promise. AB - OPINION: The treatment of advanced stage ovarian, primary peritoneal and fallopian tube cancer represents a therapeutic challenge as evidenced by the 70 % 80 % recurrence rate. Our understanding of the synergy between surgical cytoreduction and effective systemic chemotherapy continues to evolve, with research supporting maximal cytoreductive effort followed by intraperitoneal chemotherapy. Specifically, analysis of phase III clinical trials has shown a median survival of 110 months in those treated with intraperitoneal chemotherapy, when surgery results in no visible residual disease. Additionally, incorporation of hyperthermic intraperitoneal chemotherapy at the time of surgical resection has gained attention as an alternate therapeutic option, in an attempt to obviate toxicities encountered with repetitive cycles of intraperitoneal chemotherapy. Currently, surgical cytoreduction in the hands of an experienced gynecologic oncologist, followed by intraperitoneal chemotherapy is thought to portend the greatest survival benefit in patients with advanced stage ovarian cancer spectrum cancers. Additional investigation regarding the oncologic outcomes and morbidity of hyperthermic intraperitoneal chemotherapy is warranted. PMID- 24338279 TI - Efficiency, ownership, and financing of hospitals: the case of Austria. AB - While standard economic theory posits that privately owned hospitals are more efficient than their public counterparts, no clear conclusion can yet be drawn for Austria in this regard. As previous Austrian efficiency studies rely on data from the 1990s only and are based on small hospital samples, the generalizability of these results is questionable. To examine the impact of ownership type on efficiency, we apply a Data Envelopment Analysis which extends the existing literature in two respects: first, it evaluates the efficiency of the Austrian acute care sector, using data on 128 public and private non-profit hospitals from the year 2010; second, it additionally focusses on the inpatient sector alone, thus increasing the comparability between hospitals. Overall, the results show that in Austria, private non-profit hospitals outperform public hospitals in terms of technical efficiency. A multiple regression analysis confirms the significant association between efficiency and ownership type. This conclusive result contrasts some international evidence and can most likely be attributed to differences in financial incentives for public and private non-profit hospitals in Austria. Therefore, by drawing on the example of the Austrian acute care hospital sector and existing literature on the German acute care hospital sector, we also discuss the impact of hospital financing systems and their incentives on efficiency. This paper thus also aims at providing a proof of principle, pointing out the importance of the respective market conditions when internationally comparing hospital efficiency by ownership type. PMID- 24338283 TI - [From genomics to public health]. PMID- 24338284 TI - Interleukin-1beta (187-207)-induced hyperthermia is inhibited by interleukin 1beta (193-195) in rats. AB - Interleukin-1beta (IL-1beta) is a pro-inflammatory cytokine, which plays an important role in the immune response and signal transduction both in the periphery and the central nervous system (CNS). Various diseases of the CNS, including neurodegenerative disorders, vascular lesions, meningo-encephalitis or status epilepticus are accompanied by elevated levels of IL-1beta. Different domains within the IL-lbeta protein are responsible for distinct functions. The IL-lbeta domain in position 208-240 has pyrogenic properties, while the domain in position 193-195 exerts anti-inflammatory effects. Previous studies provide little evidence about the effect of the domain in position 187-207 on the body temperature. Therefore, the aim of the present study was to investigate the action of IL-1beta (187-207) and its interaction with IL-1beta (193-195) on the body temperature. IL fragments were administered intracerebroventricularly and the body temperature was measured rectally in male Wistar rats. IL-1beta (187 207) induced hyperthermia, while IL-1beta (193-195) did not influence the core temperature considerably. In co-administration, IL-1beta (193-195) completely abolished the IL-1beta (187-207)-induced hyperthermia. The non-steroid anti inflammatory drug metamizole also reversed completely the action of IL-1beta (187 207). Our results provide evidence that the IL-lbeta domain in position 187-207 has hyperthermic effect. This effect is mediated through prostaglandin E2 stimulation and other mechanisms may also be involved in the action of IL-1beta (187-207). It also suggests that IL-lbeta domain in position 187-207 and IL-1beta (193-195) fragment may serve as novel target for treatment of disorders accompanied with hyperthermia. PMID- 24338285 TI - The Work-ability Support Scale: evaluation of scoring accuracy and rater reliability. AB - PURPOSE: The Work-ability Support Scale (WSS) is a new tool designed to assess vocational ability and support needs following onset of acquired disability, to assist decision-making in vocational rehabilitation. In this article, we report an iterative process of development through evaluation of inter- and intra-rater reliability and scoring accuracy, using vignettes. The impact of different methodological approaches to analysis of reliability is highlighted. METHODS: Following preliminary evaluation using case-histories, six occupational therapists scored vignettes, first individually and then together in two teams. Scoring was repeated blind after 1 month. Scoring accuracy was tested against agreed 'reference standard' vignette scores using intraclass correlation coefficients (ICCs) for total scores and linear-weighted kappas (kw) for individual items. Item-by-item inter- and intra-rater reliability was evaluated for both individual and team scores, using two different statistical methods. RESULTS: ICCs for scoring accuracy ranged from 0.95 (95 % CI 0.78-0.98) to 0.96 (0.89-0.99) for Part A, and from 0.78 (95 % CI 0.67-0.85) to 0.84 (0.69-0.92) for Part B. Item by item analysis of scoring accuracy, inter- and intra-rater reliability all showed 'substantial' to 'almost perfect' agreement (kw >= 0.60) for all Part-A and 8/12 Part-B items, although multi-rater kappa (Fleiss) produced more conservative results (mK = 0.34-0.79). Team rating produced marginal improvements for Part-A but not Part-B. Four problematic contextual items were identified, leading to adjustment of the scoring manual. CONCLUSION: This vignette-based study demonstrates generally acceptable levels of scoring accuracy and reliability for the WSS. Further testing in real-life situations is now warranted. PMID- 24338287 TI - Effect of photo-selective nettings on post-harvest quality and bioactive compounds in selected tomato cultivars. AB - BACKGROUND: Photo-selective coloured netting is referred to as a 'new agro technological' concept adopted to manipulate light quality changes that can induce favourable responses in plants. RESULTS: Tomato (Solanum lycopersicum L.) cultivars AlvaV, Irit and SCX 248 grown under the black net (commercial net, 25% shading) showed higher weight loss, loss of firmness, ascorbic acid content and decline in the ratio of soluble solids content/titrable acidity during post harvest storage (low-temperature storage at 10 degrees C and 90% relative humidity for 21 days followed by market shelf conditions at 25 degrees C for 2 days). During post-harvest storage, lycopene, beta-carotene, total phenolic content and antioxidant scavenging activity were higher in cvs AlfaV and Irit grown under the black or pearl nets. However, the beta-carotene, total phenolic content and antioxidant scavenging activity were higher in SCX 248 grown under the red net during post-harvest storage. Cultivar AlfaV grown under the red and pearl nets had a higher number of odour active aroma compounds during post harvest storage. Panellists preferred cv. AlfaV grown under the pearl nets after storage based on taste, overall appearance and firm textured fruits. CONCLUSION: Pearl photo-selective nets retained the overall fruit quality and bioactive components in cvs AlfaV and Irit during post-harvest storage. Red photo-selective nets, however, showed greater influence on retention of overall fruit quality and bioactive compounds in cv. SCX 248 during post-harvest storage. PMID- 24338288 TI - Evaluation of a clinical pathway for sedation and analgesia of mechanically ventilated patients in a cardiac intensive care unit (CICU): The Brigham and Women's Hospital Levine CICU sedation pathways. AB - BACKGROUND: Intravenous sedation and analgesia are important therapies during mechanical ventilation (MV). However, daily interruption of these medications is associated with improved outcomes in mechanically ventilated patients. We tested a clinical pathway for the use of sedation and analgesia during MV in a cardiac intensive care unit (CICU). METHODS AND RESULTS: We evaluated all mechanically ventilated patients in a CICU during two phases: phase 1 prior to pathway implementation (PRE) and phase 2 post-pathway implementation (POST). A total of 198 patients (98 PRE and 100 POST) and 1012 days of intubation (574 PRE and 434 POST) were included in this analysis. We found an increase in the frequency of daily interruptions of sedation post-implementation (49.3% PRE and 58.4% POST, p=0.0041). There was a significant decrease in the mean duration of MV in the POST vs PRE periods (5.0+/-2.3 vs 6.1+/-2.8 days, p=0.015). There was also a significant decrease in total neuroimaging studies (9 vs 49, p=0.001) and a trend toward a decrease in tracheostomies (3.0% vs 6.1%, p=0.33). Mean CICU length of stay (LOS) and hospital LOS respectively were 10.4 days and 16.8 days PRE and 10.4 days and 17.9 days POST (p=0.99 and p=0.55). Mortality did not differ (PRE 36.7% vs POST 32.0% p=0.55). CONCLUSIONS: Implementation of a pragmatic pathway for sedation and analgesia in a CICU was associated with an increase in the daily interruption of sedation and a corresponding decrease in the duration of MV days and the need for neuroimaging. PMID- 24338289 TI - Hyperglycemia at admission and during hospital stay are independent risk factors for mortality in high risk cardiac patients admitted to an intensive cardiac care unit. AB - AIMS: Hyperglycemia is associated with increased mortality in cardiac patients. However, the predictive value of admission- and average glucose levels in patients admitted to an intensive cardiac care unit (ICCU) has not been described. METHODS: Observational study of patients admitted to the ICCU of a tertiary medical center in whom glucose levels were measured at and during admission. Over a 19-month period, 1713 patients were included. Mean age was 63+/ 14 years, 1228 (72%) were male, 228 (17%) had known diabetes. Median (interquartile) glucose levels at admission were 7.9 (6.5-10.1) mmol/l; median glucose levels during ICCU admission (873 patients with three or more measurements) were 7.3 (6.7-8.3) mmol/l. Cox regression analysis was performed including the variables age, gender, admission diagnosis, length of stay, prior (cardio)vascular disease and diabetes. RESULTS: A 1 mmol/l increase in admission glucose level (above 9 mmol/l) was associated with a 10% (95% confidence interval (CI): 7 -13%) increased risk for all-cause mortality. A 1 mmol/l higher average glucose level (above 8 mmol/l) was an additional independent predictor of mortality (HR 1.11, 95% CI: 1.03 - 1.20). At 30 days, 16.8% (97/579) of the patients with an admission glucose level in the highest tertile (>9.8 mmol/L) had died vs 5.2% (59/1134) of those with a lower admission glucose level. CONCLUSION: In a high risk ICCU population, both high admission glucose levels as well as high average glucose levels during hospitalization were independently associated with increased mortality, even when accounting for other risk factors and parameters of disease severity. PMID- 24338290 TI - Diagnostic performance of rising, falling, or rising and falling kinetic changes of high-sensitivity cardiac troponin T in an unselected emergency department population. AB - BACKGROUND: Current ESC guidelines for the diagnosis of myocardial infarction consider a rise and/or fall of cardiac biomarkers. However, whether rising or falling patterns of high-sensitivity cardiac troponin T (hs-cTnT) improve the discrimination of ST-elevation myocardial infarction (non-STEMI) from non-acute coronary syndromes (ACS) has not been evaluated yet. METHODS: We compared protocols of rising and falling absolute and relative hs-cTnT changes in an unselected emergency department population. RESULTS: A total of 635 patients with unstable angina pectoris (UAP), non-STEMI, or acute symptoms and increased hs cTnT (>99th percentile) were enrolled. Of these, 572 patients met the inclusion criteria of consistently rising patterns (n=254, 44.4%), consistently falling patterns (n=224, 39.2%), or falling patterns after an initial rise (n=94, 16.4%). Final diagnoses included 66 (11.5%) patients with UAP, 141 (24.7%) patients with non-STEMI, and 365 (63.8%) patients with hs-cTnT elevations not due to ACS. Rising values were found more frequently in patients with non-STEMI, as compared to non-ACS (OR 3.69, 95% CI 2.46-5.53; p<0.0001), and falling patterns were observed more frequently in patients with non-ACS conditions (OR 3.56, 95% CI 2.24-5.63; p<0.001). Addition of rising but not falling changes increased diagnostic performance of hs-cTnT concentrations at presentation: positive: AUC 0.680 (95% CI 0.618-0.742) vs. 0.861 (95% CI 0.822-0.900; p<0.0001), negative: AUC 0.678 (95% CI 0.545-0.812) vs. 0.741 (95% CI 0.635-0.847). A 20% criterion as proposed by ESC guidelines performed equally for positive and negative changes only when admission hs-cTnT values were considered: AUC 0.785 (95% CI 0.726 0.845) vs. AUC 0.763 (95% CI 0.681-0.845); p=ns. CONCLUSIONS: Detection of rising but not falling hs-cTnT values improves discrimination of non-STEMI from non-ACS in an unselected emergency department population. PMID- 24338291 TI - Diagnosis of MI after CABG with high-sensitivity troponin T and new ECG or echocardiogram changes: relationship with mortality and validation of the universal definition of MI. AB - AIMS: Criteria for diagnosing myocardial infarction (MI) after coronary artery bypass grafting (CABG) are controversial. Uncertainties remain around the optimal threshold for biomarker elevation and the need for associated criteria. There are no studies of high-sensitivity troponin (hs-TnT) after CABG. We assessed whether using hs-TnT to define MI after CABG was associated with 30-day and medium-term mortality and evaluated the utility of adding to the troponin criteria new Q waves or imaging evidence of new wall motion abnormality as suggested in the Universal Definition of MI. METHODS: Isolated CABG was performed in 818 patients from July 2010 to June 2012 and hs-TnT was measured 12-24 hours after CABG. Patients with rising baseline or missing troponins (n=258) were excluded. Thresholds of 140 ng/l (10-times 99th percentile upper reference limit) and 500 ng/l (10-times coefficient of variation of 10% for fourth-generation troponin T applied to hs-TnT) were prespecified. RESULTS: Mean follow up was 1.8+/-0.6 years. On multivariate analyses, isolated hs-TnT rise >140 ng/l (n=360) or >500 ng/l (n=162) were not associated with mortality. Additional ECG and/or echocardiographic criteria plus hs-TnT >140 ng/l was associated with 30-day mortality (hazard ratio, HR, 4.92, 95% CI 1.34-18.1; p=0.017) and medium-term mortality (HR 3.44, 95% CI 1.13-10.5; p=0.030), whereas ECG and/or echocardiographic abnormalities with hs-TnT >500 ng/l was not (p=0.281 and p=0.123 for 30-day and medium-term mortality, respectively). CONCLUSIONS: A definition for MI following CABG using hs-TnT with a cut point of 10-times 99th percentile upper reference limit and ECG and/or echocardiographic criteria predicts 30-day and medium-term mortality. These findings validate the Third Universal Definition of type 5 MI. PMID- 24338292 TI - Is the difference in outcome between men and women treated by primary percutaneous coronary intervention age dependent? Gender difference in STEMI stratified on age. AB - AIM: Poorer outcomes in women with ST-elevation myocardial infarction (STEMI) are often attributed to gender differences in baseline characteristics. However, these may be age dependent. We examined the importance of gender in separate age groups of patients with STEMI undergoing primary percutaneous coronary intervention (PPCI). METHODS AND RESULTS: Data of 6746 consecutive patients with STEMI admitted for PPCI between 1998 and 2008 in our hospital were evaluated. Age was stratified into two groups, <65 years (young group) and >=65 years (elderly). Endpoints were enzymic infarct size as well as 30-day and 1 year mortality. We studied a total of 4991 (74.0%) men and 1755 (26.0%) women; 40% of women were <65 years and 60% of men were <65 years of age. In the elderly group (>=65 years), women had more frequently diabetes and hypertension while they smoked less frequently than men. Younger women smoked more often than similarly aged men and had more hypertension. At angiography, single-vessel disease and TIMI 3 flow before PPCI was more present in younger women than men, whereas these differences were not found in the older age group. Patient delay before admission was shorter in men at all ages, while women had lower creatine kinase levels. Younger women had a higher mortality after 30 days (HR 2.1, 95% CI 1.3-3.4) and at 1 year (HR 1.7, 95% CI 1.2-2.6), whereas in the older age group women mortality rates were higher at 30 days (HR 1.5, 95% CI 1.1-2.0) but not at 1 year (HR 1.2, 95% CI 0.9 1.5). After multivariate analysis, 1-year mortality remained significantly higher in women at younger age (HR 1.7, 95% CI 1.1-2.5). Patient delay before admission was shorter in men in both age groups. Creatine kinase levels were in both age groups higher in men. CONCLUSIONS: Differences in mortality between men and women with STEMI treated with PPCI are age dependent. Although young women have less obstructive coronary artery disease and more often TIMI 3 flow before PCI (suggesting a lower risk), survival was worse compared to similarly aged men. Women had a longer patient delay compared to men, but this was not related to gender-specific mortality. PMID- 24338294 TI - Do clinical factors explain persistent sex disparities in the use of acute reperfusion therapy in STEMI in Sweden and Canada? AB - AIMS: This study examined clinical factors associated with sex differences in the use of acute reperfusion therapy (fibrinolysis or primary percutaneous coronary intervention) in ST-elevation myocardial infarction (STEMI) patients, and the interaction between sex and these factors in Sweden and Canada. METHODS: Patients with STEMI in Sweden (n=32,676 from the Register of Information and Knowledge about Swedish Heart Intensive Care Admissions) were compared with similar patients in Canada (n=3375 from the Canadian Global Registry of Acute Coronary Events) for the period 2004-2008. RESULTS: Unadjusted vs. age-adjusted odds ratios (OR) for no reperfusion (women vs. men) were for Sweden 1.57 (95% CI 1.49 1.64) vs. 1.14 (95% CI 1.08-1.20), and for Canada 1.61 (95% CI 1.39-1.87) vs. OR 1.18 (95% CI 1.01-1.39). Sex differences persisted after multivariable adjustments (including prehospital delay, atypical symptoms, diabetes), factors for which no interaction with sex was found. Among women <60 years, adjusting for atypical symptoms in Canada and angiographic data in Sweden made the greatest contribution to explaining observed sex differences. CONCLUSIONS: In both countries, acute reperfusion therapy in STEMI was used less often in women than in men. Factors associated with these sex differences appear to differ between older and younger women. Targeted interventions are needed to optimize care for women with STEMI, as well as sex- and age-stratified reporting of quality indicators to assess their effectiveness. PMID- 24338293 TI - Gender-related mortality trends among diabetic patients with ST-segment elevation myocardial infarction: insights from a nationwide registry 1997-2010. AB - BACKGROUND: Data on temporal trends in outcomes, gender differences, and adherence to evidence-based therapy (EBT) of diabetic patients with ST-segment elevation myocardial infarction (STEMI) are sparse. METHODS: We performed a retrospective analysis of prospectively acquired data on 3565 diabetic (2412 males and 1153 females) STEMI patients enrolled in the Swiss AMIS Plus registry between 1997 and 2010 and compared in-hospital outcomes and adherence to EBT with the nondiabetic population (n=15,531). RESULTS: In-hospital mortality dramatically decreased in diabetic patients, from 19.9% in 1997 to 9.0% in 2010 (p trend<0.001) with an age-adjusted decrease of 6% per year of admission. Similar trends were observed for age-adjusted reinfarction (OR 0.86, p<0.001), cardiogenic shock (OR 0.88, p<0.001), as well as death, reinfarction, or stroke (OR 0.92, p<0.001). However, the mortality benefit over time was observed in diabetic males (p trend=0.006) but not females (p trend=0.082). In addition, mortality remained twice as high in diabetic patients compared with nondiabetic ones (12.1 vs. 6.1%, p<0.001) and diabetes was identified as independent predictor of mortality (OR 1.23, p=0.022). Within the diabetic cohort, females had higher mortality than males (16.1 vs. 10.2%, p<0.001) and female gender independently predicted in-hospital mortality (OR 1.45, p=0.015). Adherence to EBT significantly improved over time in diabetic patients (p trend<0.001) but remained inferior - especially in women - to the one of nondiabetic individuals. CONCLUSIONS: In-hospital mortality and morbidity of diabetic STEMI patients in Switzerland improved dramatically over time but, compared with nondiabetic counterparts, gaps in outcomes as well as EBT use persisted, especially in women. PMID- 24338295 TI - Euro Heart Survey 2009 Snapshot: regional variations in presentation and management of patients with AMI in 47 countries. AB - AIMS: Detailed data on patients admitted for acute myocardial infarction (AMI) on a European-wide basis are lacking. The Euro Heart Survey 2009 Snapshot was designed to assess characteristics, management, and hospital outcomes of AMI patients throughout European Society of Cardiology (ESC) member countries in a contemporary 'real-world' setting, using a methodology designed to improve the representativeness of the survey. METHODS: Member countries of the ESC were invited to participate in a 1-week survey of all patients admitted for documented AMI in December 2009. Data on baseline characteristics, type of AMI, management, and complications were recorded using a dedicated electronic form. In addition, we used data collected during the same time period in national registries in Sweden, England, and Wales. Data were centralized at the European Heart House. RESULTS: Overall, 4236 patients (mean age 66+/-13 years; 31% women) were included in the study in 47 countries. Sixty per cent of patients had ST-segment elevation myocardial infarction, with 50% having primary percutaneous coronary intervention and 21% fibrinolysis. Aspirin and thienopyridines were used in >90%. Unfractionated and low-molecular-weight heparins were the most commonly used anticoagulants. Statins, beta-blockers, and angiotensin-converting enzyme inhibitors were used in >80% of the patients. In-hospital mortality was 6.2%. Regional differences were observed, both in terms of population characteristics, management, and outcomes. CONCLUSIONS: In-hospital mortality of patients admitted for AMI in Europe is low. Although regional variations exist in their presentation and management, differences are limited and have only moderate impact on early outcomes. PMID- 24338296 TI - Outcome up to one year following different reperfusion strategies in acute ST segment elevation myocardial infarction: the Helsinki-Uusimaa Hospital District registry of ST-Elevation Acute Myocardial Infarction (HUS-STEMI). AB - AIMS: Current guidelines prefer primary percutaneous coronary intervention (pPCI) over fibrinolysis in the treatment of acute ST-elevation myocardial infarction (STEMI). Pre-hospital fibrinolysis followed by early invasive evaluation is an alternative that we have used in patients presenting within three hours of symptom onset. We made a survey of patients suffering an acute STEMI over one year to assess mortality and adverse events following either pPCI or fibrinolysis. METHODS AND RESULTS: Of the 448 consecutive STEMI patients, 194 were treated with pPCI and 176 underwent fibrinolysis; 78 patients received no reperfusion treatment within 12 hours (NRT group). The median TIMI risk scores were 4.0, 3.0 and 4.0 in the pPCI, fibrinolysis and NRT groups, respectively (p<0.001). Mortality at one year was 14.4% following pPCI, 5.1% following fibrinolysis and 12.8% in the NRT group (p=0.011 across all groups and p=0.003 between pPCI and fibrinolysis, adjusted for differences in risk factors). The one year composite of cardiovascular death, stroke, reinfarction and new revascularization was 20.1%, 18.2% and 26.9% for the pPCI, fibrinolysis and NRT groups, respectively (p=NS). In patients presenting within three hours of symptom onset, one-year mortality was 3.7% in the fibrinolysis group (n=163) and 15.3% in the pPCI group (n=118) (adjusted p =0.001), while the composite of adverse events was 16.6% in the former group and 19.5% in the latter (p=NS). CONCLUSION: Pre hospital fibrinolysis followed by routine early invasive evaluation provides an excellent reperfusion strategy for low-risk STEMI patients presenting early after symptom onset. PMID- 24338298 TI - Screening factors influencing the production of astaxanthin from freshwater and marine microalgae. AB - Astaxanthin, a carotenoid pigment found in several aquatic organisms, is responsible for the red colour of salmon, trout and crustaceans. In this study, astaxanthin production from freshwater microalga Chlorella sorokiniana and marine microalga Tetraselmis sp. was investigated. Cell growth and astaxanthin production were determined spectrophotometrically at 620 and 480 nm, respectively. Astaxanthin was extracted using acetone and measured subsequent to biomass removal. Aerated conditions favoured astaxanthin production in C. sorokiniana, whereas Tetraselmis sp. was best cultured under unaerated conditions. C. sorokiniana produced more astaxanthin with the highest yield reached at 7.83 mg/l in 6.0 mM in nitrate containing medium compared to Tetraselmis sp. which recorded the highest yield of only 1.96 mg/l in 1.5 mM nitrate containing medium. Production in C. sorokiniana started at the early exponential phase, indicating that astaxanthin may be a growth-associated product in this microalga. Further optimization of astaxanthin production was performed using C. sorokiniana through a 2(3) full factorial experimental design, and a yield of 8.39 mg/l was achieved. Overall, the study has shown that both microalgae are capable of producing astaxanthin. Additionally, this research has highlighted C. sorokiniana as a potential astaxanthin producer that could serve as a natural astaxanthin source in the current market. PMID- 24338297 TI - Patients with microvascular obstruction after primary percutaneous coronary intervention show a gp91phox (NOX2) mediated persistent oxidative stress after reperfusion. AB - BACKGROUND: Persistent oxidative stress may play a key role in microvascular obstruction (MVO). We aimed at assessing the role of platelet gp91phox (NOX2), the catalytic subunit of NADPH oxidase in MVO. METHODS: We enrolled 40 patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention within 12 h from symptoms onset, either with angiographic MVO (n=20) or good angiographic myocardial reperfusion (MR) (n=20). Angiographic MVO was defined as a final thrombolysis in myocardial infarction (TIMI) flow <=2 or TIMI flow of 3 with myocardial blush grade <2. NOX2 and isoprostanes (8-iso PGF2alpha) levels, as assessed by enzyme-linked immunoadsorbent assay (ELISA) or by an enzyme immunoassays, respectively, were measured on admission, at 24 h and pre-discharge. RESULTS: NOX2 levels increased from baseline to pre-discharge in patients with angiographic MVO (20.25 (15-24.75) pg/ml vs 25.50 (17-29.25) pg/ml, p=0.02), but not in MR patients (p=0.45), with a significant interaction between baseline and pre-discharge levels among the two groups (p=0.04). The levels of 8 iso-PGF2alpha showed a trend to increase from baseline to pre-discharge in angiographic MVO patients (295 (183.50-389.25) pmol/l vs 322 (206-370) pmol/l, p=0.06), but not in patients with MR (p=0.56), with a trend for interaction between baseline and pre-discharge levels among the two groups (p=0.09). CONCLUSION: Patients with MVO, but not those with myocardial reperfusion, have a sustained increase of NOX2 and 8-iso-PGF2alpha. Therapies targeting NOX2 or high dosage antioxidants should be tested for MVO prevention and treatment. PMID- 24338299 TI - Enzymatic trends of fructooligosaccharides production by microorganisms. AB - Fructooligosaccharides are influential prebiotics that affect various physiological functions in such a way that they promote positive impact to health. They occur naturally in many fruits and vegetables in trace amounts. However, they are mainly produced commercially by the reaction of microbial enzymes with di- or polysaccharides, such as sucrose or inulin as a substrate. For maximum production of fructooligosaccharides on an industrial level, development of more enzymes with high activity and stability is required. This has attracted the attention of biotechnologists and microbiologists worldwide. This study aims to discuss the new trends in the production of fructooligosaccharide and its effect on numerous health qualities through which it creates great demand in the sugar market. PMID- 24338300 TI - Development of a biosensor for copper detection in aqueous solutions using an Anemonia sulcata recombinant GFP. AB - Fluorescent proteins from marine organisms represent potential candidates for biosensor development. In this paper, we described the isolation of a native green fluorescent protein from Anemonia sulcata and the cloning and purification of its equivalent as a recombinant protein in Escherichia coli. Furthermore, the spectroscopic behaviours of the native and recombinant GFPs were investigated as a function of Cu(2+), Cd(2+), Pb(2+) and Ni(2+) concentration. Our results suggest the high selectivity of both proteins at copper than the other metals and, for the recombinant protein, a great sensitivity at a very low concentration (0.1-1 MUM). Moreover, starting from these data, using the combination of molecular biology techniques and optical setup, we developed a device for the detection of Cu(2+) in water solutions. The quenching effect detected with the device showed that the relative attenuation of the signal (0.46 +/- 0.02 AU) was slightly larger than the data measured by fluorescence spectra (0.65 +/- 0.03 AU). The good sensitivity in the span of two orders of the magnitude of Cu(2+) concentration, the fact that the instrument is made up of low-cost and sturdy parts and the selective quenching of rAsGFP to copper ions make this setup suited as a low cost, on-the-field, copper ion-specific biosensor. PMID- 24338301 TI - New records and new species of mites of the subfamily Harpirhynchinae (Acariformes: Harpirhynchidae) infesting birds in Manitoba, Canada. AB - Five new species and one new genus of the subfamily Harpirhynchinae (Acariformes: Harpirhynchidae) are described from birds in Canada: Harpyrhynchoides heatherae sp. nov. from Junco hyemalis (Passeriformes: Emberizidae), H. botaurus sp. nov. from Botaurus lentiginosus (Pelecaniformes: Ardeidae), H. phalaropus sp. nov. from Phalaropus lobatus (Charadriiformes: Scolopacidae), Neharpyrhynchus loxia sp. nov. from Loxia curvirostra (Passeriformes: Fringillidae), and Fainharpirhynchus contopus gen. nov., sp. nov. from Contopus cooperi (Passeriformes: Tyrannidae). Additionally, 3 species were recorded in Canada (Manitoba) for the first time: Harpyrhynchoides tracheatus (Fritsch, 1954) from Buteo jamaicensis (Accipitriformes: Accipitridae) (new host), H. modestus (Fain, 1976) from Columba livia (Columbiformes: Columbidae) (new host), and Neharpyrhynchus pilirostris (Berlese et Trouessart, 1889) from Passer domesticus (Passeriformes: Passeridae). PMID- 24338302 TI - Ultrastructure of the digestive system and experimental study of feeding in the monogenean skin and fin parasite Macrogyrodactylus congolensis. AB - In the present study, transmission electron microscopy (TEM) has been used to study the ultrastructure of the digestive system, namely the pharynx, oesophageal glands and intestine, of the monogenean skin and fin parasite Macrogyrodactylus congolensis. The pharynx consists of an anterior highly muscular region and a posterior mainly glandular syncytial region. The anterior region is provided with six pharyngeal papillae, the centre of each of which is occupied by electron dense secretory bodies, identical with those in the posterior region of the pharynx. The intestine has an uninterrupted syncytial gastrodermis and the luminal surface is provided with many unbranched lamellae. The intestine of living specimens contains large and small granules which give it a reddish brown colour. Large particles, presumed to be lipid droplets, and small granules, presumed to be melanin granules, were found in the gastrodermis and in the intestinal lumen. Parasites were induced to feed and then preserved for TEM at the following intervals: just after feeding, 30 min after feeding, 1 h 30 min after feeding and 2 h after feeding. The specimens were then processed for TEM and sections cut through the intestine of each specimen were examined with the transmission electron microscope. Three types of vacuoles (V1, V2, V3) were detected in the gastrodermis. Vacuoles V1 have thick walls and are likely to be endocytotic, enclosing luminal contents at the surface of the gastrodermis. V2 vacuoles may be lysosomes that fuse with V1 vacuoles. V3 vacuoles may serve to dispose of residual digestive material into the lumen. PMID- 24338303 TI - Alloglossidium demshini sp. nov. (Digenea: Macroderoididae) from leeches in Minnesota. AB - Alloglossidium demshini sp. nov. is described based on specimens from leeches Haemopis grandis collected in northwestern Minnesota. The new species is morphologically closest to Alloglossidium schmidti. The two species can be readily differentiated based on several morphological characters. The cirrus sac in A. schmidti is almost entirely situated anterior to the ventral sucker while in A. demshini sp. nov. it is situated dorsal to the ventral sucker and its proximal end almost reaches the posterior end of ventral sucker or extends posterior to it. The new species has a prepharynx that is substantially longer than the esophagus while in A. schmidti the situation is the opposite. The two species also differ in the position of the ovary and the position of the testes and vitelline fields in relation to the ends of the ceca. Hirudineatrema oschmarini described from leeches in Eastern Palaearctic and Alloglossidium richardsoni described in North America demonstrate great morphological similarity. Nevertheless, Hirudineatrema cannot be synonymized with Alloglossidium at this point because of several peculiar morphological features of H. oschmarini such as a V-shaped excretory bladder and the apparent presence of a true seminal receptacle in the latter species. These features need to be re evaluated before any taxonomic decision can be made. PMID- 24338304 TI - A widespread distribution for Arostrilepis tenuicirrosa (Eucestoda: Hymenolepididae) in Myodes voles (Cricetidae: Arvicolinae) from the Palearctic based on molecular and morphological evidence: historical and biogeographic implications. AB - Hymenolepidid cestodes in Myodes glareolus from Lithuania and additional specimens originally attributed to Arostrilepis horrida from the Republic of Belarus are now referred to A. tenuicirrosa. Our study includes the first records of A. tenuicirrosa from the European (western) region of the Palearctic, and contributes to the recognition of A. horrida (sensu lato) as a complex of cryptic species distributed broadly across the Holarctic. Specimens of A. tenuicirrosa from Lithuania were compared to cestodes representing apparently disjunct populations in the eastern Palearctic based on structural characters of adult parasites and molecular sequence data from nuclear (ITS2) and mitochondrial (cytochrome b) genes. Morphological and molecular data revealed low levels of divergence between eastern and western populations. Phylogeographic relationships among populations and host biogeographic history suggests that limited intraspecific diversity within A. tenuicirrosa may reflect a Late Pleistocene transcontinental range expansion from an East Asian point of origin. PMID- 24338305 TI - Fasciola hepatica - the pilot study of in vitro assessing immune response against native and recombinant antigens of the fluke. AB - Fasciola hepatica is a liver fluke that infects 2.4 million of people and causes great economical loss in animal production. To date a 100% effective vaccine has not been developed and the disease is controlled by drug therapy. Great efforts are put into development of effective vaccine against parasite what is difficult since Fasciola spp. (like other helmints) during evolutionary process has developed sophisticated and efficient methods to evade immune response. During preliminary experiments it is convenient to use cell lines which are relatively cheap and allow for reproducible comparison of results between laboratories. We stimulated BOMA (bovine monocyte/macrophage cell line) and BOMAC (bovine macrophage cell line) with native or recombinant antigens of Fasciola hepatica and assessed IFN-gamma, IL-4 and TNF-alpha level upon stimulation. We observed diminished secretion of proinflammatory TNF-alpha in LPS activated BOMA cells stimulated with Excretory/Secretory products of adult fluke (Fh-ES). We also observed greater changes in gene expression in LPS activated BOMA cells than in non activated BOMA cells upon stimulation using Fh-ES. The results show possibility of using cell lines for in vitro research of bovine immune response against liver fluke, although this model still requires validation and further characterization. PMID- 24338306 TI - Kinetics of anti-Neospora antibodies during the period of two consecutive pregnancies in chronically infected dairy cows. AB - The course of anti-Neospora antibody kinetics during two consecutive pregnancies has been evaluated in five chronically infected dairy cows. The blood samples of cows were collected monthly. Anti-Neospora antibodies in blood sera were detected by indirect ELISA (ID-VET, France). During whole period of the study cows remained seropositive; with S/P% values (iELISA) ranging from 94 to 214%. The antibody kinetics determined by iELISA showed a significant increase (P<0.0059) of specific IgG antibodies in the third trimester of both pregnancies. The monitored cows gave birth to 10 healthy calves (4 steers and 6 heifers). To confirm the occurrence of vertical transmission of Neospora from mothers to offspring in the herd, dam-daughter serology was performed. Anti-Neospora antibodies was found in 4 from 6 heifers (>6 months old). Study presents original data reporting on the very similar persistent pattern of anti-Neospora antibody levels during the third trimester of pregnancies in all five dairies. Based on the high seropositivity of female offspring, the reactivation of a latent infection of cows rather than a re-infection can be supposed. PMID- 24338307 TI - Immune responses of B. malayi thioredoxin (TRX) and venom allergen homologue (VAH) chimeric multiple antigen for lymphatic filariasis. AB - Although multiple vaccine strategy for lymphatic filariasis has provided tremendous hope, the choice of antigens used in combination has determined its success in the previous studies. Multiple antigens comprising key vaccine candidates from different life cycle stages would provide a promising strategy if the antigenic combination is chosen by careful screening. In order to analyze one such combination, we have used a chimeric construct carrying the well studied B. malayi antigens thioredoxin (BmTRX) and venom allergen homologue (BmVAH) as a fusion protein (TV) and evaluated its immune responses in mice model. The efficacy of fusion protein vaccine was explored in comparison with the single antigen vaccines and their cocktail. In mice, TV induced significantly high antibody titer of 1,28,000 compared to cocktail vaccine TRX+VAH (50,000) and single antigen vaccine TRX (16,000) or VAH (50,000). Furthermore, TV elicited higher level of cellular proliferative response together with elevated levels of IFN-gamma, IL-4 and IL-5 indicating a Th1/Th2 balanced response. The isotype antibody profile showed significantly high level of IgG1 and IgG2b confirming the balanced response elicited by TV. Immunization with TV antigen induced high levels of both humoral and cellular immune responses compared to either cocktail or antigen given alone. The result suggests that TV is highly immunogenic in mice and hence the combination needs to be evaluated for its prophylactic potential. PMID- 24338308 TI - A transmission electron microscopical study of the tegument of Maritrema feliui (Digenea: Microphallidae). AB - The tegument of the microphallid digenean Maritrema feliui, examined by means of TEM, is described as a syncytial epithelium organised into two layers. The outer layer is an external anucleate, cytoplasmic region connected to a second region composed of nucleate perikarya (cytons) deeply embedded in the surrounding cortical parenchyma. The surface layer of the tegument is covered by a plasma membrane with many deep invaginations, which are apparently pinocytotic. This layer also bears numerous large, electron-dense spines of two types, which are intracellular and attached to the basal plasma membrane. Its cytoplasm is rich in free ribosomes, contains numerous mitochondria, disc-shaped granules frequently arranged in a rouleau, and several large, moderately electron-dense, membranous bodies. The subtegumentary perikarya and their nuclei, which are both flattened, are described in detail, as are their connections with the surface tegument. These perikarya appear to be the source of the disc-shaped granules and some of the other inclusions present in the surface layer. The main characteristics of the tegumental structure of M. feliui are commented upon in relation to the findings of previous publications and their suggested functions. PMID- 24338309 TI - Parasitism of Odonata by Arrenurus (Acari: Hydrachnidia) larvae in the Lake Swidwie, nature reserve (NW Poland). AB - Larvae of a vast majority of water mite species are parasites of aquatic insects. Owing to this, they migrate to new localities, and are able to survive unfavourable environmental conditions. This also concerns species from subgenus Arrenurus s. str., parasites of dragonflies. The detailed analysis of this phenomenon, however, has only been possible in the last several years, since the key to the identification of larvae from genus Arrenurus Dug. was published. In 2010, the parasitism of Arrenurus s. str. larvae on dragonflies in the Lake Swidwie reserve (NW Poland) was analysed. Larvae of 9 species of water mites were recorded on 107 imagines of dragonflies from 8 species. The following were identified as hosts of water mites for the first time: Anax imperator, Libellula quadrimaculata, and Leucorrhinia caudalis. The highest prevalence occurred in the case of: Erythromma najas and Lestes dryas (100%), Coenagrion pulchellum (96.5%), and C. puella (80.0%). Coenagrion pulchellum was infested by 9 species of parasites, C. puella by 6, and Erythromma najas and Lestes dryas by three species. The highest number of host species occurred in the case of Arrenurus maculator (5); followed by A. cuspidator, A. batillifer cf., A. bicuspidator, and A. tetracyphus (3 each); A. papillator, A. tricuspidator, and A. bruzelii (2 each), and A. claviger (1). Differentiation of preferences of particular parasites towards various parts of the host body was observed, probably related to the coevolution of parasites and hosts, and competition between the host species. The body sizes of the parasites suggest that approximately 50% of body size growth of water mites from subgenus Arrenurus s. str. occurs at the stage of parasitic larva. PMID- 24338310 TI - Observations on nematodes from the Indonesian shortfin eel Anguilla bicolor bicolor McClelland in India, including a revalidation of Heliconema ahiri Karve, 1941 (Physalopteridae). AB - Two species of parasitic nematodes, Heliconema ahiri Karve, 1941 (Physalopteridae) and Procamallanus (Spirocamallanus) anguillae Moravec et al., 2006 (Camallanidae), were recorded from the Indonesian shortfin eel Anguilla bicolor bicolor Mc-Clelland in the Chalakkudi River and Veli Lake, respectively, both Kerala, India. The former species (H. ahiri), rediscovered from eels in India after 82 years from its original description, has been redescribed and revalidated based on its specific feature (presence of groups of minute denticles in the mouth) distinguishing it from other congeners; its finding in A. b. bicolor represents a new host record. The latter species (P. anguillae) has been recorded in India for the first time. SEM examination of its first-stage larvae from uterus has shown that P. anguillae is another species of Procamallanus whose larvae possess a crown of digit-like processes at the tail tip. PMID- 24338311 TI - Gonad-infecting philometrid Philometra philippinensis sp. nov. (Nematoda, Philometridae) from the bigeye barracuda Sphyraena forsteri Cuvier (Sphyraenidae) off Mariveles, Bataan Province, Philippine archipelago. AB - We conducted a parasitological study to identify nematodes infecting the gonads of bigeye barracuda Sphyraena forsteri Cuvier (Sphyraenidae) caught in the West Philippine Sea, off the Mariveles coast, Bataan Province, the Philippine archipelago. Males and very tiny nongravid female philometrid nematodes were collected from the ovaries of the fish. Based on light and scanning electron microscope observations, and supported by molecular analyses of the partial nucleotide sequences of the 18S small subunit ribosomal DNA, the philometrid nematode was determined to be a new species belonging to the genus Philometra Costa, 1845 in the family Philometridae (Nematoda: Dracunculoidea), and was named P. philippinensis sp. nov. This new species was clearly distinguishable morphologically from other congeners that parasitize the gonads of marine fishes. Males have unique sickle-shaped spicules and gubernaculum, and a vulva-like cloacal opening. Following Dentirumai philippinensis Quiazon et Moravec, 2013 and Philometra robusta Moravec, Moller et Heeger, 1992, this is the third philometrid species and the first gonad-infecting philometrid from the Philippine archipelago. PMID- 24338312 TI - The first detection of nematodes Ashworthius sidemi in elk Alces alces (L.) in Poland and remarks of ashworthiosis foci limitations. AB - Ashworthius sidemi, a nematode belonging to the family of Trichostrongylidae, is a primary parasite of the Asian deer, mainly sika deer (Cervus nippon), with which it was introduced to Ukraine, as well as Slovakia, the Czech Republic and France. Migrating red deer carried this parasite from neighboring countries to Polish territory. Until now, in Poland, this parasite has been recorded in European bison, red deer, roe deer and fallow deer. As a result of post-mortem examinations of 10 elk, 2 of them from the Augustow Forest and Biebrza Marshes, A. sidemi were found in abomasa for the first time in Poland. The intensity of the invasions was 120 and 7 specimens, respectively. This finding of Ashworthius sidemi in elk indicates a further expansion of the focus of ashworthiosis in BiaLowieza towards the north into the Biebrza Marshes and the Augustowska Forest. The growth of the elk population and their tendency for long distance migrations can contribute to the spread of the parasitosis in much greater distances than deer. On the basis of our own research and data from the literature, the current spread of ashworthiosis in Poland is discussed. PMID- 24338313 TI - Trichomonas vaginalis acidic phospholipase A2: isolation and partial amino acid sequence. AB - Sexually transmitted diseases are a major cause of acute disease worldwide, and trichomoniasis is the most common and curable disease, generating more than 170 million cases annually worldwide. Trichomonas vaginalis is the causal agent of trichomoniasis and has the ability to destroy in vitro cell monolayers of the vaginal mucosa, where the phospholipases A2 (PLA2) have been reported as potential virulence factors. These enzymes have been partially characterized from the subcellular fraction S30 of pathogenic T. vaginalis strains. The main objective of this study was to purify a phospholipase A2 from T. vaginalis, make a partial characterization, obtain a partial amino acid sequence, and determine its enzymatic participation as hemolytic factor causing lysis of erythrocytes. Trichomonas S30, RF30 and UFF30 sub-fractions from GT-15 strain have the capacity to hydrolyze [2-(14)C-PA]-PC at pH 6.0. Proteins from the UFF30 sub-fraction were separated by affinity chromatography into two eluted fractions with detectable PLA A2 activity. The EDTA-eluted fraction was analyzed by HPLC using on-line HPLC tandem mass spectrometry and two protein peaks were observed at 8.2 and 13 kDa. Peptide sequences were identified from the proteins present in the eluted EDTA UFF30 fraction; bioinformatic analysis using Protein Link Global Server charged with T. vaginalis protein database suggests that eluted peptides correspond a putative ubiquitin protein in the 8.2 kDa fraction and a phospholipase preserved in the 13 kDa fraction. The EDTA-eluted fraction hydrolyzed [2-(14)C-PA]-PC lyses erythrocytes from Sprague-Dawley in a time and dose-dependent manner. The acidic hemolytic activity decreased by 84% with the addition of 100 MUM of Rosenthal's inhibitor. PMID- 24338314 TI - Prevalence of subclinical coccidiosis in river buffalo calves of southwest of Iran. AB - Despite the importance of buffalo farming in Iran, little is known in this country about the abundance and distribution of Eimeria spp. in the animal species. The present study was designed to investigate the prevalence and species characterization of Eimeria oocysts in river buffalo calves of Khuzestan province, southwest of Iran. Of the total 108 fecal samples examined for Eimeria, 108 (100%) were found infected with 11 species of the parasite. Among the identified species of Eimeria, E. bovis was found to be the predominant etiological agent (76.85%), followed in order by E. canadensis (62.96%), E. zuernii (47.2%), E. ellipsoidalis (26.85%), E. subspherica (25.92%), E. brasiliensis (19.4%), E. auburnensis (18.51%), E. alabamensis (14.81%), E. pellita (11.1%), E. illinoisensis (5.5%) and E. bukidnonensis (2.7%). In most calves multiple infections with three species were present. While, 20.7% of calves showed heavy infection, 50.4 and 24.8% of calves showed weak and moderate infection, respectively. There was no significant difference in the OPG values between the calves of different localities. There was also no significant difference between the prevalence rate of infection in males and females. A total of 16.6% of all faecal samples were found to be diarrheic. A highly significant relationship could be identified between the occurrence of diarrhea and the level of E. bovis and E. zuernii oocysts excretion. Considering the pervasive occurrence and negative effects of the infection on the health condition and the growth performance of buffalo calves, infections should receive increased attention by both farmers and veterinarians. PMID- 24338315 TI - Parasites of juvenile golden grey mullet Liza aurata Risso, 1810 in Sarikum Lagoon Lake at Sinop, Turkey. AB - Juvenile golden grey mullet, Liza aurata were collected from Sarikum Lagoon Lake which connected to the Black Sea at Sinop, Turkey and examined for parasitic fauna. A total of 219 fish were investigated throughout a 1-year period. Parasite species recovered were Trichodina lepsii, T. puytoraci, Gyrodactylus sp., Ligophorus cephali, Ligophorus mediterraneus, Solostamenides mugilis, Ascocotyle sp. (metacercaria) and Ergasilus lizae. Overall infection prevalence (%) and mean intensity values were 95.9% and 412.65 +/- 85.31 parasites per infected fish, respectively. Infection prevalence and mean intensity values for each parasite species in relation to season and fish size were also determined and discussed. While Ligophorus cephali and L. mediterraneus are new records for Turkish parasite fauna, the juvenile Liza aurata is a new host record for Ligophorus cephali and L. mediterraneus. PMID- 24338316 TI - Toxoplasma gondii, Neospora caninum and tick-transmitted bacterium Anaplasma phagocytophilum infections in one selected goat farm in Slovakia. AB - Parasitic diseases of livestock together with poor welfare conditions can negatively affect the health status and production of small ruminants. Protozoan parasites and tick-borne infectious agents are common threat of livestock including small ruminants mostly during the pasture season. Therefore the priority of the study was to analyse the circulation and presence of two protozoan parasites Toxoplasma gondii and Neospora caninum as well as tick transmitted bacterium Anaplasma phagocytophilum in one selected goat farm in Eastern Slovakia. Throughout a three-year study period we have repeatedly screened the sera and blood of goats and dogs from monitored farm. In total, 343 blood serum samples from 116 goats were examined by ELISA. The mean seropositivity for T. gondii was 56.9% (66/116, CI (95%) = 48-66.0) and 15.5% (18/116, CI (95%) = 9.3-22.7) for N. caninum. The permanent occurrence of anti Toxoplasma and anti-Neospora antibodies was detected in repeatedly examined goats during the whole monitored period. The presence of both parasites in the flock was analysed by PCR. DNA of T. gondii was confirmed in 12 out of 25 Toxoplasma seropositive goats and N. caninum in 14 samples out of 18 Neospora-seropositive animals; four goats were co-infected with both pathogens. The risk of endogenous transmission of both parasites was pursued by examination of 41 kid's sera, where seropositivity for toxoplasmosis was 31.7% and for neosporosis 14.6%. In dogs 61.1% seropositivity for T. gondii and 38.9% for N. caninum was found, however, their faeces were negative for coccidian oocysts. Eight out of 108 tested animals were infected with A. phagocytophilum, the causative agent of tick-borne fever. Seven of them were simultaneously infected with T. gondii and A. phagocytophilum, out of which four goats were concurrently infected with all three pathogens. PMID- 24338317 TI - New data on the occurrence of Acanthocephala in some fish in Admiralty Bay (South Shetland Islands). AB - New data on the infection with Acanthocephala of 33 fish caught in Admiralty Bay in November 2007 to January 2008 are given. These fish belong to 5 species: Notothenia rossii (22 immature specimens), Lindbergichthys nudifrons (n = 7), Trematomus bernacchii (n = 1), T. newnesi (n = 1) and Harpagifer antarcticus (n = 2). Three species of Echinorhynchida: Aspersentis megarhynchus, Metacanthocephalus dalmori and M. johnstoni and four species of Polymorphida: Corynosoma arctocephali, C. bullosum, C. hamanni and C. pseudohamanni, were found. Prevalence of N. rossii and L. nudifrons was 100%. The mean abundance of infection of N. rossii (125.09) was larger than that of Notothenia coriiceps (82.93). Data of infection of N. rossii in 2007 was almost identical with that in 1979 (mean abundance 118.66). The most abundant in this host were A. megarhynchus, M. johnstoni, C. hamanni and C. pseudohamanni (mean abundances 36.36, 29.77, 13.86 and 44.73, respectively). In total Echinorhynchida were more abundant than Polymorphida in 2007/08 (66.18 versus 58.91). Reverse situation was in 1979 (mean abundance 47.36 for Echinorhynchida and 71.3 for Polymorphida. Only 7 L. nudifrons were examined in 2007/08 and Echinorhynchida were more numerous in this host (mean abundance 26.71) than Polymorphida (10.29). Single specimens of other fish were infected with a few Acanthocephala belonging to species recorded in the same hosts with those found in 1978/79. PMID- 24338318 TI - Associations between Demodex species infestation and various types of cancer. AB - Tumor-associated immune system cells secrete protease and cytokines that can inhibit the immune response. In particular, T-cell effector functions could be inhibited, potentially causing an increase in parasitic infestations. Demodex species are common inhabitants of normal hair follicles. Humans are the specific host for two species Demodex folliculorum and D. brevis. The aim of this study was to investigate the incidence and infestation of D. folliculorum and D. brevis in patients with cancer. In the present study, 101 patients with cancer were selected from among patients who were diagnosed and treated for cancer. The cancer patients were divided into four groups according to cancer type. Slides were examined for parasites using light microscopy at magnifications of *40 and *100. Infestation was defined as having at least five living parasites/cm(2) of skin. The ages of the patients with cancer ranged between 38 and 82 years, with a mean of 65.5+/-10.1 years. It was determined that 77 of the 101 (76.2%) cancer patients were positive for Demodex species. Infestation was positive in 18 (47.4%) of the 38 cases in the breast cancer group, 7 (29.2%) of the 24 cases in the lung cancer group, 5 (18.5%) of the 27 cases in the gastrointestinal system cancer group, and 2 (16.7%) of the 12 cases in the urogenital system cancer group. Results showed that the rate of Demodex species infestation was higher in patients with breast cancer. Thus, cancer - and particularly breast cancer - is a risk factor for Demodex species infestation. PMID- 24338319 TI - Bat flies (Diptera: Streblidae, Nycteribiidae) and mites (Acari) associated with bats (Mammalia: Chiroptera) in a high-altitude region in southern Minas Gerais, Brazil. AB - A total of 71 bat flies belonging to families Nycteribiidae and Streblidae, and 37 mites were collected on 12 species of bats (Phyllostomidae and Vespertilionidae) from the Chapada do Abanador (Minas Gerais, Brazil), between July 2009 and April 2010. Two new occurrences of ectoparasites were recorded on Histiotus velatus (bat fly Basilia producta) and on Carollia perspicillata (mite Parichoronyssus bakeri). Five new occurrences were recorded for the state of Minas Gerais, increasing the range for bat flies Anatrichobius passosi, Paraeuctenodes similis, Basilia juquiensis, Basilia producta and for mite Periglischrus vargasi. Moreover, two new species of mites were recorded for Brazil (P. bakeri and Macronyssus aff. leislerianus). With regard to infracommunities, the most frequent association was between Anastrebla modestini and Exastinion clovisi on bat Anoura geoffroyi. This study contributed to characterize the fauna of bat ectoparasites in representative but poorly-sampled environments of the Atlantic Forest, the campos de altitude (high altitude grasslands) and cloud forests of southern Minas Gerais. PMID- 24338320 TI - Genetic diversity in human malarial parasites of Khyber Agency Pakistan. AB - Malaria is wide spread in poor world and its burden has been assessed by the enumeration of malarial parasites in blood of patients. This study was designed to find a relationship between social structure, and spread of malaria in Khyber agency. The average parasite density was 2050 parasite/MUl in Khyber Agency. Due to economic and social setup most of the people have habit of sleeping in open air thus playing role in high malaria prevalence and Plasmodium vivax remains the prevalent species. Genetic study performed on 110 Blood samples showed less genetic diversity for both Plasmodium vivax and Plasmodium falciparum. Eight alleles were distinguished both for Pvmsp 3alpha and Pvmsp 3beta in total of 20 and 39 amplified samples of P. vivax respectively. Out of 17 samples amplified for P. falciparum 11 showed genotype K1 and 10 for MAD at Pfmsp-1 while 14 alleles were identified for 3D7/1C and two for FC27 of corresponding families of Pfmsp-2 gene. This shows that Plasmodium parasites are not genetically diverse in Khyber agency. PMID- 24338322 TI - Can the studies at a spatial scale of 100s meters detect the spatiotemporal fluctuations of a parasite assemblage? AB - The importance of small-scale heterogeneity in local factors which overrides that of larger-scales factors, suggest that local factors play a major role in determining the richness and prevalence of larval digeneans in intertidal gastropods. The restricted distribution of the snail Heleobia australis along a 500 m transect in Cangrejo creek (Mar Chiquita, Argentina) provides a good opportunity to test the assumption that a study at spatial scale of 100s meters can detect spatiotemporal fluctuations of a larval digenean assemblage. To analyze that, 3600 specimens of H. australis were collected seasonally during the year 2011. A quantitative variation and a space-time interaction between sampling points and seasons of the year for the total prevalence of larval digeneans and snail's densities were found, as well as a positive correlation with abiotic factors. These results revealed that the fluctuations in the community of larval digeneans of the snail H. australis can be detected at small spatial scale, using its natural distribution of 500 m. This study also highlights the importance of seasonality as a factor that must be considered in studies focused on the search for patterns structuring the communities of larval digeneans, at medium and large scales. PMID- 24338321 TI - First report of Eucoleus boehmi in red foxes (Vulpis vulpis) in Denmark, based on coprological examination. AB - Red foxes can be infected with diverse range of parasite species that can be transmitted to humans and pet animals, and the differential diagnosis is essential for veterinary and zoonotic risk assessment. In the present study, faecal flotation and microscopy of parasite eggs was done on 31 foxes originating from two distant localities in Denmark, the city of Copenhagen in the north east part of the island Zealand and from the southern part of the peninsular Jutland. In total, eggs of Eucoleus boehmi were recovered from a surprisingly high number of foxes (n = 22 samples; 71%). The findings represent the first observations of E. boehmi in Denmark, which is likely an overlooked infection of the upper respiratory tract of red foxes, which can be also found in other canids. Several morphological features of the eggs of E. boehmi can be used to distinguish it from other the closely related trichuroid eggs. Detecting cardiopulmonary parasites by faecal examination can be indicative of the presence of cardiopulmonary parasites based on the more sensitive post mortem analysis. PMID- 24338323 TI - A survey of biting midges of the genus Culicoides Latreille, 1809 (Diptera: Ceratopogonidae) in NE Bulgaria, with respect to transmission of avian haemosporidians. AB - This study presents data from a molecular survey of the species of the genus Culicoides from the region of Kalimok Field Station (NE Bulgaria) and haemosporidian parasites occurring in them in order to investigate the host parasite specificity of haemosporidians to their dipteran vectors. The identification of Culicoides spp. was carried out by morphological and molecular genetic methods. We collected and analysed 230 individuals of the genus Culicoides. Nine species were found. Eight species were identified morphologically; Culicoides obsoletus, C. riethi, C. newsteadi, C. circumscriptus, C. festivipennis, C. punctatus, C. pictipennis and C. puncticollis. The ninth species might be classified as either of C. nubeculosus or C. riethi and its identification needs additional investigations. The total prevalence of Haemoproteus in the examined biting midges was 2.17%. Three individuals of C. pictipennis were infected with the Haemoproteus lineage TURDUS2 (prevalence 16.67%), a common parasite of thrushes (Turdidae). Two individuals of C. circumscriptus contained Haemoproteus lineages (prevalence 2.78%); these were the lineage HAWF2 (previously reported from Coccothraustes coccothraustes) and a new lineage CULCIR1 not previously reported in the literature. PMID- 24338324 TI - Human dirofilariasis due to Dirofilaria repens in Ukraine, an emergent zoonosis: epidemiological report of 1465 cases. AB - The filarial nematode Dirofilaria repens is currently considered to be one of the most extensively spreading human and animal parasites in Europe. In Ukraine, reporting cases of dirofilariasis has been mandatory since 1975, and the disease was included in the national surveillance system for notifiable diseases. Up until December 31st 2012, a total of 1533 cases have been registered, with 1465 cases occurring within the previous 16 years. Most of the cases of dirofilariasis were registered in 6 regions: Kyiv, and the Donetsk, Zaporizhzhya, Dnipropetrovsk, Kherson and Chernihiv oblasts. In the years 1997-2002 the highest incidence rate was noted in the Kherson oblast in the south of the country (9.79 per 100 000 people), and the lowest in western Ukraine (0.07-1.68 per 100 000 people). D. repens infections were registered in all oblasts. Parasitic lesions were most often located in the head, the subconjunctival tissue and around the eyes. D. repens lesions were also found in the limbs, torso, male sexual organs, and female mammary glands. Dirofilariasis was diagnosed in persons aged from 11 months to 90 years old, most often among people between 21-40 years of age. Most patients had only one parasitic skin lesion; the majority of isolated nematodes were female. The results of our analysis point to a constant increase in D. repens dirofilariasis incidence in humans in Ukraine. Despite educational efforts, infections have become more frequent and the territory in which the disease occurs has enlarged to encompass the whole of Ukraine. Nevertheless, the Ukrainian sanitary-epidemiological services managed to achieve some measure of success, e.g. by creating a registration system for D. repens infections and establishing proper diagnostics for the disease. PMID- 24338325 TI - Using the giant Australian cuttlefish (Sepia apama) mass breeding aggregation to explore the life cycle of dicyemid parasites. AB - Dicyemid mesozoan parasites, microscopic organisms found with high intensities in the renal appendages of benthic cephalopods, have a complex, partially unknown life cycle. It is uncertain at which host life cycle stage (i.e. eggs, juvenile, adult) new infection by the dispersive infusoriform embryo occurs. As adult cephalopods have a short lifespan and die shortly after reproducing only once, and juveniles are fast-moving, we hypothesize that the eggs are the life cycle stage where new infection occurs. Eggs are abundant and sessile, allowing a huge number of new individuals to be infected with low energy costs, and they also provide dicyemids with the maximum amount of time for survival compared with infection of juvenile and adult stages. In our study we collected giant Australian cuttlefish (Sepia apama) eggs at different stages of development and filtered seawater samples from the S. apama mass breeding aggregation area in South Australia, Australia, and tested these samples for the presence of dicyemid DNA. We did not recover dicyemid parasite cytochrome c oxidase subunit I (COI) nucleotide sequences from any of the samples, suggesting eggs are not the stage where new infection occurs. To resolve this unknown in the dicyemid life cycle, we believe experimental infection is needed. PMID- 24338326 TI - First record of Aedes albopictus in Slovakia. AB - During a routine inspection of the mosquito fauna in the Kosicka Basin (Eastern Slovakia), in one of the monitored locations we have caught 4 females of the invasive mosquito Aedes albopictus, using the CO2 baited CDC traps. Occurrence of this particular mosquito has already been reported in many European countries; in Slovakia, however, this is the first finding ever. The finding of Ae. albopictus extends the list of the mosquito fauna in Slovakia to 50 species and Slovakia thus ranks among other 20 European countries where this mosquito was observed. The presence of Ae. albopictus increased the probability of transmission of canine and human dirofilariosis in urban environment. PMID- 24338327 TI - Molecular survey of parasites in introduced Pelophylax perezi (Ranidae) water frogs in the Azores. AB - Water frogs, Pelophylax perezi, that are introduced in the Azores, were screened for parasites using PCR primers known to amplify Apicomplexa parasites, and using nematode-specific primers. With the former, three different organisms were detected: Hepatozoon, a trichodinid protozoan ciliate and a possible Stramenopile. Using the latter set of primers, a single unknown spirurid nematode was also detected. Phylogenetic analyses indicate that Hepatozoon detected within amphibian hosts appear to form a clade, although relationships of these parasites do not match the vertebrate intermediate host phylogeny. Regarding the possible Stramenopile, it is unclear whether this organism was actually present on the amphibian or in the water on the surface of the tissue sample. Our findings highlight that many different organisms can be detected with these primers and that they can be used to screen introduced host populations to detect parasites that have been brought with them. PMID- 24338328 TI - Detection of Dirofilaria immitis in mid-western arid Argentina. AB - Dirofilariosis, caused by Dirofilaria immitis and D. repens, is (re-) emerging worldwide. Dogs are the main reservoirs, while human infection has recently become an important focus of interest and attention. In Argentina, canine D. immitis infection has been described in eastern and northern subtropical and temperate humid regions, but never reported in mid-western arid regions so far. In this research note we report for the first time the occurrence of autochthonous human and canine D. immitis infection in the region. PMID- 24338329 TI - Effects of Echinostoma caproni miracidia dose on the neutral and polar lipids of Biomphalaria glabrata as determined by high-performance thin-layer chromatography. AB - The effects of a 5 versus 25 miracidia exposure of Echinostoma caproni on the lipid composition of Biomphalaria glabrata was studied using high performance thin layer chromatography (HPTLC)-densitometry. A 50 miracidia dose was not used because such a high level of exposure caused severe snail mortality by 3 weeks post-exposure (PE). Lipids were determined in the digestive-gland gonad complex (DGG) of the exposed snails and in the uninfected matched controls at 2 and 4 weeks PE. Extraction of lipids from DGGs was carried out by the Folch method with chloroform-methanol (2:1), and extracts were analyzed on Analtech HPTLC-HLF pre adsorbent silica gel plates with measurement of separated bands using a CAMAG Scanner 3. For neutral lipids the mobile phase was petroleum ether-diethyl ether glacial acetic acid (80:20:1) and the detection reagent was 5% ethanolic phosphoric acid, and for polar lipids chloroform-methanol-deionized water (65:25:4) mobile phase and 10% cupric sulfate in 8% phosphoric acid detection reagent were used. No significant differences in the concentrations of free sterols, free fatty acids, triacylglycerols, phosphatidylcholine, and phosphatidylethanolamine were seen at 2 weeks PE in any of the groups. At 4 weeks PE, the free fatty acid concentration increased significantly in the snails exposed to 25 miracidia compared to that of the 5 miracidia/snail group or the controls. Elevation of the free fatty acid fraction in the high dose snail group suggested that some changes occurred in the lipid metabolism of the snails in that group as a function of miracidia dose. PMID- 24338330 TI - Prime-boost vaccination with plasmid DNA followed by recombinant vaccinia virus expressing BgGARP induced a partial protective immunity to inhibit Babesia gibsoni proliferation in dogs. AB - A heterologous prime-boost vaccination regime with DNA and recombinant vaccinia virus (rvv) vectors expressing relevant antigens has been shown to induce effective immune responses against several infectious pathogens. In this study, we describe the effectiveness of the prime-boost strategy by immunizing dogs with a recombinant plasmid followed by vaccinia virus, both of which expressed the glutamic acid-rich protein (BgGARP) of Babesia gibsoni. The dogs immunized with the prime-boost regime developed a significantly high level of specific antibodies against BgGARP when compared with the control groups. The antibody level was strongly increased after a booster immunization with a recombinant vaccinia virus. Two weeks after the booster immunization with a recombinant vaccinia virus expressing BgGARP, the dogs were challenged with B. gibsoni parasite. The dogs immunized with the prime-boost regime showed partial protection, manifested as a significantly low level of parasitemia. These results indicated that this type of DNA/rvv prime-boost immunization approach may have use against B. gibsoni infection in dogs. PMID- 24338331 TI - Perioperative ketorolac increases post-tonsillectomy hemorrhage in adults but not children. AB - OBJECTIVES/HYPOTHESIS: To evaluate the risk of post-tonsillectomy hemorrhage associated with perioperative ketorolac use. STUDY DESIGN: Systematic review and meta-analysis of primary articles reporting individual-level post-tonsillectomy hemorrhage rates in subjects receiving perioperative ketorolac and matched controls. Retrospective and prospective studies were both included. METHODS: PubMed search was performed for "[ketorolac OR toradol] AND tonsillectomy." Articles fulfilling inclusion criteria were subjected to meta-analysis to determine summary relative risk (RR). RESULTS: Adults are at five times increased risk for post-tonsillectomy hemorrhage with ketorolac use (RR: 5.64; 95% confidence interval [CI]: 2.08-15.27; P < .001). In contrast, children under 18 are not at statistically significantly increased risk (RR: 1.39; 95% CI: 0.84 2.30; P = .20). Both retrospective and prospective studies yield consistent findings. There is no association of RR with pre- or postoperative administration of ketorolac. CONCLUSIONS: Ketorolac can be used safely in children, but is associated with a five-fold increased bleeding risk in adults. PMID- 24338332 TI - A promoter that drives gene expression preferentially in male transgenic rats. AB - Gender-preferential gene expression is a widespread phenomenon in humans. It is important to study how gender differences influence the pathogenesis of various diseases and response to specific drugs. The aim of this study is to determine if the mouse albumin enhancer/promoter may serve as the promoter to introduce gender preferential gene expression in transgenic animals. We created four independent transgenic rat lines in which the human C-reactive protein transgene was under the control of mouse albumin enhancer/promoter. Quantitative real time RT-PCR analysis showed that transgene expression in the liver of male rats was significantly higher than transgene expression in the female rats (P < 0.05).There was a 5.3-fold (male/female) difference in line-519, and a 12.2-fold (male/female) difference in line-488. Enzyme-linked immunosorbent assay showed that the serum of male transgenic rats had a 13- to 679-fold difference at the protein level on transgene production compared with female transgenic rats. The male-to-female difference in gene expression was 10- to 17-fold in the liver of transgenic rats. Orchiectomy dramatically reduced protein production from the transgene in the liver. Testosterone administration into female rats did not increase the transgene expression, but estrogen administration into the male rats reduced transgene expression. This study provides a valuable tool for investigating the pathological roles of genes that are expressed in a gender preferential manner in human disease. PMID- 24338333 TI - Fabrication and evaluation of physical properties and cytotoxicity of zein-based polyurethanes. AB - Polyurethane prepolymer (PUP) was first synthesized from polycaprolactone diol and isophorone diisocyanate; and then a series of zein-based polyurethane (ZEPU) sheets was fabricated from PUP and zein (ZE) using a hot press and moulding process without addition of other additives. Effects of ZE content (WZE) on the structure and properties of the resultant ZEPU sheets were investigated by Fourier transform infrared spectroscopy, scanning electron microscopy, dynamic mechanical analysis, tensile testing, and dissolubility testing in alcohol. The results indicated that cross-linking and grafting reactions occurred between ZE and PUP to form new polyurethane showing a higher thermal stability, flexibility, and alcohol-resistance than the neat ZE sheets. For example, the elongation at break of ZEPU with 50 % WZE was 211.2 %, which was 47 times higher than that of neat ZE sheet. ZE molecules acted as both cross-linkers and polymer fillers in ZEPU sheets. The cytotoxicity and cytocompatibility of ZEPU sheets were evaluated by cell culture in vitro. The ZEPU sheets showed non- or low-cytotoxicity, and L929 cells grew and expanded well on the surfaces of the sheets with WZE over 50 %. Undoubtedly, the fabrication of ZE-based polyurethanes without toxic additives such as catalysts, cross-linkers and chain extenders improved the physical properties and cytocompatibility of zein, thus widening the possible range of applications for zein-based biomaterials. PMID- 24338334 TI - Preparation of N,N-p-phenylene bismethacryl amide as a novel cross-link agent for synthesis and characterization of the core-shell magnetic molecularly imprinted polymer nanoparticles. AB - Novel magnetic molecularly imprinted nanoparticles (MMIPs) using N,N-p-phenylene bismethacryl amide as a cross linker and super paramagnetic core-shell nanoparticle as a supporter for use in controlled release were prepared by precipitation polymerization. Novel cross-linking agents were synthesized by the reaction of methacryloyl chloride with p-phenylenediamine. Then, the Fe3O4 nanoparticles were encapsulated with a SiO2 shell and functionalized with -CH=CH2 and MMIPs were further prepared by using methacrylic acid as a functional monomer, N,N-p-phenylene bismethacryl amide as a cross-linking agent and betamethasone as template. Magnetic non-MIPs were also prepared with the same synthesis procedure as with MMIPs only without the presence of the template. The obtained MMIPs were characterized by using transmission electron microscopy, Fourier transform infrared spectrum, X-ray diffraction, energy-dispersive X-ray spectroscopy, and the vibrating sample magnetometer. The performance of the MMIPs for the controlled release of betamethasone was assessed and results indicated that the magnetic MIPs also had potential applications in drug controlled release. PMID- 24338335 TI - Conceptualising loneliness in adolescents: development and validation of a self report instrument. AB - This paper reports the development and psychometric evaluations of a multidimensional model of loneliness in Australian adolescents. In the first study a new instrument was designed and administered to 1,074 adolescents (ages 10-18 years, M = 13.01). An exploratory factor analysis from data supplied by 694 of these participants yielded a 4-factor structure (friendship, isolation, negative attitude to solitude, and positive attitude to solitude). Competing measurement models were then evaluated using confirmatory factor analysis with data from the remaining 380 participants; strong support was demonstrated for the conceptual model. Significant main effects were evident for geographical location (rural remote/urban), age and sex. In a second study, involving 235 Australian adolescents (ages 10.0-16 years, M = 13.8) the superiority of the first-order model represented by four correlated factors was confirmed. The findings have clinical and practical implications for professional groups represented by child and adolescent psychiatry, pediatric and clinical psychology services, researchers, and educators. Specifically, the new self-report instrument identifies adolescents who are at risk of loneliness and its associated adverse outcomes and in doing has the potential to offer new insights into prevention and intervention. PMID- 24338336 TI - Effects and detection of raw material variability on the performance of near infrared calibration models for pharmaceutical products. AB - The impact of raw material variability on the prediction ability of a near infrared calibration model was studied. Calibrations, developed from a quaternary mixture design comprising theophylline anhydrous, lactose monohydrate, microcrystalline cellulose, and soluble starch, were challenged by intentional variation of raw material properties. A design with two theophylline physical forms, three lactose particle sizes, and two starch manufacturers was created to test model robustness. Further challenges to the models were accomplished through environmental conditions. Along with full-spectrum partial least squares (PLS) modeling, variable selection by dynamic backward PLS and genetic algorithms was utilized in an effort to mitigate the effects of raw material variability. In addition to evaluating models based on their prediction statistics, prediction residuals were analyzed by analyses of variance and model diagnostics (Hotelling's T(2) and Q residuals). Full-spectrum models were significantly affected by lactose particle size. Models developed by selecting variables gave lower prediction errors and proved to be a good approach to limit the effect of changing raw material characteristics. Hotelling's T(2) and Q residuals provided valuable information that was not detectable when studying only prediction trends. Diagnostic statistics were demonstrated to be critical in the appropriate interpretation of the prediction of quality parameters. PMID- 24338338 TI - Over-expression of survivin and VEGF in small-cell lung cancer may predict the poorer prognosis. AB - The expression of survivin, an inhibitor of apoptosis can be seen in most tumors and is correlated with the angiogenic factor vascular endothelial growth factor (VEGF). But little is known about their contribution in small-cell lung cancer (SCLC). This study was designed to investigate the expression of survivin and VEGF in SCLC, and to explore their correlation with clinical-pathological feature and prognosis. Forty-five patients with pathological histology of SCLC were entered into this study. Forty-five cases of matched adjacent non-tumor samples and 10 samples of operated patients with benign lung tumor were also included as control. The expression of survivin and VEGF was detected by immunohistochemistry (IHC, SP). These two sets of data were processed and tested for correlation with major patients' characteristics, and overall survival. The correlations between survivin and VEGF expressions and the clinical-pathological features were evaluated by chi-square test. The correlation between survivin and VEGF expressions was analyzed by Spearman's rank correlation test; the overall survival was analyzed by the Kaplan-Meier method; and the relationship between clinical and pathological features and overall survival was analyzed by the Cox proportional hazard models. Positive expression rate of survivin and VEGF was significantly higher in SCLC than those of adjacent non-tumor tissues and benign lung tumor tissues (73.3 vs. 15.6 vs. 0 %, P < 0.05) and (75.6 vs. 20 vs. 0 %, P < 0.05), respectively. Survivin and VEGF expressions were significantly associated with lymph node metastasis (P = 0.003, 0.011) and clinical stage (P = 0.006, 0.021). The expression of survivin was significantly coincident with the expression of VEGF (r = 0.644, P = 0.000). The median overall survival in survivin positive group and VEGF positive group was significantly shorter than those in survivin negative and VEGF negative group, respectively (log-rank P = 0.000). Moreover, multivariate analysis showed that survivin expression (HR 0.224; 95 % CI 0.074-0.675; P = 0.008) and VEGF expression (HR 0.172; 95 % CI 0.054-0.559; P = 0.003) were statistically independent predictive factors of poorer prognosis for SCLC patients. Our results indicated that survivin and VEGF were over-expressed in small-cell lung cancer, each of them may be an independent poor prognostic factor. PMID- 24338337 TI - Dietary stimulators of the PGC-1 superfamily and mitochondrial biosynthesis in skeletal muscle. A mini-review. AB - Mitochondrial dysfunction has been linked to many diseases including metabolic diseases such as diabetes. Peroxisome proliferator-activated receptor gamma co activator 1 (PGC-1) is a superfamily of transcriptional co-activators which are important precursors to mitochondrial biosynthesis found in most cells including skeletal muscle. The PGC-1 superfamily consists of three variants all of which are directly involved in controlling metabolic gene expression including those regulating fatty acid oxidation and mitochondrial proteins. In contrast to previous reviews on PGC-1, this mini-review summarizes the current knowledge of many known dietary stimulators of PGC-1 and the subsequent mitochondrial biosynthesis with associated metabolic benefit in skeletal muscle. PMID- 24338339 TI - Hodgkin lymphoma transformation of chronic lymphocytic leukemia: cases report and discussion. AB - B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is the most common form of leukemia affecting adults in Europe and North America. Large B-cell lymphoma known as Richter's syndrome (RS) may develop approximately in 3 15 % patients. Furthermore, other hematological malignancies may also occur as RS variants, among them-Hodgkin lymphoma (HL). CLL/SLL transformation into HL is observed in about 0.5 % of patients, and till now, fewer than 100 cases have been reported in the medical literature. We present two cases of HL transformation of CLL/SLL and review the previously published literature. PMID- 24338340 TI - How do I recommend extended adjuvant hormonal therapy? AB - OPINION STATEMENT: Estrogen-dependent growth of some breast cancers was a key observation, which led to the development of tamoxifen and aromatase inhibitors (AIs). Tamoxifen and AIs have different modes of action and side-effect profiles. Based on evidence, both in laboratory models and clinical trials, longer duration of hormone suppression therapy is beneficial. The most important factor deciding their use is "menopausal status." Sometimes, defining menopause might be challenging in clinical practice. Measuring serum follicle stimulating hormone (FSH) and estradiol levels are helpful when in doubt. Tamoxifen should be offered to those women with normal FSH and estradiol levels even with cessation of menstruation. Once menopause is defined, it is relatively clear to decide about the endocrine therapy. Premenopausal women should be treated with tamoxifen and postmenopausal women with AIs. Perimenopausal women should be treated with tamoxifen initially and later switched to AIs once they become postmenopausal. With current recent evidence, premenopausal women should be treated with 10 years of tamoxifen. Current evidence also supports 5 years of an AI alone or 5 years of tamoxifen followed by 5 years of an AI; studies evaluating longer duration of AI treatment are in progress (Figure 1). Compliance with long-term use of these adjuvant endocrine therapies depends on screening for and management of side effects. Patients taking tamoxifen should be clinically screened for thromboembolism and for endometrial cancer if abnormal bleeding occurs. Patients on AI should pay careful attention to management of other chronic health disorders. They also should be screened for optimal bone health. Management of vasomotor symptoms also helps with adherence to long-term treatment for both tamoxifen and AIs. PMID- 24338341 TI - Quercetin can reduce insulin resistance without decreasing adipose tissue and skeletal muscle fat accumulation. AB - Quercetin exhibits a wide range of biological functions. The first aim of the present work was to analyze the effects of quercetin on fat accumulation in adipose tissue and glycemic control in rats. Any potential involvement of muscle fatty acid oxidation in its effect on glycemic control was also assessed. Animals were fed a high-fat high-sucrose diet either supplemented with quercetin (30 mg/kg body weight/day), or not supplemented, for 6 weeks. One week before killing, a glucose tolerance test was carried out. Muscle triacylglycerol content, serum glucose, insulin, fructosamine and free fatty acids were measured, and homeostatic model assessment for insulin resistance (HOMA-IR) was calculated. The activities of lipogenic enzymes and lipoprotein lipase in adipose tissue, carnitine palmitoyl transferase-1b (CPT-1b) and citrate synthase in skeletal muscle, and the expression of several genes, ACO, CD36, CPT-1b, PPAR-alpha, PGC 1alpha, UCP3, TFAM and COX-2 in skeletal muscle were analyzed. Quercetin caused no significant reduction in body weight or adipose tissue sizes. However, fructosamine, basal glucose and insulin, and consequently HOMA-IR, were significantly reduced by quercetin. No changes were observed in the activity of lipogenic enzymes and lipoprotein lipase. Muscle triacylglycerol content was similar in both experimental groups. The expression of ACO, CD36, CPT-1b, PPAR alpha, PGC-1alpha, UCP3, TFAM and COX-2 remained unchanged. It can be concluded that quercetin is more effective as an anti-diabetic than as an anti-obesity biomolecule. The improvement in insulin resistance induced by this flavonoid is not mediated by a delipidating effect in skeletal muscle. PMID- 24338342 TI - Effects of arachidonic acid on the concentration of hydroxyeicosatetraenoic acids in culture media of mesenchymal stromal cells differentiating into adipocytes or osteoblasts. AB - Metabolites derived from the polyunsaturated fatty acids (PUFA) may modulate the mesenchymal stromal cell (MSC) differentiation. Such cells can differentiate into different cellular types, including adipocytes and osteoblasts. Aging favors the bone marrow MSC differentiation toward the former, causing a loss of bone density associated with pathologies like osteoporosis. The omega-6 arachidonic acid (AA) favors MSC adipogenesis to a greater extent than omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In this work, we study the joint action of both PUFA. Thus, not induced and induced to adipocyte or osteoblast MSC were treated with 20 MUM of each PUFA (either AA, AA + DHA or AA + EPA). The expression of osteogenic and adipogenic molecular markers, the alox15b lipoxygenase gene expression and the 5-, 8-, 11-, 12- and 15 hydroxyeicosatetraenoic acids (HETE) derived from the AA metabolism in the culture media were determined. The results show that the adipogenesis induction of AA is not suppressed by the joint presence of EPA and DHA. In fact, both increased the adipogenic effect of AA on MSC differentiated into osteoblasts. The different HETE concentrations increased in cultures supplemented with AA, albeit such concentrations were lower in the cultures induced to differentiate, mainly at day 21 after the induction. Furthermore, the reduction in the HETE concentration was correlated with a higher expression of the alox15b gene. These results highlight the PUFA metabolism differences between uninduced and induced MSC to differentiate into adipocytes and osteoblasts, besides the relevant role of the lipoxygenase gene expression in adipogenesis induction. PMID- 24338343 TI - The effects of interactions between selenium and zinc serum concentration and SEP15 and SLC30A3 gene polymorphisms on memory scores in a population of mature and elderly adults. AB - Memory deficits are common during aging, but little is known about the impact of environmental and genetic variables on memory. The genes SLC30A3 and SEP15 are, respectively, responsible for transporting zinc and selenium, micronutrients that are neuroprotective agents. The aim of this study was to investigate the effect of nutrigenetic interactions on the memory scores of volunteers more than 50 years old. For this cross-sectional study, 240 individuals were enrolled. Micronutrient dosage was determined using atomic absorption spectrophotometry. The SNPs rs5859, rs5854, and rs561104 in SEP15 and rs73924411 and rs11126936 in SLC30A3 were determined by real-time PCR. The evaluations of verbal and visual memory were performed using the Weschler Memory Scale-revised and the Rey's verbal learning test. A gene versus nutrient interaction was observed for SLC30A3 rs73924411 and zinc concentration. Carriers of the T allele had higher scores for short-term and long-term verbal memories than CC homozygotes only when zinc serum concentration was below the recommended level (p value for the interaction for short-term verbal memory = 0.011, p value for the interaction for long-term verbal memory = 0.039). For SEP15, C carriers of the rs5845 SNP allele had higher verbal learning memory scores than TT homozygotes (0.13 +/- 1.13 vs. -1.10 +/- 1.20, p = 0.034). Our results suggest the influence of genetic polymorphisms on memory score and identify gene versus nutrient interactions between zinc serum concentration and memory score. PMID- 24338345 TI - Psychological therapies for chronic post-traumatic stress disorder (PTSD) in adults. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is a distressing condition, which is often treated with psychological therapies. Earlier versions of this review, and other meta-analyses, have found these to be effective, with trauma focused treatments being more effective than non-trauma-focused treatments. This is an update of a Cochrane review first published in 2005 and updated in 2007. OBJECTIVES: To assess the effects of psychological therapies for the treatment of adults with chronic post-traumatic stress disorder (PTSD). SEARCH METHODS: For this update, we searched the Cochrane Depression, Anxiety and Neurosis Group's Specialised Register (CCDANCTR-Studies and CCDANCTR-References) all years to 12th April 2013. This register contains relevant randomised controlled trials from: The Cochrane Library (all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). In addition, we handsearched the Journal of Traumatic Stress, contacted experts in the field, searched bibliographies of included studies, and performed citation searches of identified articles. SELECTION CRITERIA: Randomised controlled trials of individual trauma-focused cognitive behavioural therapy (TFCBT), eye movement desensitisation and reprocessing (EMDR), non-trauma-focused CBT (non-TFCBT), other therapies (supportive therapy, non-directive counselling, psychodynamic therapy and present centred therapy), group TFCBT, or group non-TFCBT, compared to one another or to a waitlist or usual care group for the treatment of chronic PTSD. The primary outcome measure was the severity of clinician-rated traumatic-stress symptoms. DATA COLLECTION AND ANALYSIS: We extracted data and entered them into Review Manager 5 software. We contacted authors to obtain missing data. Two review authors independently performed 'Risk of bias' assessments. We pooled the data where appropriate, and analysed for summary effects. MAIN RESULTS: We include 70 studies involving a total of 4761 participants in the review. The first primary outcome for this review was reduction in the severity of PTSD symptoms, using a standardised measure rated by a clinician. For this outcome, individual TFCBT and EMDR were more effective than waitlist/usual care (standardised mean difference (SMD) -1.62; 95% CI -2.03 to -1.21; 28 studies; n = 1256 and SMD -1.17; 95% CI 2.04 to -0.30; 6 studies; n = 183 respectively). There was no statistically significant difference between individual TFCBT, EMDR and Stress Management (SM) immediately post-treatment although there was some evidence that individual TFCBT and EMDR were superior to non-TFCBT at follow-up, and that individual TFCBT, EMDR and non-TFCBT were more effective than other therapies. Non-TFCBT was more effective than waitlist/usual care and other therapies. Other therapies were superior to waitlist/usual care control as was group TFCBT. There was some evidence of greater drop-out (the second primary outcome for this review) in active treatment groups. Many of the studies were rated as being at 'high' or 'unclear' risk of bias in multiple domains, and there was considerable unexplained heterogeneity; in addition, we assessed the quality of the evidence for each comparison as very low. As such, the findings of this review should be interpreted with caution. AUTHORS' CONCLUSIONS: The evidence for each of the comparisons made in this review was assessed as very low quality. This evidence showed that individual TFCBT and EMDR did better than waitlist/usual care in reducing clinician-assessed PTSD symptoms. There was evidence that individual TFCBT, EMDR and non-TFCBT are equally effective immediately post-treatment in the treatment of PTSD. There was some evidence that TFCBT and EMDR are superior to non-TFCBT between one to four months following treatment, and also that individual TFCBT, EMDR and non-TFCBT are more effective than other therapies. There was evidence of greater drop-out in active treatment groups. Although a substantial number of studies were included in the review, the conclusions are compromised by methodological issues evident in some. Sample sizes were small, and it is apparent that many of the studies were underpowered. There were limited follow-up data, which compromises conclusions regarding the long-term effects of psychological treatment. PMID- 24338344 TI - Including adverse drug events in economic evaluations of anti-tumour necrosis factor-alpha drugs for adult rheumatoid arthritis: a systematic review of economic decision analytic models. AB - BACKGROUND: Anti-tumour necrosis factor-alpha drugs (anti-TNFs) have revolutionised the treatment of rheumatoid arthritis (RA). More effective than standard non-biological disease-modifying anti-rheumatic drugs (nbDMARDs), anti TNFs are also substantially more expensive. Consequently, a number of model-based economic evaluations have been conducted to establish the relative cost effectiveness of anti-TNFs. However, anti-TNFs are associated with an increased risk of adverse drug events (ADEs) such as serious infections relative to nbDMARDs. Such ADEs will likely impact on both the costs and consequences of anti TNFs, for example, through hospitalisations and forced withdrawal from treatment. OBJECTIVE: The aim of this review was to identify and critically appraise if, and how, ADEs have been incorporated into model-based cost-effectiveness analyses of anti-TNFs for adult patients with RA. METHODS: A systematic literature review was performed. Electronic databases (Ovid MEDLINE; Ovid EMBASE; Web of Science; NHS Economic Evaluations Database) were searched for literature published between January 1990 and October 2013 using electronic search strategies. The reference lists of retrieved studies were also hand searched. In addition, the National Institute for Health and Care Excellence technology appraisals were searched to identify economic models used to inform UK healthcare decision making. Only full economic evaluations that had used an economic model to evaluate biological DMARDs (bDMARDs) (including anti-TNFs) for adult patients with RA and had incorporated the direct costs and/or consequences of ADEs were critically appraised. To be included, studies also had to be available as a full text in English. Data extracted included general study characteristics and information concerning the methods used to incorporate ADEs and any associated assumptions made. The extracted data were synthesised using a tabular and narrative format. RESULTS: A total of 43 model-based economic evaluations of bDMARDs for adult RA were identified from 2,483 initially identified studies (2,473 published; ten technology appraisals). Of these, nine studies had incorporated the incidence and costs of ADEs and were critically reviewed. One study also explicitly estimated the potential consequences for patient utility. There was a general lack of detail specifically reporting on how ADEs were included in the economic models. Furthermore, there was substantial heterogeneity amongst the nine studies concerning the (i) application of risk-related terminology; (ii) method of incorporating the incidence, costs and consequences of ADEs; and (iii) ADE related assumptions. CONCLUSIONS: Model-based economic evaluations have played an integral role in healthcare reimbursement and funding decisions relating to anti TNFs for adult patients with RA. However, current economic models have not routinely or systematically considered the direct costs or consequences of ADEs, which may bias the estimates of the relative cost-effectiveness of anti-TNFs. Omitting information on relevant costs and consequences of interventions for RA will affect the validity of the associated recommendations for informed decision making. To improve current practice it is recommended that (i) greater efforts be made to provide appropriate long-term safety data on the use of anti-TNFs in adult RA; (ii) empirical research be undertaken to identify and quantify the impact of, and possible methods for, including ADEs in economic models to inform future good practice guidelines; and (iii) economic modelling guidelines and reference cases be updated to explicitly identify ADEs as an important treatment outcome and address how they might be incorporated into economic models. Improved consideration of the possible implications of ADEs in economic models will ensure that healthcare decision makers are provided with reliable and accurate information with which to make efficient reimbursement and financing decisions. PMID- 24338346 TI - Effect of durum wheat cultivars on physico-chemical and sensory properties of spaghetti. AB - BACKGROUND: Mixtures of different cultivars provide semolina with proper processing properties but not always good nutritional properties. In this study, the effects of mono-varietal cultivars of durum wheat on pasta quality were evaluated in order to find a good balance between nutritional and sensory properties of the final product. RESULTS: Durum wheat spaghetti was manufactured using semolina from six mono-varietal cultivars. A commercially available semolina mixture was also used to produce a control pasta sample. Instrumental (i.e. rheological and texture analysis), sensory (i.e. elasticity, firmness, adhesiveness) and nutritional (i.e. protein, ash and fibre content, glycaemic index) analyses were carried out. Results highlighted differences between selected cultivars. In particular, spaghetti obtained with Anco Marzio and Cappelli semolina (modern and old cultivars, respectively) showed the highest protein content and the lowest cooking loss, compared with the other samples. CONCLUSION: Spaghetti made with Cappelli semolina showed the lowest adhesiveness and the highest hardness; it recorded the best overall quality and presented the lowest glycaemic response. Hence, durum wheat pasta with a good balance between nutritional and cooking quality could be obtained from semolina based on mono varietal cultivars. (c) 2013 Society of Chemical Industry. PMID- 24338347 TI - Yield optimisation and molecular characterisation of uncultured CD271+ mesenchymal stem cells in the Reamer Irrigator Aspirator waste bag. AB - Bone reconstruction requires the use of autografts from patients' iliac crest (IC); for large-volume defects bone void fillers and autologous mesenchymal stem cells (MSCs) are often added. The Reamer/Irrigator/Aspirator (RIA) device provides the means of harvesting large amounts of autograft and additionally yields a waste bag containing MSCs, which is currently discarded. The aim of this study was to enumerate and characterise native MSCs from RIA waste bag and compare them to 'gold-standard' donor-matched MSCs from IC bone marrow (BM). IC BM from age matched trauma patients was used as control. In RIA waste bags the median MSC yield established using a colony-forming fibroblast assay was 314333 (range 5 x 104-1.4 x 106), equivalent to approximately one litre of IC-BM aspirate. CD271+ cells were present at high levels in RIA waste bags, had MSC surface phenotype (CD90+CD73+CD105+CD34>sup>-CD61-CD19-CD31-CD33-) and expressed genes associated with multipotentiality, osteogenesis, adipogenesis and angiogenic support. RIA- CD271+ MSCs were transcriptionally similar to donor matched IC-CD271+ MSCs (76 % transcripts); with the majority of bone-related and Wnt pathway molecules being expressed at comparable levels. Lower-level expression of MCAM/CD146 and 5/13 hypoxia-related molecules was found in RIA CD271+ MSCs, potentially reflecting their native residence in a more hypoxic environment of the endosteum and bone cortex. These data suggest that long bones contain very large numbers of MSCs, transcriptionally-similar to IC-BM MSCs; they can be procured by reaming using the RIA device and used, following concentration, as autologous and potentially allogeneic bone repair therapy. PMID- 24338349 TI - Clinical significance of high anti-entamoeba histolytica antibody titer in asymptomatic HIV-1-infected individuals. AB - BACKGROUND: Anti-Entamoeba histolytica antibody (anti- E. histolytica) is widely used in seroprevalence studies though its clinical significance has not been assessed previously. METHODS: Anti-E. histolytica titer was measured at first visit to our clinic (baseline) in 1303 patients infected with human immunodeficiency virus type 1 (HIV-1). The time to diagnosis of invasive amebiasis was assessed by Kaplan-Meier method and risk factors for the development of invasive amebiasis were assessed by Cox proportional-hazards regression analysis. For patients who developed invasive amebiasis, anti-E. histolytica titers at onset were compared with those at baseline and after treatment. RESULTS: The anti-E. histolytica seroprevalence in the study population was 21.3% (277/1303). Eighteen patients developed invasive amebiasis during the treatment-free period among 1207 patients who had no history of previous treatment with nitroimidazole. Patients with high anti-E. histolytica titer at baseline developed invasive amebiasis more frequently than those with low anti-E. histolytica titer. Most cases of invasive amebiasis who had high anti E. histolytica titer at baseline developed within 1 year. High anti-E. histolytica titer was the only independent predictor of future invasive amebiasis. Anti-E. histolytica titer was elevated at the onset of invasive amebiasis in patients with low anti-E. histolytica titer at baseline. CONCLUSIONS: Asymptomatic HIV-1-infected individuals with high anti-E. histolytica titer are at risk of invasive amebiasis probably due to exacerbation of subclinical amebiasis. PMID- 24338348 TI - IsdB-dependent hemoglobin binding is required for acquisition of heme by Staphylococcus aureus. AB - Staphylococcus aureus is a Gram-positive pathogen responsible for tremendous morbidity and mortality. As with most bacteria, S. aureus requires iron to cause disease, and it can acquire iron from host hemoglobin. The current model for staphylococcal hemoglobin-iron acquisition proposes that S. aureus binds hemoglobin through the surface-exposed hemoglobin receptor IsdB. IsdB removes heme from bound hemoglobin and transfers this cofactor to other proteins of the Isd system, which import and degrade heme to release iron in the cytoplasm. Here we demonstrate that the individual components of the Isd system are required for growth on low nanomolar concentrations of hemoglobin as a sole source of iron. An in-depth study of hemoglobin binding by IsdB revealed key residues that are required for hemoglobin binding. Further, we show that these residues are necessary for heme extraction from hemoglobin and growth on hemoglobin as a sole iron source. These processes are found to contribute to the pathogenicity of S. aureus in a murine model of infection. Together these results build on the model for Isd-mediated hemoglobin binding and heme-iron acquisition during the pathogenesis of S. aureus infection. PMID- 24338350 TI - Streptococcus pneumoniae arginine synthesis genes promote growth and virulence in pneumococcal meningitis. AB - Streptococcus pneumoniae (pneumococcus) is a major human pathogen causing pneumonia, sepsis and bacterial meningitis. Using a clinical phenotype based approach with bacterial whole-genome sequencing we identified pneumococcal arginine biosynthesis genes to be associated with outcome in patients with pneumococcal meningitis. Pneumococci harboring these genes show increased growth in human blood and cerebrospinal fluid (CSF). Mouse models of meningitis and pneumonia showed that pneumococcal strains without arginine biosynthesis genes were attenuated in growth or cleared, from lung, blood and CSF. Thus, S. pneumoniae arginine synthesis genes promote growth and virulence in invasive pneumococcal disease. PMID- 24338351 TI - Antibody kinetics in infants exposed to Chikungunya virus infection during pregnancy reveals absence of congenital infection. AB - To search for serological evidence of congenital infection in apparently healthy neonates born to women infected with the Chikungunya virus (CHIKV) during pregnancy, monitoring for CHIKV-specific antibodies was performed within the CHIMERE cohort study (Reunion island, 2006-2008). CHIKV-specific antibody kinetics showed no evidence of asymptomatic congenital infection as neonates were tested negative for CHIKV-specific IgM antibodies at birth and 368 infants with CHIKV-specific IgG antibodies seroreversed completely (mean seroreversion time: 7.7 months). Seroreversion time of transplacental CHIKV IgG antibodies was inversely correlated with the stage of pregnancy at which exposure took place and end-term small for gestational infants seroreversed earlier. PMID- 24338352 TI - Viruses associated with acute respiratory infections and influenza-like illness among outpatients from the Influenza Incidence Surveillance Project, 2010-2011. AB - BACKGROUND: The Influenza Incidence Surveillance Project (IISP) monitored outpatient acute respiratory infection (ARI; defined as the presence of >= 2 respiratory symptoms not meeting ILI criteria) and influenza-like illness (ILI) to determine the incidence and contribution of associated viral etiologies. METHODS: From August 2010 through July 2011, 57 outpatient healthcare providers in 12 US sites reported weekly the number of visits for ILI and ARI and collected respiratory specimens on a subset for viral testing. The incidence was estimated using the number of patients in the practice as the denominator, and the virus specific incidence of clinic visits was extrapolated from the proportion of patients testing positive. RESULTS: The age-adjusted cumulative incidence of outpatient visits for ARI and ILI combined was 95/1000 persons, with a viral etiology identified in 58% of specimens. Most frequently detected were rhinoviruses/enteroviruses (RV/EV) (21%) and influenza viruses (21%); the resulting extrapolated incidence of outpatient visits was 20 and 19/1000 persons respectively. The incidence of influenza virus-associated clinic visits was highest among patients aged 2-17 years, whereas other viruses had varied patterns among age groups. CONCLUSIONS: The IISP provides a unique opportunity to estimate the outpatient respiratory illness burden by etiology. Influenza virus infection and RV/EV infection(s) represent a substantial burden of respiratory disease in the US outpatient setting, particularly among children. PMID- 24338353 TI - An example of genetically distinct HIV type 1 variants in cerebrospinal fluid and plasma during suppressive therapy. AB - We sequenced the genome of human immunodeficiency virus type 1 (HIV-1) recovered from 70 cerebrospinal fluid (CSF) specimens and 29 plasma samples and corresponding samples obtained before treatment initiation from 17 subjects receiving suppressive therapy. More CSF sequences than plasma sequences were hypermutants. We determined CSF sequences and plasma sequences in specimens obtained from 2 subjects after treatment initiation. In one subject, we found genetically distinct CSF and plasma sequences, indicating that they came from HIV 1 from 2 different compartments, one potentially the central nervous system, during suppressive therapy. In addition, there was little evidence of viral evolution in the CSF during therapy, suggesting that continuous virus replication is not the major cause of viral persistence in the central nervous system. PMID- 24338354 TI - PlasmoView: a web-based resource to visualise global Plasmodium falciparum genomic variation. AB - Malaria is a global public health challenge, with drug resistance a major barrier to disease control and elimination. To meet the urgent need for better treatments and vaccines, a deeper knowledge of Plasmodium biology and malaria epidemiology is required. An improved understanding of the genomic variation of malaria parasites, especially the most virulent Plasmodium falciparum (Pf) species, has the potential to yield new insights in these areas. High-throughput sequencing and genotyping is generating large amounts of genomic data across multiple parasite populations. The resulting ability to identify informative variants, particularly single-nucleotide polymorphisms (SNPs), will lead to the discovery of intra- and inter-population differences and thus enable the development of genetic barcodes for diagnostic assays and clinical studies. Knowledge of genetic variability underlying drug resistance and other differential phenotypes will also facilitate the identification of novel mutations and contribute to surveillance and stratified medicine applications. The PlasmoView interactive web browsing tool enables the research community to visualise genomic variation and annotation (eg, biological function) in a geographic setting. The first release contains over 600,000 high-quality SNPs in 631 Pf isolates from laboratory strains and four malaria-endemic regions (West Africa, East Africa, Southeast Asia and Oceania). PMID- 24338355 TI - Association and dissociation between detection and discrimination of objects of expertise: Evidence from visual search. AB - Expertise in face recognition is characterized by high proficiency in distinguishing between individual faces. However, faces also enjoy an advantage at the early stage of basic-level detection, as demonstrated by efficient visual search for faces among nonface objects. In the present study, we asked (1) whether the face advantage in detection is a unique signature of face expertise, or whether it generalizes to other objects of expertise, and (2) whether expertise in face detection is intrinsically linked to expertise in face individuation. We compared how groups with varying degrees of object and face expertise (typical adults, developmental prosopagnosics [DP], and car experts) search for objects within and outside their domains of expertise (faces, cars, airplanes, and butterflies) among a variable set of object distractors. Across all three groups, search efficiency (indexed by reaction time slopes) was higher for faces and airplanes than for cars and butterflies. Notably, the search slope for car targets was considerably shallower in the car experts than in nonexperts. Although the mean face slope was slightly steeper among the DPs than in the other two groups, most of the DPs' search slopes were well within the normative range. This pattern of results suggests that expertise in object detection is indeed associated with expertise at the subordinate level, that it is not specific to faces, and that the two types of expertise are distinct facilities. We discuss the potential role of experience in bridging between low-level discriminative features and high-level naturalistic categories. PMID- 24338357 TI - [A growing problem worldwide]. PMID- 24338356 TI - Expression and localization of laminin 5, laminin 10, type IV collagen, and amelotin in adult murine gingiva. AB - The biochemical composition of the internal and external basal laminae in the junctional epithelium differs significantly, and the precise cellular origin of their respective molecules remains to be determined. In the present study, the expression and localization of three basement membrane-specific molecules-laminin 5 (gamma2 chain), type IV collagen (alpha1 chain), and laminin 10 (alpha5 chain) and one tooth-specific molecule, amelotin, was analyzed in adult murine gingiva by using in situ hybridization and immunohistochemistry. The results showed that the outermost cells in junctional epithelium facing the tooth enamel strongly expressed laminin 5 mRNA, supporting the immunohistochemical staining data. This suggests that laminin 5 is actively synthesized in junctional epithelial cells and that the products are incorporated into the internal basal lamina to maintain firm epithelial adhesion to the tooth enamel throughout life. Conversely, no amelotin mRNA signals were detected in the junctional epithelial cells, suggesting that the molecules localized on the internal basal lamina are mainly derived from maturation-stage ameloblasts. Weak and sporadic expression of type IV collagen in addition to laminin 10 in the gingiva indicates that these molecules undergo turnover less frequently in adult animals. PMID- 24338358 TI - [Greater acceptance of less invasiveness]. PMID- 24338359 TI - [Improved, but still insufficient vaccination]. PMID- 24338360 TI - [First published data from KiGGS wave 1]. PMID- 24338361 TI - [Everything is numbers?]. PMID- 24338362 TI - POPX2 phosphatase regulates the KIF3 kinesin motor complex. AB - The kinesin motors are important in the regulation of cellular functions such as protein trafficking, spindle organization and centrosome separation. In this study, we have identified POPX2, a serine-threonine phosphatase, as an interacting partner of the KAP3 subunit of the kinesin-2 motor. The kinesin-2 motor is a heterotrimeric complex composed of KIF3A, KIF3B motor subunits and KAP3, the non-motor subunit, which binds the cargo. Here we report that the phosphatase POPX2 is a negative regulator of the trafficking of N-cadherin and other cargoes; consequently, it markedly influences cell-cell adhesion. POPX2 affects trafficking by determining the phosphorylation status of KIF3A at serine 690. This is consistent with the observation that the KIF3A-S690A mutant is defective in cargo trafficking. Our studies also implicate CaMKII as the kinase that phosphorylates KIF3A at serine 690. These results strongly suggest that POPX2 and CaMKII are a phosphatase-kinase pair that regulates kinesin-mediated transport and cell-cell adhesion. PMID- 24338364 TI - Bora and Aurora-A continue to activate Plk1 in mitosis. AB - Polo-like kinase-1 (Plk1) is required for proper cell division. Activation of Plk1 requires phosphorylation on a conserved threonine in the T-loop of the kinase domain (T210). Plk1 is first phosphorylated on T210 in G2 phase by the kinase Aurora-A, in concert with its cofactor Bora. However, Bora was shown to be degraded prior to entry into mitosis, and it is currently unclear how Plk1 activity is sustained in mitosis. Here we show that the Bora-Aurora-A complex remains the major activator of Plk1 in mitosis. We show that a small amount of Aurora-A activity is sufficient to phosphorylate and activate Plk1 in mitosis. In addition, a fraction of Bora is retained in mitosis, which is essential for continued Aurora-A-dependent T210 phosphorylation of Plk1. We find that once Plk1 is activated, minimal amounts of the Bora-Aurora-A complex are sufficient to sustain Plk1 activity. Thus, the activation of Plk1 by Aurora-A may function as a bistable switch; highly sensitive to inhibition of Aurora-A in its initial activation, but refractory to fluctuations in Aurora-A activity once Plk1 is fully activated. This provides a cell with robust Plk1 activity once it has committed to mitosis. PMID- 24338363 TI - Biotin ligase tagging identifies proteins proximal to E-cadherin, including lipoma preferred partner, a regulator of epithelial cell-cell and cell-substrate adhesion. AB - Known proteins associated with the cell-adhesion protein E-cadherin include catenins and proteins involved in signaling, trafficking and actin organization. However, the list of identified adherens junction proteins is likely to be incomplete, limiting investigation into this essential cell structure. To expand the inventory of potentially relevant proteins, we expressed E-cadherin fused to biotin ligase in MDCK epithelial cells, and identified by mass spectrometry neighboring proteins that were biotinylated. The most abundant of the 303 proteins identified were catenins and nearly 40 others that had been previously reported to influence cadherin function. Many others could be rationalized as novel candidates for regulating the adherens junction, cytoskeleton, trafficking or signaling. We further characterized lipoma preferred partner (LPP), which is present at both cell contacts and focal adhesions. Knockdown of LPP demonstrated its requirement for E-cadherin-dependent adhesion and suggested that it plays a role in coordination of the cell-cell and cell-substrate cytoskeletal interactions. The analysis of LPP function demonstrates proof of principle that the proteomic analysis of E-cadherin proximal proteins expands the inventory of components and tools for understanding the function of E-cadherin. PMID- 24338365 TI - The human CFTR protein expressed in CHO cells activates aquaporin-3 in a cAMP dependent pathway: study by digital holographic microscopy. AB - The transmembrane water movements during cellular processes and their relationship to ionic channel activity remain largely unknown. As an example, in epithelial cells it was proposed that the movement of water could be directly linked to cystic fibrosis transmembrane conductance regulator (CFTR) protein activity through a cAMP-stimulated aqueous pore, or be dependent on aquaporin. Here, we used digital holographic microscopy (DHM) an interferometric technique to quantify in situ the transmembrane water fluxes during the activity of the epithelial chloride channel, CFTR, measured by patch-clamp and iodide efflux techniques. We showed that the water transport measured by DHM is fully inhibited by the selective CFTR blocker CFTRinh172 and is absent in cells lacking CFTR. Of note, in cells expressing the mutated version of CFTR (F508del-CFTR), which mimics the most common genetic alteration encountered in cystic fibrosis, we also show that the water movement is profoundly altered but restored by pharmacological manipulation of F508del-CFTR-defective trafficking. Importantly, whereas activation of this endogenous water channel required a cAMP-dependent stimulation of CFTR, activation of CFTR or F508del-CFTR by two cAMP-independent CFTR activators, genistein and MPB91, failed to trigger water movements. Finally, using a specific small-interfering RNA against the endogenous aquaporin AQP3, the water transport accompanying CFTR activity decreased. We conclude that water fluxes accompanying CFTR activity are linked to AQP3 but not to a cAMP-stimulated aqueous pore in the CFTR protein. PMID- 24338366 TI - Plasma membrane translocation of REDD1 governed by GPCRs contributes to mTORC1 activation. AB - The mTORC1 kinase promotes cell growth in response to growth factors by activation of receptor tyrosine kinase. It is regulated by the cellular energy level and the availability of nutrients. mTORC1 activity is also inhibited by cellular stresses through overexpression of REDD1 (regulated in development and DNA damage responses). We report the identification of REDD1 in a fluorescent live-imaging screen aimed at discovering new proteins implicated in G-protein coupled receptor signaling, based on translocation criteria. Using a sensitive and quantitative plasma membrane localization assay based on bioluminescent resonance energy transfer, we further show that a panel of endogenously expressed GPCRs, through a Ca(2+)/calmodulin pathway, triggers plasma membrane translocation of REDD1 but not of its homolog REDD2. REDD1 and REDD2 share a conserved mTORC1-inhibitory motif characterized at the functional and structural level and differ most in their N-termini. We show that the N-terminus of REDD1 and its mTORC1-inhibitory motif participate in the GPCR-evoked dynamic interaction of REDD1 with the plasma membrane. We further identify REDD1 as a novel effector in GPCR signaling. We show that fast activation of mTORC1 by GPCRs correlates with fast and maximal translocation of REDD1 to the plasma membrane. Overexpression of functional REDD1 leads to a reduction of mTORC1 activation by GPCRs. By contrast, depletion of endogenous REDD1 protein unleashes mTORC1 activity. Thus, translocation to the plasma membrane appears to be an inactivation mechanism of REDD1 by GPCRs, which probably act by sequestering its functional mTORC1-inhibitory motif that is necessary for plasma membrane targeting. PMID- 24338367 TI - The extracellular matrix glycoprotein tenascin-R regulates neurogenesis during development and in the adult dentate gyrus of mice. AB - Abnormal generation of inhibitory neurons that synthesize gamma-aminobutyric acid (GABAergic) is characteristic of neuropsychological disorders. We provide evidence that the extracellular matrix molecule tenascin-R (TNR) - which is predominantly expressed by a subpopulation of interneurons - plays a role in the generation of GABAergic and granule neurons in the murine dentate gyrus by regulating fate determination of neural stem or progenitor cells (NSCs). During development, absence of TNR in constitutively TNR-deficient (TNR(-/-)) mice results in increased numbers of dentate gyrus GABAergic neurons, decreased expression of its receptor beta1 integrin, increased activation of p38 MAPK and increased expression of the GABAergic specification gene Ascl1. Postnatally, increased GABAergic input to adult hippocampal NSCs in TNR(-/-) mice is associated not only with increased numbers of GABAergic and, particularly, parvalbumin-immunoreactive neurons, as seen during development, but also with increased numbers of granule neurons, thus contributing to the increased differentiation of NSCs into granule cells. These findings indicate the importance of TNR in the regulation of hippocampal neurogenesis and suggest that TNR acts through distinct direct and indirect mechanisms during development and in the adult. PMID- 24338368 TI - Telomerase-mediated telomere elongation from human blastocysts to embryonic stem cells. AB - High telomerase activity is a characteristic of human embryonic stem cells (hESCs), however, the regulation and maintenance of correct telomere length in hESCs is unclear. In this study we investigated telomere elongation in hESCs in vitro and found that telomeres lengthened from their derivation in blastocysts through early expansion, but stabilized at later passages. We report that the core unit of telomerase, hTERT, was highly expressed in hESCs in blastocysts and throughout long-term culture; furthermore, this was regulated in a Wnt-beta catenin-signaling-dependent manner. Our observations that the alternative lengthening of telomeres (ALT) pathway was suppressed in hESCs and that hTERT knockdown partially inhibited telomere elongation, demonstrated that high telomerase activity was required for telomere elongation. We observed that chromatin modification through trimethylation of H3K9 and H4K20 at telomeric regions decreased during early culture. This was concurrent with telomere elongation, suggesting that epigenetic regulation of telomeric chromatin may influence telomerase function. By measuring telomere length in 96 hESC lines, we were able to establish that telomere length remained relatively stable at 12.02 +/- 1.01 kb during later passages (15-95). In contrast, telomere length varied in hESCs with genomic instability and hESC-derived teratomas. In summary, we propose that correct, stable telomere length may serve as a potential biomarker for genetically stable hESCs. PMID- 24338369 TI - Mitochondrial ATP synthases cluster as discrete domains that reorganize with the cellular demand for oxidative phosphorylation. AB - Mitochondria are double membrane-bounded organelles that form a dynamic tubular network. Mitochondria energetic functions depend on a complex internal architecture. Cristae, inner membrane invaginations that fold into the matrix space, are proposed to be the site of oxidative phosphorylation, reactions by which ATP synthase produces ATP. ATP synthase is also thought to have a role in crista morphogenesis. To date, the exploration of the processes regulating mitochondrial internal compartmentalization have been mostly limited to electron microscopy. Here, we describe ATP synthase localization in living yeast cells and show that it clusters as discrete inner membrane domains. These domains are dynamic within the mitochondrial network. They are impaired in mutants defective in crista morphology and partially overlap with the crista-associated MICOS-MINOS MITOS complex. Finally, ATP synthase occupancy increases with the cellular demand for OXPHOS. Overall our data suggest that domains in which ATP synthases are clustered correspond to mitochondrial cristae. Being able to follow mitochondrial sub-compartments in living yeast cells opens new avenues to explore the mechanisms involved in inner membrane remodeling, an architectural feature crucial for mitochondrial activities. PMID- 24338370 TI - Early differences in dorsal hippocampal metabolite levels in males but not females in a transgenic rat model of Alzheimer's disease. AB - McGill-R-Thy1-APP rats express the human amyloid precursor protein carrying the Swedish and Indiana mutations. We examined the neurochemical content of the dorsal hippocampus in three-months-old male and female transgenic rats and healthy age- and gender-matched controls using in vivo (1)H MRS in order to assess early metabolite alterations and whether these were similar for both genders. Whereas male and female controls had similar levels of all metabolites, differences were evident between male and female McGill-R-Thy1-APP rats. Compared with McGill-R-Thy1-APP females, McGill-R-Thy1-APP males had lower levels of myo inositol and N-acetylaspartate (NAA). No differences in metabolite levels were evident when female control and McGill-R-Thy1-APP rats were compared, whereas McGill-R-Thy1-APP males had lower levels of glutamate, NAA and total choline compared with male controls. In addition to metabolite concentrations, metabolite ratios are reported as these are widely used. The results from this preliminary study demonstrate early metabolite alterations in the dorsal hippocampus of males in this rat model of Alzheimer's disease, and imply that very early possible neurochemical markers of the disease are different for males and females. PMID- 24338371 TI - Ultrasonographic indications for conservative treatment in pregnancy-related uterine arteriovenous malformations. AB - BACKGROUND: Uterine arteriovenous malformations (AVMs) are known to spontaneously regress. PURPOSE: To assess the predictive value of ultrasonography for patients requiring conservative treatment for pregnancy related to AVMs. MATERIAL AND METHODS: Our prospective study included 75 patients (conservative management:therapeutic management = 45:30) with vaginal bleeding from pregnancy related AVM. Clinical and ultrasonography examinations were reviewed, and the following information was gathered: complete blood count, AVM maximal diameter, AVM echogenicity, retained product of conception, number of blood vessels, and spectral Doppler (pulsatility index [PI], resistance index [RI], peak systolic velocity [PSV], time-averaged maximum velocity [TAMXV]). The Doppler criteria by Timmerman (mean PSV >70 cm/s: therapeutic management, mean PSV < 52 cm/s: conservative management) were used for the initial management selection. The association between experimental variables and outcomes was assessed to determine their usefulness for predicting conservative management. RESULTS: Features strongly associated with conservative management and their accuracy were PSV 89.6%, hemoglobin 84.7%, RI 83.1%, TAMXV 79.3%, and PI 78.6%. The overall accuracy for correct outcome classification was 64 (85.3%) of 75 patients. Most patients with conservative management had quicker improvement of symptoms and spontaneous regression at follow-up. CONCLUSION: Ultrasonography can accurately predict selection of conservative management. PMID- 24338372 TI - Synthesis and antibacterial activity of novel 5,5'-(pyridine-2,6-diyl)bis(4 arylideneamino-3-mercapto-1,2,4-triazole)-related derivatives. AB - The reaction of 5,5'-(pyridine-2,6-diyl)bis(4-amino-3-mercapto-1,2,4-triazole) with various aromatic aldehydes in acetic acid yielded the corresponding 5,5' (pyridine-2,6-diyl)bis(4-arylideneamino-3-mercapto-1,2,4-triazole) derivatives. The structures of the synthesized compounds as well as their intermediates were confirmed by elemental analysis, infrared spectra, (1)H NMR spectra and mass spectra studies. All the synthesized title compounds were screened for their antibacterial activities, and the preliminary results revealed that some of them showed good activities against Escherichia coli and Pseudomonas aeruginosa. PMID- 24338373 TI - Exponential tails of drug disposition curves: reality or appearance? AB - Since plasma drug concentration-time curves, C(t), can be examined only over a limited time range, it is unclear whether they have an exponential or power-law tail. An answer to this question is important because of the necessary extrapolation beyond the observation period (to infinity). Based on renewal theory, the present analysis shows that due to the recirculation process drug disposition curves become exponentially tailed also when the underlying organ transit time distributions have a power tail with exponent of -2 or smaller. Possible exceptions are drugs like amiodarone with anomalous distribution kinetics (deep tissue trapping) which are characterized by a power-law tail and an apparent lack of equilibrium distribution, corresponding to a fractional-in time derivative formulation of kinetics. PMID- 24338374 TI - T4a laryngeal cancer survival: retrospective institutional analysis and systematic review. AB - OBJECTIVES/HYPOTHESIS: To assess the survival outcomes of a homogeneous group of pT4a laryngeal cancer patients treated at our institution by primary total laryngectomy and neck dissection with adjuvant therapy when indicated, and to systematically review studies reporting overall survival outcomes in T4a laryngeal cancer. STUDY DESIGN: Systematic review of PubMed and Embase databases. METHODS: Records of 108 laryngeal cancer patients treated by total laryngectomy were reviewed. pT4a cases treated by primary total laryngectomy between 1998 and 2010 were included. Overall and disease-free survival at 2 and 5 years were reported. A systematic review was performed including all published studies reporting overall survival outcomes by treatment modality in T4 laryngeal cancer patients. RESULTS: Thirty cases met the inclusion criteria. At 2 years, overall and disease-free survival were 81.3% and 78%, respectively. The 5-year overall and disease-free survival rates were 60%. The systematic review retrieved 24 articles. Overall survival at 2 years ranged from 12% to 21.2% with radiotherapy, <30% to 65% with chemoradiotherapy, and from 30% to 100% with surgery. At 5 years, it ranged from 0% to 75% with radiotherapy, 16% to 50.4% with chemoradiotherapy, and 10% to 80.9% with surgery. CONCLUSIONS: Primary total laryngectomy provides a high survival rate for pT4a laryngeal cancer patients. Randomized controlled trials including homogenous patients are still needed before shifting to organ preservation protocols in these patients. LEVEL OF EVIDENCE: NA. PMID- 24338375 TI - Cooverexpression of ERBB1 and ERBB4 receptors predicts poor clinical outcome in pN+ oral squamous cell carcinoma with extranodal spread. AB - Overexpression of members of the ErbB receptor family is common in oral squamous cell carcinomas (OSCC); however, their prognostic value for aggressive OSCC has been debated. Extranodal spread to cervical lymph nodes is the most significant prognostic indicator in OSCC. In the present study, we investigated the clinical significance of single versus paired overexpression of members of the ErbB receptor family in 82 OSCC patients with lymph nodes metastasis, with or without capsular rupture (CR) followed by at least 10 years. Immunohistochemistry analysis revealed a common overexpression of ErbB1 (P = 0.021), ErbB2 (P = 0.001), ErbB4 (P = 0.048), as well as MMP-2 (P = 0.043) in OSCC cases with CR+. Increased expression of ErbB1 was associated with MMP-2 in tumors with advanced clinical stages, including poorly differentiated (grade III) tumors (P < 0.050). Vascular embolization was associated with MMP-2 (P = 0.021) and MMP-13 (P = 0.010) overexpression. Survival analysis revealed a lower survival probability in tumors overexpressing ErbB1 (P = 0.038), ErbB4 (P = 0.043), and MMP-12 (P = 0.050). As well a strong association was observed in cases with high risk of recurrence and strong immunostaining for ErbB1 (P = 0.017), ErbB4 (P = 0.008), MMP-1 (P = 0.003), MMP-2 (P = 0.016), MMP-10 (P = 0.041), and MMP-13 (P = 0.005). Stratified multivariate survival analysis revealed a strong prognostic interdependence of ErbB1 and ErbB4 cooverexpression in predicting the worst overall and disease-free survivals (P = 0.0013 and P = 0.0004, respectively). Taken together, these results support a cooperation of ErbB1, ErbB4, and members of the MMP family in predicting OSCC invasion and poor clinical outcomes. PMID- 24338376 TI - Single and composite influence of growth-related candidate gene polymorphisms on additive genetic variation of birth weight in Charolais beef cattle. AB - The objective of the present experiment work was to evaluate the effect of the inclusion of genomic information on the additive genetic variance of birth weight (BW) of Charolais cattle in Mexico. Variance components and heritability were estimated using four linear models. The first model was the base model (BM) from which single and composite effects of selected single-nucleotide polymorphism (SNP) markers were evaluated (BM1, BM2, and a composite BM3). Genetic markers were included in a regression model and analyzed by stepwise regression against adjusted BW from a panel of growth-related traits candidate gene markers. After two regression rounds, two SNPs (R (2) > 0.02) were chosen to include into the animal models as fixed effects. Growth hormone receptor gene GHR 4.2 and GHR 6.1 SNPs were selected from a panel of 39 SNPs. GHR 4.2 had a negligible effect on BW, whilst GHR6.1, interestingly, explained ~9 % of genetic variance (p = 0.0877) with an alphaG>A = 0.509. The inclusion of markers in M2 and M3 reduced 19 and 15 % of the additive genetic variance, respectively. Both adjusted significantly better the linear model (LRT = p < 0.01). Results obtained suggest that the previous selection of markers in a candidate gene approach and subsequent inclusion of selected SNPs into animal model might provide a better fit, avoiding the overestimation of genetic variance components and breeding values for BW. PMID- 24338377 TI - High expression of CXCR-2 correlates with lymph node metastasis and predicts unfavorable prognosis in resected esophageal carcinoma. AB - CXC chemokines have been reported to play critical roles in tumor growth, angiogenesis, invasion and metastasis of various human cancers. However, expression of CXC chemokines type 2 (CXCR2) and its association with clinicopathological characters and patients' prognosis in esophageal cancer are scarcely reported. We retrospectively collected clinicopathologic characteristics of 95 esophageal cancer patients undergoing esophagectomies. Immunohistochemistry was used to detect the expression of CXCR2. The survival was analyzed by the Kaplan-Meier method. Univariate and multivariate analyses were then performed to determine the relationship between CXCR2 and the clinical characteristics and to analyze whether CXCR2 expression was a significant independent prognostic factor for esophageal cancer patients. CXCR2 was highly expressed in 57.9 % of the randomly selected specimens. The expression of CXCR2 was significantly related to lymph node metastasis (P = 0.044) and predicted poor overall status in operable esophageal cancer patients (P = 0.012). Cox proportional hazard analysis regression analysis indicated that CXCR2 expression (P = 0.030) and lymphatic metastasis (P < 0.001) may serve as independent prognostic markers for esophageal cancer patients. Our results demonstrate that CXCR2 significantly correlates with lymph node metastasis and is a poor prognostic factor in resected esophageal squamous cell carcinoma. PMID- 24338378 TI - Endoscopic application of EGF-chitosan hydrogel for precipitated healing of GI peptic ulcers and mucosectomy-induced ulcers. AB - The gastrointestinal (GI) endoscopy has become a standard diagnostic tool for GI ulcers and cancer. In this study we studied endoscopic application of epidermal growth factor-containing chitosan hydrogel (EGF-CS gel) for treatment of GI ulcer. We hypothesized that directional ulcer-coating using EGF-CS gel via endoscope would precipitate ulcer-healing. EGF-CS gel was directly introduced to the ulcer-region after ulceration in acetic acid-induced gastric ulcer (AAU) and mucosal resection-induced gastric ulcer (MRU) rabbit and pig models. The ulcer dimensions and mucosal thicknesses were estimated and compared with those in the control group. Healing efficacy was more closely evaluated by microscopic observation of the ulcer after histological assays. In the AAU model, the normalized ulcer size of the gel-treated group was 2.3 times smaller than that in the non-treated control group on day 3 after ulceration (P < 0.01). In the MRU model, the normalized ulcer size of the gel-treated group was 5.4 times smaller compared to that in the non-treated control group on day 1 after ulceration (P < 0.05). Histological analysis supported the ability of EGF-CS gel to heal ulcers. The present study suggests that EGF-CS gel is a promising candidate for treating gastric bleeding and ulcers. PMID- 24338379 TI - Influence of fluoride treatment on surface properties, biodegradation and cytocompatibility of Mg-Nd-Zn-Zr alloy. AB - Fluoride treatment is a commonly used technique or pre-treatment to optimize the degradation kinetic and improve the biocompatibility of magnesium-based implant. The influence of changed surface properties and degradation kinetics on subsequent protein adsorption and cytocompatibility is critical to understand the biocompatibility of the implant. In this study, a patent magnesium alloy Mg-Nd-Zn Zr alloy (JDBM) designed for cardiovascular stent application was treated by immersion in hydrofluoric acid. A 1.5 MUm thick MgF2 layer was prepared. The surface roughness was increased slightly while the surface zeta potential was changed to a much more negative value after the treatment. Static contact angle test was performed, showing an increase in hydrophilicity and surface energy after the treatment. The MgF2 layer slowed down in vitro degradation rate, but lost the protection effect after 10 days. The treatment enhanced human albumin adsorption while no difference of human fibrinogen adsorption amount was observed. Direct cell adhesion test showed many more live HUVECs retained than bare magnesium alloy. Both treated and untreated JDBM showed no adverse effect on HUVEC viability and spreading morphology. The relationship between changed surface characteristics, degradation rate and protein adsorption, cytocompatibility was also discussed. PMID- 24338380 TI - Preparation and characterization of galactosylated glycol chitosan micelles and its potential use for hepatoma-targeting delivery of doxorubicin. AB - This study aimed to develop novel galactosylated cholesterol modified-glycol chitosan (Gal-CHGC) micelles for targeting delivery of doxorubicin (DOX) in live cancer cells. Three kinds of Gal-CHGC conjugates were synthesized and characterized. The mean particle size and critical aggregation concentration of these polymeric micelles increased with the increase of galactose substitution degree. The DOX-loaded micelles were prepared by an o/w method. The mean diameters of DOX-loaded galactosylated micelles were in the range of 387-497 nm. DOX released from drug-loaded micelles displayed a biphasic way. Cellular uptake studies demonstrated that DOX-loaded galactosylated micelles could enhance the uptake of DOX into HepG2 cells. Moreover, the cytotoxicity of DOX-loaded galactosylated micelles against HepG2 cells significantly improved in contrast with free DOX and DOX-loaded micelles without galactosylation. These results suggested that Gal-CHGC micelles could be a potential carrier for hepatoma targeting drug delivery. PMID- 24338382 TI - Surgical management of adrenal metastases. AB - In the presence of a history of cancer, adrenal masses are commonly, but not exclusively, metastases. Depending upon the status of the patient's ongoing cancer therapy, overall tumor burden, and performance score, adrenalectomy is a viable treatment option. Herein we review the prevalence, diagnostic evaluation, and selection for surgical treatment of adrenal metastases. Additional attention is paid to recent data supporting the safety and oncologic efficacy of laparoscopic adrenalectomy. PMID- 24338383 TI - Oxidative damage and alterations in antioxidant enzyme activities in the kidneys of rat exposed to trichloroacetic acid: protective role of date palm fruit. AB - In this study, we investigated the antioxidant and protective properties of date fruit aqueous extract (DFAE) on trichloroacetic acid (TCA)-induced nephrotoxicity in rat. Oral administration of TCA as drinking water (0.5 and 2 g/L) daily for 2 months caused nephrotoxicity as evident by elevated levels of plasma creatinine, urea, and uric acid. Activity of antioxidant enzymes, catalase (CAT) and glutathione peroxidase (GPx), was decreased, whereas superoxide dismutase (SOD) activity and malondialdehyde (MDA) level were increased along with histopathological injuries. The oral administration of DFAE (4 mL/kg/day) to TCA treated groups proved some significant correction by increasing the antioxidant activity of the CAT and GPx enzymes and normalizing the SOD activity and the MDA level (p < 0.05). It also protected kidney's histology and normalized the functions of this organ. It could be concluded that DFAE has a protective role against TCA-induced oxidative stress in rat, thereby protecting the renal tissue from TCA-induced damage. PMID- 24338381 TI - Animal models for depression associated with HIV-1 infection. AB - Antiretroviral therapy has greatly extended the lifespan of people living with human immunodeficiency virus (PLHIV). As a result, the long-term effects of HIV infection, in particular those originating in the central nervous system (CNS), such as HIV associated depression, have gained importance. Animal models for HIV infection have proved very useful for understanding the disease and developing treatment strategies. However, HIV associated depression remains poorly understood and so far there is neither a fully satisfactory animal model, nor a pathophysiologically guided treatment for this condition. Here we review the neuroimmunological, neuroendocrine, neurotoxic and neurodegenerative basis for HIV depression and discuss strategies for employing HIV animal models, in particular humanized mice which are susceptible to HIV infection, for the study of HIV depression. PMID- 24338384 TI - Influence of lipolysis and fatty acid availability on fuel selection during exercise. AB - The aim of the present study was to investigate the influence of substrate availability on fuel selection during exercise. Eight endurance-trained male cyclists performed 90-min exercise at 70% of their maximal oxygen uptake in a cross-over design, either in rested condition (CON) or the day after 2-h exercise practised at 70% of maximal oxygen uptake (EX). Subjects were given a sucrose load (0.75 g kg(-1) body weight) 45 min after the beginning of the 90-min exercise test. Lipolysis was measured in subcutaneous abdominal adipose tissue (SCAT) by microdialysis and substrate oxidation by indirect calorimetry. Lipid oxidation increased during exercise and tended to decrease during sucrose ingestion in both conditions. Lipid oxidation was higher during the whole experimental period in the EX group (p = 0.004). Interestingly, fuel selection, assessed by the change in respiratory exchange ratio (RER), was increased in the EX session (p = 0.002). This was paralleled by a higher rate of SCAT lipolysis reflected by dialysate glycerol, plasma glycerol, and fatty acids (FA) levels (p < 0.001). Of note, we observed a significant relationship between whole-body fat oxidation and dialysate glycerol in both sessions (r (2) = 0.33, p = 0.02). In conclusion, this study highlights the limiting role of lipolysis and plasma FA availability to whole-body fat oxidation during exercise in endurance-trained subjects. This study shows that adipose tissue lipolysis is a determinant of fuel selection during exercise in healthy subjects. PMID- 24338385 TI - Genetic diversity of Saccharum spontaneum from geographical regions of China assessed by simple sequence repeats. AB - Saccharum spontaneum is the most variable wild relative of sugarcane with potential for use in sugarcane improvement programs. In order to help preserve and exploit this species, 152 accessions from eight major geographical regions in China, including Hainan, Guangdong, Guangxi, Yunnan, Sichuan, Guizhou, Fujian, and Jiangxi provinces, were investigated by analyzing 20 simple sequence repeats (SSRs), including 11 genomic SSRs (gSSRs) and nine SSRs developed from expressed sequence tags (EST-SSRs). A total of 454 alleles were generated by the 20 SSRs, with 295 and 159 alleles detected by gSSRs and EST-SSRs respectively. The Mantel test showed significant correlation between genetic matrixes among the studied accessions revealed by gSSRs versus EST-SSRs, although the average polymorphism of EST-SSRs (17.7) was much lower than that of gSSRs (26.8). Among the eight provinces, collections from Guizhou were the most diverse and those from Guangdong were the most distinct. Clustering analysis and principal component analysis accordantly classified the accessions into four groups, which were "Southwest group", "Hainan group", "Guangdong group", and "Guangxi group", based on the geographical origin of the major accessions in each group, demonstrating that geographical factors play an important role in the pattern of genetic structure of Chinese S. spontaneum. As two (Guizhou and Yunnan) of the three provinces with highest genetic diversity are located in southwest China, we concluded that southwest China is the region with the highest genetic diversity of S. spontaneum. PMID- 24338386 TI - Acquisition of pig intramuscular preadipocytes through dedifferentiation of mature adipocytes and establishment of optimal induction conditions. AB - Intramuscular fat deposition is a major contributing factor to variations in pork quality. Understanding the mechanisms driving the differentiation and metabolism of muscle-derived adipocytes is important for regulating the fat deposition in muscle. Studies on intramuscular adipocytes commonly involve stromal-vascular (SV) cell cultures, which contain preadipocytes but also several other types of primordial cells. Hence, it is crucial to obtain pure intramuscular preadipocytes for investigating adipocyte differentiation and metabolism in muscle tissue. In this study, we established cultures of pure intramuscular preadipocytes that were derived from mature adipocytes of newborn pigs. Pure mature adipocytes were isolated from the longissimus dorsi (LD) muscle and allowed to dedifferentiate into fibroblast-like cells in ceiling culture. These fibroblast-like cells turned out to be preadipocytes; they exhibited the ability to redifferentiate into mature adipocytes when adipogenically induced in vitro. The redifferentiation process was confirmed by lipid accumulation in the cytoplasm and expression patterns of peroxisome proliferator-activated receptor gamma 2 (PPARgamma2), CCAAT/enhancer binding protein alpha (C/EBPalpha), lipoprotein lipase (LPL), and adiponectin genes, which were all similar to those observed in previous preadipocyte studies. We optimized the induction conditions for intramuscular preadipocytes by adding 0.25 nM dexamethasone (DEX), 5 MUg/mL insulin (INS), and 0.1 mM 3-isobutyl-1-methylxanthine (IBMX). Therefore, this study provides a new model for studying the mechanisms of intramuscular preadipocyte differentiation and metabolism. PMID- 24338387 TI - G2677T polymorphism can predict treatment outcome of Malaysians with complex partial seizures being treated with Carbamazepine. AB - Carbamazepine (CBZ) is used as the first line of treatment of complex partial seizures (CPS) in Malaysia. While this drug is known to be effective for the treatment of CPS, more than 30% of patients remain drug resistant to CBZ mono therapy. We examined a possible relationship between patients' response to CBZ mono-therapy and the G2677T SNP of the ABCB1 gene. Three hundred and fourteen patients with CPS were recruited from the Neurology Department of the Kuala Lumpur Hospital, of whom 152 were responders and the other 162 were non responders to CBZ mono-therapy. DNA was extracted from blood samples and real time PCR was performed to detect the G2677T SNP of the ABCB1 gene. Results were described as genotype frequencies and compared by logistic regression analysis. Among the 152 responders, 74% had the GG genotype. However, among the 162 non responders, 26.5% had the GT genotype and 39% had the TT genotype. There was a significant difference in genotype frequency (TT vs GG; odds ratio 4.70; 95% confidence interval, 2.70-8.20) between responders and non-responders. The presence of the T allele of the G2677T SNP appears to be a useful screening marker to determine if a patient is going to be resistant to CBZ as a single drug therapy in the treatment of CPS. PMID- 24338388 TI - Changes of gene expression profiles across different phases of vascular calcification in rats. AB - This study investigated the alteration of gene expression profiles in order to gain a deeper understanding into the molecular mechanism involved in different processes of vascular calcification (VC). Sprague Dawley (SD) rats were injected with 300,000 ug/kg vitamin D3 and gavaged with 25 mg/kg nicotine for 8 or 16 weeks to create 8- and 16-week VC calcification groups. Histological analysis and quantification of aortic calcium content were used to determine the severity of vascular calcification. The suppression subtractive hybridization (SSH) method was employed to screen for up and downregulated genes in early and later phases of vascular calcification. Changes in calcium and phosphorus levels in tissue were used as markers of vascular calcification. Quantification of aortic calcium content revealed that vascular calcification might regress over time. In the early phase of vascular calcification, many calcification-promoting genes were upregulated, including ossification, oxidation, and inflammatory genes. In contrast, in later phase of vascular calcification, various calcification inhibitor genes were highly expressed, including pyrophosphoric acid synthesis genes, glutamate signal peptide-related, reduction activity, and apoptosis regulation genes. The relatively higher expression of calcification-inhibitor genes compared to that of calcification-promoting genes might explain the genetic mechanism leading to the regression of vascular calcification. Therefore, this study provides a genomic basis to facilitate understanding of the molecular mechanism underlying vascular calcification regression. PMID- 24338389 TI - Novel association analysis between HLA-DQB1 polymorphisms and rectal cancer based on a cross-validation design. AB - A new study design based on cross-validation of the age at the onset of rectal cancer and the differences between the frequency distributions of relevant genes in 2 groups was developed for identification of disease-related HLA. Patients with rectal cancer were recruited and their age at the time of the first surgery was recorded. The genetic variants of HLA-DQB1 were genotyped using an HLA-DQB1 PCR-SSP typing kit. Allele frequencies were compared with control population. The mean age of patients with and without the alleles was compared. The frequency values of HLA-DQB1*02 were 12.3% higher in the cancer group than in the control population (P < 0.05). The median ages of the subjects with and without HLA DQB1*02 were 54.0 and 61.0 years, respectively, with significant difference observed between the ages for these groups (P < 0.05). The median ages of the subjects with and without HLA-DQB1*03 were 62.0 and 58.0 years, respectively, and a significant difference was observed. The cross-validation of the 2 above mentioned analytical results showed that a statistically significant difference was noted for HLA-DQB1*02 (P < 0.05), whereas no such statistically significant difference was observed for HLA-DQB1*03. HLA-DQB1*02 allele was related to cancer susceptibility. The new analysis method may be an efficient and reliable approach for the identification of disease-related HLA. PMID- 24338390 TI - Correlation of SPECT imaging, biochemical parameters and mutation with systolic dysfunction. AB - We investigated systolic dysfunction by the use of biochemical laboratory tests and perfusion single-photon emission computed tomography imaging in 32 Pakistani subjects exhibiting symptoms of this disorder. To investigate underlying genetic causes, such as familial hypercholesterolemia, DNA samples from these subjects were screened by PCR-SSCP and DNA sequencing to detect changes in the low density lipoprotein receptor gene (LDLR). A novel mutation (1171G>A) in exon 8 and two polymorphisms (1167G>A and 1413 A>G) in exons 8 and 10 of the LDLR gene were found. In silico tools such as SIFT, PolyPhen-2, KD4v, and Project HOPE were used to predict the effect of this mutation on protein structure and function. PMID- 24338391 TI - Association of the estrogen receptor-beta gene RsaI and AluI polymorphisms with human idiopathic thin endometrium. AB - The aim of this study was to investigate the potential correlation between polymorphisms of the estrogen receptor (ER)-beta gene (RsaI and AluI) and ethnic Han Chinese human idiopathic thin endometrium. A total of 120 patients with idiopathic thin endometrium and 120 sterility patients with normal endometrium thickness (controls) were included in the study. RsaI and AluI polymorphisms of the ER-beta gene were analyzed with polymerase chain reaction-restriction fragment length polymorphism. The distribution of polymorphisms, genotype, allele, and haplotype was compared between the 2 groups. A significant difference in the RsaI genotype was observed between idiopathic thin endometrium patients and controls. The distribution of the R allele of the RsaI polymorphism in idiopathic thin endometrium patients was 37.1% compared with 48.3% in controls. The odds ratio was 0.630 (95% confidence interval = 0.438 to 0.907, P = 0.013). No significant difference in the genotype of the AluI polymorphism was found between the two groups. The linkage disequilibrium between RsaI and AluI haploids was not significant in either group, with D' values of 0.2036 and 0.0685 in the idiopathic thin endometrium patients and controls, respectively. The results of this study suggest a potential role of the ER-beta gene polymorphisms in the etiology of idiopathic atrophic endometrium and the R allele as a potential protective factor in ethnic Han Chinese. PMID- 24338392 TI - Plasma chemerin level in metabolic syndrome. AB - To investigate the chemerin level in the Chinese Han population with metabolic syndrome and its relationship with each metabolic syndrome component [body mass index (BMI), blood pressure, blood lipids, and blood glucose], we selected 30 patients with metabolic syndrome and 30 healthy control subjects. The chemerin level was measured by enzyme immunoassay in these 2 groups. The subjects' weight, blood pressure, BMI, waist circumference, fasting blood glucose, fasting insulin, lipids, and glycated hemoglobin were simultaneously detected. The t-test, correlation analysis, and multiple regression analysis were used to perform statistical analysis. We found that plasma chemerin level was higher in the metabolic syndrome group than that in the control group (97.61 +/- 6.49 vs 70.26 +/- 6.97, t = 15.73, P < 0.05). The plasma chemerin level was positively correlated with systolic blood pressure, waist circumference, BMI, waist-to-hip ratio, fasting blood glucose, fasting insulin, and glycated hemoglobin (r = 0.548, 0.442, 0.359, 0.556, 0.613, 0.581, and 0.572, respectively; all P < 0.05). However, it was negatively correlated with high-density lipoprotein cholesterol (r = -0.378, P < 0.05). Therefore, we concluded that plasma chemerin level was correlated with obesity, blood pressure, and high-density lipoprotein cholesterol, suggesting that it may play a role in the pathogenesis of metabolic syndrome. PMID- 24338394 TI - Inbreeding effects in Solanum lycocarpum A. St.-Hil populations, an endangered species of the Brazilian Cerrado. AB - The inbreeding effective population size is an estimate of inbreeding and genetic drift in populations. It is an important tool for conservation genetics because it represents the number of individuals that are effectively contributing alleles to the subsequent generations. Several studies have been published in the last decades on the genetic structure of natural plant populations of the Cerrado, the Central-Brazilian savannahs, but most of them do not present effective size estimates. The objective of this study was to show such estimates for Solanum lycocarpum, a Cerrado species that is in danger of genetic erosion. We utilized microsatellites, isozymes, and 2 natural populations for each marker to estimate the population inbreeding effective size of a group of populations (N(^)e(v)) and the minimum number of populations that should be conserved (S(^)(ref)) in order to retain an effective number of 500. For the 2 markers that were utilized, only approximately 12% of the individuals are effective in the populations. The value obtained for S(^)(ref) was approximately 80. PMID- 24338393 TI - Critical evaluation of transcription factor Atf2 as a candidate modulator of alcohol preference in mouse and human populations. AB - In prior work, congenic strains carrying the DBA/2Igb (D2) region of chromosome 2 (Chr2) for alcohol preference were bred onto a C57BL/6Ibg (B6) background and as predicted were found to reduce voluntary consumption. Subsequently, interval specific congenic recombinant strains (ISCRS) were generated and also tested. These ISCRS strains reduced the quantitative trait loci (QTL) interval to a comparatively small 3.4 Mb region. Here, we have exploited an integrative approach using both murine and human populations to critically evaluate candidate genes within this region. First, we used bioinformatics tools to search for genes relevant to alcohol preference within the QTL region. Second, we searched for single nucleotide polymorphisms (SNPs) within exons of every gene in this region. Third, we conducted follow-up microarray analyses to identify differentially expressed genes between the B6 and ISCRS strains in mice from each group. Fourth, we analyzed correlations between the expression level of candidate genes and phenotypes of alcohol preference in a large family of BXD recombinant inbred strains derived from B6 and D2. Finally, we evaluated SNP segregation in both BXD mouse strains and in humans who were heavy alcohol drinkers or non-drinkers. Among several potential candidate genes in this region, we identified activating transcription factor 2 (Atf2) as the most plausible gene that would influence alcohol preference. However, the candidacy of Atf2 was only weakly supported when we used a genetic network approach and by focused reanalysis of genome-wide association study data from European-American and African-American populations. Thus, we cannot conclude that Atf2 plays a role in the regulation of the QTL of mouse Chr2. PMID- 24338395 TI - Isolation and characterization of polymorphic microsatellite markers from Coilia ectenes. AB - Coilia ectenes (Jordan and Seale 1905) is an important anadromous species that is an important resource at risk of extinction because of over-fishing, pollution, and coastal construction. To evaluate the genetic diversity of C. ectenes for use in breeding programs, elite microsatellite-enriched libraries were constructed and novel microsatellite markers were developed, and applied to genetically detect wild populations. Out of 92 randomly selected and sequenced clones, 89 contained a CA or GA repeat motif. Twenty-two pairs of primers were designed to investigate the polymorphism and genetic structure of a wild population collected from the Yellow River estuary, China. It was found that 2 loci were monomorphic and 20 loci were polymorphic. The number of alleles per polymorphic loci ranged from 3 to 13, with an average of 7.9. The expected heterozygosity per locus ranged from 0.05 to 0.89, with an average of 0.68. The isolated polymorphic markers are expected to be of use in future genetic breeding programs for C. ectenes, and in the assessment of genetic variation within this species. PMID- 24338396 TI - Kin structure and parallel dispersal in the black-and-gold howler monkey Alouatta caraya (Platyrrhini, Atelidae). AB - We here investigated the kin structure and pattern of dispersal in the black-and gold howler monkey (Alouatta caraya, Platyrrhini, Atelidae) based on genotype differences at nine microsatellite loci of 48 individuals from eight social groups along the riparian forest of the Tocantins River, Brazil. The genetic diversity (HE = 0.647) was similar to or higher than previously reported values in other Alouatta species. Given that no spatial kinship structure was detected, we found no evidence that dispersal was constrained by distance within the spatial scale analyzed (<25 km). Although no evidence was found for sex-biased dispersal, our results strongly suggest that extra-group copulations are common in A. caraya, and that both males and females disperse from their natal group. PMID- 24338397 TI - HMGB3 characterization in gastric cancer. AB - Gastric cancer is a major health problem worldwide; it is the second most common cause of cancer death in the world. Recent studies indicate that the high mobility group (HMG) of chromosomal proteins is associated with cancer progression. However, HMGB3 has been little studied. We analyzed the co expression network between HMGB3 and differentially-expressed genes in the GSE17187 database, identifying the relevant transcription factors, and the conserved domain of HMGB3 to understand the underlying regulation mechanisms involved in gastric cancer. Thirty-one relationships between 11 differentially expressed genes were included in a co-expression network; many of these genes have been identified as related to cancer, including TBX5 and TFR2. Further analysis identified nine transcription factors, these being GATA3, MZF1, GATA1, GATA2, SRY, REL, NFYB, NFYC, and NFYA, which could interact with HMGB3 to regulate target gene expression and consequently regulate gastric cancer cell proliferation, migration and invasion. The HMG-box domain was very similar in various species, with only a few amino acid changes, indicating conserved functions in HMG-box. This information helps to provide insight into the molecular mechanisms of HMGB3 in human gastric cancer. PMID- 24338398 TI - Pre-treatment with glutamine reduces genetic damage due to cancer treatment with cisplatin. AB - Cisplatin is an effective antineoplastic drug. However, it provokes considerable collateral effects, including genotoxic and clastogenic activity. It has been reported that a diet rich in glutamine can help inhibit such collateral effects. We evaluated this activity in 40 Swiss mice, distributed into eight experimental groups: G1 - Control group (PBS 0.1 mL/10 g body weight); G2 - cisplatin group (cisplatin 6 mg/kg intraperitoneally); G3, G4, G5 - glutamine groups (glutamine at 150, 300, and 600 mg/kg, respectively; orally); G6, G7, G8 - Pre-treatment groups (glutamine at 150, 300, and 600 mg/kg, respectively; orally and cisplatin 6 mg/kg intraperitonially). For the micronucleus assay, samples of blood were collected (before the first use of the drugs at T0, then 24 (T1) and 48 (T2) hours after the first administration). For the comet assay, blood samples were collected only at T2. The damage reduction percentages for the micronucleus assay were 90.0, 47.3, and 37.3% at T1 and 46.0, 38.6, and 34.7% at T2, for G6, G7, and G8 groups, respectively. For the comet assay, the damage reduction percentages were 113.0, 117.4, and 115.0% for G6, G7, and G8, respectively. We conclude that glutamine is able to prevent genotoxic and clastogenic damages caused by cisplatin. PMID- 24338399 TI - Myf5 gene polymorphisms and production performance traits in Songliao white geese. AB - To explore the relationship between Myf5 gene polymorphisms and production performance traits in Songliao white geese, we used the chicken Myf5 sequence to design primers and amplified part of the exon 1 sequence of the Songliao white goose Myf5 gene. Results of single-strand conformation polymorphism polymerase chain reaction analysis revealed polymorphisms of the amplified fragment, including three genotypes (AA, AB, and BB). Three varieties were dominated by allele A and were mainly expressed in AA genotypes. We also identified that the Myf5 gene has one single nucleotide change (A->G) on exon 1 at locus 1344, and another (G->C) at locus 1410. Analysis of variance showed significant differences between genotypes before slaughter in live weight, carcass weight, eviscerated weight, leg muscle weight, weight of the wings, and slaughter rate. There were no significant differences with respect to other growth and carcass traits evaluated. PMID- 24338400 TI - Predicting the target genes of microRNA based on microarray data. AB - MicroRNAs (miRNAs) are small non-coding RNAs of approximately 22 nucleotides in length, which play important roles in regulating gene expression post transcriptionally. Several computational methods and algorithms have been developed to predict miRNA targets. In this study, we described a method that can be used to integrate miRNA target prediction data from multiple sources and gene expression data to predict target genes of particular miRNAs. We used hsa-miR-375 as an example to test the feasibility of our method. A total of 5645 target genes of hsa-miR-375 were identified from five prediction programs, and among them, 2440 target genes were shared by at least 2 of these 5 programs. By using our method, the number was further reduced to 149 and 5 of the 149 target genes had been validated by previous study. This is a simple yet highly effective approach. PMID- 24338401 TI - Oct4 and Sox2 overexpression improves the proliferation and differentiation of bone mesenchymal stem cells in Xiaomeishan porcine. AB - Mesenchymal stem cells derived from bone marrow (BMSCs) are a population of self renewing multipotent cells that are capable of differentiating into various cellular lineages, and are widely employed in tissue engineering and cell therapy. Recently, clinical research involving BMSCs has become increasingly popular. In order to conduct appropriate research, it is first necessary to amplify large amounts of functional BMSCs in vitro. However, after several passages of expanding in vitro, the proliferation and differentiation potential of BMSCs gradually decline. To determine whether overexpression of Oct4 or Sox2 might prevent this decline, we transfected Oct4 or Sox2, which are essential for the pluripotency and self-renewal of embryonic stem cells, into BMSCs of Xiaomeishan porcine by a lentivirus. The results showed that overexpression of Sox2 or Oct4 BMSCs in culture media containing a basic fibroblast growth factor resulted in higher proliferation and differentiation compared to controls, suggesting that genetic modification of stemness-related genes is an efficient way to maintain the proliferation and differentiation potential of BMSCs. PMID- 24338402 TI - The role of Hsp90alpha in heat-induced apoptosis and cell damage in primary myocardial cell cultures of neonatal rats. AB - To understand the mechanism underlying the sudden animal death caused by acute heart failure during heat stress, the relationships among the heat-induced pathological changes and apoptosis and the variations in the levels of protective Hsp90alpha and its mRNA in the heat-stressed primary myocardial cells of neonatal rats in vitro were studied by cytopathological observation, immunoblotting, RT PCR, and analysis of the related enzymes. After a period of adaptive cell culture, the myocardial cells were immediately exposed to heat stress at 42 degrees C for 10, 20, 40, 60, 120, 240, 360, and 480 min. Levels of creatine kinase increased from the beginning of heat stress, and the cells exposed to heat stress showed acute cellular lesions characterized by vacuolar degeneration and necrosis after 40 min of heat stress, suggesting that the myocardial cells in vitro were obviously stressed and damaged by higher temperature. The levels of cleaved caspase-3 and cytochrome C, which were related to apoptosis, increased significantly after 40 min of heat stress while the Hsp90alpha protein level significantly decreased. In contrast, after 6 h of exposure to heat stress, the levels of cleaved caspase-3 and cytochrome C decreased while those of Hsp90alpha significantly increased, suggesting that early depletion of Hsp90alpha coincides with a high rate of necrosis and apoptosis in heat-stressed myocardial cells, while the Hsp90alpha level in surviving cells increases again with significantly less apoptosis after 6 h of heat stress. These findings also indicate that apoptosis of myocardial cells occurs through the activation of the cytochrome C and caspase-3 pathway. The cell repair capacity of Hsp90alpha is overstrained in the early phase of heat treatment and needs some hours to stabilize. As a result, in the primary myocardial cells in vitro, Hsp90alpha shows protective activity against damage at the end period of the heat exposure. PMID- 24338404 TI - Genome-wide multilocus analysis of intraspecific differentiation in Oryza rufipogon Griff. from China and the influence of introgression from O. sativa L. AB - Twenty-five populations of Oryza rufipogon from China and 144 cultivars of Oryza sativa were selected for this study. Based on the DNA fragment of Ehd1-4 and subspecies-specific sequence-tagged site markers in different chromosomes, intraspecific differentiation in O. rufipogon from China was analyzed. The introgression from O. sativa to O. rufipogon was also analyzed based on simple sequence repeat markers. The results revealed that the DNA fragment of Ehd1-4 could distinguish the O. sativa subspecies japonica and indica. Furthermore, although significant indica-japonica differentiation did not occur in most O. rufipogon populations from China, O. rufipogon varieties from Hainan Island and from the mainland of China showed differentiation tendencies. Japonica-like O. rufipogon varieties were predominant in Mainland China. However, more indica-like O. rufipogon varieties were found in Hainan Island. Finally, although cultivar specific alleles were found in most of the O. rufipogon varieties from Hainan Island and Guangdong Province, some varieties remain pure and non-introgressive. PMID- 24338403 TI - Differentiation of neonatal dorsal root ganglion-derived neural stem cells into oligodendrocytes after intrathecal transplantation into a cauda equina lesion model. AB - Cauda equina syndrome (CES) is characterized by varying patterns of low back pain, sciatica, lower extremity sensorimotor loss, and bowel and bladder dysfunction. The prognosis for complete recovery of CES is dependent on not only the time before surgical intervention with decompression but also the severity of the nerve damage. Delayed or severe nerve compression impairs the capability of nerve regeneration. Transplantation of neural stem cells (NSCs) may facilitate axon regeneration and functional recovery in a spectrum of neurological disorders. Our study shows that the NSCs derived from early postnatal dorsal root ganglion (DRG) are able to proliferate to form neurospheres and differentiate into O4(+) oligodendrocytes but not glial fibrillary acidic protein (GFAP(+)) astrocytes or betaIII-tubulin(+) neurons in vitro. After intrathecal transplantation into the lumbar spinal canal stenosis animal model, most of the GFP-expressing NSCs were induced to differentiate into oligodendrocytes in vivo. Although the recovery of sensorimotor function was not significantly improved in rats with transplantation therapy, our results implied that subarachnoid microinjection of NSCs may promote axon regeneration of DRG neurons in the cauda equina model after nerve injury. PMID- 24338405 TI - Improving yield and quality traits of durum wheat by introgressing chromosome segments from hexaploid wheat. AB - Durum wheat (Triticum turgidum durum; 2n = 4x = 28; genome AABB) has long been an important food resource for human diets. The projected increase of the world's population to 9.1 billion by 2050 has highlighted the importance and urgency for improving the yield and quality performance of durum wheat. A backcrossed population, which was derived from the durum wheat variety 'Bellaroi' (recurrent parent) and the hexaploid genotype 'CSCR6' (donor parent), was used to investigate the feasibility of improving yield- and quality-related traits of durum wheat by introgressing chromosome fragments from hexaploid wheat. The population means for grain protein content, gluten content, spike length, and spikelet number were improved compared with those of the recurrent parent 'Bellaroi'. A small proportion of the backcross population lines showed significant improvements in spike length and spikelet number compared with the recurrent parent 'Bellaroi'. Some loci with significant effects for plant height, spike length, spikelet number, and thousand-grain weight were identified. Several of these loci affected more than one trait. These results showed that the introgression of chromosome fragments from 'CSCR6' into the durum genetic background could be an effective method for improving yield and quality traits of durum wheat. In addition, the loci showing significant effects on desired traits in this study could be fine mapped using an F2 population obtained by backcrossing the lines that carry the positive allele(s) with the recurrent parent. PMID- 24338406 TI - Cloning and expression analysis of the 37-kDa laminin receptor precursor gene from Hyriopsis cumingii. AB - Hyriopsis cumingii is an economically important freshwater pearl mussel with high pearl quality that is endemic in China. Investigation of genes relevant to shell formation is important for increased pearl output. The substances that form mollusk shells are secreted by epithelial cells in the mantle, the proliferation of which influences secretion ability. This study focused on the proliferation related 37-kDa laminin receptor precursor (37LRP) of H. cumingii. The full-length cDNA (1133 bp) encoding this 300-amino acid protein was cloned from the mantle. Quantitative fluorescence analysis showed that 37LRP expressed in eight tissues, with the highest expression observed in the liver, and its expression pattern in the mantle reflected shell repair. During repair, 37LRP expression was higher in the experimental shell repair group than that in the control group, exhibiting an initial increase followed by a decrease in expression, and returning to basal levels on completion of the repair. A similar trend was also observed with respect to immunity and cellular metabolism. Expression of the 37LRP protein in the experimental group was significantly higher than that in the control group at the first and second days after shell injury. After 4 days, 37LRP expression in the experimental group was lower than that in the control group. In situ hybridization revealed a strong positive signal corresponding to the 37LRP mRNA at the horny grooves of the mantle, evagination, and in epithelial cells of the velum, which implicated these areas in the repair and formation of the cuticle, prismatic layer, and nacre. PMID- 24338407 TI - Fundus autofluorescence in exudative age-related macular degeneration. AB - The aim of this study was to investigate the characteristics of fundus autofluorescence (FAF) in patients with wet (exudative) age-related macular degeneration (AMD). Color fundus photographs, fundus fluorescein angiograms, indocyanine green angiograms, and FAF images were obtained from 61 patients (72 eyes) with exudative AMD. The FAF results for different patterns of exudative AMD were compared to those revealed by other fundus images. Of the 72 eyes evaluated, which were classified into three patterns based on the results of fundus fluorescein angiography, 68 had abnormal FAF. Forty-six eyes (63.9%) had classic wet AMD with abnormal FAF. Among these, 10 exhibited a slightly decreased FAF with near-normal or background FAF signal at the center of the lesion area; 36 demonstrated not only decreased FAF at the center of the lesion but also an increased FAF signal toward the lesion edge. Sixteen eyes (22.2%) had occult wet AMD, of which 12 exhibited heterogeneous fluorescence at the lesion site; 4 yielded normal FAF images. Ten eyes (13.9%) had a mixed pattern of wet AMD with abnormal FAF. FAF imaging suggested that the areas of blood and exudates decreased; however, fluorescence angiography revealed that lesions with hyperfluorescence had background or slightly increased FAF. These results showed that various patterns of wet AMD exhibit different autofluorescence characteristics. These represent the functional and metabolic features of retinal pigment epithelial cells. Therefore, FAF can be used to monitor disease development and evaluate the severity and prognosis of AMD. PMID- 24338408 TI - Determination of the genetic diversity among accessions of Senna spectabilis (canafistula) by using RAPD markers. AB - Senna spectabilis (DC.) H.S. Irwin & Barneby (Fabaceae; Caesalpinioideae), commonly known as "canafistula" or "cassia", is widely used in the semi-arid region of northeastern Brazil as a source of forage and timber. The plant presents a high nutritional content in comparison with other forage species that are native to the Brazilian Caatinga; thus, it represents a valuable resource during periods of drought. The aim of this study was to evaluate the genetic variability among eight accessions of S. spectabilis available in the forage germplasm collection of Embrapa Meio-Norte using the random-amplified polymorphic DNA technique. The 15 primers selected for use in the analysis produced 107 bands, including 59 (55.14%) that were polymorphic. A similarity matrix was generated on the basis of Jaccard coefficients, and a dendrogram was constructed using the unweighted pair group method with arithmetic mean clustering technique. The mean value of the similarity coefficients was 0.73, and the cophenetic correlation coefficient was 83.76%. Accessions CAN. 4 and CAN. 5 presented the greatest genetic similarity, while CAN. 6 and CAN. 8 were the most divergent. The S. spectabilis accessions were classified into two main groups with group I including accessions CAN. 1, CAN. 2, CAN. 4, CAN. 5, CAN. 7, CAN. 8, and CAN. 9, and group II comprising the single accession CAN. 6. The results presented herein revealed that, although the germplasm collection is presently limited, there is sufficient genetic variability among the accessions to permit future breeding programs. PMID- 24338409 TI - Isolation and characterization of novel microsatellite loci in Nibea albiflora. AB - Eleven novel microsatellite loci were isolated from a (CA)10-enriched genomic DNA library of Nibea albiflora. The characteristics of these microsatellites were determined in a sample of 48 N. albiflora individuals. The number of alleles at the 11 microsatellite loci ranged from 5 to 25, with an average of 13.5 per locus. The observed and expected heterozygosities varied from 0.583 to 0.917 and from 0.568 to 0.964, respectively. Eight of the 11 microsatellite loci conformed to the Hardy-Weinberg equilibrium. No significant linkage disequilibrium was found among all 11 loci. These polymorphic microsatellites will be useful for population genetic analyses of N. albiflora. PMID- 24338410 TI - Functions of microRNA in response to cocaine stimulation. AB - MicroRNAs (miRNAs) are a type of non-protein-coding single-stranded RNA, which are typically 20-25 nt in length. miRNAs play important roles in various biological processes, including development, cell proliferation, differentiation, and apoptosis. We aimed to detect the miRNA response to cocaine stimulations and their target genes. Using the miRNA expression data GSE21901 downloaded from the Gene Expression Omnibus database, we screened out the differentially expressed miRNA after short-term (1 h) and longer-term (6 h) cocaine stimulations based on the fold change >1.2. Target genes of differentially expressed miRNAs were retrieved from TargetScan database with the context score -0.3. Functional annotation enrichment analysis was performed for all the target genes with DAVID. A total of 121 differentially expressed miRNAs between the 1-h treatment and the control samples, 58 between the 6-h treatment and the control samples, and 69 between the 1-h and the 6-h treatment samples. Among them, miR-212 results of particular interest, since its expression level was constantly elevated responding to cocaine treatment. After functional and pathway annotations of target genes, we proved that miR-212 was a critical element in cocaine-addiction, because of its involvement in regulating several important cell cycle events. The results may pave the way for further understanding the regulatory mechanisms of cocaine-response in human bodies. PMID- 24338411 TI - Expression of calpastatin and myostatin genes associated with lamb meat quality. AB - Calpastatin (CAST) is an endogenous calpain inhibitor and its main function is to modulate the proteolytic action of enzymes responsible for post-mortem myofibril deterioration. The myostatin gene (GDF-8) acts as a negative regulator of skeletal muscle growth. The expression of these two genes, as well as their interaction, affects the quality of the meat, especially the tenderness phenotype. We evaluated the genetic groups Santa Ines, 1/2 Dorper-Santa Ines and 1/2 White Dorper-Santa Ines, slaughtered with 2.0 mm, 2.5 mm and 3.0 mm of fat thickness, comparing the levels of expression of the CAST and GDF-8 genes with the weight performance and carcass traits, especially the shear force values. We found significantly higher expression of myostatin and calpastatin in the Santa Ines genetic group. The 1/2 Dorper-Santa Ines genetic group had the lowest expression of these genes when slaughtered with 2.0 and 2.5 mm of fat thickness. In conclusion, the Santa Ines breed had the lowest phenotype values for meat tenderness, and the 1/2 Dorper-Santa Ines breed had the best performance for this characteristic. We suggest that high levels of the expression of the CAST and GDF 8 genes are associated with lower values of lamb meat tenderness, and that tenderness is related to the stage of muscular growth and development. PMID- 24338412 TI - Genetic diversity of the Arctic fox using SRAP markers. AB - Sequence-related amplified polymorphism (SRAP) is a recently developed molecular marker technique that is stable, simple, reliable, and achieves moderate to high numbers of codominant markers. This study is the first to apply SRAP markers in a mammal, namely the Arctic fox. In order to investigate the genetic diversity of the Arctic fox and to provide a reference for use of its germplasm, we analyzed 7 populations of Arctic fox by SRAP. The genetic similarity coefficient, genetic distance, proportion of polymorphic loci, total genetic diversity (Ht), genetic diversity within populations (Hs), and genetic differentiation (Gst) were calculated using the Popgene software package. The results indicated abundant genetic diversity among the different populations of Arctic fox studied in China. The genetic similarity coefficient ranged from 0.1694 to 0.0417, genetic distance ranged from 0.8442 to 0.9592, and the proportion of polymorphic loci was smallest in the TS group. Genetic diversity ranged from 0.2535 to 0.3791, Ht was 0.3770, Hs was 0.3158, Gst was 0.1624, and gene flow (Nm) was estimated at 2.5790. Thus, a high level of genetic diversity and many genetic relationships were found in the populations of Arctic fox evaluated in this study. PMID- 24338413 TI - Wilms' tumor suppressor gene mutations in girls with sporadic isolated steroid resistant nephrotic syndrome. AB - Mutations in the Wilms' tumor suppressor gene (WT1) can lead to syndromic forms of steroid-resistant nephrotic syndrome (SRNS) such as Denys-Drash or Frasier syndrome and can cause isolated SRNS. A mutation within WT1 is a frequent cause of sporadic isolated SRNS in girls. In a worldwide cohort of girls, the rate of occurrence was 10.8%. Previous reports have indicated that in Chinese girls, the detection rate of WT1 mutations is 16.7% for early onset isolated nephrotic syndrome. The detection rate of WT1 mutations in Chinese girls with sporadic isolated SRNS is unknown. We examined WT1 mutations in 14 Chinese girls with sporadic isolated SRNS using polymerase chain reaction and direct sequencing and studied a control group of 38 boys with sporadic isolated SRNS. We identified a WT1 mutation in 1 of 14 (7.1% detection rate) Chinese girls with sporadic isolated SRNS. No mutations occurred in WT1 in the remaining 13 girls or the control group. Our investigation supports the necessity of genetic examination for mutations in WT1 in girls with sporadic isolated SRNS. PMID- 24338414 TI - High genetic variation among Aschersonia placenta (Clavicipitaceae) isolates from citrus orchards in China. AB - Aschersonia placenta had been recognized as an important fungal pathogen of whiteflies. In recent years, natural occurrence of Aschersonia in whitefly populations was observed in many citrus orchards in the southern regions of China. We analyzed 60 A. placenta isolates obtained from Chinese citrus orchards, using inter-simple sequence repeats to examine the genetic diversity and to determine whether intraspecific variation is correlated with geographic origin. One hundred and fourteen fragments were generated from these isolates; 97% were polymorphic. The Nei's gene diversity (H) was estimated to be 0.1748 within the populations (range 0.0974-0.2179) and 0.3057 at the species level. Analysis of molecular variance showed that the genetic variation was found mainly within populations (74.9%). The coefficient of gene differentiation (GST = 0.4315) indicated that 56.85% of the genetic diversity resided within populations. The Mantel test revealed no significant correlation between the genetic distance and the corresponding geographical distance (r = 0.142 and P = 0.887); the unweighted pair-group method using arithmetic average clustering gave similar results. PMID- 24338415 TI - Cloning, sequencing, and polymorphisms of the Wistar-Imamichi rat growth hormone gene using PCR-SSCP. AB - We successfully cloned the Wistar-Imamichi (WI) rat growth hormone gene (GenBank accession: GQ890681), which contained 5 exons and 4 introns. Using the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) technique, a novel missense substitution single nucleotide polymorphism was identified and tested for Hardy-Weinberg equilibrium with the chi(2) test. This gene fragment was investigated in 50 adult rats and 50 neonatal rats by PCR-SSCP. Results showed that only intron 4 had a polymorphic locus at the 97th nucleotide position from A (in the AA genotype) to C (in the BB genotype). Further statistical analysis showed that this locus was in Hardy-Weinberg equilibrium. These results suggested that this specific pathogen-free WI rat population, which was bred in the barrier system of the Research Center for Laboratory Animal Science of Inner Mongolia University, has high hereditary stability. PMID- 24338416 TI - Maternal MTHFR C677T polymorphism and congenital heart defect risk in the Chinese Han population: a meta-analysis. AB - Numerous studies have evaluated the association between the maternal C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene and congenital heart defect (CHD) risk in the Chinese Han population. However, the specific association is still controversial. Six separate studies with 1089 subjects in the Chinese Han population on the relationship between the C677T polymorphism and CHDs were analyzed by meta-analysis, upon database search. The fixed-effect model or random-effect model was selected to calculate the pooled odds ratio (ORs) and its corresponding 95% confidence interval (95%CI) when appropriate. The Begg test was used to measure publication bias. Sensitivity analyses were performed to insure authenticity of the outcome. Meta-analysis of the results showed significant associations between the maternal C677T polymorphism and CHD risk (CC vs TT: OR = 0.65, 95%CI = 0.44-0.96). Limiting the analysis to the studies with controls in the Hardy-Weinberg equilibrium and the results indicate that the meta-analysis was statistically significant. Results of Begg's funnel plot showed that there was no publication bias (all P > 0.05). The present meta-analysis suggested that the maternal C677T polymorphism is a risk factor for CHDs in the Chinese Han population. PMID- 24338417 TI - Genetic variations in MOV10 and CACNB2 are associated with hypertension in a Chinese Han population. AB - Human hypertension is a complex, multifactorial disease. Multiple variants associated with hypertension have been identified in the large numbers of genome wide association studies, meta-analysis, and case-control studies. The present study investigated the association between the single nucleotide polymorphisms (SNPs) of five candidate genes and the susceptibility and prognosis of hypertension in a Chinese Han population. A hospital-based case-control study in a Chinese Han population was carried out, including 500 hypertension patients and 506 healthy controls. The five SNP markers were detected using the Sequenom MassArray((r)) iPLEX System. The association of genotypes with susceptibility to hypertension was analyzed using odds ratio, with 95% confidence interval and logistic regression. All five variants conformed to Hardy-Weinberg proportions in the controls. No significant differences were noted in the genotype distributions for AGTR1, PRRC2A, and CALCA polymorphisms in patients with hypertension (N = 500) and healthy controls (N = 506). SNP rs2932538, a variant in MOV10, was found to be significantly associated with an increased risk of hypertension. However, SNP rs4373814, a variant in CACNB2, showed a relevant association with a decreased risk of hypertension. In conclusion, the results of our case-control study confirmed the significant association of the SNP rs2932538 in MOV10 and SNP rs4373814 in CACNB2 with an increased risk of hypertension in a Chinese Han population, suggesting that the SNP rs2932538 may be a poor prognostic indicator for hypertension, while SNP rs4373814 may be a good prognostic indicator for hypertension in the same region. However, our findings need to be replicated in larger epidemiological and functional studies. PMID- 24338418 TI - Aberrant promoter methylation of the CD4 gene in peripheral blood cells of mastitic dairy cows. AB - Bovine mastitis is the most common and costly disease of dairy cattle. Cluster of differentiation 4 (CD4) is closely related to the immune response in mastitis. We quantified promoter CpG methylation levels of the CD4 gene in Chinese Holsteins with clinical mastitis (CM) and in healthy controls; these levels were quantitatively detected with bisulfite pyrosequencing assays and confirmed by cloning sequencing. We found that the bovine CD4 promoter had 16% more methyl groups in the cows with CM (75.0 +/- 5.8%) compared to the controls (59.0 +/- 8.5%). The decreased expression level of CD4 in CM cows may be downregulated by the increased DNA methylation levels in the CD4 promoter. Two-dimensional hierarchical clustering analyses showed large differences in promoter CD4 methylation between mastitic and healthy cows; the dendrogram clearly distinguished the cows with clinical mastitis from healthy controls based on methylation levels. The DNA methylation level of the CD4 gene was strongly influenced by mastitis status in all comparisons. We suggest that the DNA methylation level of the CD4 promoter can be used as a molecular marker for clinical mastitis in dairy cows. PMID- 24338419 TI - Screening for feature genes associated with hereditary hemochromatosis and functional analysis with DNA microarrays. AB - The aim of this study was to identify feature genes that are associated with hereditary hemochromatosis (HHC; iron overload) in cardiac and skeletal muscle of mice. First, the expression profile GSE9726 was downloaded from Gene Expression Omnibus database which included 12 samples. Then the differentially expressed genes (DEGs) were identified by R language. Furthermore, the KUPS software was used to identify relationships in interactions among common DEGs in the cardiac and skeletal muscles. We then used the EASE software to obtain enriched pathways in a gene interaction network. Finally, we used the plugins of the Cytoscape software, i.e., Mcode and Bingo, to conduct module analysis. By comparing diseased and normal tissue samples, 5 and 6 genes in the cardiac and skeletal muscles, respectively, were identified as DEGs. We observed that the S100a8 and S100a9 genes were common DEGs in both tissues examined. In addition, we constructed an interaction network with common DEGs and their interacting components, and identified S100a8 and S100a9 as being associated with immune responses. In view of the relationship between the early stage of myelodysplastic syndrome and the immune system, we hypothesize that the expression of the S100a8 and S100a9 genes is a feature that can be used for diagnosis during the early stage of the myelodysplastic syndrome and that the 2 genes could be used as targets in treating this disease. PMID- 24338420 TI - Evidence for inbreeding depression in the tree Robinia pseudoacacia L. (Fabaceae). AB - The magnitude of inbreeding depression within populations is important for the evolution and maintenance of mixed mating systems. However, data are sparse on the magnitude of inbreeding depression in Robinia pseudoacacia. In this study, we compared differences in the mature seed set per fruit, seed mass, germination success, and seedling growth between self- and cross-pollination treatments and estimated the inbreeding depression at 3 stages: seed maturation, seedling emergence, and seedling growth at 10 and 20 weeks. We found that progenies resulting from cross-pollination treatments showed significantly higher fitness than progenies resulting from self-pollination, causing high levels of inbreeding depression. Inbreeding depression was not uniformly manifested, however, over the 3 stages. Inbreeding depression was the greatest between fertilization and seed maturation stage (delta = 0.5419), and the seedling emergence (0.3654) stage was second. No significant differences in seedling growth were observed between selfed and crossed progenies. The cumulative inbreeding depression (delta) across all 3 stages averaged 0.7452. Inbreeding depression may promote outcrossing in R. pseudoacacia by acting as a post-pollination barrier to selfing. The large difference in the seed set between self- and cross-pollination that we detected indicated that inbreeding depression would probably be a reasonable explanation for the high abortion and low seed set in R. pseudoacacia. PMID- 24338421 TI - Genetic diversity of Cosmos species revealed by RAPD and ISSR markers. AB - The genus Cosmos is native of America and is constituted by 34 species; 28 of them are endemic of Mexico. The cosmos are used as a nematicide, antimalarial, and antioxidative agent. The aim of this study was to estimate the genetic diversity among 7 cosmos species based on random amplified polymorphic DNA (RAPD) and inter-simple sequences repeats (ISSR) markers. With RAPD markers, the obtained polymorphism was 91.7 % and the genetic diversity was 0.33, whereas these values were 65.6%, and 0.22 from ISSR markers, respectively, indicating the presence of high genetic diversity among the Cosmos species that were analyzed. The unweighted pair group method with arithmetic mean dendrograms that were obtained with both markers were notably similar, revealing 2 clusters and indicating a clear genetic differentiation among the Cosmos species that were assessed. The first cluster comprised the species Cosmos sulphureus, Cosmos pacificus, and Cosmos diversifolius, while the second cluster included the species Cosmos purpureus, Cosmos crithmifolius, Cosmos bipinnatus, and Cosmos parviflorus. Besides this, the Cosmos species were clustered according to their collection sites. The Mantel test corroborates the correlation between the genetic distance and the geographic altitude of each Cosmos species. The results suggest that it is necessary to preserve the Cosmos species in their natural habitat in addition to the germoplasm collection for ex situ conservation. PMID- 24338422 TI - Colorectal cancer susceptibility variants alter risk of breast cancer in a Chinese Han population. AB - Recent genome wide association studies (GWAS) and candidate gene studies have revealed many novel loci associated with colorectal cancer susceptibility. We evaluated the effect of these colorectal cancer-associated variants on the risk of breast cancer in a Chinese Han population. Seven single nucleotide polymorphisms (SNPs) (rs3856806 in PPARG, rs7014346 in POU5F1P1, rs989902 in PTPN13, rs1801278 in IRS1, rs7003146 in TCF7L2, rs1503185 in PTPRJ, and rs63750447 in MLH1) were genotyped in Han Chinese subjects, including 216 patients with breast cancer and 216 matched controls, using the Sequenom MassARRAY platform. The association of genotypes with susceptibility to breast cancer was analyzed using the odds ratio (OR), with 95% confidence interval (CI) and logistic regression. Three SNPs (rs7014346, rs989902, and rs7003146) were found to be significantly associated with the susceptibility of breast cancer. The GA and AA genotypes of rs7003146 in TCF7L2, and the CA and CC genotype of rs989902 in PTPN13 were associated with reduced breast cancer risk in the Chinese Han population based on the best-fit dominant model. The GG genotype of rs7014346 in POU5F1P1 was also significantly associated with decreased breast cancer risk under the best-fit additive model. Our results confirmed the association of rs7014346 in POU5F1P1, rs989902 in PTPN13, and rs7003146 in TCF7L2 with variations in the risk of breast cancer in a Chinese Han population. PMID- 24338423 TI - ReSeqTools: an integrated toolkit for large-scale next-generation sequencing based resequencing analysis. AB - Large-scale next-generation sequencing (NGS)-based resequencing detects sequence variations, constructs evolutionary histories, and identifies phenotype-related genotypes. However, NGS-based resequencing studies generate extraordinarily large amounts of data, making computations difficult. Effective use and analysis of these data for NGS-based resequencing studies remains a difficult task for individual researchers. Here, we introduce ReSeqTools, a full-featured toolkit for NGS (Illumina sequencing)-based resequencing analysis, which processes raw data, interprets mapping results, and identifies and annotates sequence variations. ReSeqTools provides abundant scalable functions for routine resequencing analysis in different modules to facilitate customization of the analysis pipeline. ReSeqTools is designed to use compressed data files as input or output to save storage space and facilitates faster and more computationally efficient large-scale resequencing studies in a user-friendly manner. It offers abundant practical functions and generates useful statistics during the analysis pipeline, which significantly simplifies resequencing analysis. Its integrated algorithms and abundant sub-functions provide a solid foundation for special demands in resequencing projects. Users can combine these functions to construct their own pipelines for other purposes. PMID- 24338424 TI - Comparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis and restricted fragment length polymorphism among fenugreek accessions. AB - Protein and DNA polymorphismswere surveyed among seven accessions of wild fenugreek (Trigonellafoenum-graecum L.) to estimate their genetic diversity and relationships. Samples were obtained from diverse ecogeographical areas in Saudi Arabia and Yemen. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS PAGE) analysis of seed storage protein showed genetic variations among fenugreek germplasms, both quantitatively and qualitatively, generating a total of 168 polypeptide bands with different molecular weights ranging from 4.5 to 300 kDa. Twenty-six of these bands were polymorphic, with a considerable polymorphism value (80.00%). Furthermore, restriction fragment length polymorphism (RFLP) analysis was also employed, which was based on the ability of four restriction enzymes (EagI, EcoRI, FspI, and HindIII) to cleave genomic DNA of the plant materials at specific target nucleotide sequences into different numbers of DNA fragments. RFLP analysis revealed 166 fragments with known sequences and variable lengths ranging from 80 to 4000 bp with a highly degree of polymorphism (88.71%). Data derived from SDS-PAGE or RFLP analyses were used to produce dendrograms, which clustered the studied fenugreek accessions into different groups based on the unweighted pair group method with arithmetic mean (UPGMA). The resulting relationships indicated that these two marker techniques were nearly equivalent, but not identical, with respect to phylogenetic information. In conclusion, SDS PAGE analysis of seed proteins should be augmented with RFLP analysis of DNA for reliable estimates of genetic diversity among fenugreek germplasms. PMID- 24338425 TI - Bulked segregant analysis of the pirarucu (Arapaima gigas) genome for identification of sex-specific molecular markers. AB - Arapaima gigas (Osteoglossidae) is one of the largest fish species in the Amazon Basin, attaining lengths of over 2.5 m and weights of over 100 kg. Its flesh is prized, and it has great potential for production in aquaculture systems. However, live pirarucu cannot be reliably sexed visually, even after sexual development, since this species does not have clear external sexual dimorphism. Simple and inexpensive methods for sexing immature pirarucu based on DNA markers would facilitate production of this species in commercial operations. We analyzed A. gigas male and female DNA pools with 566 RAPD primers, generating 2609 fragments, with an estimated 1341 segregating polymorphic markers, and an estimated average spacing of 714 kb, which corresponds to less than 0.1% of the species' genome. Two putative sex-specific fragments were initially identified in bulked samples; but they were not confirmed in a study of individual male and female samples. We suggest that A. gigas has developed a non-chromosomal system of sex determination or, alternatively, that the species has undergone a recent loss of the chromosome carrying the sex-determining locus. PMID- 24338426 TI - Genetic relationships of Pacific abalone (Haliotidae) species determined using universal rice primer-polymerase chain reaction fingerprinting. AB - Random amplified polymorphic DNA (RAPD) with universal rice primers (URP) was used to identify species and to determine phylogenetic relationships for the 6 economically important Korean Pacific abalone species: Haliotis discus hannai, H. discus discus, H. madaka, H. gigantea, H. diversicolor supertexta, and H. diversicolor diversicolor, whose morphological differentiation is difficult. Of the 12 URPs used in this study, 7 were effective in producing reproducible RAPD markers for these 6 species. Amplifications with the 7 URP primers yielded 129 reproducible amplified fragments ranging between 100 and 6000 bp in length. The dendrogram generated by the unweighted pair-group method using arithmetic averages showed that the 6 species were divided into 4 groups at 0.44 similarity level, indicating that they were genetically distant from each other and had little internal phylogenetic resolution. One group included H. discus hannai, H. discus discus, H. madaka, and H. gigantea, which were divided into 2 groups at 0.52 similarity level: one group of H. discus hannai, H. discus discus, and H. madaka, and the other of H. gigantea. H. diversicolor supertexta and H. diversicolor diversicolor belonged to the other group. Furthermore, the reproducible pattern of amplified DNA bands by URP primers indicated the possibility of using these as molecular markers for the discrimination of the 6 Pacific abalone species. These results suggest that the URP-PCR approach will be a useful tool for obtaining accurate taxonomic identification and genetic relationship of Korean Pacific abalones, which is one of the first prerequisites in effective conservation programs. PMID- 24338427 TI - Comparative genetic variability between broodstock and offspring populations of Korean starry flounder used for stock enhancement in a hatchery by using microsatellite DNA analyses. AB - Korean starry flounder, Platichthys stellatus (Pleuronectidae), is one of the most economically important fishery resources in Korea. We investigated the effect of current artificial reproduction in a hatchery facility, genetic divergence between the broodstock and their offspring populations of starry flounder in a hatchery strain to be stocked into natural sea areas was accessed using 9 polymorphic nuclear microsatellite DNA loci. High levels of polymorphism were observed between the 2 populations. A total of 96 alleles were detected at the loci, with some alleles being unique in the broodstock. Allelic variability ranged from 8 to 17 in the broodstock and from 7 to 12 in the offspring population. Average observed and expected heterozygosities were estimated at 0.565 and 0.741 in the broodstock samples and 0.629 and 0.698 in the offspring population, respectively. Although no statistically significant reductions were found in heterozygosity or allelic diversity in the offspring population, a considerable loss of rare alleles was observed in the offspring population compared with that in the broodstock. Significant genetic difference was detected between the broodstock and offspring populations (FST = 0.021, P < 0.05). These results suggest that more intensive breeding practices for stock enhancement might have resulted in a further decrease of genetic diversity. Thus, genetic variations of broodstock and progeny should ideally be monitored in both breeding and release programs as a routine hatchery operation in order to improve the starry flounder hatchery management. This information might be useful for fishery management and aquaculture industry of P. stellatus. PMID- 24338428 TI - Comparative genetic diversity of wild and hatchery-produced populations of tongue sole (Cynoglossus semilaevis) using multiplex PCR assays with polymorphic microsatellite markers. AB - The tongue sole, Cynoglossus semilaevis (Cynoglossidae), is one of the most economically important fishery resources in Korea. This study presents a preliminary investigation of the future viability of the complete aquaculture of tongue sole in Korea. Specifically, possible differences in genetic variability between wild populations of tongue sole from Korea and hatchery-produced populations of tongue sole from China were assessed using multiplex assays with 12 polymorphic nuclear microsatellite DNA loci. High levels of polymorphism were observed between the 2 populations. A total of 135 different alleles were found, varying from 5-15 alleles per locus, with some alleles being unique. These findings indicate a high level of genetic variability in both the wild and hatchery-produced populations. Although a considerable loss of rare alleles was observed in hatchery samples, there were no statistically significant reductions of heterozygosity or allelic diversity in the hatchery population compared to the wild population. Moreover, the inbreeding coefficient was very low (FIS = -0.010 0.052) for both populations. However, significant genetic heterogeneity was found between the 2 populations. These findings indicate that genetic drift has likely promoted differentiation between these 2 populations, and might have negative effects on the reproductive capacity of the stock, because genetic factors are important in the production of high quality seed for complete aquaculture. Therefore, aquaculture management should incorporate basic genetic principles into existing molecular monitoring protocols. The information compiled by this study is anticipated to provide a useful genetic basis for future complete culturing plans and management of C. semilaevis in fisheries. PMID- 24338429 TI - Auditory temporal structure processing in dyslexia: processing of prosodic phrase boundaries is not impaired in children with dyslexia. AB - Reading disability in children with dyslexia has been proposed to reflect impairment in auditory timing perception. We investigated one aspect of timing perception--temporal grouping--as present in prosodic phrase boundaries of natural speech, in age-matched groups of children, ages 6-8 years, with and without dyslexia. Prosodic phrase boundaries are characterized by temporal grouping of functionally related speech elements and can facilitate syntactic processing of speech. For example, temporary syntactic ambiguities, such as early closure structures, are processed faster when prosodic phrase boundaries are present. We examined children's prosodic facilitation by measuring their efficiency of sentence processing for temporary syntactic ambiguities spoken with (facilitating) versus without (neutral) prosodic phrase boundaries. Both groups of children benefited similarly from prosodic facilitation, displaying faster reaction times in facilitating compared to neutral prosody. These findings indicate that the use of prosodic phrase boundaries for speech processing is not impaired in children with dyslexia. PMID- 24338430 TI - In reference to extracapsular dissection for benign parotid tumors: a meta analysis. PMID- 24338431 TI - Electromagnetic fields for treating osteoarthritis. AB - BACKGROUND: This is an update of a Cochrane review first published in 2002. Osteoarthritis is a disease that affects the synovial joints, causing degeneration and destruction of hyaline cartilage and subchondral bone. Electromagnetic field therapy is currently used by physiotherapists and may promote growth and repair of bone and cartilage. It is based on principles of physics which include Wolff's law, the piezoelectric effect and the concept of streaming potentials. OBJECTIVES: To assess the benefits and harms of electromagnetic fields for the treatment of osteoarthritis as compared to placebo or sham. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 9), PreMEDLINE for trials published before 1966, MEDLINE from 1966 to October 2013, CINAHL and PEDro up to and including October 2013. Electronic searches were complemented by handsearches. SELECTION CRITERIA: Randomised controlled trials of electromagnetic fields in osteoarthritis, with four or more weeks treatment duration. We included papers in any language. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion in the review and resolved differences by consensus with a third review author. We extracted data using pre developed data extraction forms. The same review authors assessed the risk of bias of the trials independently using the Cochrane 'Risk of bias' tool. We extracted outcomes for osteoarthritis from the publications according to Outcome Measures in Rheumatology Clinical Trials (OMERACT) guidelines. We expressed results for continuous outcome measures as mean difference (MD) or standardised mean difference (SMD) with 95% confidence interval (CI). We pooled dichotomous outcome measures using risk ratio (RR) and calculated the number needed to treat (NNT). MAIN RESULTS: Nine studies with a total of 636 participants with osteoarthritis were included, six of which were added in this update of the review. Selective outcome reporting was unclear in all nine included studies due to inadequate reporting of study design and conduct, and there was high risk of bias for incomplete outcome data in three studies. The overall risk of bias across the nine studies was low for the other domains.Participants who were randomised to electromagnetic field treatment rated their pain relief 15.10 points more on a scale of 0 to 100 (MD 15.10, 95% CI 9.08 to 21.13; absolute improvement 15%) after 4 to 26 weeks' treatment compared with placebo. Electromagnetic field treatment had no statistically significant effect on physical function (MD 4.55, 95% CI -2.23 to 11.32; absolute improvement 4.55%) based on the Western Ontario and McMaster Universities osteoarthritis index (WOMAC) scale from 0 to 100 after 12 to 26 weeks' treatment. We also found no statistically significant difference in quality of life on a scale from 0 to 100 (SMD 0.09, 95% CI -0.36 to 0.54; absolute improvement 0.09%) after four to six weeks' treatment, based on the SF-36. No data were available for analysis of radiographic changes. Safety was evaluated in four trials including up to 288 participants: there was no difference in the experience of any adverse event after 4 to 12 weeks of treatment compared with placebo (RR 1.17, 95% CI 0.72 to 1.92). There was no difference in participants who withdrew because of adverse events (measured in one trial) after four weeks of treatment (RR 0.90, 95% CI 0.06 to 13.92). No participants experienced any serious adverse events. AUTHORS' CONCLUSIONS: Current evidence suggests that electromagnetic field treatment may provide moderate benefit for osteoarthritis sufferers in terms of pain relief. Further studies are required to confirm whether this treatment confers clinically important benefits in terms of physical function and quality of life. Our conclusions are unchanged from the previous review conducted in 2002. PMID- 24338432 TI - Hypothalamic control of energy homeostasis. PMID- 24338433 TI - Influence of deep brain stimulation of the subthalamic nucleus on cognitive function in patients with Parkinson's disease. AB - Deep brain stimulation (DBS) is an effective technique for treating Parkinson's disease (PD) in the middle and advanced stages. The subthalamic nucleus (STN) is the most common target for clinical treatment using DBS. While STN-DBS can significantly improve motor symptoms in PD patients, adverse cognitive effects have also been reported. The specific effects of STN-DBS on cognitive function and the related mechanisms remain unclear. Thus, it is imperative to identify the influence of STN-DBS on cognition and investigate the potential mechanisms to provide a clearer view of the various cognitive sequelae in PD patients. For this review, a literature search was performed using the following inclusion criteria: (1) at least 10 patients followed for a mean of at least 6 months after surgery since the year 2006; (2) pre- and postoperative cognitive data using at least one standardized neuropsychological scale; and (3) adequate reporting of study results using means and standard deviations. Of ~170 clinical studies identified, 25 cohort studies (including 15 self-controlled studies, nine intergroup controlled studies, and one multi-center, randomized control experiment) and one meta-analysis were eligible for inclusion. The results suggest that the precise mechanism of the changes in cognitive function after STN-DBS remains obscure, but STN-DBS certainly has effects on cognition. In particular, a progressive decrease in verbal fluency after STN-DBS is consistently reported and although executive function is unchanged in the intermediate stage postoperatively, it tends to decline in the early and later stages. However, these changes do not affect the improvements in quality of life. STN-DBS seems to be safe with respect to cognitive effects in carefully-selected patients during a follow-up period from 6 months to 9 years. PMID- 24338434 TI - Gut estimates: Pregnant women adapt to changing possibilities for squeezing through doorways. AB - Possibilities for action depend on the fit between the body and the environment. Perceiving what actions are possible is challenging, because the body and the environment are always changing. How do people adapt to changes in body size and compression? In Experiment 1, we tested pregnant women monthly over the course of pregnancy to determine whether they adapted to changing possibilities for squeezing through doorways. As women gained belly girth and weight, previously passable doorways were no longer passable, but women's decisions to attempt passage tracked their changing abilities. Moreover, their accuracy was equivalent to that of nonpregnant adults. In Experiment 2, nonpregnant adults wore a "pregnancy pack" that instantly increased the size of their bellies, and they judged whether doorways were passable. Accuracy in the "pregnant" participants was only marginally worse than that of actual pregnant women, suggesting that participants adapted to the prosthesis during the test session. In Experiment 3, participants wore the pregnancy pack and gauged passability before and after attempting passage. The judgments were grossly inaccurate prior to receiving feedback. These findings indicate that experience facilitates perceptual-motor recalibration for certain types of actions. PMID- 24338435 TI - Waist circumference and related anthropometric indices are associated with metabolic traits in severely obese subjects. AB - Increased waist circumference (WC) and related anthropometric indices have been shown to be, independently of body weight and body mass index (BMI), associated with adverse metabolic traits in many populations. It is unknown, however, whether WC also predicts adverse metabolic traits in severely obese subjects displaying a BMI greater than 35 kg/m2. To address this question, we analyzed a dataset including 838 severely obese patients (597 women, BMI 44.6 +/- 6.2 kg/m2; 241 men, BMI 44.3 +/- 5.7 kg/m2). Body weight, height, WC, hip circumference, and blood pressure were measured in all subjects along with the following metabolic blood markers: fasting glucose, insulin, glycolized hemoglobin levels, triglycerides, total cholesterol, low- and high-density cholesterol, and uric acid. Multivariate regression analyses indicated that WC as well as related anthropometric indices, in particular those accounting for subjects' height, were associated with many metabolic variables independently of body weight and BMI. In general, height-adjusted WC indices were more closely associated with metabolic traits in women than in men. Collectively, our findings suggest that body fat distribution also plays an important role in determining metabolic traits in severely obese subjects and that WC represents a valuable marker of abdominal/visceral obesity in this population. PMID- 24338436 TI - Predictive values for molecular diagnostics: converting unknown unknowns to known unknowns. PMID- 24338437 TI - The effect of genetic polymorphisms of cytochrome P450 CYP2C9, CYP2C19, and CYP2D6 on drug-resistant epilepsy in Turkish children. AB - BACKGROUND AND OBJECTIVE: Despite the availability of several antiepileptic drugs, drug resistance remains one of the major challenges in epilepsy therapy. Genetic factors are known to play a significant role in the prognosis and treatment of epilepsy. The aim of this study was to determine the frequencies of alleles for CYP2C9, CYP2C19, and CYP2D6 genes in Turkish children with epilepsy, and to investigate the relationship between the genetic polymorphism of these genes with multiple drug resistance in epilepsy patients. METHODS: We genotyped 132 epileptic patients (60 drug resistant and 72 drug responsive) and 55 healthy controls for six single nucleotide polymorphisms (SNPs) in CYP2C9, CYP2C19, and CYP2D6. Genotype, allele, and haplotype frequencies were compared between groups. RESULTS: The frequencies of CYP2C9*3/*3 genotype and CYP2C9*3 allele, and the haplotype CCGG (CYP2C9*2 C>T, CYP2C9*3 A>C, and CYP2C19*2 G>A, CYP2C19* G>A) were significantly higher in drug-resistant versus -responsive patients. CONCLUSION: Our results demonstrated the important role of the CYP2C9*3 allelic variant in preventing epilepsy patients from developing drug resistance. These data suggest that CYP2C9, CYP2C19, and CYP2D6 SNPs and haplotypes may affect the response to antiepileptic drugs. PMID- 24338438 TI - A behavioral study of regularity, irregularity and rules in the English past tense. AB - Opposing views of storage and processing of morphologically complex words (e.g., past tense) have been suggested: the dual system, whereby regular forms are not in the lexicon but are generated by rule, while irregular forms are explicitly represented; the single system, whereby regular and irregular forms are computed by a single system, using associative connections; and a system whereby phonological rules relate both regular and irregular past to present tense forms. Two reaction time experiments investigated the production of the past tense in English in response to the auditory presentation of the present tense of the verb. The first experiment addressed the methodology of presenting regulars and irregulars in blocked form as in a previous study (Jaeger et al. in Language 72:451-497, 1996). Blocked presentation results showed longer RTs for the elicitation of irregular pasts than for regular pasts; however, there were no differences between regular and irregular elicitation when the presentation was randomized, indicating that it is rules that are being primed. The second experiment tested whether the response time advantage found for blocked regular verbs in the first experiment might also extend to irregular verb forms exhibiting the same sub-regularity (e.g., sing-sang may prime ring-rang). Results showed a trend towards slower RTs when past tense forms from different sub regularities follow one another, suggesting interference between one sub regularity and another. PMID- 24338439 TI - Enhanced clinical outcome with manual massage following cryolipolysis treatment: a 4-month study of safety and efficacy. AB - BACKGROUND AND OBJECTIVES: Cryolipolysis procedures have been shown to safely and effectively reduce the thickness of fat in a treated region. This study was conducted to determine whether the addition of post-treatment manual massage would improve efficacy while maintaining the safety profile of the original cryolipolysis treatment protocol. MATERIALS AND METHODS: The study population consisted of an efficacy group (n = 10) and a safety group (n = 7). Study subjects were treated on each side of the lower abdomen with a Cooling Intensity Factor of 42 (-72.9 mW/cm(2) ) for 60 minutes. One side of the abdomen was massaged post-treatment and the other side served as the control. Immediately post-treatment, the massage side was treated for 1 minute using a vigorous kneading motion followed by 1 minute of circular massage using the pads of the fingers. For the efficacy group, photos and ultrasound measurements were taken at baseline, 2 months, and 4 months post-treatment. For the safety group, histological analysis was completed at 0, 3, 8, 14, 30, 60, and 120 days post treatment to examine the effects of massage on subcutaneous tissue over time. RESULTS: Post-treatment manual massage resulted in a consistent and discernible increase in efficacy over the non-massaged side. At 2 months post-treatment, mean fat layer reduction was 68% greater in the massage side than in the non-massage side as measured by ultrasound. By 4 months, mean fat layer reduction was 44% greater in the massage side. Histological results showed no evidence of necrosis or fibrosis resulting from the massage. CONCLUSION: Post-treatment manual massage is a safe and effective technique to enhance the clinical outcome from a cryolipolysis procedure. PMID- 24338441 TI - CCN1 promotes vascular endothelial growth factor secretion through alphavbeta 3 integrin receptors in breast cancer. PMID- 24338440 TI - Orexigenic response to tail pinch: role of brain NPY(1) and corticotropin releasing factor receptors. AB - Tail pinch stimulates food intake in rats. We investigated brain mechanisms of this response and the influence of repeated exposure. Sprague-Dawley rats received acute (5 min) or repeated (5 min/day for 14 days) tail pinch using a padded clip. Acute tail pinch increased 5-min food intake compared with control (0.92 +/- 0.2 vs. 0.03 +/- 0.01 g, P < 0.01). This response was inhibited by 76% by intracerebroventricular injection of BIBP-3226, a neuropeptide Y1 (NPY1) receptor antagonist, increased by 48% by astressin-B, a corticotropin-releasing factor (CRF) receptor antagonist, and not modified by S-406-028, a somatostatin subtype 2 antagonist. After the 5-min tail pinch without food, blood glucose rose by 21% (P < 0.01) while changes in plasma acyl ghrelin (+41%) and adrenocorticotropic hormone (+37%) were not significant. Two tail pinches (45 min apart) activate pontine and hindbrain catecholaminergic and hypothalamic paraventricular CRF neurons. After 14 days of repeated tail pinch, the 5-min orexigenic response was not significantly different from days 2 to 11 but reduced by 50% thereafter (P < 0.001). Simultaneously, the 5-min fecal pellet output increased during the last 5 days compared with the first 5 days (+58%, P < 0.05). At day 14, the body weight gain was reduced by 22%, with a 99% inhibition of fat gain and a 25% reduction in lean mass (P < 0.05). The orexigenic response to acute 5-min tail pinch is likely to involve the activation of brain NPY1 signaling, whereas that of CRF tends to dampen the acute response and may contribute to increased defecation and decreased body weight gain induced by repeated tail pinch. PMID- 24338442 TI - TGF-beta1 induces EMT reprogramming of porcine bladder urothelial cells into collagen producing fibroblasts-like cells in a Smad2/Smad3-dependent manner. AB - Activation of fibroblasts and their differentiation into myofibroblasts, excessive collagen production and fibrosis occurs in a number of bladder diseases. Similarly, conversion of epithelial cells into mesenchymal cells (EMT) has been shown to increase fibroblasts like cells. TGF-beta1 can induce the EMT and the role of TGF-beta1-induced EMT during bladder injury leading to fibrosis and possible organ failure is gaining increasing interest. Here we show that EMT and fibrosis in porcine bladder urothelial (UC) cells are Smad dependent. Fresh normal porcine bladder urothelial cells were grown in culture with or without TGF beta1 and EMT markers were assessed. TGF-beta1 treatment induced changes in cellular morphology as depicted by a significant decrease in the expression of E cadherin and corresponding increase in N-cadherin and alpha-SMA. We knocked down Smad2 and Smad3 by Smad specific siRNA. Downregulation of E-cadherin expression by TGF-beta1 was Smad3-dependent, whereas N-cadherin and alpha-SMA were dependent on both Smad2 and Smad3. Connective tissue growth factor (CTGF/CCN2), matrix metalloproteinase-2 and -9 (MMP-2, MMP-9) has been shown to play important roles in the pathogenesis of fibrosis. Induction of these genes by TGF-beta1 was found to be time dependent. Upregulation of CTGF/CCN2 by TGF-beta1 was Smad3 dependent; whereas MMP-2 was Smad2 dependent. Smad2 and Smad3 both participated in MMP-9 expression. TGF-beta1 reprogrammed mesenchymal fibroblast like cells robustly expressed collagen I and III and these was inhibited by SB-431542, a TGF-beta receptor inhibitor. Our results indicate that EMT of porcine bladder UC cells is TGF-beta1 dependent and is mediated through Smad2 and Smad3. TGF-beta1 may be an important factor in the development of bladder fibrosis via an EMT mechanism. This identifies a potential amenable therapeutic target. PMID- 24338443 TI - Simultaneous determination of polyamines and acetylpolyamines in human urine by capillary electrophoresis with fluorescence detection. AB - There has been evidence linking elevated polyamines (PAs) and acetylpolamines (AcPAs) level and cancer. So the simultaneous analysis of these compounds has become important task for cancer diagnosis and antitumor drug monitoring. A simple, fast and inexpensive CZE-LIF method has been developed for the determination of cadaverine (CAD), putrescine (PUT), spermine (SPM), spermidine (SPD), acetylspermine (ASPM), and acetylspermidine (ASPD) in human urine using 4 chloro-7-nitro-2,1,3-benzooxadiazole as a fluorescent reagent. Labeling reaction conditions were systematically investigated and were found to be 20 mM borate buffer at pH 7.4, labeling reaction time, and temperature were 10 min and 70 degrees C, respectively. Under these optimized conditions the four PAs, two AcPAs and the internal standard were separated in 6 min. An Exactive-MS with an ESI source was used for identification of the bis-derivative of the ASPM. The method was validated in term of linearity, LODs, repeatability, intra- and interday assays, recovery, and selectivity. The LODs for CAD, PUT, SPM, SPD, ASPM, and ASPD were found to be 7.6, 10.0, 9.0, 8.8,7.8, and 3.3 nM, respectively. The method was successfully applied for the analysis of PAs and AcPAs in healthy human urine samples. PMID- 24338444 TI - Cadmium, lead, copper and zinc in breast milk in Poland. AB - Mother's milk is the fundamental food for infants. It contains proteins, fat, carbohydrates and essential metals which are necessary to ensure correct functioning of the organism. Unfortunately, breast milk is a potential source of toxic metals, which are dangerous for a baby. In Poland, previous research concerning the content of metals in breast milk was very scarce or its results were unavailable. The present study aimed at assessing the content of Cd, Pb, Cu and Zn in human breast milk, as well as estimating the mean weekly intake of these metals by breast-fed infants from Poland. The average concentrations of Cd, Pb, Cu and Zn were 2.114 MUg/l, 6.331 MUg/l, 0.137 mg/l and 1.623 mg/l, respectively. The admissible levels of supply of these toxic metals has not been exceeded, but their contents were high, particularly in 6-month-old infants (nearly 85 % TWI for Cd and nearly 70 % BMDL01 for Pb). The daily intake of Cu and Zn did not fully satisfy the infant's requirements determined by Polish standards and WHO recommendations. Since the lifestyle of lactating women has a direct influence on the content of these elements in breast milk, women should be educated in this respect with particular focus on eliminating tobacco smoking, both by breastfeeding mothers and by their direct environment. PMID- 24338445 TI - A comparative study on the effects of excess iodine and herbs with excess iodine on thyroid oxidative stress in iodine-deficient rats. AB - This study aimed to compare the effect of excess iodine and herbs with excess iodine on treating iodine deficiency-induced goiter from the perspective of oxidative stress and to measure selenium values in Chinese herbs. One hundred twenty 4-week-old Wistar rats were selected and randomly divided into four groups after inducing iodine-deficiency goiter: normal control group (NC), model control group (MC), iodine excess group (IE), and herbs with iodine excess group (HIE). The activities of oxidative enzymes and levels of oxidative products were measured using biochemical tests. The expression of 4-hydroxynonenal (4-HNE) in the thyroid was detected by immunohistochemistry and the expression of peroxiredoxin 5 (PRDX5) by the Western blot and immunohistochemistry. Selenium values in iodine-excessive herbs were measured by hydride generation-atomic fluorescence spectrometry. The herbs with iodine excess were tested to contain rich selenium. The activities of superoxide dismutase (SOD) and PRDX5 increased markedly, and the values of malondialdehyde (MDA) and 4-HNE decreased significantly in the HIE group. In conclusion, compared with excess iodine, herbs with excess iodine damaged thyroid follicular cells less, which may be related to the increase of antioxidant capacity and rich selenium values in iodine-excessive herbs. PMID- 24338446 TI - Eye can read your mind: decoding gaze fixations to reveal categorical search targets. AB - Is it possible to infer a person's goal by decoding their fixations on objects? Two groups of participants categorically searched for either a teddy bear or butterfly among random category distractors, each rated as high, medium, or low in similarity to the target classes. Target-similar objects were preferentially fixated in both search tasks, demonstrating information about target category in looking behavior. Different participants then viewed the searchers' scanpaths, superimposed over the target-absent displays, and attempted to decode the target category (bear/butterfly). Bear searchers were classified perfectly; butterfly searchers were classified at 77%. Bear and butterfly Support Vector Machine (SVM) classifiers were also used to decode the same preferentially fixated objects and found to yield highly comparable classification rates. We conclude that information about a person's search goal exists in fixation behavior, and that this information can be behaviorally decoded to reveal a search target essentially reading a person's mind by analyzing their fixations. PMID- 24338447 TI - Brazilian foot and mouth disease status and meat exportation to the European Union. AB - The aim of this study was to define the differences between the Brazilian states that export and do not export meat to the European Union (EU) and to identify the variables that are important to meet the export requirements. Infrastructure and computerization of the control of animal transit in Brazil that impact on regional health status were evaluated and linked to other variables such as status for foot and mouth disease (FMD) and qualification to export meat to EU. Variables related to transit control of bovines implemented by the state agencies of animal health and inspection in each Brazilian state were evaluated. Using a discriminant analysis, four variables were selected that explained the variation between Brazilian states that were "free" and "not free" of FMD while another four were selected to explain the variation between the zones "approved" and "not approved" to export meat to the EU, including number of official veterinarians, total transit of bovines and buffaloes, total number of animal transit certificates issued for bovine and buffaloes at the state or zone level, and total number of municipalities in the state or zone. It was possible to correctly discriminate between "free" and "not free" FMD states or zones. Variables related to animal transit are important in assessing the state for the classification of animal health situation and for EU approval for the exportation of meat. PMID- 24338449 TI - Partnering with engaged patients accelerates research. PMID- 24338448 TI - High-resolution paramagnetically enhanced solid-state NMR spectroscopy of membrane proteins at fast magic angle spinning. AB - Magic angle spinning nuclear magnetic resonance (MAS NMR) is well suited for the study of membrane proteins in membrane mimetic and native membrane environments. These experiments often suffer from low sensitivity, due in part to the long recycle delays required for magnetization and probe recovery, as well as detection of low gamma nuclei. In ultrafast MAS experiments sensitivity can be enhanced through the use of low power sequences combined with paramagnetically enhanced relaxation times to reduce recycle delays, as well as proton detected experiments. In this work we investigate the sensitivity of (13)C and (1)H detected experiments applied to 27 kDa membrane proteins reconstituted in lipids and packed in small 1.3 mm MAS NMR rotors. We demonstrate that spin diffusion is sufficient to uniformly distribute paramagnetic relaxation enhancement provided by either covalently bound or dissolved CuEDTA over 7TM alpha helical membrane proteins. Using paramagnetic enhancement and low power decoupling in carbon detected experiments we can recycle experiments ~13 times faster than under traditional conditions. However, due to the small sample volume the overall sensitivity per unit time is still lower than that seen in the 3.2 mm probe. Proton detected experiments, however, showed increased efficiency and it was found that the 1.3 mm probe could achieve sensitivity comparable to that of the 3.2 mm in a given amount of time. This is an attractive prospect for samples of limited quantity, as this allows for a reduction in the amount of protein that needs to be produced without the necessity for increased experimental time. PMID- 24338450 TI - New technique using LigaSure for endoscopic mucomyotomy of Zenker's diverticulum: diverticulotomy made easier. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study is to present a new approach for treatment of Zenker's diverticulum using the LigaSure (Covidien, Mansfield, MA) technique. STUDY DESIGN: A consecutive study with follow-up of 15 patients with Zenker's diverticulum endoscopically treated using the LigaSure. METHODS: All patients underwent an endoscopic division of the bridge between the esophagus and the diverticulum through a rigid diverticuloscope using the LigaSure. Variables such as demographics, symptoms, surgical details, complications, and outcome were collected during admission, and all patients were followed up 5 to 14 months after discharge. RESULTS: The median age of patients was 76 years. The diverticula measured between 2 and 7 cm. The median time of surgery was 33 minutes. All patients but one resumed oral intake within 24 hours. One patient experienced prolonged coughing and vomiting immediately postoperatively and was hours later diagnosed with a perforation. The patient was successfully treated with antibiotics. At follow-up this patient was on a normal diet. At follow-up after 2 to 8 weeks, all patients were relieved of their preoperative symptoms. At follow-up after 5 to 14 months, all but three had relief of all symptoms. Two patients had relapse of the diverticulum and one had relapse of a stricture known from before the diverticulotomy. CONCLUSIONS: Our results show that treating Zenker's diverticulum using the LigaSure instrument safely improves the patients condition. As a new operative instrument, the LigaSure technique constitutes in our opinion a valid and easy alternative for treatment of Zenker's diverticulum compared to other endoscopic techniques. PMID- 24338451 TI - Complications following antidotal use of intravenous lipid emulsion therapy. AB - The primary objective is to identify and describe the complications associated with the use of intravenous lipid emulsion (ILE) therapy as an antidote for lipophilic drug toxicity. This study is a retrospective chart review of patients treated with ILE at two academic medical centers between 2005 and 2012. Based on previously reported complications, we hypothesized that pancreatitis, ARDS, and lipemia-induced laboratory interference might occur. Clinical definitions of these complications were defined a priori. Subjects treated with ILE who did not develop at least one complication were excluded. A total of nine patients were treated with ILE during the study period, six of whom experienced potential complications as a result of the ILE. Two patients developed pancreatitis, and four patients had lipemia-induced interference of interpretation of laboratory studies, despite ultracentrifugation. Laboratory interference precluded one patient from being an organ donor. Three patients developed ARDS; although temporally associated, a causal relationship between ILE and the development of ARDS cannot be clearly established. As ILE is increasingly used for less severe cases of drug toxicity, clinicians should be aware of potential complications associated with its use. A risk-benefit assessment for the use of ILE should be implemented on a case-by-case basis. PMID- 24338452 TI - Patient and physician views on providing cancer patient-specific survival information. AB - OBJECTIVES/HYPOTHESIS: To gather input regarding the presentation, content, and understanding of survival and support information for Prognostigram, a computer based program that uses standard cancer registry data elements to present individualized survival estimates. STUDY DESIGN: Cross-sectional survey research. METHODS: Two groups of patients (total n=40) and one group of physicians (n=5) were interviewed. The patient groups were interviewed to assess baseline patient numeracy and health literacy, and patient desire for prognostic information. The first group (n=20) was introduced to generalized survival curves in a paper booklet. The second group (n=20) was introduced to individualized survival curves from Prognostigram on the computer. Both patient groups were queried about the survival curves. The physicians were asked their opinions on sharing prognostic information with patients. RESULTS: Numeracy assessments indicated that the patients are able to understand concepts and statistics presented by Prognostigram. According to the patient interviews, the Internet is the most frequent source for survival statistics. Of the 40 patient participants, 39 reported survival statistics as being somewhat or very useful to cancer patients. All five physicians believed survival statistics were useful to patients and physicians, and noted accurate and understandable survival statistics are fundamental to facilitate discussions with patients regarding prognosis and expectations. CONCLUSIONS: Formative research indicates that cancer patients and their families actively seek survival statistics on their own. All patients indicated strong interest in Prognostigram, which is a software tool designed to produce individualized survival statistics to oncologists and cancer patients in a user-friendly manner. LEVEL OF EVIDENCE: 4. PMID- 24338453 TI - Deep vein thrombosis and novel oral anticoagulants: a clinical review. AB - Deep vein thrombosis (DVT) is a common disease associated with high rates of mortality and significant morbidity. The diagnostic approach of DVT has evolved over the years. Algorithmical use of pretest probability, D-Dimer testing and ultrasonography allow safe and accurate investigation of DVT. The anticoagulation therapy, used to treat DVT, includes vitamin K antagonists (VKAs) and low molecular-weight heparin (LMWH) or unfractionated heparin (UF). The duration of anticoagulation therapy depends on the cause of DVT and patient's clinical profile. Although these conventional therapies are effective, narrow therapeutic index, need for frequent monitoring and various food-drug interactions cause difficulties for patients. In recent decades, new oral anticoagulants have been developed. These drugs focus directly on inhibiting either Factor Xa (rivaroxaban, apixaban, edoxaban) or thrombin (dabigatran). In contrast to warfarin, these new agents have shorter half-life, fewer drug or food interactions, no necessity for a close monitoring and ease of administration. This review summarizes current knowledge about deep vein thrombosis and new treatment aspects with novel oral anticoagulants. PMID- 24338454 TI - Management of atrial fibrillation in the Emergency Department: current approach and future expectations. AB - Atrial fibrillation (AF) is the most common cardiac dysrhythmia and occurs in 3.3%-10% of emergency admissions. It is frequently quoted for people over the age of 75, but the cases of AF in young subjects without structural heart disease are also increasing, therefore, leading to the evaluation of "lonely atrial fibrillation" as a new challenge for the clinician. The first diagnosis and treatment often occur in the emergency room and the emergency physician has therefore to evaluate the initial step towards the therapeutic decisions. Although international standard guidelines are available, AF treatment in the Emergency Department (ED) is still heterogeneous in terms of the management strategy chosen. There are two main strategies for the management of AF: rate and rhythm control. Moreover, antithrombotic treatment is pivotal in AF to prevent cardioembolic stroke and it is considered a primary objective after an accurate assessment of antithrombotic treatment risks and benefits. The introduction of innovative echocardiographic approach, directly in ED, seems to improve the management and risk stratification of patients with AF. This review aims to provide an overview about the current approach and the future expectations in the management of AF in ED. This manuscript represents a synopsis of the lectures on AF management in the ED of the Third Italian GREAT Network Congress, that was hold in Rome, 15-19 October 2012. We decided to use only the most relevant references for each contribution as suggested by each participant at this review. PMID- 24338455 TI - Revealing the contribution of Cytochrome P450 to salt-sensitive hypertension using DNA microarray. AB - BACKGROUND: Salt sensitivity is an important cause of hypertension which is a major public health problem. This study aimed to investigate the contribution of Cytochrome P450 (CYP) to salt-sensitive hypertension with microarray data and bioinformatics analysis. METHODS: Gene expression data set GSE4800 was downloaded from Gene Expression Omnibus database, including 6 gene chips from 3 Dahl salt sensitive (DS) rat samples and 3 Lewis (LEW) rat samples. Raw data were preprocessed and normalized, and then differentially expressed genes (DEGs) were identified with Limma package. Interaction network was constructed by employing STRING (Search Tool for the Retrieval of Interacting Genes) tool. GO (Gene Ontology) enrichment analysis was performed using FuncAssociate tool and pathway analysis was carried out by EASE (Expressing Analysis Systematic Explorer). BLAST (Basic Local Alignment Search Tool) was applied to explore the sequence homology among CYP3A genes in rat and human based on multiple alignments. RESULTS: A total of 1264 DEGs, including 1082 up-regulated genes and 182 down-regulated genes were identified between DS and LEW samples. CYP3A2 and CYP3A9 were selected to construct the protein interaction network, which comprised 1653 pairs of interaction relationship among 100 genes. Functional analysis showed that CYP3A2 and CYP3A9 were most significantly related to oxidation reduction and metabolism of xenobiotics by cytochrome P450. Furthermore, the CYP3A2 and CYP3A9 genes in rats had high homology with genes CYP3A4and CYP3A5 in human beings. CONCLUSIONS: CYP3A4 and CYP3A5 may contribute to salt-sensitive hypertension in human which may act as biomarkers for this disease. PMID- 24338456 TI - Massive pulmonary air embolism during the implantation of pacemaker, case reports and literature analysis. AB - OBJECTIVES: Pacemaker implantation has developed into a mature technology, meanwhile, implantable cardioverter-defibrillators (ICD) and cardiac resynchronization therapy (CRT), as extended pace making technology, are both carried out in rising frequency. Massive pulmonary air embolism is a rare but fatal complication accompanying with such pace making process. The objective of this study was to investigate the epidemiology, pathophysiological mechanism, occurrence and treatment for this kind of complication. PATIENTS AND METHODS: Two cases of complicated massive pulmonary gas embolism were presented: one in CRT and the other in pacemaker implantation, both of which were captured rapidly and treated successfully by inhalation of high flow oxygen, closure of gas inflow tract, position change, and vasoactive drugs. Moreover, published literatures about air embolism in the process of pacemaker implantation or CRT/ICD were summarized and analyzed. RESULTS: Complicated massive pulmonary air embolisms could be successfully resolved with satisfied short-term prognosis. Literature analysis showed that massive pulmonary air embolism is very rare in the course of pacemaker implantation, and coughing or deep breathing, advanced age, preoperative sedation, sheath with large cavity, improperly operating the hemostasis valve and diminished compliance of pulmonary circulation might be risk factors for air embolism. CONCLUSIONS: Massive pulmonary air embolism during pace making which is very rare in the course of pacemaker implantation is one kind of life-threatening complication. Rapid judgment and timely treatment can avoid a catastrophic event, which could prevent adverse impact on the short-term prognosis, while further observation is required to explore the long-term prognosis. PMID- 24338457 TI - Office normotensives with a minimal augmentation of intima-media thickness of common carotid arteries: really normotensives? AB - BACKGROUND AND AIM: Blood pressure is an independent predictor of target organ damage (TOD). Recent data from literature suggest that TOD can be present also in pre-hypertensive subjects, diagnosed with pressure monitoring (PM). Aim of this study is to clarify whether an augmentation of the carotid Intima-Media Thickness (cIMT) in office prehypertensives is a TOD associated to monitoring prehypertension (MP). PATIENTS AND METHODS: We have analyzed our database of individuals office normotensives showing an increase of cIMT. The ambulatory blood pressure monitoring (ABPM) of these was compared with those of office monitoring normotensives, matched by age and gender, antropometric characteristics, negative for familial hypertension and other risk factors (true normotensives, TN). RESULTS: We have selected 15 presumable prehypetensives (PP) and 8 TN subjects. The ABPM (ambulatory blood pressure monitoring) analysis confirmed that neither the PP nor TN showed systolic (S) and diastolic (D) BP within-day values above their day-night upper reference limits. However the statistical comparison between PP and TN revealed that the first group had a significant elevation of SBP and DBP Daily Mean Level (DML(SBP/DBP): 121 +/- 2/81 +/- 2 vs 112 +/- 2/70 +/- 2 mmHg, respectively, p = 0.007 and p = 0.002), confirming the MP diagnosis. CONCLUSIONS: These results demonstrate that cIMT increase in PP fulfill the criteria for MP diagnosis, suggesting that MP should be undertaken in all PP with altered cIMT, but larger prospective studies are needed. PMID- 24338458 TI - Endothelial progenitor cells are influenced by serum of patients with systemic inflammatory response syndrome or multiple organ dysfunction. AB - BACKGROUND AND AIM: To investigate the effects of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndromes (MODS) on human peripheral blood endothelial progenitor cells. PATIENTS AND METHODS: Twenty patients admitted to Changhai Hospital, Second Military Medical University, from February, 2011 to November, 2011 were recruited consecutively. The serum samples were collected from the twenty patients who were divided into four groups as following: normal group, post-traumatic group without SIRS, post-traumatic group with SIRS, and post-traumatic group with MODS. Endothelial progenitor cells (EPCs) were isolated from peripheral blood of healthy subjects by using density gradient centrifugation and the effect of the serum on EPCs was detected after stimulating by the serum samples for 0, 6, 12, 24, and 36 h. RESULTS: Compared with the normal group, the proliferation of EPCs was significantly increased in a time-independent manner in the other three groups, especially in the SIRS serum treated group. The expression of pro-inflammation cytokines was increased in the other three groups compared with the normal group, but the expression of IL-10 in the normal group was higher than the other groups. CONCLUSIONS: Oxidative stress balance was also broken as the disease progressed. Serum from patients with sepsis could influence proliferation and the inflammation and oxidative stress states of EPCs. PMID- 24338459 TI - Transcriptome network analysis reveals potential candidate genes for ankylosing spondylitis. AB - OBJECTIVES: Ankylosing spondylitis (AS) is a chronic, inflammatory arthritis and autoimmune disease. BACKGROUND: The main symptom of AS is inflammatory spinal pain; with time, some patients develop ankylosis and spinal immobility. We aim to find cure available for ankylosing spondylitis. MATERIALS AND METHODS: We used the GSE11886 series to identify potential genes that related to AS to construct a regulation network. RESULTS: In the network, some of TFs and target genes have been proved related with AS in previous study, such as NFKB1, STAT1, STAT4, TNFSF10, IL2RA, and IL2RB. We also found some new TFs (Franscription Factors) and target genes response to AS, such as BXDC5, and EGFR. Further analysis indicated some significant pathways are associated with AS, including antigen processing and presentation and cytokine-cytokine receptor interaction, etc.; although not significant, there was evident that they play an important role in AS progression, such as apoptosis and systemic lupus erythematosus. CONCLUSIONS: Therefore, it is demonstrated that transcriptome network analysis is useful in identification of the candidate genes in AS. PMID- 24338460 TI - Screening of genes related with intervertebral disc disease by dynamic differential interaction network analysis. AB - AIM: Gene expression profiles for intervertebral disc (IVD) cells treated with different osmolarities were compared to identify key genes associated with intervertebral disc diseases. MATERIALS AND METHODS: Microarray data was downloaded from Gene Expression Omnibus (GEO) database and pre-processed using package of R. Gene co-expression was determined with Pearson correlation coefficient. Interaction networks were established with the protein-protein interaction (PPI) information obtained from Human Protein Reference Database (HPRD database) for the two conditions: isosmoticity and hyperosmosis, and then a comparative analysis was done to identify disease-related genes. The functional annotation was performed for these genes using network ontology analysis (NOA), which also confirmed the effectiveness of this method. RESULTS: A total of 45 feature genes were obtained through comparing 7 samples treated under isosmotic conditions and 9 high osmotic conditions. Biological processes and molecular functions were then revealed by NOA. CONCLUSIONS: A range of disease-related genes were obtained, which might serve as the potential biomarkers or drug targets. More works are needed to further elucidate their roles in the development of intervertebral disc diseases like intervertebral disc herniation. PMID- 24338461 TI - Arthroscopic debridement compared to intra-articular steroids in treating degenerative medial meniscal tears. AB - OBJECTIVES: Virtually all early cases of knee osteoarthritis have degenerative medial meniscus lesions accompanying the chondral defects on MRI. It is difficult to determine if the symptoms are caused by the unstable meniscus or by osteoarthritis, hence unclear guidance towards treatment. We, therefore, aimed to determine the clinical improvement following arthroscopic meniscectomy compared to intraarticular administration of corticosteroids for degenerative ruptures of the medial meniscus in the presence of early stage medial compartment knee osteoarthritis. PATIENTS AND METHODS: We included 120 consecutive cases of nontraumatic symptomatic knees which had degenerative lesions of the medial compartment (cartilage and meniscus) on MRI's. They were randomized to receive either intraarticular steroid injection or arthroscopic debridement. We also analyzed the correlation between BMI, age, gender, MRI, intraoperative aspect of the meniscus and cartilage and clinical improvement using the Oxford Knee Score up to one year. At one month there was significant improvement of the scores for all the examined cases. Also at one month, the arthroscopic group performed better in terms of symptom improvement. This was maintained for 79% of the knees in the arthroscopic group and 61% in the intraarticular steroid injection respectively, out of those available for follow up at one year. RESULTS: At one month, symptoms reappeared for 12 patients in the steroid group and 7 in the arthroscopy respectively. Gender and age did not correlate with treatment, whereas extrusion of the meniscus, bone marrow edema, duration of the clinical symptoms, obesity and a low preoperative score were negative prognostic factors. CONCLUSIONS: Degenerative medial meniscal tears, in the presence of osteoarthritis, can only marginally benefit from arthroscopic debridement over intraarticular steroid injections in short term follow up. When considering individual cases, factors become more predictive when analyzed in group. PMID- 24338462 TI - Low adiponectin in overweight/obese women: association with diabetes during pregnancy. AB - BACKGROUND: Overweight/obese (OW/OB) women are at high risk to develop gestational diabetes mellitus (GDM) in pregnancy. AIM: To investigate, in pregnant OW/OB women, the longitudinal changes of adiponectin plasma levels, carbohydrate and lipid metabolism, and to identify if there is any association between adipokines and subsequent development of GDM. SUBJECTS AND METHODS: Thirty-two OW/OB normotensive normoglycaemic women at the beginning of pregnancy were studied. Adiponectin, insulin sensitivity (homeostasis model assessment, HOMA) and lipid panel were measured at 1st, 2nd and 3rd trimesters of pregnancy. The bioelectrical impedance to estimate the subject's body composition was also performed. RESULTS: Sixteen OW/OB women developed GDM. There were no significant differences with regard to age, BMI and body composition. Glycaemic and insulinaemic plasma levels, HOMA and lipid panel were comparable in the two groups. Systolic, diastolic and mean blood pressure at the 1st trimester were higher in OW/OB women with GDM (p < 0.05). GDM group showed adiponectin levels significantly lower than control group, at each trimester (p < 0.05). Adiponectin, fat mass, diastolic blood pressure and HOMA are independent predictors of GDM. CONCLUSIONS: OW/OB women who will develop GDM show lower adiponectin than euglycaemic group, across all pregnancy. Furthermore, at first trimester, they showed higher body fat and blood pressure levels than NGT group. Adiponectin, body fat, DBP and HOMA are independent predictors of GDM in OW/OB pregnant women. These results suggest the possibility of using adiponectin as early marker of GDM risk, at least in this cohort of women. PMID- 24338463 TI - Pedobarography - a novel screening tool for diabetic peripheral neuropathy? AB - AIM: To investigate the diagnostic significance of foot plantar pressure distribution abnormalities in patients with diabetic peripheral neuropathy (DPN). PATIENTS AND METHODS: A total of 107 patients were divided into normal control (28 participants, 56 feet), non-DPN (56 patients, 112 feet), and DPN groups (23 patients, 46 feet). Foot plantar pressure was measured while patients walked at a constant speed over a flat floor using F-Scan pressure insoles. Recordings of six middle strides were averaged to evaluate the characteristics of foot plantar pressure distribution. RESULTS: Compared with the normal group, the time of contact (TOC) was longer in non-DPN (p < 0.05) and DPN groups (p < 0.01). The foot to floor force-time integral (FTI) was increased in DPN group (p < 0.01). The forefoot plantar force ratio increased in non-DPN and DPN patients (p < 0.05). Moreover, in DPN patients, the ratio of lateral foot plantar force increased (p < 0.05). The examination of the correlations between biomechanical parameters of the foot plantar and electrophysiological parameters of the lower limbs showed foot plantar biomechanical abnormalities correlated with abnormal sensory conduction of the sural nerve and motor conduction of the common peroneal nerve. Receiver operating characteristic (ROC) analysis showed the area under FTI curve was 0.714 (p < 0.001). CONCLUSIONS: The plantar pressure was shifted towards the side of the forefoot in DPN patients. The foot plantar biomechanical changes were closely correlated with lower limb paresthesia and contraction abnormalities of lower-limb extensor muscles. Foot plantar pressure measurement might be used as a screening tool for early diagnosis of DPN. PMID- 24338464 TI - MIR-142-5p and miR-9 may be involved in squamous lung cancer by regulating cell cycle related genes. AB - OBJECTIVE: To identify key genes associated with squamous lung cancer (SLC) through analyzing gene expression data with bioinformatic tools, which could be potential biomarkers for diagnosis and treatment. MATERIALS AND METHODS: Gene expression data set GSE3268 was downloaded from Gene Expression Omnibus, including 5 SLC samples and 5 healthy controls. Data pre-treatment and differential analysis were performed with packages of R. Cluster analysis was done based on gene expression values to globally present the difference between the two states. Differentially expressed genes (DEGs) were divided into up regulated and down-regulated genes, and then underwent functional enrichment analysis with DAVID tools. WebGestalt was used to retrieve microRNAs for the DEGs and then a regulatory network was constructed. GENECODIS was selected for functional annotation for all the genes in the network. RESULTS: A total of 537 DEGs were obtained. Functional enrichment analysis revealed that cell cycle was significantly enriched in up-regulated genes. Besides, two microRNAs (miRNAs), MIR-142-5p and miR-9, were retrieved, which were potential tools to regulate the expression of key genes. CONCLUSION: These DEGs may be involved in pathogenesis of SLC and some of them could be potential biomarkers. Besides, MIR-142-5p and miR-9 may be utilized to treat SLC as they could modulate cell cycle. PMID- 24338465 TI - Screening of biomarkers for lung cancer with gene expression profiling data. AB - OBJECTIVES: Lung cancer is one of the most common malignant tumors, but the etiology is not yet clear. Our study aims to deepen the understandings about the mechanisms of lung cancer via screening relevant key genes and functional pathways. MATERIALS AND METHODS: Microarray data set was collected and differentially expressed genes (DEGs) were selected out. KEGG pathway analysis and Gene Ontology (GO) enrichment analysis were performed for the DEGs. Interaction networks were constructed for the lung cancer-related DEGs with information from Human Protein Reference Database (HRPD) to screen out potential biomarkers. RESULTS: Functional annotation revealed that cell cycle, DNA replication, immune system, and signal molecules and interactions were significantly over-represented in all the DEGs, suggesting their close involvement in the development of lung cancer. 40 genes with high degree, betweenness and clustering coefficient were identified from the interaction network. 26 out of them are known cancer genes according to the database F census. Besides, 4 biomarkers were revealed through analyzing their interactions with oncogenes. CONCLUSIONS: Our study not only advances the understandings about the molecular mechanisms of lung cancer, but also provides several potential biomarkers for clinical use. PMID- 24338466 TI - The anaesthetic and recovery profile of two concentrations (0.25% and 0.50%), of intrathecal isobaric levobupivacaine for combined spinal-epidural (CSE) anaesthesia in patients undergoing modified Stark method caesarean delivery: a double blinded randomized trial. AB - BACKGROUND: In spinal anaesthesia for a Caesarean delivery, it is important to limit anaesthesia only at the surgical area, and to resolve fast motor block. We compared the intraoperative effectiveness, hemodynamic effects, anaesthetic recovery times and patients satisfaction after isobaric levobupivacaine (L) 0.25% versus L0.50% spinal anaesthesia during elective Caesarean deliveries performed with the Stark technique. PATIENTS AND METHODS: In this double-blinded prospective study, seventy women undergoing elective caesarean delivery were randomized to receive either intrathecal 7.5 mg Levobupivacaine 0.25% plus sufentanil 2.5 MUg (Group L0.25), or intrathecal 7.5 mg L 0.50% plus sufentanil 2.5 MUg (GroupControl). The onset time, duration of anaesthesia, analgesia and sensory and motor block and hemodynamic parameters were measured from the beginning of spinal anaesthesia until four hours after spinal anaesthesia (T240). RESULTS: Onset time, duration of anaesthesia and haemodynamic variations were similar in the two groups. No patients required general anesthesia to complete surgery. Motor block vanished faster in Group L0.25 as compared with GroupControl (p < .01). The cephalad spread of the 0.50% solution was higher than that of the 0.25% solution: no patient in Group L0.25 experienced paresthesia of the upper limbs vs 14% in GroupControl (p < .05). In GroupControl anaesthesia reached the dermatome T1 in 15% of cases. Maternal and surgeon satisfaction was good in every patient. CONCLUSIONS: Levobupivacaine 7.5 milligrams at 0.25% may be used as a suitable alternative to L 0.50% for spinal anaesthesia for caesarean deliveris with the Stark technique with good maternal satisfaction. In Group L0.25 a lower appearance of nausea and hypotension were observed and motor and sensitive block developed and diminished faster while no clinically significant differences in hemodynamic behavior was observed between groups. PMID- 24338467 TI - A novel index for predicting macular thickening after cataract surgery. AB - PURPOSE: In this study, we tried to investigate weather or not the preoperative anterior chamber depth, the lens thickness (LT) and the relation between these variables by the ratio (K) of the distance from the corneal peak to the posterior side of the lens (A) (K = A/LT) could be predictive for a surgically induced foveal thickening following uneventful cataract surgery in normal, emmetropic eyes. PATIENTS AND METHODS: A total amount of 45 eyes, 25 females and 20 males, were enrolled in this study and underwent uncomplicated phacoemulsification under topical anesthesia. A complete ophthalmological examination was performed preoperatively, including refraction, best corrected visual acuity, slit-lamp examination, biometry and optical coherence tomography of both eyes. These examinations, with the exception of the biometric examination, were repeated one day, one week and four weeks after surgery. RESULTS: The K ratio was positively correlated with the macular thickness changes after cataract surgery. The Pearson correlation analysis of K ratio and foveal thickness changes was 0.792 (y = 36.457x - 52.558, R2 = 0.6266). CONCLUSIONS: A novel ratio that incorporates preoperative ocular parameters has been described. It could be easily measured in a clinical setting, and appears to be strongly predictive for macular thickening following cataract surgery. Of course, further studies enrolling a larger amount of patients are necessary in order to confirm these preliminary data. PMID- 24338468 TI - Intermittent versus every-day mesalazine therapy in preventing complications of diverticular disease: a long-term follow-up study. AB - BACKGROUND: Mesalazine seems to be effective in preventing recurrence of acute uncomplicated diverticulitis (AUD), but the optimal mesalazine scheme to achieve these results is still debated. AIM: To assess the effectiveness of two different mesalazine-based treatments in preventing recurrence of AUD and the occurrence of other complications of diverticular disease (DD) during a long-term follow-up. PATIENTS AND METHODS: We reviewed 311 patients suffer from recent episode of AUD and undergoing to mesalazine treatment: 207 (group A, 105 males, median age 63 years, range 47-74 years) were treated with mesalazine 1.6 g for 10 days each month, whilst 104 (group B, 55 males, median age 65 years, range 50-72 years) were treated with mesalazine 1.6 g every day. Patients were followed-up every 6 months (median 7.5 months, range 5-13 months). RESULTS: Patients were followed-up for a mean time of 3 years (range 12-72 months). Overall, occurrence of complication recurred more frequently in group A than in group B (p = 0.030, log rank test). Acute diverticulitis recurred in 17 (8.2%) patients in group A and in 3 (2.9%) in group B; diverticular bleeding occurred in 4 (1.9%) patients in group A and in 1 (0.96%) patient in group B; surgery was required in 3 (1.4%) patients in group A and in no (0%) patient in group B. CONCLUSIONS: This is the first study showing that long-term mesalazine treatment is significantly better that intermittent mesalazine treatment in preventing occurrence of DD complications after an attack of acute diverticulitis. PMID- 24338469 TI - Environmental exposure and risk of uterine leiomyoma: an epidemiologic survey. AB - AIM: The present study was undertaken to explore the relationship between environmental exposure and risk of uterine leiomyoma in women using an epidemiologic survey. SUBJECTS AND METHODS: We conducted a case-control survey of premenopausal Han women aged 30-50 years in Nanjing. The subjects included 600 patients with uterine leiomyoma confirmed at the Affiliated Zhongda Hospital of Southeast University between February 2010 and June 2012 and 600 patients with non-uterine leiomyoma or healthy volunteers who presented to the above mentioned hospital for physical examination during the same period. We entered the results into a database and explored the relationship between risk factors and prevalence of uterine leiomyoma using univariate or multivariate non-conditional logistic regression analysis. RESULTS: The results showed that patients aged 40-45 years had a high prevalence of uterine leiomyoma. The prevalence of uterine leiomyoma in subjects with an education beyond high school was higher than in those with a high school education or less. Exposure to plastic products (odds ratio [OR]: 1.481; 95% confidence interval [CI]: 1.046-2.097); exposure to cosmetics and other chemicals (OR: 1.954; 95% CI: 1.479-2.582); and consumption of soybean milk (OR: 2.518; 95% CI: 1.894-3.347), food additives, sweeteners, and preserved food (OR: 3.166, 95% CI: 2.247-4.461) had a significant effect on the occurrence of uterine leiomyoma (p < 0.05). CONCLUSIONS: Exposure to plastic products, cosmetics, and other chemicals as well as intake of soybean milk, food additives, sweetener, and preserved foods may be risk factors for uterine leiomyoma. PMID- 24338470 TI - Neuropathic pain following spinal cord injury: what we know about mechanisms, assessment and management. AB - BACKGROUND: In biology, it is easy to understand how a damaged functional system may generate wrong signals, but why this should happen when the system is disconnected is less clear. For this reason, among other pain syndromes, neuropathic pain (NP) following spinal cord injury (SCI) leaves most questions unanswered. AIMS AND METHODS: Our purpose is to review current knowledge on NP after SCI, focusing on the mechanisms, assessment and management of the syndrome. RESULTS: The mechanisms responsible for NP following SCI are poorly understood: NP is classically considered a "central pain syndrome" but recent evidence from experimental models reveals a possible "peripheral sensitization". Assessment of NP following SCI is well-established: in addition to clinical evaluation and self reported scales, many neurophysiological, radiological and microscopic investigations may be performed. The management of NP following SCI is very difficult: evidence of effective drugs is lacking and alternative new treatment approaches yield different outcomes. CONCLUSIONS: Recently clinical and instrumental tools have increased our knowledge on NP, suggesting that the discovery of new treatment agents will depend on an explanation of what changes after SCI: future research must point in this direction. PMID- 24338471 TI - Concordant response to pharmacotherapy in monozygotic twins with schizoaffective disorder. AB - BACKGROUND: Schizoaffective disorder (SAD) represents one of the most confusing and controversial concepts in psychiatry. Prevalence is less than 1%, but despite that it has a major influence on an individual and community. There is an increased risk for schizophrenia and mood diorders in first degree relatives with SAD, according to DSM IV. This paper describes the concordant clinical response of a pair of monozygotic twins with SAD when treated with risperidon and valproic acid. We found that their clinical symptoms were very similar and both brothers expressed hipomanic and depressive episode prior to full onset of SAD-psychotic symptoms with correlations of elevated mood, and first psychiatric hospitalization at the age of 19 (patient A) and 18 (patient B). Their response to the combined treatment with risperidon and valproic acid has been also similar both in intensity and in the pattern of symptoms that have improved. PMID- 24338472 TI - Polo-like kinase 2, a novel ADAM17 signaling component, regulates tumor necrosis factor alpha ectodomain shedding. AB - ADAM17 (a disintegrin and metalloprotease 17) controls pro- and anti-inflammatory signaling events by promoting ectodomain shedding of cytokine precursors and cytokine receptors. Despite the well documented substrate repertoire of ADAM17, little is known about regulatory mechanisms, leading to substrate recognition and catalytic activation. Here we report a direct interaction of the acidophilic kinase Polo-like kinase 2 (PLK2, also known as SNK) with the cytoplasmic portion of ADAM17 through the C-terminal noncatalytic region of PLK2 containing the Polo box domains. PLK2 activity leads to ADAM17 phosphorylation at serine 794, which represents a novel phosphorylation site. Activation of ADAM17 by PLK2 results in the release of pro-TNFalpha and TNF receptors from the cell surface, and pharmacological inhibition of PLK2 leads to down-regulation of LPS-induced ADAM17 mediated shedding on primary macrophages and dendritic cells. Importantly, PLK2 expression is up-regulated during inflammatory conditions increasing ADAM17 mediated proteolytic events. Our findings suggest a new role for PLK2 in the regulation of inflammatory diseases by modulating ADAM17 activity. PMID- 24338473 TI - Evolutionary and structural analyses of mammalian haloacid dehalogenase-type phosphatases AUM and chronophin provide insight into the basis of their different substrate specificities. AB - Mammalian haloacid dehalogenase (HAD)-type phosphatases are an emerging family of phosphatases with important functions in physiology and disease, yet little is known about the basis of their substrate specificity. Here, we characterize a previously unexplored HAD family member (gene annotation, phosphoglycolate phosphatase), which we termed AUM, for aspartate-based, ubiquitous, Mg(2+) dependent phosphatase. AUM is a tyrosine-specific paralog of the serine/threonine specific protein and pyridoxal 5'-phosphate-directed HAD phosphatase chronophin. Comparative evolutionary and biochemical analyses reveal that a single, differently conserved residue in the cap domain of either AUM or chronophin is crucial for phosphatase specificity. We have solved the x-ray crystal structure of the AUM cap fused to the catalytic core of chronophin to 2.65 A resolution and present a detailed view of the catalytic clefts of AUM and chronophin that explains their substrate preferences. Our findings identify a small number of cap domain residues that encode the different substrate specificities of AUM and chronophin. PMID- 24338474 TI - Signature amyloid beta profiles are produced by different gamma-secretase complexes. AB - gamma-Secretase complexes are involved in the generation of amyloid-beta (Abeta) in the brain. Therefore, gamma-secretase has been proposed as a potential therapeutic target in Alzheimer disease (AD). Targeting gamma-secretase activity in AD requires the pharmacological dissociation of the processing of physiological relevant substrates and the generation of "toxic" Abeta. Previous reports suggest the differential targeting of gamma-secretase complexes, based on their subunit composition, as a valid strategy. However, little is known about the biochemical properties of the different complexes, and key questions regarding their Abeta product profiles should be first addressed. Here, we expressed, purified, and analyzed, under the same conditions, the endopeptidase and carboxypeptidase-like activities of the four gamma-secretase complexes present in humans. We find that the nature of the catalytic subunit in the complex affects both activities. Interestingly, PSEN2 complexes discriminate between the Abeta40 and Abeta38 production lines, indicating that Abeta generation in one or the other pathway can be dissociated. In contrast, the APH1 subunit mainly affects the carboxypeptidase-like activity, with APH1B complexes favoring the generation of longer Abeta peptides. In addition, we determined that expression of a single human gamma-secretase complex in cell lines retains the intrinsic attributes of the protease while present in the membrane, providing validation for the in vitro studies. In conclusion, our data show that each gamma secretase complex produces a characteristic Abeta signature. The qualitative and quantitative differences between different gamma-secretase complexes could be used to advance drug development in AD and other disorders. PMID- 24338475 TI - Structural basis for allosteric coupling at the membrane-protein interface in Gloeobacter violaceus ligand-gated ion channel (GLIC). AB - Ligand binding at the extracellular domain of pentameric ligand-gated ion channels initiates a relay of conformational changes that culminates at the gate within the transmembrane domain. The interface between the two domains is a key structural entity that governs gating. Molecular events in signal transduction at the interface are poorly defined because of its intrinsically dynamic nature combined with functional modulation by membrane lipid and water vestibules. Here we used electron paramagnetic resonance spectroscopy to delineate protein motions underlying Gloeobacter violaceus ligand-gated ion channel gating in a membrane environment and report the interface conformation in the closed and the desensitized states. Extensive intrasubunit interactions were observed in the closed state that are weakened upon desensitization and replaced by newer intersubunit contacts. Gating involves major rearrangements of the interfacial loops, accompanied by reorganization of the protein-lipid-water interface. These structural changes may serve as targets for modulation of gating by lipids, alcohols, and amphipathic drug molecules. PMID- 24338476 TI - Class I major histocompatibility complex, the trojan horse for secretion of amyloidogenic beta2-microglobulin. AB - To form extracellular aggregates, amyloidogenic proteins bypass the intracellular quality control, which normally targets unfolded/aggregated polypeptides. Human D76N beta2-microglobulin (beta2m) variant is the prototype of unstable and amyloidogenic protein that forms abundant extracellular fibrillar deposits. Here we focus on the role of the class I major histocompatibility complex (MHCI) in the intracellular stabilization of D76N beta2m. Using biophysical and structural approaches, we show that the MHCI containing D76N beta2m (MHCI76) displays stability, dissociation patterns, and crystal structure comparable with those of the MHCI with wild type beta2m. Conversely, limited proteolysis experiments show a reduced protease susceptibility for D76N beta2m within the MHCI76 as compared with the free variant, suggesting that the MHCI has a chaperone-like activity in preventing D76N beta2m degradation within the cell. Accordingly, D76N beta2m is normally assembled in the MHCI and circulates as free plasma species in a transgenic mouse model. PMID- 24338477 TI - Vinculin phosphorylation at Tyr1065 regulates vinculin conformation and tension development in airway smooth muscle tissues. AB - Vinculin localizes to membrane adhesion junctions in smooth muscle tissues, where its head domain binds to talin and its tail domain binds to filamentous actin, thus linking actin filaments to the extracellular matrix. Vinculin can assume a closed conformation, in which the head and tail domains bind to each other and mask the binding sites for actin and talin, and an open activated conformation that exposes the binding sites for talin and actin. Acetylcholine stimulation of tracheal smooth muscle tissues induces the recruitment of vinculin to the cell membrane and its interaction with talin and actin, which is required for active tension development. Vinculin phosphorylation at Tyr(1065) on its C terminus increases concurrently with tension development in tracheal smooth muscle tissues. In the present study, the role of vinculin phosphorylation at Tyr(1065) in regulating the conformation and function of vinculin during airway smooth muscle contraction was evaluated. Vinculin constructs with point mutations at Tyr(1065) (vinculin Y1065F and vinculin Y1065E) and vinculin conformation sensitive FRET probes were expressed in smooth muscle tissues to determine how Tyr(1065) phosphorylation affects smooth muscle contraction and the conformation and cellular functions of vinculin. The results show that vinculin phosphorylation at tyrosine 1065 is required for normal tension generation in airway smooth muscle during contractile stimulation and that Tyr(1065) phosphorylation regulates the conformation and scaffolding activity of the vinculin molecule. We conclude that the phosphorylation of vinculin at tyrosine 1065 provides a mechanism for regulating the function of vinculin in airway smooth muscle in response to contractile stimulation. PMID- 24338478 TI - Cardiolipin is dispensable for oxidative phosphorylation and non-fermentative growth of alkaliphilic Bacillus pseudofirmus OF4. AB - Cardiolipin (CL), a membrane phospholipid in bacteria and mitochondria, has been hypothesized to facilitate movement of protons on the outer surface of membranes in support of respiration-dependent ATP synthesis, oxidative phosphorylation (OXPHOS). If so, the high levels of membrane CL found in alkaliphilic bacteria, such as Bacillus pseudofirmus OF4, might facilitate its robust OXPHOS at pH 10.5, where the bulk protonmotive (PMF) force is low. To address the role of CL in Bacillus pseudofirmus OF4, we studied strains in which genes (cls) potentially encoding a CL synthase (CLs) were deleted: three single (DeltaclsA, DeltaclsB, and DeltaclsC), one double (DeltaclsA/B), and one triple (DeltaclsA/B/C) mutant. Two-dimensional thin layer chromatography analyses of lipid extracts from (32)P labeled strains showed that the wild-type CL content was 15% of total phospholipids at pH 10.5 versus 3% at pH 7.5 during log phase. The % CL was higher (28-33%) at both pH values during stationary phase. The clsA gene plays a major role in CL biosynthesis as no detectable CL was found in DeltaclsA containing mutants, whereas the CL precursor phosphatidylglycerol was elevated. The DeltaclsB mutant exhibited no significant reduction in CL, but clsB expression was up-regulated and appeared to support growth at pH 7.5. In the absence of detectable CL, the alkaliphile showed no significant deficits in non fermentative growth, respiration-dependent ATP synthesis, or salt tolerance. Minor deficits in respiration and ATP synthase assembly were noted in individual mutants. In long term survival experiments, significant growth defects were found in DeltaclsA strains and the DeltaclsC strain at pH 10.5. PMID- 24338479 TI - Manipulation of cardiac phosphatidylinositol 3-kinase (PI3K)/Akt signaling by apoptosis regulator through modulating IAP expression (ARIA) regulates cardiomyocyte death during doxorubicin-induced cardiomyopathy. AB - PI3K/Akt signaling plays an important role in the regulation of cardiomyocyte death machinery, which can cause stress-induced cardiac dysfunction. Here, we report that apoptosis regulator through modulating IAP expression (ARIA), a recently identified transmembrane protein, regulates the cardiac PI3K/Akt signaling and thus modifies the progression of doxorubicin (DOX)-induced cardiomyopathy. ARIA is highly expressed in the mouse heart relative to other tissues, and it is also expressed in isolated rat cardiomyocytes. The stable expression of ARIA in H9c2 cardiac muscle cells increased the levels of membrane associated PTEN and subsequently reduced the PI3K/Akt signaling and the downstream phosphorylation of Bad, a proapoptotic BH3-only protein. When challenged with DOX, ARIA-expressing H9c2 cells exhibited enhanced apoptosis, which was reversed by the siRNA-mediated silencing of Bad. ARIA-deficient mice exhibited normal heart morphology and function. However, DOX-induced cardiac dysfunction was significantly ameliorated in conjunction with reduced cardiomyocyte death and cardiac fibrosis in ARIA-deficient mice. Phosphorylation of Akt and Bad was substantially enhanced in the heart of ARIA-deficient mice even after treatment with DOX. Moreover, repressing the PI3K by cardiomyocyte specific expression of dominant-negative PI3K (p110alpha) abolished the cardioprotective effects of ARIA deletion. Notably, targeted activation of ARIA in cardiomyocytes but not in endothelial cells reduced the cardiac PI3K/Akt signaling and exacerbated the DOX-induced cardiac dysfunction. These studies, therefore, revealed a previously undescribed mode of manipulating cardiac PI3K/Akt signaling by ARIA, thus identifying ARIA as an attractive new target for the prevention of stress-induced myocardial dysfunction. PMID- 24338480 TI - The endoplasmic reticulum coat protein II transport machinery coordinates cellular lipid secretion and cholesterol biosynthesis. AB - Triglycerides and cholesterol are essential for life in most organisms. Triglycerides serve as the principal energy storage depot and, where vascular systems exist, as a means of energy transport. Cholesterol is essential for the functional integrity of all cellular membrane systems. The endoplasmic reticulum is the site of secretory lipoprotein production and de novo cholesterol synthesis, yet little is known about how these activities are coordinated with each other or with the activity of the COPII machinery, which transports endoplasmic reticulum cargo to the Golgi. The Sar1B component of this machinery is mutated in chylomicron retention disorder, indicating that this Sar1 isoform secures delivery of dietary lipids into the circulation. However, it is not known why some patients with chylomicron retention disorder develop hepatic steatosis, despite impaired intestinal fat malabsorption, and why very severe hypocholesterolemia develops in this condition. Here, we show that Sar1B also promotes hepatic apolipoprotein (apo) B lipoprotein secretion and that this promoting activity is coordinated with the processes regulating apoB expression and the transfer of triglycerides/cholesterol moieties onto this large lipid transport protein. We also show that although Sar1A antagonizes the lipoprotein secretion-promoting activity of Sar1B, both isoforms modulate the expression of genes encoding cholesterol biosynthetic enzymes and the synthesis of cholesterol de novo. These results not only establish that Sar1B promotes the secretion of hepatic lipids but also adds regulation of cholesterol synthesis to Sar1B's repertoire of transport functions. PMID- 24338481 TI - A membrane-proximal, C-terminal alpha-helix is required for plasma membrane localization and function of the G Protein-coupled receptor (GPCR) TGR5. AB - The C terminus of G protein-coupled receptors (GPCRs) is important for G protein coupling and activation; in addition, sorting motifs have been identified in the C termini of several GPCRs that facilitate correct trafficking from the endoplasmic reticulum to the plasma membrane. The C terminus of the GPCR TGR5 lacks any known sorting motif such that other factors must determine its trafficking. Here, we investigate deletion and substitution variants of the membrane-proximal C terminus of TGR5 with respect to plasma membrane localization and function using immunofluorescence staining, flow cytometry, and luciferase assays. Peptides of the membrane-proximal C-terminal variants are subjected to molecular dynamics simulations and analyzed with respect to their secondary structure. Our results reveal that TGR5 plasma membrane localization and responsiveness to extracellular ligands is fostered by a long (>= 9 residues) alpha-helical stretch at the C terminus, whereas the presence of beta-strands or only a short alpha-helical stretch leads to retention in the endoplasmic reticulum and a loss of function. As a proof-of-principle, chimeras of TGR5 containing the membrane-proximal amino acids of the beta2 adrenergic receptor (beta2AR), the sphingosine 1-phosphate receptor-1 (S1P1), or the kappa-type opioid receptor (kappaOR) were generated. These TGR5beta2AR, TGR5S1P1, or TGR5kappaOR chimeras were correctly sorted to the plasma membrane. As the exchanged amino acids of the beta2AR, the S1P1, or the kappaOR form alpha-helices in crystal structures but lack significant sequence identity to the respective TGR5 sequence, we conclude that the secondary structure of the TGR5 membrane proximal C terminus is the determining factor for plasma membrane localization and responsiveness towards extracellular ligands. PMID- 24338482 TI - Degradation of activated K-Ras orthologue via K-Ras-specific lysine residues is required for cytokinesis. AB - Mammalian cells encode three closely related Ras proteins, H-Ras, N-Ras, and K Ras. Oncogenic K-Ras mutations frequently occur in human cancers, which lead to dysregulated cell proliferation and genomic instability. However, mechanistic role of the Ras isoform regulation have remained largely unknown. Furthermore, the dynamics and function of negative regulation of GTP-loaded K-Ras have not been fully investigated. Here, we demonstrate RasG, the Dictyostelium orthologue of K-Ras, is targeted for degradation by polyubiquitination. Both ubiquitination and degradation of RasG were strictly associated with RasG activity. High resolution tandem mass spectrometry (LC-MS/MS) analysis indicated that RasG ubiquitination occurs at C-terminal lysines equivalent to lysines found in human K-Ras but not in H-Ras and N-Ras homologues. Substitution of these lysine residues with arginines (4KR-RasG) diminished RasG ubiquitination and increased RasG protein stability. Cells expressing 4KR-RasG failed to undergo proper cytokinesis and resulted in multinucleated cells. Ectopically expressed human K Ras undergoes polyubiquitin-mediated degradation in Dictyostelium, whereas human H-Ras and a Dictyostelium H-Ras homologue (RasC) are refractory to ubiquitination. Our results indicate the existence of GTP-loaded K-Ras orthologue specific degradation system in Dictyostelium, and further identification of the responsible E3-ligase may provide a novel therapeutic approach against K-Ras mutated cancers. PMID- 24338483 TI - Activation of protein kinase PKR requires dimerization-induced cis phosphorylation within the activation loop. AB - Protein kinase R (PKR) functions in a plethora of cellular processes, including viral and cellular stress responses, by phosphorylating the translation initiation factor eIF2alpha. The minimum requirements for PKR function are homodimerization of its kinase and RNA-binding domains, and autophosphorylation at the residue Thr-446 in a flexible loop called the activation loop. We investigated the interdependence between dimerization and Thr-446 autophosphorylation using the yeast Saccharomyces cerevisiae model system. We showed that an engineered PKR that bypassed the need for Thr-446 autophosphorylation (PKR(T446~P)-bypass mutant) could function without a key residue (Asp-266 or Tyr-323) that is essential for PKR dimerization, suggesting that dimerization precedes and stimulates activation loop autophosphorylation. We also showed that the PKR(T446~P)-bypass mutant was able to phosphorylate eIF2alpha even without its RNA-binding domains. These two significant findings reveal that PKR dimerization and activation loop autophosphorylation are mutually exclusive yet interdependent processes. Also, we provide evidence that Thr-446 autophosphorylation during PKR activation occurs in a cis mechanism following dimerization. PMID- 24338484 TI - Epigallocatechin-3-gallate induces apoptosis, inhibits proliferation and decreases invasion of glioma cell. AB - Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, has been considered a potential therapeutic and chemopreventive agent for cancer. Glioma is a malignant tumor with high mortality but effective therapy has not yet been developed. In this study, we found that EGCG induced apoptosis in U251 glioma cells via the laminin receptor (molecular weight 67 kDa) in a time- and dose dependent manner, decreased their invasiveness and inhibited their proliferation. The mitogen-activated protein kinase pathway was shown to be involved in glioma cell apoptosis and proliferation. Furthermore, the mRNA levels of matrix metalloproteinase (MMP)-2 and MMP-9 were reduced after EGCG treatment. These results suggest that EGCG has important therapeutic effects with low toxicity and side-effects, and could be used in cancer chemoprevention. PMID- 24338485 TI - Prospective clinical study on digital nerve repair with collagen nerve conduits and review of literature. AB - Little data are available concerning conduit repair of digital nerve lesions. We are presenting a prospective two-center cohort study on digital nerve reconstruction with collagen nerve conduits. The data are put into the context of a comprehensive review of existing literature. Over a period of 3 years, all consecutive digital nerve lesions that could not be repaired by tensionless coaptation with a gap length of less than 26 mm were reconstructed with nerve conduits made from bovine collagen I. Sensibility was assessed 1 week, 3, 6, and 12 months postoperatively by static and moving 2-point-discrimination (2PD) and monofilament testing. Forty-nine digital nerve lesions in 40 patients met the inclusion criteria. The mean nerve gap was 12.3 +/- 2.3 mm (span 5-25 mm). Forty nerve reconstructions could be included in the 12-month follow-up. Three cases, assessed 12 months postoperatively, showed excellent sensibility (static 2PD <6 mm). Seventeen achieved good (2PD 6-10 mm), 5 fair (2PD 11-15 mm), 6 poor (2PD >15 mm, but protective sensibility), and 9 achieved no sensibility. Monofilament test results were significantly better if gap length was shorter than 12 mm. Our results confirm tubulization as one possible technique in nerve reconstruction for gap lengths of 5 to 25 mm. PMID- 24338486 TI - Reconstruction of the trachea. AB - This article reviews established methods of autologous tracheal reconstruction, the various synthetic prostheses that have been used in clinical practice, and briefly describes the latest developments in stem cell tracheal bioengineering and allogeneic tracheal transplantation. Reconstruction of the trachea is challenging due to its part cervical part thoracic location, proximity to major vessels, variable blood supply, and its constant colonization with bacteria. In cases of limited resection, primary anastomosis, autologous patch grafts, local advancement rotation flaps, and locoregional cutaneous and muscle flaps will often suffice. In more extensive resections, complex composite microsurgical reconstruction with a radial forearm free flap with cartilage grafts for skeletal support has proven to be viable and reliable. Synthetic tracheal prostheses, solid as well as porous, have been trialed with disappointing results. Infection, dislodgement, migration, and obstruction are not uncommon. Reconstruction with the cadaveric tracheal allografts and aortic allografts continue to be fraught with complications, specifically graft infections. Tracheal bioengineering and tracheal allotransplantation have emerged relatively recently. Despite early promising results, long-term outcome data on these new techniques are still lacking. PMID- 24338489 TI - Serological proteome analysis of dogs with breast cancer unveils common serum biomarkers with human counterparts. AB - Canine mammary tumor is being touted as a model for investigating the human breast cancer. Breast cancer of the both species has similar biological behavior, histopathologic characteristics, and metastatic pattern. In this study, we used the serological proteome analysis to detect autoantigens that elicit a humoral response in dogs with mammary tumor in order to identify serum biomarkers with potential usefulness as diagnostic markers and to better understand molecular mechanisms underlying canine breast cancer development. Protein extract from a cell line was subject to 2DE followed by Western blotting using sera from 15 dogs with mammary tumor and sera from 15 healthy control dogs. Immunoreactive autoantigens were subsequently identified by the MALDI-TOF MS. Four autoantigens, including manganese-superoxide dismutase, triose phosphate isomerase, alpha enolase, and phosphoglycerate mutase1, with significantly higher immunoreactivity in the tumor samples than in the normal samples were identified as biomarker candidates. Immunohistochemistry and Western blotting revealed higher expression of these biomarkers in the malignant tumors than in the normal or benign tumors. The autoantigens found in this study have been reported to elicit autoantibody response in the human breast cancer, indicating the similarity of breast cancer proteome profile in dogs with that in human beings. PMID- 24338488 TI - Noninfectious immune-mediated uveitis and ocular inflammation. AB - Noninfectious uveitis encompasses a diverse group of ocular inflammatory disorders that share an underlying immune etiology and may be associated with systemic disease or confined primarily to the eye. Uveitis is commonly classified by anatomical location of inflammation into anterior, intermediate, posterior, and panuveitis. The treatment of noninfectious uveitis consists of corticosteroids, immunosuppressive agents, and surgically placed steroid implants. We review the epidemiology, immunopathology, and clinical features of several noninfectious immune-mediated uveitides, including HLA-B27 acute anterior uveitis, juvenile idiopathic arthritis, intermediate uveitis, sarcoidosis, Behcet's disease, Vogt-Koyanagi-Harada syndrome, sympathetic ophthalmia, and white dot syndromes. We also discuss the stepwise approach to medical treatment of immune-mediated uveitis as well as the characteristics, safety, and efficacy of immunosuppressive agents used to treat ocular inflammatory disease. PMID- 24338487 TI - Role of "Western diet" in inflammatory autoimmune diseases. AB - Developed societies, although having successfully reduced the burden of infectious disease, constitute an environment where metabolic, cardiovascular, and autoimmune diseases thrive. Living in westernized countries has not fundamentally changed the genetic basis on which these diseases emerge, but has strong impact on lifestyle and pathogen exposure. In particular, nutritional patterns collectively termed the "Western diet", including high-fat and cholesterol, high-protein, high-sugar, and excess salt intake, as well as frequent consumption of processed and 'fast foods', promote obesity, metabolic syndrome, and cardiovascular disease. These factors have also gained high interest as possible promoters of autoimmune diseases. Underlying metabolic and immunologic mechanisms are currently being intensively explored. This review discusses the current knowledge relative to the association of "Western diet" with autoimmunity, and highlights the role of T cells as central players linking dietary influences to autoimmune pathology. PMID- 24338490 TI - The validity of the Dutch Eating Behavior Questionnaire: some critical remarks. AB - Recent debate has considered the validity of self-reports and laboratory-based behavioral measures of emotional eating. This paper reviews the literature on self-reported emotional eating and actual eating behavior (i.e., examines the concurrent validity). As detailed in the review, the literature suggests mixed findings on the correspondence between these self-reports and actual eating behavior. Based on this, we cite characteristics of studies that support the concurrent validity of the DEBQ and address possible reasons for the lack of concurrent validity in other studies, as well as concerns about the measurement of emotional eating in the laboratory. Two reasons for the lack of concurrent validity of self-report emotional eating scales identified in this review include (1) methodological/experimental design flaws and (2) the variability of emotional eating based on participant characteristics. We argue that further research on emotional eating needs to address factors related to self-reports of emotional eating and objective emotional eating behavior (e.g., negative affect, inaccurate recall of eating behaviors, sample differences, and laboratory design). We conclude with recommendations for future research on emotional eating. PMID- 24338491 TI - Effects of chromium propionate on egg production, egg quality, plasma biochemical parameters, and egg chromium deposition in late-phase laying hens. AB - This study was conducted to investigate the effects of chromium propionate on egg production, egg quality, plasma biochemical parameters and egg chromium deposition in late-phase laying hens. Four hundred thirty-two 60-weeks old laying hens were divided into four groups of 108 birds per group according to egg production. The dietary treatments consisted of the basal diet adding with 0, 200, 400, and 600 MUg/kg chromium as chromium propionate. All laying hens were given feed and water ad libitum for 8 weeks. The addition of 400 MUg/kg Cr as chromium propionate increased egg production (P < 0.01) during the later 4 weeks, but decreased albumen height, yolk color score, and Haugh unit of eggs. Six hundred micrograms per kilogram Cr as chromium propionate supplementation improved shell thickness (P < 0.05). 200 MUg/kg Cr as chromium propionate supplementation decreased the uric acid concentration by 31 % (P < 0.05). However, supplemental Cr did not affect the egg chromium deposition of hens (P > 0.05). These data indicated that feeding of late-phase laying hens with chromium propionate could improve egg production, increase eggshell thickness, but do not result in abnormal levels of chromium deposition in eggs. PMID- 24338492 TI - Leptin in chronic kidney disease: a link between hematopoiesis, bone metabolism, and nutrition. AB - Anemia, dyslipidemia, malnutrition, together with mineral and bone disorders are common complications in patients with chronic kidney disease (CKD). All are associated with increased risk of mortality. Leptin is a small peptide hormone that is mainly but not exclusively produced in adipose tissue. It is also secreted by normal human osteoblasts, subchondral osteoblasts, placental syncytiotrophoblasts, and the gastric epithelium. Leptin binds to its receptors in the hypothalamus to regulate bone metabolism and food intake. Leptin also has several other important metabolic effects on peripheral tissues, including the liver, skeletal muscle, and bone marrow. Leptin is cleared principally by the kidney. Not surprisingly, serum leptin appears to increase concurrently with declines in the glomerular filtration rate in patients with CKD. A growing body of evidence suggests that leptin might be closely related to hematopoiesis, nutrition, and bone metabolism in CKD patients. Results are conflicting regarding leptin in patients with CKD, in whom both beneficial and detrimental effects on uremia outcome are found. This review elucidates the discovery of leptin and its receptors, changes in serum or plasma leptin levels, the functions of leptin, relationships between leptin and the complications mentioned above, and pharmaceutical interventions in serum leptin levels in patients with CKD. PMID- 24338493 TI - Cystatin C and serum creatinine as predictors of kidney graft outcome. AB - PURPOSE: Serum cystatin C (Cys C) was evaluated as a predictor of kidney graft failure progression, and its predictive ability was compared to other markers of graft function. METHODS: The following kidney graft markers were determined in 91 patients who came for regular checkups of kidney graft function to our outpatient service in February 2008: Cys C, serum creatinine (sCr), 24-h proteinuria and 24 h urinary creatinine clearance (CCr). Glomerular filtration rate (eGFR) was estimated using sCr-based and Cys C formula. Patients were regularly monitored until February 2013 or to graft failure. RESULTS: During follow-up, graft failure occurred in 21 recipients. The Cys C >=2.65 mg/l discriminated patients with and without graft failure (sensitivity of 80.95% and specificity of 92.86%). According to c statistic, the highest performance was achieved for Cys C (0.874). In addition, Cys C area under the curve (AUC) was significantly better than CCr AUC (p = 0.007), 24-h proteinuria AUC (p = 0.03), eGFR estimated by the chronic kidney disease epidemiology collaboration (EPI) AUC (p = 0.05), but not better than sCr or eGFR AUCs calculated by other formulas. In the multivariable model, sCr, CCr, Cys C and eGFRs were predictors of graft failure. Combination of Cys C, sCr and logarithm of 24 h proteinuria (0.883) or Cys C, CCr and logarithm of 24-h proteinuria (0.884) had the highest AUC for predicting graft outcome that exceed insignificantly Cys C or sCr areas. CONCLUSIONS: The most reliable predictors of graft outcome were Cys C, sCr and proteinuria. Because Cys C is unavailable in many transplant centers, from the practical point of view, sCr remains the most sensitive predictor of graft outcome. PMID- 24338494 TI - The clinical implications of integrating additional prognostic factors into the TNM. AB - BACKGROUND AND OBJECTIVES: The management of solid tumors is governed by host and tumor factors that traditionally have incorporated TNM staging with additional pathologic, biologic, and clinical host factors. Beyond the anatomic-based TNM, increasingly new prognostic and predictive factors are being discovered that have important survival and treatment implications. However, because the TNM is based on a "bin" model, additional prognostic factors would rapidly overwhelm the current system. This communication demonstrates the clinical implications and improved patient prognosis derived from a new algorithmic model based on clustering analysis. METHODS: A new algorithm is described that integrates additional factors into the TNM and calculates survival. RESULTS: The results indicate that additional factors can be integrated into the TNM staging system providing additional patient stratification without changing the TNM definitions. Adding prognostic factors to traditional TNM staging increases substratification of given stages and identifies and separates favorable and unfavorable clinical outcomes for specific TNM stages. CONCLUSION: Integration of additional prognostic factors into the TNM by a clustering algorithm can change the stratification of patient outcome. This may guide the clinician to select a more rational management program based on the additional factors and improve cohort selection for clinical trials. PMID- 24338495 TI - The cytochrome c oxidase and its mitochondrial function in the whiteleg shrimp Litopenaeus vannamei during hypoxia. AB - Cytochrome c oxidase (COX), which is located in the inner membrane of mitochondria, is a key constituent of the electron transport chain that catalyzes the reduction of oxygen. The Pacific whiteleg shrimp Litopenaeus vannamei is constantly exposed to hypoxic conditions, which affects both the central metabolism and the mitochondrial function. The purpose of this study was to isolate shrimp mitochondria, identify the COX complex and to evaluate the effect of hypoxia on the shrimp mitochondrial function and in the COX activity. A 190 kDa protein was identified as COX by immunodetection techniques. The effect of hypoxia was confirmed by an increase in the shrimp plasma L-lactate concentration. COX activity, mitochondrial oxygen uptake and protein content were reduced under hypoxic conditions, and gradually restored as hypoxia continued, this suggests an adaptive mitochondrial response and a highly effective COX enzyme. Both mitochondrial oxygen uptake and COX activity were completely inhibited by KCN and sodium azide, suggesting that COX is the unique oxidase in L. vannamei mitochondria. PMID- 24338496 TI - Telerehabilitation services for stroke. AB - BACKGROUND: Telerehabilitation is an alternative way of delivering rehabilitation services. Information and communication technologies are used to facilitate communication between the healthcare professional and the patient in a remote location. The use of telerehabilitation is becoming more viable as the speed and sophistication of communication technologies improve. However, it is currently unclear how effective this model of delivery is relative to rehabilitation delivered face-to-face. OBJECTIVES: To determine whether the use of telerehabilitation leads to improved ability to perform activities of daily living amongst stroke survivors when compared with (1) in-person rehabilitation (when the clinician and the patient are at the same physical location and rehabilitation is provided face-to-face); or (2) no rehabilitation. Secondary objectives were to determine whether use of telerehabilitation leads to greater independence in self care and domestic life and improved mobility, health-related quality of life, upper limb function, cognitive function or functional communication when compared with in-person rehabilitation and no rehabilitation. Additionally, we aimed to report on the presence of adverse events, cost effectiveness, feasibility and levels of user satisfaction associated with telerehabilitation interventions. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (November 2012), the Cochrane Effective Practice and Organization of Care Group Trials Register (November 2012), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 11, 2012), MEDLINE (1950 to November 2012), EMBASE (1980 to November 2012) and eight additional databases. We searched trial registries, conference proceedings and reference lists. SELECTION CRITERIA: Randomised controlled trials (RCTs) of telerehabilitation in stroke. We included studies that compared telerehabilitation with in-person rehabilitation or no rehabilitation. In addition, we synthesised and described the results of RCTs that compared two different methods of delivering telerehabilitation services without an alternative group. We included rehabilitation programmes that used a combination of telerehabilitation and in-person rehabilitation provided that the greater proportion of intervention was provided via telerehabilitation. DATA COLLECTION AND ANALYSIS: Two review authors independently identified trials on the basis of prespecified inclusion criteria, extracted data and assessed risk of bias. A third review author moderated any disagreements. The review authors contacted investigators to ask for missing information. MAIN RESULTS: We included in the review 10 trials involving a total of 933 participants. The studies were generally small, and reporting quality was often inadequate, particularly in relation to blinding of outcome assessors and concealment of allocation. Selective outcome reporting was apparent in several studies. Study interventions and comparisons varied, meaning that in most cases, it was inappropriate to pool studies. Intervention approaches included upper limb training, lower limb and mobility retraining, case management and caregiver support. Most studies were conducted with people in the chronic phase following stroke. PRIMARY OUTCOME: no statistically significant results for independence in activities of daily living (based on two studies with 661 participants) were noted when a case management intervention was evaluated. SECONDARY OUTCOMES: no statistically significant results for upper limb function (based on two studies with 46 participants) were observed when a computer programme was used to remotely retrain upper limb function. Evidence was insufficient to draw conclusions on the effects of the intervention on mobility, health-related quality of life or participant satisfaction with the intervention. No studies evaluated the cost-effectiveness of telerehabilitation. No studies reported on the occurrence of adverse events within the studies. AUTHORS' CONCLUSIONS: We found insufficient evidence to reach conclusions about the effectiveness of telerehabilitation after stroke. Moreover, we were unable to find any randomised trials that included an evaluation of cost effectiveness. Which intervention approaches are most appropriately adapted to a telerehabilitation approach remain unclear, as does the best way to utilise this approach. PMID- 24338497 TI - Prognostic value of estimated glomerular filtration rate in hospitalized elderly patients. AB - A multicenter observational study, REPOSI (REgistro POliterapie Societa Italiana di Medicina Interna), was conducted to assess the prognostic value of glomerular filtration rate (eGFR) on in-hospital mortality, hospital re-admission and death within 3 months, in a sample of elderly patients (n = 1,363) admitted to 66 internal medicine and geriatric wards. Based on eGFR, calculated by the new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, subjects at hospital admission were classified into three groups: group 1 with normal eGFR (>=60 ml/min/1.73 m(2), reference group), group 2 with moderately reduced eGFR (30-59 ml/min/1.73 m(2)) and group 3 with severely reduced eGFR (<30 ml/min/1.73 m(2)). Patients with the lowest eGFR (group 3) on admission were more likely to be older, to have a greater cognitive and functional impairment and a high rate of comorbidities. Multivariable logistic regression analysis showed that severely reduced eGFR at the time of admission was associated with in-hospital mortality (OR 3.00; 95% CI 1.20-7.39, p = 0.0230), but not with re-hospitalization (OR 0.97; 95% CI 0.54-1.76, p = 0.9156) or mortality at 3 months after discharge (OR 1.93; 95% CI 0.92-4.04, p = 0.1582). On the contrary, an increased risk (OR 2.60; 95% CI 1.13-5.98, p = 0.0813) to die within 3 months after discharge was associated with decreased eGFR measured at the time of discharge. Our study demonstrates that severely reduced eGFRs in elderly patients admitted to hospital are strong predictors of the risk of dying during hospitalization, and that this measurement at the time of discharge helps to predict early death after hospitalization. PMID- 24338498 TI - Recommendations for the clinical and radiological evaluation of response to treatment in metastatic renal cell cancer. AB - The evaluation of response to treatment is a critical step for determining the effectiveness of oncology drugs. Targeted therapies such as tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are active drugs in patients with metastatic renal cell carcinoma (mRCC). However, treatment with this type of drugs may not result in significant reductions in tumor size, so standard evaluation criteria based on tumor size, such as Response Evaluation Criteria in Solid Tumors (RECIST), may be inappropriate for evaluating response to treatment in patients with mRCC. In fact, targeted therapies apparently yield low response rates that do not reflect increased disease control they may cause and, consequently, the benefit in terms of time to progression. To improve the clinical and radiological evaluation of response to treatment in patients with mRCC treated with targeted drugs, a group of 32 experts in this field have reviewed different aspects related to this issue and have put together a series of recommendations with the intention of providing guidance to clinicians on this matter. PMID- 24338499 TI - Effects of alpha-tocopherol and beta-carotene supplementation on cancer incidence and mortality: 18-year postintervention follow-up of the Alpha-tocopherol, Beta carotene Cancer Prevention Study. AB - In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study among 29,133 Finnish male smokers aged 50-69 years, daily alpha-tocopherol (50 mg) for a median of 6.1 years decreased the risk of prostate cancer, whereas beta-carotene (20 mg) increased risk of lung cancer and overall mortality. To determine the postintervention effects of alpha-tocopherol and beta-carotene, 25,563 men were followed 18 years for cancer incidence and all causes of mortality through national registers. Neither supplement had significant effects on post-trial cancer incidence. Relative risk (RR) for lung cancer (n = 2,881) was 1.04 (95% confidence interval [CI], 0.96-1.11) among beta-carotene recipients compared with nonrecipients. For prostate cancer (n = 2,321), RR was 0.97 (95% CI, 0.89-1.05) among alpha-tocopherol recipients compared with nonrecipients with the preventive effect of alpha-tocopherol continuing ~8 years postintervention. Body mass index significantly modified the effect of alpha-tocopherol on prostate cancer (p for interaction = 0.01) RR 1.00 (95% CI, 0.88-1.14) in normal-weight men, 0.87 (95% CI, 0.77-0.98) in overweight men, and 1.25 (95% CI, 1.01-1.55) in obese men. The post-trial relative mortality (based on 16,686 deaths) was 1.02 (95% CI, 0.98 1.05) for alpha-tocopherol recipients compared with nonrecipients and 1.02 (95% CI, 0.99-1.05) for beta-carotene recipients compared with nonrecipients. alpha Tocopherol decreased post-trial prostate cancer mortality (RR, 0.84; 95% CI, 0.70 0.99), whereas beta-carotene increased it (RR, 1.20; 95% CI, 1.01-1.42). In conclusion, supplementation with alpha-tocopherol and beta-carotene appeared to have no late effects on cancer incidence. The preventive effect of moderate-dose alpha-tocopherol on prostate cancer continued several years post-trial and resulted in lower prostate cancer mortality. PMID- 24338500 TI - In vitro and in vivo optimization of infrared laser treatment for injured peripheral nerves. AB - BACKGROUND AND OBJECTIVE: Repair of peripheral nerve injuries remains a major challenge in restorative medicine. Effective therapies that can be used in conjunction with surgical nerve repair to improve nerve regeneration and functional recovery are being actively investigated. It has been demonstrated by a number of peer reviewed publications that photobiomodulation (PBM) supports nerve regeneration, reinnervation of the denervated muscle, and functional recovery after peripheral nerve injury. However, a key issue in the use of PBM as a treatment for peripheral nerve injury is the lack of parameter optimization for any given wavelength. The objective of this study was to demonstrate that for a selected wavelength effective in vitro dosing parameters could be translated to effective in vivo parameters. MATERIALS AND METHODS: Comparison of infra-red (810 and 980 nm wavelengths) laser treatment parameters for injured peripheral nerves was done beginning with a series of in vitro experiments using primary human fibroblasts and primary rat cortical neurons. The primary rat cortical neurons were used for further optimization of energy density for 980 nm wavelength light using measurement of total neurite length as the bioassay. For these experiments, the parameters included a 1 W output power, power density of 10 mW/cm(2) , and energy densities of 0.01, 0.1, 0.5, 2, 10, 50, 200, 1,000, and 5,000 mJ/cm(2) . For translation of the in vitro data for use in vivo it was necessary to determine the transcutaneous penetration of 980 nm wavelength light to the level of the peroneal nerve. Two anesthetized, male White New Zealand rabbits were used for these experiments. The output power of the laser was set at 1.0 or 4.0 W. Power density measurements were taken at the surface of the skin, sub-dermally, and at the level of the nerve. Laser parameters used in the in vivo studies were calculated based on data from the in vitro studies and the light penetration measurements. For the in vivo experiments, a total of 22 White New Zealand rabbits (2.34-2.89 kg) were used. Translated dosing parameters were refined in a pilot study using a transection model of the peroneal nerve in rabbits. Output powers of 2 and 4 W were tested. For the final set of in vivo experiments, the same transection nerve injury model was used. An energy density of 10 mW/cm(2) at the level of the peroneal nerve was selected and the laser parameters were further refined. The dosing parameters used were: 1.5 W output power, 43 seconds exposure, 8 cm(2) area and a total energy of 65 J. RESULTS: In vitro, 980 nm wavelength light at 10 mW/cm(2) significantly improved neurite elongation at energy densities between 2 and 200 mJ/cm(2) . In vivo penetration of the infrared light measured in anesthetized rabbits showed that on average, 2.45% of the light applied to the skin reached the depth of the peroneal nerve. The in vivo pilot study data revealed that the 4 W parameters inhibited nerve regeneration while the 2 W parameters significantly improved axonal regrowth. For the final set of experiments, the irradiated group performed significantly better in the toe spread reflex test compared to the control group from week 7 post-injury, and the average length of motor endplates returned to uninjured levels. CONCLUSION: The results of this study demonstrate that treatment parameters can be determined initially using in vitro models and then translated to in vivo research and clinical practice. Furthermore, this study establishes that infrared light with optimized parameters promotes accelerated nerve regeneration and improved functional recovery in a surgically repaired peripheral nerve. PMID- 24338501 TI - Students' Scientific Society--how to inspire students and help them to become oncologists? A tutor's perspective. PMID- 24338502 TI - Registered nurses' thoughts on blended learning in a postgraduate course in cancer care--content analyses of web surveys and a focus group interview. AB - Purpose of the research was to describe registered nurses' (RNs) (n = 53) thoughts on the blended learning format in a 'specialist nursing programme in cancer care'. The study was conducted in autumn 2007 and 2008. A content analysis of answers to open-ended questions in a web-based questionnaire and a focus group interview were carried out. The analysis revealed that the RNs appreciated blended learning. The web lectures facilitated learning and gave RNs access to the education at any time. However, according to the RNs, knowledge is gained through interaction between RNs and teachers, and this aspect needed to be improved. The RNs also thought that the content of the seminars on campus should focus on evidence-based nursing knowledge and practical skills, not just taught as stable facts and procedures. The result from the present study could help to improve the design and content of advanced nursing courses using a blended learning format. PMID- 24338503 TI - In vitro evaluation of 9-(2-phosphonylmethoxyethyl)adenine ester analogues, a series of anti-HBV structures with improved plasma stability and liver release. AB - Chronic hepatitis B virus (HBV) infection may lead to liver cirrhosis and hepatocellular carcinoma, but few drugs are available for its treatment. Acyclic nucleoside phosphonates (ANPs) have remarkable antivirus activities but are not easily absorbed from the gastrointestinal tract and accumulate in the kidneys, resulting in nephrotoxicity. Therefore, there is a need to find effective liver site-specific prodrugs. The dipivaloyloxymethyl ester of 9-(2 phosphonylmethoxyethyl)adenine (PMEA)-adefovir dipivoxil (ADV)-is a first-line therapy drug for chronic hepatitis B with a low therapeutic index because of renal toxicity and low hepatic uptake. In this study, a series of PMEA derivatives were synthesized to enhance plasma stability and liver release. The metabolic stability of ADV (Chemical I) and its two analogues (Chemicals II and III) was evaluated in rat plasma and liver homogenate in vitro. An ion-pair reverse-phase HPLC-UV method and a hybrid ion trap and high-resolution time-of flight mass spectrometry (LC-IT-TOF-MS) were used to evaluate the degradation rate of the analogues and to identify their intermediate metabolites, respectively. Chemicals I and II were hydrolyzed by cleavage of the C-O bond to give monoesters. Sufficient enzymatic activation in the liver homogenate through a relatively simple metabolic pathway, in addition to a favorable stability profile in rat plasma, made Chemical II an optimal candidate. Next, six analogues based on the structure of Chemical II were synthesized and evaluated in plasma and liver homogenate. Compared to Chemical II, these compounds generated less active PMEA levels in rat liver homogenate. Therefore, chemical modification of Chemical II may lead to new promising PMEA derivatives with enhanced plasma stability and liver activation. PMID- 24338504 TI - Preparation of microcapsules with the evaluation of physicochemical properties and molecular interaction. AB - The objective of this study was to prepare and characterize dutasteride (a hydrophobic model drug) microcapsules using ethyl cellulose as a capsule shell polymer with different drug/polymer ratios of 1:1, 1:3, and 1:5. The microcapsules were prepared by a solvent evaporation method and the prepared microcapsules were evaluated for percent yield, percent drug content, encapsulation efficiency, particle size distribution, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) spectroscopy, powder X-ray diffraction (PXRD), and in vitro drug release studies. SEM revealed the spherical shape of all prepared microcapsules. The particle size of the microcapsules was about 95-119 MUm with good yield and encapsulation efficiency. PXRD showed different X-ray patterns compared to the drug itself suggesting possibility of crystalline form change during the process. Moreover, it confirmed that ethyl cellulose was changed to amorphous state. The physical property changes may affect the overall quality and drug release behavior. In the FT-IR studies, hydrogen bonding was observed between the drug and polymer at the molecular level. DSC data provided consistent results with the FT-IR and PXRD analyses. Drug release profiles showed the overall sustained release of drug and anomalous diffusion mechanism based on the Korsmeyer-Peppas equation. Understanding the physicochemical properties of a drug and polymer including molecular interactions may facilitate formulation of microcapsules with acceptable properties and drug release behaviors. PMID- 24338505 TI - AS1069562, the (+)-isomer of indeloxazine, exerts analgesic effects in a rat model of neuropathic pain with unique characteristics in spinal monoamine turnover. AB - AS1069562 [(R)-2-[(1H-inden-7-yloxy)methyl]morpholine monobenzenesulfonate] is the (+)-isomer of indeloxazine, which had been used clinically for the treatment of cerebrovascular diseases with multiple pharmacological actions, including serotonin (5-HT) and norepinephrine (NE) reuptake inhibition. Here we investigated the analgesic effects of AS1069562 in a rat model of chronic constriction injury (CCI)-induced neuropathic pain and the spinal monoamine turnover. These effects were compared with those of the antidepressants duloxetine and amitriptyline. AS1069562 significantly elevated extracellular 5-HT and NE levels in the rat spinal dorsal horn, although its 5-HT and NE reuptake inhibition was much weaker than that of duloxetine in vitro. In addition, AS1069562 increased the ratio of the contents of both 5-HT and NE to their metabolites in rat spinal cord, whereas duloxetine slightly increased only the ratio of the content of 5-HT to its metabolite. In CCI rats, AS1069562 and duloxetine significantly ameliorated mechanical allodynia, whereas amitriptyline did not. AS1069562 and amitriptyline significantly ameliorated thermal hyperalgesia, and duloxetine tended to ameliorate it. Furthermore, AS1069562, duloxetine, and amitriptyline significantly improved spontaneous pain-associated behavior. In a gastric emptying study, AS1069562 affected gastric emptying at the same dose that exerted analgesia in CCI rats. On the other hand, duloxetine and amitriptyline significantly reduced gastric emptying at lower doses than those that exerted analgesic effects. These results indicate that AS1069562 broadly improved various types of neuropathic pain-related behavior in CCI rats with unique characteristics in spinal monoamine turnover, suggesting that AS1069562 may have potential as a treatment option for patients with neuropathic pain, with a different profile from currently available antidepressants. PMID- 24338506 TI - Cancer incidence and mortality projections up to 2020 in Catalonia by means of Bayesian models. AB - PURPOSE: To predict the burden of cancer in Catalonia by 2020 assessing changes in demography and cancer risk during 2010-2020. METHODS/PATIENTS: Data were obtained from Tarragona and Girona cancer registries and Catalan mortality registry. Population age distribution was obtained from the Catalan Institute of Statistics. Predicted cases in Catalonia were estimated through autoregressive Bayesian age-period-cohort models. RESULTS: There will be diagnosed 26,455 incident cases among men and 18,345 among women during 2020, which means an increase of 22.5 and 24.5 % comparing with the cancer incidence figures of 2010. In men, the increase of cases (22.5 %) can be partitioned in three components: 12 % due to ageing, 8 % due to increase in population size and 2 % due to cancer risk. In women, the role of each component was 9, 8 and 8 %, respectively. The increased risk is mainly expected to be observed in tobacco-related tumours among women and in colorectal and liver cancers among men. During 2010-2020 a mortality decline is expected in both sexes. CONCLUSION: The expected increase of cancer incidence, mainly due to tobacco-related tumours in women and colorectal in men, reinforces the need to strengthen smoking prevention and the expansion of early detection of colorectal cancer in Catalonia. PMID- 24338507 TI - Neuropilin-1 is overexpressed in osteosarcoma and contributes to tumor progression and poor prognosis. AB - AIM: Neuropilin (NRP)-1, a co-receptor for vascular endothelial growth factor (VEGF), plays an important role in angiogenesis and malignant progression of many cancers. However, the involvement of NRP-1 in osteosarcoma is not completely understood. The aim of this study was to investigate the expression pattern and clinical significance of NRP-1 in human osteosarcoma. METHODS: NRP-1 mRNA and protein expression levels were detected by RT-PCR and Western blot assays, respectively, using 166 pairs of osteosarcoma and noncancerous bone tissues. Then, the association of NRP-1 expression with clinicopathological factors or survival of osteosarcoma patients was further evaluated. RESULTS: RT-PCR and Western blot assays revealed that NRP-1 expression in osteosarcoma tissues was significantly higher than that in corresponding noncancerous bone tissues at both mRNA and protein levels (both P < 0.001). In addition, high NRP-1 expression more frequently occurred in osteosarcoma tissues with advanced clinical stage (P = 0.006), positive distant metastasis (P = 0.01) and poor response to chemotherapy (P = 0.006). Moreover, osteosarcoma patients with high NRP-1 expression had significantly shorter overall survival and disease-free survival (both P < 0.001) when compared with patients with the low expression of NRP-1. On Cox multivariate analysis, NRP-1 overexpression was an independent and significant prognostic factor to predict poor overall survival and disease-free survival (both P = 0.001). CONCLUSION: This is the first study to reveal that NRP-1 overexpression may be related to the prediction of metastasis potency, response to chemotherapy and poor prognosis for osteosarcoma patients, suggesting that NRP-1 may serve as a prognostic marker for the optimization of clinical treatments. PMID- 24338508 TI - Retrospective analysis of pathological response in colorectal cancer liver metastases following treatment with bevacizumab. AB - AIMS: Pathological response has been shown to be a predictor for survival after preoperative chemotherapy and surgical resection of colorectal cancer liver metastases. This retrospective analysis evaluated the effect on pathological response of adding bevacizumab to standard neoadjuvant chemotherapy in patients with metastatic colorectal cancer (mCRC) and liver metastases. METHODS: Patient records from two Spanish centres were retrospectively examined for this analysis. Patients were included if they had stage IV mCRC with liver metastases, were unresectable or marginally resectable tumour before chemotherapy, and had oxaliplatin- or irinotecan-based chemotherapy, with or without bevacizumab, before resection. Tumour response was evaluated using response evaluation criteria in solid tumours (RECIST). Pathological response was assessed by pathologists blinded to treatment. RESULTS: Ninety-five patients were included. Good pathological responses (PR0/PR1) were observed in 37 patients (39 %). The RECIST response rate was 51 %. Only 42 % of patients with a good pathological response had a complete or partial response according to RECIST, while 57 % of those with a poor pathological response had a complete or partial response according to RECIST. RECIST response rates were similar with and without bevacizumab, although 49 % of bevacizumab-treated patients had a good pathological response versus 27 % of those receiving chemotherapy alone (chi (2) P = 0.0302). CONCLUSION: Pathological response may be a better indicator of treatment efficacy than RECIST for patients with mCRC receiving bevacizumab in the neoadjuvant setting. Adding bevacizumab to chemotherapy has the potential to increase pathological response rates. Well-designed prospective clinical studies are required to establish the efficacy and tolerability of this approach. PMID- 24338509 TI - Effects of metformin on breast cancer cell proliferation, the AMPK pathway and the cell cycle. AB - AIM: The aim of this study was to compare the effects and mechanisms of action of metformin on estrogen receptor (ER)-positive and ER-negative breast cancer cell lines. METHODS: The anti-proliferative effects of metformin, and of the direct activator of adenosine monophosphate-activated protein kinase (AMPK), A-769662, on MCF-7 (ER-positive) and MDA-MB-231 (ER-negative) breast cancer cell lines were evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, a yellow tetrazole) assays. Fluorescence-activated cell sorting was also used to examine the effect of metformin on the cell cycle. Finally, phosphorylation of the metformin target AMPK, and of its potential downstream targets including acetyl-CoA carboxylase (ACC), p53, p70-S6K and Raptor, was examined using immunoblotting. RESULTS: Metformin and A-769662 caused significant, concentration dependent suppression of cell proliferation with G1 cell cycle arrest in both MCF 7 and MDA-MB-231 cells. The proliferation suppression effect was more profound in MCF-7 cells. A concentration-dependent phosphorylation of AMPK was detected following metformin treatment, as was phosphorylation of ACC in both cell lines, but not p53, p70-S6k or Raptor. CONCLUSION: Metformin acts as a growth inhibitor in both ER-positive and ER-negative breast cancer cells in vitro, and arrests cells in G1 phase, particularly in the ER-positive MCF-7 cells. The effect is likely to be mediated by AMPK activation, in part by inhibition of fatty acid synthesis via ACC phosphorylation. PMID- 24338510 TI - Dendritic cells transfected with hepatocellular carcinoma (HCC) total RNA induce specific immune responses against HCC in vitro and in vivo. AB - BACKGROUND: Immunotherapy is an effective method for preventing metastasis and recurrence of carcinoma. Hepatocellular carcinoma (HCC) is a common malignancy with a high rate of recurrence, and has not successfully been introduced to immunotherapy. METHODS: Peripheral blood mononuclear cells were isolated from whole blood of HCC patients and stimulated to transform into dendritic cells (DCs). These DCs were then transfected with RNA extracted from HepG-2 hepatoma cells to induce expression of specific antigens. RESULTS: The transfected DCs stimulated T lymphocytes to produce cytotoxic T lymphocytes, which specifically attacked HepG-2 cells. Injection of T lymphocytes from HCC patients and transfected DCs into severe combined immunodeficiency mice limited the growth of HepG-2 tumors. CONCLUSION: A specific immune response against hepatoma can be generated in vivo by administering DCs transfected with RNA from a specific tumor. This method may have therapeutic application in humans to reduce recurrence of HCC. PMID- 24338511 TI - Interplay between cancer cells, macrophages and natural killer cells may actually decide the outcome of therapy with sorafenib. PMID- 24338512 TI - Mono and dually decorated nanoliposomes for brain targeting, in vitro and in vivo studies. AB - PURPOSE: Mono- and dual-decorated (DUAL) liposomes (LIP) were prepared, by immobilization of MAb against transferrin (TfR[OX26 or RI7217]) and/or a peptide analogue of ApoEpsilon3 (APOe) -to target low-density lipoprotein receptor(LPR)-, characterized physicochemically and investigated for BBB-targeting, in-vitro and in-vivo. METHODS: Human microvascular endothelial cells (hCMEC/D3) were used as BBB model, and brain targeting was studied by in-vivo imaging of DiR-labelled formulations (at two doses and surface ligand densities), followed by ex-vivo organ imaging. RESULTS: LIP diameter was between 100 nm and 150 nm, their stability was good and they were non-cytotoxic. LIP uptake and transport across the hCMEC/D3 cell monolayer was significantly affected by decoration with APOe or MAb, the DUAL exerting an additive effect. Intact vesicle-transcytosis was confirmed by equal transport of hydrophilic and lipophilic labels. In-vivo and ex vivo results confirmed MAb and DUAL-LIP increased brain targeting compared to non targeted PEG-LIPs, but not for APOe (also targeting ability of DUAL-LIP was not higher than MAb-LIP). The contradiction between in-vitro and in-vivo results was overruled when in-vitro studies (uptake and monolayer transport) were carried out in presence of serum proteins, revealing their important role in targeted nanoformulation performance. CONCLUSIONS: A peptide analogue of ApoEpsilon3 was found to target BBB and increase the targeting potential of TfR-MAb decorated LIP, in-vitro, but not in-vivo, indicating that different types of ligands (small peptides and antibodies) are affected differently by in-vivo applying conditions. In-vitro tests, carried out in presence of serum proteins, may be a helpful predictive "targetability" tool. PMID- 24338513 TI - The p35 and ie1 of Autographa californica multiple nucleopolyhedrovirus could rescue late gene expression of Plutella xylostella granulovirus in nonpermissive cell lines. AB - There are no stable permissive cell lines available for in vitro replication of PlxyGV. In this study, several PlxyGV bacmids containing egfp and plasmids expressing the luciferase gene (luc) were constructed and used to transfect insect cell lines from Plutella xylostella, Trichoplusia ni (Hi5), and Spodoptera frugiperda. Fluorescence was observed only in the cells transfected with a bacmid with egfp driven by a PlxyGV ie1 promoter, but not by a PlxyGV vp39 or granulin promoter. In transient assays, various levels of LUC activity were detected in the cells transfected with individual reporter plasmids containing the luc driven by the promoters of PlxyGV early genes ie1, exon0, dnapol, lef1, lef9, and orf105, suggesting that the PlxyGV early genes could be activated in the cells independent of virus infection. The addition of a PlxyGV bacmid in the transfections activated luc expression from the promoters of PlxyGV late genes vp39 and granulin only at minimum levels, and caused significant reduction in luc expression from the early promoters, may be due to apoptosis triggered by the PlxyGV bacmid. PlxyGV reporter bacmids containing Autographa californica multiple nucleopolyhedrovirus (AcMNPV) genes p35 or p35 and ie1 or p35, ie1 and gp64 expressed LUC from a PlxyGV vp39 promoter at levels of 2.6, 8.3, and 23 times higher than those produced by the basic PlxyGV reporter bacmid, respectively, in transfected Hi5 cells. Green fluorescence was present in the cultures of all three cell lines transfected by a PlxyGV bacmid containing egfp with a vp39 promoter and AcMNPV ie1, p35, and gp64 with their native promoters. The fluorescence was also observed in the culture of Hi5 cells inoculated with the supernatant from the transfection. These results suggest that AcMNPV p35 could rescue late gene expression, and the ie1, p35, and gp64 may cooperatively rescue replication of PlxyGV in the cells. PMID- 24338514 TI - The evaluation of physiological and biochemical parameters and the autonomic nervous systems of children with breath-holding spells. AB - AIM: The aim of this study was to investigate the physiological and biochemical parameters of children who are experiencing breath-holding spells (BHS) and to compare the function of their autonomic nervous systems with those of healthy children. PATIENTS AND METHODS: A total of 30 children (age range, 6 months-5 years) admitted for BHS were included in the study. The control group consisted of 30 age-matched and gender-matched healthy children. Each participant underwent a detailed physical examination as well as a laboratory evaluation. Echocardiography, electrocardiography (ECG), and electroencephalography were performed in the study group. The pilocarpine eye test was administered to each participant to detect autonomic dysfunction. RESULTS: No statistically significant differences were found between the groups for mean age, gender, and anthropometric measurements, nor for the biochemical parameters, including hemoglobin concentration, hematocrit, serum iron, transferrin saturation, ferritin, vitamin D, and vitamin B12 levels (p = 0.05). Compared with the control group, the study group showed significantly abnormal hypersensitivity of pupils after instillation of pilocarpine into their eyes (p = 0.01). CONCLUSION: Autonomic dysfunction existed in the children with BHS, but no correlation was found between BHS and deficiencies of iron, vitamin D, or vitamin B12. PMID- 24338515 TI - Temporal resolvability analysis of macroscopic morphological development in neonatal cerebral magnetic resonance images. AB - OBJECTIVES: Reliable gradation of neonatal brain development is important for clinical investigation of neurological disorders. A prerequisite for such quantification of development is knowledge about temporal resolvability. METHODS: We hypothesized 2-week interval as the temporal resolvability of age-related templates to study macroscopic morphological brain development in the early weeks after birth. Therefore, we constructed two templates for the gestational age (GA) ranges of 39 to 40 and 41 to 42 weeks using T1-weighted magnetic resonance (MR) images. Then, we compared the spatial variation of anatomical landmarks and the average and the maximal length of spatial deformation in 30 subjects normalized to the two templates along x, y, and z directions. RESULTS: Multivariate analysis of variance (MANOVA) revealed significant difference between spatial variations of the above macroscopic features in the two age ranges. Furthermore, quantitative analysis of feature scattering yielded the same result even in features for which the null hypothesis was not rejected by MANOVA. Moreover, the same procedure was reiterated on two sets of subjects with the closer age range of 1 week (40 and 41 week's GA) and no significant difference could be detected. CONCLUSIONS: The results strengthen the hypothesis that 2-week is the temporal resolvability of age-related templates for macroscopic morphological studies of the developing brain in the early weeks after birth. PMID- 24338516 TI - Fulminant encephalopathy with marked brain edema and bilateral thalamic lesions. AB - We encountered two children with acute encephalopathy associated with unique clinical manifestations. Both the patients had status epilepticus at onset and neuroimaging studies revealed marked brain edema and bilateral thalamic lesions. Although they were treated with steroids and immunoglobulin, their outcomes were very poor. A thermolabile variant of carnitine palmitoyltransferase II and an elevated interleukin-6 level in cerebrospinal fluid were observed in one patient each. The constellation of clinical and neuroimaging findings in our patients is apparently not consistent with any established subtype of acute encephalopathy/encephalitis. PMID- 24338518 TI - New brain reperfusion rehabilitation therapy improves cognitive impairment in mild Alzheimer's disease: a prospective, controlled, open-label 12-month study with NIRS correlates. AB - BACKGROUND AND AIMS: A large body of evidence indicates that cerebral hypoperfusion is one of the earliest signs in the development of Alzheimer's disease (AD). The aim of our study was to evaluate whether the brain reperfusion rehabilitation therapy (BRRT) would improve verbal memory and learning and/or global cognitive impairment in mild AD. METHODS: Using a prospective, controlled, open-label 12-month study, we enrolled 15 patients with mild AD, who underwent BRRT program (BRRT group), and 10 age-sex-matched mild AD patients, who received no treatment (control group). At baseline (T0), and at the end of the 3 months (T3), 6 months (T6) and 12 months (T12) participants from both groups were given an evaluation, using Mini-Mental State Examination (MMSE) and Rey Auditory Verbal Learning Test (RAVLT). In both groups by using near-infrared spectroscopy, at T0 and T12, we measured tissue oxygen saturation (TOI) on temporal-parietal and frontal cortex of both sides. RESULTS: Ten patients from the BRRT group and 10 from the control group completed the 12-month follow-up. At the end of rehabilitation protocol, a significant improvement of MMSE and RAVLT was observed in the BRRT group as compared to control group. At T12 compared to T0, a significant improvement of TOI on frontal cortex of both sides was observed in the BRRT group as compared to control group. CONCLUSION: BRRT improves verbal memory-learning and global cognitive impairment which are associated with increased TOI values on frontal cortex of both sides. PMID- 24338517 TI - The "New Deadly Quartet" for cardiovascular disease in the 21st century: obesity, metabolic syndrome, inflammation and climate change: how does statin therapy fit into this equation? AB - Despite population-based improvements in cardiovascular risk factors, such as blood pressure, cholesterol and smoking, cardiovascular disease still remains the number-one cause of mortality in the United States. In 1989, Kaplan coined the term "Deadly Quartet" to represent a combination of risk factors that included upper body obesity, glucose intolerance, hypertriglyceridemia and hypertension [Kaplan in Arch Int Med 7:1514-1520, 1989]. In 2002, the third report of the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP III) essentially added low HDL-C criteria and renamed this the "metabolic syndrome." [The National Cholesterol Education Program (NCEP) in JAMA 285:2486-2497, 2001] However, often forgotten was that a pro-inflammatory state and pro-thrombotic state were also considered components of the syndrome, albeit the panel did not find enough evidence at the time to recommend routine screening for these risk factors [The National Cholesterol Education Program (NCEP) in JAMA 285:2486-2497, 2001]. Now over a decade later, it may be time to reconsider this deadly quartet by reevaluating the roles of obesity and subclinical inflammation as they relate to the metabolic syndrome. To complete this new quartet, the addition of increased exposure to elevated levels of particulate matter in the atmosphere may help elucidate why this cardiovascular pandemic continues, despite our concerted efforts. In this article, we will summarize the evidence, focusing on how statin therapy may further impact this new version of the "deadly quartet". PMID- 24338521 TI - Biopsychosocial factors associated with pain in veterans with the hepatitis C virus. AB - Little research has examined etiological factors associated with pain in patients with the hepatitis C virus (HCV). The purpose of this study was to evaluate the relationship between biopsychosocial factors and pain among patients with HCV. Patients with HCV and pain (n = 119) completed self-report measures of pain, mental health functioning, pain-specific psychosocial variables (pain catastrophizing, self-efficacy for managing pain, social support), prescription opioid use, and demographic characteristics. In multivariate models, biopsychosocial factors accounted for 37% of the variance in pain severity and 56% of the variance in pain interference. In adjusted models, factors associated with pain severity include pain catastrophizing and social support, whereas variables associated with pain interference were age, pain intensity, prescription opioid use, and chronic pain self-efficacy (all p values <0.05). The results provide empirical support for incorporating the biopsychosocial model in evaluating and treating chronic pain in patients with HCV. PMID- 24338522 TI - "My doctor has changed my pills without telling me": impact of generic medication switches in stroke survivors. AB - Generic (i.e. non-branded medicine) and therapeutic (i.e. a less expensive drug from the same class) substitution of medication provides considerable financial savings, but may negatively impact on patients. We report secondary qualitative/quantitative analysis of stroke survivors from a pilot randomised controlled brief intervention to increase adherence to medication. Patients' experiences of medication changes were examined in conjunction with electronically-recorded medication adherence. Twenty-eight patients reported frequent medication changes (e.g. size/shape/colour/packaging) and two-thirds of these reported negative effects, resulting in, at least, confusion and, at worst, mistakes in medication-taking. Patients reporting a direct effect on their medication-taking (n = 6) demonstrated poorer objectively-measured adherence (i.e. % doses taken on schedule) than those reporting confusion [mean difference = 19.9, 95% CI (2.0, 37.8)] or no problems [mean difference = 20.6, 95% CI (1.6, 40.0)]. Changes to medication resulting from switching between generic brands can be associated with notable problems, including poorer medication adherence, for a significant minority. PMID- 24338523 TI - Investigation of cell free BIRC5 mRNA as a serum diagnostic and prognostic biomarker for colorectal cancer. AB - BACKGROUND: BIRC5 (Survivin), a key member of inhibitor of apoptosis family, has been shown in colorectal cancer (CRC) tumorigenesis and progress. This study investigated the expression levels of cell free BIRC5 mRNA in serum of CRC and assess its diagnostic and prognostic potential. METHODS: Levels of cell free BIRC5 mRNA were detected by reverse transcription quantitative real-time PCR in serum of 92 CRC patients and 60 healthy volunteers. RESULTS: Cell free BIRC5 mRNA levels were significantly increased in serum of CRC (P < 0.001), and significantly correlated with tumor differentiation (P = 0.035), regional lymph node metastasis (P < 0.001) and TNM stage (P < 0.001). ROC curve demonstrated an optimal cut-off value of 0.128, providing a sensitivity of 84.8% and a specificity of 80.0% for discriminating CRC from controls. The area under the ROC curve for BIRC5 mRNA was significantly larger than that for CEA (0.855 vs. 0.691, P < 0.001). Furthermore, a significantly higher diagnosis capability was showed when combined BIRC5 mRNA and CEA. High serum BIRC5 mRNA expression has a lower OS, compared with low group (36.4% vs. 73.3%, P = 0.022), and was an independent prognostic factor for CRC. CONCLUSION: Serum cell free BIRC5 mRNA is a promising non-invasive biomarker for diagnosis and prognosis of CRC. PMID- 24338524 TI - The Lund concept for severe traumatic brain injury. AB - BACKGROUND: Severe traumatic brain injury is a significant cause of morbidity and mortality. Treatment strategies in management of such injuries are directed to the prevention of secondary brain ischaemia, as a consequence of disturbed post traumatic cerebral blood flow. They are usually concerned with avoiding high intracranial pressure (ICP) or adequate cerebral perfusion pressure (CPP). An alternative to this conventional treatment is the Lund concept, which emphasises a reduction in microvascular pressures. OBJECTIVES: To assess the role of the Lund concept versus other treatment modalities such as ICP-targeted therapy, CPP targeted therapy or other possible treatment strategies in the management of severe traumatic brain injury. SEARCH METHODS: We searched the Cochrane Injuries Group's Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL; Issue 10, 2013), MEDLINE (OvidSP), EMBASE (OvidSP), CINAHL Plus (EBSCO Host), ISI Web of Science (SCI-EXPANDED and CPCI-S) and trials registries. We searched the reference lists of relevant studies and published reviews found with our search. The most recent search was 5 November 2013. SELECTION CRITERIA: Randomised controlled trials (RCTs, level 1 evidence) exploring the efficacy of the Lund concept in the treatment of traumatic brain injury. DATA COLLECTION AND ANALYSIS: Two review authors independently selected papers and made decisions about the eligibility of potentially relevant studies. MAIN RESULTS: We found no studies that met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: There is no evidence that the Lund concept is a preferable treatment option in the management of severe traumatic brain injury. PMID- 24338526 TI - Modelling the effect of gap junctions on tissue-level cardiac electrophysiology. AB - When modelling tissue-level cardiac electrophysiology, a continuum approximation to the discrete cell-level equations, known as the bidomain equations, is often used to maintain computational tractability. Analysing the derivation of the bidomain equations allows us to investigate how microstructure, in particular gap junctions that electrically connect cells, affect tissue-level conductivity properties. Using a one-dimensional cable model, we derive a modified form of the bidomain equations that take gap junctions into account, and compare results of simulations using both the discrete and continuum models, finding that the underlying conduction velocity of the action potential ceases to match up between models when gap junctions are introduced at physiologically realistic coupling levels. We show that this effect is magnified by: (i) modelling gap junctions with reduced conductivity; (ii) increasing the conductance of the fast sodium channel; and (iii) an increase in myocyte length. From this, we conclude that the conduction velocity arising from the bidomain equations may not be an accurate representation of the underlying discrete system. In particular, the bidomain equations are less likely to be valid when modelling certain diseased states whose symptoms include a reduction in gap junction coupling or an increase in myocyte length. PMID- 24338525 TI - Conjugated linoleic Acid prevents ovariectomy-induced bone loss in mice by modulating both osteoclastogenesis and osteoblastogenesis. AB - Postmenopausal osteoporosis due to estrogen deficiency is associated with severe morbidity and mortality. Beneficial effects of conjugated linoleic acid (CLA) on bone mineral density (BMD) have been reported in mice, rats and humans, but the effect of long term CLA supplementation against ovariectomy-induced bone loss in mice and the mechanisms underlying this effect have not been studied yet. Eight week old ovariectomized (Ovx) and sham operated C57BL/6 mice were fed either a diet containing 0.5 % safflower oil (SFO) or 0.5 % CLA for 24 weeks to examine BMD, bone turn over markers and osteotropic factors. Bone marrow (BM) cells were cultured to determine the effect on inflammation, osteoclastogenesis, and osteoblastogenesis. SFO/Ovx mice had significantly lower femoral, tibial and lumbar BMD compared to SFO/Sham mice; whereas, no difference was found between CLA/Ovx and CLA/Sham mice. CLA inhibited bone resorption markers whereas enhanced bone formation markers in Ovx mice as compared to SFO-fed mice. Reverse transcriptase polymerase chain reaction and fluorescence activated cell sorting analyses of splenocytes revealed that CLA inhibited pro-osteoclastogenic receptor activator of NF-kappaB (RANKL) and stimulated decoy receptor of RANKL, osteoprotegerin expression. CLA also inhibited pro-inflammatory cytokine and enhanced anti-inflammatory cytokine production of lipopolysaccharide-stimulated splenocytes and BM cells. Furthermore, CLA inhibited osteoclast differentiation in BM and stimulated osteoblast differentiation in BM stromal cells as confirmed by tartrate resistant acid phosphatase and Alizarin Red staining, respectively. In conclusion, CLA may prevent postmenopausal bone loss not only by inhibiting excessive bone resorption due to estrogen deficiency but also by stimulating new bone formation. CLA might be a potential alternative therapy against osteoporotic bone loss. PMID- 24338527 TI - Hispidulin exerts anti-osteoporotic activity in ovariectomized mice via activating AMPK signaling pathway. AB - To investigate the effect of Hispidulin on ovariectomy (OVX)-induced bone loss in mice. Female mice subjected to OVX were treated with Hispidulin for 8 weeks. The total body bone mineral density was measured at the beginning and after the OVX at a time interval of 4 weeks. Micro-computed tomography of the tibia, bone histomorphometric analysis of the femur, and biomechanical analysis of tibia, vertebra, and femoral head were performed to fully evaluate the anti-osteoporotic effect of Hispidulin. Western blot analysis was performed to determine the level of activated AMPK. Hispidulin treatment effectively prevented OVX-induced body weight loss and attenuated OVX-induced bone loss. Hispidulin treatment also decreased trabecular spacing in OVX mice. The suppressing effect of Hispidulin on osteoclast surface and number was also found via histomorphometric analysis. Western blot analysis revealed that Hispidulin significantly elevated the activated AMPK levels. Our findings suggest that Hispidulin exerts anti osteoporotic and bone resorption attenuating effects via activating the AMPK signaling pathway. PMID- 24338529 TI - A slippery directional slope: Individual differences in using slope as a directional cue. AB - Navigators rely on many different types of cues to build representations of large scale spaces. Sloped terrain is an important cue that has received recent attention in comparative and human spatial research. However, the studies to date have been unable to determine how directional slope information leads to more accurate spatial representations. Moreover, whereas some studies have shown that the inclusion of slope cues improves performance on spatial tasks across participants (Kelly, 2011; Restat, Steck, Mochnatzki, & Mallot, 2004), other research has suggested individual differences in the benefits of slope cues (Chai & Jacobs, 2010; Nardi, Newcombe, & Shipley, 2011). We sought to clarify the role of sloped terrain in improving the representation of large-scale environments. In Experiment 1, participants learned the layout of buildings in one of two desktop virtual environments: either a directionally sloped terrain or a completely flat one. Participants in the sloped environment outperformed those in the flat environment. However, participants used slope information as an additional cue, rather than as a preferred reference direction. In Experiment 2, the two virtual environments were again either flat or sloped, but we increased the complexity of the relations between the slope and the path. In this experiment, better performance in the sloped environment was only seen for participants with good self-reported senses of direction. Taken together, the studies show that slope provides useful information for building environmental representations in simple cases, but that individual differences emerge in more complex situations. We suggest that good and bad navigators use different navigational strategies. PMID- 24338528 TI - Lyn regulates inflammatory responses in Klebsiella pneumoniae infection via the p38/NF-kappaB pathway. AB - Klebsiella pneumoniae (Kp) is one of the most common pathogens in nosocomial infections and is becoming increasingly multidrug resistant. However, the underlying molecular pathogenesis of this bacterium remains elusive, limiting the therapeutic options. Understanding the mechanism of its pathogenesis may facilitate the development of anti-bacterial therapeutics. Here, we show that Lyn, a pleiotropic Src tyrosine kinase, is involved in host defense against Kp by regulating phagocytosis process and simultaneously downregulating inflammatory responses. Using acute infection mouse models, we observed that lyn(-/-) mice were more susceptible to Kp with increased mortality and severe lung injury compared with WT mice. Kp infected-lyn(-/-) mice exhibited elevated inflammatory cytokines (IL-6 and TNF-alpha), and increased superoxide in the lung and other organs. In addition, the phosphorylation of p38 and NF-kappaB p65 subunit increased markedly in response to Kp infection in lyn(-/-) mice. We also demonstrated that the translocation of p65 from cytoplasm to nuclei increased in cultured murine lung epithelial cells by Lyn siRNA knockdown. Furthermore, lipid rafts clustered with activated Lyn and accumulated in the site of Kp invasion. Taken together, these findings revealed that Lyn may participate in host defense against Kp infection through the negative modulation of inflammatory cytokines. PMID- 24338530 TI - In silico study on indole derivatives as anti HIV-1 agents: a combined docking, molecular dynamics and 3D-QSAR study. AB - The HIV-1 envelope glycoprotein gp120 plays a vital role in the entry of virus into the host cells and is a potential antiviral drug target. Recently, indole derivatives have been reported to inhibit HIV-1 through binding to gp120, and this prevents gp120 and CD4 interaction to inhibit the infectivity of HIV-1. In this work, molecular docking, molecular dynamics (MD) and three-dimensional quantitative structure-activity relationship studies were carried out. Molecular docking studies of the most active and the least active compounds were performed to identify important residues in the binding pocket. We refined the docked poses by MD simulations which resulted in conformational changes. After equilibration, the structure of the ligand and receptor complex was stable. Therefore, we just took the last snapshot as the representative binding pose for this study. This pose for the most active inhibitor was used as a template for receptor-based alignment which was subsequently used for comparative molecular field analysis. Resultant 3D contour maps suggested smaller substituents are desirable at the 7 position of indole ring to avoid steric interactions with Ser375, Phe382 and Tyr384 residues in the active site. These results can be exploited to develop potential leads and for structure-based drug design of novel HIV-1 inhibitors. PMID- 24338531 TI - Simultaneous analysis of reduced glutathione and glutathione disulfide by capillary zone electrophoresis. AB - This report describes modifications to a CZE method developed by Serru et al. (Clinical Chemistry 2001, 47, 1321-1324) for the simultaneous analysis of reduced glutathione (GSH) and glutathione disulfide (GSSG). Lowering the pH of the run buffer (75 mmol/L boric acid, 25 mmol/L bis-Tris) from pH 8.4 to 7.8 markedly improved GSH peak area reproducibility and allowed multiple samples to be analyzed without changing run buffers due to ion depletion. Sample preparation using red blood cells (RBC) instead of whole blood, combined with glutathione extraction at a lower concentration of metaphosphoric acid (5%), increased assay sensitivity and decreased interference. CZE assay results for clinical samples containing 1000 to 3200 MUmol GSH/L RBC and 100 to 400 MUmol GSSG/L RBC were highly correlated (r(2) >= 0.95) with results obtained using a commercial dithionitrobenze-based glutathione assay. The modified CZE assay has proven useful for the analysis of glutathione in both mouse and human RBC. PMID- 24338532 TI - Autoimmune diseases, their pharmacological treatment and the cardiovascular system. AB - Cardiovascular system involvement is a frequent complication of autoimmune diseases (AD) such as systemic lupus erythematosus, scleroderma, rheumatoid arthritis, spondyloarthropaties or psoriatic arthritis. The most common forms of such involvement are pericarditis, myocarditis, accelerated atherosclerosis resulting in myocardial infarction or stroke, arrhythmias, conduction abnormalities or congestive heart failure. Some of these manifestations may be dramatic in their course and ultimately fatal. The treatment of AD may further affect the cardiovascular system and result in a lower quality of life, higher mortality and increased cost of healthcare. The aim of this review is to discuss possible cardiac complications of various AD and the related treatment of these diseases. PMID- 24338533 TI - The association between galectin-3 and clinical parameters in patients with first acute myocardial infarction treated with primary percutaneous coronary angioplasty. AB - BACKGROUND: Galectin-3, a biomarker associated with fibrosis and inflammation, has been implicated in development and progression of heart failure (HF) and predicts increased mortality and morbidity in this condition. HF frequently develops after myocardial infarction (MI), contributing to worse outcome. The aim of this study is to assess the association between galectin-3 levels and various clinical parameters in acute phase of first MI treated with primary percutaneous coronary intervention (pPCI) in patients without prior HF. METHODS: We included 145 consecutive patients with first acute MI treated with pPCI with stent implantation. Exclusion criteria were: prior HF, severe valvular diseases, coexisting cancers, connective tissue diseases and cirrhosis. Serum galectin-3 concentration was measured within 3-5 days after onset of acute MI. RESULTS: Thirty-six patients with the highest galectin-3 levels (4th quartile, > 16 ng/mL) were compared to 109 subjects with a biomarker concentration <= 16 ng/mL. Elevated galectin-3 levels were more often observed in females, the elderly, subjects with coexisting diabetes, renaldysfunction and permanent atrial fi brillation (AF). Galectin-3 correlated with N-terminal pro-B-type natriuretic peptide (r = 0.27, p < 0.001) and high-sensitivity C-reactive protein (r = 0.20, p < 0.05). Multivariate analysis revealed that only new-onset AF and diuretics treatment during hospitalization were independently associated with galectin-3 levels > 16 ng/mL. CONCLUSIONS: Elevated galectin-3 levels were associated with a higher rate of new-onset AF and diuretics treatment during hospitalization in patients with first MI treated with pPCI without prior HF. PMID- 24338534 TI - Cytokeratin 8 in venous grafts: a factor of unfavorable long-term prognosis in coronary artery bypass grafting patients. AB - BACKGROUND: Smooth muscle cells, present in the saphenous vein (SV) tunica media, may contribute to late occlusion of venous aortocoronary grafts. The aim of present study was to evaluate expression of selected cytoskeletal proteins in tunica media of SV grafts obtained from patients undergoing coronary artery bypass grafting (CABG) and correlate procured results to late venous graft failure observed in these patients. METHODS: The study involved 218 patients (mean age of 62.5 +/- 8.7 years) who underwent primary isolated CABG with the use of at least one venous aortocoronary bypass graft. Expressions of alpha-smooth muscle actin, smooth muscle-myosin heavy chain, calponin and cytokeratin 8 in SV wall were estimated by means of immunohistochemistry. The primary clinical endpoint was defined as the presence of any coronary artery disease (CAD) progression symptom while angiographic one as significant stenosis in the venous graft. RESULTS: Thirty-eight (18.1%) patients have reached the primary clinical endpoint. Freedom from clinical CAD deterioration was 0.95 +/- 0.02, 0.87 +/- 0.03 and 0.83 +/- 0.04, for 12-, 24-,36-month follow-up, respectively. Forty-four study participants have reached the angiographic endpoint. Multivariate logistic regression analysis revealed an increased expression of cytokeratin 8 accompanied by calponin under expression in SV tunica media were independent risk factors for venous graft failure. CONCLUSIONS: An increased expression of cytokeratin 8 and weak of calponin in tunica media of SV grafts might be useful markers of unfavorable long-term prognosis in CABG patients. In the future, assessment of their expression may enable to select the most appropriate candidates for SV grafts. PMID- 24338535 TI - Early detection of anthracycline-induced cardiotoxicity using two-dimensional speckle tracking echocardiography. AB - BACKGROUND: To examine the subclinical myocardial injury shortly after epirubicin exposure in asymptomatic patients with large B-cell non-Hodgkin lymphoma using 2 dimensional (2D) speckle tracking echocardiography. METHODS: Sixty-seven patients aged 52.58 +/- 13.86 years with large B-cell non-Hodgkin lymphoma treated with epirubicin were studied. Echocardiography was performed at baseline and 1 day after completion of the therapy. Global and regional longitudinal (LS), circumferential (CS) and radial strain (RS), standard deviation of time to peak LS (TLS-SD), CS (TCS-SD), RS(TRS-SD) were calculated using 2D speckle tracking echocardiography. RESULTS: Despite normal left ventricular ejection fraction, global LS (-18.30 +/- 1.87% vs.-16.18 +/- 1.92%; p < 0.01), CS (-20.37 +/- 2.89% vs. -18.25 +/- 2.40%, p < 0.01) and RS (39.95 +/- 5.79% vs. 36.15 +/- 5.79%, p < 0.01), were remarkably reduced compared to baseline values. However, TLS-SD, TCS SD and TRS-SD showed no significant difference after epirubicin exposure. Hypertension was an independent predictor of reduction of global LS, CS and RS. CONCLUSIONS: Subtle abnormalities in myocardial systolic function were present in asymptomatic patients shortly after anthracycline exposure, which could be detected by 2D speckle tracking echocardiography. PMID- 24338536 TI - Exendin-4 attenuates myocardial ischemia and reperfusion injury by inhibiting high mobility group box 1 protein expression. AB - BACKGROUND: High mobility group box 1 protein (HMGB1) plays an important role in myocardial ischemia and reperfusion (I/R) injury. Exendin-4 (Ex-4), glucagon-like peptide-1 receptor agonist, has been reported to attenuate myocardial I/R injury. This study was to investigate the potential mechanism by which Ex-4 attenuates myocardial I/R injury in rats. METHODS: Anesthetized male rats were once treated with Ex-4 (5 MUg/kg, i.v.) 1 h before ischemiain the absence and/or presence of exendin (9-39) (an antagonist for glucagon-like peptide-1 receptor, 5 MUg/kg, i.v.), and then subjected to ischemia for 30 min followed by reperfusion for 4 h. Lactate dehydrogenase (LDH), creatine kinase (CK), malondialdehyde (MDA), superoxide dismutase (SOD) activity and infarct size were measured. HMGB1 expression was assessed by immunoblotting. RESULTS: The results showed that pretreatment of Ex-4 could significantly decrease the infarct size and the levels of LDH and CK after 4 h reperfusion (all p < 0.05). Ex-4 could also significantly inhibit the increase of the MDA level, the decrease of the SOD level (both p < 0.05). Meanwhile, Ex-4 could significantly inhibit HMGB1 expression induced by I/R. Administration of exendin (9-39) could abolish the protective effect of Ex-4 (all p < 0.05). CONCLUSIONS: The present study suggested that Ex-4 could attenuate myocardial I/R injury which may be associated with inhibiting HMGB1 expression. PMID- 24338537 TI - Associations of fractional pulse pressure to aortic stiffness and their impact on diastolic function and coronary flow reserve in asymptomatic diabetic patients with normal coronary angiography. AB - BACKGROUND: We aimed to assess the relation of fractional pulse pressure (PPf) to aortic stiffness index and their impact on coronary flow reserve (CFR) and left ventricular diastolic function in asymptomatic diabetic patients. METHODS: One hundred and thirty five consecutive asymptomatic diabetic patients (aged 48.8 +/- 7.84 years), were included. CFR was calculated noninvasively using transthoracic echo-Doppler assessment with hyperemia induced by infusion of dipyridamole at a rate of 0.56 mg/kg over 4 min. PPf was calculated as pulse pressure divided by mean arterial pressure (SBP - DBP/MAP), while diastolic function was evaluated by means of transmitral flow and tissue Doppler imaging. Aortic stiffness indices (ASI) were measured as previously described. RESULTS: Diabetic patients with low CFR (n = 52) compared with those with normal CFR (n = 83) exhibited significantly increased PPf (75.2 +/- 11.4 vs. 64.5 +/- 6.7, p < 0.001). PPf was significantly correlated with ASI (r = 0.520, p < 0.001), E/Em ratio (r = 0.425,p < 0.001) and left atrial volume index (r = 0.462, p < 0.001). CFR was negatively correlated with both PPf (r = -0.68, p < 0.0001). After applying multivariate linear regression analysis,after correction for cardiovascular risk factors, importantly, PPf and ASI remained significant predictors of CFR (p < 0.0001 and p < 0.001, respectively). CONCLUSIONS: PPf was significantly correlated to ASI in asymptomatic diabetic patients. Likewise, increased PPf was associated with impaired CFR and subclinical diastolic dysfunction in diabetic patients. PPf could be utilized as a simple non-invasive predictor of occult atherosclerosis and diastolic dysfunction in diabetic patients. PMID- 24338538 TI - Mechanical ventilation in the early phase of ST elevation myocardial infarction treated with mechanical revascularization. AB - BACKGROUND: So far, few data have been available on the incidence and outcome of patients with acute myocardial infarction (MI) requiring mechanical ventilation (MV). The aim of the study was to assess the clinical and prognostic impact of MV at short and long term in 106 patients with ST elevation MI (STEMI) requiring mechanical ventilation. RESULTS: The incidence of mechanical ventilation was 7.6%. Reasons for intubation were as follows: cardiogenic shock in 64 (60.4%) patients, ventricular fibrillation in 32 (30.1%) patients and acute pulmonary edema in 10 (9.5%) patients. Patients submitted to MV were older (p = 0.016), more frequently had a previous percutaneous coronary intervention (PCI;p = 0.014) and a previous MI (p = 0.001). A higher in-Intensive Cardiac Care Unit death was observed in MV patients (44.3% vs. 1.5%, p < 0.001), as well as a higher mortality at follow-up (36.7% vs. 14.8%, p < 0.001). MV was associated with higher mortality rates both at short and long term. CONCLUSIONS: In a large series of consecutive STEMI patients submitted to MV, the need of MV is a strong prognostic indicator of mortality both at short and long term. Among mechanically ventilated STEMI patients infarct size (as inferred by TnI values) and PCI failure were independent predictors of early death, while the duration of MV was related to death at longterm. PMID- 24338539 TI - Efficacy of multi-electrode duty-cycled radiofrequency ablation in patients with paroxysmal and persistent atrial fibrillation. AB - BACKGROUND: Radiofrequency (RF) catheter ablation is a first-line therapy for patients withdrug-refractory atrial fibrillation (AF). Complete isolation of electrical potentials at the ostium of pulmonary vein (PV) is a challenging procedure. There are different techniques and devicesused for PV isolation (PVI). The objective of this study was to evaluate the efficacy and safety of PV ablation catheter (PVAC). METHODS: A total of 67 consecutive patients with paroxysmal and persistent AF were treated with the PVAC. The patients' information were obtained from clinical charts. Follow-up was obtained by one day Holter monitoring at 2, 4, 6, 8, 10 and 12 months after ablation and ECG registration if any symptoms or arrhythmia occurred. RESULTS: The median follow up duration was 16 months (IQR: 12-20 months). In the population which was available at follow-up (n = 60), 22 (36.7%) patients were in sustained sinus rhythm (SR) without anti-arrhythmic drugs (AAD). Overall 26 (43.3%) patients were in sustained SR with and without AAD. In the paroxysmal AF group, after a single PVAC ablation procedure (n = 39), 19 (48.7%) patients had sustained SR without AAD. In the persistent AF group (n = 15), after the single PVAC ablation, 2 (13.3%) patients had sustained SR without AAD. CONCLUSIONS: PVI with PVAC is a safe procedure with 48.7% efficacy in patients with paroxysmal AF. The efficacy of PVAC in patients with persistent or long-standing persistent AF is not acceptable. PMID- 24338540 TI - The relationship between functional capacity and ultrasonic tissue characterization in patients with idiopathic dilated cardiomyopathy. AB - BACKGROUND: Ultrasonic tissue characterization (UTC) has been widely used to investigate left ventricular (LV) dysfunction in various cardiac disorders. The aim of this study was to investigate the correlation between functional capacity and UTC in patients with idiopathic dilated cardiomyopathy (IDCM). METHODS AND RESULTS: Treadmill test according to modified-Bruce protocol was performed in 48 patients with IDCM to assess their functional capacity. Baseline clinical and echocardiographic variables were obtained and UTC was performed on images obtained from septum and posterior wall (PW). Cyclic variation (CV) index of mean gray level (MGL) was calculated according to the formula: [(MGLdiastole - MGLsystole) / MGLdiastole] * 100.PW and septum CV indices were correlated with exercise duration (r = 0.63, p = 0.001 and r = 0.67, p = 0.0001, respectively) and "MET" level (r = 0.80, p = 0.0001 and r = 0.83,p = 0.0001, respectively). The ROC curve analysis revealed that the PW CV index was a strong indicator of good exercise capacity (> 8 METs) with an AUC of 0.97 (95% CI0.90-1.0), as the interventricular septum (IVS) CV index (AUC = 0.97, 95% CI 0.89-1.0). Sensitivity, specificity, positive predictive value, and negative predictive value to identify good exercise capacity for IVS CV index were 90%, 88%, 82%, and 94%, respectively and for the PW CV index, 90%, 88%, 82%, and 94%, respectively. CONCLUSIONS: In this particular study, we found out that in patients with severe LV dysfunction good exercise capacity was related to septum and PW CV indices measured by UTC, and these indices may be used as an indirect prognostic marker in heart failure. PMID- 24338541 TI - Is abnormal myocardial repolarization associated with the occurrence of malignant tachyarrhythmias in Takotsubo cardiomyopathy? AB - BACKGROUND: Abnormalities of cardiac repolarization are a hallmark of Takotsubo cardiomyopathy (TC), but their association with the occurrence of syncope and ventricular tachyarrhythmias is unknown. This study sought to assess the relationship between myocardial repolarization and malignant tachyarrhythmias in TC. METHODS: Clinical data and electrocardiographic repolarization parameters of 28 patients with TC and ventricular tachyarrhythmias (n = 26) or syncope (n = 2) were compared to data from 20 randomly selected patients with TC but without ventricular tachyarrhythmias or syncope. RESULTS: Study patients had significantly lower ejection fraction (EF) compared with controls (35 +/- 14% vs. 46 +/- 10%, p = 0.006). On day 1, no significant differences in repolarization parameters were observed. However, in the subgroup with ventricular fi brillation ([VF]; n = 10), Tpeak-Tend in lead V6 was significantly prolonged (97 +/- 20 vs. 85 +/- 19 ms; p = 0.04). Similarly, in the subgroup with torsade de pointes ([TdP]; n = 5) Tpeak-Tend in lead V4 was prolonged (127 +/- 21 vs. 94 +/- 27 ms; p = 0.001). On day 3, Tpeak-Tend in lead V3 (130 +/- 51 vs. 105 +/- 21 ms, p = 0.049) and Tpeak-Tend dispersion (56 +/- 33 vs. 36 +/- 21 ms; p = 0.03) were significantly longer in study patients. The difference in Tpeak-Tend in lead V3 was borderline in the VF subgroup, but significant in the subgroup with TdP. The latter group had also longer Tpeak-Tend in lead V4 and longer corrected QT interval in leads V3 and V4. CONCLUSIONS: Patients with TC who experience malignant tachyarrhythmias have lower EF and a more pronounced alteration of the spatial dispersion of ventricular repolarization. PMID- 24338542 TI - Predictive value of atrial electromechanical delay for atrial fibrillation recurrence. AB - BACKGROUND: We investigated the predictive value of atrial electromechanical delay (AEMD) for recurrence of atrial fibrillation (AF) at 1-month after cardioversion. METHODS: Seventy-seven patients with persistent AF were evaluated and finally 50 patients (12 men, 38 women) were included. All patients underwent transthoracic electrical DC cardioversion under amiodarone treatment. AEMD was measured as the time interval from the onset of the P wave on electrogram (ECG) to the beginning of late diastolic wave (Am) from the ventricular annulus and atrial walls on tissue Doppler imaging, in the apical 4-chamber view 24 h after cardiversion. P wave maximum-duration (Pmax), P wave minimum-duration (Pmin) and P wave dispersion-duration (Pdis) were calculated on the 12-lead ECG at 24-h postcardioversion. We followed the heart rate and rhythm by 12-lead ECG at 24-h, 1-week and 1-month. RESULTS: At 1-month follow-up after cardioversion, 28 (56%) patients were in sinus rhythm (SR), whereas 22 (44%) patients reverted to AF. The AEMD durations were longer in AF group than SR group (p < 0.001) and were signifi cantly correlated with Pmax and Pdis (p < 0.001 for both). For AF recurrence; duration of AF, left atrial (LA) diameter, maximum LA volume index, mitral A velocity and LA lateral AEMD were significant parameters in univariate-analysis, however LA lateral AEMD was the only significant parameter in multivariate analysis (OR: 1.46; 95% CI 1.02-2.11; p = 0.03). CONCLUSIONS: Our results suggest that AEMD is associated with an increased risk of recurrence of AF within 1 month. These data may have implications for the identification of patients who are most likely to experience substantial benefit from cardiversion therapy for AF. PMID- 24338543 TI - Compliance with pharmacological treatment among patients after minimally invasive coronary bypass grafting. AB - BACKGROUND: We sought to evaluate patients' adherence to optimal pharmacotherapy as recommendedby the European Society of Cardiology, together with the assessment of potential clinical determinants of medical non-compliance in a large cohort of patients after endoscopic atraumatic coronary artery bypassing (EACAB). METHODS: This cross sectional study was conducted in a group of 706 individuals who underwent EACAB between April 1998 and December 2010. Data covering current pharmacological treatment with antiplatelet agents, beta-blockers (BB) (or heart rate lowering calcium channel blockers [CCB] in case of intolerance and/or poor efficacy of beta-blockade), angiotensin-converting enzyme (ACE) inhibitors (or angiotensin receptor blockers [ARB]) and statins was acquired. Mean duration of observation after the surgery was 2132 +/- 1313 days. RESULTS: Complete follow-up data has been obtained from 415 living patients (341 males). Amongst them, 353 (85%) received antiplatelet agents, while BB or CCB were routinely ingested by 349 (84%) patients. Statins were used by 310 (74.7%) individuals and 274 (66%) subjects took ACE inhibitors or ARB. Baseline demographic and clinical features, including major co-morbidities had no impact on patients' compliance with all investigated medications. There was no clear association between adherence to treatment and risk of rehospitalization or occurrence of major cerebral and cardiovascular events. CONCLUSIONS: EACAB patients' compliance with pharmacotherapy guidelines is insufficient and is unrelated to demographic and clinical features of the subjects. Multidisciplinary approach involving health education, enhancement in prescription drug affordability and a better rapport between doctors and patients should be incorporated into clinical practice to overcome therapeutic disobedience. PMID- 24338544 TI - Effects of age on aerobic capacity in heart failure patients under beta-blocker therapy: possible impact in clinical decision-making? AB - BACKGROUND: Heart failure (HF) is associated with impaired maximal aerobic capacity as indicated by decreases in peak oxygen uptake (peak VO(2)). Considering that aging by itself has a negative effect on this variable, the evaluation of maximum capacity is often questioned because current predicted peak VO(2) is based on subjects without heart disease or b-blocker therapy. In contrast, if decline in predicted and attained peak VO(2) were age-related, proportionally, loss of aerobic function (predicted peak VO(2), %) would remain stable over time in these patients. The purpose of this investigation is to assess the effects of age on peak VO(2) in HF patients taking b-blockers. METHODS: We retrospectively evaluated 483 (132 female) patients (aged 20-88 years, LVEF 31 +/- 11%) with non-ischemic (n = 362), ischemic (n = 74) and Chagas related HF (n = 47) who had been submitted to an incremental cardiopulmonary exercise testing on a motorized treadmill. Linear regression was used to develop the equation to predict peak VO(2), based on age. RESULTS: Peak VO(2) decreased 0.9 mL/min/kg per age-decade, maximum HR also decreased with aging and VE/VCO(2) slope was similar among all decades. The predicted new b-blocker equation to peak VO(2 bb) was 20.934 - 0.092 * age. CONCLUSIONS: Clinical interpretation of aerobic capacity impairment is influenced by aging in HF patients. This evidence must be considered when using peak VO(2) for prognostic stratification and clinical decision-making in patients with HF under b-blocker therapy. PMID- 24338545 TI - Ambulatory blood pressure monitoring: Is 24 hours necessary? AB - BACKGROUND: The variability of blood pressure (BP) makes any single measurement a poor indicator of a patient's true BP. Multiple studies have confirmed the superiority of ambulatory BP measurements over clinic BP measurements in predicting cardiovascular risk; however, this method presents the problem of patient acceptance as it causes frequent arm discomfort and sleep disturbance. We hypothesized that 6 h of daytime BP measurements would result in slightly higher BP readings, yet reveal similar clinical decision making when compared to 24 h of BP measurements. METHODS: The source for writing this article was a retrospective analysis of 30 patients who underwent ambulatory BP monitoring. Data obtained included: age, sex, ethnicity, baseline medical problems, medications, laboratory values, reason given for ordering 24-h ambulatory BP measurements, ambulatory BP measurements, and a subsequent decision to change medication. RESULTS: The average BP of the 24-h measurements was 127/75 mm Hg and the average BP of the 6 h daytime measurements was 131/79 mm Hg (SD 15, p = 0.009). Twenty-six out of 30 patients were at goal or pre-hypertensive. Two out of 30 patients had stage 1 hypertension and 2 out of 30 patients had stage 2 hypertension. Thirteen out of 30 patients had nocturnal dipping. Twelve out of 30 patients had a change in medication, but those changes were not associated with the presence or absence of nocturnal dipping (p = 0.5) or other factors beyond mean BP. CONCLUSIONS: Although there was a statistically significant, 4 mm Hg systolic difference between 24-h and 6-h average BP readings, there was no evidence that this difference led to changes in clinical management. The presence or absence of nocturnal dipping was not associated with a change in medication. We conclude that 6-h daytime ambulatory BP measurements provide sufficient information to guide clinical decision making without the problems of patient acceptance, arm discomfort, and sleep disturbance associated with 24-h BP measurements. PMID- 24338546 TI - The prognostic value of arterial stiffness in systolic heart failure. AB - BACKGROUND: Increased arterial stiffness is an indicator of mortality. This study consists of an 18-month follow-up of the mortality in advanced heart failure patients with increased arterial stiffness. METHODS: The study followed up 98 patients with a diagnosis of heart failure in NYHA class III and IV (76 males, 22 females and mean age of 60 +/- 12 years) with a left ventricular ejection fraction <= 35% as determined by the Simpson method. Augmentation index (Aix) and pulse wave propagation velocity (PWV) parameters were used as indicators of arterial stiffness. Aix and PWV values were measured by arteriography. RESULTS: 36 patients died. Both Aix and PWV were powerful determinants of mortality, independent of other prognostic variables (p = 0.013, OR: 0.805; p = 0.025, OR: 0.853). A cutoff value for Aix of -14.33 gave 91.2%, 80.3% sensitivity and specificity. A cutoff value for PWV of 11.06 gave 82.4%, 65.4% sensitivity and specificity mortality was predicted. Left ventricular ejection fraction (p = 0.008, OR: 0.859) and B-type natriuretic peptide (p = 0.01, OR: 0.833) was the other independent determinant of mortality. A significant difference was found in both Aix and PWV between the compensated measurements and decompensated heart failure measurements made in 70 patients (p = 0.035, p = 0.048). CONCLUSIONS: Measurement of arterial stiffness is a convenient, inexpensive and reliable method for predicting mortality in patients with advanced heart failure. PMID- 24338547 TI - The long and winding road. PMID- 24338548 TI - Use of Cox regression with treatment status as a time-dependent covariate to re analyze survival benefit excludes immortal time bias effect in patients with glioblastoma who received prolonged adjuvant treatment with valganciclovir. PMID- 24338549 TI - Dengue hemorrhagic fever with discolored leg syndrome in a neonate. PMID- 24338550 TI - Vibroplasty in mixed and conductive hearing loss: comparison of different coupling methods. AB - OBJECTIVES/HYPOTHESIS: To evaluate modified coupling techniques of the Vibrant Soundbridge system in patients with mixed and conductive hearing loss and to compare it with conventional vibroplasty. STUDY DESIGN: Retrospective study. METHODS: Two different groups were evaluated: 1) nine cases of conventional incus vibroplasty in comparison with 2) nine patients with modified coupling of the floating mass transducer. In the modified coupling approach, the vibrant floating mass transducer was attached to 1) the stapes/oval window, 2) the round window, or 3) the drilled promontory bone (promontory fenestration window). In three patients, an additional ossiculoplasty was performed. Preoperative and postoperative aided and unaided pure-tone and free-field audiometry and Freiburg monosyllabic word test were used to assess hearing outcome. RESULTS: Functional hearing gain obtained in patients with mixed and conductive hearing loss who underwent modified coupling was 39 dB. Patients with pure sensorineural hearing loss who received conventional incus coupling showed a functional hearing gain of 25 dB. Average functional gain was 41 dB in the oval window group, 45 dB in the round window group, and 30 dB in the promontory fenestration window group. Word recognition test revealed an average improvement of 51% and 21% in the modified and in the conventional approach, respectively. CONCLUSIONS: Modified vibroplasty is a safe and effective treatment for patients with conductive and mixed hearing loss. Coupling the floating mass transducer to the promontory bone (promontory fenestration window) is a viable option in chronically disabled ears if oval and round window coupling is not possible. LEVEL OF EVIDENCE: 4. PMID- 24338551 TI - Anti-inflammatory activity and chemical profile of Galphimia glauca. AB - Galphimia glauca, commonly known as "flor de estrella", is a plant species used in Mexican traditional medicine for the treatment of different diseases that have an acute or chronic inflammatory process in common. Aerial parts of this plant contain nor-seco-triterpenoids with anxiolytic properties, which have been denominated galphimines. Other compounds identified in the plant are tetragalloyl quinic acid, gallic acid, and quercetin, which are able to inhibit the bronchial obstruction induced by platelet-activating factor. The objective of this work was to evaluate the anti-inflammatory effect of crude extracts from G. glauca and, by means of bioguided chemical separation, to identify the compounds responsible for this pharmacological activity. n-Hexane, ethyl acetate, dichloromethane, and methanol extracts showed an important anti-inflammatory effect. Chemical separation of the active methanol extract allowed us to identify the nor-seco triterpenes galphimine-A (1) and galphimine-E (3) as the anti-inflammatory principles. Analysis of structure-activity relationships evidenced that the presence of an oxygenated function in C6 is absolutely necessary to show activity. In this work, the isolation and structural elucidation of two new nor seco-triterpenes denominated as galphimine-K (4) and galphimine-L (5), together with different alkanes, fatty acids, as well as three flavonoids (17-19), are described, to our knowledge for the first time, from Galphimia glauca. PMID- 24338552 TI - Betaine reduces serum uric acid levels and improves kidney function in hyperuricemic mice. AB - Betaine as a dietary alkaloid has attracted the attention of patients with kidney diseases. This study aimed to investigate the effects of betaine on serum uric acid levels and kidney function, and explore their underlying mechanisms in potassium oxonate-induced hyperuricemic mice. Betaine at 5, 10, 20, and 40 mg/kg was orally administered to hyperuricemic mice for 7 days and found to significantly reduce serum uric acid levels and increase fractional excretion of uric acid in hyperuricemic mice in a dose-dependent manner. It effectively restored renal protein level alterations of urate transport-related molecular proteins urate transporter 1, glucose transporter 9, organic anion transporter 1, and ATP-binding cassette subfamily G member 2 in this model, possibly resulting in the enhancement of kidney urate excretion. Moreover, betaine reduced serum creatinine and blood urea nitrogen levels and affected urinary levels of beta-2 microglobulin and N-acetyl-beta-D-glucosaminidase as well as upregulated renal protein levels of organic cation/carnitine transporters OCT1, OCTN1, and OCTN2, resulting in kidney function improvement in hyperuricemic mice. The findings from this study provide evidence that betaine has anti-hyperuricemic and nephroprotective actions by regulating protein levels of these renal organic ion transporters in hyperuricemic mice. PMID- 24338553 TI - Astragaloside IV protects against cardiac hypertrophy via inhibiting the Ca2+/CaN signaling pathway. AB - Astragaloside IV is widely used for the treatment of cardiovascular diseases in China. However, its role in cardiac hypertrophy remains unclear. In this study, we aim to determine the protective effects of astragaloside IV on myocardial hypertrophy induced by lipopolysaccharide and to identify their precise molecular and cellular mechanisms. Cell size, reorganization of actin filaments, and ANP and BNP mRNA expression were used as indices of hypertrophy; CaN and GATA-4 expression and the distribution of NFAT-3 in both cytoplasm and nucleus were determined by Western blot analysis; Ca2+ transient in Fura-2/AM-loaded cells was measured by Till image system. Our data demonstrated that lipopolysaccharide challenge induced cardiac hypertrophy, increased resting Ca2+ transient level, promoted activation of CaN and GATA-4, and enhanced nuclear translocation of NFAT 3. Administration of astragaloside IV (16, 32, and 64 uM) 1 h prior to lipopolysaccharide stimulation dose-dependently attenuated cardiac hypertrophy induced by lipopolysaccharide. Further studies demonstrated that astragaloside IV inhibited the increment of the resting intracellular free Ca2+, and its effect was similar to verapamil. Moreover, astragaloside IV also inhibited the activation of CaN and GATA-4, and the nuclear translocation of NFAT-3 induced by lipopolysaccharide. In conclusion, our results revealed that astragaloside IV had the potential to protect against cardiac hypertrophy through Ca2+-mediated CaN signaling pathways. PMID- 24338554 TI - In vitro and in vivo antitumor activities of tenacissoside C from Marsdenia tenacissima. AB - Tenacissoside C, a natural bioactive compound of C21 steroidal saponins, was isolated and purified from air-dried stems of Marsdenia tenacissima. In the present study, the MTT assay showed that tenacissoside C exhibited obvious cytotoxicity in K562 cells with IC50 values of 31.4, 22.2, and 15.1 uM for 24, 48, and 72 h, respectively. Flow cytometry analysis indicated that the antiproliferative activity induced by tenacissoside C might be executed via G0/G1 cell cycle arrest and proapoptosis in K562 cells. Western blotting analysis elucidated that: A) Tenacissoside C induced K562 cell cycle (G0/G1) arrest via downregulating cycline D1 protein expression; and B) Tenacissoside C induced K562 cell apoptosis via the mitochondrial pathway by downregulating Bcl-2 and Bcl-xL protein expression, upregulating Bax and Bak protein expression, and activating caspase-9 and caspase-3. In vivo, significant tumor growth inhibition activity of tenacissoside C was observed in K562 cell-bearing nude mice, accompanied by a significant antiangiogenic effect in vivo against K562 cells (a marked decrease in MVD) and associated with enhanced apoptotic cell death (TUNEL staining assay in vivo), both in dose-dependent manners. The treatment with tenacissoside C did not significantly affect body mass and macroscopic examination of the organs in this mouse tumor model. PMID- 24338555 TI - A feasibility study of carboplatin plus irinotecan treatment for elderly patients with extensive disease small-cell lung cancer. AB - OBJECTIVE: The role of platinum agents plus irinotecan has been unclear for elderly patients with extensive disease small-cell lung cancer. We conducted a feasibility study to evaluate the safety and efficacy of carboplatin plus irinotecan in preparation for a planned Phase III study. METHODS: Based on another Phase I study, carboplatin area under the curve of four Day 1 plus irinotecan 50 mg/m(2) Days 1 and 8 every 3 weeks for four courses was administered. Patients aged >=70 years with a performance status of 0-2 were eligible. The primary endpoint was feasibility, defined as the percentage of patients who have received three or more courses of chemotherapy. If the feasibility was >=60% in the first 10 patients, this endpoint would be considered to be met. RESULTS: Eleven patients were registered. The median age was 77 years, and nine patients had a performance status of 1. Ten patients completed four courses of treatment, and neither dose omission nor modification was required. The feasibility was 91% (10/11) and the relative dose intensity was 76.9%. Because neutropenia was frequently prolonged, the next course was delayed in 53% of all courses. Other toxicities were generally mild, and the only Grade 4 toxicity was hyponatremia. The overall response rate was 90% (9/10), and the progression-free survival and the overall survival were 5.1 and 10.9 months, respectively. CONCLUSIONS: This regimen appears to be feasible and effective. Based on these results, a Phase II/III trial comparing carboplatin plus etoposide with carboplatin plus irinotecan for elderly patients with extensive disease small-cell lung cancer is being planned by the Japan Clinical Oncology Group. PMID- 24338556 TI - Secondary osteosarcoma developing 10 years after chemoradiotherapy for non-small cell lung cancer. AB - A 53-year-old female patient was admitted with pain and a progressively enlarging mass in the right upper chest. Chest computed tomography revealed a mass lesion in the region of the right upper ribs. Ten years prior to this admission, the patient had undergone right lobectomy for lung adenocarcinoma. One year after the surgery, follow-up computed tomography had revealed tumor recurrence in the mediastinal and supraclavicular lymph nodes, and the patient had been treated by chemoradiotherapy. Thereafter, regular follow-up had revealed no evidence of recurrence of the non-small-cell lung cancer. Histopathological findings revealed proliferation of spindle-shaped malignant tumor cells in a background of osteoid, consistent with the diagnosis of osteosarcoma. The location of the tumor was consistent with the radiation field. Based on the clinicopathological findings, the patient was diagnosed as having secondary osteosarcoma occurring as a result of the chemoradiotherapy administered previously for the recurrent non-small-cell lung cancer. Unfortunately, the patient died of rapid progression of the osteosarcoma within a week of admission to the hospital. The autopsy revealed contiguous invasion by the tumor of the heart, with massive thrombus formation. The peripheral pulmonary arteries were diffusely occluded by metastatic tumors. Our case serves to highlight the risk of development of secondary sarcoma as a life-threatening late complication after chemoradiotherapy for locally advanced non-small-cell lung cancer, even after complete cure of the primary tumor. PMID- 24338557 TI - Artificial intelligence in medicine and cardiac imaging: harnessing big data and advanced computing to provide personalized medical diagnosis and treatment. AB - Although advances in information technology in the past decade have come in quantum leaps in nearly every aspect of our lives, they seem to be coming at a slower pace in the field of medicine. However, the implementation of electronic health records (EHR) in hospitals is increasing rapidly, accelerated by the meaningful use initiatives associated with the Center for Medicare & Medicaid Services EHR Incentive Programs. The transition to electronic medical records and availability of patient data has been associated with increases in the volume and complexity of patient information, as well as an increase in medical alerts, with resulting "alert fatigue" and increased expectations for rapid and accurate diagnosis and treatment. Unfortunately, these increased demands on health care providers create greater risk for diagnostic and therapeutic errors. In the near future, artificial intelligence (AI)/machine learning will likely assist physicians with differential diagnosis of disease, treatment options suggestions, and recommendations, and, in the case of medical imaging, with cues in image interpretation. Mining and advanced analysis of "big data" in health care provide the potential not only to perform "in silico" research but also to provide "real time" diagnostic and (potentially) therapeutic recommendations based on empirical data. "On demand" access to high-performance computing and large health care databases will support and sustain our ability to achieve personalized medicine. The IBM Jeopardy! Challenge, which pitted the best all-time human players against the Watson computer, captured the imagination of millions of people across the world and demonstrated the potential to apply AI approaches to a wide variety of subject matter, including medicine. The combination of AI, big data, and massively parallel computing offers the potential to create a revolutionary way of practicing evidence-based, personalized medicine. PMID- 24338558 TI - Bacillus thuringiensis as a surrogate for Bacillus anthracis in aerosol research. AB - Characterization of candidate surrogate spores prior to experimental use is critical to confirm that the surrogate characteristics are as closely similar as possible to those of the pathogenic agent of interest. This review compares the physical properties inherent to spores of Bacillus anthracis (Ba) and Bacillus thuringiensis (Bt) that impact their movement in air and interaction with surfaces, including size, shape, density, surface morphology, structure and hydrophobicity. Also evaluated is the impact of irradiation on the physical properties of both Bacillus species. Many physical features of Bt and Ba have been found to be similar and, while Bt is considered typically non-pathogenic, it is in the B. cereus group, as is Ba. When cultured and sporulated under similar conditions, both microorganisms share a similar cylindrical pellet shape, an aerodynamic diameter of approximately 1 MUm (in the respirable size range), have an exosporium with a hairy nap, and have higher relative hydrophobicities than other Bacillus species. While spore size, morphology, and other physical properties can vary among strains of the same species, the variations can be due to growth/sporulation conditions and may, therefore, be controlled. Growth and sporulation conditions are likely among the most important factors that influence the representativeness of one species, or preparation, to another. All Bt spores may, therefore, not be representative of all Ba spores. Irradiated spores do not appear to be a good surrogate to predict the behavior of non-irradiated spores due to structural damage caused by the irradiation. While the use of Bt as a surrogate for Ba in aerosol testing appears to be well supported, this review does not attempt to narrow selection between Bt strains. Comparative studies should be performed to test the hypothesis that viable Ba and Bt spores will behave similarly when suspended in the air (as an aerosol) and to compare the known microscale characteristics versus the macroscale response. PMID- 24338559 TI - Vascular cell adhesion molecule 1 expression by biliary epithelium promotes persistence of inflammation by inhibiting effector T-cell apoptosis. AB - Chronic hepatitis occurs when effector lymphocytes are recruited to the liver from blood and retained in tissue to interact with target cells, such as hepatocytes or bile ducts (BDs). Vascular cell adhesion molecule 1 (VCAM-1; CD106), a member of the immunoglobulin superfamily, supports leukocyte adhesion by binding alpha4beta1 integrins and is critical for the recruitment of monocytes and lymphocytes during inflammation. We detected VCAM-1 on cholangiocytes in chronic liver disease (CLD) and hypothesized that biliary expression of VCAM-1 contributes to the persistence of liver inflammation. Hence, in this study, we examined whether cholangiocyte expression of VCAM-1 promotes the survival of intrahepatic alpha4beta1 expressing effector T cells. We examined interactions between primary human cholangiocytes and isolated intrahepatic T cells ex vivo and in vivo using the Ova-bil antigen-driven murine model of biliary inflammation. VCAM-1 was detected on BDs in CLDs (primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic liver disease, and chronic hepatitis C), and human cholangiocytes expressed VCAM-1 in response to tumor necrosis factor alpha alone or in combination with CD40L or interleukin-17. Liver-derived T cells adhered to cholangiocytes in vitro by alpha4beta1, which resulted in signaling through nuclear factor kappa B p65, protein kinase B1, and p38 mitogen activated protein kinase phosphorylation. This led to increased mitochondrial B cell lymphoma 2 accumulation and decreased activation of caspase 3, causing increased cell survival. We confirmed our findings in a murine model of hepatobiliary inflammation where inhibition of VCAM-1 decreased liver inflammation by reducing lymphocyte recruitment and increasing CD8 and T helper 17 CD4 T-cell survival. CONCLUSIONS: VCAM-1 expression by cholangiocytes contributes to persistent inflammation by conferring a survival signal to alpha4beta1 expressing proinflammatory T lymphocytes in CLD. PMID- 24338560 TI - Lymphatic transport of alpha-linolenic acid and its conversion to long chain n-3 fatty acids in rats fed microemulsions of linseed oil. AB - In the present study we evaluated the uptake of ALA and its conversion to EPA + DHA in rats given linseed oil (LSO) in native form or as a microemulsion in whey protein or in lipoid. In a single oral dose study in which rats maintained on rodent pellets deficient in omega-3 fatty acids were intubated with 0.35 g LSO in lipoid, the amount of ALA present in lymph was increased reaching a maximum concentration of 16.23 mg/ml at 2.5 h. The amount of ALA present in lymph was increased to a maximum level of 10.95 mg/ml at 4 h in rats given LSO as a microemulsion in whey protein. When LSO was given without emulsification, the amount of ALA present in lymph was found to reach a maximum level of 7.08 mg/ml at 6 h. A similar result was observed when weaning rats were intubated with 0.15 g of LSO per day for a period of 60 days. Higher levels of ALA by 41 and 103 % were observed in lymph lipids of rats given microemulsions of LSO in whey protein and in lipoid respectively as compared to rats given LSO without pre emulsification. Very little conversion of ALA to EPA and DHA was observed in lymph lipids but higher amounts of EPA + DHA was observed in liver and serum of rats given LSO in microemulsion form. This study indicated that ALA concentration in lymph lipids was increased when LSO was given in microemulsion form in lipoid and further conversion to EPA and DHA was facilitated in liver and serum. PMID- 24338561 TI - Treatment utilization and surgical outcome of ampullary and duodenal adenocarcinoma. AB - BACKGROUND: Ampullary (AMP-A) and duodenal adenocarcinomas (DA) are rare tumors. The literature regarding treatment and outcome is very limited. The objective of this project is to compare the outcomes of AMP-A and DA. METHODS: The records for AMP-A and DA patients between July 1995 and July 2012 at Emory University were reviewed for demographics, pathology, treatment, and survival. Survival rates were estimated by Kaplan-Meier method and compared with log-rank test. A Cox proportional hazard model was fitted to estimate the adjusted effect of AMP-A versus DA on overall survival (OS). RESULTS: Ninety-five AMP-A and 66 DA patients were identified. No significant difference between patients with DA and AMP-A was observed for age, gender, or grade. DA presented with larger tumors and higher stages. Treatment included surgery, surgery followed by adjuvant therapy or chemotherapy alone. No OS difference was observed when controlled for stage. AMP A was sub-classified into intestinal (IAMP), pancreaticobiliary (PBAMP), and unspecified types. IAMP tended to present at a higher grade (P = 0.045) than PBAMP. No OS difference between the IAMP and PBAMP was observed. CONCLUSIONS: After accounting for stage, OS was not significantly different for AMP-A and DA patients. There was no OS difference comparing PBAMP with IAMP. PMID- 24338562 TI - Gastric adenocarcinoma in the context of X-linked agammaglobulinemia: case report and review of the literature. AB - The hallmarks of X-linked Agammaglobulinemia (XLA) are panhypogammaglobulinemia, absent B-cells, and recurrent sinopulmonary and gastrointestinal infections starting at an early age, as well as other infections like cellulitis, meningitis, arthritis and sepsis. A number of non-infectious complications have been reported in these patients, including autoimmune diseases and malignancy, especially lymphomas. Here, we report the case of a 30-year old man who developed gastric adenocarcinoma in the context of XLA. Previous reports of, and hypotheses addressing the development of cancer in patients with XLA, are also summarized. Solid cancer in XLA affects mainly the gastrointestinal tract and seems to be related to chronic infection. A natural evolution can be traced back from gastric adenocarcinoma to megaloblastic anemia due to achlorhydria in the context of chronic infection; periodic endoscopy thus seems justified to detect and treat carcinoma in early stages. PMID- 24338564 TI - Establishment of a spinal cord injury model in adult rats by an electrocircuit controlled impacting device and its pathological observations. AB - One of the crucial challenges in medicine is the treatment and rehabilitation of spinal cord injury (SCI). In this study, we established a stable and reproducible acute spinal cord injury model in adult rats. The SCI was inflicted by our self innovated spinal cord impact device controlled by electrical circuit. The Basso, Beattie, and Bresnahan Locomotor Rating Scale (BBB) score, electrophysiology, histological, and immunohistochemical changes after SCI were observed. The BBB score of the injured rats began to increase from the 3rd day of SCI and reached at the score 7.2 +/- 1.3 at the 28th day. The latency of cortical somatosensory evoked potentials (CSEP) was not observed 2 and 6 h after injury, but appeared 24 h after injury which was significantly prolonged. It recovered from day 3 gradually to 27.3 +/- 2.7 ms on day 28. H&E staining showed that the structure of gray and white matter was disrupted after the SCI. The result also showed dramatic neuron degenerations, cellular swelling, and the proliferation of glial cells. The immunohistochemical analysis showed that the expression of neuron specific enolase (NSE) and neurofilament 200 (NF200) started lowering at 2 h and dropped to the bottom at 24 h. Their expression rebound from day 3 and yet to the original level at day 28 (P < 0.05). The number of cells expressing glial fibrillary acidic protein (GFAP) hiked from day 3, peaked at day 14, and began recovering from day 28 (P < 0.05). The changes of NSE, NF200, GFAP, and CSEP were significantly associated with the BBB score (P < 0.05). In conclusion, our self innovated device can reproduce the injury model stably. The changes of NSE, NF, and GFAP after spinal cord injury reflect the characteristics of pathological change, which are closely associated with the functional recovery from the spinal cord injury. PMID- 24338563 TI - Modeling primary immunodeficiency disease epidemiology and its treatment to estimate latent therapeutic demand for immunoglobulin. AB - PURPOSE: Estimating the underlying demand for immunoglobulin (Ig) is important to ensure that adequate provision is made for patients with primary immune deficiency (PID) in the context of the competing demands for Ig and to ensure optimal therapeutic regimens. The concept of latent therapeutic demand (LTD) was used to estimate evidence-based requirements and compared to the actual Ig consumption in different countries. The estimates were performed for common variable immunodeficiency (CVID) and X-linked Agammaglobulinaemia (XLA), the two most commonly studied PIDs using Ig. METHODS: The LTD model for CVID and XLA was derived using decision analysis methodology. Data for the epidemiology and treatment variables were obtained from peer-reviewed publications, clinical registries and publicly-available patient surveys. Incomplete data records from registries were excluded from analysis. The variables impacting LTD were ranked in order of sensitivity through a tornado diagram. The uncertainty surrounding the variables was modeled using probabilistic distributions and evaluated using Monte Carlo simulation. RESULTS: Treatment dosage and prevalence were determined to be the most sensitive variables driving demand. The average potential usage of Ig for the treatment of CVID and XLA was estimated at 72 g per 1,000 population, which is higher than the estimated Ig usage in CVID and XLA of 27-41 g per 1,000 population in the US. CONCLUSION: The potential demand for treating CVID and XLA exceeds the currently observed usage of Ig in these disorders. Variable usage in different countries is due to varying prevalence and dosage practices. Under reporting in patient registries represents a major obstacle to calculating the true prevalence of CVID and XLA. Modeling demand relies heavily upon accurate prevalence and practice estimates which reemphasize the importance of accurate registries and improved registry methods. As better data becomes available, revision of model variables provides opportunities to anticipate and prepare for evolving patient needs. PMID- 24338565 TI - Cross-sectional study of indices of dynamic components of ambulatory blood pressure and cardiac damage in elderly male patients with essential hypertension. AB - BACKGROUND AND AIMS: Blood pressure control is closely related to target organ damage in elderly patients with hypertension. The aim of this study was to determine the relationship between ambulatory blood pressure monitoring (ABPM) indices and cardiac damage in elderly male patients with treated essential hypertension (EH). METHOD: This study included 998 Chinese men (mean age, 78.44 +/- 12.02 years) with EH. Participants underwent cardiac function assessment, laboratory testing, and ABPM, including ABP, BP variability, BP circadian rhythms, and hypertensive or hypotensive time indices. The relationships between ABPM indices and cardiac damage (expressed by shape and function) were assessed using ridge regression analysis. RESULTS: Ridge regression analysis revealed the following after adjustments for age, common cardiovascular risk factors, disease, and medications: N-terminal fragment pro-B-type natriuretic peptide was negatively correlated with the diastolic blood pressure nocturnal fall rate; the peak early/atrial velocity (E/A) ratio E/A ratio was negatively correlated with the 24 h mean systolic blood pressure (24 hmSBP), daytime SBP (dSBP), and nocturnal SBP (nSBP); and ejection fraction (EF) was negatively correlated with 24 h SBP percent time of elevation (24 hSBP PTE %) and 24 h DBP percent time of elevation (24 hDBP PTE %). Left ventricular mass (LVM) was positively correlated with the 24 hmSBP, dSBP, nSBP, 24 h mean pulse pressure (24 hmPP), day mean pulse pressure, and nocturnal mean arterial pressure, whereas LVM was negatively correlated with the NDBPF. CONCLUSIONS: Our study showed that the ABPM indices associated with cardiac damage may be regarded as an early predictive marker for cardiac function impairment in elderly male patients with EH. PMID- 24338566 TI - The use of generalized linear models and generalized estimating equations in bioarchaeological studies. AB - The current article explores whether the application of generalized linear models (GLM) and generalized estimating equations (GEE) can be used in place of conventional statistical analyses in the study of ordinal data that code an underlying continuous variable, like entheseal changes. The analysis of artificial data and ordinal data expressing entheseal changes in archaeological North African populations gave the following results. Parametric and nonparametric tests give convergent results particularly for P values <0.1, irrespective of whether the underlying variable is normally distributed or not under the condition that the samples involved in the tests exhibit approximately equal sizes. If this prerequisite is valid and provided that the samples are of equal variances, analysis of covariance may be adopted. GLM are not subject to constraints and give results that converge to those obtained from all nonparametric tests. Therefore, they can be used instead of traditional tests as they give the same amount of information as them, but with the advantage of allowing the study of the simultaneous impact of multiple predictors and their interactions and the modeling of the experimental data. However, GLM should be replaced by GEE for the study of bilateral asymmetry and in general when paired samples are tested, because GEE are appropriate for correlated data. PMID- 24338567 TI - Strand-specific recognition of DNA damages by XPD provides insights into nucleotide excision repair substrate versatility. AB - Recognition and removal of DNA damages is essential for cellular and organismal viability. Nucleotide excision repair (NER) is the sole mechanism in humans for the repair of carcinogenic UV irradiation-induced photoproducts in the DNA, such as cyclobutane pyrimidine dimers. The broad substrate versatility of NER further includes, among others, various bulky DNA adducts. It has been proposed that the 5'-3' helicase XPD (xeroderma pigmentosum group D) protein plays a decisive role in damage verification. However, despite recent advances such as the identification of a DNA-binding channel and central pore in the protein, through which the DNA is threaded, as well as a dedicated lesion recognition pocket near the pore, the exact process of target site recognition and verification in eukaryotic NER still remained elusive. Our single molecule analysis by atomic force microscopy reveals for the first time that XPD utilizes different recognition strategies to verify structurally diverse lesions. Bulky fluorescein damage is preferentially detected on the translocated strand, whereas the opposite strand preference is observed for a cyclobutane pyrimidine dimer lesion. Both states, however, lead to similar conformational changes in the resulting specific complexes, indicating a merge to a "final" verification state, which may then trigger the recruitment of further NER proteins. PMID- 24338569 TI - Solution thermodynamics and solubility prediction of glibenclamide in Transcutol + water co-solvent mixtures at 298.15-333.15 K. AB - Solution thermodynamics and solubility of glibenclamide (GBN) in binary co solvent mixtures of Transcutol + water at temperature range of 298.15-333.15 K were investigated in present study. The modified Apelblat model was used to predict the solubility of GBN in co-solvent mixtures at various temperatures. The highest and lowest solubility of GBN were observed in pure Transcutol and pure water, respectively. Moreover, all co-solvent mixtures had highest solubility at 333.15 K. The experimental solubility data of GBN was correlated well with the modified Apelblat model at each temperature studied with relative absolute deviation in the range of 0.008-5.903 %. The correlation coefficients in co solvent mixtures were observed in the range of 0.995-0.999 which indicated good fitting of experimental data with calculated one. The enthalpies and entropies for GBN dissolution were observed in the range of 2.012-38.215 kJ mol(-1) and 6.748-114.709 J mol(-1) K(-1), respectively indicating its dissolution is endothermic and an entropy-driven process. These results indicated that Transcutol can be used as a co-solvent in preformulation studies and formulation development of GBN. PMID- 24338568 TI - Control of helicase loading in the coupled DNA replication and recombination systems of bacteriophage T4. AB - The Gp59 protein of bacteriophage T4 promotes DNA replication by loading the replicative helicase, Gp41, onto replication forks and recombination intermediates. Gp59 also blocks DNA synthesis by Gp43 polymerase until Gp41 is loaded, ensuring that synthesis is tightly coupled to unwinding. The distinct polymerase blocking and helicase loading activities of Gp59 likely involve different binding interactions with DNA and protein partners. Here, we investigate how interactions of Gp59 with DNA and Gp32, the T4 single-stranded DNA (ssDNA)-binding protein, are related to these activities. A previously characterized mutant, Gp59-I87A, exhibits markedly reduced affinity for ssDNA and pseudo-fork DNA substrates. We demonstrate that on Gp32-covered ssDNA, the DNA binding defect of Gp59-I87A is not detrimental to helicase loading and translocation. In contrast, on pseudo-fork DNA the I87A mutation is detrimental to helicase loading and unwinding in the presence or absence of Gp32. Other results indicate that Gp32 binding to lagging strand ssDNA relieves the blockage of Gp43 polymerase activity by Gp59, whereas the inhibition of Gp43 exonuclease activity is maintained. Our findings suggest that Gp59-Gp32 and Gp59-DNA interactions perform separate but complementary roles in T4 DNA metabolism; Gp59 Gp32 interactions are needed to load Gp41 onto D-loops, and other nucleoprotein structures containing clusters of Gp32. Gp59-DNA interactions are needed to load Gp41 onto nascent or collapsed replication forks lacking clusters of Gp32 and to coordinate bidirectional replication from T4 origins. The dual functionalities of Gp59 allow it to promote the initiation or re-start of DNA replication from a wide variety of recombination and replication intermediates. PMID- 24338570 TI - Discounting of food, sex, and money. AB - Discounting is a useful framework for understanding choice involving a range of delayed and probabilistic outcomes (e.g., money, food, drugs), but relatively few studies have examined how people discount other commodities (e.g., entertainment, sex). Using a novel discounting task, where the length of a line represented the value of an outcome and was adjusted using a staircase procedure, we replicated previous findings showing that individuals discount delayed and probabilistic outcomes in a manner well described by a hyperbola-like function. In addition, we found strong positive correlations between discounting rates of delayed, but not probabilistic, outcomes. This suggests that discounting of delayed outcomes may be relatively predictable across outcome types but that discounting of probabilistic outcomes may depend more on specific contexts. The generality of delay discounting and potential context dependence of probability discounting may provide important information regarding factors contributing to choice behavior. PMID- 24338571 TI - An integrated proteomic and transcriptomic approach to understanding azathioprine induced hepatotoxicity in rat primary hepatocytes. AB - Azathioprine, an immunosuppressant, has gained a prominent position in the clinic for prevention of graft rejection in organ transplants, as well as dermatological autoimmune diseases. However, according to a number of research reports, hepatotoxicity, as one of the side effects, is a major obstacle in azathioprine therapy. In this study, an integrated toxicoproteomic and toxicotranscriptomic analysis was performed using rat primary hepatocytes, in order to gain insight into the in-depth pathway map related to azathioprine-induced hepatotoxicity. For proteomic and transcriptomic analysis, rat primary hepatocytes were exposed to azathioprine at IC20 concentration for 24 h. In particular, 2D LC-MS/MS and informatics-assisted label-free strategy for proteomic analysis were applied in order to increase the number of identified proteins and to improve the confidence of the quantitation results. Among 119 differentially identified protein species, 69 were upregulated and 50 were downregulated in the azathioprine-treated group. At the mRNA level, results of transcriptomic analysis showed increased transcription of 340 genes and decreased transcription of 63 genes in the azathioprine-treated group. Based on the analysis of transcriptomic and proteomic results using the DAVID program, drug metabolism/oxidative stress enzymes, xenobiotic metabolism by cytochrome P450, fatty acid metabolism, primary bile acid biosynthesis, contraction, inflammation metabolism, and mitogen-activated protein kinase (MAPK) kinase (ERK/JNK/p38 kinase) pathways were affected in azathioprine-treated hepatotoxicity. The effects on genes and proteins related to several important pathways were confirmed by real-time PCR and immunoblot analysis, respectively. This study is the first to report on relevant pathways related to azathioprine-induced hepatotoxicity through performance of integrated transcriptomic and proteomic analyses. PMID- 24338572 TI - Which patients with eosinophilic esophagitis (EoE) should receive elemental diets versus other therapies? AB - Eosinophilic esophagitis (EoE) has increasingly been identified in both children and adults. The aim of therapies is to alleviate symptoms while reducing the esophageal inflammation. Mechanical dilation is effective at relieving symptoms, but without the benefit of controlling disease inflammation. Topical steroids appear to be effective at controlling both symptoms and esophageal eosinophilia. Recurrence rates are high once steroids are discontinued. For dietary modification, both the elimination of select, specific foods and the complete elimination of food proteins via amino acid formulas have been looked at. Both forms of dietary modification are effective. Elemental diet, although not an ideal first-line therapy for EoE, provides insight into the etiology of unusual or refractory EoE. The contribution of unusual food antigens to EoE may be determined via the use of amino-acid-based formulas in patients with EoE. PMID- 24338573 TI - Treatment outcomes and clinicomicrobiological characteristics of a protocol-based approach for neonatal endogenous endophthalmitis. AB - PURPOSE: To describe the outcomes and clinicomicrobiological profile of 11 years of a protocol-based management in neonatal endogenous endophthalmitis. METHODS: This was a retrospective interventional study of endogenous endophthalmitis in 31 eyes of 26 neonates. The protocol for active infection included systemic antimicrobials, vitreous and/or aqueous tap, and intravitreal antimicrobials under topical or general anesthesia along with core vitrectomy in selected cases. Blood, urine, umbilicus, aqueous, and vitreous samples underwent microbiological evaluation. Retinopathy of prematurity screening and treatment were done when indicated. Primary outcome was anatomic status assessed by comprehensive eye examination and by fundus photography whenever possible. RESULTS: Twenty-one of 26 babies (81%) were preterm. Two types of presentations included those with a fulminant appearance (24 eyes) and those with focal retinitis detected during routine screening (7 eyes). Vitreous culture was positive in 12/20 eyes (60%). Pseudomonas aeruginosa (8) was the most common isolate. Incorrect initial diagnosis was common. Treatment included intravitreal injections in 26 eyes, 10 of which also underwent vitrectomy. Twenty-four of the 26 patients (92%) received parenteral antimicrobials and 17 had evidence of systemic infection. All eyes with a fulminant presentation developed phthisis, while all focal fungal cases were salvaged. CONCLUSIONS: Neonatal endogenous endophthalmitis has 2 distinct presentations. Focal retinal infections have good visual and anatomical outcomes while fulminant nosocomial cases do poorly. Management under topical anesthesia can be an alternative strategy for sick babies that cannot undergo surgery under general anesthesia due to systemic morbidity. Awareness about early diagnostic signs may help early referral. PMID- 24338574 TI - Atypical sino-orbital inflammatory myofibroblastic tumor with bone and cerebral invasion extending to the orbit. AB - PURPOSE: To report the case of an atypical sino-orbital inflammatory myofibroblastic tumor. METHODS: Case report. RESULTS: A 71-year-old man presented slowly progressive painless diplopia followed by unilateral proptosis of the left eye with slight edema of the upper eyelid. Visual acuity was 0.4 with a relative afferent pupillary defect (RAPD). Abduction and depression of the left eye were limited. Imaging showed a left sino-orbital tumor with mass effect on the medial rectus muscle resulting in proptosis. The lesion showed intracranial extension through the superior orbital fissure with bone erosion and sclerotic bone reaction. Endoscopic ethmoidal, maxillary, and orbital biopsies revealed an inflammatory myofibroblastic tumor. Full blood count showed an eosinophilia while antineutrophil cytoplasmic antibodies and C-reactive protein were negative. To date, 7 cases of orbital myofibroblastic tumor have been described, though none of the prior studies have described bone invasion. CONCLUSIONS: This erosive sino orbital inflammatory myofibroblastic tumor is a novel finding mimicking a malignant tumor. PMID- 24338575 TI - High magnification in vivo evaluation of the mechanism of failure of an Ex-PRESS shunt implanted under the sclera flap. AB - PURPOSE: To investigate the mechanism of fibrosis-related failure of an Ex-PRESS shunt implanted under the scleral flap in trabeculectomy. METHODS: A patient with end-stage secondary open-angle glaucoma on his only functioning right eye was referred for glaucoma valve implantation. His right eye had undergone congenital cataract surgery in early childhood and posterior chamber lens implantation 20 years ago. During the last 18 months, the right eye underwent pars plana vitrectomy with silicone oil implantation, silicone oil removal, 2 sessions of cyclophotocoagulation, 2 failed trabeculectomies (one of them combined with Ex PRESS shunt implantation under the scleral flap), and 4 trabeculectomy revisions. At presentation, the intraocular pressure varied between 47 and 52 mm Hg on maximal systemic and topical intraocular pressure-lowering medication. Serial limbus parallel scans made with the CAM-L cornea lens adapter of the Optovue Fourier-domain optical coherence tomograph revealed that the space between the inner surface of the scleral flap and the external orifice of the Ex-PRESS shunt was filled by scar tissue, and the scar tissue appeared to invade the lumen of the shunt. CONCLUSIONS: The findings suggest that failure of an Ex-PRESS shunt is not always caused by episcleral fibrosis but may also be caused by scar formation between the scleral flap and the implant, inside the surgical sclera tunnel. PMID- 24338576 TI - The impact of financial crisis on central serous chorioretinopathy in Greece: is there any correlation? AB - PURPOSE: To investigate the impact of economic crisis on central serous chorioretinopathy (CSCR) incidence in Greece, analyzing data by 3 different ophthalmology units during the period 2005-2012. METHODS: Between January 1, 2005, and December 31, 2012, all patients at 3 separate ophthalmology units, i.e., 2 public university clinics and 1 private center, presenting with the diagnosis of acute CSCR, either new cases or recurrent ones, were consecutively enrolled in the study. Patients' data, including age and sex, as well as the date of presentation, were recorded and analyzed. Recurrent cases were also recorded. RESULTS: The study sample included 580 new cases of CSCR (463 male, 117 female) and 97 recurrent cases (84 male, 13 female). The mean age was 48.8 +/- 10.3 years (range 25-90). The number of incident as well as recurrent cases increased with more recent years. As expected, the increasing trend of cases and recurrences was reproducible upon the sex-specific analyses. Moreover, the increasing trend of cases and recurrences was reproducible upon the majority of analyses stratified by age. CONCLUSIONS: Our study suggests a potential impact of financial crisis on CSCR. Our results demonstrated that CSCR incidence, in both new and recurrent cases, has increased during the years of economic crisis in Greece, especially in 2010-2011, implying that CSCR is likely to be associated with stress or other emotional stimuli caused by financial crisis. It is also important to note that the results were similar in public and private units. PMID- 24338577 TI - Serum ischemia modified albumin and vascular endothelial growth factor levels following intravitreal bevacizumab injections. AB - PURPOSE: Previous reports have demonstrated that the serum levels of vascular endothelial growth factor (VEGF) are reduced after intravitreal injections of bevacizumab. This study aimed to determine the serum levels of ischemia-modified albumin (IMA), a marker of ischemia, and VEGF following intravitreal injections of bevacizumab. METHODS: This was a prospective study. Blood samples were drawn prior to injection and at 1, 7, and 30 days after injection. RESULTS: A total of 11 patients participated in this study. Mean serum IMA levels were lower than baseline during follow-up, with statistically significant differences compared to baseline levels at day 1 and day 30 (preinjection: 49.82 +/- 15.28 ng/mL; 44.57 +/- 12.01 ng/mL, p = 0.007, and 43.71 +/- 13.82 ng/mL, p = 0.001, respectively). Mean serum VEGF levels were lower than baseline throughout the follow-up period (from 307.45 +/- 273.45 pg/mL at baseline to 159.55 +/- 120.68 pg/mL at day 30). Mean serum VEGF levels were significantly lower compared to baseline levels at day 1 and day 7 (147.09 +/- 106.08 pg/mL, p = 0.014; 72.91 +/- 50 pg/mL, p = 0.011, respectively). CONCLUSIONS: In this study, mean serum IMA and VEGF levels were lower following intravitreal bevacizumab injections. PMID- 24338578 TI - A dose-finding study of preoperative intravenous dexmedetomidine in children's emergence delirium after epiblepharon surgery. AB - PURPOSE: Emergence delirium (ED) is a leading problem in children after general anesthesia. Dexmedetomidine (DEX) can be administered prior to general anesthesia to decrease ED, although wide ranges of dose are used. This study was conducted to investigate the proper dosages of DEX to attenuate children's ED after sevoflurane anesthesia. METHODS: Twenty-five children, aged 3 to 9, undergoing repair of epiblepharon were studied. A chosen dosage of DEX was infused for 10 minutes in the preoperative holding area. The dose of DEX started from 0.25 ug/kg, and then was increased or decreased by 0.25 ug/kg depending on the response of the previous patient, using the Dixon up-and-down method. After the surgery under general anesthesia with sevoflurane, ED was assessed by the Cravero 5-point emergence agitation scale (5-point scale) at the postanesthesia care unit. The 50% and 95% effective concentrations (EC50 and EC95 ) of DEX to attenuate ED were calculated by isotonic regression estimators. RESULTS: The EC50 to attenuate ED was 1.0 (95% confidence interval [CI] 0.29 to 1.71) and EC95 was 1.43 ug/kg (95% CI -1.73 to 4.60). No patient failed parental separation while the Modified Observer's Assessment of Alertness/Sedation Scale at the end of the infusion was scattered from 1 to 5. One child who received 1.50 ug/kg had brief desaturation but recovered soon after being given a verbal command. CONCLUSIONS: Dexmedetomidine can be safely used between 1.0 and 1.43 ug/kg to attenuate children's ED after sevoflurane anesthesia. PMID- 24338579 TI - Agreement between photographic screening and hospital biomicroscopy grading of diabetic retinopathy and maculopathy. AB - PURPOSE: To examine the level of agreement and reasons for disagreement between grading of diabetic retinopathy and maculopathy using mydriatic digital photographs in a diabetic retinopathy screening service (DRSS) and hospital eye service (HES). METHODS: English NHS Diabetic Eye Screening Programme grades for diabetic retinopathy prospectively recorded on a hospital electronic medical record were compared to the grades from the DRSS event that prompted referral. In cases of disagreement, images were reviewed. RESULTS: Data for 1,501 patients (3,002 eyes) referred between 2008 and 2011 were analyzed. The HES retinopathy grades were R0 (no retinopathy) in 341 eyes, R1 (background retinopathy) in 1,712 eyes, R2 (pre-proliferative retinopathy) in 821 eyes, and R3 (proliferative retinopathy) in 128 eyes. The DRSS grades were in agreement in 2,309 eyes (76.9%), recorded a lower grade in 227 eyes, and recorded a higher grade in 466 eyes. Agreement was substantial (kappa = 0.65). The commonest cause for disagreement was overgrading of R1 as R2 by hospital clinicians. The HES maculopathy grades were M0 (no maculopathy) in 2,267 eyes and M1 (maculopathy) in 735 eyes. The DRSS were in agreement in 2,111 eyes (70.2%), recorded a lower grade in 106 eyes, and recorded a higher grade in 785 eyes. Agreement was fair (kappa = 0.39). The commonest cause for disagreement was hospital clinicians missing fine exudates. CONCLUSIONS: This study establishes a benchmark standard for agreement between HES and DRSS grading. Review of DRSS and grading reports images for newly referred patients is likely to improve levels of agreement, particularly for diabetic retinopathy, and should be strongly encouraged. PMID- 24338580 TI - Evaluation of eye movements pattern during reading process in patients with glaucoma: a microperimeter study. AB - PURPOSE: To assess eye movements pattern during reading process in patients with primary open-angle glaucoma (POAG) using a microperimeter. METHODS: Thirty-two patients with POAG at early and moderate stage, according to Glaucoma Staging System 2, and 34 healthy age- and sex-matched subjects were included in the study. Reading speed and accuracy were previously evaluated with specific tests adjusted for age. In addition, all participants performed a reading test with Microperimeter Nidek MP1. Ocular movements during the reading process were recorded and values of maximum and minimum eye movements along the horizontal (Xmax and Xmin) and vertical (Ymax and Ymin) axis and mean ocular movement speed were provided by the MP1. RESULTS: There were significant differences between patients with and without POAG in terms of Xmax and Ymax eye movement values (4.75 +/- 2.57 versus 3.38 +/- 0.67, p = 0.003; and 4.39 +/- 1.43 versus 3.34 +/- 0.52, p<0.001, respectively). These differences were significant even comparing only stage 1 patients to controls. There were no significant differences in Xmin and Ymin values and mean ocular movement speed between the 2 groups. CONCLUSIONS: The study showed significant differences in eye movements pattern in patients with POAG during the reading test performed with the MP1 when compared to the control group. These alterations may be partly the consequence of the neurodegenerative process of the central visual pathway in glaucoma. PMID- 24338581 TI - Ophthalmic manifestations in familial Mediterranean fever: a case series of 6 patients. AB - PURPOSE: To describe the ocular involvement of patients with familial Mediterranean fever (FMF) followed in a tertiary referral center. METHODS: The data of 6 patients with FMF were retrospectively reviewed. Detailed ophthalmologic examinations, type of inflammation, course of the disease, number of recurrences, treatment regimens, complications, and comorbid ocular or systemic diseases were noted. RESULTS: The mean age +/- SD at diagnosis was 29.3 +/- 19.3 (4-53) years. A total of 66.7% of the patients were male and 66.7% of the patients had bilateral disease. The anatomical distribution of the ophthalmic involvement was as follows: posterior uveitis in 2 (33.3%), anterior uveitis in 2 (33.3%), posterior scleritis in 1 (16.7%), and intermediate uveitis in 1 (16.7%) patient. The course was recurrent in 50% of the patients. Final visual acuities were favorable except in the patients with chronic course uveitis. Cystoid macula edema, epiretinal membrane, retinal ischemia, cataract, glaucoma, and band keratopathy were complications noted in the follow-up period. Both cataract and glaucoma patients (50%) needed a surgical intervention. In 33.3% of patients, Behcet disease was present as a concurrent disease. In patients with posterior uveitis and the patient with intermediate uveitis (50%), systemic immunosuppression was required. CONCLUSIONS: There was a male and bilateral involvement predominance. The course of the inflammation was recurrent in half of the patients. Since ocular involvement in FMF is very rare, it should be considered as diagnosis of exclusion. PMID- 24338582 TI - Detecting an event of progression using glaucoma probability score and the stereometric parameters of Heidelberg Retina Tomograph 3. AB - PURPOSE: To evaluate the correlation of the change in glaucoma probability score (GPS) and the stereometric optic nerve head (ONH) parameters of the Heidelberg Retina Tomograph (HRT)3 to an event of glaucomatous progression observed with stereoscopic ONH photography. METHODS: The subjects for this retrospective follow up study were monitored with the HRT and stereoscopic ONH photographs. Stable, high-quality imaging and at least 18 months of follow-up was required. The topography examinations were acquired using HRT II and calculated with HRT3 software. The event of progression was determined by masked evaluation of stereoscopic ONH photographs. RESULTS: A total of 476 eyes of 342 subjects met the inclusion criteria. All the examinations with HRT II were backwards compatible with either the GPS or the stereometric parameters of HRT3. The highest statistical significance for the correlation with progression was observed in the change in cup volume and cup:disc area ratio (p<0.0005). The vertical cup:disc ratio was the parameter with the largest area under the receiver operating characteristics curve (AUC = 0.696). The AUC calculated for the change in GPS was 0.541. The GPS showed no statistically significant correlation with progression (p = 0.213). CONCLUSIONS: Detecting an event of glaucomatous progression should not be based solely on the change in GPS or the stereometric parameters of the HRT. The good backwards compatibility between HRT II and HRT3 should allow the detection of a trend of glaucomatous progression even when changing from HRT II to HRT3 during the follow-up of glaucoma. PMID- 24338583 TI - Outcome of 110 basal cell carcinomas of the eyelid treated with frozen section controlled excision: mean follow-up over 5 years. AB - PURPOSE: To analyze the outcome and risk factors of recurrence in patients with basal cell carcinomas (BCCs) of the eyelid treated by en face frozen section controlled (FSC) excision with a mean follow-up over 5 years. METHODS: This was a retrospective series of 108 patients with 110 biopsy-proven eyelid BCCs. All lesions were excised with 2 mm margins clinically free from neoplasia at clinical examination. For each tumor, en face frozen section examination of surgical margins was employed for the histologic confirmation before the reconstruction. Subsequently, all margins were submitted for permanent paraffin sections. RESULTS: Of 110 malignancies, 80.9% represented primary carcinomas and 19.1% secondary ones. The overall recurrence rate was 1.8%, with a mean follow-up of 72.4 months (range 30-167). The mean time between the excision of the lesion and the diagnosis of the recurrence was 24 months (range 20-28). No recurrences were observed in 62 tumors followed up for at least 5 years. Secondary BCCs were associated with a higher recurrence rate compared with primary BCCs (4.8% and 1.1%, respectively, p = 0.262). CONCLUSIONS: The FSC excision of eyelid BCCs yields recurrence rates comparable to those of Mohs micrographic surgery at 5 year follow-up. Intraoperative microscopic margin control improves the cure rate of eyelid BCCs, and FSC excision with small margins (2 mm) clinically free from neoplasia is associated with easier reconstruction and better cosmetic and functional outcomes. PMID- 24338584 TI - Photoreceptor layer changes overlying drusen in eyes with age-related macular degeneration associated with vitreomacular traction. AB - PURPOSE: To investigate by spectral-domain optical coherence tomography (SD-OCT) changes of photoreceptor layers over drusen in cases of dry type age-related macular degeneration associated with vitreomacular traction (VMT). METHODS: Clinical examination, fluorescein angiography, fundus photography, and SD-OCT data were retrospectively studied for a consecutive series of 27 patients with drusen, pseudodrusen, and VMT. Control groups of 32 patients with VMT without drusen and 34 patients with drusen and pseudodrusen without VMT were also studied. RESULTS: The examination revealed disruption of the line corresponding to the inner segment ellipsoid (ISel), previously called inner segment/outer segment junction, of photoreceptor layer, and development of cystoid edema in significantly higher incidence in VMT associated with drusen group. 22 out of 32 eyes with VMT and drusen (68.75%) had disrupted ISel, compared to 8 out of 37 (21.6%) control eyes with drusen only and to 12 out of 37 (32.4%) control eyes with VMT only. Chi-square analysis showed significant association between drusen and pseudodrusen on fovea, VMT, and localization of ISel disruption. The changes of the ISel were mainly found in the area that corresponded to VMT. The SD-OCT revealed drusen throughout the macula and discontinuation of ISel only in the fovea in 4 of 32 (12.5%) eyes with VMT, whereas none of 37 control eyes with drusen only had similar appearance. CONCLUSIONS: The drusen in association with the cystoid macular edema induced by vitreous traction contribute to the photoreceptor layer defect overlying drusen in the fovea. In addition, the number of drusen and pseudodrusen was increased in the area of the vitreous traction compared to the peripheral retina. PMID- 24338585 TI - Improving Boston type 1 keratoprosthesis procedure: one-touch femtosecond assisted preparation and centration of donor carrier tissue. AB - PURPOSE: We describe a technique to avoid decentration of the visual axis of the Boston type 1 keratoprosthesis (Kpro), performing 2 concentric trephinations with femtosecond laser. METHODS: Two concentric side cuts were performed in a donor cornea using the 150-kHz Intralase FS laser. Within the same applanation procedure, an 8.5-mm-diameter anterior side cut was performed, followed by a concentric 3-mm-diameter anterior side cut. RESULTS: The technique was successfully replicated in 7 cases. CONCLUSIONS: Femtosecond laser-assisted double trephination results in a correctly prepared donor cornea, and in an inner side precisely matched with the prosthesis. At the end of the surgery, the Kpro was correctly centered. PMID- 24338586 TI - Central retinal vein occlusion in a young patient following cannabis smoke inhalation. AB - PURPOSE: To report a case of central retinal vein occlusion (CRVO) following cannabis smoke inhalation in a young patient. METHODS: An otherwise healthy 18 year-old man without risk factors for retinal vein occlusion presented with reduced visual acuity (20/200) secondary to CRVO following cannabis smoke inhalation. Central retinal vein occlusion was diagnosed on the basis of slit lamp fundus biomicroscopy and fluorescein angiography. RESULTS: Tests for systemic causes were negative. Following one intravitreal dexamethasone implant (Ozurdex) and one ranibizumab injection (Lucentis), functional (20/20 visual acuity) and anatomic improvement was recorded. Fluorescein angiography showed a decrease in the vascular caliber and tortuosity, with no signs of retinal ischemia or edema. CONCLUSIONS: We report CRVO in a young adult following cannabis smoke inhalation. Its occurrence immediately after cannabis smoking further supports a link between the use of cannabis and vascular alterations. PMID- 24338588 TI - Adenosquamous carcinoma of hypopharynx with intestinal-phenotype. AB - Adenosquamous carcinomas of the head and neck (ADSCs) are rare locally aggressive malignancies characterized by the presence of two distinctive components, a squamous cell carcinoma and an adenocarcinoma. The immunophenotype of the glandular component of ADSCs has only been rarely studied but has been reported as being positive for keratin 7 (CK7) and carcinoembryonic antigen (CEA) and negative for keratin 20 (CK20). Herein, we report a case of an ADSCs of the hypopharynx composed of a superficial squamous cell carcinoma and an adenocarcinoma with an intestinal phenotype. The patient was a 62 year-old male with a T2 N0 M0 squamous cell carcinoma (SCC) of uvula and palate and a T1 N0 M0 of right hypopharynx. The ADSCs of the hypopharynx was composed of a minimally invasive SCC and an adenocarcinoma with tubulo-glandular and cribriform architecture. The neoplastic glands were positive for CK7, CK20, CDX2, CEA and Villin. The patient underwent radiotherapy to both tumors and remains well with no evidence of recurrent disease 19 months after treatment. To the best of our knowledge, this is the first report of an ADSCs of the head and neck with an intestinal phenotype in its glandular component. PMID- 24338587 TI - SIRT1 controls liver regeneration by regulating bile acid metabolism through farnesoid X receptor and mammalian target of rapamycin signaling. AB - Sirtuin1 (SIRT1) regulates central metabolic functions such as lipogenesis, protein synthesis, gluconeogenesis, and bile acid (BA) homeostasis through deacetylation. Here we describe that SIRT1 tightly controls the regenerative response of the liver. We performed partial hepatectomy (PH) to transgenic mice that overexpress SIRT1 (SIRT). SIRT mice showed increased mortality, impaired hepatocyte proliferation, BA accumulation, and profuse liver injury after surgery. The damaging phenotype in SIRT mice correlated with impaired farnesoid X receptor (FXR) activity due to persistent deacetylation and lower protein expression that led to decreased FXR-target gene expression; small heterodimer partner (SHP), bile salt export pump (BSEP), and increased Cyp7A1. Next, we show that 24-norUrsodeoxycholic acid (NorUDCA) attenuates SIRT protein expression, increases the acetylation of FXR and neighboring histones, restores trimethylation of H3K4 and H3K9, and increases miR34a expression, thus reestablishing BA homeostasis. Consequently, NorUDCA restored liver regeneration in SIRT mice, which showed increased survival and hepatocyte proliferation. Furthermore, a leucine-enriched diet restored mammalian target of rapamycin (mTOR) activation, acetylation of FXR and histones, leading to an overall lower BA production through SHP-inhibition of Cyp7A1 and higher transport (BSEP) and detoxification (Sult2a1) leading to an improved liver regeneration. Finally, we found that human hepatocellular carcinoma (HCC) samples have increased presence of SIRT1, which correlated with the absence of FXR, suggesting its oncogenic potential. CONCLUSION: We define SIRT1 as a key regulator of the regenerative response in the liver through posttranscriptional modifications that regulate the activity of FXR, histones, and mTOR. Moreover, our data suggest that SIRT1 contributes to liver tumorigenesis through dysregulation of BA homeostasis by persistent FXR deacetylation. PMID- 24338589 TI - At the start of 2014, it is a great pleasure to present to you this slightly larger edition of the journal. Introduction. PMID- 24338590 TI - Immortal time bias in retrospective analysis: is there a survival benefit in patients with glioblastoma who received prolonged treatment of adjuvant valganciclovir? PMID- 24338591 TI - Reply to: Cognitive dysfunction in spinocerebellar ataxia type 3: variable topographies and patterns. PMID- 24338592 TI - Modelling lymphoma therapy and outcome. AB - Dose and time intensifications of chemotherapy improved the outcome of lymphoma therapy. However, recent study results show that too intense therapies can result in inferior tumour control. We hypothesise that the immune system plays a key role in controlling residual tumour cells after treatment. More intense therapies result in a stronger depletion of immune cells allowing an early re-growth of the tumour.We propose a differential equations model of the dynamics and interactions of tumour and immune cells under chemotherapy. Major model features are an exponential tumour growth, a modulation of the production of effector cells by the presence of the tumour (immunogenicity), and mutual destruction of tumour and immune cells. Chemotherapy causes damage to both, immune and tumour cells. Growth rate, chemosensitivity, immunogenicity, and initial size of the tumour are assumed to be patient-specific, resulting in heterogeneity regarding therapy outcome. Maximum-entropy distributions of these parameters were estimated on the basis of clinical survival data. The resulting model can explain the outcome of five different chemotherapeutic regimens and corresponding hazard-ratios.We conclude that our model explains observed paradox effects in lymphoma therapy by the simple assumption of a relevant anti-tumour effect of the immune system. Heterogeneity of therapy outcomes can be explained by distributions of model parameters, which can be estimated on the basis of clinical survival data. We demonstrate how the model can be used to make predictions regarding yet untested therapy options. PMID- 24338593 TI - Perils, problems, and progress in laboratory diagnosis of von Willebrand disease. AB - Diagnosis of von Willebrand disease (VWD) merits consideration of personal and family history of bleeding symptoms along with confirmatory laboratory testing. As the latter yields quantifiable results, overreliance on a laboratory diagnosis may occur. However, existing tests for VWD contain potential sources for error. Both intrinsic and extrinsic factors affecting these assays can contribute to either falsely normal or falsely abnormal results. This article will discuss the present available assays as well as new developments in diagnostic testing. A clear understanding of the limitations of VWD testing is helpful for ensuring the correct diagnosis of affected patients. PMID- 24338594 TI - Comparative gene expression signature of pig, human and mouse induced pluripotent stem cell lines reveals insight into pig pluripotency gene networks. AB - Reported pig induced pluripotent stem cells (piPSCs) have shown either a bFGF dependent state with human embryonic stem cell (ESC) and mouse epiblast stem cell (EpiSC) morphology and molecular features or piPSCs exist in a LIF-dependent state and resemble fully reprogrammed mouse iPSCs. The features of authentic piPSCs and molecular events during the reprogramming are largely unknown. In this study, we assessed the transcriptome profile of multiple piPSC lines derived from different laboratories worldwide and compared to mouse and human iPSCs to determine the molecular signaling pathways that might play a central role in authentic piPSCs. The results demonstrated that the up-regulation of endogenous epithelial cells adhesion molecule (EpCAM) was correlated with the pluripotent state of pig pluripotent cells, which could be utilized as a marker for evaluating pig cell reprogramming. Comparison of key signaling pathways JAK-STAT, NOTCH, TGFB1, WNT and VEGF in pig, mouse and human iPSCs showed that the core transcriptional network to maintain pluripotency and self-renewal in pig were different from that in mouse, but had significant similarities to human. Pig iPSCs, which lacked expression of specific naive state markers KLF2/4/5 and TBX3, but expressed the primed state markers of Otx2 and Fabp7, share defining features with human ESCs and mouse EpiSCs. The cluster of imprinted genes delineated by the delta-like homolog 1 gene and the type III iodothyronine deiodinase gene (DLK1-DIO3) were silenced in piPSCs as previously seen in mouse iPSCs that have limited ability to contribute to chimaeras. These key differences in naive state gene and imprinting gene expression suggests that so far known piPSC lines may be more similar to primed state cells. The primed state of these cells may potentially explain the rare ability of piPSCS to generate chimeras and cloned offspring. PMID- 24338595 TI - MDCT and MRI evaluation of cervical spine trauma. AB - PURPOSE: Cervical spine injuries following major trauma result in significant associated morbidity and mortality. Devastating neurological injury, including complete and incomplete tetraplegia, are common sequelae of cervical spine trauma and cause profound and life-altering medical, financial, and social consequences. Most cervical spine injuries follow motor vehicle accidents, falls, and violence. The proliferation of multidetector computed tomography allows for fast and accurate screening for potential bony and vascular injuries. Magnetic resonance imaging is useful for evaluation of the supporting ligaments and the spinal cord after the patient has been stabilised. CONCLUSION: Cervical spine injuries are approached with much caution by emergency room clinicians. Thus, it is essential that radiologists be able to differentiate between a stable and unstable injury on MDCT, as this information ultimately helps determine the management of such injuries. TEACHING POINTS: MDCT and MRI are complementary and both may be needed to define injuries and determine management. MDCT rapidly evaluates the bones, and MRI is superior for detecting ligament and cord injuries. Injury to one of the three spinal columns may be stable, and injuries to more than one are unstable. Instability may cause abnormal interspinous and interpedicular distances, or cervical malalignment. Fractures of the foramen transversarium are associated with vertebral arterial dissection. PMID- 24338596 TI - Plasma levels of 14:0, 16:0, 16:1n-7, and 20:3n-6 are positively associated, but 18:0 and 18:2n-6 are inversely associated with markers of inflammation in young healthy adults. AB - Inflammation is a recognized risk factor for the development of chronic diseases, such as type 2 diabetes and atherosclerosis. Evidence suggests that individual fatty acids (FA) may have distinct influences on inflammatory processes. The goal of this study was to conduct a cross-sectional analysis to examine the associations between circulating FA and markers of inflammation in a population of young healthy Canadian adults. FA, high-sensitivity C-reactive protein (hsCRP), and cytokines were measured in fasted plasma samples from 965 young adults (22.6 +/- 0.1 years). Gas chromatography was used to measure FA. The following cytokines were analyzed with a multiplex assay: regulated upon activation normal T cell expressed and secreted (RANTES/CCL5), interleukin 1 receptor antagonist (IL-1Ra), interferon-gamma (IFN-gamma), interferon-gamma inducible protein 10 (IP-10), and platelet-derived growth factor beta (PDGF betabeta). Numerous statistically significant associations (p < 0.05, corrected for multiple testing) were identified between individual FA and markers of inflammation using linear regression. Myristic (14:0), palmitic (16:0), palmitoleic (16:1n-7), and dihomo-gamma-linolenic (20:3n-6) acids were positively associated with all markers of inflammation. In contrast, stearic acid (18:0) was inversely associated with hsCRP and RANTES, and linoleic acid (18:2n-6) was inversely associated with hsCRP, RANTES and PDGF-betabeta. In conclusion, our results indicate that specific FA are distinctly correlated with various markers of inflammation. Moreover, the findings of this study suggest that FA profiles in young adults may serve as an early indicator for the development of future complications comprising an inflammatory component. PMID- 24338597 TI - Efficacy of group-adapted physical exercises in reducing back pain in women with postmenopausal osteoporosis. AB - PURPOSE: The clinical effects of osteoporosis include pain, fractures, and physical disability, causing a loss of independence and necessitating long-term care. Whereas the effects of exercise therapy in decreasing body mass index and preventing fractures are well established, there is no consensus on back pain and quality of life in women with osteoporosis. The aim of this study was to determine the efficacy of a brief course of rehabilitation, comprising group adapted physical exercises, with regard to back pain, disability, and quality of life in women with postmenopausal osteoporosis who had no evidence of fractures. METHODS: The enrolled patients were randomized into two groups: the treatment group underwent ten sessions of rehabilitative exercises, and the control group received an instructional booklet with descriptions and figures of exercises that were to be performed at home. RESULTS: Sixty patients completed the trial and assessments, including a 6-month follow-up. The treatment was effective versus the control group, significantly improving pain (Visual Analogue Scale: p < 0.001 at the end of the treatment and at the follow-up; McGill Pain Questionnaire: p = 0.018 at the follow-up), disability (Oswestry Disability Questionnaire: p < 0.001 at the end and follow-up), and quality of life (Shortened Osteoporosis Quality of Life Questionnaire: p = 0.021 at the end of treatment; p = 0.005 at follow-up). CONCLUSIONS: Our results suggest that group rehabilitation reduces back pain and improves functional status and quality of life in women with postmenopausal osteoporosis, maintaining these outcomes for 6 months. The use of physical exercises might strengthen the habit to training. PMID- 24338598 TI - Aspects of health in prehistoric mainland Southeast Asia: Indicators of stress in response to the intensification of rice agriculture. AB - Numerous bioarcheological investigations have suggested that as agriculture intensifies, levels of physiological stress and poor health increase. However, previous research in Southeast Asia suggests that a decline in health was not universal. This study aimed to provide the first investigation of human health during the intensification of rice agriculture in the large skeletal sample from the prehistoric site of Ban Non Wat, Northeast Thailand (1750-420 b.c.). Health was analysed using two indicators of childhood stress, the prevalence of linear enamel hypoplasia (LEH), a measure of early childhood stress, and stature, as a measure of late childhood stress, were collated for 190 adults. Sex-specific diachronic relationships between the prevalence of LEH and stature were explored. For both sexes, initially the prevalence of LEH was found to decrease and then increase over time. Stature remained constant over time for males, although for females stature increased initially, then decreased. Early childhood stress was not significantly correlated with stature in females (P = 0.185), but high levels of LEH were unexpectedly correlated with taller male stature (P = 0.017). Our findings suggest an initial improvement in health during agricultural intensification at this site, likely related to a reduction in physiological perturbations and maintenance of a nutritious diet during this time. The subsequent deterioration in health may reflect geomorphologically and archaeologically indicated variation in environmental conditions and consequential sociocultural changes. We suggest that the sex-differences in the relationship between stature and LEH may relate to the timing of stress and/or catch-up growth. PMID- 24338600 TI - Sample size requirements for the design of reliability studies: precision consideration. AB - In multilevel modeling, the intraclass correlation coefficient based on the one way random-effects model is routinely employed to measure the reliability or degree of resemblance among group members. To facilitate the advocated practice of reporting confidence intervals in future reliability studies, this article presents exact sample size procedures for precise interval estimation of the intraclass correlation coefficient under various allocation and cost structures. Although the suggested approaches do not admit explicit sample size formulas and require special algorithms for carrying out iterative computations, they are more accurate than the closed-form formulas constructed from large-sample approximations with respect to the expected width and assurance probability criteria. This investigation notes the deficiency of existing methods and expands the sample size methodology for the design of reliability studies that have not previously been discussed in the literature. PMID- 24338601 TI - Monte Carlo based statistical power analysis for mediation models: methods and software. AB - The existing literature on statistical power analysis for mediation models often assumes data normality and is based on a less powerful Sobel test instead of the more powerful bootstrap test. This study proposes to estimate statistical power to detect mediation effects on the basis of the bootstrap method through Monte Carlo simulation. Nonnormal data with excessive skewness and kurtosis are allowed in the proposed method. A free R package called bmem is developed to conduct the power analysis discussed in this study. Four examples, including a simple mediation model, a multiple-mediator model with a latent mediator, a multiple group mediation model, and a longitudinal mediation model, are provided to illustrate the proposed method. PMID- 24338599 TI - Dynamic transcriptional response of Escherichia coli to inclusion body formation. AB - Escherichia coli is used intensively for recombinant protein production, but one key challenge with recombinant E. coli is the tendency of recombinant proteins to misfold and aggregate into insoluble inclusion bodies (IBs). IBs contain high concentrations of inactive recombinant protein that require recovery steps to salvage a functional recombinant protein. Currently, no universally effective method exists to prevent IB formation in recombinant E. coli. In this study, DNA microarrays were used to compare the E. coli gene expression response dynamics to soluble and insoluble recombinant protein production. As expected and previously reported, the classical heat-shock genes had increased expression due to IB formation, including protein folding chaperones and proteases. Gene expression levels for protein synthesis-related and energy-synthesis pathways were also increased. Many transmembrane transporter and corresponding catabolic pathways genes had decreased expression for substrates not present in the culture medium. Additionally, putative genes represented over one-third of the genes identified to have significant expression changes due to IB formation, indicating many important cellular responses to IB formation still need to be characterized. Interestingly, cells grown in 3% ethanol had significantly reduced gene expression responses due to IB formation. Taken together, these results indicate that IB formation is complex, stimulates the heat-shock response, increases protein and energy synthesis needs, and streamlines transport and catabolic processes, while ethanol diminished all of these responses. PMID- 24338602 TI - Prevalence of work-related musculoskeletal symptoms among US large-herd dairy parlor workers. AB - BACKGROUND: Dairy production in the US is moving towards large-herd milking operations resulting in an increase in task specialization and work demands. METHODS: A modified version of the Standardized Nordic Questionnaire was administered to assess MSS prevalence among 452 US large-herd parlor workers. Worker demographics and MSS prevalences were assessed, and differences based on parlor configuration (i.e., herringbone, parallel, rotary) were computed. RESULTS: Three-fourths (76.4%) of parlor workers reported work-related MSS in at least one body part. Highest prevalences were reported in the upper extremity (55%). Herringbone workers reported a higher prevalence of MSS in the wrist/hand, and rotary workers reported higher prevalences of MSS in the neck, upper back, and shoulders. CONCLUSIONS: Our findings draw attention to higher work-related MSS in the upper extremity among dairy parlor workers. As the trend toward larger herd sizes on US dairy farms continues, the need for further health and safety research will increase. PMID- 24338603 TI - Margin width is not predictive of residual disease on re-excision in breast conserving therapy. AB - BACKGROUND: There is lack of consensus regarding re-excision in breast-conserving therapy (BCT) and close margins. We hypothesize that margin width does not predict residual disease. METHODS: The cancer registry was queried from 2003 to 2008 for patients with BCT who underwent re-excision for <2-mm margins. Factors associated with additional disease were evaluated. RESULTS: One thousand eight hundred forty-three patients underwent BCT. Our re-excision rate was 42%. Clinicopathologic factors from 228 patients were analyzed. One hundred five patients (46%) had additional disease; of those, 58% had BCT and 42% mastectomy. One hundred twenty-three (54%) had no additional disease; of those 82% had BCT and 18% mastectomy. Of the 66 patients who underwent mastectomy, 44 (67%) had residual disease; of the 161 who had BCT, 61 (38%) had residual disease (P < 0.01). On univariate analysis, margin width did not correlate with residual disease. Multifocality, non-invasive histology, increasing number of close margins, and higher grade predicted additional disease (P < 0.05). On multivariate analysis, only number of close margins remained significant. CONCLUSIONS: Margin width does not predict additional disease. This challenges the practice of using this to select re-excision candidates. Our data suggest that tumor behavior and extent of disease, defined by volume of residual disease and invasiveness of histology, play a more significant role. PMID- 24338604 TI - Longer time-to-pregnancy in spontaneously conceived pregnancies is associated with lower PAPP-A and free beta-hCG in first trimester screening for Down syndrome. AB - OBJECTIVE: The aim of this study was to investigate whether subfertility, measured as longer time-to-pregnancy (TTP) in spontaneously conceived pregnancies, affects the first trimester levels of pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotrophin (beta-hCG) and hence the risk estimates in Down syndrome screening. METHODS: The study included a cohort of 10 469 singleton pregnant women who underwent first trimester combined screening and responded to a questionnaire regarding TTP. PAPP-A and free beta-hCG levels were measured between gestational week 8 + 0 and 13 + 6 and were related to TTP. RESULTS: The median PAPP-A and free beta-hCG MoMs were significantly lower in women with a TTP >=24 months compared with the reference group with a TTP <6 months (PAPP-A: 0.96 vs 1.06 MoM, p = 0.003; free beta-hCG: 1.04 vs 1.12 MoM, p = 0.03). This led to an increased odds for trisomy 21 risk >=1 : 300 for TTP >=24 months compared with TTP <6 months, but when adjusting for potential confounders, the odds ratio (OR) lost significance (OR 1.4, 95% confidence interval; 0.8-2.4). CONCLUSION: Time-to-pregnancy >=24 months in spontaneously conceived pregnancies is associated with decreased levels of PAPP-A and free beta-hCG. PMID- 24338605 TI - Advances in alpha-1-antitrypsin deficiency liver disease. AB - Alpha-1-antitrypsin (a1AT) deficiency is a common, but under-diagnosed, genetic disease. In the classical form, patients are homozygous for the Z mutant of the a1AT gene (called ZZ or PIZZ), which occurs in 1 in 2,000-3,500 births. The mutant Z gene directs the synthesis of large quantities of the mutant Z protein in the liver, which folds abnormally during biogenesis and accumulates intracellularly, rather than being efficiently secreted. The accumulation mutant Z protein within hepatocytes causes liver injury, cirrhosis, and hepatocellular carcinoma via a cascade of chronic hepatocellular apoptosis, regeneration, and end organ injury. There is no specific treatment for a1AT-associated liver disease, other than standard supportive care and transplantation. There is high variability in the clinical manifestations among ZZ homozygous patients, suggesting a strong influence of genetic and environmental modifiers. New insights into the biological mechanisms of intracellular injury have led to new, rational therapeutic approaches. PMID- 24338607 TI - The potential therapeutic benefit of targeting ADAMTS13 activity. AB - Platelet-vessel wall interaction is mediated by von Willebrand factor (VWF), which thereby plays a major role in physiological hemostasis and thrombotic disease. VWF is released as ultralarge multimers from endothelial cells, whereupon it is cleaved by ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type I repeats-13). The prohemostatic properties of VWF are dependent of its multimeric size; hence, ADAMTS13 activity is an important determinant in platelet-vessel wall interaction. Deficiency of ADAMTS13 in its most classical form in thrombotic thrombocytopenic purpura can lead to severe thrombotic microangiopathy. However, there is a growing variety of diseases in which ADAMTS13 levels have been found to be decreased and in which reduced cleavage of VWF may play a role. Hence, targeting of VWF cleavage by pharmacological modulation of ADAMTS13 levels is an interesting approach in some of these conditions. This review discusses the available evidence for a role of ADAMTS13 in various disease states and the potential therapeutic benefit of restoration of ADAMTS13 levels. PMID- 24338606 TI - Prospective seroepidemiologic study on the role of Human Papillomavirus and other infections in cervical carcinogenesis: evidence from the EPIC cohort. AB - To evaluate prospectively the association between serological markers of selected infections, including HPV, and risk of developing cervical cancer (CC) and precancer, we performed a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) study that included 184 cases of invasive CC (ICC), 425 cases of cervical intraepithelial neoplasia (CIN) grade 3 or carcinoma in situ (CIS), and 1,218 matched control women. At enrollment participants completed lifestyle questionnaires and provided sera. Subjects were followed-up for a median of 9 years. Immunoassays were used to detect serum antibodies to Human Herpes Virus 2 (HHV-2), Chlamydia trachomatis (CT), Chlamydia pneumoniae, L1 proteins of mucosal and cutaneous HPV types, E6/E7 proteins of HPV16/18, as well as to four polyomaviruses. Adjusted odds ratios (OR) [and 95% confidence intervals (CI)] for CIN3/CIS and ICC risk were respectively: 1.6 (1.2-2.0) and 1.8 (1.1-2.7) for L1 seropositivity to any mucosal HPV type, 1.0 (0.4-2.4) and 7.4 (2.8-19.7) for E6 seropositivity to HPV16/18, 1.3 (0.9-1.9) and 2.3 (1.3-4.1) for CT seropositivity, and 1.4 (1.0 2.0) and 1.5 (0.9-2.6) for HHV-2 seropositivity. The highest OR for ICC was observed for HPV16 E6 seropositivity [OR = 10.2 (3.3-31.1)]. Increasing number of sexually transmitted infections (STIs) was associated with increasing risk. Non STIs were not associated with CC risk. In conclusion, this large prospective study confirms the important role of HPV and a possible contribution of CT and HHV-2 in cervical carcinogenesis. It further identifies HPV16 E6 seropositivity as the strongest marker to predict ICC well before disease development. PMID- 24338608 TI - Von Willebrand factor: form for function. AB - The mechanisms by which von Willebrand factor (VWF) achieves hemostasis lie in its structure. Whereas low-molecular-weight forms have diminished hemostatic potential, ultralarge VWF (ULVWF) in excess is potentially thrombogenic. VWF comprises many subunits, which themselves comprise many repeated domains/assemblies possessing characteristic function(s). Organization of these domains/assemblies into a multimeric structure effectively links and replicates these functions. Each domain/assembly influences the synthesis, assembly, secretion, or hemostatic potential of plasma VWF. The C-terminal CT/CK domain mediates dimerization of VWF subunits in the endoplasmic reticulum, while the N terminal D1D2 assemblies catalyzes disulfide binding between juxtaposed D3 assemblies in the trans-Golgi, creating multimers. The pH-sensitive domains (A2 CT/CK) allow ULVWF multimers to orderly pack into tubules that unravel upon secretion into the circulation. Hemodynamic forces regulate the conformation of the A2 domain and thus, its accessibility to proteolytic enzyme(s) that regulate VWF's hemostatic potential. Binding to the VWF D'D3 assemblies stabilizes coagulation factor VIII. The VWF A1 and A3 domains facilitate platelet capture onto exposed collagen(s) at sites of vascular injury. Our deeper understanding of VWF provided through the recent growth in VWF structure-function studies may potentially guide novel therapeutics for clotting or bleeding disorders. PMID- 24338609 TI - Anti-inflammatory effect of platelet-rich plasma on nucleus pulposus cells with response of TNF-alpha and IL-1. AB - The purpose of this study was to investigate the anti-inflammatory effect of platelet-rich plasma (PRP) with collagen matrix on human nucleus pulposus (NP) cell in response to pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1). NP cells from human disks were cultured in a monolayer and maintained in the collagen matrix prior to the addition of recombinant human IL-1 and TNF-alpha. After applying IL-1 and TNF alpha, PRP prepared by using a commercially available platelet concentration system was added. The response was investigated using real-time PCR for mRNA expression of type II collagen, aggrecan, matrix metalloproteinase-3 (MMP-3), and cyclooxygenase-2 (COX-2). The combination of IL-1beta and TNF-alpha led to decrease of matrix synthesis gene expression such as collagen type II and aggrecan and increase of the degradation gene expression of COX-2 and MMP-3, compared to the control. Consecutive PRP exposure significantly recovered the down-regulated gene expression of collagen type II and aggrecan and significantly reduced the increased MMP-3 and COX-2 gene expression, compared to that of control groups with pro-inflammatory cytokines. The administration of PRP with collagen matrix markedly suppressed cytokine-induced pro-inflammatory degrading enzymes and mediators in the NP cell. It also rescued gene expression concerning matrix synthesis, thereby stabilizing NP cell differentiation. PMID- 24338610 TI - Nine weeks versus 1 year adjuvant trastuzumab in patients with early breast cancer: an observational study by the Turkish Oncology Group (TOG). AB - BACKGROUND: Optimal duration of adjuvant trastuzumab in early breast cancer is an unresolved issue. In this observational study, we compared the outcome of 9 weeks and 1 year adjuvant trastuzumab in early breast cancer patients in Turkey. METHODS: Records of 680 patients with HER2-positive early breast cancer who received adjuvant trastuzumab plus chemotherapy were obtained and patients were followed up to compare the disease-free survival (DFS) outcome of 9 weeks versus 1 year trastuzumab. RESULTS: Nine weeks and 1 year trastuzumab was given to 202 (29.7 %) and 478 (70.3 %) patients, respectively. There was a significantly lower rate of patients with negative lymph nodes in the 9-week trastuzumab group. At median 3 years of follow-up from the date of starting trastuzumab, the DFS rates were 88.6 and 85.6 %, respectively (p = 0.670). When adjusted for all the prognostic factors that were significant on univariate analysis, again there was no significant difference in DFS between the groups (HR 0.675; 95 % CI 0.370 1.231; p = 0.200). Cardiac toxicity defined as a >=15 % decrease in LVEF was significantly higher in the 1-year trastuzumab group (1.88 % versus none for 1 year and 9-week trastuzumab groups, respectively; p = 0.050). CONCLUSION: The results of this observational study suggest that DFS outcome of 9 weeks of adjuvant trastuzumab may be comparable to 1 year adjuvant trastuzumab: this needs confirmation by randomized trials. PMID- 24338611 TI - The sinonasal tract: another potential "hot spot" for carcinomas with transcriptionally-active human papillomavirus. AB - While high risk human papillomavirus (HPV) is well established as causative and clinically important for squamous cell carcinoma (SCC) of the oropharynx, its role in non-oropharyngeal head and neck SCC is much less clearly elucidated. In the sinonasal region, in particular, although it is a relatively uncommon site for SCC, as many as 20 % of SCC harbor transcriptionally-active high risk HPV. These tumors almost always have a nonkeratinizing morphology and may have a better prognosis. In addition, specific variants of SCC as well as other rare carcinoma types, when arising in the sinonasal tract, can harbor transcriptionally-active HPV. This article reviews the current literature on HPV in sinonasal carcinomas, attempts to more clearly demonstrate what tumors have it and how this relates to possible precursor lesions like inverted papilloma, and discusses the possible clinical ramifications of the presence of the virus. PMID- 24338612 TI - Acute necrotizing herpetic tonsillitis: a report of two cases. AB - The finding of herpetic tonsillitis is rare. Tonsillectomies are usually done for children with recurrent chronic tonsillitis, while viral throat infections are generally self-limiting. We present two cases: A 5 year-old girl, with atypical hemolytic anemia managed with Eculizumab, who presented with a pharyngeal infection and tonsillar enlargement that did not respond to intravenous antibiotics or antifungal therapies; and a 30 year-old man who presented with upper airway obstruction and fever; bilateral tonsillectomies were performed. Histopathological examination showed a necrotizing tonsillitis with numerous ground-glass intranuclear inclusions, characteristic of herpes viral infection, further confirmed by Herpes simplex virus in situ hybridization. Both patients were managed by intravenous Acyclovir, with dramatic improvement. PMID- 24338613 TI - La Radiologia Medica progress report. PMID- 24338615 TI - Is montelukast indicated for treatment of chronic rhinosinusitis with polyposis? PMID- 24338616 TI - Imaging referral guidelines in Europe: now and in the future-EC Referral Guidelines Workshop Proceedings. AB - As an integral part of the European Commission (EC) Imaging Referral Guidelines Project a 1.5-day workshop was held in Vienna on 20-21 September, 2012. At this workshop, models and good practices regarding the appropriateness and use of imaging referral guidelines (Guidelines) in Europe and worldwide were presented, together with the results of a survey of Guidelines in Europe. The latter included ideas, innovations and wishes for future Community action. MAIN MESSAGES: Recommendations for future Community action: Stronger measures should be taken by the EC and the European competent authorities for making Guidelines available and used in all EU member states. Evidence-based Guidelines with separate guidance for children should be issued or endorsed by a trusted European organisation. Educational initiatives and electronic requesting in connection with clinical decision support (CDS) systems should be used to improve the implementation of Guidelines. Monitoring of Guidelines implementation and use should be by clinical audit, particularly external audit, but also by local/internal audit. PMID- 24338617 TI - European survey on imaging referral guidelines. AB - The objective of this study was to devise and implement a Europe-wide study on referral guidelines for radiological imaging in the EU Member States in order to identify potential major issues, important differences between Member States and good practices. A web-based survey was used to assess the availability of imaging referral guidelines, development methodology and preferences for future initiatives for European community action to facilitate justification and appropriate use of radiological diagnostic procedures. A questionnaire was distributed to representatives of national radiological and nuclear medicine societies as well as to competent authorities for radiation protection in 30 European countries, including all 28 EU Member States. Responses were collated and analysed to produce a series of conclusions and recommendations. MAIN MESSAGES: * Survey respondents in 21/30 countries were aware of legal requirements for Guidelines * Survey respondents in 18/30 countries were aware of the availability of Guidelines in their country. * The majority of responders support the development of European Guidelines. These may either be from a combination of multiple national Guidelines with consensus or Pan-European Guidelines developed centrally. * Guidelines developed in two countries included all of the following important features: radiation dose information; specific advice for imaging children; specific advice for the pregnant woman/unborn child; an evidence-based process; a formal consensus for recommendations. * Suggestions for additional measures needed to reinforce the use of Guidelines include: educational initiatives; integrating Guidelines into clinical decision support systems; clinical audit for monitoring of the availability, use and implementation of Guidelines. PMID- 24338619 TI - Capillary electrophoresis separation of human milk neutral and acidic oligosaccharides derivatized with 2-aminoacridone. AB - Human milk is a unique fluid in glycobiology due to the presence of many free structurally complex oligosaccharides emerging as important dietary factors during early life and having many biological and protective functions. Methods that allow accurate profiling of oligosaccharide mixtures in this complex biological fluid with quantification of the four known genetically determined groups are welcomed. A high-voltage CE separation and detection at 254 nm of 17 neutral and acidic human milk oligosaccharide (HMO) standard along with lactose derivatized with 2-aminoacridone, using a BGE containing 20% methanol as an organic modifier and borate, able to form on-capillary anionic borate-polyol complexes, is reported. This CE approach was able to separate both neutral HMOs and acidic HMOs, with the sialic acid residue, also in the presence of lactose in high content. This method was applied to the four secretory groups individually extracted by a rapid and simple preparative step. LODs were found ranging from ~50 to 700 fmol. We were able to measure HMO content also in the presence of excess fluorophore, or interference from proteins, peptides, salts, and other impurities normally present in this complex biological fluid. Overall, CE equipped with a UV detector is a common analytical approach and this simple CE separation offers high resolution and sensitivity for the differentiation of human milk samples related to genetic groups and days of lactation by considering that important changes in HMO content are a reflection of the lactation day. PMID- 24338618 TI - Blocking NMDA receptors delays death in rats with acute liver failure by dual protective mechanisms in kidney and brain. AB - Treatment of patients with acute liver failure (ALF) is unsatisfactory and mortality remains unacceptably high. Blocking NMDA receptors delays or prevents death of rats with ALF. The underlying mechanisms remain unclear. Clarifying these mechanisms will help to design more efficient treatments to increase patient's survival. The aim of this work was to shed light on the mechanisms by which blocking NMDA receptors delays rat's death in ALF. ALF was induced by galactosamine injection. NMDA receptors were blocked by continuous MK-801 administration. Edema and cerebral blood flow were assessed by magnetic resonance. The time course of ammonia levels in brain, muscle, blood, and urine; of glutamine, lactate, and water content in brain; of glomerular filtration rate and kidney damage; and of hepatic encephalopathy (HE) and intracranial pressure was assessed. ALF reduces kidney glomerular filtration rate (GFR) as reflected by reduced inulin clearance. GFR reduction is due to both reduced renal perfusion and kidney tubular damage as reflected by increased Kim-1 in urine and histological analysis. Blocking NMDA receptors delays kidney damage, allowing transient increased GFR and ammonia elimination which delays hyperammonemia and associated changes in brain. Blocking NMDA receptors does not prevent cerebral edema or blood-brain barrier permeability but reduces or prevents changes in cerebral blood flow and brain lactate. The data show that dual protective effects of MK-801 in kidney and brain delay cerebral alterations, HE, intracranial pressure increase and death. NMDA receptors antagonists may increase survival of patients with ALF by providing additional time for liver transplantation or regeneration. PMID- 24338620 TI - Cognitive dysfunction in spinocerebellar ataxia type 3: variable topographies and patterns. PMID- 24338621 TI - SYNTAX-justified trend toward restricting coronary artery bypass grafting to more serious cases. AB - OBJECTIVE: Since drug-eluting stents (DESs) appeared in Japan, coronary artery bypass grafting (CABG) has been indicated for more severe lesions. To understand the implications of this trend, we compared SYNTAX scores in two groups of patients treated with CABG before and after DESs approval. METHODS: Consecutive CABG patients during January 2001-July 2003 (pre-DES era patients, n = 160) and January 2008-July 2010 (DES era patients, n = 103) were included. The SYNTAX scores of both groups were compared and a cardiologist retrospectively re evaluated coronary angiograms to determine whether CABG or percutaneous coronary intervention (PCI) would be recommended under current standards. RESULTS: SYNTAX scores were significantly higher in DES era group compared with pre-DES era group (33.3 +/- 10.6 vs. 28.1 +/- 10.6, p < 0.01). Percutaneous coronary intervention would be the preferred treatment option in 66 (41 %) of pre-DES patients, whose SYNTAX scores were significantly lower than those of patients who were considered good candidates for CABG (21.9 +/- 9.3 vs. 32.5 +/- 9.1, p < 0.01). CONCLUSIONS: Although CABG is now being performed in intermediate-to-highly complex cases, DES era outcomes, including operative mortality and early graft failure, have not worsened in comparison to the pre-DES era. PMID- 24338623 TI - Ultrasonographic assessment of the femoral cartilage in osteoarthritis patients with and without osteoporosis. AB - BACKGROUND: The relationship between osteoporosis (OP) and osteoarthritis (OA) is yet unclear. AIM: To evaluate the possible effect of OP on the femoral cartilage thickness in female patients with knee OA. MATERIALS AND METHODS: Eighty patients with a diagnosis of knee OA were enrolled. Forty subjects who also had OP comprised Group I and the remaining 40 OA subjects comprised Group II. Antero posterior knee radiographs were obtained in standing position and they were evaluated according to Kelgren-Lawrence (K-L) grading scale. Femoral cartilage evaluations were performed using a linear array US probe (7-12 MHz). In addition, ultrasonographic femoral cartilage grading was also performed for each knee. RESULTS: Left knee scores pertaining to both gradings were found to be lower (p = 0.02, p = 0.04, respectively) in Group I when compared with those of Group II. The two grading scores were positively correlated for both knees-statistically significant only for the right side (r = 0.727, p = 0.01). No significant difference was found between the groups in terms of femoral cartilage thicknesses (all p > 0.05). DISCUSSION: Ultrasonographic and roentgenographic gradings were consistent and patients with OP had lower scores for both gradings. On the other hand, the presence of OP did not seem to have any effect on cartilage thickness measurements. CONCLUSIONS: To the best knowledge of the authors, this study is the first to have explored the impact of OP on OA using US in the literature. PMID- 24338624 TI - Eating disorders symptoms in pregnancy and postpartum: a prospective study in a disadvantaged population in Brazil. AB - OBJECTIVE: To assess eating disorder symptoms (EDS) from prepregancy through postpartum. METHOD: Seven hundred and twelve women with gestational age ranging from 16th to 36th week completed the eating disorder examination questionnaire (EDE-Q). A shortened version of the EDE-Q was used to assess, retrospectively, EDS during the last 28 days of the pregestational period. Follow up assessment occurred at the 4th-5th month postpartum (n = 427). Generalized structural equation models were used to estimate risk of EDS in pregestation, gestation, and postpartum. RESULTS: Women who did not participate in follow up (n = 285) were not significantly different in sociodemographic characteristics. In postpartum, a higher number of women referred shape (RR = 1.65; 95% CI 1.19-2.30) and weight concerns (RR = 1.64; 95% CI 1.16-2.31) than in pregestation. Binge eating (BE) and self-induced vomiting diminished during pregnancy (RR = 0.70, 95% CI 0.57 0.85; RR = 0.21, 95% CI 0.10-0.44, respectively) and postpartum (RR = 0.62, 95% CI 0.48-0.80; RR = 0.38, 95% CI 0.19-0.76, respectively) compared with pregestation DISCUSSION: Shape and weight concerns are highly prevalent in postpartum and may confer risk for the development of inappropriate eating behaviors. Health professionals should be trained on how to recognize these symptoms. PMID- 24338625 TI - An augmented reality home-training system based on the mirror training and imagery approach. AB - Mirror training and movement imagery have been demonstrated to be effective in treating several clinical conditions, such as phantom limb pain, stroke-induced hemiparesis, and complex regional pain syndrome. This article presents an augmented reality home-training system based on the mirror and imagery treatment approaches for hand training. A head-mounted display equipped with cameras captures one hand held in front of the body, mirrors this hand, and displays it in real time in a set of four different training tasks: (1) flexing fingers in a predefined sequence, (2) moving the hand into a posture fitting into a silhouette template, (3) driving a "Snake" video game with the index finger, and (4) grasping and moving a virtual ball. The system records task performance and transfers these data to a central server via the Internet, allowing monitoring of training progress. We evaluated the system by having 7 healthy participants train with it over the course of ten sessions of 15-min duration. No technical problems emerged during this time. Performance indicators showed that the system achieves a good balance between relatively easy and more challenging tasks and that participants improved significantly over the training sessions. This suggests that the system is well suited to maintain motivation in patients, especially when it is used for a prolonged period of time. PMID- 24338626 TI - Simplifying the interaction between cognitive models and task environments with the JSON Network Interface. AB - Process models of cognition, written in architectures such as ACT-R and EPIC, should be able to interact with the same software with which human subjects interact. By eliminating the need to simulate the experiment, this approach would simplify the modeler's effort, while ensuring that all steps required of the human are also required by the model. In practice, the difficulties of allowing one software system to interact with another present a significant barrier to any modeler who is not also skilled at this type of programming. The barrier increases if the programming language used by the modeling software differs from that used by the experimental software. The JSON Network Interface simplifies this problem for ACT-R modelers, and potentially, modelers using other systems. PMID- 24338627 TI - Safety of elective colorectal cancer surgery: non-surgical complications and colectomies are targets for quality improvement. AB - BACKGROUND: Mortality following severe complications (failure-to-rescue, FTR) is targeted in surgical quality improvement projects. Rates may differ between colon and rectal cancer resections. METHODS: Analysis of patients undergoing elective colon and rectal cancer resections registered in the Dutch Surgical Colorectal Audit in 2011-2012. Severe complication- and FTR rates were compared between the groups in univariate and multivariate analysis. RESULTS: Colon cancer (CC) patients (n = 10,184) were older and had more comorbidity. Rectal cancer (RC) patients (n = 4,906) less often received an anastomosis and had more diverting stomas. Complication rates were higher in RC patients (24.8% vs. 18.3%, P < 0.001). However, FTR rates were higher in CC patients (18.6% vs. 9.4%, P < 0.001). Particularly, FTR associated with anastomotic leakage, postoperative bleeding, and infections was higher in CC patients. Adjusted for casemix, CC patients had a twofold risk of FTR compared to RC patients (OR 1.89, 95% CI 1.06 3.37). CONCLUSIONS: Severe complication rates were lower in CC patients than in RC patients; however, the risk of dying following a severe complication was twice as high in CC patients, regardless of differences in characteristics between the groups. Efforts should be made to improve recognition and management of postoperative (non-)surgical complications, especially in colon cancer surgery. PMID- 24338628 TI - Visualizing infection spread: dual-color fluorescent reporting of virus-host interactions. AB - Although the molecular mechanisms by which host cells defend themselves against viral infection have been studied in great depth, and countermeasures viruses employ to suppress such defensive responses have been widely documented, relatively little attention has been devoted toward elucidating how such interactions between virus and host are resolved over multiple rounds of infection. Here, we describe the design, synthesis, and validation of a dual color fluorescent reporter system to study how viral infections spread through a host cell monolayer and how the cellular innate immune system mounts an antiviral response. We employed recombinant, red fluorescent protein expressing mutants of a prototypical RNA virus, vesicular stomatitis virus to enable identification and tracking of infected cells. Further, we generated stable reporter cells that use green fluorescent protein to report on the expression of IFIT2, an interferon stimulated gene involved in the interference of viral protein translation, and a marker of antiviral defense activation. The presence of the fluorescent protein reporters had minimal effects on the normal behavior of the cells or viruses. Moreover, expression of the virus and cell reporters correlated with the kinetics of viral replication and activation of an anti-viral response, respectively. This two-color system enabled us to track and quantify in live cells how viral replication and activation of host defensive responses play out over multiple rounds of infection. Initial study of propagating infections demonstrated that antiviral activation over multiple rounds was critical for slowing and ultimately halting the spread of infection. PMID- 24338629 TI - Rosiglitazone-induced CD36 up-regulation resolves inflammation by PPARgamma and 5 LO-dependent pathways. AB - PPARgamma-achieved neuroprotection in experimental stroke has been explained by the inhibition of inflammatory genes, an action in which 5-LO, Alox5, is involved. In addition, PPARgamma is known to promote the expression of CD36, a scavenger receptor that binds lipoproteins and mediates bacterial recognition and also phagocytosis. As phagocytic clearance of neutrophils is a requisite for resolution of the inflammatory response, PPARgamma-induced CD36 expression might help to limit inflammatory tissue injury in stroke, an effect in which 5-LO might also be involved. Homogenates, sections, and cellular suspensions were prepared from brains of WT and Alox5(-/-) mice exposed to distal pMCAO. BMMs were obtained from Lys-M Cre(+) PPARgamma(f/f) and Lys-M Cre(-) PPARgamma(f/f) mice. Stereological counting of double-immunofluorescence-labeled brain sections and FACS analysis of cell suspensions was performed. In vivo and in vitro phagocytosis of neutrophils by microglia/macrophages was analyzed. PPARgamma activation with RSG induced CD36 expression in resident microglia. This process was mediated by the 5-LO gene, which is induced in neurons by PPARgamma activation and at least by one of its products--LXA4--which induced CD36 independently of PPARgamma. Moreover, CD36 expression helped resolution of inflammation through phagocytosis, concomitantly to neuroprotection. Based on these findings, in addition to a direct modulation by PPARgamma, we propose in brain a paracrine model by which products generated by neuronal 5-LO, such as LXA4, increase the microglial expression of CD36 and promote tissue repair in pathologies with an inflammatory component, such as stroke. PMID- 24338630 TI - Myeloid-derived suppressor cells enhance IgE-mediated mast cell responses. AB - Mast cells and MDSCs are increased by parasitic infection and tumor growth. We previously demonstrated that enhanced MDSC development in ADAM10 transgenic mice yielded resistance to Nb infection and that coculturing MDSCs and mast cells enhanced cytokine production. In the current work, we show that MDSC-mast cell coculture selectively enhances IgE-mediated cytokine secretion among mast cells, without increasing MDSC cytokine production. This effect was independent of cell contact and elicited by Ly6C(+) and Ly6C/G+ MDSC subsets. These interactions were functionally important. MDSC depletion with the FDA-approved drug gemcitabine exacerbated Nb or Trichinella spiralis infection and reduced mast cell-dependent AHR and lung inflammation. Adoptive transfer of MDSC worsened AHR in WT but not mast cell-deficient Wsh/Wsh mice. These data support the hypothesis that MDSCs enhance mast cell inflammatory responses and demonstrate that this interaction can be altered by an existing chemotherapeutic. PMID- 24338631 TI - Mortality prediction after cardiac surgery: blood lactate is indispensible. AB - BACKGROUND: Blood lactate is accepted as a mortality risk marker in intensive care units (ICUs), especially after cardiac surgery. Unfortunately, most of the commonly used ICU risk stratification scoring systems did not include blood lactate as a variable. We hypothesized that blood lactate alone can predict the risk of mortality after cardiac surgery with an accuracy that is comparable to those of other complex models. We therefore evaluated its accuracy at mortality prediction and compared it with that of other widely used complex scoring models statistically. METHODS: We prospectively collected data of all consecutive adult patients who underwent cardiac surgery between January 1, 2007, and December 31, 2009. By using chi2 statistics, a blood lactate-based scale (LacScale) with only four cutoff points was constructed in a developmental set of patients (January 1, 2007, and May 31, 2008). LacScale included five categories: 0 (<= 1.7 mmol/L); 1 (1.8-5.9 mmol/L), 2 (6.0-9.3 mmol/L), 3 (9.4-13.3 mmol/L), and 4 (>= 13.4 mmol/L). Its accuracy at predicting ICU mortality was evaluated in another independent subset of patients (validation set, June 1, 2008, and December 31, 2009) on both study-population level (calibration analysis, overall correct classification) and individual-patient-risk level (discrimination analysis, ROC statistics). The results were then compared with those obtained from other widely used postoperative models in cardiac surgical ICUs (Sequential Organ Failure Assessment [SOFA] score, Simplified Acute Physiology Score II [SAPS II], and Acute Physiology and Chronic Health Evaluation II [APACHE II] score). RESULTS: ICU mortality was 5.8% in 4,054 patients. LacScale had a reliable calibration in the validation set (2,087 patients). It was highly accurate in predicting ICU mortality with an area under the ROC curve (area under curve [AUC]; discrimination) of 0.88. This AUC was significantly larger than that of all the other models (SOFA 0.83, SAPS II: 0.79 and APACHE II: 0.76) according to DeLong's comparison. Integrating the LacScale in those scores further improved their accuracy by increasing their AUCs (0.88, 0.81, and 0.80, respectively). This improvement was also highly significant. CONCLUSION: Blood lactate accurately predicts mortality at both individual patient risk and patient cohort levels. Its precision is higher than that of other commonly used "complex" scoring models. The proposed LacScale is a simple and highly reliable model. It can be used (at bedside without electronic calculation) as such or integrated in other models to increase their accuracy. PMID- 24338632 TI - Smoking as a major risk factor for cervical cancer and pre-cancer: results from the EPIC cohort. AB - A total of 308,036 women were selected from the European Prospective Investigation into Cancer and Nutrition (EPIC) study to evaluate the association between tobacco smoking and the risk of cervical intraepithelial neoplasia of grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC). At baseline, participants completed a questionnaire and provided blood samples. During a mean follow-up time of 9 years, 261 ICC cases and 804 CIN3/CIS cases were reported. In a nested case-control study, the baseline sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11, 16, 18, 31, 33, 35, 45, 52, 58, and antibodies against Chlamydia trachomatis (CT), and Human Herpes Virus 2 (HHV-2). Cervical samples were not available for HPV-DNA analysis in this study. Multivariate analyses were used to estimate associations between smoking and risk of CIN3/CIS and ICC in the cohort and the case-control studies. In the cohort analyses smoking status, duration and intensity showed a two-fold increased risk of CIN3/CIS and ICC, while time since quitting was associated with a two-fold reduced risk. In the nested case-control study, consistent associations were observed after adjustment for HPV, CT and HHV 2 serostatus, in both HPV seronegative and seropositive women. Results from this large prospective study confirm the role of tobacco smoking as an important risk factor for both CIN3/CIS and ICC, even after taking into account HPV exposure as determined by HPV serology. The strong beneficial effect of quitting smoking is an important finding that will further support public health policies for smoking cessation. PMID- 24338633 TI - Reference values for fetal aortic isthmus blood flow parameters at 24 to 38 weeks' gestation. AB - OBJECTIVE: The goal of this study is to establish population-specific nomograms of fetal aortic isthmus (AoI) Doppler indices in the period of 24-38 weeks' gestation. METHODS: This was a cross-sectional study of 240 Asian singleton pregnant women at 24-38 completed weeks' gestation. Fetal AoI blood flow was evaluated by Doppler study with automatic calculation of pulsatility index, resistance index, peak systolic velocity, end-diastolic velocity, and time averaged maximum velocity. The relationship of these indices and gestational age was estimated by using regression analysis, and the best predictive models were determined to define mean, 5th, and 95th centile of each gestational age. The reproducibility was expressed by intraclass correlation coefficients and limits of agreement. RESULTS: The mean maternal age was 28 +/- 5.7 years. A total of 97% of all attempts to obtain AoI Doppler waveforms were successful with high interobserver and intraobserver reproducibility. Pulsatility index and peak systolic velocity significantly correlated with gestational age (P = 0.03 and 0.001, respectively), whereas no significant change of resistance index, end diastolic velocity, and time-averaged maximum velocity with advancing gestation was observed. CONCLUSION: This study offers normative values of fetal AoI Doppler indices, which may be useful in the difficult task of fetal surveillance in growth-restricted fetuses among our population. PMID- 24338634 TI - Role of Nlrp6 and Nlrp12 in the maintenance of intestinal homeostasis. AB - There has been significant interest in understanding how interactions between the host immune system and the gut microbiota regulate intestinal homeostasis. Recent data suggest that the Nod-like receptor (NLR) family of PRRs regulate both the composition of the gut microbiota and innate immune signaling pathways that prevent pathologic intestinal inflammation and tumorigenesis. In this review, we will focus on NLRP6 and NLRP12, two members of the NLR family that have emerged as important players in the maintenance of intestinal homeostasis, and discuss the signaling pathways engaged by these receptors as well as the current models of how these receptors protect against the development of colitis and tumorigenesis. PMID- 24338635 TI - Effects of undergoing multiplex genetic susceptibility testing on parent attitudes towards testing their children. AB - BACKGROUND: Parents may pursue common disease risk information about themselves via multiplex genetic susceptibility testing (MGST) for their children. PURPOSE: To prospectively assess whether parents who received MGST disclosed their test results to their child, intended to change the child's health habits, or have the child tested. METHODS: Eighty parents who opted for free MGST completed an online survey about a child in their household before undergoing MGST and a follow-up telephone survey 3 months after receiving results. RESULTS: Few parents (21 %) disclosed results to the child. Undergoing MGST was unrelated to intentions to change the child's health habits but did increase parental willingness to test the child. Greater willingness to test a child was associated with positive attitudes toward pediatric genetic testing and intentions to change the child's health habits. CONCLUSION: The experience of receiving MGST had little impact on parents' perceptions or behaviors related to their minor child. PMID- 24338636 TI - Rational design of polyion complex nanoparticles to overcome cisplatin resistance in cancer therapy. AB - Rationally designed PIC nanoparticles as next-generation delivery system: we have developed a core-shell-corona PIC nanoparticle (?) NP/Pt@PPC-DA as a next generation delivery system. (?) NP/Pt@PPC-DA exhibits prolonged circulation and enhanced drug accumulation in tumors. Subsequently, tumor pH leads to the release of (?) NP/Pt, which facilitates cellular uptake followed by rapid intracellular cisplatin release. Using this delivery strategy cisplatin-resistant tumor growth in a murine xenograft model has been successfully suppressed. PMID- 24338637 TI - ACPSEM brachytherapy working group recommendations for quality assurance in brachytherapy. PMID- 24338638 TI - Prognostic significance of subtype and pathologic response in operable breast cancer; a pooled analysis of prospective neoadjuvant studies of JBCRG. AB - PURPOSE: In the past decade, JBCRG has conducted three studies of neoadjuvant chemotherapy which have examined sequential combination of fluorouracil, epirubicin and cyclophosphamide, and docetaxel. The present study is a pooled analysis of these studies performed to determine the prognostic significance of pathologic complete response (pCR) and predictive variables for pCR. METHODS: A total of 353 patients were included. pCR was defined as the absence of invasive cancer or only a few remaining isolated cancer cells in the breast (quasi-pCR, QpCR). RESULTS: Disease-free survival (DFS) and overall survival (OS) were not significantly different among studies, and patients who achieved a QpCR had significantly better prognosis (DFS, p < 0.001; OS, p = 0.002). Patients with triple-negative (TN) tumors had worse prognosis than patients with the other subtypes (DFS, p = 0.03; OS, p = 0.10). A Cox proportional hazards model showed node-positive, TN, and QpCR were the significant predictors for DFS and OS among study, age, tumor size, nuclear grade, nodal status, subtype, clinical response, and pathologic response (DFS; node-positive, HR = 2.29, p = 0.001; TN, HR = 3.39, p < 0.001; QpCR, HR = 0.27, p < 0.001: OS; node-positive, HR = 3.05, p = 0.003; TN, HR = 4.92, p < 0.001; QpCR, HR = 0.12, p < 0.001). In a logistic regression analysis, subtype and clinical response before surgery were the significant predictive variables for QpCR (luminal/Her2-positive, odds ratio (OR) = 4.15, p = 0.002; Her2-positive, OR = 6.24, p < 0.001; TN, OR = 4.24, p < 0.001; clinical response before surgery, OR = 2.41, p = 0.019). CONCLUSIONS: This study confirmed the prognostic significance of QpCR and nodal status and the predictive and prognostic significance of subtype in neoadjuvant chemotherapy. PMID- 24338639 TI - Eating-disordered behavior in adolescent boys: eating disorder examination questionnaire norms. AB - OBJECTIVE: We sought to provide normative data for the Eating Disorder Examination Questionnaire (EDE-Q) for adolescent boys. METHOD: The EDE-Q was completed by 531 boys aged 12-18 years recruited from a number of schools in the Australian Capital Territory (ACT) region of Australia. Data for 1,135 female adolescents, recruited as part of the same research project, are provided for comparative purposes. RESULTS: Scores on each the EDE-Q subscales and, with the exception of excessive exercise, the prevalence of each of the eating disorder behaviors assessed, were substantially higher among girls than among boys. Still, 6.0% of boys reported regular episodes of objective binge eating, 8.3% reported regular episodes of loss of control eating, 5.3% reported regular excessive exercise and 4.9% reported overvaluation of weight or shape. Eating-disordered behavior was more common among older adolescents than among younger adolescents and this was the case for both boys and girls. Reliability coefficients for the EDE-Q subscales were marginally lower in boys (0.70-0.94) than in girls (0.84 0.97). CONCLUSIONS: The EDE-Q appears to be suitable for use in adolescent boys, with the qualification that eating and weight/shape control behaviors that are largely confined to males may not be adequately assessed. The lack of assessment of subjective binge eating episodes may also be problematic. There is a need for research addressing whether and to what extent different features are associated with distress and disability in boys as well as the validity of the EDE-Q assessment of these features when compared with interview assessment. PMID- 24338640 TI - T2 * MR relaxometry and ligament volume are associated with the structural properties of the healing ACL. AB - Our objective was to develop a non-invasive magnetic resonance (MR) method to predict the structural properties of a healing anterior cruciate ligament (ACL) using volume and T2 * relaxation time. We also compared our T2 *-based structural property prediction model to a previous model utilizing signal intensity, an acquisition-dependent variable. Surgical ACL transection followed by no treatment (i.e., natural healing) or bio-enhanced ACL repair was performed in a porcine model. After 52 weeks of healing, high-resolution MR images of the ACL tissue were collected. From these images, ligament volumes and T2 * maps were established. The structural properties of the ligaments were determined via tensile testing. Using the T2 * histogram profile, each ligament voxel was binned based on its T2 * value into four discrete tissue sub-volumes defined by specific T2 * intervals. The linear combination of the ligament sub-volumes binned by T2 * value significantly predicted maximum load, yield load, and linear stiffness (R(2) = 0.92, 0.82, 0.88; p < 0.001) and were similar to the previous signal intensity based method. In conclusion, the T2 * technique offers a highly predictive methodology that is a first step towards the development of a method that can be used to assess ligament healing across scanners, studies, and institutions. PMID- 24338641 TI - VEGF ameliorates cognitive impairment in in vivo and in vitro ischemia via improving neuronal viability and function. AB - Vascular endothelial growth factor (VEGF) has recently been proved to be a potential therapeutic drug in ischemic disorders depending on the dose, route and time of administration, especially in focal cerebral ischemia. Whether VEGF could exert protection in a long-term total cerebral ischemic model is still uncertain, and the cellular mechanism has not been clarified so far. In order to answer the above issue, an experiment was performed in non-invasively giving exogenous VEGF to a total cerebral ischemic model rats and examining their spatial cognitive function by performing Morris water maze and long-term potential test. Moreover, we performed in vitro experiment to explore the cellular mechanism of VEGF protection effect. In an in vitro ischemia model oxygen-glucose deprivation (OGD), whole-cell patch-clamp recording was employed to examine neuronal function. Additionally, hematoxylin-eosin and propidium iodide staining were applied in vivo and in vitro in the neuropathological and viability study, separately. Our results showed that intranasal administration of VEGF could improve the cognitive function, synaptic plasticity and damaged hippocampal neurons in a global cerebral ischemia model. In addition, VEGF could retain the membrane potential, neuronal excitability and spontaneous excitatory postsynaptic currents in the early stage of ischemia, which further demonstrated that there was an acute effect of VEGF in OGD-induced pyramidal neurons. Simultaneously, it was also found that the death of CA1 pyramidal neuronal was significantly reduced by VEGF, but there was no similar effect in VEGF coexists with SU5416 group. These results indicated that VEGF could ameliorate cognitive impairment and synaptic plasticity via improving neuronal viability and function through acting on VEGFR-2. PMID- 24338643 TI - Culture and demography: from reluctant bedfellows to committed partners. AB - Demography and culture have had a long but ambivalent relationship. Cultural influences are widely recognized as important for demographic outcomes but are often "backgrounded" in demographic research. I argue that progress toward a more successful integration is feasible and suggest a network model of culture as a potential tool. The network model bridges both traditional (holistic and institutional) and contemporary (tool kit) models of culture used in the social sciences and offers a simple vocabulary for a diverse set of cultural concepts, such as attitudes, beliefs, and norms, as well as quantitative measures of how culture is organized. The proposed model conceptualizes culture as a nested network of meanings represented by schemas that range in complexity from simple concepts to multifaceted cultural models. I illustrate the potential value of a model using accounts of the cultural changes underpinning the transformation of marriage in the United States and point to developments in the social, cognitive, and computational sciences that could facilitate the application of the model in empirical demographic research. PMID- 24338645 TI - Three-dimensional saline infusion vaginography for sonographic assessment of the anterior vaginal wall and pelvic floor descent. AB - Ultrasound has been recognized as an important tool for pelvic floor evaluation. A main limitation of the two-dimensional transvaginal examination is in delineation of the posterior vaginal compartment and its relation to the cervix. We describe the use of three-dimensional saline infusion vaginography as a complementary technique for the assessment of the vaginal wall and pelvic floor descent. We present several cases that demonstrate the advantages of this technique in overcoming the limitations inherent in current approaches. The improved imaging obtained by this technique enabled us to measure pelvic floor parameters and assist in evaluating pelvic floor dysfunction. PMID- 24338642 TI - Mass spectrometric methods for monitoring redox processes in electrochemical cells. AB - Electrochemistry (EC) is a mature scientific discipline aimed to study the movement of electrons in an oxidation-reduction reaction. EC covers techniques that use a measurement of potential, charge, or current to determine the concentration or the chemical reactivity of analytes. The electrical signal is directly converted into chemical information. For in-depth characterization of complex electrochemical reactions involving the formation of diverse intermediates, products and byproducts, EC is usually combined with other analytical techniques, and particularly the hyphenation of EC with mass spectrometry (MS) has found broad applicability. The analysis of gases and volatile intermediates and products formed at electrode surfaces is enabled by differential electrochemical mass spectrometry (DEMS). In DEMS an electrochemical cell is sampled with a membrane interface for electron ionization (EI)-MS. The chemical space amenable to EC/MS (i.e., bioorganic molecules including proteins, peptides, nucleic acids, and drugs) was significantly increased by employing electrospray ionization (ESI)-MS. In the simplest setup, the EC of the ESI process is used to analytical advantage. A limitation of this approach is, however, its inability to precisely control the electrochemical potential at the emitter electrode. Thus, particularly for studying mechanistic aspects of electrochemical processes, the hyphenation of discrete electrochemical cells with ESI-MS was found to be more appropriate. The analytical power of EC/ESI-MS can further be increased by integrating liquid chromatography (LC) as an additional dimension of separation. Chromatographic separation was found to be particularly useful to reduce the complexity of the sample submitted either to the EC cell or to ESI-MS. Thus, both EC/LC/ESI-MS and LC/EC/ESI-MS are common. PMID- 24338646 TI - Potential of vancomycin for the enantiomeric resolution of FMOC-amino acids by capillary electrophoresis-ion-trap-mass spectrometry. AB - The potential of the antibiotic vancomycin (VC) as chiral selector for the enantiomeric separation of amino acids by CE-ESI-MS/MS2 was investigated for the first time in this work. Derivatization of amino acids with FMOC-Cl was carried out to enable their interaction with VC as well as the formation of precursor ions with larger m/z which were employed in MS2 experiments. The partial filling of a coated capillary was employed to avoid the loss in MS sensitivity originated by the introduction of VC in the ionization source. Under optimized conditions, the simultaneous enantiomeric separation and unequivocal identification of 17 amino acids (two of them being nonprotein amino acids) took place in about 20 min with LODs in the micromolar range. PMID- 24338647 TI - Bridging the credibility gap in cost effectiveness analysis. PMID- 24338648 TI - Nanoelectronic impedance detection of target cells. AB - Detection of cells is typically performed using optical fluorescence based techniques such as flow cytometry. Here we present the impedance detection of target cells using a nanoelectronic probe we have developed, which we refer to as the nanoneedle biosensor. The nanoneedle consists of a thin film conducting electrode layer at the bottom, an insulative oxide layer above, another conductive electrode layer above, and a protective oxide above. The electrical impedance is measured between the two electrode layers. Cells captured on the surface of the nanoneedle tip results in a decrease in the impedance across the sensing electrodes. The basic mechanisms behind the electrical response of cells in solution under an applied alternating electrical field stems from modulation of the relative permittivity at the interface. In this paper we discuss, the circuit model, the nanofabrication, and the testing and characterization of the sensor. We demonstrate proof of concept for detection of yeast cells with specificity. We envision the sensor presented in this paper to be combined with microfluidic pre-concentration technologies to develop low cost point-of-care diagnostic assays for the clinical setting. PMID- 24338649 TI - IABP timing and ventricular performance--comparison between a compliant and a stiffer aorta: a hybrid model study including baroreflex. AB - INTRODUCTION: The aim of this study was to investigate the effects of the intra aortic balloon pump (IABP) and of aortic compliance on left ventricular performance, including the effects of baroreflex control.? METHODS: The study was conducted using a hybrid cardiovascular simulator, including a computational cardiovascular sub-model, a hydraulic sub-model of the descending aorta, and a baroreflex computational sub-model. A 40 cc balloon was inserted into a rubber tube component of the hydraulic sub-model. A comparative analysis was conducted for two aortic compliances (C1 = 2.4 and C2 = 1.43 cm3/mmHg, corresponding to an aortic pulse pressure of 23 mmHg and 35 mmHg, respectively), driving the balloon for different trigger timings.? RESULTS: Under C1 conditions, the IABP induced higher effects on baroreflex activity (decrement of sympathetic efferent activity: 10% for C1 and 14.7% for C2) and ventricular performance (increment of cardiac output (CO): 3.7% for C1 and 5.2% for C2, increment of endocardial viability ratio (EVR): 24.8% for C1 and 55% for C2). The best balloon timing was different for C1 and C2: inflation trigger timing (from the dicrotic notch) -0.09 s for C1 and -0.04 s for C2, inflation duration 0.25 s for C1 and 0.2 s for C2.? CONCLUSIONS: Early inflation ensures better EVR, CO, and an increment of the afferent nerve activity, hence causing peripheral resistance and heart rate to decrease. The best balloon timing depends on aortic compliance, thus suggesting the need for a therapy tailored to the specific conditions of individual patients. PMID- 24338650 TI - A survey of membrane oxygenator heat-exchanger integrity testing at cardiac surgery centres in Great Britain and Ireland. AB - Membrane oxygenator heat exchanger (HE) device failure is reported to be very low for both short- and long-term extracorporeal devices. All oxygenator manufacturers provide instructions for leak testing of their HE devices prior to patient use. In addition to these recommendations, since 2006 at Nottingham University Hospitals (NUH) we have also additionally pressure tested HE devices prior to use. We conducted a national survey of cardiac centers in Great Britain and Ireland to determine the methods undertaken in individual centers for validation of the integrity of HE devices. Furthermore, we also collected information on the routine maintenance techniques utilized within these centers to inhibit microbial growth in the water used in the heater-cooler units (HCUs). In total, 34 responses were collected from the 57 centers performing cardiac surgery, producing a response rate of 60%. Of the responding centers, 71% are adhering to manufacturer's recommended guidelines of circulating the water through the device for 5 minutes. Of these centers, 17% reported detecting a leak between the HE and membrane compartment of the oxygenator. In responding centers, 29% reported using the pressure test technique. In the centers utilizing pressure testing, 60% reported detecting a leak. This survey reports an association of a greater HE leak detection rate using the pressure test technique compared to using water testing in isolation (p = 0.034). We believe the pressure testing method provides the perfusionist with confidence in the integrity of the HE for short- and long-term circulatory support devices prior to use in both elective and emergency situations. PMID- 24338651 TI - Development and analysis of semi-interpenetrating polymer networks for brain injection in neurodegenerative disorders. AB - PURPOSE: Our aim was to assess the use of injectable, biocompatible and resorbable, hydrogel-based tools for innovative therapies against brain-related neurodegenerative disorders like Alzheimer's (AD) and Parkinson's (PD) diseases. METHODS: Two compositions of semi-interpenetrating polymer networks (semi-IPNs) based on collagen and poly(ethylene glycol) (PEG) were investigated. We examined their viscoelastic properties, flow behavior, functional injectability, as well as in vitro biocompatibility with SH-SY5Y human neuroblastoma cells and murine primary neurons. We also evaluated the in vivo biological performance after subcutaneous and brain injection in mice. RESULTS: selected semi-IPNs showed a gel-like behavior and were injectable through a 30 G needle, with the maximum load ranging from 3.0 to 3.9 N. In vitro results showed that immortalized cells kept their proliferative potential and neurons maintained their viability after embedding in both materials, with better performances for the gel with the higher collagen content. For both semi-IPNs, after subcutaneous injection, the inflammatory response was negligible; after brain injection, the tissue did not show any signs of damage or degeneration. CONCLUSIONS: The results suggest that the selected semi-IPNs not only represent a proper environment for cells, but also, once injected in vivo, do not induce damage/inflammation in the surrounding brain tissue. These findings represent a crucial starting point for the development of minimally invasive and injectable hydrogel-based tools for innovative drug/cell-based therapeutic strategies against AD, PD, or other severe brain-related neurodegenerative pathologies.

PMID- 24338652 TI - Determination and extension of the limits to static cold storage using subnormothermic machine perfusion. AB - BACKGROUND/AIMS: Static cold storage (SCS) of the liver for transplantation is limited by time. Continuation of metabolic activity leads to depletion of energy stores and loss of cellular function, which results in poor post-transplant function. Machine perfusion (MP) applied at the end of preservation may improve the viability of marginal liver grafts and provides information on the quality of the organ. We attempt to define the limits to SCS in terms of easily measurable perfusion parameters and investigate whether MP can improve liver viability. ? METHODS: Rat livers were cold-stored for 0, 24, 48, 72, and 120 h, after which they were treated with subnormothermic machine perfusion (SNMP). Livers cold stored for 48 and 72 h were transplanted orthotopically with or without SNMP. During SNMP easily measurable parameters were monitored and adenosine triphosphate (ATP) content was measured following preservation and SNMP. ? RESULTS: ATP increased significantly during SNMP, but the recovered ATP content deteriorated with increased duration of SCS, with minimal improvement after 72 h of SCS. Vascular resistance during SNMP increased with extended preservation. After 48 h of SCS, orthotopic transplantation survival increased significantly from 50% to 100% with SNMP, but did not improve after 72 h. ? CONCLUSIONS: Vascular resistance and ATP recovery suggest a decrease in viability after 48 h of SCS. Survival data confirms the loss of post-transplant graft function and supports the use of ATP and vascular resistance as useful indicators. Further, we show that the recoverability of a liver using SNMP is limited to 48 h of SCS. PMID- 24338653 TI - Sterilization using electrolyzed water highly retains the biological properties in tissue-engineered porcine liver scaffold. AB - PURPOSE: The aims of this study were to investigate the effects of sterilization with peracetic acid (PAA) and ethanol on the biological activity of porcine liver scaffolds and to develop a new technique for sterilization using slightly acidic electrolyzed water (SAEW). METHODS: Decellularization of liver slices was performed using 0.1% sodium-dodecyl-sulfate, then evaluated by histological and polymerase chain reaction analyses. Decellularized slices were treated with either PAA or ethanol or SAEW, and then DNA content was quantified. We determined sterilization efficiency by culturing scaffolds in culture medium and on blood agar. We next analyzed the glycosaminoglycan and collagen contents of the scaffolds. Finally, we tested the cytotoxicity of the scaffolds as well as the effects of sterilization on host cell attachment and proliferation. RESULTS: Complete cell and antigenic epitopes removal emphasized the decellularization efficiency. PAA and SAEW treatments achieved the highest efficiency of sterilization compared to that of the ethanol treated scaffolds, and were able to remove a considerable fraction of DNA from decellularized livers. The retained glycosaminoglycan content decreased in all treatments in the following order: SAEW, ethanol, and PAA. Ethanol caused a significant loss in collagen content compared to the other groups. A cytotoxicity evaluation revealed that all scaffolds were nontoxic. SAEW-treated scaffolds supported cell attachment and proliferation at a significantly higher rate than other groups. CONCLUSIONS: These data suggest that SAEW is highly efficient for sterilizing scaffolds and allowed the scaffolds to retain their bioactivity in addition to its high efficiency for cell remnant removal. PMID- 24338654 TI - Randomized trial of frequent low-efficiency and short hemodialysis/hemofiltration in hemodialysis patients with acute brain injury. AB - PURPOSE: The aim of the study was to compare effects of frequent low-efficiency and short hemodialysis (FLESHD) and frequent low-efficiency and short hemofiltration (FLESHF) in hemodialysis (HD) patients with acute brain injury (ABI).? METHODS: We randomly divided 13 HD patients with ABI into FLESHD (n = 6) or FLESHF (n = 7) groups. Conditions for the first to third sessions were as follows. FLESHD: intravenous administration of glycerol 400 ml/session, blood flow rate (QB) 100 ml/min, dialysate flow rate 300 ml/min, and treatment duration 2 h (HD-1). FLESHF: intravenous administration of glycerol 400 ml/session, QB 150 ml/min, substitution flow rate 10 l/session, and treatment duration 4 h (HF-1). After the fourth session, we gradually changed the conditions and stopped glycerol administration (HD-2 and HF-2).? RESULTS: There were no significant differences in survival rate, consciousness level, or adverse effects during hospitalization in either group. In mixed model analysis, the level of HCO3- post FLESHF was significantly (p<0.0001) increased compared with the level post FLESHD. However, no significant differences were seen in the levels of osmolality, in blood pressure before and after either dialysis method, or in the level of HCO3- pre dialysis. The variation in the relative ratio of BUN before FLESHF was significantly higher (p<0.05) than the relative ratio before FLESHD in the sixth session. In the FLESHD groups, serum sodium was higher and serum potassium was lower than in the FLESHF groups.? CONCLUSIONS: FLESHD with glycerol under these conditions may be a better therapeutic option for managing patients with ABI, although the short-term survival rate is similar. PMID- 24338655 TI - Regional citrate anticoagulation in therapeutic plasma exchange with fresh frozen plasma--a modified protocol. AB - PURPOSE: In membrane-based therapeutic plasma exchange (TPE), regional citrate anticoagulation (RCA) is associated with difficulties because of citrate accumulation and consequent, potentially significant, metabolic complications, especially when using fresh frozen plasma (FFP) as replacement fluid. We modified the technical setup of a commercially available continuous veno-venous hemodialysis RCA module (multiFiltrate Ci-Ca(r)) to establish an RCA-protocol for TPE. METHODS: Description of the modified technical setup and retrospective analysis of the feasibility of the RCA-protocol for TPE in all patients treated between 2009 and 2010. RESULTS: 411 consecutive TPE with RCA were performed in 42 patients, all using FFP as replacement fluid. Median procedure characteristics were: blood flow 160 ml/min, filtrate flow 36 ml/min, duration 93 min, processed total plasma volume 3600 mL. Trisodium citrate was infused at a rate of 0.43 mmol/min to achieve post-filter ionized calcium levels of <0.4 mmol/l. Calcium substitution rate was 0.19 mmol/min to maintain physiologic iCa levels. RCA was well tolerated with no significant differences in pH, iCa, bicarbonate or potassium after repeated sessions. Clotting events complicated 7.3% of the procedures. Adverse events occurred in 3.4% of TPE procedures; none was severe or fatal. No significant differences were observed comparing the rate of adverse events to those observed in TPE using standard anticoagulation at our center (4.8%). CONCLUSIONS: We describe for the first time a modified protocol for RCA in TPE using an integrated citrate module. Based on our experience, this RCA protocol is a feasible alternative for anticoagulation in TPE with FFP, especially in patients with a high risk of bleeding. PMID- 24338656 TI - Improving RhoA-mediated intestinal epithelial permeability by continuous blood purification in patients with severe acute pancreatitis. AB - BACKGROUND: Early dysfunction of the intestinal mucosal barrier contributes to increasing intestinal permeability. It may play an important role in the pathophysiology of severe acute pancreatitis (SAP). A rising number of clinical data have showed that continuous blood purification (CBP) may improve the prognosis of SAP. However, the therapeutic effects of CBP on intestinal epithelial permeability have been rarely reported. METHODS: Intestinal epithelial monolayer (Caco-2) was incubated with serum samples collected at specific time points from SAP patients during CBP. Changes in intestinal epithelial monolayer permeability and configuration, and levels of cellular tight junction structural proteins including occludin and ZO-1, and RhoA mRNA expression level were recorded, respectively. In addition, serum tumor necrosis factor-alpha (TNF alpha) levels at specific time points during CBP were determined. RESULTS: Before CBP initiation, intestinal epithelial permeability was increased and tight junction structural protein level was decreased and reorganized, but RhoA mRNA expression and serum TNF-alpha were increased. However, after CBP treatment, intestinal epithelial permeability was reduced and tight junction protein levels were increased, with reorganization attenuated. Meanwhile, RhoA mRNA expression and serum TNF-alpha level was decreased. CONCLUSIONS: After CBP treatment, intestinal epithelial permeability was reduced by increasing occludin and ZO-1 protein level and attenuating reorganization. This beneficial effect of CBP on intestinal epithelial permeability is associated with down-regulation of RhoA mRNA expression, and it may be related to the removal of TNF-alpha by CBP. PMID- 24338657 TI - Prone position during ECMO is safe and improves oxygenation. AB - PURPOSE: Combination of prone positioning (PrP) and extracorporeal membrane oxygenation (ECMO) might be beneficial in severe acute respiratory distress syndrome (ARDS), because both approaches are recommended. However, PrP during ECMO might be associated with complications such as dislocation of ECMO cannulae. We investigated complications and change of oxygenation effects of PrP during ECMO to identify "responders" and discuss our results considering different definitions of response in the literature.? METHODS: Retrospective analysis of complications, gas exchange, and invasiveness of mechanical ventilation during first and second PrP on ECMO at specified time points (before, during, and after PrP). We used multivariate nonparametric analysis of longitudinal data (MANOVA) to compare changes of mechanical ventilation and hemodynamics associated with the first and second procedures.? RESULTS: In 12 ECMO patients, 74 PrPs were performed (median ECMO duration: 10 days (IQR: 6.3-?15.5 days)). No dislocations of intravascular catheters/cannulae, endotracheal tubes or chest tubes were observed. Two PrPs had to be interrupted (endotracheal tube obstruction, acute pulmonary embolism). PaO2/FiO2-ratio increased associated with the first and second PrP (p = 0.002) and lasted after PrP in 58% of these turning procedures ("responders") without changes in ECMO blood flow, respiratory pressures, minute ventilation, portion of spontaneously triggered breathing, and compliance. Hemodynamics did not change with exception of increased mean pulmonary arterial pressure during PrP and decrease after PrP (p<0.001), while norepinephrine dosage decreased (p = 0.03) (MANOVA).? CONCLUSIONS: Prone position during ECMO is safe and improves oxygenation even after repositioning. This might ameliorate hypoxemia and reduce the harm from mechanical ventilation. PMID- 24338658 TI - Implementation of recurrent artificial neural networks for nonlinear dynamic modeling in biomedical applications. AB - Simulation is indispensable during the design of many biomedical prostheses that are based on fundamental electrical and electronic actions. However, simulation necessitates the use of adequate models. The main difficulties related to the modeling of such devices are their nonlinearity and dynamic behavior. Here we report the application of recurrent artificial neural networks for modeling of a nonlinear, two-terminal circuit equivalent to a specific implantable hearing device. The method is general in the sense that any nonlinear dynamic two terminal device or circuit may be modeled in the same way. The model generated was successfully used for simulation and optimization of a driver (operational amplifier)-transducer ensemble. This confirms our claim that in addition to the proper design and optimization of the hearing actuator, optimization in the electronic domain, at the electronic driver circuit-to-actuator interface, should take place in order to achieve best performance of the complete hearing aid. PMID- 24338659 TI - Prenatal beta-thalassemia carrier screening in Australia: healthcare professionals' perspectives of clinical practice. AB - OBJECTIVE: To gain a better understanding of healthcare professionals' practice and attitudes regarding prenatal beta-thalassemia carrier screening in Australia. METHOD: Qualitative study with semi-structured interviews of healthcare professionals (obstetricians, general practitioners, midwives, genetic counselors, and hematologists) involved in prenatal thalassemia carrier screening in public and private practice. RESULTS: Twenty-three healthcare providers were interviewed and several themes emerged. Participants described and acknowledged inconsistencies in the beta-thalassemia screening processes, such as variability in ordering the tests, communicating the diagnosis, and action taken after diagnosis. They indicated a preference for more structure and valued the importance of screening guidelines but many of those involved in ordering the screening test were unaware of their availability. These healthcare professionals recognized they lacked knowledge regarding the screening process, and many had not undertaken education activities in this area in recent times. There were mixed views about the consent process, particularly at which stage this should be obtained, and what information is provided. CONCLUSIONS: beta-thalassemia screening in Victoria occurs with apparent lack of awareness of guidelines and an acknowledged preference for a more systematic process and educational support. Informed consent was not considered an important component of this screening process. PMID- 24338660 TI - Treatment and outcome of young patients with esophageal cancer in the Netherlands. AB - BACKGROUND: Esophageal cancer is increasingly recognized in younger patients. We compared clinicopathological characteristics, treatment, and survival of patients aged <=50 years with patients aged >50 years diagnosed with esophageal cancer in the Netherlands. METHODS: From the nationwide Netherlands Cancer Registry we identified all patients diagnosed with esophageal cancer between January 2000 and January 2011. Proportions were compared using the chi(2) test for categorical variables. Overall and relative survival was calculated. RESULTS: Eleven percent of the patients (n = 1,466) were aged <=50 years and adenocarcinoma was the most common tumor type (73.6%). Grade of tumor differentiation was comparable between both age groups (P = 0.460) as well as T-stage (P = 0.058). Younger patients presented more often with positive lymph nodes (70.1% vs. 66.4%, P = 0.010) and distant metastasis (50.5% vs. 44.7%, P < 0.001) but had surgery more often as compared to older patients: 40.6% versus 37.9%, P = 0.047. There was no significant difference in the 5-year relative survival between both age groups: 18.1% versus 17.2%, P > 0.05. A subgroup analysis among patients diagnosed with adenocarcinoma revealed similar results. CONCLUSIONS: Young patients with esophageal cancer present with more advanced disease stage and received more often treatment. However, they show comparable relative survival rates with their older counterparts. PMID- 24338661 TI - Success of torsional correction surgery after failed surgeries for patellofemoral pain and instability. AB - Torsional deformities of the femur and/or tibia often go unrecognized in adolescents and adults who present with anterior knee pain, and patellar maltracking or instability. While open and arthroscopic surgical techniques have evolved to address these problems, unrecognized torsion may compromise the outcomes of these procedures. We collected a group of 16 consecutive patients (23 knees), with mean age of 17, who had undergone knee surgery before torsion was recognized and subsequently treated by means of rotational osteotomy of the tibia and/or femur. By follow-up questionnaire, we sought to determine the role of rotational correction at mean 59-month follow-up. We reasoned that, by correcting torsional alignment, we might be able to optimize long-term outcomes and avert repeated knee surgery. Knee pain was significantly improved after torsional treatment (mean 8.6 pre-op vs. 3.3 post-op, p < 0.001), while 70 % of patients did have some continued knee pain postoperatively. Only 43 % of patients had continued patellar instability, and 57 % could trust their knee after surgery. Activity level remained the same or increased in 78 % of patients after torsional treatment. Excluding planned rod removal, subsequent knee surgery for continued anterior knee pain was undertaken on only 3 knees in 2 patients. We believe that malrotation of the lower limb not only raises the propensity for anterior knee symptoms, but is also a under-recognized etiology in the failure of surgeries for anterior knee pain and patellar instability. Addressing rotational abnormalities in the index surgery yields better clinical outcomes than osteotomies performed after other prior knee surgeries. PMID- 24338662 TI - Translational clinical neuroscience perspectives on the cognitive and neurobiological mechanisms underlying alcohol-related aggression. AB - Alcohol-related violence, a longstanding, serious, and pervasive social problem, has provided researchers from diverse disciplines with a model to study individual differences in aggressive and violent behavior. Of course, not all alcohol consumers will become aggressive after drinking and similarly, not all individuals with alcohol use disorders will exhibit such untoward behavior. Rather, the relationship is best conceptualized as complex and indirect and is influenced by a constellation of social, cognitive, and biological factors that differ greatly from one person to the next. Animal experiments and human studies have elucidated how these mechanisms and processes explain (i.e., mediate) the relation between acute and chronic alcohol consumption and aggressive behavior. Further, the rich body of literature on alcohol-related aggression has allowed for identification of several potential high-yield targets for clinical intervention, e.g., cognitive training for executive dysfunction; psychopharmacology targeting affect and threat perception, which may also generalize to other psychiatric conditions characterized by aggressive behavior. Here we aim to integrate pertinent findings, derived from different methodological approaches and theoretical models, which explain heterogeneity in aggressive responses to alcohol. A translational platform is provided, highlighting common factors linking alcohol and aggression that warrant further, interdisciplinary study in order to reduce the devastating social impact of this phenomenon. PMID- 24338663 TI - What the laboratory rat has taught us about social play behavior: role in behavioral development and neural mechanisms. AB - Social play behavior is the most vigorous and characteristic form of social interaction displayed by developing mammals. The laboratory rat is an ideal species to study this behavior, since it shows ample social play that can be easily recognized and quantified. In this chapter, we will first briefly describe the structure of social play behavior in rats. Next, we will discuss studies that used social isolation rearing during the period in life when social play is most abundant to investigate the developmental functions of social play behavior in rats, focusing on the consequences of play deprivation on social, cognitive, emotional, and sensorimotor development. Last, we will discuss the neural substrates of social play behavior in rats, with emphasis on the limbic corticostriatal circuits that underlie emotions and their influence on behavior. PMID- 24338665 TI - Genetic dissection of sleep homeostasis. AB - Sleep is a complex behavior both in its manifestation and regulation, that is common to almost all animal species studied thus far. Sleep is not a unitary behavior and has many different aspects, each of which is tightly regulated and influenced by both genetic and environmental factors. Despite its essential role for performance, health, and well-being, genetic mechanisms underlying this complex behavior remain poorly understood. One important aspect of sleep concerns its homeostatic regulation, which ensures that levels of sleep need are kept within a range still allowing optimal functioning during wakefulness. Uncovering the genetic pathways underlying the homeostatic aspect of sleep is of particular importance because it could lead to insights concerning sleep's still elusive function and is therefore a main focus of current sleep research. In this chapter, we first give a definition of sleep homeostasis and describe the molecular genetics techniques that are used to examine it. We then provide a conceptual discussion on the problem of assessing a sleep homeostatic phenotype in various animal models. We finally highlight some of the studies with a focus on clock genes and adenosine signaling molecules. PMID- 24338666 TI - CXCR2 inhibition enhances sulindac-mediated suppression of colon cancer development. AB - Small chemical compound sulindac has been approved as a preventive approach against colon cancer for its effectiveness in treatment of precancerous adenoma. Due to its severe toxicities in the cardiovascular, gastrointestinal and renal systems, however, a combination of low-dose sulindac with other chemopreventive agents has been sought after as an alternative therapeutic strategy that could increase its effectiveness, while minimizing its adverse effects. To identify the promising alternative approach, we investigated the therapeutic potential of targeting the interleukin (IL)-8/CXCR2 pathway in colon cancer treatment using both loss-of-function (CXCR2 knockout) and gain-of-function (IL-8 overexpression) mouse models, as the IL-8/CXCR2 pathway has been shown to be activated in intestinal tumors of both human and experimental animals. We found that deletion of CXCR2 gene and ectopic expression of IL-8 suppresses and enhances, respectively, intestinal tumor development caused by a mutation in the APC gene. Moreover, a single copy deletion of CXCR2 gene resulted in abrogation of COX-2 and Gro-alpha upregulation in intestinal tumors caused by the APC mutation. Moreover, a single copy (heterozygote) deletion of CXCR2 gene was sufficient to synergize with a low-dose sulindac treatment in suppressing APCmin-induced intestinal polyposis. Together, our study provides a therapeutic justification of combined inhibition of CXCR2 and sulindac treatment in colon cancer prevention. PMID- 24338667 TI - Multicellular assembly and light-regulation of cell-cell communication by conjugated polymer materials. AB - Using cell-surface modification and biotin-streptavidin interactions, immune cells and target tumor cells are made to form multicellular assemblies. A polythiophene derivative can undergo cellular uptake, allowing the sensitization of oxygen under light irradiation. The subsequent generation of reactive oxygen species (ROS) regulates cell-cell communication in time and space. PMID- 24338664 TI - Models of multiple system atrophy. AB - Multiple system atrophy (MSA) is a predominantly sporadic, adult-onset, fatal neurodegenerative disease of unknown etiology. MSA is characterized by autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia and pyramidal signs in any combination. MSA belongs to a group of neurodegenerative disorders termed alpha-synucleinopathies, which also include Parkinson's disease and dementia with Lewy bodies. Their common pathological feature is the occurrence of abnormal alpha-synuclein positive inclusions in neurons or glial cells. In MSA, the main cell type presenting aggregates composed of alpha-synuclein are oligodendroglial cells . This pathological hallmark, also called glial cytoplasmic inclusions (GCIs) , is associated with progressive and profound neuronal loss in various regions of the brain. The development of animal models of MSA is justified by the limited understanding of the mechanisms of neurodegeneration and GCIs formation, which is paralleled by a lack of therapeutic strategies. Two main types of rodent models have been generated to replicate different features of MSA neuropathology. On one hand, neurotoxin-based models have been produced to reproduce neuronal loss in substantia nigra pars compacta and striatum. On the other hand, transgenic mouse models with overexpression of alpha-synuclein in oligodendroglia have been used to reproduce GCIs-related pathology. This chapter gives an overview of the atypical Parkinson's syndrome MSA and summarizes the currently available MSA animal models and their relevance for pre-clinical testing of disease-modifying therapies. PMID- 24338668 TI - Plasma-based ambient mass spectrometry techniques: The current status and future prospective. AB - Plasma-based ambient mass spectrometry is emerging as a frontier technology for direct analysis of sample that employs low-energy plasma as the ionization reagent. The versatile sources of ambient mass spectrometry (MS) can be classified according to the plasma formation approaches; namely, corona discharge, glow discharge, dielectric barrier discharge, and microwave-induced discharge. These techniques allow pretreatment-free detection of samples, ranging from biological materials (e.g., flies, bacteria, plants, tissues, peptides, metabolites, and lipids) to pharmaceuticals, food-stuffs, polymers, chemical warfare reagents, and daily-use chemicals. In most cases, plasma-based ambient MS performs well as a qualitative tool and as an analyzer for semi-quantitation. Herein, we provide an overview of the key concepts, mechanisms, and applications of plasma-based ambient MS techniques, and discuss the challenges and outlook. PMID- 24338669 TI - Chitin synthase B: a midgut-specific gene induced by insect hormones and involved in food intake in Bombyx mori larvae. AB - Chitin synthase (CHS) is the key regulatory enzyme in chitin synthesis and excretion in insects, and a specific target of insecticides. We cloned a CHS B gene of Bombyx mori (BmChsB) and showed it to be midgut specific, highly expressed during the feeding process in the larva. Knockdown of BmChsB expression in the third-instar larvae increased the number of nonmolting and abnormally molting larvae. Exposure to nikkomycin Z, a CHS inhibitor, reduced the amount of chitin in the peritrophic membrane of molted larvae, whereas abnormally elevated BmChsB mRNA levels were readily detected from the end of molting and in the newly molted larvae. Exogenous 20-hydroxyecdysone (20E) and methoprene, a juvenile hormone analogue, significantly upregulated the expression of BmChsB when the levels of endogenous molting hormone (MH) were low and the levels of endogenous juvenile hormone (JH) were high immediately after molting. When levels of endogenous MH were high and those of endogenous JH were low during the molting stage, exogenous 20E did not upregulate BmChsB expression and exogenous methoprene upregulated it negligibly. When the endogenous hormone levels were low during the mulberry-leaf intake process, BmChsB expression was upregulated by exogenous methoprene. We conclude that the expression of BmChsB is regulated by insect hormones, and directly affects the chitin-synthesis-dependent form of the peritrophic membrane and protects the food intake and molting process of silkworm larvae. PMID- 24338671 TI - [Ultrasound: the only "one stop shop" for modern management of liver disease]. PMID- 24338673 TI - Cerebellar contributions to verbal working memory. AB - There is increasing evidence for a cerebellar role in working memory. Clinical research has shown that working memory impairments after cerebellar damage and neuroimaging studies have revealed task-specific activation in the cerebellum during working memory processing. A lateralisation of cerebellar function within working memory has been proposed with the right hemisphere making the greater contribution to verbal processing and the left hemisphere for visuospatial tasks. We used continuous theta burst stimulation (cTBS) to examine whether differences in post-stimulation performance could be observed based on the cerebellar hemisphere stimulated and the type of data presented. We observed that participants were significantly less accurate on a verbal version of a Sternberg task after stimulation to the right cerebellar hemisphere when compared to left hemisphere stimulation. Performance on a visual Sternberg task was unaffected by stimulation of either hemisphere. We discuss our results in the context of prior studies that have used cerebellar stimulation to investigate working memory and highlight the cerebellar role in phonological encoding. PMID- 24338674 TI - The costs of psoriasis medications. AB - INTRODUCTION: Psoriasis is a chronic disease, which contributes to the economic burden on health care. The distribution of psoriasis medication costs and the quality of life in these patients has been estimated to be around 20% of total costs. OBJECTIVES: To estimate the economic distribution of medications and the impact of multiple treatment options on a patient's quality of life. MATERIALS AND METHODS: The study was based on 236 Finnish psoriasis patients. The Finnish Social Insurance Institution had databases for all psoriasis related medications purchased. Each purchase, during the 1-year study period (1 October 2009-30 September 2010), was recorded and analyzed. The dermatological quality-of-life index was collected from the medical records. RESULTS: Total medication costs were 1,083 per year per patient. Topical treatments were the most often purchased medication and they comprised 18% of the total medication costs. Ten percent of the patients needed 3 or more medication changes during the 1-year study period. Biologics were used only by 5% of patients, but they produced 67% of total medication costs. Patients needing various treatments had higher medication costs and a poorer quality of life. CONCLUSION: A small number of patients generated a great sum of medication costs partly due to the need to change medications. These patients had the worst quality-of-life index scores. Biologics formed a major cost component. PMID- 24338675 TI - The glycemic effects of antihypertensive medications. AB - Older antihypertensive medications are believed to be associated with metabolic disturbances, especially raised glucose levels. Owing to this, many physicians shun their use. Newer antihypertensive medications are metabolically neutral or metabolically favorable; therefore, they are looked upon favorably and are chosen as primary medications for the treatment of hypertension. Here we review the literature on the glucose effects of older and newer antihypertensive medications. We also consider what, if any, impact these metabolic effects have on cardiovascular disease outcomes. We show that the diabetogenic effects of thiazide diuretics and beta blockers are small relative to the glucose effects of angiotensin-converting enzyme inhibitors (ACEIs) and calcium channel blockers, and that over time, the glucose differences between older and newer medications diminish. Importantly, we show that the diabetogenic effects of older antihypertensive medications do not translate into increased cardiovascular disease risk. PMID- 24338676 TI - Separation and quantification of RNA molecules using size-exclusion chromatography hyphenated with inductively coupled plasma-mass spectrometry. AB - The hyphenation of SEC with ICP-MS was successfully applied to RNA quantification. The developed method combines the separation technique for large biomolecules and element selective detection of ICP-MS. The separation of RNA molecules was performed under the SEC condition without additive reagents such as salts to prevent the adhesion of RNA molecules on the column resin. Fragments of RNA, which were commercially available as a ladder marker solution and certified reference materials, were successfully separated and analyzed by measuring 31P+ with this method. RNA was quantified with good repeatability (RSD of peak area; 2.7%, n = 3) and linearity (R2 = 0.999) using a P standard solution as a calibrant. LOD and absolute detection limit of RNA were 6.7 MUg/kg and 67 pg, respectively, which were equal to the values obtained by the analysis of a P standard solution. The accuracy of the proposed measurement was evaluated by measuring certified reference materials of RNA solutions for quantitative analysis (NMIJ CRM 6204-a). The results obtained by this method agreed with the certified values within uncertainty. The proposed analysis method, which demonstrates good accuracy and high precision and is free from interference by nucleotide analogues, qualifies as a method of quality control for the RNA synthesis and extraction process. PMID- 24338677 TI - Recent advances in polymer solar cells: realization of high device performance by incorporating water/alcohol-soluble conjugated polymers as electrode buffer layer. AB - This Progress Report highlights recent advances in polymer solar cells with special attention focused on the recent rapid-growing progress in methods that use a thin layer of alcohol/water-soluble conjugated polymers as key component to obtain optimized device performance, but also discusses novel materials and device architectures made by major prestigious institutions in this field. We anticipate that due to drastic improvements in efficiency and easy utilization, this method opens up new opportunities for PSCs from various material systems to improve towards 10% efficiency, and many novel device structures will emerge as suitable architectures for developing the ideal roll-to-roll type processing of polymer-based solar cells. PMID- 24338678 TI - Coexistence of thyroglobulin antibodies and thyroid peroxidase antibodies correlates with elevated thyroid-stimulating hormone level and advanced tumor stage of papillary thyroid cancer. AB - The correlation between thyroglobulin antibodies (TgAb) or thyroid peroxidase antibodies (TPOAb) and papillary thyroid cancer (PTC) remains controversial. This histological study aimed to explore the correlation between thyroid autoantibodies (TAb), thyroid-stimulating hormone (TSH), and PTC in patients with thyroid nodules (TN). This was a retrospective study. 2,132 non-autoimmune thyroid diseases (AITD) patients who underwent thyroidectomy were subdivided into: TgAb or TPOAb single positive (TgAb+ or TPOAb+) TN group; TgAb and TPOAb double positive or negative (TAb+ or TAb-) TN group. PTC patients showed a higher rate of TAb+ TN (10.24 vs. 4.89 %; P = 0.000) and a higher TSH level (1.83 +/- 0.07 vs. 1.39 +/- 0.03 mIU/L; P = 0.000) than patients with benign nodules. TAb+ TN patients showed a higher TSH level and PTC frequency than those with TAb- TN (1.91 +/- 0.17 vs. 1.47 +/- 0.03 mIU/L; P = 0.011) (41.35 vs. 22.08 %; P = 0.000). In PTC, TAb+ TN patients showed a higher TSH level (2.57 +/- 0.35 vs. 1.79 +/- 0.07 mIU/L; P = 0.032), a greater frequency of lymph node metastasis (52.73 vs. 36.51 %, P = 0.026), and a lower micro-PTC frequency (16.36 vs. 39.51 %; P = 0.001) than TAb- TN patients. PTC was correlated with TgAb+ TN (OR = 1.921, CI 1.431-2.580; P = 0.000), TPOAb+ TN (OR = 1.945, CI 1.195-3.165; P = 0.007), TAb+ TN (OR = 2.393, CI 1.635-3.501; P = 0.000), and serum TSH >1.35 mIU/L (OR = 1.742, CI 1.089-2.786; P = 0.021). Serum positive TgAb or TPOAb is an independent predictor for PTC regardless of AITD. The coexistence of TgAb and TPOAb confers a greater risk for PTC than isolated positive TgAb or TPOAb, and is correlated with elevated TSH level and advanced PTC stage. PMID- 24338679 TI - Science to practice: Imaging tools to study cognition in Parkinson's disease. PMID- 24338680 TI - The promising impact of ibrutinib, a Bruton's tyrosine kinase inhibitor, for the management of lymphoid malignancies. AB - Lymphoid malignancies comprise a heterogeneous group of disorders originating from clonal proliferation of B or T lymphocytes. Treatment of lymphoid neoplasms has traditionally been pursued with cytotoxic chemotherapy. To improve efficacy and ameliorate the adverse effects associated with classic chemotherapy, molecularly targeted therapy has been developed. At the forefront of clinical development is ibrutinib, an inhibitor of Bruton's tyrosine kinase (Btk). Btk is a protein tyrosine kinase that plays an important role in regulating B-cell signaling. Dysregulated Btk results in uncontrolled B-lymphocyte proliferation, differentiation, and survival. Ibrutinib is currently being studied in numerous malignancies of lymphoid origin including chronic lymphocytic leukemia, mantle cell lymphoma, non-Hodgkin lymphoma, follicular lymphoma, and multiple myeloma. Thus far, ibrutinib has demonstrated very promising results in treatment-naive patients as well as those with relapsed or refractory disease with an acceptable safety profile. In this article, we describe the pharmacology, efficacy, and toxicity profile of ibrutinib and depict the potential role that ibrutinib will play in the treatment paradigm of lymphoid neoplasms. PMID- 24338681 TI - Organo-gallium/indium chalcogenide complexes of copper(I): molecular structures and thermal decomposition to ternary semiconductors. AB - Several organo-gallium/indium chalcogenide complexes of copper(I), stabilized by trialkylphosphines, were isolated, structurally characterized by using single crystal X-ray diffraction, and investigated in thermolysis experiments. The syntheses with [E(Me3Si)2] (E=S, Se) as a starting material and a chalcogen source involve the elimination of volatile silyl acetate, silyl ethers, and methane from copper(I) acetate, and Group 13 metal trimethyl compounds, respectively. Chalcogenide complexes, according to the general formulas [(R3PCu)4(MeM)4E6] (1-6) and [(R3PCu)6(MeM)4M4S13] (7-9; with R=alkyl and M=Ga, In), and mixed chalcogenide-phenylchalcogenolate complexes [(iPr3PCuEPh)3(MeGaE)4] (10, 11) were isolated. The heavy atom cores of 1-6 consist of an octahedron of chalcogen atoms, interpenetrated by a cube of metal atoms. Depending on the steric demand of the phosphine ligands, two constitutions are observed; the metal atoms of the same element either forming tetrahedra, or parallelograms, respectively. This constitutional isomerism is further investigated by quantum chemical calculations. Complexes 7-9 contain a central sulfur atom, surrounded by two interpenetrating tetrahedra of Group 13 metal atoms, an octahedron of copper atoms, and an icosahedron of twelve outer sulfur atoms; the heavy atom framework of 10 and 11 is a "cut-out" of this structure. Thermolysis experiments include thermogravimetry measurements and subsequent Rietveld phase analysis of the residues by using powder X-ray diffraction. The homologous compounds 1, 3, 4, and 6 yield the respective crystalline ternary semiconductor material CuME2 at temperatures below 300 degrees C. Partial release of Me3 M during the thermolysis process results in excess copper in the residue and therefore in small amounts of additional binary copper chalcogenide phases or metallic CuM alloys. Compound 8 produces nanocrystalline CuGaS2 at about 300 degrees C. PMID- 24338682 TI - Facilitating relational framing in children and individuals with developmental delay using the relational completion procedure. AB - The Relational Completion Procedure is effective for establishing same, opposite and comparative derived relations in verbally able adults, but to date it has not been used to establish relational frames in young children or those with developmental delay. In Experiment 1, the Relational Completion Procedure was used with the goal of establishing two 3-member sameness networks in nine individuals with Autism Spectrum Disorder (eight with language delay). A multiple exemplar intervention was employed to facilitate derived relational responding when required. Seven of nine participants in Experiment 1 passed tests for derived relations. In Experiment 2, eight participants (all of whom, except one, had a verbal repertoire) were given training with the aim of establishing two 4 member sameness networks. Three of these participants were typically developing young children aged between 5 and 6 years old, all of whom demonstrated derived relations, as did four of the five participants with developmental delay. These data demonstrate that it is possible to reliably establish derived relations in young children and those with developmental delay using an automated procedure. PMID- 24338683 TI - Novel prostate acid phosphatase-based peptide vaccination strategy induces antigen-specific T-cell responses and limits tumour growth in mice. AB - Treatment options for patients with advanced prostate cancer remain limited and rarely curative. Prostatic acid phosphatase (PAP) is a prostate-specific protein overexpressed in 95% of prostate tumours. An FDA-approved vaccine for the treatment of advanced prostate disease, PROVENGE(r) (sipuleucel-T), has been shown to prolong survival, however the precise sequence of the PAP protein responsible for the outcome is unknown. As the PAP antigen is one of the very few prostate-specific antigens for which there is a rodent equivalent with high homology, preclinical studies using PAP have the potential to be directly relevant to clinical setting. Here, we show three PAP epitopes naturally processed and presented in the context of HHDII/DR1 (114-128, 299-313, and 230 244). The PAP-114-128 epitope elicits CD4(+) and CD8(+) T-cell-specific responses in C57BL/6 mice. Furthermore, when immunised in a DNA vector format (ImmunoBody(r)), PAP-114-128 prevents and reduces the growth of transgenic adenocarcinoma of mouse prostate-C1 prostate cancer cell-derived tumours in both prophylactic and therapeutic settings. This anti-tumour effect is associated with infiltration of CD8(+) tumour-infiltrating lymphocytes and the generation of high avidity T cells secreting elevated levels of IFN-gamma. PAP-114-128 therefore appears to be a highly relevant peptide on which to base vaccines for the treatment of prostate cancer. PMID- 24338685 TI - Cerebral injury in monochorionic twins with selective intrauterine growth restriction: a systematic review. AB - OBJECTIVE: To estimate incidence and risk factors of severe cerebral injury in survivors from monochorionic pregnancies with selective intrauterine growth restriction (sIUGR) and/or birth weight discordance (BWD). METHODS: Electronic databases were searched for studies describing perinatal and neurologic outcome in monochorionic twins with sIUGR and/or BWD. Exclusion criteria were twin-twin transfusion syndrome, twin anemia-polycythemia sequence, selective feticide or laser treatment. RESULTS: Eleven articles were included in the systematic review. Analysis was hampered by different methodology and definitions of cerebral injury. The incidence of severe cerebral injury varied from 0% to 33% (average 8%, 52/661), and was higher in studies including single intrauterine demise [odds ratio (OR) 2.92; 95% confidence interval (CI) 0.89-9.56] and studies with a median gestational age at birth of <=32 weeks (OR 1.56; 95% CI 1.06-2.27). The risk of severe cerebral injury was higher in pregnancies with abnormal umbilical artery Doppler (13.5% vs 2.5%; OR 7.69; 95% CI 2.56-25.00) and in larger twins (9% vs 5%; OR 1.93; 95% CI 0.95-3.92). CONCLUSIONS: The incidence of severe cerebral injury in monochorionic twins with sIUGR and/or BWD is approximately 8% and is associated with abnormal umbilical artery Doppler, larger twins, intrauterine fetal demise and low gestational age at birth. PMID- 24338684 TI - Reducing aggressive intergroup action tendencies: effects of intergroup contact via perceived intergroup threat. AB - Two studies tested the prediction that more positive intergroup contact would be associated with reduced aggressive intergroup action tendencies, an effect predicted to occur indirectly via reduced intergroup threat perceptions, and over and above well-established effects of contact on intergroup attitudes. Study 1, using data based on a cross-section of the general population of eight European countries (France, Germany, Hungary, Italy, the Netherlands, Poland, Portugal, and the UK; N = 7,042), examined this hypothesis in the context of aggressive action tendencies towards immigrants. Study 2, using longitudinal data obtained from a general population sample in Northern Ireland, considered effects on aggressive action tendencies between ethno-religious groups in conflict. Both studies confirmed our predictions, showing that while perceived threat was associated with greater intergroup aggressive tendencies, positive intergroup contact was indirectly associated with reduced aggressive action tendencies, via reduced intergroup threat. Findings are discussed in terms of the theoretical contributions of this research for understanding the relationship between intergroup contact and intergroup aggression. PMID- 24338687 TI - Chronophin dimerization is required for proper positioning of its substrate specificity loop. AB - Mammalian phosphatases of the haloacid dehalogenase (HAD) superfamily have emerged as important regulators of physiology and disease. Many of these enzymes are stable homodimers; however, the role of their dimerization is largely unknown. Here, we explore the function of the obligatory homodimerization of chronophin, a mammalian HAD phosphatase known to dephosphorylate pyridoxal 5' phosphate (PLP) and serine/threonine-phosphorylated proteins. The exchange of two residues in the murine chronophin homodimerization interface (chronophin(A194K,A195K)) yields a constitutive monomer both in vitro and in cells. The catalytic activity of monomeric chronophin toward PLP is strongly impaired. X-ray crystallographic studies of chronophin(A194K,A195K) revealed that dimer formation is essential for an intermolecular arginine-arginine-tryptophan stacking interaction that positions a critical histidine residue in the substrate specificity loop of chronophin for PLP coordination. Analysis of all available crystal structures of HAD hydrolases that are grouped together with chronophin in the C2a-type structural subfamily uncovered a highly conserved mode of dimerization that results in intermolecular contacts involving the substrate specificity loop. Our results explain how the dimerization of HAD hydrolases contributes to their catalytic efficiency and substrate specificity. PMID- 24338688 TI - Vascular endothelial tight junctions and barrier function are disrupted by 15(S) hydroxyeicosatetraenoic acid partly via protein kinase C epsilon-mediated zona occludens-1 phosphorylation at threonine 770/772. AB - Disruption of tight junctions (TJs) perturbs endothelial barrier function and promotes inflammation. Previously, we have shown that 15(S) hydroxyeicosatetraenoic acid (15(S)-HETE), the major 15-lipoxygenase 1 (15-LO1) metabolite of arachidonic acid, by stimulating zona occludens (ZO)-2 tyrosine phosphorylation and its dissociation from claudins 1/5, induces endothelial TJ disruption and its barrier dysfunction. Here, we have studied the role of serine/threonine phosphorylation of TJ proteins in 15(S)-HETE-induced endothelial TJ disruption and its barrier dysfunction. We found that 15(S)-HETE enhances ZO-1 phosphorylation at Thr-770/772 residues via PKCepsilon-mediated MEK1-ERK1/2 activation, causing ZO-1 dissociation from occludin, disrupting endothelial TJs and its barrier function, and promoting monocyte transmigration; these effects were reversed by T770A/T772A mutations. In the arteries of WT mice ex vivo, 15(S) HETE also induced ZO-1 phosphorylation and endothelial TJ disruption in a PKCepsilon and MEK1-ERK1/2-dependent manner. In line with these observations, in WT mice high fat diet feeding induced 12/15-lipoxygenase (12/15-LO) expression in the endothelium and caused disruption of its TJs and barrier function. However, in 12/15-LO(-/-) mice, high fat diet feeding did not cause disruption of endothelial TJs and barrier function. These observations suggest that the 12/15 LO-12/15(S)-HETE axis, in addition to tyrosine phosphorylation of ZO-2, also stimulates threonine phosphorylation of ZO-1 in the mediation of endothelial TJ disruption and its barrier dysfunction. PMID- 24338690 TI - Cytochrome b5 reductase 2 is a novel candidate tumor suppressor gene frequently inactivated by promoter hypermethylation in human nasopharyngeal carcinoma. AB - Cytochrome b5 reductase 2 (CYB5R2), a member of the flavoprotein pyridine nucleotide cytochrome reductase family, is associated with a number of physiological reactions. However, its role in cancer, especially nasopharyngeal carcinoma (NPC), has not been addressed. Here, we investigate the transcript levels and promoter methylation status of CYB5R2 in NPC derived cell lines and tumor biopsies and experimentally address its role as a tumor suppressor gene. We find that CYB5R2 transcript levels are decreased in NPC cell lines and tumor biopsies. Promoter hypermethylation of CYB5R2 was detected in all six tested NPC cell lines and in 84% of primary NPC tumor biopsies but not in normal nasopharyngeal epithelium. Clinically, CYB5R2 methylation was associated with lymph node metastasis in NPC patients (P < 0.05). The endogenous expression of CYB5R2 could be restored in vitro by the methyltransferase inhibitor 5-aza-2' deoxycytidine in NPC cell lines. Ectopic expression of CYB5R2 had an inhibitory effect on proliferation, clonogenicity and migration of NPC cells. Moreover, in vivo tests in nude mice indicated that ectopic expression of CYB5R2 reduces the tumorigenicity of CYB5R2-negative NPC cells. Collectively, these findings suggest that CYB5R2 may be a functional tumor suppressor gene, frequently inactivated by hypermethylation of its promoter in NPC. We report here the first instance of epigenetic downregulation in NPC tumor biopsies of a key enzyme, CYB5R2, which is responsible for the detoxification of environmental carcinogens. We propose the possibility of utilizing CYB5R2 promoter methylation as a diagnostic biomarker of NPC in the future. PMID- 24338689 TI - A review on the role of L-carnitine in the management of tamoxifen side effects in treated women with breast cancer. AB - L-carnitine is an antioxidant and is found to be a protective agent against many diseases including cancer. This review illustrates the possible role of L carnitine as an add-on therapy to breast cancer patients maintained on tamoxifen. The objectives of carnitine treatment are diverse: improving tamoxifen-related side effects, offering better cancer prognosis by reducing the risk of developing cancer recurrence or metastasis, and modulating the growth factors which may be, in part, a prospective illustration to overcome tamoxifen resistance. So, it could be recommended to supplement L-carnitine to breast cancer patients starting tamoxifen treatment. PMID- 24338691 TI - Microbially synthesized modular virus-like particles and capsomeres displaying group A streptococcus hypervariable antigenic determinants. AB - Effective and low-cost vaccines are essential to control severe group A streptococcus (GAS) infections prevalent in low-income nations and the Australian aboriginal communities. Highly diverse and endemic circulating GAS strains mandate broad-coverage and customized vaccines. This study describes an approach to deliver cross-reactive antigens from endemic GAS strains using modular virus like particle (VLP) and capsomere systems. The antigens studied were three heterologous N-terminal peptides (GAS1, GAS2, and GAS3) from the GAS surface M protein that are specific to endemic strains in Australia Northern Territory Aboriginal communities. In vivo data presented here demonstrated salient characteristics of the modular delivery systems in the context of GAS vaccine design. First, the antigenic peptides, when delivered by unadjuvanted modular VLPs or adjuvanted capsomeres, induced high titers of peptide-specific IgG antibodies (over 1 * 10(4) ). Second, delivery by capsomere was superior to VLP for one of the peptides investigated (GAS3), demonstrating that the delivery system relative effectiveness was antigen-dependant. Third, significant cross reactivity of GAS2-induced IgG with GAS1 was observed using either VLP or capsomere, showing the possibility of broad-coverage vaccine design using these delivery systems and cross-reactive antigens. Fourth, a formulation containing three pre-mixed modular VLPs, each at a low dose of 5 MUg (corresponding to <600 ng of each GAS peptide), induced significant titers of IgGs specific to each peptide, demonstrating that a multivalent, broad-coverage VLP vaccine formulation was possible. In summary, the modular VLPs and capsomeres reported here demonstrate, with promising preliminary data, innovative ways to design GAS vaccines using VLP and capsomere delivery systems amenable to microbial synthesis, potentially adoptable by developing countries. PMID- 24338692 TI - Management of left ventricular thrombosis in patients with apical aneurysm. PMID- 24338693 TI - Highly conductive PEDOT:PSS nanofibrils induced by solution-processed crystallization. PMID- 24338694 TI - Synapses lacking astrocyte appear in the amygdala during consolidation of Pavlovian threat conditioning. AB - There is growing evidence that astrocytes, long held to merely provide metabolic support in the adult brain, participate in both synaptic plasticity and learning and memory. Astrocytic processes are sometimes present at the synaptic cleft, suggesting that they might act directly at individual synapses. Associative learning induces synaptic plasticity and morphological changes at synapses in the lateral amygdala (LA). To determine whether astrocytic contacts are involved in these changes, we examined LA synapses after either threat conditioning (also called fear conditioning) or conditioned inhibition in adult rats by using serial section transmission electron microscopy (ssTEM) reconstructions. There was a transient increase in the density of synapses with no astrocytic contact after threat conditioning, especially on enlarged spines containing both polyribosomes and a spine apparatus. In contrast, synapses with astrocytic contacts were smaller after conditioned inhibition. This suggests that during memory consolidation astrocytic processes are absent if synapses are enlarging but present if they are shrinking. We measured the perimeter of each synapse and its degree of astrocyte coverage, and found that only about 20-30% of each synapse was ensheathed. The amount of synapse perimeter surrounded by astrocyte did not scale with synapse size, giving large synapses a disproportionately long astrocyte-free perimeter and resulting in a net increase in astrocyte-free perimeter after threat conditioning. Thus astrocytic processes do not mechanically isolate LA synapses, but may instead interact through local signaling, possibly via cell-surface receptors. Our results suggest that contact with astrocytic processes opposes synapse growth during memory consolidation. PMID- 24338696 TI - Reminiscences of a simple country chemist. PMID- 24338695 TI - Spatiotemporal accuracy of real-time 3D echocardiography in the neonatal and pediatric setting--validation studies using small dynamic test objects. AB - The precision of real-time 3D-echocardiography (RT3DE) is not sufficiently validated for small, fast-moving structures such as the neonatal and pediatric heart. PURPOSE: To assess the spatiotemporal accuracy of RT3DE in small, moving test objects. MATERIALS AND METHODS: Small, calibrated test objects in the size of neonatal and pediatric heart chambers were made from polyurethane foam or metal wire mesh and moved in a water bath through a calibrated dynamic test system. Using matrix transducers (X7-2, ie33 and X4-1, Sonos 7500, Philips, Andover, USA), 2 D and live 3 D datasets under variation of the motion speed (0.033 - 0.133 m/s corresponding to 50 - 200 heart cycles/minute), the volume rate and transducer position were recorded and analyzed (QLab 7.0, Philips). RESULTS: 3 D datasets of the moving test objects showed relevant spatial distortion, which was obviously related to the sequential scanning technology of the matrix transducer. Different segments of a test object were not recorded simultaneously, but rather row-by-row, so that there was a time delay between the first and the last-recorded voxel of a single 3 D volume (mean+/-SD: 28.9 +/- 7.82 m/s or 80 +/- 7 % of the time duration of a 3 D volume). With increasing motion speed of the test object and reduced 3 D volume rate, the distortion artifacts increased significantly. CONCLUSION: 3 D acquisitions using matrix technology demonstrate relevant spatiotemporal inaccuracies. This may lead to misinterpretations during the evaluation of the synchronicity of valvular or ventricular motion and incorrect definition of volume estimations. In particular, at higher heart rates and higher rates of movement, these limitations have to be taken into account in clinical practice. PMID- 24338697 TI - Carbon nanotube and graphene-based bioinspired electrochemical actuators. AB - Bio-inspired actuation materials, also called artificial muscles, have attracted great attention in recent decades for their potential application in intelligent robots, biomedical devices, and micro-electro-mechanical systems. Among them, ionic polymer metal composite (IPMC) actuator has been intensively studied for their impressive high-strain under low voltage stimulation and air-working capability. A typical IPMC actuator is composed of one ion-conductive electrolyte membrane laminated by two electron-conductive metal electrode membranes, which can bend back and forth due to the electrode expansion and contraction induced by ion motion under alternating applied voltage. As its actuation performance is mainly dominated by electrochemical and electromechanical process of the electrode layer, the electrode material and structure become to be more crucial to higher performance. The recent discovery of one dimensional carbon nanotube and two dimensional graphene has created a revolution in functional nanomaterials. Their unique structures render them intriguing electrical and mechanical properties, which makes them ideal flexible electrode materials for IPMC actuators in stead of conventional metal electrodes. Currently although the detailed effect caused by those carbon nanomaterial electrodes is not very clear, the presented outstanding actuation performance gives us tremendous motivation to meet the challenge in understanding the mechanism and thus developing more advanced actuator materials. Therefore, in this review IPMC actuators prepared with different kinds of carbon nanomaterials based electrodes or electrolytes are addressed. Key parameters which may generate important influence on actuation process are discussed in order to shed light on possible future research and application of the novel carbon nanomateials based bio-inspired electrochemical actuators. PMID- 24338698 TI - Wiskott-Aldrich syndrome protein deficiency in natural killer and dendritic cells affects antitumor immunity. AB - Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency caused by reduced or absent expression of the WAS protein (WASP). WAS patients are affected by microthrombocytopenia, recurrent infections, eczema, autoimmune diseases, and malignancies. Although immune deficiency has been proposed to play a role in tumor pathogenesis, there is little evidence on the correlation between immune cell defects and tumor susceptibility. Taking advantage of a tumor-prone model, we show that the lack of WASP induces early tumor onset because of defective immune surveillance. Consistently, the B16 melanoma model shows that tumor growth and the number of lung metastases are increased in the absence of WASP. We then investigated the in vivo contribution of Was(-/-) NK cells and DCs in controlling B16 melanoma development. We found fewer B16 metastases developed in the lungs of Was(-/-) mice that had received WT NK cells as compared with mice bearing Was(-/ ) NK cells. Furthermore, we demonstrated that Was(-/-) DCs were less efficient in inducing NK-cell activation in vitro and in vivo. In summary, for the first time, we demonstrate in in vivo models that WASP deficiency affects resistance to tumor and causes impairment in the antitumor capacity of NK cells and DCs. PMID- 24338699 TI - Economic burden and costs of chronic migraine. AB - Chronic migraine (CM) is a subtype of migraine broadly defined by the presence of headache at least 15 days per month. Emerging evidence suggests that CM and episodic migraine (EM) differ not only in headache frequency, but that they are distinct clinical entities. Because individuals with CM are more disabled, they demonstrate higher societal burden than those with EM. There have been three important surveys published within the last five years that have focused on the societal burden associated with CM. The first is the American Migraine Prevalence and Prevention (AMPP) study, a longitudinal population-based survey performed in the U.S. The second, the International Burden Migraine Study (IBMS), is a Web based survey conducted in North America, Western Europe, Asia/Pacific, and Brazil. The third is a clinic-based survey performed in Taiwan. This review discusses results of these studies with regard to healthcare resource use (and related direct costs) and loss of productivity (and related indirect costs) from the perspective of cost-effectiveness of new therapeutic approaches to CM. PMID- 24338700 TI - An update on botulinum toxin A injections of trigger points for myofascial pain. AB - Myofascial pain syndrome (MPS) is a common chronic pain condition that is characterized by distinct "trigger points." Despite current treatments with physical therapy, analgesics, anti-depressants and trigger-point injections, myofascial pain remains a challenging chronic pain condition in clinical practice. Botulinum toxin A (BTX-A) can cause prolonged muscle relaxation through inhibition of acetylcholine release. It may offer some advantages over the current treatments for MPS by providing a longer sustained period of pain relief. Despite numerous clinical trials, the efficacy of BTX-A in alleviating MPS is not well-established due to mixed results from recent clinical trials. Active trigger points are associated with referred pain and greatly impact many aspects of activities of daily living, mood, and health status. This review is designed to analyze the clinical trials regarding the efficacy of BTX-A injection of active trigger points as a treatment for MPS. The literature referenced was obtained via a computer search with Google Scholar, Pubmed, Medline and EMbase. Our search terms included "Botulinum toxin," "myofascial pain," "trigger points," "myofascial trigger points," "chronic pain." Additional references were retrieved from the reference list of the reports found via this search. Studies were considered eligible for inclusion if they were double-blinded, randomized, controlled trials evaluating the efficacy of BTX-A injections into trigger points for pain reduction, and if the trigger point selection in the trial included referred pain and/or local twitch response. Open-label studies, case reports, and other non-randomized studies were excluded. Eight trials were found according to the above criteria and are summarized in Table 1. There are well-designed clinical trials to support the efficacy of trigger-point injections with BTX-A for MPS. However, further clinical trials with considerations of minimizing placebo effect, repeated dosing, adequate coverage of trigger points, and using ultrasound confirmation and guidance are required to provide conclusive evidence for BTX-A in the treatment of myofascial pain. PMID- 24338701 TI - Intrathecal therapy for chronic pain: current trends and future needs. AB - The management of chronic pain continues to pose many challenges to healthcare providers. Intrathecal drug delivery systems (IDDS) provide an effective therapy for patients suffering from chronic pain intractable to medical management. However, the clinical growth of intrathecal therapy continues to face many challenges, and is likely underutilized secondary to its high-complexity and limited reimbursement. The clinical utility of IDDS remains limited by lack of prospective randomized, placebo-controlled studies. In addition, there remains a need to enhance physician knowledge on the pharmacodynamics and pharmacokinetics of intrathecal drug delivery and promote further research into this field and drug delivery modalities. The purpose of this article is to provide a comprehensive review of the determinants of successful intrathecal drug delivery with an emphasis on its use in noncancer pain. PMID- 24338703 TI - Role of novel and emerging oral anticoagulants for secondary prevention of acute coronary syndromes. AB - Dual antiplatelet therapy has become a mainstay of long-term management of patients after an acute coronary syndrome (ACS). Mortality for these patients remains high despite current evidence-based treatment strategies. The coagulation cascade plays a role in the pathophysiology of ACS, and trials with warfarin in combination with dual antiplatelet therapy have found decreased rates of ischemic events at the expense of increased bleeding risk. Novel oral anticoagulants (NOACs) in the direct factor Xa (FXa) inhibitor and direct thrombin inhibitor (DTI) categories have been evaluated in combination with standard post-ACS therapy. Rivaroxaban, a FXa inhibitor, reduced the rates of ischemic events but increased major bleeding rates. Apixaban did not decrease the rates of ischemic events and also increased major bleeding rates. Other FXa inhibitors have not been studied in the long-term management of ACS (e.g., otamixaban), are not currently being studied in ongoing phase III trials (e.g., TAK-442), or have been discontinued by the manufacturer (e.g., darexaban). The DTI dabigatran had a 2- to 4-fold increased risk of major bleeding with unclear benefit for reducing ischemic events. The factor IXa inhibitor pegnivacogin is an RNA-based aptamer that has been studied in patients undergoing cardiac catheterization but has not been studied for long-term post-ACS management. The European Society of Cardiology Working Group on Thrombosis recommends the use of newer antiplatelet agents over addition of NOACs. Additional guidelines are available to guide management in patients requiring triple antithrombotic therapy but do not provide definitive recommendations on NOACs. Many questions remain about the place of NOACs for long-term post-ACS management. Recent trials have evaluated double versus triple antithrombotic therapy to balance efficacy and bleeding risk, but they did not include NOACs. It also remains unclear if NOACs hold a place in post ACS therapy in the era of more potent antiplatelet agents such as prasugrel and ticagrelor. PMID- 24338704 TI - CASP3 protein expression by flow cytometry in Down's syndrome subjects. AB - Down's syndrome (DS), the most common chromosomal disorder, is caused by 21 trisomy and is featured by intellectual disability. Subjects with DS can develop some traits of Alzheimer disease (AD) at an earlier age than subjects without trisomy 21. Apoptosis is a programmed cell death process under both normal physiological and pathological conditions. Caspase-3 (CASP3) plays an important role in neuronal death during nervous system development and under certain pathological conditions. Furthermore, in vitro and in vivo studies report elevated expression and activation of CASP3 in models of AD. On this account, the expression of CASP3 gene was evaluated in cultures of fibroblasts of DS and normal subjects by flow cytometry. CASP3 protein was up-regulated in fibroblasts of DS. The data obtained from this study strengthen the hypothesis that the over expression of CASP3 gene could have a role in the activation of the apoptotic pathways acting in the neurodegenerative processes in DS. PMID- 24338702 TI - Cervical radicular pain: the role of interlaminar and transforaminal epidural injections. AB - Chronic neck pain and cervical radicular pain are relatively common in the adult population. Treatment for chronic radicular pain recalcitrant to conservative management includes surgical management as well as interventional techniques with epidural injections utilizing either an interlaminar approach or transforaminal approach. Although there have been multiple systematic reviews and randomized clinical trials of cervical interlaminar epidural injections, the literature is sparse in reference to cervical transforaminal epidural injections. Overall, there is good evidence for the effectiveness of cervical interlaminar epidural injections in managing cervical disc herniation and fair evidence in managing central spinal stenosis and postsurgery syndrome. The evidence is poor, however, for cervical transforaminal epidural injections. Complications with cervical interlaminar epidural injections are rare, but more commonly occur with transforaminal epidural injections and can be fatal. Emerging concepts in pain include further randomized trials; proper placebo design; focus on control design (either active control or placebo control); and appropriate methodologic quality assessment and evidence synthesis. PMID- 24338705 TI - Fatty acid specificity of T1 lipase and its potential in acylglycerol synthesis. AB - BACKGROUND: T1 lipase has received considerable attention due to its thermostability. Fatty acid specificity of T1 lipase (crude and purified) was investigated, and its potential in the synthesis of acylglycerols was also evaluated. RESULTS: Fatty acid specificity of T1 lipase (crude and purified) was investigated in the esterification of fatty acids (C6:0 to C18:3), suggesting that crude and purified T1 lipase had the lowest preference for C18:0 [specificity constant (1/alpha) = 0.08] followed by C18:1 (1/alpha = 0.12) and showed the highest preference for C8:0 (1/alpha = 1). A structural model was constructed to briefly explore interactions between the lipase and its substrate. Furthermore, crude T1 lipase-catalysed synthesis of diacylglycerols (DAGs) and monoacylglycerols (MAGs) by esterification of glycerol with C18:1 was studied for evaluating its potential in acylglycerols synthesis. The optimal conditions were glycerol/oleic acid molar ratio 5:1, the lipase concentration 9.7 U g(-1) of substrates, water content 50 g kg(-1) of substrates and temperature 50 degrees C, which yielded 42.25% DAGs, 26.34% MAGs and 9.18% triacylglycerols at 2 h. CONCLUSION: DAGs and MAGs were synthesised in good yields although C18:1 (a much poorer substrate) was used. Our work demonstrates that T1 lipase, which was discovered to show 1,3-regio-selectivity, is a promising biocatalyst for lipids modification. PMID- 24338706 TI - Different outcomes of allogeneic hematopoietic stem cell transplant in a pair of twins affected by juvenile myelomonocytic leukemia. AB - A twin pair affected by juvenile myelomonocytic leukemia (JMML) with the same somatic PTPN11 mutation and abnormal chromosome 7 in bone marrow samples but distinct prognostic gene expression signatures, received a matched-unrelated donor and matched-unrelated cord blood transplant, respectively. Both twins fully engrafted, but after 6 months, the twin with an acute-myeloid-like (AML-like) signature at diagnosis rejected the graft and had an autologous reconstitution. A second transplant with an unrelated 5/6-HLA-matched-loci cord blood performed after 4 months from rejection was unsuccessful. After 25 months from diagnosis, the twin with the AML-like gene expression signature died of liver failure while on progression of his JMML. The other twin, who had a non-acute-myeloid-like (non AML-like) gene expression signature at diagnosis is in complete hematological remission with full donor chimera. This observation suggests a biological diversity of JMML also in patients with a common genetic background. PMID- 24338707 TI - A trypsin-like proteinase in the midgut of Ectomyelois ceratoniae Zeller (Lepidoptera: Pyralidae): purification, characterization, and host plant inhibitors. AB - A trypsin-like proteinase was purified and characterized in the midgut of Ectomyelois ceratoniae. A purification process that used Sepharyl G-100 and DEAE cellulose fast flow chromatographies revealed a proteinase with specific activity of 66.7 MUmol/min/mg protein, recovery of 27.04 and purification fold of 23.35. Molecular weight of the purified protein was found to be 35.8 kDa. Optimal pH and temperature were obtained 9 and 20 degrees C for the purified trypsin proteinase, respectively. The purified enzyme was significantly inhibited by PMSF, TLCK, and SBTI as specific inhibitors of trypsins in which TLCK showed the highest inhibitory effect. Trypsin proteinase inhibitors were extracted from four varieties of pomegranate including Brait, Torsh-Sabz, May-Khosh, and Shirin by ion exchange chromatography. It was found that fractions 17-20 of Brait; fractions 18 and 21-26 of Torsh-Sabz; fractions 1-7, 11-17, and 19-21 of May Khosh and fraction 8 for Shirin showed presence of trypsin inhibitor in these host. Comparison of their inhibitory effects on the purified trypsin proteinase of E. ceratoniae demonstrated that fractions from May-khosh variety had the highest effect on the enzyme among other extracted fractions. Characterization of serine proteinases of insects mainly trypsins is one of the promising methods to decrease population and damages via extracting their inhibitors and providing resistant varieties. PMID- 24338708 TI - 2013: The year of renal denervation? PMID- 24338709 TI - MDM2 SNP309 is an ethnicity-dependent risk factor for digestive tract cancers. AB - Published data on the relationship between T309G polymorphism in the murine double minute 2 (MDM2) gene and susceptibility of digestive tract cancers (DTC) are inconclusive. Thus, the aim of this study is to determine whether MDM2 T309G polymorphism is associated with the risk of diverse DTC, including esophagus, stomach, liver, bile duct, pancreas, and colorectum cancers. Relevant studies were identified up to October 1, 2013. Crude odds ratio (OR) and 95% confidence interval (CI) were used as a measure of the strength of the association. The pooled result based on all studies showed that there was a statistically significant link between MDM2 T309G polymorphism and DTC susceptibility (T vs. G: OR = 0.82, 95%CI = 0.76-0.88). When stratified by race, significant associations were observed for all genetic models among Asians (especially in Chinese population), but not among Caucasians. Subgroup analyses according to tumor location indicated that the genetic variant was associated with esophageal (OR = 0.88, 95%CI = 0.81-0.96 for T vs. G), hepatocellular (OR = 0.69, 95%CI = 0.57 0.84 for T vs. G) and pancreatic cancer risk but not associated with cholangiocarcinoma or colorectum cancer susceptibility. Meanwhile, the G allele was also suggested to be associated with increased gastric cancer risk (OR = 0.68, 95%CI = 0.54-0.87 for TT + TG vs. GG for intestinal type of gastric cancer and OR = 0.18, 95%CI = 0.06-0.50 for TT vs. GG for Helicobacter pylori infection positive stomach cancer). Our study indicates that the MDM2 T309G polymorphism may be an ethnicity-dependent risk factor for DTC, especially for the upper gastrointestinal tract malignancies. PMID- 24338710 TI - Reduced mRNA expression levels of MBD2 and MBD3 in gastric carcinogenesis. AB - Aberrant methylation has been reported in several neoplasias, including gastric cancer. The methyl-CpG-binding domain (MBD) family proteins have been implicated in the chromatin remodeling process, leading to the modulation of gene expression. To evaluate the role of MBD2 and MBD3 in gastric carcinogenesis and the possible association with clinicopathological characteristics, we assessed the mRNA levels and promoter methylation patterns in gastric tissues. In this study, MBD2 and MBD3 mRNA levels were determined by RT-qPCR in 28 neoplastic and adjacent nonneoplastic and 27 gastritis and non-gastritis samples. The promoter methylation status was determined by bisulfite sequencing, and we found reduced MBD2 and MBD3 levels in the neoplastic samples compared with the other groups. Moreover, a strong correlation between the MBD2 and MBD3 expression levels was observed in each set of paired samples. Our data also showed that the neoplastic tissues exhibited higher MBD2 promoter methylation than the other groups. Interestingly, the non-gastritis group was the only one with positive methylation in the MBD3 promoter region. Furthermore, a weak correlation between gene expression and methylation was observed. Therefore, our data suggest that DNA methylation plays a minor role in the regulation of MBD2 and MBD3 expression, and the presence of methylation at CpGs that interact with transcription factor complexes might also be involved in the modulation of these genes. Moreover, reduced mRNA expression of MBD2 and MBD3 is implicated in gastric carcinogenesis, and thus, further investigations about these genes should be conducted for a better understanding of the role of abnormal methylation involved in this neoplasia. PMID- 24338711 TI - EMP1 regulates caspase-9 and VEGFC expression and suppresses prostate cancer cell proliferation and invasion. AB - This study aimed to analyze the expression, clinical significance of f epithelial membrane protejn-1 (EMP-1) in prostate carcinoma, and the biological effect in its cell line by EMP1 overexpression. Immunohistochemistry and Western blot were used to analyze EMP1 protein expression in 76 cases of prostate cancer and 34 cases of normal tissues to study the relationship between EMP1 expression and clinical factors. EMP1 lentiviral vector and empty vector were respectively transfected into prostate cancer PC-3 cell line. Quantitative real-time reverse transcription polymerase chain reaction and Western blot were used to detect the mRNA level and protein of EMP1. 3-[4,5-Dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide assay, migration, and invasion assays were also conducted as to the influence of the upregulated expression of EMP1 that might be found on PC-3 cell biological effect. Immunohistochemistry: The level of EMP1 protein expression was found to be significantly lower in prostate cancer tissue than normal tissues (P < 0.05). Western blot: The relative amount of EMP1 protein in prostate cancer tissue was found to be significantly lower than in normal tissues (P < 0.05). The level of EMP1 protein expression was not correlated with age and prostate-specific antigen (PSA) concentration (P > 0.05), but it was correlated with T stages, lymph node metastasis, clinic stage, and Gleason score (P < 0.05). The result of biological function shown that PC-3 cell transfected EMP1 had a lower survival fraction, higher cell apoptosis, significant decrease in migration and invasion, higher caspase-9, and lower VEGFC protein expression compared with PC-3 cell untransfected EMP1 (P < 0.05). EMP1 expression decreased in prostate cancer and correlated significantly T stages, lymph node metastasis, clinic stage, and Gleason score, suggesting that EMP1 may play important roles as a negative regulator to prostate cancer PC-3 cell by regulating the expression of regulation of caspase-9 and VEGFC protein. PMID- 24338712 TI - N-acetyltransferase 2 genetic variants confer the susceptibility to head and neck carcinoma: evidence from 23 case-control studies. AB - Previous evidence indicated that N-acetyltransferase 2 (NAT2) polymorphisms might be a risk factor for several cancers. A number of studies have been conducted on the association between NAT2 polymorphisms and head and neck cancer (HNC) risk. Nevertheless, the results were conflicting. Published meta-analysis on this issue has generated inconclusive results. Thus, we aimed to derive a more precise estimation of the relationship by conducting an updated meta-analysis. Published data prior to August 2013 have been searched and screened. Subgroup analysis on ethnicity, source of controls, sample size, and genotyping method were also performed. As a result, a total of 23 case-control studies including 4,028 cases and 4,872 controls were selected for analysis. Interestingly, the results showed that NAT2 polymorphisms might increase HNC risk for the overall data (OR 1.23, 95% CI 1.01-1.49). Moreover, in subgroup analyses according to ethnicity, data showed that slow acetylators might increase HNC susceptibility among Asians (OR 1.78, 95% CI 1.27-2.49), but not among Caucasians or mixed ethnicities. In conclusion, NAT2 polymorphism might be a low-penetrant risk factor for HNC among Asians. PMID- 24338713 TI - The association between the ERCC1/2 polymorphisms and the clinical outcomes of the platinum-based chemotherapy in non-small cell lung cancer (NSCLC): a systematic review and meta-analysis. AB - The relationship between the ERCC1/2 single nucleotide polymorphisms (SNPs) and the clinical outcomes of the platinum-based chemotherapy in the non-small cell lung cancer (NSCLC) is still inconsistent and inconclusive despite extensive investigations have been conducted to address this question. In this meta analysis, we aim to further explore the prognostic value of the ERCC1/2 SNPs in NSCLC by analyzing all currently available evidences. Relevant studies were searched in PubMed, Embase, and China National Knowledge Infrastructure. The inclusion criteria were platinum-based chemotherapy in NSCLC patients and evaluation of clinical outcomes in relation to the ERCC1 C118T, ERCC1 C8092A, ERCC2 Asp312Asn, and ERCC2 Lys751Gln. Clinical outcomes analyzed in this study included the overall response rate, overall survival (OS), and progression-free survival (PFS). Odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) were calculated to examine the risk or hazard associated with each SNP. A total of 46 studies including 9,407 NSCLC patients were qualified for this meta analysis. For ERCC1 C118T, the T allele was associated with a poor OS (HR = 1.35, 95% CI = 1.04-1.75); for ERCC2 Asp312Asn, the Asn variant was linked to an unfavorable OS (HR = 2.07, 95% CI = 1.11-3.88); and for ERCC2 Lys751Gln, patients with the Gln variant have a worse OS (HR = 1.22, 95% CI = 1.05-1.41) and PFS (HR = 1.35, 95% CI = 1.07-1.71). In addition, the main findings of the ERCC1/2 SNPs on chemotherapy toxicity were also summarized. This meta-analysis suggested that the ERCC1 C118T, ERCC2 Asp312Asn, and Lys751Gln may be useful biomarkers to predict the clinical outcomes of the platinum-based chemotherapy in NSCLC patients. PMID- 24338714 TI - Foxp3 promoter polymorphism (rs3761548) in breast cancer progression: a study from India. AB - Breast cancer is the most common female neoplasm that drives the transformation of normal mammary epithelial cells into highly malignant derivatives. Forkhead Box Protein3 (Foxp3), a tumor suppressor/immunomodulatory gene, which controls the function of Treg cells and oncogenes is down regulated in breast cancer. The main aim of the present study is to evaluate the potential influence of Foxp3 3279 C>A polymorphism (rs3761548) and -2383 C>T polymorphism (rs3761549) in 202 breast cancer patients and 130 normal healthy women of Indian origin. The genotypes were determined using ARMS-PCR for rs3761548 and PCR-RFLP method for rs3761549 using specific primers. The results revealed lack of association of these two polymorphisms with breast cancer susceptibility. However, with respect to AA genotype of rs3761548, we found highly significant association with the advanced stage (T3-4) of the tumor (OR = 3.90; 95% confidence interval (CI) = 1.56-9.70; p = 0.03). Stratified data also revealed an association of homozygous mutant genotype with advanced stage of tumor in premenopausal women (OR = 4.56; 95% CI = 1.07-19.38; p = 0.04) with disease duration of <6 months (OR = .10; 95% CI = 1.80-20.50; p = 0.002) suggestive of modulating effect of rs3761548 in tumor progression. We conclude that Foxp3 rs37161548 has a potential to be a polymorphic marker for tumor progression in premenopausal breast cancer patients in Indian women. PMID- 24338715 TI - Polymorphisms of the XPC gene may contribute to the risk of head and neck cancer: a meta-analysis. AB - Polymorphisms of the XPC gene have been reported to be associated with an increased risk of head and neck cancer (HNC), though the exact biological effect is still unclear. Genetic association studies (GAS) investigating the associations between three common polymorphisms (PAT, Lys939Gln, and Ala499Val) of the XPC gene and HNC risk have produced contradictory and inconclusive results. The aim of this meta-analysis is to evaluate the contributions of these polymorphisms to the risk of HNC. A literature search was conducted in the PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure databases to indentify eligible studies. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to evaluate the strength of the associations under a fixed- or random-effect model according to heterogeneity test. Twelve case-control studies were included in this meta-analysis with a total of 3,078 HNC patients and 4,311 healthy controls. For XPC PAT, a significant overall association was found under all major genetic models. Stratified analyses further indicated significant associations in the Caucasian, population-based, non-PCR-RFLP, esophageal cancer and oral cancer subgroups. For XPC Lys939Gln, few significant results were found in either the overall analysis or stratified analyses. For XPC Ala499Val, the combined results revealed a significantly increased risk of HNC for carriers of the 499Val allele. This meta analysis shows that the XPC PAT and Ala499Val polymorphisms may be associated with an increased risk of HNC, while XPC Lys939Gln may not be associated with HNC risk. Despite some limitations, this meta-analysis establishes solid statistical evidence for an association between XPC genetic polymorphisms and HNC risk that warrants further validation. PMID- 24338717 TI - Phytostabilization of moderate copper contaminated soils using co-inoculation of Vicia faba with plant growth promoting bacteria. AB - There is a need to conduct research on the selection of microbial isolates from rhizosphere of plants growing on heavy metal contaminated soils for specific restoration programs. This article suggest a consortium of bacteria combining Rhizobium sp. CCNWSX0481, Rhizobium leguminosarum bv. viciae, Enterobacter cloacae and Pseudomonas sp. 2(2010) that was examined for the ability to promote Vicia faba.L. growth when cultivated on the vineyard of soil moderately contaminated with copper. Data showed that inoculation was significant in nodulation; it increases the number and the weight of nodules of 50%. Co inoculation was also found to positively influence growth and seed yield, through increasing fresh shoot and fresh root weights by 33 and 26%, respectively, and through rising numbers of seed per pod and pods per plant. In contrast, co inoculation produced a significant reduction of accumulated copper in roots attending 35%, however, the treatment revealed no significant effects on the copper contents in pods and seeds. The tested inoculum could be an option to promote V. faba growth and to enhance soil fertilization in moderate copper contaminated soils. Further studies on the influence of co-inoculation practices on copper migration in soil-plant systems are recommended to acquire more information for evaluation of this legume safety. PMID- 24338718 TI - The development of a counterflow-assisted preconcentration technique in capillary electrophoresis electrospray-ionization mass spectrometry. AB - A preconcentration approach for CE-MS using counterflow-assisted electrokinetic injection was proposed. The proposed preconcentration method was based on a counterflow-compatible sheathless interface. The interface was fabricated using a capillary-assembled PDMS microdevice that allowed the application of a counterflow and provided liquid-film electrical conduction. During electrokinetic injection, a hydrodynamic counterflow was introduced into the separation capillary to retard the movement of the stacking boundary to the CE outlet. Accordingly, a long injection time was achieved without a loss of CE separation. With the use of reverse polarity mode and a dynamic polybrene-coated separation capillary (filled with a 1% formic acid solution), a counterflow-assisted electrokinetic injection of peptide samples (in a aqueous solution containing 1% ammonia and 50% methanol) for 10 min provided a sensitivity enhancement of 750 1480 and a detection limit of 20 pM for the five peptide standards. The proposed technique was applied to the analysis of low nanomolar concentrations myoglobin tryptic peptides. PMID- 24338719 TI - A pilot study: application of hemoglobin and cortisol levels, and a memory test to evaluate the quality of life of breast cancer patients on chemotherapy. AB - BACKGROUND: Short-term memory (STM) decline in breast cancer patients resulting from chemotherapy was evaluated by means of blood biomarkers, a questionnaire, and a computerized STM test. METHODS: This study was conducted from January 2013 to June 2013, recruiting 90 subjects: 30 breast cancer patients beginning the 3rd of 4th cycles of docetaxel and cyclophosphamide chemotherapy, 30 recovered patients (who completed 4 cycles of docetaxel for a minimum of 6 months), and 30 healthy subjects (disease-free females). The levels of hemoglobin, red and white blood cells, and cortisol in serum, and a computerized STM test were analyzed to estimate the effects of chemotherapy on STM. A questionnaire was given to all subjects to assess quality of life. RESULTS: Statistically significant differences were observed for the blood parameters (hemoglobin, red and white blood cells, and cortisol levels) between healthy and on-treatment subjects (respectively 13.47 +/- 0.96 g/dL vs 5.37 +/- 0.38 g/dL, 4.58 +/- 0.41 10(12)/L vs 2.07 +/- 0.13 10(12)/L, and 6.15 +/- 1.03 10(9)/L vs 0.86 +/- 0.41 10(9)/L). Scores of the STM test were significantly lower for patients compared to healthy subjects. As indicated by the results of the questionnaire, breast cancer patients had a higher tendency to forget than healthy controls (X(2)=3.15; p<0.0001) and recovered subjects (X(2)=3.15; p<0.0001). CONCLUSION: We found depleted levels of hemoglobin, red and white blood cells as a result of chemotherapy, and elevated levels of stress correlated with poor performances in the computerized STM test. A higher cortisol level might be an important precursor of STM deterioration. Monitoring cortisol would be beneficial for evaluating the quality of life of breast cancer patients on chemotherapy. PMID- 24338720 TI - CCX-CKR expression in colorectal cancer and patient survival. AB - Colorectal cancer is one of the most common malignant cancers, with bad prognosis when distal metastasis occurs. The current study aimed to investigate the potential value of using CCX-CKR expression for the prognosis of colorectal cancer patients. The results showed that CCX-CKR expression was a negative predictor of cancer metastasis, and that it was positively correlated to the patients’ survival rate. Finally, we found that CCX-CKR expression in vitro could modulate cellular migration and invasion abilities, potentially via the regulation of other chemotactic factors/receptors. PMID- 24338721 TI - Stem cell marker aldehyde dehydrogenase 1 (ALDH1)-expressing cells are enriched in triple-negative breast cancer. AB - The stem cell marker ALDH1 has been of particular interest to scientists since it has been successfully used as a marker to isolate cancer stem cells from breast cancers. However, little is known, especially in Chinese breast cancer patients, on whether ALDH1 enrichment is prevalent in certain subtypes of breast cancer. In this study, we performed flow cytometry and immunohistochemistry to measure the expression of ALDH1 in 10 breast cancer cell lines and in a set of tissue microarrays consisting of 101 breast cancer tissues from the Chinese population. The 101 breast cancer tissues included 4 cancer subtypes defined on bases of their ER, PR, and HER2 statuses: triple-negative (25 cases), luminal A (33 cases), luminal B (16 cases) and HER2-overexpressing (HER2-OE, 27 cases). We found that ALDH1 was expressed in 25 of the 101 cases of breast cancer tissues. When the analysis was stratified, we found that the expression of ALDH1 varied significantly among the 4 subtypes, with a higher expression in triple-negative breast cancer (TNBC, p=0.003) than in the other 3 subtypes. In a series of breast cancer cell lines, we also confirmed that ALDH1 activity was mainly found in TNBC cell lines compared with non-TNBC ones (15.6% +/- 2.45% vs 5.5% +/- 2.58%, p=0.026). These data support the concept that the expression of ALDH1 is higher in TNBC than non-TNBC, which may be clinically meaningful for a better understanding of the poor prognosis of TNBC patients. PMID- 24338722 TI - Aggressive effects of prioritizing popularity in early adolescence. AB - This study examined the moderating effects of prioritizing popularity on the association between early adolescents' popularity and their aggressive, leadership, and prosocial behaviors with peers. Participants were 288 14-year olds from The Netherlands who completed a sociometric instrument and an assessment of how much they prioritized popularity over other personal goals. Results indicated that prioritizing popularity was distinct from actual popularity in the peer group. Further, prioritizing popularity moderated the association of popularity with aggressive and leadership behaviors, with adolescents who were both popular and who prioritized popularity being particularly aggressive and scoring high on leadership behaviors. This trend was especially true for boys. The same moderating effect was not found for prosocial behaviors. Motivational and social-cognitive factors in the dynamics of peer popularity are highlighted. PMID- 24338724 TI - A novel platform for antibody library selection in mammalian cells based on a growth signalobody. AB - While many antibody-screening methods in vitro have been developed, these methods need repeated cycles of panning or sorting procedures to isolate antigen-specific antibodies. Here we developed a new antibody selection system based on antigen dependent growth of mammalian cells. In this system, a growth signalobody library, which is a naive single-chain Fv (scFv) library/cytokine receptor chimera that can transduce a growth signal in response to a specific antigen, is expressed in murine interleukin-3-dependent Ba/F3 cells. Simple culture of the cells in an antigen-containing medium results in growing cells with a high affinity scFv gene, leading to selection of the scFv specific to the target antigen without panning/sorting procedures. To demonstrate this system, we used the SD1D2g signalobody having the signaling domain of gp130 and fluorescein conjugated BSA as a target antigen, and investigated whether a fluorescein specific scFv could be selected from a naive scFv library. As a result, we successfully obtained fluorescein-binding scFv clones, and the scFv clone with the highest affinity was most abundantly selected, having the same sequence as the clone, which had been obtained through phage display. These results demonstrate the utility of our system as an affinity-based scFv selection method based on growth advantage of mammalian cells. PMID- 24338723 TI - Frequent somatic mutations of the telomerase reverse transcriptase promoter in ovarian clear cell carcinoma but not in other major types of gynaecological malignancy. AB - Up-regulated expression of telomerase reverse transcriptase (TERT) and subsequent maintenance of telomere length are essential in tumour development. Recent studies have implicated somatic gain-of-function mutations at the TERT promoter as one of the mechanisms that promote transcriptional activation of TERT; however, it remains unclear whether this genetic abnormality is prevalent in gynaecological neoplasms. We performed mutational analysis in a total of 525 gynaecological cancers, and correlated TERT promoter mutations with clinicopathological features. With the exception of ovarian clear cell carcinomas, in which mutations were found in 37 (15.9%) of 233 cases, the majority of gynaecological malignancies were wild-type. TERT promoter mutation does not appear to be an early event during oncogenesis, as it was not detected in the contiguous endometriosis associated with ovarian clear cell carcinoma. Ovarian clear cell carcinoma cell lines with TERT promoter mutations exhibited higher TERT mRNA expression than those with wild-type sequences (p = 0.0238). TERT promoter mutation tended to be mutually exclusive with loss of ARID1A protein expression (p = 4.4 * 10(-9) ) and PIK3CA mutation (p = 0.0019) in ovarian clear cell carcinomas. No associations with disease-specific survival were observed for ovarian clear cell carcinoma. The above results, in conjunction with our previous report showing longer telomeres in ovarian clear cell carcinomas relative to other types of ovarian cancer, suggests that aberrations in telomere biology may play an important role in the pathogenesis of ovarian clear cell carcinoma. PMID- 24338725 TI - Synthesis of mesoporous platinum-copper films by electrochemical micelle assembly and their electrochemical applications. AB - We have electrochemically synthesized mesoporous platinum-copper films with various compositions in an aqueous surfactant solution. By tuning the composition ratios of the platinum and copper sources in the precursor solutions, mesoporous bimetallic films with copper contents that dramatically change from 0 to 70 mol % can be successfully prepared. The obtained bimetallic films possess uniformly sized mesopores over the entire area. These mesoporous platinum-copper films are electrochemically active and show composition-dependent catalytic activity and stability for the methanol oxidation reaction. The bimetallic mesoporous films are a promising new class of electrocatalyst for the future. PMID- 24338726 TI - Omega-3 fatty acid biomarkers and subsequent depressive symptoms. AB - OBJECTIVE: We sought to determine the relationship between the omega-3 fatty acid content of red blood cell membranes (RBC), in particular docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and baseline and new-onset depressive symptoms in post-menopausal women. We secondarily sought to characterize the association between dietary omega-3 fatty acid intake and depressive symptomatology. METHODS: Study participants included 7086 members of the Women's Health Initiative Memory Study (aged 63-81 years) who had an assessment of RBC omega-3 fatty acid concentrations at the baseline screening visit. Depressive symptoms at baseline and follow-up were characterized using the Burnam eight-item scale for depressive disorders (Center for Epidemiologic Studies Depression Scale/Diagnostic Interview Schedule short form) and secondarily additionally inferred by antidepressant medication use. RESULTS: In multivariable-adjusted models, our primary exposure, RBC DHA + EPA, was not related to depressive symptoms by any measure at baseline or follow-up, nor were RBC total omega-3, DHA, or EPA (all p > 0.2). In contrast, dietary intake of omega-3 was positively associated with depressive symptoms at baseline (adjusted odds ratio 1.082, 95% confidence interval 1.004-1.166; p = 0.04 for dietary DHA + EPA and Burnam score >=0.06), although this generally did not persist at follow-up. CONCLUSION: No relationship between RBC omega-3 levels and subsequent depressive symptoms was evident, and associations between dietary omega-3 and depressive symptoms were variable. Biomarkers of omega-3 status do not appear to be related to risk of new depression in post-menopausal women. PMID- 24338727 TI - Automatic extraction of the midsagittal surface from brain MR Images using the Kullback-Leibler measure. AB - The midsagittal surface separates the two hemispheres of the cerebrum. This surface is often typified as a geometrical plane: the midsagittal plane. However, in subjects with a considerable amount of naturally occurring brain torque, the midsagittal surface deviates to a large extent from a plane. In the present study, an automated method to extract the midsagittal surface is proposed, evaluated on a large dataset, and compared to a conventional midsagittal plane representation. The midsagittal plane was extracted from MR images with a technique based on the Kullback-Leibler measure. This plane was used to initialize a surface, that was deformed to represent the midsagittal surface. One hundred subjects were selected from the SMART-MR study: fifty subjects with brain torque and fifty random subjects. Manual delineations of the midsagittal surface were used for evaluation. The extracted midsagittal planes and surfaces were compared to the manual delineations by assessing the absolute volume of misclassified cerebrum tissue. The midsagittal surface resulted in significantly better separations of the hemispheres. In the randomly selected subjects, the error reduced from 2.71 +/- 1.05 ml to 2.20 +/- 0.66 ml and in subjects with brain torque from 4.85+/-2.79 ml to 2.23+/-0.77 ml, with improvements up to 16.6 ml in individual subjects with marked brain torque. PMID- 24338728 TI - Intensity based methods for brain MRI longitudinal registration. A study on multiple sclerosis patients. AB - Registration is a key step in many automatic brain Magnetic Resonance Imaging (MRI) applications. In this work we focus on longitudinal registration of brain MRI for Multiple Sclerosis (MS) patients. First of all, we analyze the effect that MS lesions have on registration by synthetically eliminating some of the lesions. Our results show how a widely used method for longitudinal registration such as rigid registration is practically unconcerned by the presence of MS lesions while several non-rigid registration methods produce outputs that are significantly different. We then focus on assessing which is the best registration method for longitudinal MRI images of MS patients. In order to analyze the results obtained for all studied criteria, we use both descriptive statistics and statistical inference: one way ANOVA, pairwise t-tests and permutation tests. PMID- 24338730 TI - Reply to "Management of left ventricular thrombosis in patients with apical aneurysm". PMID- 24338731 TI - Sonography of peripheral lymph nodes part 2: Doppler criteria and typical findings of distinct entities. PMID- 24338729 TI - Identifying informative imaging biomarkers via tree structured sparse learning for AD diagnosis. AB - Neuroimaging provides a powerful tool to characterize neurodegenerative progression and therapeutic efficacy in Alzheimer's disease (AD) and its prodromal stage-mild cognitive impairment (MCI). However, since the disease pathology might cause different patterns of structural degeneration, which is not pre-known, it is still a challenging problem to identify the relevant imaging markers for facilitating disease interpretation and classification. Recently, sparse learning methods have been investigated in neuroimaging studies for selecting the relevant imaging biomarkers and have achieved very promising results on disease classification. However, in the standard sparse learning method, the spatial structure is often ignored, although it is important for identifying the informative biomarkers. In this paper, a sparse learning method with tree-structured regularization is proposed to capture patterns of pathological degeneration from fine to coarse scale, for helping identify the informative imaging biomarkers to guide the disease classification and interpretation. Specifically, we first develop a new tree construction method based on the hierarchical agglomerative clustering of voxel-wise imaging features in the whole brain, by taking into account their spatial adjacency, feature similarity and discriminability. In this way, the complexity of all possible multi-scale spatial configurations of imaging features can be reduced to a single tree of nested regions. Second, we impose the tree-structured regularization on the sparse learning to capture the imaging structures, and then use them for selecting the most relevant biomarkers. Finally, we train a support vector machine (SVM) classifier with the selected features to make the classification. We have evaluated our proposed method by using the baseline MR images of 830 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, which includes 198 AD patients, 167 progressive MCI (pMCI), 236 stable MCI (sMCI), and 229 normal controls (NC). Our experimental results show that our method can achieve accuracies of 90.2 %, 87.2 %, and 70.7 % for classifications of AD vs. NC, pMCI vs. NC, and pMCI vs. sMCI, respectively, demonstrating promising performance compared with other state-of-the-art methods. PMID- 24338732 TI - Outcome of mantle cell lymphoma patients treated at a single institution over the past decade. AB - Mantle cell lymphoma (MCL) is a rare non-Hodgkin's lymphoma entity with a heterogeneous clinical presentation. Various therapeutic considerations in MCL for younger and elderly patients were used over the past decade. We retrospectively analyzed all 44 patients consecutively treated in a tertiary hospital between 2000 and 2010 with newly diagnosed MCL. Patient characteristics, treatment regimens and biological markers were evaluated with regard to overall survival (OS). Treatment regimens were categorized into internationally accepted intensive standard therapies and less intensive alternative treatment regimens given with palliative intent. Biological markers were correlated with clinical outcome by univariate analysis. The median age of the entire study group was 66 years (range: 42-88), with 23 (52%) patients >=65 years. Thirty-one (70%) patients received standard regimens, the remaining 13 (30%) patients were treated with other, less intensive regimens with palliative intent. With a median follow up of 5.25 years, the three-year OS rate was 60% [95% confidence interval (CI) 0.47-0.77]. Patients treated with standard regimens had a three-year survival rate of 77% (range: 64-94%). Of these, patients younger than 65 years were observed to have better OS (83% at 3 years; 95% CI 68-100%) than those older than 65 years (69% at 3 years; 95% CI 48-99%). In univariate analysis, the only parameters with a statistically significant prognostic impact on OS were absolute monocyte count as a continuous variable, lactate dehydrogenase and absolute lymphocyte count (>0.5 * 10(9) /l) at diagnosis. In conclusion, our data of an unselected group of patients with newly diagnosed MCL treated at a single centre tertiary hospital are in line with results from larger randomized trials demonstrating an improved OS rate of younger as well as elderly MCL patients within the last decade. PMID- 24338733 TI - Updated assessment of possibilities and limits for solar cells. AB - The remarkable advances over the past few years in performance of photovoltaic cells, including the advent of new absorber materials, call for an update to the previous assessment of prospects for future progress. The same simple criteria with some refinements, based on cell and module performance data, serve to evaluate and compare most types of solar cells. Apart from Si and InP, for all types the "best cells" have improved in conversion performances (and crystalline Si modules have made major strides in cost reduction). New cell types, such as "perovskite", sustainable chalcogenide, and quantum dot cells, are included. CdTe results bring those cells in line with other well-developed ones, lending some credence to the idea that the criteria provide the reader with knowledge, useful for gauging possible future technological developments. Additionally, the developments of the past few years show that, while the advent of more new cell types cannot be predicted, it can be aided and stimulated by innovative, daring, and creative new materials research. PMID- 24338734 TI - Historical and present state of neuromodulation in chronic pain. AB - Neuromodulation is based on the revolutionary concept that paresthesia-inducing electrical stimulation could be analgesic. Its historical basis emanates from Melzack and Wall's gate control theory of pain proposed in 1965. Neuromodulation has given us ready access to the systems of pain modulation and helped mature the understanding of the pathophysiology of pain. Physiologic studies highlight the complex ascending influence of neurostimulation on sensory processing. However, the present understanding of pain is rudimentary and evidence that neuromodulation works is modest. This paper emphasizes the historical antecedents, present state, and emerging future of 3 commonly applied neuromodulatory techniques--spinal cord stimulation, peripheral nerve and field stimulation, and deep brain stimulation--for chronic pain. It is hoped this article will enhance the understanding of neuromodulation and its role in pain management. PMID- 24338735 TI - Revisiting rubisco as a protein substrate for insect midgut proteases. AB - Gene fragments encoding the large subunit (LS) of Rubisco (RBCL) were cloned from various species of host plants of phytophagous Lepidoptera and expressed as recombinant proteins in Escherichia coli. Recombinant RBCLs were compared among each other along with casein and native Rubisco as proteinaceous substrates for measuring total midgut protease activities of fourth instar larvae of Helicoverpa armigera feeding on casein, Pieris brassicae feeding on cauliflower, and Antheraea assamensis feeding on Litsea monopetala and Persea bombycina. Cognate rRBCL (from the pertinent host plant species) substrates performed similar to noncognate rRBCL reflecting the conserved nature of encoding genes and the versatile use of these recombinant proteins. Casein and recombinant RBCL generally outperformed native Rubisco as substrates, except where inclusion of a reducing agent in the enzyme assay likely unfolded the plant proteins. Levels of total midgut protease activities detected in A. assamensis larvae feeding on two primary host species were similar, suggesting that the suite(s) of digestive enzymes in these insects could hydrolyze a plant protein efficiently. Protease activities detected in the presence of protease inhibitors and the reducing agent dithiothreitol (DTT) suggested that recombinant RBCL was a suitable protein substrate for studying insect proteases using in vitro enzyme assays and substrate zymography. PMID- 24338736 TI - Effects of NOS1AP rs12742393 polymorphism on repaglinide response in Chinese patients with type 2 diabetes mellitus. AB - STUDY OBJECTIVE: To investigate the associations of NOS1AP rs12742393 polymorphism with the risk of type 2 diabetes mellitus (T2DM) and repaglinide therapeutic efficacy in Chinese patients with T2DM. DESIGN: Prospective case control study. SETTING: Academic medical center. PATIENTS: A total of 300 patients with T2DM and 200 healthy volunteers were enrolled to identify NOS1AP rs12742393 genotypes using the polymerase chain reaction-restriction fragment length polymorphism assay. Eighty-four patients with various genotypes were randomly selected to receive oral repaglinide as a single-agent therapy (3 mg/day) for 8 weeks. MEASUREMENTS AND MAIN RESULTS: Anthropometric measurements and fasting plasma glucose (FPG), postprandial plasma glucose, hemoglobin A1c , fasting serum insulin (FINS), postprandial serum insulin, homeostasis model assessment for insulin resistance (HOMA-IR), triglyceride, total cholesterol, low density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol tests were obtained before and after repaglinide treatment. The risk C allelic frequency of NOS1AP rs12742393 was higher in patients with T2DM than in healthy volunteers (p<0.001). Patients with T2DM and genotypes AA and AC at NOS1AP rs12742393 had a significant reduction in FPG (mmol/l) compared with those with genotype CC (p<0.01). Patients with CC homozygotes and AC heterozygotes had a greater increase in FINS (mU/l) than those with wild-type AA (p<0.05). In addition, the carriers of genotype CC at NOS1AP rs12742393 had higher differential values of HOMA-IR compared with genotypes AC and AA carriers (p<0.001). The effects of repaglinide treatment on FPG (p<0.01), FINS (p<0.05) and HOMA-IR (p<0.001) were reduced in patients with T2DM carrying the NOS1AP rs12742393 risk C allele compared with the AA genotype carriers. CONCLUSION: The NOS1AP rs12742393 polymorphism is associated with therapeutic efficacy of repaglinide in Chinese T2DM patients. PMID- 24338737 TI - Self-priming determines high type I IFN production by plasmacytoid dendritic cells. AB - Plasmacytoid dendritic cells (pDCs) are responsible for the robust and immediate production of type I IFNs during viral infection. pDCs employ TLR7 and TLR9 to detect RNA and CpG motifs present in microbial genomes. CpG-A was the first synthetic stimulus available that induced large amounts of IFN-alpha (type I IFN) in pDCs. CpG-B, however, only weakly activates pDCs to produce IFN-alpha. Here, we demonstrate that differences in the kinetics of TLR9 activation in human pDCs are essential for the understanding of the functional difference between CpG-A and CpG-B. While CpG-B quickly induces IFN-alpha production in pDCs, CpG-A stimulation results in delayed yet maximal IFN-alpha induction. Constitutive production of low levels of type I IFN in pDCs, acting in a paracrine and autocrine fashion, turned out to be the key mechanism responsible for this phenomenon. At high cell density, pDC-derived, constitutive type I IFN production primes pDCs for maximal TLR responsiveness. This accounts for the high activity of higher structured TLR agonists that trigger type I IFN production in a delayed fashion. Altogether, these data demonstrate that high type I IFN production by pDCs cannot be simply ascribed to cell-autonomous mechanisms, yet critically depends on the local immune context. PMID- 24338739 TI - Discordance between genotypic resistance and pseudovirus phenotypic resistance in AIDS patients after long-term antiretroviral therapy and virological failure. AB - Sixteen original recombinant pseudoviruses were generated by cloning the reverse transcriptase and protease genes of human immunodeficiency virus (HIV)-1 from patients into a plasmid vector (pNL4-3-DeltaE-EGFP). By site-directed mutagenesis two restriction endonuclease sites, ApaI and AgeI, were inserted into pNL4-3 DeltaE-EGFP. Phenotypic susceptibility of recombinant pseudoviruses to five different classes of antiretroviral drugs was determined using a luciferase reporter assay system. The results were subjected to comparative analyses to detect genotype-phenotype associations. Among 16 strains tested, 12 strains had a discordant genotype-phenotype resistance pattern to at least one drug. In five strains resistance to two, in two strains to three, and in one strain resistance to four drugs was detected. HIV resistance genotyping could predict the phenotype for nevirapine and azidothymidine. For lamivudine, 2'-3'-didehydro-2' 3'dideoxythymidine and didanosine, phenotypic resistance testing was necessary. The study showed that in patients who experienced long-term highly active antiretroviral therapy and virological failure, there is some discordance between genotypic and phenotypic HIV drug resistance. To address the issue of limited resources in China, genotypic and phenotypic resistance testing should be done for different drugs in order to guide clinical therapy more effectively. PMID- 24338740 TI - Effect of flavonoids on learning, memory and neurocognitive performance: relevance and potential implications for Alzheimer's disease pathophysiology. AB - Recent evidence has indicated that a group of plant-derived compounds known as flavonoids may exert particularly powerful actions on mammalian cognition and may reverse age-related declines in memory and learning. In addition, growing evidence is also suggestive that flavonoids may delay the development of Alzheimer's disease-like pathology, suggestive of potential dietary strategies in dementia. Although these low-molecular-weight phytochemicals are absorbed to only a limited degree, they have been found to counteract age-related cognitive declines possibly via their ability to interact with the cellular and molecular architecture of the brain responsible for memory. However, the majority of the research has been carried out at rather supraphysiological concentrations and only a few studies have investigated the neuromodulatory effects of physiologically attainable flavonoid concentrations. This review will summarize the evidence for the effects of flavonoids and their metabolites in age-related cognitive decline and Alzheimer's disease. Mechanisms of actions will be discussed and include those activating signalling pathways critical in controlling synaptic plasticity, reducing neuroinflammation and inducing vascular effects potentially capable of causing new nerve cell growth in the hippocampus. Altogether, these processes are known to be important in maintaining optimal neuronal function, to limit neurodegeneration and to prevent or reverse age dependent deteriorations in cognitive performance. PMID- 24338741 TI - Developmental trajectories of marijuana use from adolescence to adulthood: relationship with using weapons including guns. AB - This is the first study to assess the associations between the trajectories of marijuana use and other predictors of violent behavior with the use of guns or other weapons as well as stealing without the use of weapons among inner-city African Americans and Puerto Ricans (N = 838). Logistic regression analyses examined whether the longitudinal trajectories of marijuana use compared with the trajectory of no/low marijuana use predicted violent behavior. A higher Bayesian posterior probability (BPP) for the increasing marijuana use trajectory group (AOR = 3.37, P < .001), the moderate use of marijuana trajectory group (AOR = 1.98, P < .01), and the quitter trajectory group (AOR = 1.70, P < .05) was associated with an increased likelihood of engaging in violence (i.e., shooting or hitting someone with a weapon) compared with the BPP of the no use of marijuana trajectory group. Our results address a number of important public health and clinical issues. Public health funds might be spent on prevention programs focused on decreasing the use of marijuana, increasing educational retention, and decreasing contact with deviant associates. Understanding the psychosocial conditions related to the use of weapons is critical for individuals involved in the criminal justice system, physicians, and other health care providers in managing individuals who engage in violent behavior. PMID- 24338742 TI - Use of plasma in the management of central nervous system bleeding: evidence based consensus recommendations. AB - INTRODUCTION: Central nervous system (CNS) hemorrhage is a potentially life threatening condition, especially in patients with acquired coagulopathy. In this setting, treatment of CNS bleeding includes hemostatic therapy to replenish coagulation factors. There is currently a debate over the hemostatic efficacy of plasma in many clinical settings, alongside increasing concern about transfusion associated adverse events. Despite these concerns, plasma is widely used. Moreover, plasma transfusion practice is variable and there is currently no uniform approach to treatment of traumatic, surgical or spontaneous CNS hemorrhage. This study addresses the need for guidance on the indications and potential risks of plasma transfusion in these settings. An Expert Consensus Panel was convened to develop recommendations guiding the use of plasma to treat bleeding and/or coagulopathy associated with CNS hemorrhage. The panel did not advise on the best treatment available but rather proposed recommendations to be used in the formulation of local procedures to support emergency physicians in their decision-making process. METHODS: Evidence was systematically gathered from the literature and rated using methods established by the Scottish Intercollegiate Guidelines Network. The evidence was used to develop graded consensus recommendations, which are presented along with the evidence-based rationale for each in this report. RESULTS: Sixty-five articles were identified covering both vitamin K antagonist-anticoagulation reversal and treatment of bleeding/coagulopathy in non-anticoagulated patients. Recommendations were then developed in four clinical scenarios within each area, and agreed on unanimously by all members of the panel. CONCLUSION: The Panel considered plasma to be reasonable therapy for CNS hemorrhage requiring urgent correction of coagulopathy, although physicians should be prepared for potential cardiopulmonary complications, and evidence suggests that alternative therapies have superior risk-benefit profiles. Plasma could not be recommended in the absence of hemorrhage or coagulopathy. Consideration of the absolute risks and benefits of plasma therapy before transfusion is imperative. PMID- 24338738 TI - 25th anniversary article: ordered polymer structures for the engineering of photons and phonons. AB - The engineering of optical and acoustic material functionalities via construction of ordered local and global architectures on various length scales commensurate with and well below the characteristic length scales of photons and phonons in the material is an indispensable and powerful means to develop novel materials. In the current mature status of photonics, polymers hold a pivotal role in various application areas such as light-emission, sensing, energy, and displays, with exclusive advantages despite their relatively low dielectric constants. Moreover, in the nascent field of phononics, polymers are expected to be a superior material platform due to the ability for readily fabricated complex polymer structures possessing a wide range of mechanical behaviors, complete phononic bandgaps, and resonant architectures. In this review, polymer-centric photonic and phononic crystals and metamaterials are highlighted, and basic concepts, fabrication techniques, selected functional polymers, applications, and emerging ideas are introduced. PMID- 24338743 TI - Impact of high-dose chemotherapy and autologous transplantation as first-line therapy on the survival of high-risk diffuse large B cell lymphoma patients: a single-center study in Japan. AB - High-dose chemotherapy (HDT), together with autologous stem cell transplantation (ASCT), plays an important role in the treatment of diffuse large B cell lymphoma (DLBCL), especially as second-line therapy. However, its significance in up-front settings remains to be elucidated. In our institute, patients with DLBCL in both the high-intermediate and high international prognostic index (IPI) groups initially underwent CHOP/R-CHOP treatment followed by HDT/ASCT at upfront settings between 2002 and 2011. We retrospectively analyzed 25 patients who were all treated with upfront HDT/ASCT. We excluded one patient who failed to undergo transplantation because of primary refractory disease from the analysis. The median follow-up was 77 months (range 17-110 months). Five-year overall survival (OS) and progression-free survival (PFS) were 91.7 and 79.2 %, respectively, which were higher than the equivalents in previous studies. The OS and PFS in the high-risk group were lower than those in the high-intermediate group. Treatment related mortalities or fatal complication were not observed. Our results confirm that HDT/ASCT for high-risk aggressive lymphoma is a feasible and promising therapy, but patients with high IPI continued to have poor prognoses; improvements in treatment strategy are clearly needed. Since HDT/ASCT is an aggressive treatment option associated with long-term complications, we need to identify patient groups that will gain the maximum benefit from HDT/ASCT in the upfront setting. PMID- 24338744 TI - Liver disease is frequently observed in Down syndrome patients with transient abnormal myelopoiesis. AB - Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome (DS) is characterized by the transient appearance of blast cells, which resolves spontaneously. Approximately 20 % of patients with TAM die at an early age due to organ failure, including liver disease. We studied 25 DS-TAM patients retrospectively to clarify the correlation between clinical and laboratory characteristics and liver diseases. Early death (<6 months of age) occurred in four of the 25 patients (16.0 %), and two of those four patients died due to liver failure. Although physiologic jaundice improved gradually after a week, all DS patients had elevated D-Bil levels during the clinical course of TAM, except one who suffered early death. The median peak day of the WBC count, total bilirubin (T-Bil) and D-Bil levels was: day 1 (range day 0-57), day 8 (range day 1-55), and day 17 (range 1-53), respectively. Our results reveal that all patients with DS-TAM may develop liver disease irrespective of the absence or presence of symptoms and risk factors for early death. In patients of DS-TAM, careful observation of the level of D-Bil is needed by at least 1 month of age for the detection of liver disease risk. PMID- 24338745 TI - Chimeric antigen receptor modified T cell therapy for B cell malignancies. AB - Adoptive transfer of tumor-reactive T cells into cancer patients with the intent of inducing a cytotoxic anti-tumor effector response and durable immunity has long been proposed as a novel therapy for a broad range of malignancies; however, local and systemic tolerance mechanisms have hindered the generation of effective T cell therapies and limited the clinical efficacy of this approach in cancer patients. Chimeric antigen receptors (CARs) are recombinant receptors that comprise an extracellular antigen-targeting domain in conjunction with one or more intracellular T cell signaling domains that can be introduced into T cells by genetic modification to redirect their specificity to the CAR-targeted antigen. Administration of CD19-specific CAR-modified T cells that target B cell non-Hodgkin lymphomas and leukemia has been remarkably effective in recent clinical trials, energizing the field and stimulating new efforts to identify the critical parameters of CAR design and T cell engineering that are necessary for effective cancer therapy. PMID- 24338746 TI - Comparison of sensitivity and specificity among 15 criteria for chronic inflammatory demyelinating polyneuropathy. AB - INTRODUCTION: There have been 15 formal sets of criteria published for the diagnosis of CIDP. No study to date has compared the sensitivity and specificity of all published criteria in the same patient population. METHODS: We conducted a retrospective chart review of patients with CIDP (n = 56) and controls with diabetic polyneuropathy (n = 37) or amyotrophic lateral sclerosis (n = 39) who were followed in an academic neuromuscular practice. The sensitivity and specificity of each CIDP criterion was calculated, including clinical, laboratory, and electrodiagnostic components. RESULTS: Sensitivities ranged from 1.8% to 87.5%; the Dyck (87.5%), Neuropathy Association (75%), and European Federation of Neurological Societies (EFNS; 73.2%) criteria ranked highest. Specificities ranged from 65.6% to 100% and, among the 3 most sensitive criteria, the EFNS (90.8%) and Neuropathy Association (82.9%) criteria were most specific. CONCLUSIONS: In our patient population, the EFNS and Neuropathy Association criteria stand out due to high sensitivity and specificity. PMID- 24338749 TI - The impact of the EMA change in definition of "dose" on the BCS dose-solubility ratio: a review of the biowaiver monographs. AB - The Biopharmaceutics Classification System (BCS) defines the solubility characteristics of an active pharmaceutical substance based on its dose solubility ratio: for highly soluble drugs this ratio is less than 250 mL over a defined pH range. Prior to the revision of the European Medicines Agency (EMA, formerly EMEA) guideline in 2010, the "dose" in this ratio was consistently defined by the US FDA, the EMA, and the WHO biowaiver guidelines as the highest dosage strength. However, in the revised EMA guideline, the dose is defined as the highest single dose administered according to the Summary of Product Characteristics. The new EMA criterion for highly soluble may be closer to the actual conditions of use, but it is not in line with the dose that would be used in the in vivo bioequivalence study. This paper evaluates the impact on the BCS classification of the active pharmaceutical ingredients of the published biowaiver monographs and discusses the consequences of the possible change in classification on biowaiver recommendations. Using the current definition of dose by the EMA, the biowaiver recommendations for metoclopramide hydrochloride and verapamil hydrochloride are no longer valid according to EMA criteria. For prednisolone and prednisone, a reevaluation of the biowaiver recommendation, taking into account the usual dosing levels, seems appropriate. PMID- 24338750 TI - Development of new laboratory tools for assessment of granulation behavior during bulk active pharmaceutical ingredient drying. AB - Approximately 30% of active pharmaceutical ingredients (APIs) experience agglomeration, granulation, and breakage during agitated drying. Currently, there is no small-scale bench tool to help assess and observe granulation behavior of APIs in the laboratory and subsequently lead to the development of a robust drying method. As a result, more conservative drying methods are usually used at scale and much longer drying times are needed. In this work, we build on work reported in the literature and demonstrate that a mixer torque rheometer (MTR) can be a useful small-scale tool to flag potentially problematic granulation behavior of APIs under different conditions. The results from the MTR were confirmed using a second new tool involving the use of an acoustic mixer to verify and observe the granulation behavior on a small scale. We also show consistency between the data collected at the laboratory and the pilot plant scales. PMID- 24338751 TI - Iontophoresis successfully delivers dexamethasone sodium phosphate to dermis as measured by microdialysis. AB - Despite its widespread and long term use, the effectiveness of iontophoresis to increase the delivery of dexamethasone sodium phosphate (DSP) remains controversial. The goal of this study was to quantitatively compare the DSP concentrations in dermis' dialysates in two delivery scenarios: with and without iontophoresis. Interstitial fluid concentrations were measured by cutaneous microdialysis. Passive and active iontophoresis were applied simultaneously on the skin of the forearm in eight healthy adult participants using each participant as his/her own control. The iontophoresis apparatus and procedures were identical to those used in common clinical practice. Iontophoresis electrodes were loaded with 2 mL of 4.4 mg/mL of preservative-free DSP solution. Electric current (4 mA) was applied for 20 min. Dialysate samples were collected for 2 h and analyzed for DSP and its active metabolite dexamethasone (DXM). Seven out of eight iontophoresis sites contained quantifiable levels of DSP and DXM, whereas none of the samples collected at the passive site contained either form of the drug. In conclusion, this study demonstrates that iontophoresis significantly (p < 0.0001) increases delivery of DSP to the dermis compared with passive delivery of the same, and that microdialysis can be used to monitor DSP delivery and DXM formation in skin. PMID- 24338752 TI - In Vitro release from reverse poloxamine/alpha-cyclodextrin matrices: modelling and comparison of dissolution profiles. AB - Gels obtained by complexation of octablock star polyethylene oxide/polypropylene oxide copolymers (Tetronic 90R4) with alpha-cyclodextrin (alpha-CD) were evaluated as matrices for drug release. Both molecules are biocompatible so they can be potentially applied to drug delivery systems. Two different types of matrices of Tetronic 90R4 and alpha-CD were evaluated: gels and tablets. These gels are capable to gelifying in situ and show sustained erosion kinetics in aqueous media. Tablets were prepared by freeze-drying and comprising the gels. Using these two different matrices, the release of two model molecules, L tryptophan (Trp), and a protein, bovine serum albumin (BSA), was evaluated. The release profiles of these molecules from gels and tablets prove that they are suitable for sustained delivery. Mathematical models were applied to the release curves from tablets to elucidate the drug delivery mechanism. Good correlations were found for the fittings of the release curves to different equations. The results point that the release of Trp from different tablets is always governed by Fickian diffusion, whereas the release of BSA is governed by a combination of diffusion and tablet erosion. PMID- 24338754 TI - Tetrapeptidic molecular hydrogels: self-assembly and co-aggregation with amyloid fragment Abeta1-40. AB - A new family of isomeric tetrapeptides containing aromatic and polar amino acid residues that are able to form molecular hydrogels following a smooth change in pH is described. The hydrogels have been studied by spectroscopic and microscopic techniques showing that the peptide primary sequence has an enormous influence on the self-assembly process. In particular, the formation of extended hydrophobic regions and the appearance of pi-stacking interactions have been revealed as the driving forces for aggregation. Moreover, the interaction of these compounds with amyloid peptidic fragment Abeta1-40 has been studied and some of them have been shown to act as templates for the aggregation of this peptide into non-beta-sheet fibrillar structures. These compounds could potentially be used for the capture of toxic, soluble amyloid oligomers. PMID- 24338748 TI - Emerging research and clinical development trends of liposome and lipid nanoparticle drug delivery systems. AB - Liposomes are spherical-enclosed membrane vesicles mainly constructed with lipids. Lipid nanoparticles are loaded with therapeutics and may not contain an enclosed bilayer. The majority of those clinically approved have diameters of 50 300 nm. The growing interest in nanomedicine has fueled lipid-drug and lipid protein studies, which provide a foundation for developing lipid particles that improve drug potency and reduce off-target effects. Integrating advances in lipid membrane research has enabled therapeutic development. At present, about 600 clinical trials involve lipid particle drug delivery systems. Greater understanding of pharmacokinetics, biodistribution, and disposition of lipid-drug particles facilitated particle surface hydration technology (with polyethylene glycol) to reduce rapid clearance and provide sufficient blood circulation time for drug to reach target tissues and cells. Surface hydration enabled the liposome-encapsulated cancer drug doxorubicin (Doxil) to gain clinical approval in 1995. Fifteen lipidic therapeutics are now clinically approved. Although much research involves attaching lipid particles to ligands selective for occult cells and tissues, preparation procedures are often complex and pose scale-up challenges. With emerging knowledge in drug target and lipid-drug distribution in the body, a systems approach that integrates knowledge to design and scale lipid drug particles may further advance translation of these systems to improve therapeutic safety and efficacy. PMID- 24338755 TI - [Diagnostic value of routine ileum biopsy in patients with chronic diarrhoea--a prospective monocentric study]. AB - BACKGROUND AND AIMS: In patients with chronic diarrhoea of unknown origin, colonoscopy with intubation of the terminal ileum and performance of biopsies are standard in the diagnostic work-up. While the importance of random biopsies in the colon even in cases with normal endoscopic appearance has been proven in several studies, the role of biopsies in the terminal ileum under these circumstances is not well defined. PATIENTS AND METHODS: In this prospective observational 24-month study patients with chronic diarrhoea of unknown cause were included. All patients underwent colonoscopy with intubation and biopsy of the terminal ileum. These biopsies have been analysed, their diagnostic value has been compared to the endoscopic appearance and the clinical diagnosis was investigated. RESULTS: In 159 patients, the terminal ileum showed a pathological endoscopic appearance in 27 cases (17 %). In 22 (81.5 %) of these 27 patients diagnostic pathological findings were present, in 4 cases (14.8 %) non-specific histological changes were detected and in one patient (3.7 %), histology was normal. In contrast, only in one of 132 cases with normal endoscopic appearance, did histopathology show a significant pathology (celiac disease). In 30 of the 132 patients (22.7 %) with a normal endoscopic appearance, distinctive histological features were detected (slight eosinophilia or elevated mucosal immune cell count), but not classified as diagnostic. In all cases, these features were also present in simultaneously performed colonic biopsies. CONCLUSIONS: Routine biopsy of the terminal ileum, when normal endoscopic appearance is documented, does not give any additional information and cannot be recommended as a standard procedure in endoscopic work-up of chronic diarrhoea. PMID- 24338756 TI - Prospective and randomized study to evaluate the clinical impact of cap assisted colonoscopy (CAC). AB - BACKGROUND: Although colonoscopy is the standard procedure in the diagnosis of colorectal neoplasia, a significant number of clinical relevant lesions may be missed even by experienced endoscopists using current technology. A transparent cap mounted at the tip of a colonoscope may be an easy way to extend the visual field during colonoscopy and may improve the detection rate of mucosal lesions. MATERIAL AND METHODS: The significance of cap assisted (CAC) vs. conventional colonoscopy (CC) on polyp detection rate was evaluated in a prospective randomized controlled trial in 504 patients. RESULTS: CC and CAC detected polyps in 39.3 % and 31.8, not significantly different. There was also no significant difference between CAC and CC according to age, sex, indication for colonoscopy, diverticulosis, sedation, bowel cleansing, withdrawal time, time/number of attempts to intubate the cecal walve, number, localization, size or histology of polyps,. However, the time to reach the cecal floor and the overall time of colonoscopy were significantly lower for CAC (1 minute). CONCLUSION: CAC was without clinical impact on polyp detection rate or performance of colonoscopy. PMID- 24338758 TI - [Stool transplantation for relapsing Cl. difficile colitis]. PMID- 24338759 TI - The role of percutaneous balloon compression in the treatment of trigeminal neuralgia recurring after other surgical procedures. AB - Trigeminal neuralgia (TN) recurring after surgery can be difficult to treat. Treatment algorithms have not been standardized or universally accepted. Here we investigated the effectiveness of percutaneous balloon compression (PBC) in the treatment of patients with TN recurrence after other surgical techniques and analyzed the role of some clinical and operative factors in determining the prognosis. The records of 22 patients (13 M and 9 F) suffering recurrent TN after one (2 gamma knife surgery, 5 percutaneous radiofrequency rhizotomy, 6 percutaneous retrogasserian glycerol rhizotomy, 3 microvascular decompression) or more (6 patients) procedures and submitted to PBC at our institution from January 2003 to February 2012 were reviewed. Seven patients had TN related to multiple sclerosis (MS). Mean follow-up was 51.81 +/- 26.63 months. 81.81 % of patients reported an acute pain relief. No major complication was observed after PBC. Eight patients (36.36 %) experienced pain recurrence and underwent one (five patients) or more (three patients) PBC. At the last follow-up, we obtained an excellent outcome (BNI I-II) in 16 patients out of 22 (72.72 %) and a good outcome (BNI III) in the remaining six. No patients had an uncontrolled pain. The lack of history of MS (p = 0.0174), the pear-like shape of the balloon at the operation (p = 0.0234) and a compression time <5 min (p < 0.05) were associated to higher pain-free survival. Considering these results PBC could be considered a useful technique for patients whose pain recurs after other procedures. PMID- 24338757 TI - [S3-guideline exocrine pancreatic cancer]. PMID- 24338760 TI - Turner syndrome: review of clinical, neuropsychiatric, and EEG status: an experience of tertiary center. AB - We reviewed the clinical, neuropsychiatric, and EEG status of 53 turner syndrome (TS) females, aged 3-16 years, in Assiut university hospitals, Upper Egypt. The diagnosis and care of patients with TS in Egypt is still in the developing stage. Hence this study was undertaken to review the details of patients with TS with respect to the pattern of cognitive, psychiatric, and motor dysfunction. We aimed to provide a comprehensive data about the experience of our center comparable to previous studies, which have been published in this field. This will contribute to a better definition of the neuropsychiatric features that may be specific to TS that allows early and better detection and management of these cases. We found FSIQ and verbal IQ that seem to be at a nearly normal level and a decreased performance IQ. ADHD and autistic symptoms were found in 20.70 and 3.77 % of our cohort, respectively. The motor performance in TS was disturbed, with some neurological deficits present in 17 % (reduced muscle tone and reduced muscle power). In addition, females with TS in our study exhibit social and emotional problems, including anxiety (5.66 %) and depression (11.30 %). The EEG results revealed abnormalities in seven patients (13.20 %). One patient presenting with generalized tonic-clonic seizures showed generalized epileptiform activity, and six patients presenting with intellectual disabilities showed abnormal EEG background activity. PMID- 24338761 TI - Rupture of the middle cerebral artery aneurysm as a presenting symptom of late onset Pompe disease in an adult with a novel GAA gene mutation. PMID- 24338762 TI - Room temperature formation of high-mobility two-dimensional electron gases at crystalline complex oxide interfaces. AB - Well-controlled sub-unit-cell layer-bylayer epitaxial growth of spinel alumina is achieved at room temperature on a TiO2 -terminated SrTiO3 single-crystalline substrate. By tailoring the interface redox reaction, 2D electron gases with mobilities exceeding 3000 cm 2 V(-1) s(-1) are achieved at this novel oxide interface. PMID- 24338763 TI - Optimum duration of regimens for Helicobacter pylori eradication. AB - BACKGROUND: The optimal duration for Helicobacter pylori (H. pylori) eradication therapy is controversial, with recommendations ranging from 7 to 14 days. Several systematic reviews have attempted to address this issue but have given conflicting results and limited their analysis to proton pump inhibitor (PPI), two antibiotics (PPI triple) therapy. We performed a systematic review and meta analysis to investigate the optimal duration of multiple H. pylori eradication regimens. OBJECTIVES: The primary objective was to assess the relative effectiveness of different durations (7, 10 or 14 days) of a variety of regimens for eradicating H. pylori. The primary outcome was H. pylori persistence. The secondary outcome was adverse events. SEARCH METHODS: The Cochrane Library, MEDLINE, EMBASE, and CINAHL were searched up to December 2011 to identify eligible randomised controlled trials (RCTs). We also searched the proceedings of six conferences from 1995 to 2011, dissertations and theses, and grey literature. There were no language restrictions applied to any search. SELECTION CRITERIA: Only parallel group RCTs assessing the efficacy of one to two weeks duration of first line H. pylori eradication regimens in adults were eligible. Within each regimen, the same combinations of drugs at the same dose were compared over different durations. Studies with at least two arms comparing 7, 10, or 14 days were eligible. Enrolled participants needed to be diagnosed with at least one positive test for H. pylori on the basis of a rapid urease test (RUT), histology, culture, urea breath test (UBT), or a stool antigen test (HpSA) before treatment. Eligible trials needed to confirm eradication of H. pylori as their primary outcome at least 28 days after completion of eradication treatment. Trials using only serology or a polymerase chain reaction (PCR) to determine H. pylori infection or eradication were excluded. DATA COLLECTION AND ANALYSIS: Study eligibility and data extraction were performed by two independent review authors. Data analyses were performed within each type of intervention, for both primary and secondary outcomes. The relative risk (RR) and number needed to treat (NNT)/number needed to harm (NNTH) according to duration of therapy were calculated using the outcomes of H. pylori persistence and adverse events. A random-effects model was used. Subgroup analyses and sensitivity analyses were planned a priori. MAIN RESULTS: In total, 75 studies met the inclusion criteria. Eight types of regimens were reported with at least two comparative eligible durations. They included: PPI + two antibiotics triple therapy (n = 59), PPI bismuth-based quadruple therapy (n = 6), PPI + three antibiotics quadruple therapy (n = 1), PPI dual therapy (n = 2), histamine H2-receptor antagonist (H2RA) bismuth quadruple therapy (n = 3), H2RA bismuth-based triple therapy (n = 2), H2RA + two antibiotics triple therapy (n = 3), and bismuth + two antibiotics triple therapy (n = 2). Some studies provided data for more than one regimen or more than two durations.For the PPI triple therapy, 59 studies with five regimens were reported: PPI + clarithromycin + amoxicillin (PCA); PPI + clarithromycin + a nitroimidazole (PCN); PPI + amoxicillin + nitroimidazole (PAN); PPI + amoxicillin + a quinolone (PAQ); and PPI + amoxicillin + a nitrofuran (PANi). Regardless of type and dose of antibiotics, increased duration of PPI triple therapy from 7 to 14 days significantly increased the H. pylori eradication rate (45 studies, 72.9% versus 81.9%), the RR for H. pylori persistence was 0.66 (95% CI 0.60 to 0.74), NNT was 11 (95% CI 9 to 14). Significant effects were seen in the subgroup of PCA (34 studies, RR 0.65, 95% CI 0.57 to 0.75; NNT 12, 95% CI 9 to 16); PAN (10 studies, RR 0.67, 95% CI 0.52 to 0.86; NNT = 11, 95% CI 8 to 25); and in PAQ (2 studies, RR 0.37, 95% CI 0.16 to 0.83; NNT 3, 95% CI 2 to 10); but not in PCN triple therapy (4 studies, RR 0.87, 95% CI 0.71 to 1.07). Significantly increased eradication rates were also seen for PPI triple therapy with 10 versus 7 days (24 studies, 79.9% versus 75.7%; RR 0.80, 95% CI 0.72 to 0.89; NNT 21, 95% CI 15 to 38) and 14 versus 10 days (12 studies, 84.4% versus 78.5%; RR 0.72, 95% CI 0.58 to 0.90; NNT 17, 95% CI 11 to 46); especially in the subgroup of PAC for 10 versus 7 days (17 studies, RR 0.80, 95% CI 0.70 to 0.91) and for 14 versus 10 days (10 studies, RR 0.69, 95% CI 0.52 to 0.91). A trend towards increased H. pylori eradication rates was seen with increased duration of PCN for 10 versus 7 days, and of PAN for 10 versus 7 days and 14 versus 10 days, though this was not statistical significant. The proportion of patients with adverse events, defined by authors, was marginally significantly increased only between 7 days and 14 days (15.5% versus 19.4%; RR 1.21, 95% CI 1.06 to 1.37; NNTH 31, 95% CI 18 to 104) but not for other duration comparisons. The proportion of patients discontinuing treatment due to adverse events was not significantly different between treatment durations.Only limited data were reported for different durations of regimens other than PPI triple therapy. No significant difference of the eradication rate was seen for all regimens according to different durations except for H2RA bismuth quadruple therapy, where a significantly higher eradication rate was seen for 14 days versus 7 days, however only one study reported outcome data. AUTHORS' CONCLUSIONS: Increasing the duration of PPI-based triple therapy increases H. pylori eradication rates. For PCA, prolonging treatment duration from 7 to 10 or from 10 to 14 days is associated with a significantly higher eradication rate. The optimal duration of therapy for PCA and PAN is at least 14 days. More data are needed to confirm if there is any benefit of increasing the duration of therapy for PCN therapy. Information is limited for regimens other than PPI triple therapy; more studies are needed to draw meaningful conclusions for optimal duration of other H. pylori eradication regimens. PMID- 24338764 TI - Participation in biobanks for research by incapacitated adults: review and discussion of current guidelines. AB - OBJECTIVE: Biobanks for research and genetic research are important opportunities to create new understanding of complex disorders, such as psychiatric disorders and dementia. The management of biobanks for subjects with psychiatric disorders or dementia raises additional challenges because of the ethical issues regarding the potentially impaired decision-making capacities of the subjects. The aim of this paper is to study (i) how guidelines address the matter and (ii) how they can be implemented in real research situations with patients suffering from psychiatric disorders and dementia. METHOD: We collected and analysed all the relevant guidelines and position papers from national and international organizations dealing with research on biological materials and selected documents mentioning the participation of incapacitated adults in genetic research and biobanks. RESULTS: Eighteen of the 30 analysed documents contain explicit references to adults who are unable to give consent. The main topics addressed by the guidelines are the following: (i) informed consent; (ii) principles of non-therapeutic research; and (iii) ethics committee review. CONCLUSIONS: In biomedical research, guidelines are an important instrument for facilitating research while promoting subjects' rights and well-being. Compared with legally binding documents, guidelines are more flexible and can be more easily revised according to evolving research situations and for adaptation to real persons and research settings. We suggest measures to implement the analysed guidelines taking into consideration the case for the participation of patients with neuropsychiatric disorders, who can have impairment of decision-making capacities without being obviously incompetent, in genetic research and biobanks. PMID- 24338765 TI - The influence of AKT isoforms on radiation sensitivity and DNA repair in colon cancer cell lines. AB - In response to ionizing radiation, several signaling cascades in the cell are activated to repair the DNA breaks, prevent apoptosis, and keep the cells proliferating. AKT is important for survival and proliferation and may also be an activating factor for DNA-PKcs and MRE11, which are essential proteins in the DNA repair process. AKT (PKB) is hyperactivated in several cancers and is associated with resistance to radiotherapy and chemotherapy. There are three AKT isoforms (AKT1, AKT2, and AKT3) with different expression patterns and functions in several cancer tumors. The role of AKT isoforms has been investigated in relation to radiation response and their effects on DNA repair proteins (DNA-PKcs and MRE11) in colon cancer cell lines. The knockout of AKT1 and/or AKT2 affected the radiation sensitivity, and a deficiency of both isoforms impaired the rejoining of radiation-induced DNA double strand breaks. Importantly, the active/phosphorylated forms of AKT and DNA-PKcs associate and exposure to ionizing radiation causes an increase in this interaction. Moreover, an increased expression of both DNA-PKcs and MRE11 was observed when AKT expression was ablated, yet only DNA-PKcs expression influenced AKT phosphorylation. Taken together, these results demonstrate a role for both AKT1 and AKT2 in radiotherapy response in colon cancer cells involving DNA repair capacity through the nonhomologous end joining pathway, thus suggesting that AKT in combination with DNA-PKcs inhibition may be used for radiotherapy sensitizing strategies in colon cancer. PMID- 24338766 TI - Prognostic value of matrix metalloproteinase-7 expression in patients with non small cell lung cancer. AB - The prognostic value of matrix metalloproteinase-7 (MMP-7) for survival of patients with non-small cell lung cancer (NSCLC) remains controversial. We performed a meta-analysis of the literatures to clarify its impact. Trials were selected for meta-analysis if they provided an independent assessment of MMP-7 in NSCLC and reported the analysis of survival data based on MMP-7 status. Pooled hazard ratio (HR) with 95% confidence interval (95% CI) was used to evaluate the associations between MMP-7 expression and survival of NSCLC patients. Heterogeneity and publication bias were also assessed. Seven studies involving 1,446 patients were identified. The combined HR for all studies was 1.28 (95% CI 0.86-1.91; P = 0.22). Subgroup analysis revealed that MMP-7 overexpression had a favorable impact on survival in Caucasians (HR = 0.74; 95% CI 0.55-0.99; P = 0.043) but showed a poor survival prognosis in Asians (HR = 1.74; 95% CI 1.05 2.88, P = 0.031). Its effect also appeared significant when the analysis was restricted to Asian patients with squamous cell cancer (HR =3.42; 95% CI 1.92 6.11, P = 0.000) and adenocarcinoma (HR = 2.1; 95% CI 1.34-3.29, P = 0.001). Our meta-analysis suggests that there are ethnic differences in the clinical significance of MMP-7 expression for patients with NSCLC. PMID- 24338767 TI - Serum levels of osteopontin as a prognostic factor in patients with oral squamous cell carcinoma. AB - Osteopontin (OPN) is a multifunctional glycophosphoprotein that was detected in many carcinomas, and it may have a prognostic role. The aim of this study was to determine osteopontin serum levels in patients with oral squamous cell carcinoma (OSCC) and investigated its correlation with clinicopathological features of tumor. Using an ELISA kit, we assessed and compared the circulating levels of OPN in blood serum of 45 oral squamous cell carcinoma patients with 45 healthy control samples. The serum osteopontin level in patients with OSCC was significantly higher (145.8 +/- 14.6 ng/ml, n = 45) compared with the healthy controls (53.9 +/- 9.6 ng/ml, n = 45, p < 0.001). Mean serum osteopontin level was significantly higher in patients with nodal metastasis (p = 0.03) and higher stage (p = 0.02). Findings of the present study suggest that OPN may have a potential role in pathogenesis of OSCC and it may be used as a tool for monitoring tumor progression. PMID- 24338769 TI - Enhancing the water splitting efficiency of Sn-doped hematite nanoflakes by flame annealing. AB - The effect of flame annealing on the water-splitting properties of Sn decorated hematite (alpha-Fe2O3) nanoflakes has been investigated. It is shown that flame annealing can yield a considerable enhancement in the maximum photocurrent under AM 1.5 (100 mW cm(-2)) conditions compared to classic furnace annealing treatments. Optimizing the annealing time (10 s at 1000 degrees C) leads to a photocurrent of 1.1 mA cm(-2) at 1.23 V (vs. RHE) with a maximum value 1.6 mA cm( 2) at 1.6 V (vs. RHE) in 1 M KOH. The improvement in photocurrent can be attributed to the fast direct heating that maintains the nanoscale morphology, leads to optimized Sn decoration, and minimizes detrimental substrate effects. PMID- 24338770 TI - Micro solid-phase derivatization analysis of low-molecular mass aldehydes in treated water by micellar electrokinetic chromatography. AB - A MEKC method was developed for the determination of aliphatic and aromatic low molecular mass aldehydes (LMMAs) in treated water samples. The method involves the precapillary derivatization and extraction of the aldehydes on a TelosTMENV MU-SPE column impregnated with 2,4-dinitrophenylhydrazine . After elution of the hydrazones with ACN, the derivatives were analyzed using MEKC-DAD. Resolution of the MEKC procedure was studied by changing the pH and the concentration of the buffer, the type, and the concentration of surfactant, and the organic modifier content in the BGE. A running buffer consisting of a phosphate buffer (pH 7.2, 75 mM) with CTAB (50 mM) and ACN (30%) gave the best results. Linearity was established over the concentration range 0.5-500 MUg/L and LODs from 65 to 775 ng/L; the interday precision was expressed as the RSD of the aldehydes ranging from 6.6 to 8.4%. Matrix effects were shown to be negligible by comparing the response factors obtained in ultrapure and treated waters. Aldehydes were readily determined at 1.1-8.4 MUg/L levels in ozonated and chlorinated water samples, the method proposed being the first CE contribution developed for the systematic analysis of both aliphatic and aromatic LMMAs in water samples. PMID- 24338768 TI - Collagen as a double-edged sword in tumor progression. AB - It has been recognized that cancer is not merely a disease of tumor cells, but a disease of imbalance, in which stromal cells and tumor microenvironment play crucial roles. Extracellular matrix (ECM) as the most abundant component in tumor microenvironment can regulate tumor cell behaviors and tissue tension homeostasis. Collagen constitutes the scaffold of tumor microenvironment and affects tumor microenvironment such that it regulates ECM remodeling by collagen degradation and re-deposition, and promotes tumor infiltration, angiogenesis, invasion and migration. While collagen was traditionally regarded as a passive barrier to resist tumor cells, it is now evident that collagen is also actively involved in promoting tumor progression. Collagen changes in tumor microenvironment release biomechanical signals, which are sensed by both tumor cells and stromal cells, trigger a cascade of biological events. In this work, we discuss how collagen can be a double-edged sword in tumor progression, both inhibiting and promoting tumor progression at different stages of cancer development. PMID- 24338771 TI - Early diagnosis of necrotizing fasciitis. AB - BACKGROUND: Necrotizing fasciitis is a rapidly progressing skin infection characterized by necrosis of the fascia and subcutaneous tissue, accompanied by severe systemic toxicity. The objective of this systematic review was to identify clinical features and investigations that will aid early diagnosis. METHODS: A systematic literature search of PubMed was undertaken using the keywords 'necrotising fasciitis', 'necrotising skin infection', 'diagnosis' and 'outcome'. Case series of 50 or more subjects with information on symptoms and signs at initial presentation, investigations and clinical outcome were included. RESULTS: Nine case series were selected, with a total of 1463 patients. Diabetes mellitus was a co-morbidity in 44.5 per cent of patients. Contact with marine life or ingestion of seafood in patients with liver disease were risk factors in some parts of Asia. The top three early presenting clinical features were: swelling (80.8 per cent), pain (79.0 per cent) and erythema (70.7 per cent). These being non-specific features, initial misdiagnosis was common and occurred in almost three-quarters of patients. Clinical features that helped early diagnosis were: pain out of proportion to the physical findings; failure to improve despite broad spectrum antibiotics; presence of bullae in the skin; and gas in the soft tissue on plain X-ray (although this occurred in only 24.8 per cent of patients). CONCLUSION: A high index of suspicion of necrotizing fasciitis is needed in a patient presenting with cutaneous infection causing swelling, pain and erythema, with co-morbidity of diabetes or liver disease. The presence of bullae, or gas on plain X-ray can be diagnostic. Early surgical exploration is the best approach in the uncertain case. PMID- 24338774 TI - Global disease burden of conditions requiring emergency surgery (Br j surg 2014; 101: e9-e22). PMID- 24338775 TI - Contemporary management of abdominal surgical emergencies in infants and children. AB - BACKGROUND: Acute abdominal complaints in children are common presentations in the emergency department. The aetiology, presentation, diagnosis and management often differ from those in adults. METHODS: This review was based on expert paediatric surgical experience confirmed by evidence from the literature obtained by searching PubMed and the Cochrane Library. Keywords used were the combinations of 'abdominal emergencies', 'acute abdomen' and the disorders 'acute appendicitis', 'intussusception', 'volvulus', 'Meckel's diverticulum', 'incarcerated inguinal hernia', 'testicular torsion' and 'ovarian torsion' with 'children'. Information was included from reviews, randomized clinical trials, meta-analyses, and prospective and retrospective cohort studies. RESULTS: Presentation and symptoms of abdominal emergencies, especially in young children, vary widely, which renders recognition of the underlying disorder and treatment challenging. Critically targeted imaging techniques are becoming increasingly important in obtaining the correct diagnosis without unnecessary delay. Minimally invasive techniques have become the method of choice for the diagnosis and treatment of many abdominal emergencies in children. CONCLUSION: Knowledge of abdominal disorders in childhood, their specific presentation, diagnosis and treatment facilitates management of children with acute abdomen in emergency departments. Imaging and minimally invasive techniques are becoming increasingly important in the diagnosis of acute abdomen in children. Urgent operation remains the cornerstone of therapy for most acute abdominal disorders. PMID- 24338776 TI - Checklists and crisis management in surgical emergencies. PMID- 24338777 TI - Strategies to improve the outcome of emergency surgery for perforated peptic ulcer. AB - BACKGROUND: Perforated peptic ulcer (PPU) is a common surgical emergency that carries high mortality and morbidity rates. Globally, one-quarter of a million people die from peptic ulcer disease each year. Strategies to improve outcomes are needed. METHODS: PubMed was searched for evidence related to the surgical treatment of patients with PPU. The clinical registries of trials were examined for other available or ongoing studies. Randomized clinical trials (RCTs), systematic reviews and meta-analyses were preferred. RESULTS: Deaths from peptic ulcer disease eclipse those of several other common emergencies. The reported incidence of PPU is 3.8-14 per 100,000 and the mortality rate is 10-25 per cent. The possibility of non-operative management has been assessed in one small RCT of 83 patients, with success in 29 (73 per cent) of 40, and only in patients aged less than 70 years. Adherence to a perioperative sepsis protocol decreased mortality in a cohort study, with a relative risk (RR) reduction of 0.63 (95 per cent confidence interval (c.i.) 0.41 to 0.97). Based on meta-analysis of three RCTs (315 patients), laparoscopic and open surgery for PPU are equivalent, but patient selection remains a challenge. Eradication of Helicobacter pylori after surgical repair of PPI reduces both the short-term (RR 2.97, 95 per cent c.i. 1.06 to 8.29) and 1-year (RR 1.49, 1.10 to 2.03) risk of ulcer recurrence. CONCLUSION: Mortality and morbidity from PPU can be reduced by adherence to perioperative strategies. PMID- 24338778 TI - Organization of emergency surgery. PMID- 24338779 TI - Socioeconomic disparities in the presentation of acute bacterial sinusitis complications in children. AB - OBJECTIVES/HYPOTHESIS: To identify characteristics and disparities associated with presentation of pediatric acute bacterial sinusitis (ABS) complications. STUDY DESIGN: A cross-sectional study of the 2008 Nationwide Emergency Department Sample database. METHODS: A total of 101,660 children 18 years of age or younger diagnosed with ABS, 696 of whom had orbital or intracranial complications, were identified. Patient and hospital-specific characteristics were investigated for association with childhood ABS complications. RESULTS: Orbital and intracranial complications occurred in 0.7% of children with ABS. Such complications were more common in boys (odds ratio [OR]: 1.65, P<.001) and children with chronic rhinosinusitis (OR: 7.89, P<.001), and were associated with presentation to metropolitan teaching (OR: 2.15, P<.001) and nonteaching (OR: 14.39, P<.001) hospitals. Orbital complications were associated with younger age (OR: 0.96, P<.001), whereas intracranial complications were associated with older age (OR: 1.11, P<.001). A dichotomy in socioeconomic background differentiated children with orbital ABS complications from those with intracranial complications. Although orbital complications were associated with higher income (OR: 2.13, P<.001) and private insurance (OR: 1.36, P=.003), intracranial complications were associated with Medicaid (OR: 2.96, P<.001) or no insurance at all (OR: 3.73, P=.001). CONCLUSIONS: Socioeconomic disparities exist in presentation of ABS complications in children. Although hinted at by the association with urban/metropolitan hospitals, explicit evidence is provided by association of intracranial complications with markers of low socioeconomic status and poor access to healthcare. Efforts to aid early diagnosis and treatment should target providers in metropolitan areas who treat children of lower socioeconomic status. Such interventions will ideally improve outcomes and limit healthcare costs related to the high morbidity of pediatric ABS complications. LEVEL OF EVIDENCE: 2b. PMID- 24338781 TI - Platelet transfusion: basic aspects. AB - Platelet transfusions have been shown to prevent major haemorrhage and improve survival in thrombocytopenic patients. Since then, advances in the preparation of platelet components, including the introduction of pathogen reduction techniques, have been achieved. The number of transfused platelet components is still growing owing to the increasing number of patients treated for haemato-oncological diseases. Additionally, indications have been extended, for example to patients with drug-induced platelet dysfunction. This review focuses on current platelet component production and storage techniques, including pathogen reduction, indications for platelet transfusion and safety issues including alloimmunisation and management of platelet refractoriness. PMID- 24338780 TI - The collagenopathies: review of clinical phenotypes and molecular correlations. AB - Genetic defects of collagen formation (the collagenopathies) affect almost every organ system and tissue in the body. They can be grouped by clinical phenotype, which usually correlates with the tissue distribution of the affected collagen subtype. Many of these conditions present in childhood; however, milder phenotypes presenting in adulthood are increasingly recognized. Many are difficult to differentiate clinically. Precise diagnosis by means of genetic testing assists in providing prognosis information, family counseling, and individualized treatment. This review provides an overview of the current range of clinical presentations associated with collagen defects, and the molecular mechanisms important to understanding how the results of genetic testing affect medical care. PMID- 24338782 TI - Microsphere priming facilitates induction of potent therapeutic T-cell immune responses against autochthonous liver cancers. AB - Immunotherapy of solid tumors is often hampered by the low frequency of tumor specific T cells elicited by current vaccination strategies. Here, we describe a prime-boost vaccination protocol based on the administration of antigen conjugated to poly-lactic-co-glycolic acid (PLGA) microspheres followed by booster vaccination with Listeria monocytogenes vectors, which rapidly generates potent immune responses within two weeks. Compared with conventional vaccination with antigen-pulsed dendritic cells, the use of PLGA microspheres resulted in immune responses of significantly higher magnitude, which could be further enhanced via coinjection of TLR 3 agonists. In an immunocompetent model of subcutaneous hepatocellular carcinoma, PLGA/Listeria vaccination resulted in complete remission of established tumors and prolonged survival. To further test the efficacy of the novel vaccination for the treatment of solid tumors, we developed an orthotopic liver cancer model based on the injection of transposon flanked plasmids expressing oncogenes and model antigens. In this transgenic mouse model of liver cancer, PLGA/Listeria vaccination resulted in eradication of liver tumors, long-term survival of animals and establishment of stable cancer specific memory CD8(+) T-cell populations. Therefore, combined PLGA/Listeria vaccination holds promise as a novel immunotherapeutic option for the treatment of solid cancers and as a means to boost the therapeutic efficacy of established cancer vaccines. PMID- 24338783 TI - Differential gene expression in male and female fat body in the oriental fruit fly, Bactrocera dorsalis. AB - The sexual difference in gene expression in fat body between 8- and 10-day-old male and female Bactrocera dorsalis was examined using suppression subtractive hybridization. A total of 952 clones were sequenced and searched using BLAST from the subtracted cDNA library. About 22% of these clones showed homology with detoxification enzymes including cytochrome P450 monooxygenases (CYPs) and glutathione S-transferase. NADH dehydrogenases, distributed to energy metabolism, constituted about 9% of these clones. About 10% of these clones were cecropin, an antimicrobial peptide. Real-time quantitative polymerase chain reaction (qPCR) analysis showed that four transcripts were expressed at a higher level in fat body of males, compared to females. Bactrocera dorsalis cyp6g2 (Bdcyp6g2) was cloned (accession number KF469179) and the temporal profile of transcriptional expression showed that Bdcyp6g2 mRNA increased with age in males from day 3 after eclosion, but only on days 0-3 in females. Compared to females, the susceptibility of 9-day-old males to three insecticides was significantly less. These results suggested the genes expressed at a higher level in male act in its survival. PMID- 24338785 TI - Removal of the insecticide diazinon from liquid media by free and immobilized Streptomyces sp. isolated from agricultural soil. AB - From an agricultural soil that had received continuous applications of organophosphorus pesticides, 30 actinobacteria strains were isolated. Two strains, identified as Streptomyces sp. AC1-6 and Streptomyces sp. ISP4, were selected because of their tolerance to diazinon and based on the relationship between diazinon removal and microbial growth. In liquid medium with diazinon at concentrations of 25 and 50 mg L(-1), both strains were able to remove approximately 40-50% and 70-90% of the initial diazinon after 24 and 96 h of incubation, respectively. This diazinon removal was accompanied by microbial growth of the strains, an initial pH decrease, and glucose consumption in the liquid medium. Evaluation of the diazinon removal achieved by the free actinobacteria and Streptomyces sp. AC1-6 immobilized on alginate beads revealed that the immobilized cells exhibited a 60% higher diazinon removal compared with the free cells. The reusability of the encapsulated biomass was confirmed, and a diazinon removal rate of more than 50% was obtained after the second batch. This work constitutes one of the few reports that describe Streptomyces strains as diazinon degraders. Given the high diazinon removal found, the streptomycetes exhibit suitable potential as diazinon-degrading actinobacteria for elimination of diazinon from liquid residues. PMID- 24338784 TI - Lipolytic activity of Svetol(r), a decaffeinated green coffee bean extract. AB - The beneficial health effects of chlorogenic acids (CGAs), major components of coffee beans, are well known and have been attributed to multiple mechanisms of action. However, the lipolytic activity of CGAs does not appear to have been reported. We studied the effects of varying concentrations of Svetol(r), a decaffeinated green coffee bean extract enriched in CGAs, on the liberation of free fatty acids from human adipocytes following short-term (2 h) and long-term (192 h) exposure. The results showed that although lipolytic activity observed following short-term incubation could be tentatively linked to residual caffeine traces in the sample, longer-term exposure clearly showed the effects of Svetol(r) on release of free fatty acids, and this effect was not due to caffeine. The results of this study provide a further mechanism by which to explain the long-term health benefits of CGAs and Svetol(r). PMID- 24338786 TI - Bortezomib-induced Sweet's syndrome confirmed by rechallenge. AB - Sweet's syndrome, also known as acute febrile neutrophilic dermatosis, is characterized predominantly by fever, elevated neutrophil count, and erythematous skin lesions composed of plaques and nodules that appear on upper extremities, face, or neck. The incidence of Sweet's syndrome in the general population is unknown due to the rarity of the condition and potential lack of reporting. Bortezomib, an antineoplastic agent that is the standard of care in patients with multiple myeloma, has been reported to be associated with Sweet's syndrome. We describe a 69-year-old man who developed Sweet's syndrome during his initial course (after cycle 4) of bortezomib for treatment of multiple myeloma; he again experienced Sweet's syndrome 3.5 years later when rechallenged with bortezomib (after cycle 5) for treatment of relapsed multiple myeloma. The patient's signs, symptoms, and biopsy results were identical during both presentations of Sweet's syndrome. In both instances, the syndrome spontaneously resolved without incident and without supportive treatment with corticosteroids or antihistamines. To our knowledge, this is the first case report of a patient who developed Sweet's syndrome during an initial course of treatment with bortezomib and after rechallenge with bortezomib for relapsed disease. As proteasome inhibitors continue to be a mainstay of therapy for both treatment and salvage therapy for multiple myeloma, this case demonstrates that rechallenge with bortezomib is an option for patients who develop Sweet's syndrome. PMID- 24338787 TI - Biomarkers in outpatient heart failure management; Are they correlated to and do they influence clinical judgment? AB - AIMS: Heart failure (HF) management is complicated by difficulties in clinical assessment. Biomarkers may help guide HF management, but the correspondence between clinical evaluation and biomarker serum levels has hardly been studied. We investigated the correlation between biomarkers and clinical signs and symptoms, the influence of patient characteristics and comorbidities on New York Heart Association (NYHA) classification and the effect of using biomarkers on clinical evaluation. METHODS AND RESULTS: This post-hoc analysis comprised 622 patients (77 +/- 8 years, 76 % NYHA class >=3, 80 % LVEF <=45 %) participating in TIME-CHF, randomising patients to either NT-proBNP-guided or symptom-guided therapy. Biomarker measurements and clinical evaluation were performed at baseline and after 1, 3, 6, 12 and 18 months. NT-proBNP, GDF-15, hs-TnT and to a lesser extent hs-CRP and cystatin-C were weakly correlated to NYHA, oedema, jugular vein distension and orthopnoea (rho-range: 0.12-0.33; p < 0.01). NT proBNP correlated more strongly to NYHA class in the NT-proBNP-guided group compared with the symptom-guided group. NYHA class was significantly influenced by age, body mass index, anaemia, and the presence of two or more comorbidities. CONCLUSION: In HF, biomarkers correlate only weakly with clinical signs and symptoms. NYHA classification is influenced by several comorbidities and patient characteristics. Clinical judgement seems to be influenced by a clinician's awareness of NT-proBNP concentrations. PMID- 24338789 TI - Quantitative systems pharmacology for shifting the drug discovery and development paradigm. PMID- 24338790 TI - Reactivity of oxygen radical anions bound to scandia nanoparticles in the gas phase: C-H bond activation. AB - The activation of C-H bonds in alkanes is currently a hot research topic in chemistry. The atomic oxygen radical anion (O(-.)) is an important species in C-H activation. The mechanistic details of C-H activation by O(-.) radicals can be well understood by studying the reactions between O(-.) containing transition metal oxide clusters and alkanes. Here the reactivity of scandium oxide cluster anions toward n-butane was studied by using a high-resolution time-of-flight mass spectrometer coupled with a fast flow reactor. Hydrogen atom abstraction (HAA) from n-butane by (Sc2O3)(N)O(-) (N=1-18) clusters was observed. The reactivity of (Sc2O3)(N)O(-) (N=1-18) clusters is significantly sizedependent and the highest reactivity was observed for N=4 (Sc8O13(-)) and 12 (Sc24O37(-)). Larger (Sc2O3)(N)O(-) clusters generally have higher reactivity than the smaller ones. Density functional theory calculations were performed to interpret the reactivity of (Sc2O3)(N)O(-) (N=1-5) clusters, which were found to contain the O(-.) radicals as the active sites. The local charge environment around the O(-.) radicals was demonstrated to control the experimentally observed size-dependent reactivity. This work is among the first to report HAA reactivity of cluster anions with dimensions up to nanosize toward alkane molecules. The anionic O(-.) containing scandium oxide clusters are found to be more reactive than the corresponding cationic ones in the C-H bond activation. PMID- 24338791 TI - Disintegration rate and properties of active pharmaceutical ingredient particles as determined from the dissolution time profile of a pharmaceutical formulation: an inverse problem. AB - Dissolution profile of a finished dosage form (FDF) contains hidden information regarding the disintegration of the form and the particle properties of the active pharmaceutical ingredient. Here, an extraction of this information from the dissolution profile without limitation to sink conditions is provided. In the article, mathematical relationships between the continuously measured dissolution profile of an FDF containing uniform or heterogeneous particles and its disintegration rate are developed. Further, the determinability of the disintegration kinetics and particle properties released from an FDF using the derived recurrent procedure was analyzed. On the basis of the theoretical data sets, it was demonstrated that the introduced analysis of dissolution profiles correctly identifies the disintegration rate of FDF containing multiple particle types. Furthermore, for known disintegration rates, the intrinsic lifetime of particles (time needed for total particle dissolution in infinite volume) released from the FDF and their relative amount can be determined. The extractable information from FDF dissolution time profiles can be utilized in designing of the formulation process, resulting in improved understanding of FDF properties, contributing thus to the implementation of quality by design in the FDF development. PMID- 24338792 TI - Fluorides for the prevention of early tooth decay (demineralised white lesions) during fixed brace treatment. AB - BACKGROUND: Demineralised white lesions (DWLs) can appear on teeth during fixed brace treatment because of early decay around the brackets that attach the braces to the teeth. Fluoride is effective in reducing decay in susceptible individuals in the general population. Individuals receiving orthodontic treatment may be prescribed various forms of fluoride treatment. This review compares the effects of various forms of fluoride used during orthodontic treatment on the development of DWLs. This is an update of a Cochrane review first published in 2004. OBJECTIVES: The primary objective of this review was to evaluate the effects of fluoride in reducing the incidence of DWLs on the teeth during orthodontic treatment.The secondary objectives were to examine the effectiveness of different modes of fluoride delivery in reducing the incidence of DWLs, as well as the size of lesions. Participant-assessed outcomes, such as perception of DWLs, and oral health-related quality of life data were to be included, as would reports of adverse effects. SEARCH METHODS: We searched the Cochrane Oral Health Group's Trials Register (to 31 January 2013); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 12); MEDLINE via OVID (1946 to 31 January 2013); and EMBASE via OVID (1980 to 31 January 2013). SELECTION CRITERIA: We included trials if they met the following criteria: (1) parallel group randomised clinical trials comparing the use of a fluoride-containing product versus placebo, no treatment or a different type of fluoride treatment, in which (2) the outcome of enamel demineralisation was assessed at the start and at the end of orthodontic treatment. DATA COLLECTION AND ANALYSIS: At least two review authors independently, in duplicate, conducted risk of bias assessments and extracted data. Authors of trials were contacted to obtain missing data or to ask for clarification of aspects of trial methodology. The Cochrane Collaboration's statistical guidelines were followed. MAIN RESULTS: For the 2013 update of this review, three changes were made to the protocol regarding inclusion criteria. Fourteen studies included in the previous version of the review were excluded from this update for the following reasons: five previously included studies were quasi-randomised, a further five were split-mouth studies, three measured outcomes on extracted teeth only and in one, the same fluoride intervention was used in each intervention group of the study.Three studies and 458 participants were included in this updated review. One study was assessed at low risk of bias for all domains, in one study the risk of bias was unclear and in the remaining study, the risk of bias was high.One placebo-controlled study of fluoride varnish applied every six weeks (253 participants, low risk of bias), provided moderate-quality evidence of an almost 70% reduction in DWLs (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.21 to 0.44, P value < 0.001). This finding is considered to provide moderate-quality evidence for this intervention because it has not yet been replicated by further studies in orthodontic participants.One study compared two different formulations of fluoride toothpaste and mouthrinse prescribed for participants undergoing orthodontic treatment (97 participants, unclear risk of bias) and found no difference between an amine fluoride and stannous fluoride toothpaste/mouthrinse combination and a sodium fluoride toothpaste/mouthrinse combination for the outcomes of white spot index, visible plaque index and gingival bleeding index.One small study (37 participants) compared the use of an intraoral fluoride-releasing glass bead device attached to the brace versus a daily fluoride mouthrinse. The study was assessed at high risk of bias because a substantial number of participants were lost to follow-up, and compliance with use of the mouthrinse was not measured.Neither secondary outcomes of this review nor adverse effects of interventions were reported in any of the included studies. AUTHORS' CONCLUSIONS: This review found some moderate evidence that fluoride varnish applied every six weeks at the time of orthodontic review during treatment is effective, but this finding is based on a single study. Further adequately powered, double-blind, randomised controlled trials are required to determine the best means of preventing DWLs in patients undergoing orthodontic treatment and the most accurate means of assessing compliance with treatment and possible adverse effects. Future studies should follow up participants beyond the end of orthodontic treatment to determine the effect of DWLs on participant satisfaction with treatment. PMID- 24338793 TI - Overfitting, generalization, and MSE in class probability estimation with high dimensional data. AB - Accurate class probability estimation is important for medical decision making but is challenging, particularly when the number of candidate features exceeds the number of cases. Special methods have been developed for nonprobabilistic classification, but relatively little attention has been given to class probability estimation with numerous candidate variables. In this paper, we investigate overfitting in the development of regularized class probability estimators. We investigate the relation between overfitting and accurate class probability estimation in terms of mean square error. Using simulation studies based on real datasets, we found that some degree of overfitting can be desirable for reducing mean square error. We also introduce a mean square error decomposition for class probability estimation that helps clarify the relationship between overfitting and prediction accuracy. PMID- 24338794 TI - Controlling structural symmetry of a hybrid nanostructure and its effect on efficient photocatalytic hydrogen evolution. AB - The existence of lattice strain between two different materials can be used to control the fine structural configuration in a hybrid colloidal nanostructure. Enabled by such, the relative position change of Au and CdX in Au-CdX from a symmetric to an asymmetric configuration is demonstrated, which can further lead to fine tuning of plasmon-exciton coupling and different hydrogen photocatalytic performance. These results provide new insight into plasmon enhanced photocatalytic mechanisms and provide potential catalysts for photoreduction reactions. PMID- 24338795 TI - Comparison of uptake and predictors of adherence in primary and secondary prevention of cardiovascular disease in a community-based cardiovascular prevention programme (MyAction Westminster). AB - BACKGROUND: Despite the benefits of cardiac rehabilitation, uptake and adherence remain suboptimal. With the advent of NHS Health Checks, primary prevention programmes have also been advocated, but little is known about uptake and adherence rates. This study examined rates and predictors of adherence amongst patients with cardiovascular disease (CVD) and those at high multifactorial risk (HRI) attending an innovative programme integrating primary and secondary prevention. METHODS: Comparison of rates of uptake and adherence and also predictors of adherence between 401 CVD patients and 483 HRI. The outcome was the number of sessions attended and predictor variables included clinical and psychosocial variables. Differences between groups were examined using t-tests and non-parametric tests. Multivariable regression analyses examined predictors of adherence. RESULTS: Uptake to the assessment (CVD: 97%, HRI: 88%) and the programme (CVD: 78%, HRI: 74%) were high for both groups. An average of 8/12 was attended in both groups. Beliefs about treatment predicted adherence for both groups (P < 0.01). The alcohol causal belief also predicted poorer adherence amongst CVD patients (P < 0.02). Older age also predicted better adherence amongst HRI (P < 0.001). CONCLUSIONS: Rates of uptake and adherence were high for both HRI and CVD patients. Further research is needed to examine whether interventions targeting predictor variables further improve adherence. PMID- 24338796 TI - Continuous separation of multiple particles by negative and positive dielectrophoresis in a modified H-filter. AB - The article presents a new application of the modified H-filter with insulating rectangular blocks using negative and positive DEP for separation of multiple particles in a continuous pressure-driven flow. The multiple insulating blocks fabricated along the main channel induce spatially nonuniform electric fields which exert differential repulsive (negative) or attractive (positive) DEP forces on particles, depending on the size and the polarizability of particles relative to their suspending medium. As a result, particles of different sizes and polarizability can be separated into different outlets of the H-filter. Numerical simulations are also performed to analyze the effects of block gap and width on electric field distribution and DEP force characteristics near the insulating blocks so as to provide design guidelines for optimal structural dimensions of the microfluidic device. The device performance is demonstrated by separating a three-sized particles mixture, including 2 MUm fluorescent particles with an attractive DEP force and both 5 and 10 MUm nonfluorescent particles with differential repulsive DEP forces. High separation rate of 99% is successfully achieved. PMID- 24338797 TI - Band-bending in organic semiconductors: the role of alkali-halide interlayers. AB - Band-bending in organic semiconductors, occurring at metal/alkali-halide cathodes in organic-electronic devices, is experimentally revealed and electrostatically modeled. Metal-to-organic charge transfer through the insulator, rather than doping of the organic by alkali-metal ions, is identified as the origin of the observed band-bending, which is in contrast to the localized interface dipole occurring without the insulating buffer layer. PMID- 24338798 TI - Polar red-emitting rhodamine dyes with reactive groups: synthesis, photophysical properties, and two-color STED nanoscopy applications. AB - The synthesis, reactivity, and photophysical properties of new rhodamines with intense red fluorescence, two polar residues (hydroxyls, primary phosphates, or sulfonic acid groups), and improved hydrolytic stability of the amino-reactive sites (NHS esters or mixed N-succinimidyl carbonates) are reported. All fluorophores contain an N-alkyl-1,2-dihydro-2,2,4-trimethylquinoline fragment, and most of them bear a fully substituted tetrafluoro phenyl ring with a secondary carboxamide group. The absorption and emission maxima in water are in the range of 635-639 and 655-659 nm, respectively. A vastly simplified approach to red-emitting rhodamines with two phosphate groups that are compatible with diverse functional linkers was developed. As an example, a phosphorylated dye with an azide residue was prepared and was used in a click reaction with a strained alkyne bearing an N-hydroxysuccinimid (NHS) ester group. This method bypasses the undesired activation of phosphate groups, and gives an amphiphilic amino-reactive dye, the solubility and distribution of which between aqueous and organic phases can be controlled by varying the pH. The presence of two hydroxyl groups and a phenyl ring with two carboxyl residues in the dyes with another substitution pattern is sufficient for providing the hydrophilic properties. Selective formation of a mono-N-hydroxysuccinimidyl ester from 5-carboxy isomer of this rhodamine is reported. The fluorescence quantum yields varied from 58 to 92% for free fluorophores, and amounted to 18-64% for antibody conjugates in aqueous buffers. The brightness and photostability of these fluorophores facilitated two-color stimulated emission depletion (STED) fluorescence nanoscopy of biological samples with high contrast and minimal background. Selecting a pair of fluorophores with absorption/emission bands at 579/609 and 635/655 nm enabled two-color channels with low cross-talk and negligible background at approximately 40 nm resolution. PMID- 24338799 TI - The effect of exercise on behavioural and psychological symptoms of dementia: the EVIDEM-E randomised controlled clinical trial. AB - OBJECTIVE: The objective of this study is to evaluate the effectiveness of a simple dyadic (person with dementia and their main carer) exercise regimen as a therapy for the behavioural and psychological symptoms of dementia. METHOD: A two arm, pragmatic, randomised, controlled, single-blind, parallel-group trial of a dyadic exercise regimen (individually tailored walking regimen designed to become progressively intensive and last between 20-30 min, at least five times per week).Community-dwelling individuals with ICD-10 confirmed dementia with the following: clinically significant behavioural and psychological symptoms, a carer willing and able to co-participate in the exercise regimen, and no physical conditions or symptoms that would preclude exercise participation were invited by mental health or primary care services into the study. RESULTS: One hundred and thirty-one dyads were recruited to this study. There was no significant difference in Behavioural and Psychological Symptoms as measured by the Neuropsychiatric Inventory at week 12 between the group receiving the dyadic exercise regimen and those that did not (adjusted difference in means (intervention minus control) = -1.53, p = 0.6, 95% CI [-7.37, 4.32]). There was a significant between-group difference in caregiver's burden as measured by the Zarit Caregiver Burden Inventory at week 12 (OR = 0.18, p = 0.01, CI [0.05, 0.69]) favouring the exercise group. CONCLUSIONS: This study found that regular simple exercise does not appear to improve the behavioural and psychological symptoms of dementia, but did seem to attenuate caregiver burden. Further study to improve exercise uptake are needed. PMID- 24338800 TI - Blood-based diagnostic testing for Pompe disease: consistency between GAA enzyme activity in dried blood spots and GAA gene sequencing results. PMID- 24338801 TI - Bio-inspired dopamine functionalization of polypyrrole for improved adhesion and conductivity. AB - We report the functionalization of polypyrrole (PPy) with a "sticky" biomolecule dopamine (DA), which mimics the essential component of mussel adhesive protein. PPy is one of the most promising electrically conductive polymers with good biocompatibility. The research findings reveal that the DA functionalization enhances the dispersibility and stability of PPy in water and its film adhesion to substrate surface significantly. The electrical conductivity of PPy increases to a maximum value and then decreases with the increasing DA concentration. An optimal DA to pyrrole (Py) mole ratio is found to be between 0.1 and 0.2, at which both conductivity and adhesion of DA-functionalized PPy has been improved. PMID- 24338802 TI - [Current Situation of Antibiotic Prophylaxis in Obesity and Metabolic Surgery - Data Analysis from the Study for Quality Assurance in Operative Treatment of Obesity in Germany]. AB - BACKGROUND: Since January 2005, the situation of metabolic and obesity surgery in Germany has been constantly evaluated by the German Bariatric Surgery Registry (GBSR). Data registration is performed using an internet online database with prospective data collection. All registered data were analysed in cooperation with the Institute of Quality Assurance at the Otto-von-Guericke University Magdeburg. METHODS: Data collection includes primary and revision/redo procedures. A main focus of the current study is the analysis of data regarding the perioperative management, in particular, administration of antibiotics. RESULTS: Since 2005 a significant increase of primary bariatric procedures has been reported. For evaluation of the antibiotic regimen 12 296 primary operations including 684 balloons (BIB), 2950 gastric bandings (GB), 5115 Roux-en-Y-gastric bypasses (RYGBP), 120 Scopinaro's biliopancreatic diversions (BPD), 164 duodenal switches (DS), 3125 sleeve gastrectomies (SG) and 138 other procedures were analysed. In total 77.3 % of the patients with primary procedures received perioperative antibiotics. Patients without concomitant comorbidities received antibiotics significantly less often compared to those with comorbidities. Wound infection rates were comparable for patients who underwent either gastric banding or sleeve gastrectomy. CONCLUSION: Surgery has been accepted step by step as a treatment for morbid obesity and its comorbidities in Germany during the last few years. There is only little experience in the literature regarding antibiotic therapy as well as prophylaxis in bariatric surgery. Based on the results of the current study we recommend rather the selective than the routine use of antibiotics depending on different parameters, e.g., operative time, preoperative BMI and concomitant comorbidities. PMID- 24338803 TI - Investigation of overfoaming activities and gushing mechanisms of individual beer ingredients as model substances in bottled carbonated water. AB - BACKGROUND: Researchers in several disciplines are interested in understanding the spontaneous and eruptive overfoaming (gushing) of carbonated beverages, as it is an essential problem of both the brewing and beverage industries. In order to understand the mechanism(s) taking place in gushing beer, several beer ingredients have been investigated as model substances in a much simpler matrix of carbonated water. For this purpose, sinapic acid, vanillic acid, ferulic acid, cinnamic acid and palmitic acid have been chosen as model beer ingredients. RESULTS: Gushing formation of the investigated beer ingredients depends on the degree of stabilized solvated molecular carbon dioxide in water. For this purpose, functional groups capable of forming hydrogen bonds with electronegative oxygen atoms of carbon dioxide are needed. However, the solubility of the substances plays an important role in the abundance of these functional groups in undissociated form to interact with molecular carbon dioxide. CONCLUSION: The reported data provide valuable insights into the gushing problem and help to understand its formation pathways. Each gushing-positive substance has an individual mechanism related to its structural conformation and solubility level. Therefore possible gushing mechanisms have been proposed with respect to the structural changes in model substances to clarify the differences in observed overfoaming and gushing stability levels. PMID- 24338804 TI - Perceived vocal fatigue and effort in relation to laryngeal functional measures in paresis patients. AB - OBJECTIVES/HYPOTHESIS: To determine if differences in objective measures of laryngeal function can meaningfully explain different levels of self-perceptions of effort or fatigue in patients with vocal fold paresis. STUDY DESIGN: A retrospective chart review of 72 patients with vocal fold paresis diagnosed using laryngeal electromyography, who had either been observed (n=21), treated only by injection (n=24), or treated only by surgery (n=27). METHODS: Before and after treatment/observation, patients' subjective ratings of severity of vocal effort and fatigue were assessed using the Glottal Function Index. Laryngeal function was assessed using maximum phonation time and translaryngeal flow. RESULTS: None of the variables demonstrated a significant linear change across time. Post hoc Tukey analyses following analysis of variance (ANOVA) found significant differences in flow among three groups, those rating symptoms of effort as no problem, moderate problem, or severe problem. Post hoc Tukey analyses following ANOVA found significant differences in the amount that flow changed among three groups, those demonstrating no difference, minor differences, or major differences in ratings of effort before and after treatment. CONCLUSIONS: Changes in reported symptom severity of effort were related to changes in translaryngeal midvowel flow that were not explained by passage of time. LEVEL OF EVIDENCE: 4. PMID- 24338805 TI - Apoptosis induction by 13-acetoxyrolandrolide through the mitochondrial intrinsic pathway. AB - The aim of this study was to evaluate the mechanisms of cytotoxicity of the sesquiterpene lactone 13-acetoxyrolandrolide, a nuclear factor kappa B (NF kappaB) inhibitor that was previously isolated from Rolandra fruticosa. The effects associated with the inhibition of the NF-kappaB pathway included dose dependent inhibition of the NF-kappaB subunit p65 (RelA) and inhibition of upstream mediators IKKbeta and oncogenic Kirsten rat sarcoma (K-Ras). The inhibitory concentration of 13-acetoxyrolandrolide on K-Ras was 7.7 uM. The downstream effects of the inhibition of NF-kappaB activation were also investigated in vitro. After 24 h of treatment with 13-acetoxyrolandrolide, the mitochondrial transmembrane potential was depolarized in human colon cancer (HT 29) cells. The mitochondrial oxidative phosphorylation was also negatively affected, and reduced levels of nicotinamine adenine dinucleotide phosphate (NAD(P)H) were detected after 2 h of 13-acetoxyrolandrolide exposure. Furthermore, the expression of the pro-apoptotic protein caspase-3 increased in a concentration-dependent manner. Cell flow cytometry showed that 13 acetoxyrolandrolide induced cell cycle arrest at G1 , indicating that the treated cells had undergone caspase-3-mediated apoptosis, indicating negative effects on cancer cell proliferation. These results suggest that 13-acetoxyrolandrolide inhibits NF-kappaB and K-Ras and promotes cell death mediated through the mitochondrial apoptotic pathway. PMID- 24338807 TI - Optimizing the dose of three-factor prothrombin complex concentrate in traumatic brain injury patients on warfarin therapy. AB - STUDY OBJECTIVE: To determine the percentage of patients with correction of their first international normalized ratio (INR) less than 1.5 after administration of moderate-dose three-factor prothrombin complex concentrate (PCC), 35 IU/kg compared with low-dose PCC, 25 IU/kg. DESIGN: Retrospective review. SETTING: Community teaching hospital. PATIENTS: A total of 42 adult patients diagnosed with warfarin-associated traumatic brain injury (TBI) presented with an INR of 1.5 or more and received at least one dose of PCC during a 19-month study period. The low-dose group received PCC 25 IU/kg from November 2011-July 2012 and the moderate-dose group received PCC 35 IU/kg from August 2012-May 2013. MEASUREMENTS AND MAIN RESULTS: Of the 42 patients, 25 were in the low-dose group and 17 were in the moderate-dose group. Baseline characteristics were similar between both groups in regard to age, sex, weight, creatinine clearance, weekly warfarin dose, initial INR, initial Glasgow Coma Score, and injury severity score. Of the patients in the low-dose group, 12% achieved INR reversal with first measured INR after PCC administration compared with 69% in the moderate-dose group (p<0.001). The median time to INR reversal was 6.9 hours in the low-dose PCC group and 1.9 hours in the moderate-dose PCC group (p=0.04). There were no differences between the groups in other secondary end points, including stabilization of TBI, days in the intensive care unit, total days of hospitalization, blood product administration, and adverse events. CONCLUSIONS: Moderately dosed PCC at 35 IU/kg compared with a lower dosage of 25 IU/kg was associated with a higher percentage of INR reversal and more rapid time to INR normalization in patients with TBI. Future randomized controlled studies to further investigate this novel dose and the impact on potential reductions in the use of fresh frozen plasma are warranted. PMID- 24338806 TI - Breaking bad: manipulation of the host response by Porphyromonas gingivalis. AB - Recent metagenomic and mechanistic studies are consistent with a new model of periodontal pathogenesis. This model proposes that periodontal disease is initiated by a synergistic and dysbiotic microbial community rather than by a select few bacteria traditionally known as "periopathogens." Low-abundance bacteria with community-wide effects that are critical for the development of dysbiosis are now known as keystone pathogens, the best-documented example of which is Porphyromonas gingivalis. Here, we review established mechanisms by which P. gingivalis interferes with host immunity and enables the emergence of dysbiotic communities. We integrate the role of P. gingivalis with that of other bacteria acting upstream and downstream in pathogenesis. Accessory pathogens act upstream to facilitate P. gingivalis colonization and co-ordinate metabolic activities, whereas commensals-turned pathobionts act downstream and contribute to destructive inflammation. The recent concepts of keystone pathogens, along with polymicrobial synergy and dysbiosis, have profound implications for the development of therapeutic options for periodontal disease. PMID- 24338808 TI - Prospective assessment of the influence of pancreatic cancer resection on exocrine pancreatic function. AB - BACKGROUND: Exocrine insufficiency frequently develops in patients with pancreatic cancer owing to tumour ingrowth and pancreatic duct obstruction. Surgery might restore this function by removing the primary disease and restoring duct patency, but it may also have the opposite effect, as a result of resection of functional parenchyma and anatomical changes. This study evaluated the course of pancreatic function, before and after pancreatic resection. METHODS: This prospective cohort study included patients with tumours in the pancreatic region requiring pancreatic resection in a tertiary referral centre between March 2010 and August 2012. Starting before surgery, exocrine function was determined monthly by measuring faecal elastase 1 levels (normal value over 0.200 ug per g faeces). Endocrine function, steatorrhoea-related symptoms and bodyweight were also evaluated before and after surgery. Subjects were followed from diagnosis until 6 months after surgery, or until death. RESULTS: Twenty-nine patients were included, 12 with pancreatic cancer, 14 with ampullary carcinoma and three with bile duct carcinoma (median tumour size 2.6 cm). Twenty-six patients underwent pancreaticoduodenectomy and three distal pancreatectomy. Thirteen patients had exocrine insufficiency at preoperative diagnosis. After a median follow-up of 6 months, this had increased to 24 patients. Diabetes was present in seven patients at diagnosis, and developed in one additional patient within 1 month after surgery. CONCLUSION: Most patients with tumours in the pancreatic region requiring pancreatic resection either had exocrine insufficiency at diagnosis or became exocrine-insufficient soon after surgical resection. PMID- 24338809 TI - Fully semiparametric Bayesian approach for modeling survival data with cure fraction. AB - In this paper, we consider a piecewise exponential model (PEM) with random time grid to develop a full semiparametric Bayesian cure rate model. An elegant mechanism enjoying several attractive features for modeling the randomness of the time grid of the PEM is assumed. To model the prior behavior of the failure rates of the PEM we assume a hierarchical modeling approach that allows us to control the degree of parametricity in the right tail of the survival curve. Properties of the proposed model are discussed in detail. In particular, we investigate the impact of assuming a random time grid for the PEM on the estimation of the cure fraction. We further develop an efficient collapsed Gibbs sampler algorithm for carrying out posterior computation. A Bayesian diagnostic method for assessing goodness of fit and performing model comparisons is briefly discussed. Finally, we illustrate the usefulness of the new methodology with the analysis of a melanoma clinical trial that has been discussed in the literature. PMID- 24338810 TI - Genetic variability of hepatitis B and C viruses in Brazilian patients with and without hepatocellular carcinoma. AB - Most cases of hepatocellular carcinoma (HCC) are due to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection worldwide. The aim of this study was to determine the viral genotypes and frequency of 17 mutations (15 for HBV and 2 for HCV), described previously as able to influence the course of chronic liver disease, in patients with and without HCC. This transversal study included 157 Brazilian patients with chronic hepatitis B (n = 51) and C (n = 106). Of these, 12 and 40 patients had HBV- and HCV-related HCC, respectively. Nucleotide sequencing of core promoter, pre-core, and pre-S/S regions of HBV and core region of HCV strains was performed to determine their genotypes and the frequency of the respective mutations. Among the HBV isolates, subgenotype A1 was the most prevalent in both patients with (90%) and without (61%) HCC. Fourteen out of the 15 mutations under study, as well as five different pre-S deletions, were identified. Core promoter T1753V, A1762T, and G1764A mutations were more frequent in patients with HCC than in those without, although with no statistical difference. However, a significant correlation was observed between T1753V mutation and elevation of transaminases levels (P < 0.05). As for HCV, mutation at residue 70 in the core protein of genotype 1b strains was significantly more frequent in patients with cirrhosis (56.3%) than in those without (9.1%) (P = 0.018). The detection of some key mutations in the genomes of HBV and HCV might be helpful to predict the clinical outcome of patients with chronic liver disease. PMID- 24338811 TI - Significance of liver stiffness measurement by acoustic radiation force impulse (ARFI) among hepatitis C patients. AB - The degree of liver fibrosis is strongly associated with the antiviral effect of interferon on chronic hepatitis C patients. In this study, the accuracy of acoustic radiation force impulse (ARFI) in assessing liver fibrosis and the association between liver stiffness using ARFI and antiviral effects were investigated. The 124 patients with chronic hepatitis C enrolled in this study included 94 with HCV genotype 1 and 40 (30%) with moderate fibrosis (METAVIR fibrosis score >= F2). Sixty-one patients received pegylated interferon (peg-IFN) plus ribavirin combination therapy and the treatment responses were assessed. The shear wave velocity (Vs value) by ARFI had a strong correlation with the histological fibrosis stage (P < 0.001). The AUROC of the Vs value, aspartate aminotransferase platelet ratio index and FIB4 for the diagnoses of moderate fibrosis (>=F2) were 0.890, 0.779, and 0.737, respectively. HCV genotype 1 patients with the TT allele of IL28B and with a low Vs value (<1.40 m/sec) who were treated with peg-IFN plus ribavirin therapy achieved a sustained virologic response at a rate of 79% (15/19), while all patients with the TG/GG allele of IL28B and a high Vs value (>=1.40 m/sec) experienced a non-virologic response (6/6). The Vs value measured by ARFI could not predict the treatment response for patients with HCV genotype 2. It is concluded that the combination of ARFI at cut off of 1.4 m/sec and IL28B may be useful for patients with chronic hepatitis C with genotype 1 treated with peg-IFN/ribavirin combination therapy. PMID- 24338812 TI - Search for varicella zoster virus DNA in saliva of healthy individuals aged 20-59 years. AB - All neurological and ocular complications of varicella zoster virus (VZV) reactivation can occur without rash. Virological verification requires detection of VZV DNA or anti-VZV IgG antibody in cerebrospinal fluid (CSF), or anti-VZV IgM antibody in serum or CSF. If VZV were readily detected in other tissue in patients with neurological disease without rash and found to correlate with tests listed above, more invasive tests such as lumbar puncture might be obviated. Saliva is a potential source of VZV DNA. To study the potential diagnostic value of detecting VZV DNA in saliva from patients with neurological disease, saliva of healthy adults was searched for VZV DNA. A single saliva sample obtained by passive drool was centrifuged at 16,000g for 20 min. DNA was extracted from the supernatant and cell pellet and examined in triplicate for VZV DNA by real time PCR. A single random saliva sample from 80 healthy men and women aged 20-59 years revealed no VZV DNA (Table ), but was uniformly positive for cell (GAPdH) DNA. Because VZV DNA was not found in a random saliva sample from 80 individuals 20-59 year-old, a VZV-positive sample during neurologic disease may have potential significance. Further studies will determine whether VZV DNA in saliva correlates with VZV DNA or anti-VZV antibody in CSF in patients with neurological disease. PMID- 24338813 TI - Nonenhanced ECG-gated quiescent-interval single shot MRA: image quality and stenosis assessment at 3 tesla compared with contrast-enhanced MRA and digital subtraction angiography. AB - PURPOSE: To evaluate the diagnostic accuracy of a nonenhanced electrocardiograph gated quiescent-interval single shot MR-angiography (QISS-MRA) at 3 Tesla with contrast-enhanced MRA (CE-MRA) and digital subtraction angiography (DSA) serving as reference standard. MATERIALS AND METHODS: Following institutional review board approval, 16 consecutive patients with peripheral arterial disease underwent a combined peripheral MRA protocol consisting of a large field-of-view QISS-MRA, continuous table movement MRA, and an additional time-resolved MRA of the calves. DSA correlation was available in eight patients. Image quality and degree of stenosis was assessed. Sensitivity and specificity of QISS-MRA was evaluated with CE-MRA and DSA serving as the standards of reference and compared using the Fisher exact test. RESULTS: With the exception of the calf station, image quality with QISS-MRA was rated statistically significantly less than that of CE-MRA (P < 0.05, P = 0.17, and P = 0.6, respectively). A greater percentage of segments were not accessible with QISS-MRA (19.5-20.1%) in comparison to CE MRA (10.9%). Relative to DSA, sensitivity for QISS-MRA was high (100% versus 91.2% for CE-MRA, P = 0.24) in the evaluated segments; however, specificity (76.5%) was substantially less than that of CE-MRA (94.6%, P = 0.003). CONCLUSION: Overall image quality and specificity of QISS-MRA at 3T are diminished relative to CE-MRA. However, when image quality is adequate, QISS-MRA has high sensitivity and, thus, has potential use in patients with contraindications to gadolinium. PMID- 24338814 TI - 25th anniversary article: Artificial carbonate nanocrystals and layered structural nanocomposites inspired by nacre: synthesis, fabrication and applications. AB - Rigid biological systems are increasingly becoming a source of inspiration for the fabrication of next generation advanced functional materials due to their diverse hierarchical structures and remarkable engineering properties. Among these rigid biomaterials, nacre, as the main constituent of the armor system of seashells, exhibiting a well-defined 'brick-and-mortar' architecture, excellent mechanical properties, and interesting iridescence, has become one of the most attractive models for novel artificial materials design. In this review, recent advances in nacre-inspired artificial carbonate nanocrystals and layered structural nanocomposites are presented. To clearly illustrate the inspiration of nacre, the basic principles relating to plate-like aragonite single-crystal growth and the contribution of hierarchical structure to outstanding properties in nacre are discussed. The inspiration of nacre for the synthesis of carbonate nanocrystals and the fabrication of layered structural nanocomposites is also discussed. Furthermore, the broad applications of these nacre inspired materials are emphasized. Finally, a brief summary of present nacre-inspired materials and challenges for the next generation of nacre-inspired materials is given. PMID- 24338815 TI - Minimally invasive donor nephrectomy: innovations. AB - From open surgery to laparoscopic surgery, there has been an evolution in the surgical technique for live donor nephrectomy which goes beyond patient comfort. As a unique operation where the margin for error is nearly nil, and where the patient is essentially harmed for an altruistic goal, ensuring the best possible result is vital. Additionally, as the morbidity of the operation decreases, there is a theoretical increase in the donor pool. In this review, the latest techniques for minimally invasive live donor nephrectomy are covered, including new approaches such as laparoendoscopic single-site surgery, natural orifice surgery, and new tools such as robotics. PMID- 24338816 TI - Estimation of the CSA-ODF using Bayesian compressed sensing of multi-shell HARDI. AB - PURPOSE: Diffusion MRI provides important information about the brain white matter structures and has opened new avenues for neuroscience and translational research. However, acquisition time needed for advanced applications can still be a challenge in clinical settings. There is consequently a need to accelerate diffusion MRI acquisitions. METHODS: A multi-task Bayesian compressive sensing (MT-BCS) framework is proposed to directly estimate the constant solid angle orientation distribution function (CSA-ODF) from under-sampled (i.e., accelerated image acquisition) multi-shell high angular resolution diffusion imaging (HARDI) datasets, and accurately recover HARDI data at higher resolution in q-space. The proposed MT-BCS approach exploits the spatial redundancy of the data by modeling the statistical relationships within groups (clusters) of diffusion signal. This framework also provides uncertainty estimates of the computed CSA-ODF and diffusion signal, directly computed from the compressive measurements. Experiments validating the proposed framework are performed using realistic multi shell synthetic images and in vivo multi-shell high angular resolution HARDI datasets. RESULTS: Results indicate a practical reduction in the number of required diffusion volumes (q-space samples) by at least a factor of four to estimate the CSA-ODF from multi-shell data. CONCLUSION: This work presents, for the first time, a multi-task Bayesian compressive sensing approach to simultaneously estimate the full posterior of the CSA-ODF and diffusion-weighted volumes from multi-shell HARDI acquisitions. It demonstrates improvement of the quality of acquired datasets by means of CS de-noising, and accurate estimation of the CSA-ODF, as well as enables a reduction in the acquisition time by a factor of two to four, especially when "staggered" q-space sampling schemes are used. The proposed MT-BCS framework can naturally be combined with parallel MR imaging to further accelerate HARDI acquisitions. PMID- 24338818 TI - ENaC activity is increased in isolated, split-open cortical collecting ducts from protein kinase Calpha knockout mice. AB - The epithelial Na channel (ENaC) is negatively regulated by protein kinase C (PKC) as shown using PKC activators in a cell culture model. To determine whether PKCalpha influences ENaC activity in vivo, we examined the regulation of ENaC in renal tubules from PKCalpha-/- mice. Cortical collecting ducts were dissected and split open, and the exposed principal cells were subjected to cell-attached patch clamp. In the absence of PKCalpha, the open probability (P0) of ENaC was increased three-fold vs. wild-type SV129 mice (0.52 +/- 0.04 vs. 0.17 +/- 0.02). The number of channels per patch was also increased. Using confocal microscopy, we observed an increase in membrane localization of alpha-, beta-, and gamma subunits of ENaC in principal cells in the cortical collecting ducts of PKCalpha /- mice compared with wild-type mice. To confirm this increase, one kidney from each animal was perfused with biotin, and membrane protein was pulled down with streptavidin. The nonbiotinylated kidney was used to assess total protein. While total ENaC protein did not change in PKCalpha-/- mice, membrane localization of all the ENaC subunits was increased. The increase in membrane ENaC could be explained by the observation that ERK1/2 phosphorylation was decreased in the knockout mice. These results imply a reduction in ENaC membrane accumulation and P0 by PKCalpha in vivo. The PKC-mediated increase in ENaC activity was associated with an increase in blood pressure in knockout mice fed a high-salt diet. PMID- 24338820 TI - COX2 inhibition during nephrogenic period induces ANG II hypertension and sex dependent changes in renal function during aging. AB - This study was performed to test the hypothesis that ANG II contributes to the hypertension and renal functional alterations induced by a decrease of COX2 activity during the nephrogenic period. It was also examined whether renal functional reserve and renal response to volume overload and high sodium intake are reduced in 3-4- and 9-11-mo-old male and female rats treated with vehicle or a COX2 inhibitor during nephrogenic period (COX2np). Our data show that this COX2 inhibition induces an ANG II-dependent hypertension that is similar in male and female rats. Renal functional reserve is reduced in COX2np-treated rats since their renal response to an increase in plasma amino acids levels is abolished, and their renal ability to eliminate a sodium load is impaired (P < 0.05). This reduction in renal excretory ability is similar in both sexes during aging but does not induce the development of a sodium-sensitive hypertension. However, the prolonged high-sodium intake at 9-11 mo of age leads to a greater proteinuria in male than in female (114 +/- 12 MUg/min vs. 72 +/- 8 MUg/min; P < 0.05) COX2np treated rats. Renal hemodynamic sensitivity to acute increments in ANG II is unaltered in both sexes and at both ages in COX2np-treated rats. In summary, these results indicate that the reduction of COX2 activity during nephrogenic period programs for the development of an ANG II-dependent hypertension, reduces renal functional reserve to a similar extent in both sexes, and increases proteinuria in males but not in females when there is a prolonged increment in sodium intake. PMID- 24338819 TI - Effect of collecting duct-specific deletion of both Rh B Glycoprotein (Rhbg) and Rh C Glycoprotein (Rhcg) on renal response to metabolic acidosis. AB - The Rhesus (Rh) glycoproteins, Rh B and Rh C Glycoprotein (Rhbg and Rhcg, respectively), are ammonia-specific transporters expressed in renal distal nephron and collecting duct sites that are necessary for normal rates of ammonia excretion. The purpose of the current studies was to determine the effect of their combined deletion from the renal collecting duct (CD-Rhbg/Rhcg-KO) on basal and acidosis-stimulated acid-base homeostasis. Under basal conditions, urine pH and ammonia excretion and serum HCO3(-) were similar in control (C) and CD Rhbg/Rhcg-KO mice. After acid-loading for 7 days, CD-Rhbg/Rhcg-KO mice developed significantly more severe metabolic acidosis than did C mice. Acid loading increased ammonia excretion, but ammonia excretion increased more slowly in CD Rhbg/Rhcg-KO and it was significantly less than in C mice on days 1-5. Urine pH was significantly more acidic in CD-Rhbg/Rhcg-KO mice on days 1, 3, and 5 of acid loading. Metabolic acidosis increased phosphenolpyruvate carboxykinase (PEPCK) and Na(+)/H(+) exchanger NHE-3 and decreased glutamine synthetase (GS) expression in both genotypes, and these changes were significantly greater in CD-Rhbg/Rhcg KO than in C mice. We conclude that 1) Rhbg and Rhcg are critically important in the renal response to metabolic acidosis; 2) the significantly greater changes in PEPCK, NHE-3, and GS expression in acid-loaded CD-Rhbg/Rhcg-KO compared with acid loaded C mice cause the role of Rhbg and Rhcg to be underestimated quantitatively; and 3) in mice with intact Rhbg and Rhcg expression, metabolic acidosis does not induce maximal changes in PEPCK, NHE-3, and GS expression despite the presence of persistent metabolic acidosis. PMID- 24338821 TI - Susceptibility of podocytes to palmitic acid is regulated by fatty acid oxidation and inversely depends on acetyl-CoA carboxylases 1 and 2. AB - Type 2 diabetes is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are susceptible to saturated FFAs, which induce endoplasmic reticulum (ER) stress and podocyte death. Genome-wide association studies indicate that expression of acetyl-CoA carboxylase (ACC) 2, a key enzyme of fatty acid oxidation (FAO), is associated with proteinuria in type 2 diabetes. Here, we show that stimulation of FAO by aminoimidazole-4-carboxamide-1beta-D-ribofuranoside (AICAR) or by adiponectin, activators of the low-energy sensor AMP-activated protein kinase (AMPK), protects from palmitic acid-induced podocyte death. Conversely, inhibition of carnitine palmitoyltransferase (CPT-1), the rate-limiting enzyme of FAO and downstream target of AMPK, augments palmitic acid toxicity and impedes the protective AICAR effect. Etomoxir blocked the AICAR-induced FAO measured with tritium-labeled palmitic acid. The beneficial effect of AICAR was associated with a reduction of ER stress, and it was markedly reduced in ACC-1/-2 double-silenced podocytes. In conclusion, the stimulation of FAO by modulating the AMPK-ACC-CPT-1 pathway may be part of a protective mechanism against saturated FFAs that drive podocyte death. Further studies are needed to investigate the potentially novel therapeutic implications of these findings. PMID- 24338823 TI - Extracellular fetal hemoglobin induces increases in glomerular permeability: inhibition with alpha1-microglobulin and tempol. AB - Extracellular fetal hemoglobin (HbF) and adult hemoglobin (HbA) are proinflammatory and generate ROS. Increased plasma levels of extracellular HbF have recently been reported to occur in early preeclampsia. alpha1-Microglobulin (A1M) is a physiological heme-binding protein and radical scavenger that has been shown to counteract vascular permeability increases induced by HbA in the perfused placenta. The present study was performed to investigate whether HbF and HbA will increase glomerular permeability in vivo and to test whether A1M and tempol, a ROS scavenger, can prevent their effects. Anesthetized Wistar rats were continuously infused intravenously with either HbA, HbF, or cyano-inactivated HbF together with FITC-Ficoll-70/400, inulin, and (51)Cr-labeled EDTA for 2 h. Plasma samples and urine samples (left ureter) were taken repeatedly and analyzed by high-performance size exclusion chromatography to assess glomerular sieving coefficients for Ficoll of radius 10-80 A. In separate experiments, A1M or tempol was given before and during Hb infusions. Extracellular HbF caused rapid, transient increases in glomerular permeability to large Ficoll molecules (50 80A), contrary to the effects of HbA and cyano-inactivated HbF. For HbF, glomerular sieving coefficients for Ficoll of radius 60A increased from 3.85 +/- 0.85 * 10(-5) to 2.60 +/- 0.96 * 10(-4) at 15 min, changes that were abrogated by tempol and reduced by A1M. In conclusion, our data demonstrate that extracellular HbF, infused systemically, can acutely increase glomerular permeability through inducing oxidative stress. PMID- 24338824 TI - L-arginine improves endothelial function, independently of arginine uptake, in aortas from chronic renal failure female rats. AB - Endothelial cell dysfunction (ECD) is a common feature of chronic renal failure (CRF). Defective nitric oxide (NO) generation due to decreased endothelial nitric oxide synthase (eNOS) activity is a crucial parameter characterizing ECD. Decreased activity of cationic amino acid transporter-1 (CAT-1), the selective arginine transporter of eNOS, has been shown to inhibit eNOS in uremia. Recently, we failed to demonstrate a decrease in glomerular arginine transport in uremic female rats (Schwartz IF, Grupper A, Soetendorp H, Hillel O, Laron I, Chernichovski T, Ingbir M, Shtabski A, Weinstein T, Chernin G, Shashar M, Hershkoviz R, Schwartz D. Am J Physiol Renal Physiol 303: F396-F404, 2012). The current experiments were designed to determine whether sexual dimorphism which characterizes glomerular arginine transport system in uremia involves the systemic vasculature as well and to assess the effect of L-arginine in such conditions. Contractile and vasodilatory responses, ultrastructural changes, and measures of the L-arginine-NO system were performed in thoracic aortas of female rats subjected to 5/6 nephrectomy. The contractile response to KCl was significantly reduced, and acetylcholine-induced vasodilation was significantly impaired in aortas from CRF dames compared with healthy rats. Both of these findings were prevented by the administration of arginine in the drinking water. The decrease in both cGMP generation, a measure of eNOS activity, and aortic eNOS and phosphorylated eNOS abundance observed in CRF rats was completely abolished by l-arginine, while arginine transport and CAT-1 protein were unchanged in all experimental groups. Arginine decreased both serum levels of advanced glycation end products and the asymmetrical dimethylarginine/arginine ratio and restored the endothelial ultrastructure in CRF rats. In conclusion. arginine administration has a profound beneficial effect on ECD, independently of cellular arginine uptake, in CRF female rats. PMID- 24338822 TI - CDK4/6 inhibition induces epithelial cell cycle arrest and ameliorates acute kidney injury. AB - Acute kidney injury (AKI) is common and urgently requires new preventative therapies. Expression of a cyclin-dependent kinase (CDK) inhibitor transgene protects against AKI, suggesting that manipulating the tubular epithelial cell cycle may be a viable therapeutic strategy. Broad spectrum small molecule CDK inhibitors are protective in some kidney injury models, but these have toxicities and epithelial proliferation is eventually required for renal repair. Here, we tested a well-tolerated, novel and specific small molecule inhibitor of CDK4 and CDK6, PD 0332991, to investigate the effects of transient cell cycle inhibition on epithelial survival in vitro and kidney injury in vivo. We report that CDK4/6 inhibition induced G0/G1 cycle arrest in cultured human renal proximal tubule cells (hRPTC) at baseline and after injury. Induction of transient G0/G1 cycle arrest through CDK4/6 inhibition protected hRPTC from DNA damage and caspase 3/7 activation following exposure to the nephrotoxins cisplatin, etoposide, and antimycin A. In vivo, mice treated with PD 0332991 before ischemia-reperfusion injury (IRI) exhibited dramatically reduced epithelial progression through S phase 24 h after IRI. Despite reduced epithelial proliferation, PD 0332991 ameliorated kidney injury as reflected by improved serum creatinine and blood urea nitrogen levels 24 h after injury. Inflammatory markers and macrophage infiltration were significantly decreased in injured kidneys 3 days following IRI. These results indicate that induction of proximal tubule cell cycle arrest with specific CDK4/6 inhibitors, or "pharmacological quiescence," represents a novel strategy to prevent AKI. PMID- 24338825 TI - Dielectrophoretic separation of bioparticles in microdevices: a review. AB - In recent years, dielectrophoretic force has been used to manipulate colloids, inert particles, and biological microparticles, such as red blood cells, white blood cells, platelets, cancer cells, bacteria, yeast, microorganisms, proteins, DNA, etc. This specific electrokinetic technique has been used for trapping, sorting, focusing, filtration, patterning, assembly, and separating biological entities/particles suspended in a buffer medium. Dielectrophoretic forces acting on particles depend on various parameters, for example, charge of the particle, geometry of the device, dielectric constant of the medium and particle, and physiology of the particle. Therefore, to design an effective micro-/nanofluidic separation platform, it is necessary to understand the role of the aforementioned parameters on particle motion. In this paper, we review studies particularly related to dielectrophoretic separation in microfluidic devices. Both experimental and theoretical works by several researchers are highlighted in this article covering AC and DC DEP. In addition, AC/DC DEP, which uses a combination of low frequency AC and DC voltage to manipulate bioparticles, has been discussed briefly. Contactless DEP, a variation of DC DEP in which electrodes do not come in contact with particles, has also been reviewed. Moreover, dielectrophoretic force-based field flow fractionations are featured to demonstrate the bioparticle separation in microfluidic device. In numerical front, a comprehensive review is provided starting from the most simplified effective moment Stokes-drag (EMSD) method to the most advanced interface resolved method. Unlike EMSD method, recently developed advanced numerical methods consider the size and shape of the particle in the electric and flow field calculations, and these methods provide much more accurate results than the EMSD method for microparticles. PMID- 24338826 TI - Trends in anorexia nervosa research: an analysis of the top 100 most cited works. AB - Analysis of highly cited papers provides unique insights into the status of research in a given field. We sought to identify the top 100 most highly cited papers in the field of anorexia nervosa (AN). A free, publically accessible software was used to conduct an online search of publications with accompanying citation data. Search terms were selected to focus on papers dealing predominantly with AN, and the results manually screened to exclude out-of-scope publications. Papers in bulimia nervosa, eating disorder not otherwise specified and binge-eating disorder, were not included. The top 100 most highly cited papers in the AN field were identified. Of these, 34 garnered greater than 400 citations, classifying them as 'citation classics'. These works were divided into five categories, those dealing with epidemiological trends, medical/psychiatric comorbidities, treatment, mechanisms of disease and measurement/classification. Publications examining the epidemiology and underlying mechanisms of AN account for the majority of the top 100 papers. Scales and measurement tools have had the greatest impact, garnering the greatest number of average citations per paper. Although reasonably diverse, the top 100 papers highlight areas still lagging behind, including the neuroscience of AN as well as research into novel treatment strategies. PMID- 24338827 TI - Loss of control over eating: a description of the eating disorder/obesity spectrum in women. AB - GOALS: This study aimed to analyse the association, commonalities and differences between obesity and eating disorders (ED). METHOD: A total of 150 female patients [50 obese with bulimia nervosa (OB + BN), 50 obese with binge eating disorders (OB + BED), 50 obese without eating disorders (OB)] and 50 female healthy eating/weight control (CG) volunteers participated in this study. ASSESSMENT: All participants were assessed by the Eating Disorders Inventory-2 (EDI-2), the Symptom Checklist-Revised (SCL-90-R) and the Temperament and Character Inventory Revised. RESULTS: In general, all the groups differed significantly and showed linear trends (OB + BN > OB + BED > OB > CG) on general and eating psychopathology (SCL-90-R and EDI-2). Regarding personality traits, statistically significant differences across all four groups were found on Harm Avoidance and Self-Directedness. Whereas some symptoms were shared in extreme weight conditions, others were specifically related to ED. CONCLUSIONS: The presence of binge and purge symptomatology in obese patients is clinically relevant. These findings help to understand the relationship between Obesity and ED. PMID- 24338828 TI - Synthesis of molecularly encoded oligomers using a chemoselective "AB + CD" iterative approach. AB - A library of eight sequence-defined model oligomers, whose sequence is based on a (0,1) binary code, is prepared through chemoselective repeating cycles of amidification and copper-assisted alkyne-azide cycloaddition reactions from a non modified Wang resin. This library is constructed from two AB (A = acid, B = alkyne) building blocks, i.e., 4-pentynoic acid and 2-methyl-4-pentynoic acid acting, respectively, as non-coding (0) and coding (1) monomer, and 1-amino-11 azido-3,6,9-trioxaundecane as complementary CD (C = amine, D = azide) spacer building block. In particular, encoded triads are synthesized by consecutive covalent attachment of five building blocks (i.e., three coding/non-coding monomers and two spacers). In this communication, optimal protocols for the synthesis of the targeted oligomers are reported along with their full characterization by (1) H NMR, MALDI-TOF mass spectrometry, and size-exclusion chromatography. It is found that all possible encoded triads (i.e., eight possibilities) could be synthesized using this approach. Indeed, monodisperse sequence-defined oligomers are prepared and characterized in all cases. PMID- 24338829 TI - Identification of differentially expressed proteins related to organophosphorus induced delayed neuropathy in the brains of hens. AB - Some organophosphorus compounds can cause organophosphate-induced delayed neuropathy (OPIDN). Incidents have been documented for decades, however, little is known about which proteins contribute to the initiation, progression and development of OPIDN. In this study, 51 hens were divided into three groups. The tri-ortho-cresyl-phosphate (TOCP) group was treated with 1000 mg kg(-1) TOCP whereas the control group was treated with an equivalent volume of vehicle. The PMSF + TOCP group was treated subcutaneously with 40 mg kg(-1) phenylmethylsulfonyl fluoride (PMSF), followed by 1000 mg kg(-1) TOCP 24 h later. Proteins in the brains of hens were separated by two-dimensional polyacrylamide gel electrophoresis on day 5 after TOCP administration. Mass spectrometry identified eight differentially expressed proteins. Among these proteins, downregulated expression of glutamine synthetase (GS) in the brains of hens after TOCP treatment was further confirmed by real time RT-PCR and ELISA. Moreover, the brains of hens exposed to TOCP exhibited increased levels of glutamate (Glu) and cytosolic calcium concentration ([Ca(2+)](i)), and a decreased level of glutamine (Gln). However, there were no significant differences in GS expression or levels of Glu, Gln, and [Ca(2+)](i) in the brains of hens among the groups on day 21 after TOCP administration. These results indicate that TOCP exposure downregulates GS expression in the brains of hens, and that downregulation of GS is accompanied by increased levels of Glu and [Ca(2+)](i) in the early stage after TOCP administration. It is also suggested that the downregulated expression of GS might be associated with OPIDN through the disruption of homeostasis of the Glu-Gln cycle and [Ca(2+) ](i). PMID- 24338830 TI - Ibuprofen and/or paracetamol (acetaminophen) for pain relief after surgical removal of lower wisdom teeth. AB - BACKGROUND: Both paracetamol and ibuprofen are commonly used analgesics for the relief of pain following the surgical removal of lower wisdom teeth (third molars). In 2010, a novel analgesic (marketed as Nuromol) containing both paracetamol and ibuprofen in the same tablet was launched in the United Kingdom, this drug has shown promising results to date and we have chosen to also compare the combined drug with the single drugs using this model. In this review we investigated the optimal doses of both paracetamol and ibuprofen via comparison of both and via comparison with the novel combined drug. We have taken into account the side effect profile of the study drugs. This review will help oral surgeons to decide on which analgesic to prescribe following wisdom tooth removal. OBJECTIVES: To compare the beneficial and harmful effects of paracetamol, ibuprofen and the novel combination of both in a single tablet for pain relief following the surgical removal of lower wisdom teeth, at different doses and administered postoperatively. SEARCH METHODS: We searched the Cochrane Oral Health Group'sTrials Register (to 20 May 2013); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 4); MEDLINE via OVID (1946 to 20 May 2013); EMBASE via OVID (1980 to 20 May 2013) and the metaRegister of Controlled Trials (to 20 May 2013). We checked the bibliographies of relevant clinical trials and review articles for further studies. We wrote to authors of the identified randomised controlled trials (RCTs), and searched personal references in an attempt to identify unpublished or ongoing RCTs. No language restriction was applied to the searches of the electronic databases. SELECTION CRITERIA: Only randomised controlled double blinded clinical trials were included. Cross-over studies were included provided there was a wash out period of at least 14 days. There had to be a direct comparison in the trial of two or more of the trial drugs at any dosage. All trials used the third molar pain model. DATA COLLECTION AND ANALYSIS: All trials identified were scanned independently and in duplicate by two review authors, any disagreements were resolved by discussion, or if necessary a third review author was consulted. The proportion of patients with at least 50% pain relief (based on total pain relief (TOTPAR) and summed pain intensity difference (SPID) data) was calculated for all three drugs at both two and six hours postdosing and meta analysed for comparison. The proportion of participants using rescue medication over both six and eight hours was also collated and compared. The number of patients experiencing adverse events or the total number of adverse events reported or both were analysed for comparison. MAIN RESULTS: Seven studies were included, they were all parallel-group studies, two studies were assessed as at low risk of bias and three at high risk of bias; two were considered to have unclear bias in their methodology. A total of 2241 participants were enrolled in these trials.Ibuprofen was found to be a superior analgesic to paracetamol at several doses with high quality evidence suggesting that ibuprofen 400 mg is superior to 1000 mg paracetamol based on pain relief (estimated from TOTPAR data) and the use of rescue medication meta-analyses. The risk ratio for at least 50% pain relief (based on TOTPAR) at six hours was 1.47 (95% confidence interval (CI) 1.28 to 1.69; five trials) favouring 400 mg ibuprofen over 1000 mg paracetamol, and the risk ratio for not using rescue medication (also favouring ibuprofen) was 1.50 (95% CI 1.25 to 1.79; four trials).The combined drug showed promising results, with a risk ratio for at least 50% of the maximum pain relief over six hours of 1.77 (95% CI 1.32 to 2.39) (paracetamol 1000 mg and ibuprofen 400 mg) (one trial; moderate quality evidence), and risk ratio not using rescue medication 1.60 (95% CI 1.36 to 1.88) (two trials; moderate quality evidence).The information available regarding adverse events from the studies (including nausea, vomiting, headaches and dizziness) indicated that they were comparable between the treatment groups. However, we could not formally analyse the data as it was not possible to work out how many adverse events there were in total. AUTHORS' CONCLUSIONS: There is high quality evidence that ibuprofen is superior to paracetamol at doses of 200 mg to 512 mg and 600 mg to 1000 mg respectively based on pain relief and use of rescue medication data collected at six hours postoperatively. The majority of this evidence (five out of six trials) compared ibuprofen 400 mg with paracetamol 1000 mg, these are the most frequently prescribed doses in clinical practice. The novel combination drug is showing encouraging results based on the outcomes from two trials when compared to the single drugs. PMID- 24338831 TI - Strongly coupled NiCo(2)O(4)-rGO hybrid nanosheets as a methanol-tolerant electrocatalyst for the oxygen reduction reaction. AB - Strongly coupled NiCo2 O4 -rGO hybrid nanosheets are syntheiszed through a cost effective two-step strategy involving a facile polyol process and subsequent thermal annealing treatment in air. The hybrid nanosheets exhibit impressive electrocatalytic performance for the oxygen reduction reaction (ORR) with a current density and onset potential comparable to those of commercial Pt/C catalyts, while having perfect tolerance to methanol.. PMID- 24338832 TI - Conjugated BODIPY DYEmers by metathesis reactions. AB - Boron dipyrrin (BODIPY) DYEmers bridged by conjugating ethynylene and ethenylene moieties can be prepared through metal-promoted metathesis reactions. Alkyne metathesis was advantageous over alkene metathesis and Stille coupling for BODIPY substrates, but also showed specific restrictions with respect to steric encumbrance and regioselectivity. All derivatives with unhindered rotations along the bridges reside in a coplanar minimum conformation. For a hindered beta ethenylene-bridged DYEmer, the shifts in the (1) H NMR spectrum indicate a significant loss of coplanarity and conjugation. The electronic interactions of the BODIPY subchromophores, visualized by optical spectra and cyclic voltammograms, deviate significantly from those found for nonconjugated and excitonically coupled DYEmers. The observed properties can be rationalized in each case by the respective strength of conjugation through the alpha or beta position, the degree of coplanarity, and conformational dynamics. PMID- 24338833 TI - Base-catalyzed hydrosilylation of ketones and esters and insight into the mechanism. AB - Simple bases (KOtBu, KOH) catalyze the silane-promoted reduction of ketones and esters to alcohols and of aldimines to amines. The inexpensive silane PMHS (polymethylhydrosiloxane) can be used as the reducing reagent. Double and triple bonds, as well as nitro- and cyano-groups are tolerated. Careful dosing of the silane allows for chemoselective reduction of a more reactive group in the presence of a less reactive group (for example, aldehyde reduction in the presence of ketone/ketone reduction in the presence of ester group). Mechanistic studies showed that addition of base to silanes leads to silicate species, which are the acting reducing agents. Under basic conditions, hydrosiloxanes (tetramethyldisiloxane, TMDS; PMHS) convert into simple silanes (H2 SiMe2 , H3 SiMe), making this a practical method to generate these challenging silanes. PMID- 24338834 TI - Evaluation of a liver microfluidic biochip to predict in vivo clearances of seven drugs in rats. AB - We investigated metabolic clearances of phenacetin, midazolam, propranolol, paracetamol, tolbutamide, caffeine, and dextromethorphan by primary rat hepatocytes cultivated in microfluidic biochips. The levels of mRNA of the HNF4alpha, PXR, AHR, CYP3A1, and CYP1A2 genes were enhanced in the biochip cultures when compared with postextraction levels. We measured a high and rapid adsorption on the biochip walls and inside the circuit for dextromethorphan and midazolam, a moderate adsorption for phenacetin and propranolol, and a low adsorption for caffeine, tolbutamide, and paracetamol. Drug biotransformations were demonstrated by the formations of specific metabolites such as paraxanthyne (caffeine), paracetamol (phenacetin), 1-OH midazolam (midazolam), paracetamol sulfate (paracetamol and phenacetin), and dextrorphan (dextromethorphan). We used a pharmacokinetic model to estimate the adsorption and in vitro intrinsic drug clearance values. We calculated in vitro intrinsic clearance values of 0.5, 3, 12.5, 83, 100, 160, and 900 MUL/min per 10(6) cells for the tolbutamide, caffeine, paracetamol, dextromethorphan, phenacetin, midazolam, and propranolol, respectively. A second model describing the liver as a well-stirred compartment predicted in vivo hepatic clearances of 0.1, 13.8, 30, 44.1, 61, 72, 85, and 61 mL/min per kg of body mass for the tolbutamide, caffeine, paracetamol, midazolam, dextromethorphan, phenacetin, and propranolol, respectively. These values appeared consistent with previously reported data. PMID- 24338835 TI - Evaluation of work capacity in Switzerland: a survey among psychiatrists about practice and problems. AB - QUESTIONS UNDER STUDY: In Switzerland, psychiatric evaluations of work capacity for determining a person's eligibility for disability benefits are being criticised for a lack of transparency and high inter-rater variability. The aims of this study were to learn about the current practice of psychiatrists, to explore possible sources for lack of transparency and variability, and to contrast practice with current professional guidance. METHODS: A national online survey among psychiatrists who performed five or more evaluations of work capacity per year. Based on discussions with experts and a literature review, we structured questions focusing on reporting on work capacity, the description of a claimant's previous job, and measures of quality assurance. RESULTS: A total of 129 psychiatrists responded (31% of estimated 412 eligible psychiatrists). The majority reported using instructions of the insurers (77%), peer consulting (65%) and process guidelines (51%). They expressed a claimant's work capacity as free text and percentage work capacity (49%), percentage only (23%), or free text only (14%). A total of 13% used instruments to document work capacity. Psychiatrists considered three different interpretations of percentage work capacity as equally applicable. A job description was regarded as mandatory to determine work capacity by 90% but only 26% received it and found it mostly deficient. CONCLUSIONS: The transparency and reliability of Swiss psychiatrists' conclusions on a claimant's work capacity may be reduced by unsystematic reporting, variable interpretation of the percentage work capacity, lack of a detailed job description and insufficient quality control. Education, engagement of insurers and new guidelines might be effective means of implementing improvements. PMID- 24338836 TI - Application of person-centered analytic methodology in longitudinal research: exemplars from the Women's Health Initiative Clinical Trial data. AB - Despite the variety of available analytic methods, longitudinal research in nursing has been dominated by use of a variable-centered analytic approach. The purpose of this article is to present the utility of person-centered methodology using a large cohort of American women 65 and older enrolled in the Women's Health Initiative Clinical Trial (N = 19,891). Four distinct trajectories of energy/fatigue scores were identified. Levels of fatigue were closely linked to age, socio-demographic factors, comorbidities, health behaviors, and poor sleep quality. These findings were consistent regardless of the methodological framework. Finally, we demonstrated that energy/fatigue levels predicted future hospitalization in non-disabled elderly. Person-centered methods provide unique opportunities to explore and statistically model the effects of longitudinal heterogeneity within a population. PMID- 24338837 TI - Efficacious anticancer drug delivery mediated by a pH-sensitive self-assembly of a conserved tripeptide derived from tyrosine kinase NGF receptor. AB - We present herein a short tripeptide sequence (Lys-Phe-Gly or KFG) that is situated in the juxtamembrane region of the tyrosine kinase nerve growth factor (Trk NGF) receptors. KFG self-assembles in water and shows a reversible and concentration-dependent switching of nanostructures from nanospheres (vesicles) to nanotubes, as evidenced by dynamic light scattering, transmission electron microscopy, and atomic force microscopy. The morphology change was associated with a transition in the secondary structure. The tripeptide vesicles have inner aqueous compartments and are stable at pH 7.4 but rupture rapidly at pH~6. The pH sensitive response of the vesicles was exploited for the delivery of a chemotherapeutic anticancer drug, doxorubicin, which resulted in enhanced cytotoxicity for both drug-sensitive and drug-resistant cells. Efficient intracellular release of the drug was confirmed by fluorescence-activated cell sorting analysis, fluorescence microscopy, and confocal microscopy. PMID- 24338838 TI - Are newer surgical interventions for glaucoma making a difference? PMID- 24338839 TI - Astigmatism and vision: should all astigmatism always be corrected? PMID- 24338840 TI - Optimization of methyl jasmonate application to broccoli florets to enhance health-promoting phytochemical content. AB - BACKGROUND: Spray treatment of methyl jasmonate (MeJA) has been shown to increase glucosinolate (GS) concentrations and health-promoting activity in Brassica vegetables. Since there is no reported standardized protocol, several MeJA treatment studies have been conducted to maximize human health bioactivity using the F1 broccoli cultivar 'Green Magic'. RESULTS: Foliar MeJA application 4 days prior to harvest of broccoli at commercial maturity resulted in enhanced total GS concentrations. Although a single application of 250 umol L(-1) MeJA maximized GS concentrations in broccoli florets, two days of consecutive treatments (4 and 3 days prior to harvest) of 250 umol L(-1) MeJA further enhanced neoglucobrassicin concentrations and floret extract quinone reductase (QR)-inducing activity. With increasing concentrations of MeJA in spray applications to broccoli florets, concentrations of the glucosinolates glucoraphanin, gluconasturtiin and neoglucobrassicin and the isothiocyanate sulforaphane as well as anticancer and anti-inflammatory bioactivities as measured by QR induction and inhibition of nitric oxide (NO) production respectively were significantly increased. Concentrations of these phytochemicals showed strong positive correlations with QR-inducing and NO-inhibitory activities. CONCLUSION: These application protocols were found to maximize GS and GS hydrolysis product concentrations and putatively enhance the health-promoting properties of broccoli heads for consumers. PMID- 24338841 TI - Decreasing incidence of nasal adenocarcinoma in Wycombe woodworkers. AB - OBJECTIVES/HYPOTHESIS: The association between adenocarcinoma of the ethmoid sinuses and woodworkers was identified in the 1960s. Working conditions were poor, and epidemiological studies suggested the carcinogenic agent was hardwood dust created during furniture production. The objectives of this article were to describe the declining incidence of this disease in High Wycombe woodworkers between 1965 and 2012 and to explore the potential reasons for this occurrence. STUDY DESIGN: Prospective case series performed at Wycombe General Hospital. METHODS: Data were collected for all cases of nasal adenocarcinoma presenting in woodworkers to Wycombe General Hospital between 1965 and 2012. Statistical analysis was performed by calculating the Spearman rank correlation coefficient when comparing different variables from the data. RESULTS: A total of 105 reported cases of nasal adenocarcinoma were identified among woodworkers working in High Wycombe. Between 1965 and 2012, there was a statistically significant reduction in the incidence of the disease. Statistical analysis suggests that the declining incidence is not solely due to the reducing numbers of workers in the industry. Further analysis suggests a significant relationship between the individuals' ages at which diagnosis was made and the year in which they were diagnosed. Importantly, diagnoses made since 1980 were increasingly among people in their retirement years. CONCLUSIONS: This article describes a statistically significant overall reduction in the incidence of nasal adenocarcinoma in Wycombe woodworkers. This is thought to not solely be due to declining numbers of workers within the industry but also improvements in working conditions following government legislation. PMID- 24338842 TI - Tunable delivery of siRNA from a biodegradable scaffold to promote angiogenesis in vivo. PMID- 24338843 TI - Effect of fucoxanthin alone and in combination with D-glucosamine hydrochloride on carrageenan/kaolin-induced experimental arthritis in rats. AB - The objective of the present study was to investigate the effect of the fucoxanthin (FUCO) alone and in combination with glucosamine hydrochloride (GAH) on carrageenan/kaolin-induced inflammatory arthritis model in rats and to explore its underlying mechanisms. Joint swelling, muscle weight ratio (%), histopathological examination and scoring, and proteoglycan degradation were examined. Pro-inflammatory interleukin (IL-1beta) and tumor necrosis (TNF-alpha) levels, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase(iNOS) protein expression and nitric oxide (NO) level in knee synovial tissue extract were analyzed using enzyme-linked immunosorbent assay, western blotting analysis, and Griess reagent assay, respectively. FUCO and FUCO + GAH not only may significantly reduce degrees of knee joint swelling and prevent against muscle atrophy, but also may significantly attenuate inflammation in synovial tissue, cartilage erosion, and proteoglycan loss. The efficacies of FUCO + GAH were stronger than that of GAH or FUCO. FUCO alone and FUCO + GAH can significantly inhibit upregulation of COX-2 and iNOS protein expressions, decrease of IL-1beta and TNF-alpha levels, and reduce NO production in knee synovial tissue extract. These results indicated that FUCO is an effective anti-arthritis agent through an antiinflammation mechanism. FUCO may enhance therapeutic effect of GAH on rat arthritis through mechanism of antiinflammation. PMID- 24338844 TI - Exosomes derived from human macrophages suppress endothelial cell migration by controlling integrin trafficking. AB - Integrin trafficking, including internalization, recycling, and lysosomal degradation, is crucial for the regulation of cellular functions. Exosomes, nano sized extracellular vesicles, are believed to play important roles in intercellular communications. This study demonstrates that exosomes released from human macrophages negatively regulate endothelial cell migration through control of integrin trafficking. Macrophage-derived exosomes promote internalization of integrin beta1 in primary HUVECs. The internalized integrin beta1 persistently accumulates in the perinuclear region and is not recycled back to the plasma membrane. Experimental results indicate that macrophage-derived exosomes stimulate trafficking of internalized integrin beta1 to lysosomal compartments with a corresponding decrease in the integrin destined for recycling endosomes, resulting in proteolytic degradation of the integrin. Moreover, ubiquitination of HUVEC integrin beta1 is enhanced by the exosomes, and exosome-mediated integrin degradation is blocked by bafilomycin A, a lysosomal degradation inhibitor. Macrophage-derived exosomes were also shown to effectively suppress collagen induced activation of the mitogen-activated protein kinase/extracellular signal regulated kinase signaling pathway and HUVEC migration, which are both dependent on integrin beta1. These observations provide new insight into the functional significance of exosomes in the regulation of integrin trafficking. PMID- 24338847 TI - Outcomes of antibiotic prophylaxis in acute cholecystectomy in a population-based gallstone surgery registry. AB - BACKGROUND: The aim of this study was to assess the effect of antibiotic prophylaxis (AP) on postoperative infections in acute cholecystectomy. METHODS: The study was based on acute cholecystectomies registered in the nationwide Swedish Register for Gallstone Surgery and Endoscopic Retrograde Cholangiopancreatography (GallRiks) between 2006 and 2010. The association between AP and the risk of postoperative infectious complications was tested in a multivariable regression analysis, with stepwise addition of age, sex, duration of operation, indication for surgery, surgical approach (laparoscopic versus open) and American Society of Anesthesiologists (ASA) fitness grade as co variables. Postoperative infections requiring antibiotic treatment and postoperative abscesses were defined as outcome measures. RESULTS: AP was given to 9549 (68.6 per cent) of 13 911 patients. Postoperative infections requiring antibiotic treatment occurred following 1070 procedures (7.7 per cent), including 805 patients (8.4 per cent) who received AP (P < 0.001 versus patients without AP). Postoperative abscesses developed after 273 procedures (2.0 per cent), including 208 patients (2.2 per cent) who received AP (P = 0.007). In univariable analysis, the odds ratio for development of infectious complications necessitating treatment with antibiotics was 1.42 (95 per cent confidence interval 1.23 to 1.64) for those who received AP versus those who did not, and for postoperative abscesses it was 1.47 (1.11 to 1.95). In multivariable analysis, adjusting for confounders, the odds ratios were 0.93 (0.79 to 1.10) and 0.88 (0.64 to 1.21) respectively. CONCLUSION: The present study suggests that AP provides no benefit in acute cholecystectomy. PMID- 24338845 TI - Cerebrovascular reactivity mapping in patients with low grade gliomas undergoing presurgical sensorimotor mapping with BOLD fMRI. AB - PURPOSE: (i) to validate blood oxygenation level dependent (BOLD) breathhold cerebrovascular reactivity (BH CVR) mapping as an effective technique for potential detection of neurovascular uncoupling (NVU) in a cohort of patients with perirolandic low grade gliomas undergoing presurgical functional MRI (fMRI) for sensorimotor mapping, and (ii) to determine whether NVU potential, as assessed by BH CVR mapping, is prevalent in this tumor group. MATERIALS AND METHODS: We retrospectively evaluated 12 patients, with histological diagnosis of grade II glioma, who performed multiple motor tasks and a BH task. Sensorimotor activation maps and BH CVR maps were compared in two automatically defined regions of interest (ROIs), ipsilateral to the lesion (i.e., ipsilesional) and contralateral to the lesion (i.e., contralesional). RESULTS: Motor task mean T value was significantly higher in the contralesional ROIs (6.00 +/- 1.74 versus 4.34 +/- 1.68; P = 0.00004) as well as the BH mean T-value (4.74 +/- 2.30 versus 4.09 +/- 2.50; P = 0.009). The number of active voxels was significantly higher in the contralesional ROIs (Z = 2.99; P = 0.03). Actual NVU prevalence was 75%. CONCLUSION: Presurgical sensorimotor fMRI mapping can be affected by NVU-related false negative activation in low grade gliomas (76% of analyzed tasks). PMID- 24338848 TI - SUMOylated RanGAP1 prepared by click chemistry. AB - Ubiquitin and ubiquitin-like proteins such as SUMO represent important and abundant post-translational modifications involved in many cellular processes. These modifiers are reversibly attached via an isopeptide bond to lysine side chains of their target proteins by the action of specific E1, E2, and E3 enzymes. A significant challenge in studying ubiquitylation and SUMOylation is the frequently encountered inability to access desired conjugates at a defined position of the target protein and in homogenous form by using enzymatic preparation. In recent years, several chemical conjugation approaches have been developed to overcome this limitation. In this study, we aimed to selectively SUMOylate a 189-amino acid fragment of human RanGAP1 (amino acids 398-587) at the position of Lys524 by applying two recently reported approaches based on the Cu(I)-catalyzed alkyne-azide cycloaddition. Because of low yields observed for the incorporation of an unnatural amino acid with an azide moiety by the tRNA suppression technology, this route was abandoned. However, installing a single cysteine at position 524 and its selective alkylation was successful to introduce the azide group. The triazole-linked SUMO1**RanGAP1 conjugate could be obtained in good yields, purified, and was shown to specifically interact with RanBP2/Ubc9. Thus, we expand the scope of proteins accessible to chemical conjugation with ubiquitin-like proteins and underline the importance of having alternative approaches to do so. PMID- 24338854 TI - Computer-assisted zygoma reconstruction with vascularized iliac crest bone graft. AB - BACKGROUND: The reconstruction of zygoma is a challenge with regard to aesthetic and reconstructive demands. METHODS: Pre-operative CT data were imported into specific surgical planning software. The mirror-imaging technique was used. A surgical guide transferred the virtual surgery plan to the operation site, whereby it fitted uniquely to the iliac donor site. A postoperative CT scan was obtained for comparing the actual postoperative graft position and shape with the pre-operative virtual simulation. RESULTS: A mean difference of 0.71 mm (SD +/- 1.42) for the shape analysis and 3.53 mm (SD +/- 3.14) for the graft position was determined. The calculation of the closest point distance showed a surface deviation of < 2 mm for the shape analysis with 83.6% of values and for the graft position with 35.7% of values. CONCLUSION: Virtual surgical planning is a suitable method for zygoma reconstruction with vascularized iliac crest bone graft, with good accuracy for restoring the three-dimensional anatomy. PMID- 24338855 TI - Amphiphilic polymeric micelle as pseudostationary phase in electrokinetic chromatography for analysis of eight corticosteroids in cosmetics. AB - Amphiphilic polymeric micelle, as a novel pseudostationary phase in EKC was used to determine eight kinds of corticosteroids namely hydrocortisone, prednisolone, hydrocortisone acetate, prednisone, cortisone acetate, prednisolone acetate, dexamethasone, and triamcinolone acetonide in cosmetics. Amphiphilic random copolymer poly(methyl methacrylate-co-methacrylic acid) (P(MMA-co-MAA)) was micellizated via neutralization in alkaline aqueous solution. The influences of the molar ratio of monomer MMA to MAA, the concentration of polymer and pH on the polymeric micelle microstructure and EKC performances were investigated. As molar ratio of MMA to MAA in P(MMA-co-MAA) increased, both CMC and environmental polarity of the inner core in polymeric micelle decreased dramatically. With increasing monomer ratio, the size of polymeric micelles increased firstly, and then decreased, finally increased again. zeta potential of the micelle had a slight decline trend. As increment of polymer concentration, the size of the polymeric micelle increased steadily. By optimizing the monomer ratio, the polymer concentration, and pH of the running buffer, as well as operation conditions such as separation voltage and temperature, the eight analytes could be separated within 16.5 min using 7.5 mg/mL polymer with the monomer ratio of 7:3 dissolved in pH 9.2 borax buffer as the running buffer. The method has been used for analysis of corticosteroids in cosmetic samples with simple extraction; the recoveries for eight analytes were between 85.9 and 106%. This method was of accuracy, repeatability, pretreatment simplicity, and could be applied to the quality control of cosmetics. PMID- 24338856 TI - Structure-guided analysis of catalytic specificity of the abundantly secreted chitosanase SACTE_5457 from Streptomyces sp. SirexAA-E. AB - SACTE_5457 is secreted by Streptomyces sp. SirexAA-E, a highly cellulolytic actinobacterium isolated from a symbiotic community composed of insects, fungi, and bacteria. Here we report the 1.84 A resolution crystal structure and functional characterization of SACTE_5457. This enzyme is a member of the glycosyl hydrolase family 46 and is composed of two alpha-helical domains that are connected by an alpha-helical linker. The catalytic residues (Glu74 and Asp92) are separated by 10.3 A, matching the distance predicted for an inverting hydrolysis reaction. Normal mode analysis suggests that the connecting alpha helix is flexible and allows the domain motion needed to place active site residues into an appropriate configuration for catalysis. SACTE_5457 does not react with chitin, but hydrolyzes chitosan substrates with an ~4-fold improvement in k(cat)/K(M) as the percentage of acetylation and the molecular weights decrease. Analysis of the time dependence of product formation shows that oligosaccharides with degree of polymerization <4 are not hydrolyzed. By combining the results of substrate docking to the X-ray structure and end-product analysis, we deduce that SACTE_5457 preferentially binds substrates spanning the 2 to +2 sugar binding subsites, and that steric hindrance prevents binding of N acetyl-D-glucosamine in the +2 subsite and may weakly interfere with binding of N acetyl-D-glucosamine in the +1 subsites. A proposal for how these constraints account for the observed product distributions is provided. PMID- 24338857 TI - Metal-organic organopolymeric hybrid framework by reversible [2+2] cycloaddition reaction. AB - Organic polymers are usually amorphous or possess very low crystallinity. The metal complexes of organic polymeric ligands are also difficult to crystallize by traditional methods because of their poor solubilities and their 3D structures can not be determined by single-crystal X-ray crystallography owing to a lack of single crystals. Herein, we report the crystal structure of a 1D Zn(II) coordination polymer fused with an organic polymer ligand made in situ by a [2+2] cycloaddition reaction of a six-fold interpenetrated metal-organic framework. It is also shown that this organic polymer ligand can be depolymerized in a single crystal-to-single-crystal (SCSC) fashion by heating. This strategy could potentially be extended to make a range of monocrystalline metal organopolymeric complexes and metal-organic organopolymeric hybrid materials. Such monocrystalline metal complexes of organic polymers have hitherto been inaccessible for materials researchers. PMID- 24338858 TI - Surgical versus endoscopic treatment of bile duct stones. AB - BACKGROUND: Between 10% to 18% of people undergoing cholecystectomy for gallstones have common bile duct stones. Treatment of the bile duct stones can be conducted as open cholecystectomy plus open common bile duct exploration or laparoscopic cholecystectomy plus laparoscopic common bile duct exploration (LC + LCBDE) versus pre- or post-cholecystectomy endoscopic retrograde cholangiopancreatography (ERCP) in two stages, usually combined with either sphincterotomy (commonest) or sphincteroplasty (papillary dilatation) for common bile duct clearance. The benefits and harms of the different approaches are not known. OBJECTIVES: We aimed to systematically review the benefits and harms of different approaches to the management of common bile duct stones. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL, Issue 7 of 12, 2013) in The Cochrane Library, MEDLINE (1946 to August 2013), EMBASE (1974 to August 2013), and Science Citation Index Expanded (1900 to August 2013). SELECTION CRITERIA: We included all randomised clinical trials which compared the results from open surgery versus endoscopic clearance and laparoscopic surgery versus endoscopic clearance for common bile duct stones. DATA COLLECTION AND ANALYSIS: Two review authors independently identified the trials for inclusion and independently extracted data. We calculated the odds ratio (OR) or mean difference (MD) with 95% confidence interval (CI) using both fixed-effect and random-effects models meta-analyses, performed with Review Manager 5. MAIN RESULTS: Sixteen randomised clinical trials with a total of 1758 randomised participants fulfilled the inclusion criteria of this review. Eight trials with 737 participants compared open surgical clearance with ERCP; five trials with 621 participants compared laparoscopic clearance with pre-operative ERCP; and two trials with 166 participants compared laparoscopic clearance with postoperative ERCP. One trial with 234 participants compared LCBDE with intra-operative ERCP. There were no trials of open or LCBDE versus ERCP in people without an intact gallbladder. All trials had a high risk of bias.There was no significant difference in the mortality between open surgery versus ERCP clearance (eight trials; 733 participants; 5/371 (1%) versus 10/358 (3%) OR 0.51;95% CI 0.18 to 1.44). Neither was there a significant difference in the morbidity between open surgery versus ERCP clearance (eight trials; 733 participants; 76/371 (20%) versus 67/358 (19%) OR 1.12; 95% CI 0.77 to 1.62). Participants in the open surgery group had significantly fewer retained stones compared with the ERCP group (seven trials; 609 participants; 20/313 (6%) versus 47/296 (16%) OR 0.36; 95% CI 0.21 to 0.62), P = 0.0002.There was no significant difference in the mortality between LC + LCBDE versus pre-operative ERCP +LC (five trials; 580 participants; 2/285 (0.7%) versus 3/295 (1%) OR 0.72; 95% CI 0.12 to 4.33). Neither was there was a significant difference in the morbidity between the two groups (five trials; 580 participants; 44/285 (15%) versus 37/295 (13%) OR 1.28; 95% CI 0.80 to 2.05). There was no significant difference between the two groups in the number of participants with retained stones (five trials; 580 participants; 24/285 (8%) versus 31/295 (11%) OR 0.79; 95% CI 0.45 to 1.39).There was only one trial assessing LC + LCBDE versus LC+intra-operative ERCP including 234 participants. There was no reported mortality in either of the groups. There was no significant difference in the morbidity, retained stones, procedure failure rates between the two intervention groups.Two trials assessed LC + LCBDE versus LC+post-operative ERCP. There was no reported mortality in either of the groups. There was no significant difference in the morbidity between laparoscopic surgery and postoperative ERCP groups (two trials; 166 participants; 13/81 (16%) versus 12/85 (14%) OR 1.16; 95% CI 0.50 to 2.72). There was a significant difference in the retained stones between laparoscopic surgery and postoperative ERCP groups (two trials; 166 participants; 7/81 (9%) versus 21/85 (25%) OR 0.28; 95% CI 0.11 to 0.72; P = 0.008.In total, seven trials including 746 participants compared single staged LC + LCBDE versus two-staged pre-operative ERCP + LC or LC + post-operative ERCP. There was no significant difference in the mortality between single and two-stage management (seven trials; 746 participants; 2/366 versus 3/380 OR 0.72; 95% CI 0.12 to 4.33). There was no a significant difference in the morbidity (seven trials; 746 participants; 57/366 (16%) versus 49/380 (13%) OR 1.25; 95% CI 0.83 to 1.89). There were significantly fewer retained stones in the single-stage group (31/366 participants; 8%) compared with the two stage group (52/380 participants; 14%), but the difference was not statistically significantOR 0.59; 95% CI 0.37 to 0.94).There was no significant difference in the conversion rates of LCBDE to open surgery when compared with pre-operative, intra-operative, and postoperative ERCP groups. Meta-analysis of the outcomes duration of hospital stay, quality of life, and cost of the procedures could not be performed due to lack of data. AUTHORS' CONCLUSIONS: Open bile duct surgery seems superior to ERCP in achieving common bile duct stone clearance based on the evidence available from the early endoscopy era. There is no significant difference in the mortality and morbidity between laparoscopic bile duct clearance and the endoscopic options. There is no significant reduction in the number of retained stones and failure rates in the laparoscopy groups compared with the pre-operative and intra-operative ERCP groups. There is no significant difference in the mortality, morbidity, retained stones, and failure rates between the single-stage laparoscopic bile duct clearance and two-stage endoscopic management. More randomised clinical trials without risks of systematic and random errors are necessary to confirm these findings. PMID- 24338859 TI - Precision synthesis of poly(ionic liquid)-based block copolymers by cobalt mediated radical polymerization and preliminary study of their self-assembling properties. AB - A poly(ionic liquid)-based block copolymer (PIL BCP), namely, poly(vinyl acetate) b-poly(N-vinyl-3-butylimidazolium bromide), PVAc-b-PVBuImBr, is synthesized by sequential cobalt-mediated radical polymerization (CMRP). A PVAc precursor is first prepared at 30 degrees C in bulk by CMRP of VAc, using bis(acetylacetonato)cobalt(II), Co(acac)2, and a radical source (V-70). Growth of PVBuImBr from PVAc-Co(acac)2 is accomplished by CMRP in DMF/MeOH (2:1, v/v). This PIL BCP self-assembles in the sub-micron size range into aggregated core-shell micelles in THF, whereas polymeric vesicles are observed in water, as evidenced by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Thin-solid sample cut from raw materials analyzed by TEM shows an ordered lamellar organization by temperature-dependent synchrotron small-angle X-ray scattering (SAXS). Anion exchange can be accomplished to achieve the corresponding PIL BCP with bis(trifluorosulfonyl)imide (Tf2 N(-)) anions, which also gives rise to an ordered lamellar phase in bulk samples. A complete suppression of SAXS second-order reflection suggests that this compound has a symmetric volume fraction (f ~ 0.5). SAXS characterization of both di- and triblock PIL BCP analogues previously reported also shows a lamellar phase of very similar behavior, with only an increase of the period by about 8% at 60 degrees C. PMID- 24338860 TI - Directing the structural features of N(2)-phobic nanoporous covalent organic polymers for CO(2) capture and separation. AB - A family of azo-bridged covalent organic polymers (azo-COPs) was synthesized through a catalyst-free direct coupling of aromatic nitro and amine compounds under basic conditions. The azo-COPs formed 3D nanoporous networks and exhibited surface areas up to 729.6 m(2) g(-1) , with a CO2 -uptake capacity as high as 2.55 mmol g(-1) at 273 K and 1 bar. Azo-COPs showed remarkable CO2 /N2 selectivities (95.6-165.2) at 298 K and 1 bar. Unlike any other porous material, CO2 /N2 selectivities of azo-COPs increase with rising temperature. It was found that azo-COPs show less than expected affinity towards N2 gas, thus making the framework "N2 -phobic", in relative terms. Our theoretical simulations indicate that the origin of this unusual behavior is associated with the larger entropic loss of N2 gas molecules upon their interaction with azo-groups. The effect of fused aromatic rings on the CO2 /N2 selectivity in azo-COPs is also demonstrated. Increasing the pi-surface area resulted in an increase in the CO2 -philic nature of the framework, thus allowing us to reach a CO2 /N2 selectivity value of 307.7 at 323 K and 1 bar, which is the highest value reported to date. Hence, it is possible to combine the concepts of "CO2 -philicity" and "N2 -phobicity" for efficient CO2 capture and separation. Isosteric heats of CO2 adsorption for azo COPs range from 24.8-32.1 kJ mol(-1) at ambient pressure. Azo-COPs are stable up to 350 degrees C in air and boiling water for a week. A promising cis/trans isomerization of azo-COPs for switchable porosity is also demonstrated, making way for a gated CO2 uptake. PMID- 24338861 TI - A new class of dendritic metallogels with multiple stimuli-responsiveness and as templates for the in situ synthesis of silver nanoparticles. AB - A new class of poly(aryl ether) dendritic ligands containing a pyridine functionality at the focal point and the corresponding Ag(I) complexes through metal-ligand coordination were designed, synthesized, and fully characterized. Compared with the dendritic ligands, the corresponding dendritic complexes exhibited much better gelation ability for various organic solvents at very low critical gelation concentrations. The gel-sol phase transition temperatures and morphologies could be finely tuned by binding silver ion to the ligand. A preliminary study revealed that multiple noncovalent interactions, such as Ag(I) pyridine coordination, solvophobic interaction, and pi-pi stacking, synergistically enable the formation of stable metallogels. Interestingly, these metallogels could intelligently respond to multiple external stimuli including temperature, chemicals, and shear stress, leading to gel-sol phase transitions. In addition, these dendritic metallogels were successfully applied as templates for the in situ formation and stabilization of silver nanoparticles without the use of any chemical reducing/stabilizing agents. PMID- 24338862 TI - Influence of drug property and product design on in vitro-in vivo correlation of complex modified-release dosage forms. AB - The present study examines how drug's inherent properties and product design influence the evaluation and applications of in vitro-in vivo correlation (IVIVC) for modified-release (MR) dosage forms consisting of extended-release (ER) and immediate-release (IR) components with bimodal drug release. Three analgesic drugs were used as model compounds, and simulations of in vivo pharmacokinetic profiles were conducted using different release rates of the ER component and various IR percentages. Plasma concentration-time profiles exhibiting a wide range of tmax and maximum observed plasma concentration (Cmax) were obtained from superposition of the simulated IR and ER profiles based on a linear IVIVC. It was found that depending on the drug and dosage form design, direct use of the superposed IR and ER data for IVIVC modeling and prediction may (1) be acceptable within errors, (2) become unreliable and less meaningful because of the confounding effect from the non-negligible IR contribution to Cmax, or (3) be meaningless because of the insensitivity of Cmax to release rate change of the ER component. Therefore, understanding the drug, design and drug release characteristics of the product is essential for assessing the validity, accuracy, and reliability of IVIVC of complex MR products obtained via directly modeling of in vivo data. PMID- 24338863 TI - Simultaneous multislice spectral-spatial excitations for reduced signal loss susceptibility artifact in BOLD functional MRI. AB - PURPOSE: Simultaneous multislice (SMS) imaging can significantly increase image acquisition rates and improve temporal resolution and contrast in gradient-echo blood oxygen level-dependent (BOLD) functional MRI (fMRI) experiments. Through plane signal loss due to B(0) inhomogeneities at air-tissue interfaces limits fMRI of structures near the nasal cavity and ear canals. This study implemented spectral-spatial (SPSP) radiofrequency pulses for reduced through-plane signal loss across multiple simultaneously excited slices. THEORY AND METHODS: Multiband (MB) and power independent of number of slices (PINS) methods are combined with SPSP excitation for signal loss compensation in slice-accelerated human brain imaging. Nine simultaneous slices of 5-mm thickness and 20 mm apart were excited using standard MB radiofrequency pulses and the proposed SPSP-SMS pulses, yielding coverage of 36 slices in four shots with 350-ms volume pulse repetition time. The pulses were compared in breath-hold fMRI at 3T. RESULTS: The SPSP-SMS pulses recovered ~45% of voxels with signal loss in standard SMS images. Activation in areas of signal recovery increased by 26.4% using a 12.6-ms SPSP-MB pulse and 20.3% using a 12.1-ms SPSP-PINS pulse. CONCLUSIONS: It is demonstrated that SPSP-SMS pulses can improve BOLD sensitivity in areas of signal loss across simultaneous multiple slices. PMID- 24338864 TI - Predictors of attrition among rural breast cancer survivors. AB - Attrition can jeopardize both internal and external validity. The goal of this secondary analysis was to examine predictors of attrition using baseline data of 432 participants in the Rural Breast Cancer Survivors study. Attrition predictors were conceptualized based on demographic, social, cancer treatment, physical health, and mental health characteristics. Baseline measures were selected using this conceptualization. Bivariate tests of association, discrete-time Cox regression models and recursive partitioning techniques were used in analysis. Results showed that 100 participants (23%) dropped out by Month 12. Non-linear tree analyses showed that poor mental health and lack of health insurance were significant predictors of attrition. Findings contribute to future research efforts to reduce research attrition among rural underserved populations. PMID- 24338865 TI - Characterization and antimicrobial properties of food packaging methylcellulose films containing stem extract of Ginja cherry. AB - BACKGROUND: Food contamination and spoilage is a problem causing growing concern. To avoid it, the use of food packaging with appropriate characteristics is essential; ideally, the packaging should protect food from external contamination and exhibit antibacterial properties. With this aim, methylcellulose (MC) films containing natural extracts from the stems of Ginja cherry, an agricultural by product, were developed and characterized. RESULTS: The antibacterial activity of films was screened by the disc diffusion method and quantified using the viable cell count assay. The films inhibited the growth of both Gram-positive and Gram negative strains (Listeria innocua, methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus, Salmonella Enteritidis, Escherichia coli). For the films with lower extract content, effectiveness against the microorganisms depended on the inoculum concentration. Scanning electron microscope images of the films showed that those containing the extracts had a smooth and continuous structure. UV-visible spectroscopy showed that these materials do not transmit light in the UV. CONCLUSION: This study shows that MC films containing agricultural by-products, in this case Ginja cherry stem extract, could be used to prevent food contamination by relevant bacterial strains and degradation by UV light. Using such materials in food packaging, the shelf life of food products could be extended while utilizing an otherwise wasted by-product. PMID- 24338866 TI - Resolution/separation of enantiomers. PMID- 24338867 TI - Three versus five micrometer chlorinated polysaccharide-based packings in chiral capillary electrochromatography: performance evaluation. AB - In this study, a test set of 44 nonacidic compounds was analyzed on four 3 um chlorinated polysaccharide-based chiral stationary phases with cellulose tris (3 chloro-4-methylphenylcarbamate) (Lux Cellulose-2(r); LC2), amylose tris (5-chloro 2-methylphenylcarbamate) (Lux Amylose-2(r), LA2), cellulose tris (4-chloro-3 methylphenylcarbamate) (Lux Cellulose-4(r); LC4) and cellulose tris (3,5 dichlorophenylcarbamate) (Sepapak-5(r), Sp5) as selectors. The analysis times, retention factors, efficiencies and enantioselectivities were compared with the results obtained on their 5 um analogs. All 3 um packings, except for LA2, individually separated more compounds than their 5 um analogs. When the cumulative success rates on the 3 and 5 um packings were considered, it was observed that they were similar for both particle sizes; the combination of three or four 5 um columns separated one compound more from the considered test set than that of the same number of 3 um columns. Furthermore, it was observed that the 3 and 5 um packings showed some complementarity. Only four compounds were not separated on any of the columns, while the use of only either the 3 or 5 um columns resulted in 10 and nine not-separated compounds, respectively. The analyses on 5 um LC2 and Sp5 were faster than on their 3 um analogs. For LC4 the 3 um packing showed the shortest analysis times and diverse analysis times for both particle sizes were obtained on LA2. Furthermore, three out of four 3 um packings, that is, LC2, LC4, and Sp5, were found to be more efficient than their 5 um analogs. PMID- 24338869 TI - Synthesis of metal nanoparticles inside living human cells based on the intracellular formation process. AB - Intracellular and extracellular formation of Au and Ag NPs with different sizes and shapes using human cells has been developed as green method, which does not require the use of any reducing agents. Also, the cell lysis is used for production of different metal NPs. Our results demonstrate that treatment of human cells with various metal ions cause cell fixation. PMID- 24338870 TI - Empirical comparison study of approximate methods for structure selection in binary graphical models. AB - Looking for associations among multiple variables is a topical issue in statistics due to the increasing amount of data encountered in biology, medicine, and many other domains involving statistical applications. Graphical models have recently gained popularity for this purpose in the statistical literature. In the binary case, however, exact inference is generally very slow or even intractable because of the form of the so-called log-partition function. In this paper, we review various approximate methods for structure selection in binary graphical models that have recently been proposed in the literature and compare them through an extensive simulation study. We also propose a modification of one existing method, that is shown to achieve good performance and to be generally very fast. We conclude with an application in which we search for associations among causes of death recorded on French death certificates. PMID- 24338871 TI - A perfectly periodic three-dimensional protein/silica mesoporous structure produced by an organism. AB - The discovery of perfectly ordered 3D mesoporous protein/silica structure in the axial filament of the marine sponge Monorhaphis chuni is reported. The structure belongs to body-centered tetragonal symmetry system (a=9.88 nm, c=10.83 nm) and comprises interconnecting lattices of protein and silica, templated by the self assembled, enzymatically active protein-silicatein, whose primary function is the precipitation of silica. PMID- 24338872 TI - Photo-cross-linking probes for trapping G-quadruplex DNA. AB - We have developed a straightforward synthetic pathway to a set of six photoactivatable G-quadruplex ligands with a validated G4-binding motif (the bisquinolinium pyridodicarboxamide PDC-360A) tethered through various spacers to two different photo-cross-linking groups: benzophenone and an aryl azide. The high quadruplex-versus-duplex selectivity of the PDC core was retained in the new derivatives and resulted in selective alkylation of two well-known G-quadruplexes (human telomeric G4 and oncogene promoter c-myc G4) under conditions of harsh competition. The presence of two structurally different photoactivatable functions allowed the selective alkylation of G-quadruplex structures at specific nucleobases and irreversible G4 binding. The topology and sequence of the quadruplex matrix appear to influence strongly the alkylation profile, which differs for the telomeric and c-myc quadruplexes. The new compounds are photoactive in cells and thus provide new tools for studying G4 biology. PMID- 24338873 TI - Bemisia tabaci nomenclature: lessons learned. AB - BACKGROUND: The nomenclature used within the whitefly research community for different putative species within Bemisia tabaci (sensu Russell) remains highly variable and confused. This was evident by the many different naming schemes researchers were using in their presentations at the 1st International Whitefly Symposium in Kolymbari, Crete, Greece (20-24 May 2013). I wanted to try to document how we, as a community, have arrived at such a state of confused nomenclature. This also included an investigation of the nomenclature used in the literature (from 2002 to 2012) by means of two online search tools (Web of Science and Scirus). RESULTS: Nomenclatural data were collected at the 1st International Whitefly Symposium, based on oral presentations and posters. There were 17 different names used for the MED species and 12 different names used for the MEAM1 species of the B. tabaci species complex. Investigation of the literature revealed limited uptake of the intermediate names. CONCLUSION: The intermediate names for the various species in the B. tabaci species complex - MED, MEAM1, New World, etc. - are not being used by the wider whitefly community. To move forwarrd as a community, we must work towards a formal revision of the B. tabaci complex. PMID- 24338874 TI - Flavonoids from Sophora moorcroftiana and their synergistic antibacterial effects on MRSA. AB - Synergy is now a widely recognized approach that has direct applicability for new pharmaceuticals. The ethanolic extract of the aerial parts of the herb Sophora moorcroftiana showed significant antibacterial activity against drug-resistant Staphylococcus aureus, and its minimum inhibitory concentration (MIC) was 8 ug/mL. In a phytochemical study of the extract, five flavonoids were obtained. However, the isolates exhibited antibacterial activity in the range of 32-128 ug/mL, which was weaker than the extract. In combination with antibiotics, the antibacterially inactive compound genistein (1) and diosmetin (4) showed significant synergistic activity against drug-resistant S. aureus. In combination with norfloxacin, genistein (1) reduced the MIC to 16 ug/mL and showed synergy against strain SA1199B with a fractional inhibitory concentration index (FICI) of 0.38. With the antibiotics norfloxacin, streptomycin and ciprofloxacin, diosmetin (4) showed synergy against SA1199B, RN4220 and EMRSA-15, with FICI values of 0.38, 0.38 and 0.09, respectively. In an efflux experiment to elucidate a plausible mechanism for the observed synergy, genistein showed marginal inhibition of the NorA efflux protein. PMID- 24338875 TI - Correlation of skeletal muscle blood oxygenation level-dependent MRI and skin laser Doppler flowmetry in patients with systemic sclerosis. AB - PURPOSE: To investigate the origin of skeletal muscle BOLD MRI alterations in patients with systemic sclerosis (SSc) by correlating BOLD MRI T2* signal of calf muscles with microcirculatory blood flow of calf skin measured by laser Doppler flowmetry (LDF). MATERIALS AND METHODS: BOLD MRI (3T) and LDF measurements were performed in 12 consecutive SSc patients (6 women, 6 men; mean age 54.0 +/- 10.0 years) and 12 healthy volunteers (4 men, 8 women; mean age 44.7 +/- 13.1 years). For both modalities, the same cuff compression paradigm at mid-thigh level was used. LDF datasets were acquired using a PeriScan PIM II Imager (Perimed AB, Stockholm, Sweden) at the upper calf corresponding to the level of MR imaging. Cross-correlations of BOLD and LDF signal intensity changes depending on time lags between both time series were calculated. RESULTS: Maximal cross correlations of BOLD T2* and LDF measurements were calculated as 0.93 (healthy volunteers) and 0.94 (SSc patients) for a BOLD time lag of approximately 10 s. Key parameter analysis suggested that in contrast to hyperemic BOLD signal loss at maximum value in SSc patients, ischemic T2* decrease cannot be explained by differences of tissue perfusion. CONCLUSION: Skeletal muscle BOLD T2* signal in SSc patients is closely correlated with changes of microperfusion as detected by LDF. PMID- 24338876 TI - In reference to simultaneous pericranial and nasoseptal flap reconstruction of anterior skull base defects following endoscopic-assisted craniofacial resection. PMID- 24338877 TI - Activation and retention: a magnetic resonance probe for the detection of acute thrombosis. AB - Blood-clot formation that results in the complete occlusion of a blood vessel (thrombosis) often leads to serious life-threatening events, such as strokes and heart attacks. As the composition of a thrombus changes as it matures, new imaging methods that are capable of distinguishing new clots from old clots may yield important diagnostic and prognostic information. To address this need, an activatable magnetic resonance (MR) probe that is responsive to a key biochemical process associated with recently formed clots has been developed. PMID- 24338878 TI - On-line process monitoring of coffee roasting by resonant laser ionisation time of-flight mass spectrometry: bridging the gap from industrial batch roasting to flavour formation inside an individual coffee bean. AB - Resonance-enhanced multiphoton ionisation time-of-flight mass spectrometry (REMPI TOFMS) enables the fast and sensitive on-line monitoring of volatile organic compounds (VOC) formed during coffee roasting. On the one hand, REMPI-TOFMS was applied to monitor roasting gases of an industrial roaster (1500 kg/h capacity), with the aim of determining the roast degree in real-time from the transient chemical signature of VOCs. On the other hand, a previously developed MU-probe sampling device was used to analyse roasting gases from individual coffee beans. The aim was to explore fundamental processes at the individual bean level and link these to phenomena at the batch level. The pioneering single-bean experiments were conducted in two configurations: (1) VOCs formed inside a bean were sampled in situ, i.e. via a drilled MU-hole, from the interior, using a MU probe (inside). (2) VOCs were sampled on-line in close vicinity of a single coffee bean's surface (outside). The focus was on VOCs originating from hydrolysis and pyrolytic degradation of chlorogenic acids, like feruloyl quinic acid and caffeoyl quinic acid. The single bean experiments revealed interesting phenomena. First, differences in time-intensity profiles between inside versus outside (time shift of maximum) were observed and tentatively linked to the permeability of the bean's cell walls material. Second, sharp bursts of some VOCs were observed, while others did exhibit smooth release curves. It is believed that these reflect a direct observation of bean popping during roasting. Finally, discrimination between Coffea arabica and Coffea canephora was demonstrated based on high-mass volatile markers, exclusively present in spectra of Coffea arabica. PMID- 24338879 TI - Unexpected [M-H]+ ions in cyclopenta[b]indoles detection by electrospray ionization mass spectrometry. PMID- 24338880 TI - Application of 13C isotope labeling using liquid chromatography mass spectrometry (LC-MS) to determining phosphate-containing metabolic incorporation. AB - Here, we describe an approach wherein negative electrospray ionization mass spectrometry has used to understand the relative flux through phosphate containing metabolic intermediates associated with central carbon metabolism after administering cells with 13C-labeled substrates. The method was applied to examine the 13C incorporation through glycolysis in T47D breast cancer cells and showed reduction of glycolytic relative flux upon treatment with 2-Deoxyglucose. PMID- 24338881 TI - Rapid identification of disaccharides by tandem mass spectrometry. PMID- 24338882 TI - Microscale enzyme reactors comprising gold nanoparticles with immobilized trypsin for efficient protein digestion. PMID- 24338883 TI - Alternative two-step matrix application method for imaging mass spectrometry to avoid tissue shrinkage and improve ionization efficiency. AB - Mass spectrometry (MS) was used to measure the concentrations of drug and biological compounds in plasma and tissues. Matrix-assisted laser desorption/ionization (MALDI) imaging MS (IMS) has recently been applied to the analysis of localized drugs on biological tissue surfaces. In MALDI-IMS, matrix application process is crucial for successful results. However, it is difficult to obtain homogeneous matrix crystals on the tissue surface due to endogenous salts and tissue surface heterogeneity. Consequently, the non-uniform crystals degrade the quality of the spectrum and likely cause surface imaging artifacts. Furthermore, the direct application of matrix solution can cause tissue shrinkage due to the organic solvents. Here, we report an alternative two-step matrix application protocol which combines the vacuum deposition of matrix crystals and the spraying of matrix solution to produce a homogeneous matrix layer on the tissue surface. Our proposed technique can also prevent cracking or shrinking of the tissue samples and improve the ionization efficiency of the distributed exogenous material. PMID- 24338884 TI - Mycotoxin profile of Fusarium langsethiae isolated from wheat in Italy: production of type-A trichothecenes and relevant glucosyl derivatives. AB - Fusarium langsethiae, formally described as a new species over a decade ago, has been identified as the main producer of HT-2 (HT2) and T-2 (T2) toxins in Europe in small cereal grains. Mycotoxin contamination caused by this Fusarium species can represent a food safety hazard that deserves further attention. In the present work, the mycotoxin profile in wheat cultures of F. langsethiae is presented with particular reference to the production of major type-A trichothecenes and their glucosyl derivatives. F. langsethiae isolates, representative of the major Italian wheat cultivation areas, were tested for the production of T2, HT2, diacetoxyscirpenol (DAS) and neosolaniol (NEO), and relevant glucosyl derivatives. Liquid chromatography-tandem mass spectrometry (LC MS/MS) was used for the identification and chemical characterization of these metabolites. F. langsethiae isolates under investigation resulted to be potent producers of T2, HT2 and NEO. Furthermore, a well-defined set of isolates, all originating from Central Italy, produced also DAS. All isolates were found to be able to produce HT2 glucosyl derivatives, whereas only traces of T2 glucoside were detected in one sample. Furthermore, two mono-glucosyl derivatives of NEO and one mono-glucoside derivative of DAS were identified and characterized. The screening for the presence/absence of glucosylated trichothecenes in analyzed fungal extracts revealed a general co-occurrence of these derivatives with the parent toxin at levels that could be roughly estimated to account up to 37% of the relevant unconjugated toxin. This is the first report of the production of glucosylated trichothecenes by F. langsethiae cultured on small grains. PMID- 24338885 TI - In-chain neutral hydrocarbon loss from crocin apocarotenoid ester glycosides and the crocetin aglycon (Crocus sativus L.) by ESI-MS(n) (n=2, 3). AB - The stigmas of Crocus sativus L. have been used as spice and colorant agent (i.e. saffron) for more than 4000 years. For an updated structural investigation of the aglycon present in the glycosylated crocetin apocarotenoids (i.e. crocins), seven representative derivatives ranging from one up to five glucosyl-residues with a maximum number of three monosaccharides per glycosylation site (glucose, gentiobiose, gentiotriose and neapolitanose) were isolated and purified by high performance liquid chromatography. The compounds selected for further mass spectrometric investigation include glucosyl-, bis-glucosyl-, gentiobiosyl-, gentiobiosyl-glucosyl-, bis-gentiobiosyl-, gentiobiosyl-gentiotriosyl- and gentiobiosyl-neapolitanosyl-crocetin. Electrospray ionization in combination with low-energy collision-induced dissociation/tandem mass spectrometry of sodiated crocin precursor ions utilizing either a 3D-ion trap (MS(n) , n = 2, 3) or a QqTOF instrument, with the latter providing accurate mass determination with an accuracy of +/-1-3 ppm or better at a resolution of 10,000 (full width at half maximum), was used. Major fragmentation pathways included loss of either one or two carbohydrate substituents leading to the sodiated aglycon without interglycosidic bond cleavage during in MS(2) -experiments. All sodiated precursor ions and major product ions were accompanied by a loss of 92 Da, which was elucidated as C7 H8 -loss from the aglycon by skeletal rearrangement via an eight-membered transition state as previously described for intact C40 carotenoids. PMID- 24338886 TI - Glycosylation characterization of recombinant human erythropoietin produced in glycoengineered Pichia pastoris by mass spectrometry. AB - Glycosylation plays a critical role in the in vivo efficacy of both endogenous and recombinant erythropoietin (EPO). Using mass spectrometry, we characterized the N-/O-linked glycosylation of recombinant human EPO (rhEPO) produced in glycoengineered Pichia pastoris and compared with the glycosylation of Chinese hamster ovary (CHO) cell-derived rhEPO. While the three predicted N-linked glycosylation sites (Asn24, Asn38 and Asn83) showed complete site occupancy, Pichia- and CHO-derived rhEPO showed distinct differences in the glycan structures with the former containing sialylated bi-antennary glycoforms and the latter containing a mixture of sialylated bi-, tri- and tetra-antennary structures. Additionally, the N-linked glycans from Pichia-produced rhEPO were similar across all three sites. A low level of O-linked mannosylation was detected on Pichia-produced rhEPO at position Ser126, which is also the O-linked glycosylation site for endogenous human EPO and CHO-derived rhEPO. In summary, the mass spectrometric analyses revealed that rhEPO derived from glycoengineered Pichia has a highly uniform bi-antennary N-linked glycan composition and preserves the orthogonal O-linked glycosylation site present on endogenous human EPO and CHO-derived rhEPO. PMID- 24338887 TI - Dehydrogenation and dehalogenation of amines in MALDI-TOF MS investigated by isotopic labeling. AB - Secondary and tertiary amines have been reported to form [M-H](+) that correspond to dehydrogenation in matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS). In this investigation, we studied the dehydrogenation of amines in MALDI-TOF MS by isotopic labeling. Aliphatic amines were labeled with deuterium on the methylene of an N-benzyl group, which resulted in the formation of [M-D](+) and [M-H](+) ions by dedeuteration and dehydrogenation, respectively. This method revealed the proton that was removed. The spectra of most tertiary amines with an N-benzyl group showed high-intensity [M-D](+) and [M-H](+) ion peaks, whereas those of secondary amines showed low intensity ion peaks. Ratios between the peak intensities of [M-D](+) and [M-H](+) greater than 1 suggested chemoselective dehydrogenation at the N-benzyl groups. The presence of an electron donor group on the N-benzyl groups enhanced the selectivity. The dehalogenation of amines with an N-(4-halobenzyl) group was also observed alongside dehydrogenation. The amino ions from dehalogenation can undergo second dehydrogenation. These results provide the first direct evidence about the position at which dehydrogenation of an amine occurs and the first example of dehalogenation of haloaromatic compounds in MALDI-TOF MS. These results should be helpful in the structural identification and elucidation of synthetic and natural molecules. PMID- 24338888 TI - Quadrupole mass filter operation under the influence of magnetic field. AB - This work demonstrates resolution enhancement of a quadrupole mass filter (QMF) under the influence of a static magnetic field. Generally, QMF resolution can be improved by increasing the number of rf cycles an ion experiences when passing through the mass filter. In order to improve the resolution, the dimensions of the QMF or the operating parameters need to be changed. However, geometric modifications to improve performance increase the manufacturing cost and usually the size of the instrument. By applying a magnetic field, a low-cost, small footprint instrument with reduced power requirements can be realized. Significant improvement in QMF resolution was observed experimentally for certain magnetic field conditions, and these have been explained in terms of our theoretical model developed at the University of Liverpool. This model is capable of accurate simulation of spectra allowing the user to specify different values of mass spectrometer dimensions and applied input signals. The model predicts enhanced instrument resolution R>26,000 for a CO2 and N2 mixture with a 200-mm long mass filter operating in stability zone 3 via application of an axial magnetic field. PMID- 24338889 TI - Specificity enhancement by electrospray ionization multistage mass spectrometry- a valuable tool for differentiation and identification of 'V'-type chemical warfare agents. AB - The use of chemical warfare agents has become an issue of emerging concern. One of the challenges in analytical monitoring of the extremely toxic 'V'-type chemical weapons [O-alkyl S-(2-dialkylamino)ethyl alkylphosphonothiolates] is to distinguish and identify compounds of similar structure. MS analysis of these compounds reveals mostly fragment/product ions representing the amine-containing residue. Hence, isomers or derivatives with the same amine residue exhibit similar mass spectral patterns in both classical EI/MS and electrospray ionization-MS, leading to unavoidable ambiguity in the identification of the phosphonate moiety. A set of five 'V'-type agents, including O-ethyl S-(2 diisopropylamino)ethyl methylphosphonothiolate (VX), O-isobutyl S-(2 diethylamino)ethyl methylphosphonothiolate (RVX) and O-ethyl S-(2 diethylamino)ethyl methylphosphonothiolate (VM) were studied by liquid chromatography/electrospray ionization/MS, utilizing a QTRAP mass detector. MS/MS enhanced product ion scans and multistage MS(3) experiments were carried out. Based on the results, possible fragmentation pathways were proposed, and a method for the differentiation and identification of structural isomers and derivatives of 'V'-type chemical warfare agents was obtained. MS/MS enhanced product ion scans at various collision energies provided information-rich spectra, although many of the product ions obtained were at low abundance. Employing MS(3) experiments enhanced the selectivity for those low abundance product ions and provided spectra indicative of the different phosphonate groups. Study of the fragmentation pathways, revealing some less expected structures, was carried out and allowed the formulation of mechanistic rules and the determination of sets of ions typical of specific groups, for example, methylphosphonothiolates versus ethylphosphonothiolates. The new group-specific ions elucidated in this work are also useful for screening unknown 'V'-type agents and related compounds, utilizing precursor ion scan experiments. PMID- 24338890 TI - Comparison of CID versus ETD-based MS/MS fragmentation for the analysis of doubly derivatized steroids. AB - Electrospray ionization coupled with collision-induced dissociation (CID) and tandem mass spectrometry (MS/MS) is a commonly used technique to analyze the chemical composition of steroids. However, steroids are structurally similar compounds, making it difficult to interpret their product-ion spectra. Electron transfer dissociation (ETD), a relatively new technique for protein and peptide fragmentation, has been shown to provide more detailed structural information. In this study, we compared the ability of CID with that of ETD to differentiate between eight 3,20-dioxosteroids that had been derivatizated with a quaternary ammonium salt, Girard reagent P (GirP), at room temperature or after exposure to microwave irradiation to generate doubly charged ions. We found that the derivatization of steroid with GirP hydrazine occurred in less than 10 min when the reaction was carried out in the presence of microwave irradiation compared to 30 min when the reaction was carried out at room temperature. According to the MS/MS spectra, CID provided rich, structurally informative ions; however, the spectra were complex, thereby complicating the peak assignment. In contrast, ETD generated simpler spectra, making it easier to recognize individual peaks. Remarkably, both CID and ETD were allowed to differentiate of steroid isomers, 17alpha-hydroxyprogesterone (17OHP) and deoxycorticosterone (DOC), but the signature ions obtained from CID were less intense than those generated by ETD, which generated much clearer spectra. These results indicate that ETD in conjunction with CID can provide more structural information for precise characterization of steroids. PMID- 24338891 TI - Photosensitized oxidation of phosphatidylethanolamines monitored by electrospray tandem mass spectrometry. AB - Photodynamic therapy combines visible light and a photosensitizer (PS) in the presence of molecular oxygen to generate reactive oxygen species able to modify biological structures such as phospholipids. Phosphatidylethanolamines (PEs), being major phospholipid constituents of mammalian cells and membranes of Gram negative bacteria, are potential targets of photosensitization. In this work, the oxidative modifications induced by white light in combination with cationic porphyrins (Tri-Py(+)-Me-PF and Tetra-Py(+)-Me) were evaluated on PE standards. Electrospray ionization mass spectrometry (ESI-MS) and tandem mass spectrometry (ESI-MS/MS) were used to identify and characterize the oxidative modifications induced in PEs (POPE: PE 16:0/18:1, PLPE: PE 16:0/18:2, PAPE: PE 16:0/20:4). Photo-oxidation products of POPE, PLPE and PAPE as hydroxy, hydroperoxy and keteno derivatives and products due to oxidation in ethanolamine polar head were identified. Hydroperoxy-PEs were found to be the major photo-oxidation products. Quantification of hydroperoxides (PE-OOH) allowed differentiating the potential effect in photodamage of the two porphyrins. The highest amounts of PE-OOH were notorious in the presence of Tri-Py(+)-Me-PF, a highly efficient PS against bacteria. The identification of these modifications in PEs is an important key point in the understanding cell damage processes underlying photodynamic therapy approaches. PMID- 24338893 TI - Semiparametric methods for multistate survival models in randomised trials. AB - Transform methods have proved effective for networks describing a progression of events. In semi-Markov networks, we calculated the transform of time to a terminating event from corresponding transforms of intermediate steps. Saddlepoint inversion then provided survival and hazard functions, which integrated, and fully utilised, the network data. However, the presence of censored data introduces significant difficulties for these methods. Many participants in controlled trials commonly remain event-free at study completion, a consequence of the limited period of follow-up specified in the trial design. Transforms are not estimable using nonparametric methods in states with survival truncated by end-of-study censoring. We propose the use of parametric models specifying residual survival to next event. As a simple approach to extrapolation with competing alternative states, we imposed a proportional incidence (constant relative hazard) assumption beyond the range of study data. No proportional hazards assumptions are necessary for inferences concerning time to endpoint; indeed, estimation of survival and hazard functions can proceed in a single study arm. We demonstrate feasibility and efficiency of transform inversion in a large randomised controlled trial of cholesterol-lowering therapy, the Long-Term Intervention with Pravastatin in Ischaemic Disease study. Transform inversion integrates information available in components of multistate models: estimates of transition probabilities and empirical survival distributions. As a by-product, it provides some ability to forecast survival and hazard functions forward, beyond the time horizon of available follow-up. Functionals of survival and hazard functions provide inference, which proves sharper than that of log-rank and related methods for survival comparisons ignoring intermediate events. PMID- 24338894 TI - Analysis of cerebrospinal fluid gamma-aminobutyric acid by capillary electrophoresis with laser-induced fluorescence detection. AB - The measurement of gamma-aminobutyric acid (GABA) is suitable for investigating various neurological disorders. In this study, a sensitive and selective method for free GABA quantification in cerebrospinal fluid (CSF) has been standardised. This method is based on CE with LIF detection using 4-fluoro-7-nitrobenzo-2-oxa 1,3-diazole (NBD-F) as a derivatisating agent. The reaction conditions (NBD-F concentration, pH, temperature and reaction time) and the electrophoretic parameters (run buffer composition and pH and separation voltage) were optimised to obtain the maximum derivatisation efficiency and electrophoretic resolution. The best resolution was obtained using 200 mM sodium borate, 10 mM SDS, 8.5 mM beta-CD, pH 10 and 20 kV voltage. The method was linear in the concentration range of 2.5-1000 nM with good inter- and intra-assay precision values. The effects of CSF handling on free GABA concentrations were also evaluated. Our results show that the time delay between CSF collection and freezing strongly increases the CSF GABA values. Age-related reference values were established in 55 paediatric controls. The influence of antiepileptic therapy on free CSF GABA was studied in 38 neuropaediatric patients. Significantly, higher GABA values were obtained in patients taking valproic acid or vigabatrin therapy, which are antiepileptic drugs that modulate GABA metabolism. PMID- 24338895 TI - Effect of delaying same-admission cholecystectomy on outcomes in patients with diabetes. AB - BACKGROUND: Recent studies have suggested that same-admission delayed cholecystectomy is a safe option. Patients with diabetes have been shown to have less favourable outcomes after cholecystectomy, but the impact of timing of operation for acute cholecystitis during the same admission is unknown. METHODS: This was a retrospective analysis of patients undergoing laparoscopic cholecystectomy for acute cholecystitis between 2004 and 2010, from the American College of Surgeons National Surgical Quality Improvement Program database. Patients with no significant co-morbidities (American Society of Anesthesiologists grade I or II) were included. Propensity score matching (PSM) was used to match patients with diabetes with those who did not have diabetes, in a ratio of 1:3, to ensure homogeneity of the two groups. Logistic regression models were applied to adjust for differences between early (within 24 h) and delayed (24 h or more) surgical treatment. The primary outcome was development of local and systemic infectious complications. Secondary outcomes were duration of operation and length of hospital stay. RESULTS: From a total of 2892 patients, 144 patients with diabetes were matched with 432 without diabetes by PSM. Delaying cholecystectomy for at least 24 h after admission in patients with diabetes was associated with significantly higher odds of developing surgical site infections (adjusted odds ratio 4.11, 95 per cent confidence interval 1.11 to 15.22; P = 0.034) and a longer hospital stay. For patients with no diabetes, however, delaying cholecystectomy had no impact on complications or length of hospital stay. CONCLUSION: Patients with diabetes who undergo laparoscopic cholecystectomy 24 h or more after admission may have an increased risk of postoperative surgical-site infection and a longer hospital stay than those undergoing surgery within 24 h of admission. PMID- 24338896 TI - Structures of reduced and ligand-bound nitric oxide reductase provide insights into functional differences in respiratory enzymes. AB - Nitric oxide reductase (NOR) catalyzes the generation of nitrous oxide (N2O) via the reductive coupling of two nitric oxide (NO) molecules at a heme/non-heme Fe center. We report herein on the structures of the reduced and ligand-bound forms of cytochrome c-dependent NOR (cNOR) from Pseudomonas aeruginosa at a resolution of 2.3-2.7 A, to elucidate structure-function relationships in NOR, and compare them to those of cytochrome c oxidase (CCO) that is evolutionarily related to NOR. Comprehensive crystallographic refinement of the CO-bound form of cNOR suggested that a total of four atoms can be accommodated at the binuclear center. Consistent with this, binding of bulky acetaldoxime (CH3-CH=N-OH) to the binuclear center of cNOR was confirmed by the structural analysis. Active site reduction and ligand binding in cNOR induced only ~0.5 A increase in the heme/non heme Fe distance, but no significant structural change in the protein. The highly localized structural change is consistent with the lack of proton-pumping activity in cNOR, because redox-coupled conformational changes are thought to be crucial for proton pumping in CCO. It also permits the rapid decomposition of cytotoxic NO in denitrification. In addition, the shorter heme/non-heme Fe distance even in the bulky ligand-bound form of cNOR (~4.5 A) than the heme/Cu distance in CCO (~5 A) suggests the ability of NOR to maintain two NO molecules within a short distance in the confined space of the active site, thereby facilitating N-N coupling to produce a hyponitrite intermediate for the generation of N2O. PMID- 24338897 TI - Transcription factor ELF4 promotes development and function of memory CD8(+) T cells in Listeria monocytogenes infection. AB - Most differentiated CD8(+) T cells die off at the end of an infection, revealing two main subsets of memory T cells - central and effector memory - which can be found in lymphoid tissues or circulating through nonlymphoid organs, respectively. The cell intrinsic regulation of the differentiation of CD8(+) T cells to effector and central memory remains poorly studied. Herein, we describe a novel role of the ETS transcription factor ELF4 in the development and function of memory CD8(+) T cells following infection with Listeria monocytogenes. Adoptively transferred Elf4(-/-) naive CD8(+) T cells produced lower numbers of effector memory CD8(+) T cells despite a normal pool of central memory. This was caused by suboptimal priming and decreased survival of CD8(+) T cells at the peak of response while enhanced Notch1 signaling and upregulation of eomesodermin correlated with "normal" development of Elf4(-/-) central memory. Finally, loss of ELF4 impaired the expansion of both central and effector memory CD8(+) T cells in a recall response by also activating Notch1 signaling. Altogether, ELF4 emerges as a novel transcriptional regulator of CD8(+) T-cell differentiation in response to infection. PMID- 24338899 TI - Comparative pharmacokinetics study of a kaurane diterpenoid after oral administration of monomer and Siegesbeckiae pubescens Makino extract to rats. AB - In this paper, a sensitive, rapid and reproducible high-performance liquid chromatography-tandem mass spectrometry method was developed to analyze 16alpha hydro-ent-kauran-17,19-dioic acid in rat plasma. First, this study compared the pharmacokinetics of 16alpha-hydro-ent-kauran-17,19-dioic acid after oral administration of monomer and Siegesbeckiae pubescens Makino extract in rat plasma with approximately the same dosage of 6.0 mg/kg. Second, chromatographic separation was performed on a Waters Symmetry C18 column (2.1 * 100 mm, 3.5 um) with isocratic elution using methanol-water containing 5 mmol/L ammonium acetate (70:30, v/v) as mobile phase at a flow rate of 0.2 mL/min. The calibration curves were linear over the range of 30-12000 ng/mL for monomer. At different time points (0, 0.083, 0.25, 0.75, 1, 2, 4, 6, 8, 12, 18, 24, 36, 48, 60 and 72 h) after administration, the concentrations of monomer in rat plasma were determined and main pharmacokinetic parameters were estimated. The double absorption presented in this study indicates that the pharmacokinetics of monomer in rat plasma have significant differences between different groups. PMID- 24338900 TI - Inhibitory effect of valsartan on the intestinal absorption and renal excretion of bestatin in rats. AB - Peptidomimetic drugs have favorable bioavailability owing to H(+)/peptide transporter 1 (PEPT1) located in the intestine. Sartans are commonly used and likely coadministered with peptidomimetic drugs in the clinic; however, in vivo interactions between sartans and peptidomimetic drugs have not been systemically understood. Herein, the effect and mechanism of sartans on the intestinal absorption and renal excretion of the dipeptide-like drug bestatin were investigated. Following oral combination with valsartan, the plasma concentration and area under the plasma concentration-time curve of bestatin in rats decreased significantly. Bestatin absorption in rat-everted intestinal sacs was dramatically reduced by valsartan. Sartans exhibited concentration-dependent inhibition on the uptake of bestatin in human PEPT1 (hPEPT1)-HeLa cells. The cumulative urinary excretion and renal clearance of the two drugs in rats decreased after intravenous coadministration. Moreover, decreased uptake of the two drugs was observed in rats' kidney slices and human organic anion transporter (hOAT)1/hOAT3-transfected cells when coadministered. The results suggest that the intestinal absorption and renal excretion of bestatin in rats were inhibited by coadministered valsartan. Interestingly, the half-maximal inhibitory concentration (IC50) values of valsartan for PEPT1 and OAT1/3 were comparable to the theoretically estimated local drug concentration and the clinical unbound concentration, respectively, proposing possible drug-drug interaction in humans via PEPT1 and OAT1/3, which should be paid particular attention when bestatin and valsartan are coadministrated clinically. PMID- 24338902 TI - Stereoselective synthesis of fluoroalkenoates and fluorinated isoxazolidinones: N substituents governing the dual reactivity of nitrones. AB - alpha-Fluoroalkenoates and 4-fluoro-5-isoxazolidinones are of vast interest due to their potential biological applications. We now demonstrate the syntheses of (E)-alpha-fluoroalkenoates and 4-fluoro-5-isoxazolidinones by the reactions between nitrones and alpha-fluoro-alpha-bromoacetate. By altering N-substituents in nitrones, (E)-alpha-fluoroalkenoates and 4-fluoro-5-isoxazolidinones can be achieved, respectively, with high chemo- and stereoselectivities. Experimental and computational studies have been conducted to elucidate the reaction mechanisms. Linear free energy relationship studies further revealed that the N substituent effects are primarily of electronic origin. PMID- 24338901 TI - Whole-brain three-dimensional T2-weighted BOLD functional magnetic resonance imaging at 7 Tesla. AB - PURPOSE: A new acquisition scheme for T2-weighted spin-echo BOLD fMRI is introduced. METHODS: It uses a T2-preparation module to induce blood-oxygenation level-dependent (BOLD) contrast, followed by a single-shot three-dimensional (3D) fast gradient-echo readout with short echo time (TE). It differs from most spin echo BOLD sequences in that BOLD contrast is generated before the readout, which eliminates the "dead time" due to long TE required for T2 contrast, and substantially improves acquisition efficiency. This approach, termed "3D T2prep GRE," was implemented at 7 Tesla (T) with a typical spatial (2.5 * 2.5 * 2.5 mm(3) ) and temporal (TR = 2.3 s) resolution for functional MRI (fMRI) and whole brain coverage (55 slices), and compared with the widely used 2D spin-echo EPI sequence. RESULTS: In fMRI experiments of simultaneous visual/motor activities, 3D T2prep-GRE showed minimal distortion and little signal dropout across the whole brain. Its lower power deposition allowed greater spatial coverage (55 versus 17 slices with identical TR, resolution and power level), temporal SNR (60% higher) and CNR (35% higher) efficiency than 2D spin-echo EPI. It also showed smaller T2* contamination. CONCLUSION: This approach is expected to be useful for ultra-high field fMRI, especially for regions near air cavities. The concept of using T2-preparation to generate BOLD contrast can be combined with many other sequences at any field strength. PMID- 24338903 TI - Conservative interventions for treating work-related complaints of the arm, neck or shoulder in adults. AB - BACKGROUND: Work-related upper limb disorder (WRULD), repetitive strain injury (RSI), occupational overuse syndrome (OOS) and work-related complaints of the arm, neck or shoulder (CANS) are the most frequently used umbrella terms for disorders that develop as a result of repetitive movements, awkward postures and impact of external forces such as those associated with operating vibrating tools. Work-related CANS, which is the term we use in this review, severely hampers the working population. OBJECTIVES: To assess the effects of conservative interventions for work-related complaints of the arm, neck or shoulder (CANS) in adults on pain, function and work-related outcomes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, 31 May 2013), MEDLINE (1950 to 31 May 2013), EMBASE (1988 to 31 May 2013), CINAHL (1982 to 31 May 2013), AMED (1985 to 31 May 2013), PsycINFO (1806 to 31 May 2013), the Physiotherapy Evidence Database (PEDro; inception to 31 May 2013) and the Occupational Therapy Systematic Evaluation of Evidence Database (OTseeker; inception to 31 May 2013). We did not apply any language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-randomised controlled trials evaluating conservative interventions for work-related complaints of the arm, neck or shoulder in adults. We excluded trials undertaken to test injections and surgery. We included studies that evaluated effects on pain, functional status or work ability. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted data and assessed risk of bias of the included studies. When studies were sufficiently similar, we performed statistical pooling of reported results. MAIN RESULTS: We included 44 studies (62 publications) with 6,580 participants that evaluated 25 different interventions. We categorised these interventions according to their working mechanisms into exercises, ergonomics, behavioural and other interventions.Overall, we judged 35 studies as having a high risk of bias mainly because of an unknown randomisation procedure, lack of a concealed allocation procedure, unblinded trial participants or lack of an intention-to-treat analysis.We found very low-quality evidence showing that exercises did not improve pain in comparison with no treatment (five studies, standardised mean difference (SMD) -0.52, 95% confidence interval (CI) -1.08 to 0.03), or minor intervention controls (three studies, SMD -0.25, 95% CI -0.87 to 0.37) or when provided as additional treatment (two studies, inconsistent results) at short term follow-up or at long-term follow-up. Results were similar for recovery, disability and sick leave. Specific exercises led to increased pain at short-term follow-up when compared with general exercises (four studies, SMD 0.45, 95% CI 0.14 to 0.75)We found very low-quality evidence indicating that ergonomic interventions did not lead to a decrease in pain when compared with no intervention at short-term follow-up (three studies, SMD -0.07, 95% CI -0.36 to 0.22) but did decrease pain at long-term follow-up (four studies, SMD -0.76, 95% CI -1.35 to -0.16). There was no effect on disability but sick leave decreased in two studies (risk ratio (RR) 0.48, 95% CI 0.32 to 0.76). None of the ergonomic interventions was more beneficial for any outcome measures when compared with another treatment or with no treatment or with placebo.Behavioural interventions had inconsistent effects on pain and disability, with some subgroups showing benefit and others showing no significant improvement when compared with no treatment, minor intervention controls or other behavioural interventions.In the eight studies that evaluated various other interventions, there was no evidence of a clear beneficial effect of any of the interventions provided. AUTHORS' CONCLUSIONS: We found very low-quality evidence indicating that pain, recovery, disability and sick leave are similar after exercises when compared with no treatment, with minor intervention controls or with exercises provided as additional treatment to people with work-related complaints of the arm, neck or shoulder. Low-quality evidence also showed that ergonomic interventions did not decrease pain at short-term follow-up but did decrease pain at long-term follow up. There was no evidence of an effect on other outcomes. For behavioural and other interventions, there was no evidence of a consistent effect on any of the outcomes.Studies are needed that include more participants, that are clear about the diagnosis of work-relatedness and that report findings according to current guidelines. PMID- 24338904 TI - Synthesis, solid-state NMR characterization, and application for hydrogenation reactions of a novel Wilkinson's-type immobilized catalyst. AB - Silica nanoparticles (SiNPs) were chosen as a solid support material for the immobilization of a new Wilkinson's-type catalyst. In a first step, polymer molecules (poly(triphenylphosphine)ethylene (PTPPE); 4-diphenylphosphine styrene as monomer) were grafted onto the silica nanoparticles by surface-initiated photoinferter-mediated polymerization (SI-PIMP). The catalyst was then created by binding rhodium (Rh) to the polymer side chains, with RhCl3?x H2O as a precursor. The triphenylphosphine units and rhodium as Rh(I) provide an environment to form Wilkinson's catalyst-like structures. Employing multinuclear ((31)P, (29)Si, and (13)C) solid-state NMR spectroscopy (SSNMR), the structure of the catalyst bound to the polymer and the intermediates of the grafting reaction have been characterized. Finally, first applications of this catalyst in hydrogenation reactions employing para-enriched hydrogen gas (PHIP experiments) and an assessment of its leaching properties are presented. PMID- 24338905 TI - Antitags: SERS-encoded nanoparticle assemblies that enable single-spot multiplex protein detection. AB - Simultaneous detection of multiple proteins on a single spot can be efficiently achieved by using multiplexed surface-enhanced Raman spectroscopy (SERS)-encoded nanoparticle 'antitags' consisting of poly(ethylene glycol) (PEG)-protected silver dimers (and higher aggregates) and antibody-tagging entities. The effective SERS-based multivariate deconvolution approach guarantees an accurate and successful distinguishable identification of single and multiple proteins in complex samples. Their potential application in multiplexed SERS bioimaging technology can be easily envisaged. PMID- 24338906 TI - An introduction to exemplar research: a definition, rationale, and conceptual issues. AB - The exemplar methodology represents a useful yet underutilized approach to studying developmental constructs. It features an approach to research whereby individuals, entities, or programs that exemplify the construct of interest in a particularly intense or highly developed manner compose the study sample. Accordingly, it reveals what the upper ends of development look like in practice. Utilizing the exemplar methodology allows researchers to glimpse not only what is but also what is possible with regard to the development of a particular characteristic. The present chapter includes a definition of the exemplar methodology, a discussion of some of key conceptual issues to consider when employing it in empirical studies, and a brief overview of the other chapters featured in this volume. PMID- 24338907 TI - Why a true account of human development requires exemplar research. AB - This chapter uses moral psychology to illustrate why exemplar methods are essential for building a valid, complete understanding of key domains of human development. Social psychological, economic, and biological-evolutionary paradigms for studying morality rely on samples drawn from the general population. This research reveals a bleak picture of morality, highlighting its irrational, self-interested, externally controlled aspects. If the subjects in these studies are confused, pliable, or profit-maximizing, these studies conclude that people in general are morally irrational and self-interested. In contrast, studies that investigate morally exceptional individuals reveal a more thoughtful, ideal-driven, self-reflective, creative version of moral functioning. Any account that neglects this high-functioning segment of the range is seriously misleading and cannot provide the basis for aspiration or education. PMID- 24338908 TI - Exemplars' moral behavior is self-regarding. AB - What fundamentally motivates moral behavior? What is the nature and source of moral motivation? The argument developed in this chapter is that moral action is not merely other-regarding; it also can, and should be, self-regarding. When there is something significant for the self in the moral enterprise, it can legitimately be self-enhancing and, thus, powerfully motivating. The empirical warrant for this argument is found in the study of the psychological functioning of moral exemplars. The research reviewed here indicates that moral exemplars do synergistically integrate their self-promoting agentic motivation in service to their other-promoting communal values. Therein is the powerful motivational impetus for doing good and living rightly. PMID- 24338909 TI - Cultural and contextual issues in exemplar research. AB - This chapter specifically addresses how exemplar methods are especially relevant to examining cultural and contextual issues. Cross-cultural, cultural, and indigenous psychologies are discussed in order to highlight how studying actual exemplars in their unique and complex developmental contexts has the potential to identify themes that either differ between or hold constant across distinct peoples and cultures. The chapter addresses basic assumptions of exemplar research and specifics of the method that are sensitive to the incorporation of cultural and contextual influences. Suggestions are made as to how exemplarity research can be even more effective to explore development in a valid means across cultures and be more attentive and applicable to local cultures. PMID- 24338910 TI - The making of an environmental activist: a developmental psychological perspective. AB - This chapter reviews the research on environmental exemplars, or activists. General themes that have been identified in the literature include early experiences in nature, the influence of other people and organizations, opportunities for environmental education, environmental self and identity formation, and generativity. With these themes in hand, we construct a developmental model suggesting a possible trajectory toward environmental activism. We also discuss possible implications of these findings with reference to the current state of our planet and what may be done to reverse current trends. PMID- 24338911 TI - Informative and inspirational contributions of exemplar studies. AB - The authors of this volume showcase the unique insights that can be gained from examining the lives of exemplars. For example, as individuals who stand out for living reflective, ethical lives, exemplars can reveal the human capacity to behave in exceptional ways despite most people's tendency to not exhibit these behaviors. The authors also discuss various advantages of the exemplar approach relative to the typical methods employed by social science. Using a person centered approach, for instance, enables researchers of exemplar studies to delve more deeply into the details and dynamics of an individual's thought processes and behaviors. Through the combined efforts of the authors, this volume illuminates the potential learning opportunities from studying exemplars, provides accounts of lives that can inspire readers, and suggests potential paths for readers' own spiritual and moral fulfillment. PMID- 24338912 TI - High-performance hybrid white organic light-emitting devices without interlayer between fluorescent and phosphorescent emissive regions. AB - By using mixed hosts with bipolar transport properties for blue emissive layers, a novel phosphorescence/fluorescence hybrid white OLED without using an interlayer between the fluorescent and phosphorescent regions is demonstrated. The peak EQE of the device is 19.0% and remains as high as 17.0% at the practical brightness of 1000 cd m(-2) . PMID- 24338913 TI - Health care service utilization among patients with chronic rhinosinusitis: a population-based study. AB - OBJECTIVES/HYPOTHESIS: Previous studies showed that chronic rhinosinusitis (CRS) accounts for billions of dollars in healthcare resource utilization. However, all such study estimates of the economic burden of CRS were based on subpopulations in Western societies. This study aimed to investigate differences in the utilization of healthcare services between subjects with CRS and comparison subjects using Taiwan's National Health Insurance database. STUDY DESIGN: A cross sectional study. METHODS: In total, 5,849 CRS subjects and 17,547 selected comparison subjects were included in this study. We evaluated healthcare resource utilization in a 1-year period. Variables of healthcare resource utilization included the following: numbers of outpatient visits and inpatient days, and the mean costs of outpatient and inpatient treatment. We also divided healthcare resource utilization into ear, nose, and throat (ENT) and non-ENT services. RESULTS: On the utilization of ENT services, CRS subjects had significantly more outpatient visits (3.9 vs. 1.4, P < .001) and significantly higher outpatient costs (US$77.7 vs. US$19.4, P < .001) than comparison subjects. As for the use and costs of all healthcare services, CRS subjects had significantly more outpatient visits (27.9 vs. 18.3, P < .001) and significantly higher outpatient (US$953 vs. US$665, P < .001) and total (US$1319 vs. US$946, P < .001) costs than comparison subjects. Namely, on average, CRS subjects had 152% more outpatient visits and 139% higher total costs than comparison subjects. CONCLUSIONS: This study found that subjects with CRS had significantly higher use of all healthcare services and costs than aged-matched controls. LEVEL OF EVIDENCE: 2c. PMID- 24338914 TI - Nitroxide-mediated radical ring-opening copolymerization: chain-end investigation and block copolymer synthesis. AB - Well-defined, degradable copolymers are successfully prepared by nitroxide mediated radical ring opening polymerization (NMrROP) of oligo(ethylene glycol) methyl ether methacrylate (OEGMA) or methyl methacrylate (MMA), a small amount of acrylonitrile (AN) and cyclic ketene acetals (CKAs) of different structures. Phosphorous nuclear magnetic resonance allows in-depth chain-end characterization and gives crucial insights into the nature of the copoly-mer terminal sequences and the living chain fractions. By using a small library of P(OEGMA-co-AN-co-CKA) and P(MMA-co-AN-co-CKA) as macroinitiators, chain extensions with styrene are performed to furnish (amphiphilic) block copolymers comprising a degradable segment. PMID- 24338915 TI - Can real time location system technology (RTLS) provide useful estimates of time use by nursing personnel? AB - Accurate, precise, unbiased, reliable, and cost-effective estimates of nursing time use are needed to insure safe staffing levels. Direct observation of nurses is costly, and conventional surrogate measures have limitations. To test the potential of electronic capture of time and motion through real time location systems (RTLS), a pilot study was conducted to assess efficacy (method agreement) of RTLS time use; inter-rater reliability of RTLS time-use estimates; and associated costs. Method agreement was high (mean absolute difference = 28 seconds); inter-rater reliability was high (ICC = 0.81-0.95; mean absolute difference = 2 seconds); and costs for obtaining RTLS time-use estimates on a single nursing unit exceeded $25,000. Continued experimentation with RTLS to obtain time-use estimates for nursing staff is warranted. PMID- 24338916 TI - Latent variable models with nonparametric interaction effects of latent variables. AB - Renal disease is one of the common complications of diabetes, especially for Asian populations. Moreover, cardiovascular and renal diseases share common risk factors. This paper proposes a latent variable model with nonparametric interaction effects of latent variables for a study based on the Hong Kong Diabetes Registry, which was established in 1995 as part of a continuous quality improvement program at the Prince of Wales Hospital in Hong Kong. Renal outcome (outcome latent variable) is regressed in terms of cardiac function and diabetes (explanatory latent variables) through an additive structural equation formulated using a series of unspecified univariate and bivariate smooth functions. The Bayesian P-splines approach, along with a Markov chain Monte Carlo algorithm, is proposed to estimate smooth functions, unknown parameters, and latent variables in the model. The performance of the developed methodology is demonstrated via a simulation study. The effect of the nonparametric interaction of cardiac function and diabetes on renal outcome is investigated using the proposed methodology. PMID- 24338917 TI - Overcoming the unexpected functional inversion of a PqsR antagonist in Pseudomonas aeruginosa: an in vivo potent antivirulence agent targeting pqs quorum sensing. AB - The virulence regulator PqsR of Pseudomonas aeruginosa is considered as an attractive target for attenuating the bacterial pathogenicity without eliciting resistance. However, despite efforts and desires, no promising PqsR antagonist has been discovered thus far. Now, a surprising functionality change of a highly affine PqsR antagonist in P. aeruginosa is revealed, which is mediated by a bacterial signal molecule synthase and responsible for low cellular potency. Blockade of the susceptible position led to the discovery of the first antivirulence compound that is potent in vivo and targets PqsR, thus providing a proof of concept for this novel antivirulence therapy. PMID- 24338918 TI - Hyperoside regulates the level of thymic stromal lymphopoietin through intracellular calcium signalling. AB - Hyperoside (HYP) is the principle active component of Crataegus pinnatifida. Thymic stromal lymphopoietin (TSLP) plays a vital role in the pathogenesis of allergic reactions. Here, we investigated how HYP regulates the levels of TSLP in a human mast cell line, HMC-1 cells. We analyzed the levels of TSLP by treatment with HYP in phorbol myristate acetate plus calcium ionophore A23187-stimulated HMC-1 cells with ELISA and a polymerase chain reaction analysis. We also analyzed the pathway that HYP regulates TSLP by measuring the level of fluorescent intracellular calcium and using a Western blot analysis. HYP decreased the level of intracellular calcium in stimulated HMC-1 cells. It also significantly decreased the production and mRNA expression of TSLP in stimulated HMC-1 cells. It significantly decreased the levels of receptor-interacting protein 2 and active caspase-1 in stimulated HMC-1 cells. HYP significantly decreased the translocation of NF-kappaB into the nucleus and degradation of IkappaBalpha in the cytoplasm in stimulated HMC-1 cells. Furthermore, it significantly decreased the production and mRNA expression of interleukin-1beta and interleukin-6 in stimulated HMC-1 cells. Taken together, our findings establish HYP as a potential agent for the treatment of allergic reactions. PMID- 24338919 TI - Quality characterization of wheat, maize and sorghum steamed breads from Lesotho. AB - BACKGROUND: In Lesotho, traditional bread covers different types of dumplings prepared with cereal flour, water, salt and sourdough. This study characterized eight steamed breads prepared from wheat, maize and sorghum. Breads were prepared from both commercial and self-milled flours according to the procedures followed in rural and urban areas of Lesotho. Descriptive sensory evaluation was conducted to profile sensory properties of the breads. Flour particle sizes, sourdough properties and bread colour, volume and texture were also characterized. RESULTS: The type of cereal and milling properties of the flour used had substantial effects on the physical and sensory properties of the bread. Steamed wheat breads had greater volume, softer crumb and more bland flavour compared with sorghum and maize breads. Both sorghum and maize steamed breads prepared according to traditional Basotho procedures were characterized by low loaf volume, denser crumb, more complex and strong flavours and aroma, notably sour, musty, malty, dairy sour and fermented aroma. The texture of the non-wheat bread types was heavy, chewy, dry, fibrous and more brittle and needed a higher compression force to deform. CONCLUSION: This study provided insight on the sensory properties of steamed bread as prepared in Lesotho. Further research is needed to optimize sensory properties of the non-wheat steamed breads by controlling the flour particle size, compositing non-wheat flours with different levels of wheat flour, addition of protein sources and gums, altering the amount of water, improving the pre-gelatinization process and optimizing the steaming method of cooking bread. PMID- 24338920 TI - Auer-rod like inclusions in multiple myeloma. PMID- 24338921 TI - Integrated PET/MR. AB - Integrated whole-body PET/MR hybrid imaging combines excellent soft tissue contrast and various functional imaging parameters provided by MR with high sensitivity and quantification of radiotracer metabolism provided by positron emission tomography (PET). While clinical evaluation now is under way, integrated PET/MR demands for new technologies and innovative solutions, currently subject to interdisciplinary research. Attenuation correction of human soft tissues and of hardware components has to be MR-based to maintain quantification of PET imaging because computed tomography (CT) attenuation information is missing. This brings up the question of how to provide bone information with MR imaging. The limited field-of-view in MR imaging leads to truncations in body imaging and MR based attenuation correction. Another research field is the implementation of motion correction technologies to correct for breathing and cardiac motion in view of the relatively long PET data acquisition times. Initial clinical applications of integrated PET/MR in oncology, neurology, pediatric oncology, and cardiovascular disease are highlighted. The hybrid imaging workflow here has to be tailored to the clinical indication to maximize diagnostic information while minimizing acquisition time. PET/MR introduces new artifacts that need special observation and innovative solutions for correction. Finally, the rising need for appropriate phantoms and standardization efforts in PET/MR hybrid imaging is discussed. PMID- 24338922 TI - Highly efficient four-component synthesis of 4(3H)-quinazolinones: palladium catalyzed carbonylative coupling reactions. AB - Given the importance of quinazolinones and carbonylative transformations, a palladium-catalyzed four-component carbonylative coupling system for the synthesis of diverse 4(3H)-quinazolinone in a concise and convergent fashion has been developed. Starting from 2-bromoanilines (1 mmol), trimethyl orthoformate (2 mmol), and amines (1.1 mmol), under 10 bar of CO, the desired products were isolated in good yields in the presence of Pd(OAc)2 (2 mol %), BuPAd2 (6 mol %) in 1,4-dioxane (2 mL) at 100 degrees C, using N,N-diisopropylethylamine (2 mmol) as the base. Notably, the process tolerates the presence of various reactive functional groups and is very selective for quinazolinones, and was used in the synthesis of the precursor to the bioactive dihydrorutaempine. PMID- 24338923 TI - The joint contribution of pain and insomnia to sickness absence and disability retirement: a register-linkage study among Norwegian and Finnish employees. AB - BACKGROUND: Pain and insomnia are both independently associated with work disability. Although pain and insomnia often co-occur, their joint associations with subsequent sickness absence and disability retirement have not been studied. We aimed to examine these associations in two prospective occupational cohorts while considering key covariates. METHODS: Norwegian Hordaland Health Study (n = 6892, 59% women) and Finnish Helsinki Health Study (n = 6060, 78% women) data were used. Those with only pain, only insomnia or both conditions at baseline were compared with those with no pain and no insomnia. Work disability outcomes were derived from national and employers' register data. Medically certified sickness absence spells lasting 2 weeks or more and all-cause disability retirement were examined. Register-based follow-up was 4 years for sickness absence and 5 years for disability retirement. Covariates were sex, age, marital status, education, smoking, alcohol use, body mass index and blood pressure. Poisson and Cox regression models were fitted. RESULTS: Both pain and insomnia were associated with subsequent sickness absence and disability retirement, but the associations were stronger for those reporting co-morbid pain and insomnia with support for a synergistic interaction effect, particularly regarding disability retirement. The associations were largely similar in both cohorts and remained after full adjustments. CONCLUSIONS: This study is the first to report the separate and combined effects of pain and insomnia on objective health outcomes. Common patterns observed in two separate cohorts suggest that the combination of pain and insomnia might be particularly relevant for subsequent disability retirement. PMID- 24338925 TI - Towards design rules for covalent nanostructures on metal surfaces. AB - The covalent molecular assembly on metal surfaces is explored, outlining the different types of applicable reactions. Density functional calculations for on surface reactions are shown to yield valuable insights into specific reaction mechanisms and trends across the periodic table. Finally, it is shown how design rules could be derived for nanostructures on metal surfaces. PMID- 24338924 TI - Extracellular Hsp90 mediates an NF-kappaB dependent inflammatory stromal program: implications for the prostate tumor microenvironment. AB - BACKGROUND: The tumor microenvironment (TME) plays an essential role in supporting and promoting tumor growth and progression. An inflammatory stroma is a widespread hallmark of the prostate TME, and prostate tumors are known to co evolve with their reactive stroma. Cancer-associated fibroblasts (CAFs) within the reactive stroma play a salient role in secreting cytokines that contribute to this inflammatory TME. Although a number of inflammatory mediators have been identified, a clear understanding of key factors initiating the formation of reactive stroma is lacking. METHODS: We explored whether tumor secreted extracellular Hsp90 alpha (eHsp90alpha) may initiate a reactive stroma. Prostate stromal fibroblasts (PrSFs) were exposed to exogenous Hsp90alpha protein, or to conditioned medium (CM) from eHsp90alpha-expressing prostate cancer cells, and evaluated for signaling, motility, and expression of prototypic reactive markers. In tandem, ELISA assays were utilized to characterize Hsp90alpha-mediated secreted factors. RESULTS: We report that exposure of PrSFs to eHsp90 upregulates the transcription and protein secretion of IL-6 and IL-8, key inflammatory cytokines known to play a causative role in prostate cancer progression. Cytokine secretion was regulated in part via a MEK/ERK and NF-kappaB dependent pathway. Secreted eHsp90alpha also promoted the rapid and durable activation of the oncogenic inflammatory mediator signal transducer and activator of transcription (STAT3). Finally, eHsp90 induced the expression of MMP-3, a well-known mediator of fibrosis and the myofibroblast phenotype. CONCLUSIONS: Our results provide compelling support for eHsp90alpha as a transducer of signaling events culminating in an inflammatory and reactive stroma, thereby conferring properties associated with prostate cancer progression. PMID- 24338926 TI - Resistance to AHAS inhibitor herbicides: current understanding. AB - Acetohydroxyacid synthase (AHAS) inhibitor herbicides currently comprise the largest site-of-action group (with 54 active ingredients across five chemical groups) and have been widely used in world agriculture since they were first introduced in 1982. Resistance evolution in weeds to AHAS inhibitors has been rapid and identified in populations of many weed species. Often, evolved resistance is associated with point mutations in the target AHAS gene; however non-target-site enhanced herbicide metabolism occurs as well. Many AHAS gene resistance mutations can occur and be rapidly enriched owing to a high initial resistance gene frequency, simple and dominant genetic inheritance and lack of major fitness cost of the resistance alleles. Major advances in the elucidation of the crystal structure of the AHAS (Arabidopsis thaliana) catalytic subunit in complex with various AHAS inhibitor herbicides have greatly improved current understanding of the detailed molecular interactions between AHAS, cofactors and herbicides. Compared with target-site resistance, non-target-site resistance to AHAS inhibitor herbicides is less studied and hence less understood. In a few well-studied cases, non-target-site resistance is due to enhanced rates of herbicide metabolism (metabolic resistance), mimicking that occurring in tolerant crop species and often involving cytochrome P450 monooxygenases. However, the specific herbicide-metabolising, resistance-endowing genes are yet to be identified in resistant weed species. The current state of mechanistic understanding of AHAS inhibitor herbicide resistance is reviewed, and outstanding research issues are outlined. PMID- 24338927 TI - Processes involved in sweeping as sample enrichment method in cyclodextrin modified micellar electrokinetic chromatography of hydrophobic basic analytes. AB - Sweeping is an enrichment method in MEKC, which includes following steps: stacking/destacking of the micelles, sweeping of analyte by the stacked/destacked micelles, destacking/stacking of the swept analyte zone and additional focusing/defocusing due to the retention factor gradient effect (RFGE). In this study, we investigate additional processes, regarding online focusing in cyclodextrin-modified MEKC (CD-MEKC) of hydrophobic basic analytes: dynamic pH junction (sample with pH different from that of BGE) and adsorption of analyte onto the capillary wall within the sample zone. It is demonstrated that the developed method for the assessment of the sweeping efficiency is also applicable to CD-MEKC taking ethylparaben as an example of acidic analytes and desloratadine as an example of basic analytes using different types of beta-cyclodextrin. Our previous results regarding RFGE as an additional focusing/defocusing effect in sweeping-MEKC are confirmed for the case that the apparent distribution coefficient differs for the sample and the BGE due to a different content of the complex-forming agent cyclodextrin and due to a pH difference between the sample and the BGE. Despite being significantly more hydrophobic than ethylparaben, desloratadine shows an unexpectedly low enrichment factor. This enrichment factor is nearly unaffected by the addition of CD to the BGE. This unexpected behavior is attributed to wall adsorption of the protonated hydrophobic basic analyte within the sample zone, which significantly counteracts the sweeping process. This assumption is corroborated by an improvement in the enrichment factor achieved via addition of a dynamic coating agent (triethylamine) to the sample solution. PMID- 24338928 TI - A racemic and enantiopure unsymmetric diiron(III) complex with a chiral o carborane-based pyridylalcohol ligand: combined chiroptical, magnetic, and nonlinear optical properties. AB - The design of molecule-based systems combining magnetic, chiroptical and second order optical nonlinear properties is still very rare. We report an unusually unsymmetric diiron(III) complex 1, in which three bulky chiral carboranylpyridinealkoxide ligands (oCBhmp(-)) bridge both metal ions and the complex shows the above-mentioned properties. The introduction of o-carborane into the 2-(hydroxymethyl)pyridine (hmpH) architecture significantly alters the coordination of the simple or aryl-substituted 2-hmpH. The unusual architecture observed in 1 seems to be triggered by the poor nucleophilicity of our alkoxide ligand (oCBhmp(-)). A very rare case of spontaneous resolution takes place on precipitation or exposure to solvent vapor for the bulk compound, as confirmed by a combination of single-crystal and powder X-ray diffraction, second-harmonic generation, and circular dichroism. The corresponding enantiopure complexes (+)1 and (-)1 have also been synthesized and fully characterized. This research provides a new building block with unique geometry and electronics to construct coordination complexes with multifunctional properties. PMID- 24338929 TI - Cell-extrinsic CTLA4-mediated regulation of dendritic cell maturation depends on STAT3. AB - Regulatory T (Treg) cells suppress immune responses by downregulating the expression of costimulatory molecules CD80 and CD86 on dendritic cells (DCs) through cytotoxic T lymphocyte antigen 4 (CTLA4). However, it is unclear whether inducible Treg (iTreg) cells can hamper immune responses via the same mechanism. Moreover, whether a reverse signal sent by CTLA4 alone is sufficient to prevent maturation of DCs has never been evaluated. Here, we demonstrate that stimulation of DCs with CTLA4, either expressed by inducible Treg cells or by cross-linking with CTLA4Fc fusion protein, can significantly inhibit LPS-induced CD80 and CD86 mRNA and protein expression in both mouse and human DCs. Importantly, CTLA4Fc treated DCs had reduced ability to stimulate CD4(+) and CD8(+) T-cell proliferation and cytokine production in both syngeneic and allogeneic settings. We also investigated the molecular mechanism involved in the induction of tolerogenic DCs by CTLA4. We determined that the interaction of CTLA4 with its high affinity ligand CD80 on DCs induces STAT3 phosphorylation followed by reduction of NF-kappaB activity, leading to suppression of CD80 and CD86 gene transcription and protein production. Our work opens new windows for the generation of tolerogenic DCs that could ultimately be used for treating autoimmune diseases and transplant rejection. PMID- 24338930 TI - A reversible multi-stimuli-responsive fluorescence probe and the design for combinational logic gate operations. AB - Here, a novel multi-stimuli-responsive fluorescence probe is developed by incorporating spiropyran group into the coumarin-substituted polydiacetylene (PDA) vesicles. The fluorescence of PDA can be turned on upon heating, and can be quenched upon exposure to UV light irradiation or pH stimuli owing to the fluorescene resonance energy transfer (FRET) between the red-phase PDA and the open merocyanine (MC) form of spiropyran. Moreover, we have designed and experimentally realized a set of logic gate operations for the first time based on the fluorescence modulation of the designed system upon thermal, photo, and pH stimuli. This novel type of resettable logic gates augur well for practical applications in information storage, optical recording, and sensing in complicated microenvironments. PMID- 24338931 TI - Formylborane formation with frustrated Lewis pair templates. AB - Boranes R2 BH react with carbon monoxide by forming the respective borane carbonyl compounds R2 BH(CO). The formation of (C6 F5 )2 BH(CO) derived from the Piers borane, HB(C6 F5 )2 , is a typical example. Subsequent CO-hydroboration does not take place, since the formation of the formylborane is usually endothermic. However, an "eta(2) -formylborane" was formed by CO-hydroboration with the Piers borane at vicinal phosphane/borane frustrated Lewis pair (FLP) templates. Subsequent treatment with pyridine liberated the intact formylborane from the FLP framework, and (pyridine)(C6 F5 )2 B?CHO was then isolated as a stable compound. This product underwent typical reactions of carbonyl compounds, such as Wittig olefination. PMID- 24338932 TI - Perovskite-based hybrid solar cells exceeding 10% efficiency with high reproducibility using a thin film sandwich approach. AB - Organometal halide perovskites have tremendous potential as light absorbers for photovoltaic applications. In this work we demonstrate hybrid solar cells based on the mixed perovskite CH3 NH3 PbI2 Cl in a thin film sandwich structure, with unprecedented reproducibility and generating efficiencies up to 10.8%. The successfulness of our approach is corroborated by the experimental electronic structure determination of this perovskite. PMID- 24338934 TI - Vitamin D status of human immunodeficiency virus-positive patients with advanced liver disease enrolled in the solid organ transplantation in HIV: multi-site study. AB - An optimal vitamin D status may benefit liver transplantation (LT) patients. Higher levels of 25-hydroxyvitamin D [25(OH)D] mitigate steroid-induced bone loss after LT, correlate with better hepatitis C virus treatment responses, and increase graft survival. This study investigated 25(OH)D levels and assessed strategies for vitamin D deficiency prevention in human immunodeficiency virus (HIV)-positive patients with advanced liver disease who were enrolled in the Solid Organ Transplantation in HIV: Multi-Site Study. 25(OH)D was measured in banked specimens from 154 LT candidates/recipients with the DiaSorin assay; deficiency was defined as a 25(OH)D level < 20 ng/mL. Information about vitamin D supplement use after LT was obtained from medication logs and via surveys. Logistic regression, Cox regression, and linear repeated measures analyses were performed with SAS software. We found that none of the 17 academic medical centers in the United States routinely recommended vitamin D supplements before LT, and only a minority (4/17) recommended vitamin D supplements to all patients after LT. Seventy-one percent of the 139 patients with pre-LT values had vitamin D deficiency, which was significantly associated with cirrhosis (P = 0.01) but no other variable. The vitamin D status improved modestly after LT; however, the status was deficient for 40% of the patients 1 year after LT. In a multivariate linear repeated measures model, a higher pre-LT 25(OH)D level (P < 0.001), specimen collection in the summer (P < 0.001), a routine vitamin D supplementation strategy after LT (P < 0.001), and the time elapsing since LT (P = 0.01) were significantly associated with increases in the post-LT 25(OH)D level; black race was associated with a decreased level (P = 0.02). In conclusion, the majority of patients awaiting LT were vitamin D deficient, and approximately half were vitamin D deficient after LT. More extensive use of vitamin D supplements, more sun exposure, or both are needed to prevent this deficiency in HIV-positive LT candidates and recipients. PMID- 24338935 TI - Resistant hypertension optimal treatment trial: a randomized controlled trial. AB - The prevalence of resistant hypertension (ReHy) is not well established. Furthermore, diuretics, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and calcium channel blockers are largely used as the first 3 drug combinations for treating ReHy. However, the fourth drug to be added to the triple regimen is still controversial and guided by empirical choices. We sought (1) to determine the prevalence of ReHy in patients with stage II hypertension; (2) to compare the effects of spironolactone vs clonidine, when added to the triple regimen; and (3) to evaluate the role of measuring sympathetic and renin angiotensin-aldosterone activities in predicting blood pressure response to spironolactone or clonidine. The Resistant Hypertension Optimal Treatment (ReHOT) study (ClinicalTrials.gov NCT01643434) is a prospective, multicenter, randomized trial comprising 26 sites in Brazil. In step 1, 2000 patients will be treated according to hypertension guidelines for 12 weeks, to detect the prevalence of ReHy. Medical therapy adherence will be checked by pill count monitoring. In step 2, patients with confirmed ReHy will be randomized to an open label 3-month treatment with spironolactone (titrating dose, 12.5-50 mg once daily) or clonidine (titrating dose, 0.1-0.3 mg twice daily). The primary endpoint is the effective control of blood pressure after a 12-week randomized period of treatment. The ReHOT study will disseminate results about the prevalence of ReHy in stage II hypertension and the comparison of spironolactone vs clonidine for blood pressure control in patients with ReHy under 3-drug standard regimen. PMID- 24338936 TI - A powerful association test of multiple genetic variants using a random-effects model. AB - There is an emerging interest in sequencing-based association studies of multiple rare variants. Most association tests suggested in the literature involve collapsing rare variants with or without weighting. Recently, a variance component score test [sequence kernel association test (SKAT)] was proposed to address the limitations of collapsing method. Although SKAT was shown to outperform most of the alternative tests, its applications and power might be restricted and influenced by missing genotypes. In this paper, we suggest a new method based on testing whether the fraction of causal variants in a region is zero. The new association test, T REM , is derived from a random-effects model and allows for missing genotypes, and the choice of weighting function is not required when common and rare variants are analyzed simultaneously. We performed simulations to study the type I error rates and power of four competing tests under various conditions on the sample size, genotype missing rate, variant frequency, effect directionality, and the number of non-causal rare variant and/or causal common variant. The simulation results showed that T REM was a valid test and less sensitive to the inclusion of non-causal rare variants and/or low effect common variants or to the presence of missing genotypes. When the effects were more consistent in the same direction, T REM also had better power performance. Finally, an application to the Shanghai Breast Cancer Study showed that rare causal variants at the FGFR2 gene were detected by T REM and SKAT, but T REM produced more consistent results for different sets of rare and common variants. PMID- 24338937 TI - Hexyl glucoside and hexyl maltoside inhibit light-induced oxidation of tryptophan. AB - We investigated the photo-protective effect of sugar-based surfactants--hexyl glucoside and hexyl maltoside--against light-induced oxidation of a monoclonal antibody. Reactive oxygen species are generated in solutions in the presence of light; these reactive species readily oxidize amino acids such as tryptophan. Hexyl glucosides and hexyl maltosides scavenge these reactive species and protect tryptophan residues from light-induced oxidation in a concentration-dependent manner. As a result of the scavenging process, hydrogen peroxide is formed, especially at high (millimolar) concentrations of the alkyl glycoside surfactants. These results suggest that hexyl glucoside and hexyl maltoside have the potential to protect tryptophan residues against light-induced oxidation. PMID- 24338938 TI - Regional analysis of femoral head perfusion following displaced fractures of the femoral neck. AB - PURPOSE: To assess regional variations in the arterial and venous blood supply to the femoral head following displaced fracture of the femoral neck using dynamic contrast enhanced (DCE)-MRI quadrant analysis. MATERIALS AND METHODS: A total of 27 subjects with displaced femoral neck fractures were enrolled in the study. Quadrant specific DCE-MRI perfusion analysis was performed on a 1.5 Tesla MRI scanner. Simultaneous imaging of control and displaced fractured hips was done for comparison. RESULTS: Quadrant specific decreases were found in the arterial (A (0.52 versus 0.27; P = 5.7E-13), Akep (1.0/min(-1) versus 0.41/min(-1) ; P = 1.3E-9) and venous (kel (0.05/min(-1) versus -0.02/min(-1) ; P = 5.1E-5) supply to the femoral head between control and injured sides using a two-factor analysis of variance test. The fractional perfusion (initial area under the curve) in the supero/inferolateral quadrants was 49% min/54% min, in the supero/inferomedial quadrants was 43% min/46% min and for the total femoral head was 39% min on the fracture versus control sides. CONCLUSION: Quadrant specific decreases in arterial and venous perfusion on the fracture side were observed when compared with control. PMID- 24338939 TI - Impact of postremission consolidation chemotherapy on outcome after reduced intensity conditioning allogeneic stem cell transplantation for patients with acute myeloid leukemia in first complete remission: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. AB - BACKGROUND: The objective of the current study was to investigate the role of postremission consolidation chemotherapy before reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (alloSCT) for patients with acute myeloid leukemia (AML) in first complete remission (CR1). METHODS: Of the 789 consecutive patients with AML in CR1 who underwent RIC alloSCT from a human leukocyte antigen-matched sibling or matched unrelated donor peripheral stem cell grafts between 2001 and 2010, 591 patients received at least 1 cycle of consolidation chemotherapy and 198 patients did not receive any consolidation chemotherapy before alloSCT. To minimize inherent survival bias in favor of patients who underwent transplant long after achieving CR1, the study focused on 373 patients who underwent transplant within the median time frame between achievement of CR1 and alloSCT (3 months for patients who underwent alloSCT from matched siblings and 4 months for patients who underwent alloSCT from matched unrelated donors). In this subgroup, 151 patients did not receive any consolidation chemotherapy and 222 patients received >= 1 consolidation chemotherapy cycle. RESULTS: With a median follow-up of 36 months (range, 2 months-135 months), the 3-year cumulative recurrence incidence (RI) was not significantly different between the groups (36% +/- 4% for the group treated without consolidation chemotherapy vs 38% +/- 3% for patients who received consolidation chemotherapy; P = .89). In addition, leukemia-free survival was similar between the groups (45% +/- 4% and 47% +/- 3%, respectively; P = .41). Dose intensity of cytarabine given during consolidation chemotherapy appeared to have no influence on RI. On multivariate analysis, pretransplant consolidation (>= 1 cycle vs 0 cycles) was found to have no significant impact on RI (hazards ratio, 1.29; 95% confidence interval, 0.84-1.97 [P = .24]) or leukemia-free survival (hazards ratio, 1.00; 95% confidence interval, 0.71-1.42 [P = .99]). CONCLUSIONS: The data from the current study suggest no apparent advantage for postremission consolidation chemotherapy before RIC alloSCT, provided a donor is readily available. PMID- 24338940 TI - Hair growth-promoting effect of Carthamus tinctorius floret extract. AB - The florets of Carthamus tinctorius L. have traditionally been used for hair growth promotion. This study aimed to examine the potential of hydroxysafflor yellow A-rich C. tinctorius extract (CTE) on hair growth both in vitro and in vivo. The effect of CTE on cell proliferation and hair growth-associated gene expression in dermal papilla cells and keratinocytes (HaCaT) was determined. In addition, hair follicles from mouse neonates were isolated and cultured in media supplemented with CTE. Moreover, CTE was applied topically on the hair-shaved skin of female C57BL/6 mice, and the histological profile of the skin was investigated. C. tinctorius floret ethanolic extract promoted the proliferation of both dermal papilla cells and HaCaT and significantly stimulated hair growth promoting genes, including vascular endothelial growth factor and keratinocyte growth factor. In contrast, CTE suppressed the expression of transforming growth factor-beta1 that is the hair loss-related gene. Furthermore, CTE treatment resulted in a significant increase in the length of cultured hair follicles and stimulated the growth of hair with local effects in mice. The results provided the preclinical data to support the potential use of CTE as a hair growth promoting agent. PMID- 24338941 TI - Adult post-mortem imaging in traumatic and cardiorespiratory death and its relation to clinical radiological imaging. AB - The use of post-mortem imaging is expanding throughout the world with increasing use of advanced imaging techniques, such as contrast-enhanced CT and MRI. The questions asked of post-mortem imaging are complex and can be very different, for example for natural sudden death investigation will focus on the cause, whereas for trauma the cause of death is often clear, but injury patterns may be very revealing in investigating the background to the incident. Post-mortem imaging is different to clinical imaging regarding both the appearance of pathology and the information required, but there is much to learn from many years of clinical research in the use of these techniques. Furthermore, it is possible that post mortem imaging research could be used not only for investigating the cause of death but also as a model to conduct clinically relevant research. This article reviews challenges to the development of post-mortem imaging for trauma, identification and cardiorespiratory death, and how they may be influenced by current clinical thinking and practice. PMID- 24338942 TI - Vasculogenesis: a crucial player in the resistance of solid tumours to radiotherapy. AB - Tumours have two main ways to develop a vasculature: by angiogenesis, the sprouting of endothelial cells from nearby blood vessels, and vasculogenesis, the formation of blood vessels from circulating cells. Because tumour irradiation abrogates local angiogenesis, the tumour must rely on the vasculogenesis pathway for regrowth after irradiation. Tumour irradiation produces a marked influx of CD11b(+) myeloid cells (macrophages) into the tumours, and these are crucial to the formation of blood vessels in the tumours after irradiation and for the recurrence of the tumours. This process is driven by increased tumour hypoxia, which increases levels of HIF-1 (hypoxia-inducible factor 1), which in turn upregulates SDF-1 (stromal cell-derived factor 1 or CXCL12), the main driver of the vasculogenesis pathway. Inhibition of HIF-1 or of its downstream target SDF-1 prevents the radiation-induced influx of the CD11b(+) myeloid cells and delays or prevents the tumours from recurring following irradiation. Others and we have shown that with a variety of tumours in both mice and rats, the inhibition of the SDF-1/CXCR4 pathway delays or prevents the recurrence of implanted or autochthonous tumours following irradiation or following treatment with vascular disrupting agents or some chemotherapeutic drugs such as paclitaxel. In addition to the recruited macrophages, endothelial progenitor cells (EPCs) are also recruited to the irradiated tumours, a process also driven by SDF-1. Together, the recruited proangiogenic macrophages and the EPCs reform the tumour vasculature and allow the tumour to regrow following irradiation. This is a new paradigm with major implications for the treatment of solid tumours by radiotherapy. PMID- 24338943 TI - Morphological diversity and evolution of the spermatozoon in the mouse-related clade of rodents. AB - Most species in the three highly speciose families of the mouse-related clade of rodents, the Muridae, Cricetidae, and Nesomyidae (superfamily Muroidea), have a highly complex sperm head in which there is an apical hook but there are few data available for the other related families of these rodents. In the current study, using light and electron microscopies, we investigated the structure of the spermatozoon in representative species of four other families within the mouse related clade, the Dipodidae, Spalacidae, Pedetidae, and Heteromyidae, that diverged at or near the base of the muroid lineage. Our results indicate that a diverse array of sperm head shapes and tail lengths occurs but none of the species in the families Spalacidae, Dipodidae, or Pedetidae has a sperm head with an apical hook. By contrast, a rostrally extending apical hook is present in spermatozoa of members of the Family Heteromyidae which also invariably have comparatively long sperm tails. These findings suggest that the hook-shaped sperm head in the murid, cricetid, and nesomyid rodents evolved after divergence of this lineage from its common ancestor with the other families of the mouse related clade, and that separate, and independent, convergent evolution of a similar sperm head form, and long sperm tail, occurred in the Heteromyidae. PMID- 24338945 TI - Chlorogenic acid in raw materials for the production of chicory coffee. AB - BACKGROUND: Chicory coffee is produced from traditional raw materials. Other materials are added to improve its aroma. The aim of this study was to test new raw materials with a high content of chlorogenic acid (CGA) as the criterion for their selection. This acid is degraded in the course of roasting and is a source of phenolic compounds affecting coffee aroma. For this reason, contents of CGAs were analyzed in traditional and new materials before and after roasting and compared with the chemicals formed in the roasted pure standard of chlorogenic acid (5-CQA). RESULTS: It was shown that the novel raw materials contained considerable amounts of 5-CQA, frequently higher than in traditional chicory. The roasting process caused significant losses of 5-CQA in the tested raw materials, amounting to 55-91%. In turn, the analysis of volatile compounds in roasted materials showed the presence of certain phenolic and heterocyclic compounds that were also formed as degradation products of the pure 5-CQA chemical standard. CONCLUSION: Novel raw materials, mainly chokeberry, artichoke and lovage, are rich sources of CGAs, particularly 5-CQA. Their application in the production of chicory coffee may result in an increased content of primarily phenolic compounds in its aroma. PMID- 24338944 TI - Noncontrast enhanced four-dimensional dynamic MRA with golden angle radial acquisition and K-space weighted image contrast (KWIC) reconstruction. AB - PURPOSE: To explore the feasibility of 2D and 3D golden-angle radial acquisition strategies in conjunction with k-space weighted image contrast (KWIC) temporal filtering to achieve noncontrast enhanced dynamic MRA (dMRA) with high spatial resolution, low streaking artifacts and high temporal fidelity. METHODS: Simulations and in vivo examinations in eight normal volunteers and an arteriovenous malformation patient were carried out. Both 2D and 3D golden angle radial sequences, preceded by spin tagging, were used for dMRA of the brain. The radial dMRA data were temporally filtered using the KWIC strategy and compared with matched standard Cartesian techniques. RESULTS: The 2D and 3D dynamic MRA image series acquired with the proposed radial techniques demonstrated excellent image quality without discernible temporal blurring compared with standard Cartesian based approaches. The image quality of radial dMRA was equivalent to or higher than that of Cartesian dMRA by visual inspection. A reduction factor of up to 10 and 3 in scan time was achieved for 2D and 3D radial dMRA compared with the Cartesian-based counterparts. CONCLUSION: The proposed 2D and 3D radial dMRA techniques demonstrated image quality comparable or even superior to those obtained with standard Cartesian methods, but within a fraction of the scan time. PMID- 24338946 TI - Unfolding of beta-lactoglobulin on the surface of polystyrene nanoparticles: experimental and computational approaches. AB - Structural changes ensuing from the non-covalent absorption of bovine beta lactoglobulin (BLG) on the surface of polystyrene nanoparticles were investigated by using spectroscopic approaches, by assessing the reactivity of specific residues, and by limited proteolysis/mass spectrometry. Also, the immunoreactivity of absorbed and free BLG was compared. All these approaches indicated substantial rearrangements of the protein structure in the absorbed state, in spite of the reported structural rigidity of BLG. Changes made evident by experimental measurements were confirmed by computational approaches. These indicate that adsorption-related changes are most marked in the area between the main C-terminal alpha helix and the beta-barrel, and lead to full exposure of the thiol on Cys121 , consistent with experimental measurements. In the computational model of bound BLG, both Trp61 and Trp19 also move away from their neighboring quenchers and become solvent-exposed, as indicated by fluorescence measurement. Upon binding, the beta-barrel also loosens, with a substantial increase in immunoreactivity and with noticeable changes in the trypsinolytic pattern. The possible general significance of the structural changes reported here for non covalently adsorbed BLG is discussed with respect to recognition events involving surface-bound proteins, as are aspects related to the carrier function(s) of BLG, and to its use as a common ingredient in many food systems. PMID- 24338948 TI - An inexpensive blue filter for fluorescein-assisted repair of cerebrospinal fluid rhinorrhea. PMID- 24338947 TI - Perceived social support mediates anxiety and depressive symptom changes following primary care intervention. AB - BACKGROUND: The current study tested whether perceived social support serves as a mediator of anxiety and depressive symptom change following evidence-based anxiety treatment in the primary care setting. Gender, age, and race were tested as moderators. METHODS: Data were obtained from 1004 adult patients (age M = 43, SD = 13; 71% female; 56% White, 20% Hispanic, 12% Black) who participated in a randomized effectiveness trial (coordinated anxiety learning and management [CALM] study) comparing evidence-based intervention (cognitive-behavioral therapy and/or psychopharmacology) to usual care in the primary care setting. Patients were assessed with a battery of questionnaires at baseline, as well as at 6, 12, and 18 months following baseline. Measures utilized in the mediation analyses included the Abbreviated Medical Outcomes (MOS) Social Support Survey, the Brief Symptom Index (BSI)-Somatic and Anxiety subscales, and the Patient Health Questionnaire (PHQ-9). RESULTS: There was a mediating effect over time of perceived social support on symptom change following treatment, with stronger effects for 18-month depression than anxiety. None of the mediating pathways were moderated by gender, age, or race. CONCLUSIONS: Perceived social support may be central to anxiety and depressive symptom changes over time with evidence-based intervention in the primary care setting. These findings possibly have important implications for development of anxiety interventions. PMID- 24338949 TI - A high-energy room-temperature sodium-sulfur battery. AB - Employing small sulfur molecules as the active cathode component for room temperature Na-S batteries, reveals a novel mechanism that is verified for the batteries' electrochemistry. The sulfur cathode enables a complete two-electron reaction to form Na2 S, bringing a tripled specific capacity and an increased specific energy compared with traditional high-temperature Na-S batteries. At the same time, it offers better cycling stability endowing the batteries with a longer lifespan. PMID- 24338951 TI - Well-defined, nanometer-sized LiH cluster compounds stabilized by pyrazolate ligands. AB - The assembly of well-defined large cluster compounds of ionic light metal hydrides is a synthetic challenge and of importance for synthesis, catalysis, and hydrogen storage. The synthesis and characterization of a series of neutral and anionic pyrazolate-stabilized lithium hydride clusters with inorganic cores in the nanometer region is now reported. These complexes were prepared in a bottom up approach using alkyl lithium and lithium pyrazolate mixtures with silanes in hydrocarbon solutions. Structural characterization using synchrotron radiation revealed isolated cubic clusters that contain up to 37 Li(+) cations and 26 H(-) ions. Substituted pyrazolate ligands were found to occupy all corners and some edges for the anionic positions. PMID- 24338950 TI - Honokiol inhibits androgen receptor activity in prostate cancer cells. AB - BACKGROUND: We have shown previously that honokiol (HNK), a bioactive component of the medicinal plant Magnolia officinalis, inhibits growth of human prostate cancer cells in vitro and in vivo. However, the effect of HNK on androgen receptor (AR) signaling has not been studied. METHODS: LNCaP, C4-2, and TRAMP-C1 cells were used for various assays. Trypan blue dye exclusion assay or clonogenic assay was performed for determination of cell viability. The effects of HNK and/or its analogs on protein levels of AR and its target gene product prostate specific antigen (PSA) were determined by western blotting. RNA interference of p53 was achieved by transient transfection. Reverse transcription-polymerase chain reaction was performed for mRNA expression of AR. Nuclear level of AR was visualized by microscopy. Apoptosis was quantified by DNA fragmentation assay or flow cytometry after Annexin V-propidium iodide staining. RESULTS: HNK and its dichloroacetate analog (HDCA) were relatively more effective in suppressing cell viability and AR protein level than honokiol epoxide or biseugenol. Nuclear translocation of AR stimulated by a synthetic androgen (R1881) was markedly suppressed in the presence of HNK. Downregulation of AR protein resulting from HNK exposure was attributable to transcriptional repression as well as proteasomal degradation. HNK-mediated suppression of AR protein was maintained in LNCaP cells after knockdown of p53 protein. HNK-induced apoptosis was not affected by R1881 treatment. CONCLUSIONS: The present study demonstrates, for the first time, that HNK inhibits activity of AR in prostate cancer cells regardless of the p53 status. PMID- 24338952 TI - Capillary electrophoresis of microbial aggregates. AB - Uncontrolled aggregation of bacterial cells is a significant disadvantage of electrophoretic separations. Various aspects of the electrophoretic behavior of different strains of Gram-positive Bacillus cereus, Bacillus subtilis, Sarcina lutea, Staphylococcus aureus(1), and Micrococcus luteus bacteria and Gram negative Escherichia coli bacteria were investigated in this study. Our findings indicate that bacteria can be rapidly analyzed by CZE with surface charge modification by calcium ions (Ca(2+)). Bound Ca(2+) ions increase zeta potential to more than 2.0 mV and significantly reduce repulsive forces. Under the above conditions, bacterial cells create compact aggregates, and fewer high-intensity signals are observed in electropherograms. The above can be attributed to the bridging effect of Ca(2+) between bacterial cells. CE was performed to analyze bacterial aggregates in an isotachophoretic mode. A single peak was observed in the electropherogram. PMID- 24338953 TI - Modulable and highly diastereoselective carbometalations of cyclopropenes. AB - The copper-catalyzed carbomagnesiation reaction of cyclopropenyl esters 1 leads to various substituted cyclopropanes species 3 in good yields with very high diastereoselectivities. The reaction proceeds through a syn-chelated carbomagnesiation reaction and could be extended to various cyclopropenylmethyl ester derivatives 5. The potential of this approach was illustrated by the preparation of two consecutive all-carbon quaternary stereocenters. However, the carbometalation reaction needs to be performed at temperature ranging from -35 to -20 degrees C to avoid subsequent fragmentation reaction into stereodefined beta,gamma-nonconjugated unsaturated esters 4. Alternatively, the carbocupration reaction with organocopper species could also be performed to leads to configurationally stable cyclopropyl copper species 2[Cu]. Additionally, when the Lewis acid character of the copper center is decreased (i.e., RCuCNLi), the reaction proceed with an anti-selectivity. The diastereodivergent behavior of these organometallic species is of synthetic interest, since both diastereomers syn-3 and anti-3 can be obtained, at will, from the same precursor cyclopropenyl esters 1. PMID- 24338954 TI - Occurrence of fungicide resistance in populations of Botryotinia fuckeliana (Botrytis cinerea) on table grape and strawberry in southern Italy. AB - BACKGROUND: Botryotinia fuckeliana (Botrytis cinerea) is a pathogen with a high risk of development of resistance to fungicides. Fungicide resistance was monitored during 2008-2011 in B. fuckeliana populations from both table-grape vineyards and greenhouse-grown strawberries in southern Italy. RESULTS: Isolates showing different levels of resistance to anilinopyrimidines (APs) were detected at high frequency (up to 98%) in fields treated intensively with APs (4-7 sprays season(-1) ). A slight decrease in sensitivity to fludioxonil, always combined with AP resistance, was generally found at lower frequencies. The repeated use of fenhexamid on grapevine (3-8 sprays season(-1) ) led to a strong selection of highly resistant isolates (up to 100%). Boscalid-resistant mutants were detected at very variable frequencies (0-73%). Occurrence of resistance to quinone outside inhibitors (QoIs) was also ascertained. Multiple fungicide resistance to 2-6 different modes of action were frequently recovered. Single nucleotide polymorphisms (SNPs) in the target genes Erg27, SdhB and cytb were associated with resistance to fenehexamid, boscalid and QoIs respectively. CONCLUSION: Resistance to the fungicides commonly used against grey mould on table grape and strawberry is quite common in southern Italy. This is an outcome of the incorrect use of fungicides, often because of the maximum number of detectable residues of plant protection products imposed by big international retailers, and underlines the crucial role of antiresistance strategies in integrated pest management. PMID- 24338955 TI - Frequently Used Coping Scales: A Meta-Analysis. AB - This article reports the frequency of the use of coping scales in academic journals published from 1998 to 2010. Two thousand empirical journal articles were selected from the EBSCO database. The COPE, Ways of Coping Questionnaire, Coping Strategies Questionnaire, Coping Inventory for Stressful Situations, Religious-COPE and Coping Response Inventory were frequently mentioned. In particular, the COPE (20.2%) and Ways of Coping Questionnaire (13.6%) were used the most frequently. In this literature reviewed, coping scales were most often used to assess coping with health issues (e.g. illness, pain and medical diagnoses) over other types of stressors, and patients were the most frequent participants. Further, alpha coefficients were estimated for the COPE subscales, and correlations between the COPE subscales and coping outcomes were calculated, including depressive symptoms, anxiety, negative affect, psychological distress, physical symptoms and well-being. PMID- 24338956 TI - Pseudo-value approach for comparing survival medians for dependent data. AB - Survival median is commonly used to compare treatment groups in cancer-related research. The current literature focuses on developing tests for independent survival data. However, researchers often encounter dependent survival data such as matched pair data or clustered data. We propose a pseudo-value approach to test the equality of survival medians for both independent and dependent survival data. We investigate the type I error and power of the proposed method by a simulation study, in which we examine independent and dependent data. The simulation study shows that the proposed method performs equivalently to the existing methods for independent survival data and performs better for dependent survival data. A study comparing survival median times for bone marrow transplants illustrates the proposed method. PMID- 24338957 TI - Ethane-bridged periodic mesoporous organosilicas functionalized with high loadings of carboxylic acid groups: synthesis, bifunctionalization, and fabrication of metal nanoparticles. AB - Well-ordered periodic mesoporous organosilicas (PMOs) functionalized with high contents of carboxylic acid (?COOH) groups, up to 85 mol % based on silica, were synthesized by co-condensation of 1,2-bis(triethoxysilyl)ethane (BTEE) and carboxyethylsilanetriol sodium salt (CES) under acidic conditions by using alkyl poly(oxyethylene) surfactant Brij 76 as a structure-directing agent. A variety of techniques including powder X-ray diffraction (XRD), nitrogen adsorption/desorption, Fourier-transformed infrared (FTIR), transmission electron microscopy (TEM), (13) C- and (29) Si solid-state nuclear magnetic resonance (NMR) were used to characterize the products. The materials thus obtained were used as an effective support to synthesize metal nanoparticles (Ag and Pt) within the channel of 2D hexagonal mesostructure of PMOs. The size and distribution of the nanoparticles were observed to be highly dependent on the interaction between the carboxylic acid functionalized group and the metal precursors. The size of Pt nanoparticles reduced from 3.6 to 2.5 nm and that of Ag nanoparticles reduced from 5.3 to 3.4 nm with the increase in the ?COOH loading from 10 to 50 %. PMID- 24338958 TI - Absence of a role for interleukin-13 in inflammatory bowel disease. AB - IL-13 has been implicated in the pathogenesis of ulcerative colitis (UC), and may have a role in animal models of gut fibrosis. We studied the involvement of IL-13 in inflammation and fibrosis in UC and Crohn's disease (CD). Intestinal biopsies and anti-CD3/CD28- or anti-CD2/CD28-stimulated lamina propria mononuclear cells from UC and CD patients and control subjects were cultured, and IL-13, IL-4, IL 5, IL-17A and IFN-gamma production was measured. Mucosal IL-13-producing cells were characterised by flow cytometry. Gut explants from strictured CD, non strictured CD and healthy donors were cultured ex vivo, and secreted IL-13, IL 1beta and collagen were measured. IL-13 production by mucosal explants and activated lamina propria mononuclear cells did not differ between CD, UC and control subjects, and was at least a log lower than IFN-gamma and IL-17A. IL-13 producing cells, and in particular natural killer T cells, were uniformly low in all groups. IL-4 and IL-5 were undetectable in culture supernatants. Explants of CD strictures produced low amounts of IL-13, whereas IL-1beta and collagen were elevated. We could not confirm that UC or strictured CD are associated with elevated IL-13 production. These data suggest that an anti-IL-13 Ab would not be an appropriate therapeutic strategy in inflammatory bowel disease. PMID- 24338959 TI - Compliance with joint commission measures in state-designated stroke centers. AB - BACKGROUND: Comparison of state-designated primary and comprehensive stroke centers (PSCs and CSCs) with regard to adherence to nationally accepted performance standards are scarce. The objective of this study was to examine if a significant association exists between level of designation and fulfillment of Joint Commission (JC) stroke core measures. METHODS: A retrospective comparative data analysis of the New Jersey acute stroke registry for the calendar years 2010 and 2011 was performed. JC core measures were compared by hospital level (PSCs vs CSCs). Adjusted odds ratios (aOR) were estimated for association between hospital levels and fulfillment of JC core measures. Median door-to-thrombolytic time was also compared. RESULTS: There were 36,892 acute stroke admissions. PSCs had 60% of the patients, whereas CSCs had 40%. Hemorrhagic stroke admissions were about 2 times more frequent at CSCs than PSCs (13.3% and 7.1%, respectively). CSCs adhered better to 6 of the 8 JC measures than PSCs. Of eligible patients, 19.5% received thrombolytic therapy at CSCs compared to 9.6% at PSCs, with a 44% difference in provision of thrombolytic therapy (aOR = 0.28, 95% confidence interval: 0.24-0.34). Median door-to-thrombolytic drug times was 65 minutes at CSCs compared to 74.0 minutes at PSCs (P < 0.0001). CONCLUSIONS: New Jersey state designated CSCs are better at adhering to the JC core stroke measures and have shorter door-to-thrombolytic drug times. PMID- 24338960 TI - Combined use of warfarin and oral P2Y12 inhibitors in patients with atrial fibrillation and acute coronary syndrome. AB - BACKGROUND: Although atrial fibrillation (AF) occurs frequently in patients hospitalized with acute coronary syndrome (ACS), strategies for prevention of thromboembolic complications are poorly characterized. HYPOTHESIS: We sought to examine exposure to warfarin and P2Y12 inhibitors and clinical outcomes among patients with AF and ACS. METHODS: Patients age >65 years hospitalized with a primary diagnosis of ACS and a secondary diagnosis of AF between 2007 and 2010 were identified in the Medicare 5% sample. Medication exposure was ascertained during a 90-day period following the index discharge using Medicare drug claims. Among patients who were alive and not readmitted during the ascertainment period, we examined the cumulative incidence of all-cause mortality and all-cause readmission by medication exposure at 1 year. RESULTS: A total of 2509 Medicare beneficiaries met the inclusion criteria. Among the 1633 patients (65%) who were alive and not readmitted during the 90-day ascertainment period, 24.0% received warfarin, 38.9% received P2Y12 inhibitors, 10.2% received combination therapy, and 26.8% received neither therapy. Readmission rates were high in all groups at 1 year (warfarin, 47.5%; P2Y12 inhibitors, 46.6%; combination therapy, 38.0%; and neither therapy, 39.3%), and the overall 1-year mortality rate was 12.5%. CONCLUSIONS: Among Medicare beneficiaries with AF and ACS, combination therapy with warfarin and P2Y12 inhibitor was uncommon during the 90-day ascertainment period, and more than one-quarter of patients had no claims for warfarin or P2Y12 inhibitors. Rates of all-cause readmission and mortality within 1 year of hospitalization for ACS were high. PMID- 24338961 TI - Automatic iceball segmentation with adapted shape priors for MRI-guided cryoablation. AB - PURPOSE: To develop and evaluate an automatic segmentation method that extracts the 3D configuration of the ablation zone, the iceball, from images acquired during the freezing phase of MRI-guided cryoablation. MATERIALS AND METHODS: Intraprocedural images at 63 timepoints from 13 kidney tumor cryoablation procedures were examined retrospectively. The images were obtained using a 3 Tesla wide-bore MRI scanner and axial HASTE sequence. Initialized with semiautomatically localized cryoprobes, the iceball was segmented automatically at each timepoint using the graph cut (GC) technique with adapted shape priors. RESULTS: The average Dice Similarity Coefficients (DSC), compared with manual segmentations, were 0.88, 0.92, 0.92, 0.93, and 0.93 at 3, 6, 9, 12, and 15 min timepoints, respectively, and the average DSC of the total 63 segmentations was 0.92 +/- 0.03. The proposed method improved the accuracy significantly compared with the approach without shape prior adaptation (P = 0.026). The number of probes involved in the procedure had no apparent influence on the segmentation results using our technique. The average computation time was 20 s, which was compatible with an intraprocedural setting. CONCLUSION: Our automatic iceball segmentation method demonstrated high accuracy and robustness for practical use in monitoring the progress of MRI-guided cryoablation. PMID- 24338962 TI - Direct analysis of sterols by derivatization matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and tandem mass spectrometry. AB - RATIONALE: Free sterols are neutral molecules that are difficult to analyze by MALDI or ESI and their molecular ions easily fragment. In order to increase their ionization efficiency and selectivity, sterols were derivatized by different reagents. METHODS: Selected sterols were converted into their corresponding picolinyl esters, N-methylpyridyl ethers and sulphated esters. The derivatives were optimized for MALDI-TOFMS analysis through proper selection of the matrix. MALDI-TOF/TOF experiments were carried out to study the fragmentation pathways of the derivatives and their use in structural elucidation. Lipid extracts from mussels were used as test samples for MALDI analysis of sterols in biological samples also analyzed by GC/MS for comparison. RESULTS: Sterol picolinyl esters were identified as sodiated adducts [M+Na](+) and the signal significantly enhanced after addition of sodium acetate (20 mM). Sterol N-methylpyridyl ethers were easily detected as [M](+) while sulphated sterols were best detected as [M H](-). The ester bonds of picolinyl and sulphated esters easily cleaved in MS/MS resulting in diagnostic derivative fragments at m/z 146.03 and 96.89, respectively. Cleavage of the ether bond of N-methylpyridyl ethers gave a diagnostic fragment ion at m/z 110.04. Sterol profiles in mussels obtained by MALDI-TOFMS were in close agreement with those obtained by GC/MS. Two sterols (cholesterol and beta-sitosterol) were selected for quantification as their sulphated and picolinyl esters. Calibration curves gave excellent correlation coefficients. CONCLUSIONS: Suitable matrices for picolinyl esters are DHB and THAP, for N-methylpyridyl ethers THAP, and for sulphated esters p-nitroaniline and dithranol. Using cholesterol, the limits of detection (LODs) for sulphated esters were 0.2 ug/mL and for picolinyl esters, 1.5 ug/mL. N-Methylpyridyl ethers were found unsuitable for sterol quantitation. PMID- 24338963 TI - Arsenic speciation in water by high-performance liquid chromatography/inductively coupled plasma mass spectrometry-method validation and uncertainty estimation. AB - RATIONALE: In order to obtain reliable analytical results for the separation and determination of arsenic species by high-performance liquid chromatography/inductively coupled plasma mass spectrometry (HPLC/ICP-MS), the analytical procedure must be fully validated and the measurement uncertainty of the analytical result should be estimated. METHODS: The total arsenic concentration of the samples was determined by ICP-MS. Separation of the arsenic species, AsB, As(III), DMA, MMA and As(V), was accomplished by liquid chromatography, which was hyphenated to inductively coupled plasma mass spectrometry, used for detection purposes. Automated handling of these systems was achieved with Chromera software. RESULTS: The separation capability between the analytical signals of arsenic species, AsB-As(III), As(III)-DMA, DMA-MMA and MMA-As(V), was 1.3, 1.1, 5.1 and 4.6, respectively. The limit of detection (LOD) values ranged from 0.070 ug L(-1) for DMA to 0.13 ug L(-1) for MMA. The expanded uncertainty U [%] values for coverage factor k = 2 estimated for AsB, As(III), DMA, MMA and As(V) were 12 %, 13 %, 5.6 %, 9.6 % and 8.6 %, respectively. CONCLUSIONS: This study reports, for the first time, building the uncertainty budgets for five arsenic species and estimation of the expanded uncertainty (for k = 2). The qualitative and quantitative parameters determined in the validation process indicate that the presented analytical procedure can be applied for the determination of AsB, As(III), DMA, MMA and As(V) in water. PMID- 24338964 TI - High-energy collision-induced dissociation tandem mass spectrometry of regioisomeric lactose palmitic acid monoesters using matrix-assisted laser desorption/ionization. AB - RATIONALE: Structural characterization and differentiation of three newly synthesized lactose monopalmitate regioisomers at positions O-3, O-3' and O-6' were realized by single-stage matrix-assisted laser desorption/ionization time-of flight/time-of-flight mass spectrometry (MALDI-TOF/TOF-MS) in the positive ion mode and by high-energy collision-induced dissociation tandem mass spectrometry (CID-MS/MS). METHODS: A MALDI-TOF/TOF analyzer was utilized for the analysis of these isobaric lactose monopalmitate regioisomers. The CID-MS/MS spectra were acquired using high-energy cid with a 2 kV potential difference between the source acceleration voltage and the collision cell. RESULTS: High-energy (CID) tandem mass spectrometry (MS/MS) analyses of the sodiated molecules, [M + Na](+), showed distinguishing cross-ring product ions and characteristic fingerprint product ions, which allowed the straight-forward mass spectrometric characterization of these different regiosiomers. CONCLUSIONS: This investigation allowed us to unravel the novel fragmentation behavior of the sodiated regioisoimer molecules obtained from the mono-substituted D-lactose fatty acid esters using high-energy CID-TOF/TOF-MS/MS analyses. The high-energy CID of the [M + Na](+) ions from the isobaric lactose monopalmitate regioiosmers promoted the formation of characteristic (0,2) A2 cross-ring cleavage product ions. PMID- 24338965 TI - Insulin, islet amyloid polypeptide and C-peptide interactions evaluated by mass spectrometric analysis. AB - RATIONALE: Insulin, islet amyloid polypeptide (IAPP), and the C-peptide part of proinsulin are co-secreted from the pancreatic beta cell granules. IAPP aggregation can be inhibited by insulin and insulin aggregation by C-peptide, but different binding and disaggregating interactions may apply for the peptide complexes. A more detailed knowledge of these interactions is necessary for the development strategies against diabetic complications that stem from peptide aggregations. METHODS: Mass spectrometry (MS) is utilized to investigate pH dependencies, sequence determinants and association strengths of interactions between pairs of all three peptides. Electrospray ionization (ESI)-MS was used to monitor complex formation and interaction stoichiometries at different pH values. Collision-induced dissociation (CID) was employed to probe relative association strengths and complex dissociation pathways. RESULTS: IAPP, like C-peptide, removes insulin oligomers observable by ESI-MS. Both C-peptide and IAPP form stable 1:1 heterodimers with insulin. Complexes of the negatively charged C peptide with the positively charged IAPP, on the other hand, are easily dissociated. Replacement of the conserved glutamic acid residues in C-peptide with alanine residues increases the stability, indicating that net charge alone does not predict association strength. Binding to insulin has been suggested to stabilize a helical fold in IAPP via charge and hydrophobic interactions, which is in agreement with the now observed high gas-phase stability and sensitivity to low pH. CONCLUSIONS: Combined, these results suggest that the C-peptide-insulin and IAPP-insulin interactions are mediated by a defined binding site, while such a feature is not apparent in the IAPP-C-peptide association. Hence, IAPP and C peptide are interacting in similar manners and with similar monomerizing effects on insulin, suggesting that both peptides can prevent insulin aggregation. Simultaneous interactions of all three peptides cannot be excluded but appear unlikely from the uneven pairwise binding strengths. PMID- 24338966 TI - Whole-body tissue distribution study of drugs in neonate mice using desorption electrospray ionization mass spectrometry imaging. AB - RATIONALE: Although Desorption Electrospray Ionization (DESI) Mass Spectrometry Imaging (MSI) is uniquely suited for whole-body (WB) tissue distribution study of drugs, success in this area has been difficult. Here, we present WB tissue distribution studies using DESI-MSI and a new histological tissue-friendly solvent system. METHODS: Neonate pups were dosed subcutaneously (SC) with clozapine, compound 1, compound 2, or compound 3. Following euthanization by hypothermia, neonates underwent a transcardiac perfusion (saline) to remove blood. After cryosectioning, DESI-MSI was conducted for the WB tissue slides, followed sequentially by histological staining. RESULTS: Whole-body tissue imaging showed that clozapine and its N-oxide metabolite were distributed in significant amounts in the brain, spinal cord, liver, heart (ventricle), and lungs. Compound 1 was distributed mainly in the liver and muscle, and its mono oxygenated metabolite was detected by DESI-MSI exclusively in the liver. Compound 2 was distributed mainly in the muscle and fatty tissue. Compound 3 was distributed mainly in fatty tissue and its metabolites were also mainly detected in the same tissue. CONCLUSIONS: The results demonstrate the successful application of DESI-MSI in whole-body tissue distribution studies of drugs and metabolites in combination with sequential histology staining for anatomy. The results also identified lipophilicity as the driving force in the tissue distribution of the three Amgen compounds. PMID- 24338967 TI - Discrimination of large maltooligosaccharides from isobaric dextran and pullulan using ion mobility mass spectrometry. AB - RATIONALE: Ion mobility mass spectrometry (IMMS) has previously been shown to resolve small isobaric oligosaccharides, but larger alpha-oligoglucans are also abundant in biology and are of industrial importance. If conformational differences between such isomers are retained in the gas phase, IMMS could be used to address questions in biology and industry. METHODS: Negative mode electrospray ionization (ESI) travelling-wave IMMS was used to resolve large isobaric alpha-glucan ions on the basis of their different gas-phase conformations. alpha,omega-Dicarboxy-terminated polystyrene was used to calibrate the instrument allowing the collision cross-sections (CCSs) of ions to be determined. RESULTS: alpha-1,4-Linked maltooligosaccharides with a degree of polymerisation of up to 35 could be discriminated from alpha-1,6-linked dextran and alpha-1,4/1,6-linked pullulan using IMMS. Fragmentation spectra of ions separated by IMMS could also distinguish isomers. Two conformational isomers of maltohexaose were resolvable by IMMS, likely reflecting extended and V6 helical conformations. IMMS was also able to identify a product within a mixture of maltooligosaccharides treated with the potential anti-tuberculosis drug target Mycobacterium tuberculosis GlgB branching enzyme. CONCLUSIONS: Biological samples of complex isobaric oligosaccharides can be analysed using IMMS in the negative mode providing facile analyses and high sensitivity without the need for either derivatisation or chromatographic separation. PMID- 24338968 TI - Large-volume injection combined with gas chromatography/isotope ratio mass spectrometry for the analysis of polycyclic aromatic hydrocarbons. AB - RATIONALE: Compound-specific stable isotope analyses of carbon require relatively large amounts of sample for reliable analyses. Commonly applied injections of 1 MUL may thus be insufficient for samples with low concentrations of pollutants (e.g. air particulate matter) or when the amount of a sample is limited. METHODS: A Large-Volume Injection (LVI) method for carbon stable isotope ratio analysis of Polycyclic Aromatic Hydrocarbons (PAHs) was optimized in this study. Gas chromatography/combustion/isotope ratio mass spectrometry (GCCIRMS) and ion trap mass spectrometry (ITMS) were used for the determination of stable carbon isotope ratios and quantification of compounds, respectively. RESULTS: The optimized method resulted in very good reproducibility, even for the most volatile PAH, naphthalene, when a small amount of higher boiling co-solvent was used. No significant fractionation of isotope ratios could be seen and the recoveries of analytes were similar to or better than that of a splitless cold injection. CONCLUSIONS: Injection of 100 MUL, instead of the commonly used 1 MUL, increases the detection limit for PAHs significantly and/or simplifies the sample preparation step. Using our optimized method, stable carbon isotope ratios can be reliably measured in samples with concentrations of PAHs down to 0.05-0.1 ng MUL( 1). PMID- 24338969 TI - A high dynamic range pulse counting detection system for mass spectrometry. AB - RATIONALE: A high dynamic range pulse counting system has been developed that demonstrates an ability to operate at up to 2e8 counts per second (cps) on a triple quadrupole mass spectrometer. Previous pulse counting detection systems have typically been limited to about 1e7 cps at the upper end of the systems dynamic range. Modifications to the detection electronics and dead time correction algorithm are described in this paper. METHODS: A high gain transimpedance amplifier is employed that allows a multi-channel electron multiplier to be operated at a significantly lower bias potential than in previous pulse counting systems. The system utilises a high-energy conversion dynode, a multi-channel electron multiplier, a high gain transimpedance amplifier, non-paralysing detection electronics and a modified dead time correction algorithm. Modification of the dead time correction algorithm is necessary due to a characteristic of the pulse counting electronics. RESULTS: A pulse counting detection system with the capability to count at ion arrival rates of up to 2e8 cps is described. This is shown to provide a linear dynamic range of nearly five orders of magnitude for a sample of aprazolam with concentrations ranging from 0.0006970 ng/mL to 3333 ng/mL while monitoring the m/z 309.1 -> m/z 205.2 transition. This represents an upward extension of the detector's linear dynamic range of about two orders of magnitude. CONCLUSIONS: A new high dynamic range pulse counting system has been developed demonstrating the ability to operate at up to 2e8 cps on a triple quadrupole mass spectrometer. This provides an upward extension of the detector's linear dynamic range by about two orders of magnitude over previous pulse counting systems. PMID- 24338970 TI - Sensitive hydrophilic interaction liquid chromatography/tandem mass spectrometry method for rapid detection, quantification and confirmation of cathinone-derived designer drugs for doping control in equine plasma. AB - RATIONALE: Cathinone derivatives are new amphetamine-like stimulants that can evade detection when presently available methods are used for doping control. To prevent misuse of these banned substances in racehorses, development of a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method became the impetus for undertaking this study. METHODS: Analytes were recovered via liquid-liquid extraction using methyl tert-butyl ether. Analyte separation was achieved on a hydrophilic interaction column using liquid chromatography and mass analysis was performed on a QTRAP mass spectrometer in positive electrospray ionization (ESI) mode with multiple reaction monitoring (MRM). Analyte identification was carried out by screening for a specified MRM transition. Quantification was conducted using an internal standard. Confirmation was performed by establishing a match in retention time and ion intensity ratios comparison. RESULTS: The method was linear over the range 0.2-50 ng/mL. The specificity was evaluated by analysis of six different batches of blank plasma and those spiked with each analyte (0.2 ng/mL). The recovery of analytes from plasma at three different concentrations was >70%. The limits of detection, quantification and confirmation were 0.02 0.05, 0.2-1.0 and 0.2-10 ng/mL, respectively. The matrix effect was insignificant. The intra-day and inter-day precision were 1.94-12.08 and 2.58 13.32%, respectively. CONCLUSIONS: The method is routinely employed in screening for the eleven analytes in post-competition samples collected from racehorses in Pennsylvania to enforce the ban on the use of these performance-enhancing agents in racehorses. The method is sensitive, fast, effective and reliably reproducible. PMID- 24338971 TI - Efficient injection of low-mass ions into high magnetic field Fourier transform ion cyclotron resonance mass spectrometers. AB - RATIONALE: Low-mass cut-off restrictions for injecting ions from external ion sources into high magnetic fields impose limitations for wide mass range analyses with Fourier transform ion cyclotron resonance (FTICR) instruments. Radio frequency (RF)-only quadrupole ion guides (QIGs) with higher frequencies can be used to overcome low-mass cut-off in FTICR instruments. METHODS: RF signals (1.0 MHz to 10.0 MHz) were applied to QIGs to transfer externally generated ions from either electron ionization (EI) or electrospray ionization (ESI) sources into ICR cells of 9.4 T FTICR mass spectrometers. Efficiencies of QIGs were evaluated using externally generated ions from: EI of acetone, air, and perfluorotributylamine mixture, EI of gas chromatography (GC)-separated components of a standard sample mixture, and ESI of complex mixtures such as petroleum and fulvic acid samples. RESULTS: We were able to transfer ions with m/z as low as 26 from an external EI source into the ICR cell of a 9.4 T FTICR mass spectrometer and extend the operational low-mass range for ESI-FTICR analyses. High mass resolving power and mass measurement accuracy of GC/FTICR mass spectrometry were utilized to discriminate between oxygenated and non oxygenated compounds in a 'Grob' sample. Ion losses based on SIMION ion trajectory predictions were consistent with experimental findings. CONCLUSIONS: We demonstrated that the use of high-frequency QIGs can extend the operational lower m/z range for both external EI- and ESI-FTICR mass spectrometers. By considering both ICR and Mathieu equations of motions to describe ion trajectories, theoretical ion ejection thresholds (consistent with our experimental findings) could be predicted. PMID- 24338972 TI - Near-equilibrium chemical vapor deposition of high-quality single-crystal graphene directly on various dielectric substrates. AB - By using near-equilibrium chemical vapor deposition, it is demonstrated that high quality single-crystal graphene can be grown on dielectric substrates. The maximum size is about 11 MUm. The carrier mobility can reach about 5650 cm(2) V( 1) s(-1) , which is comparable to those of some metal-catalyzed graphene crystals, reflecting the good quality of the graphene lattice. PMID- 24338974 TI - Characterization and optimization of glycerol/sebacate ratio in poly(glycerol sebacate) elastomer for cell culture application. AB - Poly(glycerol-sebacate) (PGS) is an elastomeric biodegradable polyester. Our previous series of studies have showed that PGS has good biocompatibility. In view of the potential use of PGS in bioengineering, we attempt to characterize the PGS polymer with different ratio of glycerol and sebacic acid, and the cell adhesion and growth on these polymers. PGSs with different proportion of glycerol and sebacic acid were synthesized by polycondensation reaction. The microstructure of the series PGSs were characterized by infrared spectroscopy and X-ray diffraction analysis (XRD). Results showed that, with the increase of the ratio of sebacic acid in PGS from 1:0.8, 1:1, to 1:1.2 (ratio of glycerol to sebacic acid), the main diffraction peak in XRD, the sol content and gel swelling increased but then decreased, suggesting that the degree of crosslinking and the inherent degree of order of the series PGS increased and then decreased. With the increase of sebacic acid proportion, water absorption increased and then decreased, and the water absorption ranged from 9.62% to 10.66%. The mass loss of the series of samples in degradation experiments ranged from 24.63% to 40.06% on the 32nd day of degradation. Cell culture data suggested that the polymer with the ratio of 1:0.8 for glycerol and sebacate was suitable for cell adhesion and growth. In conclusion, PGS can be used as the cell culture matrix by modifying the composition ratio of glycerol and sebacic acid to improve the properties of cell adhesion and growth. PMID- 24338975 TI - Discovery of multiple interacting partners of gankyrin, a proteasomal chaperone and an oncoprotein--evidence for a common hot spot site at the interface and its functional relevance. AB - Gankyrin, a non-ATPase component of the proteasome and a chaperone of proteasome assembly, is also an oncoprotein. Gankyrin regulates a variety of oncogenic signaling pathways in cancer cells and accelerates degradation of tumor suppressor proteins p53 and Rb. Therefore gankyrin may be a unique hub integrating signaling networks with the degradation pathway. To identify new interactions that may be crucial in consolidating its role as an oncogenic hub, crystal structure of gankyrin-proteasome ATPase complex was used to predict novel interacting partners. EEVD, a four amino acid linear sequence seems a hot spot site at this interface. By searching for EEVD in exposed regions of human proteins in PDB database, we predicted 34 novel interactions. Eight proteins were tested and seven of them were found to interact with gankyrin. Affinity of four interactions is high enough for endogenous detection. Others require gankyrin overexpression in HEK 293 cells or occur endogenously in breast cancer cell line- MDA-MB-435, reflecting lower affinity or presence of a deregulated network. Mutagenesis and peptide inhibition confirm that EEVD is the common hot spot site at these interfaces and therefore a potential polypharmacological drug target. In MDA-MB-231 cells in which the endogenous CLIC1 is silenced, trans-expression of Wt protein (CLIC1_EEVD) and not the hot spot site mutant (CLIC1_AAVA) resulted in significant rescue of the migratory potential. Our approach can be extended to identify novel functionally relevant protein-protein interactions, in expansion of oncogenic networks and in identifying potential therapeutic targets. PMID- 24338976 TI - Chemical composition and bioactivity of dried fruits and honey of Ficus carica cultivars Dottato, San Francesco and Citrullara. AB - BACKGROUND: The aim of this study is to evaluate, for the first time, the chemical profile, antioxidant properties and cholinesterase inhibitory activity of dried fruits and honey of Ficus carica (fig) cultivars Dottato, Citrullara, and San Francesco. RESULTS: Gas chromatography-mass spectrometry (GC-MS) analysis of fig extracts identified terpenes, sterols and fatty acids as major constituents. The aroma profile of honey obtained from a mixture of the three cultivars was investigated by solid-phase micro-extraction/GC-MS. 5 (Hydroxymethyl)-2-furancarboxaldehyde, 2,3-dihydro-3,5-dihydroxy-6-methyl-4H pyran-4-one and 1,3-dihydroxy-2-propanone were the main compounds. Total phenol, flavonoid and anthocyanin content are also reported. The San Francesco cultivar is characterised by the highest phenol and flavonoid content, while Dottato showed the major anthocyanin content. The Dottato cultivar exhibited the best radical scavenging activity against both 2,2'-azinobis-(3-ethylbenzothiazoline-6 sulfonic acid) and 2,2-diphenyl-1-picrylhydrazyl radicals (IC50 values of 5.4 and 22.6 ug mL(-1) , respectively). This cultivar also showed the highest inhibitory activity against both acetylcholinesterase and butyrylcholinesterase, with IC50 values of 26.9 and 31.8 ug mL(-1) , respectively. CONCLUSION: Dried figs are a convenient source of bioactive compounds that demonstrated potential neuroprotection and antioxidant effects. Therefore, the addition of figs to the human diet should be recommended by dieticians and nutritionists. PMID- 24338977 TI - Vital staining of the stick insect digestive system identifies appendices of the midgut as novel system of excretion. AB - The stick insects or phasmids (Phamsatodea) have a series of pyriform ampulles with long, thin filaments on the posterior end of their midgut referred to as the "appendices of the midgut." Found only in phasmids, their function had never been determined until now. Their similarity to the Malpighian tubules, which are ubiquitous insect organs of excretion, suggested a similar function. To differentiate between the appendices and the Malpighian tubules and compare functional differences between the two tissue types, vital staining (the injection of histological stains into living organisms) was done in conjunction with light and scanning electron microscopy in multiple phasmid species. The results showed that the appendices originated in the basal phasmids (Timematidae) and grew more numerous in derived species. The appendices stain selectively, notably failing to pick up the indicators of the two known systems of invertebrate excretory function, indigo carmine and ammonium carmine. Appendices sequester stains in the ampule portion before eliminating the compounds into the midgut. We conclude by confirming that the appendices do have an excretory function, but one unlike any other known in invertebrates. Their function is likely cation excretion, playing a role in calcium regulation and/or organic alkaloid sequestration. The appendices must thus be considered distinct organs from the Malpighian tubules. PMID- 24338978 TI - Influence analysis on crossover design experiment in bioequivalence studies. AB - Crossover designs are commonly used in bioequivalence studies. However, the results can be affected by some outlying observations, which may lead to the wrong decision on bioequivalence. Therefore, it is essential to investigate the influence of aberrant observations. Chow and Tse in 1990 discussed this issue by considering the methods based on the likelihood distance and estimates distance. Perturbation theory provides a useful tool for the sensitivity analysis on statistical models. Hence, in this paper, we develop the influence functions via the perturbation scheme proposed by Hampel as an alternative approach on the influence analysis for a crossover design experiment. Moreover, the comparisons between the proposed approach and the method proposed by Chow and Tse are investigated. Two real data examples are provided to illustrate the results of these approaches. Our proposed influence functions show excellent performance on the identification of outlier/influential observations and are suitable for use with small sample size crossover designs commonly used in bioequivalence studies. PMID- 24338979 TI - Mechanisms of larval midgut damage following exposure to phoxim and repair of phoxim-induced damage by cerium in Bombyx mori. AB - Bombyx mori is an important economic animal for silk production. However, it is liable to be infected by organophosphorus pesticide that can contaminate its food and growing environment. It has been known that organophosphorus pesticide including phoxim exposure may damage the digestive systems, produce oxidative stress and neurotoxicity in silkworm B. mori, whereas cerium treatment has been demonstrated to relieve phoxim-induced toxicity in B. mori. However, very little is known about the molecular mechanisms of midgut injury due to phoxim exposure and B. mori protection after cerium pretreatment. The aim of this study was to evaluate the midgut damage and its molecular mechanisms, and the protective role of cerium in B. mori following exposure to phoxim. The results showed that phoxim exposure led to severe midgut damages and oxidative stress; whereas cerium relieved midgut damage and oxidative stress caused by phoxim in B. mori. Furthermore, digital gene expression suggested that phoxim exposure led to significant up-regulation of 94 genes and down-regulation of 52 genes. Of these genes, 52 genes were related with digestion and absorption, specifically, the significant alterations of esterase, lysozyme, amylase 48, and lipase expressions. Cerium pretreatment resulted in up-regulation of 116 genes, and down regulation of 29 genes, importantly, esterase 48, lipase, lysozyme, and alpha amylase were up-regulated. Treatment with Phoxim + CeCl3 resulted in 66 genes up regulation and 39 genes down-regulation; specifically, levels of esterase 48, lipase, lysozyme, and alpha-amylase expression in the midgut of silkworms were significantly increased. Therefore, esterase 48, lipase, lysozyme, and alpha amylase may be potential biomarkers of midgut toxicity caused by phoxim exposure. These findings may expand the application of rare earths in sericulture. PMID- 24338980 TI - An unusual example of hypervalent silicon: a five-coordinate silyl group bridging two palladium or nickel centers through a nonsymmetrical four-center two-electron bond. AB - Pd and Ni dimers supported by PSiP ligands in which two hypervalent five coordinate Si atoms bridge the two metal centers are reported. Crystallographic characterization revealed a rare square-pyramidal geometry at Si and an unusual asymmetric M2 Si2 core (M=Pd or Ni). DFT calculations showed that the unusual structure of the core is also found in a model in which the phosphine and Si centers are not part of a pincer group, thus indicating that the observed geometry is not imposed by the PSiP ligand. NBO analysis showed that an asymmetric four-center two-electron (4c-2e) bond stabilizes the hypervalent Si atoms in the M2 Si2 core. PMID- 24338981 TI - Tailoring the molecular structure to suppress extrinsic disorder in organic transistors. AB - In organic field-effect transistors, the structure of the constituent molecules can be tailored to minimize the disorder experienced by charge carriers. Experiments on two perylene derivatives show that disorder can be suppressed by attaching longer core substituents - thereby reducing potential fluctuations in the transistor channel and increasing the mobility in the activated regime - without altering the intrinsic transport properties. PMID- 24338982 TI - Medical management of chronic rhinosinusitis in cystic fibrosis: a systematic review. AB - OBJECTIVES/HYPOTHESIS: To systematically review existing literature on the effectiveness of medical management of chronic rhinosinusitis (CRS) in cystic fibrosis (CF) patients. STUDY DESIGN: Systematic review. METHODS: We performed a literature search of PubMed, Embase, and Cochrane CENTRAL from 1987 to 2012. Inclusion criteria included English language as containing original data, with five or more subjects, measurable clinical outcomes, and readily available interventions. Data were systematically collected on study design, patient demographics, clinical characteristics and outcomes, and level of evidence. Two investigators independently reviewed all manuscripts and performed a comprehensive quality assessment. RESULTS: Of 415 abstracts identified, 12 articles were included. These 12 studies reported on 701 adult and pediatric CF patients who underwent medical therapy. Medical treatment included antibiotics (4/12), topical steroids (4/12), dornase alfa (3/12), and ibuprofen (1/12). Outcome measures included symptom scores (7/12), endoscopic findings (7/12), radiographic findings (4/12), pulmonary function testing (4/12), and rhinomanometry (2/12). Most studies found improvement in at least one of the outcome measures. There was statistical significance in clinical outcomes with dornase alfa, beclomethasone, and betamethasone. Most studies were level 3 or 4 evidence (9/12), but three studies were level 1 or 2 evidence (two dornase alfa studies, one betamethasone study). CONCLUSIONS: Dornase alfa and, to a lesser extent, topical steroids demonstrated significant benefits in the medical treatment CRS in CF. There was a lack of evidence to support antibiotic therapy in the outcomes assessed. Further high-quality studies should be carried out to determine the efficacy of various medical therapies for CRS in CF. LEVEL OF EVIDENCE: NA. PMID- 24338983 TI - Functional polymorphism in the brain-derived neurotrophic factor gene interacts with stressful life events but not childhood maltreatment in the etiology of depression. AB - BACKGROUND: We test the hypothesis that the functional Val66Met polymorphism of BDNF interacts with recent life events to produce onset of new depressive episodes. We also explore the possibility that the Met allele of this polymorphism interacts with childhood maltreatment to increase the risk of chronic depression. METHODS: In a risk-enriched combined sample of unrelated women, childhood maltreatment and current life events were measured with the Childhood Experience of Care and Abuse, and Life Events and Difficulties Schedule interviews. Chronic episodes of depression (12 months or longer) during adulthood and onset of a major depressive episode during a 12-month follow-up were established with the Schedules for Clinical Assessment in Neuropsychiatry interview. RESULTS: Met alleles of BDNF moderated the relationship between recent life events and adult onsets of depression in a significant gene-environment interaction (interaction risk difference 0.216, 95% CI 0.090-0.342; P =.0008). BDNF did not significantly influence the effect of childhood maltreatment on chronic depression in the present sample. CONCLUSIONS: The Met allele of BDNF increases the risk of a new depressive episode following a severe life event. The BDNF and the serotonin transporter gene length polymorphism (5-HTTLPR) and BDNF may contribute to depression through distinct mechanisms involving interactions with childhood and adulthood adversity respectively, which may, in combination, be responsible for a substantial proportion of depression burden in the general population. PMID- 24338984 TI - Electrophoretic mobilities of neutral analytes and electroosmotic flow markers in aqueous solutions of Hofmeister salts. AB - Small neutral organic compounds have traditionally the role of EOF markers in electrophoresis, as they are expected to have zero electrophoretic mobility in external electric fields. The BGE contains, however, ions that have unequal affinities to the neutral molecules, which in turn results in their mobilization. In this study we focused on two EOF markers-thiourea and DMSO, as well as on N methyl acetamide (NMA) as a model of the peptide bond. By means of CE and all atom molecular dynamics simulations we explored mobilization of these neutral compounds in large set of Hofmeister salts. Employing a statistical mechanics approach, we were able to reproduce by simulations the experimental electrophoretic mobility coefficients. We also established the role of the chemical composition of marker and the BGE on the measured electrophoretic mobility coefficient. For NMA, we interpreted the results in terms of the relative affinities of cations versus anions to the peptide bond. PMID- 24338985 TI - Grape seed proanthocyanidin extract improves the hepatic glutathione metabolism in obese Zucker rats. AB - SCOPE: Increased oxidative stress may play an important role in metabolic syndrome and related manifestations, including obesity, atherosclerosis, hypertension, and insulin resistance. Its relation to obesity is due to increased reactive oxygen species and/or decreased glutathione (GSH) antioxidant metabolism. Consequently, the activation of glutathione metabolism appears to be a central defense response to prevent oxidative stress. In this sense, dietary supplements with natural antioxidant molecules, including proanthocyanidins, may present a useful strategy of controlling and reducing complications of obesity, including hepatic steatosis. MATERIALS AND RESULTS: We assessed the grape seed proanthocyanidin extract (GSPE) effect on oxidative alterations related to genetically obese rats (Zucker rats) and, more specifically, to hepatic GSH metabolism. We demonstrate that the administration of GSPE reduced the oxidized glutathione accumulation increasing the total GSH/oxidized glutathione hepatic ratio and consequently decreasing the activation of antioxidant enzymes, including glutathione peroxidase, glutathione reductase, and glutathione S transferase, and increasing the total antioxidant capacity of the cell. CONCLUSION: In Zucker rats, the obesity-induced oxidative stress related to liver glutathione alteration was mitigated by GSPE administration. PMID- 24338987 TI - Self-assembly of a highly organized, hexameric supramolecular architecture: formation, structure and properties. AB - Two derivatives, (3)L and (9)L, of a ditopic, multiply hydrogen-bonding molecule, known for more than a decade, have been found, in the solid state as well as in solvents of low polarity at room temperature, to exist not as monomers, but to undergo a remarkable self-assembly into a complex supramolecular species. The solid-state molecular structure of (3)L, determined by single-crystal X-ray crystallography, revealed that it forms a highly organized hexameric entity (3)L6 with a capsular shape, resulting from the interlocking of two sets of three monomolecular components, linked through hydrogen-bonding interactions. The complicated (1)H NMR spectra observed in o-dichlorobenzene (o-DCB) for (3)L and (9)L are consistent with the presence of a hexamer of D3 symmetry in both cases. DOSY measurements confirm the hexameric constitution in solution. In contrast, in a hydrogen-bond-disrupting solvent, such as DMSO, the (1)H NMR spectra are very simple and consistent with the presence of isolated monomers only. Extensive temperature-dependent (1)H NMR studies in o-DCB showed that the L6 species dissociated progressively into the monomeric unit on increasing th temperature, up to complete dissociation at about 90 degrees C. The coexistence of the hexamer and the monomer indicated that exchange was slow on the NMR timescale. Remarkably, no species other than hexamer and monomer were detected in the equilibrating mixtures. The relative amounts of each entity showed a reversible sigmoidal variation with temperature, indicating that the assembly proceeded with positive cooperativity. A full thermodynamic analysis has been applied to the data. PMID- 24338986 TI - Comparison of abiraterone acetate versus ketoconazole in patients with metastatic castration resistant prostate cancer refractory to docetaxel. AB - BACKGROUND: Abiraterone, a potent CYP 17 inhibitor, is standard treatment in docetaxel refractory, metastatic castrate resistant prostate cancer (mCRPC). However, in countries where abiraterone has not been approved yet, or for patients who cannot afford it, ketoconazole is used as an alternative CYP 17 inhibitor. Although preclinical data suggests that ketoconazole is a less potent inhibitor of CYP 17, there are limited clinical data comparing both agents. We aimed to compare the clinical effectiveness of abiraterone versus ketoconazole in docetaxel refractory mCRPC. METHODS: Records from mCRPC patients treated with ketoconazole (international multicenter database, n = 162) were reviewed retrospectively. Twenty-six patients treated post docetaxel were individually matched by clinicopathologic factors to patients treated with abiraterone (national multicenter database, n = 140). We compared the PSA response, biochemical and radiological progression free survival (PFS), and overall survival (OS) between the groups. PFS and OS were determined by Cox regression. RESULTS: The groups were matched by Gleason score, pre-treatment disease extent, ECOG PS, pre-treatment risk category (Keizman, Oncologist 2012). Furthermore, they were balanced regarding other known confounding risk factors. In the groups of abiraterone versus ketoconazole, PSA response was 46% versus 19% (OR 4.3, P = 0.04), median biochemical PFS 7 versus 2 months (HR 1.54, P = 0.02), median radiological PFS 8 versus 2.5 months (HR 1.8, P = 0.043), median OS 19 versus 11 months (HR 0.53, P = 0.79), and treatment interruption d/t severe adverse events 8% (n = 2) versus 31% (n = 8) (0R 0.6, P = 0.023). CONCLUSIONS: In docetaxel refractory mCRPC, the outcome of abiraterone treatment may be superior to ketoconazole. PMID- 24338988 TI - Investigation of the structure and dynamics of the capsid-spacer peptide 1 nucleocapsid fragment of the HIV-1 gag polyprotein by solution NMR spectroscopy. AB - Structural studies of HIV-1 Gag, the primary structural polyprotein involved in retroviral assembly, have been challenging, owing to its flexibility and conformational heterogeneity. Using residual dipolar couplings, we show that the four structural units of the capsid (CA)-spacer peptide 1 (SP1)-nucleocapsid (NC) fragment of HIV-1 Gag (namely, the N- and C-terminal domains of capsid, and the N and C-terminal Zn knuckles of nucleocapsid) have the same structures as their individually isolated counterparts, and tumble semi-independently of one another in the absence of nucleic acids. Nucleic acids bind exclusively to the nucleocapsid domain and fix the orientation of the two Zn knuckles relative to one another so that the nucleocapsid domain/nucleic acid complex behaves as a single structural unit. The low (15) N-{(1) H} heteronuclear NOE values (<=0.4), the close to zero values for the residual dipolar couplings of the backbone amides, and minimal deviations from random-coil chemical shifts for the C terminal tail of capsid and SP1, both in the absence and presence of nucleic acids, indicate that these regions are intrinsically disordered in the context of CA-SP1-NC. PMID- 24338989 TI - Enantioselective aziridination of cyclic enals facilitated by the fluorine iminium ion gauche effect. AB - The enantioselective, organocatalytic aziridination of small, medium and macro cyclic enals is reported using (S)-2-(fluorodiphenyl methyl)-pyrrolidine. Central to the reaction design is the reversible formation of a beta-fluoroiminium ion intermediate, which is pre-organised on account of the fluorine-iminium ion gauche effect. This conformational effect positions the fluorine substituent synclinal-endo to the electropositive nitrogen centre thus benefiting from favourable stereoelectronic and electrostatic interactions (sigmaC-H ->sigmaC-F *; F(delta-...?) N(+) ). Consequently, one of the shielding groups on the fluorine-bearing carbon atom is positioned above the pi-system, forming the basis of an enantioinduction strategy. Treatment of this intermediate with a "nitrene" source furnished a series of novel, optically active aziridines (e.r. up to 99.5:0.5). Further derivatisation of the product aziridines gives facile access to various amino acid derivatives, including beta-fluoroamino acids. Crystallographic analyses of both the aziridines and their derivatives are disclosed. PMID- 24338991 TI - Current European corn borer, Ostrinia nubilalis, injury levels in the northeastern United States and the value of Bt field corn. AB - BACKGROUND: Recent evidence indicates that some populations of European corn borer (ECB), Ostrinia nubilalis (Hubner), have declined to historic lows owing to widespread adoption of Bt corn hybrids. To understand current ECB populations in Pennsylvania field corn, the authors assessed larval damage in Bt and non-Bt corn hybrids at 29 sites over 3 years. The influence of Bt adoption rates, land cover types and moth activity on levels of ECB damage was also considered. RESULTS: Bt hybrids reduced ECB damage when compared with non-Bt, but these differences inconsistently translated to higher yields and, because of higher seed costs, rarely improved profits. No relationships were detected between land use or Bt adoption and ECB damage rates, but positive relationships were found between plant damage and captures of Z-race ECB moths in pheromone traps in the PestWatch network. CONCLUSIONS: ECB damage levels were generally low and appear to be declining across Pennsylvania. In many locations, farmers may gain greater profits by planting competitive non-Bt hybrids; however, Bt hybrids remain valuable control options, particularly in the parts of Pennsylvania where ECB populations persist. Moth captures from PestWatch appear to provide insight into where Bt hybrids are most valuable. PMID- 24338990 TI - Risk factors for clinician-reported symptom clusters in patients with advanced head and neck cancer in a phase 3 randomized clinical trial: RTOG 0129. AB - BACKGROUND: Chemoradiotherapy has become the standard of care for head and neck squamous cell carcinoma; however, those patients often experience multiple treatment-related symptoms or symptom clusters. Two symptom clusters have been identified for this population. Little is known about the risk factors of these symptom clusters. METHODS: Subjects comprised 684 patients who were treated with concurrent chemoradiotherapy in a phase 3 randomized clinical trial. This trial compared standard fractionation radiotherapy to accelerated fractionation radiotherapy. Symptom clusters were evaluated at the end of the first and the second cycle of chemotherapy, and 3 months after the start of radiotherapy. Mixed effect modeling was used to observe risk factors for symptom clusters. RESULTS: Race and education were independent predictors for the head and neck cluster, whereas sex and history of tobacco use were independent predictors for the gastrointestinal cluster. Primary cancer site was only significant for the head and neck cluster when other factors were not controlled: patients with oropharyngeal cancer had more severe symptoms in the head and neck clusters than did patients with laryngeal cancer. In addition, patients receiving accelerated fractionation radiotherapy experienced more symptoms of radiomucositis, pain, and nausea at 3 months after the start of radiotherapy than those receiving standard fractionation radiotherapy. CONCLUSIONS: Demographic characteristics were more predictive to symptom clusters, whereas clinical characteristics, such as cancer site and treatment arms, were more significant for individual symptoms. Knowing the risk factors will enhance the capability of clinicians to evaluate patients' risk of severe symptom clusters and to personalize management strategies. PMID- 24338992 TI - Probing starch-iodine interaction by atomic force microscopy. AB - We explored the interaction of iodine with three crystalline type starches, corn, potato, and sweet potato starches using atomic force microscopy. Results revealed that starch molecules aggregated through interaction with iodine solution as well as iodine vapor. Detailed fine structures such as networks, chains, and super helical structures were found in iodide solution tests. The nanostructures formed due to iodine adsorption could help to understand the formation and properties of the starch-iodine complex. PMID- 24338994 TI - Elimination of photon quenching by a transition layer to fabricate a quenching shield sandwich structure for 800 nm excited upconversion luminescence of Nd3+ sensitized nanoparticles. AB - Nd3+-sensitized quenching-shield sandwich-structured upconversion nanoparticles are reported, which exhibit highly efficient upconversion photoluminescence under excitation by an 800 nm continuous-wave laser. The transition-layer structure is essential to bridge energy transfer from the sensitizer to the activator and simultaneously block energy back-transfer from the activator to the sensitizer. These 800 nm-excited upconversion nanoparticles are a key step toward the development of upconversion nanophosphors for biological applications. PMID- 24338993 TI - Quantitative magnetization transfer imaging of rodent glioma using selective inversion recovery. AB - Magnetization transfer (MT) provides an indirect means to detect noninvasively variations in macromolecular contents in biological tissues, but, so far, there have been only a few quantitative MT (qMT) studies reported in cancer, all of which used off-resonance pulsed saturation methods. This article describes the first implementation of a different qMT approach, selective inversion recovery (SIR), for the characterization of tumor in vivo using a rodent glioma model. The SIR method is an on-resonance method capable of fitting qMT parameters and T1 relaxation time simultaneously without mapping B0 and B1 , which is very suitable for high-field qMT measurements because of the lower saturation absorption rate. The results show that the average pool size ratio (PSR, the macromolecular pool versus the free water pool) in rat 9 L glioma (5.7%) is significantly lower than that in normal rat gray matter (9.2%) and white matter (17.4%), which suggests that PSR is potentially a sensitive imaging biomarker for the assessment of brain tumor. Despite being less robust, the estimated MT exchange rates also show clear differences from normal tissues (19.7 Hz for tumors versus 14.8 and 10.2 Hz for gray and white mater, respectively). In addition, the influence of confounding effects, e.g. B1 inhomogeneity, on qMT parameter estimates is investigated with numerical simulations. These findings not only help to better understand the changes in the macromolecular contents of tumors, but are also important for the interpretation of other imaging contrasts, such as chemical exchange saturation transfer of tumors. PMID- 24338996 TI - Dehydrogenative Meyer-Schuster-like rearrangement: a gold-catalyzed reaction generating an alkyne. AB - Easily accessible propargylic esters are converted to the inverted alkynyl ketones in an oxidative gold-catalyzed reaction. Gagosz's catalyst in combination with PhI(OAc)2 is the best system for this conversion and 18 examples with yields up to 80 % are reported. The results indicate that the triple bond in the product is formed by elimination from a vinylgold intermediate. In a formal sense the new conversion overall is a dehydrogenative Meyer-Schuster rearrangement. PMID- 24338995 TI - Phase II clinical trials with time-to-event endpoints: optimal two-stage designs with one-sample log-rank test. AB - Phase II clinical trials are often conducted to determine whether a new treatment is sufficiently promising to warrant a major controlled clinical evaluation against a standard therapy. We consider single-arm phase II clinical trials with right censored survival time responses where the ordinary one-sample logrank test is commonly used for testing the treatment efficacy. For planning such clinical trials, this paper presents two-stage designs that are optimal in the sense that the expected sample size is minimized if the new regimen has low efficacy subject to constraints of the type I and type II errors. Two-stage designs, which minimize the maximal sample size, are also determined. Optimal and minimax designs for a range of design parameters are tabulated along with examples. PMID- 24338997 TI - Ag and IL-2 immune complexes efficiently expand Ag-specific Treg cells that migrate in response to chemokines and reduce localized immune responses. AB - An intravenous administration of a high-dose antigen (Ag) can induce immune tolerance and suppress the immune response, but the mechanism remains unclear. We recently proved that a combined i.v. administration of OVA and IL-2-anti-IL-2 Ab immune complexes (IL-2 ICs) efficiently expands OVA-specific Treg cells in the thymus and induces their migration into peripheral blood, by using OVA-specific TCR Tg-expressing DO11.10 mice. Here, we demonstrate that the expanded OVA specific Treg cells rapidly move into the air pouch after OVA injection in DO11.10 mice. The migration was inhibited by blocking the axis of a chemokine receptor, CCR2. Moreover, prior treatment with OVA and IL-2 ICs enhanced OVA specific Treg-cell migration and inhibited OVA-induced delayed-type hypersensitivity (DTH) reactions in the skin of BM chimeric mice with 15% of T cells expressing OVA-specific TCR. Blocking the CCR2 axis reversed this suppression of DTH in these mice. Furthermore, prior treatment with OVA and IL-2 ICs effectively reduced DTH reactions even in WT mice possessing only a very small population of OVA-specific T cells. Thus, the treatment with Ag and IL-2 ICs can efficiently expand Ag-specific Treg cells with the capacity to migrate and reduce localized immune responses. PMID- 24338998 TI - Phloretin suppresses thrombin-mediated leukocyte-platelet-endothelial interactions. AB - SCOPE: Thrombin playing a pivotal role in coagulation cascade may influence the onset and progression of atherosclerosis as a pro-inflammatory mediator. This study investigated whether phloretin found in apple tree leaves, severed a linkage between thrombosis and atherosclerosis by thrombin. METHODS AND RESULTS: Human endothelial cells were pre-treated with 1-20 MUM phloretin and stimulated with 10 U/mL thrombin. Phloretin attenuated adhesion of THP-1 monocytes and platelets to thrombin-inflamed endothelial cells with concurrent inhibition of protease-activated receptor (PAR-1) induction. The thrombin induction of endothelial CD40, endothelial integrin beta3 and P-selectin, and monocytic CD40L was dampened by phloretin. Additionally, phloretin inhibited monocyte secretion of MCP-1, IL-6 and IL-8 responsible for pro-inflammatory activity of thrombin inducing endothelial CD40. The monocyte COX-2 induction and PGE2 secretion due to thrombin were down-regulated by phloretin, deterring endothelial CD40 expression. Thrombin promoted production of PAI-1 and tissue factor in monocytes was attenuated by phloretin through blocking PAR-1 and CD40. Thrombin up-regulated the induction of endothelial connective tissue growth factor independent of PAR-1 activation, which was reversed by phloretin. CONCLUSION: Phloretin disturbed tethering and stable adhesion of monocytes and platelets onto endothelium during increased thrombosis by thrombin. Phloretin would be a potent agent preventing thrombosis and atherosclerosis. PMID- 24338999 TI - Comparison of optimized long echo time STEAM and PRESS proton MR spectroscopy of lipid olefinic protons at 3 Tesla. AB - PURPOSE: To investigate the response of lipid olefinic protons (~ 5.35 ppm) as a function of STEAM (Stimulated Echo Acquisition Mode) mixing time (TM), and echo time (TE), to find values that resolve the olefinic resonance from water in vivo while retaining sufficient olefinic signal. MATERIALS AND METHODS: PRESS (Point RESolved Spectroscopy) and STEAM experiments with varying timing parameters (TE and also TM for STEAM) were conducted on nine oils (almond, canola, cod liver, corn, linseed, peanut, sesame, sunflower, and walnut oil), and on vertebral bone marrow in vivo at 3 Tesla (T). Olefinic and methylene (methyl + methylene in vivo) peak areas were measured. RESULTS: Optimal STEAM parameters were found to be TM = 20 ms and TE = 100 ms. The STEAM olefinic/methylene area ratios (ranging between 0.1 and 0.4) calculated for each oil correlated well with ratios deduced from oil compositions in the literature (R(2) = 0.975). The optimized STEAM sequence resolved the olefinic peak from water in vivo and yielded on average 1.91 times more olefinic signal compared with a previously optimized PRESS (TE = 200 ms) sequence tailored for the same purpose. Olefinic/(methyl + methylene) area ratios obtained with optimized STEAM and PRESS in vivo were linearly correlated (R(2) = 0.972). CONCLUSION: A STEAM sequence with TE = 100 ms and TM = 20 ms provides an alternative to the previously optimized PRESS (TE = 200 ms) sequence for determining relative amounts of lipid unsaturation at 3T. PMID- 24339000 TI - Mitochondria in metabolic disease: getting clues from proteomic studies. AB - Mitochondria play a key role as major regulators of cellular energy homeostasis, but in the context of mitochondrial dysfunction, mitochondria may generate reactive oxidative species and induce cellular apoptosis. Indeed, altered mitochondrial status has been linked to the pathogenesis of several metabolic disorders and specially disorders related to insulin resistance, such as obesity, type 2 diabetes, and other comorbidities comprising the metabolic syndrome. In the present review, we summarize information from various mitochondrial proteomic studies of insulin-sensitive tissues under different metabolic states. To that end, we first focus our attention on the pancreas, as mitochondrial malfunction has been shown to contribute to beta cell failure and impaired insulin release. Furthermore, proteomic studies of mitochondria obtained from liver, muscle, and adipose tissue are summarized, as these tissues constitute the primary insulin target metabolic tissues. Since recent advances in proteomic techniques have exposed the importance of PTMs in the development of metabolic disease, we also present information on specific PTMs that may directly affect mitochondria during the pathogenesis of metabolic disease. Specifically, mitochondrial protein acetylation, phosphorylation, and other PTMs related to oxidative damage, such as nitrosylation and carbonylation, are discussed. PMID- 24339001 TI - Assessment of ligand binding site predictions in CASP10. AB - The identification of amino acid residues in proteins involved in binding small molecule ligands is an important step for their functional characterization, as the function of a protein often depends on specific interactions with other molecules. The accuracy of computational methods aiming to predict such binding residues was evaluated within the "function prediction (prediction of binding sites, FN)" category of the critical assessment of protein structure prediction (CASP) experiment. In the last edition of the experiment (CASP10), 17 research groups participated in this category, and their predictions were evaluated on 13 prediction targets containing biologically relevant ligands. The results of this experiment indicate that several methods achieved an overall good performance, showing the usefulness of such methods in predicting ligand binding residues. As in previous years, methods based on a homology transfer approach were dominating. In comparison to CASP9, a larger fraction of the top predictors are automated servers. However, due to the small number of targets and the characteristics of the prediction format, the differences observed among the first ten methods were not statistically significant and it was also not possible to analyze differences in accuracy for different ligand types or overall structure, difficulty. To overcome these limitations and to allow for a more detailed evaluation, in future editions of CASP, methods in the FN category will no longer be evaluated on the "normal" CASP targets, but assessed continuously by CAMEO (continuous automated model evaluation) based on weekly prereleased sequences from the PDB. PMID- 24339005 TI - Theoretical and structural analysis of long C-C bonds in the adducts of polycyanoethylene and anthracene derivatives and their connection to the reversibility of Diels-Alder reactions. AB - X-ray structure determinations on four Diels-Alder adducts derived from the reactions of cyano- and ester-substituted alkenes with anthracene and 9,10 dimethylanthracene have shown the bonds formed in the adduction to be particularly long. Their lengths range from 1.58 to 1.62 A, some of the longest known for Diels-Alder adducts. Formation of the four adducts is detectably reversible at ambient temperature and is associated with free energies of reaction ranging from -2.5 to -40.6 kJ mol(-1). The solution equilibria have been experimentally characterised by NMR spectroscopy. Density-functional-theory calculations at the MPW1K/6-31+G(d,p) level with PCM solvation agree with experiment with average errors of 6 kJ mol(-1) in free energies of reaction and structural agreement in adduct bond lengths of 0.013 A. To understand more fully the cause of the reversibility and its relationship to the long adduct bond lengths, natural-bond-orbital (NBO) analysis was applied to quantify donor acceptor interactions within the molecules. Both electron donation into the sigma*-anti-bonding orbital of the adduct bond and electron withdrawal from the sigma-bonding orbital are found to be responsible for this bond elongation. PMID- 24339002 TI - Involvement of mitochondrial signalling pathway in HGFs/S. mitis coculture response to TEGDMA treatment. AB - Although triethylene glycol dimethacrylate (TEGDMA), a resin monomer widely used in dental practice, has been shown to have cytotoxic effects on eukaryotic cells, little is known about how the oral environment influences the cytotoxicity of this biomaterial. The aim of this study was to evaluate eukaryotic cell reaction to TEGDMA in terms of the production of reactive oxygen species (ROS), the expression of Bax, the disturbance of mitochondrial membrane potential (MMP), and the occurrence of apoptosis in an in vitro coculture model of human gingival fibroblasts (HGFs) and Streptococcus mitis strain in presence of saliva. We found that S. mitis and saliva reduced the production of ROS (from 2.2 to 1.8 fold), the occurrence of apoptosis (from 11.3 to 4.7%), and the decrease of MMP (from 0.75 to 0.9 fold) induced by TEGDMA treatment. Addition of N-acetylcysteine, a well known antioxidant, improved cell viability in all experimental conditions. The results obtained in this study suggest that the presence of S. mitis and saliva in the periodontal environment could protect cells against TEGDMA toxicity. These results, shedding more light on the biological and molecular events that occur in conjuction with TEGDMA treatment in vitro in a coculture model that mimics the environment of the oral cavity, confirm the key role played by oral bacteria and saliva in preventing toxic events that can occur in vivo in HGFs. PMID- 24339006 TI - Comparative biodistribution studies of technetium-99 m radiolabeled amphiphilic nanoparticles using three different reducing agents during the labeling procedure. AB - Considering the confusing biodistribution data through the literature and few reported alerts as well as our preliminary biodistribution results, we decided to evaluate the interaction and interference of the commonly present (99m) Tc (technetium-99m)-stannic oxide colloid during the direct stannous chloride (99m) Tc-labeling procedure and to assess its influence on the biodistribution pattern of amphiphilic poly(lactic-co-glycolic acid) nanoparticles. In order to confirm our thesis, beside stannous chloride, we employed two different reducing agents that don't form colloidal particles. The use of sodium borohydride was previously reported in the literature, whereas sodium dithionite was adapted for the first time in the (99m) Tc direct labeling procedure for nanoparticles. The results in our paper clearly differentiate among samples with and without colloidal impurities originating from the labeling procedure with a logical follow up of the radiochemical, physicochemical evaluation, and biodistribution studies clarifying previously reported data on stannic oxide colloidal interference. (99m) Tc-nanoparticle complex labeled with sodium dithionite as reducing agent illustrated appropriate labeling efficacy, stability, and potential for further use in biodistribution studies thus providing solution for the problem of low complex stability when sodium borohydride is used and colloidal stannic oxide interference for stannous chloride procedure. PMID- 24339007 TI - Facile synthesis of deuterated and [(14) C]labeled analogs of vanillin and curcumin for use as mechanistic and analytical tools. AB - Curcumin is a dietary diphenol with antioxidant, antinflammatory, and antitumor activity. We describe facile procedures for the synthesis of [(14) C2 ]curcumin (4 mCi/mmol), [d6 ]curcumin, [d3 ]curcumin, [(13) C5 ]curcumin, and [d6 ]bicyclopentadione, the major oxidative metabolite of curcumin. We also describe synthesis of the labeled building blocks [(14) C]vanillin, [d3 ]vanillin, and [(13) C5 ]acetylacetone. The overall molar yields of the labeled products were 52 ([(14) C]) and 47% ([d3 ]) for vanillin and 25 ([(14) C2 ]) and 27% ([d6 ]) for curcumin. The compounds can be used as radiotracers in biotransformation studies and as isotopic standards for mass spectrometry-based quantification in pharmacokinetic analyses. PMID- 24339008 TI - Synthesis, characterization and pre-clinical evaluation of (99m) Tc-tricarbonyl complexes as potential myocardial perfusion imaging agents. AB - Myocardial perfusion imaging is an established Nuclear Medicine investigation. Current myocardial perfusion imaging agents sestamibi and tetrofosmin have number of drawbacks; low heart uptake coupled with uptake into the surrounding tissues leads to a poorer image quality. There is a need for continued research into designing and evaluating potentially superior myocardial imaging agents. Tri carbonyl-technetium and rhenium complexes were prepared by combination with mono dentate and bi-dentate ligands. Complexes were characterized by HPLC, MAS, nuclear magnetic resonance, infrared, single-crystal X-ray diffraction and partition coefficient determinations. (99m) Tc(CO)3 complexes were administered intravenously to Sprague Dawley rats, and tissue distribution studies were carried out at 15 min and 1 h p.i. Radiochemical purity was assessed as >90%. 1 10-phenanthroline, 2,2'-bipyridine and imidazole complexes gave the highest heart uptake. The percentage injected dose per gram (n = 3) at 1 h for 1-10 phenanthroline/imidazole was blood 0.21 +/- 0.01, heart 1.12 +/- 0.11, kidney 3.61 +/- 1.13, liver 0.62 +/- 0.06, lung 0.28 +/- 0.12, spleen 0.24 +/- 0.05, small intestine contents 1.87 +/- 0.92; and for 2,2'-bipyridine /imidazole was blood 0.23 +/- 0.02, heart 1.07 +/- 0.18, kidney 3.31 +/- 1.28, liver 0.56 +/- 0.09, lung 0.14 +/- 0.02, spleen 0.2 +/- 0.1, small intestine content 1.05 +/- 0.48. Further investigation to evaluate more complexes based on 1,10 phenanthroline, 2,2'-bipyridine and imidazole derivatives could potentially lead to agents with an increased heart uptake and faster clearance from the liver and gastrointestinal tract. PMID- 24339009 TI - Radiolabeling of new generation magnetic poly(HEMA-MAPA) nanoparticles with (131) I and preliminary investigation of its radiopharmaceutical potential using albino Wistar rats. AB - In this study, N-methacryloyl-l-phenylalanine (MAPA) containing poly(2 hydroxyethylmethacrylate) (HEMA)-based magnetic poly(HEMA-MAPA) nanobeads [mag poly(HEMA-MAPA)] were radiolabeled with (131) I [(131) I-mag-poly(HEMA-MAPA)], and the radiopharmaceutical potential of (131) I-mag-poly(HEMA-MAPA) was investigated. Quality control studies were carried out by radiochromatographic method to be sure that (131) I binded to mag-poly(HEMA-MAPA) efficiently. In this sense, binding yield of (131) I-mag-poly(HEMA-MAPA) was found to be about 95 100%. In addition to this, optimum radiodination conditions for (131) I-mag poly(HEMA-MAPA) were determined by thin-layer radiochromatography studies. In addition to thin-layer radiochromatography studies, lipophilicity (partition coefficient) and stability studies for (131) I-mag-poly(HEMA-MAPA) were realized. It was determined that lipophilicities of mag-poly(HEMA-MAPA) and (131) I-mag poly(HEMA-MAPA) were 0.12 +/- 0.01 and 1.79 +/- 0.76 according to ACD/logP algorithm program, respectively. Stability of the radiolabeled compound was investigated in time intervals given as 0, 30, 60, 180, and 1440 min. It was found that (131) I-mag-poly(HEMA-MAPA) existed as a stable complex in rat serum within 60 min. After that, biodistribution and scintigraphy studies were carried out by using albino Wistar rats. It was determined that the most important (131) I activity uptake was observed in the breast, the ovary, and the pancreas. Scintigraphy studies well supported biodistribution results. PMID- 24339010 TI - Radiosynthesis of 11-[(18) F]fluoroundecyltriphenylphosphonium (MitoF) as a potential mitochondria-specific positron emission tomography radiotracer. AB - Changes in the magnitude of the mitochondrial membrane potential occur in a range of important pathologies. To assess changes in membrane potential in patients, we set out to develop an improved mitochondria-targeted positron emission tomography probe comprising a lipophilic triphenylphosphonium cation attached to a fluorine 18 radionuclide via an 11-carbon alkyl chain, which is well-established to effectively transport to and localise within mitochondria. Here, we describe the radiosynthesis of this probe, 11-[(18) F]fluoroundecyl-triphenylphosphonium (MitoF), from no-carrier-added [(18) F]fluoride and a fully automated synthetic protocol to prepare it in good radiochemical yields (2-3 GBq at end-of-synthesis) and radiochemical purity (97-99%). PMID- 24339011 TI - Synthesis of a series of carbon-14 labeled tetrahydropyrido[4,3-d]pyrimidin-4(3H) ones. AB - A series of tetrahydropyrido[4,3-d]pyrimidin-4(3H)-ones labeled with carbon-14 in the 2-position of pyrimidinone moiety were prepared as part of a 3-step sequence from benz[amidino-(14) C]amidine hydrochloride as a key synthetic intermediate. PMID- 24339012 TI - One-step radiosynthesis of 4-nitrophenyl 2-[(18) F]fluoropropionate ([(18) F]NFP); improved preparation of radiolabeled peptides for PET imaging. AB - The versatile (18) F-labeled prosthetic group, 4-nitrophenyl 2-[(18) F]fluoropropionate ([(18) F]NFP), was synthesized in a single step in 45 min from 4-nitrophenyl 2-bromopropionate, with a decay corrected radiochemical yield of 26.2% +/- 2.2%. Employing this improved synthesis of [(18) F]NFP, [(18) F]GalactoRGD - the current 'gold standard' tracer for imaging the expression of alphaV beta3 integrin - was prepared with high specific activity in 90 min and 20% decay corrected radiochemical yield from [(18) F]fluoride. PMID- 24339013 TI - Development of a new precursor-minimizing base control method and its application for the automated synthesis and SPE purification of [(18) F]fluoromisonidazole ([(18) F]FMISO). AB - Bases such as potassium carbonate and potassium bicarbonate (KHCO3 ) are essential for the elution of trapped [(18) F]fluoride from ion exchange cartridges and for the prevention of [(18) F]fluoride adsorption on the silica glass vial during the preparation of radiopharmaceuticals for positron emission tomography imaging. However, these bases promote the chemical decomposition of precursor compounds and the creation of unwanted organic impurities. Thus, the goal of the current study was to develop a new method for synthesizing [(18) F]fluoride-labeled radiopharmaceuticals (e.g., [(18) F]fluoromisonizadole ([(18) F]FMISO)) that permits the fine control of base concentrations while minimizing adverse events. Non-decay-corrected radiochemical yields of 25.1 +/- 5.0% and 13.3 +/- 5.1% (n = 3) were achieved after solid-phase extraction purification using automatic synthesis with GE TRACERlab MX and KHCO3 at concentrations of 14.1 and 33.0 umol, respectively, and 1 mg of precursor (1-(2'-nitro-1' imidazolyl)-2-O-tetra-hydropyranyl-3-O-toluenesulfonyl propanediol (NITTP)). The newly developed synthesis protocol with fine base control and low precursor content permits high radiochemical yields with minimal impurities. PMID- 24339014 TI - A concise radiosynthesis of the tau radiopharmaceutical, [(18) F]T807. AB - Fluorine-18 labeled 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole ([(18) F]T807) is a potent and selective agent for imaging paired helical filaments of tau and is among the most promising PET radiopharmaceuticals for this target in early clinical trials. The present study reports a simplified one-step method for the synthesis of [(18) F]T807 that is broadly applicable for routine clinical production using a GE TRACERlabTM FXFN radiosynthesis module. Key facets of our optimized radiosynthesis include development and use of a more soluble protected precursor, tert-butyl 7-(6-nitropyridin-3-yl)-5H-pyrido[4,3-b]indole-5 carboxylate, as well as new HPLC separation conditions that enable a facile one step synthesis. During the nucleophilic fluorinating reaction with potassium cryptand [(18) F]fluoride (K[(18) F]/K222 ) in DMSO at 130 degrees C over 10 min the precursor is concurrently deprotected. Formulated [(18) F]T807 was prepared in an uncorrected radiochemical yield of 14 +/- 3%, with a specific activity of 216 +/- 60 GBq/umol (5837 +/- 1621 mCi/umol) at the end of synthesis (60 min; n = 3) and validated for human use. This methodology offers the advantage of faster synthesis in fewer steps, with simpler automation that we anticipate will facilitate widespread clinical use of [(18) F]T807. PMID- 24339016 TI - Effective cancer cell killing by hydrophobic nanovoid-enhanced cavitation under safe low-energy ultrasound. AB - beta-Cyclodextrin (beta-CD)-capped mesoporous silica nanoparticles with hydrophobic internal nanovoids were prepared and used for effective cancer cell killing in synergistic combination with low-energy ultrasound (<=1.0 W cm(-2) , 1 MHz). The water-dispersible nanoparticles with hydrophobic internal nanovoids can be taken up by cancer cells and subsequently evoke a remarkable cavitation effect under irradiation with mild low-energy ultrasound (<=1.0 W cm(-2) , 1 MHz). A significant cancer cell killing effect was observed in cancer cells and in a mouse xenograft tumor model treated with the nanoagents together with the low energy ultrasound, showing a distinct dependence on the concentration of nanoagents and ultrasound intensity. By contrast, an antitumor effect was not observed when either low-energy ultrasound or nanoagents were applied alone. These findings are significant as the technique promises a safe, low-cost, and effective treatment for cancer therapy. PMID- 24339017 TI - The SIMEX approach to measurement error correction in meta-analysis with baseline risk as covariate. AB - This paper investigates the use of SIMEX, a simulation-based measurement error correction technique, for meta-analysis of studies involving the baseline risk of subjects in the control group as explanatory variable. The approach accounts for the measurement error affecting the information about either the outcome in the treatment group or the baseline risk available from each study, while requiring no assumption about the distribution of the true unobserved baseline risk. This robustness property, together with the feasibility of computation, makes SIMEX very attractive. The approach is suggested as an alternative to the usual likelihood analysis, which can provide misleading inferential results when the commonly assumed normal distribution for the baseline risk is violated. The performance of SIMEX is compared to the likelihood method and to the moment-based correction through an extensive simulation study and the analysis of two datasets from the medical literature. PMID- 24339018 TI - Role of endocytic uptake in transfection efficiency of solid lipid nanoparticles based nonviral vectors. AB - BACKGROUND: As has been shown for different vector systems, the entry pathway(s) impacts upon the transfection efficiency. The present study aimed to explore the cellular uptake mechanisms of three different vectors based on solid lipid nanoparticles (SLN) in HeLa cells. The use of endocytosis inhibitors that affect specific internalization pathways provides a tool for the study of these routes. METHODS: We prepared three vectors based on solid lipid nanoparticles: without protamine, with protamine, and with protamine and dextran. Uptake, percentage of transfected HeLa cells and enhanced green fluorescent protein (EGFP) production were all analyzed in the presence or absence of different endocytosis inhibitors. In addition, co-localization studies using lysosomal markers were carried out to determine the influence of the trafficking to late endosomal compartments on the transfection capacity of the vectors. RESULTS: Uptake and transfection of each vector was affected differently by each endocytosis inhibitor. Ethylisopropylamiloride (EIPA) did not affect uptake of the DNA-SLN vector, whereas all of the inhibitors affected transfection. In the case of protamine-DNA SLN and dextran-protamine-DNA-SLN vectors, EIPA affected uptake and dynasore did not decrease transfection. CONCLUSIONS: DNA-SLN vector appear to enter productively by multiple pathways in HeLa cells. By contrast, dynamin does not appear to be essential in the productive entry of protamine-containing vectors. In addition, enhancement of the macropinocytic route increases EGFP production when dextran is added to the vector. PMID- 24339019 TI - Gold(I)-catalyzed diastereoselective hydroacylation of terminal alkynes with glyoxals. AB - The reaction of an alpha-ketoaldehyde and a terminal alkyne in the presence of piperidine and a catalytic amount of AuCl delivers 1,2-dicarbonyl-3-enes, products of the formal hydroacylation of the triple bond. The scope of the method is broad; different aryl substituents on the dicarbonyl unit and on the alkyne are well tolerated. The products can be transformed selectively into vinylquinoxalines. Mechanistic studies, including isotope-labeling experiments, indicate that after an initial A(3) -type conversion to propargylic amines, a subsequent base-mediated alkyne-to-allene isomerization and a hydrolysis of the enamine substructure during the workup deliver the formal hydroacylation products. PMID- 24339020 TI - Reactivity of Tp(Me2) -supported yttrium alkyl complexes toward aromatic N heterocycles: ring-opening or C-C bond formation directed by C-H activation. AB - Unusual chemical transformations such as three-component combination and ring opening of N-heterocycles or formation of a carbon-carbon double bond through multiple C-H activation were observed in the reactions of Tp(Me2) -supported yttrium alkyl complexes with aromatic N-heterocycles. The scorpionate-anchored yttrium dialkyl complex [Tp(Me2) Y(CH2 Ph)2 (THF)] reacted with 1-methylimidazole in 1:2 molar ratio to give a rare hexanuclear 24-membered rare-earth metallomacrocyclic compound [Tp(Me2) Y(MU-N,C-Im)(eta(2) -N,C-Im)]6 (1; Im=1 methylimidazolyl) through two kinds of C-H activations at the C2- and C5 positions of the imidazole ring. However, [Tp(Me2) Y(CH2 Ph)2 (THF)] reacted with two equivalents of 1-methylbenzimidazole to afford a C-C coupling/ring-opening/C C coupling product [Tp(Me2) Y{eta(3) -(N,N,N)-N(CH3 )C6 H4 NHCH?C(Ph)CN(CH3 )C6 H4 NH}] (2). Further investigations indicated that [Tp(Me2) Y(CH2 Ph)2 (THF)] reacted with benzothiazole in 1:1 or 1:2 molar ratio to produce a C-C coupling/ring-opening product {(Tp(Me2) )Y[MU-eta(2) :eta(1) -SC6 H4 N(CH?CHPh)](THF)}2 (3). Moreover, the mixed Tp(Me2) /Cp yttrium monoalkyl complex [(Tp(Me2) )CpYCH2 Ph(THF)] reacted with two equivalents of 1-methylimidazole in THF at room temperature to afford a trinuclear yttrium complex [Tp(Me2) CpY(MU N,C-Im)]3 (5), whereas when the above reaction was carried out at 55 degrees C for two days, two structurally characterized metal complexes [Tp(Me2) Y(Im Tp(Me2) )] (7; Im-Tp(Me2) =1-methyl-imidazolyl-Tp(Me2) ) and [Cp3 Y(HIm)] (8; HIm=1-methylimidazole) were obtained in 26 and 17 % isolated yields, respectively, accompanied by some unidentified materials. The formation of 7 reveals an uncommon example of construction of a C?C bond through multiple C-H activations. PMID- 24339021 TI - Highly sensitive capillary electrophoretic immunoassay of rheumatoid factor in human serum with gold nanoparticles enhanced chemiluminescence detection. AB - A new CE-based immunoassay method for the determination of rheumatoid factor was developed using chemiluminescent reaction of luminol and hydrogen peroxide catalyzed by gold nanoparticles (AuNPs). In this method, AuNPs were synthesized and conjugated with anti-RF (antibody, Ab) to form tagged Ab (AuNPs-Ab, Ab*), which subsequently linked to limited amount of RF (antigen, Ag) to produce Ab*-Ag complex by a noncompetitive immunoreaction. AuNPs were used to label antibody and amplify chemiluminescent signal. Under the optimized conditions, the mixture of free Ab* and Ab*-Ag complex was well separated and detected. This method yields a wide linear range of 0.01-20 MUg/mL with a correlation coefficient of 0.997, and the detection limit of RF reaches 5.95 ng/mL (ca. 6.0 pmol/L, S/N = 3). The proposed method was successfully applied for the quantification of RF in human sera from patients with rheumatoid arthritis. This highly sensitive and selective method could be developed into a promising and useful technique for biological molecules determination in clinical analysis. PMID- 24339024 TI - A new architecture for printable photovoltaics overcoming conventional module limits. AB - A new architecture for manufacturing large-area polymer solar cells that does not produce concomitant aperture and Ohmic losses is presented. By introducing the innovative concept of metal-filamentary nanoelectrodes, which are vertically formed inside the main active layers, loss-free, widely expandable solar cells with the highest relative power conversion efficiency (ca. 90%) in organic photovoltaic systems are demonstrated. PMID- 24339023 TI - d-Phenothrin-induced oxidative DNA damage in rat liver and kidney determined by HPLC-ECD/DAD. AB - The objective of this study was to assess the risk of genotoxicity of d phenothrin by measuring the oxidative stress it causes in rat liver and kidney. The level of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG)/10(6) 2' deoxyguanosine (dG) was measured by using high performance liquid chromatography (HPLC) with a diode array (DAD) and an electrochemical detector (ECD). Sixty male Wistar albino rats were randomly divided into five experimental groups and one control group of 10 rats/group. d-phenothrin was administered intraperitoneally (IP) to the five experimental groups at 25 mg/kg (Group I), 50 mg/kg (Group II), 66.7 mg/kg (Group III), 100 mg/kg (Group IV), and 200 mg/kg (Group V) for 14 consecutive days, and the control group received only the vehicle, dimethyl sulfoxide (DMSO). DNA from samples frozen in liquid nitrogen was isolated with a DNA isolation kit. Following digestion with nuclease P1 and alkaline phosphatase (ALP), hydrolyzed DNA was subjected to HPLC. The dG and 8-oxodG levels were analyzed with a DAD and ECD, respectively. In the experimental groups, the mean 8 oxodG/10(6) dG levels were 48.15 +/- 7.43, 68.92 +/- 20.66, 82.07 +/- 14.15, 85.08 +/- 28.50, and 89.14 +/- 21.73 in livers and 39.06 +/- 7.63, 59.69 +/- 14.22, 61.13 +/- 17.46, 65.13 +/- 23.40, and 72.66 +/- 19.04 in kidneys of Groups I, II, III, IV, and V, respectively. The mean 8-oxodG/10(6) dG levels in the control groups were 44.96 +/- 12.66 for the liver and 39.07 +/- 4.80 for the kidney. A statistically significant (p < 0.05), dose-dependent increase in oxidative DNA damage was observed in both organs of animals exposed to d phenothrin when compared to controls. Furthermore, the liver showed a significantly higher level of oxidative DNA damage than the kidney (p < 0.01). In conclusion, d-phenothrin administered to rats intraperitoneally for 14 consecutive days generated free radical species in a dose-dependent manner and caused oxidative DNA damage in the liver and kidney. PMID- 24339025 TI - Mass transfer of a neutral solute in porous microchannel under streaming potential. AB - The mass transport of a neutral solute in a porous wall, under the influence of streaming field, has been analyzed in this study. The effect of the induced streaming field on the electroviscous effect of the fluid for different flow geometries has been suitably quantified. The overall electroosmotic velocity profile and expression for streaming field have been obtained analytically using the Debye-Huckel approximation, and subsequently used in the analysis for the mass transport. The analysis shows that as the solution Debye length increases, the strength of the streaming field and, consequently, the electroviscous effect diminishes. The species transport equation has been coupled with Darcy's law for quantification of the permeation rate across the porous wall. The concentration profile inside the mass transfer boundary layer has been solved using the similarity transformation, and the Sherwood number has been calculated from the definition. In this study, the variation of the permeation rate and solute permeate concentration has been with the surface potential, wall retention factor and osmotic pressure coefficient has been demonstrated for both the circular as well as rectangular channel cross-section. PMID- 24339026 TI - Large arrays and properties of 3-terminal graphene nanoelectromechanical switches. AB - Large arrays of 3-terminal nanoelectromechanical graphene switches are fabricated. The switch is designed with a novel geometry that leads to low actuation voltages and improved mechanical integrity, while reducing adhesion forces, which improves the reliability of the switch. A finite element model including non-linear electromechanics is used to simulate the switching behavior and to deduce a scaling relation between the switching voltage and device dimensions. PMID- 24339027 TI - Correlation of apparent diffusion coefficient value with prognostic parameters of endometrioid carcinoma. AB - PURPOSE: To correlate the apparent diffusion coefficient (ADC) of endometrioid carcinoma with histological tumor grade and degree of myometrial invasion. MATERIALS AND METHODS: 3T diffusion-weighted (DW) magnetic resonance (MR) images of 63 patients were retrospectively reviewed. Two readers measured tumor ADC according to a freehand region of interest (ROI) and a round ROI. Mean and minimum ADCs were correlated with prognostic parameters. RESULTS: The minimum ADC was 0.64 * 10(-3) mm(2)/s for grade 1 (G1, n = 42), 0.62 for grade 2 (G2, n = 14), 0.46 for grade 3 (G3, n = 7) on freehand ROI. There were significant differences between G1 and G3 (P = 0.007), and G2 and G3 (P = 0.038). No significant correlation was found between tumor grade and mean ADC (0.85 for G1, 0.82 for G2, and 0.72 for G3, P = 0.166). The minimum ADC was significantly lower for patients with deep (n = 21, 0.54) than for those with superficial (n = 39, 0.65) myometrial invasion. Conversely, mean ADC did not differ significantly (0.84 for superficial and 0.78 for deep myometrial invasion, P = 0.081). The same tendency was shown on round ROI. CONCLUSION: The minimum ADC correlates with prognostic parameters of endometrial carcinoma more strongly than mean ADC. Lower minimum ADC is associated with higher histological tumor grade and higher degree of myometrial invasion. PMID- 24339029 TI - Understanding the complex nature of salinity and drought-stress response in cereals using proteomics technologies. AB - Worldwide, crop productivity is drastically reduced by drought and salinity stresses. In order to develop food crops with increased productivity in marginal areas, it is important to first understand the nature of plant stress response mechanisms. In the past decade, proteomics tools have been extensively used in the study of plants' proteome responses under experimental conditions mimicking drought and salinity stresses. A lot of proteomic data have been generated using different experimental designs. However, the precise roles of these proteins in stress tolerance are yet to be elucidated. This review summarises the applications of proteomics in understanding the complex nature of drought and salinity stress effects on plants, particularly cereals and also highlights the usefulness of sorghum as the next logical model crop for use in understanding drought and salinity tolerance in cereals. With the vast amount of proteomic data that have been generated to date, a call for integrated efforts across the agricultural, biotechnology, and molecular biology sectors is also highlighted in an effort to translate proteomics data into increased food productivity for the world's growing population. PMID- 24339028 TI - An open-label, single-arm, phase 2 trial of the Polo-like kinase inhibitor volasertib (BI 6727) in patients with locally advanced or metastatic urothelial cancer. AB - BACKGROUND: Polo-like kinases (Plks) control multiple steps during the cell cycle, and Plk1 is overexpressed in urothelial cancer (UC). Volasertib (BI 6727), a Plk inhibitor, has demonstrated antitumor activity in several malignancies, including UC. In this phase 2 trial, the authors investigated volasertib as a second-line treatment in advanced/metastatic UC. METHODS: Patients who progressed within 2 years of 1 prior chemotherapy regimen received 300 mg volasertib on day 1 every 3 weeks. The dose was escalated to 350 mg in cycle 2 if volasertib was tolerated in cycle 1. The primary endpoint was tumor response, which was assessed every 6 weeks; secondary endpoints were progression-free survival, overall survival, duration of response, safety, and pharmacokinetics. RESULTS: Fifty patients were enrolled, and the median patient age was 68.5 years (range, 52-83 years). All patients had received prior platinum, 94% of patients had relapsed <=2 years after prior therapy, 36% had liver metastases, and 54% had lung metastases. The median number of treatment cycles was 2 (range, 1-27 treatment cycles), and 23 patients were dose escalated at cycle 2. Seven patients (14%) had a partial response, 13 (26%) had stable disease, and 30 (60%) progressed within 6 weeks. The median response duration was 41 weeks (range, 29.1-77.3 weeks). The median progression-free survival was 1.4 months, and the median overall survival was 8.5 months. The most frequent grade 3 and 4 adverse events were neutropenia (28%), thrombocytopenia (20%), and anemia (16%). No cumulative toxicity was observed. CONCLUSIONS: Volasertib as second-line treatment for advanced/metastatic UC had an acceptable safety profile but demonstrated insufficient antitumor activity for further evaluation as a monotherapy. PMID- 24339030 TI - Inflammatory response of prostate epithelial cells to stimulation by Trichomonas vaginalis. AB - BACKGROUND: Trichomonas vaginalis is known as the most common cause of sexually transmitted infection. However, its prevalence may have been underestimated. Trichomonads are detected in prostatic tissue in benign prostatic hyperplasia, prostatitis, and prostate cancer. Our objective was to investigate whether T. vaginalis could induce an inflammatory response in prostate epithelium. METHODS: The cytokine production by human prostate epithelial cell (RWPE-1) activated with T. vaginalis was determined by ELISA and real-time PCR. Intracellular ROS was evaluated by flow cytometry or spectrofluorometry. The protein levels of MAP kinase, NF-kappaB were analyzed by Western blot. The migration of neutrophil and monocyte were performed in 24-well microplates with filter insert. RESULTS: Incubation of cells of a human prostate epithelial cell line with a live T. vaginalis T016 isolate increased expression of the inflammatory mediators IL 1beta, CCL2, and CXCL8. In addition, ROS, MAPK, and NF-kappaB activities increased, while inhibitors of ROS, ERK, and NF-kappaB reduced IL-1beta production. Medium conditioned by incubation of RWPE-1 cells with T. vaginalis contained IL-1beta and stimulated the migration of human neutrophils and monocytes (THP-1 cell line). CONCLUSIONS: We conclude that T. vaginalis may increase IL-1beta expression in human prostate epithelium through activation of ROS, ERK, and NF-kappaB, and this in turn may induce the migration of neutrophils and monocytes and lead to an inflammatory response. This research is the first attempt to confirm inflammatory reaction caused by T. vaginalis in prostate epithelial cell. PMID- 24339034 TI - Poisonous plants: effects on embryo and fetal development. AB - Poisonous plant research in the United States began over 100 years ago as a result of livestock losses from toxic plants as settlers migrated westward with their flocks, herds, and families. Major losses were soon associated with poisonous plants, such as locoweeds, selenium accumulating plants, poison hemlock, larkspurs, Veratrum, lupines, death camas, water hemlock, and others. Identification of plants associated with poisoning, chemistry of the plants, physiological effects, pathology, diagnosis, and prognosis, why animals eat the plants, and grazing management to mitigate losses became the overarching mission of the current Poisonous Plant Research Laboratory. Additionally, spin-off benefits resulting from the animal research have provided novel compounds, new techniques, and animal models to study human health conditions (biomedical research). The Poisonous Plant Research Laboratory has become an international leader of poisonous plant research as evidenced by the recent completion of the ninth International Symposium on Poisonous Plant Research held July 2013 in Hohhot, Inner Mongolia, China. In this article, we review plants that negatively impact embryo/fetal and neonatal growth and development, with emphasis on those plants that cause birth defects. Although this article focuses on the general aspects of selected groups of plants and their effects on the developing offspring, a companion paper in this volume reviews current understanding of the physiological, biochemical, and molecular mechanisms of toxicoses and teratogenesis. PMID- 24339035 TI - Plant alkaloids that cause developmental defects through the disruption of cholinergic neurotransmission. AB - The exposure of a developing embryo or fetus to alkaloids from plants, plant products, or plant extracts has the potential to cause developmental defects in humans and animals. These defects may have multiple causes, but those induced by piperidine and quinolizidine alkaloids arise from the inhibition of fetal movement and are generally referred to as multiple congenital contracture-type deformities. These skeletal deformities include arthrogyrposis, kyposis, lordosis, scoliosis, and torticollis, associated secondary defects, and cleft palate. Structure-function studies have shown that plant alkaloids with a piperidine ring and a minimum of a three-carbon side-chain alpha to the piperidine nitrogen are teratogenic. Further studies determined that an unsaturation in the piperidine ring, as occurs in gamma coniceine, or anabaseine, enhances the toxic and teratogenic activity, whereas the N-methyl derivatives are less potent. Enantiomers of the piperidine teratogens, coniine, ammodendrine, and anabasine, also exhibit differences in biological activity, as shown in cell culture studies, suggesting variability in the activity due to the optical rotation at the chiral center of these stereoisomers. In this article, we review the molecular mechanism at the nicotinic pharmacophore and biological activities, as it is currently understood, of a group of piperidine and quinolizidine alkaloid teratogens that impart a series of flexure-type skeletal defects and cleft palate in animals. PMID- 24339036 TI - Animal models of brain maldevelopment induced by cycad plant genotoxins. AB - Cycads are long-lived tropical and subtropical plants that contain azoxyglycosides (e.g., cycasin, macrozamin) and neurotoxic amino acids (notably beta-N-methylamino-l-alanine l-BMAA), toxins that have been implicated in the etiology of a disappearing neurodegenerative disease, amyotrophic lateral sclerosis and parkinsonism-dementia complex that has been present in high incidence among three genetically distinct populations in the western Pacific. The neuropathology of amyotrophic lateral sclerosis/parkinsonism-dementia complex includes features suggestive of brain maldevelopment, an experimentally proven property of cycasin attributable to the genotoxic action of its aglycone methylazoxymethanol (MAM). This property of MAM has been exploited by neurobiologists as a tool to study perturbations of brain development. Depending on the neurodevelopmental stage, MAM can induce features in laboratory animals that model certain characteristics of epilepsy, schizophrenia, or ataxia. Studies in DNA repair-deficient mice show that MAM perturbs brain development through a DNA damage-mediated mechanism. The brain DNA lesions produced by systemic MAM appear to modulate the expression of genes that regulate neurodevelopment and contribute to neurodegeneration. Epigenetic changes (histone lysine methylation) have also been detected in the underdeveloped brain after MAM administration. The DNA damage and epigenetic changes produced by MAM and, perhaps by chemically related substances (e.g., nitrosamines, nitrosoureas, hydrazines), might be an important mechanism by which early-life exposure to genotoxicants can induce long term brain dysfunction. PMID- 24339038 TI - Pregnancy outcomes, embryonic and fetal development in maternal exposure to Chinese medicines. AB - Chinese medicine is a common name for a collection of Chinese Materia Medica with therapeutic properties for medical treatment and healing. Similar to Western pharmaceuticals, Chinese medicines are not free of risk, and have the potential to cause adverse pregnancy outcomes and affect embryonic and fetal development. However, most clinical data concerning safety of maternal exposure to Chinese medicines during pregnancy are not available and the conclusion remains elusive. Some individual clinical trials of Chinese medicines reported some minor adverse effects during pregnancy, whereas few animal studies identified some adverse maternal and perinatal effects, as well as embryotoxic potentials. Basic research and mechanistic studies of the teratogenicity of Chinese medicines are still lacking. There is an urgent need for testing the safety of Chinese medicines before recommendation and commercialization. Until more reliable and scientific research data become available, clinicians should consider both the risks and benefits before recommending Chinese medicines to pregnant women. More systematic investigations of the safety implications of the use of Chinese medicines are highly recommended, in addition to more clinical trials with a larger sample size to confirm its safety during pregnancy. This review includes a critical overview of available clinical and experimental data and provides directions to study the safety issue of Chinese medicines for pregnancy. PMID- 24339039 TI - Flavonoids, derived from traditional Chinese medicines, show roles in the differentiation of neurons: possible targets in developing health food products. AB - Flavonoids, a family of phenolic compounds, are distributed in a variety of fruits, vegetables, tea, and wine. More importantly, many flavonoids are served as the active ingredients in traditional Chinese herbal medicines, which in general do not have side effects. Several lines of evidence support that flavonoids have impacts on many aspects of human health, including anti-tumor, anti-oxidation, and anti-inflammation. Recently, there is significant attention focused on the neuronal beneficial effects of flavonoids, including the promotion of nervous system development, neuroprotection against neurotoxin stress, as well as the promotion of memory, learning, and cognitive functions. Here, the activities of flavonoids on the development of nervous system are being summarized and discussed. The flavonoids from diverse herbal medicines have significant effects in different developmental stages of nervous systems, including neuronal stem cell differentiation, neurite outgrowth, and neuronal plasticity. These findings imply that flavonoids are potential candidates for the development of health supplements in preventing birth defects and neuronal diseases. PMID- 24339037 TI - Prenatal effects of maternal consumption of polyphenol-rich foods in late pregnancy upon fetal ductus arteriosus. AB - Fetal circulation has characteristic features, being morphologically and functionally different from extrauterine circulation. The ductus arteriosus plays a fundamental role in directing the blood flow to fetal inferior body parts. Basically, the ductus arteriosus directs 80-85% of the right ventricular output arising from the superior vena cava, coronary sinus, and a small part from the inferior vena cava to descending aorta. Its histological structure is made up predominantly by a thick muscular layer, differently from the aorta and the pulmonary artery, which increases with gestational age. The fibers have a circumferential orientation, especially at the external layers, facilitating and making effective ductal constriction. These factors may generate lumen alterations which may cause fetal and neonatal complications, such as heart failure, hydrops, neonatal pulmonary hypertension, and even death. Classically, maternal administration of indomethacin and/or other antiinflammatory drugs interfere in prostaglandins metabolism, causing ductal constriction. However, many cases of fetal ductal constriction, as well as of persistent neonatal pulmonary artery hypertension, remain without an established etiology, being referred as "idiopathic." In recent years, a growing body of evidence has shown that herbs, fruits, nuts, and a wide diversity of substances commonly used in daily diets have definitive effects upon the metabolic pathway of inflammation, with consequent inhibition of prostaglandins synthesis. This antiinflammatory action, especially of polyphenols, when ingested during the third trimester of pregnancy, may influence the dynamics of fetal ductus arteriosus flow. The goal of this review is to present these new observations and findings, which may influence dietary orientation during pregnancy. PMID- 24339042 TI - The role of proteomics in understanding biological mechanisms of sepsis. AB - Sepsis is a systemic inflammatory state caused by infection. Complications of this infection with multiple organ failure lead to more lethal conditions, such as severe sepsis and septic shock. Sepsis is one of the leading causes of US deaths. Novel biomarkers with high sensitivity and specificity may be helpful for early diagnosis of sepsis and for improvement of patient outcomes through the development of new therapies. Mass spectrometry-based proteomics offers powerful tools to identify such biomarkers and furthermore to give insight to fundamental mechanisms of this clinical condition. In this review, we summarize findings from proteomics studies of sepsis and how their applications have provided more understanding into the pathogenesis of septic infection. Literatures related to "proteomics", "sepsis", "systemic inflammatory response syndrome", "severe sepsis", "septic infection", and "multiple organ dysfunction syndrome" were searched using PubMed. Findings about neonatal and adult sepsis are discussed separately. Within the adult sepsis studies, results are grouped based on the models (e.g., human or animal). Across investigations in clinical populations and in rodent and mammalian animal models, biological pathways, such as inflammatory and acute phase response, coagulation, complement, mitochondrial energy metabolism, chaperones, and oxidative stress, are altered at the protein level. These proteomics studies have discovered many novel biomarker candidates of septic infection. Validation the clinical use of these biomarker candidates may significantly impact the diagnosis and prognosis of sepsis. In addition, the molecular mechanisms revealed by these studies may also guide the development of more effective treatments. PMID- 24339043 TI - Sensing acetylcholine and anticholinesterase compounds. AB - Acetylcholine is a key neurotransmitter, and anticholinesterase agents are essential compounds used as medical drugs, pesticides, and chemical warfare agents. A semisynthetic fluorescence-based probe for the direct, real-time detection of acetylcholine and anticholinesterase compounds is introduced. The probe possesses good sensitivity, tunable detection range, and can be selectively targeted to cell surfaces, thereby making it an attractive tool for applications in analytical chemistry and quantitative biology. PMID- 24339041 TI - Quantum mechanics/molecular mechanics study on the oxygen binding and substrate hydroxylation step in AlkB repair enzymes. AB - AlkB repair enzymes are important nonheme iron enzymes that catalyse the demethylation of alkylated DNA bases in humans, which is a vital reaction in the body that heals externally damaged DNA bases. Its mechanism is currently controversial and in order to resolve the catalytic mechanism of these enzymes, a quantum mechanics/molecular mechanics (QM/MM) study was performed on the demethylation of the N(1) -methyladenine fragment by AlkB repair enzymes. Firstly, the initial modelling identified the oxygen binding site of the enzyme. Secondly, the oxygen activation mechanism was investigated and a novel pathway was found, whereby the catalytically active iron(IV)-oxo intermediate in the catalytic cycle undergoes an initial isomerisation assisted by an Arg residue in the substrate binding pocket, which then brings the oxo group in close contact with the methyl group of the alkylated DNA base. This enables a subsequent rate determining hydrogen-atom abstraction on competitive sigma- and pi-pathways on a quintet spin-state surface. These findings give evidence of different locations of the oxygen and substrate binding channels in the enzyme and the origin of the separation of the oxygen-bound intermediates in the catalytic cycle from substrate. Our studies are compared with small model complexes and the effect of protein and environment on the kinetics and mechanism is explained. PMID- 24339044 TI - First-trimester uterine artery Doppler and adverse pregnancy outcome: a meta analysis involving 55,974 women. AB - OBJECTIVES: To determine the accuracy with which uterine artery Doppler in the first trimester of pregnancy predicts pre-eclampsia and fetal growth restriction, particularly early-onset disease. METHODS: We searched MEDLINE (1951-2012), EMBASE (1980-2012) and the Cochrane Library (2012) for relevant citations without language restrictions. Two reviewers independently selected studies that evaluated the accuracy of first-trimester uterine artery Doppler to predict adverse pregnancy outcome and performed data extraction to construct 2 * 2 tables. We synthesized sensitivity and specificity for various Doppler indices using a bivariate random-effects model. RESULTS: From 1866 citations, we identified 18 studies (55,974 women). The sensitivity and specificity of abnormal uterine artery flow velocity waveform (FVW) in the prediction of early-onset pre eclampsia were 47.8% (95% CI: 39.0-56.8) and 92.1% (95% CI: 88.6-94.6), and in the prediction of early-onset fetal growth restriction were 39.2% (95% CI: 26.3 53.8) and 93.1% (95% CI: 90.6-95.0), respectively. The sensitivities for predicting any pre-eclampsia and fetal growth restriction were 26.4% (95% CI: 22.5-30.8) and 15.4% (95% CI: 12.4-18.9), respectively, and the specificities were 93.4% (95% CI: 90.4-95.5%) and 93.3% (95% CI: 90.9-95.1), respectively. The number needed to treat (NNT) with aspirin to prevent one case of early-onset pre eclampsia fell from 1000 to 173 and from 2500 to 421 for background risks varying between 1% and 0.4%, respectively. CONCLUSIONS: First-trimester uterine artery Doppler is a useful tool for predicting early-onset pre-eclampsia, as well as other adverse pregnancy outcomes. Based on the NNT, abnormal uterine artery Doppler in low-risk women achieves a sufficiently high performance to justify aspirin prophylaxis in those who test positive. PMID- 24339045 TI - Ferromagnetic ordering in the layer-structured Pd(HS(2)O(7))(2). AB - The reaction of (NO2 )(CF3 SO3 ) and elemental palladium in oleum (65 % SO3 ) leads to violet single crystals of Pd(HS2 O7 )2 (monoclinic, P21 /c, Z=2, a=927.80(9), b=682.58(7), c=920.84(9) pm, beta=117.756(2) degrees , wR2 =0.0439). In the crystal structure, the Pd(2+) ions show an uncommon octahedral coordination of six oxygen atoms belonging to six HS2 O7 (-) ions. The linkage of [PdO6 ] octahedra and the hydrogendisulfate anions leads to a layer structure, and the layers are held together by hydrogen bonds. The unusual coordination of the Pd(2+) ions results in an electronic d(8) high-spin configuration, which leads to the paramagnetic behavior of the compound. Moreover, at low temperature, a ferromagnetic ordering was observed with a Curie temperature of 8 K. PMID- 24339046 TI - Efficient capillary electrophoresis separation and determination of free amino acids in beer samples. AB - Simultaneous detection of various o-phthalaldehyde (OPA)-labeled amino acids (AAs) in food samples was reported based on CE separation. Ionic liquid was used for the first time for CE analysis of AAs with in-capillary derivatization. Several other additives, including SDS, alpha/beta-CD, and ACN, as well as key parameters for CE separation (buffer pH value, separation voltage), were also investigated. Our results show that the multiple additive strategy exhibits good stable and repeatable character for CE analysis of OPA-labeled AAs, for either in capillary derivatization or CE separation, and allows simultaneous quantification of different OPA-labeled AAs in a large concentration range of 50 MUM to 3.0 mM with LOD down to 10 MUM. Seventeen OPA-labeled AAs, except for two pairs of AAs (His/Gln and Phe/Leu), which were separated with resolutions of 1.1 and 1.2, respectively, were baseline separated and identified within 23 min using the present multiple additive strategy. The method was successfully applied for simultaneous analysis of AAs in seven beer samples and as many as eleven trace amount AAs were detected and quantified, indicating the valuable potential application of the present method for food analysis. PMID- 24339047 TI - Orthopedics management of acromicric dysplasia: follow up of nine patients. AB - Acromicric dysplasia (AD) is an autosomal dominant disorder characterized by short stature, short extremities, stiff joint and skeleton features including brachymetacarpia, cone-shaped epiphyses, internal notch of the femoral head, and delayed bone age. Recently, we identified fibrillin 1 (FBN1) as the disease gene of AD. The aim of our study was to further describe the long-term follow up of AD patients with an emphasis on orthopedic management. Nine patients with FBN1 mutations were included in the study ranging in age from 5.5 to 64 years. For all, detailed clinical and radiological data were available. RESULTS: Birth parameters were always normal and patients progressively developed short stature <-3 SD. Carpal tunnel syndrome was observed in four patients. We found discrepancy between the carpal bone age and the radius and ulna epiphysis bone ages, a variable severity of hip dysplasia with acetabular dysplasia, epiphyseal and metaphyseal femoral dysplasia resembling Legg-Perthes-Calve disease and variable pelvic anteversion and hyperlordosis. Orthopedic surgery was required in two patients for hip dysplasia, in one for limb lengthening and in three for carpal tunnel syndrome. Our observations expand the AD phenotype and emphasize the importance of regular orthopedic survey. PMID- 24339048 TI - Synthesis of silk fibroin micro- and submicron spheres using a co-flow capillary device. AB - A custom-made co-flow capillary device is used to synthesize monodisperse silk fibroin micro- and submicron-spheres with diameters tunable over a wide range of sizes. A model drug release is examined and control of degradation kinetics is obtained by changing sphere diameter. PMID- 24339049 TI - Activation of a photodissociative ruthenium complex by triplet-triplet annihilation upconversion in liposomes. AB - Liposomes capable of generating photons of blue light in situ by triplet-triplet annihilation upconversion of either green or red light, were prepared. The red-to blue upconverting liposomes were capable of triggering the photodissociation of ruthenium polypyridyl complexes from PEGylated liposomes using a clinical grade photodynamic therapy laser source (630 nm). PMID- 24339050 TI - Ideal three-dimensional electrode structures for electrochemical energy storage. AB - Three-dimensional electrodes offer great advantages, such as enhanced ion and electron transport, increased material loading per unit substrate area, and improved mechanical stability upon repeated charge-discharge. The origin of these advantages is discussed and the criteria for ideal 3D electrode structure are outlined. One of the common features of ideal 3D electrodes is the use of a 3D carbon- or metal-based porous framework as the structural backbone and current collector. The synthesis methods of these 3D frameworks and their composites with redox-active materials are summarized, including transition metal oxides and conducting polymers. The structural characteristics and electrochemical performances are also reviewed. Synthesis of composite 3D electrodes is divided into two types - template-assisted and template-free methods - depending on whether a pre-made template is required. The advantages and drawbacks of both strategies are discussed. PMID- 24339052 TI - Diabetes, dysglycemia and cognitive dysfunction. AB - Evidence from the last decade supports the hypothesis that diabetes may be viewed as a disease of accelerated cognitive ageing. It is a risk factor for the development of dementia, for an accelerated rate of cognitive decline and for cognitive dysfunction. Thus, 'diabetes-related cognitive dysfunction' may be viewed as another long-term complication of diabetes. This article will review the evidence supporting this hypothesis and will elaborate on the implications for patient care, as well as discuss potential treatment options and their limitation. The final section reviews possible mechanistic explanations. PMID- 24339051 TI - Racial variation in the quality of surgical care for bladder cancer. AB - BACKGROUND: Differences in quality of care may contribute to racial variation in outcomes of bladder cancer (BCa). Quality indicators in patients undergoing surgery for BCa include the use of high-volume surgeons and high-volume hospitals, and, when clinically indicated, receipt of pelvic lymphadenectomy, receipt of continent urinary diversion, and undergoing radical cystectomy instead of partial cystectomy. The authors compared these quality indicators as well as adverse perioperative outcomes in black patients and white patients with BCa. METHODS: The Healthcare Cost and Utilization Project State Inpatient Databases for New York, Florida, and Maryland (1996-2009) were used, because they consistently included race, surgeon, and hospital identifiers. Quality indicators were compared across racial groups using regression models adjusting for age, sex, Elixhauser comorbidity sum, insurance, state, and year of surgery, accounting for clustering within hospital. RESULTS: Black patients were treated more often by lower volume surgeons and hospitals, they had significantly lower receipt of pelvic lymphadenectomy and continent diversion, and they experienced higher rates of adverse outcomes compared with white patients. These associations remained significant for black patients who received treatment from surgeons and at hospitals in the top volume decile. CONCLUSIONS: Black patients with BCa had lower use of experienced providers and institutions for BCa surgery. In addition, the quality of care for black patients was lower than that for whites even if they received treatment in a high-volume setting. This gap in quality of care requires further investigation. PMID- 24339053 TI - Locally instilled tumor necrosis factor alpha antisense oligonucleotide contributes to inhibition of TH 2-driven pulmonary fibrosis via induced CD4+ CD25+ Foxp3+ regulatory T cells. AB - BACKGROUND: Anti-tumor necrosis factor alpha therapeutics has the potential to alleviate pulmonary fibrosis. However, the systemic administration of anti-tumor necrosis factor alpha agents has brought about contradictory results and frequent adverse effects, such as infections, immunogenicity and malignancies, amongst others. In the present study, we attempted the local administration of tumor necrosis factor alpha antisense oligonucleotide and evaluated the treatment effects on pulmonary fibrosis in a bleomycin-induced pulmonary fibrosis mouse model. METHODS: Flow cytometry for regulatory T cells, reverse transcriptase polymerase chain reaction for crucial gene expression, western blotting for crucial protein products, immunofluorescent analysis for T(H)2 cells and myofibroblasts, as well as histology analysis for pathological examination, were used. RESULTS: By local administration of tumor necrosis factor alpha antisense oligonucleotide, we investigated whether tumor necrosis factor alpha expression in epithelial cells was significantly inhibited and extracellular matrix overexpression was dramatically reduced. These treatment effects were associated with induced regulatory T cells, reduced T(H)2 cells and generally decreased T(H)2-type cytokine expression. Systemic immunosuppression was not triggered by local antisense oligonucleotide administration because the proportion of regulatory T cells in the blood, thymus or spleen was not affected. CONCLUSIONS: These findings demonstrate that local administration of tumor necrosis factor alpha antisense oligonucleotide contributes to anti-fibrotic action via a sustained up-regulated level of regulatory T cells, which inhibits T(H)2-biased responses, pro-fibrotic mediator production and extracellular matrix deposition, with no systemic immunosupression associated with systemically induced regulatory T cells. PMID- 24339054 TI - Dynamic protein interaction network construction and applications. AB - With more dynamic information available, researchers' attention has recently shifted from static properties to dynamic properties of protein-protein interaction networks. To compensate the limited ability of technologies of detecting dynamic protein-protein interactions, dynamic protein interaction networks (DPINs) can be constructed by involving proteomic, genomic, and transcriptome analyses. Two groups of DPIN construction methods are classified based on the different focuses on dynamic information extracted from gene expression data. The dynamics of one kind of DPINs is reflected by the changes in protein presence varying with time, while that of the other kind of DPINs is reflected by the differences of coexpression under different conditions. In this review, the applications on DPINs will be discussed, including protein complexes/functional modules and network organization analysis, biomarkers detection in the progression or prognosis of the disease, and network medicine. We also point out the challenges in DPINs construction and future directions in the research of DPINs at the end of this review. PMID- 24339055 TI - IQ and obesity in adolescence: a population-based, cross-sectional study. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Low IQ is associated with high BMI in childhood. There are inconsistent findings on the association between low SES and high BMI. Youth with low IQ have been reported to have poorer health behaviors, such as poor nutrition and less physical activity. WHAT THIS STUDY ADDS: Low IQ is significantly associated with obesity for both male and female adolescents, though more strongly for female adolescents. Physical activity has a mediating effect on the association between low IQ and obesity among both male and female adolescents, though more strongly for male adolescents. The association between low IQ and obesity is strongest among adolescents from high SES backgrounds. BACKGROUND: Previous studies have shown an association between low intelligence quotient (IQ), high body mass index and low socioeconomic status (SES). OBJECTIVES: This study examined the cross-sectional association between IQ and obesity, exploring the roles of gender, SES and physical activity in this association. METHODS: Subjects were 235,663 male and 169,259 female adolescents assessed by the Israeli military draft board. RESULTS: Low IQ was significantly associated with increased odds of obesity among male (odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.36-1.52) and female adolescents (OR = 1.61, 95% CI = 1.51-1.73); this association was significantly stronger among female adolescents. Sobel tests indicated that physical activity had a significant mediating effect on this association for male and female adolescents, although more strongly for male adolescents. Dividing the sample according to SES, the association between low IQ and obesity was strongest in the high SES group (male adolescents: OR = 1.26, 95% CI = 1.10-1.43, female adolescents: OR = 1.61, 95% CI = 1.38-1.89), even when controlling for physical activity. CONCLUSIONS: The findings suggest that low IQ is associated with increased odds of obesity, particularly in female adolescents and in adolescents with high SES. Physical activity has a mediating effect on this association, although more strongly for male than for female adolescents. Public health measures on decreasing obesity might focus on these groups. PMID- 24339056 TI - Clinical use of oxygen-enhanced T1 mapping MRI of the lung: reproducibility and impact of closed versus loose fit oxygen delivery system. AB - PURPOSE: To evaluate the reproducibility of oxygen-enhanced magnetic resonance imaging (MRI), and the influence of different gas delivery methods, in a clinical environment. MATERIALS AND METHODS: Twelve healthy volunteers were examined on two visits with an inversion recovery snapshot fast low angle shot sequence on a 1.5 T system. Coronal slices were obtained breathing room air as well as 100% oxygen with a flow rate of 15 L/min. For oxygen delivery a standard nontight face mask and a full closed air-cushion face mask were used. T1 relaxation times and the oxygen transfer function (OTF) were calculated. RESULTS: The mean T1 values did not change significantly between the two visits (P > 0.05). The T1 values breathing 100% oxygen obtained using the full closed mask were significantly lower (1093 +/- 38 msec; P < 0.05) compared to the standard mask (1157 +/- 52 msec). Accordingly, the OTF was significantly higher for the full closed mask (P < 0.05). The OTF changed significantly on the second visit using the standard mask (P < 0.05). The full closed mask showed lower interindividual variation for both the T1 values (3.5% vs. 4.5%) as well as the OTF (12.4% vs. 22.0%) and no difference of the OTF on the second visit (P > 0.05). CONCLUSION: Oxygen-enhanced T1 mapping MRI produces reproducible data when using a full closed face mask. PMID- 24339058 TI - Cyanobuta-1,3-dienes as novel electron acceptors for photoactive multicomponent systems. AB - The synthesis, electrochemical, and photophysical properties of five multicomponent systems featuring a Zn(II) porphyrin (ZnP) linked to one or two anilino donor-substituted pentacyano- (PCBD) or tetracyanobuta-1,3-dienes (TCBD), with and without an interchromophoric bridging spacer (S), are reported: ZnP-S PCBD (1), ZnP-S-TCBD (2), ZnP-TCBD (3), ZnP-(S-PCBD)2 (4), and ZnP-(S-TCBD)2 (5). By means of steady-state and time-resolved absorption and luminescence spectroscopy (RT and 77 K), photoinduced intramolecular energy and electron transfer processes are evidenced, upon excitation of the porphyrin unit. In systems equipped with the strongest acceptor PCBD and the spacer (1, 4), no evidence of electron transfer is found in toluene, suggesting ZnP->PCBD energy transfer, followed by ultrafast (<10 ps) intrinsic deactivation of the PCBD moiety. In the analogous systems with the weaker acceptor TCBD (2, 5), photoinduced electron transfer occurs in benzonitrile, generating a charge separated (CS) state lasting 2.3 MUs. Such a long lifetime, in light of the high Gibbs free energy for charge recombination (DeltaG(CR)=-1.39 eV), suggests a back electron transfer process occurring in the so-called Marcus inverted region. Notably, in system 3 lacking the interchromophoric spacer, photoinduced charge separation followed by charge recombination occur within 20 ps. This is a consequence of the close vicinity of the donor-acceptor partners and of a virtually activationless electron transfer process. These results indicate that the strongly electron-accepting cyanobuta-1,3-dienes might become promising alternatives to quinone-, perylenediimide-, and fullerene-derived acceptors in multicomponent modules featuring photoinduced electron transfer. PMID- 24339057 TI - Increased IL-6 expression in osteoclasts is necessary but not sufficient for the development of Paget's disease of bone. AB - Measles virus nucleocapsid protein (MVNP) expression in osteoclasts (OCLs) and mutation of the SQSTM1 (p62) gene contribute to the increased OCL activity in Paget's disease (PD). OCLs expressing MVNP display many of the features of PD OCLs. Interleukin-6 (IL-6) production is essential for the pagetic phenotype, because transgenic mice with MVNP targeted to OCLs develop pagetic OCLs and lesions, but this phenotype is absent when MVNP mice are bred to IL-6(-/-) mice. In contrast, mutant p62 expression in OCL precursors promotes receptor activator of NF-kappaB ligand (RANKL) hyperresponsivity and increased OCL production, but OCLs that form have normal morphology, are not hyperresponsive to 1,25 dihydroxyvitamin D3 (1,25-(OH)2 D3 ), nor produce elevated levels of IL-6. We previously generated p62(P394L) knock-in mice (p62KI) and found that although OCL numbers were increased, the mice did not develop pagetic lesions. However, mice expressing both MVNP and p62KI developed more exuberant pagetic lesions than mice expressing MVNP alone. To examine the role of elevated IL-6 in PD and determine if MVNP mediates its effects primarily through elevation of IL-6, we generated transgenic mice that overexpress IL-6 driven by the tartrate-resistant acid phosphatase (TRAP) promoter (TIL-6 mice) and produce IL-6 at levels comparable to MVNP mice. These were crossed with p62KI mice to determine whether IL-6 overexpression cooperates with mutant p62 to produce pagetic lesions. OCL precursors from p62KI/TIL-6 mice formed greater numbers of OCLs than either p62KI or TIL-6 OCL precursors in response to 1,25-(OH)2 D3 . Histomorphometric analysis of bones from p62KI/TIL-6 mice revealed increased OCL numbers per bone surface area compared to wild-type (WT) mice. However, micro-quantitative CT (uQCT) analysis did not reveal significant differences between p62KI/TIL-6 and WT mice, and no pagetic OCLs or lesions were detected in vivo. Thus, increased IL-6 expression in OCLs from p62KI mice contributes to increased responsivity to 1,25 (OH)2 D3 and increased OCL numbers, but is not sufficient to induce Paget's-like OCLs or bone lesions in vivo. PMID- 24339059 TI - Dementia Knowledge Assessment Tool Version Two: development of a tool to inform preparation for care planning and delivery in families and care staff. AB - Care for the person with dementia requires understanding of the person's perspective and preferences, integrated with knowledge of dementia's trajectory and appropriate care. Version One of the Dementia Knowledge Assessment Tool addressed such knowledge in care workers; Version Two is for families as well as staff. Content validity was established during development. Revisions addressed clarity, time for completion, and reliability. When 671 staff completed Version One before an education intervention, internal consistency reliability estimates exceeded 0.70. Validity was supported by higher scores in professional versus nonprofessional staff and following the education. Version Two was used with 34 family carers and 70 staff members. Internal consistency reliability (Cronbach's alpha coefficient) was promising (0.79, both groups). Completion was within 15 minutes. Median correct responses (from 21) were 14 for families (range 4-20) and 16 for the staff (range 3-21). Eighteen staff members (26%) and two family carers (6%) reported substantive dementia education. Inclusion of the person with dementia in care planning is often limited because of a late diagnosis and the progressive impacts of the condition. Establishing a shared staff-family understanding of the dementia trajectory and care strategies likely to be helpful is therefore critical to embarking upon the development and implementation of collaborative long term and end-of-life care plans. Version Two can help establish needs for, and outcomes of, education programs and informational resources in a way that is feasible, minimises burden, and facilitates comparisons across family and staff carer groups. PMID- 24339060 TI - Impact of dementia on marriage: a qualitative systematic review. AB - This qualitative review explored the impact of dementia on marriage. The method was informed by systematic review and qualitative research methodologies. A comprehensive search of major databases was undertaken. The search identified 115 studies on the topic; 23 met the inclusion criteria and 19 were appraised as being of good methodological quality. Two major themes and five sub-themes emerged from the analysis of included studies, transition and loss. The theme of transition encompassed the three sub-themes of relationship, roles and intimacy and reflected the changes in the marriage and marital relationship that accompanied dementia. The theme of loss encompassed the two sub-themes of loss of a partner and loss of a marriage, which reflected the many losses that accompanied dementia. However, transition and loss were inter-related, because each change was accompanied by loss and each loss produced another change in the marriage. PMID- 24339061 TI - Understanding the sleep problems of people with dementia and their family caregivers. AB - Sleep disturbances are common with dementia and can adversely affect waking function. However, the perspectives of people with dementia and their family caregivers concerning their sleep are under-researched. We conducted three focus groups with 12 community-dwelling pairs (a person with dementia and their family caregiver). Discussions addressed sleep disturbances, coping strategies, and beliefs and attitudes surrounding sleep. Thematic analysis indicated that dementia-related sleep disturbances were common, including confused awakenings and dementia-related behaviors at night, changes to sleep timing, and nightmares. Common issues for caregivers included being woken at night, having problems getting back to sleep, trips to the bathroom, and daytime sleepiness. Participants often normalized their sleeping problems and had developed a number of coping strategies. These findings highlight the impact that sleep disturbances can have on people living with dementia. Their experiences and beliefs need to be considered for developing effective interventions to improve sleep, waking function, and wellbeing. PMID- 24339062 TI - Evaluating educational initiatives to improve palliative care for people with dementia: a narrative review. AB - Dementia accounts for one in three deaths among people aged 65 and over, but end of-life care for people with dementia is often sub-optimal. Palliative care for people with dementia poses particular challenges to those providing services, and current policy initiatives recommend education and training in palliative care for those working with patients with dementia. However, there are few evaluations of the effectiveness of dementia education and training. This paper presents a narrative review undertaken in 2011-2012 of evaluations of palliative care education for those working with people with dementia at the end of life. A total of eight papers were identified that described and evaluated such palliative care education; none reported benefits for people with dementia. There is a clear need to develop and evaluate educational interventions designed to improve palliative and end-of-life care for people with dementia. Some suggestions for educationally sound approaches are discussed. PMID- 24339063 TI - Development and evaluation of a telehealth videoconferenced support group for rural spouses of individuals diagnosed with atypical early-onset dementias. AB - Atypical and early-onset dementias can be particularly problematic for family caregivers, and support groups aimed at memory loss and Alzheimer's disease are not always helpful. Unfortunately, little has been developed specifically for caregivers of individuals with atypical dementias such as the frontotemporal dementias. Compounding the lack of access to interventions targeted specifically at caregivers of individuals with atypical and early-onset dementias are the unique needs of rural caregivers. Due to the relative infrequency of these particular dementias and the large geographical distances between rural caregivers, technology-facilitation is required for any group-based intervention. This paper describes the development of a secure telehealth videoconferenced support group for rural spouses of individuals with atypical and early-onset dementias. In addition, we provide preliminary evidence of effectiveness and describe a template for future groups based on the key therapeutic aspects of this novel technology-facilitated intervention. PMID- 24339064 TI - Framing spaces in places: creating "respite spaces" in dementia care settings. AB - Research on dementia care settings has primarily focused on routine aspects of life, including mealtimes, bathing procedures, etc. However, studies rarely explore how individuals with dementia interact in these settings during the intervals between routines. This study aimed to analyze how residents actively carved out spaces that provided temporary respite from institutional life, termed "framing respite spaces." Ethnographic data was collected over five months in a dementia care setting in Sweden. Frame analysis was employed to investigate residents' shared understanding of non-task-orientated situations. The results showed that individuals with dementia adjusted to institutional order, but also actively created respite spaces through conversation. Interestingly, individuals with dementia interpreted conversational cues and often acted logically according to a shared definition of the specific situation. These findings showed that looking beyond task-orientated interactions between staff and residents can provide a more detailed picture of everyday life in dementia care settings. PMID- 24339065 TI - Dementia and its influence on quality of life and what it means to be valued: family members' perceptions. AB - This pragmatic, exploratory qualitative study, as part of a larger funded research project, sought to explore families' perspectives on what it means to value a person with dementia and how this value might influence the quality of life of people with dementia. In-depth interviews were conducted with 20 family members who used one long-term care service provider in Australia. Families described the factors influencing a positive quality of life for the person with dementia as being related to the environment and, in particular, to the resident's room, supportive staff and individualised care that valued the person's life experience. Family also reported a negative impact on quality of life when staff and the care facility neglected to provide an individualised approach. This study highlights the importance of demonstrating the value of the person with dementia, the family role and partnerships of care. PMID- 24339066 TI - Towards living well with young onset dementia: An exploration of coping from the perspective of those diagnosed. AB - There is increasing recognition that dementia in people under 65 years represents a unique challenge to sufferers and services alike. However, by either ignoring this population or sampling them together with older adults, current research has failed to reflect this. This study explored the specific experience of living and coping with Alzheimer's disease in younger life from the perspective of those diagnosed. Semi-structured interviews were analysed using interpretive phenomenological analysis, and four themes were identified: 'disruption of the life-cycle', 'identity', 'social orientation' and 'agency'. The experience of living and coping with young onset Alzheimer's disease was strongly situated within an individual's social context. Most significantly, participants felt too young to develop the disease and felt out of time with age-related psychological tasks. Coping strategies that attempted to redress and normalise the life-cycle were identified. The contributions of the study are discussed in the context of the human development literature. PMID- 24339067 TI - Complexity in cognitive assessment of elderly British minority ethnic groups: Cultural perspective. AB - AIM: To study the influence of cultural believes on the acceptance and accessibility of dementia services by patients from British Minority Ethnic (BME) groups. RESULTS: It is noted that non-White ethnic populations rely more on cultural and religious concepts as coping mechanisms to overcome carer stress. In British Punjabi families, ageing was seen as an accepted reason for withdrawal and isolation, and cognitive impairment was rarely identified. Illiteracy added another complexity, only 35% of older Asians in a UK city could speak English, 21% could read and write English, while 73% could read and write in their first language. False positive results using Mini Mental State Examination was found to be 6% of non-impaired white people and 42% of non-impaired black people. Cognitive assessment tests under-estimate the abilities in BME groups. Wide range of variations among white and non-White population were found, contributors are education, language, literacy and culture-specific references. PMID- 24339068 TI - Dementia: The need for attitudinal change. AB - OBJECTIVE: To undertake a systematic inquiry into the experience of living with dementia in the community. DESIGN: Action research, underpinned by critical hermeneutics, brought together action and reflection, theory and practice to generate knowledge. Data were gathered by interviews and observations in participants' homes, and focus group discussions in community settings. PARTICIPANTS: Eleven people with mild to moderate dementia and their primary caregiver aged 59-84, living in Auckland, New Zealand. RESULTS: The findings reveal a conflict between living positively with dementia, and enduring the negative attitudes that typify the dominant social discourse. The central argument arising from the findings is the significance of personal attitudes. CONCLUSIONS: Implications for policy makers, health care providers, and caregivers highlight the need to change the ways in which dementia is perceived. The pursuit of positive attitudes will do much to change social perceptions and enable people with dementia to live with a sense of well-being. PMID- 24339069 TI - Exploring the affective dimension of the life review process: Facilitators' interactional strategies for fostering personhood and social value among older adults with early dementia. AB - We employed an auto-ethnography approach to explore the affective dimension of life review sessions with community-dwelling older military veterans with minor cognitive impairment (MCI) and early dementia. Using researchers' analytic memos, we identified facilitators' interactional strategies that fostered the participant's sense of personal identity, dignity and social self-worth. Interaction among participant, caregiver, and facilitators evoked a range of emotional responses, offering a window into the affective world of MCI and early dementia. Positive emotional responses outnumbered negative emotional responses by a ratio of two-to-one in the life review sessions; however, negative emotions were more revelatory of current struggles with declines in health and function. Facilitators utilized two interactional strategies, in particular, to foster personhood and social value of participants: focusing on the participant and creating an empathic connection with the participant. Further work is needed to understand the role of emotions in research interactions and to examine the psychosocial mechanisms through which positive affect functions in promoting identity, personhood and social value among persons with MCI and early dementia. PMID- 24339070 TI - Finding meaning in everyday life with dementia: A case study. AB - This paper presents a case study exploring an older woman's perspective on the quality of her life with dementia. The case study establishes the importance of coherence across the life course in understanding how she evaluates her changed situation in the present compared to the past. The metaphoric description of moving from 'up there' to 'down here' represents the perceived struggle to maintain a sense of worth despite a marginalised social position. Being able to define self and social identity in ways that preserve a sense of social status is important to find meaning in everyday life. Finding meaning involves looking backwards to sustain continuity with the past and looking forwards to maintain momentum and keep going. A narrative framework is valuable in showing that quality of life is a dimension of meaning associated with maintaining a sense of social worth. PMID- 24339071 TI - Attachment and coping of dementia care staff: The role of staff attachment style, geriatric nursing self-efficacy, and approaches to dementia in burnout. AB - Past research suggests that dementia care staff are vulnerable to the development of burnout, which has implications for staff well-being and hence the quality of care for people with dementia. Studying personal vulnerability factors in burnout is important as it can guide staff training and support. Attachment theory suggests that adult attachment styles affect caregiving relationships and individuals' responses to stress, providing a framework for understanding caregivers' styles of coping. This cross-sectional survey study examined relationships between staff attachment styles, geriatric nursing self-efficacy, and approaches to dementia in burnout. Seventy-seven members of dementia care staff working on inpatient wards for older people completed self-report questionnaires. Insecure attachment, lower levels of self-efficacy, and more optimistic attitudes in staff were related to higher levels of burnout. Staff training on the role of attachment in dementia care is recommended. Further research is required to explore mediating factors between adult attachment styles and burnout. PMID- 24339072 TI - 'We need to know what's going on': views of family members toward the sexual expression of people with dementia in residential aged care. AB - This paper reports on a study which explored the views and attitudes of family members towards the sexual expression of residents with dementia in residential aged care facilities in two states in Australia. Recruitment was challenging and only seven family members agreed to an interview on this topic. Data were analysed using a constant comparative method. Family were generally supportive of residents' rights to sexual expression, but only some types of behaviours were approved of. There was an acknowledgement that responding to residents' sexuality was difficult for staff and many families believed that they should be kept informed of their relative's sexual behaviours and moreover be involved in decision making about it. Findings suggest the need for family education and a larger study to better understand the views and motivations of family carers and how these might impact on the sexual expression of the older person with dementia living in residential aged care. PMID- 24339073 TI - Christian worship leaders' attitudes and observations of people with dementia. AB - BACKGROUND: The cognitive, emotional, and psychological consequences of dementia are profound and can include memory loss, processing and, communication difficulties, social isolation and agitation. Procedural memory remains fairly intact in people with dementia (PWD) and is readily triggered via sensory cues and prompts. As religious services are often highly structured, it is likely that PWD can participate competently, potentially enhancing their quality of life, and wellbeing. AIMS: This study aimed to investigate Christian worship leaders' attitudes and observations of PWD attending religious services, to identify recurring themes, and to generate hypotheses regarding the effects of participation in religious services on PWD. METHOD: The participants were Christian worship leaders experienced in conducting religious services for PWD. The study adopted a grounded theory approach consisting of two phases: a focus group of four worship leaders at Phase 1 and a series of one-to-one interviews with eight worship leaders at Phase 2. RESULTS: Five linked themes emerged: familiarity and structure; enhanced sensory cues; significance of worship leader's approach; social support from and for family and carers; and the personality and characteristics of the PWD. These themes were used to develop a conceptual model, sharing the moderating and mediating factors of wellbeing. CONCLUSION: Religious worship appeared to constitute a naturalistic psychosocial intervention comprised of the service itself and the social context. Further investigation and conceptualisation of the interaction between PWD and their social environment is warranted, and collaboration with those people who constitute the PWD's social support network. PMID- 24339075 TI - Evaluation of an education intervention to implement a capability model of dementia care. AB - This paper outlines an intervention protocol used to educate carers in a project that implemented and evaluated a capability model of dementia care (CMDC) in three long-term aged care facilities. It outlines an evaluation of the content of the education and processes used to deliver the intervention through an analysis of surveys and reflective field notes. The education protocol was designed for adult learners and grounded in the six assumptions of Knowles' learning theory. Results suggest the education protocol positively impacted on the knowledge, skills and attitudes of participants towards providing quality dementia care to residents in long-term care. The paper also acknowledges the challenges involved in sustaining a practice change through an educational intervention. PMID- 24339074 TI - 'Brightness in dark places': theatre as an arena for communicating life with dementia. AB - The aim of this study was to use artistic expressions on a theatrical stage for communicating life with dementia, as portrayed in literary texts and to explore whether such communication would help relatives of people suffering from dementia gain knowledge of their situation. Life with dementia was portrayed through four theatre performances with actors reading excerpts from literary texts combined with music. Relatives were invited to the performances and to participate in focus groups following the events. Analysis revealed that the participants recognized episodes in the texts and were touched. This resulted in new knowledge. The aesthetic expression was of great significance. The use of the theatre stage as an arena for communicating knowledge became a meaningful experience. The performances enabled identification with roles on the stage, created a feeling of community with the audience and contributed to an experience of dignity. PMID- 24339076 TI - The dance of communication: retaining family membership despite severe non-speech dementia. AB - There is minimal research investigating non-speech communication as a result of living with severe dementia. This phenomenological study explores retained awareness expressed through non-speech patterns of communication in a family member living with severe dementia. Further, it describes reciprocal efforts used by all family members to engage in alternative patterns of communication. Family interactions were filmed to observe speech and non-speech relational communication. Participants were four family groups each with a family member living with non-speech communication as a result of severe dementia. Overall there were 16 participants. Data were analysed using thematic analysis. One superordinate theme, Dance of Communication, describes the interactive patterns that were observed during family communication. Two subordinate themes emerged: (a) in-step; characterised by communication that indicated harmony, spontaneity and reciprocity, and; (b) out-of-step; characterised by communication that indicated disharmony, syncopation, and vulnerability. This study highlights that retained awareness can exist at levels previously unrecognised in those living with limited or absent speech as a result of severe dementia. A recommendation for the development of a communication program for caregivers of individuals living with dementia is presented. PMID- 24339077 TI - 'It's a huge maze, the system, it's a terrible maze': dementia carers' constructions of navigating health and social care services. AB - Dementia is a challenging, progressive set of conditions which present a large care burden to informal, familial carers. A complex array of health and social care services are needed to support people living with dementia. Drawing on the interlinked 'Duties to Care' and 'Dementia Talking' projects, in this article we focus on British carers' talk about health and social care services. We explore data from a mixed-method questionnaire (n = 185), four focus groups and eleven interviews with informal carers of people living with dementia using thematic discourse analysis. Three themes are discussed: (1) services as a 'maze'; (2) services as overly limited - 'beyond our remit'; and (3) the battle and fighting discourse deployed by these carers. Our analysis highlights that carers find navigating systemic issues in dementia care time-consuming, unpredictable and often more difficult than the caring work they undertake. PMID- 24339078 TI - Learning and using technology in intertwined processes: a study of people with mild cognitive impairment or Alzheimer's disease. AB - People with mild cognitive impairment and Alzheimer's disease are likely to be challenged by the multitude of everyday technology in today's society. The aim of this study was to explore how they try to prohibit, avoid or solve problems in everyday technology use, maintain skills, and learn to use new technology. To explore how the participants applied and reasoned about using everyday technology in real-life situations interviews were conducted while the participants used their own technology in their homes. Interviews were conducted with 20 participants with mild cognitive impairment (n = 10) or Alzheimer's disease (n = 10). The analyses were inspired from grounded theory and resulted in one core category and three sub-categories that represent sub-processes in the core. The core finding presents a continuous, intertwined process of learning and using everyday technology, highlighting how the context was interwoven in the processes. The participants used a rich variety of management strategies when approaching technology, including communication with the everyday technologies on different levels. The findings underscore that it is important to support continued use of everyday technology as long as it is valued and relevant to the person with mild cognitive impairment or Alzheimer's disease. The intertwined process of learning and using everyday technology suggests how support could target different sub-processes. PMID- 24339079 TI - Enriching the care of patients with dementia in acute settings? The Dementia Champions Programme in Scotland. AB - Admission to hospital has been found to have a negative impact on people with dementia. The Scottish Dementia Champions programme was developed to prepare health and social service Dementia Champions working in acute settings as Change Agents. The programme was initially delivered to a cohort of 100 health professionals via blended learning, and comprised five study days, a half day spent in a local community setting, and e-learning. In order to complete the programme and graduate, participants were required to complete and submit reports relating to three work-based activities. The evaluation of the project adopted a two-pronged approach: Impact on programme participants was assessed by scores derived from the Approaches to Dementia Questionnaire (ADQ) (Lintern, 1996) completed at Study Days 1 and 5, and analysis of qualitative data derived from the three written assignments. Participants were asked to evaluate course materials and input for each of the five study days, as well as satisfaction with delivery. Analysis of data derived from the ADQ and 100 reflective reports of the community experience indicate that participants' perceptions of people with dementia shifted significantly during the Programme. Participants identified a range of issues which should be addressed with a view to improving the experiences of people with dementia in acute settings, and put in place actions to bring about change. The format of the programme provided a cost effective means to prepare NHS and Social Service Dementia Champions as Change Agents for practice within a relatively short period of time, and would be transferrable to other staff groups as well as different organisational structures in other countries. PMID- 24339080 TI - Conversation analysis as a method for investigating interaction in care home environments. AB - This article gives an outline of how the socio-linguistic approach of conversation analysis can be applied to the analysis of carer-patient interaction in care homes. A single case study from a routine encounter in a residential care home is presented. This is used to show how the conversation analysis method works, the kinds of interactional and communication features it can expose, and what specific contribution this kind of micro-interactional approach may make to improving quality of care in these environments. PMID- 24339081 TI - Attachment in people with dementia and their caregivers: a systematic review. AB - Attachment bonds are important for personality development, emotion regulation and mental health throughout the lifespan. This systematic review explores the relevance of attachment for people with dementia, and how attachment influences the experience of caregivers of people with dementia. Eighteen studies were included. Three focused on attachment in terms of parent fixation in dementia, three examined attachment behaviour in dementia, five addressed attachment and dementia-related behavioural problems, and seven concentrated on attachment in caregivers. Attachment behaviours were evident at various stages of dementia and the presence of parent fixation was observed when attachment needs were not being met. Insecure attachment was related to neuropsychiatric symptoms. Attachment security had important consequences for caregiver psychological health. Implications of methodological issues such as the choice of respondent, measurement issues, and the lack of a longitudinal perspective are discussed. The implications of attachment for the support of people with dementia and caregivers are considered. PMID- 24339082 TI - Psycho-educational support for relatives of people with a recent diagnosis of mild to moderate dementia: an evaluation of a 'Course for Carers'. AB - Currently there are 820,000 people with dementia in the UK, a figure projected to reach 1.7 million by 2050. Policy and practice emphasis on early intervention in dementia and support of family carers foreground a need to explore service efficacy for relatives of those with a recent diagnosis. Existing evidence suggests that psycho-educational interventions can significantly enhance carer well being especially when well targeted and group based. A rolling programme of seven psycho-educational Courses for 'new carers' in one area of England was the subject of a systematic evaluation incorporating a quantitative rating scale and qualitative data. Findings suggest that the Courses achieved a number of intersecting aims: they provided psychological support; offered advice; enhanced coping skills; boosted confidence; increased knowledge; and prepared the carer for the future. That the Courses were designed and delivered by specialist staff primarily psychologists, offered a social dimension, were time limited and free are noteworthy features. The evaluation suggests that as a model the Course has considerable short and longer term preventive potential; also that it could be replicated elsewhere in the country and achieve similar outcomes. PMID- 24339083 TI - The experience of sons caring for a parent with dementia. AB - This study explored the experiences of sons caring for a parent with dementia. Individual, semi-structured interviews were conducted with a purposeful sample of sons (n = 13) in a rural part of Ireland. Interviews were audiotaped, transcribed verbatim and analysed for common themes. The key themes that emerged were 'the parental bond', 'a binding role', 'coordinating care and support' and a 'getting on with it' approach to care. The study highlighted the commitment of sons to their caregiving role and the strong sense of duty that motivated them to provide care. The findings suggested that while many aspects of the caregiving experience such as lack of information and support are gender neutral, there are differences in the caregiving experiences of men and women in how they view their relationship with their parent and in the management of their caregiving role that merit further investigation. PMID- 24339084 TI - Caregiving stress and coping: a thematic analysis of Chinese family caregivers of persons with dementia. AB - PURPOSE: This study aims to identify caregiving stressors and coping strategies in a sample of family caregivers of persons with dementia living in Shanghai, China. METHODS: A sample of 18 family caregivers participated in semi-structured face-to-face interviews. Information regarding caregiver appraisal of caregiving situations, difficulties with care provision, and ways of dealing with stressors were obtained. Thematic analysis was used to assess the interview data. RESULTS: In addition to stressors directly related to caregiving demands (i.e., burden due to care recipient limitations in physical, cognitive, or behavioral functions), other salient stressors that emerged were role strains, family conflicts, and pressure from the social environment. Yet, caregivers demonstrated resilience by drawing on their coping resources from a variety of sources, including personal experience, family, technology and information, religion, and governmental support. IMPLICATIONS: Specific attention needs to be given to help family caregivers alleviate stress due to family conflicts and pressure from the social environment. Policy formulation and program design needs to build on caregiver strengths to support and empower Chinese families caring for relatives with dementia patients. PMID- 24339085 TI - Is gardening a stimulating activity for people with advanced Huntington's disease? AB - This study evaluated adapted gardening as an activity for people with advanced Huntington's disease (HD) and explored its therapeutic aspects. Visitors and staff completed a questionnaire and participated in structured interviews to capture further information, whereas a pictorial questionnaire was designed for residents with communication difficulties. Staff reported that gardening was a constructive, outdoor activity that promoted social interaction, physical activity including functional movement and posed cognitive challenges. Half the staff thought the activity was problem free and a third used the garden for therapy. Visitors used the garden to meet with residents socially. Despite their disabilities, HD clients enjoyed growing flourishing flowers and vegetables, labelling plants, being outside in the sun and the quiet of the garden. The garden is valued by all three groups. The study demonstrates the adapted method of gardening is a stimulating and enjoyable activity for people with advanced HD. PMID- 24339086 TI - A narrative analysis of poetry written from the words of people given a diagnosis of dementia. AB - This study is underpinned by social constructionist epistemology, which points to the socially constructed character of our worlds, in that we co-create and are co created by (including experience and identity) our social realities. Through narrative analysis of some poems from the words of people given a diagnosis of dementia, this study engaged in the process of meaning-making in relation to Self construct and the wider social world. Some narratives evidenced speakers' lack of agency over their experiences, not because of the 'dementia' but due to treatment and care contexts. Some narratives provided instances in which others positioned speakers into identity constructions contradictory to their life-long Self constructs. Other narratives demonstrated that, through acknowledging and supporting 'personhood', speakers retained a sense of well-being and purpose in their social worlds. It is hoped that focusing on the words of individuals given dementia diagnoses, away from predominant bio-medical discourses, may facilitate professionals' continuous reflection and person-centred practice. PMID- 24339087 TI - Staging casual conversations for people with dementia. AB - Social isolation is a key concern for individuals with dementia in long-term care. A possible solution is to promote social interaction between residents. A first step toward facilitating positive relationships between residents with dementia is to understand the mechanisms behind their interactions with each other, and also how their relationships with each other are built through such interactions. Drawing on casual conversations between residents in a special care unit for dementia, this paper uses systemic functional linguistics to examine how people with dementia use language to enact and construct their role-relations with each other. Results suggest people with dementia are able and willing conversationalists. However, factors such as the extent of communication breakdown and compatibility of the interlocutors may influence whether positive relations develop or not. Casual conversation is suggested to be a promising activity to encourage positive interpersonal processes between individuals with dementia in residential care. PMID- 24339088 TI - Creativity and dementia: does artistic activity affect well-being beyond the art class? AB - The Alzheimer's Association's Memories in the Making (MIM) art activity program is intended to enhance the well-being of individuals who are living with dementia. Previous evaluations of MIM have found that participants show benefits on several well-being domains measured by the Greater Cincinnati Chapter Well Being Observation Tool. The current study extended those findings by looking for evidence of carry-over effects beyond the temporal boundaries of MIM sessions. Additionally, this study evaluated key psychometric qualities of the assessment instrument. Seventy-six MIM participants with middle- to late-stage dementia were evaluated by interns and care facility staff at the beginning, middle and end of a 12-week MIM program. Interns focused on behavior within MIM sessions and staff rated functioning outside MIM sessions. Staff reported no significant changes in resident well-being across the 12-week program. Interns reported significant improvements from the beginning to middle and end of the program on five well being domains. Psychometric analyses of the Greater Cincinnati Chapter Well-Being Observation Tool identified weaknesses in inter-rater reliability and found that the instrument measures two orthogonal factors--interpreted as 'Well-Being' and 'Ill-Being' - not the seven domains claimed. Quantitative evidence for the effectiveness of MIM is ambiguous, but anecdotal observations indicate that the program is beneficial for some participants, if only fleetingly. PMID- 24339089 TI - Medication management concerns of ethnic minority family caregivers of people living with dementia. AB - This qualitative study explored the medication management experiences of Australian ethnic minority family caregivers of people living with dementia. From the perspective of this group of caregivers, medication management was a source of stress resulting from the progressive loss of ability of care recipients to manage their own medications; the complexity of the medication regime and the caregiver's lack of trust of the care recipient to safely and effectively manage medications. Caregivers used various strategies to manage medications and avoid conflict with care recipients including being watchful and involving other family members in medication management tasks. Family caregivers indicated that a lack of information and access to support to inform their medication management role added to their stress, which was exacerbated in some cases by limited English proficiency. Supportive factors noted by caregivers included a well-established relationship with a community pharmacist, involvement of a geriatrician, family support and caregiver support group participation. PMID- 24339090 TI - Caregivers' willingness-to-pay for Alzheimer's disease medications in Canada. AB - We studied caregivers' willingness-to-pay for Alzheimer's disease drug therapy. We recruited 216 caregivers of persons with mild or moderate Alzheimer's disease and presented them with four scenarios describing a hypothetical Alzheimer's disease medication. The scenarios described the medication as capable of either treating the symptoms of disease or modifying the course of disease. The scenarios also presented two different probabilities of adverse effects occurrence, i.e., 0% or 30%. Most caregivers said they would pay out-of-pocket for the medication, with support for such payment ranging from 68% to 93%, depending on the specific scenario. The highest level of support was for the 'disease modifying and no adverse effects' scenario, while the lowest level was for the 'symptom treatment and 30% chance of adverse effects' scenario. On average, caregivers' monthly willingness-to-pay out-of-pocket for the medication ranged from $214 to $277 (Canadian dollars). Dollar amounts were highest for the 'disease modifying and no adverse effects' scenario and lowest for the 'symptom treatment and 30% chance of adverse effects' scenario. Support for out-of-pocket payment and specific dollar amounts were highest when the medication did not involve adverse effects. Caregivers placed more value on the absence of adverse effects than on drug efficacy. PMID- 24339091 TI - A technology roadmap of assistive technologies for dementia care in Japan. AB - The number of elderly people in Japan is growing, which raises the issue of dementia, as the probability of becoming cognitively impaired increases with age. There is an increasing need for caregivers, who are well-trained, experienced and can pay special attention to the needs of people with dementia. Technology can play an important role in helping such people and their caregivers. A lack of mutual understanding between caregivers and researchers regarding the appropriate uses of assistive technologies is another problem. A vision of person-centred care based on the use of information and communication technology to maintain residents' autonomy and continuity in their lives is presented. Based on this vision, a roadmap and a list of challenges to realizing assistive technologies have been developed. The roadmap facilitates mutual understanding between caregivers and researchers, resulting in appropriate technologies to enhance the quality of life of people with dementia. PMID- 24339092 TI - From evidence to practice: using the RE-AIM framework to adapt the REACHII caregiver intervention to the community. AB - This article describes how the multi-step mid-course assessment of the REACH II community translation project in North Carolina was guided by the RE-AIM framework, and summarizes adaptations made to enhance the feasibility of adoption and maintenance while at the same time assuring fidelity to program core elements. The two-stage assessment involved both quantitative (survey) and qualitative (discussion group) components. Results indicated a need to focus primarily on tailoring pre-intervention training, streamlining and clarifying intervention guides and tools, targeting specific participant recruitment messages, addressing issues of session length, and clarifying what flexibilities family consultants could exercise in terms of specific session content addressed and other supportive materials used. The use of the RE-AIM framework and the mixed-method process allowed the program staff to thoroughly assess program satisfaction and areas of concern, and ultimately ensured that the family consultants implementing the intervention had a voice in the adaptation process. PMID- 24339093 TI - The comparison of quality of life among people with mild dementia in nursing home and home care--a preliminary report. AB - BACKGROUND: Living arrangements play an important role in determining the quality of life (QoL) of people with dementia. Although informal care (home-based) is favored, the transition to formal (institutional) care often becomes necessary, especially in the later stages of dementia. Nevertheless, there is currently no definitive evidence showing that informal or formal care provides a higher QoL for those with dementia. OBJECTIVE: To compare the QoL of people with dementia in the nursing home and home care, and identify factors that differentiate their QoL. DESIGN AND METHODS: This was a cross-sectional survey. A total of 49 people with dementia >=60 years old were recruited from government nursing homes and hospitals (home care). Consenting participants were assessed on cognitive severity, QoL, activities of daily living (ADLs), depression, and social isolation/connectedness by the Short Mini Mental State Examination (SMMSE), the WHO-8 (the EUROHIS-QOL), Short Assessment of Quality of Life (AQoL-8), Barthel Index (BI), Cornell Scale for Depression (CSDD), and Friendship Scale (FS). RESULTS: There were significant differences in QoL, HRQoLs, ADLs, and social connectedness among people with dementia in home care (n = 19) and those in nursing homes (n = 30) (p < 0.01). No significant differences were found by socio demographic factors, cognitive severity, or depression between the study cohorts. CONCLUSIONS: Older adults with dementia who were living at home experienced higher QoL, ADLs, and social connectedness compared with those living in institutional care. Support should be provided enabling home care and empowering caregivers to provide better care for people with dementia. PMID- 24339094 TI - Gradually losing one's foothold--a fragmented existence when living alone with dementia. AB - The number of persons with dementia who lives at home for a longer period of time after diagnosis is increasing. Even if the literature in the dementia field is growing, there is a need for more knowledge about everyday life of persons with a dementia disease; particularly the lived perspective of persons who live alone. The aim of this study was to elucidate the phenomenon of living alone with dementia and having a manifest care need. This phenomenological study was carried out from a reflective lifeworld approach. The data material in the study consisted of field notes from 32 visits and transcriptions from 11 tape-recorded conversations with six participants. The results reveal that the person with dementia who lives alone ends up in a vague existence where they cannot survive alone. The person's level of activity comes to a halt and body movement becomes slower. Daily life becomes more difficult to manage and the person's earlier natural way of relating to the world and the people around them is gradually lost. This is followed by a loneliness and forgetfulness that cloud the meaning of life. This study highlights the importance of the patient's perspective needed to better understand the inner life of a person who suffers from dementia. This understanding is important in the organization of help and care as well as for caregivers to better understand these individuals and their needs. PMID- 24339095 TI - Grief in caregivers of persons with Alzheimer's disease and related dementia: a qualitative synthesis. AB - This article provides a meta-synthesis of studies focusing on grief in caregivers of people with Alzheimer's disease or related dementia. Through a systematic search, 11 articles met the inclusion criteria that care receivers had a diagnosis of Alzheimer's disease or related dementia, caregivers were informal caregivers, and the study focused on caregiver grief. The meta-synthesis followed a meta-ethnography approach based on reciprocal translation. Six themes were identified, namely challenges of caregiving, losses and changes in the relationship, the role of dementia in grief, striving despite dementia, utilising social support and death as a relief from caregiving. Themes are discussed within an integrated framework showing the connected relationships between themes. The devised framework of themes illustrates the general experience of caregiver grief and can be used to devise specific, targeted interventions to help caregivers to identify and work through their grief. PMID- 24339096 TI - But does it do any good? Measuring the impact of music therapy on people with advanced dementia: (Innovative practice). AB - This article describes the impact of music therapy upon a group of nine people with advanced dementia in a hospital setting. It demonstrates how the impact of music therapy was measured using the case notes completed by nursing and care staff and how these notes suggested that music therapy had a positive effect on the mood and behaviour on eight of the nine people receiving music therapy. PMID- 24339097 TI - Comparison of iPad applications with traditional activities using person-centred care approach: impact on well-being for persons with dementia. AB - Professionals working with people with dementia need to develop new activities that occupy patients and increase positive emotions. Dementia care mapping is a reliable method of measuring well-being during activities with people with dementia. The iPad has many applications that may be suitable as a group activity for persons with dementia. Six people with dementia took part in two traditional and two iPad activities over two days. Well-being was recorded using dementia care mapping. Subjects displayed similar or better levels of well-being during iPad activities than traditional activities. A larger variation of behaviors was seen during iPad activities than traditional activities. With detailed planning using a person-centred care approach, iPad group activity has the potential to be as effective and engaging as other conventional activities in achieving well being. PMID- 24339098 TI - The experiences of staff in a specialist mental health service in relation to development of skills for the provision of person centred care for people with dementia. AB - It is estimated that 820,000 people in the UK have dementia. Dementia costs the UK 17 billion a year and in the next 30 years this will treble to over L50 billion a year. There is a need to raise competence of staff delivering care to people living with dementia across health, social and voluntary sector provision. Effective education and training will build capacity and improve staff knowledge. However, at present not enough is known about the experiences of staff involved in gaining the skills, knowledge and attitudes required to support provision of high quality care for people with dementia. This study was conducted within a large National Health Service Trust in the UK serving an urban, ethnically mixed population, in collaboration with a local university. The trust responded to government policy by seeking to identify staff training needs. The aim was to explore the experiences of staff working within a specialist mental health service in relation to development of skills for the provision of person-centred care for people with dementia. To achieve this, staff roles, experiences of dementia training and the ways in which staff feel they learn were explored through focus group interviews. Relatives' views of staff competencies necessary for effective care provision were also explored to supplement the data from staff. A total of 70 staff and 16 family carers participated and data were subjected to inductive thematic analysis. Five themes emerged: competency-based skills, beliefs, enablers and barriers and ways of learning. Findings suggested participants felt that skills for person-centred care were innate and could not be taught, while effective ways of learning were identified as learning by doing, learning from each other and learning from experience. PMID- 24339099 TI - The feasibility of measuring social networks among older adults in assisted living and dementia special care units. AB - BACKGROUND: Studies indicate that social integration has a significant influence on physical and mental health. Older adults experience an increased risk of social isolation as their social networks decline with fewer traditional opportunities to add new social relationships. Deaths of similar aged friends, cognitive and functional impairments, and relocating to a nursing home (NH) or assisted-living (AL) facility contribute to difficulties in maintaining one's social network. Due to the paucity of research examining the social networks of people residing in AL and NH, this study was designed to develop and test the feasibility of using a combination of methodological approaches to capture social network data among older adults living in AL and a dementia special care unit NH. METHODS: Social network analysis of both egocentric and sociocentric networks was conducted to visualize the social networks of 15 residents of an AL neighborhood and 12 residents of a dementia special care unit NH and to calculate measures network size, centrality, and reciprocity. RESULTS: The combined egocentric and sociocentric method was feasible and provided a robust indicator of resident social networks highlighting individuals who were socially integrated as well as isolated. PMID- 24339100 TI - Changes in daily cognition and behavior of Alzheimer's patients over time: a three-year evaluation using a daily cognition and behavior for Alzheimer's disease scale. AB - BACKGROUND: In Japan, the number of older people with dementia was 2.26 million as of 2010, and Alzheimer's disease accounted for the greatest morbidity rate among older people with dementia. OBJECTIVE: The purposes of this longitudinal study were to assess whether the Daily Cognition and Behavior for Alzheimer's Disease scale might help observe changes in daily cognition and behavior among Alzheimer's disease patients and to determine whether the scale could be used by non-professional caregivers. METHODS: Data obtained from 111 rater-patient pairs were analysed. The scores for Daily Cognition and Behavior for Alzheimer's Disease used by staff members were compared with those for two other scales designed for professional use. Comparisons were made using one-way repeated measures ANOVA. RESULTS: The scores for Daily Cognition and Behavior for Alzheimer's Disease indicated a declining pattern similar to those for the other scales. There was no significant difference in scores by rater occupations. CONCLUSION: Findings suggest Daily Cognition and Behavior for Alzheimer's Disease might help observe changes in daily cognition and behavior among Alzheimer's disease patients, and that Daily Cognition and Behavior for Alzheimer's Disease can be used by non-professional caregivers. PMID- 24339101 TI - Balancing needs: the role of motivations, meanings and relationship dynamics in the experience of informal caregivers of people with dementia. AB - This paper investigates how meaning, motivation and relationship dynamics influence the caregivers' subjective experience of caregiving. We interviewed 12 family caregivers of relatives with dementia. We analysed transcripts of these interviews using interpretative phenomenological analysis. Six key themes emerged from the analysis, which were encompassed under an overarching theme of 'balancing needs'. This describes the caregivers' constant struggle to balance their own needs against those of their relative, which created a series of dilemmas. These dilemmas emerged from the desire to try to preserve the caregivers' relationship with their relative, while recognising that this relationship was changing. The caregivers' relationship with their relative influenced the caregivers' motivations to provide care and gave caregiving meaning. Although caregivers were motivated to provide care the battle to balance needs meant that the caregivers recognised there might come a time when they may need to cease caregiving. PMID- 24339102 TI - 'You have to be mindful of whose story it is': the challenges of undertaking life story work with people with dementia and their family carers. AB - INTRODUCTION: Life story work is increasingly being used with people with dementia; this work offers a critical appraisal of some challenges that may be faced in practice. DESIGN AND METHODS: An in-depth case study analysis was undertaken to understand the experiences of people with dementia, family carers and care staff in using life story work in an NHS Mental Health and Social Care Trust. Data collection included semi-structured interviews, observation, conversations and field notes. FINDINGS: Private memories were sometimes recalled by the person with dementia that were not for inclusion in any written product; enabling the person with dementia to tell their own life story could be a challenge; quality of the life story books was variable and; at times, life story work may be overused with the person with dementia. CONCLUSION: Services should not be deterred from undertaking life story work with people with dementia, but there is a need to adopt a planned approach to its implementation that includes facilitation, education and supervision. PMID- 24339103 TI - The psychological impact of a diagnosis of Alzheimer's disease. AB - Research on the experience of receiving and living with a diagnosis of dementia is sparse. Existing studies have focused on the initial reactions to the diagnosis rather than longer term adjustment and coping. The current study uses interpretative phenomenological analysis to explore personal experiences of receiving a diagnosis and to investigate aspects of the experience of adjusting and adapting to dementia. This is a cross-sectional study drawing on semi structured interviews with 10 participants who had a diagnosis of mild Alzheimer's disease. The findings illustrated the importance, to people with Alzheimer's disease, of understanding and making sense of the diagnosis to help them deal with issues of loss and to make positive adjustments to their lives through employing specific coping strategies. The findings also appeared to challenge misconceptions held by some professionals in relation to possible negative effects of disclosing a diagnosis of dementia. PMID- 24339104 TI - Gnosall Primary Care Memory Clinic: Eldercare facilitator role description and development. AB - The Gnosall Primary Care Memory Clinic has been operating since 2006 and adds the skills of a specialist old age psychiatrist to the extensive skills and knowledge available in primary care. Key to the organisation and function of the clinic is the eldercare facilitator, a new role situated in primary care and linking with the specialist and a wide range of other agencies and people. In order to facilitate replication of the model elsewhere, the function, role and competencies of existing and previous eldercare facilitators in the clinic have been reviewed, clarified and related to a competency framework and to similar initiatives in the literature. The selection and training of people with the attributes and skills required to become an eldercare facilitator will determine whether extension of the model is successful elsewhere. PMID- 24339105 TI - Generative acts of people with dementia in a long-term care setting. AB - Although generativity is used as a central cultural construct within life course theory to illustrate how older persons create interpersonal ties, it is also tied to key concepts in social exchange theory since generative acts can provide a way for achieving more equity in intergenerational power relationships. Without opportunities for older adults to invest themselves in younger generations, they may no longer feel needed within their family or community. In this article, we discuss the relationship of generativity and dementia through the generative activities of older persons with cognitive decline. Field notes from 8 months of research in a dementia-care setting as well as interviews with 20 residents were thematically analyzed to identify: (a) generative acts among people with dementia; (b) residents' expressions regarding giving to others; and (c) barriers to generativity. Examining generativity among people with dementia requires that one considers the subjective experience of the condition and understands that many social behaviors remain intact irrespective of any quantified cognitive loss (captured here through the use of case examples). PMID- 24339106 TI - Qualitative evaluation of a self-management intervention for people in the early stage of dementia. AB - Self-management programs are effective for people living with chronic illnesses. However, there has been little research addressing self-management for people with dementia in the early stages. This study presents a qualitative evaluation of the experiences of attending a novel self-management program and initial process evaluation. The program was designed with and for people with dementia. It addresses: (a) relationship with family, (b) maintenance of an active lifestyle, (c) psychological well-being, (d) techniques to cope with memory changes and (e) information about dementia. Six participants with early stage dementia completed the intervention that was co-delivered by lay and clinical professional tutors. Participants and tutors attended focus group and interviews at the end of the program to explore their perceptions of the intervention. These were audio-recorded, transcribed verbatim and analysed thematically. Participants reported enjoyment and benefits from the intervention. This was despite some reporting concerns relating to their memory difficulties. The program's flexible nature, focus on strengths and the opportunity to spend time with other people living with dementia were particularly well received. Participants and tutors outlined areas for further improvement. The program was feasible and its flexible delivery appeared to facilitate participant benefit. Emphasis should be placed on maintaining activity and relationships, improving positive well-being and social interaction during the program. Memory of the pleasant experience and strengths focus was evidenced, which may impact positively on quality of life. The results highlight the usefulness and acceptability of self-management for people with early stage dementia and provide initial support for the program's structure and content. PMID- 24339107 TI - The role of a clinical nurse consultant dementia specialist: A qualitative evaluation. AB - Delay in diagnosis and difficulties in accessing appropriate health care services plague dementia care delivery in the community setting, potentiating the risk for misdiagnosis, inappropriate management, poor psychological adjustment and reduced coping capacity and ability to forward plan. We evaluated a clinical nurse consultant role with a speciality in dementia to provide person-centred pre diagnosis support in the community. Clients, with a six-month history of cognitive and functional decline in the absence of delirium but no formal diagnosis of dementia, were recruited from a Home Care Nursing Service and an Aged Care Assessment Service located in the Western Suburbs of Melbourne, Victoria, Australia. The role of a clinical nurse consultant was highly regarded by clients and other health professionals. This paper discussing the CNC role and the outcomes of the role suggests it was successful in providing timely assistance and support for consumers and support for other health professionals. PMID- 24339108 TI - Community practitioner involvement in collaborative research. AB - This paper focuses on the benefits and limitations of collaborative research in community-based service settings explored through the implementation of a psychosocial intervention. The study aimed to establish the effectiveness of working with dementia dyads (person with dementia and family caregiver) in the early stages of dementia and to recruit and train an existing practitioner workforce to deliver a psychosocial intervention designed to assist dementia dyads to manage the consequences of dementia. Seven intervention staff participated in post-intervention semi-structured interviews. Whilst staff recruitment and retention proved challenging the degree to which staff demonstrated the required communication skills and competence was an important component in dyad acceptability of the intervention. Participatory factors, collaborative development, selective recruitment, focused training and ongoing specialist support, can assist the implementation of practice-based research. However, intervention staff participation and therefore intervention delivery can be hampered by workplace culture and workforce demands. PMID- 24339109 TI - Effects of using nursing home residents to serve as group activity leaders: lessons learned from the RAP project. AB - Previous research has demonstrated that persons with early to moderate stage dementia are capable of leading small group activities for persons with more advanced dementia. In this study, we built upon this previous work by training residents in long-term care facilities to fill the role of group activity leaders using a Resident-Assisted Programming (RAP) training regimen. There were two stages to the program. In the first stage, RAP training was provided by researchers. In the second stage, RAP training was provided to residents by activities staff members of long-term care facilities who had been trained by researchers. We examine the effects of RAP implemented by researchers and by activities staff member on long-term care resident with dementia who took part in these RAP activities. We also examined effects produced by two types of small group activities: two Montessori-based activities and an activity which focuses on persons with more advanced dementia, based on the work of Jitka Zgola. Results demonstrate that levels of positive engagement seen in players during RAP (resident-led activities) were typically higher than those observed during standard activities programming led by site staff. In general, Montessori-Based Dementia Programming(r) produced more constructive engagement than Zgola-based programming (ZBP), though ZBP did increase a positive form of engagement involving observing activities with interest. In addition, RAP implemented by activities staff members produced effects that were, on the whole, similar to those produced when RAP was implemented by researchers. Implications of these findings for providing meaningful social roles for persons with dementia residing in long-term care, and suggestions for further research in this area, are discussed. PMID- 24339110 TI - The development and evaluation of an educational intervention for primary care promoting person-centred responses to dementia. AB - BACKGROUND: Early diagnosis of dementia within primary care is important to allow access to support. However, dementia remains under-detected in general practice. AIM: This work aimed to develop and evaluate an educational intervention for primary care promoting person-centred responses to people experiencing cognitive decline. METHOD: A prototype educational intervention was pilot tested and refined; the final version of the educational intervention was then evaluated in four volunteer practices. A questionnaire was administered pre- and post-training to 94 practice staff to assess knowledge and attitudes to dementia. The responses of general practitioners (who make diagnostic, referral and treatment decisions) were compared with those from other staff who do not have such roles. FINDINGS: Post-training, there were statistically significant improvements in understanding of person-centred care for people with dementia; attitudes to early diagnosis; awareness of non-cognitive dementia symptoms; and awareness of the role that non clinical staff may have in recognising dementia. CONCLUSIONS: A dementia education intervention for primary care which fosters person-centred attitudes can involve all members of a primary care team. Further research is needed to ascertain if improvements in knowledge and attitudes translate into improved practice. PMID- 24339111 TI - Differences in diagnosis, follow-up and treatment of patients with dementia living in the peripheral areas compared with the central areas of Israel. AB - We compared data regarding diagnosis, treatment and follow-up of patients with dementia in the central and the peripheral areas of Israel. Data were collected from the medical records of 164 patients with advanced dementia, all residents of dementia special care units - 97 patients from a central nursing home and 67 patients from the peripheral areas. The data collected related to the period prior to hospitalization and included: demographic data, imaging tests, follow-up by a memory clinic and drug treatment prior to admission. Mini Mental State Examination on admission was also recorded. Patients in the peripheral areas were hospitalized while having better cognitive function, as demonstrated by the Mini Mental State Examination (p < 0.05). More patients in the central areas versus the peripheral areas were aided by an in-house worker prior to admission (p < 0.001). More patients with dementia in the central areas were followed up by a memory clinic (p < 0.001) and underwent brain imaging (p < 0.01) compared with patients with dementia living in the peripheral areas. Although not significant, patients from the central areas were more commonly treated with atypical neuroleptics for behavioral problems (p = 0.05). On the basis of the current data, we suggest that there are differences in the diagnosis, follow-up and drug treatment among patients with dementia living in the central areas versus those living in the peripheral ones. Patients in the peripheral areas are hospitalized while their cognitive abilities are relatively better than those of the patients in central areas. PMID- 24339112 TI - Family caregivers' perspectives on dementia-related dressing difficulties at home: The preservation of self model. AB - Alzheimer's caregiving literature acknowledges dressing as a major daily stressor but research on this topic is negligible. A qualitative grounded theory approach was used to explore Alzheimer's family caregivers' perspectives about issues that arise when their family members lose the ability to dress independently. Three focus groups and seven individual interviews were conducted and audio recorded with 25 information rich caregivers. Constant comparative analyses and coding of the transcripts identified six major themes leading to a 'Preservation of Self Model: Care Recipient to Care Giver' that portrays the caregiving trajectory. Initially, caregivers tried to protect the self dignity of the family member by maintaining usual routines and absorbing blame for difficulties. Dressing 'battles' occurred and caregivers learned management through trial and error. Crossing adult-child-gender role boundaries escalated discomfort. When facing unrelenting demands, concern shifted to preservation of the caregivers' health and self. Results suggest that caregivers would benefit from more pro-active dressing counseling to shorten the trial and error periods, dressing aids more relevant to dementia and more knowledgeable helpers. The preservation model can facilitate understanding of the caregiving trajectory and guide intervention support. PMID- 24339113 TI - A family living with Alzheimer's disease: The communicative challenges. AB - Alzheimer's disease irrevocably challenges a person's capacity to communicate with others. Earlier research on these challenges focused on the language disorders associated with the condition and situated language deficit solely in the limitations of a person's cognitive and semantic impairments. This research falls short of gaining insight into the actual interactional experiences of a person with Alzheimer's and their family. Drawing on a UK data set of 70 telephone calls recorded over a two-and-a-half year period (2006-2008) between one elderly woman with Alzheimer's disease, and her daughter and son-in-law, this paper explores the role which communication (and its degeneration) plays in family relationships. Investigating these interactions, using a conversation analytic approach, reveals that there are clearly communicative difficulties, but closer inspection suggests that they arise due to the contingencies that are generated by the other's contributions in the interaction. That being so, this paper marks a departure from the traditional focus on language level analysis and the assumption that deficits are intrinsic to the individual with Alzheimer's, and instead focuses on the collaborative communicative challenges that arise in the interaction itself and which have a profound impact on people's lives and relationships. PMID- 24339114 TI - Dementia service centres in Austria: A comprehensive support and early detection model for persons with dementia and their caregivers - theoretical foundations and model description. AB - Despite the highly developed social services in Austria, the County of Upper Austria, one of the nine counties of Austria had only very limited specialized services for persons with dementia and their caregivers in 2001. Support groups existed in which the desire for more specialized services was voiced. In response to this situation, funding was received to develop a new structure for early disease detection and long term support for both the person with dementia and their caregivers. This article describes the development of the model of the Dementia Service Centres (DSCs) and the successes and difficulties encountered in the process of implementing the model in six different rural regions of Upper Austria. The DSC was described in the First Austrian Dementia Report as one of the potential service models for the future. PMID- 24339115 TI - Aggressive behaviors between residents with dementia in an assisted living residence. AB - Aggressive behavior between residents with dementia in long-term care residences is a concerning but understudied phenomenon. The goal of the study was to identify the circumstances, sequence of events, and triggers that lead to these behaviors. I collected the data during 10 months in two special care units of an assisted living residence. I used participant observation as the primary data collection strategy, complemented by review of clinical records and semi structured interviews with care staff and managers. As the analytic framework, I used Grounded Theory informed by Miles and Huberman's approach. In a substantial number of the reported 85 incidents, I identified observable early warning signs; in the majority, I identified observable causes or triggers prior to the aggressive acts. The majority of incidents were situational-reactive (circumstance-driven) and therefore potentially modifiable. Twelve effective staff prevention strategies were identified. I suggest incorporating the study findings into care staff training programs. PMID- 24339116 TI - Older adults' views and experiences of doll therapy in residential care homes. AB - BACKGROUND AND PURPOSE: The mechanisms underlying the success of doll therapy are poorly understood. The aims of this study were to explore how people in care, doll users and non-users, make sense of doll use in their settings. METHODOLOGY: A grounded theory approach was used, recruiting participants from three residential care homes involving four male and 12 female residents. Data collection occurred in two phases; five participants took part in a focus group and later 11 participants were interviewed individually. Eight of the 11 participants had dementia, and four participants were actively using dolls. RESULTS AND CONCLUSION: The results are presented as themes, and sub-themes, consisting of four main categories (intrapersonal features, interpersonal features, behavioural benefits, ethical and moderating factors). This thematic analysis shows that residents generally support the use of dolls, believing that dolls can have a positive impact on some users. The mechanisms by which this impact is achieved are discussed together with the ethical concerns. PMID- 24339117 TI - The effects of perceived stigma on quality of life outcomes in persons with early stage dementia: Longitudinal findings: Part 2. AB - This article is the second report from a study examining perceived stigma in persons with dementia with findings regarding the association between stigma and quality of life outcomes being reported here. Fifty persons with dementia and 47 family caregivers were sampled, with data being collected at baseline and six, 12, and 18 months. The modified Stigma Impact Scale measured perceived stigma. Quality of life outcomes included: depression, anxiety, behavioral symptoms, personal control, physical health, self-esteem, social support, and activity participation. Linear mixed model or generalized linear mixed model (for depression) analyses revealed that some aspect of perceived stigma was associated with each outcome. Social rejection was associated with anxiety, behavioral symptoms, health, and activity participation. Internalized shame was associated with anxiety, personal control, health, self-esteem, social support understanding and assistance, and activity participation. Finally, social isolation was associated with depression, anxiety, personal control, health, self-esteem, social support understanding, and activity participation. The complexity of relationships between perceived stigma and quality of life outcomes is evident from these findings. PMID- 24339118 TI - Experiences of using a memory aid to structure and support daily activities in a small-scale group accommodation for people with dementia. AB - BACKGROUND: Use of technology to structure and support the daily activities of the residents in a small-scale group accommodation (SSGA) for dementia is a new innovation in the Netherlands. This paper presents the process of development of this new way of structuring activities and the findings of a pilot study looking at the experiences of using this device in people with dementia. METHOD: A qualitative method was chosen, data were collected using individual interviews with the residents (n = 6), focus groups interviews with informal carers (n = 5) and members of staff (n = 6). Data were analysed using Ritchie & Spencer's framework (1994). FINDINGS: Three main themes emerged: issues regarding the implementation, needs for further development and the learning experiences acquired during the development. The majority of the residents were happy with the use and function of the memory aid. However, the occurrence of installation errors, limited ease of use and a lack of knowledge regarding the function and use of the memory aid were issues that prevented a successful implementation. Findings highlighted shared views about ways of improving through adaptation of the software program and additional technological applications; internet connectivity, improving its accessibility by using a remote control and adding videos and photos. CONCLUSION: Lessons are learned about the use and transferability of this innovation in people with dementia and other vulnerable target groups including those with learning disabilities as well as its limitation and the needs for further development. PMID- 24339119 TI - The impact of dementia on length of stay in acute hospitals in Ireland. AB - The outcomes for those with dementia admitted to acute hospitals are often poor, with higher mortality, increased risk of institutionalisation and longer length of stay. The aim of this study was to examine the impact of dementia on length of stay and the associated cost of care in acute hospitals in Ireland. People with a recorded diagnosis of dementia were found to have a significantly longer length of stay than those with no recorded dementia. Multiplying the excess length of stay by the number of dementia-related admissions gave an estimate of 246,908 additional hospital days per annum due to dementia at an associated additional annual cost of over ?199 million. Improving the experience of those with dementia in acute hospitals will likely lead to cost savings for the health service; however, it will require a number of measures including: earlier diagnosis, training for medical professionals and improvements in the built environment. PMID- 24339120 TI - Couples with dementia: Positioning the 'we'. AB - The aim of this article is to investigate how spouses in couples with dementia position themselves in relation to each other by analysing their use of pronouns, especially the we. The study uses joint interviews with 11 couples. Based on a quantitative analysis of pronoun use, it is argued that the pronoun we is used by all the spouses; however, it is used less frequently by the spouses with dementia in comparison with healthy spouses. A qualitative analysis of the use of the pronoun we shows that the spouses position, experience and consider themselves as a couple and that they position and experience themselves as individuals in relation to the couple. One of the challenges for couples with dementia is to be able to retain a we in face of the progression of the dementia disease. By positioning themselves in various ways, the spouses establish and negotiate quite a complex and emotionally charged web of relationships. PMID- 24339121 TI - 'What I want to do is get half a dozen of them and go and see Simon Cowell': Reflecting on participation and outcomes for people with dementia taking part in a creative musical project. AB - This paper presents the findings from an evaluation of a creative musical project led by Scottish Opera. The project included people with dementia and their carers in the development, writing, design and performance of a musical production about their experiences of love. The project involved professional singers, artists and choreographers from the opera company. Activities involved practice sessions and performances. People with dementia and their carers reflected on positive outcomes from the project including improved confidence; being part of a group; improved physical strength and people seeing them in a new way. Within the evaluation framework they also reported on how the project had been run and gave ideas for future development. Key elements in the success of this project were the involvement of professionals, the kudos of working with a national organisation and the performances that, while daunting, provided unique and rewarding experiences. PMID- 24339122 TI - Perceived stigma in persons with early-stage dementia: Longitudinal findings: Part 1. AB - This longitudinal study examined perceived stigma in persons with dementia, with 50 persons with dementia, and 47 corresponding family caregivers. Data were collected at baseline and at 6, 12, and 18 months. Study results are reported in two parts, with findings regarding the stability of perceived stigma, measured using the modified Stigma Impact Scale, and relationship of stigma to person centered variables being reported here. Findings included stability in perceived stigma, which did not show a downward trend until 18 months. Significant differences at baseline were found only for geographic location (rural vs. urban) with persons living in urban areas having higher levels of Stigma Impact Scale internalized shame compared to rural counterparts. Cognitive functioning was significantly, positively related to the Stigma Impact Scale social rejection and social isolation subscales. Findings support the enduring nature of perceived stigma over the early disease stages and the relationship of perceived stigma to some person-centered characteristics. PMID- 24339123 TI - The social positioning of older people living with Alzheimer's disease who scream in long-term care homes. AB - This article describes the social positioning of older people living with Alzheimer's disease who scream in a long-term care home. Few studies have focused on the social positions taken by older people, their family and formal caregivers during interaction and their effects on screams. A secondary data analysis was conducted using Harre and Van Langenhove's positioning theory. The results show that older people are capable of positioning and repositioning themselves in relational patterns. Family and formal caregivers position older people who scream according to their beliefs about their lived experience. They also react emotionally to older people and try to influence their behaviors. Understanding the social positioning of older people with Alzheimer's disease brought out their capacities and their caregivers' concerns for their well-being. Interventions should focus on these strengths and on promoting healthy relations in the triads to enhance quality of care in long-term care homes. PMID- 24339124 TI - Privileging place: Reflections on involving people with dementia in a residency. AB - Although attention is paid to involving people with dementia as collaborators in research, the issue of place - where involvement actually occurs - has been neglected. This is significant because we know from the academic literature that places can adversely affect social relations and a person's ability to participate as equal partners. This paper privileges place and documents our experiences of running residencies in the English Lake District with people with dementia - Houston, Gardiner and Wallace all have some form of dementia. In doing so we provide a model to reference for involving people with dementia in research and knowledge production, while simultaneously strengthening the evidence base for the residency as a method for participatory research. People with dementia participated in two residencies to co-produce a touring exhibition and educational resource as part of a research dissemination project. We found that by privileging place a more equitable, productive, healthier, and respectful way of involving people with dementia as collaborators in research dissemination could be realised. The project has wider implications for the involvement of people with dementia in not only research, but also public consultations, service evaluations, and policy-related work. PMID- 24339125 TI - Understanding the mutual impact of interaction between hydrophobic nanoparticles and pulmonary surfactant monolayer. AB - Interaction between hydrophobic nanoparticles (NPs) and a pulmonary surfactant (PS) film leads to a shift in molecular packing of surfactant molecules in the PS film around the interacting NPs. The resultant structural arrangement of surfactants around the NPs may be a potential structural factor responsible for their high retention ability within the film. Moreover, during this interaction, surfactant molecules coat the NPs and change their surface properties. PMID- 24339126 TI - Increased understanding of the impact of environmental exposures on the epigenome. PMID- 24339127 TI - In vivo non-invasive monitoring of collagen remodelling by two-photon microscopy after micro-ablative fractional laser resurfacing. AB - Non-linear optical microscopy is becoming popular as a non-invasive in vivo imaging modality in dermatology. In this study, combined TPF and SHG microscopy were used to monitor collagen remodelling in vivo after micro-ablative fractional laser resurfacing. Papillary dermis of living subjects, covering a wide age range, was imaged immediately before and forty days after treatment. A qualitative visual examination of acquired images demonstrated an age-dependent remodelling effect on collagen. Additional quantitative analysis of new collagen production was performed by means of two image analysis methods. A higher increase in SHG to TPF ratio, corresponding to a stronger treatment effectiveness, was found in older subjects, whereas the effect was found to be negligible in young, and minimal in middle age subjects. Analysis of collagen images also showed a dependence of the treatment effectiveness with age but with controversial results. While the diagnostic potential of in vivo multiphoton microscopy has already been demonstrated for skin cancer and other skin diseases, here we first successfully explore its potential use for a non-invasive follow-up of a laser-based treatment. PMID- 24339128 TI - Total synthesis of (-)-ophiodilactone A and (-)-ophiodilactone B. AB - The first asymmetric total synthesis of (-)-ophiodilactone A and (-) ophiodilactone B, isolated from the ophiuroid (Ophiocoma scolopendrina), is reported. The key features of the synthesis include the highly stereocontrolled construction of the structurally congested gamma-lactone/delta-lactone skeleton through an asymmetric epoxidation, diastereoselective iodolactonization, and intramolecular epoxide-opening with a carboxylic acid, and biomimetic radical cyclization of ophiodilactone A to ophiodilactone B. PMID- 24339130 TI - Starry sky liver in twin anemia-polycythemia sequence. PMID- 24339129 TI - Abnormal junctions and permeability of myelin in PMP22-deficient nerves. AB - OBJECTIVE: The peripheral myelin protein-22 (PMP22) gene is associated with the most common types of inherited neuropathies, including hereditary neuropathy with liability to pressure palsies (HNPP) caused by PMP22 deficiency. However, the function of PMP22 has yet to be defined. Our previous study has shown that PMP22 deficiency causes an impaired propagation of nerve action potentials in the absence of demyelination. In the present study, we tested an alternative mechanism relating to myelin permeability. METHODS: Utilizing Pmp22(+) (/) (-) mice as a model of HNPP, we evaluated myelin junctions and their permeability using morphological, electrophysiological, and biochemical approaches. RESULTS: We show disruption of multiple types of cell junction complexes in peripheral nerve, resulting in increased permeability of myelin and impaired action potential propagation. We further demonstrate that PMP22 interacts with immunoglobulin domain-containing proteins known to regulate tight/adherens junctions and/or transmembrane adhesions, including junctional adhesion molecule C (JAM-C) and myelin-associated glycoprotein (MAG). Deletion of Jam-c or Mag in mice recapitulates pathology in HNPP. INTERPRETATION: Our study reveals a novel mechanism by which PMP22 deficiency affects nerve conduction not through removal of myelin, but through disruption of myelin junctions. PMID- 24339131 TI - Activated solutions enabling low-temperature processing of functional ferroelectric oxides for flexible electronics. AB - Functional ferroelectric oxides for flexible electronics are achieved from activated solutions enabling low-temperature processing and large-area deposition directly on polymeric substrates. This processing technology reaches the lower limit temperature of crystallization at 300 degrees C, using a strategy that combines seeded diphasic precursors and photochemical solution deposition. Properties of these materials are comparable to those of high-temperature processed counterparts and organic ferroelectrics. PMID- 24339132 TI - CD133 and CD133-regulated nucleophosmin linked to 5-fluorouracil susceptibility in human colon cancer cell line SW620. AB - Cancer stem cells (CSCs) are known to be resistant to conventional chemotherapy and radiotherapy. Specific CSC targeting and eradication is therefore a therapeutically important challenge. CD133 is a colorectal CSC marker with unknown function(s). Assessing proteomic changes induced by CD133 may provide clues not only to new CD133 functions but also to the chemotherapy and radiation susceptibility of colon cancer cells. To identify the proteins affected by CD133, CD133-positive (CD133+), and CD133-negative (CD133-) human colon cancer cells were obtained by cell sorting. Whole proteomes were profiled from SW620/CD133+ and SW620/CD133- cells and analyzed by 2D-based proteome analysis. Nucleophosmin (NPM1) was identified as a protein regulated by CD133. CD133 protein level was not affected by NPM1, and an interaction between the two proteins was not observed. CD133 and NPM1 protein levels were positively correlated in 11 human colon cancer cell lines. The CD133+ subpopulation percentage or its value normalized against CD133 protein level was only linked to intrinsic susceptibility of human colon cancer cells to 5-fluorouracil (5-FU). However, either suppression of CD133 or NPM1 significantly increased 5-FU susceptibility of SW620. The present study suggests that CD133-regulated NPM1 protein level may provide a clue to novel CD133 function(s) linked to human colon cancer cell susceptibility to chemotherapy. PMID- 24339133 TI - Synthesis of PbI(2) single-layered inorganic nanotubes encapsulated within carbon nanotubes. AB - The template assisted growth of single-layered inorganic nanotubes is reported. Single-crystalline lead iodide single-layered nanotubes have been prepared using the inner cavities of carbon nanotubes as hosting templates. The diameter of the resulting inorganic nanotubes is merely dependent on the diameter of the host. This facile method is highly versatile opening up new horizons in the preparation of single-layered nanostructures. PMID- 24339134 TI - Cobalt imidazolate metal-organic frameworks photosplit CO(2) under mild reaction conditions. AB - Metal-organic frameworks (MOFs) have shown great promise for CO2 capture and storage. However, the operation of chemical redox functions of framework substances and organic CO2 -trapping entities which are spatially linked together to catalyze CO2 conversion has had much less attention. Reported herein is a cobalt-containing zeolitic imidazolate framework (Co-ZIF-9) which serves as a robust MOF cocatalyst to reduce CO2 by cooperating with a ruthenium-based photosensitizer. The catalytic turnover number of Co-ZIF-9 was about 450 within 2.5 hours under mild reaction conditions, while still keeping its original reactivity during prolonged operation. PMID- 24339135 TI - Prognostic factors for squamous cell cancer of the parotid gland: an analysis of 2104 patients. AB - BACKGROUND: Parotid gland squamous cell cancer (SCC) occurs as metastasis from cutaneous SCC or primary malignancy. There is limited data on incidence, prognosis, and treatment outcomes. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database (1988-2009) identified 2104 adult patients with parotid SCC. RESULTS: SCC is the second most common parotid malignancy, and its incidence is increasing (annual percentage change 1.7%; ptrend = .004). Age >=85 years, tumor size >=4 cm, extraparenchymal extension, cervical metastases, and distant metastases were independently associated with disease-specific mortality. Compared to no surgery, surgery was associated with improved 5-year disease specific survival (DSS; 44.4% vs 71.0%; p < .001), whereas radiation alone was similar to no treatment (47.0% vs 41.6%; p = .28). CONCLUSION: Surgery and adjuvant radiation therapy (RT) are associated with improved survival compared to radiation alone and no treatment. Patients >=85 years of age account for nearly 20% of all patients and have a poor prognosis independent of treatment. PMID- 24339136 TI - Neurophysiologic effect of GWAS derived schizophrenia and bipolar risk variants. AB - Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) as disease associated variants for schizophrenia (SCZ), bipolar disorder (BPD), or both. Although these results are statistically robust, the functional effects of these variants and their role in the pathophysiology of SCZ or BPD remain unclear. Dissecting the effects of risk genes on distinct domains of brain function can provide important biological insights into the mechanisms by which these genes may confer illness risk. This study used quantitative event related potentials to characterize the neurophysiological effects of well-documented GWAS-derived SCZ/BPD susceptibility variants in order to map gene effects onto important domains of brain function. We genotyped 199 patients with DSM-IV diagnoses of SCZ or BPD and 74 healthy control subjects for 19 risk SNPs derived from previous GWAS findings and tested their association with five neurophysiologic traits (P3 amplitude, P3 latency, N1 amplitude, P2 amplitude, and P50 sensory gating responses) known to be abnormal in psychosis. The TCF4 SNP rs17512836 risk allele showed a significant association with reduced auditory P3 amplitude (P = 0.00016) after correction for multiple testing. The same allele was also associated with delayed P3 latency (P = 0.005). Our results suggest that a SCZ risk variant in TCF4 is associated with neurophysiologic traits thought to index attention and working memory abnormalities in psychotic disorders. These findings suggest a mechanism by which TCF4 may contribute to the neurobiological basis of psychotic illness. PMID- 24339137 TI - Sequence analysis of 17 NRXN1 deletions. AB - BACKGROUND: Genome instability plays fundamental roles in human evolution and phenotypic variation within our population. This instability leads to genomic rearrangements that are involved in a wide variety of human disorders, including congenital and neurodevelopmental disorders, and cancers. Insight into the molecular mechanisms governing such genomic rearrangements may increase our understanding of disease pathology and evolutionary processes. Here we analyse 17 carriers of non-recurrent deletions in the NRXN1 gene, which have been associated with neurodevelopmental disorders, e.g. schizophrenia, autism and epilepsies. METHODS: 17 non-recurrent NRXN1 deletions identified by GWA were sequenced to map the breakpoints of each. Meme ... etc. was used to identify shared patterns between the deletions and compare these were previously studies on non-recurrent deletions. RESULTS: We discovered two novel sequence motifs shared between all 17 NRXN1 deletions and a significantly higher AT nucleotide content at the breakpoints, compared to the overall nucleotide content on chromosome 2. We found different alteration of sequence at the breakpoint; small insertions and duplications giving rise to short microhomology sequences. CONCLUSIONS: No single mechanism seems to be implicated in the deletion events, but the results suggest that NHEJ, FoSTeS or MMBIR is implicated. The two novel sequence motifs together with a high AT content in all in NRXN1 deletions may lead to increased instability leading to a increase susceptibility to a single stranded structures. This favours potentially repaired by NHEJ mechanism of double strand breaks or may leading to replication errors. (c) 2013 Wiley Periodicals, Inc. PMID- 24339138 TI - Genetic susceptibility for bipolar disorder and response to antidepressants in major depressive disorder. AB - The high heterogeneity of response to antidepressant treatment in major depressive disorder (MDD) makes individual treatment outcomes currently unpredictable. It has been suggested that resistance to antidepressant treatment might be due to undiagnosed bipolar disorder or bipolar spectrum features. Here, we investigate the relationship between genetic susceptibility for bipolar disorder and response to treatment with antidepressants in MDD. Polygenic scores indexing risk for bipolar disorder were derived from the Psychiatric Genomics Consortium Bipolar Disorder whole genome association study. Linear regressions tested the effect of polygenic risk scores for bipolar disorder on proportional reduction in depression severity in two large samples of individuals with MDD, treated with antidepressants, NEWMEDS (n=1,791) and STAR*D (n=1,107). There was no significant association between polygenic scores for bipolar disorder and response to treatment with antidepressants. Our data indicate that molecular measure of genetic susceptibility to bipolar disorder does not aid in understanding non-response to antidepressants. PMID- 24339139 TI - Differences in gestational weight gain between pregnancies before and after maternal bariatric surgery correlate with differences in birth weight but not with scores on the body mass index in early childhood. AB - BACKGROUND: Large maternal gestational weight gain (GWG) is associated with increased birth weight and increased risk of obesity in offspring, but these associations may be confounded by genetic and environmental factors. The aim was to investigate the effects of differences in GWG in all three trimesters on differences in birth weight and in body mass index (BMI) scores at 4 and 6 years of age, within siblings born before and after bariatric surgery. METHOD: Women with at least one child born before and one after bariatric surgery were identified in national Swedish registers. Series of weight (and height) measurements were collected from antenatal medical records, with data on the nearest pregnancies before and after bariatric surgery. RESULTS: The age-adjusted means of pre- and post-operative GWG of 124 women were 11.3 (standard deviation [SD] 7.2) and 8.3 (SD 6.4) kg, respectively (P = 0.01). Adjusted fixed effects regression models showed positive associations of differences in mean total GWG with differences in siblings' birth weight, 0.023 kg per 1-kg greater weight gain (95% confidence interval [CI]: 0.014-0.069) and for second trimester 0.53 kg for each 1-kg greater weight per week (95% CI: 0.32-1.61), whereas no associations were found with BMI in pre-school age. CONCLUSION: This study showed positive associations between differences in total and second trimester maternal GWG and differences in children's birth weight, but no association with BMI scores in pre school age. Maternal genetic, social and lifestyle factors fixed from one pregnancy to the next were taken into account in the analyses by the study design. PMID- 24339140 TI - Tone conditioning potentiates rather than overshadows context fear in adult animals following adolescent ethanol exposure. AB - We have shown that adults exposed to ethanol during adolescence exhibit a deficit in the retention of context fear, reminiscent of that normally seen in preweanling rats. However, preweanlings have been reported to exhibit a potentiation of context fear when they are conditioned in the presence of a tone. Therefore, this study examined context retention 24 hr after tone or context conditioning in male Sprague-Dawley rats exposed intragastrically to 4 g/kg ethanol or water every 48 hr (total of 11 exposures) during adolescence [Postnatal day (P) 28-48] or adulthood (P70-90). Approximately 3 weeks following exposure, retention of fear to the context in animals exposed to ethanol during adolescence was attenuated after context conditioning, but enhanced after tone conditioning. Comparable adult ethanol exposure groups showed typical overshadowing of context fear retention after tone conditioning. These data suggest that adolescent ethanol exposure may induce an immature pattern of cognitive processing. PMID- 24339141 TI - Osteocalcin is inversely associated with glucose levels in middle-aged Tibetan men with different degrees of glucose tolerance. AB - BACKGROUND: Research on the characteristics and mechanisms of diabetes in Tibetans is scant. Especially, there is no study on the relationship between osteocalcin and glucose metabolism. The objective of this study was to investigate the associations of serum total osteocalcin (tOC) and undercarboxylated osteocalcin (ucOC) with glucose and lipid metabolism in Chinese indigenous Tibetans with different degrees of glucose tolerance. METHODS: In this study, 160 middle-aged Tibetan men were involved, including 46 subjects with normal glucose tolerance (NGT), 52 subjects with impaired glucose regulation (IGR) and 62 subjects with type 2 diabetes. The homeostasis model assessment (HOMA) parameters, including HOMA-IR and HOMA-B, were used to estimate insulin resistance and beta-cell function, respectively. Adiponectin, leptin, testosterone, 1,25-dihydroxyvitamin D, tOC and ucOC were measured using ELISA kits. RESULTS: After adjustment for age and body mass index, plasma tOC level was correlated negatively with fasting and 30-min post-OGTT glucose, HOMA-IR, leptin and testosterone; plasma ucOC level was correlated negatively with 30-min post OGTT glucose, total cholesterol and 1,25-dihydroxyvitamin D; ucOC : tOC was correlated positively with leptin. The negative association between HOMA-IR and tOC remained significant after correcting for adiponectin; however, the association disappeared after correcting for leptin. HOMA-IR was correlated negatively with age, adiponectin and tOC, and positively with total cholesterol, triglyceride and leptin. Stepwise linear regression analysis revealed that total cholesterol, leptin and adiponectin were independent predictors for HOMA-IR in all subjects. CONCLUSIONS: Our data support a link between osteocalcin and glucose metabolism in middle-aged Tibetan men. The improved glucose tolerance exerted by tOC may be related to improved insulin sensitivity rather than improved beta-cell function. PMID- 24339142 TI - Identification of toxin inhibitors using a magnetic nanosensor-based assay. AB - A magnetic nanosensor-based method is described to screen a library of drugs for potential binding to toxins. Screening is performed by measuring changes in the magnetic relaxation signal of the nanosensors (bMR nanosensors) in aqueous suspension upon addition of the toxin. The Anthrax lethal factor (ALF) is selected as a model toxin to test the ability of our bMR nanosensor-based screening method to identify potential inhibitors of the toxin. Out of 30 molecules screened, sulindac, naproxen and fusaric acid are found to bind LF, with dissociation constants in the low micromolar range. Further biological analysis of the free molecules in solution indicate that sulindac and its metabolic products inhibited LF cytotoxicity to macrophages with IC50 values in the micromolar range. Meanwhile, fusaric acid is found to be less effective at inhibiting LF cytotoxicity, while naproxen does not inhibit LF toxicity. Most importantly, when the sulindac and fusaric acid-bMR nanosensors themselves are tested as LF inhibitors, as opposed to the corresponding free molecules, they are stronger inhibitors of LF with IC50 values in the nanomolar range. Taken together, these studies show that a bMR nanosensors-based assay can be used to screen known drugs and other small molecules for inhibitor of toxins. The method can be easily modified to screen for inhibitors of other molecular interactions and not only the selected free molecule can be study as potential inhibitors but also the bMR nanosensors themselves achieving greater inhibitory potential. PMID- 24339143 TI - The primary function of gp130 signaling in osteoblasts is to maintain bone formation and strength, rather than promote osteoclast formation. AB - Interleukin-6 (IL-6) family cytokines act via gp130 in the osteoblast lineage to stimulate the formation of osteoclasts (bone resorbing cells) and the activity of osteoblasts (bone forming cells), and to inhibit expression of the osteocyte protein, sclerostin. We report here that a profound reduction in trabecular bone mass occurs both when gp130 is deleted in the entire osteoblast lineage (Osx1Cre gp130 f/f) and when this deletion is restricted to osteocytes (DMP1Cre gp130 f/f). This was caused not by an alteration in osteoclastogenesis, but by a low level of bone formation specific to the trabecular compartment. In contrast, cortical diameter increased to maintain ultimate bone strength, despite a reduction in collagen type 1 production. We conclude that osteocytic gp130 signaling is required for normal trabecular bone mass and proper cortical bone composition. PMID- 24339144 TI - Characterization of normal regional myocardial function by MRI cardiac tagging. AB - PURPOSE: The aim of this study was to establish reference values for segmental myocardial strain measured by magnetic resonance (MR) cardiac tagging in order to characterize the regional function of the heart. MATERIAL AND METHODS: We characterized the left ventricular (LV) systolic deformation in 39 subjects (26 women and 13 men, age 58.8 +/- 11.6 years) whose cardiological study had not revealed any significant abnormality. The deformation was measured from MR-tagged (Siemens 1.5T MR) images using an algorithm based on sine wave modeling. Circumferential and radial peak systolic strain values along with the torsion angle and circumferential-longitudinal (CL) shear were determined in 16 LV segments in order to settle the reference values for these parameters. RESULTS: Circumferential strain was highest at the anterior and lateral walls (-20.2 +/- 4.0% and -21.8 +/- 4.3%, respectively; P < 0.05) and was lowest at the base level (-17.2 +/- 3.1% vs. -20.1 +/- 3.1% "mid level," P < 0.05; -17.2 +/- 3.1% vs. 20.3 +/- 3.0% "apical level," P < 0.05). Radial strain highest values were from inferior and lateral walls (13.7 +/- 7.4% and 12.8 +/- 7.8%, respectively; P < 0.05) and it was lowest medially (9.4 +/- 4.1% vs. 13.1 +/- 4.1% "base level," P < 0.05; 9.4 +/- 4.1% vs. 12.1 +/- 4.4% "apical level," P < 0.05). Torsion angle (counterclockwise when viewed from the apex) increased with the distance from the base (7.9 +/- 2.4 degrees vs. 16.8 +/- 4.4 degrees , P < 0.05), and the highest and lowest values were found at lateral (medial lateral: 12.0 +/- 4.4 degrees , apical lateral: 25.1 +/- 6.4 degrees , P < 0.05) and septal wall (medial septal: 3.6 +/- 2.1 degrees , apical septal: 8.3 +/- 5.3 degrees , P < 0.05), respectively. These differences were found again in CL shear values, around the LV circumference. However, CL shear remained constant with increasing distance from the base (9.1 +/- 2.6 degrees , medium and 9.8 +/- 2.4 degrees , apex). CONCLUSION: In summary, this study provides reference values for the assessment of regional myocardial function by MR cardiac tagging. Comparison of patient deformation parameters with normal deformation patterns may permit early detection of regional systolic dysfunction. PMID- 24339145 TI - CrossTalk proposal: Cell volume changes are an essential step in the cell death machinery. PMID- 24339146 TI - CrossTalk opposing view: The triggering and progression of the cell death machinery can occur without cell volume perturbations. PMID- 24339147 TI - Rebuttal from Florian Lang and Else K. Hoffmann. PMID- 24339148 TI - Rebuttal from Sergei N. Orlov, Michael M. Model and Ryszard Grygorczyk. PMID- 24339149 TI - Carotid body chemotransduction gets the human touch. PMID- 24339150 TI - Muscle nuclei remember to cheat death. PMID- 24339151 TI - Cardiac troponin I phosphorylation and the force-length relationship. PMID- 24339152 TI - HSL and ATGL: the movers and shakers of muscle lipolysis. PMID- 24339153 TI - Non-invasive prenatal testing for fetal chromosomal abnormalities by low-coverage whole-genome sequencing of maternal plasma DNA: review of 1982 consecutive cases in a single center. AB - OBJECTIVE: To review the performance of non-invasive prenatal testing (NIPT) by low-coverage whole-genome sequencing of maternal plasma DNA at a single center. METHODS: The NIPT result and pregnancy outcome of 1982 consecutive cases were reviewed. NIPT was based on low coverage (0.1*) whole-genome sequencing of maternal plasma DNA. All subjects were contacted for pregnancy and fetal outcome. RESULTS: Of the 1982 NIPT tests, a repeat blood sample was required in 23 (1.16%). In one case, a conclusive report could not be issued, probably because of an abnormal vanished twin fetus. NIPT was positive for common trisomies in 29 cases (23 were trisomy 21, four were trisomy 18 and two were trisomy 13); all were confirmed by prenatal karyotyping (specificity=100%). In addition, 11 cases were positive for sex-chromosomal abnormalities (SCA), and nine cases were positive for other aneuploidies or deletion/duplication. Fourteen of these 20 subjects agreed to undergo further investigations, and the abnormality was found to be of fetal origin in seven, confined placental mosaicism (CPM) in four, of maternal origin in two and not confirmed in one. Overall, 85.7% of the NIPT suspected SCA were of fetal origin, and 66.7% of the other abnormalities were caused by CPM. Two of the six cases suspected or confirmed to have CPM were complicated by early-onset growth restriction requiring delivery before 34 weeks. Fetal outcome of the NIPT-negative cases was ascertained in 1645 (85.15%). Three chromosomal abnormalities were not detected by NIPT, including one case each of a balanced translocation, unbalanced translocation and triploidy. There were no known false negatives involving the common trisomies (sensitivity=100%). CONCLUSIONS: Low-coverage whole-genome sequencing of maternal plasma DNA was highly accurate in detecting common trisomies. It also enabled the detection of other aneuploidies and structural chromosomal abnormalities with high positive predictive value. PMID- 24339154 TI - Roles of nurse practitioners and physician assistants in rheumatology practices in the US. AB - OBJECTIVE: A recent workforce study of rheumatology in the US suggests that during the next several decades, the demand for rheumatology services will outstrip the supply of rheumatologists. Midlevel providers such as nurse practitioners and physician assistants may be able to alleviate projected shortages. METHODS: We administered a nationwide survey of midlevel providers during 2012. Invitations with the survey were sent with one followup reminder. The survey contained questions regarding demographics, training, level of practice independence, responsibilities, drug prescribing, use of objective outcome measures, and knowledge and use of treat-to-target (TTT) strategies. RESULTS: The invitation was sent to 482 eligible midlevel providers via e-mail and 90 via US mail. We received a total of 174 responses (30%). The mean age was 46 years and 83% were women. Nearly 75% had <=10 years of experience and 53% had received formal training in rheumatology. Almost two-thirds reported having their own panel of patients. The top 3 practice responsibilities described were performing patient education (99%), adjusting medication doses (98%), and conducting physical examinations (97%). More than 90% felt very or somewhat comfortable diagnosing rheumatoid arthritis (RA) and a similar percentage prescribed disease-modifying antirheumatic drugs. Three-quarters reported using disease activity measures for RA and 56% reported that their practices used TTT strategies. CONCLUSION: Most respondents reported that they had substantial patient care responsibilities, used disease activity measures for RA, and incorporated TTT in their practice. These data suggest midlevel providers may help to reduce shortages in the rheumatology workforce and conform with recommendations to employ TTT strategies in RA treatment. PMID- 24339155 TI - Birth, survival and differentiation of neurons in an adult crustacean brain. AB - Life-long neurogenesis is a characteristic feature of many vertebrate and invertebrate species. In decapod crustaceans, new neurons are added throughout life to two cell clusters containing local (cluster 9) and projection (cluster 10) interneurons in the olfactory pathway. Adult-born neurons in clusters 9 and 10 in crayfish have the anatomical properties and chemistry of mature neurons by 6 months after birth. Here we use 5-bromo-2'-deoxyuridine (BrdU) incorporation to pulse label mitotically active cells in these cell clusters, followed by a survival time of up to 8 months, during which crayfish (Cherax destructor) were sacrificed at intervals and the numbers of BrdU-labeled cells quantified. We find a decrease in the numbers of BrdU-labeled cells in cell cluster 10 between the first and second weeks following BrdU exposure, suggesting a period of cell death shortly after proliferation. Additional delayed cell divisions in both cell clusters are indicated by increases in labeled cells long after the BrdU clearing time. The differentiation time of these cells into neurons was defined by detection of the first immunoreactivity for the transmitter SIFamide in cluster 10 BrdU-labeled cells, which begins at 4 weeks after BrdU labeling; the numbers of SIFamide-labeled cells continues to increase over the following month. Experiments testing whether proliferation and survival of Cluster 10 cells are influenced by locomotor activity provided no evidence of a correlation between activity levels and cell proliferation, but suggest a strong influence of locomotor activity on cell survival. PMID- 24339156 TI - Gold nanocage assemblies for selective second harmonic generation imaging of cancer cell. AB - Second harmonic generation (SHG) imaging using near infrared laser light is the key to improving penetration depths, leading to biological understanding. Unfortunately, currently SHG imaging techniques have limited capability due to the poor signal-to-noise ratio, resulting from the low SHG efficiency of available dyes. Targeted tumor imaging over nontargeted tissues is also a challenge that needs to be overcome. Driven by this need, in this study, the development of two-photon SHG imaging of live cancer cell lines selectively by enhancement of the nonlinear optical response of gold nanocage assemblies is reported. Experimental results show that two-photon scattering intensity can be increased by few orders of magnitude by just developing nanoparticle self assembly. Theoretical modeling indicates that the field enhancement values for the nanocage assemblies can explain, in part, the enhanced nonlinear optical properties. Our experimental data also show that A9 RNA aptamer conjugated gold nanocage assemblies can be used for targeted SHG imaging of the LNCaP prostate cancer cell line. Experimental results with the HaCaT normal skin cell lines show that bioconjugated nanocage-based assemblies demonstrate SHG imaging that is highly selective and will be able to distinguish targeted cancer cell lines from other nontargeted cell types. After optimization, this reported SHG imaging assay could have considerable application for biology. PMID- 24339158 TI - Pneumonia in pediatric acute neuromuscular respiratory failure. PMID- 24339157 TI - Youth and environmental enrichment generate serum exosomes containing miR-219 that promote CNS myelination. AB - Although commonly considered a disease of white matter, gray matter demyelination is increasingly recognized as an important component of multiple sclerosis (MS) pathogenesis, particularly in the secondary progressive disease phase. Extent of damage to gray matter is strongly correlated to decline in memory and cognitive dysfunction in MS patients. Aging likewise occurs with cognitive decline from myelin loss, and age-associated failure to remyelinate significantly contributes to MS progression. However, recent evidence demonstrates that parabiotic exposure of aged animals to a youthful systemic milieu can promote oligodendrocyte precursor cell (OPC) differentiation and improve remyelination. In the current study, we focus on this potential for stimulating remyelination, and show it involves serum exosomes that increase OPCs and their differentiation into mature myelin-producing cells-both under control conditions and after acute demyelination. Environmental enrichment (EE) of aging animals produced exosomes that mimicked this promyelinating effect. Additionally, stimulating OPC differentiation via exosomes derived from environmentally enriched animals is unlikely to deplete progenitors, as EE itself promotes proliferation of neural stem cells. We found that both young and EE serum-derived exosomes were enriched in miR-219, which is necessary and sufficient for production of myelinating oligodendrocytes by reducing the expression of inhibitory regulators of differentiation. Accordingly, protein transcript levels of these miR-219 target mRNAs decreased following exosome application to slice cultures. Finally, nasal administration of exosomes to aging rats also enhanced myelination. Thus, peripheral circulating cells in young or environmentally enriched animals produce exosomes that may be a useful therapy for remyelination. PMID- 24339160 TI - Proteomics of aluminum tolerance in plants. AB - Aluminum (Al) toxicity is a major constraint for plant root development and growth as well as crop yield in acidic soils, which constitute approximately 40% of the potentially arable lands worldwide. The mechanisms of Al tolerance in plants are not well understood. As a whole systems approach, proteomic techniques have proven to be crucial as a complementary strategy to explore the mechanism in Al toxicity. Review here focuses on the potential of proteomics to unravel the common and plant species-specific changes at proteome level under Al stress, via comparative analysis of the Al-responsive proteins uncovered by recent proteomic studies using 2DE. Understanding the mechanisms of Al tolerance in plants is critical to generate Al resistance crops for developing sustainable agriculture practices, thereby contributing to food security worldwide. PMID- 24339159 TI - 2-dimensional transition metal dichalcogenides with tunable direct band gaps: MoS2(1-x) Se2x monolayers. AB - MoS2(1-x) Se2x single-layer films are prepared using a mixture of organic selenium and sulfur precursors as well as a solid molybdenum source. The direct bandgaps are found to scale nearly linearly with composition in the range of 1.87 eV (pure single-layer MoS2 ) to 1.55 eV (pure single-layer MoSe2 ) permitting straightforward bandgap engineering. PMID- 24339161 TI - PhI(OAc)(2) -mediated radical trifluoromethylation of vinyl azides with Me(3)SiCF(3). AB - The fluorine-containing organic motif is becoming privileged in pharmaceuticals, agrochemicals, and functional materials, owing to its unique properties such as electron-withdrawing character, metabolic stability, and lipophilicity. Described herein is the PhI(OAc)2 -mediated radical trifluoromethylation of vinyl azides with Me3 SiCF3 to efficiently generate alpha-trifluoromethyl azines. The resulting alpha-trifluoromethyl azines were successfully transformed to valuable fluorine-containing molecules such as alpha-trifluoromethyl ketones, beta trifluoromethyl amines, 5-fluoropyrazoles, and trifluoroethyl isoquinolines. PMID- 24339162 TI - On the physicochemical properties of pyridohelicenes. AB - A comprehensive study on the physicochemical properties of a series of mono- and diaza[5]helicenes as well as mono- and diaza[6]helicenes is reported. Through the use of both computational and experimental methods, these helically chiral pyridohelicenes with the nitrogen atom(s) in various positions are characterised according to their inversion barriers, protonation constants and redox potentials. By using DFT calculations, kinetic measurements, UV/Vis titrations, cyclic voltammetry and EPR spectroscopy, a self-contained picture of their behaviour under conventional treatment by heat, acids and oxidising/reducing agents is provided. PMID- 24339163 TI - Protein engineering from "scratch" is maturing. AB - Precisely tuning the active site by protein engineering has led to the development of a highly efficient Kemp eliminase (see structure with substrate in the binding pocket). The starting protein scaffold with only low activity originated from computational design, as no natural enzyme with this activity was known. This is a breakthrough in protein design, as novel catalytic activities are now in reach that match those of natural enzymes. PMID- 24339164 TI - Copper-boxmi complexes as highly enantioselective catalysts for electrophilic trifluoromethylthiolations. AB - The enantioselective trifluoromethylthiolation of beta-ketoesters using chiral copper-boxmi complexes as catalysts is reported. A number of alpha-SCF3 substituted beta-ketoesters have been obtained with up to >99% enantiomeric excess (ee), and the trifluoromethylthiolated products were then transformed diastereoselectively to alpha-SCF3-beta-hydroxyesters with two adjacent quaternary stereocenters. PMID- 24339165 TI - Systemic inflammatory markers as independent prognosticators of head and neck squamous cell carcinoma. AB - BACKGROUND: The purpose of this study was to investigate the prognostic value of the pretreatment inflammatory markers platelet-to-lymphocyte ratio (PLR) and the neutrophil-to-lymphocyte ratio (NLR) in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: We conducted a retrospective analysis of patients diagnosed with HNSCC at McGill University Health Center from 2000 to 2011 (273 patients were retained). Hematologic parameters were recorded within 4 weeks of diagnosis. Mortality and recurrence rates were compared according to various PLR and NLR thresholds. RESULTS: Of the total patients, 20.5% died and 11.0% had disease recurrence. PLR >170 was associated with higher mortality (p = .008). The subgroup with a combination of PLR >170 and NLR <=3.0 was associated with higher T classification and highest mortality (43%). NLR above 4.2 predicted higher rates of recurrence (p < .0001). The NLR/PLR combination was at least as good as TNM staging in predicting survival. CONCLUSION: PLR is an independent predictor of mortality; NLR is an independent predictor of recurrence in HNSCC. These parameters might be used to identify advanced stages rapidly and economically. PMID- 24339166 TI - Innate defense regulator peptide 1018 protects against perinatal brain injury. AB - OBJECTIVE: There is currently no pharmacological treatment that provides protection against brain injury in neonates. It is known that activation of an innate immune response is a key, contributing factor in perinatal brain injury; therefore, the neuroprotective therapeutic potential of innate defense regulator peptides (IDRs) was investigated. METHODS: The anti-inflammatory effects of 3 IDRs was measured in lipopolysaccharide (LPS)-activated murine microglia. IDRs were then assessed for their ability to confer neuroprotection in vivo when given 3 hours after neonatal brain injury in a clinically relevant model that combines an inflammatory challenge (LPS) with hypoxia-ischemia (HI). To gain insight into peptide-mediated effects on LPS-induced inflammation and neuroprotective mechanisms, global cerebral gene expression patterns were analyzed in pups that were treated with IDR-1018 either 4 hours before LPS or 3 hours after LPS+HI. RESULTS: IDR-1018 reduced inflammatory mediators produced by LPS-stimulated microglia cells in vitro and modulated LPS-induced neuroinflammation in vivo. When administered 3 hours after LPS+HI, IDR-1018 exerted effects on regulatory molecules of apoptotic (for, eg, Fadd and Tnfsf9) and inflammatory (for, eg, interleukin 1, tumor necrosis factor alpha, chemokines, and cell adhesion molecules) pathways and showed marked protection of both white and gray brain matter. INTERPRETATION: IDR-1018 suppresses proinflammatory mediators and cell injurious mechanisms in the developing brain, and postinsult treatment is efficacious in reducing LPS-induced hypoxic-ischemic brain damage. IDR-1018 is effective in the brain when given systemically, confers neuroprotection of both gray and white matter, and lacks significant effects on the brain under normal conditions. Thus, this peptide provides the features of a promising neuroprotective agent in newborns with brain injury. PMID- 24339167 TI - Association analysis of BMD-associated SNPs with knee osteoarthritis. AB - Osteoarthritis (OA) risk is widely recognized to be heritable but few loci have been identified. Observational studies have identified higher systemic bone mineral density (BMD) to be associated with an increased risk of radiographic knee osteoarthritis. With this in mind, we sought to evaluate whether well established genetic loci for variance in BMD are associated with risk for radiographic OA in the Osteoarthritis Initiative (OAI) and the Johnston County Osteoarthritis (JoCo) Project. Cases had at least one knee with definite radiographic OA, defined as the presence of definite osteophytes with or without joint space narrowing (Kellgren-Lawrence [KL] grade >= 2) and controls were absent for definite radiographic OA in both knees (KL grade <= 1 bilaterally). There were 2014 and 658 Caucasian cases, respectively, in the OAI and JoCo Studies, and 953 and 823 controls. Single nucleotide polymorphisms (SNPs) were identified for association analysis from the literature. Genotyping was carried out on Illumina 2.5M and 1M arrays in Genetic Components of Knee OA (GeCKO) and JoCo, respectively and imputation was done. Association analyses were carried out separately in each cohort with adjustments for age, body mass index (BMI), and sex, and then parameter estimates were combined across the two cohorts by meta analysis. We identified four SNPs significantly associated with prevalent radiographic knee OA. The strongest signal (p = 0.0009; OR = 1.22; 95% CI, 1.08 1.37) maps to 12q3, which contains a gene coding for SP7. Additional loci map to 7p14.1 (TXNDC3), 11q13.2 (LRP5), and 11p14.1 (LIN7C). For all four loci the allele associated with higher BMD was associated with higher odds of OA. A BMD risk allele score was not significantly associated with OA risk. This meta analysis demonstrates that several genomewide association studies (GWAS) identified BMD SNPs are nominally associated with prevalent radiographic knee OA and further supports the hypothesis that BMD, or its determinants, may be a risk factor contributing to OA development. (c) 2014 American Society for Bone and Mineral Research. PMID- 24339170 TI - A decrease in the addition of new cells in the nucleus accumbens and prefrontal cortex between puberty and adulthood in male rats. AB - Adolescence involves shifts in social behaviors, behavioral flexibility, and adaptive risk-taking that coincide with structural remodeling of the brain. We previously showed that new cells are added to brain regions associated with sexual behaviors, suggesting that cytogenesis may be a mechanism for acquiring adult-typical behaviors during adolescence. Whether pubertal cell addition occurs in brain regions associated with behavioral flexibility or motivation and whether these patterns differ between pubertal and adult animals had not been determined. Therefore, we assessed patterns of cell proliferation or survival in the prefrontal cortex and nucleus accumbens. Pubertal and adult male rats were given injections of bromo-deoxyuridine (BrdU). To assess cell proliferation, half of the animals from each group were sacrificed 24 h following the last injection. The remaining animals were sacrificed at Day 30 following the last injection to evaluate cell survival. Adult animals had significantly lower densities of BrdU immunoreactive (ir) cells in the prefrontal cortex, irrespective of post-BrdU survival time, whereas in the nucleus accumbens, adult animals had a lower density of BrdU-ir cells at the short survival time; however, the density of BrdU ir cells was equivalent in pubertal and adult animals at the longer survival time. These data provide evidence that cell addition during puberty may contribute to the remodeling of brain regions associated with behavioral flexibility and motivation, and this cell addition continues into adulthood, albeit at lower levels. Higher levels of cell proliferation or survival in younger animals may reflect a higher level of plasticity, possibly contributing to the dynamic remodeling of the pubertal brain. PMID- 24339171 TI - Synthesis of single-enantiomer bioactive molecules: a brief overview. AB - Chiral-center enantiomers have been shown to differ significantly in biological activity, pharmacodynamics, pharmacokinetics and toxicity. New developments in the stereoselective organic synthesis have enriched the vast literature of synthetic methodologies applicable to access natural products as well as bioactive molecules. These compounds also include new drugs, drug candidates and reagents used to explore biological processes. The article reviews the synthesis of optically pure drugs, biologically active intermediates and amino alcohols by using different methods. PMID- 24339172 TI - Usefulness of cerebral NIRS in detecting the effects of pediatric sleep apnea. AB - BACKGROUND: Children with sleep apnea have increased morbidity if the sleep apnea is untreated. Polysomnography (PSG) is used to detect sleep apnea, but in children, there are technical difficulties that make the diagnosis more difficult. Cerebral near infrared spectroscopy (NIRS) has the ability to detect tissue hypoxia by measuring regional oxygen saturation (rSO2 ). We hypothesized that when used as an adjunct to PSG testing, cerebral NIRS would better detect the effects of sleep apnea in children than arterial pulse oximetry (SpO2 ). Specifically, we aimed to show that the apnea/hypopnea index (AHI) calculated with rSO2 from the NIRS would be greater than that calculated with SpO2 . METHODS: Forty-seven patients under 18 years of age who underwent PSG testing for sleep apnea were evaluated. Cerebral NIRS was utilized in addition to PSG. The AHI was calculated using SpO2 and compared to the AHI calculated using the rSO2 . A pediatric pulmonologist who was unaware of the NIRS data evaluated each patient for sleep apnea. Data are median (interquartile range). RESULTS: The median AHI(rSO2 ) was 2.4(1.2,5.1), significantly greater (P < 0.0001) than the AHI(SpO2 ) of 0.7(0.4,1.2). Four patients were diagnosed with sleep apnea; however, only one had an AHI(SpO2 ) >= 5, a typical threshold for the diagnosis of sleep apnea. All 4 subjects had an AHI(rSO2 ) >= 5 but 10 patients without sleep apnea had a value >=5. The sensitivity and specificity for using the AHI(rSO2 ) to diagnose sleep apnea was 100% and 76.7%, respectively. CONCLUSION: Consistent with the ability of NIRS to detect tissue hypoxia, we found that the AHI calculated with rSO2 was greater than that using SpO2 . We conclude that NIRS has potential as a valuable adjunct to PSG in evaluating patients for sleep apnea and warrants further investigation for this purpose. PMID- 24339173 TI - Real-time monitoring of incision profile during laser surgery using shock wave detection. AB - Lack of sensory feedback during laser surgery prevents surgeons from discerning the exact location of the incision, which increases duration and complexity of the treatment. In this study we demonstrate a new method for monitoring of laser ablation procedures. Real-time tracking of the exact three dimensional (3D) lesion profile is accomplished by detection of shock waves emanating from the ablation spot and subsequent reconstruction of the incision location using time of-flight data obtained from multiple acoustic detectors. Here, incisions of up to 9 mm in depth, created by pulsed laser ablation of fresh bovine tissue samples, were successfully monitored in real time. It was further observed that, by utilizing as little as 12 detection elements, the incision profile can be characterized with accuracy below 0.5 mm in all three dimensions and in good agreement with histological examinations. The proposed method holds therefore promise for delivering high precision real-time feedback during laser surgeries. PMID- 24339174 TI - A multistimuli-responsive photochromic metal-organic gel. AB - A photochromic metal-organic gel with thermo-, photo-, and anion-responsive behavior is obtained. Unusually, heating of the Al-ligand solution leads to gel formation and cooling to room temperature reverses the process to reform the solution. The gel is sensitive to weakly coordinating anions. Additionally, reversible photochromic transformations take place both in the solution and gel states, accompanied by reversibly switched luminescence. PMID- 24339175 TI - Nanosheet-stacked chiral silica transcribed from metal ion- and pH-tuned supramolecular crystalline complexes of polyamine-D-glucarate. AB - D-glucaric acid (D-Glc) associates with linear poly(ethyleneimine) (PEI) through hydrogen bonding and electrostatic interactions in aqueous media to form nanostructured crystalline PEI/D-Glc/H2O complexes with PEI/D-Glc/H2O ratios of 2:1:2. These complexes can serve as templates for silica depositions from hydrolytic condensation of tetramethoxysilane to guide morphologically duplicated silica under very mild conditions. Their microscale morphologies are tunable by use of the crystalline complexes regulated in the different pH of the PEI/D-Glc solutions. It was also found that some metal ions added in the PEI/D-Glc complexation process could have a synergistic effect under a certain pH regimes, bringing about remarkable changes in the hierarchy of the resulting complexes. Especially, the complexes formed through fine-tuning of the complexation conditions could direct torsionally stacked silica nanosheets, in which the nanosheets are composed of orderly-bundled nanofibrils. Final elimination of organic components of the templates afforded chiral inorganic silica while retaining the morphologically higher-order structures. The chirality of the silica, which was obtained after calcination at 600 degrees C, was characterized by means of diffused reflectance circular dichroism (DRCD) spectroscopy with a remote confirmation of the appearance of induced-CD (ICD) signals of achiral or racemic chromophores covalently linked on the silica frames. Interestingly, the shapes and signs of these ICD signals are dramatically changed depending on the pH-tuned templates used in silicification and are strongly correlated to that of the CD signals of the complex templates, indicating that the chiral transcription proceeds accurately with imprinting the higher-order chirality of the complexes on the morphologically structured silica networks. PMID- 24339168 TI - Biomarker discovery study design for type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study. AB - AIMS: The Environmental Determinants of Diabetes in the Young planned biomarker discovery studies on longitudinal samples for persistent confirmed islet cell autoantibodies and type 1 diabetes using dietary biomarkers, metabolomics, microbiome/viral metagenomics and gene expression. METHODS: This article describes the details of planning The Environmental Determinants of Diabetes in the Young biomarker discovery studies using a nested case-control design that was chosen as an alternative to the full cohort analysis. In the frame of a nested case-control design, it guides the choice of matching factors, selection of controls, preparation of external quality control samples and reduction of batch effects along with proper sample allocation. RESULTS AND CONCLUSION: Our design is to reduce potential bias and retain study power while reducing the costs by limiting the numbers of samples requiring laboratory analyses. It also covers two primary end points (the occurrence of diabetes-related autoantibodies and the diagnosis of type 1 diabetes). The resulting list of case-control matched samples for each laboratory was augmented with external quality control samples. PMID- 24339176 TI - Generation of a mouse line harboring a Bi-transgene expressing luciferase and tamoxifen-activatable creER(T2) recombinase in cartilage. AB - We have used an aggrecan gene enhancer to generate a transgenic murine line (Acan CreER-Ires-Luc) expressing firefly luciferase and tamoxifen activatable Cre recombinase (Cre-ER(T2) ). The expression and efficiency of the inducible Cre recombinase activity were tested in double transgenic mice created by crossing the Acan-CreER-Ires-Luc line with a Rosa26-lacZ reporter mouse. The expression pattern of the transgene of our line was restricted to cartilage from embryonic to adult stages. beta-galactosidase staining was observed in growth plate, articular cartilage, as well as fibrocartilage of meniscus, trachea, and intervertebral discs. Similar staining was observed in a previously described Agc1 (tm(IRES-creERT2)) murine line. The presence of luciferase in our transgene allows the visualization of the transgene expression in live animals. Weekly measurements from 2 to 8 weeks of age showed a reduction in luminescence in knee joints between 2 and 4 weeks of age, but stabilization thereafter. Following the surgical induction of osteoarthritis at 12 weeks of age, the level of luminescence remained the same in the knee joints for 8 weeks. This Acan-CreER Ires-Luc murine line allows indirect monitoring of the transcriptional activity of the Acan gene via expression of luciferase, while the inducible Cre recombinase activity facilitates studies involving gain or loss of gene expression in cartilage. PMID- 24339177 TI - Cell surface protein glycosylation in cancer. AB - Glycosylation of proteins is one of the most important PTMs, with more than half of all human proteins estimated to be glycosylated. It is widely known that aberrant glycosylation has been implicated in many different diseases due to changes associated with biological function and protein folding. In cancer, there is increasing evidence pertaining to the role of glycosylation in tumour formation and metastasis. Alterations in cell surface glycosylation, particularly terminal motifs, can promote invasive behaviour of tumour cells that ultimately lead to the progression of cancer. While a majority of studies have investigated protein glycosylation changes in cancer cell lines and tumour tissue for individual cancers, the review presented here represents a comprehensive, in depth overview of literature on the structural changes of glycosylation and their associated synthetic enzymes in five different cancer types originating from the breast, colon, liver, skin and ovary. More importantly, this review focuses on key similarities and differences between these cancers that reflect the importance of structural changes of cell surface N- and O-glycans, such as sialylation, fucosylation, degree of branching and the expression of specific glycosyltransferases for each cancer. It is envisioned that the understanding of these biologically relevant glycan alterations on cellular proteins will facilitate the discovery of novel glycan-based biomarkers which could potentially serve as diagnostic and prognostic indicators of cancer. PMID- 24339178 TI - Bright single-chain conjugated polymer dots embedded nanoparticles for long-term cell tracing and imaging. AB - Single-chain conjugated polymer (CP) dots embedded nanoparticles (NPs) bearing cell penetration peptide (TAT) as surface ligands are synthesized for long term cancer cell tracing applications. The CPNPs are fabricated by matrix encapsulation method and the embedded CPs can be modulated into spherical dots with different size upon alteration of feed concentrations. Single-chain CP dots are formed upon decreasing feed concentration to 0.2 mg/mL, where CPNPs exhibit highest fluorescence quantum yield of 32%. Maleimide is introduced as the new NP surface functional group, which favors easy conjugation with cell penetration peptide via click chemistry to preserve its biofunctions. The obtained CPNPs show high brightness and good biocompatibility, which allow cell tracing for over 9 generations, superior to commercial cell tracker Qtracker 585. PMID- 24339180 TI - Catalytic effect of cesium cation adduct formation on the decarboxylation of carboxylate ions in the gas phase. AB - The effect of Cs(+) ligation on the decarboxylation of malonic acids (unsubstituted and methyl-, dimethyl-, ethyl-, and phenyl-substituted) in their carboxylate form was studied in the gas phase using tandem mass spectrometry. The study is based on the comparison of the decarboxylation of the bare monoanion (hydrogen malonates) and of the cesium adduct of the cesium salt (Cs(+) [cesium hydrogen malonates]) under collisional activation. Energy-resolved dissociation curves of the negative and positive ions exhibit major differences. Decarboxylation of the cationic adducts of substituted malonic acid salts occurs at significantly lower collisional activation than for the corresponding bare hydrogen malonate anions. The conclusions from these experiments are supported by DFT calculations. The calculated activation parameters (enthalpy and Gibbs energy) confirm that the cesium cation coordination assists the decarboxylation of the carboxylate form. PMID- 24339179 TI - Effect of certolizumab pegol on multiple facets of psoriatic arthritis as reported by patients: 24-week patient-reported outcome results of a phase III, multicenter study. AB - OBJECTIVE: To examine the effect of certolizumab pegol (CZP) on patient-reported outcomes (PROs) in psoriatic arthritis (PsA) patients with and without prior tumor necrosis factor (TNF) inhibitor exposure. METHODS: The ongoing phase III RAPID-PsA trial was double blind and placebo controlled to week 24. Patients were randomized 1:1:1 to placebo every 2 weeks or CZP 400 mg at weeks 0, 2, and 4, followed by either CZP 200 mg every 2 weeks or CZP 400 mg every 4 weeks. PRO measures evaluated were the Health Assessment Questionnaire (HAQ) disability index (DI), health status (measured by the Short Form 36 [SF-36] health survey), Psoriatic Arthritis Quality of Life (PsAQOL), Fatigue Assessment Scale, patient assessment of pain (visual analog scale), and Dermatology Life Quality Index (DLQI). Post hoc analyses of PROs in patients with and without prior TNF inhibitor exposure were conducted. Change from baseline for all PROs was analyzed for the randomized population using analysis of covariance with last observation carried forward imputation. RESULTS: A total of 409 patients were randomized. Twenty percent had received a prior TNF inhibitor. Baseline demographics were similar between the treatment groups. At week 24, clinically meaningful differences in HAQ DI, SF-36, PsAQOL, fatigue, pain, and DLQI were observed in both CZP arms versus placebo (P < 0.001), irrespective of prior TNF inhibitor exposure. More CZP-treated patients reached SF-36 general population norms than placebo-treated patients. CONCLUSION: Both CZP dosing schedules provided rapid improvements in PROs across multiple disease aspects in patients with PsA. The benefits of CZP treatment for health-related quality of life were seen across generic, PsA-specific, and dermatology-specific measures and were observed in patients regardless of prior TNF inhibitor exposure. PMID- 24339181 TI - How long have adult humans been consuming milk? AB - Lactase is the enzyme that breaks down the milk sugar lactose, and in most mammals, including most humans, lactase activity is down-regulated after the weaning period is completed. However, in about 35% of adults worldwide, lactase continues to be expressed throughout adulthood, a feature termed lactase persistence (LP). Genetic evidence indicates that LP is a recent human adaptation, and its current geographic distribution correlates with the relative historical importance of dairying in different human populations. Investigating archaeological evidence for fresh milk consumption has proved crucial in building an account of the joint evolution of LP and dairying. A powerful technique for investigating food processing, including milk processing, in ancient populations is lipid residue analysis on archaeological pottery. We review here the archaeological and genetic evidence available that have contributed to a better understanding of the gene-culture co-evolution of LP and dairying. PMID- 24339182 TI - A new SCARB2 mutation in a patient with progressive myoclonus ataxia without renal failure. PMID- 24339183 TI - Transfer hydrogenation of ketones catalyzed by surface-active ruthenium and rhodium complexes in water. AB - An improved, high-yield, one-pot synthetic procedure for water-soluble ligands functionalized with trialkyl ammonium side groups H2 N(CH2 )2 NHSO2 -p-C6 H4 CH2 [NMe2 (Cn H2n+1 )](+) ([HL(n) ](+) ; n=8, 16) was developed. The corresponding new surface-active complexes [(p-cymene)RuCl(L(n) )] and [Cp*RhCl(L(n) )] (Cp*=eta(5) -C5 Me5 ) were prepared and characterized. For n=16 micelles are formed in water at concentrations as low as 0.6 mM, as demonstrated by surface tension measurements. The complexes were used for catalytic transfer hydrogenation of ketones with formate in water. Highly active catalyst systems were obtained in the case of complexes bearing C16 tails due to their ability to be adsorbed at the water/substrate interface. The scope of these catalyst systems in aqueous solutions was extended from partially water soluble aryl alkyl ketones (acetophenone, butyrophenone) to hydrophobic dialkyl ketones (2-dodecanone). PMID- 24339184 TI - Evaluation of patients with head and neck cancer performing standard treatment in relation to body composition, resting metabolic rate, and inflammatory cytokines. AB - BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) usually emerges as a set of signs and symptoms that, either alone or in combination with standard treatment, may lead to malnutrition and weight loss. METHODS: This study evaluated patients with SCCHN before day 0 and 30 days after the end of treatment, with/without tumor resection. Each individual patient underwent analyses of body composition and resting metabolic rate, as well as assessment of serum glucose, insulin, leptin, adiponectin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), IL-1beta, and insulin sensitivity. RESULTS: There was body mass loss during treatment and significant reduction in body fat and free fat mass. Early nutritional monitoring and tumor resection before treatment led to a better nutritional status and reduced inflammatory state. CONCLUSION: Early nutritional monitoring and resection of the tumor by surgery may be important factors for patients to better tolerate treatment. PMID- 24339185 TI - Influence of the absolute configuration of npe-caged cytosine on DNA single base pair stability. AB - Photolabile protecting groups are a versatile tool to trigger reactions by light irradiation. In this study, we have investigated the influence of the absolute configuration of the 1-(2-nitrophenyl)ethyl (NPE) cage group on a 15-base-pair duplex DNA. Using UV melting, we determined the global stability of the unmodified and the selectively (S)- and (R)-NPE-modified DNA sequences, respectively. We observe a differently destabilizing effect for the two NPE stereoisomers on the global stability. Analysis of the temperature dependence of imino proton exchange rates measured by NMR spectroscopy reveals that this effect can be attributed to decreased base pair stabilities of the caged and the 3' neighbouring base pair, respectively. Furthermore, our NMR based structural models of the modified duplexes provide a structural basis for the distinct effect of the (S)- and the (R)-NPE group. PMID- 24339186 TI - Priming effect and microbial diversity in ecosystem functioning and response to global change: a modeling approach using the SYMPHONY model. AB - Integration of the priming effect (PE) in ecosystem models is crucial to better predict the consequences of global change on ecosystem carbon (C) dynamics and its feedbacks on climate. Over the last decade, many attempts have been made to model PE in soil. However, PE has not yet been incorporated into any ecosystem models. Here, we build plant/soil models to explore how PE and microbial diversity influence soil/plant interactions and ecosystem C and nitrogen (N) dynamics in response to global change (elevated CO2 and atmospheric N depositions). Our results show that plant persistence, soil organic matter (SOM) accumulation, and low N leaching in undisturbed ecosystems relies on a fine adjustment of microbial N mineralization to plant N uptake. This adjustment can be modeled in the SYMPHONY model by considering the destruction of SOM through PE, and the interactions between two microbial functional groups: SOM decomposers and SOM builders. After estimation of parameters, SYMPHONY provided realistic predictions on forage production, soil C storage and N leaching for a permanent grassland. Consistent with recent observations, SYMPHONY predicted a CO2 -induced modification of soil microbial communities leading to an intensification of SOM mineralization and a decrease in the soil C stock. SYMPHONY also indicated that atmospheric N deposition may promote SOM accumulation via changes in the structure and metabolic activities of microbial communities. Collectively, these results suggest that the PE and functional role of microbial diversity may be incorporated in ecosystem models with a few additional parameters, improving accuracy of predictions. PMID- 24339187 TI - Nuchal translucency in twins according to mode of assisted conception and chorionicity. AB - OBJECTIVES: The impact of nuchal translucency (NT) screening in twins conceived after use of assisted reproduction technology (ART) has not been addressed properly in the literature. The aim of the current study was to assess, in a large cohort from a single center, NT in twins following various modes of ART as compared with NT in spontaneously-conceived twins and to differentiate results with regard to chorionicity. METHODS: Retrospective data from 825 twin pregnancies were available for this study. All pregnant women underwent NT screening and chorionicity determination between 11 + 0 and 13 + 6 weeks' gestation in our center. Information about mode of conception and pregnancy outcome was obtained from hospital records and by telephone interviews. Twins were classified as having been conceived after in-vitro fertilization (IVF) with the woman's own or a donated embryo, after non-IVF ART or spontaneously. NT distribution in subgroups of fetuses was compared on the basis of the multiple of the normal median (MoM), SD of log10 MoM estimated by the 90(th) -10(th) centile range divided by 2.563 and the proportion of NT values exceeding the normal 95(th) centile which was 1.641 MoM in the singletons. RESULTS: NT values were statistically significantly higher in ART pregnancies as compared with spontaneously-conceived pregnancies (Wilcoxon rank-sum test, P < 0.05) with medians of 1.073 and 1.038 MoM, respectively, but the proportion with values above the normal 95(th) percentile did not differ (chi-square test, P = 0.89). Among the ART twins, NT values were significantly higher for those conceived using IVF methods (P < 0.005), with a median of 1.082 MoM, compared with a median of 1.022 MoM using other methods. However, although a greater proportion exceeded the 95(th) centile (7.3% compared with 4.8%) this difference did not reach statistical significance (P = 0.17). There were no differences in NT values according to chorionicity (Wilcoxon rank-sum test, P = 0.75). The standard deviation of log10 NT was similar for all subgroups of twins. The correlation coefficient between fetuses in ART pregnancies was statistically significantly lower than that in spontaneously-conceived pregnancies (P < 0.05) but no significant differences were found between types of ART or according to chorionicity. CONCLUSIONS: There was a small but significant increase in NT levels among ART pregnancies, which appeared to be confined to those conceived using IVF, and a small reduction in the correlation between fetuses. These effects probably have little impact on the estimated risk based on algorithms in use today. PMID- 24339189 TI - Quantitative measurement of blood velocity in zebrafish with optical vector field tomography. AB - Microscopy techniques can readily visualize the finest details of embryo vasculature, but still lack to provide a complete three-dimensional representation of blood flow parameters. We present an in-vivo 3D imaging technique, able to reconstruct the blood cell velocity vector over a large volume of zebrafish embryos. This low cost and relatively simple technique is exploited to quantitatively assess blood velocity in the zebrafish tail at different stages of development. PMID- 24339191 TI - Anatomy and adaptations of the chewing muscles in Daubentonia (Lemuriformes). AB - The extractive foraging behavior in aye-ayes (Daubentonia madagascariensis) is unique among primates and likely has led to selection for a specialized jaw adductor musculature. Although this musculature has previously been examined in a subadult, until now, no one has reported the fascicle length, weight, and physiological cross-sectional area (PCSA) for these muscles in an adult aye-aye specimen. For the present study, we dissected an adult wild-born aye-aye from the Tsimbazaza Botanical and Zoological Park, Antananarivo, Madagascar. The aye-aye follows the general strepsirrhine pattern in its overall jaw adductor muscle anatomy, but has very large muscles and PCSA relative to body size. Fascicle length is also relatively great, but not nearly as much as in the juvenile aye aye previously dissected. Perhaps chewing muscle fascicles begin relatively long, but shorten through use and growth as connective tissue sheets expand and allow for pinnation and increased PCSA. Alternately, it may be that aye-ayes develop fascicular adaptation to wide gapes early in ontogeny, only to increase PCSA through later development into adulthood. The functional demands related to their distinctive manner of extractive foraging are likely responsible for the great PCSA in the jaw adductor muscles of the adult aye-aye. It may be that great jaw adductor PCSA in the adult, as compared to the juvenile, is a means of increasing foraging efficiency in the absence of parental assistance. Anat Rec, 297:308-316, 2014. (c) 2013 Wiley Periodicals, Inc. PMID- 24339190 TI - Comparing the utility of homogeneous subtypes of cocaine use and related behaviors with DSM-IV cocaine dependence as traits for genetic association analysis. AB - Because DSM-IV cocaine dependence (CD) is heterogeneous, it is not an optimal phenotype to identify genetic variation contributing to risk for cocaine use and related behaviors (CRBs). We used a cluster analytic method to differentiate homogeneous, highly heritable subtypes of CRBs and to compare their utility with that of the DSM-IV CD as traits for genetic association analysis. Clinical features of CRBs and co-occurring disorders were obtained via a poly-diagnostic interview administered to 9,965 participants in genetic studies of substance dependence. A subsample of subjects (N = 3,443) were genotyped for 1,350 single nucleotide polymorphisms (SNPs) selected from 130 candidate genes related to addiction. Cluster analysis of clinical features of the sample yielded five subgroups, two of which were characterized by heavy cocaine use and high heritability: a heavy cocaine use, infrequent intravenous injection group and an early-onset, heavy cocaine use, high comorbidity group. The utility of these traits was compared with the CD diagnosis through association testing of 2,320 affected subjects and 480 cocaine-exposed controls. Analyses examined both single SNP (main) and SNP-SNP interaction (epistatic) effects, separately for African Americans and European-Americans. The two derived subtypes showed more significant P values for 6 of 8 main effects and 7 of 8 epistatic effects. Variants in the CLOCK gene were significantly associated with the heavy cocaine use, infrequent intravenous injection group, but not with the DSM-IV diagnosis of CD. These results support the utility of subtypes based on CRBs to detect risk variants for cocaine addiction. PMID- 24339192 TI - Difluorophenylglycinols as new modulators of proteolytic processing of amyloid precursor proteins. AB - Synthesis and evaluation of difluorophenylglycinols as new modulators of proteolytic processing of the amyloid-beta precursor proteins for Alzheimer's therapies were described. A range of N-substituted (R)- and (S) difluorophenylglycinols, structured on the amino alcohol framework, were explored by incorporating the arylsulfonyl moieties and various N-substituents. Evans' chiral auxiliary strategy was employed for the asymmetric synthesis of these enantiomeric difluorophenylglycinols. Compounds with effects on the gamma secretase inhibition and ERK-mediated signaling pathways were evaluated on cell based assays. Among them, N-cyclopropylmethyl derivatives R-12c and R-13c showed modest gamma-secretase inhibition as well as ERK-dependent activation. PMID- 24339193 TI - Protocadherin PAPC is expressed in the CNC and can compensate for the loss of PCNS. AB - Protocadherins represent the biggest subgroup within the cadherin superfamily of transmembrane glycoproteins. In contrast to classical type I cadherins, protocadherins in general exhibit only moderate adhesive activity. During embryogenesis, they are involved in cell signaling and regulate diverse morphogenetic processes, including morphogenetic movements during gastrulation and neural crest migration. The two protocadherins paraxial protocadherin (PAPC) and axial protocadherin (AXPC) are indispensable for proper gastrulation movements in Xenopus and zebrafish. The closest relative PCNS instead, is required for neural crest and somite formation. Here, we show that cranial neural crest (CNC) cells in addition to PCNS express PAPC, but not AXPC. Overexpression of PAPC resulted in comparable migration defects as knockdown of PCNS. Moreover, reconstitution experiments revealed that PAPC is able to replace PCNS in CNC cells, indicating that both protocadherins can regulate CNC migration. PMID- 24339194 TI - Discovery and identification of serum potential biomarkers for pulmonary tuberculosis using iTRAQ-coupled two-dimensional LC-MS/MS. AB - Pulmonary tuberculosis (TB) caused by Mycobacterium tuberculosis is a chronic disease. Currently, there are no sufficiently validated biomarkers for early diagnosis of TB infection. In this study, a panel of potential serum biomarkers was identified between patients with pulmonary TB and healthy controls by using iTRAQ-coupled 2D LC-MS/MS technique. Among 100 differentially expressed proteins screened, 45 proteins were upregulated (>1.25-fold at p < 0.05) and 55 proteins were downregulated (<0.8-fold at p < 0.05) in the TB serum. Bioinformatics analysis revealed that the differentially expressed proteins were related to the response to stimulus, the metabolic and immune system processes. The significantly differential expression of apolipoprotein CII (APOCII), CD5 antigen like (CD5L), hyaluronan-binding protein 2 (HABP2), and retinol-binding protein 4 (RBP4) was further confirmed using immunoblotting and ELISA analysis. By forward stepwise multivariate regression analysis, a panel of serum biomarkers including APOCII, CD5L, and RBP4 was obtained to form the disease diagnostic model. The receiver operation characteristic curve of the diagnostic model was 0.98 (sensitivity = 93.42%, specificity = 92.86%). In conclusion, APOCII, CD5L, HABP2, and RBP4 may be potential protein biomarkers of pulmonary TB. Our research provides useful data for early diagnosis of TB. PMID- 24339195 TI - Antimicrobial activity of water-soluble triazole phenazine clickamers against E. coli. AB - The antimicrobial potency of phenazine derivatives is attenuated by their inherently hydrophobic nature, complicating their use as antibiotic drugs. We have analyzed the cytotoxicity and mode of action of water-soluble bis-triazolyl phenazines against E. coli and a human epithelial (HaCat) cell line. We observed complete inhibition of bacterial growth over concentration ranges that do not affect the viability of human epithelial cells. Confocal fluorescence microscopy revealed a high degree of interaction between the phenazine compounds and E. coli, as well as evidence of membrane damage in phenazine-treated E. coli. Additional data suggests that the potency of these particular water-soluble phenazine compounds does not result from the production of reactive oxygen species, but rather from cytotoxic interference with metabolic electron-transfer cascades. PMID- 24339188 TI - Integrated micro/nanoengineered functional biomaterials for cell mechanics and mechanobiology: a materials perspective. AB - The rapid development of micro/nanoengineered functional biomaterials in the last two decades has empowered materials scientists and bioengineers to precisely control different aspects of the in vitro cell microenvironment. Following a philosophy of reductionism, many studies using synthetic functional biomaterials have revealed instructive roles of individual extracellular biophysical and biochemical cues in regulating cellular behaviors. Development of integrated micro/nanoengineered functional biomaterials to study complex and emergent biological phenomena has also thrived rapidly in recent years, revealing adaptive and integrated cellular behaviors closely relevant to human physiological and pathological conditions. Working at the interface between materials science and engineering, biology, and medicine, we are now at the beginning of a great exploration using micro/nanoengineered functional biomaterials for both fundamental biology study and clinical and biomedical applications such as regenerative medicine and drug screening. In this review, an overview of state of the art micro/nanoengineered functional biomaterials that can control precisely individual aspects of cell-microenvironment interactions is presented and they are highlighted them as well-controlled platforms for mechanistic studies of mechano-sensitive and -responsive cellular behaviors and integrative biology research. The recent exciting trend where micro/nanoengineered biomaterials are integrated into miniaturized biological and biomimetic systems for dynamic multiparametric microenvironmental control of emergent and integrated cellular behaviors is also discussed. The impact of integrated micro/nanoengineered functional biomaterials for future in vitro studies of regenerative medicine, cell biology, as well as human development and disease models are discussed. PMID- 24339196 TI - Reversible self-assembly of terpyridine-functionalized graphene oxide for energy conversion. AB - Terpyridine-functionalized graphene oxides were prepared for self-assembly into 3D architectures with various metal ions (e.g., Fe, Ru). The resulting electrode materials showed significantly improved electroactivities for efficient energy conversion and storage. They showed promise for application in the oxygen reduction reaction (ORR), photocurrent generation, and supercapacitance. PMID- 24339197 TI - Invasion of differentiated intestinal Caco-2 cells is a sporadic property among atypical enteropathogenic Escherichia coli strains carrying common intimin subtypes. AB - Atypical enteropathogenic Escherichia coli (aEPEC) strains produce attaching effacing (AE) lesions on enterocytes due to the interaction of the adhesin intimin with its translocated receptor. aEPEC strain 1551-2 was previously shown to invade HeLa and T84 cells by means of the uncommon intimin subtype omicron. Other aEPEC strains carrying uncommon intimin subtypes have also been shown to invade differentiated T84 intestinal cells. In this study, seven aEPEC strains carrying the most common EPEC intimin subtypes (alpha, beta, and gamma) were evaluated regarding the ability to invade differentiated intestinal Caco-2 cells. Although all strains adhered to and promoted AE lesions, the numbers of cell associated bacteria varied significantly between the different strains regardless of the intimin subtype (P < 0.05). Gentamicin protection assay and transmission electron microscopy analyses showed that in comparison with the invasive strain 1551-2, only one strain (aEPEC EC423/03, intimin beta) was invasive (P = 0.05). Although both strains persisted intracellularly until 48 h, the number of viable bacteria of EC423/03 decreased, whereas that of 1551-2 increased significantly up to 24 h and then decreased. In conclusion, invasiveness is a sporadic property among aEPEC strains carrying some common intimin subtypes. PMID- 24339198 TI - Lung function in African infants: a pilot study. AB - BACKGROUND: The burden of childhood respiratory illness is large in low and middle income countries (LMICs). Infant lung function (ILF) testing may provide useful information about lung growth and susceptibility to respiratory disease. However, ILF has not been widely available in LMICs settings where the greatest burden of childhood respiratory disease occurs. AIM: To implement and evaluate a pilot study of ILF testing in a semi-rural setting in South Africa. METHOD: Infant lung function testing was established at a community hospital in South Africa. All measures were done in unsedated infants during sleep. Measurements, made with the infant quietly breathing through a face mask and bacterial filter, included tidal breathing (TBFVL), exhaled nitric oxide (eNO), and sulphur hexafluoride multiple breath washout (MBW) measures using an ultrasonic flow meter and chemoluminescent NO analyzer. RESULTS: Twenty infants, mean age of 7.7 (SD 2.9) weeks were tested; 8 (40%) were Black African and 12 (60%) were mixed race. Five (25%) infants were preterm. There were 19 (95%) successful TBFVL and NO tests and 18 (90%) successful MBW tests. The mean tidal volume was 30.5 ml (SD 5.9), respiratory rate 50.2 breaths per minute (SD 8.7), and eNO 10.4 ppb (SD 7.3). The mean MBW measures were: functional residual capacity 71 ml (SD 13) and the lung clearance index 7.6 (SD 0.5). The intra-subject coefficient of variations (CV) of lung function measures were similar to published normative data for Caucasian European infants. CONCLUSION: In this study we demonstrate that unsedated infant lung function measures of tidal breathing, MBW, and eNO are feasible in a semi-rural African setting with rates comparable to those reported from high income countries. PMID- 24339199 TI - Determination of melamine impurities by capillary zone electrophoresis with UV- and quadrupole time-of-flight mass spectrometric detection. AB - A method based on CZE coupled to quadrupole TOF MS (Q-TOF MS), which is suitable to analyze seven common melamine impurities is presented. MS compatible formic acid based BGEs with various concentrations of organic modifiers were investigated using UV detection to determine the best separation system regarding resolution and speed. The optimized BGE consisted of 350 mM formic acid with 10% ACN and migration times were <6 min. The detection limits were considerably improved when ESI MS was applied instead of UV detection. In addition the instrument allows quantification with good linearity and repeatability in the relevant concentration range. The analytical characteristics of the method were evaluated for melamine, guanylurea, diaminotriazine, ureidomelamine, guanlymelamine, melam, methylmelamine, and dimethylmelamine both with UV and MS detection. Several different melamine samples were analyzed und the determined impurity levels were in the range from 0.02 to 2.3%. PMID- 24339200 TI - Quinonediimine-induced oxidative coupling of organomagnesium reagents. AB - N,N'-Diphenyl-p-benzoquinonediimine, a redox-active unit of polyaniline, efficiently induced the oxidative homocoupling of various aryl- and vinylmagnesium reagents in suppressing the side reactions, such as 1,2- or 1,4 addition reaction. PMID- 24339201 TI - Stereoselective bromofunctionalization of alkenes. AB - The stereoselective bromofunctionalization of alkenes, particularly the enantioselective format, has been a subject of intense research in recent years. The ground-breaking works are documented in recent reviews. On the other hand, this account will provide an insight into our group's approach in tackling the challenges in enantioselective bromocyclization of alkenes as well as the development of diastereoselective N-bromosuccinimide-initiated multicomponent reactions. PMID- 24339202 TI - Multi-temperature zone, droplet-based microreactor for increased temperature control in nanoparticle synthesis. AB - Microreactors are an emerging technology for the controlled synthesis of nanoparticles. The Multi-Temperature zone Microreactor (MTM) described in this work utilizes thermally isolated heated and cooled regions for the purpose of separating nucleation and growth processes as well as to provide a platform for a systematic study on the effect of reaction conditions on nanoparticle synthesis. PMID- 24339203 TI - Analysis of trial data for infliximab and golimumab: baseline C-reactive protein level and prediction of therapeutic response in patients with psoriatic arthritis. AB - OBJECTIVE: Anti-tumor necrosis factor medications have demonstrated good efficacy in treating psoriatic arthritis (PsA). Clinical responses at the primary end point in recent clinical trials of golimumab in PsA subjects yielded lower American College of Rheumatology 20% criteria for improvement (ACR20) responses than those seen in the Infliximab Multinational Psoriatic Arthritis Controlled Trial 2 infliximab study. However, baseline C-reactive protein (CRP) levels of PsA subjects enrolled in these trials differed significantly. We hypothesized that baseline CRP levels predict the observed differing clinical response rates at the primary end point. METHODS: Combining the data from the infliximab and golimumab trials, we stratified the data by baseline CRP levels and then correlated these cohorts with response to treatment, specifically the Psoriasis Area and Severity Index and the ACR20, ACR50, and ACR70 responses. RESULTS: The mean baseline CRP level in the infliximab trial was 1.9 mg/dl versus 1.4 mg/dl in the golimumab trial. Only 23% of golimumab subjects had a CRP level >=1.7 mg/dl versus 35% of infliximab subjects (P = 0.0023). All subjects with a CRP level >=1.7 mg/dl at baseline achieved higher ACR20, ACR50, ACR70 response rates (56%, 36%, and 18%, respectively) at the primary end point of 14 weeks in the infliximab and golimumab clinical trials than any subjects with a CRP level <1.7 mg/dl (48%, 28%, and 13%, respectively [P = 0.045, P = 0.027, and P = 0.089, respectively]). CONCLUSION: These results demonstrate that an increased baseline CRP level predicted improved therapeutic response at the primary end point for subjects treated with both golimumab and infliximab. To allow for comparison between future drug development studies and meta-analyses, baseline CRP levels should be factored into the multivariate analysis PMID- 24339204 TI - Downregulation of miR-7 upregulates Cullin 5 (CUL5) to facilitate G1/S transition in human hepatocellular carcinoma cells. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that participate in the regulation of gene expression. In this study, we demonstrate that miR-7 was downregulated in hepatocellular carcinoma (HCC) tissues compared to adjacent non-tumor tissue. Over-expression of miR-7 in QGY-7703 and HepG2 cell lines inhibited colony formation and induced G1/S phase arrest, whereas knockdown of miR-7 produced the opposite phenotype. A tumor suppressor gene, CUL5, was identified as a direct target of miR-7, and CUL-5 is upregulated upon the binding of miR-7 to its 3'UTR. Furthermore, suppression of CUL5 also suppressed cell colony formation and induced cell cycle arrest. Ectopic expression of CUL5 abrogated the effects of miR-7 inhibition on QGY-7703 and HepG2 cell lines. These results indicate that miR-7 suppresses colony formation and causes cell cycle arrest via upregulation of CUL5, and it may function as a tumor suppressor in HCC. PMID- 24339205 TI - Enhancing the electrochemical performance of the LiMn(2)O(4) hollow microsphere cathode with a LiNi(0.5)Mn(1.5)O(4) coated layer. AB - Spinel cathode materials consisting of LiMn2 O4 @LiNi0.5 Mn1.5 O4 hollow microspheres have been synthesized by a facile solution-phase coating and subsequent solid-phase lithiation route in an atmosphere of air. When used as the cathode of lithium-ion batteries, the double-shell LiMn2 O4 @LiNi0.5 Mn1.5 O4 hollow microspheres thus obtained show a high specific capacity of 120 mA h g(-1) at 1 C rate, and excellent rate capability (90 mAhg(-1) at 10 C) over the range of 3.5-5 V versus Li/Li(+) with a retention of 95 % over 500 cycles. PMID- 24339206 TI - Microfluidic channel-assisted screening of hematopoietic malignancies. AB - A simple microfluidic fluorescence in situ hybridization (FISH) device allowing accurate analysis of interphase nuclei in 1 hr in narrow channels is presented. Photolithography and fluorosilicic acid etching were used to fabricate microfluidic channels (referred to as FISHing lines) that allowed analysis of 10 samples on a glass microscope slide 0.2 ul of sample volume was used to fill a micro-channel, which resembled a 250-fold reduction compared to conventional FISH. FISH signals were comparable to conventional FISH, with 50-fold less probe consumption and 10-fold less time. Cells were immobilized in single file in channels just exceeding the diameter of the cells, and were used for minimal residual disease (MRD) analysis. To test the micro-channels for application in FISH, MRD was simulated by mixing K562 cells (an established chronic myeloid leukemia cell line) carrying the BCR/ABL fusion gene across 1:1 to 1:1,000 Jurkat cells (an established acute lymphoblastic leukemia cell line). The limit of detection was seen to be 1:100 cells and 1:1,000 cells for FISHing lines and conventional FISH, respectively; however, the conventional method seemed to over score the presence of K562 cells. This may in part be attributed to FISHing lines practically eliminating the chance of duplicate screening of cells and hastened the time of screening, enhancing scoring of all cells within the channels. This was compared to 1 in 500 cells on the slide being analyzed with the conventional FISH. PMID- 24339207 TI - Cumulative geoecological effects of 62 years of infrastructure and climate change in ice-rich permafrost landscapes, Prudhoe Bay Oilfield, Alaska. AB - Many areas of the Arctic are simultaneously affected by rapid climate change and rapid industrial development. These areas are likely to increase in number and size as sea ice melts and abundant Arctic natural resources become more accessible. Documenting the changes that have already occurred is essential to inform management approaches to minimize the impacts of future activities. Here, we determine the cumulative geoecological effects of 62 years (1949-2011) of infrastructure- and climate-related changes in the Prudhoe Bay Oilfield, the oldest and most extensive industrial complex in the Arctic, and an area with extensive ice-rich permafrost that is extraordinarily sensitive to climate change. We demonstrate that thermokarst has recently affected broad areas of the entire region, and that a sudden increase in the area affected began shortly after 1990 corresponding to a rapid rise in regional summer air temperatures and related permafrost temperatures. We also present a conceptual model that describes how infrastructure-related factors, including road dust and roadside flooding are contributing to more extensive thermokarst in areas adjacent to roads and gravel pads. We mapped the historical infrastructure changes for the Alaska North Slope oilfields for 10 dates from the initial oil discovery in 1968 2011. By 2010, over 34% of the intensively mapped area was affected by oil development. In addition, between 1990 and 2001, coincident with strong atmospheric warming during the 1990s, 19% of the remaining natural landscapes (excluding areas covered by infrastructure, lakes and river floodplains) exhibited expansion of thermokarst features resulting in more abundant small ponds, greater microrelief, more active lakeshore erosion and increased landscape and habitat heterogeneity. This transition to a new geoecological regime will have impacts to wildlife habitat, local residents and industry. PMID- 24339208 TI - Spray-painted binder-free SnSe electrodes for high-performance energy-storage devices. AB - SnSe nanocrystal electrodes on three-dimensional (3D) carbon fabric and Au-coated polyethylene terephthalate (PET) wafer have been prepared by a simple spray painting process and were further investigated as binder-free active-electrodes for Lithium-ion batteries (LIBs) and flexible stacked all-solid-state supercapacitors. The as-painted SnSe nanocrystals/carbon fabric electrodes exhibit an outstanding capacity of 676 mAh g(-1) after 80 cycles at a current density of 200 mA g(-1) and a considerable high-rate capability in lithium storage because of the excellent ion transport from the electrolyte to the active materials and the efficient charge transport between current collector and electrode materials. The binder-free electrodes also provide a larger electrochemical active surface compared with electrodes containing binders, which leads to the enhanced capacities of energy-storage devices. A flexible stacked all-solid-state supercapacitor based on the SnSe nanocrystals on Au-coated PET wafers shows high capacitance reversibility with little performance degradation at different current densities after 2200 charge-discharge cycles and even when bent. This allows for many potential applications in facile, cost-effective, spray-paintable, and flexible energy-storage devices. The results indicate that the fabrication of binder-free electrodes by a spray painting process is an interesting direction for the preparation of high-performance energy-storage devices. PMID- 24339209 TI - Attenuation of the aggregation and neurotoxicity of amyloid-beta peptides by catalytic photooxygenation. AB - Alzheimer's disease (AD), a progressive severe neurodegenerative disorder, is currently incurable, despite intensive efforts worldwide. Herein, we demonstrate that catalytic oxygenation of amyloid-beta peptides (Abeta) might be an effective approach to treat AD. Abeta1-42 was oxygenated under physiologically-relevant conditions (pH 7.4, 37 degrees C) using a riboflavin catalyst and visible light irradiation, with modifications at the Tyr(10) , His(13) , His(14) , and Met(35) residues. The oxygenated Abeta1-42 exhibited considerably lower aggregation potency and neurotoxicity compared with native Abeta. Photooxygenation of Abeta can be performed even in the presence of cells, by using a selective flavin catalyst attached to an Abeta-binding peptide; the Abeta cytotoxicity was attenuated in this case as well. Furthermore, oxygenated Abeta1-42 inhibited the aggregation and cytotoxicity of native Abeta. PMID- 24339210 TI - Detecting and characterizing cellular responses to Mycobacterium tuberculosis from histology slides. AB - Infection with Mycobacterium tuberculosis (M.tb) results in immune cell recruitment to the lungs, forming macrophage-rich regions (granulomas) and lymphocyte-rich regions (lymphocytic cuffs). The objective of this study was to accurately identify and characterize these regions from hematoxylin and eosin (H&E)-stained tissue slides. The two target regions (granulomas and lymphocytic cuffs) can be identified by their morphological characteristics. Their most differentiating characteristic on H&E slides is cell density. We developed a computational framework, called DeHiDe, to detect and classify high cell-density regions in histology slides. DeHiDe employed a novel internuclei geodesic distance calculation and Dulmange Mendelsohn permutation to detect and classify high cell-density regions. Lung tissue slides of mice experimentally infected with M.tb were stained with H&E and digitized. A total of 21 digital slides were used to develop and train the computational framework. The performance of the framework was evaluated using two main outcome measures: correct detection of potential regions, and correct classification of potential regions into granulomas and lymphocytic cuffs. DeHiDe provided a detection accuracy of 99.39% while it correctly classified 90.87% of the detected regions for the images where the expert pathologist produced the same ground truth during the first and second round of annotations. We showed that DeHiDe could detect high cell-density regions in a heterogeneous cell environment with non-convex tissue shapes. PMID- 24339212 TI - Venturing into the no-man's land of the retina in Parkinson's disease. AB - The development of optical coherence tomography (OCT) has led to increasing interest in the retina in Parkinson's disease (PD). The retina is a multilayered tissue: looking into the eye from the outside, these layers comprise the nerve fiber layer (NFL); the ganglion cell layer (GCL); the inner plexiform layer (IPL), which contains the interconnecting plexus, including tyrosine hydroxylase positive (dopaminergic) fibers of amacrine cells; the inner nuclear layer; and several outer retinal layers. Commercial spectral-domain OCT has a specific program for detecting peripapillary NFL defects and a different macular program for diabetic retinopathy. Specific programs for PD are not commercially available. Taking all studies together, it seems that macular programs have a higher diagnostic yield than NFL programs, but the numbers of studies and examined patients are relatively small. It is not certain that all retinal thinning in PD is due to dopaminergic neuronal loss. When applying OCT, the where (region of interest) and the what of the focus of automated programs must be considered. With these caveats, one could take advantage of the power of OCT for looking in-depth into the terra incognita of individual retinal layers at the fovea and perhaps at other appropriate retinal locations. PMID- 24339211 TI - Large enhancement of quantum dot fluorescence by highly scalable nanoporous gold. AB - Dealloyed nanoporous gold (NPG) dramatically enhances quantum dot (QD) fluorescence by amplifying near-field excitation and increasing the radiative decay rate. Originating from plasmonic coupling, the fluorescence enhancement is highly dependent upon the nanopore size of the NPG. In contrast to other nanoengineered metallic structures, NPG exhibits fluorescence enhancement of QDs over a large substrate surface. PMID- 24339213 TI - Carbohydrate analysis: from sample preparation to HPLC on different stationary phases coupled with evaporative light-scattering detection. AB - After 20 years of development, evaporative light-scattering detection (ELSD) has become the mainstream choice for the detection of various classes of natural products. ELSD continues to grow in popularity as a "quasi-universal" technique because of the specificity of the detection method, which is based on the scattering of laser light from nonvolatile analyte particles. It represents an attractive alternative compared to other types of detection, such as refractive index detection and/or ultraviolet detection. This review presents issues concerned with the separation of carbohydrates in plant materials by HPLC and ELSD, as well as the advantages and limitations relating to the ELSD method. Additionally, an overview of possible ELSD applications in the analysis of carbohydrates in natural products is presented. PMID- 24339214 TI - Optimization of a phenol extraction-based protein preparation method amenable to downstream 2DE and MALDI-MS based analysis of bacterial proteomes. AB - 2DE is one of the most efficient and widely used methods for resolving complex protein mixtures. For efficient analysis of complex samples, high-resolution separation of proteins on 2D gel is essential, and for that purpose good sample preparation is crucial. In this study, we have improvized a method for preparing bacterial total cellular proteome, from a strategy applied earlier to recalcitrant plant tissues, which gave high-quality resolution on 2DE. The method involving phenol extraction followed by methanol/ammonium acetate precipitation was first optimized for the chemolithotrophic proteobacteria Tetrathiobacter kashmirensis WT001 and Pseudaminobacter salicylatoxidans KCT001 that did not yield quality protein preps in conventional trichloroacetic acid/acetone precipitation method. Subsequently, to validate its general applicability, the method was evaluated against the trichloroacetic acid/acetone precipitation method for two other model bacteria, i.e. Escherichia coli DH5alpha and Mycobacterium smegmatis mc(2) 6. Identification of at least four proteins each from the outer membrane, periplasm, and cytoplasm of T. kashmirensis by MALDI-MS not only proved the efficiency of the method in extracting proteins from the different cellular compartments but also the amenability of the obtained protein spots toward MALDI-MS based identification. PMID- 24339216 TI - Dimers of N-heterocyclic carbene copper, silver, and gold halides: probing metallophilic interactions through electron density based concepts. AB - Homobimetallic metallophilic interactions between copper, silver, and gold-based [(NHC)MX]-type complexes (NHC=N-heterocyclic carbene, i.e, 1,3,4-trimethyl-4,5 dihydro-1H-1,2,4-triazol-5-ylidene; X=F, Cl, Br, I) were investigated by means of ab initio interaction energies, Ziegler-Rauk-type energy-decomposition analysis, the natural orbital for chemical valence (NOCV) framework, and the noncovalent interaction (NCI) index. It was found that the dimers of these complexes predominantly adopt a head-to-tail arrangement with typical M???M distance of 3.04-3.64 A, in good agreement with the experimental X-ray structure determined for [{(NHC)AuCl}2 ], which has an Au???Au distance of 3.33 A. The interaction energies between silver- and gold-based monomers are calculated to be about -25 kcal mol(-1) , whereas that for the Cu congener is significantly lower (-19.7 kcal mol(-1) ). With the inclusion of thermal and solvent contributions, both of which are destabilizing, by about 15 and 8 kcal mol(-1) , respectively, an equilibrium process is predicted for the formation of dimer complexes. Energy decomposition analysis revealed a dominant electrostatic contribution to the interaction energy, besides significantly stabilizing dispersion and orbital interactions. This electrostatic contribution is rationalized by NHC(delta(+) )???halogen(delta(-) ) interactions between monomers, as demonstrated by electrostatic potentials and derived charges. The dominant NOCV orbital indicates weakening of the pi backdonation in the monomers on dimer formation, whereas the second most dominant NOCV represents an electron-density deformation according to the formation of a very weak M???M bond. One of the characteristic signals found in the reduced density gradient versus electron density diagram corresponds to the noncovalent interactions between the metal centers of the monomers in the NCI plots, which is the manifestation of metallophilic interaction. PMID- 24339217 TI - Self-assembly of carboxylic acid appended naphthalene diimide derivatives with tunable luminescent color and electrical conductivity. AB - Self-assembly of a series of carboxylic acid-functionalized naphthalene diimide (NDI) chromophores with a varying number (n=1-4) of methylene spacers between the NDI ring and the carboxylic acid group has been studied. The derivatives show pronounced aggregation due to the synergistic effects of H-bonding between the carboxylic acid groups in a syn-syn catemer motif and pi stacking between the NDI chromophores. Solvent-dependent UV/Vis studies reveal the existence of monomeric dye molecules in a "good" solvent such as chloroform and self-assembly in "bad" solvents such as methylcyclohexane. The propensity of self-assembly is comparable for all samples. Temperature-dependent spectroscopic studies show high thermal stability of the H-bonding-mediated self-assembled structures. In the presence of a protic solvent such as MeOH, self-assembly can be suppressed, suggesting a decisive role of H-bonding, whereas pi stacking is more a consequence of than a cause for self-assembly. Syn-syn catemer-type H-bonding is supported by powder XRD studies and the results corroborate well with DFT calculations. The morphology as determined by AFM is found to be dependent on the value of n; with increasing n, the morphology gradually shifts from 2D nanosheets to 1D nanofibers. Emission spectra show sharp emission bands with relatively small Stokes shifts. In addition, a rather broad emission band is observed at longer wavelengths because of the in situ formation of excimer-type species. Due to such a heterogeneous nature, the emission spectrum spans almost the entire red-green blue region. Depending on the value of n, the ratio of intensities of the two emission bands is changed, which results in a tunable luminescent color. Furthermore, in the case of n=1 and 3, almost pure white light emission is observed. Time-resolved photoluminescence spectra show a very short lifetime (a few picoseconds) of monomeric dye molecules and biexponential decays with longer lifetimes (on the order of nanoseconds) for aggregated species. Current-voltage measurements show electrical conductivity in the range of 10(-4) S cm(-1) for the aggregated chromophores, which is four orders of magnitude higher than the value for a structurally similar NDI control molecule lacking the H-bonding functionality. PMID- 24339215 TI - Childhood Arthritis and Rheumatology Research Alliance consensus treatment plans for new-onset polyarticular juvenile idiopathic arthritis. AB - OBJECTIVE: There is no standardized approach to the initial treatment of polyarticular juvenile idiopathic arthritis (JIA) among pediatric rheumatologists. Understanding the comparative effectiveness of the diverse therapeutic options available will result in better health outcomes for polyarticular JIA. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans (CTPs) for use in clinical practice to facilitate such studies. METHODS: A case-based survey was administered to CARRA members to identify the common treatment approaches for new-onset polyarticular JIA. Two face-to-face consensus conferences employed modified nominal group technique to identify treatment strategies, operational case definition, end points, and data elements to be collected. A core workgroup reviewed the relevant literature, refined plans, and developed medication dosing and monitoring recommendations. RESULTS: The initial case-based survey identified significant variability among treatment approaches for new-onset polyarticular JIA. We developed 3 CTPs based on treatment strategies for the first 12 months of therapy, as well as case definitions and clinical and laboratory monitoring schedules. The CTPs include a step-up plan (nonbiologic disease-modifying antirheumatic drug [DMARD] followed by a biologic DMARD), an early combination plan (nonbiologic and biologic DMARD combined within a month of treatment initiation), and a biologic only plan. This approach was approved by 96% of the CARRA JIA Research Committee members attending the 2013 CARRA face-to-face meeting. CONCLUSION: Three standardized CTPs were developed for new-onset polyarticular JIA. Coupled with data collection at defined intervals, use of these CTPs will enable the study of their comparative effectiveness in an observational setting to optimize initial management of polyarticular JIA. PMID- 24339218 TI - Long-term recovery after parapneumonic empyema in children. AB - BACKGROUND: The incidence of parapneumonic empyema in children has increased worldwide, but the long-term anatomical and functional consequences in the lungs after empyema are not known. METHODS: We investigated the long-term outcome of childhood empyema in 26 patients by physical examination, chest radiograph and magnetic resonance image (MRI) of the lungs, and pulmonary function tests. RESULTS: At follow-up 3-19 years (mean 8 years) after empyema, all patients had normal findings in the physical examination. Spirometry was normal in 80% of patients, and evidence of obstructive airway disease was detected in 16%. Thirty six percent of patients had abnormal findings in the chest radiograph and 92% in the MRI of the lungs. In six patients, the MRI revealed significant pleural scarring (extension longer than 1 cm). Thirteen patients (50%) reported persistent respiratory symptoms, such as impaired tolerance of physical activity or prolonged cough after a common cold. During the follow-up four patients suffered a second pneumonia. CONCLUSIONS: The long-term recovery of children with parapneumonic empyema is good, since most patients subsequently have normal lung function, chest radiograph, and clinical recovery. Half of the patients reported subjective respiratory symptoms and most patients had minor lung abnormalities, mostly pleural scars, detected in the MRI many years after empyema. However, as long-term impairment of lung function was rarely found, the clinical significance of the anatomical residues seen in the lung MRI seems to be minor. PMID- 24339219 TI - Heightened exposure: researchers promote exposomics to clarify cancer's contributors. PMID- 24339221 TI - Invasive hypermucoid variant of group A Streptococcus is defective in growth and susceptible to DNA-damaging treatments. AB - Hyaluronic acid capsule is one of the most important virulence factors of group A Streptococcus (GAS). Over-production of capsule has been thought to enhance GAS virulence during infections. However, although the increased of capsule expression associates with increased bacterial virulence and invasive ability, over-production of capsule has not often been observed among clinical isolates. In the present study, we identified two mucoid emm12 type isolates that can convert to the hypermucoid morphology under both in vitro and in vivo conditions. Consistent with previous studies, hypermucoid variants are more invasive in the mouse air-pouch infection model. However, one of the hypermucoid variants showed a growth-defective phenotype in regular broth culture conditions and is significantly more susceptible to various DNA-damaging treatments when compared with the mucoid variant. These properties of the hypermucoid variant may be adverse factors inhibiting its adaptation to the host environment during infections. PMID- 24339222 TI - Investigation of a lithium-halogen exchange flow process for the preparation of boronates by using a cryo-flow reactor. AB - Conducting low-temperature organometallic reactions under continuous flow conditions offers the potential to more accurately control exotherms and thus provide more reproducible and scalable processes. Herein, progress towards this goal with regards to the lithium-halogen exchange/borylation reaction is reported. In addition to improving the scope of substrates available on a research scale, methods to improve reaction profiles and expedite purification of the products are also described. On moving to a continuous system, thermocouple measurements have been used to track exotherms and provide a level of safety for continuous processing of organometallic reagents. The use of an in-line continuous liquid-liquid separation device to circumvent labour intensive downstream off-line processing is also reported. PMID- 24339224 TI - Dentate gyrus mediates cognitive function in the Ts65Dn/DnJ mouse model of Down syndrome. AB - In the Ts65Dn/DnJ mouse model of Down syndrome (DS), hippocampal deficits of learning and memory are the most robust features supporting this mouse as a valid cognitive model of DS. Although dentate gyrus (DG) dysfunction is suggested by excessive GABAergic inhibition, its role in perturbing DG functions in DS is unknown. We hypothesize that in the Ts65Dn/DnJ mouse, the specific role of the DG is disturbed in its support of contextual and spatial information. Support for this hypothesis comes from rats with DG lesions that show similar deficits. In order to test this hypothesis, we have developed a novel series of spontaneous exploratory tasks that emphasize the importance of recognizing spatial and contextual cues and that involve DG function. The results with this exploratory battery show that Ts65Dn/DnJ mice are impaired in DG-dependent short-term recognition tests involving object recognition with contextual cues, in place recognition and in metric distance recognition relative to wild type littermate controls. Further, whereas Ts65Dn/DnJ mice can recognize object novelty in the absence of contextual cues after a 5-min delay, they cannot do so after a delay of 24 h, suggesting a problem with CA1-mediated consolidation. The results also show that Ts65Dn/DnJ mice are not impaired in tasks (object recognition and configural object recognition) that are mediated by the perirhinal cortex (PRh). These results implicate the DG as a specific therapeutic target and the PRh as a potential therapeutic strength for future research to ameliorate learning and memory in DS. PMID- 24339225 TI - Halogen bonds with benzene: an assessment of DFT functionals. AB - The performance of an extensive set of density functional theory functionals has been tested against CCSD(T) and MP2 results, extrapolated to the complete basis set (CBS) limit, for the interaction of either DCl or DBr (D = H, HCC, F, and NC) with the aromatic system of benzene. It was found that double hybrid functionals explicitly including dispersion, that is, B2PLYPD and mPW2PLYPD, provide the better agreement with the CCSD(T)/CBS results on both energies and equilibrium geometry, indicating the importance of dispersive contributions in determining this interaction. Among the less expensive functionals, the better performance is provided by the omegaB97X and M062X functionals, while the omegaB97XD and B97D functionals are shown to work very well for bromine complexes but not so well for chlorine complexes. PMID- 24339226 TI - Extended nanofluidic immunochemical reaction with femtoliter sample volumes. AB - The growing need to optimize immunoassay performance driven by interest in analyzing individual cells has resulted in a decrease in the amount of sample required. Miniaturized immunoassays that use ultra-small femtoliter to attoliter sample volumes, a range known as the extended nanospace, can satisfy this analytical need; however, capturing every targeted molecule without loss in extended nanochannels for subsequent detection remains challenging. This is the first report of a successful extended nanofluidics-based quantitative immunochemical reaction capable of high capture efficiency using a femtoliter scale sample volume. A novel patterning method using a photolithographic technique with vacuum ultraviolet light and low-temperature (100 degrees C) bonding enables patterning of functional groups for antibody immobilization before bonding, resulting in an immunochemical reaction space of only 86 fL. Reaction rate analyses indicate a decrease in the required sample volume to 810 fL and improvement in the limit of detection to 3 zmol, 5-6 orders of magnitude better than possible with the microfluidic immunoassay format. Highly efficient (near 100%) immunochemical reactions on a seconds time scale are possible due to the nm-scale diffusion length, which should be advantageous for the analysis of ultra-low-volume samples. PMID- 24339227 TI - Synthesis and biological screening of novel indolalkyl arenes targeting the serotonine transporter. AB - A series of functionalized indolylalkylarenes 3-16(a and b) were synthesized and their affinities for the serotonin transporter were investigated in vitro. Compounds 3-12(a and b) were obtained by nucleophilic substitution of 3-(1H-indol 3-yl)propyl-4-methylbenzenesulfonates 2(a and b) with a series of azaheterocycles. Compounds 14-16(a and b) were prepared in a two-step sequence by reaction of 3-(1H-indol-3-yl)-2-methylpropanal with substituted 1,2 phenylenediamines. Compounds 3b, 4b, and 5b showed good binding affinities (K(i) = 33.0, 48.0, and 17 nM, respectively). The other synthesized compounds showed moderate or no affinity in the binding studies. PMID- 24339228 TI - Chromatographic separation and assignment of absolute configuration of hydroxywarfarin isomers. AB - The absolute configuration of several hydroxywarfarin isomers was assigned using a comparison of elution order on chiral stationary phases, optical rotation, and circular dichroism (CD) spectra, with confirmation of assignments made by comparison between experimental and calculated CD spectra and selective synthesis of hydroxywarfarin isomers from enantiopure warfarin using human liver microsomes. PMID- 24339229 TI - Atom-efficient route for converting incineration ashes into heavy metal sorbents. AB - Bottom ashes produced from municipal solid-waste incineration are suitable for sorbent synthesis because of their inherent composition, high alkalinity, metastable mineralogy, and residual heat. This work shows that bottom ashes can be atom-efficiently converted into valuable sorbents without the need for costly and hazardous chemicals. The ashes were hydrothermally treated in rotary autoclaves at autogenic pH conditions to promote the conversion of precursor mineral phases into zeolites and layered silicate hydrates. Two main mineral phases were formed: katoite and sodium aluminum phosphate silicate hydrate. These mineral alterations are accompanied by a tenfold increase in specific surface area and a twofold reduction in average particle size. Performance evaluation of the new sorbents for Cd(2+), Zn(2+), and Pb(2+) adsorption at pH5 indicates sorption capacities of 0.06, 0.08, and 0.22 mmol g(-1), respectively, which are similar to those of natural adsorbents and synthetic materials obtained from more demanding synthesis conditions. PMID- 24339230 TI - Highly efficient platinum group metal free based membrane-electrode assembly for anion exchange membrane water electrolysis. AB - Low-temperature electricity-driven water splitting is an established technology for hydrogen production. However, the two main types, namely proton exchange membrane (PEM) and liquid alkaline electrolysis, have limitations. For instance, PEM electrolysis requires a high amount of costly platinum-group-metal (PGM) catalysts, and liquid alkaline electrolysis is not well suited for intermittent operation. Herein we report a highly efficient alkaline polymer electrolysis design, which uses a membrane-electrode assembly (MEA) based on low-cost transition-metal catalysts and an anion exchange membrane (AEM). This system exhibited similar performance to the one achievable with PGM catalysts. Moreover, it is very suitable for intermittent power operation, durable, and able to efficiently operate at differential pressure up to 3 MPa. This system combines the benefits of PEM and liquid alkaline technologies allowing the scalable production of low-cost hydrogen from renewable sources. PMID- 24339231 TI - Ultrasound-assisted fabrication of a biocompatible magnetic hydroxyapatite. AB - This work describes the fabrication and characterization of a biocompatible magnetic hydroxyapatite (HA) using an ultrasound-assisted co-precipitation method. X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and transmission electron microscopy (TEM) were used to characterize the structure and chemical composition of the produced samples. The M-H loops of synthesized materials were traced using a vibrating sample magnetometer (VSM) and the biocompatibility was evaluated by cell culture and MTT (3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Furthermore, in vivo histopathological examinations were used to evaluate the potential toxicological effects of Fe3O4-HA composites on kidney of SD rats injected intraperitoneally with Fe3O4-HA particles. The results showed that magnetic iron oxide particles first replace OH ions of HA, which are parallel to the c axis, and then enter the HA crystal lattice which produces changes in the crystal surface of HA. Chemical bond interaction was observed between PO43- groups of HA and iron ions of Fe3O4. The saturation magnetization (MS ) of Fe3O4-HA composites was 46.36 emu/g obtained from VSM data. Cell culture and MTT assays indicated that HA could affect the growth and proliferation of HEK-293 cells. This Fe3O4-HA composite produced no negative effects on cell morphology, viability, and proliferation and exhibited remarkable biocompatibility. Moreover, no inflammatory cell infiltration was observed in kidney histopathology slices. Therefore, this study succeeds to develop a Fe3O4-HA composite as a prospective biomagnetic material for future applications. PMID- 24339232 TI - Interactions between CO2 enhancement and N addition on net primary productivity and water-use efficiency in a mesocosm with multiple subtropical tree species. AB - Carbon dioxide (CO2 ) enhancement (eCO2 ) and N addition (aN) have been shown to increase net primary production (NPP) and to affect water-use efficiency (WUE) for many temperate ecosystems, but few studies have been made on subtropical tree species. This study compared the responses of NPP and WUE from a mesocosm composing five subtropical tree species to eCO2 (700 ppm), aN (10 g N m(-2) yr( 1) ) and eCO2 * aN using open-top chambers. Our results showed that mean annual ecosystem NPP did not changed significantly under eCO2 , increased by 56% under aN and 64% under eCO2 * aN. Ecosystem WUE increased by 14%, 55%, and 61% under eCO2 , aN and eCO2 * aN, respectively. We found that the observed responses of ecosystem WUE were largely driven by the responses of ecosystem NPP. Statistical analysis showed that there was no significant interactions between eCO2 and aN on ecosystem NPP (P = 0.731) or WUE (P = 0.442). Our results showed that increasing N deposition was likely to have much stronger effects on ecosystem NPP and WUE than increasing CO2 concentration for the subtropical forests. However, different tree species responded quite differently. aN significantly increased annual NPP of the fast-growing species (Schima superba). Nitrogen-fixing species (Ormosia pinnata) grew significantly faster only under eCO2 * aN. eCO2 had no effects on annual NPP of those two species but significantly increased annual NPP of other two species (Castanopsis hystrix and Acmena acuminatissima). Differential responses of the NPP among different tree species to eCO2 and aN will likely have significant implications on the species composition of subtropical forests under future global change. PMID- 24339233 TI - Harnessing localized ridges for high-aspect-ratio hierarchical patterns with dynamic tunability and multifunctionality. AB - A simple method for fabricating high-aspect-ratio, hierarchical, and dynamically tunable surface patterns is invented by harnessing localized-ridge instabilities in gold nanofilms coated on elastomer substrates (a); a theoretical model to calculate the critical parameters (e.g., wavelength and amplitude) for designing the new patterns is developed (b); and novel applications of the patterns as super-hydrophobic coatings (c) and biomimetic cell-culture substrates (d) capable of on-demand tunability are demonstrated. PMID- 24339234 TI - Double-blind study of the actively transported levodopa prodrug XP21279 in Parkinson's disease. AB - The objective of this study was to assess the efficacy, safety, and pharmacokinetics of XP21279-carbidopa in patients with Parkinson's disease who experience motor fluctuations compared with immediate-release carbidopa-levodopa tablets. XP21279 is a levodopa prodrug that is actively absorbed by high-capacity nutrient transporters expressed throughout the gastrointestinal tract and then rapidly converted to levodopa by carboxylesterases. XP21279-carbidopa sustained release bilayer tablets were developed to overcome pharmacokinetic limitations of levodopa by providing more continuous exposure. Patients with motor fluctuations who required carbidopa-levodopa four or five times daily were optimized for 2 weeks each on carbidopa-levodopa four or five times daily and XP21279-carbidopa three times daily in a randomized sequence. Next, they received each optimized treatment for 2 weeks in a double-blind/double-dummy, randomized sequence. The primary outcome measure was change from baseline in daily off time at the end of each double-blind treatment period. All patients at 2 sites underwent pharmacokinetic analyses. Twenty-eight of 35 enrolled patients completed both double-blind treatments. The mean total daily off time was reduced from baseline by a mean (+/- standard error) of 2.7 hours (+/- 0.48 hours) for immediate release carbidopa-levodopa and 3.0 hours (+/- 0.57 hours) for XP21279-carbidopa (P = 0.49). Among 11 patients who completed pharmacokinetic sampling on each optimized treatment, the percentage deviation from the mean levodopa concentration was lower (P < 0.05) for XP21279-carbidopa than carbidopa-levodopa. Both treatments had a similar incidence of new or worsening dyskinesias. XP21279 carbidopa administered three times daily produced a reduction in off time similar to that of carbidopa-levodopa administered four or five times daily, and the difference was not statistically significant. XP21279-carbidopa significantly reduced variability in levodopa concentrations compared with carbidopa-levodopa. PMID- 24339235 TI - The cystic fibrosis gender gap: potential roles of estrogen. AB - Cystic fibrosis (CF) is a complex, multi-system, autosomal recessive disease predominantly affecting Caucasians that leads to vigorous airway inflammation and chronic respiratory infection, commonly with Pseudomonas aeruginosa. A variety of factors significantly modify the progression and severity of CF lung disease and the timing of the resulting mortality. We summarize here data indicating that there is in CF a female disadvantage in survival and morbidity, called the "CF gender gap". Although controversy exists regarding the nature and relative importance of the various contributing mechanisms involved, gender affects the progression of CF disease with respect to lung infection, decline in pulmonary function and nutritional status. These interrelated factors in turn have a negative impact on survival. This review will emphasize the increasing evidence that suggest a role for the effects of gender, and particularly the female sex hormone estrogen, on infection, inflammation and transepithelial ion transport, all major determinants of CF lung disease. Future elucidation of the pathophysiology of hormonal aggravation of CF lung disease may pave the way for novel therapeutic interventions. This, combined with the magnitude of the gender gap in CF mortality, strongly suggests that further work in this field is well justified. PMID- 24339236 TI - Epicocconone staining: a powerful loading control for Western blots. AB - Western blot analysis is routinely employed for quantifying differences in protein levels between samples. To control equal loading and to arithmetically compensate loading differences, immunodetection of housekeeping proteins is commonly used. Due to potential biases, this approach has been criticized. Here, we evaluate epicocconone-based total protein staining (E-ToPS) as an alternative. We compared it with two other total protein stainings (Coomassie and Sypro Ruby) and with immunodetection of housekeeping proteins (beta-tubulin and glyceraldehyde 3-phosphate dehydrogenase). Evaluation comprised both the natural and the synthetic epicocconone compound. Both compounds produced highly congruent results and showed more sensitive (<= 1 MUg) and less variable staining properties than the other variants. The high sensitivity of E-ToPS, covering minute protein amounts, makes it a powerful loading control, especially for precious samples. Regarding biological and technical variances, E-ToPS outperformed immunostaining against beta-tubulin and glyceraldehyde 3-phosphate dehydrogenase. Furthermore, E-ToPS had no impact on subsequent immunodetection, allowing for an early control of proper loading prior to immunodetection. In contrast to earlier studies, we found logarithmic staining properties for E-ToPS, which should be considered when using it for arithmetic normalization. In conclusion, we demonstrate the superior power of E-ToPS as a loading control for Western blots. PMID- 24339237 TI - Human papillomavirus (HPV) assays for testing fine-needle aspiration specimens in patients with head and neck squamous cell carcinoma. PMID- 24339238 TI - Transalkylation of higher trifluoromethylated fullerenes with C70: a pathway to new addition patterns of C70(CF3)8. AB - We report three new isomers of C70(CF3)8, structurally related to p(7)mp C70(CF3)10, that are inaccessible by direct trifluoromethylation, but can be easily identified among the products of the transalkylation of higher trifluoromethylfullerenes with C70. The reported compounds are characterized by UV/Vis, 1 D and 2 D COSY (19)F NMR spectroscopy, and DFT calculations. A rather unusual addition pattern is observed in p(6),i-C70(CF3)8 in which one addend is attached remotely from the others; polarization of the adjacent unsaturated bonds by the addend makes the molecule readily oxidizable. PMID- 24339239 TI - Cost offsets to medicare attributable to receipt of hip, knee, and shoulder arthroplasty. AB - OBJECTIVE: To estimate trends in numbers of and Medicare payments for hip, knee, and shoulder arthroplasties for beneficiaries with osteoarthritis (OA) and potential savings to Medicare from arthroplasty during followup. METHODS: The analysis was based on longitudinal 5% Medicare enrollment and claims data for 1992-2010. The analysis of changes in Medicare payments attributable to total arthroplasty receipt used propensity score matching to obtain beneficiary control groups matched on demographic characteristics, general health, joint pain, and Medicare payments by major condition in the year preceding the index arthroplasty. An average treatment effect on the treated (ATT) overall and for each major condition was calculated for payments for care 7-36 months following the index arthroplasty procedure. RESULTS: Growth in incident OA diagnoses of the hip, knee, and shoulder was substantially higher than growth in real Medicare spending on hip, knee, and shoulder arthroplasties. ATTs showed a mean saving to Medicare of $471/beneficiary/procedure for hip, no difference for knee, and a payment increase of $1,062 for shoulder arthroplasty during followup. For hip arthroplasty, the largest savings was for the circulatory system. For shoulder arthroplasty, increased payments during followup reflected increased payments for musculoskeletal care, especially for hip and knee arthroplasty. Overall, payment differences during followup by major condition were small. CONCLUSIONS: Provision of hip but not knee and shoulder arthroplasty generated savings to Medicare during followup, but even for hip arthroplasty, the cost offset during followup was small relative to the program cost for the procedure itself. PMID- 24339240 TI - Fischer-Tropsch catalysts for the production of hydrocarbon fuels with high selectivity. AB - Fischer-Tropsch synthesis is a key reaction in the utilization of non-petroleum carbon resources, such as methane (natural gas, shale gas, and biogas), coal, and biomass, for the sustainable production of clean liquid fuels from synthesis gas. Selectivity control is one of the biggest challenges in Fischer-Tropsch synthesis. This Minireview focuses on the development of new catalysts with controllable product selectivities. Recent attempts to increase the selectivity to C5+ hydrocarbons by preparing catalysts with well-defined active phases or with new supports or by optimizing the interaction between the promoter and the active phase are briefly highlighted. Advances in developing bifunctional catalysts capable of catalyzing both CO hydrogenation to heavier hydrocarbons and hydrocracking/isomerization of heavier hydrocarbons are critically reviewed. It is demonstrated that the control of the secondary hydrocracking reactions by using core-shell nanostructures or solid-acid materials, such as mesoporous zeolites and carbon nanotubes with acid functional groups, is an effective strategy to tune the product selectivity of Fischer-Tropsch synthesis. Very promising selectivities to gasoline- and diesel-range hydrocarbons have been attained over some bifunctional catalysts. PMID- 24339241 TI - Versatile online SPE-HPLC method for the analysis of Irinotecan and its clinically relevant metabolites in biomaterials. AB - Monitoring levels of Irinotecan and its metabolites during cancer therapy could help link broad interpatient variations in antitumor activity and toxicity to the patient's metabolic status. We have developed and validated a versatile and highly sensitive method for the simultaneous determination of Irinotecan and its clinically relevant metabolites 7-ethyl-10-hydroxy-camptothecin (SN-38) and SN-38 glucuronide. Sample clean-up involves precipitation by acetone/methanol/0.5 M trichloroacetic acid at 4:4:2 v/v followed by extraction of the metabolites on an SPE column by 20% methanol in 25 mM KH2 PO4 pH 2.9. Online transfer to an analytical MUBondapak C18 column, elution with 24% acetonitrile (ACN) in 0.1 M KH2 PO4 pH 2.9 and fluorescence detection with excitation at 375 nm and emission at 430 nm for SN-38 glucuronide and Irinotecan or 540 nm for SN-38 results in high sensitivity (1-2 pg) and short (~10 min) run times. The method was used to determine the degree of SN-38 glucuronidation in mice after Irinotecan administration and in cultured cancer cells exposed to SN-38. The method may be used to better understand Irinotecan metabolism, personalize therapy, and develop Irinotecan-based tumor targeting therapies. PMID- 24339243 TI - First demonstration of gold nanorods-mediated photodynamic therapeutic destruction of tumors via near infra-red light activation. AB - Previously, a large volume of papers reports that gold nanorods (Au NRs) are able to effectively kill cancer cells upon high laser doses (usually 808 nm, 1-48 W/cm2) irradiation, leading to hyperthermia-induced destruction of cancer cells, i.e, photothermal therapy (PTT) effects. Combination of Au NRs-mediated PTT and organic photosensitizers-mediated photodynamic therapy (PDT) were also reported to achieve synergistic PTT and PDT effects on killing cancer cells. Herein, we demonstrate for the first time that Au NRs alone can sensitize formation of singlet oxygen (1O2) and exert dramatic PDT effects on complete destrcution of tumors in mice under very low LED/laser doses of single photon NIR (915 nm, <130 mW/cm2) light excitation. By changing the NIR light excitation wavelengths, Au NRs-mediated phototherapeutic effects can be switched from PDT to PTT or combination of both. Both PDT and PTT effects were confirmed by measurements of reactive oxygen species (ROS) and heat shock protein (HSP 70), singlet oxygen sensor green (SOSG) sensing, and sodium azide quenching in cellular experiments. In vivo mice experiments further show that the PDT effect via irradiation of Au NRs by 915 nm can destruct the B16F0 melanoma tumor in mice far more effectively than doxorubicin (a clinically used anti-cancer drug) as well as the PTT effect (via irradiation of Au NRs by 780 nm light). In addition, we show that Au NRs can emit single photon-induced fluorescence to illustrate their in vivo locations/distribution. PMID- 24339242 TI - Spatial organization of NG2 glial cells and astrocytes in rat hippocampal CA1 region. AB - Similar to astrocytes, NG2 glial cells are uniformly distributed in the central nervous system (CNS). However, little is known about the interspatial relationship, nor the functional interactions between these two star-shaped glial subtypes. Confocal morphometric analysis showed that NG2 immunostained cells are spatially organized as domains in rat hippocampal CA1 region and that each NG2 glial domain occupies a spatial volume of ~178, 364 MUm(3) . The processes of NG2 glia and astrocytes overlap extensively; each NG2 glial domain interlaces with the processes deriving from 5.8 +/- 0.4 neighboring astrocytes, while each astrocytic domain accommodates processes stemming from 4.5 +/- 0.3 abutting NG2 glia. In CA1 stratum radiatum, the cell bodies of morphologically identified glial cells often appear to make direct somatic-somata contact, termed as doublets. We used dual patch recording and postrecording NG2/GFAP double staining to determine the glial identities of these doublets. We show that among 44 doublets, 50% were NG2 glia-astrocyte pairs, while another 38.6% and 11.4% were astrocyte-astrocyte and NG2 glia-NG2 glia pairs, respectively. In dual patch recording, neither electrical coupling nor intercellular biocytin transfer was detected in astrocyte-NG2 glia or NG2 glia-NG2 glia doublets. Altogether, although NG2 glia and astrocytes are not gap junction coupled, their cell bodies and processes are interwoven extensively. The anatomical and physiological relationships revealed in this study should facilitate future studies to understand the metabolic coupling and functional communication between NG2 glia and astrocytes. PMID- 24339244 TI - Composite PET membrane with nanostructured Ag/AgTCNQ Schottky junctions: electrochemical nanofabrication and charge-transfer properties. AB - Large-area nanostructured Ag/Ag-tetracyanoquinodimethane (TCNQ) Schottky junctions are fabricated electrochemically on a mesoporous polyethylene terephthalate (PET) membrane-supported water/1, 2-dichloroethane (DCE) interface. When the interface is polarized, Ag(+) ions transfer across the PET membrane from the aqueous phase and are reduced to form metallic Ag on the PET membrane, which reacts further with tetracyanoquinodimethane (TCNQ) in the DCE phase to form nanostructured Ag/AgTCNQ Schottky junctions. Once the mesoporous membrane is blocked by metallic Ag, a bipolar mechanism is proposed to explain the successive growth of AgTCNQ nanorods and Ag film on each side of the PET membrane. Due to the well-formed nanostructure of Ag/AgTCNQ Schottky junctions, the direct electrochemical behavior is observed, which is essential to explain the physicochemical mechanism of its electric performance. Moreover, the composite PET membrane with nanostructured Ag/AgTCNQ Schottky junctions is tailorable and can be assembled directly into electric devices without any pretreatment. PMID- 24339245 TI - PPh(3).HBr-DMSO mediated expedient synthesis of gamma-substituted beta,gamma unsaturated alpha-ketomethylthioesters and alpha-bromo enals: application to the synthesis of 2-methylsulfanyl-3(2H)-furanones. AB - An efficient chemoselective general procedure for the synthesis of gamma substituted beta,gamma-unsaturated alpha-ketomethylthioesters from alpha,beta unsaturated ketones has been achieved through an unprecedented PPh3 ?HBr-DMSO mediated oxidative bromination and Kornblum oxidation sequence. The newly developed reagent system serves admirably for the synthesis of alpha-bromoenals from enals. Furthermore, AuCl3 -catalyzed efficient access to 3(2H)-furanones from the above intermediates under extremely mild conditions are described. PMID- 24339246 TI - Polymer-based resistive memory materials and devices. AB - Due to the advantages of good scalability, flexibility, low cost, ease of processing, 3D-stacking capability, and large capacity for data storage, polymer based resistive memories have been a promising alternative or supplementary devices to conventional inorganic semiconductor-based memory technology, and attracted significant scientific interest as a new and promising research field. In this review, we first introduced the general characteristics of the device structures and fabrication, memory effects, switching mechanisms, and effects of electrodes on memory properties associated with polymer-based resistive memory devices. Subsequently, the research progress concerning the use of single polymers or polymer composites as active materials for resistive memory devices has been summarized and discussed. In particular, we consider a rational approach to their design and discuss how to realize the excellent memory devices and understand the memory mechanisms. Finally, the current challenges and several possible future research directions in this field have also been discussed. PMID- 24339247 TI - Ushering in a new and exciting era of online sources in physiotherapy. PMID- 24339248 TI - Microflow1, a sheathless fiber-optic flow cytometry biomedical platform: demonstration onboard the international space station. AB - A fiber-optic based flow cytometry platform was designed to build a portable and robust instrument for space applications. At the core of the Microflow1 is a unique fiber-optic flow cell fitted to a fluidic system and fiber coupled to the source and detection channels. A Microflow1 engineering unit was first tested and benchmarked against a commercial flow cytometer as a reference in a standard laboratory environment. Testing in parabolic flight campaigns was performed to establish Microflow1's performance in weightlessness, before operating the new platform on the International Space Station. Microflow1 had comparable performances to commercial systems, and operated remarkably and robustly in weightlessness (microgravity). Microflow1 supported immunophenotyping as well as microbead-based multiplexed cytokine assays in the space environment and independently of gravity levels. Results presented here provide evidence that this fiber-optic cytometer technology is inherently compatible with the space environment with negligible compromise to analytical performance. PMID- 24339249 TI - Transcatheter Sapien valve implantation in a native tricuspid valve after failed surgical repair. AB - OBJECTIVES: We describe the first report of a transcatheter Sapien implantation in a native tricuspid valve after multiple failed surgical repairs with a lack of prosthetic material and radiographic landmarks. METHODS AND RESULTS: A 47-year old female underwent multiple valve repairs and replacements including three tricuspid valve repairs without surgical ring or bioprosthesis implantation. She developed signs of right heart failure associated with a mixed tricuspid disease combining a severe stenosis and regurgitation. After surgical turn down, a revalvulation using a transcatheter approach was attempted. The challenges in this case were the absence of a stiff region to anchor the percutaneous valve, the lack of radiographic landmarks and the difficulties of precise annulus measurements. The applied strategy was -under general anesthesia and extracorporeal membrane oxygenation-: balloon sizing, prestenting of the tricuspid annulus using covered stents followed by Sapien valve implantation through the femoral vein under fluoroscopy and transoesophageal echocardiography (TEE). The procedure was successfull, solving the tricuspid leak and stenosis (peak gradient from 22 to 3 mm Hg) using two Sapien for a perfect positioning. It was complicated by pulmonary bleeding due to a distal wire exit, treated successfully by coil embolization. The clinical and echocardiographic outcome was good up to 5 months. CONCLUSIONS: Transcatheter Sapien valve implantation in a native tricuspid valve after failed multiple surgical repairs is feasible by the femoral vein. Technical challenges due to the lack of rigid landing zone and fluoroscopic markers were solved by prestenting and valve implantation under bi plane fluoroscopic and TEE guidance. PMID- 24339250 TI - Serendipitous discovery of a potent influenza virus a neuraminidase inhibitor. AB - We have previously reported a potent neuraminidase inhibitor that comprises a carbocyclic analogue of zanamivir in which the hydrophilic glycerol side chain is replaced by the hydrophobic 3-pentyloxy group of oseltamivir. This hybrid inhibitor showed excellent inhibitory properties in the neuraminidase inhibition assay (Ki =0.46 nM; Ki (zanamivir) =0.16 nM) and in the viral replication inhibition assay in cell culture at 10(-8) M. As part of this lead optimization, we now report a novel spirolactam that shows comparable inhibitory activity in the cell culture assay to that of our lead compound at 10(-7) M. The compound was discovered serendipitously during the attempted synthesis of the isothiourea derivative of the original candidate. The X-ray crystal structure of the spirolactam in complex with the N8 subtype neuraminidase offers insight into the mode of inhibition. PMID- 24339251 TI - STRESS-responsive deacetylase SIRT3 is up-regulated by areca nut extract-induced oxidative stress in human oral keratinocytes. AB - Areca chewing is an important environmental risk factor for development of oral premalignant lesions and cancer. Epidemiological evidence indicates that areca chewing is tightly linked to oral carcinogenesis. However, the pathogenetic impacts of areca nut extract (ANE) on normal human oral keratinocytes (HOKs) are unclear and possibly involve oxidative stress via redox imbalance. Sirtuin 3 (SIRT3) is a member of the sirtuin family of proteins that play an important role in regulating cellular reactive oxygen species (ROS) production. Recent studies have confirmed that ANE and other areca ingredients can induce ROS. In this study, we examined the role of SIRT3 in the regulation of ANE-induced ROS in HOK cells. We examined HOK cell viability following treatment with various ANE concentrations. ANE-induced cytotoxicity increased in a dose-dependent manner and was approximately 48% at a concentration of 50 MUg/ml after 24 h. SIRT3 expression and enzyme activity were up-regulated in HOK cells by ANE-induced oxidative stress. Additionally, we identified that SIRT3 controls the enzymatic activity of mitochondrial proteins, such as forkhead box O3a (Foxo3a) transcription factor and antioxidant-encoding gene superoxide dismutase 2 (SOD2), by deacetylation in HOK cells. Moreover, SIRT3-mediated deacetylation and activation of Foxo3a promotes nuclear localization in vivo. These findings suggest that SIRT3 is an endogenous negative regulator in response to ANE-induced oxidative stress and demonstrate an essential role for redox balance in HOK cells. PMID- 24339252 TI - Overexpression of Myo1e in mouse podocytes enhances cellular endocytosis, migration, and adhesion. AB - Podocytes are a terminally differentiated and highly specialized cell type in the glomerulus that forms a crucial component of the glomerular filtration barrier. Recently, Myo1e was identified in the podocytes of glomeruli. Myo1e podocyte specific knockout mice exhibit proteinuria, podocyte foot process effacement, glomerular basement membrane disorganization, signs of chronic renal injury, and kidney inflammation. After overexpression of Myo1e in a conditionally immortalized mouse podocyte cell line (MPC5), podocyte migration was evaluated via transwell assay, endocytosis was evaluated using FITC-transferrin, and adhesion was evaluated using a detachment assay after puromycin aminonucleoside treatment. Myo1e overexpression significantly increased the adherence of podocytes. ANOVA analysis indicated significant differences for cell adhesion between the overexpression and control groups (overexpression vs. control, t = 11.3199, P = 0.005; overexpression vs. negative control, t = 12.0570, P = 0.0006). Overexpression of Myo1e inhibited puromycin aminonucleoside-induced podocyte detachment, and the number of cells remaining on the bottom of the culture plate increased. Cell migration was enhanced in Myo1e-overexpressing podocytes in the transwell migration assay. Internalization of FITC-transferrin also increased in Myo1e-overexpressing podocytes relative to control cells. Overexpression of Myo1e can enhance podocyte migration ability, endocytosis, and attachment to the glomerular basement membrane. Restoration of Myo1e expression in podocytes may therefore strengthen their functional integrity against environmental and mechanical injury. PMID- 24339253 TI - Quantitative three-dimensional assessment of port-wine stain clearance after laser treatments. AB - BACKGROUND AND OBJECTIVES: Outcomes analysis of laser treatment for port-wine stains (PWS) has been hampered by the lack of an objective measure of surface area and volume; moreover, treatment success is often gauged by clinician subjective assessment. Three-dimensional (3D) surface imaging has been applied in several medical disciplines to quantify surface changes, with promising results. We hypothesized that 3D surface imaging could be used to objectively measure changes in area and volume of PWS following laser treatment. STUDY DESIGN/MATERIALS AND METHODS: We performed a retrospective review of consecutive patients with PWS treated over a 20-month time period. Area and volume of the lesions were measured using 3dMD photogrammetric software (3dMD; Atlanta, GA) before and after a series of sequential pulsed dye laser and/or alexandrite laser treatments. RESULTS: Fifty-five patients with 59 PWS were included in the study. The initial average measured area was 45.6 cm(2) ; final average measured area decreased to 34.6 cm(2) (P < 0.001). The average volume change was 1.20 ml for all PWS included in the study and 1.90 ml for lesions that received at least five laser treatments within the study period. CONCLUSION: Three-dimensional photography demonstrated area and volume changes in patients with PWS after laser treatments. Future studies to determine if statistically significant changes correlate with clinically appreciable changes are warranted. PMID- 24339254 TI - Detailed in vitro study of the photosensitization reaction of extracellular Talaporfin sodium in rat myocardial cells. AB - BACKGROUND AND OBJECTIVE: We proposed a new non-thermal treatment for tachyarrhythmia that employs an extracellular photosensitization reaction. Oxygen depletion may easily occur in in vitro studies of this reaction because the photosensitizing agent is often highly concentrated in such studies. The aim of the current study was to examine the progress of the extracellular photosensitization reaction and the photocytotoxicity of extracellular Talaporfin sodium on myocardial cells for application in tachyarrhythmia therapy. MATERIALS AND METHODS: Photosensitization reactions were performed in single wells of 96 well plates; Talaporfin sodium solution concentrations from 5 to 40 ug/ml, radiant exposures up to 40 J/cm(2) , and irradiance of 0.29 W/cm(2) from a continuous wave (CW) red diode laser (wavelength: 663 nm) were used. We measured transient changes of temperature, photosensitizer fluorescence, dissolved oxygen pressure, and photosensitizer solution absorbance to monitor the progress of the photosensitization reaction in the system during laser irradiation. Rat myocardial cells were cultured in 96-well plates, and the drug-light interval was set to 15 minutes. We used a WST assay to measure cell lethality 2 hours after laser irradiation. RESULTS: A strong photosensitization reaction occurred several seconds after initiation of laser irradiation; this initial reaction depended upon dissolved oxygen. A gentler continuous photosensitization reaction followed the initial reaction, and was associated with temperature increases of less than 10 degrees C. The oxygen pressure was kept in approximately 40 mmHg of the myocardial tissue oxygen pressure in the gentle photosensitization reaction phase. At radiant exposures from 10 to 40 J/cm(2) , a photosensitizer concentration of approximately 15 ug/ml was the threshold for myocardial cell necrosis in this in vitro system. The dependencies of photocytotoxicity on radiant exposure were separated into two distinct groups based on the molecular density ratio between Talaporfin sodium and albumin. CONCLUSIONS: This in vitro system for the extracellular photosensitization reaction may reflect the situation in live myocardial tissue. We found that the extracellular photosensitization reaction progressed in two distinctive phases; the first phase depended upon dissolved oxygen, and the second upon the molar density ratio between Talaporfin sodium and albumin. Cell lethality due to the extracellular photosensitization reaction was influenced by both of these factors in our in vitro system. We suggest that a photosensitizer concentration of 25 ug/ml might be necessary to treat myocardial tissue with therapies involving the extracellular photosensitization reaction. PMID- 24339256 TI - Establishment of a proteomic profile associated with gonocyte and spermatogonial stem cell maturation and differentiation in neonatal mice. AB - Initiation of the first wave of spermatogenesis in the neonatal mouse testis is characterized by differentiation of a transient population of germ cells called gonocytes in the center of the seminiferous tubules. After resuming mitotic activity, gonocytes relocate on the basement membrane, giving rise to spermatogonial stem cells (SSCs). These processes begin from birth in mice, and differentiated type A spermatogonia first appear by day 6 postpartum. During these processes, Sertoli cells within the seminiferous tubules and Leydig cells in the interstitial tissue form the stem cell "niche," and influence SSC fate decisions. Thus, we collected whole mouse testis tissues during the first wave of spermatogenesis at specific time points (days 0.5, 1.5, 2.5, 3.5, 4.5, and 5.5 postpartum) and constructed a comparative proteomic profile. We identified 252 differentially expressed proteins classified into three clusters based on expression, and bioinformatics analysis correlated each protein pattern to specific cell processes. Expression patterns of nine selected proteins were verified via Western blot, and cellular localizations of three proteins with little known information in testes were further investigated during spermatogenesis. Taken together, the results provide an important reference profile of a functional proteome during neonatal mouse gonocyte and SSC maturation and differentiation. PMID- 24339258 TI - Sequence-specific DNA recognition by cyclic pyrrole-imidazole cysteine-derived polyamide dimers. AB - Pyrrole-imidazole (PI) polyamides bind to the minor groove of the DNA duplex in a sequence-specific manner and thus have the potential to regulate gene expression. To date, various types of PI polyamides have been designed as sequence-specific DNA binding ligands. One of these, cysteine cyclic PI polyamides containing two beta-alanine molecules, were designed to recognize a 7 bp DNA sequence with high binding affinity. In this study, an efficient cyclization reaction between a cysteine and a chloroacetyl residue was used for dimerization in the synthesis of a unit that recognizes symmetrical DNA sequences. To evaluate specific DNA binding properties, dimeric PI polyamide binding was measured by using a surface plasmon resonance (SPR) method. Extending this molecular design, we synthesized a large dimeric PI polyamide that can recognize a 14 bp region in duplex DNA. PMID- 24339259 TI - Cervista HPV assays for fine-needle aspiration specimens are a valid option for human papillomavirus testing in patients with oropharyngeal carcinoma. AB - BACKGROUND: The objectives of this study were to evaluate the validity of Cervista human papillomavirus (HPV) assays in head and neck fine-needle aspiration (FNA) specimens from patients with head and neck squamous carcinomas and to verify that the Cervista assay in FNA specimens is a valid option for determining HPV status in patients with oropharyngeal carcinomas. METHODS: The authors retrospectively retrieved 64 head and neck FNA specimens from patients who had head and neck squamous carcinoma. The specimens were tested for HPV types 16 and 18 (HPV16/18) and for high-risk (HR) HPV DNA using the Cervista HPV16/18 and HPV HR assays, respectively. The results from those assays were compared with the results from polymerase chain reaction (PCR)-based HPV assays in the same tissues and with the results from HPV in situ hybridization assays/p16 immunostaining in the corresponding primary tumors. RESULTS: In total, 64 FNA specimens were analyzed. The Cervista HPV16/18 and/or HPV HR assays were positive in 48 of 64 specimens (75%), and there was a predominance of HPV16 (42 of 48 specimens; 88%). In the 49 specimens that had PCR-based test results, overall agreement with Cervista assay results was 96% (47 of 49 specimens; kappa = 0.883). In the 49 specimens that had PCR-based HPV16/18 genotyping results, overall agreement with the Cervista HPV16/18 results was 94% (46 of 49 specimens; kappa = 0.847). In the 36 primary carcinoma specimens that had valid HPV in situ hybridization/p16 immunostaining results, overall agreement with the Cervista assay results was 92% (33 of 36 specimens; kappa = 0.679). CONCLUSIONS: Cervista HPV16/18 and Cervista HPV HR testing of head and neck FNA specimens is a valid option for determining HPV16/18 status in patients with oropharyngeal carcinoma. PMID- 24339261 TI - Regional vulnerability of hippocampal subfields to aging measured by structural and diffusion MRI. AB - In the past few years, there has been an increasing awareness of the regional vulnerability of the hippocampus to age-related processes. However, to date, no studies have assessed the effects of age on different structural magnetic resonance parameters in the specific hippocampal subfields. In this study, we measured volume, mean diffusivity (MD) and fractional anisotropy (FA) in the presubiculum, subiculum, fimbria, cornu ammonis (CA) 1,2-3,4-DG and the whole hippocampus in fifty cognitively intact elder adults between 50 and 75 years of age (20 men, 30 women). Segmentation of hippocampal subfields was performed using FreeSurfer. Individual MD and FA images were coregistered to T1-weighted volumes using FLIRT of FSL. Linear regression analyses were performed to assess the effects of age on the anatomical measures of each subfield. In addition, multiple regression analyses were also carried out to assess which of the anatomical measures that showed a correlation with age in the previous analyses, were the best age predictors in the hippocampus. In agreement with previous studies, our results showed a significant association between age and volume (P < 0.001) as well as MD (P < 0.001) in the whole hippocampus. Regarding the specific hippocampal subfields, we found that age had a significant negative effect on volume in CA2-3 (P < 0.001) and CA4-DG (P < 0.001). Importantly, we found a positive effect of age on MD in CA2-3 (P < 0.001) and fimbria (P < 0.001) as well as a negative age effect on FA in the subiculum (P < 0.001). Multiple regression analyses revealed that the best overall predictors of age in the hippocampus were MD in the fimbria and volume of CA2-3, which explained 73.8% of the age variance. These results indicate that age has an effect both on volume and diffusion tensor imaging measures in different subfields, suggesting they provide complementary information on age-related processes in the hippocampus. PMID- 24339260 TI - Complex dynamic substrate control: dual-tone hydrogel photoresists allow double dissociation of topography and modulus. AB - Complex substrate control is demonstrated with a dual-tone hydrogel photoresist. By exposing a photodegradable hydrogel to UV light through a photomask, both swollen and eroded micropatterns with a decreased modulus can be created on the surface under different exposure conditions. This provides an important tool for investigating the synergistic effects of spatially heterogeneous mechanical and topological cues on cell behavior. PMID- 24339262 TI - GeneXpert MTB/RIF on bronchoalveolar lavage samples in children with suspected complicated intrathoracic tuberculosis: a pilot study. AB - BACKGROUND: Children with complicated intrathoracic tuberculosis (TB) require rapid confirmation of TB diagnosis and of drug susceptibility to institute appropriate therapy. In a pilot study, we evaluated the feasibility and potential utility of GeneXpert (Xpert) on bronchoalveolar lavage (BAL) samples in children undergoing routine diagnostic bronchoscopy. METHODS: We included children <13 years of age undergoing bronchoscopy for suspected complicated intrathoracic TB at Tygerberg Children's Hospital, October 1, 2012-May 15, 2013. A minimum of two respiratory specimens in addition to BAL were obtained from each child. In addition to fluorescent smear microscopy and automated liquid culture performed on all samples, BAL samples were analyzed by Xpert. Drug susceptibility was confirmed by GenoType((r)) MTBDRplus. RESULTS: Fourteen children (2 HIV positive, median age 16 months) were included. The Mantoux tuberculin skin test was positive in 11. On chest radiograph, six children had expansile pneumonia and nine had airway compression (one had both). The median duration of TB treatment before bronchoscopy was 8 days. TB was confirmed by either culture or Xpert from any sample in 11 (78%) children. Among 9/14 (64%) cases confirmed by culture, BAL Xpert was positive in 7 (78% sensitivity); in addition, Xpert confirmed 2 cases who had negative culture (14% additional diagnostic yield). Two drug resistant cases were identified: one by BAL Xpert and one from genotypic testing of a culture from gastric aspirate. All children were initiated on anti-TB treatment and responded well to therapy. CONCLUSION: BAL Xpert resulted in additional diagnostic yield and also in the rapid detection of drug resistance in children with complicated intrathoracic TB. The clinical impact of this modality should be further evaluated in children. PMID- 24339263 TI - Are older adults missing from low back pain clinical trials? A systematic review and meta-analysis. AB - OBJECTIVE: There is evidence to suggest that older adults are underrepresented in randomized controlled trials of health interventions. The aim of this review was to systematically examine the age-related inclusion criteria distribution of participants in randomized controlled trials (RCTs) of low back pain (LBP) interventions and to investigate if this distribution pattern changes over time. METHODS: We identified, in PubMed, 1,047 RCTs on nonspecific LBP published since 1992, of which a random sample of 400 was assessed for inclusion in the review. Included studies were grouped according to treatment type. Data were extracted on year of publication, types of treatment, total number of participants, age inclusion criteria, and age of included participants. RESULTS: A total of 274 RCTs published between 1992 and 2010 met the inclusion criteria. A total of 41.6% (n = 114) of the included trials excluded people ages >65 years. The pooled mean age of participants was 44.3 years (95% confidence interval 42.4-46.3); the pooled minimum age for inclusion was 19.8 years and the pooled maximum age for inclusion was 65.4 years. We found no trend of including older participants in RCTs on LBP over time. CONCLUSION: Despite an aging population around the globe, older adults are largely excluded from RCTs evaluating management of LBP, and there is no evidence of change in this practice over the last 2 decades. PMID- 24339264 TI - Ferric chloride-graphite intercalation compounds as anode materials for Li-ion batteries. AB - Ferric chloride-graphite intercalation compounds (FeCl3 -GICs) with stage 1 and stage 2 structures were synthesized by reacting FeCl3 and expanded graphite (EG) in air in a stainless-steel autoclave. As rechargeable Li-ion batteries, these FeCl3 -GICs exhibit high capacity, excellent cycling stability, and superior rate capability, which could be attributed to their unique intercalation features. This work may enable new possibilities for the fabrication of Li-ion batteries. PMID- 24339265 TI - Redo MitraClip mitral valve repair after a late single leaflet detachment. AB - Percutaneous mitral valve repair with the MitraClip(r) (Abbott, Abbott Park, IL) can reduce mitral regurgitation (MR) and improve symptoms and quality of life in patients with severe mitral regurgitation. While this therapy is safe, there have been reports of single leaflet detachment where the MitraClip remains attached only to one leaflet of the mitral valve after deployment. Most of these cases occur within the first month of the procedure but there have been reports of late detachment occurring after this period. This case report describes a patient with severe functional MR who underwent an initial successful MitraClip procedure with implantation of two clips but subsequently developed late detachment of one clip. It also discusses the challenges and feasibility of performing a repeat MitraClip procedure in these patients. PMID- 24339266 TI - Pyrene-based fluorescent ambidextrous gelators: scaffolds for mechanically robust SWNT-gel nanocomposites. AB - With the rapid progress in the development of supramolecular soft materials, examples of low-molecular-weight gelators (LMWGs) with the ability to immobilise both water and organic solvents by the same structural scaffold are very limited. In this paper, we report the development of pyrene-containing peptide-based ambidextrous gelators (AGs) with the ability to efficiently gelate both organic and aqueous solvents. The organo- and hydrogelation efficiencies of these gelators are in the range 0.7-1.1% w/v in various organic solvents and 0.5-5% w/v in water at certain acidic pH values (pH 2.0-4.0). Moreover, for the first time, AGs have been utilised to prepare single-walled carbon-nanotube (SWNT)-included soft nanocomposites in both hydro- and organogel matrices. The influence of different non-covalent interactions such as hydrogen bonding, hydrophobic, pi-pi and van der Waals interactions in self-assembled gelation has been studied in detail by circular dichroism, FTIR, variable-temperature NMR, 2D NOESY and luminescence spectroscopy. Interestingly, the presence of the pyrene moiety in the structure rendered these AGs intrinsically fluorescent, which was quenched upon successful integration of the SWNTs within the gel. The prepared hydro- and organogels along with their SWNT-integrated nanocomposites are thermoreversible in nature. The supramolecular morphologies of the dried gels and SWNT-gel nanocomposites have been studied by transmission electron microscopy, fluorescence microscopy and polarising optical microscopy, which confirmed the presence of three-dimensional self-assembled fibrillar networks (SAFINs) as well as the integrated SWNTs. Importantly, rheological studies revealed that the inclusion of SWNTs within the ambidextrous gels improved the mechanical rigidity of the resulting soft nanocomposites up to 3.8-fold relative to the native gels. PMID- 24339267 TI - Quantifying spore viability of the honey bee pathogen Nosema apis using flow cytometry. AB - Honey bees are hosts to more than 80 different parasites, some of them being highly virulent and responsible for substantial losses in managed honey bee populations. The study of honey bee pathogens and their interactions with the bees' immune system has therefore become a research area of major interest. Here we developed a fast, accurate and reliable method to quantify the viability of spores of the honey bee gut parasite Nosema apis. To verify this method, a dilution series with 0, 25, 50, 75, and 100% live N. apis was made and SYTO 16 and Propidium Iodide (n = 35) were used to distinguish dead from live spores. The viability of spores in each sample was determined by flow cytometry and compared with the current method based on fluorescence microscopy. Results show that N. apis viability counts using flow cytometry produced very similar results when compared with fluorescence microscopy. However, we found that fluorescence microscopy underestimates N. apis viability in samples with higher percentages of viable spores, the latter typically being what is found in biological samples. A series of experiments were conducted to confirm that flow cytometry allows the use of additional fluorescent dyes such as SYBR 14 and SYTOX Red (used in combination with SYTO 16 or Propidium Iodide) to distinguish dead from live spores. We also show that spore viability quantification with flow cytometry can be undertaken using substantially lower dye concentrations than fluorescence microscopy. In conclusion, our data show flow cytometry to be a fast, reliable method to quantify N. apis spore viabilities, which has a number of advantages compared with existing methods. PMID- 24339268 TI - Clinical predictors in chronic articular adult-onset Still's disease: comment on the article by Ichida et al. Reply. PMID- 24339270 TI - Prevention of water permeation by strong adhesion between graphene and SiO2 substrate. PMID- 24339269 TI - Fluorescent probes based on nucleophilic substitution-cyclization for hydrogen sulfide detection and bioimaging. AB - The design, synthesis, properties, and cell imaging applications of a series of 2 pyridyl disulfide based fluorescent probes (WSP1, WSP2, WSP3, WSP4 and WSP5) for hydrogen sulfide detection are reported. The strategy is based on the dual nucleophilicity of hydrogen sulfide. A hydrogen sulfide mediated tandem nucleophilic substitution-cyclization reaction is used to release the fluorophores and turn on the fluorescence. The probes showed high sensitivity and selectivity for hydrogen sulfide over other reactive sulfur species, including cysteine and glutathione. PMID- 24339271 TI - Oxidative addition of 2-halogenoazoles-direct synthesis of palladium(II) complexes bearing protic NH,NH-functionalized NHC ligands. AB - The chemistry of N-heterocyclic carbenes (NHCs) is dominated by N,N'-dialkylated or -diarylated derivatives. Such NHC ligands are normally obtained by C2 deprotonation of azolium cations or by reductive elimination from azol-2-thiones. A simple one-step procedure is described that leads to complexes with NH,NH functionalized NHC ligands by the oxidative addition of 2-halogenoazoles to complexes of zero-valent transition metals. PMID- 24339272 TI - Effect of competing binding modes on retention in chromatography and capillary electrophoresis. A theoretical consideration. AB - A mathematical formalism has been developed to describe equilibrium in a system involving a single selector and a selectand molecule capable of binding to this selector by different modes. The generalization of this model to a multiselector system has also been considered. Applications of the developed equations in chromatography and CE are discussed. PMID- 24339273 TI - The Otago Exercise Program performed as group training versus home training in fall-prone older people: a randomized controlled Trial. AB - BACKGROUND AND PURPOSE: Exercise programs targeting muscle strength and balance can reduce falls. The study aimed to compare the Otago Exercise Program (OEP), originally designed as supervised home training (HT), with the same programme performed as GT, on functional balance and muscle strength, mobility, fall efficacy and self-reported health. METHODS: A single-blind randomized controlled trial with assessments at baseline (T1), following the 12-week intervention (T2), and 3 months following intervention (T3), was performed. 125 people, mean age 82.5 (SD = 5.7) years, 73% women, referred to a Falls Outpatient Clinic, participated. 74% had fallen, and 37% had a fall-related hospital stay during the previous year. OEP supervised by physiotherapists was performed as GT twice weekly or as HT three times a week, for 12 weeks. Total exercise time was comparable between groups. The primary outcome was the Berg Balance Scale assessed at T2. RESULTS: From T1-T2, Berg Balance Scale improved significantly more in the GT group than in the HT group (mean group difference in change of 3.2 points, 95%CI = 0.7-5.8, p = 0.014). Of the secondary outcomes, the 30-second sit to-stand test (p = 0.004), and physical health measured by the Short Form-36 (p = 0.004), improved significantly more for the GT group. Change in mobility measured by the Timed Up and Go test, mental health by the Short Form-36, and fall efficacy by the Fall Efficacy Scale International did not differ between groups. The 30-second sit-to-stand test and the Timed Up and Go, but not the Berg Balance Scale, was still better in the GT group at T3. DISCUSSION: In fall-prone home dwelling older people, the OEP performed as GT is more effective for improving functional balance, muscle strength and physical health, but not fall efficacy and mental health than when performed as HT. The OEP provided as GT should be considered in this population. PMID- 24339276 TI - Advanced functional polymers for medicine. PMID- 24339277 TI - In vitro investigations of smart drug delivery systems based on redox-sensitive cross-linked micelles. AB - Redox-sensitive micelles are designed by using block copolymers of different architectures composed of a hydrophilic block of poly(ethylene oxide), and hydrophobic blocks of poly(epsilon-caprolactone) and poly(alpha-azide-epsilon caprolactone). Stability of these micelles is insured in diluted media by cross linking their core via the addition of a bifunctional cross-linker, while redox sensitivity is provided to these micelles by inserting a disulfide bridge in the cross-linker. The potential of these responsive micelles to be used as nanocarriers is studied in terms of cytotoxicity and cellular internalization. The release profiles are also investigated by varying the environment reductive strength. PMID- 24339278 TI - Repetitive noxious neonatal stimuli increases dentate gyrus cell proliferation and hippocampal brain-derived neurotrophic factor levels. AB - Neonatal noxious stimulation has been proposed to model pain triggered by diagnostic/therapeutic invasive procedures in premature infants. Previous studies have shown that hippocampal neurogenesis rate and the behavioral repertoire of adult rats may be altered by neonatal noxious stimuli. The purpose of this study was to evaluate whether noxious stimulation during neonatal period alters the nociceptive response and dentate gyrus neurogenesis when compared to rats subjected to a single noxious stimulus in late infancy. Plasma corticosterone and hippocampal brain-derived neurotrophic factor (BDNF) levels were measured. Neurogenesis in the dentate gyrus was evaluated in adolescent rats (postnatal day 40; P40) exposed twice to intra-plantar injections of Complete Freund's adjuvant (CFA) on P1 and P21 (group P1P21) or P8 and P21 (P8P21) or exposed once on P21 (pubertal). On P21, one subset of animals received 5-bromo-2'-deoxyuridine (BrdU) and was euthanized on P40 for identification of proliferating cells in the dentate gyrus. Another subset was sampled for thermal response or plasma corticosterone measurement and hippocampal BDNF levels. Proliferative cell rate in dentate gyrus was the highest in all re-exposed groups (P < 0.001), except for P8 females (P8P21F), revealing also a sex difference, where P8P21 males showed higher rate than females (P < 0.001). Stimulated groups took longer than CTL animals to lick the paws (P < 0.001), regardless of the age when the noxious stimulus was applied. Re-exposed groups had lower corticosterone plasma level (P1P21 M and F, P8P21M) than controls. On the contrary, hippocampal BDNF was increased in males from both re-exposed groups. These results show that infant noxious stimulation in neonatally previously stimulated rats is related to high proliferation in the DG and this association seems to be modified by the animal's sex. The new generated dentate granule cells in the hippocampus may have a role in the long-term behavioral responses to neonatal nociceptive stimulation. Noxious stimulation in the neonatal period results in sex-dependent neurogenic response. PMID- 24339279 TI - Case Study Interpretation: Report from the ICCS Annual Meeting, Fort Lauderdale, 2013. PMID- 24339280 TI - Extracting extra-telomeric phenotypes from telomerase mouse models. AB - Telomerase reverse transcriptase (TERT) is the protein component of telomerase and combined with an RNA molecule, telomerase RNA component, forms the telomerase enzyme responsible for telomere elongation. Telomerase is essential for maintaining telomere length from replicative attrition and thus contributes to the preservation of genome integrity. Although diverse mouse models have been developed and studied to prove the physiological roles of telomerase as a telomere- elongating enzyme, recent studies have revealed non-canonical TERT activities beyond telomeres. To gain insights into the physiological impact of extra-telomeric roles, this review revisits the strategies and phenotypes of telomerase mouse models in terms of the extra-telomeric functions of telomerase. PMID- 24339281 TI - Clinical outcomes and prognostic factors of empirical antifungal therapy with itraconazole in the patients with hematological malignancies: a prospective multicenter observational study in Korea. AB - PURPOSE: To identify prognostic factors for the outcomes of empirical antifungal therapy, we performed a multicenter, prospective, observational study in immunocompromised patients with hematological malignancies. MATERIALS AND METHODS: Three hundred seventy-six patients (median age of 48) who had neutropenic fever and who received intravenous (IV) itraconazole as an empirical antifungal therapy for 3 or more days were analyzed. The patients with possible or probable categories of invasive fungal disease (IFD) were enrolled. RESULTS: The overall success rate was 51.3% (196/376). Age >50 years, underlying lung disease (co-morbidity), poor performance status [Eastern Cooperative Oncology Group (ECOG) >=2], radiologic evidence of IFD, longer duration of baseline neutropenic fever (>=4 days), no antifungal prophylaxis or prophylactic use of antifungal agents other than itraconazole, and high tumor burden were associated with decreased success rate in univariate analysis. In multivariate analysis, age >50 years (p=0.009) and poor ECOG performance status (p=0.005) were significantly associated with poor outcomes of empirical antifungal therapy. Twenty-two patients (5.9%) discontinued itraconazole therapy due to toxicity. CONCLUSION: We concluded that empirical antifungal therapy with IV itraconazole in immunocompromised patients is effective and safe. Additionally, age over 50 years and poor performance status were poor prognostic factors for the outcomes of empirical antifungal therapy with IV itraconazole. PMID- 24339282 TI - Change in tinnitus after treatment of vestibular schwannoma: microsurgery vs. gamma knife radiosurgery. AB - PURPOSE: Tinnitus is a very common symptom of vestibular schwannoma, present in 45 to 80% of patients. We evaluated changes in tinnitus after translabyrinthine microsurgery (TLM) or gamma knife radiosurgery (GKS). MATERIALS AND METHODS: Among 78 patients with vestibular schwannoma who underwent TLM or GKS at Severance Hospital from 2009-2012, 46 patients with pre- or postoperative tinnitus who agreed to participate were enrolled. Pure tone audiometry, tinnitus handicap inventory (THI), visual analogue scale (VAS) scores for loudness, awareness, and annoyance were measured before and after treatment. Changes of THI and VAS were analysed and compared according to treatment modality, tumour volume, and preoperative residual hearing. RESULTS: In the TLM group (n=27), vestibulocochlear nerves were definitely cut. There was a higher rate of tinnitus improvement in TLM group (52%) than GKS group (16%, p=0.016). The GKS group had a significantly higher rate of tinnitus worsening (74%) than TLM group (11%, p<0.001). Mean scores of THI and VAS scores significantly decreased in the TLM group in contrast to significant increases in the GKS group. Tumor volume and preoperative hearing did not affect the changes in THI or VAS. CONCLUSION: GKS can save vestibulocochlear nerve continuity but may damage the cochlea, cochlear nerve and can cause worsening tinnitus. In cases where hearing preservation is not intended, microsurgery with vestibulocochlear neurectomy during tumor removal can sometimes relieve or prevent tinnitus. PMID- 24339283 TI - Development of smartphone application that aids stroke screening and identifying nearby acute stroke care hospitals. AB - PURPOSE: The benefits of thrombolytic treatment are time-dependent. We developed a smartphone application that aids stroke patient self-screening and hospital selection, and may also decrease hospital arrival time. MATERIALS AND METHODS: The application was developed for iPhone and Android smartphones. Map data for the application were adopted from the open map. For hospital registration, a web page (http://stroke119.org) was developed using PHP and MySQL. RESULTS: The Stroke 119 application includes a stroke screening tool and real-time information on nearby hospitals that provide thrombolytic treatment. It also provides information on stroke symptoms, thrombolytic treatment, and prescribed actions when stroke is suspected. The stroke screening tool was adopted from the Cincinnati Prehospital Stroke Scale and is displayed in a cartoon format. If the user taps a cartoon image that represents abnormal findings, a pop-up window shows that the user may be having a stroke, informs the user what to do, and directs the user to call emergency services. Information on nearby hospitals is provided in map and list views, incorporating proximity to the user's location using a Global Positioning System (a built-in function of smartphones). Users can search for a hospital according to specialty and treatment levels. We also developed a web page for hospitals to register in the system. Neurology training hospitals and hospitals that provide acute stroke care in Korea were invited to register. Seventy-seven hospitals had completed registration. CONCLUSION: This application may be useful for reducing hospital arrival times for thrombolytic candidates. PMID- 24339284 TI - Application of array-based comparative genomic hybridization to pediatric neurologic diseases. AB - PURPOSE: Array comparative genomic hybridization (array-CGH) is a technique used to analyze quantitative increase or decrease of chromosomes by competitive DNA hybridization of patients and controls. This study aimed to evaluate the benefits and yield of array-CGH in comparison with conventional karyotyping in pediatric neurology patients. MATERIALS AND METHODS: We included 87 patients from the pediatric neurology clinic with at least one of the following features: developmental delay, mental retardation, dysmorphic face, or epilepsy. DNA extracted from patients and controls was hybridized on the Roche NimbleGen 135K oligonucleotide array and compared with G-band karyotyping. The results were analyzed with findings reported in recent publications and internet databases. RESULTS: Chromosome imbalances, including 9 cases detected also by G-band karyotyping, were found in 28 patients (32.2%), and at least 19 of them seemed to be causally related to the abnormal phenotypes. Regarding each clinical symptom, 26.2% of 42 developmental delay patients, 44.4% of 18 mental retardation patients, 42.9% of 28 dysmorphic face patients, and 34.6% of 26 epilepsy patients showed abnormal array results. CONCLUSION: Although there were relatively small number of tests in patients with pediatric neurologic disease, this study demonstrated that array-CGH is a very useful tool for clinical diagnosis of unknown genome abnormalities performed in pediatric neurology clinics. PMID- 24339285 TI - Prognosis after implantation of cardioverter-defibrillators in Korean patients with Brugada syndrome. AB - PURPOSE: Our study aims to analyze prognosis after implantable cardioverter defibrillator (ICD) implantation in Korean patients with Brugada syndrome (BrS). MATERIALS AND METHODS: This was a retrospective study of BrS patients implanted with an ICD at one of four centers in Korea between January 1998 and April 2012. Sixty-nine patients (68 males, 1 female) were implanted with an ICD based on aborted cardiac arrest (n=38, 55%), history of syncope (n=17, 25%), or induced ventricular tachyarrhythmia on electrophysiologic study in asymptomatic patients (n=14, 20%). A family history of sudden cardiac death and a spontaneous type 1 electrocardiography (ECG) were noted in 13 patients (19%) and 44 patients (64%), respectively. RESULTS: During a mean follow-up of 59+/-46 months, 4.6+/-5.5 appropriate shocks were delivered in 19 patients (28%). Fourteen patients (20%) experienced 5.2+/-8.0 inappropriate shocks caused by supraventricular arrhythmia, lead failure, or abnormal sensing. Six patients were admitted for cardiac causes during follow-up, but no cardiac deaths occurred. An episode of aborted cardiac arrest was a significant predictor of appropriate shock, and the composite of cardiac events in the Cox proportional hazard model [hazard ratio (95% confidence interval) was 11.34 (1.31-97.94) and 4.78 (1.41-16.22), respectively]. However, a spontaneous type 1 ECG was not a predictor of cardiac events. CONCLUSION: Appropriate shock (28%) and inappropriate shock (20%) were noted during a mean follow-up of 59+/-46 months in Korean BrS patients implanted with an ICD. An episode of aborted cardiac arrest was the most powerful predictor of cardiac events. PMID- 24339286 TI - Prognostic usefulness of metabolic syndrome compared with diabetes in Korean patients with critical lower limb ischemia treated with percutaneous transluminal angioplasty. AB - PURPOSE: Metabolic syndrome (MS) is a clinical condition that shares many common characteristics with diabetes. However, unlike diabetes, the usefulness of MS as a prognostic entity in peripheral arterial disease is uncertain. This study evaluated the prognostic usefulness of MS in critical lower limb ischemia (CLI) patients. MATERIALS AND METHODS: We compared the 2-year clinical outcomes in 101 consecutive CLI patients (66+/-14 years; 78% men) with 118 affected limbs treated with percutaneous transluminal angioplasty (PTA) according to the presence of MS and diabetes. RESULTS: The number of MS patients was 53 (52%), of which 45 (85%) had diabetes. During a 2-year follow-up, the incidence of clinical outcomes, including reintervention, major amputation, minor amputation, and survival, was not significantly different between MS and non-MS patients; however, the incidence of minor amputation was significantly higher in diabetic than in non diabetic patients (42% vs. 17%; p=0.011). Cox regression analysis for the 2-year primary patency demonstrated no association between MS and 2-year primary patency [hazard ratio (HR), 1.02; 95% confidence interval (CI), 0.45-2.30; p=0.961], whereas there was a significant association between diabetes and 2-year primary patency (HR, 2.81; 95% CI, 1.02-7.72; p=0.046). Kaplan-Meier analysis revealed no significant difference in the 2-year primary patency between MS and non-MS patients; however, the 2-year primary patency was lower in diabetic than in non diabetic patients (p=0.038). CONCLUSION: As a prognostic concept, MS might conceal the adverse impact of diabetes on the prognosis of CLI patients treated with PTA. PMID- 24339287 TI - Efficacy of short-term growth hormone treatment in prepubertal children with idiopathic short stature. AB - PURPOSE: It has been reported that daily recombinant human growth hormone (GH) treatment showed beneficial effects on growth in prepubertal children with idiopathic short stature (ISS). The present study aimed to validate the GH (Eutropin(r)) effect on growth promotion and safety after short-term GH treatment. MATERIALS AND METHODS: This study was an open-label, multicenter, interventional study conducted at nine university hospitals in Korea between 2008 and 2009. Thirty six prepubertal children with ISS were enrolled in this study to receive 6-month GH treatment. Yearly growth rate, height standard deviation score (SDS), and adverse events were investigated during treatment. RESULTS: After 26 weeks of GH treatment, the height velocity significantly increased by 6.36+/-3.36 cm/year (p<0.001). The lower end of one-sided 95% confidence interval was 5.22 cm/year, far greater than the predefined effect size. The gain in height SDS at week 26 was 0.57+/-0.27 (p<0.0001). Bone age significantly increased after GH treatment, however, bone maturation rate (bone age for chronological age) showed limited advancement. This 26-week GH treatment was effective in increasing serum levels of insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 from baseline (p<0.0001). Eutropin was well tolerated and there were no withdrawals due to adverse events. No clinically significant changes in laboratory values were observed. CONCLUSION: This 6-month daily GH treatment in children with ISS demonstrated increased height velocity, improved height SDS, and increased IGF-I and IGFBP-3 levels with a favorable safety profile. PMID- 24339288 TI - The assessment of the oncological safety margin of insufficient lymph node dissection in pT2 (pm) gastric cancer. AB - PURPOSE: To identify the effect of insufficient lymph node dissection (LND) on the survival of patients with pT2 gastric cancer. MATERIALS AND METHODS: A total of 340 patients (120 patients with insufficient LND and others with D2 LND) who underwent gastrectomy for pT2 gastric cancer between January 2008 and December 2010 were included. RESULTS: The incidence of preoperatively diagnosed early gastric cancer was higher and there were fewer metastatic lymph nodes (LNs) in the insufficient LND group than the D2 group, but there was no survival difference between two groups (p=0.365). Among the 89 patients with metastatic LNs after D2 LND, 13 patients (14.6%) had metastatic LNs at selected N2 stations (#10, 11, or 12a), but none of these patients were in the pN1 category. One patient had five metastatic LNs at station #11p with no metastatic LNs at any other stations. The number of metastatic LNs was identified as the only risk factor for LN metastasis at selected N2 stations by logistic regression. CONCLUSION: If a patient has pN0 or pN1 category after insufficient LND for pT2 gastric cancer, the surgery can be regarded as secure. However, for patients with pN2 or pN3 category, more careful examination is required. PMID- 24339289 TI - Feasibility and outcomes of hypofractionated simultaneous integrated boost intensity modulated radiotherapy for malignant gliomas: a preliminary report. AB - PURPOSE: The aim of this study was to assess the feasibility and efficacy of hypofractionated simultaneous integrated boost-intensity modulated radiotherapy (SIB-IMRT) using three-layered planning target volumes (PTV) for malignant gliomas. MATERIALS AND METHODS: We conducted a retrospective analysis of 12 patients (WHO grade IV-10; III-2) postoperatively treated with SIB-IMRT with concurrent temozolomide. Three-layered PTVs were contoured based on gadolinium enhanced magnetic resonance imaging as follows; high risk PTV (H-PTV) as the area of surgical bed including residual gross tumor with a 0.5 cm margin; low risk PTV (L-PTV) as the area surrounding the high risk PTV with 1.5 cm margin; moderate risk PTV (M-PTV) as a line at one-third the distance from high risk PTV to low risk PTV. Total dose to high risk PTV was 70 Gy in 8 and 62.5 Gy in 4 patients. RESULTS: The median follow-up time was 52 months in surviving patients. The 2- and 5-year overall survival (OS) rates were 66.6% and 47.6%, respectively. The 2- and 5-year progression-free survival (PFS) rates were 57.1% and 45.7%, respectively. The median OS and PFS were 48 and 31 months, respectively. Six patients (50%) progressed: in-field only in one, out-field or disseminated in 4, and both in one patient. All patients completed planned treatments without a toxicity-related gap. Asymptomatic radiation necrosis was observed in 4 patients at post-radiotherapy 9-31 months. CONCLUSION: An escalated dose of hypofractionated SIB-IMRT using three-layered PTVs can be safely performed in patients with malignant glioma, and might contribute to better tumor control and survival. PMID- 24339290 TI - Clinical experiences of incidental prostate cancer after transurethral resection of prostate (TURP) according to initial treatment: a study of a Korean high volume center. AB - PURPOSE: These are the clinical experiences of Korean incidental prostate cancer patients detected by transurethral resection of the prostate according to initial treatment: active surveillance (AS), radical prostatectomy (RP) and hormone therapy (HT). MATERIALS AND METHODS: We retrospectively reviewed the records of 156 incidental prostate cancer patients between 2001 and 2012. The clinicopathologic outcomes were reviewed and follow-up results were obtained. RESULTS: Among 156 patients, 97 (62.2%) had T1a and 59 (37.8%) had T1b. Forty-six (29.5%) received AS, 67 (42.9%) underwent RP, 34 (21.8%) received HT, 4 (2.6%) received radiotherapy, and 5 (3.2%) chose watchful waiting. Of 46 patients on AS, prostate-specific antigen (PSA) progression occurred in 12 (26.1%) patients. Among them, 3 patients refused treatment despite PSA progression. Five patients, who underwent RP as an intervention, all had organ-confined Gleason score <=6 disease. In 67 patients who underwent RP, 50 (74.6%) patients had insignificant prostate cancer and 8 (11.9%) patients showed unfavorable features. During follow up, biochemical recurrence occurred in 2 patients. Among 34 patients who received HT, 3 (8.8%) patients had PSA progression. Among 156 patients, 6 patients died due to other causes during follow-up. There were no patients who died due to prostate cancer. CONCLUSION: The clinical outcomes of incidental prostate cancer were satisfactory regardless of the initial treatment. However, according to recent researches and guidelines, immediate definite therapy should be avoided without a careful assessment. We also believe that improved clinical staging is needed for these patients. PMID- 24339291 TI - The clinical, radiological, and bronchoscopic findings and outcomes in patients with benign tracheobronchial tumors. AB - PURPOSE: We evaluated the characteristics of and treatment outcomes in patients with benign tracheobronchial tumors. MATERIALS AND METHODS: We reviewed the records of patients with benign tracheobronchial tumors who underwent bronchoscopic intervention with mechanical removal and Nd: YAG laser cauterization, and evaluated the characteristics and treatment outcomes of 55 patients with hamartomas, leiomyomas, papillomas, typical carcinoids, or schwannomas seen between April 1999 and July 2012. RESULTS: The most common tumors were hamartoma (n=24), leiomyoma (n=16), papilloma (n=7), typical carcinoid (n=5), and schwannoma (n=3). Forty-one patients (75%) had symptoms. On chest computed tomography, 35 patients (64%) had round or ovoid lesions, accompanied by atelectasis (n=26, 47%) or obstructive pneumonia (n=17, 31%). Fatty components (n=9, 16%) and calcifications (n=7, 13%) were observed only in hamartomas, leiomyomas, and typical carcinoids. At bronchoscopy, the typical findings were categorized according to tumor shape, surface, color, and visible vessels. Fifty (91%) patients underwent complete resection. Forty patients (73%) achieved successful bronchoscopic removal defined as complete resection without complications or recurrence. Recurrences occurred in four papillomas, one leiomyoma, and one typical carcinoid. The proportions of tumor types (p=0.029) differed between the successful and unsuccessful removal groups, and a pedunculated base (p<0.001) and no spontaneous bleeding (p=0.037) were more frequent in the successful removal group. CONCLUSION: We described clinical, radiological, and typical bronchoscopic findings in patients with benign tracheobronchial tumors; these findings might help to differentiate such tumors. Bronchoscopic intervention was a useful treatment modality, and tumor type, pedunculated base, and vascularity may influence successful tumor removal. PMID- 24339292 TI - Does medical emergency team intervention reduce the prevalence of emergency endotracheal intubation complications? AB - PURPOSE: Emergency endotracheal intubation (EEI) is a complex process that leads to various complications. Previous studies mainly demonstrated that the Medical Emergency Team (MET) intervention reduced the incidence of cardiac arrest, however, the impact of a MET on airway management has not been investigated in detail. Our purpose was to confirm the impact of a MET on airway management and compare the incidence of complications of EEI before and after MET intervention in a general ward. MATERIALS AND METHODS: We performed an observational study and reviewed 318 patients intubated by a MET in a general ward. RESULTS: The patients enrolled during the control (2007) and study (2009) periods were 103 and 215, respectively. Cardiopulmonary resuscitation requiring emergency intubation in a general ward was reduced after MET intervention at the Asan Medical Center (39.8% vs. 19.1%, p<0.001). Pre-intubation and post-intubation oxygen saturation levels were higher after MET intervention (pre-intubation, 80% before vs. 92% after MET, p<0.001; post-intubation, 95% before vs. 99% after MET, p<0.001). The use of vasopressors after intubation decreased as a result of MET intervention (62.1% before vs. 36.7% after MET, p<0.001). Hypotension was also reduced (34% before vs. 8.8% after MET, p<0.001). CONCLUSION: Early interventions of a MET changed the causes of emergency intubation in a general ward from cardiopulmonary resuscitation to respiratory distress or shock and improved hypoxemia and hypotension related to emergency intubation. The MET intervention is safe and effective system for emergency intubation in a general ward. PMID- 24339293 TI - Rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, restores alveolar and pulmonary vascular development in a rat model of bronchopulmonary dysplasia. AB - PURPOSE: We tested whether rosiglitazone (RGZ), a peroxisome proliferator activated receptor-gamma agonist, can restore alveolar development and vascular growth in a rat model of bronchopulmonary dysplasia (BPD). MATERIALS AND METHODS: A rat model of BPD was induced through intra-amniotic delivery of lipopolysaccharide (LPS) and postnatal hyperoxia (80% for 7 days). RGZ (3 mg/kg/d, i.p.) or vehicle was given daily to rat pups for 14 days. This model included four experimental groups: No BPD+vehicle (V), No BPD+RGZ, BPD+V, and BPD+RGZ. On D14, alveolarization, lung vascular density, and right ventricular hypertrophy (RVH) were evaluated. RESULTS: Morphometric analysis revealed that the BPD+RGZ group had significantly smaller and more complex airspaces and larger alveolar surface area than the BPD+V group. The BPD+RGZ group had significantly greater pulmonary vascular density than the BPD+V group. Western blot analysis revealed that significantly decreased levels of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 by the combined exposure to intra-amniotic LPS and postnatal hyperoxia were restored by the RGZ treatment. RVH was significantly lesser in the BPD+RGZ group than in the BPD+V group. CONCLUSION: These results suggest that RGZ can restore alveolar and pulmonary vascular development and lessen pulmonary hypertension in a rat model of BPD. PMID- 24339294 TI - Clinical characteristics of primary Epstein Barr virus hepatitis with elevation of alkaline phosphatase and gamma-glutamyltransferase in children. AB - PURPOSE: The aim of the present study was to evaluate the clinical characteristics of the primary Epstein-Barr virus (EBV) hepatitis with elevation of both serum alkaline phosphatase (ALP) and gamma-glutamyltransferase (gamma-GT) levels in children. MATERIALS AND METHODS: A retrospective study was performed by reviewing of the medical records of 36 patients who were diagnosed with primary EBV hepatitis. The patients were divided into 2 groups: patients with elevated serum ALP and gamma-GT levels (group 1) and patients without (group 2). RESULTS: The classic features of infectious mononucleosis (fever, pharyngitis and/or tonsillitis, and cervical lymphadenitis) were seen in 20 (57.1%) of group 1 patients and 18 (50.0%) of group 2 patients. Hepatitis with elevated serum ALP and gamma-GT levels were present in 14 (38.9%) of the all patients. Of these patients, Jaundice occurred in only 2 (5.6%). The mean levels of aspartate aminotransferase and alanine aminotransferase (ALT) as well as the number of patients with ALT greater than 400 IU/L were significantly different between the groups (177 IU/L vs. 94 IU/L, 418 IU/L vs. 115 IU/L, and 50.0% vs. 13.6%; p=0.001, p=0.001, p=0.026, respectively). The mean duration of elevated serum ALT levels was 17.5 days in group 1 and 9.0 days in group 2 (p=0.013). All patients recovered fully without any chronic or serious complications. CONCLUSION: Primary EBV hepatitis with predominant biochemical abnormalities of the elevation of ALP and gamma-GT is frequent and mostly anicteric. This may represent a benign disease, but a delay in recovery of liver function as well. PMID- 24339295 TI - Positive maternal C-reactive protein predicts neonatal sepsis. AB - PURPOSE: To evaluate the diagnostic performance of maternal inflammatory marker: C-reactive protein (CRP) in predicting early onset neonatal sepsis (that occurring within 72 hours after birth). MATERIALS AND METHODS: 126 low birth weight newborns (gestation 32+/-3.2 wk, birth weight 1887+/-623 g) and their mothers were included. Neonates were divided into sepsis group (n=51) including both proven (positive blood culture) and suspected (negative blood culture but with more than 3 abnormal clinical signs), and controls (n=75). Mothers were subgrouped into CRP positive >=1.22 mg/dL (n=48) and CRP negative <1.22 mg/dL (n=78) group, determined by Receiver Operating Characteristic curves, and odds ratio was calculated for neonatal sepsis according to maternal condition. RESULTS: Maternal CRP was significantly higher in neonatal sepsis group than in control (3.55+/-2.69 vs. 0.48+/-0.31 mg/dL, p=0.0001). Maternal CRP (cutoff value >1.22 mg/dL) had sensitivity 71% and specificity 84% for predicting neonatal sepsis. Maternal CRP positive group had more neonatal sepsis than CRP negative group (71% vs. 29%, p<0.001). Odds ratio of neonatal sepsis in maternal CRP positive group versus CRP negative group was 10.68 (95% confidence interval: 4.313-26.428, p<0.001). CONCLUSION: The risk of early onset neonatal sepsis significantly increased in the case of positive maternal CRP (>=1.22 mg/dL). In newborn of CRP positive mother, the clinician may be alerted to earlier evaluation for possible neonatal infection prior to development of sepsis. PMID- 24339296 TI - Inhaled colistin for treatment of pneumonia due to colistin-only-susceptible Acinetobacter baumannii. AB - PURPOSE: Colistin is used for the treatment of pneumonia associated with multidrug- resistant Acinetobacter baumannii and Pseudomonas aeruginosa. However, the best route of administration and dosage is not known. We report our experience with aerosolized colistin in twelve patients with pneumonia caused by colistin-only-susceptible (COS) A. baumannii. MATERIALS AND METHODS: We retrospectively reviewed patients' medical records who were treated with aerosolized colistin for the treatment of pneumonia. RESULTS: Ten patients were treated only with aerosolized colistin inhalation and two patients received a 3 day course intravenous colistin, and then switched to colistin inhalation therapy. The median duration of aerosolized colistin therapy was 17 days (5-31 days). Four patients were treated only with aerosolized colistin, whereas 4 patients received concomitant glycopeptides, and 4 received concomitant levofloxacin or cefoperazone/sulbactam. At the end of the therapy, the clinical response rate and bacteriological clearance rate was 83% and 50%, respectively. Colistin-resistant strains were isolated from 3 patients after aerosolized colistin therapy; however, all of them showed favorable clinical response. The median interval between inhalation therapy and resistance was 7 days (range 5-19 days). Acute kidney injury developed in 3 patients. Two patients experienced Clostridium difficile associated diarrhea. One patient developed fever and skin rash after aerosolized colistin therapy. No patient developed neurotoxicity or bronchospasm. CONCLUSION: Colistin inhalation therapy is deemed tolerable and safe, and could be beneficial as an adjuctive therapy for the management of pneumonia due to COS A. baumannii. However, the potential development of colistin resistance cannot be overlooked. PMID- 24339297 TI - The immunogenicity of a single dose of hepatitis A virus vaccines (Havrix(r) and Epaxal(r)) in Korean young adults. AB - PURPOSE: Assessing the immunogenicity of a single dose of hepatitis A virus (HAV) vaccines is important because some people receive only a single dose. However, previous studies have shown variable results and have not examined the effects of demographic characteristics other than gender. This study was performed to examine the immunogenicity of a single dose of HAV vaccine according to the vaccine type and demographic characteristics in young adults. MATERIALS AND METHODS: Seronegative medical school students were randomly allocated to receive either Havrix or Epaxal. RESULTS: After approximately 11 months, the seroconversion rate in 451 participants was 80.7%. In men, the Havrix group showed a significantly higher seroconversion rate (81.9%) than the Epaxal group (69.2%), whereas both vaccine groups showed similarly high immunogenicity in women (Havrix: 90.1%, Epaxal: 92.9%; P for interaction=0.062). According to the results of a multivariate analysis, Epaxal showed significantly lower immunogenicity than Havrix only in men. Age, obesity, drinking, smoking, and follow-up time did not significantly affect seroconversion in either gender. CONCLUSION: The seroconversion rate of single-dose HAV vaccines was low in men, particularly in those who received Epaxal. Our results suggest that gender effects should be considered when comparing the immunogenicity of different HAV vaccines. PMID- 24339298 TI - Concomitant impact of high-sensitivity C-reactive protein and renal dysfunction in patients with acute myocardial infarction. AB - PURPOSE: The present study aimed to investigate the impact of high-sensitivity C reactive protein (hs-CRP) and renal dysfunction on clinical outcomes in acute myocardial infarction (AMI) patients. MATERIALS AND METHODS: The study involved a retrospective cohort of 8332 patients admitted with AMI. The participants were divided into 4 groups according to the levels of estimated glomerular filtration rate (eGFR) and hs-CRP: group I, no renal dysfunction (eGFR >=60 mL.min(-1).1.73 m(-2)) with low hs-CRP (<=2.0 mg/dL); group II, no renal dysfunction with high hs CRP; group III, renal dysfunction with low hs-CRP; and group IV, renal dysfunction with high hs-CRP. We compared major adverse cardiac events (MACE) over a 1-year follow-up period. RESULTS: The 4 groups demonstrated a graded association with increased MACE rates (group I, 8.8%; group II, 13.8%; group III, 18.6%; group IV, 30.1%; p<0.001). In a Cox proportional hazards model, mortality at 12 months increased in groups II, III, and IV compared with group I [hazard ratio (HR) 2.038, 95% confidence interval (CI) 1.450-2.863, p<0.001; HR 3.003, 95% CI 2.269-3.974, p<0.001; HR 5.087, 95% CI 3.755-6.891, p<0.001]. CONCLUSION: High hs-CRP, especially in association with renal dysfunction, is related to the occurrence of composite MACE, and indicates poor prognosis in AMI patients. PMID- 24339300 TI - Three-year experience of pouch dilatation and slippage management after laparoscopic adjustable gastric banding. AB - PURPOSE: Pouch dilatation and band slippage are the most common long-term complications after laparoscopic adjustable gastric banding (LAGB). The aim of the study is to present our experience of diagnosis and management of these complications. MATERIALS AND METHODS: The pars flaccida technique with anterior fixation of the fundus was routinely used. All band adjustments were performed under fluoroscopy. We analyzed the incidence, clinico-radiologic features, management, and revisional surgeries for treatment of these complications. We further presented the outcome of gastric plication techniques as a measure for prevention of these complications. RESULTS: From March 2009 to March 2012, we performed LAGB on 126 morbidly obese patients. Among them, 14 patients (11.1%) were diagnosed as having these complications. Four patients (3.2%) had concentric pouch dilatations, which were corrected by band adjustment. Ten (7.9%) had eccentric pouch with band slippage. Among the ten patients, there were three cases of posterior slippage, which were corrected by reoperation, and seven cases of eccentric pouch dilatation with anterior slippage. Three were early anterior slippage, which was managed conservatively. Two were acute anterior slippage, one of whom underwent a revision. There were two cases of chronic anterior slippage, one of whom underwent a revision. The 27 patients who underwent gastric plication did not present with eccentric pouch with band slippage during the follow-up period. CONCLUSION: The incidence of pouch dilatation with/without band slippage was 11.1%. Management should be individualized according to clinico-radiologic patterns. Gastric plication below the band might prevent these complications. PMID- 24339299 TI - Effect of peritoneal dialysis modality on the 1-year rate of decline of residual renal function. AB - PURPOSE: The effect of different peritoneal dialysis (PD) modalities on the decline in residual renal function (RRF) is unclear due to inconsistencies among studies. In particular, the effect of automated peritoneal dialysis (APD) modalities [continuous cyclic peritoneal dialysis (CCPD) and nightly intermittent peritoneal dialysis (NIPD)] on RRF has not been examined in a large cohort. MATERIALS AND METHODS: We conducted a single-center retrospective study to investigate the association between PD modalities and decline in RRF in 142 incident PD patients [34 on CCPD, 36 on NIPD, and 72 on continuous ambulatory peritoneal dialysis (CAPD)]. RRF was measured within 2 months from PD start and at 1 year after PD initiation. RESULTS: The RRF at 1 year after PD initiation was 1.98+/-2.20 mL/min/1.73 m2 in CCPD patients and 3.63+/-3.67 mL/min/1.73 m2 in NIPD patients, which were moderately lower than 4.23+/-3.51 mL/min/1.73 m2 in CAPD patients (p=0.064). Moreover, there was no significant difference in the 1 year rate of decline of RRF between CCPD and NIPD patients, although APD patients had a faster 1-year RRF decline rate than CAPD patients (CCPD and NIPD vs. CAPD: 45.68 and -36.69 vs. 1.17%/year, p=0.045). APD was associated with a more rapid decline in RRF in patients with end-stage renal disease undergoing PD, although multivariate analysis attenuated the significance of this finding (beta=-31.50; 95% CI, -63.61 to 0.62; p=0.052). CONCLUSION: Our results suggest that CAPD might be more helpful than APD for preserving RRF during the first year of dialysis therapy, although there was no significant difference in the 1-year rate of decline of RRF between the two APD modalities. PMID- 24339301 TI - Clinical characteristics and management of benign transient non-organic ileus of neonates: a single-center experience. AB - PURPOSE: The term benign transient non-organic ileus of neonates (BTNIN) is applied to neonates who present symptoms and plain radiographic findings of Hirschsprung's disease, but do not have aganglionic bowel and are managed well by conservative treatment. It can often be difficult to diagnose BTNIN because its initial symptoms are similar to those of Hirschsprung's disease. The aim of this study is to evaluate the clinical characteristics and proper treatment of BTNIN. MATERIALS AND METHODS: A retrospective review was made on the clinical data of 19 neonates who were treated for BTNIN between January 2008 and December 2011 at a single facility. RESULTS: Abdominal distension occurred in every patient (19/19). Other common symptoms included emesis (5/19), explosive defecation (5/19), and constipation (4/19). The vast majority of patients (15/19) experienced the onset of symptoms between 2 and 4 weeks of age. Radiograph findings from all of the patients were similar to Hirschsprung's disease. A barium study showed a transition zone in 33.4% (6/18) of the patients. However, rectal biopsy revealed ganglion cells in the distal rectum in 88.2% (15/17) of the patients, and anorectal manometry showed a normal rectoanal inhibitory reflex in 90% (9/10). All patients responded well to conservative treatment. Symptoms disappeared at the mean age of 4.9+/-1.0 months, and the abdominal radiographs normalized. CONCLUSION: BTNIN had an excellent outcome with conservative treatment, and must be differentiated from Hirschsprung's disease. A rectal biopsy and anorectal manometry were useful diagnostic tools in the differential diagnosis. PMID- 24339302 TI - Totally laparoscopic Roux-en-Y gastrojejunostomy after laparoscopic distal gastrectomy: analysis of initial 50 consecutive cases of single surgeon in comparison with totally laparoscopic Billroth I reconstruction. AB - PURPOSE: Roux-en-Y reconstruction (RY) in laparoscopic distal gastrectomy for gastric cancer is a more complicated procedure than Billroth-I (BI) or Billroth II. Here, we offer a totally laparoscopic simple RY using linear staplers. MATERIALS AND METHODS: Each 50 consecutive patients with totally laparoscopic distal gastrectomy with RY and BI were enrolled in this study. Technical safety and surgical outcomes of RY were evaluated in comparison with BI. RESULTS: In all patients, RY gastrectomy using linear staplers was safely performed without any events during surgery. The mean operation time and anastomosis time were 177.0+/ 37.6 min and 14.4+/-5.6 min for RY, respectively, which were significantly longer than those for BI (150.4+/-34.0 min and 5.9+/-2.2 min, respectively). There were no differences in amount of blood loss, time to flatus passage, diet start, length of hospital stay, and postoperative inflammatory response between the two groups. Although there was no significant difference in surgical complications between RY and BI (6.0% and 14.0%), the RY group showed no anastomosis site related complications. CONCLUSION: The double stapling method using linear staplers in totally laparoscopic RY reconstruction is a simple and safe procedure. PMID- 24339303 TI - Changes in sexual function and comparison of questionnaires following surgery for pelvic organ prolapse. AB - PURPOSE: The aim of this study was to evaluate the effect of surgical repair of pelvic organ prolapse on female sexual function and to assess correlations between the two using two current standardized questionnaires. MATERIALS AND METHODS: From October 2009 to September 2010, 143 patients with posterior compartment or combined vaginal prolapse were included. We assessed surgical outcomes according to anatomical change in the vagina and results of the Female Sexual Function Index (FSFI) and Pelvic Organ Prolapse/Urinary Incontinence Sexual Function questionnaire (PISQ-12) both pre- and postoperatively. RESULTS: Among the 143 preoperative patients, 99 and 84 patients responded to the PISQ-12 and FSFI, respectively. The mean PISQ-12 score increased after surgery (p<0.001). Specifically, postoperative scores for questions 8 and 12 were higher than their respective preoperative scores (p<0.001). Postoperatively, mean FSFI score changed only slightly (p=0.76), and only the score for the satisfaction domain was improved (p=0.023). In regards to vaginal anatomy, vaginal length was significantly greater postoperatively (6.99+/-0.18 vs. 7.56+/-1.08, p<0.001), and postoperative vaginal caliber was narrowed to a two-finger width. CONCLUSION: In this study, surgery for pelvic organ prolapse was shown to affect female sexual function. Moreover, menopause was associated with a change in postoperative sexual function. PMID- 24339304 TI - Gradual lengthening of the ulna in patients with multiple hereditary exostoses with a dislocated radial head. AB - PURPOSE: Multiple hereditary exostoses of the forearm typically form in the distal ulna, causing disturbances in the growth of the ulna and functional disability. Multiple hereditary exostoses inhibit the growth of the ulna, leading to an acquisition of a varus deformity in the radius, which sometimes leads to dislocation of the radial head, the development of limitations in the pronation supination of the forearm, and cosmetic problems. MATERIALS AND METHODS: We retrospectively reviewed the cases of four patients who had deformities of the forearm with radial head dislocation associated with multiple hereditary exostoses, and evaluated the radiologic and clinical results of excision of the osteochondromas from the distal ulna and gradual ulnar lengthening with an Ilizarov external fixator. RESULTS: Good clinical and radiological results were obtained after a mean follow-up of 25 months. At the most recent follow-up, radial bowing, ulnar shortening, carpal slip, and the pronation/supination arch of the forearm had improved. There was little change in terms of preoperative radial articular angle and the flexion/extension arch of the elbow by the most recent follow-up. CONCLUSION: Treatment of four forearms from four patients by excision of osteochondromas and gradual lengthening of the ulna with an Ilizarov external fixator spontaneously reduced dislocations of the radial heads without the need for any additional operative intervention. All patients were satisfied with the final results. PMID- 24339305 TI - Transient receptor potential vanilloid 1-immunoreactive innervation increases in fractured rat femur. AB - PURPOSE: Pain from vertebral or femoral neck fractures is a particularly important problem in clinical orthopaedics. Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel, and there are recent reports on an association between bone pain and TRPV1. However, an increase in TRPV1 activity has not been reported following femoral fracture. MATERIALS AND METHODS: We applied a neurotracer [Fluoro-gold (FG)] onto femur to detect dorsal root ganglia (DRGs) innervating the cortex of the femur in 30 Sprague Dawley rats. Seven days after application, a closed mid-diaphyseal fracture of the femur was performed. FG labeled TRPV1-immunoreactive (ir) DRGs innervating the femur were examined in nonfractured controls, and 3 days, 1 week, 2 weeks, and 4 weeks after fracture. We evaluated bone healing of the femur and compared the ratio of TRPV1-ir DRG neurons innervating the femur at the time points. RESULTS: Four weeks after fracture, complete bone union was observed. There was no significant difference in the ratio of FG labeled DRG neurons to total DRG neurons at each time point. The percentages of TRPV1-ir neurons in DRGs innervating the femur at 3 days and 1 week after fracture were significantly higher than those in control, 2 weeks, and 4 weeks after fracture (p<0.05). CONCLUSION: Fracture induced an increase of TRPV1-ir neurons in DRGs innervating the fractured femur within 3 days, and decreased during bone healing over 4 weeks. These findings show that TRPV1 may play a role in sensory sensation of bone fracture pain. PMID- 24339306 TI - The effect of obturator nerve block on hip lateralization in low functioning children with spastic cerebral palsy. AB - PURPOSE: Hip adductor spasticity has a great impact on developing hip displacement in children with cerebral palsy (CP). Obturator nerve (ON) block is less invasive intervention rather than soft tissue surgery for reduction of hip adductor spasticity. The aim of this study is to investigate the effect of ON block on hip lateralization in low functioning children with spastic CP. MATERIALS AND METHODS: The study was performed by retrospective investigation of the clinical and radiographic follow-up data of low functioning children [gross motor function classification system (GMFCS) level III to V] with spastic cerebral palsy whose hip was subluxated. Migration percentage (MP) was measured on hip radiographs and its annual change was calculated. In intervention group, ON block was done with 50% ethyl alcohol under the guidance of electrical stimulation. RESULTS: The data of 49 legs of 25 children for intervention group and the data of 41 legs of 23 children for nonintervention group were collected. In intervention group, the MP were significantly reduced at 1st follow-up and the MPs at 2nd and last follow-up did not show significant differences from initial MP. Whereas in nonintervention group, the MPs at 1st, 2nd and last follow-up were all significantly increased compared to initial MPs. CONCLUSION: ON block with ethyl alcohol is useful as an early effective procedure against progressive hip displacement in these children with spastic CP. PMID- 24339307 TI - Epithelial wound healing after cataract surgery comparing two different topical fluoroquinolones. AB - PURPOSE: To compare the epithelial wound healing response of two preservative free fluoroquinolones, moxifloxacin and levofloxacin, in patients who underwent cataract surgery. MATERIALS AND METHODS: In this prospective, evaluator-masked, randomized clinical trial, 59 eyes of 50 patients who underwent cataract surgery were enrolled. Patients were randomized to receive moxifloxacin 0.5% (n=32 eyes) or levofloxacin 0.5% (n=27 eyes). All patients instilled moxifloxacin or levofloxain four times daily for 1 week prior to surgery and 2 weeks after surgery. The epithelial wound healing status in the corneal incision site was scanned with a raster scan mode of fourier-domain optical coherence tomography (FD-OCT). The number of eyes showing epithelial defect images and average number of corneal epithelial defect cuts per eye were compared between groups. All patients were evaluated on postoperative days 1, 2, 3, and 10. RESULTS: On postoperative days 1, 2, and 3, the number of eyes showing epithelial defects in FD-OCT was not statistically different (all p>0.05). The average number of corneal epithelial defect cuts was also not statistically different between the two groups (all p>0.05). No eyes showed epithelial defects on postoperative day 10 in either group. CONCLUSION: There were no differences on epithelial wound healing comparing these two different fluoroquinolones at the incision site of cataract surgery. PMID- 24339308 TI - Inflammatory cytokine and osmolarity changes in the tears of dry eye patients treated with topical 1% methylprednisolone. AB - PURPOSE: To evaluate changes in clinical outcomes, inflammatory cytokine levels, and tear osmolarity in the tears of patients with moderate to severe dry eye syndrome before and after the application of topical 1% methylprednisolone. MATERIALS AND METHODS: Thirty-two patients with moderate to severe dry eye unresponsive to previous aqueous enhancement therapy were enrolled. Five patients were lost to follow up, and twenty-seven patients were eligible for analysis. Patients were instructed to apply topical 1% methylprednisolone four times per day, as well as to continue applying their current therapy of preservative-free 0.1% sodium hyaluronate four times per day. Corneal and conjunctival staining scores, tear film breakup time (TFBUT), Schirmer test, and tear osmolarity were assessed at baseline, 4 weeks, and 8 weeks. Tear samples were collected at every visit for cytokine analysis. RESULTS: Corneal and conjunctival staining scores and TFBUT showed significant improvement at 4 (p<0.001, <0.001, <0.001 respectively) and 8 (p<0.001, <0.001, <0.001 respectively) weeks. Tear osmolarity decreased significantly at 8 weeks (p=0.008). Interleukin (IL)-1beta, IL-8, and monocyte chemoattractant protein-1 were significantly decreased at 8 weeks compared with those at baseline (p=0.041, 0.001, 0.008 respectively). CONCLUSION: Short-term treatment with topical 1% methylprednisolone not only improved clinical outcomes, but also decreased tear osmolarity and cytokine levels. By measuring the changes in cytokine levels and tear osmolarity, we could objectively evaluate the anti-inflammatory effects of topical methylprednisolone applied in the treatment of patients with moderate to severe dry eye syndrome. PMID- 24339309 TI - Effect of dexmedetomidine on sevoflurane requirements and emergence agitation in children undergoing ambulatory surgery. AB - PURPOSE: Dexmedetomidine, a potent selective alpha2-adrenergic agonist, produces sedation and analgesia. This study was conducted to assess the effect of dexmedetomidine infusion on sevoflurane requirements, recovery profiles, and emergence agitation in children undergoing ambulatory surgery. MATERIALS AND METHODS: Forty children undergoing ambulatory hernioplasty or orchiopexy were randomized into two groups. The dexmedetomidine group (Group D, n=20) received dexmedetomidine 1 MUg/kg, followed by 0.1 MUg/kg/h until the end of surgery, whereas the saline group (Group S, n=20) received volume-matched normal saline. Sevoflurane was used for induction and maintenance of anesthesia and caudal block was performed in all children. End-tidal sevoflurane concentration (ET-sevo), the incidence of emergence agitation, pain scores, and sedation scores were recorded. Hemodynamic changes and other adverse effects were assessed in the perioperative period. RESULTS: ET-sevo of Group D was significantly reduced in 23.8-67% compared to Group S during surgery. The incidence of emergence agitation was lower in Group D than in Group S (5% vs. 55%, p=0.001). Postoperative pain was comparable, and discharge time was not different between the groups. Mean arterial pressure and heart rate were significantly lower in Group D during surgery. CONCLUSION: Intraoperative infusion of dexmedetomidine reduced sevoflurane requirements and decreased emergence agitation without delaying discharge in children undergoing ambulatory surgery. However, caution should be taken in regard to bradycardia and hypotension. PMID- 24339310 TI - Effects of seasonal differences in testosterone and cortisol levels on pain responses under resting and anxiety conditions. AB - PURPOSE: This study investigated whether hormones and pain perception are associated with exam anxiety, and also whether exam anxiety is affected by seasonal differences in testosterone and cortisol levels. MATERIALS AND METHODS: Forty-six healthy males were recruited from a medical college. Anxiety was induced by having participants perform the Objective Structured Clinical Examination. Pressure was applied to the participants to induce pain. Pain thresholds, pain ratings, anxiety ratings, blood pressure, heart rate, salivary testosterone and cortisol levels were measured under resting and anxiety conditions in the spring and summer. Data were collected from 46 participants during the spring (n=25) and summer (n=21). RESULTS: Pain thresholds and testosterone levels were significantly lower under anxiety than at rest for all participants (n=46), while cortisol levels, pain ratings, and anxiety ratings were significantly higher under anxiety than at rest. In the spring (n=25), testosterone levels were significantly higher at rest than under anxiety, while there was no difference in cortisol levels between resting and anxiety conditions. In the summer (n=21), cortisol levels were significantly higher under anxiety than at rest, while there was no difference in testosterone levels between resting and anxiety conditions. There were no significant seasonal differences in pain and anxiety ratings and pain threshold. CONCLUSION: These results indicate that seasonal differences in testosterone and cortisol levels under anxiety and at rest may affect pain responses. These results also suggest that acute clinical pain may be relieved by managing anxiety that is related to a decrease of testosterone in spring and a large increase of cortisol in summer. PMID- 24339311 TI - The influence of hypothermia on transfusion requirement in patients who received clopidogrel in proximity to off-pump coronary bypass surgery. AB - PURPOSE: Hypothermia adversely affects the coagulation that could be of clinical significance in patients receiving clopidogrel. We evaluated the influence of hypothermia on transfusion requirements in patients undergoing isolated off-pump coronary artery bypass surgery (OPCAB) who continued clopidogrel use within 5 days of surgery. MATERIALS AND METHODS: Protocol-based, prospectively entered data of 369 patients were retrospectively reviewed. The time-weighted average of intraoperative temperatures and the temperature upon ICU admission (TWA-temp) was assessed. Patients were divided into normothermia (>=36 degrees C, n=224) and hypothermia (<36 degrees C, n=145) group. The transfusion requirement for perioperative blood loss was assessed and compared. RESULTS: Patients with hypothermia were older and had lower body surface area (BSA) than patients with normothermia. Age and BSA adjusted transfusion requirement was significantly larger in the hypothermia group [patients requiring transfusion: 64% versus 48%, p=0.003; number of units: 0 (0-2) units versus 2 (0-3) units, p=0.002]. In multivariate analysis of predictors of perioperative multiple transfusion requirements, hypothermia was identified as an independent risk factor along with age, female gender, BSA, chronic kidney disease, and congestive heart failure. CONCLUSION: Hypothermia was associated with increased transfusion requirement in patients undergoing OPCAB who received clopidogrel in proximity to surgery. Considering the high prevalence and the possibility of hypothermia being a modifiable risk factor, aggressive measures should be undertaken to maintain normothermia in those patients. PMID- 24339312 TI - Comprehensive variant screening of the UGT gene family. AB - PURPOSE: UGT1A1, UGT2B7, and UGT2B15 are well-known pharmacogenes that belong to the uridine diphosphate glucuronyltransferase gene family. For personalized drug treatment, it is important to study differences in the frequency of core markers across various ethnic groups. Accordingly, we screened single nucleotide polymorphisms (SNPs) of these three genes and analyzed differences in their frequency among five ethnic groups, as well as attempted to predict the function of novel SNPs. MATERIALS AND METHODS: We directly sequenced 288 subjects consisting of 96 Korean, 48 Japanese, 48 Han Chinese, 48 African American, and 48 European American subjects. Subsequently, we analyzed genetic variability, linkage disequilibrium (LD) structures and ethnic differences for each gene. We also conducted in silico analysis to predict the function of novel SNPs. RESULTS: A total of 87 SNPs were detected, with seven pharmacogenetic core SNPs and 31 novel SNPs. We observed that the frequencies of UGT1A1 *6 (rs4148323), UGT1A1 *60 (rs4124874), UGT1A1 *93 (rs10929302), UGT2B7 *2 (rs7439366), a part of UGT2B7 *3 (rs12233719), and UGT2B15 *2 (rs1902023) were different between Asian and other ethnic groups. Additional in silico analysis results showed that two novel promoter SNPs of UGT1A1 -690G>A and -689A>C were found to potentially change transcription factor binding sites. Moreover, 673G>A (UGT2B7), 2552T>C, and 23269C>T (both SNPs from UGT2B15) changed amino acid properties, which could cause structural deformation. CONCLUSION: Findings from the present study would be valuable for further studies on pharmacogenetic studies of personalized medicine and drug response. PMID- 24339313 TI - Effect of an oral hygienic care program for stroke patients in the intensive care unit. AB - PURPOSE: The effects of an oral hygienic care program (OHCP) have been reported in several diseases. However, no study exists investigating the influence of an OHCP on stroke patients or patients in the intensive care unit (ICU) has been reported, thus we sought to investigate the potential effect of an OHCP. MATERIALS AND METHODS: Fifty-six consecutive stroke patients who were admitted to the ICU were randomly assigned to two groups: the intervention (29 patients) and control groups (27 patients). The OHCP included tooth brushing with an inter dental brush and tongue cleaner and cleaning with chlorhexidine was administered to patients by one dentist once per day during admission in the ICU (mean, 2.2 weeks). The plague index, gingival index, clinical attachment loss, and colonization degree of candida albicans were assessed. RESULTS: After OHCP, the plaque index, gingival index, and colonization degree of candida albicans in saliva showed a significant decrease in the intervention group compared to those of the control group (p<0.05). However, no significant difference was observed in clinical attachment loss and the colonization degree of candida albicans on the tongue (p>0.05). CONCLUSION: Our OHCP was effective in improving the oral hygienic status and periodontal health of stroke patients during their stay in the ICU. Therefore, we recommend administration of the OHCP for stroke patients during their stay in the ICU. PMID- 24339314 TI - Diagnostic role of conventional ultrasonography and shearwave elastography in asymptomatic patients with diffuse thyroid disease: initial experience with 57 patients. AB - PURPOSE: Thyroid ultrasonography (US) is a useful diagnostic tool in the evaluation of diffuse thyroid disease (DTD), whereas shearwave elastography is a dynamic technique that can provide information about tissue hardness by using acoustic shearwaves remotely induced by a focused ultrasonic beam. This study aims at investigating the role of conventional US and shearwave elastography in the diagnosis of asymptomatic patients with DTD. MATERIALS AND METHODS: Fifty seven patients who underwent both conventional US and shearwave elastography were included in this study. Interobserver variability of the three radiologists in assessment of underlying thyroid echogenicity on conventional US was analyzed. Diagnostic performances for diagnosing DTD on conventional US and shearwave elastography were calculated and compared. RESULTS: Fair agreement was observed in the identification of DTD with conventional US (kappa value= 0.27). The area under the receiver operating characteristic curve (Az) were 0.52-0.585 on conventional US by three radiologists. The Az values when using the mean and maximum elasticity values as a diagnostic criteria for DTD were 0.619 and 0.59 on shearwave elastography. Patients with DTD showed higher mean [24.1+/-10 kilo Pascals (kPa)] and maximum (36.4+/-13.3 kPa) elasticity values on shearwave elastography when compared to the normal group (23.4+/-10.8 kPa and 33.7+/-12.4 kPa, respectively), although without statistical significance (p=0.802 and p=0.452, respectively). CONCLUSION: Conventional US did not show reliable interobserver agreement in the diagnosis of DTD. Although not statistically significant, shearwave elastography may provide additional information in the diagnosis of DTD. Therefore, larger prospective studies are needed to define the values of shearwave elastography for diagnosing DTD. PMID- 24339315 TI - Psychological and social factors affecting Internet searches on suicide in Korea: a big data analysis of Google search trends. AB - PURPOSE: The average mortality rate for death by suicide among OECD countries is 12.8 per 100000, and 33.5 for Korea. The present study analyzed big data extracted from Google to identify factors related to searches on suicide in Korea. MATERIALS AND METHODS: Google search trends for the search words of suicide, stress, exercise, and drinking were obtained for 2004-2010. Analyzing data by month, the relationship between the actual number of suicides and search words per year was examined using multi-level models. RESULTS: Both suicide rates and Google searches on suicide in Korea increased since 2007. An unconditional slope model indicated stress and suicide-related searches were positively related. A conditional model showed that factors associated with suicide by year directly affected suicide-related searches. The interaction between stress related searches and the actual number of suicides was significant. CONCLUSION: A positive relationship between stress- and suicide-related searches further confirmed that stress affects suicide. Taken together and viewed in context of the big data analysis, our results point to the need for a tailored prevention program. Real-time big data can be of use in indicating increases in suicidality when search words such as stress and suicide generate greater numbers of hits on portals and social network sites. PMID- 24339316 TI - Nutritional outcomes in children with epidermolysis bullosa: the experiences of two centers in Korea. AB - PURPOSE: Epidermolysis bullosa (EB) is associated with variable risks of extracutaneous manifestations and death. Currently, there is limited information on the clinical course and prognosis of EB in Korea. This study analyzed the nutritional outcomes, clinical morbidity, and mortality of children with EB. MATERIALS AND METHODS: Thirty patients, admitted to Severance Hospital and Gangnam Severance Hospital, from January 2001 to December 2011, were retrospectively enrolled. All patients were diagnosed with EB classified by dermatologists. RESULTS: Among the 30 patients, 5 patients were diagnosed with EB simplex, four with junctional EB, and 21 with dystrophic EB. Wound infection occurred in 47% of the patients, and blood culture-proven sepsis was noted in 10% of the patients. Two (9.2%) patients had esophageal stricture and 11 (52.4%) of the dystrophic EB patients received reconstructive surgery due to distal extremity contracture. There were five mortalities caused by sepsis, failure to thrive, and severe metabolic acidosis with dehydration. According to nutrition and growth status, most of the infants (97%) were born as appropriate for gestational age. However, at last follow-up, 56% of the children were below the 3rd percentile in weight, and 50% were below the 3rd percentile in weight for height. Sixty percent of the children had a thrive index below -3. CONCLUSION: Postnatal growth failure is a serious problem in children with EB. Strategies to maximize nutritional support could alleviate growth failure in children with EB, and thus improve clinical outcomes. PMID- 24339317 TI - A case of pneumomediastinum and parapneumonic effusions following pharyngeal perforation caused by shouting. AB - Spontaneous pneumomediastinum is an uncommon disorder, and usually affects young men and has a benign course. Common triggers are asthma, the smoking of illicit drugs, the Valsalva maneuver, and respiratory infections. Most cases are usually due to alveolar rupture into the pulmonary interstitium caused by excess pressure. The air dissects to the hilum along the peribronchovascular sheaths and spreads into the mediastinum. However, pneumomediastinum following pharyngeal perforation is very rare, and has only been reported in relation to dental procedures, head and neck surgery, or trauma. We report a case of pneumomediastinum that developed in a 43-year-old patient with pharyngeal perforation after shouting. His course was complicated by mediastinitis and parapneumonic effusions. PMID- 24339318 TI - Renovascular hypertension treated by renal artery embolization. AB - Renovascular hypertension is caused by narrowing of the arteries supplying the kidneys. There are several methods to treat renal artery stenosis, such as medications, percutaneous transluminal renal angioplasty, and atherosclerosis. A boy presented to our hospital with severe hypertension. Computed tomography angiogram revealed severe narrowing of the left renal artery and hypoplastic left kidney. Total renal artery embolizaton was performed to make a complete occlusion of the left renal artery. Follow-up renin and aldosterone levels were gradually decreased. The main advantage of renal artery embolization is that it is minimally invasive compared with extensive surgical procedures. Therefore, renal artery embolization should be considered as an alternative to surgical nephrectomy in pediatric patients with renovascular hypertension. PMID- 24339319 TI - A five-year survivor without recurrence following robotic anterior radical antegrade modular pancreatosplenectomy for a well-selected left-sided pancreatic cancer. AB - Radical antegrade modular pancreatosplenectomy (RAMPS) is regarded as a reasonable approach for margin-negative and systemic lymph node clearance in left sided pancreatic cancer. We present a patient with more than 5 years disease-free survival after robotic anterior RAMPS for pancreatic ductal adenocarcinoma in the body of the pancreas. The distal part of pancreas, soft tissue around the celiac trunk, and the origin of splenic vessels was dissected with the underlying fascia between the pancreas and adrenal gland. Resected specimen was removed through small vertical abdominal incision. Robot working time was about 8 hours, and blood loss was about 700 mL without blood transfusion. He returned to an oral diet on the postoperative first day and recovered without any clinically relevant complications. There was no lymph node metastasis, perineural or lymphovascular invasion. Both the pancreatic resection margin and the tangential posterior margin were free of carcinoma. The patient received only postoperative adjuvant radiotherapy around the tumor bed. The patient has survived for more than 5 years without evidence of cancer recurrence. Minimally invasive radical left-sided pancreatectomy with splenectomy may be oncologically feasible in well-selected pancreatic cancer. PMID- 24339320 TI - Cryopreserved autologous fat injections as a filler agent for facial augmentation: are they still safe? PMID- 24339321 TI - Malignancy risk associated with diagnostic categories defined by the Papanicolaou Society of Cytopathology pancreaticobiliary guidelines. AB - BACKGROUND: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is currently the predominant method for obtaining a preoperative tissue diagnosis for pancreatic lesions suspicious for malignancy. The diagnostic sensitivity and specificity of EUS-FNA are well documented, but malignancy risk associated with the diagnostic categories proposed by the Papanicolaou Society of Cytopathology is poorly defined. METHODS: The records of the Departments of Pathology at Duke University and the University of Utah were searched for all cases of EUS-FNA performed for the investigation of pancreatic lesions. All cases with follow-up surgical diagnosis or greater than 3 years of clinical follow-up were selected. Cytologic diagnostic categories were "nondiagnostic," "benign," "atypical (not otherwise specified)," "suspicious for malignancy," "neoplasm," and "malignant." Correlation of cytologic diagnosis with surgical and/or clinical follow-up was made and risk of malignancy calculated for each category. RESULTS: Three hundred seventeen EUS-FNAs with adequate surgical or clinical follow-up were obtained. Risk of malignancy for nondiagnostic specimens was 21%;, benign specimens, 13%; atypical cases, 74%; suspicious for malignancy, 82%; the neoplasm category, 14%; and the malignant category, 97% CONCLUSIONS: The cytologic categories proposed by the Papanicolaou Society of Cytopathology demonstrate an increasing risk for malignancy extending from benign to malignant. Aspirates designated benign have the lowest risk of malignancy (13%) and aspirates designated malignant the highest (97%). The proposed categorization scheme stratifies risk for malignancy giving useful information to clinicians treating patients with pancreatic lesions. PMID- 24339322 TI - Low-temperature, selective catalytic deoxygenation of vegetable oil in supercritical fluid media. AB - The effects of supercritical fluids on the production of renewable diesel-range hydrocarbons from natural triglycerides were investigated. Various supercritical fluids, which included CO2 (scCO2 ), propane (scC3 H8 ) and n-hexane (scC6 H14 ), were introduced with H2 and soybean oil into a fixed-bed reactor that contained pre-activated CoMo/gamma-Al2 O3 . Among these supercritical fluids, scC3 H8 and scC6 H14 efficiently allowed the reduction of the reaction temperature by as much as 50 degrees C as a result of facilitated heat and mass transfer and afforded similar yields to reactions in the absence of supercritical fluids. The compositional analyses of the gas and liquid products indicated that the addition of scC3 H8 during the hydrotreatment of soybean oil promoted specific deoxygenation pathways, decarbonylation and decarboxylation, which consumed less H2 than the hydrodeoxygenation pathway. As a result, the quantity of H2 required to obtain a high yield of diesel-range hydrocarbons could be reduced to 57 % if scC3 H8 was used. As decarboxylation and decarbonylation are mildly endothermic reactions, the reduced heat transfer resistance in scC3 H8 may drive the deoxygenation reaction to thermodynamically favourable pathways. PMID- 24339323 TI - Structural basis for antimicrobial activity of lasiocepsin. AB - Lasiocepsin is a unique 27-residue antimicrobial peptide, isolated from Lasioglossum laticeps (wild bee) venom, with substantial antibacterial and antifungal activity. It adopts a well-defined structure consisting of two alpha helices linked by a structured loop. Its basic residues form two distinct positively charged regions on the surface whereas aliphatic side chains contribute to solvent-accessible hydrophobic areas, thus emphasising the amphipathic character of the molecule. Lasiocepsin structurally belongs to the ShK family and shows a strong preference for anionic phospholipids; this is further augmented by increasing concentrations of cardiolipin, such as those found at the poles of bacterial cells. The membrane-permeabilising activity of the peptide is not limited to outer membranes of Gram-negative bacteria. The peptide interacts with phospholipids initially through its N terminus, and its degree of penetration is strongly dependent on the presence of cardiolipin. PMID- 24339324 TI - Relationship of meeting physical activity guidelines with health-related utility. AB - OBJECTIVE: Health-related utility measures overall health status and quality of life and is commonly incorporated into cost-effectiveness analyses. This study investigates whether attainment of federal physical activity guidelines translates into better health-related utility in adults with or at risk for knee osteoarthritis (OA). METHODS: Cross-sectional data from 1,908 adults with or at risk for knee OA participating in the accelerometer ancillary study of the Osteoarthritis Initiative were assessed. Physical activity was measured using 7 days of accelerometer monitoring and was classified as 1) meeting guidelines (>=150 bouted moderate-to-vigorous [MV] minutes per week); 2) insufficiently active (>=1 MV bout[s] per week but below guidelines); or 3) inactive (zero MV bouts per week). A Short Form 6D health-related utility score was derived from patient-reported health status. Relationship of physical activity levels to median health-related utility adjusted for socioeconomic and health factors was tested using quantile regression. RESULTS: Only 13% of participants met physical activity guidelines, and 45% were inactive. Relative to the inactive group, median health-related utility scores were significantly greater for the meeting guidelines group (0.063; 95% confidence interval [95% CI] 0.055, 0.071) and the insufficiently active group (0.059; 95% CI 0.054, 0.064). These differences showed a statistically significant linear trend and strong cross-sectional relationship with physical activity level even after adjusting for socioeconomic and health factors. CONCLUSION: We found a significant positive relationship between physical activity level and health-related utility. Interventions that encourage adults, including persons with knee OA, to increase physical activity even if recommended levels are not attained may improve their quality of life. PMID- 24339325 TI - Fast and efficient (18) F-labeling by [(18) f]fluorophenylazocarboxylic esters. AB - Introduction of [(18) F]fluoride ion into the aromatic core of phenylazocarboxylic esters was achieved in only 30 seconds, with radiochemical yields of up to 95 % (85(+/-10) %). For labeling purposes, the resulting (18) F substituted azoester can be further converted in radical-arylation reactions to give biaryls, or in substitutions at its carbonyl unit to produce azocarboxamides. PMID- 24339326 TI - Highly enantioselective copper(I)-catalyzed conjugate addition of terminal alkynes to 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones: new ester/amide surrogates in asymmetric catalysis. AB - A highly enantioselective copper-catalyzed conjugate alkynylation of monoactivated enones, namely 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones, is described. The reaction products are obtained with good yields and excellent enantioselectivities (from 92 to 99% ee). The beta-alkynylated difluoro(phenylsulfonyl) ketones can be converted into the corresponding beta alkynylated difluoro- and trifluoromethyl ketones, esters and amides. This is the first example on the use of 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones as substrates in an enantioselective reaction, which have been shown to be new ester/amide surrogates. PMID- 24339327 TI - Study on the binding of chlorogenic acid to pepsin by spectral and molecular docking. AB - The interaction of pepsin with chlorogenic acid (CHA) was investigated using fluorescence, UV/vis spectroscopy and molecular modeling methods. Stern-Volmer analysis indicated that the fluorescence quenching of pepsin by CHA resulted from a static mechanism, and the binding constant was 1.1846 * 10(5) and 1.1587 * 10(5) L/mol at 288 and 310 K, respectively. The distance between donor (pepsin) and acceptor (CHA) was calculated to be 2.39 nm and the number of binding sites for CHA binding on pepsin was ~ 1. The results of synchronous fluorescence and three-dimensional fluorescence showed that binding of CHA to pepsin could induce conformational changes in pepsin. Molecular docking experiments found that CHA bonded with pepsin in the area of the hydrophobic cavity with Van der Waals' forces or hydrogen bonding interaction, which were consistent with the results obtained from the thermodynamic parameter analysis. Furthermore, the binding of CHA can inhibit pepsin activity in vitro. PMID- 24339328 TI - Sb(2)Se(3) -sensitized inorganic-organic heterojunction solar cells fabricated using a single-source precursor. AB - The photovoltaic performance of Sb2 Se3 -sensitized heterojunction solar cells, which were fabricated by a simple deposition of Sb2 Se3 on mesoporous TiO2 by an approach that features multiple cycles of spin coating with a single-source precursor solution and thermal decomposition, is reported. Poly[2,6-(4,4-bis(2 ethylhexyl)-4H-cyclopenta[2,1-b;3,4-b']dithiophene)-alt-4,7(2,1,3 benzothioadiazole)] was used as the hole-transporting material. The most efficient cell exhibited a short-circuit current density of 22.3 mA cm(-2) , an open-circuit voltage of 304.5 mV, and a fill factor of 47.2 %, yielding a power conversion efficiency of 3.21 % under standard test conditions (irradiation of 1000 W m(-2) , air mass=1.5 G). The results of this study imply that the developed approach has a high potential as a simple and effective route for the fabrication of efficient and inexpensive solar cells. PMID- 24339330 TI - Hybrid helical magnetic microrobots obtained by 3D template-assisted electrodeposition. AB - Hybrid helical magnetic microrobots are achieved by sequential electrodeposition of a CoNi alloy and PPy inside a photoresist template patterned by 3D laser lithography. A controlled actuation of the microrobots by a rotating magnetic field is demonstrated in a fluidic environment. PMID- 24339329 TI - A prospective study of cognitive function in men with non-seminomatous germ cell tumors. AB - OBJECTIVE: Longitudinal neuropsychological assessments were performed to determine if adjuvant chemotherapy was associated with cognitive dysfunction in men with non-seminomatous germ cell tumors (NSGCT). METHODS: Patients with NSGCT status post-orchiectomy that either received adjuvant chemotherapy (n = 55) or did not (n = 14) were recruited. Patients were tested before chemotherapy, 1 week post-chemotherapy (or 3 months later in the surveillance group) and 12 months after the baseline evaluation. RESULTS: Compared with the surveillance group, patients treated with chemotherapy had higher rates of cognitive decline at 12 months (overall cognitive decline: 0%, 52%, and 67% in the surveillance, low exposure (LE), and high exposure (HE) group, respectively), greater number of tests that declined (mean of 0.1, 1.4, and 2.0 in the surveillance, LE, and HE group, respectively), and more frequent worsening in motor dexterity (0%, 48%, and 46% in the surveillance, LE, and HE group, respectively). Compared with the surveillance group, patients receiving more cycles of chemotherapy demonstrated worse psychomotor speed and learning and memory. Younger age was associated with greater incidence of overall cognitive decline at 12-month follow-up. CONCLUSIONS: Men with NSGCT that received chemotherapy demonstrated greater rates of cognitive decline in a dose-response manner. Reductions in motor dexterity were most common. Decline in learning and memory also was evident particularly at later follow-up time points and in men receiving more chemotherapy. Men that receive chemotherapy for NSGCT are at risk for cognitive decline and may benefit from monitoring and referral for psychosocial care. PMID- 24339331 TI - Introduction to Special Issue: A Review of the International Classification of Functioning, Disability and Health and Physical Therapy over the Years. AB - BACKGROUND AND PURPOSE: The International Classification of Functioning, Disability and Health (ICF) of the World Health Organization was developed as a common framework to understand health and to describe the impact of health condition on functioning. The purpose of this paper is to summarize the literature on the use of the ICF in physical therapy practice and research. METHODS: We performed a scoping-narrative review and searched for relevant English language articles from 2001 to 2012 in multiple databases that included MEDLINE, PsycINFO, PubMed and Physiotherapy Evidence Database. Our keywords for the search consisted of ['physical therapy' OR 'physiotherapy'] AND ['ICF']. All types of articles were considered. RESULTS: We found 268 articles; out of which, 79 were reviewed. The years with most publications were 2011 (n = 16), 2008 (n = 15) and 2010 and 2012 (both with n = 13). Publications mostly came from the United States with 27% of the articles. The journal Physical Therapy leads with almost a third of ICF-related physical therapy publications. The ICF has been mostly used in studies of musculoskeletal and neuromuscular conditions. We found a wide array of application of the ICF in research, clinical practice and teaching (classroom and clinical education). Emerging topics included using the ICF in resource allocation and prevention and wellness. CONCLUSION: The use of the ICF in physical therapy practice and research is promising and continues to evolve. With recent developments in ICF-based measurement and integration in assessment tools for use in the clinics, research and teaching, the need to show the added value of using the ICF in practice and research remains. PMID- 24339332 TI - Clinical predictors in chronic articular adult-onset Still's disease: comment on the article by Ichida et al. PMID- 24339333 TI - Phenotype of mice with inducible ablation of GluA1 AMPA receptors during late adolescence: relevance for mental disorders. AB - Adolescence is characterized by important molecular and anatomical changes with relevance for the maturation of brain circuitry and cognitive function. This time period is of critical importance in the emergence of several neuropsychiatric disorders accompanied by cognitive impairment, such as affective disorders and schizophrenia. The molecular mechanisms underlying these changes at neuronal level during this specific developmental stage remains however poorly understood. GluA1-containing AMPA receptors, which are located predominantly on hippocampal neurons, are the primary molecular determinants of synaptic plasticity. We investigated here the consequences of the inducible deletion of GluA1 AMPA receptors in glutamatergic neurons during late adolescence. We generated mutant mice with a tamoxifen-inducible deletion of GluA1 under the control of the CamKII promoter for temporally and spatially restricted gene manipulation. GluA1 ablation during late adolescence induced cognitive impairments, but also marked hyperlocomotion and sensorimotor gating deficits. Unlike the global genetic deletion of GluA1, inducible GluA1 ablation during late adolescence resulted in normal sociability. Deletion of GluA1 induced redistribution of GluA2 subunits, suggesting AMPA receptor trafficking deficits. Mutant animals showed increased hippocampal NMDA receptor expression and no change in striatal dopamine concentration. Our data provide new insight into the role of deficient AMPA receptors specifically during late adolescence in inducing several cognitive and behavioral alterations with possible relevance for neuropsychiatric disorders. PMID- 24339334 TI - Enantiomeric distribution of major chiral volatile organic compounds in juniper flavored distillates. AB - The enantiomeric ratios of chiral volatile organic compounds in juniper-flavored spirits produced by various processing technologies in different EU countries were determined by multidimensional GC using solid-phase microextraction and liquid-liquid extraction as a sample pretreatment procedure. In total, more than 260 compounds were detected in studied spirits from which linalool, alpha terpineol, 4-terpineol, linalool oxides, alpha-pinene, and verbenone were selected for enantiomeric separation. The significant differences in enantiomeric ratio of linalool and cis-linalool oxide allowed us to distinguish between samples produced in Slovakia and the United Kingdom from those produced in Germany, Czech Republic, and Belgium. The pure enantiomer of trans-linalool oxide was found only in samples from Germany. It was shown that the enantiomeric ratio is independent of the sample treatment procedure, and only small differences up to 1% were observed. PMID- 24339335 TI - Case Study Interpretation-Fort Lauderdale: Case 3. PMID- 24339337 TI - Ti-catalyzed straightforward synthesis of exocyclic allenes. AB - Exocyclic allenes constitute useful building blocks in organic synthesis and have recently been identified as key intermediates in the synthesis of natural products. Here the first general method for the most straightforward synthesis of exocyclic allenes reported to date is presented. This method is based on the Barbier-type cyclization of propargyl halides catalyzed by titanium; a safe, abundant, and ecofriendly metal. The reaction proceeds under mild conditions compatible with different functional groups and provides good yields of five-, six-, and seven-membered carbocycles and nitrogen-containing heterocycles bearing an exocyclic allene group. Experimental evidence supporting the proposed reaction mechanism is also provided. Moreover, this procedure can be carried out in an enantioselective manner by using chiral titanocene(III) catalysts. The utility of this method has been proved in the synthesis of the natural alkaloid stemoamide. PMID- 24339336 TI - Modulation of CD14 and TLR4.MD-2 activities by a synthetic lipid A mimetic. AB - Monosaccharide lipid A mimetics based on a glucosamine core linked to two fatty acid chains and bearing one or two phosphate groups have been synthesized. Compounds 1 and 2, each with one phosphate group, were practically inactive in inhibiting LPS-induced TLR4 signaling and cytokine production in HEK-blue cells and murine macrophages, but compound 3, with two phosphate groups, was found to be active in efficiently inhibiting TLR4 signal in both cell types. The direct interaction between compound 3 and the MD-2 coreceptor was investigated by NMR spectroscopy and molecular modeling/docking analysis. This compound also interacts directly with the CD14 receptor, stimulating its internalization by endocytosis. Experiments on macrophages show that the effect on CD14 reinforces the activity on MD-2.TLR4 because compound 3's activity is higher when CD14 is important for TLR4 signaling (i.e., at low LPS concentration). The dual targeting of MD-2 and CD14, accompanied by good solubility in water and lack of toxicity, suggests the use of monosaccharide 3 as a lead compound for the development of drugs directed against TLR4-related syndromes. PMID- 24339338 TI - Comparison of sexual compatibility in crosses between the southern and northern populations of the cabbage beetle Colaphellus bowringi. AB - It is widely accepted that the genetic divergence and reproductive incompatibility between closely related species and/or populations is often viewed as an important step toward speciation. In this study, sexual compatibility in crosses between the southern XS population and the northern TA population of the polyandrous cabbage beetle Colaphellus bowringi was investigated by testing their mating preferences, mating latency, copulation duration, and reproductive performances of post-mating. In choice mating experiments, the percentages of matings were significantly higher in intra population crosses than in inter-population crosses. Both isolation index (I) and index of pair sexual isolation (IPSI ) indicated partial mating incompatibility or assortative mating in crosses between the two different geographical populations. In single pair mating experiments, XS females in inter-population crosses mated significantly later and copulated significantly shorter than those in intra-population crosses. However, TA females in inter-population crosses mated significantly earlier and copulated longer than those in intra-population crosses, suggesting that larger XS males may enhance heterotypic mating. The lifetime fecundity was highest in XS homotypic matings, lowest in TA homotypic matings, and intermediate in heterotypic matings between their parents. The inter population crosses resulted in significantly lower egg hatching rate and shorter female longevity than intra-population crosses. These results demonstrated that there exist some incompatibilities in premating, postmating-prezygotic, and postzygotic stages between the southern XS population and northern TA population of the cabbage beetle Colaphellus bowringi. PMID- 24339340 TI - Gold nanoparticles embedded within mesoporous cobalt oxide enhance electrochemical oxygen evolution. AB - Gold nanoparticles incorporated in mesoporous cobalt oxides (Au/mCo3 O4 ) are fabricated by a nanocasting method using porous silica as the hard template. The Au/mCo3 O4 material exhibits enhanced catalytic activity towards water oxidation compared to bulk mCo3 O4 in both alkaline and neutral solutions. The superior catalytic performance is ascribed to the synergistic effect of electronegative metal gold, which facilitates the generation of active Co(IV) sites, as well as the large specific surface area and the preferential exposure of catalytic active crystalline lattice. PMID- 24339339 TI - Gut permeability in autism spectrum disorders. AB - OBJECTIVE: To test whether gut permeability is increased in autism spectrum disorders (ASD) by evaluating gut permeability in a population-derived cohort of children with ASD compared with age- and intelligence quotient-matched controls without ASD but with special educational needs (SEN). PATIENTS AND METHODS: One hundred thirty-three children aged 10-14 years, 103 with ASD and 30 with SEN, were given an oral test dose of mannitol and lactulose and urine collected for 6 hr. Gut permeability was assessed by measuring the urine lactulose/mannitol (L/M) recovery ratio by electrospray mass spectrometry-mass spectrometry. The ASD group was subcategorized for comparison into those without (n = 83) and with (n = 20) regression. RESULTS: There was no significant difference in L/M recovery ratio (mean (95% confidence interval)) between the groups with ASD: 0.015 (0.013 0.018), and SEN: 0.014 (0.009-0.019), nor in lactulose, mannitol, or creatinine recovery. No significant differences were observed in any parameter for the regressed versus non-regressed ASD groups. Results were consistent with previously published normal ranges. Eleven children (9/103 = 8.7% ASD and 2/30 = 6.7% SEN) had L/M recovery ratio > 0.03 (the accepted normal range cut-off), of whom two (one ASD and one SEN) had more definitely pathological L/M recovery ratios > 0.04. CONCLUSION: There is no statistically significant group difference in small intestine permeability in a population cohort-derived group of children with ASD compared with a control group with SEN. Of the two children (one ASD and one SEN) with an L/M recovery ratio of > 0.04, one had undiagnosed asymptomatic celiac disease (ASD) and the other (SEN) past extensive surgery for gastroschisis. PMID- 24339341 TI - Combined inhibitor free-energy landscape and structural analysis reports on the mannosidase conformational coordinate. AB - Mannosidases catalyze the hydrolysis of a diverse range of polysaccharides and glycoconjugates, and the various sequence-based mannosidase families have evolved ingenious strategies to overcome the stereoelectronic challenges of mannoside chemistry. Using a combination of computational chemistry, inhibitor design and synthesis, and X-ray crystallography of inhibitor/enzyme complexes, it is demonstrated that mannoimidazole-type inhibitors are energetically poised to report faithfully on mannosidase transition-state conformation, and provide direct evidence for the conformational itinerary used by diverse mannosidases, including beta-mannanases from families GH26 and GH113. Isofagomine-type inhibitors are poor mimics of transition-state conformation, owing to the high energy barriers that must be crossed to attain mechanistically relevant conformations, however, these sugar-shaped heterocycles allow the acquisition of ternary complexes that span the active site, thus providing valuable insight into active-site residues involved in substrate recognition. PMID- 24339342 TI - Induction of the ganglion cell differentiation program in human retinal progenitors before cell cycle exit. AB - BACKGROUND: Despite the disease relevance, understanding of human retinal development lags behind that of other species. We compared the kinetics of gene silencing or induction during ganglion cell development in human and murine retina. RESULTS: Induction of POU4F2 (BRN3B) marks ganglion cell commitment, and we detected this factor in S-phase progenitors that had already silenced Cyclin D1 and VSX2 (CHX10). This feature was conserved in human and mouse retina, and the fraction of Pou4f2+ murine progenitors labeled with a 30 min pulse of BrdU matched the fraction of ganglion cells predicted to be born in a half-hour period. Additional analysis of 18 markers revealed many with conserved kinetics, such as the POU4F2 pattern above, as well as the surprising maintenance of "cell cycle" proteins KI67, PCNA, and MCM6 well after terminal mitosis. However, four proteins (TUBB3, MTAP1B, UCHL1, and RBFOX3) showed considerably delayed induction in human relative to mouse retina, and two proteins (ISL1, CALB2) showed opposite kinetics, appearing on either side of terminal mitosis depending on the species. CONCLUSION: With some notable exceptions, human and murine ganglion cell differentiation show similar kinetics, and the data add weight to prior studies supporting the existence of biased ganglion cell progenitors. PMID- 24339343 TI - Which inorganic structures are the most complex? AB - The discovery of the diffraction of X-rays on crystals opened up a new era in our understanding of nature, leading to a multitude of striking discoveries about the structures and functions of matter on the atomic and molecular scales. Over the last hundred years, about 150,000 of inorganic crystal structures have been elucidated and visualized. The advent of new technologies, such as area detectors and synchrotron radiation, led to the solution of structures of unprecedented complexity. However, the very notion of structural complexity of crystals still lacks an unambiguous quantitative definition. In this Minireview we use information theory to characterize complexity of inorganic structures in terms of their information content. PMID- 24339344 TI - Primary Sjogren's syndrome: fatigue is an ever-present, fluctuating, and uncontrollable lack of energy. AB - OBJECTIVE: To examine how fatigue may differ from ordinary tiredness in patients with primary Sjogren's syndrome (SS). METHODS: A purposive, heterogeneous sample of individuals with primary SS who had participated in a study that examined the effects of medication on fatigue was asked to participate in individual interviews. Patients were asked about their fatigue before and after the onset of illness, changes due to medications, and how fatigue was experienced in daily life. An inductive thematic analysis founded on a social constructionist perspective was performed. RESULTS: Five women and 4 men ages 27-76 years participated. Two themes were identified. "A heavy, resistant body and ever present lack of vitality" represented a profound, ever-present lack of energy along with an unfamiliar bodily heaviness quite different from the experience after alleviation by the drug and being healthy. The patients had scaled down their everyday life in different ways to manage this lack of energy. "Unpredictable and uncontrollable fluctuations in fatigue" expressed how the level of fatigue fluctuated from day to day and even within a particular day. The informants tried to portion out their energy without knowing exactly how much energy they would have at any time. On bad days, patients felt that their "batteries were flat," and they had to put their life on hold. CONCLUSION: Fatigue in primary SS clearly differs from ordinary tiredness. Patients describe it as an ever-present, fluctuating, and nonrelievable lack of vitality being beyond one's own control. PMID- 24339345 TI - The role of etching in the formation of Ag nanoplates with straight, curved and wavy edges and comparison of their SERS properties. AB - We investigate the role of etching in the formation of Ag nanoplates with different morphologies. By examining the reduction of AgNO3 with poly(vinyl pyrrolidone) in an aqueous solution under a hydrothermal condition, we confirm that etching plays an essential role in promoting the growth of Ag triangular nanoplates with straight edges at the expense of multiple twinned particles via Ostwald ripening. Once all the multiple twinned particles are gone, etching will continue at the corners of nanoplates, leading to the formation of enneahedral nanoplates with curved edges. When the nanoplates with straight edges are transferred into ethanol and subjected to a solvothermal treatment, we obtain nanoplates with wavy edges and sharp corners due to etching on the edges. A comparison study indicates that, at the same particle concentration, Ag nanoplates with wavy edges embraces a SERS enhancement factor at least 6 and 13 times stronger than those with straight and curved edges, respectively. The results from finite difference time domain calculations support our experimental observation that the sharp features on nanoplates with wavy edges are the most active sites for SERS. PMID- 24339347 TI - Case Study Interpretation - Fort Lauderdale: Case 4. PMID- 24339346 TI - Switching of EBV cycles between latent and lytic states. AB - The EBV is a human gamma-herpesvirus that is associated with a variety of neoplasms. Upon primary infection, it transiently runs a short lytic program and then predominantly establishes latent infection. Only a small percentage of infected cells switch from the latent stage into the lytic cycle and produce progeny viruses. Although EBV in cancer cells is mostly in the latent state, the lytic cycle of the virus is also expected to play a pivotal role in development and maintenance of tumors because of its association with secretion of cytokines or growth factors. Moreover, if efficient artificial induction of lytic replication could somehow be achieved, development of oncolytic therapy for EBV positive cancers would be conceivable. Thus, understanding the switching mechanism is of essential importance. Reactivation of the virus from latency is dependent on expression of the viral BZLF1 protein. The BZLF1 promoter (Zp) normally exhibits only low basal activity but is activated in response to chemical or biological inducers, such as 12-O-tetradecanoylphorbol-13-acetate, calcium ionophore, or histone deacetylase inhibitors. Transcription from the Zp is regulated by the balance between active and suppressive epigenetic histone marks, including histone acetylation, histone H3 Lysine 4 trimethylation and histone H3 lysine 27 trimethylation, being mediated by multiple transcription factors, such as myocyte enhancer factor 2, specificity protein 1, and zinc finger E-box binding homeobox. This review will focus on such molecular mechanisms by which the EBV lytic switch is controlled and discuss the physiological significance of the switching for oncogenesis. PMID- 24339348 TI - Culturable aerobic and facultative bacteria from the gut of the polyphagic dung beetle Thorectes lusitanicus. AB - Unlike other dung beetles, the Iberian geotrupid, Thorectes lusitanicus, exhibits polyphagous behavior; for example, it is able to eat acorns, fungi, fruits, and carrion in addition to the dung of different mammals. This adaptation to digest a wider diet has physiological and developmental advantages and requires key changes in the composition and diversity of the beetle's gut microbiota. In this study, we isolated aerobic, facultative anaerobic, and aerotolerant microbiota amenable to grow in culture from the gut contents of T. lusitanicus and resolved isolate identity to the species level by sequencing 16S rRNA gene fragments. Using BLAST similarity searches and maximum likelihood phylogenetic analyses, we were able to reveal that the analyzed fraction (culturable, aerobic, facultative anaerobic, and aerotolerant) of beetle gut microbiota is dominated by the phyla Proteobacteria, Firmicutes, and Actinobacteria. Among Proteobacteria, members of the order Enterobacteriales (Gammaproteobacteria) were the most abundant. The main functions associated with the bacteria found in the gut of T. lusitanicus would likely include nitrogen fixation, denitrification, detoxification, and diverse defensive roles against pathogens. PMID- 24339349 TI - Achieving a rare breathing behavior in a polycatenated 2D to 3D net through a pillar-ligand extension strategy. AB - Through a pillar-ligand extension strategy, a rare breathing behavior in polycatenated 2D->3D nets has been achieved. Three variants exhibit interesting sorption properties that range from non-breathing to breathing behaviors, which is influenced by the angles between the pillars and the single honeycomb layers. The increase in pillar length does not lead to an increase in polycatenation multiplicity, which is controlled by the length of intralayer tripodal carboxylate. It also does not induce obviously expanded interlayer separations but occupies much more the free voids, and as a consequence, a smaller pore volume is obtained. This suggests that in 2D->3D polycatenated bilayer metal organic frameworks, the porosity is not always enhanced by increasing the length of the interlayer pillars with the intralayer linker remaining unchanged. PMID- 24339350 TI - Ionic liquid with a dual-redox couple for efficient dye-sensitized solar cells. AB - A new type of ionic liquid that contains a nitroxide radical (N-O(.)) and iodide as two redox couples, JC-IL, has been successfully synthesized for high performance dye-sensitized solar cells (DSSCs). Both of the redox couples exhibit distinct redox potentials and attractive electrochemical characteristics. The UV/Vis absorption spectra of JC-IL shows a low-intensity peak compared to the strong absorption of I2 in the wavelength region of 350-500 nm. The high open circuit voltage of DSSCs with JC-IL is over 850 mV, which is approximately 150 mV higher than that of the DSSCs with a standard iodide electrolyte. The dramatic increase in the standard heterogeneous electron-transfer rate constant leads to an increase in the short-circuit current for JC-IL compared to that of 2,2,6,6 tetramethylpiperidin-N-oxyl (TEMPO). DSSCs with the JC-IL electrolyte show promising cell efficiencies if coupled with dyes CR147 (8.12%) or D149 (6.76%). The efficiencies of the DSSCs based on the JC-IL electrolyte are higher than those of DSSCs based on either TEMPO electrolyte or standard iodide electrolyte alone. PMID- 24339351 TI - Comparison of four cholesterol-based stationary phases for the separation of steroid hormones. AB - The chromatographic behavior of steroid hormones on four cholesterol-bonded stationary phases with different structures in binary methanol/water mobile phases was studied. Of the stationary phases tested, the commercially available stationary phases Cogent UDC cholesterolTM and COSMOSIL cholesterTM provided better separations of steroid hormones in comparison to homemade aminocholesterol and diaminocholesterol stationary phases. The results show that the temperature has a significant influence on the retention and selectivity for steroid hormones separation. The temperature increase may cause changes in the elution order. From the dependences of the retention (ln k) on temperature (1/T), the standard partial molar enthalpy and standard partial molar entropy were calculated and their enthalpic and entropic contributions to the retention were compared. The enthalpic effects principally control the retention mechanism. PMID- 24339352 TI - Sociodemographic, disease, health system, and contextual factors affecting the initiation of biologic agents in rheumatoid arthritis: a longitudinal study. AB - OBJECTIVE: To analyze the effect of sociodemographic, disease, and health system characteristics and contextual features about the community of residence on the subsequent initiation of treatment with biologic agents for rheumatoid arthritis (RA). METHODS: We analyzed data from the University of California, San Francisco Rheumatoid Arthritis Panel Study for the years 1999-2011. Principal data collection was by a structured annual phone survey. We estimated Kaplan-Meier curves of the time until initiation of biologic agents, stratified by age and income. We also used Cox regression to estimate the effect of individual-level sociodemographic and medical factors, contextual-level socioeconomic status measures, and density of health providers in the local community on the probability of initiating therapy with biologic agents for RA. RESULTS: In total, 527 persons were included in the panel in 1999, and 229 persons (44%) had initiated therapy with biologic agents by 2011. In multivariable Cox regression models, age <70 years (hazard ratio [HR] for ages 19-54 years 1.89 [95% confidence interval (95% CI) 1.24-2.87] and HR for ages 55-69 years 1.25 [95% CI 0.84-1.87]), Hispanic ethnicity (HR 2.02 [95% CI 1.05-3.86]), household income >=$30,000/year (HR 1.61 [95% CI 1.12-2.32]), being married or with a partner (HR 1.39 [95% CI 1.00-1.92]), and residence in rural environments (HR 1.96 [95% CI 1.28-2.99]) were associated with a higher probability of initiating biologic agents. Having no (HR 0.18 [95% CI 0.08-0.40]) or only 1-4 rheumatology visits in the year prior to interview (HR 0.60 [95% CI 0.45-0.81]) and living in an area with >=1 federally qualified health centers (HR 0.63 [95% CI 0.41-0.96]) were associated with a lower probability. CONCLUSION: The probability of initiating therapy with biologic agents is affected by sociodemographic and health system characteristics as well as the nature of the community of residence, resulting in disparities in access to these medications. PMID- 24339353 TI - Bio-based aliphatic polyurethanes through ADMET polymerization in bulk and green solvent. AB - A new route to alpha,omega-diene urethane monomer is proposed by converting 10 undecenoic acid into the corresponding acyl azide, followed by urethanization with 10-undecenol. ADMET polymerizations of this alpha,omega-diene urethane monomer as well as other bio-based alpha,omega-dienes bearing various organic functions (ester, carbonate, ether, amide) were carried out in bulk and solution conditions. A screening of the most commonly used metathesis catalysts allows to evaluate their tolerance toward the urethane function as well as toward Polarclean, a "green" and nontoxic high boiling point solvent. The influence of the nature of the central organic function in these alpha,omega-diene monomers on the thermomechanical properties is investigated. PMID- 24339354 TI - A differential fluorescent receptor for nucleic acid analysis. AB - Differential receptors use an array of sensors to recognize analytes. Each sensor in the array can recognize not one, but several analytes with different rates, so a single analyte triggers a response of several sensors in the array. The receptor thus produces a pattern of signals that is unique for each analyte, thereby enabling identification of a specific analyte by producing a "fingerprint" pattern. We applied this approach for the analysis of DNA sequences of Mycobacterium tuberculosis strains that differ by single nucleotide substitutions in the 81-bp hot-spot region that imparts rifampin resistance. The technology takes advantage of the new multicomponent, selfassembling sensor, which produces a fluorescent signal in the presence of specific DNA sequences. A differential fluorescent receptor (DFR) contained an array of three such sensors and differentiated at least eight DNA sequences. The approach requires only one molecular-beacon-like fluorescent reporter, which can be used by all three sensors. The DFR developed in this study represents a cost-efficient alternative to molecular diagnostic technologies that use fluorescent hybridization probes. PMID- 24339355 TI - Quantification of mineral oil accumulation and movement in potato plants and its significance in potato virus Y management. AB - BACKGROUND: Mineral oils are increasingly sprayed to manage potato virus Y (PVY). However, the mode of accumulation and movement of mineral oil in the potato plant has not been understood. This information is important for optimisation of the concentration and frequency of spraying. During the 2012 season, cvs Russet Burbank and Shepody were planted in the field and in the greenhouse, respectively, and were subjected to mineral oil treatments. The plant samples from the treatment plots were collected, and oil was extracted and quantified using gas chromatography-mass spectrometry. RESULTS: Mineral oil stayed in the vicinity of the sprayed leaves and did not move from leaflet to leaflet or from leaflet to stem, stolon, tuber or root. Following spraying, the oil content in the plant leaves diluted as time progressed. At plant maturity, leaves sampled from the greenhouse sprayed plants had about 4 times more oil content than those sampled from the field sprayed plants. Plots treated with regular spray of mineral oil showed low PVY incidences at crop harvest. CONCLUSION: The information generated in this study on the pattern of accumulation and movement of mineral oil in greenhouse- and field-grown potato plants shows that, as the oil does not move from leaflet to leaflet, frequent mineral oil sprays from crop emergence to harvest are required to prevent PVY infection in newly emerged leaflets and seasonal spread of PVY. The frequency of sprays may be kept higher from early to mid-stage, when plant growth is faster, and lower close to plant maturity. PMID- 24339359 TI - Oxygen electrochemistry as a cornerstone for sustainable energy conversion. AB - Electrochemistry will play a vital role in creating sustainable energy solutions in the future, particularly for the conversion and storage of electrical into chemical energy in electrolysis cells, and the reverse conversion and utilization of the stored energy in galvanic cells. The common challenge in both processes is the development of-preferably abundant-nanostructured materials that can catalyze the electrochemical reactions of interest with a high rate over a sufficiently long period of time. An overall understanding of the related processes and mechanisms occurring under the operation conditions is a necessity for the rational design of materials that meet these requirements. A promising strategy to develop such an understanding is the investigation of the impact of material properties on reaction activity/selectivity and on catalyst stability under the conditions of operation, as well as the application of complementary in situ techniques for the investigation of catalyst structure and composition. PMID- 24339357 TI - Diamagnetic chemical exchange saturation transfer (diaCEST) liposomes: physicochemical properties and imaging applications. AB - Chemical exchange saturation transfer (CEST) is a new type of magnetic resonance imaging (MRI) contrast based on labile spins which rapidly exchange with solvent, resulting in an amplification of signal which allows detection of solute protons at millimolar to micromolar concentrations. An additional feature of these agents is that natural organic and biodegradable compounds can provide strong CEST contrast, allowing the development of diamagnetic CEST (diaCEST) MRI contrast agents. The sensitivity of the CEST approach per unit of agent increases further when diaCEST contrast agents are loaded into liposomes to become diaCEST liposomes. In this review, we will discuss the unique and favorable features of diaCEST liposomes which are well suited for in vivo imaging. diaCEST liposomes are nanocarriers which feature high concentrations of encapsulated contrast material, controlled release of payload, and an adjustable coating for passive or active tumor targeting. These liposomes have water permeable bilayers and both the interior and exterior can be fine-tuned for many biomedical applications. Furthermore, a number of liposome formulations are used in the clinic including DoxilTM, which is an approved product for treating patients with cancer for decades, rapid translation of these materials can be envisaged. diaCEST liposomes have shown promise in imaging of cancer, and monitoring of chemotherapy and cell transplants. The unique features of diaCEST liposomes are discussed to provide an overview of the applications currently envisioned for this new technology and to provide an overall insight of their potential. PMID- 24339360 TI - Au-thiol interaction chemistry to influence the structural transformation of semiconductor nanocrystals and formation of giant nanostructures. AB - Giant nanostructures which are difficult to design by the classical growth process can be fabricated in a facilitated and well programmed surface ligand removal protocol employing the thiol-gold strong interaction chemistry. When thiol capped small ZnSe seed nanocrystals are treated with amine capped gold particles, gold snatches the thiol ligands from ZnSe and forces them to agglomerate leading to the giant crystalline ZnSe nanostructures. PMID- 24339361 TI - Primary Sjogren's syndrome: diagnostic and prognostic value of salivary gland ultrasonography using a simplified scoring system. AB - OBJECTIVE: To determine the usefulness and prognostic value of a simplified salivary gland ultrasonography (SGUS) scoring system in primary Sjogren's syndrome (SS). METHODS: Patients with primary SS (n = 105) and controls (n = 57) were evaluated using a simplified SGUS scoring system. Parenchymal homogeneity in salivary glands was graded from 0 to 3, with grades 0 (normal) and 1 (mild inhomogeneity) being interpreted as normal or unspecific, and grades 2 (several rounded) and 3 (numerous or confluent hypoechoic lesions) as primary SS typical. Associations between SGUS and clinical, histologic, and laboratory disease characteristics were analyzed. RESULTS: The characteristic hypoechoic lesions (score 2 or 3) were found in 52% of primary SS patients and in 1 (1.8%) of controls (P < 0.001). Specificity and positive predictive value of abnormal SGUS for primary SS were both 98%, sensitivity and negative predictive values were 52% and 53%, respectively. Age or disease duration did not influence the SGUS result. Dryness did not differ between normal or abnormal SGUS. However, patients with pathologic SGUS had significantly more often signs and symptoms of systemic complications, higher disease activity, and more frequently markers of lymphoma development, such as salivary gland swelling, skin vasculitis, germinal center like structures in salivary gland biopsy findings, and CD4+ T cell lymphopenia. CONCLUSION: SGUS using a simplified score for assessment of parenchyma dyshomogeneity is highly specific for primary SS and offers the advantage of identifying patients with severe disease or at risk of lymphoma. However, early disease may be missed. SGUS is easy and rapidly performed and may be considered as an item in future modified classification criteria. PMID- 24339356 TI - Assessing the barriers to image-guided drug delivery. AB - Imaging has become a cornerstone for medical diagnosis and the guidance of patient management. A new field called image-guided drug delivery (IGDD) now combines the vast potential of the radiological sciences with the delivery of treatment and promises to fulfill the vision of personalized medicine. Whether imaging is used to deliver focused energy to drug-laden particles for enhanced, local drug release around tumors, or it is invoked in the context of nanoparticle based agents to quantify distinctive biomarkers that could risk stratify patients for improved targeted drug delivery efficiency, the overarching goal of IGDD is to use imaging to maximize effective therapy in diseased tissues and to minimize systemic drug exposure in order to reduce toxicities. Over the last several years, innumerable reports and reviews covering the gamut of IGDD technologies have been published, but inadequate attention has been directed toward identifying and addressing the barriers limiting clinical translation. In this consensus opinion, the opportunities and challenges impacting the clinical realization of IGDD-based personalized medicine were discussed as a panel and recommendations were proffered to accelerate the field forward. PMID- 24339362 TI - Single-molecule sensing of environmental pH--an STM break junction and NEGF-DFT approach. AB - Sensors play a significant role in the detection of toxic species and explosives, and in the remote control of chemical processes. In this work, we report a single molecule-based pH switch/sensor that exploits the sensitivity of dye molecules to environmental pH to build metal-molecule-metal (m-M-m) devices using the scanning tunneling microscopy (STM) break junction technique. Dyes undergo pH-induced electronic modulation due to reversible structural transformation between a conjugated and a nonconjugated form, resulting in a change in the HOMO-LUMO gap. The dye-mediated m-M-m devices react to environmental pH with a high on/off ratio (~100:1) of device conductivity. Density functional theory (DFT) calculations, carried out under the non-equilibrium Green's function (NEGF) framework, model charge transport through these molecules in the two possible forms and confirm that the HOMO-LUMO gap of dyes is nearly twice as large in the nonconjugated form as in the conjugated form. PMID- 24339363 TI - Application of DNA barcoding to the identification of Hymenoptera parasitoids from the soybean aphid (Aphis glycines) in China. AB - Aphis glycines Matsumura is an important pest of soybean in Asia and North America. Hymenoptera parasitoids play a key role in the control of the soybean aphid. The correct identification of parasitoids is a critical step that precedes the assessment of their potential biological control agents. Accurate identification of the majority of the species attacking the soybean aphid often requires elaborate specimen preparation and expert taxonomic knowledge. In this study, we facilitated the identification of soybean aphid parasitoids by applying a DNA barcoding approach following a preliminary morphological identification. We generated DNA sequence data from the mitochondrial COI gene and the D2 region of 28S rDNA to assess the genetic variation within and between parasitoid species emerging from the soybean aphid in China. Fifteen Hymenoptera parasitoid species belonging to 10 genera of five families were identified with little intra specific variation (0.09% +/- 0.06% for 28S and 0.36% +/- 0.18% for COI) and large inter-specific divergence (30.46% +/- 3.42% for 28S and 20.4% +/- 1.20% for COI). PMID- 24339364 TI - Pancreaticogastrostomy following distal pancreatectomy prevents pancreatic fistula-related complications. AB - BACKGROUND: The most common postoperative complication after distal pancreatectomy (DP) is still postoperative pancreatic fistula (POPF), which is closely associated with other major complications and remains an unsolved problem. METHODS: This retrospective study included 47 consecutive patients who underwent a distal pancreatectomy with (DP-PG group, n = 21) or without (DP group, n = 26) duct-to-mucosa pancreaticogastrostomy from June 2010 to May 2012. Clinical data including POPF-related complications (POPF, fluid collection, intra abdominal abscess, bleeding and delayed gastric emptying) as a primary endpoint were compared between the two groups. RESULTS: The frequencies of POPF-related complications as well as overall POPF and complications in the DP-PG group were lower than in the DP group (P = 0.037, P < 0.001, respectively). The 30 days morbidity after hospital discharge in the DP-PG group was less than in the DP group (P = 0.014). In both groups median hospital stay was similar. Although additional time needed for pancreaticogastrostomy was 35 (20-55) min, there was no difference in operative times. Patients in the DP group had a higher medical cost for hospitalization than the DP-PG group (P = 0.048). CONCLUSION: Pancreaticogastrostomy as an additional procedure following distal pancreatectomy was associated with a reduced rate of POPF-related complications that resulted in relatively lower medical cost for hospitalization. PMID- 24339365 TI - Hepatic steatosis: effect on hepatocyte enhancement with gadoxetate disodium enhanced liver MR imaging. AB - PURPOSE: To investigate the effect of hepatic steatosis on enhancement of liver parenchyma with gadoxetate disodium-enhanced MR imaging. MATERIALS AND METHODS: Gadoxetate disodium-enhanced MR images of 166 patients were analyzed. Liver spleen contrast and liver-spleen relative enhancement ratio on three-dimensional gradient echo T1-weighted images with fat suppression 20 minutes after injection of gadoxetate disodium were evaluated in correlation with fat signal fraction using the Pearson correlation coefficient and also compared between patients with normal liver parenchyma (n = 115) and with liver steatosis (n = 51) using the Student t-test. RESULTS: The liver-spleen contrast at hepatobiliary phase showed inverse correlations with the fat signal fraction (r = -0.36; P < 0.01), while the liver-spleen relative enhancement ratio showed no statistical correlation with the fat signal fraction (P = 0.80). The liver-spleen contrast in the group with steatotic liver was significantly lower than that in the group with normal livers (P < 0.001). There was no significant difference in the relative enhancement ratio between the two groups (P = 0.85). CONCLUSION: Our results may suggest that hepatic steatosis does not affect the uptake of gadoxetate disodium into hepatocytes and are considered crucial as background knowledge in extending the use of gadoxetate disodium-enhanced MR imaging to quantitate liver function. PMID- 24339366 TI - Estimation of aortic pulse pressure using Fourier velocity encoded M-mode MR. AB - PURPOSE: To use a simplified hemodynamic model and Fourier-encoded velocity data to measure pulse pressure (PP) in the descending aorta. MATERIALS AND METHODS: A one-dimensional, cylindrically localized pulse sequence with Fourier velocity encoding (FVE) was used to obtain time-dependent velocity distributions along the descending aorta. Numerical evaluation of a simplified hemodynamic model, based on a cross-sectionally averaged form of the mass conservation equation, allowed estimation of the average pressure waveform and PP along 6-cm-long segments located within the descending aorta. Magnetic resonance (MR)-derived pressures were compared against applanation tonometry (AT) performed in healthy subjects (n = 18) and intravascular pressure measurements (IVPM) obtained in patients (n = 4) undergoing diagnostic cardiac angiography and then found to be either normal or with clinically insignificant coronary artery disease. RESULTS: The root mean square (RMS) error between MR- and AP-derived pressure waveforms was 11.7 +/- 5.8%. With respect to IVPM, the RMS error ranged from 4.2% to 14.7%. In terms of pulse pressures, there was good agreement with both AT (bias = 0.99 mmHg; 95% limits of agreement (LOA) = [-5.0 to 7.0 mmHg]; range = 12.0 mmHg) and IVPM (bias = -1.82 mmHg; 95% LOA = [-7.2 to 3.5 mmHg]; range = 10.7 mmHg). CONCLUSION: FVE M mode and numerical evaluation of a simplified flow model can be used to estimate central pulse pressures noninvasively and accurately with respect to well established gold standards. PMID- 24339367 TI - Puerarin: a review of pharmacological effects. AB - Puerarin is the major bioactive ingredient isolated from the root of the Pueraria lobata (Willd.) Ohwi, which is well known as Gegen (Chinese name) in traditional Chinese medicine. As the most abundant secondary metabolite, puerarin was isolated from Gegen in the late 1950s. Since then, its pharmacological properties have been extensively investigated. It is available in common foods and is used in alternative medicine. It has been widely used in the treatment of cardiovascular and cerebrovascular diseases, diabetes and diabetic complications, osteonecrosis, Parkinson's disease, Alzheimer's disease, endometriosis, and cancer. The beneficial effects of puerarin on the various medicinal purposes may be due to its wide spectrum of pharmacological properties such as vasodilation, cardioprotection, neuroprotection, antioxidant, anticancer, antiinflammation, alleviating pain, promoting bone formation, inhibiting alcohol intake, and attenuating insulin resistance. However, the direct molecular mechanisms and targets remain unclear. This review provides a comprehensive summary of the pharmacological effects of puerarin. PMID- 24339368 TI - Structural and mutational studies on the unusual substrate specificity of meso diaminopimelate dehydrogenase from Symbiobacterium thermophilum. AB - Wild-type meso-diaminopimelate dehydrogenase (DAPDH) is usually specific to the native substrate, meso-2,6-diaminopimelate. Recently, a DAPDH from Symbiobacterium thermophilum (StDAPDH) was found to exhibit expanded substrate specificity. As such, its crystal structures in apo form and in complex with NADP(+) and both NADPH and meso-DAP were investigated to reveal the structural basis of its unique catalytic properties. Structural analysis results show that StDAPDH should prefer an ordered kinetic catalytic mechanism. A second substrate entrance tunnel with Met152 at its bottleneck was found, through which pyruvate/D alanine might bind and enter the catalytic cavity, providing some structural insights into its high activity toward pyruvate. The side chain of Met152 might interact with Asp92 and Asn253, thus affecting the domain motion and catalysis. These results offer useful information for understanding the unique catalytic properties of StDAPDH and guiding further engineering of this enzyme. PMID- 24339369 TI - Insight into IKBKG/NEMO locus: report of new mutations and complex genomic rearrangements leading to incontinentia pigmenti disease. AB - Incontinentia pigmenti (IP) is an X-linked-dominant Mendelian disorder caused by mutation in the IKBKG/NEMO gene, encoding for NEMO/IKKgamma, a regulatory protein of nuclear factor kappaB (NF-kB) signaling. In more than 80% of cases, IP is due to recurrent or nonrecurrent deletions causing loss-of-function (LoF) of NEMO/IKKgamma. We review how the local architecture of the IKBKG/NEMO locus with segmental duplication and a high frequency of repetitive elements favor de novo aberrant recombination through different mechanisms producing genomic microdeletion. We report here a new microindel (c.436_471delinsT, p.Val146X) arising through a DNA-replication-repair fork-stalling-and-template-switching and microhomology-mediated-end-joining mechanism in a sporadic IP case. The LoF mutations of IKBKG/NEMO leading to IP include small insertions/deletions (indel) causing frameshift and premature stop codons, which account for 10% of cases. We here present 21 point mutations previously unreported, which further extend the spectrum of pathologic variants: 14/21 predict LoF because of premature stop codon (6/14) or frameshift (8/14), whereas 7/21 predict a partial loss of NEMO/IKKgamma activity (two splicing and five missense). We review how the analysis of IP-associated IKBKG/NEMO hypomorphic mutants has contributed to the understanding of the pathophysiological mechanism of IP disease and has provided important information on affected NF-kB signaling. We built a locus-specific database listing all IKBKG/NEMO variants, accessible at http://IKBKG.lovd.nl. PMID- 24339370 TI - Determination of sulfonamides in milk samples by HPLC with amperometric detection using a glassy carbon electrode modified with multiwalled carbon nanotubes. AB - A sensitive and accurate method for determining five sulfonamides based on HPLC with amperometric detection and using a glassy carbon electrode modified with multiwalled carbon nanotubes is proposed. Optimal conditions for the quantitative separation of selected sulfonamides were studied, and glassy carbon electrodes with and without modification with carbon nanotubes were systematically investigated as electrodic materials. Statistical analysis of the obtained results demonstrated that these modified electrodes achieved considerably better stability and sensitivity than the conventional unmodified ones. Detection limits were in the 1.2-6.0 ng/mL range. The usefulness of the method was demonstrated by the analysis of milk samples, taking into account the European legislation on residues in food products, following both a screening method to classify the samples and a confirmation method to provide more detailed information in the case of positive samples. PMID- 24339371 TI - Bioreducible nanocapsules prepared from the self-assembly of branched polymer in nanodroplet. AB - Though great attention has been paid in constructing well-defined nano-structures via the self-assembly of amphiphilic macromolecules, the self-assembly of non amphiphilic macromolecules in nanodroplet has drawn less attention up to now. Recently, we prepared a temperature-responsive PEG-based branched polymer with disulfide bonds in its backbone via reversible addition-fragmentation chain transfer (RAFT) polymerization of 2-(2-methoxyethoxy) ethyl methacrylate, oligo(ethylene glycol) methacrylate, and N,N'-cystamine bisacrylamide. Subsequently, we loaded the branched polymer into nanodroplets, and have found that the self-assembly behaviors of this branched poly-mer in the nanodroplet are different from those in common solution. Bioreducible nanocapsules with tunable size can easily formed in nanodroplet even at high concentration. PMID- 24339372 TI - Synthesis and catalytic activities of porphyrin-based PCP pincer complexes. AB - 2,18-Bis(diphenylphosphino)porphyrins undergo peripheral cyclometalation with group 10 transition-metal salts to afford the corresponding porphyrin-based PCP pincer complexes. The porphyrinic plane and the PCP-pincer unit are apparently coplanar, with small strain. The catalytic activities of the porphyrin-based pincer complexes at the periphery were investigated in the allylation of benzaldehyde with allylstannane and in the 1,4-reduction of chalcone to discover the electronic interplay between the inner metal and the outer metal in catalysis. PMID- 24339373 TI - Patients' willingness to trade off between the duration and frequency of rheumatoid arthritis treatments. AB - OBJECTIVE: Biologic treatments for rheumatoid arthritis (RA) vary widely in both the time required to administer treatment and treatment frequency. This study aimed to quantify the rate at which RA patients are willing to trade off between the time required to administer treatment (duration) and treatment frequency. METHODS: Respondents with a self-reported physician diagnosis of moderate to severe RA completed an online discrete choice experiment survey (also known as conjoint analysis). Respondents were presented with a series of treatment-choice questions. Each hypothetical treatment included 6 attributes: response rate, mode of administration, treatment duration, treatment frequency, and the risks of immediate mild and serious treatment reactions. Preference weights, also called marginal utilities or relative importances, were estimated using mixed-logit methods and then used to calculate the marginal rates of substitution between attributes, including treatment duration and treatment frequency. RESULTS: Among the 901 respondents, 505 were in the RA Information, Service, and Education group (www.risesupport.com) and 396 were members of an online panel. The marginal utility of changes in treatment features was largest for a 1-hour change in treatment duration, while a 1-unit change in the annual frequency of treatment was the second least important change. The marginal utility of changes in annual treatment frequency depends on the treatment duration and vice versa. CONCLUSION: Respondents would accept treatments with lower efficacy and greater risk to achieve lower duration and frequency. Previous studies have linked patient preferences to treatment adherence, suggesting that reductions in duration or frequency could improve adherence and health outcomes. PMID- 24339374 TI - The poppy seed defense: a novel solution. AB - A major toxicological challenge is distinguishing whether morphine in urine, in the absence of 6-monoacetylmorphine (6-MAM), originates from 'street' heroin use or poppy seed ingestion. Manufacturing byproducts from the synthesis of illicit heroin include those that originate from the reaction of acetic anhydride with the alkaloid impurity, thebaine, which undergoes skeletal rearrangement, resulting in compounds with a 2-(N-methylacetamido)ethyl side-chain. The hypothesis that the tertiary amide in this side-chain is resistant to endogenous hydrolysis was supported from in-vitro experiments; a glucuronide metabolite (designated 'ATM4G') was identified that may be used as a marker of 'street' heroin administration. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis for this metabolite was then performed on selected urine specimens from 22 known heroin users, these being negative on routine testing for 6-MAM by gas chromatography-mass spectrometry (GC-MS), using the generally applied reporting threshold of 10 ng/mL, but positive for the presence of morphine. Peaks corresponding to the retention time for the metabolite marker were clearly observed for 16 of the 22 samples, with variations of the ratios of its three dependent ions being within +/- 30% of that produced in vitro. Conversely, 6-MAM was detected in only 3 samples, but at concentrations <1 ng/mL. Such a high frequency for the presence of the metabolite marker in urine, in the absence of 6 MAM, is noteworthy and suggests that detection of this metabolite may offer an important advance in forensic toxicology, allowing the development of a new and more definitive test for heroin abuse and thus a potential solution to the so called 'poppy seed defense'. PMID- 24339375 TI - The assessment of stat laboratory test ordering practice and impact of targeted individual feedback in an urban teaching hospital. AB - BACKGROUND: Overuse of inpatient stat laboratory orders ("stat" is an abbreviation of the Latin word "statim," meaning immediately, without delay) is a major problem in the modern healthcare system. OBJECTIVE: To understand patterns of stat laboratory ordering practices at our institution and to assess the effectiveness of individual feedback in reducing these orders. INTERVENTION: Medicine and General Surgery residents were given a teaching session about appropriate stat ordering practice in January 2010. Individual feedback was given to providers who were the highest utilizers of stat laboratory orders by their direct supervisors from February through June of 2010. MEASUREMENTS: The proportion of stat orders out of total laboratory orders per provider was the main outcome measure. All inpatient laboratory orders from September 2009 to June 2010 were analyzed. RESULTS: The median proportion of stat orders out of total laboratory orders was 41.6% for nontrainee providers (N = 500), 38.7% for Medicine residents (N = 125), 80.2% for General Surgery residents (N = 32), and 24.2% for other trainee providers (N = 150). Among 27 providers who received feedback (7 nontrainees, 16 Medicine residents, and 4 General Surgery residents), the proportion of stat laboratory orders per provider decreased by 15.7% (95% confidence interval: 5.6%-25.9%, P = 0.004) after feedback, whereas the decrease among providers who were high utilizers but did not receive feedback (N = 39) was not significant (4.5%; 95% confidence interval: 2.1%-11.0%, P = 0.18). Monthly trends showed reduction in the proportion of stat orders among Medicine and General Surgery residents, but not among other trainee providers. CONCLUSIONS: The frequency of stat ordering was highly variable among providers. Individual feedback to the highest utilizers of stat orders was effective in decreasing these orders. PMID- 24339377 TI - Very strong organosuperbases formed by combining imidazole and guanidine bases: synthesis, structure, and basicity. AB - New structural motives for organosuperbases, that are easy to prepare and highly basic are urgently required in many areas of chemistry. The synthesis of N,N' bis(imidazolyl)guanidine bases (BIG bases) is reported. Their pKalpha values are determined as 26.1-29.3 in THF. They are thus probably the strongest known phosphorous-free organic bases both in solution and in the gas phase. Calculations help to determine the structural and electronic factors giving rise to the high basicity. PMID- 24339376 TI - RNA in development: how ribonucleoprotein granules regulate the life cycles of pathogenic protozoa. AB - Ribonucleoprotein (RNP) granules are important posttranscriptional regulators of messenger RNA (mRNA) fate. Several types of RNP granules specifically regulate gene expression during development of multicellular organisms and are commonly referred to as germ granules. The function of germ granules is not entirely understood and probably diverse, but it is generally agreed that one main function is posttranscriptional regulation of gene expression during early development, when transcription is silent. One example is the translational repression of maternally derived mRNAs in oocytes. Here, I hope to show that the need for regulation of gene expression by RNP granules is not restricted to animal development, but plays an equally important role during the development of pathogenic protozoa. Apicomplexa and Trypanosomatidae have complex life cycles with frequent host changes. The need to quickly adapt gene expression to a new environment as well as the ability to suppress translation to survive latencies is critical for successful completion of life cycles. Posttranscriptional gene regulation is not necessarily simpler in protozoa. Apicomplexa surprise with the presence of micro RNA (miRNAs) and upstream open reading frames (uORFs). Trypanosomes have an unusually large repertoire of different RNP granule types. A better understanding of RNP granules in protozoa may help to gain insight into the evolutionary origin of RNP granules: Trypanosomes for example have two types of granules with interesting similarities to animal germ granules. PMID- 24339378 TI - Lack of platelet-activating factor receptor protects mice against diet-induced adipose inflammation and insulin-resistance despite fat pad expansion. AB - OBJECTIVE: The role of platelet-activating factor (PAF) on diet-induced inflammatory and metabolic dysfunction is unknown. The effects of diet-induced metabolic and inflammatory dysfunction in mice with deletion of the PAF receptor (PAFR(-/-) ) were evaluated in this study. METHODS: Wild-type and PAFR(-/-) mice were fed chow (WT-C and PAFR(-/-) -C) or high-refined carbohydrate-containing diet (WT-HC and PAFR(-/-) -HC). PAFR(-/-) - RESULTS: HC mice gained more weight and adiposity than PAFR(-/-) -C and WT-HC mice. Lipogenesis increased and hormone sensitive lipase expression decreased in PAFR(-/-) -HC compared to WT-HC mice. WT HC mice had impaired glucose tolerance and insulin sensitivity compared to WT-C mice. In contrast, glucose tolerance and insulin sensitivity in PAFR(-/-) -HC mice were similar to that of lean littermates. PAFR(-/-) -HC mice expressed significantly more peroxisome proliferator-activator receptor gamma (PPARgamma) than PAFR(-/-) -C and WT-C mice. Resistin increased in WT-HC mice compared to WT C mice. However, the levels of resistin were 35% lower in PAFR(-/-) -HC mice than WT-HC mice. PAFR(-/-) presented with less HC diet-induced adipose tissue inflammation than WT mice. Adipocytes isolated from PAFR(-/-) mice incubated in media containing normal or high levels of glucose secreted less interleukin-6 and tumor necrosis factor alpha and presented lower rate of lipolysis than WT mice. CONCLUSION: PAFR deficiency resulted in less inflammation in adipose tissue and improvement in glucose homeostasis when fed the HC diet. The higher adiposity observed in PAFR(-/-) mice fed HC diet could be owing to the maintenance of insulin sensitivity, decreased adipocyte lipolysis rate, high lipogenesis and PPARgamma expression, and lower inflammatory milieu in adipose tissue. PMID- 24339381 TI - Aptamers act as activators for the thrombin mediated-hydrolysis of peptide substrates. AB - Thrombin is the typical target in anticlotting therapy for many serious diseases such as heart attack and stroke. DNA aptamers are well-known thrombin inhibitors that prevent fibrinogen hydrolysis. We have discovered that exosite-targeting antithrombin aptamers enhance the activity of thrombin toward a small peptide substrate, Sar(N-methylglycine)-Pro-Arg-paranitroanilide, and that the activation of the enzyme by these aptamers is strongly inhibited by their complementary DNAs. Our study reveals that treatment with mixed aptamers or with a dual-aptamer construct led to an 8.6- or 7.8-fold enhancement in peptide hydrolysis relative to thrombin alone, a synergistic effect much higher than the activation observed with a monofunctional aptamer (1.5-fold for Apt27 or 2.7-fold for Apt15). In addition, we discovered that Apt27 is a biofunctional molecule for thrombin because of its activation effect. An enzyme kinetic study indicates that the binding of aptamers to exosites I and II significantly activates thrombin towards the peptide substrate, thus illustrating that binding of aptamers to exosites can allosterically regulate the active site of thrombin. Our study suggests the necessity of considering possible side effects when DNA aptamers are used for clinical applications involving the inhibition of thrombin-mediated clotting. PMID- 24339383 TI - Patient Crying in Psychotherapy: Who Cries and Why? AB - AIM: The aim of the present study is to further the understanding of who cries in therapy and the relation of technique with crying behaviour in therapy. METHOD: Psychological assessment feedback sessions, prior to the initiation of formal therapy for 52 patients beginning psychotherapy at a university-based clinic were coded for discrete crying segments. Data about patient characteristics and the process of the session were collected at the time of the session. Therapist's interventions were recorded verbatim and independently rated. RESULTS: The number of times a patient cried during their session correlated negatively with global assessment of functioning scores and positively with measures of borderline personality disorder pathology as well as a measure of severity of childhood sexual abuse. Patients' crying behaviour demonstrated significant negative correlations with the overall experience of the session (bad/good), smoothness and positivity. Group differences between criers and non-criers reflected these trends as well. No significant correlations or group differences were found with regard to patient-rated or therapist-rated alliance as it relates to crying behaviour. Analysis indicates that therapist intervention prior to patient crying most often encouraged the exploration and expression of difficult affect, new perspectives on key issues or the patient's fantasies and wishes. DISCUSSION: Our study addresses a significant gap in the clinical literature on crying. Crying behaviour seems to be related to certain clinical variables and has a negative impact on patient experience of the session in which they cry, although the alliance remained unaffected. LIMITATIONS: Small sample, outpatients with mild/moderate psychopathology and graduate trainees provided therapy. KEY PRACTITIONER MESSAGE: Patients with greater problems in emotional dysregulation, borderline personality disorder symptoms and greater severity of childhood sexual abuse are more likely to display greater affective intensity during the beginning of treatment. Results suggest that the alliance may remain strong despite patients experiencing a session in which they cried as difficult. Therapeutic interventions that focus on affect, new understanding of old patterns and patient fantasies with outpatient clinical populations appeared to be associated with crying in session. PMID- 24339382 TI - Burden of systemic lupus erythematosus on employment and work productivity: data from a large cohort in the southeastern United States. AB - OBJECTIVE: To examine the burden of systemic lupus erythematosus (SLE) on work loss, unemployment, and work productivity impairment in an SLE cohort from the southeastern US. METHODS: We examined 689 SLE patients ages 18-64 years from the Georgians Organized Against Lupus (GOAL) cohort. GOAL is a longitudinal cohort predominantly derived from the Georgia Lupus Registry, a population-based registry established in metropolitan Atlanta. We used the Kaplan-Meier method to assess the proportion of patients who self-reported work loss since diagnosis. We compared unemployment between SLE patients and the general population from the same geographic area, calculating the standardized unemployment ratio (SUR) within demographic and disease strata. We also calculated the percentage of work productivity impairment by disease outcomes. RESULTS: Of 511 patients employed at diagnosis, 249 (49%) experienced work loss within an average disease duration of 13 years. The proportion of patients who lost their jobs since diagnosis was almost twice for African Americans than for whites. However, the SURs were similar across demographic characteristics, including race. Patients with severe disease activity and severe organ damage had the highest SUR at 4.4 and 5.6, respectively. Among those that remained employed, patients with severe fatigue, neurocognitive symptoms, and musculoskeletal symptoms had the highest impairment of work productivity. CONCLUSION: SLE imposes a substantial toll on individuals and burden on society. Major factors that negatively impact work outcomes are fatigue, disease activity, and organ damage. More effective treatments along with coping strategies at the workplace are needed to reduce the burden of SLE on work outcomes. PMID- 24339384 TI - Enhanced osseointegration and antibacterial action of zinc-loaded titania nanotube-coated titanium substrates: in vitro and in vivo studies. AB - Poor osseointegration and infection resulting from implants are serious medical issues, and it is not straightforward to manufacture implants that can simultaneously address both of these problems. In this study, we produced coatings containing titania nanotubes (TiO2 -NTs) incorporated with zinc (NT-Zn) on Ti substrates by anodization and hydrothermal treatment. The zinc content was controlled by varying the duration of the hydrothermal treatment. The NT-Zn implants not only exhibited improved bone formation (shown by both in vitro and in vivo studies), which enhances osseointegration between bone and implant, but also inhibited growth of bacteria. The cytotoxicity of locally high concentrations of zinc in the NT-Zn3h specimens observed during in vitro studies was mitigated by the effects of dilution in vivo. PMID- 24339385 TI - Carbon nanotubes as SPE sorbents for the extraction of salicylic acid from river water. AB - This paper deals with the ability of different types of carbon nanotubes to adsorb salicylic acid in river water samples. The use of these nanoparticles as a sorbent in a SPE procedure prior to CE analysis is essential for improving the enrichment factor and the recovery values. Several experimental variables were optimized in order to maximize the extraction efficiency. The proposed analytical method is simple, fast, and entails low solvent consumption. Furthermore, salicylic acid could be extracted from river water providing good recovery values in the range from 76.2 to 102.0% (RSD<8.2%). The combination of the specific chemical properties of analyte and the unique physicochemical features of carbon nanotubes sheds new light on the use of these nanoparticles as excellent sorbent materials of pharmaceutical compounds in environmental matrices. PMID- 24339386 TI - The strongest Bronsted acid: protonation of alkanes by H(CHB(11)F(11)) at room temperature. AB - What is the strongest acid? Can a simple Bronsted acid be prepared that can protonate an alkane at room temperature? Can that acid be free of the complicating effects of added Lewis acids that are typical of common, difficult to-handle superacid mixtures? The carborane superacid H(CHB11 F11 ) is that acid. It is an extremely moisture-sensitive solid, prepared by treatment of anhydrous HCl with [Et3 Si?H?SiEt3 ][CHB11 F11 ]. It adds H2 O to form [H3 O][CHB11 F11 ] and benzene to form the benzenium ion salt [C6 H7 ][CHB11 F11 ]. It reacts with butane to form a crystalline tBu(+) salt and with n-hexane to form an isolable hexyl carbocation salt. Carbocations, which are thus no longer transient intermediates, react with NaH either by hydride addition to re-form an alkane or by deprotonation to form an alkene and H2 . By protonating alkanes at room temperature, the reactivity of H(CHB11 F11 ) opens up new opportunities for the easier study of acid-catalyzed hydrocarbon reforming. PMID- 24339388 TI - The future for weed control and technology. AB - This review is both a retrospective (what have we missed?) and prospective (where are we going?) examination of weed control and technology, particularly as it applies to herbicide-resistant weed management (RWM). Major obstacles to RWM are discussed, including lack of diversity in weed management, unwillingness of many weed researchers to conduct real integrated weed management research or growers to accept recommendations, influence or role of agrichemical marketing and governmental policy and lack of multidisciplinary research. We then look ahead to new technologies that are needed for future weed control in general and RWM in particular, in areas such as non-chemical and chemical weed management, novel herbicides, site-specific weed management, drones for monitoring large areas, wider application of 'omics' and simulation model development. Finally, we discuss implementation strategies for integrated weed management to achieve RWM, development of RWM for developing countries, a new classification of herbicides based on mode of metabolism to facilitate greater stewardship and greater global exchange of information to focus efforts on areas that maximize progress in weed control and RWM. There is little doubt that new or emerging technologies will provide novel tools for RMW in the future, but will they arrive in time? PMID- 24339387 TI - Whole blood cells loaded with messenger RNA as an anti-tumor vaccine. AB - The use of a cell-based vaccine composed of autologous whole blood cells loaded with mRNA is described. Mice immunized with whole blood cells loaded with mRNA encoding antigen develop anti-tumor immunity comparable to DC-RNA immunization. This approach offers a simple and affordable alternative to RNA-based cellular therapy by circumventing complex, laborious and expensive ex vivo manipulations required for DC-based immunizations. PMID- 24339389 TI - Interpretation of hair findings in children: about a case involving carbamazepine. AB - This office has been recently involved in a case dealing with child custody, where the final outcome was difficult to establish. The following concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the hair of a 21-month-old girl: 154 (0-1 cm), 198 (1-2 cm), 247 (2-3 cm), and 368 pg/mg (3-4 cm) after decontamination. Obviously, the concentrations measured in the hair were much lower than those observed in patients under daily treatment. In this sense, the frequency of exposures appears as infrequent (low level of exposure), with marked decrease in the more recent period. However, the girl was never prescribed carbamazepine and the mother, who was under carbamazepine therapy, denied any administration. The Judge asked if this could result from a single exposure and at which period. At least, three possible interpretations of the measured carbamazepine concentrations were addressed: (1) decrease in administration in the more recent period; (2) increase of body weight due to growing, so the same dosage will result in lower concentrations in hair; and (3) sweat contamination from the mother at the time the girl is with her in bed, the older hair being in contact longer with the bedding. In this case, it was impossible to conclude that the child was deliberately administered carbamazepine. The results of the analysis of hair could indicate that she was in an environment where carbamazepine was being used and where the drug was not being handled and stored with appropriate care. There are many differences between the hair from children and those from adults: hair from children is thinner and more porous, the ratio anagen and catagen phases are not maintained, and the growth rate can be different, at some periods, from the usual 1 cm/month. These differences, together with the influence of PK-PD parameters are reviewed in this paper, as a basis for suitable interpretation. In view of these results it is proposed that a single hair analysis should not be used firmly to discriminate long-term exposure to a drug when dealing with children. PMID- 24339390 TI - Only minor additional metabolic health benefits of high as opposed to moderate dose physical exercise in young, moderately overweight men. AB - OBJECTIVE: The dose-response effects of exercise training on insulin sensitivity, metabolic risk, and quality of life were examined. METHODS: Sixty-one healthy, sedentary (VO2max: 35 +/- 5 ml/kg/min), moderately overweight (BMI: 27.9 +/- 1.8), young (age: 29 +/- 6 years) men were randomized to sedentary living (sedentary control group; n = 18), moderate (moderate dose training group [MOD]: 300 kcal/day, n = 21), or high (high dose training group [HIGH]: 600 kcal/day, n = 22) dose physical exercise for 11 weeks. RESULTS: The return rate for post intervention testing was 82-94% across groups. Weekly exercise amounted to 2,004 +/- 24 and 3,774 +/- 68 kcal, respectively, in MOD and HIGH. Cardiorespiratory fitness increased (P < 0.001) 18 +/- 3% in MOD and 17 +/- 3% in HIGH, and fat percentage decreased (P < 0.001) similarly in both exercise groups (MOD: 32 +/- 1 to 29 +/- 1%; HIGH: 30 +/- 1 to 27 +/- 1%). Peripheral insulin sensitivity increased (P < 0.01) (MOD: 28 +/- 7%; HIGH: 36 +/- 8%) and the homeostasis model assessment of insulin resistance decreased (P < 0.05) (MOD: -17 +/- 7%; HIGH: -18 +/- 10%). The number of subjects meeting the criteria of the metabolic syndrome decreased by 78% in MOD (P < 0.01) and by 80% in HIGH (P < 0.05). General health assessed by questionnaire increased similarly in MOD (P < 0.05) and HIGH (P < 0.01). CONCLUSIONS: Only minor additional health benefits were found when exercising ~3,800 as opposed to ~2,000 kcal/week in young moderately overweight men. This finding may have important public health implications. PMID- 24339391 TI - A case of anaphylaxis after a proven penicillin tolerance. PMID- 24339393 TI - Boosting the resolution of 1H NMR spectra by homonuclear broadband decoupling. AB - Broadband homonuclear decoupling of proton spectra, that is, the collapse of all multiplets into singlets, has the potential of boosting the resolution of (1)H NMR spectra. Several methods have been described in the last 40 years to achieve this goal. Most of them can only be applied in the indirect dimension of multi dimensional NMR spectra or special data processing is necessary to yield decoupled 1D proton spectra. Recently, complete decoupling of proton spectra during acquisition has been introduced; this not only significantly reduced the experimental time to record these spectra, but also removed the need for any sophisticated processing schemes. Here we present an introduction and overview of the techniques and applications of broadband proton-decoupled proton experiments. PMID- 24339394 TI - In vitro evaluation of human fetal osteoblast response to magnesium loaded mesoporous TiO2 coating. AB - This work aimed to evaluate the in vitro response of Transfected Human Foetal Osteoblast (hFOB) cultured on a magnesium-loaded mesoporous TiO2 coating. The application of mesoporous films on titanium implant surfaces has shown very promising potential to enhance osseointegration. This type of coating has the ability to act as a framework to sustain bioactive agents and different drugs. Magnesium is the element that, after calcium, is the most frequently used to dope titanium implant surfaces, since it is crucial for protein formation, growth factor expression, and aids for bone mineral deposition on implant surfaces. Mesoporous TiO2 films with an average pore-size of 6 nm were produced by the evaporation-induced self-assembly method (EISA) and deposited onto titanium discs. Magnesium loading was performed by soaking the mesoporous TiO2 discs in a magnesium chloride solution. Surface characterization was conducted by SEM, XPS, optical interferometry, and AFM. Magnesium release profile was assessed at different time points using a Magnesium Detection kit. Cell morphology and spreading were observed with SEM. The cytoskeletal organization was stained with TRITC-conjugated Phalloidin and cell viability was evaluated through a mitochondrial colorimetric (MTT) assay. Furthermore, gene expression of bone markers and cell mineralization were analyzed by real time RT-PCR and alizarin red staining, respectively. The surface chemical analysis by XPS revealed the successful adsorption of magnesium to the mesoporous coating. The AFM measurements revealed the presence of a nanostructured surface roughness. Osteoblasts viability and adhesion as well as the gene expression were unaffected by the addition of magnesium possibly due to its rapid burst release, however, were enhanced by the 3D nanostructure of the TiO2 layer. PMID- 24339395 TI - Effect of methotrexate, anti-tumor necrosis factor alpha, and rituximab on the immune response to influenza and pneumococcal vaccines in patients with rheumatoid arthritis: a systematic review and meta-analysis. AB - OBJECTIVE: To assess the current literature on the impact of rheumatoid arthritis (RA) treatments on the humoral response to pneumococcal and influenza vaccines. METHODS: We systematically searched the literature for studies evaluating the immune response to vaccines in RA patients receiving methotrexate (MTX) and/or biologic agents. The efficacy of vaccination, assessed by the response rate based on increased antibody titers before and 3-6 weeks after vaccination, was extracted by one investigator and verified by another. RESULTS: In total, 12 studies were included. RA patients mainly received MTX, anti-tumor necrosis factor alpha (anti-TNFalpha), or rituximab (RTX). Influenza vaccination response was reduced for RTX (43 patients; pooled odds ratio [OR] 0.44 [95% confidence interval (95% CI) 0.17-1.12] for H1N1, OR 0.11 [95% CI 0.04-0.31] for H3N2, and OR 0.29 [95% CI 0.10-0.81] for B) but not for anti-TNFalpha (308 patients; OR 0.93 [95% CI 0.36-2.37] for H1N1, OR 0.79 [95% CI 0.34-1.83] for H3N2, and OR 0.79 [95% CI 0.37-1.70] for B). For MTX, results differed depending on the method of analysis (222 patients; OR 0.35 [95% CI 0.18-0.66] for at least 2 strains, ORs were close to 1.0 in the single strain analysis). Pneumococcal vaccination response was reduced for 139 patients receiving MTX compared with controls (OR 0.33 [95% CI 0.20-0.54] for serotype 6B and OR 0.58 [95% CI 0.36-0.94] for 23F) but not for anti-TNFalpha (258 patients; OR 0.96 [95% CI 0.57-1.59] for 6B and OR 1.20 [95% CI 0.57-2.54] for 23F). For RTX, the response was reduced (88 patients; OR 0.25 [95% CI 0.11-0.58] for 6B and OR 0.21 [95% CI 0.04-1.05] for 23F). CONCLUSION: MTX decreases humoral response to pneumococcal vaccination and may impair response to influenza vaccination. The immune response to both vaccines is reduced with RTX but not with anti-TNFalpha therapy in RA patients. PMID- 24339396 TI - Selective hydrogen production from methanol with a defined iron pincer catalyst under mild conditions. AB - Molecularly well-defined iron pincer complexes promote the aqueous-phase reforming of methanol to carbon dioxide and hydrogen, which is of interest in the context of a methanol and hydrogen economy. For the first time, the use of earth abundant iron complexes under mild conditions for efficient hydrogen generation from alcohols is demonstrated. PMID- 24339397 TI - Localisation of bovine colostral odorant-binding protein (bcOBP) mRNAs in several tissues of bovine body. AB - Bovine colostral odorant-binding protein (bcOBP) is a novel protein found in bovine colostrum and belonging to the lipocalin superfamily. Most of them are secretory proteins. We have examined the localisation of bcOBP messenger RNA in several tissues. The expression of bcOBP messenger RNAs was followed in bovine principal organs and female reproductive tracts with in situ hybridisation, but the localisation of it was not detected. The expression levels of bcOBP mRNAs were also extremely low in those tissues. On the other hand, the expression of bcOBP messenger RNAs has not been found in the airway epithelia and the gallbladder. These results suggest that bcOBP messenger RNAs are expressed in bovine several tissues without its localisation. In conclusion, the localisation of bcOBP messenger RNAs in bovine several tissues was not found. PMID- 24339399 TI - In response to "discharge against medical advice: how often do we intervene?". PMID- 24339403 TI - Degradation kinetics of anilofos in soil and residues in rice crop at harvest. AB - BACKGROUND: Pesticides used on rice, which is widely grown in India in the rainy season, must be investigated for the persistence and magnitude of their residues in the crop and soil to ensure human and environmental safety. Anilofos is widely used in rice, and its persistence and dissipation behaviour in soil and rice was investigated in field trials under subhumid and subtropical conditions. RESULTS: The persistence of anilofos in soil, husk, grain and rice straw was evaluated at two application rates (0.4 and 0.8 kg AI ha(-1) ) by RP-HPLC. In soil, residues were detected up to 45 and 75 days after application at 0.4 and 0.8 kg AI ha(-1) respectively. No residue was observed in soil, husk, grain or rice straw at the time of harvest at either application rate. Detector response was linear within the concentration range 0.1-5.0 ug mL(-1) at 2.22% standard deviation. The limit of detection was 0.003 ug mL(-1) , and the limit of quantification of the method for soil, straw, grain and husk was 0.007, 0.01, 0.008 and 0.01 ug g(-1) respectively. CONCLUSION: The dissipation of herbicide from soil appeared to occur in a single phase and conformed to pseudo-first-order kinetics. The calculated half-life values of anilofos residue in soil were 13 days for the lower rate of application (0.4 kg AI ha(-1) ) and 15.5 days for the higher rate (0.8 kg AI ha(-1) ). Anilofos residues were below the maximum residue level in soil, husk, rice grain and rice straw at harvest. PMID- 24339398 TI - Vaginal delivery of paclitaxel via nanoparticles with non-mucoadhesive surfaces suppresses cervical tumor growth. AB - Local delivery of chemotherapeutics in the cervicovaginal tract using nanoparticles may reduce adverse side effects associated with systemic chemotherapy, while improving outcomes for early-stage cervical cancer. It is hypothesized here that drug-loaded nanoparticles that rapidly penetrate cervicovaginal mucus (CVM) lining the female reproductive tract will more effectively deliver their payload to underlying diseased tissues in a uniform and sustained manner compared with nanoparticles that do not efficiently penetrate CVM. Paclitaxel-loaded nanoparticles are developed, composed entirely of polymers used in FDA-approved products, which rapidly penetrate human CVM and provide sustained drug release with minimal burst effect. A mouse model is further employed with aggressive cervical tumors established in the cervicovaginal tract to compare paclitaxel-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (conventional particles, or CP) and similar particles coated with Pluronic F127 (mucus-penetrating particles, or MPP). CP are mucoadhesive and, thus, aggregated in mucus, while MPP achieve more uniform distribution and close proximity to cervical tumors. Paclitaxel-MPP suppress tumor growth more effectively and prolong median survival of mice compared with unencapsulated paclitaxel or paclitaxel-CP. Histopathological studies demonstrate minimal toxicity to the cervicovaginal epithelia, suggesting paclitaxel-MPP may be safe for intravaginal use. These results demonstrate the in vivo advantages of polymer-based MPP for treatment of tumors localized to a mucosal surface. PMID- 24339404 TI - Twentieth international symposium on electro- and liquid-phase separation techniques (ITP2013): highlights. AB - The 20th edition of the International Symposium on Electro- and Liquid-Phase Separation Techniques (ITP2013) took place on October 6-9, 2013, at Puerto de la Cruz in Tenerife, Canary Islands (Spain). This article reviews the highlights of this new edition of the symposia, also including the different activities that took place as well as the awards presented. PMID- 24339405 TI - Healthcare provider accuracy at estimating women's BMI and intent to provide counseling based on appearance alone. AB - OBJECTIVE: To assess healthcare providers' ability to estimate women's body mass index (BMI) based on physical appearance and determine the prevalence of, and barriers to, weight-related counseling. METHODS: A web-based survey was distributed to healthcare providers ("participants") at a university-based hospital and contained photographs of anonymous women ("photographed women (PW)") as well as questions regarding participant demographics. Participants were asked to estimate BMI category based on physical appearance, state whether they would provide weight-loss counseling for each PW and identify barriers to counseling. RESULTS: One hundred forty-two participants completed the survey. BMI estimations were poor among all participants, with an overall accuracy of only 41% and a large proportion of underestimations. Standardization of PW clothing did not improve accuracy; 41% for own clothing versus 40% for scrubs, P = 0.2. BMI assessments were more accurate for Caucasian versus African American PW (45% versus 36%, P < 0.001) and PW with normal weight (84%) and obesity III (38%) compared to PW with mid-range BMI (P < 0.001). Although the frequency of weight loss counseling was positively associated with PW BMI, participants only intended to counsel 69% of overweight and obese PW. The most commonly cited reason for lack of counseling was time constraints (54%). CONCLUSIONS: Healthcare providers are inaccurate at appearance-based BMI categorization and thus, BMI should be routinely calculated in order to improve identification of those in need of counseling. When appropriately identified, time constraints may prevent practitioners from providing appropriate weight-loss counseling-further complicating the already difficult task of fighting obesity. PMID- 24339406 TI - Small-angle neutron scattering studies of hemoglobin confined inside silica tubes of varying sizes. AB - In addition to the chemical nature of the surface, the dimensions of the confining host exert a significant influence on confined protein structures; this results in immense biological implications, especially those concerning the enzymatic activities of the protein. This study probes the structure of hemoglobin (Hb), a model protein, confined inside silica tubes with pore diameters that vary by one order of magnitude (~20-200 nm). The effect of confinement on the protein structure is probed by comparison with the structure of the protein in solution. Small-angle neutron scattering (SANS), which provides information on protein tertiary and quaternary structures, is employed to study the influence of the tube pore diameter on the structure and configuration of the confined protein in detail. Confinement significantly influences the structural stability of Hb and the structure depends on the Si-tube pore diameter. The high radius of gyration (Rg) and polydispersity of Hb in the 20 nm diameter Si-tube indicates that Hb undergoes a significant amount of aggregation. However, for Si tube diameters greater or equal to 100 nm, the Rg of Hb is found to be in very close proximity to that obtained from the protein data bank (PDB) reported structure (Rg of native Hb=23.8 A). This strongly indicates that the protein has a preference for the more native-like non-aggregated state if confined inside tubes of diameter greater or equal to 100 nm. Further insight into the Hb structure is obtained from the distance distribution function, p(r), and ab initio models calculated from the SANS patterns. These also suggest that the Si tube size is a key parameter for protein stability and structure. PMID- 24339407 TI - Monovinyl sulfone beta-cyclodextrin. A flexible drug carrier system. AB - Cyclodextrins have been conjugated to target various receptors and have also been functionalized with carbohydrates for targeting specific organs. However, this approach is based on a rigid design that implies the ad hoc synthesis of each cyclodextrin-targeting agent conjugate. We hypothesized that: 1)a modular design that decouples the carrier function from the targeting function leads to a flexible system, 2) combining the reactivity of the vinyl sulfone group toward biomolecules that act as targeting agents with the ability of cyclodextrin to form complexes with a wide range of drugs may yield a versatile system that allows the targeting of different organs with different drugs, and 3) the higher reactivity of histidine residues toward the vinyl sulfone group can be exploited to couple the cyclodextrin to the targeting system with a degree of regioselectivity. As a proof of concept, we synthesized a monovinyl sulfone beta cyclodextrin (module responsible for the payload), which, after coupling to recombinant antibody fragments raised against Trypanosoma brucei (module responsible for targeting) and loading with nitrofurazone (module responsible for therapeutic action) resulted in an effective delivery system that targets the surface of the parasites and shows trypanocidal activity. PMID- 24339408 TI - Biocompatibility and enhanced osteogenic differentiation of human mesenchymal stem cells in response to surface engineered poly(D,L-lactic-co-glycolic acid) microparticles. AB - Tissue engineering strategies can be applied to enhancing osseous integration of soft tissue grafts during ligament reconstruction. Ligament rupture results in a hemarthrosis, an acute intra-articular bleed rich in osteogenic human mesenchymal stem cells (hMSCs). With the aim of identifying an appropriate biomaterial with which to combine hemarthrosis fluid-derived hMSCs (HF-hMSCs) for therapeutic application, this work has investigated the biocompatibility of microparticles manufactured from two forms of poly(D,L-lactic-co-glycolic acid) (PLGA), one synthesized with equal monomeric ratios of lactic acid to glycolic acid (PLGA 50:50) and the other with a higher proportion of lactic acid (PLGA 85:15) which confers a longer biodegradation time. The surfaces of both types of microparticles were functionalized by plasma polymerization with allylamine to increase hydrophilicity and promote cell attachment. HF-hMSCs attached to and spread along the surface of both forms of PLGA microparticle. The osteogenic response of HF-hMSCs was enhanced when cultured with PLGA compared with control cultures differentiated on tissue culture plastic and this was independent of the type of polymer used. We have demonstrated that surface engineered PLGA microparticles are an appropriate biomaterial for combining with HF-hMSCs and the selection of PLGA is relevant only when considering the biodegradation time for each biomedical application. PMID- 24339409 TI - Value of questionnaire-based screening as a proxy for neurocognitive testing in childhood-onset systemic lupus erythematosus. AB - OBJECTIVE: To investigate the utility of questionnaire-based assessment of cognitive function and behavioral/emotional symptoms to screen for neurocognitive dysfunction in childhood-onset systemic lupus erythematosus (cSLE). METHODS: Forty children with cSLE and 24 healthy controls ages 10-16 years were enrolled. Formal neurocognitive testing (FNCT) was done to determine cognitive performance in 4 key areas that appear to be sensitive to the adverse effects of cSLE: attention, working memory, psychomotor speed, and visuoconstructional ability. Paper and pencil questionnaires sampling cognitive functioning and behavioral/emotional symptoms were also completed: the Subjective Awareness of Neuropsychological Deficits for Children (SAND-C) questionnaire by patients, and the Child Behavioral Checklist and the Behavior Rating Inventory of Executive Function (BRIEF) by parents. RESULTS: Domain and summary scores of the BRIEF and SAND-C correlated modestly with participants' performance on FNCT. Questionnaire ratings did not discriminate subjects with different levels of cognitive ability as measured by FNCT. CONCLUSION: Contrary to some reports in adults with SLE, self-administered questionnaires of cognitive functioning and parent ratings of executive functioning do not appear well suited to replace FNCT in screening for neurocognitive impairment of children and adolescents with cSLE. However, they may provide information that is complementary to FNCT and therefore play a useful role in clinical followup. PMID- 24339410 TI - Effect of downregulation of ZEB1 on vimentin expression, tumour migration and tumourigenicity of melanoma B16F10 cells and CSCs. AB - Zinc-finger E-box binding homeobox 1 (ZEB1) is a master regulator of epithelial mesenchymal transition (EMT) and has been implicated in primary epithelial cancer biological processes, such as invasion and metastasis. However, the role of ZEB1 in progression of melanoma and cancer stem cells (CSCs) remains obscure. In this study, the recombinant plasmids of t3 shRNAs targeting mouse ZEB1 were constructed and transfected into melanoma B16F10 cells. The stable transfected cells were selected and the characteristics of ZEB1 downregulated B16F10 cells was assessed. The tumourigenicity of CD44(+) CD133(+) CSCs isolated from B16F10 cells stably transfected with the ZEB1-shRNA2 recombinant was also assessed. ZEB1 shRNAs B16F10 showed a lower expression of ZEB1 and vimentin, weaker migration, invasiveness, colony forming, and proliferation, and a lower tumourigenicity than the control cells. The tumourigenicity of the ZEB1-shRNA2 CD44(+) CD133(+) CSCs was also inhibited. In conclusion, ZEB1-shRNA2-mediated downregulation of ZEB1 expression in B16F10 cells and CSCs is involved in the inhibition of the EMT process. ZEB1 may be a potential target in melanoma targeted. PMID- 24339411 TI - Automated image analysis method for detecting and quantifying macrovesicular steatosis in hematoxylin and eosin-stained histology images of human livers. AB - Large-droplet macrovesicular steatosis (ld-MaS) in more than 30% of liver graft hepatocytes is a major risk factor for liver transplantation. An accurate assessment of the ld-MaS percentage is crucial for determining liver graft transplantability, which is currently based on pathologists' evaluations of hematoxylin and eosin (H&E)-stained liver histology specimens, with the predominant criteria being the relative size of the lipid droplets (LDs) and their propensity to displace a hepatocyte's nucleus to the cell periphery. Automated image analysis systems aimed at objectively and reproducibly quantifying ld-MaS do not accurately differentiate large LDs from small-droplet macrovesicular steatosis and do not take into account LD-mediated nuclear displacement; this leads to a poor correlation with pathologists' assessments. Here we present an improved image analysis method that incorporates nuclear displacement as a key image feature for segmenting and classifying ld-MaS from H&E-stained liver histology slides. 52,000 LDs in 54 digital images from 9 patients were analyzed, and the performance of the proposed method was compared against the performance of current image analysis methods and the ld-MaS percentage evaluations of 2 trained pathologists from different centers. We show that combining nuclear displacement and LD size information significantly improves the separation between large and small macrovesicular LDs (specificity = 93.7%, sensitivity = 99.3%) and the correlation with pathologists' ld-MaS percentage assessments (linear regression coefficient of determination = 0.97). This performance vastly exceeds that of other automated image analyzers, which typically underestimate or overestimate pathologists' ld-MaS scores. This work demonstrates the potential of automated ld-MaS analysis in monitoring the steatotic state of livers. The image analysis principles demonstrated here may help to standardize ld-MaS scores among centers and ultimately help in the process of determining liver graft transplantability. PMID- 24339412 TI - Enhancement of cationic antimicrobial materials via cholesterol incorporation. AB - Cationic antimicrobial materials are an attractive option for treating drug resistant bacteria. Their membrane lytic mechanism can provide broad spectrum antimicrobial activity while largely negating natural resistance development. Selectivity is achieved using non-specific electrostatic interactions since microbial membranes display significantly more peripheral negative charge than due eukaryotic bilayers. Following membrane association, structural changes occur causing bilayer destabilization and cell lysis. Herein, antimicrobial effects of enhanced membrane assimilation are examined. Cholesterol, a functionalizable small molecule that assimilates abundantly within cell membranes, is chosen to increase membrane penetration ability to improve antimicrobial activity. Furthermore, cholesterol has an ability to template interesting nanostructures due to its propensity for rotative face-on-face stacking. The installation of cationic polycarbonates with systematically varied chain lengths from three separate cholesteryl initiators is accomplished using organocatalytic ring opening polymerization. Introduction of cholesteryl oligomers into aqueous media creates "coin" shaped self-assemblies possessing high exterior cationic charge density. Continued evaluation of these assemblies demonstrates broad spectrum activity against S. epidermidis, S. aureus, E. coli, P. aeraginosa, and C. albicans. Additional results show that, despite repeated sub-lethal dosing, E. coli does not evolve drug-resistance and maintains the wild-type minimum inhibitory concentration of 31.3 mg L(-1) . PMID- 24339413 TI - In reference to "discharge against medical advice: how often do we intervene?". PMID- 24339414 TI - Novel metal-ion-mediated, complex-imprinted solid-phase microextraction fiber for the selective recognition of thiabendazole in citrus and soil samples. AB - A novel metal-ion-mediated complex-imprinted-polymer-coated solid-phase microextraction (SPME) fiber used to specifically recognize thiabendazole (TBZ) in citrus and soil samples was developed. The complex-imprinted polymer was introduced as a novel SPME coating using a "complex template" constructed with Cu(II) ions and TBZ. The recognition and enrichment properties of the coating in water were significantly improved based on the metal ion coordination interaction rather than relying on hydrogen bonding interactions that are commonly applied for the molecularly imprinting technique. Several parameters controlling the extraction performance of the complex-imprinted-polymer-coated fiber were investigated including extraction solvent, pH value, extraction time, metal ion species, etc. Furthermore, SPME coupled with HPLC was developed for detection of TBZ, and the methods resulted in good linearity in the range of 10.0-150.0 ng/mL with a detection limit of 2.4 ng/mL. The proposed method was applied to the analysis of TBZ in spiked soil, orange, and lemon with recoveries of 80.0-86.9% and RSDs of 2.0-8.1%. This research provides an example to prepare a desirable water-compatible and specifically selective SPME coating to extract target molecules from aqueous samples by introducing metal ions as the mediator. PMID- 24339416 TI - Vocational rehabilitation and occupational therapy: impact of a knowledge translation initiative. PMID- 24339415 TI - Surface design of antibody-immobilized thermoresponsive cell culture dishes for recovering intact cells by low-temperature treatment. AB - Antibody-immobilized thermoresponsive poly(N-isopropylacrylamide-co-2 carboxyisopropylacrylamide) [poly(IPAAm-co-CIPAAm)]-grafted cell culture surfaces were designed to enhance both the initial adhesion of weakly adhering cells and the ability of cells to detach in response to low temperature through the regulation of affinity binding between immobilized antibodies and antigens on the cellular surface. Ty-82 cells and neonatal normal human dermal fibroblasts (NHDFs), which express CD90 on the cell surface, adhered to anti-CD90 antibody immobilized thermoresponsive surfaces at 37 degrees C, a condition at which the grafted thermoresponsive polymer chains shrank. Adherent Ty-82 cells were detached from the surfaces by lowering the temperature to 20 degrees C and applying external forces, such as pipetting, whereas cultured NHDF sheets spontaneously detached themselves from the surface in response to reduced temperature alone. When the temperature was decreased to 20 degrees C, the swelling of grafted thermoresponsive polymer chains weakened the affinity binding between immobilized antibody and antigen on the cells due to the increasing steric hindrance of the polymer chains around the antigen-recognition site of the immobilized antibodies. No contamination was detected on cells harvested from covalently immobilized antibodies on the culture surfaces by low-temperature treatment, whereas a carryover of the antibody and avidin from the avidin-biotin binding surface was observed. Furthermore, the initial adhesion of adipose tissue derived cells, which adhere weakly to PIPAAm-grafted surfaces, was enhanced on the antibody-immobilized thermoresponsive surfaces. PMID- 24339417 TI - The synthesis and biological evaluation of multifunctionalised derivatives of noscapine as cytotoxic agents. AB - Noscapine, a phthalideisoquinoline alkaloid derived from Papaver somniferum, is a well-known antitussive drug that has a relatively safe in vitro toxicity profile. Noscapine is also known to possess weak anticancer efficacy, and since its discovery, efforts have been made to design derivatives with improved potency. Herein, the synthesis of a series of noscapine analogues, which have been modified in the 6', 9', 1 and 7-positions, is described. In a previous study, replacement of the naturally occurring N-methyl group in the 6'-position with an N-ethylaminocarbonyl was shown to promote cell-cycle arrest and cytotoxicity against three cancer cell lines. Here, this modification has been combined with other structural changes that have previously been shown to improve anticancer activity, namely halo substitution in the 9'-position, regioselective O demethylation to reveal a free phenol in the 7-position, and reduction of the lactone to the corresponding cyclic ether in the 1-position. The incorporation of new aryl substituents in the 9'-position was also investigated. The study identified interesting new compounds able to induce G2/M cell-cycle arrest and that possess cytotoxic activity against the human prostate carcinoma cell line PC3, the human breast adenocarcinoma cell line MCF-7, and the human pancreatic epithelioid carcinoma cell line PANC-1. In particular, the ethyl urea cyclic ether noscapinoids and a compound containing a 6'-ethylaminocarbonyl along with 9'-chloro, 7-hydroxy and lactone moieties exhibited the most promising biological activities, with EC50 values in the low micromolar range against all three cancer cell lines, and these derivatives warrant further investigation. PMID- 24339418 TI - Validation of relapse risk biomarkers for routine use in patients with juvenile idiopathic arthritis. AB - OBJECTIVE: The myeloid-related proteins 8 and 14 (MRP-8/MRP-14) and neutrophil derived S100A12 are biomarkers of inflammation. They can be used to determine the relapse risk in patients with juvenile idiopathic arthritis (JIA) after stopping antiinflammatory treatment. In this study, we tested the performance of different enzyme-linked immunosorbent assays (ELISAs) in order to validate systems available for routine use. METHODS: MRP-8/MRP-14 and S100A12 serum concentrations of 188 JIA patients in remission were analyzed. Commercially available test systems were compared to experimental ELISAs established in house. The ability of the assays to identify JIA patients at risk for relapse was analyzed. RESULTS: For MRP-8/MRP-14, the PhiCal Calprotectin and Buhlmann MRP8/14 Calprotectin ELISAs revealed hazard ratios of 2.3 and 2.1, respectively. For S100A12, the CircuLex S100A12/EN-RAGE ELISA revealed a hazard ratio of 3.1. The commercial assays allowed a JIA relapse prediction that was at least comparable to the experimental ELISAs. CONCLUSION: For the prediction of JIA relapse after stopping medication, the biomarkers MRP-8/MRP-14 and S100A12 can be determined by using assays that are available for routine use. The tested commercial MRP-8/MRP-14 and S100A12 ELISAs showed a performance comparable to well-established experimental ELISA protocols when assay-specific cutoffs for the indication of relapse prediction are thoroughly applied. PMID- 24339419 TI - The top-down, middle-down, and bottom-up mass spectrometry approaches for characterization of histone variants and their post-translational modifications. AB - Epigenetic regulation of gene expression is, at least in part, mediated by histone modifications. PTMs of histones change chromatin structure and regulate gene transcription, DNA damage repair, and DNA replication. Thus, studying histone variants and their modifications not only elucidates their functional mechanisms in chromatin regulation, but also provides insights into phenotypes and diseases. A challenge in this field is to determine the best approach(es) to identify histone variants and their PTMs using a robust high-throughput analysis. The large number of histone variants and the enormous diversity that can be generated through combinatorial modifications, also known as histone code, makes identification of histone PTMs a laborious task. MS has been proven to be a powerful tool in this regard. Here, we focus on bottom-up, middle-down, and top down MS approaches, including CID and electron-capture dissociation/electron transfer dissociation based techniques for characterization of histones and their PTMs. In addition, we discuss advances in chromatographic separation that take advantage of the chemical properties of the specific histone modifications. This review is also unique in its discussion of current bioinformatic strategies for comprehensive histone code analysis. PMID- 24339420 TI - Biopolymer/Calcium phosphate scaffolds for bone tissue engineering. AB - With nearly 30 years of progress, tissue engineering has shown promise in developing solutions for tissue repair and regeneration. Scaffolds, together with cells and growth factors, are key components of this development. Recently, an increasing number of studies have reported on the design and fabrication of scaffolding materials. In particular, inspired by the nature of bone, polymer/ceramic composite scaffolds have been studied extensively. The purpose of this paper is to review the recent progress of the naturally derived biopolymers and the methods applied to generate biomimetic biopolymer/calcium phosphate composites as well as their biomedical applications in bone tissue engineering. PMID- 24339421 TI - Electrospun biodegradable polyorganophosphazene fibrous matrix with poly(dopamine) coating for bone regeneration. AB - Biodegradable polyphosphazenes were categorized as osteoinductive materials because of their phosphorus-containing feature; however, they were less supportive in cell attachment and proliferation at earlier points in comparison with biodegradable aliphatic polyesters. Therefore, mussel-inspired surface modification of poly(alanine ethyl ester-co-glycine ethyl ester)phosphazene (PAGP) was studied, intending to circumvent the above-mentioned disadvantage of polyphosphazene. To this end, PAGP and poly(L-lactide) (PLLA) were electrospun into nanofibrous substrates and surface treated with dopamine aqueous solution. With the analysis of scanning electron microscope, transmission electron microscope, X-ray photoelectron spectroscope, and Fourier transform infrared spectroscope, the successful poly(dopamine) coating was identified on both PAGP and PLLA nanofibers. MC3T3-E1 osteoblasts were found attaching and proliferating much well on poly(dopamine)-modified nanofibrous substrates in comparison with the pristine ones. In addition, the poly(dopamine) coating demonstrated high activity in promoting osteogenous differentiation. Because the phosphorus content on nanofiber surface was decreased with the poly(dopamine) coating, the poly(dopamine)-coated PAGP nanofibrous substrate was slightly inferior to pure PAGP nanofibrous substrate in osteogenous differentiation. In a summary, the results confirmed that poly(dopamine)-modified polyphosphazenes were promising scaffold materials with both high cell affinity and high osteocompatibility for bone regeneration. PMID- 24339422 TI - Human adipocyte extracellular vesicles in reciprocal signaling between adipocytes and macrophages. AB - OBJECTIVE: Extracellular vesicles (EVs) released by human adipocytes or adipose tissue (AT)-explants play a role in the paracrine interaction between adipocytes and macrophages, a key mechanism in AT inflammation, leading to metabolic complications like insulin resistance (IR) were determined. METHODS: EVs released from in vitro differentiated adipocytes and AT-explants ex vivo were characterized by electron microscopy, Western blot, multiplex adipokine profiling, and quantified by flow cytometry. Primary monocytes were stimulated with EVs from adipocytes, subcutaneous (SCAT) or omental-derived AT (OAT), and phenotyped. Macrophage supernatant was subsequently used to assess the effect on insulin signaling in adipocytes. RESULTS: Adipocyte and AT-derived EVs differentiated monocytes into macrophages characteristic of human adipose tissue macrophages (ATM), defined by release of both pro- and anti-inflammatory cytokines. The adiponectin-positive subset of AT-derived EVs, presumably representing adipocyte-derived EVs, induced a more pronounced ATM-phenotype than the adiponectin-negative AT-EVs. This effect was more evident for OAT-EVs versus SCAT-EVs. Furthermore, supernatant of macrophages pre-stimulated with AT-EVs interfered with insulin signaling in human adipocytes. Finally, the number of OAT derived EVs correlated positively with patients HOMA-IR. CONCLUSIONS: A possible role for human AT-EVs in a reciprocal pro-inflammatory loop between adipocytes and macrophages, with the potential to aggravate local and systemic IR was demonstrated. PMID- 24339423 TI - Comment on "the impact of penicillin skin testing on clinical practice and antimicrobial stewardship". PMID- 24339424 TI - Design, synthesis and structure-activity relationships studies on the D ring of the natural product triptolide. AB - Triptolide is a diterpene triepoxide natural product isolated from Tripterygium wilfordii Hook F, a traditional Chinese medicinal herb. Triptolide has previously been shown to possess antitumor, anti-inflammatory, immunosuppressive, and antifertility activities. Earlier reports suggested that the five-membered unsaturated lactone ring (D ring) is essential for potent cytotoxicity, however, to the best of our knowledge, systematic structure-activity relationship studies have not yet been reported. Here, four types of D ring-modified triptolide analogues were designed, synthesized and evaluated against human ovarian (SKOV-3) and prostate (PC-3) carcinoma cell lines. The results suggest that the D ring is essential to potency, however it can be modified, for example to C18 hydrogen bond acceptor and/or donor furan ring analogues, without complete loss of cytotoxic activity. Interestingly, evaluation of the key series of C19 analogues showed that this site is exquisitely sensitive to polarity. Together, these results will guide further optimization of this natural product lead compound for the development of potent and potentially clinically useful triptolide analogues. PMID- 24339426 TI - The next level of complexity: crosstalk of posttranslational modifications. AB - Beside gene expression and translational control, which are relatively slow, PTM of proteins represents the major level of regulation, from very fast and reversible to slow or irreversible processes. PTMs affect protein structure and act as molecular switches, which regulate the interaction of proteins with DNA, cofactors, lipids, and other proteins. In the past few years, evidence for extensive crosstalk between PTMs has accumulated. The combination of different PTMs on protein surfaces can create a "PTM code," which can be recognized by specific effectors to initiate/inhibit downstream events, only inducing/retaining a signal once the complementary incoming signals are present at the same time and place. Although MS-based proteomics has substantially improved our knowledge about PTMs, currently sensitive and dedicated analytical strategies are available only for few different types of PTM. Several recent studies focused on the combinatorial analysis of PTMs, but preferentially utilized peptide-centric bottom-up strategies might be too restricted to decipher complex PTM codes. Here, we discuss the current state of PTM crosstalk research and how proteomics may contribute to understanding PTM codes, representing the next level of complexity and one of the biggest challenges for future proteomics research. PMID- 24339427 TI - In vivo normative atlas of the hippocampal subfields using multi-echo susceptibility imaging at 7 Tesla. AB - OBJECTIVES: To generate a high-resolution atlas of the hippocampal subfields using images acquired from 7 T, multi-echo, gradient-echo MRI for the evaluation of epilepsy and neurodegenerative disorders as well as investigating R2* (apparent transverse relaxation rate) and quantitative volume magnetic susceptibility (QS) of the subfields. EXPERIMENTAL DESIGN: Healthy control subjects (n=17) were scanned at 7 T using a multi-echo gradient-echo sequence and susceptibility-weighted magnitude images, R2* and QS maps were reconstructed. We defined a hippocampal subfield labeling protocol for the magnitude image produced from the average of all echoes and assessed reproducibility through volume and shape metrics. A group-wise diffeomorphic registration procedure was used to generate an average atlas of the subfields for the whole subject cohort. The quantitative MRI maps and subfield labels were then warped to the average atlas space and used to measure mean values of R2* and QS characterizing each subfield. PRINCIPAL OBSERVATIONS: We were able to reliably label hippocampal subfields on the multi-echo susceptibility images. The group-averaged atlas accurately aligns these structures to produce a high-resolution depiction of the subfields, allowing assessment of both quantitative susceptibility and R2* across subjects. Our analysis of variance demonstrates that there are more apparent differences between the subfields on these quantitative maps than the normalized magnitude images. CONCLUSION: We constructed a high-resolution atlas of the hippocampal subfields for use in voxel-based studies and demonstrated in vivo quantification of susceptibility and R2* in the subfields. This work is the first in vivo quantification of susceptibility values within the hippocampal subfields at 7 T. PMID- 24339428 TI - Body composition and insulin sensitivity after high-intensity interval training in overweight/obese patients. PMID- 24339429 TI - Intraductal tubulopapillary neoplasm with expansile invasive carcinoma of the pancreas diagnosed by endoscopic ultrasonography-guided fine needle aspiration: a case report. AB - Intraductal tubulopapillary neoplasm (ITPN) of the pancreas, a novel entity included in the World Health Organization 2010 classification, accounts for <1% of all pancreatic exocrine neoplasms and the number of reported cases is limited in the English literature. Herein we describe the cytologic features of ITPN with invasive carcinoma showing expansile growth on endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) cytology. A 74-year-old male patient is presented with a 6.2 cm irregular mass in the head of the pancreas. Microscopic examination of EUS-FNA material showed abundant branching clusters of cells, with some scattered discohesive cells. High power magnification revealed tubular and cribriform patterns with central lumina, containing mucinous or proteinaceous secretions. The constituent cells were relatively uniform and showed mild to intermediate nuclear atypia. Intracytoplasmic mucin was not identified. On cell block preparation, luminal spaces of clusters contained wispy luminal mucin. Immunohistochemically, constituent cells were positive for MUC1 and MUC6, and were negative for MUC5AC. The large cribriform and tubular clusters with luminal spaces containing wispy mucin were considered to be diagnostic clues for the cytologic diagnosis of ITPN by EUS-FNA. MUC1, MUC6, and MUC5AC immunohistochemistry for cell-block preparation appears to be a useful adjunctive tool to confirm the diagnosis. On EUS-FNA, ITPN should be included in the differential diagnosis of a pancreatic mass lesion showing good circumscription. PMID- 24339430 TI - Sinonasal extramedullary plasmacytoma: a systematic review of 175 patients. AB - BACKGROUND: This study reviews the published literature related to extramedullary sinonasal plasmacytomas. Clinical presentation, demographics, treatment, and outcomes of this uncommon disease are reported. METHODS: A systematic review of studies for sinonasal plasmacytomas from 1950 to 2012 was conducted. A PubMed database search, both for articles related to this condition along with bibliographies of those selected articles, was performed. Articles were examined for patient data that reported disease outcome. RESULTS: Sixty-seven journal articles were included in this analysis, comprising a total of 175 cases. Radiotherapy was the most common treatment modality, used in 89 cases, followed by a combination of surgery and radiotherapy, and surgery alone. A total of 71.8% of patients were alive after a median follow-up of 39 months, independent of treatment modality. A combination of radiotherapy and chemotherapy was rarely used but had the best treatment outcome, with 88.9% of patients (8/9 patients) alive. Of the 3 most common treatment modalities, a combination of radiotherapy and surgery had the most favorable outcomes. Sixteen patients (9.1%) converted to multiple myeloma, with the majority of these patients (75.0%) receiving radiotherapy alone as their treatment modality. CONCLUSION: This review contains the largest pool of sinonasal plasmacytoma patients to date and suggests aggressive radiotherapy is the most common treatment modality for this condition. Of the 3 most common treatment modalities, a combination of surgery and radiotherapy was shown to have the best survival outcomes. PMID- 24339425 TI - Impact of psychological factors on subjective disease activity assessments in patients with severe rheumatoid arthritis. AB - OBJECTIVE: The Disease Activity Score in 28 joints (DAS28), used to assess disease activity in rheumatoid arthritis (RA), is a composite score comprising clinical, biochemical, and patient self-report measures. We hypothesized that psychological factors (cognitions and mood) would be more strongly associated with patient-reported components of the DAS28 than clinical or biochemical components. METHODS: A cross-sectional, observational study of 322 RA patients with active disease (mean DAS28 6.0) awaiting therapy with a biologic agent was undertaken. Patients' illness beliefs, treatment beliefs, and mood were measured using the Brief Illness Perception Questionnaire (IPQ), the Beliefs about Medicines Questionnaire (BMQ), and the Hospital Anxiety and Depression Scale (HADS), respectively. Relationships between psychological factors and 1) total DAS28 and 2) individual components of the DAS28 were analyzed using linear regression. RESULTS: Total DAS28 produced significant but weak associations with 2 of the Brief IPQ items, but no associations with BMQ or HADS scores. There were larger significant associations between the patient-reported visual analog scale (VAS) with 5 items of the Brief IPQ and with HADS depression. Low illness coherence was associated with higher tender joint count. Three Brief IPQ items and HADS anxiety scores were significantly associated with C-reactive protein level or erythrocyte sedimentation rate. No psychological factors were associated with the swollen joint count. CONCLUSION: One of the subjective components of the DAS28, patient VAS, was highly correlated with cognitive factors and depression in those with severe RA. By reporting individual DAS28 components, clinicians may be better able to assess the impact of therapies on each component, adjusting approaches according to patients' needs. PMID- 24339431 TI - Treatment of single peripheral pulmonary emboli: patient outcomes and factors associated with decision to treat. AB - BACKGROUND: Increasing use of computed tomography pulmonary angiography together with higher-resolution scanners has increased the detection of peripheral filling defects. Physicians face the dilemma of whether to treat patients with these findings, especially single defects. The aims of this study were to compare the outcomes of treated and untreated patients with single peripheral filling defects (SPFD) and identify factors associated with treatment. METHODS: All cases with SPFDs over 66 months in a single institution were identified. Patient and treatment information were abstracted and data on 90-day mortality and postdischarge venous thromboembolism (VTE) were collected. RESULTS: A total of 4906 computed tomography pulmonary angiograms were reviewed. A SPFD was identified in 3.1% (n = 153). Of the 153 patients, 134 met criteria for study inclusion. In 99 of 134 (73.9%) studies, the defect was called a pulmonary embolus (PE) by the initial radiologist. Treatment was administered to 61 of 134 (45.5%) patients; 5 patients died in each group. Postdischarge VTE occurred in 3 treated and 2 untreated patients. In 52 of 153 cases, an additional study was performed. None of the patients with normal ventilation perfusion scan and compression ultrasound received treatment. Immobility (odds ratio [OR]: 3.90, 95% confidence interval [CI]: 1.45-10.60), previous VTE (OR: 3.72, 95% CI: 1.18 11.70), and determination of PE by the radiologist (OR: 24.68, 95% CI: 5.40 112.90) were associated with treatment. CONCLUSIONS: There was no difference in 90-day mortality or recurrence between treated and untreated patients. The most influential factor associated with treatment was the radiologist's interpretation. When secondary lung imaging studies were negative, no patient received treatment. PMID- 24339432 TI - Prevalence of doctor-diagnosed thumb carpometacarpal joint osteoarthritis: an analysis of Swedish health care. AB - OBJECTIVE: While the prevalence of radiographic thumb carpometacarpal (CMC1) osteoarthritis (OA) is well-described, little is known about clinically symptomatic disease presenting to physicians for care. We sought to determine the prevalence of doctor-diagnosed CMC1 OA. METHODS: Using health care data from Skane in southern Sweden (population 1.24 million), we identified all adults ages >20 years who consulted a physician at least once and received a diagnosis for CMC1 OA (International Classification of Diseases, Tenth Revision, code M18). Data from the 15-year period 1998-2012 were analyzed. Using cross-referencing with the Swedish population register to exclude subjects who were deceased or had relocated, we obtained point estimates of the proportion of the population consulting for CMC1 OA. RESULTS: The prevalence of doctor-diagnosed CMC1 OA in adults was estimated at 1.4% (2.2% in women and 0.62% in men). The mean+/-SD age in the prevalent CMC1 cohort (n=11,111) was 67.7+/-11.4 years; 78.5% of diagnoses were in women. Prevalence peaked in women ages 70-74 years with an estimate of 5.3% and in men ages 80-84 years with an estimate of 1.7%. Age at initial diagnosis also differed, with women presenting between ages 60-69 years and men presenting between ages 70-79 years. CONCLUSION: The clinically important prevalence of CMC1 OA is 3 to 4 times higher in women than men. By the end of2012, more than 1 in 20 elderly women had consulted a physician for CMC1 OA over the last 15 years. The high prevalence of this subset of hand OA is a concern in an aging population. PMID- 24339433 TI - Applications of mass spectrometry for quantitative protein analysis in formalin fixed paraffin-embedded tissues. AB - Proteomic analysis of tissues has advanced in recent years as instruments and methodologies have evolved. The ability to retrieve peptides from formalin-fixed paraffin-embedded tissues followed by shotgun or targeted proteomic analysis is offering new opportunities in biomedical research. In particular, access to large collections of clinically annotated samples should enable the detailed analysis of pathologically relevant tissues in a manner previously considered unfeasible. In this paper, we review the current status of proteomic analysis of formalin fixed paraffin-embedded tissues with a particular focus on targeted approaches and the potential for this technique to be used in clinical research and clinical diagnosis. We also discuss the limitations and perspectives of the technique, particularly with regard to application in clinical diagnosis and drug discovery. PMID- 24339434 TI - Asymmetric chromosome segregation in Xanthomonas citri ssp. citri. AB - This study was intended to characterize the chromosome segregation process of Xanthomonas citri ssp. citri (Xac) by investigating the functionality of the ParB factor encoded on its chromosome, and its requirement for cell viability and virulence. Using TAP tagging we show that ParB is expressed in Xac. Disruption of parB increased the cell doubling time and precluded the ability of Xac to colonize the host citrus. Moreover, Xac mutant cells expressing only truncated forms of ParB exhibited the classical phenotype of aberrant chromosome organization, and seemed affected in cell division judged by their reduced growth rate and the propensity to form filaments. The ParB-GFP localization pattern in Xac was suggestive of an asymmetric mode of replicon partitioning, which together with the filamentation phenotype support the idea that Xac may control septum placement using mechanisms probably analogous to Caulobacter crescentus, and perhaps Vibrio cholerae, and Corynebacterium glutamicum. Xac exhibits asymmetric chromosome segregation, and the perturbation of this process leads to an inability to colonize the host plant. PMID- 24339436 TI - Response letter. PMID- 24339437 TI - Relationship between objectively assessed physical activity and fatigue in patients with rheumatoid arthritis: inverse correlation of activity and fatigue. AB - OBJECTIVE: Fatigue is generally associated with low physical activity in patients with various chronic medical conditions. However, such an association has not been reported among patients with rheumatoid arthritis (RA). The objectives of this study were to investigate whether daily activity level is associated with fatigue in patients with RA, and whether pain, disability, coping, and/or cognition are associated with the level of daily activity. METHODS: Patients with RA who visited our outpatient clinic were recruited consecutively. Fatigue severity was measured using the Checklist Individual Strength (CIS20). Physical activity was measured for 14 consecutive days using an ankle-worn actometer. The daily activity level of each patient was calculated, and each patient was classified as having a low or high activity level with respect to the group average. Data were analyzed by linear regression. RESULTS: A total of 167 patients were included in the analysis; 25% had a low activity level and 75% had a high activity level. A regression analysis revealed that higher activity levels were associated with reduced fatigue (P = 0.008). The mean +/- SD CIS fatigue score was 30.9 +/- 12.3 among the patients with a high activity level and 35.7 +/ 12.8 among the patients with a low activity level (P = 0.03). Pain, disability, coping, and cognition were not associated significantly with daily activity level. CONCLUSION: Among patients with RA, a higher level of daily physical activity was associated with reduced levels of fatigue. This relationship was not explained by differences in sex, age, disease duration, pain, disability, or other fatigue-related factors. PMID- 24339435 TI - SULF2 strongly prediposes to fasting and postprandial triglycerides in patients with obesity and type 2 diabetes mellitus. AB - OBJECTIVE: Hepatic overexpression of sulfatase-2 (SULF2), a heparan sulfate remodeling enzyme, strongly contributes to high triglyceride (TG) levels in obese, type 2 diabetic (T2DM) db/db mice. Nevertheless, data in humans are lacking. Here, the association of human hepatic SULF2 expression and SULF2 gene variants with TG metabolism in patients with obesity and/or T2DM was investigated. METHODS: Liver biopsies from 121 obese subjects were analyzed for relations between hepatic SULF2 mRNA levels and plasma TG. Associations between seven SULF2 tagSNPs and TG levels were assessed in 210 obese T2DM subjects with dyslipidemia. Replication of positive findings was performed in 1,316 independent obese T2DM patients. Postprandial TRL clearance was evaluated in 29 obese T2DM subjects stratified by SULF2 genotype. RESULTS: Liver SULF2 expression was significantly associated with fasting plasma TG (r = 0.271; P = 0.003) in obese subjects. The SULF2 rs2281279(A>G) SNP was reproducibly associated with lower fasting plasma TG levels in obese T2DM subjects (P < 0.05). Carriership of the minor G allele was associated with lower levels of postprandial plasma TG (P < 0.05) and retinyl esters levels (P < 0.001). CONCLUSIONS: These findings implicate SULF2 as potential therapeutic target in the atherogenic dyslipidemia of obesity and T2DM. PMID- 24339438 TI - Ten years of proteomics in multiple sclerosis. AB - Multiple sclerosis, which is the most common cause of chronic neurological disability in young adults, is an inflammatory, demyelinating, and neurodegenerative disease of the CNS, which leads to the formation of multiple foci of demyelinated lesions in the white matter. The diagnosis is based currently on magnetic resonance image and evidence of dissemination in time and space. However, this could be facilitated if biomarkers were available to rule out other disorders with similar symptoms as well as to avoid cerebrospinal fluid analysis, which requires an invasive collection. Additionally, the molecular mechanisms of the disease are not completely elucidated, especially those related to the neurodegenerative aspects of the disease. The identification of biomarker candidates and molecular mechanisms of multiple sclerosis may be approached by proteomics. In the last 10 years, proteomic techniques have been applied in different biological samples (CNS tissue, cerebrospinal fluid, and blood) from multiple sclerosis patients and in its experimental model. In this review, we summarize these data, presenting their value to the current knowledge of the disease mechanisms, as well as their importance in identifying biomarkers or treatment targets. PMID- 24339439 TI - Adolescent varicocelectomy: does artery sparing influence recurrence rate and/or catch-up growth? AB - The prevalence of varicocoeles is 15% in the general adolescent and adult male population and in 35-40% of men evaluated for infertility. While varicocelectomy can be performed using various methods and techniques, the laparoscopic approach allows for clear visualization of the testicular artery and lymphatics. Amongst urologists, particularly paediatric urologists, and andrologists there is much debate regarding the significance of testicular artery sparing when performing a varicocelectomy, with some believing that ligating the testicular artery impairs catch-up growth and future fertility. On the other hand, several studies have reported higher failure rates with artery preservation. To help resolve the debate regarding the significance of artery sparing, we sought to compare varicocoele recurrence rate and catch-up growth in patients who underwent artery sparing laparoscopic varicocelectomy compared with those who had the artery sacrificed. We identified 524 laparoscopic varicocelectomies in 425 patients from our adolescent varicocoele database. Only patients who had ultrasound determined testicular volume measurements pre-operatively and at least 6 months post operatively were included. Post-operative persistence/recurrence of varicocoele, testicular atrophy and repeat varicocelectomy were noted. Catch-up growth was compared between procedures in those with significant pre-operative asymmetry. Four hundred and forty primary laparoscopic varicocelectomies were performed in 355 patients (mean age: 15.5 years, range 9.3-20.6; mean follow-up: 32.9 months, range 6.0-128.9) who had both pre- and post-varicocelectomy scrotal Duplex Doppler ultrasound performed. The testicular artery was preserved in 54 varicocoeles (41 patients) and ligated in 384 varicocoeles (312 patients). We observed an increased rate of persistent/recurrent varicocoele in the artery sparing vs. artery ligating patients (12.2% vs. 5.4%, p = 0.09). In addition, there was no difference in catch-up growth and no instance of testicular atrophy. As artery sparing varicocelectomy offered no advantage in regards to catch-up growth and was associated with a higher incidence of recurrent varicocoele, preservation of the artery does not appear to be routinely necessary in adolescent varicocelectomy. PMID- 24339440 TI - Maternal pre-pregnancy body mass index and pubertal development among sons. AB - Maternal overweight and obesity in pregnancy has been associated with earlier age of menarche in daughters as well as reduced semen quality in sons. We aimed at investigating pubertal development in sons born by mothers with a high body mass index (BMI). The study included 2522 sons of mothers that during pregnancy in 1984-1987 were enrolled in a mother-child cohort and gave information on their pre-pregnancy height and weight from which we calculated their BMI. Information on sons' pubertal development, assessed by age when starting regular shaving, voice break, acne and first nocturnal emission, was obtained from web-based questionnaires in 2005, when sons were 18-21 years old. Multiple linear regression analyses showed that sons of obese mothers on average started to shave regularly 8.3 (95% confidence interval: 2.5-14.0) months earlier than sons of normal weight mothers. For the three other indicators of pubertal development, results also indicated earlier pubertal development among sons of obese mothers. After excluding sons of underweight mothers in a subanalysis, we observed an inverse trend between maternal pre-pregnancy BMI and age at regular shaving, acne and first nocturnal emission. In conclusion, maternal pre-pregnant obesity may be related to earlier timing of pubertal milestones among sons. More research, preferably based on prospectively collected information about pubertal development, is needed to draw firm conclusions. PMID- 24339442 TI - The roles of extracellular vesicles in cancer biology: toward the development of novel cancer biomarkers. AB - Recent important progress in cancer biology was the identification of the significant roles played by extracellular vesicles (EVs). EVs are secreted by a variety of mammalian cell types and have been revealed to play important roles in intercellular communications. EVs serve as unique communication vehicles in many ways. First, unlike cytokine signaling, EVs enable transportation not only of proteins, but also of nucleic acids, including mRNAs and microRNAs. Recent reports showing the functionality of these nucleic acids in the recipient cells have opened up a new avenue of cell-to-cell communication research. Second, EVs have been revealed to transport membrane components including receptors, such as epithelial growth factor receptor. These findings have provided significant insights into understanding the molecular mechanisms of cancer development. Third, EVs protect their contents from clearance by degrading enzymes present in the extracellular space, which allows for remote transportation of the contents, even between organs. This concept is highlighted by recent reports that suggest the deep involvement of cancer cell derived EVs in metastasis. From these points of view, we will summarize recent studies on the relevance of EVs in cancer biology. We will also highlight the possibility of novel diagnostic technologies using circulating EVs in body fluid. PMID- 24339441 TI - Design and development of a decision support package for low back pain. AB - OBJECTIVE: To develop a decision support package for people with low back pain (LBP) referred for physiotherapy. METHODS: We used a program of exploratory work, including literature reviews, a Delphi study, a nominal group with physiotherapists, focus groups with patients, and secondary analysis of existing interview data. RESULTS: We developed an information booklet describing the evidence-based treatment modalities available in a physiotherapy department. This includes data on likely benefits and risks and how the intervention is delivered. The booklet specifically addresses questions identified as important in our exploratory work. Space is provided for patients to note down the pros and cons of each treatment and what matters to them when choosing treatments. The patient is subsequently directed to a section that explores any gaps in knowledge, values, support, and choice before finally clarifying if a treatment decision is possible. At this stage they are encouraged to note down any questions or concerns they have to be discussed at the first physiotherapy consultation. This overall package includes patient material in the form of a booklet posted prior to their consultation, plus the enhanced consultation with the specially trained physiotherapist. Patients then receive their chosen treatment. In addition we developed a training package for physiotherapists that explains the content of the booklet and supports them in using informed, shared decision making in their consultation. CONCLUSION: This package has the potential to improve effectiveness of treatments and patient satisfaction for LBP by facilitating patient choice and therefore matching patients more effectively to different treatments. PMID- 24339443 TI - Inflammatory cytokines in exhaled breath condensate in children with inflammatory bowel diseases. AB - BACKGROUND: Although inflammatory bowel diseases (IBD) affect mainly the gastrointestinal tract, the extra-intestinal manifestations are not uncommon. Different diagnostic methods have been applied to assess pulmonary involvement in patients with IBD, but majority of these methods show significant limitations in children. The aim of our study was to evaluate the usefulness of exhaled breath condensate (EBC) measurements of pro-inflammatory cytokines in children with IBD. MATERIAL AND METHODS: Twenty-two children with Crohn's disease (CD) (mean age 13.8 +/- 3.3 years), 25 with ulcerative colitis (UC) (mean age 14.1 +/- 3.3 years) and 37 healthy volunteers (mean age 13.9 +/- 3.6 years) were studied. IBD activity was assessed using appropriate scoring systems. None of the patients had signs or symptoms of pulmonary disease. Exhaled breath condensate was collected and EBC concentration of interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta), and interleukin 8 (IL-8) was measured. RESULTS: The concentrations of all the assessed cytokines were significantly higher in the study group as compared to controls. A negative correlation between IL-1beta and CD activity index was found. There were no significant relationships between TNF-alpha, IL-6, or IL-8 level and CD activity index as well as between IL-1beta, TNF-alpha, IL-6, IL-8 and UC activity index. No significant correlation between the concentration of IL-1beta, TNF-alpha, IL-6, IL-8, and IBD duration or treatment duration was found. CONCLUSIONS: Elevated concentration of pro inflammatory cytokines in EBC in children with IBD may suggest the presence of asymptomatic inflammation in the lower airways. PMID- 24339444 TI - Understanding presenteeism in patients with ankylosing spondylitis: contributing factors and association with sick leave. AB - OBJECTIVE: To understand the impact of ankylosing spondylitis (AS) on presenteeism and to explore its relationship to sick leave. METHODS: AS patients completed a questionnaire consisting of sociodemographics, disease characteristics, and work outcomes, including sick leave and presenteeism, assessed by the Work Limitations Questionnaire (WLQ). Associations between a broad range of explanatory variables with the WLQ and AS-related sick leave were assessed by zero-inflated negative binomial and zero-inflated Poisson regressions. RESULTS: Of 311 employed patients (204 men [65.6%]), 18% had sick leave in the past month. Limitations in meeting time management demands (33.7%), physical demands (30.2%), mental-interpersonal demands (20.2%), and output (19.0%) were noted. With the mean +/- SD WLQ index score of 6.7 +/- 5.9, the average decrease in work productivity attributable to health was 6.3%; an extra 7.1% of work hours would be needed to compensate for lost productivity. Helplessness, female sex, and impaired health-related quality of life (Ankylosing Spondylitis Quality of Life instrument [ASQoL]) were major contributors to the level of presenteeism (P < 0.01). At-work limitations (WLQ) and lower quality of life (ASQoL) were significantly associated with probability of sick leave, while the length of sick leave was strongly associated with lower educational level and helplessness (P < 0.01), and in some models, also with disease duration and country of residence (P < 0.05). CONCLUSION: AS hinders patients' work, mainly in time management and physical demand domains. The WLQ and ASQoL are able to identify patients who incur sick leave. Helplessness contributes independently to the level of presenteeism and the length of sick leave. PMID- 24339445 TI - Natural surfactant combined with superoxide dismutase and catalase decreases oxidative lung injury in the preterm lamb. AB - We performed a randomized study in preterm lambs to assess the hypothesis that treatment with a natural surfactant combined with superoxide dismutase (SOD) and catalase (CAT) might decrease pulmonary oxidative stress in an animal model of respiratory distress syndrome (RDS). Animals received 200 mg/kg of porcine natural surfactant or 200 mg/kg of natural surfactant combined with 2 mg/ml of SOD and 3,000 U/ml of CAT. Lung tissue oxidation was studied by measuring total hydroperoxide (TH), advanced oxidation protein products (AOPP), and non-protein bound iron (NPBI) in bronchial aspirate samples. In addition, the animal's lung mechanics were evaluated. TH, AOPP, and NPBI were lower in the groups treated with surfactant plus SOD and CAT than in the surfactant group, while lung mechanics did not vary. We concluded that natural surfactant combined with SOD and CAT is effective in reducing the oxidative lung stress in an animal model of RDS. PMID- 24339446 TI - Fluorine NMR-based screening on cell membrane extracts. AB - The possibility of measuring the action of inhibitors of specific enzymatic reactions in intact cells, cell lysates or membrane preparations represents a major advance in the lead discovery process. Despite the relevance of assaying in physiological conditions, only a small number of biophysical techniques, often requiring complex set-up, are applicable to these sample types. Here, we demonstrate the first application of n-fluorine atoms for biochemical screening (n-FABS), a homogeneous and versatile assay based on (19) F NMR spectroscopy, to the detection of high- and low-affinity inhibitors of a membrane enzyme in cell extracts and determination of their IC50 values. Our approach can allow the discovery of novel binding fragments against targets known to be difficult to purify or where membrane-association is required for activity. These results pave the way for future applications of the methodology to these relevant and complex biological systems. PMID- 24339447 TI - Sarcoidosis in children: HRCT findings and correlation with pulmonary function tests. AB - RATIONALE: High-resolution computed tomography (HRCT) plays an important role in the diagnosis and staging of pulmonary sarcoidosis, but implies radiation exposure. In this light, we aimed to describe HRCT findings as well as their relationship with pulmonary function tests (PFT) in children with pulmonary sarcoidosis. METHODS: In a retrospective study, 18 pediatric patients with sarcoidosis, including 12 with pulmonary abnormalities (PA group) and 6 without pulmonary abnormalities (APA group) were followed over a 16-year period. Relationships between HRCT scores and PFT were studied by non-parametric Spearman's test at diagnosis and by restricted maximum likelihood (REML) analysis during follow-up. RESULTS: Forty-three HRCT were scored. Twelve patients showed abnormal HRCT findings at diagnosis with multiple nodules or micronodules, while ground-glass opacities were seen in 11 patients. Ten patients exhibited pleural thickening or thickening of the fissure and 6 had interlobular septal thickening at diagnosis. No correlation between HRCT and forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1), forced expiratory flow during the mid-half of the FVC (FEF(25-75)) and specific dynamical compliance (SpecC(Ldyn)) was found at diagnosis. However, linear mixed models showed that changes in total HRCT scores over time were significantly associated with SpecC(Ldyn), FVC, and FEV1 modifications. CONCLUSION: Radiologic findings in children with pulmonary sarcoidosis were similar to those in adults. HRCT and PFT are both essential investigations at diagnosis; however, the correlation between HRCT pulmonary parenchymal findings and PFT over time suggests the possibility of reducing the number of HRCT during follow-up to decrease unnecessary radiation exposure. PMID- 24339448 TI - Switchable substrates for analyzing and engineering cellular functions. AB - Cellular activity is highly dependent on the extracellular environment, which is composed of surrounding cells and extracellular matrices. This focus review summarizes recent advances in chemically and physically engineered switchable substrates designed to control such cellular microenvironments by application of an external stimulus. Special attention is given to their molecular design, switching strategies, and representative examples for bioanalytical and biomedical applications. PMID- 24339450 TI - Partnership for Research & Education in Plants (PREP): Involving High School Students in Authentic Research in Collaboration with Scientists. AB - A partnership between scientists, high school teachers, and their students provides authentic research experiences to help students understand the nature and processes of science. The Partnership for Research and Education in Plants (PREP) engages students in a large-scale genomics research project using classroom-tested protocols that can help to find the function of a disabled gene in the widely studied plant Arabidopsis thaliana. Here, we describe the framework of PREP in the classroom within the context of the National Science Education Standards. PMID- 24339449 TI - Does the "Hispanic paradox" occur in rheumatoid arthritis? Survival data from a multiethnic cohort. AB - OBJECTIVE: Despite lower socioeconomic status (SES) and higher disease burden, Hispanics in the US paradoxically display equal or lower mortality on average than non-Hispanic whites. Our objective was to determine if the "Hispanic paradox" occurs among patients with rheumatoid arthritis (RA). METHODS: In a cohort of 706 RA patients, we compared differences in RA severity and comorbidity between Hispanic and non-Hispanic white ethnic groups at baseline. Cox proportional hazards models were used to estimate and compare mortality risk between Hispanics and non-Hispanic whites. RESULTS: We studied 706 patients with RA, of whom 434 were Hispanic and 272 were non-Hispanic white. Hispanics had significantly lower SES, greater inflammation, as well as higher tender and swollen joint counts. Patients were observed for 6,639 patient-years, during which time 229 deaths occurred by the censoring date (rate 3.4 per 100 person years; 95% confidence interval 3.0, 3.9). Age- and sex-adjusted mortality was not significantly different between the 2 ethnic groups (hazard ratio [HR] 0.96). After adjustment for comorbidities, RA severity, and level of acculturation, mortality among Hispanics was lower (HR 0.56, P = 0.004). CONCLUSION: Despite greater severity in most clinical manifestations and lower SES among Hispanics, paradoxically, their mortality was not increased. Further research is needed to understand the mechanisms underlying this survival paradox. PMID- 24339451 TI - The Contributions of Immigrants to American Culture. AB - The standard account of American immigration focuses on the acculturation and assimilation of immigrants and their children to American society. This analysis typically ignores the significant contributions of immigrants to the creation of American culture through the performing arts, sciences, and other cultural pursuits. Immigrants and their children are not born with more creative talents than native-born citizens, but their selectivity and marginality may have pushed and pulled those with ability into high-risk career paths that reward creative work. The presence of large numbers of talented immigrants in Hollywood, academia, and the high-tech industries has pushed American institutions to be more meritocratic and open to innovation than they would be otherwise. PMID- 24339452 TI - Perceptual Contrast Enhancement with Dynamic Range Adjustment. AB - Recent years, although great efforts have been made to improve its performance, few Histogram equalization (HE) methods take human visual perception (HVP) into account explicitly. The human visual system (HVS) is more sensitive to edges than brightness. This paper proposes to take use of this nature intuitively and develops a perceptual contrast enhancement approach with dynamic range adjustment through histogram modification. The use of perceptual contrast connects the image enhancement problem with the HVS. To pre-condition the input image before the HE procedure is implemented, a perceptual contrast map (PCM) is constructed based on the modified Difference of Gaussian (DOG) algorithm. As a result, the contrast of the image is sharpened and high frequency noise is suppressed. A modified Clipped Histogram Equalization (CHE) is also developed which improves visual quality by automatically detecting the dynamic range of the image with improved perceptual contrast. Experimental results show that the new HE algorithm outperforms several state-of-the-art algorithms in improving perceptual contrast and enhancing details. In addition, the new algorithm is simple to implement, making it suitable for real-time applications. PMID- 24339453 TI - The Impact of Race and Ethnicity, Immigration, and Political Context on Participation in American Electoral Politics. AB - This study uses national survey data in federal election years during 1996-2004 to examine voter registration and voting. It shows that racial/ethnic disparities in socio-economic resources and rootedness in the community do not explain overall group differences in electoral participation. It contradicts the expectation from an assimilation perspective that low levels of Latino participation are partly attributable to the large share of immigrants among Latinos. In fact net differences show higher average Latino participation than previously reported. The study focuses especially on contextual factors that could affect collective responses of group members. Moving beyond past research, significant effects are found for the group's representation among office holders, voting regulations, and state policies related to treatment of immigrants. PMID- 24339454 TI - CAUSAL INFERENCE FOR CONTINUOUS-TIME PROCESSES WHEN COVARIATES ARE OBSERVED ONLY AT DISCRETE TIMES. AB - Most of the work on the structural nested model and g-estimation for causal inference in longitudinal data assumes a discrete-time underlying data generating process. However, in some observational studies, it is more reasonable to assume that the data are generated from a continuous-time process and are only observable at discrete time points. When these circumstances arise, the sequential randomization assumption in the observed discrete-time data, which is essential in justifying discrete-time g-estimation, may not be reasonable. Under a deterministic model, we discuss other useful assumptions that guarantee the consistency of discrete-time g-estimation. In more general cases, when those assumptions are violated, we propose a controlling-the-future method that performs at least as well as g-estimation in most scenarios and which provides consistent estimation in some cases where g-estimation is severely inconsistent. We apply the methods discussed in this paper to simulated data, as well as to a data set collected following a massive flood in Bangladesh, estimating the effect of diarrhea on children's height. Results from different methods are compared in both simulation and the real application. PMID- 24339455 TI - PET/MRI in the infarcted mouse heart with the Cambridge split magnet. AB - Chronic heart failure, as a result of acute myocardial infarction, is a leading cause of death worldwide. Combining diagnostic imaging modalities may aid the direct assessment of experimental treatments targeting heart failure in vivo. Here we present preliminary data using the Cambridge combined 18FDG PET/MRI imaging system in a mouse model of acute myocardial infarction. The split-magnet design can deliver uncompromised MRI and PET performance, for better assessment of disease and treatment in a preclinical environment. PMID- 24339456 TI - An update on oral human papillomavirus infection. AB - Human papillomavirus (HPV) constitutes the majority of newly acquired sexually transmitted infections (STIs) in United States as per the centers for disease control factsheet 2013. Genital HPV is the most common STI with incidence of about 5.5 million world-wide, nearly 75% of sexually active men and women have been exposed to HPV at some point in their lives. Oral Sexual behavior is an important contributor to infection of HPV in the oral mucosa especially in cases known to practice high risk behavior and initiating the same at an early age. HPV infection of the oral mucosa currents is believed to affect 1-50% of the general population, depending on the method used for diagnosis. The immune system clears most HPV naturally within 2 years (about 90%), but the ones that persist can cause serious diseases. HPV is an essential carcinogen being implicated increasingly in association with cancers occurring at numerous sites in the body. Though there does not occur any specific treatment for the HPV infection, the diseases it causes are treatable such as genital warts, cervical and other cancers. PMID- 24339457 TI - Prevalence of symptoms suggestive of reproductive tract infections/sexually transmitted infections in women in an urban area of Ludhiana. AB - BACKGROUND: RTIs/STIs present a huge burden of disease, adversely impact reproductive health, and cause suffering for both men and women with consequences more devastating and widespread among women. These infections often go undiagnosed and untreated. OBJECTIVES: 1) To identify the most common reported symptoms of RTI/STI among married women aged 15-44 years in an urban population of Ludhiana. 2) To identify important risk factors associated with symptoms of RTI/STI in the study population. MATERIALS AND METHODS: A cross-sectional study was carried out among married women aged 15-44 years in an urban area in Ludhiana, using the WHO-Syndromic Approach for diagnosis and management of RTIs/STIs. The sample consisted of 260 eligible women obtained by systematic random sampling, from amongst those residing in the population served by one MPHW (F). RESULTS: The prevalence of symptoms suggestive of RTIs/STIs in the study population was found to be 17.3%. The most common symptoms reported by the women sufferers were urinary (dysuria 57.8%, frequent urination 53.3%), followed by dyspareunia (26.7%), unusual vaginal discharge (24.4%) and vaginal itching (22.2%). Age 35-44 years, gravidity >4, education high school/above, joint families, history of abortion, and using ordinary cloth during menstruation were found to be significant risk factors. 64.4% of those with symptoms were untreated, 68.7% of those treated reported partial relief, most of those treated preferred private doctors, and the partners were not treated. PMID- 24339458 TI - Dermatological manifestations in human immunodeficiency virus infected patients: Morphological spectrum with CD4 correlation. AB - BACKGROUND: More than 90% of human immunodeficiency virus (HIV) infected patients develop skin lesions at some time throughout the course of the disease. Several skin diseases have proved to be sensitive and useful indicators of progression of HIV infection. Although these conditions may be seen in general healthy population, their occurrence in patients with acquired immunodeficiency syndrome is often atypical, more severe and explosive. AIMS: The present study was carried out to categorize the skin lesions by histopathology using punch biopsy or cytology when feasible in HIV infected patients and to see the correlation for various skin lesions with CD4 counts. MATERIALS AND METHODS: In total 110 known HIV positive patients with the symptomatic skin lesions, cytology and punch biopsy was correlated with CD4 counts. RESULTS: Maximum patients were between 31 and 40 years. 53 (48.18%) patients had infectious and 37 (34.55%) patients had non-infectious lesions. Out of 110 patients, CD4 counts were available in 70 patients. The spectrum of various non-infectious and infectious lesions such as viral, bacterial, fungal, protozoa and their association with CD4 counts is discussed. CONCLUSIONS: CD4 counts below 200 were associated with the maximum infectious lesions, whereas CD4 counts more than 350 showed more of the non infectious lesions. Most common infectious lesion was Molluscum contagiosum. The most common non-infectious lesion was pruritic papular eruptions. PMID- 24339459 TI - Detection of human immunodeficiency virus using oral mucosal transudate by rapid test. AB - CONTEXT: On the cusp of the fourth decade of the acquired immunodeficiency syndrome epidemic, the world has turned the corner - it has halted and began to reverse the spread of human immunodeficiency virus (HIV). Oral fluid-based Rapid tests have potential advantages over blood-based tests hence the time is ripe for their use to scale up HIV screening and testing programmes. AIMS AND OBJECTIVES: To detect HIV using oral mucosal transudate (OMT) and to assess the sensitivity and specificity of the HIV Rapid test using OMT. SETTINGS AND DESIGN: OraQuick Rapid HIV-1/2 Diagnostic test was evaluated in sera and oral fluids from 83 subjects. MATERIALS AND METHODS: The study group comprised of 50 HIV seropositive subjects and the control group comprised of 33 seronegative subjects. Serum samples were collected using the standard phlebotomy technique and oral samples were collected using OraQuick Rapid HIV 1/2 Antibody test OMT collecting device. STATISTICAL ANALYSIS USED: The statistical analysis was done using statistical package for social sciences version 16.0, SPSS Inc., 233 South Wacker Drive, 11(th) Floor, Chicago, IL 60606-6412. The Sensitivity, specificity, positive predictive value, negative predictive value were used. RESULTS: All the subjects who tested either positive/reactive or negative/non-reactive with Western blot/enzyme-linked immunosorbent assay (ELISA) produced similar results with Rapid test using OMT in study, our study also revealed that the subjects whether on anti-retroviral therapy or not had 100% sensitivity and specificity with the Rapid test using OMT. CONCLUSIONS: The Rapid test using OMT is highly accurate as the diagnostic efficacy in our study was 100% for HIV antibody detection and produced similar results to that of conventional Western blot/ELISA tests. PMID- 24339460 TI - Value of human papillomavirus typing for detection of anal cytological abnormalities. AB - PURPOSE: The objective of this study was to evaluate anal cytology and human papillomavirus (HPV) typing in patients with human immunodeficiency virus infection. MATERIALS AND METHODS: Anal samples were collected from 61 patients (44 men and 17 women) and analyzed by PapilloCheck test and conventional cytology. RESULTS: Of all anal samples, 37.7% had cytological abnormalities, 47.54% were negative and 14.75% were unsatisfactory. High-risk HPV, multiple high risk HPV and HPV 16 infection was detected in 91.13%, 78.26% and 47.82% of the samples with cytological abnormalities and in 47.54%, 6.89% and 3.44% of the negative samples, respectively. High-risk HPV infection was significantly more frequent in anal samples with cytological abnormalities than in negative samples (P = 0.0005, Fisher's test), particularly multiple high-risk HPV infection (P < 0.0001) and HPV 16 infection (P = 0.0002). CONCLUSIONS: High-risk HPV, multiple high-risk HPV and HPV 16 infections are significantly associated with anal cytological abnormalities. Furthermore, the frequency of HPV infection in anal cytological samples suggests that high-risk HPV detection has high sensitivity, but low specificity for detection of anal cytological abnormalities, but multiple high-risk HPV typing and HPV 16 typing have a lower sensitivity and high specificity. Results suggest that HPV typing may be useful as an adjunct to cytology to screen patients for high-resolution anoscopy and biopsy. PMID- 24339461 TI - Musculoskeletal and rheumatological disorders in HIV infection: Experience in a tertiary referral center. AB - BACKGROUND: Musculoskeletal involvement in human immunodeficiency virus (HIV) infected patients are important disease manifestations, responsible for increased morbidity and also decreased quality of life. OBJECTIVES: To study the spectrum of different musculoskeletal involvement in HIV infected patients and its impact on quality of life. PATIENTS AND METHODS: Three hundred (n = 300) HIV-1 reactive patients were evaluated in respect to different musculoskeletal involvement including the quality of life from January 2010 to January 2011. RESULTS: Male to female ratio was 11:1 with a mean age of 35 (+/-6.4) years and mean duration of the disease was 3 (+/-1.54) years. Majority of cases were truck drivers, motel workers, and jewelry workers. Musculoskeletal disorders were observed in a total of 190 cases (63.33%). The spectrum of musculoskeletal involvement was: Body ache in 140 (46.7%), arthralgia in 80 (26.7%), mechanical low back pain in 25 (8.3%), osteoporosis in 20 (6.7%), painful articular syndrome in 10 (3.3%), hypertrophic osteoarthropathy in two (0.7%), pyomyositis in two (0.7%), osteomyelitis in one (0.3%), and avascular bone necrosis in one patient (0.3%). Rheumatologic disorders associated were: Reactive arthritis in seven (2.3%), fibromyalgia in four (1.3%), septic arthritis in three (1%), acute gout in three (1%), spondyloarthropathy in two (0.7%), rheumatoid arthritis in two (0.7%), dermatomyositis in one (0.3%), and systemic lupus erythematosus (SLE) in one patient (0.3%). But HIV associated arthritis and diffuse infiltrative lymphocytosis syndrome (DILS) were not detected. Most of the patients had decreased quality of life. CONCLUSIONS: Musculoskeletal involvement was common in HIV patients causing increased morbidity, so early detection and timely intervention is essential to improve quality of life. PMID- 24339462 TI - Changing incidence of nevirapine-induced cutaneous drug reactions: After revised guideline Nov 2011. AB - AIMS AND OBJECTIVES: To study the change in the incidence and pattern of nevirapine (NVP)-induced adverse cutaneous reactions (ADR) after commencement of revised National AIDS Control Organisation (NACO) guidelines for initiation of antiretroviral therapy (ART) since Nov 2011. MATERIALS AND METHODS: The study was conducted on patients who developed cutaneous reactions after starting NVP based regimen. According to the revised NACO ART initiation guidelines Nov 2011, ART should be started if CD4 count is < 350 cells/mm(3) in stages 1, and 2 and irrespective of CD4 count in stages 3, and 4. Patients were divided in groups A and B. Group A consisted of patients enrolled on NVP-based regimen during Jan 2011 to Oct 2011, whereas, in Group B patients from Nov 2011 to Aug 2012 were included. Grading of rash, appropriate investigations and management was done. OBSERVATIONS: In Group A, out of 645 patients 30 (4.66%) patients developed cutaneous reactions, where as in Group B out of 720, 65 (9.03%) patients presented with drug reaction. In Group A (n = 30) developed reaction as Grade 1 in 1.55% (n = 10), Grade 2 in 1.86% (n = 12), grades 3 and 4 in 0.76% (n = 5) and 0.47% (n = 3), respectively. In Group B (n = 65) developed reaction, out of which Grade 1 reaction was seen in 1.39% (n = 10), Grade 2 was seen in 2.78% (n = 20), grades 3 and 4 was seen in 3.33% (n = 24) and, 1.53% (n = 11), respectively. CONCLUSION: There is a striking increase in the incidence of NVP-induced cutaneous reactions of all forms and considerable increase in frequency of severe kind of reactions with the revised guidelines. PMID- 24339463 TI - Triple protozoal enteropathy of the small intestine in an immunocompromised male: A rare histopathology report. AB - Enteric protozoan parasites remain the most commonly encountered parasitic diseases in HIV infected patients. Opportunistic protozoal infections that infect GIT most commonly and cause diarrhea in HIV-infected patients are cryptosporidium parvum, microsporidia and Isospora belli. Developing an infection with enteric protozoan parasites is dependent on absolute CD4+ cell counts, with lower counts associated with more severe, more atypical disease, and a greater risk of disseminated disease. We present histopathological features in a patient, where all three parasitic infections co-existed in HIV infected patient, who was under antitubercular therapy in addition to antiretroviral therapy and herpes zoster infection being treated by acyclovir. PMID- 24339464 TI - Pseudoepitheliomatous keratotic and micaceous balanitis. AB - Many premalignant and malignant lesions affect the genitalia of elderly men. These include conditions like erythroplasia of Queyret, giant condyloma acuminata, verrucous carcinoma, invasive squamous cell carcinoma (SCC), which are relatively common. We report a case of a 65-year-old male with pseudoepitheliomatous keratotic and micaceous balanitis which is a rare penile condition affecting the elderly. It is considered as a distinct clinical entity by some, while others consider it as a condition that overlaps with verrucous carcinoma. It can also be considered a premalignant condition, as progression to invasive SCC has been noted. PMID- 24339465 TI - Bullous disorders as a manifestation of immune reconstitution inflammatory syndrome: A series of three cases. AB - Bullous disorders such as pemphigus vulgaris, bullous pemphigoid after the initiation of highly active antiretroviral therapy in certain human immunodeficiency virus reactive individuals have been described in this case series as a manifestation of an immune reconstitution inflammatory syndrome. This phenomenon should be suspected in individuals who present with bullous lesions within 3-8 weeks after initiation of therapy despite of improved immunological response. Strong clinical suspicion, through clinical examination, appropriate laboratory investigation such as CD4 T-cell count, histopathological examinations with H and E stain, direct immunofluorescence test are required for diagnosis. PMID- 24339466 TI - Myiasis in female external genitalia. AB - Myiasis is derived from the Greek word-"Myia", meaning "fly". The term was first introduced by Hope in 1840 and refers to the infestation of human beings with dipterous larvae (maggots). Presence of maggots on exposed parts is already known, but on covered parts like external genitalia it is very rare. We hereby describe a case of young unmarried female who presented with multiple sinuses over external genitalia along with maggots coming out of it. PMID- 24339467 TI - Papulonecrotic tuberculid of glans penis: A common disease at an uncommon site. AB - A 65-year-old man presented with multiple asymptomatic papulo-pustules and ulcers over glans penis since last 1 year. The lesions used to resolve spontaneously in a few days with scarring. The clinical features and histopathology were suggestive of papulonecrotic tuberculids of the glans penis. PMID- 24339468 TI - Condyloma lata in a preschooler: The dilemma of sexual abuse versus non-abuse. AB - It is well-known that syphilis is a sexually-transmitted or an inherited infection. Syphilis in preschoolers is rarely described in modern medical literature. Our case represents the difficulty or dilemma faced by dermatologists after diagnosing syphilis in a girl child due to inability of the young children to provide a history of sexual abuse and more over the parents/guardians also try to hide the history of sexual-abuse. Although rare, we can consider non-sexual transmission after we have thoroughly investigated and ruled out even the remote possibility of sexual abuse, because misdiagnosis of both abuse and non-abuse can be devastating to the patient and family. PMID- 24339469 TI - Penile pyoderma gangrenosum. AB - A 70-year-old man presented with indurated penile ulcers of 1-month duration. Initial biopsy was reported as chronic ulcer. A repeat biopsy done due to inadequate response to doxycycline showed features of pyoderma gangrenosum. The ulcer healed with a course of steroids and has not recurred till date. PMID- 24339470 TI - Nucleoside reverse transcriptase inhibitors (zidovudine and stavudine) side effects in people living with human immunodeficiency virus/acquired immunodeficiency syndrome attending the antiretroviral treatment center of B.J. Medical College and Civil Hospital at Ahmedabad, Gujarat, India. PMID- 24339471 TI - Saxophone penis after unilateral inguinal bubo of lymphogranuloma venereum. PMID- 24339472 TI - Seroprevalence of HIV among blood donors in a teaching hospital at Kolar, South India. PMID- 24339473 TI - Hemophagocytic lymphohistiocytosis in an infant with probable HIV infection. PMID- 24339474 TI - Maternal Depressive Symptoms and Child Behavior Problems among Latina Adolescent Mothers: The Buffering Effect of Mother-reported Partner Child Care Involvement. AB - We examined the relations between maternal depressive symptoms and child internalizing and externalizing problems in a sample of 125 adolescent Latina mothers (primarily Puerto Rican) and their toddlers. We also tested the influence of mother-reported partner child care involvement on child behavior problems and explored mother-reported partner characteristics that related to this involvement. Results suggested that maternal depressive symptoms related to child internalizing and externalizing problems when accounting for contextual risk factors. Importantly, these symptoms mediated the link between life stress and child behavior problems. Mother-reported partner child care interacted with maternal depressive symptoms for internalizing, not externalizing, problems. Specifically, depressive symptoms related less strongly to internalizing problems at higher levels of partner child care than at lower levels. Participants with younger partners, co-residing partners, and in longer romantic relationships reported higher partner child care involvement. Results are discussed considering implications for future research and interventions for mothers, their children, and their partners. PMID- 24339475 TI - Abstracts of the 7th International Workshop on AT, November 1997, Clermont Ferrand, France. PMID- 24339476 TI - Preschoolers' academic readiness: What role does the teacher-child relationship play? AB - We examined the role of the teacher-child relationship quality (close, dependent, and conflictive) on preschoolers' (N = 95) academic readiness for kindergarten, and we tested children's prosocial and aggressive behavior and peer group exclusion as mediators of this relation. A unique feature of this study is the ethnically and socio-economically diverse preschool-aged sample. The association between close teacher-child relationships and academic readiness was partially mediated by prosocial behavior and peer group exclusion. There was also evidence of a transactional association between close teacher-child relationships and children's behavior. Additionally, children's behavior and peer group exclusion mediated the relation between negative teacher-child relationships (dependent and conflictive) and academic readiness. The findings suggest that teacher training, education, and support for establishing close teacher-child relationships may maximize preschoolers' academic readiness by promoting social adaptation. PMID- 24339477 TI - When Does Improving Health Raise GDP? Comments on Ashraf, Lester, and Weil (2008). PMID- 24339478 TI - College Student Drug Use: Patterns, Concerns, Consequences, and Interest in Intervention. AB - Although previous surveys have indicated high rates of illicit and prescription drug misuse among college students, few have assessed negative consequences, personal concerns, or interest in interventions for drug use. In a survey of 262 college students who self-reported lifetime use of an illicit drug, 69% reported at least one negative consequence over the course of their lifetime and 63% in the past year. Many also reported being moderately concerned (28%) about their drug or medication misuse and moderately interested in some form of intervention (76%). The frequency of marijuana use and medication misuse in the past month was related to increased negative consequences and personal concerns even when controlling for the frequency of past month alcohol use. There were relatively few differences as a function of gender or year in college. PMID- 24339479 TI - Relative reliability of three objective tests of limb muscle strength. AB - If measures of muscle strength are to be broadly applied, they should be objective, portable, quick, and reliable. Through this component of the NIH Toolbox study we sought to compare the test-retest reliability of 3 tests of muscle strength that are objective, portable, and quick: the five-repetition sit to-stand test (FRSTST), hand-grip dynamometry (HGD), and belt-stabilized hand held dynamometry (BSHHD) of knee extension. Three sets of each test were performed- 1 warm-up and 2 maximal. Measures from the maximal tests obtained 4 to 10 days apart were compared. Reliability was described using descriptive statistics, intraclass correlation coefficients (ICCs) and 4 measures of response stability: standard error of measurement (SEM), method error (ME), coefficient of variation of SEM (SEM CV ), and coefficient of variation of variation of ME (ME CV ). The ICCs of all tests were good (>= 0.853). Measures of response stability showed less variability between test and retest for FRSTST and HGD than for BSHHD. In conclusions all 3 tests demonstrated good test-retest reliability. However, greater differences would need to be observed between tests sessions to conclude that a real change had occurred in measures obtained by BSHHD. PMID- 24339480 TI - Issues in the management of drug resistant tuberculosis in India. PMID- 24339481 TI - Does climate mould the influence of mold on asthma? PMID- 24339482 TI - Prevalence of multidrug resistance among retreatment pulmonary tuberculosis cases in a tertiary care hospital, Hyderabad, India. AB - BACKGROUND: India is one of the high tuberculosis (TB) burden countries in the world. India ranks second in harboring multi drug resistant (MDR)-TB cases. About 50,000 of MDR cases are recorded in retreatment pulmonary TB cases. This study was conducted in a tertiary care facility (Government General and Chest Hospital) in Hyderabad, India. OBJECTIVES: TOASSESS: Proportion of the TB patients having MDR-TB at the initiation of retreatment regimen; the prevalence of isoniazid (INH) resistance in this geographical area. MATERIALS AND METHODS: An analytical, observational, prospective cohort study of patients attending the out-patient department from December 2010 to March 2011. RESULTS: Sputum samples from 100 patients were subjected to acid fast bacilli (AFB) culture and drug sensitivity testing. Of these, 28 (28%) were MDR-TB, 42 (42%) were non-MDR-TB and 39% being INH resistance. CONCLUSIONS: In conclusion, one third of the retreatment pulmonary TB cases attending a tertiary care institute for TB will be MDR-TB at the initiation of treatment and there is a need to include ethambutol in the continuation phase of new TB case treatment in view of high INH resistance. PMID- 24339483 TI - A local perspective to asthma management in the accident and emergency department in Malta. AB - AIM: This study was performed to assess the management of adult patients presenting to the Mater Dei Hospital Accident and Emergency (A&E) department with acute asthma. SUBJECTS AND METHODS: Asthmatic patients age 14 or older who presented to A&E department between January and October 2010 with asthma exacerbations were included. Data were collected from the clinical notes and analyzed. RESULTS: A total of 244 patients (67.2% females) were included, 126 (51.6%) were admitted, 97 (39.8%) discharged and 21 (8.6%) discharged themselves against medical advice. There was a decline in the presentations between January and July, followed by an upward trend until October (P = 0.42). Pulse oximetry was performed in 207 patients (84.8%), arterial blood gases in 133 (54.5%), peak expiratory flow rate in 106 (43.4%) and chest radiography in 206 (84.4%) patients. The respiratory rate was documented in 151 (61.8%), heart rate in 204 (83.6%) and ability to complete sentences in 123 (50.4%) patients. One hundred and ninety six patients (80.3%) were given nebulized bronchodilators, 103 (42.2%) intravenous corticosteroids, 7 (2.87%) oral corticosteroids, 109 (44.7%) oxygen, 28 (11.5%) antibiotics and 9 (3.69%) magnesium. Systemic corticosteroids and antibiotics were more commonly prescribed to patients admitted (P < 0.001). CONCLUSION: Management of acute asthma in Malta requires optimization in order to compare with international guidelines. PMID- 24339484 TI - Radiographic characteristics of asthma. AB - OBJECTIVES: A novel and interesting observation is that ribs go less sloped in asthma patients' radiograph than non-asthmatics people. The aim of this study was to investigate whether a smaller horizontal curve of the ribs is a special trait on chest radiograph of asthma patients. MATERIALS AND METHODS: A retrospective review of the chest radiographs of 57 cases of asthma who were admitted between January 2011 and February 2011, and 57 non-asthma patients was performed. Chest radiographs were examined and lines drawn horizontally through the middle point of the sixth rib, and to where the sixth rib reaches the thoracic cage. The angle between these two lines was defined as the angle of rib curve (ARC). The ARCs were then compared between groups using the Student's t-test. RESULTS: The mean ARC was smaller in asthma patients than in non-asthma patients (10.7 +/- 4.7 degrees vs. 14.3 +/- 4.7 degrees , P < 0.0001). In the asthma group, the mean male ARC was smaller than the mean female ARC (8.4 +/- 4.1 degrees vs. 11.5 +/- 4.7 degrees , P = 0.026); however, there was no statistical difference in gender in the non-asthma group (P = 0.405). CONCLUSIONS: This is the first study to report that the ribs of asthma patients are less sloped than in patients without asthma. This photographic trait may be helpful in daily practice for suspecting a diagnosis of bronchial asthma. PMID- 24339485 TI - Quality of life impairment in patients of obstructive sleep apnea and its relation with the severity of disease. AB - BACKGROUND: Several studies have demonstrated considerable impairment of quality of life (QOL) in obstructive sleep apnea (OSA) patients, but its relation with severity of OSA is yet unclear. STUDY OBJECTIVES: To investigate the effects of OSA on the QOL and its association with the disease severity. DESIGN AND SETTING: Observational, prospective case-control study. MATERIALS AND METHODS: QOL of 69 OSA patients and 41 healthy controls were assessed using the Calgary sleep apnea quality of life index (SAQLI) on the morning following the polysomnography (PSG) study. STATISTICS: All statistical analyses were performed using the SPSS 17.0 (SPSS Inc., Chicago). Differences between sleep-related symptoms and SAQLI subscales scores were assessed with the Chi-square test and the Student t-test. Due to non-normal distribution, differences between SAQLI scores of controls and OSA patients were evaluated using a non-parametric Mann-Whitney test. Spearman correlation and backward multiple regression analysis were used to analyze the association between SAQLI scores and sleep indices and anthropometric variables and PSG variables. RESULTS: Study included 69 cases (57 male and 12 females) with a mean age, weight, height, neck circumference, and body mass index 48.45 +/- 10.12 years, 83.03 +/- 16.48 kg, 159.75 +/- 28.29 cm, 44.01 +/- 3.23 cm and 30.77 +/- 6.71 kg/m(2). Mean apnea-hypopnea index was 26.39 +/- 16.62. The median score of four SAQLI domains daily function, social interaction, emotional, symptoms and total mean SAQLI score were 3.64 (3.46-3.90), 3.77 (3.51-3.88), 3.64 (3.53-3.83), 4.80 (4.68-5.11), 4.09 (3.88-4.09),and 1.36 (1.29-1.71), 1.38 (1.24-1.62), 1.45 (1.23-1.62), 2.00 (1.78-2.26), 1.55 (1.46-1.73) for patients and controls respectively. All the individual domain scores and the mean SAQLI scores of patients were significantly higher than the controls. CONCLUSION: OSA causes significant impairment of QOL, but the severity of impairment is not directly proportional to the severity of OSA. PMID- 24339487 TI - HIV-TB coinfection: Clinico-epidemiological determinants at an antiretroviral therapy center in Southern India. AB - BACKGROUND: HIV-TB (tuberculosis) coinfection has emerged as a major public health threat. Given the multifactorial enabling environment in a resource constrained setting like India, the consequences are of epidemic proportions. AIMS: This study was aimed at identifying the clinical and epidemiological determinants underlying HIV-TB coinfection. SETTINGS AND DESIGN: A retrospective review of patient records was done from the antiretroviral therapy center (ART) center at a district hospital in southern India between May and August 2012. MATERIALS AND METHODS: Secondary data of 684 patients on ART as well as pre-ART were collected between July 2008 and June 2012 and were analyzed. STATISTICAL ANALYSIS: Descriptive analysis, chi(2), and Wilcoxon signed rank tests were used with SPSS version 15.0 to draw significant statistical inferences. RESULTS: HIV TB coinfection was diagnosed in 18.9% with higher prevalence among males (75.3%), in the sexually active age group 31-45 years (61.3%), with less than primary education (44.15%), who were married (56.1%), laborers (42.4%), from rural backgrounds (88.2%), and having low income-earning capacity (94.4%). Transmission was predominantly through the heterosexual route. The key entry point was the integrated counseling and testing center (ICTC) (47.4%). Pulmonary tuberculosis (58.8%) was predominantly found followed by extrapulmonary tuberculosis (38.2%) and both in 3.1%. A favorable outcome was observed in 69.3% of coinfected patients with 89.2% on ART and 97.2% currently on DOTS therapy. The Wilcoxon signed-rank test found significant association between rises in CD4 counts after the 6(th)-month follow up (P < 0.05). Coinfected patients had a case fatality rate of 25%. CONCLUSIONS: The prevalence of HIV-TB coinfection recorded in this sample was 18.86%. ICTC implemented by NACO emerged as an effective entry point, while Revised National Tuberculosis Control Program referred 1.6% (n = 11) of the patients to the ART center. Coinfection is associated with lower CD4 counts than those with HIV alone, which could translate into increased morbidity and progression of HIV to AIDS. PMID- 24339486 TI - Is serum cholesterol a risk factor for asthma? AB - BACKGROUND: Proinflammatory role of serum cholesterol in asthma has been recently explored with contradicting results. Clarity on the link between serum cholesterol and asthma may lead to new evolutions in planning management strategies. The objective of our study was to examine the relationship between the serum cholesterol, asthma and its characteristics. MATERIALS AND METHODS: A total of 40 asthmatics and 40 normal subjects were examined cross-sectionally and their serum fasting cholesterol and serum high sensitivity C reactive protein (hsCRP) levels were measured along with other baseline investigations. All subjects were non-smokers. RESULTS: Serum total cholesterol (mean +/- SD) among asthmatics was 176.45 +/- 30.77 mgs/dL as compared to 163.33 +/- 26.38 mgs/dL among normal subjects (P < 0.05). This higher serum cholesterol level was found to be associated with asthma independent of age, gender, body mass index (BMI), socio-economic status and serum hsCRP levels. However, the association was only modest (adjusted odds ratio 1.033; 95% confidence interval [CI] 1.008-1.059). There was no association between the serum cholesterol and asthma characteristics such as duration of illness, intake of inhaled steroids and frequency of emergency department visits. Other risk factors identified were poor ventilation (adjusted odds ratio 9.27; 95%CI 1.83-46.99) and overcrowding (adjusted odds ratio 41.9; 95% CI 3.15-557.46) at home. CONCLUSION: Our study found a modest but significant association between higher levels of serum cholesterol and asthma, which is independent of age, gender, BMI, socio-economic status and serum hsCRP. Future research is required in a larger population to substantiate above association and its clinical implications. Poor ventilation and overcrowding at home are risk factors for asthma possibly facilitating increased exposure to indoor allergens. PMID- 24339488 TI - Noninvasive mechanical ventilation: An 18-month experience of two tertiary care hospitals in north India. AB - BACKGROUND: Noninvasive mechanical ventilation (NIMV) is the delivery of positive pressure ventilation through an interface to upper airways without using the invasive airway. Use of NIMV is becoming common with the increasing recognition of its benefits. OBJECTIVES: This study was done to evaluate the feasibility and outcome of NIMV in tertiary care centres. MATERIALS AND METHODS: An observational, retrospective study conducted over a period of 18 months in two tertiary level hospitals of north India on 184 consecutive patients who were treated by NIMV, regardless of the indication. NIMV was given in accordance with the arterial blood gas (ABG) parameters defining respiratory failure (Type 1/Type 2). RESULTS: The most common indication of NIMV in our hospitals was acute exacerbation of chronic obstructive pulmonary disease (AE-COPD 80.43%), and 90.54% AE-COPD patients were improved by NIMV. Application of NIMV resulted in significant improvement of pH and blood gases in COPD patients, while non-COPD patients showed significant improvement in partial pressure of oxygen (PaO2) alone. The mean duration of NIMV was 8.35 +/- 5.98 days, and patients of interstitial lung disease (ILD) were on NIMV for the maximum duration (17 +/- 8.48 days). None of the patients of acute respiratory distress syndrome were cured by NIMV; 13.04% patients on NIMV required intubation and mechanical ventilation. CONCLUSION: This study demonstrates and encourages the use of NIMV as the first-line ventilatory treatment in AE-COPD patients with respiratory failure. It also supports NIMV usage in other causes of respiratory failure as a promising step toward prevention of mechanical ventilation. PMID- 24339489 TI - Compliance monitoring of prohibition of smoking (under section-4 of COTPA) at a tertiary health-care institution in a smoke-free city of India. AB - BACKGROUND: India enacted a comprehensive tobacco control law known as cigarettes and other tobacco products act (COTPA) in 2003. However, enforcement of the provisions under the law is still a matter of concern. Compliance survey is an effective tool to measure the status of implementation of the law at various public places. Smoke-free hospital campus demonstrates commitment to good health and sends a pro-healthy signal to the community. OBJECTIVE: The objective of this study was to assess the compliance to the prohibition of smoking at public places (under section-4 of COTPA) in a tertiary health-care institution in a smoke-free city of India. MATERIALS AND METHODS: An observational cross-sectional study was conducted at 40 different venues within a tertiary health-care institution in a smoke-free city of India. These places were observed for certain parameters of assessment by a structured checklist, which included evidence of active smoking, evidence of recent smoking, display of signages, presence of smoking aids, cigarette butts and bidi ends. RESULTS: Overall compliance rate for section-4 of COTPA was found to be mere 23%. Evidence of active smoking was observed in 21 (52.5%) venues. Signages were seen at only 8 places (20%). Butt ends and other smoking aids were seen in 37 (92.5%) and 26 (65%) places respectively. CONCLUSION: These dismal findings suggest non-compliance to the provisions under COTPA, which calls for a sensitization workshop and advocacy for all the stakeholders. PMID- 24339490 TI - Clinical profile and treatment outcomes of drug-resistant tuberculosis before directly observed treatment strategy plus: Lessons for the program. AB - BACKGROUND: Characteristics and treatment outcomes of patients with drug resistant tuberculosis (DR TB) before introduction of directly observed treatment strategy (DOTS) plus are infrequently reported. AIMS: To study clinical characteristics and treatment outcomes of drug-resistant TB patients. SETTING: A TB unit in Mumbai. MATERIALS AND METHODS: A retrospective analysis of DR TB patients attending a TB unit and taking treatment at NGOs was performed. Of the 34 cases, 5 (14%) had mycobacterium other than tuberculosis, 24 were pulmonary TB, 4 extra-pulmonary TB, and one both. Three were HIV-infected, two had diabetes. Two cases were treatment naive. Of the 29 cases studied, 3 (11%) were mono-resistant, 20 (69%) were multidrug-resistant (MDR) TB with E/Z/EZ resistance; 4 were pure MDR TB. One case had XDR TB, 13 (44.8%) had resistance to at least one conventional second-line drug. Seven cases had adverse drug reaction, four requiring drug substitution. Two patients are on treatment; 14 of the remaining 27 (51%) were successfully treated, 5 (18%) died, 2 (7%) failed treatment, 5 (18%) were lost to follow-up, one migrated. CONCLUSION: DST profiles suggest high levels of drug resistance due to amplification which leads to poor outcomes. There is an urgent need for Indian Revised National TB Control Program to introduce daily DOTS for susceptible cases, DST for all new cases, and scaling up DST for second-line drugs. There is also a need to use individualized treatment for DR TB. PMID- 24339491 TI - Role of DR-70 immunoassay in suspected malignant pleural effusion. AB - CONTEXT: A good proportion of patients with undiagnosed pleural effusion (PE) turn into malignancy over a period of time. Identification of positive biomarker may help in selecting the individuals who require close follow-up. AIMS: The aims of this study were to evaluate the role of DR-70 immunoassay in suspected malignant PE. SETTINGS AND DESIGN: We conducted a cross-sectional study among 89 patients of suspected malignant PE and 50 normal subjects (NS) were taken as control. MATERIALS AND METHODS: Patients with exudative PE; who had pleural fluid lymphocyte count greater than 50% and adenosine deaminase less than 30 U/L were taken as cases. We had selected NSs among relatives of patients having normal blood chemistry and radiological investigations. Sensitivity and specificity of the test to differentiate malignant and non-malignant PE and also to identify PE with underlying malignancy was analyzed. RESULTS: Mean value of DR-70 in NS was found to be 0.83 +/- 0.273 mg/L without any significant difference between males (0.82 mg/L) and females (0.85 mg/L). Mean value of DR-70 in PE with underlying cancer was 5.03 +/- 3.79 mg/L. Sensitivity (80%) and specificity (77.78%) of the test was maximum in PE with underlying cancer using cut-off value of 2 mg/L. Mean value DR-70 in malignant PE was 5.18 +/- 3.75 mg/L and in non-malignant PE was 3.73 +/- 3.74 mg/L without any statistically significant difference (P = 0.08). CONCLUSIONS: DR-70 assay has high sensitivity in detecting underlying lung cancer, but has no role in differentiating malignant PE from non-malignant PE. PMID- 24339492 TI - A systematic approach to interpretation of heterogeneous lung attenuation on computed tomography of the chest. AB - Computed tomography (CT) chest is widely used as an adjunct to clinical examination and pulmonary function tests in the evaluation of unexplained dyspnoea. In such patients, heterogeneous lung attenuation is a common finding on CT. Heterogeneous lungs can be caused by varying regional aeration, varying regional perfusion, and ground glass opacities (GGO) representing airspace or interstitial pathology. It does not serve the referring clinicians or the patients well if the radiology report simply mentions the heterogeneity of the lungs without due analysis of the cause of heterogeneity and a meaningful differential diagnosis. Therefore, it is imperative for the radiologist and the treating pulmonologist to have an in-depth understanding of the pathogenesis of pulmonary heterogeneity. This, in conjunction with clinical data, can narrow the differential diagnosis or, at times, lead to specific diagnoses. The purpose of this review is to familiarize readers with the CT representation of heterogeneities in aeration and perfusion of the lung, relate patterns of GGO to underlying pathology, and provide illustrative case studies highlighting the radiological approach to heterogeneous lungs. PMID- 24339493 TI - Aspergillus colonization in hydatid cyst: Addition of a case. AB - Aspergillus is a common saprophytic fungus that causes invasive or non-invasive disease in humans. It commonly colonizes pre-existing lung cavities. It has been earlier reported to coexist in previously operated or ruptured hydatid cysts. However there have been only few case reports of its occurrence in previously unoperated cysts in immunocompetent hosts. The present case adds to this category. PMID- 24339494 TI - Recovery of fluconazole sensitive Candida ciferrii in a diabetic chronic obstructive pulmonary disease patient presenting with pneumonia. AB - Chronic obstructive pulmonary disease (COPD) exacerbations admitted in intensive care units (ICUs) occur rarely due to fungal respiratory tract infections, but may occur when associated co-morbidities like diabetes mellitus coexist. Candida ciferrii is a new agent, recently was isolated from lung infections but usually resistant to fluconazole. Here, we report a rare case of pneumonia due to fluconazole sensitive Candida ciferrii in a COPD patient with known diabetes, admitted in our ICU. PMID- 24339495 TI - Internal mammary artery pseudoaneurysm: A rare fatal complication of tubercular empyema. AB - Vascular complications in the chest due to tuberculosis (TB) involve the pulmonary as well as bronchial vasculature. Mycotic pseudoaneurysms of internal mammary artery (IMA) are a sparsely reported clinical entity in the literature occurring due to TB. We report a rare case of IMA pseudoaneurysm due to the tubercular empyema in a patient with massive hemoptysis who was treated by endovascular coil embolization; however, the patient died due to refractory shock. PMID- 24339496 TI - An unusual masquerade of community acquired pneumonia: Left-side unilateral pulmonary edema. AB - The diagnosis of pneumonia is clinical, based on the history of lower respiratory tract symptoms, physical, and/or radiographic signs of consolidation. Several diseases such as congestive heart failure, pulmonary embolism, and chemical pneumonitis may present with similar symptoms, signs, and chest radiographs, thus delaying the definitive diagnosis and initiation of appropriate treatment. Unilateral pulmonary edema (UPE) is a rare clinical entity that is often misdiagnosed at first as a focal lung disease. We have presented an unusual case of left-sided UPE in a 76-year-old man who developed acute heart failure resulting from dietary and pharmacological noncompliance. The patient was successfully managed with decongestive therapy and non-invasive mechanical ventilation. PMID- 24339497 TI - Pulmonary cryptococcosis: An unusual presentation. AB - Cryptococcal infection of the lung is usually asymptomatic in immunocompetent hosts. Symptomatic cryptococcal lung infection presenting as an endobronchial mass lesion in an immunocompetent host is rare. We report our experience with an immunocompetent young patient presenting with an endobronchial mass lesion caused by cryptococcal infection. This male patient presented with left sided collapse, consolidation on computed tomography scanning, and was found to have a polypoid lesion in the left main bronchus. The diagnosis was confirmed by bronchial biopsy and the patient responded well to parenteral antifungal therapy. The case report is followed by a review of pulmonary cryptococcosis including clinical features, diagnosis, and treatment. PMID- 24339498 TI - Cystic lung disease in tuberculosis: An unusual presentation. AB - Cysts in the lung can arise due to large number of causes out of which tuberculosis is very rare, We report a case of tuberculosis in a young female presenting as a febrile illness and respiratory failure with radiological features of cystic lung disease. With treatment,fever and respiratory distress subsided and cysts in the lungs showed partial regression. We highlight the need to consider tuberculosis in the differential diagnoses of cystic lung disease under appropriate circumstances. PMID- 24339499 TI - Pleural effusion presenting as mediastinal widening. AB - We report a case of middle-aged female presenting with mediastinal widening on chest radiograph owing to pleural effusion. The pleural effusion presenting as mediastinal widening on chest radiograph is rarely reported. PMID- 24339500 TI - Fruiting bodies of Aspergillus: An unusual finding in histopathology. AB - A-62-year-old lady presented with complaints of cough, dyspnea and hemoptysis of 3 months duration. A radiological evaluation revealed a mass lesion in the left lung along with significant lymphadenopathy. With a clinical and radiological diagnosis of carcinoma of the lung, the patient was taken up for biopsy. The specimen consisted mainly of grey-white friable soft-tissue, which on histopathological evaluation showed small cell carcinoma, which was confirmed with immunohistochemistry. Apart from the carcinomatous component, many hyphae and fruiting bodies of Aspergillus were also seen. We are reporting this case because, though the finding of hyphal forms of Aspergillus is not so uncommon in lung biopsies, detection of fruiting bodies of Aspergillus in histopathological section is an extremely rare finding. The hyphal forms of Aspergillus can be confused with the hyphal forms of other fungi, but when fruiting bodies are present a definite diagnosis is possible at the histopathology level itself. We would also like to highlight that contamination should be excluded before labeling a case as Aspergillosis because of the potentially toxic medication implicated in the treatment. PMID- 24339501 TI - A case of spontaneous pneumothorax following radiation therapy for non-small cell lung cancer. AB - Spontaneous pneumothorax (SPTX) is a potentially devastating rare complication of the thoracic radiation therapy. Most of the cases in the medical literature, have been described in lymphoma patients receiving radiation therapy. The pathogenesis of this adverse event remains undefined although different mechanisms have been proposed. We present a case of post-radiation therapy SPTX in a non-small cell lung cancer (NSCLC), following intensity modulated radiation therapy (IMRT), which to our knowledge is the first such reported case related to this newer mode of radiation therapy. This report highlights the importance of keeping a close eye for this complication as timely treatment with chest tube insertion and drainage of the pneumothorax can be a lifesaving in these patients. PMID- 24339502 TI - Rifampicin induced adrenal crisis in an uncommon setting. AB - Adrenal crisis occurs when there is decreased secretions of steroid hormones (mainly cortisol) from the adrenal glands due to varied reasons. It may arise due to a primary adrenal condition or due to decreased hormonal signals from the pituitary secondary to a hypofunctioning pituitary. Hypopituitarism may result due to direct causes like trauma, tumour, infection or it may be due to some vascular insult as seen in Sheehan syndrome. We report an unusual presentation of Sheehan syndrome in the form of life-threatening adrenal crisis precipitated by the usage of rifampicin. PMID- 24339503 TI - A young smoker with hemoptysis. AB - A young man presented with complaints of dry cough, right lower chest pain, and streaky hemoptysis for duration of 3 months. A nonresolving opacity on chest radiograph and mass-like consolidation on computed tomography (CT), led to biopsy of the mass under CT guidance. Histopathology provided the diagnosis. The radiological features were retrospectively evaluated. PMID- 24339504 TI - Unilateral hyperlucent lung: Always think ACROSS. PMID- 24339505 TI - Difficult to treat bronchial asthma with radiological opacities. PMID- 24339506 TI - Differentiating pulmonary lymphangioleiomyomatosis from pulmonary langerhans cell histiocytosis and Birt-Hogg-Dube syndrome. PMID- 24339507 TI - Specimen collection from chest tubes: A novel method. PMID- 24339508 TI - Pulmonary alveolar microlithiasis. PMID- 24339509 TI - Authors' reply. PMID- 24339510 TI - Filariasis and pleural effusion. PMID- 24339511 TI - Organizing pneumonia in swine flu. PMID- 24339512 TI - Authors' reply. PMID- 24339513 TI - Spectacle sign. PMID- 24339514 TI - Current practice of conventional intermittent hemodialysis for acute kidney injury. AB - The use of conventional intermittent hemodialysis (IHD) represents a mainstay of supportive care of patients with acute kidney injury (AKI). However, a number of fundamental questions regarding the optimal management of IHD remain unanswered after more than six decades of renal replacement therapy (RRT). This review summarizes current evidence regarding the timing of initiation of intermittent hemodialysis, the comparative outcomes (mortality and recovery of renal function), the prescription of the intensity of this therapy and discontinuation of dialysis. The way conventional IHD is performed has an impact on the outcome of sick patients with AKI. The value of regular education and training of those who provide IHD cannot be emphasized enough. However, we must be realistic in our expectations that no mode of RRT per se will substantially alter the excessive mortality of critically ill-patients with AKI. PMID- 24339515 TI - Influence of steroid maintenance on the outcomes in deceased donor kidney transplant recipients experiencing delayed graft function. AB - Delayed graft function (DGF) is a risk factor for poor long-term graft and patient survival after kidney transplantation. The aim of our study was to explore the beneficial effect of steroid maintenance on outcomes in deceased donor kidney (DDK) transplant recipients with DGF. Using organ procurement and transplant network/United network of organ sharing (OPTN/UNOS) database, we identified adult patients who developed DGF following DDK transplantation performed between January 2000 and December 2008. They received induction with rabbit antithymocyte globulin (r-ATG), alemtuzumab or an interluekin-2 receptor blocker (IL-2B) and were discharged on a calcineurin inhibitor (CNI)/mycophenolate (MMF) based immunosuppression with or without steroids. Adjusted graft and patient survivals were compared between steroid versus no steroid groups for each induction modality. Median follow-up was 29.6 months for the 10,058 patients who developed DGF. There were 5624 patients in r-ATG (steroid, n = 4569, no steroid, n = 1055), 819 in alemtuzumab (steroid, n = 301, no steroid, n = 518) and 3615 in IL-2B (steroid, n = 3380, no steroid, n = 235) groups. Adjusted graft survivals were similar for steroid versus no-steroid groups in patients who received r-ATG (HR: 0.98, 95% CI 0.85-1.13, P = 0.75), alemtuzumab (HR 0.88, 95% CI 0.65-1.19, P = 0.41), and IL-2B (HR 1.01, 95%CI 0.78 1.30, P = 0.96) inductions. The adjusted patient survivals were also similar in r ATG (HR: 1.19, 95% CI 0.96-1.46, P = 0.19), alemtuzumab (HR: 0.89, 95% CI: 0.57 1.39, P = 0.96), and IL-2R (HR: 1.07, 95% CI: 0.77-1.49, P = 0.96) groups. Our study failed to show any significant graft or patient survival benefits associated with steroid addition to CNI/MMF regimen in DDK recipients with DGF. This may be related to the early immunogenic and non-immunogenic allograft damage from DGF with long-term consequences that are unaltered by steroids. PMID- 24339516 TI - Efficacy of basiliximab induction in poorly matched living donor renal transplantation. AB - Non-depleting antibody induction has the best safety profile in transplant recipients without an increased risk of infection or malignancy. This observational study was performed in intermediate immunologic risk live donor renal transplants to assess basiliximab efficacy in patients on tacrolimus, mycophenolate, and prednisolone immunosuppression. A total of 46 patients on basiliximab induction were compared to risk matched 56 controls at the end of 6 and 12 months post-transplant. An additional cost of approximately Rs. 100,000/patient was incurred by the basiliximab group. The incidence of biopsy proven acute rejection in the control group (12.5%, 6 months and 20.5%, 1 year) and the basiliximab group (13%, 6 months and 18.9%, 1 year) was similar. At 6 months, there was a non-significant trend toward more steroid sensitive rejections and better glomerular filtration rate preservation in the basiliximab group (83.3%, 71.9 ml/min) versus the control group (28.6%, 62.2 ml/min). However, this difference was lost at 1 year (70.1 ml/min vs. 67.6 ml/min). The incidence of infections was similar and none of the patients had a malignancy. Death censored graft survival (94.6% basiliximab and 94.8% control) and the mean number of hospitalizations for all reasons at the end of 1 year were not different among the two groups. In our study, basiliximab induction did not confer an additional advantage in the intermediate risk live donor transplants in patients on tacrolimus and mycophenolate based triple drug immunosuppression. PMID- 24339517 TI - Interleukin receptor antagonist induction in kidney transplantation: Is it worth the price? PMID- 24339518 TI - Granulomatous interstitial nephritis: Our experience of 14 patients. AB - Granulomatous interstitial nephritis (GIN) is a rare condition. Drugs, infections, immune processes, and foreign body reaction are the main causes. We identified a total of 14 patients with GIN during a period of 13 years in 2798 renal biopsies. There were 8 males and 6 females in the age range of 20-70 (mean 35 +/- 12) years. The serum creatinine at presentation was 6.7 +/- 3.8 (range: 2.3-14.7) mg/dl. In nine patients tuberculosis was the causative agent. Drugs (n = 2) and Wegener's granulomatosis (n = 1) were other etiologies. Systemic lupus erythematosis (SLE) and Immunoglobulin A nephropathy (IgAN) were seen in one patient each. Patients with tuberculosis were treated with antituberculous therapy and three of them improved. Four out of six patients who required dialysis at presentation remained dialysis dependent, one of whom underwent renal transplantation. Two patients progressed to end stage renal disease after 7 years and 9 years each. The patients with drug induced GIN had improvement in renal function after prednisolone treatment. Patients with SLE, and Wegener's granulomatosis responded to immunosuppression. Patient with IgAN was on conservative management. Finally, six patients were on conservative management for chronic renal failure. PMID- 24339519 TI - Cyclosporine/ketoconazole reduces treatment costs for nephrotic syndrome. AB - Cyclosporine A (CyA) is an effective agent for the treatment of glucocorticoid dependent idiopathic nephrotic syndrome (GCDNS), but costs are prohibitive in resource-poor societies. The objectives of this study were to evaluate the efficacy and safety of reducing the dose of CyA by co-administering ketoconazole. A prospective study targeting children 2-18 years of age with GCDNS in remission with CyA monotherapy was conducted. CyA dose was reduced by 50% and ketoconazole was added at 25% of the recommended therapeutic dose, and the drug levels and therapeutic and adverse effects (AE) were monitored. Continued combined therapy after completion of the 4-week trial period was offered. Ten patients (median age 9.5 years, range 3.0-16.0 years) were enrolled in the study. At week 4, the CyA dose was 2.2 +/- 0.7 mg/kg/day compared with 5.6 +/- 0.9 mg/kg/day at enrolment (P < 0.0001). No AE were noted. All patients continued ketoconazole treatment for at least 3 months. CyA drug cost savings were 61%, and approximately 60% with ketoconazole cost included. The combination of an expensive immunosuppressive drug with a cheap metabolic inhibitor reduced the treatment costs by> 50% without increased adverse events or drug monitoring needs. This intervention demonstrates how access of patients with limited resources to needed drugs can be improved by interference with physiological drug elimination. PMID- 24339520 TI - Elevated human chorionic gonadotropin levels in patients with chronic kidney disease: Case series and review of literature. AB - Women are often subjected to serum human chorionic gonadotropin (HCG) testing prior to diagnostic and therapeutic interventions. A positive result leads to further testing to rule out pregnancy and avoid possible fetal teratogenicity. The impact of chronic kidney disease (CKD) on HCG testing has not been studied. We report a series of 5 women out of 62 with CKD, who had a positive HCG test on routine pre-transplant screening at a single transplant center. We analyzed their case records retrospectively. Despite aggressive investigation, their elevated HCG levels remained unexplained. The positive test contributed to delays in transplantation and increased overall cost of treatment. PMID- 24339521 TI - Accuracy of spot urine protein creatinine ratio in measuring proteinuria in chronic kidney disease stage 3 and 4. AB - We studied the accuracy of spot urine protein creatinine ratio (SpUr-PCR) to assess 24 h urine protein excretion (24 h-UP) in patients with chronic kidney disease (CKD). A total of 100 proteinuric CKD patients of stages 3 and 4 were studied. 24 h urine was collected to measure 24 h-UP and creatinine. A random day time urine sample was analyzed to measure the PCR. A formula to estimate 24 h creatinine excretion was derived from linear regression analysis and a correction factor was introduced to assess whether this improves the accuracy of the SpUr PCR in predicting 24 h-UP. Accuracy of the SpUr-PCR was assessed by Pearson's correlation, regression analysis, and Bland Altman analysis. Mean age was 51.85 +/- 12 years and 81% of the patients were male. SpUr-PCR predicted 24 h-UP with good accuracy (r = 0.86 on a data transformed to a logarithmic scale, P < 0.001) and there was a good agreement between these two measures of proteinuria. However, SpUr-PCR was inaccurate in the subgroup with nephrotic range proteinuria (r = 0.35, P = 0.062), but when a correction factor for 24-h urine creatinine (24 h-UCr) was introduced, the accuracy of SpUr-PCR improved significantly in this group (r = 0.45, P = 0.013). Introduction of the correction factor improved the degree of agreement between these two measures in women, but not the correlation. Overall, SpUr-PCR accurately predicted 24 h-UP. Adding a correction factor for 24 h-UCr improved correlation in the subgroup of patients with the nephrotic range proteinuria and the degree of agreement in female patients, and hence may be used in expressing proteinuria measured by SpUr-PCR to improve its accuracy in them. PMID- 24339522 TI - Anti-C reactive protein antibodies in Indian patients with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is characterized by over production of autoantibodies. C-reactive protein (CRP) is a phylogenetically highly conserved plasma protein that participates in the systemic response to inflammation. Anti CRP antibodies might have biological functions of pathogenetic interest in SLE. We evaluated anti-CRP antibodies in Indian SLE patients and their association with anti-dsDNA antibodies and complement levels (C3 and C4). One hundred SLE patients diagnosed according to the American College of Rheumatology criteria were included. Disease activity was assessed using SLE disease activity index (SLEDAI). Anti-CRP autoantibodies were detected by enzyme linked immunosorbent assay. Anti-dsDNA antibodies were detected by indirect immunofluroscence test (Euroimmun Lubeck, Germany). High sensitivity CRP and complement levels (C3, C4) were detected using a Nephelometer. (BN ProSpec, Dade Behring, Germany). Anti-CRP antibodies were detected in 26% of SLE patients. Mean age of disease onset among anti-CRP positives was 22.4 +/- 7.5, and 26.6 +/- 9.3 years among anti-CRP negatives (P > 0.05). Anti-dsDNA positivity was significantly higher among anti CRP positives (32.7%) as compared to anti-CRP negatives (16%) (P = 0.00519). No statistically significant difference was observed in SLEDAI scores of anti-CRP positive group and anti-CRP negative group (P > 0.05). We observed a positive correlation between anti-CRP antibodies and anti-dsDNA antibodies. PMID- 24339523 TI - Contribution of GSTM1, GSTT1, and MTHFR polymorphisms to end-stage renal disease of unknown etiology in Mexicans. AB - Oxidative stress is increased in chronic kidney disease, owing to an imbalance between the oxidative and antioxidant pathways as well as a state of persistent hyperhomocysteinemia. The enzymes glutathione S-transferases (GSTs) and methylenetetrahydrofolate reductase (MTHFR) are implicated in the regulation of these pathways. This study investigates the association between polymorphisms in the Glutathione S-transferase Mu 1 (GSTM1), glutathione S-transferase theta 1 (GSTT1), and MTHFR genes and end-stage renal disease (ESRD) of unknown etiology in patients in Mexico. A Case-control study included 110 ESRD patients and 125 healthy individuals. GSTM1 and GSTT1 genotypes were determined using the multiplex polymerase chain reaction (PCR). The MTHFR C677T polymorphism was studied using a PCR/restriction fragment length polymorphism method. In ESRD patients, GSTM1 and GSTT1 null genotype frequencies were 61% and 7% respectively. GSTM1 genotype frequencies differed significantly between groups, showing that homozygous deletion of the GSTM1 gene was associated with susceptibility to ESRD of unknown etiology (P = 0.007, odds ratios = 2.05, 95% confidence interval 1.21 3.45). The MTHFR C677T polymorphism genotype and allele distributions were similar in both groups (P > 0.05), and the CT genotype was the most common genotype in both groups (45.5% and 46.6%). Our findings suggest that the GSTM1 null polymorphism appears to be associated with the ESRD of unknown etiology in patients in Mexico. PMID- 24339524 TI - Emphysematous pyelonephritis: Outcome with conservative management. AB - Emphysematous pyelonephritis is a life-threatening condition characterized by necrotising gas forming infection of the renal parenchyma. We describe eight patients seen over a period of 2 years, 62.5% males and 37.5% females with age range between 21 and 65 years. About 75% patients had diabetes mellitus. Six patients were managed conservatively. One patient required nephrectomy with percutaneous drainage and one patient died without surgical intervention. PMID- 24339525 TI - Successful renal transplantation from a brain-dead deceased donor with head injury, disseminated intravascular coagulation and deranged renal functions. AB - Deceased donors (DDs) with the brain death due to head injury are the major source of organs for transplantation. The incidence of post-head injury disseminated intravascular coagulation (DIC) ranges from 24% to 50%. Many centers do not accept organs from donors with DIC due to increased risk of primary graft non-function and/or high chances of morbidity/mortality. We performed two successful renal transplants from a DD with head injury with DIC and deranged renal function. One of the recipients developed transient thrombocytopenia, but there was no evidence of DIC or delayed graft functions in either of the recipients. Over a follow-up of 1 month, both are doing well with stable graft function and hematological profile. Thus, a carefully selected DD with severe DIC even with deranged renal function is not a contraindication for organ donation if other risk factors for primary non-function are excluded. This approach will also help in overcoming organ shortage. PMID- 24339526 TI - Distal renal tubular acidosis and amelogenesis imperfecta: A rare association. AB - Renal tubular acidosis (RTA) is characterized by a normal anion gap with hyperchloremic metabolic acidosis. Primary distal RTA (type I) is the most common RTA in children. Childhood presentation of distal RTA includes vomiting, failure to thrive, metabolic acidosis, and hypokalemia. Amelogenesis imperfecta (AI) represents a condition where the dental enamel and oral tissues are affected in an equal manner resulting in the hypoplastic or hypopigmented teeth. We report a 10-year-old girl, previously asymptomatic presented with the hypokalemic paralysis and on work-up found out to have type I RTA. The discoloration of teeth and enamel was diagnosed as AI. PMID- 24339527 TI - Chronic type B aortic dissection in association with Hemolyticuremic syndrome in a child. AB - Aortic dissection (AD) is a potentially life-threatening medical emergency usually encountered in the elderly. Here, we report a 9-year-old child who was incidentally detected to have asymptomatic chronic type B dissecting aneurysm of aorta when he presented with relapse of Hemolytic uremic syndrome (HUS) without any genetic abnormalities like Marfan or Ehler-Danlos syndrome. To the best of our knowledge, this is the first case of AD associated with HUS in a child without any known associated genetic or inherited risk factors. PMID- 24339528 TI - Cystic partially differentiated nephroblastoma: A rare renal tumor. PMID- 24339529 TI - Hydatid cyst of urinary bladder. PMID- 24339530 TI - Prospective analysis of utility and feasibility of ambulatory blood pressure monitoring service in a pediatric nephrology set up. PMID- 24339532 TI - Pseudohyperphosphatemia in Waldenstrom's Macroglobulinemia. PMID- 24339531 TI - Peritonitis due to nontuberculous mycobacterium. PMID- 24339533 TI - Utility of renal allograft biopsy: An audit of 80 allograft biopsies. PMID- 24339534 TI - Aplastic anemia, membranous nephropathy and mercury. PMID- 24339535 TI - Guidewire fragmentation complicating hemodialysis catheter insertion. PMID- 24339536 TI - Is bullous skin lesion a risk factor for renal amyloidosis in patients with familial mediterranean fever? PMID- 24339537 TI - Warfarin pharmacogenetics: How close are we to clinical practice? PMID- 24339538 TI - Hemoglobin E disorder: Newborn screening program. AB - Hemoglobin E (Hb E) disorder is an important kind of hemoglobinopathy. It can be seen around the world with the highest prevalence in Southeast Asia. The screening for this disorder becomes the public health policies in many countries. The screening can be performed in several population groups. The newborn screening program for Hb E disorder is an important issue in pediatric genetics. In this brief review, the author discusses on important laboratory tests for screening for Hb E disorder in newborn. PMID- 24339540 TI - Usage of U7 small nuclear ribonucleic acid in gene therapy of hemoglobin D Punjab disorder: Rationale? AB - BACKGROUND: Hemoglobin (Hb) D Punjab disorder is a congenital hemoglobinopathy described in India. It is a disorder due to defect in beta-globin gene. MATERIALS AND METHODS: Here, the author assesses the possibility of U7.623 gene therapy for Hb D Punjab disorder. A standard bioinformatic analysis to study the effect of co expression between nucleic acid sequence for human Hb D Punjab beta-globin chain and U7.623 was performed. RESULT: It can be seen that fully recovery of Hb function and biological process can be derived via gene ontology study. CONCLUSION: Here, there is a rationale to use U7 small nuclear ribonucleic acid as a possible tool for gene therapy in Hb D Punjab disorder. PMID- 24339539 TI - An overview of gene therapy in head and neck cancer. AB - Gene therapy is a new treatment modality in which new gene is introduced or existing gene is manipulated to cause cancer cell death or slow the growth of the tumor. In this review, we have discussed the different treatment approaches for cancer gene therapy; gene addition therapy, immunotherapy, gene therapy using oncolytic viruses, antisense ribonucleic acid (RNA) and RNA interference-based gene therapy. Clinical trials to date in head and neck cancer have shown evidence of gene transduction and expression, mediation of apoptosis and clinical response including pathological complete responses. The objective of this article is to provide an overview of the current available gene therapies for head and neck cancer. PMID- 24339541 TI - Polymorphism at P21 codon 31 and dinucleotide polymorphism of P73 gene and susceptibility to bladder cancer in individuals from North India. AB - BACKGROUND AND AIM: p73, a novel P53 homolog and plays an important role in modulating cell cycle control, apoptosis and cell growth while P21, functions to negatively control the cell cycle. P53 up regulates p21 expression in response to deoxyribonucleic acid damage leading to cell cycle arrest at G1 checkpoint. In the present study, we are targeting p21 codon 31 and p73 gene variants of G4C14 to-A4T14 (Exon 2) polymorphism for bladder cancer (BC) risk in North Indians. MATERIALS AND METHODS: The above gene variants of P21 and P73 were assessed in the case-control study comprising of 200 BC cases and 200 healthy controls of the same age, gender and similar ethnicity. Genotyping was performed by polymerase chain reaction (PCR) restriction fragment length polymorphism method and PCR based confronting two-pair primers (PCR with CTPP). RESULTS: The variant genotype of p73Exon 2 polymorphism showed significant risk for BC (p = 0.014). While combining with heterozygous genotype, variant genotype of p73Exon2 showed a significant association with BC risk (p = 0.010). While in case of p21 codon31 showed no significant association for BC risk at genotypic level. Significant association between p73Exon2 polymorphism and smoking was observed for BC risk. Furthermore, gene combination analysis revealed that AT/AT-Ser/Ser is associated with risk for BC. Variant genotype of P73Exon2 was associated with reduced risk of recurrence (p = 0.039) in superficial BC patients receiving Bacillus Calmette Guerin treatment thus showing least survival (log rank = 0.029). CONCLUSION: Our study provided evidence that the p73 G4C14 > A4T14 (Exon2) polymorphisms were associated with higher risk of BC in North Indian population. PMID- 24339542 TI - Inter and intra ethnic variation of vitamin K epoxide reductase complex and cytochrome P450 4F2 genetic polymorphisms and their prevalence in South Indian population. AB - BACKGROUND: Genetic variation in the vitamin K epoxide reductase complex (VKORC1) and cytochrome P450 4F2 (CYP4F2) genes were found to be strongly associated with the oral anticoagulant (OA) dose requirement. The distribution of genetic variation in these two genes was found to show large inter- and intra-ethnic difference. MATERIALS AND METHODS: A total of 470 unrelated, healthy volunteers of South Indians of either sex (age: 18-60 years) were enrolled for the study. A 5 ml of venous blood was collected and the genomic deoxyribonucleic acid (DNA) was extracted by using phenol-chloroform extraction method. Real-time quantitative polymerase chain reaction (RT-PCR) method was used for genotyping. RESULTS: The variant allele frequencies of VKORC1 rs2359612 (T), rs8050894 (C), rs9934438 (T) and rs9923231 (A) were found to be 11.0%, 11.8%, 11.7% and 12.0%, respectively. The variant allele VKORC1 rs7294 was (80.1%) more frequent and the variant allele CYP4F2 * 3 was found to be 41.8% in South Indians. The allele, genotype and haplotype frequencies of VKORC1 and CYP4F2 gene were distinct from other compared HapMap populations (P < 0.0001). CONCLUSION: The findings of our study provide the basic genetic information for further pharmacogenetic based investigation of OA therapy in the population. PMID- 24339543 TI - Phenotypic spectrum in uniparental disomy: Low incidence or lack of study? AB - CONTEXT: Alterations in the human chromosomal complement are expressed phenotypically ranging from (i) normal, via (ii) frequent fetal loss in otherwise normal person, to (iii) sub-clinical to severe mental retardation and dysmorphism in live births. A subtle and microscopically undetectable chromosomal alteration is uniparental disomy (UPD), which is known to be associated with distinct birth defects as per the chromosome involved and parental origin. UPD can be evident due to imprinted genes and/or activation of recessive mutations. AIMS: The present study comprises of data mining of published UPD cases with a focus on associated phenotypes. The goal was to identify non-random and recurrent associations between UPD and various genetic conditions, which can possibly indicate the presence of new imprinted genes. SETTINGS AND DESIGN: Data mining was carried out using the homepage "http://www.fish.uniklinikum jena.de/UPD.html.", an online catalog of published cases with UPD. MATERIALS AND METHODS: The UPD cases having normal karyotype and with or without clinical findings were selected to analyze the associated phenotypes for each chromosome, maternal or paternal involved in UPD. RESULTS: Our results revealed many genetic conditions (other than the known UPD syndromes) to be associated with UPD. Even in cases of bad obstetric history as well as normal individuals chance detection of UPD has been reported. CONCLUSIONS: The role of UPD in human genetic disorders needs to be studied by involving larger cohorts of individuals with birth defects as well as normal population. The genetic conditions were scrutinized in terms of inheritance patterns; majority of these were autosomal recessive indicating the role of UPD as an underlying mechanism. PMID- 24339544 TI - Index of opportunity for natural selection among the Gowdas of Kodagahalli village, Karnataka, India. AB - BACKGROUND: In order to understand how selection is operating in the Gowda population, the index of opportunity for selection was calculated and the present findings were compared with some related findings from other South Indian (SI) populations. MATERIALS AND METHODS: Crow (1958) and the modified method by Johnston and Kensinger (1971) were used for the present purpose. RESULTS AND DISCUSSION: The index of total selection intensity (I) was found to be moderate taking into consideration the range for many Indian populations. Considering certain differences in fertility and mortality heritable, it appears that natural selection play an important role in shaping the genetic constitution of the Gowda population. Analysis of data indicates that the index due to fertility seems to contribute more towards selection than mortality. This trend might be because of better living condition and health-care system among the Gowdas which have a positive impact on the lower contribution of mortality for the evolution mechanism of the Gowda population through natural selection. PMID- 24339545 TI - No CAG repeat expansion of polymerase gamma is associated with male infertility in Tamil Nadu, South India. AB - Mitochondria contains a single deoxyribonucleic acid (DNA) polymerase, polymerase gamma (POLG) mapped to long arm of chromosome 15 (15q25), responsible for replication and repair of mitochondrial DNA. Exon 1 of the human POLG contains CAG trinucleotide repeat, which codes for polyglutamate. Ten copies of CAG repeat were found to be uniformly high (0.88) in different ethnic groups and considered as the common allele, whereas the mutant alleles (not -10/not -10 CAG repeats) were found to be associated with oligospermia/oligoasthenospermia in male infertility. Recent data suggested the implication of POLG CAG repeat expansion in infertility, but are debated. The aim of our study was to explore whether the not -10/not -10 variant is associated with spermatogenic failure. As few study on Indian population have been conducted so far to support this view, we investigated the distribution of the POLG CAG repeats in 61 infertile men and 60 normozoospermic control Indian men of Tamil Nadu, from the same ethnic background. This analysis interestingly revealed that the homozygous wild type genotype (10/-10) was common in infertile men (77% - 47/61) and in normozoospermic control men (71.7% - 43/60). Our study failed to confirm any influence of the POLG gene polymorphism on the efficiency of the spermatogenesis. PMID- 24339546 TI - Linkage study of DFNB3 responsible for hearing loss in human. AB - BACKGROUND: Hearing disorders represent a significant health problem worldwide. Recessive inherited cases of the deafness are more prevalent in Pakistan due to consanguineous marriages. Deafness caused by DFNB3 is due to mutation in the gene MYO XVA and its prevalence among Pakistani population is about 5%. MATERIALS AND METHODS: Families with at least two or more individual affected with deafness were selected from different areas of District Okara of Pakistan. Six consanguineous families of different ethnic groups having deaf individuals were studied. All these families had three or more deaf individuals in either two or more sib ships. Family history was taken to minimize the chances of other abnormalities. Pedigrees drawn by using Cyrillic software (version 2.1) showed that all the marriages were consanguineous and the families have recessive mode of inheritance. Three STR markers were selected and amplified on all the samples of six families through PCR. The PCR products were then genotyped on non denaturing polyacrylamide gel electrophoresis (PAGE). Haplotypes were constructed to determine the pattern of inheritance and also to determine whether a family was linked or unlinked with known DFNB3 locus. RESULTS: One out of six families showed linkage to the DFNB3 while rest of the families remained unlinked. Carriers of deafness genes were identified and information was provided to the families on request. CONCLUSION: Knowledge about the genetic causes of deafness provide insight into the variable expression of genes involved in this hereditary problem and may allow the prediction and prevention of associated health problems. PMID- 24339547 TI - Genetic and molecular analysis of the CLDN14 gene in Moroccan family with non syndromic hearing loss. AB - BACKGROUND: Hearing loss is the most prevalent human genetic sensorineural defect. Mutations in the CLDN14 gene, encoding the tight junction claudin 14 protein expressed in the inner ear, have been shown to cause non-syndromic recessive hearing loss DFNB29. AIM: We describe a Moroccan SF7 family with non syndromic hearing loss. We performed linkage analysis in this family and sequencing to identify the mutation causing deafness. MATERIALS AND METHODS: Genetic linkage analysis, suggested the involvement of CLDN14 and KCNE1 gene in deafness in this family. Mutation screening was performed using direct sequencing of the CLDN14 and KCNE1 coding exon gene. RESULTS: Our results show the presence of c.11C>T mutation in the CLDN14 gene. Transmission analysis of this mutation in the family showed that the three affected individuals are homozygous, whereas parents and three healthy individuals are heterozygous. This mutation induces a substitution of threonine to methionine at position 4. CONCLUSION: These data show that CLDN14 gene can be i mplicated in the development of hearing loss in SF7 family; however, the pathogenicity of c.11C>T mutation remains to be determined. PMID- 24339548 TI - Analysis of hemoglobin electrophoresis results and physicians investigative practices in Saudi Arabia. AB - BACKGROUND AND OBJECTIVES: Riyadh and central province falls in a moderate prevalent zone of hemoglobinopathies in Saudi Arabia. However, it has been observed that the physicians working in Saudi Arabia invariably advise all cases of anemia for hemoglobin electrophoresis (HE). The present work was carried out to study the yield of the HE in Riyadh and the investigative practices of the physicians advising HE. SETTINGS AND DESIGN: The study was carried out in the hospitals of King Saud University from 2009 to 2011 in order to assess the yield of HE in referred cases of clinical anemia. MATERIALS AND METHODS: A total of 1073 cases divided in two groups of males and females had undergone complete blood count and red blood cell morphology. Cellulose acetate HE was performed and all the positive results were reconfirmed on the high performance liquid chromatography (HPLC). The results were analyzed for the type of hemoglobinopathies. For statistical analysis Statistical Package for Social Sciences 15 version (SPSS Inc., Chicago, IL, USA) was used. RESULTS: A total of 405 males and 668 females blood samples were included in the present study. 116 (28.5%) males and 167 (25%) females showed an abnormal pattern on HE. The incidence of beta thalassemia trait was higher in females while sickle cell trait was predominantly seen in males. Red cell indices were reduced considerably in thalassemias, but were unaffected in sickle cell disorders, except those which had concurrent alpha trait. The total yield of HE was 26.6% which was much less than expected. CONCLUSION: The physicians are advised to rule out iron deficiency and other common causes of anemia before investigating the cases for hemoglobinopathies, which employs time consuming and expensive tests of HE and HPLC. PMID- 24339549 TI - Population based family history analysis of Brahmins in a small town in India for the prevalence of type-2 diabetes mellitus. AB - OBJECTIVES: The objective of this study is to determine the inheritance pattern of type-2 diabetes and make stratification for the general population risk. MATERIALS AND METHODS: A questionnaire was developed for o btaining the family history. Analysis of the data was carried out by using student and Chi-square tests and for stratification; the guidelines of Scheuner et al. were followed. RESULTS: The pattern of inheritance is the male sex specific (chi2 =13.44). The mean age of onset of diabetes in parents was 58.61 +/- 2.94 and in offspring 46.75 +/- 2.54. In all 47.22 +/- 11.53% families were found in high risk and 31.94 +/- 10.77% in the moderate risk category. In female diabetics, the onset was in the age range of 41-60 years. CONCLUSION: We found a high-risk of diabetes and familial clustering in successive generations of Brahmins with prominent male sex specificity. In females onset of diabetes was coinciding with the period around menopause. PMID- 24339550 TI - Mosaic double aneuploidy: Down syndrome and XYY. AB - Chromosomal abnormalities are seen in nearly 1% of live born infants. We report a 5-year-old boy with the clinical features of Down syndrome, which is the most common human aneuploidy. Cytogenetic analysis showed a mosaicism for a double aneuploidy, Down syndrome and XYY. The karyotype was 47, XY,+21[19]/48, XYY,+21[6]. ish XYY (DXZ1 * 1, DYZ1 * 2). Mosaic double aneuploidies are very rare and features of only one of the aneuploidies may predominate in childhood. Cytogenetic analysis is recommended even if the typical features of a recognized aneuploidy are present so that any associated abnormality may be detected. This will enable early intervention to provide the adequate supportive care and management. PMID- 24339551 TI - Poland syndrome a rare congenital anomaly. AB - Poland syndrome is a rare congenital anomaly classically consisting of unilateral hypoplasia of the sternocostal head of the pectoralis major muscle and ipsilateral brachysyndactyly. It was first described by Alfred Poland in 1840 and may occur with different gravity. Our patient is an eight-year-old Nigerian girl with left-sided anterior chest wall defect with no detectable structural heart abnormality but presented with repeated episodes of syncopal attacks following minor trauma to the anterior chest wall. PMID- 24339552 TI - Hemoglobin Fontainebleau [a21(B2)Ala>Pro]: The second report from India. AB - Structural hemoglobin (Hb) variants are mainly due to point mutations in the globin genes resulting in single amino acid substitutions. Until date, about 200 alpha chain variants have been identified and they are usually detected during the hemoglobinopathy screening programs. Under a community control program for hemoglobinopathies, which involved screening of antenatal cases followed by prenatal diagnosis if indicated. Here, we report a rare alpha globin gene variant Hb Fontainebleau [a21(B2)Ala>Pro] detected in the heterozygous condition in a 35 year-old pregnant lady screened during this program. This is the second report of this alpha globin variant from India. Unlike the earlier case from India where Hb Fontainebleau was reported in a neonate who was also a carrier of Hb Sickle and had no clinical problems, this case presented with a bad obstetric history associated with the secondary infertility. However, the presence of the variant and the obstetric complications may be unrelated. PMID- 24339553 TI - Genetic analysis of a family with complete androgen insensitivity syndrome. AB - Androgen insensitivity causes impaired embryonic sex differentiation leading to developmental failure of normal male external genitalia in 46 XY genetic men. It results from diminished or absent biological actions of androgens, which is mediated by the androgen receptor (AR) in both the embryo and secondary sexual development. Mutations in the AR located on the X chromosome are responsible for the disease. Almost 70% of affected individuals inherit the mutation from their carrier mother. We hereby report a 10-year-old girl with all the characteristics of complete androgen insensitivity syndrome (CAIS). Similar scenario was observed in 3 maternal aunts, Sequencing of the AR gene in all the family members revealed C 2754 to T transition in exon 6. It was concluded that the C 2754 to T transition rendered the AR incapable of both ligand-binding and activating the transcription and was the cause of CAIS in the patient. PMID- 24339554 TI - Type 2 diabetes mellitus: An unusual association with Down's syndrome. AB - Down's syndrome (DS) is known to be associated with autoimmune disease including type 1 diabetes. To the best of our knowledge, there are no reports of DS with type 2 diabetes mellitus in the literature. We hereby report two cases of DS with type 2 diabetes. PMID- 24339555 TI - A case of primary amenorrhea with 46+XY genotype from Kashmir Valley. AB - Primary amenorrhea is one of the common reproductive disorder affecting females. It leads to the absence of menarche in the reproductive age group in females and/or complete absence of reproductive organs. There are many causes which lead to PA, including genetic aberrations which are the leading factors. PMID- 24339556 TI - Hypoparathyroidism-retardation-dysmorphism syndrome. AB - Congenital hypoparathyroidism, growth retardation and facial dysmorphism is a rare autosomal recessive disorder seen among children born to consanguineous couple of Arab ethnicity. This syndrome is commonly known as Sanjad-Sakati or hypoparathyroidism-retardation-dysmorphism syndrome (HRD). We report 13-year-old Hindu boy with hypoparathyroidism, tetany, facial dysmorphism and developmental delay, compatible with HRD syndrome. PMID- 24339557 TI - A novel ABCB11 mutation in an Iranian girl with progressive familial intrahepatic cholestasis. AB - Progressive familial intrahepatic cholestasis is an autosomal recessive liver disorder caused by (biallelic) mutations in the ATP8B1 of ABCB11 gene. A nine year-old girl with cholestasis was referred for genetic counseling. She had a family history of cholestasis in two previous expired siblings. Genetic analysis of the ABCB11 gene led to the identification of a novel homozygous mutation in exon 25. The mutation 3593- A > G lead to a missense mutation at the amino acid level (His1198Arg). This mutation caused PFIC2 due to abnormal function in the bile salt export pump protein (BSEP). PMID- 24339558 TI - Genetic mutations in Gorlin-Goltz syndrome. AB - Gorlin-Goltz syndrome is a rare multisystemic disease inherited in a dominant autosomal at a high level of penetrance and variable expressiveness. It is mainly characterized by basal cell carcinoma, odontogenic keratocyst and skeletal anomalies. Diagnosis is based upon established major and minor clinical and radiographic criteria and gene mutation analysis. This article presents a case of Gorlin-Goltz syndrome, its genetic predisposition, diagnosis and management. PMID- 24339559 TI - Novel three missense mutations observed in Von Hippel-Lindau gene in a patient reported with renal cell carcinoma. AB - Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer syndrome that predisposes to the development of a variety of benign and malignant tumors, especially cerebellar hemangioblastomas, retinal angiomas and clear-cell renal cell carcinomas (RCC). We have identified of VHL gene using immunohistochemistry in a patient who was diagnosed for RCC. In order to understand the involvement of mutation in the VHL gene exon 1 was amplified and sequenced (accession number: JX 401534). The sequence analysis revealed the presence of novel missense mutations c.194 C>T, c.239 G>A, c.278 G>A, c.319 C>G, c. 337 C > G leading to the following variations p.Ala 65 Val, p.Gly 80 Asp, p.Gly 93 Glu, p.Gln 107 Glu, p.Gln 113 Glu in the protein. PMID- 24339560 TI - Possible impact of factor V Leiden genotype on warfarin induced bleeding. PMID- 24339561 TI - Neurology in India. PMID- 24339562 TI - Historical perspective of Indian neurology. AB - OBJECTIVE: To chronicle the history of medicine and neurology in India with a focus on its establishment and evolution. BACKGROUND: THE HISTORY OF NEUROLOGY IN INDIA IS DIVIDED INTO TWO PERIODS: ancient and modern. The ancient period dates back to the mid-second millennium Before Christ (B.C.) during the creation of the Ayurvedic Indian system of Medicine, which detailed descriptions of neurological disorders called Vata Vyadhi. The early 20(th) century witnessed the birth of modern Indian medicine with the onset of formal physician training at the nation's first allopathic medical colleges located in Madras (1835), Calcutta (1835) and Mumbai (1848). Prior to India's independence from Britain in 1947, only 25 medical schools existed in the entire country. Today, there are over 355. In 1951, physicians across the field of neurology and neurosurgery united to create the Neurological Society of India (NSI). Four decades later in 1991, neurologists branched out to establish a separate organization called the Indian Academy of Neurology (IAN). DESIGN/METHODS: Information was gathered through literature review using PubMed, MD Consult, OVID, primary texts and research at various academic institutions in India. RESULTS: Neurological disorders were first described in ancient India under Ayurveda. The transition to modern medicine occurred more recently through formal training at medical schools beginning in the 1930's. Early pioneers and founders of the NSI (1951) include Dr. Jacob Chandy, Dr. B Ramamurthi, Dr. S. T. Narasimhan and Dr. Baldev Singh. Later, Dr. J. S. Chopra, a prominent neurologist and visionary, recognized the need for primary centers of collaboration and subsequently established the IAN (1991). The future of Neurology in India is growing rapidly. Currently, there are 1100 practicing neurologists and more than 150 post-graduate trainees who join the ranks every year. As the number of neurologists rises across India, there is an increase in the amount of basic, clinical and epidemiological research being conducted across the country every day. CONCLUSIONS: The history of neurology in India roots back to its rich culture and tradition. Over time, there has been great structural and organizational evolution and the future of neurology in India appears to be bright. However, the number of neurologists and research in neurology needs to experience a significant growth in the future to ensure the best patient care. PMID- 24339564 TI - Design and data analysis case-controlled study in clinical research. AB - Clinicians during their training period and practice are often called upon to conduct studies to explore the association between certain exposures and disease states or interventions and outcomes. More often they need to interpret the results of research data published in the medical literature. Case-control studies are one of the most frequently used study designs for these purposes. This paper explains basic features of case control studies, rationality behind applying case control design with appropriate examples and limitations of this design. Analysis of sensitivity and specificity along with template to calculate various ratios are explained with user friendly tables and calculations in this article. The interpretation of some of the laboratory results requires sound knowledge of the various risk ratios and positive or negative predictive values for correct identification for unbiased analysis. A major advantage of case control study is that they are small and retrospective and so they are economical than cohort studies and randomized controlled trials. PMID- 24339563 TI - Neurology as career option among postgraduate medical students. AB - BACKGROUND: In the context of inadequacy of neurology workforce in India, it is important to understand factors that post-graduate medical students consider for and against choosing neurology as their career option. Understanding these factors will help in planning strategies to encourage students to pursue a career in neurology. At present, there is a paucity of studies addressing this issue in India. AIMS AND OBJECTIVES: (1) To analyze factors, which post-graduate students consider for and against choosing neurology as a career specialty. (2) To access the level and quality of neurology exposure in the current MBBS and MD curricula. MATERIALS AND METHODS: Statewide questionnaire based study was conducted in the state of Maharashtra for students eligible to take DM neurology entrance examination (MD Medicine and MD Pediatrics). RESULTS: In this survey, 243 students were enrolled. Factors bringing students to neurology were - intellectual challenge and logical reasoning (72%), inspired by role model teachers (63%), better quality-of-life (51%) and scope for independent practice without expensive infrastructure (48%). Factors preventing students from taking neurology were - perception that most neurological diseases are degenerative (78%), neurology is mainly an academic specialty (40%), neurophobia (43%) and lack of procedures (57%). Inadequate exposure and resultant lack of self confidence were common (31%, 70-80%). 84% of the students felt the need for a short term certification course in neurology after MD. CONCLUSIONS: To attract more students to neurology, "role model" teachers of neurology could interact and teach students extensively. Neurologists' efforts to shed their diagnostician's image and to shift their focus to therapeutics will help change the image of neurology. Out-patient neurology clinics should be incorporated early in the student's career. Procedures attract students; hence, they should be made conversant with procedures and interventions. Increasing the level of neurological exposure in our current MBBS and MD curriculum is necessary. A case could be made for consideration of short certification course in neurology for physicians. PMID- 24339565 TI - Knowledge, attitude and practice of stroke in India versus other developed and developing countries. AB - Rising stroke and higher mortality among Indian population needs focused attention for prevention and early management of stroke. In India, very few studies have been carried out to determine the causes of deficiencies in knowledge, attitude and practice (KAP) of stroke among Indians. Study on KAP is essential to improve the awareness about stroke, early diagnosis and institution of appropriate management. In this article, we have reviewed the existing literature on this issue and tried to compare it with those of developed countries and suggested the measures we need to adopt in India to improve awareness and knowledge base. PMID- 24339566 TI - Clot composition and treatment approach to acute ischemic stroke: The road so far. AB - Recent histological studies of thrombi retrieved from patients with an acute ischemic stroke using the endovascular thrombectomy devices and correlation with early vessel computed tomography (CT) and magnetic resonance imaging (MRI) characteristics have given relevant insights into the pathophysiology of thrombotic lesions and may facilitate the development of improved reperfusion treatment approaches. We present a review of recent studies on the histopathologic analysis of thrombi, studies of MRI, and CT imaging correlation with thrombus histology, and detailed structural analysis of thromboemboli retrieved by thrombectomy devices during an acute ischemic stroke. PMID- 24339567 TI - Low-density lipoprotein subfraction, carotid artery intima-media thickness, nitric oxide, and tumor necrosis factor alpha are associated with newly diagnosed ischemic stroke. AB - OBJECTIVES: Small dense (sd) low-density lipoprotein (LDL), tumor necrosis factor (TNF) alpha (alpha), and nitric oxide (NO) have recently emerged as important stroke risk factors. The aim of the study was to investigate the effects of increased levels of small LDL particle size, TNF-alpha and NO on the developed ischemic stroke and increased carotid artery intima-media thickness (CIMT). MATERIALS AND METHODS: A total of 29 women and 25 men (a total of 54 ischemic stroke patients) and a similar age group of 50 controls (29 females and 21 males) were included in the study. CIMT, C-reactive protein (CRP), TNF-alpha, NO, and lipid subfraction test of the two groups were measured. RESULTS: The mean LDL particle size was smaller in patients with stroke than in the controls (26.8 +/- 0.31 nm vs. 27.0 +/- 0.31 nm, P = 0.003). sd-LDL, TNF-alpha, NO, CRP, right CIMT, and left CIMT were higher in patients with stroke than in the controls (respectively; 8.2 +/- 7.8 mg/dL vs. 3.3 +/- 3.5 mg/dL, P < 0.001;75.6 +/- 25.0 pg/mL vs. 65.4 +/- 9.1 pg/mL, P = 0.009;76.4 +/- 53.3 mmol/L vs. 41.5 +/- 27.0 mmol/L, P < 0.001;1.9 +/- 2.6 mm vs. 0.4 +/- 0.3 mm P < 0.001;0.97 +/- 0.38 mm vs. 0.83 +/- 0.15 mm, P = 0.007;1.04 +/- 0.44 mm vs. 0.87 +/- 0.19 mm, P = 0.010). CONCLUSION: These results show that sd-LDL is independently associated with the incidence of stroke and may be a risk factor in the development of stroke. In addition, TNF-alpha, NO, right CIMT, and left CIMT may be a risk factor in the development of ischemic stroke. PMID- 24339568 TI - Correlation between serum neuron specific enolase and functional neurological outcome in patients of acute ischemic stroke. AB - CONTEXT: The use of biomarkers to predict stroke prognosis is gaining particular attention nowadays. Neuron specific enolase (NSE), which is a dimeric isoenzyme of the glycolytic enzyme enolase and is found mainly in the neurons is one such biomarker. AIMS: This study was carried out on patients of acute ischemic stroke with the aims to determine the correlation between NSE levels on the day of admission with infarct volume, stroke severity, and functional neurological outcome on day 30. MATERIALS AND METHODS: Seventy five patients of acute ischemic stroke admitted in the Department of Medicine were included in the study. Levels of NSE were determined on day 1 using the human NSE ELISA kit (Alpha Diagnostic International Texas 78244, USA). Volume of infarct was measured by computed tomography (CT) scan using the preinstalled software Syngo (version A40A) of Siemen's medical solutions (Forchheim, Germany). Stroke severity at admission was assessed using Glasgow coma scale (GCS) and functional neurological outcome was assessed using modified Rankin scale (mRS) on day 30. STATISTICAL ANALYSIS USED: Statistical analysis was performed using the SPSS software for windows version 15.0 (SPSS). RESULTS: A positive correlation was found between concentration of NSE on day 1 and infarct volume determined by CT scan (r = 0.955, P < 0.001). A strong negative correlation was found between GCS at presentation and concentration of NSE on day 1 (r = -0.806, P < 0.001). There was a positive correlation between NSE levels at day 1 and functional neurological outcome assessed by mRS at day 30 (r = 0.744, P < 0.001). CONCLUSIONS: Serum levels of NSE in first few days of ischemic stroke can serve as a useful marker to predict stroke severity and early functional outcome. However, larger studies with serial estimation of NSE are needed to establish these observations more firmly. PMID- 24339569 TI - Outcome after decompressive craniectomy in patients with dominant middle cerebral artery infarction: A preliminary report. AB - INTRODUCTION: Life-threatening, space occupying, infarction develops in 10-15% of patients after middle cerebral artery infarction (MCAI). Though decompressive craniectomy (DC) is now standard of care in patients with non-dominant stroke, its role in dominant MCAI (DMCAI) is largely undefined. This may reflect the ethical dilemma of saving life of a patient who may then remain hemiplegic and dysphasic. This study specifically addresses this issue. MATERIALS AND METHODS: This retrospective analysis studied patients with DMCAI undergoing DC. Patient records, operation notes, radiology, and out-patient files were scrutinized to collate data. Glasgow outcome scale (GOS), Barthel index (BI) and improvement in language and motor function were evaluated to determine functional outcome. RESULTS: Eighteen patients between 22 years and 72 years of age were included. 6 week, 3 month, 6 month and overall survival rates were 66.6% (12/18), 64% (11/17), 62.5% (10/16) and 62.5% (10/16) respectively. Amongst ten surviving patients with long-term follow-up, 60% showed improvement in GOS, 70% achieved BI score >60 while 30% achieved full functional independence. In this group, motor power and language function improved in 9 and 8 patients respectively. At last follow-up, 8 of 10 surviving patients were ambulatory with (3/8) or without (5/8) support. Age <50 years corresponded with better functional outcome amongst survivors (P value -0.0068). CONCLUSION: Language and motor outcomes after DC in patients with DMCAI are not as dismal as commonly perceived. Perhaps young patients (<50 years) with DMCAI should be treated with the same aggressiveness that non-DMCAI is currently dealt with. PMID- 24339570 TI - Prevalence and association of lifestyle factors with extracranial carotid atherosclerosis in non-cardioembolic anterior circulation strokes in adult males less than 50 years: One year cross-sectional study. AB - BACKGROUND: Data is scarce on prevalence of extracranial carotid atherosclerosis (ECA) in strokes <50 years and its association with lifestyle factors. OBJECTIVE: Study role of (a) ECA in non-cardio-embolic anterior circulation young strokes, and (b) smoking and alcohol in ECA. MATERIALS AND METHODS: Cardiovascular risk factors and evidence of ECA on carotid doppler ultrasound (CDUS) was evaluated in an one-year preliminary cross-sectional study of consecutive strokes between 20 years and 49 years. Females were excluded. RESULTS: There were 46 male strokes (mean age 38.26 yrs), 17.39% had hypertension, 2.23% had coronary artery disease; none was diabetic. Tobacco users and alcohol consumers were 24/46 (52.17%) cases each. ECA was found in 14/46 (30.44%) cases. Seven of these 14 (50%) i.e., 7/46 cases (15.21%) had carotid occlusion, four had <50%, three had >70% stenosis. 'Smoking and smokeless tobacco use' was found in 71.42% (10/14) symptomatic carotid lesions compared to 43.75% (14/32) strokes without carotid lesions. Prevalence odds ratio for tobacco use and ECA was 3.21 (95% CI: 0.83-12.44) while that of alcohol and ECA was 1.33 (95% CI: 0.38-4.72). CONCLUSION: Prevalence of ECA in strokes <50 years was high due to lifestyle factors which predispose to atherosclerosis at younger age. PMID- 24339571 TI - Cerebral revascularization with superficial temporal - middle cerebral artery anastomosis for complete carotid occlusion: An emerging modality for preventing recurrent stroke. AB - Complete long segment carotid occlusion presents a treatment challenge. These patients cannot be managed adequately by endarterectomy or stenting. Despite best medical management, many continue to develop recurrent strokes. In this select group of patients, there may be role for flow augmentation techniques like superficial temporal-middle cerebral artery bypass. We report a patient who was thus successfully treated and remains asymptomatic. The relevant literature is reviewed. PMID- 24339572 TI - Hemorrhage and ischemia in different hemispheres in a child with moyamoya disease: Case report and review of literature. AB - Hemorrhagic type of moyamoya disease (MMD) is extremely rare in children. Ischemia following hemorrhage is very rare in MMD. There are only 11 reports of mixed-type of MMD, with the patient having both hemorrhage and ischemia in the same hemisphere at the time of presentation, or at different time periods. The ischemia is usually secondary to a precipitating cause. However, there are no reports of a child presenting with both ischemia and hemorrhage in different hemispheres. We present a previously unreported phenomenon of MMD, presenting as hemorrhage and ischemia in opposite hemispheres and review the relevant literature. PMID- 24339573 TI - Clinical profile of patients with nascent alcohol related seizures. AB - AIM: The aim of this study is to characterize the clinical profile of patients with alcohol related seizures (ARS) and to identify the prevalence of idiopathic generalized epilepsy (IGE) in the same. MATERIALS AND METHODS: 100 consecutive male patients presenting to a tertiary care center in South India with new onset ARS were analyzed with alcohol use disorders identification test (AUDIT) score. All underwent 19 channel digital scalp electroencephalography (EEG) and at least computed tomography (CT) scan. RESULTS: A total of 27 patients (27%) who had cortical atrophy on CT had a mean duration of alcohol intake of 23.62 years compared with 14.55 years in patients with no cortical atrophy (P < 0.001). Twenty-two patients (22%) had clustering in the current episode of whom 18 had cortical atrophy. Nearly, 88% patients had generalized tonic clonic seizures while 12% who had partial seizures underwent magnetic resonance imaging (MRI), which identified frontal focal cortical dysplasia in one. Mean lifetime duration of alcohol intake in patients presenting with seizures within 6 hours (6H-gp) of intake of alcohol was significantly lower (P = 0.029). One patient in the 6H-gp with no withdrawal symptoms had EEG evidence for IGE and had a lower AUDIT score compared with the rest. CONCLUSION: CT evidence of cortical atrophy is related to the duration of alcohol intake and portends an increased risk for clustering. Partial seizures can be a presenting feature of ARS and those patients may benefit from MRI to identify underlying symptomatic localization related epilepsy (8.3% of partial seizures). IGE is more likely in patients presenting with ARS within first 6 hours especially if they do not have alcohol withdrawal symptoms and scalp EEG is helpful to identify this small subgroup (~1%) who may require long-term anti-epileptic medication. PMID- 24339574 TI - Obstetric and birth outcomes in pregnant women with epilepsy: A hospital-based study. AB - INTRODUCTION: In addition to changes in seizure frequency, pregnant women with epilepsy (WWE) are at increased risk of complications during pregnancy or delivery. In the absence of a nationwide WWE registry, hospital-based studies may provide important information regarding current management and outcomes in these patients. OBJECTIVES: The aims of this study were to determine changes in seizure frequency, and pregnancy and birth outcomes among pregnant WWE. MATERIALS AND METHODS: We conducted a retrospective review of medical records of pregnant patients with epilepsy, who obtained medical care (from 2006 to 2011) at one of the general hospitals in the North-Eastern State of Malaysia. Data were collected for seizure frequency before and during the pregnancy, concurrent medications, pregnancy complications, and neonatal outcomes. RESULTS: We reviewed records of 25 patients with a total of 33 different pregnancies. All patients were treated with antiepileptic medications during their pregnancies, with 42% monotherapy and 58% polytherapy. Seizure frequency decreased in 5 (15.2%), increased in 18 (54.5%) and unchanged in 10 (30.3%) cases of pregnancies. Pregnancy complications were anemia, gestational diabetes mellitus, gestational hypertension, intrauterine growth retardation, premature rupture of membrane, and vaginal bleeding. Preterm deliveries were recorded in 11 (33.3%) infants. CONCLUSION: In our setting, many patients were being on polytherapy during their pregnancies. This underscores the need for planned pregnancies so that antiepileptic medications can be optimized prior to pregnancy. PMID- 24339575 TI - Knowledge, attitude and practices of students about first aid epilepsy seizures management in a Northern Indian City. AB - BACKGROUND: Knowledge about epilepsy and its management is not satisfactory among school students in developing countries. The present study was planned to ascertain the knowledge, attitude and practices (KAP) of students regarding first aid management of epilepsy seizures in school setting. MATERIALS AND METHODS: A total of 177 students of government schools of Chandigarh, a city of northern India, were taken. They were administered with a pre-tested semi-structured questionnaire (for knowledge and attitude assessment) and an observational checklist after role play (for practice assessment) on first-aid management of epilepsy. A scoring system was devised to quantify the knowledge and practices of students. RESULTS: Seventy-one percent of them had either heard or read about epilepsy. Half of the students believed epilepsy as a hindrance to education. Ayurvedic treatment was preferred by more than half of the students; however, many believed that visit to religious places and exorcism as ways to cure epilepsy. Nearly 74% of students would call a doctor as first-aid measure for seizure in a person with epilepsy. CONCLUSION: We concluded that the knowledge about various aspects of epilepsy was average among school students in Chandigarh. However, there was no significant difference in knowledge, attitude and practice between students who lived in urban, urban slum and rural areas. It is recommended that first-aid management of seizures in epilepsy should be a part of school curriculum. PMID- 24339576 TI - Women with epilepsy and infertility have different reproductive hormone profile than others. AB - PURPOSE: One-third of women with epilepsy (WWE) may experience infertility (failure to conceive after 12 months of regular unprotected intercourse). We aimed to compare the hormone profile of WWE and infertility (WWE-I) with that of WWE who had conceived earlier (WWE-F). MATERIALS AND METHODS: In the Kerala Registry of Epilepsy and Pregnancy, we compared the clinical and hormone profile of 50 WWE-I and 40 age-matched WWE-F. Subjects were examined and blood samples were drawn in follicular phase (1-14 days) for 21 WWE-I and 18 WWE-F, in luteal phase (15-30 days) for 23 WWE-I and 15 WWE-F and beyond 30 days for 6 WWE-I and WWE-F who had irregular cycles. RESULTS: The two groups were comparable regarding physical, epilepsy syndrome, duration of epilepsy, body mass index, and serum cholesterol levels. Menstrual periods were irregular for 6 WWE-I and 5 WWE-F. The WWE-I group (compared to the WWE-F group) had significantly (P < 0.01) higher levels of dehydroepiandrostenedione (2.0 +/- 1.7 ug/mL vs. 1.0 +/- 0.7 ug/mL) and luteinizing hormone-LH (26.4 +/- 37.3 mIU/mL vs. 9.9 +/- 14.5 mIU/mL) and lower levels of progesterone (5.2 +/- 9.2 ng/mL vs. 10.4 +/- 13.4 ng/mL). There was no significant difference in the levels of FT3, FT4, thyroid stimulating hormone, prolactin, follicle-stimulating hormone (FSH), progesterone, testosterone, or androstenedione levels. The WWE-I had 8.5 times higher risk (95% confidence interval 1.2-59.9) of abnormal LH/FSH ratio. WWE who were on antiepileptic drugs (AEDs) (compared to WWE who were not on AEDs) had higher risk of elevated LH/FSH ratio. CONCLUSION: The hormone profile of WWE-I is significantly different from that of WWE-F. These variations need to be interpreted with caution as a causal relationship to epilepsy or use of antiepileptic drugs need to be established through further studies. PMID- 24339577 TI - Clinical profile and follow-up of 51 pediatric neurocysticercosis cases: A study from Eastern India. AB - INTRODUCTION: Our present observational study attempted to evaluate the clinical profiles, diagnosis, treatment and follow-up results of 51 pediatric neurocysticercosis patients over a mean duration of five years (from January 2006 to December 2010). MATERIALS AND METHODS: Diagnosis was mainly based on clinical features, computed tomography (CT)/magnetic resonance imaging scan and exclusion of other causes. Patients with active, transitional cysts and seizure were treated with albendazole for 28 days, steroids and anticonvulsants. RESULTS: A total of 38 patients completed this study. Mean age of the presentation was 8.47 +/- 3.19 years 52.6% of the patients were female. Overall patients presented with generalized seizure in 55.3%, focal in 31.6%, headache +/- vomiting in 63.2%, focal neurodeficit in 10.5% and combination of symptoms in 60.5% cases. Contrast CT brain showed a solitary lesion in 27 (71.1%) and multiple in the rest. At presentation lesions were transitional in 58.2%, inactive in 20% and mixed in 14.6%. After a mean of 2 years, seizure persisted in 9 (23.7%) and headache in 8 (21.1%) of whom six had normal electroencephalography (EEG) while one each showed focal slowing, generalized slowing and epileptiform discharges. During the follow up, CT scan brain 44.7% lesions calcified, 31.6% disappeared, 10.5% regressed and the rest persisted. CONCLUSION: Solitary ring enhancing lesions (transitional stage) involving the parietal lobe was the commonest CT picture at presentation. Generalized tonic-clonic seizure was the most common type of seizure. Number of lesions, persistence of lesion, number of seizures, EEG abnormality at presentation were not found to be prognostically significant (P > 0.05). PMID- 24339578 TI - Benign occipital lobe seizures: Natural progression and atypical evolution. AB - Benign occipital seizure syndromes are benign childhood epilepsy syndromes and are mainly of two types, Panayiotopoulos syndrome, an autonomic epilepsy and idiopathic childhood occipital epilepsy of Gastaut (ICOE-G) including the idiopathic photosensitive occipital lobe epilepsy. Although both these types are categorized as occipital seizures, they are distinct in presentation and management. They can also be tricky to diagnose as visual symptoms may not always be the presenting feature and it is also not very easy to elicit visual hallucinations during history taking. These seizures have a good response to treatment; however, there could be atypical evolution and refractoriness to treatment especially with ICOE-G. We describe three children who presented with visual and non-visual symptoms and the electroencephalography (EEG) in all the three cases showed occipital paroxysms. We have emphasized the clues in the clinical history and EEG leading to the diagnosis of these distinct epilepsy syndromes. We have also discussed the natural course of these epilepsy syndromes with some atypical evolution, which clinicians need to be aware of during treatment of these children. PMID- 24339579 TI - Recurrent prolonged fugue states as the sole manifestation of epileptic seizures. AB - A fugue state is defined as an altered state of consciousness with varying degrees of motor activity and amnesia for the event. It may last for hours to days and may be psychogenic or organic in nature. Epileptic fugue states can be encountered in patients with absence or complex partial nonconvulsive status epilepticus or may occur as a postictal phenomenon in patients with generalized seizures. "absence status epilepticus" (AS) is rare and seen in only 2.6% of the cases with "childhood absence epilepsy" (CAE). The diagnosis of AS can be elusive, but sudden onset and termination of the fugue state, classical electroencephalogram (EEG) features, and response to a therapeutic trial of benzodiazepines helps in confirming the diagnosis and differentiating it from nonepileptic fugue states. We report a childhood onset case, with a 10 years history of recurrent episodes of prolonged fugue state lasting for up to 24 h, as the sole manifestation of epileptic seizures. The EEG features were suggestive of an AS, but there was no history of typical absences, myoclonus, or generalized tonic clonic seizures. This unusual and rare case cannot be categorized into one of the defined epilepsy syndromes like CAE but belongs to a recently identified syndrome of idiopathic generalized epilepsy known as "Absence status epilepsy" in which AS is the sole or the predominant seizure type. PMID- 24339580 TI - Opercular myoclonic-anarthric status epilepticus: A report of two cases. AB - Opercular myoclonic-anarthric status epilepticus (OMASE) is an uncommon disorder of diverse etiology. This condition is characterized by fluctuating cortical dysarthria associated with epileptic myoclonus involving glossopharyngeal musculature bilaterally. We report two cases of OMASE of vascular etiology in adults. In both patients, ictally clonic expression was consistent with epilepsia partialis continua and bilateral, symmetrical involvement of soft palate in one patient and tongue, lips, chin and inferior jaw in both patients due to bilateral projections of the inferior corticonuclear pathways. The inferior rolandic area of dominant and high frontal region in non-dominant hemispheres were involved by an epileptogenic lesion of vascular etiology, which was confirmed by magnetic resonance imaging of brain and single photon emission computerized tomography. Carotid Doppler study showed thrombosis of internal carotid artery in both patients, suggestive of an embolic origin. Early recognition of OMASE is important for early management of carotid occlusive disease. PMID- 24339581 TI - Clinical and imaging perspective and unanswered questions in a case of metronidazole induced encephalopathy. AB - We discuss the clinical and imaging perspective in a case of a 78-year-old male who developed slurring of speech and ataxia acute in onset for the last 3 days. During his hospital stay, he developed multiple episodes of focal seizures without secondary generalization involving the angle of mouth on the right side. The patient had ataxia and positive cerebellar signs. In the past, the patient was treated for amoebic liver abscess and had undergone percutaneous aspiration of abscess. The patient was prescribed oral metronidazole and was discharged. This time, the patient underwent magnetic resonance imaging examination, which revealed lesion highly suggestive of metronidazole-induced encephalopathy. The offending drug was discontinued immediately after which the patient improved clinically. A follow-up scan was performed after 12 days and showed complete resolution of lesions. PMID- 24339582 TI - Optimizing the management of neuromyelitis optica and spectrum disorders in resource poor settings: Experience from the Mangalore demyelinating disease registry. AB - BACKGROUND: In resource-poor settings, the management of neuromyelitis optica (NMO) and NMO spectrum (NMOS) disorders is limited because of delayed diagnosis and financial constraints. AIM: To device a cost-effective strategy for the management of NMO and related disorders in India. MATERIALS AND METHODS: A cost effective and disease-specific protocol was used for evaluating the course and treatment outcome of 70 consecutive patients. RESULTS: Forty-five patients (65%) had a relapse from the onset and included NMO (n = 20), recurrent transverse myelitis (RTM; n = 10), and recurrent optic neuritis (ROPN; n = 15). In 38 (84.4%) patients presenting after multiple attacks, the diagnosis was made clinically. Only 7 patients with a relapsing course were seen at the onset and included ROPN (n = 5), NMO (n = 1), and RTM (n = 1). They had a second attack after a median interval of 1 +/- 0.9 years, which was captured through our dedicated review process. Twenty-five patients had isolated longitudinally extensive transverse myelitis (LETM), of which 20 (80%) remained ambulant at follow-up of 3 +/- 1.9 years. Twelve patients (17%) with median expanded disability status scale (EDSS) of 8.5 at entry had a fatal outcome. Serum NMO-IgG testing was done in selected patients, and it was positive in 7 of 18 patients (39%). Irrespective of the NMO-IgG status, the treatment compliant patients (44.4%) showed significant improvement in EDSS (P <= 0.001). CONCLUSIONS: Early clinical diagnosis and treatment compliance were important for good outcome. Isolated LETM was most likely a post-infectious demyelinating disorder in our set up. NMO and NMOS disorders contributed to 14.9% (45/303) of all demyelinating disorders in our registry. PMID- 24339583 TI - Autoimmune encephalitis: A potentially reversible cause of status epilepticus, epilepsy, and cognitive decline. AB - OBJECTIVES: To review clinical characteristics and response to immunomodulation therapy in autoimmune encephalitis presenting with status epilepticus (SE), epilepsy, and cognitive decline. DESIGN: Observational, prospective case series. SETTING: All India Institute of Medical Sciences, New Delhi, India. MATERIALS AND METHODS: Prospective analysis of 15 patients, who presented with SE, epilepsy, cognitive decline, and other neurological symptoms with positive autoantibodies. Demographic and clinical characteristics were recorded. Brain magnetic resonance imaging (MRI), cerebrospinal-fluid analysis (CSF), and tumor screening were done periodically. Treatment received and responses (categorized as per patients and treating doctor's information) were noted. RESULTS: There were 15 (males = 10) patients of autoimmune encephalitis. The mean age of presentation was 24 years (range: 2-64 years). The most common onset was subacute (64%) and four (29%) patients presented as SE. Predominant clinical presentations were seizures (100%) almost of every semiology. CSF was done in 10 patients; it was normal in 60%. Brain MRI was done in all patients, in six (40%) it was normal, six (40%) showed T2W and FLAIR hyperintensities in bilateral limbic areas. Antibodies found were the N-methyl-D-aspartate receptor antibody in seven (50%), voltage-gated potassium channel antibody in five (36%), two of antiglutamic acid decarboxylase, and one patient with double stranded DNA (dsDNA) antibodies. None showed evidence of malignancy. Patients received immunotherapy, either steroids, intravenous immunoglobulin, or both. Follow-up showed significant improvement in majority of cases, neither further seizures nor relapse in nine (67%) cases. One death occurred, due to delayed presentation. CONCLUSIONS: Uncommon but potentially reversible causes of SE, epilepsy, and cognitive decline may be immune-related and high index of suspicion will prevent missing the diagnosis. PMID- 24339584 TI - Quick screening of cognitive function in Indian multiple sclerosis patients using Montreal cognitive assessment test-short version. AB - BACKGROUND: Cognitive impairments in multiple sclerosis (MS) are now well recognized worldwide, but unfortunately this domain has been less explored in India due to many undermining factors. The aim of this study was to evaluate cognitive impairments in Indian MS patients with visual or upper limb motor problems with the help of short version of Montreal cognitive assessment test (MoCA). SUBJECTS AND METHODS: Thirty MS patients and 50 matched controls were recruited for the 12 points MoCA task. Receiver operating characteristic curve (ROC) analysis was performed to determine optimal sensitivity and specificity of the 12 points MoCA in differentiating cognitively impaired patients and controls. RESULTS: The mean 12 points MoCA scores of the controls and MS patients were 11.56 +/- 0.67 and 8.06 +/- 1.99, respectively. In our study, the optimal cut-off value for 12 points MoCA to be able to differentiate patients with cognitive impairments from controls is 10/12. Accordingly, 73.3% patients fell below the cut off value. Both the groups did not have significant statistical differences with regard to age and educational years. CONCLUSION: The 12 points, short version of MoCA, is a useful brief screening tool for quick and early detection of mild cognitive impairments in subjects with MS. It can be administered to patients having visual and motor problems. It is of potential use by primary care physicians, nurses, and other allied health professionals who need a quick screening test. No formal training for administration is required. Financial and time constraints should not limit the use of the proposed instrument. PMID- 24339585 TI - Facio-brachio-crural dystonic episodes and drop attacks due to leucine rich glioma inactivated 1 encephalitis in two elderly Indian women. AB - Two women in their 60's are presented to us with sudden falls of acute onset. Prolonged observation revealed a gradually evolving syndrome of paroxysmal right sided faciobrachial dystonic (FBD) posturing lasting seconds. Both patients went on to develop hyponatremia, following which the episodes worsened and appeared on both sides. In both cases, prolonged electroencephalography monitoring and magnetic resonance imaging brain were normal and the response to conventional anticonvulsants was poor. One patient improved spontaneously over 6 months. The 2(nd) patient developed an amnestic syndrome and was started on intravenous methylprednisolone with which her movement disorder abated. Her amnestic syndrome improved and she was discharged on oral steroids. Both patients tested positive for leucine-rich glioma inactivated 1 (LGi1) antibodies. We present the first case reports of FBD episodes and drop attacks owing to LGi1 encephalitis from India and review the relevant literature pertinent to the subject. PMID- 24339586 TI - Voltage gated potassium channel antibodies positive autoimmune encephalopathy in a child: A case report and literature review of an under-recognized condition. AB - Autoimmune limbic encephalitis (LE) associated with voltage gated potassium channel antibodies (VGKC-Abs) in children is more common than previously thought and is not always paraneoplastic. Non-neoplastic, autoimmune LE associated with VGKC-Abs has been described recently. However, only few case reports in children as the disease is predominantly described in the adult population. It is likely that this type of autoimmune encephalitis is currently under-diagnosed and hence, under-treated, especially in children. We present a 13-year-old previously fit and healthy African girl diagnosed with LE and we reviewed the literature for its current management. PMID- 24339587 TI - Entrapment neuropathy secondary to tubercular abscess: Uncommon presentation of a common disease. PMID- 24339588 TI - The profile of behavioral and psychological symptoms in vascular cognitive impairment with and without dementia. AB - OBJECTIVE: The objective of this study was to compare the occurrence and severity of behavioral and psychological symptoms of dementia (BPSD) between vascular dementia (VaD) and vascular cognitive impairment-no dementia (VCI-ND). MATERIALS AND METHODS: Consecutive patients presenting with cognitive impairment at least 3 months after an ischemic stroke and with a Hachinski Ischemic Score >=4 were included. VaD was diagnosed as per National Institute of Neurological Disorders and Stroke - Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria for probable VaD and VCI-ND on the lines of the Canadian study of health and aging. The severity of cognitive impairment and the behavioral/psychological symptoms were studied by means of the clinical dementia rating scale and the neuropsychiatric inventory (NPI) respectively. RESULTS: All patients with VaD and 89% of those with VCI-ND had at least one BPSD. The mean no. of symptoms per patient and the total NPI scores were higher in VaD than in VCI-ND. Apathy and night-time behavior disturbances were significantly more common and severe in VaD. CONCLUSIONS: BPSD are very common both in VCI-ND and in VaD. The profile of BPSD is similar in both groups, albeit more severe in VaD. The net burden of BPSD is higher in VaD as compared to VCI-ND. PMID- 24339589 TI - The neuroprotective effect of immune serum of adeno-associated virus vaccine containing Abeta1-15 gene on amyloid toxicity. AB - OBJECTIVE: The aim of this study was to explore the effect of adeno-associated virus (AAV) serotype 2 vector vaccine containing amyloid-beta peptide (Abeta) 1 15 gene fragment (AAV-Abeta15) immunized mice sera on counteracting Abeta1-42 peptide toxicity towards a primary culture cortical neurons. MATERIALS AND METHODS: BALB/c mice were vaccinated via the intramuscular immunization route with AAV-Abeta15. The anti-Abeta antibody titer of immunized mice sera was quantified by sandwich Enzyme-Linked ImmunoSorbent Assay. The toxicity of Abeta1 42 peptide on neurons was assessed by morphology with an inverse microscopy and cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. RESULTS: AAV-Abeta15 could induce an Abeta specific immunoglobulin G (IgG) humoral immune response in /c mice the anti-Abeta antibodies were detectable at 1 month after immunization, significantly increased at 2 and 4 months after immunization, and the immunized sera could attenuate cytotoxicity of Abeta1-42 peptide on primary culture cortical neurons. CONCLUSIONS: The immune serum of AAV-Abeta15 could play a neuroprotective effect against Abeta1-42 peptide toxicity, which would be beneficial for Alzheimer's disease patients. PMID- 24339590 TI - Transcranial motor evoked potential monitoring outcome in the high-risk brain and spine surgeries: Correlation of clinical and neurophysiological data - An Indian perspective. AB - OBJECTIVE: The objective of this study is to assess the safety, feasibility and clinical value of transcranial motor evoked potential (MEP) monitoring by electrical stimulation. SETTING: Clinical neurophysiology department of tertiary reach hospital. MATERIALS AND METHODS: MEP monitoring was attempted in 44 "high risk" patients. Intraoperative surgical, anesthesia and neurophysiological findings were documented prospectively. MEP monitoring results were correlated with motor outcome. RESULTS: The success for reliable MEP recording from the lower limbs was 75%. Incidence of new permanent post-operative motor deficit was zero. Nearly, 76.5% of the cases (13 out of 17 cases) who showed unobtainable and unstable MEP outcome had lesion location in the spine as compared with 23.5% (4 out of 17 cases) that had lesion location in the brain. Chi-square test demonstrated a statistically significant difference between these two groups (P = 0.0020). Out of these 13 spine surgery cases, 8 (62%) were operated for deformity. Seven out of 12 (60%) patients less than 12 years of age had a poor MEP monitoring outcome suggesting that extremes of age and presence of a spine deformity may be associated with a lesser incidence of successful MEP monitoring. No complications related to the repetitive transcranial electrical stimulation for eliciting MEP were observed. CONCLUSION: MEP monitoring is safe. The protocol used in this study is simple, feasible for use and has a fairly high success rate form the lower limbs. Pediatric age group and spine lesions, particularly deformities have an adverse effect on stable MEP recording. PMID- 24339591 TI - Low luminance/eyes closed and monochromatic stimulations reduce variability of flash visual evoked potential latency. AB - CONTEXT: Visual evoked potentials are useful in investigating the physiology and pathophysiology of the human visual system. Flash visual evoked potential (FVEP), though technically easier, has less clinical utility because it shows great variations in both latency and amplitude for normal subjects. AIM: To study the effect of eye closure, low luminance, and monochromatic stimulation on the variability of FVEPs. SUBJECTS AND METHODS: Subjects in self-reported good health in the age group of 18-30 years were divided into three groups. All participants underwent FVEP recording with eyes open and with white light at 0.6 J luminance (standard technique). Next recording was done in group 1 with closed eyes, group 2 with 1.2 and 20 J luminance, and group 3 with red and blue lights, while keeping all the other parameters constant. Two trials were given for each eye, for each technique. The same procedure was repeated at the same clock time on the following day. STATISTICAL ANALYSIS: Variation in FVEP latencies between the individuals (interindividual variability) and the variations within the same individual for four trials (intraindividual variability) were assessed using coefficient of variance (COV). The technique with lower COV was considered the better method. RESULTS: Recording done with closed eyes, 0.6 J luminance, and monochromatic light (blue > red) showed lower interindividual and intraindividual variability in P2 and N2 as compared to standard techniques. CONCLUSIONS: Low luminance flash stimulations and monochromatic light will reduce FVEP latency variability and may be clinically useful modifications of FVEP recording technique. PMID- 24339592 TI - Transcranial magnetic stimulation in patients with early cortical dementia: A pilot study. AB - CONTEXT: The diagnostic accuracy of the currently available tools carries poor sensitivity resulting in significant delay in specific diagnosis of cortical dementias. Considering the properties of default mode networking of the brain it is highly probable that specific changes may be seen in frontotemporal dementias (FTDs) and Alzheimer's disease sufficiently early. AIM: The aim of this study is to look for changes in Transcranial Magnetic Stimulation (TMS) in cortical dementia. MATERIALS AND METHODS: Evaluated with a single pulse TMS with the figure of eight coil and recorded from right first dorsal interossei (FDI). Resting Motor Threshold (RMT) was estimated on the opposite motor cortex (T1). Second site of stimulation was cervical spine at C7-T2. Central motor conduction time (CMCT) is equal toT1-T2. Silent Period (SP) identified by applying TMS pulse to contracting FDI. CONCLUSIONS: RMT was reduced in seven out of eight Alzheimer's dementias. CMCT was in the upper limit of normal in both patients with FTD. The most consistent observation was that SP was reduced and there were escape discharges noticed during the SP suggesting increased cortical excitability and decreased cortical inhibition. This suggests probable early asymptomatic changes in the gamma-aminobutyric acid (GABA) nergic and cholinergic system is taking place. This if confirmed may give some insight into early diagnosis and therapeutic role of GABA agonists in these disorders. PMID- 24339593 TI - A study of interpolation method in diagnosis of carpal tunnel syndrome. AB - CONTEXT: The low correlation between the patients' signs and symptoms of carpal tunnel syndrome (CTS) and results of electrodiagnostic tests makes the diagnosis challenging in mild cases. Interpolation is a mathematical method for finding median nerve conduction velocity (NCV) exactly at carpal tunnel site. Therefore, it may be helpful in diagnosis of CTS in patients with equivocal test results. AIM: The aim of this study is to evaluate interpolation method as a CTS diagnostic test. SETTINGS AND DESIGN: Patients with two or more clinical symptoms and signs of CTS in a median nerve territory with 3.5 ms <= distal median sensory latency <4.6 ms from those who came to our electrodiagnostic clinics and also, age matched healthy control subjects were recruited in the study. MATERIALS AND METHODS: Median compound motor action potential and median sensory nerve action potential latencies were measured by a MEDLEC SYNERGY VIASIS electromyography and conduction velocities were calculated by both routine method and interpolation technique. STATISTICAL ANALYSIS USED: Chi-square and Student's t-test were used for comparing group differences. Cut-off points were calculated using receiver operating characteristic curve. RESULTS: A sensitivity of 88%, specificity of 67%, positive predictive value (PPV) and negative predictive value (NPV) of 70.8% and 84.7% were obtained for median motor NCV and a sensitivity of 98.3%, specificity of 91.7%, PPV and NPV of 91.9% and 98.2% were obtained for median sensory NCV with interpolation technique. CONCLUSIONS: Median motor interpolation method is a good technique, but it has less sensitivity and specificity than median sensory interpolation method. PMID- 24339594 TI - A study on the standard of documentation of lumbar puncture in neurology department of a major Irish Teaching Hospital in Ireland. AB - OBJECTIVE: Poor documentation following lumbar puncture (LP) had always been a matter of concern. This study aimed to investigate the documentation pattern of neurology house officers, registrars (Regs), and specialist Regs following LP in a major teaching hospital. MATERIALS AND METHODS: Total hundred patient records were examined in the light of a carefully designed proforma containing 15 important indicators of good-quality LP documentation. RESULT: Mean number of indicators overall documented by doctors was found to be 6.24 +/- 3.0037. The mean number of indicators recorded by house officers was 5.11 +/- 3.01 and Regs was 7.56 +/- 3.28. A total of 33% LPs were performed without a documented consent. Only 36% performers documented the type and size of needle they used during the procedure. Only 46% documents revealed the strength and name of the local anesthetic used. Statistically significant difference between senior house officers and Regs in terms of numbers of indicators documented was noted. CONCLUSION: The documentation standard among neurology junior doctors remained poor. PMID- 24339595 TI - Subacute sclerosing panencephalitis: A clinical appraisal. AB - INTRODUCTION: Subacute sclerosing panencephalitis (SSPE) is a rare chronic, progressive encephalitis affecting primarily children and young adults, caused by a persistent infection of immune resistant measles virus. The aim of the present study is to describe the clinical profile and natural history of patients with SSPE. METHODS: We collected data of patients with SSPE during 2004-2010 who fulfilled Dyken's criteria. We analyzed demographical, clinical, electrophysiological, and imaging features. RESULTS: Study included 34 patients, 26 (76.5%) males with age of onset from 3 to 31 years. Twenty one patients were below 15 years of age formed childhood SSPE and 13 above 15 years of age constituted adult onset group. 85.3% had low-socioeconomic status. Eleven received measles vaccination and seven were unvaccinated. 59.9% patients had measles history. Most common presenting symptom was scholastic backwardness (52.5%) followed by seizures (23.5%). Three patients each had cortical blindness, macular degeneration, decreased visual acuity, and optic atrophy. Electroencephalographic (EEG) showed long interval periodic complexes and cerebrospinal fluid anti-measles antibody was positive in all. Magnetic resonance imaging was done in 70.5% with was abnormal in 52.5%. Mean incubation period of SSPE after measles was 9.6 years. The follow-up duration was 1-10 years, (average of 2 years). Only one patient died from available data of follow-up, 9 were stable and 10 deteriorated in the form of progression of staging. CONCLUSION: SSPE is common in low-socioeconomic status. The profile of adult onset did not differ from childhood onset SSPE, except for a longer interval between measles infection and presence of the ophthalmic symptom as presenting feature in adult onset group. PMID- 24339597 TI - Identifying risk for dementia across populations: A study on the prevalence of dementia in tribal elderly population of Himalayan region in Northern India. AB - INTRODUCTION: Studies have suggested that dementia is differentially distributed across populations with a lower prevalence in developing regions than the developed ones. A comparison in the prevalence of dementia across populations may provide an insight into its risk factors. Keeping this in view, a study was planned to evaluate the prevalence of dementia in tribal elderly population. MATERIALS AND METHODS: A cross-sectional comprehensive two-phase survey of all residents aged 60 years and older was conducted. Phase one involved screening of all individuals aged 60 and above with the help of a cognitive screen specifically developed for the tribal population. Phase two involved clinical examination of individuals who were suspected of dementia as per the developed cognitive screening test. RESULTS: The results revealed that no individual above 60 years of age in the studied population was diagnosed as a case of dementia. Thereby, pointing out at some unknown factors, which are responsible for prevention of dementia. DISCUSSION: The differences between the prevalence rate in this study and other studies in India appear to be a function of a valid regional difference. Environmental, phenotypic and genetic factors may contribute to regional and racial variations in dementia. Societies living in isolated hilly and tribal areas seem less predisposed to dementia, particularly age related neurodegenerative and vascular dementia, which are the most common causes for dementia in elderly. This may be because some environmental risk factors are much less prevalent in these settings. PMID- 24339596 TI - Effectiveness of mirror therapy on lower extremity motor recovery, balance and mobility in patients with acute stroke: A randomized sham-controlled pilot trial. AB - OBJECTIVE: To evaluate the effectiveness of mirror therapy on lower extremity motor recovery, balance and mobility in patients with acute stroke. DESIGN: A randomized, sham-controlled, assessor blinded, pilot trial. SETTING: Inpatient stroke rehabilitation unit. SUBJECTS: First time onset of stroke with mean post stroke duration of 6.41 days, able to respond to verbal instructions, and Brunnstrom recovery stage 2 and above were enrolled. INTERVENTION: Mirror therapy group performed 30 minutes of functional synergy movements of non-paretic lower extremity, whereas control group underwent sham therapy with similar duration. In addition, both groups were administered with conventional stroke rehabilitation regime. Altogether 90 minutes therapy session per day, six days a week, for two weeks duration was administered to both groups. OUTCOME MEASURES: Lower extremity motor subscale of Fugl Meyer Assessment (FMA), Brunnel Balance Assessment (BBA) and Functional Ambulation Categories (FAC). RESULTS: Amongst the 22 patients included, equal number of patients participated in mirror group (N = 11) and control group (N = 11). Baseline variables were similar in both groups, except for Brunnstrom recovery stage. There was no statistical difference between groups, except for FAC. (FMA: P = 0.894; BBA: P = 0.358; FAC: P = 0.02). Significance was set at P < 0.05. CONCLUSION: Administration of mirror therapy early after stroke is not superior to conventional treatment in improving lower limb motor recovery and balance, except for improvement in mobility. PMID- 24339598 TI - Diagnostic value of latex agglutination test in diagnosis of acute bacterial meningitis. AB - OBJECTIVES: To know the incidence of bacterial meningitis in children below five years of age. To compare conventional culture and antigen detection methods (Latex agglutination test). MATERIALS AND METHODS: 100 CSF samples of clinically suspected meningitis cases in children below 5 years of age were included. The samples were subjected to cell count, Gram stain, culture and LAT. The organisms isolated in the study were characterized according to standard procedures. RESULTS: Of the 100 cases studied, 31 cases were diagnosed as ABM by Gram stain, culture and latex agglutination test as per WHO criteria. The hospital frequency of ABM was 1.7%. 15 (48.38) cases were culture positive. Gram stain was positive in 22(70.96) cases and LAT in 17(54.83) cases. Haemophilus influenzae was the most common causative agent of acute bacterial meningitis followed by S.pneumoniae. Case fatality rate was 45.16%. The sensitivity and specificity of LAT was 66.66% and 87.91% respectively. CONCLUSION: Bacterial meningitis is a medical emergency and early diagnosis and treatment is life saving and reduces chronic morbidity. LAT was more sensitive compared to conventional Gram stain and Culture technique in identifying the fastidious organisms like H.influenzae, S.pneumoniae and Group B Streptococcus. However, the combination of Gram stain, Culture and LAT proved to be more productive than any of the single tests alone. PMID- 24339599 TI - Interrelationships between chronic tension-type headache, musculoskeletal pain, and vitamin D deficiency: Is osteomalacia responsible for both headache and musculoskeletal pain? AB - BACKGROUND: Headache, musculoskeletal symptoms, and vitamin D deficiency are common in the general population. However, the interrelations between these three have not been delineated in the literature. MATERIALS AND METHODS: We retrospectively studied a consecutive series of patients who were diagnosed as having chronic tension-type headache (CTTH) and were subjected to the estimation of serum vitamin D levels. The subjects were divided into two groups according to serum 25(OH) D levels as normal (>20 ng/ml) or vitamin D deficient (<20 ng/ml). RESULTS: We identified 71 such patients. Fifty-two patients (73%) had low serum 25(OH) D (<20 ng/dl). Eighty-three percent patients reported musculoskeletal pain. Fifty-two percent patients fulfilled the American College of Rheumatology criteria for chronic widespread pain. About 50% patients fulfilled the criteria for biochemical osteomalacia. Low serum 25(OH) D level (<20 ng/dl) was significantly associated with headache, musculoskeletal pain, and osteomalacia. DISCUSSION: These suggest that both chronic musculoskeletal pain and chronic headache may be related to vitamin D deficiency. Musculoskeletal pain associated with vitamin D deficiency is usually explained by osteomalacia of bones. Therefore, we speculate a possibility of osteomalacia of the skull for the generation of headache (osteomalacic cephalalgia?). It further suggests that both musculoskeletal pain and headaches may be the part of the same disease spectrum in a subset of patients with vitamin D deficiency (or osteomalacia), and vitamin D deficiency may be an important cause of secondary CTTH. PMID- 24339600 TI - Case series of probable sporadic Creutzfeldt-Jakob disease from Eastern India. AB - BACKGROUND: Creutzfeldt-Jakob disease is a rapidly progressive, fatal, transmissible neurodegenerative disorder caused by prion protein. It is still considered rare in countries like India. This is probably due to nonavailability of autopsy studies in majority of the center. The recent European diagnostic criterion for sporadic CJD (sCJD) is useful for making an early diagnosis. OBJECTIVE: To report a series of patients of probable sCJD from a neurology institute of eastern India. MATERIALS AND METHODS: Patients of rapidly developing dementia fulfilling the diagnostic criteria for sCJD were included. All were investigated in detail to find out any possible treatable cause including electroencephalography (EEG), magnetic resonance imaging (MRI) of brain, and cerebrospinal fluid analysis. RESULTS: A total 10 patients of probable sCJD diagnosed using the European diagnostic criterion between December 2011 and January 2013. The clinical features are consistent with other reported series. While 60% of patients had the classical EEG findings, 100% had typical MRI features. Eight patients died within a mean duration of 4.56 months from the disease onset. CONCLUSIONS: The clinical features are similar to other reported series. Our observation raises question about the prevalence of this disease in India which needs more elaborate studies. PMID- 24339602 TI - Hyperkeratosis as a clue to diagnosis in a patient with myopathy. PMID- 24339601 TI - Electromyographic and histological features of postpartum hypernatremic rhabdomyolysis. AB - INTRODUCTION: Rhabdomyolysis results from many causes including hypernatremia. Postpartum hypernatremia with osmotic cerebral demyelination is a rare cause of reversible rhabdomyolysis. Electromyographic studies in postpartum hypernatremia have not been reported. MATERIALS AND METHODS: Electromyography (EMG) was performed in five women with postpartum hypernatremia and muscle biopsy was performed in one of them. RESULTS: Among the five women presenting with postpartum hypernatremia associated with marked elevation of serum creatine kinase, four had quadriparesis. All had varying degrees of encephalopathy at admission and recovered without residual deficits after gradual correction of hypernatremia. Needle EMG revealed fibrillations with positive sharp waves in five patients and myotonic discharges in three patients. Serial EMG in one patient revealed the occurrence of transient fibrillations, positive sharp waves and myotonic discharges. Muscle biopsy revealed extensive rhabdomyolysis in one patient. CONCLUSION: EMG in hypernatremic rhabdomyolysis revealed spontaneous activity including fibrillations, positive sharp waves and myotonic discharges along with myopathic potentials. Electromyographic findings depend on the interval from the onset and the degree of rhabdomyolysis. PMID- 24339603 TI - White matter changes on magnetic resonance imaging in a patient with neurodegenerative disease. PMID- 24339604 TI - Hot cross bun sign in HIV-related progressive multifocal leukoencephalopathy. PMID- 24339605 TI - Cerebral proliferative angiopathy: A rare clinical entity with peculiar angiographic features. PMID- 24339606 TI - Ictal PET in presurgical workup of refractory extratemporal epilepsy. AB - Ictal Pet in presurgical workup of refractory epilepsy is seldom performed and limited due to technical difficulties. In carefully selected patient subset with frequent extratemporal seizures, ictal PET depicts 'seizure onset zone' with high spatial resolution even within a widespread pathology. We here depict a four year old with posterior quadrant dysplasia evaluated with ictal PET. PMID- 24339607 TI - Autosomal recessive bilateral frontal polymicrogyria with ectopia lentis and chorioretinal dystrophy. AB - Polymicrogyria is a type of cortical dysplasia with cortical organizational defect. Bilateral polymicrogyria are distinct with genetic basis in a subset. We hereby report a case of bilateral frontal polymicrogyria (BFP) in association with chorioretinal dystrophy and ectopia lentis (EL) in a 26-year-old lady born of a consanguineous parentage. Her male sibling also had chorioretinal dystrophy and EL. This combination of autosomal recessive inheritance has not been reported earlier in the literature and suggests a role of connective tissue genes in BFP. PMID- 24339608 TI - Guillain Barre syndrome as a manifestation of neurological melioidosis. AB - Neurological melioidosis is a very rare and very few cases have been reported from India. Presentation is an extremely varied and as this disease is associated with high mortality, high index of suspicion is needed to diagnose and treat. In this context, we report a patient presenting as Guillain Barre syndrome evaluated as melioidosis. PMID- 24339609 TI - A case of peduncular hallucinosis presenting as a primary psychiatric disorder. AB - Peduncular hallucinosis usually occurs due to vascular or infectious midbrain lesions or brain stem compression by tumors. We present a peduncular hallucinosis case in a 63-year-old female with brain stem infarction, which can easily be misdiagnosed as a psychiatric disorder. PMID- 24339610 TI - "Dry" and "wet" beriberi mimicking critical illness polyneuropathy. AB - Three cases with manifestations of right heart failure, shock, metabolic acidosis, and renal failure in varying combination were admitted with paraparesis. Nerve conduction study suggested predominantly motor and mainly axonal type of neuropathy. Rapid reversal of shock, acidosis, and multi-organ dysfunction with timely infusion of thiamine was followed by the complete neurological recovery. PMID- 24339611 TI - Osteomalacia induced peripheral neuropathy after obesity reduction surgery. AB - Osteomalacia and rickets are important reversible causes of debilitating muscular weakness and bony pains in India among all socio-economic strata and at all ages. Osteomalacia after bariatric surgery is documented in literature. Most reports on osteomalacic weakness note myopathic pattern on electromyography. We present the case of a young obese girl from a good socio-economic status who developed severe muscular weakness after sleeve gastrectomy surgery. The patient was found to have osteomalacia with normal vitamin B12 and folate levels. Electrodiagnostic studies demonstrated neuropathic pattern while radiological tests confirmed osteopenia and Looser's zones. Specific vitamin D supplementation was associated with improvement though contribution of other micronutrients in diet cannot be ruled out. Relevance of vitamin D deficiency and urgent need for its correction in the population all over the world and especially in Asia is an emerging health issue. Peripheral motor neuropathy is a rare, seldom reported presentation of osteomalacia. PMID- 24339612 TI - Focal neuromyotonia as a presenting feature of lumbosacral radiculopathy. AB - Neuromyotonia is characterized by motor, sensory, and autonomic features along with characteristic electrophysiologic findings, resulting from hyperexcitability of the peripheral nerves. We describe the case of a 36-year-old man, who presented with the disabling symptoms suggestive of focal neuromyotonia involving both the lower limbs. His neurological examination revealed continuous rippling of both the calf muscles with normal power, reflexes, and sensory examination. Electrophysiology revealed spontaneous activity in the form of doublets, triplets, and neuromyotonic discharges along with the neurogenic motor unit potentials in bilateral L5, S1 innervated muscles. Magnetic resonance imaging lumbosacral spine revealed lumbar intervertebral disc protrusion with severe foraminal and spinal canal stenosis. Patient had good response to steroids and carbamazepine. The disabling focal neuromyotonia, occurring as a result of chronic active radiculopathy, brought the patient to medical attention. Patient responded to medical management. PMID- 24339613 TI - Acute myeloneuropathy: An uncommon presentation of Sjogren's syndrome. AB - Sjogren's syndrome is associated with central and peripheral nervous system involvement. The peripheral neuropathy is usually a sensory predominant neuropathy or a cranial neuropathy. Myelopathy is usually of focal, subacute, chronic or relapsing type. Acute myeloneuropathy as the predominant manifestation has not been described in the literature. We describe a middle aged woman who presented with an acute onset motor quadriparesis and bladder dysfunction. She had dryness of eyes and mouth for 8 months. Nerve conduction studies revealed motor axonal neuropathy and magnetic resonance imaging of spinal cord showed T2 hyperintensities involving entire cord. Mild perineural fibrosis, focal foamy changes in endoneurium and lymphocytic infiltration were seen in sural nerve biopsy specimen. Patient improved clinically after intravenous methylprednisolone therapy. PMID- 24339614 TI - Two cases of medically-refractory spontaneous orthostatic headaches with normal cerebrospinal fluid pressures responding to epidural blood patching: Intracranial hypotension versus hypovolemia and the need for clinical awareness. AB - The diagnosis of spontaneous intracranial hypotension or cerebrospinal fluid (CSF) hypovolemia syndrome requires a high index of suspicion and meticulous history taking, demonstration of low CSF pressure and/or neuroimaging features. A 31-year-old male, presented with subacute onset moderate occipital and sub occipital headaches precipitated by upright posture and relieved on recumbency and neck pain for 2 years. There was no trauma, cranial/spinal surgery. Clinical examination was normal and CSF opening pressure and laboratory study were normal. Magnetic resonance imaging (MRI) brain showed thin subdural hygroma. Another patient, 41-year-old male presented with 1 month of subacute onset severe bifrontal throbbing orthostatic headaches (OHs). CSF opening pressure was normal. Contrast MRI brain showed the presence of bilateral subdural hygromas, diffuse meningeal enhancement, venous distension, sagging of the brain, and tonsillar herniation. We report two cases of "spontaneous OHs" with normal CSF pressures who were successfully treated with epidural blood patching after poor response to conservative management. PMID- 24339615 TI - Spinocerebellar ataxia 17: Inconsistency between phenotype and neuroimage findings. AB - Spinocerebellar ataxia 17 (SCA17) is an autosomal dominant neurodegenerative disease clinically characterized by the presence of cerebellar ataxia in combination with variable neurological symptoms. Here we report a Chinese SCA17 family which proband's clinical manifestation was inconsistent with the neuroimage findings. PMID- 24339616 TI - Two case reports of an unusual association between Klippel-Feil syndrome and amyotrophic lateral sclerosis: Do they share same genetic defect? AB - Klippel-Feil syndrome (KFS) is an unusual skeletal disorder characterized by congenital fusion of two or more cervical vertebrae which can be sporadic or familial. KFS emerges to be a failure of the normal segmentation and fusion of the mesodermal somites during 3(rd) and 8(th) weeks of embryonic development. The triad of low posterior hairline, short neck, and restricted neck motion is present only in 50% and often associated with scoliosis, spina bifida, Sprengel's deformity, cervical ribs, deafness, cleft palate, renal anomalies, congenital heart defects, and so on because of heterogeneous nature of the disease. The significance of KFS lies in the secondary effects produced on the nervous system, which usually presents with features of progressive cord and brain stem compression with relatively minor trauma. We here report two cases of KFS presented in association with amyotrophic lateral sclerosis. Only two such cases have been described in the literature in 1954 and 1975. PMID- 24339617 TI - Spinocerebellar ataxia type 7: Report of an Indian family. AB - Spinocerebellar ataxia type 7 (SCA7) is a form of autosomal dominant cerebellar ataxia which is associated with pigmentary retinal degeneration. It is known for its world-wide rarity except in the Scandinavian countries. It is very rarely reported from India and the neighbouring Asian countries. The present report describes the neurogenetic findings of a family of SCA7, from the northern part of Karnataka in South India. It documents the wide intrafamilial phenotypic variability, which could be correlated with the CAG repeat counts and phenomenon of anticipation. Genotype phenotype correlation highlighted certain disparities in comparison with the previous studies. The report highlights the need for multiethnic population studies and the role of genetic counseling and prenatal testing in SCA7 patients. PMID- 24339618 TI - Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis. AB - Bethlem myopathy and Ullrich congenital muscular dystrophy form a spectrum of collagenopathies caused by genetic mutations encoding for any of the three subunits of collagen VI. Bethlem phenotype is relatively benign and is characterized by proximal dominant myopathy, keloids, contractures, distal hyperextensibility, and follicular hyperkeratosis. Three patients from a single family were diagnosed to have Bethlem myopathy based on European Neuromuscular Centre Bethlem Consortium criteria. Affected father and his both sons had slowly progressive proximal dominant weakness and recurrent falls from the first decade. Both children aged 18 and 20 years were ambulant at presentation. All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy. Creatinine kinase was mildly elevated and electromyography revealed myopathic features. Muscle imaging revealed severe involvement of glutei and vasti with "central shadow" in rectus femoris. Muscle biopsy in the father showed dystrophic changes with normal immmunostaining for collagen VI, sarcoglycans, and dysferlin. PMID- 24339620 TI - Multiple sulfatase deficiency: A case series of four children. AB - Multiple sulfatase deficiency is biochemically characterized by the accumulation of sulfated lipids and acid mucopolysaccharides. The gene sulfatase-modifying factor 1 (SUMF1), recently identified, encodes the enzyme responsible for post translational modification of a cysteine residue, which is essential for the activity of sulfatases. We describe clinical findings and mutation analysis of four patients. The patients presented with hypotonia, developmental delay, coarse face, ichthyosis, and hepatosplenomegaly. The diagnosis was made through clinical findings, enzymatic assays, and mutation analysis. We were detected to be homozygous for a novel missense mutation c. 739G > C causing a p.G247R amino acid substitution in the SUMF1 protein. PMID- 24339619 TI - The combination of thermal dysregulation and agenesis of corpus callosum: Shapiro's or/and reverse Shapiro's syndrome. AB - Shapiro syndrome is an extremely rare condition consisting the clinical triad of recurrent hypothermia, hyperhydrosis and agenesis of the corpus callosum. On the other hand, reverse Shapiro's sydrome is characterized periodic hyperthermia and agenesis of the corpus callosum. Here, we describe a 3.5-year-old girl with complete agenesis of corpus callosum presenting with recurrent fever and vomiting. She also had hypothermia attacks with accompanying diaphoresis. To the best of our knowledge, there is no described case with episodes of hyperthermia, hypothermia, and vomiting associated with agenesis of the corpus callosum. Recurrent vomiting may be a newly defined symptom associated with these syndromes. PMID- 24339621 TI - An unusual presentation of subdural empyema caused by Porphyromonas gingivalis. AB - Subdural empyema is an uncommon clinical entity. The first case of Porphyromonas gingivalis subdural empyema is reported. We report a case of 34-year-old male who presented with subdural empyema and sinusitis. Through the utilization of polymerase chain reaction (PCR) tests on subdural pus, we were able to confirm the diagnosis and institute appropriate treatment. Early surgical intervention and intravenous antibiotics meant that the patient recovered fully. Infections caused by P. gingivalis should be considered in differential diagnoses of central nervous system (CNS) abscesses or subdural empyema especially in patients with precedent periodontal diseases and sinusitis. PMID- 24339622 TI - Opinions about the use of brain natriuretic peptide among acute ischemic stroke patients. PMID- 24339623 TI - Levetiracetam induced encephalopathy in a patient with normal renal function: An unusual clinical encounter. PMID- 24339624 TI - Bilateral facial nerve palsy: A rare association with hepatitis A. PMID- 24339625 TI - Racemose neurocysticercosis and reversible dementia. PMID- 24339626 TI - Brachial plexitis following bee sting. PMID- 24339627 TI - Electrocardiographic abnormalities in acute cerebrovascular events. PMID- 24339628 TI - A rare presentation of subacute sclerosing panencephalitis with acute fulminant course and atypical radiological features. PMID- 24339629 TI - Moyamoya disease with exaggerated startle response: A rare co-occurrence. PMID- 24339630 TI - A rare presentation of methanol toxicity. PMID- 24339631 TI - Authors' reply: A rare presentation of methanol toxicity. PMID- 24339632 TI - Chlorpyrifos toxicity causing delayed myeloneuropathy. PMID- 24339633 TI - A cryptic message in the brain. PMID- 24339634 TI - Magnetic resonance imaging and computed tomography scan findings in methanol poisoning. PMID- 24339635 TI - Auditing costs of intensive care in cancer patients in India: A new area explored. PMID- 24339636 TI - H1N1 influenza pandemic: What we did and what we learnt? PMID- 24339637 TI - Predictors of septic shock following gastrointestinal anastomotic leaks: Only signposts, no destination. PMID- 24339639 TI - To study the clinical efficacy and nephrotoxicity along with the risk factors for acute kidney injury associated with parenteral polymyxin B. AB - AIM: The aim of this study was to evaluate the clinical efficacy and nephrotoxicity along with the risk factors for acute kidney injury (AKI) associated with the parenteral polymyxin B in patients with the multidrug resistance (MDR) gram -ve infections in a tertiary Intensive care unit (ICU). MATERIALS AND METHODS: A retrospective cohort study (March 2010-October 2011) was conducted in Medical ICU of a 23 bedded tertiary care hospital in Northern India. RESULTS: Out of 71 ICU patients who were administered polymyxin B, only 32 (M:F = 1:0.8) met the inclusion criteria. Patients with concurrent administration of nephrotoxic drugs were excluded from the study. Mean age of patients was 48.53 +/ 13.90 years ranging from 16 years to 68 years. 6 out of 32 (18.7%) patients progressed to AKI, whereas renal functions remained normal in 26 (81.2%) patients. No statistically significant difference was observed in mortality between AKI and non AKI patients at the end of therapy (33.3% vs. 26.9%, P value 0.756). Older age (62.33 +/- 11.90 vs. 45.34 +/- 2.45, P value 0.005) was found to be an independent risk factor for causing nephrotoxicity. CONCLUSION: In the present scenario of rising infections with MDR gram -ve micro-organisms, this pilot study suggests that polymyxin B can be used effectively and safely in patients not receiving other nephrotoxic drugs, with cautious administration in older patients as they are more vulnerable to nephrotoxicity caused by polymyxin B. PMID- 24339638 TI - Predictors of mortality and length of stay in hospitalized cases of 2009 influenza A (H1N1): Experiences of a tertiary care center. AB - AIM: To study the clinical characteristics and outcome of admitted patients of H1N1 (hemagglutinin -H neuraminidase -N) influenza in a tertiary level hospital, from Oct 2009 to Dec 2010. MATERIALS AND METHODS: A retrospective analysis of 77 confirmed patients admitted in this unit with H1N1 infection. RESULTS: Of the 77 patients studied, 33 (42.8%) were female. Mean age was 40.88 +/- 13.45 years, majority (70.13%) being less than 50 years. Thirty eight (49.3%) patients had at least one co-morbidity, diabetes mellitus being the most common (n = 15, 19.5%). The most common presenting symptom was fever in 75 (97.4%) patients, cough in 67 (87%) and dyspnoea in 59 (76.6%) patients. At admission, mean PaO2/FiO2 ratio was 213.16 +/- 132.75 mmHg (n = 60) while mean PaCO2 was 40.14 +/- 14.86 mmHg. One or more organ failure was present in 45 (58.4%) patients. Nineteen (24.60%) patients required invasive mechanical ventilation. Circulatory failure was observed in 10 (13%) patients while 2 patients required hemodialysis. Overall, 13% mortality (n = 10) was observed. PaCO2 level at admission (OR 1.093; 95% confidence interval: 1.002-1.193; P = 0.044) and number of organ failure (OR 8.089; 95% confidence interval: 1.133-57.778; P = 0.037) were identified as independent risk- factors for mortality. CONCLUSION: Increased duration of dyspnoea prior to admission, pneumonia, low PaO2/FiO2 ratio at admission and 24 hours later, higher PaCO2 values on admission, higher O2 requirement, number of organ failures and use of corticosteroids and delay in specialized treatment were associated with a poorer outcome. PMID- 24339640 TI - Pediatric index of mortality 2 score as an outcome predictor in pediatric Intensive Care Unit in India. AB - BACKGROUND AND AIMS: Pediatric index of mortality (PIM) 2 score is one of the severity scoring systems being used for predicting outcome of patients admitted to intensive care units (ICUs). The aim of the present study was to evaluate the usefulness of PIM2 score in predicting mortality in a tertiary care pediatric ICU (PICU) and to assess the associated factors in predicting mortality such as presence of shock, need for assisted ventilation and Glasgow coma scale <8. MATERIALS AND METHODS: This was a prospective observation study done at tertiary care PICU from May 2011 to July 2011. Consecutive 119 patients admitted to PICU (aged 1 month to 12 years) were enrolled in the study. PIM2 scoring was done for all patients. The outcome was recorded as death or discharge. The associated factors for mortality were analyzed with SPSS 17. RESULTS: PIM2 score discriminated between death and survival at a 99.8 cut-off, with area under receiver operating characteristic curve 0.843 with 95% confidence interval (CI) (0.765, 0.903). Most patients were referred late to this hospital, which explains higher death rate (46.2%), lesser length of hospital stay (mean 2.98 days) in the mortality group, and increased rate of mechanical ventilation (68.1%). Presence of shock was independently associated with mortality, as evidenced by binary logistic regression. CONCLUSION: PIM2 score discriminated well between survivors and death at PICU. Presence of shock was significantly associated with mortality. PMID- 24339641 TI - A prospective audit of costs of intensive care in cancer patients in India. AB - BACKGROUND: The costs of healthcare are increasing. Intensive care poses largest burden on the hospital budget, even in developed countries. We attempted to find out the costs of intensive care in an Indian cancer hospital. MATERIALS AND METHODS: Cost data was prospectively collected for patient-related and non patient-related activities in a mixed surgical, medical cancer ICU. Demographic data, source, reason, and length of ICU stay were recorded. Total per day costs, costs for patients admitted from wards and operating rooms, and effective cost per survivor (ECPS) were calculated. RESULTS: Data was collected for 101 consecutive ICU patients. Fifty-five patients were admitted after surgery (total patient hours 3485 i.e., 145.21 patient days). The mean (SD) intensive care unit length of stay (ICU LOS) was 64.84 (58.47) hrs. (8.25 to 552). Fifty-three patients survived to discharge. Forty-six patients were admitted from wards (hematooncology) or casualty and stayed 3980.25 patient hrs (165.84 patient days). The mean (SD, range) ICU LOS was 106.84 (64.05, 1-336) hrs. Of these, 26 patients survived to discharge. The effective cost per survivor (ECPS) was significantly higher for patients admitted from wards. [Rs. 83,558 = 00 (USD 1856.84) vs. Rs. 15,049 = 00 (USD 334.42)]. CONCLUSION: The costs of ICU place much higher burden on the patients as the Indian GDP and per capita income is much lower. Better selection process is needed for hemato-oncology patients for ICU admission for better utilization of scarce resources. Such data as ours can be used to inform families and physicians about anticipated costs. PMID- 24339642 TI - Predictors of septic shock following anastomotic leak after major gastrointestinal surgery: An audit from a tertiary care institute. AB - BACKGROUND: Anastomotic leak is a serious complication after major gastrointestinal surgery and majority of deaths occur due to septic shock. Therefore, the early identification of risk factors of septic shock may help reduce the adverse outcomes. OBJECTIVE: The aim of this audit was to determine the predictors of septic shock in patients with anastomotic leak after major gastrointestinal surgery. DESIGN: Retrospective, audit. MATERIALS AND METHODS: The patients admitted in the gastrosurgical intensive care unit ICU) of our institute between September 2009 and April 2012 with anastomotic leakage after surgery were identified. The ICU charts were retrieved from the database to identify the patients progressing to septic shock. A comparison of risk factors was made between the patients who developed septic shock (septic shock group) against the patients who did not (non-septic shock group). RESULTS: The study sample comprised of 103 patients with anastomotic leak, of which 72 patients developed septic shock. The septic shock group had a higher APACHE II score, lower MAP, and higher HR at the time of ICU admission. They received greater transfusion of packed red blood cells during their ICU stay. Septic shock was more common after pancreaticojejunostomy and hepaticojejunostomy leaks. CONCLUSION: Presence of malignancy, chronic obstructive pulmonary disease (COPD), packed red blood cell transfusion, bacteremia, and hepaticojejunostomy or pancreaticojejunostomy leaks were independent predictors of mortality and length of ICU stay. To the best of our knowledge there are no available studies in the literature on the predictors of risk factors of septic shock in patients with anastomotic leakage. PMID- 24339644 TI - Cerebral infarction leading to hemiplegia: A rare complication of acute pancreatitis. AB - Peripancreatic vascular thrombosis is a known complication of acute pancreatitis (AP) and chronic pancreatitis. However, hemiplegia resulting from cerebral infarction due to cerebral arterial thrombosis is a rare complication of AP. Here, we report a case of alcohol related severe AP with multi-organ dysfunction, which was complicated by large left sided middle cerebral artery territory infarct - leading to right sided hemiplegia in a 48-year-old male patient. The neurological and vascular thrombotic complications of pancreatitis, their pathogenesis and management are discussed in brief. PMID- 24339643 TI - Elizabethkingia meningoseptica: Emerging nosocomial pathogen in bedside hemodialysis patients. AB - Elizabethkingia meningoseptica, a ubiquitous gram-negative aerobic bacillus, is an emerging hospital acquired pathogen in patients on dialysis. It has been isolated in the hospital environment in water supplies, disinfectants, and medical devices. We present here an analysis of eight healthcare-acquired infections with this organism in adults. To the best of our our knowledge, this is the first report of infections with this organism in patients on hemodialysis. MATERIALS AND METHODS: Over a 6-month period, eight patients were infected with E. meningoseptica in our hospital. These patients had bacteremia and lower respiratory tract infection. All these patients were on on mechanical ventilation and undergoing bedside hemodialysis in the intensive care unit (ICU). Environmental surveillance was done to detect the possible source. RESULTS: These patients had a common denominator of bedside hemodialysis, and use of broad spectrum antibiotics. E. meningoseptica was isolated from the water and sink of the ICU. CONCLUSION: E. meningoseptica is emerging as a nosocomial pathogen among patients on hemodialysis. Its unusual resistance pattern coupled with inherent resistance to colistin makes this organism difficult to treat unless susceptibility patterns are available. Isolation of this organism in handwash sink and water is a significant finding as they have been reported to survive in chlorinated water. Disinfecting the sinks and using filtered water for hand washing in critical areas may help in preventing infections with this organism. PMID- 24339645 TI - Fatal overdose of iron tablets in adults. AB - Acute iron toxicity is usually seen in children with accidental ingestion of iron containing syrups. However, the literature on acute iron toxicity with suicidal intent in adults is scant. We report, the first instance of two adults with fatal ingestion of a single drug overdose with iron tablets from India. Two young adults developed severe gastro-intestinal bleeding and fulminant hepatic failure 48 h after deliberate consumption of large doses of iron tablets. Serum iron levels measured 36 h after ingestion were normal presumably due to the redistribution of iron to the intracellular compartment. Despite aggressive supportive management in medical intensive care unit of a tertiary care hospital, the patients succumbed to the toxic doses of iron. PMID- 24339646 TI - A case of pulmonary alveolar proteinosis treated with whole lung lavage. AB - Pulmonary alveolar proteinosis represents a rare syndrome characterized by the accumulation of proteinaceous phospholipid-laden material in the alveoli. This leads to impaired gas exchange and arterial hypoxemia of varying degrees. The diagnosis is confirmed by lung biopsy. Sequential whole-lung lavage (WLL) first described in 1963 is the standard of care. We report a case of a male diagnosed of having pulmonary alveolar proteinosis (PAP) on transbroncial lung biopsy (TBLB). He was treated with sequential WLL (Left followed by right, Left being more involved on chest X-ray) followed by recombinant GM-CSF, with good result. PMID- 24339647 TI - Posterior reversible encephalopathy syndrome-an under recognized manifestation of Chronic Kidney Disease. AB - First Report of the Indian Chronic Kidney Disease (CKD) Registry showed that patient with CKD in India more frequently presented in Stage V. Many patients have uncontrolled hypertension and uremia due to noncompliance or non affordability of renal replacement therapy which can lead to complications such as posterior reversible encephalopathy syndrome (PRES). A 17-year-old female had end stage renal disease (ESRD) due to malignant hypertension. She developed headaches, altered consciousness, visual disturbances and seizures. A non contrast brain computed tomography revealed bilateral symmetrical white matter hypodensity in parietal, temporal, and occipital region suggesting PRES. Intravenous lorazepam was given for acute control of seizure and she required phenytoin, valproic acid, levetiracetam to control seizures. She was started on more frequent hemodialysis. She required five types of antihypertensive drugs to control blood pressure. We report successful renal transplantation (RTx) in a CKD patient with PRES. Constraints in operating an effective maintenance dialysis program leave RTx as the only viable option for ESRD patients in our country to prevent complications like PRES associated with uremia and uncontrolled hypertension. PMID- 24339648 TI - Neem oil poisoning: Case report of an adult with toxic encephalopathy. AB - Neem oil has widespread use in Indian subcontinent due to its many bioactive properties. Azadirachtin, an active ingredient, is implicated in causing the effects seen in neem oil poisoning. Neem oil poisoning is rare in adults. This report highlights the toxicity associated with neem oil poisoning in an elderly male. The patient presented with vomiting, seizures, metabolic acidosis, and toxic encephalopathy. The patient recovered completely with symptomatic treatment. PMID- 24339649 TI - A simple clinical method to detect mal-positioning during subclavian venous cannulation. PMID- 24339650 TI - Comments on chronic subdural hematoma in a child with acute myeloid leukemia after leukocytosis. PMID- 24339651 TI - Unrestricted prescription of dabigatran: Is it safe in a resource-limited setting. PMID- 24339652 TI - An unusual cause of decrease in GCS in a patient with craniofacial injury. PMID- 24339653 TI - Whats New in Emergencies, Trauma and Shock? Hematuria in hemodialysis patients. PMID- 24339654 TI - Pattern, severity, and management of cranio-maxillofacial soft-tissue injuries in Port Harcourt, Nigeria. AB - BACKGROUND: The pattern of craniofacial soft-tissue injuries occurring either in isolation or in association with fractures vary in different societies and is multiply influenced. The effects are enormous because of the prominence of the face; therefore, the purpose of this study was to document any changing pattern, severity and management of these craniofacial injuries in our center. PATIENTS AND METHOD: Cranio-maxillofacial region was classified into upper, middle and lower face. The cause, type, and site of the injuries were documented. Gunshot injuries were further categorized as penetrating, perforating or avulsions. Further, classification of injuries into mild, moderate, and severe was carried out based on multiple factors. RESULT: A total of 126 patients with soft-tissue injuries presented to our hospital out of which 85 (67.5%) were males and 41 (32.5) were females. The age range of the patients was between 10 months and 90 years with a mean +/- SD of 26.4 +/- 15.5 years. Road traffic accident was the most common etiology of which vehicular accidents constituted 50 (54.9%) and the motorcycle was 2 (2.2%). Assault contributed 16 (17.6%) while cases due to gun shots were 13 (14.3%). A total of 19 (15.1%) patients had associated head injuries, 11 (8.7%) patients had craniofacial fractures involving any of the bones while 3 (2.4%) patients had limb fractures and 2 (1.6%) patients had rib fractures. There were 51 (41.8%) cases classified as mild injuries, 37 (30.3%) cases as moderate injuries and 24 (19.7%) cases as severe injuries. Total of 126 cases managed, 121 (96.0%) received primary closure of the wounds while 5 (4.0%) received delayed closure under general anesthesia. PMID- 24339655 TI - A retrospective analysis of determinants of self-extubation in a tertiary care intensive care unit. AB - BACKGROUND: Self-extubation is a common event in intensive care units (ICUs) world-wide. The most common factor attributed in various studies is lack of optimal sedation. However, the factors that lead to this inadequacy of sedation are not analyzed. AIMS: The present study aimed to evaluate the determinants of factors leading to self-extubation in our ICU. Relation of patient profile, nature of sedation and any diurnal variation in extubation frequency was analyzed. MATERIALS AND METHODS: Retrospective explorative analysis was carried out for patients admitted to ICU from January 2011 to January 2012. Information from medical records for the above parameters was extracted and descriptive statistics was used for assessing the outcomes. RESULTS: In the present study, there was a higher incidence of self-extubation in ventilated ICU patients during the changeover periods of the ICU staff. There was no relation of frequency of self-extubation with the medications used for sedation once the sedation was titrated to a common endpoint. A higher incidence of self-extubation was seen in the surgical and younger age group of patients. CONCLUSIONS: It is recommended that the duty shift finishing time of ICU staff (medical and paramedical) staff should be staggered and should have minimal overlap to prevent self-extubation. A continuous reassessment of level of sedation of patients independent of the type sedative medication should be carried out. PMID- 24339656 TI - Ventilator-associated pneumonia in trauma patients with open tracheotomy: Predictive factors and prognosis impact. AB - OBJECTIVE: To assess the predictive factors of ventilator associated pneumonia (VAP) occurrence following open tracheotomy in trauma patients. MATERIALS AND METHODS: We conducted an observational, prospective study over 15 months, between 01/08/2010 and 30/11/2011. All trauma patients (except those with cervical spine trauma), older than 15 years, undergoing open tracheotomy during their ICU stay were included. All episode of VAP following tracheotomy were recorded. Predictive factor of VAP onset were studied. RESULTS: We included 106 patients. Mean age was 37.9 +/- 15.5 years. Mean Glasgow coma Scale (GCS) was 8.5 +/- 3.7 and mean Injury Severity Score (ISS) was 53.1 +/- 23.8. Tracheotomy was performed for 53 patients (50%) because of prolonged ventilation whereas 83 patients (78.3%) had tracheotomy because of projected long mechanical ventilation. Tracheotomy was performed within 8.6 +/- 5.3 days. Immediate complications were bleeding events (22.6%) and barotrauma (0.9%). Late complications were stomal infection (28.3%) and VAP (52.8%). In multivariate analysis, independent factors predicting VAP onset were delayed tracheotomy (OR = 0.041; CI95% [1.02-7.87]; P = 0.041) and stomal infection (OR = 3.04; CI95% [1.02-9.93]; P = 0.045). Thirty three patients died in ICU (31.1%) without significant impact of VAP on mortality. CONCLUSION: Late tracheotomy and stomal infection are independent factors predicting VAP onset after open tracheotomy in trauma patients. The occurrence of VAP prolongers mechanical ventilation duration and intensive care unit (ICU) length of stay (LOS) but doesn't increase mortality. PMID- 24339657 TI - Risk factors for cervical spine injury among patients with traumatic brain injury. AB - BACKGROUND: Diagnosis of cervical spine injury (CSI) is difficult in patients with an altered level of consciousness as a result of a traumatic brain injury (TBI). Patients with TBI and older adults are at increased risk for CSI. This study examined the various risk factors for CSI among trauma patients with TBI and whether adults who were older (>=55 years) were at higher risk for CSI when they sustained a fall-related TBI. MATERIALS AND METHODS: Data used was the 2007 National Trauma Data Bank (NTDB), National Sample Project (NSP) for adults who sustained a TBI. This dataset contains 2007 admission records from 82 level I and II trauma centers. Logistic regression was used to identify potential risk factors for CSI and to test for interaction between age and injury mechanism. Additional model variables included gender, race, Glasgow Coma Score, multiple severe injuries, hypotension and respiratory distress. RESULTS: An analysis of the NTDB NSP identified 187,709 adults with TBI, of which 16,078 were diagnosed with a concomitant CSI. In motor vehicle traffic injuries, the older age group had significantly higher odds of CSI (odds ratio [OR] = 1.26 [1.15-1.39]). In fall-related injuries the older age group did not have a higher odds of CSI compared to the younger age group. Skull/face fracture, other spine fracture/dislocation, upper limb injury, thorax injury, and hypotension were significantly associated with CSI. Pelvic injuries had an inverse association with CSI (OR = 0.60 [0.54-0.67]). Black had significantly higher odds of CSI compared to Whites (OR = 1.25 [1.07-1.46]). CONCLUSION: The identification of associated injuries and factors may assist physicians in evaluating CSI in patients with TBI. PMID- 24339658 TI - An exploratory analysis of transfer times in a rural trauma system. AB - BACKGROUND: Delays to definitive care are of particular concern in rural trauma systems, where prehospital times are significantly longer than average. AIMS: We evaluated for differences between transferring hospitals in the total time required to transport patients to definitive care, and analyzed for associations between transport times and outcomes. SETTINGS AND DESIGN: We employed a cross sectional design to analyze Level One Trauma Center registry data on interfacility transfer of 3,303 acute trauma patients. MATERIALS AND METHODS: We calculated time in minutes from injury to definitive care (total elapsed time (TET)), and analyzed for associations between TET and both mortality and length of hospital stay at our center. We mapped hospitals and catchment areas to illustrate statistics by transferring hospital. STATISTICAL ANALYSIS: We employed analysis of covariance (ANCOVA) to analyze for the effect of TET and injury severity category upon hospital length of stay, and for the effects of TET and air transport as compared to ground transport. We evaluated for likelihood of in hospital mortality using logistic regression. RESULTS: TET had little or no effect upon length of hospital stay or in-hospital mortality. The effect of injury severity upon both length of stay and mortality was progressively greater with each categorical increase in severity. Air transport as compared to ground transport was associated with mild increases in length of stay and likelihood of mortality. Mapping revealed spatial patterns that were not evident by statistical analysis alone. CONCLUSIONS: Mapping of geographic variations holds promise as a supplement to quantitative needs assessments of trauma systems in rural regions and developing countries. PMID- 24339659 TI - Further characterization of the influence of crowding on medication errors. AB - STUDY OBJECTIVES: Our prior analysis suggested that error frequency increases disproportionately with Emergency department (ED) crowding. To further characterize, we measured this association while controlling for the number of charts reviewed and the presence of ambulance diversion status. We hypothesized that errors would occur significantly more frequently as crowding increased, even after controlling for higher patient volumes. MATERIALS AND METHODS: We performed a prospective, observational study in a large, community hospital ED from May to October of 2009. Our ED has full-time pharmacists who review orders of patients to help identify errors prior to their causing harm. Research volunteers shadowed our ED pharmacists over discrete 4- hour time periods during their reviews of orders on patients in the ED. The total numbers of charts reviewed and errors identified were documented along with details for each error type, severity, and category. We then measured the correlation between error rate (number of errors divided by total number of charts reviewed) and ED occupancy rate while controlling for diversion status during the observational period. We estimated a sample size requirement of at least 45 errors identified to allow detection of an effect size of 0.6 based on our historical data. RESULTS: During 324 hours of surveillance, 1171 charts were reviewed and 87 errors were identified. Median error rate per 4-hour block was 5.8% of charts reviewed (IQR 0-13). No significant change was seen with ED occupancy rate (Spearman's rho = -.08, P = .49). Median error rate during times on ambulance diversion was almost twice as large (11%, IQR 0-17), but this rate did not reach statistical significance in univariate or multivariate analysis. CONCLUSIONS: Error frequency appears to remain relatively constant across the range of crowding in our ED when controlling for patient volume via the quantity of orders reviewed. Error quantity therefore increases with crowding, but not at a rate greater than the expected baseline error rate that occurs in uncrowded conditions. These findings suggest that crowding will increase error quantity in a linear fashion. PMID- 24339660 TI - Accidental phosgene gas exposure: A review with background study of 10 cases. AB - Here, authors present a review on clinical presentation and management of exposure of phosgene gas after reviewing the literature by searching with keywords phosgene exposure on Google, Cochrane, Embase and PubMed with a background of experience gained from 10 patients who were admitted to our institute after an accidental phosgene exposure in February 2011 nearby a city in India. Phosgene is a highly toxic gas, occupational workers may have accidental exposure. The gas can also be generated inadvertently during fire involving plastics and other chemicals and solvents containing chlorine, which is of concern to emergency responders. Phosgene inhalation may cause initially symptoms of respiratory tract irritation, patients feel fine thereafter, and then die of choking a day later because of build up of fluid in the lungs (delayed onset non cardiogenic pulmonary edema). Phosgene exposure is associated with significant morbidity and mortality. Patients with a history of exposure should be admitted to the hospital for a minimum of 24 h for observation because of the potential for delayed onset respiratory failure and acute respiratory distress syndrome. PMID- 24339661 TI - Unusual causes of Hematuria in dialysis patients: Diagnostic dilemma, risks and management. AB - Two male patients with end-stage renal disease (ESRD) developed a spontaneous hemorrhage of one of their native kidneys and were referred to our institution. Symptoms included sudden onset abdominal pain, hematuria and shock. Symptoms were associated with a hemoglobin decrease. Computerized tomography (CT) was done and nephrectomy undertaken in both the cases. Histologic findings confirmed bleeding and there was no abnormality other than those related to renal insufficiency (cysts and atrophy). In chronic hemodialysis (HD) patients with hematuria, if other common causes are not identified spontaneous subcapsular or renal cyst rupture should be kept in mind. Surgery is our preferred treatment because of the diagnostic dilemma of tumors and the potential mortality of massive hematomas in morbid patients. PMID- 24339662 TI - Pulmonary embolism: An abdominal pain masquerader. AB - Abdominal pain is an uncommon presenting symptom for pulmonary embolism (PE). A delay in the diagnosis when a patient presents with atypical symptoms can postpone proper treatment and can be catastrophic. We report the case of a 48 year-old male who presented to the emergency department with worsening right upper quadrant abdominal pain. Abnormal findings on biliary ultrasound and chest radiograph could have resulted in misdiagnosis. Instead, the physician maintained a high index of suspicion, and further diagnostic testing revealed a large central PE in the right main pulmonary artery. The present article discusses the dangers of using a pattern recognition approach to medical decision making in patients with abdominal pain. Included are the various pathophysiologic mechanisms that may contribute to the development of abdominal pain in patients with PE. Additionally, we review the role of chest radiography in the setting of PE and present the findings that ultimately lead to the diagnosis. PMID- 24339663 TI - Post-partum sequential occurrence of two diverse transfusion reactions (transfusion associated circulatory overload and transfusion related acute lung injury). AB - Transfusion associated circulatory overload (TACO) and transfusion related acute lung injury (TRALI) are two dissimilar pathological conditions associated with transfusion of blood products where the time course of the events and clinical presentation overlap leading to uncertainty in establishing the diagnosis and initiating the treatment, which otherwise differs. We encountered a case where a patient of post-partum hemorrhage developed TACO in the immediate post-operative period due to aggressive resuscitative attempts with blood products. The patient's condition was appropriately diagnosed and was managed according to the clinical scenario, and the condition abated. Subsequently, on the third post operative day the patient again required blood product transfusions following which the patient developed TRALI, the diagnosis of which was also established and adequate treatment strategy was undertaken. PMID- 24339664 TI - A case of emphysematous pyelonephritis induced by Citrobacter freundii infection. AB - A 79-year-old female with diabetes mellitus had general fatigue, a high fever and vomiting. A CT revealed acute emphysematous pyelonephritis (EPN). A nephrectomy was performed on the 2(nd) hospital day. The results of the blood culture showed the presence of Citrobacter freundii infection. The patient's post-operative course was uneventful. This case is the second reported case of EPN induced by Citrobacter freundii. Bacteremia induced by Citrobacter freundii infection typically results in a high mortality rate. In this case, the early diagnosis of the EPN using CT and immediate medical treatment, including urgent elective nephrectomy, were key to the favorable outcome. PMID- 24339665 TI - Timely management of penetrating neck trauma: Report of three cases. AB - In head and neck surgery, penetrating neck injuries are uncommon. The neck contains many important structures, so such trauma can cause significant morbidity and mortality. A patient with penetrating neck trauma should be examined promptly in the emergency room. If possible, damaged tissue and organ fragments should be preserved carefully. PMID- 24339666 TI - Cut-it-out technique for ocular fish-hook injury. AB - An 11-year-old boy was involved in an injury with a fish-hook to his eye. The hook had impaled itself to the cornea and deeper structures. There was associated corneal edema and hyphema, making visualization difficult. In this case, we performed the unusual "cut-it-out" technique to remove the hook from the eye. PMID- 24339667 TI - A fatal case of Perthes syndrome. AB - Perthes syndrome, or traumatic asphyxia, is a clinical syndrome associating cervicofacial cyanosis with cutaneous petechial haemorrhages and subconjonctival bleeding resulting from severe sudden compressive chest trauma. Deep inspiration and a Valsalva maneuver just prior to rapid and severe chest compression, are responsible for the development of this syndrome. Current treatment is symptomatic: urgent relief of chest compression and cardiopulmonary resuscitation if needed. Outcome may be satisfactory depending on the duration and severity of compression. Prolonged thoracic compression may sometimes lead to cerebral anoxia, irreversible neurologic damage and death. We report a fatal case of Perthes syndrome resulting from an industrial accident. PMID- 24339668 TI - An unusual stab wound to the buttock. AB - Stab wounds to the buttock are uncommon injuries that are rarely seen in surgical civilian practice. Although, the wound appears trivial, it may cause major life threatening visceral and vascular injuries. Failure to detect these injuries may lead to serious morbidity and mortality. Herein, we report a patient with a single gluteal stab wound, which was initially sutured and treated conservatively. Two days later, patient developed fever, lower abdominal pain and tenderness with leakage of fecal material from the wound. Exploratory laparotomy revealed an extraperitoneal rectal perforation for which a Hartmann's procedure was performed. Computed tomography scanning is recommended as a diagnostic tool for stable patients having buttock stab wounds. Diverging colostomy is the standard surgical procedure for extraperitonal rectal injuries that cannot be properly visualized and repaired during a laparotomy. More evidence is needed to assess the fecal non-diversion approach in the treatment of these patients. PMID- 24339669 TI - Acute nonsteroidal anti-inflammatory drug-induced colitis. AB - Resulting from direct toxicity on the bowel mucosa, nonsteroidal anti inflammatory drug (NSAID)-induced colitis is an underestimated although potentially serious condition. Plain abdominal radiographs and multidetector computed tomography allow to identify a right-sided acute colitis with associated pericolonic inflammation, progressively diminished changes along the descending and sigmoid colon, and rectal sparing, consistent with the hypothesized pathogenesis of NSAID colitis. Increased awareness of this condition should reduce morbidity through both prevention and early recognition. High clinical suspicion and appropriate patient questioning, together with consistent instrumental findings, negative biochemistry, and stool investigations should help physicians not to miss this important diagnosis. PMID- 24339670 TI - Urgent-setting magnetic resonance imaging allows triage of extensive penoscrotal hematoma following blunt trauma. AB - Although uncommon, blunt trauma to the perineum may cause serious injury to the penis. Differentiation between penile fracture with torn tunica albuginea versus extratunical or cavernosal hematomas is crucial because the former condition needs early surgical repair to avoid future deformity and erectile dysfunction, whereas approach is conservative with even large penoscrotal hematomas with albugineal integrity. Urgent-setting magnetic resonance imaging including multiplanar images of the injured penoscrotal region allows precise identification or exclusion of presence, site, and extent of tears of the tunica albuginea, providing a consistent basis for therapeutic choice. PMID- 24339671 TI - Ultrasonographic delineation of a foreign body in the calf. PMID- 24339672 TI - Diagnostic value of abdominal ultrasonography in patients with blunt abdominal trauma. PMID- 24339673 TI - Bilateral luxatio erecta humeri with a unilateral brachial plexus injury. PMID- 24339674 TI - Very bad clinical aspect towards diagnosis of deep femoral artery injury: Hypovolemic shock. PMID- 24339675 TI - New insights into the management of diabetic retinopathy. PMID- 24339676 TI - Evolving strategies in the management of diabetic retinopathy. AB - Diabetic retinopathy (DR), the most common long-term complication of diabetes mellitus, remains one of the leading causes of blindness worldwide. Tight glycemic and blood pressure control has been shown to significantly decrease the risk of development as well as the progression of retinopathy and represents the cornerstone of medical management of DR. The two most threatening complications of DR are diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). Focal/grid photocoagulation and panretinal photocoagulation are standard treatments for both DME and PDR, respectively. Focal/grid photocoagulation is a better treatment than intravitreal triamcinolone acetonide in eyes with DME. Currently, most experts consider combination focal/grid laser therapy and pharmacotherapy with intravitreal antivascular endothelial growth factor agents in patients with center-involving DME. Combination therapy reduces the frequency of injections needed to control edema. Vitrectomy with removal of the posterior hyaloid seems to be effective in eyes with persistent diffuse DME, particularly in eyes with associated vitreomacular traction. Emerging therapies include fenofibrate, ruboxistaurin, renin-angiotensin system blockers, peroxisome proliferator-activated receptor gamma agonists, pharmacologic vitreolysis, and islet cell transplantation. PMID- 24339677 TI - Surgical management of diabetic retinopathy. AB - Surgery for late complications of proliferative diabetic retinopathy remains the cornerstone of management even in patients who have received optimal laser photocoagulation and medical therapy. With improvisation in the surgical techniques and development of micro-incision surgical techniques for vitrectomy, the indications for surgical intervention are expanding to include diabetic macular edema with a greater number of patients undergoing early intervention. This review describes the current indications, surgical techniques, adjunctive anti-vascular endothelial growth factor therapy, surgical outcomes, and postoperative complications of pars plana vitrectomy for proliferative diabetic retinopathy and macular edema. PMID- 24339678 TI - Epidemiological issues in diabetic retinopathy. AB - There is currently an epidemic of diabetes in the world, principally type 2 diabetes that is linked to changing lifestyle, obesity, and increasing age of the population. Latest estimates from the International Diabetes Federation (IDF) forecasts a rise from 366 million people worldwide to 552 million by 2030. Type 1 diabetes is more common in the Northern hemisphere with the highest rates in Finland and there is evidence of a rise in some central European countries, particularly in the younger children under 5 years of age. Modifiable risk factors for progression of diabetic retinopathy (DR) are blood glucose, blood pressure, serum lipids, and smoking. Nonmodifiable risk factors are duration, age, genetic predisposition, and ethnicity. Other risk factors are pregnancy, microaneurysm count in an eye, microaneurysm formation rate, and the presence of any DR in the second eye. DR, macular edema (ME), and proliferative DR (PDR) develop with increased duration of diabetes and the rates are dependent on the above risk factors. In one study of type 1 diabetes, the median individual risk for the development of early retinal changes was 9.1 years of diabetes duration. Another study reported the 25 year incidence of proliferative retinopathy among population-based cohort of type 1 patients with diabetes was 42.9%. In recent years, people with diabetes have lower rates of progression than historically to PDR and severe visual loss, which may reflect better control of glucose, blood pressure, and serum lipids, and earlier diagnosis. PMID- 24339679 TI - Systemic medical management of diabetic retinopathy. AB - Diabetes mellitus (DM) has assumed epidemic proportions and as a consequence, diabetic retinopathy is expected to be a major societal problem across the world. Diabetic retinopathy (DR) affects the vision by way of proliferative disease that results in vitreous hemorrhage and traction retinal detachment or by way of diabetic maculopathy (DME). The present-day management of diabetic retinopathy revolves around screening the diabetics for evidence of retinopathy and treating the retinopathy with laser photocoagulation. DME is treated with laser photocoagulation and/or intra- vitreal injection of anti-vascular endothelial growth factor (VEGF) agents or steroids. Laser remains the mainstay of treatment and is potentially destructive. Systemic management aims at preventing or delaying the onset of retinopathy; reversing the early retinopathy; or delaying the progression of established retinopathy. Evidence from multiple studies has confirmed the protective role of rigid control of blood glucose and blood pressure. The evidence for lipid control versus maculopathy was less definitive. However, the use of fenofibrates (originally used for lowering serum lipids) has shown a benefit on both proliferative disease and maculopathy outside their lipid lowering effect. Other drugs being tried are the Protein Kinase C (PKC) inhibitors, other peroxisome proliferator-activated receptors (PPAR) agonists, Forsoklin (which binds GLUT 1 receptor), minocycline (for its anti inflammatory effect), and Celecoxib (Cox-2 inhibitor). PMID- 24339680 TI - Should we start all patients with diabetic retinopathy on fenofibrates? AB - There remains a need for strategies that are effective in preventing diabetic retinopathy (DR) or slowing down its progression, which is safe, well-tolerated, and more effective, have a lower risk profile, easy to perform, have more predictable results with less morbidity than the current regimens. Physicians caring for diabetic patients not only need to maximize glycemic control, but also closely monitor and treat other systemic conditions. The consistency of clinical data from the fenofibrate studies showed consistent beneficial effects with fenofibrate in slowing the progression of DR. They demonstrated significant benefit on micro-vascular (i.e., retinopathy and nephropathy) outcome, possibly independent of lipid levels. Can we combine the effectiveness of the current standard procedures with the prevention and slowing down of progression of DR that fenofibrates can offer? Knowledge of the primary mode of action of fenofibrate will be useful for both physicians and patients in determining how best to use this drug as an adjunct in the management of DR and ultimately facilitating the translation of clinical trial data to clinical practice. PMID- 24339681 TI - Combined therapy for diabetic macular edema. AB - Diabetic macular edema (DME) is the main cause of visual impairment in diabetic patients. Macular edema within 1 disk diameter of the fovea is present in 9% of the diabetic population. The management of DME is complex and often multiple treatment approaches are needed. This review demonstrates the benefits of intravitreal triamcinolone, bevacizumab and ranibizumab as adjunctive therapy to macular laser treatment in DME. The published results indicate that intravitreal injections of these agents may have a beneficial effect on macular thickness and visual acuity, independent of the type of macular edema that is present. Therefore, pharmacotherapy could complement focal/grid laser photocoagulation in the management of DME. For this review, we performed a literature search and summarized recent findings regarding combined therapy for DME. PMID- 24339682 TI - Diabetic retinopathy and its risk factors at the university hospital in Jamaica. AB - PURPOSE: To determine the frequency of diabetic retinopathy and its risk factors in diabetic patients attending the eye clinic at the University Hospital of the West Indies (UHWI). MATERIALS AND METHODS: This was a prospective cohort study of diabetic outpatients attending the Eye Clinic at the UHWI. Data were collected on age, gender, type of diabetes mellitus (DM), type of diabetic retinopathy, other ocular diseases, visual acuity, blood glucose and blood pressure. RESULTS: There were 104 patients (208 eyes) recruited for this study. There were 58.6% (61/104) females (mean age 53.6 +/- 11.9 years) and 41.4% (43/104) males (mean age 61.7 +/ 12.1 years). Type II DM was present in 68.3% (56% were females) of the patients and Type I DM was present in 31.7% (69.7% were females). Most patients (66%) were compliant with their diabetic medications. The mean blood glucose was 11.4 +/- 5.3 mmol/L. Elevated blood pressure (<130/80) was present in 82.7% of patients. The mean visual acuity was 20/160 (logMAR 0.95 +/- 1.1). The frequency of diabetic retinopathy was 78%; 29.5% had background retinopathy, and 50.5% of eyes had proliferative diabetic retinopathy (PDR) of which 34% had tractional retinal detachments. The odds ratio of developing PDR was 1.88 (95% confidence intervals (CI): 1.02-3.3) for Type I DM compared to 0.74 (95% CI: 0.55-0.99) for Type II DM. PDR was more prevalent in females (chi(2), P = 0.009) in both Type I and II DM. CONCLUSIONS: Jamaica has a high frequency of PDR which is more common in Type I diabetics and females. This was associated with poor glucose and blood pressure control. PMID- 24339683 TI - Posterior vitreous detachment and retinal detachment after implantation of the Visian phakic implantable collamer lens. AB - INTRODUCTION: To evaluate the vitreoretinal complications in myopes after Visian implantable collamer lenses (ICL) implantation. MATERIALS AND METHODS: This is a retrospective, observational, non-comparative clinical study that evaluated 617 consecutive myopes who underwent ICL implantation at the Department of Refractive Surgery, Yemen Magrabi Hospital, Sana'a, Yemen between July 2006 and May 2010. Follow up ranged from 6 months to 40 months. Preoperative and postoperative patient evaluation included manifest and cycloplegic refractions, uncorrected (UCVA) and best spectacle-corrected visual acuity (BSCVA), slit-lamp biomicroscopy, intraocular pressure and dilated retinal examination. Investigations included corneal topography, central corneal thickness, anterior chamber depth and white to white diameter. Retinal diseases and complications were recorded and analyzed preoperatively and postoperatively. RESULTS: Preoperatively, 61 (9.9%) eyes had posterior segment pathology requiring prophylactic laser photocoagulation. One eye developed spontaneous rhegmatogenous retinal detachment (RRD), one eye developed traumatic retinal detachment and two eyes required laser treatment postoperatively. The overall retinal detachment rate post-ICL was 0.32%. CONCLUSIONS: Posterior segment complications are rare after ICL implantation but dilated vitreoretinal assessment is important before and after the procedure. Patients with suspicious retinal lesions need a comprehensive vitreoretinal evaluation by a retinal specialist. If a patient develops floaters or blurry vision he/she requires further assessment by a vitreoretinal specialist. PMID- 24339684 TI - Long-term change in intraocular pressure after extracapsular cataract extraction with posterior chamber intraocular lens implantation versus phacoemulsification with posterior chamber intraocular lens implantation in Indians. AB - PURPOSE: The purpose of the study is to evaluate the long-term changes in intraocular pressure (IOP) after extracapsular cataract extraction (ECCE) with posterior chamber intraocular lens (PCIOL) implantation versus phacoemulsification with PCIOL implantation in otherwise normal cataract patients in India. MATERIALS AND METHODS: The study was conducted in the Department of Ophthalmology, King George's Medical College, Lucknow between August 2000 and August 2001. One hundred and seventeen eyes of 115 patients were included in the study. 84 patients were randomly selected for ECCE with PCIOL implantation (ECCE group) and 31 patients were selected for phacoemulsification with PCIOL implantation (Phaco group). IOP was measured pre-operatively and post operatively, from the 1(st) month to the 12(th) month. Statistical significance was indicated by P > 0.05. RESULTS: There was a mean fall in IOP of 2.70 mm Hg (19.74%) in the ECCE group and 2.74 mm Hg (20.57%) in the phaco group. The decrease in the mean post-operative IOP from baseline was statistically significant (P > 0.01) at the end of 2 months in both groups. There was no statistically significant difference in post-operative IOP at any visit between groups (P < 0.05, all post-operative visits). After 4(th) monthpost-operatively, the IOP was mostly stable, but it was significantly lower than the pre-operative IOP. CONCLUSION: Significant IOP reduction may be expected after cataract surgery with either ECCE or phacoemulsification with IOL implantation. The lowering of IOP became statistically significant at about 2 months post-operatively, but became almost stable after the 4(th) month. PMID- 24339685 TI - Topical ocular anesthetic abuse among Iranian welders: time for action. AB - PURPOSE: The purpose of this study is to estimate the prevalence of topical ocular anesthetic abuse among welders in Iran and suggest public health solutions for this issue. METHODS: In this cross-sectional study, 390 welders were randomly recruited and queried on the use of anesthetic drops. A questionnaire was administered through structured one-on-one interviews conducted by the first author. RESULTS: A total of 314 welders (80.5%) declared that they had used topical anesthetics at least once during their working lives. Almost 90% of them stated a preference for self-treatment over seeking help from a physician due to cultural and financial reasons. The most commonly used topical anesthetic was tetracaine. Most of the subjects (97.4%) had obtained the drugs from pharmacies without a prescription. CONCLUSIONS: The prevalence of topical ocular anesthetic abuse among welders in Iran is alarmingly high and may partially be due to cultural issues. Although most physicians are aware that topical anesthetics should only be used as a diagnostic tool, there is a crucial need to re-emphasize the ocular risks associated with chronic use of these medications. Educational programs for both physicians and the public are necessary to address the problem. PMID- 24339686 TI - Current practice of ophthalmic anesthesia in Nigeria. AB - PURPOSE: To assess the current techniques of ophthalmic anesthesia in Nigeria. MATERIALS AND METHODS: A cross sectional survey among Nigerian ophthalmology delegates attending the 36(th) Annual Scientific Congress of the Ophthalmology Society of Nigeria. Self administered and anonymous questionnaires were used and data were collected to include details of the institution, preferred local anesthesia techniques, the grade of doctor who administers the local anesthesia, complications, preferred facial block techniques (if given separately), and type of premedication (if used). RESULTS: Out of the 120 questionnaires distributed, 81 forms were completed (response rate 67.5%). Out of the 74 who indicated their grade, 49 (66.2%) were consultants, 22 (29.7%) were trainees, and 3 (7.1%) were ophthalmic medical officers. For cataract surgery, peribulbar anesthesia was performed by 49.1% of the respondents, followed by retrobulbar anesthesia (39.7%). Others techniques used were topical anesthesia (5.2%), subtenon anesthesia (4.3%), subconjunctival anesthesia (2.6%), and intracameral anesthesia (0.9%). For glaucoma surgery, 47.2% of the respondents use peribulbar anesthesia, 32.1% use retrobulbar anesthesia, 9.4% used general anesthesia, and 6.6% used subconjunctival anesthesia. Among the trainees, 57.8% routinely perform retrobulbar anesthesia while 55.6% routinely perform peribulbar anesthesia. At least one complication from retrobulbar anesthesia within 12 months prior to the audit was reported by 25.9% of the respondents. Similarly, 16.1% of the respondents had experienced complications from peribulbar anesthesia within the same time period. Retrobulbar hemorrhage is the most common complication experienced with both peribulbar and retrobulbar anesthesia. CONCLUSION: Presently, the most common technique of local anesthesia for an ophthalmic procedure in Nigeria is peribulbar anesthesia, followed by retrobulbar anesthesia. Twelve months prior to the study, 25.9% of the respondents had experienced at least one complication from retrobulbar anesthesia and 16.1% from peribulbar anesthesia. Retrobulbar hemorrhage was the most common complication reported. PMID- 24339687 TI - Comparison of visual acuity results in preschool children with lea symbols and Bailey-Lovie E chart. AB - PURPOSE: To compare visual acuity with two visual acuity charts in preschool children. MATERIALS AND METHODS: Visual acuity measurement with Lea symbols and Bailey-Lovie tumbling E chart was performed on children between 3 and 6 years of age. Visual acuity data from the two charts were analyzed with Bland-Altman plot to determine the limits of agreement. The Wilcoxon signed test was performed in children aged 3-4 years and in children aged 5-6 years separately to evaluate the influence of age. The inter-eye difference between the two charts were further analyzed with the paired t-test. A p value > 0.05 was considered statistically significant. RESULTS: A total of 47 children were enrolled for the study. The average logarithm of the Minimum Angle of Resolution (LogMAR) monocular visual acuity with Lea symbols (0.17 +/- 0.13) was better than the Bailey-Lovie tumbling E chart (0.22 +/- 0.14). The mean difference between Bailey-Lovie tumbling E chart and Lea symbol chart was 0.05 +/- 0.12 in logMAR units. A second analysis eliminating outliers showed the same result but lower differences (n = 43, 0.05 +/- 0.05 logMAR units). Visual acuity results between the two charts in children aged 3-4 years showed a significant difference (p = 0.000), but not for children aged 5-6 years (p = 0.059). Inter-eye differences between the two charts was not statistically significant (p = 0.77). CONCLUSION: Bailey-Lovie tumbling E chart is comparable to the Lea symbols chart in pre-school children. But preference should be given to Lea symbols for children aged 3-4 years as the symbols are more familiar than a directional test for this age group. PMID- 24339688 TI - Probing for congenital nasolacrimal duct obstruction in older children. AB - PURPOSE: The purpose of this study was to evaluate the role of probing in congenital nasolacrimal duct obstruction in children age 2 years and older and to establish factors predictive of the outcome. MATERIALS AND METHODS: A prospective study was conducted on consecutive patients older than 24 months with congenital nasolacrimal duct obstruction. All patients were treated with a simple nasolacrimal duct probing as primary treatment. Outcome measures included an ophthalmologic examination plus a parental history of residual symptoms at one and 6 months after surgery. RESULTS: A total of 82 children with a mean age of 34.5 months (range, 24 months to 60 months) underwent nasolacrimal duct probing. The complete response rate was 54%. Partial response and failure were observed in 25% and 20.8% of the eyes, respectively. Bilateral obstruction was associated with failure of probing (P = 0.007, Odds Ratio: 5.76). However, age older than 36 months was not associated with the failure rate. CONCLUSION: Primary probing maintains a high success rate without any age related decline in congenital nasolacrimal duct obstruction. PMID- 24339689 TI - Bilateral proliferative retinopathy as the initial presentation of chronic myeloid leukemia. AB - The authors report a rare case of a 48-year-old male with chronic myeloid leukemia (CML) who initially presented with a bilateral proliferative retinopathy. The patient complained of recent visual loss and floaters in both eyes (BE). Ophthalmologic evaluation revealed a best corrected visual acuity (BCVA) of 20/50 in the right eye and 20/200 in the left eye (LE). Fundoscopy showed the presence of bilateral peripheral capillary dropout with multiple retinal sea fan neovascularisations, which were confirmed on fluorescein angiography. Full blood count revealed hyperleukocytosis, thrombocytosis, anemia, and hyperuricemia. Bone marrow aspiration and biopsy showed the reciprocal chromosomal translocation t (9;22), diagnostic of CML. The patient was started on hydroxyurea, allopurinol and imatinib mesylate. He received bilateral panretinal laser photocoagulation and a vitrectomy was performed in the LE. The patient has been in complete hematologic, cytogenetic, and major molecular remission while on imatinib and his BCVA is 20/25 in BE. PMID- 24339690 TI - Inverted autologous internal limiting membrane for management of optic disc pit with macular detachment. AB - Macular detachment causes visual deterioration in 25-75% of patients with congenital optic disc pit. A number of treatment options have been reported to manage the macular detachment in optic pit. An optic disc pit represents a defect in the lamina cribrosa; theoretically, an ideal procedure to treat optic pit associated macular detachment would be one that prevents the flow of fluid across the pit by creating an additional barrier. We present a new surgical technique that employs an autologous internal limiting membrane (ILM) to create this barrier. The technique involves standard vitrectomy along-with ILM peeling. Subsequently, the peeled ILM was inverted and transplanted onto the optic disc pit to close the optic nerve pit. This technique showed satisfactory anatomic result with good functional improvement in visual acuity. PMID- 24339691 TI - Long term result of intravitreal bevacizumab in a patient newly transformed to proliferative macular telangiectasia type 2. AB - The clinical and imaging findings and therapeutic outcomes of intravitreal bevacizumab injection in a patient with macular telangiectasia type 2 are described. The patient first presented with the non-proliferative stage of the disease for 4 months, then the disease transformed to the proliferative stage. In the proliferative period, the patient was treated with intravitreal bevacizumab injections as-clinically warranted. Over a follow up period lasting 26 months, the patient received 6 intravitreal bevacizumab injections, the visual acuity improved from 20/100 to 20/40, the central retinal thickness decreased from 318 microns to 198 microns. This case implies that the patients with non proliferative macular telangiectasia type 2 should be followed carefully for proliferative transformation, and intravitreal bevacizumab treatment seems to be effective for proliferative macular telangiectasia type 2. PMID- 24339692 TI - Recurrent Central Serous Chorioretinopathy with Dexamethasone Eye Drop used Nasally for Rhinitis. AB - Central serous chorioretinopathy (CSC) is characterized by serous retinal detachment at the posterior pole. Several factors have been implicated in the pathogenesis, and endogenous or exogenous corticosteroids are thought to play a major role. Here we present a case of a 35-year-old male with complaints of a dark circle in front of his right eye. Fundus examination, optical coherence tomography and fundus fluorescein angiography were performed. The patient was diagnosed with CSC. CSC resolved completely within seven weeks. Four weeks later the CSC recurred and spontaneously resolved over eight weeks. Overall, the patient had three additional recurrences of CSC in the same eye over the next year. A detailed history taking revealed the patient was using 0.1% dexamethasone eye drops nasally for recurrent rhinitis for few days prior to each episode of CSC. This indicates the strong correlation between steroids given by any route and the pathogenesis of CSC. PMID- 24339693 TI - Trichilemmal cyst of the bulbar conjunctiva: a rare presentation. AB - We report a rare case of trichilemmal cyst involving the bulbar conjunctiva. A 55 year-old female presented with a history of a painless, progressive swelling in the left bulbar conjunctiva adjacent to the nasal limbus of 3 years duration. Wide excision biopsy was performed. Histopathologic examination findings were consistent with those of trichilemmal cyst. Trichilemmal cyst should be considered as differential diagnosis in a case of limbal nodule. PMID- 24339694 TI - Visual hallucinations (Charles Bonnet syndrome) associated with neurosarcoidosis. AB - The Charles Bonnet syndrome (CBS) refers to lucid and complex visual hallucinations in cognitively normal patients with acquired vision loss. It can be associated with any type of vision loss including that related to macular degeneration, corneal disease, diabetic retinopathy, and occipital infarct. Neurosarcoidosis, a multi-systemic inflammatory granulomatous disease affecting both the central and peripheral nervous systems, is rarely associated with CBS. We report a patient with biopsy-confirmed neurosarcoidosis who experienced visual hallucinations following the development of a right seventh-nerve palsy, right facial paresthesia, and bilateral progressive visual loss. This case highlights the importance of recognizing that the CBS can occur in visual loss of any etiology. PMID- 24339695 TI - FIESTA imaging for problem-solving in early Duane's retraction syndrome. PMID- 24339696 TI - Is it safe to eat fish? PMID- 24339697 TI - Comparison of the safety of seven iodinated contrast media. AB - We aimed to determine the characteristic adverse events (AEs) of iodinated contrast media (IOCM) and to compare the safety profiles of different IOCM. This study used the database of AEs reports submitted by healthcare professionals from 15 Regional Pharmacovigilance Centers between June 24, 2009 and December 31, 2010 in Korea. All reports of IOCM, including iopromide, iohexol, iopamidol, iomeprol, ioversol, iobitridol and iodixanol, were analyzed. Safety profiles were compared between different IOCM at the system organ level using the proportional reporting ratio (PRR) and 95% confidence interval (95% CI). Among a total of 48,261 reports, 6,524 (13.5%) reports were related to the use of IOCM. Iopromide (45.5%), iohexol (16.9%), iopamidol (14.3%) and iomeprol (10.3%) were identified as frequently reported media. 'Platelet, bleeding & clotting disorders' (PRR, 29.6; 95%CI, 1.9-472.6) and 'urinary system disorders' (PRR, 22.3; 95% CI, 17.1 29.1) were more frequently reported for iodixanol than the other IOCM. In conclusion, the frequency of AEs by organ class was significantly different between individual media. These differences among different IOCM should be considered when selecting a medium among various IOCM and when monitoring patients during and after its use to ensure optimum usage and patient safety. PMID- 24339698 TI - Impact of combined acute rejection on BK virus-associated nephropathy in kidney transplantation. AB - BK virus-associated nephropathy (BKVAN) is one of the major causes of allograft dysfunction in kidney transplant (KT) patients. We compared BKVAN combined with acute rejection (BKVAN/AR) with BKVAN alone in KT patients. We retrospectively analyzed biopsy-proven BKVAN in KT patients from 2000 to 2011 at Seoul National University Hospital. Among 414 biopsies from 951 patients, biopsy-proven BKVAN was found in 14 patients. Nine patients had BKVAN alone, while 5 patients had both BKVAN and acute cellular rejection. BKVAN in the BKVAN alone group was detected later than in BKVAN/AR group (21.77 vs 6.39 months after transplantation, P=0.03). Serum creatinine at diagnosis was similar (2.09 vs 2.00 mg/dL). Histological grade was more advanced in the BKVAN/AR group (P=0.034). Serum load of BKV, dose of immunosuppressants, and tacrolimus level showed a higher tendency in the BKVAN alone group; however it was not statistically significant. After anti-rejection therapy, immunosuppression was reduced in the BKVAN/AR group. Renal functional deterioration over 1 yr after BKVAN diagnosis was similar between the two groups (P=0.665). These findings suggest that the prognosis of BKVAN/AR after anti-rejection therapy followed by anti-BKV therapy might be similar to that of BKVAN alone after anti-BKV therapy. PMID- 24339699 TI - A clinical trial and extension study of infliximab in Korean patients with active rheumatoid arthritis despite methotrexate treatment. AB - Currently, infliximab is given for disease control for active rheumatoid arthritis (RA) patients despite methotrexate treatment. However, the efficacy and safety of infliximab in Korean patients has not been assessed appropriately. Therefore, we performed placebo-controlled, double-blind, randomized study and extension study. One-hundred forty-three patients with active RA were randomized to receive placebo or infliximab 3 mg/kg intravenously at week 0, 2, 6, 14, and 22 with methotrexate maintenance. Primary endpoint was American College of Rheumatology 20% improvement criteria (ACR20) at 30 week. After the clinical trial, patients on placebo (Group 1) and patients on infliximab who showed ACR20 response (Group 2) were treated with infliximab through another 84 week for evaluation of safety. During clinical trial, patients in infliximab group showed higher ACR20 at week 30 than patients in placebo group (50.1% vs 30.6%, P=0.014). A total of 92 patients participated in the extension study. The maintenance rate of infliximab was 62.0% at 84 weeks of extension study. The overall rate of adverse events was not different between Group 1 and Group 2. In Korean patients with active RA despite methotrexate treatment, infliximab in combination with methotrexate is effective and the long-term treatment with infliximab is well tolerated. (ClinicalTrials.gov No. NCT00202852, NCT00732875). PMID- 24339700 TI - Role of regulatory T cells in transferable immunological tolerance to bone marrow donor in murine mixed chimerism model. AB - Constructing a bone marrow chimera prior to graft transplantation can induce donor-specific immune tolerance. Mixed chimerism containing hematopoietic cells of both recipient- and donor-origin has advantages attributed from low dose of total body irradiation. In this study, we explored the mechanism of mixed chimerism supplemented with depletion of Natural Killer cells. Mixed chimerism with C57BL/6 bone marrow cells was induced in recipient BALB/c mice which were given 450 cGy of gamma-ray irradiation (n = 16). As revealed by reduced proliferation and cytokine production in mixed leukocyte reaction and ELISpot assay (24.6 vs 265.5), the allo-immune response to bone marrow donor was reduced. Furthermore, the induction of transferable immunological tolerance was confirmed by adoptive transfer and subsequent acceptance of C57BL/6 skin graft (n = 4). CD4(+)FoxP3(+) regulatory T cells were increased in the recipient compartment of the mixed chimera (19.2% -> 33.8%). This suggests that regulatory T cells may be therapeutically used for the induction of graft-specific tolerance by mixed chimerism. PMID- 24339701 TI - Application of the multiplex cytokine analysis to monitor xenogeneic immune responses to the porcine islet graft in non-human primate. AB - Non-human primate studies must be conducted prior to the clinical trial of xenotransplantation. In order to develop clinically applicable immune-modulatory regimen through non-human primate studies, close monitoring of xenogeneic immune responses is required. We adopted multiplex cytokine analysis in assessment of the immune status during the course of pig-to-non-human primate islet transplantation. This study aimed to assess the feasibility of this multiplex cytokine assay in the development of immune-modulatory regimen. Using this assay, we were able to detect different cytokines with a minimal usage of blood samples, and this allowed us to detect various immunological situations in the recipients. Detection of TNF-alpha surge (347.8 pg/mL) guided us to block TNF-alpha in the early phase of transplantation. Supportive information for in vivo efficacy of cytokine neutralizing antibody could be speculated by in vitro neutralization assay (1,250 pg/mL -> 0 pg/mL). In addition, periodic monitoring of cytokines in peripheral blood allowed the detection of the infection episode prior to other routine assays. These benefits of multiplex cytokine assay may be generally applied to other pre-clinical research, which is a prerequisite for clinical trials. PMID- 24339702 TI - The association between the socioeconomic status and thyroid cancer prevalence; based on the Korean National Health and Nutrition Examination Survey 2010-2011. AB - The incidence of thyroid cancer has recently increased in most industrialized countries, including Korea. To date, few studies have examined the association between thyroid cancer and socioeconomic status (SES). The current study was based on data collected from a total of 12,276 subjects (5,277 men and 6,999 women) by the Korean National Health and Nutrition Examination Survey (KNHANES) between 2010 and 2011. Univariate and multivariate logistic regression analysis revealed that older age (odds ration [OR], 1.03; 95% confidence interval [CI], 1.00-1.05), being female (OR, 8.16; 95%CI, 2.99-22.24), being overweight (OR, 1.04; 95%CI, 1.01-1.06), monthly household income (OR, 3.27; 95%CI, 1.16-9.20 for medium-highest household income vs lowest household income; OR, 3.30; 95%CI, 1.16 9.34 for highest household income vs lowest household income), educational level (OR, 2.74; 95%CI, 1.16-6.46 for 10-12 yr vs < 7 yr) and alcohol consumption (OR, 1.89; 95%CI 1.08-3.32) were significant risk factors for thyroid cancer. Our results indicate that the recent increase in thyroid cancer is attributable to better early detection rather than to any increase in actual prevalence. PMID- 24339703 TI - Proactive multifactorial intervention strategy reduces the risk of cardiovascular disease estimated with region-specific risk assessment models in Pacific Asian patients participating in the CRUCIAL trial. AB - Despite race, ethnic, and regional differences in cardiovascular disease risk, many worldwide hypertension management guidelines recommend the use of the Framingham coronary heart disease (CHD) risk equation to guide treatment decisions. This subanalysis of the recently published CRUCIAL trial compared the treatment-related reductions in calculated CHD and stroke risk among Pacific Asian (PA) patients using a variety of region-specific risk assessment models. As a result, greater reductions in systolic and diastolic blood pressure, low density lipoprotein cholesterol, and triglycerides were observed in the proactive multifactorial intervention (PMI) arm compared with the usual care arm at Week 52 for PA patients. The relative percentage change in 10-yr CHD risk between baseline and Week 52 in the PMI versus usual care arms was greatest using the NIPPON DATA80 fatal CHD model (LS [least square] mean difference -42.6%), and similar in the SCORE fatal CHD and Framingham total CHD models (LS mean difference -29.4% and -30.8%, respectively). The single-pill based PMI approach is consistently effective in reducing cardiovascular disease risk, evaluated using a variety of risk assessment models. (ClinicalTrials.gov registration number: NCT00407537). PMID- 24339704 TI - Differential prognostic impacts of diabetes over time course after acute myocardial infarction. AB - This study was performed to evaluate the effects of diabetes on short- and mid term clinical outcomes in patients with acute myocardial infarction (AMI). Between October 2005 and December 2009, a total of 22,347 patients with AMI from a nationwide registry was analyzed. At the time point of the day 30 after AMI onset, landmark analyses were performed for the development of major adverse cardiovascular events (MACEs), including death, re-infarction and revascularization. In this cohort, 6,131 patients (27.4%) had diabetes. Short term MACEs, which occurred within 30 days of AMI onset, were observed in 1,364 patients (6.1%). Among the 30-day survivors (n = 21,604), mid-term MACEs, which occurred between 31 and 365 days after AMI onset, were observed in 1,181 patients (5.4%). After adjustment for potential confounders, diabetes was an independent predictor of mid-term MACEs (HR, 1.25; 95% CI, 1.08-1.45; P = 0.002), but not of short-term MACEs (HR: 1.16; 95% CI: 0.93-1.44; P = 0.167). Diabetes is a poor prognostic factor for mid-term clinical outcomes but not for short-term outcomes in AMI patients. Careful monitoring and intensive care should be considered in diabetic patients, especially following the acute stage of AMI. PMID- 24339705 TI - De Vega annuloplasty for functional tricupsid regurgitation: concept of tricuspid valve orifice index to optimize tricuspid valve annular reduction. AB - We evaluated long-term results of De Vega annuloplasty measured by cylindrical sizers for functional tricuspid regurgitation (FTR) and analyzed the impact of measured annular size on the late recurrence of tricuspid valve regurgitation. Between 2001 and 2011, 177 patients (57.9+/-10.5 yr) underwent De Vega annuloplasty for FTR. Three cylindrical sizers (actual diameters of 29.5, 31.5, and 33.5 mm) were used to reproducibly reduce the tricuspid annulus. Long-term outcomes were evaluated and risk factor analyses for the recurrence of FTR >=3+ were performed. Measured annular diameter indexed by patient's body surface area was included in the analyses as a possible risk factor. Operative mortality occurred in 8 patients (4.5%). Ten-year overall and cardiac death-free survivals were 80.5% and 90.8%, respectively. Five and 10-yr freedom rates from recurrent FTR were 96.5% and 93.1%, respectively. Cox proportional hazard model revealed that higher indexed annular size was the only risk factor for the recurrence of FTR (P=0.006). A minimal P value approach demonstrated that indexed annular diameter of 22.5 mm/m(2) was a cut-off value predicting the recurrence of FTR. De Vega annuloplasty for FTR results in low rates of recurrent FTR in the long-term. Tricuspid annulus should be reduced appropriately considering patients' body size to prevent recurrent FTR. PMID- 24339706 TI - A prospective study of epicardial adipose tissue and incident metabolic syndrome: the ARIRANG study. AB - Increased epicardial adipose tissue (EAT) may be closely associated with the development of metabolic abnormalities. We investigated whether EAT predicts the incident metabolic syndrome in a community-based, middle-aged population. The study subjects were comprised of 354 adults (134 men and 220 women) aged 40 to 70 yr without metabolic syndrome. Baseline EAT thickness, measured by echocardiography, was compared between subjects who developed new-onset metabolic syndrome at follow-up survey and those who did not. After an average of 2.2 yr of follow-up, 32 men (23.9%) and 37 women (16.8%) developed metabolic syndrome. Median EAT thickness at baseline was significantly higher in male subjects who developed metabolic syndrome than those who did not (1.52 mm vs 2.37 mm, P<0.001). The highest quartile of EAT thickness (>=2.55 mm) was associated with increased risk of progression to metabolic syndrome (Odds ratio [OR], 3.09; 95% confidence interval [CI], 1.11-8.66) after adjustment for age, smoking, alcohol intake, regular exercise, total energy intake, high sensitive C-reactive protein and homeostasis model assessment of insulin resistance in men. A significant association of EAT with incident metabolic syndrome was not seen in women (OR, 1.25; 95% CI, 0.54-2.90). In conclusion, increased EAT thickness is an independent predictor for incident metabolic syndrome in men. PMID- 24339707 TI - Incidence of metabolic syndrome and relative importance of five components as a predictor of metabolic syndrome: 5-year follow-up study in Korea. AB - The aim of this study was to describe the incidence of metabolic syndrome and to identify five components as metabolic syndrome predictors. The final study included 1,095 subjects enrolled in a rural part of Daegu Metropolitan City, Korea for a cohort study in 2003. Of these, 762 (69.6%) subjects had participated in the repeat survey. During the five-year follow-up, incidence density was significantly higher for women than for men (men, 30.0/1,000 person-years; women, 46.4/1,000 person-years). In both men and women, incidence of metabolic syndrome showed a significant increase with increasing number of metabolic syndrome components at baseline. Compared with individuals presenting none of components at baseline, relative risks were increased 1.22 (men; 95% CI, 0.43-3.51), 2.21 (women; 95% CI, 0.98-4.97) times more for individuals with one component of metabolic syndrome and 5.30 (men; 95% CI, 2.31-12.13), 5.53 (women; 95% CI, 2.78 11.01) times more for those who had two components. In multivariate analysis, the most powerful risk factor for metabolic syndrome was abdominal obesity in men and low HDL-cholesterol in women (adjusted relative risk, 3.28, 2.53, respectively). Consequently, finding a high risk group for metabolic syndrome according to gender and prevention of metabolic syndrome through lifestyle modification are essential. PMID- 24339708 TI - Change in somatostatinergic tone of acromegalic patients according to the size of growth hormone-producing pituitary tumors. AB - The aim of this study was to investigate the relationship between somatostatinergic tone (SST) and the size of growth hormone (GH)-producing pituitary tumors. GH levels of 29 patients with newly diagnosed acromegaly were measured using a 75-gram oral glucose tolerance test (OGTT), an insulin tolerance test (ITT), and an octreotide suppression test (OST). Differences between GH levels during the ITT and the OGTT (DeltaGHIO), and between the OGTT and the OST at the same time point (DeltaGHOS) were compared according to the size of the tumor and the response pattern to the OST. DeltaGHIO of macroadenomas (n=22) was non-significantly higher than those of microadenomas while DeltaGHOS of macroadenomas were significantly higher than those of microadenomas. According to further analyses of macroadenomas based on the response pattern to the OST, GH levels during the ITT were significantly higher in non-responders. DeltaGHOS showed near-significant differences between responders and non-responders. In conclusion, as the size of the pituitary tumor increases, the effect of glucose on SST appears to be attenuated. Macroadenomas that are non-responders to the OST possess a portion of GH secretion exceeding the range of regulation by SST. PMID- 24339709 TI - Comparison of complications between endoscopic and percutaneous replacement of percutaneous endoscopic gastrostomy tubes. AB - When replacing percutaneous endoscopic gastrostomy (PEG) tubes, an internal bolster may be retrieved either percutaneously or endoscopically. The aim of this study was to compare the complications of percutaneous and endoscopic method during PEG tube replacement. The medical records of 330 patients who received PEG tube replacement were retrospectively analyzed. According to the removal method of internal bolster, we categorized as endoscopic group and percutaneous group. Demographic data, procedure-related complications and risk factors were investigated. There were 176 cases (53.3%) in endoscopic group and 154 cases (46.7%) in percutaneous group. The overall immediate complication rate during PEG tube replacement was 4.8%. Bleeding from the stoma (1.3%) occurred in percutaneous group, whereas esophageal mucosal laceration (7.4%) and microperforation (0.6%) occurred in endoscopic group. The immediate complication rate was significantly lower in the percutaneous method (OR, 6.57; 95% CI, 1.47 29.38, P=0.014). In multivariate analysis, old age was a significant risk factor of esophageal laceration and microperforation during PEG tube replacement (OR, 3.83; 95% CI, 1.04-14.07, P=0.043). The percutaneous method may be more safe and feasible for replacing PEG tubes than the endoscopic method in old patients. PMID- 24339710 TI - Cross-cultural adaptation of the korean version of the minneapolis-manchester quality of life instrument-adolescent form. AB - We verified the reliability and validity of the Korean version of the Minneapolis Manchester Quality of Life Instrument-Adolescent Form (KMMQL-AF) among Korean childhood cancer survivors. A total of 107 childhood cancer patients undergoing cancer treatment and 98 childhood cancer survivors who completed cancer treatment were recruited. To assess the internal structure of the KMMQL-AF, we performed multi-trait scaling analyses and exploratory factor analysis. Additionally, we compared each domains of the KMMQL-AF with those of the Karnofsky Performance Status Scale and the Revised Children's Manifest Anxiety Scale (RCMAS). Internal consistency of the KMMQL-AF was sufficient (Cronbach's alpha: 0.78-0.92). In multi-trait scaling analyses, the KMMQL-AF showed sufficient construct validity. The "physical functioning" domain showed moderate correlation with Karnofsky scores and the "psychological functioning" domain showed moderate-to-high correlation with the RCMAS. The KMMQL-AF discriminated between subgroups of different adolescent cancer survivors depending on treatment completion. The KMMQL-AF is a sufficiently reliable and valid instrument for measuring quality of life among Korean childhood cancer survivors. PMID- 24339711 TI - Diagnostic role of prostate resection in the elderly patients who experience significant co-morbidity with a high clinical suspicion of prostate cancer. AB - The necessity of routine prostate biopsy prior to transurethral resection of the prostate (TURP) in elderly comorbid patients with a high prostate specific antigen (PSA) level remains controversial. We assessed the role of TURP in prostate cancer diagnosis in these individuals. A total of 197 patients underwent TURP in conjunction with prostatic needle biopsy. Pathologic reviews of specimens of TUR chips and biopsy cores were analyzed. Overall, prostate cancer (CaP) was detected in 114 patients (57.6%). Ninety-eight cancers (86%) were detected with TURP and biopsy, and seven cancers (6.1%) with only TURP. The Gleason score of a TUR-specimen was identical to that of the biopsy-core in 43.9% of cases. Variables associated with diagnostic accuracy in the TUR-specimens included the prebiopsy PSA level, prostate specific antigen density (PSAD), and the Gleason score in biopsy cores. In patients with a PSA level and a PSAD that was greater than 15.4 ng/mL and 0.69 ng/mL/g, respectively, 100% of the cancers were detected in the TUR-specimens. Our results suggest that a prostatic biopsy might be omitted prior to TURP in elderly patients with significant co-morbidity and levels for PSA of >15.4 ng/mL. PMID- 24339713 TI - Knee pain and its severity in elderly Koreans: prevalence, risk factors and impact on quality of life. AB - This study investigated the epidemiology (prevalence, risk factors, and impact on quality of life) of knee pain and its severity in elderly Koreans. The subjects (n=3,054) were participants aged >=50 yr from the fifth Korea National Health and Nutrition Examination Survey, conducted in 2010. Knee pain was defined as pain in the knee lasting >=30 days during the most recent 3 months; severity was categorized as mild, moderate, or severe. EQ-5D was used to measure quality of life. The prevalence of knee pain was 23.1% (11.7% in men, 31.9% in women). The prevalences of mild, moderate, and severe knee pain were 4.3%, 9.1%, and 9.7%, respectively (2.8%, 5.4%, and 3.5% in men and 5.4%, 12.0%, and 14.4% in women). Old age, female gender, a low level of education, a manual occupation, obesity, and radiographic osteoarthritis were risk factors for knee pain, and were associated with increased severity of knee pain. Excluding men with mild knee pain, people with knee pain had significantly lower quality of life than those without knee pain. Early interventional approaches are needed to reduce the medical, social, and economic burden of knee pain in elderly Koreans. PMID- 24339712 TI - Antibodies to interferon beta in patients with multiple sclerosis receiving CinnoVex, rebif, and betaferon. AB - Treatment with interferon beta (IFN-beta) induces the production of binding antibodies (BAbs) and neutralizing antibodies (NAbs) in patients with multiple sclerosis (MS). NAbs against IFN-beta are associated with a loss of IFN-beta bioactivity and decreased clinical efficacy of the drug. The objective of this study was to evaluate the incidence and the prevalence of binding antibodies (BAbs) and neutralizing antibodies (NAbs) to IFN-beta in MS patients receiving CinnoVex, Rebif, or Betaferon. The presence of BAbs was studied in serum samples from 124 MS patients using one of these IFN-beta medications by ELISA. The NAbs against IFN-beta were measured in BAb-positive MS patients receiving IFN-beta using an MxA gene expression assay (real-time RT-PCR). Of the 124 patients, 36 (29.03%) had BAbs after at least 12 months of IFN-beta treatment. The proportion of BAb+ was 38.1% for Betaferon, 21.9% for Rebif, and 26.8% for CinnoVex. Five BAb-positive MS patients were lost to follow-up; thus 31 BAb-positive MS patients were studied for NAbs. NAbs were present in 25 (80.6%) of BAb-positive MS patients receiving IFN-beta. In conclusion, the three IFN-beta preparations have different degrees of immunogenicity. PMID- 24339714 TI - Injuries associated with the 580 km university student grand voluntary road march: focus on foot injuries. AB - College student volunteers (n = 142) completed a 580 km road march for 21 consecutive days. Each volunteer carried a backpack that weighed 14.1 +/- 1.4 kg on the average. We investigated the incidence and location of blisters associated with the road march using a foot map along with other injuries. Overall, 95.1% of the subjects (135 of 142) sustained one or more injuries. All injured subjects had foot blisters, and 18% had other foot injuries. The most common locations of blister development were the right 5th toe (61%) and the left 5th toe (57%). The little toes seem to have been subjected to the greatest friction and shearing forces. March-related injuries, excluding foot injuries, were ankle pain (12.7%), knee pain (12.7%) and Achilles tendon pain (7.7%). Six subjects (4.2%) needed extra medical treatment for more than 2 weeks prior to returning to their daily lives after completion of the march due to associated injuries. The present study observed a very high incidence rate of injuries (95.1%) associated with the 580 km university students grand road march. These injuries posed an obstacle against completion of the road march and against returning to daily life. Active preventive interventions such as physical therapy and customized reinforced shoes and education program are recommended for reducing incidence rate and severity of injuries. PMID- 24339715 TI - Performance assessment of the SOFA, APACHE II scoring system, and SAPS II in intensive care unit organophosphate poisoned patients. AB - This study assessed the ability of the Sequential Organ Failure Assessment (SOFA) and Acute Physiology, Chronic Health Evaluation (APACHE) II scoring systems, as well as the Simplified Acute Physiology Score (SAPS) II method to predict group mortality in intensive care unit (ICU) patients who were poisoned with organophosphate. The medical records of 149 organophosphate poisoned patients admitted to the ICU from September 2006 to December 2012 were retrospectively examined. The SOFA, APACHE II, and SAPS II were calculated based on initial laboratory data in the Emergency Department, and during the first 24 hr of ICU admission. The probability of death was calculated for each patient based on the SOFA score, APACHE II score, and SAPS II equations. The ability to predict group mortality by the SOFA score, APACHE II score, and SAPS II method was assessed using two by two decision matrices and receiver operating characteristic (ROC) curve analysis. A total of 131 patients (mean age, 61 yr) were enrolled. The sensitivities, specificities, and accuracies were 86.2%, 82.4%, and 83.2% for the SOFA score, respectively; 65.5%, 68.6%, and 67.9% for the APACHE II scoring system, respectively; and 86.2%, 77.5%, and 79.4% for the SAPS II, respectively. The areas under the curve in the ROC curve analysis for the SOFA score, APACHE II scoring system, and SAPS II were 0.896, 0.716, and 0.852, respectively. In conclusion, the SOFA, APACHE II, and SAPS II have different capability to discriminate and estimate early in-hospital mortality of organophosphate poisoned patients. The SOFA score is more useful in predicting mortality, and easier and simpler than the APACHE II and SAPS II. PMID- 24339716 TI - Hemolytic anemia case caused by an inverted inner felt after bentall operation. AB - A 26-yr-old male patient reported worsened dyspnea, dizziness one year after an emergency Bentall operation for type A aortic dissection. There was evidence of hemolytic anemia and aortogram revealed a significant stenosis at the distal anastomosis site. During the reoperation, we found the inner felt at the distal anastomosis was inverted causing a significant stenosis. The reoperation successfully resolved this problem. Here, we report a rare case of hemolytic anemia caused by an inverted inner felt after Bentall operation. PMID- 24339717 TI - Immunoglobulin g4 non-related sclerosing disease with intracardiac mass mimicking mitral stenosis: case report. AB - The cardiovascular system may be one of the target organs of both immunoglobulin G4 related and non-related systemic multifocal fibrosclerosis. We present a case of IgG4 non-related systemic multifocal fibrosclerosis mimicking mitral stenosis on echocardiography. For a more detailed differential diagnosis, we used multimodal imaging techniques. After surgical biopsy around the abdominal aortic area in the retroperitoneum, histological examination revealed IgG4 non-related systemic multifocal fibrosclerosis. We describe the multimodal imaging used to diagnose IgG4 non-related systemic multifocal fibrosclerosis and a positive response to steroid treatment. There have been no previous case reports of IgG4 non-related systemic multifocal fibrosclerosis with intracardiac involvement. Here, we report a case of IgG4 non-related systemic multifocal fibrosclerosis mimicking mitral stenosis. PMID- 24339718 TI - A case of liver fibrosis with splenomegaly after oxaliplatin-based adjuvant chemotherapy for colon cancer. AB - Previous studies reported that oxaliplatin is associated with sinusoidal obstruction syndrome. However few reports on oxaliplatin induced liver fibrosis are found in the literature. Furthermore pathogenesis of liver fibrosis is not well known. We report a case of 45-yr-old Korean man in whom liver fibrosis with splenomegaly developed after 12 cycles of oxaliplatin based adjuvant chemotherapy for colon cancer (T4N2M0). Thorough history taking and serological examination revealed no evidence of chronic liver disease. Restaging CT scans demonstrated a good response to chemotherapy. Five month after chemotherapy, he underwent right hepatectomy due to isolated metastatic lesion. The liver parenchyma showed diffuse sinusoidal dilatation and centrilobular vein fibrosis with necrosis without steatosis. We could conclude that splenomegaly was due to perisinusoidal liver fibrosis and liver cell necrosis induced portal hypertension by oxaliplatin. In addition, to investigate the pathogenesis of liver fibrosis, immunohistochemical stains such as CD31 and alpha-smooth muscle actin (alpha-SMA) were conducted with control group. The immunohistochemical stains for CD31 and alpha-SMA were positive along the sinusoidal space in the patient, while negative in the control group. Chemotherapy with oxaliplatin induces liver fibrosis which should be kept in mind as a serious complication. PMID- 24339719 TI - A case of acute motor and sensory axonal neuropathy following hepatitis a infection. AB - Acute motor and sensory axonal neuropathy (AMSAN) are recently described subtypes of Guillain-Barre syndrome characterized by acute onset of distal weakness, loss of deep tendon reflexes, and sensory symptoms. A 21-yr-old male was transferred to our hospital due to respiration difficulties and progressive weakness. In laboratory findings, immunoglobulin M antibodies against hepatitis A were detected in blood and cerebrospinal fluid. The findings of motor nerve conduction studies showed markedly reduced amplitudes of compound muscle action potentials in bilateral peroneal, and posterior tibial nerves, without evidence of demyelination. Based on clinical features, laboratory findings, and electrophysiologic investigation, the patient was diagnosed the AMSAN following acute hepatitis A viral infection. The patient was treated with intravenous immunoglobulin and recovered slowly. Clinicians should consider this rare but a serious case of AMSAN following acute hepatitis A infection. PMID- 24339721 TI - SHS-Related Pediatric Sick Visits are Linked to Maternal Depressive Symptoms among Low-Income African American Smokers: An Opportunity for Intervention in Pediatrics. AB - Maternal smoking and depressive symptoms are independently linked to poor child health outcomes. However, little is known about factors that may predict maternal depressive symptoms among low-income, African American maternal smokers - an understudied population with children known to have increased morbidity and mortality risks. The objective of this study was to test the hypothesis that secondhand smoke exposure (SHSe)-related pediatric sick visits are associated with significant maternal depressive symptoms among low-income, African American maternal smokers in the context of other depression-related factors. Prior to randomization in a behavioral counseling trial to reduce child SHSe, 307 maternal smokers in Philadelphia completed the CES-D and questionnaires measuring stressful events, nicotine dependence, social support, child health and demographics. CES-D was dichotomized at the clinical cutoff to differentiate mothers with significant vs. low depressive symptoms. Results from direct entry logistic regression demonstrated that maternal smokers reporting more than one SHSe-related sick visit (OR 1.38, p<.001), greater perceived life stress (OR 1.05, p<.001) and less social support (OR 0.82, p<.001) within the last 3 months were more likely to report significant depressive symptoms than mothers with fewer clinic visits, less stress, and greater social support. These results suggest opportunities for future hypothesis-driven evaluation, and exploration of intervention strategies in pediatric primary care. Maternal depression, smoking and child illness may present as a reciprocally-determined phenomenon that points to the potential utility of treating one chronic maternal condition to facilitate change in the other chronic condition, regardless of which primary presenting problem is addressed. Future longitudinal research could attempt to confirm this hypothesis. PMID- 24339722 TI - p53 E3 ubiquitin protein ligase homolog regulates p53 in vivo in the adult mouse eye lens. AB - PURPOSE: p53 is a transcription factor that plays an important role in preventing cancer development. p53 participates in relevant aspects of cell biology, including apoptosis and cell cycle control and must be strictly regulated to maintain normal tissue homeostasis. p53 E3 ubiquitin protein ligase homolog (Mdm2) is an important negative regulator of p53. The purpose of this study was to determine if Mdm2 regulates p53 in vivo in the adult lens. METHODS: We analyzed mice expressing human p53 transgene (Tgp53) selectively in the lens in the presence or absence of Mdm2. Mice with the required genotypes were obtained by crossing transgenic, mdm2 (+/-), and p53 (-/-) mice. Eye phenotype and lens histology and ultrastructure were analyzed in adult mice. RESULTS: In a wild-type genetic background (mdm2 (+/+)), lens damage and microphthalmia were observed only in mice homozygous for Tgp53 ((t/t)). However, in an mdm2 null background, just one allele of Tgp53 (mdm2 (-/-)/Tgp53 (t/0) mice) was sufficient to cause lens damage and microphthalmia. Furthermore, Mdm2 in only one allele was sufficient to rescue these deleterious effects, since the mdm2 (+/-)/Tgp53 (t/0) mice had eye size and lens morphology similar to the control mice. CONCLUSIONS: Mdm2 regulates p53 in the adult lens in vivo. This information may have relevance for analyzing normal and pathological conditions of the lens, and designing cancer therapies targeting Mdm2-p53 interaction. PMID- 24339723 TI - Aldose reductase inhibitor counteracts the enhanced expression of matrix metalloproteinase-10 and improves corneal wound healing in galactose-fed rats. AB - PURPOSE: We investigated the effect of an aldose reductase inhibitor (ARI) and the role of matrix metalloproteinase (MMP)-10 on recovery after corneal epithelium removal in a rat diabetic keratopathy model. METHODS: Three-week-old Sprague-Dawley rats were fed the following diets for 6 weeks: normal MF chow (MF), 50% galactose (Gal), and 50% Gal containing 0.01% ARI (Gal +ARI). The corneal epithelium was removed using n-heptanol, and the area of epithelial defects was photographed and measured every 24 h. Real-time reverse transcriptase PCR, western blotting, and immunohistochemistry were used to determine the expression profile of MMP-10 and integrin alpha3. RESULTS: Compared to the MF control group, the amount of galactitol in the Gal group increased approximately 200-fold, which was reduced to sevenfold by ARI treatment. The area of corneal erosion in the Gal group was significantly larger than in the MF group at 72 h and thereafter (p<0.01, unpaired t test). The expression level of MMP-10 was enhanced at both the protein and mRNA levels by exposure to a high concentration of Gal, while integrin alpha3 expression decreased at the protein level but remained unchanged at the mRNA level. Delayed epithelial wound healing and alterations in the expression levels of MMP-10 and integrin alpha3 were normalized by ARI. The corneal erosion closure rate was significantly decreased with topical recombinant MMP-10. CONCLUSIONS: These studies confirm that the increased expression of MMP-10 induced by Gal feeding is counteracted by ARI treatment and suggest a role of MMP-10 in modulating corneal epithelial wound healing. PMID- 24339724 TI - Homozygosity mapping in autosomal recessive retinitis pigmentosa families detects novel mutations. AB - PURPOSE: Autosomal recessive retinitis pigmentosa (arRP) is a genetically heterogeneous disease resulting in progressive loss of photoreceptors that leads to blindness. To date, 36 genes are known to cause arRP, rendering the molecular diagnosis a challenge. The aim of this study was to use homozygosity mapping to identify the causative mutation in a series of inbred families with arRP. METHODS: arRP patients underwent standard ophthalmic examination, Goldman perimetry, fundus examination, retinal OCT, autofluorescence measurement, and full-field electroretinogram. Fifteen consanguineous families with arRP excluded for USH2A and EYS were genotyped on 250 K SNP arrays. Homozygous regions were listed, and known genes within these regions were PCR sequenced. Familial segregation and mutation analyzes were performed. RESULTS: We found ten mutations, seven of which were novel mutations in eight known genes, including RP1, IMPG2, NR2E3, PDE6A, PDE6B, RLBP1, CNGB1, and C2ORF71, in ten out of 15 families. The patients carrying RP1, C2ORF71, and IMPG2 mutations presented with severe RP, while those with PDE6A, PDE6B, and CNGB1 mutations were less severely affected. The five families without mutations in known genes could be a source of identification of novel genes. CONCLUSIONS: Homozygosity mapping combined with systematic screening of known genes results in a positive molecular diagnosis in 66.7% of families. PMID- 24339725 TI - Analysis of superoxide dismutase 1, dual-specificity phosphatase 1, and transforming growth factor, beta 1 genes expression in keratoconic and non keratoconic corneas. AB - PURPOSE: To quantitatively assess the superoxide dismutase 1 (SOD1), transforming growth factor, beta 1 (TGF-beta1), and dual-specificity phosphatase 1 (DUSP1) messenger ribonucleic acid (mRNA) expression levels as the main intracellular reactive oxygen species neutralizers, wound healing mediators, and immunomodulators (respectively) in keratoconic (KCN) and non-KCN corneas. METHODS: Total RNA was extracted from normal and keratoconic cultured corneal stromal fibroblasts. Semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) was used to measure the relative expression levels of mRNAs of the SOD1, TGF-beta1, and DUSP1 genes. RESULTS: The mRNA expression of TGF-beta1 and DUSP1 was augmented in the KCN corneas (three- and fivefold, respectively; both p<0.05). The KCN and non-KCN samples showed no difference in comparative SOD1 mRNA levels. CONCLUSIONS: This study demonstrated a higher level of DUSP1 and TGF-beta1 expression as known molecules in the inflammatory process. These results may provide new insight into the complex molecular pathways underlying KCN for investigating other inflammatory molecules. PMID- 24339726 TI - Evaluation of a Sibling-Mediated Imitation Intervention for Young Children with Autism. AB - Parents and peers have been successful at implementing interventions targeting social interactions in children with autism; however, few interventions have trained siblings as treatment providers. This study used a multiple-baseline design across six sibling dyads (four children with autism) to evaluate the efficacy of sibling-implemented reciprocal imitation training. All six typically developing siblings were able to learn and use contingent imitation, four of the six siblings were able to learn and use linguistic mapping, and all six siblings increased their use of at least one component of the imitation training procedure. Three of the four children with autism showed increases in overall imitation and all four showed evidence of increases in joint engagement. Parents and siblings reported high satisfaction with the intervention and ratings by naive observers indicated significant changes from pre- to post-treatment. These results suggest that sibling-implemented reciprocal imitation training may be a promising intervention for young children with autism. PMID- 24339727 TI - Dealing with disjunct concentration measurements in eddy covariance applications: a comparison of available approaches. AB - Using proton transfer reaction mass spectrometry equipped with a quadrupol mass analyser to quantify the biosphere-atmosphere exchange of volatile organic compounds (VOC), concentrations of different VOC are measured sequentially. Depending on how many VOC species are targeted and their respective integration times, each VOC is measured at repeat rates on the order of a few seconds. This represents an order of magnitude longer sample interval compared to the standard eddy covariance (EC) method (5-20 Hz sampling rates). Here we simulate the effect of disjunct sampling on EC flux estimates by decreasing the time resolution of CO2 and H2O concentrations measured at 20 Hz above a temperate mountain grassland in the Austrian Alps. Fluxes for one month are calculated with the standard EC method and compared to fluxes calculated based on the disjunct data (1, 3 and 5 s sampling rates) using the following approaches: i) imputation of missing concentrations based on the nearest neighbouring samples (iDECnn), ii) imputation by linear interpolation (iDECli), and iii) virtual disjunct EC (vDEC), i.e. flux calculation based solely on the disjunct concentrations. It is shown that the two imputation methods result in additional low-pass filtering, longer lag times (as determined with the maximum cross-correlation method) and a flux loss of 3-30 % as compared to the standard EC method. A novel procedure, based on a transfer function approach, which specifically corrects for the effect of data treatment, was developed, resulting in improved correspondence (to within 2 %). The vDEC method yields fluxes which approximate the true (20 Hz) fluxes to within 3-7 % and it is this approach we recommend because it involves no additional empirical corrections. The only drawback of the vDEC method is the noisy nature of the cross-correlations, which poses problems with lag determination - practical approaches to overcome this limitation are discussed. PMID- 24339728 TI - Nanoparticles influence droplet formation in a T-shaped microfluidic. AB - Droplet formation in the presence of nanoparticles was studied in a T-shaped microfluidic device numerically. Nanoparticles in continuous phase did not influence droplet formation dynamics obviously. Contrarily, the presence of nanoparticles in dispersed phase will influence evidently droplet formation dynamics, likely reasons are the accumulation of nanoparticles at the liquid liquid interface leading to the variation of interfacial tension and the anisotropy of nanoparticles' movement at interface. The droplet size decreases almost linearly with increasing of the volume fraction of nanoparticles in dispersed phase when the volume fraction of nanoparticles not exceeding a critical value (about 0.2 %), because very high concentration of nanoparticles results in particle aggregation so as to not decrease interfacial tension so obviously any more. A complicated mechanism of temperature influences on droplet formation may exist combining the variations of effective viscosity and interfacial tension. Discussions on microscopic mechanism of droplet formation in the presence of nanoparticles were carried out. PMID- 24339729 TI - Gender differences in histamine-induced depolarization and inward currents in vagal ganglion neurons in rats. AB - Evidence has shown gender differences regarding the critical roles of histamine in the prevalence of asthma, anaphylaxis, and angina pectoris. Histamine depolarizes unmyelinated C-type neurons without any effects on myelinated A-type vagal ganglion neurons (VGNs) in male rats. However, little is known if VGNs from females react to histamine in a similar manner. Membrane depolarization and inward currents were tested in VGNs isolated from adult rats using a whole-cell patch technique. Results from males were consistent with the literature. Surprisingly, histamine-induced depolarization and inward currents were observed in both unmyelinated C-type and myelinated A- and Ah-type VGNs from female rats. In Ah-type neurons, responses to 1.0 MUM histamine were stronger in intact females than in males and significantly reduced in ovariectomized (OVX) females. In C-type neurons, histamine-induced events were significantly smaller (pA/pF) in intact females compared with males and this histamine-induced activity was dramatically increased by OVX. Female A-types responded to histamine, which was further increased following ovariectomy. Histamine at 300 nM depolarized Ah-types in females, but not Ah-types in OVX females. In contrast, the sensitivity of A- and C-types to histamine was upregulated by OVX. These data demonstrate gender differences in VGN chemosensitivity to histamine for the first time. Myelinated Ah-types showed the highest sensitivity to histamine across female populations, which was changed by OVX. These novel findings improve the understanding of gender differences in the prevalence of asthma, anaphylaxis, and pain. Changes in sensitivity to histamine by OVX may explain alterations in the prevalence of certain pathophysiological conditions when women reach a postmenopausal age. PMID- 24339730 TI - Genistein promotion of osteogenic differentiation through BMP2/SMAD5/RUNX2 signaling. AB - To investigate the effects of Genistein on the osteogenic related gene expression profiles during osteoblastic differentiation of human bone marrow mesenchymal stem cell (hBMSC) cultures, the hBMSCs were cultured under osteogenic differentiation medium with the addition of Genistein (10(-8)~10(-5) M) for 12 days. The cell proliferation was measured by BrdU incorporation, while the osteoblastic differentiation in hBMSC cultures was assessed by cellular alkaline phosphatase (ALP) activity. The cell apoptosis was determined by caspase 3/7 activation. GEArray Q series human osteogenesis gene array was used to analyze large-scale gene expression in Genistein-treated hBMSC cultures compared to the control group. Quantitative real-time RT-PCR, small interfering RNA (siRNA), and western blot analysis were used to confirm the microarray data in five representative transcripts. Genistein (10(-8)~10(-6) M) dose- and time dependently increased cell proliferation and cellular ALP activity, but had no significant effect on cell apoptosis in hBMSC cultures. The 96-gene array analysis indicated that 22 genes were upregulated more than 2-fold and 7 genes were downregulated at least 1.5-fold. The expressions of bone morphogenetic proteins (BMPs), small mothers against decapentaplegic homologs (SMADs), and Runt related transcription factor 2 (RUNX2) were concomitantly increased under Genistein treatment while insulin-like growth factor 2 and inhibitory SMADs 6 and 7 expressions were significantly decreased. The results of the real-time RT-PCR had a correlation with the results of microarray analysis and were estrogen receptor dependent. Specific gene siRNAs knock-down further confirmed the osteogenic effects of Genistein on BMP2, SMAD5 and RUNX2 protein expression. Genistein enhanced osteogenic differentiation in cultured hBMSCs mainly through the BMP-dependent SMADs and RUNX2 signaling. PMID- 24339731 TI - Development of a rapid streptavidin capture-based assay for the tyrosine phosphorylated CSF-1R in peripheral blood mononuclear cells. AB - A novel assay was developed to measure ratio of p-FMS (phospho FMS) to FMS using the Meso Scale Discovery((r)) (MSD) technology and compared to the routinely used, IP-Western based approach. The existing IP-Western assay used lysed PBMCs (Peripheral Blood Mononuclear Cells) that were immunoprecipitated (IP) overnight, and assayed qualitatively by Western analysis. This procedure takes three days for completion. The novel IP-MSD method described in this paper employed immunoprecipitation of the samples for one hour, followed by assessment of the samples by a ruthenium labeled secondary antibody on a 96-well Streptavidin coated MSD plate. This IP-MSD method was semi-quantitative, could be run in less than a day, required one-eighth the volume of sample, and compared well to the IP Western method. In order to measure p-FMS/FMS, samples from healthy volunteers (HV) were first stimulated with CSF-1(Macrophage colony-stimulating factor) to initiate the changes in the phosphotyrosyl signaling complexes in FMS. The objective of the present work was to develop a high throughput assay that measured p-FMS/FMS semi-quantitatively, with minimal sample requirement, and most importantly compared well to the current IP-Western assay. PMID- 24339732 TI - Macrophage migration inhibitory factor promotes proliferation and neuronal differentiation of neural stem/precursor cells through Wnt/beta-catenin signal pathway. AB - Macrophage migration inhibitory factor (MIF) is a highly conserved and evolutionarily ancient mediator with pleiotropic effects. Recent studies demonstrated that the receptors of MIF, including CD44, CXCR2, CXCR4 and CD74, are expressed in the neural stem/progenitor cells (NSPCs). The potential regulatory effect of MIF on NSPCs proliferation and neuronal differentiation, however, is largely unknown. Here, we investigated the effect of MIF on NSPC proliferation and neuronal differentiation, and further examined the signal pathway by which MIF transduced these signal effects in mouse NSPCs in vitro. The results showed that both Ki67-positive cells and neurosphere volumes were increased in a dose-dependent manner following MIF treatment. Furthermore, the expression of nuclear beta-catenin was significantly stronger in MIF-stimulated groups than that in control groups. Conversely, administration of IWR-1, the inhibitor of Wnt/beta-catenin pathway, significantly inhibited the proliferative effect of MIF on NSPCs. Immunostaining and Western blot further indicated that doublecortin (DCX) and Tuj 1, two neuronal markers, were evidently increased with MIF stimulation during NSPC differentiation, and there were more Tuj1-positive cells migrated out from neurospheres in MIF-stimulated groups than those in control groups. During NSPC differentiation, MIF increased the activity of beta galactosidase that responds to Wnt/beta-catenin signaling. Wnt1 and beta-catenin proteins were also up-regulated with MIF stimulation. Moreover, the expression of DCX and Tuj 1 was inhibited significantly by IWR-1. Taken together, the present study indicated that MIF enhances NSPC proliferation and promotes the neuronal differentiation, by activating Wnt/beta-catenin signal pathway. The interaction between MIF and Wnt/beta-catenin signal pathway may play an important role in modulating NSPC renewal and fate during brain development. PMID- 24339733 TI - The regulation of the autophagic network and its implications for human disease. AB - Autophagy has attracted a lot of attention in recent years. More and more proteins and signaling pathways have been discovered that somehow feed into the autophagy regulatory pathways. Regulation of autophagy is complex and condition specific, and in several diseases, autophagic fluxes are changed. Here, we review the most well-established concepts in this field as well as the reported signaling pathways or components which steer the autophagy machinery. Furthermore, we will highlight how autophagic fluxes are changed in various diseases either as cause for or as response to deal with an altered cellular homeostasis and how modulation of autophagy might be used as potential therapy for such diseases. PMID- 24339734 TI - The epigenomics of embryonic stem cell differentiation. AB - Embryonic stem cells (ESCs) possess an open and highly dynamic chromatin landscape, which underlies their plasticity and ultimately maintains ESC pluripotency. The ESC epigenome must not only maintain the transcription of pluripotency-associated genes but must also, through gene priming, facilitate rapid and cell type-specific activation of developmental genes upon lineage commitment. Trans-generational inheritance ensures that the ESC chromatin state is stably transmitted from one generation to the next; yet at the same time, epigenetic marks are highly dynamic, reversible and responsive to extracellular cues. Once committed to differentiation, the ESC epigenome is remodeled and resolves into a more compact chromatin state. A thorough understanding of the role of chromatin modifiers in ESC fate and differentiation will be important if they are to be used for therapeutic purposes. Recent technical advances, particularly in next-generation sequencing technologies, have provided a genome scale view of epigenetic marks and chromatin modifiers. More affordable and faster sequencing platforms have led to a comprehensive characterization of the ESC epigenome and epigenomes of differentiated cell types. In this review, we summarize and discuss the recent progress that has highlighted the central role of histone modifications, histone variants, DNA methylation and chromatin modifiers in ESC pluripotency and ESC fate. We provide a detailed and comprehensive discussion of genome-wide studies that are pertinent to our understanding of mammalian development. PMID- 24339735 TI - Identification of molecular tumor markers in renal cell carcinomas with TFE3 protein expression by RNA sequencing. AB - TFE3 translocation renal cell carcinoma (tRCC) is defined by chromosomal translocations involving the TFE3 transcription factor at chromosome Xp11.2. Genetically proven TFE3 tRCCs have a broad histologic spectrum with overlapping features to other renal tumor subtypes. In this study, we aimed for characterizing RCC with TFE3 protein expression. Using next-generation whole transcriptome sequencing (RNA-Seq) as a discovery tool, we analyzed fusion transcripts, gene expression profile, and somatic mutations in frozen tissue of one TFE3 tRCC. By applying a computational analysis developed to call chimeric RNA molecules from paired-end RNA-Seq data, we confirmed the known TFE3 translocation. Its fusion partner SFPQ has already been described as fusion partner in tRCCs. In addition, an RNA read-through chimera between TMED6 and COG8 as well as MET and KDR (VEGFR2) point mutations were identified. An EGFR mutation, but no chromosomal rearrangements, was identified in a control group of five clear cell RCCs (ccRCCs). The TFE3 tRCC could be clearly distinguished from the ccRCCs by RNA-Seq gene expression measurements using a previously reported tRCC gene signature. In validation experiments using reverse transcription-PCR, TMED6-COG8 chimera expression was significantly higher in nine TFE3 translocated and six TFE3-expressing/non-translocated RCCs than in 24 ccRCCs (P < .001) and 22 papillary RCCs (P < .05-.07). Immunohistochemical analysis of selected genes from the tRCC gene signature showed significantly higher eukaryotic translation elongation factor 1 alpha 2 (EEF1A2) and Contactin 3 (CNTN3) expression in 16 TFE3 translocated and six TFE3-expressing/non-translocated RCCs than in over 200 ccRCCs (P < .0001, both). PMID- 24339736 TI - Mapping in vivo tumor oxygenation within viable tumor by 19F-MRI and multispectral analysis. AB - Quantifying oxygenation in viable tumor remains a major obstacle toward a better understanding of the tumor micro-environment and improving treatment strategies. Current techniques are often complicated by tumor heterogeneity. Herein, a novel in vivo approach that combines (19)F magnetic resonance imaging ((19)F-MRI) R 1 mapping with diffusion-based multispectral (MS) analysis is introduced. This approach restricts the partial pressure of oxygen (pO2) measurements to viable tumor, the tissue of therapeutic interest. The technique exhibited sufficient sensitivity to detect a breathing gas challenge in a xenograft tumor model, and the hypoxic region measured by MS (19)F-MRI was strongly correlated with histologic estimates of hypoxia. This approach was then applied to address the effects of antivascular agents on tumor oxygenation, which is a research question that is still under debate. The technique was used to monitor longitudinal pO2 changes in response to an antibody to vascular endothelial growth factor (B20.4.1.1) and a selective dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor (GDC-0980). GDC-0980 reduced viable tumor pO2 during a 3-day treatment period, and a significant reduction was also produced by B20.4.1.1. Overall, this method provides an unprecedented view of viable tumor pO2 and contributes to a greater understanding of the effects of antivascular therapies on the tumor's microenvironment. PMID- 24339737 TI - The oncogenic polycomb histone methyltransferase EZH2 methylates lysine 120 on histone H2B and competes ubiquitination. AB - The histone methyltransferase enhancer of zeste 2 (EZH2) is known to be a polycomb protein homologous to Drosophila enhancer of zeste and catalyzes the addition of methyl groups to histone H3 at lysine 27 (H3K27). We previously reported that EZH2 was overexpressed in various types of cancer and plays a crucial role in the cell cycle regulation of cancer cells. In the present study, we demonstrated that EZH2 has the function to monomethylate lysine 120 on histone H2B (H2BK120). EZH2-dependent H2BK120 methylation in cancer cells was confirmed with an H2BK120 methylation-specific antibody. Overexpression of EZH2 significantly attenuated the ubiquitination of H2BK120, a key posttranslational modification of histones for transcriptional regulation. Concordantly, knockdown of EZH2 increased the ubiquitination level of H2BK120, suggesting that the methylation of H2BK120 by EZH2 may competitively inhibit the ubiquitination of H2BK120. Subsequent chromatin immunoprecipitation-Seq and microarray analyses identified downstream candidate genes regulated by EZH2 through the methylation of H2BK120. This is the first report to describe a novel substrate of EZH2, H2BK120, unveiling a new aspect of EZH2 functions in human carcinogenesis. PMID- 24339738 TI - Estrogen receptor beta isoform 5 confers sensitivity of breast cancer cell lines to chemotherapeutic agent-induced apoptosis through interaction with Bcl2L12. AB - Alternative splicing of estrogen receptor beta (ERbeta) yields five isoforms, but their functions remain elusive. ERbeta isoform 5 (ERbeta5) has been positively correlated with better prognosis and longer survival of patients with breast cancer (BCa) in various clinical studies. In this study, we investigated the inhibitory role of ERbeta5 in BCa cells. Although ERbeta5 does not reduce proliferation of BCa cell lines MCF-7 and MDA-MB-231, its ectopic expression significantly decreases their survival by sensitizing them to doxorubicin- or cisplatin-induced apoptosis through the intrinsic apoptotic pathway. Moreover, we discovered Bcl2L12, which belongs to the Bcl-2 family regulating apoptosis, to be a specific interacting partner of ERbeta5, but not ERbeta1 or ERalpha, in an estradiol-independent manner. Knockdown of Bcl2L12 enhanced doxorubicin- or cisplatin-induced apoptosis, and this process was further promoted by ectopic expression of ERbeta5. Whereas Bcl2L12 was previously shown to inhibit apoptosis through binding to caspase 7, such interaction is reduced in the presence of ERbeta5, suggesting a mechanism by which ERbeta5 sensitizes cells to apoptosis. In conclusion, ERbeta5 interacts with Bcl2L12 and functions in a novel estrogen independent molecular pathway that promotes chemotherapeutic Agent-Induced in vitro apoptosis of BCa cell lines. PMID- 24339739 TI - Cyclin G2 promotes hypoxia-driven local invasion of glioblastoma by orchestrating cytoskeletal dynamics. AB - Microenvironmental conditions such as hypoxia potentiate the local invasion of malignant tumors including glioblastomas by modulating signal transduction and protein modification, yet the mechanism by which hypoxia controls cytoskeletal dynamics to promote the local invasion is not well defined. Here, we show that cyclin G2 plays pivotal roles in the cytoskeletal dynamics in hypoxia-driven invasion by glioblastoma cells. Cyclin G2 is a hypoxia-induced and cytoskeleton associated protein and is required for glioblastoma expansion. Mechanistically, cyclin G2 recruits cortactin to the juxtamembrane through its SH3 domain-binding motif and consequently promotes the restricted tyrosine phosphorylation of cortactin in concert with src. Moreover, cyclin G2 interacts with filamentous actin to facilitate the formation of membrane ruffles. In primary glioblastoma, cyclin G2 is abundantly expressed in severely hypoxic regions such as pseudopalisades, which consist of actively migrating glioma cells. Furthermore, we show the effectiveness of dasatinib against hypoxia-driven, cyclin G2-involved invasion in vitro and in vivo. Our findings elucidate the mechanism of cytoskeletal regulation by which severe hypoxia promotes the local invasion and may provide a therapeutic target in glioblastoma. PMID- 24339740 TI - Hepatitis B virus X protein inhibits tumor suppressor miR-205 through inducing hypermethylation of miR-205 promoter to enhance carcinogenesis. AB - The infection of hepatitis B virus (HBV) is closely associated with the development of hepatocellular carcinoma (HCC), in which HBV X protein (HBx) plays crucial roles. MicroRNAs are involved in diverse biologic functions and in carcinogenesis by regulating gene expression. In the present study, we aim to investigate the underlying mechanism by which HBx enhances hepatocarcinogenesis. We found that miR-205 was downregulated in 33 clinical HCC tissues in comparison with adjacent noncancerous hepatic tissues. The expression levels of miR-205 were inversely correlated with those of HBx in abovementioned tissues. Then, we demonstrated that HBx was able to suppress miR-205 expression in hepatoma and liver cells. We validated that miR-205 directly targeted HBx mRNA. Ectopic expression of miR-205 downregulated HBx, whereas depletion of endogenous miR-205 upregulated HBx in hepatoma cells. Notably, our data revealed that HBx downregulated miR-205 through inducing hypermethylation of miR-205 promoter in the cells. In terms of function, the forced miR-205 expression remarkably inhibited the HBx-enhanced proliferation of hepatoma cells in vitro and in vivo, suggesting that miR-205 is a potential tumor-suppressive gene in HCC. HBx transgenic mice showed that miR-205 was downregulated in the liver. Importantly, HBx was able to abrogate the effect of miR-205 on tumor suppression in carcinogenesis. Therefore, we conclude that HBx is able to inhibit tumor suppressor miR-205 to enhance hepatocarcinogenesis through inducing hypermethylation of miR-205 promoter during their interaction. Therapeutically, miR-205 may be useful in the treatment of HCC. PMID- 24339741 TI - ETV6/RUNX1 induces reactive oxygen species and drives the accumulation of DNA damage in B cells. AB - The t(12;21)(p13;q22) chromosomal translocation is the most frequent translocation in childhood B cell precursor-acute lymphoblastic leukemia and results in the expression of an ETV6/RUNX1 fusion protein. The frequency of ETV6/RUNX1 fusions in newborns clearly exceeds the leukemia rate revealing that additional events occur in ETV6/RUNX1-positive cells for leukemic transformation. Hitherto, the mechanisms triggering these second hits remain largely elusive. Thus, we generated a novel ETV6/RUNX1 transgenic mouse model where the expression of the fusion protein is restricted to CD19(+) B cells. These animals harbor regular B cell development and lack gross abnormalities. We established stable pro-B cell lines carrying the ETV6/RUNX1 transgene that allowed us to investigate whether ETV6/RUNX1 itself favors the acquisition of second hits. Remarkably, these pro-B cell lines as well as primary bone marrow cells derived from ETV6/RUNX1 transgenic animals display elevated levels of reactive oxygen species (ROS) as tested with ETV6/RUNX1 transgenic dihydroethidium staining. In line, intracellular phospho-histone H2AX flow cytometry and comet assay revealed increased DNA damage indicating that ETV6/RUNX1 expression enhances ROS. On the basis of our data, we propose the following model: the expression of ETV6/RUNX1 creates a preleukemic clone and leads to increased ROS levels. These elevated ROS favor the accumulation of secondary hits by increasing genetic instability and double-strand breaks, thus allowing preleukemic clones to develop into fully transformed leukemic cells. PMID- 24339743 TI - Multiple constraints on grassland evapotranspiration: implications for closing the energy balance. AB - When using the eddy covariance (EC) method for measuring the ecosystem-atmosphere exchange of sensible and latent heat, it is not uncommon to find that these two energy fluxes fall short of available energy by 20-30 %. As the causes for the energy imbalance are still under discussion, it is currently not clear how the energy balance should be closed. The objective of the present paper is to use independent measurements of evapotranspiration (ET) for empirically devising on how to best close the energy balance. To this end ET of a temperate mountain grassland was quantified during two measurement campaigns using both an open- and a closed-path EC system, lysimeters and an approach scaling up leaf-level stomatal conductance to canopy level transpiration. Our study showed that both EC systems underestimated ET measured independently by lysimeters and the up-scaling approach. Best correspondence to independently measured ET was achieved by assigning the entire energy imbalance to ET and by adjusting ET according to the average energy balance ratio during the first and second measurement campaign, respectively. Due to a large spatial variability in ET during the first measurement campaign and given large differences in spatial scale between the EC and the independent methods, we are more confident with the comparison of approaches during the second measurement campaign and thus recommend forcing energy balance closure by adjusting for the average energy balance ratio. PMID- 24339742 TI - Alternative lengthening of telomeres: recurrent cytogenetic aberrations and chromosome stability under extreme telomere dysfunction. AB - Human tumors using the alternative lengthening of telomeres (ALT) exert high rates of telomere dysfunction. Numerical chromosomal aberrations are very frequent, and structural rearrangements are widely scattered among the genome. This challenging context allows the study of telomere dysfunction-driven chromosomal instability in neoplasia (CIN) in a massive scale. We used molecular cytogenetics to achieve detailed karyotyping in 10 human ALT neoplastic cell lines. We identified 518 clonal recombinant chromosomes affected by 649 structural rearrangements. While all human chromosomes were involved in random or clonal, terminal, or pericentromeric rearrangements and were capable to undergo telomere healing at broken ends, a differential recombinatorial propensity of specific genomic regions was noted. We show that ALT cells undergo epigenetic modifications rendering polycentric chromosomes functionally monocentric, and because of increased terminal recombinogenicity, they generate clonal recombinant chromosomes with interstitial telomeric repeats. Losses of chromosomes 13, X, and 22, gains of 2, 3, 5, and 20, and translocation/deletion events involving several common chromosomal fragile sites (CFSs) were recurrent. Long-term reconstitution of telomerase activity in ALT cells reduced significantly the rates of random ongoing telomeric and pericentromeric CIN. However, the contribution of CFS in overall CIN remained unaffected, suggesting that in ALT cells whole-genome replication stress is not suppressed by telomerase activation. Our results provide novel insights into ALT-driven CIN, unveiling in parallel specific genomic sites that may harbor genes critical for ALT cancerous cell growth. PMID- 24339745 TI - Agl, the multitasking motor protein. PMID- 24339744 TI - A versatile class of cell surface directional motors gives rise to gliding motility and sporulation in Myxococcus xanthus. AB - Eukaryotic cells utilize an arsenal of processive transport systems to deliver macromolecules to specific subcellular sites. In prokaryotes, such transport mechanisms have only been shown to mediate gliding motility, a form of microbial surface translocation. Here, we show that the motility function of the Myxococcus xanthus Agl-Glt machinery results from the recent specialization of a versatile class of bacterial transporters. Specifically, we demonstrate that the Agl motility motor is modular and dissociates from the rest of the gliding machinery (the Glt complex) to bind the newly expressed Nfs complex, a close Glt paralogue, during sporulation. Following this association, the Agl system transports Nfs proteins directionally around the spore surface. Since the main spore coat polymer is secreted at discrete sites around the spore surface, its transport by Agl-Nfs ensures its distribution around the spore. Thus, the Agl-Glt/Nfs machineries may constitute a novel class of directional bacterial surface transporters that can be diversified to specific tasks depending on the cognate cargo and machinery-specific accessories. PMID- 24339746 TI - Encourage sustainability by giving credit for marine protected areas in seafood certification. PMID- 24339747 TI - Escherichia coli ribosomal protein S1 unfolds structured mRNAs onto the ribosome for active translation initiation. AB - Regulation of translation initiation is well appropriate to adapt cell growth in response to stress and environmental changes. Many bacterial mRNAs adopt structures in their 5' untranslated regions that modulate the accessibility of the 30S ribosomal subunit. Structured mRNAs interact with the 30S in a two-step process where the docking of a folded mRNA precedes an accommodation step. Here, we used a combination of experimental approaches in vitro (kinetic of mRNA unfolding and binding experiments to analyze mRNA-protein or mRNA-ribosome complexes, toeprinting assays to follow the formation of ribosomal initiation complexes) and in vivo (genetic) to monitor the action of ribosomal protein S1 on the initiation of structured and regulated mRNAs. We demonstrate that r-protein S1 endows the 30S with an RNA chaperone activity that is essential for the docking and the unfolding of structured mRNAs, and for the correct positioning of the initiation codon inside the decoding channel. The first three OB-fold domains of S1 retain all its activities (mRNA and 30S binding, RNA melting activity) on the 30S subunit. S1 is not required for all mRNAs and acts differently on mRNAs according to the signals present at their 5' ends. This work shows that S1 confers to the ribosome dynamic properties to initiate translation of a large set of mRNAs with diverse structural features. PMID- 24339748 TI - A downy mildew effector attenuates salicylic acid-triggered immunity in Arabidopsis by interacting with the host mediator complex. AB - Plants are continually exposed to pathogen attack but usually remain healthy because they can activate defences upon perception of microbes. However, pathogens have evolved to overcome plant immunity by delivering effectors into the plant cell to attenuate defence, resulting in disease. Recent studies suggest that some effectors may manipulate host transcription, but the specific mechanisms by which such effectors promote susceptibility remain unclear. We study the oomycete downy mildew pathogen of Arabidopsis, Hyaloperonospora arabidopsidis (Hpa), and show here that the nuclear-localized effector HaRxL44 interacts with Mediator subunit 19a (MED19a), resulting in the degradation of MED19a in a proteasome-dependent manner. The Mediator complex of ~25 proteins is broadly conserved in eukaryotes and mediates the interaction between transcriptional regulators and RNA polymerase II. We found MED19a to be a positive regulator of immunity against Hpa. Expression profiling experiments reveal transcriptional changes resembling jasmonic acid/ethylene (JA/ET) signalling in the presence of HaRxL44, and also 3 d after infection with Hpa. Elevated JA/ET signalling is associated with a decrease in salicylic acid (SA) triggered immunity (SATI) in Arabidopsis plants expressing HaRxL44 and in med19a loss-of-function mutants, whereas SATI is elevated in plants overexpressing MED19a. Using a PR1::GUS reporter, we discovered that Hpa suppresses PR1 expression specifically in cells containing haustoria, into which RxLR effectors are delivered, but not in nonhaustoriated adjacent cells, which show high PR1::GUS expression levels. Thus, HaRxL44 interferes with Mediator function by degrading MED19, shifting the balance of defence transcription from SA-responsive defence to JA/ET-signalling, and enhancing susceptibility to biotrophs by attenuating SA-dependent gene expression. PMID- 24339750 TI - Data sharing in a humanitarian organization: the experience of Medecins Sans Frontieres. PMID- 24339749 TI - Circadian period integrates network information through activation of the BMP signaling pathway. AB - Living organisms use biological clocks to maintain their internal temporal order and anticipate daily environmental changes. In Drosophila, circadian regulation of locomotor behavior is controlled by ~150 neurons; among them, neurons expressing the PIGMENT DISPERSING FACTOR (PDF) set the period of locomotor behavior under free-running conditions. To date, it remains unclear how individual circadian clusters integrate their activity to assemble a distinctive behavioral output. Here we show that the BONE MORPHOGENETIC PROTEIN (BMP) signaling pathway plays a crucial role in setting the circadian period in PDF neurons in the adult brain. Acute deregulation of BMP signaling causes period lengthening through regulation of dClock transcription, providing evidence for a novel function of this pathway in the adult brain. We propose that coherence in the circadian network arises from integration in PDF neurons of both the pace of the cell-autonomous molecular clock and information derived from circadian relevant neurons through release of BMP ligands. PMID- 24339751 TI - HIV-1 transmission during early infection in men who have sex with men: a phylodynamic analysis. AB - BACKGROUND: Conventional epidemiological surveillance of infectious diseases is focused on characterization of incident infections and estimation of the number of prevalent infections. Advances in methods for the analysis of the population level genetic variation of viruses can potentially provide information about donors, not just recipients, of infection. Genetic sequences from many viruses are increasingly abundant, especially HIV, which is routinely sequenced for surveillance of drug resistance mutations. We conducted a phylodynamic analysis of HIV genetic sequence data and surveillance data from a US population of men who have sex with men (MSM) and estimated incidence and transmission rates by stage of infection. METHODS AND FINDINGS: We analyzed 662 HIV-1 subtype B sequences collected between October 14, 2004, and February 24, 2012, from MSM in the Detroit metropolitan area, Michigan. These sequences were cross-referenced with a database of 30,200 patients diagnosed with HIV infection in the state of Michigan, which includes clinical information that is informative about the recency of infection at the time of diagnosis. These data were analyzed using recently developed population genetic methods that have enabled the estimation of transmission rates from the population-level genetic diversity of the virus. We found that genetic data are highly informative about HIV donors in ways that standard surveillance data are not. Genetic data are especially informative about the stage of infection of donors at the point of transmission. We estimate that 44.7% (95% CI, 42.2%-46.4%) of transmissions occur during the first year of infection. CONCLUSIONS: In this study, almost half of transmissions occurred within the first year of HIV infection in MSM. Our conclusions may be sensitive to un-modeled intra-host evolutionary dynamics, un-modeled sexual risk behavior, and uncertainty in the stage of infected hosts at the time of sampling. The intensity of transmission during early infection may have significance for public health interventions based on early treatment of newly diagnosed individuals. PMID- 24339752 TI - Early HIV infection in the United States: a virus's eye view. PMID- 24339753 TI - Experiences with policing among people who inject drugs in Bangkok, Thailand: a qualitative study. AB - BACKGROUND: Despite Thailand's commitment to treating people who use drugs as "patients" not "criminals," Thai authorities continue to emphasize criminal law enforcement for drug control. In 2003, Thailand's drug war received international criticism due to extensive human rights violations. However, few studies have since investigated the impact of policing on drug-using populations. Therefore, we sought to examine experiences with policing among people who inject drugs (PWID) in Bangkok, Thailand, between 2008 and 2012. METHODS AND FINDINGS: Between July 2011 and June 2012, semi-structured, in-depth interviews were conducted with 42 community-recruited PWID participating in the Mitsampan Community Research Project in Bangkok. Interviews explored PWID's encounters with police during the past three years. Audio-recorded interviews were transcribed verbatim, and a thematic analysis was conducted to document the character of PWID's experiences with police. Respondents indicated that policing activities had noticeably intensified since rapid urine toxicology screening became available to police. Respondents reported various forms of police misconduct, including false accusations, coercion of confessions, excessive use of force, and extortion of money. However, respondents were reluctant to report misconduct to the authorities in the face of social and structural barriers to seeking justice. Respondents' strategies to avoid police impeded access to health care and facilitated transitions towards the misuse of prescribed pharmaceuticals. The study's limitations relate to the transferability of the findings, including the potential biases associated with the small convenience sample. CONCLUSIONS: This study suggests that policing in Bangkok has involved injustices, human rights abuses, and corruption, and policing practices in this setting appeared to have increased PWID's vulnerability to poor health through various pathways. Novel to this study are findings pertaining to the use of urine drug testing by police, which highlight the potential for widespread abuse of this emerging technology. These findings raise concern about ongoing policing practices in this setting. PMID- 24339754 TI - Investigating the intersection of policing and public health. PMID- 24339755 TI - Sharpness of spike initiation in neurons explained by compartmentalization. AB - In cortical neurons, spikes are initiated in the axon initial segment. Seen at the soma, they appear surprisingly sharp. A standard explanation is that the current coming from the axon becomes sharp as the spike is actively backpropagated to the soma. However, sharp initiation of spikes is also seen in the input-output properties of neurons, and not only in the somatic shape of spikes; for example, cortical neurons can transmit high frequency signals. An alternative hypothesis is that Na channels cooperate, but it is not currently supported by direct experimental evidence. I propose a simple explanation based on the compartmentalization of spike initiation. When Na channels are placed in the axon, the soma acts as a current sink for the Na current. I show that there is a critical distance to the soma above which an instability occurs, so that Na channels open abruptly rather than gradually as a function of somatic voltage. PMID- 24339756 TI - Transformation of stimulus correlations by the retina. AB - Redundancies and correlations in the responses of sensory neurons may seem to waste neural resources, but they can also carry cues about structured stimuli and may help the brain to correct for response errors. To investigate the effect of stimulus structure on redundancy in retina, we measured simultaneous responses from populations of retinal ganglion cells presented with natural and artificial stimuli that varied greatly in correlation structure; these stimuli and recordings are publicly available online. Responding to spatio-temporally structured stimuli such as natural movies, pairs of ganglion cells were modestly more correlated than in response to white noise checkerboards, but they were much less correlated than predicted by a non-adapting functional model of retinal response. Meanwhile, responding to stimuli with purely spatial correlations, pairs of ganglion cells showed increased correlations consistent with a static, non-adapting receptive field and nonlinearity. We found that in response to spatio-temporally correlated stimuli, ganglion cells had faster temporal kernels and tended to have stronger surrounds. These properties of individual cells, along with gain changes that opposed changes in effective contrast at the ganglion cell input, largely explained the pattern of pairwise correlations across stimuli where receptive field measurements were possible. PMID- 24339757 TI - Membrane binding of MinE allows for a comprehensive description of Min-protein pattern formation. AB - The rod-shaped bacterium Escherichia coli selects the cell center as site of division with the help of the proteins MinC, MinD, and MinE. This protein system collectively oscillates between the two cell poles by alternately binding to the membrane in one of the two cell halves. This dynamic behavior, which emerges from the interaction of the ATPase MinD and its activator MinE on the cell membrane, has become a paradigm for protein self-organization. Recently, it has been found that not only the binding of MinD to the membrane, but also interactions of MinE with the membrane contribute to Min-protein self-organization. Here, we show that by accounting for this finding in a computational model, we can comprehensively describe all observed Min-protein patterns in vivo and in vitro. Furthermore, by varying the system's geometry, our computations predict patterns that have not yet been reported. We confirm these predictions experimentally. PMID- 24339758 TI - Determinants of cell-to-cell variability in protein kinase signaling. AB - Cells reliably sense environmental changes despite internal and external fluctuations, but the mechanisms underlying robustness remain unclear. We analyzed how fluctuations in signaling protein concentrations give rise to cell to-cell variability in protein kinase signaling using analytical theory and numerical simulations. We characterized the dose-response behavior of signaling cascades by calculating the stimulus level at which a pathway responds ('pathway sensitivity') and the maximal activation level upon strong stimulation. Minimal kinase cascades with gradual dose-response behavior show strong variability, because the pathway sensitivity and the maximal activation level cannot be simultaneously invariant. Negative feedback regulation resolves this trade-off and coordinately reduces fluctuations in the pathway sensitivity and maximal activation. Feedbacks acting at different levels in the cascade control different aspects of the dose-response curve, thereby synergistically reducing the variability. We also investigated more complex, ultrasensitive signaling cascades capable of switch-like decision making, and found that these can be inherently robust to protein concentration fluctuations. We describe how the cell-to-cell variability of ultrasensitive signaling systems can be actively regulated, e.g., by altering the expression of phosphatase(s) or by feedback/feedforward loops. Our calculations reveal that slow transcriptional negative feedback loops allow for variability suppression while maintaining switch-like decision making. Taken together, we describe design principles of signaling cascades that promote robustness. Our results may explain why certain signaling cascades like the yeast pheromone pathway show switch-like decision making with little cell-to-cell variability. PMID- 24339759 TI - Systems modeling of anti-apoptotic pathways in prostate cancer: psychological stress triggers a synergism pattern switch in drug combination therapy. AB - Prostate cancer patients often have increased levels of psychological stress or anxiety, but the molecular mechanisms underlying the interaction between psychological stress and prostate cancer as well as therapy resistance have been rarely studied and remain poorly understood. Recent reports show that stress inhibits apoptosis in prostate cancer cells via epinephrine/beta2 adrenergic receptor/PKA/BAD pathway. In this study, we used experimental data on the signaling pathways that control BAD phosphorylation to build a dynamic network model of apoptosis regulation in prostate cancer cells. We then compared the predictive power of two different models with or without the role of Mcl-1, which justified the role of Mcl-1 stabilization in anti-apoptotic effects of emotional stress. Based on the selected model, we examined and quantitatively evaluated the induction of apoptosis by drug combination therapies. We predicted that the combination of PI3K inhibitor LY294002 and inhibition of BAD phosphorylation at S112 would produce the best synergistic effect among 8 interventions examined. Experimental validation confirmed the effectiveness of our predictive model. Moreover, we found that epinephrine signaling changes the synergism pattern and decreases efficacy of combination therapy. The molecular mechanisms responsible for therapeutic resistance and the switch in synergism were explored by analyzing a network model of signaling pathways affected by psychological stress. These results provide insights into the mechanisms of psychological stress signaling in therapy-resistant cancer, and indicate the potential benefit of reducing psychological stress in designing more effective therapies for prostate cancer patients. PMID- 24339760 TI - Dimensionality of carbon nanomaterials determines the binding and dynamics of amyloidogenic peptides: multiscale theoretical simulations. AB - Experimental studies have demonstrated that nanoparticles can affect the rate of protein self-assembly, possibly interfering with the development of protein misfolding diseases such as Alzheimer's, Parkinson's and prion disease caused by aggregation and fibril formation of amyloid-prone proteins. We employ classical molecular dynamics simulations and large-scale density functional theory calculations to investigate the effects of nanomaterials on the structure, dynamics and binding of an amyloidogenic peptide apoC-II(60-70). We show that the binding affinity of this peptide to carbonaceous nanomaterials such as C60, nanotubes and graphene decreases with increasing nanoparticle curvature. Strong binding is facilitated by the large contact area available for pi-stacking between the aromatic residues of the peptide and the extended surfaces of graphene and the nanotube. The highly curved fullerene surface exhibits reduced efficiency for pi-stacking but promotes increased peptide dynamics. We postulate that the increase in conformational dynamics of the amyloid peptide can be unfavorable for the formation of fibril competent structures. In contrast, extended fibril forming peptide conformations are promoted by the nanotube and graphene surfaces which can provide a template for fibril-growth. PMID- 24339761 TI - A sequential vesicle pool model with a single release sensor and a Ca(2+) dependent priming catalyst effectively explains Ca(2+)-dependent properties of neurosecretion. AB - Neurotransmitter release depends on the fusion of secretory vesicles with the plasma membrane and the release of their contents. The final fusion step displays higher-order Ca(2+) dependence, but also upstream steps depend on Ca(2+). After deletion of the Ca(2+) sensor for fast release - synaptotagmin-1 - slower Ca(2+) dependent release components persist. These findings have provoked working models involving parallel releasable vesicle pools (Parallel Pool Models, PPM) driven by alternative Ca(2+) sensors for release, but no slow release sensor acting on a parallel vesicle pool has been identified. We here propose a Sequential Pool Model (SPM), assuming a novel Ca(2+)-dependent action: a Ca(2+)-dependent catalyst that accelerates both forward and reverse priming reactions. While both models account for fast fusion from the Readily-Releasable Pool (RRP) under control of synaptotagmin-1, the origins of slow release differ. In the SPM the slow release component is attributed to the Ca(2+)-dependent refilling of the RRP from a Non-Releasable upstream Pool (NRP), whereas the PPM attributes slow release to a separate slowly-releasable vesicle pool. Using numerical integration we compared model predictions to data from mouse chromaffin cells. Like the PPM, the SPM explains biphasic release, Ca(2+)-dependence and pool sizes in mouse chromaffin cells. In addition, the SPM accounts for the rapid recovery of the fast component after strong stimulation, where the PPM fails. The SPM also predicts the simultaneous changes in release rate and amplitude seen when mutating the SNARE-complex. Finally, it can account for the loss of fast- and the persistence of slow release in the synaptotagmin-1 knockout by assuming that the RRP is depleted, leading to slow and Ca(2+)-dependent fusion from the NRP. We conclude that the elusive 'alternative Ca(2+) sensor' for slow release might be the upstream priming catalyst, and that a sequential model effectively explains Ca(2+)-dependent properties of secretion without assuming parallel pools or sensors. PMID- 24339762 TI - Actions, action sequences and habits: evidence that goal-directed and habitual action control are hierarchically organized. AB - Behavioral evidence suggests that instrumental conditioning is governed by two forms of action control: a goal-directed and a habit learning process. Model based reinforcement learning (RL) has been argued to underlie the goal-directed process; however, the way in which it interacts with habits and the structure of the habitual process has remained unclear. According to a flat architecture, the habitual process corresponds to model-free RL, and its interaction with the goal directed process is coordinated by an external arbitration mechanism. Alternatively, the interaction between these systems has recently been argued to be hierarchical, such that the formation of action sequences underlies habit learning and a goal-directed process selects between goal-directed actions and habitual sequences of actions to reach the goal. Here we used a two-stage decision-making task to test predictions from these accounts. The hierarchical account predicts that, because they are tied to each other as an action sequence, selecting a habitual action in the first stage will be followed by a habitual action in the second stage, whereas the flat account predicts that the statuses of the first and second stage actions are independent of each other. We found, based on subjects' choices and reaction times, that human subjects combined single actions to build action sequences and that the formation of such action sequences was sufficient to explain habitual actions. Furthermore, based on Bayesian model comparison, a family of hierarchical RL models, assuming a hierarchical interaction between habit and goal-directed processes, provided a better fit of the subjects' behavior than a family of flat models. Although these findings do not rule out all possible model-free accounts of instrumental conditioning, they do show such accounts are not necessary to explain habitual actions and provide a new basis for understanding how goal-directed and habitual action control interact. PMID- 24339763 TI - Designing molecular dynamics simulations to shift populations of the conformational states of calmodulin. AB - We elucidate the mechanisms that lead to population shifts in the conformational states of calcium-loaded calmodulin (Ca(2+)-CaM). We design extensive molecular dynamics simulations to classify the effects that are responsible for adopting occupied conformations available in the ensemble of NMR structures. Electrostatic interactions amongst the different regions of the protein and with its vicinal water are herein mediated by lowering the ionic strength or the pH. Amino acid E31, which is one of the few charged residues whose ionization state is highly sensitive to pH differences in the physiological range, proves to be distinctive in its control of population shifts. E31A mutation at low ionic strength results in a distinct change from an extended to a compact Ca(2+)-CaM conformation within tens of nanoseconds, that otherwise occur on the time scales of microseconds. The kinked linker found in this particular compact form is observed in many of the target-bound forms of Ca(2+)-CaM, increasing the binding affinity. This mutation is unique in controlling C-lobe dynamics by affecting the fluctuations between the EF-hand motif helices. We also monitor the effect of the ionic strength on the conformational multiplicity of Ca(2+)-CaM. By lowering the ionic strength, the tendency of nonspecific anions in water to accumulate near the protein surface increases, especially in the vicinity of the linker. The change in the distribution of ions in the vicinal layer of water allows N- and C- lobes to span a wide variety of relative orientations that are otherwise not observed at physiological ionic strength. E31 protonation restores the conformations associated with physiological environmental conditions even at low ionic strength. PMID- 24339764 TI - Understanding variation in transcription factor binding by modeling transcription factor genome-epigenome interactions. AB - Despite explosive growth in genomic datasets, the methods for studying epigenomic mechanisms of gene regulation remain primitive. Here we present a model-based approach to systematically analyze the epigenomic functions in modulating transcription factor-DNA binding. Based on the first principles of statistical mechanics, this model considers the interactions between epigenomic modifications and a cis-regulatory module, which contains multiple binding sites arranged in any configurations. We compiled a comprehensive epigenomic dataset in mouse embryonic stem (mES) cells, including DNA methylation (MeDIP-seq and MRE-seq), DNA hydroxymethylation (5-hmC-seq), and histone modifications (ChIP-seq). We discovered correlations of transcription factors (TFs) for specific combinations of epigenomic modifications, which we term epigenomic motifs. Epigenomic motifs explained why some TFs appeared to have different DNA binding motifs derived from in vivo (ChIP-seq) and in vitro experiments. Theoretical analyses suggested that the epigenome can modulate transcriptional noise and boost the cooperativity of weak TF binding sites. ChIP-seq data suggested that epigenomic boost of binding affinities in weak TF binding sites can function in mES cells. We showed in theory that the epigenome should suppress the TF binding differences on SNP containing binding sites in two people. Using personal data, we identified strong associations between H3K4me2/H3K9ac and the degree of personal differences in NFkappaB binding in SNP-containing binding sites, which may explain why some SNPs introduce much smaller personal variations on TF binding than other SNPs. In summary, this model presents a powerful approach to analyze the functions of epigenomic modifications. This model was implemented into an open source program APEG (Affinity Prediction by Epigenome and Genome, http://systemsbio.ucsd.edu/apeg). PMID- 24339765 TI - Protein-protein interactions in a crowded environment: an analysis via cross docking simulations and evolutionary information. AB - Large-scale analyses of protein-protein interactions based on coarse-grain molecular docking simulations and binding site predictions resulting from evolutionary sequence analysis, are possible and realizable on hundreds of proteins with variate structures and interfaces. We demonstrated this on the 168 proteins of the Mintseris Benchmark 2.0. On the one hand, we evaluated the quality of the interaction signal and the contribution of docking information compared to evolutionary information showing that the combination of the two improves partner identification. On the other hand, since protein interactions usually occur in crowded environments with several competing partners, we realized a thorough analysis of the interactions of proteins with true partners but also with non-partners to evaluate whether proteins in the environment, competing with the true partner, affect its identification. We found three populations of proteins: strongly competing, never competing, and interacting with different levels of strength. Populations and levels of strength are numerically characterized and provide a signature for the behavior of a protein in the crowded environment. We showed that partner identification, to some extent, does not depend on the competing partners present in the environment, that certain biochemical classes of proteins are intrinsically easier to analyze than others, and that small proteins are not more promiscuous than large ones. Our approach brings to light that the knowledge of the binding site can be used to reduce the high computational cost of docking simulations with no consequence in the quality of the results, demonstrating the possibility to apply coarse grain docking to datasets made of thousands of proteins. Comparison with all available large-scale analyses aimed to partner predictions is realized. We release the complete decoys set issued by coarse-grain docking simulations of both true and false interacting partners, and their evolutionary sequence analysis leading to binding site predictions. Download site: http://www.lgm.upmc.fr/CCDMintseris/ PMID- 24339766 TI - Handling uncertainty in dynamic models: the pentose phosphate pathway in Trypanosoma brucei. AB - Dynamic models of metabolism can be useful in identifying potential drug targets, especially in unicellular organisms. A model of glycolysis in the causative agent of human African trypanosomiasis, Trypanosoma brucei, has already shown the utility of this approach. Here we add the pentose phosphate pathway (PPP) of T. brucei to the glycolytic model. The PPP is localized to both the cytosol and the glycosome and adding it to the glycolytic model without further adjustments leads to a draining of the essential bound-phosphate moiety within the glycosome. This phosphate "leak" must be resolved for the model to be a reasonable representation of parasite physiology. Two main types of theoretical solution to the problem could be identified: (i) including additional enzymatic reactions in the glycosome, or (ii) adding a mechanism to transfer bound phosphates between cytosol and glycosome. One example of the first type of solution would be the presence of a glycosomal ribokinase to regenerate ATP from ribose 5-phosphate and ADP. Experimental characterization of ribokinase in T. brucei showed that very low enzyme levels are sufficient for parasite survival, indicating that other mechanisms are required in controlling the phosphate leak. Examples of the second type would involve the presence of an ATP:ADP exchanger or recently described permeability pores in the glycosomal membrane, although the current absence of identified genes encoding such molecules impedes experimental testing by genetic manipulation. Confronted with this uncertainty, we present a modeling strategy that identifies robust predictions in the context of incomplete system characterization. We illustrate this strategy by exploring the mechanism underlying the essential function of one of the PPP enzymes, and validate it by confirming the model predictions experimentally. PMID- 24339767 TI - A network inference method for large-scale unsupervised identification of novel drug-drug interactions. AB - Characterizing interactions between drugs is important to avoid potentially harmful combinations, to reduce off-target effects of treatments and to fight antibiotic resistant pathogens, among others. Here we present a network inference algorithm to predict uncharacterized drug-drug interactions. Our algorithm takes, as its only input, sets of previously reported interactions, and does not require any pharmacological or biochemical information about the drugs, their targets or their mechanisms of action. Because the models we use are abstract, our approach can deal with adverse interactions, synergistic/antagonistic/suppressing interactions, or any other type of drug interaction. We show that our method is able to accurately predict interactions, both in exhaustive pairwise interaction data between small sets of drugs, and in large-scale databases. We also demonstrate that our algorithm can be used efficiently to discover interactions of new drugs as part of the drug discovery process. PMID- 24339768 TI - Detecting genetic association of common human facial morphological variation using high density 3D image registration. AB - Human facial morphology is a combination of many complex traits. Little is known about the genetic basis of common facial morphological variation. Existing association studies have largely used simple landmark-distances as surrogates for the complex morphological phenotypes of the face. However, this can result in decreased statistical power and unclear inference of shape changes. In this study, we applied a new image registration approach that automatically identified the salient landmarks and aligned the sample faces using high density pixel points. Based on this high density registration, three different phenotype data schemes were used to test the association between the common facial morphological variation and 10 candidate SNPs, and their performances were compared. The first scheme used traditional landmark-distances; the second relied on the geometric analysis of 15 landmarks and the third used geometric analysis of a dense registration of ~30,000 3D points. We found that the two geometric approaches were highly consistent in their detection of morphological changes. The geometric method using dense registration further demonstrated superiority in the fine inference of shape changes and 3D face modeling. Several candidate SNPs showed potential associations with different facial features. In particular, one SNP, a known risk factor of non-syndromic cleft lips/palates, rs642961 in the IRF6 gene, was validated to strongly predict normal lip shape variation in female Han Chinese. This study further demonstrated that dense face registration may substantially improve the detection and characterization of genetic association in common facial variation. PMID- 24339769 TI - Extrapolating weak selection in evolutionary games. AB - In evolutionary games, reproductive success is determined by payoffs. Weak selection means that even large differences in game outcomes translate into small fitness differences. Many results have been derived using weak selection approximations, in which perturbation analysis facilitates the derivation of analytical results. Here, we ask whether results derived under weak selection are also qualitatively valid for intermediate and strong selection. By "qualitatively valid" we mean that the ranking of strategies induced by an evolutionary process does not change when the intensity of selection increases. For two-strategy games, we show that the ranking obtained under weak selection cannot be carried over to higher selection intensity if the number of players exceeds two. For games with three (or more) strategies, previous examples for multiplayer games have shown that the ranking of strategies can change with the intensity of selection. In particular, rank changes imply that the most abundant strategy at one intensity of selection can become the least abundant for another. We show that this applies already to pairwise interactions for a broad class of evolutionary processes. Even when both weak and strong selection limits lead to consistent predictions, rank changes can occur for intermediate intensities of selection. To analyze how common such games are, we show numerically that for randomly drawn two-player games with three or more strategies, rank changes frequently occur and their likelihood increases rapidly with the number of strategies [Formula: see text]. In particular, rank changes are almost certain for [Formula: see text], which jeopardizes the predictive power of results derived for weak selection. PMID- 24339770 TI - Cortical and hippocampal correlates of deliberation during model-based decisions for rewards in humans. AB - How do we use our memories of the past to guide decisions we've never had to make before? Although extensive work describes how the brain learns to repeat rewarded actions, decisions can also be influenced by associations between stimuli or events not directly involving reward - such as when planning routes using a cognitive map or chess moves using predicted countermoves - and these sorts of associations are critical when deciding among novel options. This process is known as model-based decision making. While the learning of environmental relations that might support model-based decisions is well studied, and separately this sort of information has been inferred to impact decisions, there is little evidence concerning the full cycle by which such associations are acquired and drive choices. Of particular interest is whether decisions are directly supported by the same mnemonic systems characterized for relational learning more generally, or instead rely on other, specialized representations. Here, building on our previous work, which isolated dual representations underlying sequential predictive learning, we directly demonstrate that one such representation, encoded by the hippocampal memory system and adjacent cortical structures, supports goal-directed decisions. Using interleaved learning and decision tasks, we monitor predictive learning directly and also trace its influence on decisions for reward. We quantitatively compare the learning processes underlying multiple behavioral and fMRI observables using computational model fits. Across both tasks, a quantitatively consistent learning process explains reaction times, choices, and both expectation- and surprise-related neural activity. The same hippocampal and ventral stream regions engaged in anticipating stimuli during learning are also engaged in proportion to the difficulty of decisions. These results support a role for predictive associations learned by the hippocampal memory system to be recalled during choice formation. PMID- 24339772 TI - An increasing danger of zoonotic orthopoxvirus infections. AB - On May 8, 1980, the World Health Assembly at its 33(rd) session solemnly declared that the world and all its peoples had won freedom from smallpox and recommended ceasing the vaccination of the population against smallpox. Currently, a larger part of the world population has no immunity not only against smallpox but also against other zoonotic orthopoxvirus infections. Recently, recorded outbreaks of orthopoxvirus diseases not only of domestic animals but also of humans have become more frequent. All this indicates a new situation in the ecology and evolution of zoonotic orthopoxviruses. Analysis of state-of-the-art data on the phylogenetic relationships, ecology, and host range of orthopoxviruses- etiological agents of smallpox (variola virus, VARV), monkeypox (MPXV), cowpox (CPXV), vaccinia (VACV), and camelpox (CMLV)--as well as the patterns of their evolution suggests that a VARV-like virus could emerge in the course of natural evolution of modern zoonotic orthopoxviruses. Thus, there is an insistent need for organization of the international control over the outbreaks of zoonotic orthopoxvirus infections in various countries to provide a rapid response and prevent them from developing into epidemics. PMID- 24339773 TI - The evolution of transmissible prions: the role of deformed templating. PMID- 24339771 TI - Hepatitis B virus disrupts mitochondrial dynamics: induces fission and mitophagy to attenuate apoptosis. AB - Human hepatitis B virus (HBV) causes chronic hepatitis and is associated with the development of hepatocellular carcinoma. HBV infection alters mitochondrial metabolism. The selective removal of damaged mitochondria is essential for the maintenance of mitochondrial and cellular homeostasis. Here, we report that HBV shifts the balance of mitochondrial dynamics toward fission and mitophagy to attenuate the virus-induced apoptosis. HBV induced perinuclear clustering of mitochondria and triggered mitochondrial translocation of the dynamin-related protein (Drp1) by stimulating its phosphorylation at Ser616, leading to mitochondrial fission. HBV also stimulated the gene expression of Parkin, PINK1, and LC3B and induced Parkin recruitment to the mitochondria. Upon translocation to mitochondria, Parkin, an E3 ubiquitin ligase, underwent self-ubiquitination and facilitated the ubiquitination and degradation of its substrate Mitofusin 2 (Mfn2), a mediator of mitochondrial fusion. In addition to conventional immunofluorescence, a sensitive dual fluorescence reporter expressing mito-mRFP EGFP fused in-frame to a mitochondrial targeting sequence was employed to observe the completion of the mitophagic process by delivery of the engulfed mitochondria to lysosomes for degradation. Furthermore, we demonstrate that viral HBx protein plays a central role in promoting aberrant mitochondrial dynamics either when expressed alone or in the context of viral genome. Perturbing mitophagy by silencing Parkin led to enhanced apoptotic signaling, suggesting that HBV-induced mitochondrial fission and mitophagy promote cell survival and possibly viral persistence. Altered mitochondrial dynamics associated with HBV infection may contribute to mitochondrial injury and liver disease pathogenesis. PMID- 24339774 TI - Cytoplasmic viruses: rage against the (cellular RNA decay) machine. PMID- 24339775 TI - Signatures of pleiotropy, economy and convergent evolution in a domain-resolved map of human-virus protein-protein interaction networks. AB - A central challenge in host-pathogen systems biology is the elucidation of general, systems-level principles that distinguish host-pathogen interactions from within-host interactions. Current analyses of host-pathogen and within-host protein-protein interaction networks are largely limited by their resolution, treating proteins as nodes and interactions as edges. Here, we construct a domain resolved map of human-virus and within-human protein-protein interaction networks by annotating protein interactions with high-coverage, high-accuracy, domain centric interaction mechanisms: (1) domain-domain interactions, in which a domain in one protein binds to a domain in a second protein, and (2) domain-motif interactions, in which a domain in one protein binds to a short, linear peptide motif in a second protein. Analysis of these domain-resolved networks reveals, for the first time, significant mechanistic differences between virus-human and within-human interactions at the resolution of single domains. While human proteins tend to compete with each other for domain binding sites by means of sequence similarity, viral proteins tend to compete with human proteins for domain binding sites in the absence of sequence similarity. Independent of their previously established preference for targeting human protein hubs, viral proteins also preferentially target human proteins containing linear motif binding domains. Compared to human proteins, viral proteins participate in more domain-motif interactions, target more unique linear motif-binding domains per residue, and contain more unique linear motifs per residue. Together, these results suggest that viruses surmount genome size constraints by convergently evolving multiple short linear motifs in order to effectively mimic, hijack, and manipulate complex host processes for their survival. Our domain-resolved analyses reveal unique signatures of pleiotropy, economy, and convergent evolution in viral-host interactions that are otherwise hidden in the traditional binary network, highlighting the power and necessity of high-resolution approaches in host-pathogen systems biology. PMID- 24339776 TI - Brucella induces an unfolded protein response via TcpB that supports intracellular replication in macrophages. AB - Brucella melitensis is a facultative intracellular bacterium that causes brucellosis, the most prevalent zoonosis worldwide. The Brucella intracellular replicative niche in macrophages and dendritic cells thwarts immune surveillance and complicates both therapy and vaccine development. Currently, host-pathogen interactions supporting Brucella replication are poorly understood. Brucella fuses with the endoplasmic reticulum (ER) to replicate, resulting in dramatic restructuring of the ER. This ER disruption raises the possibility that Brucella provokes an ER stress response called the Unfolded Protein Response (UPR). In this study, B. melitensis infection up regulated expression of the UPR target genes BiP, CHOP, and ERdj4, and induced XBP1 mRNA splicing in murine macrophages. These data implicate activation of all 3 major signaling pathways of the UPR. Consistent with previous reports, XBP1 mRNA splicing was largely MyD88-dependent. However, up regulation of CHOP, and ERdj4 was completely MyD88 independent. Heat killed Brucella stimulated significantly less BiP, CHOP, and ERdj4 expression, but induced XBP1 splicing. Although a Brucella VirB mutant showed relatively intact UPR induction, a TcpB mutant had significantly compromised BiP, CHOP and ERdj4 expression. Purified TcpB, a protein recently identified to modulate microtubules in a manner similar to paclitaxel, also induced UPR target gene expression and resulted in dramatic restructuring of the ER. In contrast, infection with the TcpB mutant resulted in much less ER structural disruption. Finally, tauroursodeoxycholic acid, a pharmacologic chaperone that ameliorates the UPR, significantly impaired Brucella replication in macrophages. Together, these results suggest Brucella induces a UPR, via TcpB and potentially other factors, that enables its intracellular replication. Thus, the UPR may provide a novel therapeutic target for the treatment of brucellosis. These results also have implications for other intracellular bacteria that rely on host physiologic stress responses for replication. PMID- 24339777 TI - Genome-wide detection of fitness genes in uropathogenic Escherichia coli during systemic infection. AB - Uropathogenic Escherichia coli (UPEC) is a leading etiological agent of bacteremia in humans. Virulence mechanisms of UPEC in the context of urinary tract infections have been subjected to extensive research. However, understanding of the fitness mechanisms used by UPEC during bacteremia and systemic infection is limited. A forward genetic screen was utilized to detect transposon insertion mutants with fitness defects during colonization of mouse spleens. An inoculum comprised of 360,000 transposon mutants in the UPEC strain CFT073, cultured from the blood of a patient with pyelonephritis, was used to inoculate mice intravenously. Transposon insertion sites in the inoculum (input) and bacteria colonizing the spleen (output) were identified using high-throughput sequencing of transposon-chromosome junctions. Using frequencies of representation of each insertion mutant in the input and output samples, 242 candidate fitness genes were identified. Co-infection experiments with each of 11 defined mutants and the wild-type strain demonstrated that 82% (9 of 11) of the tested candidate fitness genes were required for optimal fitness in a mouse model of systemic infection. Genes involved in biosynthesis of poly-N-acetyl glucosamine (pgaABCD), major and minor pilin of a type IV pilus (c2394 and c2395), oligopeptide uptake periplasmic-binding protein (oppA), sensitive to antimicrobial peptides (sapABCDF), putative outer membrane receptor (yddB), zinc metallopeptidase (pqqL), a shikimate pathway gene (c1220) and autotransporter serine proteases (pic and vat) were further characterized. Here, we report the first genome-wide identification of genes that contribute to fitness in UPEC during systemic infection in a mammalian host. These fitness factors may represent targets for developing novel therapeutics against UPEC. PMID- 24339778 TI - Combining regulatory T cell depletion and inhibitory receptor blockade improves reactivation of exhausted virus-specific CD8+ T cells and efficiently reduces chronic retroviral loads. AB - Chronic infections with human viruses, such as HIV and HCV, or mouse viruses, such as LCMV or Friend Virus (FV), result in functional exhaustion of CD8(+) T cells. Two main mechanisms have been described that mediate this exhaustion: expression of inhibitory receptors on CD8(+) T cells and expansion of regulatory T cells (Tregs) that suppress CD8(+) T cell activity. Several studies show that blockage of one of these pathways results in reactivation of CD8(+) T cells and partial reduction in chronic viral loads. Using blocking antibodies against PD-1 ligand and Tim-3 and transgenic mice in which Tregs can be selectively ablated, we compared these two treatment strategies and combined them for the first time in a model of chronic retrovirus infection. Blocking inhibitory receptors was more efficient than transient depletion of Tregs in reactivating exhausted CD8(+) T cells and reducing viral set points. However, a combination therapy was superior to any single treatment and further augmented CD8(+) T cell responses and resulted in a sustained reduction in chronic viral loads. These results demonstrate that Tregs and inhibitory receptors are non-overlapping factors in the maintenance of chronic viral infections and that immunotherapies targeting both pathways may be a promising strategy to treat chronic infectious diseases. PMID- 24339779 TI - Myeloid dendritic cells induce HIV-1 latency in non-proliferating CD4+ T cells. AB - Latently infected resting CD4(+) T cells are a major barrier to HIV cure. Understanding how latency is established, maintained and reversed is critical to identifying novel strategies to eliminate latently infected cells. We demonstrate here that co-culture of resting CD4(+) T cells and syngeneic myeloid dendritic cells (mDC) can dramatically increase the frequency of HIV DNA integration and latent HIV infection in non-proliferating memory, but not naive, CD4(+) T cells. Latency was eliminated when cell-to-cell contact was prevented in the mDC-T cell co-cultures and reduced when clustering was minimised in the mDC-T cell co cultures. Supernatants from infected mDC-T cell co-cultures did not facilitate the establishment of latency, consistent with cell-cell contact and not a soluble factor being critical for mediating latent infection of resting CD4(+) T cells. Gene expression in non-proliferating CD4(+) T cells, enriched for latent infection, showed significant changes in the expression of genes involved in cellular activation and interferon regulated pathways, including the down regulation of genes controlling both NF-kappaB and cell cycle. We conclude that mDC play a key role in the establishment of HIV latency in resting memory CD4(+) T cells, which is predominantly mediated through signalling during DC-T cell contact. PMID- 24339780 TI - The TFPI-2 derived peptide EDC34 improves outcome of gram-negative sepsis. AB - Sepsis is characterized by a dysregulated host-pathogen response, leading to high cytokine levels, excessive coagulation and failure to eradicate invasive bacteria. Novel therapeutic strategies that address crucial pathogenetic steps during infection are urgently needed. Here, we describe novel bioactive roles and therapeutic anti-infective potential of the peptide EDC34, derived from the C terminus of tissue factor pathway inhibitor-2 (TFPI-2). This peptide exerted direct bactericidal effects and boosted activation of the classical complement pathway including formation of antimicrobial C3a, but inhibited bacteria-induced activation of the contact system. Correspondingly, in mouse models of severe Escherichia coli and Pseudomonas aeruginosa infection, treatment with EDC34 reduced bacterial levels and lung damage. In combination with the antibiotic ceftazidime, the peptide significantly prolonged survival and reduced mortality in mice. The peptide's boosting effect on bacterial clearance paired with its inhibiting effect on excessive coagulation makes it a promising therapeutic candidate for invasive Gram-negative infections. PMID- 24339781 TI - HIV-1 Vpr accelerates viral replication during acute infection by exploitation of proliferating CD4+ T cells in vivo. AB - The precise role of viral protein R (Vpr), an HIV-1-encoded protein, during HIV-1 infection and its contribution to the development of AIDS remain unclear. Previous reports have shown that Vpr has the ability to cause G2 cell cycle arrest and apoptosis in HIV-1-infected cells in vitro. In addition, vpr is highly conserved in transmitted/founder HIV-1s and in all primate lentiviruses, which are evolutionarily related to HIV-1. Although these findings suggest an important role of Vpr in HIV-1 pathogenesis, its direct evidence in vivo has not been shown. Here, by using a human hematopoietic stem cell-transplanted humanized mouse model, we demonstrated that Vpr causes G2 cell cycle arrest and apoptosis predominantly in proliferating CCR5(+) CD4(+) T cells, which mainly consist of regulatory CD4(+) T cells (Tregs), resulting in Treg depletion and enhanced virus production during acute infection. The Vpr-dependent enhancement of virus replication and Treg depletion is observed in CCR5-tropic but not CXCR4-tropic HIV-1-infected mice, suggesting that these effects are dependent on the coreceptor usage by HIV-1. Immune activation was observed in CCR5-tropic wild type but not in vpr-deficient HIV-1-infected humanized mice. When humanized mice were treated with denileukin diftitox (DD), to deplete Tregs, DD-treated humanized mice showed massive activation/proliferation of memory T cells compared to the untreated group. This activation/proliferation enhanced CCR5 expression in memory CD4(+) T cells and rendered them more susceptible to CCR5-tropic wild-type HIV-1 infection than to vpr-deficient virus. Taken together, these results suggest that Vpr takes advantage of proliferating CCR5(+) CD4(+) T cells for enhancing viremia of CCR5-tropic HIV-1. Because Tregs exist in a higher cycling state than other T cell subsets, Tregs appear to be more vulnerable to exploitation by Vpr during acute HIV-1 infection. PMID- 24339782 TI - Mycobacterial MazG safeguards genetic stability via housecleaning of 5-OH-dCTP. AB - Generation of reactive oxygen species and reactive nitrogen species in phagocytes is an important innate immune response mechanism to eliminate microbial pathogens. It is known that deoxynucleotides (dNTPs), the precursor nucleotides to DNA synthesis, are one group of the significant targets for these oxidants and incorporation of oxidized dNTPs into genomic DNA may cause mutations and even cell death. Here we show that the mycobacterial dNTP pyrophosphohydrolase MazG safeguards the bacilli genome by degrading 5-OH-dCTP, thereby, preventing it from incorporation into DNA. Deletion of the (d)NTP pyrophosphohydrolase-encoding mazG in mycobacteria leads to a mutator phenotype both under oxidative stress and in the stationary phase of growth, resulting in increased CG to TA mutations. Biochemical analyses demonstrate that mycobacterial MazG can efficiently hydrolyze 5-OH-dCTP, an oxidized nucleotide that induces CG to TA mutation upon incorporation by polymerase. Moreover, chemical genetic analyses show that direct incorporation of 5-OH-dCTP into mazG-null mutant strain of Mycobacterium smegmatis (Msm) leads to a dose-dependent mutagenesis phenotype, indicating that 5-OH-dCTP is a natural substrate of mycobacterial MazG. Furthermore, deletion of mazG in Mycobacterium tuberculosis (Mtb) leads to reduced survival in activated macrophages and in the spleen of infected mice. This study not only characterizes the mycobacterial MazG as a novel pyrimidine-specific housecleaning enzyme that prevents CG to TA mutation by degrading 5-OH-dCTP but also reveals a genome safeguarding mechanism for survival of Mtb in vivo. PMID- 24339783 TI - Genomic imprinting in the Arabidopsis embryo is partly regulated by PRC2. AB - Genomic imprinting results in monoallelic gene expression in a parent-of-origin dependent manner and is regulated by the differential epigenetic marking of the parental alleles. In plants, genomic imprinting has been primarily described for genes expressed in the endosperm, a tissue nourishing the developing embryo that does not contribute to the next generation. In Arabidopsis, the genes MEDEA (MEA) and PHERES1 (PHE1), which are imprinted in the endosperm, are also expressed in the embryo; whether their embryonic expression is regulated by imprinting or not, however, remains controversial. In contrast, the maternally expressed in embryo 1 (mee1) gene of maize is clearly imprinted in the embryo. We identified several imprinted candidate genes in an allele-specific transcriptome of hybrid Arabidopsis embryos and confirmed parent-of-origin-dependent, monoallelic expression for eleven maternally expressed genes (MEGs) and one paternally expressed gene (PEG) in the embryo, using allele-specific expression analyses and reporter gene assays. Genetic studies indicate that the Polycomb Repressive Complex 2 (PRC2) but not the DNA METHYLTRANSFERASE1 (MET1) is involved in regulating imprinted expression in the embryo. In the seedling, all embryonic MEGs and the PEG are expressed from both parents, suggesting that the imprint is erased during late embryogenesis or early vegetative development. Our finding that several genes are regulated by genomic imprinting in the Arabidopsis embryo clearly demonstrates that this epigenetic phenomenon is not a unique feature of the endosperm in both monocots and dicots. PMID- 24339784 TI - Positive and negative regulation of Gli activity by Kif7 in the zebrafish embryo. AB - Loss of function mutations of Kif7, the vertebrate orthologue of the Drosophila Hh pathway component Costal2, cause defects in the limbs and neural tubes of mice, attributable to ectopic expression of Hh target genes. While this implies a functional conservation of Cos2 and Kif7 between flies and vertebrates, the association of Kif7 with the primary cilium, an organelle absent from most Drosophila cells, suggests their mechanisms of action may have diverged. Here, using mutant alleles induced by Zinc Finger Nuclease-mediated targeted mutagenesis, we show that in zebrafish, Kif7 acts principally to suppress the activity of the Gli1 transcription factor. Notably, we find that endogenous Kif7 protein accumulates not only in the primary cilium, as previously observed in mammalian cells, but also in cytoplasmic puncta that disperse in response to Hh pathway activation. Moreover, we show that Drosophila Costal2 can substitute for Kif7, suggesting a conserved mode of action of the two proteins. We show that Kif7 interacts with both Gli1 and Gli2a and suggest that it functions to sequester Gli proteins in the cytoplasm, in a manner analogous to the regulation of Ci by Cos2 in Drosophila. We also show that zebrafish Kif7 potentiates Gli2a activity by promoting its dissociation from the Suppressor of Fused (Sufu) protein and present evidence that it mediates a Smo dependent modification of the full length form of Gli2a. Surprisingly, the function of Kif7 in the zebrafish embryo appears restricted principally to mesodermal derivatives, its inactivation having little effect on neural tube patterning, even when Sufu protein levels are depleted. Remarkably, zebrafish lacking all Kif7 function are viable, in contrast to the peri-natal lethality of mouse kif7 mutants but similar to some Acrocallosal or Joubert syndrome patients who are homozygous for loss of function KIF7 alleles. PMID- 24339785 TI - CRIS-a novel cAMP-binding protein controlling spermiogenesis and the development of flagellar bending. AB - The second messengers cAMP and cGMP activate their target proteins by binding to a conserved cyclic nucleotide-binding domain (CNBD). Here, we identify and characterize an entirely novel CNBD-containing protein called CRIS (cyclic nucleotide receptor involved in sperm function) that is unrelated to any of the other members of this protein family. CRIS is exclusively expressed in sperm precursor cells. Cris-deficient male mice are either infertile due to a lack of sperm resulting from spermatogenic arrest, or subfertile due to impaired sperm motility. The motility defect is caused by altered Ca(2+) regulation of flagellar beat asymmetry, leading to a beating pattern that is reminiscent of sperm hyperactivation. Our results suggest that CRIS interacts during spermiogenesis with Ca(2+)-regulated proteins that--in mature sperm--are involved in flagellar bending. PMID- 24339786 TI - Evidence that masking of synapsis imperfections counterbalances quality control to promote efficient meiosis. AB - Reduction in ploidy to generate haploid gametes during sexual reproduction is accomplished by the specialized cell division program of meiosis. Pairing between homologous chromosomes and assembly of the synaptonemal complex at their interface (synapsis) represent intermediate steps in the meiotic program that are essential to form crossover recombination-based linkages between homologs, which in turn enable segregation of the homologs to opposite poles at the meiosis I division. Here, we challenge the mechanisms of pairing and synapsis during C. elegans meiosis by disrupting the normal 1:1 correspondence between homologs through karyotype manipulation. Using a combination of cytological tools, including S-phase labeling to specifically identify X chromosome territories in highly synchronous cohorts of nuclei and 3D rendering to visualize meiotic chromosome structures and organization, our analysis of trisomic (triplo-X) and polyploid meiosis provides insight into the principles governing pairing and synapsis and how the meiotic program is "wired" to maximize successful sexual reproduction. We show that chromosomes sort into homologous groups regardless of chromosome number, then preferentially achieve pairwise synapsis during a period of active chromosome mobilization. Further, comparisons of synapsis configurations in triplo-X germ cells that are proficient or defective for initiating recombination suggest a role for recombination in restricting chromosomal interactions to a pairwise state. Increased numbers of homologs prolong markers of the chromosome mobilization phase and/or boost germline apoptosis, consistent with triggering quality control mechanisms that promote resolution of synapsis problems and/or cull meiocytes containing synapsis defects. However, we also uncover evidence for the existence of mechanisms that "mask" defects, thus allowing resumption of prophase progression and survival of germ cells despite some asynapsis. We propose that coupling of saturable masking mechanisms with stringent quality controls maximizes meiotic success by making progression and survival dependent on achieving a level of synapsis sufficient for crossover formation without requiring perfect synapsis. PMID- 24339787 TI - Selection on plant male function genes identifies candidates for reproductive isolation of yellow monkeyflowers. AB - Understanding the genetic basis of reproductive isolation promises insight into speciation and the origins of biological diversity. While progress has been made in identifying genes underlying barriers to reproduction that function after fertilization (post-zygotic isolation), we know much less about earlier acting pre-zygotic barriers. Of particular interest are barriers involved in mating and fertilization that can evolve extremely rapidly under sexual selection, suggesting they may play a prominent role in the initial stages of reproductive isolation. A significant challenge to the field of speciation genetics is developing new approaches for identification of candidate genes underlying these barriers, particularly among non-traditional model systems. We employ powerful proteomic and genomic strategies to study the genetic basis of conspecific pollen precedence, an important component of pre-zygotic reproductive isolation among yellow monkeyflowers (Mimulus spp.) resulting from male pollen competition. We use isotopic labeling in combination with shotgun proteomics to identify more than 2,000 male function (pollen tube) proteins within maternal reproductive structures (styles) of M. guttatus flowers where pollen competition occurs. We then sequence array-captured pollen tube exomes from a large outcrossing population of M. guttatus, and identify those genes with evidence of selective sweeps or balancing selection consistent with their role in pollen competition. We also test for evidence of positive selection on these genes more broadly across yellow monkeyflowers, because a signal of adaptive divergence is a common feature of genes causing reproductive isolation. Together the molecular evolution studies identify 159 pollen tube proteins that are candidate genes for conspecific pollen precedence. Our work demonstrates how powerful proteomic and genomic tools can be readily adapted to non-traditional model systems, allowing for genome-wide screens towards the goal of identifying the molecular basis of genetically complex traits. PMID- 24339788 TI - Dual Regulation of the mitotic exit network (MEN) by PP2A-Cdc55 phosphatase. AB - Exit from mitosis in budding yeast is triggered by activation of the key mitotic phosphatase Cdc14. At anaphase onset, the protease separase and Zds1 promote the downregulation of PP2A(Cdc55) phosphatase, which facilitates Cdk1-dependent phosphorylation of Net1 and provides the first wave of Cdc14 activity. Once Cdk1 activity starts to decline, the mitotic exit network (MEN) is activated to achieve full Cdc14 activation. Here we describe how the PP2A(Cdc55) phosphatase could act as a functional link between FEAR and MEN due to its action on Bfa1 and Mob1. We demonstrate that PP2A(Cdc55) regulates MEN activation by facilitating Cdc5- and Cdk1-dependent phosphorylation of Bfa1 and Mob1, respectively. Downregulation of PP2A(Cdc55) initiates MEN activity up to Cdc15 by Bfa1 inactivation. Surprisingly, the premature Bfa1 inactivation observed does not entail premature MEN activation, since an additional Cdk1-Clb2 inhibitory signal acting towards Dbf2-Mob1 activity restrains MEN activity until anaphase. In conclusion, we propose a clear picture of how PP2A(Cdc55) functions affect the regulation of various MEN components, contributing to mitotic exit. PMID- 24339789 TI - A novel intergenic ETnII-beta insertion mutation causes multiple malformations in polypodia mice. AB - Mouse early transposon insertions are responsible for ~10% of spontaneous mutant phenotypes. We previously reported the phenotypes and genetic mapping of Polypodia, (Ppd), a spontaneous, X-linked dominant mutation with profound effects on body plan morphogenesis. Our new data shows that mutant mice are not born in expected Mendelian ratios secondary to loss after E9.5. In addition, we refined the Ppd genetic interval and discovered a novel ETnII-beta early transposon insertion between the genes for Dusp9 and Pnck. The ETn inserted 1.6 kb downstream and antisense to Dusp9 and does not disrupt polyadenylation or splicing of either gene. Knock-in mice engineered to carry the ETn display Ppd characteristic ectopic caudal limb phenotypes, showing that the ETn insertion is the Ppd molecular lesion. Early transposons are actively expressed in the early blastocyst. To explore the consequences of the ETn on the genomic landscape at an early stage of development, we compared interval gene expression between wild type and mutant ES cells. Mutant ES cell expression analysis revealed marked upregulation of Dusp9 mRNA and protein expression. Evaluation of the 5' LTR CpG methylation state in adult mice revealed no correlation with the occurrence or severity of Ppd phenotypes at birth. Thus, the broad range of phenotypes observed in this mutant is secondary to a novel intergenic ETn insertion whose effects include dysregulation of nearby interval gene expression at early stages of development. PMID- 24339790 TI - Identification of sphingolipid metabolites that induce obesity via misregulation of appetite, caloric intake and fat storage in Drosophila. AB - Obesity is defined by excessive lipid accumulation. However, the active mechanistic roles that lipids play in its progression are not understood. Accumulation of ceramide, the metabolic hub of sphingolipid metabolism, has been associated with metabolic syndrome and obesity in humans and model systems. Here, we use Drosophila genetic manipulations to cause accumulation or depletion of ceramide and sphingosine-1-phosphate (S1P) intermediates. Sphingolipidomic profiles were characterized across mutants for various sphingolipid metabolic genes using liquid chromatography electrospray ionization tandem mass spectroscopy. Biochemical assays and microscopy were used to assess classic hallmarks of obesity including elevated fat stores, increased body weight, resistance to starvation induced death, increased adiposity, and fat cell hypertrophy. Multiple behavioral assays were used to assess appetite, caloric intake, meal size and meal frequency. Additionally, we utilized DNA microarrays to profile differential gene expression between these flies, which mapped to changes in lipid metabolic pathways. Our results show that accumulation of ceramides is sufficient to induce obesity phenotypes by two distinct mechanisms: 1) Dihydroceramide (C14:0) and ceramide diene (C14:2) accumulation lowered fat store mobilization by reducing adipokinetic hormone- producing cell functionality and 2) Modulating the S1P: ceramide (C14:1) ratio suppressed postprandial satiety via the hindgut-specific neuropeptide like receptor dNepYr, resulting in caloric intake-dependent obesity. PMID- 24339791 TI - Targeted ablation of CRB1 and CRB2 in retinal progenitor cells mimics Leber congenital amaurosis. AB - Development in the central nervous system is highly dependent on the regulation of the switch from progenitor cell proliferation to differentiation, but the molecular and cellular events controlling this process remain poorly understood. Here, we report that ablation of Crb1 and Crb2 genes results in severe impairment of retinal function, abnormal lamination and thickening of the retina mimicking human Leber congenital amaurosis due to loss of CRB1 function. We show that the levels of CRB1 and CRB2 proteins are crucial for mouse retinal development, as they restrain the proliferation of retinal progenitor cells. The lack of these apical proteins results in altered cell cycle progression and increased number of mitotic cells leading to an increased number of late-born cell types such as rod photoreceptors, bipolar and Muller glia cells in postmitotic retinas. Loss of CRB1 and CRB2 in the retina results in dysregulation of target genes for the Notch1 and YAP/Hippo signaling pathways and increased levels of P120-catenin. Loss of CRB1 and CRB2 result in altered progenitor cell cycle distribution with a decrease in number of late progenitors in G1 and an increase in S and G2/M phase. These findings suggest that CRB1 and CRB2 suppress late progenitor pool expansion by regulating multiple proliferative signaling pathways. PMID- 24339792 TI - Active transport and diffusion barriers restrict Joubert Syndrome-associated ARL13B/ARL-13 to an Inv-like ciliary membrane subdomain. AB - Cilia are microtubule-based cell appendages, serving motility, chemo-/mechano /photo- sensation, and developmental signaling functions. Cilia are comprised of distinct structural and functional subregions including the basal body, transition zone (TZ) and inversin (Inv) compartments, and defects in this organelle are associated with an expanding spectrum of inherited disorders including Bardet-Biedl syndrome (BBS), Meckel-Gruber Syndrome (MKS), Joubert Syndrome (JS) and Nephronophthisis (NPHP). Despite major advances in understanding ciliary trafficking pathways such as intraflagellar transport (IFT), how proteins are transported to subciliary membranes remains poorly understood. Using Caenorhabditis elegans and mammalian cells, we investigated the transport mechanisms underlying compartmentalization of JS-associated ARL13B/ARL 13, which we previously found is restricted at proximal ciliary membranes. We now show evolutionary conservation of ARL13B/ARL-13 localisation to an Inv-like subciliary membrane compartment, excluding the TZ, in many C. elegans ciliated neurons and in a subset of mammalian ciliary subtypes. Compartmentalisation of C. elegans ARL-13 requires a C-terminal RVVP motif and membrane anchoring to prevent distal cilium and nuclear targeting, respectively. Quantitative imaging in more than 20 mutants revealed differential contributions for IFT and ciliopathy modules in defining the ARL-13 compartment; IFT-A/B, IFT-dynein and BBS genes prevent ARL-13 accumulation at periciliary membranes, whereas MKS/NPHP modules additionally inhibit ARL-13 association with TZ membranes. Furthermore, in vivo FRAP analyses revealed distinct roles for IFT and MKS/NPHP genes in regulating a TZ barrier to ARL-13 diffusion, and intraciliary ARL-13 diffusion. Finally, C. elegans ARL-13 undergoes IFT-like motility and quantitative protein complex analysis of human ARL13B identified functional associations with IFT-B complexes, mapped to IFT46 and IFT74 interactions. Together, these findings reveal distinct requirements for sequence motifs, IFT and ciliopathy modules in defining an ARL 13 subciliary membrane compartment. We conclude that MKS/NPHP modules comprise a TZ barrier to ARL-13 diffusion, whereas IFT genes predominantly facilitate ARL-13 ciliary entry and/or retention via active transport mechanisms. PMID- 24339794 TI - And baby makes three: genomic imprinting in plant embryos. PMID- 24339793 TI - Genome-wide screen reveals replication pathway for quasi-palindrome fragility dependent on homologous recombination. AB - Inverted repeats capable of forming hairpin and cruciform structures present a threat to chromosomal integrity. They induce double strand breaks, which lead to gross chromosomal rearrangements, the hallmarks of cancers and hereditary diseases. Secondary structure formation at this motif has been proposed to be the driving force for the instability, albeit the mechanisms leading to the fragility are not well-understood. We carried out a genome-wide screen to uncover the genetic players that govern fragility of homologous and homeologous Alu quasi palindromes in the yeast Saccharomyces cerevisiae. We found that depletion or lack of components of the DNA replication machinery, proteins involved in Fe-S cluster biogenesis, the replication-pausing checkpoint pathway, the telomere maintenance complex or the Sgs1-Top3-Rmi1 dissolvasome augment fragility at Alu IRs. Rad51, a component of the homologous recombination pathway, was found to be required for replication arrest and breakage at the repeats specifically in replication-deficient strains. These data demonstrate that Rad51 is required for the formation of breakage-prone secondary structures in situations when replication is compromised while another mechanism operates in DSB formation in replication-proficient strains. PMID- 24339795 TI - Basolateral Mg2+ extrusion via CNNM4 mediates transcellular Mg2+ transport across epithelia: a mouse model. AB - Transcellular Mg(2+) transport across epithelia, involving both apical entry and basolateral extrusion, is essential for magnesium homeostasis, but molecules involved in basolateral extrusion have not yet been identified. Here, we show that CNNM4 is the basolaterally located Mg(2+) extrusion molecule. CNNM4 is strongly expressed in intestinal epithelia and localizes to their basolateral membrane. CNNM4-knockout mice showed hypomagnesemia due to the intestinal malabsorption of magnesium, suggesting its role in Mg(2+) extrusion to the inner parts of body. Imaging analyses revealed that CNNM4 can extrude Mg(2+) by exchanging intracellular Mg(2+) with extracellular Na(+). Furthermore, CNNM4 mutations cause Jalili syndrome, characterized by recessive amelogenesis imperfecta with cone-rod dystrophy. CNNM4-knockout mice showed defective amelogenesis, and CNNM4 again localizes to the basolateral membrane of ameloblasts, the enamel-forming epithelial cells. Missense point mutations associated with the disease abolish the Mg(2+) extrusion activity. These results demonstrate the crucial importance of Mg(2+) extrusion by CNNM4 in organismal and topical regulation of magnesium. PMID- 24339796 TI - Somatic mtDNA mutation spectra in the aging human putamen. AB - The accumulation of heteroplasmic mitochondrial DNA (mtDNA) deletions and single nucleotide variants (SNVs) is a well-accepted facet of the biology of aging, yet comprehensive mutation spectra have not been described. To address this, we have used next generation sequencing of mtDNA-enriched libraries (Mito-Seq) to investigate mtDNA mutation spectra of putamen from young and aged donors. Frequencies of the "common" deletion and other "major arc" deletions were significantly increased in the aged cohort with the fold increase in the frequency of the common deletion exceeding that of major arc deletions. SNVs also increased with age with the highest rate of accumulation in the non-coding control region which contains elements necessary for translation and replication. Examination of predicted amino acid changes revealed a skew towards pathogenic SNVs in the coding region driven by mutation bias. Levels of the pathogenic m.3243A>G tRNA mutation were also found to increase with age. Novel multimeric tandem duplications that resemble murine control region multimers and yeast rho( ) mtDNAs, were identified in both young and aged specimens. Clonal ~50 bp deletions in the control region were found at high frequencies in aged specimens. Our results reveal the complex manner in which the mitochondrial genome alters with age and provides a foundation for studies of other tissues and disease states. PMID- 24339798 TI - Recommendations from Jane Gitschier's Bookshelf. PMID- 24339797 TI - Contributions of protein-coding and regulatory change to adaptive molecular evolution in murid rodents. AB - The contribution of regulatory versus protein change to adaptive evolution has long been controversial. In principle, the rate and strength of adaptation within functional genetic elements can be quantified on the basis of an excess of nucleotide substitutions between species compared to the neutral expectation or from effects of recent substitutions on nucleotide diversity at linked sites. Here, we infer the nature of selective forces acting in proteins, their UTRs and conserved noncoding elements (CNEs) using genome-wide patterns of diversity in wild house mice and divergence to related species. By applying an extension of the McDonald-Kreitman test, we infer that adaptive substitutions are widespread in protein-coding genes, UTRs and CNEs, and we estimate that there are at least four times as many adaptive substitutions in CNEs and UTRs as in proteins. We observe pronounced reductions in mean diversity around nonsynonymous sites (whether or not they have experienced a recent substitution). This can be explained by selection on multiple, linked CNEs and exons. We also observe substantial dips in mean diversity (after controlling for divergence) around protein-coding exons and CNEs, which can also be explained by the combined effects of many linked exons and CNEs. A model of background selection (BGS) can adequately explain the reduction in mean diversity observed around CNEs. However, BGS fails to explain the wide reductions in mean diversity surrounding exons (encompassing ~100 Kb, on average), implying that there is a substantial role for adaptation within exons or closely linked sites. The wide dips in diversity around exons, which are hard to explain by BGS, suggest that the fitness effects of adaptive amino acid substitutions could be substantially larger than substitutions in CNEs. We conclude that although there appear to be many more adaptive noncoding changes, substitutions in proteins may dominate phenotypic evolution. PMID- 24339800 TI - Alterations in blood glucose and plasma glucagon concentrations during deep brain stimulation in the shell region of the nucleus accumbens in rats. AB - Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is an effective therapy for obsessive compulsive disorder (OCD) and is currently under investigation as a treatment for eating disorders. DBS of this area is associated with altered food intake and pharmacological treatment of OCD is associated with the risk of developing type 2 diabetes. Therefore we examined if DBS of the NAc shell (sNAc) influences glucose metabolism. Male Wistar rats were subjected to DBS, or sham stimulation, for a period of 1 h. To assess the effects of stimulation on blood glucose and glucoregulatory hormones, blood samples were drawn before, during and after stimulation. Subsequently, all animals were used for quantitative assessment of Fos immunoreactivity in the lateral hypothalamic area (LHA) using computerized image analysis. DBS of the sNAc rapidly increased plasma concentrations of glucagon and glucose while sham stimulation and DBS outside the sNAc were ineffective. In addition, the increase in glucose was dependent on DBS intensity. In contrast, the DBS-induced increase in plasma corticosterone concentrations was independent of intensity and region, indicating that the observed DBS-induced metabolic changes were not due to corticosterone release. Stimulation of the sNAc with 200 MUA increased Fos immunoreactivity in the LHA compared to sham or 100 MUA stimulated animals. These data show that DBS of the sNAc alters glucose metabolism in a region- and intensity- dependent manner in association with neuronal activation in the LHA. Moreover, these data illustrate the need to monitor changes in glucose metabolism during DBS-treatment of OCD patients. PMID- 24339799 TI - Inhibition Studies on Enzymes Involved in Isoprenoid Biosynthesis: Focus on Two Potential Drug Targets: DXR and IDI-2 Enzymes. AB - Isoprenoid compounds constitute an immensely diverse group of acyclic, monocyclic and polycyclic compounds that play important roles in all living organisms. Despite the diversity of their structures, this plethora of natural products arises from only two 5-carbon precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). This review will discuss the enzymes in the mevalonate (MVA) and methylerythritol phosphate (MEP) biosynthetic pathways leading to IPP and DMAPP with a particular focus on MEP synthase (DXR) and IPP isomerase (IDI), which are potential targets for the development of antibiotic compounds. DXR is the second enzyme in the MEP pathway and the only one for which inhibitors with antimicrobial activity at pharmaceutically relevant concentrations are known. All of the published DXR inhibitors are fosmidomycin analogues, except for a few bisphosphonates with moderate inhibitory activity. These far, there are no other candidates that target DXR. IDI was first identified and characterised over 40 years ago (IDI-1) and a second convergently evolved isoform (IDI-2) was discovered in 2001. IDI-1 is a metalloprotein found in Eukarya and many species of Bacteria. Its mechanism has been extensively studied. In contrast, IDI-2 requires reduced flavin mononucleotide as a cofactor. The mechanism of action for IDI-2 is less well defined. This review will describe how lead inhibitors are being improved by structure-based drug design and enzymatic assays against DXR to lead to new drug families and how mechanistic probes are being used to address questions about the mechanisms of the isomerases. PMID- 24339802 TI - ICA model order selection of task co-activation networks. AB - Independent component analysis (ICA) has become a widely used method for extracting functional networks in the brain during rest and task. Historically, preferred ICA dimensionality has widely varied within the neuroimaging community, but typically varies between 20 and 100 components. This can be problematic when comparing results across multiple studies because of the impact ICA dimensionality has on the topology of its resultant components. Recent studies have demonstrated that ICA can be applied to peak activation coordinates archived in a large neuroimaging database (i.e., BrainMap Database) to yield whole-brain task-based co-activation networks. A strength of applying ICA to BrainMap data is that the vast amount of metadata in BrainMap can be used to quantitatively assess tasks and cognitive processes contributing to each component. In this study, we investigated the effect of model order on the distribution of functional properties across networks as a method for identifying the most informative decompositions of BrainMap-based ICA components. Our findings suggest dimensionality of 20 for low model order ICA to examine large-scale brain networks, and dimensionality of 70 to provide insight into how large-scale networks fractionate into sub-networks. We also provide a functional and organizational assessment of visual, motor, emotion, and interoceptive task co activation networks as they fractionate from low to high model-orders. PMID- 24339803 TI - Not all that glitters is gold: off-target recombination in the somatostatin-IRES Cre mouse line labels a subset of fast-spiking interneurons. PMID- 24339801 TI - The role of the striatum in social behavior. AB - Where and how does the brain code reward during social behavior? Almost all elements of the brain's reward circuit are modulated during social behavior. The striatum in particular is activated by rewards in social situations. However, its role in social behavior is still poorly understood. Here, we attempt to review its participation in social behaviors of different species ranging from voles to humans. Human fMRI experiments show that the striatum is reliably active in relation to others' rewards, to reward inequity and also while learning about social agents. Social contact and rearing conditions have long-lasting effects on behavior, striatal anatomy and physiology in rodents and primates. The striatum also plays a critical role in pair-bond formation and maintenance in monogamous voles. We review recent findings from single neuron recordings showing that the striatum contains cells that link own reward to self or others' actions. These signals might be used to solve the agency-credit assignment problem: the question of whose action was responsible for the reward. Activity in the striatum has been hypothesized to integrate actions with rewards. The picture that emerges from this review is that the striatum is a general-purpose subcortical region capable of integrating social information into coding of social action and reward. PMID- 24339804 TI - Autobiographical memory: a clinical perspective. AB - Autobiographical memory (ABM) comprises memories of one's own past that are characterized by a sense of subjective time and autonoetic awareness. Although ABM deficits are among the primary symptoms of patients with major psychiatric conditions such as mild cognitive impairment (MCI) and Alzheimer Disease (AD) or chronic schizophrenia large clinical studies are scarce. We therefore summarize and discuss the results of our clinical studies on ABM deficits in the respective conditions. In these studies ABM was assessed by using the same instrument - i.e., the Erweitertes Autobiographisches Gedachtnis Inventar (E-AGI) - thus allowing a direct comparison between diagnostic groups. Episodic ABM, especially the richness of details was impaired already in MCI and in beginning AD. Semantic memories were spared until moderate stages, indicating a dissociation between both memory systems. A recency effect was detectable in cognitively unimpaired subjects and vanished in patients with AD. A similar pattern of deficits was found in patients with chronic schizophrenia but not in patients with major depression. These ABM deficits were not accounted for by gender, or education level and did not apply for the physiological ageing process in otherwise healthy elderly. In conclusion, ABM deficits are frequently found in AD and chronic schizophrenia and primarily involve episodic rather than semantic memories. This dissociation corresponds to the multiple trace theory which hypothesized that these memory functions refer to distinct neuronal systems. The semi-structured interview E-AGI used to discern ABM changes provided a sufficient reliability measures, moreover potential effects of a number of important confounders could be falsified so far. These findings underline the relevance of ABM-assessments in clinical practice. PMID- 24339805 TI - Auditory and visual systems organization in Brodmann Area 8 for gaze-shift control: where we do not see, we can hear. PMID- 24339806 TI - Disentangling conscious and unconscious processing: a subjective trial-based assessment approach. AB - The most common method for assessing similarities and differences between conscious and unconscious processing is to compare the effects of unconscious (perceptually weak) stimuli, with conscious (perceptually strong) stimuli. Awareness of these stimuli is then assessed by objective performance on prime identification tasks. While this approach has proven extremely fruitful in furthering our understanding of unconscious cognition, it also suffers from some critical problems. We present an alternative methodology for comparing conscious and unconscious cognition. We used a priming version of a Stroop paradigm and after each trial, participants gave a subjective rating of the degree to which they were aware of the prime. Based on this trial-by-trial awareness assessment, conscious, uncertain, and unconscious trials were separated. Crucially, in all these conditions, the primes have identical perceptual strength. Significant priming was observed for all conditions, but the effects for conscious trials were significantly stronger, and no difference was observed between uncertain and unconscious trials. Thus, awareness of the prime has a large impact on congruency effects, even when signal strength is controlled for. PMID- 24339807 TI - Music improves verbal memory encoding while decreasing prefrontal cortex activity: an fNIRS study. AB - Listening to music engages the whole brain, thus stimulating cognitive performance in a range of non-purely musical activities such as language and memory tasks. This article addresses an ongoing debate on the link between music and memory for words. While evidence on healthy and clinical populations suggests that music listening can improve verbal memory in a variety of situations, it is still unclear what specific memory process is affected and how. This study was designed to explore the hypothesis that music specifically benefits the encoding part of verbal memory tasks, by providing a richer context for encoding and therefore less demand on the dorsolateral prefrontal cortex (DLPFC). Twenty-two healthy young adults were subjected to functional near-infrared spectroscopy (fNIRS) imaging of their bilateral DLPFC while encoding words in the presence of either a music or a silent background. Behavioral data confirmed the facilitating effect of music background during encoding on subsequent item recognition. fNIRS results revealed significantly greater activation of the left hemisphere during encoding (in line with the HERA model of memory lateralization) and a sustained, bilateral decrease of activity in the DLPFC in the music condition compared to silence. These findings suggest that music modulates the role played by the DLPFC during verbal encoding, and open perspectives for applications to clinical populations with prefrontal impairments, such as elderly adults or Alzheimer's patients. PMID- 24339808 TI - Differential responses in dorsal visual cortex to motion and disparity depth cues. AB - We investigated how interactions between monocular motion parallax and binocular cues to depth vary in human motion areas for wide-field visual motion stimuli (110 * 100 degrees ). We used fMRI with an extensive 2 * 3 * 2 factorial blocked design in which we combined two types of self-motion (translational motion and translational + rotational motion), with three categories of motion inflicted by the degree of noise (self-motion, distorted self-motion, and multiple object motion), and two different view modes of the flow patterns (stereo and synoptic viewing). Interactions between disparity and motion category revealed distinct contributions to self- and object-motion processing in 3D. For cortical areas V6 and CSv, but not the anterior part of MT(+) with bilateral visual responsiveness (MT(+)/b), we found a disparity-dependent effect of rotational flow and noise: When self-motion perception was degraded by adding rotational flow and moderate levels of noise, the BOLD responses were reduced compared with translational self motion alone, but this reduction was cancelled by adding stereo information which also rescued the subject's self-motion percept. At high noise levels, when the self-motion percept gave way to a swarm of moving objects, the BOLD signal strongly increased compared to self-motion in areas MT(+)/b and V6, but only for stereo in the latter. BOLD response did not increase for either view mode in CSv. These different response patterns indicate different contributions of areas V6, MT(+)/b, and CSv to the processing of self-motion perception and the processing of multiple independent motions. PMID- 24339809 TI - Speech monitoring and phonologically-mediated eye gaze in language perception and production: a comparison using printed word eye-tracking. AB - The Perceptual Loop Theory of speech monitoring assumes that speakers routinely inspect their inner speech. In contrast, Huettig and Hartsuiker (2010) observed that listening to one's own speech during language production drives eye movements to phonologically related printed words with a similar time-course as listening to someone else's speech does in speech perception experiments. This suggests that speakers use their speech perception system to listen to their own overt speech, but not to their inner speech. However, a direct comparison between production and perception with the same stimuli and participants is lacking so far. The current printed word eye-tracking experiment therefore used a within subjects design, combining production and perception. Displays showed four words, of which one, the target, either had to be named or was presented auditorily. Accompanying words were phonologically related, semantically related, or unrelated to the target. There were small increases in looks to phonological competitors with a similar time-course in both production and perception. Phonological effects in perception however lasted longer and had a much larger magnitude. We conjecture that this difference is related to a difference in predictability of one's own and someone else's speech, which in turn has consequences for lexical competition in other-perception and possibly suppression of activation in self-perception. PMID- 24339810 TI - Hyperactivation of the habenula as a link between depression and sleep disturbance. AB - Depression occurs frequently with sleep disturbance such as insomnia. Sleep in depression is associated with disinhibition of the rapid eye movement (REM) sleep. Despite the coincidence of the depression and sleep disturbance, neural substrate for depressive behaviors and sleep regulation remains unknown. Habenula is an epithalamic structure regulating the activities of monoaminergic neurons in the brain stem. Since the imaging studies showed blood flow increase in the habenula of depressive patients, hyperactivation of the habenula has been implicated in the pathophysiology of the depression. Recent electrophysiological studies reported a novel role of the habenular structure in regulation of REM sleep. In this article, we propose possible cellular mechanisms which could elicit the hyperactivation of the habenular neurons and a hypothesis that dysfunction in the habenular circuit causes the behavioral and sleep disturbance in depression. Analysis of the animals with hyperactivated habenula would open the door to understand roles of the habenula in the heterogeneous symptoms such as reduced motor behavior and altered REM sleep in depression. PMID- 24339811 TI - Predicting speech fluency and naming abilities in aphasic patients. AB - There is a need to identify biomarkers that predict degree of chronic speech fluency/language impairment and potential for improvement after stroke. We previously showed that the Arcuate Fasciculus lesion load (AF-LL), a combined variable of lesion site and size, predicted speech fluency in patients with chronic aphasia. In the current study, we compared lesion loads of such a structural map (i.e., AF-LL) with those of a functional map [i.e., the functional gray matter lesion load (fGM-LL)] in their ability to predict speech fluency and naming performance in a large group of patients. The fGM map was constructed from functional brain images acquired during an overt speaking task in a group of healthy elderly controls. The AF map was reconstructed from high-resolution diffusion tensor images also from a group of healthy elderly controls. In addition to these two canonical maps, a combined AF-fGM map was derived from summing fGM and AF maps. Each canonical map was overlaid with individual lesion masks of 50 chronic aphasic patients with varying degrees of impairment in speech production and fluency to calculate a functional and structural lesion load value for each patient, and to regress these values with measures of speech fluency and naming. We found that both AF-LL and fGM-LL independently predicted speech fluency and naming ability; however, AF lesion load explained most of the variance for both measures. The combined AF-fGM lesion load did not have a higher predictability than either AF-LL or fGM-LL alone. Clustering and classification methods confirmed that AF lesion load was best at stratifying patients into severe and non-severe outcome groups with 96% accuracy for speech fluency and 90% accuracy for naming. An AF-LL of greater than 4 cc was the critical threshold that determined poor fluency and naming outcomes, and constitutes the severe outcome group. Thus, surrogate markers of impairments have the potential to predict outcomes and can be used as a stratifier in experimental studies. PMID- 24339812 TI - The "Visual Shock" of Francis Bacon: an essay in neuroesthetics. AB - In this paper we discuss the work of Francis Bacon in the context of his declared aim of giving a "visual shock."We explore what this means in terms of brain activity and what insights into the brain's visual perceptive system his work gives. We do so especially with reference to the representation of faces and bodies in the human visual brain. We discuss the evidence that shows that both these categories of stimuli have a very privileged status in visual perception, compared to the perception of other stimuli, including man-made artifacts such as houses, chairs, and cars. We show that viewing stimuli that depart significantly from a normal representation of faces and bodies entails a significant difference in the pattern of brain activation. We argue that Bacon succeeded in delivering his "visual shock" because he subverted the normal neural representation of faces and bodies, without at the same time subverting the representation of man-made artifacts. PMID- 24339813 TI - The potential of corticomuscular and intermuscular coherence for research on human motor control. PMID- 24339814 TI - A plastic corticostriatal circuit model of adaptation in perceptual decision making. AB - The ability to optimize decisions and adapt them to changing environments is a crucial brain function that increase survivability. Although much has been learned about the neuronal activity in various brain regions that are associated with decision making, and about how the nervous systems may learn to achieve optimization, the underlying neuronal mechanisms of how the nervous systems optimize decision strategies with preference given to speed or accuracy, and how the systems adapt to changes in the environment, remain unclear. Based on extensive empirical observations, we addressed the question by extending a previously described cortico-basal ganglia circuit model of perceptual decisions with the inclusion of a dynamic dopamine (DA) system that modulates spike-timing dependent plasticity (STDP). We found that, once an optimal model setting that maximized the reward rate was selected, the same setting automatically optimized decisions across different task environments through dynamic balancing between the facilitating and depressing components of the DA dynamics. Interestingly, other model parameters were also optimal if we considered the reward rate that was weighted by the subject's preferences for speed or accuracy. Specifically, the circuit model favored speed if we increased the phasic DA response to the reward prediction error, whereas the model favored accuracy if we reduced the tonic DA activity or the phasic DA responses to the estimated reward probability. The proposed model provides insight into the roles of different components of DA responses in decision adaptation and optimization in a changing environment. PMID- 24339815 TI - White matter hyperintensities segmentation: a new semi-automated method. AB - White matter hyperintensities (WMH) are brain areas of increased signal on T2 weighted or fluid-attenuated inverse recovery magnetic resonance imaging (MRI) scans. In this study we present a new semi-automated method to measure WMH load that is based on the segmentation of the intensity histogram of fluid-attenuated inversion recovery images. Thirty patients with mild cognitive impairment with variable WMH load were enrolled. The semi-automated WMH segmentation included removal of non-brain tissue, spatial normalization, removal of cerebellum and brain stem, spatial filtering, thresholding to segment probable WMH, manual editing for correction of false positives and negatives, generation of WMH map, and volumetric estimation of the WMH load. Accuracy was quantitatively evaluated by comparing semi-automated and manual WMH segmentations performed by two independent raters. Differences between the two procedures were assessed using Student's t-tests and similarity was evaluated using linear regression model and Dice similarity coefficient (DSC). The volumes of the manual and semi-automated segmentations did not statistically differ (t-value = -1.79, DF = 29, p = 0.839 for rater 1; t-value = 1.113, DF = 29, p = 0.2749 for rater 2), were highly correlated [R (2) = 0.921, F (1,29) = 155.54, p < 0.0001 for rater 1; R (2) = 0.935, F (1,29) = 402.709, p < 0.0001 for rater 2] and showed a very strong spatial similarity (mean DSC = 0.78, for rater 1 and 0.77 for rater 2). In conclusion, our semi-automated method to measure the load of WMH is highly reliable and could represent a good tool that could be easily implemented in routinely neuroimaging analyses to map clinical consequences of WMH. PMID- 24339816 TI - Characteristic interactivity of landiolol, an ultra-short-acting highly selective beta1-blocker, with biomimetic membranes: Comparisons with beta1-selective esmolol and non-selective propranolol and alprenolol. AB - Although beta1-blockers have been perioperatively used to reduce the cardiac disorders associated with general anesthesia, little is known about the mechanistic characteristics of ultra-short-acting highly selective beta1-blocker landiolol. We studied its membrane-interacting property in comparison with other selective and non-selective beta1-blockers. Biomimetic membranes prepared with phospholipids and cholesterol of varying compositions were treated with beta1 selective landiolol and esmolol and non-selective propranolol and alprenolol at 0.5-200 MUM. The membrane interactivity and the antioxidant activity were determined by measuring fluorescence polarization and by peroxidizing membrane lipids with peroxynitrite, respectively. Non-selective beta1-blockers, but not selective ones, intensively acted on 1,2-dipalmitoylphosphatidylcholine (DPPC) liposomal membranes and cardiomyocyte-mimetic membranes to increase the membrane fluidity. Landiolol and its inactive metabolite distinctively decreased the fluidity of DPPC liposomal membranes, suggesting that a membrane-rigidifying effect is attributed to the morpholine moiety in landiolol structure but unlikely to clinically contribute to the beta1-blocking effect of landiolol. Propranolol and alprenolol interacted with lipid raft model membranes, whereas neither landiolol nor esmolol. All drugs fluidized mitochondria-mimetic membranes and inhibited the membrane lipid peroxidation with the potency correlating to their membrane interactivity. Landiolol is characterized as a drug devoid of the interactivity with membrane lipid rafts relating to beta2-adrenergic receptor blockade. The differentiation between beta1-blocking selectivity and non selectivity is compatible with that between membrane non-interactivity and interactivity. The mitochondrial membrane fluidization by landiolol independent of blocking beta1-adrenergic receptors is responsible for the antioxidant cardioprotection common to non-selective and selective beta1-blockers. PMID- 24339817 TI - Branchial Na(+):K(+):2Cl(-) cotransporter 1 and Na(+)/K(+)-ATPase alpha-subunit in a brackish water-type ionocyte of the euryhaline freshwater white-rimmed stingray, Himantura signifer. AB - Himantura signifer is a freshwater stingray which inhabits rivers in Southeast Asia. It can survive in brackish water but not seawater. In brackish water, it becomes partially ureosmotic, but how it maintains its plasma hypoionic to the external medium is enigmatic because of the lack of a rectal gland. Here, we report for the first time the expression of Na(+):K(+):2Cl(-) cotransporter 1 (nkcc1) in the gills of freshwaterH. signifer, and its moderate up-regulation (~2 fold) in response to brackish water (salinity 20) acclimation. The absence of the Ste20-related proline-alanine-rich kinase and oxidation stress response kinase 1 interaction site from the N-terminus of H. signifer Nkcc1 suggested that it might not be effectively activated by stress kinases in response to salinity changes as in more euryhaline teleosts. The increased activity of Nkcc1 during salt excretion in brackish water would lead to an influx of Na(+) into ionocytes, and the maintenance of intracellular Na(+) homeostasis would need the cooperation of Na(+)/K(+)-ATPase (Nka). We demonstrated for the first time the expression of nkaalpha1, nkaalpha2 and nkaalpha3 in the gills of H. signifer, and the up regulation of the mRNA expression of nkaalpha3 and the overall protein abundance of Nkaalpha in response to acclimation to brackish water. Immunofluorescence microscopy revealed the presence of a sub-type of ionocyte, co-expressing Nkcc1 and Nkaalpha, near the base of the secondary lamellae in the gills of H. signifer acclimated to brackish water, but this type of ionocyte was absent from the gills of fish kept in fresh water. Hence, there could be a change in the function of the gills of H. signifer from salt absorption to salt excretion during brackish water acclimation in the absence of a functioning rectal gland. PMID- 24339819 TI - Release the BEESTS: Bayesian Estimation of Ex-Gaussian STop-Signal reaction time distributions. AB - The stop-signal paradigm is frequently used to study response inhibition. In this paradigm, participants perform a two-choice response time (RT) task where the primary task is occasionally interrupted by a stop-signal that prompts participants to withhold their response. The primary goal is to estimate the latency of the unobservable stop response (stop signal reaction time or SSRT). Recently, Matzke et al. (2013) have developed a Bayesian parametric approach (BPA) that allows for the estimation of the entire distribution of SSRTs. The BPA assumes that SSRTs are ex-Gaussian distributed and uses Markov chain Monte Carlo sampling to estimate the parameters of the SSRT distribution. Here we present an efficient and user-friendly software implementation of the BPA-BEESTS-that can be applied to individual as well as hierarchical stop-signal data. BEESTS comes with an easy-to-use graphical user interface and provides users with summary statistics of the posterior distribution of the parameters as well various diagnostic tools to assess the quality of the parameter estimates. The software is open source and runs on Windows and OS X operating systems. In sum, BEESTS allows experimental and clinical psychologists to estimate entire distributions of SSRTs and hence facilitates the more rigorous analysis of stop-signal data. PMID- 24339818 TI - Age does not count: resilience of quantity processing in healthy ageing. AB - Quantity skills have been extensively studied in terms of their development and pathological decline. Recently, numerosity discrimination (i.e., how many items are in a set) has been shown to be resilient to healthy ageing despite relying on inhibitory skills, but whether processing continuous quantities such as time and space is equally well-maintained in ageing participants is not known. Life-long exposure to quantity-related problems may progressively refine proficiency in quantity tasks, or alternatively quantity skills may decline with age. In addition, is not known whether the tight relationship between quantity dimensions typically shown in their interactions is preserved in ageing. To address these questions, two experimental paradigms were used in 38 younger and 32 older healthy adults who showed typical age-related decline in attention, executive function and memory tasks. In both groups we first assessed time and space discrimination independently using a two-choice task (i.e., "Which of two horizontal lines is longer in duration or extension?"), and found that time and space processing were equally accurate in younger and older participants. In a second paradigm, we assessed the relation between different quantity dimensions which were presented as a dynamic pattern of dots independently changing in duration, spatial extension and numerosity. Younger and older participants again showed a similar profile of interaction between number, cumulative area and duration, although older adults showed a greater sensitivity to task-irrelevant information than younger adults in the cumulative area task but lower sensitivity in the duration task. Continuous quantity processing seems therefore resilient to ageing similar to numerosity and to other non-quantity skills like vocabulary or implicit memory; however, ageing might differentially affect different quantity dimensions. PMID- 24339820 TI - Working with(out) a net: improvisational theater and enhanced well-being. PMID- 24339821 TI - Thermal adaptation of decomposer communities in warming soils. AB - Temperature regulates the rate of biogeochemical cycles. One way it does so is through control of microbial metabolism. Warming effects on metabolism change with time as physiology adjusts to the new temperature. I here propose that such thermal adaptation is observed in soil microbial respiration and growth, as the result of universal evolutionary trade-offs between the structure and function of both enzymes and membranes. I review the basis for these trade-offs and show that they, like substrate depletion, are plausible mechanisms explaining soil respiration responses to warming. I argue that controversies over whether soil microbes adapt to warming stem from disregarding the evolutionary physiology of cellular metabolism, and confusion arising from the term thermal acclimation to represent phenomena at the organism- and ecosystem-levels with different underlying mechanisms. Measurable physiological adjustments of the soil microbial biomass reflect shifts from colder- to warmer-adapted taxa. Hypothesized declines in the growth efficiency of soil microbial biomass under warming are controversial given limited data and a weak theoretical basis. I suggest that energy spilling (aka waste metabolism) is a more plausible mechanism for efficiency declines than the commonly invoked increase in maintenance-energy demands. Energy spilling has many fitness benefits for microbes and its response to climate warming is uncertain. Modeled responses of soil carbon to warming are sensitive to microbial growth efficiency, but declines in efficiency mitigate warming-induced carbon losses in microbial models and exacerbate them in conventional models. Both modeling structures assume that microbes regulate soil carbon turnover, highlighting the need for a third structure where microbes are not regulators. I conclude that microbial physiology must be considered if we are to have confidence in projected feedbacks between soil carbon stocks, atmospheric CO2, and climate change. PMID- 24339822 TI - Past and future of a century old Citrus tristeza virus collection: a California citrus germplasm tale. AB - Citrus tristeza virus (CTV) isolates collected from citrus germplasm, dooryard and field trees in California from 1914 have been maintained in planta under quarantine in the Citrus Clonal Protection Program (CCPP), Riverside, California. This collection, therefore, represents populations of CTV isolates obtained over time and space in California. To determine CTV genetic diversity in this context, genotypes of CTV isolates from the CCPP collection were characterized using multiple molecular markers (MMM). Genotypes T30, VT, and T36 were found at high frequencies with T30 and T30+VT genotypes being the most abundant. The MMM analysis did not identify T3 and B165/T68 genotypes; however, biological and phylogenetic analysis suggested some relationships of CCPP CTV isolates with these two genotypes. Phylogenetic analysis of the CTV coat protein (CP) gene sequences classified the tested isolates into seven distinct clades. Five clades were in association with the standard CTV genotypes T30, T36, T3, VT, and B165/T68. The remaining two identified clades were not related to any standard CTV genotypes. Spatiotemporal analysis indicated a trend of reduced genotype and phylogenetic diversity as well as virulence from southern California (SC) at early (1907-1957) in comparison to that of central California (CC) isolates collected from later (1957-2009) time periods. CTV biological characterization also indicated a reduced number and less virulent stem pitting (SP) CTV isolates compared to seedling yellows isolates introduced to California. This data provides a historical insight of the introduction, movement, and genetic diversity of CTV in California and provides genetic and biological information useful for CTV quarantine, eradication, and disease management strategies such as CTV-SP cross protection. PMID- 24339823 TI - Raman spectroscopy in halophile research. AB - Raman spectroscopy plays a major role in robust detection of biomolecules and mineral signatures in halophile research. An overview of Raman spectroscopic investigations in halophile research of the last decade is given here to show advantages of the approach, progress made as well as limits of the technique. Raman spectroscopy is an excellent tool to monitor and identify microbial pigments and other biomolecules in extant and extinct halophile biomass. Studies of bottom gypsum crusts from salterns, native evaporitic sediments, halite inclusions, and endoliths as well as cultures of halophilic microorganisms permitted to understand the content, distribution, and behavior of important molecular species. The first papers describing Raman spectroscopic detection of microbiological and geochemical key markers using portable instruments are highlighted as well. PMID- 24339824 TI - Pathological mobilization and activities of dendritic cells in tumor-bearing hosts: challenges and opportunities for immunotherapy of cancer. AB - A common characteristic of solid tumors is the pathological recruitment of immunosuppressive myeloid cells, which in certain tumors includes dendritic cells (DCs). DCs are of particular interest in the field of cancer immunotherapy because they induce potent and highly specific anti-tumor immune responses, particularly in the early phase of tumorigenesis. However, as tumors progress, these cells can be transformed into regulatory cells that contribute to an immunosuppressive microenvironment favoring tumor growth. Therefore, controlling DC phenotype has the potential to elicit effective anti-tumor responses while simultaneously weakening the tumor's ability to protect itself from immune attack. This review focuses on the dual nature of DCs in the tumor microenvironment, the regulation of DC phenotype, and the prospect of modifying DCs in situ as a novel immunotherapeutic approach. PMID- 24339825 TI - Dendritic cell-targeted approaches to modulate immune dysfunction in the tumor microenvironment. AB - There has been enormous progress this past decade in the understanding of the biology of dendritic cells (DCs) along with increasing attention for the development of novel dendritic cell (DC)-based cancer therapies. However, the clinical impact of DC-based vaccines remains to be established. This limited success could be explained by suboptimal conditions for generating potent immunostimulatory DCs as well as immune suppression mediated by the tumor microenvironment (TME). Therefore, strategies that optimize the potency of DC vaccines along with newly described therapies that target the TME in order to overcome immune dysfunction may provide durable tumor-specific immunity. These novel interventions hold the most promise for successful cancer immunotherapies. PMID- 24339826 TI - Granuloma formation in pulmonary sarcoidosis. AB - Sarcoidosis is a granulomatous disorder of unknown cause, affecting multiple organs, but mainly the lungs. The exact order of immunological events remains obscure. Reviewing current literature, combined with careful clinical observations, we propose a model for granuloma formation in pulmonary sarcoidosis. A tight collaboration between macrophages, dendritic cells, and lymphocyte subsets, initiates the first steps toward granuloma formation, orchestrated by cytokines and chemokines. In a substantial part of pulmonary sarcoidosis patients, granuloma formation becomes an on-going process, leading to debilitating disease, and sometimes death. The immunological response, determining granuloma sustainment is not well understood. An impaired immunosuppressive function of regulatory T cells has been suggested to contribute to the exaggerated response. Interestingly, therapeutical agents commonly used in sarcoidosis, such as glucocorticosteroids and anti-TNF agents, interfere with granuloma integrity and restore the immune homeostasis in autoimmune disorders. Increasing insight into their mechanisms of action may contribute to the search for new therapeutical targets in pulmonary sarcoidosis. PMID- 24339827 TI - TWEAK/Fn14 and Non-Canonical NF-kappaB Signaling in Kidney Disease. AB - The incidence of acute kidney injury (AKI) and chronic kidney disease (CKD) is increasing. However, there is no effective therapy for AKI and current approaches only slow down, but do not prevent progression of CKD. TWEAK is a TNF superfamily cytokine. A solid base of preclinical data suggests a role of therapies targeting the TWEAK or its receptor Fn14 in AKI and CKD. In particular TWEAK/Fn14 targeting may preserve renal function and decrease cell death, inflammation, proteinuria, and fibrosis in mouse animal models. Furthermore there is clinical evidence for a role of TWEAK in human kidney injury including increased tissue and/or urinary levels of TWEAK and parenchymal renal cell expression of the receptor Fn14. In this regard, clinical trials of TWEAK targeting are ongoing in lupus nephritis. Nuclear factor-kappa B (NF-kappaB) activation plays a key role in TWEAK-elicited inflammatory responses. Activation of the non-canonical NF-kappaB pathway is a critical difference between TWEAK and TNF. TWEAK activation of the non-canonical NF-kappaB pathways promotes inflammatory responses in tubular cells. However, there is an incomplete understanding of the role of non-canonical NF-kappaB activation in kidney disease and on its contribution to TWEAK actions in vivo. PMID- 24339828 TI - Tim-3: an activation marker and activation limiter of innate immune cells. AB - Tim-3 was initially identified on activated Th1, Th17, and Tc1 cells and induces T cell death or exhaustion after binding to its ligand, Gal-9. The observed relationship between dysregulated Tim-3 expression on T cells and the progression of many clinical diseases has identified this molecule as an important target for intervention in adaptive immunity. Recent data have shown that it also plays critical roles in regulating the activities of macrophages, monocytes, dendritic cells, mast cells, natural killer cells, and endothelial cells. Although the underlying mechanisms remain unclear, dysregulation of Tim-3 expression on these innate immune cells leads to an excessive or inhibited inflammatory response and subsequent autoimmune damage or viral or tumor evasion. In this review, we focus on the expression and function of Tim-3 on innate immune cells and discuss (1) how Tim-3 is expressed and regulated on different innate immune cells; (2) how it affects the activity of different innate immune cells; and (3) how dysregulated Tim-3 expression on innate immune cells affects adaptive immunity and disease progression. Tim-3 is involved in the optimal activation of innate immune cells through its varied expression. A better understanding of the physiopathological role of the Tim-3 pathway in innate immunity will shed new light on the pathogenesis of clinical diseases, such as autoimmune diseases, chronic viral infections, and cancer, and suggest new approaches to intervention. PMID- 24339829 TI - Responses of nitrogen metabolism and seed nutrition to drought stress in soybean genotypes differing in slow-wilting phenotype. AB - Recent advances in soybean breeding have resulted in genotypes that express the slow-wilting phenotype (trait) under drought stress conditions. The physiological mechanisms of this trait remain unknown due to the complexity of trait * environment interactions. The objective of this research was to investigate nitrogen metabolism and leaf and seed nutrients composition of the slow-wilting soybean genotypes under drought stress conditions. A repeated greenhouse experiment was conducted using check genotypes: NC-Roy (fast wilting), Boggs (intermediate in wilting); and NTCPR94-5157 and N04-9646 (slow-wilting, SLW) genotypes. Plants were either well-watered or drought stressed. Results showed that under well-watered conditions, nitrogen fixation (NF), nitrogen assimilation (NA), and leaf and seed composition differed between genotypes. Under drought stress, NF and NA were higher in NTCPR94-5157 and N04-9646 than in NC-Roy and Boggs. Under severe water stress, however, NA was low in all genotypes. Leaf water potential was significantly lower in checks (-2.00 MPa) than in the SLW genotypes (-1.68 MPa). Leaf and seed concentrations of K, P, Ca, Cu, Na, B were higher in SLW genotypes than in the checks under drought stress conditions. Seed protein, oleic acid, and sugars were higher in SLW genotypes, and oil, linoleic and linolenic acids were lower in SLW genotypes. This research demonstrated that K, P, Ca, Cu, Na, and B may be involved in SLW trait by maintaining homeostasis and osmotic regulation. Maintaining higher leaf water potential in NTCPR94-5157 and N04-9646 under drought stress could be a possible water conservation mechanism to maintain leaf turgor pressure. The increase in osmoregulators such as minerals, raffinose, and stachyose, and oleic acid could be beneficial for soybean breeders in selecting for drought stress tolerance. PMID- 24339830 TI - Plant species distributions along environmental gradients: do belowground interactions with fungi matter? AB - The distribution of plants along environmental gradients is constrained by abiotic and biotic factors. Cumulative evidence attests of the impact of biotic factors on plant distributions, but only few studies discuss the role of belowground communities. Soil fungi, in particular, are thought to play an important role in how plant species assemble locally into communities. We first review existing evidence, and then test the effect of the number of soil fungal operational taxonomic units (OTUs) on plant species distributions using a recently collected dataset of plant and metagenomic information on soil fungi in the Western Swiss Alps. Using species distribution models (SDMs), we investigated whether the distribution of individual plant species is correlated to the number of OTUs of two important soil fungal classes known to interact with plants: the Glomeromycetes, that are obligatory symbionts of plants, and the Agaricomycetes, that may be facultative plant symbionts, pathogens, or wood decayers. We show that including the fungal richness information in the models of plant species distributions improves predictive accuracy. Number of fungal OTUs is especially correlated to the distribution of high elevation plant species. We suggest that high elevation soil show greater variation in fungal assemblages that may in turn impact plant turnover among communities. We finally discuss how to move beyond correlative analyses, through the design of field experiments manipulating plant and fungal communities along environmental gradients. PMID- 24339831 TI - Circ2Traits: a comprehensive database for circular RNA potentially associated with disease and traits. AB - Circular RNAs are new players in regulation of post transcriptional gene expression. Animal genomes express many circular RNAs from diverse genomic locations. A recent study has validated a fairly large number of circular RNAs in human, mouse, and nematode. Circular RNAs play a crucial role in fine tuning the level of miRNA mediated regulation of gene expression by sequestering the miRNAs. Their interaction with disease associated miRNAs indicates that circular RNAs are important for disease regulation. In this paper we studied the potential association of circular RNAs (circRNA) with human diseases in two different ways. Firstly, the interactions of circRNAs with disease associated miRNAs were identified, following which the likelihood of a circRNA being associated with a disease was calculated. For the miRNAs associated with individual diseases, we constructed a network of predicted interactions between the miRNAs and protein coding, long non-coding and circular RNA genes. We carried out gene ontology (GO) enrichment analysis on the set of protein coding genes in the miRNA- circRNA interactome of individual diseases to check the enrichment of genes associated with particular biological processes. Secondly, disease associated SNPs were mapped on circRNA loci, and Argonaute (Ago) interaction sites on circular RNAs were identified. We compiled a database of disease-circRNA association in Circ2Traits (http://gyanxet-beta.com/circdb/), the first comprehensive knowledgebase of potential association of circular RNAs with diseases in human. PMID- 24339832 TI - Estimating carbon dioxide fluxes from temperate mountain grasslands using broad band vegetation indices. AB - The broad-band normalised difference vegetation index (NDVI) and the simple ratio (SR) were calculated from measurements of reflectance of photosynthetically active and short-wave radiation at two temperate mountain grasslands in Austria and related to the net ecosystem CO2 exchange (NEE) measured concurrently by means of the eddy covariance method. There was no significant statistical difference between the relationships of midday mean NEE with narrow- and broad band NDVI and SR, measured during and calculated for that same time window, respectively. The skill of broad-band NDVI and SR in predicting CO2 fluxes was higher for metrics dominated by gross photosynthesis and lowest for ecosystem respiration, with NEE in between. A method based on a simple light response model whose parameters were parameterised based on broad-band NDVI allowed to improve predictions of daily NEE and is suggested to hold promise for filling gaps in the NEE time series. Relationships of CO2 flux metrics with broad-band NDVI and SR however generally differed between the two studied grassland sites indicting an influence of additional factors not yet accounted for. PMID- 24339833 TI - BVOC fluxes above mountain grassland. AB - Grasslands comprise natural tropical savannah over managed temperate fields to tundra and cover one quarter of the Earth's land surface. Plant growth, maintenance and decay result in volatile organic compound (VOCs) emissions to the atmosphere. Furthermore, biogenic VOCs (BVOCs) are emitted as a consequence of various environmental stresses including cutting and drying during harvesting. Fluxes of BVOCs were measured with a proton-transfer-reaction-mass-spectrometer (PTR-MS) over temperate mountain grassland in Stubai Valley (Tyrol, Austria) over one growing season (2008). VOC fluxes were calculated from the disjunct PTR-MS data using the virtual disjunct eddy covariance method and the gap filling method. Methanol fluxes obtained with the two independent flux calculation methods were highly correlated (y = 0.95*-0.12, R2 = 0.92). Methanol showed strong daytime emissions throughout the growing season - with maximal values of 9.7 nmol m-2 s-1, methanol fluxes from the growing grassland were considerably higher at the beginning of the growing season in June compared to those measured during October (2.5 nmol m-2 s-1). Methanol was the only component that exhibited consistent fluxes during the entire growing periods of the grass. The cutting and drying of the grass increased the emissions of methanol to up to 78.4 nmol m-2 s 1. In addition, emissions of acetaldehyde (up to 11.0 nmol m-2 s-1), and hexenal (leaf aldehyde, up to 8.6 nmol m-2 s-1) were detected during/after harvesting. PMID- 24339835 TI - Design and development of a prototype electrotherapy device. AB - This article describes a complete prototype system that can be used in electrotherapy treatments, that is, in medical treatments involving electric currents. The system is composed of two main blocks: the master and the slave. The Master block, whose main component is a CPU, controls the user interface. The Slave block, which is composed of a microcontroller and a wave generator, produces the appropriated voltages and currents compatible with the desired treatment. The whole system is powered by a 12 V power supply and the output signal voltage ranges between -100 V and 100 V. Despite the prototype being able of performing all the electrotherapy treatments in the low-medium frequency ranges, it was tested in aesthetic mesotherapy, namely in anticellulite, located anticellulite, antistretch, and antiflaccidity. In these treatments, the output signal is composed of an overlap of two frequencies: the first one is selected in the range of 1.2 kHz - 1.8 kHz and the second in the range of 0.07 Hz - 2 Hz. The system was tested in a clinical environment with real patients. It showed good results both in effectiveness of treatments and in terms of pain suffered by the patients. PMID- 24339836 TI - Human CT Measurements of Structure/Electrode Position Changes During Respiration with Electrical Impedance Tomography. AB - For pulmonary applications of Electrical Impedance Tomography (EIT) systems, the electrodes are placed around the chest in a 2D ring, and the images are reconstructed based on the assumptions that the object is rigid and the measured resistivity change in EIT images is only caused by the actual resistivity change of tissue. Structural changes are rarely considered. Previous studies have shown that structural changes which result in tissue/organ and electrode position changes tend to introduce artefacts to EIT images of the thorax. Since EIT reconstruction is an ill-posed inverse problem, any small inaccurate assumptions of object may cause large artefacts in reconstructed images. Accurate information on structure/electrode position changes is a need to understand factors contributing to the measured resistivity changes and to improve EIT reconstruction algorithm. Our previous study using MRI technique showed that chest expansion leads to electrode and tissue/organ movements but not significant as proposed. The accuracy of the measurements by MRI may be limited by its relatively low temporal and spatial resolution. In this study, structure/electrode position changes during respiration cycle in patients who underwent chest CT scans are further investigated. For each patient, sixteen fiduciary markers are equally spaced around the surface, the same as the electrode placement for EIT measurements. A CT scanner with respiration-gated ability is used to acquire images of the thorax. CT thoracic images are retrospectively reconstructed corresponding temporally to specific time periods within respiration cycle (from 0% to 90%, every 10%). The average chest expansions are 2 mm in anterior-posterior and -1.6 mm in lateral directions. Inside tissue/organ move down 9.0+/-2.5 mm with inspiration of tidal volume (0.54+/-0.14 liters), ranging from 6 mm to 12 mm. During normal quiet respiration, electrode position changes are smaller than expected. No general patterns of electrode position changes are observed. The results in this study provide guidelines for accommodating the motion that may introduce artefacts to EIT images. PMID- 24339834 TI - Meta-analysis of safety for low event-rate binomial trials. AB - This article focuses on meta-analysis of low event-rate binomial trials. We introduce two forms of random effects: (1) 'studies at random' (SR), where we assume no more than independence between studies; and (2) 'effects at random' (ER), which forces the effect size distribution to be independent of the study design. On the basis of the summary estimates of proportions, we present both unweighted and study-size weighted methods, which, under SR, target different population parameters. We demonstrate mechanistically that the popular DerSimonian-Laird (DL) method, as DL actually warned in their paper, should never be used in this setting. We conducted a survey of the major cardiovascular literature on low event-rate studies and found that DL using odds ratios or relative risks to be the clear method of choice. We looked at two high profile examples from diabetes and cancer, respectively, where the choice of weighted versus unweighted methods makes a large difference. A large simulation study supports the accuracy of the coverage of our approximate confidence intervals. We recommend that before looking at their data, users should prespecify which target parameter they intend to estimate (weighted vs. unweighted) but estimate the other as a secondary analysis. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 24339837 TI - A New Hybrid Viscoelastic Soft Tissue Model based on Meshless Method for Haptic Surgical Simulation. AB - This paper proposes a hybrid soft tissue model that consists of a multilayer structure and many spheres for surgical simulation system based on meshless. To improve accuracy of the model, tension is added to the three-parameter viscoelastic structure that connects the two spheres. By using haptic device, the three-parameter viscoelastic model (TPM) produces accurate deformationand also has better stress-strain, stress relaxation and creep properties. Stress relaxation and creep formulas have been obtained by mathematical formula derivation. Comparing with the experimental results of the real pig liver which were reported by Evren et al. and Amy et al., the curve lines of stress-strain, stress relaxation and creep of TPM are close to the experimental data of the real liver. Simulated results show that TPM has better real-time, stability and accuracy. PMID- 24339838 TI - Type of Valvular Heart Disease Requiring Surgery in the 21st Century: Mortality and Length-of-Stay Related to Surgery. AB - AIM: While the incidence of rheumatic heart disease has declined dramatically over the last half-century, the number of valve surgeries has not changed. This study was undertaken to define the most common type of valvular heart disease requiring surgery today, and determine in-hospital surgical mortality and length of-stay (LOS) for isolated aortic or mitral valve surgery in a United States tertiary-care hospital. METHODS: Patients with valve surgery between January 2002 to June 2008 at The Ohio State University Medical Center were studied. Patients only with isolated aortic or mitral valve surgery were analyzed. RESULTS: From 915 patients undergoing at least aortic or mitral valve surgery, the majority had concomitant cardiac proce-dures mostly coronary artery bypass grafting (CABG); only 340 patients had isolated aortic (n=204) or mitral (n=136) valve surgery. In hospital surgical mortality for mitral regurgitation (n=119), aortic stenosis (n=151), aortic insufficiency (n=53) and mitral stenosis (n=17) was 2.5% (replacement 3.4%; repair 1.6%), 3.9%, 5.6% and 5.8%, respectively (p=NS). Median LOS for aortic insufficiency, aortic stenosis, mitral regurgitation, and mitral stenosis was 7, 8, 9 (replacement 11.5; repair 7) and 11 days, respectively (p<0.05 for group). In-hospital surgical mortality for single valve surgery plus CABG was 10.2% (p<0.005 compared to single valve surgery). CONCLUSIONS: Aortic stenosis and mitral regurgitation are the most common valvular lesions requiring surgery today. Surgery for isolated aortic or mitral valve disease has low in hospital mortality with modest LOS. Concomitant CABG with valve surgery increases mortality substantially. Hospital analysis is needed to monitor quality and stimulate improvement among Institutions. PMID- 24339839 TI - Vitamin B12 supplementation in treating major depressive disorder: a randomized controlled trial. AB - BACKGROUND/OBJECTIVE: Recent literature has identified links between vitamin B12 deficiency and depression.We compared the clinical response of SSRI-monotherapy with that of B12-augmentation in a sample of depressed patients with low normal B12 levels who responded inadequately to the first trial with the SSRIs. METHODS: Patients with depression and low normal B12 levels were randomized to a control arm (antidepressant only) or treatment arm (antidepressants and injectable vitamin B12 supplementation). RESULTS: A total of 199 depressed patients were screened. Out of 73 patients with low normal B12 levels 34 (47%) were randomized to the treatment group while 39 (53%) were randomized to the control arm. At three months follow up 100% of the treatment group showed at least a 20% reduction in HAM-D score, while only 69% in the control arm showed at least a 20% reduction in HAM-D score (p<0.001). The findings remained significant after adjusting for baseline HAM-D score (p=0.001). CONCLUSION: Vitamin B12 supplementation with antidepressants significantly improved depressive symptoms in our cohort. PMID- 24339840 TI - High Fat Diet Regulation of beta-Cell Proliferation and beta-Cell Mass. AB - Type 2 Diabetes (T2D) is characterized by relative insulin insufficiency, caused when peripheral tissues such as liver, muscle, and adipocytes have a decreased response to insulin. One factor that elevates the risk for insulin resistance and T2D is obesity. In obese patients without T2D and initially in people who develop T2D, pancreatic beta-cells are able to compensate for insulin resistance by increasing beta-cell mass, effected by increased proliferation and hypertrophy, as well as increased insulin secretion per beta-cell. In patients that go on to develop T2D, however, this initial period of compensation is followed by beta cell failure due to decreased proliferation and increased apoptosis. The forkhead box transcription factor FoxM1 is required for beta-cell replication in mice after four weeks of age, during pregnancy, and after partial pancreatectomy. We investigated whether it is also required for beta-cell proliferation due to diet induced obesity. PMID- 24339841 TI - Therapeutic Strategies to Increase Human beta-Cell Growth and Proliferation by Regulating mTOR and GSK-3/beta-Catenin Pathways. AB - This perspective delineates approaches to develop therapeutic strategies to stimulate the proliferative potential of adult human beta-cells in vitro. Previous findings demonstrated that nutrients, through regulation of mTOR signaling, promote regenerative processes including DNA synthesis, cell cycle progression and beta-cell proliferation in rodent islets but rarely in human islets. Recently, we discovered that regulation of the Wnt/GSK-3/beta-catenin pathway by directly inhibiting GSK-3 with pharmacologic agents, in combination with nutrient activation of mTOR, was required to increase growth and proliferation in human islets. Studies also revealed that nuclear translocation of beta-catenin in response to GSK-3 inhibition regulated these processes and was rapamycin sensitive, indicating a role for mTOR. Human islets displayed a high level of insulin resistance consistent with the inability of exogenous insulin to activate Akt and engage the Wnt pathway by GSK-3 inhibition. This insulin resistance in human islets is not present in rodent islets and may explain the differential requirement in human islets to inhibit GSK-3 to enhance these regenerative processes. Human islets exhibited normal insulin secretion but a loss of insulin content, which was independent of all treatment conditions. The loss of insulin content may be related to insulin resistance, the isolation process or culture conditions. In this perspective, we provide strategies to enhance the proliferative capacity of adult human beta-cells and highlight important differences between human and rodent islets: the lack of a nutrient response, requirement for direct GSK-3 inhibition, insulin resistance and loss of insulin content that emphasize the physiological significance of conducting studies in human islets. PMID- 24339842 TI - DETERMINANTS OF CUTANEOUS INJECTION-RELATED INFECTIONS AMONG INJECTION DRUG USERS AT AN EMERGENCY DEPARTMENT. AB - INTRODUCTION: Cutaneous injection-related infections (CIRI) are a primary reason injection drug users (IDU) access the emergency department (ED). METHODOLOGY: Using Cox proportional hazard regression, we examined predictors of ED use for CIRI, stratified by sex, among 1083 supervised injection facility (SIF) users. RESULTS: Over a four-year period, 289 (27%) visited the ED for CIRI, yielding an incidence density for females of 23.8 (95% confidence interval (CI): 19.3 - 29.0) and males of 19.2 per 100 person-years (95% CI: 16.7 - 22.1). Factors associated with ED use for CIRI among females included residing in the Downtown Eastside (DTES) (adjusted hazard ratio [AHR] = 2.06 [1.13 - 3.78]) and being referred to hospital by SIF nurses (AHR = 4.48 [2.76 - 7.30]). Among males, requiring assistance with injection (AHR = 1.38 [1.01 - 1.90]), being HIV-positive (AHR = 1.85 [1.34 - 2.55]), and being referred to hospital by SIF nurses (AHR = 2.97 [1.93 - 4.57]) were associated with an increased likelihood of an ED visit for CIRI. CONCLUSION: These results suggest SIF nurses have facilitated referral of hospital treatment for CIRI, highlighting the need for continued development of efficient and collaborative efforts to reduce the burden of CIRI. PMID- 24339843 TI - Staged subtalar fusion for severe calcaneus fractures with bone loss. AB - BACKGROUND: With high energy fractures to the calcaneus there is the potential for significant bone loss. The loss of bone can make it difficult to fully regain calcaneal alignment. In addition these fractures are often associated with significant soft tissue injury. These two factors make it difficult to address this injury in a single stage, and can have significant complications. To address these issues our initial goal in treatment has been restoration of calcaneal alignment and stabilization of the surrounding soft tissue, followed by delayed/staged subtalar arthrodesis. METHODS: Patients with calcaneus fractures treated by a single surgeon from 2002 to 2012 were reviewed. Injuries which were found to have medial extrusion of the posterior facet and bone loss, and subsequently underwent a staged protocol involving early provisional fixation and late subtalar fusion were included. RESULTS: We treated 6 calcaneus fractures with bone loss. All patients were treated with staged subtalar fusion after initial irrigation and debridement and provisional fixation. No soft-tissue complications were noted after the fusion procedure in any of the six cases. Fusion occurred in all six patients at an average of 20.6 weeks (range, 13-23 weeks). All patients were able to ambulate and wear a regular shoe by one year following the initial injury. CONCLUSION: It is important in the high energy calcaneus fracture to assess for both soft tissue integrity and bone loss. A thorough debridement of both the soft tissues and any devitalized bone should be performed as well as provisional fixation which attempts to restore near normal calcaneal anatomy. Definitive fusion should not be performed until the soft tissues have fully recovered. PMID- 24339844 TI - The Advantage of a Total Knee Arthroplasty with Rotating Platform is Only Theoretical: Prospective Analysis of 1,152 Arthroplasties. AB - BACKGROUND: The aim of total knee surgery is to provide patients with end-stage osteoarthritis of the knee with both pain relief and a functional range of motion with a securely fixed prosthesis for the long term. Many types of implants are designed to achieve these goals. Only clinical outcome studies are able to substantiate the superiority of one design over another. Our primary research question was to determine whether patients receiving a rotating platform implant had a better functional outcome. METHODS: A total of 1,152 Performance Total Knee Arthroplastiesin 943 patients were studied prospectively. In 561 cases, the cruciate retaining model (CR) was used. In 591 cases the cruciate substituting with posterior-stabilized model (PS) was implanted (324 cases with a fixed bearing (PSFB) and 267 cases with a rotating platform (PSRP)). RESULTS: The Clinical KSS score was similar for the three types at 1, 5, 10 and 15 years post operatively. The Functional score also remained similar for all types until 10 years; at 15 years functional results of the CR group decreased. CONCLUSIONS: Neither clinically nor radiographically did the use of a rotating platform prove to be more advantageous than fixed bearing tibial components. Thus, the advantage of a Total Knee Arthroplasty with Rotating Platform remains theoretical. PMID- 24339845 TI - Direct evidence of progressive cardiac dysfunction in a transgenic mouse model of Huntington's disease. AB - HD is a progressive genetic neurological disorder, characterized by motor as well as cognitive impairments. The gene carrying the mutation causing Huntington's disease (HD) is not brain specific, and there is increasing evidence for peripheral, as well as brain pathology in this disorder. Here, we used in vivo and ex vivo techniques to assess the cardiac function of mice transgenic for the HD mutation. Using magnetic resonance imaging (MRI) of the beating heart, we show that abnormalities previously reported in end-stage mice are present by mid stages of the disease. We also found abnormalities that have not been hitherto reported, including changes in cardiac efficiency and a mechanical distortion of the beating heart. Using the Langendorff preparation, we show reduced coronary blood flow, impaired myocardial contractility and reduced left ventricular developed pressure in HD mouse hearts. Together, our findings suggest that there is significant pathology of the HD mouse heart, even by mid stages of disease. Previous clinical research has demonstrated that the risk of cognitive symptoms increases markedly in patients with heart failure. R6/2 mice show significant progressive cognitive abnormalities, so we hypothesize that cardiac pathology in the R6/2 mouse may contribute, not only to their progressive decline and death, but also to their cognitive dysfunction. We suggest that closer attention should be paid to cardiovascular symptoms in HD patients. PMID- 24339846 TI - Dielectrophoresis based discrimination of human embryonic stem cells from differentiating derivatives. AB - Assessment of the dielectrophoresis (DEP) cross-over frequency (f xo), cell diameter, and derivative membrane capacitance (C m) values for a group of undifferentiated human embryonic stem cell (hESC) lines (H1, H9, RCM1, RH1), and for a transgenic subclone of H1 (T8) revealed that hESC lines could not be discriminated on their mean f xo and C m values, the latter of which ranged from 14 to 20 mF/m(2). Differentiation of H1 and H9 to a mesenchymal stem cell-like phenotype resulted in similar significant increases in mean C m values to 41-49 mF/m(2) in both lines (p < 0.0001). BMP4-induced differentiation of RCM1 to a trophoblast cell-like phenotype also resulted in a distinct and significant increase in mean C m value to 28 mF/m(2) (p < 0.0001). The progressive transition to a higher membrane capacitance was also evident after each passage of cell culture as H9 cells transitioned to a mesenchymal stem cell-like state induced by growth on a substrate of hyaluronan. These findings confirm the existence of distinctive parameters between undifferentiated and differentiating cells on which future application of dielectrophoresis in the context of hESC manufacturing can be based. PMID- 24339847 TI - Bacterial aggregation and biofilm formation in a vortical flow. AB - Bacterial aggregation and patchiness play an important role in a variety of ecological processes such as competition, adaptation, epidemics, and succession. Here, we demonstrate that hydrodynamics of their environment can lead to their aggregation. This is specially important since microbial habitats are rarely at rest (e.g., ocean, blood stream, flow in porous media, and flow through membrane filtration processes). In order to study the dynamics of bacterial collection in a vortical flow, we utilize a microfluidic system to mimic some of the important microbial conditions at ecologically relevant spatiotemporal scales. We experimentally demonstrate the formation of "ring"-shaped bacterial collection patterns and subsequently the formation of biofilm streamers in a microfluidic system. Acoustic streaming of a microbubble is used to generate a vortical flow in a microchannel. Due to bacteria's finite-size, the microorganisms are directed to closed streamlines and trapped in the vortical flow. The collection of bacteria in the vortices occurs in a matter of seconds, and unexpectedly, triggers the formation of biofilm streamers within minutes. Swimming bacteria have a competitive advantage to respond to their environmental conditions. In order to investigate the role of bacterial motility on the rate of collection, two strains of Escherichia coli bacteria with different motilities are used. We show that the bacterial collection in a vortical flow is strongly pronounced for high motile bacteria. PMID- 24339848 TI - Dielectrophoretic properties of engineered protein patterned colloidal particles. AB - This work determines the dielectrophoretic response of surface modified polystyrene and silica colloidal particles by experimentally measuring their Clausius-Mossotti factors. Commercial charged particles, fabricated ones coated with fibronectin, and Janus particles that have been grafted with fibronectin on one side only were investigated. We show that the dielectrophoretic response of such particles can be controlled by the modification of the chemistry or the anisotropy of their surface. Moreover, by modelling the polarizabilities of those particles, the dielectric parameters of the particles and the grafted layer of protein can be measured. PMID- 24339849 TI - Multi-function microsystem for cells migration analysis and evaluation of photodynamic therapy procedure in coculture. AB - Cell migration is an important physiological process, which is involved in cancer metastasis. Therefore, the investigation of cell migration may lead to the development of novel therapeutic approaches. In this study, we have successfully developed a microsystem for culture of two cell types (non-malignant and carcinoma) and for analysis of cell migration dependence on distance between them. Finally, we studied quantitatively the influence of photodynamic therapy (PDT) procedures on the viability of pairs of non-malignant (MRC5 or Balb/3T3) and carcinoma (A549) cells coculture. The proposed geometry of the microsystem allowed for separate introduction of two cell lines and analysis of cells migration dependence on distance between the cells. We found that a length of connecting microchannel has an influence on cell migration and viability of non malignant cells after PDT procedure. Summarizing, the developed microsystem can constitute a new tool for carrying out experiments, which offers a few functions: cell migration analysis, carcinoma and non-malignant cells coculture, and evaluation of PDT procedure in the various steps of cell migration. PMID- 24339850 TI - Selective cell capture and analysis using shallow antibody-coated microchannels. AB - Demand for analysis of rare cells such as circulating tumor cells in blood at the single molecule level has recently grown. For this purpose, several cell separation methods based on antibody-coated micropillars have been developed (e.g., Nagrath et al., Nature 450, 1235-1239 (2007)). However, it is difficult to ensure capture of targeted cells by these methods because capture depends on the probability of cell-micropillar collisions. We developed a new structure that actively exploits cellular flexibility for more efficient capture of a small number of cells in a target area. The depth of the sandwiching channel was slightly smaller than the diameter of the cells to ensure contact with the channel wall. For cell selection, we used anti-epithelial cell adhesion molecule antibodies, which specifically bind epithelial cells. First, we demonstrated cell capture with human promyelocytic leukemia (HL-60) cells, which are relatively homogeneous in size; in situ single molecule analysis was verified by our rolling circle amplification (RCA) method. Then, we used breast cancer cells (SK-BR-3) in blood, and demonstrated selective capture and cancer marker (HER2) detection by RCA. Cell capture by antibody-coated microchannels was greater than with negative control cells (RPMI-1788 lymphocytes) and non-coated microchannels. This system can be used to analyze small numbers of target cells in large quantities of mixed samples. PMID- 24339861 TI - The use of pill counts as a facilitator of adherence with antiretroviral therapy in resource limited settings. AB - BACKGROUND: Pill counts are often used to measure adherence to ART, but there is little data on how they affect adherence. We previously showed a bivariate relationship between clinicians counting pills and adherence in patients receiving HIV care in Kenya. We present a secondary analysis of the relationship between numbers of pill counts and clinical outcomes in resource limited settings. METHODS: Patients initiating ART at Kijabe Hospital were monitored for the number of discretionary pill counts performed by their clinician in the first 6 months of ART. Subjects were followed for at least 1 year after enrollment. The number of clinician pill counts was correlated to ART adherence. The primary endpoints were time to treatment failure, defined as a detectable HIV-1 viral load, death; or loss to follow-up. RESULTS: Clinician pill counts were done at 68% of clinic visits for 304 subjects. There was a positive correlation between the number of clinician pill counts and ART adherence (r = 0.21, p <0.001). Patients were divided into 3 groups (0 counts, 1 to 3 counts, 4 to 7 counts) and exhibited adherence of 76%, 84%, and 92%, respectively (p = 0.004). Time to treatment failure for these groups was 220 days, 438 days, and 497 days (P<0.01), respectively. Time to virologic failure in living patients remaining in the cohort was longer in those with more pill count (P =0.02). Multi-variate analysis adjusting for co-variates affecting time to treatment failure found that that clinician pill counts were associated with a decreased risk of treatment failure (HR = 0.69, p =0.04). CONCLUSIONS: The number of clinician pill count performed was independently associated with better adherence and a decreased risk of treatment failure. The use of clinician pill counts should be further studied as an adherence promoter through a randomized clinical trial. PMID- 24339862 TI - PLZF mediates the PTEN/AKT/FOXO3a signaling in suppression of prostate tumorigenesis. AB - Promyelocytic leukemia zinc finger (PLZF) protein expression is closely related to the progression of human cancers, including prostate cancer (PCa). However, the according context of a signaling pathway for PLZF to suppress prostate tumorigenesis remains greatly unknown. Here we report that PLZF is a downstream mediator of the PTEN signaling pathway in PCa. We found that PLZF expression is closely correlated with PTEN expression in a cohort of prostate cancer specimens. Interestingly, both PTEN rescue and phosphoinositide 3-kinase (PI3K) inhibitor LY294002 treatment increase the PLZF expression in prostate cancer cell lines. Further, luciferase reporter assay and chromatin immunoprecipitation assay demonstrate that FOXO3a, a transcriptional factor phosphorylated by PI3K/AKT, could directly bind to the promoter of PLZF gene. These results indicate that PTEN regulates PLZF expression by AKT/FOXO3a. Moreover, our animal experiments also demonstrate that PLZF is capable of inhibiting prostate tumorigenesis in vivo. Taken together, our study defines a PTEN/PLZF pathway and would shed new lights for developing therapeutic strategy of prostate cancer. PMID- 24339863 TI - Mutation of the TYTLE motif in the cytoplasmic tail of the sendai virus fusion protein deeply affects viral assembly and particle production. AB - Enveloped viruses contain glycoproteins protruding from the viral membrane. These proteins play a crucial role in the extra-cellular steps of the virus life cycle, namely attachment to and entry into cells. Their role during the intracellular late phase of virus multiplication has been less appreciated, overlooked by the documented central organizer role of the matrix M protein. Sendai virus, a member of the Paramyxoviridae family, expresses two trans-membrane proteins on its surface, HN and F. In previous work, we have shown that suppression of F in the context of an infection, results in about 70% reduction of virus particle production, a reduction similar to that observed upon suppression of the matrix M protein. Moreover, a TYTLE motif present in F cytoplasmic tail has been proposed essential for virus particle production. In the present work, using original alternate conditional siRNA suppression systems, we generated a double F gene recombinant Sendai virus expressing wt-F and a nonviable mutated TYTLE/5A F protein (F5A). Suppression of the wild type F gene expression in cells infected with this virus allowed the analysis of F5A properties in the context of the infection. Coupling confocal imaging analysis to biochemical characterization, we found that F5A i) was not expressed at the cell surface but restricted to the endoplasmic reticulum, ii) was still capable of interaction with M and iii) had profound effect on M and HN cellular distribution. On the basis of these data, we propose a model for SeV particle formation based on an M/F complex that would serve as nucleation site for virus particle assembly at the cell surface. PMID- 24339865 TI - Inferring the rate-length law of protein folding. AB - We investigate the rate-length scaling law of protein folding, a key undetermined scaling law in the analytical theory of protein folding. Available data yield statistically significant evidence for the existence of a rate-length law capable of predicting folding times to within about two orders of magnitude (over 9 decades of variation). Unambiguous determination of the functional form of such a law could provide key mechanistic insight into folding. Four proposed laws from literature (power law, exponential, and two stretched exponentials) are tested against one another, and it is found that the power law best explains the data by a modest margin. We conclude that more data is necessary to unequivocally infer the rate-length law. Such data could be obtained through a small number of protein folding experiments on large protein domains. PMID- 24339864 TI - Mice deficient in Sfrp1 exhibit increased adiposity, dysregulated glucose metabolism, and enhanced macrophage infiltration. AB - The molecular mechanisms involved in the development of obesity and related complications remain unclear. Wnt signaling plays an important role in preadipocyte differentiation and adipogenesis. The expression of a Wnt antagonist, secreted frizzled related protein 1 (SFRP1), is increased in response to initial weight gain, then levels are reduced under conditions of extreme obesity in both humans and animals. Here we report that loss of Sfrp1 exacerbates weight gain, glucose homeostasis and inflammation in mice in response to diet induced obesity (DIO). Sfrp1(-/-) mice fed a high fat diet (HFD) exhibited an increase in body mass accompanied by increases in body fat percentage, visceral white adipose tissue (WAT) mass, and adipocyte size. Moreover, Sfrp1 deficiency increases the mRNA levels of key de novo lipid synthesis genes (Fasn, Acaca, Acly, Elovl, Scd1) and the transcription factors that regulate their expression (Lxr-alpha, Srebp1, Chreb, and Nr1h3) in WAT. Fasting glucose levels are elevated, glucose clearance is impaired, hepatic gluconeogenesis regulators are aberrantly upregulated (G6pc and Pck1), and glucose transporters are repressed (Slc2a2 and Slc2a4) in Sfrp1(-/-) mice fed a HFD. Additionally, we observed increased steatosis in the livers of Sfrp1(-/-) mice. When there is an expansion of adipose tissue there is a sustained inflammatory response accompanied by adipokine dysregulation, which leads to chronic subclinical inflammation. Thus, we assessed the inflammatory state of different tissues and revealed that Sfrp1( /-) mice fed a HFD exhibited increased macrophage infiltration and expression of pro-inflammatory markers including IL-6, Nmnat, Tgf-beta2, and SerpinE1. Our findings demonstrate that the expression of Sfrp1 is a critical factor required for maintaining appropriate cellular signaling in response to the onset of obesity. PMID- 24339866 TI - Low hepcidin levels in severely anemic malawian children with high incidence of infectious diseases and bone marrow iron deficiency. AB - INTRODUCTION: A reliable diagnostic biomarker of iron status is required for severely anemic children living in malarious areas because presumptive treatment with iron may increase their infection risk if they are not iron deficient. Current biomarkers are limited because they are altered by host inflammation. In this study hepcidin concentrations were assessed in severely anemic children living in a highly malarious area of Malawi and evaluated against bone marrow iron in order to determine the usefulness of hepcidin as a point of care test. METHODS: 207 severely anemic children were assessed for levels of hepcidin, ferritin, serum transferrin receptor, erythropoietin, hematological indices, C reactive protein, interleukin-6, malaria parasites and HIV infection. Deficiency of bone marrow iron stores was graded and erythroblast iron incorporation estimated. Interaction of covariates was assessed by structural-equation modeling. RESULTS AND CONCLUSION: Hepcidin was a poor predictor of bone marrow iron deficiency (sensitivity 66.7%; specificity 48.5%), and of iron incorporation (sensitivity 54.2%; specificity 61.8%), and therefore would have limitations as a point of care test in this category of children. As upregulation of hepcidin by inflammation and iron status was blunted by erythropoietin in this population, enhanced iron absorption through the low hepcidin values may increase infection risk. Current recommendations to treat all severely anemic children living in malarious areas with iron should therefore be reconsidered. PMID- 24339867 TI - Quantitative proteomic profiling identifies DPYSL3 as pancreatic ductal adenocarcinoma-associated molecule that regulates cell adhesion and migration by stabilization of focal adhesion complex. AB - Elucidation of how pancreatic cancer cells give rise to distant metastasis is urgently needed in order to provide not only a better understanding of the underlying molecular mechanisms, but also to identify novel targets for greatly improved molecular diagnosis and therapeutic intervention. We employed combined proteomic technologies including mass spectrometry and isobaric tags for relative and absolute quantification peptide tagging to analyze protein profiles of surgically resected human pancreatic ductal adenocarcinoma tissues. We identified a protein, dihydropyrimidinase-like 3, as highly expressed in human pancreatic ductal adenocarcinoma tissues as well as pancreatic cancer cell lines. Characterization of the roles of dihydropyrimidinase-like 3 in relation to cancer cell adhesion and migration in vitro, and metastasis in vivo was performed using a series of functional analyses, including those employing multiple reaction monitoring proteomic analysis. Furthermore, dihydropyrimidinase-like 3 was found to interact with Ezrin, which has important roles in cell adhesion, motility, and invasion, while that interaction promoted stabilization of an adhesion complex consisting of Ezrin, c-Src, focal adhesion kinase, and Talin1. We also found that exogenous expression of dihydropyrimidinase-like 3 induced activating phosphorylation of Ezrin and c-Src, leading to up-regulation of the signaling pathway. Taken together, the present results indicate successful application of combined proteomic approaches to identify a novel key player, dihydropyrimidinase like 3, in pancreatic ductal adenocarcinoma tumorigenesis, which may serve as an important biomarker and/or drug target to improve therapeutic strategies. PMID- 24339868 TI - Differential gene expression of cardiac ion channels in human dilated cardiomyopathy. AB - BACKGROUND: Dilated cardiomyopathy (DCM) is characterized by idiopathic dilation and systolic contractile dysfunction of the cardiac chambers. The present work aimed to study the alterations in gene expression of ion channels involved in cardiomyocyte function. METHODS AND RESULTS: Microarray profiling using the Affymetrix Human Gene(r) 1.0 ST array was performed using 17 RNA samples, 12 from DCM patients undergoing cardiac transplantation and 5 control donors (CNT). The analysis focused on 7 cardiac ion channel genes, since this category has not been previously studied in human DCM. SCN2B was upregulated, while KCNJ5, KCNJ8, CLIC2, CLCN3, CACNB2, and CACNA1C were downregulated. The RT-qPCR (21 DCM and 8 CNT samples) validated the gene expression of SCN2B (p < 0.0001), KCNJ5 (p < 0.05), KCNJ8 (p < 0.05), CLIC2 (p < 0.05), and CACNB2 (p < 0.05). Furthermore, we performed an IPA analysis and we found a functional relationship between the different ion channels studied in this work. CONCLUSION: This study shows a differential expression of ion channel genes involved in cardiac contraction in DCM that might partly underlie the changes in left ventricular function observed in these patients. These results could be the basis for new genetic therapeutic approaches. PMID- 24339869 TI - Mice overexpressing beta-1,4-Galactosyltransferase I are resistant to TNF-induced inflammation and DSS-induced colitis. AB - Glycosylation is an essential post-translational modification, which determines the function of proteins and important processes such as inflammation. beta-1,4 galactosyltransferase I (betaGalT1) is a key enzyme involved in the addition of galactose moieties to glycoproteins. Intestinal mucins are glycoproteins that protect the gut barrier against invading pathogens and determine the composition of the intestinal microbiota. Proper glycosylation of mucus is important in this regard. By using ubiquitously expressing betaGalT1 transgenic mice, we found that this enzyme led to strong galactosylation of mucus proteins, isolated from the gut of mice. This galactosylation was associated with a drastic change in composition of gut microbiota, as TG mice had a significantly higher Firmicutes to Bacteroidetes ratio. TG mice were strongly protected against TNF-induced systemic inflammation and lethality. Moreover, betaGalT1 transgenic mice were protected in a model of DSS-induced colitis, at the level of clinical score, loss of body weight, colon length and gut permeability. These studies put betaGalT1 forward as an essential protective player in exacerbated intestinal inflammation. Optimal galactosylation of N-glycans of mucus proteins, determining the bacterial composition of the gut, is a likely mechanism of this function. PMID- 24339870 TI - Tension monitoring during epithelial-to-mesenchymal transition links the switch of phenotype to expression of moesin and cadherins in NMuMG cells. AB - Structural alterations during epithelial-to-mesenchymal transition (EMT) pose a substantial challenge to the mechanical response of cells and are supposed to be key parameters for an increased malignancy during metastasis. Herein, we report that during EMT, apical tension of the epithelial cell line NMuMG is controlled by cell-cell contacts and the architecture of the underlying actin structures reflecting the mechanistic interplay between cellular structure and mechanics. Using force spectroscopy we find that tension in NMuMG cells slightly increases 24 h after EMT induction, whereas upon reaching the final mesenchymal-like state characterized by a complete loss of intercellular junctions and a concerted down regulation of the adherens junction protein E-cadherin, the overall tension becomes similar to that of solitary adherent cells and fibroblasts. Interestingly, the contribution of the actin cytoskeleton on apical tension increases significantly upon EMT induction, most likely due to the formation of stable and highly contractile stress fibers which dominate the elastic properties of the cells after the transition. The structural alterations lead to the formation of single, highly motile cells rendering apical tension a good indicator for the cellular state during phenotype switching. In summary, our study paves the way towards a more profound understanding of cellular mechanics governing fundamental morphological programs such as the EMT. PMID- 24339871 TI - Evaluation of relapse-free survival in T3N0 colon cancer: the role of chemotherapy, a multicentric retrospective analysis. AB - BACKGROUND: Adjuvant chemotherapy (AC) in Stage II Colon Cancer (CC) is still under debate. Choice should be based on patients and disease characteristics. According to guidelines AC should be considered in high-risk T3N0 patients. No data are available for better option in low-risk patients. The aim of the study is to retrospectively evaluate relapse-free survival (RFS) and disease-free survival (DFS) according to treatment received in T3N0 CC. METHODS: RFS and DFS are evaluated with Kaplan-Meier method. Multivariate Cox proportional hazard model was developed using stepwise regression, enter limit and remove limit were p = 0.10 and p = 0.15, respectively. RESULTS: 834 patients with T3N0 CC were recruited. Median age was 69 (29-93), M/F 463/371, 335 low-risk patients (40.2%), 387 high-risk (46.4%), 112 unknown (13.4%); 127 (15.2%) patients showed symptoms at diagnosis. Median sampled lymph nodes were 15 (1-76); 353 (42.3%) patients were treated with AC. Median follow up was 5 years (range 3-24). The 5-years RFS was 78.4% and the 5-years DFS was 76.7%. At multivariate analysis symptoms, lymph nodes, and adjuvant chemotherapy were prognostic factors for RFS. AC is prognostic factor for all endpoints. In low-risk group 5-years RFS was 87.3% in treated patients and 74.7% in non-treated patients (p 0.03); in high-risk group was respectively 82.7% and 71.4% (p 0.005). CONCLUSIONS: Data confirmed the role of known prognostic factors and suggest the relevance of adjuvant chemotherapy also in low-risk stage II T3N0 CC patients. However, the highest risk in low-risk subgroup should be identified to be submitted to AC. PMID- 24339872 TI - Moral foundations predict religious orientations in New Zealand. AB - The interplay between religion, morality, and community-making is a core theme across human experience, yet scholars have only recently begun to quantify these links. Drawing on a sample of 1512 self-identified religious - mainly Christian (86.0%) - New Zealanders, we used structural equation modeling to test hypothesized associations between Religious Orientations (Quest, Intrinsic, Extrinsic Personal, Extrinsic Social) and Moral Foundations (Care/Harm, Fairness/Cheating, Loyalty/Betrayal, Authority/Subversion, Sanctity/Degradation). Our results show, for the first time in a comprehensive model, how different ways of valuing communities are associated with different ways of valuing religion. PMID- 24339873 TI - First partial skeleton of a 1.34-million-year-old Paranthropus boisei from Bed II, Olduvai Gorge, Tanzania. AB - Recent excavations in Level 4 at BK (Bed II, Olduvai Gorge, Tanzania) have yielded nine hominin teeth, a distal humerus fragment, a proximal radius with much of its shaft, a femur shaft, and a tibia shaft fragment (cataloged collectively as OH 80). Those elements identified more specifically than to simply Hominidae gen. et sp. indet are attributed to Paranthropus boisei. Before this study, incontrovertible P. boisei partial skeletons, for which postcranial remains occurred in association with taxonomically diagnostic craniodental remains, were unknown. Thus, OH 80 stands as the first unambiguous, dentally associated Paranthropus partial skeleton from East Africa. The morphology and size of its constituent parts suggest that the fossils derived from an extremely robust individual who, at 1.338+/-0.024 Ma (1 sigma), represents one of the most recent occurrences of Paranthropus before its extinction in East Africa. PMID- 24339875 TI - Enhanced syllable discrimination thresholds in musicians. AB - Speech processing inherently relies on the perception of specific, rapidly changing spectral and temporal acoustic features. Advanced acoustic perception is also integral to musical expertise, and accordingly several studies have demonstrated a significant relationship between musical training and superior processing of various aspects of speech. Speech and music appear to overlap in spectral and temporal features; however, it remains unclear which of these acoustic features, crucial for speech processing, are most closely associated with musical training. The present study examined the perceptual acuity of musicians to the acoustic components of speech necessary for intra-phonemic discrimination of synthetic syllables. We compared musicians and non-musicians on discrimination thresholds of three synthetic speech syllable continua that varied in their spectral and temporal discrimination demands, specifically voice onset time (VOT) and amplitude envelope cues in the temporal domain. Musicians demonstrated superior discrimination only for syllables that required resolution of temporal cues. Furthermore, performance on the temporal syllable continua positively correlated with the length and intensity of musical training. These findings support one potential mechanism by which musical training may selectively enhance speech perception, namely by reinforcing temporal acuity and/or perception of amplitude rise time, and implications for the translation of musical training to long-term linguistic abilities. PMID- 24339874 TI - Adult human glia, pericytes and meningeal fibroblasts respond similarly to IFNy but not to TGFbeta1 or M-CSF. AB - The chemokine Interferon gamma-induced protein 10 (IP-10) and human leukocyte antigen (HLA) are widely used indicators of glial activation and neuroinflammation and are up-regulated in many brain disorders. These inflammatory mediators have been widely studied in rodent models of brain disorders, but less work has been undertaken using human brain cells. In this study we investigate the regulation of HLA and IP-10, as well as other cytokines and chemokines, in microglia, astrocytes, pericytes, and meningeal fibroblasts derived from biopsy and autopsy adult human brain, using immunocytochemistry and a Cytometric Bead Array. Interferongamma (IFNgamma) increased microglial HLA expression, but contrary to data in rodents, the anti-inflammatory cytokine transforming growth factor beta1 (TGFbeta1) did not inhibit this increase in HLA, nor did TGFbeta1 affect basal microglial HLA expression or IFNgamma-induced astrocytic HLA expression. In contrast, IFNgamma-induced and basal microglial HLA expression, but not IFNgamma-induced astrocytic HLA expression, were strongly inhibited by macrophage colony stimulating factor (M-CSF). IFNgamma also strongly induced HLA expression in pericytes and meningeal fibroblasts, which do not basally express HLA, and this induction was completely blocked by TGFbeta1, but not affected by M-CSF. In contrast, TGFbeta1 did not block the IFNgamma-induced increase in IP-10 in pericytes and meningeal fibroblasts. These results show that IFNgamma, TGFbeta1 and M-CSF have species- and cell type-specific effects on human brain cells that may have implications for their roles in adult human brain inflammation. PMID- 24339876 TI - BMPR1B up-regulation via a miRNA binding site variation defines endometriosis susceptibility and CA125 levels. AB - BACKGROUND: Bone morphogenetic protein receptor I B (BMPR1B) is a transmembrane receptor mediating TGF-beta signal transduction. Recent studies indicate a tumor suppressor role for BMPR1B in ovarian cancer. Polymorphism at BMPR1B 3'UTR within the miR-125b binding site alters its binding affinity toward the miRNA, which may result in insufficient post-transcriptional repression. METHODS: Single nucleotide polymorphisms rs1970801, rs1434536, and rs11097457 near the miR-125b binding site in BMPR1B were genotyped by Taqman assay on 193 endometriosis patients and 202 healthy controls. BMPR1B and CA125 levels in ectopic endometrial tissues were evaluated by quantitative PCR and immunohistochemistry. Luciferase reporter assay was utilized to verify regulatory roles of BMPR1B 3'UTR with allelic variants of rs1434536 in a cell line model. Cell proliferation and migration were recorded, while expression of BMPR1B, CA125, glucocorticoid receptor (GCCR) and IL-1beta were measured by quantitative PCR in endometrial cells transfected with wild-type or mutated miR-125b. RESULTS: This study found two endometriosis-associated SNPs, rs1434536 (P = 0.010) and rs1970801 (P = 0.0087), located within and next to a miR-125b binding site on BMPR1B. Interestingly, patients with homozygous variant alleles at rs1434536 showed significantly lower serum CA125 levels. Immunohistochemistry staining further confirmed inverse correlation between BMPR1B and CA125 levels in three rs1434536 genotypes. Cell assays demonstrated the variant allele of rs1434536 up-regulating BMPR1B at both mRNA and protein levels, which negatively correlated with CA125 and IL-1beta levels. Disruption of the binding between miR-125b and BMPR1B hampered abnormal cell proliferation. CONCLUSIONS: SNPs of BMPR1B within and next to the miR-125b binding site manifested strong correlation with endometriosis development in a Taiwanese cohort. Disrupting the binding of miR-125b toward BMPR1B would increase protein expression, diminishing abnormal cell proliferation as well as serum and cellular CA125 levels. Genetic variation at the miR-125b binding site may play functional roles to protect against endometriosis progression. PMID- 24339878 TI - Biomechanical properties of insect wings: the stress stiffening effects on the asymmetric bending of the Allomyrina dichotoma beetle's hind wing. AB - Although the asymmetry in the upward and downward bending of insect wings is well known, the structural origin of this asymmetry is not yet clearly understood. Some researchers have suggested that based on experimental results, the bending asymmetry of insect wings appears to be a consequence of the camber inherent in the wings. Although an experimental approach can reveal this phenomenon, another method is required to reveal the underlying theory behind the experimental results. The finite element method (FEM) is a powerful tool for evaluating experimental measurements and is useful for studying the bending asymmetry of insect wings. Therefore, in this study, the asymmetric bending of the Allomyrina dichotoma beetle's hind wing was investigated through FEM analyses rather than through an experimental approach. The results demonstrated that both the stressed stiffening of the membrane and the camber of the wing affect the bending asymmetry of insect wings. In particular, the chordwise camber increased the rigidity of the wing when a load was applied to the ventral side, while the spanwise camber increased the rigidity of the wing when a load was applied to the dorsal side. These results provide an appropriate explanation of the mechanical behavior of cambered insect wings, including the bending asymmetry behavior, and suggest an appropriate approach for analyzing the structural behavior of insect wings. PMID- 24339877 TI - Molecular profiling of the lateral habenula in a rat model of depression. AB - OBJECTIVE: This study systematically investigated the effect of chronic mild stress and response to antidepressant treatment in the lateral habenula at the whole genome level. METHODS: Rat whole genome expression chips (Affymetrix) were used to detect gene expression regulations in the lateral habenula of rats subjected to chronic mild stress (mild stressors exchanged twice a day for 8 weeks). Some rats received antidepressant treatment during fifth to eights week of CMS. The lateral habenula gene expression profile was studied through the gene ontology and signal pathway analyses using bioinformatics. Real-time quantitative polymerase chain reaction (RT-PCR) was used to verify the microarray results and determine the expression of the Fcrla, Eif3k, Sec3l1, Ubr5, Abca8a, Ankrd49, Cyp2j10, Frs3, Syn2, and Znf503 genes in the lateral habenula tissue. RESULTS: In particular we found that stress and antidepressant treatment affected intracellular cascades like growth factor receptor signaling, G-protein-coupled receptor signaling, and Wnt signaling - processes involved in the neuroplastic changes observed during the progression of depression and antidepressant treatment. CONCLUSION: The present study suggests an important role of the lateral habenula in the development of depression-like conditions and correlates to previous studies demonstrating a significant role of the lateral habenula in depressive-like conditions and antidepressant treatment. PMID- 24339879 TI - Impact of noise on molecular network inference. AB - Molecular entities work in concert as a system and mediate phenotypic outcomes and disease states. There has been recent interest in modelling the associations between molecular entities from their observed expression profiles as networks using a battery of algorithms. These networks have proven to be useful abstractions of the underlying pathways and signalling mechanisms. Noise is ubiquitous in molecular data and can have a pronounced effect on the inferred network. Noise can be an outcome of several factors including: inherent stochastic mechanisms at the molecular level, variation in the abundance of molecules, heterogeneity, sensitivity of the biological assay or measurement artefacts prevalent especially in high-throughput settings. The present study investigates the impact of discrepancies in noise variance on pair-wise dependencies, conditional dependencies and constraint-based Bayesian network structure learning algorithms that incorporate conditional independence tests as a part of the learning process. Popular network motifs and fundamental connections, namely: (a) common-effect, (b) three-chain, and (c) coherent type-I feed-forward loop (FFL) are investigated. The choice of these elementary networks can be attributed to their prevalence across more complex networks. Analytical expressions elucidating the impact of discrepancies in noise variance on pairwise dependencies and conditional dependencies for special cases of these motifs are presented. Subsequently, the impact of noise on two popular constraint-based Bayesian network structure learning algorithms such as Grow-Shrink (GS) and Incremental Association Markov Blanket (IAMB) that implicitly incorporate tests for conditional independence is investigated. Finally, the impact of noise on networks inferred from publicly available single cell molecular expression profiles is investigated. While discrepancies in noise variance are overlooked in routine molecular network inference, the results presented clearly elucidate their non-trivial impact on the conclusions that in turn can challenge the biological significance of the findings. The analytical treatment and arguments presented are generic and not restricted to molecular data sets. PMID- 24339880 TI - Signature of circulating microRNAs as potential biomarkers in vulnerable coronary artery disease. AB - AIMS: MicroRNAs (miRNAs) play important roles in the pathogenesis of cardiovascular diseases. Circulating miRNAs were recently identified as biomarkers for various physiological and pathological conditions. In this study, we aimed to identify the circulating miRNA fingerprint of vulnerable coronary artery disease (CAD) and explore its potential as a novel biomarker for this disease. METHODS AND RESULTS: The Taqman low-density miRNA array and coexpression network analyses were used to identify distinct miRNA expression profiles in the plasma of patients with typical unstable angina (UA) and angiographically documented CAD (UA group, n = 13) compared to individuals with non-cardiac chest pain (control group, n = 13). Significantly elevated expression levels of miR 106b/25 cluster, miR-17/92a cluster, miR-21/590-5p family, miR-126*, and miR-451 were observed in UA patients compared to controls. These findings were validated by real-time PCR in another 45 UA patients, 31 stable angina patients, and 37 controls. In addition, miR-106b, miR-25, miR-92a, miR-21, miR-590-5p, miR-126* and miR-451 were upregulated in microparticles (MPs) isolated from the plasma of UA patients (n = 5) compared to controls (n = 5). Using flow cytometry and immunolabeling, we further found that Annexin V(+) MPs were increased in the plasma samples of UA patients compared to controls, and the majority of the increased MPs in plasma were shown to be Annexin V(+) CD31(+) MPs. The findings suggest that Annexin V(+) CD31(+) MPs may contribute to the elevated expression of the selected miRNAs in the circulation of patients with vulnerable CAD. CONCLUSION: The circulating miRNA signature, consisting of the miR-106b/25 cluster, miR-17/92a cluster, miR-21/590-5p family, miR-126* and miR-451, may be used as a novel biomarker for vulnerable CAD. TRIAL REGISTRATION: Chinese Clinical Trial Register, ChiCTR-OCH-12002349. PMID- 24339881 TI - Stereoscopic depth perception using a model based on the primary visual cortex. AB - This work describes an approach inspired by the primary visual cortex using the stimulus response of the receptive field profiles of binocular cells for disparity computation. Using the energy model based on the mechanism of log-Gabor filters for disparity encodings, we propose a suitable model to consistently represent the complex cells by computing the wide bandwidths of the cortical cells. This way, the model ensures the general neurophysiological findings in the visual cortex (V1), emphasizing the physical disparities and providing a simple selection method for the complex cell response. The results suggest that our proposed approach can achieve better results than a hybrid model with phase-shift and position-shift using position disparity alone. PMID- 24339882 TI - Disproportional representation of primates in the ecological literature. AB - We address the question why papers dealing with the ecology of primates are so sparsely represented in the general ecological literature. A literature analyses based on entries in Web of Science and PrimateLit reveals that despite a large number of papers published on primates in general and on the ecology of primates, only a very small fraction of these papers is published in high-ranking international ecological journals. We discuss a number of potential reasons for the disproportion and highlight the problems associated with experimental research on wild primates and constraints on sample size as major issues. PMID- 24339883 TI - Physicians' characteristics associated with exploring suicide risk among patients with depression: a French panel survey of general practitioners. AB - BACKGROUND: General practitioners (GPs) have a key role to play in suicide prevention, but the rates at which they question patients with depression about suicidal thoughts and plans are rather low. Little is known about GPs' characteristics associated with such inquiries. Our objectives were to describe GPs' attitudes, perceived barriers, and self-reported practices in this questioning of these patients and to analyze factors associated with these practices. METHODOLOGY: This cross-sectional survey was conducted among participants in a panel of randomly selected French GPs (1249/1431 participated: 87.3%). GPs were interviewed with a standardized questionnaire covering their professional and personal characteristics, attitudes, and practices in exploring the suicide risk of their patients with depression. We built a suicide inquiry score by summing the responses to 5 items and used a multiple linear regression analysis to explore the characteristics associated with this score. PRINCIPAL FINDINGS: Most GPs reported inquiring about the presence of suicidal ideation often or very often; less than 30% reported that they frequently explored signs of a specific suicide plan. The mean suicide inquiry score was 12.4 (SD, 2.9; range, 5-20). False ideas, such as thinking that patients who report suicidal ideas do not often commit suicide, were frequent (42.3%). Previous continuing medical education on suicide, participation in a formal mental health network, and patients who committed suicide in the past 5 years were associated with a higher score. Reluctance to question patients about suicide and perception of insufficient skill were associated with a lower score. CONCLUSIONS/SIGNIFICANCE: This study showed great variability in French GPs' practices in exploring suicide risk in patients with depression. Interventions aiming at improving GPs' initial training and continuing medical education in suicide and/or depression, and their collaboration with mental health specialists should be developed, and their impacts assessed. PMID- 24339884 TI - Does an isoniazid prophylaxis register improve tuberculosis contact management in South African children? AB - SETTING: We compared the change in child household contact management of pulmonary tuberculosis (TB) cases before and after the implementation of an isoniazid preventive therapy (IPT) register in an urban clinic setting in Cape Town, South Africa. OBJECTIVES: We determined if the presence of an IPT register was associated with an increase in the number of child contacts identified per infectious case and the proportion of identified children who were started on IPT. DESIGN: We reviewed routine programme data on IPT delivery to children during two time periods (May 2008-October 2008 and May 2011-October 2011), before and after the implementation of an IPT register used by routine clinic personnel. RESULTS: Adult TB case demographic and clinical characteristics from the two observation periods were similar. During the post-register period, more child contacts per adult case were identified (0.7 (54 children) vs. 0.3 (24 children)), more of the identified children were started on IPT (54 vs. 4) and 37% of those who started, completed six months of treatment compared to the pre register period where no adherence information was recorded. CONCLUSIONS: After pilot implementation of an IPT register, documented identification of child contacts, IPT initiation and IPT adherence documentation in TB exposed children was improved. Our findings support further exploration of the potential impact of using standardised IPT recording and reporting in routine clinics in high-burden TB settings to improve TB prevention efforts targeted at young children. Future efforts to improve IPT delivery should be systematic and comprehensive in order to support a change in current operational IPT delivery practices in TB programs. PMID- 24339885 TI - Complexity reduction of rate-equations models for two-choice decision-making. AB - We are concerned with the complexity reduction of a stochastic system of differential equations governing the dynamics of a neuronal circuit describing a decision-making task. This reduction is based on the slow-fast behavior of the problem and holds on the whole phase space and not only locally around the spontaneous state. Macroscopic quantities, such as performance and reaction times, computed applying this reduction are in agreement with previous works in which the complexity reduction is locally performed at the spontaneous point by means of a Taylor expansion. PMID- 24339886 TI - Employing a Monte Carlo algorithm in Newton-type methods for restricted maximum likelihood estimation of genetic parameters. AB - Estimation of variance components by Monte Carlo (MC) expectation maximization (EM) restricted maximum likelihood (REML) is computationally efficient for large data sets and complex linear mixed effects models. However, efficiency may be lost due to the need for a large number of iterations of the EM algorithm. To decrease the computing time we explored the use of faster converging Newton-type algorithms within MC REML implementations. The implemented algorithms were: MC Newton-Raphson (NR), where the information matrix was generated via sampling; MC average information(AI), where the information was computed as an average of observed and expected information; and MC Broyden's method, where the zero of the gradient was searched using a quasi-Newton-type algorithm. Performance of these algorithms was evaluated using simulated data. The final estimates were in good agreement with corresponding analytical ones. MC NR REML and MC AI REML enhanced convergence compared to MC EM REML and gave standard errors for the estimates as a by-product. MC NR REML required a larger number of MC samples, while each MC AI REML iteration demanded extra solving of mixed model equations by the number of parameters to be estimated. MC Broyden's method required the largest number of MC samples with our small data and did not give standard errors for the parameters directly. We studied the performance of three different convergence criteria for the MC AI REML algorithm. Our results indicate the importance of defining a suitable convergence criterion and critical value in order to obtain an efficient Newton-type method utilizing a MC algorithm. Overall, use of a MC algorithm with Newton-type methods proved feasible and the results encourage testing of these methods with different kinds of large-scale problem settings. PMID- 24339887 TI - Urinary prognostic biomarkers and classification of IgA nephropathy by high resolution mass spectrometry coupled with liquid chromatography. AB - IgA nephropathy is the most common cause of primary glomerulonephritis. There are different pathologic biopsy-based scoring systems in use, but there is no consensus among nephrologists yet regarding the best classification method. Our aim was to test urine proteomics as a non-invasive method for classification of IgA nephropathy. This aim was pursued by discovering novel prognostic protein biomarkers in urine, and linking them to pathogenesis of the disease through known signaling and metabolic pathways. 13 urine samples of the patients with biopsy-proven IgA nephropathy were analyzed via two proteomics approaches: nanoflow LC-MS/MS and GeLC-MS/MS. The results of label-free quantification were subjected to multivariate statistical analysis, which could classify patients into two groups, broadly corresponding to the primary and advance stages. The proteome classification correlated well with biopsy-based scoring systems, especially endocapillary hypercellularity score of the Oxford's classification. Differentially excreted candidate proteins were found as potential prognostic biomarkers: afamin, leucine-rich alpha-2-glycoprotein, ceruloplasmin, alpha-1 microgolbulin, hemopexin, apolipoprotein A-I, complement C3, vitamin D-binding protein, beta-2-microglobulin, and retinol-binding protein 4. Pathway analysis suggested impairment of Extra Cellular Matrix (ECM)-Receptor Interaction pathways as well as activation of complement and coagulation pathway in progression of IgA nephropathy. PMID- 24339888 TI - Systematically studying kinase inhibitor induced signaling network signatures by integrating both therapeutic and side effects. AB - Substantial effort in recent years has been devoted to analyzing data based large scale biological networks, which provide valuable insight into the topologies of complex biological networks but are rarely context specific and cannot be used to predict the responses of cell signaling proteins to specific ligands or compounds. In this work, we proposed a novel strategy to investigate kinase inhibitor induced pathway signatures by integrating multiplex data in Library of Integrated Network-based Cellular Signatures (LINCS), e.g. KINOMEscan data and cell proliferation/mitosis imaging data. Using this strategy, we first established a PC9 cell line specific pathway model to investigate the pathway signatures in PC9 cell line when perturbed by a small molecule kinase inhibitor GW843682. This specific pathway revealed the role of PI3K/AKT in modulating the cell proliferation process and the absence of two anti-proliferation links, which indicated a potential mechanism of abnormal expansion in PC9 cell number. Incorporating the pathway model for side effects on primary human hepatocytes, it was used to screen 27 kinase inhibitors in LINCS database and PF02341066, known as Crizotinib, was finally suggested with an optimal concentration 4.6 uM to suppress PC9 cancer cell expansion while avoiding severe damage to primary human hepatocytes. Drug combination analysis revealed that the synergistic effect region can be predicted straightforwardly based on a threshold which is an inherent property of each kinase inhibitor. Furthermore, this integration strategy can be easily extended to other specific cell lines to be a powerful tool for drug screen before clinical trials. PMID- 24339889 TI - A trifunctional dextran-based nanovaccine targets and activates murine dendritic cells, and induces potent cellular and humoral immune responses in vivo. AB - Dendritic cells (DCs) constitute an attractive target for specific delivery of nanovaccines for immunotherapeutic applications. Here we tested nano-sized dextran (DEX) particles to serve as a DC-addressing nanocarrier platform. Non functionalized DEX particles had no immunomodulatory effect on bone marrow (BM) derived murine DCs in vitro. However, when adsorbed with ovalbumine (OVA), DEX particles were efficiently engulfed by BM-DCs in a mannose receptor-dependent manner. A DEX-based nanovaccine containing OVA and lipopolysaccharide (LPS) as a DC stimulus induced strong OVA peptide-specific CD4(+) and CD8(+) T cell proliferation both in vitro and upon systemic application in mice, as well as a robust OVA-specific humoral immune response (IgG1>IgG2a) in vivo. Accordingly, this nanovaccine also raised both a more pronounced delayed-type hypersensitivity response and a stronger induction of cytotoxic CD8(+) T cells than obtained upon administration of OVA and LPS in soluble form. Therefore, DEX-based nanoparticles constitute a potent, versatile and easy to prepare nanovaccine platform for immunotherapeutic approaches. PMID- 24339890 TI - Supratentorial gliomas in eloquent areas: which parameters can predict functional outcome and extent of resection? AB - BACKGROUND: To date, few parameters have been found that can aid in patient selection and surgical strategy for eloquent area gliomas. AIMS: The aim of the study was to analyze preoperative and intraoperative factors that can predict functional outcome and extent of resection in eloquent area tumors. PATIENTS AND METHODS: A retrospective analysis was conducted on 60 patients harboring supratentorial gliomas in eloquent areas undergoing awake surgery. The analysis considered clinical, neuroradiologic (morphologic), intraoperative, and postoperative factors. End-points were extent of resection (EOR) as well as functional short- and long-term outcome. Postoperatively, MRI objectively established the EOR. chi(2) analyses were used to evaluate parameters that could be predictive. Multivariate logistic regression analyses were used to evaluate the best combination to predict binary positive outcomes. RESULTS: In 90% of the cases, subcortical stimulation was positive in the margins of the surgical cavity. Postoperatively, 51% of the patients deteriorated but 90% of the patients regained their preoperative neurological score. Factors negatively affecting EOR were volume, degree of subcortical infiltration, and presence of paresis (P<0.01). Sharp margins and cystic components were more amenable to gross total resection (P<0.01). Contrast enhancement (P<0.02), higher grade (P<0.01), paresis (P<0.01), and residual tumor in the cortex (P<0.02) negatively affected long-term functional outcomes, whereas postoperative deterioration could not be predicted for any factor other than paresis. Subcortical stimulation did not correlate with deterioration, both postoperatively (P<0.08) and at follow-up (P<0.042). CONCLUSIONS: Biological and morphological factors such as type of margins, volume, preoperative neurological status, cystic components, histology and the type of infiltration into the white matter must be considered when planning intraoperative mapping. PMID- 24339891 TI - Evaluation of the toxic potential of graphene copper nanocomposite (GCNC) in the third instar larvae of transgenic Drosophila melanogaster (hsp70-lacZ)Bg(9.). AB - Graphene, a two-dimensional carbon sheet with single-atom thickness, have attracted the scientific world for its potential applications in various field including the biomedical areas. In the present study the graphene copper nanocomposite (GCNC) was synthesized, characterized and evaluated for its toxic potential on third instar larvae of transgenic Drosophila melanogaster (hsp70 lacZ)Bg(9) . The synthesized GCNC was analyzed by X-ray diffraction (XRD), scanning/transmission electron microscopy (SEM/TEM), atomic force microscopy (AFM), and fourier transform infrared spectroscopy (FTIR). The GCNC in 0.1% DMSO was sonicated for 10 min and the final concentration of 0.033, 0.099, 0.199 and 3.996 ug/ul of diet were established. The third instar larvae were allowed to feed on it separately for 24 and 48 hrs. The hsp70 expression was measured by O nitrophenyl-beta-D-galactopyranoside assay, tissue damage by trypan blue exclusion test and beta-galactosidase activity was monitored by in situ histochemical beta-galactosidase staining. Oxidative stress was monitored by performing lipid peroxidation assay and total protein estimation. Ethidium bromide/acridine orange staining was performed on midgut cells for apoptotic index and the comet assay was performed for the DNA damage. The results of the present study showed that the exposure of 0.199 and 3.996 ug/ul of GCNC were toxic for 24 hr of exposure and for 48 hr of exposure: 0.099, 0.199 and 3.996 ug/ul of GCNC was toxic. The dose of 0.033 ug/ul of GCNC showed no toxic effects on its exposure to the third instar larvae for 24 hr as well as 48 hrs. This dose can be considered as No Observed Adverse Effect Level (NOAEL). PMID- 24339892 TI - Transcriptome sequencing analysis reveals the regulation of the hypopharyngeal glands in the honey bee, Apis mellifera carnica Pollmann. AB - Transcriptome sequencing has become the main methodology for analyzing the relationship between genes and characteristics of interests, particularly those associated with diseases and economic traits. Because of its role of functional food for humans, commercial royal jelly (RJ) and its production are major research focuses in the field of apiculture. Multiple lines of evidence have demonstrated that many factors affect RJ output by activating or inhibiting various target genes and signaling pathways. Available coding sequences from the Honey Bee Genome Sequencing Consortium have permitted a pathway-based approach for investigating the development of the hypopharyngeal glands (HGs). In the present study, 3573941, 3562730, 3551541, 3524453, and 3615558 clean reads were obtained from the HGs of five full-sister honey bee samples using Solexa RNA sequencing technology. These reads were then assembled into 18378, 17785, 17065, 17105, and 17995 unigenes, respectively, and aligned to the DFCI Honey Bee Gene Index database. The differentially expressed genes (DEGs) data were also correlated with detailed morphological data for HGs acini. PMID- 24339893 TI - Visual impairment as a function of visual acuity in both eyes and its impact on patient reported preferences. AB - PURPOSE: To assess the impact of VA loss on patient reported utilities taking both eyes into account compared to taking only the better or the worse eye into account. METHODS: In this cross-sectional study 1085 patients and 254 controls rated preferences with the generic health-related (EQ-5D; n = 868) and vision specific (Vision and Quality of Life Index (VisQoL); n = 837) multi-attribute utility instruments (MAUIs). Utilities were calculated for three levels of VA in the better and worse eyes, as well as for 6 different vision states based on combinations of the better and worse eye VA. RESULTS: Using the VisQoL, utility scores decreased significantly with deteriorating vision in both the better and worse eyes when analysed separately. When stratified by the 6 vision states, VisQoL utilities decreased as VA declined in the worse eye despite stable VA in the better eye. Differences in VisQoL scores were statistically significant for cases where the better eye had no vision impairment and the worse seeing fellow eye had mild, moderate or severe vision impairment. In contrast, the EQ-5D failed to capture changes in better or worse eye VA, or any of the six vision states. CONCLUSIONS: Calculating utilities based only on better eye VA or using a generic MAUI is likely to underestimate the impact of vision impairment, particularly when the better eye has no or little VA loss and the worse eye is moderately to severely visually impaired. These findings have considerable implications for the assessment of overall visual impairment as well as economic evaluations within eye health. PMID- 24339894 TI - Glucose-coated gold nanoparticles transfer across human brain endothelium and enter astrocytes in vitro. AB - The blood-brain barrier prevents the entry of many therapeutic agents into the brain. Various nanocarriers have been developed to help agents to cross this barrier, but they all have limitations, with regard to tissue-selectivity and their ability to cross the endothelium. This study investigated the potential for 4 nm coated gold nanoparticles to act as selective carriers across human brain endothelium and subsequently to enter astrocytes. The transfer rate of glucose coated gold nanoparticles across primary human brain endothelium was at least three times faster than across non-brain endothelia. Movement of these nanoparticles occurred across the apical and basal plasma membranes via the cytosol with relatively little vesicular or paracellular migration; antibiotics that interfere with vesicular transport did not block migration. The transfer rate was also dependent on the surface coating of the nanoparticle and incubation temperature. Using a novel 3-dimensional co-culture system, which includes primary human astrocytes and a brain endothelial cell line hCMEC/D3, we demonstrated that the glucose-coated nanoparticles traverse the endothelium, move through the extracellular matrix and localize in astrocytes. The movement of the nanoparticles through the matrix was >10 um/hour and they appeared in the nuclei of the astrocytes in considerable numbers. These nanoparticles have the correct properties for efficient and selective carriers of therapeutic agents across the blood-brain barrier. PMID- 24339895 TI - A function accounting for training set size and marker density to model the average accuracy of genomic prediction. AB - Prediction of genomic breeding values is of major practical relevance in dairy cattle breeding. Deterministic equations have been suggested to predict the accuracy of genomic breeding values in a given design which are based on training set size, reliability of phenotypes, and the number of independent chromosome segments ([Formula: see text]). The aim of our study was to find a general deterministic equation for the average accuracy of genomic breeding values that also accounts for marker density and can be fitted empirically. Two data sets of 5'698 Holstein Friesian bulls genotyped with 50 K SNPs and 1'332 Brown Swiss bulls genotyped with 50 K SNPs and imputed to ~600 K SNPs were available. Different k-fold (k = 2-10, 15, 20) cross-validation scenarios (50 replicates, random assignment) were performed using a genomic BLUP approach. A maximum likelihood approach was used to estimate the parameters of different prediction equations. The highest likelihood was obtained when using a modified form of the deterministic equation of Daetwyler et al. (2010), augmented by a weighting factor (w) based on the assumption that the maximum achievable accuracy is [Formula: see text]. The proportion of genetic variance captured by the complete SNP sets ([Formula: see text]) was 0.76 to 0.82 for Holstein Friesian and 0.72 to 0.75 for Brown Swiss. When modifying the number of SNPs, w was found to be proportional to the log of the marker density up to a limit which is population and trait specific and was found to be reached with ~20'000 SNPs in the Brown Swiss population studied. PMID- 24339896 TI - Influence of the C242T polymorphism of the p22-phox gene (CYBA) on the interaction between urinary sodium excretion and blood pressure in an urban Brazilian population. AB - BACKGROUND: Reactive oxygen species are implicated in the physiopathogenesis of salt-induced hypertension and the C242T polymorphism of the p22-phox gene has been associated with higher superoxide production. This study investigated the impact of this polymorphism on the relationship between urinary sodium excretion (USE) and blood pressure levels in an urban Brazilian population. METHODS: We cross-sectionally evaluated 1,298 subjects from the city of Vitoria-ES, located in the Southeast region of Brazil, by clinical history, physical examination, anthropometry, analysis of laboratory parameters, USE measurement and p22-phox C242T polymorphism genotyping. RESULTS: No significant differences in studied parameters were detected between the studied genotype groups (CC vs. CT+TT). Systolic blood pressure exhibited significant correlation with USE only in T allele carriers (r = 0.166; p<0.001), while diastolic blood pressure and hypertension status correlated with USE in both genotypes albeit more weakly in subjects with CC genotype (r = 0.098; p = 0.021 and r = 0.105; p = 0.013, respectively) than in T carriers (r = 0.236; p<0.001 and r = 0.213; p<0.001, respectively). Regression analyses adjusted for confounding factors showed that USE remained independently associated with systolic (p<0.001) and diastolic blood pressure (p<0.001) and hypertension status (p = 0.004) only in T allele carriers. Finally, higher diastolic and systolic blood pressure levels were detected in T allele carriers than in CC genotype individuals in the highest tertile of USE. CONCLUSIONS: The p22-phox 242T allele is associated with higher blood pressure levels among subjects with higher USE in an urban Brazilian population. PMID- 24339897 TI - Subinhibitory antibiotic concentrations mediate nutrient use and competition among soil streptomyces. AB - Though traditionally perceived as weapons, antibiotics are also hypothesized to act as microbial signals in natural habitats. However, while subinhibitory concentrations of antibiotics (SICA) are known to shift bacterial gene expression, specific hypotheses as to how SICA influence the ecology of natural populations are scarce. We explored whether antibiotic 'signals', or SICA, have the potential to alter nutrient utilization, niche overlap, and competitive species interactions among Streptomyces populations in soil. For nine diverse Streptomyces isolates, we evaluated nutrient utilization patterns on 95 different nutrient sources in the presence and absence of subinhibitory concentrations of five antibiotics. There were significant changes in nutrient use among Streptomyces isolates, including both increases and decreases in the capacity to use individual nutrients in the presence vs. in the absence of SICA. Isolates varied in their responses to SICA and antibiotics varied in their effects on isolates. Furthermore, for some isolate-isolate-antibiotic combinations, competition-free growth (growth for an isolate on all nutrients that were not utilized by a competing isolate), was increased in the presence of SICA, reducing the potential fitness cost of nutrient competition among those competitors. This suggests that antibiotics may provide a mechanism for bacteria to actively minimize niche overlap among competitors in soil. Thus, in contrast to antagonistic coevolutionary dynamics, antibiotics as signals may mediate coevolutionary displacement among coexisting Streptomyces, thereby hindering the emergence of antibiotic resistant phenotypes. These results contribute to our broad understanding of the ecology and evolutionary biology of antibiotics and microbial signals in nature. PMID- 24339898 TI - CCAAT/enhancer-binding protein homologous (CHOP) protein promotes carcinogenesis in the DEN-induced hepatocellular carcinoma model. AB - BACKGROUND AND AIMS: C/EBP homologous protein (CHOP) plays pro-apoptotic roles in the integrated stress response. Recently, a tumor suppressive role for CHOP was demonstrated in lung cancer via regulation of tumor metabolism. To explore the role of CHOP in hepatocarcinogenesis, we induced hepatocellular carcinoma (HCC) in wild type (wt) and CHOP knockout (KO) mice using the carcinogen N diethylnitrosamine (DEN). RESULTS: Analysis of tumor development showed reduced tumor load, with markedly smaller tumor nodules in the CHOP KO animals, suggesting oncogenic roles of CHOP in carcinogen-induced HCC. In wt tumors, CHOP was exclusively expressed in tumor tissue, with minimal expression in normal parenchyma. Analysis of human adenocarcinomas of various origins demonstrated scattered expression of CHOP in the tumors, pointing to relevance in human pathology. Characterization of pathways that may contribute to preferential expression of CHOP in the tumor identified ATF6 as a potential candidate. ATF6, a key member of the endoplasmic reticulum stress signaling machinery, exhibited a similar pattern of expression as CHOP and strong activation in wt but not CHOP KO tumors. Because HCC is induced by chronic inflammation, we assessed whether CHOP deficiency affects tumor-immune system crosstalk. We found that the number of macrophages and levels of IFNgamma and CCL4 mRNA were markedly reduced in tumors from CHOP KO relative to wt mice, suggesting a role for CHOP in modulating tumor microenvironment and macrophage recruitment to the tumor. CONCLUSION: Our data highlights a role for CHOP as a positive regulator of carcinogen-induced HCC progression through a complex mechanism that involves the immune system and modulation of stress signaling pathways. PMID- 24339899 TI - Sequence-based SSR marker development and their application in defining the Introgressions of LA0716 (Solanum pennellii) in the background of cv. M82 (Solanum lycopersicum). AB - The introgression lines (ILs) from cv. M82 (Solanum lycopersicum) * LA0716 (S. pennellii) have been proven to be exceptionally useful for genetic analysis and gene cloning. The introgressions were originally defined by RFLP markers at their development. The objectives of this study are to develop polymorphic SSR markers, and to re-define the DNA introgression from LA0716 in the ILs. Tomato sequence data was scanned by software to generate SSR markers. In total, 829 SSRs, which could be robustly amplified by PCR, were developed. Among them, 658 SSRs were dinucleotide repeats, 162 were trinucleotide repeats, and nine were tetranucleotide repeats. The 829 SSRs together with 96 published RFLPs were integrated into the physical linkage map of S. lycopersicum. Introgressions of DNA fragments from LA0716 were re-defined among the 75 ILs using the newly developed SSRs. A specific introgression of DNA fragment from LA0716 was identified in 72 ILs as described previously by RFLP, whereas the specific DNA introgression described previously were not detected in the ILs LA4035, LA4059 and LA4091. The physical location of each investigated DNA introgression was finely determined by SSR mapping. Among the 72 ILs, eight ILs showed a shorter and three ILs (IL3-2, IL12-3 and IL12-3-1) revealed a longer DNA introgression than that framed by RFLPs. Furthermore, 54 previously undefined segments were found in 21 ILs, ranging from 1 to 11 DNA introgressions per IL. Generally, the newly developed SSRs provide additional markers for genetic studies of tomatoes, and the fine definition of DNA introgressions from LA0716 would facilitate the use of the ILs for genetic analysis and gene cloning. PMID- 24339900 TI - Global nanotribology research output (1996-2010): a scientometric analysis. AB - This study aims to assess the nanotribology research output at global level using scientometric tools. The SCOPUS database was used to retrieve records related to the nanotribology research for the period 1996-2010. Publications were counted on a fractional basis. The level of collaboration and its citation impact were examined. The performance of the most productive countries, institutes and most preferred journals is assessed. Various visualization tools such as the Sci(2) tool and Ucinet were employed. The USA ranked top in terms of number of publications, citations per paper and h-index, while Switzerland published a higher percentage of international collaborative papers. The most productive institution was Tsinghua University followed by Ohio State University and Lanzhou Institute of Chemical Physics, CAS. The most preferred journals were Tribology Letters, Wear and Journal of Japanese Society of Tribologists. The result of author keywords analysis reveals that Molecular Dynamics, MEMS, Hard Disk and Diamond like Carbon are major research topics. PMID- 24339901 TI - Historical versus contemporary climate forcing on the annual nesting variability of loggerhead sea turtles in the Northwest Atlantic Ocean. AB - A recent analysis suggested that historical climate forcing on the oceanic habitat of neonate sea turtles explained two-thirds of interannual variability in contemporary loggerhead (Caretta caretta) sea turtle nest counts in Florida, where nearly 90% of all nesting by this species in the Northwest Atlantic Ocean occurs. Here, we show that associations between annual nest counts and climate conditions decades prior to nest counts and those conditions one year prior to nest counts were not significantly different. Examination of annual nest count and climate data revealed that statistical artifacts influenced the reported 31 year lag association with nest counts. The projected importance of age 31 neophytes to annual nest counts between 2020 and 2043 was modeled using observed nest counts between 1989 and 2012. Assuming consistent survival rates among cohorts for a 5% population growth trajectory and that one third of the mature female population nests annually, the 41% decline in annual nest counts observed during 1998-2007 was not projected for 2029-2038. This finding suggests that annual nest count trends are more influenced by remigrants than neophytes. Projections under the 5% population growth scenario also suggest that the Peninsular Recovery Unit could attain the demographic recovery criteria of 106,100 annual nests by 2027 if nest counts in 2019 are at least comparable to 2012. Because the first year of life represents only 4% of the time elapsed through age 31, cumulative survival at sea across decades explains most cohort variability, and thus, remigrant population size. Pursuant to the U.S. Endangered Species Act, staggered implementation of protection measures for all loggerhead life stages has taken place since the 1970s. We suggest that the 1998-2007 nesting decline represented a lagged perturbation response to historical anthropogenic impacts, and that subsequent nest count increases since 2008 reflect a potential recovery response. PMID- 24339902 TI - The proteasome inhibitor bortezomib induces an inhibitory chromatin environment at a distal enhancer of the estrogen receptor-alpha gene. AB - Expression of the estrogen receptor-alpha (ERalpha) gene, ESR1, is a clinical biomarker used to predict therapeutic outcome of breast cancer. Hence, there is significant interest in understanding the mechanisms regulating ESR1 gene expression. Proteasome activity is increased in cancer and we previously showed that proteasome inhibition leads to loss of ESR1 gene expression in breast cancer cells. Expression of ESR1 mRNA in breast cancer cells is controlled predominantly through a proximal promoter within ~400 base pair (bp) of the transcription start site (TSS). Here, we show that loss of ESR1 gene expression induced by the proteasome inhibitor bortezomib is associated with inactivation of a distal enhancer located 150 kilobases (kb) from the TSS. Chromatin immunoprecipitation assays reveal several bortezomib-induced changes at the distal site including decreased occupancy of three critical transcription factors, GATA3, FOXA1, and AP2gamma. Bortezomib treatment also resulted in decreased histone H3 and H4 acetylation and decreased occupancy of histone acetyltransferase, p300. These data suggest a mechanism to explain proteasome inhibitor-induced loss of ESR1 mRNA expression that highlights the importance of the chromatin environment at the -150 kb distal enhancer in regulation of basal expression of ESR1 in breast cancer cells. PMID- 24339903 TI - Evidence for the high importance of co-morbid factors in HFE C282Y/H63D patients cared by phlebotomies: results from an observational prospective study. AB - Despite type I haemochromatosis (HC) is mainly associated with the HFE C282Y/C282Y genotype, a second genotype -C282Y/H63D- has mostly been described in other patients. Its association with HC, apart from any associated co-morbid factors, remains unclear and complex to interpret for physicians. This study assesses the weight of this genotype and the role of co-morbid factors in the occurrence of iron overload. This prospective study included the C282Y/C282Y (n = 172) and C282Y/H63D (n = 58) patients enrolled in a phlebotomy program between 2004 and 2007 in a blood centre of western Brittany (Brest, France), where HC is frequent. We compared prevalence of these two genotypes, as well as patients' profile regarding degree of iron overload and prevalence of co-morbid factors. First, we confirmed the obvious deficit of C282Y/H63D compound heterozygotes among patients cared by phlebotomies. This genotype was 3.0 times less frequent than the C282Y/C282Y genotype among those patients (18.9% vs. 56.0%) whereas it was 4.9 times more frequent in the general population (4.3% vs. 0.9%; p<0.0001). Despite a similar level of hyperferritinaemia, the C282Y/H63D patients who came to medical attention had a milder plasma iron overload, reflected by a lower transferrin saturation median (52.0% vs. 84.0%; p<0.0001). They also exhibited more frequently co-morbid factors, as heavy drinking (26.0% vs. 13.9%; p = 0.0454), overweight (66.7% vs. 39.4%; p = 0.0005) or both (21.3% vs. 2.6%; p<0.0001). Ultimately, they required a lower amount of iron removed to reach depletion (2.1 vs. 3.4 g; p<0.0001), clearly reflecting their lower tissue iron. This study confirms that H63D is a discrete genetic susceptibility factor whose expression is most visible in association with other co-factors. It highlights the importance of searching for co-morbidities in these diagnostic situations and of providing lifestyle and dietary advice. PMID- 24339904 TI - Study on the absorbed fingerprint-efficacy of yuanhu zhitong tablet based on chemical analysis, vasorelaxation evaluation and data mining. AB - Yuanhu Zhitong Tablet (YZT) is an example of a typical and relatively simple clinical herb formula that is widely used in clinics. It is generally believed that YZT play a therapeutical effect in vivo by the synergism of multiple constituents. Thus, it is necessary to build the relationship between the absorbed fingerprints and bioactivity so as to ensure the quality, safety and efficacy. In this study, a new combinative method, an intestinal absorption test coupled with a vasorelaxation bioactivity experiment in vitro, was a simple, sensitive, and feasible technique to study on the absorbed fingerprint-efficacy of YZT based on chemical analysis, vasorelaxation evaluation and data mining. As part of this method, an everted intestinal sac method was performed to determine the intestinal absorption of YZT solutions. YZT were dissolved in solution (n = 12), and the portion of the solution that was absorbed into intestinal sacs was analyzed using rapid-resolution liquid chromatography coupled with quadruple time of-flight mass spectrometry (RRLC-Q-TOF/MS). Semi-quantitative analysis indicated the presence of 34 compounds. The effect of the intestinally absorbed solution on vasorelaxation of rat aortic rings with endothelium attached was then evaluated in vitro. The results showed that samples grouped by HCA from chemical profiles have similar bioactivity while samples in different groups displayed very different. Moreover, it established a relationship between the absorbed fingerprints and their bioactivity to identify important components by grey relational analysis, which could predict bioactive values based on chemical profiles and provide an evidence for the quantification of multi-constituents. PMID- 24339905 TI - Alcohol and smoking affect risk of uncomplicated colonic diverticulosis in Japan. AB - Colonic diverticula are located predominantly on the right side in Asia and on the left side in Europe and the United States. Factors associated with uncomplicated colonic diverticulosis and its distribution pattern have been unknown. Our aims are to investigate the prevalence and risk factors for uncomplicated colonic diverticulosis. We conducted a prospective cross-sectional study in adults who underwent colonoscopy. Alcohol, alcohol related flushing, smoking, medications, and comorbidities were assessed by interview on the colonoscopy day. Alcohol consumption was categorized as nondrinker, light (1-180 g/week), moderate (181-360 g/week), and heavy (>=361 g/week). Smoking index was defined as the number of cigarettes per day multiplied by the number of smoking years and categorized as nonsmoker, <400, 400-799, and >=800. A total of 2,164 consecutive patients were enrolled. Overall, 542 patients (25.1%) had uncomplicated colonic diverticulosis located on the right side (50%), bilaterally (29%), and on the left side (21%). Univariate analysis revealed age, male, smoking index, alcohol consumption, aspirin use, anticoagulants use, corticosteroid use, hypertension, and atherosclerotic disease as factors significantly associated with diverticulosis. Alcohol related flushing was not associated with the disease. Multivariate analysis showed increasing age (P<0.01), increasing alcohol consumption (P<0.01) and smoking (P<0.01), and atherosclerotic disease (P<0.01) as significantly associated factors. Alcohol and smoking were associated with right-sided and bilateral diverticula. In conclusion, one in four Japanese adults have colonic diverticulosis (50% right sided). Age, alcohol consumption, and smoking were found to be significant risk factors for uncomplicated colonic diverticulosis, particularly right-sided and bilateral. PMID- 24339906 TI - Rapid and precise measurement of serum branched-chain and aromatic amino acids by isotope dilution liquid chromatography tandem mass spectrometry. AB - BACKGROUND: Serum branched-chain and aromatic amino acids (BCAAs and AAAs) have emerged as predictors for the future development of diabetes and may aid in diabetes risk assessment. However, the current methods for the analysis of such amino acids in biological samples are time consuming. METHODS: An isotope dilution liquid chromatography tandem mass spectrometry (ID-LC/MS/MS) method for serum BCAAs and AAAs was developed. The serum was mixed with isotope-labeled BCAA and AAA internal standards and the amino acids were extracted with acetonitrile, followed by analysis using LC/MS/MS. The LC separation was performed on a reversed-phase C18 column, and the MS/MS detection was performed via the positive electronic spray ionization in multiple reaction monitoring mode. RESULTS: Specific analysis of the amino acids was achieved within 2 min. Intra-run and total CVs for the amino acids were less than 2% and 4%, respectively, and the analytical recoveries ranged from 99.6 to 103.6%. CONCLUSION: A rapid and precise method for the measurement of serum BCAAs and AAAs was developed and may serve as a quick tool for screening serum BCAAs and AAAs in studies assessing diabetes risk. PMID- 24339907 TI - A comparative study of protocols for mouse embryonic stem cell culturing. AB - Most stem cell laboratories still rely on old culture methods to support the expansion and maintenance of mouse embryonic stem (ES) cells. These involve growing cells on mouse embryonic fibroblast feeder cells or on gelatin in media supplemented with fetal bovine serum and leukemia inhibitory factor (LIF). However, these techniques have several drawbacks including the need for feeder cells and/or use of undefined media containing animal derived components. Culture of stem cells under undefined conditions can induce spontaneous differentiation and reduce reproducibility of experiments. In recent years several new ES cell culture protocols, using more well-defined conditions, have been published and we have compared the standard culture protocols with two of the newly described ones: 1) growing cells in semi-adherence in a medium containing two small molecule inhibitors (CHIR99021, PD0325901) and; 2) growing cells in a spheroid suspension culture in a defined medium containing LIF and bFGF. Two feeder dependent mouse ES (mES) cell lines and two cell lines adapted to feeder independent growth were used in the study. The overall aim has not only been to compare self-renewal and differentiation capacity, but also ease-of-use and cost efficiency. We show that mES cells when grown adherently proliferate much faster than when grown in suspension as free-floating spheres, independent of media used. Although all the tested culture protocols could maintain sustained pluripotency after prolonged culturing, our data confirm previous reports showing that the media containing two chemical inhibitors generate more pure stem cell cultures with negligible signs of spontaneous differentiation as compared to standard mES media. Furthermore, we show that this medium effectively rescues and cleans up cultures that have started to deteriorate, as well as allow for effective adaption of feeder-dependent mES cell lines to be maintained in feeder free conditions. PMID- 24339908 TI - Self-esteem modulates the time course of self-positivity bias in explicit self evaluation. AB - Researchers have suggested that certain individuals may show a self-positivity bias, rating themselves as possessing more positive personality traits than others. Previous evidence has shown that people evaluate self-related information in such a way as to maintain or enhance self-esteem. However, whether self-esteem would modulate the time course of self-positivity bias in explicit self evaluation has never been explored. In the present study, 21 participants completed the Rosenberg self-esteem scale and then completed a task where they were instructed to indicate to what extent positive/negative traits described themselves. Behavioral data showed that participants endorsed positive traits as higher in self-relevance compared to the negative traits. Further, participants' self-esteem levels were positively correlated with their self-positivity bias. Electrophysiological data revealed smaller N1 amplitude and larger late positive component (LPC) amplitude to stimuli consistent with the self-positivity bias (positive-high self-relevant stimuli) when compared to stimuli that were inconsistent with the self-positivity bias (positive-low self-relevant stimuli). Moreover, only in individuals with low self-esteem, the latency of P2 was more pronounced in processing stimuli that were consistent with the self-positivity bias (negative-low self-relevant stimuli) than to stimuli that were inconsistent with the self-positivity bias (positive-low self-relevant stimuli). Overall, the present study provides additional support for the view that low self-esteem as a personality variable would affect the early attentional processing. PMID- 24339909 TI - Chorioamnionitis and subsequent lung function in preterm infants. AB - OBJECTIVE: To explore the relationship between prematurity, gender and chorioamnionitis as determinants of early life lung function in premature infants. METHODS: Placenta and membranes were collected from preterm deliveries (<37 weeks gestational age) and evaluated for histological chorioamnionitis (HCA). Patients were followed and lung function was performed in the first year of life by Raised Volume-Rapid Thoracic Compression Technique. RESULTS: Ninety five infants (43 males) born prematurely (median gestational age 34.2 weeks) were recruited. HCA was detected in 66 (69%) of the placentas, and of these 55(58%) were scored HCA Grade 1, and 11(12%) HCA Grade 2. Infants exposed to HCA Grade 1 and Grade 2, when compared to those not exposed, presented significantly lower gestational ages, higher prevalence of RDS, clinical early-onset sepsis, and the use of supplemental oxygen more than 28 days. Infants exposed to HCA also had significantly lower maximal flows. There was a significant negative trend for z scores of lung function in relation to levels of HCA; infants had lower maximal expiratory flows with increasing level of HCA. (p = 0.012 for FEF50, p = 0.014 for FEF25-75 and p = 0.32 for FEV0.5). Two-way ANOVA adjusted for length and gestational age indicated a significant interaction between sex and HCA in determining expiratory flows (p<0.01 for FEF50, FEF25-75 and p<0.05 for FEV0.5). Post-hoc comparisons revealed that female preterm infants exposed to HCA Grade 1 and Grade 2 had significant lower lung function than those not exposed, and this effect was not observed among males. CONCLUSIONS: Our findings show a sex specific negative effect of prenatal inflammation on lung function of female preterm infants. This study confirms and expands knowledge upon the known association between chorioamnionitis and early life chronic lung disease. PMID- 24339910 TI - Learning reflectance confocal microscopy of melanocytic skin lesions through histopathologic transversal sections. AB - Histopathologic interpretation of dermoscopic and reflectance confocal microscopy (RCM) features of cutaneous melanoma was timidly carried out using perpendicular histologic sections, which does not mimic the same plane of the image achieved at both techniques (horizontal plane). The aim of this study was to describe the transverse histologic sections research technique and correlate main dermoscopic features characteristic of cutaneous melanoma (atypical network, irregular globules and pseudopods) with RCM and histopathology in perpendicular and transverse sections in order to offer a more precise interpretation of in vivo detectable features. Four melanomas and 2 nevi with different dermoscopic clues have been studied. Lesion areas that showed characteristic dermoscopic features were imaged by dermoscopy and confocal microscopy and directly correlated with histopathology in perpendicular and transverse sections. We presented the possibility to perform transverse sections as a new approach to understand RCM features. Atypical network showed different aspects in the 2 melanomas: in one case it was characterized by pleomorphic malignant melanocytes with tendency to form aggregates, whereas in the other elongated dendritic cells crowded around dermal papillae, some of them forming bridges that resembled the mitochondrial aspect at confocal and histopathology transversal sections. Pigment globules in melanomas and nevi differed for the presence of large atypical cells in the former, and pseudopods showed up as elongated nests protruded toward the periphery of the lesion. Transverse histologic research sections have a consistent dermoscopic and confocal correlate, and it may represent an help in confocal feature interpretation and an advance in improving melanoma diagnosis and knowledge of the biology of melanocytic lesions. PMID- 24339911 TI - Association between exposure to environmental tobacco smoke and biomarkers of oxidative stress among patients hospitalised with acute myocardial infarction. AB - OBJECTIVE: To determine whether exposure to environmental tobacco smoke was associated with oxidative stress among patients hospitalised for acute myocardial infarction. DESIGN: An existing cohort study of 1,261 patients hospitalised for acute myocardial infarction. SETTING: Nine acute hospitals in Scotland. PARTICIPANTS: Sixty never smokers who had been exposed to environmental tobacco smoke (admission serum cotinine >=3.0 ng/mL) were compared with 60 never smokers who had not (admission serum cotinine <=0.1 ng/mL). INTERVENTION: None. MAIN OUTCOME MEASURES: Three biomarkers of oxidative stress (protein carbonyl, malondialdehyde (MDA) and oxidised low-density lipoprotein (ox-LDL)) were measured on admission blood samples and adjusted for potential confounders. RESULTS: After adjusting for baseline differences in age, sex and socioeconomic status, exposure to environmental tobacco smoke was associated with serum concentrations of both protein carbonyl (beta coefficient 7.96, 95% CI 0.76, 15.17, p = 0.031) and MDA (beta coefficient 10.57, 95% CI 4.32, 16.81, p = 0.001) but not ox-LDL (beta coefficient 2.14, 95% CI -8.94, 13.21, p = 0.703). CONCLUSIONS: Exposure to environmental tobacco smoke was associated with increased oxidative stress. Further studies are requires to explore the role of oxidative stress in the association between environmental tobacco smoke and myocardial infarction. PMID- 24339912 TI - Cytokines as mediators of chemotherapy-associated cognitive changes: current evidence, limitations and directions for future research. AB - OBJECTIVES: While various clinical and pharmacological determinants for chemotherapy-associated cognitive impairment have been identified, conflicting evidence suggests that cytokines might play an intermediary role. The objective of this systematic review was to evaluate the current evidence pertaining to the associations among chemotherapy, cytokines induction and cognitive impairment in cancer patients. METHODS: A literature search with PubMed and SciVerse Scopus was conducted in March 2013 to gather relevant articles and abstracts that fulfilled the inclusion and exclusion criteria. This review included studies that had performed objective and/or subjective cognitive assessments and cytokine measurements on defined populations of cancer patients who received chemotherapy. RESULTS: High methodological heterogeneity existed among the selected studies which differed in cancer populations, subject characteristics, cognitive endpoints, types of cytokines tested and their measurement methods. Weak to moderate correlations were observed between IL-1beta, IL-6, TNF-alpha levels, and different degrees of cognitive impairment. Different types of chemotherapy treatments might lead to varying presentations and severities of cytokine-induced cognitive impairment. Notably, the time concordance between the onset of cytokine induction and occurrence of cognitive impairment was not well elucidated. A number of confounding factors was identified to interfere with the expression levels of cytokines; these confounders included subjects' cancer types, ages, genders, genetics and psychosocial characteristics such as anxiety, depression and fatigue. CONCLUSION: Although existing studies observed cognitive impairment and cytokine dysregulation in patients who receive chemotherapy, our results suggest that the intermediary role of cytokines in post-chemotherapy cognitive impairment is still controversial and requires further evaluation. A list of methodological recommendations is proposed to harmonize future studies of this subject matter. PMID- 24339913 TI - HIV-1 replication fitness of HLA-B*57/58:01 CTL escape variants is restored by the accumulation of compensatory mutations in gag. AB - Expression of HLA-B*57 and the closely related HLA-B*58:01 are associated with prolonged survival after HIV-1 infection. However, large differences in disease course are observed among HLA-B*57/58:01 patients. Escape mutations in CTL epitopes restricted by these HLA alleles come at a fitness cost and particularly the T242N mutation in the TW10 CTL epitope in Gag has been demonstrated to decrease the viral replication capacity. Additional mutations within or flanking this CTL epitope can partially restore replication fitness of CTL escape variants. Five HLA-B*57/58:01 progressors and 5 HLA-B*57/58:01 long-term nonprogressors (LTNPs) were followed longitudinally and we studied which compensatory mutations were involved in the restoration of the viral fitness of variants that escaped from HLA-B*57/58:01-restricted CTL pressure. The Sequence Harmony algorithm was used to detect homology in amino acid composition by comparing longitudinal Gag sequences obtained from HIV-1 patients positive and negative for HLA-B*57/58:01 and from HLA-B*57/58:01 progressors and LTNPs. Although virus isolates from HLA-B*57/58:01 individuals contained multiple CTL escape mutations, these escape mutations were not associated with disease progression. In sequences from HLA-B*57/58:01 progressors, 5 additional mutations in Gag were observed: S126N, L215T, H219Q, M228I and N252H. The combination of these mutations restored the replication fitness of CTL escape HIV-1 variants. Furthermore, we observed a positive correlation between the number of escape and compensatory mutations in Gag and the replication fitness of biological HIV-1 variants isolated from HLA-B*57/58:01 patients, suggesting that the replication fitness of HLA-B*57/58:01 escape variants is restored by accumulation of compensatory mutations. PMID- 24339914 TI - PADI2 is significantly associated with rheumatoid arthritis. AB - Citrullination, a posttranslational modification of peptidyl arginine to citrulline, plays an essential role in rheumatoid arthritis (RA). Citrullination is catalyzed by a group of peptidylarginine deiminases (PADs) including PADI 1, 2, 3, 4 and 6. Many studies have indicated that the gene encoding PADI4 is a factor in susceptibility to RA. Some studies have detected PADI2 expression in RA synovial tissues, suggesting that PADI2 also plays an important role in the disease. This study evaluated the possible association between the PADI2-encoding gene and RA. Seventeen tag SNPs across the PAD locus were genotyped using a custom-designed Illumina 96-SNP VeraCode microarray. Peripheral blood samples were collected from patients with RA (n = 267), ankylosing spondylitis (AS, n = 51) and healthy controls (n = 160). The results of genotyping were verified using Sequenom MassARRAY in an independent cohort of 307 patients with RA, 324 patients with AS and 509 healthy controls. A western blot analysis was performed using synovial tissue from patients with RA (n = 7), osteoarthritis (OA, n = 7) and AS (n = 5) to determine the levels of expression of PADI2. A microarray analysis revealed a significant association between three selected PADI2 SNPs (rs2235926, rs2057094, rs2076616) and the presence of RA. The increased susceptibility to RA associated with rs2235926 (OR = 1.706733, 95% CI = [1.576366-1.866587], p = 0.000839) and rs2057094 (OR = 1.360432, 95% CI = [1.065483-1.869482], p = 0.003291) was further confirmed by the Sequenom MassARRAY. No tag SNPs in the PADI2 locus showed a significant association with AS. Increased expression of PADI2 was detected in RA synovial tissues compared with samples from patients with OA and AS. PADI2 is significantly associated with RA and may be involved in the pathogenesis of the disease. PMID- 24339915 TI - Pleiotropic actions of forskolin result in phosphatidylserine exposure in primary trophoblasts. AB - Forskolin is an extract of the Coleus forskholii plant that is widely used in cell physiology to raise intracellular cAMP levels. In the field of trophoblast biology, forskolin is one of the primary treatments used to induce trophoblastic cellular fusion. The syncytiotrophoblast (ST) is a continuous multinucleated cell in the human placenta that separates maternal from fetal circulations and can only expand by fusion with its stem cell, the cytotrophoblast (CT). Functional investigation of any aspect of ST physiology requires in vitro differentiation of CT and de novo ST formation, thus selecting the most appropriate differentiation agent for the hypothesis being investigated is necessary as well as addressing potential off-target effects. Previous studies, using forskolin to induce fusion in trophoblastic cell lines, identified phosphatidylserine (PS) externalization to be essential for trophoblast fusion and showed that widespread PS externalization is present even after fusion has been achieved. PS is a membrane phospholipid that is primarily localized to the inner-membrane leaflet. Externalization of PS is a hallmark of early apoptosis and is involved in cellular fusion of myocytes and macrophages. We were interested to examine whether PS externalization was also involved in primary trophoblast fusion. We show widespread PS externalization occurs after 72 hours when fusion was stimulated with forskolin, but not when stimulated with the cell permeant cAMP analog Br-cAMP. Using a forskolin analog, 1,9-dideoxyforskolin, which stimulates membrane transporters but not adenylate cyclase, we found that widespread PS externalization required both increased intracellular cAMP levels and stimulation of membrane transporters. Treatment of primary trophoblasts with Br-cAMP alone did not result in widespread PS externalization despite high levels of cellular fusion. Thus, we concluded that widespread PS externalization is independent of trophoblast fusion and, importantly, provide evidence that the common differentiation agent forskolin has previously unappreciated pleiotropic effects on trophoblastic cells. PMID- 24339916 TI - BioMog: a computational framework for the de novo generation or modification of essential biomass components. AB - The success of genome-scale metabolic modeling is contingent on a model's ability to accurately predict growth and metabolic behaviors. To date, little focus has been directed towards developing systematic methods of proposing, modifying and interrogating an organism's biomass requirements that are used in constraint based models. To address this gap, the biomass modification and generation (BioMog) framework was created and used to generate lists of biomass components de novo, as well as to modify predefined biomass component lists, for models of Escherichia coli (iJO1366) and of Shewanella oneidensis (iSO783) from high throughput growth phenotype and fitness datasets. BioMog's de novo biomass component lists included, either implicitly or explicitly, up to seventy percent of the components included in the predefined biomass equations, and the resulting de novo biomass equations outperformed the predefined biomass equations at qualitatively predicting mutant growth phenotypes by up to five percent. Additionally, the BioMog procedure can quantify how many experiments support or refute a particular metabolite's essentiality to a cell, and it facilitates the determination of inconsistent experiments and inaccurate reaction and/or gene to reaction associations. To further interrogate metabolite essentiality, the BioMog framework includes an experiment generation algorithm that allows for the design of experiments to test whether a metabolite is essential. Using BioMog, we correct experimental results relating to the essentiality of thyA gene in E. coli, as well as perform knockout experiments supporting the essentiality of protoheme. With these capabilities, BioMog can be a valuable resource for analyzing growth phenotyping data and component of a model developer's toolbox. PMID- 24339917 TI - Effect of lycium barbarum (wolfberry) polysaccharides on preserving retinal function after partial optic nerve transection. AB - Lycium Barbarum Polysaccharides (LBP) are the active components of Wolfberry (a traditional Chinese medicine) which has long been used for improving visual function. This study aims to investigate localized changes of retinal function in a partial optic nerve transection (PONT) model, and effects of LBP on visual function. The multifocal electroretinograms (mfERG) were obtained from 30 eyes of 30 Sprague-Dawley rats. The rats were divided into 6 groups (five treatment groups and one control group). Starting from the first day of the experiment, the rats in the (PONT+LBP) group and the (LBP) group were dosed with LBP; rats in the (PONT+PBS (phosphate buffered saline)) group and the (PBS) group were dosed with PBS via nasogastric tube every day until euthanized. The dorsal part of the optic nerve was transected in the (PONT), (PONT+LBP) and (PONT+PBS) groups at the end of week 1 (day 7 after LBP or PBS feeding began). The mfERG was measured at three time points: week 2, week 3 and week 5. Significant reduction of P1 and PhNR amplitudes of the mfERG were observed in all retinal regions a week after PONT. Feeding with LBP prior to PONT preserved retinal function. All mfERG responses returned to the normal range in the superior retina, which corresponds to the transected dorsal region of the optic nerve, while most of the inferior retinal responses were significantly increased at week 4 after PONT. The ventral part of the retina had secondary degeneration which was not only limited to the ganglion cell layer, but is a widespread effect affecting the outer retina. LBP altered the functional reduction caused by PONT by regulating the signal from the outer retina. PMID- 24339918 TI - Loss of progesterone receptor-mediated actions induce preterm cellular and structural remodeling of the cervix and premature birth. AB - A decline in serum progesterone or antagonism of progesterone receptor function results in preterm labor and birth. Whether characteristics of premature remodeling of the cervix after antiprogestins or ovariectomy are similar to that at term was the focus of the present study. Groups of pregnant rats were treated with vehicle, a progesterone receptor antagonist (onapristone or mifepristone), or ovariectomized on day 17 postbreeding. As expected, controls given vehicle delivered at term while rats delivered preterm after progesterone receptor antagonist treatment or ovariectomy. Similar to the cervix before term, the preterm cervix of progesterone receptor antagonist-treated rats was characterized by reduced cell nuclei density, decreased collagen content and structure, as well as a greater presence of macrophages per unit area. Thus, loss of nuclear progesterone receptor-mediated actions promoted structural remodeling of the cervix, increased census of resident macrophages, and preterm birth much like that found in the cervix at term. In contrast to the progesterone receptor antagonist-induced advance in characteristics associated with remodeling, ovariectomy-induced loss of systemic progesterone did not affect hypertrophy, extracellular collagen, or macrophage numbers in the cervix. Thus, the structure and macrophage census in the cervix appear sufficient for premature ripening and birth to occur well before term. With progesterone receptors predominantly localized on cells other than macrophages, the findings suggest that interactions between cells may facilitate the loss of progesterone receptor-mediated actions as part of a final common mechanism that remodels the cervix in certain etiologies of preterm and with parturition at term. PMID- 24339919 TI - The yeast Shu complex utilizes homologous recombination machinery for error-free lesion bypass via physical interaction with a Rad51 paralogue. AB - DNA-damage tolerance (DDT) is defined as a mechanism by which eukaryotic cells resume DNA synthesis to fill the single-stranded DNA gaps left by replication blocking lesions. Eukaryotic cells employ two different means of DDT, namely translesion DNA synthesis (TLS) and template switching, both of which are coordinately regulated through sequential ubiquitination of PCNA at the K164 residue. In the budding yeast Saccharomyces cerevisiae, the same PCNA-K164 residue can also be sumoylated, which recruits the Srs2 helicase to prevent undesired homologous recombination (HR). While the mediation of TLS by PCNA monoubiquitination has been extensively characterized, the method by which K63 linked PCNA polyubiquitination leads to template switching remains unclear. We recently identified a yeast heterotetrameric Shu complex that couples error-free DDT to HR as a critical step of template switching. Here we report that the Csm2 subunit of Shu physically interacts with Rad55, an accessory protein involved in HR. Rad55 and Rad57 are Rad51 paralogues and form a heterodimer to promote Rad51 ssDNA filament formation by antagonizing Srs2 activity. Although Rad55-Rad57 and Shu function in the same pathway and both act to inhibit Srs2 activity, Shu appears to be dedicated to error-free DDT while the Rad55-Rad57 complex is also involved in double-strand break repair. This study reveals the detailed steps of error-free lesion bypass and also brings to light an intrinsic interplay between error-free DDT and Srs2-mediated inhibition of HR. PMID- 24339920 TI - Elevated CO(2) modifies N acquisition of Medicago truncatula by enhancing N fixation and reducing nitrate uptake from soil. AB - The effects of elevated CO2 (750 ppm vs. 390 ppm) were evaluated on nitrogen (N) acquisition and assimilation by three Medicago truncatula genotypes, including two N-fixing-deficient mutants (dnf1-1 and dnf1-2) and their wild-type (Jemalong). The proportion of N acquisition from atmosphere and soil were quantified by (15)N stable isotope, and N transportation and assimilation-related genes and enzymes were determined by qPCR and biochemical analysis. Elevated CO2 decreased nitrate uptake from soil in all three plant genotypes by down regulating nitrate reductase (NR), nitrate transporter NRT1.1 and NR activity. Jemalong plant, however, produced more nodules, up-regulated N-fixation-related genes and enhanced percentage of N derived from fixation (%Ndf) to increase foliar N concentration and N content in whole plant (Ntotal Yield) to satisfy the requirement of larger biomass under elevated CO2. In contrast, both dnf1 mutants deficient in N fixation consequently decreased activity of glutamine synthetase/glutamate synthase (GS/GOGAT) and N concentration under elevated CO2. Our results suggest that elevated CO2 is likely to modify N acquisition of M. truncatula by simultaneously increasing N fixation and reducing nitrate uptake from soil. We propose that elevated CO2 causes legumes to rely more on N fixation than on N uptake from soil to satisfy N requirements. PMID- 24339921 TI - Non-local means denoising of dynamic PET images. AB - OBJECTIVE: Dynamic positron emission tomography (PET), which reveals information about both the spatial distribution and temporal kinetics of a radiotracer, enables quantitative interpretation of PET data. Model-based interpretation of dynamic PET images by means of parametric fitting, however, is often a challenging task due to high levels of noise, thus necessitating a denoising step. The objective of this paper is to develop and characterize a denoising framework for dynamic PET based on non-local means (NLM). THEORY: NLM denoising computes weighted averages of voxel intensities assigning larger weights to voxels that are similar to a given voxel in terms of their local neighborhoods or patches. We introduce three key modifications to tailor the original NLM framework to dynamic PET. Firstly, we derive similarities from less noisy later time points in a typical PET acquisition to denoise the entire time series. Secondly, we use spatiotemporal patches for robust similarity computation. Finally, we use a spatially varying smoothing parameter based on a local variance approximation over each spatiotemporal patch. METHODS: To assess the performance of our denoising technique, we performed a realistic simulation on a dynamic digital phantom based on the Digimouse atlas. For experimental validation, we denoised [Formula: see text] PET images from a mouse study and a hepatocellular carcinoma patient study. We compared the performance of NLM denoising with four other denoising approaches - Gaussian filtering, PCA, HYPR, and conventional NLM based on spatial patches. RESULTS: The simulation study revealed significant improvement in bias-variance performance achieved using our NLM technique relative to all the other methods. The experimental data analysis revealed that our technique leads to clear improvement in contrast-to-noise ratio in Patlak parametric images generated from denoised preclinical and clinical dynamic images, indicating its ability to preserve image contrast and high intensity details while lowering the background noise variance. PMID- 24339922 TI - Role of IGF-binding protein 3 in the resistance of EGFR mutant lung cancer cells to EGFR-tyrosine kinase inhibitors. AB - Most patients treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) eventually develop acquired resistance. Loss of expression of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) has been suggested as a possible mechanism of resistance to EGFR-TKIs in the A431 and HN11 cell lines. Here, we investigated IGFBP-3 expression in two EGFR mutant lung cancer cell lines with resistance to EGFR-TKIs and examined the value of serum IGFBP-3 level as a marker of resistance. The effect of the induction or suppression of IGFBP-3 expression on resistance was also evaluated. HCC827 sublines with resistance to gefitinib (HCC827/GR) and erlotinib (HCC827/ER) were established. Loss of IGFBP-3 expression was detected by Western blotting in both cell lines without changes in transcriptional activity, and ELISA showed significantly lower amounts of secreted IGFBP-3 in the culture media of the mutant cell lines than in that of the parental line. Despite the loss of IGFBP-3 expression, IGFR signalling activity remained unchanged. Forced expression of IGFBP-3 by adenovirus-mediated transfection or recombinant IGFBP-3 slightly increased the growth-inhibitory and apoptotic effects of EGFR-TKIs, whereas suppression of IGFBP-3 did not affect sensitivity to EGFR-TKI. Serum IGFBP-3 levels measured by ELISA before and after the development of EGFR-TKI resistance in 20 patients showed no significant changes (1815.3+/-94.6 ng/mL before treatment vs. 1778.9+/-87.8 ng/mL after EGFR TKI resistance). In summary, although IGFBP-3 downregulation is associated with the acquisition of resistance to EGFR-TKIs regardless of the mechanism, its effect on resistance was not significant, indicating that IGFBP-3 may not play an important role in resistance to EGFR-TKIs and serum IGFBP-3 level is not a reliable indicator of resistance. PMID- 24339923 TI - Associations of forest type, parasitism and body condition of two European passerines, Fringilla coelebs and Sylvia atricapilla. AB - Human-induced forest modification can alter parasite-host interactions and might change the persistence of host populations. We captured individuals of two widespread European passerines (Fringilla coelebs and Sylvia atricapilla) in southwestern Germany to disentangle the associations of forest types and parasitism by haemosporidian parasites on the body condition of birds. We compared parasite prevalence and parasite intensity, fluctuating asymmetries, leukocyte numbers, and the heterophil to lymphocyte ratio (H/L-ratio) among individuals from beech, mixed-deciduous and spruce forest stands. Based on the biology of bird species, we expected to find fewer infected individuals in beech or mixed-deciduous than in spruce forest stands. We found the highest parasite prevalence and intensity in beech forests for F. coelebs. Although, we found the highest prevalence in spruce forests for S. atricapilla, the highest intensity was detected in beech forests, partially supporting our hypothesis. Other body condition or health status metrics, such as the heterophil to lymphocyte ratio (H/L-ratio), revealed only slight differences between bird populations inhabiting the three different forest types, with the highest values in spruce for F. coelebs and in mixed-deciduous forests for S. atricapilla. A comparison of parasitized versus non-parasitized individuals suggests that parasite infection increased the immune response of a bird, which was detectable as high H/L-ratio. Higher infections with blood parasites for S. atricapilla in spruce forest indicate that this forest type might be a less suitable habitat than beech and mixed-deciduous forests, whereas beech forests seem to be a suboptimal habitat regarding parasitism for F. coelebs. PMID- 24339924 TI - Evaluation of anti-A/Udorn/307/1972 antibody specificity to influenza A/H3N2 viruses using an evanescent-field coupled waveguide-mode sensor. AB - Discrimination of closely related strains is a key issue, particularly for infectious diseases whose incidence fluctuates according to variations in the season and evolutionary changes. Among infectious diseases, influenza viral infections are a worldwide cause of pandemic disease and mortality. With the emergence of different influenza strains, it is vital to develop a method using antibodies that can differentiate between viral types and subtypes. Ideally, such a system would also be user friendly. In this study, a polyclonal antibody generated against A/Udorn/307/1972 (H3N2) was used as a probe to distinguish between influenza H3N2 viruses based on the interaction between the antibody and hemagglutinin, demonstrating its applicability for viral discrimination. Clear discrimination was demonstrated using an evanescent-field-coupled waveguide-mode sensor, which has appealing characteristics over other methods in the viewpoint of improving the sensitivity, measurement time, portability and usability. Further supporting evidence was obtained using enzyme-linked immunosorbent assays, hemagglutination-inhibition assays, and infectivity neutralization assays. The results obtained indicate that the polyclonal antibody used here is a potential probe for distinguishing influenza viruses and, with the aid of a handheld sensor it could be used for influenza surveillance. PMID- 24339925 TI - Optical waveguide lightmode spectroscopic techniques for investigating membrane bound ion channel activities. AB - Optical waveguide lightmode spectroscopic (OWLS) techniques were probed for monitoring ion permeation through channels incorporated into artificial lipid environment. A novel sensor set-up was developed by depositing liposomes or cell derived membrane fragments onto hydrophilic polytetrafluoroethylene (PTFE) membrane. The fibrous material of PTFE membrane could entrap lipoid vesicles and the water-filled pores provided environment for the hydrophilic domains of lipid embedded proteins. The sensor surface was kept clean from the lipid holder PTFE membrane by a water- and ion-permeable polyethylene terephthalate (PET) mesh. The sensor set-up was tested with egg yolk lecithin liposomes containing gramicidin ion channels and with cell-derived membrane fragments enriched in GABA-gated anion channels. The method allowed monitoring the move of Na(+) and organic cations through gramicidin channels and detecting the Cl(-)-channel functions of the (alpha5beta2gamma2) GABAA receptor in the presence or absence of GABA and the competitive GABA-blocker bicuculline. PMID- 24339926 TI - Predictive factors for reintubation following noninvasive ventilation in patients with respiratory complications after living donor liver transplantation. AB - BACKGROUND: Postoperative respiratory complications are a major cause of mortality following liver transplantation (LT). Noninvasive ventilation (NIV) appears to be effective for respiratory complications in patients undergoing solid organ transplantation; however, mortality has been high in patients who experienced reintubation in spite of NIV therapy. The predictors of reintubation following NIV therapy after LT are not exactly known. METHODS: Of 511 adult patients who received living-donor LT, data on the 179 who were treated by NIV were retrospectively examined. RESULTS: Forty-three (24%) of the 179 patients who received NIV treatment required reintubation. Independent factors associated with reintubation by multivariate logistic regression analysis were controlled preoperative infections (odds ratio [OR] 8.88; 95% confidence interval (CI) 1.64 to 48.11; p = 0.01), ABO-incompatibility (OR 4.49; 95% CI, 1.50 to 13.38; p = 0.007), and presence of postoperative pneumonia at the time of starting NIV (OR 3.28; 95% CI, 1.02 to 11.01; p = 0.04). The reintubated patients had a significant higher rate of postoperative infectious complications and a significantly longer intensive care unit stay than those in whom NIV was successful (p<0.0001). Of the 43 reintubated patients, 22 (51.2%) died during hospitalization following LT vs. 8 (5.9%) of the 136 patients in whom NIV was successful (p<0.0001). CONCLUSIONS: Because controlled preoperative infection, ABO-incompatibility or pneumonia prior to the start of NIV were independent risk factors for reintubation following NIV, caution should be used in applying NIV in patients with these conditions considering the high rate of mortality in patients requiring reintubation following NIV. PMID- 24339927 TI - Correlation between national influenza surveillance data and google trends in South Korea. AB - BACKGROUND: In South Korea, there is currently no syndromic surveillance system using internet search data, including Google Flu Trends. The purpose of this study was to investigate the correlation between national influenza surveillance data and Google Trends in South Korea. METHODS: Our study was based on a publicly available search engine database, Google Trends, using 12 influenza-related queries, from September 9, 2007 to September 8, 2012. National surveillance data were obtained from the Korea Centers for Disease Control and Prevention (KCDC) influenza-like illness (ILI) and virologic surveillance system. Pearson's correlation coefficients were calculated to compare the national surveillance and the Google Trends data for the overall period and for 5 influenza seasons. RESULTS: The correlation coefficient between the KCDC ILI and virologic surveillance data was 0.72 (p<0.05). The highest correlation was between the Google Trends query of H1N1 and the ILI data, with a correlation coefficient of 0.53 (p<0.05), for the overall study period. When compared with the KCDC virologic data, the Google Trends query of bird flu had the highest correlation with a correlation coefficient of 0.93 (p<0.05) in the 2010-11 season. The following queries showed a statistically significant correlation coefficient compared with ILI data for three consecutive seasons: Tamiflu (r = 0.59, 0.86, 0.90, p<0.05), new flu (r = 0.64, 0.43, 0.70, p<0.05) and flu (r = 0.68, 0.43, 0.77, p<0.05). CONCLUSIONS: In our study, we found that the Google Trends for certain queries using the survey on influenza correlated with national surveillance data in South Korea. The results of this study showed that Google Trends in the Korean language can be used as complementary data for influenza surveillance but was insufficient for the use of predictive models, such as Google Flu Trends. PMID- 24339929 TI - Large animal model for development of functional restoration paradigms using epidural and intraspinal stimulation. AB - Restoration of movement following spinal cord injury (SCI) has been achieved using electrical stimulation of peripheral nerves and skeletal muscles. However, practical limitations such as the rapid onset of muscle fatigue hinder clinical application of these technologies. Recently, direct stimulation of alpha motor neurons has shown promise for evoking graded, controlled, and sustained muscle contractions in rodent and feline animal models while overcoming some of these limitations. However, small animal models are not optimal for the development of clinical spinal stimulation techniques for functional restoration of movement. Furthermore, variance in surgical procedure, targeting, and electrode implantation techniques can compromise therapeutic outcomes and impede comparison of results across studies. Herein, we present a protocol and large animal model that allow standardized development, testing, and optimization of novel clinical strategies for restoring motor function following spinal cord injury. We tested this protocol using both epidural and intraspinal stimulation in a porcine model of spinal cord injury, but the protocol is suitable for the development of other novel therapeutic strategies. This protocol will help characterize spinal circuits vital for selective activation of motor neuron pools. In turn, this will expedite the development and validation of high-precision therapeutic targeting strategies and stimulation technologies for optimal restoration of motor function in humans. PMID- 24339928 TI - BCR-ABL1-associated reduction of beta catenin antagonist Chibby1 in chronic myeloid leukemia. AB - Beta Catenin signaling is critical for the self-renewal of leukemic stem cells in chronic myeloid leukemia. It is driven by multiple events, enhancing beta catenin stability and promoting its transcriptional co-activating function. We investigated the impact of BCR-ABL1 on Chibby1, a beta catenin antagonist involved in cell differentiation and transformation. Relative proximity of the Chibby1 encoding gene (C22orf2) on chromosome 22q12 to the BCR breakpoint (22q11) lets assume its involvement in beta catenin activation in chronic myeloid leukemia as a consequence of deletions of distal BCR sequences encompassing one C22orf2 allele. Forty patients with chronic myeloid leukemia in chronic phase were analyzed for C22orf2 relocation and Chibby1 expression. Fluorescent in situ hybridization analyses established that the entire C22orf2 follows BCR regardless of chromosomes involved in the translocation. In differentiated hematopoietic progenitors (bone marrow mononuclear cell fractions) of 30/40 patients, the expression of Chibby1 protein was reduced below 50% of the reference value (peripheral blood mononuclear cell fractions of healthy persons). In such cell context, Chibby1 protein reduction is not dependent on C22orf2 transcriptional downmodulation; however, it is strictly dependent upon BCR-ABL1 expression because it was not observed at the moment of major molecular response under tyrosine kinase inhibitor therapy. Moreover, it was not correlated with the disease prognosis or response to therapy. Most importantly, a remarkable Chibby1 reduction was apparent in a putative BCR-ABL1+ leukemic stem cell compartment identified by a CD34+ phenotype compared to more differentiated hematopoietic progenitors. In CD34+ cells, Chibby1 reduction arises from transcriptional events and is driven by C22orf2 promoter hypermethylation. These results advance low Chibby1 expression associated with BCR-ABL1 as a component of beta catenin signaling in leukemic stem cells. PMID- 24339930 TI - T cell-specific overexpression of TGFbeta1 fails to influence atherosclerosis in ApoE-deficient mice. AB - Clinical data have indicated a negative correlation between plasma TGFbeta1 concentrations and the extent of atherosclerosis and have thus led to the hypothesis that the pleiotropic cytokine may have anti-atherogenic properties. T cells are currently discussed to significantly participate in atherogenesis, but the precise role of adaptive immunity in atherogenesis remains to be elucidated. TGFbeta1 is known to strongly modulate the function of T-cells, however, inhibition of TGFbeta1 signalling in T-cells of atherosclerosis-prone knock-out mice failed to unequivocally clarify the role of the cytokine for the development of atherosclerosis. In the present study, we thus tried to specify the role of TGFbeta1 in atherogenesis by using the murine CD2-TGFbeta1 transgenic strain which represents a well characterized model of T-cell specific TGFbeta1 overexpression. The CD2-TGFbeta1 transgenic mice were crossed to ApoE knock-out mice and quantity and quality of atherosclerosis regarding number of macrophages, smooth muscle cells, CD3 positive T-cells and collagen was analyzed in CD2 TGFbeta1 ApoE double mutants as well as non-transgenic ApoE controls on both normal and atherogenic diet of a duration of 8, 16 or 24 weeks, respectively. In all experimental groups investigated, we failed to detect any influence of TGFbeta1 overexpression on disease. Total number of CD3-positive T-lymphocytes was not significantly different in atherosclerotic lesions of CD2-TGFbeta1 ApoE( /-) females and isogenic ApoE(-/-) controls, even after 24 weeks on the atherogenic diet. The synopsis of these data and our previous study on TGFbeta1 overexpressing macrophages suggests that potential effects of TGFbeta1 on atherosclerosis are most probably mediated by macrophages rather than T-cells. PMID- 24339931 TI - Intracellular nucleic acid delivery by the supercharged dengue virus capsid protein. AB - Supercharged proteins are a recently identified class of proteins that have the ability to efficiently deliver functional macromolecules into mammalian cells. They were first developed as bioengineering products, but were later found in the human proteome. In this work, we show that this class of proteins with unusually high net positive charge is frequently found among viral structural proteins, more specifically among capsid proteins. In particular, the capsid proteins of viruses from the Flaviviridae family have all a very high net charge to molecular weight ratio (> +1.07/kDa), thus qualifying as supercharged proteins. This ubiquity raises the hypothesis that supercharged viral capsid proteins may have biological roles that arise from an intrinsic ability to penetrate cells. Dengue virus capsid protein was selected for a detailed experimental analysis. We showed that this protein is able to deliver functional nucleic acids into mammalian cells. The same result was obtained with two isolated domains of this protein, one of them being able to translocate lipid bilayers independently of endocytic routes. Nucleic acids such as siRNA and plasmids were delivered fully functional into cells. The results raise the possibility that the ability to penetrate cells is part of the native biological functions of some viral capsid proteins. PMID- 24339933 TI - Stability-based comparison of class discovery methods for DNA copy number profiles. AB - MOTIVATION: Array-CGH can be used to determine DNA copy number, imbalances in which are a fundamental factor in the genesis and progression of tumors. The discovery of classes with similar patterns of array-CGH profiles therefore adds to our understanding of cancer and the treatment of patients. Various input data representations for array-CGH, dissimilarity measures between tumor samples and clustering algorithms may be used for this purpose. The choice between procedures is often difficult. An evaluation procedure is therefore required to select the best class discovery method (combination of one input data representation, one dissimilarity measure and one clustering algorithm) for array-CGH. Robustness of the resulting classes is a common requirement, but no stability-based comparison of class discovery methods for array-CGH profiles has ever been reported. RESULTS: We applied several class discovery methods and evaluated the stability of their solutions, with a modified version of Bertoni's [Formula: see text] based test [1]. Our version relaxes the assumption of independency required by original Bertoni's [Formula: see text]-based test. We conclude that Minimal Regions of alteration (a concept introduced by [2]) for input data representation, sim [3] or agree [4] for dissimilarity measure and the use of average group distance in the clustering algorithm produce the most robust classes of array-CGH profiles. AVAILABILITY: The software is available from http://bioinfo.curie.fr/projects/cgh-clustering. It has also been partly integrated into "Visualization and analysis of array-CGH"(VAMP)[5]. The data sets used are publicly available from ACTuDB [6]. PMID- 24339932 TI - Deciphering small noncoding RNAs during the transition from dormant embryo to germinated embryo in Larches (Larix leptolepis). AB - Small RNAs (sRNAs), as a key component of molecular biology, play essential roles in plant development, hormone signaling, and stress response. However, little is known about the relationships among sRNAs, hormone signaling, and dormancy regulation in gymnosperm embryos. To investigate the roles of sRNAs in embryo dormancy maintenance and release in Larix leptolepis, we deciphered the endogenous "sRNAome" in dormant and germinated embryos. High-throughput sequencing of sRNA libraries showed that dormant embryos exhibited a length bias toward 24-nt while germinated embryos showed a bias toward 21-nt lengths. This might be associated with distinct levels of RNA-dependent RNA polymerase2 (RDR2) and/or RDR6, which is regulated by hormones. Proportions of miRNAs to nonredundant and redundant sRNAs were higher in germinated embryos than in dormant embryos, while the ratio of unknown sRNAs was higher in dormant embryos than in germinated embryos. We identified a total of 160 conserved miRNAs from 38 families, 3 novel miRNAs, and 16 plausible miRNA candidates, of which many were upregulated in germinated embryos relative to dormant embryos. These findings indicate that larches and possibly other gymnosperms have complex mechanisms of gene regulation involving miRNAs and other sRNAs operating transcriptionally and posttranscriptionally during embryo dormancy and germination. We propose that abscisic acid modulates embryo dormancy and germination at least in part through regulation of the expression level of sRNA-biogenesis genes, thus changing the sRNA components. PMID- 24339934 TI - Engagement of two distinct binding domains on CCL17 is required for signaling through CCR4 and establishment of localized inflammatory conditions in the lung. AB - CCL17 (TARC) function can be completely abolished by mAbs that block either one of two distinct sites required for CCR4 signaling. This chemokine is elevated in sera of asthma patients and is responsible for establishing inflammatory sites through CCR4-mediated recruitment of immune cells. CCL17 shares the GPCR CCR4, with CCL22 (MDC) but these two chemokines differentially affect the immune response. To better understand chemokine mediated effects through CCR4, we have generated chimeric anti-mouse CCL17 surrogate antibodies that inhibit function of this ligand in vitro and in vivo. The affinities of the surrogate antibodies for CCL17 range from 685 pM for B225 to 4.9 nM for B202. One antibody, B202, also exhibits weak binding to CCL22 (KD~2 uM) and no binding to CCL22 is detectable with the second antibody, B225. In vitro, both antibodies inhibit CCL17-mediated calcium mobilization, beta-arrestin recruitment and chemotaxis; B202 can also partially inhibit CCL22-mediated beta-arrestin recruitment. Both B202 and B225 antibodies neutralize CCL17 in vivo as demonstrated by reduction of methacholine induced airway hyperreactivity in the A. fumigatus model of asthma. That both antibodies block CCL17 function but only B202 shows any inhibition of CCL22 function suggests that they bind CCL17 at different sites. Competition binding studies confirm that these two antibodies recognize unique epitopes that are non overlapping despite the small size of CCL17. Taking into consideration the data from both the functional and binding studies, we propose that effective engagement of CCR4 by CCL17 involves two distinct binding domains and interaction with both is required for signaling. PMID- 24339935 TI - Site distribution at the edge of the palaeolithic world: a nutritional niche approach. AB - This paper presents data from the English Channel area of Britain and Northern France on the spatial distribution of Lower to early Middle Palaeolithic pre-MIS5 interglacial sites which are used to test the contention that the pattern of the richest sites is a real archaeological distribution and not of taphonomic origin. These sites show a marked concentration in the middle-lower reaches of river valleys with most being upstream of, but close to, estimated interglacial tidal limits. A plant and animal database derived from Middle-Late Pleistocene sites in the region is used to estimate the potentially edible foods and their distribution in the typically undulating landscape of the region. This is then converted into the potential availability of macronutrients (proteins, carbohydrates, fats) and selected micronutrients. The floodplain is shown to be the optimum location in the nutritional landscape (nutriscape). In addition to both absolute and seasonal macronutrient advantages the floodplains could have provided foods rich in key micronutrients, which are linked to better health, the maintenance of fertility and minimization of infant mortality. Such places may have been seen as 'good (or healthy) places' explaining the high number of artefacts accumulated by repeated visitation over long periods of time and possible occupation. The distribution of these sites reflects the richest aquatic and wetland successional habitats along valley floors. Such locations would have provided foods rich in a wide range of nutrients, importantly including those in short supply at these latitudes. When combined with other benefits, the high nutrient diversity made these locations the optimal niche in northwest European mixed temperate woodland environments. It is argued here that the use of these nutritionally advantageous locations as nodal or central points facilitated a healthy variant of the Palaeolithic diet which permitted habitation at the edge of these hominins' range. PMID- 24339936 TI - CT angiography of the head-and-neck vessels acquired with low tube voltage, low iodine, and iterative image reconstruction: clinical evaluation of radiation dose and image quality. AB - OBJECTIVES: We aimed to assess the effectiveness and feasibility of head-and-neck Computed Tomography Angiography (CTA) with low tube voltage and low concentration contrast media combined with iterative reconstruction algorithm. METHODS: 92 patients were randomly divided into group A and B: patients in group A received a conventional scan with 120 kVp and contrast media of 320 mgI/ml. Patients in group B, 80 kVp and contrast media of 270 mgI/ml were used along with iterative reconstruction algorithm techniques. Image quality, radiation dose and the effectively consumed iodine amount between two groups were analyzed and compared. RESULTS: Image quality of CTA of head-and-neck vessels obtained from patients in group B was significantly improved quantitatively and qualitatively. In addition, CT attenuation values in group B were also significantly higher than that in group A (p<0.001). Furthermore, compared with the protocol whereby 120 kVp and 320 mgI/dl were administrated, the mean radiation dose and consumed iodine amount in protocol B were also reduced by 50% and 15.6%, respectively (p<0.001). CONCLUSIONS: With the help of iterative reconstruction algorithm techniques, the head-and-neck CTA with diagnostic quality can be adequately acquired with low tube voltage and low concentration contrast media. This method could be potentially extended to include any part of the body to reduce the risks related to ionizing radiation. PMID- 24339937 TI - Nuclear modifier MTO2 modulates the aminoglycoside-sensitivity of mitochondrial 15S rRNA C1477G mutation in Saccharomyces cerevisiae. AB - The phenotypic manifestations of mitochondrial DNA (mtDNA) mutations are modulated by mitochondrial DNA haplotypes, nuclear modifier genes and environmental factors. The yeast mitochondrial 15S rRNA C1477G (P(R) or P(R) 454) mutation corresponds to the human 12S rRNA C1494T and A1555G mutations, which are well known as primary factors for aminoglycoside-induced nonsyndromic deafness. Here we report that the deletion of the nuclear modifier gene MTO2 suppressed the aminoglycoside-sensitivity of mitochondrial 15S rRNA C1477G mutation in Saccharomyces cerevisiae. First, the strain with a single mtDNA C1477G mutation exhibited hypersensitivity to neomycin. Functional assays indicated that the steady-state transcription level of mitochondrial DNA, the mitochondrial respiratory rate, and the membrane potential decreased significantly after neomycin treatment. The impaired mitochondria could not produce sufficient energy to maintain cell viability. Second, when the mto2 null and the mitochondrial C1477G mutations co-existed (mto2(P(R))), the oxygen consumption rate in the double mutant decreased markedly compared to that of the control strains (MTO2(P(S)), mto2(P(S)) and MTO2(P(R))). The expression levels of the key glycolytic genes HXK2, PFK1 and PYK1 in the mto2(P(R)) strain were stimulated by neomycin and up-regulated by 89%, 112% and 55%, respectively. The enhanced glycolysis compensated for the respiratory energy deficits, and could be inhibited by the glycolytic enzyme inhibitor. Our findings in yeast will provide a new insight into the pathogenesis of human deafness. PMID- 24339938 TI - In vitro susceptibilities of wild and drug resistant leishmania donovani amastigote stages to andrographolide nanoparticle: role of vitamin E derivative TPGS for nanoparticle efficacy. AB - Visceral leishmaniasis (VL) is a chronic protozoan infection in humans associated with significant global morbidity and mortality. There is an urgent need to develop drugs and strategy that will improve therapeutic response for effective clinical treatment of drug resistant VL. To address this need, andrographolide (AG) nanoparticles were designed with P-gp efflux inhibitor vitamin E TPGS (D alpha-tocopheryl polyethyleneglycol 1000 succinate) for sensitivity against drug resistant Leishmania strains. AG loaded PLGA (50?50) nanoparticles (AGnps) stabilized by vitamin E TPGS were prepared for delivery into macrophage cells infested with sensitive and drug resistant amastigotes of Leishmania parasites. Physico-chemical characterization of AGnps by photon correlation spectroscopy exhibited an average particle size of 179.6 nm, polydispersity index of 0.245 and zeta potential of -37.6 mV. Atomic force microscopy and transmission electron microscopy visualization revealed spherical nanoparticles with smooth surfaces. AGnps displayed sustained AG release up to 288 hours as well as minimal particle aggregation and drug loss even after three months study period. Antileishmanial activity as revealed from selectivity index in wild-type strain was found to be significant for AGnp with TPGS in about one-tenth of the dosage of the free AG and one-third of the dosage of the AGnp without TPGS. Similar observations were also found in case of in vitro generated drug resistant and field isolated resistant strains of Leishmania. Cytotoxicity of AGnp with and without TPGS was significantly less than standard antileishmanial chemotherapeutics like amphotericin B, paromomycin or sodium stibogluconate. Macrophage uptake of AGnps was almost complete within one hour as evident from fluorescent microscopy studies. Thus, based on these observations, it can be concluded that the low selectivity of AG in in vitro generated drug resistant and field isolated resistant strains was improved in case of AG nanomedicines designed with vitamin E TPGS. PMID- 24339939 TI - Bronchial smooth muscle cells of asthmatics promote angiogenesis through elevated secretion of CXC-chemokines (ENA-78, GRO-alpha, and IL-8). AB - BACKGROUND: Airway wall remodelling is a key pathology of asthma. It includes thickening of the airway wall, hypertrophy and hyperplasia of bronchial smooth muscle cells (BSMC), as well as an increased vascularity of the sub-epithelial cell layer. BSMC are known to be the effector cells of bronchoconstriction, but they are increasingly recognized as an important source of inflammatory mediators and angiogenic factors. OBJECTIVE: To compare the angiogenic potential of BSMC of asthmatic and non-asthmatic patients and to identify asthma-specific angiogenic factors. METHODS: Primary BSMC were isolated from human airway tissue of asthmatic and non-asthmatic patients. Conditioned medium (CM) collected from BSMC isolates was tested for angiogenic capacity using the endothelial cell (EC) spheroid in vitro angiogenesis assay. Angiogenic factors in CM were quantified using a human angiogenesis antibody array and enzyme linked immunosorbent assay. RESULTS: Induction of sprout outgrowth from EC-spheroids by CM of BSMC obtained from asthma patients was increased compared with CM of control BSMC (twofold, p < 0.001). Levels of ENA-78, GRO-alpha and IL-8 were significantly elevated in CM of BSMC from asthma patients (p < 0.05 vs. non-asthmatic patients). SB 265610, a competitive antagonist of chemokine (CXC-motif) receptor 2 (CXCR2), attenuated the increased sprout outgrowth induced by CM of asthma patient-derived BSMC. CONCLUSIONS: BSMC isolated from asthma patients exhibit increased angiogenic potential. This effect is mediated through the CXCR2 ligands (ENA78, GRO-alpha and IL-8) produced by BSMC. IMPLICATIONS: CXCR2 ligands may play a decisive role in directing the neovascularization in the sub-epithelial cell layers of the lungs of asthma patients. Counteracting the CXCR2-mediated neovascularization by pharmaceutical compounds may represent a novel strategy to reduce airway remodelling in asthma. PMID- 24339940 TI - A fluorescence-based thermal shift assay identifies inhibitors of mitogen activated protein kinase kinase 4. AB - Prostate cancer (PCa) is the second highest cause of cancer death in United States males. If the metastatic movement of PCa cells could be inhibited, then mortality from PCa could be greatly reduced. Mitogen-activated protein kinase kinase 4 (MAP2K4) has previously been shown to activate pro-invasion signaling pathways in human PCa. Recognizing that MAP2K4 represents a novel and validated therapeutic target, we sought to develop and characterize an efficient process for the identification of small molecules that target MAP2K4. Using a fluorescence-based thermal shift assay (FTS) assay, we first evaluated an 80 compound library of known kinase inhibitors, thereby identifying 8 hits that thermally stabilized MAP2K4 in a concentration dependent manner. We then developed an in vitro MAP2K4 kinase assay employing the biologically relevant downstream substrates, JNK1 and p38 MAPK, to evaluate kinase inhibitory function. In this manner, we validated the performance of our initial FTS screen. We next applied this approach to a 2000 compound chemically diverse library, identified 7 hits, and confirmed them in the in vitro kinase assay. Finally, by coupling our structure-activity relationship data to MAP2K4's crystal structure, we constructed a model for ligand binding. It predicts binding of our identified inhibitory compounds to the ATP binding pocket. Herein we report the creation of a robust inhibitor-screening platform with the ability to inform the discovery and design of new and potent MAP2K4 inhibitors. PMID- 24339941 TI - Electrophysiological correlates of amnestic mild cognitive impairment in a simon task. AB - Amnestic mild cognitive impairment (aMCI) represents a prodromal stage of Alzheimer's disease (AD), especially when additional cognitive domains are affected (Petersen et al., 2009). Thus, single-domain amnestic MCI (sdaMCI) and multiple-domain-amnestic MCI (mdaMCI) biomarkers are important for enabling early interventions to help slow down progression of the disease. Recording event related potentials (ERPs) is a non-invasive and inexpensive measure of brain activity associated with cognitive processes, and it is of interest from a clinical point of view. The ERP technique may also be useful for obtaining early sdaMCI and mdaMCI biomarkers because ERPs are sensitive to impairment in processes that are not manifested at behavioral or clinical levels. In the present study, EEG activity was recorded in 25 healthy participants and 30 amnestic MCI patients (17 sdaMCI and 13 mdaMCI) while they performed a Simon task. The ERPs associated with visuospatial (N2 posterior-contralateral - N2pc -) and motor (lateralized readiness potential - LRP -) processes were examined. The N2pc amplitude was smaller in participants with mdaMCI than in healthy participants, which indicated a decline in the correlates of allocation of attentional resources to the target stimulus. In addition, N2pc amplitude proved to be a moderately good biomarker of mdaMCI subtype (0.77 sensitivity, 0.76 specificity). However, the LRP amplitude was smaller in the two MCI groups (sdaMCI and mdaMCI) than in healthy participants, revealing a reduction in the motor resources available to execute the response in sdaMCI and mdaMCI patients. Furthermore, the LRP amplitude proved to be a valid biomarker (0.80 sensitivity, 0.92 specificity) of both amnestic MCI subtypes. PMID- 24339943 TI - ReliefSeq: a gene-wise adaptive-K nearest-neighbor feature selection tool for finding gene-gene interactions and main effects in mRNA-Seq gene expression data. AB - Relief-F is a nonparametric, nearest-neighbor machine learning method that has been successfully used to identify relevant variables that may interact in complex multivariate models to explain phenotypic variation. While several tools have been developed for assessing differential expression in sequence-based transcriptomics, the detection of statistical interactions between transcripts has received less attention in the area of RNA-seq analysis. We describe a new extension and assessment of Relief-F for feature selection in RNA-seq data. The ReliefSeq implementation adapts the number of nearest neighbors (k) for each gene to optimize the Relief-F test statistics (importance scores) for finding both main effects and interactions. We compare this gene-wise adaptive-k (gwak) Relief F method with standard RNA-seq feature selection tools, such as DESeq and edgeR, and with the popular machine learning method Random Forests. We demonstrate performance on a panel of simulated data that have a range of distributional properties reflected in real mRNA-seq data including multiple transcripts with varying sizes of main effects and interaction effects. For simulated main effects, gwak-Relief-F feature selection performs comparably to standard tools DESeq and edgeR for ranking relevant transcripts. For gene-gene interactions, gwak-Relief-F outperforms all comparison methods at ranking relevant genes in all but the highest fold change/highest signal situations where it performs similarly. The gwak-Relief-F algorithm outperforms Random Forests for detecting relevant genes in all simulation experiments. In addition, Relief-F is comparable to the other methods based on computational time. We also apply ReliefSeq to an RNA-Seq study of smallpox vaccine to identify gene expression changes between vaccinia virus-stimulated and unstimulated samples. ReliefSeq is an attractive tool for inclusion in the suite of tools used for analysis of mRNA-Seq data; it has power to detect both main effects and interaction effects. Software Availability: http://insilico.utulsa.edu/ReliefSeq.php. PMID- 24339942 TI - Epistatic effects on abdominal fat content in chickens: results from a genome wide SNP-SNP interaction analysis. AB - We performed a pairwise epistatic interaction test using the chicken 60 K single nucleotide polymorphism (SNP) chip for the 11(th) generation of the Northeast Agricultural University broiler lines divergently selected for abdominal fat content. A linear mixed model was used to test two dimensions of SNP interactions affecting abdominal fat weight. With a threshold of P<1.2*10(-11) by a Bonferroni 5% correction, 52 pairs of SNPs were detected, comprising 45 pairs showing an Additive*Additive and seven pairs showing an Additive*Dominance epistatic effect. The contribution rates of significant epistatic interactive SNPs ranged from 0.62% to 1.54%, with 47 pairs contributing more than 1%. The SNP-SNP network affecting abdominal fat weight constructed using the significant SNP pairs was analyzed, estimated and annotated. On the basis of the network's features, SNPs Gga_rs14303341 and Gga_rs14988623 at the center of the subnet should be important nodes, and an interaction between GGAZ and GGA8 was suggested. Twenty-two quantitative trait loci, 97 genes (including nine non-coding genes), and 50 pathways were annotated on the epistatic interactive SNP-SNP network. The results of the present study provide insights into the genetic architecture underlying broiler chicken abdominal fat weight. PMID- 24339944 TI - Circulating endothelial cells in patients with venous thromboembolism and myeloproliferative neoplasms. AB - BACKGROUND: Circulating endothelial cells (CEC) may be a biomarker of vascular injury and pro-thrombotic tendency, while circulating endothelial progenitor cells (CEP) may be an indicator for angiogenesis and vascular remodelling. However, there is not a universally accepted standardized protocol to identify and quantify these cells and its clinical relevancy remains to be established. OBJECTIVES: To quantify CEC and CEP in patients with venous thromboembolism (VTE) and with myeloproliferative neoplasms (MPN), to characterize the CEC for the expression of activation (CD54, CD62E) and procoagulant (CD142) markers and to investigate whether they correlate with other clinical and laboratory data. PATIENTS AND METHODS: Sixteen patients with VTE, 17 patients with MPN and 20 healthy individuals were studied. The CEC and CEP were quantified and characterized in the blood using flow cytometry, and the demographic, clinical and laboratory data were obtained from hospital records. RESULTS: We found the CEC counts were higher in both patient groups as compared to controls, whereas increased numbers of CEP were found only in patients with MPN. In addition, all disease groups had higher numbers of CD62E+ CEC as compared to controls, whereas only patients with VTE had increased numbers of CD142+ and CD54+ CEC. Moreover, the numbers of total and CD62+ CEC correlated positively with the white blood cells (WBC) counts in both groups of patients, while the numbers of CEP correlated positively with the WBC counts only in patients with MPN. In addition, in patients with VTE a positive correlation was found between the numbers of CD54+ CEC and the antithrombin levels, as well as between the CD142+ CEC counts and the number of thrombotic events. CONCLUSIONS: Our study suggests that CEC counts may reveal endothelial injury in patients with VTE and MPN and that CEC may express different activation-related phenotypes depending on the disease status. PMID- 24339945 TI - Physiological conjunction of allelochemicals and desert plants. AB - Plants exchange signals with other physical and biological entities in their habitat, a form of communication termed allelopathy. The underlying principles of allelopathy and secondary-metabolite production are still poorly understood, especially in desert plants. The coordination and role of secondary metabolites were examined as a cause of allelopathy in plants thriving under arid and semiarid soil conditions. Desert plant species, Origanum dayi, Artemisia sieberi and Artemisia judaica from two different sources (cultivar cuttings and wild seeds) were studied in their natural habitats. Growth rate, relative water content, osmotic potential, photochemical efficiency, volatile composition and vital factors of allelopathy were analyzed at regular intervals along four seasons with winter showing optimum soil water content and summer showing water deficit conditions. A comprehensive analysis of the volatile composition of the leaves, ambient air and soil in the biological niche of the plants under study was carried out to determine the effects of soil water conditions and sample plants on the surrounding flora. Significant morpho-physiological changes were observed across the seasons and along different soil water content. Metabolic analysis showed that water deficit was the key for driving selective metabolomic shifts. A. judaica showed the least metabolic shifts, while A. sieberi showed the highest shifts. All the species exhibited high allelopathic effects; A. judaica displayed relatively higher growth-inhibition effects, while O. dayi showed comparatively higher germination-inhibition effects in germination assays. The current study may help in understanding plant behavior, mechanisms underlying secondary-metabolite production in water deficit conditions and metabolite physiological interrelationship with allelopathy in desert plants, and can help cull economic benefits from the produced volatiles. PMID- 24339946 TI - Interleukin-8 responses of multi-layer gingival epithelia to subgingival biofilms: role of the "red complex" species. AB - Periodontitis is an infectious inflammatory disease that results in the destruction of the tooth-supporting (periodontal) tissues. The Gram-negative anaerobic species Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola, (also known as the "red complex" species) are highly associated with subgingival biofilms at periodontitis-affected sites. A major chemokine produced by the gingival epithelium in response to biofilm challenge, is interleukin (IL) 8. The aim of this in vitro study was to investigate the relative effect of the "red complex" species as constituents of subgingival biofilms, on the regulation of IL-8 by gingival epithelia. Multi-layered organotypic human gingival epithelial cultures were challenged with a 10-species in vitro subgingival biofilm model, or its 7-species variant, excluding the "red complex". IL-8 gene expression and secretion analyses were performed by qPCR and ELISA, respectively. After 3 h, both biofilms up-regulated IL-8 gene expression, but the presence of the "red complex" resulted in 3-fold greater response. IL-8 secretion was also up regulated by both biofilms, with no differences between them. After 24 h, the 10 species biofilm reduced IL-8 secretion to 50% of the control, but this was not affected when the "red complex" was absent. In conclusion, as part of biofilms, "red complex" species differentially regulate IL-8 in gingival epithelia, potentially affecting the chemotactic responses of the tissue. PMID- 24339947 TI - Serological evidence for multiple strains of canine norovirus in the UK dog population. AB - Noroviruses are associated with intestinal disease in humans, cows, pigs, mice, and, more recently, dogs. In 2007, the first canine norovirus (CNV) was identified and characterized in Italy. Subsequent studies have identified CNV in stools of dogs from Portugal, Greece, and the United States. To investigate the prevalence of CNV in the UK dog population, 228 canine stool samples were screened for CNV by qPCR, and 396 serum samples were screened for anti-CNV antibodies. qPCR of RNA extracted from canine stool samples did not reveal any CNV-positive samples, based on samples collected from diarrhoeic and control dogs in 2012-2013. CNV virus-like particles to three different CNV strains were produced using recombinant baculoviruses and a seroprevalence screen undertaken. Anti-CNV antibodies were identified at significant levels in canine serum; 38.1% of samples collected between 1999-2001 and 60.1% of samples collected in 2012 2013 were seropositive. The increase in seroprevalence over time (p<0.001) suggests that the CNV strains screened for are becoming more widespread. Variation in seroprevalence to different CNV strains was also identified. Two thirds of the dogs were seropositive to a single strain, whereas the remaining third were seropositive to two or three of the strains analysed. This study has provided the first evidence that CNV is present in the UK, with seroprevalence identified to multiple circulating strains. This warrants further study and increased awareness of this recently discovered canine virus. PMID- 24339948 TI - Transformation of lipid bodies related to hydrocarbon accumulation in a green alga, Botryococcus braunii (Race B). AB - The colonial microalga Botryococcus braunii accumulates large quantities of hydrocarbons mainly in the extracellular space; most other oleaginous microalgae store lipids in the cytoplasm. Botryococcus braunii is classified into three principal races (A, B, and L) based on the types of hydrocarbons. Race B has attracted the most attention as an alternative to petroleum by its higher hydrocarbon contents than the other races and its hydrocarbon components, botryococcenes and methylsqualenes, both can be readily converted into biofuels. We studied race B using fluorescence and electron microscopy, and clarify the stage when extracellular hydrocarbon accumulation occurs during the cell cycle, in a correlation with the behavior and structural changes of the lipid bodies and discussed development of the algal colony. New accumulation of lipids on the cell surface occurred after cell division in the basolateral region of daughter cells. While lipid bodies were observed throughout the cell cycle, their size and inclusions were dynamically changing. When cells began dividing, the lipid bodies increased in size and inclusions until the extracellular accumulation of lipids started. Most of the lipids disappeared from the cytoplasm concomitant with the extracellular accumulation, and then reformed. We therefore hypothesize that lipid bodies produced during the growth of B. braunii are related to lipid secretion. New lipids secreted at the cell surface formed layers of oil droplets, to a maximum depth of six layers, and fused to form flattened, continuous sheets. The sheets that combined a pair of daughter cells remained during successive cellular divisions and the colony increased in size with increasing number of cells. PMID- 24339950 TI - Evidence of physiological decoupling from grassland ecosystem drivers by an encroaching woody shrub. AB - Shrub encroachment of grasslands is a transformative ecological process by which native woody species increase in cover and frequency and replace the herbaceous community. Mechanisms of encroachment are typically assessed using temporal data or experimental manipulations, with few large spatial assessments of shrub physiology. In a mesic grassland in North America, we measured inter- and intra annual variability in leaf delta(13)C in Cornus drummondii across a grassland landscape with varying fire frequency, presence of large grazers and topographic variability. This assessment of changes in individual shrub physiology is the largest spatial and temporal assessment recorded to date. Despite a doubling of annual rainfall (in 2008 versus 2011), leaf delta(13)C was statistically similar among and within years from 2008-11 (range of -28 to -270/00). A topography*grazing interaction was present, with higher leaf delta(13)C in locations that typically have more bare soil and higher sensible heat in the growing season (upland topographic positions and grazed grasslands). Leaf delta(13)C from slopes varied among grazing contrasts, with upland and slope leaf delta(13)C more similar in ungrazed locations, while slopes and lowlands were more similar in grazed locations. In 2011, canopy greenness (normalized difference vegetation index - NDVI) was assessed at the centroid of individual shrubs using high-resolution hyperspectral imagery. Canopy greenness was highest mid-summer, likely reflecting temporal periods when C assimilation rates were highest. Similar to patterns seen in leaf delta(13)C, NDVI was highest in locations that typically experience lowest sensible heat (lowlands and ungrazed). The ability of Cornus drummondii to decouple leaf physiological responses from climate variability and fire frequency is a likely contributor to the increase in cover and frequency of this shrub species in mesic grassland and may be generalizable to other grasslands undergoing woody encroachment. PMID- 24339949 TI - Effectors of epidermal growth factor receptor pathway: the genetic profiling ofKRAS, BRAF, PIK3CA, NRAS mutations in colorectal cancer characteristics and personalized medicine. AB - Mutations in KRAS oncogene are recognized biomarkers that predict lack of response to anti- epidermal growth factor receptor (EGFR) antibody therapies. However, some patients with KRAS wild-type tumors still do not respond, so other downstream mutations in BRAF, PIK3CA and NRAS should be investigated. Herein we used direct sequencing to analyze mutation status for 676 patients in KRAS (codons 12, 13 and 61), BRAF (exon 11 and exon 15), PIK3CA (exon 9 and exon 20) and NRAS (codons12, 13 and 61). Clinicopathological characteristics associations were analyzed together with overall survival (OS) of metastatic colorectal cancer patients (mCRC). We found 35.9% (242/674) tumors harbored a KRAS mutation, 6.96% (47/675) harbored a BRAF mutation, 9.9% (62/625) harbored a PIK3CA mutation and 4.19% (26/621) harbored a NRAS mutation. KRAS mutation coexisted with BRAF, PIK3CA and NRAS mutation, PIK3CA exon9 mutation appeared more frequently in KRAS mutant tumors (P = 0.027) while NRAS mutation almost existed in KRAS wild-types (P<0.001). Female patients and older group harbored a higher KRAS mutation (P = 0.018 and P = 0.031, respectively); BRAF (V600E) mutation showed a higher frequency in colon cancer and poor differentiation tumors (P = 0.020 and P = 0.030, respectively); proximal tumors appeared a higher PIK3CA mutation (P<0.001) and distant metastatic tumors shared a higher NRAS mutation (P = 0.010). However, in this study no significant result was found between OS and gene mutation in mCRC group. To our knowledge, the first large-scale retrospective study on comprehensive genetic profile which associated with anti-EGFR MoAbs treatment selection in East Asian CRC population, appeared a specific genotype distribution picture, and the results provided a better understanding between clinicopathological characteristics and gene mutations in CRC patients. PMID- 24339951 TI - Can Chinese herbal medicine improve outcomes of in vitro fertilization? A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: A large number of infertile couples are choosing Chinese herbal medicine (CHM) as an adjuvant therapy to improve their success when undergoing in vitro fertilization (IVF). There is no systematic review to evaluate the impact of CHM on the IVF outcomes. OBJECTIVE: To evaluate the effectiveness of CHM with concurrent IVF versus IVF alone on the outcomes of IVF and its safety. METHODS: The protocol of this study is registered at PROSPERO. Eligible RCTs searched from 8 databases which compared a combination of CHM and IVF with IVF alone were included. Two authors independently selected studies, extracted data and assessed methodological quality. Meta-analysis of RCTs was conducted if there was non significant heterogeneity (evaluated by I(2) test) among trials. All statistical analysis was performed using RevMan 5.1 software. RESULTS: Twenty trials involving 1721 women were included in the meta-analysis. Three trials were evaluated as having an unclear risk of bias. The remaining trials were evaluated as having a high risk of bias. Combination of CHM and IVF significantly increases clinical pregnancy rates (OR 2.04, 95%CI 1.67 to 2.49, p<0.00001) and ongoing pregnancy rates (OR 1.91, 95%CI 1.17 to 3.10, p = 0.009). Use of CHM after embryo transfer had no better outcome in reducing the rate of ovarian hyper stimulation syndrome (OR 0.39, 95%CI 0.14 to 1.11, p = 0.08). CONCLUSIONS: This meta-analysis showed that combination of IVF and CHM used in the included trials improve IVF success, however due to the high risk of bias observed with the trials, the significant differences found with the meta-analysis are unlikely to be accurate. No conclusion could be drawn with respect to the reproductive toxicity of CHM. Further large randomized placebo controlled trials are warranted to confirm these findings before recommending women to take CHM to improve their IVF success. PMID- 24339952 TI - The newly discovered cytokine IL-34 is expressed in gingival fibroblasts, shows enhanced expression by pro-inflammatory cytokines, and stimulates osteoclast differentiation. AB - BACKGROUND: Interleukin-34 (IL-34) is a recently discovered cytokine functionally overlapping macrophage colony stimulating factor (M-CSF), a mediator of inflammation and osteoclastogenesis in bone-degenerative diseases such as rheumatoid arthritis. The objective of this study was to assess the expression of IL-34 in human gingival fibroblasts and investigate if the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and Interleukin-1Beta (IL 1beta) modulate its expression, and moreover if IL-34 could contribute to recruitment of bone-resorbing osteoclasts. METHODS: IL-34 expression was evaluated in gingival fibroblasts by real time PCR following stimulation by TNF alpha, IL-1beta, and treatment with inhibitors of intracellular pathways. The formation of osteoclasts was evaluated by tartrate-resistant acid phosphatase (TRAP) staining of bone marrow macrophages treated with IL-34 or M-CSF in addition to receptor activator of nuclear factor kappa-B ligand (RANKL). RESULTS: IL-34 was expressed in gingival fibroblasts. The expression was enhanced by TNF alpha and IL-1beta, regulated by the transcription factor nuclear factor kappa B (NF-kappaBeta) and activation of c-Jun N-terminal kinase (JNK). Further, IL-34 supports RANKL-induced osteoclastogensis of bone marrow macrophages, independently of M-CSF. SUMMARY: In conclusion, this study shows for the first time IL-34 expression in human gingival fibroblasts, stimulated by TNF-alpha and IL-1beta, key mediators of periodontal inflammation. Furthermore, IL-34 can be substituted for M-CSF in RANKL-induced osteoclastogenesis. IL-34 may contribute to inflammation and osteoclastogenesis in bone-degenerative diseases such as periodontitis. PMID- 24339953 TI - Patrilineal background of esophageal cancer and gastric cardia cancer patients in a Chaoshan high-risk area in China. AB - The Taihang Mountain range of north-central China, the Southern region area of Fujian province, and the Chaoshan plain of Guangdong province are 3 major regions in China well known for their high incidence of esophageal cancer (EC). These areas also exhibit high incidences of gastric cardia cancer (GCC). The ancestors of the Chaoshanese, now the major inhabitants in the Chaoshan plain, were from north-central China. We hypothesized that EC and GCC patients in Chaoshan areas share a common ancestry with Taihang Mountain patients. We analyzed 16 East Asian specific Y-chromosome biallelic markers (single nucleotide polymorphisms; Y-SNPs) and 6 Y-chromosome short tandem repeat (Y-STR) loci in 72 EC and 48 GCC patients from Chaoshan and 49 EC and 63 GCC patients from the Taihang Mountain range. We also compared data for 32 Chaoshan Hakka people and 24 members of the aboriginal She minority who live near the Chaoshan area. Analysis was by frequency distribution and principal component, correlation and hierarchical cluster analysis of Y-SNP. Chaoshan patients were closely related to Taihang Mountain patients, even though they are geographically distant. Y-STR analysis revealed that the 4 patient groups were more closely related with each other than with other groups. Network analysis of the haplogroup O3a3c1-M117 showed a high degree of patient-specific substructure. We suggest that EC and GCC patients from these 2 areas share a similar patrilineal genetic background, which may play an important role in the genetic factor of EC and GCC in these populations. PMID- 24339954 TI - Gene expression profiles accurately predict outcome following liver resection in patients with metastatic colorectal cancer. AB - PURPOSE: The aim of this study was to build a molecular prognostic model based on gene signatures for patients with completely resected hepatic metastases from colorectal cancer (MCRC). METHODS: Using the Illumina HumanHT-12 gene chip, RNA samples from the liver metastases of 96 patients who underwent R0 liver resection were analyzed. Patients were randomly assigned to a training (n = 60) and test (n = 36) set. The genes associated with disease-specific survival (DSS) and liver recurrence-free survival (LRFS) were identified by Cox-regression and selected to construct a molecular risk score (MRS) using the supervised principle component method on the training set. The MRS was then evaluated in the independent test set. RESULTS: Nineteen and 115 genes were selected to construct the MRS for DSS and LRFS, respectively. Each MRS was validated in the test set; 3-year DSS/LRFS rates were 42/32% and 79/80% for patients with high and low MRS, respectively (p = 0.007 for DSS and p = 0.046 for LRFS). In a multivariate model controlling for a previously validated clinical risk score (CRS), the MRS remained a significant predictor of DSS (p = 0.001) and LRFS (p = 0.03). When CRS and MRS were combined, the patients were discriminated better with 3-year DSS/LRFS rates of 90/89% in the low risk group (both risk scores low) vs 42/26% in the high risk group (both risk scores high), respectively (p = 0.002/0.004 for DSS/LRFS). CONCLUSION: MRS based on gene expression profiling has high prognostic value and is independent of CRS. This finding provides a potential strategy for better risk-stratification of patients with liver MCRC. PMID- 24339955 TI - Sequencing and de novo assembly of the transcriptome of the glassy-winged sharpshooter (Homalodisca vitripennis). AB - BACKGROUND: The glassy-winged sharpshooter Homalodisca vitripennis (Hemiptera: Cicadellidae), is a xylem-feeding leafhopper and important vector of the bacterium Xylella fastidiosa; the causal agent of Pierce's disease of grapevines. The functional complexity of the transcriptome of H. vitripennis has not been elucidated thus far. It is a necessary blueprint for an understanding of the development of H. vitripennis and for designing efficient biorational control strategies including those based on RNA interference. RESULTS: Here we elucidate and explore the transcriptome of adult H. vitripennis using high-throughput paired end deep sequencing and de novo assembly. A total of 32,803,656 paired-end reads were obtained with an average transcript length of 624 nucleotides. We assembled 32.9 Mb of the transcriptome of H. vitripennis that spanned across 47,265 loci and 52,708 transcripts. Comparison of our non-redundant database showed that 45% of the deduced proteins of H. vitripennis exhibit identity (e value <=1(-5)) with known proteins. We assigned Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations, and potential Pfam domains to each transcript isoform. In order to gain insight into the molecular basis of key regulatory genes of H. vitripennis, we characterized predicted proteins involved in the metabolism of juvenile hormone, and biogenesis of small RNAs (Dicer and Piwi sequences) from the transcriptomic sequences. Analysis of transposable element sequences of H. vitripennis indicated that the genome is less expanded in comparison to many other insects with approximately 1% of the transcriptome carrying transposable elements. CONCLUSIONS: Our data significantly enhance the molecular resources available for future study and control of this economically important hemipteran. This transcriptional information not only provides a more nuanced understanding of the underlying biological and physiological mechanisms that govern H. vitripennis, but may also lead to the identification of novel targets for biorationally designed control strategies. PMID- 24339956 TI - Effectiveness of link prediction for face-to-face behavioral networks. AB - Research on link prediction for social networks has been actively pursued. In link prediction for a given social network obtained from time-windowed observation, new link formation in the network is predicted from the topology of the obtained network. In contrast, recent advances in sensing technology have made it possible to obtain face-to-face behavioral networks, which are social networks representing face-to-face interactions among people. However, the effectiveness of link prediction techniques for face-to-face behavioral networks has not yet been explored in depth. To clarify this point, here we investigate the accuracy of conventional link prediction techniques for networks obtained from the history of face-to-face interactions among participants at an academic conference. Our findings were (1) that conventional link prediction techniques predict new link formation with a precision of 0.30-0.45 and a recall of 0.10 0.20, (2) that prolonged observation of social networks often degrades the prediction accuracy, (3) that the proposed decaying weight method leads to higher prediction accuracy than can be achieved by observing all records of communication and simply using them unmodified, and (4) that the prediction accuracy for face-to-face behavioral networks is relatively high compared to that for non-social networks, but not as high as for other types of social networks. PMID- 24339957 TI - Improving embryonic stem cell expansion through the combination of perfusion and Bioprocess model design. AB - BACKGROUND: High proliferative and differentiation capacity renders embryonic stem cells (ESCs) a promising cell source for tissue engineering and cell-based therapies. Harnessing their potential, however, requires well-designed, efficient and reproducible expansion and differentiation protocols as well as avoiding hazardous by-products, such as teratoma formation. Traditional, standard culture methodologies are fragmented and limited in their fed-batch feeding strategies that afford a sub-optimal environment for cellular metabolism. Herein, we investigate the impact of metabolic stress as a result of inefficient feeding utilizing a novel perfusion bioreactor and a mathematical model to achieve bioprocess improvement. METHODOLOGY/PRINCIPAL FINDINGS: To characterize nutritional requirements, the expansion of undifferentiated murine ESCs (mESCs) encapsulated in hydrogels was performed in batch and perfusion cultures using bioreactors. Despite sufficient nutrient and growth factor provision, the accumulation of inhibitory metabolites resulted in the unscheduled differentiation of mESCs and a decline in their cell numbers in the batch cultures. In contrast, perfusion cultures maintained metabolite concentration below toxic levels, resulting in the robust expansion (>16-fold) of high quality 'naive' mESCs within 4 days. A multi-scale mathematical model describing population segregated growth kinetics, metabolism and the expression of selected pluripotency ('stemness') genes was implemented to maximize information from available experimental data. A global sensitivity analysis (GSA) was employed that identified significant (6/29) model parameters and enabled model validation. Predicting the preferential propagation of undifferentiated ESCs in perfusion culture conditions demonstrates synchrony between theory and experiment. CONCLUSIONS/SIGNIFICANCE: The limitations of batch culture highlight the importance of cellular metabolism in maintaining pluripotency, which necessitates the design of suitable ESC bioprocesses. We propose a novel investigational framework that integrates a novel perfusion culture platform (controlled metabolic conditions) with mathematical modeling (information maximization) to enhance ESC bioprocess productivity and facilitate bioprocess optimization. PMID- 24339959 TI - The yule approximation for the site frequency spectrum after a selective sweep. AB - In the area of evolutionary theory, a key question is which portions of the genome of a species are targets of natural selection. Genetic hitchhiking is a theoretical concept that has helped to identify various such targets in natural populations. In the presence of recombination, a severe reduction in sequence diversity is expected around a strongly beneficial allele. The site frequency spectrum is an important tool in genome scans for selection and is composed of the numbers S(1),...,S(n-1), where S(k) is the number of single nucleotide polymorphisms (SNPs) present in k from n individuals. Previous work has shown that both the number of low- and high-frequency variants are elevated relative to neutral evolution when a strongly beneficial allele fixes. Here, we follow a recent investigation of genetic hitchhiking using a marked Yule process to obtain an analytical prediction of the site frequency spectrum in a panmictic population at the time of fixation of a highly beneficial mutation. We combine standard results from the neutral case with the effects of a selective sweep. As simulations show, the resulting formula produces predictions that are more accurate than previous approaches for the whole frequency spectrum. In particular, the formula correctly predicts the elevation of low- and high frequency variants and is significantly more accurate than previously derived formulas for intermediate frequency variants. PMID- 24339958 TI - Bcl-xL silencing induces alterations in hsa-miR-608 expression and subsequent cell death in A549 and SK-LU1 human lung adenocarcinoma cells. AB - Bcl-xL is an anti-apoptotic protein that is frequently found to be overexpressed in non-small cell lung cancer leading to an inhibition of apoptosis and poor prognosis. Recently, the role of miRNAs in regulating apoptosis and cell survival during tumorigenesis has become evident, with cancer cells showing perturbed expression of various miRNAs. In this study, we utilized miRNA microarrays to determine if miRNA dysregulation in bcl-xL silenced lung adenocarcinoma cells could be involved in regulating cell death. Short interfering RNA-based transfection of A549 and SK-LU1 lung adenocarcinoma cells was successful in inducing a reduction in bcl-xL expression levels, resulting in a decrease in cell viability. A total of 10 miRNAs were found to be significantly differentially expressed when compared between siRNA-transfected and non-transfected cells including hsa-miR-181a, hsa-miR-769-5p, hsa-miR-361-5p, hsa-miR-1304 and hsa-miR 608. When overexpression studies on hsa-miR-608 was performed via transfection of miRNA mimics, cell death was found to be induced in A549 and SK-LU1 cells in comparison to untreated cells. This effect was reversed when knockdown studies involving anti-sense inhibitors were introduced. Combination of siRNA based silencing of bcl-xL (siBcl-xL) followed by anti-sense inhibitor transfection led to a decrease in the apoptotic population of A549 and SK-LU1 cells in comparison to cells only treated with siBcl-xL, illustrating the connection between bcl-xL, hsa-miR-608 and cell death. Gene target prediction analysis implicated the PI3K/AKT, WNT, TGF-beta, and ERK signaling pathways as targets of bcl-xL induced miRNA alterations. We have demonstrated that bcl-xL silencing in A549 and SK-LU1 cells leads to the occurrence of cell death through the dysregulation of specific miRNAs. This study also provides a platform for anti-sense gene therapy whereby miRNA expression can be exploited to increase the apoptotic properties in lung adenocarcinoma cells. PMID- 24339960 TI - Spatio-temporal structure of hooded gull flocks. AB - We analyzed the spatio-temporal structure of hooded gull flocks with a portable stereo camera system. The 3-dimensional positions of individuals were reconstructed from pairs of videos. The motions of each individual were analyzed, and both gliding and flapping motions were quantified based on the velocity time series. We analyzed the distributions of the nearest neighbor's position in terms of coordinates based on each individual's motion. The obtained results were consistent with the aerodynamic interaction between individuals. We characterized the leader-follower relationship between individuals by a delay time to mimic the direction of a motion. A relation between the delay time and a relative position was analyzed quantitatively, which suggested the basic properties of the formation flight that maintains order in the flock. PMID- 24339961 TI - Association between low levels of Mannan-binding lectin and markers of autoimmune thyroid disease in pregnancy. AB - Functional deficiency of mannan-binding lectin (MBL) has been associated with adverse pregnancy outcome. Adverse events during pregnancy have also been described in women with autoimmune thyroid diseases (AITD), and thyroid hormones have been shown to influence serum levels of MBL. Therefore, the aim of this study was to analyse the impact of MBL-deficiency on the outcome of pregnancy in relation to the presence of AITD. Almost one year after delivery, we assessed serum MBL levels and MBL2-genotypes in 212 women positively screened for AITD in pregnancy. In 103 of these women, we could also measure MBL levels in frozen serum samples from the 9-12(th) gestational week, obtaining 96 pairs of MBL values (pregnancy vs. follow-up). As controls, 80 sera of pregnant women screened negatively for AITD were used. MBL2-genotyping was performed using multiplex PCR. Women with thyroid dysfunction and/or thyroid peroxidase antibodies (TPOAb) had lower MBL levels during pregnancy than controls, (3275 vs. 5000 ng/ml, p<0.05). The lowest levels were found in women with elevated thyroid-stimulating hormone (TSH) levels in the absence of TPOAb (2207 ng/ml; p<0.01 as compared to controls). MBL2 genotype distribution did not differ between subgroups. At a median follow-up period of 17 months (range: 3-78 months) after delivery, median MBL level had decreased further to 1923 ng/ml (p<0.0001) without significant changes in TSH. In an explorative survey, functional MBL-deficiency was neither linked to a history of spontaneous abortion, nor other obstetric complications, severe infections throughout life/pregnancy or antibiotics use in pregnancy. In conclusion, hypothyroidism during pregnancy is associated with decreased MBL levels, and the levels decreased further after delivery. PMID- 24339962 TI - Biological experimental observations of an unnoticed chaos as simulated by the Hindmarsh-Rose model. AB - An unnoticed chaotic firing pattern, lying between period-1 and period-2 firing patterns, has received little attention over the past 20 years since it was first simulated in the Hindmarsh-Rose (HR) model. In the present study, the rat sciatic nerve model of chronic constriction injury (CCI) was used as an experimental neural pacemaker to investigate the transition regularities of spontaneous firing patterns. Chaotic firing lying between period-1 and period-2 firings was observed located in four bifurcation scenarios in different, isolated neural pacemakers. These bifurcation scenarios were induced by decreasing extracellular calcium concentrations. The behaviors after period-2 firing pattern in the four scenarios were period-doubling bifurcation not to chaos, period-doubling bifurcation to chaos, period-adding sequences with chaotic firings, and period-adding sequences with stochastic firings. The deterministic structure of the chaotic firing pattern was identified by the first return map of interspike intervals and a short-term prediction using nonlinear prediction. The experimental observations closely match those simulated in a two-dimensional parameter space using the HR model, providing strong evidences of the existence of chaotic firing lying between period-1 and period-2 firing patterns in the actual nervous system. The results also present relationships in the parameter space between this chaotic firing and other firing patterns, such as the chaotic firings that appear after period-2 firing pattern located within the well-known comb-shaped region, periodic firing patterns and stochastic firing patterns, as predicted by the HR model. We hope that this study can focus attention on and help to further the understanding of the unnoticed chaotic neural firing pattern. PMID- 24339963 TI - The enhanced in vivo activity of the combination of a MEK and a PI3K inhibitor correlates with [18F]-FLT PET in human colorectal cancer xenograft tumour-bearing mice. AB - Combined targeting of the MAPK and PI3K signalling pathways in cancer may be necessary for optimal therapeutic activity. To support clinical studies of combination therapy, 3'-deoxy-3'-[(18)F]-fluorothymidine ([(18)F]-FLT) uptake measured by Positron Emission Tomography (PET) was evaluated as a non-invasive surrogate response biomarker in pre-clinical models. The in vivo anti-tumour efficacy and PK-PD properties of the MEK inhibitor PD 0325901 and the PI3K inhibitor GDC-0941, alone and in combination, were evaluated in HCT116 and HT29 human colorectal cancer xenograft tumour-bearing mice, and [(18)F]-FLT PET investigated in mice bearing HCT116 xenografts. Dual targeting of PI3K and MEK induced marked tumour growth inhibition in vivo, and enhanced anti-tumour activity was predicted by [(18)F]-FLT PET scanning after 2 days of treatment. Pharmacodynamic analyses using the combination of the PI3K inhibitor GDC-0941 and the MEK inhibitor PD 0325901 revealed that increased efficacy is associated with an enhanced inhibition of the phosphorylation of ERK1/2, S6 and 4EBP1, compared to that observed with either single agent, and maintained inhibition of AKT phosphorylation. Pharmacokinetic studies indicated that there was no marked PK interaction between the two drugs. Together these results indicate that the combination of PI3K and MEK inhibitors can result in significant efficacy, and demonstrate for the first time that [(18)F]-FLT PET can be correlated to the improved efficacy of combined PI3K and MEK inhibitor treatment. PMID- 24339964 TI - Association between human urotensin II and essential hypertension--a 1:1 matched case-control study. AB - OBJECTIVE: We aimed to evaluate the controversial association between human urotensin II and essential hypertension in untreated hypertensive cases and normotensive controls. METHODS: 197 newly diagnosed hypertensive patients and 197 age- and sex-matched normotensive controls were studied. Plasma urotensin II, nitric oxide metabolites, and other traditional biomarkers were examined. RESULTS: Hypertensive patients had higher urotensin ii [median (interquartile rang): 9.32 (7.86-11.52) ng/mL vs 8.52 (7.07-10.41) ng/mL] and lower nitric oxide metabolites [19.19 (2.55-38.48) umol/L vs 23.83 (11.97-43.40) umol/L] than normotensive controls. Urotensin II was positively correlated with systolic blood pressure (r = 0.169, P<0.001) and diastolic blood pressure (r = 0.113, P = 0.024) while negatively correlated with nitric oxide metabolites (r = -0.112, P = 0.027). In multivariate regression analysis, subjects in the highest quartile of urotensin II were more likely to have hypertension than those in the lowest quartile (OR, 2.58; 95% CI, 1.21-5.49). Sub-group analyses in 106 pairs of cases and controls with either both normal or both abnormal nitric oxide metabolites levels showed that the association between urotensin II levels and hypertension persisted (P value for trend = 0.039). CONCLUSION: Human urotensin II is markedly associated with essential hypertension, and the association is independent of nitric oxide metabolites. Our results indicated that urotensin II might be an independent risk factor for essential hypertension. PMID- 24339965 TI - Mosquito-host interactions during and after an outbreak of equine viral encephalitis in Eastern Panama. AB - Mosquito blood meals provide information about the feeding habits and host preference of potential arthropod-borne disease vectors. Although mosquito-borne diseases are ubiquitous in the Neotropics, few studies in this region have assessed patterns of mosquito-host interactions, especially during actual disease outbreaks. Based on collections made during and after an outbreak of equine viral encephalitis, we identified the source of 338 blood meals from 10 species of mosquitoes from Aruza Abajo, a location in Darien province in eastern Panama. A PCR based method targeting three distinct mitochondrial targets and subsequent DNA sequencing was used in an effort to delineate vector-host relationships. At Aruza Abajo, large domesticated mammals dominated the assemblage of mosquito blood meals while wild bird and mammal species represented only a small portion of the blood meal pool. Most mosquito species fed on a variety of hosts; foraging index analysis indicates that eight of nine mosquito species utilize hosts at similar proportions while a stochastic model suggests dietary overlap among species was greater than would be expected by chance. The results from our null model analysis of mosquito diet overlap are consistent with the hypothesis that in landscapes where large domestic animals dominate the local biomass, many mosquito species show little host specificity, and feed upon hosts in proportion to their biomass, which may have implications for the role of livestocking patterns in vector-borne disease ecology. PMID- 24339966 TI - Temperature sensitivity and basal rate of soil respiration and their determinants in temperate forests of North China. AB - The basal respiration rate at 10 degrees C (R10) and the temperature sensitivity of soil respiration (Q10) are two premier parameters in predicting the instantaneous rate of soil respiration at a given temperature. However, the mechanisms underlying the spatial variations in R10 and Q10 are not quite clear. R10 and Q10 were calculated using an exponential function with measured soil respiration and soil temperature for 11 mixed conifer-broadleaved forest stands and nine broadleaved forest stands at a catchment scale. The mean values of R10 were 1.83 umol CO2 m(-2) s(-1) and 2.01 umol CO2 m(-2) s(-1), the mean values of Q10 were 3.40 and 3.79, respectively, for mixed and broadleaved forest types. Forest type did not influence the two model parameters, but determinants of R10 and Q10 varied between the two forest types. In mixed forest stands, R10 decreased greatly with the ratio of coniferous to broadleaved tree species; whereas it sharply increased with the soil temperature range and the variations in soil organic carbon (SOC), and soil total nitrogen (TN). Q10 was positively correlated with the spatial variances of herb-layer carbon stock and soil bulk density, and negatively with soil C/N ratio. In broadleaved forest stands, R10 was markedly affected by basal area and the variations in shrub carbon stock and soil phosphorus (P) content; the value of Q10 largely depended on soil pH and the variations of SOC and TN. 51% of variations in both R10 and Q10 can be accounted for jointly by five biophysical variables, of which the variation in soil bulk density played an overwhelming role in determining the amplitude of variations in soil basal respiration rates in temperate forests. Overall, it was concluded that soil respiration of temperate forests was largely dependent on soil physical properties when temperature kept quite low. PMID- 24339967 TI - Decreased galectin-9 and increased Tim-3 expression are related to poor prognosis in gastric cancer. AB - INTRODUCTION: Galectin-9 (Gal-9) induces adhesion and aggregation of certain cell types and inhibits the metastasis of tumor cells. T-cell immunoglobulin-and mucin domain-3-containing molecule 3 (TIM-3) plays a pivotal role in immune regulation. The aim of this study is to investigate Gal-9 and TIM-3 alterations in gastric cancer and their prognostic values. METHODS: Gal-9 and Tim-3 expression was evaluated using a tissue microarray immunohistochemistry method in 305 gastric cancers, of which 84 had paired adjacent normal samples. Cell lines SGC-7901, BGC 823, MGC-803, MKN45 and GES-1 were also stained. Correlations were analyzed between expression levels of Gal-9 and Tim-3 protein and tumor parameters or clinical outcomes. RESULTS: Gal-9 and Tim-3 stained positive on tumor cells in 86.2% (263/305), and 60.0% (183/305) patients with gastric cancer, respectively. Gal-9 expression was significantly higher in cancer than in normal mucosa (P<0.001). Reduced Gal-9 expression was associated with lymph-vascular invasion, lymph node metastasis, distant metastasis and worse TNM staging (P = 0.034, P = 0.009, P = 0.002 and P = 0.043, respectively). In contrast, Tim-3 expression was significantly lower in cancer than in control mucosa (P<0.001). Patients with lymph-vascular invasion had higher expression levels of Tim-3 (P<0.001). Moreover, multivariate analysis shows that both high Gal-9 expression and low Tim 3 expression were significantly associated with long overall survival (P = 0.002, P = 0.010, respectively); the combination of Gal-9 and Tim-3 expression was an independent prognostic predictor for patients with gastric cancer (RR: 0.43; 95%CI: 0.20-0.93). H.pylori infection status was not associated with Gal-9 and Tim-3 expression (P = 0.102, P = 0.565). CONCLUSION: The results suggest that expression of Gal-9 and Tim-3 in tumor cells may be a potential, independent prognostic factor for patients with gastric cancer. Gal-9 and TIM-3 may play an important part in the gastric carcinogenesis. PMID- 24339968 TI - An improved detection and quantification method for the coral pathogen Vibrio coralliilyticus. AB - DNA- and RNA-based PCR and reverse-transcription real-time PCR assays were developed for diagnostic detection of the vcpA zinc-metalloprotease implicated in the virulence of the coral pathogen Vibrio coralliilyticus. Both PCR methods were highly specific for V. coralliilyticus and failed to amplify strains of closely related Vibrio species. The assays correctly detected all globally occurring V. coralliilyticus isolates including a newly-described isolate [TAV24] infecting gorgonians in the Mediterranean Sea and highlighted those isolates that had been potentially misidentified, in particular V. tubiashii strains ATCC 19105 and RE22, historically described as important oyster pathogens. The real-time assay is sensitive, detecting 10 gene copies and the relationships between gene copy number and cycle threshold (C T ) were highly linear (R(2)>= 99.7). The real-time assay was also not affected by interference from non-target DNA. These assays are useful for rapid detection of V. coralliilyticus and monitoring of virulence levels in environmental samples, allowing for implementation of timely management steps to limit and possibly prevent losses due to V. coralliilyticus infection, as well as furthering investigations of factors affecting pathogenesis of this important marine pathogen. PMID- 24339969 TI - Tropism of avian influenza A (H5N1) virus to mesenchymal stem cells and CD34+ hematopoietic stem cells. AB - The presence of abnormal hematologic findings such as lymphopenia, thrombocytopenia, and pancytopenia were diagnosed in severe cases of avian influenza A H5N1. Whether direct viral dissemination to bone marrow (BM) cells causes this phenomenon remains elusive. We explore the susceptibility of the two stem cell types; hematopoietic stem cells (HSCs) and mesenchymal stromal cells (MSCs) isolated from human BM cells or cord blood, to infection with avian H5N1 viruses. For the first time, we demonstrated that the H5N1 virus could productively infect and induce cell death in both human stem cell types. In contrast, these activities were not observed upon human influenza virus infection. We also determined whether infection affects the immunomodulatory function of MSCs. We noted a consequent dysregulation of MSC-mediated immune modulation as observed by high cytokine and chemokine production in H5N1 infected MSCs and monocytes cocultures. These findings provide a better understanding of H5N1 pathogenesis in terms of broad tissue tropism and systemic spread. PMID- 24339970 TI - Hypothermic machine perfusion reduces delayed graft function and improves one year graft survival of kidneys from expanded criteria donors: a meta-analysis. AB - BACKGROUND: Expanded criteria donors (ECDs) are currently accepted as potential sources to increase the donor pool and to provide more chances of kidney transplantation for elderly recipients who would not survive long waiting periods. Hypothermic machine perfusion (HMP) is designed to mitigate the deleterious effects of simple cold storage (CS) on the quality of preserved organs, particularly when the donor is in a marginal status. METHODS: We compared the transplant outcomes in patients receiving ECD kidneys with either HMP or CS graft preservation. Articles from the MEDLINE, EMBASE and Cochrane Library databases were searched and all studies reporting outcomes from HMP versus CS methods of kidney preservation were included in this meta-analysis. The parameters analyzed included the incidence of delayed graft function (DGF), primary non-function (PNF) and one-year graft and patient survival. RESULTS: A total of seven studies qualified for the review, involving 2374 and 8716 kidney grafts with HMP or CS preservation respectively, all from ECD donors. The incidence of delayed graft function (DGF) was significantly reduced with an odd ratio(OR) of 0.59 (95% CI 0.54-0.66, P<0.001) and one-year graft survival was significantly improved with an OR of 1.12 (95% CI 1.03-1.21, P = 0.005) in HMP preservation compared to CS. However, there was no difference in the incidence of PNF (OR 0.54, 95% CI 0.21-1.40, P = 0.20), and one-year patient survival (OR 0.98, 95% CI 0.94-1.02, P = 0.36) between HMP and CS preservation. CONCLUSIONS: HMP was associated with a reduced incidence of DGF and an with increased one-year graft survival, but it was not associated with the incidence of PNF and one-year patient survival. PMID- 24339972 TI - Development by design in Colombia: making mitigation decisions consistent with conservation outcomes. AB - Mitigation policy and regulatory frameworks are consistent in their strong support for the mitigation hierarchy of: (1) avoiding impacts, (2) minimizing impacts, and then (3) offsetting/compensating for residual impacts. While mitigation frameworks require developers to avoid, minimize and restore biodiversity on-site before considering an offset for residual impacts, there is a lack of quantitative guidance for this decision-making process. What are the criteria for requiring impacts be avoided altogether? Here we examine how conservation planning can guide the application of the mitigation hierarchy to address this issue. In support of the Colombian government's aim to improve siting and mitigation practices for planned development, we examined five pilot projects in landscapes expected to experience significant increases in mining, petroleum and/or infrastructure development. By blending landscape-level conservation planning with application of the mitigation hierarchy, we can proactively identify where proposed development and conservation priorities would be in conflict and where impacts should be avoided. The approach we outline here has been adopted by the Colombian Ministry of Environment and Sustainable Development to guide licensing decisions, avoid piecemeal licensing, and promote mitigation decisions that maintain landscape condition. PMID- 24339971 TI - Unique activity spectrum of colicin FY: all 110 characterized Yersinia enterocolitica isolates were colicin FY susceptible. AB - Colicin FY is a plasmid encoded toxin that recognizes a yersinia-specific outer membrane protein (YiuR) as a receptor molecule. We have previously shown that the activity spectrum of colicin FY comprises strains of the genus Yersinia. In this study, we analyzed the activity of colicin FY against 110 Yersinia enterocolitica isolates differing in geographical origin and source. All isolates were characterized through analysis of 16S rRNA genes, serotyping, biotyping, restriction profiling of genomic DNA, detection of virulence markers and susceptibility to antibiotics. This confirmed the broad variability of the collection, in which all 110 Y. enterocolitica isolates, representing 77 various strains, were inhibited by colicin FY. Although isolates showed variable levels of susceptibility to colicin FY, it was not associated with any strain characteristic. The universal susceptibility of Y. enterocolitica strains to colicin FY together with the absence of activity towards strains outside the Yersinia genus suggests potential therapeutic applications for colicin FY. PMID- 24339973 TI - Novel data on the ecology of Cochranella mache (Anura: Centrolenidae) and the importance of protected areas for this critically endangered glassfrog in the neotropics. AB - We studied a population of the endangered glassfrog, Cochranella mache, at Bilsa Biological Station, northwestern Ecuador, from 2008 and 2009. We present information on annual abundance patterns, behavioral ecology, habitat use and a species distribution model performed with MaxEnt. We evaluate the importance of the National System of Protected Areas (SNAP) in Colombia and Ecuador, under scenarios of climate change and habitat loss. We predicted a restricted environmental suitability area from 48,509 Km(2) to 65,147 Km(2) along western Ecuador and adjacent Colombia; ~ 8% of the potential distribution occurs within SNAP. We examined four aspects of C. mache ecology: (1) ecological data suggests a strong correlation between relative abundance and rainfall, with a high probability to observe frogs through rainy months (February-May); (2) habitat use and the species distribution model suggest that this canopy dweller is restricted to small streams and rivulets in primary and old secondary forest in evergreen lowland and piedmont forest of western Ecuador, with predictions of suitability areas in adjacent southern Colombia; (3) the SNAP of Colombia and Ecuador harbor a minimum portion of the predicted model of distribution (<10%); and (4) synergetic effects of habitat loss and climate change reduces in about 95% the suitability areas for this endangered frog along its distributional range in Protected Areas. The resulting model allows the recognition of areas to undertake conservation efforts and plan future field surveys, as well as forecasting regions with high probability of C. mache occurrence in western Ecuador and southern Colombia. Further research is required to assess population tendencies, habitat fragmentation and target survey zones to accelerate the discovery of unknown populations in unexplored areas with high probability of suitability. We recommend that Cochranella mache must be re-categorized as "Critically Endangered" species in national and global status, according with criteria and sub-criteria A4, B1ab(i,ii,iii,iv),E. PMID- 24339974 TI - Malignant transformation potentials of human umbilical cord mesenchymal stem cells both spontaneously and via 3-methycholanthrene induction. AB - Human umbilical cord mesenchymal stem cells (HUMSCs) are highly proliferative and can be induced to differentiate into advanced derivatives of all three germ layers. Thus, HUMSCs are considered to be a promising source for cell-targeted therapies and tissue engineering. However there are reports on spontaneous transformation of mesenchymal stem cells (MSCs) derived from human bone marrows. The capacity for HUMSCs to undergo malignant transform spontaneously or via induction by chemical carcinogens is presently unknown. Therefore, we isolated HUMSCs from 10 donors and assessed their transformation potential either spontaneously or by treating them with 3-methycholanthrene (3-MCA), a DNA damaging carcinogen. The malignant transformation of HUMSCs in vitro was evaluated by morphological changes, proliferation rates, ability to enter cell senescence, the telomerase activity, chromosomal abnormality, and the ability to form tumors in vivo. Our studies showed that HUMSCs from all 10 donors ultimately entered senescence and did not undergo spontaneous malignant transformation. However, HUMSCs from two of the 10 donors treated with 3-MCA displayed an increased proliferation rate, failed to enter senescence, and exhibited an altered cell morphology. When these cells (tHUMSCs) were injected into immunodeficient mice, they gave rise to sarcoma-like or poorly differentiated tumors. Moreover, in contrast to HUMSCs, tHUMSCs showed a positive expression of human telomerase reverse transcriptase (hTERT) and did not exhibit a shortening of the relative telomere length during the long-term culture in vitro. Our studies demonstrate that HUMSCs are not susceptible to spontaneous malignant transformation. However, the malignant transformation could be induced by chemical carcinogen 3-MCA. PMID- 24339975 TI - AMPK activation through mitochondrial regulation results in increased substrate oxidation and improved metabolic parameters in models of diabetes. AB - Modulation of mitochondrial function through inhibiting respiratory complex I activates a key sensor of cellular energy status, the 5'-AMP-activated protein kinase (AMPK). Activation of AMPK results in the mobilization of nutrient uptake and catabolism for mitochondrial ATP generation to restore energy homeostasis. How these nutrient pathways are affected in the presence of a potent modulator of mitochondrial function and the role of AMPK activation in these effects remain unclear. We have identified a molecule, named R419, that activates AMPK in vitro via complex I inhibition at much lower concentrations than metformin (IC50 100 nM vs 27 mM, respectively). R419 potently increased myocyte glucose uptake that was dependent on AMPK activation, while its ability to suppress hepatic glucose production in vitro was not. In addition, R419 treatment of mouse primary hepatocytes increased fatty acid oxidation and inhibited lipogenesis in an AMPK dependent fashion. We have performed an extensive metabolic characterization of its effects in the db/db mouse diabetes model. In vivo metabolite profiling of R419-treated db/db mice showed a clear upregulation of fatty acid oxidation and catabolism of branched chain amino acids. Additionally, analyses performed using both (13)C-palmitate and (13)C-glucose tracers revealed that R419 induces complete oxidation of both glucose and palmitate to CO2 in skeletal muscle, liver, and adipose tissue, confirming that the compound increases mitochondrial function in vivo. Taken together, our results show that R419 is a potent inhibitor of complex I and modulates mitochondrial function in vitro and in diabetic animals in vivo. R419 may serve as a valuable molecular tool for investigating the impact of modulating mitochondrial function on nutrient metabolism in multiple tissues and on glucose and lipid homeostasis in diabetic animal models. PMID- 24339976 TI - Galectin-4, a novel predictor for lymph node metastasis in lung adenocarcinoma. AB - Metastasis is still a major issue in cancer, and the discovery of biomarkers predicting metastatic capacity is essential for the development of better therapeutic strategies for treating lung adenocarcinoma. By using a proteomic approach, we aimed to identify novel predictors for lymph node metastasis in lung adenocarcinoma. Two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis showed 6 spots differentially expressed between lymph node metastasis-positive and lymph node metastasis-negative groups in a discovery set. Subsequent mass spectrometry showed that 2 of these spots were derived from galectin-4, and western blot analysis confirmed the overexpression of galectin-4 in metastatic samples. The predictive value of galectin-4 was confirmed by immunohistochemical analysis for a validation set consisting of 707 surgically resected specimens of lung adenocarcinomas (stages I to IV). We observed that 148 lung adenocarcinomas (20.9%) expressed galectin-4, which was significantly associated with variables of disease progression such as tumor size (p<0.0001), pleural invasion (p = 0.0071), venous invasion (p = 0.0178), nodal status (p = 0.0007), and TNM stage (p<0.0001). By the multivariate analysis, Galectin-4 expression was revealed as one of the independent predictor for lymph node metastasis, together with solid predominant and micropapillary histologic pattern. Furthermore, galectin-4 expression was revealed to be an independent predictor for lymph node metastasis and an adverse survival factor in patients with lung adenocarcinoma of acinar predominant type. Galectin-4 plays an important role in metastatic process of lung adenocarcinoma. Immunohistochemical testing for galectin-4 expression may be useful together with the detection of specific histology to predict the metastatic potential of lung adenocarcinoma. PMID- 24339977 TI - Construction and application of elastin like polypeptide containing IL-4 receptor targeting peptide. AB - Various human solid tumors highly express IL-4 receptors which amplify the expression of some of anti-apoptotic proteins, preventing drug-induced cancer cell death. Thus, IL-4 receptor targeted drug delivery can possibly increase the therapeutic efficacy in cancer treatment. Macromolecular carriers with multivalent targeting moieties offered great advantages in cancer therapy as they not only increase the plasma half-life of the drug but also allow delivery of therapeutic drugs to the cancer cells with higher specificity, minimizing the deleterious effects of the drug on normal cells. In this study we designed a library of elastin like polypeptide (ELP) polymers containing tumor targeting AP1 peptide using recursive directional ligation method. AP1 was previously discovered as an atherosclerotic plaque and breast tumor tissue homing peptide using phage display screening method, and it can selectively bind to the interleukin 4 receptor (IL-4R). The fluorescently labeled [AP1-V12]6, an ELP polymer containing six AP1 enhanced tumor-specific targeting ability and uptake efficiency in H226 and MDA-MB-231 cancer cell lines in vitro. Surface plasmon resonance analysis showed that multivalent presentation of the targeting ligand in the ELP polymer increased the binding affinity towards IL-4 receptor compared to free peptide. The binding of [AP1-V12]6 to cancer cells was remarkably reduced when IL-4 receptors were blocked by antibody against IL-4 receptor further confirmed its binding. Importantly, the Cy5.5-labeled [AP1-V12]6 demonstrated excellent homing and longer retention in tumor tissues in MDA-MB-231 xenograft mouse model. Immunohistological studies of tumor tissues further validated the targeting efficiency of [AP1-V12]6 to tumor tissue. These results indicate that designed [AP1-V12]6 can serve as a novel carrier for selective delivery of therapeutic drugs to tumors. PMID- 24339978 TI - PI3K/Akt signal pathway involved in the cognitive impairment caused by chronic cerebral hypoperfusion in rats. AB - Chronic cerebral hypoperfusion (CCH) is a common pathophysiological state that usually occurs in conditions such as vascular dementia and Alzheimer's disease, both of which are characterized by cognitive impairment. In previous studies we found that learning capacity and memory were gradually impaired with CCH, which altered the expression of synaptophysin, microtubule associated protein-2, growth associated protein-43, brain-derived neurotrophic factor, nerve growth factor, N methyl-D-aspartate receptor subunit 1, cAMP response element-binding protein and tau hyperphosphorylation in the hippocampus. However, the molecular basis of cognitive impairment in CCH remains obscure. Here we explore the hypothesis that the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signal pathway is involved in this type of cognitive impairment. In order to determine if the expression of PI3K, Akt and phosphorylated Akt (p-Akt) proteins are altered at different stages of CCH with differing levels of cognitive impairment. we performed permanent, bilateral occlusion of the common carotid arteries (2-VO) to induce CCH. Adult male SD rats were randomly divided into sham-operated group, 2 VO 1 week group, 2-VO 4 weeks group and 2-VO 8 weeks group. Behavior tests were utilized to assess cognitive abilities, while western blots were utilized to evaluate protein expression. Rats in the 2-VO groups spent less time exploring novel objects than those in the sham-operated group, and the discrimination ratio of the 2-VO 8 weeks group and the sham-operated group were higher than chance (0.50). Escape latencies in the Morris water maze task in the 2-VO 1 week group were longer than those in the sham-operated group on day 4 and day 5, while escape latencies in the 2-VO 4 weeks group were longer than those in the sham operated group from day 3 to day 5. Escape latencies in 2-VO 8 weeks group were longer than those in the sham-operated group from day 2 to day 5. NE (northeast) square swimming times in the 2-VO 1 week group, 2-VO 4 weeks group and 2-VO 8 weeks group were shorter than that in the sham-operated group. Western blotting showed that the PI3K expression in the 2-VO 1 week group was lower than that in sham-operated group, while p-Akt expression in the 2-VO 8 weeks group was higher than that in the sham-operated group. There was a linear relationship between the PI3K expression and the discrimination ratio, as well as a linear relationship between the PI3K and NE square swimming time. Thus, we propose that the PI3K/Akt signal pathway is an important cell pathway that is associated with the cognitive impairment following CCH. PMID- 24339979 TI - New conformational state of NHERF1-CXCR2 signaling complex captured by crystal lattice trapping. AB - NHERF1 is a PDZ adaptor protein that scaffolds the assembly of diverse signaling complexes and has been implicated in many cancers. However, little is known about the mechanism responsible for its scaffolding promiscuity or its ability to bind to multiple targets. Computational studies have indicated that PDZ promiscuity may be attributed to its conformational dynamics, but experimental evidence for this relationship remains very limited. Here we examine the conformational flexibility of the NHERF1 PDZ1 domain using crystal lattice trapping via solving PDZ1 structure of a new crystal form. The structure, together with prior PDZ1 structures of a different space group, reveals that 4 of 11 ligand-interacting residues undergo significant crystal packing-induced structural changes. Most of these residues correspond to the residues involved in allosteric transition when a peptide ligand binds. In addition, a subtle difference in ligand conformations causes the same peptide to bind in slightly different modes in different crystal forms. These findings indicate that substantial structural flexibility is present in the PDZ1 peptide-binding pocket, and the structural substate trapped in the present crystal form can be utilized to represent the conformational space accessible to the protein. Such knowledge will be critical for drug design against the NHERF1 PDZ1 domain, highlighting the continued need for experimentally determined PDZ1-ligand complexes. PMID- 24339980 TI - Extreme costs of mating for male two-spot ladybird beetles. AB - Male costs of mating are now thought to be widespread. The two-spot ladybird beetle (Adalia bipunctata) has been the focus of many studies of mating and sexual selection, yet the costs of mating for males are unknown. The mating system of A. bipunctata involves a spermatophore nuptial gift ingested by females after copulation. In this study, we investigate the cost to males of mating and of transferring spermatophores in terms of lifespan, ejaculate production and depletion of nutritional reserves. We found that males faced a strong trade-off between mating and survival, with males that were randomly assigned to mate a single time experiencing a 53% reduction in post-mating lifespan compared to non mating males. This is among the most severe survival costs of a single mating yet reported. However, spermatophore transfer did not impact male survival. Instead, the costs associated with spermatophores appeared as a reduced ability to transfer spermatophores in successive matings. Furthermore, males ingested more food following spermatophore transfer than after matings without spermatophores, suggesting that spermatophore transfer depletes male nutritional reserves. This is to our knowledge the first report of an effect of variation in copulatory behaviour on male foraging behaviour. Overall, our study highlights the advantages of assessing mating costs using multiple currencies, and suggests that male A. bipunctata should exhibit mate choice. PMID- 24339981 TI - Chicken CRTAM binds nectin-like 2 ligand and is upregulated on CD8+ alphabeta and gammadelta T lymphocytes with different kinetics. AB - During a search for immunomodulatory receptors in the chicken genome, we identified a previously cloned chicken sequence as CRTAM homologue by its overall identity and several conserved sequence features. For further characterization, we generated a CRTAM specific mab. No staining was detectable in freshly isolated cell preparations from thymus, bursa, caecal tonsils, spleen, blood and intestine. Activation of splenocytes with recombinant IL-2 increased rapid CRTAM expression within a 2 h period on about 30% of the cells. These CRTAM(+) cells were identified as CD8(+) gammadelta T lymphocytes. In contrast, CRTAM expression could not be stimulated on PBL with IL-2, even within a 48 h stimulation period. As a second means of activation, T cell receptor (TCR) crosslinking using an anti alphabeta-TCR induced CRTAM on both PBL and splenocytes. While CRTAM expression was again rapidly upregulated on splenocytes within 2 h, it took 48 h to reach maximum levels of CRTAM expression in PBL. Strikingly, albeit the stimulation of splenocytes was performed with anti-alphabeta-TCR, CRTAM expression after 2 h was mainly restricted to CD8(+) gammadelta T lymphocytes, however, the longer anti TCR stimulation of peripheral blood lymphocytes (PBL) resulted in CRTAM expression on alphabeta T lymphocytes. In order to characterize the potential ligand we cloned and expressed chicken Necl-2, a member of the nectin and nectin like family which is highly homologous to its mammalian counterpart. Three independent assays including a reporter assay, staining with a CRTAM-Ig fusion protein and a cell conjugate assay confirmed the interaction of CRTAM with Necl-2 which could also be blocked by a soluble CRTAM-Ig fusion protein or a CRTAM specific mab. These results suggest that chicken CRTAM represents an early activation antigen on CD8(+) T cells which binds to Necl-2 and is upregulated with distinct kinetics on alphabeta versus gammadelta T lymphocytes. PMID- 24339982 TI - High prevalence of illicit drug use in men who have sex with men with HIV-1 infection in Japan. AB - OBJECTIVE: To examine the prevalence of illicit drug use among men who have sex with men (MSM) with HIV-1 infection in Japan, where the life-time prevalence of illicit drug use in the general population is only 2.9%. DESIGN: A single-center cross-sectional study at a large HIV clinic in Tokyo, which treats approximately 15% of HIV-1 infected patients in Japan. METHODS: The prevalence of illicit drug use and the association of characteristics and social demographics of the patients with illicit drug use were examined. Patients who visited the clinic for the first time from 2005 to 2010 were enrolled. Relevant variables were collected using a structured interview and from the medical records. Multivariate logistic regression analyses were applied to estimate the odds of association of MSM over non-MSM HIV-infected patients with illicit drug use. RESULTS: 1,196 patients were enrolled. They were mostly Japanese men of relatively young age. Illicit drug use (including injection drugs) was reported by 35% of the patients (by 40% of MSM), and 4% were IDU while 5% were on methamphetamine. 2% of the population was arrested due to illicit drugs. MSM was significantly associated with illicit drug use (adjusted OR = 4.60; 95% CI, 2.88-7.36; p<0.01). Subgroup analysis of the patients stratified by three age groups (<= 30, 31 to 40, and >40) showed that the odds of association of MSM with illicit drug use was the strongest in the youngest age group (<= 30 years: adjusted OR = 7.56; 95% CI, 2.86-20.0; p<0.01), followed by the oldest (>40 years: adjusted OR = 6.15; 95% CI, 2.40-15.8; p<0.01), and the weakest in the group aged 31 to 40 (adjusted OR = 3.39; 95% CI, 1.73-6.63; p<0.01). CONCLUSIONS: The prevalence of illicit drug use is high among MSM patients with HIV-1 infection in Japan. Effective intervention for illicit drug use in this population is warranted. PMID- 24339983 TI - Aspirin in primary prevention of cardiovascular disease and cancer: a systematic review of the balance of evidence from reviews of randomized trials. AB - BACKGROUND: Aspirin has been recommended for primary prevention of cardiovascular disease (CVD) and cancer, but overall benefits are unclear. We aimed to use novel methods to re-evaluate the balance of benefits and harms of aspirin using evidence from randomised controlled trials, systematic reviews and meta-analyses. METHODS AND FINDINGS: Data sources included ten electronic bibliographic databases, contact with experts, and scrutiny of reference lists of included studies. Searches were undertaken in September 2012 and restricted to publications since 2008. Of 2,572 potentially relevant papers 27 met the inclusion criteria. Meta-analysis of control arms to estimate event rates, modelling of all-cause mortality and L'Abbe plots to estimate heterogeneity were undertaken. Absolute benefits and harms were low: 60-84 major CVD events and 34 36 colorectal cancer deaths per 100,000 person-years were averted, whereas 46-49 major bleeds and 68-117 gastrointestinal bleeds were incurred. Reductions in all cause mortality were minor and uncertain (Hazard Ratio 0.96; 95% CI: 0.90-1.02 at 20 years, Relative Risk [RR] 0.94, 95% CI: 0.88-1.00 at 8 years); there was a non significant change in total CVD (RR 0.85, 95% CI: 0.69-1.06) and change in total cancer mortality ranged from 0.76 (95% CI: 0.66-0.88) to 0.93 (95% CI: 0.84-1.03) depending on follow-up time and studies included. Risks were increased by 37% for gastrointestinal bleeds (RR 1.37, 95% CI: 1.15-1.62), 54%-66% for major bleeds (Rate Ratio from IPD analysis 1.54, 95% CI: 1.30-1.82, and RR 1.62, 95% CI: 1.31 2.00), and 32%-38% for haemorrhagic stroke (Rate Ratio from IPD analysis 1.32; 95% CI: 1.00-1.74; RR 1.38; 95% CI: 1.01-1.82). CONCLUSIONS: Findings indicate small absolute effects of aspirin relative to the burden of these diseases. When aspirin is used for primary prevention of CVD the absolute harms exceed the benefits. Estimates of cancer benefit rely on selective retrospective re-analysis of RCTs and more information is needed. PMID- 24339984 TI - To control false positives in gene-gene interaction analysis: two novel conditional entropy-based approaches. AB - Genome-wide analysis of gene-gene interactions has been recognized as a powerful avenue to identify the missing genetic components that can not be detected by using current single-point association analysis. Recently, several model-free methods (e.g. the commonly used information based metrics and several logistic regression-based metrics) were developed for detecting non-linear dependence between genetic loci, but they are potentially at the risk of inflated false positive error, in particular when the main effects at one or both loci are salient. In this study, we proposed two conditional entropy-based metrics to challenge this limitation. Extensive simulations demonstrated that the two proposed metrics, provided the disease is rare, could maintain consistently correct false positive rate. In the scenarios for a common disease, our proposed metrics achieved better or comparable control of false positive error, compared to four previously proposed model-free metrics. In terms of power, our methods outperformed several competing metrics in a range of common disease models. Furthermore, in real data analyses, both metrics succeeded in detecting interactions and were competitive with the originally reported results or the logistic regression approaches. In conclusion, the proposed conditional entropy based metrics are promising as alternatives to current model-based approaches for detecting genuine epistatic effects. PMID- 24339985 TI - Genetic variants ofLRRK2 in Taiwanese Parkinson's disease. AB - Genetic variants of leucine-rich repeat kinase 2 (LRRK2) were reported to alter the risk for Parkinson's disease (PD). However, the genetic spectrum of LRRK2 variants has not been clearly disclosed yet in Taiwanese population. Herein, we sequenced LRRK2 coding region in 70 Taiwanese early onset PD patients (age at onset <= 50), and found six amino acid-changing single nucleotide polymorphisms (SNPs, N551K, R1398H, R1628P, S1647T, G2385R and M2397T), one reported (R1441H) and 2 novel missense (R767H and S885N) mutations. We examined the frequency of identified LRRK2 variants by genotyping 573 Taiwanese patients with PD and 503 age-matched control subjects. The results showed that PD patients demonstrated a higher frequency of G2385R A allele (4.6%) than control subjects (2.1%; odds ratio = 2.27, 95% confidence interval: 1.38-3.88, P = 0.0017). Fewer PD patients (27.7%) carried the 1647T-2397T haplotype as compared with the control subjects (33.0%; odds ratio = 0.80, 95% confidence interval: 0.65-0.97, P = 0.0215). However, the frequency of 1647T-2385R-2397T haplotype (4.3%) in PD patients was still higher than in control subjects (1.9%, odds ratio: 2.15, 95% confidence interval: 1.27-3.78, P = 0.0058). While no additional subject was found to carry R767H and R1441H, one more patient was observed to carry the S885N variant. Our results indicate a robust risk association regarding G2385R and a new possible protective haplotype (1647T-2397T). Gene-environmental interaction and a larger cohort study are warranted to validate our findings. Additionally, two new missense mutations (R767H and S885N) regarding LRRK2 in PD patients were identified. Functional studies are needed to elucidate the effects of these LRRK2 variants on protein function. PMID- 24339986 TI - Structural characterisation of the nuclear import receptor importin alpha in complex with the bipartite NLS of Prp20. AB - The translocation of macromolecules into the nucleus is a fundamental eukaryotic process, regulating gene expression, cell division and differentiation, but which is impaired in a range of significant diseases including cancer and viral infection. The import of proteins into the nucleus is generally initiated by a specific, high affinity interaction between nuclear localisation signals (NLSs) and nuclear import receptors in the cytoplasm, and terminated through the disassembly of these complexes in the nucleus. For classical NLSs (cNLSs), this import is mediated by the importin-alpha (IMPalpha) adaptor protein, which in turn binds to IMPbeta to mediate translocation of nuclear cargo across the nuclear envelope. The interaction and disassembly of import receptor:cargo complexes is reliant on the differential localisation of nucleotide bound Ran across the envelope, maintained in its low affinity, GDP-bound form in the cytoplasm, and its high affinity, GTP-bound form in the nucleus. This in turn is maintained by the differential localisation of Ran regulating proteins, with RanGAP in the cytoplasm maintaining Ran in its GDP-bound form, and RanGEF (Prp20 in yeast) in the nucleus maintaining Ran in its GTP-bound form. Here, we describe the 2.1 A resolution x-ray crystal structure of IMPalpha in complex with the NLS of Prp20. We observe 1,091 A(2) of buried surface area mediated by an extensive array of contacts involving residues on armadillo repeats 2-7, utilising both the major and minor NLS binding sites of IMPalpha to contact bipartite NLS clusters (17)RAKKMSK(23) and (3)KR(4), respectively. One notable feature of the major site is the insertion of Prp20NLS Ala(18) between the P0 and P1 NLS sites, noted in only a few classical bipartite NLSs. This study provides a detailed account of the binding mechanism enabling Prp20 interaction with the nuclear import receptor, and additional new information for the interaction between IMPalpha and cargo. PMID- 24339987 TI - Streptococcus pneumoniae from Palestinian nasopharyngeal carriers: serotype distribution and antimicrobial resistance. AB - Infections of Streptococcus pneumoniae in children can be prevented by vaccination; left untreated, they cause high morbidity and fatalities. This study aimed at determining the nasopharyngeal carrier rates, serotype distribution and antimicrobial resistance patterns of S. pneumoniae in healthy Palestinian children under age two prior to the full introduction of the pneumococcal 7 valent conjugate vaccine (PCV7), which was originally introduced into Palestine in a pilot trial in September, 2010. In a cross sectional study, nasopharyngeal specimens were collected from 397 healthy children from different Palestinian districts between the beginning of November 2012 to the end of January 2013. Samples were inoculated into blood agar and suspected colonies were examined by amplifying the pneumococcal-specific autolysin gene using a real-time PCR. Serotypes were identified by a PCR that incorporated different sets of specific primers. Antimicrobial susceptibility was measured by disk diffusion and MIC methods. The resulting carrier rate of Streptococcus pneumoniae was 55.7% (221/397). The main serotypes were PCV7 serotypes 19F (12.2%), 23F (9.0%), 6B (8.6%) and 14 (4%) and PCV13 serotypes 6A (13.6%) and 19A (4.1%). Notably, serotype 6A, not included in the pilot trial (PCV7) vaccine, was the most prevalent. Resistance to more than two drugs was observed for bacteria from 34.1% of the children (72/211) while 22.3% (47/211) carried bacteria were susceptible to all tested antibiotics. All the isolates were sensitive to cefotaxime and vancomycin. Any or all of these might impinge on the type and efficacy of the pneumococcal conjugate vaccines and antibiotics to be used for prevention and treatment of pneumococcal disease in the country. PMID- 24339988 TI - Elucidating poor decision-making in a rat gambling task. AB - Although poor decision-making is a hallmark of psychiatric conditions such as attention deficit/hyperactivity disorder, pathological gambling or substance abuse, a fraction of healthy individuals exhibit similar poor decision-making performances in everyday life and specific laboratory tasks such as the Iowa Gambling Task. These particular individuals may provide information on risk factors or common endophenotypes of these mental disorders. In a rodent version of the Iowa gambling task--the Rat Gambling Task (RGT), we identified a population of poor decision makers, and assessed how these rats scored for several behavioral traits relevant to executive disorders: risk taking, reward seeking, behavioral inflexibility, and several aspects of impulsivity. First, we found that poor decision-making could not be well predicted by single behavioral and cognitive characteristics when considered separately. By contrast, a combination of independent traits in the same individual, namely risk taking, reward seeking, behavioral inflexibility, as well as motor impulsivity, was highly predictive of poor decision-making. Second, using a reinforcement-learning model of the RGT, we confirmed that only the combination of extreme scores on these traits could induce maladaptive decision-making. Third, the model suggested that a combination of these behavioral traits results in an inaccurate representation of rewards and penalties and inefficient learning of the environment. Poor decision-making appears as a consequence of the over-valuation of high-reward-high-risk options in the task. Such a specific psychological profile could greatly impair clinically healthy individuals in decision-making tasks and may predispose to mental disorders with similar symptoms. PMID- 24339989 TI - Characterization of the microRNAome in porcine reproductive and respiratory syndrome virus infected macrophages. AB - Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), a member of the arterivirus family, is the causative agent of Porcine Reproductive and Respiratory Syndrome (PRRS). PRRS is characterized by late term abortions and respiratory disease, particularly in young pigs. Small regulatory RNAs termed microRNA (miRNA) are associated with gene regulation at the post-transcriptional level. MiRNAs are known to play many diverse and complex roles in viral infections. To discover the impact of PRRSV infections on the cellular miRNAome, Illumina deep sequencing was used to construct small RNA expression profiles from in vitro cultured PRRSV-infected porcine alveolar macrophages (PAMs). A total of forty cellular miRNAs were significantly differentially expressed within the first 48 hours post infection (hpi). The expression of six miRNAs, miR-30a-3p, miR-132, miR-27b*, miR-29b, miR-146a and miR-9-2, were altered at more than one time point. Target gene identification suggests that these miRNAs are involved in regulating immune signaling pathways, cytokine, and transcription factor production. The most highly repressed miRNA at 24 hpi was miR-147. A miR-147 mimic was utilized to maintain miR-147 levels in PRRSV-infected PAMs. PRRSV replication was negatively impacted by high levels of miR-147. Whether down regulation of miR-147 is directly induced by PRRSV or if it is part of the cellular response and PRRSV indirectly benefits remains to be determined. No evidence could be found of PRRSV-encoded miRNAs. Overall, the present study has revealed that a large and diverse group of miRNAs are expressed in swine alveolar macrophages and that the expression of a subset of these miRNAs is altered in PRRSV infected macrophages. PMID- 24339990 TI - Do images of 'watching eyes' induce behaviour that is more pro-social or more normative? A field experiment on littering. AB - Displaying images of eyes causes people to behave more pro-socially in a variety of contexts. However, it is unclear whether eyes work by making people universally more pro-social, or by making them more likely to conform to local norms. If the latter, images of eyes could sometimes make people less pro-social if pro-social behaviour is not the local norm. To separate these hypotheses we conducted a field experiment in which we explored whether manipulating a local descriptive norm altered the eyes effect. We recorded litter dropping decisions on a university campus in a 2 x 2 design, comparing situations with and without litter already on the ground (a manipulation of the local descriptive norm) and with and without large signs displaying images of watching eyes. We additionally recorded the number of potential human observers in the vicinity at the time of each littering decision. We observed a norm effect: the presence of litter on the ground increased littering, replicating previous findings. We also found that images of watching eyes reduced littering, although contrary to previous findings this was only when there were larger numbers of people around. With regard to our central aim, we found no evidence that litter on the ground interacted non additively with images of eyes to induce increased littering behaviour. Our data therefore support the hypothesis that images of eyes induce more pro-social behaviour, independent of local norms. This finding has positive implications for the application of eye images in combating anti-social behaviour. PMID- 24339991 TI - Functional expression of human NKCC1 from a synthetic cassette-based cDNA: introduction of extracellular epitope tags and removal of cysteines. AB - The Na-K-Cl cotransporter (NKCC) couples the movement of Na(+), K(+), and Cl(-) ions across the plasma membrane of most animal cells and thus plays a central role in cellular homeostasis and human physiology. In order to study the structure, function, and regulation of NKCC1 we have engineered a synthetic cDNA encoding the transporter with 30 unique silent restriction sites throughout the open reading frame, and with N-terminal 3xFlag and YFP tags. We show that the novel cDNA is appropriately expressed in HEK-293 cells and that the YFP-tag does not alter the transport function of the protein. Utilizing the Cl(-) -sensing capability of YFP, we demonstrate a sensitive assay of Na-K-Cl cotransport activity that measures normal cotransport activity in a fully activated transporter. In addition we present three newly developed epitope tags for NKCC1 all of which can be detected from outside of the cell, one of which is very efficiently delivered to the plasma membrane. Finally, we have characterized cysteine mutants of NKCC1 and found that whereas many useful combinations of cysteine mutations are tolerated by the biosynthetic machinery, the fully "cys less" NKCC1 is retained in the endoplasmic reticulum. Together these advances are expected to greatly assist future studies of NKCC1. PMID- 24339992 TI - Structural insights into the globular tails of the human type v myosins Myo5a, Myo5b, And Myo5c. AB - Vertebrate type V myosins (MyoV) Myo5a, Myo5b, and Myo5c mediate transport of several different cargoes. All MyoV paralogs bind to cargo complexes mainly by their C-terminal globular domains. In absence of cargo, the globular domain of Myo5a inhibits its motor domain. Here, we report low-resolution SAXS models for the globular domains from human Myo5a, Myo5b, and Myo5c, which suggest very similar overall shapes of all three paralogs. We determined the crystal structures of globular domains from Myo5a and Myo5b, and provide a homology model for human Myo5c. When we docked the Myo5a crystal structure into a previously published electron microscopy density of the autoinhibited full-length Myo5a, only one domain orientation resulted in a good fit. This structural arrangement suggests the participation of additional region of the globular domain in autoinhibition. Quantification of the interaction of the Myo5a globular domain with its motor complex revealed a tight binding with dissociation half-life in the order of minutes, suggesting a rather slow transition between the active and inactive states. PMID- 24339993 TI - Probing the effect of the non-active-site mutation Y229W in New Delhi metallo beta-lactamase-1 by site-directed mutagenesis, kinetic studies, and molecular dynamics simulations. AB - New Delhi metallo-beta-lactamase-1 (NDM-1) has attracted extensive attention for its high catalytic activities of hydrolyzing almost all beta-lactam antibiotics. NDM-1 shows relatively higher similarity to subclass B1 metallo-beta-lactamases (MbetaLs), but its residue at position 229 is identical to that of B2/B3 MbetaLs, which is a Tyr instead of a B1-MbetaL-conserved Trp. To elucidate the possible role of Y229 in the bioactivity of NDM-1, we performed mutagenesis study and molecular dynamics (MD) simulations. Although residue Y229 is spatially distant from the active site and not contacting directly with the substrate or zinc ions, the Y229W mutant was found to have higher kcat and Km values than those of wild type NDM-1, resulting in 1 ~ 7 fold increases in k(cat) /K(m) values against tested antibiotics. In addition, our MD simulations illustrated the enhanced flexibility of Loop 2 upon Y229W mutation, which could increase the kinetics of both substrate entrance (kon) and product egress (koff). The enhanced flexibility of Loop 2 might allow the enzyme to adjust the geometry of its active site to accommodate substrates with different structures, broadening its substrate spectrum. This study indicated the possible role of the residue at position 229 in the evolution of NDM-1. PMID- 24339994 TI - Calcium channel blocker enhances beneficial effects of an angiotensin II AT1 receptor blocker against cerebrovascular-renal injury in type 2 diabetic mice. AB - Recent clinical trials have demonstrated that combination therapy with renin angiotensin system inhibitors plus calcium channel blockers (CCBs) elicits beneficial effects on cardiovascular and renal events in hypertensive patients with high cardiovascular risks. In the present study, we hypothesized that CCB enhances the protective effects of an angiotensin II type 1 receptor blocker (ARB) against diabetic cerebrovascular-renal injury. Saline-drinking type 2 diabetic KK-A(y) mice developed hypertension and exhibited impaired cognitive function, blood-brain barrier (BBB) disruption, albuminuria, glomerular sclerosis and podocyte injury. These brain and renal injuries were associated with increased gene expression of NADPH oxidase components, NADPH oxidase activity and oxidative stress in brain and kidney tissues as well as systemic oxidative stress. Treatment with the ARB, olmesartan (10 mg/kg/day) reduced blood pressure in saline-drinking KK-A(y) mice and attenuated cognitive decline, BBB disruption, glomerular injury and albuminuria, which were associated with a reduction of NADPH oxidase activity and oxidative stress in brain and kidney tissues as well as systemic oxidative stress. Furthermore, a suppressive dose of azelnidipine (3 mg/kg/day) exaggerated these beneficial effects of olmesartan. These data support the hypothesis that a CCB enhances ARB-associated cerebrovascular-renal protective effects through suppression of NADPH oxidase-dependent oxidative stress in type 2 diabetes. PMID- 24339995 TI - Outbreak of H3N2 influenza at a US military base in Djibouti during the H1N1 pandemic of 2009. AB - BACKGROUND: Influenza pandemics have significant operational impact on deployed military personnel working in areas throughout the world. The US Department of Defense global influenza-like illness (ILI) surveillance network serves an important role in establishing baseline trends and can be leveraged to respond to outbreaks of respiratory illness. OBJECTIVE: We identified and characterized an operationally unique outbreak of H3N2 influenza at Camp Lemonnier, Djibouti occurring simultaneously with the H1N1 pandemic of 2009 [A(H1N1)pdm09]. METHODS: Enhanced surveillance for ILI was conducted at Camp Lemonnier in response to local reports of a possible outbreak during the A(H1N1)pdm09 pandemic. Samples were collected from consenting patients presenting with ILI (utilizing a modified case definition) and who completed a case report form. Samples were cultured and analyzed using standard real-time reverse transcriptase PCR (rt-RT-PCR) methodology and sequenced genetic material was phylogenetically compared to other published strains. RESULTS: rt-RT-PCR and DNA sequencing revealed that 25 (78%) of the 32 clinical samples collected were seasonal H3N2 and only 2 (6%) were A(H1N1)pdm09 influenza. The highest incidence of H3N2 occurred during the month of May and 80% of these were active duty military personnel. Phylogenetic analysis revealed that sequenced H3N2 strains were genetically similar to 2009 strains from the United States of America, Australia, and South east Asia. CONCLUSIONS: This outbreak highlights challenges in the investigation of influenza among deployed military populations and corroborates the public health importance of maintaining surveillance systems for ILI that can be enhanced locally when needed. PMID- 24339996 TI - Nogo-receptor 1 deficiency has no influence on immune cell repertoire or function during experimental autoimmune encephalomyelitis. AB - The potential role of Nogo-66 Receptor 1 (NgR1) on immune cell phenotypes and their activation during neuroinflammatory diseases such as multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), is unclear. To further understand the function of this receptor on haematopoietically-derived cells, phenotypic and functional analyses were performed using NgR1-deficient (ngr1-/-) animals. Flow cytometry-based phenotypic analyses performed on blood, spleen, thymus, lymph nodes, bone marrow and central nervous-system (CNS)-infiltrating blood cells revealed no immunological defects in naive ngr1-/- animals versus wild-type littermate (WTLM) controls. EAE was induced by either recombinant myelin oligodendrocyte glycoprotein (rMOG), a model in which B cells are considered to contribute pathogenically, or by MOG35-55 peptide, a B cell-independent model. We have demonstrated that in ngr1-/- mice injected with MOG35-55, a significant reduction in the severity of EAE correlated with reduced axonal damage present in the spinal cord when compared to their WTLM controls. However, despite a reduction in axonal damage observed in the CNS of ngr1-/- mice at the chronic stage of disease, no clinical differences could be attributed to a specific genotype when rMOG was used as the encephalitogen. Following MOG35-55-induction of EAE, we could not derive any major changes to the immune cell populations analyzed between ngr1-/- and WTLM mice. Collectively, these data demonstrate that NgR1 has little if any effects on the repertoire of immune cells, their activation and trafficking to the CNS. PMID- 24339997 TI - Spatio-temporal correlation tensors reveal functional structure in human brain. AB - Resting state functional magnetic resonance imaging (fMRI) has been commonly used to measure functional connectivity between cortical regions, while diffusion tensor imaging (DTI) can be used to characterize structural connectivity of white matter tracts. In principle combining resting state fMRI and DTI data could allow characterization of structure-function relations of distributed neural networks. However, due to differences in the biophysical origins of their signals and in the tissues to which they apply, there has been no direct integration of these techniques to date. We demonstrate that MRI signal variations and power spectra in a resting state are largely comparable between gray matter and white matter, that there are temporal correlations of fMRI signals that persist over long distances within distinct white matter structures, and that neighboring intervoxel correlations of low frequency resting state signals showed distinct anisotropy in many regions. These observations suggest that MRI signal variations from within white matter in a resting state may convey similar information as their corresponding fluctuations of MRI signals in gray matter. We thus derive a local spatio-temporal correlation tensor which captures directional variations of resting-state correlations and which reveals distinct structures in both white and gray matter. This novel concept is illustrated with in vivo experiments in a resting state, which demonstrate the potential of the technique for mapping the functional structure of neural networks and for direct integration of structure function relations in the human brain. PMID- 24339998 TI - Evidence accumulation in the magnitude system. AB - Perceptual interferences in the estimation of quantities (time, space and numbers) have been interpreted as evidence for a common magnitude system. However, if duration estimation has appears sensitive to spatial and numerical interferences, space and number estimation tend to be resilient to temporal manipulations. These observations question the relative contribution of each quantity in the elaboration of a representation in a common mental metric. Here, we elaborated a task in which perceptual evidence accumulated over time for all tested quantities (space, time and number) in order to match the natural requirement for building a duration percept. For this, we used a bisection task. Experimental trials consisted of dynamic dots of different sizes appearing progressively on the screen. Participants were asked to judge the duration, the cumulative surface or the number of dots in the display while the two non-target dimensions varied independently. In a prospective experiment, participants were informed before the trial which dimension was the target; in a retrospective experiment, participants had to attend to all dimensions and were informed only after a given trial which dimension was the target. Surprisingly, we found that duration was resilient to spatial and numerical interferences whereas space and number estimation were affected by time. Specifically, and counter-intuitively, results revealed that longer durations lead to smaller number and space estimates whether participants knew before (prospectively) or after (retrospectively) a given trial which quantity they had to estimate. Altogether, our results support a magnitude system in which perceptual evidence for time, space and numbers integrate following Bayesian cue-combination rules. PMID- 24339999 TI - Differential responses of neuronal and spermatogenic cells to the doppel cytotoxicity. AB - Although structurally and biochemically similar to the cellular prion (PrP(C)), doppel (Dpl) is unique in its biological functions. There are no reports about any neurodegenerative diseases induced by Dpl. However the artificial expression of Dpl in the PrP-deficient mouse brain causes ataxia with Purkinje cell death. Abundant Dpl proteins have been found in testis and depletion of the Dpl gene (Prnd) causes male infertility. Therefore, we hypothesize different regulations of Prnd in the nerve and male productive systems. In this study, by electrophoretic mobility shift assays we have determined that two different sets of transcription factors are involved in regulation of the Prnd promoter in mouse neuronal N2a and GC-1 spermatogenic (spg) cells, i.e., upstream stimulatory factors (USF) in both cells, Brn-3 and Sp1 in GC-1 spg cells, and Sp3 in N2a cells, leading to the expression of Dpl in GC-1 spg but not in N2a cells. We have further defined that, in N2a cells, Dpl induces oxidative stress and apoptosis, which stimulate ataxia-telangiectasia mutated (ATM)-modulating bindings of transcription factors, p53 and p21, to Prnp promoter, resulting the PrP(C) elevation for counteraction of the Dpl cytotoxicity; in contrast, in GC-1 spg cells, phosphorylation of p21 and N-terminal truncated PrP may play roles in the control of Dpl-induced apoptosis, which may benefit the physiological function of Dpl in the male reproduction system. PMID- 24340000 TI - CyTargetLinker: a cytoscape app to integrate regulatory interactions in network analysis. AB - INTRODUCTION: The high complexity and dynamic nature of the regulation of gene expression, protein synthesis, and protein activity pose a challenge to fully understand the cellular machinery. By deciphering the role of important players, including transcription factors, microRNAs, or small molecules, a better understanding of key regulatory processes can be obtained. Various databases contain information on the interactions of regulators with their targets for different organisms, data recently being extended with the results of the ENCODE (Encyclopedia of DNA Elements) project. A systems biology approach integrating our understanding on different regulators is essential in interpreting the regulation of molecular biological processes. IMPLEMENTATION: We developed CyTargetLinker (http://projects.bigcat.unimaas.nl/cytargetlinker), a Cytoscape app, for integrating regulatory interactions in network analysis. Recently we released CyTargetLinker as one of the first apps for Cytoscape 3. It provides a user-friendly and flexible interface to extend biological networks with regulatory interactions, such as microRNA-target, transcription factor-target and/or drug-target. Importantly, CyTargetLinker employs identifier mapping to combine various interaction data resources that use different types of identifiers. RESULTS: Three case studies demonstrate the strength and broad applicability of CyTargetLinker, (i) extending a mouse molecular interaction network, containing genes linked to diabetes mellitus, with validated and predicted microRNAs, (ii) enriching a molecular interaction network, containing DNA repair genes, with ENCODE transcription factor and (iii) building a regulatory meta-network in which a biological process is extended with information on transcription factor, microRNA and drug regulation. CONCLUSIONS: CyTargetLinker provides a simple and extensible framework for biologists and bioinformaticians to integrate different regulatory interactions into their network analysis approaches. Visualization options enable biological interpretation of complex regulatory networks in a graphical way. Importantly the incorporation of our tool into the Cytoscape framework allows the application of CyTargetLinker in combination with a wide variety of other apps for state-of-the art network analysis. PMID- 24340001 TI - Broad-scale phosphoprotein profiling of beta adrenergic receptor (beta-AR) signaling reveals novel phosphorylation and dephosphorylation events. AB - beta-adrenergic receptors (beta-ARs) are model G-protein coupled receptors that mediate signal transduction in the sympathetic nervous system. Despite the widespread clinical use of agents that target beta-ARs, the signaling pathways that operate downstream of beta-AR stimulation have not yet been completely elucidated. Here, we utilized a lysate microarray approach to obtain a broad scale perspective of phosphoprotein signaling downstream of beta-AR. We monitored the time course of phosphorylation states of 54 proteins after beta-AR activation mouse embryonic fibroblast (MEF) cells. In response to stimulation with the non selective beta-AR agonist isoproterenol, we observed previously described phosphorylation events such as ERK1/2(T202/Y204) and CREB(S133), but also novel phosphorylation events such as Cdc2(Y15) and Pyk2(Y402). All of these events were mediated through cAMP and PKA as they were reproduced by stimulation with the adenylyl cyclase activator forskolin and were blocked by treatment with H89, a PKA inhibitor. In addition, we also observed a number of novel isoproterenol induced protein dephosphorylation events in target substrates of the PI3K/AKT pathway: GSK3beta(S9), 4E-BP1(S65), and p70s6k(T389). These dephosphorylations were dependent on cAMP, but were independent of PKA and correlated with reduced PI3K/AKT activity. Isoproterenol stimulation also led to a cAMP-dependent dephosphorylation of PP1alpha(T320), a modification known to correlate with enhanced activity of this phosphatase. Dephosphorylation of PP1alpha coincided with the secondary decline in phosphorylation of some PKA-phosphorylated substrates, suggesting that PP1alpha may act in a feedback loop to return these phosphorylations to baseline. In summary, lysate microarrays are a powerful tool to profile phosphoprotein signaling and have provided a broad-scale perspective of how beta-AR signaling can regulate key pathways involved in cell growth and metabolism. PMID- 24340002 TI - Behavioral and electrophysiological effects of cortical microstimulation parameters. AB - Electrical microstimulation has been widely used to artificially activate neural circuits on fast time scales. Despite the ubiquity of its use, little is known about precisely how it activates neural pathways. Current is typically delivered to neural tissue in a manner that provides a locally balanced injection of positive and negative charge, resulting in negligible net charge delivery to avoid the neurotoxic effects of charge accumulation. Modeling studies have suggested that the most common approach, using a temporally symmetric current pulse waveform as the base unit of stimulation, results in preferential activation of axons, causing diffuse activation of neurons relative to the stimulation site. Altering waveform shape and using an asymmetric current pulse waveform theoretically reverses this bias and preferentially activates cell bodies, providing increased specificity. In separate studies, measurements of downstream cortical activation from sub-cortical microstimulation are consistent with this hypothesis, as are recent measurements of behavioral detection threshold currents from cortical microstimulation. Here, we compared the behavioral and electrophysiological effects of symmetric vs. asymmetric current waveform shape in cortical microstimulation. Using a go/no-go behavioral task, we found that microstimulation waveform shape significantly shifts psychometric performance, where a larger current pulse was necessary when applying an asymmetric waveform to elicit the same behavioral response, across a large range of behaviorally relevant current amplitudes. Using voltage-sensitive dye imaging of cortex in anesthetized animals with simultaneous cortical microstimulation, we found that altering microstimulation waveform shape shifted the cortical activation in a manner that mirrored the behavioral results. Taken together, these results are consistent with the hypothesis that asymmetric stimulation preferentially activates cell bodies, albeit at a higher threshold, as compared to symmetric stimulation. These findings demonstrate the sensitivity of the pathway to varying electrical stimulation parameters and underscore the importance of designing electrical stimuli for optimal activation of neural circuits. PMID- 24340003 TI - Development of the acoustically evoked behavioral response in larval plainfin midshipman fish, Porichthys notatus. AB - The ontogeny of hearing in fishes has become a major interest among bioacoustics researchers studying fish behavior and sensory ecology. Most fish begin to detect acoustic stimuli during the larval stage which can be important for navigation, predator avoidance and settlement, however relatively little is known about the hearing capabilities of larval fishes. We characterized the acoustically evoked behavioral response (AEBR) in the plainfin midshipman fish, Porichthys notatus, and used this innate startle-like response to characterize this species' auditory capability during larval development. Age and size of larval midshipman were highly correlated (r(2) = 0.92). The AEBR was first observed in larvae at 1.4 cm TL. At a size >= 1.8 cm TL, all larvae responded to a broadband stimulus of 154 dB re1 uPa or -15.2 dB re 1 g (z-axis). Lowest AEBR thresholds were 140-150 dB re 1 uPa or -33 to -23 dB re 1 g for frequencies below 225 Hz. Larval fish with size ranges of 1.9-2.4 cm TL had significantly lower best evoked frequencies than the other tested size groups. We also investigated the development of the lateral line organ and its function in mediating the AEBR. The lateral line organ is likely involved in mediating the AEBR but not necessary to evoke the startle-like response. The midshipman auditory and lateral line systems are functional during early development when the larvae are in the nest and the auditory system appears to have similar tuning characteristics throughout all life history stages. PMID- 24340004 TI - Helicobacter pylori genomic microevolution during naturally occurring transmission between adults. AB - The human gastric pathogen Helicobacter pylori is usually acquired during childhood and, in the absence of treatment, chronic infection persists through most of the host's life. However, the frequency and importance of H. pylori transmission between adults is underestimated. Here we sequenced the complete genomes of H. pylori strains that were transmitted between spouses and analysed the genomic changes. Similar to H. pylori from chronic infection, a significantly high proportion of the determined 31 SNPs and 10 recombinant DNA fragments affected genes of the hop family of outer membrane proteins, some of which are known to be adhesins. In addition, changes in a fucosyltransferase gene modified the LPS component of the bacterial cell surface, suggesting strong diversifying selection. In contrast, virulence factor genes were not affected by the genomic changes. We propose a model of the genomic changes that are associated with the transmission and adaptation of H. pylori to a new human host. PMID- 24340005 TI - Proteomic analysis in nitrogen-deprived Isochrysis galbana during lipid accumulation. AB - The differentially co-expressed proteins in N-deprived and N-enriched I. galbana were comparatively analyzed by using two dimensional electrophoresis (2-DE) and matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight-mass spectrometry (MALDI-TOF/TOF-MS) with the aim of better understanding lipid metabolism in this oleaginous microalga. Forty-five of the 900 protein spots showed dramatic changes in N-deprived I. galbana compared with the N-enriched cells. Of these, 36 protein spots were analyzed and 27 proteins were successfully identified. The identified proteins were classified into seven groups by their molecular functions, including the proteins related to energy production and transformation, substance metabolism, signal transduction, molecular chaperone, transcription and translation, immune defense and cytoskeleton. These altered proteins slowed cell growth and photosynthesis of I. galbana directly or indirectly, but at the same time increased lipid accumulation. Eight key enzymes involved in lipid metabolism via different pathways were identified as glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK), enolase, aspartate aminotransferase (AST), fumarate hydratase (FH), citrate synthase (CS), O-acetyl-serine lyase (OAS-L) and ATP sulfurylase (ATPS). The results suggested that the glycolytic pathway and citrate transport system might be the main routes for lipid anabolism in N-deprived I. galbana, and that the tricarboxylic acid (TCA) cycle, glyoxylate cycle and sulfur assimilation system might be the major pathways involved in lipid catabolism. PMID- 24340006 TI - Measuring dilution of microbicide gels with optical imaging. AB - We present a novel approach for measuring topical microbicide gel dilution using optical imaging. The approach compares gel thickness measurements from fluorimetry and multiplexed low coherence interferometry in order to calculate dilution of a gel. As a microbicide gel becomes diluted at fixed thickness, its mLCI thickness measurement remains constant, while the fluorimetry signal decreases in intensity. The difference between the two measurements is related to the extent of gel dilution. These two optical modalities are implemented in a single endoscopic instrument that enables simultaneous data collection. A preliminary validation study was performed with in vitro placebo gel measurements taken in a controlled test socket. It was found that change in slope of the regression line between fluorimetry and mLCI based measurements indicates dilution. A dilution calibration curve was then generated by repeating the test socket measurements with serial dilutions of placebo gel with vaginal fluid simulant. This methodology can provide valuable dilution information on candidate microbicide products, which could substantially enhance our understanding of their in vivo functioning. PMID- 24340007 TI - Methylene blue modulates transendothelial migration of peripheral blood cells. AB - Vasoplegia is a severe complication after cardiac surgery. Within the last years the administration of nitric oxide synthase inhibitor methylene blue (MB) became a new therapeutic strategy. Our aim was to investigate the role of MB on transendothelial migration of circulating blood cells, the potential role of cyclic cGMP, eNOS and iNOS in this process, and the influence of MB on endothelial cell apoptosis. Human vascular endothelial cells (HuMEC-1) were treated for 30 minutes or 2 hours with different concentrations of MB. Inflammation was mimicked by LPS stimulation prior and after MB. Transmigration of PBMCs and T-Lymphocytes through the treated endothelial cells was investigated. The influence of MB upon the different subsets of PBMCs (Granulocytes, T- and B-Lymphocytes, and Monocytes) was assessed after transmigration by means of flow-cytometry. The effect of MB on cell apoptosis was evaluated using Annexin-V and Propidium Iodide stainings. Analyses of the expression of cyclic cGMP, eNOS and iNOS were performed by means of RT-PCR and Western Blot. Results were analyzed using unpaired Students T-test. Analysis of endothelial cell apoptosis by MB indicated a dose-dependent increase of apoptotic cells. We observed time- and dose-dependent effects of MB on transendothelial migration of PBMCs. The prophylactic administration of MB led to an increase of transendothelial migration of PBMCs but not Jurkat cells. Furthermore, HuMEC-1 secretion of cGMP correlated with iNOS expression after MB administration but not with eNOS expression. Expression of these molecules was reduced after MB administration at protein level. This study clearly reveals that endothelial response to MB is dose- and especially time-dependent. MB shows different effects on circulating blood cell-subtypes, and modifies the release patterns of eNOS, iNOS, and cGMP. The transendothelial migration is modulated after treatment with MB. Furthermore, MB provokes apoptosis of endothelial cells in a dose/time dependent manner. PMID- 24340008 TI - Bright fluorescence monitoring system utilizing Zoanthus sp. green fluorescent protein (ZsGreen) for human G-protein-coupled receptor signaling in microbial yeast cells. AB - G-protein-coupled receptors (GPCRs) are currently the most important pharmaceutical targets for drug discovery because they regulate a wide variety of physiological processes. Consequently, simple and convenient detection systems for ligands that regulate the function of GPCR have attracted attention as powerful tools for new drug development. We previously developed a yeast-based fluorescence reporter ligand detection system using flow cytometry. However, using this conventional detection system, fluorescence from a cell expressing GFP and responding to a ligand is weak, making detection of these cells by fluorescence microscopy difficult. We here report improvements to the conventional yeast fluorescence reporter assay system resulting in the development of a new highly-sensitive fluorescence reporter assay system with extremely bright fluorescence and high signal-to-noise (S/N) ratio. This new system allowed the easy detection of GPCR signaling in yeast using fluorescence microscopy. Somatostatin receptor and neurotensin receptor (implicated in Alzheimer's disease and Parkinson's disease, respectively) were chosen as human GPCR(s). The facile detection of binding to these receptors by cognate peptide ligands was demonstrated. In addition, we established a highly sensitive ligand detection system using yeast cell surface display technology that is applicable to peptide screening, and demonstrate that the display of various peptide analogs of neurotensin can activate signaling through the neurotensin receptor in yeast cells. Our system could be useful for identifying lead peptides with agonistic activity towards targeted human GPCR(s). PMID- 24340009 TI - The role of alpha7 nicotinic acetylcholine receptor in modulation of heart rate dynamics in endotoxemic rats. AB - Previous reports have indicated that artificial stimulation of the vagus nerve reduces systemic inflammation in experimental models of sepsis. This phenomenon is a part of a broader cholinergic anti-inflammatory pathway which activates the vagus nerve to modulate inflammation through activation of alpha7 nicotinic acetylcholine receptors (alpha7nACHR). Heart rate variability represents the complex interplay between autonomic nervous system and cardiac pacemaker cells. Reduced heart rate variability and increased cardiac cycle regularity is a hallmark of clinical conditions that are associated with systemic inflammation (e.g. endotoxemia and sepsis). The present study was aimed to assess the role of alpha7nACHR in modulation of heart rate dynamics during systemic inflammation. Systemic inflammation was induced by injection of endotoxin (lipopolysaccharide) in rats. Electrocardiogram and body temperature were recorded in conscious animals using a telemetric system. Linear and non-linear indices of heart rate variability (e.g. sample entropy and fractal-like temporal structure) were assessed. RT-PCR and immunohistochemistry studies showed that alpha7nACHR is expressed in rat atrium and is mainly localized at the endothelial layer. Systemic administration of an alpha7nACHR antagonist (methyllycaconitine) did not show a significant effect on body temperature or heart rate dynamics in naive rats. However, alpha7nACHR blockade could further reduce heart rate variability and elicit a febrile response in endotoxemic rats. Pre-treatment of endotoxemic animals with an alpha7nACHR agonist (PHA-543613) was unable to modulate heart rate dynamics in endotoxemic rats but could prevent the effect of endotoxin on body temperature within 24 h experiment. Neither methyllycaconitine nor PHA 543613 could affect cardiac beating variability of isolated perfused hearts taken from control or endotoxemic rats. Based on our observations we suggest a tonic role for nicotinic acetylcholine receptors in modulation of heart rate dynamics during systemic inflammation. PMID- 24340010 TI - Inter-subunit interactions across the upper voltage sensing-pore domain interface contribute to the concerted pore opening transition of Kv channels. AB - The tight electro-mechanical coupling between the voltage-sensing and pore domains of Kv channels lies at the heart of their fundamental roles in electrical signaling. Structural data have identified two voltage sensor pore inter-domain interaction surfaces, thus providing a framework to explain the molecular basis for the tight coupling of these domains. While the contribution of the intra subunit lower domain interface to the electro-mechanical coupling that underlies channel opening is relatively well understood, the contribution of the inter subunit upper interface to channel gating is not yet clear. Relying on energy perturbation and thermodynamic coupling analyses of tandem-dimeric Shaker Kv channels, we show that mutation of upper interface residues from both sides of the voltage sensor-pore domain interface stabilizes the closed channel state. These mutations, however, do not affect slow inactivation gating. We, moreover, find that upper interface residues form a network of state-dependent interactions that stabilize the open channel state. Finally, we note that the observed residue interaction network does not change during slow inactivation gating. The upper voltage sensing-pore interaction surface thus only undergoes conformational rearrangements during channel activation gating. We suggest that inter-subunit interactions across the upper domain interface mediate allosteric communication between channel subunits that contributes to the concerted nature of the late pore opening transition of Kv channels. PMID- 24340012 TI - Effectiveness of a video-feedback and questioning programme to develop cognitive expertise in sport. AB - The importance within sport expertise of cognitive factors has been emphasised in many research studies. Adaptations that take place in athletes' long-term memories are going to condition their decision-making and performance, and training programmes must be developed that improve these adaptations. In our study, we provide a tactical-cognitive training programme based on video-feedback and questioning in order to improve tactical knowledge in tennis players and verify its effect when transferred to athletes' decision-making. 11 intermediate tennis players participated in this study (12.9 +/- 0.7 years old), distributed into two groups (experimental, n = 5; control, n = 6). Tactical knowledge was measured by problem representation and strategy planning with a verbal protocol. Decision-making was measured by a systematic observation instrument. Results confirm the effectiveness of a combination of video-feedback and questioning on cognitive expertise, developing adaptations in long-term memory that produce an improvement in the quality of tactical knowledge (content, sophistication and structure). This, in turn, is transferred to the athletes' decision-making capacity, leading to a higher percentage of successful decisions made during game play. Finally, we emphasise the need to develop effective programmes to develop cognitive expertise and improve athletes' performance, and include it in athletes' formative stages. PMID- 24340011 TI - Upregulation of endocan by Epstein-Barr virus latent membrane protein 1 and its clinical significance in nasopharyngeal carcinoma. AB - Endocan (or called Esm-1) has been shown to have tumorigenic activities and its expression is associated with poor prognosis in various cancers. Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV)-encoded oncoprotein and has been shown to play an important role in the pathogenesis of EBV-associated nasopharyngeal carcinoma (NPC). To further understand the role of LMP1 in the pathogenesis of NPC, microarray analysis of LMP1-regulated genes in epithelial cells was performed. We found that endocan was one of the major cellular genes upregulated by LMP1. This induction of endocan by LMP1 was confirmed in several epithelial cell lines including an NPC cell line. Upregulation of endocan by LMP1 was found to be mediated through the CTAR1 and CTAR2 domains of LMP1 and through the LMP1-activated NF-kappaB, MEK-ERK and JNK signaling pathways. To study whether endocan was expressed in NPC and whether endocan expression was associated with LMP1 expression in NPC, the expression of endocan and LMP1 in tumor tissues from 42 NPC patients was evaluated by immunohistochemistry. Expression of endocan was found in 52% of NPC specimens. Significant correlation between LMP1 and endocan expression was observed (p<0.0001). Moreover, NPC patients with endocan expression were found to have a shorter survival than NPC patients without endocan expression (p=0.0104, log-rank test). Univariate and Multivariate analyses revealed that endocan was a potential prognostic factor for NPC. Finally, we demonstrated that endocan could stimulate the migration and invasion ability of endothelial cells and this activity of endocan was dependent on the glycan moiety and the phenylalanine-rich region of endocan. Together, these studies not only identify a new molecular marker that may predict the survival of NPC patients but also provide a new insight to the pathogenesis of NPC. PMID- 24340013 TI - Influence of ovarian hormones on cortical spreading depression and its suppression by L-kynurenine in rat. AB - Migraine is sexually dimorphic and associated in 20-30% of patients with an aura most likely caused by cortical spreading depression (CSD). We have previously shown that systemic L-kynurenine (L-KYN), the precursor of kynurenic acid, suppresses CSD and that this effect depends on the stage of the estrous cycle in female rats. The objectives here are to determine the influence of ovarian hormones on KCl-induced CSD and its suppression after L-KYN by directly modulating estradiol or progesterone levels in ovariectomized rats. Adult female rats were ovariectomized and subcutaneously implanted with silastic capsules filled with progesterone or 17beta-estradiol mixed with cholesterol, with cholesterol only or left empty. Two weeks after the ovariectomy/capsule implantation, the animals received an i.p. injection of L-KYN (300 mg/kg) or NaCl as control. Thirty minutes later CSDs were elicited by applying KCl over the occipital cortex and recorded by DC electrocorticogram for 1 hour. The results show that both estradiol and progesterone increase CSD frequency after ovariectomy. The suppressive effect of L-KYN on CSD frequency, previously reported in normal cycling females, is not found anymore after ovariectomy, but reappears after progesterone replacement therapy. Taken together, these results emphasize the complex role of sex hormones on cortical excitability. The CSD increase by estradiol and, more surprisingly, progesterone may explain why clinically migraine with aura appears or worsens during pregnancy or with combined hormonal treatments. PMID- 24340014 TI - Oncogenic K-Ras and loss of Smad4 mediate invasion by activating an EGFR/NF kappaB Axis that induces expression of MMP9 and uPA in human pancreas progenitor cells. AB - Activating K-Ras mutations and inactivating mutations of Smad4 are two common genetic alterations that occur in the development and progression of pancreatic ductal adenocarcinomas (PDAC). To further study the individual and combinatorial roles of these two mutations in the pathogenesis of PDAC, immortalized human pancreas nestin postive cells (HPNE) were genetically modified by either expressing oncogenic K-Ras (HPNE/K-Ras), by shRNA knock down of Smad4 (HPNE/ShSmad4) or by creating both alterations in the same cell line (HPNE/K Ras/ShSmad4). We previously found that expression of oncogenic K-Ras caused an increase in expression of EGFR and loss of Smad4 further enhanced the up regulation in expression of EGFR and that this increase in EGFR was sufficient to induce invasion. Here we further investigated the mechanism that links mutational alterations and EGFR expression with invasion. The increase in EGFR signaling was associated with up regulation of MMP9 and uPA protein and activity. Moreover, the increase in EGFR signaling promoted a nuclear translocation and binding of RelA (p65), a subunit of NF-kappaB, to the promoters of both MMP-9 and uPA. Treatment of HPNE/K-Ras/ShSmad4 cells with an inhibitor of EGFR reduced EGF-mediated NF kappaB nuclear translocation and inhibitors of either EGFR or NF-kappaB reduced the increase in MMP-9 or uPA expression. In conclusion, this study provides the mechanism of how a combination of oncogenic K-Ras and loss of Smad4 causes invasion and provides the basis for new strategies to inhibit metastases. PMID- 24340016 TI - Estimation of parameters influencing waterborne transmission of infectious hematopoietic necrosis virus (IHNV) in Atlantic salmon (Salmo salar). AB - Understanding how pathogenic organisms spread in the environment is crucial for the management of disease, yet knowledge of propagule dispersal and transmission in aquatic environments is limited. We conducted empirical studies using the aquatic virus, infectious hematopoietic necrosis virus (IHNV), to quantify infectious dose, shedding capacity, and virus destruction rates in order to better understand the transmission of IHN virus among Atlantic salmon marine net pen aquaculture. Transmission of virus and subsequent mortality in Atlantic salmon post-smolts was initiated with as low as 10 plaque forming units (pfu) ml( 1). Virus shedding from IHNV infected Atlantic salmon was detected before the onset of visible signs of disease with peak shed rates averaging 3.2 * 10(7) pfu fish(-1) hour(-1) one to two days prior to mortality. Once shed into the marine environment, the abundance of free IHNV is modulated by sunlight (UV A and B) and the growth of natural biota present in the seawater. Virus decayed very slowly in sterilized seawater while rates as high as k = 4.37 d(-1) were observed in natural seawater. Decay rates were further accelerated when exposed to sunlight with virus infectivity reduced by six orders of magnitude within 3 hours of full sunlight exposure. Coupling the IHNV transmission parameter estimates determined here with physical water circulation models, will increase the understanding of IHNV dispersal and provide accurate geospatial predictions of risk for IHNV transmission from marine salmon sites. PMID- 24340015 TI - Identification and functional characterization of three NoLS (nucleolar localisation signals) mutations of the CDC73 gene. AB - Hyperparathyroidism Jaw-Tumour Syndrome (HPT-JT) is characterized by primary hyperparathyroidism (PHPT), maxillary/mandible ossifying fibromas and by parathyroid carcinoma in 15% of cases. Inactivating mutations of the tumour suppressor CDC73/HRPT2 gene have been found in HPT-JT patients and also as genetic determinants of sporadic parathyroid carcinoma/atypical adenomas and, rarely, typical adenomas, in familial PHPT. Here we report the genetic and molecular analysis of the CDC73/HRPT2 gene in three patients affected by PHPT due to atypical and typical parathyroid adenomas, in one case belonging to familial PHPT. Flag-tagged WT and mutant CDC73/HRPT2 proteins were transiently transfected in HEK293 cells and functional assays were performed in order to investigate the effect of the variants on the whole protein expression, nuclear localization and cell overgrowth induction. We identified four CDC73/HRPT2 gene mutations, three germline (c.679_680delAG, p.Val85_Val86del and p.Glu81_Pro84del), one somatic (p.Arg77Pro). In three cases the mutation was located within the Nucleolar Localisation Signals (NoLS). The three NoLS variants led to instability either of the corresponding mutated protein or mRNA or both. When transfected in HEK293 cells, NoLS mutated proteins mislocalized with a predeliction for cytoplasmic or nucleo-cytoplasmic localization and, finally, they resulted in overgrowth, consistent with a dominant negative interfering effect in the presence of the endogenous protein. PMID- 24340017 TI - Mir-29 repression in bladder outlet obstruction contributes to matrix remodeling and altered stiffness. AB - Recent work has uncovered a role of the microRNA (miRNA) miR-29 in remodeling of the extracellular matrix. Partial bladder outlet obstruction is a prevalent condition in older men with prostate enlargement that leads to matrix synthesis in the lower urinary tract and increases bladder stiffness. Here we tested the hypothesis that miR-29 is repressed in the bladder in outlet obstruction and that this has an impact on protein synthesis and matrix remodeling leading to increased bladder stiffness. c-Myc, NF-kappaB and SMAD3, all of which repress miR 29, were activated in the rat detrusor following partial bladder outlet obstruction but at different times. c-Myc and NF-kappaB activation occurred early after obstruction, and SMAD3 phosphorylation increased later, with a significant elevation at 6 weeks. c-Myc, NF-kappaB and SMAD3 activation, respectively, correlated with repression of miR-29b and miR-29c at 10 days of obstruction and with repression of miR-29c at 6 weeks. An mRNA microarray analysis showed that the reduction of miR-29 following outlet obstruction was associated with increased levels of miR-29 target mRNAs, including mRNAs for tropoelastin, the matricellular protein Sparc and collagen IV. Outlet obstruction increased protein levels of eight out of eight examined miR-29 targets, including tropoelastin and Sparc. Transfection of human bladder smooth muscle cells with antimiR-29c and miR 29c mimic caused reciprocal changes in target protein levels in vitro. Tamoxifen inducible and smooth muscle-specific deletion of Dicer in mice reduced miR-29 expression and increased tropoelastin and the thickness of the basal lamina surrounding smooth muscle cells in the bladder. It also increased detrusor stiffness independent of outlet obstruction. Taken together, our study supports a model where the combined repressive influences of c-Myc, NF-kappaB and SMAD3 reduce miR-29 in bladder outlet obstruction, and where the resulting drop in miR 29 contributes to matrix remodeling and altered passive mechanical properties of the detrusor. PMID- 24340018 TI - Proliferation of purple sulphur bacteria at the sediment surface affects intertidal mat diversity and functionality. AB - There is a relative absence of studies dealing with mats of purple sulphur bacteria in the intertidal zone. These bacteria display an array of metabolic pathways that allow them to disperse and develop under a wide variety of conditions, making these mats important in terms of ecosystem processes and functions. Mass blooms of purple sulphur bacteria develop during summer on sediments in the intertidal zone especially on macroalgal deposits. The microbial composition of different types of mats differentially affected by the development of purple sulphur bacteria was examined, at low tide, using a set of biochemical markers (fatty acids, pigments) and composition was assessed against their influence on ecosystem functions (sediment cohesiveness, CO2 fixation). We demonstrated that proliferation of purple sulphur bacteria has a major impact on intertidal mats diversity and functions. Indeed, assemblages dominated by purple sulphur bacteria (Chromatiaceae) were efficient exopolymer producers and their biostabilisation potential was significant. In addition, the massive growth of purple sulphur bacteria resulted in a net CO2 degassing whereas diatom dominated biofilms represented a net CO2 sink. PMID- 24340019 TI - Completion of proteomic data sets by Kd measurement using cell-free synthesis of site-specifically labeled proteins. AB - The characterization of phosphotyrosine mediated protein-protein interactions is vital for the interpretation of downstream pathways of transmembrane signaling processes. Currently however, there is a gap between the initial identification and characterization of cellular binding events by proteomic methods and the in vitro generation of quantitative binding information in the form of equilibrium rate constants (Kd values). In this work we present a systematic, accelerated and simplified approach to fill this gap: using cell-free protein synthesis with site specific labeling for pull-down and microscale thermophoresis (MST) we were able to validate interactions and to establish a binding hierarchy based on Kd values as a completion of existing proteomic data sets. As a model system we analyzed SH2-mediated interactions of the human T-cell phosphoprotein ADAP. Putative SH2 domain-containing binding partners were synthesized from a cDNA library using Expression-PCR with site-specific biotinylation in order to analyze their interaction with fluorescently labeled and in vitro phosphorylated ADAP by pull down. On the basis of the pull-down results, selected SH2's were subjected to MST to determine Kd values. In particular, we could identify an unexpectedly strong binding of ADAP to the previously found binding partner Rasa1 of about 100 nM, while no evidence of interaction was found for the also predicted SH2D1A. Moreover, Kd values between ADAP and its known binding partners SLP-76 and Fyn were determined. Next to expanding data on ADAP suggesting promising candidates for further analysis in vivo, this work marks the first Kd values for phosphotyrosine/SH2 interactions on a phosphoprotein level. PMID- 24340020 TI - Pharmacophore modeling and virtual screening for the discovery of new type 4 cAMP phosphodiesterase (PDE4) inhibitors. AB - Type 4 cAMP phosphodiesterase (PDE4) inhibitors show a broad spectrum of anti inflammatory effects in almost all kinds of inflamed cells, by an increase in cAMP levels which is a pivotal second messenger responsible for various biological processes. These inhibitors are now considered as the potential drugs for treatment of chronic inflammatory diseases. However, some recently marketed inhibitors e.g., roflumilast, have shown adverse effects such as nausea and emesis, thus restricting its use. In order to identify novel PDE4 inhibitors with improved therapeutic indexes, a highly correlating (r = 0.963930) pharmacophore model (Hypo1) was established on the basis of known PDE4 inhibitors. Validated Hypo1 was used in database screening to identify chemical with required pharmacophoric features. These compounds are further screened by using the rule of five, ADMET and molecular docking. Finally, twelve hits which showed good results with respect to following properties such as estimated activity, calculated drug-like properties and scores were proposed as potential leads to inhibit the PDE4 activity. Therefore, this study will not only assist in the development of new potent hits for PDE4 inhibitors, but also give a better understanding of their interaction with PDE4. On a wider scope, this will be helpful for the rational design of novel potent enzyme inhibitors. PMID- 24340021 TI - The development of nasal polyp disease involves early nasal mucosal inflammation and remodelling. AB - Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by both a chronic inflammation and tissue remodelling; as indicated by extracellular matrix protein deposition, basement membrane thickening, goblet cell hyperplasia and subepithelial edema, with reduced vessels and glands. Although remodelling is generally considered to be consequence of persistent inflammation, the chronological order and relationship between inflammation and remodelling in polyp development is still not clear. The aim of our study was therefore to investigate the pathological features prevalent in the development of nasal polyps and to elucidate the chronological order and relationship between inflammation and remodelling, by comparing specific markers of inflammation and remodelling in early stage nasal polyps confined to the middle turbinate (refer to as middle turbinate CRSwNP) obtained from 5 CRSwNP patients with bilateral polyposis, mature ethmoidal polyps from 6 CRSwNP patients, and normal nasal mucosal tissue from 6 control subjects. Middle turbinate CRSwNP demonstrated significantly more severe epithelial loss compared to mature ethmoidal polyps and normal nasal mucosa. The epithelial cell junction molecules E-cadherin, ZO-1 and occludin were also expressed in significantly lower amounts in mature ethmoidal polyps compared to healthy mucosa. Middle turbinate CRSwNP were further characterized by significantly increased numbers of subepithelial eosinophils and M2 type macrophages, with a distinct lack of collagen and deposition of fibronectin in polyp part. In contrast, the turbinate area of the middle turbinate CRSwNP was characterized by an increase in TGF-beta activated myofibroblasts expressing alpha-SMA and vimentin, an increase in the number of pSmad2 positive cells, as well as increased deposition of collagen. These findings suggest a complex network of processes in the formation of CRSwNP; including gross epithelial damage and repair reactions, eosinophil and macrophage cell infiltration, and tissue remodelling. Furthermore, remodelling appears to occur in parallel, rather than subsequent to inflammation. PMID- 24340022 TI - Moderate exercise during pregnancy in Wistar rats alters bone and body composition of the adult offspring in a sex-dependent manner. AB - Exercise during pregnancy may have long-lasting effects on offspring health. Musculoskeletal growth and development, metabolism, and later-life disease risk can all be impacted by the maternal environment during pregnancy. The skeleton influences glucose handling through the actions of the bone-derived hormone osteocalcin. The purpose of this study was to test the effects of moderate maternal exercise during pregnancy on the bone and body composition of the offspring in adult life, and to investigate the role of osteocalcin in these effects. Groups of pregnant Wistar rats either performed bipedal standing exercise to obtain food/water throughout gestation but not lactation, or were fed conventionally. Litters were reduced to 8/dam and pups were raised to maturity under control conditions. Whole body dual-energy x-ray absorptiometry, and ex vivo peripheral quantitative computed tomography scans of the right tibia were performed. At study termination blood and tissue samples were collected. Serum concentrations of fully and undercarboxylated osteocalcin were measured, and the relative expression levels of osteocalcin, insulin receptor, Forkhead box transcription factor O1, and osteotesticular protein tyrosine phosphatase mRNA were quantified. Body mass did not differ between the offspring of exercised and control dams, but the male offspring of exercised dams had a greater % fat and lower % lean than controls (p=0.001 and p=0.0008, respectively). At the mid tibial diaphysis, offspring of exercised dams had a lower volumetric bone mineral density than controls (p=0.01) and in the male offspring of exercised dams the bone: muscle relationship was fundamentally altered. Serum concentrations of undercarboxylated osteocalcin were significantly greater in the male offspring of exercised dams than in controls (p=0.02); however, the relative expression of the measured genes did not differ between groups. These results suggest that moderate exercise during pregnancy can result in lasting changes to the musculoskeletal system and adiposity in offspring, in a sex-specific manner. PMID- 24340023 TI - Vitamin a is a negative regulator of osteoblast mineralization. AB - An excessive intake of vitamin A has been associated with an increased risk of fractures in humans. In animals, a high vitamin A intake leads to a reduction of long bone diameter and spontaneous fractures. Studies in rodents indicate that the bone thinning is due to increased periosteal bone resorption and reduced radial growth. Whether the latter is a consequence of direct effects on bone or indirect effects on appetite and general growth is unknown. In this study we therefore used pair-feeding and dynamic histomorphometry to investigate the direct effect of a high intake of vitamin A on bone formation in rats. Although there were no differences in body weight or femur length compared to controls, there was an approximately halved bone formation and mineral apposition rate at the femur diaphysis of rats fed vitamin A. To try to clarify the mechanism(s) behind this reduction, we treated primary human osteoblasts and a murine preosteoblastic cell line (MC3T3-E1) with the active metabolite of vitamin A; retinoic acid (RA), a retinoic acid receptor (RAR) antagonist (AGN194310), and a Cyp26 inhibitor (R115866) which blocks endogenous RA catabolism. We found that RA, via RARs, suppressed in vitro mineralization. This was independent of a negative effect on osteoblast proliferation. Alkaline phosphatase and bone gamma carboxyglutamate protein (Bglap, Osteocalcin) were drastically reduced in RA treated cells and RA also reduced the protein levels of Runx2 and Osterix, key transcription factors for progression to a mature osteoblast. Normal osteoblast differentiation involved up regulation of Cyp26b1, the major enzyme responsible for RA degradation, suggesting that a drop in RA signaling is required for osteogenesis analogous to what has been found for chondrogenesis. In addition, RA decreased Phex, an osteoblast/osteocyte protein necessary for mineralization. Taken together, our data indicate that vitamin A is a negative regulator of osteoblast mineralization. PMID- 24340025 TI - Coral reef habitat response to climate change scenarios. AB - Coral reef ecosystems are threatened by both climate change and direct anthropogenic stress. Climate change will alter the physico-chemical environment that reefs currently occupy, leaving only limited regions that are conducive to reef habitation. Identifying these regions early may aid conservation efforts and inform decisions to transplant particular coral species or groups. Here a species distribution model (Maxent) is used to describe habitat suitable for coral reef growth. Two climate change scenarios (RCP4.5, RCP8.5) from the National Center for Atmospheric Research's Community Earth System Model were used with Maxent to determine environmental suitability for corals (order Scleractinia). Environmental input variables best at representing the limits of suitable reef growth regions were isolated using a principal component analysis. Climate-driven changes in suitable habitat depend strongly on the unique region of reefs used to train Maxent. Increased global habitat loss was predicted in both climate projections through the 21(st) century. A maximum habitat loss of 43% by 2100 was predicted in RCP4.5 and 82% in RCP8.5. When the model is trained solely with environmental data from the Caribbean/Atlantic, 83% of global habitat was lost by 2100 for RCP4.5 and 88% was lost for RCP8.5. Similarly, global runs trained only with Pacific Ocean reefs estimated that 60% of suitable habitat would be lost by 2100 in RCP4.5 and 90% in RCP8.5. When Maxent was trained solely with Indian Ocean reefs, suitable habitat worldwide increased by 38% in RCP4.5 by 2100 and 28% in RCP8.5 by 2050. Global habitat loss by 2100 was just 10% for RCP8.5. This projection suggests that shallow tropical sites in the Indian Ocean basin experience conditions today that are most similar to future projections of worldwide conditions. Indian Ocean reefs may thus be ideal candidate regions from which to select the best strands of coral for potential re-seeding efforts. PMID- 24340024 TI - Distribution of LGR5+ cells and associated implications during the early stage of gastric tumorigenesis. AB - Lgr5 was identified as a promising gastrointestinal tract stem cell marker in mice. Lineage tracing indicates that Lgr5(+) cells may not only be the cells responsible for the origin of tumors; they may also be the so-called cancer stem cells. In the present study, we investigated the presence of Lgr5(+) cells and their biological significance in normal human gastric mucosa and gastric tumors. RNAscope, a newly developed RNA in situ hybridization technique, specifically labeled Lgr5(+) cells at the basal glands of the gastric antrum. Notably, the number of Lgr5(+) cells was remarkably increased in intestinal metaplasia. In total, 76% of gastric adenomas and 43% of early gastric carcinomas were positive for LGR5. Lgr5(+) cells were found more frequently in low-grade tumors with active Wnt signaling and an intestinal gland type, suggesting that LGR5 is likely involved in the very early stages of Wnt-driven tumorigenesis in the stomach. Interestingly, similar to stem cells in normal tissues, Lgr5(+) cells were often restricted to the base of the tumor glands, and such Lgr5(+) restriction was associated with high levels of intestinal stem cell markers such as EPHB2, OLFM4, and ASCL2. Thus, our findings show that Lgr5(+) cells are present at the base of the antral glands in the human stomach and that this cell population significantly expands in intestinal metaplasias. Furthermore, Lgr5(+) cells are seen in a large number of gastric tumors ; their frequent basal arrangements and coexpression of ISC markers support the idea that Lgr5(+) cells act as stem cells during the early stage of intestinal-type gastric tumorigenesis. PMID- 24340026 TI - Cathepsin E deficiency impairs autophagic proteolysis in macrophages. AB - Cathepsin E is an endosomal aspartic proteinase that is predominantly expressed in immune-related cells. Recently, we showed that macrophages derived from cathepsin E-deficient (CatE(-/-)) mice display accumulation of lysosomal membrane proteins and abnormal membrane trafficking. In this study, we demonstrated that CatE(-/-) macrophages exhibit abnormalities in autophagy, a bulk degradation system for aggregated proteins and damaged organelles. CatE(-/-) macrophages showed increased accumulation of autophagy marker proteins such as LC3 and p62, and polyubiquitinated proteins. Cathepsin E deficiency also altered autophagy related signaling pathways such as those mediated by the mammalian target of rapamycin (mTOR), Akt, and extracellular signal-related kinase (ERK). Furthermore, immunofluorescence microscopy analyses showed that LC3-positive vesicles were merged with acidic compartments in wild-type macrophages, but not in CatE(-/-) macrophages, indicating inhibition of fusion of autophagosome with lysosomes in CatE(-/-) cells. Delayed degradation of LC3 protein was also observed under starvation-induced conditions. Since the autophagy system is involved in the degradation of damaged mitochondria, we examined the accumulation of damaged mitochondria in CatE(-/-) macrophages. Several mitochondrial abnormalities such as decreased intracellular ATP levels, depolarized mitochondrial membrane potential, and decreased mitochondrial oxygen consumption were observed. Such mitochondrial dysfunction likely led to the accompanying oxidative stress. In fact, CatE(-/-) macrophages showed increased reactive oxygen species (ROS) production and up-regulation of oxidized peroxiredoxin-6, but decreased antioxidant glutathione. These results indicate that cathepsin E deficiency causes autophagy impairment concomitantly with increased aberrant mitochondria as well as increased oxidative stress. PMID- 24340028 TI - Molecular phylogeny and barcoding of Caulerpa (Bryopsidales) based on the tufA, rbcL, 18S rDNA and ITS rDNA genes. AB - The biodiversity assessment of different taxa of the genus Caulerpa is of interest from the context of morphological plasticity, invasive potential of some species and biotechnological and pharmacological applications. The present study investigated the identification and molecular phylogeny of different species of Caulerpa occurring along the Indian coast inferred from tufA, rbcL, 18S rDNA and ITS rDNA nucleotide sequences. Molecular data confirmed the identification of 10 distinct Caulerpa species: C. veravalensis, C. verticillata, C. racemosa, C. microphysa, C. taxifolia, C. sertularioides, C. scalpelliformis, C. serrulata, C. peltata and C. mexicana. All datasets significantly supported the sister relationship between C. veravalensis and C. racemosa var. cylindracea. It was also concluded from the results that the specimen identified previously as C. microphysa and C. lentillifera could not be considered as separate species. The molecular data revealed the presence of multiple lineages for C. racemosa which can be resolved into separate species. All four markers were used to ascertain their utility for DNA barcoding. The tufA gene proved a better marker with monophyletic association as the main criteria for identification at the species level. The results also support the use of 18S rDNA insertion sequences to delineate the Caulerpa species through character-based barcoding. The ITS rDNA (5.8S-ITS2) phylogenetic analysis also served as another supporting tool. Further, more sequences from additional Caulerpa specimens will need to be analysed in order to support the role of these two markers (ITS rDNA and 18S insertion sequence) in identification of Caulerpa species. The present study revealed the phylogeny of Caulerpa as complete as possible using the currently available data, which is the first comprehensive report illustrating the molecular phylogeny and barcoding of the genus Caulerpa from Indian waters. PMID- 24340027 TI - Crosstalk between Wnt/beta-catenin and estrogen receptor signaling synergistically promotes osteogenic differentiation of mesenchymal progenitor cells. AB - Osteogenic differentiation from mesenchymal progenitor cells (MPCs) are initiated and regulated by a cascade of signaling events. Either Wnt/beta-catenin or estrogen signaling pathway has been shown to play an important role in regulating skeletal development and maintaining adult tissue homeostasis. Here, we investigate the potential crosstalk and synergy of these two signaling pathways in regulating osteogenic differentiation of MPCs. We find that the activation of estrogen receptor (ER) signaling by estradiol (E2) or exogenously expressed ERalpha in MPCs synergistically enhances Wnt3A-induced early and late osteogenic markers, as well as matrix mineralization. The E2 or ERalpha-mediated synergy can be effectively blocked by ERalpha antagonist tamoxifen. E2 stimulation can enhance endochondral ossification of Wnt3A-transduced mouse fetal limb explants. Furthermore, exogenously expressed ERalpha significantly enhances the maturity and mineralization of Wnt3A-induced subcutaneous and intramuscular ectopic bone formation. Mechanistically, we demonstrate that E2 does not exert any detectable effect on beta-catenin/Tcf reporter activity. However, ERalpha expression is up regulated within the first 48h in AdWnt3A-transduced MPCs, whereas ERbeta expression is significantly inhibited within 24h. Moreover, the key enzyme for the biosynthesis of estrogens aromatase is modulated by Wnt3A in a biphasic manner, up-regulated at 24h but reduced after 48h. Our results demonstrate that, while ER signaling acts synergistically with Wnt3A in promoting osteogenic differentiation, Wnt3A may crosstalk with ER signaling by up-regulating ERalpha expression and down-regulating ERbeta expression in MPCs. Thus, the signaling crosstalk and synergy between these two pathways should be further explored as a potential therapeutic approach to combating bone and skeletal disorders, such as fracture healing and osteoporosis. PMID- 24340029 TI - The ecology of medical care in Beijing. AB - BACKGROUND: We presented the pattern of health care consumption, and the utilization of available resources by describing the ecology of medical care in Beijing on a monthly basis and by describing the socio-demographic characteristics associated with receipt care in different settings. METHODS: A cohort of 6,592 adults, 15 years of age and older were sampled to estimate the number of urban-resident adults per 1,000 who visited a medical facility at least once in a month, by the method of three-stage stratified and cluster random sampling. Separate logistic regression analyses assessed the association between those receiving care in different types of setting and their socio-demographic characteristics. RESULTS: On average per 1,000 adults, 295 had at least one symptom, 217 considered seeking medical care, 173 consulted a physician, 129 visited western medical practitioners, 127 visited a hospital-based outpatient clinic, 78 visited traditional Chinese medical practitioners, 43 visited a primary care physician, 35 received care in an emergency department, 15 were hospitalized. Health care seeking behaviors varied with socio-demographic characteristics, such as gender, age, ethnicity, resident census register, marital status, education, income, and health insurance status. In term of primary care, the gate-keeping and referral roles of Community Health Centers have not yet been fully established in Beijing. CONCLUSIONS: This study represents a first attempt to map the medical care ecology of Beijing urban population and provides timely baseline information for health care reform in China. PMID- 24340030 TI - Bone marrow stromal cells derived MCP-1 reverses the inhibitory effects of multiple myeloma cells on osteoclastogenesis by upregulating the RANK expression. AB - Multiple myeloma (MM) cells are responsible for aberrant osteoclast (OC) activation. However, when cocultured monocytes, but not OC precursors, with MM cells, we made a novel observation that MM cells inhibited receptor activator of nuclear factor kappaB ligand (RANKL)-induced increase of OC differentiation, OC gene expression, signaling pathways and bone resorption activity. Our results showed that MM cells produced multiple inhibitory cytokines of osteoclastogenesis, such as IL-10, which activated STAT3 signaling and induce OC inhibition. However, cocultures of bone marrow stromal cells (BMSCs) reversed MM induced OC inhibition. We found that MM cells increased production of MCP-1 from BMSCs and BMSC-derived MCP-1 enhanced OC formation. Mechanistic studies showed that IL-10 downregulated RANK expression in monocytes and thus, inhibited RANKL induced OC formation. In contrast, MCP-1 upregulated RANK expression and thus, enhanced OC formation. Overall, our studies for the first time demonstrated that MM cell have inhibitory effects on osteoclastogenesis by producing inhibitory cytokines. Our results further indicate that activation of osteoclastogenesis in bone marrow requests the crosstalk of MM cells, BMSCs and their produced cytokines. Thus, our studies provide evidences that targeting bone marrow microenvironmental cells and/or cytokines may be a new approach to treating MM bone destruction. PMID- 24340031 TI - Structural insights into RbmA, a biofilm scaffolding protein of V. cholerae. AB - V. cholerae can form sessile biofilms associated with abiotic surfaces, cyanobacteria, zoo-plankton, mollusks, or crustaceans. Along with the vibrio polysaccharide, secreted proteins of the rbm gene cluster are key to the biofilm ultrastructure. Here we provide a thorough structural characterization of RbmA, a protein involved in mediating cell-cell and cell-biofilm contacts. We correlate our structural findings with initial ligand specificity screening results, NMR protein-ligand interaction analysis, and complement our results with a full biocomputational study. PMID- 24340032 TI - Reinvestment--the cause of the yips? AB - The yips is a multi-etiological phenomenon consisting of involuntary movements during the execution of a skill (e.g., a golf putt). Reinvestment, the conscious control of a movement that detrimentally affects automated movements, is thought to be a potential mechanism leading to the yips. Preventing yips-affected golfers from consciously controlling their movement, therefore, should be beneficial. The aim of the study was to be the first to empirically test in a laboratory whether reinvestment causes the yips and to explore if the tendency to reinvest can explain yips behavior. Nineteen yips-affected golfers participated in a lab experiment. They putted with the dominant arm in a skill-focus and an extraneous condition, in which they had to perform different dual tasks designed either to direct their focus on their own skill or to distract them from it. The tendency to reinvest was estimated via the Movement-Specific Reinvestment Scale. Yips behavior was assessed by putting performance and movement variability. Although the dual-task performance showed that the attentional manipulation worked, the tendency to reinvest did not predict the behavior of the yips-affected golfers in either putting condition. The yips-affected golfers also showed no difference in yips behavior between the skill-focus and the extraneous condition. In other words, the attentional manipulation did not change yips behavior. The data do not support the assumption that there is a link between the yips and reinvestment, likely because of the multi-etiological nature of the yips. Other psychological or neurological mechanisms such as conditioned reactions may better explain the yips and should be investigated. PMID- 24340033 TI - Dopamine modulates the excitability of projection neurons in the robust nucleus of the arcopallium in adult zebra finches. AB - BACKGROUND: The nervous system in songbirds is an accessible system for studying vocal learning and memory in vertebrates. In the song system, the anterior forebrain pathway (AFP) is essential for song learning and the vocal motor pathway (VMP) is necessary for song production. The premotor robust nucleus of the arcopallium (RA) located in the VMP receives input from the AFP. The RA receives dopaminergic innervations from the periaqueductal gray and ventral tegmental area-substantia nigra pars compacta, but the physiological functions of this projection remain unclear. In this study, we investigated the effects of dopamine (DA) on the excitability of projection neurons (PNs) in the RA. METHODOLOGY: We recorded the electrophysiological changes from neurons in brain slices of male adult zebra finches using a whole-cell recording technique. CONCLUSIONS/SIGNIFICANCE: We found that DA significantly increased the excitability of RA PNs. Furthermore, a D1-like receptor agonist increased the excitability of RA PNs, and a D1-like receptor antagonist suppressed the excitability induced by DA. However, a D2-like receptor agonist had no effect on the excitability of RA PNs. Moreover, the D2-like receptor agonist did not change the excitability induced by the D1 receptor agonist. These findings suggest that DA can significantly increase the excitability of RA PNs and that D1 receptors play the main role in regulating the excitability of RA PNs in response to DA, thereby providing direct evidence toward understanding the mechanism of DA signal mediation by its receptors to modulate the excitability of RA PNs. PMID- 24340034 TI - Maternal education and micro-geographic disparities in nutritional status among school-aged children in rural northwestern China. AB - OBJECTIVES: Prior evidence suggests geographic disparities in the effect of maternal education on child nutritional status between countries, between regions and between urban and rural areas. We postulated its effect would also vary by micro-geographic locations (indicated by mountain areas, plain areas and the edge areas) in a Chinese minority area. METHODS: A cross-sectional study was conducted with a multistage random sample of 1474 school children aged 5-12 years in Guyuan, China. Child nutritional status was measured by height-for-age z scores (HAZ). Linear mixed models were used to examine its association with place of residence and maternal education. RESULTS: Micro-geographic disparities in child nutritional status and the level of socioeconomic composition were found. Children living in mountain areas had poorer nutritional status, even after adjusting for demographic (plain versus mountain, beta = 0.16, P = 0.033; edge versus mountain, beta = 0.29, P = 0.002) and socioeconomic factors (plain versus mountain, beta = 0.12, P = 0.137; edge versus mountain, beta = 0.25, P = 0.009). The disparities significantly widened with increasing years of mothers' schooling (maternal education*plain versus mountain: beta = 0.06, P = 0.007; maternal education*edge versus mountain: beta = 0.07, P = 0.005). Moreover, the association between maternal education and child nutrition was negative (beta = 0.03, P = 0.056) in mountain areas but positive in plain areas (beta = 0.02, P = 0.094) or in the edge areas (beta = 0.04, P = 0.055). CONCLUSIONS: Micro geographic disparities in child nutritional status increase with increasing level of maternal education and the effect of maternal education varies by micro geographic locations, which exacerbates child health inequity. Educating rural girls alone is not sufficient; improving unfavorable conditions in mountain areas might make such investments more effective in promoting child health. Nutrition programs targeting to the least educated groups in plain and in edge areas would be critical to their cost-effectiveness. PMID- 24340035 TI - Epigenetic regulation of depot-specific gene expression in adipose tissue. AB - In humans, adipose tissue is distributed in subcutaneous abdominal and subcutaneous gluteal depots that comprise a variety of functional differences. Whereas energy storage in gluteal adipose tissue has been shown to mediate a protective effect, an increase of abdominal adipose tissue is associated with metabolic disorders. However, the molecular basis of depot-specific characteristics is not completely understood yet. Using array-based analyses of transcription profiles, we identified a specific set of genes that was differentially expressed between subcutaneous abdominal and gluteal adipose tissue. To investigate the role of epigenetic regulation in depot-specific gene expression, we additionally analyzed genome-wide DNA methylation patterns in abdominal and gluteal depots. By combining both data sets, we identified a highly significant set of depot-specifically expressed genes that appear to be epigenetically regulated. Interestingly, the majority of these genes form part of the homeobox gene family. Moreover, genes involved in fatty acid metabolism were also differentially expressed. Therefore we suppose that changes in gene expression profiles might account for depot-specific differences in lipid composition. Indeed, triglycerides and fatty acids of abdominal adipose tissue were more saturated compared to triglycerides and fatty acids in gluteal adipose tissue. Taken together, our results uncover clear differences between abdominal and gluteal adipose tissue on the gene expression and DNA methylation level as well as in fatty acid composition. Therefore, a detailed molecular characterization of adipose tissue depots will be essential to develop new treatment strategies for metabolic syndrome associated complications. PMID- 24340037 TI - The neural circuitry of reward processing in complex social comparison: evidence from an event-related FMRI study. AB - In this study, Functional magnetic resonance imaging (fMRI) was conducted to investigate the mechanisms by which the brain activity in a complex social comparison context. One true subject and two pseudo-subjects were asked to complete a simple number estimate task at the same time which including upward and downward comparisons. Two categories of social comparison rewards (fair and unfair rewards distributions) were mainly presented by comparing the true subject with other two pseudo-subjects. Particularly, there were five conditions of unfair distribution when all the three subjects were correct but received different rewards. Behavioral data indicated that the ability to self-regulate was important in satisfaction judgment when the subject perceived an unfair reward distribution. fMRI data indicated that the interaction between the ventral striatum and the prefrontal cortex was important in self-regulation under specific conditions in complex social comparison, especially under condition of reward processing when there were two different reward values and the subject failed to exhibit upward comparison. PMID- 24340036 TI - Reliability and validity of instruments for assessing perinatal depression in African settings: systematic review and meta-analysis. AB - BACKGROUND: A major barrier to improving perinatal mental health in Africa is the lack of locally validated tools for identifying probable cases of perinatal depression or for measuring changes in depression symptom severity. We systematically reviewed the evidence on the reliability and validity of instruments to assess perinatal depression in African settings. METHODS AND FINDINGS: Of 1,027 records identified through searching 7 electronic databases, we reviewed 126 full-text reports. We included 25 unique studies, which were disseminated in 26 journal articles and 1 doctoral dissertation. These enrolled 12,544 women living in nine different North and sub-Saharan African countries. Only three studies (12%) used instruments developed specifically for use in a given cultural setting. Most studies provided evidence of criterion-related validity (20 [80%]) or reliability (15 [60%]), while fewer studies provided evidence of construct validity, content validity, or internal structure. The Edinburgh postnatal depression scale (EPDS), assessed in 16 studies (64%), was the most frequently used instrument in our sample. Ten studies estimated the internal consistency of the EPDS (median estimated coefficient alpha, 0.84; interquartile range, 0.71-0.87). For the 14 studies that estimated sensitivity and specificity for the EPDS, we constructed 2 x 2 tables for each cut-off score. Using a bivariate random-effects model, we estimated a pooled sensitivity of 0.94 (95% confidence interval [CI], 0.68-0.99) and a pooled specificity of 0.77 (95% CI, 0.59-0.88) at a cut-off score of >= 9, with higher cut-off scores yielding greater specificity at the cost of lower sensitivity. CONCLUSIONS: The EPDS can reliably and validly measure perinatal depression symptom severity or screen for probable postnatal depression in African countries, but more validation studies on other instruments are needed. In addition, more qualitative research is needed to adequately characterize local understandings of perinatal depression-like syndromes in different African contexts. PMID- 24340038 TI - UV-photoconversion of ethosuximide from a longevity-promoting compound to a potent toxin. AB - The anticonvulsant ethosuximide has been previously shown to increase life span and promote healthspan in the nematode Caenorhabditis elegans at millimolar concentrations. Here we report that following exposure to ultraviolet irradiation at 254 nm, ethosuximide is converted into a compound that displays toxicity toward C. elegans. This effect is specific for ethosuximide, as the structurally related compounds trimethadione and succinimide do not show similar toxicities following UV exposure. Killing by UV-irradiated ethosuximide is not attenuated in chemosensory mutants that are resistant to toxicity associated with high doses of non-irradiated ethosuximide. Non-irradiated ethosuximide extends life span at 15 degrees C or 20 degrees C, but not at 25 degrees C, while irradiated ethosuximide shows similar toxicity at all three temperatures. Dietary restriction by bacterial deprivation does not protect against toxicity from irradiated ethosuximide, while non-irradiated ethosuximide further extends the long life spans of restricted animals. These data support the model that ethosuximide extends life span by a mechanism that is, at least partially, distinct from dietary restriction by bacterial deprivation and demonstrates an unexpected photochemical conversion of ethosuximide into a toxic compound by UV light. PMID- 24340039 TI - Chloroplasts of salt-grown Arabidopsis seedlings are impaired in structure, genome copy number and transcript levels. AB - The chloroplast is the most prominent and metabolically active plastid in photosynthetic plants. Chloroplasts differentiate from proplastids in the plant meristem. Plant plastids contain multiple copies of a small circular genome. The numbers of chloroplasts per mesophyll cell and of plastid genome copies are affected by developmental stage and environmental signals. We compared chloroplast structure, gene expression and genome copy number in Arabidopsis seedlings germinated and grown under optimal conditions to those in seedlings germinated and grown in the presence of NaCl. Chloroplasts of the NaCl-grown seedlings were impaired, with less developed thylakoid and granum membranes than control seedlings. In addition, chloroplasts of salt-grown Arabidopsis seedlings accumulated more starch grains than those in the respective control plants. Steady-state transcript levels of chloroplast-encoded genes and of nuclear genes encoding chloroplast proteins were reduced in salt-grown seedlings. This reduction did not result from a global decrease in gene expression, since the expression of other nuclear genes was induced or not affected. Average cellular chloroplast genome copy number was reduced in salt-grown seedlings, suggesting that the reduction in steady-state transcript levels of chloroplast-encoded genes might result from a decrease in template DNA. PMID- 24340040 TI - Polymorphic cytochrome P450 enzymes (CYPs) and their role in personalized therapy. AB - The cytochrome P450 (CYP) enzymes are major players in drug metabolism. More than 2,000 mutations have been described, and certain single nucleotide polymorphisms (SNPs) have been shown to have a large impact on CYP activity. Therefore, CYPs play an important role in inter-individual drug response and their genetic variability should be factored into personalized medicine. To identify the most relevant polymorphisms in human CYPs, a text mining approach was used. We investigated their frequencies in different ethnic groups, the number of drugs that are metabolized by each CYP, the impact of CYP SNPs, as well as CYP expression patterns in different tissues. The most important polymorphic CYPs were found to be 1A2, 2D6, 2C9 and 2C19. Thirty-four common allele variants in Caucasians led to altered enzyme activity. To compare the relevant Caucasian SNPs with those of other ethnicities a search in 1,000 individual genomes was undertaken. We found 199 non-synonymous SNPs with frequencies over one percent in the 1,000 genomes, many of them not described so far. With knowledge of frequent mutations and their impact on CYP activities, it may be possible to predict patient response to certain drugs, as well as adverse side effects. With improved availability of genotyping, our data may provide a resource for an understanding of the effects of specific SNPs in CYPs, enabling the selection of a more personalized treatment regimen. PMID- 24340041 TI - POGs2: a web portal to facilitate cross-species inferences about protein architecture and function in plants. AB - The Putative orthologous Groups 2 Database (POGs2) (http://pogs.uoregon.edu/) integrates information about the inferred proteomes of four plant species (Arabidopsis thaliana, Zea mays, Orza sativa, and Populus trichocarpa) in a display that facilitates comparisons among orthologs and extrapolation of annotations among species. A single-page view collates key functional data for members of each Putative Orthologous Group (POG): graphical representations of InterPro domains, predicted and established intracellular locations, and imported gene descriptions. The display incorporates POGs predicted by two different algorithms as well as gene trees, allowing users to evaluate the validity of POG memberships. The web interface provides ready access to sequences and alignments of POG members, as well as sequences, alignments, and domain architectures of closely-related paralogs. A simple and flexible search interface permits queries by BLAST and by any combination of gene identifier, keywords, domain names, InterPro identifiers, and intracellular location. The concurrent display of domain architectures for orthologous proteins highlights errors in gene models and false-negatives in domain predictions. The POGs2 layout is also useful for exploring candidate genes identified by transposon tagging, QTL mapping, map based cloning, and proteomics, and for navigating between orthologous groups that belong to the same gene family. PMID- 24340042 TI - Reasons for unmet need for child and family health services among children with special health care needs with and without medical homes. AB - OBJECTIVES: Medical homes, an important component of U.S. health reform, were first developed to help families of children with special health care needs (CSHCN) find and coordinate services, and reduce their children's unmet need for health services. We hypothesize that CSHCN lacking medical homes are more likely than those with medical homes to report health system delivery or coverage problems as the specific reasons for unmet need. METHODS: Data are from the 2005 2006 National Survey of Children with Special Health Care Needs (NS-CSHCN), a national, population-based survey of 40,723 CSHCN. We studied whether lacking a medical home was associated with 9 specific reasons for unmet need for 11 types of medical services, controlling for health insurance, child's health, and sociodemographic characteristics. RESULTS: Weighted to the national population, 17% of CSHCN reported at least one unmet health service need in the previous year. CSHCN without medical homes were 2 to 3 times as likely to report unmet need for child or family health services, and more likely to report no referral (OR= 3.3), dissatisfaction with provider (OR=2.5), service not available in area (OR= 2.1), can't find provider who accepts insurance (OR=1.8), and health plan problems (OR=1.4) as reasons for unmet need (all p<0.05). CONCLUSIONS: CSHCN without medical homes were more likely than those with medical homes to report health system delivery or coverage reasons for unmet child health service needs. Attributable risk estimates suggest that if the 50% of CSHCN who lacked medical homes had one, overall unmet need for child health services could be reduced by as much as 35% and unmet need for family health services by 40%. PMID- 24340043 TI - Natural killer cell-dependent anti-fibrotic pathway in liver injury via Toll-like receptor-9. AB - The toll-like receptor-9 (TLR9) agonist cytosine phosphate guanine (CpG), activates hepatic stellate cells (HSCs) and mediates fibrosis. We investigated the TLR9 effects on lymphocyte/HSCs interactions. Liver fibrosis was induced in wild-type (WT) mice by intra-peritoneal carbon-tetrachloride (CCl4) induction for 6 weeks. Fibrotic groups were intravenously treated by a vehicle versus CpG along last 2 weeks. Compared to vehicle-treated fibrotic WT, the in-vivo CpG-treatment significantly attenuated hepatic fibrosis and inflammation, associated with decreased CD8 and increased NK liver cells. In-vitro, co-cultures with vehicle treated fibrotic NK cells increased HSCs proliferation (P<0.001) while their CpG treated counterparts achieved a significant decrease. To investigate the role of lymphocytes, TLR9(-/-) mice induced-hepatic fibrosis were used. Although TLR9(-/ ) mice manifested lower fibrotic profile as compared to their wild-type (WT) counterparts, senescence (SA-beta-Gal activity) in the liver and ALT serum levels were significantly greater. In an adoptive transfer model; irradiated WT and TLR9(-/-) recipients were reconstituted with naive WT or TLR9(-/-) lymphocytes. The adoptive transfer of TLR9(-/-) versus WT lymphocytes led to increased fibrosis of WT recipients. TLR9(-/-) fibrotic recipients reconstituted with TLR9( /-) or WT lymphocytes showed no changes in hepatic fibrosis severity or ALT serum levels. TLR9 activation had inconsistent effects on lymphocytes and HSCs. The net balance of TLR9 activation in WT, displayed significant anti-fibrotic activity, accompanied by CD8 suppression and increased NK-cells, activity and adherence to HSCs. The pro-fibrotic and pro-inflammatory properties of TLR9(-/-) lymphocytes fail to activate HSCs with an early senescence in TLR9(-/-) mice. PMID- 24340044 TI - Selenium supplementation restores innate and humoral immune responses in footrot affected sheep. AB - Dietary selenium (Se) alters whole-blood Se concentrations in sheep, dependent upon Se source and dosage administered, but little is known about effects on immune function. We used footrot (FR) as a disease model to test the effects of supranutritional Se supplementation on immune function. To determine the effect of Se-source (organic Se-yeast, inorganic Na-selenite or Na-selenate) and Se dosage (1, 3, 5 times FDA-permitted level) on FR severity, 120 ewes with and 120 ewes without FR were drenched weekly for 62 weeks with different Se sources and dosages (30 ewes/treatment group). Innate immunity was evaluated after 62 weeks of supplementation by measuring neutrophil bacterial killing ability. Adaptive immune function was evaluated by immunizing sheep with keyhole limpet hemocyanin (KLH). The antibody titer and delayed-type hypersensitivity skin test to KLH were used to assess humoral immunity and cell-mediated immunity, respectively. At baseline, FR-affected ewes had lower whole-blood and serum-Se concentrations; this difference was not observed after Se supplementation. Se supplementation increased neutrophil bacterial killing percentages in FR-affected sheep to percentages observed in supplemented and non-supplemented healthy sheep. Similarly, Se supplementation increased KLH antibody titers in FR-affected sheep to titers observed in healthy sheep. FR-affected sheep demonstrated suppressed cell-mediated immunity at 24 hours after intradermal KLH challenge, although there was no improvement with Se supplementation. We did not consistently prevent nor improve recovery from FR over the 62 week Se-treatment period. In conclusion, Se supplementation does not prevent FR, but does restore innate and humoral immune functions negatively affected by FR. PMID- 24340045 TI - B cells contribute to heterogeneity of IL-17 producing cells in rheumatoid arthritis and healthy controls. AB - Secretion of the proinflammatory cytokine Interleukin-17A (IL-17A) is the hallmark of a unique lineage of CD4 T cells designated Th17 cells, which may play a crucial role in the pathogenesis of rheumatoid arthritis (RA) and many autoimmune diseases. Recently, IL-17-producing cells other than T cells have been described, including diverse innate immune cells. Here, we show that the cellular sources of IL-17A in RA include a significant number of non-T cells. Multicolour fluorescence analysis of IL-17-expressing peripheral blood mononuclear cells (PBMC) revealed larger proportions of IL-17(+)CD3(-) non-T cells in RA patients than in healthy controls (constitutive, 13.6% vs. 8.4%, and after stimulation with PMA/ionomycin 17.4% vs. 7.9% p < 0.001 in both cases). The source of IL-17 included CD3(-)CD56(+) NK cells, CD3(-)CD14(+) myeloid cells as well as the expected CD3(+)CD4(+) Th17 cells and surprisingly a substantial number of CD3( )CD19(+) B cells. The presence of IL-17A-expressing B cells was confirmed by specific PCR of peripheral MACS-sorted CD19(+) B cells, as well as by the analysis of different EBV-transformed B cell lines. Here we report for the first time that in addition to Th17 cells and different innate immune cells B cells also contribute to the IL-17A found in RA patients and healthy controls. PMID- 24340046 TI - Deficiency in clonogenic endometrial mesenchymal stem cells in obese women with reproductive failure--a pilot study. AB - OBJECTIVES: The mechanisms of obesity associated reproductive complications remain poorly understood. Endometrial mesenchymal stem-cells are critical for cyclic renewal and uterine function. Recently, W5C5(+) cells, with high clonogenicity, capable of producing endometrial stroma in vivo, have been described. We sought to investigate the abundance and cloning efficiency of W5C5(+) and W5C5(-) endometrial cells in relation to Body Mass Index, age and reproductive outcome. DESIGN: W5C5(+) and W5C5(-) cells were purified from mid luteal endometrial biopsies (n = 54) by magnetic bead separation and subjected to in vitro colony-forming assays. RESULTS: First trimester pregnancy losses were significantly higher in obese subjects (n = 12) compared to overweight (n = 20) and subjects with normal Body Mass Index (n = 22) (P<0.05, P<0.01, respectively). W5C5(+) cells (%) were significantly lower in obese subjects compared to subjects with normal Body Mass Index (P<0.05). W5C5(+) cloning efficiency was significantly lower in obese subjects compared to overweight and subjects with normal Body Mass Index (P<0.05, respectively). W5C5(-) cloning efficiency was significantly lower in obese subjects compared to subjects with normal Body Mass Index (P<0.05). Body Mass Index was significantly negatively correlated with W5C5(+) cloning efficiency and W5C5(-) cloning efficiency (P<0.01, respectively), and positively correlated with first trimester loss (P<0.01). We found no significant results with age (P>0.05). CONCLUSIONS: Our observations suggest that the regenerative capacity and plasticity of the endometrium of obese women is suboptimal, which in turn may account for the increased risk of reproductive complications associated with obesity. PMID- 24340047 TI - Anomopterellidae restored, with two new genera and its phylogeny in Evanioidea (Hymenoptera). AB - BACKGROUND: Anomopterellidae was originally classified as a family within the Evanioidea, and later lowered to a subfamily, Anomopterellinae, of Praeaulacidae. Up to date, only Rasnitsyn 1975, with four species, was assigned to Anomopterellinae. Due to their special wing venation and their metasomal attachment similar to those known in Evanioidea, the systematic position of Anomopterellinae in Evanioidea has been in contention. PRINCIPAL FINDINGS: Here we report a new fossil genus Synaphopterella gen. nov. and six species from the Middle Jurassic of China and transfer Anomopterella stenocera Rasnitsyn, 1975, from Upper Jurassic of Kazakhstan, to Choristopterella gen. nov. We place these three genera in the restored family Anomopterellidae and provide a key to known genera and species. CONCLUSIONS/SIGNIFICANCE: Based on new fossil specimens and phylogenetic analyses, Praeaulacidae has the most basal position in Evanioidea and it is justifiable to restore Anomopterellidae Rasnitsyn, 1975 as a full family. Comparing the size of all described anomopterellids from China, Mongolia and Kazakhstan, we conclude that the species from China have larger bodies and forewings. Diversity of the Praeaulacidae and Anomopterellidae in the late Middle Jurassic of Daohugou suggests that Evanioidea appeared at least before the late Middle Jurassic. PMID- 24340048 TI - Consumption of Lactobacillus casei fermented milk prevents Salmonella reactive arthritis by modulating IL-23/IL-17 expression. AB - Reactive arthritis is the development of sterile joint inflammation as a sequel to a remote infection, often in the gut. We have previously shown that a low dose of S. enteritidis inoculated to streptomycin-pretreated mice generates a self limiting enterocolitis suitable for studying reactive arthritis. Here we show that consumption of Lactobacillus casei prior to infection abolishes intestinal and joint inflammation triggered by Salmonella. BALB/c mice were sacrificed after infection; intestinal and joint samples were analyzed for histological changes and expression of cytokines. TNF-alpha was measured by ELISA and the expression of IL-1beta, IL-6, IL-10, IL-17, IL-23 and TGF-beta was assessed by qPCR. L. casei consumption prevented Salmonella-induced synovitis, the increment of TNF alpha in knees and the increase of IL-17 expression in popliteal and inguinal lymph nodes. At intestinal level consumption of L. casei drastically diminished S. enteritidis invasiveness and shortened splenic persistence of the pathogen. Bacterial loads recovered at days 2 and 5 from Peyer's patches were 10-fold lower in mice fed with L. casei. In accordance, we found that the augment in gut permeability induced during enterocolitis was decreased in those animals. Consumption of L. casei prior to infection failed to increase anti- inflammatory molecules such as IL-10 and TGF-beta in the intestine. On the other hand, consumption of L. casei abrogated the expression of TNF-alpha, IL-17, IL-23, IL 1beta and IL-6 in cecum and mesenteric lymph nodes. These cytokines are needed for differentiation of immune cells involved in the development of reactive arthritis such as Th17 and gammadelta T cells. Trafficking of these inflammatory cells from the gut to the joints has been proposed as a mechanism of generation of reactive arthritis. Our results suggest that L. casei consumption prevents Salmonella-induced synovitis by altering the intestinal milieu necessary for differentiation of cells involved in the generation of joint inflammation. PMID- 24340049 TI - SPIN90 knockdown attenuates the formation and movement of endosomal vesicles in the early stages of epidermal growth factor receptor endocytosis. AB - The finding that SPIN90 colocalizes with epidermal growth factor (EGF) in EEA1 positive endosomes prompted us to investigate the role of SPIN90 in endocytosis of the EGF receptor (EGFR). In the present study, we demonstrated that SPIN90 participates in the early stages of endocytosis, including vesicle formation and trafficking. Stable HeLa cells with knockdown of SPIN90 displayed significantly higher levels of surface EGFR than control cells. Analysis of the abundance and cellular distribution of EGFR via electron microscopy revealed that SPIN90 knockdown cells contain residual EGFR at cell membranes and fewer EGFR-containing endosomes, both features that reflect reduced endosome formation. The delayed early endosomal targeting capacity of SPIN90 knockdown cells led to increased EGFR stability, consistent with the observed accumulation of EGFR at the membrane. Small endosome sizes and reduced endosome formation in SPIN90 knockdown cells, observed using fluorescent confocal microscopy, strongly supported the involvement of SPIN90 in endocytosis of EGFR. Overexpression of SPIN90 variants, particularly the SH3, PRD, and CC (positions 643 - 722) domains, resulted in aberrant morphology of Rab5-positive endosomes (detected as small spots located near the cell membrane) and defects in endosomal movement. These findings clearly suggest that SPIN90 participates in the formation and movement of endosomes. Consistent with this, SPIN90 knockdown enhanced cell proliferation. The delay in EGFR endocytosis effectively increased the levels of endosomal EGFR, which triggered activation of ERK1/2 and cell proliferation via upregulation of cyclin D1. Collectively, our findings suggest that SPIN90 contributes to the formation and movement of endosomal vesicles, and modulates the stability of EGFR protein, which affects cell cycle progression via regulation of the activities of downstream proteins, such as ERK1/2, after EGF stimulation. PMID- 24340050 TI - Down-regulation of Filamin A interacting protein 1-like Is associated with promoter methylation and an invasive phenotype in breast, colon, lung and pancreatic cancers [corrected]. AB - Identifying key mediators of cancer cell invasion and metastasis is critical to the development of more effective cancer therapies. We previously identified Filamin A interacting protein 1-like (FILIP1L) as an important inhibitor of cell migration and invasion in ovarian cancer. FILIP1L expression was inversely correlated with the invasive potential of ovarian cancer cell lines and ovarian cancer specimens. We also demonstrated that DNA methylation in the FILIP1L promoter was a mechanism by which FILIP1L was down-regulated in ovarian cancer. In our present study, we tested this observation in other cancer histologies: breast, colon, lung and pancreatic cancers. Both mRNA and protein expression of FILIP1L were down-regulated in these cancer cells compared with their normal epithelial cells. As in ovarian cancer, DNA methylation is a mechanism by which FILIP1L is down-regulated in these cancer histologies. Methylation status of the FILIP1L promoter was inversely correlated with FILIP1L expression. Reduced methylation in the FILIP1L promoter following treatment with a DNA demethylating agent was associated with restoration of FILIP1L expression in these cancer cells. Further, FILIP1L expression was inversely correlated with the invasive potential of these cancer cells. Re-expression of FILIP1L in FILIP1L-low expressing, highly-invasive cancer cell lines resulted in inhibition of cell invasion. Correspondingly, knockdown of FILIP1L in FILIP1L-high expressing, low invasive cancer cell lines resulted in increase of cell invasion. Overall, these findings suggest that down-regulation of FILIP1L associated with DNA methylation is related with the invasive phenotype in various cancers. Thus, modulation of FILIP1L expression has the potential to be a target for cancer therapy. PMID- 24340051 TI - Tentative identification of the second substrate binding site in Arabidopsis phytochelatin synthase. AB - Phytochelatin synthase (PCS) uses the substrates glutathione (GSH, gammaGlu-Cys Gly) and a cadmium (Cd)-bound GSH (Cd?GS2) to produce the shortest phytochelatin product (PC2, (gammaGlu-Cys)2-Gly) through a ping-pong mechanism. The binding of the 2 substrates to the active site, particularly the second substrate binding site, is not well-understood. In this study, we generated a structural model of the catalytic domain of Arabidopsis AtPCS1 (residues 12-218) by using the crystal structure of the gammaGlu-Cys acyl-enzyme complex of the PCS of the cyanobacterium Nostoc (NsPCS) as a template. The modeled AtPCS1 revealed a cavity in proximity to the first substrate binding site, consisting of 3 loops containing several conserved amino acids including Arg152, Lys185, and Tyr55. Substitutions of these amino acids (R152K, K185R, or double mutation) resulted in the abrogation of enzyme activity, indicating that the arrangement of these 2 positive charges is crucial for the binding of the second substrate. Recombinant AtPCS1s with mutations at Tyr55 showed lower catalytic activities because of reduced affinity (3-fold for Y55W) for the Cd?GS2, further suggesting the role of the cation-pi interaction in recognition of the second substrate. Our study results indicate the mechanism for second substrate recognition in PCS. The integrated catalytic mechanism of PCS is further discussed. PMID- 24340052 TI - Absence of auditory M100 source asymmetry in schizophrenia and bipolar disorder: a MEG study. AB - BACKGROUND: Whether schizophrenia and bipolar disorder are the clinical outcomes of discrete or shared causative processes is much debated in psychiatry. Several studies have demonstrated anomalous structural and functional superior temporal gyrus (STG) symmetries in schizophrenia. We examined bipolar patients to determine if they also have altered STG asymmetry. METHODS: Whole-head magnetoencephalography (MEG) recordings of auditory evoked fields were obtained for 20 subjects with schizophrenia, 20 with bipolar disorder, and 20 control subjects. Neural generators of the M100 auditory response were modeled using a single equivalent current dipole for each hemisphere. The source location of the M100 response was used as a measure of functional STG asymmetry. RESULTS: Control subjects showed the typical M100 asymmetrical pattern with more anterior sources in the right STG. In contrast, both schizophrenia and bipolar disorder patients displayed a symmetrical M100 source pattern. There was no significant difference in the M100 latency and strength in bilateral hemispheres within three groups. CONCLUSIONS: Our results indicate that disturbed asymmetry of temporal lobe function may reflect a common deviance present in schizophrenia and bipolar disorder, suggesting the two disorders might share etiological and pathophysiological factors. PMID- 24340053 TI - Genetic interaction between mutations in c-Myb and the KIX domains of CBP and p300 affects multiple blood cell lineages and influences both gene activation and repression. AB - Adult blood cell production or definitive hematopoiesis requires the transcription factor c-Myb. The closely related KAT3 histone acetyltransferases CBP (CREBBP) and p300 (EP300) bind c-Myb through their KIX domains and mice homozygous for a p300 KIX domain mutation exhibit multiple blood defects. Perplexingly, mice homozygous for the same KIX domain mutation in CBP have normal blood. Here we test the hypothesis that the CBP KIX domain contributes subordinately to hematopoiesis via a genetic interaction with c-Myb. We assessed hematopoiesis in mice bearing compound mutations of c-Myb and/or the KIX domains of CBP and p300, and measured the effect of KIX domain mutations on c-Myb dependent gene expression. We found that in the context of a p300 KIX mutation, the CBP KIX domain mutation affects platelets, B cells, T cells, and red cells. Gene interaction (epistasis) analysis provides mechanistic evidence that blood defects in KIX mutant mice are consistent with reduced c-Myb and KIX interaction. Lastly, we demonstrated that the CBP and p300 KIX domains contribute to both c Myb-dependent gene activation and repression. Together these results suggest that the KIX domains of CBP, and especially p300, are principal mediators of c-Myb dependent gene activation and repression that is required for definitive hematopoiesis. PMID- 24340054 TI - New insights into the phylogeny and molecular classification of nicotinamide mononucleotide deamidases. AB - Nicotinamide mononucleotide (NMN) deamidase is one of the key enzymes of the bacterial pyridine nucleotide cycle (PNC). It catalyzes the conversion of NMN to nicotinic acid mononucleotide, which is later converted to NAD(+) by entering the Preiss-Handler pathway. However, very few biochemical data are available regarding this enzyme. This paper represents the first complete molecular characterization of a novel NMN deamidase from the halotolerant and alkaliphilic bacterium Oceanobacillus iheyensis (OiPncC). The enzyme was active over a broad pH range, with an optimum at pH 7.4, whilst maintaining 90 % activity at pH 10.0. Surprisingly, the enzyme was quite stable at such basic pH, maintaining 61 % activity after 21 days. As regard temperature, it had an optimum at 65 degrees C but its stability was better below 50 degrees C. OiPncC was a Michaelian enzyme towards its only substrate NMN, with a K m value of 0.18 mM and a kcat/K m of 2.1 mM(-1) s(-1). To further our understanding of these enzymes, a complete phylogenetic and structural analysis was carried out taking into account the two Pfam domains usually associated with them (MocF and CinA). This analysis sheds light on the evolution of NMN deamidases, and enables the classification of NMN deamidases into 12 different subgroups, pointing to a novel domain architecture never before described. Using a Logo representation, conserved blocks were determined, providing new insights on the crucial residues involved in the binding and catalysis of both CinA and MocF domains. The analysis of these conserved blocks within new protein sequences could permit the more efficient data curation of incoming NMN deamidases. PMID- 24340055 TI - Ex vivo cytokine release and pattern recognition receptor expression of subjects exposed to dampness: pilot study to assess the outcome of mould exposure to the innate immune system. AB - In rooms with moisture damage, the indoor air can be enriched with microorganisms causing a variety of symptoms. Due to the highly diverse composition of bioaerosols and the multiple effects on humans, an assessment of the health risk is not sufficiently possible. The aim of this study was to characterize the features of innate immunity using blood from subjects exposed to moisture damage compared to control subjects living in houses without visible moisture damage. We investigated the expression of TLR-2, TLR-4 and dectin-1 on the surface of monocytes from both fresh blood and after in vitro stimulation with the model substances E. coli endotoxin, zymosan A, Pam3Cys and Aspergillus versicolor in 25 exposed subjects and 25 control subjects. In vitro stimulation of whole blood with the same components was performed for 20 h and the release of inflammatory mediators IL-8 and IL-1beta were quantified. In addition to an enhanced number of blood leucocytes, the expression of the receptors TLR-2, TLR-4 and dectin-1 on blood monocytes was significantly enhanced in exposed subjects. In contrast, no different alteration in expression was detected between exposed and control group after in vitro stimulation with the model substances. The release of IL-8 and IL 1beta after stimulation of whole blood with A. versicolor was increased in subjects exposed to moisture damage. Furthermore, in the exposed subjects the IL 1beta release was significantly enhanced after in vitro stimulation with E. coli endotoxin (1000 pg/mL). In conclusion, features of the innate immune system (receptor expression and mediator release of monocytes) are altered in subjects exposed to moisture damage which may be a potential explanation for the increased incidence of respiratory health diseases observed in these populations. PMID- 24340056 TI - Serum uric acid is associated with left ventricular hypertrophy independent of serum parathyroid hormone in male cardiac patients. AB - BACKGROUND: Several studies have shown that serum uric acid (UA) is associated with left ventricular (LV) hypertrophy. Serum levels of parathyroid hormone (PTH), which has bbe shown to be correlated with UA, is also known to be associated with cardiac hypertrophy; however, whether the association between UA and cardiac hypertrophy is independent of PTH remains unknown. PURPOSE: We investigated whether the relationship between serum uric acid (UA) and LV hypertrophy is independent of intact PTH and other calcium-phosphate metabolism related factors in cardiac patients. METHODS AND RESULTS: In a retrospective study, the association between UA and left ventricular mass index was assessed among 116 male cardiac patients (mean age 65 +/- 12 years) who were not taking UA lowering drugs. The median UA value was 5.9 mg/dL. Neither age nor body mass index differed significantly among the UA quartile groups. Patients with higher UA levels were more likely to be taking loop diuretics. UA showed a significant correlation with intact PTH (R = 0.34, P<0.001) but not with other calcium phosphate metabolism-related factors. Linear regression analysis showed that log transformed UA showed a significant association with left ventricular mass index, and this relationship was found to be significant exclusively in patients who were not taking loop and/or thiazide diuretics. Multivariate logistic regression analysis showed that log-transformed UA was independently associated with LV hypertrophy with an odds ratio of 2.79 (95% confidence interval 1.48-5.28, P = 0.002 per one standard deviation increase). CONCLUSIONS: Among cardiac patients, serum UA was associated with LV hypertrophy, and this relationship was, at least in part, independent of intact PTH levels, which showed a significant correlation with UA in the same population. PMID- 24340058 TI - Usefulness of high suction pressure for sufficient tissue collection during endobronchial ultrasound guided transbronchial needle aspiration. AB - INTRODUCTION: The optimal suction pressure during endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) remains to be determined. The aim of this study was to compare suction pressures for performance in collecting sufficient tissue specimens from mediastinal and hilar lymph nodes during EBUS TBNA. METHODS: Retrospective analysis of consecutive patients with mediastinal and hilar lymphadenopathy who underwent EBUS-TBNA over a 3-year period. Results from patients who underwent EBUS-TBNA using a dedicated 20-mL VacLoc (Merit Medical Systems, Inc, South Jordan, UT) syringe (conventional method, group C) were compared with results from patients in whom a disposable 30-mL syringe (high pressure group, group H) was used. The yield for sufficient histologic specimen retrieval and amount of tissue obtained were compared between the 2 groups. RESULTS: Of 178 patients who underwent EBUS-TBNA, 131 had lung cancer confirmed by EBUS-TBNA: 35 in group C and 96 in group H. There were 7 patients in group C and 6 in group H who received final diagnoses by cytology alone. There were 28 in group C and 90 in group H who were diagnosed by both cytology and histology. There was a statistically significant difference between the groups in terms of the rate of sufficient sampling for histological specimens (p = 0.04). The H group revealed a tissue area approximately twice that of the C group (p = 0.003). There were no major procedure-related complications in either group. CONCLUSION: Higher suction pressures with larger syringe volumes during EBUS-TBNA may be useful for safely collecting sufficient tissue specimens. PMID- 24340057 TI - Genetic variations in radiation and chemotherapy drug action pathways and survival in locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy. AB - BACKGROUND AND PURPOSE: Treatment outcomes vary greatly in patients with nasopharyngeal carcinoma (NPC). The purpose of this study is to evaluate the influence of radiation and chemotherapy drug action pathway gene polymorphisms on the survival of patients with locoregionally advanced NPC treated with cisplatin- and fluorouracil-based chemoradiotherapy. MATERIAL AND METHODS: Four hundred twenty-one consecutive patients with locoregionally advanced NPC were prospectively recruited. We utilized a pathway approach and examined 18 polymorphisms in 13 major genes. Polymorphisms were detected using the LDR-PCR technique. Multifactor dimensionality reduction (MDR) analysis was performed to detect potential gene-gene interaction. RESULTS: After adjustment for clinicopathological characteristics, overall survival was significantly decreased in patients with the MPO rs2243828 CT/CC genotype (HR=2.453, 95% CI, 1.687-3.566, P<0.001). The ERCC1 rs3212986 CC (HR=1.711, 95% CI, 1.135-2.579, P=0.010), MDM2 rs2279744 GT/GG (HR=1.743, 95% CI, 1.086-2.798, P=0.021), MPO rs2243828 CT/CC (HR=3.184, 95% CI, 2.261-4.483, P<0.001) and ABCB1 rs2032582 AT/AA (HR=1.997, 95% CI, 1.086-3.670, P=0.026) genotypes were associated with poor progression-free survival. Prognostic score models based on independent prognostic factors successfully classified patients into low-, intermediate-, and high-risk groups. Furthermore, MDR analysis showed no significant interaction between polymorphisms. CONCLUSIONS: Four single nucleotide polymorphisms were associated with survival in patients with locoregionally advanced NPC treated with cisplatin and fluorouracil-based chemoradiotherapy. Combining clinical prognostic factors with genetic information was valuable in identifying patients with different risk. PMID- 24340059 TI - NEDD4-1 regulates migration and invasion of glioma cells through CNrasGEF ubiquitination in vitro. AB - Neuronal precursor cell-expressed developmentally down-regulated 4-1 (NEDD4-1) plays a great role in tumor cell growth, but its function and mechanism in cell invasive behavior are totally unknown. Here we report that NEDD4-1 regulates migration and invasion of malignant glioma cells via triggering ubiquitination of cyclic nucleotide Ras guanine nucleotide exchange factor (CNrasGEF) using cultured glioma cells. NEDD4-1 overexpression promoted cell migration and invasion, while its downregulation specifically inhibited them. However, NEDD4-1 did not affect the proliferation and apoptosis of glioma cells. NEDD4-1 physically interacted with CNrasGEF and promoted its poly-ubiquitination and degradation. Contrary to the effect of NEDD4-1, CNrasGEF downregulation promoted cell migration and invasion, while its overexpression inhibited them. Importantly, downregulation of CNrasGEF facilitated the effect of NEDD4-1-induced cell migration and invasion. Interestingly, aberrant up-regulated NEDD4-1 showed reverse correlation with CNrasGEF protein level but not with its mRNA level in glioma tissues. Combined with the in vitro results, the result of glioma tissues indicated post-translationally modification effect of NEDD4-1 on CNrasGEF. Our study suggests that NEDD4-1 regulates cell migration and invasion through ubiquitination of CNrasGEF in vitro. PMID- 24340060 TI - Risk acceptance in multiple sclerosis patients on natalizumab treatment. AB - OBJECTIVE: We aimed to investigate the ability of natalizumab (NTZ)-treated patients to assume treatment-associated risks and the factors involved in such risk acceptance. METHODS: From a total of 185 patients, 114 patients on NTZ as of July 2011 carried out a comprehensive survey. We obtained disease severity perception scores, personality traits' scores, and risk-acceptance scores (RAS) so that higher RAS indicated higher risk acceptance. We recorded JC virus status (JCV+/-), prior immunosuppression, NTZ treatment duration, and clinical characteristics. NTZ patients were split into subgroups (A-E), depending on their individual PML risk. Some 22 MS patients on first-line drugs (DMD) acted as controls. RESULTS: No differences between treatment groups were observed in disease severity perception and personality traits. RAS were higher in NTZ than in DMD patients (p<0.01). Perception of the own disease as a more severe condition tended to predict higher RAS (p=0.07). Higher neuroticism scores predicted higher RAS in the NTZ group as a whole (p=0.04), and in high PML-risk subgroups (A-B) (p=0.02). In low PML-risk subgroups (C-E), higher RAS were associated with a JCV+ status (p=0.01). Neither disability scores nor pre treatment relapse rate predicted RAS in either group. CONCLUSIONS: Risk acceptance is a multifactorial phenomenon, which might be partly explained by an adaptive process, in light of the higher risk acceptance amongst NTZ-treated patients and, especially, amongst those who are JCV seropositive but still have low PML risk, but which seems also intimately related to personality traits. PMID- 24340061 TI - Inflammatory and antimicrobial responses to methicillin-resistant Staphylococcus aureus in an in vitro wound infection model. AB - Treatment of patients with burn wound infections may become complicated by the presence of antibiotic resistant bacteria and biofilms. Herein, we demonstrate an in vitro thermal wound infection model using human skin equivalents (HSE) and biofilm-forming methicillin-resistant Staphylococcus aureus (MRSA) for the testing of agents to combat such infections. Application of a liquid nitrogen cooled metal device on HSE produced reproducible wounds characterized by keratinocyte death, detachment of the epidermal layer from the dermis, and re epithelialization. Thermal wounding was accompanied by up-regulation of markers for keratinocyte activation, inflammation, and antimicrobial responses. Exposure of thermal wounded HSEs to MRSA resulted in significant numbers of adherent MRSA/HSE after 1 hour, and multiplication of these bacteria over 24-48 hours. Exposure to MRSA enhanced expression of inflammatory mediators such as TLR2 (but not TLR3), IL-6 and IL-8, and antimicrobial proteins human beta-defensin-2, -3 and RNAse7 by thermal wounded as compared to control HSEs. Moreover, locally applied mupirocin effectively reduced MRSA counts on (thermal wounded) HSEs by more than 99.9% within 24 hours. Together, these data indicate that this thermal wound infection model is a promising tool to study the initial phase of wound colonization and infection, and to assess local effects of candidate antimicrobial agents. PMID- 24340062 TI - Applying physics-based scoring to calculate free energies of binding for single amino acid mutations in protein-protein complexes. AB - Predicting changes in protein binding affinity due to single amino acid mutations helps us better understand the driving forces underlying protein-protein interactions and design improved biotherapeutics. Here, we use the MM-GBSA approach with the OPLS2005 force field and the VSGB2.0 solvent model to calculate differences in binding free energy between wild type and mutant proteins. Crucially, we made no changes to the scoring model as part of this work on protein-protein binding affinity--the energy model has been developed for structure prediction and has previously been validated only for calculating the energetics of small molecule binding. Here, we compare predictions to experimental data for a set of 418 single residue mutations in 21 targets and find that the MM-GBSA model, on average, performs well at scoring these single protein residue mutations. Correlation between the predicted and experimental change in binding affinity is statistically significant and the model performs well at picking "hotspots," or mutations that change binding affinity by more than 1 kcal/mol. The promising performance of this physics-based method with no tuned parameters for predicting binding energies suggests that it can be transferred to other protein engineering problems. PMID- 24340063 TI - Elevated levels of interferon-gamma production by memory T cells do not promote transplant tolerance resistance in aged recipients. AB - Immunosenescence predisposes the elderly to infectious and autoimmune diseases and impairs the response to vaccination. We recently demonstrated that ageing also impedes development of transplantation tolerance. Unlike their young counterparts (8-12 weeks of age) aged male recipients (greater than 12 months of age) transplanted with a full MHC-mismatched heart are resistant to tolerance mediated by anti-CD45RB antibody. Surprisingly, either chemical or surgical castration restored tolerance induction to levels observed using young recipients. Based on the strong impact of endocrine modulation on transplant tolerance, we explored the impact of ageing and castration on the immune system. Here we report a significant increase in the percentage of T cells that produce interferon-gamma (IFN-gamma) in aged male versus young male animals and that the overall increase in IFN-gamma production was due to an expansion of IFN-gamma producing memory T cells in aged animals. In contrast to IFN-gamma production, we did not observe differences in IL-10 expression in young versus old male mice. We hypothesized that endocrine modulation would diminish the elevated levels of IFN gamma production in aged recipients, however, we observed no significant reduction in the percentage of IFN-gamma+ T cells upon castration. Furthermore, we neutralized interferon-gamma by antibody and did not observe an effect on graft survival. We conclude that while elevated levels of interferon-gamma serves as a marker of tolerance resistance in aged mice, other as yet to be identified factors are responsible for its cause. Defining these factors may be relevant to design of tolerogenic strategies for aged recipients. PMID- 24340065 TI - Simple patterned nanofiber scaffolds and its enhanced performance in immunoassay. AB - Cancer has become the leading cause of death worldwide; early diagnosis and treatment of cancers is critical for the survival of the patients. The concentration of cancer markers in easy-to-access biological fluids can provide great assistance in screening for occult primary cancers, distinguishing malignant from benign findings, determining prognosis and prediction for cancer patients. The multiplex detection technology of a panel of cancer markers can greatly increase the accuracy of disease diagnosis. Herein, we briefly fabricate a high-throughput micro-immunoassay based on the electrospun polystyrene (PS) substrates to improve detection sensitivity. The immunoassay was evaluated by analyzing three different cancer biomarkers (AFP, CEA, VEGF). For AFP, CEA, VEGF immunofluorescence assay, the LOD of assay conducted on electrospun PS substrates before or after plasma and the conventional PS substrates were 0.42, 0.10, 1.12 ng/mL, 0.57, 0.09, 1.24 ng/mL, and 159.75, 26.19, 385.59 pg/mL, respectively (P < 0.05). Due to the high porosity and large surface area-to-volume ratio which is the foremost merit of nanostructures, and the plasma treatment which make the hydrophobic PS nanofibers hydropholic, the nanofibers substrates showed sufficient retention of immunoassay functionality and high potential for capture molecules immobilization. Consequently, the immunofluorescence assay conducted on electrospun PS substrates could significantly enhance the sensitivity and limits of detection. PMID- 24340064 TI - Molecular epidemiology of coxsackievirus A16: intratype and prevalent intertype recombination identified. AB - Coxsackievirus A16 (CVA16) is responsible for nearly 50% of all the confirmed hand, foot, and mouth disease (HFMD) cases in mainland China, sometimes it could also cause severe complications, and even death. To clarify the genetic characteristics and the epidemic patterns of CVA16 in mainland China, comprehensive bioinfomatics analyses were performed by using 35 CVA16 whole genome sequences from 1998 to 2011, 593 complete CVA16 VP1 sequences from 1981 to 2011, and prototype strains of human enterovirus species A (EV-A). Analysis on complete VP1 sequences revealed that subgenotypes B1a and B1b were prevalent strains and have been co-circulating in many Asian countries since 2000, especially in mainland China for at least 13 years. While the prevalence of subgenotype B1c (totally 20 strains) was much limited, only found in Malaysia from 2005 to 2007 and in France in 2010. Genotype B2 only caused epidemic in Japan and Malaysia from 1981 to 2000. Both subgenotypes B1a and B1b were potential recombinant viruses containing sequences from other EV-A donors in the 5'-untranslated region and P2, P3 non-structural protein encoding regions. PMID- 24340066 TI - Immunohistochemical detection of a unique protein within cells of snakes having inclusion body disease, a world-wide disease seen in members of the families Boidae and Pythonidae. AB - Inclusion body disease (IBD) is a worldwide disease in captive boa constrictors (boa constrictor) and occasionally in other snakes of the families Boidae and Pythonidae. The exact causative agent(s) and pathogenesis are not yet fully understood. Currently, diagnosis of IBD is based on the light microscopic identification of eosinophilic intracytoplasmic inclusion bodies in hematoxylin and eosin stained tissues or blood smears. An antigenically unique 68 KDa protein was identified within the IBD inclusion bodies, called IBD protein. A validated immuno-based ante-mortem diagnostic test is needed for screening snakes that are at risk of having IBD. In this study, despite difficulties in solubilizing semi purified inclusion bodies, utilizing hybridoma technology a mouse anti-IBD protein monoclonal antibody (MAB) was produced. The antigenic specificity of the antibody was confirmed and validated by western blots, enzyme-linked immunosorbent assay, immuno-transmission electron microscopy, and immunohistochemical staining. Paraffin embedded tissues of IBD positive and negative boa constrictors (n=94) collected from 1990 to 2011 were tested with immunohistochemical staining. In boa constrictors, the anti-IBDP MAB had a sensitivity of 83% and specificity of 100% in detecting IBD. The antibody also cross-reacted with IBD inclusion bodies in carpet pythons (Morelia spilota) and a ball python (python regius). This validated antibody can serve as a tool for the development of ante-mortem immunodiagnostic tests for IBD. PMID- 24340067 TI - Selection and validation of reference genes for real-time quantitative PCR in hyperaccumulating ecotype of Sedum alfredii under different heavy metals stresses. AB - Real-time Quantitative PCR (RT-qPCR) has become an effective method for accurate analysis of gene expression in several biological systems as well as under different experimental conditions. Although with high sensitivity, specificity and broad dynamic range, this method requires suitable reference genes for transcript normalization in order to guarantee reproducible and meaningful results. In the present study, we evaluated five traditional housekeeping genes and five novel reference genes in Hyperaccumulating ecotype of Sedum alfredii, a well known hyperaccumulator for heavy metals phytoremediation, under Cd, Pb, Zn and Cu stresses of seven different durations. The expression stability of these ten candidates were determined with three programs--geNorm, NormFinder and BestKeeper. The results showed that all the selected reference genes except for SAND could be used for RT-qPCR normalization. Among them UBC9 and TUB were ranked as the most stable candidates across all samples by three programs together. For the least stable reference genes, however, BestKeeper produced different results compared with geNorm and NormFinder. Meanwhile, the expression profiles of PCS under Cd, Pb, Zn and Cu stresses were assessed using UBC9 and TUB respectively, and similar trends were obtained from the results of the two groups. The distinct expression patterns of PCS indicated that various strategies could be taken by plants in adaption to different heavy metals stresses. This study will provide appropriate reference genes for further gene expression quantification using RT qPCR in Hyperaccumulator S. alfredii. PMID- 24340068 TI - Prevalence and predictors of antibiotic administration during pregnancy and birth. AB - BACKGROUND: Antibiotic treatment during pregnancy and birth is very common. In this study, we describe the estimated prevalence of antibiotic administration during pregnancy and birth in the COPSAC2010 pregnancy cohort, and analyze dependence on social and lifestyle-related factors. METHODS: 706 pregnant women from the novel unselected Copenhagen Prospective Study on Asthma in Childhood (COPSAC2010) pregnancy cohort participated in this analysis. Detailed information on oral antibiotic prescriptions during pregnancy filled at the pharmacy was obtained and verified longitudinally. Information on intrapartum antibiotics, social, and lifestyle-factors was obtained by personal interviews. RESULTS: The prevalence of antibiotic use was 37% during pregnancy and 33% intrapartum. Lower maternal age at birth; adjusted odds ratio (aOR) 0.94, 95% CI, [0.90-0.98], p = 0.003 and maternal smoking; aOR 1.97, 95% CI, [1.07-3.63], p = 0.030 were associated with use of antibiotics for urinary tract infection during pregnancy. Maternal educational level (low vs. high), aOR 2.32, 95% CI, [1.24-4.35], p = 0.011, maternal asthma; aOR 1.99, 95% CI, [1.33-2.98], p < 0.001 and previous childbirth; aOR 1.80, 95% CI, [1.21-2.66], p = 0.004 were associated with use of antibiotics for respiratory tract infection during pregnancy. Lower gestational age; aOR 0.72, 95% CI, [0.61-0.85], p < 0.001, maternal smoking; aOR 2.84, 95% CI, [1.33-6.06], p = 0.007, and nulliparity; aOR 1.79, 95% CI, [1.06-3.02], p = 0.030 were associated with administration of intrapartum antibiotics in women giving birth vaginally. CONCLUSION: Antibiotic administration during pregnancy and birth may be influenced by social and lifestyle-factors. Understanding such risk factors may guide preventive strategies in order to avoid unnecessary use of antibiotics. PMID- 24340069 TI - Cell cycle-dependent turnover of 5-hydroxymethyl cytosine in mouse embryonic stem cells. AB - Hydroxymethylcytosine in the genome is reported to be an intermediate of demethylation. In the present study, we demonstrated that maintenance methyltransferase Dnmt1 scarcely catalyzed hemi-hydroxymethylated DNA and that the hemi-hydroxymethylated DNA was not selectively recognized by the SRA domain of Uhrf1, indicating that hydroxymethylcytosine is diluted in a replication dependent manner. A high level of 5-hydroxymethylcytosine in mouse embryonic stem cells was produced from the methylcytosine supplied mainly by de novo-type DNA methyltransferases Dnmt3a and Dnmt3b. The promoter regions of the HoxA gene cluster showed a high hydroxymethylation level whilst the methylcytosine level was quite low, suggesting that methylated CpG is actively hydroxylated during proliferation. All the results indicate that removal and production of hydroxymethylcytosine are regulated in replication-dependent manners in mouse embryonic stem cells. PMID- 24340070 TI - Klotho suppresses cardiomyocyte apoptosis in mice with stress-induced cardiac injury via downregulation of endoplasmic reticulum stress. AB - Cardiomyocyte apoptosis is a common pathological alteration in heart disease which results in systolic dysfunction or sudden death. Klotho is a novel anti aging hormone. We tested the effects of klotho on cell apoptosis in isoproterenol treated cardiomyocytes. In BALB/c mice, cardiac injury was induced by subcutaneous injection of isoproterenol (5 mg/kg, for 9 days, s.c.). Klotho (0.01 mg/kg, every other day for 4 days, i.p.) was administered to determine the changes in isoproterenol-induced apoptosis. Mouse heart was harvested at day 2, day 5, and day 9 after isoproterenol injection. Isoproterenol induced cardiac apoptosis and endoplasmic reticulum (ER) stress in a time-dependent manner. However, klotho partly reversed isoproterenol-induced cardiac apoptosis and ER stress. These same effects were observed in cultured cardiomyocytes. Furthermore, the results also showed that SB203580, a p38 inhibitor, and SP600125, a c-Jun NH2 terminal kinase (JNK) inhibitor, reduced cardiomyocyte apoptosis and ER stress, however, klotho suppressed isoproterenol-induced activation of p38 and JNK. Taken together, these results indicated that cardioprotection by klotho was related to the attenuation of ER stress and ER stress-induced apoptosis, at least partly, through suppressing activation of the p38 and JNK pathway. PMID- 24340071 TI - Ala54Thr fatty acid-binding protein 2 (FABP2) polymorphism in recurrent depression: associations with fatty acid concentrations and waist circumference. AB - BACKGROUND: Fatty acid (FA)-alterations may mediate the mutual association between Major Depressive Disorder (MDD) and cardiovascular disease (CVD). However, etiology of observed FA-alterations in MDD and CVD remains largely unclear. An interesting candidate may be a mutation in the fatty acid-binding protein 2 (FABP2)-gene, because it regulates dietary FA-uptake. Therefore, we aimed to test the hypotheses that in MDD-patients the FABP2 Ala54Thr-polymorphism would be (I) more prevalent than in sex- and age-matched controls, (II) associated with observed alterations in FA-metabolism, and (III) associated with CVD-risk factor waist circumference. METHODS: We measured concentrations of 29 different erythrocyte FAs, FABP2-genotype, and waist circumference in recurrent MDD-patients and matched never-depressed controls. RESULTS: FABP2-genotype distribution did not significantly differ between the 137 MDD-patients and 73 matched controls. However, patients with the Ala54Thr-polymorphism had (I) higher concentrations of especially eicosadienoic acid (C20:2omega6; P=.009) and other 20-carbon FAs, and associated (II) lower waist circumference (P=.019). In addition, FABP2-genotype effects on waist circumference in patients seemed (I) mediated by its effect on C20:2omega6, and (II) different from controls. CONCLUSIONS: Although Ala54Thr-polymorphism distribution was not associated with recurrent MDD, our results indicate that FABP2 may play a role in the explanation of observed FA-alterations in MDD. For Ala54Thr-polymorphism patients, potentially adaptive conversion of increased bioavailable dietary precursors into eicosadienoic acid instead of arachidonic acid might be related to a low waist circumference. Because this is the first investigation of these associations, replication is warranted, preferably by nutrigenetic studies applying lipidomics and detailed dietary assessment. PMID- 24340072 TI - Preconditioning via angiotensin type 2 receptor activation improves therapeutic efficacy of bone marrow mononuclear cells for cardiac repair. AB - BACKGROUND: The therapeutic efficiency of bone marrow mononuclear cells (BMMNCs) autologous transplantation for myocardial infarction (MI) remains low. Here we developed a novel strategy to improve cardiac repair by preconditioning BMMNCs via angiotensin II type 2 receptor (AT2R) stimulation. METHODS AND RESULTS: Acute MI in rats led to a significant increase of AT2R expression in BMMNCs. Preconditioning of BMMNCs via AT2R stimulation directly with an AT2R agonist CGP42112A or indirectly with angiotensin II plus AT1R antagonist valsartan led to ERK activation and increased eNOS expression as well as subsequent nitric oxide generation, ultimately improved cardiomyocyte protection in vitro as measured by co-culture approach. Intramyocardial transplantation of BMMNCs preconditioned via AT2R stimulation improved survival of transplanted cells in ischemic region of heart tissue and reduced cardiomyocyte apoptosis and inflammation at 3 days after MI. At 4 weeks after transplantation, compared to DMEM and non-preconditioned BMMNCs group, AT2R stimulated BMMNCs group showed enhanced vessel density in peri infarct region and attenuated infarct size, leading to global heart function improvement. CONCLUSIONS: Preconditioning of BMMNCs via AT2R stimulation exerts protective effect against MI. Stimulation of AT2R in BMMNCs may provide a new strategy to improving therapeutic efficiency of stem cells for post MI cardiac repair. PMID- 24340073 TI - Beauvericin ameliorates experimental colitis by inhibiting activated T cells via downregulation of the PI3K/Akt signaling pathway. AB - Crohn's disease is a common, chronic inflammatory bowel condition characterized by remission and relapse. Accumulating evidence indicates that activated T cells play an important role in this disease. In the present study, we aimed to examine the effect of beauvericin, a natural cyclic peptide, on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice, which mimics Crohn's disease. Beauvericin significantly reduced weight loss, diarrhea and mortality, accompanied with notable alleviation of macroscopic and microscopic signs. In addition, this compound decreased serum levels of tumor necrosis factor (TNF) alpha and interferon (IFN)-gamma in a concentration-dependent manner in mice with experimental colitis. These effects of beauvericin are attributed to its inhibition on activated T cells. Flow cytometry and immunoblot assay data showed that beauvericin suppressed T-cell proliferation, activation and IFN-gamma-STAT1 T-bet signaling and subsequently led to apoptosis of activated T cells by suppressing Bcl-2 and phosphorylated Bad as well as increasing cleavage of caspase-3, -9, -12 and PARP. Furthermore, inhibition of PI3K/Akt signaling, which was an upstream regulator of cell activation and survival in activated T cells, contributed to the effect of beauvericin. Overall, these results supported beauvericin as a novel drug candidate for the treatment of colonic inflammation mainly by targeting PI3K/Akt in activated T cells. PMID- 24340074 TI - Social structure of a semi-free ranging group of mandrills (Mandrillus sphinx): a social network analysis. AB - The difficulty involved in following mandrills in the wild means that very little is known about social structure in this species. Most studies initially considered mandrill groups to be an aggregation of one-male/multifemale units, with males occupying central positions in a structure similar to those observed in the majority of baboon species. However, a recent study hypothesized that mandrills form stable groups with only two or three permanent males, and that females occupy more central positions than males within these groups. We used social network analysis methods to examine how a semi-free ranging group of 19 mandrills is structured. We recorded all dyads of individuals that were in contact as a measure of association. The betweenness and the eigenvector centrality for each individual were calculated and correlated to kinship, age and dominance. Finally, we performed a resilience analysis by simulating the removal of individuals displaying the highest betweenness and eigenvector centrality values. We found that related dyads were more frequently associated than unrelated dyads. Moreover, our results showed that the cumulative distribution of individual betweenness and eigenvector centrality followed a power function, which is characteristic of scale-free networks. This property showed that some group members, mostly females, occupied a highly central position. Finally, the resilience analysis showed that the removal of the two most central females split the network into small subgroups and increased the network diameter. Critically, this study confirms that females appear to occupy more central positions than males in mandrill groups. Consequently, these females appear to be crucial for group cohesion and probably play a pivotal role in this species. PMID- 24340076 TI - Sugars increase non-heme iron bioavailability in human epithelial intestinal and liver cells. AB - Previous studies have suggested that sugars enhance iron bioavailability, possibly through either chelation or altering the oxidation state of the metal, however, results have been inconclusive. Sugar intake in the last 20 years has increased dramatically, and iron status disorders are significant public health problems worldwide; therefore understanding the nutritional implications of iron sugar interactions is particularly relevant. In this study we measured the effects of sugars on non-heme iron bioavailability in human intestinal Caco-2 cells and HepG2 hepatoma cells using ferritin formation as a surrogate marker for iron uptake. The effect of sugars on iron oxidation state was examined by measuring ferrous iron formation in different sugar-iron solutions with a ferrozine-based assay. Fructose significantly increased iron-induced ferritin formation in both Caco-2 and HepG2 cells. In addition, high-fructose corn syrup (HFCS-55) increased Caco-2 cell iron-induced ferritin; these effects were negated by the addition of either tannic acid or phytic acid. Fructose combined with FeCl3 increased ferrozine-chelatable ferrous iron levels by approximately 300%. In conclusion, fructose increases iron bioavailability in human intestinal Caco-2 and HepG2 cells. Given the large amount of simple and rapidly digestible sugars in the modern diet their effects on iron bioavailability may have important patho physiological consequences. Further studies are warranted to characterize these interactions. PMID- 24340075 TI - Label retention identifies a multipotent mesenchymal stem cell-like population in the postnatal thymus. AB - Thymic microenvironments are essential for the proper development and selection of T cells critical for a functional and self-tolerant adaptive immune response. While significant turnover occurs, it is unclear whether populations of adult stem cells contribute to the maintenance of postnatal thymic epithelial microenvironments. Here, the slow cycling characteristic of stem cells and their property of label-retention were used to identify a K5-expressing thymic stromal cell population capable of generating clonal cell lines that retain the capacity to differentiate into a number of mesenchymal lineages including adipocytes, chondrocytes and osteoblasts suggesting a mesenchymal stem cell-like phenotype. Using cell surface analysis both culture expanded LRCs and clonal thymic mesenchymal cell lines were found to express Sca1, PDGFRalpha, PDGFRbeta,CD29, CD44, CD49F, and CD90 similar to MSCs. Sorted GFP-expressing stroma, that give rise to TMSC lines, contribute to thymic architecture when reaggregated with fetal stroma and transplanted under the kidney capsule of nude mice. Together these results show that the postnatal thymus contains a population of mesenchymal stem cells that can be maintained in culture and suggests they may contribute to the maintenance of functional thymic microenvironments. PMID- 24340077 TI - Plasmablasts as migratory IgG-producing cells in the pathogenesis of neuromyelitis optica. AB - Neuromyelitis optica (NMO) is an inflammatory disease characterized by recurrent attacks of optic neuritis and myelitis. It is generally accepted that autoantibodies against aquaporin 4 water channel protein play a pathogenic role in neuromyelitis optica. We have recently reported that plasmablasts are increased in the peripheral blood of this autoimmune disease, and are capable of producing autoantibodies against aquaporin 4. Here, we demonstrate that CD138(+)HLA-DR(+) plasmablasts, a subset of IgG-producing cells, are increased in the peripheral blood and are enriched among the cerebrospinal fluid (CSF) lymphocytes during the relapse of neuromyelitis optica. Notably, these CD138(+)HLA-DR(+) plasmablasts overexpress CXCR3, whose ligands are present in the cerebrospinal fluid during the relapse of neuromyelitis optica. These results led us to speculate that plasmablasts producing anti-aquaporin 4 autoantibodies might traffic toward the central nervous system (CNS). Furthermore, we performed single-cell sorting of plasmablasts from peripheral blood and CSF samples from NMO and sequenced the complementarity-determining regions (CDRs) of the IgG heavy chain expressed by the sorted plasmablast clones. There were high frequencies of mutations in the CDRs compared with framework regions, indicating that these plasmablast clones would represent a post-germinal center B-cell lineage. Consistent with the preceding results, the plasmablast clones from the peripheral blood shared the same CDR sequences with the clones from the CSF. These results indicate that IgG-producing plasmablasts, which are guided by helper T-cells, may migrate from the peripheral blood preferentially to the CSF. Since migratory plasmablasts could be involved in the inflammatory pathology of NMO, the B-cell subset and their migration might be an attractive therapeutic target. PMID- 24340078 TI - Association between traffic-related air pollution, subclinical inflammation and impaired glucose metabolism: results from the SALIA study. AB - BACKGROUND: Environmental and lifestyle factors regulate the expression and release of immune mediators. It has been hypothesised that ambient air pollution may be such an external factor and that the association between air pollution and impaired glucose metabolism may be attributable to inflammatory processes. Therefore, we assessed the associations between air pollution, circulating immune mediators and impaired glucose metabolism. METHODS: We analysed concentrations of 14 pro- and anti-inflammatory immune mediators as well as fasting glucose and insulin levels in plasma of 363 women from the Study on the influence of Air pollution on Lung function, Inflammation and Aging (SALIA, Germany). Exposure data for a group of pollutants such as nitrogen oxides (NO2, NOx) and different fractions of particulate matter were available for the participants' residences. We calculated the association between the pollutants and impaired glucose metabolism by multiple regression models. RESULTS: The study participants had a mean age of 74.1 (SD 2.6) years and 48% showed impaired glucose metabolism based on impaired fasting glucose or previously diagnosed type 2 diabetes. Only long term exposure NO2 and NOx concentrations showed positive associations (NO2: OR 1.465, 95% CI 1.049-2.046, NOx: OR 1.409, 95% CI 1.010-1.967) per increased interquartile range of NO2 (14.65 ug/m(3)) or NOx (43.16 ug/m(3)), respectively, but statistical significance was lost after correction for multiple comparisons. Additional adjustment for circulating immune mediators or the use of anti inflammatory medication had hardly any impact on the observed ORs. CONCLUSIONS: Our results suggest that exposure to nitrogen oxides may contribute to impaired glucose metabolism, but the associations did not reach statistical significance so that further studies with larger sample sizes are required to substantiate our findings. Our data do not preclude a role of inflammatory mechanisms in adipose or other tissues which may not be reflected by immune mediators in plasma. PMID- 24340079 TI - Assessing plasma levels of selenium, copper, iron and zinc in patients of Parkinson's disease. AB - Trace elements have been recognized to play an important role in the development of Parkinson's disease (PD). However, it is difficult to precisely identify the relationship between these elements and the progression of PD because of an insufficient number of patients. In this study, quantifications of selenium (Se), copper (Cu), iron (Fe) and zinc (Zn) by atomic absorption spectrophotometry were performed in plasma from 238 PD patients and 302 controls recruited from eastern China, which is so far the largest cohort of PD patients and controls for measuring plasma levels of these elements. We found that plasma Se and Fe concentrations were significantly increased whereas Cu and Zn concentrations decreased in PD patients as compared with controls. Meanwhile, these four elements displayed differential changes with regard to age. Linear and logistic regression analyses revealed that both Fe and Zn were negatively correlated with age in PD patients. Association analysis suggests that lower plasma Se and Fe levels may reduce the risk for PD, whereas lower plasma Zn is probably a PD risk factor. Finally, a model was generated to predict PD patients based on the plasma concentrations of these four trace elements as well as other features such as sex and age, which achieved an accuracy of 80.97+/-1.34% using 10-fold cross validation. In summary, our data provide new insights into the roles of Se, Cu, Fe and Zn in PD progression. PMID- 24340080 TI - Age-related differences in motor coordination during simultaneous leg flexion and finger extension: influence of temporal pressure. AB - Although the effect of temporal pressure on spatio-temporal aspects of motor coordination and posture is well established in young adults, there is a clear lack of data on elderly subjects. This work examined the aging-related effects of temporal pressure on movement synchronization and dynamic stability. Sixteen young and eleven elderly subjects performed series of simultaneous rapid leg flexions in an erect posture paired with ipsilateral index-finger extensions, minimizing the difference between heel and finger movement onsets. This task was repeated ten times under two temporal conditions (self-initiated [SI] vs. reaction-time [RT]). Results showed that, first, temporal pressure modified movement synchronization; the finger extension preceded swing heel-off in RT, and inversely in SI. Synchronization error and associated standard deviation were significantly greater in elderly than in young adults in SI only, i.e. in the condition where proprioception is thought to be crucial for temporal coordination. Secondly, both groups developed a significantly shorter mediolateral (ML) anticipatory postural adjustment duration in RT (high temporal pressure) than in SI. In both groups, this shortening was compensated by an increase in the anticipatory peak of centre-of-gravity (CoG) acceleration towards the stance-leg so that ML dynamic stability at foot-off, quantified with the "extrapolated centre-of-mass", remained unchanged across temporal conditions. This increased CoG acceleration was associated with an increased anticipatory peak of ML centre-of-pressure shift towards the swing-leg in young adults only. This suggested that the ability to accelerate the CoG with the centre-of-pressure shift was degraded in elderly, probably due to weakness in the lower limb muscles. Dynamic stability at foot-off was also degraded in elderly, with a consequent increased risk of ML imbalance and falling. The present study provides new insights into the ability of elderly adults to deal with temporal pressure constraints in adapting whole-body coordination of postural and focal components of paired movement. PMID- 24340081 TI - A soluble fucose-specific lectin from Aspergillus fumigatus conidia--structure, specificity and possible role in fungal pathogenicity. AB - Aspergillus fumigatus is an important allergen and opportunistic pathogen. Similarly to many other pathogens, it is able to produce lectins that may be involved in the host-pathogen interaction. We focused on the lectin AFL, which was prepared in recombinant form and characterized. Its binding properties were studied using hemagglutination and glycan array analysis. We determined the specificity of the lectin towards l-fucose and fucosylated oligosaccharides, including alpha1-6 linked core-fucose, which is an important marker for cancerogenesis. Other biologically relevant saccharides such as sialic acid, d mannose or d-galactose were not bound. Blood group epitopes of the ABH and Lewis systems were recognized, Le(Y) being the preferred ligand among others. To provide a correlation between the observed functional characteristics and structural basis, AFL was crystallized in a complex with methyl-alpha,L selenofucoside and its structure was solved using the SAD method. Six binding sites, each with different compositions, were identified per monomer and significant differences from the homologous AAL lectin were found. Structure derived peptides were utilized to prepare anti-AFL polyclonal antibodies, which suggested the presence of AFL on the Aspergillus' conidia, confirming its expression in vivo. Stimulation of human bronchial cells by AFL led to IL-8 production in a dose-dependent manner. AFL thus probably contributes to the inflammatory response observed upon the exposure of a patient to A. fumigatus. The combination of affinity to human epithelial epitopes, production by conidia and pro-inflammatory activity is remarkable and shows that AFL might be an important virulence factor involved in an early stage of A. fumigatus infection. PMID- 24340082 TI - A prognostic model for triple-negative breast cancer patients based on node status, cathepsin-D and Ki-67 index. AB - OBJECTIVE: The aim of this study was to evaluate clinicopathologic factors that could possibly affect the outcome of patients with triple negative breast cancer and subsequently build a prognostic model to predict patients' outcome. METHODS: We retrospectively analyzed clinicopathologic characteristics and outcome of 504 patients diagnosed with triple-negative invasive ductal breast cancer. 185 patients enrolled between 2000 and 2002 were designated to the training set. The variables that had statistically significant correlation with prognosis were combined to build a model. The prognostic value of the model was further validated in the separate validation set containing 319 patients enrolled between 2003 and 2006. RESULTS: The median follow-up duration was 66 months. 174 patients experienced recurrence, and 111 patients died. Positivity for >=4 lymph nodes, Cathepsin-D positivity, and Ki-67 index >=20% were independent factors for DFS, while the lymph nodes status and Ki-67 index were the prognostic factors for OS. The prognostic model was established based on the sum of all three factors, where positivity for >=4 lymph nodes, Cathepsin-D and Ki-67 index >=20% would individually contribute 1 point to the risk score. The patients in the validation set were assigned to a low-risk group (0 and 1 point) and a high-risk group (2 and 3 points). The external validation analysis also demonstrated that our prognostic model provided the independent high predictive accuracy of recurrence. CONCLUSION: This model has a considerable clinical value in predicting recurrence, and will help clinicians to design an appropriate level of adjuvant treatment and schedule adequate appointments of surveillance visits. PMID- 24340083 TI - Trajectories of self-rated health in people with diabetes: associations with functioning in a prospective community sample. AB - BACKGROUND: Self-rated health (SRH) is a single-item measure that is one of the most widely used measures of general health in population health research. Relatively little is known about changes and the trajectories of SRH in people with chronic medical conditions. The aims of the present study were to identify and describe longitudinal trajectories of self-rated health (SRH) status in people with diabetes. METHODS: A prospective community study was carried out between 2008 and 2011. SRH was assessed at baseline and yearly at follow-ups (n=1288). Analysis was carried out through trajectory modeling. The trajectory groups were subsequently compared at 4 years follow-up with respect to functioning. RESULTS: Four distinct trajectories of SRH were identified: 1) 72.2% of the participants were assigned to a persistently good SRH trajectory; 2) 10.1% were assigned to a persistently poor SRH trajectory; 3) mean SRH scores changed from good to poor for one group (7.3%); while 4) mean SRH scores changed from poor to medium/good for another group (10.4%). Those with a persistently poor perception of health status were at higher risk for poor functioning at 4 years follow-up than those whose SRH scores decreased from good to poor. CONCLUSIONS: SRH is an important predictor for poor functioning in diabetes, but the trajectory of SRH seems to be even more important. Health professionals should pay attention to not only SRH per se, but also changes in SRH over time. PMID- 24340084 TI - Impact of early colonizers on in vitro subgingival biofilm formation. AB - The aim of this study was to investigate the impact of early colonizing species on the structure and the composition of the bacterial community developing in a subgingival 10-species biofilm model system. The model included Streptococcus oralis, Streptococcus anginosus, Actinomycesoris, Fusobacterium nucleatum subsp. nucleatum, Veillonella dispar, Campylobacter rectus, Prevotella intermedia, Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola. Based on literature, we considered Streptococcus oralis, Streptococcus anginosus, and Actinomyces oris as early colonizers and examined their role in the biofilms by either a delayed addition to the consortium, or by not inoculating at all the biofilms with these species. We quantitatively evaluated the resulting biofilms by real-time quantitative PCR and further compared the structures using confocal laser scanning microscopy following fluorescence in situ hybridisation. The absence of the early colonizers did not hinder biofilm formation. The biofilms reached the same total counts and developed to normal thickness. However, quantitative shifts in the abundances of individual species were observed. In the absence of streptococci, the overall biofilm structure appeared looser and more dispersed. Moreover, besides a significant increase of P. intermedia and a decrease of P. gingivalis , P. intermedia appeared to form filamented long chains that resembled streptococci. A. oris, although growing to significantly higher abundance in absence of streptococci, did not have a visible impact on the biofilms. Hence, in the absence of the early colonizers, there is a pronounced effect on P. intermedia and P. gingivalis that may cause distinct shifts in the structure of the biofilm. Streptococci possibly facilitate the establishment of P. gingivalis into subgingival biofilms, while in their absence P. intermedia became more dominant and forms elongated chains. PMID- 24340085 TI - Effectiveness of hospital-wide methicillin-resistant Staphylococcus aureus (MRSA) infection control policies differs by ward specialty. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of preventable nosocomial infections and is endemic in hospitals worldwide. The effectiveness of infection control policies varies significantly across hospital settings. The impact of the hospital context towards the rate of nosocomial MRSA infections and the success of infection control is understudied. We conducted a modelling study to evaluate several infection control policies in surgical, intensive care, and medical ward specialties, each with distinct ward conditions and policies, of a tertiary public hospital in Sydney, Australia. We reconfirm hand hygiene as the most successful policy and find it to be necessary for the success of other policies. Active screening for MRSA, patient isolation in single bed rooms, and additional staffing were found to be less effective. Across these ward specialties, MRSA transmission risk varied by 13% and reductions in the prevalence and nosocomial incidence rate of MRSA due to infection control policies varied by up to 45%. Different levels of infection control were required to reduce and control nosocomial MRSA infections for each ward specialty. Infection control policies and policy targets should be specific for the ward and context of the hospital. The model we developed is generic and can be calibrated to represent different ward settings and pathogens transmitted between patients indirectly through health care workers. This can aid the timely and cost effective design of synergistic and context specific infection control policies. PMID- 24340087 TI - Rice performance and water use efficiency under plastic mulching with drip irrigation. AB - Plastic mulching with drip irrigation is a new water-saving rice cultivation technology, but little is known on its productivity and water-saving capacity. This study aimed to assess the production potential, performance, and water use efficiency (WUE) of rice under plastic mulching with drip irrigation. Field experiments were conducted over 2 years with two rice cultivars under different cultivation systems: conventional flooding (CF), non-flooded irrigation incorporating plastic mulching with furrow irrigation (FIM), non-mulching with furrow irrigation (FIN), and plastic mulching with drip irrigation (DI). Compared with the CF treatment, grain yields were reduced by 31.76-52.19% under the DI treatment, by 57.16-61.02% under the FIM treatment, by 74.40-75.73% under the FIN treatment, which were mainly from source limitation, especially a low dry matter accumulation during post-anthesis, in non-flooded irrigation. WUE was the highest in the DI treatment, being 1.52-2.12 times higher than with the CF treatment, 1.35-1.89 times higher than with the FIM treatment, and 2.37-3.78 times higher than with the FIN treatment. The yield contribution from tillers (YCFTs) was 50.65-62.47% for the CF treatment and 12.07-20.62% for the non-flooded irrigation treatments. These low YCFTs values were attributed to the poor performance in tiller panicles rather than the total tiller number. Under non-flooded irrigation, root length was significantly reduced with more roots distributed in deep soil layers compared with the CF treatment; the DI treatment had more roots in the topsoil layer than the FIM and FIN treatments. The experiment demonstrates that the DI treatment has greater water saving capacity and lower yield and economic benefit gaps than the FIM and FIN treatments compared with the CF treatment, and would therefore be a better water-saving technology in areas of water scarcity. PMID- 24340086 TI - Utilizing twins as controls for non-twin case-materials in genome wide association studies. AB - Twin registries around the globe have collected DNA samples from large numbers of monozygotic and dizygotic twins. The twin sample collections are frequently used as controls in disease-specific studies together with non-twins. This approach is unbiased under the hypothesis that twins and singletons are comparable in terms of allele frequencies; i.e. there are no genetic variants associated with being a twin per se. To test this hypothesis we performed a genome-wide association study comparing the allele frequency of 572,352 single nucleotide polymorphisms (SNPs) in 1,413 monozygotic (MZ) and 5,451 dizygotic (DZ) twins with 3,720 healthy singletons. Twins and singletons have been genotyped using the same platform. SNPs showing association with being a twin at P-value < 1 * 10(-5) were selected for replication analysis in 1,492 twins (463 MZ and 1,029 DZ) and 1,880 singletons from Finland. No SNPs reached genome-wide significance (P-value < 5 * 10(-8)) in the main analysis combining MZ and DZ twins. In a secondary analysis including only DZ twins two SNPs (rs2033541 close to ADAMTSL1 and rs4149283 close to ABCA1) were genome-wide significant after meta-analysis with the Finnish population. The estimated proportion of variance on the liability scale explained by all SNPs was 0.08 (P-value=0.003) when MZ and DZ were considered together and smaller for MZ (0.06, P-value=0.10) compared to DZ (0.09, P-value=0.003) when analyzed separately. In conclusion, twins and singletons can be used in genetic studies together with general population samples without introducing large bias. Further research is needed to explore genetic variances associated with DZ twinning. PMID- 24340089 TI - Short amplexus duration in a territorial anuran: a possible adaptation in response to male-male competition. AB - Mating duration is a reproductive behaviour that can impact fertilization efficiency and offspring number. Previous studies of factors influencing the evolution of mating duration have focused on the potential role of internal sperm competition as an underlying source of selection; most of these studies have been on invertebrates. For vertebrates with external fertilization, such as fishes and frogs, the sources of selection acting on mating duration remain largely unknown due, in part, to the difficulty of observing complete mating behaviours in natural conditions. In this field study, we monitored breeding activity in a population of the territorial olive frog, Rana adenopleura, to identify factors that affect the duration of amplexus. Compared with most other frogs, amplexus was short, lasting less than 11 min on average, which included about 8 min of pre oviposition activity followed by 3 min of oviposition. We evaluated the relationship between amplexus duration and seven variables: male body size, male condition, operational sex ratio (OSR), population size, clutch size, territory size, and the coverage of submerged vegetation in a male's territory. We also investigated the influence of these same variables, along with amplexus duration, on fertilization rate. Amplexus duration was positively related with clutch size and the degree of male-bias in the nightly OSR. Fertilization rate was directly related to male body size and inversely related to amplexus duration. Agonistic interactions between males in amplexus and intruding, unpaired males were frequent. These interactions often resulted in mating failure, prolonged amplexus duration, and reduced fertilization rates. Together, the pattern of our findings indicates short amplexus duration in this species may be an adaptive reproductive strategy whereby males attempt to reduce the risks of mating and fertilization failures and territory loss resulting from male-male competition. PMID- 24340088 TI - Identification and characterization of a PutAMT1;1 gene from Puccinellia tenuiflora. AB - Nitrogen is one of the most important limiting factors for plant growth. However, as ammonium is readily converted into ammonia (NH3) when soil pH rises above 8.0, this activity depletes the availability of ammonium (NH4(+)) in alkaline soils, consequently preventing the growth of most plant species. The perennial wild grass Puccinellia tenuiflora is one of a few plants able to grow in soils with extremely high salt and alkaline pH (>9.0) levels. Here, we assessed how this species responds to ammonium under such conditions by isolating and analyzing the functions of a putative ammonium transporter (PutAMT1;1). PutAMT1;1 is the first member of the AMT1 (ammonium transporter) family that has been identified in P. tenuiflora. This gene (1) functionally complemented a yeast mutant deficient in ammonium uptake (2), is preferentially expressed in the anther of P. tenuiflora, and (3) is significantly upregulated by ammonium ions in both the shoot and roots. The PutAMT1;1 protein is localized in the plasma membrane and around the nuclear periphery in yeast cells and P. tenuiflora suspension cells. Immunoelectron microscopy analysis also indicated that PutAMT1;1 is localized in the endomembrane. The overexpression of PutAMT1;1 in A. thaliana enhanced plant growth, and increased plant susceptibility to toxic methylammonium (MeA). Here, we confirmed that PutAMT1;1 is an ammonium-inducible ammonium transporter in P. tenuiflora. On the basis of the results of PutAMT1;1 overexpression in A. thaliana, this gene might be useful for improving the root to shoot mobilization of MeA (or NH4(+)). PMID- 24340090 TI - Preparing uniform-thickness corneal endothelial grafts from donor tissues using a non-amplified femtosecond laser. AB - Corneal grafts for Descemet's Stripping Automated Endothelial Keratoplasty are commonly prepared using mechanical microkeratomes. However, the cuts produced in such way render corneal lenticules that are thinner centrally than peripherally, thus inducing a hyperopic shift. Here we describe a novel device for preparing donor corneal grafts, in which a single low-energy femtosecond laser system is used as both a light source for optical coherence tomography and for cutting the graft illuminating from the endothelial side. The same laser is first utilized to obtain three-dimensional optical coherence tomography images of the donor tissue for guiding the dissection and obtaining grafts of uniform thickness with no applanation or contact. This device allows an optimal procedure for preparing consistently thin posterior grafts for transplantation. PMID- 24340091 TI - Pregnant mothers with resolved anxiety disorders and their offspring have reduced heart rate variability: implications for the health of children. AB - OBJECTIVE: Active anxiety disorders have lasting detrimental effects on pregnant mothers and their offspring but it is unknown if historical, non-active, maternal anxiety disorders have similar effects. Anxiety-related conditions, such as reduced autonomic cardiac control, indicated by reduced heart rate variability (HRV) could persist despite disorder resolution, with long-term health implications for mothers and children. The objective in this study is to test the hypotheses that pregnant mothers with a history of, but not current anxiety and their children have low HRV, predicting anxiety-like offspring temperaments. METHODS: The participants in this case-control study consist of 56 women during their first trimester and their offspring (15 male, 29 female). Women had a history of an anxiety disorder (n=22) or no psychopathology (n=34) determined using the Mini-International Neuropsychiatric Interview. The main outcome measures were indices of autonomic cardiac control including root mean square of successive differences (RMSSD) and high frequency (HF) variability. Children's fearfulness was also assessed using the Laboratory Temperament Assessment Battery (Lab-TAB)-Locomotor Version. RESULTS: HRV was lower in women and children in the past anxiety group compared to controls. HRV measures for mothers and children were positively correlated in the anxiety group only. In all children, low HRV measures at 2-4 months were associated with a higher chance of fearful behavior at 9-10 months. CONCLUSIONS: Pregnant women with previous but not current anxiety and their children have low HRV. Children with low HRV tend to show more fearfulness. These findings have implications for identifying children at risk of anxiety disorders and point to possible underlying mechanisms of child psychopathology. PMID- 24340092 TI - Cell adhesion and shape regulate TGF-beta1-induced epithelial-myofibroblast transition via MRTF-A signaling. AB - Myofibroblasts, specialized cells that play important roles in wound healing and fibrosis, can develop from epithelial cells through an epithelial-mesenchymal transition (EMT). During EMT, epithelial cells detach from neighboring cells and acquire an elongated, mesenchymal-like morphology. These phenotypic changes are accompanied by changes in gene expression patterns including upregulation of a variety of cytoskeletal associated proteins which contribute to the ability of myofibroblasts to exert large contractile forces. Here, the relationship between cell shape and cytoskeletal tension and the expression of cytoskeletal proteins in transforming growth factor (TGF)-beta1-induced EMT is determined. We find that culturing cells in conditions which permit cell spreading and increased contractility promotes the increased expression of myofibroblast markers and cytoskeletal associated proteins. In contrast, blocking cell spreading prevents transdifferentiation to the myofibroblast phenotype. Furthermore, we find that cell shape regulates the expression of cytoskeletal proteins by controlling the subcellular localization of myocardin related transcription factor (MRTF)-A. Pharmacological inhibition of cytoskeletal tension or MRTF-A signaling blocks the acquisition of a myofibroblast phenotype in spread cells while overexpression of MRTF-A promotes the expression of cytoskeletal proteins for all cell shapes. These data suggest that cell shape is a critical determinant of myofibroblast development from epithelial cells. PMID- 24340093 TI - Centrosomal localisation of the cancer/testis (CT) antigens NY-ESO-1 and MAGE-C1 is regulated by proteasome activity in tumour cells. AB - The Cancer/Testis (CT) antigen family of genes are transcriptionally repressed in most human tissues but are atypically re-expressed in many malignant tumour types. Their restricted expression profile makes CT antigens ideal targets for cancer immunotherapy. As little is known about whether CT antigens may be regulated by post-translational processing, we investigated the mechanisms governing degradation of NY-ESO-1 and MAGE-C1 in selected cancer cell lines. Inhibitors of proteasome-mediated degradation induced the partitioning of NY-ESO 1 and MAGE-C1 into a detergent insoluble fraction. Moreover, this treatment also resulted in increased localisation of NY-ESO-1 and MAGE-C1 at the centrosome. Despite their interaction, relocation of either NY-ESO-1 or MAGE-C1 to the centrosome could occur independently of each other. Using a series of truncated fragments, the regions corresponding to NY-ESO-1(91-150) and MAGE-C1(900-1116) were established as important for controlling both stability and localisation of these CT antigens. Our findings demonstrate that the steady state levels of NY ESO-1 and MAGE-C1 are regulated by proteasomal degradation and that both behave as aggregation-prone proteins upon accumulation. With proteasome inhibitors being increasingly used as front-line treatment in cancer, these data raise issues about CT antigen processing for antigenic presentation and therefore immunogenicity in cancer patients. PMID- 24340094 TI - Avian community responses to variability in river hydrology. AB - River flow is a major driver of morphological structure and community dynamics in riverine-floodplain ecosystems. Flow influences in-stream communities through changes in water velocity, depth, temperature, turbidity and nutrient fluxes, and perturbations in the organisation of lower trophic levels are cascaded through the food web, resulting in shifts in food availability for consumer species. River birds are sensitive to spatial and phenological mismatches with aquatic prey following flow disturbances; however, the role of flow as a determinant of riparian ecological structure remains poorly known. This knowledge is crucial to help to predict if, and how, riparian communities will be influenced by climate induced changes in river flow characterised by more extreme high (i.e. flood) and/or low (i.e. drought) flow events. Here, we combine national-scale datasets of river bird surveys and river flow archives to understand how hydrological disturbance has affected the distribution of riparian species at higher trophic levels. Data were analysed for 71 river locations using a Generalized Additive Model framework and a model averaging procedure. Species had complex but biologically interpretable associations with hydrological indices, with species' responses consistent with their ecology, indicating that hydrological-disturbance has implications for higher trophic levels in riparian food webs. Our quantitative analysis of river flow-bird relationships demonstrates the potential vulnerability of riparian species to the impacts of changing flow variability and represents an important contribution in helping to understand how bird communities might respond to a climate change-induced increase in the intensity of floods and droughts. Moreover, the success in relating parameters of river flow variability to species' distributions highlights the need to include river flow data in climate change impact models of species' distributions. PMID- 24340095 TI - The urotensin system is up-regulated in the pre-hypertensive spontaneously hypertensive rat. AB - Urotensin II (UII) concentrations are raised both in humans with hypertension and in spontaneously hypertensive rats (SHR). Since the urotensin system acts to regulate glomerular filtration in the kidney it may play a greater role in the pre-hypertensive SHR in which renal dysfunction is known to precede the onset of severe hypertension. This study aimed to determine the renal actions and expression of the urotensin system in the young SHR. Intravenous rat UII (6 pmol. min(-1). 100 g body weight(-1)) had no significant effect on GFR; however urotensin-related peptide (URP) reduced GFR (P<0.05) in 4-5 week old SHR. Administration of the UT antagonist SB-706375 evoked marked increases in GFR (baseline 0.38 +/- 0.07 vs antagonist 0.76 +/- 0.05 ml. min(-1). 100 g body weight(-1), P<0.05), urine flow and sodium excretion (baseline 2.5 +/- 0.4 vs antagonist 9.1 +/- 2.1 umol. min(-1). 100 g body weight(-1), P<0.05) in the SHR. Normotensive Wistar-Kyoto rats showed little response to UT antagonism. Quantitative RT-PCR showed that neither UII nor UT mRNA expression differed between the kidneys of young SHR and WKY rats; however expression of URP was 4 fold higher in the SHR kidney. Renal transcriptional up-regulation indicates that URP is the major UT ligand in young SHR and WKY rats. Enhanced tonic UT activation may contribute to known renal dysfunction in pre-hypertensive SHR. PMID- 24340096 TI - Mechanisms of rapid reactive oxygen species generation in response to cytosolic Ca2+ or Zn2+ loads in cortical neurons. AB - Excessive "excitotoxic" accumulation of Ca(2+) and Zn(2+) within neurons contributes to neurodegeneration in pathological conditions including ischemia. Putative early targets of these ions, both of which are linked to increased reactive oxygen species (ROS) generation, are mitochondria and the cytosolic enzyme, NADPH oxidase (NOX). The present study uses primary cortical neuronal cultures to examine respective contributions of mitochondria and NOX to ROS generation in response to Ca(2+) or Zn(2+) loading. Induction of rapid cytosolic accumulation of either Ca(2+) (via NMDA exposure) or Zn(2+) (via Zn(2+)/Pyrithione exposure in 0 Ca(2+)) caused sharp cytosolic rises in these ions, as well as a strong and rapid increase in ROS generation. Inhibition of NOX activation significantly reduced the Ca(2+)-induced ROS production with little effect on the Zn(2+)- triggered ROS generation. Conversely, dissipation of the mitochondrial electrochemical gradient increased the cytosolic Ca(2+) or Zn(2+) rises caused by these exposures, consistent with inhibition of mitochondrial uptake of these ions. However, such disruption of mitochondrial function markedly suppressed the Zn(2+)-triggered ROS, while partially attenuating the Ca(2+) triggered ROS. Furthermore, block of the mitochondrial Ca(2+) uniporter (MCU), through which Zn(2+) as well as Ca(2+) can enter the mitochondrial matrix, substantially diminished Zn(2+) triggered ROS production, suggesting that the ROS generation occurs specifically in response to Zn(2+) entry into mitochondria. Finally, in the presence of the sulfhydryl-oxidizing agent 2,2'-dithiodipyridine, which impairs Zn(2+) binding to cytosolic metalloproteins, far lower Zn(2+) exposures were able to induce mitochondrial Zn(2+) uptake and consequent ROS generation. Thus, whereas rapid acute accumulation of Zn(2+) and Ca(2+) each can trigger injurious ROS generation, Zn(2+) entry into mitochondria via the MCU may do so with particular potency. This may be of particular relevance to conditions like ischemia in which cytosolic Zn(2+) buffering is impaired due to acidosis and oxidative stress. PMID- 24340097 TI - Modeling the dynamics of a non-limited and a self-limited gene drive system in structured Aedes aegypti populations. AB - Recently there have been significant advances in research on genetic strategies to control populations of disease-vectoring insects. Some of these strategies use the gene drive properties of selfish genetic elements to spread physically linked anti-pathogen genes into local vector populations. Because of the potential of these selfish elements to spread through populations, control approaches based on these strategies must be carefully evaluated to ensure a balance between the desirable spread of the refractoriness-conferring genetic cargo and the avoidance of potentially unwanted outcomes such as spread to non-target populations. There is also a need to develop better estimates of the economics of such releases. We present here an evaluation of two such strategies using a biologically realistic mathematical model that simulates the resident Aedes aegypti mosquito population of Iquitos, Peru. One strategy uses the selfish element Medea, a non-limited element that could permanently spread over a large geographic area; the other strategy relies on Killer-Rescue genetic constructs, and has been predicted to have limited spatial and temporal spread. We simulate various operational approaches for deploying these genetic strategies, and quantify the optimal number of released transgenic mosquitoes needed to achieve definitive spread of Medea-linked genes and/or high frequencies of Killer-Rescue-associated elements. We show that for both strategies the most efficient approach for achieving spread of anti-pathogen genes within three years is generally to release adults of both sexes in multiple releases over time. Even though females in these releases should not transmit disease, there could be public concern over such releases, making the less efficient male-only release more practical. This study provides guidelines for operational approaches to population replacement genetic strategies, as well as illustrates the use of detailed spatial models to assist in safe and efficient implementation of such novel genetic strategies. PMID- 24340098 TI - Leptin inhibits glucose intestinal absorption via PKC, p38MAPK, PI3K and MEK/ERK. AB - The role of leptin in controlling food intake and body weight is well recognized, but whether this is achieved by modulating nutrient absorption is still a controversial issue. The aim of this work was to investigate the direct effect of luminal leptin on glucose intestinal absorption and elucidate for the first time its signaling pathway. Fully differentiated Caco-2 cells grown on transwell filters were used for glucose transport studies. Leptin caused a significant reduction in glucose absorption. Individual and simultaneous inhibition of ERK, p38MAPK, PI3K or PKC abrogated completely the inhibitory effect of leptin. Activating PKC, lead to a stimulatory effect that appeared only when ERK, p38MAPK, or PI3K was inactive. Moreover, leptin increased the phosphorylation of ERK, Akt and p38MAPK. This increase changed into a decrease when p38MAPK and PKC were inactivated individually. Inhibiting ERK maintained the leptin-induced up regulation of p-Akt and p-p38MAPK while inhibiting PI3K reduced the level of p ERK and p-Akt but maintained the increase in p-p38MAPK. These results suggest that leptin reduces glucose absorption by activating PKC. Although the latter modulates glucose absorption via a stimulatory and an inhibitory pathway, only the latter is involved in leptin's action. Active PKC leads to a sequential activation of p38MAPK, PI3K and ERK which exerts an inhibitory effect on glucose absorption. The results reveal a modulatory role of leptin in nutrient absorption in addition to its known satiety inducing effect. PMID- 24340099 TI - Economic evaluation of first-line adjuvant chemotherapies for resectable gastric cancer patients in China. AB - BACKGROUND: First-line postoperative adjuvant chemotherapies with S-1 and capecitabine and oxaliplatin (XELOX) were first recommended for resectable gastric cancer patients in the 2010 and 2011 Chinese NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer; however, their economic impact in China is unknown. OBJECTIVE: The aim of this study was to compare the cost effectiveness of adjuvant chemotherapy with XELOX, with S-1 and no treatment after a gastrectomy with extended (D2) lymph-node dissection among patients with stage II-IIIB gastric cancer. METHODS: A Markov model, based on data from two clinical phase III trials, was developed to analyse the cost-effectiveness of patients in the XELOX group, S-1 group and surgery only (SO) group. The costs were estimated from the perspective of Chinese healthcare system. The utilities were assumed on the basis of previously published reports. Costs, quality adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICER) were calculated with a lifetime horizon. One-way and probabilistic sensitivity analyses were performed. RESULTS: For the base case, XELOX had the lowest total cost ($44,568) and cost-effectiveness ratio ($7,360/QALY). The relative scenario analyses showed that SO was dominated by XELOX and the ICERs of S-1 was $58,843/QALY compared with XELOX. The one-way sensitivity analysis showed that the most influential parameter was the utility of disease-free survival. The probabilistic sensitivity analysis predicted a 75.8% likelihood that the ICER for XELOX would be less than $13,527 compared with S-1. When ICER was more than $38,000, the likelihood of cost-effectiveness achieved by S-1 group was greater than 50%. CONCLUSIONS: Our results suggest that for patients in China with resectable disease, first-line adjuvant chemotherapy with XELOX after a D2 gastrectomy is a best option comparing with S-1 and SO in view of our current study. In addition, S-1 might be a better choice, especially with a higher value of willingness-to-pay threshold. PMID- 24340100 TI - Risk levels of invasive Fusarium oxysporum f. sp. in areas suitable for date palm (Phoenix dactylifera) cultivation under various climate change projections. AB - Global climate model outputs involve uncertainties in prediction, which could be reduced by identifying agreements between the output results of different models, covering all assumptions included in each. Fusarium oxysporum f.sp. is an invasive pathogen that poses risk to date palm cultivation, among other crops. Therefore, in this study, the future distribution of invasive Fusarium oxysporum f.sp., confirmed by CSIRO-Mk3.0 (CS) and MIROC-H (MR) GCMs, was modeled and combined with the future distribution of date palm predicted by the same GCMs, to identify areas suitable for date palm cultivation with different risk levels of invasive Fusarium oxysporum f.sp., for 2030, 2050, 2070 and 2100. Results showed that 40%, 37%, 33% and 28% areas projected to become highly conducive to date palm are under high risk of its lethal fungus, compared with 37%, 39%, 43% and 42% under low risk, for the chosen years respectively. Our study also indicates that areas with marginal risk will be limited to 231, 212, 186 and 172 million hectares by 2030, 2050, 2070 and 2100. The study further demonstrates that CLIMEX outputs refined by a combination of different GCMs results of different species that have symbiosis or parasite relationship, ensure that the predictions become robust, rather than producing hypothetical findings, limited purely to publication. PMID- 24340101 TI - Differentiation and migration of bone marrow mesenchymal stem cells transplanted through the spleen in rats with portal hypertension. AB - AIMS: The goals of this paper were to evaluate the differentiation of bone marrow mesenchymal stem cells (BMSCs) into hepatocyte-like cells in vitro, and to determine whether stem cells can migrate and plant into the liver with portal hypertension accompanied by the end-stage of liver disease. METHODS: BMSCs were isolated from rats and amplified with hepatocyte growth factor (HGF) and fibroblast growth factor-4 (FGF-4). The expression of alpha-fetoprotein (AFP), cytokeratin 18 (CK-18), and albumin (ALB) was detected by immunofluorescence in induced cells. Rats were randomly divided into experimental (with common bile duct ligation) and control groups. After injection of fluorescence labeled cells, cell distribution was observed under a fluorescence microscope. The integrated optical density (IOD) and cell distribution scores were evaluated using Image-Pro Plus 6.0 software. The portal pressure was measured before the rats were killed. RESULTS: After being induced with HGF and FGF-4, the Golgi apparatus, endoplasmic reticulum, ribosomes, and mitochondria all significantly increased in the fifth generation cells. Immunofluorescent analysis showed that the induced cells expressed AFP, CK-18, and ALB. BMSCs were stained by CM-Dil, and the labeling rate was as high as 95.5%. The portal pressure in experimental group was much higher than that of the control group (18.04+/-2.35 vs. 9.75+/-1.40 cm H2O p<0.01). The IOD of transplanted cells in the experimental group was also significantly higher than that of the control group (11.30+/-2.09*10(5) vs. 2.93+/-0.88*10(5), p<0.01). In addition, the cell distribution score in the experimental group was lower than that of the control group (1.99+/-0.36 vs. 2.36+/-0.27, P<0.05). CONCLUSIONS: The combination of HGF and FGF-4 induces the differentiation of BMSCs into hepatocyte-like cells, which express AFP, CK-18, and ALB. In addition, the recruitment of BMSCs (after transplantation in the spleen) was improved in rats with portal hypertension. PMID- 24340102 TI - Simple method for Shiga toxin 2e purification by affinity chromatography via binding to the divinyl sulfone group. AB - Here we describe a simple affinity purification method for Shiga toxin 2e (Stx2e), a major causative factor of edema disease in swine. Escherichia coli strain MV1184 transformed with the expression plasmid pBSK-Stx2e produced Stx2e when cultivated in CAYE broth containing lincomycin. Stx2e bound to commercial D galactose gel, containing alpha-D-galactose immobilized on agarose resin via a divinyl sulfone linker, and was eluted with phosphate-buffered saline containing 4.5 M MgCl2. A small amount of Stx2e bound to another commercial alpha-galactose immobilized agarose resin, but not to beta-galactose-immobilized resin. In addition, Stx2e bound to thiophilic adsorbent resin containing beta mercaptoethanol immobilized on agarose resin via a divinyl sulfone, and was purified in the same manner as from D-galactose gel, but the Stx2e sample contained some contamination. These results indicate that Stx2e bound to D galactose gel mainly through the divinyl sulfone group on the resin and to a lesser extent through alpha-D-galactose. With these methods, the yields of Stx2e and attenuated mutant Stx2e (mStx2e) from 1 L of culture were approximately 36 mg and 27.7 mg, respectively, and the binding capacity of the D-galactose gel and thiophilic adsorbent resin for Stx2e was at least 20 mg per 1 ml of resin. In addition, using chimeric toxins with prototype Stx2 which did not bind to thiophilic adsorbent resin and some types of mutant Stx2e and Stx2 which contained inserted mutations in the B subunits, we found that, at the least, asparagine (amino acid 17 of the B subunits) was associated with Stx2e binding to the divinyl sulfone group. The mStx2e that was isolated exhibited vaccine effects in ICR mice, indicating that these methods are beneficial for large-scale preparation of Stx2e toxoid, which protects swine from edema disease. PMID- 24340103 TI - Dietary methionine intake and risk of incident colorectal cancer: a meta-analysis of 8 prospective studies involving 431,029 participants. AB - BACKGROUND: Methionine is one of the key components of one carbon metabolism. Experimental studies indicate that methionine may reduce inflammation-induced colon cancer. However, epidemiologic findings as to whether dietary methionine intake influences colorectal cancer incidence in humans are inconsistent. OBJECTIVE: To investigate the relationship between dietary methionine intake and risk of colorectal cancer by performing a meta-analysis of prospective studies. METHODS: Eligible studies were identified by searching PubMed and Embase and by reviewing the bibliographies of the retrieved publications. The summary risk estimates were computed using both a random- effects and a fixed-effects model. RESULTS: Eight eligible prospective cohort studies involving 431,029 participants and 6,331 colorectal cancer cases were identified. According to the random effects model, the summary relative risks (RRs) for the highest compared with the lowest intake of methionine were 0.89 (95% confidence interval [CI] = 0.77-1.03) for colorectal cancer, 0.77 (95% CI = 0.64-0.92) for colon cancer, and 0.88 (95% CI = 0.55-1.42) for rectal cancer. In the stratified analysis, a significant inverse association between dietary methionine intake and risk of colorectal cancer was observed in studies with longer follow-up time (RR=0.81, 95% CI= 0.70 0.95), in Western studies (RR= 0.83, 95% CI = 0.73-0.95) and in men (RR = 0.75, 95% CI= 0.57-0.99). We found no indication of publication bias. CONCLUSION: This meta-analysis indicates that dietary methionine intake may be associated with decreased risk of colorectal cancer, especially colon cancer. More prospective studies with long follow-up time are needed to confirm these findings. PMID- 24340104 TI - Revisiting Surface-Enhanced Raman Scattering on Realistic Lithographic Gold Nanostripes. AB - In this article, we investigate the Surface-Enhanced Raman Scattering (SERS) efficiency of methylene blue (MB) molecules deposited on gold nanostripes which, due to their fabrication by electron beam lithography and thermal evaporation, present various degrees of crystallinity and nanoscale surface roughness (NSR). By comparing gold nanostructures with different degrees of roughness and crystallinity, we show that the NSR has a strong effect on the SERS intensity of MB probe molecules. In particular, the NSR features of the lithographic structures significantly enhance the Raman signal of MB molecules, even when the excitation wavelength lies far from the localized surface plasmon resonance (LSPR) of the stripes. These results are in very good agreement with numerical calculations of the SERS gain obtained using the discrete dipole approximation (DDA). The influence of NSR on the optical near-field response of lithographic structures thus appears crucial since they are widely used in the context of nano optics or/and molecular sensing. PMID- 24340105 TI - Over-expression of 60s ribosomal L23a is associated with cellular proliferation in SAG resistant clinical isolates of Leishmania donovani. AB - BACKGROUND: Sodium antimony gluconate (SAG) unresponsiveness of Leishmania donovani (Ld) had effectively compromised the chemotherapeutic potential of SAG. 60s ribosomal L23a (60sRL23a), identified as one of the over-expressed protein in different resistant strains of L.donovani as observed with differential proteomics studies indicates towards its possible involvement in SAG resistance in L.donovani. In the present study 60sRL23a has been characterized for its probable association with SAG resistance mechanism. METHODOLOGY AND PRINCIPAL FINDINGS: The expression profile of 60s ribosomal L23a (60sRL23a) was checked in different SAG resistant as well as sensitive strains of L.donovani clinical isolates by real-time PCR and western blotting and was found to be up-regulated in resistant strains. Ld60sRL23a was cloned, expressed in E.coli system and purified for raising antibody in swiss mice and was observed to have cytosolic localization in L.donovani. 60sRL23a was further over-expressed in sensitive strain of L.donovani to check its sensitivity profile against SAG (Sb V and III) and was found to be altered towards the resistant mode. CONCLUSION/SIGNIFICANCE: This study reports for the first time that the over expression of 60sRL23a in SAG sensitive parasite decreases the sensitivity of the parasite towards SAG, miltefosine and paramomycin. Growth curve of the tranfectants further indicated the proliferative potential of 60sRL23a assisting the parasite survival and reaffirming the extra ribosomal role of 60sRL23a. The study thus indicates towards the role of the protein in lowering and redistributing the drug pressure by increased proliferation of parasites and warrants further longitudinal study to understand the underlying mechanism. PMID- 24340106 TI - The burden of cholera in Uganda. AB - INTRODUCTION: In 2010, the World Health Organization released a new cholera vaccine position paper, which recommended the use of cholera vaccines in high risk endemic areas. However, there is a paucity of data on the burden of cholera in endemic countries. This article reviewed available cholera surveillance data from Uganda and assessed the sufficiency of these data to inform country-specific strategies for cholera vaccination. METHODS: The Uganda Ministry of Health conducts cholera surveillance to guide cholera outbreak control activities. This includes reporting the number of cases based on a standardized clinical definition plus systematic laboratory testing of stool samples from suspected cases at the outset and conclusion of outbreaks. This retrospective study analyzes available data by district and by age to estimate incidence rates. Since surveillance activities focus on more severe hospitalized cases and deaths, a sensitivity analysis was conducted to estimate the number of non-severe cases and unrecognized deaths that may not have been captured. RESULTS: Cholera affected all ages, but the geographic distribution of the disease was very heterogeneous in Uganda. We estimated that an average of about 11,000 cholera cases occurred in Uganda each year, which led to approximately 61-182 deaths. The majority of these cases (81%) occurred in a relatively small number of districts comprising just 24% of Uganda's total population. These districts included rural areas bordering the Democratic Republic of Congo, South Sudan, and Kenya as well as the slums of Kampala city. When outbreaks occurred, the average duration was about 15 weeks with a range of 4-44 weeks. DISCUSSION: There is a clear subdivision between high risk and low-risk districts in Uganda. Vaccination efforts should be focused on the high-risk population. However, enhanced or sentinel surveillance activities should be undertaken to better quantify the endemic disease burden and high-risk populations prior to introducing the vaccine. PMID- 24340107 TI - On-chip imaging of Schistosoma haematobium eggs in urine for diagnosis by computer vision. AB - BACKGROUND: Microscopy, being relatively easy to perform at low cost, is the universal diagnostic method for detection of most globally important parasitic infections. As quality control is hard to maintain, misdiagnosis is common, which affects both estimates of parasite burdens and patient care. Novel techniques for high-resolution imaging and image transfer over data networks may offer solutions to these problems through provision of education, quality assurance and diagnostics. Imaging can be done directly on image sensor chips, a technique possible to exploit commercially for the development of inexpensive "mini microscopes". Images can be transferred for analysis both visually and by computer vision both at point-of-care and at remote locations. METHODS/PRINCIPAL FINDINGS: Here we describe imaging of helminth eggs using mini-microscopes constructed from webcams and mobile phone cameras. The results show that an inexpensive webcam, stripped off its optics to allow direct application of the test sample on the exposed surface of the sensor, yields images of Schistosoma haematobium eggs, which can be identified visually. Using a highly specific image pattern recognition algorithm, 4 out of 5 eggs observed visually could be identified. CONCLUSIONS/SIGNIFICANCE: As proof of concept we show that an inexpensive imaging device, such as a webcam, may be easily modified into a microscope, for the detection of helminth eggs based on on-chip imaging. Furthermore, algorithms for helminth egg detection by machine vision can be generated for automated diagnostics. The results can be exploited for constructing simple imaging devices for low-cost diagnostics of urogenital schistosomiasis and other neglected tropical infectious diseases. PMID- 24340108 TI - Biochemical diversity in the Trypanosoma congolense trans-sialidase family. AB - Trans-sialidases are key enzymes in the life cycle of African trypanosomes in both, mammalian host and insect vector and have been associated with the disease trypanosomiasis, namely sleeping sickness and nagana. Besides the previously reported TconTS1, we have identified three additional active trans-sialidases, TconTS2, TconTS3 and TconTS4, and three trans-sialidase like genes in Trypanosoma congolense. At least TconTS1, TconTS2 and TconTS4 are found in the bloodstream of infected animals. We have characterised the enzymatic properties of recombinant proteins expressed in eukaryotic fibroblasts using fetuin as model blood glycoprotein donor substrate. One of the recombinant trans-sialidases, TconTS2, had the highest specific activity reported thus far with very low sialidase activity. The active trans-sialidases share all the amino acids critical for the catalytic reaction with few variations in the predicted binding site for the leaving or acceptor glycan. However, these differences cannot explain the orders of magnitudes between their transfer activities, which must be due to other unidentified structural features of the proteins or substrates selectivity. Interestingly, the phylogenetic relationships between the lectin domains correlate with their specific trans-sialylation activities. This raises the question whether and how the lectin domains regulate the trans-sialidase reaction. The identification and enzymatic characterisation of the trans sialidase family in T. congolense will contribute significantly towards the understanding of the roles of these enzymes in the pathogenesis of Animal African Trypanosomiasis. PMID- 24340109 TI - Individual correlates of podoconiosis in areas of varying endemicity: a case control study. AB - BACKGROUND: Podoconiosis is a non-filarial form of elephantiasis resulting in lymphedema of the lower legs. Previous studies have suggested that podoconiosis arises from the interplay of individual and environmental factors. Here, our aim was to understand the individual-level correlates of podoconiosis by comparing 460 podoconiosis-affected individuals and 707 unaffected controls. METHODS/PRINCIPAL FINDINGS: This was a case-control study carried out in six kebeles (the lowest governmental administrative unit) in northern Ethiopia. Each kebele was classified into one of three endemicity levels: 'low' (prevalence <1%), 'medium' (1-5%) and 'high' (>5%). A total of 142 (30.7%) households had two or more cases of podoconiosis. Compared to controls, the majority of the cases, especially women, were less educated (OR = 1.7, 95% CI = 1.3 to 2.2), were unmarried (OR = 3.4, 95% CI = 2.6-4.6) and had lower income (t = -4.4, p<0.0001). On average, cases started wearing shoes ten years later than controls. Among cases, age of first wearing shoes was positively correlated with age of onset of podoconiosis (r = 0.6, t = 12.5, p<0.0001). Among all study participants average duration of shoe wearing was less than 30 years. Between both cases and controls, people in 'high' and 'medium' endemicity kebeles were less likely than people in 'low' endemicity areas to 'ever' have owned shoes (OR = 0.5, 95% CI = 0.4-0.7). CONCLUSIONS: Late use of shoes, usually after the onset of podoconiosis, and inequalities in education, income and marriage were found among cases, particularly among females. There were clustering of cases within households, thus interventions against podoconiosis will benefit from household-targeted case tracing. Most importantly, we identified a secular increase in shoe-wearing over recent years, which may give opportunities to promote shoe-wearing without increasing stigma among those at high risk of podoconiosis. PMID- 24340110 TI - Soulamarin isolated from Calophyllum brasiliense (Clusiaceae) induces plasma membrane permeabilization of Trypanosoma cruzi and mytochondrial dysfunction. AB - Chagas disease is caused by the parasitic protozoan Trypanosoma cruzi. It has high mortality as well as morbidity rates and usually affects the poorer sections of the population. The development of new, less harmful and more effective drugs is a promising research target, since current standard treatments are highly toxic and administered for long periods. Fractioning of methanol (MeOH) extract of the stem bark of Calophyllum brasiliense (Clusiaceae) resulted in the isolation of the coumarin soulamarin, which was characterized by one- and two dimensional (1)H- and (13)C NMR spectroscopy as well as ESI mass spectrometry. All data obtained were consistent with a structure of 6-hydroxy-4-propyl-5-(3 hydroxy-2-methyl-1-oxobutyl)-6",6"-dimethylpyrane-[2",3":8,7]-benzopyran-2-one for soulamarin. Colorimetric MTT assays showed that soulamarin induces trypanocidal effects, and is also active against trypomastigotes. Hemolytic activity tests showed that soulamarin is unable to induce any observable damage to erythrocytes (cmax. = 1,300 uM). The lethal action of soulamarin against T. cruzi was investigated by using amino(4-(6-(amino(iminio)methyl)-1H-indol-2 yl)phenyl)methaniminium chloride (SYTOX Green and 1H,5H,11H,15H-Xantheno[2,3,4 ij:5,6,7-i'j']diquinolizin-18-ium, 9-[4-(chloromethyl)phenyl]-2,3,6,7,12,13,16,17 octahydro-chloride (MitoTracker Red) as fluorimetric probes. With the former, soulamarin showed dose-dependent permeability of the plasma membrane, relative to fully permeable Triton X-100-treated parasites. Spectrofluorimetric and fluorescence microscopy with the latter revealed that soulamarin also induced a strong depolarization (ca. 97%) of the mitochondrial membrane potential. These data demonstrate that the lethal action of soulamarin towards T. cruzi involves damages to the plasma membrane of the parasite and mitochondrial dysfunction without the additional generation of reactive oxygen species, which may have also contributed to the death of the parasites. Considering the unique mitochondrion of T. cruzi, secondary metabolites of plants affecting the bioenergetic system as soulamarin may contribute as scaffolds for the design of novel and selective drug candidates for neglected diseases, mainly Chagas disease. PMID- 24340111 TI - Elimination and eradication of neglected tropical diseases with mass drug administrations: a survey of experts. AB - BACKGROUND: Lymphatic filariasis, onchocerciasis, schistosomiasis, soil transmitted helminths, and trachoma are the five most prevalent neglected tropical diseases in the world, and each is frequently treated with mass drug administrations. We performed a survey of neglected tropical diseases experts to elicit their opinions on the role of mass drug administrations for the elimination of these infections. METHODOLOGY/PRINCIPAL FINDINGS: We sent an online survey to corresponding authors who had published an article about a neglected tropical disease from 2007 to 2011. Of 825 unique authors who were invited to complete the survey, 365 (44.2%) responded, including 234 (28.4%) who answered questions regarding one of the five most prevalent neglected tropical diseases. Respondents had varying opinions about the goals of programmatic activities for their chosen neglected tropical disease, with elimination or eradication identified as the most important goal by 87% of lymphatic filariasis respondents, 66% of onchocerciasis respondents, 55% of trachoma respondents, 24% of schistosomiasis respondents, and 21% of soil-transmitted helminth respondents. Mass drug administrations, other non-medication health measures, and education were generally thought to be more important for elimination than vector control, development of a new tool, or the presence of a secular trend. Drug resistance was thought to be a major limitation of mass drug administrations for all five neglected tropical diseases. Over half of respondents for lymphatic filariasis and trachoma thought that repeated mass drug administrations could eliminate infection within ten years of the initiation of mass treatments. CONCLUSIONS/SIGNIFICANCE: Respondents for lymphatic filariasis, onchocerciasis, and trachoma were more enthusiastic about the prospects of elimination and eradication than were respondents for schistosomiasis or soil-transmitted helminths. Mass drug administrations were generally believed to be among the most important factors for the success of elimination efforts for each of the five neglected tropical diseases, highlighting the opportunity for integrating drug distributions. PMID- 24340112 TI - Burden of Mycobacterium ulcerans disease (Buruli ulcer) and the underreporting ratio in the territory of Songololo, Democratic Republic of Congo. AB - BACKGROUND: Cutaneous infection by Mycobacterium ulcerans, also known as Buruli ulcer (BU), represents the third most common mycobacterial disease in the world after tuberculosis and leprosy. Data on the burden of BU disease in the Democratic Republic of Congo are scanty. This study aimed to estimate the prevalence rate and the distribution of BU in the Songololo Territory, and to assess the coverage of the existing hospital-based reporting system. METHODS: We conducted a cross-sectional survey (July-August 2008) using the door-to-door method simultaneously in the two rural health zones (RHZ) of the Songololo Territory (RHZ of Kimpese and Nsona-Mpangu), each containing twenty health areas. Cases were defined clinically as active BU and inactive BU in accordance with WHO case definitions. RESULTS: We detected 775 BU patients (259 active and 516 inactive) in a total population of 237,418 inhabitants. The overall prevalence of BU in Songololo Territory was 3.3/1000 inhabitants, varying from 0 to 27.5/1000 between health areas. Of the 259 patients with active BU, 18 (7%) had been reported in the hospital-based reporting system at Kimpese in the 6-8 months prior to the survey. CONCLUSION: The survey demonstrated a huge variation of prevalence between health areas in Songololo Territory and gross underreporting of BU cases in the hospital-based reporting system. Data obtained may contribute to better targeted and improved BU control interventions, and serve as a baseline for future assessments of the control program. PMID- 24340113 TI - Canada's neglected tropical disease research network: who's in the core-who's on the periphery? AB - BACKGROUND: This study designed and applied accessible yet systematic methods to generate baseline information about the patterns and structure of Canada's neglected tropical disease (NTD) research network; a network that, until recently, was formed and functioned on the periphery of strategic Canadian research funding. METHODOLOGY: MULTIPLE METHODS WERE USED TO CONDUCT THIS STUDY, INCLUDING: (1) a systematic bibliometric procedure to capture archival NTD publications and co-authorship data; (2) a country-level "core-periphery" network analysis to measure and map the structure of Canada's NTD co-authorship network including its size, density, cliques, and centralization; and (3) a statistical analysis to test the correlation between the position of countries in Canada's NTD network ("k-core measure") and the quantity and quality of research produced. PRINCIPAL FINDINGS: Over the past sixty years (1950-2010), Canadian researchers have contributed to 1,079 NTD publications, specializing in Leishmania, African sleeping sickness, and leprosy. Of this work, 70% of all first authors and co authors (n = 4,145) have been Canadian. Since the 1990s, however, a network of international co-authorship activity has been emerging, with representation of researchers from 62 different countries; largely researchers from OECD countries (e.g. United States and United Kingdom) and some non-OECD countries (e.g. Brazil and Iran). Canada has a core-periphery NTD international research structure, with a densely connected group of OECD countries and some African nations, such as Uganda and Kenya. Sitting predominantly on the periphery of this research network is a cluster of 16 non-OECD nations that fall within the lowest GDP percentile of the network. CONCLUSION/SIGNIFICANCE: The publication specialties, composition, and position of NTD researchers within Canada's NTD country network provide evidence that while Canadian researchers currently remain the overall gatekeepers of the NTD research they generate; there is opportunity to leverage existing research collaborations and help advance regions and NTD areas that are currently under-developed. PMID- 24340114 TI - De novo assembly of a field isolate genome reveals novel Plasmodium vivax erythrocyte invasion genes. AB - Recent sequencing of Plasmodium vivax field isolates and monkey-adapted strains enabled characterization of SNPs throughout the genome. These analyses relied on mapping short reads onto the P. vivax reference genome that was generated using DNA from the monkey-adapted strain Salvador I. Any genomic locus deleted in this strain would be lacking in the reference genome sequence and missed in previous analyses. Here, we report de novo assembly of a P. vivax field isolate genome. Out of 2,857 assembled contigs, we identify 362 contigs, each containing more than 5 kb of contiguous DNA sequences absent from the reference genome sequence. These novel P. vivax DNA sequences account for 3.8 million nucleotides and contain 792 predicted genes. Most of these contigs contain members of multigene families and likely originate from telomeric regions. Interestingly, we identify two contigs containing predicted protein coding genes similar to known Plasmodium red blood cell invasion proteins. One gene encodes the reticulocyte-binding protein gene orthologous to P. cynomolgi RBP2e and P. knowlesi NBPXb. The second gene harbors all the hallmarks of a Plasmodium erythrocyte-binding protein, including conserved Duffy-binding like and C-terminus cysteine-rich domains. Phylogenetic analysis shows that this novel gene clusters separately from all known Plasmodium Duffy-binding protein genes. Additional analyses showing that this gene is present in most P. vivax genomes and transcribed in blood-stage parasites suggest that P. vivax red blood cell invasion mechanisms may be more complex than currently understood. The strategy employed here complements previous genomic analyses and takes full advantage of next-generation sequencing data to provide a comprehensive characterization of genetic variations in this important malaria parasite. Further analyses of the novel protein coding genes discovered through de novo assembly have the potential to identify genes that influence key aspects of P. vivax biology, including alternative mechanisms of human erythrocyte invasion. PMID- 24340115 TI - Characteristics of the human host have little influence on which local Schistosoma mansoni populations are acquired. AB - BACKGROUND: Brazil remains the country in the Americas with the highest prevalence of schistosomiasis. A combination of control efforts and development, however, has sharply reduced its intensity and distribution. The acquisition of specific schistosome populations may be dependent on host characteristics such as sex, age, geography, work, habits and culture. How these and other host characteristics align with parasite subpopulations may guide approaches to improve control. METHODOLOGY: A cohort of more than 90% of the residents in two rural communities in Brazil participated in an epidemiologic survey of demographic, socio-economic and behavioral characteristics. The variables sex, age, intensity of infection, socio-economic index, % lifetime spent on site, previous infection, and trips outside the district were used to group parasites infecting individuals. Schistosoma mansoni infection status was determined by examination of stools submitted on 3 different days. The aggregate of eggs collected from the whole stool was used to determine degree of population differentiation from allele frequencies for 15 microsatellites. CONCLUSIONS/SIGNIFICANCE: Infection prevalence was 41% for these communities, and the epidemiologic characteristics were similar to many of the endemic areas of Brazil and the world. Parasite population structuring was observed between the two communities (Jost's D 0.046, CI95% 0.042-0.051), although separated by only 8 km and connected by a highway. No structuring was observed when infected individuals were stratified by host's biologic, demographic or epidemiologic characteristics. Those most heavily infected best reflected the communities' overall parasite diversity. The lack of differentiation within villages suggests that individuals are likely to get infected at the same sites or that the same parasite multilocus genotypes can be found at most sites. The geographic structuring between villages and the lack of structuring by age of the host further supports the impression of a population little affected by migration or drift. PMID- 24340116 TI - Molecular identification of nocardia isolates from clinical samples and an overview of human nocardiosis in Brazil. AB - BACKGROUND: Nocardia sp. causes a variety of clinical presentations. The incidence of nocardiosis varies geographically according to several factors, such as the prevalence of HIV infections, transplants, neoplastic and rheumatic diseases, as well as climate, socio-economic conditions and laboratory procedures for Nocardia detection and identification. In Brazil the paucity of clinical reports of Nocardia infections suggests that this genus may be underestimated as a cause of human diseases and/or either neglected or misidentified in laboratory specimens. Accurate identification of Nocardia species has become increasingly important for clinical and epidemiological investigations. In this study, seven clinical Nocardia isolates were identified by multilocus sequence analysis (MLSA) and their antimicrobial susceptibility was also determined. Most Nocardia isolates were associated to pulmonary disease. METHODOLOGY/PRINCIPAL FINDINGS: The majority of Brazilian human isolates in cases reported in literature were identified as Nocardia sp. Molecular characterization was used for species identification of Nocardia nova, Nocardia cyriacigeorgica, Nocardia asiatica and Nocardia exalbida/gamkensis. Data indicated that molecular analysis provided a different Nocardia speciation than the initial biochemical identification for most Brazilian isolates. All Nocardia isolates showed susceptibility to trimethoprim-sulfamethoxazole, the antimicrobial of choice in the treatment nocardiosis. N. nova isolated from different clinical specimens from one patient showed identical antimicrobial susceptibility patterns and two distinct clones. CONCLUSIONS/SIGNIFICANCE: Although Brazil is the world's fifth-largest country in terms of land mass and population, pulmonary, extrapulmonary and systemic forms of nocardiosis were reported in only 6 of the 26 Brazilian states from 1970 to 2013. A least 33.8% of these 46 cases of nocardiosis proved fatal. Interestingly, coinfection by two clones may occur in patients presenting nocardiosis. Nocardia infection may be more common throughout the Brazilian territory and in other developing tropical countries than is currently recognized and MLSA should be used more extensively as an effective method for Nocardia identification. PMID- 24340117 TI - Knockdown of asparagine synthetase A renders Trypanosoma brucei auxotrophic to asparagine. AB - Asparagine synthetase (AS) catalyzes the ATP-dependent conversion of aspartate into asparagine using ammonia or glutamine as nitrogen source. There are two distinct types of AS, asparagine synthetase A (AS-A), known as strictly ammonia dependent, and asparagine synthetase B (AS-B), which can use either ammonia or glutamine. The absence of AS-A in humans, and its presence in trypanosomes, suggested AS-A as a potential drug target that deserved further investigation. We report the presence of functional AS-A in Trypanosoma cruzi (TcAS-A) and Trypanosoma brucei (TbAS-A): the purified enzymes convert L-aspartate into L asparagine in the presence of ATP, ammonia and Mg(2+). TcAS-A and TbAS-A use preferentially ammonia as a nitrogen donor, but surprisingly, can also use glutamine, a characteristic so far never described for any AS-A. TbAS-A knockdown by RNAi didn't affect in vitro growth of bloodstream forms of the parasite. However, growth was significantly impaired when TbAS-A knockdown parasites were cultured in medium with reduced levels of asparagine. As expected, mice infections with induced and non-induced T. brucei RNAi clones were similar to those from wild-type parasites. However, when induced T. brucei RNAi clones were injected in mice undergoing asparaginase treatment, which depletes blood asparagine, the mice exhibited lower parasitemia and a prolonged survival in comparison to similarly-treated mice infected with control parasites. Our results show that TbAS-A can be important under in vivo conditions when asparagine is limiting, but is unlikely to be suitable as a drug target. PMID- 24340118 TI - Dengue virus in sub-tropical northern and central Viet Nam: population immunity and climate shape patterns of viral invasion and maintenance. AB - Dengue virus transmission occurs in both epidemic and endemic cycles across tropical and sub-tropical regions of the world. Incidence is particularly high in much of Southeast Asia, where hyperendemic transmission plagues both urban and rural populations. However, endemicity has not been established in some areas with climates that may not support year-round viral transmission. An understanding of how dengue viruses (DENV) enter these environments and whether the viruses persist in inapparent local transmission cycles is central to understanding how dengue emerges in areas at the margins of endemic transmission. Dengue is highly endemic in tropical southern Vietnam, while increasingly large seasonal epidemics have occurred in northern Viet Nam over the last decade. We have investigated the spread of DENV-1 throughout Vietnam to determine the routes by which the virus enters northern and central regions of the country. Phylogeographic analysis of 1,765 envelope (E) gene sequences from Southeast Asia revealed frequent movement of DENV between neighboring human populations and strong local clustering of viral lineages. Long-distance migration of DENV between human population centers also occurred regularly and on short time scales, indicating human-mediated viral invasion into northern Vietnam. Human populations in southern Vietnam were found to be the primary source of DENV circulating throughout the country, while central and northern Vietnam acted as sink populations, likely due to reduced connectedness to other populations in the case of the central regions and to the influence of temperature variability on DENV replication and vector survival and competence in the north. Finally, phylogeographic analyses suggested that viral movement follows a gravity model and indicates that population immunity and physical and economic connections between populations may play important roles in shaping patterns of DENV transmission. PMID- 24340119 TI - Geographic distribution and genetic characterization of Lassa virus in sub Saharan Mali. AB - BACKGROUND: Lassa fever is an acute viral illness characterized by multi-organ failure and hemorrhagic manifestations. Lassa fever is most frequently diagnosed in Nigeria, Sierra Leone, Liberia, and Guinea, although sporadic cases have been recorded in other West African countries, including Mali. The etiological agent of Lassa fever is Lassa virus (LASV), an Arenavirus which is maintained in nature and frequently transmitted to humans by Mastomys natalensis. The purpose of this study was to better define the geographic distribution of LASV-infected rodents in sub-Saharan Mali. METHODOLOGIES/PRINCIPAL FINDINGS: Small mammals were live trapped at various locations across Mali for the purpose of identifying potential zoonotic pathogens. Serological and molecular assays were employed and determined LASV infected rodents were exclusively found in the southern Mali near the border of Cote d'Ivoire. Overall, 19.4% of Mastomys natalensis sampled in this region had evidence of LASV infection, with prevalence rates for individual villages ranging from 0 to 52%. Full-length genomic sequences were determined using high throughput sequencing methodologies for LASV isolates generated from tissue samples of rodents collected in four villages and confirmed the phylogenetic clustering of Malian LASV with strain AV. CONCLUSIONS/SIGNIFICANCE: The risk of human infections with LASV is greatest in villages in southern Mali. Lassa fever should be considered in the differential diagnosis for febrile individuals and appropriate diagnostic techniques need to be established to determine the incidence of infection and disease in these regions. PMID- 24340120 TI - Transmission assessment surveys (TAS) to define endpoints for lymphatic filariasis mass drug administration: a multicenter evaluation. AB - BACKGROUND: Lymphatic filariasis (LF) is targeted for global elimination through treatment of entire at-risk populations with repeated annual mass drug administration (MDA). Essential for program success is defining and confirming the appropriate endpoint for MDA when transmission is presumed to have reached a level low enough that it cannot be sustained even in the absence of drug intervention. Guidelines advanced by WHO call for a transmission assessment survey (TAS) to determine if MDA can be stopped within an LF evaluation unit (EU) after at least five effective rounds of annual treatment. To test the value and practicality of these guidelines, a multicenter operational research trial was undertaken in 11 countries covering various geographic and epidemiological settings. METHODOLOGY: The TAS was conducted twice in each EU with TAS-1 and TAS 2 approximately 24 months apart. Lot quality assurance sampling (LQAS) formed the basis of the TAS survey design but specific EU characteristics defined the survey site (school or community), eligible population (6-7 year olds or 1(st)-2(nd) graders), survey type (systematic or cluster-sampling), target sample size, and critical cutoff (a statistically powered threshold below which transmission is expected to be no longer sustainable). The primary diagnostic tools were the immunochromatographic (ICT) test for W. bancrofti EUs and the BmR1 test (Brugia Rapid or PanLF) for Brugia spp. EUs. PRINCIPAL FINDINGS/CONCLUSIONS: In 10 of 11 EUs, the number of TAS-1 positive cases was below the critical cutoff, indicating that MDA could be stopped. The same results were found in the follow-up TAS-2, therefore, confirming the previous decision outcome. Sample sizes were highly sex and age-representative and closely matched the target value after factoring in estimates of non-participation. The TAS was determined to be a practical and effective evaluation tool for stopping MDA although its validity for longer-term post-MDA surveillance requires further investigation. PMID- 24340121 TI - the intestinal expulsion of the roundworm Ascaris suum is associated with eosinophils, intra-epithelial T cells and decreased intestinal transit time. AB - Ascaris lumbricoides remains the most common endoparasite in humans, yet there is still very little information available about the immunological principles of protection, especially those directed against larval stages. Due to the natural host-parasite relationship, pigs infected with A. suum make an excellent model to study the mechanisms of protection against this nematode. In pigs, a self-cure reaction eliminates most larvae from the small intestine between 14 and 21 days post infection. In this study, we investigated the mucosal immune response leading to the expulsion of A. suum and the contribution of the hepato-tracheal migration. Self-cure was independent of previous passage through the liver or lungs, as infection with lung stage larvae did not impair self-cure. When animals were infected with 14-day-old intestinal larvae, the larvae were being driven distally in the small intestine around 7 days post infection but by 18 days post infection they re-inhabited the proximal part of the small intestine, indicating that more developed larvae can counter the expulsion mechanism. Self-cure was consistently associated with eosinophilia and intra-epithelial T cells in the jejunum. Furthermore, we identified increased gut movement as a possible mechanism of self-cure as the small intestinal transit time was markedly decreased at the time of expulsion of the worms. Taken together, these results shed new light on the mechanisms of self-cure that occur during A. suum infections. PMID- 24340122 TI - Estimating leptospirosis incidence using hospital-based surveillance and a population-based health care utilization survey in Tanzania. AB - BACKGROUND: The incidence of leptospirosis, a neglected zoonotic disease, is uncertain in Tanzania and much of sub-Saharan Africa, resulting in scarce data on which to prioritize resources for public health interventions and disease control. In this study, we estimate the incidence of leptospirosis in two districts in the Kilimanjaro Region of Tanzania. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a population-based household health care utilization survey in two districts in the Kilimanjaro Region of Tanzania and identified leptospirosis cases at two hospital-based fever sentinel surveillance sites in the Kilimanjaro Region. We used multipliers derived from the health care utilization survey and case numbers from hospital-based surveillance to calculate the incidence of leptospirosis. A total of 810 households were enrolled in the health care utilization survey and multipliers were derived based on responses to questions about health care seeking in the event of febrile illness. Of patients enrolled in fever surveillance over a 1 year period and residing in the 2 districts, 42 (7.14%) of 588 met the case definition for confirmed or probable leptospirosis. After applying multipliers to account for hospital selection, test sensitivity, and study enrollment, we estimated the overall incidence of leptospirosis ranges from 75-102 cases per 100,000 persons annually. CONCLUSIONS/SIGNIFICANCE: We calculated a high incidence of leptospirosis in two districts in the Kilimanjaro Region of Tanzania, where leptospirosis incidence was previously unknown. Multiplier methods, such as used in this study, may be a feasible method of improving availability of incidence estimates for neglected diseases, such as leptospirosis, in resource constrained settings. PMID- 24340124 TI - OXIDATIVE STRESS RESPONSE TO SHORT DURATION BOUT OF SUBMAXIMAL AEROBIC EXERCISE IN HEALTHY YOUNG ADULTS. AB - PURPOSE: The purpose of this study was to investigate the oxidative stress response to a short duration bout of submaximal exercise in a cohort of healthy young adults. METHODS: 15 apparently healthy college age males and females completed a modified Bruce-protocol treadmill test to 75-80% of their heart rate reserve. Blood samples collected immediately before (pre-exercise), immediately after, 30, 60 and 120 minutes post-exercise were assayed for total antioxidant capacity (TAC), superoxide disumutase (SOD), thiobarbituric acid-reactive substances (TBARS), and protein carbonyls (PC). RESULTS: SOD activity was significantly increased from pre-exercise levels at 30 minutes (77%), 60 minutes (33%), and 120 minutes (37%) post-exercise. TAC levels were also significantly increased from pre-exercise levels at 60 minutes (30%) and 120 minutes (33%) post exercise. There were no significant changes in biomarkers for reactive oxygen/nitrogen species (RONS) mediated damage (TBARS and PC) across all post exercise time points. CONCLUSIONS: In a cohort of healthy young adults, a short duration bout of submaximal aerobic exercise elicited increases in antioxidant activity/concentration, but did not evoke changes in oxidative stress-induced damage. These results may suggest that: (1) short duration bouts of submaximal aerobic exercise are sufficient to induce RONS generation; and (2) the antioxidant defense system is capable of protecting against enhanced RONS production induced by a short duration, submaximal exercise bout in healthy young adults. PMID- 24340123 TI - NLRP3 inflammasome activation by Paracoccidioides brasiliensis. AB - Paracoccidioides brasiliensis is the etiologic agent of paracoccidioidomycosis (PCM), the most prevalent systemic mycosis that is geographically confined to Latin America. The pro-inflammatory cytokine IL-1beta that is mainly derived from the activation of the cytoplasmic multiprotein complex inflammasome is an essential host factor against opportunistic fungal infections; however, its role in infection with a primary fungal pathogen, such as P. brasiliensis, is not well understood. In this study, we found that murine bone marrow-derived dendritic cells responded to P. brasiliensis yeast cells infection by releasing IL-1beta in a spleen tyrosine kinase (Syk), caspase-1 and NOD-like receptor (NLR) family member NLRP3 dependent manner. In addition, P. brasiliensis-induced NLRP3 inflammasome activation was dependent on potassium (K+) efflux, reactive oxygen species production, phagolysosomal acidification and cathepsin B release. Finally, using mice lacking the IL-1 receptor, we demonstrated that IL-1beta signaling has an important role in killing P. brasiliensis by murine macrophages. Altogether, our results demonstrate that the NLRP3 inflammasome senses and responds to P. brasiliensis yeast cells infection and plays an important role in host defense against this fungus. PMID- 24340125 TI - Lingual pyogenic granuloma gravidarum. PMID- 24340126 TI - Uterine vascular lesions. AB - Vascular lesions of the uterus are rare; most reported in the literature are arteriovenous malformations (AVMs). Uterine AVMs can be congenital or acquired. In recent years, there has been an increasing number of reports of acquired vascular lesions of the uterus following pregnancy, abortion, cesarean delivery, and curettage. It can be seen from these reports that there is confusion concerning the terminology of uterine vascular lesions. There is also a lack of diagnostic criteria and management guidelines, which has led to an increased number of unnecessary invasive procedures (eg, angiography, uterine artery embolization, hysterectomy for abnormal vaginal bleeding). This article familiarizes readers with various vascular lesions of the uterus and their management. PMID- 24340127 TI - Hyperperfusion syndrome after MCA embolectomy - a rare complication? AB - PATIENT: Female, 78 FINAL DIAGNOSIS: Cerebral hyperperfusion syndrome Symptoms: - MEDICATION: - Clinical Procedure: Endovascular embolectomy Specialty: Neurology. OBJECTIVE: Unknown ethiology. BACKGROUND: Cerebral hyperperfusion syndrome (cHS) is a well known but rare complication after carotid endarterectomy, carotid angioplasty with stenting, and stenting of intracranial arterial stenosis. The clinical presentation may vary from acute onset of focal oedema (stroke-like presentation) and intracerbral hemorrhage to delayed (>24h hours after the procedure) presentation with seizures, focal motor weakness, or late intracerebral hemorrhage. The incidence of cHS after carotid endarterectomy ranges from 0-3% and defined as an increase of the ipsilateral cerebral blood flow up to 40% over baseline in ultrasound. CASE REPORT: We present a case of a 78-year-old woman with an acute ischemic stroke due to left side middle cerebral artery territory with right sided hemiparesis and aphasia (NIHSS 16). After systemic thrombolysis embolectomy using a retractable stent (Solitaire((r)) device) was performed and resulted in complete and successful recanalization of MCA including its branches about 210 minutes after symptom onset but, partial dislocation of thrombotic material into the anterior cerebral artery (ACA). CONCLUSIONS: Cerebral hyperperfusion syndrome should be considered in patients with clinical deterioration after successful recanalisation and the early diagnosis and treatment may be important for neurological outcome after endovascular embolectomy. PMID- 24340128 TI - DRESS syndrome following ciprofloxacin exposure: An unusual association. AB - PATIENT: Female, 24 FINAL DIAGNOSIS: DRESS syndrome Symptoms: Fever * rash * facial and body swelling * muscular pain * diarrhea MEDICATION: Ciprofloxacin Clinical Procedure: - Specialty: Internal Medicine * Hematology. OBJECTIVE: Unusual or unexpected effect of treatment. BACKGROUND: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a rare, potentially life threatening drug reaction with a mean latency period of 3.9 weeks. It has been described in association with many medications; yet, Ciprofloxacin was reported once in literature to be the offending drug. We are presenting a rare case of Ciprofloxacin-induced DRESS syndrome with symptom onset 2 days after exposure. CASE REPORT: A 24-year-old female presented with symptoms suggestive of UTI and was prescribed Ciprofloxacin. Two days later she started to complain of fever, diffuse rash, swelling of her face, arms and flanks, watery diarrhea and muscular pain. Five days after symptom onset she presented to our institution with WBC count 38,810 cells/MUL and absolute Eosinophil count 17,080 cell/MUL. Peripheral blood smear showed immature Eosinophilic myelocytes and metamyelocytes. Skin biopsy showed superficial perivascular lymphocytic infiltration with dermal edema. Further workup was negative for parasitic infestations, HIV and viral hepatitis, allergic diseases, hematologic and non-hematologic malignancies, vasculitides and autoimmune processes. Ciprofloxacin was discontinued upon admission and the patient started to improve quickly. PATIENT was followed in clinic after 3 weeks and was completely asymptomatic with WBC count 7,250 cell/MUL and absolute Eosinophil count 2,900 cell/MUL. CONCLUSIONS: DRESS syndrome is a possible complication of Ciprofloxacin treatment that clinicians should consider. Shorter latency period might be a unique feature of Fluoroquinolone-induced DRESS syndrome. According to RegiSCAR scoring system, our case is categorized as (probable) with a score of (4). In fact, the vast majority of reported cases are classified as (probable/definite). PMID- 24340129 TI - Not another case of mono: Epstein-Barr virus (EBV) associate hemophagocytic lymphohistiocytosis (HLH). AB - PATIENT: Male, 30 FINAL DIAGNOSIS: Hemophagocytic lymphohistiocytosis (LHL) Symptoms: Abdominal pain * fever * hypotension * pancytopenia MEDICATION: - Clinical Procedure:- Specialty: Infectious Diseases. OBJECTIVE: Rare disease. BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a result of dysregulated cellular response system. Primary HLH is an autosomal recessive disorder of childhood, with defects in cellular cytotoxicity. Secondary HLH is an acquired syndrome that presents in young adulthood secondary to a variety of inflammatory conditions: viral infections, rheumatologic conditions, or malignant processes. The inflammatory nature of certain conditions triggers a cytokine release in individuals who have abnormal T cell activation. CASE REPORT: A 30-year-old Hispanic male presented with worsening abdominal pain for 5 months and was found to have fever, pancytopenia, and hypotension. Serial CT scans of the abdomen/pelvis showed splenomegaly but no abscesses, areas of infection, or masses. Infectious causes were considered but results of all cultures and tests were negative except for a high Epstein-Barr viral load. The patient deteriorated and required intubation on hospital day 28. Repeat bone marrow biopsy on day 32 suggested a diagnosis of hemophagocytic lymphohistiocytosis, although there was no evidence of hemophagocytosis within the bone marrow. The patient continued to deteriorate and was too unstable to receive treatment with chemotherapy. He died on hospital day 34. CONCLUSIONS: This case highlights the importance of early consideration and treatment of secondary HLH in an individual presenting with progressive fever, hepatomegaly, and cytopenias. PMID- 24340130 TI - Nucleation of Organic Molecules via a Hot Precursor State: Pentacene on Amorphous Mica. AB - Organic thin films have attracted considerable interest due to their applicability in organic electronics. The classical scenario for thin film nucleation is the diffusion-limited aggregation (DLA). Recently, it has been shown that organic thin film growth is better described by attachment-limited aggregation (ALA). However, in both cases, an unusual relationship between the island density and the substrate temperature was observed. Here, we present an aggregation model that goes beyond the classical DLA or ALA models to explain this behavior. We propose that the (hot) molecules impinging on the surface cannot immediately equilibrate to the substrate temperature but remain in a hot precursor state. In this state, the molecules can migrate considerable distances before attaching to a stable or unstable island. This results in a significantly smaller island density than expected by assuming fast equilibration and random diffusion. We have applied our model to pentacene film growth on amorphous Muscovite mica. PMID- 24340131 TI - Rethinking quasispecies theory: From fittest type to cooperative consortia. AB - Recent investigations surprisingly indicate that single RNA "stem-loops" operate solely by chemical laws that act without selective forces, and in contrast, self ligated consortia of RNA stem-loops operate by biological selection. To understand consortial RNA selection, the concept of single quasi-species and its mutant spectra as drivers of RNA variation and evolution is rethought here. Instead, we evaluate the current RNA world scenario in which consortia of cooperating RNA stem-loops (not individuals) are the basic players. We thus redefine quasispecies as RNA quasispecies consortia (qs-c) and argue that it has essential behavioral motifs that are relevant to the inherent variation, evolution and diversity in biology. We propose that qs-c is an especially innovative force. We apply qs-c thinking to RNA stem-loops and evaluate how it yields altered bulges and loops in the stem-loop regions, not as errors, but as a natural capability to generate diversity. This basic competence-not error-opens a variety of combinatorial possibilities which may alter and create new biological interactions, identities and newly emerged self identity (immunity) functions. Thus RNA stem-loops typically operate as cooperative modules, like members of social groups. From such qs-c of stem-loop groups we can trace a variety of RNA secondary structures such as ribozymes, viroids, viruses, mobile genetic elements as abundant infection derived agents that provide the stem-loop societies of small and long non-coding RNAs. PMID- 24340132 TI - Cathepsins mediate tumor metastasis. AB - Cathepsins are highly expressed in various human cancers, associated with tumor metastasis. It is superfamily, concluding A, B, C, D, E, F, G, H, L, K, O, S, V, and W family members. As a group of lysosomal proteinases or endopeptidases, each member has a different function, playing different roles in distinct tumorigenic processes such as proliferation, angiogenesis, metastasis, and invasion. Cathepsins belong to a diverse number of enzyme subtypes, including cysteine proteases, serine proteases and aspartic proteases. The contribution of cathepsins to invasion in human cancers is well documented, although the precise mechanisms by which cathepsins exert their effects are still not clear. In the present review, the role of cathepsin family members in cancer is discussed. PMID- 24340133 TI - Lipidomic mass spectrometry and its application in neuroscience. AB - Central and peripheral nervous systems are lipid rich tissues. Lipids, in the context of lipid-protein complexes, surround neurons and provide electrical insulation for transmission of signals allowing neurons to remain embedded within a conducting environment. Lipids play a key role in vesicle formation and fusion in synapses. They provide means of rapid signaling, cell motility and migration for astrocytes and other cell types that surround and play supporting roles neurons. Unlike many other signaling molecules, lipids are capable of multiple signaling events based on the different fragments generated from a single precursor during each event. Lipidomics, until recently suffered from two major disadvantages: (1) level of expertise required an overwhelming amount of chemical detail to correctly identify a vast number of different lipids which could be close in their chemical reactivity; and (2) high amount of purified compounds needed by analytical techniques to determine their structures. Advances in mass spectrometry have enabled overcoming these two limitations. Mass spectrometry offers a great degree of simplicity in identification and quantification of lipids directly extracted from complex biological mixtures. Mass spectrometers can be regarded to as mass analyzers. There are those that separate and analyze the product ion fragments in space (spatial) and those which separate product ions in time in the same space (temporal). Databases and standardized instrument parameters have further aided the capabilities of the spatial instruments while recent advances in bioinformatics have made the identification and quantification possible using temporal instruments. PMID- 24340134 TI - Adaptive and maladaptive expression of the mRNA regulatory protein HuR. AB - The RNA-binding proteins involved in regulation of mRNA post-transcriptional processing and translation control the fates of thousands of mRNA transcripts and basic cellular processes. The best studied of these, HuR, is well characterized as a mediator of mRNA stability and translation, and more recently, as a factor in nuclear functions such as pre-mRNA splicing. Due to HuR's role in regulating thousands of mRNA transcripts, including those for other RNA-binding proteins, HuR can act as a master regulator of cell survival and proliferation. HuR itself is subject to multiple post-translational modifications including regulation of its nucleocytoplasmic distribution. However, the mechanisms that govern HuR levels in the cell have only recently begun to be defined. These mechanisms are critical to cell health, as it has become clear in recent years that aberrant expression of HuR can lead alternately to decreased cell viability or to promotion of pathological proliferation and invasiveness. HuR is expressed as alternate mRNAs that vary in their untranslated regions, leading to differences in transcript stability and translatability. Multiple transcription factors and modulators of mRNA stability that regulate HuR mRNA expression have been identified. In addition, translation of HuR is regulated by numerous microRNAs, several of which have been demonstrated to have anti-tumor properties due to their suppression of HuR expression. This review summarizes the current state of knowledge of the factors that regulate HuR expression, along with the circumstances under which these factors contribute to cancer and inflammation. PMID- 24340135 TI - Effect of alcohol exposure on hepatic superoxide generation and hepcidin expression. AB - AIM: To understand the role of mitochondrial-produced superoxide (O2 (*-)) in the regulation of iron-regulatory hormone, hepcidin by alcohol in the liver. METHODS: For alcohol experiments, manganese superoxide dismutase knockout mice heterozygous for Sod2 gene expression (Sod2 (+/-)) and age-matched littermate control mice (LMC), expressing Sod2 gene on both alleles, were exposed to either 10% (w/v) ethanol in the drinking water or plain water (control) for 7 d. Total cellular O2 (*-) levels in hepatocytes isolated from the livers of mice were measured by electron paramagnetic resonance spectroscopy. The mitochondrial targeted, O2 (*-)-sensitive fluorogenic probe, MitoSOX Red and flow cytometry were utilized to measure O2 (*-) in mitochondria. Gene and protein expression were determined by Taqman Real-time quantitative PCR and Western blotting, respectively. RESULTS: Sod2 (+/-) mice expressed 40% less MnSOD protein (SOD2) in hepatocytes compared to LMC mice. The deletion of Sod2 allele did not alter the basal expression level of hepcidin in the liver. 10% ethanol exposure for 1 wk inhibited hepatic hepcidin mRNA expression three-fold both in Sod2 (+/-) and LMC mice. O2 (*-) levels in hepatocytes of untreated Sod2 (+/-) mice were three-fold higher than in untreated LMC mice, as observed by electron paramagnetic resonance spectroscopy. O2 (*-) levels in mitochondria of Sod2 (+/) mice were four-fold higher than in mitochondria of untreated LMC mice, as measured by MitoSOX Red fluorescence and flow cytometry. Alcohol induced a two-fold higher increase in O2 (*-) levels in hepatocytes of LMC mice than in Sod2 (+/-) mice compared to respective untreated counterparts. In contrast, 1 wk alcohol exposure did not alter mitochondrial O2 (*-) levels in both Sod2 (+/-) and control mice. CONCLUSION: Mitochondrial O2 (*-) is not involved in the inhibition of liver hepcidin transcription and thereby regulation of iron metabolism by alcohol. These findings also suggest that short-term alcohol consumption significantly elevates O2 (*-) levels in hepatocytes, which appears not to originate from mitochondria. PMID- 24340136 TI - High-density lipoprotein endocytosis in endothelial cells. AB - AIM: To describe the way stations of high-density lipoprotein (HDL) uptake and its lipid exchange in endothelial cells in vitro and in vivo. METHODS: A combination of fluorescence microscopy using novel fluorescent cholesterol surrogates and electron microscopy was used to analyze HDL endocytosis in great detail in primary human endothelial cells. Further, HDL uptake was quantified using radio-labeled HDL particles. To validate the in vitro findings mice were injected with fluorescently labeled HDL and particle uptake in the liver was analyzed using fluorescence microscopy. RESULTS: HDL uptake occurred via clathrin coated pits, tubular endosomes and multivesicular bodies in human umbilical vein endothelial cells. During uptake and resecretion, HDL-derived cholesterol was exchanged at a faster rate than cholesteryl oleate, resembling the HDL particle pathway seen in hepatic cells. In addition, lysosomes were not involved in this process and thus HDL degradation was not detectable. In vivo, we found HDL mainly localized in mouse hepatic endothelial cells. HDL was not detected in parenchymal liver cells, indicating that lipid transfer from HDL to hepatocytes occurs primarily via scavenger receptor, class B, type I mediated selective uptake without concomitant HDL endocytosis. CONCLUSION: HDL endocytosis occurs via clathrin-coated pits, tubular endosomes and multivesicular bodies in human endothelial cells. Mouse endothelial cells showed a similar HDL uptake pattern in vivo indicating that the endothelium is one major site of HDL endocytosis and transcytosis. PMID- 24340137 TI - Changes in aminoacidergic and monoaminergic neurotransmission in the hippocampus and amygdala of rats after ayahuasca ingestion. AB - AIM: To evaluate changes in neurotransmission induced by a psychoactive beverage ayahuasca in the hippocampus and amygdala of naive rats. METHODS: The level of monoamines, their main metabolites and amino acid neurotransmitters concentrations were quantified using high performance liquid chromatography (HPLC). Four groups of rats were employed: saline-treated and rats receiving 250, 500 and 800 mg/kg of ayahuasca infusion (gavage). Animals were killed 40 min after drug ingestion and the structures stored at -80 degrees C until HPLC assay. The data from all groups were compared using Analysis of variance and Scheffe as post test and P < 0.05 was accepted as significant. RESULTS: The results showed decreased concentrations of glycine (GLY) (0.13 +/- 0.03 vs 0.29 +/- 0.07, P < 0.001) and gamma-aminobutyric acid (GABA) (1.07 +/- 0.14 vs 1.73 +/ 0.25, P < 0.001) in the amygdala of rats that received 500 of ayahuasca. Animals that ingested 800 mg/kg of ayahuasca also showed a reduction of GLY level (0.11 +/- 0.01 vs 0.29 +/- 0.07, P < 0.001) and GABA (0.98 +/- 0.06 vs 1.73 +/- 0.25, P < 0.001). In the hippocampus, increased GABA levels were found in rats that received all ayahuasca doses: 250 mg/kg (1.29 +/- 0.19 vs 0.84 +/- 0.21, P < 0.05); 500 mg/kg (2.23 +/- 038 vs 084 +/- 0.21, P < 0.05) and 800 mg/kg (1.98 +/- 0.92 vs 0.84 +/- 0.21, P < 0.05). In addition, an increased utilization rate of all monoamines was found in the amygdala after ayahuasca administration in doses: 250 mg/kg (noradrenaline: 0.16 +/- 0.02 vs 0.36 +/- 0.06, P < 0.01; dopamine: 0.39 +/- 0.012 vs 2.39 +/- 0.84, P < 0.001; serotonin: 1.02 +/- 0.22 vs 4.04 +/- 0.91, P < 0.001), 500 mg/kg (noradrenaline: 0.08 +/- 0.02 vs 0.36 +/- 0.06, P < 0.001; dopamine: 0.33 +/- 0.19 vs 2.39 +/- 0.84, P < 0.001; serotonin: 0.59 +/- 0.08 vs 4.04 +/- 0.91, P < 0.001) and 800 mg/kg (noradrenaline: 0.16 +/- 0.04 vs 0.36 +/- 0.06, P < 0.001; dopamine: 0.84 +/- 0.65 vs 2.39 +/- 0.84, P < 0.05; serotonin: 0.36 +/- 0.02 vs 4.04 +/- 0.91, P < 0.001). CONCLUSION: Our data suggest increased release of inhibitory amino acids by the hippocampus and an increased utilization rate of monoamines by the amygdala after different doses of ayahuasca ingestion. PMID- 24340138 TI - Taurine supplementation in spontaneously hypertensive rats: Advantages and limitations for human applications. AB - Taurine (2-aminoethanesulfonic acid) is a beta-amino acid found in many tissues particularly brain, myocardium, and kidney. It plays several physiological roles including cardiac contraction, antioxidation, and blunting of hypertension. Though several lines of evidence indicate that dietary taurine can reduce hypertension in humans and in animal models, evidence that taurine supplementation reduces hypertension in humans has not been conclusive. One reason for the inconclusive nature of past studies may be that taurine having both positive and negative effects on cardiovascular system depending on when it is assessed, some effects may occur early, while others only appear later. Further, other consideration may play a role, e.g., taurine supplementation improves hypertension in spontaneously hypertensive rats on a low salt diet but fails to attenuate hypertension on a high salt diet. In humans, some epidemiologic studies indicate that people with high taurine and low salt diets display lower arterial pressure than those with low taurine and high salt diets. Differences in techniques for measuring arterial pressure, duration of treatment, and animal models likely affect the response in different studies. This review considers both the positive and negative effects of taurine on blood pressure in animal models and their applications for human interventions. PMID- 24340139 TI - The importance of avoiding unnecessary right ventricular pacing in clinical practice. AB - Symptomatic bradycardia is effectively treated with the implantation of a cardiac pacemaker. Although a highly successful therapy, during recent years there has been a focus on the negative effects associated with long-term pacing of the apex of the right ventricle (RV). It has been shown in both experimental and clinical studies that RV pacing leads to ventricular dyssynchrony, similar to that of left bundle branch block, with subsequent detrimental effects on cardiac structure and function, and in some cases adverse clinical outcomes such as atrial fibrillation, heart failure and death. There is substantial evidence that patients with reduced left ventricular function (LVEF) are at particular high risk of suffering the detrimental clinical effects of long-term RV pacing. The evidence is, however, incomplete, coming largely from subanalyses of pacemaker and implantable cardiac defibrillator studies. In this group of patients with reduced LVEF and an expected high amount of RV pacing, biventricular pacing (cardiac resynchronization therapy) devices can prevent the negative effects of RV pacing and reduce ventricular dyssynchrony. Therefore, cardiac resynchronization therapy has emerged as an attractive option with promising results and more clinical studies are underway. Furthermore, specific pacemaker algorithms, which minimize RV pacing, can also reduce the negative effects of RV stimulation on cardiac function and may prevent clinical deterioration. PMID- 24340140 TI - Trend in prevalence of uncontrolled total serum cholesterol for cardio-cerebro vascular disease in a mediterranean area, 1988/89-2008/09. AB - AIM: To examine trends of uncontrolled total serum cholesterol, treatment and control in a Mediterranean region (Campania). METHODS: We considered and compared the data collected as part of "Montecorvino Rovella Project" 1988-1989 and cross sectional data from the two phases of the "VIP Project-Valle dell'Irno Prevenzione": 1998-1999 (1(st) phase) and 2008-2009 (2(nd) phase), in the 35-74 year-old-population. RESULTS: Data show a reduction of mean cholesterolemia in the last twenty years of 7.3 mg/dL for men and unchanged values for women. In the three surveys the mean values for serum cholesterol are in men: 205.2 +/- 47.1 mg/dL (1988/89), 200 +/- 38.9 mg/dL (1998/99) and 197.9 +/- 40.2 mg/dL (2008/09); in the women: 203.1 +/- 42.5 mg/dL (1988/89), 198.9 +/- 37.9 mg/dL (1998/99) and 203.3 +/- 39.3 mg/dL (2008/09). Prevalence of uncontrolled high cholesterol >= 240 mg/dL for men decreased from 20.8% (1988/89) to 14.3% (1998/99) and 13.9% (2008/9), P = 0.002; for women the values decreased from 19.9% (1988/89), to 18.2% (1998/99) and 18.1% (2008/09), P = 0.007. Is statistically increased the number of patients treated and those treated to target. CONCLUSION: Encouraging increases in awareness, treatment, and control of hypercholesterolemia occurred from 1988 through 2008. Nevertheless, control of hypercholesterolemia remains poor. PMID- 24340141 TI - Positive influence of aspirin on coronary endothelial function: Importance of the dose. AB - AIM: To investigate the effects of different doses of aspirin on coronary endothelial function. METHODS: The study included 139 Japanese subjects (mean age, 60 years; 53 women) with angiographically normal coronary arteries. Patients were distributed into Group I (n = 63), who was administered aspirin and Group II (n = 76), the control, who were not administered aspirin. Group I was further divided into Group Ia (n = 50, low-dose aspirin, 100 mg) and Group Ib (n = 13, high-dose aspirin, 500 mg). After a routine coronary angiography, acetylcholine (ACh; 3 and 30 MUg/min successively) and nitroglycerin (NTG) were infused into the left coronary ostium over 2 min. The change in the diameter of the coronary artery in response to each drug was expressed as the percentage change from baseline values. RESULTS: The patient characteristics did not differ between the two groups. The change in coronary diameter in response to ACh was greater in Group I than in Group II (P = 0.0043), although the NTG-induced coronary vasodilation was similar between groups. ACh-induced dilation was greater in Group Ia than in Group Ib (P = 0.0231). Multivariate regression analysis showed that a low-dose of aspirin (P = 0.0004) was one of the factors associated with ACh-induced dilation at 30 MUg/min. CONCLUSION: In subjects with angiographically normal coronary arteries, aspirin only had a positive influence on coronary endothelial function at the low dose of 100 mg. This improvement of coronary endothelial function may be involved in the preventive effect of aspirin against future coronary events. PMID- 24340142 TI - Myocardial bridging analysis by coronary computed tomographic angiography in a Saudi population. AB - AIM: To assess the incidence, location, morphology and clinical association of myocardial bridging in a Saudi population using coronary computed tomographic angiography (CCTA). METHODS: A total of 350 CCTA of Saudi patients were included in this study (236 men, 114 women) with a mean age of 56.3 years. All patients were examined for appropriateness criteria of CCTA indications (typical chest pain, recent onset cardiomyopathy, left bundle branch block, etc.). The scans were retrospectively reviewed for the presence of myocardial bridging and any other pathological association. RESULTS: Myocardial bridging was found in 89 of 350 (22.5%) patients. Most of the intramuscular segments were of the superficial type and found in the mid left anterior descending (LAD) (24.6%), followed by distal LAD (3.7%), diagonal branches (2%), ramus intermedius artery (1.4%) and obtuse marginal artery (0.8%). No myocardial bridging was detected in the right coronary or circumflex arteries. No significant differences were found between males and females (P = 0.14). Coronary artery atherosclerosis was found in 51 of 89 (57.3%) patients with MB. Atherosclerotic plaques were not detected in the intramuscular or distal segment of bridging arteries. Dynamic compression was observed in 35 (94.5%) patients with full encasement. No evidence of myocardial hypoperfusion was found in the territories supplied by the bridging arteries. CONCLUSION: CCTA is excellent in analyzing myocardial bridging in a Saudi population and the results are comparable to other populations. However, finding the real incidence may need a large multicenter study. PMID- 24340143 TI - Uncommon indications for reverse total shoulder arthroplasty. AB - Total shoulder arthroplasty and shoulder hemiarthroplasty have been the traditional method for treating a variety of shoulder conditions, including arthritis, cuff tear arthropathy, and some fracture types. However, these procedures did not provide consistently good results for patients with torn rotator cuffs. The development of the reverse prosthesis by Grammont in the late 20th century revolutionized the treatment of the rotator-cuff-deficient shoulder with arthritis. The main indication for the reverse prosthesis remains the patient with cuff tear arthropathy who has pain and loss of motion. Because the reverse total shoulder arthroplasty produced such good results in these patients, the indications for the reverse prosthesis have expanded to include other shoulder conditions that have previously been difficult to treat successfully and predictably. This review discusses and critically reviews these newer indications for the reverse total shoulder arthroplasty. PMID- 24340145 TI - Treatment outcomes of open pelvic fractures associated with extensive perineal injuries. AB - BACKGROUND: The main causes of death in patients with open pelviperineal injuries are uncontrollable bleeding and pelvic sepsis. The aim of this study was to evaluate the management outcomes of open pelvic fractures associated with extensive perineal injuries. METHODS: We retrospectively studied 15 cases with open pelvic fractures associated with extensive perineal injuries (urethral and anal canal laceration) admitted between August 2006 and September 2010. Mechanism of injury, Injury Severity Score, associated injuries, hemodynamic status on arrival, resuscitation and transfusion requirements, operative techniques, intra- and postoperative complications, length of intensive care unit and hospital stay, and mortality were recorded in a computerised database for further evaluation and analysis. RESULTS: The male to female ratio was 12:3 with an average age of 38.6 years (ranged, 11 to 65 years). The average packed red blood cell units used were 8 units (ranged, 4 to 21 units). All patients were initially transferred to the operating room for colostomy, radical debridement and fixation of the pelvic fracture by an external fixator. One patient had acute renal failure, which improved with medical treatment and 2 patients (13.3%) died, one with type III anteroposterior compression fracture due to hemorrhagic shock and the other due to septicemia. CONCLUSIONS: Open pelvic fractures with extensive perineal injuries are associated with high mortality rates. Early diagnosis and appropriate treatment, including reanimation, colostomy, cystostomy, vigorous and repeated irrigation and debridement, and fixation by an external fixator can improve the outcomes and reduce the mortality rate. PMID- 24340144 TI - Posterior cruciate ligament: focus on conflicting issues. AB - There is little consensus on how to optimally reconstruct the posterior cruciate ligament (PCL) and the natural history of injured PCL is also unclear. The graft material (autograft vs. allograft), the type of tibial fixation (tibial inlay vs. transtibial tunnel), the femoral tunnel position within the femoral footprint (isometric, central, or eccentric), and the number of bundles in the reconstruction (1 bundle vs. 2 bundles) are among the many decisions that a surgeon must make in a PCL reconstruction. In addition, there is a paucity of information on rehabilitation after reconstruction of the PCL and posterolateral structures. This article focused on the conflicting issues regarding the PCL, and the scientific rationales behind some critical points are discussed. PMID- 24340146 TI - Sexual activity after total hip replacement in Korean patients: how they do, what they want, and how to improve. AB - BACKGROUND: Concerns of patients on sexual activity after total hip arthroplasty have not been well studied in Asian patients. This study aimed to determine the following: (1) what are the concerns of patients related to sexual activity after total hip arthroplasty? (2) what are the changes in sexual activity after total hip replacement in Korean patients? METHODS: Details of sexual activity and concerns were obtained using a questionnaire designed specifically for the study. The questionnaire was administered to 64 patients in a face-to-face interview at an outpatient clinic. RESULTS: Preoperatively, 53.1% of patients experienced difficulties, primarily due to hip pathology and limitations of motion. The median time to the resumption of sexual activity was 3 months postoperatively, and most patients had no increase in the frequency of sexual activity after the total hip replacement. In 39.1% of patients were seen having difficulties with leg positioning following total hip replacement, and they were likely to change coital positions. The most common concern regarding sexual activity of patients was the fear of dislocation. Furthermore, patients with a higher stress level had lower satisfaction rates. Most patients were unable to obtain information on sexual activity following the total hip arthroplasty, and they did not consult with a physician due to the private nature of the topic. CONCLUSIONS: Dislocation was the most common concern of patients during sexual activity following a total hip arthroplasty, and a higher stress level was found to be associated with a lower satisfaction rate. Because most patients were unprepared to consult a physician, the provision of appropriate information before a consultation might be beneficial. PMID- 24340147 TI - Remnant preservation is helpful to obtain good clinical results in posterior cruciate ligament reconstruction: comparison of clinical results of three techniques. AB - BACKGROUND: The purpose of the present study was to compare the clinical results of 3 posterior cruciate ligament reconstruction techniques according to the time from injury to surgery and remnant PCL status and to evaluate the efficiency of each technique. METHODS: The records of 89 patients who underwent primary PCL reconstructions with a posterolateral corner sling were analyzed retrospectively. Thirty-four patients were treated by anterolateral bundle (ALB) reconstruction with preservation of the remnant PCL using a transtibial tunnel technique in the acute and subacute stages of injury (group 1). Forty patients were treated with remnant PCL tensioning and an ALB reconstruction using the modified inlay technique in the chronic stage (group 2), and fifteen patients were treated with double-bundle reconstruction using the modified inlay technique (group 3). The double-bundle reconstruction was performed if there was a very weak or no PCL remnant. RESULTS: The mean side-to-side differences in posterior tibial translation on the stress radiographs were reduced from 10.1 +/- 2.5 mm in group 1, 10.6 +/- 2.4 mm in group 2, and 12.8 +/- 3.2 mm in group 3 preoperatively to 2.3 +/- 1.4 mm in group 1, 2.3 +/- 1.5 mm in group 2, and 4.0 +/- 2.5 mm in group 3 at the last follow-up (p < 0.001, p < 0.001, and p < 0.001, respectively). Statistical analyses revealed that group 1 and group 2 were similar in terms of side-to-side difference changes in posterior tibial translation on the stress radiographs; however, group 3 was inferior to group 1 and group 2 at the last follow-up (p = 0.022). The clinical results were not significantly different among the three groups. CONCLUSIONS: Excellent posterior stability and good clinical results were achieved with ALB reconstruction preserving the injured remnant PCL in the acute and subacute stages and remnant PCL tensioning with ALB reconstruction in the chronic stage. The PCL injuries could be surgically corrected with different techniques depending on both the remnant PCL status and the interval between the knee trauma and operation. PMID- 24340148 TI - Comparison of complete distal release of the medial collateral ligament and medial epicondylar osteotomy during ligament balancing in varus knee total knee arthroplasty. AB - BACKGROUND: During ligament balancing for severe medial contracture in varus knee total knee arthroplasty (TKA), complete distal release of the medial collateral ligament (MCL) or a medial epicondylar osteotomy can be necessary if a large amount of correction is needed. METHODS: This study retrospectively reviewed 9 cases of complete distal release of the MCL and 11 cases of medial epicondylar osteotomy which were used to correct severe medial contracture. The mean follow up periods were 46.5 months (range, 36 to 78 months) and 39.8 months (range, 32 to 65 months), respectively. RESULTS: There were no significant differences in the clinical results between the two groups. However, the valgus stress radiograph revealed significant differences in medial instability. In complete distal release of the MCL, some stability was obtained by repair and bracing but the medial instability could not be removed completely. CONCLUSIONS: Medial epicondylar osteotomy for a varus deformity in TKA could provide constant medial stability and be a useful ligament balancing technique. PMID- 24340149 TI - The effect of zoledronic acid on the volume of the fusion-mass in lumbar spinal fusion. AB - BACKGROUND: Few studies have explored the effects of bisphosphonates on bony healing in patients undergoing spinal fusion surgery. Most previous studies used animal models and found that bisphosphonate shows negative effects on spinal fusion consolidation. We intended to evaluate the effect of a single-dose of zoledronic acid on the volume of the fusion-mass in lumbar spinal fusion. METHODS: A retrospective review was carried out on 44 patients with symptomatic degenerative lumbar spinal stenosis who underwent one or two-level posterolateral fusion from January 2008 and January 2011. They were divided into 4 groups: group 1, autograft and zoledronic acid; group 2, allograft and zoledronic acid; group 3, autograft alone; and group 4, allograft alone. Functional radiography and three-dimensional computed tomography scans were used to evaluate and quantify the volume of the fusion-mass. The visual analog scale (VAS), the Oswestry disability index (ODI), and the short form 36 (SF-36) were used to evaluate the clinical outcomes. RESULTS: The mean volume of the fusion-mass per level was 8,814 mm(3), 8,035 mm(3), 8,383 mm(3), and 7,550 mm(3) in groups 1, 2, 3, and 4, respectively, but there were no significant differences between the groups (p = 0.829). There were no significant decreases in the volume of the fusion-mass (p = 0.533) in the zoledronic acid groups (groups 1 and 2). The VAS, the ODI, and the SF-36 at the 6-month follow-up after surgery were not significantly different (p > 0.05) among the 4 groups. The VAS, the ODI, and the SF-36 were not correlated with the volume of the fusion-mass (p = 0.120, 0.609, 0.642). CONCLUSIONS: A single dose of zoledronic acid does not decrease the volume of the fusion-mass in patients undergoing spinal fusion with osteoporosis. Therefore, we recommend that zoledronic acid may be used after spinal fusion in osteoporotic patients. PMID- 24340150 TI - Biomechanical comparison of an intramedullary and extramedullary free-tissue graft reconstruction of the acromioclavicular joint complex. AB - BACKGROUND: Several different surgical techniques have been described to address the coracoclavicular (CC) ligaments in acromioclavicular (AC) joint injuries. However, very few techniques focus on reconstructing the AC ligaments, despite its importance in providing stability. The purpose of our study was to compare the biomechanical properties of two free-tissue graft techniques that reconstruct both the AC and CC ligaments in cadaveric shoulders, one with an extramedullary AC reconstruction and the other with an intramedullary AC reconstruction. We hypothesized intramedullary AC reconstruction will provide greater anteroposterior translational stability and improved load to failure characteristics than an extramedullary technique. METHODS: Six matched cadaveric shoulders underwent translational testing at 10 N and 15 N in the anteroposterior and superoinferior directions, under AC joint compression loads of 10 N, 20 N, and 30 N. After the AC and CC ligaments were transected, one of the specimens was randomly assigned the intramedullary free-tissue graft reconstruction while its matched pair received the extramedullary graft reconstruction. Both reconstructed specimens then underwent repeat translational testing, followed by load to failure testing, via superior clavicle distraction, at a rate of 50 mm/min. RESULTS: Intramedullary reconstruction provided significantly greater translational stability in the anteroposterior direction than the extramedullary technique for four of six loading conditions (p < 0.05). There were no significant differences in translational stability in the superoinferior direction for any loading condition. The intramedullary reconstructed specimens demonstrated improved load to failure characteristics with the intramedullary reconstruction having a lower deformation at yield and a higher ultimate load than the extramedullary reconstruction (p < 0.05). CONCLUSIONS: Intramedullary reconstruction of the AC joint provides greater stability in the anteroposterior direction and improved load to failure characteristics than an extramedullary technique. Reconstruction of the injured AC joint with an intramedullary free tissue graft may provide greater strength and stability than other currently used techniques, allowing patients to have improved clinical outcomes. PMID- 24340151 TI - Clinical and radiological evaluation after arthroscopic rotator cuff repair using suture bridge technique. AB - BACKGROUND: We retrospectively assessed the clinical outcomes and investigated risk factors influencing retear after arthroscopic suture bridge repair technique for rotator cuff tear through clinical assessment and magnetic resonance arthrography (MRA). METHODS: Between January 2008 and April 2011, sixty-two cases of full-thickness rotator cuff tear were treated with arthroscopic suture bridge repair technique and follow-up MRA were performed. The mean age was 56.1 years, and mean follow-up period was 27.4 months. Clinical and functional outcomes were assessed using range of motion, Korean shoulder score, Constant score, and UCLA score. Radiological outcome was evaluated with preoperative and follow-up MRA. Potential predictive factors that influenced cuff retear, such as age, gender, geometric patterns of tear, size of cuff tear, acromioplasty, fatty degeneration, atrophy of cuff muscle, retraction of supraspinatus, involved muscles of cuff and osteolysis around the suture anchor were evaluated. RESULTS: Thirty cases (48.4%) revealed retear on MRA. In univariable analysis, retear was significantly more frequent in over 60 years age group (62.5%) than under 60 years age group (39.5%; p = 0.043), and also in medium to large-sized tear than small-sized tear (p = 0.003). There was significant difference in geometric pattern of tear (p = 0.015). In multivariable analysis, only age (p = 0.036) and size of tear (p = 0.030) revealed a significant difference. The mean active range of motion for forward flexion, abduction, external rotation at the side and internal rotation at the side were significantly improved at follow-up (p < 0.05). The mean Korean shoulder score, Constant score, and UCLA score increased significantly at follow up (p < 0.01). The range of motion, Korean shoulder score, Constant score, and UCLA score did not differ significantly between the groups with retear and intact repairs (p > 0.05). The locations of retear were insertion site in 10 cases (33.3%) and musculotendinous junction in 20 cases (66.7%; p = 0.006). CONCLUSIONS: Suture bridge repair technique for rotator cuff tear showed improved clinical results. Cuff integrity after repair did not affect clinical results. Age of over 60 years and size of cuff tear larger than 1 cm were factors influencing rotator cuff retear after arthroscopic suture bridge repair technique. PMID- 24340152 TI - Treatment outcomes of advanced stage malignant melanoma in hand and foot after amputation in Korean patients. AB - BACKGROUND: A retrospective study was conducted to review the overall survival and treatment outcomes of high grade melanoma in the extremity to explore the clinical features of malignant melanoma of the hand and foot, and the therapeutic efficacies and survival rate after amputation. METHODS: The clinical data of 30 patients with malignant melanoma of the hand and foot (confirmed by pathological examination), who were admitted and treated in our hospital between 2001 and 2010, were analyzed retrospectively. We analyzed variables affecting overall and disease-free survival. RESULTS: Thirty patients (18 men and 12 women) treated with an amputation procedure for malignant melanoma in the hand or foot constituted the study cohort. The average age of the patients at the time of diagnosis was 58.7 years. Univariate analysis for overall melanoma survival revealed that diagnosis at over 70 years of age, postoperative lymph node metastasis, and location of the tumor were significant prognostic factors. And on the Kaplan-Meier survival curve, old age, American Joint Committee on Cancer stage and postoperative lymph node metastasis showed statistically significant differences in the 5-year survival rate. Also, amputation with aggressive lymph node dissection showed improved long term survival in advanced stage melanoma. CONCLUSIONS: In Korean melanoma patients, for the treatment of high grade melanomas in the extremities after amputation, early diagnosis and postoperative follow-up for evaluation of lymph node metastasis are critical factors for long term survival. And by performing lymph node dissection during amputation, we may improve the survival rate in advanced stage melanoma patients. PMID- 24340153 TI - Locking compression plate in musculoskeletal oncology 'a friend in need'. AB - BACKGROUND: We are presenting our experience in the use of locking compression plate (LCP) after juxta-articular oncological resections in addition to its use in pathologic fracture. METHODS: A retrospective audit of skeletal reconstruction using LCP in 25 cases of long bone tumors was performed from 2008 to 2010. Reconstruction following limb salvage surgery was done in 17 patients and internal fixation of pathological fracture was done in 8 patients. All patients were available for > 12 months of follow-up, and thus assessed for union at the resected ends. RESULTS: There were 8 males and 17 females in the study. The average age at the time of surgery was 30 years (range, 9 to 66 years). The minimum follow-up was 12 months (range, 12 to 32 months). All patients except three went on to heal successfully. Complications occurred in those three patients: wound infection in one, nonunion in another, and periprosthetic fracture in the other patient. In the remaining patients, union was achieved at an average of 6.5 months after reconstruction in curative resection and 4.75 months after fixation of pathological fractures. CONCLUSIONS: Joint sparing limb salvage surgery was made successfully possible after sekeletal reconstruction with LCP. Its use was also quite effective in pathological fractures with poor bone quality. Use of locking plates for musculoskeletal oncological reconstruction resulted in a good and predictable rate of union. PMID- 24340154 TI - Biologic fixation through bridge plating for comminuted shaft fracture of the clavicle: technical aspects and prospective clinical experience with a minimum of 12-month follow-up. AB - For comminuted shaft fracture of clavicle, the operative goal, aside from sound bone healing without complications of direct reduction, is maintenance of the original length in order to maintain the normal biomechanics of adjacent joint. Our bridge plating technique utilizing distraction through a lumbar spreader was expected to be effective for restoring clavicular length with soft tissue preservation. However, there are two disadvantages. First, there is more exposure to radiation compared to conventional plating; and second, it is difficult to control the rotational alignment. Despite these disadvantages, our technique has important benefits, in particular, the ability to preserve clavicular length without soft tissue injury around the fracture site. PMID- 24340155 TI - Glomus tumor of Hoffa's fat pad and its management by arthroscopic excision. AB - We present a rare case of glomus tumor of Hoffa's fat pad in a 42-year-old woman. Magnetic resonance imaging findings along with the characteristic clinical picture led us to suspect a glomus tumor as the possible etiology. An ischemia test was found to be positive and this further substantiated our diagnosis. An arthroscopic excision was performed and the histology confirmed the diagnosis of glomus tumor of Hoffa's fat pad. The patient responded well to the excision with immediate complete resolution of pain and she remains asymptomatic at the last follow-up after 15 months. To our knowledge, this is the second reported case of glomus tumor of Hoffa's fat pad and the first ever to be managed by simple arthroscopic excision. The tumor poses a great challenge to an orthopedic surgeon. However, knowledge of its characteristic clinical presentation and the recognition of such a rare entity can help achieve an early diagnosis and timely management. PMID- 24340156 TI - Retrograde intramedullary nailing for distal femur fractures with osteoporosis: an appraisal: to the editor. PMID- 24340157 TI - Plagiarism detection. PMID- 24340158 TI - Peer review process in medical journals. AB - Reviewers play key roles in manuscript processing and publication. This article describes in detail how the reviewer serves their two key roles as a gatekeeper of making publication recommendations for the editorial board and a consultant providing constructive comments to authors to improve the quality of the manuscripts to be published. PMID- 24340159 TI - The role of paternal drinking problems in the psychological characteristics of high school students. AB - BACKGROUND: It has been reported that children with parental drinking problems are at increased risk of drinking problems or psychiatric diseases in adulthood. The present study was conducted to examine the psychiatric characteristics of high school students according to paternal drinking problems. METHODS: The subjects were 950 high school students (390 male and 560 female). The paternal drinking problems were assessed by using the Father-Short Michigan Alcoholism Screening Test. The Alcohol Use Disorders Identification Test, Beck's depression inventory, and Beck's anxiety inventory were used to evaluate the drinking behavior, depression, and anxiety of high school students. RESULTS: While male students with paternal drinking problems showed significantly increased risk of anxiety (odds ratio [OR], 2.21; 95% confidence interval [CI], 1.05 to 4.63), female students with paternal drinking problems showed significantly increased risk of depression (OR, 1.84; 95% CI, 1.24 to 2.74) according to the results of logistic regression analysis with adjustments for participants' age, whether they live together with parents, their religion, club activities, and smoking habits on the basis of students without paternal drinking problems. CONCLUSION: The above results suggest that paternal drinking problems lead to unstable mentalities in both male and female students, and that a family physician should address the mental state of teenagers with paternal drinking problems during clinical encounters. PMID- 24340160 TI - Sociodemographic characteristics of underweight korean adults: Korea national health and nutrition examination survey, 2007-2010. AB - BACKGROUND: Underweight is associated with increased risk of mortality and morbidity. It is reported that the prevalence of underweight is increasing among Korean young women. However, there have been few studies on sociodemographic factors related to being underweight. This study was conducted to elucidate the sociodemographic characteristics of Korean underweight adults. METHODS: This study is a cross-sectional study of 7,776 adults aged 25 to 69 years using data from the Korea National Health and Nutrition Examination Survey, 2007-2010. Study subjects were composed of underweight and normal-weight adults excluding overweight adults. Body mass index was calculated from measured height and weight. Health behaviors such as smoking, drinking, and physical activity were surveyed through self-administered questionnaires, and socioeconomic status, marital status, and history of morbidity were surveyed through face-to-face interviews. RESULTS: Women had a higher frequency of underweight (10.4% vs. 7.0%, P < 0.001) than men. Among men, current smoking (odds ratio [OR], 1.62) and past history of cancer (OR, 2.55) were independently related to underweight. Among women, young age (OR, 2.06), former smoking (OR, 1.69), and being unmarried (OR, 1.56) were identified as independently related factors of underweight. In addition, among both men and women, alcohol drinking (men OR, 0.57; women OR, 0.77) and past history of chronic diseases (men OR, 0.55; women OR, 0.43) were independently related to a lower frequency of underweight. CONCLUSION: We showed that various sociodemographic factors were associated with underweight. It was ascertained that there were differences in the sociodemographic factors related to underweight between Korean men and women. PMID- 24340161 TI - Weight control attempts in underweight korean adults: Korea national health and nutrition examination survey, 2007-2010. AB - BACKGROUND: Underweight refers to the weight range in which health risk can increase, since the weight is lower than a healthy weight. Negative attitudes towards obesity and socio-cultural preference for thinness could induce even underweight persons to attempt weight control. This study was conducted to investigate factors related to weight control attempts in underweight Korean adults. METHODS: This was a cross-sectional study on 690 underweight adults aged 25 to 69 years using data from the Korea National Health and Nutrition Examination Survey, 2007-2010. Body image perception, weight control attempts during the past one year, various health behaviors, history of chronic diseases, and socioeconomic status were surveyed. RESULTS: Underweight women had a higher rate of weight control attempts than underweight men (25.4% vs. 8.1%, P < 0.001). Among underweight men, subjects with the highest physical activity level (odds ratio [OR], 7.75), subjects with physician-diagnosed history of chronic diseases (OR, 7.70), and subjects with non-manual jobs or other jobs (OR, 6.22; 12.39 with reference to manual workers) had a higher likelihood of weight control attempts. Among underweight women, subjects who did not perceive themselves as thin (OR, 4.71), subjects with the highest household income level (OR, 2.61), and unmarried subjects (OR, 2.08) had a higher likelihood of weight control attempts. CONCLUSION: This study shows that numbers of underweight Korean adults have tried to control weight, especially women. Seeing that there are gender differences in factors related to weight control attempts in underweight adults, gender should be considered in helping underweight adults to maintain a healthy weight. PMID- 24340162 TI - Trends in Cardiovascular Health Metrics among Korean Adults. AB - BACKGROUND: American Heart Association (AHA) defined 7 cardiovascular health metrics for the general population to improve cardiovascular health in 2010: not smoking; having normal blood pressure; being physically active; normal body mass index, blood glucose, and total cholesterol levels; and eating a healthy diet. To investigate trends in cardiovascular health metrics in Korea, we used data from the third and fourth Korean National Health and Nutrition Examination Surveys. METHODS: We defined seven cardiovascular health metrics similar to the one defined by AHA but physical activity, body mass index, and healthy diet were properly redefined to be suited for the Korean population. We compared each cardiovascular health metric and calculated the sum of cardiovascular health metrics after dichotomizing each health metric to ideal (scored 1) and poor (scored 0). RESULTS: Health metric scores of smoking in males (P value for trend < 0.001), physical activity both in males and females (P-value for trend < 0.001 both), body mass index in females (P-value for trend = 0.030), and blood pressure both in males and females (P-value for trend < 0.001, both) were improved. On the other hand, health metric scores of healthy diet in males (P-value for trend = 0.002), and fasting blood glucose both in males and females (P-value for trend < 0.001 both) got worse. The total scores of seven health metrics were stationary. CONCLUSION: Total scores were not changed but each metric showed various trends. A long-term study is necessary for analyzing exact trends. PMID- 24340163 TI - Factors Associated with Serum Levels of Carcinoembryonic Antigen in Healthy Non smokers. AB - BACKGROUND: Carcinoembryonic antigen (CEA), a serological marker of malignant tumors, demonstrates a modest increase under nonmalignant conditions such as aging and smoking. Also, recent study results suggested that serum CEA levels may be related to insulin resistance or low-grade inflammation. The aim of this study was to investigate the factors associated with serum CEA levels in healthy non smokers. METHODS: Data was gathered from 21,501 adults aged 20 and over. We excluded 19,081 subjects who had omissions in anthropometric measurements or laboratory tests, or who had previous or current smoking history. RESULTS: The mean CEA level was 1.18 +/- 0.85 ng/dL in males and 0.93 +/- 0.73 ng/dL in females. After adjustment for age, CEA level was positively correlated with fasting glucose, glycosylated hemoglobin (HbA1C), high density lipoprotein (HDL) cholesterol, estimated glomerular filtration rate in males. In females, CEA level was positively correlated with fasting glucose, HbA1C, HDL cholesterol, aspartate aminotransferase, and high-sensitivity C-reactive protein. In both gender groups, HbA1C had a strong influence on CEA levels when all other variables were included in the regression model (P < 0.05). CONCLUSION: Within normal range, serum CEA levels were significantly associated with HbA1C levels but not with homeostasis model assessment of insulin resistance in the non-smoking population. These findings suggest that serum CEA levels are influenced by the glucose level itself instead of insulin resistance. PMID- 24340164 TI - The Association between Oxidative Stress and Metabolic Syndrome in Adults. AB - BACKGROUND: In this Study, we investigated the effects of lifestyle and metabolic syndrome on free oxygen radical levels in men and women in Korea. METHODS: A total of 254 adults were included in this study from February 2011 to June 2012 at a health promotion center. Information of the lifestyles and presence of metabolic syndrome factors was obtained. Biochemical markers were measured and free oxygen radicals test (FORT) was performed on the blood. RESULTS: Of the 254 subjects, 86 (33.9%) had metabolic syndrome, and 187 (73.6%) were men. Between the subjects with and without metabolic syndrome, there was a significant increase in alanine aminotransferase and serum FORT values in the subjects with metabolic syndrome. Multiple linear regression analysis showed that high sensitivity C-reactive protein (hs-CRP) (P = 0.004), metabolic syndrome (P = 0.037), and female gender (P = 0.030) were independent predictors of serum FORT values. The subjects with high fasting blood sugar level or low high density lipoprotein cholesterol levels showed high serum FORT values. CONCLUSION: High hs CRP, the presence of metabolic syndrome, and female gender were associated with the high oxidative stress. High oxidative stress was associated with the presence of metabolic syndrome. PMID- 24340165 TI - A case of acute aortic dissection presenting with chest pain relieved by sublingual nitroglycerin. AB - Acute aortic dissection is an uncommon disorder which can have fatal results in the event of treatment delay or misdiagnosis. This case examines a 77-year-old woman presenting with chest pain relieved by nitroglycerin. She was referred to the emergency room with clinical suspicion of acute coronary syndrome (ACS). However, she was later diagnosed with acute aortic dissection and an emergency operation was performed with successful recovery. Aortic dissection may manifest in various ways depending on the site involved and may mimic other disorders such as ACS or pulmonary embolism. Therefore, clinicians must always be aware of aortic dissection and its different clinical manifestations must be understood. PMID- 24340166 TI - Comments on statistical issues in november 2013. PMID- 24340167 TI - Erratum: correction to authors names and institutional affiliation. PMID- 24340168 TI - Pediatric Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. AB - Research on pediatric Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is reviewed in this article. Many recent articles in this area highlight the existence of key differences between the adult and pediatric forms of the illness. This review article provides an overview of pediatric ME/CFS, including epidemiology, diagnostic criteria, treatment, and prognosis. Challenges to the field are identified with the hope that in the future pediatric cases of ME/CFS can be more accurately diagnosed and successfully managed. PMID- 24340169 TI - The Discovery of Novel 10,11-Dihydro-5H-dibenz[b,f]azepine SIRT2 Inhibitors. AB - Isoform selective inhibitors of the sirtuins (NAD+-dependent histone deacetylases) should enable an in depth study of the molecular biology underpinning these targets and how they are deregulated in diseases such as cancer and neurodegeneration. Herein, we present the discovery of structurally novel SIRT2 inhibitors. Hit molecule 8 was discovered through the chemical synthesis and biological characterization of a small-molecule compound library based around the 10,11-dihydro-5H-dibenz[b,f]azepine scaffold. In vitro screening assays revealed compound 8 to have an IC50 of 18 MUM against SIRT2 and to exhibit more than 30-fold selectivity compared to SIRT1. Cellular assays, performed on MCF-7 cells, confirmed the in vitro selectivity and showed hit 8 to have antiproliferative activity at a concentration of 30 MUM. Computational studies were performed to predict the SIRT2 binding mode and to rationalise the observed selectivity. PMID- 24340170 TI - Negative Generalization and Symptoms of Anxiety Disorders. AB - The tendency to generalize from a single failure to one's entire self-worth is an important correlate and predictor of depression. Despite conceptual overlap between cognitive biases in anxiety and depression, little research has examined whether negative generalization relates to anxiety symptoms. We examined associations of negative generalization with symptoms of several anxiety disorders, above and beyond its association with lifetime symptoms of depression, among 248 undergraduates. After controlling for lifetime symptoms of major depression, negative generalization was significantly correlated with symptoms of each anxiety disorder tested, most notably generalized anxiety and social phobia. PMID- 24340171 TI - Linking sleep duration and obesity among black and white US adults. AB - AIMS: The effect of race/ethnicity on the risk of obesity associated with short or long sleep durations is largely unknown. This study assessed whether the sleep obesity link differentially affects black and whites. METHODS: Analysis was based on data obtained from 29,818 adult American respondents from the 2005 National Health Interview Survey, a cross-sectional household interview survey. RESULTS: Multivariate-adjusted odds ratios for obesity associated with short sleep (<=6 h) among blacks and whites were 1.98 (95% CI: 1.69-2.30) and 1.20 (95% CI: 1.10 1.31), respectively, and with long sleep (>=9 h) for blacks and whites were 1.48 (95% CI: 1.14-1.93) and 0.77 (95% CI: 0.67-0.89), respectively (all p < 0.001). CONCLUSION: Race/ethnicity may have significantly influenced the likelihood of reporting obesity associated with short and long sleep durations. Relative to white respondents, an excess of 78% of black respondents showed increased obesity odds associated with short sleep. Black long sleepers also showed increased odds for obesity, but white long sleepers may be at a reduced obesity risk. PMID- 24340173 TI - Bacterial colonization and extinction on marine aggregates: stochastic model of species presence and abundance. AB - Organic aggregates provide a favorable habitat for aquatic microbes, are efficiently filtered by shellfish, and may play a major role in the dynamics of aquatic pathogens. Quantifying this role requires understanding how pathogen abundance in the water and aggregate size interact to determine the presence and abundance of pathogen cells on individual aggregates. We build upon current understanding of the dynamics of bacteria and bacterial grazers on aggregates to develop a model for the dynamics of a bacterial pathogen species. The model accounts for the importance of stochasticity and the balance between colonization and extinction. Simulation results suggest that while colonization increases linearly with background density and aggregate size, extinction rates are expected to be nonlinear on small aggregates in a low background density of the pathogen. Under these conditions, we predict lower probabilities of pathogen presence and reduced abundance on aggregates compared with predictions based solely on colonization. These results suggest that the importance of aggregates to the dynamics of aquatic bacterial pathogens may be dependent on the interaction between aggregate size and background pathogen density, and that these interactions are strongly influenced by ecological interactions and pathogen traits. The model provides testable predictions and can be a useful tool for exploring how species-specific differences in pathogen traits may alter the effect of aggregates on disease transmission. PMID- 24340174 TI - Satellite-derived estimations of spatial and seasonal variation in tropospheric carbon dioxide mass over China. AB - China has frequently been questioned about the data transparency and accuracy of its energy and emission statistics. Satellite-derived remote sensing data potentially provide a useful tool to study the variation in carbon dioxide (CO2) mass over areas of the earth's surface. In this study, Greenhouse gases Observing SATellite (GOSAT) tropospheric CO2 concentration data and NCEP/NCAR reanalysis tropopause data were integrated to obtain estimates of tropospheric CO2 mass variations over the surface of China. These variations were mapped to show seasonal and spatial patterns with reference to China's provincial areas. The estimates of provincial tropospheric CO2 were related to statistical estimates of CO2 emissions for the provinces and considered with reference to provincial populations and gross regional products (GRP). Tropospheric CO2 masses for the Chinese provinces ranged from 53 +/- 1 to 14,470 +/- 63 million tonnes were greater for western than for eastern provinces and were primarily a function of provincial land area. Adjusted for land area troposphere CO2 mass was higher for eastern and southern provinces than for western and northern provinces. Tropospheric CO2 mass over China varied with season being highest in July and August and lowest in January and February. The average annual emission from provincial energy statistics of CO2 by China was estimated as 10.3% of the average mass of CO2 in the troposphere over China. The relationship between statistical emissions relative to tropospheric CO2 mass was higher than 20% for developed coastal provinces of China, with Shanghai, Tianjin, and Beijing having exceptionally high percentages. The percentages were generally lower than 10% for western inland provinces. Provincial estimates of emissions of CO2 were significantly positively related to provincial populations and gross regional products (GRP) when the values for the provincial municipalities Shanghai, Tianjin, and Beijing were excluded from the linear regressions. An increase in provincial GRP per person was related to a curvilinear increase in CO2 emissions, this being particularly marked for Beijing, Tianjin, and especially Shanghai. The absence of detection of specific elevation of CO2 mass in the troposphere above these municipalities may relate to the rapid mixing and dispersal of CO2 emissions or the proportion of the depth of the troposphere sensed by GOSAT. PMID- 24340172 TI - Differences in boldness are repeatable and heritable in a long-lived marine predator. AB - Animal personalities, composed of axes of consistent individual behaviors, are widely reported and can have important fitness consequences. However, despite theoretical predictions that life-history trade-offs may cause and maintain personality differences, our understanding of the evolutionary ecology of personality remains poor, especially in long-lived species where trade-offs and senescence have been shown to be stronger. Furthermore, although much theoretical and empirical work assumes selection shapes variation in personalities, studies exploring the genetic underpinnings of personality traits are rare. Here we study one standard axis of personality, the shy-bold continuum, in a long-lived marine species, the wandering albatross from Possession Island, Crozet, by measuring the behavioral response to a human approach. Using generalized linear mixed models in a Bayesian framework, we show that boldness is highly repeatable and heritable. We also find strong differences in boldness between breeding colonies, which vary in size and density, suggesting birds are shyer in more dense colonies. These results demonstrate that in this seabird population, boldness is both heritable and repeatable and highlights the potential for ecological and evolutionary processes to shape personality traits in species with varying life-history strategies. PMID- 24340175 TI - A multievent approach to estimating pair fidelity and heterogeneity in state transitions. AB - Fidelity rates of pair-bonded individuals are of considerable interest to behavioral and population biologists as they can influence population structure, mating rates, population productivity, and gene flow. Estimates of fidelity rates calculated from direct observations of pairs in consecutive breeding seasons may be biased because (i) individuals that are not seen are assumed to be dead, (ii) variation in the detectability of individuals is ignored, and (iii) pair status must be known with certainty. This can lead to a high proportion of observations being ignored. This approach also restricts the way variation in fidelity rates for different types of individuals, or the covariation between fidelity and other vital rates (e.g., survival) can be analyzed. In this study, we develop a probabilistic multievent capture-mark-recapture (MECMR) modeling framework for estimating pair fidelity rates that accounts for imperfect detection rates and capture heterogeneity, explicitly incorporates uncertainty in the assessment of pair status, and allows estimates of state-dependent survival and fidelity rates to be obtained simultaneously. We demonstrate the utility of our approach for investigating patterns of fidelity in pair-bonded individuals, by applying it to 30 years of breeding data from a wild population of great tits Parus major Linnaeus. Results of model selection supported state-dependent recapture, survival, and fidelity rates. Recapture rates were higher for individuals breeding with their previous partner than for those breeding with a different partner. Faithful birds that were breeding with the same partner as in the previous breeding season (i.e., at t - 1) experienced substantially higher survival rates (between t and t + 1) and were also more likely to remain faithful to their current partner (i.e., to remain in the faithful state at t + 1). First year breeders were more likely to change partner than older birds. These findings imply that traditional estimates, which do not account for state-dependent parameters, may be both inaccurate and biased, and hence, inferences based on them may conceal important biological effects. This was demonstrated in the analysis of simulated capture histories, which showed that our MECMR model was able to estimate state-dependant survival and pair fidelity rates in the face of varying state-dependant recapture rates robustly, and more accurately, than the traditional method. In addition, this new modeling approach provides a statistically rigorous framework for testing hypothesis about the causes and consequences of fidelity to a partner for natural populations. The novel modeling approach described here can readily be applied, either in its current form or via extension, to other populations and other types of dyadic interactions (e.g., between nonpaired individuals, such as parent-offspring relationships, or between individuals and locations, such as nest-site fidelity). PMID- 24340176 TI - Plant chemical defense allocation constrains evolution of tolerance to community change across a range boundary. AB - Because transplant experiments show that performance usually decreases across species range boundaries, some range limits might develop from factors and processes that prevent adaptation to stressful environments. Here, we determined whether an ecological cost of plant defense involving stress associated with changes in the local plant community may contribute to range limit development in the upland mustard species Boechera stricta. In a common garden experiment of 499 B. stricta plants, performance decreased and a multivariate axis of community structure increased across the boundary, indicating increased stress associated with the community change. There was also significant genetic variation (evolutionary potential) among marker-inferred inbred lines of B. stricta for tolerance to the stress; however, lines with high basal levels of glucosinolate toxins had lower tolerance to the change in community structure. We suggest that defense allocation, which is also needed across the range, may impede adaptation to the stress associated with the community change and thus contribute to range limit development. PMID- 24340177 TI - Ensemble modeling to predict habitat suitability for a large-scale disturbance specialist. AB - To conserve habitat for disturbance specialist species, ecologists must identify where individuals will likely settle in newly disturbed areas. Habitat suitability models can predict which sites at new disturbances will most likely attract specialists. Without validation data from newly disturbed areas, however, the best approach for maximizing predictive accuracy can be unclear (Northwestern U.S.A.). We predicted habitat suitability for nesting Black-backed Woodpeckers (Picoides arcticus; a burned-forest specialist) at 20 recently (<=6 years postwildfire) burned locations in Montana using models calibrated with data from three locations in Washington, Oregon, and Idaho. We developed 8 models using three techniques (weighted logistic regression, Maxent, and Mahalanobis D (2) models) and various combinations of four environmental variables describing burn severity, the north-south orientation of topographic slope, and prefire canopy cover. After translating model predictions into binary classifications (0 = low suitability to unsuitable, 1 = high to moderate suitability), we compiled "ensemble predictions," consisting of the number of models (0-8) predicting any given site as highly suitable. The suitability status for 40% of the area burned by eastside Montana wildfires was consistent across models and therefore robust to uncertainty in the relative accuracy of particular models and in alternative ecological hypotheses they described. Ensemble predictions exhibited two desirable properties: (1) a positive relationship with apparent rates of nest occurrence at calibration locations and (2) declining model agreement outside surveyed environments consistent with our reduced confidence in novel (i.e., "no analogue") environments. Areas of disagreement among models suggested where future surveys could help validate and refine models for an improved understanding of Black-backed Woodpecker nesting habitat relationships. Ensemble predictions presented here can help guide managers attempting to balance salvage logging with habitat conservation in burned-forest landscapes where black-backed woodpecker nest location data are not immediately available. Ensemble modeling represents a promising tool for guiding conservation of large-scale disturbance specialists. PMID- 24340178 TI - Predicting grey-sided vole occurrence in northern Sweden at multiple spatial scales. AB - Forestry is continually changing the habitats for many forest-dwelling species around the world. The grey-sided vole (Myodes rufocanus) has declined since the 1970s in forests of northern Sweden. Previous studies suggested that this might partly be caused by reduced focal forest patch size due to clear-cutting. Proximity and access to old pine forest and that microhabitats often contains stones have also been suggested previously but never been evaluated at multiple spatial scales. In a field study in 2010-2011 in northern Sweden, we investigated whether occurrence of grey-sided voles would be higher in (1) large focal patches of >60 years old forest, (2) in patches with high connectivity to surrounding patches, and (3) in patches in proximity to stone fields. We trapped animals in forest patches in two study areas (Vasterbotten and Norrbotten). At each trap station, we surveyed structural microhabitat characteristics. Landscape-scale features were investigated using satellite-based forest data combined with geological maps. Unexpectedly, the vole was almost completely absent in Norrbotten. The trap sites in Norrbotten had a considerably lower amount of stone holes compared with sites with voles in Vasterbotten. We suggest this might help to explain the absence in Norrbotten. In Vasterbotten, the distance from forest patches with voles to stone fields was significantly shorter than from patches without voles. In addition, connectivity to surrounding patches and size of the focal forest patches was indeed related to the occurrence of grey-sided voles, with connectivity being the overall best predictor. Our results support previous findings on the importance of large forest patches, but also highlight the importance of connectivity for occurrence of grey-sided voles. The results further suggest that proximity to stone fields increase habitat quality of the forests for the vole and that the presence of stone fields enhances the voles' ability to move between nearby forest patches through the matrix. PMID- 24340179 TI - Coalescent analyses show isolation without migration in two closely related tropical orioles: the case of Icterus graduacauda and Icterus chrysater. AB - The Isthmus of Tehuantepec has played an important role in shaping the avian diversity of Mexico, as well as the rest of the Western Hemisphere. It has been both a barrier and a land connector between North and South America for many groups of birds. Furthermore, climatic change over the Pleistocene has resulted in ecological fluctuations that led to periods of connection and isolation of the highlands in this area. Here we studied the divergence of two species of orioles whose distribution in the highlands is separated by the lowlands of the Isthmus of Tehuantepec: Icterus graduacauda (west of the Isthmus) and Icterus chrysater (east of the Isthmus). We sequenced multiple loci (one mitochondrial gene and six nuclear introns) and performed coalescent analyses (Isolation with Migration) to test whether their divergence resulted from prior occupancy of the ancestral area followed by a vicariant event or recent dispersal from one side or the other of this Isthmus. Results strongly indicate a vicariant event roughly 300,000 years ago in the Pleistocene followed by little or no gene flow. Both mitochondrial and nuclear genes show that the Isthmus of Tehuantepec is a strong barrier to gene flow. Thus, these two species appear to not exchange genes despite their recent divergence and the close geographic proximity of their ranges. PMID- 24340180 TI - Hybridization promotes color polymorphism in the aposematic harlequin poison frog, Oophaga histrionica. AB - Whether hybridization can be a mechanism that drives phenotypic diversity is a widely debated topic in evolutionary biology. In poison frogs (Dendrobatidae), assortative mating has been invoked to explain how new color morphs persist despite the expected homogenizing effects of natural selection. Here, we tested the complementary hypothesis that new morphs arise through hybridization between different color morphs. Specifically, we (1) reconstructed the phylogenetic relationships among the studied populations of a dart-poison frog to provide an evolutionary framework, (2) tested whether microsatellite allele frequencies of one putative hybrid population of the polymorphic frog O. histrionica are intermediate between O. histrionica and O. lehmanni, and (3) conducted mate choice experiments to test whether putatively intermediate females prefer homotypic males over males from the other two populations. Our findings are compatible with a hybrid origin for the new morph and emphasize the possibility of hybridization as a mechanism generating variation in polymorphic species. Moreover, because coloration in poison frogs is aposematic and should be heavily constrained, our findings suggest that hybridization can produce phenotypic novelty even in systems where phenotypes are subject to strong stabilizing selection. PMID- 24340181 TI - Early growth, dominance acquisition and lifetime reproductive success in male and female cooperative meerkats. AB - In polygynous species, variance in reproductive success is higher in males than females. There is consequently stronger selection for competitive traits in males and early growth can have a greater influence on later fitness in males than in females. As yet, little is known about sex differences in the effect of early growth on subsequent breeding success in species where variance in reproductive success is higher in females than males, and competitive traits are under stronger selection in females. Greater variance in reproductive success has been documented in several singular cooperative breeders. Here, we investigated consequences of early growth for later reproductive success in wild meerkats. We found that, despite the absence of dimorphism, females who exhibited faster growth until nutritional independence were more likely to become dominant, whereas early growth did not affect dominance acquisition in males. Among those individuals who attained dominance, there was no further influence of early growth on dominance tenure or lifetime reproductive success in males or females. These findings suggest that early growth effects on competitive abilities and fitness may reflect the intensity of intrasexual competition even in sexually monomorphic species. PMID- 24340182 TI - Molecular identification of the prey range of the invasive Asian paper wasp. AB - The prey range of the invasive Asian paper wasp, Polistes chinensis antennalis, was studied using molecular diagnostics. Nests of paper wasps were collected from urban residential and salt marsh habitats, larvae were removed and dissected, and DNA in the gut of the paper wasp larvae was amplified and sequenced with cytochrome c oxidase subunit I (COI). Seventy percent of samples (211/299) yielded medium-to high-quality sequences, and prey identification was achieved using BLAST searches in BOLD. A total of 42 taxa were identified from 211 samples. Lepidoptera were the majority of prey, with 39 taxa from 91% of samples. Diptera was a relatively small component of prey (three taxa, 19 samples). Conclusive species-level identification of prey was possible for 67% of samples, and genus-level identification, for another 12% of samples. The composition of prey taken was different between the two habitats, with 2.5* more native prey species being taken in salt marsh compared with urban habitats. The results greatly extend the prey range of this invasive species. The technique is a more effective and efficient approach than relying on the collection of "prey balls", or morphological identification of prey, for the study of paper wasps. PMID- 24340183 TI - Nucleotide diversity of vernalization and flowering-time-related genes in a germplasm collection of meadow fescue (Festuca pratensis Huds. syn. Lolium pratense (Huds.) Darbysh.). AB - In plant species, control of flowering time is an important factor for adaptation to local natural environments. The Vrn1 , CO , FT1 and CK2alpha genes are key components in the flowering-specific signaling pathway of grass species. Meadow fescue is an agronomically important forage grass species, which is naturally distributed across Europe and Western Asia. In this study, meadow fescue flowering-time-related genes were resequenced to assess nucleotide diversity in European and Western Asian subpopulations. Identified sequence polymorphisms were then converted into PCR-based molecular genetic markers, and a meadow fescue germplasm collection was genotyped to investigate global allelic variation. Lower nucleotide diversities were observed for the Vrn1 and CO orthologs, while relatively higher values were observed for the FT1 and casein kinase II alpha subunit (CK2alpha) orthologs. The nucleotide diversity for FT1 orthologs in the Western Asian subpopulation was significantly higher than those of the European subpopulation. Similarly, significant differences in nucleotide diversity for the remaining genes were observed between several combinations of subpopulation. The global allele distribution pattern was consistent with observed level of nucleotide diversity. These results suggested that the degree of purifying selection acting on the genes differs according to geographical location. As previously shown for model plant species, functional specificities of flowering time-related genes may also vary according to environmental conditions. PMID- 24340184 TI - Parasite predators exhibit a rapid numerical response to increased parasite abundance and reduce transmission to hosts. AB - Predators of parasites have recently gained attention as important parts of food webs and ecosystems. In aquatic systems, many taxa consume free-living stages of parasites, and can thus reduce parasite transmission to hosts. However, the importance of the functional and numerical responses of parasite predators to disease dynamics is not well understood. We collected host-parasite-predator cooccurrence data from the field, and then experimentally manipulated predator abundance, parasite abundance, and the presence of alternative prey to determine the consequences for parasite transmission. The parasite predator of interest was a ubiquitous symbiotic oligochaete of mollusks, Chaetogaster limnaei limnaei, which inhabits host shells and consumes larval trematode parasites. Predators exhibited a rapid numerical response, where predator populations increased or decreased by as much as 60% in just 5 days, depending on the parasite:predator ratio. Furthermore, snail infection decreased substantially with increasing parasite predator densities, where the highest predator densities reduced infection by up to 89%. Predators of parasites can play an important role in regulating parasite transmission, even when infection risk is high, and especially when predators can rapidly respond numerically to resource pulses. We suggest that these types of interactions might have cascading effects on entire disease systems, and emphasize the importance of considering disease dynamics at the community level. PMID- 24340185 TI - A hierarchical nest survival model integrating incomplete temporally varying covariates. AB - Nest success is a critical determinant of the dynamics of avian populations, and nest survival modeling has played a key role in advancing avian ecology and management. Beginning with the development of daily nest survival models, and proceeding through subsequent extensions, the capacity for modeling the effects of hypothesized factors on nest survival has expanded greatly. We extend nest survival models further by introducing an approach to deal with incompletely observed, temporally varying covariates using a hierarchical model. Hierarchical modeling offers a way to separate process and observational components of demographic models to obtain estimates of the parameters of primary interest, and to evaluate structural effects of ecological and management interest. We built a hierarchical model for daily nest survival to analyze nest data from reintroduced whooping cranes (Grus americana) in the Eastern Migratory Population. This reintroduction effort has been beset by poor reproduction, apparently due primarily to nest abandonment by breeding birds. We used the model to assess support for the hypothesis that nest abandonment is caused by harassment from biting insects. We obtained indices of blood-feeding insect populations based on the spatially interpolated counts of insects captured in carbon dioxide traps. However, insect trapping was not conducted daily, and so we had incomplete information on a temporally variable covariate of interest. We therefore supplemented our nest survival model with a parallel model for estimating the values of the missing insect covariates. We used Bayesian model selection to identify the best predictors of daily nest survival. Our results suggest that the black fly Simulium annulus may be negatively affecting nest survival of reintroduced whooping cranes, with decreasing nest survival as abundance of S. annulus increases. The modeling framework we have developed will be applied in the future to a larger data set to evaluate the biting-insect hypothesis and other hypotheses for nesting failure in this reintroduced population; resulting inferences will support ongoing efforts to manage this population via an adaptive management approach. Wider application of our approach offers promise for modeling the effects of other temporally varying, but imperfectly observed covariates on nest survival, including the possibility of modeling temporally varying covariates collected from incubating adults. PMID- 24340186 TI - Multilocus analyses indicate a mosaic distribution of hybrid populations in ground squirrels (genus Ictidomys). AB - DNA sequence data from mitochondrial cytochrome-b (Cytb) and Y-linked structural maintenance of chromosomes (SmcY) genes were combined with 478 nuclear loci obtained from amplified fragment length polymorphisms (AFLP) to assess the extent of hybridization and genetic spatial structure of populations in two hybridizing species of ground squirrel (Ictidomys parvidens and Ictidomys tridecemlineatus). Based on AFLP analyses of 134 individuals from 28 populations, 10 populations were identified that possessed hybrid individuals. Overall estimates of F ST values revealed strong support for population structure in the Cytb data set; however, analyses of the SmcY gene and the AFLP data indicated ongoing gene flow between species. Pairwise F ST comparisons of populations were not significant for the SmcY gene; although they were significant for the Cytb gene, indicating that these populations were structured and that gene flow was minimal. Therefore, gene flow between I. parvidens and I. tridecemlineatus appeared to be restricted to populations that exhibited hybridization. In addition, the fragmented nature of the geographic landscape suggested limited gene flow between populations. As a result, the distributional pattern of interspersed parental and hybrid populations were compatible with a mosaic hybrid zone model. Because ground squirrels display female philopatry and male-biased dispersal, the ecology of these species is compatible with this hypothesis. PMID- 24340187 TI - Comparative phylogeography of two sympatric beeches in subtropical China: Species specific geographic mosaic of lineages. AB - In subtropical China, large-scale phylogeographic comparisons among multiple sympatric plants with similar ecological preferences are scarce, making generalizations about common response to historical events necessarily tentative. A phylogeographic comparison of two sympatric Chinese beeches (Fagus lucida and F. longipetiolata, 21 and 28 populations, respectively) was conducted to test whether they have responded to historical events in a concerted fashion and to determine whether their phylogeographic structure is exclusively due to Quaternary events or it is also associated with pre-Quaternary events. Twenty three haplotypes were recovered for F. lucida and F. longipetiolata (14 each one and five shared). Both species exhibited a species-specific mosaic distribution of haplotypes, with many of them being range-restricted and even private to populations. The two beeches had comparable total haplotype diversity but F. lucida had much higher within-population diversity than F. longipetiolata. Molecular dating showed that the time to most recent common ancestor of all haplotypes was 6.36 Ma, with most haplotypes differentiating during the Quaternary. [Correction added on 14 October 2013, after first online publication: the timeunit has been corrected to '6.36'.] Our results support a late Miocene origin and southwards colonization of Chinese beeches when the aridity in Central Asia intensified and the monsoon climate began to dominate the East Asia. During the Quaternary, long-term isolation in subtropical mountains of China coupled with limited gene flow would have lead to the current species-specific mosaic distribution of lineages. PMID- 24340188 TI - Metacommunity structuring in stream networks: roles of dispersal mode, distance type, and regional environmental context. AB - Within a metacommunity, both environmental and spatial processes regulate variation in local community structure. The strength of these processes may vary depending on species traits (e.g., dispersal mode) or the characteristics of the regions studied (e.g., spatial extent, environmental heterogeneity). We studied the metacommunity structuring of three groups of stream macroinvertebrates differing in their overland dispersal mode (passive dispersers with aquatic adults; passive dispersers with terrestrial adults; active dispersers with terrestrial adults). We predicted that environmental structuring should be more important for active dispersers, because of their better ability to track environmental variability, and that spatial structuring should be more important for species with aquatic adults, because of stronger dispersal limitation. We sampled a total of 70 stream riffle sites in three drainage basins. Environmental heterogeneity was unrelated to spatial extent among our study regions, allowing us to examine the effects of these two factors on metacommunity structuring. We used partial redundancy analysis and Moran's eigenvector maps based on overland and watercourse distances to study the relative importance of environmental control and spatial structuring. We found that, compared with environmental control, spatial structuring was generally negligible, and it did not vary according to our predictions. In general, active dispersers with terrestrial adults showed stronger environmental control than the two passively dispersing groups, suggesting that the species dispersing actively are better able to track environmental variability. There were no clear differences in the results based on watercourse and overland distances. The variability in metacommunity structuring among basins was not related to the differences in the environmental heterogeneity and spatial extent. Our study emphasized that (1) environmental control is prevailing in stream metacommunities, (2) dispersal mode may have an important effect on metacommunity structuring, and (3) some factors other than spatial extent or environmental heterogeneity contributed to the differences among the basins. PMID- 24340189 TI - Colonization of islands in the Mona Passage by endemic dwarf geckoes (genus Sphaerodactylus) reconstructed with mitochondrial phylogeny. AB - Little is known about the natural history of the Sphaerodactylus species endemic to the three islands located in the Mona Passage separating the Greater Antillean islands of Hispaniola and Puerto Rico. In this study, parts of two mitochondrial genes, 16S rRNA and 12S rRNA, were sequenced to determine the relationships between the sphaerodactylids that live in the Mona Passage and other Caribbean species from the same genus. While the main goal was to identify the biogeographical origin of these species, we also identified a genetically distinct type of dwarf gecko that warrants future evaluation as a possible new species. According to the reconstructed phylogenies, we propose a stepwise model of colonization wherein S. nicholsi from southwestern Puerto Rico or a very close ancestor gave rise through a founder event to Sphaerodactylus monensis on Mona Island. In a similar fashion, S. monensis or a very close ancestor on Mona Island gave rise to S. levinsi on Desecheo Island. This study also suggests that the most recent common ancestor between the species from the islands in the Mona Passage and Puerto Rico existed approximately 3 MYA. PMID- 24340191 TI - Deflective and intimidating eyespots: a comparative study of eyespot size and position in Junonia butterflies. AB - Eyespots are conspicuous circular features found on the wings of several lepidopteran insects. Two prominent hypotheses have been put forth explaining their function in an antipredatory role. The deflection hypothesis posits that eyespots enhance survival in direct physical encounters with predators by deflecting attacks away from vital parts of the body, whereas the intimidation hypothesis posits that eyespots are advantageous by scaring away a potential predator before an attack. In the light of these two hypotheses, we investigated the evolution of eyespot size and its interaction with position and number within a phylogenetic context in a group of butterflies belonging to the genus Junonia. We found that larger eyespots tend to be found individually, rather than in serial dispositions. Larger size and conspicuousness make intimidating eyespots more effective, and thus, we suggest that our results support an intimidation function in some species of Junonia with solitary eyespots. Our results also show that smaller eyespots in Junonia are located closer to the wing margin, thus supporting predictions of the deflection hypothesis. The interplay between size, position, and arrangement of eyespots in relation to antipredation and possibly sexual selection, promises to be an interesting field of research in the future. Similarly, further comparative work on the evolution of absolute eyespot size in natural populations of other butterfly groups is needed. PMID- 24340190 TI - High genetic diversity is not essential for successful introduction. AB - Some introduced populations thrive and evolve despite the presumed loss of diversity at introduction. We aimed to quantify the amount of genetic diversity retained at introduction in species that have shown evidence of adaptation to their introduced environments. Samples were taken from native and introduced ranges of Arctotheca populifolia and Petrorhagia nanteuilii. Using microsatellite data, we identified the source for each introduction, estimated genetic diversity in native and introduced populations, and calculated the amount of diversity retained in introduced populations. These values were compared to those from a literature review of diversity in native, confamilial populations and to estimates of genetic diversity retained at introduction. Gene diversity in the native range of both species was significantly lower than for confamilials. We found that, on average, introduced populations showing evidence of adaptation to their new environments retained 81% of the genetic diversity from the native range. Introduced populations of P. nanteuilii had higher genetic diversity than found in the native source populations, whereas introduced populations of A. populifolia retained only 14% of its native diversity in one introduction and 1% in another. Our literature review has shown that most introductions demonstrating adaptive ability have lost diversity upon introduction. The two species studied here had exceptionally low native range genetic diversity. Further, the two introductions of A. populifolia represent the largest percentage loss of genetic diversity in a species showing evidence of substantial morphological change in the introduced range. While high genetic diversity may increase the likelihood of invasion success, the species examined here adapted to their new environments with very little neutral genetic diversity. This finding suggests that even introductions founded by small numbers of individuals have the potential to become invasive. PMID- 24340192 TI - Meta-analysis reveals profound responses of plant traits to glacial CO2 levels. AB - A general understanding of the links between atmospheric CO2 concentration and the functioning of the terrestrial biosphere requires not only an understanding of plant trait responses to the ongoing transition to higher CO2 but also the legacy effects of past low CO2. An interesting question is whether the transition from current to higher CO2 can be thought of as a continuation of the past trajectory of low to current CO2 levels. Determining this trajectory requires quantifying the effect sizes of plant response to low CO2. We performed a meta analysis of low CO2 growth experiments on 34 studies with 54 species. We quantified how plant traits vary at reduced CO2 levels and whether C3 versus C4 and woody versus herbaceous plant species respond differently. At low CO2, plant functioning changed drastically: on average across all species, a 50% reduction in current atmospheric CO2 reduced net photosynthesis by 38%; increased stomatal conductance by 60% and decreased intrinsic water use efficiency by 48%. Total plant dry biomass decreased by 47%, while specific leaf area increased by 17%. Plant types responded similarly: the only significant differences being no increase in SLA for C4 species and a 16% smaller decrease in biomass for woody C3 species at glacial CO2. Quantitative comparison of low CO2 effect sizes to those from high CO2 studies showed that the magnitude of response of stomatal conductance, water use efficiency and SLA to increased CO2 can be thought of as continued shifts along the same line. However, net photosynthesis and dry weight responses to low CO2 were greater in magnitude than to high CO2. Understanding the causes for this discrepancy can lead to a general understanding of the links between atmospheric CO2 and plant responses with relevance for both the past and the future. PMID- 24340194 TI - Projected marine climate change: effects on copepod oxidative status and reproduction. AB - Zooplankton are an important link between primary producers and fish. Therefore, it is crucial to address their responses when predicting effects of climate change on pelagic ecosystems. For realistic community-level predictions, several biotic and abiotic climate-related variables should be examined in combination. We studied the combined effects of ocean acidification and global warming predicted for year 2100 with toxic cyanobacteria on the calanoid copepod, Acartia bifilosa. Acidification together with higher temperature reduced copepod antioxidant capacity. Higher temperature also decreased egg viability, nauplii development, and oxidative status. Exposure to cyanobacteria and its toxin had a negative effect on egg production but, a positive effect on oxidative status and egg viability, giving no net effects on viable egg production. Additionally, nauplii development was enhanced by the presence of cyanobacteria, which partially alleviated the otherwise negative effects of increased temperature and decreased pH on the copepod recruitment. The interactive effects of temperature, acidification, and cyanobacteria on copepods highlight the importance of testing combined effects of climate-related factors when predicting biological responses. PMID- 24340193 TI - Introgressive hybridization in a trophically polymorphic cichlid. AB - Trophically polymorphic species could represent lineages that are rapidly diverging along an ecological axis or could phenotypically mark the collapse of species through introgressive hybridization. We investigated patterns of introgression between the trophically polymorphic cichlid fish Herichthys minckleyi and its relative H. cyanoguttatus using a combination of population genetics and species tree analyses. We first examined the distribution of mitochondrial haplotypes within the alternative H. minckleyi pharyngeal jaw morphotypes that are endemic to the small desert valley of Cuatro Cienegas. We recovered two clusters of mitochondrial haplotypes. The first contained a number of slightly differentiated cytochrome b (cytb) haplotypes that showed some phylogeographic signal and were present in both jaw morphotypes. The other haplotype was monomorphic, highly differentiated from the other cluster, present in equal frequencies in the morphotypes, and identical to H. cyanoguttatus haplotypes found outside Cuatro Cienegas. Then, we investigated whether H. minckleyi individuals with the H. cyanoguttatus cytb were more evolutionarily similar to H. cyanoguttatus or other H. minckleyi using a species tree analysis of 84 nuclear loci. Both H. minckleyi pharyngeal morphotypes, regardless of their cytb haplotype, were quite distinct from H. cyanoguttatus. However, hybridization could be blurring subdivision within H. minckleyi as the alternative jaw morphotypes were not genetically distinct from one another. Accounting for introgression from H. cyanoguttatus will be essential to understand the evolution of the trophically polymorphic cichlid H. minckleyi. PMID- 24340196 TI - Combining food web and species distribution models for improved community projections. AB - The ability to model biodiversity patterns is of prime importance in this era of severe environmental crisis. Species assemblage along environmental gradients is subject to the interplay of biotic interactions in complement to abiotic filtering and stochastic forces. Accounting for complex biotic interactions for a wide array of species remains so far challenging. Here, we propose using food web models that can infer the potential interaction links between species as a constraint in species distribution models. Using a plant-herbivore (butterfly) interaction dataset, we demonstrate that this combined approach is able to improve species distribution and community forecasts. The trophic interaction network between butterfly larvae and host plant was phylogenetically structured and driven by host plant nitrogen content allowing forecasting the food web model to unknown interactions links. This combined approach is very useful in rendering models of more generalist species that have multiple potential interaction links, where gap in the literature may occur. Our combined approach points toward a promising direction for modeling the spatial variation in entire species interaction networks. PMID- 24340195 TI - Phylogeography of the California sheephead, Semicossyphus pulcher: the role of deep reefs as stepping stones and pathways to antitropicality. AB - In the past decade, the study of dispersal of marine organisms has shifted from focusing predominantly on the larval stage to a recent interest in adult movement. Antitropical distributions provide a unique system to assess vagility and dispersal. In this study, we have focused on an antitropical wrasse genus, Semicossyphus, which includes the California sheephead, S. pulcher, and Darwin's sheephead, S. darwini. Using a phylogenetic approach based on mitochondrial and nuclear markers, and a population genetic approach based on mitochondrial control region sequences and 10 microsatellite loci, we compared the phylogenetic relationships of these two species, as well as the population genetic characteristics within S. pulcher. While S. pulcher and S. darwini are found in the temperate eastern Pacific regions of the northern and southern hemispheres, respectively, their genetic divergence was very small (estimated to have occurred between 200 and 600 kya). Within S. pulcher, genetic structuring was generally weak, especially along mainland California, but showed weak differentiation between Sea of Cortez and California, and between mainland California and Channel Islands. We highlight the congruence of weak genetic differentiation both within and between species and discuss possible causes for maintenance of high gene flow. In particular, we argue that deep and cooler water refugia are used as stepping stones to connect distant populations, resulting in low levels of genetic differentiation. PMID- 24340197 TI - Patterns of species diversity and phylogenetic structure of vascular plants on the Qinghai-Tibetan Plateau. AB - Large-scale patterns of species richness and the underlying mechanisms regulating these patterns have long been the central issues in biogeography and macroecology. Phylogenetic community structure is a result of combined effects of contemporary ecological interactions, environmental filtering, and evolutionary history, and it links community ecology with biogeography and trait evolution. The Qinghai-Tibetan Plateau provides a good opportunity to test the influence of contemporary climate on shaping species richness because of its unique geological history, cold climate, and high biodiversity. In this study, based on high resolution distributions of ~9000 vascular plant species, we explored how species richness and phylogenetic structure of vascular plants correlate with climates on the highest (and species rich) plateau on the Earth. The results showed that most of the vascular plants were distributed on the eastern part of the plateau; there was a strong association between species richness and climate, even after the effects of habitat heterogeneity were controlled. However, the responses of richness to climate remarkably depended on life-forms. Richness of woody plants showed stronger climatic associations than that of herbaceous plants; energy and water availability together regulated richness pattern of woody plants; whereas water availability predominantly regulated richness pattern of herbaceous plants. The phylogenetic structure of vascular species clustered in most areas of the plateau, suggesting that rapid speciation and environment filtering dominated the assembly of communities on the plateau. We further propose that biodiversity conservation in this area should better take into account ecological features for different life-forms and phylogenetic lineages. PMID- 24340198 TI - The genetics of phenotypic plasticity. XII. Temporal and spatial heterogeneity. AB - To understand empirical patterns of phenotypic plasticity, we need to explore the complexities of environmental heterogeneity and how it interacts with cue reliability. I consider both temporal and spatial variation separately and in combination, the timing of temporal variation relative to development, the timing of movement relative to selection, and two different patterns of movement: stepping-stone and island. Among-generation temporal heterogeneity favors plasticity, while within-generation heterogeneity can result in cue unreliability. In general, spatial variation more strongly favors plasticity than temporal variation, and island migration more strongly favors plasticity than stepping-stone migration. Negative correlations among environments between the time of development and selection can result in seemingly maladaptive reaction norms. The effects of higher dispersal rates depend on the life history stage when dispersal occurs and the pattern of environmental heterogeneity. Thus, patterns of environmental heterogeneity can be complex and can interact in unforeseen ways to affect cue reliability. Proper interpretation of patterns of trait plasticity requires consideration of the ecology and biology of the organism. More information on actual cue reliability and the ecological and developmental context of trait plasticity is needed. PMID- 24340199 TI - The importance of selection at the level of the pair over 25 years in a natural population of birds. AB - Knowledge of the pattern of selection in natural populations is fundamental for our understanding of the evolutionary process. Selection at higher levels has gained considerable theoretical support in recent years, and one possible level of selection is the breeding pair where fitness is a function of the pair and cannot be reduced to single individuals. We analyzed the importance of pair-level selection over 25 years in a natural population of the collared flycatcher. Pair level selection was significant in five and probably in another 9 years. The relative importance of pair-level selection varied over years and can have stronger or the same strength as directional selection. This means that selection can act on the combination of the breeding pair in addition to selection on each individual separately. Overall, the conservative estimates obtained here show that this is a potentially important form of selection. PMID- 24340217 TI - Intravenous BPs and atypical fracture risk in cancer patients. PMID- 24340216 TI - Postoperative management of hip fractures: interventions associated with improved outcomes. AB - The annual number of hip fractures worldwide is expected to exceed 6 million by 2050. Currently, nearly 50% of hip fracture patients will develop at least one short-term complication including infection, delirium, venous thromboembolism (VTE), pressure ulcers or cardiovascular events. More than half will experience an adverse long-term outcomes including worsened ambulation or functional status, additional fractures and excess mortality. This paper summarizes current evidence for postoperative interventions attempting to improve these outcomes, including pain management, anemia management, delirium prevention strategies, VTE prophylaxis, rehabilitation type, nutritional supplements, anabolic steroids and secondary fracture prevention. Models of care that have been tested in this population including interdisciplinary orthogeriatric services, clinical pathways and hospitalist care are summarized. In general, good quality evidence supports routine use of VTE prophylaxis, and moderate quality evidence supports multifactorial delirium prevention protocols, and a conservative transfusion strategy. Aggressive pain control with higher doses of opiates and/or regional blocks are associated with lower delirium rates. Low-moderate quality evidence supports the use of clinical pathways, and dedicated orthogeriatric consultative services or wards. After hospital discharge, good quality evidence supports the use of bisphosphonates for secondary fracture prevention and mortality reduction. Rehabilitation services are important, but evidence to guide quantity, type or venue is lacking. Additional research is needed to clarify the role of nutritional supplements, anabolic steroids, home care and psychosocial interventions. PMID- 24340218 TI - Mitochondrial function, intracellular ATP levels and bone resorption. PMID- 24340219 TI - PTH treatment converts inactive lining cells to active osteoblasts. PMID- 24340220 TI - ADT in men with prostate cancer leads to osteoporosis and vertebral fractures. PMID- 24340221 TI - Osteoporosis due to hyperthyroidism is worse when TSH signaling is lost. PMID- 24340222 TI - The effect of glucocorticoids on energy metabolism is mediated by osteoblasts. PMID- 24340224 TI - Molecular Biomarkers of Response to Antiangiogenic Therapy for Cancer. AB - Antiangiogenic therapy for cancer has gone from an intriguing hypothesis in the 1970s to an accepted treatment approach for many cancer types. It has also become a standard of care for certain eye diseases. Yet, despite the use of molecularly targeted drugs with well defined targets, to date there are no biomarkers to guide the use of antiangiogenic therapy in patients. The mechanisms of action of these drugs are also being debated. This paper discusses some of the emerging biomarker candidates for this type of cancer therapy, which have provided mechanistic insight and might be useful in the future for optimizing cancer treatment. PMID- 24340223 TI - ASTROCYTES: EMERGING STARS IN LEUKODYSTROPHY PATHOGENESIS. AB - Astrocytes are the predominant glial cell population in the central nervous system (CNS). Once considered only passive scaffolding elements, astrocytes are now recognised as cells playing essential roles in CNS development and function. They control extracellular water and ion homeostasis, provide substrates for energy metabolism, and regulate neurogenesis, myelination and synaptic transmission. Due to these multiple activities astrocytes have been implicated in almost all brain pathologies, contributing to various aspects of disease initiation, progression and resolution. Evidence is emerging that astrocyte dysfunction can be the direct cause of neurodegeneration, as shown in Alexander's disease where myelin degeneration is caused by mutations in the gene encoding the astrocyte-specific cytoskeleton protein glial fibrillary acidic protein. Recent studies point to a primary role for astrocytes in the pathogenesis of other genetic leukodystrophies such as megalencephalic leukoencephalopathy with subcortical cysts and vanishing white matter disease. The aim of this review is to summarize current knowledge of the pathophysiological role of astrocytes focusing on their contribution to the development of the above mentioned leukodystrophies and on new perspectives for the treatment of neurological disorders. PMID- 24340226 TI - Ruptured mycotic cerebral aneurysm development from pseudoocclusion due to septic embolism. AB - BACKGROUND: Cerebral mycotic aneurysms are rare sequelae of systemic infections that can cause profound morbidity and mortality with rupture. Direct bacterial extension and vessel integrity compromise from septic emboli have been implicated as mechanisms for formation of these lesions. We report the 5-day development of a ruptured mycotic aneurysm arising from a septic embolism that caused a focal M1 pseudoocclusion. CASE DESCRIPTION: A 14-year-old girl developed acute left-sided hemiparesis while hospitalized for subacute bacterial endocarditis that was found after she presented with a 2-week history of fever, myalgia, shortness of breath, and lethargy. Mitral valve vegetations were confirmed in the setting of hemophilus bacteremia. Brain magnetic resonance (MR) imaging and angiography confirmed middle cerebral artery infarct with focal pseudoocclusion of the distal M1 segment. Given that further middle cerebral artery territory was at risk, a trial of heparin was attempted for revascularization but required discontinuation owing to hemorrhagic conversion. Decline of the patient's mental status necessitated craniectomy for decompression. Postoperatively, her mental status improved with residual left hemiparesis. On the third postoperative day (5 days after MR angiography), the patient's neurologic condition acutely declined, with development of right-sided mydriasis. Computed tomography (CT) angiography revealed a ruptured 19 * 16 mm pseudoaneurysm arising from the M1 site of the previous occlusion. Emergent coiling of aneurysm and parent vessel followed by hematoma evacuation ensued. At discharge, the patient had residual left hemiparesis but intact speech and cognition. CONCLUSION: Focal occlusions due to septic emboli should be considered high-risk for mycotic aneurysm formation, prompting aggressive monitoring with neuroimaging and treatment when indicated. PMID- 24340227 TI - What the neurosurgeon should know about hemangioblastoma, both sporadic and in Von Hippel-Lindau disease: A literature review. AB - BACKGROUND: Hemangioblastomas are associated with Von Hippel-Lindau disease (VHLD) in 10-40% of cases. Based upon a literature review we state the core features the neurosurgeon should be aware of. METHODS: We performed a selective literature (Cochrane and Medline) search for hemangioblastoma, both sporadic and VHL associated. We reviewed general characteristics (epidemiology, symptomatology, diagnosis, and management) and focused on follow-up as well as screening modalities for sporadic and VHL associated lesions. RESULTS: Based upon our literature search, we established guidelines for screening and follow-up in both sporadic and VHL associated hemangioblastoma patients. CONCLUSIONS: Screening for retinal angiomas, abdominal masses, and pheochromocytomas as well as genetic analysis is recommended for every patient with a newly diagnosed hemangioblastoma. Follow-up is by magnetic resonance imaging (MRI) of the clinical neuronal region at 6 and at 12-24 months postoperatively. For VHL associated hemangioblastomas yearly investigation for craniospinal hemangioblastoma by MRI and yearly screening and follow-up for retinal angiomas is recommended. Annual abdominal ultrasound with triennial computed tomography (CT) imaging for abdominal masses is postulated. Annual audiometry is to be performed for possible endolymphatic sac tumor, detailed radiographic imaging of the skull base should be performed upon abnormality in auditory testing. Investigations for cystadenomas of the epidydimis and broad ligament only are mandatory on indication. Annual investigation for pheochromocytoma is recommended. PMID- 24340228 TI - Method for securing titanium cerebellar retractors. AB - BACKGROUND: Traditional stainless steel retractors can interfere with electromagnetic neuronavigation and intraoperative magnetic resonance imaging (ioMRI). In such cases, titanium instruments are frequently used; however, they often shift during the procedure. The authors describe a simple technique, illustrated with intraoperative photographs, for securing titanium cerebellar retractors into place to keep both the retractors and tissues in their desired locations throughout a craniotomy. METHODS: Titanium retractors were used by our institute's neurosurgical service during operations utilizing electromagnetic neuronavigation or ioMRI. Once the retractor was in the desired position, a 2-0 silk suture was placed around a retractor tong and tied outside the skin. Two sutures were placed on either side of the titanium retractor in the same fashion. RESULTS: Retractors were subsequently noted to remain in their desired position throughout the operative procedure. CONCLUSIONS: The authors describe a technique for securing titanium cerebellar retractors into their desired position during a craniotomy to minimize their movement during the procedure. This simple technique can help to eliminate a potential frequent source of surgeon frustration, and has proven to be quick to perform, safe, and practicable. PMID- 24340229 TI - Long-term therapeutic effects of corticoamygdalohippocampectomy for bilateral mesial temporal lobe epilepsy. AB - BACKGROUND: Some cases of paradoxical mesial temporal lobe epilepsy (MTLE) are shown to be bilateral MTLE (BMTLE) by intracranial electrodes. The treatment for BMTLE is difficult, which poses several questions. Can corticoamygdalohippocampectomy (CAH) be applied to treat BMTLE? What are the long term therapeutic effects if CAH is performed in BMTLE patients? METHODS: Four patients were shown to have BMTLE through bilateral intracranial electrode implantation. CAH was performed on the side with relatively more seizure originations. These patients were followed-up at 6 months, 1 year, 2 years and longer, in some cases, after the CAH. The postoperative seizure frequency was recorded. Preoperative and postoperative clinical memory tests and a postoperative 4-hour video electroencephalography (EEG) were conducted in the hospital at different follow-up times. The average seizure frequencies and memory quotient scores were analyzed. RESULTS: The average seizure frequency significantly decreased by 80.8%, 83.5%, and 84.3% at different postoperative times. Although no patient was seizure free, the intensity of the seizures was reduced in all cases. The postoperative average memory quotient score was moderately decreased by 15.8%, 11.7%, and 16.6% at different postoperative times. Both the average values of the postoperative seizure frequency (5.5, 4.75, and 4.5 per month) and the average values of the postoperative memory quotient (73.7, 77.3, and 73) at different postoperative times were approximately the same. CONCLUSIONS: CAH reduced the seizure frequency and intensity in these BMTLE patients. Mild hypomnesis occurred in every case. We observed the long-term treatment effects at 6 months after the CAH and showed that the effects did not change at that time or over the next few years. PMID- 24340230 TI - An unusual case of pediatric bow hunter's stroke. AB - BACKGROUND: Bow Hunter's syndrome/stroke is defined as symptomatic, vertebrobasilar insufficiency provoked by physiologic head rotation. It is a diagnostically challenging cause of posterior circulation stroke in children. While there have been prior reports of this rare disorder, we describe an exceptional case of pediatric Bow Hunter's stroke resulting from a near complete occlusion the right vertebral artery (VA) secondary to an anomalous spur emanating from the right occipital condyle. Surgical and endovascular options and approaches are also detailed herein. CASE DESCRIPTION: A 16-year-old male presented with multiple posterior circulation ischemic strokes. A dynamic computerized tomography angiogram performed with the patient's head in a rotated position revealed a near complete occlusion of the V3 segment of the right VA from a bone spur arising from his occipital condyle. The spur caused a focal dissection of the distal right VA with associated thrombus. He was initially managed with a cervical collar, antiplatelet therapy with aspirin 81 mg and anticoagulation with coumadin (INR goal 2-3) for 3 months. Despite the management plan, he had a subsequent thromboembolic event and a right VA sacrifice with coil embolization was then performed. At the 3-month follow-up, the patient was doing well with no reports of any subsequent strokes. CONCLUSION: We report the first reported pediatric case of Bow Hunter's stroke due to dynamic right VA occlusion from an occipital condylar bone spur. The vascular compression from this spur led to a right VA dissection and thrombus formation and ultimately caused multiple posterior circulation thromboembolic strokes. Endovascular treatment options including vessel sacrifice should be considered in cases that have failed maximal medical management. PMID- 24340225 TI - Pancreatic cancer diagnosis by free and exosomal miRNA. AB - Patients with pancreatic adenocarcinoma (PaCa) have a dismal prognosis. This is in part due to late diagnosis prohibiting surgical intervention, which provides the only curative option as PaCa are mostly chemo- and radiation resistance. Hope is raised on a reliable non-invasive/minimally invasive diagnosis that is still missing. Recently two diagnostic options are discussed, serum MicroRNA (miRNA) and serum exosomes. Serum miRNA can be free or vesicle-, particularly, exosomes enclosed. This review will provide an overview on the current state of the diagnostic trials on free serum miRNA and proceed with an introduction of exosomes that use as a diagnostic tool in serum and other body fluids has not received sufficient attention, although serum exosome miRNA in combination with protein marker expression likely will increase the diagnostic and prognostic power. By their crosstalk with host cells, which includes binding-initiated signal transduction, as well as reprogramming target cells via the transfer of proteins, mRNA and miRNA exosomes are suggested to become a most powerful therapeutics. I will discuss which hurdles have still to be taken as well as the different modalities, which can be envisaged to make therapeutic use of exosomes. PaCa are known to most intensely crosstalk with the host as apparent by desmoplasia and frequent paraneoplastic syndromes. Thus, there is hope that the therapeutic application of exosomes brings about a major breakthrough. PMID- 24340231 TI - Are recommended spine operations either unnecessary or too complex? Evidence from second opinions. AB - BACKGROUND: In 2011, Epstein and Hood documented that 17.2% of 274 patients with cervical/lumbar complaints seen in first or second opinion over one year were told they needed "unnecessary" spine surgery (e.g., defined as for pain alone, without neurological deficits, or significant radiographic abnormalities). Subsequently, in 2012 Gamache found that 69 (44.5%) of the 155 second opinion patients seen over a 14-month period were told by outside spine surgeons that they needed surgery; the second opinion surgeon (Gamache) found those operations to be unnecessary. Increasingly, patients, spine surgeons, hospitals, and insurance carriers should not only be questioning whether spinal operations are "unnecessary", but also whether they are "wrong" (e.g., overly extensive, anterior vs. posterior operations), or "right" (appropriate). METHODS: Prospectively, 437 patients with cervical or lumbar complaints were seen in spinal consultation over a 20-month period. Of the 254 (58.1%) patients coming in for first opinions those with surgical vs. non-surgical lesions were identified. Of the 183 (41.9%) patients coming in for second opinions, who were previously told by outside surgeons that they needed spine operations, the second opinion surgeon documented the number of "unnecessary", "wrong", or "right" operations previously recommended. RESULTS: Surgical pathology was identified in 138 (54.3%) patients presenting for first opinions. For patients seen in second opinion, 111 (60.7%) were told by outside surgeons that they required "unnecessary", 61 (33.3%) the "wrong", or 11 (6%) the "right" operations. CONCLUSIONS: Of 183 second opinions seen over 20 months, the second opinion surgeon documented that previous spine surgeons recommended "unnecessary" (60.7%), the "wrong" (33.3%), or the "right" (6%) operations. PMID- 24340232 TI - Spontaneous spinal epidural hematoma and spinal cord infarction following orthotopic liver transplantation: Case report and review of the literature. AB - BACKGROUND: Spinal epidural hematomas are rare conditions. Although the exact cause remains unknown in up to 40% of cases, anticoagulation therapy, neoplasm, thrombolytic therapy, internal jugular vein thrombosis, and prolonged Valsalva maneuvers associated with pregnancy may be contributing factors. The source of bleeding appears to be the dorsal internal vertebral venous plexus (IVVP). CASE DESCRIPTION: A 65-year-old female patient with hepatitis C-related cirrhosis underwent orthotopic liver transplantation (OLT). The patient developed SSEH due to congestion of the IVVP in the peri-transplant period. Concurrent spinal cord infarction occurred, likely secondary to hypoperfusion during a cardiac arrest. CONCLUSION: This case study should increase awareness of SSEH as a complication of OLT. PMID- 24340234 TI - Primary elective spine arthrodesis: Audit of institutional cross matched to transfused (C/T) ratio to develop blood product ordering guidelines. AB - BACKGROUND: Currently, there are no uniform guidelines regarding the appropriate amount of blood products ordered prior to spine surgery. Here, we audited our own institution's practices along with preoperative variables that contributed to perioperative transfusion requirements for elective spinal arthrodesis. METHODS: This study utilized a single institution retrospective chart review of patients undergoing elective spinal fusion over a 2 year period. The cross matched to transfused (C/T) ratio was utilized to compare different patient groups. Sub group multivariate analysis enabled us to identify possible predictors of transfusion for this patient population. RESULTS: Eighty-five patients were included in the study. Of the 292 units of packed red blood cells ordered preoperatively, only 66 were transfused (C/T ratio 4.4:1). Those undergoing arthrodesis for degenerative disease (6.9:1) or cervical spine arthrodesis (23:1) had the highest C/T ratios. Univariate analysis revealed several factors contributing to a relatively high probability of perioperative transfusions, while multivariate analysis showed that the indication for surgery was the only factor independently associated with the requirement for transfusion. CONCLUSION: We found an unacceptably high C/T ratio at our institution. Based on the results of our univariate analysis, we recommend that two units packed cells to be arranged for patients with preoperative hemoglobin levels <9 g/dl, trauma, and Adult Idiopathic Scoliosis (AIS) cases, or where more than two levels were being decompressed and/or arthrodesed. For the remainder of the cases, a group and hold policy should be sufficient. PMID- 24340233 TI - Vertebral artery injuries in cervical spine surgery. AB - BACKGROUND: Vertebral artery injuries during cervical spine surgery are rare, but potentially fatal. When performing cervical spine surgery, it is imperative that the surgeon has a systematic approach for avoiding, and if necessary, dealing with a vertebral artery injury. METHODS: This is a review paper. RESULTS: Upper posterior cervical spine surgeries put the vertebral artery at the highest risk, as opposed to anterior subaxial cervical spine procedures, which put the artery at the least risk. A thorough understanding of the complex anatomy of the vertebral artery is mandatory prior to performing cervical spine surgery, and since the vertebral artery can have a variable course, especially in the upper cervical spine, the surgeon must minimize the possibility of an arterial injury by preoperatively assessing the artery with a computed tomography (CT) scan or magnetic resonance imaging (MRI). Intraoperatively, the surgeon must be aware of when the vertebral artery is most at risk, and take precautions to avoid an injury. In the event of an arterial injury, the surgeon must have a plan of action to (1) Achieve control of the hemorrhage. (2) Prevent acute central nervous system ischemia. (3) Prevent postoperative complications such as embolism and pseudoaneurysm. CONCLUSION: Prior to performing cervical spine surgery, one must understand the four A's of vertebral artery injuries: Anatomy, Assessment, Avoidance, and Action. PMID- 24340235 TI - Editorial on two chronic low back pain studies: A major change in surgical management of disc disease? AB - In two recent publications, the authors' hypothesis was that Modic type 1 changes seen in patients with chronic low back pain and herniated lumbar discs may be attributed to bacterial infection/inflammation. The first study showed that many herniated discs were infected with Proprionibacterium acnes, a common anaerobic skin organism, also found in sarcoidosis, and possibly, arthritic joints. In the second double-blind randomized study, 162 patients with disc herniation and Modic type 1 changes were treated with 100 days of oral Bioclavid (Amoxicillin/Clavulanic acid) vs. placebo; those treated with antibiotics improved in all dimensions (e.g., reduced chronic low back/leg pain, reduced disability). Together, the implications of these studies for spine surgeons and pain practitioners are momentous. If a few weeks of oral antibiotic treatment resolves chronic low back pain, then much currently performed spine surgery (e.g. including internal fixation/fusion), as well as chronic pain management/rehabilitation and psychological strategies may be rendered unnecessary. PMID- 24340236 TI - Analysis of inter-provider conflicts among healthcare providers. AB - BACKGROUND: Patient safety is a top priority of healthcare organizations. The Joint Commission (TJC) is now requiring that healthcare organizations promulgate polices to investigate and resolve disruptive behavior among employees. METHODS: OUR AIMS IN THIS INVESTIGATION UTILIZING THE PROVIDER CONFLICT QUESTIONNAIRE (PCQ: Appendix A) included; determining what conflicts exist among a large sample of healthcare providers, how to assess the extent and frequency of disruptive behaviors, and what types of consequences result from these conflicts. The PCQ was distributed utilizing electronic postings, and predetermined e-mail lists to nurses and physicians across the US. RESULTS: The convenience sample included 617 respondents to the questionnaire. All incomplete responses (failure to answer all 17 items on the questionnaire) were excluded from data analysis. Our major finding was that disruptive behavior was the greatest problem observed in 82% of organizations; 74% personally witnessed these behaviors, while 5% personally experienced these behaviors. Friedman analysis of variance (ANOVA) analyses demonstrated that the difference between these three estimates were significant (chi(2) = 207.8 df = 2, P < 0.0001). CONCLUSION: Healthcare organizations in the US are bound by TJC regulations to develop leadership standards that address disruptive behavior. These organizations can no longer stand by and ignore behaviors that threaten not only the bottom line of the institution, but also most critically, patient safety. As more attention is being paid to recommendations and mandates from the TJC and the Institute of Medicine (IOM), we will need more data, like those provided from this study, to better document how to address, resolve, and prevent future "misbehaviors". PMID- 24340237 TI - The need to add motor evoked potential monitoring to somatosensory and electromyographic monitoring in cervical spine surgery. AB - Intraoperative neural monitoring (IONM), utilizing somatosensory evoked potentials (SEP) and electromyography (EMG), was introduced to cervical spine surgery in the late 1980's. However, as SEP only provided physiological data regarding the posterior cord, new motor deficits were observed utilizing SEP alone. This prompted the development of motor evoked potential monitoring (MEP) which facilitated real-time assessment of the anterior/anterolateral spinal cord. Although all three modalities, SEP, EMG, and MEP, are routinely available for IONM of cervical spine procedures, MEP are not yet routinely employed. The purpose of this review is to emphasize that MEP should now routinely accompany SEP and EMG when performing IONM of cervical spine surgery. Interestingly, one of the most common reasons for malpractice suits involving the cervical spine, is quadriparesis/quadriplegia following a single level anterior cervical diskectomy and fusion (ACDF). Previously, typical allegations in these suits included; negligent surgery, lack of informed consent, failure to diagnose/treat, and failure to brace. Added to this list, perhaps, as the 5(th) most reason for a suit will be failure to monitor with MEP. This review documents the value of MEP monitoring in addition to SEP and EMG monitoring in cervical spine surgery. The addition of MEP0 should minimize major motor injuries, and more accurately and reliably detect impending anterior cord deterioration that may be missed with SEP monitoring alone. PMID- 24340239 TI - A blunt needle (Epimed((r))) does not eliminate the risk of vascular penetration during transforaminal epidural injection. AB - BACKGROUND: Transforaminal epidural injection of local anesthetics and corticosteroids is a common practice in patients with radicular pain. However, serious morbidity has also been reported, which can be attributed to an arterial or venous injection of the medication especially particulate glucocorticoid preparations. Using a blunt needle in contrast to sharp needle has been suggested to reduce this risk in a study on animals. CASE DESCRIPTION: We present a 59-year old female with L5 lumbar radicular symptoms and left L5-S1 foraminal narrowing who underwent transforaminal epidural injection with fluoroscopic guidance using a 22-gauge blunt curved needle (Epimed((r)), Johnstown, NY). Intravascular needle placement was detected during real-time contrast injection under live fluoroscopy after a negative aspiration and local anesthetic test dose. The needle was slightly withdrawn and correct distribution of the contrast was confirmed along the target nerve root and into the epidural space. CONCLUSION: This case report discusses vascular penetration utilizing an Epimed((r)) blunt needle to perform transforaminal injections in a clinical setting. This topic was previously discussed in earlier animal studies. We also reemphasize that neither negative aspiration or local anesthetic test doses are reliable techniques to ensure the safety of transforaminal epidural injections. PMID- 24340238 TI - Infection with spinal instrumentation: Review of pathogenesis, diagnosis, prevention, and management. AB - BACKGROUND: Instrumentation has become an integral component in the management of various spinal pathologies. The rate of infection varies from 2% to 20% of all instrumented spinal procedures. Every occurrence produces patient morbidity, which may adversely affect long-term outcome and increases health care costs. METHODS: A comprehensive review of the literature from 1990 to 2012 was performed utilizing PubMed and several key words: Infection, spine, instrumentation, implant, management, and biofilms. Articles that provided a current review of the pathogenesis, diagnosis, prevention, and management of instrumented spinal infections over the years were reviewed. RESULTS: There are multiple risk factors for postoperative spinal infections. Infections in the setting of instrumentation are more difficult to diagnose and treat due to biofilm. Infections may be early or delayed. C Reactive Protein (CRP) and Magnetic Resonance Imaging (MRI) are important diagnostic tools. Optimal results are obtained with surgical debridement followed by parenteral antibiotics. Removal or replacement of hardware should be considered in delayed infections. CONCLUSIONS: An improved understanding of the role of biofilm and the development of newer spinal implants has provided insight in the pathogenesis and management of infected spinal implants. This literature review highlights the mechanism, pathogenesis, prevention, and management of infection after spinal instrumentation. It is important to accurately identify and treat postoperative spinal infections. The treatment is often multimodal and prolonged. PMID- 24340240 TI - Solute Carrier Family SLC41, what do we really know about it? AB - The 41st family of solute carriers (SLC41) comprises three members A1, A2 and A3, which are distantly homologous to bacterial Mg2+ channel MgtE. SLC41A1 was recently characterized as being an Na+/Mg2+ exchanger (NME; a predominant cellular Mg2+ efflux system). Little is known about the exact function of SLC41A2 and SLC41A3, although, these proteins have also been linked to Mg2+ transport in human (animal) cells. The molecular biology (including membrane topology, cellular localization, transcriptomics and proteomics) of SLC41A2 and SLC41A3 compared with SLC41A1 has only been poorly explored. Significantly more data with regard to function, functional regulation, involvement in cellular signalling, complex-forming ability, spectrum of binding partners and involvement in the pathophysiology of human diseases are available for SLC41A1. Three recent observations namely the identification of the null mutation, c.698G>T, in SLC41A1 underlying the nephronophthisis-like phenotype, the recognition of a putative link between SLC41A1 and Parkinson's disease, and the observation that nearly 55% of preeclamptic placental samples overexpress SLC41A1, marks the protein as a possible therapeutic target of these diseases. A potential role of the SLC41 family of Mg2+ transporters in the pathophysiology of human diseases is further substantiated by the finding that SLC41A3 knockout mice develop abnormal locomotor coordination. PMID- 24340241 TI - Histological assessments of intestinal immuno-morphology of tiger grouper juvenile, Epinephelus fuscoguttatus. AB - Histological assessments on the intestinal morphology and immunity of tiger grouper juveniles, Epinephelus fuscoguttatus help in determining the earliest age to start an oral vaccination. This study describes the morphological development of the intestinal immunity of tiger grouper of various ages. Clinically healthy tiger groupers were selected and divided into 4 groups of 20 fish per group. Groups 1, 2, 3 and 4 consisted of juveniles of 30, 60, 90 and 120 days old, respectively. The whole intestine was collected and divided into three regions, the anterior, mid and posterior intestine and fixed in 10% buffered formalin before slides were prepared for microscopic examinations. It was found that the histological structures of the anterior intestine were for absorption of nutrient from digested food particles. The significantly (p < 0.05) higher number and length of the intestinal villi and smaller gap between villi were observed in the anterior intestine, which were structures for absorption. Structures of the posterior intestine were for immunity especially the adaptive immunity with included significantly (p < 0.05) higher numbers of the lymphoid and goblet cells, and significantly (p < 0.05) thicker lamina propria, which were structures for immunity. The mid intestine was the transition structure that involved in both absorption and innate immunity. The results also revealed that leukocytes existed in the lamina propria of 30-days old tiger groupers, an indication that the immune system was present at that particular age. PMID- 24340242 TI - The negative effect of ceria on the propene selectivity for isopropanol decomposition over phosphated and phosphate-free ceria/alumina catalysts. AB - Consequences of loading level of ceria (5, 10 and 20-wt%) on the structural, textural and surface acid-base properties as well as the impacts on catalytic activity towards isopropanol decomposition on pure and phosphated alumina is described. The obtained results indicated that composites mainly kept gamma alumina structure and the addition of ceria and/or phosphate has no effect on the bulk structure of alumina. Textural characteristics show that the phosphated composites have higher surface area than phosphate free samples. Pyridine adsorption as followed by FTIR indicated the presence of Lewis acid sites with different strengths. Moreover, results of gas phase decomposition of isopropanol show a systematic inhibition in propene selectivity based on ceria ratio. PMID- 24340244 TI - A study of the controlled degradation of polypropylene containing pro-oxidant agents. AB - Intentional degradation by pro-oxidant agents, many of which are metal-based, can result in uncertainty as to the time of biodegradation. Polyacetal (POM) is a thermoplastic polymer commercially classified as an engineering polymer and contains carbon, hydrogen and oxygen. The depolymerization of POM during processing can enhance thermal decomposition. The aim of this study was to investigate the controlled degradation of polypropylene induced by the degradation of POM or d2w(r). Mixtures of polypropylene containing different concentrations of POM or d2w(r) were prepared by extrusion. The properties of the mixtures (blends) were evaluated based on the melt index (MFI), tensile properties, Fourier transform infrared spectroscopy (FTIR), Time inductive oxidation (OIT) and Thermogravimetric analysis (TGA). The two additives (POM and d2w(r)) enhanced the oxidative thermal degradation of polypropylene and the degradation of the polypropylene/POM mixture could be controlled by altering the POM concentration. PMID- 24340243 TI - Invasive ductolobular carcinoma of the breast: spectrum of mammographic, ultrasound and magnetic resonance imaging findings correlated with proportion of the lobular component. AB - PURPOSE: The aim of this study was to describe the imaging features of patients with invasive ductolobular carcinoma of the breast in comparison with the proportion of the lobular component. MATERIALS AND METHODS: We retrospectively reviewed mammographic, sonographic and MRI records of 113 patients with proven ductolobular carcinoma diagnosed between January 2008 and October 2012 according to the BI-RADS (r) lexicon, and correlated these to the proportion of the lobular component. RESULTS: At mammography the most common finding (62.9%) for invasive ductolobular carcinoma was an irregular, spiculated and isodense mass. On ultrasound an irregular and hypoechoic mass, with spiculated margins and posterior acoustic shadowing was observed in 46.8% of cases. Isolated mass and mass associated with non-mass like enhancement (NMLE) were the most common findings by MRI (89.4%). Washout pattern in delayed phase was seen in 61.2% and plateau curve was more frequently observed in patients with larger lobular component. Additional malignant findings (multifocality, multicentricity and contralateral disease) did not correlate significantly with the proportion of the lobular component. CONCLUSION: Invasive ductolobular carcinoma mainly presents as an irregular, spiculated mass, isodense on mammography and hypoechoic with posterior acoustic shadowing. On MRI it is usually seen as an isolated mass or as a dominant mass surrounded by smaller masses or NMLE. Washout is the most ordinary kinetic pattern of these tumors. In general, the imaging characteristics did not vary significantly with the proportion of the lobular component. PMID- 24340246 TI - Results of a clinical practice algorithm for the management of thoracostomy tubes placed for traumatic mechanism. AB - INTRODUCTION: The management and removal of thoracostomy tubes for trauma-related hemothorax and pneumothorax is controversial. General recommendations exist; however, institutional data related to an algorithmic approach has not been well described. The difficulty in establishing an algorithm centers about individualized patients' needs for subsequent management after thoracostomy tube placement. In our institution, we use the same protocol for all trauma patients who receive a thoracostomy tube with minimal complications. PURPOSE: To present the clinical outcomes of patients who required a tube thoracostomy for traumatic injury and were managed by an institutional protocol. METHODS: A retrospective chart review of 313 trauma patients at a single level I trauma institution from January 2008 through June 2012 was conducted. Inclusion criteria were patient age >= 18 years, involvement in a trauma, and requirement of a thoracostomy tube. The patients' charts were reviewed for demographic data, injury severity score (ISS), length of stay (LOS), and chest-tube specific data. Thoracostomy tube complications were defined as persistent air leak, persistent pneumothorax, recurrent pneumothorax, and clotting of thoracostomy tube. The patients were managed per our institutional algorithm. Descriptive statistics were performed. RESULTS: Most of the patients who required a thoracostomy tube had blunt-related traumas (271/313; 86.6%), while 42 patients (13.4%) sustained penetrating injuries. There were 215 (68.7%) male patients. The average age at time of injury was 45.7 +/- 21.1 years and the mean ISS was 24.9 +/- 15.9 (mean +/- SD). Elevated alcohol levels were found in 65 of the 247 patients who were tested upon admission (26.3%). Overall, 15 patients (4.8%) developed a thoracostomy tube related complication: persistent air leak in six patients, persistent pneumothorax in six patients, recurrent pneumothorax in two patients, and clotted thoracostomy tube in one patient. The average LOS was 10.4 +/- 8.4 days, and the mean length of thoracostomy tube placement was 5.9 +/- 4.3 days. CONCLUSIONS: Our algorithmic thoracostomy tube management protocol resulted in a complication rate of 4.8%. By managing thoracostomy tubes in a systematic manner, our patients have improved outcomes following placement and removal compared to other studies. PMID- 24340247 TI - The value of access to water: livestock farming in the Nyagatare District, Rwanda. AB - In Rwanda, access to water is seen as a significant constraint to development in both urban and rural areas. The government and foreign donors give priority to improving access to water for agricultural use. In this paper we study whether and, if so, to what extent the revenue generated by livestock farming in the Nyagatare District is affected by the distance that cattle need to go in order to reach the nearest water point. Our findings suggest that this distance does not affect the revenue from livestock farming much, indicating that improved access to water is not a major constraint to livestock farming at present. Therefore, other water needs can be given greater weight. PMID- 24340245 TI - Adiposity, inflammation, genetic variants and risk of post-menopausal breast cancer findings from a prospective-specimen-collection, retrospective-blinded evaluation (PRoBE) design approach. AB - Chronic internal inflammation secondary to adiposity is a risk factor for sporadic breast cancer and Post-Menopausal Breast Cancer (PMBC) is largely defined as such. Adiposity is one of the clinical criteria for the diagnosis of Metabolic Syndrome (MetS) and is a risk factor for PMBC. We examined SNPs of eight genes implicated in adiposity, inflammation and cell proliferation in a Prospective-specimen-collection, Retrospective-Blinded-Evaluation (PRoBE) design approach. A total of 180 cases and 732 age-matched controls were identified from the MyCode prospective biobank database and then linked to the Clinical Decision Information System, an enterprise-wide data warehouse, to retrieve clinico demographic data. Samples were analyzed in a core laboratory where the personnel were masked to their status. Results from multivariate logistic regression yielded one SNP (rs2922126) in the GHSR as protective against PMBC among homozygotes for the minor allele (A/A) (OR = 0.4, 95% CI 0.18-.89, P-value = .02); homozygosity for the minor allele (C/C) of the SNP (rs889312) of the gene MAP3K1 was associated with the risk of PMBC (OR = 2.41, 95% CI 1.25-4.63 P-value = .008). Advanced age was protective against PMBC (OR = 0.98, 95% CI 0.95-0.99, P value = .02). Family history of breast cancer (OR = 2.22, 95% CI 1.14-4.43. P = .02), HRT (OR = 3.35; 95% CI 2.15-5.21, P < .001), and MetS (OR = 14.83, 95% CI 5.63-39.08, P < .001) and interaction between HRT and MetS (OR = 39.38, 95% CI 15.71-98.70, P < .001) were associated with the risk of PMBC. We did not detected significant interactions between SNPs or between the SNPs and the clinico demographic risk factors. Our study further confirms that MetS increases the risk of PMBC and argues in favor of reducing exposure to HRT. Our findings are another confirmation that low penetrance genes involved in the inflammatory pathway, i.e. MAP3KI gene, may have a plausible causative role in PMBC. Given the fact that genetic constitutionality of individuals cannot be changed, efforts should be focused on life style modification. PMID- 24340248 TI - Critical elements in implementations of just-in-time management: empirical study of cement industry in Pakistan. AB - In recent years, inventory management is continuous challenge for all organizations not only due to heavy cost associated with inventory holding, but also it has a great deal to do with the organizations production process. Cement industry is a growing sector of Pakistan's economy which is now facing problems in capacity utilization of their plants. This study attempts to identify the key strategies for successful implementation of just-in-time (JIT) management philosophy on the cement industry of Pakistan. The study uses survey responses from four hundred operations' managers of cement industry in order to know about the advantages and benefits that cement industry have experienced by Just in time (JIT) adoption. The results show that implementing the quality, product design, inventory management, supply chain and production plans embodied through the JIT philosophy which infect enhances cement industry competitiveness in Pakistan. JIT implementation increases performance by lower level of inventory, reduced operations & inventory costs was reduced eliminates wastage from the processes and reduced unnecessary production which is a big challenge for the manufacturer who are trying to maintain the continuous flow processes. JIT implementation is a vital manufacturing strategy that reaches capacity utilization and minimizes the rate of defect in continuous flow processes. The study emphasize the need for top management commitment in order to incorporate the necessary changes that need to take place in cement industry so that JIT implementation can take place in an effective manner. PMID- 24340249 TI - Risk-Attributable Burden of Chronic Diseases and Cost of Prevention in Bangladesh. PMID- 24340250 TI - Perfecting video capsule endoscopy: is there need for training? PMID- 24340251 TI - Long-term outcome of endoscopic papillary large balloon dilatation. PMID- 24340252 TI - Endoscopic molecular imaging: status and future perspective. AB - During the last decade, researchers have made great progress in the development of new image processing technologies for gastrointestinal endoscopy. However, diagnosis using conventional endoscopy with white light optical imaging is essentially limited, and ultimately, we still rely on the histopathological diagnosis from biopsy specimens. Molecular imaging represents the most novel imaging methods in medicine, and the future of endoscopic diagnosis is likely to be impacted by a combination of biomarkers and technology. Endoscopic molecular imaging can be defined as the visualization of molecular characteristics with endoscopy. These innovations will allow us not only to locate a tumor or dysplastic lesion but also to visualize its molecular characteristics and the activity of specific molecules and biological processes that affect tumor behavior and/or its response to therapy. In the near future, these promising technologies will play a central role in endoluminal oncology. PMID- 24340253 TI - Application of Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Imaging Mass Spectrometry (MALDI-TOF IMS) for Premalignant Gastrointestinal Lesions. AB - Imaging mass spectrometry (IMS) is currently receiving large attention from the mass spectrometric community, although its use is not yet well known in the clinic. As matrix-assisted laser desorption/ionization time-of-flight (MALDI)-IMS can show the biomolecular changes in cells as well as tissues, it can be an ideal tool for biomedical diagnostics as well as the molecular diagnosis of clinical specimens, especially aimed at the prompt detection of premalignant lesions much earlier before overt mass formation, or for obtaining histologic clues from endoscopic biopsy. Besides its use for pathologic diagnosis, MALDI-IMS is also a powerful tool for the detection and localization of drugs, proteins, and lipids in tissue. Measurement of parameters that define and control the implications, challenges, and opportunities associated with the application of IMS to biomedical tissue studies might be feasible through a deep understanding of mass spectrometry. In this focused review series, new insights into the molecular processes relevant to IMS as well as other field applications are introduced. PMID- 24340254 TI - Optical molecular imaging for diagnosing intestinal diseases. AB - Real-time visualization of the molecular signature of cells can be achieved with advanced targeted imaging techniques using molecular probes and fluorescence endoscopy. This molecular optical imaging in gastrointestinal endoscopy is promising for improving the detection of neoplastic lesions, their characterization for patient stratification, and the assessment of their response to molecular targeted therapy and radiotherapy. In inflammatory bowel disease, this method can be used to detect dysplasia in the presence of background inflammation and to visualize inflammatory molecular targets for assessing disease severity and prognosis. Several preclinical and clinical trials have applied this method in endoscopy; however, this field has just started to evolve. Hence, many problems have yet to be solved to enable the clinical application of this novel method. PMID- 24340255 TI - Performance and clinical role of endoscopic ultrasound fine needle aspiration for diagnosing gastrointestinal intramural lesions. AB - BACKGROUND/AIMS: We evaluated the performance, clinical role, and diagnostic accuracy of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in gastrointestinal intramural lesions. METHODS: Procedural and pathologic data were reviewed from consecutive patients undergoing EUS-FNA for intramural lesions. Final diagnoses were determined by surgical histopathologic conformation and the diagnosis of malignancy, including clinical follow-up with repeat imaging. RESULTS: Forty-six patients (mean age, 47 years; 24 males) underwent EUS-FNA. Lesions were located in the stomach (n=31), esophagus (n=5), and duodenum (n=10). The median lesion size was 2 cm (range, 1 to 20.6). Final diagnoses were obtained in 22 patients (48%). EUS-FNA was diagnostic in 40 patients (87%). The diagnostic accuracy of cytology for differentiating between benign and malignant lesions was 82%; diagnostic error occurred in three patients (6%). The cytologic results influenced clinical judgment in 78% cases. The primary reasons for negative or no clinical impact were false-negative results, misdirected patient management, and inconclusive cytology. CONCLUSIONS: EUS-FNA exhibited an 87% diagnostic yield for gastrointestinal intramural lesions; the accuracy of cytology for differentiating malignancy was 82%. The limitations of EUS-FNA were primarily because of nondiagnostic sampling (9%) and probable diagnostic error (6%); these factors may influence the clinical role of EUS-FNA. PMID- 24340256 TI - Learning curve of capsule endoscopy. AB - BACKGROUND/AIMS: Capsule endoscopy (CE) has become an important tool for the diagnosis of small bowel disease. Although CE does not require the skill of endoscope insertion, the images should be interpreted by a person with experience in assessing images of the gastrointestinal mucosa. This investigation aimed to document the number of cases needed by trainees to gain the necessary experience for CE competency. METHODS: Fifteen cases were distributed to 12 trainees with no previous experience of CE during their gastroenterology training as clinical fellows. Twelve trainees and an expert were asked to read CE images from one patient each week for 15 weeks. The diagnosis was reported using five categories (no abnormalities detected, small bowel erosion or ulcer, small bowel tumor, Crohn disease, and active small bowel bleeding with no identifiable source). We then examined, using the kappa coefficient, how the degree of mean agreements between the trainees and the expert changed as the training progressed each week. RESULTS: The agreement rate of CE diagnosis increased as the frequencies of interpretation increased. Most of the mean kappa coefficients were >0.60 and >0.80 after week 9 and 11, respectively. CONCLUSIONS: Experience with approximately 10 cases of CE is appropriate for trainees to attain CE competency. PMID- 24340257 TI - Late Complications and Stone Recurrence Rates after Bile Duct Stone Removal by Endoscopic Sphincterotomy and Large Balloon Dilation are Similar to Those after Endoscopic Sphincterotomy Alone. AB - BACKGROUND/AIMS: Between endoscopic sphincterotomy (ES) alone and combined endoscopic sphincterotomy and large balloon dilation (ES-LBD) groups, efficacy and long-term complications, difference in biliary stone recurrence rate, and risk factors of stone recurrence were compared. METHODS: Medical records of 222 patients who underwent ERCP for biliary stone removal were retrospectively reviewed. Patients with dilated CBD >=11 mm and follow-up longer than 6 months were included. RESULTS: There were 101 patients in ES-LBD group and 121 patients in ES group. Mean follow-up duration was 25.0 (6-48) months and 13.0 (6-43) months, respectively (p=0.001). There was no difference in number of ERCP sessions, brown pigment stones, angle between mid and distal common bile duct (CBD angle) <135 degrees , and lithotripsy rate. Complete retrieval success rate was excellent in both groups (100% vs. 99%). Early complication rate of ES-LBD and ES alone group was 4 and 4.1%, respectively (p=1.000). One patient in ES-LBD group died from delayed bleeding. Late complication rate was 5.9 and 3.3%, respectively (p=1.000). Stone recurrence rate was 6.9% and 5.8%, respectively (p=0.984). The only Independent risk factor of stone recurrence was presence of periampullary diverticulum. CONCLUSIONS: Late complication and stone recurrence rates were similar between ES-LBD and ES alone groups. PMID- 24340258 TI - Intralesional steroid injection to prevent stricture after near-circumferential endosopic submucosal dissection for superficial esophageal cancer. AB - Stricture frequently occurs after endoscopic submucosal dissection (ESD) for superficial esophageal carcinoma with near- or whole-circumferential mucosal defects, and post-ESD stricture is difficult to treat and usually requires multiple sessions of endoscopic balloon dilatation. Intralesional steroid injection has previously been used to prevent stricture; however, there have been few experiences with this method after near- or whole-circumferential ESD. We present a case of a single session of intralesional steroid injection performed immediately after near-circumferential ESD to prevent post-ESD stricture. After a follow-up period of 6 months, the patient showed good outcome without dysphagia. PMID- 24340259 TI - A polypoid mucosa-associated lymphoid tissue lymphoma of the stomach treated with endoscopic polypectomy. AB - Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach is the most common extranodal lymphoma of the gastrointestinal tract. It is usually accompanied by Helicobacter pylori infection, and eradication of H. pylori remains the mainstay of treatment for gastric MALT lymphoma. However, there is no consensus on the second-line treatment for patients with gastric MALT lymphoma who do not improve after successful H. pylori eradication. Here, we report the case of a 34-year-old woman who presented with a polypoid type of gastric MALT lymphoma on the greater curvature side of the upper body. Despite successful H. pylori eradication, the tumor did not regress after 6 months. Because the tumor had a semipedunculated polypoid morphology, gastric polypectomy was implemented as a second-line treatment. No recurrence occurred during the 3-year follow-up period. We suggest that gastric polypectomy be considered an alternative treatment modality for polypoid gastric MALT lymphoma that is unresponsive to H. pylori eradication. PMID- 24340260 TI - Gastric outlet obstruction due to gastric amyloidosis mimicking malignancy in a patient with ankylosing spondylitis. AB - Amyloidosis is a group of disorders characterized by the extracellular accumulation of insoluble, fibrillar proteins in various organs and tissues. It is classified, on the basis of the identity of the precursor protein, as primary, secondary, or familial amyloidosis. Gastrointestinal amyloidosis usually presents as bleeding, ulceration, malabsorption, protein loss, and diarrhea. However, gastric amyloidosis with gastric outlet obstruction mimicking linitis plastica is rare. We report a case of gastrointestinal amyloidosis with gastric outlet obstruction in a patient with ankylosing spondylitis. The patient was indicated for subtotal gastrectomy because of the aggravation of obstructive symptoms, but refused the operation and was transferred to another hospital. Three months later, the patient died of aspiration pneumonia during medical treatment. PMID- 24340261 TI - Endoscopic treatment of duodenal neuroendocrine tumors. AB - Duodenal neuroendocrine tumors (NETs) are rare neoplasms. In this study, the medical records of 14 patients with duodenal NETs diagnosed at Chonnam National University Hospital from July 2001 to August 2011 were reviewed and analyzed retrospectively. Four patients were diagnosed in the first 5 years, and 10 patients were diagnosed in the latter 5 years of the study. Ten of 12 patients (83.3%) who underwent endoscopic biopsy were confirmed to have NET before resection. Endoscopic resection was performed in 12 patients, surgical resection in one patient, and regular follow-up in one patient who refused resection. None of the patients showed recurrence or distant metastasis. Duodenal NETs are increasingly observed and are mostly detected during screening upper gastrointestinal endoscopy. Careful endoscopic examination and biopsy can improve the diagnostic yield of NETs. Most well-differentiated, nonfunctional duodenal NETs that are limited to the mucosa/submucosa can be treated effectively with endoscopic resection. PMID- 24340262 TI - Gastrostomy in a patient with situs inversus totalis. AB - Situs inversus totalis (SIT) is a rare condition in which there is complete right to left reversal of the abdominal and thoracic organs. SIT generally does not bear any pathophysiological significance, and the survival rate of patients with SIT does not differ from that of healthy individuals. However, patients with SIT require a thorough radiological examination to identify the presence of associated anatomic variations before undergoing invasive procedures such as surgery or hemostasis of gastrointestinal hemorrhage because they may have accompanying abnormalities in anatomical structures along with reversed organs. Percutaneous endoscopic gastrostomy (PEG) is a relatively safe procedure that is most commonly performed for the enteral feeding of patients with dysphagia and a normal gastrointestinal function. However, the procedure requires extracaution because minor complications may lead to life-threatening situations due to the underlying illnesses. Here, we report the case of a patient with SIT who underwent a PEG procedure without complications, and review the existing literature on this subject. PMID- 24340263 TI - A case of early gastric cancer with solitary metastasis to the pleura. AB - The incidence of early gastric cancer (EGC) has increased to >50% in Korea owing to a higher detection rate caused by rapid advances in diagnostic instrumentation. EGC with distant metastasis has been rarely reported. Here, we report the case of a 76-year-old woman in whom general EGC was initially diagnosed by endoscopy and endoscopic ultrasonography. She subsequently underwent endoscopic submucosal dissection (ESD). Histological examination of the ESD specimen revealed that neoplastic cells were located predominantly in the submucosal layer and submucosal lymphatic channels. Metastatic cancer cells were also found in the pleural effusion. After conducting all analyses, including immunohistochemical staining, we concluded that the patient had primary EGC with pleural metastasis. PMID- 24340264 TI - A case of parasite invasion of the intestinal tract: a missed diagnosis in irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is a gastrointestinal disorder characterized by chronic abdominal pain and altered bowel habits in the absence of any organic cause. As the clinical manifestations are very diverse and associated with nonspecific symptoms, research seeking to identify organic causes to rule out IBS and to enable differential diagnosis is required. A 24-year-old man was referred to our hospital for specialized management of IBS. He had a 7-month history of intermittent epigastric and lower abdominal pain. On the basis of clinical examination, he was diagnosed with IBS and administered medication at a primary clinic. However, his symptoms did not improve after treatment. We performed capsule endoscopy at our hospital and identified a parasite (Ancylostoma duodenale) in the proximal jejunum. We therefore report a case of parasitic infection found by additional examination while evaluating symptoms associated with a previous diagnosis of refractory IBS. PMID- 24340265 TI - Intestinal capillariasis diagnosed by endoscopic biopsy. AB - Many new parasitic infections have emerged in Korea, with >35 new species appearing since the 1980s. Among them, Capillaria species are unique for contributing to morbidity in many countries as well as in Korea. Since the first reported case of a 41-year-old male patient diagnosed with intestinal capillariasis in 1991, a total of six cases have been reported thus far. In this case report, we present another imported case of intestinal capillariasis in Korea, in which a 42-year-old male patient presented with intractable diarrhea and weight loss. The diagnosis was confirmed by biopsy of the ileum. The pathognomonic radiographic presentation of a ribbon-like appearance in a small bowel series was crucial in raising an early suspicion of capillariasis and in deciding to perform diagnostic biopsy. PMID- 24340266 TI - Percutaneous Cholangioscopic Lithotripsy for Afferent Loop Syndrome Caused by Enterolith Development after Roux-en-Y Hepaticojejunostomy: A Case Report. AB - Afferent loop obstruction caused by enterolith formation is rare and cannot be easily treated with endoscopy because of the difficulty associated with the nonsurgical removal of enteroliths. A 74-year-old woman was admitted with fever and acute abdominal pain. Clinical features and imaging studies suggested afferent loop obstruction caused by an enterolith after Roux-en-Y hepaticojejunostomy. Percutaneous transhepatic biliary drainage was initially performed because of severe cholangitis with septic shock. The enterolith was located in the jejunal limb adjacent to the hepaticojejunostomy site. Cholangioscopic lithotripsy was performed through the percutaneous transhepatic route to the enterolith, and the fragments were moved into the efferent loop using scope push and saline flush methods. Here, we describe a case of afferent loop syndrome caused by an enterolith that developed after Roux-en-Y hepaticojejunostomy and was treated with percutaneous transhepatic cholangio enteroscopic lithotripsy. PMID- 24340267 TI - A Second Assisting Endoscope for the Removal of an Accidentally Unreleased Detachable Snare during Colon Polypectomy. PMID- 24340268 TI - Dermatology in the military field: What physicians should know? AB - In the civilian dermatological setting, the top 5 skin diseases usually seen are eczema/dermatitis, acne, benign skin tumors, viral infections and pigmentary disorders. In comparison, the top 5 skin conditions encountered in the military sector are usually fungal infections, eczema/dermatitis, insect bite reactions, bacterial infections and acne. This is not surprising as military personnel, due to the special environment and vocations they are in, are prone to getting eczema as heat, sweating and wearing of the military uniform aggravate the condition. Fungal infections are common in those who wear the army boots. Insect bite reactions are not an uncommon sight among those who have to go to the jungle regularly for outfield training. Grass allergy or intolerance, contact dermatitis or acneiform eruption due to the application of military camouflage cream on the face, contact dermatitis to insect repellents, and military uniform allergy and intolerance are amongst the commonest dermatological problems encountered in the military field, and physicians should recognize them, investigate and manage these problems accordingly. Lastly, a diagnosis not to be missed in the military field is cutaneous melioidosis, especially when a military personnel presents with a non-healing ulcer. PMID- 24340269 TI - Ingested bone fragment in the bowel: Two cases and a review of the literature. AB - Generally, ingested foreign bodies are excreted from the digestive tract without any complications or morbidity. In adults, ingestion of foreign bodies frequently occurs in alcoholics and elderly individuals with dentures. The most commonly ingested foreign bodies are food stuffs or their parts, such as fish bones or fragments of bone and phytobezoars. Sharp foreign bodies like fish and chicken bones can lead to intestinal perforation and peritonitis. We report herein two cases, one of bowel perforation and another of anal impaction, both caused by ingested bone fragments. Complications due to ingested bone fragments are not common and preoperative diagnosis remains a challenge and therefore it must be considered in susceptible cases. PMID- 24340270 TI - Splenic hamartoma: A case report and review of the literature. AB - Splenic hamartoma is a rare benign malformation, composed of an anomalous mixture of normal splenic elements, often found incidentally while working up other complaints or at autopsy. A splenic mass was incidentally found while evaluating the effects of a traffic accident in a 63-year-old woman. Abdominal computed tomography revealed a well-defined splenic mass with rim enhancement. The patient underwent splenectomy. The resected spleen contained a well-defined mass lesion measuring 3.5 cm * 3.0 cm. Microscopic examination revealed disorganized slit like vascular channels lined by plump endothelial cells without atypia. The cells lining the vascular channels were positive for CD8, CD31, CD34 and vimentin. Endothelial cells that are positive for CD8 are a key feature that differentiates hamartoma from other vascular lesions of the spleen. Although this tumor is very rare, it must be included in the differential diagnosis of splenic mass-forming lesions. PMID- 24340271 TI - Cytomegalovirus enteritis with jejunal perforation in a patient with endometrial adenocarcinoma. AB - Cytomegalovirus (CMV) infection of the gastrointestinal tract has been reported most frequently in the setting of immunodeficiency. The whole gastrointestinal tract can be affected; however, the small bowel is rarely affected. We report a case of CMV enteritis with jejunal perforation in a 53-year-old woman with a history of chemoradiation therapy for endometrial cancer 8 years previously. At follow-up evaluation, lower abdominal pain, diarrhea and vomiting appeared. Abdominal computed tomography showed intra-abdominal free air in the subphrenic space and porta hepatis. The jejunal segment revealed serosal purulent exudates with a perforation. The resected jejunal segment showed a large geographic ulcerative mucosal lesion. The microscopic findings revealed a diffuse ulcerative mucosal change with a prominent granulation tissue formation and many large atypical vascular endothelial cells and stromal fibroblasts with intranuclear or intracytoplasmic inclusion bodies. These cells were positive for CMV antibody. The final diagnosis was CMV-associated jejunitis with a jejunal perforation. PMID- 24340272 TI - Pneumomediastinum, pneumorachis, subcutaneous emphysema: An unusual complication of leukemia in a child. AB - Pneumorrhachis (PR), or epidural emphysema, denotes the presence of air in the spinal epidural space. It can be associated with a variety of etiologies, including trauma; recent iatrogenic manipulations during surgical, anesthesiological and diagnostic interventions; malignancy and its associated therapy. It usually represents an asymptomatic epiphenomenon but also can be symptomatic by itself, as well as by its underlying pathology, and rarely can be fatal. The pathogenesis and etiology of PR are varied and can sometimes be a diagnostic challenge. As such, there are no standard guidelines for the management of symptomatic PR and its treatment is often individualized. Here, we present a case of a 14-year-old boy treated for leukemia who developed this complication and whether chemotherapy related or not, it proved to be fatal for him. To our knowledge, this is the first case in the literature of this complication with acute lymphoblastic leukemia. PMID- 24340273 TI - Unusual case of insitu (intracystic) papillary carcinoma of breast. AB - The term "intracystic papillary ductal carcinoma in situ", has recently changed and is now more appropriately referred to as "intracystic papillary carcinoma'' constituting only 0.5% to 1% of all breast cancers. Herein, we discuss an unusual case of intracystic insitu papillary carcinoma of breast in a postmenopausal woman, the diagnosis of which was made on histopathology and confirmed by immunohistochemistry. Patient responded well to postoperative adjuvant radiotherapy without any recurrence, thereby preventing further morbidity and mortality related to invasion or tumor progression. So careful histopathological evaluation is the mainstay to arrive at the correct diagnosis to avoid untoward complications related to under diagnosis and /over diagnosis. PMID- 24340274 TI - Mongolian spots: How important are they? AB - Mongolian spots (MS) are congenital birthmarks seen most commonly over the lumbosacral area. They are bluish-green to black in color and oval to irregular in shape. They are most commonly found in individuals of African or Asian ethnic background. Although these lesions resolve by one to two years of age, widespread, extrasacral and dark colored MS sometimes persist into adulthood. Aberrant MS over occiput, temple, mandibular area, shoulders and limbs may be confused with other dermal melanocytoses and bruises secondary to child abuse, thus necessitating documentation at birth. Although traditionally believed to be benign in nature, they have now been shown to co-exist with inborn errors of metabolism, most commonly GM1 gangliosidosis and mucopolysaccharidosis type I (Hurler's disease), followed by mucopolysaccharidosis type II (Hunter's syndrome), mucolipidosis, Niemann-Pick disease and mannosidosis. They have also been seen to co-exist with various vascular or other pigmented birthmarks like cafe-au-lait macules. Co-existing Mongolian spots and vascular birthmarks like nevus flammeus, nevus anemicus or nevus spilus is termed as phakomatosis pigmentovascularis. This review focuses on the important associations of Mongolian spots and stresses upon the importance of screening babies with extensive MS. PMID- 24340275 TI - Non-pharmacological cognitive intervention for aging and dementia: Current perspectives. AB - In recent years, cognitive difficulties associated with normal aging and dementia have been receiving increased attention from both public and scientific communities. With an increase in overall lifespan, promoting healthy cognition has become a priority and a necessity for minimizing and preventing individual and societal burdens associated with cognitive dysfunctions in the elderly. The general awareness concerning the efficacy of preventive (e.g., lifestyles) and palliative treatment strategies of cognitive impairments, related to either healthy or unhealthy trajectories in cognitive aging, is continuously rising. There are several therapeutic strategies which can be broadly classified as either pharmacological or non-pharmacological/psychosocial. In face of the modest evidence for success of pharmacological treatments, especially for dementia related impairments, psychosocial interventions are progressively considered as a complementary treatment. Despite the relative spread of psychosocial interventions in clinical settings, research in this area is rather scarce with evidence for success of these therapies remaining controversial. In this work we provide an evidence based perspective on cognitive intervention(s) for healthy aging, pre-dementia (mild cognitive impairment), and dementia populations. Current evidence and future directions for improving cognitive functions in the elderly are discussed as well. PMID- 24340276 TI - Spinal pedicle subtraction osteotomy for fixed sagittal imbalance patients. AB - In addressing spinal sagittal imbalance through a posterior approach, the surgeon now may choose from among a variety of osteotomy techniques. Posterior column osteotomies such as the facetectomy or Ponte or Smith-Petersen osteotomy provide the least correction, but can be used at multiple levels with minimal blood loss and a lower operative risk. Pedicle subtraction osteotomies provide nearly 3 times the per-level correction of Ponte/Smith-Petersen osteotomies; however, they carry increased technical demands, longer operative time, and greater blood loss and associated significant morbidity, including neurological injury. The literature focusing on pedicle subtraction osteotomy for fixed sagittal imbalance patients is reviewed. The long-term overall outcomes, surgical tips to reduce the complications and suggestions for their proper application are also provided. PMID- 24340277 TI - Priming the tooth surface with chlorhexidine and antibacterial activity of resin cement. AB - AIM: To evaluate the effect of priming the tooth surface with 2% chlorhexidine gluconate on antibacterial activity of resin cement. METHODS: Ten patients in whom a single missing tooth was present on both the right and left side in the upper or lower arch were selected. Two fixed partial dentures (FPDs) in each patient on the right and left side were planned. Each FPD was assigned either to the control or test group. In the control group, FPD was luted with resin cement and in the test group, the tooth surface was primed with 2% chlorhexidine gluconate before luting with resin cement. Bacteriological samples were collected at base line level, as the patient came to the outpatient department before the start of any treatment, 5 wk prior to cementation of FPD and at 13 wk (8 wk after final cementation). Microbiological processing of all samples was done and the results were statistically analyzed. RESULTS: In the test group, a predominance of aerobic/facultative gram positive cocci rod was seen which indicates a healthy periodontal site, whereas in the control group, a predominance of anaerobic gram negative rods was present which indicates an unhealthy periodontal condition. This is evident by the fact that the anaerobic bacteria percentage in the control sample is 57% and 15% in the test sample after 13 wk, whereas the aerobic/facultative bacteria percentage is 43% in the control sample and 85% in the test sample after 13 wk. The percentage of gram negative bacteria in the control sample is 61% and in the test sample is 20% after 13 wk, whereas the percentage of gram positive bacteria in the control sample is 39% and in the test sample is 80% after 13 wk. The shift from anaerobic gram negative bacteria to aerobic gram positive bacteria is clearly seen from the control to test sample after 13 wk. CONCLUSION: The present study demonstrated that priming the tooth surface with 2% chlorhexidine gluconate may enhance antibacterial activity of the resin cement. PMID- 24340278 TI - Cortical laminar necrosis related to migrainous cerebral infarction. AB - We present a 29-year-old woman with a long history of attacks of migraine with and without visual aura. She was a heavy smoker (20 cigarettes/d) and was currently taking oral contraceptives. During a typical migraine attack with aura, she developed dysarthria, left brachial hemiparesis and hemihypoesthesia and brief and autolimited left clonic facial movements. Four hours after onset, vascular headache and focal sensorimotor neurological deficit were the only persisting symptoms and, on seventh day, she was completely recovered. Brain magnetic resonance imaging on day 20 after onset showed a subacute ischemic lesion in the right temporo-parietal cortex compatible with cortical laminar necrosis (CLN). Extensive neurological work-up done to rule out other known causes of cerebral infarct with CLN was unrevealing. Only ten of 3.808 consecutive stroke patients included in our stroke registry over a 19-year period fulfilled the strictly defined International Headache Society criteria for migrainous stroke. The present case is the unique one in our stroke registry that presents CLN related to migrainous cerebral infarction. Migrainous infarction can result in CLN. PMID- 24340279 TI - Heat stroke induced cerebellar dysfunction: A "forgotten syndrome". AB - We report a case of heat stroke induced acute cerebellar dysfunction, a rare neurological disease characterized by gross cerebellar dysfunction with no acute radiographic changes, in a 61 years old ship captain presenting with slurred speech and gait ataxia. A systematic review of the literature on heat stroke induced cerebellar dysfunction was performed, with a focus on investigations, treatment and outcomes. After review of the literature and detailed patient investigation it was concluded that this patient suffered heat stroke at a temperature less than that quoted in the literature. PMID- 24340280 TI - Experiences of Oxford House Residents Living with the Hepatitis C Virus. AB - Hepatitis C virus (HCV) is the most prevalent chronic blood-borne infection in the United States and the leading cause of chronic liver disease. HCV is transmitted through blood-to-blood contact. New infections remain common among IDUs, prisoners, and others likely to be exposed to infected blood. The purpose of this study was to use qualitative methods to gain insight into the experiences of HCV-infected residents, an approach that has proved informative in helping individuals manage similar challenging chronic illnesses. Semi-structured interviews were conducted with four Oxford House female residents living with HCV. The semi-structure qualitative interview consisted of 18 questions which were designed to focus on three broad areas: experiences of contracting and being diagnosed with HCV, ways in which HCV affected their lives, and experiences living in an Oxford House. Overall, participants were not surprised at their diagnosis, but it did impact their mood. Participants had difficulty with social functioning, experienced physical and psychological symptoms, and received a substantial amount of social support from family and Oxford House residents. PMID- 24340281 TI - Trust, verify and replicate. PMID- 24340282 TI - Should we treat nonsleepy patients with obstructive sleep apnea and atrial fibrillation with CPAP? PMID- 24340283 TI - Treatment of obstructive sleep apnea syndrome with nasal positive airway pressure improves golf performance. AB - STUDY OBJECTIVES: Obstructive sleep apnea syndrome (OSAS) is associated with impairment of cognitive function, and improvement is often noted with treatment. Golf is a sport that requires a range of cognitive skills. We evaluated the impact of nasal positive airway pressure (PAP) therapy on the handicap index (HI) of golfers with OSAS. METHODS: Golfers underwent a nocturnal polysomnogram (NPSG) to determine whether they had significant OSAS (respiratory disturbance index > 15). Twelve subjects with a positive NPSG were treated with PAP. HI, an Epworth Sleepiness Scale (ESS), and sleep questionnaire (SQ) were submitted upon study entry. After 20 rounds of golf on PAP treatment, the HI was recalculated, and the questionnaires were repeated. A matched control group composed of non-OSAS subjects was studied to assess the impact of the study construct on HI, ESS, and SQ. Statistical comparisons between pre- and post-PAP treatment were calculated. RESULTS: The control subjects demonstrated no significant change in HI, ESS, or SQ during this study, while the OSAS group demonstrated a significant drop in average HI (11.3%, p = 0.01), ESS, (p = 0.01), and SQ (p = 0.003). Among the more skilled golfers (defined as HI <= 12), the average HI dropped by an even greater degree (31.5%). Average utilization of PAP was 91.4% based on data card reporting. CONCLUSIONS: Treatment of OSAS with PAP enhanced performance in golfers with this condition. Treatment adherence was unusually high in this study. Non-medical performance improvement may be a strong motivator for selected subjects with OSAS to seek treatment and maximize adherence. PMID- 24340284 TI - Does treating obstructive sleep apnea in golfers improve their handicap? PMID- 24340285 TI - Sleep and insulin-like growth factors in the Cardiovascular Health Study. AB - STUDY OBJECTIVES: Sleep and sleep disordered breathing (obstructive sleep apnea [OSA]) are known to affect the growth hormone/insulin-like growth factor (GH/IGF) axis. There are few relevant population studies in this area, particularly in the elderly. We conducted this study to investigate the relationship between sleep (architecture and OSA) and circulating IGF-I (insulin-like growth factor-1), IGFBP-1 (insulin-like growth factor binding protein-1), and IGFBP-3 (insulin-like growth factor binding protein-3) levels in an elderly population. DESIGN SETTING: Cross-sectional analysis of participants from the year 9 visit of the Cardiovascular Health Study (CHS) who were enrolled in the Sleep Heart Health Study (SHHS). PATIENTS OR PARTICIPANTS: 1,233 elderly participants from the CHS and SHHS. MEASUREMENTS AND RESULTS: The mean age of males (n = 526) and females (n = 697) was 77 years. The mean value of IGF-I (ng/mL) in males was 112.4 vs. 97.1 in females (p < 0.01). Mean IGFBP-1 and IGFBP-3 levels were higher in females than males (p < 0.01). As expected, slow wave sleep was better preserved in females compared to males (22% total sleep time vs. 9% total sleep time, p < 0.01). Furthermore, as expected, OSA (apneahypopnea index [AHI] >= 5/h) was more prevalent in males compared to females (60% vs. 46%, p < 0.01). Multivariable linear regression was used to determine the relationship between objective sleep parameters and circulating IGF-I, IGFBP-1, and IGFBP-3 levels, with adjustment for age, sex, race, BMI, diabetes, estrogen use, progestin use, and physical activity. We did not detect a significant association between slow wave sleep (SWS) (per 5 min) and IGF-I, IGFBP-1, and IGFBP-3 levels (ng/mL). We found no significant linear association between OSA (AHI >= 5/h) and IGF-I, IGFBP-1, and IGFBP-3 levels. Gender-stratification of the entire cohort did not alter these findings. Sensitivity analyses excluding diabetics revealed that moderate OSA (AHI >= 5 and < 15) is inversely associated with IGFBP-3 levels in women. Conclusions The relationship between SWS and GH/IGF system is not significant in the elderly. Furthermore, OSA does not appear to adversely influence the GH/IGF axis, as reported in younger individuals. Whether our study findings are due to diminished GH/IGF-I axis activity in elderly needs further investigation by replication in other large population based elderly cohorts. PMID- 24340286 TI - The comorbidity of sleep apnea and mood, anxiety, and substance use disorders among obese military veterans within the Veterans Health Administration. AB - OBJECTIVES: To determine the relations between obstructive sleep apnea (OSA) diagnosis, the likelihood of being diagnosed with a psychological condition, among obese veterans, after accounting for severity of obesity and the correlated nature of patients within facility. We hypothesized that (1) individuals with a diagnosis of OSA would be more likely to receive a diagnosis of a (a) mood disorder and (b) anxiety disorder, but not (c) substance use disorder. DESIGN: Cross-sectional retrospective database review of outpatient medical records between October 2009 and September 2010, conducted across all 140 Veterans Health Administration (VHA) facilities. SETTING: The entire VA Health Care System. PATIENTS OR PARTICIPANTS: Population-based sample of veterans with obesity (N = 2,485,658). MAIN OUTCOME MEASURES: Physician- or psychologist-determined diagnosis of psychological conditions including mood, anxiety, and substance use disorders. RESULTS: Using generalized linear mixed modeling, after accounting for the correlated nature of patients within facility and the severity of obesity, individuals with a diagnosis of sleep apnea had increased odds of receiving a mood disorder diagnosis (OR = 1.85; CI = 1.71-1.72; p < 0.001), anxiety disorder diagnosis (OR = 1.82; CI = 1.77-1.84; p < 0.001), but not a diagnosis of substance use disorder. CONCLUSIONS: Among obese veterans within VA, OSA is associated with increased risk for having a mood and anxiety disorder, but not substance use disorder, with the strongest associations observed for posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). In addition, this relation remained after accounting for severity of BMI. PMID- 24340287 TI - Comparing a combination of validated questionnaires and level III portable monitor with polysomnography to diagnose and exclude sleep apnea. AB - STUDY OBJECTIVES: Questionnaires have been validated as screening tools in adult populations at risk for obstructive sleep apnea (OSA). Portable monitors (PM) have gained acceptance for confirmation of OSA in some patients with a high pretest probability of the disorder. We evaluated the combined diagnostic utility of 3 validated questionnaires and a Level III PM in the diagnosis and exclusion of OSA, as compared with in-laboratory polysomnography (PSG) derived apnea hypopnea index (AHI). METHODS: Consecutive patients referred to the Sleep Disorders Clinic completed 3 testing components: (1) 3 questionnaires (Berlin, STOP-Bang, and Sleep Apnea Clinical Score [SACS]); (2) Level III at-home PM (MediByte) study; and (3) Level I in-laboratory PSG. The utility of individual questionnaires, the Level III device alone, and the combination of questionnaires and the Level III device were compared with the PSG. RESULTS: One hundred twenty eight patients participated in the study (84M, 44F), mean +/- SD age 50 +/- 12.3years, BMI 31 +/- 6.6 kg/m(2). At a PSG threshold AHI = 10, the PM derived respiratory disturbance index (RDI) had a sensitivity and specificity of 79% and 86%, respectively. The sensitivity and specificity for the other screening tools were: Berlin 88%, 25%; STOP-Bang 90%, 25%; SACS 33%, 75%. The sensitivity and specificity at a PSG AHI = 15 were: PM 77%, 95%; Berlin 91%, 28%; STOP-Bang 93%, 28%; SACS 35%, 78%. CONCLUSIONS: Questionnaires alone, possibly given a reliance on sleepiness as a symptom, cannot reliably rule out the presence of OSA. Objective physiological measurement is critical for the diagnosis and exclusion of OSA. PMID- 24340288 TI - Excessive daytime sleepiness is associated with longer culprit lesion and adverse outcomes in patients with coronary artery disease. AB - STUDY OBJECTIVES: We assessed whether excessive daytime sleepiness was associated with coronary plaque phenotype and subsequent adverse cardiovascular events. METHODS: Prospective cohort study. Intravascular ultrasound (IVUS) examination of the culprit coronary stenosis was performed. The Epworth Sleepiness Scale (ESS) questionnaire was administered, and the patients were divided into 2 groups-(1) sleepier and (2) less sleepy-based on the ESS score. Adverse cardiovascular outcomes were defined as cardiac death, myocardial infarction, stroke, unplanned revascularization, or heart failure admission. RESULTS: One hundred seventeen patients undergoing urgent or non-urgent coronary angiography were recruited. Compared with the less sleepy group (ESS <= 10, n = 87), the sleepier group (ESS > 10, n = 30) had higher serum levels of total cholesterol and of low-density lipoprotein cholesterols (p < 0.05 for both). The IVUS examinations indicated coronary stenoses were longer in the sleepier group than in the less sleepy group (p = 0.011). The cumulative incidence of adverse cardiovascular events at 16 month follow-up was higher in the sleepier than the less sleepy group (12.5% versus 6.9%, p = 0.03). Cox regression analysis adjusting for age and smoking showed increased hazard of adverse cardiovascular events in sleepier group as compared to less sleepy group (HR = 3.44, 95% CI 1.01-11.72). CONCLUSION: In patients presenting with coronary artery disease, excessive daytime sleepiness based on ESS > 10 was associated with longer culprit lesions and future adverse cardiovascular events. PMID- 24340289 TI - Types of primary insomnia: is hyperarousal also present during napping? AB - STUDY OBJECTIVES: The objective of this study was to identify if hyperarousal is a 24-hour phenomenon in insomnia by comparing sleep during napping between good sleepers (GS) and Insomnia sufferers (INS) (subdivided into paradoxical "PARA-I" and psychophysiological "PSY-I") following a mentally challenging battery of cognitive tests. DESIGN: Cross-sectional comparisons of GS, PSY-I, and PARA-I. SETTING: Participants slept for 4 consecutive nights in the laboratory where PSG was recorded. Upon awakening on mornings 2 and 3, cognitive testing (lasting 90 120 min) was administered, followed by a 20-minute nap. PARTICIPANTS: Fourteen PSY-I, 12 PARA-I, and 23 GS completed the study, comprising home questionnaires, clinical interviews, night PSG recordings, cognitive testing, and nap PSG recordings. All participants were between 25 and 50 years of age and met inclusion criteria for PSY-I, PARA-I, or GS. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: On objective nap parameters, GS had a longer total sleep time (TST; p = 0.008) and better sleep efficiency (SE; p = 0.009), than PSY-I and PARA-I, and both groups of INS were awake significantly longer than GS (p = 0.003). Also, PARA-I took significantly more time than GS to fall asleep (p = 0.014). Subjectively reported sleepiness was comparable across the three groups. Positive relationships were observed between SE over the night and SE over the nap the following day. CONCLUSIONS: Results show that GS sleep better than INS during naps following prolonged cognitive testing, suggesting that, in INS, hyperarousal predominates over mental fatigue resulting from these tests. These results may parallel what is observed at night when INS experience increased cognitive load but are unable to fall asleep. PMID- 24340290 TI - Predictors of treatment response to brief behavioral treatment of insomnia (BBTI) in older adults. AB - STUDY OBJECTIVES: The extant literature on predictors of treatment response to behavioral treatments for insomnia is equivocal and limited in scope. The current study examined demographic, clinical, and sleep characteristics as predictors of clinically significant treatment response to brief behavioral treatment of insomnia (BBTI) in older adults with insomnia. METHODS: Thirty-nine older adults with insomnia (67% females, mean age: 72.54 years) were randomized to BBTI treatment. Treatment outcomes were defined according to 2 criteria: (1) "response," defined as change in Pittsburgh Sleep Quality Index (PSQI) score >= 3 points or increase in sleep diary sleep efficiency >= 10%); or (2) remission, defined as absence of a clinical diagnosis of insomnia according to standard diagnostic criteria. Logistic regression examined whether baseline demographic, clinical, or sleep characteristics predicted treatment outcomes at 1 month follow up. RESULTS: Demographic variables did not predict treatment outcomes for either criterion. Higher anxiety, depression, poorer sleep quality, and longer polysomnography (PSG)-assessed sleep latency predicted greater likelihood of response at follow-up (p < 0.05). Longer sleep duration at baseline (measured by sleep diary and PSG) predicted greater likelihood of the remission at follow-up (p < 0.05). CONCLUSION: Patients with insomnia who have greater distress at baseline or prolonged sleep latency are more likely to show positive response to BBTI. In contrast, short sleepers at baseline are less likely to have resolution of insomnia diagnosis following BBTI, perhaps due to the sleep restriction component of the treatment. Identifying the characteristics that predict positive BBTI treatment outcomes can facilitate personalized behavioral treatments to improve outcomes. PMID- 24340291 TI - The sleep and technology use of Americans: findings from the National Sleep Foundation's 2011 Sleep in America poll. AB - STUDY OBJECTIVES: To describe the technology use and sleep quality of Americans, and the unique association between technology use and sleep disturbances. METHODS: Interviews were conducted via random digit dialing (N = 750) or the Internet (N = 758). 1,508 Americans (13-64 years old, 50% males) matched to 2009 U.S. Census data provided complete interviews. The sample was further divided into adolescents (13-18 years, N = 171), young adults (19-29 years, N = 293), middle-aged adults (30-45 years, N = 469), and older adults (46-64 years, N = 565) to contrast different generations' technology use. Participants answered a 47-item semi-structured survey, including questions about their sleep habits, and the presence and use of technology in the hour before bed in the past 2 weeks. RESULTS: Nine of 10 Americans reported using a technological device in the hour before bed (e.g., TVs the most popular; 60%). However, those under 30 years of age were more likely to use cell phones (72% of adolescents, 67% of young adults) than those over 30 years (36% of middle-aged, and 16% of older adults). Young adults' sleep patterns were significantly later than other age groups on both weekdays and weekend nights. Unlike passive technological devices (e.g., TV, mp3 music players), the more interactive technological devices (i.e., computers/laptops, cell phones, video game consoles) used in the hour before bed, the more likely difficulties falling asleep (beta = 9.4, p < 0.0001) and unrefreshing sleep (beta = 6.4, p < 0.04) were reported. CONCLUSIONS: Technology use near bedtime is extremely prevalent in the United States. Among a range of technologies, interactive technological devices are most strongly associated with sleep complaints. PMID- 24340292 TI - The use of technology at night: impact on sleep and health. PMID- 24340293 TI - Investigating reasons for CPAP adherence in adolescents: a qualitative approach. AB - STUDY OBJECTIVES: Adolescents with obstructive sleep apnea syndrome (OSAS) represent an important but understudied subgroup of long-term continuous positive airway pressure (CPAP) users. The purpose of this qualitative study was to identify factors related to adherence from the perspective of adolescents and their caregivers. METHODS: Individual open-ended, semi-structured interviews were conducted with adolescents (n = 21) and caregivers (n = 20). Objective adherence data from the adolescents' CPAP machines during the previous month was obtained. Adolescents with different adherence levels and their caregivers were asked their views on CPAP. Using a modified grounded theory approach, we identified themes and developed theories that explained the adolescents' adherence patterns. RESULTS: Adolescent participants (n = 21) were aged 12-18 years, predominantly male (n = 15), African American (n = 16), users of CPAP for at least one month. Caregivers were mainly mothers (n = 17). Seven adolescents had high use (mean use 381 +/- 80 min per night), 7 had low use (mean use 30 +/- 24 min per night), and 7 had no use during the month prior to being interviewed. Degree of structure in the home, social reactions, mode of communication among family members, and perception of benefits were issues that played a role in CPAP adherence. CONCLUSIONS: Understanding the adolescent and family experience of using CPAP may be key to increasing adolescent CPAP adherence. As a result of our findings, we speculate that health education, peer support groups, and developmentally appropriate individualized support strategies may be important in promoting adherence. Future studies should examine these theories of CPAP adherence. PMID- 24340294 TI - The accuracy of eyelid movement parameters for drowsiness detection. AB - STUDY OBJECTIVES: Drowsiness is a major risk factor for motor vehicle and occupational accidents. Real-time objective indicators of drowsiness could potentially identify drowsy individuals with the goal of intervening before an accident occurs. Several ocular measures are promising objective indicators of drowsiness; however, there is a lack of studies evaluating their accuracy for detecting behavioral impairment due to drowsiness in real time. METHODS: In this study, eye movement parameters were measured during vigilance tasks following restricted sleep and in a rested state (n = 33 participants) at three testing points (n = 71 data points) to compare ocular measures to a gold standard measure of drowsiness (OSLER). The utility of these parameters for detecting drowsiness related errors was evaluated using receiver operating characteristic curves (ROC) (adjusted by clustering for participant) and identification of optimal cutoff levels for identifying frequent drowsiness-related errors (4 missed signals in a minute using OSLER). Their accuracy was tested for detecting increasing frequencies of behavioral lapses on a different task (psychomotor vigilance task [PVT]). RESULTS: Ocular variables which measured the average duration of eyelid closure (inter-event duration [IED]) and the ratio of the amplitude to velocity of eyelid closure were reliable indicators of frequent errors (area under the curve for ROC of 0.73 to 0.83, p < 0.05). IED produced a sensitivity and specificity of 71% and 88% for detecting >= 3 lapses (PVT) in a minute and 100% and 86% for >= 5 lapses. A composite measure of several eye movement characteristics (Johns Drowsiness Scale) provided sensitivities of 77% and 100% for detecting 3 and >= 5 lapses in a minute, with specificities of 85% and 83%, respectively. CONCLUSIONS: Ocular measures, particularly those measuring the average duration of episodes of eye closure are promising real-time indicators of drowsiness. PMID- 24340295 TI - Salivary biomarkers of physical fatigue as markers of sleep deprivation. AB - STUDY OBJECTIVE: Determine whether a salivary biomarker of physical fatigue, referred to as the fatigue biomarker index (FBI), can discriminate a control group from a sleep deprived group when saliva is collected under controlled conditions. The study expands on previous work examining changes in the composition of saliva during periods of prolonged exercise. METHODS: Thirty (30) young adults (14 Control [CON]; 16 Sleep Deprived [SDEP]) were monitored for mood state (Profile of Mood States [POMS]), cognitive performance (Stroop Color Conflict Tests), and salivary biomarkers of physical fatigue over a 48-h period with sampling at 3-h intervals. Trials lasted from 06:00 on day 1 (time = -3 h) to 09:00 on day 3 (time = 48 h). Levels of salivary biomarkers were calculated from liquid chromatography-mass spectrometry (LC-MS) data. Statistical comparisons were made using Wilcoxon rank sum tests with a Bonferroni correction to limit type 1 error. Receiver-operator characteristic (ROC) analysis was used to evaluate the ability of the various parameters to distinguish the SDEP population from the CON population. RESULTS: Longitudinal analysis demonstrated significant between-group differences in all three parameters. ROC analysis demonstrated that cognitive performance tests and salivary biomarkers of physical fatigue distinguish the SDEP population from the CON population. CONCLUSIONS: A previously identified salivary biomarker of physical fatigue may provide an alternative method for discriminating sleep deprived from rested individuals. The salivary biomarker of physical fatigue holds promise as an objective measure of sleep deprivation, perhaps eventually removing the reliance on self-reported sleep diaries and/or repeated polysomnographs for longitudinal tracking of sleep quality and/or diagnosis of sleep disorders. PMID- 24340297 TI - Treatment of cataplexy in a three-year-old using venlafaxine. AB - Narcolepsy with cataplexy is rare in children under 5 years of age. There is limited information on safe and effective treatment of cataplexy in young children. We describe successful treatment of cataplexy in a 3-year-old using venlafaxine and subsequently followed for over 2 years. PMID- 24340296 TI - A twin study of genetic influences on diurnal preference and risk for alcohol use outcomes. AB - OBJECTIVE: The population-based University of Washington Twin Registry (UWTR) was used to examine (1) genetic influences on chronobiology and (2) whether these genetic factors influence alcohol-use phenotypes. METHODS: We used a reduced Horne-Ostberg Morningness-Eveningness Questionnaire (rMEQ) to survey UWTR participants for diurnal preference. Frequency and quantity of alcohol use, as well as binge drinking (6+ drinks per occasion), were assessed on a 5-point Likert scale. Both diurnal preference and alcohol use were self-reported. Twin data were analyzed by using structural equation models. RESULTS: The sample consisted of 2,945 participants (mean age = 36.4 years), including 1,127 same-sex and opposite-sex twin pairs and 691 individual twins. The rMEQ range was 4-25, with a mean score of 15.3 (SD 4.0). Diurnal "morning types" comprised 30.7% (N = 903) of participants, while 17.4% (N = 513) were "evening types." Regarding alcohol use, 21.2% (N = 624) reported never drinking. Among drinkers, 35.7% (N = 829) reported >= 3 drinks per occasion and 48.1% (N = 1,116) reported at least one instance of binge drinking. Genetic influences accounted for 37% of the variance in diurnal preference, with the remaining 63% due to non-shared environmental influences. Genetic propensities toward diurnal eveningness were significantly associated with increased alcohol quantity (beta = -0.17; SE = 0.05, p < 0.001) and increased binge drinking (beta = -0.19; SE = 0.04, p < 0.001), but not with frequency of alcohol use. Environmental paths between diurnal preference and alcohol use phenotypes were not significant. CONCLUSIONS: Genetic influences on diurnal preference confer elevated risk for problematic alcohol use, including increased quantity and binge drinking. Differences in circadian rhythm may be an important and understudied pathway of risk for genetic influences on alcohol use. PMID- 24340298 TI - Does the clinical phenotype of fatal familial insomnia depend on PRNP codon 129 methionine-valine polymorphism? AB - Fatal familial insomnia (FFI) is a rare, hereditary prion-protein disease. Methionine-valine polymorphism at codon 129 of the prion-protein gene (PRNP) determines the phenotype in other hereditary prion-protein diseases, but association with the clinical phenotype in FFI remains uncertain. Early clinical findings in FFI comprise disturbances of the sleep-wake cycle and mild neuropsychiatric changes which typically emerge during middle to late adulthood. Here we describe an unusually early onset and rapid progression of FFI associated with dorsal midbrain involvement in a female patient with PRNP mutation at codon 178 and homozygote methionine polymorphism at codon 129. Early dorsal midbrain involvement became apparent by total loss of REM sleep and isolated bilateral trochlear nerve palsy. Early onset and rapid progression disease type associated with dorsal midbrain involvement may indicate a different spatiotemporal distribution of the neurodegenerative process in FFI patients with PRNP mutation and codon 129 methionine homozygosity compared to methioninevaline heterozygosity. PMID- 24340299 TI - Alternobaric vertigo in a patient on positive airway pressure therapy. AB - Continuous positive airway pressure (CPAP) is a safe therapy for the management of obstructive sleep apnea (OSA). Complications such as sinus infection, bronchitis, ear pain, nasal congestion, and dryness of mucous membranes secondary to CPAP use have been reported. To follow, we describe a rare case of alternobaric vertigo secondary to CPAP therapy. To date, there has been only one reported case of hearing loss and vertigo during CPAP treatment with complete resolution of symptoms after cessation of PAP. However, re-challenging the patient with CPAP at gradual increments was never reported. PMID- 24340301 TI - Nocturnal oral movements in a patient with schizophrenia. Edentulous oral dyskinesia. PMID- 24340300 TI - Sleep and pregnancy-induced hypertension: a possible target for intervention? AB - Sleep disturbances in the general population are associated with elevated blood pressure. This may be due to several mechanisms, including sympathetic activation and hypothalamic-pituitary-adrenal (HPA) axis disturbance. Elevated blood pressure in pregnancy can have devastating effects on both maternal and fetal health and is associated with increased risk for preeclampsia and poor delivery outcomes. Preliminary evidence suggests that mechanisms linking sleep and blood pressure in the general population may also hold in the pregnant population. However, the effects of disturbed sleep on physiologic mechanisms that may directly influence blood pressure in pregnancy have not been well studied. The role that sleep disturbance plays in gestational blood pressure elevation and its subsequent consequences warrant further investigation. This review evaluates the current literature on sleep disturbance and elevated blood pressure in pregnancy and proposes possible treatment interventions. PMID- 24340302 TI - Nucleotide substitutions in the Candida albicans ERG11 gene of azole-susceptible and azole-resistant clinical isolates. AB - One of the mechanisms of Candida albicans resistance to azole drugs used in antifungal therapy relies on increased expression and presence of point mutations in the ERG11 gene that encodes sterol 14alpha demethylase (14DM), an enzyme which is the primary target for the azole class of antifungals. The aim of the study was to analyze nucleotide substitutions in the Candida albicans ERG11 gene of azole-susceptible and azole-resistant clinical isolates. The Candida albicans isolates represented a collection of 122 strains selected from 658 strains isolated from different biological materials. Samples were obtained from hospitalized patients. Fluconazole susceptibility was tested in vitro using a microdilution assay. Candida albicans strains used in this study consisted of two groups: 61 of the isolates were susceptible to azoles and the 61 were resistant to azoles. Four overlapping regions of the ERG11 gene of the isolates of Candida albicans strains were amplified and sequenced. The MSSCP (multitemperature single strand conformation polymorphism) method was performed to select Candida albicans samples presenting genetic differences in the ERG11 gene fragments for subsequent sequence analysis. Based on the sequencing results we managed to detect 19 substitutions of nucleotides in the ERG11 gene fragments. Sequencing revealed 4 different alterations: T495A, A530C, G622A and A945C leading to changes in the corresponding amino acid sequence: D116E, K128T, V159I and E266D. The single nucleotide changes in the ERG11 gene did not affect the sensitivity of Candida albicans strains, whereas multiple nucleotide substitutions in the ERG11 gene fragments indicated a possible relation with the increase in resistance to azole drugs. PMID- 24340303 TI - A computational approach to structural properties of glycoside hydrolase family 4 from bacteria. AB - Structural bioinformatics approaches applied to the alpha- and beta-glycosidases from the GH4 enzyme family reveal that, despite low sequence identity, these enzymes possess quite similar global structural characteristics reflecting a common reaction mechanism. Locally, there are a few distinctive structural characteristics of GH4 alpha- and beta-glycosidases, namely, surface cavities with different geometric characteristics and two regions with highly dissimilar structural organizations and distinct physicochemical properties in the alpha- and beta-glucosidases from Thermotoga maritima. We suggest that these structurally dissimilar regions may be involved in specific protein-protein interactions and this hypothesis is sustained by the predicted distinct functional partners of the investigated proteins. Also, we predict that alpha- and beta-glycosidases from the GH4 enzyme family interact with difenoconazole, a fungicide, but there are different features of these interactions especially concerning the identified structurally distinct regions of the investigated proteins. PMID- 24340304 TI - Dynamics of reactive oxygen species generation in the presence of copper(II) histidine complex and cysteine. AB - Histidine-copper(II) complex (Cu-His2) is a form of bound copper necessary for cellular copper uptake. Due to the high affinity of histidine to copper(II) ions, the binding of copper(II) by histidine is considered a substantial part of plasma antioxidative defense. Also cysteine plays a role in the antioxidative system. However, we show here that in the presence of oxygen the histidine-copper(II) complex plus cysteine produces reactive oxygen species (ROS). Cysteine concentration was assayed using a thiol specific silver-mercury electrode. Hydrogen peroxide was assayed amperometrically using platinum electrode. ROS formation was followed by chemiluminescence of luminol-fluoresceine-enhanced system. Addition of cysteine to Cu-His2 solution at pH 7.4 in the presence of atmospheric oxygen initiates the synthesis of H2O2 and generation of ROS, which manifests as a burst of chemiluminescence. The reaction has two stages; in the first stage, cysteine is utilized for the synthesis of an unstable intermediary product which becomes a substrate for ROS formation. Anaerobic conditions inhibit ROS formation. Increased cysteine concentration enhances the lag phase of the oxidative burst without influencing the amount of ROS. The synthesis of ROS (measured by chemiluminescence) is proportional to the concentration of Cu-His2 employed. ROS production can be repetitively initiated by further additions of cysteine to the reaction medium. The study suggests that Cu-His2 catalyzes cysteine-dependent reduction of oxygen to superoxide employing an intermediary cysteine-copper(I) complex and enabling Fenton reaction with copper and hydrogen peroxide produced as a secondary product. In effect, Cu-His2 with cysteine may be a source of ROS in biological media. PMID- 24340305 TI - Alternative 3' acceptor site in the exon 2 of human PAX8 gene resulting in the expression of unknown mRNA variant found in thyroid hemiagenesis and some types of cancers. AB - PAX8 gene encodes one of the transcription factors engaged in the regulation of proper development of thyroid gland as well as Mullerian and renal/upper urinary tracts. So far, six alternatively spliced transcripts were reported, however, sequences of only four were deposited in the NCBI database. Here, we evaluate a fragment of a novel variant of PAX8 mRNA formed by an alternative 3' acceptor site located in the second exon. The molecular outcome encompasses extension of the 5' untranslated region of exon two by 97 nucleotides as is evident from mRNA. This new insert may impair binding of mRNA to the ribosome and in consequence significantly decrease expression of the PAX8 protein. Here, we show for the first time that the novel insert in exon two might be associated with congenital thyroid hemiagenesis and influence development of different types of cancer. PMID- 24340306 TI - Nanosilver - does it have only one face? AB - Silver nanoparticles (NPs) have at least one dimension of a particle smaller than 100 nm and contain 20-15,000 silver atoms. Due to its antibacterial activity nanosilver (NS) is used for medical purposes. NS particles can be obtained by various methods. Potentially, the best method of the NS synthesis for medical purposes is based on a brief flow of electric current between two silver electrodes placed in deionized water. It is accepted that the major antibacterial effect of silver is its partial oxidation and releasing silver ions, which interact with thiol groups of peptidoglicans of bacterial cell wall, and proteins of the cell membrane causing cell lysis. Silver ions can also bind to bacterial DNA preventing its replication and stopping synthesis of bacterial proteins. The rise in exposure to silver NPs has spurred interest into their toxicology. NS undergoes a set of biochemical transformations including accelerated oxidative dissolution in gastric acid, binding to thiol groups of serum and tissue proteins, exchange between thiol groups, sulfides and selenides, binding to selenoproroteins and photoreduction in skin to zerovalent metallic silver. Animal studies have shown that exposure to NS may lead to liver and spleen damage. NS can also stimulate an increased secretion of proinflammatory cytokines by monocytes. As a spectrum of NS applications is still growing, the complex evaluation of a safety of its use becomes an important task. This requires an elucidation of not only the influence of NS on human cells and organism, but also its biotransformation in organism and in environment. PMID- 24340307 TI - Concentrations of heavy metals (Mn, Co, Ni, Cr, Ag, Pb) in coffee. AB - AIM: Technologies involved in roasting coffee beans, as well as the methods used to prepare infusions, vary according to culture, and contribute to differences in the concentration of elements in the drink. MATERIALS AND METHODS: Concentrations of six elements: manganese (Mn), cobalt (Co), nickel (Ni), chrome (Cr), silver (Ag) and lead (Pb) were investigated in coffee infusions from eleven samples of coffee, roasted and purchased in four countries: Bosnia and Herzegovina, Brazil, Lebanon and Poland. Metal concentrations were determined using an induction coupled plasma technique in combination with mass spectrometry (ICP-MS, Perkin Elmer) which measures total metal (ionic and non-ionic) content. RESULTS: Metal intake estimated for individual countries (in the respective order; mean consumption per person per year) was as follows: Mn: 26.8-33.1, 28.3-29.5, 29.7, 12.6-18.9 mg; Co: 0.33-0.48, 0.42-0.35, 0.32, 0.12-0.17 mg; Ni: 3.83-5.68, 4.85 5.51, 4.04, 2.06-2.24 mg; Cr: 0.17-0.41, 0.21-0.47, 0.17, 0.09-0.28 mg; Ag: 0.16 1.13, 0.26-0.70, 0.61, 0.33-1.54 mg, Pb: 4.76-7.56, 3.59-5.13, 3.33, 1.48-2.43 mg. CONCLUSIONS: This finding gives new data for Mn, Co, Ni, Cr, and Ag intake from coffee , and suggests that the amounts are negligible. However, the data for Pb consumption in heavy drinkers, for example in Bosnia and Herzegovina, indicate that Pb intake from coffee may contribute to the disease burden. The high lead level in some coffees suggests the need for a more precise control of coffee contamination. PMID- 24340308 TI - A polyp from another polyp. PMID- 24340309 TI - Endoscopic ultrasonographic features of gastric mucosa-associated lymphoid tissue lymphoma with a 'pseudocircumvolutory' appearance. PMID- 24340310 TI - Endoscopic submucosal dissection in the colorectum: Feasibility in the Canadian setting. AB - Endoscopic submucosal dissection is a minimally invasive endoscopic technique for the removal of gastrointestinal tumours that is increasingly being used for colonic neoplasms to spare resection of colon in selected patients. Colonic endoscopic submucosal dissection is technically challenging and was initially pioneered in Japan but increasingly used in selected western centres. Its use in Canada is currently limited, and the authors review the challenges and opportunities, in addition to the unique training infrastructure required to practice the procedure under supervision. Specific tools are required to perform endoscopic submucosal dissection and meticulous attention to detail is essential. The authors provide a combined Japanese and Canadian perspective to this technique, and discuss training and performance of endoscopic submucosal dissection as well as potential indications. PMID- 24340311 TI - What is the best regimen for Helicobacter pylori eradication in Canadian Arctic Aboriginals? PMID- 24340312 TI - Putting an end to the misuse of the fecal occult blood test in diagnostic medicine. PMID- 24340313 TI - Improving the quality of colonoscopy bowel preparation using an educational video. AB - Colonoscopy is the preferred modality for colon cancer screening. A successful colonoscopy requires proper bowel preparation. Adequate bowel preparation continues to remain a limiting factor. One hundred thirty-three patients scheduled for an outpatient colonoscopy were prospectively randomized in a single blinded manner to video or nonvideo group. In addition to written bowel preparation instructions, patients in the video group viewed a brief instructional video. Quality of colon preparation was measured using the Ottawa Bowel Preparation Quality scale, while patient satisfaction with preparation was evaluated using a questionnaire. Statistical analyses were used to evaluate the impact of the instructional colonoscopy video. There were significant differences in the quality of colonoscopy preparation between the video and the nonvideo groups. Participants who watched the video had better preparation scores in the right colon (P=0.0029), mid-colon (P=0.0027), rectosigmoid (P=0.0008), fluid content (P=0.03) and aggregate score (median score 4 versus 5; P=0.0002). There was no difference between the two groups with regard to patient satisfaction. Income, education level, sex, age and family history of colon cancer had no impact on quality of colonoscopy preparation or patient satisfaction. The addition of an instructional bowel preparation video significantly improved the quality of colon preparation. PMID- 24340314 TI - A randomized controlled trial comparing sequential with triple therapy for Helicobacter pylori in an Aboriginal community in the Canadian North. AB - BACKGROUND: Helicobacter pylori infection occurs more frequently in Arctic Aboriginal settings than elsewhere in North America and Europe. Research aimed at reducing health risks from H pylori infection has been conducted in the Aboriginal community of Aklavik, Northwest Territories. OBJECTIVE: To compare the effectiveness of the Canadian standard therapy with an alternative therapy for eliminating H pylori infection in Aklavik. METHODS: Treatment-naive H pylori positive individuals were randomly assigned to a 10-day regimen (oral twice-daily doses) with rabeprazole (20 mg): standard triple therapy (proton pump inhibitor, added clarithromycin [500 mg] and amoxicillin [1 g] [PPI-CA]); sequential therapy (ST) added amoxicillin (1 g) on days 1 to 5, and metronidazole (500 mg) and clarithromycin (500 mg) on days 6 to 10. Participants with clarithromycin resistant H pylori were randomly assigned to ST or quadruple therapy. Treatment effectiveness was estimated as per cent (95% CI) with a negative urea breath test at least 10 weeks after treatment. RESULTS: Of 104 (53 PPI-CA, 51 ST) randomized participants, 89 (49 PPI-CA, 40 ST) had post-treatment results. Per-protocol treatment effectiveness was 59% (95% CI 45% to 73%) for PPI-CA and 73% (95% CI 58% to 87%) for ST. Based on intention to treat, effectiveness was 55% (95% CI 41% to 69%) for PPI-CA and 57% (95% CI 43% to 71%) for ST. Of 77 participants (43 PPI-CA, 34 ST) with 100% adherence, effectiveness was 63% (95% CI 43% to 82%) for PPI-CA and 81% (95% CI 63% to 99%) for ST. CONCLUSIONS: While additional evidence is needed to confirm that ST is more effective for Arctic Aboriginal communities than the Canadian standard H pylori treatment, these results show standard PPI-CA treatment to be inadequate for communities such as Aklavik. PMID- 24340315 TI - Treatment of chronic hepatitis C in a Canadian Aboriginal population: results from the PRAIRIE study. AB - BACKGROUND: The Aboriginal population of Canada is at increased risk of exposure to the hepatitis C virus (HCV). Previous data indicate that spontaneous clearance of HCV occurs more often in Aboriginals than Caucasians. Whether this enhanced response extends to antiviral therapy for chronic HCV remains to be determined. OBJECTIVES: To document and compare the biochemical and virological responses to antiviral therapy in HCV-infected Canadian Aboriginals and Caucasians. METHODS: A total of 101 treatment-naive adult patients (46 Aboriginal, 55 Caucasian) with chronic HCV genotype 1 infections were prospectively treated with pegylated interferon and ribavirin and followed as per national guidelines. RESULTS: Aboriginals had higher HCV-RNA loads at baseline (6.42log(10) versus 5.98log(10); P<0.03). Although normalization of serum aminotransferase levels, decreases in viral loads, and rapid, early and end-of-treatment virological responses were similar in the two cohorts, sustained virological responses were significantly lower in Aboriginals (35% versus 55%; P=0.047). Premature discontinuation of treatment and/or loss of patients to follow-up was common (Aboriginals 37%, Caucasians 27%). Treatment-related side effects were similar in the two cohorts. CONCLUSION: Despite higher rates of spontaneous HCV clearance, the response to antiviral therapy was similar, if not lower, in Aboriginals compared with Caucasians with chronic HCV genotype 1 infections. Compliance with treatment is an issue that needs to be addressed in the management of these patients. PMID- 24340316 TI - Use of fecal occult blood test in hospitalized patients: survey of physicians practicing in a large central Canadian health region and Canadian gastroenterologists. AB - BACKGROUND: Although the fecal occult blood test (FOBT) was developed for colorectal cancer screening in the outpatient setting, it continues to be used among hospitalized patients. No previous study has evaluated the knowledge, beliefs and attitudes of practicing physicians on the use of FOBT among hospitalized patients and compared practices among physicians with different medical specialty training. OBJECTIVE: To survey physicians in the Winnipeg Regional Health Authority (WRHA) and Canadian gastroenterologists (GIs) on the use of FOBT in hospitals. METHODS: A survey was distributed by e-mail to internists (n=198), emergency medicine (EM) physicians (n=118), general surgeons (n=47) and family medicine (FM) physicians with admitting privileges (n=29) in the WRHA. Canadian GIs were surveyed through the membership database of the Canadian Association of Gastroenterology (CAG) (n=449). The survey included items regarding demographics of the respondents and their current use of FOBT in hospitals. RESULTS: Response rates ranged from 18% among CAG members to 69% among FM physicians in the WRHA. General internal medicine, general surgeon and GI respondents were less likely to order a FOBT and less likely to believe that an FOBT was useful in assessing emergency room or hospitalized patients when compared with FM and EM respondents (P<0.001). The most common indications for ordering a FOBT were black stools and anemia with and without iron deficiency. Two-thirds of EM physicians preferred point-of-care testing rather than laboratory reporting of FOBT. CONCLUSIONS: The present survey suggests that FOBTs are commonly used in hospitals by EM and FM physicians for indications such as anemia and black stools. PMID- 24340317 TI - Evaluation of funding gastroenterology research in Canada illustrates the beneficial role of partnerships. AB - BACKGROUND: Funders of health research in Canada seek to determine how their funding programs impact research capacity and knowledge creation. OBJECTIVE: To evaluate the impact of a focused grants and award program that was cofunded by the Canadian Institutes of Health Research Institute of Nutrition, Metabolism and Diabetes, and the Canadian Association of Gastroenterology; and to measure the impact of the Program on the career paths of funded researchers and assess the outcomes of research supported through the Program. METHODS: A survey of the recipients of grants and awards from 2000 to 2008 was conducted in 2012. The CIHR Funding Decisions database was searched to determine subsequent funding; a bibliometric citation analysis of publications arising from the Program was performed. RESULTS: Of 160 grant and award recipients, 147 (92%) completed the survey. With >$17.4 million in research funding, support was provided for 131 fellowship awards, seven career transition awards, and 22 operating grants. More than three-quarters of grant and award recipients continue to work or train in a research-related position. Combined research outputs included 545 research articles, 130 review articles, 33 book chapters and 11 patents. Comparative analyses indicate that publications supported by the funding program had a greater impact than other Canadian and international comparators. CONCLUSIONS: Continuity in support of a long-term health research funding partnership strengthened the career development of gastroenterology researchers in Canada, and enhanced the creation and dissemination of new knowledge in the discipline. PMID- 24340318 TI - Navigation in total knee arthroplasty: truth, myths, and controversies. PMID- 24340319 TI - The economic recession and its effect on utilization of elective total joint arthroplasty. AB - The United States economy entered a recession in December 2007. This study aims to determine whether the utilization of elective orthopedic surgeries has been impacted by this recession. From January 2007 to December 2009 at a single private practice in New Jersey, 4820 total joint replacement procedures were scheduled, of which 649 of those were cancelled. The rate of cancellation for financial reasons was compared to multiple economic measures by linear regression analysis. The results show that the rate of financially motivated cancellations increased over time concurring with multiple financial markers reflecting the economic recession. The results suggest that the recession has created a financial barrier for a significant number of Americans, leading to decreased utilization of care. While there was a statistically significant increase in cancellations for financial reasons, the overall rate of cancellations in the total joint population is still low, representing only about 1% of all cases. PMID- 24340320 TI - Surgeons' perception of fluoroscopic radiation hazards to vision. AB - Exposure to ionizing radiation, such as that used in fluoroscopy, can lead to cataracts. This is relevant in orthopedic surgery as fluoroscopic procedures are commonly performed. In this study, we determined perceived level of: (1) personal risk, (2) awareness of risk for cataract formation due to ionizing radiation exposure, (3) awareness of occupational dose limits for ophthalmologic radiation exposure, (4) current radioprotective practices amongst orthopedic surgeons. Canadian Orthopaedic Association members were asked to participate and 264 responses (23%) were received. Many respondents believed that they were at least at moderate risk for cataract formation due to occupational radiation exposure (n = 107; 41%). Fifty-nine respondents (22%) indicated that they lacked sufficient knowledge to estimate risk and almost half (n = 120; 45%) reported having minimal awareness that ionizing radiation may contribute to cataractogenesis; almost 75% (n = 197) reported having minimal awareness that dose limits exist. The association between perceived risk and awareness was significant (P<.001). There is an information deficit among orthopedic surgeons regarding awareness of either the potential cataractogenesis risk due to radiation exposure or the dose limits. PMID- 24340321 TI - Osteolytic pseudotumor after cemented total knee arthroplasty. AB - Wear debris leading to local inflammatory reactive changes and osteolysis is a common complication after total knee arthroplasty (TKA). While massive osteolytic lesions may be commonly encountered in the revision setting, the appearance and location of these lesions rarely mimic expansile bone lesions. We report a case of severe osteolysis in a cemented TKA design, which presented as a pseudotumor of the fibular head. The diagnostic work-up and pathologic analysis are included in this report of a pseudotumor secondary to wear debris osteolysis. PMID- 24340322 TI - Phialophora verrucosa as a cause of deep infection following total knee arthroplasty. AB - Deep joint infection is one of the most feared complications following total joint replacement. Prompt diagnosis and treatment with 2-staged revision is currently the gold standard for treatment. We report a case of a chronic infection following total knee replacement caused by Phialophora verrucosa, a form of dematiaceous fungus. The patient was treated with an antibiotic spacer and a course of oral anti-fungal agents. To our knowledge, there have been no reported cases of P verrucosa as a cause of infection in hip or knee arthroplasty. PMID- 24340323 TI - Acute compartment syndrome following distal biceps tendon rupture in an otherwise healthy male. AB - This case presents acute compartment syndrome of the anterior upper arm following a distal biceps tendon rupture in an otherwise healthy 33-year-old male. Biceps compartment syndrome following biceps tendon rupture has been rarely reported, and to our knowledge, only 2 other cases have been reported in the literature. In both of these previous cases, it was associated with anticoagulation therapy in elderly men. This is the only case reported of a biceps compartment syndrome in an otherwise healthy young male. PMID- 24340324 TI - Impact of mild chronic hyponatremia on falls, fractures, osteoporosis, and death. AB - There is emerging evidence that mild chronic hyponatremia (MCH), highly prevalent in the elderly and once considered asymptomatic, is a major independent risk factor for falls, fall-related fractures (independent of osteoporosis, age, and sex), impaired attention and gait, reductions in bone mineral density (BMD), and even death. Although research on MCH and bone health is emerging and ongoing, it has not been recognized in orthopedics. Orthopedic surgeons must be educated regarding the impact of hyponatremia on bone, as osteoporotic fractures have enormous socioeconomic consequences, and the problem will worsen. Orthopedic surgeons should also be included in research, in education, and in the establishment of diagnostic and treatment protocols. In this article, we review the current concepts of MCH and its impacts on the skeletal system. PMID- 24340325 TI - Usefulness of intraoperative radiographs in reducing errors of cup placement and leg length during total hip arthroplasty. AB - Traditional methods of component placement during total hip arthroplasty (THA) can lead to errors in cup abduction angle and leg length. Intraoperative radiographs were used to assess and correct errors during surgery in a consecutive series of 278 THAs performed by a single surgeon. After exclusions, 262 cases were available for cup abduction angle assessment and 224 for leg length discrepancy (LLD) assessment. Components were initially placed in a position determined as appropriate by the surgeon. Intraoperative radiographs were taken and appropriate corrections made. Postoperative radiographs were assessed at 6 weeks. Mean abduction angle on intraoperative radiographs was 39.6 degrees +/-5.9 degrees versus 38.6 degrees +/-4.1 degrees on postoperative radiographs. Thirty-eight cups were outside the target abduction range on intraoperative radiographs versus 4 on postoperative radiographs. Mean LLD was 3.7 mm +/- 3.6 mm on intraoperative radiographs and 2.5 mm +/- 2.7 mm on postoperative radiographs. Use of intraoperative radiographs is a valid, useful technique for minimizing errors in THA. PMID- 24340326 TI - Tibia-based referencing for standard proximal tibial radiographs during intramedullary nailing. AB - Limited information exists to define standard tibial radiographs. The purpose of this study was to define new landmarks on the proximal tibia for standard anteroposterior and lateral radiographs. In 10 cadaveric knees, fibular head bisection was considered the anteroposterior image, and femoral condyle overlap the lateral image. In another 10 knees, a "twin peaks" anteroposterior view, showing the sharpest profile of the tibial spines, was used. The "flat plateau" lateral image was obtained by aligning the femoral condyles then applying a varus adjustment with overlap of the tibial plateaus. Medial peritendinous approaches were performed, and an entry reamer used to open the medullary canal. A priori analysis showed good to excellent intra-/inter-observer reliability with the new technique (intra-class correlation coefficient ICC 0.61-0.90). The "twin peaks" anteroposterior radiograph was externally rotated 2.7+/-2.1 degrees compared to the standard radiograph with fibular head bisection. Portal position and incidence of damage to intra-articular structures did not significantly differ between groups (P>.05). The "twin peaks" anteroposterior view and "flat plateau" lateral view can safely be used for nail entry portal creation in the anatomic safe zone. Tibia-based radiographic referencing is useful for intramedullary nailing cases in which knee or proximal tibiofibular joint anatomy is altered. PMID- 24340327 TI - Strategies for treating scoliosis in children with spinal muscular atrophy. AB - Progressive pulmonary dysfunction is a major complication of spinal muscular atrophy (SMA). Growing constructs are a well-established alternative to spinal arthrodesis to maximize pulmonary growth. We describe patients who demonstrated sustained pulmonary function and improved quality of life following hybrid growing construct implantation. The purpose of this article is to demonstrate a range of approaches for managing scoliosis in children with SMA by utilizing vertical expandable prosthetic titanium rib implantation or growing rods with lateral rib fixation to improve clinical and patient-reported outcomes. Pulmonary compromise and quality of life decline are leading concerns in the SMA population. This case series highlights important surgical strategies that can be utilized to treat scoliosis in patients with SMA. PMID- 24340328 TI - How well do you know your patients? PMID- 24340329 TI - Self-management of type 2 diabetes? Yes! PMID- 24340330 TI - Take family medicine in a new direction. PMID- 24340331 TI - An algorithmic approach to otitis media with effusion. PMID- 24340332 TI - Treatment in the face of uncertainty following traumatic anhydrous ammonia exposure. PMID- 24340333 TI - Gastroesophageal reflux disease: the case for improving patient education in primary care. AB - PURPOSE: Gastroesophageal reflux disease (GERD) affects up to 25% of the western population, and the annual expenditure for managing GERD is estimated to be more than $14 billion. Most GERD patients do not consult a specialist, but rather rely on their primary care physician for symptom management. Research has shown that many patients--regardless of diagnosis--do not fully understand what their doctors tell them and remain uncertain as to what they are supposed to do to take care of themselves. To determine if patients are adequately educated in the management of GERD, we conducted a survey. METHOD: We administered a survey to patients with GERD in an outpatient setting and explored their knowledge of such management practices as modification of behavior and diet and use of medication. RESULTS: Of 333 patients enrolled, 66% reported having an in-depth discussion with their primary care physician. Among patients taking a proton pump inhibitor, 85% of those who'd had an in-depth discussion were aware of the best time to take their medication, compared with only 18% of those who did not have an in-depth discussion. In addition, patients who'd had in-depth conversations were significantly more likely than those who didn't to know some of the behavior modification measures that might improve their symptoms. CONCLUSION: Our study underscores the need for primary care providers to fully discuss GERD with their patients to improve overall management of the disease. PMID- 24340334 TI - Statin therapy: when to think twice. PMID- 24340335 TI - Lung cancer screening: USPSTF revises its recommendation. PMID- 24340336 TI - Mediterranean diet: higher fat but lower risk. PMID- 24340337 TI - Abrupt onset of abdominal pain. Duodenal perforation caused by indomethacin. PMID- 24340338 TI - Clinical inquiry. What clinical clues differentiate migraine from sinus headaches? Pulsatile quality, duration of 4 to 72 hours, unilateral location, nausea or vomiting, and disabling intensity. PMID- 24340339 TI - Clinical inquiry. What is the best age to start vitamin D supplementation to prevent rickets in breastfed newborns? Breastfed infants who take vitamin D beginning at 3 to 5 days of life don't develop rickets. PMID- 24340340 TI - Clinical inquiry. Does ultrasound guidance improve outcomes for steroid joint injections? Yes, at least in the short term. PMID- 24340341 TI - How to safely prescribe long-acting opioids. PMID- 24340342 TI - Diagnosing fibromyalgia and myofascial pain syndrome: a guide. PMID- 24340343 TI - A blueprint to managing multiple chronic conditions and pain. PMID- 24340344 TI - Individualizing care with injectable glucose-lowering agents. AB - Insulin and GLP-1R agonists are important treatment options for the management of patients with T2DM, yet provider and patient concerns limit their use. Effective strategies, including ongoing patient education, can be easily implemented to overcome concerns and streamline initiation and ongoing use of injectables. The use of a GLP-1R agonist, for example, is 1 strategy recommended when avoidance of hypoglycemia or weight gain is a specific treatment goal. PMID- 24340345 TI - Engaging the patient in diabetes self-management. PMID- 24340346 TI - Preparing for success: redesigning the diabetes office practice. AB - Improving health outcomes of patients with T2DM whose management includes injectable glucose-lowering therapy may require a redesign of the diabetes office practice to support patients' medical and psychosocial needs. This redesign may include the development of a participatory office practice wherein care is provided by a multidisciplinary diabetes care team. To make stepwise improvements in any facet of patient care, the PDSA cycle can be integrated into routine clinical practice. Value-based health care and accountable care are evolving approaches intended to improve patient outcomes. PMID- 24340347 TI - Optimizing the use of injectable therapies for type 2 diabetes. Introduction. AB - By at least 1 indicator, the diabetes fight is becoming worse. The percentage of people with diabetes who achieved a glycosylated hemoglobin (HbA1c) level <7.0% actually declined from 2003-2006 to 2007-2010 (57.0% vs 52.5%, respectively). PMID- 24340348 TI - Increased priority for regimens involving incretin-based and insulin therapy. AB - The ADA/EASD and AACE guidelines emphasize the importance of individualizing treatment to best meet each patient's situation. Metformin remains the preferred choice as initial therapy for most patients. The 2009 AACE algorithm elevated the role of incretin-based therapies (GLP-1R agonists and DPP-4 inhibitors) relative to previous algorithms and this has been endorsed by subsequent algorithms and guidelines. The incretin-based therapies and insulin therapy should be considered with very high priority. Either incretin-based therapy or insulin therapy can be used as monotherapy or in combination with other agents. The GLP-1R agonists are especially useful when attempting to reduce the risk of hypoglycemia and when assisting the patient to achieve weight loss. Insulin therapy is especially useful when the HbA1c level is >9.0% or when symptoms of glucotoxicity are present. Insulin is the recommended treatment when other agents fail to achieve the desired target levels for HbA1c, FPG, and PPG. The combination of a GLP-1R agonist with basal insulin can provide better glycemic control than either agent alone, with less weight gain and glycemic outcomes for combined therapy with a long-acting basal insulin analog and a glucagon-like peptide-1 receptor agonist a markedly lower incidence of hypoglycemia than with use of basal insulin alone. PMID- 24340350 TI - Realizing nano electrospray ionization using disposable pipette tips under super atmospheric pressure. AB - Nano electrospray with a solution flow rate below 100 nL min(-1) is usually performed using a metallized pulled glass capillary with an inner diameter tip of <10 MUm. In this paper, we demonstrated that it was possible to achieve a stable solution flow rate of ~10 nL min(-1) for an aqueous solution using a disposable plastic pipette tip with an inner diameter of 100 MUm as an ESI emitter. This pipette tip (gel loading tip) was originally designed for the loading of sample onto the gel in gel electrophoresis. The inner and outer diameters were much larger than those of a nanoESI emitter, but the low solution flow rate could be sustained by conducting the electrospray under a super-atmospheric gas pressure. The high pressure condition ensured the absence of electrical discharge which was essential for stable electrospray of aqueous solution. ESI with this low cost tip was equally as sensitive as the standard nanoESI emitter and capable of producing a long lasting signal from a small amount of sample liquid. Due to a small initial droplet size under the low flow rate regime, ESI with the present method exhibited the property of nanoESI where the ion suppression of the hydrophilic analyte by the hydrophobic compound present in the solution was greatly reduced. Furthermore, owing to its larger inner diameter, the tip relatively easily avoided the clogging problem often encountered when dealing with "dirty" samples when compared with a nanoESI emitter made from a fine glass capillary. PMID- 24340351 TI - Structured illumination for tomographic X-ray diffraction imaging. AB - Tomographic imaging of the molecular structure of an object is important for a variety of applications, ranging from medical and industrial radiography to security screening. X-ray diffraction imaging is the preeminent technique for performing molecular analysis of large volumes. Here we propose and demonstrate a new measurement architecture to improve the source and detector efficiency for diffraction imaging. In comparison with previous techniques, our approach reduces the required overall scan time by 1-2 orders of magnitude, which makes possible real-time scanning of a broad range of materials over a large volume using a table-top setup. This method, which relies on structuring spatially the illumination incident on an object moving relative to the X-ray source, is compatible with existing systems and has the potential to significantly enhance performance in an array of areas, such as medical diagnostic imaging and explosives detection. PMID- 24340352 TI - Take action: competence. AB - As our nursing specialty evolves, competency in the rapidly changing healthcare environment remains a key component in our ability to produce positive patient outcomes. Competency gives us confidence to care for our patients. But developing competency is just one step to becoming an expert nurse. Nurses' expertise and competency grows over the years--a product of experiences. PMID- 24340353 TI - [Regarding "Active tuberculosis in a cohort of HIV-infected inmates in a prison in Mexico City: epidemiological and clinical characteristics"]. PMID- 24340354 TI - [Authors' response]. PMID- 24340355 TI - [Tegumentary leishmaniasis: a forgotten disease]. PMID- 24340356 TI - Medicare program; revisions to payment policies under the physician fee schedule, clinical laboratory fee schedule & other revisions to Part B for CY 2014. Final rule with comment period. AB - This major final rule with comment period addresses changes to the physician fee schedule, clinical laboratory fee schedule, and other Medicare Part B payment policies to ensure that our payment systems are updated to reflect changes in medical practice and the relative value of services. This final rule with comment period also includes a discussion in the Supplementary Information regarding various programs. (See the Table of Contents for a listing of the specific issues addressed in the final rule with comment period.) PMID- 24340357 TI - [Fetal neck tumors -- cystic neck tumor, lymphangioma]. PMID- 24340358 TI - [Cerebral abnormalities in fetal MRI -- prenatal diagnosis of tuberous sclerosis]. PMID- 24340359 TI - [An interview with Janos Furedi]. PMID- 24340360 TI - [Interview with Laszlo Tringer]. PMID- 24340361 TI - WHO Expert Committee on Biological Standardization. AB - This report presents the recommendations of a WHO expert committee commissioned to coordinate activities leading to the adoption of international recommendations for the production and control of vaccines and other biologicals and the establishment of international biological reference materials. Following a brief introduction, the report summarizes a number of general issues brought to the attention of the Committee. The next part of the report, of particular relevance to manufacturers and national regulatory authorities, sets out revised WHO Guidelines on the quality, safety and efficacy of candidate dengue tetravalent vaccines (live, attenuated), along with revised WHO Recommendations in relation to the production and quality control of bacille Calmette-Guerin (BCG) vaccines and of acellular pertussis vaccines. In addition, a generic protocol for the calibration of seasonal and pandemic influenza antigen working reagents is included. Revised WHO Guidelines for thromboplastins and plasma used to control oral anticoagulant therapy with vitamin K antagonists are then presented. Finally, new WHO assessment criteria for national blood regulatory systems are provided. Subsequent sections of the report then provide information on the current status and proposed development of international reference materials in the areas of antibiotics; biotherapeutics other than blood products; blood products and related substances; in vitro diagnostic device reagents; and vaccines and related substances. A series of annexes are then presented which include an updated list of WHO Recommendations, Guidelines and other documents on biological substances used in medicine (Annex 1), followed by a series of WHO Recommendations and Guidelines adopted on the advice of the Committee (Annexes 2 7). All additions made during the meeting to the list of International Standards and Reference Reagents for biological substances maintained by WHO are then summarized in Annex 8, and are also available at: http://www. who.int/biologicals. PMID- 24340362 TI - 401(k) participants in the wake of the financial crisis: changes in account balances, 2007-2011. PMID- 24340363 TI - [40 years of diabetes mellitus. It is already evident in the hand shake strength]. PMID- 24340364 TI - [Burnout syndrome. Beware of long sick leaves! (interview by Dr. Christine Starostzik)]. PMID- 24340365 TI - [In one word, Mrs. Merkel!]. PMID- 24340366 TI - [Prescribing subcutaneous infusions]. PMID- 24340367 TI - [Family practitioners may soon employ radiologists or laboratory physicians]. PMID- 24340368 TI - [Caution in sharing patient data]. PMID- 24340369 TI - [Active contract physicians are liable for recourse claims of "passive" contract physicians]. PMID- 24340370 TI - [Is the great GOA breakthrough finally here?]. PMID- 24340371 TI - [Do you know this phenomenon?]. PMID- 24340372 TI - [A serious outrage]. PMID- 24340373 TI - [Why a sports health certificate can save lives]. PMID- 24340374 TI - [Without ergometry no sports health certificate! (interview by Dr. med. Horst Gross)]. PMID- 24340375 TI - [Which children will outgrow asthma?]. PMID- 24340376 TI - [Has the vaccine failed?]. PMID- 24340377 TI - [Safety is the issue again]. PMID- 24340378 TI - [First sex after an infarct - what you should advise your patients]. PMID- 24340379 TI - [Are big earners really happier?]. PMID- 24340380 TI - [Very elderly getting fitter]. PMID- 24340381 TI - [Harlequin-baby]. PMID- 24340382 TI - [Crying children predict autism?]. PMID- 24340383 TI - [Overestimated corticosteroids in "sciatica"]. PMID- 24340384 TI - [Involuntary weight loss]. PMID- 24340385 TI - [How to approach a patient with non traumatic acute painful knee swelling]. PMID- 24340386 TI - ["I can not get rid of my cough". Chronic cough in adults, a frequent problem in general practice]. PMID- 24340387 TI - [I have a persistent runny nose]. PMID- 24340388 TI - [Emergency checklist: phlegmon of the hand]. PMID- 24340389 TI - [The serious physical illeness and sexuality]. PMID- 24340390 TI - [Medical confidentiality]. PMID- 24340392 TI - [Guidelines recommend herbal phytotherapy for acute cough]. PMID- 24340391 TI - [Arterial hypertension and chronic kidney disease]. PMID- 24340394 TI - WHO quantitative immunization and vaccine-related research meeting, October 2011- summary. PMID- 24340393 TI - Detection of influenza virus subtype A by polymerase chain reaction: WHO external quality assessment project summary analysis, 2011. PMID- 24340396 TI - Monthly report on dracunculiasis cases, January-December 2011. PMID- 24340395 TI - Dengue and severe dengue factsheet (revised in January 2012). PMID- 24340397 TI - Update on human cases of highly pathogenic avian influenza A(H5N1) virus infection, 2011. PMID- 24340398 TI - Performance of acute flaccid paralysis (AFP) surveillance and incidence of poliomyelitis, 2011. PMID- 24340399 TI - Pneumococcal vaccines WHO position paper--2012. PMID- 24340400 TI - Eradication of yaws--the Morges strategy. PMID- 24340401 TI - Progress towards global interruption of wild poliovirus transmission, January 2011-March 2012. PMID- 24340402 TI - Meeting of the Strategic Advisory Group of Experts on immunization, April 2012- conclusions and recommendations. PMID- 24340403 TI - Soil-transmitted helminthiases: number of children treated in 2010. PMID- 24340404 TI - Mumps virus nomenclature update: 2012. PMID- 24340405 TI - Dracunculiasis eradication--global surveillance summary, 2011. PMID- 24340406 TI - Monthly report on dracunculiasis cases, January-March 2012. PMID- 24340407 TI - The intersection of evidence and values in clinical guidelines: who decides what constitutes acceptable risk in the care of children? PMID- 24340408 TI - The prevalence of bacteremia in pediatric patients with community-acquired pneumonia: guidelines to reduce the frequency of obtaining blood cultures. AB - OBJECTIVE: The goal of this study was to determine the prevalence of bacteremia in pediatric patients with community-acquired pneumonia (CAP) at our institution and to test the effectiveness of newly developed guidelines for obtaining blood cultures. METHODS: Using recent literature and local expert opinion, institutional guidelines for obtaining blood cultures in pediatric patients with CAP were developed. A retrospective chart review of children treated in the emergency department or admitted for CAP from January 2010 through June 2011 was conducted. Demographic and clinical data were collected, including results of blood cultures. Chi2 tests assessed for variables associated with bacteremia, whether a blood culture was obtained, and if the decision to obtain a culture was appropriate based on our guidelines. RESULTS: The study included 330 patients; 155 (47%) blood cultures were obtained in our patient population. Five cultures were true-positive findings, making the prevalence of bacteremia 3.2% in patients with blood cultures and 1.5% in all patients. All 5 true positive results met criteria for blood culture based on our guidelines. Applying our guidelines retrospectively, the decision to obtain a blood culture met criteria in 55% of the cases. Bivariate analysis showed that patients discharged from the emergency department had higher rates of guideline-appropriate decisions than patients admitted. Radiographic findings were associated with making a guideline appropriate decision regarding blood culture. CONCLUSIONS: Instituting local guidelines that limit the frequency of obtaining blood cultures in pediatric patients with CAP is likely to capture any patient with bacteremia. This study suggests that blood cultures may not need to be routinely obtained in all patients admitted to the hospital with CAP. PMID- 24340409 TI - Time to detection of bacterial cultures in infants aged 0 to 90 days. AB - OBJECTIVE: To determine the time to detection (TTD) of positive results on blood, urine, and cerebrospinal fluid (CSF) cultures taken during the evaluation for serious bacterial infection (SBI) in otherwise healthy infants aged 0 to 90 days. METHODS: This study was a retrospective chart review of infants aged 0 to 90 days with positive blood, urine, or CSF cultures drawn during evaluation for SBI in the emergency department or inpatient setting. The TTD of positive culture results, reason for testing, and age of the infant were recorded. RESULTS: A total of 283 charts were reviewed related to 307 positive culture results. Of the 101 positive results on blood culture, 38% were true pathogens with a mean TTD of 13.3 hours; 97% were identified in < or = 36 hours. Blood cultures with TTD > or = 36 hours were 7.8 times more likely to be contaminants compared with those with TTD < 36 hours. Of 192 positive results on urine culture, 58% were true pathogens with a mean TTD of 21 hours; 95% were identified in < or = 36 hours. Fifty percent of 14 positive CSF culture results were true pathogens with a mean TTD of 28.9 hours; 86% were identified in < or = 36 hours. When data for infants < or = 28 days of age were analyzed separately, TTD followed the same patterns for positive blood and urine culture results as seen in all infants aged 0 to 90 days. CONCLUSIONS: In certain clinical situations, the inpatient observation period for infants under evaluation for SBI may be decreased to 36 hours. PMID- 24340410 TI - Blood culture associations in children with a diagnosis of cellulitis in the era of methicillin-resistant Staphylococcus aureus. PMID- 24340411 TI - Decreasing patient identification band errors by standardizing processes. AB - OBJECTIVE: Patient identification (ID) bands are an essential component in patient ID. Quality improvement methodology has been applied as a model to reduce ID band errors although previous studies have not addressed standardization of ID bands. Our specific aim was to decrease ID band errors by 50% in a 12-month period. METHODS: The Six Sigma DMAIC (define, measure, analyze, improve, and control) quality improvement model was the framework for this study. ID bands at a tertiary care pediatric hospital were audited from January 2011 to January 2012 with continued audits to June 2012 to confirm the new process was in control. After analysis, the major improvement strategy implemented was standardization of styles of ID bands and labels. Additional interventions included educational initiatives regarding the new ID band processes and disseminating institutional and nursing unit data. RESULTS: A total of 4556 ID bands were audited with a preimprovement ID band error average rate of 9.2%. Significant variation in the ID band process was observed, including styles of ID bands. Interventions were focused on standardization of the ID band and labels. The ID band error rate improved to 5.2% in 9 months (95% confidence interval: 2.5-5.5; P < .001) and was maintained for 8 months. CONCLUSIONS: Standardization of ID bands and labels in conjunction with other interventions resulted in a statistical decrease in ID band error rates. This decrease in ID band error rates was maintained over the subsequent 8 months. PMID- 24340412 TI - Development of performance tracking for a pediatric hospitalist division. AB - OBJECTIVES: Our goal was to develop a comprehensive performance tracking process for a large pediatric hospitalist division. We aimed to use established dimensions and theory of health care quality to identify measures relevant to common inpatient diagnoses, reflective of current standards of clinical care, and applicable to individual physician performance. We also sought to implement a reproducible data collection strategy that minimizes manual data collection and measurement bias. METHODS: Washington University Division of Pediatric Hospital Medicine provides clinical care in 17 units within 3 different hospitals. Hospitalist services were grouped into 5 areas, and a task group was created of divisional leaders representing clinical services. The group was educated on the health care quality theory and tasked to search clinical practice standards and quality resources. The groups proposed a broad spectrum of performance questions that were screened for electronic data availability and modified into measurable formulas. RESULTS: Eighty-seven performance questions were identified and analyzed for their alignment with known clinical guidelines and value in measuring performance. Questions were distributed across quality domains, with most addressing safety. They reflected structure, outcome, and, most commonly, process. Forty-seven questions were disease specific, and 79 questions reflected individual physician performance; 52 questions had electronically available data. CONCLUSIONS: We describe a systematic approach to the development of performance indicators for a pediatric hospitalist division that can be used to measure performance on a division and physician level. We outline steps to develop a broad-spectrum quality tracking process to standardize clinical care and build invaluable resources for quality improvement research. PMID- 24340413 TI - Care of the complex chronically ill child by generalist pediatricians: lessons learned from pediatric palliative care. AB - BACKGROUND AND OBJECTIVE: Parents of children with complex chronic conditions report fragmented care, unmet medical needs, and financial strain from health care costs. The aim of this study was to identify both prevalent themes discussed during pediatric palliative care consultation of patients with complex chronic conditions cared for by pediatric generalists and variation in consultation content by age and timing of consultation in disease course. METHODS: Forty randomly selected initial inpatient or outpatient consultation notes authored by the pediatric palliative care team at an academic, tertiary care children's hospital. Inclusion required that patients were primarily cared for by general pediatricians, pediatric hospitalists, or pediatric intensivists, instead of subspecialists. Qualitative analysis by 5 team members utilizing consensus-based findings was used to develop themes. Descriptive statistics were used to describe variations in themes across age and disease course. RESULTS: Common themes included thorough review of patient baseline functioning, current symptoms, assessment of family's understanding of the prognosis of the patient, coordination of communication with other medical teams and outpatient health care services, consideration of caregiver resources and burdens, and offering a framework for decision-making. Variation in consult themes by age/disease course included more discussion of communication problems and symptom management when patients were at their baseline, but otherwise little variation was found. CONCLUSIONS: Common themes covered in initial consultations correspond with documented unmet needs for chronically ill children. There was no significant variation in consultation themes by age/disease course, suggesting that generalists could broadly apply palliative care techniques to improve family centered care. PMID- 24340414 TI - When and how pediatric history and physical diagnosis are taught in medical school: a survey of pediatric clerkship directors. AB - BACKGROUND: [corrected] History and physical diagnosis skills (HPDS) are required curriculum in medical schools (MS) with pediatric HPDS (PHPDS) necessitating instruction in addition to adult HPDS. Perceived deficiencies in these skills on the pediatric clerkship prompted investigation of when and how other MS taught PHPDS. The concern of whether medical students are adequately taught PHPDS needed to be addressed. METHODS: With the use of the Council on Medical Student Education in Pediatrics listserv, pediatric clerkship directors from 129 US, 15 Canadian, and 2 Puerto Rican MS were contacted via e-mail to complete an anonymous online questionnaire, focused on MS demographics, PHPDS timing, teaching methods, and barriers. RESULTS: Seventy-two (49%) of 146 MS responded to the survey; 18.1% of MS responders did not offer PHPDS in the first 2 years. Methodologies used to educate students included didactic lectures, physician shadowing, hands-on with patients, pairing with preceptor, instructional video, and examination of newborns. Each teaching method had < 3 hours dedicated to medical students during their first 2 years at a majority of the MS. Of the responders, 85.1% concurred that medical students should be exposed to PHPDS before starting the clerkship. Barriers to providing PHPDS included MS time allotment, preceptor availability, and total number of students to accommodate. CONCLUSIONS: This study demonstrated striking variability among MS in how and when medical students were taught PHPDS. Clarification of the role of PHPDS instruction in preclinical years and standardized effective approaches to PHPDS instruction are both needed so that MS curriculum optimizes physician training. PMID- 24340415 TI - A pediatric residency experience with surgical co-management. AB - BACKGROUND AND OBJECTIVE: Acquisition of knowledge and skills in the care of surgical patients is defined as an essential element of training by the Pediatric Residency Review Committee. The pediatric-surgical comanagement model of care is increasingly utilized, yet its impact on residency training has not been described. The goal of this study was to describe a 5-year experience with a co management model in a pediatric residency program. METHODS: We describe the planning and implementation of a surgical co-management model in a pediatric residency program and report on case volume and diversity from 2005 to 2010. We assessed the experience of pediatric residents and faculty through rotation evaluations, program leadership meetings, and an anonymous online survey. In the survey, residents rated the value of their exposure on knowledge and skills in selected perioperative domains and their experience with interprofessional teamwork. RESULTS: The volume of co-managed patients increased threefold from 2005 to 2010; most (79%) had concurrent medical conditions, and one-third (36%) were children with special health care needs (CYSHCN). Residents reported that co management helped them gain knowledge and skills in pain management, fluid and electrolytes, respiratory, and nutritional support, as well as in interprofessional teamwork. Other strengths included greater exposure to CYSHCN and subspecialty faculty, and preparedness for critical care rotations. Challenges included clarity of roles and responsibilities between pediatric and surgery residents and interservice communication. CONCLUSIONS: A surgical co management model in pediatric residency training presented important opportunities for development of residents' knowledge and skills in perioperative care and interprofessional teamwork. PMID- 24340416 TI - Morphine is associated with acute chest syndrome in children hospitalized with sickle cell disease. AB - OBJECTIVE: To determine if intravenous morphine is associated with acute chest syndrome (ACS) in children with homozygous for hemoglobin S sickle cell disease (SCD) hospitalized with acute pain. METHODS: Health records of patients with homozygous for hemoglobin S SCD aged 2 to 18 years hospitalized with acute pain were reviewed. Patients developed ACS at least 12 hours after emergency department triage; controls did not develop ACS. Survival analyses were performed. RESULTS: There were 38 cases and 45 randomly selected controls. The mean hourly dose of morphine 1, 2, and 3 hours before ACS and cumulative mean morphine dose up to 5 hours before ACS were significantly associated with ACS (P < .05). Adjusted analysis showed that 1 hour before ACS, the mean morphine dose was significantly higher in cases (40 microg/kg) compared with controls (34 microg/kg), and the risk of ACS increased by 23% for each additional 10 microg/kg of morphine received (P = .02). CONCLUSIONS: We recommend close observation for ACS in hospitalized patients with SCD who are receiving morphine. PMID- 24340417 TI - A randomized trial of facilitated family-centered rounds. AB - BACKGROUND: Family-centered rounds (FCR) are becoming the status quo for inpatient pediatric medical care; however, barriers still exist. The use of facilitators in FCR is gaining popularity. Although facilitators can increase comfort with FCR, the choice of preferred facilitator has not been studied by using rigorous methodology. In this study, we performed a randomized trial of facilitated FCR with bunnies and clowns, 2 commonly mentioned facilitators, and compared their results with the usual care condition. METHODS: The 3 floor teams were randomized to have rounds facilitated with bunnies and clowns or the usual care model facilitated by distracted residents and overbearing attending physicians. Infection control procedures were instituted. Outcome measures were parent satisfaction scores, use of anxiolytic agents during examinations as part of FCR, resident satisfaction, and the number of times presenters were interrupted by their attending. Differences between the experimental and control groups were analyzed by using ttests, chi2 statistics, and multiple regression analysis. Qualitative analyses were also performed by using participant observers. RESULTS: Bunnies had the best overall improvement in parent satisfaction, anxiety, and resident satisfaction. Both intervention groups were successful at reducing attending interruptions. The clown arm was suspended by the Data Safety Monitoring Board before study completion due to adverse events. DISCUSSION: Facilitated FCR has the potential to improve satisfaction among parents, patients, and residents, and to decrease attending interruptions. Care needs to be taken, however, to avoid unanticipated adverse effects from potentially emotionally damaging interventions. Tularemia was not identified in any of our treatment conditions. PMID- 24340418 TI - Pediatric hospitalist perceptions of the impact of duty hour changes on education and patient care. AB - OBJECTIVE: The goal of this study was to measure the impact of the new 2011 Accreditation Council for Graduate Medical Education duty hour standards (DHS) on education, patient care, and overall satisfaction as perceived by pediatric hospitalist faculty. METHODS: We undertook a nonrandomized but controlled study of 23 pediatric hospitalist faculty members during a trial of the new DHS in 2011. During the intervention (January), residents piloted schedules that complied with the new DHS, and in the control period (February), resident schedules complied with previous DHS. Daily surveys solicited faculty perceptions of the amount and quality of teaching provided, time with patients, quality of patient care, and overall faculty satisfaction. Faculty were also surveyed on their years of experience as a hospitalist and clinical teaching activity. Multiple logistic regression analysis with generalized estimating equations was used to examine outcome associations after adjusting for census and accounting for multiple attending reports. RESULTS: Census volumes were higher in the control group. During the intervention, faculty were less likely to rate their quality of teaching (odds ratio [OR]: 0.40 [95% confidence interval (CI): 0.18 0.88]) and overall satisfaction with the shift (OR: 0.23 [95% CI: 0.08-0.66]) as good/excellent compared with controls. During the intervention, more years of experience as a hospitalist were associated with rating quality of patient care provided as good/excellent (OR: 1.77 [95% CI: 1.23-2.54]). CONCLUSIONS: Faculty were less likely to rate their quality of teaching and overall satisfaction as good/excellent during a trial of the 2011 DHS. In addition, more experienced faculty were more likely to rate the quality of care highly. PMID- 24340419 TI - Simulation training as a mechanism for procedural and resuscitation education for pediatric residents: a systematic review. AB - BACKGROUND: Pediatric residents often finish their training lacking sufficient procedural proficiency and resuscitation experience in the care of critically ill children. Simulation is gaining favor in pediatric residency programs as a modality for procedural and resuscitation education. We reviewed the literature assessing simulation and its role in pediatric resident training. METHODS: We conducted a Medline and PubMed search of simulation training in pediatric resident education from January 2007 to July 2012. RESULTS: Eight studies were included and divided into simulated procedural assessments and simulated resuscitation scenario assessments. The studies varied widely in their approach and analysis, and they yielded mixed results. CONCLUSIONS: Although some studies show the merits of simulation in the procedural and resuscitation training of pediatric residents, more research is needed to assess the effectiveness of simulation as an educational tool. Goals of future simulation research should include creation of validated assessment tools and applying skills learned to patient care outcomes. PMID- 24340420 TI - Do all children hospitalized with community-acquired pneumonia require blood cultures? PMID- 24340421 TI - Community-acquired pneumonia: judicious use of antibiotics or treatment failure? PMID- 24340422 TI - Color TVs and prepaid dental benefit plans. PMID- 24340423 TI - Are the students our guinea pigs: what's happening to dental education? PMID- 24340424 TI - Morals, ethics, integrity. PMID- 24340425 TI - Permission to speak. PMID- 24340426 TI - Managing caries in virtual dental homes using interim therapeutic restorations. AB - The Pacific Center for Special Care at the University of the Pacific, Arthur A. Dugoni School of Dentistry has developed the virtual dental home (VDH) system, which uses allied dental professionals trained to place interim therapeutic restorations (ITR) under the general supervision of dentists. This paper reviews the scientific basis for the ITR, as used in the VDH system, in managing caries lesions and delivering oral health care to underserved and vulnerable populations. PMID- 24340427 TI - Bilateral impacted inverted mesiodens associated with dentigerous cyst. AB - Mesiodens, the most common type of supernumerary tooth, usually results in malocclusion, poor esthetics and cyst formation. The occurrence of a dentigerous cyst around the crown of an unerupted supernumerary tooth is infrequent. We present a case of a dentigerous cyst associated with a nonsyndromic bilateral impacted inverted supernumerary tooth in a 13-year-old boy. A thorough clinical workup, including 3-D reconstruction image and histological examination confirming the features of a dentigerous cyst is presented in this report. PMID- 24340428 TI - Lesion characteristics and responses after CO2 laser vaporization in five patients With gingival leukoplakia. AB - Gingival leukoplakia, a premalignant condition, can pose difficulties to surgical access because of the presence of teeth and potential extensions into the periodontal ligament. We present a series of five patients with gingival leukoplakia who were treated with carbon dioxide laser vaporization. We describe lesion characteristics and recurrence patterns suggesting that presence of gingival leukoplakia on facial and palatal/lingual aspect through the interproximal areas may increase the risk of recurrence after conservative surgical removal. PMID- 24340429 TI - Coronoid hyperplasia in a pediatric patient: case report and review of the literature. AB - Coronoid hyperplasia is a rare entity of unknown etiology due to increased and persistent bone growth that has been associated with trauma, inflammation, hormonal influence and hypervascularization. A case of coronoid hyperplasia in a pediatric patient with restriction in mandibular movements and an absence of painful symptoms initially misdiagnosed as a functional temporomandibularjoint (TMJ) abnormality is presented. Causative factors and management strategies are emphasized to enhance the recognition and understanding of mandibular hypomobilities. PMID- 24340430 TI - United we debate. PMID- 24340431 TI - [Opioid dependence: New national guidelines must allow maintenance treatment]. PMID- 24340432 TI - [Measuring patient safety culture. Survey instrument and handbook revised]. PMID- 24340433 TI - [DSM-5 focuses on culture and context. Interview tool adapts psychiatry to the multicultural society]. PMID- 24340434 TI - [More active treatment is necessary in spontaneous intracerebral hematomas. Acute management in Vasterbotten compared with international guidelines]. PMID- 24340435 TI - [Pediatric reference ranges for clinical chemistry analyzes]. PMID- 24340436 TI - [The immune system in atherosclerosis. Immunomodulatory or anti-inflammatory treatment that is effective against atherosclerosis and its complications are needed to ensure the hypothesis]. PMID- 24340437 TI - [After the Swedish National Council on Medical Ethics report: Lively public debate on assisted reproduction]. PMID- 24340438 TI - [Reply to Bengt Jarhult: Several shades of professionalism]. PMID- 24340439 TI - [The Swedish polio vaccine - a success story]. PMID- 24340440 TI - First impressions of a complex organisation. PMID- 24340441 TI - Nurses must show compassion for former president. PMID- 24340442 TI - Nurse can't ignore her conscience. PMID- 24340443 TI - FLuoride debate continues. PMID- 24340444 TI - Anti-smoking tool for students. PMID- 24340445 TI - All aboard--think locally. PMID- 24340446 TI - Seeking a vision for the future. PMID- 24340447 TI - 'Cultural safety should be reviewed'. PMID- 24340448 TI - Hypersensitivity and anaphylaxis. PMID- 24340449 TI - Envisioning nursing's future. PMID- 24340450 TI - Could e-cigarettes perpetuate addiction? PMID- 24340451 TI - Celebrating the Te Rau Kokiri journey. PMID- 24340452 TI - Challenging Maori health inequities. PMID- 24340453 TI - The next challenge to interoperability? A first look at robotic system wireless interoperability in emergency response. AB - System interoperability enables public safety agencies to communicate and share information. Past failures have demonstrated that systems of different agencies are not inherently interoperable. Therefore, as efforts continue toward the resolutions of these problems, it is incumbent on technology developers to assess the interoperability of new systems. Robotic systems can offer new capabilities to public safety personnel; however, these systems also include new communication technology to share and distribute information. Research has been initiated to examine the interoperability of public safety robotic systems. Definitions for robotic communication interoperability types are introduced. PMID- 24340454 TI - Using a simulation cell for exercise realism. AB - A simulation cell or SimCell is an effective and flexible tool for control of emergency management exercises. It allows exercise participants to interact, via simulation, with a wide variety of nonplaying organizations and officials. Adapted from military application, the Chemical Stockpile Emergency Preparedness Program (CSEPP) applied, developed, and refined the SimCell concept for emergency management exercises. It has now been incorporated into national exercise guidance through the Homeland Security Exercise and Evaluation Program, and has been used in a wide variety of national, regional, and local exercises. This article reviews development of the SimCell concept in CSEPP, briefly surveys current practice incorporating SimCells in exercise control, and offers practical lessons-learned and tips on using a SimCell to best advantage. Lessons learned include using a SimCell as an exercise-control hub; preparing inject material for exercise controllers as part of the Master Scenario Event List; laying the groundwork for success through exercise player and controller training; developing protocol for SimCell communications; and capturing feedback from SimCell controllers for inclusion in the exercise evaluation reporting process. The SimCell concept is flexible and can be applied to a variety of exercise types and through a variety of methods. PMID- 24340455 TI - Mainland China nurses' willingness to report to work in a disaster. AB - A cross-sectional study among a convenience sample of nurses in China was conducted to understand the factors affecting Chinese nurses' willingness to report to work in a disaster. A total of 946 questionnaires were collected. Nearly 90 percent of nurses regarded disaster self-help information, an evacuation plan, and contingency measures a must in preparing for disaster care. Many nurses indicated willingness to work during a disaster that may threaten the safety of their family members than when there is a life-threatening infectious disease outbreak (83.6 and 69.6 percent, p = 0.000). Nurses with longer years of clinical experience were more willing to work in both situations (p = 0.014 and 0.000). Fear of contracting an infectious disease and spreading it to family members was a major factor for nurses' unwillingness to report to work. Hospital administrators should understand their workforce's willingness in reporting to work and provide appropriate disaster training and support to maximize workforce in a disaster. PMID- 24340456 TI - Exposure levels for chemical threat compounds: information to facilitate chemical incident response. AB - Although not widely known, a robust set of peer-reviewed public health and occupational exposure levels presently exist for key chemical warfare agents (CWAs) and certain acutely toxic industrial chemicals (TICs) identified as terrorist attack threats. Familiarity with these CWA and TIC exposure levels and their historic applications has facilitated emergency management decision-making by public and environmental health decision-makers. Specifically, multiple air, soil, and water exposure levels for CWAs and TICs summarized here have been extensively peer-reviewed and published; many have been recognized and are in use by federal and state health agencies as criteria for hazard zone prediction and assessment, occupational safety, and "how clean is clean enough" decisions. The key, however, is to know which criteria are most appropriate for specific decisions. While public safety is critical, high levels of concern often associated with perceived or actual proximity to extremely toxic chemical agents could result in overly cautious decisions that generate excessive delays, expenditure of scarce resources, and technological difficulties. Rapid selection of the most appropriate chemical exposure criteria is recommended to avoid such problems and expedite all phases of chemical incident response and recovery. PMID- 24340457 TI - Contingency planning at the flotilla level in the United States Coast Guard Auxiliary: flotilla 81-a case study. AB - This article presents a case study of United States Coast Guard Auxiliary Flotilla 81. Flotilla 81 created its first formal, single agency contingency plan. The research question addressed is "How can a flotilla successfully develop a contingency plan?" Five emergent themes are identified. They are offered as suggested promising practices for other flotillas in need of creating a contingency plan. Findings suggest successful contingency planning is a result of effective collaboration with community partners. Network management theory is a key to an effective contingency planning process. PMID- 24340458 TI - Alarms #1 tech risk despite focus, according to ECRI. PMID- 24340459 TI - Are we there yet? Quality quest continues. PMID- 24340460 TI - Stopping workarounds means changing culture. PMID- 24340461 TI - It's not always what you say that counts. PMID- 24340462 TI - Telemedicine brings more risk with more use. PMID- 24340463 TI - Continuing Medical Education II: MOC, CME, ABD, ABMS, ACGME, CMS, FSMB, IOM, MOL, PQRS, SMB, etcetera et ad nauseum. PMID- 24340464 TI - Drug reactions with involvement of the proximal nail fold. PMID- 24340465 TI - Use of granulocyte colony-stimulating factor in the treatment of toxic epidermal necrolysis--experience with 3 patients. AB - The use of recombinant granulocyte colony-stimulating factor has recently been advocated in the treatment of toxic epidermal necrolysis as it may help in faster regeneration of detached skin. Three patients who presented with toxic epidermal necrolysis were managed as per the protocol followed at our department. In addition, they received recombinant granulocyte colony-stimulating factor in a dose of 300 microg/d (5 microg/ kg/d) for 5 days. Severity of Illness Score for Toxic Epidermal Necrolysis was calculated on day 1 and the lesions were observed for re-epithelialization. The 3 patients were aged 16 years, 20 years, and 65 years, with the latter showing leucopenia at presentation. All 3 patients showed a significant rise in total leukocyte count (reaching up to 45,000/mm3) after administering recombinant granulocyte colony-stimulating factor, with the rise being comparatively less in the third patient (maximum of 12,000/mm3). A similar pattern was seen in re-epithelialization of skin, with rapid re-epithelialization occurring in the first 2 patients and much slower re-epithelialization in the third. The first two survived but the third died from refractory sepsis. Recombinant granulocyte colony-stimulating factor improves epithelialization of skin and should be used for treating toxic epidermal necrolysis irrespective of the leucopenic status of the patient. PMID- 24340466 TI - Polypharmacy in dermatology: analysis of a nationally representative sample of 46,273 dermatology patient visits in the United States from 1995 to 2009. AB - There are no large-scale studies ofpolypharmacy (PP) in dermatology. The authors examined trends in PP (simultaneous use of > or = 4 medications in our study) and associated clinical factors among a nationally representative sample of 46,273 (weighted count +/- standard error [SE]: 617,970,596 +/- 25,187,959) dermatology related (International Classification of Diseases, Ninth Revision, Clinical Modification codes 680-709) patient visits from 1995 to 2009. Data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Care Survey were examined. The overall frequency (+/- SE) of PP was 8.9% +/- 0.4%. There was almost a doubling in the frequency of PP in dermatology from 1995 to 2009 (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.67-2.44, after controlling for comorbidities and sex). This increase was noted among patients with > 1 diagnoses, and all age groups including the younger than 25 age category (PP frequency +/- SE, 7.4% +/- 0.4%; OR, 1.45; 95% CI, 1.12-1.88), and not just among patients in the geriatric age range with multiple complex dermatologic problems. Some of the most frequent conditions in the PP group included acne, psoriasis, atopic dermatitis, and infections of the skin and subcutaneous tissue, conditions that are known to be affected by psychodermatologic factors. PP among these patients may in part be an indication of their complex presentation caused by psychosocial vs dermatopathologic factors. PMID- 24340467 TI - Aging and facial changes--documenting clinical signs, part 1: clinical changes of the aging face. AB - The process of aging induces the transformation of the face with changes that are usually classified as either chronological or photo-induced and that affect the shape, the texture, and the color of the face. Facial shape is mainly transformed by the evolution of bones and soft tissues (muscles, fat, and skin) in addition to noticeable effects of gravity. Skin texture is mainly determined by wrinkles, which arise from atrophy of the skin layers, elastosis, and facial expressions. Skin color is related to the distribution of skin chromophores and the structure of the dermis, which affects light scattering. All facial changes are dependant on sex, ethnicity, and lifestyle. They affect self-perception and social interactions and can sometimes be slowed down or reversed using appropriate clinical procedures (eg, dermatological, surgical, cosmetic interventions). PMID- 24340468 TI - Hair biology and its comprehensive sequence in female pattern baldness: treatment modalities--part III. PMID- 24340469 TI - Atypia without pleomorphism and atypia without atypia: when you can't even see the trees for the trees. PMID- 24340470 TI - Epiduo (adapalene 0.1% and benzoyl peroxide 2.5%) approval in children 9 years and older. PMID- 24340471 TI - Is it time to revise CFR title 21-Food Drugs & Cosmetics Act for skin care products? PMID- 24340472 TI - Multiple cystic disease: K17 dysfunction? AB - Our patient is a 29-year-old woman without any previous disease who presented with different kinds of lesions on her face, neck, and chest. She first noticed the lesions 10 years ago and, since that time, they have become more numerous. She has no affected relatives. On physical examination, she had multiple cystic lesions on her neck, chest, and vulva, which were between 0.3 cm and 1 cm and skin-colored or yellowish (Figure 1). She presented with small, white papules on her face measuring approximately 0.2 cm, localized on her forehead and cheeks. Some of these papules had a blueish appearance (Figure 2). She also presented clinically typical eruptive syringomas on her upper and lower eyelids and neck and multiple facial milia. Finally, a sacrococcygeal pilonidal cyst was diagnosed and surgically removed. Her nails and teeth were clinically normal. Biopsies of each kind of lesion were performed, with the following results: (1) neck cystic lesion: steatocystoma; (2) small, white facial papule: eccrine hidrocystoma; (3) blueish facial papule: apocrine hidrocystoma; and (4) small neck papule: syringoma (Figure 3). With these findings, our diagnosis was steatocystoma multiplex with multiple eccrine and apocrine hidrocystomas, eruptive syringomas, and sacrococcygeal pilonidal cyst. PMID- 24340473 TI - Multiple giant vulvar syringoma: an extraordinary report. AB - A 26 year-old woman presented with asymptomatic multiple skin-colored eruptions affecting the vulva. She claimed that the lesions had started at the age of 15. The eruptions have been increasing in size and extent since her presentation. There was a family history of similar eruptions around the eyes of one of her sisters. Examination of the skin surface was marked by the presence of multiple, 2- to 3-cm firm, skin-colored, nodules on the labia majora (Figure 1). They were bilateral and symmetrical. One of the lesions was excised, and histopathologic serial sections were prepared and stained with hematoxylin and eosin. Sections showed clusters of small comma-shaped ducts lined by 2 cell-thick epithelium surrounded by a fibrotic stroma. Solid strands of basophilic epithelial cells independent of ducts were documented in the dermis (Figure 2). Accordingly, a diagnosis of syrangoma was made. PMID- 24340474 TI - Epidermolysis bullosa pruriginosa affecting 3 successive generations. AB - A 24-year-old man presented with multiple mildly itchy flesh-colored papules and plaques on both legs for the past decade. The lesions were preceded by transient vesicles that contained clear fluid. The papules and plaques used to develop on sites where vesicles had healed. Many family members in three generations had similar lesions (Figure 1). On examination, multiple discrete flesh-colored papules and plaques were found on both lower extremities, extending from the feet up to the knees (Figures 2 and 3). A few of the plaques were excoriated. No vesicles or bullae were noted, and the skin in between the lesions appeared normal. The nail of left great toe was discolored and dystrophic. The rest of the mucocutaneous examination was unremarkable. Bullous lichen planus, Neckam's disease, lichenoid amyloidosis, and epidermolysis bullosa pruriginosa (EBP) were considered as differential diagnoses. Histopathology from the plaque showed a subepidermal cleft with no inflammatory cells. The epidermis was acanthotic at places, and the dermis appeared normal (Figure 4a and 4b). Based on clinical presentation and histopathology, a diagnosis of EBP was made. PMID- 24340475 TI - An unusual presentation and distribution of generalized eruptive syringomas. AB - A 19-year-old Caucasian man presented with numerous erythematous to flesh-colored papules that appeared in crops on his neck, axillae, buttocks, and lower back. The lesions started on his anterior neck at age 12. At 18 years, new crops of papules appeared on his axillae, back, and buttocks over several months. He reported pruritus in the lesions following exercise and perspiration. He denied any family history of similar lesions. His primary care physician treated him with topical triamcinolone 0.1% cream, which made the lesions smaller, less erythematous, and less pruritic; however, the papules never fully resolved. After discontinuation of the steroids, these erythematous pruritic papules gradually recurred in the same areas of his body. The patient denied any other medical complaints. PMID- 24340476 TI - An unusual presentation of perforating metastatic calcinosis cutis. AB - A 37-year-old white man diagnosed with multiple myeloma was admitted for respiratory distress. He was found to have hypercalcemia (13.1 mg/dL), hyperphosphatemia (7.2 mg/dL), hyponatremia (121 mEq/L), and acute renal failure (serum urea nitrogen, 116 mg/dL; creatinine, 4.9 mg/dL). On hospital day 7, skin lesions over his elbows, wrists, and fingers were noticed and the dermatology department was consulted. Physical examination revealed 0.5- to 3.0-cm erythematous denuded patches with yellow crusts at the periphery that were localized to the bilateral interdigital web spaces, medial elbows, and volar wrists (Figure 1 and Figure 2). No oral mucosal or conjunctival findings were present. Results from skin biopsies of the lesions revealed focal epidermal necrosis with zones of amorphous basophilic material that focally appeared to perforate the epidermis (Figure 3). Results from Congo red and Verhoeff-van Gieson stains were negative, and results from Von Kossa stain were positive, confirming the perforating material as calcium. Ten days after initial dermatology examination, the patient's respiratory distress worsened and he subsequently died. Autopsy revealed diffuse pulmonary calcinosis and renal tubular calcification. As a result of the autopsy findings, the patient was diagnosed with perforating metastatic calcinosis cutis. PMID- 24340477 TI - Acneiform eruption and pruritus in a patient with quetiapine therapy. PMID- 24340478 TI - Acquired reactive perforating collagenosis. PMID- 24340479 TI - Regulating professional behavior: codes of ethics or law? Suggested criteria. AB - This paper suggests considering a few parameters when making policy decisions as to the proper "tool" to regulate professional behavior: law or professional ethics. This is done on the background of understanding the place of codes of professional ethics between "pure" ethics and law. Suggested criteria are then illustrated using a few examples. Further discourse may reveal additional factors to support a more rational process of decision-making in this field. PMID- 24340480 TI - Can ethics survive the onslaught of science? AB - The issue on which I will attempt to cast some light is certainly not novel. It has been ongoing for many years but the pace of scientific progress is gathering and the retreat of ethical barriers is relentless. I will illustrate my thesis by using examples of legal decisions from the realm of assisted human procreation and the posthumous conception of children from the sperm of deceased fathers e.g., the cases of Diane Blood, Parpalaix and Nikolas Coltan Evans. I will also highlight the recent case of Ashley X, a nine year old girl whose parents authorised radical medical treatment to arrest her development. I will argue that the law is being driven to roll back the ethical standards derived from our legacy of Natural Law by the imperatives of human rights e.g., the right to found a family, and the quest for patient autonomy. These are both admirable goals but fulfilling these goals comes at a cost to cherished ethical values e.g., that children are conceived by living fathers and that indulging the personal desires of every individual cannot forever be encompassed. As our legislators and courts chip away at our core network of ethical values, are they replacing them with equivalent values or do their decisions amount to a hollowing out of the core ethical values e.g., Thou shalt not kill and that human life is sacrosanct? Yet abortion is legal in many countries as is euthanasia. Paradoxically there is legislative protection for embryos by limiting experimentation on these clusters of cells. How do you construct a rational ethical framework with such blatant legal inconsistencies in the protection of human life? The sanctity of human life constitutes one of the fundamental pillars of ethical values which, in turn, support much more of the structure of ethics. Is a society that permits freezing the development of a nine year old child not a society whose ethics are so compromised that it is doomed to defend an ever diminishing mass of ethical values? Is there a core of ethics which is sacrosanct or is every ethical frontier fair game for invasion? Are the Ethics Committees, which approve and monitor research in the field of bioethics in Universities. Hospitals and laboratories failing in their duty as gatekeepers? They are after all the first line of defence for the survival of crucial ethical values. Can we continue to indulge the whims and needs of every individual under the guise of human rights or patient autonomy? Can a civilised society endure as such with an ever diminishing mass of ethical values? PMID- 24340481 TI - The Ethics Committee at the Patient's Bedside (ECatPB): a retrospective view on the past two years. AB - The Ethics Committee at the Patient's Bedside (ECatPB) was established at Beilinson Hospital and began its activity a few years ago. A retrospective viewpoint will enable us to reflect on moral dilemmas and ethical conflicts as sources of professionals' moral distress. The activities of the ECatPB will be reviewed through sample cases and in the light of the promotion of optimal treatment. Five dominant contributions of the ECatPB will be discussed: prevention of moral distress; positioning the committee as an integral and inseparable component of the medical institution's daily life; cultivating the advisory, rather than punitive, character of the committee; maintaining constant ethics dialogues with patients, caregivers and professionals; and communications with guardians in light of informed consent or informed refusal. The summary ofthis paper will include conclusions, recommendations and personal notes. PMID- 24340482 TI - Bio-ethical dilemmas related to medical treatment in pre-modern Jewish society, as a portal for raising current ethical issues. AB - Real-life ethical issues that concern those engaged in medical practice existed and were discussed in earlier ages. It seems that many of the same dilemmas that we face today occupied our ancestors as well. An investigation of historical sources may be useful in showing earlier methods of coping with the dilemmas relating to health and illness. In this article we will present several such topics taken from the sources of Jewish society in pre-modern Europe. These sources served as the basis for a course given to medical students as part of the Medical Humanities track. The "raw materials" are historical, written Hebrew and Yiddish sources from Jewish society. Genres include Minute books, the huge corpus of Responsa, historical elegies written about epidemics, memoirs, and instruction books written by Jewish physicians. Profound bio-ethical issues can be found in historical sources. Main issues discussed are: physician's fees, obligations, and rights; personal characteristics expected of physicians; physician's obligations when his/her own life is endangered; medicalization of certain human conditions; and ideological questions regarding the relationship between traditional folk medicine and modern, academic medicine. The historical distance facilitates a freer discussion about distant people, while getting in touch with our own attitudes. PMID- 24340483 TI - Should teachers of medical ethics and health professionals remain value neutral in order to respect the autonomy of students and patients? AB - This article describes the pedagogical and ethical problems that ensue when ethical neutrality is mandated as the sole acceptable stance for teachers of ethics and health professionals (especially in public institutions). This paper argues that such a mandate can (1) violate public employees' own ethical integrity by forcing them to adopt the current legal order as their own ethical code; (2) erode trust, by requiring that the professional or teacher betray the honesty that patients and students commonly expect; and, finally, (3) undermine- by affirming that all opinions are equally acceptable--he pedagogical aim of generating critical thinking. Nevertheless, the article warns teachers and professionals against defending their own convictions by appealing to authority or the power of public office. The correct way to avoid ethical neutrality, this article asserts, is by distinguishing "opinion" from "argument": by not merely articulating, but providing convincing arguments for, one's own professional ethical opinions. PMID- 24340484 TI - Finding a balance between patients' rights, responsibilities and obligations. AB - Patients' rights have developed over recent decades in many countries, resulting in improved access to high quality medical care. The alliance between patients and physicians is a moral obligation, backed up by patient rights. Poor patient compliance with medical recommendations constitutes a public health issue, illustrating the difficulty of obliging patients to comply with treatment. The legal recognition of patients' responsibilities is defined in a few legislative and regulatory texts, but is primarily based on jurisprudence. Patients, who despite being fully aware and informed about the risks adopt a behaviour that is harmful to their health, tend to be considered as being irresponsible. This judicial approach raises a number of questions, as it fails to take into account the complexity of the human factors involved in a behaviour with either positive or negative health effects. PMID- 24340485 TI - How do you know when it is torture? AB - The forensic psychiatric expert's assessment of torture survivors who manifest Post Traumatic Stress Disorder and apply for refugee asylum is a paradigmatic example of the interface of psychiatry and the law. While it is necessary to acknowledge the utility of current dominant and well-established protocols, it is also imperative to note and correct their failures and limitations. This paper illustrates a model which simultaneously comprehends and designates the negative dimensions of the humanitarian catastrophe of torture and brings forth monumental and profound positive strengths of character which sustain survivors. One case drawn from two decades of evaluations of torture demonstrates this innovative update of mainstream medical-scientific practice. A reproducible and easily communicated heuristic model respects clinical variables and reports the interactivity of individual psychological factors with the cultural/ political nexus. A consistent pattern emerged from review of country reports, survivors' affidavits, interviews, reports and testimonies to the court. Ordinary means led to extraordinary findings that were needed to incorporate and supersede the previous paradigms that have defined torture and designated capacities of psychological response. Torture is a crime of specific intent- to deconstruct and shatter the human connections of their subjects. Survivors had the force of human ties to sustain them. Necessary and legitimate methods achieve valid examination and forensic reporting. Professionals have the force to do right-verifiable objective means nurture justice and social progress. PMID- 24340486 TI - Patents on inventions related to human embryonic stem cells: the morality clause after Brustle v. Greenpeace. AB - This paper analyses the meaning of Article 6, para. 2, sub c of the Biotechnology Directive prohibiting patents on inventions using human embryos for industrial or commercial purposes. It first examines the evolution ofthe Court of Justice ofthe EU's interpretation of this provision (which is part of the morality clause) and focuses on its most recent decision, Brustle v. Greenpeace. This is considered a landmark case for three reasons: firstly, because it defines for the first time the term "embryo" in patent law; secondly, because it is the Court of Justice (and not EPO) that ruled on patent law; the third reason is its very broad interpretation of the morality exclusion. The exclusion is no longer limited to embryos but is extended to (even banked) embryonic stem cells and all downstream products made with them. It then looks into the consequences for the patentability of inventions using cells derived from human embryonic stem cells, such as Brustle's invention. The recent decision by Germany's Federal Court of Justice on the validity of Brustle's patent emphasises the limited influence on the patentability of those inventions. After that, the paper addresses possible cuts in funding stem cell research and even legislative bans of this type of research. This is followed by an evaluation of the existence and content of the morality exclusion. After a comparative analysis with the US, which is lacking in such morality exclusion, the paper concludes that the morality clause as a whole paid its dues but the provision on the use of human embryos is questionable as there is no European consensus against the use of human embryos for industrial or commercial purposes. PMID- 24340487 TI - The POLST paradigm for patients with advanced, irreversible illness: a therapeutic jurisprudence basis for legal codification. AB - The Physician Orders for Life Sustaining Treatment (POLST) Paradigm attempts to improve the experiences of individuals with serious, irreversible illness, and their families. In some jurisdictions, the POLST is authorized in law. In other jurisdictions, efforts are underway or contemplated to encourage use of POLST for appropriate individuals, but the concept is not yet in law. An argument needs to be made to policymakers that POLST will have a therapeutic effect on patients and families. In making that argument, the analytical lens of therapeutic jurisprudence (TJ) may be useful. This article proposes a POLST legal strategy using TJ. TJ may be used to evaluate data regarding psychological effects on patients and families who are experiencing medical care with or without POLST; the TJ analysis then should be considered by policymakers in enacting POLST laws to codify clinical consensus, and in turn the law so enacted would exert a positive impact on therapeutic benefit-producing behavior by health care providers. PMID- 24340489 TI - Caries control in health service practice. PMID- 24340488 TI - Neuroscience research involving older persons in Canada: some legal and neuroethical concerns. AB - In this paper, I will examine some legal and ethical issues that arise in relation to neuroscience research involving older persons in Canada. Such research includes research relating to dementia, including Alzheimer's disease. Dementias such as Alzheimer's are organic diseases affecting mainly older persons. They adversely affect mental acuity. There is still much that is unknown about such illnesses, making research on these diseases particularly necessary. In this paper, I will identify and focus on particular concerns with respect to the participation of older persons in research. These concerns are: Inclusion in and Access to Research; Informed Consent; Incidental Findings; and Advance Directives. I will discuss each of these concerns in the context of Canadian research ethics policy and law. The aim of this paper is not to provide an exhaustive discussion of these issues, each of which may rightfully demand a full paper. The aim of this paper is to identify and paint a canvass of these particularly relevant issues, discuss the policy and law on them, identify any existing gaps and propose some solutions to remedy these gaps and protect older persons who participate in research. PMID- 24340491 TI - FGDP(UK) urges greater focus on oral health in older people. PMID- 24340490 TI - The effective management of caries. PMID- 24340492 TI - Facial aesthetics in the spotlight. PMID- 24340493 TI - The FGDP(UK) diploma in restorative dentistry--a student's perspective. PMID- 24340494 TI - Key contact: Margaret Wheatcroft. PMID- 24340495 TI - Effectively managing dental caries: prevention and disease ownership. AB - Better prevention will result in smaller carious lesions being diagnosed at an earlier stage White spot lesions are amenable to being repaired using biomimetic technologies Digital technology will improve diagnosis but will also assist practitioners in the monitoring of lesions When operative intervention is indicated it will be of a minimal nature. Following validation, newer techniques for caries removal will become the norm. PMID- 24340496 TI - The contemporary approach to tooth preservation: minimum intervention (MI) caries management in general practice. AB - The minimum intervention (MI) approach summarises a clinical, evidence-based rationale for the preventive and cause-related approach to oral diseases in general and to caries in particular. MI oral care with respect to the management of patients suffering from dental caries is a concept based on an updated understanding of the histopathological carious process as well as the development of diagnostic technologies and adhesive, bioactive restorative materials. A patient-centred MI care plan for use in general dental practice is described, detailing the four phases of identifying disease, controlling/preventing disease, refurbishing/repairing tooth surfaces/restorations and recall consultations. PMID- 24340497 TI - Are general dental practitioners providing best practice in prevention in everyday general practice? AB - AIMS: To discover whether general dental practitioners are providing best practice in prevention, as defined by the 'Delivering Better Oral Health' toolkit, in everyday general practice. METHOD: A questionnaire was created with five scenarios describing the key findings of the examination of five hypothetical patients. Dentists attending a postgraduate meeting were asked to list all the preventive treatment and advice they would give each patient. The content of their answers was compared with the toolkit by two researchers. RESULTS: Twenty four dentists completed the questionnaire. In general terms, they did not mention much of the specific advice or recommend the treatment listed in the toolkit except that a significant proportion would apply fluoride varnish to children's teeth and all would give smoking cessation advice where appropriate. Suitable recall intervals, defined by the National Institute for Clinical Excellence, were suggested for three of the scenarios but the advice was inconsistent for the other two scenarios. CONCLUSION: This small investigation suggests that dentists' implementation of prevention, as advised by the toolkit, is not thorough or consistent. Comprehensive adoption of prevention in dentistry will require intensive multifaceted education and organisational change such as might be provided by the new contracts being piloted at present. PMID- 24340498 TI - Management of dental caries in the anxious adult patient. PMID- 24340499 TI - The illusion of caries from anatomical variance: a case report. AB - This paper presents two examples of unusual radiolucencies caused by grossly distorted anatomy. In the circumstances these could easily have been misdiagnosed as caries. Some of the more common artefacts presenting as caries are discussed. This article highlights the importance of combining radiographical and clinical findings to produce an accurate diagnosis. PMID- 24340500 TI - Clinical governance and caries management: prevention through professional development. PMID- 24340501 TI - Does the general dental practitioner have a role in tackling oral health inequalities? PMID- 24340502 TI - Caries risk assessment: new perspectives for the dental team. PMID- 24340503 TI - A dental hygienist's view of caries management. PMID- 24340504 TI - The National Institute for Health and Care Excellence (NICE): what can it do for you? PMID- 24340505 TI - The rise and fall of mercury amalgam. PMID- 24340506 TI - The rationale for implementation of HPV testing in routine cervical screening in Romania. PMID- 24340507 TI - Zenker's diverticulum, a rare cause of upper gastrointestinal bleeding. AB - The most common complication of Zenker's diverticulum is aspiration pneumonia, compression of the trachea and esophageal obstruction with large diverticulum, and increased risk of development of carcinoma. Thus bleeding occurs rarely, can be massive and life threatening, with ulceration being the most common cause. MATERIAL AND METHODS: We describe a patient with sever upper gastrointestinal bleeding as a result of a Zenker's diverticulum. A 75 year-old woman was referred to the emergency room and hospitalized for hematemesis, melena, asthenia and total dysphagia. In this particular case we preferred open technique because of the diverticulum dimensions and bleeding episode. Left cervicotomy was practiced on the anterior edge of the sternocleidomastoid muscle, being known that Zenker diverticulum extend into the left neck 90% of the time, fact also confirmed by radiology in this case. RESULTS: Postoperatively, the patient showed a complication free recovery. Five days after treatment the patient resumed nourishment. Several days later our patient was able to return home. Follow-up at 12 months after the operation showed complete recovery. Ulcer of the basis of Zenker's diverticulum is a rare entity and, only a few cases were reported in the literature to date. Omitting thecricomyotomy predisposes to fistula or diverticulum recurrence due to the persistence of a high pharyngeal intraluminal pressure that acts on the posterior wall just proximal to the upper esophageal sphincter. CONCLUSIONS: Zenker's diverticulum is an unusual site of origin for clinically significant upper gastrointestinal hemorrhage and differential diagnosis must include other more frequent causes of upper gastrointestinal bleeding. In our opinion, classicalsurgical therapy is indicated when distal esophageal imaging cannot be obtained during endoscopic examination, there is a large diverticulum or in an emergency setting when fast control over the bleeding source is required. PMID- 24340508 TI - Effectiveness of the immunochemical fecal test (FIT) for detection of advanced adenomas in colorectal carcinoma screening in an asymptomatic population. AB - AIM: The aim of the study was to evaluate the benefit of the immunochemical fecal blood test (FIT) for detection of advanced adenomas. MATERIAL AND METHODS: We have conducted a screening study on a average-risk cohort of subjects, aged 50 74 years. We used a rapid quantitative FIT to perform the screening. Colonoscopy was recommended in all participants with positive FIT. We assessed the participation rate and analyzed advanced adenomas detected in the screening examinations. RESULTS: Our study enrolled 1111 asymptomatic participants. Immunochemical test results were positive in 72 subjects (6.5%). Colonoscopy was performed by 50/72 (69.4%) subjects. The detection rate for advanced adenomas was 2.2%. A total number of 28 advanced adenomas were detected in 24 subjects, meaning 1.2 advanced adenoma/subject. Analyzing the 3 characteristics of advanced adenomas, we observed in our study that 25/28 adenomas (89.3%) had sizes > or = 10 mm, 11/28 adenomas (39.3%) were tubulovillous/villous and 19/28 adenomas (67.9%) had high dysplasia. The majority of advanced adenomas were found in the left colon as compared to the right colon: 71.4% vs. 28.6%. p = 0.0008. CONCLUSIONS: In our study was obtained a 2.2% detection rate for advanced adenomas, most of them (71.4%) being located in the left colon. The dominant feature of advanced adenomas detected was the size > or = 10 mm (89.3% of cases). PMID- 24340509 TI - Influence of metabolic syndrome profile on cardiovascular risk. AB - AIM: The trial was conducted on patients with metabolic syndrome hospitalized between 01.01.2012-31.12.2012 at Cardiovascular Rehabilitation Clinic of the Rehabilitation Hospital Iasi. MATERIAL AND METHODS: Patients included in the study were analyzed according to age and sex, criteria for the clinical definition of the metabolic syndrome, known cardiovascular diseases, diabetes mellitus type 2 or type 1. RESULTS: Metabolic syndrome components analysis showed statistical differences between the sexes, in case of certain cardiovascular risk factors. The frequency of cardiovascular risk factors (obesity, hypertriglyceridemia, hypertension, glycemic profile modification) was higher among women, the only risk factor most common in males was the decrease of HDL cholesterol. The statistically significant difference occurs in hypertriglyceridemia (p = 0.001) and HDL-Cholesterol (p = 0.000). Patients included in the study were studied depending on the frequency of the main cardiovascular diseases, secondary to the metabolic syndrome: ischemic heart disease, stroke, peripheral arterial disease of the lower extremities. CONCLUSIONS: Association of impaired glucose tolerance/diabetes mellitus, arterial hypertension and hypertriglyceridemia recorded an additional risk of developing CIC or ischemic stroke, independent of sex. PMID- 24340510 TI - The role of rifaximine in the prevention of the spontaneous bacterial peritonitis. AB - Cirrhosis is characterized by an increased susceptibility to infection. Spontaneous bacterial peritonitis (SBP) is the most common infectious complication, the main causes being the bowel bacterial overpopulation, the increased intestinal permeability and bacterial translocation. Antibiotic prophylaxis with Norfloxacin increases the rate of PBS with G+ multiresistant bacteria. PURPOSE: To demonstrate the advantage of using rifaximin, nonresorbable broad spectrum antibiotic, in SBP prophylaxy. MATERIAL AND METHODS: The study is a prospective case-control, which included 46 patients diagnosed with Child class C cirrhosis and refractory ascites, based on clinical, biological, ultrasound and endoscopic findings, followed over a period of 6 months. Protein level in ascitic fluid (AF) was higher 14 g/dl. SBP was defined as the presence of > 250 PMN/mm3. Patients were divided into 2 groups, group 1 comprised 22 patients who received rifaximin treatment during the study for a previous episode of hepatic encephalopathy (HE), and group 2 consisted of 24 patients who did not receive antibiotic treatment during follow-up. RESULTS: Rifaximin significantly decreases the polymorpho-nucleares (PMN) in ascitic fluid from patients, one single case of neutroascitic SBP with negative cultures were recorded in this group, with a net improvement of the general condition. In group 2 who did not follow any antibiotic treatment, SBP was recorded in 4 patients, an increase of PMN in ascitic fluid at 14 patients, an approximately constant value in 4 patients, a decrease in 2 subjects. CONCLUSIONS: The study suggests that rifaximin causes a significant decrease in PMN in AF, producing a decrease in SBP frequency and improvement of life in cirrhotic patients with refractory ascites. In this study, the effects of rifaximin on intestinal bacterial overpopulation and bacterial translocation, decisive factors in SBP, are consistent with literature data. Use of rifaximin as an alternative method to prevent SBP deserves more attention. PMID- 24340511 TI - Phenotypic variability in Patau syndrome. AB - Patau syndrome has an incidence of 1/10.000-20.000, the clinical diagnosis being suggested by the triad cleft lip and palate, microphthalmia/anophthalmia and postaxial polydactyly. Most frequent cytogenetic abnormality is free and homogeneous trisomy 13 (80.0%), rarely being detected trisomy mosaics or Robertsonian translocations. The objective of the study was to identify phenotypic features of trisomy 13. MATERIAL AND METHODS: The retrospective study was conducted on a trial group of 14 cases diagnosed cytogenetically with trisomy 13 between January 2000 and December 2012 at lasi Medical Genetics Centre. RESULTS: Of the 14 cases, 3 were evaluated pathologically (two aborted foetuses and one stillborn), 8 cases were detected in the neonatal period, and 3 in infancy. Clinical diagnosis was supported by the identification of a model of abnormal development, mainly characterized by: maxillary cleft (lip and palate--5 cases; lip--1 case), ocular abnormalities (microphthalmia/anophthalmia--7 cases; cyclopia--1 case), postaxial polydactyly (7 cases), scalp defects (6 cases), congenital heart anomalies (10 cases, 6 patients with atrial septal defect), complete holoprosencephaly (4 cases), ear abnormalities (11 cases), broad nasal root (10 cases). An important issue in confirming the phenotypic variability of Patau syndrome is that the classic clinical triad was identified only in one case. CONCLUSIONS: Patau syndrome is a disease with variable expression and is characterized by a pattern of abnormal prenatal development characterized by facial dysmorphia, polydactyly and severe birth defects (heart, brain) that generate an increased in utero and perinatal mortality. PMID- 24340512 TI - The assessment of treatment efficacy in age related macular degeneration by evaluating the oxidative stress markers and OCT measurements. AB - Age related macular degeneration (AMD) is the most frequent cause of blindness in the elderly. AIM: To establish the role of oxidative stress in retinal structural lesions in AMD and to monitor the evolution of oxidative stress markers and OCT measurements before and after treatment. MATERIAL AND METHODS: This is a case control study that included 19 patients diagnosed with AMD and 40 matched healthy controls. According to the AREDS classification, patients were divided into mild, moderate and severe AMD and received treatment with antioxidants, neurotrophic drugs, intravitreal corticosteroids and/or anti-VEGF. We followed the patients by assessment of visual acuity, optical coherence tomography (OCT) and oxidative stress markers, such as superoxide-dismutase (SOD), thiobarbituric acid reactive substances (TBARS), and C-reactive protein (CRP) from blood samples before and after treatment. RESULTS: The OCT showed that the macular edema in patients with severe disease was significantly reduced after treatment, while the cases with normal retinal thickness increased significantly (p = 0.005). Comparing the mean values of SOD, TBARS and CRP in the two groups, we found that they were significantly higher in the study group compared to controls (p < 0.01), being higher in patients with severe disease. These values decreased post treatment, but they were still higher than in controls. CONCLUSIONS: The present research supports the role of oxidative stress and inflammation in AMD and highlights the role of therapy directed against these risk factors. By monitoring the oxidative stress markers in the evolution of the disease, we showed that high values persist after treatment, thus supporting the idea that treatment should be followed for a long time. PMID- 24340513 TI - Quality of life of patients with esophageal replacement for congenital and acquired esophageal anomalies. AB - AIM: To assess the long-term quality of life (QoL) and symptoms experienced by patients who underwent esophageal replacement for congenital and acquired children esophageal pathology. MATERIAL AND METHODS: The study group comprised 71 patients divided into 2 groups, group I: 34 patients who underwent gastric tube esophagoplasty, and group II: 37 patients who underwent colic tube esophagoplasty. QoL score was assessed using a 24-item original questionnaire covering aspects of eating, disease-specific symptoms, physical and psychological development, and social integration. RESULTS: QoL scores based on patient and parental responses were very close. Long-term postoperative functional outcomes for the two groups were comparable. CONCLUSIONS: The QoL scores and general life status were not influenced by the used technique and this pathology should be approached according to the particularity of each case and surgeon's personal experience and preference. PMID- 24340514 TI - Body composition alterations in chronic obstructive pulmonary disease. AB - Metabolic disorders are involved in the pathogenesis of some comorbid conditions such as atherosclerosis and cardiovascular diseases, which frequently occur in COPD patient. These disorders may also associate alterations in body composition. AIM: To determine the particularities of body composition, assessing its relationship with respiratory function and clinical status in COPD patients. MATERIAL AND METHODS: A prospective case-control study including 31 patients with COPD admitted to the Clinic of Pulmonary Diseases lasi from April 2011 to September 2012, and 29 subjects without lung diseases which served as controls. Body composition (body fat, lean body mass, body water) and basal metabolic rate were measured using bioelectrical impedance analysis. Other assessments included anthropometric parameters, spirometry, 6-minute walk test. In COPD patients, dyspnea scale and health impairment assessment by St George's Respiratory Questionnaire (SGRQ) were used. RESULTS: In COPD group, 67% of the patients were normal weight, 10% underweight, 10% overweight and 13% obese. The results showed that lean body mass (p < 0.001), dry lean mass (p < 0.001), total body water (p < 0.001) and basal metabolic rate (p < 0.001) were lower in the COPD patients as compared to the controls. These findings significantly correlate with age, dyspnea, severity of airway obstruction and exercise capacity in patients with COPD. No significant differences between study groups were observed in body fat mass. CONCLUSIONS: Lean body mass, dry lean mass, and total body water are altered in COPD patients and significantly correlate with age, clinical and functional severity of COPD. PMID- 24340515 TI - The role and interactions of ghrelin concerning the nutritional and inflammatory status. AB - Ghrelin is an important neuroendocrine peptide having as main purpose the stimulation of growth hormone (GH) secretion. It is also an important regulator of the long-term energy balance and short-term nutritional intake. Ghrelin has several other biological actions, among which the capacity to regulate gastrointestinal motility, to modulate the reproductive and stress axes as well as the glucose metabolism, and other well-defined actions within the cardiovascular and renal physiology. Due to its numerous effects, ghrelin is considered on one hand a potential target in the treatment of obesity and on the other, a therapeutic option in other dysfunctions and illnesses. PMID- 24340516 TI - Coxarthrosis--disease of multifactorial etiology methods of prevention and treatment. The role of kinesitherapy in coxarthrosis. AB - Coxarthrosis is a disorder of the physiological balance between the strength of the articular cartilage and articular bone, and between the pressures exerted on the joint. It is a disease with a slow progressive and long course. Its insidious onset and progression, marked by variable periods of stagnation lasting months or even years make it difficult to establish the time of onset. MATERIAL AND METHODS: The study was conducted between January 2012 and December 2012, on a series of 27 coxarthrosis patients, diagnosed at the Rheumatology Clinic of the lasi Rehabilitation Hospital. RESULTS AND DISCUSSION: Of the 27 patients, 11 (40.74%) had primary bilateral coxarthrosis, 8 (29.63%) early coxarthrosis. right, 6 (22.22%) coxarthrosis, left, secondary to aseptic femoral head osteonecrosis, and 2 (7.41%) patients had bilateral coxarthrosis secondary to acetabular insufficiency. Kinesitherapy proved to be highly effective in the rehabilitation of coxarthrosis patients by alleviating pain, mechanical protection of the hip joint, walking rehabilitation in total hip arthroplasty, and social and professional integration of the patients. The massage besides its analgesic effect also acted as a muscle relaxant. Once the objectives have been met, the kinesiology program becomes global and functional rather than analytical, as it aims at reintegrating the coxofemoral joint into normal movement patterns. CONCLUSIONS: Kinesitherapy has been shown to be a physical treatment that can not be replaced by other rehabilitation methods and is crucial in the recovery of lost functions. PMID- 24340517 TI - Peripartum cardiomyopathy: a challenge for cardiologist. AB - Peripartum cardiomyopathy (PPCM) is a rare but potentially life-threatening condition that occurs in previously healthy women during the last month of pregnancy and up to 5-6 months postpartum. The etiology and pathophysiology remain uncertain, although recent observations strongly suggest the specific role of prolactin cleavage secondary to unbalanced peri/postpartum oxidative stress. PPCM is a diagnosis of exclusion, as it shares many clinical characteristics with other forms of systolic heart failure secondary to cardiomyopathy. The management of heart failure requires a multidisciplinary approach during pregnancy, considering the possible adverse effects on the fetus. After delivery, the treatment is in accordance with the current guidelines for heart failure. Some novel therapies, such as prolactin blockade, are proposed to either prevent or treat the patients with PPCM. A critical individual counseling concerning the risks of subsequent pregnancy must be considered. Because of its rare incidence, geographical differences, and heterogeneous presentation, PPCM continues to be incompletely characterized and understood. For all these reasons, PPCM remains a challenge in clinical practice, so future epidemiological trials and national registries are needed to learn more about the disease. PMID- 24340518 TI - Is there a risk for lymphoma or extracolonic cancer in patients with inflammatory bowel disease? AB - An important issue in the management of inflammatory bowel disease (IBD) is the risk for lymphatic or extracolonic malignancies reported in patients receiving prolonged immunosuppressive therapy and/or therapies with biological agents. Azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate. and anti-TNF (infliximab, adalimumab) are reference drugs for IBD forms unresponsive to conventional therapies. The administration of these drugs is a high responsibility because IBD itself is associated with an increased risk for cancer, namely colon cancer. The possibility of a drug-induced additional risk remains controversial, the relative risk for lymphoma being estimated at 1.2%. For extracolonic malignancies, there are variations in standardized incidence per reference population in terms of location (skin, liver and biliary tract, uterine cervix, prostate, etc.), and also IBD phenotype (ulcerative colitis or Crohn's disease). The uncertainty regarding the occurrence of neoplasia in IBD patients for many years on immunosuppressive therapy and/or biological agents is a strong argument both for treatment discontinuation and it's monitoring by inclusion in screening programs. In this paper we aimed to approach the conceptual model risk benefit in the therapy with imunosuppressive and biological agents given the controversies in the literature generated by the drug-induced risk for malignant lymphatic and extracolonic tumor in patients with IBD. PMID- 24340519 TI - Clinical and therapeutic aspects of amiodarone induced thyroid dysfunction. AB - Discovered in 1961 by Tondeur and Binon, two Belgian chemists, amiodarone was widely used, especially in Europe, initially as an antianginal agent, and later as an antiarrhythmic one (following the experiments conducted at the University of Oxford by Dr. Bramah Singh). Thus, the role of amiodarone was reconsidered, becoming, together with Sotalol, a class III antiarrhythmic--a group characterized by the action of extending the potassium channels refractory period. In time, amiodarone has proven its effectiveness in the treatment of both atrial and potentially malignant ventricular arrhythmias, being considered one of the antiarrhythmic agents involved in the prevention of sudden cardiac death due to arrhythmias. In December 1985, amiodarone was approved by the FDA (Food and Drug Administration) for the treatment of atrial fibrillation and the prevention of recurrent ventricular tachycardias. Despite this positive effect, the prescription of amiodarone began to be limited because serious side effects occurred, some of them disastrous, which were associated with the chronic use of the substance. PMID- 24340520 TI - Pulmonary rehabilitation--from guidelines to practice. AB - Pulmonary rehabilitation is an integral part of clinical management and health maintenance of patients with chronic respiratory disease who remain symptomatic or continue to have decreased function despite standard medical therapy. It is a spectrum of evidence-based, multidisciplinary, and comprehensive intervention for patients with chronic respiratory problems. Most evidence for the efficacy of respiratory rehabilitation is for patients with chronic obstructive pulmonary disease but there are encouraging results for extending its indications. Current programs of pulmonary rehabilitation are based on guidelines which formally grade the level of scientific evidence and on practical recommendations developed by several prestigious societies. The main components of a pulmonary rehabilitation program are patient selection and assessment, exercise training, education and self-management of the disease, psychosocial and behavioral intervention, nutritional support, outcome assessment and enhancement of long-term adherence to the rehabilitation recommendations. Exercise training is the central component of respiratory rehabilitation, aiming at physical reconditioning, and upper and lower limb muscle training, using several strategies to optimize training. Outcome assessment is an integral part of the program including the measurement of several valid, interpretable and easy to administer parameters. The beneficial effects of pulmonary rehabilitation are the improvement of dyspnea and degree of physical and social disability, less hospitalizations and exacerbations, better overall quality of life by increasing independence. PMID- 24340521 TI - Orthostatic intolerance and chronic fatigue syndrome--possible related conditions. AB - The connection between orthostatic intolerance and chronic fatigue syndrome was first introduced in 1995. It was demonstrated that many patients with chronic fatigue syndrome also had some form of orthostatic intolerance. Some studies suggested that dysautonomia may be the common problem in patients with these syndromes. Although these conditions affect an important number of people, especially younger adults, orthostatic intolerance and chronic fatigue syndrome are among the least understood of the autonomic disorders and sustained research is focused particularly on elucidating their pathogenesis and identifying the most effective methods of treatment. PMID- 24340522 TI - Osteoporosis in rheumatoid arthritis. AB - Osteoporosis (OP) is a disease of great medical and social importance and it is reported frequently and precociously in rheumatoid arthritis (RA) patients. MATERIAL AND METHODS: A retrospective study was conducted on a random sample of 180 patients admitted in the period 2011-2012 to the Rheumatology Clinic of the lasi Rehabilitation Hospital. The patients were diagnosed with RA and osteoporosis and some clinical and biological parameters were analyzed. Patients were divided into two groups for a comparative study: group I--seropositive = 115 cases (63.89%); group II-- seronegative = 65 cases (36.11%). RESULTS AND DISCUSSION: The 180 patients diagnosed with RA and osteoporoses were randomized into other two groups. The serum rheumatoid factor (RF) in RA and osteoporosis patients was determined by Latex and Waaler Rose reaction. The radiological examination showed that 23.47% of patients in group I and 9.23% of patients in group II have experienced at least one fracture. DXA (Dual X-Ray Absorptiometry) testing showed a value of <-3.5 in group I (13,04%) and in group II ( 9.23%), these results indicating a high risk of fracture, particularly in group I (seropositive). CONCLUSIONS: The results confirm that RA patients are at increased risk ofosteoporosis, and the additional risk of disability and serious socioeconomic implications negatively affect the prevention and development of the disease. PMID- 24340523 TI - Markers of insulin resistance in a case of Launois-Bensaude syndrome. AB - Launois-Bensaude syndrome (benign symmetric lipoma-tosis) is a rare disease characterized by symmetric fat deposits localized in the cervical region, shoulders and proximal parts of upper and lower limbs. We present the case of a 63-year-old male who presented the typical location of fatty masses and a history of chronic alcoholism associated with elements defining the metabolic syndrome. The biological profile indicated high-atherogenic mixed dyslipidemia, high basal insulinemia (30 microU/ml), and multiple markers of insulin resistance (Reaven index, lipid accumulation product, homeostatic model, insulin sensitivity index, and modified glycemic curve following oral glucose load). The particularity of the presented case is the discordance between the severity of metabolic disturbances and their clinical expression, raising the question whether this patient's cardiometabolic risk is increased or rather lowered by the association of benign symmetric lipomatosis. PMID- 24340524 TI - Percutaneous Herbert screw osteosynthesis in trans-scaphoid perilunate fracture dislocations. AB - Trans-scaphoid perilunate fracture-dislocation is the most common variety of fracture-dislocations of the wrist. Because of the carpal scaphoid fracture association, post-reduction stability is poor, often requiring surgery. Of the several surgical techniques used over time, percutaneous screw fixation for scaphoid fracture is currently preferred. MATERIAL AND METHODS: Six cases of trans-scaphoid perilunate fracture-dislocation were surgically treated by percutaneous reduction of the scaphoid fracture and percutaneous insertion of Herbert screw in a proximal to distal manner. Postoperative immobilization was followed by rapid resumption of wrist mobility. RESULTS: Four of the six patients have resumed normal, painless mobility of the wrist within 3 to 6 weeks post immobilization; in the remaining two cases there were a slight wrist stiffness attributed to persistent slight rotatory deficiency between the fractured scaphoid fragments. CONCLUSIONS: The percutaneous Herbert screw fixation provides a firm fixation with good compaction of scaphoid fracture, enough stability to allow minimal soft tissue and local damage, early mobilization following minimal immobilization, and thus rapid healing. PMID- 24340525 TI - Controlled ovarian hyperstimulation and IVF pregnancy prognosis. AB - IVF (in vitro fertilization) often represents the ultimate step in our attempt to treat infertility. Nowadays this method is more and more used, couple's expectations are higher and higher, so that optimizing the chance that one IVF pregnancy became a healthy newborn child is becoming an important issue. In this study we analyzed the controlled ovarian hyperstimulation impact on IVF pregnancy prognosis. We studied 307 patients who had IVF fresh procedures in "Panait Sirbu" Clinical Hospital of Obstetrics and Gynecology - Department of Assisted Human Reproduction between 01.01.2008 - 31.12.2010 and obtained pregnancy; pregnancy rate according to our statistics is 34%. For statistic analysis we used the odd Student test. Our data proved better results (defined as a better birth/abortion ratio) for the patients where recombinant FSH was used towards patients where highly purified urinary gonadotropin or the combination of the two drugs was used. Our statistical data also proved that none of the variables: age, BMI (body mass index), endometrium thickness, number of oocytes, number of embryos or number of days of stimulation is a favorable variable for this better result, but the number of units of gonadotropin is a favorable variable for a better birth/abortion ratio. We consider that our data gives an interesting perspective upon the connection between controlled ovarian hyperstimulation and pregnancy outcome, especially these days when tendencies are to obtain as many oocytes in one procedure as we can, which often means to use high doses of gonadotropin. PMID- 24340526 TI - Complex utrasound study of the atherosclerotic plaque. AB - Carotid surgery concept is wining ground both among neurologists who recommend and vascular surgeons who perform an increased number of interventions. Regardless of the technique, we are interested in the tendency of the plaque to grow and determine stenosis. Ultrasound (US) is 91-94% sensitive and 85-99% specific in detecting a significant stenosis of the internal carotid artery. AIM: To establish a correlation between the preoperative US and intraoperative plaque characteristics in order to determine the restenosis rate. MATERIAL AND METHODS: From January 1, 2012 to December 31, 2012, 70 consecutive patients were included in this study. Two groups were formed: 35 patients with stenotic ICA and 35 patients presenting stenosis at the femoral artery bifurcation (control group). The comparison between these two groups started from the premise of a similar pattern for internal carotid artery--deep femoral artery and external carotid artery- superficial femoral artery. US scans were performed on admission in all patients. All images were normalized and Gray Scale Median (GSM) was calculated. RESULTS: Femoral plaque GSM values were higher in relation with hyperechogenicity highlighting the intensely calcified structure. Unstable plaques were more heterogenic, with higher transparency and lower GSM than stable plaques. This was the case of carotid plaques. During follow-up US revealed no restenosis. CONCLUSIONS: Femoral bifurcation plaques are calcified and determine chronic ischemic symptoms, while carotid bifurcation plaques are unstable and determine cerebral symptoms. US remain the gold standard non-invasive technique both for screening and diagnosis and set the therapeutic coordinates. PMID- 24340527 TI - Natural conception following total fertilization failure with intracytoplasmic sperm injection in a couple with unexplained infertility: a case report. AB - With the introduction of intracytoplasmic sperm injection (ICSI), couples with severe male factor infertility have been able to achieve fertilization and clinical pregnancy rates comparable to other in vitro fertilization patients. However, despite the utilization of microsurgical sperm injection techniques, failure of fertilization still occurs in a few patients. How such fertilization failure after ICSI might impact later ICSI treatments is less understood. We report a case of total fertilization failure after ICSI using sperm from a normozoospermic husband of a patient with unexplained infertility. Six months after the cancelled cycle, the couple conceived naturally. Unfortunately, it was an ectopic pregnancy, which required laparoscopy and surgical removal of the right fallopian tube. This case shows that a failed ICSI cycle, therefore, does not imply a hopeless prognosis for future ICSI treatment. Moreover, in cases with unexplained ICSI failure, natural conception can subsequently occur. The aim of this study is two-fold: to discuss a rare case of a spontaneous pregnancy after total fertilization failure with ICSI and to develop counseling material for patients and doctors who are faced with such a rare situation. To our knowledge, this is the first report of a case of spontaneous pregnancy after total fertilization failure with ICSI. PMID- 24340528 TI - Necrotizing enterocolitis, a rare but severe condition with insidious postoperative complications. AB - Necrotizing enterocolitis (NEC) is one of the most frequent causes of gastrointestinal perforation in premature neonates, only few case series and reports being described in adult patients. Early in the course of the disease, superficial mucosal ulceration, sub mucosal edema and hemorrhage occur. Further progression leads to transmural necrosis leading sometimes to bowel perforation. Six cases encountered in our clinic in recent years led us to resume discussions on necrotizing enteritis, not because it is a rare disease, but due to the severe postoperative complications. MATERIAL AND METHODS: Our lot consisted of four stage 1 patients and two with Bell stage III NEC and severe intestinal injury, necrosis, and perforation. All of the patients were diagnosed preoperatory with other surgical conditions, like appendicitis with peritonitis, perforated duodenal ulcer or acute cholecystitis. RESULTS: We present to review two cases. For patients undergoing laparotomy, resection of the involved intestine mandates either enterostomy formation or primary anastomosis. An intermediate option is laparotomy with intestinal resection and delayed anastomosis 48 to 72 hours later. Because of the small number of patients in our lot, we cannot advise a certain surgical treatment, but a strategy involving bienterostomyper primam should be further analyzed. The choice of operative intervention reflects multiple variables, including age, physiologic status, institutional resources and surgeon preference based on experience. Primary peritoneal drainage for perforated NEC may help to resuscitate and treat a critically ill patient initially, and in some instances, may be definitive operative intervention. CONCLUSIONS: Relatively rare disease, of unknown etiology and elusive pathogenesis, NEC has initial non-specific symptoms and clinical features that mimic more common surgical diseases. There is considerable controversy regarding which procedure is preferable. Currently, in the absence of rigorous evidence supporting the superiority of one approach over the other, surgical intervention depends mostly on the treating institution or the individual surgeon. PMID- 24340529 TI - Rad52 protein function study by fluorescence tagging. AB - Rad52 protein plays a significant role in DNA lesions repair by homologous recombination in eukariotic cells. Human Rad52 function somewhat overlaps with BRCA2 and has a role in cell survival in the absence of BRCA1-BRCA2 mediated recombination. Additional Rad52 function analysis and intracellular localization studies are probably necessary. We present a method for Rad22 protein tagging, a Schizosaccharomyces pombe Rad52 homologue, by Crerecombinase-mediated cassette exchange (RMCE) using the versatile pAW8 plasmid. Rad22 protein was C-termini yEGFP tagged; the resulting strain was analyzed by fluorescence microscopy. The yEGFP signal was observed (Rad22 foci) for 7.5 microM camptothecin, 0.005% methyl methanesulfonate, and 4 mM hydroxyurea treated cells. The RMCE method was efficient, and the presence of tagged Rad22 protein was confirmed by Western-Blot and fluorescence microscopy. PMID- 24340531 TI - Antimicrobial resistance in septic-purulent infections. AB - Evaluating the spread of antibiotic-resistant microorganisms from a multi-profile hospital. MATERIALS AND METHODS: There were analyzed 3940 strains of antibiotic resistant microorganisms from patients with septic-purulent infections. RESULTS: From the total, 51.44% samples of isolated strains showed resistance to antibiotics, including Gram negative (61.66%), and Gram positive ones (40.25%). A higher degree of resistance showed strains of Acinetobacter spp. (86.87%), P. rettegeri (83.40%) and K. pneumoniae (73.35%). Etiological structure of septic purulent infections, as well as the degree of resistance, has proved to be varied, depending on the hospital profile unit. Isolated strains showed a higher resistance to penicillins and cephalosporins. CONCLUSION: Microorganisms isolated from patients with nosocomial septic-purulent infections have showed a higher resistance to antibiotics. PMID- 24340530 TI - Prenatal diagnosis of gonosomal anomalies: limitations of the FISH method and genetic counseling difficulties in 15 cases. AB - Prenatal diagnosis (PD) by FISH or cell culture is today an important tool for the prevention of chromosomal anomalies. A difficult issue is prenatal detection of gonosomal anomalies. Most gonosomal anomalies neither affect life expectancy nor cause psychomotor retardation, but sexualization disorders and the lack of reproductive potential are a constant finding. AIM: This study aimed at identifying the medical problems the specialists and the parental couple are faced with at the time of the diagnosis of fetal gonosomal anomalies. MATERIAL AND METHODS: This retrospective study (2004-2012) was conducted in the Prenatal Genetic Diagnosis Department of "CuzaVoda" Maternity by FISH technique in 1685 pregnancies. The AneuVysion probes were used for identifying and enumerating chromosomes 13, 18, 21, X, and Y via fluorescence in situ hybridization (FISH) in interphase nuclei obtained from amniotic fluid. RESULTS: Fifteen fetuses were selected in which we were faced with difficulties interpreting the number of gonosomes: monosomy X (5 cases), pseudomosaicism XX/XY (3), trisomy XXY (3 cases), trisomy XYY (1 case), 45,X/46.XX mosaicism (1 case) and triploidy XXX (2 cases). Later, by repeating the analysis, 2 cases with pseudomosaicism XX/XY were excluded. A case highlighting the limitations of the FISH test was that of a fetus in which the FISH test revealed trisomy XXY, while postnatal karyotyping showed a six cell line mosaicism (marker and ring X chromosomes). CONCLUSIONS: All parental couples received nondirective genetic counseling, respecting the individuals' dignity and rights of self-determination. Parents received information on the natural course of the disease, treatment options, and psychological support and were involved in their child's recovery. PMID- 24340532 TI - The seroprevalence of hepatitis C virus infection among blood donors from the North West region of Romania. AB - The infection with hepatitis C virus (HCV) known also as a blood-borne infection can be life-threatening by delayed consequences of persistent infection. This study aimed to estimate the hepatitis C infection prevalence, its epidemiological mode of manifestation and its recent evolution among blood donors from North West region of Romania. We made a chronological study using the HCV seropositive confirmed results to serological blood donors screening, provided by two Blood Transfusion Centres, chosen for their quality of provided data: Cluj and Satu Mare. The statistics were descriptive and the time series modelling used the polynomial regression. In both counties, about three fourth of donors were male and in Satu Mare, female donors (29.2%; p < 0.001) have been significantly more represented than in Cluj (24.6%). Hepatitis C virus seroprevalence was significantly (p < 0.01) higher in Satu Mare (279.8/10(5) donors, CI: 241.7 317.9/10(5) donors) than in Cluj (212.6/10(5) donors, CI: 187.4-237.8/10(5) donors). The mode of manifestation was endemic in different patterns, one with wave and a stable one with a particular high value of 1.091.1/10(5) female donors (CI: 674-1508.2/10(5) donors) seroprevalence, in 2008, in Satu Mare. The variation of the prevalence value was higher for women and particularly (coefficient of variation: 91.9%) for those from Satu Mare. The hepatitis C virus seroprevalence among blood donors reflected a stable, endemic manifestation with particular variation and high transmission in female populational subgroups. PMID- 24340533 TI - Viral meningitis admitted to an infectious diseases hospital: a retrospective case series. AB - Given its epidemic potential and development of severe forms of disease, viral meningitis (VM) is a serious public health problem. AIM: to characterize the main clinical, epidemiologic features, the etiology and treatment of VM cases admitted to the Iasi Infectious Diseases Hospital, in 2012. MATERIAL AND METHODS: We retrospectively analyzed the medical records of the patients admitted for viral meningitis at the Iasi "St. Parascheva" Infectious Diseases Hospital in the interval January 1- December 31, 2012 (98 cases). The etiologic diagnosis was made by determining the IgM/IgG antibodies against Coxsackie virus and/or West Nile virus in blood/CSF. RESULTS: There was a fourfold increase in the number of cases as compared to the average for the years 2009-2011. Most cases (73.5%) were children aged 1 to 14 years. 61.8% of patients were males, 51.7% from urban areas. The most common symptom was headache (85.7%), followed by fever (77.6%), and vomiting (66.3%). Neck stiffness was absent in 28.6% cases. In43.5% of the 39 patients serologically investigated a Coxsackie virus infection was confirmed and 1/20 was positive for West Nile virus; three varicella-zoster virus infections and one mumps infection were diagnosed clinically. 68.3% of the patients received first-line antibiotic treatment. CONCLUSIONS: The illness mainly affected children, fever and neck stiffness being sometimes absent. The etiology was known in 22.4% of cases; enter viruses being the most frequent causative agent. Most patients received antibiotic therapy. The course was favorable in all cases. PMID- 24340534 TI - An indirect evaluation of the national program of diabetes mellitus--study case of Romania. AB - Diabetes mellitus (DM) represents an important problem of public health according to the worldwide statistical data. In Romania, the national program is facing the same situation: increasing incidence (both for children and adults) and prevalence of this disease. AIM: To evaluate the results of the national program for DM through some indirect indicators. MATERIAL AND METHODS: This study represents a descriptive analysis of hospitalized DM cases between 1.01.2009 and 31.03.2013, in Romania. The lack of statistical data available from the Ministry of Public Health (the latest update on the web page for DM is from 2007) makes the evaluation of the outcomes of this program quite difficult. An indirect evaluation is possible using the national hospital registrations for DM complications, recorded by the National School of Management and Public Health. For diagnostic registration was used the classification for Diagnostic Related Group (DRG), version HCFA DRG v. 18. RESULTS: Despite the facilities offered to diabetic patients through the program, the burden of DM over the health system is quite large due to the large number of patients having complications. CONCLUSIONS: Even the objectives of the program appear to be accomplished; the indirect outcomes of the evaluation suggest that could be a gap between the hospital specialist and family doctors and a lack of health education for patients with DM. PMID- 24340535 TI - The clinical-epidemological study of drugs used to treat arterial hypertension and associated comorbidities. AB - AIM: The objective of this study was to investigate the drug treatment of AHT according to the grade and associated comorbidities: diabetes, chronic kidney disease, angina pectoris. MATERIAL AND METHODS: This study is a retrospective one, comprising a total of 1064 patients admitted to the Clinical Rehabilitation Hospital lasi, Cardiovascular Rehabilitation Clinic between 01.01.2011 - 31.12.2012. We noted the epidemiological data on the distribution of AHT according to area of origin, sex, age, and the pharmacological treatment according to the AHT grade and related diseases. RESULTS: The results obtained were statistically analyzed by comparing drugs used together, their number depending on the AHT grade and associated comorbidities in order to achieve target values of blood pressure and reduce cardiovascular risk. The strategies used to control blood pressure were the gradual increase of the dose of drug or its replacement, switching from monotherapy to combination therapy, starting treatment with two drugs or administration of fixed combinations. CONCLUSIONS: The most used antihypertensive drugs were the angiotensin receptor blockers, ACE inhibitors, calcium blockers, diuretics and beta blockers. Some patients have even received triple therapy. PMID- 24340536 TI - The third age--a current issue for the family physician. AB - Since our birth, we are programmed to experience predetermined stages of life whose passage is inevitable as the passage of time (childhood, youth, adulthood, old age). Although each of these stages of development differs in its specific tasks, the old age seems to be the most burdensome, resulting in significant changes: physical and intellectual decline, major changes in the importance of the professional, marital, parental and social role. One of the main indicators of the quality of life, the average life expectancy increased significantly in the last 3-4 decades and the mankind gained decades of active life in a relatively short period of time. Therefore, one of the goals of medicine has become the prolongation of life, the pursuit of old age, the wish to remain healthy, to be able of physical and intellectual performance and useful in the private and social life. The old age is conditioned by a complex combination of factors: the individual genetic predisposition, the lifestyle of society and the environment, all of which affect the opinions regarding health and subsequently the attitude towards health. The family physician has the social obligation to research and promote health, to fight diseases. The family physician achieves this by researching the aging field and by trying to find solutions to improve the quality of life in the elderly, which is a prerequisite of maintaining the integration of the elderly into family life and society, of preserving the biological and social independence of aged persons. The maintenance of an active private and social life is a method of fighting premature aging associated with infirmity and disease. This action cannot be successful without the active involvement of the elderly and without their acceptance in the society. Aging is a biological process that affects the entire body, following the period of development and it is considered the final stage of biomorphosis. PMID- 24340537 TI - Predictors of quantitative microbiological analysis of spatter and aerosolization during scaling. AB - The aim of this study is to analyze the infection risk through spatter and aerosolization during scaling and to create a prediction model of the total number of hemolytic bacteria. MATERIAL AND METHODS: Air samples were collected prior to patient's arrival and spatter and aerosol samples were collected during scaling procedure in 80 patients of 4 different dental clinics. The dentists calculated DI, CI, DMFT. Only patients with CI > = 1 were included. The bacteriological results (CFU/m3) were correlated with clinical indicators. Patients were divided into 2 groups: one that rinse with sterile water and the other with chlohexidine mouth rinse 0.1%. RESULTS AND CONCLUSIONS: Medium size effect positive correlations were found between the number of decayed teeth and the total number of bacteria and the total number of hemolytic bacteria that grew on plate attached to the dentist's mask. The mean number of bacteria and the mean number of hemolytic bacteria that grew on plate attached to the dentist's mask were significantly lower in the group that rinse with chlorhexidine 0.1%, when compared to the group that rinsed with sterile water. When controlling for the total number of bacteria and the total number of hemolytic bacteria from air sampling, the total number of hemolytic bacteria that grew on the plate attached to the dentist's mask can be predicted by CI, group membership and DMFT score. PMID- 24340538 TI - Value of ICDAS index in a preschool community from Iasi. AB - The International Caries Detection and Assessment System (ICDAS) is a clinical scoring system for use in dental education, clinical practice, research, and epidemiology. The ICDAS is designed to: lead to better quality information to inform decisions about appropriate diagnosis, prognosis, and clinical management at both the individual and public health levels. It provides a framework to support and facilitate personalized management of the caries process and dental decay for improved long-term health outcomes. AIM: This baseline study aims to find out the distribution of the caries lesions in primary teeth and their associations between the socio-economic statuses of families, in an lasi town preschool community (Romania). MATERIAL AND METHODS: The study series included 500 children (276 girls, 224 boys), aged 3-7 years old ( 43 subjects aged 3-3, 9 years, 126 subjects aged 4-4, 9 years, 186 subjects aged 5-5, 9 years, 136 subjects aged 6-6, 9 years and 9 subjects aged 7 years), attending a Iasi town kindergarten, in which the ICDAS index, was applied. RESULTS: The visits to the dentist are statistically correlated only with the average number of healthy teeth from the frontal and the lateral area. In other areas of the dental arch, there is no statistically significant data, but in the frontal area, the children that had visited the dentist present an average number of 3.5 healthy teeth, and the children that had not been to the dentist present an average number of 3.717 healthy teeth. The number of teeth with enamel destruction without dentin visibility is much reduced in children also, statistically significances being present only in lateral mandibular and maxillary areas. Though in lateral mandible area, this value varies from 0 (for children between 6-7 years old), to 0.1176 (for children between 5-6 years old). The frequency of tooth brushing, has a significant influence on the (ICDAS = 4) value in lateral mandibular and maxillary areas, where these values decrease, as the tooth brushing is more often. Though in lateral maxillary area, the value is 0.066 for the children that brush their teeth twice a day, for the children that brush their teeth once a day, the value is 0.0353 and for the children that brush their teeth occasionally the value is 0.018. CONCLUSIONS: This study confirmed the high caries level in this region. The total caries experience indicators are normally higher, in the mixed dentition because the primary teeth have been exposed longer for the risk factors of dental caries for example frequent sugar snacks and drinks. It can be concluded that ICDAS method, gives much more relevant information about caries process than other methods. The distributions of the ICDAS codes are correlated between the primary and the permanent molars of the mixed dentition. PMID- 24340539 TI - Conservative treatment of dental trauma: case presentation-direct adhesive restoration techniques of the 4 upper incisors with different types of fractures on the coronal level. AB - Dental trauma creates serious functional, aesthetic and psychological problems for the patient. The known developments in recent years in the area of materials and techniques related to direct composite resin restorations provide for the dentists direct conservative solutions that allow both morphology and aesthetic restoration and preservation of pulp vitality in many of the clinical situations encountered. A careful clinical examination and an accurate diagnosis (in terms of classification of the trauma) will allow the dentist to choose the most conservative therapeutic solution. We recommend the use of the diagnostic and therapeutic guidelines mentioned in the article. PMID- 24340540 TI - Validation of a spectrophotometric assay method for bisoprolol using picric acid. AB - Bisoprolol is a drug belonging to beta blockers drugs used primarily for the treatment of cardiovascular diseases. AIM: A spectrophotometric method for quantitative determination of bisoprolol was developed based on the formation of a complex combination between bisoprolol and picric acid. MATERIAL AND METHODS: The complex combination of bisoprolol and picric acid has a maximum absorbance peak at 420 nm. Optimum working conditions were established and the method was validated. RESULTS: The method presented a good linearity in the concentration range 5-120 microg/ml (regression coefficient r2 = 0.9992). The RSD for the precision of the method was 1.74 and for the intermediate precision 1.43, and recovery values ranged between 98.25-101.48%. CONCLUSIONS: The proposed and validated spectrophotometric method for the determination of bisoprolol is simple and cost effective. PMID- 24340541 TI - Sulfadiazine modified CS/HA PEC destined to wound dressing. AB - AIM: To present the research results concerning enhanced antimicrobial and release properties of the chitosan derivative with sulfadiazine/hyaluronic acid polyelectrolyte complex (PEC) hydrogel. MATERIAL AND METHODS: The PECs have been prepared from chitosan of different molecular weight, sulfadiazine chitosan derivative and sodium hyaluronate. The complex structure was assessed by FT-IR spectroscopic method and swelling capacity was followed by weighing measurements. RESULTS: It has been establish that chitosan derivative influenced both PEC properties and swelling capacity. CONCLUSIONS: Incorporation in PEC of the sulfadiazine chitosan is a new way to combine bacteriostatic effect of chitosan with that of sulfadiazine, to control properties, antimicrobial activity in the treatment of the wound. PMID- 24340542 TI - New derivatives of aryl-propionic acid. Synthesis and biological evaluation. AB - AIM: To design new derivatives of aryl-propionic acid with potential antibacterial and antioxidant activity. MATERIAL AND METHODS: New hydrazone of ibuprofen (2-(4-isobutylphenyl)propionic acid) have been synthesized by reaction of ethyl ester of ibuprofen with hydrazine hydrate and then condensation of corresponding hydrazide with various aromatic aldehydes. RESULTS: The synthesized compounds were screened for their antibacterial activity against Gram positive (Staphylococcus aureus ATCC 25923, Sarcinalutea ATCC 9341, Bacillus cereus ATCC 14579, Bacillus subtilis) and Gram negative bacterial strains (Escherichia coli ATCC 25922). Some of them were found to have good antibacterial activity. The antioxidant activity of these compounds was also tested using the total antiox idant capacity test. CONCLUSIONS: The chemical modulations performed on ibuprofen structure have a good influence on the biological activity of the synthesized compounds. PMID- 24340543 TI - New hydrazones with pyrazolone structure: synthesis, characterization and biological evaluation. AB - AIM: To design new hydrazones with pyrazolone structure with improved biological properties. MATERIAL AND METHODS: New hydrazones of antipyrine have been prepared by reaction of 4-aminophenazone (4-aminoantipyrine) with chloracetylchoride and hydrazine hydrate and then condensation with various aromatic aldehydes. RESULTS: The synthesized compounds were screened for their antibacterial activity against Gram positive (Staphylococcus aureus ATCC 25923, Sarcinalutea ATCC 9341, Bacillus cereus ATCC 14579, Bacillus subtilis) and Gram negative bacterial strains (Escherichia coli ATCC 25922) and pathogenic yeasts (Candida albicans ATCC 10231, Candida sake, Candidaglabrata). Some of them were found to have good antibacterial and antifungal activity. The antioxidant activity of these compounds was also evaluated using the total antioxidant capacity test. CONCLUSIONS: The chemical modulations performed on antipyrine structure have a good influence on the biological activity of the synthesized compounds. PMID- 24340544 TI - Polyphenolic content and antioxidant activity of an extractive fraction from Abies alba bark. AB - The wood of mature Abies alba Mill. (silver fir) trees is used in construction and furniture industries, the bark being the main waste product. AIM: This study aimed to investigate possible therapeutic applications of Abies alba bark waste. MATERIAL AND METHODS: A raw extract and four extractive fractions were obtained from silver fir bark. They were also studied regarding their polyphenolic content (Folin-Ciocalteu assay). The ethyl acetate extractive fraction was further studied regarding its ability to scavenge free radicals (DPPH, superoxide anion and hydroxyl radicals) and to chelate ferrous ions. RESULTS AND DISCUSSION: The ethyl acetate fraction contained the highest amount of polyphenols (47.72 +/- 0.38 g gallic acid equivalents/100 g). Its DPPH scavenging and ferrous ions chelating abilities (EC50 = 7.9 +/- 0.1 and 1.56 +/- 0.05 microg/ml) were comparable to those of the positive controls, catechin (EC50 = 7.10 +/- 0.05 microg/ml) and EDTA-Na2 (EC50 = 1.27 +/- 0.01 microg/ml), respectively. It also scavenged superoxide anion and hydroxyl radicals with EC50 values of 53.30 +/- 5.91 and 63.12 +/- 1.78 microg/ml, respectively. CONCLUSIONS: The ability of the ethyl acetate fraction to scavenge free radicals and chelate ferrous ions justifies further studies on the possible therapeutic applications of its antioxidant potential. PMID- 24340545 TI - Bioactivity screening of Pinus brutia bark extracts: superoxide dismutase-like and nitric oxide scavenging effects. AB - In the Eastern Mediterranean region the wood of Pinus brutia Ten. is used as building material, the bark being the main waste of the wood production processes. A study was designed to explore possible medicinal applications for the bark waste. This paper reports on the superoxide dismutase-like and NO scavenging effects of bark extracts. MATERIAL AND METHODS: Bark extracts (a raw hydromethanolic extract and its fractions) were initially screened regarding their ability to scavenge DPPH radical. The superoxide dismutase-like and NO scavenging effects were further evaluated. Catechin and quercetin were the positive controls in all antioxidant assays. RESULTS AND DISCUSSION: According to the EC50 values, all extracts (11.8 +/- 0.1 - 21.10 +/- 0.05 microg/ml) efficiently scavenged DPPH radical in comparison to quercetin (3.13 +/- 0.05 microg/ml) and catechin (6.36 +/- 0.05 microg/ml). The raw extract, diethyl ether and ethyl acetate fractions (449.46 +/- 1.75, 115.43 +/- 0.25 and 278.3 +/- 2.3 microg/ml, respectively) exhibited higher superoxide dismutase-like effects in comparison to catechin (> 645.1 microg/ml). In NO scavenging assay, the raw extract, ethyl acetate and aqueous fractions (160.63 +/- 0.85, 162.96 +/- 0.52 and 160.23 +/- 2.35 microg/ml, respectively) showed a scavenging ability similar to that of quercetin (156.76 +/- 5.05 microg/ml) and higher than the one developed by catechin (242.66 +/- 7.65 microg/ml). CONCLUSIONS: As superoxide anion and NO are important mediators in inflammation, our results support a possible use of Pinus brutia bark waste to develop nutraceuticals with efficiency in disorders involving oxidative and inflammatory stress. PMID- 24340546 TI - Importance of sulfonamide moiety in current and future therapy. AB - Sulfonamides and their different derivatives are extensively used in therapy due to their pharmacological properties. Sulfa drugs were amongst the oldest synthesized antimicrobial agents and are still widely used today to treat different microbial infections. Clinical treatment with sulfonamides has regained confidence with the use of a combination of sulfamethoxazole and trimethoprim to treat urinary tract bacterial infections. Today, they are widely used as antimicrobial agents, chiefly because of their low cost, low toxicity and excellent activity against bacterial diseases. Over the course of time, the application of sulfonamides has been extended from their use as antimicrobial agents to anticancer agents, antiglaucoma agents, inhibitors of gamma-secretase, cyclooxgenase-2 and lipoxygenase, anticonvulsivant agents, hypoglycemic agents. PMID- 24340547 TI - Chitosan/hyaluronic acid polyelectrolyte complex hydrogels in the management of burn wounds. AB - AIM: This paper is a short review on the state-of-the-art of the use of polyelectrolyte complexes containing polysaccharides for wound and burn healing and treatment using the chitosan/hyaluronic acid polyelectrolyte complex (PEC) hydrogel. RESULTS AND CONCLUSIONS: PEC is suitable for wound healing because a wet treatment can be realized and both components of PEC contribute by their properties to the enhanced antimicrobial activity, promote wound healing and prevent wound damage during treatment. PMID- 24340548 TI - Differential equations with applications in cancer diseases. AB - Mathematical modeling is a process by which a real world problem is described by a mathematical formulation. The cancer modeling is a highly challenging problem at the frontier of applied mathematics. A variety of modeling strategies have been developed, each focusing on one or more aspects of cancer. MATERIAL AND METHODS: The vast majority of mathematical models in cancer diseases biology are formulated in terms of differential equations. We propose an original mathematical model with small parameter for the interactions between these two cancer cell sub-populations and the mathematical model of a vascular tumor. We work on the assumption that, the quiescent cells' nutrient consumption is long. One the equations system includes small parameter epsilon. The smallness of epsilon is relative to the size of the solution domain. RESULTS: MATLAB simulations obtained for transition rate from the quiescent cells' nutrient consumption is long, we show a similar asymptotic behavior for two solutions of the perturbed problem. In this system, the small parameter is an asymptotic variable, different from the independent variable. The graphical output for a mathematical model of a vascular tumor shows the differences in the evolution of the tumor populations of proliferating, quiescent and necrotic cells. The nutrient concentration decreases sharply through the viable rim and tends to a constant level in the core due to the nearly complete necrosis in this region. CONCLUSIONS: Many mathematical models can be quantitatively characterized by ordinary differential equations or partial differential equations. The use of MATLAB in this article illustrates the important role of informatics in research in mathematical modeling. The study of avascular tumor growth cells is an exciting and important topic in cancer research and will profit considerably from theoretical input. Interpret these results to be a permanent collaboration between math's and medical oncologists. PMID- 24340549 TI - University Professor Doctor Emanoil Grigorescu at 90 years. PMID- 24340550 TI - HCV drug resistance and DAA agents. AB - New treatment options for HCV infection with Direct-Acting Antivirals (DAAs) increased SVR rate in treated patients but on the other hand drew attention to the problem of HCV drug resistance. Drug-resistant HCV mutants are present in all infected patients even before the treatment initiation and their number grows significantly over the first few days of DAAs therapy. But HCV has no known genetic form of intra-cellular persistence (does not integrate with host's genome and cannot produce episomal forms) which enables its total eradication. It is likely that the effective interferon-free, based on all-oral DAAs drug combination will be available within the next few years. This paper reviews HCV resistance mechanisms and their significance in treatment. I also presents results of recent DAAs trials. PMID- 24340551 TI - SNP RS12979860 related spontaneous clearance of hepatitis c virus infection in HCV/HIV-1 coinfected patients. AB - CC genotype of SNP rs 12979860 promotes spontaneous HCV clearance in monoinfected patients. The aim of this analysis was evaluation of impact of rs12979860 polymorphism on HIV or HCV viral load, CD3, CD4 and CD8 count as well as HCV clearance among HCV/HIV coinfected patients. MATERIALS AND METHODS: The study included 41 consecutive HCV/HIV coinfected patients. HIV RNA, HCV RNA, HCV genotype and rs12979860 polymorphism sequence as well as CD3, CD4 and CD8 cells count were analyzed in all patients. RESULTS: CC genotype rs12979860 was identified in 16 from 41 patients. During at least 4 years follow-up, five genotype CC patients (31%) became HCV RNA undetectable, that was not a case in CT and TT patients. No statistical differences in HIV viral load and the number of CD3, CD4 and CD8 related to rs12979860 polymorphism were observed. The baseline level of HCV RNA in patients with CC genotype was significantly lower compared to patients with non-CC genotypes (88546 +/- 74181 vs. 726021 +/- 30709 IU/mL). CONCLUSION: CC genotype related to SNP rs 12979860 can affect the lower level of HCV viral load compared to patients with CT and TT genotypes and promotes spontaneous clearance of HCV RNA in HCV/HIV coinfected patients. PMID- 24340552 TI - Prevalence of hepatitis C virus mutants resistant to protease inhibitors among Polish HCV genotype 1-infected patients. AB - AIM: The aim of this study was to evaluate prevalence of hepatitis C virus (HCV) harbouring mutations associated with decreased susceptibility to protease inhibitors (Boceprevir/Telaprevir) among Polish untreated patients infected with HCV genotype 1. MATERIAL AND METHOD: Population sequencing was used, sequencing data were interpreted by web based geno2pheno algorithm. A total of 91 serum samples were obtained from patients infected with HCV genotype 1, admitting Outpatient Clinics of Hospital of Infectious Diseases, Warsaw. RESULTS: Sequencing analysis of the NS3 protease catalytic domain was successful in 85 out of 91 subjects. In seventy three (85.9%) out of 85 samples wild-type HCV was detected; in 12 (14.1%) samples mutations associated with clinically observed Boceprevir/Telaprevir-decreased susceptibility were detected. SUMMARY AND CONCLUSIONS: Obtained results document the presence of HCV strains harbouring protease inhibitors (PIs) resistance-associated mutations among Polish therapy naive patients. The determined prevalence of drug resistant HCV variants is 14.1%. Further and continuous surveillance is necessary to estimate how preexisting and emerging drug resistance mutations influence clinical outcome in triple-therapy experienced patients. PMID- 24340553 TI - Evaluation of cerebrospinal fluid S100B protein concentration in patients with purulent, bacterial meningitis - own observations. AB - The aim of the study was evaluation of usefulness of cerebrospinal fluid (CSF) S100 B protein concentration assessment in adults with purulent, bacterial meningoencephalitis. MATERIAL AND METHODS: The investigation was performed in 16 subjects hospitalized at the Department of Infectious Diseases of Medical University of Silesia in Bytom in 2008 - 2012 due to purulent, bacterial meningoencephalitis. All patients were divided into two groups according to the severity of their clinical condition: I group - very severe course of the disease, II group - moderate and mild course of the disease. In all individuals CSF S100 B protein concentration was evaluated during the first 24 hours ofhospitalization. RESULTS: Mean CSF S100 B protein concentration in patients in very severe clinical condition (group I) was 1215.63 pg/mL compared to 419.56 pg/mL in subjects of group II with moderate and mild course of disease. The difference between CSF mean concentration of this protein was statistically significant (p<0.01). No correlations were assessed between CSF S100 B protein concentrations and other CSF inflammatory parameters. Control assays performed in 7 patients from group I revealed only slightly decrease of CSF S100 B protein level in fatal course of the disease. In survivals with recovery CSF concentration of this protein was evident decreased compared to initial level. CONCLUSIONS: The obtained results indicate the usefulness of CSF S100 B protein concentration assessment in estimation of severity of the patient's clinical condition. The level of this protein concentration also seems to be helpful as prognostic marker in purulent, bacterial meningoencephalitis. PMID- 24340554 TI - Bacterial meningitis - principles of antimicrobial treatment. AB - Bacterial meningitis is associated with significant morbidity and mortality despite the availability of effective antimicrobial therapy. The management approach to patients with suspected or proven bacterial meningitis includes emergent cerebrospinal fluid analysis and initiation of appropriate antimicrobial and adjunctive therapies. The choice of empirical antimicrobial therapy is based on the patient's age and underlying disease status; once the infecting pathogen is isolated, antimicrobial therapy can be modified for optimal treatment. Successful treatment of bacterial meningitis requires the knowledge on epidemiology including prevalence of antimicrobial resistant pathogens, pathogenesis of meningitis, pharmacokinetics and pharmacodynamics of antimicrobial agents. The emergence of antibiotic-resistant bacterial strains in recent years has necessitated the development of new strategies for empiric antimicrobial therapy for bacterial meningitis. PMID- 24340555 TI - Patients with sepsis in infectious diseases department in years 1997-2010 - epidemiology and clinical features. AB - INTRODUCTION: Sepsis is a clinical syndrome that complicates severe infection. The incidence of sepsis is increasing worldwide. Aim of the study was evaluation of demographic data and clinical picture of patients hospitalized in Infectious Diseases Ward with a diagnosis of sepsis and severe sepsis. MATERIAL AND METHODS The retrospective study included 107 patients with sepsis and severe sepsis hospitalized in 1997-2010. RESULTS: Sepsis was diagnosed in 48.6% of patients and severe sepsis - in 51.4% ofpatients. The mortality rate in patients with severe sepsis was 30.9%. Blood cultures were positive in 55.1% cases. Gram-positive bacteria were isolated most frequently - 71.7%. The most common source of infection overall was pneumonia (21.5%). Odontogenic infections (25%) and urinary tract infections (21.2%) dominated in patients with sepsis. 25.2% of patients developed bacterial meningitis. CONCLUSIONS: Despite advances in diagnostics and treatment sepsis is still a major medical problem with high mortality. Patients with severe sepsis and meningitis should be treated in ICU setting. Decayed teeth should be considered as a potential source of sepsis of unknown origin. PMID- 24340556 TI - Typing of Staphylococcus aureus in order to determine the spread of drug resistant strains inside and outside hospital environment. AB - Staphylococcus aureus is one of the most important etiological factors of both nosocomial and community-acquired infections. Multidrug-resistant S. aureus is frequently isolated nowadays. Antibiotics used on the hospital ward exert a selective pressure on the strains and favor resistant strains. Multidrug resistant and highly virulent strains can spread not only within the hospital but also between hospitals. Numerous studies show a predominance of one clone on a specific territory. The spread of such dangerous clones to neighboring countries and the entire continent is possible. Typing methods are very useful in infection control and prevention. Modern methods which are based on sequencing are necessary in rationalizing of infection control programs. Typing of Staphylococcus aureus includes methods that allow to determine the spread of drug resistant pathogens. 'Gold standard' is pulsed-field gel electrophoresis (PFGE), which relies on separating the DNA fragments after restriction cutting. MLST (Multi Locus Sequence Typing) is based on a comparison of"housekeeping" gene sequences controlling the basic cell functions. With the MLST method, it is possible to demonstrate a broad, international spread of the specific clones. However, for epidemiological investigations, MLST seems to be too time-consuming and expensive to be used as a basic typing tool. The complementary method is spa typing, based on the sequencing of short repetitive sequences of the polymorphic X region from the gene encoding protein A. This method can be used for studying molecular evolution of S. aureus, as well as for testing for hospital outbreaks. It is faster and cheaper than MLST. It is also necessary to subtype the elements responsible for methycillin resistance (SCCmec), which allows to distinguish MRSA (Methicillin-resistant Staphylococcus aureus) clones with a common ancestor, but different epidemiological origin. All of those methods have their specific advantages and disadvantages and there is no single method efficient and suitable in any case. PMID- 24340557 TI - Surgical site infections in patients of orthopedic - trauma unit in district hospital in 2008-2012. AB - THE PURPOSE OF THE STUDY: The purpose of this study was to evaluate the prevalence and structure of surgical site infections in the Department of Orthopaedis - Trauma Unit in Regional Hospital. St. Luke in Tarnow in 2008-2012. MATERIALS AND METHODS: Data analysis included 7189 patients operated in 2008 2012. The data collection and analysis used standard statistical tools and definitions for nosocomial infections issued by the U.S. Centers for Disease Control and Prevention (CDC). RESULTS: In the study group it was 91 cases of SSI (surgical site infection), including 35 patients (38%) with post-operative open reduction of long bone fracture (FX), 16 (18%) with reduction of closed fractures (CR), 15 patients (16%) undergoing hip endoprosthesis (HPRO), 13 (14%) with open reduction surgery of small bones (OR-OTHER), 4 (4%) after knee endoprosthesis surgery (KPRO), and 8 (9%), after treatments of other infections (OTHER). The latter have not been taken into account in the further analysis due to the small number and variety of surgical procedures. The incidence of SSI was for: FX from 2.6 (2008) to 4.1 (2011); CR from 1.2 (2012) 4.8 (2008), HPRO from 0.7 (2012) to 1.3 (2009 r.), OR-OTHER from 0 (2009) to 4.5 (2010); KPRO from 0 (2010-2012) to 2.1 (2009). Among the etiological factors isolated from clinical materials derived from patients diagnosed with infections dominated Gram-positive bacteria, especially Staphylococcus-aureus: HPRO-40%, KPRO-75% FX-46%, OR-OTHER-62%, CR 63%, OTHER -38%. Strains resistant to methicillin (MRSA) were not reported. CONCLUSION: Prevention measures implemented in many areas of the potential impact on risk factors for SSI, has helped to achieve in 2012, the lowest rate of infection for all the analyzed procedures in the last 5 years. Conducting targeted surveillance of surgical site infection keeps morbidity associated with SSI at an acceptably low level and allows for precise planning of the preventive measures in this area. PMID- 24340558 TI - An analysis of risk factors of Clostridiumdifficile infection in patients hospitalized in the teaching hospital in 2008. AB - The last decade saw an increase in the incidence of Clostridium difficile infections.Approximately 80% of these infections occur in hospitalized patients. There are ongoing studies on the increase in the incidence of infections with this microorganism. OBJECTIVE: The objective of this study was to assess the risk factors of C. dicfficile infections in patients hospitalized in the teaching hospital in Warsaw in 2008. MATERIAL AND METHODS: A case-control study was conducted to achieve this objective. The study group comprised 266 patients. Patients in the study group were assessed for the following factors: sex; age; place of residence; hospitalizations; the use of proton pump inhibitors (IPP), various antibiotics, probiotics; hospital stay conditions, and the patient's condition. RESULTS: The statistical analysis showed that out of the assessed risk factors, hospitalization within the 3 months preceding hospital admission (OR 5.02; P<0.003) and antibiotic therapy (OR 4.85; P<0.003) were associated with the highest risk of C. difficile infection. Hospital stay conditions, including a stay in a multi-bed room (OR 1.64; P=0.05) or in a room without an en suite toilet (OR 1.59; P=0.01), were also shown to play a role. The risk of a C. difficile infection was also increased in the case of "bed-ridden" patients requiring the assistance of hospital staff for their daily hygiene (OR 1.69; P=0.01). CONCLUSIONS: This study demonstrated that hospitalization itself, including the frequency and conditions of hospital stay, as well as receiving antibiotic therapy were significant risk factors of C. difficile infections in patients hospitalized at the SP CSK. Therefore, our analysis showed that C. difficile infections are mostly nosocomial. PMID- 24340559 TI - Is measles elimination possible in WHO European region up to 2015? AB - STUDY OBJECTIVE: The assessment ofepidemiological situation of measles in WHO European Region during last decade in terms of progress in disease elimination. MATERIAL AND METHODS: [corrected] The surveillance data regarding measles control and vaccination coverage in entire region were compared to the targets that should be achieved at the last stage of measles elimination program. RESULTS: There were not sufficient vaccination coverage to protect population against measles outbreaks in many areas of WHO European Region during last decade. The incidence of measles was significantly higher than is required on that stage of measles elimination i.e. 1/1,000,000 excluding imported cases. Furthermore, there were notified 42 fatal cases related to measles during considered period. CONCLUSIONS: The insufficient vaccination coverage in many countries of the region causes the sustainable virus transmission in population. That situation lies behind the high probability of measles outbreaks in nearly future, that could delay the disease elimination in the set limit of time. PMID- 24340560 TI - Looking for the new preparations for antibacterial therapy III. New antimicrobial agents from the quinolones group in clinical trials. AB - There is an essential need for searching for the new compounds effective in the treatment of infections caused by multidrug-resistant bacteria. This paper is the third part of a series associated with the exploration of new antibacterial agents and it discusses the compounds belonging to the group of quinolones and substances possessing a hybrid structure composed of the quinolone molecule and other compounds. Eleven new substances at the stage of clinical trials are presented. Three of them belong to the group of non-fluorinated quinolone (nemonoxacin, ozenoxacin and KRP-AM 1977X), while six are the quinolones containing fluorine atom at 6 position of the carbon atom in the quinoline ring (zabofloxacin, finafloxacin, delafloxacin, JNJ-Q2, WCK771 and KPI-10). The remaining two compounds possess a hybrid construction composed of the quinolone structure and other molecules (cadazolid and CBR-2092). There is a chance in the near future, that the presented compounds can extend the range of existing antibacterial drugs and provide an alternative to currently available medicinal products. PMID- 24340562 TI - Salmonellosis in Poland in 2011. AB - THE PURPOSE OF THE STUDY: To assess the epidemiological situation of salmonellosis in Poland in 2011 as compared with previous years. MATERIALS AND METHODS: The assessment was based on the results of analysis of the data from the newsletter "Infectious diseases and poisonings in Poland 2011", information from laboratories of sanitary-epidemiological stations and reports of epidemiological investigations performed in outbreaks of salmonellosis, sent by the sanitary epidemiological stations to the Department of Epidemiology and also on the data from the Department for Demographic Research, Central Statistical Office. For the purpose of surveillance disease were classified in accordance with the current case definition. RESULTS: In 2011, the total number of cases of zoonotic salmonellosis registered in Poland was 8 813. Out of it 8 652 cases were of intestinal salmonellosis and 161 of parenteral. The overall incidence was 22.9/100 000. Over 95% of cases met criteria of confirmed case. The number of registered cases was the lowest ever recorded, indicating a continuing downward trend in incidence of salmonellosis in Poland. Maintains a high percentage of hospitalization, almost 70% of people infected with zoonotic Salmonella - but in outbreaks the figure is more than two and a half times lower and is less than 27%. The incidence was highest among children less then five years old. No deaths were registered with the salmonellosis indicated as the underlying cause. In 2011 there were reported 174 outbreaks caused by Salmonella, in which 1774 people fell ill. They were mostly small family outbreaks. Still the most common etiologic factor in Poland is S. Enteritidis. In 2011, fraction of Salmonella rods without confirmed species increased by 13% compared to 2010. In the province of Pomorskie it was the highest and reached 45%. CONCLUSION: A very high percentage of hospitalized cases of salmonellosis that persists for many years at 70%, testifies to the recognition and reporting mostly the more severe cases. This means that reporting ofsalmonellosis in Poland is largely under-diagnosed and underreported. The fact that increasing the percentage of Salmonella that are not serotyped is another problem of concern. PMID- 24340561 TI - Foodborne infections and intoxications in Poland in 2011. AB - THE PURPOSE OF THE STUDY: To assess the epidemiological situation of food poisoning and infections in Poland in 2011. MATERIALS AND METHODS: The assessment was based on information from the forms of the epidemiological investigations in outbreaks of foodborne poisoning and infections, sent by the sanitary epidemiological stations to the Department of Epidemiology, NIPH-NIH (NIZP-PZH) and the results of the analysis of annual bulletins (Czarkowski MP et al. "Infectious diseases and poisonings in Poland"- 2005 - 2011. Warsaw, NIZP-PZH and GIS). RESULTS: In 2011 it was observed decrease in the number of infections and food poisoning of bacterial etiology and steady marked increase in the incidence of those of viral etiology, classified as "viral and other intestinal infections." In 2011 there were registered 490 outbreaks of poisoning / infection of food, which had affected 6 386 people, including 1,718 children under 14. Among them 1364 people required hospitalization. The predominant etiologic factor in outbreaks were viruses - 36.5% of outbreaks and 40.6% of cases then zoonotic Salmonella types - 35.5% of outbreaks and 27.8% of cases. In 22.2% of outbreaks etiological factor was not established. Most of the outbreaks occurred in households - 235 and in hospital - 118. As in previous years, the most common carrier of infection was food prepared from milk and eggs -11.4% of outbreaks and egg only dishes - 9.8%. In more than 61% of outbreaks etiologic factor has not been established. In 2011, there were five outbreaks, in which got ill 100 people or more. CONCLUSION: Since the seasonality of outbreaks of unknown etiologic factor is similar to outbreaks of viral etiology; they occur in the autumn and winter, one should pay special attention to the testing samples taken for viral agents. PMID- 24340564 TI - Premature mortality due to cancer in Swietokrzyskie Province (Poland) in 1999 2010. AB - THE PURPOSE OF THE STUDY: The purpose of the study was to analyze the level and the trends of premature mortality caused by selected cancers in Swietokrzyskie Province in years 1999-2010. MATERIAL AND METHODS: The material for the study was the data published in the Swietokrzyskie Cancer Registry on the number of deaths caused by cancers as well as the information from the Central Statistical Office on the number of deaths due to general death causes in Swietokrzyskie Province in years 1999-2010. The premature mortality analysis was conducted with the use of PYLL indicator (PYLL - potential years of life lost). PYLL rate was calculated according to the method proposed by J. Romeder, according to which the premature mortality was defined as death before the age of 70. Time trends of PYLL rate and the average annual percent change (APC - annual percent change) were assessed usingjointpoint models as well as the Jointpoint Regression Program (Version 4.0.1 - January 2013). RESULTS: In year 2010 cancers were responsible for 18.3% of PYLL in men and 48.1% in women. In years 1999-2010 PYLL rate in men decreased due to lung cancer (APC=0.75%) and stomach cancer (APC=1.2%). The increase in rate of PYLL was noted for colorectal cancer (APC=3.3%, p<0.05) and prostate cancer (APC=1.6%). In women, rate of PYLL increased due to lung cancer (APC=6.2%, p<0.05), colorectal cancer (APC=2.9%), breast cancer (APC=1.8%) and ovarian cancer (APC=0.15%). Rate of PYLL decreased due to cervical cancer (APC=4.3%, p<0.05) and stomach cancer (APC=1.5%). SUMMARY AND CONCLUSIONS: During the analysed period the highest increase of premature mortality was observed in colorectal cancer in both sexes and lung cancer in women, a slightly smaller increase was noted for breast cancer and prostate cancer. What is particularly important is the trend and a slight decrease of premature mortality rate caused by lung cancer in men and its significant decrease for cervical cancer as well as stomach cancer in both sexes. PMID- 24340563 TI - Rabies in Poland in 2011. AB - AIM: To assess epidemiological situation of rabies in Poland in 2011. MATERIAL AND METHODS: The assessment was based on the results of the data analysis from questionnaires (People vaccinated against rabies post-exposure surveys in Poland and people vaccinated against rabies after exposure in other countries) submitted by the Sanitary-Epidemiological Stations and data from the annual newsletter "Infectious diseases and poisonings in Poland in 2011" (Czarkowski MP et al., Warsaw, NIZP-PZH and GIS) and epizootic data provided by the General Veterinary Inspectorate. RESULTS: In 2011, in Poland, 160 cases of rabies (in 2010 - 152 cases) were reported. Animal cases occurred primarily in the Malopolska province, where an increase in animal rabies cases has been observed since September 2010 and in Podkarpackie province. A single case of fox rabies was reported in Silesia, where there was no disease for many years. Rabies among terrestrial animals also occurred in the provinces ofLubelskie, Warminsko-Mazurskie and Podlaskie. In other regions of the country there were recorded only isolated cases of bat rabies. In 2011, number of people vaccinated against rabies was 7 543 (in 2010 - 7,243), of which 300 (4%) due to exposure to the animals that were confirmed to have rabies. Among those vaccinated because of contact with the rabid animal, 68 people (over 22%) were vaccinated after contact with fox. As in previous years, people were mainly vaccinated after exposure to dogs and cats in which rabies could not be ruled out - 5 874 persons (78%). CONCLUSIONS: The number of registered animals with confirmed rabies remains at the same level and the disease epizootic situation is good. This is a consequence of the implementation of the oral vaccination of wild animals introduced in the country in 1993. Epizootic situation in the country has a small influence on the number of people vaccinated against rabies who have come into contact with the animal potentially infected with the rabies. Serum is given in a few cases, including a few people at contact with rabid animals or deeply wounded by animals in which rabies cannot be excluded. PMID- 24340565 TI - Stability of the mental and motor Bayley Scales of Infant Development (2nd ed.) in infants over first three years of life. AB - Despite the Bayley Scales of Infant Development second edition (BSID-II) are wide used both clinically and in research settings, only a few published studies have been examined their stability over time. AIM OF STUDY: The aim of this study was to examine the stability of mental and motor BSID-II scores over the first three years of life. MATERIAL AND METHODS: All children included in this study were a sample followed up in a study on the susceptibility of the fetus and child to environmental factors. The cohort recruited prenatally in Krakow Poland, included 408 children. The mental and motor scales of BSID-II were administered to infants at the end of 12th, 24th and 36th month of life. Stability of the test scores from first to second and third assessment was evaluated using the Pearson's correlation coefficient calculated for the entire group of infants, and for the each gender separately. RESULTS: The older infants obtained the better outcomes in BSID-II. The correlation between the first and second assessments for the Psychomotor Developmental Index (PDI) was r = 0.30, for the Mental Developmental Index (MDI) was r = 0.33, and between the second and third assessments the correlation for the PDI was r = 0.40, for the MDI was r = 0.59. That results suggest a low or moderate degree of relationship between the tests outcomes. Only 8,8% to 34,8% of variance in the infants later BSID-II scores could be explained by their earlier scores. The correlation between the tests scores was higher between outcomes obtained by girls than boys. CONCLUSION: The BSID-II should not be treated as a useful measure for predictive purposes of infants development. PMID- 24340566 TI - Usefulness of maternal assessment of children development based on reported age of achieved milestones. AB - STUDY OBJECTIVE: The aim of the study was to examine the usefulness of maternal recall of selected developmental milestones by testing their correlations with the Bayley Scales of Infant Development (BSID-II). MATERIAL AND METHODS: Prospective cohort study. The cohort recruited prenatally, included 387 children. The BSID-II tests were carried out in each child at the end of the 12th, 24th and 36th month of life. When children were 3 years old, mothers were questioned about their child's age at attainment of 8 significant developmental milestones. RESULTS: The infants who attained developmental milestones earlier in their first years of life were more likely to achieved a better scores on the motor scale of the BSID-II. Correlation coefficients ranged from -0.117 for bladder control to 0.424 for standing without assistance and -0.586 for walking unassisted. Correlation arose when the difference between the time of achieving a particular milestone and time of managing the BSID-II was smaller. CONCLUSION: Our study demonstrated that maternal reports of developmental milestones of children under 3 years old are sufficiently reliable to be used in clinical judgment. PMID- 24340567 TI - Quality of life in stoma patients in Poland: multicentre cross-sectional study using WHOQOL-BREF questionnaire. AB - INTRODUCTION: Previous studies on quality of life of patients with stoma in Poland included small groups of respondents and were based either on the non validated questionnaires created ad hoc, or on the disease-specific oncologic questionnaires. OBJECTIVES: To assess quality of life of Polish patients with a stoma using validated generic questionnaire. MATERIAL AND METHODS: Adult patients with colostomy, ileostomy or urostomy performed in Poland between July 2009 and March 2010 were included. Patients completed satisfaction survey at the discharge from the hospital, and The World Health Organization Quality of Life-BREF (WHOQOL BREF) generic questionnaire at 3 months after surgery. RESULTS: The study involved 737 patients (71%, 18%, 11% with colostomy, ileostomy and urostomy, respectively). The studied population was highly diversified in terms of: dependence on medical treatment, pain and discomfort, satisfaction with health and acceptance of physical appearance. 59% of patients with a stoma defined their quality of life as very good or good (mean 3.56 points; range: 1 to 5; SD 0.74). The subjects were characterized by low quality of life assessment in the physical health and psychological domains (52.9 and 60.1 pts.) and by high evaluation in the environment and social relationships domains (69.7 and 70.1 pts.). Respondents highly assessed: the level of social support, home environment, physical environment, personal relationships. Low assessment was related to: sexual activity, ability to work, dependence on medical treatment, financial resources, satisfaction with health. CONCLUSIONS: Quality of life in patients with a stoma, assessed at three months after the surgery, is higher when compared to typical patients hospitalized in the internal medicine ward. Identified quality of life limitations relate in particular to sexual life. PMID- 24340568 TI - Regional and temporal variability of GP concultations due to asthma in children aged 0-18 years in Silesian voivodeship. AB - The aim of this study was to analyze the spatial and temporal variability of the ratio describing outpatient medical visits due to asthma in children aged 0-18 years, living in Silesian voivodeship. MATERIAL AND METHODS: Descriptive study was conducted, in which secondary epidemiological data concerning number of medical outpatient visits due to asthma of children in the age of 0-18 years, were analyzed. The required data from the period 2007-2010 were reported on the MZ-11 form. To assess the temporal or spatial variability in Silesian voivodeship the ArcGIS 9.2 Software was used. RESULTS: Significant spatial and temporal variability of outpatient medical visits due to asthma in children have been discovered. The systematical increase of outpatient visits rate was observed (respectively 20.8 and 26.9% compared to the starting year). The largest values of the ratio concern the central region of the Silesian voivodeship. Most frequently outpatient medical visits due to asthma were related to children aged 5-14 years. CONCLUSIONS: Systematic and detailed analysis of the data collected in the health care system can replace the routine reporting and may be used to identify needs for public health. PMID- 24340569 TI - Objectivity of reimbursement decisions - does it always has to pay off? AB - Rising health care needs impose increased pressure on limited budgets of health care systems around the world. Not only life expectancy is improved, but also increases awareness of patients on modern treatments. It, as a result, leads to the constant search for ways to rationalize health services better attuned to the ability to pay. THE PURPOSE OF THE STUDY: Analysis of the pricing and reimbersement criteria included in the Polish law. MATERIALS AND METHODS: Based on a literature review to specify criteria for the allocation of resources in the health sector and to compare them to those included in the "Act on reimbursement of medicines, foodstuffs intended for particular nutritional and medical devices". RESULTS: Economic criteria dominate the rules governing the reimbursement process of pharmacotherapy in Poland. Referring to the principle of equity they focus on the ability to improve health. Two aspects are repeated frequently: cost-effectiveness and impact on payer's budget. CONCLUSION: Selection of the allocation criteria was carried out in the Polish law to a limited extend, which may give rise to difficulties in making objective reimbursement decisions. PMID- 24340570 TI - [Nonallergic hypersensitivity to environmental factors]. AB - The prevalence and severity of manifestations of non-allergic hypersensitivity to chemical environmental factors pose the question about the need to study the mechanisms of its formation in population. It should be borne in mind that, in the absence of immunological mechanisms of formation of the mentioned state, the term "chemical sensitization" must be replaced by the term "non-allergic hypersensitivity." The investigation of this problem should permit to reduce the risk of formation of different types of hypersensitivity in population. PMID- 24340571 TI - [Safety of nanoparticles and nanomaterials for environmental and occupational space]. AB - National and international experience, international standards, reports and recommendations relating to the assessment of harm to health, safety in the new nanoscale production for environmental and occupational space (ISO / TR 12885:2008 (E), BSI PD 6699-1:2007, etc .) have been analyzed. PMID- 24340572 TI - [Regulatory supervision and radiation survey in the area of location of former military technical bases]. AB - Activities related to the rehabilitation of areas and facilities of the temporary storage of spent nuclear fuel and radioactive waste (SNF and RW) at Andreeva Bay and Gremikha on the Kola Peninsula and in the Primorsky Krai in the Russian Far East is an important component of the regulatory functions of the Federal Medical biological Agency (FMBA of Russia). Technical support to the FMBA of Russia in this activity is provided by A.L Burnazyan Federal Medical Biophysical Center Main research interests include evaluation of radiological threats to determine the priority directions of regulation, a detailed analysis of the radiation situation at areas, territories and in vicinity of temporary waste storage facilities, radiation control and environmental monitoring, the development of digital maps and geoinformation systems, project expertise in the field of rehabilitation of PVC including the management of SNF and RW Implementation of these natural, practical and theoretical works is completed by development a set of regulatory documents ensuring adherence to radiation safety for the stuff population and the environment, and the also documents governing the management of SNF and RW waste in the territories of PVC. PMID- 24340573 TI - [Instability and sensitivity of the genome of healthy children in Magnitogorsk]. AB - Problem of the influence of factors of the industrial city on the hereditary apparatus of its residents has not been fully resolved, because of traditionally in such studies only the pollution of environment components is taken into account. However the existence of a set of contributing socialfactors that modify the genotoxic effects ofpollution, requires the creation of a new methodology for genetic and toxicological studies. For this purpose, in Magnitogorsk, where one of Russia's largest steel plants is located, we conducted a comprehensive survey, whose tasks included the analysis of the influence of the complex of exogenous and endogenous factors on the genome of children. In this publication there are presented the results of the fifth fragment of this work - the analysis of instability and individual sensitivity of the genome of 166 children of 5-7 years, residing in two districts of Magnitogorsk: around the steel plant and on the opposite bank of Ural river, where there are no large-scale industrial enterprises. The study was conducted in the micronucleus test on peripheral blood lymphocytes cultured with cytochalasin B. For assessment of individual sensitivity of genome blood cultures were exposed to standard N-methyl-N-nitro-N nitrosoguanidine (MNNG) mutagen. Cytogenetic analysis was performed in binucleated cells accordingly to international protocol, as well as with the use of an extended protocol including 32 indices. Average group frequency of binuclear cells with micronuclei (0.5-0.7%) were found not differ from the levels defined in children residing in Europe, and not differ between areas of the town. However the extended protocol of cytogenetic analysis discovered that the real frequency of dividing cells with lesions in blood cultures of children was 1,49 1,66%. Higher spontaneous proliferative activity of the cells and the frequency of dividing cells with injuries were found in blood cultures of children residing in settlements around the Magnitogorsk steel plant, while the individual sensitivity of the genome in these children was lower than that of their peers from the opposite bank of the Ural river A similar conclusion, but already in relation to the state of the systems for adaptation of entire body has been made from results of other fragments of the study, published earlier. PMID- 24340574 TI - [Blood trace elements content in adolescents in an industrial town]. AB - A cohort blind study of blood trace elements content in children-adolescents aged 14-16 years old, residing in an industrial town, where large industrial enterprises of ferrous and non-ferrous metallurgy have been functioning for long periods, has been performed There was established a lack of vital important element selenium in the blood, that causes the accumulation of toxic metals, cadmium and mercury. PMID- 24340575 TI - [Monitoring of quality of drinking groundwaters on the territory of the Republic of Mari El]. AB - In the paper the hygienic characteristics of groundwaters used for drinking water supply of the population of the Republic of Mari El is presented The features of the quality of groundwaters in different areas of the country have been detected, the causes of the deterioration of drinking water, which can act as a risk to public health have been shown. PMID- 24340576 TI - [Actual problems of the impact of production and management of industrial waste on the environment and public health (review of literature)]. AB - In the modern society the importance and applicability of the problem concerning the negative effect of production and consumption waste on the objects of the environment and the state sa people's health is related to their daily emergency, large tonnage, storage, and utilization. Wastes and places of their storage and waste burial constitute an toxicological and epidemiological risk. Chemical and biological contamination of solid waste is a threat to its penetration into the soil, air, groundwater and surface water bodies, vegetation, directly or indirectly, cause variations in health status of the population. PMID- 24340577 TI - [Assessment of risk of contamination of drinking water for the health of children in Tula region]. AB - The hygienic analysis of centralized drinking water supply in Tula region has been performed Thepriority contaminants of drinking water have been detected On the basis of risk assessment methodology non-carcinogenic health risks to the child population was calculated. A direct relationship between the incidence of some diseases in childhood population and pollution by chemical contaminants of drinking water has been established. PMID- 24340578 TI - [Problems of harmonization of sanitary regulations of the electromagnetic fields of mobile radio communication equipment]. AB - In the article there are presented data on the probable adverse effects of electromagnetic fields generated by means of mobile cellulary radio communication equipment, a comparative analysis of hygienic rating and methods of measurement of their parameters in Russia and abroad has been performed, and the ways of harmonizing hygienic rules have been outlined, the necessity of further research to risk assessment of the use of cellular radio communication devices by population and preventive measures have been substantiated. PMID- 24340579 TI - [Proper use of gas masks as prevention of occupational diseases]. AB - In the paper there are considered the problems arising from the use of respirators: 1. Modern methods used to replace the gas mask filter, 2. Conditions for safe re-use filters which are not fully developed their service life period 3. The conditions of safe use ofrespiratory protective equipment (RPE) in the immediately dangerous air pollution. Measures for the protection of health, based on the common practice of using RPE in the developed countries, which include: the development and application of regulations governing the selection and the use of respirators, filter replacement, training of staff have been proposed. PMID- 24340580 TI - [On the problem of permissible levels of emergency and subsequent occupational radiation exposure for people of reproductive age]. AB - The results of studies of indices of reproductive function in 3 groups of males examined accordingly to an unified method: Group 1 - The staff of the Kalinin Nuclear Power Plant (KNPP) and the Smolensk Nuclear Power Plant (SNPP), who worked for liquidation of consequences of the accident (LCA) in 1986-87 at the Chernobyl Nuclear Power Plant (ChNPP), group 2 - the staff of the KNPP and the SNPP who did not work for LCA in ChNPP and the group 3 - the liquidators of the accident at ChNPP who were not included in the staff but are registered in the register of LPA participants in the Ryazan region are presented. The occurrence of congenital malformations (CM) and intrauterine growth retardation (IUGR) in infants, indices of unfavourable outcomes of pregnancy (UOP) in the families of males, describing the possible radiation-induced genetic effects in male germ cells was evaluated It was made a conclusion that the given in NRB-99/2009 constraints for emergency and subsequent occupational radiation exposures of males fail to provide protection from genetic effects in the offspring. The necessity to increase the duration of the protected reproductive period in males, on which there are extended restrictions for occupational and emergency radiation exposures from 30 years of age, as it is now accepted to the age of 35 years is demonstrated. PMID- 24340581 TI - [The structure of a professional viral hepatitis morbidity in medical staff in the Primorsky Krai]. AB - The study of cases with occupational parenteral viral hepatitis "B", "C" in the medical personnel of health institutions was conducted on 238 epidemiological maps infectious focus (Form 357/u)for the period 1996-2011. At the same time 1,000 employees of health facilities were surveyed with the aim to determine the awareness of health professionals workers about the risk of parenteral viral hepatitis "B", "C", ways of the transmission and danger level of infection, the level of knowledge on prevention of occupational infection, prevention of infringement of the measures in the work of medical staff that increase the risk of transmission of viral hepatitis. The age of the subjects ranged from 20 to 73 years. The average age was 43,9 +/- 1,8 years. 83.1% out of them were females, 16.9% - males There is an urgent need to study the occupational occurrence of parenteral viral hepatitis in health staff in the dynamics for the development and timely adoption measures for prevention PMID- 24340582 TI - [Peculiarities of bronchopulmonary pathology in copper industry workers in the Kola High North]. AB - A survey of 1097 workers of metallurgical enterprises showed that a chronic bronchitis is the most common bronchopulmonary disease (8,8-13,3%) in copper production workers There are much less detected chronic obstructive pulmonary disease (0.8-1.7%), asthma (0.3-0.4%), and only in copper-smelting plant workers a toxic chemical pneumosclerosis (0.6%). Working conditions determine a higher prevalence of respiratory diseases and their development in less industrial work record in the manufacturing workers employed in electrolytic processing of copper and auxiliary shops. The conclusion about the need to improve working conditions and the use of more effective personal respiratory protection devices for copper production workers has been made. PMID- 24340583 TI - [Methodological approaches to the training optimization for students in radiation hygiene]. AB - In the article the psycho-pedagogical and physiological-hygienic aspects of improvement of student's learning in radiation hygiene at the Health-prophylactic Faculty of the medical institution within a framework of the requirements of the new Federal State Educational Standard -3 are considered. PMID- 24340584 TI - [Health promoting schools and health of schoolchildren (analytical review)]. AB - The determinants of the decrease in health of the school age children, connected with their studies are discussed. The educational institutions are considered as the subjects of healthy way of life formation and strengthening of health of schoolchildren. There is a number of"health schools", using in their activity various approaches and health promoting methods for preservation and strengthening of health of schoolchildren. The results of activity of these schools are shown. PMID- 24340585 TI - [Mental capacity and the incidence of children with mental retardation in preschool education institutions of compensating type]. AB - The study is devoted to the investigation of the mental capacity of children 6-7 years old with mental retardation in preschool educational institutions of compensating type. Under observation there were 160 children, out of them - 87 patients with mental retardation and 73 mental age-matched cases - the control group. The features of the dynamics of task performance in children with mental retardation in comparison with the cases from control group have been revealed. Indices of their mental capacity were found to be in dependence on the organization of upbringing and education space, which can be achieved only in a preschool educational institutions of compensating type. Mental retardation in children was found to be in a greater degree associated with somatogenic causes. PMID- 24340586 TI - [Chemical composition of breast milk in females with preterm deliveries in the Primorsky Krai]. AB - In the article there are presented data on the chemical composition of breast milk in females with preterm labor in the Primorye Territory, who were in the Department of newborns for premature babies of the Municipal Institution of Health "Children's city clinical hospital" in Vladivostok during 2010-2011 to care for their newborn infants. Laboratory studies were performed in the Federal State Institution of Health "Center of Hygiene and Epidemiology in the Primorye Territory." PMID- 24340587 TI - [The functional state of the organism of 8- 16 years old schoolchildren residing in Moscow and Kiev]. AB - An assessment of the functional state of the organism in 2929 Moscow and 2043 Kiev schoolchildren aged 8 - 16 years. It was shown that in terms of main physiometric indices ofphysical development Moscow and Kiev children 8 - 16 years differ from each other There were established statistically significant difference in the force capacities: in Kiev children aged 8 - 9 years muscle strength was significantly higher than that of their peers in Moscow. The force capacities of 10 - 14 year old girls and 16 - year old boys residing in Kiev were acknowledged to be significantly lower than that of in children of the same age residing in Moscow. Respiratory capacities in Kiev schoolchildren in all age and gender groups were significantly lower than in Muscovites of the same age. It was suggested to activate preventive measures aimed at increasing the functional capacities of the cardio-respiratory system, in the first place for the children residents of Kiev. PMID- 24340588 TI - [Influence of high altitude on the functional status and morbidity of teenagers]. AB - With the aim to determine the influence of the high latitudes on the main indices of the blood and morbidity, physical development of adolescents of 14 years old residing in Kirov (n = 139) and Ukhta (n = 253), the evaluation of basic parameters of their blood, physical development and morbidity has been performed accordingly to standards methods. The inhabitancy of adolescents in high latitudes (Ukhta) in comparison with their peers from temperate latitudes (Kirov) leads to body weight gain of 4.7 kg in girls and 5.8 kg in boys, gives rise to the increase in gender diferences in hemoglobin concentrations and ESR and boosts overall morbidity. PMID- 24340589 TI - [Peculiarities of hemodynamics in junior students with a hereditary history of arterial hypertension during examination stresses]. AB - The functional state ofthe students was investigated on the basis ofchanges in central hemodynamic indices immediately during exams, in dependence on family history of hypertension. The significant variation in the character of the response of systemic hemodynamics, as depending on the stage of examination (preparation, answering the ticket, and after the exam), the dominance of the type of the autonomic nervous system, and the family history of hypertension has been revealed These changes in hemodynamics in students with family history of hypertension were established to be more pronounced and prolonged. PMID- 24340590 TI - [Correcting influence of music on the students' functional state]. AB - The influence of listening to classical music on integral indices of the activity of the regulatory mechanisms of the heart rhythm in students after teaching load was tested with the method of variational pulsometry accordingly to R.M Baevsky procedure. Registration and analysis of ECG was realized on Pentium 4 in three experimental situations: before the start of lessons (norm), after lessons, after listening to the music. Two types of response of students 'functional state to the teaching load: sympathetic and parasympathetic have been established. After teaching load music therapy session was found to led to the shift of levels of all examined indices of heart rhythm toward the original data (norm), most expressed in students with a sympathetic response type. PMID- 24340591 TI - [Biological adaptation and immune status of preschool children with visual function disorders in conditions of preschool educational institutions of compensating type]. AB - For implementation of a comprehensive approach in the elaboration of preventive and corrective measures in children with impaired visual function in conditions of preschool educational institutions of compensating type there were studied adaptation reserves of their organism, as well as indices of immune status. Biological adaptation was studied with the help ofcardiointervalography in 111 children aged 6-7years. With the use of ELISA 88 children were examined in terms of IgA, IgM, IgG, slgA in saliva. PMID- 24340592 TI - [On the implementation by Rospotrebnadzor (Federal service for the oversight of consumer protection and welfare) common principles and rules of technical regulation within the agreement of the Customs Union]. AB - In accordance with the Agreement of the Customs Union on sanitary measures between the Government of the Russian Federation, the Republic of Belarus and the Republic of Kazakhstan in the customs territory of the Customs Union the Uniform sanitary and epidemiological and hygienic requirements for goods subject to sanitary-epidemiological control are applied. Common sanitary requirements are binding for executive authorities of the Member States of the Customs union, local authorities, legal persons, whatever legalform, individual entrepreneurs, individuals. Currently, out of 47 planned to take priority technical regulations of the Customs Union 31 regulation, including the safety of railway rolling stock, production of perfumery and cosmetics, toys and products for children and teenagers, food products, grain, and other furniture products was adopted. PMID- 24340593 TI - [Chemical safety as a problem of epidemiology of non-infectious diseases]. AB - Based on the analysis of adopted in sanitary science methodology for the study and evaluation of the biological action and hygienic significance of environmental factors there was shown the need for the use of laws and methodology of classical epidemiology to ensure the chemical safety in the recognition and elimination of the group of diseases of chemical etiology, outbreaks of similar non infectious diseases. It is stated that individually small "non-toxic" doses of chemicals, but "loading" a large population and forming a large collective dose apparently can be implemented in a stochastic population health damage, detectable only on the basis of large-scale epidemiological studies to assess the risk. These approaches are presented to be especially important for agents in the environment, optimal for which is not absence, but the presence for provision of necessary target effect (pesticides, disinfectants and other household products, etc.). The main task of the epidemiological analysis of local toxic "bursts" and large-scale "epidemics" of this kind is an optimization of the complex of measures implemented by an adequate assessment of their medical, social and economic performance. PMID- 24340594 TI - [Analysis of radiation-hygienic and medical consequences of the Chernobyl accident]. AB - Since the day of "the Chernobyl accident" in 1986 more than 25 years have been past. Radioactively contaminated areas 14 subjects of the Russian Federation with a total area of more than 50 thousand km2, where 1.5 million people now reside were exposed to radioactive contamination. Currently, a system of comprehensive evaluation of radiation doses of the population affected by the "Chernobyl accidents", including 11 guidance documents has been created. There are methodically provided works on the assessment of average annual, accumulated and predicted radiation doses of population and its critical groups, as well as doses to the thyroid gland The relevance of the analysis of the consequences of the "Chernobyl accident" is demonstrated by the events in Japan, at nuclear power Fukusima-1. In 2011 - 20/2 there were carried out comprehensive maritime expeditions under the auspices of the Russian Geographical Society with the participation of relevant ministries and agencies, leading academic institutions in Russia. In 2012, work was carried out on radiation protection of the population from the potential transboundary impact of the accident at the Japanese nuclear power plant Fukushima-l. The results provide a basis for the favorable outlook for the radiation environment in our Far East and the Pacific coast of Russia. PMID- 24340595 TI - [Problems in the system of state regulation of chemical safety]. AB - In the paper the analysis of the problems of chemical safety abroad and in Russian Federation is presented, possible ways for their solutions, including the need for legal and scientific-methodical support for population health risk assessment are considered. PMID- 24340597 TI - [Justification of the significance of Pseudomonas aeruginosa index in assessing the quality of drinking water]. AB - The analysis of literature data was carried out and performed research justifying the epidemic value of detection in water P. aeruginosa in drinking and domestic water use. The were revealed features of the vital activity of P aeruginosa in water bodies as opposed to conventional microbiological indicators. It was shown that the coliform group indices can not guarantee the epidemic safety of drinking water use in relation to P aeruginosa. The data obtained justify the need for the introduction of P aeruginosa as an additional index in monitoring the water quality of centralized and decentralized water supply. PMID- 24340596 TI - [Ecological problems of reproductive health]. AB - In the article there are presented the current literature data on environmentally determined reproductive pathology Ecology dependent pathological processes cause the reduction in fertility, the increase of the risk of gestational complications, the risk of low birth weight infants, miscarriage. In a situation of ecological trouble maintenance the health of the female as reproductive potential of nation, is possible only with identification, quantitative parameterization of risks for reproductive health and regional specification of programmes for the social and hygienic monitoring and preventive measures. PMID- 24340598 TI - [Cytomorphological assessment of the epithelial cells of the nasal cavity in the population of urban areas]. AB - There presented results of cytomorphological studies of the mucous membrane of the nasal cavity in children 6-7 years old, 14-15 years old adolescents and adults of all ages (from 20 to 59 years) living in Ekibastuz and the settlement Solnechnyy. Significant unidirectional subatrophic changes in nasal mucosal epithelium were found in 20.6 to 52.63%. Out of 180 examined children and adults in Ekibastuz and the settlement Solnechnyy 42.0% showed an increased number of apoptotic cells. At the same time in 20.9% out of the 110 examined adults in Ekibastuz in nasal epithelium a large number of binuclear and trinuclear cells was revealed, that indicating a high chemical load. PMID- 24340599 TI - [Evaluation of the content of harmful substances in the air of sewage treatment facilities of Astrakhan gas processing plant]. AB - Despite the fact that the progress in regard to the degree of processing of natural gas and condensate in the Astrakhan gas processing plant is significant, necessary hygienic normalization of working environment on the part of the content of harmful substances in the air of working areas is still unable. Harmful substances were detected in the breathing zone of workers of sewage treatment plant almost constantly. In this connection there is a need in the further joint work hygienists, designers and manufacturers for the development and justification of new, more effective decisions - both on the part of as well technology as hardware design - with the purpose of improvement of working conditions. PMID- 24340600 TI - [The dependence of the prevalence of hypertension on the severity of the professional aging]. AB - On the example of 5437 employees of enterprises and institutions of the Kemerovo region, compiled into 14 occupational groups, an analysis of the relationship between age structure and the frequency of arterial hypertension due to the working conditions has been performed At high levels of hardness of employment and the impact of physical factors, a shift in the age structure toward younger age is seen, which is considered as a demographic consequence of professional ageing. In turn, expressed professional ageing causes the reduction in the prevalence of hypertension, which is, probably is implemented by the effect of "healthy worker". PMID- 24340601 TI - [The role of genetic factors in the development of chronic dust bronchitis in workers of coal mining enterprises of Kuzbass]. AB - The distribution of genotypes of HP, GC, EsD, AsP and polymorphisms GSTT1 (GST theta1) and GSTM1 (GST-micro1) and NOS3 (polymorphism VNTR4) in miners with chronic dust bronchitis, and in those without this occupational disease has been studied The carriers of genotypes of genotypes EsD 1-2, AsP bb were shown to be more prone to develop chronic dust bronchitis. Endogenous factors of resistance to the disease are the genotypes GC 1-1, EsD 1-1, AsP bc. PMID- 24340602 TI - [The development of a comprehensive assessment of occupational risk by taking into account the total hazard of working conditions]. AB - In the paper the methodological problems of establishing a general class of working conditions on the results of certification of workplaces are analyzed There is proposed the use of an additional parameter - the index of harm, characterizing the degree of correspondence of the general level of harmful occupational factors to applicable health standards with taking into account the nonequivalence of their display. The recommendations for the use of hazard index as the main criterion for a priori evaluation ofthe category ofsuspected occupational risk and the tool to establish by the correlation methods cause-and effect relations between indices of health status and the impact ofoccupational factors are presented. As exemplified by real working conditions the possibilities of the use the index of harm as an indicator describing the hazard probability are considered with comprehensive assessment of occupational risk of health problems on the basis of the matrix method with the use of the table of vectors and nomograms "probability of harm - the severity of the consequences". The use of index of harm will permit to increase the objectivity of the assessment and the efficacy of management of occupational hazards in the workplaces. PMID- 24340603 TI - [Methodological approaches to the development of environmentally benign technology for the use of solid waste in iron metallurgy]. AB - On the basis of the life cycle of materials, containing wastes of iron and steel industry, new methodological approaches to the assessment of technologies of the secondary use of wastes are developed A complex criteria for selection of the technology for the use of resource potential of solid waste of iron and steel industry are developed with taking into account environmental, technological and economic indices. The technology of the use of wastes of ferrovanadium industry as bulk solid materials at the solid waste landfill is shown. PMID- 24340604 TI - [The concept of "psychological risk" in the professional activity of employees of fly-in fly-out method of labor organization on the example of oil and gas companies in the Far North]. AB - Professional work in shift team in the Far North contributes to the formation of unfavorable functional states and the development of destructive personality traits of employees, which lead to a decrease in the level of mental health, productivity and work efficiency With the aim to predict the professional efficiency of the rotational personnel it is necessary to determine the probability of negative psychological states, properties and qualities that will prevent its implementation, i.e, the psychological risks in professional activities. Psychological risk in the professional activity is the probability of occurrence of a professional personal destructions and the formation of unfavorable functional states of employees when performing job functions due to the prolonged negative impact of social-household and occupational factors in the lack of personal and environmental resource. PMID- 24340605 TI - [Factors of anxiety and autonomic tonus in senior preschool children from Magnitogorsk]. AB - In the paper there are presented the results of a study of anxiety and balance ofparts of autonomous nervous system in healthy children 5-7 years old, residing in different parts of Magnitogorsk. It is shown that state of heightened and high alert was shown to be more common among children living on the left bank of the Urals river around the Magnitogorsk Metallurgical Integrated Plant. In these children an imbalance in the work of the parts of the autonomic nervous system was detected more frequently, at that shifts were observed mainly in the direction to ergotropic tone. At the same time balanced work of the parts of the autonomic nervous system was observed more frequently in children living on the right bank of the Urals river. Discovered psychosomatic features of examined children turned out to be associated with both the social characteristics of family lifestyle and the emotional stress of parents, and the contents of some organic compounds in total snow samples collected in the territories of kindergartens which they attended. One ofthe most significant results ofthe work we consider the detection of a correlation relationship between emotional stress of parents and activity of key enzymes in their children, reflecting the protective and adaptive reactions of the organism. On the basis of these and previously obtained data, we suggest that social and psychological factors of the family are not only a potential source of maladaptation of the child, but, probably, can have an impact on the stability and sensitivity of the genome of children. PMID- 24340606 TI - [Evaluation of psycho-emotional state of university students]. AB - There was studied the psycho-emotional state of university students. The change in subjective well-being, the level of anxiety and personality types during the learning process has been shown. PMID- 24340607 TI - [Carcinogenic and mutagenic activity of chrysotile, processed with iron chloride (III)]. AB - This work is devoted to the study of the role of iron ions in the carcinogenic and mutagenic activity of chrysotile. For this aim natural chrysotile was treated with ferric chloride (III), washed, crushed and intratracheally introduced into Wistar rats. When administered to rats intact chrysotile induced mesotheliomas in 27,9 + 4,6% of cases, and chrysotile modified with ferric chloride - in 1,3 +/- 1,3%. Mutagenicity of the same samples was studied in the micronucleus test when administered intraperitoneally to mice Fl (CBA x S57Bl6). Polychromatic erythrocytes in the bone marrow were investigated 24 hours after intraperitoneal administration. The frequency of polychromatic erythrocytes with micronuclei was decreased from 7,4 +/- 0,18 by 1000 due to the action of chrysotile, from 2,8 +/- 0,42 for 1000 after the introduction of a modified sample. It is hypothesized that the ferric chloride modifies the surface of asbestos fibers that reduces the induction of free radicals which are the primary cause of and carcinogenic effects of chrysotile. PMID- 24340608 TI - [Department of general hygiene and ecology of Saratov State Medical University named after V.I. Razumovsky -100 years (1912 -2012)]. PMID- 24340609 TI - [Academician F.G. Krotkov - outstanding hygienist]. PMID- 24340610 TI - [Museum of Hygiene by professor A. V. Mol'kov]. PMID- 24340611 TI - [Systemic inflammation: theoretical and methodological approaches to description of general pathological process model. Part 3. Backgroung for nonsyndromic approach]. AB - Theoretical and methodological approaches to description of systemic inflammation as general pathological process are discussed. It is shown, that there is a need of integration of wide range of types of researches to develop a model of systemic inflammation. PMID- 24340612 TI - [To the Fas-induced neurons apoptosis mechanisms in stroke pathogenesis]. AB - The goal of the present study was to investigate the plasma levels of proteins regulating Fas-induced apoptosis in acute stroke and to relate ones to brain damage and clinical features. By means of ELISA soluble Fas receptor (sFas) and soluble Fas ligand (sFasL) plasma levels were detected. Fas protein (CD95) expression on CD3 lymphocytes surfaces was detected using flow cytometry. It is summarized, that Fas-induced apoptosis play significant role in stroke pathogenesis. As the result, prognostic significance of sFasL plasma level is showed. Fas induced apoptosis mechanisms seems to be perspective target for search new therapy stroke patients. PMID- 24340613 TI - [The saving role of glutamate antibodies with the acute ischemic damage of the rat brain prefrontal cortex]. AB - On the model of acute ischemic damage of prefrontal areas of the rats brain cortex was shown, that intranasal injection of glutamate antibodies over one hour after ischemic damage of brain prefrontal areas leads to diminishing of glutamate content in hippocampus and prefrontal cortex. PMID- 24340614 TI - [The role of M4-subtype of cholinoreceptors in acethilinecholine vasoconstriction]. AB - In experiments on rats using high frequency ultrasonic measurement technique and selective M4-cholinoreceptor antagonist tropicamide it was shown that i/v injection of the cholinolitic block agent in large doses exceeding of its selective threshold (1 mg/kg) causes pronounced inhibition of the cardiovascular system in rats. Severe transitory hypotension and bradycardia are developed, general vascular resistance, minute cardiac output, are decreased. The block of M4-cholinoreceptors with smaller doses of tropicamide (0.1-0.001 mg/kg) causes transitory dose-depended effect on hemodynamic--system blood pressure and vascular resistance, pulse, minute cardiac output, as soon as velocity of aortic blood flow, strike cardiac output are increased on the contrary. The following decrease the dose of the high selective M4-cholinolitic antagonist (0.0001 mg/kg) reveals that its negative chronotropic effect are not detected practically but tropicamide vessel action (decrease of system blood pressure and vascular resistance) are preserved distinctly. The obtained data are discussed in aspect of the possible involvement of M4-muscarinic receptor subtype in acetylcholine induced vasoconstriction in rats. PMID- 24340615 TI - [Characteristics of the autonomic nervous system state in children with myopia associated with undifferentiated connective tissue dysplasia]. AB - Autonomic nervous system disorders occur in 100% cases in patients with connective tissue dysplasia. Biomechanism of accommodation and autonomic innervation of ciliary body was not investigated clearly and presented as area of further research. The goal of the study was to evaluate features of autonomic nervous system in patients with myopia associated with connective tissue dysplasia. 50 children with myopia associated with connective tissue dysplasia went through ophtholmological examination. To evaluate function of autonomic nervous system all patients were observed with the machine "Valenta" which has ECG recording. As a result we found that children with myopia and connective tissue dysplasia have unsatisfactory adaptive reserves with imbalance of sympathetic and parasympathetic input, autonomic nervous system wasn't available to provide homeostasis in demanding level. We hypothesized that autonomic nervous system might be a reason which lead to disorders in process of accommodation during myopia and assist its progressing. PMID- 24340616 TI - [The role of antibodies to neurotransmitters of antinociceptive system in mechanisms of neuropathic pain]. AB - The present investigation was undertaken in order to study the role of the antibodies to neurotransmitters of antinociceptive system in pathogenesis of neuropathic pain on models of neuropathic pain. It was shown that the development of experimental neuropathic pain syndrome is accompanied with induction of autoantibodies to CABA, serotonin, noradrenalin and dopamine. It was established that the antibodies to neurotransmitters of antinociceptive system have a pronociceptive effect. PMID- 24340617 TI - [Co-administration of RJR-2403 with low dose of 17beta-estradiol on spatial learning in ovariectomized rats]. AB - The aim of this work was to study the influence of stimulation or blockade Nalpha7-cholinoreceptors on dynamics of spatial learning in water Morris maze and on behavior in the "open field" test in adult ovariectomized (OVX) females given with a low dose of 17beta-estradiol. Agonist of Nalpha7-cholinoreceptors - RJR 2403 (1.0 mg/kg, i.p.) or antagonist of Nalpha7-cholinoreceptors - mecamylamine (1.0 mg/kg, i.p.) treated chronically (14 days) alone and in a combination with low dose of 17beta-estradiol (0.5 micro/rat, s.c.) to OVX rats. Co-administration of RJR-2403 with low dose of 17beta-estradiol completely restored impaired spatial learning in water Morris maze in OVX females. Moreover, OVX rats treated with RJR-2403 and low dose of 17beta-estradiol demonstrated increased exploratory and grooming behavior in the "open field" test. Both mecamylamine alone and in combination with low dose of 17beta-estradiol failed to influence on spatial learning and failed to modify behavior in the "open field" test in OVX rats. The results of the present study suggest a positive effect of RJR-2403 in combination with low dose of 17beta-estradiol on spatial learning at estrogen deficiency. PMID- 24340619 TI - [Factors significant for cerebral circulacion in patients with supratentorial brain tumors]. AB - Using the Doppler ultrasonography method the condition of brain blood circulation of 90 patients with supratentorial brain tumors (gliomas--43, meningiomas--34, metastasis--9) during pre-surgical period was studied. The factors changing brain blood circulation at patients with with supratentorial brain tumors were brain displacement, increase of intracranial pressure, histologic structure and the first symptoms duration of illness. Localization (for an exception of an occipital lobe) and the size of a tumor directly didn't render influence on blood circulation parameters. PMID- 24340618 TI - [Assessing of the role superoxide, nitric oxide and redox metals in cytotoxic effect of the H2O2 and amyloid-beta-protein]. AB - On the cells of neuroendocrine tumor of rats (line PC12) in culture was estimating of the governing mechanisms of the cytotoxicity of the oxidative stress and the role of the amyloids in increasing this stress. Using flowcytometric assessment of the cytotoxicity H2O2 and fragment beta-amyloid (Abeta) peptide (25-35) has been shown the dose-dependent increasing of the quote of the cells with DNA content < 2c. Isoeffective consentrations were 1 MM H2O2 and 5 MkappaM Abeta. The cytotoxicity H2O2 and A were accompanig with the increasing of the intracellular level of O2-. The treatment of the cells GSNO (donor of NO) and o-phenantrolin (chelators of Fe ions) significantly decreased the intracellular level of O2- as well as the cytotoxicity H2O2 and Abeta. Thus, in direct experiments has been shown of the part amyloids in the increasing of the oxidative stress and participation of the reactive oxide radicals in the cytotoxic effect of the Abeta. The addition argument which confirmed contribution of the oxidative stress in the cytotoxic effect of the Abeta was the similarity of the cellular response on the action of the oxidative agent - H2O2 and Abeta. PMID- 24340620 TI - [Plasma lipid spectrum and survival in rats with heart failure varied by severity under the influence of neurohormonal modulators]. AB - In rats with relatively mild chronic heart failure (CHF) there was an increase in plasma LDL levels. In turn, in severe CHF it was revealed a significant decrease in total cholesterol concentration due to LDL levels decline. ACE inhibitors (captopril, enalapril and lisinopril) and the most selective beta1-adrenoblockers (metoprolol, nebivolol) had not any significant influence on plasma lipids. Less selective and especially nonselective beta-adrenoblockers pindolol and propranolol brought up the atherogenic potential of plasma because of HDL levels reduction in mild CHF whereas in case of severe model--due to the trends toward decrease in HDL concentration and toward increase in LDL levels. Lipophilic ACE inhibitors and beta-adrenoblockers without intrinsic sympathomimetic activity improved survival in rats with mild CHF to the equal extent. On the contrary in severe CHF beta-adrenoblockers, especially non-selective, had an advantage over ACE inhibitors on the survival effect. PMID- 24340621 TI - [Investigation of multyphytoadaptogene anti-radiation activity in mice]. AB - The aim of the work was to elucidate the radioprotective activity of multyphytoadaptogene (MPA) in mice in various conditions of gamma radiation and MPA application. Males of CBA x C57BL/6 F1 mice were given 15% MPA solution with drinking water 2 weeks before the radiating (preventive application), 2 weeks before and 2 weeks after the radiating (preventive and therapeutic application) and also 2 weeks after the radiating only (therapeutic application). Animals of control groups received radiation or were given 5% ethanol solution in drinking water in the same application schemes. MPA increased the mice survival in preventive, preventive and therapeutic as well as therapeutic applications after 7.5 Gy radiation (66.7: 66.4 and 40.2% correspondingly). After 11.0 Gy radiation MPA increased the mice survival in preventive as well as preventive and therapeutic applications (75.0 and 76.9% correspondingly). MPA administration improved the somatic state, weight of animals, quality of life. MPA has no side effects. The data suggest the radioprotective activity of MPA. PMID- 24340622 TI - [Comparative efficacy of hypoxia, hypercapnia and hypercapnic hypoxia increases body resistance to acute hypoxia in rats]. AB - The relative efficiency of trainings with isolated hypoxia, hypercapnia and hypoxia in aggregate with hypercapnia in order to enhance the resistance of organism to the effect of an extreme hypoxia was studied. The combined effect of the hypoxia and hypercapnia was shown to influence more greatly in comparison with the effect of an isolated hypoxia. This effect was supported with an increase in the time of the loss position and the time of the animal's life under the condition of an extreme hypoxia. Also it is shown that the hypercapnia in a combination to a hypoxia makes dominating impact on formation of nonspecific resistance as the isolated hypercapnia enlarges indicators of nonspecific resistance, than the isolated hypoxia more effectively. PMID- 24340623 TI - [The influence of hepatocyte growth factor on lipid peroxidation processes in stress]. AB - The influence of hepatocyte growth factor (HCF) on the activation of lipid peroxidation (LP) and activity of antioxidant enzymes in rat plasma was investigated in immobilization stress. It was established that investigated peptide decreases stress-induced activation of lipid peroxidation manifesting by the decrease of the content of intermediate and final metabolites of LP in plasma. HCF causes the increase of the activity of catalase (enzyme of antioxidant system) also, which decreased under stress influence. PMID- 24340624 TI - [Conception for permanent activation of nuclear factor kbeta as molecular basis for metabolic syndrom pathogenesis]. AB - The analysis of new data concerning the development of pathology due to the community of evolutionary new pathological factors was done. Author provides the comparison of well-known and new definition for "metabolic syndrome" and diagnostic criteria of this pathology. The conception for permanent activation of nuclear factor kbeta as possible typic pathological process was discussed. Suppose that NF-kbeta is the possible key molecule in the initiation and formation of "vicious circle"--insulinresistance--inflammation--atherosclerosis. PMID- 24340625 TI - [Signaling mechanism of neuroprotective effect of ischemic preconditioning of brain]. AB - Analysis of published data indicates that Ras-protein and kinases PI3K, Akt, MEK1/2, ERK1/2, PKC, CaMKII are involved in the signaling mechanism of ischemic preconditioning. In addition, it is established that cyclooxigenase-2, NO synthase and mitK(ATP)-channel are involved in delayed preconditioning. Signaling mechanism of early ischemic preconditioning of brain is remained unstudied. PMID- 24340626 TI - [The stimulation of reparative regeneration in the treatment of fractures of the extremities with the use of new biotechnologies]. AB - The paper presents the results of a study of Russian and foreign authors on modern methods of stimulation of reparative regeneration of bone tissue. Highlight general principles for the construction and use of bioplastic materials. An attempt to classify the most famous of biomaterials based on their physico-chemical and biological properties, as well as identified trends in the further development of tissue engineering and its importance in traumatology and orthopedics. PMID- 24340627 TI - [The system of assessment of the severity of ultrasound epilepsy in rats]. AB - The method of induction of epileptic reactions in rats by ultrasound (24.3 kHz; 116dB) and the system of severity estimation of epileptic reaction was developed. Ultrasound--frequency above 20 kHz--absolutely silent for a person, may cause epileptic reaction in 3-9% of the rats. The possibility of using ultrasound- induced epilepsy in rats to evaluate anticonvulsant activity of drugs it is shown. PMID- 24340628 TI - [About the human health safety estimation of ractopamine intake together with the food]. AB - The analysis of scientific data including American and European scientific communities concerning use of ractopamine as a growth factor in food animal production and the argumentation of the maximum permitted levels of ractopamine and levels of ractopamine in meat and byproducts (offal) is carried out. The position of the Russian side stated at the Codex Alimentarius commission 35th session that acceptable ractopamine daily intake is insufficiently validated and cannot be used for the determination of maximum permitted levels of ractopamine in meat and byproducts (offal) is confirmed. It is represented that residual ractopamine intake together with food on the levels which are recommended by the Codex Alimentarius commission and by taking into account the levels of animal products consumption in Russian Federation will lead to unacceptable human health risk level that will promote increasing heart diseases and life expectancy reduction. In this connection Russia states against of acceptance of maximum permitted levels of ractopamine in food. PMID- 24340629 TI - [Medical-epidemiological and methodological approaches to forecasting indicators of adolescent health in the modern period]. AB - Data on features of formation of health of different groups of the population in the development process of the country and its regions are an important information base for the development and implementation of measures for the maintenance and strengthening ofpublic health. The aim of the study was to determine and predict trends in indicators of primary disease incidence and prevalence among adolescent population over the next 10 years. Materials provided to analyze the data of the consolidated annual report forms .o 12 "The number of registered diseases in patients living in the service area of the medical establishment"for showing trends over the 10-year period (2001-2010). Calculation and analysis of dynamics were integral coefficients, determined the level of adolescent health violations from "low" to "high". Incidence rate of incidence and prevalence of disease were evaluated by calculating the dynamic coefficient of determination R approximation. The article presents results of forecasting over the next 10 years in the adolescent population (15-17years) changes the primary indicators incidence and prevalence of diseases. This technique was used by the authors. In view of the projected increase in detected trends data set of indicators at 40, 7-50,2%. Sex predicted dynamics of increase in juniors at 42,1 58.9%, the girls - the 31,2-49,6%. These data characterize negatively predicted for the near future a regional trend in incidence rates in the analyzed populations. They must be taken into account when deciding on the preservation and strengthening of health of the rising generation, including - in shaping regional social programs and health care programs. PMID- 24340630 TI - [Invasive streptococcal (group A) infection of soft tissues in a Moscow surgical hospital]. AB - AIM: To study features and risk factors of soft tissue's invasive streptococcal infection in surgical unit's patients: a) emm-types of the most often recovered streptococcus; b) human immune response for streptococcal antigens (streptolysin O and the group A carbohydrate antigen); c) main patient's conditions that complicate the course of soft tissue's streptococcal infection. PATIENTS AND METHODS: 101 surgical unit's patients with soft tissue's infection, which group A streptococcal (GAS) nature, were examined. Emm-types were determined by comparison ofemm gene sequenced part with data of CDC Streptococcus Laboratory. ASO and specific anti-group-carbohydrate IgM were measured with photometry and ELISA4 accordingly. Patient's personal data were analyzed by standard statistical programs. RESULTS: Among 34 emm-types of all streptococcal isolates emm28 and emm64 were registered only in invasive infection. Emm-types 1, 49, 60, 66, 77, 84, 88 were most often. Among 23 sera from invasive GAS-infection's patients, 15(65%) were ASO-negative, 6 (26%) were ASO-low-positive, and 2 (8%) were positive, but negative for the anti-group-A-carbohydrate IgM. CONCLUSION: Lower levels of the humoral immune response as well as risk factors such as trauma, alcoholism, diabetes, chronic venous insufficiency contributed to development of severe forms of GAS-infection. The main streptococcal emm-types for soft tissue's invasive GAS infection in one of Moscow surgical unit's patients in 2008-2011 were registered. PMID- 24340631 TI - [Etiological structure of acute respiratory viral infections morbidity in Novosibirsk and Novosibirsk region in epidemic season 2011-2012]. AB - INTRODUCTION: ARI occupying the first place in the structure of total human morbidity. The aim of the study was to investigate the species diversity of the viruses causing AR among residents of the Novosibirsk region during epidemic season (October to April). MATERIALS AND METHODS: 164 nasopharyngeal swabs were collected and analyzed. Viral RNA/DNA, cDNA synthesis and PCR were carried out employing "RIBO-prep" "eReverta-L", "AmpliSens Influenza virus A/B-FL" and "AmpliSens ARI-screen-FL" kits (CRI of Epidemiology). RESULTS: Etiological agent of the disease was found in 69(43%) samples. Monoinfection was found in 58 (35%). In 14 (9%) samples were detected serogroup I coronaviruses, in 13 (8%) rhinoviruses, in 7 (4%) respiratory syncytial virus, in 6 (4%) parainfluenza virus type 1, in 5 (3%) parainfluenza virus type 3. Adenoviruses and bocavirus were identified in 3 (2%) samples. Parainfluenza virus type 2 and 4, metapneumovirus, serogroup Il coronaviruses (HKU1 and OC43) were presented in 2 (1%) samples. In 11 (7%) samples was found mixed infection. CONCLUSION: The majority of common colds were caused by serogroup I coronaviruses (NL63 and 229E), rhinoviruses and mixed infections. The peak of species variability of viruses caused acute respiratory infections was determined in age group of children 2-4 years old. In older age groups the species variability of analyzed viruses was decreased, rhinovirus infection becomes prevalent. PMID- 24340632 TI - [Microbiotic factor influencing the mononuclear phagocyte system development]. AB - Mononuclear-phagocyte system plays an important role in natural immunity and nonspecific resistance reactions of the organism against infection. The experimental studies using conventional laboratory animals with uncontrolled microflora have certain limitations to fully appreciate the role of autoflora (microbiota) in both development and functional activity of mononuclear-phagocyte system. In the present review of the author' systemic studies the value of microbiologically controlled animals (gnotobiotes) showing the multifaceted role of microbial factor on various manifistations of mononuclear-phagocyte system including phagocytic activity of the cells of both ageing aspects and pathology conditions (inflammation, burns), influence on the colonization resistance and barrier function against translocations of microorganisms from the intestines, temperature reactions and other host defense mechanisms to infection are demonstrated. In a complex body defence, activity of both cellular and humoral factors is being stimulated and modulated by microbiotic factor. Gnotobiotic modeling approach is prospective one for modeling and analysis of molecular and cellular mechanisms in an assessment of the "host-microbiota" interactions, evaluating the effectiveness of new probiotic candidates and further microbial control development in the clinical settings. PMID- 24340633 TI - [Perinantal programming of arterial hypertension in child]. AB - There is a growing number of evidence linking fetal intrauterine malnutrition, other adverse events or exposures and arterial hypertension during the following life. After important epidemiological studiesfrom many countries, research now focuses on mechanisms of organ dysfunction and on refining the understanding of the interaction between common elements ofadverse perinatal conditions and normal development. This review focused on advances in comprehension of the influence of intrauterine malnutrition on developmental programming of hypertension. Significant decrease in nephrons number was demonstrated as a result of fetal asymmetrical growth restriction syndrome both in human and experimental animal model. The role of malnutrition and dexametasone induced rennin-angiotensin system inhibition in fetal and newborn nephrogenesis is discussed. Recent studies have revealed important mechanisms of altered vascular function and structure as well as sympathetic regulation of the cardiovascular system in perinatal hypertension models. Some of adverse effects on nephrogenesis and blood pressure regulation could be reversed by special diet and treatment during first two years of life. While the complexity of the interactions between antenatal and postnatal influences on blood pressure is increasingly recognized, the importance of early postnatal life in modulating developmental programming offers the hope of a critical 1000 days window of opportunity to reverse programming and prevent or reduce child hypertension. PMID- 24340634 TI - [Changes in structural and functional plasticity of the brain induced by environmental enrichment]. AB - The review contains current data on structural and functional brain plasticity mechanisms under the enriched environment. Enriched environment contains social and non-social stimuli acting on different aspects of the development and functioning of the brain. Special attention is devoted to the modeling of enriched environment in the experiment. Enriched environment implies the action of social stimuli, new objects, therefore the enriched environment in animals can be considered as an adequate model to study changes in brain structure and function in people during learning or acquiring complex skills. The review describes the theory of enriched environment's influence on neurogenesis, the neuron-glia relationships, and the impact of enriched environment on damaged brain as well as the possibilities of using the paradigm of enriched envimronmentfor neurorenhabilitation. Molecular mechanisms of synaptic transmission, which has a correlation with the performance of cognitive functions, are the possible target for the action of environmental factors at the brain under (patho)physiological conditions. The considerable progress has been done in understanding the mechanisms that mediate the effects of enriched environment on the brain, but still there are many non-resolved questions in the neurochemistry and neurobiology of this phenomenon. Overall, the experience induced neuroplasticity is a unique mechanism for the development and recovery of brain functions. It opens new perspectives in neuropharmacology and neurorehabilitation. PMID- 24340635 TI - [Nervous regulation of thyroid function]. AB - Review examines the autonomic regulation of thyroid function. Review examines the issues of autonomic regulation of the thyroid gland. Activation of the central a adrenergic mechanisms increases the release of thyroid-stimulating hormone of pituitary mainly due to the stimulation of its secretion. Dopamine inhibits the secretion of this hormone, acting on D2-receptors tireotropotsitov. Acetylcholine and other cholinomimetics inhibit the functional activity of thyrocitebl with the participation of muscarinic receptors. Along the sympathetic and parasympathetic special attention paid to the role of the serotonergic division of vegetative system. Serotonin can inhibit the secretion of thyrotropin by the pituitary gland, but has a direct stimulatory effect on thyrocytes. This stimulatory effect is mediated by the serotonin 5-HT2 receptors. In hypothyroidism synthesis and metabolism of serotonin in the brain are slowed down. Depression is accompanied by inhibition of the enzyme activity deiodinase type 2, thereby reducing the concentration of serotonin. Activation of 5-HTI receptor lead to increased levels of intracellular calcium, causing inhibition of the promoter of calcitonin gene associated peptide. PMID- 24340636 TI - [Modern medical problems of energy exchange in humans]. AB - In a living organism 72% of energy exchange occur in the visceral organs, which comprise only 5-6% of the total body mass. The remaining energy is spent at the expense of the skin, bones, connective tissues, resting muscles. The level ofenergy expenditure determines the general physiological state of a human organism, serves for the diagnostics of various diseases, in particular, the diseases of endocrine system, the disruptions of thermoregulation, protein, carbohydrate, and lipometabolism, etc. It should be mentioned that in modern textbooks of physiology, pathophysiology, and biology the problem of energy exchange in humans and animals is given inadequate consideration. Traditionally it occupies only 2-2.5% of the content. Meanwhile, new problems of energy exchange have appeared recently, which almost never were advanced earlier. These are,for example, the reasons and mechanisms of high energy expenditure under conditions of metabolism, the significance of the coefficient of efficiency of a human organism in physiology, special processes previously unknown of the organism heat exchange with the environment, physiological and social components of human energy exchange. There is also a problem of a theoretical possibility of life without energy. PMID- 24340637 TI - [International approaches to the regulation of cell therapy products]. AB - This article is a review of the main methods and approaches used in regulation of cell therapy products in the United States of America, Canada, European Union, Australia, Japan and South Korea. Intensive developments ofscientific and technological aspects in stem cell and tissue engineering have led to the wide use of human cells and tissues for the treatment of various diseases and injuries of organs and tissues. Drug regulatory agencies of different countries are working on implementation of a risk-based legal framework with some common features. In many countries there is a multilevel control system that assures quality and safety of used cell products. Competent authorities establish strict requirements both to safety of the products and to the implemented standards of good laboratory, manufacturing, clinical and tissue practices. PMID- 24340638 TI - [Oncogynecological aspects of adnexal masses]. AB - Adnexal masses are frequently found in both symptomatic and asymptomatic women. The frequency of them is 7,8% in reproductive aged women and 2,5-18% in postmenopausal patients. AIM: to investigate clinical significance of the Risk of Malignancy Index (RMI) and to compare it with histological findings in patients with adnexal masses. PATIENTS AND METHODS: 345 patients with adnexal masses were evaluated. Depending on the menopausal status, serum CA-125 level and ultrasonographic findings RMI scores were calculated for each of patients. RESULTS: according to RMI all the patients were divided in to two groups: first group - 283 (62%) of patients with RMI less then 200 and the second group -52 (38%) women with RMI more then 200. The patients of the second group were referred to the oncologist. Among the patients with RMI <200, 137(48,4%) endometriomas, 73(25,8%) serous cystadenoma, 45(15,9%) dermoid cysts, 22(7,8%) paraovarian cysts, 2 (0,7%) adenocarcinoma were detected after histological examination. In patients with RMI >200, 25% of benign ovarian tumors, 34,6% of borderline and 40, 4% of malignant tumors were verified. CONCLUSIONS: RMI when used in the presence of a pelvic mass is a useful triage tool to determine those women who should be referred to a gynaecological oncologist. During laparoscopy, in cases of intraoperative malignancy suspicion staging should be performed: videorecord of the surgery, biopsy of the adnexal mass and contralateral ovary, biopsy of the omentum and peritoneum, and aspiration of the peritoneal fluid for cytological examination. PMID- 24340639 TI - [Role of the genetic factors, detoxication systems and oxidative stress in the pathogenesis of endometriosis and infertility (review)]. AB - The aim of this paper is to provide a systematic review of the role of the genetic factors, detoxication systems and oxidative stress in the pathogenesis of endometriosis and infertility. Endometriosis and infertility are still both the most uncommon diseases in gynecology. Many aspects of female reproductive function are strongly influenced by genetic factors, and numerous studies have attempted to identify susceptibility genes for disorders affecting female fertility such as polycystic ovary syndrome, endometriosis, fibroids, cancer (ovarian, vulvar, cervical), premature ovarian failure, recurrent pregnancy loss and pre-eclampsia. The most solid evidence linking specific polymorphisms to endometriosis is showed by the studies investigating a phase II detoxification enzyme. No data were found concerning influences of the genetic factors on the female infertility. Contrary, a lot of studies devoted to the genetic factors of male infertility are presented. It's known that endometriosis associated with increased systemic oxidative stress. The implication of increased systemic oxidative stress in disease progression or the association with other oxidative stress-related pathologic conditions needs to be addressed in further studies. The majority of studies suggest a reduced antioxidant capacity in infertile wome with endometriosis. In the present review we discussed the role of the genetic factors in the pathogenesis of endometriosis and infertility. NAT2 polimorphism, xenobiotic methabolism and exogenous factors are somehow related with these diseases. An altered balance between pro-oxidant antioxidant activities may have an impact on folliculogenesis and adequate embryo development. PMID- 24340640 TI - [The micrometric characteristic of placentae's villiferous tree in women in childbirth who have given birth to newborns with developmental anomalies]. AB - One of the actual problems of modern obstetrics isfetoplacental insufficiency. The purpose of the Research is micrometric characteristic ofplacentas villferous tree of women at 38-40 weeks, who gave birth to babies with congenital developmental abnormalities. Patients and methods. The resulting material was distributed in 3 groups. The control group - 40 placentas, conditional control group - 45 placentas, the basic group - 64 placentas. The results of a complex analysis have shown the presence of degenerative, dystrophic, proliferative disorders of the placentas in the basic group. CONCLUSIONS: Our data showed the presence of ischemic and necrotic areas with the presence of immature terminal villi. PMID- 24340641 TI - [Epidemiology-biological features of the acute intestinal infections caused by Staphylococcus aureus]. AB - Nowadays the structure of acute intestinal infections pathogens changed substantially. It is caused by constant evolution of bacteria and involvement of the opportunistic pathogens in the pathological processes. The aim of the study was to investigate the prevalence of the acute intestinal infections caused by staphylococci in the North-Eastern region of Ukraine, to determine the pathogenic factors in isolated pathogens. The materials for the study were the data of statistical reporting of Sumy regional sanitary-epidemiological station. Biological properties of the 50 Staphylococcus aureus strains were investigated. In the work used The descriptive and analytical techniques of the epidemiological, bacteriological and statistical methods were used. In the 2007 2012 the incidence of acute intestinal infections caused by staphylococci was in the range 17,1-20,3 on the 100 thousand. 2 years children were prevailed in the age structure. The largest numbers of cases were recorded in January, February, April, June and August. Strains of Staphylococcus aureus, isolated from the patients were characterized by a wide spectrum of pathogenic and persistence factors. Anti-lisozym activity was in 100% of the investigated cultures, anti interferon and anti-complement activity were detected in 96,0 and 64,0% stains, ability to adhesion was present in 36,0% stains. At the same time anti-lisozym, anti-interferon and anti-complement activity were showed in the 52,0% stains of the Staphylococcus aureus. These data characterize negatively predicted for the near future regional trends in morbidity. PMID- 24340642 TI - [Experimental whooping cough of nonhuman primate]. AB - Despite considerable success in study of Bordetella pertussis virulence factors, pathogenesis of whooping cough, duration of B. pertussis bacteria persistence, types and mechanisms of immune response are still keep underinvestigated. It can be explained by the absence ofadequate experimental animal model for pertussis study. Our study estimates clinical and laboratory parameters of whooping cough in non-human primates of the Old World in the process of intranasan infection by virulent B. pertussis bacteria. Also the duration of B. pertussis bacteria persistence in animals was investigated. 14 animal units of 4 species of non human primates of the Old World were used for intranasal infection. The examination of infect animals included: visual exploration of nasopharynx, thermometry, clinical and biochemical blood analyses, identification ofB. pertussis, using microbiologic and molecular genetic analyses, estimation of innate and adoptive immune factors. The development of infectious process was accompanied by generation of B. pertussis bacteria, catarrhal inflammation of nasopharyngeal mucosa, leucocytosis, hypoglycemia specific for pertussis, and activation of innate and adaptive immunity for all primates regardless of specie were seen. While repeated experimental infection in primates single bacterial colonies were registered during only first week after challenge. It occurs like the absence of inflammation of nasopharyngeal mucosa and the lack of laboratory marks of whooping cough, recorded after first challenge. The evident booster effect of humoral immunity was observed. As a model for investigation of B. pertussis bacteria persistence and immune response against whooping cough we suggest the usage of rhesus macaque as more available to experiments. PMID- 24340643 TI - [Modern concepts of etiology, pathogenesis and treatment approaches to endo-perio lesions]. AB - A combination ofperiodontitis and pulp or periapical tissues inflammation in one tooth is known as endo-periodontal lesions. Such kind of lesion is serious problem of modern dentistry. It was found that pathogenic microflora of periodontal pocket and root canal of tooth with eno-perio lesion is almost the equal and consist of anaerobic microorganisms. Pathogenic effects have not only microorganisms but also their life products. Apical foramen, lateral and additional canals are physiological ways for pathogens migration. Inflammatory processes in these structures complicate each other. Lack of information among dentists about treatment possibilities of endo-perio lesions is a main reasons of extraction such kind of teeth. Simultaneous elimination of pathogens both from periodontal pocket and root canal is a key factor for effective treatment. Periodontal status is main factor for prognosis of tooth with endo-perio lesion, because of it treatment of endo-perio lesions should consist of two stages: infection elimination and regeneration of tooth-supported structures. PMID- 24340644 TI - [Nanoparticles as drug delivery system for antituberculous drugs]. AB - The increase of tuberculosis incidence in last decade stimulated elaboration of both new antituberculous drugs and also searches ofoptimiting delivery systems for existing drugs. It is determined by their side effects and low bioavailability of effective first line drug rifampicin. Various nanosystems for transport of antituberculous drugs are considered on the basis of various polymers, liposomes, lipid nanoparticles, nanoemulsios, nanosuspensions, dendrimers, cyclodextrines. Influence of drug incorporation into nanoparticles, most often for rifampicin, on pharmacokinetics and efficiency in tuberculosis models is discussed. The most of works are devoted to polymer nanoparticles for oral administration where increased circulation time and efficiency were shown. The best results were observed after drug inclusion into solid lipid nanoparticles. The liposomes formulations were investigated mostly for inhalation and injection administrations. Positive results were also observed. Authors underline the viability of incorporation of antituberculous drugs into phospholipid nanoparticles that may increase intestinal absorption and bioavailability. It is confirmed by authors' own data that showed increase of rifampicin efficiency after their incorporation into such nanoparticles. PMID- 24340645 TI - [Role of hepatoprotectors and immunomodulators in regulation of hepatocyte apoptosis induced by antituberculosis treatment]. AB - It was currently shown that hepatopathy due to drug toxicity is associated with increased apoptosis of hepatocytes. Therefore, development of drugs which regulate cell death is of great importance. AIM: To involve some hepatoprotectors (ademethionine, reamberin, remaxol) and immunomodulators (cycloferon) into regulation of apoptosis in experimental models of liver first-line antituberculousis drugs (isoniazid, rifampicin, pyraztinamide). MATERIALS AND METHODS: Levels of apoptoasis (TUNEL), expression of CD95 (receptor of tumor necrosis factor - by immunohistochemistry), expression of caspase-8, caspase-3 and pS3 (Western-blotting) were measured. RESULTS: Exposition offirst-line antituberculousis drugs leads to dysthrophia of liver parenchyma cells with increased apoptosis of hepatocytes and activation of CD95, caspase-8 (external way) and overexpression of p53 and caspase-3. It was found that reamberin, cycloferon and remaxol have hepatoprotective effect improving liver histology; ademethionine administered by intraperitoneal injection showed no positive effects. Reamberin demonstrated apoptosis-inhibiting effect in the experiment whereas other drugs were found to be apoptosis inductors for hepatocytes in toxic hepatopathy. CONCLUSIONS: Legulation of apoptosis by cycloferon and remaxol mediated by external and p53-dependent pathway is confirmed by increased expression of CD95 and p53 protein. Ademethionine might induce apoptosis by the intrinsic pathway. PMID- 24340646 TI - A bumpier roll-out than expected. PMID- 24340647 TI - 5 ways to support an integrated system. PMID- 24340648 TI - Buyer's brief: Integrated operating rooms. PMID- 24340649 TI - Managing 'tail liability'. AB - To reduce and control their level of tail liability, hospitals should: Utilize a self-insurance vehicle; Consider combined limits between the hospital and physicians; Communicate any program changes to the actuary, underwriter, and auditor; Continue risk management and safety practices; Ensure credit is given to the organization's own medical malpractice program. PMID- 24340650 TI - Achieving clinical integration. AB - To develop an effective and sustainable clinically integrated network (CIN) that positions a healthcare organization for value-based payment and other effects of healthcare reform, leaders of CIN initiatives should: Embrace progress rather than perfection; Constrain the development timeline by project managing in reverse; Ensure that physician leaders play an oversight role in the development process. PMID- 24340651 TI - Jonathan Perlin: Assessing the ROI of EHRs. Interviewed by Karen Thomas. PMID- 24340652 TI - Affiliation options for independents. AB - Many independent hospitals and medical groups are pursuing affiliations with partner organizations to meet the challenges posed by healthcare reform and value based payments. Before embarking on such a strategy, however, these organizations should: Clearly define their objectives of pursuing an affiliation; Assess potential affiliation options; Identify a preferred strategy based on evaluation of different affiliation scenarios. PMID- 24340653 TI - How rolling forecasting facilitates dynamic, agile planning. AB - Rolling forecasting may be used to replace or supplement the annual budget process. The rolling forecast typically builds on the organization's strategic financial plan, focusing on the first three years of plan projections and comparing the strategic financial plan assumptions with the organization's expected trajectory. Leaders can then identify and respond to gaps between the rolling forecast and the strategic financial plan on an ongoing basis. PMID- 24340654 TI - Data key to quest for quality. AB - Late-binding data warehousing reduces the time it takes to obtain data needed to make crucial decisions. Late binding refers to when and how tightly data from the source applications are bound to the rules and vocabularies that make it useful. In some cases, data can be seen in real time. In historically paper-driven environments where data-driven decisions may be a new concept, buy-in from clinicians, physicians, and hospital leaders is key to success in using data to improve outcomes. PMID- 24340655 TI - HFMA announces new best practices for patient financial communications. PMID- 24340656 TI - Elevating the role of finance at Mary Lanning Healthcare. AB - To effectively partner with hospital operations leaders, healthcare finance leaders should: Streamline and align financial planning and budgeting functions across the organization; Ensure capital planning is regarded as a strategic process; Optimize performance monitoring across management levels. PMID- 24340657 TI - SEC actions compel new focus on disclosure. AB - Practical steps that healthcare organizations should take in creating disclosure programs that meet the Securities and Exchange Commission's guidelines for disclosure include: Establishing procedures for disclosure of financial and operational data; Conducting an internal audit of disclosure practices; Designating personnel responsible for disclosure and ensuring they receive appropriate training; Reassessing the organization's historic deal pattern; Making effective use of counsel; Establishing clearly defined policies for website disclosure. PMID- 24340658 TI - The structure of value. PMID- 24340659 TI - Using shared decision-making to improve healthcare value. PMID- 24340660 TI - Using real estate to hedge against interest rate risk. PMID- 24340661 TI - Effects of a flat facility fee for ED visits. PMID- 24340662 TI - [Special reports on advanced drugs and cellular and tissue-based products]. PMID- 24340663 TI - [Regulatory science promoting improvement in developing environment of innovative drugs]. AB - Importance of regulatory science in development of innovative drugs is pointed out by the Council for Science and Technology Policy in the Cabinet Office, and the pharmaceuticals-related divisions in the NIHS have begun the regulatory science research for promoting improvement in developing environment of innovative drugs since 2012. Nano-medicines, fully engineered protein drugs, nucleic acid drugs, and gene therapy drugs have been selected as innovative drugs, and the point-to-consider documents for evaluating mainly quality and non clinical safety of these drugs will be developed. In addition, the conditions for the first-in-human trial will be also proposed, especially from the standpoints of quality and non-clinical safety evaluation. PMID- 24340664 TI - [Evaluation of the safety of innovative drugs against viruses and infectious agents]. AB - Recently, several novel cellular therapy products and biological drugs are being developed to treat various previously untreatable diseases. One of the most important issues regarding these innovations is how to ensure safety over infectious agents, including viruses and prions, in the earliest treatments with these products. The object of this study is a risk assessment of cases of human infectious with the agents and to present a sample risk management plan based on a collaboration among the National Institute of Health Sciences, universities, marketing authorization holders, and scientific societies. There are three subjects of study: (1) the viral safety of cellular therapy products, (2) the viral safety of biological drugs, and (3) the safety of prions. In this report, we describe the objects of the study, the project members, the study plan outline, and the ongoing plans. The results of the viral risk identification and the risk analysis of cellular therapy products will also be described, based on a review of the literature and case reports obtained during the first year of this project. PMID- 24340665 TI - [Regulatory science research to facilitate the development of cell/tissue processed products]. AB - Regenerative medicine is regarded as innovative therapy for severe diseases and damages caused by tissue loss and functional impairment. In Japan, regenerative medicine is one of the most important subjects issued by Council for Science and Technology Policy and also referred to in Medical Innovation of New Growth Strategy. Cell/tissue-processed products are living cells, which have been manipulated or processed for the purpose of regenerative medicine, and are extensively developing. Human somatic cells, somatic stem cells, embryonic stem cells, and induced pluripotent stem cells are cell sources used for regenerative medicine. Since we lack in experiences with cell/tissue-processed products, technical development of safety and quality assessment is urgently needed. National Institute of Health Sciences has carried out a mission of Regulatory Science and worked on safety assessment of pharmaceuticals and medical devices and their guideline development. The objective of our study is to develop safety and quality assessment methods for cell/tissue-processed products derived from stem cells, based on recent progresses in life science. We are currently developing methods to evaluate products as follows; a) useful and quantitative tumorigenicity tests to detect contamination of undifferentiated and/or abnormal cells in products, b) quality assessment by gene expression analysis and detection of genetic stability in a manufacturing process, and c) analysis of quality attributes associated with propensity of undifferentiated cells to set acceptable criteria of cell banks. We will be able to provide indicators to control the quality, efficacy and safety of stem cell-processed products and support efficient and economical promotion of the products. Especially, this study would help translate stem cell science into therapeutic products to patients with severe and life-threatening diseases, consequently contributing to administrative policy of Ministry of Health, Labor and Welfare. PMID- 24340666 TI - [Toward acceleration of drug development with proteomic and metabolomic biomarkers]. AB - Biomarkers, reflecting disease states or predicting/assessing drug efficacy or adverse reactions, are expected to play pivotal roles in effective drug development and promoting proper usage of drugs. To accelerate biomarker identification and usage, administrative guidance can direct to design appropriate exploration, validation and utilization studies and show examination procedures. However, very limited number of guidance or its draft were released from Japanese, US and European regulatory authorities so far. From 2012, we have been conducting proteomic and metabolomic studies using blood and urine samples from human and rat, in order to establish draft guidance for sampling/storage of these biofluid and for extrapolation of biomarker candidates from animals in the non-clinical to humans in the clinical studies. The results are still partial and the rest of the analysis is ongoing. However, we developed sensitive proteomic system for urine and found large inter-sex differences in the proteomic profiles of rat. In addition, matrix-, sex- and generation-differences were also observed in the metabolite levels in human blood, some of which showed over 2-fold differences. We continue this regulatory science studies for contribution to accelerated novel biomarker findings and its usage by generation of the draft guidance. PMID- 24340667 TI - [Developing and standardizing experimental protocols using human iPS-derived cells to predict adverse drug reactions in pre-clinical safety studies]. AB - In this study, we have standardized experimental protocols to evaluate the possibility of using cells differentiated from human induced pluripotent stem cells (hiPSCs) in the pre-clinical studies for the drug approval processes. Cells differentiated from hiPSC, especially cardiomyocytes, neurons and hepatocytes, are expected to be used as new pharmacological and toxicological assay tools. Current preclinical test methods have limitations for predicting clinical adverse drug reactions. This is because of the so-called 'problem of species difference'. Drug-induced arrhythmia, cognitive impairment and hepatotoxicity which can't be predicted in pre-clinical studies are major causes of the high rate attrition of new-drug candidates in clinical studies and of withdrawal of products from the market. The development of new pre-clinical test methods using cells differentiated from hiPSCs would resolve these problems, in addition to solving the issue of "the replacement, refinement and reduction (3Rs)" of animal experiments. From 2010 to 2011, we surveyed companies belonging to the Japan Pharmaceutical Manufacturers Association (JPMA) and academic researchers about the usage of differentiated cells in their laboratories. We found that studies were performed using differentiated cells from different cell lines of hiPSC with laboratory-specific differentiation methods. The cells were cultured in various conditions and their activities were measured using different methods. This resulted in a variety of pharmacological responses of the cells. It is therefore impossible to compare reproducibility and ensure reliability of experiments using these cells. To utilize the cells in the drug approval processes, we need robust, standardized test methods to accurately reproduce these methods in all laboratories. We will then be able to compare and analyze the obtained results. Based on the survey, the Ministry of Health, Labor and Welfare funded our study. In our study, we standardize pharmacological methods among several laboratories, including our laboratory, to develop robust tests, using the same lot of cells, the same culture conditions, reference compounds, experimental protocols, and analysis methodology. In conclusion, to standardize robust test methods, we need a consistent supply of high-quality differentiated cells. Further, indexes to quantify the quality of the differentiated cells will be needed for their effective usage in the pre-clinical safety studies. PMID- 24340668 TI - [Topics from "Overseas Drug Safety Information" in the past five years]. AB - The Drug Safety Information Section of the Division of Safety Information on Drug, Food and Chemicals has been providing bulletins titled "Overseas Drug Safety Information" in Japanese since 2003. These bulletins comprise summarized and translated reports of important post-marketing drug safety information that are published by foreign regulatory agencies such as the US Food and Drug Administration (FDA) and the European Medical Agency. A new issue of the bulletin is posted every two weeks on the website of the National Institute of Health Sciences, Japan; to date (May 2013), a total of 280 issues have been posted, covering approximately 2400 foreign news items and articles since its inception. Recently, visits to the bulletin website have been increasing: the number of hits for each issue totaled 570,000 in fiscal 2012. Among the "Overseas Drug Safety Information" issued in the past five years, I briefly describe here several topics which interested me: erythropoietin-stimulating agents in chronic kidney disease and their cardiovascular risk; bisphosphonates and atypical femur fracture; effectiveness of oral liquid cough medicines containing codeine in children; bevacizumab for metastatic breast cancer; and congenital abnormality associated with the use of antiepileptic drugs by pregnant women. I also describe the potential safety signals identified by FDA using its Adverse Event Reporting System, and their importance in ensuring the safe use of drugs in the post marketing phase. PMID- 24340669 TI - [Comparative study of the time period between the initiation of various interferon therapies and the onset of suicide- or diabetes-related side effect]. AB - To compare the safety profiles of the various interferon (IFN) therapies, the time period between the initiation of IFN therapy and the onset of suicide- or diabetes-related side effects and clinical outcomes was extracted from open source data obtained from spontaneous reports published on the homepage of the Pharmaceutical and Medical Devices Agency on October 18, 2012. The analysis of the time period between the initiation of therapy and the onset of diabetes related side effects in 114 cases showed that the period of the group treated with IFN-alpha (median 0.78 years, interquartile range 0.44-1.19) was significantly longer than those of the IFN-beta group (0.12, 0.04-0.48) and the pegylated IFN group (0.48, 0.27-0.76) (P < 0.05). In the case of suicide-related side effects, the analysis of 68 cases showed that the time period did not differ significantly between the IFN-alpha group (0.09 years, 0.05-0.49) and the IFN beta group (0.31, 0.11-0.65) , but was significantly shorter than that of the pegylated IFN group (0.32, 0.18-0.58) (P < 0.05). In clinical outcomes, the percentage of deaths was 56% (10/18) in the IFN-alpha group, 7% (1/14) in the INF beta group, and 29% (9/31) in the pegylated IFN group. These results suggested that the side-effect profiles differed among the various IFNs. PMID- 24340670 TI - [Comprehensive analyses of hydrolyzed wheat protein using shotgun proteomics]. AB - Hydrolyzed wheat protein (HWP; hydrolyzed gluten) is used in various types of products worldwide. Several cases of wheat-dependent, exercise-induced anaphylaxis following exposure to HWP (Glupearl 19S) in cosmetics have been reported. Glupearl 19S was produced from the gluten after partial hydrolysis with hydrogen chloride, and its allergenicity is larger than that of gluten (Adachi R., Allergy 2012;67:1392-9.). It is considered that provocation of allergic manifestations is caused by deamidated gluten in food and/or non-food products. Moreover, an increasing number of studies have shown that HWP can induce IgE mediated hypersensitivity by skin contact and/or food ingestion. However, the essential molecular properties and profiles of HWP are still unknown. In this study, bioinformatic and multivariate analyses using shotgun proteomics have revealed that 27 proteins significantly decreased in Glupearl 19S compared with intact gluten as shown by the ratio of ion signal intensity of tryptic peptides. In contrast, a single protein significantly increased in HWP compared with intact gluten as shown by the ratio of ion signal intensity of tryptic peptides. Furthermore, we have identified six Glupearl 19S-specific peptides using shotgun proteomics, database searches on Mascot Sequence Query, and de novo sequencing. The six peptides were identified as the specific markers of Glupearl 19S. PMID- 24340671 TI - [Ion-pair HPLC analysis of B vitamins in syrup products in Indonesia]. AB - A training course for analysis of B vitamins in syrup products was undertaken at the National Agency of Drug and Food Control at Jakarta as part of the project to deliver safe drugs to people in Indonesia by Japan International Cooperation Agency. Analytical methods have been developed for quantitative determination of B vitamins by ion-pair high-performance liquid chromatography using 1 hexanesulfonic acid sodium salt. Measurements were performed for two syrup products removed from a drug store in Jakarta to determine the amount of each vitamin B. The measured values of riboflavin 5'-phosphate sodium, nicotinamide and pyridoxine hydrochloride were almost the same with those of nominal content for both products. While the measured values of thiamine hydrochloride, pantothenol and cyanocobalamin were approximately twice the amount of nominal contents. PMID- 24340672 TI - [Characterization of cases contravening of regulations regarding primary aromatic amines originating from azo dyes in commercial textile products and leather products in European Union]. AB - Contraventions of regulations regarding primary aromatic amines (PAAs) originating from azo dyes in commercial textile products and leather products in European Union (EU), notified in the period between 2006 and 2012 were collected from the Rapid Alert System for non-food consumer products (RAPEX), were characterized. Various types of products (clothes, footwear, bedding, etc.) and their raw materials (cotton, silk, viscose, leather, etc.) were reported to have contravened the regulations. The contravention frequencies for products made in China and India were higher than those for other countries. Ten percentage of the country in which the reported products were produced was unknown. The notification frequencies for benzidine and 4-aminoazobenzene were higher than those for other PAAs. Contravention of regulations regarding benzidine, 4 aminoazobenzene, and 3,3'-dimethoxybenzidine were notified every year. Contraventions of regulations regarding five PAAs--classified as IARC group 1- were notified one or several times. Since the scale of the survey conducted in Japan were small compared with RAPEX, it is necessary that many kinds and number of products should be surveyed in Japan. In addition, it is also necessary to pay attention to 4-aminoazobenzene, while it has not been detected in the previous studies conducted in Japan. PMID- 24340673 TI - [Perioperative cardiac infarction - an underdiagnosed problem]. AB - Perioperative cardiac infarction (PMI) associated with surgery and the postoperative period significantly restricts the outcome of operative treatment. PMI is encountered in 0.5 to 1% of surgical patients, but among high-risk patients the incidence exceeds 10%. The disorder is associated with a mortality of 10 to 25%, corresponding to at least 1 000 patient deaths annually, as adjusted to the numbers of operative treatment in Finland, and its care requires at least 20000 extra days of hospitalization. PMID- 24340674 TI - [Metabolomics in psychosis research]. AB - Metabolomics is utilized for comprehensive investigations on the structure, function and interactions of low molecular weight metabolites. The method provides a momentary overall picture of metabolism in the organ system. Investigations into metabolic disturbances aim at understanding the etiology of the disease, studying the effects of therapy, as well as identifying biological marker substances applicable to the prediction of the course of the disease and treatment response. Among psychotic disorders, schizophrenia is in particular associated with significant changes in the metabolism of glucose, amino acids, lipids and energy. Of these changes only some are related to the disease process itself, while some are explained by the effect of drug therapy and habits of life. PMID- 24340675 TI - [Dormancy of tumor cells]. AB - Whereas tumor dormancy occurs in melanomas, renal carcinomas and non-Hodgkin lymphomas, late recurrence is characteristic of breast cancer in particular. In the early stage, cancer cells break away from the primary tumor into the circulation, some of which are able to attach themselves to a new target tissue and avoid apoptosis. This condition represents dormancy of tumor cells, in which the cell cycle has either stopped or cell division and cell death are in mutual balance. Cessation of the dormancy state and the growth spurt that follows may result from the initiation of angiogenesis (angiogenic switch). PMID- 24340676 TI - [Sleep, memory, and learning]. AB - The relationship between sleep and memory and learning has proved multifilament. Besides supporting cognitive functions needed to encode, storage and retrieve materials while awake, sleep is a state during which some of the memory traces are reactivated and consolidated. Also, sleep disorders such as insomnia, obstructive sleep apnea and insufficient sleep in children and adolescents are accompanied with impairments of memory and learning as well as work and school performance. There are treatments for these disorders such as congnitive behavioural therapy and continuous positive airway pressure, which, at least to some extent, mitigate cognitive impairments and consequently support memory and learning. PMID- 24340677 TI - [Many dimensions of extracellular matrix research]. AB - In addition to the important structural function in supporting tissues, extracellular matrix regulates the responses of cells to their environment during development, cellular division, maturation and differentiation, migration of cells from one site to another, in the homeostasis of the body and in cancer cell invasion. An essential group of extracellular matrix molecules, the matrisome, is formed by approximately 300 molecules that can be grouped into collagens, proteoglycans and glycoproteins. Information obtained from the synthesis of collagens and gene defects can be utilized in the development of diagnostics and treatment methods for hereditary diseases. PMID- 24340678 TI - [Treatment of the scaphoid fracture]. AB - The scaphoid fracture is a typical consequence of a young person falling on an outstretched arm. The diagnosis is based on clinical examination and conventional radiography as well as computed tomography or MR imaging, when necessary. More detailed investigations should be directed to patients having a high likelihood of fracture. Nondisplaced scaphoid waist fractures are treated with a dorsal plaster splint. A scaphoid fracture with good position will usually unite within 5 to 8 weeks. Fractures within the proximal part of the bone as well as displaced fractures are recommended to be treated operatively. PMID- 24340679 TI - [Chronic sclerosing sialadenitis - Kuttner tumor]. AB - Chronic sclerosing sialadenitis i.e. Kuttner tumor is a rare inflammatory disease most commonly affecting the submandibular gland, due to clinical findings easily interpreted even as a malignant tumor. Our 45-year-old patient sought medical care due to a solid lump that had appeared under the right mandibular angle. The submandibular gland and associated hard mass were excised in a surgical operation conducted after the investigations. Histologic examination proved that the seldom diagnosed reactive Kuttner tumor was in question. PMID- 24340680 TI - [Update on Current Care Guideline: Sinusitis]. AB - Patients with common cold have often symptoms similar to sinusitis. These symptoms often resolve in time, but symptomatic treatment (e.g. analgesics, decongestants) may be used. If symptoms continue for over 10 days, or severe symptoms continue for over 3 days, or symptoms turn worse in the course of the disease, bacterial sinusitis should be suspected. Diagnosis is based on clinical findings, and can be confirmed with ultrasound examination. Amoxicillin, penicillin or doxicyclin are recommended for bacterial sinusitis. Patients with chronic or recurrent sinusitis should be referred to specialist care. PMID- 24340681 TI - [Dramatic present tense and the language of event description on death certificate]. AB - After the completion of a death certificate, the determination of the cause of death has ended. In Finland the event data on the death certificate play a central role in the description of the course of death. Although traditions within the field dictate the mode of expression of patient records, features can be pointed out in the language of these event descriptions that have been regarded as stylistic devices used to enliven stories in other narrative genres. One of these is the dramatic present tense, which presents past events as if they were ongoing at the moment of narration. PMID- 24340682 TI - [Magazine or controversy]. PMID- 24340683 TI - [Current guidelines for antibiotic prophylaxis in patients with a joint prosthesis are inadequate]. AB - A haematogenous infection of a joint prosthesis is rare, but the consequences can be very serious. For that reason, guidelines issued by medical professional organizations for antibiotic prophylaxis in treatments which involve risk have long existed. On the basis of experience in the United States and the Netherlands, it is clear that successive guidelines sometimes contradict each other and are often not appropriately applied in daily practice. This may be due to insufficient clarity concerning the most important patient risk factors. It remains, for example, unclear when there is a question of reduced immunity in the patient and when the oral region has to be considered to be infected. An appeal is made to follow the existing guidelines better, and, if possible, to achieve a more multidisciplinary revision of the guidelines 'Total hip prosthesis, so that they would be more widely adhered to. PMID- 24340684 TI - [Dental healthcare providers trapped in regulations?]. AB - At the request of the editorial board, H.S. Brand offers a reaction from the perspective of dental care professionals to G.H.I.M. Walenkamp's article about the present regulations for antibiotic prophylaxis for patients with prosthetic joints. PMID- 24340685 TI - [Painful submandibular swelling appears to be a rare odontogenic tumour]. AB - A 15-year-old girl was referred to an oral and maxillofacial surgeon due to a painful submandibular swelling that had been present for 4 to 5 months. After surgical excision and histopathological examination it appeared to be a relatively rare adenomatoid odontogenic tumour. Approximately 4.6% of all odontogenic tumours are adenomatoid odontogenic tumours. This type of tumour is mainly diagnosed between the ages of 10 and 30. Surgical excision is an effective treatment and the adenomatoid odontogenic tumour has a favourable prognosis. The most recent article in Dutch literature on the adenomatoid odontogenic tumour dates back to 1975. PMID- 24340686 TI - [Dissertations 25 years after the date 36. Dental development and facial growth during adolescence]. AB - Dental development does not end with the shedding of the deciduous dentition. Partly as a result of the continuing facial growth up to adulthood, adaptations in the position of the teeth and the occlusion occur after the second phase of eruption. The dissertation Gebissentwicklung und Gesichtswachstum in der Adoleszenz, from 1988, was concerned with research into tooth development, facial growth and their interrelationship during the first decade after the second phase of tooth eruption. Changes in the dental arches go together with changes in the occlusion. These physiological changes in the dentition can largely be attributed to the shift of the mandibular dental arch to a more ventral position, with respect to the maxillary dental arch. Facial growth and changes in the morphology of the craniofacial skeleton up to adulthood are especially a result of adaptations which take place under the floor of the nose and as a result of the enlargement of the mandible. Later research in patients up to the age of approximately 40 years, revealed that these dental and skeletal changes continued to occur. PMID- 24340687 TI - [Oral medicine 11. Red and blue lesions of the oral mucosa]. AB - A red or blue mucous membrane disorder of the oral cavity can arise in response to a local cause of irritation, as a cause of an inflammation reaction to an infection, an auto-immune reaction to a local factor, and as an expression of an underlying systemic disorder. Moreover, it can be an expression of a premalignant or malignant mucous membrane disorder. Knowledge about and recognition of the different red and blue mucous membrane disorders can hasten the diagnosis and possible treatment. In the case of a premalignant (erythroplakia) or a malignant mucous membrane disorder (squamous cell carcinoma), the prognosis is better with early diagnosis and treatment than at a later stage of the disease. PMID- 24340688 TI - [Determining and recording maxillomandibular relationships for the fabrication of single-unit and multi-unit fixed dental prostheses]. AB - In a correctly functioning occlusal system, the design of the occlusal parts of single-unit and multi-unit fixed dental prostheses is generally determined by the maximum intercuspation. Determining and recording the maxillomandibular relationships is only required in case the adjacent teeth do not offer adequate support or reference to put the maxillary and mandibular cast in maximum intercuspation or in case the existing occlusion needs a well-structured alteration. The maxillomandibular relationships can be determined and registered analogously and digitally and on that basis the maxillary and mandibular casts can be mounted in a (virtual) occludator or articulator. In the absence of a distinct occlusal plane, one may consider first carrying out a facebow recording and transfer. Usually, the accuracy of determining and recording the maxillomandibular relationships does not increase when using more complicated methods. PMID- 24340689 TI - [Attaching single- and multi-unit fixed dental prostheses]. AB - A single- or multi-unit fixed dental prosthesis can be attached to the abutment teeth through mechanical retention and gap sealing or by adhesion. For sealing the gap, water-soluble cements are appropriate, such as zinc phosphate, polycarboxylate, and (resin-modified) glasionomer cement. Attachment through adhesion can be performed with composite cement. If the hard tooth tissue is prepared adequately, composite cement provides sufficient adhesion, but self adhesive composite cement is now also available. For the adhesion of the composite cement to the restorative materials of the single- or multi-unit fixed dental prosthesis, surface sandblasting, silanizing, and tin coating and the application of a metal primer or chemically active composite are available. Cementing a single- or multi-unit dental prosthesis involves 3 phases: 1. Cleansing the single- or multi-unit dental prosthesis and the abutment tooth/teeth; 2. Preparing the hard tooth tissue, mixing the cement and placing the single- or multi-unit dental prosthesis; 3. Removing the excess cement. PMID- 24340690 TI - WHO Expert Committee on Biological Standardization. AB - This report presents the recommendations of a WHO expert committee commissioned to coordinate activities leading to the adoption of international recommendations for the production and control of vaccines and other biologicals and the establishment of international biological reference materials. The report starts with a discussion of general issues brought to the attention of the Committee and provides information on the status and development of reference materials for various antibodies, antigens, blood products and related substances, cytokines, growth factors, endocrinological substances and in vitro diagnostic devices. The second part of the report, of particular relevance to manufacturers and national regulatory authorities, contains revised WHO Recommendations for production and control of live attenuated influenza vaccines and for production and control of pneumococcal conjugate vaccines. New WHO Guidelines on the regulatory evaluation of similar biotherapeutic medicines are also provided. Also included are a list of Recommendations, Guidelines and other documents for biological substances used in medicine, and of International Standards and Reference Reagent for biological substances. PMID- 24340691 TI - Connecting over inclusion: new online diversity resources available. PMID- 24340692 TI - Adapting services for bigger clients: cattle veterinarians discuss varied practice models at AABP conference. PMID- 24340693 TI - Cat-friendly message targets public: AAFP continues its message of awareness, preventive medicine. PMID- 24340694 TI - Health assessments show pet disease risks. PMID- 24340695 TI - The authors respond. PMID- 24340696 TI - What's the difference between an ovariohysterectomy and a spay? PMID- 24340697 TI - More on AVMA governance changes. PMID- 24340698 TI - Early Pancreas Organogenesis: Morphogenesis, Tissue Interactions, and Mass Effects. PMID- 24340699 TI - Ultrastructural study on pronuclear development in fertilized eggs from goldfish, Carassius auratus. AB - The formation of male and female pronuclei in physiologically monospermic fertilized eggs of the goldfish, Carassius auratus, has been investigated with transmission electron microscopy. Ultrastructural observations show that at 26 degrees C the transformation of the sperm nucleus takes place very quickly. The sperm nuclear envelope degenerates and is replaced by a large number of smooth surface vesicles 1 min post-insemination. Concomitantly, most of the condensed sperm chromatin is dispersed and is surrounded by vesicles. Dispersion of the chromatin is followed by the fusion of vesicles and the formation of a new bilaminar pronuclear envelope. Within 5-10 min post-insemination, a spheroid male pronucleus with intranuclear annulate lamellae is produced. The formation of a female pronucleus is slightly different to that of the male pronucleus. The dispersing chromatin of the egg is divided into many groups, most of which are surrounded by multilaminar envelopes 5 min post-insemination. An ellipsoid female pronucleus with a continuous bilaminar pronuclear envelope and intranuclear annulate lamellae is formed 15 min post-insemination. Subsequently, the two pronuclei migrate towards one another. When the fully developed male and female pronuclei are located in the center of the blastodisc, each changes itself into a saccular complex 25 min post-insemination. PMID- 24340700 TI - Re: Neuroscience in Nazi Europe part III: victims of the Third Reich. Can J Neurol Sci. 2012;39:729-746. PMID- 24340701 TI - Device-tax repeal surfaces as key in budget stalemate. White House says it's unwilling to compromise until shutdown ends. AB - As lawmakers in D.C. continue to wrangle over how to solve the government shutdown and debt ceiling impasse, the Affordable Care Act's medical device tax is emerging as a likely bargaining chip. But many wonder how the tax's $29.1 billion in funding for coverage expansion will be replaced. Minnesota GOP Rep. Erik Paulsen, says he's encouraged that there is a strong chance the device tax could be overturned. PMID- 24340702 TI - Exchange variables. Finding providers depends on state. PMID- 24340703 TI - Exchange exclusion suit. Higher-cost hospitals may be affected. PMID- 24340704 TI - Insurers lower cost-sharing for preventive drugs. Aetna, Wellpoint, Humana cut patients' costs to improve compliance, outcomes. PMID- 24340705 TI - A make-or-break year for health IT. With ICD-10 looming in 2014, CIOs face tough decisions in deploying resources. PMID- 24340706 TI - Part of the solution. Physicians can and want to improve quality, lower cost of healthcare. PMID- 24340707 TI - Zeroing in on best procurement practices. Supply chain execs discuss strategies for savings on physician-preference items. PMID- 24340708 TI - A period of adjustment. Post-acute providers feel growing pains as they shift to Medicare and Medicaid managed-care contracting. PMID- 24340709 TI - Progress, but still a long way to go. Researchers see promise in safety measures, but gains uneven. PMID- 24340710 TI - Most frequently billed DRGs. PMID- 24340711 TI - [Mechanisms of insulin resistance]. AB - Insulin resistance refers to an aberrant physiological response to insulin in its target tissues. Several signal transduction mechanisms sensing intracellular stress are activated in situations where energy supply exceeds the cells' energy requirements. This stress interferes with insulin-induced intracellular signal transduction and leads to an inflammatory state. The activation of inflammatory responses in peripheral tissues and central nervous system weakens the body's insulin sensitivity, glucose tolerance and predisposes to obesity. Insulin resistance is thus a crucial metabolic disorder in obesity, type 2 diabetes and cardiovascular diseases. PMID- 24340713 TI - [Psychoeducation in the treatment and rehabilitation of psychoses]. AB - Psychoeducation is one of the most effective psychosocial forms of treatment for psychoses. It appears to prevent recurrence of psychosis and hospitalization periods and to increase treatment compliance. Psychoeducation should be included in the treatment and rehabilitation of psychoses as part of the overall rehabilitation, and is particularly important for persons with first-episode psychosis and their family. At least the vulnerability-stress model, basics of pyschosis as well as the recognition and management of warning signals and long term symptoms should be discussed with the patient and her/his family. PMID- 24340712 TI - [Genetic etiology of eating disorders]. AB - Most twin studies suggest a heritability of SO to 80% for liability to eating disorders. At least moderate heritability is further supported by family and adoption studies. Polymorphisms of the 5-HT2A and BDNF genes appear robust candidates for anorexia nervosa and bulimia nervosa, while linkage studies suggest loci for anorexia nervosa in chromosome 1 and a locus in chromosome 10 for bulimia nervosa. Contemporary Western culture has a salient role in the rising incidence of eating disorders, and epigenetic mechanisms are suggested to be involved. In the near future, GWAS will likely provide compelling new data of genetic etiology and mechanisms of eating disorders. PMID- 24340714 TI - [The effects of dancing on the brain and possibilities as a form of rehabilitation in severe brain injuries]. AB - Very little research has been done on the effect of dancing on the rehabilitation of patients having a severe brain injury. In addition to motor problems, the symptom picture of the sequelae of severe brain injuries often involves strong fatigability, reduced physiological arousal, disturbances of coordination of attention, difficulties of emotional control and impairment of memory. This review deals with the neural foundation of dancing and the possibilities of dancing in the rehabilitation of severe brain injuries. PMID- 24340716 TI - [Cronkhite-Canada syndrome - a rare intestinal polypotic syndrome]. AB - Cronkhite-Canada syndrome is a rare polypotic disease of the gastrointestinal tract. There are no specific diagnostic criteria for this syndrome. Suspicion may arise if both an endoscopic and a histopathologic finding together with the patient's symptom picture are indicative of the disease. Other polypotic conditions should be excluded. No established treatment is available for the syndrome. The principles of treatment have remained almost unchanged at least over the past decade. With a large proportion of the patients eventually developing a gastrointestinal malignancy, the prognosis of the disease is mostly poor. PMID- 24340715 TI - [Treatment of drug-resistant depression]. AB - Depression is drug-resistant, if the severity of the symptoms has not decreased to half of the starting situation, despite appropriately conducted treatment with two antidepressants belonging to two different pharmacological categories. The incidence of drug-resistant depression in Finland is approximately 1%, and it is being treated too passively, whereby the number of disability pensions is rising. Current treatments include combinations of antidepressants, additional drugs for depression, psychotherapy, electrotherapy and serial magnetic stimulation. Ketamine infusions are also an effective, yet still experimental form of treatment. PMID- 24340717 TI - [Magnetic resonance imaging of the breasts]. AB - Not even magnetic resonance imaging is a perfect method for imaging of the breasts. Quality of the equipment, imaging parameters as well as the experience and competence of radiographers and radiologists have a significant effect on the final outcome of the study. Since interpretation of magnetic resonance imaging of the breasts is challenging, the radiologist should have access to a comprehensive medical history and previous images, including the reports. Feedback from the reports made and multidisciplinary postoperative meetings are important. Since magnetic resonance imaging is expensive and has low availability, it should be targeted at the correct patient groups. PMID- 24340718 TI - [A domestic human case of hepatitis E in Finland]. AB - We describe the first verified domestic HEV case in a previously healthy 53-year old man who presented a three-day history of upper stomach pain, nausea, fever, arthralgia and fatigue. At the first phase laboratory tests revealed high levels of AST and ALT and at the second phase high levels of bilirubin. Serum was positive for anti-HEV IgM and for HEV RNA confirming the diagnosis of acute hepatitis E. The HEV was genotype 3. Jaundice resolved in three months. In nonendemic areas autochthonous hepatitis E is more common than previously recognized and is possible in patients with acute hepatitis. PMID- 24340719 TI - [Commencement of and adherence to CPAP treatment of patients with sleep disordered breathing]. AB - BACKGROUND: We evaluated the changes in nasal CPAP treatment and adherence in patients with sleep-disordered breathing (SDB). MATERIAL AND METHODS: Information from the clinic database of 4,385 patients commencing CPAP treatment during 2002 2009. RESULTS: Average CPAP adherence was 74%. In mild SDB over 60% were adherent whereas in severe SDB 18% did not accept the treatment. Low hours of CPAP use right after commencing the treatment indicated poor long-term adherence. CONCLUSIONS: In the 2000s the number of patients starting CPAP treatment increased, but the selection of patients did not change much. Overall CPAP adherence was good. PMID- 24340720 TI - Public unhappy over impasse. Polls show ACA divide, disapproval over shutdown. PMID- 24340721 TI - Finding their way home. Despite mixed evidence, providers and payers are adopting patient-centered medical homes to improve health and cut costs. AB - Medical homes are proliferating, though not everyone is convinced they'll produce savings. Don't tell that to the Michigan Blues, which since 2008 has helped more than 1,200 primary-care practices qualify as medical homes, with another 1,000 in the process. The insurer calculates that the project saved it $155 million in 2012 alone. "Those are dollar savings observed in claims data--these are not back of-the-envelope calculations," says Dr. David Share, of the Michigan Blues. PMID- 24340722 TI - Traffic jam. As millions head to exchange websites, government officials race to fix glitches. PMID- 24340723 TI - Counselors' training to help consumers enroll hits roadblocks. PMID- 24340724 TI - Private Medicaid option. Some states eye Ark. alternative expansion model. PMID- 24340725 TI - New drugs carry hefty price tags. Makers of leading-edge orphan products asked to cut prices, take smaller profits. PMID- 24340726 TI - PhRMA sues on 340B orphans. PMID- 24340727 TI - Just the beginning. Growing demand for insurance could lead to transparency, competition. PMID- 24340728 TI - The business of care delivery. Medical practice executives have a billion opportunities to help patients. PMID- 24340729 TI - Law of the land. Bumpy start to exchanges no surprise, but some opponents' tactics outrageous. PMID- 24340730 TI - Moving into the age of data. Outgoing tech czar Mostashari offers thoughts on incentive payments, interoperability, IT centers. Interview by Joseph Conn. PMID- 24340731 TI - Largest medical group practices. PMID- 24340732 TI - Sparking controversy. Rise in e-cigarette use has public health experts questioning their safety, effectiveness as harm-reduction device. AB - The rise of e-cigarettes in the past decade has been accompanied by a debate over the public health consequences of using the devices. Many see them as beneficial. "T'his is basically what I would call a harm-reduction strategy," says Dr. Michael Siegel, a professor of community health sciences at Boston University, comparing e-cigarette use to how methadone is prescribed to heroin addicts. PMID- 24340733 TI - Gaining strength. Actuaries see rise in healthcare spending growth. PMID- 24340734 TI - 'It's long overdue'. Home-care agencies cheer, jeer rule as change nears. PMID- 24340735 TI - Narrowing it down. Systems seeking single supplier for interoperability. PMID- 24340736 TI - Managing population health. Docs look at why it's such a struggle to prevent disease. PMID- 24340737 TI - Obamacare's positive economic news. Improved insurance coverage may be just the boost the economy needs. PMID- 24340738 TI - Physicians and clinical trials. To avoid federal scrutiny, take care when determining fair market value. PMID- 24340739 TI - HIPAA hurdles. New rules pose complex challenges for providers. PMID- 24340740 TI - EHR vendors with most installations in ambulatory-care offices. PMID- 24340741 TI - [The role of biomarkers in diagnostics and forecasting of effectiveness of modern therapy of rheumatoid arthritis]. AB - The rheumatoid arthritis is one of the most severe and widespread systemic inflammatory autoimmune diseases. The modern laboratory diagnostic of rheumatoid arthritis includes detection of large spectrum of biomarkers (autoantibodies, indicators of acute phase of inflammation, cytokines, markers of activation of endothelium, subpopulations of lymphocytes, products of metabolism of bone and cartilaginous tissue, genetic markers) in blood, synovial fluid, and synovial tissue. Alongside with common techniques of immunodiagnostics, the multiplex analysis of biomarkers based on genetic, transcript and proteomic technologies is applied. The results of identification of biomarkers are an important instrument of early diagnostics, activity evaluation, severity of disease course and disease prognosis and effectiveness of applied therapy. Among biomarkers associated with rheumatoid arthritis the most clinical value have antibodies (rheumatoid factor class IgM, antibodies to citrullinized proteins) and acute phase indicators (erythrocyte sedimentation rate, C-reactive protein) which are diagnostic criteria of rheumatoid arthritis and can be used in evaluation of prognosis of this disease. On basis of multi-parametric analysis of 12 key proteins of blood serum the new index of activity of rheumatoid arthritis (Vectra DA) is developed Nowadays, the potential biomarkers are detected providing to implement immunologic monitoring and prognosis of effectiveness of therapy of rheumatoid arthritis with genetic engineering biologic preparations. The laboratory tests are developed to evaluate immunogenicity of genetic engineering biologic preparations and diagnostic of latent tuberculosis infection in patients with rheumatoid arthritis against the background of therapy with using this group of pharmaceuticals. PMID- 24340742 TI - [The placental growth factor and fms-similar tyrosine kinase-1 as markers of pre eclampsy in dynamics of pregnancy]. AB - The article presents reference limits of concentrations of placental growth factor and fms-similar tyrosine kinase-1 and values of their ratio in dynamics of physiologic pregnancy and in female patients with pre-eclampsy of different degree of severity in 1 and III trimesters of pregnancy. It is established that in female patients with pre-eclampsy ratio of fms-similar tyrosine kinase-1 and placental growth factor significantly exceed ratio in female patients with physiological course of pregnancy. The degree of increase of values of ration between fms-similar tyrosine kinase-1 and placental growth factor correlates with degree of severity of pre-eclampsy. PMID- 24340743 TI - [The immunologic disorders and dysfunction of endothelium as predictors of development of hypertrophy of left ventricle of heart in patients with hypertension disease]. AB - The sampling included 231 patient with hypertension disease of stage I-II. The hypertrophy of left ventricle of heart was established in 97 patients (group I) and 134 patients had no hypertrophy of left ventricle of heart (group II). The control group consisted of 25 healthy persons. The increase of tumor necrosis factor alpha and interleukin beta was established in group I as compared with group II and control group. In patients of group I the expressed dysfunction of endothelium was observed. The increase of endothelin I and number of desquamated endotheliocytes as compared with group II and healthy persons was established. The direct relationship between increase of concentration of analyzed cytokines and presence of hypertrophy of left ventricle of heart is revealed. PMID- 24340744 TI - [The cerebral sodium uretric peptide (see text symbol) patients with chronic cardiac insufficiency under decreased and preserved ejection fraction]. AB - The concentration of cerebral sodium uretic peptide was analyzed in patients with chronic cardiac insufficiency and in healthy volunteers. The study established that concentration of cerebral sodium uretic peptide was higher in patients with chronic cardiac insufficiency as compared control group and reflected severity of pathologic process. In patients with decreased ejection fraction the levels cerebral sodium uretic peptide were higher as compared with patients with preserved ejection fraction. According data of the present study the existing threshold of concentration of cerebral sodium uretic peptide has a lower diagnostic sensitivity to exclude chronic cardiac insufficiency (100 pg). PMID- 24340745 TI - [The identification of viruses of human papilloma of high carcinogenic risk and evaluation of physical status of viral DNA using technique of polymerase-chain reaction under affection of cervical epithelium]. AB - The DNA of virus of human papilloma of high carcinogenic risk was detected in 116 cervical samples. At that, the morphological symptoms of background processes are detected in 19 samples, CIN 1 in 9, CIN 2 in 23, CIN 3 in 54 (and out of them carcinoma in situ in 13), epidermoid cancer (squamous cell carcinoma) in 11 cases. The viral load of human papilloma of high carcinogenic risk in all samples of DNA exceeded threshold of clinical value (3 lg copies of DNA of human papilloma/105 cells). The genetic typing of human papilloma of high carcinogenic risk revealed the dominance of human papilloma of type 16 in 49.7%, type 33 in 15.3%, type 31 in 12.3% and type 45 in 5.5%. In women with background processes in cervix of the uterus DNA of human papilloma type 16 was detected more often in episome form. In case of dysplastic alterations of epithelium and cervical cancer DNA of human papilloma type 16 is detected in mixt form with different degree of integration into cell genome. PMID- 24340746 TI - [The autoimmune markers of diabetes]. PMID- 24340747 TI - [The experience of implementation of system of quality management in the Department of Laboratory Diagnostic of the N.V. Sklifosofskiy Research Institute of Emergency Care of Moscow Health Department: a lecture]. AB - The article presents the experience of implementation of system of quality management into the practice of multi-field laboratory of emergency medical care hospital. The analysis of laboratory errors is applied and the modes of their prevention are demonstrated. The ratings of department of laboratory diagnostic of the N. V. Sklifosofskiy research institute of emergency care in the program EQAS (USA) Monthly Clinical Chemistry from 2007 are presented. The implementation of the system of quality management of laboratory analysis into department of laboratory diagnostic made it possible to support physicians of clinical departments with reliable information. The confidence of clinicians to received results increased. The effectiveness of laboratory diagnostic increased due to lowering costs of analysis without negative impact to quality of curative process. PMID- 24340748 TI - [The circulating tumor cells under breast cancer: systems of detection, molecular characteristic and issues of future studies]. PMID- 24340749 TI - [The bacteriophages Yersinia pseudotuberculosis: the detection in strains of different O-serovars and their identification]. AB - The sample included five indicator pseudotuberculosis strains. The application of these strains permitted to isolate out of 161 strains of Y. pseudotuberculosis 9 bacteriophages identical by their morphologic and serologic characteristics but having individual particularities in their lytic activity. The test on sensitivity to bacteriophages can be used in laboratory diagnostic to differentiate the strains of Yersinia pseudotuberculosis. PMID- 24340750 TI - [The Bayesian framework of detection of cariesgenic Streptoccocus in dental plaque in children with distal occlusion under orthodontic treatment]. AB - The application of Bayes theorem in medical diagnostic includes such important step as derivation for every symptom and diagnosis data values of finite or a posteriori probability of presence of germ, for instance S. sanguis, in patients receiving orthodontic treatment. This value expresses importance of the given symptoms for detection of germ presence. In the implemented studies the Bayes theorem was applied to evaluate probability of presence of particular germ in particular concentration (degree of semination, CO) under concrete symptom group. The rates were used to calculate probability of presence of cariesgenic streptococcus S. mutans and S. sanguis in prospect patient. The rates were calculated for the group with fixed orthodontic apparatuses. The high degree of risk of development of caries in children under orthodontic treatment is conditioned by a whole complex of existing unfavorable factors present in oral cavity. Hence, a powerful negative potential to develop expressed cariesgenic situation in oral cavity is present. The analysis of medical data of patients with distal occlusion was applied using Bayes theorem from the point of view their diagnostic value. The study established 36 symptoms, factors, risk factors and background diseases common in case of distal occlusion in children. The probability to detect the mentioned characteristics and likelihood ratio under different degree of concentration of cariesgenic Streptococcus mutans and Streptococcus sanguis in dental plaque of children was considered. The establishment of character of likelihood ratio for different qualitative content of streptococcus in case of isolation from biotope of dental plaque permitted to determine the informative characteristics. The Bayesian model can be applied in clinics as a computer program to process incoming information about patients with distal occlusion under active orthodontic treatment. The developed diagnostic algorithm in a fast and simple mode of clinical detection of caries and determination of concentration of cariesgenic Streptococcus. PMID- 24340751 TI - [The external evaluation of study quality: the role in maintaining the reliability of laboratory information]. AB - The external evaluation of quality of clinical laboratory examinations was gradually introduced in USSR medical laboratories since 1970s. In Russia, in the middle of 1990 a unified all-national system of external evaluation quality was organized known as the Federal center of external evaluation of quality at the basis of laboratory of the state research center of preventive medicine. The main positions of policy in this area were neatly formulated in the guidance documents of ministry of Health. Nowadays, the center of external evaluation of quality proposes 100 and more types of control studies and permanently extends their specter starting from interests of different disciplines of clinical medicine. The consistent participation of laboratories in the cycles of external evaluation of quality intrinsically promotes improvement of indicators of properness and precision of analysis results and increases reliability of laboratory information. However, a significant percentage of laboratories does not participate at all in external evaluation of quality or takes part in control process irregularly and in limited number of tests. The managers of a number of medical organizations disregard the application of the proposed possibilities to increase reliability of laboratory information and limit financing of studies in the field of quality control. The article proposes to adopt the national standard on the basis of ISO 17043 "Evaluation of compliance. The common requirements of professional competence testing". PMID- 24340752 TI - [Working conditions and health among transport drivers in Saint Petersburg]. AB - The authors present data on working conditions and health state among professional transport drives in Saint Petersburg. PMID- 24340753 TI - [Physiological and hygienic grounding 8-hour and 12-hour shifts at process production]. AB - On workplaces of an oil refining factory for an estimation of 8-hour and 12-hour shifts the criterion of tiresomeness of work - speed of decrease in working capacity on hours on hours of the working day. Conditions of the industrial environment, physiological intensity of work (density and rate of labour actions), dynamics of parameters of a functional state of an organism of workers, data about symptoms of acute and chronic weariness were analyzed. It is supposed, that at absence of harmful factors of the industrial environment the opportunity of lengthening of a work day till 12-hour is defined by physiological intensity of work - a combination of duration of the working day and week with density and rate of labour actions. PMID- 24340754 TI - [Study of the effectiveness of drugs in experimental models of poisoning neuropathy in malathion]. AB - For the study developed of the experimental model of toxic neuropathy, using malathion. In this was examined the effectiveness of a course of administration of pharmacological agents with different mechanisms of action: gliatilin, galantamine, memantine, and the recombinant (PRD), nerve growth factor (NGF). From all agents only galantamine, PRD and NGF significantly reduced the degree of impairment of conduction of the sciatic nerve in rats after sub-acute poisoning with malathion. PMID- 24340755 TI - [Occupational myofibrosis - main aspects of clinics, diagnosis and treatment]. AB - Occupational chronic myofibrosis is a disease resulting from physical overstrain and functional overload of upper extremities and shoulder girdle and beeing the most prevalent occupational diseases related to the so-called "working hand". Myofibrosis occur among persons employed actually in all industries, building and agriculture and may develop as an isolated disease or combined with other occupational diseases of musculoskeletal and peripheral nervous systems. Today problems of diagnostics, especially at the early stage of the disease, and the development of knew methods of treatment are still topical. PMID- 24340756 TI - [The importance of behavioral risk factors for bronchopulmonary pathology in copper-nickel industry workers]. AB - The effect of harmful behavioral factors on the development of chronic bronchopulmonary diseases (CBPD) was investigated in 1811 copper-nickel industry workers. The study showed that the most pronounced negative impact on respiratory system was caused by smoking. It manifested itself both by a decrease in the number of healthy individuals and by an increased risk for developing chronic bronchitis and chronic obstructive pulmonary disease. Excessive alcohol consumption and obesity did not significantly affect the development of CBPD. However, when combined with smoking, they potentiate its negative pneumotropic action. It is concluded that early detection and management of modifiable non productive risk factors for CBPD is an effective way to improve the respiratory health of this category of workers. PMID- 24340757 TI - [The problems of classification of the occupational interstitial lung diseases, approaches to solving]. AB - The analysis of the applied in Russia classifications of pneumoconiosis and occupational hypersensitivity pneumonitis in relation to the international classifications of occupational lung diseases and the classification of interstitial lung diseases (ILD) was performed. The necessity of a new approach to the classification of occupational ILD was proved and solutions of the problem were offered. PMID- 24340758 TI - [Path optimization of professional expertise in patients with hearing loss]. AB - The article is devoted to finding ways to optimize the expertise of professional suitability of patients with hearing loss on the basis of practical experience. The paper discusses the need for the revision of the criteria for determining contraindications to continuing to work in noise and other harmful factors on the basis of current evidence-based medicine. PMID- 24340759 TI - [Low-intensity laser radiation in preventive measures]. AB - Results of preventive measures introduction in 524 PC users, 98 jewelry polishers and 64 metallic ship hull assemblers are given. The use of preventive measures, based on low-intensity laser radiation, was shown to prevent development of visual overfatigue and occupational musculoskeletal system diseases. PMID- 24340760 TI - [Opportunity to use the low-level laser therapy in the treatment of the occupational peripheral nervous system diseases (review of literature)]. AB - Occupational diseases of the peripheral nervous system are a wide and heterogeneous group. Until now, the researchers still look for new treatment techniques, because complaints, clinical, instrumental and laboratory findings persist for years even after discontinued occupational exposure to the factors that induced these diseases. The aim of this article is a review of low-intensity laser therapy methods which are used in treatment of various diseases including peripheral nervous system diseases. PMID- 24340761 TI - [Grounds for the procedure of laser projector safety assessment]. AB - Grounds for the procedure of laser projector safety assessment are given. The method allows to measure maximum intensity of diffused and diffusely reflected radiation of laser projectors, irrespective of graphic effects being used. It also makes it possible to standardize the procedure of laser safety assessment, laser devices being used to produce a show. PMID- 24340762 TI - [Medical and biological assessment of preventive drinks use among workers exposed to adverse working conditions]. AB - Studies on the assessment of the effect of treatment-and-preventive drinks, i.e. "Leovit" dietary kissels, and "Zosterin-Ultra" biologically active food additive, on copper, nickel and cobalt ion concentrations in urine and on lead blood concentrations in workers employed at the "Kola Mining Company" limited liability joint-stock company and exposed to long-term metal aerosol effects, were carried out. Dependence of ion concentrations of these metals in biological media on exposure duration was reported. The study findings reveal the advisability of use of the above-mentioned food additives, having detoxication properties, while carrying out preventive measures among workers exposed to heavy metals. PMID- 24340763 TI - [Infrared thermography and electroneuromyography in occupational polyneuropathy diagnosis]. AB - We have evaluated diagnostic value of the combination of infrared thermography and electromyography in professional polyneuropathy diagnosis. 20 patients with working-hand syndrome and 5 controls were enrolled. In 18 cases (90%) both methods were sensitive: on EMG CNV slowing and amplitudes drop were seen, as well as M-response shape changes, and thermography have detected focal hypothermia in hands in some cases and appearance of obscure hypothermia in others. Thus, both methods demonstrated good sensitivity. We recommend using thermography as a screening test and EMG as a following investigation. PMID- 24340764 TI - [On health protection for members of Russian Federation national sports teams]. AB - The article covers main results of activities provided by Federal Medical and Biologic Agency on medical, sanitary and biologic support of Russian Federation national sport teams members. Through example of Bournazian FMBC of FMBA of Russian, Sports Medicine and Rehabilitation Center, the authors represented results of scientific, educational and clinical work of specific establishment in this sphere. PMID- 24340765 TI - [Self-evaluation of health state in athletes]. AB - The article covers scientific basis and elaboration of system concerning self evaluation of athletes' health state. The study comprised 2 steps. During the first step, a group of 62 athletes (45 males and 17 females) performed methods of self-evaluation of health state through a list of changes, tests and stress testing. The second step included processing and generalization of the data obtained and specification of an integral scale of self-evaluation of athletes health state. PMID- 24340766 TI - [Immune state in athletes with mitral valve prolapse]. AB - The authors evaluated immune state in 541 professional athletes. The athletes with vitral valve prolapse (132 subjects) appeared to have immune changes - lower immunoglobulines levels, general leucocytes count, if compared to the athletes without mitral valve prolapse. PMID- 24340767 TI - [Extracorporeal shock wave therapy in athletes with degenerative and dystrophic disorders of locomotory system]. AB - Degenerative and dystrophic changes of joints and ligaments are among the most prevalent disorders in professional athletes. Specification of a complex system for these diseases is an important task in sports medicine. Extracorporeal shock wave therapy is a modern and highly effective method of rehabilitation. PMID- 24340768 TI - [Potential of using inertial sensors in high level sports]. AB - The article thoroughly covers development of wireless inertial sensors technology in medicine. The authors describe main criteria of diagnostic value of inertial sensors, advantages and prospects of using these systems in sports medicine, in comparison with other conventional methods of biomechanical examination in sports medicine. The results obtained necessitate further development of this approach, specifically creation of algorithms and methods of biomechanic examination of highly qualified athletes in high achievements sports. PMID- 24340769 TI - [Cytoprotectors and their application in sports medicine]. AB - The article presents data of literature review on potential use of cytoprotectors in sports medicine (exemplified by Mildronat medication). This group of medications improve metabolism and energy supply in tissues. One of leading indications to Mildronat use is state of low mental and physical performance, including that of athletes. PMID- 24340770 TI - [Influence of frozen-dried antlers of Siberian stags on humoral homeostasis in athletes of cyclic sports]. AB - The authors evaluated effects of antlers of Siberian stags on humoral homeostasis parameters in highly qualified athletes during contest period. Medication based on antlers of Siberian stags provides more balanced operation of energy supplying processes, maintains stable lipid metabolism, favors balance in "prooxidants - antioxidants" system. PMID- 24340771 TI - [Gender analysis of efficiency provided by general bath containing antlers of Siberian stags in skiers]. AB - The authors performed gender analysis of efficiency caused by general bath containing antlers of Siberian stags in athletes engaged into winter sports. Male athletes demonstrated increased physical performance, low RBC membrane response to epinephrine, decreased cortisol level, higher testosterone level and longer time of breath-holding in Stange's test. Female athletes demonstrated no reliable changes in the mentioned parameters. PMID- 24340772 TI - [High technology examination methods in athletes with tricuspidal insufficiency]. AB - The article exemplifies solving problem of permit for coaching and contest in athletes with marked tricuspidal regurgitation. Invasive study analysis of intracardiac hemodynamic parameters at rest and during electrostimulation-induced tachycardia helps to differentiate primary and functional tricuspidal insufficiency, to reveal latent cardiac insufficiency and unfavorable disorders of cardiac rhythm and conductivity. This investigation method has to be used in cases when other modalities are unable to assess the risk of fatal events at the highest submaximal heart rate. PMID- 24340773 TI - [Method of individual evaluation of athletes' tolerance of maximal physical exertion under exposure to changed hypoxic and hypothermal environment]. AB - The article covers a program determining order and method of gradual examination of highly qualified athletes engaged into winter sports in Sports Medicine and Rehabilitation Center in Bournazian FMBC of the FMBA of Russia, to assess physical performance and individual tolerance in changed climate (hypoxic and hypothermal) conditions. PMID- 24340774 TI - [Increased functional resources in athletes of cyclic sports]. AB - The article covers individual coaching program specified by specialists in Sports Medicine and Rehabilitation Center in Bournazian FMBC of the FMBA of Russia, to improve functional durability of highly qualified athletes. PMID- 24340775 TI - [Information technologies in industrial medicine]. AB - The authors describe information technologies for solving problems that are faced by industrial medicine, through modem mathematical methods. These problems include early diagnosis of diseases associated with work conditions, prenosology assessment of workers' health, evaluation of psycho-physiologic adaptation of workers during periodic medical examinations and others. The discussion also covers advantages and limitations of linear (factorial, dicriminant, canonical discriminant, cluster analysis) and nonlinear (artificial neural networks) mathematical methods if used in occupational medicine. PMID- 24340776 TI - Response. PMID- 24340777 TI - Medicare and Medicaid programs: hospital outpatient prospective payment and ambulatory surgical center payment systems and quality reporting programs; Hospital Value-Based Purchasing Program; organ procurement organizations; quality improvement organizations; Electronic Health Records (EHR) Incentive Program; provider reimbursement determinations and appeals. Final rule with comment period and final rules. AB - : This final rule with comment period revises the Medicare hospital outpatient prospective payment system (OPPS) and the Medicare ambulatory surgical center (ASC) payment system for CY 2014 to implement applicable statutory requirements and changes arising from our continuing experience with these systems. In this final rule with comment period, we describe the changes to the amounts and factors used to determine the payment rates for Medicare services paid under the OPPS and those paid under the ASC payment system. In addition, this final rule with comment period updates and refines the requirements for the Hospital Outpatient Quality Reporting (OQR) Program, the ASC Quality Reporting (ASCQR) Program, and the Hospital Value-Based Purchasing (VBP) Program. In the final rules in this document, we are finalizing changes to the conditions for coverage (CfCs) for organ procurement organizations (OPOs); revisions to the Quality Improvement Organization (QIO) regulations; changes to the Medicare fee-for service Electronic Health Record (EHR) Incentive Program; and changes relating to provider reimbursement determinations and appeals. PMID- 24340778 TI - Civilian Health and Medical Program of the Uniformed Services (CHAMPUS)/TRICARE: pilot program for refills of maintenance medications for TRICARE for Life beneficiaries through the TRICARE mail order program. Interim final rule. AB - This interim final rule implements Section 716 of the National Defense Authorization Act for Fiscal Year 2013 which establishes a five year pilot program that would generally require TRICARE for Life beneficiaries to obtain all refill prescriptions for covered maintenance medications from the TRICARE mail order program or military treatment facility pharmacies. Covered maintenance medications are those that involve recurring prescriptions for chronic conditions, but do not include medications to treat acute conditions. Beneficiaries may opt out of the pilot program after one year of participation. This rule includes procedures to assist beneficiaries in transferring covered prescriptions to the mail order pharmacy program. This regulation is being issued as an interim final rule in order to comply with the express statutory intent that the program begin early in calendar year 2013. Public comments, however, are invited and will be considered for possible revisions to this rule for the second year of the program. PMID- 24340779 TI - EnhancEd invasive pneumococcal disease surveillance working group - quarterly surveillance report. PMID- 24340781 TI - NatioNal Notifiable Diseases Surveillance System tables. PMID- 24340780 TI - Meningococcal Surveillance Australia reporting period 1 January to 31 March 2013. PMID- 24340782 TI - Revised surveillance case definitions. PMID- 24340783 TI - Long-term outcome of infantile gratification phenomena. AB - BACKGROUND: Infantile gratification phenomena are self-stimulatory behaviors that are often misdiagnosed as epilepsy. Although the prognosis is thought to be benign, limited long-term follow-up studies exist. This was the objective of our study in addition to exploring the risks of future developmental, behavioral, or neurological abnormalities. METHODS: Series of consecutive infants with gratification phenomena were identified both retrospectively and prospectively over an eight year period from a single pediatric neurology service. The diagnosis was based on descriptive history, review of videotaped events, lack of neurological or developmental abnormalities, and normal routine electroencephalogram. RESULTS: Nineteen infants were followed for 3-11 years (mean 7.1). Their ages ranged between 4-13 months (mean 7) with 79% females. The diagnosis was not reached by the referring physician and 74% were misdiagnosed as epilepsy or movement disorder. The episodes recurred with variable frequency with gradual reduction in number and increase in length of attack-free periods with advancing age. Complete remission was noted in all patients by age 1-3 years (mean 1.9). However, 4 children (21%) developed features of attention deficit hyperactivity disorders (ADHD) on long-term follow up. In this group, the gratification phenomena appeared at a younger age with higher attack frequency. CONCLUSIONS: Gratification phenomena in infants are benign and self-limited, often spontaneously disappearing by two years of age. A correlation with future ADHD was found; however, larger prospective studies are needed to further examine this possible association. PMID- 24340784 TI - Re: Intracranial pressure monitors in traumatic brain injury: a systematic review. Can J Neurol Sci.2012;39:571-576. PMID- 24340785 TI - Re: Intracranial pressure monitors in traumatic brain injury: a systematic review. Can J Neurol Sci.2013;40:433-434. PMID- 24340786 TI - Bacillus thuringiensis poisoning related acute transverse myelitis. PMID- 24340787 TI - Cerebral amyloid angiopathy presenting with TIA-like episodes. PMID- 24340788 TI - [Treatment in children with hearing impairment]. PMID- 24340789 TI - [Diagnosis and treatment for head cancer]. PMID- 24340790 TI - [Diagnosis and treatment for head and neck cancer- knowledge for prevention-]. PMID- 24340791 TI - [Diagnosis and treatment for head and neck cancer-virus association and characterization-]. PMID- 24340792 TI - [Diagnosis and treatment for head and neck cancer-early detection-]. PMID- 24340793 TI - [Diagnosis and treatment for head and neck cancer- current progress of radiotherapy-]. PMID- 24340794 TI - WHO Expert Committee on Biological Standardization. AB - This report presents the recommendations of a WHO expert committee commissioned to coordinate activities leading to the adoption of international recommendations for the production and control of vaccines and other biologicals and the establishment of international biological reference materials. The report starts with a discussion of general issues brought to the attention of the Committee and provides information on the status and development of reference materials for various antibodies, antigens, blood products and related substances, cytokines, growth factors, endocrinological substances and in vitro diagnostic devices. The second part of the report, of particular relevance to manufacturers and national regulatory authorities, contains revised WHO Recommendations for evaluation of animal cell cultures as substrates for the manufacture of biological medicinal products, for production and control of hepatitis B vaccines and for production and control of yellow fever vaccines. New WHO Guidelines on the independent lot release of vaccines are also included. Finally, there is an update to the procedure for the prequalification of vaccines. Also included are lists of Recommendations, Guidelines and other documents related to the manufacture and control of biological substances used in medicine, and of International Standards and Reference Reagents for biological substances. PMID- 24340795 TI - Relationships among refraining from catastrophic thinking, worrying, and metacognitive beliefs. AB - The Refraining from Catastrophic Thinking Scale is a self-report measure that assesses the perceived skills to detach from and to suspend negative thinking that were fostered in cognitive behavioral therapy. This study examined the relationships between this scale and the variables in Wells' metacognitive model of emotional disorders, and worrying. A survey of 470 students revealed that the Refraining from Catastrophic Thinking was negatively related to negative metacognitive beliefs about worrying, and that it explained additional variance in worrying beyond the existing metacognitive variables. Therefore, the Refraining from Catastrophic Thinking is unique in predicting worrying and has a meaningful relationship with metacognitive beliefs. It may thus be a useful tool for examining therapeutic change in metacognitive and related therapies. PMID- 24340796 TI - Measuring Maslow's hierarchy of needs. AB - Two scales have been proposed to measure Maslow's hierarchy of needs in college students, one by Lester (1990) and one by Strong and Fiebert (1987). In a sample of 51 college students, scores on the corresponding scales for the five needs did not correlate significantly and positively, except for the measures of physiological needs. Furthermore, there was limited support for Maslow's hypothesis that need deprivation would predict psychopathology (specifically, mania and depression). PMID- 24340797 TI - Autobiographical memory, mental disorders, and emotional valence: comment on Young, et al. (2012). AB - Young, Erickson, and Drevets (2012) reported that positive and neutral cue words elicited less positive memories among patients with major depression than among healthy controls, while memories from patients were less specific than those from controls, regardless of their intrinsic valence. These results suggested methodological refinements that may shed light on several aspects of autobiographical memory impairment in mental disorders. PMID- 24340798 TI - Exploring individual differences in children's mathematical skills: a correlational and dimensional approach. AB - Individual differences in mathematical skills are typically explained by an innate capability to solve mathematical tasks. At the behavioural level this implies a consistent level of mathematical achievement that can be captured by strong relationships between tasks, as well as by a single statistical dimension that underlies performance on all mathematical tasks. To investigate this general assumption, the present study explored interrelations and dimensions of mathematical skills. For this purpose, 68 ten-year-old children from two schools were tested using nine mathematics tasks from the Basic Knowledge in Mathematics Test. Relatively low-to-moderate correlations between the mathematics tasks indicated most tasks shared less than 25% of their variance. There were four principal components, accounting for 70% of the variance in mathematical skill across tasks and participants. The high specificity in mathematical skills was discussed in relation to the principle of task specificity of learning. PMID- 24340799 TI - Regional analysis of big five personality factors and suicide rates in Russia. AB - Extending cross-national and intranational studies on possible aggregate-level associations between personality dimensions and suicide prevalence, this study examined the associations of the Big Five personality factors and suicide rates across 32 regions of the Russian Federation. Failing to replicate one key finding of similar geographic studies, namely, a correspondence of higher suicide rates with lower Agreeableness and Conscientiousness (i.e., higher Psychoticism) scores, higher suicide rates corresponded to higher Agreeableness scores. This effect was obtained with one available data source (regional-level Big Five ratings based on the National Character Survey), but not with another (based on the NEO-PI-R measure). All in all, regional suicide rates across Russia were dissociated from regional variation in personality dimensions. PMID- 24340800 TI - Parity influences the difficulty of simple addition and subtraction but not multiplication problems in children. AB - In the present paper, the results of early 20th century studies of children's difficulties with basic addition, subtraction, and multiplication problems are analyzed for parity effects. Parity influenced the difficulty of addition and subtraction problems, tasks in which any parity influence must be implicit, but did not influence difficulty of multiplication problems. Solution of multiplication problems relies to a greater extent on retrieval of rote-memorized answers. Addition and subtraction problems rely more on non-retrieval strategies. It is these latter strategies that depend on internal representations sensitive to the parity status of the numbers being processed. That parity affected responding in tasks where parity was irrelevant and no overt motor responses were made poses problems for the Markedness of Response Codes (MARC) and polarity explanations of parity effects in reaction time. Both these explanations require that an explicit parity judgment indicated by a binary motor response be made for a parity effect to be seen. PMID- 24340801 TI - Sex differences in the development of perceived family cohesion and depressive symptoms in Taiwanese adolescents. AB - This study investigates the progression of family cohesion perceptions and depressive symptoms during the character development stage in adolescents. Data were used from the Taiwan Youth Project. The final sample comprised 2,690 adolescents with 1,312 girls (48.8%; M age = 13.0 yr., SD = 0.5). Latent curve growth analysis was employed to explore these developments. Seventh-grade girls reported greater family cohesion and more depressive symptoms than boys, and boys reported greater growth in family cohesion than girls. However, progression of depressive symptoms was not associated with the child's sex. Higher perceived family cohesion in Grade 7 correlated with less increase of depressive symptoms from Grades 9 to 11. The long-term positive influence of family cohesion on depressive symptoms is discussed. PMID- 24340802 TI - Reactions of religious fundamentalists to taboo images and words. AB - Some view religious fundamentalism as inclusive of fear of the world as a dangerous place. Fundamentalists are known to have extensive taboo lists, but research concerning their reactions to taboo stimuli is sparse. If fear is a basic component of fundamentalism, then reactions to taboo stimuli should be somewhat similar to common fear reactions, including subjective appraisal of discomfort, psychophysiological arousal, cognitive interference, and behavioral avoidance. The current research addressed some of these questions with three studies to examine subjective discomfort to religiously-taboo and religiously neutral words and photographs (N = 160), physiological arousal to these same photographs (N = 129), and attentional bias on a modified Stroop test of these same words (N = 182). Although subjective appraisals of discomfort to taboo words and photographs among fundamentalists were confirmed, this research did not find that physiological responses or cognitive interference to taboo stimuli were elevated in those scoring high in religious fundamentalism. PMID- 24340803 TI - The effect of facial makeup on the frequency of drivers stopping for hitchhikers. AB - Judgments of photographs have shown that makeup enhances ratings of women's facial attractiveness. The present study assessed whether makeup affects the stopping behavior of drivers in response to a hitchhiker's signal. Four 20- to 22 year-old female confederates wore facial makeup, or not, while pretending to be hitchhiking. Frequency of stopping was compared in 1,600 male and female drivers. Facial makeup was associated with an increase in the number of male drivers who stopped to offer a ride. Makeup did not affect frequency of stopping by female drivers. PMID- 24340804 TI - Regional intelligence and suicide rate in Germany, revisited. AB - Across the 10 westerly and 6 easterly states of Germany, better-than-average school-end grades, taken as a proxy for intelligence, corresponded to higher regional suicide rates. This finding adds to similar evidence from other countries (Austria, Belarus, British Isles, Denmark, Netherlands, and USA), suggestive of positive ecologic (group-level) associations between indicators for cognitive ability and suicide prevalence, whilst offsetting prior inconclusive evidence for Germany from Voracek (2006) on the same question. PMID- 24340805 TI - Responding to moral dilemmas: the roles of empathy and collectivist values among the Chinese. AB - The present study assessed how empathy and vertical collectivism are related to moral competency in a sample of Hong Kong Chinese university students (N = 153; 70 men, 83 women). The Emotional Tendency Scale, Individualism-Collectivism Scale, and Moral Judgment Test were used to quantify empathy, vertical collectivism, and moral competency, respectively. Results showed that empathy was not statistically significantly correlated with moral judgment. The interaction of vertical collectivism and empathy predicted a theoretically important portion of the variance in moral competency. The role of culture in moral development was discussed. PMID- 24340806 TI - Rationality in conspiracy beliefs: the role of perceived motive. AB - Previous work has raised the possibility that the perception of motive may contribute to conspiracy beliefs. The current study tested the prediction that conspiracy beliefs will strengthen as the apparent motive of the alleged conspirators strengthens. Participants (N = 57) rated the plausibility of fictional conspiracy theories, manipulated for the strength of direct evidence for the conspiracy and the type of outcome (gain vs. no gain) experienced by the alleged conspirators after the event. Ratings revealed that participants were more likely to believe conspiracy claims not only if the evidence was strong but also if the apparent motive was high, and that the effect of apparent motive was independent of the strength of the evidence. The findings suggested that information about apparent motive may help create and sustain conspiracy beliefs. PMID- 24340807 TI - Relationships between individual differences in motivation and borderline personality disorder, psychopathy, and maladjustment. AB - Two studies investigate relationships between individual differences in motivation and borderline personality disorder, psychopathy, and maladjustment. Participants completed the Brief Assessment of Individual Motives 1--Revised, a measure of 15 putative evolved motives (i.e., "traits of action"). In Study 1, N = 147 adult participants also completed the Borderline Personality Questionnaire and Self-Report Psychopathy III Questionnaire (SRP III). In Study 2, N = 135 college age participants also completed the SRP III and the Counseling Center Assessment of Psychological Symptoms-62. Regression analyses suggested that individual differences in motivational traits account for moderate amounts of variance in measures of antisocial personality disorder, psychopathy, and maladjustment. They also suggested that lower motivation to engage in cooperative behaviors (e.g., sharing resources and forming coalitions) is related to impaired interpersonal relationships and maladjustment. PMID- 24340808 TI - Consumer hypnotic-like suggestibility: possible mechanism in compulsive purchasing. AB - The authors hypothesize a concept, Consumer Hypnotic-Like Suggestibility (CHLS), defined as an altered state of consciousness, as a state causing a tendency to respond positively to messages aimed at inducing consumers to make unplanned purchases. This study aims to investigate the associations of CHLS with interpersonal variables and compulsive purchasing--a frequent and uncontrollable preoccupation with buying or impulses to buy. A study was conducted on a sample of 232 subjects (n = 111 men; M age = 41 yr.), through the administration of a questionnaire, which measured: CHLS, compulsive purchasing, consumer susceptibility to interpersonal influence (the necessity to enhance one's image in the opinion of others through the consumption of products), and consumer atmospherics, i.e., environmental stimuli known to influence purchasing decisions. Modeling and mediation analyses suggested that internal and external drivers--Consumer Susceptibility to Interpersonal Influence and atmospherics--are positively related to CHLS which affects compulsive purchasing. PMID- 24340809 TI - Educational attainment and self-rated health status among single mothers in rural Alabama. AB - Using previous data from a random sample of 300 single mothers from rural Alabama, multiple regression analysis indicated that food insecurity and employment status had a modest effect on self-rated health status, while educational attainment and income had the greatest effect. These variables explained 29% of the variance in health status. Social and economic policies that affect educational attainment and income distribution may have important consequences for health status in these rural areas. PMID- 24340810 TI - Internal marketing, customer orientation, and organizational commitment: moderating effects of work status. AB - Associations among internal marketing, customer orientation, and organizational commitment were examined, particularly with regard to the moderating effects of work status on the relationships between internal marketing and customer orientation or organizational commitment, in a cross-sectional design with structural equation modeling. Two studies (Ns = 119 and 251) were conducted among full- and part-time service employees at Taipei Sports Centers. Internal marketing was associated with organizational commitment and customer orientation. Customer orientation was associated with organizational commitment and partially mediated the relation between internal marketing and organizational commitment. Furthermore, work status significantly moderated the relationships between internal marketing and customer orientation but not between internal marketing and organizational commitment. Implications and directions for future research were discussed. PMID- 24340811 TI - Effects of approach-avoidance training on implicit and explicit evaluations of neutral, angry, and smiling face stimuli. AB - A growing body of evidence shows that the prolonged execution of approach movements towards stimuli and avoidance movements away from them affects their evaluation. However, there has been no systematic investigation of such training effects. Therefore, the present study compared approach-avoidance training effects on various valenced representations of one neutral (Experiment 1, N = 85), angry (Experiment 2, N = 87), or smiling facial expressions (Experiment 3, N= 89). The face stimuli were shown on a computer screen, and by means of a joystick, participants pulled half of the faces closer (positive approach movement), and pushed the other half away (negative avoidance movement). Only implicit evaluations of neutral-expression were affected by the training procedure. The boundary conditions of such approach-avoidance training effects are discussed. PMID- 24340812 TI - Similarity facilitates relationships on social networks: a field experiment on facebook. AB - People interact more readily with someone with whom they think they have something in common, but the effect of an incidental similarity has never been examined on social networks. Facebook users were contacted by a stranger who also possessed a Facebook page and who asked them to become his friend. The request message contained one item of similarity, two items of similarity, or none. Compliance to the request was the dependent variable. Increased compliance to the request was found when comparing the two similarity conditions with the control no-similarity condition. However, no difference was found between the two similarity conditions. Similarity appears to foster relationships on social networks. PMID- 24340813 TI - What can we learn from studies based on small sample sizes? Comment on Regan, Lakhanpal, and Anguiano (2012). AB - In a recent article, Regan, Lakhanpal, and Anguiano (2012) highlighted the lack of evidence for different relationship outcomes between arranged and love-based marriages. Yet the sample size (n = 58) used in the study is insufficient for making such inferences. This reply discusses and demonstrates how small sample sizes reduce the utility of this research. PMID- 24340814 TI - Chinese children's predictions of emotion in rule situations. AB - This study investigated children's predictions in contexts in which desires conflict with forbidden rules. Forty-eight children participated: 4-year-olds, 5 year-olds, and 7-year-olds, with 8 boys and 8 girls in each group. The children listened to stories and were asked to predict behaviors and emotions. The story portrayed one child who wanted to engage in an activity in a certain domain (personal or prudential), but an authority (adult or peer) prohibited him/her from doing so. Only 5- and 7-year-olds predicted more positive emotions for breaking the rule and more negative emotions for complying with the rule in the personal domain than in the prudential domain. The results indicated that older children differentiated the personal domain from the prudential domain. Older children can differentiate adult authority from peer authority. When rules were given by an adult authority, 7-year-olds predicted more positive emotions for transgression and more negative emotions for compliance than when the rules were given by peer authority. Four- and 5-year-olds' predictions did not differ when rules were stated by either of the two authorities. PMID- 24340815 TI - Semantic and affective verbal fluency: sex differences. AB - Sex may have an important influence on verbal fluency. The aim of this study is to examine possible sex differences in different types of verbal fluency. Four tasks of verbal fluency were used in this study: two tasks of semantic verbal fluency (Animals, Fruits) and two tasks of affective verbal fluency (Pleasant, Unpleasant). The results were analysed for 200 adults aged 18 to 70 years. The number of correctly enumerated words, the number of phonemic clusters, the number of semantic clusters, and the number of phonemic and semantic switches were recorded. The results confirmed data about sex differences in verbal fluency performance. Statistically significant differences in verbal fluency between men and women were found only in affective tasks. Sex is not a strong predictor of semantic verbal fluency performance, but a statistically significant predictor for negative affective verbal fluency. PMID- 24340816 TI - Making inferences about intention: perceptual control theory as a "theory of mind" for psychologists. AB - Theory of Mind (ToM) assumes that humans and possibly other primates understand behavior in terms of inferences about intentions. While there is evidence that primates make such inferences, little attention has been paid to the question of their validity. In order to answer this question it is necessary to know the true intentions underlying behavior. The present paper shows that Perceptual Control Theory can provide a scientific basis for making such determinations using methods derived from control engineering. These methods--called the "Test for the Controlled Variable" (TCV)--are based on the assumption that intentional behavior is equivalent to the process of control. The TCV provides an objective approach to inferring the intentions underlying behavior in terms of the perceptual variables under control and the goal states of those variables. Thus, Perceptual Control Theory represents an empirical ToM for psychologists--one that can be used to understand behavior in terms of inferences about intention that are based on the results of active experimentation rather than passive observation. PMID- 24340817 TI - An Arabic version of the effort-reward imbalance questionnaire: translation and validation study. AB - An Arabic version of the Effort-Reward Imbalance Questionnaire was developed and validated through a translation process with cross-cultural considerations. The translated questionnaire was evaluated for reliability and validity. A Principal Components Analysis was conducted following assessment of the suitability of data for factor analysis. Components with high eigenvalues were extracted, followed by Varimax rotation. Three components with eigenvalues greater than 1.0 (50% of variance) were indicated. The analysis showed Cronbach's alpha coefficients of .82 for the Effort scale, .88 for the Reward scale, and .74 for the Overcommitment scale. The test-retest reliability was high with intra-correlation coefficients of > or = .86. The Arabic version of the Effort-Reward Imbalance Questionnaire showed adequate reliability and validity and is a suitable instrument to assess work stress in Arabic-speaking people. PMID- 24340818 TI - Longitudinal stability of IRT and equivalent-groups linear and equipercentile equating. AB - A multiscale criterion-referenced test that featured two presumably equivalent forms (A and B), was administered to 1,667 Head Start children at each of four points over an academic year. Using a randomly equivalent groups design, three equating methods were applied: common-item IRT equating using concurrent calibration, linear transformation, and equipercentile transformation. The methods were compared by examining mean score differences, weighted mean squared difference, and Kolmogorov's D statistics for each subscale. The results indicated that over time the IRT equating method and conventional equating methods exhibited different patterns of discrepancy between the two test forms. IRT equating yielded marginally smaller form-to-form mean score differences and generated slightly fewer distributional discrepancies between Forms A and B than both linear and equipercentile equating. However, the results were mixed indicating that more studies are needed to provide additional information on the relative merits and weaknesses of each approach. PMID- 24340819 TI - Menarche and eating disorders. AB - 160 undergraduate women (M age = 20.3, SD = 1.52) were assessed for depression, drug abuse, and eating disorders. The age of menarche was positively correlated with higher scores on a screening measure for eating disorders, a finding opposite to past studies for adolescent girls. PMID- 24340820 TI - Death distress among two samples of lower and higher stress in health care professionals. AB - A convenience sample of 195 volunteer nurses working in different medical departments was recruited (77 Kuwaiti, 118 non-Kuwaiti from 10 countries; 55 men, 140 women; ages 25 to 51 years). Participants responded in English to the Arabic Scale of Death Anxiety, the Death Depression Scale, the Death Obsession Scale, and the Reasons for Death Fear Scale. Pearson correlations between the four scales were statistically significant and positive. The only significant sex difference was on the Death Depression Scale with men reporting more stress. It was also found that nurses dealing with critical cases and working in higher stress departments (Intensive Care Unit and Heart Department) obtained higher mean scores on the Death Depression Scale, Death Obsession Scale, and Reasons for Death Fear Scale than their counterparts working in lower stress departments such as internal medicine. It was concluded that working in higher stress nursing departments affected death distress. Nurses with high scores on death distress may benefit from a thanatopsis program. There is reason to believe that this may ameliorate relations with patients. PMID- 24340821 TI - Materialism and addictive buying in women: the mediating role of anxiety and depression. AB - There is empirical evidence regarding the interrelationships between materialism, negative emotions, and addictive buying. The aim of this study was to clarify the direction of the relationships among these variables. Specifically, the main objective was to explore the possible mediating roles of anxiety and depression in the link between materialism and addictive buying. Path analysis results, using a sample of 685 women, generally supported the suitability of the proposed model in which anxiety and depression mediated the effects of the materialism dimensions, "importance" and "success," on addictive buying, and that depression also mediates the influence of the "importance" and "happiness" dimensions. Moreover, a direct effect of the importance dimension on addictive buying was found. PMID- 24340822 TI - A pilot study of the relation between humor styles and the past-positive and past negative time perspectives. AB - Those who use self-enhancing and affiliative humor styles tend to recall positive experiences with their parents and primary caretakers, whereas those who use the self-defeating humor style tend to recall negative experiences with them. Considering the importance of experiences with parents and primary caretakers for life satisfaction and happiness, it was hypothesized that the affiliative and self-enhancing humor styles would be positively correlated with past-positive experiences and negatively correlated with past-negative experiences, and that the self-defeating humor style would be positively correlated with past-negative experiences and negatively correlated with past-positive experiences. The Humor Styles Questionnaire and the Past-Positive and Past-Negative subscales of the Zimbardo Time Perspective Inventory were administered to 114 undergraduates. The hypotheses were partially supported despite the retrospective nature of the Past Positive and Past-Negative Subscales and the correlational nature of the study, indicating further research is needed. PMID- 24340824 TI - No sisyphean task: how the FDA can regulate electronic cigarettes. AB - The adverse effects of smoking have fostered a natural market for smoking cessation and smoking reduction products. Smokers attempting to quit or reduce consumption have tried everything: "low" or "light" cigarettes; nicotine-infused chewing gum, lozenges, and lollipops; dermal patches; and even hypnosis. The latest craze in the quest to find a safer source of nicotine is the electronic cigarette. Electronic cigarettes (e-cigarettes) have swept the market, reaching a rapidly expanding international consumer base. Boasting nicotine delivery and the tactile feel of a traditional cigarette without the dozens of other chemical constituents that contribute to carcinogenicity, e-cigarettes are often portrayed as less risky, as a smoking reduction or even a complete smoking cessation product, and perhaps most troubling for its appeal to youth, as a flavorful, trendy, and convenient accessory. The sensationalism associated with e-cigarettes has spurred outcry from health and medical professional groups, as well as the Food and Drug Administration (FDA), because of the unknown effects on public health. Inhabiting a realm of products deemed "tobacco products" under recent 2009 legislation, e-cigarettes pose new challenges to FDA regulation because of their novel method of nicotine delivery, various mechanical and electrical parts, and nearly nonexistent safety data. Consumer use, marketing and promotional claims, and technological characteristics of e-cigarettes have also raised decades old questions of when the FDA can assert authority over products as drugs or medical devices. Recent case law restricting FDA enforcement efforts against e cigarettes further confounds the distinction among drugs and medical devices, emerging e-cigarette products, and traditional tobacco products such as cigarettes, cigars, and smokeless tobacco. This Article investigates the e cigarette phenomenon in the wake of the recently enacted Family Smoking Prevention and Tobacco Control Act of 2009 (TCA). It examines the tumultuous history of attempts at tobacco regulation by reflecting on the history of Congressional activity to regulate tobacco sales and promotion. Furthermore, this Article suggests a feasible approach to strengthening regulation of e-cigarettes under the existing statutory framework. This approach includes increased scrutiny of manufacturer and distributor claims that trigger drug and medical device provisions, utilization of new tobacco product and modified risk tobacco product provisions, and promulgation of new FDA regulations and guidance specifically directed at e-cigarettes. PMID- 24340823 TI - The Affordable Care Act and the Medicare program: the engines of true health reform. AB - The Patient Protection and Affordable Care Act and its amendments by the Health Care and Education Reconciliation Act of 2010 constitute landmark legislation known as the Affordable Care Act (ACA). The ACA has made many changes in the Medicare program as part of comprehensive health reform for the U.S. health care sector. Title III of the ACA pertains to improving the efficiency and quality of health care. Title VI calls for greater program integrity for all federally funded health insurance programs. Collectively, the changes in Medicare in these two titles address the three major problems that the Medicare program has faced since its inception: cost and volume inflation, quality assurance, and fraud and abuse. These changes, if successfully implemented, will have a dramatic impact on the reform of the American health care sector. The policy-making process in the Medicare program is exemplary of the process of "muddling through," as described by the Yale economist Charles E. Lindblom. Nevertheless, these changes may also prepare the Medicare program to be transformed, through several incremental changes in upcoming years, into a single payer system. PMID- 24340825 TI - EPCRA: a retrospective on the environmental Right-to-Know Act. AB - October 2011 marked the 25th Anniversary of the Emergency Planning and Community Right-to-Know Act (EPCRA), which was celebrated for its "significant role in protecting human health and the environment over the last quarter century by providing communities and emergency planners with valuable information on toxic chemical releases in their area." This Note aims to evaluate the effectiveness of three important provisions of the statute-the Toxics Release Inventory, the emergency planning mandate, and the citizen suit provision-through a case study of their implementation in Institute, West Virginia, the site of an industrial accident that prompted the enactment of EPCRA in 1986. This Note argues that although EPCRA made significant improvements to industry transparency in terms of its production and release of hazardous substances, there remain significant barriers concerning adequate resources, informational tools, and enforcement measures. These challenges must be addressed to ensure that citizens are provided with equitable opportunities to inform and ultimately protect their communities from health and environmental hazards. Through interviews with Institute residents and members of a local community advocacy group, along with analyses of the current informational tools available to the public under the statute, the Note will discuss specific challenges facing industrial communities, and offer a series of practical and legal solutions to increase the effectiveness of the statute, particularly in the most economically and politically vulnerable communities. PMID- 24340826 TI - Reproductive medicine and the law: egg donation in Germany, Spain and other European countries. AB - This paper analyzes the key legal issues raised by Reproductive Medicine practiced in Europe, with special attention to the rules prevailing in countries such as Germany and Spain. Thus, the paper involves a detailed study of the regulation in force in those countries, comparing their solutions with the rules adopted in other EU countries. It also highlights the high risk of com modification in oocyte donation. In light of this, the differences between the laws of EU countries -some of them, very restrictive with prohibitions or requirements for recipient women and others more permissive with the use of reproductive technologies- can lead to a "reproductive tourism" between countries, as indeed is happening nowadays. PMID- 24340827 TI - [The right to human reproduction. Should surrogate maternity be allowed?]. AB - Is addressed in this work if you can accept that in Spain a reproductive rights through the use of assisted reproductive techniques, especially when the client is a single woman and when the baby has undergone a substitution pregnancy or surrogacy, regardless of those who have come to this possibility, which still continues to be considered without any efficacy in the rules governing the matter. PMID- 24340828 TI - [International regulation of ethics committees on biomedical research as protection mechanisms for people: analysis of the Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research of the Council of Europe]. AB - The article explores and analyses the content of the Council of Europe's Additional Protocol to the Convention on Human Rights and Biomedicine concerning Biomedical Research regarding the standard legal instrument in biomedical research, issued by an international organization with leadership in bioethics. This implies ethics committees are mechanisms of protection of humans in biomedical research and not mere bureaucratic agencies and that a sound inescapable international regulatory framework exists for States to regulate biomedical research. The methodology used focuses on the analysis of the background, the context in which it is made and the nature and scope of the Protocol. It also identifies and analyses the characteristics and functions of ethics committees in biomedical research and, in particular, the information that should be provided to this bodies to develop their functions previously, during and at the end of research projects. This analysis will provide guidelines, suggestions and conclusions for the awareness and training of members of these committees in order to influence the daily practice. This paper may also be of interest to legal practitioners who work in different areas of biomedical research. From this practical perspective, the article examines the legal treatment of the Protocol to meet new challenges and classic issues in research: the treatment of human biological samples, the use of placebos, avoiding double standards, human vulnerability, undue influence and conflicts of interest, among others. Also, from a critical view, this work links the legal responses to develop work procedures that are required for an effective performance of the functions assigned of ethics committees in biomedical research. An existing international legal response that lacks doctrinal standards and provides little support should, however, serve as a guide and standard to develop actions that allow ethics committees -as key bodies for States- to advance in the protection of humans in biomedical research. PMID- 24340829 TI - "Adios Sui Generis": a study of the legal feasibility of the sui generis right in the context of research biobanks. AB - The European protection of databases has been criticized for having a negative impact on the scientific development and the process of discovery. In the paper it is checked whether one of the most important research infrastructures, such as biobanks, could be entitled with the sui generis right as shaped within the current European legal system. PMID- 24340830 TI - [Ruling of the Inter-American Court of Human Rights, the Case of Artavia Murillo et al (in vitro fertilization) v. Costa Rica; new hopes for the reproductive freedom in Latin America]. AB - Modern reproductive technology has not been completely accepted and, especially in-vitro fertilization, IVF has generated serious social, political and legal controversies in Latin America. We may distinguish two trends that show us the oppositions; on one hand, the primacy of the embryo's live and its protection during artificial reproductive process and on the other, the primacy of liberal access to assisted reproduction techniques. The debate came to the fore, after a ruling by the Costa Rica's Constitutional Chamber who banned de IVF in 2000. The damaged couples after fulfilling the process toward the Inter-American Commission on Human Rights, present a petition to the Inter-American Court of Human Rights. The Court's sentence and its arguments will be the subject of these comments as well that will allow to considered that both of them should be considered as a very important step towards the construction of a secular liberal vision over the assisted reproduction in Latin America. PMID- 24340831 TI - [Human genes patents: yes or no? Reflections on the ruling of the Supreme Court of the United States]. AB - In the present work, the opinion of the Supreme Court of the United States (13 june 2013) on patentability of human genes is analyzed (No. 12-398, Association for Molecular Pathology et al. v. Myriad Genetics, Inc. et al) in relation to the BRCA1 and BRCA2 genes which predispose women to breast cancer and ovarian cancer. The legal status in the European Union and in Spain is also analyzed. PMID- 24340832 TI - Synthetic biology between challenges and risks: suggestions for a model of governance and a regulatory framework, based on fundamental rights. AB - This paper deals with the emerging synthetic biology, its challenges and risks, and tries to design a model for the governance and regulation of the field. The model is called of "prudent vigilance" (inspired by the report about synthetic biology, drafted by the U.S. Presidential Commission on Bioethics, 2010), and it entails (a) an ongoing and periodically revised process of assessment and management of all the risks and concerns, and (b) the adoption of policies - taken through "hard law" and "soft law" sources - that are based on the principle of proportionality (among benefits and risks), on a reasonable balancing between different interests and rights at stake, and are oriented by a constitutional frame, which is represented by the protection of fundamental human rights emerging in the field of synthetic biology (right to life, right to health, dignity, freedom of scientific research, right to environment). After the theoretical explanation of the model, its operability is "checked", by considering its application with reference to only one specific risk brought up by synthetic biology - biosecurity risk, i.e. the risk of bioterrorism. PMID- 24340833 TI - Supreme Court of the United States syllabus. Association for Molecular Pathology et al. v. Myriad Genetics, Inc., et al. certiorari to the United States Court of Appeals for the Federal Circuit. PMID- 24340834 TI - Decreased nocturnal glucose variability in non-diabetic patients with sleep apnea: a pilot study. AB - BACKGROUND: Obstructive sleep apnea has been sho be associated with impaired glucose metabolism and overt diabetes mellitus. However, the effect of hypoxic episodes on nocturnal glucose regulation in non-diabetic patients is unknown. OBJECTIVES: To investigate the effect of hypoxemia and nocturnal glucose homeosatsis in non-diabetic patients with sleep apnea. METHODS: Seven non diabetic patients with moderate to severe sleep apnea were connected to a continuous glucose-monitoring sensor while undergoing overnight polysomnography. Mean SpO2 and percentage of time spent at SpO2 90% were recorded. The correlation between mean glucose levels, the difference between consecutive mean glucose measurements (glucose variability) and the corresponding oxygen saturation variables were determined in each patient during REM and non-REM sleep. RESULTS: No consistent correlation was found forthe individual patient between oxygen saturation variables and glucose levels during sleep. However, a lower mean SpO2 correlated with decreased glucose variability during sleep (r = 0.79, P = 0.034). This effect was primarily evident during REM sleep in patients with significant, compared to those with mild, oxygen desaturations during sleep (> 30% vs. < 10% of sleeping tim spent with SpO2 < 90%) (P = 0.03). CONCLUSIONS: Severe nocturnal hypoxemia in non-diabetic patients with moderate to severe sleep apnea might affect glucose regulation primarily during REM sleep. PMID- 24340835 TI - Long-term clinical and echocardiographic follow-up of the freestyle stentless aortic bioprosthesis: the Tel Aviv Medical Center experience. AB - BACKGROUND: Stentless aortic bioprostheses were designed to provide improved hemodynamic performance and potentially better survival. OBJECTIVES: To report the outcomes of patients after aortic valve replacement with the Freestyle stentless bioprosthesis at the Tel Aviv Medical Center followed for < or = 15 years. METHODS AND RESULTS: Between 1997 and 2011, 268 patients underwent primary aortic valve replacement with a Freestyle bioprosthesis, 211 (79%) of them in the sub-coronary position. Mean age, Charlson comorbidity index and Euro-score were 71.0 +/- 9.2 years, 4.2 +/- 1.5 and 10.2 +/- 11 respectively, and 156 (58%) were male. Peak and mean trans-aortic gradient decreased significantly (75.0 +/- 29.1 vs. 22.8 +/- 9.6 mmHg, P < 0.0001; and 43.4 +/- 17.2 vs. 12.1 +/- 5.4 mmHg, P < 0.0001 respectively) during 3 months of follow-up. Mean overall follow-up was 4.9 +/- 3.1 years and was complete in all patients. In-hospital mortality was 4.1% (n=11) but differed significantly between the first 100 patients operated before 2006 and the last 168 patients operated after January 2006 (8 vs. 3 patients, 8.0% vs. 1.8%, P = 0.01). Overall, 5 and 10 year survival rates were 85 +/- 2.5% and 57.2 +/- 5.7%, respectively. Five year survival was markedly improved in patients operated after January 2006 compared to those operated in the early years of the experience (92.3 +/- 2.3% vs. 76.0 +/- 4.4%, P = 0.0009). All the 21 octogenarians operated after January 2006 survived surgery, with excellent 5 year survival (85.1 +/- 7.9%). Six patients required reoperation during follow-up: structural valve deterioration in five and endocarditis in one. CONCLUSIONS: Aortic valve replacement with the Freestyle bioprosthesis provides good long-term hemodynamic and clinical outcomes, even in octogenarians. Valve calcification is the major (and rare) mode of valve deterioration leading to reoperation in these patients. PMID- 24340836 TI - Association of the M3151 variant in the transient receptor potential vanilloid receptor-1 (TRPV1) gene with type 1 diabetes in an Ashkenazi Jewish population. AB - BACKGROUND: Type 1 diabetes in humans is an autoimmune disease in which Tcells target pancreatic islets of Langerhans, leading to the progressive destruction of the insulin-producing beta cells. Both genetic and environmental factors contribute to the development of autoimmune diabetes. The non-obese diabetic (NOD) mouse model of human type 1 diabetes demonstrates two missense mutations in the transient receptor potentialvanilloid receptor-1 (TRPVi) gene. OBJECTIVES: To investigate whether polymorphism in the TRPV1 gene may play a role in the predisposition to human type 1 diabetes. METHODS: We genotyped 146 Ashkenazi Jewish type 1 diabetic patients and 205 Ashkenazi Jewish healthy controls for the rs222747 (M3151), rs224534 (T4691) and rs8065080 (1585V) variants of the TRPV1 gene. RESULTS: There was a significant increase in the rs222747 (M3151) variant of the TRPV1 gene in the type 1 diabetes cohort compared to the control: rs222747 (M3151) homozygous: (61% vs. 48.3%, P = 0.02). Logistic regression analysis revealed that type 1 diabetes was significantly associated with rs222747 (M3151), such that having diabetes increased the odds of rs222747 homozygosity (M3151) by 67.2%, odds ratio 1.6, 95% confidence interval 1.08-2.57, P < 0.02. No difference was found in the rs224534 (T4691) and rs8065080 (1585V) allelic variants. There was no difference in any of the TRPV1 variants by gender, age when type 1 diabetes was diagnosed, body mass index, glycemic control, blood pressure, positive autoantibodies (ICA, GAD, IAA), and other autoimmune diseases. CONCLUSIONS: Our study demonstrates that TRPV1 may be a susceptible gene for type 1 diabetes in an Ashkenazi Jewish population. These results should be replicated in the same ethnic group and in other ethnic groups. PMID- 24340837 TI - Catastrophic antiphospholipid syndrome: a case series. AB - BACKGROUND: Antiphospholipid syndrome (APS) is an autoimmune disease with clinical manifestations of arterial and venous thrombosis, obstetric manifestations, and the presence of antiphospholipid antibodies or lupus anticoagulant. Catastrophic APS is a rare variant of APS, defined as acute failure of at least three tissues, organs or systems caused predominantly by small vessel thrombosis confirmed by histopathologic evidence. Catastrophic APS develops rapidly and leads to death in 30% of cases. METHODS: We evaluated 11 patients with catastrophic APS -8 of them with a probable diagnosis of catastrophic APS and 3 with a definite diagnosis--admitted to Beilinson hospital during the period 2003-2011. RESULTS: Overall venous events numbered 18 and overall arterial events 10. The event duration per patient was 2.6 +/- 1.2 weeks (mean +/- SD). Deep vein thrombosis of the legs was quite common (7 events), as was venous intraabdominal thrombosis (10 events). Eight patients had microangiopathic anemia with schizocytes seen in the blood smear. The mean +/- SD hemoglobin level was 10.3 +/- 3.6 g/dl and the mean +/- SD creatinine level 0.98 +/- 0.78 mg/dl. All our patients had high acute-phase reactant and all had lupus anticoagulant positivity, The most common positive antibodies were immunoglobulin G anticardiolipin (8 patients) and IgG beta2-glycoprotein (7 patients). During the events warfarin was stopped and the patients were given intravenous heparin. All the patients received steroids in variable doses. Five patients underwent plasma exchange, two patients received rituximab and two patients intravenous immunoglobulin. CONCLUSIONS: Catastrophic APS, a rare syndrome, is important because of its major morbidity and mortality among young patients. PMID- 24340838 TI - Do ventricular arrhythmias in athletes subside over time? AB - BACKGROUND: Sudden death in athletes can occur during sport activities and is presumably related to ventricular arrhythmias. OBJECTIVES: To investigate the long-term follow-up ofathletes with ventricular arrhythmias during an exercise test. METHODS: From a database of 56,462 athletes we identified 192 athletes (35 years old who had ventricular arrhythmias during an exercise test. Ninety athletes had > or =3 ventricular premature beats (VPB) (group A) and 102 athletes had ventricular couplets or non-sustained ventricular tachycardia during an exercise test (group B). A control group of 92 athletesfrom without ventricular arrhythmias was randomly seleclted from the database (group C). Of the 192 athletes 39 returnied for a repeat exercise test after a mean follow-up period of 70 +/- 25 months and they constitute the study population. RESULTS: Twelve athletes from group A, 21 fromgroup B and 6 from group C returned for a repeat exercise test. The athletes reached a significantly lower peak heart rate during their follow-up exercise test (P = 0.001). More athletes were engaged in competitive sports during their initialexercise test than in the follow-up test (P = 0.021). Most of theathletes who had VPB and/orventricular couplets and/or NSVT during their initial exercise test had far fewer ventricular arrhythmias in the follow-up exercise test (P = 0.001). CONCLUSIONS: Athletes engaged in competitive sports are more likely to develop ventricular arrhythmias during exercise. These arrhythmias subside over time when athletes are engaged in non competitive sports. PMID- 24340839 TI - Simulation-based interpersonal communication skills training for neurosurgical residents. AB - BACKGROUND: Communication skills are an important component of the neurosurgery residency training program. We developed a simulation-based training module for neurosurgery residents in which medical, communication and ethical dilemmas are presented by role-playing actors. OBJECTIVES: To assess the first national simulation-based communication skills training for neurosurgical residents. METHODS: Eight scenarios covering different aspects of neurosurgery were developed by our team: (1) obtaining informed consent for an elective surgery, (2) discharge of a patient following elective surgery, (3) dealing with an unsatisfied patient, (4) delivering news of intraoperative complications, (5) delivering news of a brain tumor to parents of a 5 year old boy, (6) delivering news of brain death to a family member, (7) obtaining informed consent for urgent surgery from the grandfather of a 7 year old boy with an epidural hematoma, and (8) dealing with a case of child abuse. Fifteen neurosurgery residents from all major medical centers in Israel participated in the training. The session was recorded on video and was followed by videotaped debriefing by a senior neurosurgeon and communication expert and by feedback questionnaires. RESULTS: All trainees participated in two scenarios and observed another two. Participants largely agreed that the actors simulating patients represented real patients and family members and that the videotaped debriefing contributed to the teaching of professional skills. CONCLUSIONS: Simulation-based communication skill training is effective, and together with thorough debriefing is an excellent learning and practical method for imparting communication skills to neurosurgery residents. Such simulation-based training will ultimately be part of the national residency program. PMID- 24340840 TI - Spinal epidural abscess: in search of reasons for an increased incidence. AB - BACKGROUND: Spinal epidural abscess (SEA) is a rare disease with a potentially devastating outcome, and a reported incidence traditionally estimated at 0.2-2 cases/10,000 hospital admissions. Since the implementation in October 2007 of a program to increase medical personnel's awareness of SEA, we have documented a sharp increase in the incidence of SEA at our medical center OBJECTIVES: To investigate the cause of the increased incidence of SEA. METHODS: All cases diagnosed with SEA during the period 1998-2010 were retrospectively reviewed. Cases diagnosed before 2007 were compared with those diagnosed thereafter. RESULTS: From January 1998 to October 2007 SEA was diagnosed in 22 patients (group A), giving an annual incidence of 0.14-0.6 cases per 10,000 admissions. During the period November 2007 to April 2010, 26 additional patients were diagnosed (group B), yielding an incidence of 0.81-1.7 cases per 10,000 admissions (P < 0.01). The two groups did not differ significantly in epidemiological, clinical or laboratory characteristics, or in the causative bacteria isolated. CONCLUSIONS: The threefold rise in the incidence of SEA observed at a tertiary medical center in Tel Aviv since November 2007 was not explained by different host characteristics or by more virulent bacterial isolates. We suggest that heightened awareness of the clinical presentation and timely utilization of MR imaging has resulted in more cases being identified. PMID- 24340841 TI - Post-laryngectomy voice rehabilitation: comparison of primary and secondary tracheoesophageal puncture. AB - BACKGROUND: Voice restoration following total laryngectomy is an important part of patients' rehabilitation and long-term quality of life. OBJECTIVES: To evaluate the long-term outcome of indwelling voice prostheses inserted during (primary procedure) or after (secondary procedure) total laryngectomy. METHODS: The study group included 90 patients who underwent total laryngectomy and tracheoesophageal puncture (TEP) with placement of voice prosthesis at a tertiary medical center during the period 1990-2008. Background, clinical and outcome data were collected by medical file review. Findings were compared between patients in whom TEP was performed as a primary or a secondary procedure. RESULTS: TEP was performed as a primary procedure in 64 patients and a secondary procedure in 26. Corresponding rates of satisfactory voice rehabilitation were 84.4% and 88.5% respectively. There was no association of voice quality with either receipt of adjuvant radiation/chemoradiation or patient age. The average lifetime of the voice prosthesis was 4.2 months for primary TEP and 9.06 months for secondary TEP (P= 0.025). CONCLUSIONS: Primary TEP provides almost immediate and satisfactory voice rehabilitation. However, it is associated with a significantly shorter average prosthesis lifetime than secondary TEP. Chemoradiotherapy and patient age do not affect voice quality with either procedure. PMID- 24340842 TI - Low circulating monocyte count is associated with severe aortic valve stenosis. AB - BACKGROUND: The pathophysiology of aortic stenosis (AS) involves inflammatory features including infiltration of the aortic valve (AV) by activated macrophages and T cells, deposition of lipids, and heterotopic calcification. OBJECTIVES: To evaluate the correlation between white blood cell (WBC) differential count and the occurrence and progression of AS. METHODS: We identified in our institutional registry 150 patients with AS who underwent two repeated echo studies at least 6 months apart. We evaluated the association between the average of repeated WBC differential counts sampled during the previous 3 years and subsequent echocardiographic AS indices. RESULTS: There was no significant difference in total WBC, lymphocyte or eosinophil count among mild, moderate or severe AS groups. There was a progressive decrease in monocyte count with increasing AS severity (P = 0.046), more prominent when comparing the mild and severe groups. There was a negative correlation between AV peak velocity or peak or mean gradient and monocyte count in the entire group (r = -0.31, -0.24, and -0.25 respectively, all P < 0.01). Similar partial correlations controlling for age, gender, hypertension, smoking, dyslipidemia and ejection fraction remained significant. The median changes over time in peak velocity and peak gradients in AS patients were 0.44 (0-1.3) m/sec/ year and 12 (0-39) mmHg/year, respectively. There was no correlation between any of the WBC differential counts and the change in peak velocity or peak gradient per year. CONCLUSIONS: Severe AS is associated with decreased total monocyte count. These findings may provide further clues to the mechanism underlying the pathogenesis of aortic stenosis. PMID- 24340843 TI - Clinical and radiographic outcomes of 139 hips with articular surface replacement total hip arthroplasty*. AB - BACKGROUND: The articular surface replacement (ASR) total hip arthroplasty (THA) was recently recalled from the market due to high failure rates. This modality was used frequently by surgeons at our medical center. OBJECTIVES: To assess the clinical and radiographic outcomes in patients following the surgery and determine the revision rate in our cohort. METHODS: Between 2007 and 2010 139 hips were operated on and evaluated in our clinic. All patients underwent a clinical interview, function and pain evaluation, as well as physical examination and radiographic evaluation. When necessary, patients were sent for further tests, such as measuring cobalt-chromium levels and magnetic resonance hip imaging. RESULTS: With an average follow-up of 42 months the revision rate was 2% (3/139). Patients reported alleviation of pain (from 8.8 to 1.7 on the Visual Analog Scale, P < 0.001), good functional outcomes on the Harris Hip Score, and improved quality of life. Overall satisfaction was 7.86 on the reversed VAS. For patients who required further tests, clinical and radiographic outcomes were significantly poorer than for the rest of the cohort. Average blood ion levels were high above the normal (cobalt 31.39 ppb, chromium 13.32 ppb), and the rate of inflammatory collection compatible with pseudotumors on MRI was 57%. DISCUSSION: While our study favors the use of the ASR implant both clinically and radiographically, some patients with abnormal ion levels and inflammatory collections on MRI might require revision in the future. PMID- 24340844 TI - Sleep apnea, glucose regulation and diabetes in patients with sleep apnea. PMID- 24340845 TI - Who determines the treatment for pressure ulcers in the elderly? AB - The issue of professional responsibility for the treatment and care of the patient with pressure ulcers (PU) is crucial as it impacts on mortality, financial costs and the patient's quality of life. Pressure ulcers in the elderly present a complicated health problem with multifactorial etiologies. Since the pressure ulcer is the final common pathway of multiple underlying factors and medical conditions, the approach when dealing with the elderly is not only local wound management but systemic--i.e., it relates to the patient's overall condition, comorbidities, nutritional status, and disabilities. With the increase in longevity and disability, the prevalence of PU is higher and has concomitant severity and complications. For treatment to be effective it must be comprehensive and multidisciplinary. The traditional, and pivotal, role of the nurse in coordinating treatment has expanded and now includes more active collaboration with the physician and the multidisciplinary team regarding the development and course of the wound. Physicians are required to be knowledgeable, actively involved, and alert to reversible multifactorial etiologies, in order to determine the goal and level of aggressive treatment during the course of PU. PMID- 24340846 TI - Anti-citrullinated peptide antibodies is more than an accurate tool for diagnosis of rheumatoid arthritis. AB - Anti-citrullinated peptide antibodies (ACPA) are detected in the sera of rheumatoid arthritis (RA) patients and have a profound role in diagnosis of the disease. In this review we discuss the different cohorts of RA patients in whom the presence, sensitivity and specificity of ACPA were evaluated. The significance of ACPA in the pathogenesis and prognosis RA is also interpreted. Recent advances in the understanding of molecular pathways involved in the pathogenesis of RA have led to the identification of novel biologic agents that are now widely used in patients with RA. PMID- 24340847 TI - Reversible myocardial dysfunction in septic shock. PMID- 24340848 TI - Diclofenac-lnduced coronary spasm in the absence of anaphylaxis or allergic manifestation. PMID- 24340849 TI - A case of severe hypokalemic myopathy due to clay ingestion. PMID- 24340850 TI - Wernicke encephalopathy after surgery for morbid obesity. PMID- 24340851 TI - Wernicke encephalopathy after surgery for morbid obesity. PMID- 24340852 TI - Questionable eponyms: paraparesis and rhabdomyolysis. PMID- 24340853 TI - Running out of time. AB - After a glitch-plagued rollout of state and federal healthcare exchanges, officials are scrambling to fix the marketplaces before a crucial mid-November deadline. If the problems can't be fixed in time for consumers to get enrolled by Jan. 1, it will hand ammunition to Republicans who want to delay the ACA's individual mandate. "If you can't enroll people, how can you penalize them?" asks Tom Miller of the American Enterprise Institute. PMID- 24340854 TI - States do it better. State-run exchanges fix glitches and enroll consumers. PMID- 24340855 TI - Security fixation. Privacy protections blamed for computer glitches. PMID- 24340856 TI - Cautiously hopeful. But docs still unsure about exchange participation. PMID- 24340857 TI - Selling hospitals, not doctors. Devicemakers look to meet providers' priorities. PMID- 24340858 TI - Damage isn't over. How the government shutdown undermined Medicare. PMID- 24340859 TI - Not ready for prime time. The Affordable Care Act will not solve our health insurance problems. PMID- 24340860 TI - Poverty's impact on health. Experts discuss roles of environment, lifestyle. Interview by Andis Roeznieks. PMID- 24340861 TI - Two for the price of one. Michigan, Illinois collaboration on Medicaid IT system saves on cost--and may open doors for more partnerships. PMID- 24340862 TI - Medicaid budgets by state. PMID- 24340863 TI - Joint Commission president and CEO contends new approaches necessary to improve health care. PMID- 24340864 TI - Revised criterion for including physician practices in surveys. PMID- 24340865 TI - Accreditation and certification manual products. PMID- 24340866 TI - Revised ventricular assist device destination therapy requirements. PMID- 24340867 TI - What the CMS Life Safety Code waivers mean for you. PMID- 24340869 TI - Questions and answers: the perinatal care core measure set. PMID- 24340868 TI - Performance measurement requirements increasing in 2014. PMID- 24340870 TI - Addendum to business associate agreements posted on extranet. PMID- 24340871 TI - Communicative responses to the painful self-disclosures of familial and non familial older adults. AB - Data from 365 college students were used to assess young adults' communicative responses to older persons' painful self-disclosures (PSDs). Coupland, Coupland, and Giles (1991) proposed that recipients of PSD may respond to such disclosures via a variety of"next moves." These responses may broadly be considered to reflect forms of pro-social engagement, passive disengagement, and active disengagement. We investigated whether young adults' tendency to use certain responses to PSD were influenced by their affective reactions to PSD, their communicative background and characteristics, and the sociorelational context of the encounter in which PSD occurred. Results are discussed with respect to their implications for intergenerational interaction, and interpreted through the lens of communication accommodation theory. PMID- 24340872 TI - Social support and life satisfaction among older adults in China: family-based support versus community-based support. AB - Family-based support has been the traditional care arrangement for the elderly in China. With the maturing of its "one child per couple" policy and the changing scenarios of family structure and cultural norms, these traditional care arrangements for the Chinese elderly are becoming dismantled. Centers and associations within the community have gradually become the major infrastructures to provide old age service and support in China. This study examined the effects of family-based and community-based support on life satisfaction among older Chinese adults, using data from the pilot survey of China Health and Retirement Longitudinal Study (CHARLS) in 2008. A series of multilevel models were assessed with statistical package SAS 9.2 among 1,398 Chinese adults aged 45 or older. The results suggest that even with the inclusion of community-based support, family based support variable, the perceived future help from family members, still significantly predicted the life satisfaction among older Chinese adults. PMID- 24340873 TI - Volunteerism and positive aging in Hong Kong: a cultural perspective. AB - This study aims to examine factors related to volunteerism and explore the relationship between volunteerism and positive aging across three age groups. A total of 1,170 Hong Kong Chinese respondents aged between 15 years and 79 years were recruited for the study via a random household survey. Results found that age was negatively related to participation in voluntary work. Older adults aged 60 years to 75 years demonstrated the lowest volunteer participation rate compared with younger adults (aged 15 years to 39 years) and midlife adults (aged 40 years to 59 years). Paradoxically, older volunteers exhibited the highest frequency of volunteering, operationalized as spending 10 hours or more on volunteer work in the past month. Compared with younger and midlife adults, older adults were motivated to volunteer by societal concern and esteem enhancement. Participation in voluntary work was associated with three positive aging outcomes: good health, caring engagement with significant others, and productive engagement in the community. The findings suggest great potential in promoting volunteering in old age because older volunteers tend to contribute more hours than younger volunteers do, and volunteering is associated with positive aging. PMID- 24340874 TI - Community engagement: an essential component of well-being in older African American adults. AB - Active engagement in life is a critical factor for successful aging. Research indicates that community engagement is strongly associated with health and well being in late life. However, less is understood regarding the influence of neighborhood conditions on health and well-being, particularly in older African American adults. The current study describes a convenience sample of older African Americans (N = 501, mean age = 70.7 [range 55-95] years) living in Detroit. The specific goal is to examine the relationships between their perceptions of neighborhood conditions, level of community engagement, and their health and well-being. Survey findings reveal a sample of highly engaged older African Americans in reasonable health who perceive their neighborhoods favorably. Regression analysis results indicate that community engagement is closely associated with both neighborhood perceptions and well-being in this sample. We propose that community engagement or "participation" mediates the relationship between neighborhood conditions and well-being for older African Americans living in Detroit. PMID- 24340875 TI - Bet on one big idea--or diversify? PMID- 24340876 TI - The unfulfilled promise of Obamacare. PMID- 24340877 TI - The proboscis files. PMID- 24340878 TI - Painful prescription. PMID- 24340879 TI - Enterprise engagement. PMID- 24340880 TI - The future of health care philanthropy. PMID- 24340881 TI - Surviving a hospital merger. PMID- 24340882 TI - Success with a small shop capital campaign. PMID- 24340883 TI - Taking the mystery out of metrics. PMID- 24340884 TI - Make a remarkable case for your cause. PMID- 24340885 TI - The big bull backup. PMID- 24340886 TI - [H. pylori infections in children: clinical, diagnostic and treatment implications]. AB - Helicobacter pylori is the most widespread infection all over the Word. The rate of this infection varies, depending on age, geographic region, socioeconomic and hygienic conditions. Most infected children live in the poor, developing countries without adequate living and hygienic conditions. Prevalence of H. pylori infections in children in Poland was 32.01%. The course of infection in children depends on individual predisposition, environmental factors and virulence of H. pylori. In children in Poland infection with cagA+s1m1 genotype occurs most frequently. In children, a connection of H. pylori infection to ulcer disease of the duodenum was demonstrated. Additionally, the diagnostic tests of infection and diagnostic assessing eradication were discussed in the work. Recommendations on the treatment of H. pylori taking into account the necessity of the assessment of bacteria sensitivity to antibiotics were outlined. It is particularly important in the regions with high resistance of H. pylori to clarythromycin, which in children can exceed 20%. PMID- 24340887 TI - [Polymorphism of helicobacter pylori and the presence of genes babA2 and sabA and endoscopic and histopathological changes in patients infected with Heicobacter pylori]. AB - The infection of Helicobacter pylori is the main reason of a duodenal and gastric ulcer disease. Among other virulence factors of Helicobacter pylori, there are outer membrane proteins (OMPs), such as babA2 and sabA. THE AIM OF THE STUDY: An assessment of a relationship between the presence of genes babA2 and sabA and endoscopic and histopathologic changes during gastritis, duodenitis and an ulcer disease. MATERIAL AND METHODS: We included 119 patients aged from 3 to 17 (average 13.6) with gastritis and duodenitis and the infection of Helicobacter pylori. The endoscopy was conducted with taking samples of the mucosa for the histopathologic and genetic examination. The degree of endoscopic and histopatologic changes were determined according to Sydney's classification. The patients were devided in the extra groups with a small level (without erosion) and with a large level (with erosion) of endoscopic changes. To identify the infection of Helicobacter pylori, the PCR technique was used and then the presence of the babA2 and sabA genes of Helicobacter pylori was verified. The genetic confirmation of Helicobacter pylori infection was obtained in 88 patients and material was directed to the further examination. RESULTS: Not statistically significant differences were determined between endoscopic and histopathologic pictures and either the presence or absence of the genes babA2 and sabA. CONCLUSION: The presence of the genes babA2 and sabA is not related with level of endoscopic and histopathologic changes in pediatrics patients. PMID- 24340889 TI - [The evaluation of discomfort and anxiety in the patient undergoing coronary angioplasty]. AB - Coronary heart disease is now the leading cause of death in the world and in Poland. Every year, the acute coronary syndromes (ACS) falls over a hundred thousand people, of whom the vast majority are treated invasively. Percutaneous coronary intervention (PCI) carries a possible complication. The possibility of their occurrence is one of the reasons to feel fear and discomfort prior to the study. THE AIM OF STUDY: Was to assess of the level of discomfort and anxiety experienced by those undergoing percutaneous coronary intervention. MATERIAL AND METHODS: The study included 100 consecutive patients undergoing percutaneous coronary intervention for ACS or stable angina. The research method used in the survey was a questionnaire form, includes a total of 23 questions. The survey was carried out 24 hours after the execution diagnostic procedure or therapy. RESULTS: PCI was performed significantly more often with radial access--65%, than femoral--35%. People undergo PCI in 77% had knowledge of it. The main source of information was the hospital staff (48%), GPs (20%) and to a lesser extent, the Internet (16%) and friends (12%). To assess the discomfort uses a linear scale of points. Depending on the vascular access was obtained an average of 5.7 points for radial access and 8.8 points for femoral access, corresponding to moderate and very large intensity of discomfort. The degree of discomfort was lower (42%) or compatible (27%) of the representations before the treatments. The intensity of the perceived fear determined the 53% of the very large, and 21% as large. On average, a 10-point scale, respondents have identified him at 7.9 points. Significantly negatively correlated on the level of education (r = -0.421, P < 0.05) and with the degree of knowledge of the declared procedure (r = -0.519, P < 0.01) and positively correlated with the intensity of reported discomfort (r = 0.497 p < 0.05). CONCLUSIONS: Reducing discomfort and anxiety in patients undergoing PCI is very important. This affects the success of the procedure and for appropriate treatment and rehabilitation. Active detection of factors affecting these phenomena and their reduction should be one of the tasks of the personnel involved in the treatment. It is necessary to proper education, including get familiar with the methods of endovascular interventions. PMID- 24340888 TI - [The assessment of glucose and lipid parameters in children with a positive family history of hypertension]. AB - Arterial hypertension in adults is often associated with excess body weight, and lipid or carbohydrate disorders. The incidence of hypertension in children is growing, although its connection with metabolic disorders and family history of hypertension has not been previously understood. THE AIM OF THE STUDY: To evaluate the relationship between a family history of hypertension and metabolic parameters (carbohydrate and lipid metabolism) and anthropometric measurements in children and adolescents. MATERIAL AND METHODS: The study group consists of 40 children (mean age 13.6 years +/-2.7 years) with a positive family history of hypertension, and a comparative group of 44 children with a negative family history of hypertension. Anthropometric measurements, blood pressure, plasma insulin, glucose, homeostasis model assessment insulin resistants (HOMA IR), and lipid profiles were determined in all children. RESULTS: Body weight, BMI, WHR, and measurements of skinfolds did not differ significantly between the groups. Systolic blood pressure was significantly higher in the study group (108 vs. 100 Me mmgHg, p = 0.031) Significant differences were observed in the levels of glucose (80 vs. Me. 67 mg/dl, p < 0.001), and insulin (8.89 vs. Me. 5.34 microIU / ml, p = 0.024). The HOMA index showed values significantly higher in the study group (1.68 vs. 0.80 Me p = 0.007). Children with a positive family history of hypertension were characterized by insignificantly higher values of total cholesterol, TG, LDL-cholesterol, and lower HDL-cholesterol. CONCLUSIONS: A positive family history of hypertension correlates with higher systolic blood pressure and changes in carbohydrate metabolism parameters in the direction of the development of insulin resistance in children. PMID- 24340890 TI - [The importance of folic acid deficiency in the pathogenesis of vascular, mixed and Alzheimer's disease dementia]. AB - Alzheimer's disease (AD), vascular dementia (VaD) and mixed dementia (MD) are the most common dementia diseases among the elderly. Currently, there is no effective treatment of these diseases and, therefore, it seems justified to develop the principles of prevention, taking into account the elimination of risk factors. Among them folic acid deficiency may play an important role. THE AIM OF THE STUDY: To evaluate possible relationship of folate deficiency with the development of selected dementia diseases: vascular dementia (VaD), Alzheimer's disease (AD), mixed dementia (MD). MATERIAL AND METHODS: The study involved 166 people, including 47 people with the diagnosis of AD, 41 with VaD and 36 with MD. The control group consisted of 42 persons without cognitive impairment. All patients underwent a general physical, neurological, psychiatric and extensive neuropsychological examination, as well as routine blood and biochemical screening tests and neuroimaging. The level of serum folate (Fol) was measured by electrochemiluminescence immunoassay. To assess the correlation of Fol level with the cognitive impairment neuropsychometric scales: Mini Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) were used. RESULTS: In patients with dementia, compared with the control group, there were significantly lower levels of folic acid (p = 0.04). There was no difference in the concentration of Fol in groups of patients (p = 0.0889). In people without cognitive impairment (CDR 0) levels of folic acid were significantly higher compared to the group with moderate dementia (CDR 2, p = 0.0475). CONCLUSIONS: The results may suggest that folic acid deficiency is one of the possible causes of dementia, but does not determine its type. Determination of serum Fol in the elderly and supplementation of this vitamin deficiency may play an important role in the prevention of the most common dementias. PMID- 24340891 TI - [Assessment of the relationship of depressive disorders in men with lumbosacral pain syndrome]. AB - Coincidence of pain in various somatic diseases of depression was confirmed in many epidemiological studies. Lumbosacral pain can be classified as one of the most aggravating National Health budget. THE AIM OF THIS STUDY: To assess the relationship between the presence of pain, depression, and emotional functioning of male patients. MATERIAL AND METHODS: 56 men with lumbosecral pain syndrome took part in this study. Some of them were diagnosed as depressive disorders patients. In this study we used scales to measure the degree of pain and depression and Emotional Control Questionnaire to determine subjects emotional functioning. RESULTS: This paper presents the relationship between the occurrence of lumbosacral pain syndrome and depressive disorders. The results confirm the existence of a relationship between the severity of pain and depression and emotional disorders. CONCLUSIONS: The study shows that there is a correlation between the intensity of lumbosacral pain in male patients and the incidence of depressive and emotional disorders. Men with back pain syndrome and depressive disorders during pain increase period have less emotional excitability and rationally motivated behavior. Men with back pain syndrome without depressive disorders during pain increase period have a greater control of emotional expression, and less control of the situation emotiogenic situation. PMID- 24340892 TI - [Risk sharing schemes--what does foreign experience tell us?]. AB - A new healthcare act dated from 2011 has introduced risk sharing instruments into the Polish reimbursement system. It is a form of pricing and reimbursement (P & R) arrangement. The reimbursement is granted provided that certain conditions are met. THE AIM OF STUDY: To perform the systematic review to identify publications presenting different P & R arrangements implemented in foreign jurisdictions. MATERIAL AND METHODS: 876 articles were reviewed based on predefined inclusion criteria. In total, 22 publications were included. Results. As many as 33 different sort of P&R arrangements were identified. CONCLUSIONS: The systematic review revealed variety approaches to P & R arrangements. The most advanced forms included the collection of real life data, the least advanced were based on financial measures. Based on preformed systematic review, a list of recommendations for further incorporation of P & R arrangements into the Polish environment were elicited for the Polish decision makers. PMID- 24340893 TI - [Pseudomyxoma peritonei spread into the right inguinal hernia sac--a case report]. AB - Pseudomyxoma peritonei (PMP) is a rare, progressive disease of unknown origin. The incidence is estimated at about 1-2/100,000,000 per year. The primary tumor site is usually discovered in the appendix or- in case of women--in ovaries, appearing as tumors of low malignancy. Making an accurate diagnosis causes difficulties--symptoms tend to be misleading, suggesting more frequent pathologies of the abdominal cavity. It is also not rare that the patient is for a long time asymptomatic. We present a case of a 68-year-old patient of the Surgical Oncology Department treated for pseudomyxoma peritonei, diagnosed incidentally at the time of clinical examination for the reasons of chronic hypertension. The symptoms reported by the patient did not suggest any neoplastic process of the peritoneal cavity. Systemic chemotherapy of two paths (a total number of 10 cycles) did not result and at the time of post-treatment control, due to no response to standard chemotherapy, it was decided to administer chemotherapy intraperitoneally in hyperthermia (HIPEC). During the operation, peritoneal cytoreduction prior to the scheduled HIPEC was performed; the right sided inguinal hernia was repaired. Within the hernia sac the implanted myxoid cells were found, their presence inside was probably the main reason of clinical manifestation of the disease. PMID- 24340894 TI - [Diseases of the respiratory system in systemic lupus erythematosus]. AB - The following paper discusses the aspect of respiratory system diseases, that are present in the course of systemic lupus erythematosus. Taking into consideration that SLE is a nonspecific systemic autoimmune condition, lungs as well as respiratory tract could be affected in the process of the disease. The main contributing factors are circulating antibodies and immune complexes, that are deposited in tissues. SLE affects mostly women in reproductive age and is characterized by variable intensity of symptoms. The most commonly observed are: hyperthermia, malar rash, erythematous-cicatrical skin changes, photosensitivity, oral ulcers, polyarthralgia, nonerosive arthritis with no visible changes in radiogram, pleurisy and pericarditis, neuropsychiatric disorders, renal changes, hematologic disorders, as well as, abnormalities in circulatory and respiratory system. The respiratory conditions include pleuritis with or without pleural effusion, lupus pneumonitis, pulmonary hemorrhage, interstitial lung disease, pulmonary thromboembolic disease, pulmonary arterial hypertension, alveolitis, bronchitis obliterans and inflammatory myopathy, as well as acute alveolar capillary injury, which in the course of SLE is associated with deposits of immune complexes in pulmonary alveoli, capillaries and interstitial tissue. PMID- 24340895 TI - [The role of chronic venous insufficiency in the pathogenesis of brain diseases]. AB - Recent data from the literature suggest a greater role of chronic venous insufficiency in the pathogenesis of a variety of brain disorders than previously thought. The more perfect method of imaging the structure and brain function contributed to it. The method of choice in the diagnosis of cerebral venous insufficiency are: Color Doppler of neck vessels, TCCD (transcranial color coded duplex) and TOF (time of flight) MR angiography of the brain and carotid vessels. Under physiological conditions, the flow in veins of the brain is one-way, to the heart. In pathological conditions, there is a reverse blood flow to the brain, which is the essence of the chronic venous insufficiency of brain. It is considered that cerebral venous disorders may underlie a number of diseases of the nervous system. This paper describes the role of venous circulatory disorders of the brain in pathogenesis of multiple sclerosis, the total transient amnesia, Alzheimer's disease, Parkinson's disease, transient monocular blindness, headaches, spontaneous intracranial hypertension. It seems that the correct function of the venous system plays an important role in maintaining brain function. We need further research in this area to better understanding the relationship between the venous pathology of the brain and diseases of the nervous system. PMID- 24340896 TI - [Erythema migrans as a patognomic symptom of lyme disease]. AB - Erythema migrans (EM) is an early localized form of Lyme borreliosis (LB). EM appears 3-30 days after tick bite and presents as annular homogenous erythema, marked from unaffected skin. Typical EM has more than 5 cm in diameter, but there are reports of mini-EM in literature. Moreover, multiple or bullous EM are described. Diagnosis is based on clinical picture. In treatment antibiotics must be used. The aim of this paper was to draw attention to still existing problem of LB in Poland, not only in endemic areas and to the necessity of proper diagnosis, early implementation of antibiotics. It may prevent from late form of LB development, which may lead to irreversible damage, especially in nervous system or joints. EM presence in history increases the probability of subsequent LB forms such as neuroborreliosis or arthritis. Otherwise, symptoms may be misinterpreted, as they resemble the other in the course of more common diseases. PMID- 24340897 TI - [Unconventional methods of "treatment"]. AB - Unconventional methods used in the course of treatment are also called alternative, holistic, complementary or natural medicine and according to accounts given by different people, patients often use those methods. In the primitive societies there are shamans or curaderos performing those treatments, whereas in the highly developed countries also arise surgeries offering those unconventional methods of treatment. This study is a review of most commonly used methods in the geographical aspect, both historically and currently. PMID- 24340898 TI - [Pharmacologists in the camps In the Third Reich--part one]. AB - The outbreak of World War II is considered as the inception of the pharmacology of the III Reich. Hitler's soldiers are decimated on the front lines by malaria, typhoid, gas gangrene, they need efficient and easy accessible medicines. From now on German forces are engaged into pharmacology of war. Only augmentation of Fuehrer's army effectiveness is reckoned with. Research centers in the concentrations camps are being organized, prisoners are used as the human subject. In the investigations many noted and respected personages are involved. Dr. Helmut Vetter and Dr. Ding Erwing Schuler studied chemicals which may had potential use in the prevention and treatment of typhoid. Professor Eugen Haagen carried out experiments concerning the use of vaccines against typhoid. The latter, although sentenced to life imprisonment, he returned to research in 1952 as a result of the amnesty activities in the former West Germany, and then worked as a researcher. His studies were reflected in the book, and scientific publications. Professor. Eugen Haagen died of natural causes in 1972. PMID- 24340899 TI - [Pharmacologists in the camps in the Third Reich--part second]. AB - SS Hygiene Institute provided adequate funding for research on the treatment of mycobacterial infections, and two scientists who became famous in the subject were Dr. Waldemar Hoven (KL Buchenwald) and Dr. Kurt Heissmeyer (KL Neuengamme). They conducted researches not only on adult prisoners, but also on the Jewish children. Studies of tuberculosis were also conducted under the auspices of the German Medical Association by Dr. Rudolf Brachtel. In turn, Dr. Klaus Schilling dealt with the treatment and immunoprophylaxis of malaria. He tested such substances, as pyramidon, aspirin, quinine and atebrin on more than 1200 prisoners. These sulfonamide-derived drugs, were also studied by prof. Karl Gebhardt and Dr. Fritz Fischer. They assessed the efficacy of these drugs in the treatment of "dirty" wounds incurred by German soldiers. Dr. Heinrich Schutz, Karl Babor and Waldemar Wolter they were enthusiasts in so-called biochemical therapy, based on the use of substances of natural origin, such as salt. After termination of War, during the Nuremberg Trials, many of them evaded responsibility, they were running medical practices, some were publishing. However, despite those facts, trials of Nazi war criminals were not result less, they opened world's eyes for the necessity of clarifying rudiments of human subject research, they gave foundations to define records like The Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine or Good Clinical Practice. PMID- 24340900 TI - [Status and actualization of tasks to improve the scientific-methodological and regulatory frameworks in the field of human ecology and environmental health]. AB - Contemporary factors that affect the health of the population have been analyzed. There was shown the growing activity of chemical pollution of the environment. Therefore, in order to prevent the growth of negative health and environment consequences caused by increased levels of exposure to chemicals preventive potential for solutions of this complex problem and all strenuous efforts to assist possibly of the sound management of the chemicals should be enhanced. Problematic issues of harmonization of the Russian normative and guidance documents have been actualized. Perspective directions of science development in the field of human ecology and environmental health are suggested. PMID- 24340901 TI - [The potential of the member states of the European Region of WHO in the field of prevention of adverse effects of chemicals on human health and measures for its strengthening]. AB - The issue of providing chemical safety for the population, and especially for the most vulnerable groups remains to be actual in relation to the significant contribution of the impact of hazardous chemicals in the forming of morbidity rate, industrial growth and return of chemical products, rapid development and introduction of new technologies. The international community has adopted a series of mandatory and voluntary initiatives in the field of chemical safety. Strategic document for the WHO European Region, determining priorities in this area, is the Parma Declaration. Implementation of a wide range of arrangements set out in the Declaration requires sufficient capacity of the health sector and other concerned parties, the scope of which is addressed to aspects of healthcare from exposure to hazardous chemicals. Performed by the WHO European Centre for Environment and Health (ECEH) the assessment of existing in this area capacity based on the survey permitted to identify significant gaps in the legislative regulation, policies and planning, human and technical resources, the collection and exchange of information, education and training. With the participation of national experts ECEH developed a set of recommended measures aimed to the creation and strengthening the potential. Development and implementation of effective national strategies/plans/actions with regard to regional priorities and recommended actions will allow to increase the level of chemical safety for the population of the region as a whole. PMID- 24340902 TI - [The advantages and problems of implementation of the globally harmonized system (GHS) of classification and labelling of chemicals in the practice of the national preventive toxicology and hygiene]. AB - GHS, aimed at unifying and objective assessment of risk has significant differences from current classifications of toxicity and danger applied in the Russian Federation. However, the need to implement the international commitments of the Russian Federation, the reluctance of the Russian industry twice classify and label products for the domestic and international market demand introduction of the International Classification into the practice of national preventive toxicology. PMID- 24340903 TI - [Composition of the dust for the assessment of the exposure to the population in the areas of influence of industrial emissions of stationary sources]. AB - The results of instrumental studies of the dispersion and component composition of the solid component of the dust gaseous emissions from industrial stationary sources of engineering and metallurgical enterprises are presented. Dust and gas mixtures were established to contain up to 80% fractions with a particle size less than 10 microns (PM10), and 40% of fractions with size smaller than 2.5 microns (PM2.5). In the composition of the dusts particles in the nano-sized range have been identified. The main chemical components of dusts are iron, silicon, aluminum and their oxides, but in the set of dusts manganese, chromium, vanadium, and other toxic metals account for 25% of the weight. Accounting disperse composition of dusts in the evaluation of pollution allows to establish the zone of influence of sources more accurately, correctly assess the exposure to the population with bearing in mind the such hygienic criteria as PM10 and PM2.5 sampling. PMID- 24340904 TI - [Current aspects of the state and improvement of sanitary and epidemiological welfare of workers and passengers of Russian railways]. AB - The data on the sanitary-epidemiological state of Railways objects of Russia are presented. Bacteriological examination of drinking water taken from the water systems of passenger cars showed that 3.9-5.0% of the samples did not meet the health standards (p < 0.01). Samples of workplace air in industrial enterprises did not meet hygienic standards: on vapors and gases--4.6%, dust and aerosols- 13.6%. In 52.9 +/- 2.6% of examined drivers cabs there was revealed noncompliance to hygienic standards on physical factors: on the noise--45.1 +/- 2.7%, vibration -35.6 +/- 2.7%, etc. Out of the total number of occupational diseases locomotive drivers account for about 40% of cases, including sensorineural hearing loss up to 80%. Morbidity with temporary disability among drivers of locomotives are 20 25% higher (p < 0.05), than in the whole railway transport. The suggestions on the improvement of sanitary-hygienic monitoring in rail transport are given. PMID- 24340905 TI - [Hygienic aspects of the use of LED light sources for general illumination in schools]. AB - For the time present becoming more common semiconductor sources of artificial lighting has become a more and more frequent practice. With the aim to study the impact of LEDs on the health of schoolchildren studies in experimental conditions (specially equipped classrooms) were performed. The comparative analysis of the state of vision, mental health and emotional state of pupils in primary, middle and high schools under fluorescent and LED lighting, meeting to the regulatory requirements, has revealed that the physiological cost of schooling in the use of LED units in classrooms is lower than in a traditional, fluorescent lighting. PMID- 24340906 TI - [Experience of the implementation of the method of the integral assessment of drinking water on indicators of chemical harmlessness in St. Petersburg]. AB - Providing population with quality drinking water--one of the priority tasks of the state policy aimed at maintaining the health of citizens. Hygienic rating of the drinking water quality envisages requirements to assurance its safety in the epidemiological and radiation relations, harmlessness of chemical composition and good organoleptic properties. There are numerous data proving the relationship between the chemical composition of drinking water and human health, and therefore the issue of taking a hygienically sound measures to improve the efficiency of water treatment has more and more priority. High water quality--the result of complex solution of tasks, including an integral approach to assessment of the quality of drinking water the use of hygienically sound decisions in the modernization of water treatment systems. The results of the integral assessment of drinking water on the properties of harmlessness have shown its actuality in the development and implementation of management decisions. The use of the spatial characteristics of integrated indices permits to visualize changes in the quality of drinking water in all stages of production and transportation from the position of health risks, evaluate the effectiveness of technological solutions and set priorities for investing. PMID- 24340907 TI - [The influence of the oil and gas industry on environmental safety and population health in the Khanty-Mansiiskii Region - Iugra]. AB - Production activities of oil and gas industry plants are related to technogenic impact on the environment, which has a high environmental risk. This is associated with low levels of environmental orientation of sheer technological processes of exploration and exploitation of hydrocarbons and also used in this technical means, materials and chemical reagents. The main pollutants that deteriorate the toxic characteristics of drilling waste, are the most likely drilling fluids, mud flush agents and chemicals, which enter into their composition. Existing methods of disposal of drilling wastes are not effective, the technology of their use is often violated. Dumping drilling waste into water bodies and burying toxic waste in water protection areas under the guise of processed waste has been observed. In the region there are significantly exceeded the national average values rate of morbidity of allergic, cardiovascular, pulmonary and cancer diseases, mediated by environmental factors and new monofactorial and multifactorial diseases appear. PMID- 24340909 TI - [Main direction of harmonization of Russian and international requirements on providing of biological safety when handling pathogenic biological agents]. AB - The actuality of harmonization of Russian and international requirements when handling with pathogenic biological agents (PBA) is caused by the need to ensure biological security on the basis of control of biorisks. One of the basic conditions for harmonization is development and implementation of the Russian standard for biorisk management based on international standard CWA 15793:2008. PMID- 24340908 TI - [Features of changes in the electrochemical properties of water activated with structurally stressed calcium carbonate in micellar form]. AB - The results of studies of electrochemical indices of waters activated with structurally stressed calcium carbonate tension in micellar form during storage are presented and these indicators of water were shown to change over time. In this case, waters, having initially superior activity over time reduce it, giving place to the waters that have at this moment an activity greater than the activity of the sample leading at the beginning. Established that the cause of this oscillatory over time change in activity is a non-local interaction between macroscopic quantum systems of activated waters located at a distance from each other. Oscillatory changes of the electrochemical indices of activated water during storage reflect the dynamic of changes in its biological properties. These changes in the electrochemical indices should be considered in evaluation of the structural and energetic state of the activated water during storage by means of introducing the correction factors. PMID- 24340910 TI - [Harmonization of microbiologicaland parasitological indices of epidemic safety of drinking water with the international requirements]. AB - For the purpose of harmonization of microbiological and parasitological indices and benchmarks there was performed the comparative analysis of the requirements for the quality of drinking water in respect of the epidemic safety on the basic regulations of Russia, the Directive Council of the European Union EU, WHO, the United States, Canada, Australia, Finland, Sweden, Brazil, France, Japan and China. As a result, there were revealed the priority bacteriological, virological and parasitological parameters: E. coli--indicator of recent fecal contamination, coliforms, heterotrophic bacteria colony count (Heterotrophic plate count), which is in the water legislation of the Russian Federation is characterized as total bacterial count (TBC), being an integral index of the quality of wastewater treatment technologies and hygienic condition of the water supply systems, coliphages as an indicator of viral contamination. In the Guidelines for drinking water quality control, WHO and a set of countries there is recommended a more wide range of indicators: enterococci, Clostridium perfringens, Pseudomonas aeruginosa, enteroviruses, parasitological indices. With aim of harmonization of the requirements for the quality of drinking water in the Russian Federation with international approaches to the revision of the Sanitary Regulations and Norms (SanPin) 2.1.4.1074 into the project there are introduced priority indicator parameters of bacterial, viral and parasitic contamination of water, evidence based guidelines. PMID- 24340911 TI - [The European approaches to the microbiological food safety assessment]. AB - The purpose of the study was the analysis of the results of the study of the quality of food products and environment of food industries on microbiological indicators according to domestic and European regulations (EU). The analysis of the quality of food, studied during 2008-2012, showed an increase in the number of samples that do not meet the requirements of regulations at the same time on several factors: mesophilic aerobes and facultatively anaerobic microorganisms, bacteria of the family Enterobacteriaceae and fungi (molds and yeasts). The results of research in dining facilities, food industries and distribution network for 2008-2011. indicate that in the swabs used for sampling surfaces the incidence of sanitary-indicative microorganisms ranged from 2.91 to 8.87%. There was absent dynamics of the improvement in the sanitary-epidemiological status of institutions for food processing. The highest rate of contamination (81.1-82.4%) was observed on the surfaces of tables, dishes, utensils, equipment, and most positive samples were represented by bacteria of the family Enterobacteriaceae. There was performed a critical analysis of European approaches to the study of food. It was made a draw about premature introduction of the Order of the Ministry of Health of Ukraine No 548 dated 19.07.2012, the "Microbiological Criteria for detection of safety of food products," based on the provisions of Regulation number 2073/2005 in Ukraine. PMID- 24340912 TI - [Problems of improving the assessment of health risk for assurance of the sanitary and epidemiological well-being]. AB - There are considered the current problems of improving population health risk assessment for assurance of the sanitary and epidemiological well-being. Their solution permit to improve the risk assessment methodology in Russia and overcome unnecessary barriers in the way of a practical application of the criteria of acceptable risk and damage to health to support management decisions. PMID- 24340913 TI - [Methodology of the approach to express-estimation of radiation risk for public health under the influence of radionuclides present in the ground waters]. AB - The methodological approach for the express-estimation of the value of individual lifetime cancer risk due to the groundwater use by population for drinking is supposed. The calculation of risk is performed with the use of only the values of specific activity of 226Ra in underground water. The formulas for calculating the value of individual lifetime cancer risk in the groundwater use by the population in drinking aims for oral and inhalation routes of exposure are suggested. PMID- 24340914 TI - [Identification of social risk factors for health of preschool children residing in areas with high anthropogenic load]. AB - In the article there is substantiated the need to include social factors (particularly lifestyle factors) in the risk assessment procedure of the health of children residing in conditions of anthropogenic impact on the environment. The purpose and algorithm for identification of social risk factors are disclosed. There are reported results of testing of author's approaches as exemplified of the Perm region (sample size--642 people). There is established high prevalence of behavioral risk factors for the health of children residing in industrialized areas--wrong nutrition, hypodynamia, exposure to secondhand smoke, and the irresponsible behavior of parents with regards to the health of children. On the base of the results of an epidemiological analysis accordingly to the odds ratio there is determined that the socio-economic status of the family appears as a key condition for the formation of a behavioral risk for the health of preschool children. The parents' education was found to contribute to the formation of behavioral risks to children's health more, than the level of family income. PMID- 24340915 TI - [The dynamics of the risk of morbidity in the industrial cities of Irkutsk region]. AB - An assessment of the dynamics of medical and environmental situation in the industrialized cities of Irkutsk region on the relative risks of morbidity in children and adolescents due to changes in environmental loads in recent years (air pollution levels) was performed. The data presented indicate to environmental troubles in territories of considered industrial cities over the past two decades due to the high degree of intensity of medical and environmental situation on levels of morbidity (accordingly to medical aid appealability rate) of child and adolescent population. PMID- 24340916 TI - [Identification of the main risk factors for non infectious diseases: method of classification trees]. AB - There is presented ideology of the application of one of the methods for assessment of the influence of multi-factor influence of risk factors on population health--the method of classification trees. The method of classification trees is a hierarchical procedure for constructing a decision rule that allows to divide the population into groups with higher and lower morbidity "in the coordinates of" risk factors. The main advantage of the method--the possibility of finding the complex of risk factors having the greatest impact on the health of the population (in contrast to common methods, analyzing only the single-factor effects). In the paper there are presented two possible variants of application of classification trees: 1) the finding of the complex of environmental risk factors (RF), which provides the maximum impact on the prevalence of non infectious diseases in preschool children) in Yekaterinburg (environmental risk factors--the pollution of air drinking water, in the presence of a gas stove in the child's flat, etc.). It is shown that, together with socio economic risk factors environmental risk factors increase the prevalence of respiratory diseases in preschool children in Ekaterinburg in 2.5-4 times (depending on the list and the number of environmental RF), 2) finding the complex of non-environmental factors that most effectively compensating the negative effect of environmental pollution on human health. This posing of the problem is associated with the fact that pollution environmental factors are (usually) unmodified, while family, behavioral or social factors can be partially or completely eliminated Implementation of the recommendations presented in the paper can reduce the incidence of circulatory diseases in preschool children in Yekaterinburg more than 2 times. PMID- 24340917 TI - [Development of technologies of population health management in Kazakhstan based on an integrated assessment of the combined exposure to environmental factors]. AB - At present there is overdue necessity of an integral approach to the assessment of health status and the impact of environmental factors on it, in the development of science-based management decisions and programs on improvement of the health status of the population of Kazakhstan and in the increase in life expectancy from the birth and healthy life expectancy. The purpose of the proposed program--improving health and increasing life expectancy from the birth and healthy life expectancy of the population of Kazakhstan. OBJECTIVES: Based on a meta-analysis to justify the target age group in which an implementation of complex of preventive measures will increase both the life expectancy from the birth and healthy life expectancy, to perform a comprehensive health screening for the basic classes of diseases and behavioral characteristics of the target group in the course of a multicentre studies to give a comprehensive hygienic characteristics of the ecological status of the studied regions and to develop the Health Passport of the region, to develop a model of the combined effects of environmental factors on health; to create a theoretical model for the calculation of life expectancy from the birth and healthy life expectancy, taking into account the limits of modifiability of factors that affect them, and justify a comprehensive program of management decisions on modification of factors, to carry out pilot studies on the development and validation technological (managemental) solutions to control modifiable factors that affect life expectancy from the birth and healthy life expectancy. PMID- 24340918 TI - [Optimization of accounting for radiation exposure of patients as a basis for assessing the risk of stochastic effects due to medical X-ray diagnostic irradiation]. AB - The work is devoted to optimization of the control and accounting for radiation exposure of patients in the X-ray examinations by means of improving existing forms of state statistical survey (form #3-DOZ.). The analysis of the radiation exposure of patients in medical institutions of the Rostov region for the period of 2005-2011 was carried out. It is proposed to exclude the information about the individual patient doses received by calculation; differentiate a group of "adult patients' on age and gender, selecting the reproductive age, discriminate as a separate category of dose-generating, intervention methods of research that will allow to more accurately calculate the risk of the development of stochastic effects of the medical radiation exposure to population. PMID- 24340919 TI - [The study of spatial distribution of Helicobacter pylori infection rate in able bodied population of Moscow in the course of medical examination of the manufacturing contingents]. AB - Numerous studies have shown that Helicobacter pylori (H. pylori) is a leading etiologic factor in the development of chronic atrophic gastritis, one gastric ulcer and duodenal ulcer and gastric cancer. Effective prevention of gastroduodenal pathology requires the right information about its prevalence in the population and risk factors. The most reliable information can be obtained during medical examination of the able-bodied population, which provides in-depth clinical examination of contingents with the identification of asymptomatic pathology, detection of risk groups, the substantiation ofprophylactic measures and tracking their efficacy. MATERIAL AND METHODS: During the clinical examination of the manufacturing contingents there was performed a study of the presence of infection Helicobacter pylori (H. pylori) in 2414 people aged 19 to 74 years. For more details on the presence of gastroduodenal pathology 991 people were examined with the use of clinical methods and interviews. The aggregation of information presented in the form of estimates for its geocoding and mapping has been made. Cluster analysis was performed. RESULTS: H. pylori infection was diagnosed in 2,182 people accounting for 90.4% out of 2414 examined cases. Infections occurred equally in males--91.7% and females--89.6%. The risk of development of gastroduodenal pathology in individuals infected with H. pylori is 4.4 times greater than the risk in seronegative individuals (95%, confidence interval 1.9-6.4). Cluster analysis revealed a statistically significant clusters for the strata with a prevalence of 100% (X2 = 45.5204) and below 50% of infection rate (X2 = 7.36). It is in prospect to analyze in more detail the data relating to these areas in order to identify the factors contributing to the different degree of infection rate of residents, including the assessment of drinking water. PMID- 24340920 TI - [Hygienic evaluation and prediction of population morbidity in the region of the Karachaganak field]. AB - The state of pollution of the environment in the area of operation of the Karachaganak oil and gas field depends on the development and operation of oil and gas objects. According to the analysis of retrospective studies, periods of the increase in air pollution have two peaks occurring in 1990 and 1997. However, these negative environmental moments are significantly different. In 1990, due to a sharp increase in the production of hydrocarbon crude, as well as the low efficiency of gas cleaning devices air pollution has increased significantly. The second period was characterized by a slight increase in the concentration of nitrogen dioxide only that was directly connected to the introduction of new technologies reducing environmental pollution. At the same time, the average population morbidity rate in settlement Berezovka is 336.8 cases per 1,000 surveyed, which is lower in 1.6 times than the reference data in the control townships. The leading place in the structure of morbidity are taken by digestive diseases, respiratory diseases and diseases of the nervous system, diseases of the eye and its appendages, diseases of the genitourinary system, diseases of the circulatory system, accounting for 87.6% of all diseases of the surveyed residents of settlement Berezovka. There was shown a multi-dimensional model of the dependence of general population morbidity in settlement Berezovka on the concentration of SO2 and NO2 in air. Also found depending on the influence of the concentrations of H2S, SO2 and NO2 in the air on the population on basic classes of diseases. PMID- 24340921 TI - [The spread of ecology-dependent diseases of the genitourinary system in bioclimatic zones of the Primorskii region]. AB - The estimation of the prevalence of a class of diseases of the genitourinary system (ICD-10) of the population in the bioclimatic zones of the Primorsky Krai, with taking into account the environmental situation has been performed. The study of the prevalence of diseases of the genitourinary system was carried out with the use of the classical method of data analysis--descriptive statistics. To determine the impact of water quality correlation and regression analysis of the statistical software package SPP has been applied. The study revealed that the diseases of the genitourinary system occupy in the structure of ecology-dependent morbidity in adults--14.9%, in adolescents--13.1% and in children--5.2%, respectively. During the period of 2000-2011 there is noted a trend of the growth of the level of pathology of the genitourinary system. Over the past 5 years, the number of uronefrological patients doubled. Using the a chi-square test for independence, we found that there is a statistically significant correlation (p < or = 0.001) between the level of diseases of the genitourinary system, the bio climatic zones and zones of ecological situation in all age groups. The use of regression analysis (multiple regression equation) allowed to determine the main parameters of the water module affecting the rate of spread of diseases of the genitourinary system in different bioclimatic zones. The prevalence level of diseases of the genitourinary system in each age group and bioclimatic zone is affected by a certain combination of parameters of the chemical composition of drinking water. The priority of them are by microbial number, Cl-, Fe sum, NO3-, HCO3-, PH, Mg2+, Ca2+. Ranking of the territory in terms of morbidity permitted to determine the problematic situation in the administrative bodies that was taken into account in the development of the program on the prevention of the ecology-dependent diseases of the genitourinary system. PMID- 24340922 TI - [Hygienic evaluation of the influence of environmental factors on the functional indices of schoolchildren]. AB - Muscle strength of the hands (carpal dynamometry)--is an integral indicator of the functional state of the nervous and muscular systems of the child, as well as the index of fitness and stamina. The drop in functional indices of children has been noted by many researchers from different regions of Russia. In this study, an analysis of endogenous and exogenous factors in children and adolescents with different muscle strength has been performed. The level of the biological development, especially in adolescence, was found to have a significant impact on the muscle strength. The reduction in muscle strength in pupils is due to exogenous factors, such as low physical activity, high study loads. PMID- 24340923 TI - [On prediction the hygienic standards of chemical substances having a selective action, in the atmospheric air of populated areas]. AB - There are proposed new mathematical models for calculation the TSELs of substances with selective (with a predominant effect on the nervous system, liver and specific irritant action) or polytropic character of influence on the organism body in a single inhalation exposure. For substances with a predominant effect on the nervous system and the simultaneous effect on the kidney, liver and nervous system there was established high correlation between the TSELs and Limac. PMID- 24340924 TI - [On the question of occurrence and the problem of hygiene rating of fungal air pollution of the environment of residential and public buildings]. AB - Comprehensive sanitary examinations of fungal pollution of the environment of residential and public buildings were performed. There is established the occurrence of sensitization of the population associated with the fungal contamination of the wallings of buildings and presence of viable mold spores in the indoor air environment. Major factors determining the degree of fungal contamination of indoor environments: increasing humidity of indoor air due to leaks and bays, the area of enclosure structures and the temperature factor have been identified. PMID- 24340925 TI - [Polymorphisms Ser447Ter of lipoprotein-lipase gene, Cys112Arg and Arg158Cys of apolipoprotein E gene in patients with obesity]. AB - The distribution of allele Ser447Ter of lipoprotein lipase gene (LPL) and polymorphic markers E2 and E4 of the apolipoprotein E gene (ApoE) were examined in 100 obese patients at the age of 18-66 years (28 men and 72 women, 40.6 +/- 2.1 years old). The first group included patients with I degree of obesity (n = 26, BMI = 32.5 +/- 0.2), the second group--patients with II degree of obesity (n = 33, BMI = 37.1 +/- 0.2), the third group--patients with grade III obesity (n = 41, BMI = 46.3-1.1) and control group were 18 healthy individuals aged from 22 to 55 years (7 men and 11 women, 36.5 +/- 0.9 years old, BMI = 22.4 +/- 1.8). Maximal frequency of allelic polymorphism epsilon2 has been revealed in patients with I degree of obesity, and allele epsilon4--in patients with III degree of obesity. The most common genotype of ApoE gene was epsilon3/epsilon3 in all three groups of patients with obesity. In a comparative analysis of allelic variants of the Apo E gene occurrence it has been found that the frequency of a polymorphic variant epsilon2/epsilon2 tended to decrease with BMI increasing, whereas a higher rate of detection of genotypes epsilon4/epsilon3, epsilon4/epsilon4 and epsilon2/epsilon4 was found in patients with III degree of obesity. The data obtained suggest that the epsilon4 allele of the Apo E gene is associated with the development of morbid obesity, rather than allele epsilon2. This phenomenon can be explained by the fact that apoE4 isoform has reduced affinity for LDL in comparison with apolipoprotein E3. The maximum concentration of cholesterol, triglycerides and LDL cholesterol has been observed in patients with epsilon2/epsilon4 genotype of ApoE gene, and it was significantly higher than in the control group (p < 0.05). The content of blood lipid fractions in patients with epsilon3/epsilon4 genotype of ApoE gene, in contrast, was the lowest among obese and did not exceed the values of the control group (p > 0.05). These data indicates a small contribution of epsilon4 polymorphism in heterozygous form to the development of dyslipidemia in obesity. The most positive effect of diet treatment was achieved in patients with genotype epsilon3/epsilon3 and epsilon3/epsilon4. An integrated approach to the assessment of lipid metabolism in patients with obesity, including the analysis of polymorphic genetic loci, can optimize and personalize the diet therapy. PMID- 24340926 TI - [Body structure and serum concentration of adiponectin and cytokines (IL-6, -10 and TNF-alpha) in rheumatoid arthritis combined with obesity]. AB - In the study the comparative assessment of the main markers of body structure and serum concentrations of adiponectin and cytokines (IL-6, TNF-alpha, IL-10) has been carried out in 26 rheumatoid arthritis patients at a normal body mass index (BMI) [Me; 25; 75 percentile = 24,1 (23,5; 28,6)] and in 15 obese patients [BMI = 33,4 (31,3; 42,7)]. The control group consisted of 25 apparently healthy individuals [BMI = 23,5 (21,8; 24,4)] randomized by sex and age with the main group. The expressed increase of production of pro-inflammatory cytokines--TNF alpha and IL-6 in both groups has been established, in the group of patients with obesity serum concentration of these cytokines 1,8-2,4 fold exceeded similar in group with a normal BMI and amounted 245,3 (89,3; 302,3) and 54,4 (18,4; 72,3) microg/ml correspondingly. Anti-inflammatory cytokine IL-10 increased more significantly at normal BMI [227,2 (143,4; 282,3) pg/ml)] in comparison with group of rheumatoid arthritis patients with obesity [122,2 (89,3; 164,3) pg/ml] while in control group its content was 60,8 (24,3; 75,4) pg/ml. It has been shown that serum concentration of adiponectin was higher in group with normal BMI [9,2 (6,3; 15,3) mcg/ml] and was lower in patients with obesity [3,2 (2,3; 8,3) mcg/ml] than in healthy subjects [7,4 (4,4; 9,2) mcg/ml]. The analysis of the body structure markers demonstrate that fatty tissue content increase both in patients with normal BMI (1,7 fold) and at obesity (2,6 fold). PMID- 24340927 TI - [Hematological indices of rats having complete and vitamin-deficient diets enriched with dietary fibers]. AB - The hematological indices in 48 rats Wistar male with initial body weight 58.1+/- 0.5g has been studied. The rats were divided into 6 group and fed the complete semi-synthetic diet, containing 100% or 20% of vitamin mixture (Vit) with or without addition of dietary fiber (DF) in the form of wheat bran (5% of diet mass) during 4 weeks. The animals of the 1 group received 100% of vitamin mixture (100% Vit); of the 2 group--100% Vit+DF; 3 group--20% of vitamin mixture (20% Vit); 4 group--20% of vitamin mixture and DF (20% Vit+DF). The next 5 days rats from vitamin-deficient groups were fed with diets supplemented with 80% of Vit: (5 group--20% Vit+ 80% Vit; 6 group--20% Vit+DF+80% Vit). The animals fed vitamin deficient diet lag significantly in growth from animals fed a complete diet. The growth curve of rats fed a diet with DF took an intermediate position. The studies were carried out at the Hematology analyzer "Coulter AC TTM 5 diff OV" (Beckman Coulter, USA) under the program, developed for the study of rat blood. Mean corpuscular volume (MCV) and mean corpuscular hemoglobin content (MCHC) were significantly decreased in rats with combined vitamin deficiency (20% Vit) in the diet compared with those of control group rats, while the compensatory increase in the number of red blood cells (RBC) and leukocytopenia took place. The enrichment of vitamin-deficient diet with DF (20% Vit+DF) prevented MCV and RBC changes, but MCHC left reduced in comparison with the indicator of the rats in control group. Indicators characterizing the state of platelets had no statistically significant differences between the groups. Compensation of vitamin deficiency in the diet of rats from group 5 (20% Vit+80% Vit) led only to the normalization of MCV. After vitamin restore in the diet of group 6 (20% Vit+DF+80% Vit) all investigated parameters were indistinguishable from the parameters of the control group. This indicates a positive effect of wheat bran DF consumption on the studied hematological indices. PMID- 24340928 TI - [Effect of intragastrically injection of phytoecdysteroids on some indicators of hormonal status in rats]. AB - The experiment in vivo in growing male Wistar rats was carried out. The animals of the experimental 2-4 groups were daily intragastrically injected water solutions of the dried extract from the leaves of Seratulla coronata L. in volume of 1.0 ml, containing 2, 20 and 50 mg of phytoecdysteroids per kg of animal weight, accordingly. Animals of control group were daily injected 1.0 ml of water. The content of phytoecdysteroids in the dry extract was analyzed by high performance liquid chromatography (HPLC). The concentration of the sum of phytoecdysteroids in dry extract was 6.15%, 66% of which was 20-hydroxyecdysone and 23% was 25S-inokosteron. On the 15th day animals were taken out of the experiment by the decapitation. The content of corticosterone, prostaglandin E2 and beta-endorphin in rat blood plasma were determined by ELISA test. The pathological--anatomical analysis and weighing of the liver did not reveal any adverse changes of this organ in the animals of all groups. The average concentration of blood plasma corticosterone reduced with increasing of the dose of the extract injected to the animals, reaching significant differences relative to the control group (60.9 +/- 9.4 ng/ml) for 3 and 4 groups (22.7 +/- 6.6 and 17.6 +/- 7.3 ng/ml, accordingly). Beta-endorphin and prostaglandin E2 levels did not differ. The ratio of the mediator of stress (corticosterone) and inhibitors of stress (beta-endorphin and prostaglandin E2) has been calculated. A monotonic decrease of corticosterone/beta-endorphin and corticosterone/prostaglandin E2 ratio has been found with extract dose increasing. Taken together the results of determination of biochemical parameters of the general adaptation syndrome the dose-dependent stress-protective effect of Seratulla coronata L extract has been demonstrated. PMID- 24340929 TI - [The state of the antioxidant status of children of different ages]. AB - The parameters of lipid peroxidation (blood plasma content of primary products of lipid peroxidation and the end of TBA-active products) and indexes of antioxidant protection (total antioxidant activity, the content of fat-soluble vitamins A and E in blood plasma and riboflavin in blood) has been evaluated in 75 healthy children living in Irkutsk. All respondents were divided into three age periods: preschool age (3-6 years old, mean 4.7 +/- 1.0 - 21 children), primary school age (7-8 years, 7.6 +/- 0.4, - 28 children) and middle-school age (9-11 years, 9.9 +/ 0.7, 26 children). We used spectrophotometric and fluorometric methods. Identified the distinctive features of the metabolic reactions in children at different ages. The increase of the content of the primary products of lipid peroxidation in the early school years and of the end of TBA-active products for children of secondary school age in comparison with the preschool children has been determined. At the same time an increase in the level of total antioxidant activity and fat-soluble vitamins and riboflavin content in young and middle school aged children in comparison with the pre-school children has been observed. The measurement of vitamins status demonstrated the insufficiency of alpha-tocopherol in half of pre-school children, in 36% of primary school children and 38% of children of secondary school age. Retinol and riboflavin deficiency has been detected in a small proportion of children of all ages. In this regard, the additional supply with vitamins of children in pre-school and middle-school period is essential. PMID- 24340930 TI - [Allergic reactions to cereals in children with atopy]. AB - Cereals are the necessary and the major products in the diet. The aim of the study was to determine the dependence of frequency of sensitization to various cereals in children with atopy upon the age and diagnosis on the basis of anamnesis, the results of elimination diets, skin tests and the presence of specific IgE antibodies. 416 children and adolescents aged from 6 months to 17 years with atopic dermatitis (n = 359) and asthma (n = 57) has been investigated. The frequency of sensitization to cereals in children with atopic dermatitis according to skin tests ranged from 31 to 43%. Expressed sensitization (skin test +++, ++++) on the large majority of groats did not exceed 3% and only on corn and barley, it took place in 5.8 and 3.8%, respectively, while 81% of these children data coincided with a case history. The percentage of severe sensitization in boys was generally higher than that among girls. The percentage of pronounced sensitization to cereals increased with age in patients with atopy. The reason why the frequency of marked sensitization to maize in asthmatic children older than 7 years reached 20% and in children with atopic dermatitis reached 7.5% at the age of younger 1 year and 7.7% at the age from 3 to 7 years, remains unclear and requires further study. PMID- 24340931 TI - [Correction of polyhypovitaminosis in rats, having standard and enriched with polyunsaturated fatty acids family omega-3 diets with different doses of vitamins]. AB - The efficiency of the correction of combined alimentary vitamin deficit in male Wistar rats (body weight 90-121 g) fed standard diet or enriched with omega-3 polyunsaturated fatty acids diet (by replacing sunflower oil (4.5% of the diet) with linseed oil) with different doses (physiological and enhanced) of vitamins has been investigated. The control group of animals (n = 12) received a complete semisynthetic diet during all experimental period (42 d). The animals of the test groups (each of 20 rats) received vitamin-deficient diet containing sunflower or linseed oil and 20% per cent of vitamin mixture amount in control diet from which vitamin E had been excluded. After 28 days of such feeding each of test groups was divided into two subgroups (6-8 rats in each), and the next 14 days the animals of subgroups received the diet with different degree of vitamin compensation (50 or 180% percent of vitamin content in the diet of the control group). The addition of both low and high vitamin dose in deficient diet based on standard fat component did not compensate the reduced liver vitamin A content, which amounted to 47.4% of the level in the liver of the control group. The lack of vitamin E in animals was eliminated only after adding of the enhanced dose of vitamin E to the ration. Recovering of decreased plasma and liver B2 level, plasma 25(OH)D and liver vitamin B1 content have been occurred after addition of the low dose of these vitamins to rat diet. Increasing of omega-3 PUFA diet level improved vitamins A and D sufficiency to some extent, but was accompanied by the significant reduction of rat liver alfa-tocopherol content both under combined vitamin deficiency (by 14%) and increased vitamins consumption (by 43%). PUFA enrichment of the diet of rats with vitamin deficiency had no impact on vitamin B1 and B2 liver level. The use of high doses of vitamins for a long time to eliminate a combined deficiency of vitamins has been proved. PMID- 24340932 TI - [Direct detection of T-2- and HT-2-mycotoxins producers of fungi the genus Fusarium in food grain by PCR (report 2)]. AB - The improvement of the Fusarium DNA extraction method has been undertaken in order to reduce the error of PCR analysis for detection of toxigenic Fusarium species, including those contained in the grain in the uncultureted state, directly in the grain. The efficiency of Fusarium DNA extraction methods (nucleotides sorption and CTAB method) has been compared. The efficiency of CTAB method combined with 10-fold weight increase of milled grain sample has been demonstrated. This approach revealed a greater number of Fusarium species, than PCR analysis of combined Fusarium mycelium from the same samples. The uncultureted F. langsethiae was detected in the DNA extract from a sample of barley, which was not identified in the combined sample of the mycelium. This sample of the grain has the highest levels of T-2/NT-2-toxins--0,075/0,345 mg/kg (determined by HPLC) among positive samples. F. sporotrichioides--a potential producer of T-2- and HT-2-toxins has been revealed by PCR method in other grain samples both containing and not containing these toxins. The biosynthesis of T-2- and HT-2-toxins on the PSA-medium in vitro has been studied for 10 single-spores F. sporotrichioides isolates, allocated from grain. Synthesized T-2-toxin content (measured by ELISA) ranged from 0.4 to 184.5 mg per l of medium. Three strains showed very high levels from 117.2 to 184.4 mg/l, two of which have been isolated from barley which don't contain these toxins. The absence of the toxin in grain samples does not guarantee the absence of high-level producers of mycotoxins. The direct detection of Fusarium spp. in grain by PCR analysis with extraction of fungal DNA by CTAB method along with increased sample weight has been shown to make possible the detection of a more number of species of Fusarium (including uncultureol strains) compared with mycological method with PCR analysis of the combined sample of the mycelium. PMID- 24340933 TI - [Influence of dietotherapy enriched with conjugated linoleic acid on anthropometrical indicators and body composite structure in patients with an overweight]. AB - The clinical efficiency of dietotherapy enriched with conjugated linoleic acid (3 g per day) in patients, suffering from the excess mass of a body and obesity of I and II degrees has been investigated. Dynamics of anthropometrical indicators and body composite structure before and after the treatment of patients from the main (n = 20) and control groups were estimated. Studied parameters were fixed in day 0, 14 and 28. Statistically significant reduction of the weight, body mass index (BMI), anthropometrical parameters (volumes of a waist, hips, a shoulder), indicators of body composite structure (fatty weight, area of splanchnic fat, muscular weight) has been revealed as a result of the carried-out course of treatment, and they were more expressed in patients of the main group. In particular, the waist size authentically decreased by 6.5% in patients from the main group, while in patients from the group of comparison the decrease reached only 4.2%. Average change of waist volume was--7.0 cm in the main group and--4.5 cm in the control group. The grasp of hips in the main group decreased by 4.2%, in the group of comparison for 2.8%. Absolute change of hips volume in the main group 1.67 fold exceeded that in the group of comparison (p < 0.005). The shin grasp in the main group decreased by 9.7%, while in the control group remained invariable. BMI decreased by 7.2% and 5%, respectively. Thus, the reduction of body fatty weight was 10% in patients from the main group and 4% in patients from the group of comparison. The body total liquid decreased by 1.4 l in the main group, and only by 0.3 l in the group of comparison. The received intergroup distinctions are statistically reliable (p < 0.05). PMID- 24340934 TI - [Legislative regulation of production and turnover of products for people with different diseases]. AB - This article presents results of analysis of existing regulatory documents and approaches to the legislative regulation of production and turnover of special dietary products for people with specific diseases in EU, Ukraine and Russian Federation. According to the EU legislation, production and turnover of food products for nutritional support of people during specific diseases and the rehabilitation period are regulated by the Commission Directive 1999/21/EC, 2009/39/ES, by Regulation Commission (EU) No 953/2009 and documents of Codex Committee. Special food products for people with specific diseases in Ukrainian legislation are classified as nutrition products for special dietary use and are regulated by the following Laws of Ukraine "On the safety and quality of food", "On ensuring of sanitary and epidemiological welfare of the population", "On Consumer Rights Protection", "On advertising" and by other non-legislative acts. According to the current legislation of the Russian Federation, the products for people with specific diseases are classified as healthy dietary food products. The basis of the legal framework are federal laws "On the quality and safety of food", "On the sanitary-epidemiological welfare of the populations", "On technical regulations and technical regulations of the Customs Union "On Food Safety" and "On the safety of certain types of specialized food products, including healthy dietary food products and therapeutic dietary food products". There is no common approach to the legal regulation of production and turnover of products for people with specific diseases in the world. The proposals for further harmonization of regulatory control in this area have been developed. PMID- 24340935 TI - [Investigation of actual nutrition and some factors of physical status in rugby players]. AB - Physical status and nutrition and energy value of factual diets of 18 rugby players (15-30 years old) assessed during current medical observation were analyzed. Anthropometric data (height, body mass--BM, waist circumference/ hip circumference index, body mass index--BMI), body composition data and resting metabolic rate by bioimpedance method (analyzer ABC-01 "Medass") were determined. These indices were found to be normal except more high level of BMI due to high levels of lean and skeletal muscle mass, but not a result of obesity. Estimation of factual nutrition based on 1-day feeding (nutrition-screening questionnaire method) has demonstrate that it was not optimal both for energy and nutrition value for this group of physical activity. Energy value ranged from 1889 kcal to 3175 kcal (22.5-35.1 kcal/kg BM/day) with lower carbohydrate intake (46.9%) and higher fat intake (35.8%) were found. Nutrition value ranges: protein--67-144 g (0.71-1.38 kcal/kg BM/day), fat--75-140 g (0.88-1.51 kcal/kg BM/day), carbohydrate--173-420 g (2.17-4.66 kcal/kg BM/day) were observed. The findings suggest the need to pay more attention to in-depth study of dietary intake of athletes to maintain health and to create optimal conditions for a professional sports activities. PMID- 24340936 TI - [Vitamin and mineral status of oarsmen during the training-competition cycles]. AB - Vitamin and minerals status of 30 sportsmen aged 16.8 +/- 0.2 years (trained in boat racing 5.0 +/- 0.3 years) during the training--competition cycles in autumn and winter has been studied. A significant decrease of vitamin A level in the range of reference limits was found in 30.8% of sportsmen during autumn season, but such decrease was revealed in 100% of examined sportsmen during winter Vitamin B1 and B2 deficiency has been detected in both seasons. The portion of persons with vitamin B2 deficiency increased during training cycles. A significant decrease of magnesium (in 56.3% of sportsmen) and sodium level (in 33.3% of sportsmen) was detected during autumn season. Irrespective of the season a significant decrease of blood serum of calcium (in 40.0-66.7% of sportsmen); potassium (in 53.3-66.7% of sportsmen according to both absolute and individual data); chlorides (in 50.0-90.0% of sportsmen), and iron (in 53.3-60.0% of sportsmen) has been revealed. The data obtained indicate the need for diagnostics and correction of vitamin and minerals status in sportsmen. PMID- 24340937 TI - [Food contamination by pathogens of acute intestinal infections and survival of microorganisms in them under some variants of thermal processing and storage]. AB - The contamination of the surface of vegetables and fruits with conditionally pathogenic enterobacteria, intestinal protozoa and enteric viruses has been revealed. The experiment showed an opportunity of penetration of enteric viruses inside of vegetables and fruits with intact (without visible damages) surface. S. enteritidis survive on the shells of the eggs 4 months in the refrigerator, in the albumen and yolk--more than 5 months and in the long storage (more than one month) of chicken eggs in the refrigerator S. enteritidis could penetrate into the egg through the intact shell and multiply in the yolk. It was shown in the experiment on the condition laying of chicken eggs of room temperature in cold water and their subsequent cooking S. enteritidis full destruction of pathogens comes on the 5 minute of heat processing, when the temperature inside the eggs reaches more than 80 degrees C. In mayonnaise at the temperature of the refrigerator S. enteritidis reproduce, but remain viable for 13 days. In the egg powder at the room temperature noted smooth death of S. enteritidis, term viability of microorganisms is 5 months. Addition 10% acetic acid to egg powder in the ratio 1:2 provides for the death of S. enteritidis for a minute. In experimental conditions was established that the processing of chicken on the grill in the process of cooking "Shaverma" provides exemption meat from Salmonella only in the thickness of a piece of up to 2 centimeters. The deeper layers of meat and meat juice which accumulates on the pallet grill, throughout the duration of thermal processing may remain contaminated Salmonella. PMID- 24340938 TI - [The medium chain fat acids. Content in food. Physiology, characteristics of metabolism and application in clinical practice]. AB - It is rational, according to biology laws and purposes for which cells use fatty acids, to distinguish between saturated (without double bonds in chain), monoene (with one bond), unsaturated (with 2 and 3 double bonds) and polyene (with 4, 5 and 6 double bonds) acids. The saturated and monoene fatty acids are mainly the substratum for oxygenation and working out of energy by cells. The unsaturated fatty acids are the substratum for formation of membranes. The polyene fatty acids are the predecessors of synthesis of eicosanoids and aminophosphotides. With subject to characteristics of metabolism and transfer in vivo, the fatty acids are subdivided into short chain C4 - C8 and medium chain C-10 - C-14 fatty acids. The etherification occurs with glycerin into "short" triglycerides which are not bounded with apoproteins. The long chain fatty acids form "long" triglycerides which in enterocytes are structured by apoprotein B-48 into composition of chylomicrons. It is possible to validly consider that difference in outflow from enterocytes to veins of portal system (which includes veins of omentum) of medium chain fatty acids in the form of short triglycerides can directly input into pathogenesis of syndrome of isolated omental obesity and metabolic syndrome. The another input into the mentioned conditions is the secretion through ductus thoracicus into large veins of greater systemic circulation of long chain fatty acids in the form of triglycerides in the content of chylomicrons. The omental obesity is the only specific symptom of metabolic syndrome. PMID- 24340939 TI - [The analysis of concentration of cyclosporine A in blood using liquid chromatographic mass spectrometry]. AB - The method of analysis of concentration of immunosuppressant of cyclosporine A in whole blood was developed. The highly effective liquid chromatography with mass spectrometric detection was applied using device of "ionic trap" type. The optimal conditions of analysis are established. The tryout of method was carried out using blood samples of healthy donors and patients underwent allotransplantation of organs. The comparison was made of the developed method with method of fluorescence polarized immunoassay Abbott TDX applied in clinical diagnostic. The higher selectivity of the proposed method to cyclosporine A as compared with Abbott TDX was established. PMID- 24340940 TI - [The enzymes of blood plasma and hepatic tissue in children are dependent on stage of transition to chronic state of viral hepatitis]. AB - The detection of activity of enzymes in hepatic tissue and whole blood in children aged 12-16 years with chronic viral hepatitis was carried out. The results of study demonstrated that the level of metabolic parameters during the third stage of transition of disease to the chronic state as compared with the second stage testifies the presence of deeper functional affection of hepatic cells and more expressed metabolism disorders. The character of ratio of levels of activity of enzymes in liver and blood of children under the second and third stages of transition of disease to chronic state was analyzed. It is affirmed that the blood enzymatic indicators reflect specificity and direction of alterations of metabolic processes in hepatic cells under chronic hepatitis C. This process can be used as a basis for development of new diagnostic approaches to this form of pathology. PMID- 24340941 TI - [The dynamics of changes in lysozyme activity and content of lactoferrin content of patients with chronic osteomyelitis]. AB - The article demonstrates that the examination of patients with chronic osteomyelitis treated using the transosseous osteosynthesis technique established the ambiguous character of changes in concentration of lactoferrin and lysozyme in blood serum as compared with pre-surgery values. It is demonstrated that closer to the end of 2-3 months after surgery the normalization of analyzed indicators occurs. The complex detection of lactoferrin, lysozyme applied additionally to basal examination of cell immunity can be used to monitor the chronic osteomyelitis. This approach can play a significant diagnostic and prognostic role in evaluation of severity on infection process. PMID- 24340942 TI - [About the biochemical criteria of heroin (narcotic) intoxication]. AB - The article deals with the data of study of biochemical indicators and activity of particular proteolytic enzymes in blood serum of patients with heroin drug addiction. The results can be applied to detect the typical laboratory changes intrinsic to this kind of intoxication. PMID- 24340943 TI - [The impact of anemia on content and physical chemical characteristics of membranes of erythrocytes in pregnant women]. AB - The article deals with the study of deformability of erythrocytes, lipid protein content and physical chemical characteristics was cytoplasmic membrane of erythrocytes in women aged 21-26 years with pregnancy taking normal course and complicated with anemia. In women with pregnancy complicated with anemia, by the period of 32-34 weeks in membranes of erythrocytes the percentage of lysophosphatids and cholesterol is decreased while the number of whole phospholipids and phosphatidyl inositols is decreased. The variance analysis demonstrated that the percentage of impact of anemia on the content of whole phospholipids consisted 11.1% and on ratio of phospholipids and cholesterol about 23.9%. The changes in content of membranes of erythrocytes had no impact on their physical chemical characteristics and deformability of erythrocytes. PMID- 24340944 TI - [The application of different types of liquid technologies in cytology]. AB - The article discusses the results of comparative study of traditional smears and three different liquid technologies of making ready of cytological preparations (CytoSpin3, E-Prep Processor BD TriPath) using material from 112 patients with pathological processes of such different localizations as exudative liquids (31), soft tissues (22), lymphatic nodes (18), mammal glands (20), saliva glands (7), lungs (9), thyroid gland (5). It is established that under joint application of liquid and traditional cytology the effectiveness of cytological analysis increases up to 3.3%-5% depending on localization of pathologic nidus. The implementation of liquid technologies expands the possibilities of applying immunocitochemistry and molecular genetics to cytological materials. PMID- 24340945 TI - [The clinical safety of patient and reliability of laboratory information]. AB - The diagnostic and curative measures during medical care support can be related with direct and indirect risks for patient. The clinical safety of patient is determined by both proper and timely diagnostic of pathology and application of appropriate curative measures on purpose to achieve safe outcome of case of disease. The important condition of clinical safety is the reliability of applied laboratory information which depends on degree of impact of factors deflecting value of analytical test result from true value of analyzed variable in organism of patient. The implementation of system of corrective measures, quality indicators, inner laboratory and external quality control and the referent system of laboratory medicine are needed to overcome the impact of deflecting factors. PMID- 24340946 TI - [The two-phase growth medium for sub-culturing of Helicobacter pylori]. AB - A. Pylori is a very undemanding microorganism needing the in support of complex of conditions including particular atmosphere, temperature of culturing and composition of growth medium. The two-phase growth medium is recommended to sub culturing in Petri dishes with diameter of 90 mm. The growth medium consists of chocolate agar with addition of Schedler broth and enriched with 10% serum of cattle. PMID- 24340947 TI - [The development and testing of reagents kit for detection and qualitative evaluation of DNA of methicillin sensitive and methicillin resistant Staphylococcus aureus and also methicillin resistant coagulase negative Staphylococcus spp. applying technique of polymerase chain reaction in "real time" mode]. AB - The reagents kit is developed to identify and quantitatively detect DNA of methicillin sensitive and methicillin resistant Staphylococcus aureus, methicillin resistant coagulase negative Staphylococcus spp. in biological material using technique of polymerase chain reaction with hybridizational fluorescent detection and having higher analytical and diagnostic characteristics. The application of the given reagents kit makes it possible to optimize the epidemiologic monitoring of propagation of methicillin resistant strains of Staphylococcus spp. Significantly decreasing duration and laboriousness of study. PMID- 24340948 TI - [The first experience of application of standardized genotype technique of identification of HIV-tropism]. AB - The antagonists of co-receptor CCR5 are an ultimately new class of preparations to treat HIV-infection. The mechanism of action of the preparations of this class is in the selective binding with co-receptor CCR5. This process results in the prevention of penetration of HIV into cell. Before prescribing the CCR5 antagonists the detection of viral tropism has to be done. Recently, in Russia the genotype technique of tropism detection was registered which can be used in clinical practice. The present article describes first experience of application of the given technique to clinical samples. The high correlation was established while comparing with the results of reference laboratory. PMID- 24340949 TI - [The detection of activating somatic mutations in gene KRAS using pyrosequencing technique]. AB - The technique to detect all possible variants of mutations in 12, 13 and 15 codons of gene KRAS was developed on the basis of the pyrosequencing technology. The analytical characteristics of the developed technique were identified. The limit of detection for mutations G34T, G35A and G38A detected on the cloned control samples consisted 3%. The limit of blank for various mutations consisted from 0.3% to 4.1%. The system was tested on clinical samples. The 7 different types of mutations were identified and detected in quantitative format. No discrepancy of pyrosequencing data with results of sequencing according Sanger was established. PMID- 24340950 TI - [The diagnostic of anaerobic infection induced by Clostridium perfringens in patient with post-traumatic phlegmon: a clinical case]. AB - The article presents uncommon clinical case of anaerobic gas-producing infection induced by Clostridium perfringens. The disease resulted in lethal outcome at fourth day after admission of patient into hospital. The successful treatment requires timely diagnostic of clostridium infection based on complex of microbiologic, clinical and laboratory data. The early diagnostic is possible in case of bacteriologic analysis of native material. PMID- 24340951 TI - [The phenomenon of increasing of activity of aspartate transaminase in blood plasma ("macro-AST") in healthy persons]. AB - The article considers the case of several years long increased level of activity of aspartate transaminase in blood plasma of clinically healthy persons from one family (belonging to Caucasioni type)--the father 35 years old and two biologic children, daughter 4 years old and son 3 years old. In all family members with hyper aspartate transaminasemia chronic diseases, alcohol and drugs consumption, regular use of certain medications and dietary supplements or impact of exogenous (ecologic) chemical factors producing persistent increase of activity of aspartate transaminase in blood plasma were totally excluded. On the basis of totality of anamnesis and results of clinical and laboratory examination the given condition was considered as "macro-AST" being a variant of biochemical phenomenon of "macro-enzymes". PMID- 24340952 TI - [The external quality measurement: actual problems and future directions]. PMID- 24340953 TI - [The news of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC)]. PMID- 24340954 TI - [Prognostic value of uteroplacental circulation impairment in 1st trimester of pregnancy in patients with complicated obstetric history]. AB - One of the urgent problems of modern obstetrics is the early detection of irregularities in the development of the uteroplacental vessels system in patients with severe disorders in the history. AIM: To evaluate the predictive value of re-development of obstetric pathology on the basis of the uterine artery Doppler on 11-14 weeks of pregnancy. PATIENTS AND METHODS: 410 patients in I trimester of pregnancy were examined with fetal growth restriction, preeclampsia and/or fetal death and/or a history of preterm delivery were. The influence of physical factors and obstetric history on the state of uterine blood flow in the I trimester of pregnancy was studied. RESULTS: The optimal Doppler indexes was calculated; a high predictive ability of the pulsation index in the uterine arteries with respect to pregnancy complications with early clinical manifestation, severe preeclampsia and combined obstetric complications was detected. CONCLUSIONS: Our data support the possibility of preclinical diagnosis of obstetrical complications in patients with complicated obstetric history. PMID- 24340955 TI - [Glutathion as an important component of thiosulfid system of infertility pathogenesis in overweight men]. AB - AIM: To study the glutathionic part of thiosulfid system and oxidative stress in infertile men with different body mass index. PATIENTS AND METHODS: Examined 60 infertile men with normal and overweight, and 40 healthy men with proven fertility. Active components of the antioxidant defense system of the body was assessed by the level of reduced and oxidized glutathione by the method of PY Hissin, determination of TBA-active products was carried out by the method VB Gavrilova. In the analysis of inter-group differences for independent samples was used parametric Student criterion. RESULTS: The oxidative stress in obese men was characterized by significant elevation of oxidized form of glutathione (GSSG) in comparison with its reduced form. We discussed our results in the context of GSSG "quantivalence" to numerous of cellular processes in the setting of metabolic disorders in infertile and obese men. The ratio of reduced glutathione to oxidized infertile men decreased by 1,5 times in patients with obesity and 1,2 times in those with normal body mass index. CONCLUSIONS: Glutathione is the most important link in the study of oxidative stress in men with infertility. Raising the level of oxidized glutathione is due to the presence of his additional functions that are implemented at higher values of body mass index, especially in association with infertility. PMID- 24340956 TI - [Lipid, adipokine and ghrelin concentrations in myocardial infarction patients with insulin resistance]. AB - AIM: The estimate insulin resistance in myocardial infarction. PATIENTS AND METHODS: The study involved 200 patients with myocardial infarction, in which on the 1st and 12th day of hospitalization measured glucose, insulin, insulin resistance index (IR), lipid profile, the concentration of adipokines and ghrelin. RESULTS: IR was detected in 77% of patients and was associated with a history of factors of cardiovascular risk, adverse clinical course of the disease, lipid disorders. The most important marker was the level of free fatty acids. High risk associated with increased in 9 times the concentration of free fatty acids in blood plasma. Patients with IR observed increased concentrations of leptin, resistin, and reduced the protective effect of adiponectin. The high specificity and sensitivity characteristic of the concentration of ghrelin: its reduction by 4 times in the acute phase of myocardial infarction increases the risk of MI by 78%. CONCLUSIONS: Significant risk factors for MI myocardial infarction, along with insulinemia and glycemia, is to increase the concentration of free fatty acids and the disbalance in the system adipokines against deficiency of ghrelin in acute and early recovery periods of the disease. Free fatty acids and ghrelin are promising markers to stratify the risk of insulin myocardial infarction. resistance in patients with myocardial infarction. PMID- 24340957 TI - [The success of heart rate variability biofeedback parameters in persons with different levels of blood pressure]. AB - OBJECTIVE: The aim was to determine the nature of cardiovascular reactions during a single session of heart rate variability (HRV) biofeedback in order to increase vagal effects on heart rhythm in patients with different initial levels of blood pressure (BP). PARTICIPANTS AND METHODS: 33 people with normal blood pressure (group I), 20 people with uncorrected arterial hypertension (AH) grade 1-2 (group II) and 22 people with AH grade 1-2 taking antihypertensive drugs (group III) were observed. The parameters of heart rate variability (HRV), BP and pulse aximetry in the initial stage, during a single HRV biofeedback session and after this session in order to increase the total power of the HRV spectrum (each stage 5 min). RESULTS: In patients of group II low success of HRV biofeedback session, a high sympathetic reactivity and reduced oxygen blood saturation were determined. A reactivity of vagal mechanism is more pronounced in persons of group III than in those of group II. It is reflected in a significant increase in their total power of the HRV spectrum compared to the initial values and in uptrend saturation levels during the biofeedback session. CONCLUSION: The ability to HRV biofeedback in order to increase the total power of the HRV spectrum for standard short recording (5 min) can be seen as a test to determine the safety reserves of vagal autonomic cardiovascular regulation in persons with increased blood pressure. PMID- 24340958 TI - [Local fibrinolysis in surgical treatment of non-traumatic intracranial hemorrhages]. AB - More than 70% of hypertensive hemorrhages are located in deep brain structures. The removal of such hematomas using encephalotomy is accompanied by additional cerebral trauma and often results in unsatisfactory outcomes. The puncture aspiration with local fibrinolysis is one of the minimal invasive methods for treatment of intracerebral hematomas (ICH). The puncture and aspiration of liquid part of ICH (not more than 20% of ICH volume) is performed via small burr hole. Afterward the catheter is placed into ICH cavity and fibrinolytic is injected via this catheter in postoperative period for lysis of ICH solid part. The lysed blood is aspirated within 1-4 days. The last generations of fibrinolytics are very effective concerning intensity of blood clot lysis and practically have no systematic effect on blood coagulation system during their local usage. Morphological examinations showed that usage of fibrinolysis leads to formation of smaller cysts in the region of former hematoma as well as reparative processes in perihemorrhagical zone are expressed better comparing with treatment methods without usage of fibrinolytics. The morphological pattern is also confirmed by clinical signs of neurological deficit regress corresponding to damage focus. We operated 124 patients with parenchymal hemorrhages and 28 patients with intraventricular hemorrhages using described minimally invasive method at the base of Scientific Research Institute of Emergency Care n.a. N. V. Sklifosovsky. The applied method allowed decreasing lethality from 35% to 21% among patients with parenchymal ICH and from 98% to 48%--among patients with ventricular hemotamponade underwent usage of ventricular drainage combined with local fibrinolysis. PMID- 24340959 TI - [Brain bioelectric activity forming in adolescents living in different endemic goiter area of European North]. AB - Northern European regions are goiter endemic and iodine-deficient areas, and also differ in the degree of extreme weather conditions in the Polar and Subpolar latitudes. The age formation of the nervous system in adolescents depends on these discomfort climatic factors. AIM: The study of functional brain activity depending on the thyroid profile in adolescents living in the European North. PATIENTS AND METHODS: 211 adolescents (male and female) aged 15-16 years living in the Subpolar (64 degrees 30' N) and Polar (67 degrees 40' N) Russian regions were observed. An electroencephalogram in a state of quiet wakefulness with eyes closed monopolar 16 standard leads was recorded. Electroencephalogram characteristic were performed by the values: of the wave amplitudes, index and absolute spectral power in each frequency band: 4-7 Hz, 8-12 Hz and 13-24 Hz. In serum samples by immune-enzyme assay thyrotropin, triiodothyronine and thyroxine levels were determined. All the described changes were statistically significant at p < 0.05-0.001. RESULTS: A higher activity of diencephalic subcortical brain structures, expressed in the form of increased -activity and photic driver reactions were determined in adolescents living in Polar region. Background thyroid status determines the age formation of brain activity. In adolescents living in the Polar region a high concentration of thyrotropin in the blood and the availability of significant relations with thyroid hormones levels with a brain theta-activity were detected. In adolescents living in Subpolar region is more intense age optimization of neural processes, as well as the greatest number of neuro-endocrine relationships. PMID- 24340960 TI - [Indices of matrix metalloproteinases (MMP-2, MMP-9, TIMP-1) with juvenile arthritis in children]. AB - One of the perspectives of modern rheumatology is the study of matrix metalloproteinases (MMP) in juvenile arthritis--enzymes that play a key role in the process of joint destruction. AIM: To analyse the content of matrix MMP-2 and MMP-9 and their tissue inhibitor (TIMP-1) in blood serum and synovial fluid in various embodiments of juvenile arthritis in children. PATIENTS AND METHODS: The study involved 82 children with juvenile arthritis, and 20 healthy children. The level of MMP-2, MMP-9 and TIMP-1 were determined in serum and synovial fluid by ELISA. RESULTS: It was found out that with any form of arthritis serum concentrations of MMP-2, MMP-9 and TIMP-1 was significantly higher than control values, but the level of MMP-2 in a subset of enthesitis-related arthritis, didn't differ from the control. Studied parameters in the synovial fluid were much higher than the serum level. With the development of uveitis TIMP-1 in blood serum was lower than in the absence of eye damage. On treatment of patients significant changes in the studied enzymes weren't established. On a good response to therapy the level of MMP-9 in serum decreased, on the lack of effectiveness - increased. CONCLUSIONS: The analysis results confirm the involvement of MMP-2, MMP-9 and TIMP-1 in the processes of inflammatory changes of the joints in juvenile idiopathic arthritis (JIA) and reactive arthritis, regardless the patients' sex or age. PMID- 24340961 TI - [Immunologic indexes, enzyme status of lymphocytes and functional activity of blood neutrophils in children with infectious mononucleosis caused by Epstein Barr virus]. AB - AIM: Explore the immunological parameters, levels of activity of NAD(P)-dependent dehydrogenases lymphocytes, interferon status parameters, phagocytic activity and chemiluminescence response of neutrophils in the blood of children in the acute phase of infectious mononucleosis caused by the Epstein-Barr virus. PATIENTS AND METHODS: 65 children at the age of 4-6 years old with infectious mononucleosis caused by EBV in acute phase were observed. Such indexes as cell-mediated, humoral and interferon immunity, NAD(P)-depended dehydrogenases activity in blood lymphocyte, phagocytes activity, levels of spontaneous and induced chemiluminescence ofperipheral blood neutrophils were studied. RESULTS: Children with EVB-infection have immunophenotype spectrum changes and changes of enzymes status of blood lymphocytes against the increasing in leucocytes and the useful increasing in lymphocytes. The useful increasing in IgA, IgM, IgG contenting in serum blood were found. The decreasing of spontaneous production of IFN alpha and the decreasing of induced production of IFNalpha, IFNgamma were determined. The breach of phagocytes activity and chemiluminescent response of blood neutrophils were found. CONCLUSIONS: The children in the acute phase of infectious mononucleosis caused by the Epstein-Barr virus, there are changes in the immune status, changes the activity of NAD(P)-dependent dehydrogenases in blood lymphocytes, marked changes in functional and metabolic state of peripheral blood neutrophils. PMID- 24340962 TI - [Changes in auditory function during first 6 months in premature children with intrauterine growth retardation]. AB - AIM: To define an influence of intrauterine growth restriction to forming of hearing function of preterm infants. PATIENTS AND METHODS: The audiological test by the method of distortion product otoacoustic emission (DPOAE) was performed 3 times (during supposed dates of birth; 3 months old; 6 months old) in 136 premature children born while different gestation periods. Children were divided into 2 groups: premature children with intrauterine growth restriction (IUGR) and premature children with normal weight for their gestation age (normotrophy). RESULTS: During checkup in supposed date of birth of children with IUGR, DPOAE was detected less than children with normotrophy and with the same gestation period. Test results in all 3 months old premature children of gestation period less than 32 weeks were significantly lower in comparison with children of another date of gestation. Results in 6 months old children with IUGR and with normotrophy were almost identical. In 17% of children with IUGR born at term gestation less than 32 weeks of auditory function is not available. Children with normotrophy from the same subgroup lack of auditory function were noted in 12% of cases. CONCLUSIONS: Premature children with IUGR maturing of auditory function is likely not to end in 6 months and can continue after 6 months. PMID- 24340963 TI - [Association of polymorphism Rs6737848 in the Socs5 gene with bronchial asthma]. AB - AIM: To investigate the role of polymorphic variants of immune-response modifying genes in predisposition to asthma. PATIENTS AND METHODS: The analysis of restriction fragments length polymorphism was used to investigate 10 single nucleotide polymorphisms: IFNG rs2069705, IFNGR2 rs17880053, IL4 rs 2070874, IL4RA rs 1805010, GATA3 rs10905277, TBX21 rs11652969, PIASY rs3760903, PIAS3 rs12756687, STATS rs16967593, and SOCS5 rs6737848 in 106 asthma patients and 115 healthy people. RESULTS: The rs6737848 SOCS5 polymorphism was significantly associated with asthma in additive model (p = 0.05, OR = 0.338, 95% CI 0.158 0.723) and in dominant model (p = 0.02, OR = 0.284, CI 0.126-0.638). None of the polymorphisms of the studied genes was associated with total IgE levels. CONCLUSIONS: This is the first report on the association of rs6737848 SOCS5 with asthma. PMID- 24340964 TI - [Mycoplasma and Chlamydia as ethiological factors of bronchial asthma in terms of ethnogenesis]. AB - AIM: The study of the prevalence and clinical peculiarities of Mycoplasmosis and Chlamydiosis in patients with different pathogenic forms of bronchial asthma (BA) taking into account ethnicity of a patient. SUBJECTS AND METHODS: The research covered 239 subjects--both the Europeoids and the Mongoloids in the city of Krasnoyarsk and the town of Kyzyl, all of them being BA patients of different stages, including acute stage and practically healthy. We had determined antigens Mycoplasma pneumoniae, Mycoplasma hominis, Chlamydophila pneumoniae, Chlamydophila psittaci and Chlamydia trachomatis in smears of mucosa of pharynx and antibodies to these antigens in peripheral blood serum. RESULTS: We found high frequency of Mycoplasmosis and Chlamydiosis in the inhabitants of Eastern Siberia, BA patients with different pathogenic forms as compared to control group. We had determined ethnic peculiarities of specific immune response: IgM to M. pneumoniae was revealed in the Europoids more frequently than in the Mongoloids, but IgM to C. pneumoniae and to C. trachomatis, C. trachomatis antigens had been revealed more often in the Mongoloids than in the Europoids. We accepted as clinical equivalents of Mycoplasmosis and Chlamydiosis diagnostics the following signs: temperature around 37C (subfebrile temperature), non intensive but stable coughing with scanty mucous and muco-purulent sputum, dyspnea of mixed character. CONCLUSIONS: Mycoplasma and Chlamydia are meaningful etiologic factors of bronchial asthma. We have found the peculiarities of immune response depending on ethnicity of a patient (ethnic belonging). Clinical markers of Mycoplasmosis and Chlamydiosis should be taken into account in bronchial asthma in order to provide diagnostics timely as well as eradication of infection agents. Because of insufficient knowledge of problem of bronchial asthma related to contamination with Mycoplasma and Chlamydia we put the goal to study the frequency of Mycoplasmosis and Chlamydiosis occurrence in bronchial asthma patients and determine the characteristics clinical course of diseases. We defined antigens Mycoplasma pneumoniae, Mycoplasma hominis, Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamydia trachomatis in smears of oropharynx mucosa and antibodies to them in blood serum. PMID- 24340965 TI - [The srategy of programed multistage surgical treatment ("damage control surgery") of neurotrauma]. AB - A retrospective analysis of diagnostics and surgical treatment was made in 440 patients with polytrauma, who were on the treatment in hospitals in Saint Petersburg, Syktyvkar and Omsk during 2009-2012. The neurotrauma was the dominating damage. The patients were divided into two groups: the main and the control group, using the equal quantitative ratio according to the sex, age, circumstances of trauma and type of damages. The strategy of programmed multistage surgical treatment ("damage control surgery") was used in the main group (220 patients, average age 31.7 +/- 5.2 years). The traditional strategy of treatment was applied in the control group (220 patients, average age 30.7 +/- 5.4 years). The damage control surgery allows the reduction of lethality in neurotrauma by 15.0% and improvement of social adaptation of patients by 12.7%. PMID- 24340966 TI - [Results of classic carotid endarterectomy using temporary carotid shunt]. AB - The main method of elimination of stenosis of carotid arteries in atherosclerosis is the surgical operation. Meanwhile, there is no general opinion concerning the most efficient way of the performance of the operation. This research generalized an experience of performing the classic carotid endarterectomy with usage the temporary shunt and an autovenous patch in 167 patients. The most frequent complications were analyzed in standard groups. The advantages of the given method were determined, facilitating to the reduction of intraoperative risks and the increase of technical quality of performance of different stages of the operation. The work quotes 8 works. PMID- 24340967 TI - [Comparative analysis of immediate results of reoperative coronary artery bypass surgery depending on the procedure of operative intervention]. AB - The operations of coronary artery bypass surgery were performed in 52 patients over the period of time since June 2004 till November 2012. The age of the patients was from 46 till 77 years (on average 60.8 +/- 7.8 years). These patients were divided three groups on the basis of features of methods of coronary artery bypass surgery. The groups were matched between each other due to the initial clinic data. Acute cardiovascular insufficiency predominated in the structure of complications of the early postoperative period in 9 (17.3%) patients. These 6 (11%) patients were operated under condition of the artificial circulation used. An average time of in-patient treatment was 13.6 +/- 5.6, 10.7 +/- 3.5 and 15.2 +/- 6.1 days of hospitalization respectively. The hospital lethality made up 3.8%. Reoperative myocardial revascularization is an effective method of treatment of recurrence of myocardial ischemia after coronary artery bypass surgery. The performance of coronary revascularization on the working heart facilitates to the reduction of the risk of the development of postoperative complications, including cardial ones and can lead to quick recovery. PMID- 24340968 TI - [Transthoracal puncture biopsy under ultrasonic induction in tumors of the anterior mediastinum]. AB - Differential diagnostics of tumors of anterior mediastinum is one of the most difficult problems of thoracic surgery and oncology. The authors conducted a retrospective analysis of the results of transthoracal puncture biopsy under ultrasonic induction in 44 patients with the tumors of the anterior mediastinum. Transthoracal biopsy was carried out using the device for biopsy (Multiple Biopsy Device-MBD-23) and ultrasonic scanner (Voluson 730 Expert), the patients being under intravenous (38 patients) and under local (6 patients) anesthetization. The diagnosis was made as a result of morphological research in all 100% of patients, the biopsy being performed the second time in one patient. The general information value of puncture biopsy under ultrasonic induction was 98%. A complication (localized pneumothorax, cupping off by itself) took place only in one of the follow-up study (2%). The analysis of presented material let the authors make a conclusion that transthoracal puncture biopsy under ultrasonic induction is a safe and highly informative method of diagnostics of tumors of the anterior mediastinum in selected patients. PMID- 24340969 TI - [Possibilities of surgical treatment of cicatrical stenosis of the trachea]. AB - The treatment of cicatrical stenosis of the trachea was performed in 193 patients at the age 8-65 years (132 of men and 61 women). The length of cicatrical stenosis shaped mainly by growth of granulation tissue and its different combinations consisted of 0.5 to 2.5 cm, getting 3.0 cm and more in 74 cases. The peculiar features of such cicatrical changes were characterized differently depending on its dominating localization on the length of the trachea--in the area of the neck or in the range of the mediastinum. Respiratory distresses, which were the main clinical manifestation of the disease, depended on the degree of stenisis of the trachea opening with the cicatrical process in each case. The decrease of size of the trachea opening with respect to natural size on 1/3 was considered as the first degree of stenosis, on 2/3 - II degree, more than on 2/3 III degree. The efficiency of endoscopic methods of treatment was the most significant in cicatrical stenosis of trachea with the length not more than 0.5 1.5 cm and dramatically decreased with the increase of length. The cicatrical stenosis of trachea with the length more than 3.5-3.0 cm should be considered as the indication for radical surgical intervention such as resection and plasty of trachea with forming of intertracheal or laryngotracheal anastomosis. PMID- 24340970 TI - [The assessment of surgical treatment of patients with malignant pleural effusion]. AB - An analysis of results of 498 patients with malignant pleural effusion was made. All patients were divided into three groups depending on methods of treatment: in the first group of patients the puncture of pleural cavity and the evacuation of liquid were made against the background of complex treatment; in the second group of patients the thoracocentesis and suspension induction were performed; in the third group the video thoracoscopy was carried out. In an assessment of each method of treatment, the researchers came to the conclusion that in case when the patient had the sufficient functional capabilities, the doctors should give preference to the thoracoscopy operations and in case of severe somatic status the doctors should give preference to the drainage of pleural cavity with release from exudates and with subsequent introduction of talc as the most effective sclerosing agent. PMID- 24340971 TI - [Miniinvasive interventions in treatments of pancreatic cysts]. AB - The article presents the results of surgical treatment of 58 patients with pancreatic cysts. An analysis of efficiency of various current miniinvasive surgical methods of treatment is given. Criteria of differential approach to the choice of the kind of miniinvasive intervention in pancreatic and parapancreatic cysts were formulated. PMID- 24340972 TI - [New approaches in treatment of patients with perforated duodenal ulcer]. AB - The results of examination and treatment of 152 patients with perforated duodenal ulcer were analyzed with the aim to make the ground of systemic approach to their surgical treatment in consideration of contemporary achievements of laboratorial and instrumental diagnostics and the opportunities of minimally invasive surgery. The results of conducted clinical study showed that in order to establish the correct preoperative diagnosis and the choice of rational treatment of patients with perforated duodenal ulcer it is necessary to conduct a purposeful complex investigation, including an assessment of general somatic state and the operative anaesthetic risk of patients and changes of pyloroduodenal zone and the severity of peritonitis and prediction of lethality. The diagnostic algorithm let the authors make a diagnosis of perforated duodenal ulcer before the operation and decide on an adequate volume of surgical intervention. It is established, that the integral assessment of the examination results and surgery, the evaluation of the titres of antibody to ulcerogenic strains Helicobacter pylori, studying of psychophysiological profile of patient can justify the complex program of medicamentous therapy in postoperative period, providing the remission of peptic ulcer. PMID- 24340973 TI - [Advantages of blocking intramedullary osteosynthesis in treatment of patients with fractures of the forearm bones]. AB - The blocking intramedullary osteosynthesis (BIO) of the forearm bones possesses quite a number of advantages in comparison with the bone and transosseous methods. The BIO allows the restoration of the anatomy and biomechanics of the forearm, it shortens the term of disability and restores the function of the extremity in proximate terms. The BIO of the forearm bones consists of great number of nuances, each of them is really important. It is necessary to have the X-ray unit with electron-optical image for the intraoperative monitoring of operation stages and to follow the well-defined algorithm of technology of performing BIO of the forearm bones with special reference to all possible features of anatomy. PMID- 24340974 TI - [Treatment of patients with damage of the hip joint and proximal section of the femur in polytrauma resulting in shock]. AB - The research of efficiency of operative and conservative methods of treatment was conducted in 426 patients with damage of the hip joint, brought to the Dzhanelidze Research Institute of Emergency Medicine, Saint-Petersburg with severe mechanical shockogeneous trauma, resulted in shock since 1997 till 2008. The operative interventions were performed using the methods suggested by the authors. The results were estimated by Harris scale and showed significant advantages of operative methods over conservative ones. PMID- 24340975 TI - [Meta-analysis: the possibility of atrophy of testicle in acute testicular appendage problems in children]. AB - A meta-analysis of extensive statistical data of "acute scrotal" syndrome in children was made. The two databases were considered. The first consisted of 1342 observations and described the nosologic structure of "acute scrotal" syndrome in children. The second included 440 patients and showed the long-term results of conservative treatment in children with acute scrotal problems. When a mathematical analysis of initial data was carried out, the authors determined, that the possibility of atrophy of stricken gonad in conservative treatment of acute hydatid problems belonged to the segment from 0.303 till 0.684. PMID- 24340976 TI - [The influence of modern plasma substitutes on the course of abdominal compartment syndrome in patients with abdominal sepsis]. AB - The changes of intra-abdominal pressure (IAP) were followed up in 244 patients with abdominal sepsis after operation. The influence of liquid "resuscitation" with different types of plasma substitutes on the rates of IAP was studied and the dependence of changes IAP from filling of vascular bed was investigated. The impedance technique was used to determine the circulating blood volume and its percentage from proper index was estimated according to the sex, age and constitution. The percentage of interstitial liquid in organism was calculated by analogy. The severity of manifestations of abdominal compartment syndrome (ACS) increases with the assessment of severity of the general condition to APACHE-II scale. The most severe ACS course was while using the crystalloid solutions in the complex of infusion therapy. The inclusion of colloids in the infusion therapy facilitated more full volume filling of vascular bed with the liquid, reduced the capillary leakage, accelerated the process of reduction of ACS. The advantage was shown by using the derivatives of hydroxyethylstarch, which promoted the elimination of deficiency of intravascular liquid in the best way. PMID- 24340977 TI - [The indices dynamics of platelet pool and the level of TGF-beta1 in different forms of acute pancreatitis]. AB - The results of study of quantitative functional characteristics of platelets are shown in patients with acute pancreatitis. The patients (57 people) with acute pancreatitis were examined: 40 patients had a mild clinical course of acute pancreatitis and 40 patients had a severe clinical course of acute pancreatitis. The circular functional mass of platelets and the level of TGF-beta1 were determined in dynamics in patients with acute destructive pancreatitis. A correlated analysis was made among the results obtained by means of laboratory and instrumental examinations and clinical course of acute pancreatitis. It was found, that the increase of TGF-beta1 and circular functional mass of platelets in the course of several days was really a good prognostic factor of clinical course of acute pancreatitis. The data obtained showed that the changes of indices of quantitative and functional characteristics of platelets are the important pathogenetic criterion of prognosis for severity of clinical course of acute pancreatitis. PMID- 24340978 TI - [Radical breast resection with skin-muscular latissimus dorsi flap grafting]. AB - The oncological breast surgeries with single-stage replacement of the lost volume by means of autogeneous tissue using distant flaps grafting (particularly by skin -muscular flaps of the latissimus dorsi) allow obtaining satisfactory and stable aesthetic results without the decrease of indices of relapse-free and general survival. The early results of the application of the skin-muscular flaps of the latissimus dorsi for single-stage breast reconstruction after radical breast resection are presented in this work in 3 patients with breast cancer. The technique allows performance of the extensive radical resection with single-stage grafting in patients with breast cancer and obtaining an objective clinical response against the background of neoadjuvant therapy with subsequent applying radiation therapy and systemic treatment. PMID- 24340979 TI - [Influence of lifting of muscular aponeurotic tissues of the hypogastrium area on quality of life in abdominoplasty patients]. AB - An analysis of complex clinical and ultrasonic investigations of the abdominal wall and the following surgery in 42 women with ventral hernia of big size accompanied by the ptosis of the abdomen was made. The patients were divided into two groups, each consisting of 21 patients.The endoprosthesis replacement of defect of the abdominal wall was made with standard polypropylene implant in the first group. The endoprosthesis replacement was complemented by lifting of muscular aponeurotic tissues of the hypogastrium using the implant of the original construction in the second group. The polypropylene endoprosthesis includes the main flap (15 x 15 cm) with rounded corners and the additional flap (5 x 40 cm) as a broad band situated at the lower edge of main flap in across track direction. The increase of physical component of health was noted in 1.8 times in the second group patients and psychological component raised in 2.5 times. PMID- 24340980 TI - [Retrograde colangiopancreatography (RCG) and endoscopic papillosphincterography (EPG) in new scheme of endosurgical strategy of treatment of cholecystitis accompanied by bilirubinemia]. AB - The article is devoted to the substantiation of strategy changes in acute cholecystitis and the bilirubinemia of obscure etiology. At the first stage the treatment was started from RCG in 120 patients and RCG with EPG in 232 patients. The results obtained were not very good, there being many organizational problems. At the second stage the laparoscopic cholecystectomy with drainage of the common bile duct (228 patients) were performed in 248 patients with acute cholecystitis and increased bilirubin from 29.54 till 167.16 millimole/l. Futhermore, the postoperative transdrainage cholangiography was made in 184 (74.2%) patients, the stones or the obstruction of bile secretion weren't found. The classical intervention on common bile duct was required only to 4 patients, for the rest EPG was performed according to the indications. EPG was the most effective and the results were the best. PMID- 24340981 TI - [Experience of treatment of pancreatonecrosis in hospital in the extreme north]. AB - Criteria of pancreatonecrosis are described in the article. Clinical and ultrasonic signs, the applied ways of treatment of acute pancreatitis are considered in 715 patients. The methods of treatment of complications of pancreatonecrosis are described. The lethality of the patients with pancreatonecrosis was 13.2% and between operated patients--16.4%. The lethality was 2.8% in the group of patients with pancreatitis. PMID- 24340982 TI - [Experience of using of octreotide-depot in prevention of the development and treatment of external pancreatic fistulas of different genesis]. AB - In the period from 2011 till 2012 the Otcreotide-depot was used by the authors in treatment of 34 patients. The patients were divided into two groups: the first group--the prevention of development and the second group--the treatment of external pancreatic fistulas. Ocreotide-depot was applied in 17 patient of the first group: as part of the complex therapy of severe pancreatitis in 4 patients and after pacreaticoduodenectomy in 13 patients. Ocreotide-depot was used in 17 patients of the second group: 7 cases of patients after different types of pancreatic resections and after external drainage of pancreatic cysts in 10 patients. The positive effect of using the drug was obtained in 30 patients (88.25%): the cases of preventive application of drug in 17 patients and during the treatment of external pancreatic fistulas in 13 patients. The preventive and therapeutic usage of Ocreotide-depot facilitated an uncomplicated postoperative period in 13 cases and the healing of the external pancreatic fistulas in terms from 5 till 7 days in 13 patients. The application of Ocreotide-depot could be recommended as a preventive measure against the incompetence of pancreaticojejunoanastomosis after pancreaticoduodenectomy in complex therapy of severe pancreatitis and also in treatment of external pancreatic fistulas after pancreaticoduodenectomy and percutaneous drainage of postnecrotic pseudocysts. PMID- 24340983 TI - [Bilateral multicentric cancer of parathyroid glands against the background of chronic pyelonephritis of solitary kidney complicated by chronic renal insufficiency, tertiary hyperparathyroidism and cervical hip fracture]. PMID- 24340984 TI - [The part of direct angiography as specification for an excision of giant recurrent tumor of retroperitoneal space]. PMID- 24340985 TI - [A temporary electrocardiostimulation in patients with planned surgical intervention]. PMID- 24340986 TI - [The diagnostic algorithm in patients with severe chronic constipaton without aganglionosis of the large intestine]. AB - The algorithm of special study in patients with severe chronic constipations includes the chronometry of passage of sulphate barium along the gastric tract with the assessment of evacuation function of each part of the large intestine, the irrigoscopy, the fibrocolonoscopy, the investigation of motor function of sigmoid colon. The proposed diagnostic algorithm allows the determination of part or parts of the large intestine with incompetent motor and evacuation functions and decision on the necessary extent of resection of the colon. PMID- 24340987 TI - [Choice of optimal perfusion flow rate during surgical correction of combined acquired heart diseases]. AB - Cardiac output during the use of cardiopulmonary bypass (CPB) is defined by perfusion flow rate, which is calculated by multiplying the perfusion index (PI) on the body surface area. To date, there is no clear definition of an optimal PI and flow rate of perfusion. 60 patients operated with CPB were enrolled in the prospective study to determine the relations between different modes of perfusion and oxygen transport during surgical correction of combined valvular heart disease. Calculation of the CPB flow rate was based on PI 2.5 and 3.0 l/min/m2. Results of the study demonstrate that perfusion based on PI 2.5 l/min/m2 provides more stable oxygen transport parameters and reduces the time of ICU stay in comparison with the flow rate based on PI 3.0 l/min/m2. PMID- 24340988 TI - [Inhalation anaesthesia and total intravenous anaesthesia for hepatic resections]. AB - Recently number of surgeries in patients with pathology of the liver increases. Therefore optimal and safe anaesthetic management for these surgeries is very topical. The article deals with analysis of 51 anaesthesia cases: 26 cases (51%) of multimodal balanced anaesthesia with sevoflurane inhalation and 25 cases (49%) of multimodal balanced anaesthesia with continuous propofol infusion. Both techniques provide optimal anaesthetic protection, however sevoflurane use influences on the liver metabolism more significantly. PMID- 24340989 TI - [Controlled myorelaxation in patients with aldosteroma]. AB - Purpose of the study was to develop techniques of controlled myorelaxation during surgeries in patients with aldosteroma. 46 patients were involved in the study. Adrenalectomy was performed by videoendoscopy from retroperitoneal access. All patients were operated under general anaesthesia with sevoflurane with obligate monitoring of neuromuscular conduction (NMC). Patients were divided into 4 groups. Myorelaxation in patients of the group 1 (n = 14) was performed by continuous infusion of 0.4 mg/kg/hr rocuronium bromide (esmeron). Myorelaxation in patients of groups 2 (n = 11), 3 (n = 11) and 4 (n = 10) was performed by bolus administration of 0.15 mg/kg/hr esmeron. Patients of groups 1 and 2 were not decurarized. Decurarization in the group 3 was performed by proserin and in the group 4 by sugammadex. In patients of the group 1 esmeron consumption was minimal due to continuous infusion of the drug. Time of neuromuscular blockade recovery (TOF 0.9) was longer than 19 min. Worst data of neuromuscular blockade recovery accrued in the group 2. In patients of the group 3 time of neuromuscular blockade recovery (TOF 0.9) reduced 2.5-3 times in comparison with groups 1 and 2. The use of sugammadex in the group 4 provided almost 4.7 times faster neuromuscular blockade recovery than proserin administration. Controlled myorelaxation in patients with aldosteroma is possible when monitoring of neuromuscular conduction is provided. Infusion administration of esmeron provides decreasing of its consumption and high quality of myorelaxation. Sugammadex administration provides 4.7 times faster neuromuscular blockade recovery (TOF 0.9) than proserin administration without risk of neuromuscular block reverse. PMID- 24340990 TI - [Rocuronium bromide as component of general anaesthesia in patients with traumatic cerebral compression]. AB - The choice of myorelaxation agent for rapid sequence tracheal intubation for surgical cerebral decompression is a less studied question in neuroanaesthesiology. 32 patients with cerebral trauma (GCS<8) were involved in the study. Influence of succinylcholine and rocuronium bromide on cerebral circulation, intracranial pressure, cerebral perfusion pressure and systemic haemodynamics was assessed. Rocuronium bromide in dose 0.6 mg/kg provides good conditions for tracheal intubation in 40-60 seconds and does not influence on studied parameters. Rocuronium bromide is a drug of choice for general anaesthesia in patients with traumatic cerebral compression. PMID- 24340991 TI - [Dynamics of intracerebral and cerebral perfusion pressure during major abdominal surgery]. AB - Purpose of the study was to compare an influence of anaesthesia with sevoflurane and propofol on intracerebral and cerebral perfusion pressure by data of ophthalmo-dynamometry of the central retinal vein. MATERIALS AND METHODS: The article deals with study of 75 patients which were undergoing major abdominal surgery. Combined anaesthesia with sevoflurane and fentanyl and total intravenous anaesthesia with propofol and fentanyl were used during the operations. Subgroups were identified in the groups of patients depended on the basic intracerebral pressure (ICP); subgroup of patients with normal ICP (< or = 12 mmHg) and subgroup of patients with intracerebral hypertension (ICP > 12 mmHg) RESULTS: Intracerebral pressure increased by 56% and cerebral perfusion pressure decreased by 35% in patients with intracerebral hypertension during the application of combined anaesthesia with sevoflurane. ICP decreased to normal parameters during application of total intravenous anaesthesia with propofol in patients with intracerebral hypertension. There was no changes of intracerebral and cerepral perfusion pressure (CPP) in patients without cerebral hypertension. Awaking time in patients with intracerebral hypertension was longer by 1.6 times after anaesthesia with sevoflurane than after anaesthesia with propofol. CONCLUSION: Combined inhalation anaesthesia with sevoflurane causes the increasing of ICP and decreasing of CPP and increasing of awaking time. Total intravenous anaesthesia with propofol and fentanyl provides stable cerebral haemodynamics. Total intravenous anaesthesia with propofol is a technique of choice in patients with underling intracerebral hypertension. PMID- 24340992 TI - [Express diagnostics of endotoxaemia during postoperative period in cardiac surgical patients]. AB - Medical technologies development and recent approaches in management of patients with septic complications during the early postoperative period present new obstacles to the laboratory service. Endotoxin is a main agent in the systemic inflammatory cascade and plays important role in sepsis pathogenesis. Recent express methods of diagnostics allow determining blood activity of endotoxin during 30-50 min. 55 ICU patients with clinical and laboratory signs of systemic inflammatory response syndrome (SIRS) after cardiac surgery were studied in the single-center prospective research. Endotoxaemia was diagnosed by express tests. Level of endotoxaemia was assessed before and after sorption in 15 patients receiving complex intensive care with selective lipopolysaccharide (LPS) adsorption. Endotoxaemia level assessment allows to define indications for different programs of intensive care in time and to assess its efficiency. Test systems for assessment endotoxin level based on the principle of interaction antigen - antibody (EAA and MACH-endotox spp.) is a most efficient for express diagnostics of endotoxaemia. PMID- 24340993 TI - [SCD14-ST (presepsin) level monitoring in cardiac surgical patients during perioperative period]. AB - Purpose of the study was to define prognostic ability of presepsin (sCD14-ST) as a predictor of complications in cardiac surgical patients during perioperative period. METHODS: Patients operated for acquired heart valvular diseases with cardiopulmonary bypass were involved in the study (n = 51, age 58 +/- 11 years). Following parameters were studied; demographic data, duration of cardiopulmonary bypass, time of aorta clamping, severity-of-disease by APACHE II scale before surgery, on 1st, 2nd, 3rd and 6th day after surgery, routine clinical laboratory data and sCD14-ST. RESULTS: there were no clinical laboratory evidences of inflammation before surgery in all patients. There was no difference between biomarkers in patients who had normal condition during postoperative period and in patients who had complications and/or untoward outcomes during postoperative period. Presepsin level in 6 patients (11.8%) was 543 (519-602) ng/ml, maximal 1597 ng/ml. Infection complications accrued in 19 patients (37%). Hospital mortality was 13.7% (7 patients), all cases of death was in group of patients with infection complications. Statistically significant differences in the level of presepsin and severity-of-disease by APACHE II in groups of patients with infection complications and without accrued on 1st and 2nd days of postoperative period. Optimal split point were 702 ng/ml, 8.5 points and 3.3 ng/ml. Increased postoperative level of presepsin is associated with a risk of infection complications and untoward outcomes. CONCLUSION: sCD14-ST monitoring with the use of severity-of-disease scales and recent biomarkers allow to identify patients with high risk of infection complications and untoward outcomes. PMID- 24340994 TI - [Assessment of oxygen status in critical patients with systemic inflammatory reaction]. AB - Diagnostic ability of alveolar-arterial oxygen gradient (A-aDO2 and respiratory index (RI) for acute respiratory distress syndrome was underestimated before recent time. 68 patients with severe inhomogeneous lung injure (severe concomitant trauma, pneumonia, and pancreonecrosis) were involved in the study. Patients were divided into two groups (basic group--34 patients and control group -34 patients). There were no differences in data of severity-of-disease by APACHE II and SOFA scales and J.F. Murrey lung injury score in both groups. Conventional volume controlled and pressure control respiratory techniques were used in patients of control group. Multi-level ventilation with three levels was used in patients of basic group. Blood gas containing, A-aDO2 and RI were studied. Gas status data improved both to gas exchange efficacy in patients of basic group. The data were significant different in the control group. Thus multilevel ventilation improves alveolar ventilation and arterial oxygenation, decreases pulmonary shunt and lung injury and improves respiratory lung functions. PMID- 24340995 TI - [Application of hyperosmotic iso-oncotic solutions for prolonged veno-venous haemofiltration in patients with gramm negative sepsis]. AB - Dynamics of circulation and elimination of low and medium molecular weight substances and lipopolysaccharides of Gramm negative bacteria were studied during prolonged veno-venous haemofiltration in patients with Gramm negative sepsis. Positive effect of HyperHAES solution for endotoxicosis compensation has been defined in the study. HyperHAES can be used repeatedly during prolonged veno venous haemofiltration. PMID- 24340997 TI - [Assessment of lung functional residual capacity and oxygen consumption during PEEP trial procedure]. AB - Purpose of the study was to compare the functional residual capacity and oxygen consumption with compliance and partial pressure of oxygen during automatic PEEP trial procedure--"PEEP INview". MATERIAL AND METHODS: Dynamics of functional residual capacity, oxygen consumption, compliance and partial pressure of oxygen were studied in 14 patients at cardiac surgical unit during automatic PEEP trial procedure--"PEEPINview". RESULTS: Significant dynamics of compliance and carbon dioxide production was not found. Partial pressure of oxygen cannot be used as the guideline in this study. Functional residual capacity increased in each incremental level of PEEP. Oxygen consumption increased during the PEEP changing from 6 to 8 cmH2O. CONCLUSION: It is defined that oxygen consumption is sensitive to PEEP level. Therefore the maximum diagnostics value of functional residual capacity measuring is expected in patients with restrictive lung disease. PMID- 24340996 TI - [Homeostasis changes during rehabilitation period after acute chemical poisoning]. AB - The article deals with review of 78 patients of rehabilitation toxicological unit. The patients received resuscitation and detoxification. All patients were divided into three groups; 1st group--patients after poisoning with psychopharmaceuticals, 2nd group--patients after poisoning with cauterizing liquids and 3rd group--patients with encephalopathy after poisoning with neurotoxin (psychopharmaceuticals, narcotics and ethanol). Disorders of rheology, haemostasis and endotoxicosis accrued in all groups. These disorders were a signs of the erythrocytes and platelets aggregation developing and viscoelasticity disorder. Homeostasis changes during rehabilitation period need an accurate diagnostics for purposeful treatment of the defined disorders. PMID- 24340998 TI - [Odontogenic pain syndrome: integrated approach in analgesia]. AB - The article deals with the study of 96 patients (69 women and 27 men) with odontogenic facial pain syndrome. All patients received complex neurodentist examination with radiological assessment of maxillofacial area and additional functional methods. Patients were divided into two groups, 48 patients in each group. All patients received usual therapy; mouth cavity sanitation, selective grinding of teeth, drug therapy (anticonvulsants, B vitamins) and physiotherapy. Patients in group 2 received corporeal acupuncture. Efficacy of the therapy was assessed by changes of basic subjective and objective significatives on 10th, 30th and 60th day of treatment. Reflective anaesthesia techniques using allowed to stop the pain faster and decreased the dosage of drugs in patients of group 2. PMID- 24340999 TI - [Prediction of postoperative pain on the basis of the psychological characteristics of patients and standard pain stimuli]. AB - Practical physicians do not have instruments for objective pain assessment despite recent advances of neurophysiology and pain pharmacology. The article deals with the study of relations between preoperative pain sensitivity (finger prick and venipuncture) and pain level after surgery. 60 patients involved in the study were divided into two groups. Pain sensitivity was assessed in all patients by visual analogue scale before surgery, after awaking, in 1 hour and in 3 hours after awaking and in 1 day after the surgery. Psychological status of patients was assessed by integration anxious test, neurotic disorders questionnaire and type of attitude to the disease questionnaire. All patients were assessed by 70 criteria (54 psychological). Results of the study show that postoperative pain syndrome is affected by different psychophysiological factors. Therefore it is difficult to forecast the level of postoperative pain syndrome. PMID- 24341000 TI - [Pharmacotherapy for acute postoperative pain based on use of NMDA receptors associated drugs]. PMID- 24341001 TI - [Use of enteral immune mixture in program of intensive care for acute parenchimal lung injury]. AB - The article deals with a case of successful acute lung injure syndrome treatment. Patient received enteral nutritive treatment with balanced polysubstrate mixture- immune liquid additionally to antibacterial, infusion, respiratory and symptomatic therapy. The case shows that immune liquid corrects hypermetabolic syndrome and effects on decreasing of organs dysfunctions especially lung dysfunction. PMID- 24341002 TI - [Concept, definition and classification of intra-abdominal hypertension in pregnancy]. AB - The article stresses methodological aspects of intaabdominal hypertension at pregnancy. Formal-logical analysis of conceptual framework and available classifications of intaabdominal hypertension was carried out. The article presents new definition and classification of intaabdominal hypertension. PMID- 24341003 TI - [Improvement of the system of medico-evacuational interventions in the troops with the help of mobile specialized elements]. AB - Taking into account the historical experience the authors considered the main principles of improvement of the system of preventive and curative interventions in the troops with the help of mobile functional elements. The authors suggested to develop medical reinforcement groups which satisfy requirements of high mobility and self-contained operations. 3 types of functional elements must be developed: 17 specialized doctor-nurse teams of the central military--treatment facilities, 10 doctor-nurse teams of district military (navy) clinical hospitals, 11 doctor-nurse teams of branches of district military hospitals. Assignment of air transport with the following reconversion in evacuation transport with the medical air station and medical helicopter station is concerned. PMID- 24341004 TI - [Prospects of material and technical development of the department of anaesthesia and intensive care]. AB - The author of the article came to conclusion that in view of electronics breakthrough, nanotechnology and genetic engineering development it is necessary to reconsider the system of emergency care, anesthesia and intensive care service on the battlefield, reduction of the influence of pathologic factors and secure evacuation to special treatment department. One of the main criteria is constant improvement of material and technical equipment for heavy rescue. Necessity of dislocation, problems with communications infrastructure, poor medical gas supply are the main problems which cause the necessity of development of special equipment which must be equal characteristics and security level of analogues, used in peace time. The last equipment can not be used by troops for various reasons. Probably, due to the absence mass sanitary loss, reduction of medical service in consequence of material and technical equipment must be proven. It is necessary to emphasize, that the department of anaesthesia and intensive care of the Ministry of Defence of the Russian Federation copes with the tasks of war and peacetime throughout the history. PMID- 24341005 TI - [Experimental evaluation of actoprotective activity of nitrogen-containing heterocyclic compounds derivatives in extreme conditions]. AB - In experiments on nonlinear male mice the ability of new derivatives of nitrogen containing heterocyclic compounds to increase the physical working capacity in conditions of hyperthermia, hypothermia and acute normobaric hypoxia and hypercapnia has been investigated. It is established, that pyridine derivative IBHF-11 has more expressed positive action in the said conditions. It provided increase of the working capacity of animals at all kinds of extreme influence, and the value of positive action was comparable, and in conditions of acute normobaric hypoxia and hypercapnia exceeded those at the reference products bemitil and bromantan. PMID- 24341006 TI - [Improvement of the system of medical equipmet rationing for military units during the wartime]. AB - The authors analyze new legal regulatory document--Medical equipment and reserves supply rate for military units and organisations of the Armed Forces of the Russian Federation, developed in the process of modernization of the system of medical equipment rationing for military units. New legal regulatory document was developed with the aim to replace the similar document d.d 1996-1997. The authors came to conclusion that costs of new medical equipment and reserves supply rates are similar to previous rates. At the same time costs new medical equipment supply rates for medical service increased more than 25%. It is related to change of the role of medical service in the system of medical supply of the Armed Forces of the Russian Federation. Modernization of the system of medical equipment supply rates for military unit of the Armed Forces of the Russian Federation, performed for the purpose of medical supplement for military unit in accordance with new state of the Armed Forces of the Russian Federation, allowed to actualize the regulatory framework of medical supply by means of development and adoption of new Supply and reserves rates be the Ministry of defence. Use if these rates will increase effectiveness and quality of medical supply during the wartime, provide a commonality of reserves of medical equipment and maintenance of established level of combat readiness of medical service of the Armed Forces of the Russian Federation. PMID- 24341007 TI - [Evolution of treatment options for hypertension]. AB - In the early 20th century hypertension became a medical problem because of the prevalence. The process of clinical research of the etiopathogenesis of hypertension is associated with a scientific and technical progress and state of medical science at every historical stage. The first stage (end of the 19th century--beginning of the 20th (century) was characterised by a research of hypertension and monitoring of its natural history. The second stage (early--mid 20th century) was characterised by attempts to influence on the natural history of hypertension. The basis of the attempts was neurohumoral concept. The third stage (end of 50s--beginning of 70s)--was characterised by the application of angiotensin-converting enzyme inhibitor, calcium channel blocker and thiazide diuretic along with beta-adrenergic blockers. The fourth stage (end of 20th century--beginning of 21st) was characterised by discovery of the renin angiotensin-aldosterone system, development of complex treatment options for hypertension, based on stratification of risk factors of cardiovascular complication. Clinical picture of hypertension haven't changed significally during the last 100 years. Cerebral and cardiac manifestations of hypertension remain dominat in 21st century as well as in 20th century. In the beginning of 21st century such systems as eyes and kidneys are not affected by the hypertension. Hypertension remains the main cause of progression of cardiac muscle and vessel wall structural changes. PMID- 24341008 TI - [The influence of the postoperative nutritional support on immune status in patients undergoing abdominal operations]. AB - At the present day inclusion of the immune enhancing enteral nutrition in the program of the postoperative nutritional support is considered to be the most prospective method of the treatment of intestinal failure, hypermetabolism, hypercatabolism and systemic inflammatory response syndrome in patients undergoing abdominal operations. 60 patients, undergoing gastro pancreaticoduodenal resections and gastrectomy, were examined. During the postoperative period the first group (experimental group) received standard enteral nutrition. The second group (control group) received immune enhancing enteral nutrition. It was revealed that immune enhancing enteral nutrition modulates the immune response and provides its stability in patients undergoing abdominal operations. PMID- 24341009 TI - [Particular features of erythropoiesis in high altitude and possibilities of applying of hypoxic hypoxia methodology for the patients with hemopoietic suppression]. AB - Conditions of hypoxic hypoxia at 3200 m height exert significant positive changes in hemopoiesis, normalizing erythropoiesis and coagulation system. Hypoxic climate therapy can be regarded as an additional efficient method to the pathogenetic treatment for patient with unpainful aplastic anemia and idiopathic thrombocytopenic purpura. It should be emphasized that patients must be out of immunosuppressive therapy when getting high altitude stationary. PMID- 24341010 TI - [Prospects of the use of radioprotectors for improvement of anti-radiation medicine in the Armed Forces]. AB - rThe author presented review of foreign and domestic literature concerning the problem of researching of new types of radioprotectors. The most effective radioprotectors are non-androgen steroids, organic compounds of protein, organic and chemical antioxidants. The methods of local delivery of radioprotectors to bioplast are under development. PMID- 24341011 TI - [Dynamics of echocardiographic index in aquanauts during the period of long-term effects of deep diving (to 500 m)]. AB - The authors presented the echocardiography and doppler sonography of aquanauts during the period of long-term effects of deep diving (to 500 m). According to the analysis of the given data the following was revealed: imperceptible atrium distensibility, left ventricular concentric remodeling without myocardial hypertrophy, saving of general and regional myocardial contractile function, left ventricular diastolic dysfunction grade 1, intact right ventricle, orthoarteriotony in pulmonary artery, change of size and distensibility of the aortic root. The authors came to conclusion that there are 2 different process in the structural ventricular remodeling during the period of long-term effects of deep diving--envolving myocardial consolidation and heart chamber dilation. These two processes is connected with temporary factor atypical for natural age dynamic. The aortic root has a atherosclerotic change and distensibility. There is no further dynamic distensibility. The abovementioned changes in heart and aorta can progress in aquanauts, which have too many dives. Patients in the study group haven't dived over the years, but nevertheless have the abovementioned changes. PMID- 24341012 TI - [Typhus fever morbidity among the military personnel and civilians in the regions around Volga river during World War I]. AB - The article is concerned to the materials about epidemiologic situation of typhus fever in the regions around Volga river (Saratovsky, Samarsky and others) during World War I (1914-1918) among the military personnel of the Russian army and among the civilians. The main reasons for spread of infection, ways of the transmission, and also measures for decreasing of level of morbidity on the different stages of evacuation of patients with typhus fever in the safer hospitals are shown. The most important methods of fighting against epidemic of typhus fever were: isolation of patients in separate special hospitals, desincection and disinfection measures in the foci of infection and organization appropriate sanitary conditions for military man in the army and among civilians. Acquired valuable experience of territorial and military doctors during the period of epidemic of typhus fever allowed receiving complex effective antiepidemic measures of fighting and prevention from this disease. PMID- 24341013 TI - [Mineral springs on the north-east of Caucasus and its role in the treatment of soldiers of the Russian army in XIX--beginning XX c]. AB - The article is concerned to the history of formation of sanitary-treatment stations on the North Caucasus, in Chechnya (Goryachevodsky and Mikhailovsky mineral springs) till 1917 year. The basis of the article are archive documents, scientific papers of contemporaries and official documents. Goryachevodsky and Mikhailovsky mineral springs were more than 70 years the one the best recreative base of the Caucasian standing army including the caucasian cossack troop. The sanitary-treatment stations were of great importance during the active military actions with Hill people within the territory of Chechnya and Dagestan, during the Crimean War (1853-1856), The Russo-Turkish War of 1877-1878 and the First World War (1914-1918), when the amount of the wounded and ill soldiers increased. PMID- 24341014 TI - [Synergetic basis of the system of specialized medical care, specialized treatment and medical rehabilitation of minimally injured and minimally ill]. AB - The article is devoted to analysis of the current system of specialized medical care, specialized treatment and medical rehabilitation of military casualties of minor nature. The author suggested a synergistic approach to combination of the given system with the aim of determination of development conception. Two main schemes of organization of specialized medical care are considered: medical care during the military conflict and local war; medical care during the regional and large-scale war. Taking into account the function of military field hospital for the treatment of walking wounded it was suggested to add a word combination "center of rehabilitation". The functions of the hospital are considered. PMID- 24341015 TI - [Health status comparative analysis of the emercom of Russia Federal fire service employees and contract servicemen in the Russian Army]. AB - Results of health status comparative analysis of the emercom of Russia Federal fire service employees and contract servicemen in the Russian Army are submitted as following. The emercom of russia firemen's average annual rate of primary morbidity is 459,1, that of labor losses' days 8430,8, of disability 0,9, and mortality cases 0,7. The russian army contract servicemen's average annual rate of primary morbidity during the covered period comes to 410,3, that of discharges 7,4, and mortality cases 1,3. The results of comparative analysis show that the rate of contract servicemen's primary morbidity is lower than that of emercom of Russia firemen below 10.6% (p < 0.001), whereas their discharge level is higher above 87% (p < 0.001). In the course of comparison of the emercom of Russia Federal fire service employees' and the Russian Army contract servicemen's primary morbidity structure it was revealed that the indexes of the diseases of respiratory system, traumas and poisoning are higher among the first ones. On the contrary, their indexes were lower in the sphere of circulatory system, skin and hypodermic cellulose diseases. The indexes of circulatory system diseases in the disability (discharge level) structure of the emercom of Russia Federal fire service employees were higher than those of other diseases. It is expedient to use the results of this research in forming of priority assignments and conducting of a complex of curative and prophylactic measures organized by the medical service of the emercom of Russia. PMID- 24341016 TI - [About professional education of future military physicians]. AB - One of the effective methods of professional education of future military physicians is art. Art as a form of artistic-image reflection of reality fully discloses the specifics of the activities of the military-medical specialists in times of peace and war. Variety of different kinds of art and availability of their use in the educational process promotes the final self-determination of students in their choice of profession, higher quality of its development and ensures the formation of their personal qualities as defenders of the homeland. PMID- 24341017 TI - [Clinical and epidemiological value of adenovirus infection in the military personnel]. AB - Adenovirus infections occur in different military groups as acute respiratory diseases combined with backsets and pneumonia. At definition of etiological structure of acute respiratory diseases in 1606 soldiers of 1-2 year of service, placed in the division of infectious diseases of the military medical academy in 2000-2011, dominance of an adenoviral infection (37.4%) was revealed, especially in non-epidemic periods of influenza (77% in 2007-2008). Adenoviral diseases among the hospitalized patients became complicated pneumonia in 17.8% of cases, and the proportion of adenoviral pneumonia in the overall community-acquired pneumonia with acute respiratory disease was 55.2%. PMID- 24341018 TI - [Pathogenesis and early diagnosis of deep vein thrombosis in case of polytrauma]. AB - Pathogenesis and early diagnosis characteristics of acute deep vein thrombosis (advt) have been studied in 323 polytrauma patients (iss: 29.4 +/- 2.0 score). Acute vein thrombosis, confirmed by us examination, was determined in 22.3% of patients (in the case of severe craniocerebral trauma--scct--12.6%, extremity trauma--60.5%, spinal trauma 75%, severe sepsis--25%). Despite the complex diagnosis and prophylaxis (thrombus removal, thrombosed veins ligation, external iliac vein and inferior vena cava clipping, permanent and removable cava-filters positioning) pulmonary artery thromboembolism (pate) developed in 3.1%. ADVT in patients with polytrauma developed as a pathogenic basis of systemic inflammatory response syndrome (sirs), which was observed to be associated with endothelium damage and thrombophilia. Hence, thrombophilia values (high levels of crp, f.viiia, D-dimer, low levels of antithrombin iii--at-iii), which are characteristic of sirs, lose their informativeness in the early diagnosis of advt and pate risks identification. In this regard, early advt diagnosis in polytrauma should be based on doppler study results, and the adequacy of anticoagulant and antiplatelet therapy should be determined by the levels of crp, f.viiia, D-dimer, activated partial thromboplastin time--aptt, anti- xa heparin activity, international normalized ratio--inr, platelet aggregation, thrombodynamic potential, at-iii. PMID- 24341019 TI - [Application of high technology in liver surgery]. AB - The PlasmaJet, a modem device that provides a high energy flow of ionized gas which seals small blood and lymph vessels has been recently introduced into clinical practice. A comparative retrospective analysis of results of 59 liver surgery with the help of new surgical technologies and standard surgical technique was performed. Liver resection with the use of high technology was accompanied by significantly less intraoperative blood loss, as well as a significant decrease of postoperative complications. PMID- 24341020 TI - [Main concepts of preventive health care for the air staff of sea-based aviation]. AB - The authors researched the air-stuff and complex of adverse factors uncharacteristic for the air-staff of land-based aircraft. It was determined that adverse factors affect the air-staff foremost in 4-5 months of a blue-water sailing, except cardiovascular system diseases. In a month of a blue-water sailing was registered a hypotonic state. Systolic blood pressure varied from 100 105 mm Hg and lower, dystolic blood pressure varied from 60-65 mm Hg and lower. The lowest ranges of blood pressure were registered in three months after the beginning of the sailing. In the following, the hypotonic state, registered during the monthly medical examinations, remained till the end of the sailing. Normal averages of blood pressure were restored in two weeks after the end of sailing. Low red cell count (for more than 1100 points) was registered in 61.5% of patients, (for more than 550 points) in 38.4% of patients. Low white cell count (for more than 4800 points) was registered in 33.3% of patients, (for more than 3300 points) in 41% of patients, (for more than 1330 points) in 25% of patients. Input data was: red cell count--4250 points, white cell count--7300 points in 1 ml of blood. After the sailing haematological indices were restored. The authors suggested guidelines for primary and secondary disease prevention. PMID- 24341021 TI - [Theoretical foundations of ergonomic designing of the military-medical ergatic systems]. AB - The theoretical basis of the ergonomic designing of the military-medical ergatic systems (MMES) consists of the general model of a medical specialist activities, the physiological theory of functional systems and the psychological theory of activities. It is underlined that at ergonomical designing must be considered all potential interactions between medical specialist and wounded, as well as between them and medical equipment. When designing MMES an important place should be given to the distribution of functions between the healthcare professional and technical means. When designing jobs for medical specialists must necessarily be taken into account emotional stress due to conditions as external (of the combat) of the situation, and the gravity of the wounds of the victims. PMID- 24341022 TI - [The state of health of the US Armed Forces military personnel in 2012]. AB - The current article is dedicated to the state of health of the US Armed Forces military active component personnel in 2012 according to the report published by the Armed Forces Health Surveillance Center in April 2013 issue of Center's Medical Surveillance Monthly Report. Sequentially, the key characteristics of ambulatory visits and hospitalization for the leading disease chapters and certain disease groups have been presented. The data have been given for the total personnel as well as for male and female separately. The general hospitalization has also been presented for the US Armed Forces components. PMID- 24341023 TI - [To the 175th anniversary of Irkutsk military hospital]. AB - The article is dedicated to the 175th anniversary of the Irkutsk military hospital and highlights the key historical moments of the establishment and activity of the oldest hospital in Eastern Siberia and work of doctors, nurses, paramedical hospital. The article presents historical information about famous personalities which have worked and served in the hospital and have contributed to the development of military medicine. PMID- 24341024 TI - [Professor Sergey Stepanovich Tkachenko (to the 90-th anniversary of the birth)]. AB - The article is dedicated to the memory of the outstanding Russian trauma orthopedist, scientist and educator, former head of the department of military traumatology and orthopedics military medical academy, doctor of medicine, professor, major-general of medical service S.S. Tkachenko. PMID- 24341025 TI - [At the cutting edge of Russian pharmacy: from the department materia medica to the department of military-medical supply and pharmacy]. AB - The authors presented a historical sketch abouth the department of military medical supply and pharmacy of the military-medical academy since 1798. During the whole history of the department the academic staff has successfully combined educational and research work with solution of a practical questions of improvement of medical supply of the russian army and navy. During the different historical periods and on the basis of current requirements of military medicine and pharmacy it is necessary to develop theory and practice of medical supply and normative legal acts of the system of medical supply, to develop new examples of medical property, to develop manufacturing processes of medicinal products, quality management, to perform researches in the area of radiochemistry of medical products, forensic chemistry, toxicology, research of medical plants, medicinal water and etc. PMID- 24341026 TI - [Occupational therapy: achievements and problems]. AB - Occupational therapy is topical and attracts attention of various medical specialists, for being on junction between clinical, hygienic, social and economical sciences. The authors present major directions of research and practical work of the Institute from its foundation till nowadays. PMID- 24341027 TI - [Contemporary medical technologies in diagnosis and evaluating risk of occupational diseases]. AB - Laboratory tests in occupational medicine get more importance and are used in clinical practice for diagnosis and evaluating the treatment efficiency, as well as for assessing risk of occupational, occupationally mediated diseases and more advanced forms of noninfectional diseases, to reveal early manifestations of diseases in workers exposed to hazardous work conditions. The article covers contemporary molecular technologies to diagnose and evaluate risk of occupational diseases, that are used nowadays in FSBI "RIOH" RAMS. PMID- 24341028 TI - [Laboratory medicine in the clinic of occupational diseases: achievements and prospects]. AB - The article presents the achievements and prospects of the priorities of research and development on laboratory aspects of preserving and strengthening the health of the working population. Modern methods of clinical laboratory diagnostics (hematology, cytochemistry, immunology, cytogenetics, hemostasis), an assessment of their implications for the clinic of occupational diseases, in particular for the study of the pathogenesis, diagnosis, evaluation of the effectiveness of the treatment, prevention of diseases of the respiratory system, skin, otolaryngology, etc. PMID- 24341029 TI - [X-ray imaging in occupational therapy]. AB - X-ray imaging of occupational diseases remains topical so far. Contemporary methods of X-ray imaging of occupational broncho-pulmonary diseases, locomotory disorders and spinal diseases helped to emphasize importance of various X-ray methods combining various approaches in obtaining new X-ray images for better quality of diagnostic and therapeutic measures in occupational therapy. X-ray methods not only widen diagnostic potentialities in occupational therapy, but also can be major methods of in-vivo diagnosis of some occupational diseases. PMID- 24341030 TI - [Pneumoconioses in contemporary industry]. AB - The article deals with features of development and formation of various pneumoconioses diagnosed after 1996: less benign course, early complaints, marked functional and X-ray changes in lungs, early complications--these result mainly from lower content of chemicals with fibrogenous effect in industrial aerosol and presence of allergic, cytotoxic and irritating agents. That helped to formulate a concept of contemporary pneumoconiosis caused by complex industrial aerosol over last 10-15 years. PMID- 24341031 TI - [Occupational skin diseases as social-economic problem]. AB - The article deals with factors causative of high social-economic importance of occupational skin diseases, presents parameters of occupational skin diseases prevalence, exogenous and endogenous risk factors of occupational skin diseases. This conditions appear to have negative influence on everyday life and occupational activities of the patients, induce lower quality of life and work performance. Pathogenesis and clinical signs, laboratory values characterizing atopic and allergic dermatitis are discussed. The authors necessitated a search of signs or complex of signs, that can point to predisposition for sensitization of individuals exposed to occupational hazards. PMID- 24341032 TI - [Establishment and activities of scientific school of industrial toxicology in institute]. AB - The article deals with stages of establishment and development of toxicologic studies in the Institute over 90 years. The authors stress the role of professor N.S. Pravdin and RAMSc Corresponding Member I.V. Sanotsky in formulation and solving major problems of toxicology, in specifying its methodologic background. Priority directions in theoretic and applied research are presented, main results are given. PMID- 24341033 TI - [Vibroacoustic factors hygienic regulation principles in Russia and abroad evolution and succession]. AB - Brief historical summary about Institute' vibroacoustic factors investigations development in the XXth century is presented. There are shown the data of noise, vibration, ultra- and infrasound hygienic rating in comparison with international approaches; the ways of its international harmonization in modern social and economic situation are selected. PMID- 24341034 TI - [Effects of xenon anesthesia on cerebral blood flow in neurosurgical patients without intracranial hypertension]. AB - Among anesthetic agents used in neurosurgery xenon appears to be the most advantageous. It preserves arterial blood pressure, assures rapid recovery and neuroprotection. But the data is lacking on xenon effect upon cerebral blood flow under anesthetic conditions. We measured flow velocity in middle cerebral artery in neurosurgical patients without intracranial hypertension during closed circuit xenon anesthesia comparing propofol and xenon effect in the same patients. In our study xenon didn't seem to induce clinically relevant changes in cerebral blood flow and preserved cerebral vascular reactivity thus proving its safety in patients without intracranial hypertension. PMID- 24341035 TI - [Prevention of cognitive disorders in postoperative period after carotid endarterectomy]. AB - 238 patients with atherosclerosis of carotid arteries after reconstructive operations under different types of anesthesia were enrolled in the study. Neuropsychological survey with Montreal cognitive assessment scale, frontal assessment battery and clock drawing test was performed in dynamics. Minimal cognitive dysfunction was mentioned in patients with symptomatic and asymptomatic stenosis after combined anesthesia with regional anesthesia. Postoperative cognitive dysfunction was developed after sevoflurane and propofol anesthesia in patients with asymptomatic stenosis. After inhalation anesthesia it was more severe. Prevention of postoperative cognitive dysfunction with ceraxon was clinically effective. This therapy can facilitate mental functions recovery and improve quality of life. PMID- 24341036 TI - [Mass-spectrometric control of compound A during minimal flow anesthesia and its influence on liver and kidneys functions]. AB - The article contains results of mass-spectrometric control of sevoflurane and compound A concentrations during inhalation anesthesia with minimal flow (< or = 0.5 l/min) and its influence on liver and kidney function. 40 patients (ASA I-II) were included in the study. Transsphenoidal pituitary adenomectomy was performed in all cases. Patients didn't have any signs of liver or kidneys disfunctions preoperatively. We used quadrupole mass spectrometer "Prisma Plus" (Pfeiffer vacuum, Germany) to determine the real time concentration of sevoflurane and compound A. Intensity of m/z = 131 peak sevoflurane and m/z = 128 peak compound A were registered. Laboratory blood tests to assess liver and kidney function were carried out before anesthesia, after anesthesia, and on the 1st day after anesthesia. They included: AST, ALT, total bilirubin, total protein, urea, creatinine. Quantitative analysis of the compound A and blood test before and after anesthesia showed only a tendency to increase biochemical markers levels within normal range, except small, but significant, AST elevation and total protein reduction in postoperative period. We concluded that maximal registered level of compound A (275 ppm/h) during minimal flow anesthesia didn't associate with significant liver and kidneys injury in healthy patients. PMID- 24341037 TI - [Patient positioning on the operating table in neurosurgery: sitting or lying]. AB - Efficacy and safety of microvascular decompression of trigeminal nerve depending on the position on the operating table were assessed in 200 neurosurgical patients in retrospective observational study It was shown that efficacy doesn't depend on positioning. Lying position eliminates probability of such complications as postural hypotension, hypotension during surgery, tension pneumocephalus and peripheral nerves injury. Sitting position increases risk of air venous embolism by 25 times. Lying position increases risk of postoperative nasal liquorrhea by 4 times, but eliminates risk of postoperative paresis of trigeminal nerve. It is also decreases risk of corneal reflex reduction by 3 times, hyperpathia by 2 times and paresthesias by 5 times, but increases probability of postoperative hyperesthesia by 4 times. Microvascular decompression of trigeminal nerve in lying position is safer than similar operation in sitting position. PMID- 24341038 TI - [Morphological changes in the lumbar dorsal root ganglion of the domestic porcine after pulsed radiofrequency stimulation]. AB - Pulsed radiofrequency (PRF) is a percutaneous minimal invasive procedure that can be used when conservative pain therapy methods have been ineffective. The effectiveness of PRF was demonstrated in various good quality randomized control studies, but mechanisms of action are still unclear. The aim of our study is to analyse the histological effects of PRF on the domestic porcine dorsal root ganglion (DRG), and evaluate the expression of biomarkers in gangliocytes. 3 domestic porcines were investigated. Under general anaesthesia and X-ray control, DRG PRF was performed. Four lumbar DRGs (L1, L2, L3, L4) were randomly treated. The opposite side DRGs was used as control. One month after the procedure the animal was euthanized. The lumbar region of the spine was placed in 10% formaldehyde for a month. After this fixation DRG samples were prepared for slide analysis. They were embedded in paraffin in order to obtain 3 microm thick sections, which were then cut by microtome and collected on slide glasses. Using standard immunohistochemical reactions, the materials were tinted to define biomarkers NF, GFAP, Hsp-70 expression and apoptosis by TUNEL kit. The number of cells with NF (26.0 +/- 3.0 vs 16.1 +/- 3.3; p < 0.05), GFAP (12.0 +/- 1.3 vs 3.2 +/- 0.9; p < 0.05) and Hsp-70 (10.0 +/- 1.6 vs 4.2 +/- 1.0; p < 0.05) expression, were larger in the PRF side comparing with the control side. Additionally, glial cells in spinal ganglia of both sides demonstrated immunoreactivity. The instances of apoptosis were not significantly different, in statistical terms, between the control and experimental sides (18.0 +/- 4.0 vs 20.0 +/- 4.0; p = 0.35). PRF in spinal gangliocytes of lumbar region increases neural tissue cytoskeleton factors like NF and GFAP suggesting about active regeneration processes into the cells 1 month after the procedure. Spinal gangliocytes one month after PRF treatment notably increases Hsp-70 expression suggesting about activation of cellular activity and inhibitory role reducing of oxidative stress. Similar number of apoptotic cells in spinal ganglia of lumbar region after PRF and control side suggests about inhibitory role of PRF on programmed cell death and stimulation of cell survival. PMID- 24341039 TI - [Cerebral and extracerebral insufficiency in patients with poor prognosis of surgical treatment of cerebrovascular circulation disorders of hemorrhagic type]. AB - Objective of the study was to investigate cerebral and extracerebral insufficiency in survived and died patients after surgical treatment of hemorrhagic stroke for outcome prognosis and decision making on postoperative intensive care. The study included 224 patients after transcranial surgery for hemorrhagic stroke. 119 patients survived and 105 patients died SOFA scale and SIRS criteria were used to assess severity of the patients state. Hemorrhagic stroke before the operation was accompanied with cerebral insufficiency (Glasgow Coma Scale < or = 9) in 19% of patients. Lungs and kidneys dysfunction (SOFA = 1 2) were common. In the early postoperative period 54% of patients had cerebral insufficiency and 36%--organ dysfunction. Acute cerebral insufficiency was closely associated with systemic inflammatory response. Severity of organs (heart, lungs, kidneys) failure and SIRS correlated with GCS score in early postoperative period. There was close correlation between MODS and SIRS scores in survived patients and there wasn't such phenomenon in died patients. This indicates leading role of CNS in homeostasis regulation. SOFA scale using for express diagnosis of perioperative complications is useful for providing adequate intensive therapy. PMID- 24341040 TI - [Perfusion-metabolic interaction in acute cerebral insufficiency. ACIPS study Part I. Cerebral blood flow evaluation]. AB - Basic physiological position that metabolic requirements of brain determine perfusion characteristics of cerebral blood flow underlies the definition of syndrome of acute cerebral insufficiency. So there is a perfusion-metabolic interaction (PMI) in brain tissue at every moment. Based on this paradigm we should synchronize measurement of these components in intensive care practice. The goal of ACIPS study (Acute Cerebral Injury Protection System) is creating methodology of monitoring PMI and treatment algorithm based on this monitoring. In this article we present data that volume cerebral blood flow can be assessed by summing volume bloodflows on brachiocephalic vessels measured with triplex ultrasound. Such results are comparable with CT-perfusion results. Both methods can be used interchangeably if difference in -0.6-11.8 ml/kg/min isn't clinical significant. PMID- 24341041 TI - [Dynamics of intracranial pressure in patients with massive ischemic stroke after decompressive craniotomy]. AB - The goal of the study was assessment of the value of ICP monitoring in patients with massive ischemic stroke after decompressive craniotomy. 12 patients with massive ischemic stroke were performed ICP monitoring after decompressive craniotomy. We identified 3 types of ICP dynamics: a) normal ICP, which no need to treat; b) ICP elevation to 20 mm Hg and more in postoperative period, which can be treated by nonsurgical therapy; c) refractory to therapy ICP elevation to 20 mm Hg and more with development of intracranial hypertension. We consider that ICP monitoring in patients with massive ischemic stroke after decompressive craniotomy can be useful for optimization of the therapy and correction of intracranial hypertension. PMID- 24341042 TI - [Intracranial pressure plateau waves in patients with severe traumatic brain injury]. AB - The goal of the study was to assess frequency of plato waves, their influence on outcomes and define factors leading to plato waves. Ninety eight patients with severe traumatic brain injury (TBI) were included. Blood pressure (BP), intracranial pressure (ICP), cerebral perfusion pressure (CPP) and pressure reactivity index (Prx) were registered. Age was 34 +/- 13.6. There were 73 male and 25 female. Glasgow Coma Scale (GCS) was 6 +/- 1.4. Plato waves developed in 24 patients (group 1), 74 patients (group 2) did not have plato waves. Median of plato waves in the 1st group was 7[3.5; 7]. They developed on 3rd [2;4.5] day. Maximum level of ICP during plato waves was 47.5 [40;53] mmHg, its duration was 8.5 [7;27] minutes. In the group 1 Prx was significantly lower during first day, than in the group 2. Duration of ICP monitoring was longer in the group I due to presence of plato waves in these patients. CPP did not differ in groups, because CPP was strictly controlled. Patients of the group I had preserved autoregulation and less severe trauma (predominance of closed trauma and Marshall I, II type of brain damage). Plato waves did not predict bad outcomes. PMID- 24341043 TI - [Citicoline as component of the therapy of postoperative delirium in neurosurgical patients]. AB - Delirium is a clinical sign of acute cerebral dysfunction. It is characterized by consciousness alterations with attention impairment and mentally disorganization. Frequency of delirium is 40-80% in general intensive care and more in patients in neurointensive care unit. We tried to assess citicoline (Ceraxon, Nycomed) safety and efficacy in treatment of postoperative delirium in patients with tumors of chiasm-sellar area of brain. 12 patients were included in citicoline group and 8- in control group. In both group combined type of delirium was common: 83.3% and 75%, accordingly. Citicoline didn't influence on delirium duration. Median of duration of mechanical ventilation was 1.5 and 6 days; mean and standard deviation were 10.5 +/- 15.4 and 17.5 +/- 27.9 days. Median of length of stay in ICU was 7 and 9.5 days; mean and standard deviation were 25.4 +/- 33.1 and 14.9 +/- 15.1 days. These results show that citicoline didn't influence on duration of mechanical ventilation and length of stay in ICU. Outcomes were similar in both groups, but frequency of full functional state recovery in citicoline group was significantly higher: 5 (41.7%) to 2 (25%) in control group (p < 0.05). We consider that citicoline therapy is safe for patients with tumors of chiasm sellar area and lead to increasing of frequency of full functional state recovery. PMID- 24341044 TI - [Influence of cerebral perfusion pressure and cardiac output on brain oxygenation and metabolism]. AB - The article contains results of examination of correlation between systemic hemodynamic and brain oxygenation and metabolism in patients with intracranial hemorrhage. Cardiac index (CI) and cerebral perfusion pressure (CPP) levels were compared to brain oxygenation and metabolism in 8 patients with intracranial hemorrhage (137 measurements). CI alterations didn't influence on PbrO2, glucose level or lactate/pyruvate ratio in the brain interstitial fluid in patients with traumatic brain injury. CPP elevation led to cerebral metabolism improvement. Optimal metabolic state was mentioned in CPP > 80 mm Hg. CPP elevation led to PbrO2 increasing in patients with subarachnoid hemorrhage due to aneurism rupture. This phenomenon can be explained by damage mechanisms of cerebral blood flow autoregulation. In these cases CI elevation was accompanied by worsening of aerobic metabolism in theoretically intact regions and improving it in injured brain regions. PMID- 24341045 TI - [Prognostic value of D-dimer fibrin level in neurosurgical patients before elective hospitalization]. AB - Deep vein thrombosis and pulmonary embolism in postoperative period are very dangerous complications for patient with any surgical pathology. Frequency of deep vein thrombosis in neurosurgical patient can be up to 25-30%. D-dimer level is considered as one of the most reliable indicator of thrombosis. We measured D dimer level before hospitalization for elective surgery in 4052 patients with different neurosurgical pathology. It was found clear correlation with elevated D dimer level and frequency of ultrasound signs of thrombosis. In patients with simultaneous presence of elevated D-dimer level and external signs of varicose veins diagnosis was confirmed by ultrasound in every cases. We consider that D dimer can be reliable screening method for assessment the risk of thrombosis in neurosurgical patients in preoperative period. PMID- 24341046 TI - [Endoscopic diagnosis, treatment and prevention of intubation related injuries of the larynx and trachea in neurosurgical patients]. AB - The goal of the study was to assess of efficacy of endoscopic diagnosis, prevention and treatment of intubation related larynx and tracheal injuries in patients with acute neurosurgical pathology and prolonged mechanical ventilation. 199 patients with different neurosurgical pathology were enrolled in the study group. Mean age was 50 +/- 14. Control group consisted of 399 patient. Mean age was 43 +/- 12. Clinical state of patient from both group were similar. Endoscopic method in the study group included revision of airways via nasal route with tracheostomy tube inserted. Larynx and tracheal injuries by endoscopy were identified in 42 patients (33.6%) in the study group and in 12 patients (7.6) in the control group. Such injuries weren't mentioned in 83 patients in study group and in 146 patients of the control group. Tracheal stenosis was developed in the study group in 0,8% of patients, which is by 7,9 times lower than in the control group (6.3%). We consider that this result was achieved due to our approach to treatment and prevention of tracheal stenosis. PMID- 24341047 TI - [Effect of normobaric hyperoxia on cerebral oxygenation, metabolism and oxidative stress in patients with subarachnoid hemorrhage caused by intracranial aneurysm rupture]. AB - The development of cerebral vasospasm in subarachnoid hemorrhage (SAH) due to cerebral aneurysms rupture results in cerebral circulation disturbances. Application of normobaric hyperoxia can be an effective way for improving of oxygen delivery to injured brain tissues. The purpose of this study was to assess of normobaric hyperoxia influence on intracranial pressure (ICP), cerebral oxygenation and metabolism, oxidative stress and endogenous factors of vascular regulation in II critically ill patients with nontraumatic SAH due to cerebral aneurysms rupture. Increase of FiO2 from 0.3 to 0.5 and 1.0 was accompanied with brain oxygen tension (PbrO2) increase and cerebral extraction ratio for oxygen (O2ER) decrease. Application of normobaric hyperoxia had no effect on ICP, cerebral perfusion pressure, arterial blood pressure and cerebral metabolism. The results obtained from patients with nontraumatic SAH showed an evident increase of oxidative stress which had a significant effect on vascular endothelial function, causing an imbalance in the endogenous regulation of vascular tone. Application of normobaric hyperoxia was not accompanied by an increase of free radical processes in critically ill patients with nontraumatic SAH due to cerebral aneurysms rupture. PMID- 24341048 TI - [Coronary artery stents and neurosurgery: choosing the lesser of two evils]. AB - Patients with coronary artery stents are extremely dependent on antiplatelet therapy whose discontinuation may lead to stent thrombosis with major cardiac adverse events. In neurosurgery chronic antiplatelet medications uptake is supposed to be the major factor of postoperative intracranial hematoma associated with poor outcome and high mortality. Thus planning neurosurgical procedure in patients with coronary stents needs a thorough evaluation of all risk factors pondering possible profit and danger. We discuss current recommendations on perioperative management for high risk bleeding surgery in high risk thrombosis patients emphasizing the role of individual approach and multidisciplinary collaboration. PMID- 24341050 TI - Gestational diabetes mellitus (GDM) in the Republic of Kosovo: a retrospective pilot study. AB - BACKGROUND: GDM is a condition in which women without previously diagnosed diabetes exhibit high blood glucose levels during pregnancy. Pregnancy causes some insulin resistance in all women, but only a few develop GDM. OBJECTIVE: To test the hypothesis that women with GDM have impaired regulation of blood iron storage and transport, decreased renal function due to decreased glomerular filtration rate and occurrence of urinary tract infection (UTI). STUDY DESIGN AND METHODS: Incidence of blood iron storage was investigated in n=30 pregnant kosovar women with GDM after mild of pregnancy and in n=30 pregnant women without GDM (years 2010-2012). RESULTS AND DISCUSSION: Baby weights, both systolic and diastolic BP, creatinine, albumin, lymphocytes, monocytes, WBC and granulocytes in both groups were within their normal ranges in both groups. Compared to control group, glucose was higher in women with GDM (mean +/- SD: 7.43 +/- 2.23 mg/dL vs. 4.33 +/- 0.63 mg/dL; P < 0.001). Women with GDM had also higher RBC (mean +/- SD: 4.4 +/- 0.8% vs. 3.8 +/- 0.3%; P < 0.005) and HGB (mean +/- SD: 13.0 +/- 3.2 g/dL vs. 11.2 +/- 1.4 mg/dL; P < 0.05), and decreased renal functionality (MDRD-GFR: 92.8 +/- 25.8 g/dL vs. 108.2 +/- 38.2 g/dL; P < .05). CONCLUSION: There is a potential association between iron status and GDM. The role of iron from diet and/or from supplementation in GDM pathogenesis needs still to be examined. In addition we have observed a decrease of glomerular filtration rate in women with GDM. Due to the lack of studies on the relationships between GDM and UTI, and to the retrospective design of the present investigation, it is difficult to establish whether UTI may be a GDM causal factor or a consequence of GDM symptoms, signs and/or of its correlated pathologies. PMID- 24341049 TI - Glucosa-Insulin-Potassium (GIK) solution used with diabetic patients provides better recovery after coronary bypass operations. AB - INTRODUCTION: Tight blood glucose control has become a therapeutical goal for anesthetic management for patients scheduled for cardiac surgery, especially if they are diabetic patients. AIM: This study was created to confirm the benefits of intraoperative GIK solution usage during coronary bypass operation of diabetic patients. METHODS: Patients with type 1 and 2 diabetes mellitus (DM) referred for coronary artery bypass grafting (CABG) were randomized to receive GIK solution (GIK--study group) in the first 24 hours intraoperatively or to receive official Clinical protocol without GIK solution (non GIK - control group). The primary clinical outcome was the cardiac index (CI) since it represents the most sensitive measure of cardiac work in the immediate postoperative period, and the secondary clinical outcomes were the glycemic control, insulin consumption, duration of mechanical ventilation (MV), potassium level and atrial fibrillation (AF) appearance. RESULTS: One hundred diabetic patients, divided into two groups, were included in the study. The cardiac index did not show a significant difference, although the study group had CI with only minor variations than those of the controlled group, hence the reason we considered the study group as the more stable. The atrial fibrillation showed a difference between two groups, with 14 (28%) patients with postoperative AF in the control group compared with 3 (6%) patients with postoperative AF in the study group. As potassium values were stable in study group, we concluded that it can be one of the reasons for less postoperative AF in this group. The duration of MV showed a significant difference (0,003) between the two groups as well. In the study group the average MV time was 534,38 minutes, compared with the control group with 749,20 minutes. The average value of glucose was 11.1 mmol/l in the control group vs. 9.8 mmol/l in the study group. The study group had less insulin consumption in order to maintain target glycemia (p = 0.001). In the non GIK group average insulin consumption was 44 IJ per patient vs. 28.5 IJ in the GIK group. CONCLUSION: Intraoperative GIK solution given to diabetic patients with CABG operation provides more stable CI, shorter time of MV, more stable values of potassium which provides normal rhythm and less AF onset, less insulin to maintain target glycemia. All the above mentioned provides more stable intraoperative hemodynamic and better recovery of diabetic PMID- 24341051 TI - Vitiligo and autoimmunity. AB - BACKGROUND: Vitiligo is an acquired skin disorder characterized by depigmented maculae resulting from a reduction of the number and function of melanocytes. The etiopathogenesis of the disease is still unclear, but there is evidence that autoimmunity may be involved. OBJECTIVE: The aim of this study was to determine the prevalence and significance of antinuclear (ANA) and thyroid peroxidase (anti TPO) antibodies in patients with vitiligo and control group. METHODS: In a prospective case-control study, we compared the frequency of antibodies (ANA and anti-TPO) in 40 patients with vitiligo and in 40 healthy volunteers. RESULTS: ANA were positive in 7 (17%) patients, which was insignificantly higher than control group, 2 (5%). Anti-TPO were positive in 11 (27%) patients. In control group, only two subjects (5%) had positive anti-TPO. Compared with the control group, the frequency anti-TPO were significantly higher in those with vitiligo (p < 0.05). CONCLUSION: Our findings show a significant association between vitiligo and thyroid autoimmunity, and that tests to detect anti-TPO are useful markers in patients with vitiligo. In contrary, ANA seems to have limited diagnostic relevance in routine clinical practice. Additional studies of a wider sample are warranted to confirm these findings and allow a detailed analysis. PMID- 24341053 TI - The influence of cardiopulmonary by-pass on respiratory function in patients who underwent coronary disease surgery. AB - AIM: The study is designed to show influence of cardiopulmonary by-pass (CPB) on respiratory function in patients who underwent cardiac surgery. PATIENTS AND METHODS: With respect on operative technique the patients were divided into two groups consisted of 40 patients, who underwent with or without CPB. On the bases of the hemodynamic measurements and counting alveolar arterial oxygen difference (A-a)DO2, saturation of mixed venous blood (SvO2), direct intrapulmonary shunt (V/Q) and hypoxemic score (PaO2/FiO2) preoperative and postoperative respiratory function in these patients is assumed. There were one preoperative and four postoperative measurements. RESULTS AND DISCUSSION: Statistically significant difference is found between the examined groups between mean values of alveolar arterial oxygen difference (A-a)DO2 in three postoperative measurements (p = 0.035, p = 0.015 and p = 0.011), direct intrapulmonary shunt (V/Q) in four postoperative measurements (p = 0.037, p = 0.023, p = 0.014 and p = 0.04), saturation of mixed venous blood (SvO2) in four postoperative measurements (p = 0.01, p = 0.023, p = 0.020 and p = 0.020) and hypoxemic score (PaO2/FO2) in four postoperative measurements (p = 0.018, p = 0.028, p = 0.017 and p = 0.038). The comparative analyses of parameters of respiratory function in both groups showed increased degree of acute lung injury (ALI) in group of patients underwent CPB. CONCLUSION: Early discovering parameters of acute lung injury in early postoperative period in patients underwent cardiac surgery with cardiopulmonary by-pass can prevent development of postoperative complications and duration of hospitalization. Key words: PMID- 24341052 TI - Association between aerobic vaginitis, bacterial vaginosis and squamous intraepithelial lesion of low grade. AB - GOAL: To determine frequency of HPV infection, aerobic vaginitis and bacterial vaginosis in respondents with squamous intraepithelial lesion of lower grade comparing to respondents with normal PAP test results. MATERIAL AND METHODS: Prospective research of 100 respondents has been conducted at University-Clinic Center Tuzla and Gynecology and Obstetrics Department at Primary Health Care Center Tuzla in period from May 2011 untill January 2012. Examination program included: anamnesis, clinical gynecological examination, HPV typization, microbiological examination of vaginal and cervical smear and PAP test. RESULTS: High risk HPV group has been found more frequently among the respondents with LG SIL 46% (23) than in those with normal PAP result 14% (7) p < 0.05. Aerobic vaginitis has been found in the respondents with LG SIL in 28% (14) and there is statistically significant difference of this vaginitis comparing to the respondents with normal PAP result (p < 0.05). Bacterial vaginosis has been found in 12% (6) of the respondents with LG SIL and in 4% (2) of those with normal PAP result which is not statistically significant. In women with LG SIL and aerobic vaginitis in 9 cases E. coli has been isolated, in 4 E. faecalis and in 1 Staphylococcus aureus, while in women with normal PAP test results 3 cases of E.coli have been isolated. Examining changes in pH value of vaginal environment, higher measured values have been found in the respondents with LG SIL- 5.26 while in the respondents with normal PAP test result was 4.94 (p < 0.05). There is also statistically significant increase in the number of leukocytes in the respondents with LG SIL in relation to those with normal result. CONCLUSION: In women with LG SIL aerobic vaginitis is very common but is not an indicator of HPV infection. An adequate treatment of aerobic vaginitis would decrease the frequency of LG SIL and number of precancerous lesions which may PMID- 24341054 TI - Left ventricular hypertrophy: a comparison among Kurdish patients with first-ever ischemic versus first-ever hemorrhagic stroke. AB - BACKGROUND AND AIM: Left ventricular hypertrophy (LVH) has been proposed to be associated with an increased risk of stroke. We compared the prevalence of LVH among patients with first-ever ischemic versus first-ever hemorrhagic strokes. MATERIAL AND METHODS: This observational study, which was conducted at the Sulaimaniya general teaching hospital from November 2009 to March 2012, involved 100 consecutive patients with their first-ever stroke. Fifty patients had ischemic stroke while the rest (n = 50) developed hemorrhagic stroke. The presence of LVH was detected using transthoracic echocardiography and a comparison with respect to its prevalence between the 2 aforementioned groups was made. RESULTS: The mean age of patients in the hemorrhagic group was 61.7 +/- SD 11.2 years while in the ischemic group it was 63.9 +/- SD 6.1 years. Out of 100 patients, 66 (66%) patients were males (31 in the hemorrhagic group and 35 in the ischemic group) while the rest (n = 34; 34%) were females (19 in the hemorrhagic group and 15 in the ischemic one). Ninety one (91%) patients were hypertensive (47 in the hemorrhagic group and 34 in the ischemic group). Fifty three (53%) out of 100 patients demonstrated LVH (31 in the hemorrhagic group and 22 in the ischemic group). A head-to-head comparison between the two groups with respect to gender demonstrated no statistically significant difference in terms of the presence of LVH among patients with hemorrhagic versus ischemic strokes; males (P value < 0.26; 95% CI 3.4-39.3); females (P value < 0.43; 95% CI 16.7-43.8). However, a univariate analysis after correction for age and gender revealed a statistically significant difference between these groups (P-value < 0.001; 95% CI 2.7-46.2). CONCLUSION: LVH was more common in Kurdish patients with first-ever hemorrhagic stroke than in those who had sustained their first-ever ischemic stroke. Further analytic studies are required to clarify the prevalence of LVH in patients with ischemic stroke. PMID- 24341055 TI - The optimal chemotherapy timing in patients with inoperable locally advanced non small cell lung cancer. AB - BACKGROUND: Only 20% of patients with stage III NSCLC are cured by surgery. There is a disagreement among the oncologists in terms of whether which regimen (induction chemotherapy followed chemoradiotherapy, concurrent chemoradiation or concurrent chemoradiation followed consolidation chemotherapy) is best choice in inoperable LA NSCLC. OBJECTIVE: To evaluate chemotherapy timing in inoperable LA NSCLC (before, only concomitant or after curative chemotherapy). MATERIALS AND METHODS: Total of 74 consecutive patient with LA NSCLC which was inoperable due to medical condition or stage from Kayseri Research and Training Hospital were analyzed retrospectively. The patients were divided into three groups according to treatment protocols: Induction chemotherapy followed chemoradiotherapy (Ind. CTaCRT), chemoradiotherapy (CRT) and chemoradiotherapy followed consolidation chemotherapy (CRTaCons. CT). RESULTS: When evaluating progression free survival (PFS), PFS did not significantly differed among the groups (p=0,078). We found significant difference among groups (p = 0.047) in terms of overall survival. While CRTaCons. CT arm had highest mean and median survival times, Ind. CTaCRT arm had worst OS. CONCLUSIONS: CRTaCons. CT treatment modality seems preferable regimen for treatment of inoperable LA NSCLC. PMID- 24341056 TI - Initial treatment of isolated thoracic injuries. AB - INTRODUCTION: Isolated thoracic injuries are relatively common and they are on the second place as a cause of death overall trauma. Most patients with isolated thoracic injuries are treated on an outpatient basis while only serious cases are hospitalized. The basis of the treatment of thoracic trauma is efficient cardiopulmonary reanimation followed by an early detection and treatment of life threatening injuries. Less than 15% of patients with thoracic trauma require thoracotomy. PATIENTS: Only the patients with exclusively isolated thoracic trauma were analyzed. RESULTS: Based on initial diagnostic procedures initial conservative treatment was indicated and sufficient for 63.75% (204/320) cases while initial surgery treatment was necessary in 36.25% (116/320) of the injured. In relation to the type of surgery the thoracic drainage was performed in 81.03% (94/116) while thoracotomy and VATS procedure was necessary for 7.75% (9/116) of the injured. After the secondary examination or shorter monitoring of the status of the injured, the additional diagnostic procedure was suggested and performed in only 5% (16/320) of the injured. The average period of the hospitalization for all injured with isolated thoracic trauma was 5.9 +/- 4.0 days (from 6 hours to 16 days). In cases of patients with blunt injuries the average period of hospitalization was 6.07 +/- 4.26 days, while for the patients with penetrating trauma it was 5.4 +/- 3.36 days. The calculated value oft-student test (0.2766 > 0.05) indicates that there is no statistically significant difference in the period of the hospitalization in relation to the type of trauma (blunt vs. penetrating). The average period of thoracic drainage was 5.58 +/- 3.3 days (from 3 to 17 days). The average duration of thoracic drainage in the patients with blunt trauma was 5.81 +/- 2.67 days, while in the patients with penetrating trauma it was 5.08 +/- 1.99 days. The calculated value of the probability of t test (0.1478 > 0.05) shows that there is no significant difference in the period of drainage in cases of blunt and penetrating trauma. Out of total number of patients, 98.0% (315/320) of the injured were successfully treated. The complications were found in 1.25% (4/320) cases. Death was the outcome in 1.5% (5/320) of injured. CONCLUSION: Based on the results of the initial diagnostic treatment, in majority of injured with isolated thoracic trauma, it was possible to conduct the relevant and appropriate therapeutic procedures. On the basis of relatively short period of thoracic drainage, hospitalization and low rates of morbidity and mortality, it may be confirmed that the application of initial diagnostic and therapeutic protocols of the Clinic for thoracic surgery resulted in the achievement of the successful treatments in majority of the injured for this type of the PMID- 24341057 TI - OSA-18 survey in evaluation of sleep-disordered breathing in children with adenotonsillar hypertrophy. AB - BACKGROUND/AIM: The aim of this study was to estimate the quality of life (QOL) in children with sleep-disordered breathing (SDB) before and after adenoidectomy and before and after adenotonsillectomy using the OSA-18 survey. SETTING AND DESIGN: The prospective study included sixty children with symptoms of SDB caused by enlarged adenoids or tonsils, of both sexes, aged 3-12 years, consecutively admitted into the ENT Clinic in Tuzla, for adenoidectomy or adenotonsillectomy. METHODS: Patients were divided in two subgroups: thirty patients who underwent adenoidectomy and thirty patients who underwent adenotonsillectomy. Parents or caregivers completed the OSA-18 survey before surgery and 5 weeks after surgery. For statistical analysis was used Student's t-test of pared samples. The values p < 0.05 were accepted as significant. RESULTS: Mean total score before adenoidectomy was 3.44 (SD = 0.77) and after surgery was 1.30 (SD = 0.46).Mean total score before adenotonsillectomy was 3.69 (SD = 0.80), after surgery was 1.22 (SD = 0.27). The difference between preoperative and postoperative scores in both subgroups of patients was significant (p < 0.01). CONCLUSION: Adenoidectomy and adenotonsillectomy improve QOL in children with SDB, which is caused by adenotonsillar hypertrophy. The OSA-18 survey is a useful tool for the selection of children for surgery with SDB caused by adenotonsillar hypertrophy and to assess quality of life after surgery. PMID- 24341058 TI - Rehabilitation after surgery repair of flexor tendon injuries of the hand with Kleinert early passive mobilization protocol. AB - INTRODUCTION: Rehabilitation after surgery repair of flexor tendon injuries of the hand remains challenging and requires experienced professionals and interdisciplinary approaches. AIM: The aim of this study was to evaluate rehabilitation results after surgery repair of flexor tendon injuries in the hand with the early passive mobilization--Kleinert protocol. MATERIALS AND METHODS: In this retrospective case-series study rehabilitation results of flexor tendon injuries in the hand with the early passive mobilization--Kleinert protocol were evaluated in 35 patients, treated in the Orthopaedic Clinic University Clinical Centre of Kosovo between December 2007 and November 2008. Patients had unilateral injuries on right hand without associated injuries. Patients were divided in three groups: patient with injury of FPL (n = 15), patient with injury of FDP and FDS dig. I-V (n = 10) and patient with injury of FDP and FDS dig.II (n = 10). Patients were included in a rehabilitation program using the Kleinert-early passive mobilization protocol. Functional evaluation was made using the mean improvement on MCP, PIP and DIP joints motion, mean functional are of motion (FAM) and total active motion (TAM) scoring system of The American Society of Surgery of Hand. The functional outcomes were analyzed by Paired t-test, and One way Analysis of Variance, while the mean TAM score were compared using the Wilcoxon Matched-Pairs Signed-Ranks test with significance set at p < 0.05. RESULTS: About 67% of patients with FPL injuries achieved excellent range TAM score, and about 22% of patients with FDS&FDP injuries achieved excellent and 74% good range of total active motion. CONCLUSIONS: With earlier performed primary surgical tendon repair followed by Kleinert-early passive mobilization protocol may achieves satisfactory functional results for any flexor tendon injuries in zones I-IV of the hand. PMID- 24341059 TI - Predilection role diabetes mellitus and dyslipidemia in the onset of ischemic stroke. AB - INTRODUCTION: Stroke is the third leading cause of mortality, disability and dementia, but leading cause of epileptic manifestations in the elderly. Diabetes mellitus as permanently elevated blood glucose, often accompanied by dyslipidemia, is among the leading causes of atherosclerotic alteration in blood vessels and is also increasing in the world. GOAL: To determine the existence and predilection of diabetes mellitus and dyslipidemia, in the development of ischemic stroke. MATERIAL AND METHODS: During the 2011 are analyzed all people with stroke admitted at the Neurology Clinic. All patients underwent neurological tests and the laboratory test with special emphasis on the value of blood glucose and lipid levels, with brain CT which confirmed the existence of a stroke, EEG and internist examination. RESULTS: During the one-year period the stroke was confirmed in 1184 patients, aged 33-81 years and 37% in the younger age group (up to 50 yrs.). There was 50.67% male and 49.33% female patients. Ischemic stroke was confirmed in 78.0% (56% with thrombotic and 22% with embolic genesis), of which the 32% was lacunar infarcts (up to 1.5 cm) and hemorrhagic in 22% (SAH in 4.8%, and intracerebral hemorrhage in 17.2%). The most frequent risk factors were hypertension 85%, then smoking in 65%, diabetes mellitus in 39.0%, in 27.38% dyslipidemia, previous stroke in 26.69%, in 23.57% arrhythmia In the baseline sample 30.06% of patients had previously diabetes mellitus and in 8.94% the diabetes was diagnosed during hospitalization, while dyslipidemia was known from earlier in 22.0% and in 5.38% cases was detected during the hospitalization. Among treated patients 79.01% survived, while 20.09% have a fatal outcome. CONCLUSIONS: Diabetes mellitus and dyslipidemia, along with hypertension and smoking are the leading risk factors for the occurrence of stroke. By timely detection and treatment can be controlled slow atherosclerotic changes in blood vessels and thus prevent stroke. PMID- 24341061 TI - Evaluate the ability of clinical decision support systems (CDSSs) to improve clinical practice. AB - INTRODUCTION: Prevalence of new diseases, medical science promotion and increase of referring to health care centers, provide a good situation for medical errors growth. Errors can involve medicines, surgery, diagnosis, equipment, or lab reports. Medical errors can occur anywhere in the health care system: In hospitals, clinics, surgery centers, doctors' offices, nursing homes, pharmacies, and patients' homes. According to the Institute of Medicine (IOM), 98,000 people die every year from preventable medical errors. In 2010 from all referred medical error records to Iran Legal Medicine Organization, 46/5% physician and medical team members were known as delinquent. One of new technologies that can reduce medical errors is clinical decision support systems (CDSSs). METHODS: This study was unsystematic-review study. The literature was searched on evaluate the "ability of clinical decision support systems to improve clinical practice" with the help of library, books, conference proceedings, data bank, and also searches engines available at Google, Google scholar. For our searches, we employed the following keywords and their combinations: medical error, clinical decision support systems, Computer-Based Clinical Decision Support Systems, information technology, information system, health care quality, computer systems in the searching areas of title, keywords, abstract, and full text. In this study, more than 100 articles and reports were collected and 38 of them were selected based on their relevancy. DISCUSSION AND CONCLUSION: The CDSSs are computer programs, designed for help to health care careers. These systems as a knowledge-based tool could help health care manager in analyze evaluation, improvement and selection of effective solutions in clinical decisions. Therefore, it has a main role in medical errors reduction. The aim of this study was to express ability of the CDSSs to improve PMID- 24341060 TI - Group B Streptococci investigation in pre-term labors. AB - BACKGROUND: Pre-term delivery is still a main cause of perinatal mortality and morbidities. This study was designed to find any association between maternal Group B Streptococcus (GBS) colonization and pre-term delivery. METHOD: This case control study was conducted from March 2010 to May 2011 at two referral university hospitals (Al-Zahra and Shaheed Beheshty), Isfahan University of Medical Sciences, Isfahan, Iran. The study sample of pregnant women was composed of a control group of 200 term pregnancy with at least 37 complete weeks, and a case group of another 200 women between 20 to 37 weeks of pregnancy with pre-term labor. Maternal GBS colonization was compared between two groups. RESULTS: Maternal age (26.03 +/- 4.81 vs. 27.19 +/-5.60, P = 0.07) and gravid (1.75 +/- 0.88 vs. 1.83 +/-1.08, P = 0.52) were similar in case and control groups. Level of education and gestational age were significantly higher in control versus case group (P = 0.01, P = 0.00). History ofantibiotic use during pregnancywas more frequent in case group compared with control group (P = 0.00). There were 59/151 (39.1%) positive vaginal samples in case group compared with 36/178 (20.2%) in control group (P = 0.000). There were 55/151 (36.4%) positive rectal samples in case group versus 30/178 (16.9%) in control group (P = 0.000). CONCLUSION: This study showed that GBS colonization was statistically higher in pre-term labors compared with term deliveries. To understand the mechanism of GBS effect on pregnancy, large observational studies are needed, with clearly defined outcomes, and with prognostic risk factors for pre-term delivery taken into account. PMID- 24341062 TI - Performance evaluation of the suggestion system. AB - This cross-sectional research evaluated the suggestion system of Isfahan University of Medical Sciences (IUMS) using CIPP model. METHODS: The population consisted of all members of executive committee of suggestion system and the members of professional and general committee of IUMS; regarding to some limitations, sampling was not done. The tool of gathering data was a self constructed questionnaire that its content validity approved by the professors' ideas, and calculating Cronbach's alpha confirmed its reliability. Collected data was analyzed using SPSS software. RESULTS AND DISCUSSION: Analyzed data showed that the average score of the performance of the mentioned system was 50.47 +/- 14.8; based on this result it can be claimed that most of the participants (about 91%) evaluated the performance of the system moderate. The comparison of the average score of the four dimensions of CIPP model showed that the input dimension had the highest score and process, product and context dimensions were next on the hierarchy. CONCLUSION: Planning some programs for paying awards, facilitating and accelerating the personnel's and notifying the procedures of the suggestion system implementation are some useful strategy that could be used to increase the staff's participants. PMID- 24341063 TI - The impact of top management turnover on quality management implementation. AB - INTRODUCTION: The purpose of this study was to investigate the impact of top management turnover on Strategic Collaborative Quality Management (SCQM) implementation in healthcare organizations. The role of top management turnover in the process and impact of the SCQM model was investigated using a case study of a public hospital. METHODS: Both qualitative and quantitative methods were used for data collection. RESULTS AND DISCUSSION: Top management turnover is a major threat to the long-term success of the SCQM intervention and makes it very difficult to sustain its benefits. Successful quality management implementation needs supportive and committed leadership and management. Top management stability encourages long-term planning and commitment to pursuing long-term objectives. CONCLUSION: This paper has highlighted the critical role of top management stability during the course of quality management implementation. PMID- 24341064 TI - Klippel-Feil syndrome associated with atrial septal defect. AB - INTRODUCTION: Three major features result from this abnormality: a short neck, a limited range of motion in the neck, and a low hairline at the back of the head. Most affected people have one or two of these characteristic features. Less than half of all individuals with Klippel-Feil syndrome have all three classic features of this condition. The etiology of Klippel-Feil syndrome and its associated conditions is unknown. The syndrome can present with a variety of other clinical syndromes, including fetal alcohol syndrome, Goldenhar syndrome, anomalies of the extremities etc. Associated anomalies occur in the auditory system, neural axis, cardiovascular system, and the musculoskeletal system. RESULTS AND DISCUSSION: Cardiovascular anomalies, mainly septal defects, were found in 7 patients in Hensinger's series, with 4 of these individuals requiring corrective surgery. In our case we have had registered a nonrestrictive atrial septal defect and corrective surgical intervention at age 18 months in the Santa Rosa Children's Hospital (USA) has been done successfully. Careful examinations of specialist exclude anomalies in other organs and systems. Radiographs and MRI of the thoracic and lumbosacral spine are obtained and other anomalies have been excluded. PMID- 24341065 TI - Amyand's hernia in forensic autopsy: case report and review of the literature. AB - The presence of vermiform appendix in inguinal hernia is rare and is known as Amyand's hernia. Reported case was 73 years old man admitted to the hospital with chest pain who dead soon after admittance in the emergency department of the university hospital. In the macroscopic autopsy investigation, after opening the hernial sac, the vermiform appendix and caecum were detected free, without adhesions in the hernial sac. Death was reported due to acute myocardial infarction. Investigation of this rare entity in forensic autopsy is important for scientific classification, description and also correct pre-postoperative management and appropriate surgery. PMID- 24341066 TI - Medical informatics (MI) institutions. AB - Future of the MI Institution is described, the advances in the reliability of international telecommunications and the value placed on computerization in businesses and society. Today, computing is everywhere for school and universally present. Most countries use IT to improve their socioeconomic status. PMID- 24341067 TI - Bosnian and Herzegovinian medical scientists in PubMed database. AB - In this paper it is shortly presented PubMed as one of the most important on-line databases of the scientific biomedical literature. Also, the author has analyzed the most cited authors, professors of the medical faculties in Bosnia and Herzegovina, from the published papers in the biomedical journals abstracted and indexed in PubMed. PMID- 24341068 TI - Abulcasis, the father of modern surgery. PMID- 24341069 TI - [Social neuroscience and psychiatry]. AB - The topics of emotion, decision-making, and consciousness have been traditionally dealt with in the humanities and social sciences. With the dissemination of noninvasive human neuroimaging techniques such as fMRI and the advancement of cognitive science, neuroimaging studies focusing on emotions, social cognition, and decision-making have become established. I overviewed the history of social neurosciences. The emerging field of social brain research or social neuroscience will greatly contribute to clinical psychiatry. In the first part. I introduced our early fMRI studies on social emotions such as guilt, embarrassment, pride, and envy. Dysfunction of social emotions can be observed in various forms of psychiatric disorder, and the findings should contribute to a better understanding of the pathophysiology of psychiatric conditions. In the second part, I introduced our recent interdisciplinary neuroscience approach combining molecular neuroimaging techniques(positron emission tomography: PET), cognitive sciences, and economics to understand the neural as well as molecular basis of altered decision-making in neuropsychiatric disorders. An interdisciplinary approach combing molecular imaging techniques and cognitive neuroscience and clinical psychiatry will provide new perspectives for understanding the neurobiology of impaired decision-making in neuropsychiatric disorders and drug development. PMID- 24341070 TI - [A case report of early-onset Alzheimer's disease with multiple psychotic symptoms, finally diagnosed as APPV717I mutation by genetic testing]. AB - It is difficult to confirm a diagnosis of early-onset Alzheimer's disease (EOAD) because patients sometimes have non-specific cortical features, such as psychiatric symptoms, executive functional impairment, and pyramidal symptoms, along with typical symptoms, such as recent memory impairment and disorientation. We encountered a patient with multiple psychotic symptoms, finally diagnosed with EOAD on genetic testing. A right-handed sixty-year-old man, whose mother was suspected of having dementia, developed memory impairment at the age of fifty, disorientation at the age of fifty-six, and both visual hallucination and dressing apraxia at the age of fifty-nine. After admission to a psychiatric hospital for treatment, his symptoms disappeared with antipsychotic medication. However, his ADL were declining and so he was referred to our university hospital. He had frontal lobe symptoms, pyramidal signs, and extrapyramidal signs with severe dementia. Neuropsychological examinations were not possible because of sedation. On brain MRI, he showed diffuse atrophy of the cerebral cortex and hippocampus. HMPO-SPECT showed hypoperfusion of cerebral cortices diffusely. We decided to perform genetic testing because he had both family and alcohol abuse histories. He showed EOAD with V717I mutation of the amyloid precursor protein gene. After the discontinuation of antipsychotics, excessive sedation and extrapyramidal signs disappeared. A dose of 10 mg of donepezil was effective to improve motivation and activity, and his mini mental examination score was calculable after recovery. The case supports usefulness of applying genetic testing for Alzheimer's disease to patients with early onset dementia, even when they do not have a family history. PMID- 24341071 TI - [Neuropsychological testing in medicolegal cases]. AB - Because the assessment of cognitive function is among the most important diagnostic evaluations in medicolegal cases, neuropsychological testing, the optimal scientific method available to determine the manifestation of brain dysfunction, is a potentially very strong tool in those cases. However, the use of neuropsychological testing in a medicolegal setting should be done with caution. Firstly, the nature of any neuropsychological testing is complex, and cannot be simplified as "Test A measures Function A' ". Oversimplified explanation of a test is misleading, resulting in serious misjudgment in the legal procedure. Secondly, the result of the test shows someone's cognitive function at the time of the test, not the time of the act in question (i. e., a crime). Finally and most importantly, the cognitive function measured by neuropsychological testing does not directly correspond to the legal questions being asked, even when the terms used in the fields of law and neuroscience are similar. In determining whether an individual meets a specified legal standard (e. g., criminal responsibility), the results of neuropsychological testing are far from sufficient and substantial additional information is required. With these caveats in mind, an expert witness should carefully choose the neuropsychological testing battery in each case, which may greatly help to understand the individual's mental state at the time of the act in question. PMID- 24341072 TI - [The use of operational criteria for evaluations of mental competency]. AB - Today, either the DSM-IV or the ICD-10 is generally used for forensic purposes, especially for evaluations of mental competency. The use of operational criteria, such as the DSM-IV, in forensic settings has some risks. Here, these risks, as well as the advantages of operational criteria and precautions for their use, are discussed. Compared with the DSM-IV, the ICD-10 is preferred because this tool is less likely to complicate evaluations of the mental status of a criminal at the time of the crime when sufficient information is not available to make a diagnosis. The evaluation consists of two steps. The first step, which is based on empirical science, is to provide a psychiatric diagnosis. The second step, which is based on normative science, is to allocate the diagnosis to one of four categories of a forensic frame of reference and to provide useful information for judicial members to make a judgment about the mental competency of the criminal. To standardize evaluations, the use of not only global standard criteria, but also a general rule for the judgment of mental competency within each allocated category is needed. PMID- 24341073 TI - [Eight-step structured decision-making process to assign criminal responsibility and seven focal points for describing relationship between psychopathology and offense]. AB - The author suggested that it is essential for lawyers and psychiatrists to have a common understanding of the mutual division of roles between them when determining criminal responsibility (CR) and, for this purpose, proposed an 8 step structured CR decision-making process. The 8 steps are: (1) gathering of information related to mental function and condition, (2) recognition of mental function and condition,(3) psychiatric diagnosis, (4) description of the relationship between psychiatric symptom or psychopathology and index offense, (5) focus on capacities of differentiation between right and wrong and behavioral control, (6) specification of elements of cognitive/volitional prong in legal context, (7) legal evaluation of degree of cognitive/volitional prong, and (8) final interpretation of CR as a legal conclusion. The author suggested that the CR decision-making process should proceed not in a step-like pattern from (1) to (2) to (3) to (8), but in a step-like pattern from (1) to (2) to (4) to (5) to (6) to (7) to (8), and that not steps after (5), which require the interpretation or the application of section 39 of the Penal Code, but Step (4), must be the core of psychiatric expert evidence. When explaining the relationship between the mental disorder and offense described in Step (4), the Seven Focal Points (7FP) are often used. The author urged basic precautions to prevent the misuse of 7FP, which are: (a) the priority of each item is not equal and the relative importance differs from case to case; (b) each item is not exclusively independent, there may be overlap between items; (c) the criminal responsibility shall not be judged because one item is applicable or because a number of items are applicable, i. e., 7FP are not "criteria," for example, the aim is not to decide such things as 'the motive is understandable' or 'the conduct is appropriate', but should be to describe how psychopathological factors affected the offense specifically in the context of understandability of motive or appropriateness of conduct; (d) it is essential to evaluate each item from a neutral point of view rather than only from one perspective, for example, looking at the case from the aspects of both comprehensibility and incomprehensibility of motive or from aspects of both oriented, purposeful, organized behavior and disoriented, purposeless, disorganized behavior during the offense; (e) depending on the case, there are some items that do not require any consideration (there are some cases in which there are less than seven items); (f) 7FP are not exhaustive and there are instances in which, depending on the case, there should be a focus on points that are not included in these. PMID- 24341074 TI - [Forensic psychiatric examination in Japanese citizen judge system, saiban-in]. AB - In a criminal court, the forensic psychiatrist is required to give a report that is easy to understand by the saiban-in (lay judge). However, a method to provide such a report has yet to be established. To extract and clarify the current problems with the saiban-in justice system, a questionnaire survey was conducted involving 19 forensic psychiatrists and 18 judges, public prosecutors, and lawyers. Based on the results of this survey, it is recommended that written reports from psychiatrists should be evaluated by legal professionals and psychiatrists, and points of controversy should be examined prior to the trial. In the hearing, a presentation by the psychiatrist should be made, and an oral testimony should follow. PMID- 24341075 TI - [Psychoeducation for bipolar disorder: what we have to know and what we should disclose]. AB - Treatment is comprised of three components, clinical expertise, clinical research evidence, and patients' preferences. Therefore, clinicians have to provide psychoeducation to enable patients to understand their treatment plan based on clinical expertise and research evidence, and play roles as an important partner. Psychoeducation should be conducted based on mutual participation and understanding between clinicians and patients, and not just as one-sided teaching. Moreover, the aim of pychoeducation is the development of the patient's true insight, composed of recognition of illness, treatment adherence, and relabeling of psychiatric symptoms. A structured group-psychoeducatinal program for bipolar disorders established by Colom et al. is composed of 21 sessions of 90 minutes, each aimed at improving 5 main issues: illness awareness, treatment compliance, substance abuse avoidance, early detection of prodromal symptoms and recurrence and lifestyle regularity. The program has been proven to have long lasting prophylactic effects and good cost-effectiveness for individuals with bipolar disorders. Reconstruction of the diagnostic system for mental disorders based on elucidation of the pathogenesis and pathophysiology of these conditions is required to acquire a better mutual understanding between psychiatrists and patients. PMID- 24341076 TI - Improving the quality of health care: where law, accreditation, and professionalism collide. PMID- 24341077 TI - Direct and enhanced disclosure of researcher financial conflicts of interest: the role of trust. AB - In earlier writing, I recommended direct disclosure of major researcher financial conflicts of interest in per capita funding arrangements--the practice of providing researchers with a fixed sum for each subject recruited and enrolled in a study. This Article adds a recommendation for enhanced direct disclosure. The enhancement in the disclosure is a summary of why per capita and excess payments are being discussed and further includes whether the sponsors of the research and the researchers have claimed that there are no excess payments. The reason per capita payments are being discussed is because of the risk--with special caution when sponsors and researchers are not willing to claim that there are no excess payments--of introducing bias into researchers' decisions regarding study design, implementation, and interpretation, as well as concerning whom to enroll or keep in studies. Researchers' claims that there are no excess payments do not vitiate the risk of such payments. Nevertheless, a special admonition when sponsors and researchers do not claim the absence of excess payments would hopefully encourage them to eschew excess payments. My recommendations are required by the rights to bodily integrity and autonomy embedded in informed consent. Several arguments have been made against my recommendations, many of which relate to supposed effects on trust. My rights-based recommendations should not be rejected because of objections based on propositions that (1) are conceptually unclear because of a failure to unbundle different kinds and degrees of trust and (2) have not been empirically proven even where concepts are clarified. In some instances, the required strong empirical confirmation cannot be made because of practical or ethical restraints, including the fact that some of the necessary studies would require invasion of the right to informed consent. Finally, I suggest and partially apply an organizational method to generate empirical questions and guidance for future research in this area. Even the few hypothetical scenarios addressed demonstrate how complex--and sometimes practically or ethically impossible--the empirical studies must be to adduce proofs sufficient to overcome the imperative of informed consent. PMID- 24341078 TI - An exploration of compulsory licensing as an effective policy tool for antiretroviral drugs in India. AB - Access to affordable drugs for the treatment of HIV/AIDS and other diseases is increasingly challenging in many developing countries such as Brazil, South Africa, and India. These challenges are in part the result of strengthened patent laws mandated by the 1994 Trade-Related Aspects of Intellectual Property Rights (TRIPS) treaty. However, there are underutilized instruments within TRIPS that governments can use to limit the adverse effects of patent protection and thereby ensure a supply of affordable generic drugs to their people. One such instrument is compulsory licensing, which allows generic manufacturers to produce pharmaceutical products that are currently subject to patent protection. Compulsory licensing has been used by a number of countries in the last few years, including the United States, Canada, Indonesia, Malaysia, Brazil, and Thailand, and is particularly significant for countries such as India, where large numbers of people are infected with HIV. This Article explores the feasibility of compulsory licensing as a tool to facilitate access to essential medicines within the current patent regime in India, drawing on the experiences of other countries. PMID- 24341079 TI - The good, the bad, and the ugly: the unnecessarily broad impact of qui tam civil False Claims Act cases on rural health care providers. AB - The civil False Claims Act (FCA) imposes harsh penalties against parties who misappropriate federal funds. The statute's qui tam whistle-blower provisions create strong financial incentives for private individuals to bring and pursue FCA cases against health providers on the government's behalf--even where government attorneys decline to intervene. FCA cases where the government declined to intervene account for less than 2 percent of all recoveries in health care FCA cases. Yet the costs of defending such cases may be very high, especially for rural providers with small operating margins. Federal provider self-referral and anti-kickback laws carve out various exceptions to support the financial viability of rural providers. The FCA, however, contains no such exceptions. Although Department of Justice (DOJ) policy directs officials to take into account community access to care in pursuing FCA cases against rural providers, the ability for private whistleblowers to pursue cases where the government declines to intervene undermines the DOJ's ability to achieve that aim. This Article highlights the liability risks rural providers commonly face under the FCA and argues for amending the FCA to allow a whistleblower claim to proceed against providers serving designated underserved areas only where government authorities intervene in the case. PMID- 24341080 TI - Challenging the FDA's authority to regulate autologous adult stem cells for therapeutic use: Celltex therapeutics' partnership with RNL Bio, substantial medical risks, and the implications of United States v. Regenerative Sciences. AB - This Article examines the convergence of three corporations that have attempted to capitalize on translating emerging research into clinical procedures by manufacturing and facilitating the process for patients to obtain mesenchymal stem cell (MSC) injections. Although the Food and Drug Administration (FDA) has asserted its authority to regulate somatic cell therapy products like MSCs under the Public Health Service Act and the Food, Drug, and Cosmetic Act, some manufacturers have attempted to circumvent FDA regulation through various mechanisms and argue that their products do not fall within the definition of a biological product or drug. However, scientific knowledge of using MSCs for clinical therapy remains in its infancy, and MSCs pose a number of serious risks to patients. This Article focuses on the development of Celltex, a company based in Sugar Land, Texas that manufactures and facilitates the injection of autologous MSCs; RNL Bio, a company that licenses its operations technology to Celltex; and Regenerative Sciences, a company based in Broomfield, Colorado that was recently involved in litigation with the FDA. Corporate circumvention of intended regulatory oversight exposes patients to potentially inefficacious products that could contribute to serious medical injuries such as viruses, myocardial infarction, cancer, or death. PMID- 24341081 TI - Nanotechnology: using co-regulation to bring regulation of modern technologies into the 21st century. PMID- 24341082 TI - "I hate my doctor": reputation, defamation, and physician-review websites. PMID- 24341083 TI - A proposal for congressionally mandated federal regulation of child-directed food and beverage television advertisements to combat childhood obesity. PMID- 24341084 TI - In reply. PMID- 24341085 TI - In reply. PMID- 24341086 TI - [Regulation of the self-renewal and differentiation of spermatogonial stem cells]. AB - Spermatogonial stem cells (SSCs) play an important role in spermatogenesis and have a unique mode of replication. A single SSC can produce two differentiating cells, or one stem cell and one differentiating cell. The self-renewal and differentiation of SSCs are precisely regulated as relating the niche of SSCs, glial cell line-derived neurotrophic factor, and several signaling pathways. This article reviews the self-renewal and differentiation of SSCs and their regulation mechanisms, which may offer a deeper insight into spermatogenesis and male infertility and pave a theoretical ground for studying testicular tumorigenesis and searching for new potential approaches to the treatment of testicular cancer and other related diseases. PMID- 24341087 TI - [Expression of insulin-like factor 3 in the testis of flutamide-induced cryptorchidism mice and its significance]. AB - OBJECTIVE: To study the changes in the mRNA expression of insulin-like factor 3 (INSL-3) in the testis of mouse models of flutamide-induced cryptorchidism. METHODS: We randomized pregnant BALB/c mice to groups A (control) , B, C, D and E to receive continuous gavage of flutamide at 0, 150, 300, 500 and 700 mg/kg body weight, respectively, from gestation day 12 to 21. We detected the expression of INSL-3 mRNA in the testis of the neonates by real-time PCR at 4 and 8 postnatal weeks. RESULTS: No cryptorchidism was found in group A; unilateral cryptorchidism was seen in groups B (10.0%) and C (25.0%); and bilateral cryptorchidism was observed in groups D (21.1%) and E (40.0%). The expression of INSL-3 mRNA was reduced with the increased dose of flutamide, not significantly changed in groups B and C (P > 0.05) but remarkably decreased in D and E as compared with A (P < 0.05). CONCLUSION: Administration of flutamide to pregnant mice can induce unilateral cryptorchidism at 150 and 300 mg/kg and bilateral cryptorchidism at 500 and 700 mg/kg in their male offspring, which may be related with its reducing effect on the expression of INSL-3 in the testis of the mice. PMID- 24341088 TI - [Correlation of carbon monoxide with cell apoptosis in the penile tissue of aging rats]. AB - OBJECTIVE: To explore the pathogenesis of male sexual dysfunction by studying cell apoptosis and carbonate monoxide (CO) contents in the penile tissue of rats at different ages. METHODS: We equally divided 24 male Wistar rats into an adult group (8 months old), an elderly group (16 months old) and an aged group (24 months old), and detected cell apoptosis by HE staining and TUNEL and CO levels in the penile tissues of different groups by modified dual-wavelength spectrophotometry. RESULTS: Cell apoptosis increased with aging: 4.38 +/- 1.06 in the adult, 9.38 +/- 1.69 in the elderly and 18.50 +/- 1.60 in the aged group, while the CO content decreased with aging: 12.19 +/- 0.87 in the adult, 7.93 +/- 0.63 in the elderly and 5.68 +/- 0.62 in the aged group, both with statistically significant differences among the 3 groups (P < 0.05). The change of cell apoptosis showed a good negative correlation with that of the CO content (r = 0.889, P < 0.01). CONCLUSION: Cell apoptosis and CO content change in the penile tissue of aging rats, and CO may participate in the development of ED by regulating cell apoptosis. PMID- 24341089 TI - [Detecting testis- and epididymis-specific methylated promoters in human cell free seminal DNA by MeDIP-qPCR]. AB - OBJECTIVE: To establish a method of methyl-DNA immunoprecipitation (MeDIP)-real time quantitative PCR (qPCR) for detecting the promoter methylation level in cell free seminal DNA (cfsDNA). METHODS: We obtained cfsDNA samples from 6 normozoospermia men (the NZ group) and 6 post-vasectomy patients (the PV group), and mixed the samples from different individuals of each group, respectively. Then we made DNA fragments by ultrasonication, separated the methylated DNA fragments by MeDIP, and determined the methylation level of the promoters in cfsDNA by qPCR. RESULTS: The methylation levels of the promoters PRAME, PEG10, MORC1, GML, HOXA5, DNMT3L, SNURF, MSH4, DAZ1 and CLPB were 14.93, 2.64, 0.69, 2.66, 17.50, 21.10, 5.98, 2.28, 13.50 and 3.86%, respectively, in the NZ group, obviously lower than 121.25, 73.62, 16.25, 42.90, 76.74, 112.40, 59.79, 25.85, 91.90 and 64.53% in the PV group. The results of MeDIP-qPCR for the methylation of PRAME, MORC1, GML, HOXA5, DNMT3L, SNURF, MSH4 and DAZ1 were coincident with the results of genome-wide promoter methylation microarray. CONCLUSION: MeDIP qPCR can quantitatively measure the promoter methylation level in cfsDNA, and effectively determine the testis- and epididymis-specific methylated promoters in human semen. PMID- 24341090 TI - [Management of Fournier's gangrene in HIV-positive patients: report of 29 cases]. AB - OBJECTIVE: To review the clinical characteristics and treatment strategies of Fournier's gangrene in HIV-positive patients. METHODS: We retrospectively analyzed the clinical characteristics and therapeutic methods of 29 HIV-positive cases of Fournier's gangrene. RESULTS: The patients were aged 21-81 (mean 34.2) years, 27 < or = 47 years and the other two 79 and 81 years old, respectively. All the patients were HIV positive and diagnosed as having Fournier's gangrene, with CD4+ T lymphocyte count < 320/mm3, and none had received any antiretroviral therapy. The two aged patients were complicated by diabetes mellitus. All the cases originated in scrotal or penile infection, with later involvement of the surrounding skin soft tissues. Aggressive surgical debridement, incision-drainage and broad-spectrum antibiotic medication were initiated right after admission, and scrotoplasty was performed for 4 cases. Twenty-six of the patients were recovered and the other 3 (10.3%) died after surgery, 1 from infectious shock and 2 from diabetes mellitus complicated by pulmonary infection and renal failure. CONCLUSION: Timely aggressive surgical debridement, incision-drainage and broad spectrum antibiotic medication are essential for the treatment of Fournier's gangrene in HIV-positive patients. We did not find any direct adverse impact of HIV infection on the prognosis of Fournier's gangrene. PMID- 24341091 TI - [Distal cavernosal-glan shunt for ischemic priapism: a long-term follow-up study]. AB - OBJECTIVE: To investigate the management of ischemic priapism (IP) by analyzing the clinical and follow-up data of IP patients. METHODS: We retrospectively reviewed the clinical data of 8 IP patients treated in our hospital from January 2004 to June 2010 and analyzed the results of follow-ups by telephone calls and clinic visits. RESULTS: The average age of the patients was 34.5 (23 -41) years and the mean duration of priapism was 84.5 (36 -132) hours. All the patients had received previous detumescence treatment but failed before referred to our hospital. Irrigation/aspiration was performed at first, which achieved complete detumescence in 1 case and partial or transitional detumescence in the other 7. Subsequently, bilateral Al-Ghorab shunt was tried and succeeded in 2 cases but failed in 5. Finally, T-shunt was conducted, which achieved complete resumption in all the remaining 5 cases. Follow-up data were available in 5 of the cases, which were followed up for 12 -66 (mean 54) months. Of the 5 cases, moderate ED occurred in 2, and complete ED in 3. The latter 3 had suffered a longer duration of IP than the former 2. CONCLUSION: If detumescence failes, early intervention by T-shunt can improve the success rate of IP treatment. PMID- 24341092 TI - [PDE5 inhibitors for the management of temporary penile erectile dysfunction during treatment with assisted reproductive technology]. AB - OBJECTIVE: To evaluate phosphodiesterase type 5 (PDE5) inhibitors in the management of temporary penile erectile dysfunction (ED) in patients undergoing assisted reproductive technology (ART). METHODS: This study included 75 male patients that experienced ejaculation failure due to temporary ED during ART treatment. We treated the patients with PDE5 inhibitors sildenafil, tadanafil and vardenafil, and then evaluated the hardness of penile erection using Erection Hardness Score (EHS) and analyzed the end-point efficacy. RESULTS: Sildenafil was administered to 28 of the patients, tadanafil to 25, and vardenafil to 22. Of the total number of patients, 61 (81.3%) achieved effective erection, but no significant differences were observed in the rate of effectiveness among the sildenafil (24 cases, 85.7%), tadanafil (20 cases, 80.0%) and vardenafil (17 cases, 77.3%) groups (P > 0.05). After medication, 53 (70.7%) of the patients successfully ejaculated, but there were no remarkable differences in the success rate among the sildenafil (21 cases, 75.0%), tadanafil (17 cases, 68.0%) and vardenafil (15 cases, 68.2%) groups (P > 0.05). Of the 75 patients, 37 received the recommended initial dose and 38 the maximum recommended dose of PDE5 inhibitors, but no significant differences were found in the rate of successful sperm retrieval between the former (28 cases, 75.7%) and the latter group (25 cases, 65.8%) (P > 0.05). Mild adverse events, including transient flush and dizziness, occurred in 5 cases (6.7%). CONCLUSION: PDE5 inhibitors can help temporary ED patients to achieve penile erection and ejaculation during ART treatment. PMID- 24341093 TI - [Preventive administration of antibiotics to patients with benign prostatic hyperplasia before urodynamic examination]. AB - OBJECTIVE: To discuss the effect and safety of preventive administration of antibiotics to patients with benign prostatic hyperplasia (BPH) before urodynamic examination. METHODS: A total of 256 BPH patients to undergo urodynamic examination were randomly divided into a control group (n = 118) and a trial group (n = 138). The former received no pre-treatment while the latter were given cefoxitin sodium iv at 1.0 g 30 minutes before complete urodynamic examination. Then we compared the incidence rates of urinary tract infection between the two groups. RESULTS: Statistically significant differences were found in the incidence rate of urinary tract infection between the control and trial groups (20.3% [24/118] vs 7.3% [10/138], P < 0.01), as well as in those with diabetes mellitus (6.7% [3/45] vs 23.5% [8/34], P < 0.05), those with residual urine > 50 ml (5.4% [3/56] vs 18.5% [10/54], P < 0.05), and those with both diabetes mellitus and residual urine (9.5% [2/21] vs 44.4% [8/18], P < 0.05). Only 3 patients (2.2%) in the trial group had mild adverse drug reactions. CONCLUSION: For BPH patients, particularly those with diabetes mellitus and residual urine, preventive administration of antibiotics before urodynamic examination is safe and can effectively protect the patients against urinary tract infection. PMID- 24341094 TI - [Application value of diagnostic TURP for patients with serum PSA abnormality]. AB - OBJECTIVE: To assess the application value of diagnostic transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH) patients with persistently abnormal serum PSA levels. METHODS: We performed TURP for 71 BPH patients with the PSA level > 4 microg/L, and analyzed the Gleason scores and prognosis of the cases pathologically confirmed as prostate cancer (PCa). We conducted follow-up visits to all the patients, obtained the PSA levels and International Prostate Symptom scores (IPSS) at 6 and 12 months after TURP, analyzed their changes and assessed the value of TURP in the diagnosis and treatment of BPH with serum PSA abnormality. RESULTS: Among the 40 patients with negative prostate biopsy and persistent serum PSA abnormality, 2 cases were diagnosed as Gleason score 6 prostatic adenocarcinoma by TURP biopsy, and 1 case as Gleason score 6 PCa by repeated biopsy. All the 3 patients underwent radical prostatectomies and were well recovered during the follow-up visits. Of the 31 patients who had refused biopsy, 9 cases were confirmed by postoperative pathology as Gleason score 7 -9 PCa, 1 treated by radical prostatectomy and the other 8 by endocrine therapy. Another 59 cases were pathologically diagnosed as BPH, of which, the serum PSA level was restored to normal in 56 and significantly reduced in the other 3, and IPSS was remarkably increased in 53 and improved in the other 6 following urethral soundings. CONCLUSION: Diagnostic TURP can increase the early diagnosis rate of PCa, improve lower urinary tract symptoms (LUTS) and help to normalize the serum PSA level. Therefore, it can be chosen for those with persistent serum PSA abnormality, LUTS and negative prostate biopsy. PMID- 24341095 TI - [Elective microscopic resection of dorsal penile nerves for primary premature ejaculation: a clinical observation]. AB - OBJECTIVE: To evaluate the effect of elective microscopic resection of dorsal penile nerves in the treatment of primary premature ejaculation (PPE). METHODS: Seventy-eight PPE patients received elective microscopic resection of dorsal penile nerves, 5 branches in 9 cases, 6 in 17, 7 in 15, 8 in 14, 9 in 8, 10 in 6, 11 in 6, and 12 in 3. The patients were followed up for 12 months, and their intravaginal ejaculation latency time (IELT) and sexual intercourse satisfaction scores were recorded before and after treatment. RESULTS: Compared with the baseline, the IELT was significantly prolonged after surgery ([0.86 +/- 0.32] vs [6.65 +/- 3.9] min, P < 0.01), and the sexual intercourse satisfaction scores of the patients were dramatically increased (7.32 +/- 2.52 vs 12.32 +/- 3.76, P < 0.01), so were those of their sexual partners (4.46 +/- 1.36 vs 12.73 +/- 1.45, P < 0.01). CONCLUSION: Elective microscopic resection of dorsal penile nerves is safe and effective for the treatment of PPE. PMID- 24341096 TI - [Diagnosis and treatment of yolk sac tumor of the testis with hydrocele in children: report of 7 cases]. AB - OBJECTIVE: To study the clinical characteristics of yolk sac tumor of the testis with concomitant testicular hydrocele in children and the association between the two conditions in order to improve the diagnosis and treatment of the disease. METHODS: We retrospectively analyzed the clinical data of 7 cases of stage-I yolk sac tumor of the testis with concomitant testicular hydrocele. The patients ranged in age from 6 to 14 (mean 11) months. As treatment, we performed radical high spermatic cord orchiectomy after diagnosis established on intraoperative frozen sections, and conducted follow-up visits by medical examination, serum alpha-fetoprotein (AFP) detection, chest X-ray, ultrasonography and CT for 3-41 (mean 17) months, every month in the first year, every 3 months in the second year and every 6 months in the third year after surgery. RESULTS: Postoperative pathology confirmed yolk sac tumor in all the cases, with negative incisal margin. The level of serum AFP were decreased to normal in 6 cases within 1 month after surgery, all diagnosed as at stage I, and cured without chemotherapy. The other 1 case, with the serum AFP level of 116 microg/L at 1 month after operation, was diagnosed as at stage II and received PVC chemotherapy, but lost to follow-up at 3 months post-operatively. CONCLUSION: Yolk sac tumor of the testis with concomitant testicular hydrocele is easily misdiagnosed in children. Ultrasonography is necessitated as routine examination in its diagnosis. Radical high spermatic cord orchiectomy can be performed for patients in stage I, and chemotherapy should follow for those in stage II. Its prognosis is similar to that of other yolk sac tumors. Hitherto, there has been no evidence for a definitive correlation between yolk sac tumor of the testis and hydrocele in children. PMID- 24341097 TI - [Detection of DPY19L2 gene mutation in a globozoospermia patient]. AB - OBJECTIVE: Globozoospermia is mostly associated with homozygous deletion of the DPY19L2 gene. This study aimed to investigate the DPY19L2 gene mutation in a globozoospermia patient. METHODS: We observed the sperm histomorphology of a patient with globozoospermia using Wright-Giemsa's staining and transmission electron microscopy, detected the mutation of the DPY19L2 gene by PCR amplification and DNA sequencing, and compared the findings with the sequences issued in the Genbank. RESULTS: Wright-Giemsa's staining showed that all the spermatozoa were round-headed and lacked the acrosome, with the head nucleus darkly, fully and densely stained. Transmission electron microscopy revealed larger round sperm heads, with an even layer of unit membrane surrounding the nuclei and dispersed cytoplasmic vacuoles but no acrosomal structure. No DPY19L2 gene mutation was found by PCR amplification and DNA sequencing. CONCLUSION: No homozygous mutation of the DPY19L2 gene was found in the globozoospermia patient, and therefore some other disease-causing genes might be involved. PMID- 24341098 TI - [Ectopic mesonephric duct cyst with ectopic testicular malignancy: a case report and literature review]. AB - OBJECTIVE: To report a rare case of ectopic mesonephric duct cyst with ectopic testicular malignancy and improve the diagnosis and treatment of the disease. METHODS: We retrospectively analyzed the clinical data of a case of ectopic mesonephric duct cyst with ectopic testicular malignancy, reviewed relevant literature at home and abroad, and investigated the pathogenesis, diagnosis and treatment of the disease. RESULTS: A large cyst and the right ectopic malignant testis were removed via abdominal incision, and the left undescended testis was lowered into the scrotum. Pathological examination confirmed the lesion to be right ectopic mesonephric duct cyst with right ectopic testicular seminoma. No metastasis was found during a year of follow-up. CONCLUSION: Ectopic mesonephric duct cyst with ectopic testicular malignancy was a rare disease. Imaging examination contributes to its diagnosis, but it has to be confirmed by pathology. Surgical removal should be performed as early as possible and follow up treatment depends on the pathologic type and stage of ectopic testicular malignancy. PMID- 24341099 TI - [Transperitoneal versus extraperitoneal laparoscopic radical prostatectomy for localized prostate cancer: a meta analysis]. AB - OBJECTIVE: To evaluate the effects and safety of transperitoneal laparoscopic radical prostatectomy (TLRP) and extraperitoneal laparoscopic radical prostatectomy (ELRP) in the treatment of localized prostate cancer. METHODS: We searched the Cochrane Library, Medline, Chinese Journal Full-text Database, Wanfang and CBM for clinical controlled trials addressing TLRP and ELRP in the treatment of localized prostate cancer. Two independent reviewers extracted comparable data from eligible studies and performed meta-analysis with the Statal 2.0 software on the relevant indexes of operation time, intraoperative blood loss, postoperative catheterization, postoperative intestinal function recovery, and postoperative hospital stay. RESULTS: Nine clinical controlled trials with 942 cases were included in this analysis, 492 treated by TLRP and the other 450 by ELRP. Meta-analysis showed no statistically significant differences between the TLRP and ELRP groups in operation time (SMD = 0.60, 95% CI: -0.06,1.26), intraoperative blood loss (SMD = 0.01, 95% CI: -0.35, 0.36) , postoperative catheterization time (SMD = 0.10, 95% CI: -0.21, 0.40) and postoperative hospital stay (SMD = 0.45, 95% CI: -0.01, 0.91), except in the time of postoperative intestinal function recovery, which was significantly shorter in the ELRP than in the TLRP group (SMD = 1.18, 95% CI: 0.26, 2.10). CONCLUSION: For the treatment of localized prostate cancer, ELRP is similar to TLRP with respect to operation time, intraoperative blood loss, postoperative catheterization and postoperative hospital stay, but superior to the latter in postoperative intestinal function recovery. PMID- 24341100 TI - [Protective effect of Rhodiola extract against cisplatin-induced damage to TM4 sertoli cells in mice]. AB - OBJECTIVE: To investigate the preventive effect of Rhodiola extract on cisplatin (cDDP)-induced testicular toxicity in mouse TM4 Sertoli cell line and its possible mechanism in vitro. METHODS: We treated mouse TM4 Sertoli cells with Rhodiola extract and/or cDDP. Then we detected the proliferation of the TM4 cells by MTT assay, observed their morphological changes, and determined the contents of malondialdehyde (MDA), superoxide dismutase (T-SOD) and glutathione (GSH) in the cells. RESULTS: MTT assay showed that Rhodiola extract at the concentration of 0.0125-2.5 mg/L significantly inhibited the cDDP-induced decrease in the proliferation of the TM4 cells (P < 0.01) and improved their morphological changes. Anti-oxidation test exhibited a dramatically increased level of MDA in the TM4 cells treated with cDDP at 0.0147 g/L as compared with the normal control cells ([3.63 +/- 0.02] vs [2.15 +/- 0.02] nmol/mg prot, P < 0.01) and decreased levels of T-SOD ([6.57 +/- 0.05] vs [10.86 +/- 0.02] U/mg prot, P < 0.01) and GSH ([1.42 +/- 0.06] vs [2.59 +/- 0.05] mg/g prot, P < 0.01). Rhodiola extract at 0.1 mg/L significantly reduced the MDA content ([1.94 +/- 0.00] nmol/mg prot, P < 0.01) and the activity of T-SOD ([8.50 +/- 0.02] U/mg prot, P < 0.01) and GSH ([2.41 +/- 0.04] mg/g prot, P < 0.01) in the TM4 cells treated with cDDP. CONCLUSION: Rhodiola extract can significantly inhibit cDDP-induced damage to TM4 cells in mice, which may be associated with its antioxidant activity. PMID- 24341101 TI - [Clinical efficacy of Shuganyiyang capsule combined with Western medicine for the treatment of type III prostatitis complicated by erectile dysfunction]. AB - OBJECTIVE: To investigate the clinical efficacy of Shuganyiyang Capsule combined with conventional Western medicine (tamsulosin hydrochloride sustained release tablets + prostat tablets) for the treatment of type III prostatitis complicated by erectile dysfunction (ED). METHODS: Eighty patients with type III prostatitis complicated by ED were equally randomized to an experimental and a control group, the former treated with Shuganyiyang Capsule combined with tamsulosin hydrochloride sustained release tablets and prostat tablets, while the latter with tamsulosin hydrochloride and prostat only, both for 8 weeks. Then the prostatitis symptoms, erectile function and psychological conditions of the patients were evaluated using NIH-CPSI, IIEF-5, and hospital anxiety and depression scale (HADA and HADD) respectively. The rates of recovery, excellence, effectiveness and ineffectiveness were calculated. RESULTS: The scores on NIH CPSI, IIEF-5, HADA and HADD obtained at 4 and 8 weeks after treatment showed statistically significant differences between the two time points as well as from the baseline (P < 0.01). At 8 weeks, the scores on NIH-CPSI, IIEF-5, HADA and HADD were 6.83 +/- 4.96, 21.03 +/- 2.54, 6.05 +/- 1.62, and 5.35 +/- 3.30 in the experimental group, as compared with 7.55 +/- 4.89, 17.68 +/- 4.15, 6.88 +/- 2.45, and 7.85 +/- 3.77 in the control (P < 0.05). The rate of effectiveness was significantly higher in the experimental than in the control group (90% [36/40] vs 70% [28/40], P < 0.05). CONCLUSION: Shuganyiyang Capsule combined with conventional Western medicine, such as alpha blockers and galenica, produces definite effect on chronic prostatitis complicated by ED, improves the psychological conditions of the patient, and enhances the therapeutic efficiency of chronic prostatits. PMID- 24341102 TI - [MicroRNAs in seminal plasma: an update]. AB - MicroRNAs (miRNAs), present abundantly in human body fluids, may serve as biomarkers for the diagnosis of a variety of diseases. Recent studies show that they are also abundantly and stably expressed in the seminal plasma of men. Some seminal plasma-specific miRNAs can be used as potential markers for forensic body fluid identification. Furthermore, the expression profile of seminal plasma miRNAs in normal fertile men is quite different from that in idiopathic infertile patients. The specifically altered profile of seminal plasma miRNA is closely related with male infertility and spermatogenic dysfunction and therefore can be used as a novel biomarker for the diagnosis of male infertility. A deeper insight into the specific changes of seminal miRNA may point a new direction in the studies of the molecular mechanisms of male infertility. PMID- 24341103 TI - [Progress in researches on the sperm centrosome]. AB - In humans and most mammals, the sperm centrosome is primarily responsible for nucleating and organizing the sperm astar, which pushes the sperm head toward the oocyte center and guides the migration of the female pronucleus, completing the fertilization process. There are about 200 kinds of protein in the human sperm centrosome. Currently, most of the researches focus on the centrin protein. Further studies on the functions of different human sperm centrosomal proteins may contribute to the understanding of the causes of the failures in assisted reproductive technology (ART). And in ART, morphological observation of the sperm neck integrity is the only way for primary evaluation of the function of the sperm centrosome. PMID- 24341104 TI - Editorial: informal care. PMID- 24341105 TI - Powerful drivers for maintenance. AB - A UPS system is the central building block of a Power Continuity Plan in medical facilities, but such equipment requires careful maintenance to continue fulfilling its vital role in delivering power resilience, and avoid catastrophic downtime, and potentially tens of thousands of pounds in costs to rectify the issues caused by poor maintenance. In our latest technical guidance article, Steve Mason, MD at Bender UK, one of the leading providers of isolated power supplies, theatre control panels, UPS systems, and Steris surgical products, and a turnkey provider of solutions for safe handling of electrical power and advanced provision of critical care products, examines some of the issue surrounding UPS maintenance. PMID- 24341106 TI - Campaign starts for next year's event. AB - Scott Buckler, Founder, 4 All of Us, which will be co-hosting next March's NHS Sustainability Day 2014 with Barts Health, outlines some of the key aims of the 2014 IHEEM-backed campaign, looks back at the success of this year's event, explains how Health Estate Journal will be the official Media Partner next year, and emphasises the important role that sustainability plays in health. PMID- 24341107 TI - Cutting the cost of NHS procurement. AB - With the NHS spending over 20 billion sterling pounds annually on goods and services--accounting, typically, for around 30 per cent of each hospital's operating costs--but, in the view of Health Minister, Dr Dan Poulter MP, still 'failing to harness its enormous purchasing power', the Minister recently unveiled a new Procurement Development Programme for the service, (HEJ - September 2013) the goal being to help NHS Trusts 'find' over 1.5 billion sterling pounds of 'procurement efficiencies' over the next three years. HEJ reports. PMID- 24341108 TI - Ensuring effective device management. AB - In an article that first appeared in the August 2013 issue of HEJ's sister magazine, The Clinical Services Journal, John Sandham IEng MIET MIHEEM, discusses the need to put in place effective healthcare technology management policies, and highlights some of the barriers, including lack of management expertise, and insufficient commitment, that are making achieving this goal more difficult and, in the process, may be contributing to hospitals and other healthcare facilities being unable to comply with regulatory standards in this important area. PMID- 24341109 TI - Multidisciplinary input on 6.8 m sterling pounds conversion. AB - With substantial capital funding for new build NHS healthcare facilities increasingly scarce, many Trusts are now focusing ever harder on maximising use of existing space, and, where it is not being effectively used, on converting it for new or alternative clinical and non-clinical use. In an excellent example of how an existing under-utilised building can be cost-effectively refurbished to provide valuable new facilities that improve patient care and meet growing demand, the Wrightington, Wigan and Leigh (WWL) NHS Foundation Trust in north west England recently converted a run-down, partly deserted, 1970s building to create a new diagnostic and treatment centre. The impressive facility combines women's healthcare services, urology and gastroenterology diagnosis and treatment, and a state-of-the-art endoscope reprocessing facilities, under one roof. HEJ editor, Jonathan Baillie reports. PMID- 24341110 TI - A vision for better healthcare in India. AB - Ian Hinitt, until the Summer of 2012 deputy director of Estates at Bradford Teaching Hospitals NHS Foundation Trust, is spearheading an ambitious joint venture project between Apex 4D, he and his business partner, Balbir Panesar's recently established Bradford-based outsourced FM company, and Leeds headquartered architectural practice, Bowman Riley, which the project partners hope will initiate the construction of a new generation of modular buildings to improve healthcare provision throughout India, and, in the process, generate significant reciprocal trade opportunities for both UK and Indian suppliers to the sector. HEJ editor, Jonathan Baillie, reports. PMID- 24341111 TI - Off-site build speeds mortuary completion. AB - A new mortuary and bereavement facility at one of North Wales's largest acute hospitals, the Ysbyty Glan Clwyd near Rhyl, formed from 16 steel-framed modules that were manufactured off site, and subsequently craned into position to greatly speed project completion, was delivered 'well below original cost budget, four weeks ahead of schedule', by turnkey construction specialist, MTX Contracts. As HEJ editor, Jonathan Baillie, reports, this is MTX's second substantial project in the past two years at Glan Clwyd, reporting to the principal contractor on a major redevelopment programme currently ongoing at the hospital, Laing O'Rourke. PMID- 24341112 TI - Keeping electronic records secure. AB - Are electronic engineering maintenance records relating to the hospital estate or a medical device as important as electronic patient records? Computer maintenance management systems (CMMS) are increasingly being used to manage all-round maintenance activities. However, the accuracy of the data held on them, and a level of security that prevents tampering with records, or other unauthorised changes to them to 'cover' poor practice, are both essential, so that, should an individual be injured or killed on hospital grounds, and a law suit follow, the estates team can be confident that it has accurate data to prove it has fulfilled its duty of care. Here David Easton MSc CEng FIHEEM MIET, director of Zener Engineering Services, and chair of IHEEM's Medical Devices Advisory Group, discusses the issues around maintenance databases, and the security and integrity of maintenance data. PMID- 24341113 TI - Making design 'work' for all user groups. AB - Regina Kennedy, an architect and urbanist with a Master's degree in healthcare facility planning and design, who is currently a programme manager at Hamad Medical Corporation (HMC), the state of Qatar's 'premier' non-profit healthcare provider, examines how, during the design process, the right principles can be applied to ensure that hospitals and other healthcare facilities 'work' for all user groups. PMID- 24341114 TI - Forthcoming 'energy crunch' imminent. AB - A looming energy crisis will hit the UK within the next five years, energy regulator Ofgem has warned on a number of occasions already this year, and public sector organisations, commercial businesses, and households, can all expect a series of price hikes as demand outstrips local resources. So says Shamir Jiwa, founder and MD of MAXIM Eyes UK, a Surrey-based energy consultancy that serves business and organisations across the UK and Poland. Here he gives his personal view on some of the key short- to medium-term energy and resource management issues facing both hospitals and other healthcare facilities, and the wider UK, in the face of dwindling supplies of some, and especially fossil-fuel derived, forms of energy. PMID- 24341115 TI - RFID solution benefits Cambridge hospital. AB - Keeping track of thousands of pieces of equipment in a busy hospital environment is a considerable challenge, but, according to RFID tagging and asset tracking specialist, Harland Simon, RFID technology can make the task considerably simpler. Here Andrew James, the company's RFID sales manager, describes the positive benefits the technology has brought the Medical Equipment Library (MEL) at Addenbrooke's Hospital, one of the world's most famous teaching hospitals. PMID- 24341116 TI - Boosting capacity, enhancing service. AB - How can estates managers guarantee uninterrupted surgical provision during refurbishment projects, or boost capacity when waiting lists look dangerously at risk? Vanguard Healthcare, which operates what is reportedly the world's largest fleet of mobile healthcare facilities, explains how estates and facilities personnel, who it believes are increasingly playing a vital role in the economic, as well the clinical, productivity of hospitals, are increasingly turning to interim mobile facilities. PMID- 24341117 TI - Sustaining surfaces in tip-top condition. AB - Flooring is a crucial element in healthcare settings, so choosing the most appropriate materials, and employing the correct cleaning methods, should be high on the list of priorities for all healthcare estate managers, as Lesley Davis, a regional area manager at supplier of industrial and commercial floor cleaning machines, Truvox International, explains. PMID- 24341118 TI - 3D printing technology speeds development. AB - James McGowan, R&D product designer for Monodraught, a specialist in 'natural ventilation, natural daylight, and natural cooling systems', discusses the development of Cool-phase, the company's latest innovative application of phase change material (PCM) as a thermal energy store used to actively ventilate and cool buildings. As he explains, when the company decided to re-design an already successful product to further enhance its performance, the use of 3D modelling greatly speeded up prototyping, and helped the design process progress considerably more quickly. PMID- 24341119 TI - Offering a smarter and brighter choice. AB - Colin Lawson, head of sales and marketing at Tamlite Lighting, argues that when selecting new lighting for healthcare facilities, estates and facilities managers need to make 'smart, well-informed decisions' in order to balance energy saving with patient comfort. Estates personnel selecting LED lighting in particular, he cautions in this article, need also to be confident that the products they are buying are of the requisite quality, and will give long-lasting, stable, and even performance, amid the backdrop of a growing flood of 'sub-standard' imports from the Far East in particular. PMID- 24341120 TI - Classification in karyometry: performance testing and prediction error. AB - Classification plays a central role in quantitative histopathology. Success is expressed in terms of the accuracy of prediction for the classification of future data points and an estimate of the prediction error. The prediction error is affected by the chosen procedure, e.g., the use of a training set of data points, a validation set, an independent test set, the sample size and the learning curve of the classification algorithm. For small samples procedures such as the "jackknife," the "leave one out" and the "bootstrap" are recommended in order to arrive at an unbiased estimate of the true prediction error. All of the procedures rest on the assumption that the data set used to derive a classification rule is representative for the diagnostic categories involved. It is this assumption that in quantitative histopathology has to be carefully verified before a clinically generally valid classification procedure can be claimed. PMID- 24341121 TI - IgG4-related sclerosing disease: an emerging entity frequently misdiagnosed. AB - IgG4-related sclerosing disease, a multiorgan system disease that has been identified in the last 10 years, is a fibroinflammatory condition with a marked propensity to manifest itself as mass forming lesions characterized by three main histological features (sclerosis, obliterative phlebitis and lymphoplasmacytic infiltrate) and by the presence of abundant IgG4+ plasma cells, frequent elevation of serum IgG4 and a dramatic initial response to steroid therapy. The aim of this mini-review is to increase the capacity to identify the characteristic features of IgG4-related sclerosing disease in specific organs and in two newly proposed entities (urethral caruncle and paratesticular fibrous pseudotumor) using biopsy specimens and methods of counting IgG4. In addition we examine the relationship between IgG4-related sclerosing disease and malignancy. In fact, an increased ability to recognize the characteristic features of IgG4 related sclerosing disease would play an extremely important role in avoiding unnecessary surgery in favor of initiating corticosteroid therapy. PMID- 24341122 TI - Canine peripheral blood lymphocyte phenotyping by 7-color multiparameter flow cytometry. AB - OBJECTIVE: To characterize baseline canine lymphocyte phenotypes including lymphocytes coexpressing multiple markers by novel 7-color multiparameter flow cytometry. STUDY DESIGN: Fresh canine peripheral blood lymphocytes of 79 healthy 26-week-old Beagle or Beagle-mix dogs were stained and analyzed. RESULTS: The high number of samples and acquired flow data (averaging 1.9 x 10(5) cells/sample) allowed the detection of minor lymphocyte subsets coexpressing multiple lymphocyte markers. The averaged percentages of major lymphocyte subsets of CD3+, CD4+, CD8+, CD21+ and gammadelta TCR+ cells from this study were 74.0, 43.6, 14.3, 9.6, and 0.2, respectively, which were comparable but uniquely different from other reports as they were simultaneously detected in the same sample. We demonstrated that the commonly used CD21 and CD3 monoclonal antibody (mAb) clones, previously recommended not to be used in the same staining, could and should be used together with the proper steps of lymphocyte gating. We found a high percentage (10.3%) of unidentified CD21- CD3+ CD4- CD8-gammadelta TCR- lymphocyte subset that has never been reported. The intensive gating strategy and the mean percentages of each lymphocyte subset to their parent subsets and to the total lymphocyte population are presented and discussed. CONCLUSION: The canine lymphocyte phenotypes were fully characterized. This novel multiparameter flow cytometry method is a powerful approach to in-crease the accuracy of lymphocyte phenotyping in dogs. PMID- 24341123 TI - The ejaculatory ducts and their implications in prostate adenocarcinoma. AB - OBJECTIVE: To describe the histological characteristics of the ejaculatory duct and their importance in prostate adenocarcinoma. STUDY DESIGN: Anatomical dissection of the prostate and seminal vesicles was performed in 20 autopsies of males without clinical evidence of prostatic pathology. Specimens were totally sampled to study the complete route of the ejaculatory ducts within the prostate, focusing specifically on the histological characteristics of the stroma enfolding the ducts. RESULTS: Ejaculatory ducts are covered by a distinct fibrous capsule that includes lymphatics and blood vessels with a specific spatial and architectural arrangement. Although easy to recognize in normal conditions, the positive nuclear immunostaining of epithelial cells with PAX-2 and PAX-8 may be of help to recognize the ejaculatory epithelium in problematic cases. These arteriolymphatic units made of hyalinized arteries and ectatic lymphatic vessels run parallel to the ejaculatory duct along its intraprostatic course and continue outside the prostate gland in the subadventitial tissue of seminal vesicles. CONCLUSION: The ejaculatory ducts have a unique characteristic histology that allows its recognition in transrectal core biopsies. The issue matters in daily practice and may have prognostic implications in prostate adenocarcinoma since the invasion of this structure has been associated with a high percentage of extraprostatic disease. PMID- 24341124 TI - Comparison of HSCORE assessment of endometrial beta3 integrin subunit expression with digital HSCORE using computerized image analysis (ImageJ). AB - OBJECTIVE: To compare intraobserver and interobserver variation between traditional histological score (HSCORE) and digital HSCORE (D-HSCORE) performed by expert and naive researchers. STUDY DESIGN: Immunohistochemical analysis of beta3 integrin subunit of 100 endometrial biopsies obtained from the midluteal phase of the menstrual cycle were reanalyzed using ImageJ software (D-HSCORE). Mean intensity of 3,3'-diaminobenzidine on endometrial glands was read by an expert (HSCORE) versus inexperienced observer using HSCORE and D-HSCORE. RESULTS: The mean correlation [r(s)(95% CI)] between both methods was 0.86 (0.79-0.90) and highly significant (p < 0.0001) for the experienced individual. The naive researcher overestimated immunostaining, resulting (HSCORE) in negative samples. No discrepancies were seen with D-HSCORE. Interobserver variation for the inexperienced reader was 50% using HSCORE (cutoff 0.7) but 0% with D-HSCORE. Intraobserver variation using ImageJ was 0%. CONCLUSION: The D-HSCORE performed by an inexperienced researcher has high correlation to traditional HSCORE performed by an expert. PMID- 24341125 TI - Role of the trigeminal system on posterior communicating artery remodelization after bilateral common carotid artery ligation. AB - OBJECTIVE: To examine whether or not there is a possible relationship between the neuron density of trigeminal ganglion (TGG) and the severity of posterior communicating artery (PComA) vasodilation values after permanent bilateral common carotid artery ligation (BCCAL). STUDY DESIGN: This study included 25 rabbits. Both the common carotid arteries of 20 rabbits were explored and denervated. Five animals served as controls. Permanent BCCAL was applied in 15 of the 20 rabbits, and the other 5 were used as the SHAM group without ligation. All animals were followed for 2 months and then sacrificed. Their brains and cranial nerves were extracted and fixed in 10% formalin solution. The relationship between PComA vasodilation values and TGG neuron densities were compared. RESULTS: Elongation, convolution and enlargement were detected in all the basilar arteries of all ligated animals and 2 from the SHAM group. On histopathogical examination vascular wall thinning, luminal enlargement, flattened inner elastic membrane, flattened vessel muscle cells, endothelial desquamation and intimal erosions were detected. An inverse relationship was discovered between the neuron density of TGG and the severity of PComA vasodilation index. CONCLUSION: BCCAL may lead to important beneficial and hazardous histomorphological changes at the posterior communicating artery. The high neuron density of TGG may provide a beneficial effect by facilitating PComA enlargement via its vasodilatory properties for the increase of decreased cerebral circulation, although this situation may be hazardous for certain subjects with congenital or acquired cerebrovascular pathologies. PMID- 24341126 TI - Value of argyrophilic nucleolar organizing region protein determinations in nondiagnostic fine needle aspiration samples (due to insufficient cell groups) of thyroid nodules. AB - OBJECTIVE: To evaluate the diagnostic value of argyrophilic nucleolar organizing regions (AgNORs) in the nondiagnostic fine needle aspiration biopsy (NFNAB) specimens (due to insufficient cell groups) of cases with thyroid nodules. STUDY DESIGN: Thirty-five patients with NFNAB were included in the study. FNAB stained with Giemsa was faded using the McKee technique, then stained for AgNOR detection according to a specific protocol. One hundred nuclei per individual were evaluated to detect the AgNOR count/nucleus and total AgNOR area/ nuclear area (TNA/NA) of individual cells by using a computer program. RESULTS: The AgNOR values of patients with NFNAB were between 1.2-2.4% for AgNOR count/ nucleus and between 3.1-9.1%for TNA/NA. When the cutoff values were taken as > 3 for AgNOR count/nucleus and > 8 for TNA/NA, the sensitivity ratios were 100% and 97% for AgNOR count/nucleus and TNA/ NA for discriminating benign/malignant lesions. CONCLUSION: By using some cutoff values obtained from a modified AgNOR staining method, benign/malignant potential of thyroid aspirations with NFNAB may be estimated. (Anal Quant Cytopathol Histopathol PMID- 24341127 TI - Rapidly fatal leukemia comprising pleomorphic large granular lymphocytes: a report of 2 cases. AB - BACKGROUND: Large granular lymphocytes (LGLs) are either cytotoxic T or natural killer (NK) cells exhibiting round nuclei and azurophilic cytoplasmic granules. Morphologically, neoplastic LGLs of T cell lineage (T-LGLLs) are usually indistinguishable from normal LGLs, while there is a wide morphological range of aggressive NK cell leukemia (ANKL). CASES: We present 2 consecutive cases of leukemia comprising pleomorphic LGLs. One patient presented with drowsy consciousness and unstable hemodynamics. Her peripheral blood smear disclosed a significant number of LGLs with pleomorphic nuclei expressing CD2, CD56 and HLA DR but not surface or cytoplasmic CD3 (cCD3). The second patient, previously healthy, presented with a sudden death. Her peripheral blood revealed LGLs ranging from round to pleomorphic nuclei with a CD2+ cCD3+ surface CD3- CD56+ phenotype and clonally rearranged T cell receptor gene. The findings of the first patient were consistent with ANKL and the second, T-LGLL. Both patients passed away shortly before treatment. CONCLUSION: The 2 cases highlight the importance of a multidisciplinary approach in addition to cytological examination to reach accurate diagnoses of such rare leukemia cases. PMID- 24341129 TI - Jobs. PMID- 24341128 TI - Isolated oral Kaposi sarcoma in an HIV-negative patient: a case report. AB - BACKGROUND: Kaposi sarcoma is a well-known vascular tumor first described by Moriz Kaposi in 1872. Oral involvement is seen as an AIDS-related malignant neoplasm but is rarely described in HIV-negative and non-immunosuppressed individuals. CASE: We report a case of oral Kaposi sarcoma in a 75-year-old, HIV negative woman. Diagnosis was achieved according to clinical, histopathological and positive polymerase chain reaction for human herpes virus 8. The tumor was surgically excised and no recurrence was detected in the following 6 months. CONCLUSION: Oral Kaposi sarcoma is rare in HIV-negative patients and is associated with HHV-8 infection. Lesions are usually solitary and can be treated surgically. It should be included in the differential diagnoses of oral lesions that are clinically suspicious and resistant to therapy. PMID- 24341130 TI - Reputation clipping. PMID- 24341131 TI - Dental student research. PMID- 24341132 TI - Volumetric assessment of cleft lip and palate defects using cone beam computed tomography. AB - A possible avenue to improve the clinical success of bone graft procedures in cleft lip and palate cases is to predetermine the bone donor site and the volume of graft material required for the recipient site. This study utilized cone beam computed tomography to generate three-dimensional reconstructions and volumetrically assess unilateral cleft lip and palate defects. Access to this information can assist in determining an optimal donor site for secondary alveolar bone grafting. PMID- 24341133 TI - Evaluation of serum biomarkers IL-17 and CTX for BRONJ: a pilot clinical case control study. AB - A serious complication of bisphosphonate (BP) therapy is BP-related osteonecrosis of the jaw (BRONJ). Currently, no biomarkers exist to identify patients at risk. We evaluated whether interleukin-17 and C-telopeptide correlate with BRONJ development. We conducted a case-control study using patients with a history of BP therapy. Quantitative enzyme-linked immunosorbent assay and Student's t-test were done. Both markers were significantly higher in BRONJ, suggesting altered immune responses and bone remodeling may play roles in BRONJ development. PMID- 24341134 TI - Photodynamic therapy of Porphyromonas gingivalis via liposome-encapsulated sensitizers. AB - Photodynamic therapy exploits the light-activation of a photosensitizer to cause cytotoxicity. Liposomes can be used to deliver hydrophobic photosensitizers to bacteria. Positively charged dioleoyltrimethylammoniumpropane:palmitoyloleoylphosphatidylcholine (1:1) liposomes bound quantitatively to the periodontal pathogen, Porphyromonas gingivalis. Following illumination, free and liposomal zinc phthalocyanine reduced the colony-forming unit (CFU) to 65 percent and 23 percent of controls, respectively. Thus, localization of the photosensitizer at the surface of bacteria via liposome binding enhanced the photodynamic cytotoxicity of zinc phthalocyanine. PMID- 24341135 TI - Expression of EMMPRIN modulates mediators of tumor invasion in oral squamous cell carcinoma. AB - Squamous cell carcinoma (SCC) accounts for 96 percent of all intraoral malignancies. The five-year survival rate is 50 percent and has not improved in 60 years. During SCC progression, subsets of SCC cells undergo an epithelial-to mesenchymal transition (EMT) to become highly invasive. The extracellular matrix metalloproteinase inducer (EMMPRIN) contributes to EMT by activating local matrix metalloproteinases (MMPs). In this study, we found that EMMPRIN modulates the invasive phenotype and may be a potential therapeutic target. PMID- 24341136 TI - Segmenting the business of dentistry. PMID- 24341137 TI - The numbers game. PMID- 24341138 TI - Severe congenital neutropenia in two siblings related to HAX1 mutation without neurodevelopmental disorders. AB - Severe congenital neutropenia (SCN) is a rare primary myelopoiesis disorder, characterized by reduced absolute neutrophil counts from birth, increased susceptibility to recurrent and life-threatening infections, and a preleukemic predisposition. Herein, we describe two siblings with SCN born from consanguineous parents who were referred for complaints of recurrent cutaneous infections, gingivitis, purulent otitis media, and both lower and upper respiratory tract infections. Bone marrow aspiration of one patient demonstrated a maturation arrest in the myeloid lineage at the promyelocyte-myelocyte stages. Genetic analysis revealed a homozygous mutation in exon 2 c.130-131insA; p.W44X in the HAX1 gene. Although identical mutations were detected in both siblings, there was a clear discrepancy between the clinical course of the brother, who eventually required granulocyte colony stimulating factor (G-CSF) therapy, and the sister, who did not. Although SCN is a rare disorder, the early onset of recurrent infections and severe neutropenia, especially in children born from consanguineous parents, should always raise suspicion and warrant further evaluation. PMID- 24341139 TI - Subtelomeric fish findings in Turkish patients with idiopathic mental retardation. AB - Subtelomeric rearrangements are the major cause of idiopathic mental retardation (IMR). This study included 67 Turkish children with IMR. Subtelomere fluorescence in situ hybridization (FISH) was used to determine the subtelomeric rearrangements. Submicroscopic subtelomeric deletions were identified in 5 patients, with a detection rate of 7.4%. The deletions involved 5 different subtelomeric regions (1p, 2q, 8p, 9p and 10p). The detection of subtelomeric rearrangements is of great importance in offering genetic counseling and prenatal diagnosis. PMID- 24341140 TI - Multiloculated hydrocephalus of intrauterine-onset: a case report of an unexpected MTHFR A1298C positive test result. AB - Loculated hydrocephalus is a condition in which discrete fluid-filled compartments form in association with the ventricular system of the brain. Multiloculated hydrocephalus is a subgroup of this entity involving more than one segment of the ventricular system. Abnormal descent of the cerebellar components can cause multiloculated hydrocephalus due to various pathogenesis. However, studies report no more than 10% of correlation between cerebellar herniation and hydrocephalus. We report an infant with MTHFR A1298C homozygosity, who had hydrocephalus of intrauterine-onset. Alterations in the folate metabolism might lead to congenital hydrocephalus and there is growing data on the prothrombotic effects of MTHFR polymorphisms. To the best of our knowledge, there has been no reported case of MTHFR A1298C homozygosity and intrauterine-onset multiloculated hydrocephalus as a co-existence in the literature. PMID- 24341141 TI - Crigler-Najjar syndrome type I in a Turkish newborn caused by a novel mutation and Gilbert type genetic defect. AB - Crigler-Najjar syndrome (CNS), caused by deficiency of bilirubin uridine diphosphate glucuronosyltransferase (UGT) 1A1, is a rare and autosomal recessive inherited disorder characterized by severe unconjugated nonhemolytic hyperbilirubinemia since birth. We present a girl with CNS type I caused by a novel mutation and Gilbert type genetic defect. Gilbert's Syndrome (GS) and CNS type I both involve abnormalities in bilirubin conjugation secondary to deficiency of bilirubin UGT. The combined defects even in benign genetic forms were shown to cause more serious clinical disease. The patient has been treated with daily home-based phototherapy for more than nine months and considered as a candidate for liver transplantation. PMID- 24341142 TI - Bamforth syndrome: is porencephaly a new finding? AB - Bamforth syndrome is a rare inherited condition whose main features are congenital hypothyroidism due to thyroid dysplasia, cleft palate, and spiky hair, with or without choanal atresia and bifid epiglottis. This syndrome is caused by mutations in the gene encoding thyroid transcription factor 2 (TTF-2). Here we report on a newborn with facial dysmorphism, cleft palate, spiky hair, congenital hypothyroidism and that are observed with Bamforth syndrome. This is the first case with Bamforth syndrome in which porencephaly has been observed. PMID- 24341143 TI - A new patient with Andermann syndrome: an underdiagnosed clinical genetics entity? AB - Andermann syndrome is an autosomal recessive disorder characterized by the agenesis of the corpus callosum and peripheral neuropathy (ACCPN). People affected by Andermann syndrome have mental retardation, areflexia and severe progressive neuropathy often accompanied by psychiatric symptoms, and they typically die in the third decade of their life. We here report the case of a 5 year-old Turkish boy born to consanguineous parents. He presented to clinical attention with delayed development and epilepsy and was found to have dysmorphic characteristics, areflexia and severe neuropathy on exam. Imaging studies were remarkable for agenesis of corpus callosum. SLC12A6 screening revealed the presence of R1011X mutation; potentially responsible for the changes in intracellular and extracellular ion concentrations, leading to defects in cortical electrical activity. PMID- 24341144 TI - De novo dup(7)(q21q22.2) and cytogenetics of 7q21q34 duplications. AB - We report on a constitutional dup(7)(q21q22.2) and compile 25 similar mid-7q imbalances in order to sort out relevant cytogenetic aspects. The propositus was first karyotyped elsewhere at 2 years of age and found to have a de novo 7q+ chromosome. When reassessed at 22 years of age, he exhibited overt mental disability, marked speech delay, mild short stature, frontal bossing, and mild dysmorphisms. The patient's chromosomes were analyzed in metaphases from a lymphocyte culture by means of G-banding and FISH assays with a wcp 7 and two dual probes, namely ELN (7q11)/D7S2686 (7q22) and ELN (7q11)/D7S486, D7S522 (q31). G-bands revealed a 7q21q22.2 direct duplication that was confirmed by FISH: the 7q+ was entirely painted with the wcp and had two 7q22 signals but a single 7q31 signal. Thus, the patient's karyotype was 46,XY, dup(7)(q21q22.2).ish dup(7)(q21 q22.2)(wcp7+, ELN+, D7S2686++, D7S486+)dn. Among 26 interstitial duplications confined to the segment 7q21q34, 13 were contiguous de novo duplications, one was due to a de novo ins (19;7), and 12 were inherited from carriers of inter-/intrachromosomal insertions or complex rearrangements. Mean paternal and maternal ages in de novo contiguous duplications of paternal/unknown (n = 9) or maternal/unknown (n = 10) descent were 33.44 and 30.9 yr whereas median ages were 29 and 30, respectively. The patient's clinical picture confirms the mild or moderate phenotypical repercussion of mid-7q duplications; among 25 patients born alive, 24 (including six teenagers or older) were still alive when reported on. PMID- 24341145 TI - A 45 X male patient with 7q distal deletion and rearrangement with SRY gene translocation: a case report. AB - Here we present a male newborn with multiple congenital anomalies who also has an extremely rare form of testicular disorder of sex development (DSD). His karyotype was 45X, without any mosaicism. SRY gene was positive by polymerase chain reaction (PCR), and rearranged on distal part of the 7th chromosome by fluorescence in situ hybridization (FISH) analysis. SRY, normally located on the Y chromosome, is the most important gene that plays a role in the development of male sex. SRY gen may be translocated onto another chromosome, mostly X chromosome in the XX testicular DSD. On the other hand very few cases of 45 X testicular DSD were published to date. Other clinical manifestations of our patient were compatible with distal 7 q deletion syndrome. To the best of our knowledge this is the first case of 45 X testicular DSD with SRY gene rearranged on the 7th autosomal chromosome. PMID- 24341147 TI - Syndrome of inappropriate antidiuretic hormone secretion refractory to treatment in a newborn with alobar holoprosencephaly. AB - Alobar holoprosencephaly (AHP) is a serious malformation of the central nervous system characterized by complete failure of cleavage of the prosencephalon resulting in fusion of the cerebral hemispheres and a massive single ventricular midline fluid collection. Secretion of inappropriate antidiuretic hormone syndrome (SIADH) is a disorder of fluid-electrolyte balance caused by the inability to suppress the secretion of antidiuretic hormone (ADH) resulting in the development of hyponatremia. Coexistence of both of these entities has not been described in the literature. We report a newborn infant with AHP who had resistant SIADH refractory to treatment, to draw attention to the coexistence of these entities and to contribute to the literature with the management of this challenging condition. PMID- 24341146 TI - Anophthalmia-plus syndrome with unusual findings. A clinical report and review of the literature. AB - We present a male child at 3 years old with Anophthalmia-Plus Syndrome (APS). He has asymmetry of the face and head, left choanal atresia, a sunken facial appearance, microphthalmia in the right eye, severe microphthalmia in the left eye, bilateral low-set ears, scarring from cleft palate surgery. Magnetic resonance imaging (MRI) sections revealed decreased right globe volume, an undeveloped left globe, decreased left optical nerve thickness, Chiari type 2 malformation, left choanal atresia and cleft palate. Echocardiography and abdominal ultrasonography were normal. The patient has a 45 dB conductive hearing loss in the left ear. Repeated thyroid function tests were evaluated as compatible with central hypothyroidism. We report a Fryns Anophthalmia-Plus Syndrome in a child with unusual findings including central hypothyroidism, chiari type 2 malformation, conductive hearing loss and developmental regression. Summary of the features reported in the present case and all 14 previous cases that might be defined as APS. PMID- 24341148 TI - Prenatal diagnosis of Goldenhar syndrome with unusual features by 3D ultrasonography. AB - Oculoauriculo-vertebral spectrum, or Goldenhar syndrome, is characterized by varying degrees of prevalently unilateral underdevelopment of craniofacial structures (orbit, ear, and mandible) and spinal anomalies. We report a patient with unusual features diagnosed prenatally by 3D ultrasonography at 21 weeks' gestation without a family history. An early diagnosis was suggested by observation of a maxillary cleft-plate, multiple vertebral segmentation defects and hypoplastic thumb. Postnatal evaluation also revealed ambiguous genitalia and club feet in addition to the prenatally and postnatally diagnosed classical Goldenhar syndrome features like hemifacial microsomia, preauricular and facial skin tags, coloboma of eyelids, epibulbar dermoid. PMID- 24341149 TI - The clinical features and genetic mutations of chronic granulomatous disease: results from a reference centre at middle Anatolia. AB - AIM: Chronic granulomatous disease (CGD) is a rare innate immune deficiency with neutrophil function disorder. In this retrospective study, we aimed to evaluate the clinical features of the patients with CGD. MATERIAL AND METHOD: We presented eight patients (6 boys, 2 girls) with CGD which were evaluated at Erciyes University Medical Faculty hospital between 1996 and 2012. The initial complaints, age at diagnosis, consanguinity of the parents, similar disease history or death of the siblings, physical examination, diagnostic tests, clinical courses, and genetic characteristics were analyzed. RESULTS: The initial complaints were started before the age of one in four patients; whereas only two patients diagnosed before the first birth day. Lymphadenomegally, suppurative infections, pneumonia, diarrhea were the most noted initial complaints. All parents were consanguineous. The clinical features were mild; and the ages of diagnosis were late in patients with p47 and p67 defect. The patient with X linked CGD was diagnosed when he was 3 months old; his clinical course was complicated with chronic otitis media, zygomatic abscess, lung abscess, and facial paralysis. The patient with p22 defect was diagnosed at two months of age; and gastric wall granuloma, inflammation in proximal femur was detected. CONCLUSIONS: The awareness of the clinicians about CGD will result in early diagnosis and consequently reduce the mortality and morbidity of this disease. PMID- 24341151 TI - Partial trisomy 11q and partial monosomy 12p due to the maternal translocation (11q;12p). PMID- 24341150 TI - Pulmonary agenesis and pulmonary sling anomaly in an infant with Down syndrome. AB - Pulmonary agenesis is a rare congenital anomaly presenting with normal karyotype in most of the cases. Rarely pulmonary agenesis is associated with chromosomal abnormalities and other genetic disorders such as Oculo-auriculo-vertebral spectrum, VACTERL association and velo-cardio-facial syndrome. This report presents a patient with pulmonary agenesis, pulmonary sling anomaly and Down syndrome. PMID- 24341152 TI - Cytogenetic study in recurrent pregnancy loss: an experience from tertiary care centre. PMID- 24341153 TI - Femoral hypoplasia-unusual facies syndrome with renal agenesis and patent ductus arteriosus. PMID- 24341154 TI - Membership with benefits: opportunities for professional growth. PMID- 24341155 TI - Kombucha brewing under the Food and Drug Administration model Food Code: risk analysis and processing guidance. AB - Kombucha is a fermented beverage made from brewed tea and sugar. The taste is slightly sweet and acidic and it may have residual carbon dioxide. Kombucha is consumed in many countries as a health beverage and it is gaining in popularity in the U.S. Consequently, many retailers and food service operators are seeking to brew this beverage on site. As a fermented beverage, kombucha would be categorized in the Food and Drug Administration model Food Code as a specialized process and would require a variance with submission of a food safety plan. This special report was created to assist both operators and regulators in preparing or reviewing a kombucha food safety plan. PMID- 24341156 TI - Preschool children's environmental exposures: a case-control epidemiological study of the presence of asthma-like symptoms. AB - The heterogeneity of asthma and asthma-like symptoms results in difficulty defining, diagnosing, and therefore estimating environmental exposures and associations with wheezing or asthma-like symptoms. Determining the disease burden for young children is particularly challenging. In the study described in this article, counter-matched sampling design was used to select participants from the Woman, Infants, and Children (WIC) program for this nested case-control study (N = 691, with 412 controls). Data were collected through structured interviews. Exposure to wood or oil smoke, soot, or exhaust was significantly associated with early-life asthma, as was exposure to cockroaches. Multivariate analyses showed that increasing age, male gender, presence of allergies (although not the type of allergies), and the presence of eczema at birth predicted wheezing behaviors in the authors' study. The authors estimated the prevalence of wheezing behavior in a population of low-income preschool children was 31% with prevalence rates higher among African-American children as compared to other races/ethnicities. Fifty-one percent of those children whose caregivers reported wheezing, however, had not received a diagnosis of asthma. Further study is recommended to compare the differences in the wheezing experiences between those diagnosed with asthma and those who are undiagnosed, with the intent of designing primary prevention interventions tailored to parents and caregivers of young children. PMID- 24341157 TI - Radon-contaminated drinking water from private wells: an environmental health assessment examining a rural Colorado mountain community's exposure. AB - In the study discussed in this article, 27 private drinking water wells located in a rural Colorado mountain community were sampled for radon contamination and compared against (a) the U.S. Environmental Protection Agency's (U.S. EPA's) proposed maximum contaminant level (MCL), (b) the U.S. EPA proposed alternate maximum contaminate level (AMCL), and (c) the average radon level measured in the local municipal drinking water system. The data from the authors' study found that 100% of the wells within the study population had radon levels in excess of the U.S. EPA MCL, 37% were in excess of the U.S. EPA AMCL, and 100% of wells had radon levels greater than that found in the local municipal drinking water system. Radon contamination in one well was found to be 715 times greater than the U.S. EPA MCL, 54 times greater than the U.S. EPA AMLC, and 36,983 times greater than that found in the local municipal drinking water system. According to the research data and the reviewed literature, the results indicate that this population has a unique and elevated contamination profile and suggest that radon contaminated drinking water from private wells can present a significant public health concern. PMID- 24341158 TI - The efficacy of a theory-based, participatory recycling intervention on a college campus. AB - Recycling solid waste is an important primary prevention focus to protect environmental resources and human health. Recycling reduces energy consumption and emissions and the need to harvest raw material, which protects air, water, and land. In the study described in this article, the authors conducted an eight week field study to test the efficacy of an intervention aimed to increase can and bottle recycling on a college campus. Recycling volume was assessed in three campus buildings (two treatments and one control) over eight weeks. The control building had standard outdoor-only recycling. The treatment buildings had standard outdoor recycling plus four weeks with the treatment indoor recycling. Total can and bottle recycling volume increased 65%-250% in the treatment buildings compared to the control building. Recycling significantly increased in both the classroom (t = -2.9, p < .05) and administrative (t = -12.4, p < .001) treatment buildings compared to the control building (t = -.13, p = .91). Results suggest that convenience of receptacles alone, without education or additional promotion, resulted in significantly more recycling. Health promoters should prioritize efforts to make recycling easy and convenient. PMID- 24341159 TI - Investigation of radon and heavy metals in Xuanwei and Fuyuan, high lung cancer incidence areas in China. AB - Xuanwei and Fuyuan, two counties located in southwest China, are areas with known high lung cancer incidence. Pollution relative to coal combustion, especially serious air pollution generated by burning smoky coals in unvented households, has been thought to be the most predominant cause. Possible inorganic carcinogenic matter including radon in air and arsenic, lead, chromium, cadmium, nickel, and beryllium in water, soil, and coal were sampled and examined to find the current pollution status, distributions, characteristics, and relationships to the lung cancer incidence. The concentrations of mercury in air of Xuanwei and Fuyuan ranged from 1.7 to 205.3 ng/m3 (indoor), 1.3 to 7.5 ng/m3 (ambient). No radon concentration exceeded the World Health Organization standard. Results indicated that household stove improvement by changing stoves from unvented to vented obviously alleviated the indoor air pollution of carcinogenic metals. Most of the carcinogenic metals were also found at very low levels in water and soil, which therefore had little influence on human health. Concentrations of these elements at different sites did not vary in any relation to lung cancer incidence. The study described in this article added basic data; the results of the authors' study will be helpful in determining pollution status and to future studies on the etiology of lung cancer. PMID- 24341160 TI - Groundwater vulnerability assessments: prioritizing water safety in times of austerity. PMID- 24341161 TI - By 2030 over 50% of colleges will collapse: part 2. PMID- 24341162 TI - The NEHA e-journal is here! PMID- 24341163 TI - Management of tinnitus and jaw-muscle tenderness using an intraoral appliance and acupuncture. AB - Associations between signs and symptoms from the masticatory system and tinnitus have been reported.The aim of the study was to evaluate the effect of intraoral splint therapy and acupuncture on jaw-muscle tenderness and tinnitus. The study comprised 45 patients (24 men, 21 women; mean age 48 +/- 12 years) with long standing tinnitus (duration 6.5 +/- 5.9 years).The patients were referred from the audiology department at the University hospital in Orebro, Sweden, where a complete audiological survey was performed. Jaw muscles were palpated and the subjective tinnitus evaluated on a 100 mm scale (VAS) at baseline and after one year. All patients received stabilization (Michigan type) splints at start of treatment. After 6 months, nonresponders (n=25) were subjected to acupuncture (6 sessions with duration of 30 minutes). Standard statistical methods were used. All patients had tender jaw muscles at palpation. Patients reported a significant decrease of the intensity of tinnitus during the observation period (from 78 +/- 20 mm to 52 +/- 24 mm after one year; P < 0.001). Only 6 (13%) of the 45 patients did not report any improvement of their tinnitus.The number of jaw muscles tender to palpation also decreased significantly from 7.9 +/- 5.9 to 4.6 +/- 5.3; (P<0.001). In conclusion, all 45 patients with tinnitus had tenderjaw muscles. Intraoral splint therapy and acupuncture had a favorable effect on tinnitus and the jaw muscle symptoms. One year after the start of treatment, all but 6 of the 45 patients reported improvement of their tinnitus. Based on the results it is suggested that many tinnitus patients with jaw muscle tenderness can benefit by a treatment including intraoral splint and acupuncture. PMID- 24341164 TI - Timing of mineralization of homologues permanent teeth--an evaluation of the dental maturation in panoramic radiographs. AB - Clinically the condition Molar Incisor Hypomineralization (MIH),varies considerably between individuals, where any number of molars, from one to all four permanent first molars, may be affected with different degrees of hypomineralized enamel within the same dentition. An explanation to these variations could be that the start of the enamel mineralization differs between homologues teeth. The aim of this study was to compare the dental development between homologues teeth in digital panoramic radiographs (PRs),from children aged 7 to 11 years, using the Gleiser & Hunt method on second and third molars and to calculate the crown/root ratio for the mandibular premolars.77 PRs, from individuals between 7.3 and 11.0 years of age, were studied. Differences in developmental stages between homologues teeth (second and third molars) were studied. In 72 of these PRs, the crown/root ratio of mandibular premolars was also compared. In 31 of the PRs, a difference in development was found between the right and left maxillary second molar. In 22 PRs, a difference in development between the right and left mandibular second molar was found. In 17 of the PRs, a difference in development was found between the right and left maxillary third molars. In 26 PRs,a difference in-between the right and left mandibular third molar was found. In 72 PRs, the crown/root ratio of mandibular premolars was measured and differences were found. All these differences were significant. A possible explanation to the variations in expressivity of MIH may be a result of differences in the start of mineralization between homologues teeth. Timing of mineralization of homologues permanent teeth--An evaluation of the dental maturation in panoramic radiographs. PMID- 24341166 TI - Patients' choice of payment system in the Swedish Public Dental Service--views on dental care and oral health. AB - The aim of this study was to generate new knowledge of considerations and factors having impacted the patients' choice of payment system and their views on oral health. Moreover, their later attitudes to the prepaid risk-related payment system, having been enrolled or not, were explored. A qualitative design was chosen and data was collected through semi-structured interviews.Twenty patients in the Public Dental Service (PDS) in western Sweden were strategically sampled with reference to gender, age (older/younger adults), residence (rural/urban), and choice of payment system:fee-for-service or capitation plan.The interview guide covered areas concerning the payment systems, patient considerations before choosing system, views of their own oral health and experiences of received dental care within the chosen system.The analysis was performed according to basic principles of qualitative content analysis. The results revealed two themes expressing the latent content. In the theme "The individual's relation to the PDS", expectations of the care, feelings of safety and aspects of responsibility emerged.The theme"Health-related attitudes and perceptions" revealed that views on health and self-assessment of oral health influenced the patients' considerations. Moreover, the perceived influence on oral health and risk thinking emerged as important factors in this theme. The conclusion was that the individual's relation to the PDS together with his/her health-related attitudes and perceptions were the main factors impacting the choice of payment system in the PDS. A health promotion perspective should be applied, empowering the patients to develop their risk awareness and their own resources. PMID- 24341165 TI - An interview study of persons who attribute health problems to dental filling materials--part two in a triangulation study on 65 and 75 years old Swedes. AB - Dental materials are perceived as a health problem by some people, although scientists do not agree about possible causes of such problems. The aim of this paper was to gain a deeper knowledge and understanding of experiences from living with health problems attributed to dental materials. Addressed topics were the type of problem, both as to general and oral health, perceived causes of the problems,their experienced effect on life, and reception by health professionals. Persons, who in a previous large questionnaire study had answered that they had experienced troubles from dental materials and also agreed to answer follow-up questions, were contacted with a request to take part in an interview study. Eleven individual interviews were held.The interviews were transcribed verbatim and the material was analysed according to the Qualitative Content Analysis method. Meaning units were extracted and condensed into a number of codes, which were combined into subcategories, categories, and themes. Four themes were identified: 1) Long-term oral, mental, and somatic difficulties of varying character, caused by dental amalgam. 2) Problems treated mainly by replacement of dental material in fillings. 3) Powerful effects on life, mostly negative. 4) The reception by health professionals was generally good, but with elements of encounters where they felt treated with nonchalance and lack of respect. In conclusion, people who attributed their health difficulties to dental materials had a complex range of problems and the perception was that amalgam/mercury was the cause of the troubles. The reception from health professionals was perceived as generally good, although with occasional negative experiences. PMID- 24341167 TI - Porcelain bonding to titanium with two veneering principles and two firing temperatures. AB - Dental literature, as well as dental laboratories, has described problems with ceramic veneering of titanium, while clinical and in vitro studies have reported good results. The objective of this study was to investigate the effect of firing temperature, thermo cycling, and veneering methods on bond strength between porcelain and titanium. Eighty titanium specimens were prepared with one of two methods: a bonding agent firing or an oxidation firing. During veneering, half of the specimens in each group were fired at 30 degrees C above and half at the manufacturer's recommended temperature. In the bonding agent group and in the oxidation group, half of each firing group was thermocycled. Bond strength was calculated in a three-point bending test. Scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS) analyses of the titanium and the porcelain fracture surfaces of one specimen from each subgroup was used in order to study the composition of the interface between titanium and porcelain surfaces after fracture. No significant difference in bond strength was found when firing at a higher temperature compared with firing at the recommended temperature. An oxidation firing before veneering yielded significantly higher bond strength in a three-point bending test than when firing with a bonding agent. SEM and EDS analyses indicated a higher frequency of titanium oxide fractures in the oxidation than in the bonding agent group.The main finding is that firing at 30 degrees C above the recommended temperature does not significantly affect bond strength between titanium and porcelain. SEM and EDS analysis indicate that fractures occur in the titanium oxide layer by oxidation firing and in the interface between titanium oxide layer and veneering material by bonding agent firing.This finding might indicate that three- point bending test is not a relevant method for determining bond strength in this case, since the firing methods might influence the ductility of the samples. PMID- 24341168 TI - Pulp exposures in adults--choice of treatment among Swedish dentists. AB - This study comprises a survey of Swedish dentists'treatment preferences in cases of carious exposure of the dental pulp in adults.The survey was conducted as part of a comprehensive report on methods of diagnosis and treatment in endodontics, published in 2010 by the Swedish Council on Health Technology Assessment. A questionnaire was mailed to a random subsample of 2012 dental offices where one dentist at each office was requested to answer all questions. Each questionnaire contained one of three sets of questions about endodontic practice routines.Thus around one-third of the subsample received case-specific questions about treating carious exposure. Only general practitioners aged below 70 years were included.The final study sample comprised 412 participants.The dentists were presented with two case scenarios. In Case 1 a 22-year old patient had a deep carious lesion in tooth 36 and in Case 2 a 50-year old patient had a deep carious lesion in tooth 14.The participants were asked to nominate their treatment of choice: pulp capping, partial pulpotomy or pulpectomy. For Case 1, 17 per cent of the respondents selected pulpectomy; the corresponding rate for Case 2 was 47 per cent. Female gender and age group 25-49 years were predictive of selection of less invasive treatment options. However, according to recent guidelines (2011) from the National Board of Health and Wellfare, Swedish dentists are recommended to elect pulpectomy prior to pulp capping/partial pulpotomy when confronted with a tooth having a cariously exposed pulp in adults. PMID- 24341169 TI - Health I.T. vs influenza. Are health networks and social media efforts ready for prime time? PMID- 24341170 TI - An image problem? PMID- 24341171 TI - Accounting for challenges. PMID- 24341172 TI - Simplifying finance: HIPAA rules. PMID- 24341173 TI - [Regulation mechanism of bone remodeling]. PMID- 24341174 TI - [Nutritional assessment upon admission for predicting delay in negative bacillary conversion among patients treated for pulmonary tuberculosis]. AB - Negative conversion of pulmonary tuberculous bacilli is determined by using a discharge standard. The primary goal of tuberculosis treatment is early negative conversion of bacilli. Nutritional factors upon admission that might predict a delay in negative bacillary conversion were investigated. The study cohort comprised 554 inpatients who were treated for pulmonary tuberculosis between April 2005 and March 2007 at the National Hospital Organization Kinki-chuo Chest Medical Center. Factors that might delay negative conversion that were investigated included: age, sex, body mass index (BMI), serum albumin (Alb), C reactive protein (CRP), hemoglobin A1c (HbA1c), hospital meal intake, percent of recommended dietary allowance of energy (RDA % energy), percent of recommended dietary allowance of protein (RDA % protein), and sputum smear test. Variables were entered into a univariable log-rank test and multivariate regression analysis was performed. Univariate analysis yielded the following hospitalization nourishment factors associated with a delay in negative conversion: male gender, BMI < 18.5 kg/m2, Alb < or = 3.0 g/dL, CRP > or = 0.3 mg/dL, HbA1c > or = 6.5%, RDA% energy < 87%, and sputum smear test 2+ - 3+. Multivariate regression analysis yielded the following hospitalization nourishment factors that were associated with a significant delay in negative conversion: HbA1c, CRP, and BMI. Nutritional assessment of patients with pulmonary tuberculosis indicated that HbA1c, CRP, and BMI could be used to predict a delay in negative conversion. PMID- 24341175 TI - [Drunkenness caused by isoniazid in a tuberculosis patient with extrapulmonary lesions on hemodialysis: a case report]. AB - The patient was a 55-year-old man who had been on hemodialysis for 6 years for diabetic nephropathy. He was clinically diagnosed with pulmonary tuberculosis with extrapulmonary lesion after 3 years of chronic fever. His fever subsided immediately after the beginning of antituberculosis drug therapy and the antituberculosis drugs were discontinued 3 days after the initiation of the therapy. He experienced a sense of drunkenness when he received isoniazid, apparently not in association with any of the other antituberculosis drugs given. His blood trough concentration of isoniazid was nearly equal to the usual peak levels measured in patients with normal renal function. Isoniazid is often prescribed for patients with chronic renal failure without dose-reduction, because of its hepatic metabolism. But blood level of INH was found to accumulate at high levels in this patient. The high blood concentration of isoniazid in this patient with chronic renal failure may have elicited his neurological side effect. PMID- 24341176 TI - Improving care for people after stroke: how change was actively facilitated. AB - PURPOSE: This paper aims to report on the approach to change used in the development of a tool to assess patient status six months after stroke (the Greater Manchester Stroke Assessment Tool: GM-SAT). DESIGN/METHODOLOGY/APPROACH: The overall approach to change is based on the Promoting Action on Research Implementation in Health Services (PARiHS) Framework, which involves extensive stakeholder engagement before implementation. A key feature was the use of a facilitator without previous clinical experience. FINDINGS: The active process of change involved a range of stakeholders--commissioners, patients and professionals--as well as review of published research evidence. The result of this process was the creation of the GM-SAT. PRACTICAL IMPLICATIONS: The details of the decision processes within the tool included a range of perspectives; the process of localisation led commissioners to identify gaps in care provision as well as learning from others in terms of how services might be provided and organised. The facilitator role was key at all stages in bringing together the wide range of perspectives; the relatively neutral perceived status of the facilitator enabled resistance to change to be minimised. SOCIAL IMPLICATIONS: The output of this project, the GM-SAT, has the potential to significantly improve patients' physical, psychological and social outcomes and optimise their quality of life. This will be explored further in future phases of work. ORIGINALITY/VALUE: A structured process of change which included multiple stakeholder involvement throughout, localisation of approaches and a dedicated independent facilitator role was effective in achieving the development of a useful tool (GM-SAT). PMID- 24341177 TI - "Fact" and "fiction": enlivening health care education. AB - PURPOSE: This paper aims to demonstrate how close analysis of cultural narratives can be employed as effective pedagogical tools in the explication and critique of specific workplace issues relevant to health management education. DESIGN/METHODOLOGY/APPROACH: Two narratives have been selected to illustrate this point: the apparently "fictional" UK-based medical television drama series Bodies (2005-2006) and the apparently "factual" report of an Australian state government public inquiry into acute health care, the Garling Report. FINDINGS: Through their demonstration of how analyses of selected segments of these texts can be used in health management education, the authors conclude that the comparative analyses of ostensibly "fictional" and "factual" narratives allow for analysis and critique of the inadequacies of new public management (NPM) applied to the health care industry, leading to a greater understanding of wider ideological effects on public perceptions. PRACTICAL IMPLICATIONS: The authors argue that these understandings enliven students' learning experiences, and that such comparative analyses should be applied more widely across health management education to develop students' critical skills and openness to exploring alternative models. ORIGINALITY/VALUE: Comparative analysis of cultural texts is novel in health care education, and allows for the interrogation of ideology and its effects. PMID- 24341178 TI - The development and deployment of electronic personal health records records: a strategic positioning perspective. AB - PURPOSE: The purpose of this study is to examine the impact of strategic position on the ability of an entrepreneurial firm to successfully develop and deploy electronic personal health records technology within the US healthcare industry. DESIGN/METHODOLOGY/APPROACH: This study uses an in-depth longitudinal case study methodology. FINDINGS: The study contributes by juxtaposing a longitudinal view of how the focal firm proposed and acted on different strategic positions in an attempt to achieve development and deployment success. In doing so, the study also elaborates on Porter's recognition that firms need to make trade-offs when choosing a strategic position, as the purposeful limitation of service offerings can protect against the degradation of existing value creating activities. RESEARCH LIMITATIONS/IMPLICATIONS: The authors' study highlights the enormous challenge of facilitating the adoption and diffusion of technology enabled interventions in the US healthcare ecosystem. Future research that combines both interdisciplinary and multi-level investigation and analysis is sorely needed to develop a more sophisticated understanding of the phenomenon and to encourage the development and deployment of useful technology enabled interventions within the US healthcare industry. PRACTICAL IMPLICATIONS: While the fragmented nature of the healthcare industry provides opportunities for entrepreneurial firms, such complexity within the ecosystem should not be underestimated as a reason for concern for small firms. SOCIAL IMPLICATIONS: Total economic burden due to chronic diseases and other healthcare-related expenses is massive for the USA. Consequently, prevention and early detection of future disease states has become a core component of the current healthcare reform debate. EPHRs are considered one core component of a broader healthcare strategy to improve health outcomes and lower costs. By deepening our understanding of how best to develop and deploy such interventions, society will surely benefit. ORIGINALITY/VALUE: The longitudinal nature of the authors' study provides a unique opportunity to understand the dynamic interrelationships between context, position, and performance within the US healthcare industry. PMID- 24341179 TI - User involvement in service integration and carers' views of co-locating children's services. AB - PURPOSE: There has been considerable discussion about the benefits of health and social care integration over the last decade but less research on the purpose and effectiveness of carer and user involvement in service changes and service evaluation. The paper aims to report the findings of a study of two learning disabilities services in Wales that undertook co-location in a children development centre. DESIGN/METHODOLOGY/APPROACH: The study investigated whether carers of children with learning disabilities had any knowledge of organisational changes that occurred as a result of co-locating services. The study used a mixed method approach. The authors conducted semi-structured interviews with all parental representatives on the service planning groups and then asked local staff to facilitate a survey to parents of children with learning disabilities in their area. FINDINGS: Carers in both locations were mainly unaware of any changes, unless they were personally involved in service changes through advocacy or parental support groups. Carer responses mainly reflected national debates, such as service cuts, rather than the local context. Whilst there was significant support for co-location in general, parental views differed considerably on the merits of service changes depending on the needs of their own child. ORIGINALITY/VALUE: These results caution against assuming a simple pathway from parental views of local services to defining service needs to plan new services. The authors argue that parents lack sufficient knowledge of organisational changes to make an informed decision on whether these changes would bring about service improvements. Implications for research and professional practice are spelled out. PMID- 24341180 TI - From words to action: visibility of management in supporting interdisciplinary team working in an acute rehabilitative geriatric hospital. AB - PURPOSE: The following case study aims to explore management's, health professionals' and patients' experiences on the extent to which there is visibility of management support in achieving effective interdisciplinary team working, which is explicitly declared in the mission statement of a 60-bed acute rehabilitative geriatric hospital in Malta. DESIGN/METHODOLOGY/APPROACH: A total of 21 semi-structured interviews were conducted with the above-mentioned key stakeholders. FINDINGS: Three main distinct yet interdependent themes emerged as a result of thematic analysis: "managing a team-friendly hospital", "interdisciplinary team components", and "interdisciplinary team processes". The findings show that visibility of management support and its alignment with the process and content levels of interdisciplinary teamwork are key to integrated care for acute rehabilitative geriatric patients. RESEARCH LIMITATIONS/IMPLICATIONS: The emerging phenomena may not be reproducible in a different context; although many of the emerging themes could be comfortably matched with the existing literature. PRACTICAL IMPLICATIONS: The implications are geared towards raising the consciousness and conscientiousness of good practice in interdisciplinary teamwork in hospitals, as well as in emphasizing organizational and management support as crucial factors for team-based organizations. SOCIAL IMPLICATIONS: Interdisciplinary teamwork in acute rehabilitative geriatrics provides optimal quality and integrated health care delivery with the aim that the older persons are successfully discharged back to the community. ORIGINALITY/VALUE: The authors draw on solid theoretical frameworks--the complexity theory, team effectiveness model and the social identity theory--to support their major finding, namely the alignment of organizational and management support with intra-team factors at the process and content level. PMID- 24341181 TI - Are healthcare middle management jobs extreme jobs? AB - PURPOSE: The purpose of this paper is to explore the incidence of "extreme jobs" among middle managers in acute hospitals, and to identify individual and organizational implications. DESIGN/METHODOLOGY/APPROACH: The paper is based on interviews and focus groups with managers at six hospitals, a "proof of concept" pilot with an operations management team, and a survey administered at five hospitals. FINDINGS: Six of the original dimensions of extreme jobs, identified in commercial settings, apply to hospital management: long hours, unpredictable work patterns, tight deadlines with fast pace, broad responsibility, "24/7 availability", mentoring and coaching. Six healthcare-specific dimensions were identified: making life or death decisions, conflicting priorities, being required to do more with fewer resources, responding to regulatory bodies, the need to involve many people before introducing improvements, fighting a negative climate. Around 75 per cent of hospital middle managers have extreme jobs. RESEARCH LIMITATIONS/IMPLICATIONS: This extreme healthcare management job model was derived inductively from a qualitative study involving a small number of respondents. While the evidence suggests that extreme jobs are common, further research is required to assess the antecedents, incidence, and implications of these working practices. PRACTICAL IMPLICATIONS: A varied, intense, fast-paced role with responsibility and long hours can be rewarding, for some. However, multi-tasking across complex roles can lead to fatigue, burnout, and mistakes, patient care may be compromised, and family life may be adversely affected. ORIGINALITY/VALUE: As far as the authors can ascertain, there are no other studies exploring acute sector management roles through an extreme jobs lens. PMID- 24341182 TI - Development of a culture of sustainability in health care organizations. AB - PURPOSE: This paper aims to examine the concept of sustainability in health care organizations and the key managerial competencies and change management strategies needed to implant a culture of sustainability. Competencies and management development strategies needed to engrain this corporate culture of sustainability are analyzed in this document. DESIGN/METHODOLOGY/APPROACH: This paper draws on the experience of the authors as health care executives and educators developing managerial competencies with interdisciplinary and international groups of executives in the last 25 years, using direct observation, interviews, discussions and bibliographic evidence. FINDINGS: With a holistic framework for sustainability, health care managers can implement strategies for multidisciplinary teams to respond to the constant change, fine tune operations and successfully manage quality of care. Managers can mentor students and provide in-service learning experiences that integrate knowledge, skills, and abilities. RESEARCH LIMITATIONS/IMPLICATIONS: Further empirical research needs to be conducted on these interrelated innovative topics. PRACTICAL IMPLICATIONS: Health care organizations around the world are under stakeholders' pressure to provide high quality, cost-effective, accessible and sustainable services. Professional organizations and health care providers can collaborate with university graduate health management education programs to prepare competent managers in all the dimensions of sustainability. SOCIAL IMPLICATIONS: The newly designated accountable care organizations represent an opportunity for managers to address the need for sustainability. ORIGINALITY/VALUE: Sustainability of health care organizations with the holistic approach discussed in this paper is an innovative and practical approach to quality improvement that merits further development. PMID- 24341183 TI - [The point-of-care technologies in clinic of emergency states]. AB - The article considers the issues of implementation of the point-of-care technology (diagnostic testing at treatment place) in modern clinic of emergency states. The economic practicability and advantages of point-of-care tests as compared with analyses in central laboratory is considered. The data concerning the characteristics of quality control under point-of-care are presented. Separately, the application of basic laboratory analyses using point-of-care technologies in case of emergency states is examined PMID- 24341184 TI - [The point-of-care testing and security of patient: advantages and risks]. AB - The point-of-care testing obtains growing prevalence in medical practice due to application of portative analytical devices of advanced technologies. The advantages of these devises are more prompt analysis results and more simple procedure of application disposable for duplication by laymen. However, in practical work, are obvious the shortcomings related to direct and potential risks for patient in case of using unreliable analysis results as a validation of implementation of treatment measures harmful for patient. Under implementation and application of point-of-care testing the ratio advantages/risks is to be carefully assessed. PMID- 24341185 TI - [The percentage of errors in point-of-care testing]. PMID- 24341186 TI - [the quality of point-of-care testing: something 19 positive and something negative too]. PMID- 24341187 TI - [The palmitic and oleic modes of metabolism of fatty acids. The exogenous syndrome of resistance to insulin under disorder of biologic function of nutrition (trophology)]. AB - The hyperglycemia and insulin are two phylogenetically different humoral regulators of metabolism in vivo. The development of hyperglycemia occurred billions years hitherto under implementation of nutrition function. The insulin was formed in the process of development of biologic function of locomotion. The syndrome of resistance to insulin consists in the derangement of humoral regulation of metabolism of fatty acids and glucose at the phylogenetically different levels in vivo both in paracrine cells cenosis and at the level of organism. The exogenous and endogenic syndromes of resistance to insulin are distinguished. The exogenous resistance to insulin is formed under physiologic function of insulin system when hormone effect is prevented by derangement of biologic function of trophology (nutrition)--the formation of such palmitinic mode of metabolism of fatty acids as substrates for oxidation in mitochondria. The endogenic syndrome of resistance to insulin consists in discrepancy of regulation of biologic functions at the level of organism under realization of locomotion function and at the level of paracrine cells cenosis under realization of biologic function of adaptation, endoecology (support of "cleanness" of intracellular medium) and its biologic reaction of inflammation, homeostasis function. The syndrome of resistance to insulin is energetic issue in vivo. Primarily, insulin regulates metabolism of fatty acids and only secondly metabolic transformations of glucose. In case ofpalmitinic mode of metabolism offatty acids in the enzymes with the same parameters are involved in biologic reactions. The palmitinic triglycerides are not optimal due to aphysiological slow biochemical and physico-chemical reactions. PMID- 24341188 TI - [The modern approaches to laboratory diagnostic of urogenital chlamydia infection: a lecture]. AB - The article considers the characteristics of chlamydia biology. The actual approaches to laboratory diagnostic of urogenital chlamydia infection and corresponding diagnostic possibilities are presented. PMID- 24341189 TI - [The chylomicronemia under interpretation of the results of detection of lipid profile of blood]. AB - The lipid profile of blood of several population screenings was studied in the framework of the international project HAPIEE. The sampling consisted of 9357 patients aged from 45 to 69 years. All participants of the study were notified in advance about blood sampling on an empty stomach for analysis. The blood serum was not totally clear and triglycerides concentration of 2.65 mmol/l in 16% of cases. The examined patients approved in 3.5% that blood was not taken on an empty stomach. The diabetes mellitus was diagnosed in 1.6% of patients. Among the rest 10.9% of patients with blood samples not totally clear half of them had concentration of glucose in blood higher than 5.5 mmol/l. Some of them probably came to screening not on an empty stomach and did not approve it. The epidemiologic studies require a strict regulation of daytime of food intake prior to blood sampling for analysis. The degree of blood clearness and blood glucose concentrations are to be regulated to and in some case the analysis is to be repeated. PMID- 24341190 TI - [The content of substances of low and medium molecular mass in biologic liquids in patients with erysipelas]. AB - The endogenic intoxication is a metabolic response to any aggressive factor. The concentration of substances of low and medium molecular mass biologic liquids of organism w and medium molecular mass is a common indicator of intoxication syndrome. The study analyzed the role of uptake of substances of low and medium molecular mass in biologic liquids of organism in pathogenesis of erysipelas depending on period, form and ration of disease. The sampling included 76 patients with erysipelas aged from 27 to 62 years being in infection hospital for treatment. The concentration of substances of low and medium molecular mass was detected using M. Ya. Malakhova technique (1996). It is established that under erysipelas in organism occurs uptake of toxic substances in blood and gradual increase of concentration of substances of low and medium molecular mass in blood plasma and erythrocytes paralleled by corresponding changes of their concentration in urine. The altitude of increase of concentration level of substances of low and medium molecular mass and their reapportion between biologic mediums of organisms depends on period, form, ratio of course and degree of severity of pathologic process. PMID- 24341191 TI - [The ratio between basic microelements (Fe, Cu, Zn) under anemia of different etiology]. AB - The homeostasis of basic microelements (Fe, Cu and Zn) is ultimately important for normal functioning of organism. The article presents the data concerning the detection of these metals both in blood serum and urine of patients with anemia of different etiology. The indicators of excretion can provide additional information for diagnostics and needed therapy. The article describes in details simple colorimetric methods of detection of mentioned metals in urine. It is demonstrated that under anemia the positive balance of cuprum is noted. This occurrence can be a possible cause of coagulation complications. PMID- 24341192 TI - [The stability of cell composition of fetus blood in norm and under hypoferric anemia]. AB - The article deals with indicators of cell composition of umbilical blood (fetus blood) in case of normal pregnancy (n = 38) and hypoferric anemia of light degree (n = 14)10 the hematologic analyzer of medium class was applied. The parameters of erythrocytes of fetus blood in case of hypoferric anemia of light degree were sufficiently stable and had no differences with normal values both in mean values and variability. The variety of adaptive index of fetus blood (Garkavi index) was significantly higher in case of hypoferric anemia as compared with normal values. This occurrence testifies higher stability of indicators of adaptation in case of moderate ferric deficiency. The study results testify the informativity of applied approach related to assessment of stability of cell composition of fetus blood. PMID- 24341193 TI - [The standardization of diagnostic of paroxysmal night hemoglobinuria cytometry]. AB - The flow cytometry becomes a more and more largely applied technique. However, the sufficient novelty of technique has no worked-out standards of diagnostic of many diseases. The lacking of external control of quality promotes development of large variety of approaches to diagnostic of diseases and impossibility to compare the study results from different laboratories. The paroxysmal night hemoglobinuria is an acquired clonal disease characterized by proliferation of stem cells with partial or total loss of expression of glykosylphosphosphatidyl inositol anchor needed to conjugate a number of surface proteins. The flow cytometry is a basic technique of detection and monitoring of clone of paroxysmal night hemoglobinuria. The article presents the results of paroxysmal night hemoglobinuria testing of 8 patients in 6 independent laboratories using flow cytometry by standard protocol recommended by the International society of clinical cytometrists (ICCS). PMID- 24341194 TI - [The morphologic evaluation of adhesive activity]. AB - The morphologic evaluation of adhesive activity of human thrombocytes using both vital dye of cells and registration of adhesion process with fluorescent microscope is proposed. The regression dependence between adhesive activity of human thrombocytes and morpho-functional and aggregative activity of thrombocytes is established. The blood samples of 100 blood donors, 100 patients with hematologic pathology, 110 patients of traumatology, 50 patients with acute exogenous intoxications and 20 patients with chronic trophic ulcers were analyzed. The drastic decrease of adhesive activity of human thrombocytes and number of adhesively active thrombocytes was established in circulating blood of patients with bleedings of various etiology and hematologic patients. The significant increase of adhesive activity of human thrombocytes and number of adhesively active thrombocytes in patients with thrombosis is established. The morphologic evaluation of quality of thrombocytes is effective in case of analysis of biologic value of all population of circulating cells. PMID- 24341195 TI - [The evaluation of secretory immunity under herpetic affection of oral cavity]. AB - The study is based upon the results of clinical laboratory examination of 33 patients with diagnosis of recurrent herpetic stomatitis. The control group included 26 healthy persons. In patients with manifestations of herpetic infection of mucous tunic of oral cavity the pronounced abnormalities of indicators of secretory immunity (lactoferrin, secretory immunoglobulin A) correlating with hygiene index are established. At the same time, indicator of antiviral immunity (alpha-interferon) characterized by absence of significant changes in this group of patients. PMID- 24341196 TI - [Methods of substance abuse prevention in the Armed Forces]. AB - Dynamics of substance abuse morbidity in the Armed Forces of the Russian Federation during the last 10 years (2002-2012) was analyzed. Results of performed analysis showed decreasing tendency since 2007 in conscripts (0.07% in 2012) and in contract soldiers (0.3% in 2012). Alcoholism prevailed in the structure of substance abuse in conscripts (0.05%), drug abuses were diagnosed 2,5 times less often (0.02%). In contract soldiers non-alcohol abuses were diagnosed in 0.004% of cases. It is stated that the major aims of substance abuse prevention are qualitative recruiting of military units (especially in troops maintaining the combat readiness) and departments (subunits) of military education, creating conditions for propaganda for healthy lifestyle, prohibition of drugs and psychopharmaceuticals in military units. For early detection of persons liable to substance abuse and facts of drug consumption it is necessary to perform a medical examination with the help of special program apparatus complex (such as "Addicts") and take into account clinical signs of addiction. Besides, it is necessary to introduce planned and unexpected medical examinations of servicemen. Algorithm of measures in case of detection of serviceman with alcohol or drug intoxication is given. In conclusion the main organizational principals of substance abuse prevention in the Armed Forces are given. PMID- 24341197 TI - [Clinical and and epidemiologic monitoring of polytrauma and concomitant injuries]. AB - Current forms of medical reports cannot be used for clinical and epidemiological and medical and economic researches because they don't contain information about competitive, associated diseases and its complications. Authors developed the method of clinical and epidemiological monitoring of nosologic structure of patients in military-medical institutions based on personalized record-keeping of patients with additional informational resources for recording of all diagnoses and performed medical service. With the help of the given method were analyzed nosologic structure and treatment results of 548 patients with vehicular trauma from the 442nd District Military Clinical Hospital. Polytrauma was revealed in 22% of patients, concomitant injury--in 39%, combined injures--in 0.4%. Besides, in 8% of patients were revealed associated chronic diseases that not only confound trauma, but also make difficult to diagnose and assess the severity of trauma. PMID- 24341198 TI - [Optimization of educational activity of departments of educational creativity in the Extension Course Institute for Medical Practitioners MUNKTs n. a. P.V.Mandryka]. AB - Educational creativity is the key component of educational activity. The article is devoted to logical structure of educational creativity, difficulties and problems of formation and development of educational creativity in lecturers participating in educative process with participants of the Extension Course Institute for Medical Practitioners MUNKTs n. a. P.V. Mandryka. Heuristic activity and methods that are a huge part of educational creativity are emphasized. Specific features of heuristic activity are shown; classification of heuristic methods is presented. For the first time authors gave characteristic of qualitative levels of educational creativity. PMID- 24341199 TI - [Acute allergy in practice of military physician]. AB - Increasing number of patients with allergy observed in recent years is accompanied with increasing number of health encounters due to acute allergy. The sudden beginning and unpredictable course characterize acute allergy. These factors can be fatal for patient and must be treated immediately. Allergic rhinitis, allergic conjunctivitis, acute urticaria, angioedema and anaphylaxis refer to diseases based on acute allergy. The most dangerous diseases, characterized by fatal conditions, are generalised urticaria, angioedema and anaphylaxis. Knowledge of first aid principles is the most important factor of effective treatment because quickness of allergy progression requires prompt decisions. Use of the whole complex of modern therapeutic possibilities is the most important and durable. Modern methods of first aid for acute allergy, based on recommendations from foreign and domestic publications, are given in the article. PMID- 24341200 TI - [Early diagnosis of dementia with the help of MR-morphometry in patients with Parkinson's disease]. AB - 54 patients with idiopathic Parkinson's disease were examined. 1,5 Tesla MRI with T1 gradient-echo protocol and following calculating by FreeSurfer software was performed. Dementia was revealed in 23 patients. Significant changes of different zones of brain-cortex were revealed in patients with Parkinson's disease accompanied by dementia. Changes were revealed in the hemispheres, particularly in frontal, temporal and occipital lobes. Thickness of lingual medial occipitotemporal gyrus can be used as a criterion for dementia prognosis. Individual patient monitoring and cortex alteration evaluation allow prognosticating increasing risk of cognitive disorders development and prescribing proper therapy. PMID- 24341201 TI - [Treatment of rupture of abdominal aortic aneurism in multi-field military hospital]. AB - For the last 5 years in the center of vascular surgery of Vishnevskiy 3rd Central Military Clinical Hospital 218 patients with abdominal aortic aneurism were treated, 96 planned surgical operations for abdominal aortic aneurism (post operative mortality 3.1%) were performed. 11 patients underwent urgent surgical operation because of rupture of abdominal aortic aneurism. 1 of 11 patients died at the stage of laparotomy, the second patient died after clipping of ruptured aneurysm. In other 9 cases surgical operation was performed successfully. But 2 of 9 patients died in a few hours after surgery. In summary, 4 of 11 patients underwent surgical operation for rupture of abdominal aortic aneurism survived. The postoperative mortality was 63.6%. Authors gave an example of successful treatment of patient with rupture of abdominal aortic aneurism. It was concluded that successful treatment of rupture of abdominal aortic aneurism is possible only in case of well-run integration of different treatment and diagnostic departments. CT angiography is crucial for instrumental diagnostics of rupture of abdominal aortic aneurism. Successful surgical operation is impossible without organized blood supply service, refusion and donor blood. Artificial lung ventilation, extracorporal detoxication and adequate pharmacological supply help to avoid severe complications during the postoperative period, even in patients with associated pathology. PMID- 24341202 TI - [Low-intensity impulse suprasonic stimulation of osteogenesis for bone fractures and nearthrosis in ambulance situation]. AB - The author tried to draw attention of orthopaedic traumatologists to effective innovative technology--low-intensity impulse suprasonic stimulation of osteogenesis for fractures of bones and nearthrosis not only in outpatient, but also in in-patient departments. Mechanisms of the given methodic are described. It is showed that after the treatment fracture union signs that can be diagnosed by radiology are registered: from mild periosteal union to the signs of central callus formation and its remodeling. Amount of sessions in case of delayed hip fracture union (osteosynthesis)--50; delayed crus fracture union and nearthrosis- from 40 to 45 sessions; shoulder nearthrosis--40 sessions. The author came to conclusion that it is necessary to study mechanisms of osteogenesis and homeostasis of other tissues. That will help to change treatment programme for patients with musculoskeletal disorders and traumas, for functional recovery and improvement of quality of life. PMID- 24341203 TI - [Hypertensive heart disease and noninsulin-dependent diabetes mellitus: modern strategies in antihypertensive therapy]. AB - Hypertension (HTN) and noninsulin-dependent diabetes mellitus (NIDDM) are two non communicable pandemic of the late 20th century and early 21st century. Despite the active prophylaxis measures performed by the State, there is a tendency to increase of HTN in Russia. Incidence rate of hypertension is depending of age and increases in patients of elderly age (80%). According to the International Diabetes Federation, 10% of people in Russia suffer NIDDM of different genesis. The authors covered the topical issues of modern strategies in antihypertensive therapy in patients with NIDDM and HTN according to large randomized trials. The authors analyzed the possibilities of conventional and modern therapies of hypertension, organoprotection, metabolic neutrality and impact on prognosis in patients with NIDDM. It is underlined that the renin-angiotensin-aldosterone system is a part of the cardiovascular continuum and links various risk factors, like end-stage of cardiovascular disease and chronic renal disease. Monitoring of arterial blood pressure is crucial for patients with essential hypertension and NIDDM. Pharmacological blockade of the renin-angiotensin-aldosterone system is the most desirable method of treatment of hypertension and noninsulin-dependent diabetes mellitus. This method reduces the risk of cardiovascular complications. PMID- 24341204 TI - [Clinicopathologic and endoscopic characteristics of chronic gastritis in flight personnel]. AB - Surveyed 119 men in flight personnel. All were performed esophagogastroduodenoscopy and morphological study of biopsy material. Level of specific antibodies to Helicobacter pylorus (Hp) by enzyme immunoassay was determined, performed breathing Helika-test; Hp was determined by cytological method. Performed acidogastrometry. In 8 patients revealed erosive antral gastritis, 99--chronic gastritis, 12 patients have no stomach or duodenal ulcers. All patients with erosive gastritis were infected with Hp. antibodies to Hp were detected in all patients with chronic gastritis, and Helika-test and cytology for Hp were negative in 18.2% of patients in this group. PMID- 24341205 TI - [Health status of female soldiers serving in the Northern Fleet]. AB - Authors analyzed the health status and morbidity among female soldiers serving under the contract in the Northern Fleet, age peculiarities, results of medical in-patient examination and expert assessment, put in medical records in accordance with prophylactic medical examination service and medical examination. Annual data about military troops, morbidity and medical examination among female soldiers in the period 2002-2010 (n-14,5 thousand of people) are included into analysis. 502 medical records of female soldiers approved by military physician board were analyzed. Authors presented statistic data about primary diseases and chronic pathology and considered causes of changing of the category of fitness for military service and its gender peculiarities. Authors suggest changing the recruiting concept for female soldiers and the system of medical in-patient examination. PMID- 24341206 TI - [From the history of military-medical examination in the Far East (to the 60th anniversary of the 4th Branch of the Main center of military-medical examination of the Ministry of Defense of RF)]. AB - Military-medical examination is a part of medical service of the Armed Forces of the Russian Federation and plays a significant role in recruiting military troops with healthy, physically vigorous soldiers, in saving and improving of health of military personnel, in undertaking prophylaxis and therapeutic measures, in solving social problems of servicemen and their families. Military-medical examination board of Eastern Command plays a significant role in the system of military-medical examination of the Armed Forces of the Russian Federation. The article is devoted to the history of formation and development of military medical examination in the Far East depending on aims and goals of military medical service at different stages of military formation. Eastern Command dated back to the Civil War, has changed its organization, boundaries, structure and name many times. According these changes many new military-medical departments, including military-medical examination board, were reorganized, disbanded and created. Various military-medical commissions alternating or working simultaneously at different military units were created in the Far East. PMID- 24341207 TI - [Conservative methods of treatment of wounds during the great patriotic war (according to the magazine "the hospital case")]. AB - The article investigates reasons of increase of labour-saving innovations and inventions made by physicians during the great patriotic war. It is proved that suggestions made during the analyzed period (1942) showed no much novelty and originality. From the article it follows that soviet physicians at the beginning of the Great Patriotic War had no proper knowledge about military surgery. PMID- 24341208 TI - [Leading role of infection in formation of placental insufficiency]. AB - AIM: Evaluate the role of endotoxinemia in pregnancy complicated with placental insufficiency. MATERIALS AND METHODS: Complex clinical-laboratory examination of 130 pregnant women in 70 of which placental insufficiency was diagnosed (main group) was carried out. The examinees of the main group were divided into 3 subgroups: 36, 20 and 14 pregnant women with compensated, subcompensated and decompensated placental insufficiency, respectively. The control group was composed of 60 pregnant women with physiological course of gestation. Levels of LPS, LPS-binding protein and IgG against core-region, cytokines (TNF-alpha, IL13, IL2, IL4, IL6, IL8, IL10, IFNgamma), C-reactive protein were determined in blood plasma. Infection by Chlamydia trachomatis, Mycoplasma genitalium, Treponema vaginalis, Neisseria gonorrhoeae, Mycoplasma hominis, Ureaplasma urealyticum, Ureaplasma parvum were evaluated by PCR. RESULTS: In the main group in 64.2% of cases the presence of genital tract infection was established, in 47.0%--urinary system. An increase of LPS level, titers of IgG against LPS core-region and LPS binding protein in blood plasma of pregnant women with placental insufficiency was shown. Cytokine profile in placental dysfunction was characterized by a significant increase of IL1beta, IL8, TNF-alpha Th1 cytokine and IL10 Th2 cytokine concentrations and a decrease of pro-inflammatory IL2, IFNgamma levels. CONCLUSION: The results indicate a leading role of infection in formation of placental dysfunction as well as prove involvement of LPS Gram-negative bacteria in pathogenesis of this complication. PMID- 24341209 TI - [Effect of plant extracts on cytotoxic activity of Vibrio cholerae hemolysin]. AB - AIM: Study of plant extracts that have the ability to neutralize cytotoxic activity of hemolysin. MATERIALS AND METHODS: Preparations of purified and recombinant V. cholerae eltor hemolysin as well as supernatants of V. cholerae strains were used. Determination ofcytotoxic activity of hemolysin and neutralizing activity of plant extracts were carried out by using cell cultures CHO-K1 and CaCo2. RESULTS: Out of 9 water extracts only 3 - extracts of Rhei rhizome, Limonium gmelinii and Quercus robur neutralized hemolysin in cell culture CHO-K1 and CaCo2, whereas the other extracts--Humulus lupulus, Ocimum basilicum, Chelidonium majus, Juglans regia, Achillea milefolium and Hypericum perforatum did not have anti-cytotoxic effect. Neutralizing properties of extracts are exhibited during their co-incubation with hemolysin preparations and supernatants of V. cholerae strains already within 10 minutes. CONCLUSION: Plant extracts that have anti-cytotoxic activity against hemolysin are perspective for development oftherapeutic-prophylaxis preparations. PMID- 24341210 TI - [Multilocus sequencing of Corynebacterium diphtheriae strains isolated in Russia in 2002 - 2012]. AB - AIM: Characterization of contemporary C. diphtheriae strains isolated in Russia by using multilocus DNA sequencing (MLST). MATERIALS AND METHODS: 28 toxigenic C. diphtheriae strains isolated in Russia in 2002-2012 and sent to diphtheria and pertussis reference center of Gabrichevsky Research Institute of Epidemiology and Microbiology were studied. C. diphtheriae strain genotyping was performed by using MLST based on atpA, dnaE, dnaK, fusA, leuA, odhA and rpoB gene fragments. Identification of alleles and ST was carried out according to EMBL/GenBank and PubMLST, eBurst approach was used for cluster analysis. RESULTS: By using MLST contemporary toxigenic C. diphtheriae strains isolated in Russia in 2002 - 2012 were characterized. 8 genotypes (ST41, ST5, ST8, ST28, ST25, ST44, ST-new1 and ST new2) were identified, 3 among them were dominating--ST8, ST28 and ST-new1. Most of the toxigenic strains belong to biovar gravis and ST8. Among biovar mitis strains a higher heterogeneity by ST membership was noted, but with prevalence of ST28 strains. CONCLUSION: Use of MLST allowed to characterize contemporary circulating population of toxigenic C. diphtheriae strains isolated in Russia and showed perspective of application of this method for characterization of diphtheria causative agent population and detection of epidemically significant strains, as well as juxtaposing of them with genetic structure of foreign strains. PMID- 24341211 TI - [Epidemiologic surveillance and prophylaxis of hemorrhagic fever with renal syndrome in Russian Federation]. AB - Hemorrhagic fever with renal syndrome (HFRS) remains an actual natural-focal non transmissible infection comprising more than 90% in structure of all the hemorrhagic fevers registered on the territory of Russian Federation. On the whole in multiyear dynamics of HFRS morbidity in Russia a pronounced tendency of growth with an average increase of morbidity of 1.7% per year that is caused by both improvement of clinical and laboratory diagnostics and objective increase of morbidity is noted. Currently a regulatory methodical base for organization of epidemiologic surveillance and prophylaxis of HFRS in Russian Federation is created. PMID- 24341212 TI - [Anti-pertussis immunity in children in the cities of Northwestern Federal District with various population]. AB - AIM: Evaluate the state of immunity against pertussis in children living in St. Petersburg and regional centers of Northwestern Federal District (NFD). MATERIALS AND METHODS: The level of anti-pertussis antibodies by EIA and agglutinin reaction (AR) was studied in 419 children living in St. Petersburg and by AR in 239 children living in regional centers of NFD. Blood sera in AR were studied by using liquid pertussis diagnosticum (Biomed, Russia). RESULTS: In St. Petersburg the frequency of detection of high level of antibodies was the highest in the 15 17 age group that indicates a high level of latent morbidity in grownups. The frequency of detection of high level of antibodies in the 3 - 4 and 9 - 10 age groups in regional centers was significantly lower, and the fraction of sera with undetected level of antibodies--significantly higher compared with St. Petersburg, that gives evidence on low circulation of causative agent, lack of "epidemizing" of children in small cities. CONCLUSION: The question of introduction of second revaccination against pertussis in children at the age of 6 is actual, because one vaccination is not enough for prolonged sustaining of population immunity intensity. PMID- 24341213 TI - [Study of etiologic factors of infectious diseases of respiratory tract in school age children during period of remission of a respiratory disease]. AB - AIM: Detect features of microflora of upper respiratory tract on the example of flora of palatine tonsils and level of antibodies against intracellular parasites as markers of etiologic factors of respiratory infections in school-age children in remission period. MATERIALS AND METHODS: 466 children from frequently and episodically ill groups were examined. Bacteriologic study of smears from the surface of palatine tonsils was carried out in all the children. By using EIA with the corresponding commercial test systems IgG level against Herpes simplex virus, Cytomegalovirus, Chlamydophila pneumoniae, Mycoplasma pneumoniae, Human respiratory syncytial virus was determined in blood sera according to instruction manual. RESULTS: During remission period of infectious process in the structure of microflora of upper respiratory tract in frequently ill children characteristic differences from their episodically ill peers were detected. In children with frequent respiratory infections a higher occurrence of antibodies against intracellular causative agents of these diseases was also detected. In the group of frequently ill, a direct correlation between frequency of infectious diseases of respiratory tract and occurrence of carriage of pathogenic and opportunistic microorgan isms as well as increase of antibodies against Herpesviridae, Cytomegalovirus, C. pneumoniae and M. pneumoniae was detected. CONCLUSION: Higher occurrence ofintra- and extra-cellular infectious agents as well as their associations may be considered as one of the reasons of insufficient effectiveness of prophylaxis measures in frequently ill children. PMID- 24341214 TI - [Comparative evaluation of prevalence of infections caused by hepatitis B and C viruses among individuals of various groups with high risk of infection]. AB - AIM: Determination of breadth of spread of hepatitis B and C viruses among members of 5 groups with high risk of infection. MATERIALS AND METHODS: By enzyme immunoassay 3219 sera of members of groups with high risk of infection and 1541 sera of blood donors were studied for the presence of HBsAg and anti-HCV. In 5 risk groups were included: HIV-infected individuals, lung tuberculosis patients, hemoblastosis patients, chronic renal failure patients on hemodialysis and users of injectable drugs, permanently residing in Republic of Azerbaijan. RESULTS: Frequency of detection of HBsAg and anti-HCV in these individuals was significantly higher than in control groups. HBsAg and anti-HCV most frequently occurred in HIV-infected individuals and users of injectable drugs--more than 50% of all the infected belonged to these groups. Average prevalence of these viruses was among hemoblastosis patients and chronic renal failure patients on hemodialysis--both markers were determined in approximately a third of patients of each group. The least prevalence was among lung tuberculosis patients--HBsAg and anti-HCV were determined in less than 25% of cases. CONCLUSION: Serologic study carried out among members of groups of high risk residing in Azerbaijan allowed us to make a conclusion that all these individuals belong to groups with high prevalence of HBsAg and anti-HCV and by this be a collective reservoir of HVB and HVC in population. PMID- 24341215 TI - [Morphofunctional evaluation of the state of cells of APUD-system biomodel during anti-plague vaccine process]. AB - AIM: Study reaction of cells of APUD-system of lymphoid organs and intestine of guinea pigs at the stages of morpho- and immunogenesis in response to administration of Yersinia pestis EV Research Institute of Epidemiology and Hygiene (RIEH) line vaccine strain. MATERIALS AND METHODS: Vaccine process was modeled in guinea pigs during subcutaneous infection of animals with culture of Yersinia pestis EV RIEH line vaccine strain. Pieces of thymus, spleen, lymphatic nodes and an area of duodenum were taken for histological study. The preparations were stained by solution of hematoxylin and eosin, impregnated with silver by Grimelius and Masson in Hamperl modification. RESULTS: Dose-dependent character of effect of anti-plague vaccination on reaction of apudocytes in immunocompetent organs and duodenum biomodels was established, that indirectly reflects the direction of processes of immunogenesis in central and peripheral organs of immune system. Changes in quantity and morphofunctional state of apudocytes in the intestine of immunized guinea pigs gives evidence of the interest of this segment of APUD-system in the processes of immunogenesis during plague. CONCLUSION: Range of changes of quantity and functional state of apudocytes in lymphoid organs and intestine of animals during anti-plague vaccination was established. Quantitative parameters of morphofunctional state of intestine adipocytes that may be used for characterization of the intensity of adaptation compensatory process in the organism of biomodels during modeling of any experimental vaccine process as well as an additional indirect indicator during evaluation of reactogenicity of live anti-plague vaccines were determined. PMID- 24341216 TI - [Level of sIgA, IgG, IgA in vaginal secretion in women with chronic inflammatory disease of small pelvis organs]. AB - AIM: Determine levels of sIgA, IgG, IgA in vaginal secretion and saliva of women of reproductive age with chronic inflammatory diseases of small pelvis organs (IDSPO) at exacerbation stage and remission period. MATERIALS AND METHODS: Clinical-laboratory and gynecological examination of 105 women was carried out. Based on the results obtained 3 groups were formed: patients with IDSPO at exacerbation stage; patients at remission stage; clinically healthy women. sIgA, IgG, IgA parameters were studied in vaginal secretion and saliva in women with IDSPO at exacerbation stage and remission period by radial immune diffusion in gel by Manchini method. RESULTS: An increase of immunoglobulin level in vaginal secretion of women with IDSPO at remission period and a sharper increase of these parameters during exacerbation of the disease compared with women of the control group were detected. During analysis of sIgA, IgG, IgA levels in saliva in the same groups of women the results were obtained that give evidence that the presence of IDSPO and local immune reaction do not lead to the changes of these parameters. CONCLUSION: The obtained parameters on the dependence of an increase of immunoglobulin levels in vaginal secretions and the degree of intensity of the inflammatory process give basis to use them with the aim of additional diagnostics. PMID- 24341217 TI - [Effect of metabolites of H2O2-producing lactobacilli on functional activity of lysozyme]. AB - AIM: Study the effect of metabolites of H2O2-producing lactobacilli on enzymatic and bactericidal activity of lysozyme. MATERIALS AND METHODS: 9 H2O2-producing vaginal lactobacilli, Micrococcus luteus NCTC 2665, Escherichia coli State Institute of Standardization and Control No 240367, Lactobacillus acidophilus Institute of Cellular and Intracellular Symbiosis No 37 were used. Ability of lactobacilli to produce H2O2 was evaluated by oxidation of tetramethylbenzidine by peroxidase. Lysozyme was modified by mixing with equal volumes of lactobacilli metabolites, metabolites of H2O2-producing vaginal lactobacilli previously treated with catalase were used in control. Lysozyme enzymatic activity was determined by speed of M. luteus lysis, bactericidal--by survivability of E. coli in Endo medium and L. acidophilus--in MRS medium. RESULTS: Decrease of enzymatic activity of lysozyme due to its contact with H2O2-producing lactobacilli metabolites was detected. This effect is accompanied by growth of bactericidal activity of lysozyme against E. coli and decrease against L. acidophilus. The degree of changes of enzymatic and bactericidal activity of lysozyme by lactobacilli metabolites depended on concentration of hydrogen peroxide in them. CONCLUSION: Modification of lysozyme by H2O2-producing lactobacilli metabolites resulting in opposite changes of its activity against autochthonous and allchthonous bacteria is one of the mechanisms of formation of stable microbial biocenosis in human organism. PMID- 24341218 TI - [Effect of IL-1beta on growth properties of vaginal microsymbionts]. AB - AIM: Study the effect of IL-1beta in concentrations that are characteristic for vaginal normo- and pathocenosis on growth properties of vaginal microsymbionts. MATERIALS AND METHODS: Concentration of IL-1beta in vaginal contents of women during bacterial vaginosis and normocenosis was determined by using enzume immunoassay. Changes of growth characteristics and biofilm formation ability of Staphylococcus aureus, Escherichia coli, Lactobacilus spp., Corynebacterium spp. under the effect of various IL-1beta concentrations by method of O'Toole G.A. (1999) were studied. RESULTS: IL-1beta in concentrations characteristic for normocenosis was shown to be able to cause stimulating effect on growth properties of lactobacilli and corynebacteria and suppress growth of S. aureus and E. coli in both plankton and biofilm cultures. IL-1beta concentrations characteristic for vaginal dysbiosis on the contrary result in suppression of growth of lactobacilli biomass against the background of stimulation of growth properties and biofilm formation ability of S. aureus and E. coli. CONCLUSION: Differential dose-dependent effect of IL-1beta on biomass growth and biofilm formation ability of vaginal microsymbionts is a mechanism of regulation of vaginal microbiocenosis. PMID- 24341219 TI - [Characteristic of microflora isolated during mechanical lung ventilation]. AB - AIM: Study species composition and biological properties of microorganisms isolated from lower respiratory tract of 34 patients of surgical departments during mechanical lung ventilation. MATERIALS AND METHODS: 59 strains of microorganisms were isolated and identified by established methods from tracheobronchial secretion during intubation and extubation. Hemolytic and anti lysozyme activity was determined in isolates by methods described previously (O.V. Bukharin, 1999). RESULTS: During extubation an increase of seeding of tracheobronchial secretion in patients, increase of microorganism species diversity and frequency of occurrence of highly virulent strains characterized by the ability to hemolyze erythrocytes and high values of anti-lysozyme activity were established. CONCLUSION: The data obtained may be used to prognose the risk of development of diseases of respiratory system. PMID- 24341220 TI - [Complex evaluation of intestine microbiocenosis condition in patients with chronic pancreatitis]. AB - AIM: Study the state of intestine microbiocenosis in patients with chronic pancreatitis, give comparative evaluation of diagnostic significance of bacterial and gas-liquid chromatography analysis. MATERIALS AND METHODS: 96 patients with chronic pancreatitis (CP) were examined bacteriologically for dysbacteriosis. In parallel in 42 individuals gas-liquid chromatography analysis (GLC-analysis) was carried out. RESULTS: During bacteriological examination in 93.7% of patients various dysbiotic disorders were detected. The main indicators of GLC-analysis-- anaerobic index, cumulative content of volatile fatty acids and their isoforms also gave evidence on imbalance of intestine microflora. GLC-analysis as a rule confirmed the data of bacteriological examination. CONCLUSION: During parallel use ofbacteriological and gas-liquid chromatography analysis in almost all the CP patients intestine dysbacteriosis of various degree of intensity was detected. Combined use of these methods increases effectiveness of examination. PMID- 24341221 TI - [Combined determination of spontaneous and antigen-induced production of cytokines for differential diagnostics of active tuberculosis of lungs and latent tuberculosis infection]. AB - AIM: Choice of informative biomarkers for diagnostics of Mycobacterium tuberculosis infection and differential diagnostics of active tuberculosis (TB) of lungs and latent tuberculosis infection (LTBI). MATERIALS AND METHODS: 54 tuberculosis patients, 47 contact by TB, individuals and 43 healthy donors were examined. All the individuals included into the study had QuantiFERON-TB Gold In Tube (Cellestis, Australia) carried out. Values of spontaneous (NIL) and antigen induced (AG) production of 10 cytokines (EGF, MIP-1beta, VEGF, IL-2, IL-4, IL-6, IL-1alpha, IFN-alpha2, TGFalpha, TNFalpha) as well as sIL-2Ralpha and sCD40L using XMap technology were measured. IP-10 level was also determined in 48 individuals by using EIA. RESULTS: 6 out of 13 biomarkers distinguished active TB and LTBI. As a result of construction of a decision tree in JMP 9.0 program 3 most significant markers were selected. Use of combination of IFN(gammaAG-NIL), TGFalpha NIL and IL-6AG cytokines allowed to divide TB patients and contact individuals with sensitivity of 96.3% and specificity of 80.7% (AUC = 0.9). We also observed very high levels of IP-10 and IL-2 that correlated with IFN(gammaAG NIL) (r = 0.71 and 0.79, respectively). CONCLUSION: IL-2 and IP-10 as well as IFNgamma may be used as helpful biomarkers as a first stage for diagnostics of (M.tb.) infection. At the second stage determination of IL-6, IFNgamma and TGFalpha for differential diagnostics of active TB and LTBI is proposed. PMID- 24341222 TI - [Is resistance to disinfectants a mandatory feature of a hospital strain of causative agents of nosocomial purulent-septic infections?]. AB - AIM: Evaluate resistance to working solutions of disinfectants by Staphylococcus haemolyticus and Klebsiella pneumoniae isolated from newborns and hospital environment objects of obstetric hospital during registration of group purulent septic infections (PSI). MATERIALS AND METHODS: Analysis of 2 epidemic situations on PSI morbidity of newborns caused by S. haemolyticus and K. pneumoniae was carried out. Sensitivity to antibiotics of S. haemolyticus and K. pneumoniae strains isolated from newborns and hospital environment was studied by disc diffusion method and genotyping of K. pneumoniae--by using polymerase chain reaction with universal primer M 13 (RAPD-PCR). Sensitivity of S. haemolyticus and K. pneumoniae to working solutions of disinfectants was determined on test surfaces (glass, metal, plastic, wood, oilcloth). RESULTS: The detected identity of antibiotic phenotype of S. haemolyticus and K. pneumoniae strains as well as genotype of K. pneumoniae strains combined with registration of group PSI morbidity among newborns confirms that the circulating strains (clones) of the causative agents were hospital. S. haemolyticus and K. pneumoniae strains in most cases were sensitive to working solutions of disinfectants. CONCLUSION: Resistance of causative agents of nosocomial PSI to disinfectants is not an unconditional feature of a hospital strain, and concurrence of resistance profile of microorganisms to disinfectant preparations--a mandatory feature of the presence of epidemiologic connection between the diseased. PMID- 24341223 TI - [Antimicrobial peptides of lactobacilli]. AB - Data on antimicrobial peptides (AMP) of lactobacilli, mechanism of their damagin effect, chemical nature and genetic control are presented. Regardless of the source of isolation AMP of lactobacilli except reuterin are peptides with low molecular weight (4 - 6 kDa), differ from each other by chemical structure, sensitivity to temperature, effect of various enzymes, active at neutral or more frequently low pH. Especially important are mechanisms ensuring fine regulation of phenotypic expression of bacteriocin synthesis and formation of immunity against their effect. Activity and most importantly the level of their production depend on the conditions in which these bacteria are present and are controlled by a three-component regulation system. This system includes signal peptide (pheromone), sensory histidine kinase, regulator protein activating transcription. Resistance of the producer to the effect of its own bacteriocin is ensured by the so called immunity protein. AMP of lactobacilli are able to influence septoformation, peptidoglycan and protein synthesis, affect cytoplasmic membranes causing their destabilization. Stages of this damaging effect are described: interaction of effector peptides with the membrane of the sensitive cell, positioning of the peptide in the region of connection with protein receptor, submerging into the core of the spiral structure membranes with the formation of a pore and exhaustion of ATP pool leading to cell death. Protection from AMP is determined by specific proteins blocking pore formation in the membrane by direct binding of damaging molecules or their receptors. Perspectives of further studies of the role of antimicrobial peptides of lactobacilli are discussed. PMID- 24341224 TI - [Raman spectroscopy in microbiological diagnostics: achievements, advantages, perspectives]. AB - Despite all the diversity of existing methods of detection of microorganisms the question of accelerated diagnostics of causative agents of severe diseases, nosocomial infections and other microbial agents that have epidemiologic significance remains unsolved. In the cases when the result of the study must be available as soon as possible, methods that do not require special prolonged preparation of the studied material and isolation of pure culture of microorganisms are necessary. These include optical-spectral methods, among those combinative light scattering spectroscopy or Raman spectroscopy deserves the most attention, the review being dedicated to its application. The ability to obtain information on components comprising the studied sample within several minute allows to use Raman spectroscopy in many fields of biology and medicine. High specificity of the method is based on absolute uniqueness of specters of various substances and in practice is 96 - 97%, sensitivity - 95%. Full automation of the process, use of the newest mathematical apparatus for readout and provision of the results of the study allow to avoid the effect of human factor and increase the objectivity of the data obtained. Analytical reliability, timely reception of the result and economical effectiveness entitle to consider Raman spectrometry as a perspective universal express method in microbiological diagnostics. PMID- 24341225 TI - [The informative value of oral mucosal biopsy for the diagnosis of systemic amyloidosis]. AB - One hundred and thirteen oral mucosal biopsy specimens were analyzed in patients suspected of having systemic amyloidosis. Histological, immunohistochemical, and genetic studies and polarized light microscopy revealed oral amyloid deposits in 72.6% of cases, including 63.5% with metabolic syndrome and 36.5% with another etiology of chronic heart failure (coronary heart disease, cardiomyopathy). Systemic amyloidosis was found in 13.4% of cases (hereditary transthyretin, AL, and senile forms in 1.8, 10.5, and 1.1% cases, respectively). An anterior abdominal wall skin flap was a valid location to reveal the systemic forms of amyloidosis. Patients with metabolic syndrome and periodontal diseases may have local oral amyloidosis. PMID- 24341226 TI - [Pathomorphology of periventricular leukomalacia and other white matter lesions in infants]. AB - The paper describes white matter lesions that differ from periventricular leukomalacia (PVL), such as diffuse leukomalacia (DL) and telencephalic gliosis (TG). There are three types of cerebral leukomalacias: PVL, DL, and subcortical leukomalacia. The morphological differences between PVL and DL are considered. The diffuse form of PVL is described. It is pointed out that colliquation PVL foci frequently occur in infants with birth weight less than 1500 g. There are data on the morphology of TG in which generalized and occasionally large-focal astrogliosis develops in the cerebral hemispheric white matter. It is suggested that it is inexpedient to identify the focal and diffuse components of PVL. The immunihistochemical findings led to the conclusion that PVL, DL, and TG did not result from the direct effects of pathogens of inherited infections on brain tissue. PMID- 24341227 TI - [Comparative immunohistochemical evaluation of vascular endothelial growth factor and its receptors in the placental villi in gestational diabetes mellitus and type 1 diabetes]. AB - The authors performed a comparative immunohistochemical study of placental vascular endothelial growth factor (VEGF) and its receptors (VEGFR-1, VEGFR-2 and VEGFR-3) in gestational diabetes mellitus and type 1 diabetes. The expression of VEGF and its receptors was ascertained to be increased in the placental terminal and stem villi, mostly in type 1 diabetes. The changes found in the immunophenotype of terminal and stem villi suggest that the placenta is damaged and this may accordingly lead to intrauterine growth disturbances in the fetus and further to diseases in the neonatal infant. PMID- 24341228 TI - [Time course of morphological changes in humoral renal allograft rejection in ABO incompatibility between donor and recipient]. AB - One hundred and five biopsy specimens taken in different periods after 34 ABO incompatible mismatched related kidney transplantations were examined to establish the patterns of humoral activity from the morphological changes and expression of C4d deposits in the peritubular capillaries. Severe reversible forms of acute humoral rejection (AHR) (2 patients) and minimal morphological manifestations (13 patients) were observed in the biopsy specimens taken as long as 2 months later in Group 1 (C4d+). In the early period, the minimal manifestations of AHR did not cause organ dysfunction; but in the late period, 5 of them developed chronic humoral rejection in persistent humoral activity; 4 grafts were removed 531,720, 1019, and 1252 days later. Group 2 (C4d-) (n = 19) showed no graft losses or significant chronic changes; the late minimal manifestations of AHR had no impact on the duration of organ function in 3 recipients. The timely detection of early humoral activity and minimal manifestations of AHR is needed for the measures taken to reduce a risk for late function loss of the grafted organ. PMID- 24341229 TI - [Characteristics of CD99 expression in the skin of psoriasis patients]. AB - The pattern of CD99 expression in the skin was studied in 22 patients with disseminated psoriasis. The patients' skin biopsy specimens were immunohistochemically stained by the standard procedure using monoclonal antibodies to CD99. The progression of psoriasis was characterized by the increased expression of the protein in the dermis (lymphocytes and vascular endothelium) and epidermis (keratinocytes) with the antigen being located not only in the cytoplasm, but also in the membrane. In remission, the content of CD99-positive cells in the dermis and epidermis was significantly reduced with the prevalence of cytoplasmic localization in the epidermal keratinocytes. It is assumed that the expression of CD99 plays an important role in the pathogenesis of psoriasis, in the processes of emigration of leukocytes, and in their tropism toward to the epidermis. PMID- 24341230 TI - [Effect of the intercellular adhesion molecule E-cadherin on the prognosis of non small cell lung cancer]. AB - The effect of E-cadherin on the prognosis of Stage I-II non-small cell lung cancer (NSCLC) was investigated. Tumor E-cadherin expression and its correlation with the clinical and morphological characteristics of a patient, as well as the prognostic role of this marker were studied. It was ascertained that the E cadherin expression did not depend on patient gender and age, tumor histological pattern, location, grade, and pT category, but it was significantly related to the pN1 category (p < 0.0001). Univariate analysis revealed that the histological pattern of a tumor, nodal status, resection type (lobectomy/pulmonectomy), and E cadherin expression level were significantly correlated with patient survival. Multivariate analysis showed that the important predictors were tumor histological pattern and resection type (p = 0.01 and p = 0.00004, respectively). A more complete study of the prognostic and predictive role of E-cadherin expression in patients with Stage I-II NSCLC will help identify a prognostically unfavorable group of patients who may be given additional treatment in the postoperative period. PMID- 24341231 TI - [Atypical teratoid/rhabdoid tumors of childhood]. AB - The paper describes 6 cases of atypical teratoid/rhabdoid tumors (ATRT) in the complete absence of classical rhabdoid elements isolated from 25 INI1-negative central nervous system tumors investigated in the period 2006 to the present time. Analysis of the specific features of the histological structure of INI1 negative tumors could identify a few histological types of ATRT according to the conventionally standardized criteria for diagnostic search. PMID- 24341232 TI - [Sclerosing mucoepidermoid carcinoma with eosinophilia of the thyroid gland]. AB - The paper characterizes sclerosing mucoepidermoid carcinoma with eosinophilia, a rare thyroid tumor, including histological and immunohistochemical features. The authors give their observation of a 26-year-old patient. The immunohistochemical findings (positive p63 and TTF-1 tumor cell nuclear staining) show the dual nature of a tumor arising from the cells of the ultimobranchial body and follicular epithelium. PMID- 24341233 TI - [Osteochondrosis as a possible cause of pharyngeal dysphagia]. AB - Dysphageal complaints in a 65-year-old woman were regarded as a manifestation of mental illness. The autopsy of the patient weighing 32 kg who died from bilateral pneumonia revealed 9-mm osteophytes on the anterior surface of the cervical spine as the cause of dysphagia. Twenty-nine cases of cervical osteochondrosis-induced dysphagia, published in the literature, were analyzed. PMID- 24341234 TI - [Giant chorioangioma of the placenta]. AB - The paper describes a case of giant (123 x 109 x 70-mm) placental chorioangioma that is a capillary hemangioma in structure, which led to significantly impaired placental-fetal blood flow to give rise to non-immune hydrops and right heart failure in the fetus at 33 weeks' gestation; obvious polyhydramnios developed. This served as an indication for preterm one-stage cesarean delivery. A premature live girl was born with a weight of 2430 g, a height of 44 cm, Apgar score 6-7. Dynamic echographic monitoring makes it possible to record increased placental tumor sizes and fetal abnormalities and to make a timely decision on delivery, which promotes perinatal death prevention. At 11-month follow-up, the child's physical and mental developments were for age. PMID- 24341235 TI - [Metanephric adenoma of the kidney]. AB - The paper describes metanephric adenoma, a rare adenoma, diagnosed in a patient 20 years after surgery. It provides a histological description of the tumor and a concise review of the literature. PMID- 24341236 TI - [Cell and cytokine markers in the synovial membrane in rheumatoid arthritis]. AB - The paper considers the morphological signs of rheumatoid synovitis, their association with clinical manifestations and therapy. Synovial changes in rheumatoid arthritis indicate that there is variability and subclasses of this disease. There is evidence that it is necessary to quantify morphological changes, by using digital imaging techniques, and to study the classes and subclasses of cellular elements of inflammation. Inflammatory infiltration of the synovial membrane contains T and B lymphocytes and their subclasses. The expression of cell markers and proinflammatory and anti-inflammatory cytokines is characterized. The points of therapy with genetically engineered biological agents are shown. Further morphological investigation of the synovial membrane should aim to detect the diagnostic and prognostic signs of synovitis and to identify risk-group patients with the persistent and destructive types of the disease. The findings may be of importance in studying the pathogenesis, identifying the subclasses of rheumatoid arthritis, and searching for new effective applications of the biological agents. PMID- 24341237 TI - [Melanoma: from molecular studies to the treatment breakthrough]. AB - Melanoma holds a leading position in the mortality from skin tumors. Standard treatment of metastatic melanoma allows tumor remission to be achieved only in a small subset of patients. Studies on melanoma molecular pathogenesis led to the identification of several causative genetic events and, consequently, to the development of novel targeted drugs. More than a half of melanomas contain amine acid substitutions in serine-threonine kinase BRAF. Clinical trials involving specific BRAF inhibitors--vemurafenib and dabrafenib--demonstrated high efficacy of these agents towards BRAF-mutated melanoma. MEK inhibitors may show activity against both BRAF--and NRAS-driven tumors. Mucosal and acral melanomas frequently contain mutation in KIT receptor and can be successfully treated by imatinib. There are novel therapeutic monoclonal antibodies targeted against immunosuppressive molecules CTLA4, PD-1 and PD-L1. In some instances these drugs allow to obtain exceptionally prolonged responses. Whole genome sequencing led to the identification of new melanoma genes, e.g. GRIN2A, TRRAP, PREX2, RAC1, STK19, PPP6C, etc. Molecular testing, especially BRAF mutation analysis, has become a mandatory part of melanoma diagnosis. Nevertheless, despite the revolution in melanoma treatment, the prevention of excessive ultraviolet exposure, cancer awareness and early diagnosis remain the main tools for the management of this disease. PMID- 24341238 TI - [German Fedorovich Tseidler (1861-1940)]. PMID- 24341239 TI - [Features of surgical treatment of moderate ischemic mitral regurgitation in high risk patients]. AB - The experience of surgical treatment of high risk group patients with ischemic mitral regurgitation of different degree of manifestations was analyzed. The basic approaches to the management and the choice of treatment strategy are reported in this article. The authors suggested the priority strategy on the background of completed investigation: 1) the performance of the annuloplasty on pressure ring in combination with coronary bypass surgery in surgical treatment of ischemic mitral regurgitation of Ill degree, as most effective kind of intervention; 2) the performance of operation of isolated coronary bypass surgery on working heart for high risk patients with the presence of moderate ischemic mitral regurgitation, that allows the significant improvement of indices of postoperative period and the decrease of evidence of mitral regurgitation at the expense of a salvage of myocardial contractility. PMID- 24341240 TI - [Opportunities of correction of rheological properties of blood in intensive therapy in patients with peritonitis and acute bowel obstruction]. AB - An analysis of efficacy of 1.5% reamberin solution usage was made in 80 patients for correction of blood rheological properties disorder in the case of peritonitis and bowel obstruction. It was established, that reamberin, which was administered in the dose of 500 ml after 12 hours of the beginning of intensive care during 48 hours, efficiently corrected the rheological disorders. It was because the erythron and reticulocyte production were activated, the hyposmolarity was removed, the intensity of free radical oxidation and peroxide oxidation of lipids was decreased and the antioxidant status was restored. This facilitated the hydrophily and erythrocyte volume decrease, the haemolysis reduction and qualitative gas exchange at the level of tissues. PMID- 24341241 TI - [Efficacy of combined surgical and endoscopic means of diffuse peritonitis treatment]. AB - An analysis of complex examination and treatment of 123 patients with diffuse purulent peritonitis was made. The patients were divided into two groups. The first group consists of 68 patients, whom conservative surgical intervention was performed at the first stage and videoimage endoscopic sanation of the abdominal cavity with the administration of sodium hypochlorite water solution was made at the second stage. The main group consists of 55 patients, who had the same treatment except that the abdominal cavity was processed with pulsating stream of antiseptic with immobilized forms of sodium hypochlorite at the second stage. It is established, that the application of developed technology allows decreasing of the frequency of postoperative complications on 8.3% and postoperative lethality 4.8%. PMID- 24341242 TI - [Features of chronic pancreatitis pathomorphism in the validity of surgical approaches]. AB - The results of examination and surgical treatment of 298 patients with chronic pancreatitis and the original morphological investigations of material of the pancreas were studied. The data allowed the detection of additional criteria features of inclusion of the patients with chronic pancreatitis to be made in groups according to foreign Marseilles-Roman classification (1988). It is shown, that the basis of study of morphogenesis of chronic pancreatitis is immunohistochemical method, which let the authors diagnose not only the pathological changes of exo- and endocrine sections of pancreas, but at the same time the structural features of nervous apparatus and vessels of microcircular bed. The revealed morphological features of different forms of chronic pancreatitis vs clinical finding characteristics and the data of instrumental and laboratory methods of research allow the substantiation of surgical treatment version to be made. PMID- 24341243 TI - [Long-term results of combined x-ray endovascular surgical treatment of patients with ductal adenocarcinoma of the pancreatic head]. AB - On the basis of the results of treatment of 105 patients with locally advanced ductal adenocarcinoma of the pancreatic head the authors present the results of work over a period of time since 1999 to 2009. In the main group the combined treatment was used for 51 patients: the non-adjuvant selective chemoembolization of the pancreatic head adenocarcinoma was performed, than standard gastropancreatoduodenal resection with lymphodesection and 6 cycles of adjuvant chemoinfusion in celiac trunk were completed. In control group standard gastropancreatoduodenal resection was performed. In the group of combined treatment the 1-, 2-, 3-year survival rates consist of 80.4%, 58.8% and 43.1%, respectively. The average life span was 22.3+/-2.1 months. The average life span of 54 patient of control group was 8.4+/-2.1 months and a common 3-year survival consists of 13%. There was no lethality after the performance of X-ray endovascular procedures and gastropancreatoduodenal resection. Postoperative complications reliably didn't differ in both groups. PMID- 24341244 TI - [Hemodynamic abnormalities in different kind of arteriovenous access for hemodialysis]. AB - On the basis of examination of 35 dialytic patients, who had clinical findings of progressed chronic cardiac insufficiency against the background of the large arteriovenous shunt through existing vascular access, the authors show the complications. The volume of blood circulation along the arteriovenous fistula, which was more than 30% of cardiac output, caused dilatation of heart cavities with cardiac decompensation. If the largest potency to volume remodeling of native proximal arteriovenous fistulas is taken into account, this kind of access could cause hemodynamic abnormalities more often than others (in 22 (62.9%) of patients). The best primary survival was demonstrated by arteriovenous shunts (87.1%) during 2 years. However, long-term survival of native arteriovenous fistulas dramatically outperformed the other kinds of accesses. The choice of constant vascular access for hemodialysis is an important and difficult task in chronic renal disease of V degree patients. PMID- 24341245 TI - [Mechanisms of development and sclerosurgical treatment methods of acute surface varicothrombophlebitis]. AB - An analysis of complex laboratory, ultrasonic investigations and following treatment of 120 patients with acute surface varicothrombophlebitis was made. The patients were divided into two groups, each being 60 people. In the first control group the treatment was conducted in one step: standard venectomy was performed at high point of inflammatory process. In the main group, the development of thrombotic process was prevented by sclerosurgical technology at the first stage. Radical treatment was carried out at the second stage after 4-6 weeks. The number of complications in near-term postoperative period decreased in 5% and in long term in 13.3%, the quality of life increased in 13.3% in second group patients. PMID- 24341246 TI - [Treatment of patients with open complicated forearm fractures]. AB - The blocking osteosynthesis is preferable in the case of open forearm fractures of the I degree. The treatment of patients with open comminuted complicated forearm fractures should be reasonable to perform in two stages: at the first stage, healing of soft tissues with fixation in the apparatus of external fixation should be obtained. At the second stage, the conversion of external fixator on interlocking nail with single-stage performance of osteoplasty as needed should be carried out. The presented experience of treatment of healing failure, pseudoarthroses and forearm bone defects by developed method allows the practical application of the method to be recommended. PMID- 24341247 TI - [The single-stage and delayed reconstructive plasty in breast cancer patients]. AB - An absence of breast is the irreversible cosmetic and physical defect, which reduces the self-assessment and psyco-emotional status of women. Nowadays the necessity of reconstruction after mastectomy will gain more popularity and plays a fundamental role in psychological and social rehabilitation of breast cancer patients. The article analyzes the experience of reconstructive plasty of 26 patients with I-III stages of breast cancer. PMID- 24341248 TI - [Formation of vascularized bone grafts and their use for treatment of pseudoarthroses and bone defects]. AB - An analysis of 135 transplant surgeries of vascularised bone grafts in treatment of pseudoarthroses and defects of the clavicle, humerous, ulnar, radial, metacarpal,wrist and fingers bones was made. The fusion was noticed in 130 operated patients. The earlier removal of immobilization (in 2), the repeated trauma (in 2) and osteomyelitis of the transplanted graft, which required its removal in 1 patient, were the causes of failure in 5 (3.7%) patients. PMID- 24341249 TI - [Modified method of inguinal hernioplasty]. AB - The work is devoted to the hernioplasty method, which provides the strengthening of back wall of the inguinal canal by autogenous tissues, which were the walls of the hernial sac. After dissection of hernial sac, two muscle flaps were formed and fixed to transverse fascia on the whole perimeter of the inguinal canal. The control group consists of 64 patients and main group - 66 (90.4%). The Liechtenstein operation was performed in control group. In contrast, the method, suggested by the authors, was used in the main group. The patients with hernioplasty were carefully and sufficiently examined in order to make an objective comparative analysis of the results. The results of the review allow the authors to confirm, that the suggested hernioplasty method provides stable local homeostasis of tissues and high quality of life. PMID- 24341250 TI - [Postoperative ventral hernia in patients, who undergone the liver transplantation operation]. AB - The development of postoperative ventral hernia was observed in 8 patients from 114, who undergone the liver transplantation operation. The patients were followed in terms up to 14.5 years. The authors consider the indications and features of surgical treatment of such postoperative hernias. PMID- 24341251 TI - [Injuries of the neck without damage of essential structures: the features of surgical strategy]. PMID- 24341252 TI - [Successful surgical intervention concerning the complicated cytomegaloviral pneumonia in HIV patients]. PMID- 24341253 TI - [Cystic medianecrosis as the cause of splenic arterial aneurysm]. PMID- 24341255 TI - [The response to the article of E. A. Korymasov concerning the article "proceedings of the organization of treatment and diagnostic assistance in non varicose gastrointestinal bleedings"]. PMID- 24341254 TI - [Concerning the article of M. P. Korolev "proceedings of the organization of treatment and diagnostic assistance in non-varicose gastrointestinal bleedings", (Herald of Surgery. 2012. no 5. p. 94-101)]. PMID- 24341256 TI - [Creation of software to help cardiac surgeons: CordaBase]. AB - BACKGROUND: The writing of surgical and hospitalization reports is time-consuming and does not necessarily enable the increment of a statistical database, tool that is indispensable nowadays to evaluate unit activity or to carry out scientific studies. In order to prevent this double data capture, a computer tool, named CordaBase, has been developed by surgeons and set up in a cardiac surgery unit. MATERIALS AND METHODS: CordaBase is an interactive software that stores medical data. Thanks to its intuitive interface, CordaBase stores data which is classified chronologically in the following categories: past medical history, preoperative assessment, operating gesture, stay in intensive care unit, stay in wards and evolution/monitoring after discharge. This date, stored in an Access base, are then used in the creation of personalized surgical and hospitalization reports. All the data is permanently available and can be used for the carrying out of scientific works or for the evaluation of the unit activity. RESULTS: From March 2009 to December 2010, 2617 consecutive patients operated on in a Cardiac Surgery Unit were recorded prospectively in the software. All of this stored data assisted the surgeon in his or her administrative tasks, thanks to personalized surgical and hospitalization reports, immediately at the secretariat's disposal. The database, which is requisitely filled by administrative work, enables the carrying out of any statistical study on all unit activity. CONCLUSION: With a hindsight of almost 2 years, CordaBase has proven its usefulness in an active cardiac surgery unit, both on an administrative and scientific level. The computerized reports have lightened the medical secretariat's workload and statistical studies have now become possible without having to take the paper medical files out again. In the years to come, the accumulation of medical data prospectively or retrospectively stored will surely confirm the potential of the use of such a software. PMID- 24341257 TI - [Interest of evaluation of teaching in thoracic and cardiovascular surgery]. AB - The aim of this work is to reflect on different teaching methods can be used in a surgical teaching and its assessment methods. TWO sessions of Multiple Choice Questions (MCQ) have been proposed, the first before all education, the second after education in order to assess its impact on knowledge. Script Concordance Test (SCT) will replace the traditional interactive case report. Eighteen participants (Group 1) completed both sessions of MCQ: 9 residents (R), 2 equivalent resident (ER), 4 Clinical Fellow (CF), 1 Professor (Pr) and 2 senior surgeons (SS). Sixteen participants (group 2) were present at the first session of MCQ: 6 R, 1 ER, 4 CF, 2 Pr, 2 SS and 1 indeterminate status. Finally, 12 participants (group 3) were present at the second session: 6 R, 1 ER, 1 CF, 1 SS and 3 indeterminate status. The results of"seniors" in Group 1 were higher than those of "juniors" at the first session. MCQ results for the second session were higher in the subgroup CF. A more marked progression in knowledge was observed in resident and Clinical Fellow. Finally, the score obtained by the group 3 was lower than in group 1. The format of the MCQ was particularly heterogeneous. The SCT will help to assess the capacity of decision making in a context of uncertainty (as unexpected surgery requiring quick decisions with immediate effect, surgical strategy in an unusual clinical situation). The different tools available would allow the establishment of an evaluation of teaching, but also to assess the development of thinking skills in situations of uncertainty. Their implementation will take place with the participation and support of the largest number of teachers in our specialty. PMID- 24341258 TI - [Dmitrii Petrovich Kuznetskii (1875-1939)]. PMID- 24341259 TI - [Is the bowel intubation effective in acute intestinal obstruction? Old dogmata and evolution of views]. PMID- 24341260 TI - Training the intelligent eye: understanding illustrations in early modern astronomy texts. AB - Throughout the early modern period, the most widely read astronomical textbooks were Johannes de Sacrobosco's De sphaera and the Theorica planetarum, ultimately in the new form introduced by Georg Peurbach. This essay argues that the images in these texts were intended to develop an "intelligent eye." Students were trained to transform representations of specific heavenly phenomena into moving mental images of the structure of the cosmos. Only by learning the techniques of mental visualization and manipulation could the student "see" in the mind's eye the structure and motions of the cosmos. While anyone could look up at the heavens, only those who had acquired the intelligent eye could comprehend the divinely created order of the universe. Further, the essay demonstrates that the visual program of the Sphaera and Theorica texts played a significant and hitherto unrecognized role in later scientific work. Copernicus, Galileo, and Kepler all utilized the same types of images in their own texts to explicate their ideas about the cosmos. PMID- 24341261 TI - Mutant utopias: evening primroses and imagined futures in early twentieth-century America. AB - Hugo de Vries's mutation theory is now little more than a footnote to the history of biology, a failed theory that briefly led a few biologists astray. However, for the first quarter of the twentieth century it attracted considerable attention from both professional biologists and laypeople. De Vries's theory- together with the plant, Oenothera lamarckiana, that had supplied most of his evidence--became the focus of a surprising variety of imaginative hopes. Scientists and their various publics were fascinated by the utopian possibilities that the primrose seemed to offer, and their discussions shaped a public culture around biology that would help define the twentieth century as the "century of the gene." From a conventional history of science perspective (which, in the case of twentieth-century biology, often remains focused on the content of scientific theories and the professional communities that shaped them), the mutation theory seems unimportant. However, while De Vries's new theory of evolution ultimately failed to persuade the scientific community, it was much more important than is now realized, particularly because it helped make biology part of a wide variety of public debates. Understanding the mutation theory's story more fully suggests that we may need to rethink much of the rest of the century of the gene's history, to think less in terms of what happened in the lab and more about how biology came to function as public culture. PMID- 24341263 TI - Ordering the discipline: classification in the history of science. Introduction. AB - Classification of the history of science has a long history, and the essays in this Focus section explore that history and its consequences from several different angles. Two of the papers deal with how classifying schemes in bibliography have evolved. A third looks at the way archival organization has changed over the years. Finally, the last essay explores the intersection of human and machine classifying systems. All four contributions look closely at the ramifications of the digital revolution for the way we organize the knowledge of the discipline. PMID- 24341262 TI - Paul Ehrenfest and the dilemmas of modernity. AB - This essay considers the highly ambivalent attitude of the Austrian-Dutch physicist Paul Ehrenfest toward contemporary developments in both science and society. On the one hand, he was in the vanguard of the quantum and relativity revolutions, supported industrialization and economic planning based on mathematical models, and, in general, cherished technocratic ideals. The essay highlights several influences that shaped his attitude in these respects, from his ties with the Philips Physics Laboratory and his sojourns in the United States to the utopian visions of H. G. Wells. On the other hand, he was extremely worried about the harmful consequences of contemporary changes in science and society, such as specialization, the growing pace of city life, and the increasing dependence on modern technologies, be they material or mathematical. In this regard, he agreed with cultural critics such as Max Nordau, Henri Bergson, Ostwald Spengler, and Ludwig Klages. Rather than attempting to solve this paradox, the essay suggests that this kind of ambiguity characterized a great deal of innovative science in the period. PMID- 24341264 TI - Organizing knowledge in the Isis bibliography from Sarton to the early twenty first century. AB - This essay explores various ways in which bibliographies have exhibited "sociality." Bibliographies are both products of the social contexts that have created them and engines of social interaction in scholarly communities. By tracing the history of the Isis Bibliography, the longest-running and most comprehensive bibliography in its field, this essay explains how different Isis classification systems have been tied to major twentieth-century cataloging efforts. By looking at classification, the essay also attends to the ways in which aspects of the Isis Bibliography in different decades have reflected social mores of their period. Finally, it demonstrates how critical the Isis Bibliography was in the formation of the discipline of history of science and goes on to discuss how that disciplinary connection is evolving in the twenty first century. By thinking of the bibliography as a network of scholars, not just scholarly works, the essay asks us to reflect on the nature and purpose of bibliography in the digital age. PMID- 24341265 TI - Organization of knowledge and the complex identity of history of science. AB - History of science as a formal and autonomous field of research crosses over disciplinary boundaries. For this reason, both its production and its working materials are difficult to classify and catalog according to discipline-based systems of organization of knowledge. Three main problems might be pointed out in this regard: the disciplines themselves are subject to a historical process of transformation; some objects of scientific inquiry resist constraint within rigid disciplinary grids but, rather, extend across several disciplinary boundaries; and the so-called digital revolution has replaced spatial with temporal display sequences and shifted the traditional emphasis on knowledge to user-oriented approaches. The first part of this essay is devoted to a conceptual analysis of the various approaches to the organization of knowledge formulated over time, whereas the second considers the new possibilities afforded by a faceted model of knowledge organization compatible with user-oriented relational databases to the research materials and production of history of science. PMID- 24341266 TI - The organization and description of science archives in America. AB - The creation of science archives, the historical study of modern science, and major changes in archival practice roughly coincided in the 1950s and 1960s. This has allowed science archives to respond to contemporary issues in the history of science. It has also allowed them to develop as an integral part of the revolution in archival practice since that time, adopting international archival standards that make science archives more accessible to researchers. We are now on the cusp of new technologies and approaches that promise to make a sizable number of collections available online for the first time. This essay describes the development of modern archival principles and practices and discusses the impact they are having on science collections. PMID- 24341268 TI - Letters to the editor. PMID- 24341267 TI - Cross-cutting categorization schemes in the digital humanities. AB - Digital access to large amounts of scholarly text presents both challenges and opportunities for researchers in the humanities. Meeting these challenges depends on having high-quality representations of the contents of digital resources suitable for both machines and humans to use. Different ways of categorizing these contents are appropriate for different purposes, leading to the further problem of relating the contents of different categorization schemes to each other. This essay discusses the rationale for categorizing philosophical concepts and surveys some of the main approaches to doing so for materials that are continuously changing. It describes the goals and methods of the Indiana Philosophy Ontology (InPhO) project and provides an example of the kind of analysis that is made possible by powerful modeling methods. PMID- 24341269 TI - [Research progress and discovery process of facultative methanotrophs--a review]. AB - Facultative methanotrophs are a group of phylogenetically diverse microorganisms characterized by their ability to use methane and some other compounds containing C-C bond as their sole source of carbon and energy. Recently, which belong to the facultative methanotrophs in the genera Methylocella, Methylocapsa and Methylocystis, which belong to the Alphaproteobacteria, have been reported that can grow on larger organic acids or ethanol for some species, as well as methane. In this paper, the research history of facultative methanotrophs was summarized systematically, some other facultative methane-oxidizing microorganisms were introduced, the metabolic mechanisms of utilizing multi-carbon compounds by facultative methanotrophs were analyzed, and the current problems and the future engineering applications were discussed. PMID- 24341270 TI - [Non-coding RNA in fungi--a review]. AB - Non-coding RNAs (ncRNAs) existing widely in many living organisms are functional RNA molecules, function directly as structural or regulatory RNAs in organisms. Although large and diverse populations of ncRNAs have been extensively studied and well understood in animals and plants, few reports could be found about ncRNAs in fungi. Recently, with the development of modern biological techniques, a number of ncRNAs have been identified in fungi, including snoRNA-derived RNAs, long non-coding RNAs, small interfering RNAs (siRNAs), dsRNA Killer viruses, and novel classes of ncRNAs discovered in filamentous fungi. These ncRNAs play important roles in gene transcription and translation, RNA processing and modifying, chromatin structure, and even fungal pathogenicity. Therefore, studies on ncRNAs in fungi may shed light on the regulatory system of gene expression and the characteristics of fungal growth, and even provide some clues towards understanding pathogenic mechanisms of pathogenic fungi, which will contribute to the treatment of fungal diseases. Here, we reviewed the discovery of fungal ncRNAs, their origins and processing, classification, and biological functions, aiming to establish a theoretical foundation and basis for deep understanding of fungal ncRNAs in future. PMID- 24341271 TI - [New isolation methods and phylogenetic diversity of actinobacteria from hypersaline beach in Aksu]. AB - OBJECTIVE: We explored 4 new methods to improve the isolation of actinobacterial resources from high salt areas. METHODS: Optimized media based on 4 new strategies were used for isolating actinobacteria from hypersaline beaches. Glycerin-arginine, trehalose-creatine, glycerol-asparticacid, mannitol-casein, casein-mannitol, mannitol-alanine, chitosan-asparagineand GAUZE' No. 1 were used as basic media. New isolation strategy includes 4 methods: ten-fold dilution culture, simulation of the original environment, actinobacterial culture guided by uncultured molecular technology detected, and reference of actinobacterial media for brackish marine environment. The 16S rRNA genes of the isolates were amplified with bacterial universal primers. The results of 16S rRNA gene sequences were compared with sequences obtained from GenBank databases. We constructed phylogenetic tree with the neighbor-joining method. RESULTS: No actinobacterial strains were isolated by 8 media of control group, while 403 strains were isolated by new strategies. The isolates by new methods were members of 14 genera (Streptomyces, Streptomonospora, Saccharomonospora, Plantactinospora, Nocardia, Amycolatopsis, Glycomyces, Micromonospora, Nocardiopsis, Isoptericola, Nonomuraea, Thermobifida, Actinopolyspora, Actinomadura) of 10 families in 8 suborders. The most abundant and diverse isolates were the two suborders of Streptomycineae (69.96%) and Streptosporangineaesuborder (9.68%) within the phylum Actinobacteria, including 9 potential novel species. CONCLUSION: New isolation methods significantly improved the actinobacterial culturability of hypersaline areas, and obtained many potential novel species, which provided a new and more effective way to isolate actinobacteria resources in hypersaline environments. PMID- 24341272 TI - [A novel gene (Aa-accA ) encoding acetyl-CoA carboxyltransferase alpha-subunit of Alkalimonas amylolytica N10 enhances salt and alkali tolerance of Escherichia coli and tobacco BY-2 cells]. AB - OBJECTIVE: Acetyl-CoA carboxylase (ACC) catalyzes the first step of fatty acid synthesis. In most bacteria, ACC is composed of four subunits encoded by accA, accB, accC, and accD. Of them, accA encodes acetyl-CoA carboxyltransferase alpha subunit. Our prior work on proteomics of Alkalimonas amylolytica N10 showed that the expression of the Aa-accA has a remarkable response to salt and alkali stress. This research aimed to find out the Aa-accA gene contributing to salt and alkali tolerance. METHODS: The Aa-accA was amplified by PCR from A. amylolytica N10 and expressed in E. coli K12 host. The effects of Aa-accA expression on the growth of transgenic strains were examined under different NaCl concentration and pH conditions. Transgenic tobacco BY-2 cells harboring Aa-accA were also generated via Agrobacterium-mediated transformation. The viability of BY-2 cells was determined with FDA staining method after salt and alkali shock. RESULTS: The Aa-accA gene product has 318 amino acids and is homologous to the carboxyl transferase domain of acyl-CoA carboxylases. It showed 76% identity with AccA (acetyl-CoA carboxylase carboxyltransferase subunit alpha) from E. coli. Compared to the wild-type strains, transgenic E. coli K12 strain containing Aa-accA showed remarkable growth superiority when grown in increased NaCl concentrations and pH levels. The final cell density of the transgenic strains was 2.6 and 3.5 times higher than that of the control type when they were cultivated in LB medium containing 6% (W/V) NaCl and at pH 9, respectively. Complementary expression of Aa-accA in an accA-depletion E. coli can recover the tolerance of K12 delta accA to salt and alkali stresses to some extent. Similar to the transgenic E. coli, transgenic tobacco BY-2 cells showed higher percentages of viability compared to the wild BY-2 cells under the salt or alkali stress condition. CONCLUSION: We found that Aa-accA from A. amylolytica N10 overexpression enhances the tolerance of both transgenic E. coli and tobacco BY-2 cells to NaCl and alkali stresses. PMID- 24341273 TI - [One-step fermentation converting glucose in gamma-aminobutyric acid by a recombinant Corynebacterium crenatum]. AB - OBJECTIVE: We constructed an integrative recombinant Corynebacterium crenatum that could directly convert glucose in gamma-aminobutyric acid (GABA). METHODS: Using overlap PCR, we obtained delta argB fragment that lacked 491 bp of N acetylglutamate kinase (NAGK) gene. The glutamate decarboxylase (GAD) gene attached tac promoter was amplified and inserted into delta argB fragment. Using the upstream and downstream of delta argB as homologous arms, we constructed pK18 delta argB::tacgad which was used for the integration of tacgad gene onto the C. crenatum genome. Through two homologous recombinations, we got an argB blocked strain C. crenatum delta argB::tacgad which could successfully express GAD. We also fermented the recombinant strain with glucose as substrate and the production of GABA was detected. RESULTS: In C. crenatum delta argB::tacgad, NAGK was totally inactivated and no L-arginine was detected though L-glutamic acid was accumulated. As a result of the efficient expression of GAD, part of L-glutamic acid was transformed into GABA, and the final yield of GABA was about 8.28 g/L. CONCLUSION: We successfully constructed a recombinant strain that could efficiently produce GABA by one-step fermentation from glucose. This research provided a new approach for GABA production. PMID- 24341274 TI - [Anti-diatom compounds from marine bacterium Pseudomonas putida]. AB - OBJECTIVE: In order to provide more natural antifouling compounds, marine bacterium Pseudomonas putida isolated from the sponge Haliclona sp. was explored to test its anti-diatom compounds. METHODS: The strain was identified by colonial morphology, scanning electron microscope (SEM) and 16S rDNA sequence analysis. The separation procedure was guided by bioactive (Anti-diatom) and chemical (TLC, DAD-HPLCand 1H NMR) analysis, and their structures were elucidated by spectrographic techniques. The anti-diatom activity of all purified compounds was assayed. RESULTS: Strain 272 isolated from the sponge Haliclona sp. was identified as Pseudomonas putida. Six diketopiperazine compounds were isolated from the culture of this strain and their structures were determined as cyclo(Leu Pro) (1), cyclo (Leu-Ala) (2), cyclo(Phe-Ala) (3), cyclo(Val-Tyr) (4), cyclo(Ala Tyr) (5), cyclo(Ala-Trp) (6); Compounds 3 and 6 displayed significant anti-diatom activity with the inhibitory rate of 50% and 85% at the concentration of 50 microg/mL, respectively. CONCLUSION: The anti-diatom compounds isolated from marine bacterium Pseudomonas putida were cyclo (Phe-Ala) and cyclo (Ala-Trp). PMID- 24341275 TI - [Cloning, expression and characterization of tRNA-isopentenyltransferase genes (tRNA-ipt) from paulownia witches'-broom phytoplasma]. AB - OBJECTIVE: To identify the tRNA-ipt gene of phytoplasmas and analyze the relationship between tRNA-ipt and synthesis of cytokinin as well as pathogenesis in phytoplasmas. METHODS: The paulownia witches'-broom phytoplasma (PaWB) tRNA ipt gene was expressed in E. coli and specific antibody was prepared. Then the growth curve and cytokinin contents of E. coli with PaWB tRNA-ipt were measured by photodensitometry and ELISA respectively. RESULTS: The length of tRNA-ipt genes from PaWB as well as mulberry dwarf, periwinkle virescence and Chinaberry witches'-broom phytoplasmas were 876 bp. All these genes encoded the proteins consisting of 291 amino acids. They contained and indentical motif (GPTASGKT) at N-terminal region related to the ATP or GTP binding sites. Four phytoplasma tRNA IPTs shared the 99.1-99.5%, amino acid sequence indentity with each other, shared 95.4-99.3% sequence identity with the same group phytoplasmas, whereas the less than 70% identity with 16SrX apple proliferation and 16SrXII Australia grapevine yellows phytoplasmas. The expression of the tRNA-IPT protein and localization in the phloem in phytoplasma-infected paulownia were confirmed by Western blotting and immunofluorescence detection. The determination of growth curve suggested that the growth rate increase of E. coli was affected by the transformation of exogenous tRNA-ipt gene,which might be associated with the cytokinin accumulation. CONCLUSION: This protein was assumed to be involved in the cytokinin synthesis in phytoplasmas as well as other bacteria, which may play an important role in pathogenic processes of phytoplasmas and symptom development. PMID- 24341276 TI - [Effect of antagonistic bacteria and soil disinfectant on soil bacterium community in banana Fusarium wilt disease area]. AB - OBJECTIVE: The objective of the present study is to elucidate the effects of the application of cake fertilizer fermentation fluid with antagonistic bacteria and soil disinfectant chlorine dioxide on the occurrence of banana fusarium wilt disease and soil bacterium community. METHOD: Under the field cultivation conditions, the Biolog and T-RFLP method was used to investigate the soil bacterium diversity and community features in different treatments at different periods. RESULT: The results show that both cake fertilizer fermentation fluid with antagonistic bacteria and soil disinfectant could reduce disease index of banana fusarium wilt disease significantly, the highest control effect could reach 60.82% with the combined application of these two methods. The result of Biolog eco plate shows that the application of cake fertilizer fermentation fluid with antagonistic bacteria could improve soil microbial AWCD (average well color development) and population uniformity, the use of soil disinfectant significantly reduced the soil microbial population's abundance and the uniformity. Principal component analysis shows that the soil microbial population using carbon source had an increasing trend throughout the banana growing season, the main carbon sources in the early stage were amino acids, carboxylic acids, amphiphilic compounds and carbohydrates, and the increased main carbon sources in the later stage were carboxylic acids and amphiphilic compounds. Soil bacterial diversity analysis by T-RFLP shows that the treatments of cake fertilizer fermentation fluid with antagonistic bacteria had the highest bacterial TRFs (Terminal restriction fragment) fragments, which resulted from the increase of Flavobacterium, Pseudomona and Lactobacillus population in the soil. CONCLUSION: The application of cake fertilizer fermentation fluid with antagonistic bacteria combining soil disinfectant could increase antagonistic microorganisms species, enhance soil microbial diversity, improve soil microbial ecological structure on the basis of reducing pathogen in soil, finally achieve the goal of improving the control effects of banana fusarium wilt disease. PMID- 24341277 TI - [Isolation of a methanol-utilizing strain and its application for determining methanol]. AB - OBJECTIVE: To isolate and characterize bacteria that can be used todevelop microbial biosensor for methanol (MeOH) determination. METHODS: We used selective medium and streak plate to isolate bacteria. Morphological, physiological characteristics and 16S rDNA sequence analysis were used to identify the strain. An MeOH biosensor was then developed by immobilizing M211 along with dissolved oxygen (O2) sensor. RESULT: An MeOH utilizing bacterium was isolated from biogas producing tank using methanol as the sole carbon source, and identified as Methylobacteriumorganophilium. Decrease of O2 concentration is linearly related to the MeOH concentration in the range from 0.02% to 1%, with the MeOH detection limit of 0.27 mg/L. The response time of the biosensor is within 20 min. Furthermore, the result of interference test and the detection of methanol sample are both satisfactory. CONCLUSION: Good results are obtained in interference test and the detection of methanol sample. The proposed method seems very attractive in monitoring methanol. PMID- 24341278 TI - [ESX-1 secreted protein ESAT-6 of Mycobacterium tuberculosis enhances the phagocytosis of RAW264.7 macrophages]. AB - OBJECTIVE: To investigate the effects of Mycobacterium tuberculosis ESX-1 protein early secreted antigenic target of 6 kDa (ESAT-6) in modulating phagocytosis of RAW264.7 cells. METHODS: RAW264.7 cells were transfected with recombinant plasmids pFLAG-ESAT-6 and pFLAG-EGFP by liposome. After screening with a high level of G418, the macrophage cell lines stably expressing flag-ESAT-6 or flag EGFP proteins were obtained. The cell lines were further identified by PCR, RT PCR and western blot. The phagocytosis of those cell lines was analyzed for ingested fluorescent beads by flow cytometry and for phagocytized Escherichia coli (E. coli) by colony count and confocalmicroscopy. RESULTS: We established successfully RAW-E6 cell line stably expressing flag-ESAT-6 and RAW-EGFP cell line stably expressing flag-EGFP. Flow cytometric analysis shows that the percentage of phagocytosis of RAW-E6 was higher than that of RAW264.7 and RAW EGFP. Colony count and confocal microscopy test also show that RAW-E6 had higher phagocytosis ability than RAW264.7 and RAW-EGFP. CONCLUSION: The secreted protein ESAT-6 can enhance the phagocytosis of macrophages, which provides new evidence to understand the pathogenesis of Mycobacterium tuberculosis. PMID- 24341279 TI - [IFN-alpha-induced gp96 upregulation negatively affects the anti-HBV efficiency of IFN-alpha]. AB - OBJECTIVE: To investigate the effect of the Interferon-alpha-induced gp96 upregulation on the anti-HBV efficiency of Interferon-alpha (IFN-alpha). METHODS: The effect of IFN-alpha on the transcription and expression of heat shock protein gp96 was determined by real-time PCR, luciferase reporter assay and Western blot. The effect of over-expression or knock-down of gp96 by transfection or RNA interference, and treatment with IFN-alpha on HBV expression and replication was examined by ELISA and RT-PCR. RESULTS: IFN-alpha treatment led to increased gp96 expression in a time- and dose-dependent manner. The overexpression of gp96 enhanced HBV expression and replication, whereas downregulation of gp96 resulted in decreased HBV replication. Finally, we verified that blocking IFN-alpha induced upregulation of gp96 significantly enhanced IFN-alpha-mediated HBV inhibitory effects. CONCLUSION: IFN-alpha-induced upregulation of gp96 may negatively affect the anti-HBV function of IFN-alpha. These data provide valuable insight for enhancing the antiviral efficacy of IFN-alpha by simultaneous inhibition of gp96. PMID- 24341280 TI - [Determination of the in vitro antiviral activity of an engineered M1GS ribozyme that targets to the core gene of hepatitis C virus]. AB - OBJECTIVE: Hepatitis C virus (HCV) is one of the major pathogens that lead to viral hepatitis. At present, Interferon treatment in combination with ribavirin is the first line clinical therapeutic approach. However, the responses are usually poor and the viral infection reoccurs. Therefore, exploring new antiviral agents and therapies is under urgent needs. METHODS: The sequence and structure of the core coding region of HCV genome were analyzed through the two computer software, DNAMAN and RNA Structure. The cytosine 52 nt downstream of the AUG initiation triplet was identified as the optimal target cleavage site. Based on the flanking sequence of this assumed cleavage site, a guide sequence (GS) was designed and covalently linked to the 3 prime terminus of the M1 RNA, which is catalytic subunit of the RNase P derived from Escherichia coli using PCR. We named this new targeting ribozyme M1GS-HCV/C52 and it antiviral activities were analyzed in cultured cells. RESULTS: In the in vitro cleavage assay, M1GS-HCV/C52 ribozyme could effectively cleave the HCV target RNA into two fragments at the specific cleavage site. Moreover, comparing to the blank control, this engineered M1GS ribozyme could reduce the core protein expression of more than 80% in the HCV-infected host cell and lead to a 1500-fold reduction of HCV RNA copies in the culture supernatant. An another M1GS ribozyme, M1GS-HCV/C52*, which has the same guide sequence but does not contain a 24nt-long bridge sequence, did not exhibit apparent inhibition for the expression of HCV core gene and viral proliferation in our paralleled assay. CONCLUSION: We successfully constructed an M1GS ribozyme showing affective and specific cleavage of target viral RNA. Further results showed that the engineering ribozyme had notably antiviral activity in cultured cells, thus provided a new promising approach for clinical anti-HCV therapeutic strategy. PMID- 24341281 TI - [Polysaccharides inhibiting cucumber mosaic virus and their influence on tobacco defensive enzyme activities]. AB - OBJECTIVE: Polysaccharides inhibiting cucumber mosaic virus (CMV) on tobacco were screened and their influence on tobacco defensive enzyme activities was explored. METHOD: We detected the deactivating, preventing and treating effect of 21 polysaccharides on CMV by half leaf method on Nitcotiana tabacum var. Samsun NN. We detected the variation of enzyme activity of Nitcotianatabacum var. NC89 handled by antiviral polysaccharide. RESULT: Results show that Marasmiu sandrosaceus polysaccharide had good deactivating and preventing effect on CMV. The preventing rate could reach 83.41% when the tobacco was dealt with the admixture of its 200-fold dilution and equivalent virus liquid for 30 min. The inhibition rate could reach 93.15% when the tobacco was inoculated after spraying with M. androsaceus polysaccharide for 24h. Moreover, the diversification of enzyme activity of tobacco-related was detected. Results show that peroxidase (POD) , polyphenol oxidase (PPO) andphenylalanine ammonia lyase (PAL) activities significantly enhanced. M. androsaceus polysaccharide sprayed on tobacco after inoculating CMV for 24h. Its enzyme activities increased. The peaksof POD, PPO and PAL activities ofthe treatment were 2.74, 3.45 and 2.82 times of the value of comparison, respectively. CONCLUSION: M. androsaceus polysaccharide can increase the resistance of tobacco on CMV by enhancing defense enzyme activity of tobacco. PMID- 24341282 TI - [Identification of lactic acid bacteria in commercial yogurt and their antibiotic resistance]. AB - OBJECTIVE: To identify lactic acid bacteria (LAB) in commercial yogurts and investigate their antibiotic resistance. METHODS: LABs were cultured from 5 yogurt brands and the isolates were identified at the species level by 16S rRNA sequence. Genotyping was performed by repetitive extragenic palindromic PCR (rep PCR). The sensitivity to 7 antibiotics was tested for all LAB isolates by Kirby Bauer paper diffusion (K-B method). Meanwhile, 9 antibiotic resistance genes (ARGs), including erythromycin resistance genes (ermA and ermB) and tetracycline resistance genes (tetM, tetK, tetS, tetQ, tetO, tetL and tetW), were detected by PCR amplification in the identified LAB isolates. The PCR products were confirmed by sequencing. RESULTS: Total 100 LABs were isolated, including 23 Lactobacillus delbrueckii ssp. bulgaricus, 26 Lactobacillus casei, 30 Streptococcus thermophilus, 5 Lactobacillus acidophilus, 6 Lactobacillus plantarum, and 10 Lactobacillus paracasei. The drug susceptibility test shows that all 100 isolates were resistant to gentamicin and streptomycin, 42 isolates were resistant to vancomycin, and on the contrary all were sensitive to cefalexin, erythromycin, tetracycline and oxytetracycline. Moreover, 5 ARGs were found in the 28 sequencing confirmed isolates, ermB gene was detected in 8 isolates, tet K in 4 isolates, tetL in 2 isolates, tetM in 4 isolates, tetO in 2 isolates. erm A, tet S, tet Q and tet W genes were not detected in the isolates. Antibiotic resistance genes were found in 53.57% (15/28) sequenced isolates, 2 -3 antibiotic resistance genes were detected in 4 isolates of L. delbrueckii ssp. bulgaricus. CONCLUSIONS: Some LABs were not labeled in commercial yogurt products. Antibiotic resistance genes tend to be found in the starter culture of L. delbrueckii ssp. Bulgaricus and S. thermophilus. All the LAB isolates were sensitive to erythromycin and tetracycline, even though some carried erythromycin and/or tetracycline resistance genes. We proved again that LAB could carry antibiotic resistance gene(s) though it is sensitive to antibiotics. PMID- 24341283 TI - Ground-state kinetics of bistable redox-active donor-acceptor mechanically interlocked molecules. AB - The ability to design and confer control over the kinetics of theprocesses involved in the mechanisms of artificial molecular machines is at the heart of the challenge to create ones that can carry out useful work on their environment, just as Nature is wont to do. As one of the more promising forerunners of prototypical artificial molecular machines, chemists have developed bistable redox-active donor-acceptor mechanically interlocked molecules (MIMs) over the past couple of decades. These bistable MIMs generally come in the form of [2]rotaxanes, molecular compounds that constitute a ring mechanically interlocked around a dumbbell-shaped component, or [2]catenanes, which are composed of two mechanically interlocked rings. As a result of their interlocked nature, bistable MIMs possess the inherent propensity to express controllable intramolecular, large-amplitude, and reversible motions in response to redox stimuli. In this Account, we rationalize the kinetic behavior in the ground state for a large assortment of these types of bistable MIMs, including both rotaxanes and catenanes. These structures have proven useful in a variety of applications ranging from drug delivery to molecular electronic devices. These bistable donor acceptor MIMs can switch between two different isomeric states. The favored isomer, known as the ground-state co-conformation (GSCC) is in equilibrium with the less favored metastable state co-conformation (MSCC). The forward (kf) and backward (kb) rate constants associated with this ground-state equilibrium are intimately connected to each other through the ground-state distribution constant, KGS. Knowing the rate constants that govern the kinetics and bring about the equilibration between the MSCC and GSCC, allows researchers to understand the operation of these bistable MIMs in a device setting and apply them toward the construction of artificial molecular machines. The three biggest influences on the ground-state rate constants arise from (i) ground-state effects, the energy required to breakup the noncovalent bonding interactions that stabilize either the GSCC or MSCC, (ii) spacer effects, where the structures overcome additional barriers, either steric or electrostatic or both, en route from one co-conformation to the other, and (iii) the physical environment of the bistable MIMs. By managing all three of these effects, chemists can vary these rate constants over many orders of magnitude. We also discuss progress toward achieving mechanostereoselective motion, a key principle in the design and realization of artificial molecular machines capable of doing work at the molecular level, by the strategic implementation of free energy barriers to intramolecular motion. PMID- 24341285 TI - Orientation and alignment in reactive beam collisions: recent progress. AB - The concept of directional axis distributions and orientation-dependent reaction cross sections is used to describe the effect of the mutual orientation of reagents on the outcome of reactive beam collisions. The axis distributions and cross sections are expanded in series of Legendre polynomials and real spherical harmonics, respectively, and characterized by the expansion coefficients (moments). The interrelations between the moments of the cross sections and the directionally dependent experimental data (steric effects) on the one hand and the anisotropic properties of the potential energy surfaces on the other hand are presented. Recent progress in the field of dynamical stereochemistry results from the prep- aration of molecular orientation and alignment by using the novel brute force technique and an optical method, respectively. The theories of both methods are summarized, and typical experimental arrangements are presented. All experimental results based on these techniques are reviewed. Among the most important ones are the first orientation effects observed in a reaction with a (1)Sigma: molecule (K + ICl) and the alignment effects found in the bench mark reaction Li + HF -> LiF + H. PMID- 24341286 TI - Global perspectives on resilience in children and youth. AB - Global concerns about the consequences of disasters, political violence, disease, malnutrition, maltreatment, and other threats to human development and well-being have sparked a surge of international interest in resilience science. This article highlights progress and issues in research that aims to understand variations in human adaptation to adverse experiences. Two key questions are considered: Why is a new wave of global research on resilience important for developmental science? and Why is developmental science important for global resilience? The conclusion calls for developmental scientists to engage in international efforts to promote resilience. PMID- 24341287 TI - In vitro effects of cilostazol, a phosphodiesterase 3A inhibitor, on mouse oocyte maturation and morphology. AB - Inhibition of phosphodiesterase 3A (PDE3A) in oocytes has been reported to arrest oocyte maturation and to increase intra-oocyte cyclic adenosine monophosphate levels. Although many PDE3A inhibitors have been found to arrest oocyte maturation in different species, including humans, the most commonly prescribed PDE3A inhibitor named cilostazol (CLZ) has not yet been fully evaluated in reproduction. The present study was designed to investigate the potential inhibitory effects of CLZ on oocyte maturation and morphology in vitro. Antral oocytes were recovered from hyperstimulated mice and allocated to 10 different CLZ concentrations (0.00-67.66 MUmol/L). Oocytes were then assessed after 24 and 48 h of incubation for maturation and morphology. Some of the evaluated CLZ concentrations (1.06-4.23 MUmol/L) were made similar to those observed in human clinical trials. CLZ arrested oocyte maturation at the germinal vesicle (GV) stage at concentrations as low as 1.06 MUmol/L (P < 0.0001). A selective degenerative impact of CLZ targeting arrested oocytes at the GV stage was observed during 24 h of incubation (r = -0.781, P < 0.0001). This was not the case with non-arrested oocytes (r = -0.082, P = 0.64). Such degenerative impact was dose-dependent (P < 0.0001), suggesting a role for cyclic adenosine monophosphate in this degenerative process. The degenerated oocytes were of distorted oolema or fragmented cytoplasm. Based on the experiments, it is concluded that CLZ can inhibit oocyte maturation in vitro, at concentrations similar to those observed in humans taking CLZ, and under such conditions the prolonged maintenance of oocytes at the GV stage is harmful. PMID- 24341288 TI - Reliability tests and validation tests of the client satisfaction questionnaire (CSQ-8) as an index of satisfaction with childbirth-related care among Filipino women. AB - BACKGROUND: Satisfaction is an important indicator of the quality of care during childbirth. Previous research found that a good environment at a health facility can increase the number of deliveries at that facility. In contrast, an unsatisfying childbirth experience could cause postpartum mental disorder. Therefore it is important to measure mothers' satisfaction with their childbirth experiences. We tested whether the eight-item Client Satisfaction Questionnaire (CSQ-8) provided useful information about satisfaction with childbirth-related care. The government of the Philippines promotes childbirth at health facilities, so we tested the CSQ-8 in the Philippine cities of Ormoc and Palo. METHODS: This was a cross-sectional study. We targeted multigravid mothers whose last baby had been delivered at a hospital (without complications) and whose 2nd-to-last baby had been delivered at a hospital or at home (without complications). We developed versions of the CSQ-8 in Cebuano and Waray, which are two of the six major Filipino languages. Reliability tests and validation tests were done with data from 100 Cebuano-speaking mothers and 106 Waray-speaking mothers. RESULTS: Both the Cebuano and Waray versions of the CSQ-8 had high coefficients of internal consistency reliability (greater than 0.80). Both versions were also unidimensional, which is generally consistent with the English CSQ-8 in a mental health setting. As hypothesized, the scores for data regarding the second-to-last delivery were higher for mothers who had both their second-to-last and their last delivery in a hospital, than for mothers who had their second-to-last delivery at home and their last delivery in a hospital (Cebuano: p < 0.001, rho = 0.51, Waray: p < 0.001, rho = 0.55). CONCLUSIONS: Scores on the CSQ-8 can be used as indices of general satisfaction with childbirth-related services in clinical settings. This study also exemplifies a convenient method for developing versions of the CSQ-8 in more than one language. These versions of the CSQ-8 can now be used to assess mothers' satisfaction, so that mothers' opinions can be taken into account in efforts to improve childbirth-related services, which could increase the proportion of deliveries in medical facilities and thus reduce maternal mortality. PMID- 24341290 TI - Evaluation of a stranger safety training programme for adults with Williams syndrome. AB - BACKGROUND: Individuals with Williams syndrome (WS) are reported to display increased sociability towards strangers, leading to increased social vulnerability. No research has examined real life interactions of adults with WS towards strangers and no interventions have been implemented to teach stranger safety skills to this population. METHOD: Twenty-one adults with WS participated in 3 days of behaviour skills training to learn how to respond to a stranger lure. Skill acquisition was assessed in situ; confederate strangers approached participants, presented a lure and recorded the participants' response. RESULTS: Prior to intervention, 14% of participants walked away from a stranger. Participants were able to accurately use the skills in role play. After training, 62% of participants said 'no' and walked away and only 14% agreed to leave with the stranger during in situ assessments. CONCLUSIONS: Individuals with WS are at risk but can learn how to appropriately respond to lures from strangers. Further research is needed to increase use of safety skills in various conditions. PMID- 24341289 TI - The peripheral blood transcriptome reflects variations in immunity traits in swine: towards the identification of biomarkers. AB - BACKGROUND: Immune traits (ITs) are potentially relevant criteria to characterize an individual's immune response. Our aim was to investigate whether the peripheral blood transcriptome can provide a significant and comprehensive view of IT variations in pig. RESULTS: Sixty-day-old Large White pigs classified as extreme for in vitro production of IL2, IL10, IFNgamma and TNFalpha, phagocytosis activity, in vivo CD4-/CD8+ or TCRgammadelta + cell counts, and anti-Mycoplasma antibody levels were chosen to perform a blood transcriptome analysis with a porcine generic array enriched with immunity-related genes. Differentially expressed (DE) genes for in vitro production of IL2 and IL10, phagocytosis activity and CD4-/CD8+ cell counts were identified. Gene set enrichment analysis revealed a significant over-representation of immune response functions. To validate the microarray-based results, a subset of DE genes was confirmed by RT qPCR. An independent set of 74 animals was used to validate the covariation between gene expression levels and ITs. Five potential gene biomarkers were found for prediction of IL2 (RALGDS), phagocytosis (ALOX12) or CD4-/CD8+ cell count (GNLY, KLRG1 and CX3CR1). On average, these biomarkers performed with a sensitivity of 79% and a specificity of 86%. CONCLUSIONS: Our results confirmed that gene expression profiling in blood represents a relevant molecular phenotype to refine ITs in pig and to identify potential biomarkers that can provide new insights into immune response analysis. PMID- 24341292 TI - The influence of circulating anti-Mullerian hormone on ovarian responsiveness to ovulation induction with gonadotrophins in women with polycystic ovarian syndrome: a pilot study. AB - BACKGROUND: Women with polycystic ovarian syndrome (PCOS) are known to have elevated circulating Anti-Mullerian hormone (AMH), which has been found to desensitize ovarian follicles to follicle stimulating hormone (FSH). The purpose of this study was to investigate the impact of high circulating AMH on ovarian responsiveness to ovulation induction with gonadotrophins in PCOS women. METHODS: This prospective observational pilot study was conducted in two collaborating Fertility Centres in the UK and Egypt. The study included 20 consecutive anovulatory women with PCOS who underwent 34 cycles of human menopausal gonadotrophin (hMG) ovarian stimulation using chronic low-dose step up protocol. Blood samples were collected for the measurement of serum AMH concentrations in the early follicular (day 2-3) phase in all cycles of hMG treatment. The serum levels of AMH were compared between cycles with good vs. poor response. The good response rates and the total dose and duration of hMG treatment were compared between cycles with high vs. low serum AMH concentrations. RESULTS: Cycles with poor response (no or delayed ovulation requiring >20 days of hMG treatment) had significantly (p = .007) higher median{range} serum AMH concentration (6.5{3.2 13.4}ng/ml) compared to that (4.0{2.2-10.2}ng/ml) of cycles with good response (ovulation within 20 days of hMG treatment). ROC curve showed AMH to be a useful predictor of poor response to hMG stimulation (AUC, 0.772; P = 0.007). Using a cut-off level of 4.7 ng/ml, AMH had a sensitivity of 100% and specificity of 58% in predicting poor response. The good response rate was significantly (p < .001) greater in cycles with lower AMH (<4.7 ng/ml) compared to that in those with AMH > = 4.7 ng/ml (100% vs. 35%, respectively). All cycles with markedly raised serum AMH levels (> 10.2 ng/ml) were associated with poor response. Cycles with high AMH (> = 4.7 ng/ml) required significantly (p < .001) greater amounts (median {range}, 1087{450-1650}IU) and longer duration (20 {12-30}days) of hMG stimulation than cycles with lower AMH (525 {225-900}IU and 8{6-14}days). CONCLUSIONS: PCOS women with markedly raised circulating AMH seem to be resistant to hMG ovulation induction and may require a higher starting dose. PMID- 24341293 TI - Echocardiography in patients with complications related to pacemakers and cardiac defibrillators. AB - The evolving indications and uses for implantable cardiac devices have led to a significant increase in the number of implanted devices each year. Implantation of endocardial leads for permanent pacemakers and cardiac defibrillators can cause many delayed complications. Complications may be mechanical and related to the interaction of the device leads with the valves and endomyocardium, e.g., perforation, infection, and thrombosis, or due to the electrical pacing of the myocardium and conduction abnormalities, e.g., left ventricular dyssynchrony. Tricuspid regurgitation, another delayed complication in these patients, may be secondary to both mechanical and pacing effects of the device leads. Echocardiography plays an important role in the diagnosis of these device-related complications. Both two-dimensional transthoracic echocardiography and transesophageal echocardiography provide useful diagnostic information. Real time three-dimensional echocardiography is a novel technique that can further enhance the detection of lead-related complications. PMID- 24341294 TI - Accuracy of endoscopic intraoperative assessment of urologic stone size. AB - INTRODUCTION: Endoscopic treatment of renal calculi relies on surgeon assessment of residual stone fragment size for either basket removal or for the passage of fragments postoperatively. We therefore sought to determine the accuracy of endoscopic assessment of renal calculi size. MATERIALS AND METHODS: Between January and May 2013, five board-certified endourologists participated in an ex vivo artificial endoscopic simulation. A total of 10 stones (pebbles) were measured (mm) by nonparticipating urologist (N.D.P.) with electronic calibers and placed into separate labeled opaque test tubes to prevent visualization of the stones through the side of the tube. Endourologists were blinded to the actual size of the stones. A flexible digital ureteroscope with a 200-MUm core sized laser fiber in the working channel as a size reference was placed through the ureteroscope into the test tube to estimate the stone size (mm). Accuracy was determined by obtaining the correlation coefficient (r) and constructing an Altman-Bland plot. RESULTS: Endourologists tended to overestimate actual stone size by a margin of 0.05 mm. The Pearson correlation coefficient was r=0.924, with a p-value<0.01. The estimation of small stones (<4 mm) had a greater accuracy than large stones (>=4 mm), r=0.911 vs r=0.666. Altman-bland plot analysis suggests that surgeons are able to accurately estimate stone size within a range of -1.8 to +1.9 mm. CONCLUSIONS: This ex vivo simulation study demonstrates that endoscopic assessment is reliable when assessing stone size. On average, there was a slight tendency to overestimate stone size by 0.05 mm. Most endourologists could visually estimate stone size within 2 mm of the actual size. These findings could be generalized to state that endourologists are accurately able to intraoperatively assess residual stone fragment size to guide decision making. PMID- 24341295 TI - The slow death of print. PMID- 24341296 TI - Invasive pneumococcal disease in children: cross-disciplinary frameworks. PMID- 24341297 TI - Dietary advice, weight loss and exercise: addressing non-adherence by diabetic patients. PMID- 24341298 TI - Neurotrauma - a multidisciplinary disease. AB - Traumatic brain injury is one of the most important diseases of our time, both in terms of morbidity, mortality and economic loss. Public health policy is key to reducing its incidence. Integrated multidisciplinary clinical care is vital to minimise its morbidity and mortality. PMID- 24341299 TI - Antifungal step-down therapy based on hospital intravenous to oral switch policy and susceptibility testing in adult patients with candidaemia: a single centre experience. AB - AIMS: Echinocandins are recommended for the treatment of candidaemia in moderately severe to severely ill patients. Step-down or de-escalation from echinocandin to fluconazole is advised in patients who are clinically stable but data in relation to step-down therapy are sparse. Using our hospital intravenous to oral switch therapy (IVOST) policy to guide antifungal de-escalation in patients with candidaemia, we aimed to determine what proportion of patients are de-escalated to fluconazole, the timescale to step-down, associated reduction in consumption of echinocandins and antifungal cost savings. METHODOLOGY: Patients with candidaemia were followed from April 2011 to March 2013. RESULTS: A total of 37 episodes of candidaemia were documented during the study period. Twenty-seven patients were commenced on an echinocandin or voriconazole and 19 (70.3%) were de escalated to fluconazole based on the IVOST policy. The mean and median number of days to de-escalation of therapy was 4.6 and 5 days, respectively. One patient whose therapy was de-escalated relapsed. The overall 30 day crude mortality was 37.1%. The step-down approach led to significant saving in antifungal drug cost of L1133.88 per candidaemic episode and L2208.08 per de-escalation. CONCLUSION: Implementation of IVOST policy led to streamlining of antifungal therapy. PMID- 24341301 TI - A randomised, double-blind, placebo-controlled, duloxetine-referenced study of the efficacy and tolerability of vortioxetine in the acute treatment of adults with generalised anxiety disorder. AB - AIMS: This study aims to evaluate the efficacy and tolerability of vortioxetine 2.5-, 5- and 10-mg once-daily doses vs. placebo in the treatment of generalised anxiety disorder (GAD). METHODS: In this 8-week, multicentre, double-blind, placebo-controlled, parallel-group, phase 3 study, patients with a primary GAD diagnosis were randomised to receive placebo (n = 157), vortioxetine 2.5 mg, vortioxetine 5 mg, vortioxetine 10 mg or duloxetine 60 mg once daily (n = 156 each). The primary end-point, mean change from baseline in Hamilton Anxiety Scale (HAM-A) total score and key secondary end-points for the 5- and 10-mg vortioxetine doses were analysed in a prespecified sequential testing procedure (all at week 8). Sexual dysfunction was evaluated using the Arizona Sexual Experiences Scale. RESULTS: Differences from placebo in the primary efficacy end point were not statistically significant for the vortioxetine groups. The mean difference from placebo was significant in the duloxetine arm. For all secondary efficacy end-points, results were similar among the vortioxetine groups and did not reach statistical significance. The vortioxetine 10-mg group showed separation from placebo on the Hospital Anxiety and Depression anxiety subscore (nominal p = 0.036). Duloxetine 60 mg significantly improved the primary end point (p < 0.05 vs. placebo), validating the study. Nausea, dry mouth, diarrhoea, nasopharyngitis, headache, dizziness, somnolence, vomiting, dyspepsia, constipation and fatigue were reported in >= 5% of patients receiving vortioxetine. Rates of treatment-emergent sexual dysfunction (TESD) in the vortioxetine dosing groups were similar to placebo. CONCLUSION: In this study, vortioxetine 2.5-, 5- and 10-mg once-daily doses showed no significant improvement in HAM-A total scores vs. placebo. Vortioxetine was well tolerated at all doses and was not associated with TESD. PMID- 24341302 TI - Evaluation of the psychometric characteristics of the Spanish version of the Anorectic Behaviour Observation Scale. AB - AIMS: The Anorectic Behaviour Observation Scale (ABOS) was designed to obtain information from relatives about behaviours and attitudes of patients with eating disorders (ED). The aim of this study was to validate the ABOS into Spanish. METHODS: We evaluated the psychometric characteristics of the Spanish version of the ABOS in a clinical ED sample (239 caregivers of 143 ED patients). Instrument reliability (internal consistency), validity (construct, convergent and discriminant, known groups), responsiveness and goodness-of-fit were measured. RESULTS: Data from the Spanish population revealed a three-factor structure similar to that of the original ABOS, although the composition of subscales differed somewhat from the original. An ABOS cut-point of 21 was identified. The Cronbach's alpha coefficient for the total ABOS score was 0.81. Correlations with other instruments demonstrated convergent and divergent validity. Among caregivers, the total ABOS score and Factor scores significantly discriminated between anxiety, depression and health-related quality of life, while among ED patients they discriminated between diagnosis, severity and level of ED symptoms evidence of known-groups validity. CONCLUSION: These findings suggest that the ABOS can be reliably and validly used in Spain in a number of different clinical contexts, by researchers and clinicians alike. PMID- 24341303 TI - Tadalafil - a therapeutic option in the management of BPH-LUTS. AB - BACKGROUND/AIMS: Men with signs of benign prostatic hyperplasia (BPH) may experience lower urinary tract symptoms (LUTS) such as urinary frequency, urgency, intermittence, nocturia, straining, incomplete emptying or a weak urinary stream. The effective management of LUTS suggestive of BPH (BPH-LUTS) requires careful consideration of several factors, including the severity of a patient's symptoms, concurrent or other coexisting medical conditions, the ability to improve symptoms and impact quality of life (QOL), as well as the potential side effects of available treatment options. Several clinical studies have assessed phosphodiesterase type 5 (PDE5) inhibitors in reducing LUTS; however, tadalafil is the only PDE5 inhibitor approved for the treatment of signs and symptoms of BPH, as well as in men with both erectile dysfunction (ED) and the signs and symptoms of BPH. This review examined articles that assessed tadalafil in patients with signs and symptoms of BPH, with or without erectile dysfunction (ED), which led to regulatory approval in the United States and Europe. RESULTS: In dose-ranging and confirmatory studies, results demonstrate that tadalafil significantly improved total International Prostate Symptom Score (IPSS) following 12 weeks of treatment with once daily tadalafil 5 mg. Statistically significant improvements in Benign Prostatic Hyperplasia Impact Index (BII), IPSS subscores, IPSS QOL and International Index of Erectile Function (IIEF) were also observed. Improvement in urinary symptoms occurred regardless of age, previous treatment with an alpha1 -adrenergic blocker, BPH LUTS severity at baseline or ED status. CONCLUSIONS: While tadalafil is most frequently recognised as a standard treatment option for men with ED, it also represents a well-tolerated and effective treatment option in men with moderate to severe BPH-LUTS. PMID- 24341304 TI - Hypomagnesaemia in patients hospitalised in internal medicine is associated with increased mortality. AB - BACKGROUND: Magnesium is the major intracellular divalent cation. Hypomagnesaemia is common among critically ill patients; it's prevalence is not known in patients admitted to general internal medicine. We sought to quantify hypomagnesaemia, and attempted to correlate it with clinical outcomes in internal medicine patients. MATERIALS AND METHODS: Retrospective chart review. Hypomagnesaemic patients admitted from 1 October 2010 through 18 November 2010 compared with normomagnesaemic patients. Laboratory tests, medical and demographic data were analysed. RESULTS: In 627 consecutive admissions, overall frequency of hypomagnesaemia was 20.1% (87 patients). Hypomagnesaemic patients were a little older (mean age of 75) and more likely to be women (62%). There was a significant difference in mortality between the normomagnesaemic group (7.2%) and the hypomagnesaemic group (17.2%) (p = 0.0067). There was also a significant difference for length of stay (5.00 +/- 5.3 vs. 7.0 +/- 8.2, p = 0.0001). CONCLUSION: The prevalence of hypomagnesaemia in internal medicine is very high. It is associated with higher mortality and longer hospital stay in our population. It can be a useful tool in predicting morbidity and mortality. Although no causal role can be defined for it at present, the low cost and minimal discomfort of measuring magnesium justifies its routine measurement and replacement in patients hospitalised in internal medicine. PMID- 24341305 TI - Screening electrocardiograms in psychiatric research: implications for physicians and healthy volunteers. AB - AIMS: While there is controversy regarding utility of screening electrocardiograms (ECGs) in competitive athletes and children exposed to psychostimulants, there is no data on the use of screening ECGs in psychiatric research. We aimed to examine the prevalence and clinical significance of ECG abnormalities and their impact on eligibility for studies. METHODS: We analysed 500 consecutive ECG reports from physically healthy volunteers who had a negative cardiac history, normal cardiovascular examination and no other significant medical illnesses. For the purpose of this report, all ECGs were over-read by one cardiologist. RESULTS: The mean age of our cohort was 28.3 +/- 8.0 years. A total of 112 (22.4%) ECGs were reported as abnormal (14.2%) or borderline (8.2%). These abnormalities were considered clinically insignificant in all but eight subjects (1.6%) who underwent evaluation with an echocardiogram. All echocardiograms were normal. No subject was excluded from studies. After the over-reading, no abnormalities or isolated bradycardia were present in 37 of 112 (33%) ECGs that were initially reported as abnormal or borderline, while minor abnormalities were found in 7 of 204 (3.4%) ECGs that were reported as normal. CONCLUSIONS: Although screening ECGs did not detect significant cardiac pathology or affect eligibility for our studies, over 20% of subjects were labelled as having an abnormal or borderline ECG which was incorrect in one-third of cases. Strategies to minimise unintended consequences of screening are discussed. PMID- 24341306 TI - The prognostic implications of lack of palpitations in patients hospitalised with atrial fibrillation: observations from a 20-year registry. AB - OBJECTIVES: It is well recognised that patients differ in the clinical presentation of atrial fibrillation (AF), ranging from the typical symptom of palpitations, atypical symptoms in others and a substantial that are asymptomatic. Whether the different patterns of presentation are associated with differences in outcomes is not known. The aim of this study was to evaluate the prevalence and the prognostic implications of lack of palpitations among patients hospitalised with AF in a large prospective registry. METHODS: Retrospective analysis of all patients hospitalised with AF in Qatar from 1991 to 2010 was made. Patients were divided into two groups according to the presence or absence of palpitations on presentation. Clinical characteristics and outcome were analysed. RESULTS: During the 20-year period, 3850 patients were hospitalised for AF; 1724 (44.8%) had palpitations on presentation while 2126 (55.2%) had no palpitations. Patients who lacked palpitations were 9 years older, had a higher prevalence of diabetes mellitus (64.7% vs. 35.3%), underlying coronary artery disease (CAD; 14.6% vs. 6.2%) and severe left ventricular dysfunction on echocardiography (25.5% vs. 6.6%), (all, p = 0.001). There were 141 deaths among the group with no palpitations compared with 19 among the group with palpitations (6.6% vs. 1.1%). Multivariate analysis of mortality predictors identified 'lack of palpitations' as an independent predictor of in-hospital mortality (relative risk 5.56; 95% confidence interval 1.20-25.0, p = 0.03). CONCLUSIONS: Our study demonstrates for the first time that lack of palpitations as the presenting symptom of patients with AF is associated with worse in-hospital outcome independent of other risk factors or therapy. The underlying mechanisms and the role of confounders warrant further investigation. PMID- 24341300 TI - Glycaemic control and implementation of the ADA/EASD-2006 consensus algorithm in type 2 diabetes mellitus patients in primary care in Spain. AB - BACKGROUND: In 2006, the American Diabetes Association and the European Association for the Study of Diabetes established a consensus algorithm (ADA/EASD 2006) for the adjustment of drug therapy for type 2 diabetes mellitus (T2DM). AIMS: To study glycaemic control in T2DM patients and the implementation of the ADA/EASD-2006 recommendations in primary care centres in Spain. METHODS: Prospective observational study in 1194 patients with T2DM conducted in 250 primary care centres in Spain. Patients were assessed at study inclusion (V0) and at 3 (V1) and 6 months (V2) post baseline. Information was collected at the level of DM control, HbA(1c) < 7% (HbC) and implementation of the ADA/EASD-2006 guidelines. RESULTS: Type 2 diabetes mellitus patients (53% women; mean age 64.9 years) had a mean (SD) HbA(1c) 7.8 (1.4)% and HbC 25.2% at baseline, 95% of them were receiving oral antihyperglycaemic agents (AAs) only. At V1, HbA(1c) was 7.3 (1.1)% and HbC was 38.1%; 65.0% of patients were receiving oral AAs, 5.6% insulin and 27.9% oral AAs plus insulin. At V2, HbA(1c) was 7.1 (0.9)% and HbC was 48.0%; 57.1% of patients were receiving oral AAs, 5.0% insulin and 36.9% oral AAs plus insulin. The ADA/EASD-2006 algorithm was adhered to in 33% patients up to study month 3, vs. 17.2% throughout the entire 6-month period. CONCLUSION: In patients with T2DM seen in primary care, the HbA1c target was met in 48.0% after adjusting their AAs. However, this is not reflected in greater implementation of the ADA/EASD-2006 guidelines, which are adhered to in only 17%. PMID- 24341307 TI - The clinical significance of anaemia and disturbed iron homeostasis in chronic respiratory failure. AB - BACKGROUND: Anaemia is a frequent, clinically relevant condition in various chronic diseases. It seems also to be prevalent in patients with chronic respiratory failure (CRF). We studied the characteristics of anaemia in CRF and its associations with clinical outcome. METHODS: In a prospective design, 271 consecutive patients with CRF were evaluated; patients with other conditions often associated with anaemia were excluded. Haematological laboratory and physiological parameters, health-related quality of life (HRQL), dyspnoea and 48 month survival were determined. Anaemia was defined according to WHO [haemoglobin (Hb)< 13 g/l (male); Hb< 12 g/dl (female)] and using an established algorithm. RESULTS: Among 185 patients included, 18.4% showed anaemia, not depending on chronic obstructive pulmonary disease (COPD) vs. non-COPD (17.6% vs. 19.0%; p = 0.851) or on gender [16.5% (female) vs. 19.8% (male); p = 0.702]. Anaemic patients had higher age, creatinine (p < 0.05 each) and erythropoietin levels (p < 0.001), but lower transferrin saturation (TSAT), serum iron and vitamin B12 levels (p < 0.01 each). By definition, most anaemic patients (67.6%) had disturbances in iron homeostasis according to 'anaemia of chronic disease' and/or true iron deficiency anaemia. Hb was independently related to dyspnoea and HRQL, while TSAT >= 20% was linked to less dyspnoea and better subjective exercise capability. Non-survivors had lower Hb and serum iron levels (p < 0.05 each). In multivariate analysis, lower serum iron levels and TSAT were independently associated with mortality (p < 0.05 each). CONCLUSION: Anaemia was common in patients with CRF and often because of disturbed iron homeostasis. Hb and TSAT were linked to functional outcome and HRQL. Lower serum iron levels and TSAT were independent prognostic parameters. PMID- 24341308 TI - Thirty-day readmission rates and hospital quality. PMID- 24341309 TI - Predictors of exacerbations in COPD patients: the role of anaemia. PMID- 24341310 TI - Predictors of exacerbations in COPD patients: the role of anaemia - a reply. PMID- 24341311 TI - Patient satisfaction with specialized mental health service for obsessive compulsive disorder. AB - BACKGROUND: Patient satisfaction is an important outcome variable that is increasingly used in mental health service evaluation. There are no results available for patients with obsessive-compulsive disorder (OCD) yet. METHODS: Using the Verona Service Satisfaction Scale, patient satisfaction with a specialized mental health service was examined in patients with OCD. RESULTS: OCD patients were overall satisfied with the professional help provided, whereas satisfaction with the professional involvement of relatives within the treatment and health care process was found to be quite low. Patients with more severe OCD, as measured by the Yale-Brown Obsessive-Compulsive Scale, as well as chronically ill and more disabled patients were more likely to be dissatisfied with the overall care they received. Patient satisfaction plays an important role in the long-term course of an illness such OCD. This seems to be decreased so longer illness is not or badly treated. There is a stronger need for involvement of family members in the treatment and health care of patients with OCD. CONCLUSIONS: More OCD-specific treatment offers have to be established for patients with this long-term illness such as psychotherapy in groups. PMID- 24341312 TI - Predicting cadmium accumulation and toxicity in a green alga in the presence of varying essential element concentrations using a biotic ligand model. AB - This study refines the Biotic Ligand Model (BLM) approach by integrating the modulating effects of various essential elements on cadmium (Cd) uptake kinetics in the freshwater alga Chlamydomonas reinhardtii. The algae were first acclimated to a low (LM) or high trace metal (HM) medium as well as to low or high free Cd(2+) and Co(2+) concentrations. The short-term Cd transport capacity and affinity were then quantified in exposure media in which essential trace metals and calcium concentrations were manipulated. The results show that after acclimation to the LM medium, exposure to high free Ca(2+) decreases the capacity of the Cd transport system. Also, acclimation to high (10(-9) M free Co(2+)) or low (10(-11) M free Co(2+)) did not significantly affect Cd uptake rates. When all essential trace metals were simultaneously increased in the acclimation (and exposure) medium, the capacity of the transport system decreased by ~ 60%, a decrease close to that due to high [Zn(2+)] alone, suggesting that Zn is the main trace metal modulator of the Cd transporter capacity. Changes in Cd toxicity (growth inhibition) in the presence of different essential trace metal concentrations were strongly related to the steady-state concentration of intracellular cadmium, regardless of the cell's nutritional state. Our BLM incorporating the physiological effects of Ca(2+) and other trace metals predicts steady-state Cd accumulation in the presence of varying concentrations of essential elements at 7 nM free Cd(2+), but predictions over a wide range of free [Cd(2+)] proved to be more difficult. PMID- 24341314 TI - Superoxide signaling in perivascular adipose tissue promotes age-related artery stiffness. AB - We tested the hypothesis that superoxide signaling within aortic perivascular adipose tissue (PVAT) contributes to large elastic artery stiffening in old mice. Young (4-6 months), old (26-28 months), and old treated with 4-Hydroxy-2,2,6,6 tetramethylpiperidine 1-oxyl (TEMPOL), a superoxide scavenger (1 mm in drinking water for 3 weeks), male C57BL6/N mice were studied. Compared with young, old had greater large artery stiffness assessed by aortic pulse wave velocity (aPWV, 436 +/- 9 vs. 344 +/- 5 cm s(-1)) and intrinsic mechanical testing (3821 +/- 427 vs. 1925 +/- 271 kPa) (both P < 0.05). TEMPOL treatment in old reversed both measures of arterial stiffness. Aortic PVAT superoxide production was greater in old (P < 0.05 vs. Y), which was normalized with TEMPOL. Compared with young, old controls had greater pro-inflammatory proteins in PVAT-conditioned media (P < 0.05). Young recipient mice transplanted with PVAT from old compared with young donors for 8 weeks had greater aPWV (409 +/- 7 vs. 342 +/- 8 cm s(-1)) and intrinsic mechanical properties (3197 +/- 647 vs. 1889 +/- 520 kPa) (both P < 0.05), which was abolished with TEMPOL supplementation in old donors. Tissue-cultured aortic segments from old in the presence of PVAT had greater mechanical stiffening compared with old cultured in the absence of PVAT and old with PVAT and TEMPOL (both, P < 0.05). In addition, PVAT-derived superoxide was associated with arterial wall hypertrophy and greater adventitial collagen I expression with aging that was attenuated by TEMPOL. Aging or TEMPOL treatment did not affect blood pressure. Our findings provide evidence for greater age-related superoxide production and pro-inflammatory proteins in PVAT, and directly link superoxide signaling in PVAT to large elastic artery stiffness. PMID- 24341313 TI - Short stimulation of electro-responsive PAA/fibrin hydrogel induces collagen production. AB - Acrylic acid/fibrin hydrogel can mechanically stimulate cells when an external electrical field is applied, enabling them to migrate and align throughout the depth of the gel. The ability of electro-responsive polyacrylic acid (PAA)/fibrin hydrogel to promote collagen production and remodeling has been investigated by three-dimensional (3D) culturing and conditioning of smooth muscle cells (SMCs). SMCs-seeded hydrogels were subjected to an alternating electrical field (0.06 V/mm) for 2 h for one, two, or three times per week during 4 weeks of culturing. Fluorescent images of collagen structure and accumulation, assessed by CNA-35 probe, showed increased collagen content (>100-fold at 1* stimulation/week) in the center of the hydrogels after 4 weeks of culture. The increase in collagen production correlated with increasing extracellular matrix gene expression and resulted in significantly improved mechanical properties of the stimulated hydrogels. Matrix metalloproteinase (MMP)-2 activity was also significantly enhanced by stimulation, which probably has a role in the reorganization of the collagen. Short stimulation (2 h) induced a favorable response in the cells and enhanced tissue formation and integrity of the scaffold by inducing collagen production. The presented set up could be used for conditioning and improving the functionality of current tissue-engineered vascular grafts. PMID- 24341315 TI - Affinity precipitation of human serum albumin using a thermo-response polymer with an L-thyroxin ligand. AB - BACKGROUND: Affinity precipitation has been reported as a potential technology for the purification of proteins at the early stage of downstream processing. The technology could be achieved using reversible soluble-insoluble polymers coupled with an affinity ligand to purify proteins from large volumes of dilute solution material such as fermentation broths or plasma. In this study, a thermo-response polymer was synthesized using N-methylol acrylamide, N-isopropyl acrylamide and butyl acrylate as monomers. The molecular weight of the polymer measured by the viscosity method was 3.06 * 104 Da and the lower critical solution temperature (LCST) was 28.0 degrees C.The recovery of the polymer above the LCST was over 95.0%. Human serum albumin (HSA) is the most abundant protein in the human serum system, and it has important functions in the human body. High purity HSA is required in pharmaceuticals. Safe and efficient purification is a crucial process during HSA production. RESULTS: A thermo-response polymer was synthesized and L thyroxin immobilized on the polymer as an affinity ligand to enable affinity precipitation of HSA. The LCST of the affinity polymer was 31.0 degrees C and the recovery was 99.6% of its original amount after recycling three times. The optimal adsorption condition was 0.02 M Tris-HCl buffer (pH 7.0) and the HSA adsorption capacity was 14.9 mg/g polymer during affinity precipitation. Circular dichroism spectra and a ForteBio Octet system were used to analyze the interactions between the affinity polymer and HSA during adsorption and desorption. The recovery of total HSA by elution with 1.0 mol/L NaSCN was 93.6%. When the affinity polymer was applied to purification of HSA from human serum, HSA could be purified to single-band purity according to SDS-PAGE. CONCLUSION: A thermo-response polymer was synthesized and L-thyroxin was attached to the polymer. Affinity precipitation was used to purify HSA from human serum. PMID- 24341316 TI - Introduction to December 2013 issue. AB - In this introduction to the December 2013 issue of the Journal of Experimental Psychology: Applied, the editor discusses her goals to get the Journal back on track. She gives thanks for the research that continues to advance both science and practice in experimental psychology. PMID- 24341317 TI - Portion size me: plate-size induced consumption norms and win-win solutions for reducing food intake and waste. AB - Research on the self-serving of food has empirically ignored the role that visual consumption norms play in determining how much food we serve on different sized dinnerware. We contend that dinnerware provides a visual anchor of an appropriate fill-level, which in turn, serves as a consumption norm (Study 1). The trouble with these dinnerware-suggested consumption norms is that they vary directly with dinnerware size--Study 2 shows Chinese buffet diners with large plates served 52% more, ate 45% more, and wasted 135% more food than those with smaller plates. Moreover, education does not appear effective in reducing such biases. Even a 60 min, interactive, multimedia warning on the dangers of using large plates had seemingly no impact on 209 health conference attendees, who subsequently served nearly twice as much food when given a large buffet plate 2 hr later (Study 3). These findings suggest that people may have a visual plate-fill level--perhaps 70% full--that they anchor on when determining the appropriate consumption norm and serving themselves. Study 4 suggests that the Delboeuf illusion offers an explanation why people do not fully adjust away from this fill-level anchor and continue to be biased across a large range of dishware sizes. These findings have surprisingly wide-ranging win-win implications for the welfare of consumers as well as for food service managers, restaurateurs, packaged goods managers, and public policy officials. PMID- 24341318 TI - The NICHD investigative interview protocol: an analogue study. AB - One hundred twenty-eight 5- to 7-year-old children were interviewed using the National Institute of Child Health and Human Development (NICHD) Investigative Interview Protocol about an event staged 4 to 6 weeks earlier. Children were prepared for talking about the investigated event using either an invitational or directive style of prompting, with or without additional practice describing experienced events. The open invitation prompts (including those using children's words to encourage further reporting) elicited more detailed responses than the more focused directive prompts without reducing accuracy. Children were most responsive when they had received preparation that included practice describing experienced events in response to invitation prompts. Overall, children were highly accurate regardless of prompt type. Errors mostly related to peripheral rather than central information and were more likely to be elicited by directive or yes/no questions than by invitations. Children who provided accounts when asked about a false event were less accurate when describing the true event. Children who received preparation that included practice recalling a recent event in response to directive and yes/no questions were least accurate when questioned about the false event first. The data provide the first direct evaluation of the accuracy of information elicited using different prompt types in the course of NICHD Protocol interviews, and underscore the importance of how children are prepared for subsequent reporting. PMID- 24341319 TI - A little bias goes a long way: the effects of feedback on the strategic regulation of accuracy on formula-scored tests. AB - Under formula-scoring rules for multiple-choice exams, a penalty is applied to incorrect responses to reduce noise in the observed score. To avoid the penalty individuals are allowed to "pass," and therefore they must be able to strategically regulate the accuracy of their reporting by deciding which and how many questions to answer. To investigate the effect of bias within this framework, Higham (2007) introduced bias profiles, which show the score obtained under formula scoring (corrected score) as a function of the omission rate. Bias profiles estimate the optimal number of questions that should be answered to maximize the corrected score (i.e., optimal bias). Our initial research showed that individuals tend to be too conservative when setting reporting criteria, "omitting" too many answers. The present three experiments introduced a feedback manipulation whereby participants were informed of the optimal omission rate after completing a test and asked to alter their reporting decisions accordingly. This feedback and concomitant alteration of reporting decisions led to improved corrected scores on true/false (Experiment 1), 2-alternative tests (Experiments 2), and 4-alternative tests (Experiment 3). Importantly, corrected scores at optimal bias also were higher than at forced-report for both true/false and 2 alternative tests. Furthermore, in Experiment 3, feedback based on one test improved scores on a second test, and participants were more likely to perform optimally on a third test without feedback. These effects suggest that optimal bias feedback may have long-term effects and generalize to new tests. PMID- 24341320 TI - Pulsed addition of HMF and furfural to batch-grown xylose-utilizing Saccharomyces cerevisiae results in different physiological responses in glucose and xylose consumption phase. AB - BACKGROUND: Pretreatment of lignocellulosic biomass generates a number of undesired degradation products that can inhibit microbial metabolism. Two of these compounds, the furan aldehydes 5-hydroxymethylfurfural (HMF) and 2 furaldehyde (furfural), have been shown to be an impediment for viable ethanol production. In the present study, HMF and furfural were pulse-added during either the glucose or the xylose consumption phase in order to dissect the effects of these inhibitors on energy state, redox metabolism, and gene expression of xylose consuming Saccharomyces cerevisiae. RESULTS: Pulsed addition of 3.9 g L-1 HMF and 1.2 g L-1 furfural during either the glucose or the xylose consumption phase resulted in distinct physiological responses. Addition of furan aldehydes in the glucose consumption phase was followed by a decrease in the specific growth rate and the glycerol yield, whereas the acetate yield increased 7.3-fold, suggesting that NAD(P)H for furan aldehyde conversion was generated by acetate synthesis. No change in the intracellular levels of NAD(P)H was observed 1 hour after pulsing, whereas the intracellular concentration of ATP increased by 58%. An investigation of the response at transcriptional level revealed changes known to be correlated with perturbations in the specific growth rate, such as protein and nucleotide biosynthesis. Addition of furan aldehydes during the xylose consumption phase brought about an increase in the glycerol and acetate yields, whereas the xylitol yield was severely reduced. The intracellular concentrations of NADH and NADPH decreased by 58 and 85%, respectively, hence suggesting that HMF and furfural drained the cells of reducing power. The intracellular concentration of ATP was reduced by 42% 1 hour after pulsing of inhibitors, suggesting that energy requiring repair or maintenance processes were activated. Transcriptome profiling showed that NADPH-requiring processes such as amino acid biosynthesis and sulfate and nitrogen assimilation were induced 1 hour after pulsing. CONCLUSIONS: The redox and energy metabolism were found to be more severely affected after pulsing of furan aldehydes during the xylose consumption phase than during glucose consumption. Conceivably, this discrepancy resulted from the low xylose utilization rate, hence suggesting that xylose metabolism is a feasible target for metabolic engineering of more robust xylose-utilizing yeast strains. PMID- 24341321 TI - Does hepcidin play a role in the pathogenesis of aphthae in Behcet's disease and recurrent aphthous stomatitis? AB - BACKGROUND: Aphthae constitute one of the major signs in Behcet's disease (BD) and recurrent aphthous stomatitis (RAS). No scientific study has yet explored the relationship of hepcidins, which have antimicrobial effects, with RAS and BD. OBJECTIVES: In this study, we aimed to evaluate by immunohistochemistry whether hepcidin is synthesized by the salivary glands and to measure levels of prohepcidin and hepcidin (an antibacterial peptide) in the serum and saliva of patients with BD and RAS. METHODS: The study included 25 BD patients and 30 RAS patients, as well as a control group comprising 25 healthy individuals. Serum and saliva samples were collected at the same time from all subjects. Levels of prohepcidin and hepcidin were measured by ELISA. The presence of hepcidin in salivary glands was assessed by immunohistochemistry. RESULTS: Hepcidin was localized in the striated ducts of the sublingual and parotid glands. Saliva prohepcidin and hepcidin levels were correlated with blood levels. Saliva prohepcidin levels were found to be lower in RAS patients than in BD patients and healthy controls (P < 0.001 and P = 0.007 respectively). In addition, RAS patients had lower saliva hepcidin levels than did the control group (P = 0.03). CONCLUSIONS: The lower serum and saliva prohepcidin and hepcidin concentrations found in RAS and BD patients indicate that hepcidin may be involved in the aetiopathogenesis of these diseases. Because it can be obtained non-invasively and easily, saliva may provide a useful alternative to serum in quantifying prohepcidin and hepcidin concentrations. PMID- 24341322 TI - Terminally ill patients as customers: the patient's perspective. AB - BACKGROUND: Consumerism in health care defines patients as self-determined, rational customers. Yet, it is questionable whether vulnerable patients, such as the terminally ill, also fulfill these criteria. Vulnerable contexts and the patient's perspective on being a customer remain relatively unexplored. The present study addresses this research gap by analyzing terminally ill patients' views on being customers. AIM: To explore the ways in which patients in palliative care refer to themselves as patients/customers, and how the patients' concepts of self-determination are related to their attitudes toward the patient/customer role. DESIGN: Qualitative interviews were conducted. Data were analyzed in three steps: narrative analysis, thematic content analysis, and typology construction. SETTING/PARTICIPANTS: Researchers recruited 25 patients via the Department of Palliative Care, University Medical Center Freiburg, Germany. RESULTS: In many ways, palliative patients contradict the image of a self-determined customer. The palliative patient role is characterized by the concept of relational self-determination rather than an unrestricted self determination. Self-attribution as a customer still occurs when positively associated with a person-centered, individualized treatment. Thus, the customer and patient role overlap within the palliative care setting because of the focus on the individual. CONCLUSIONS: The idealized customer role cannot be arbitrarily applied to all medical fields. Palliative patients are dependent on the physician, regardless of whether the customer or patient role is preferred. Hence, self-determination must be understood in relational terms, and physicians must recognize their crucial role in promoting patients' self-determination in the context of shared decision-making. PMID- 24341323 TI - Outcome measures other than morbidity and mortality for patients with incurable cancer and gastrointestinal obstruction. AB - OBJECTIVE: To prospectively evaluate outcome measures of patients undergoing palliative surgical evaluation for gastrointestinal obstruction. METHODS: Patients with an incurable malignancy undergoing consultation for gastrointestinal obstruction were prospectively enrolled from November 2009 to July 2012. We evaluated two patient-reported outcome measures of quality of life (Functional Assessment of Cancer Therapy-General [FACT-G]) and treatment satisfaction (Functional Assessment of Chronic Illness Therapy-Treatment Satisfaction-General Version 1 [FACIT-TS-G]) and five observational outcome measures (symptom improvement, 30 "good days," ability to tolerate diet at discharge, discharge home, and death within 90 days). RESULTS: Of 53 patients enrolled, 13 had gastric outlet obstruction, 22 had small bowel obstruction, and 18 had large bowel obstruction. Patient-reported measures could not be analyzed because only 19 patients (36%) completed the FACT-G and FACIT-TS-G survey at 1 month follow-up. However, we were able to obtain results for the 5 clinical observational outcomes in all patients. Symptom improvement was obtained in 41 (77%) patients, 30 "good days" in 40 (75%), ability to tolerate diet at discharge in 45 (85%), discharge to home in 46 (87%), and 18 (34%) of patients died within 90 days of evaluation. Large bowel obstruction was associated with symptom improvement, and noncolorectal cancer histology and carcinomatosis were negatively associated with having 30 "good days." The ability to tolerate oral intake at discharge was associated with Eastern Cooperative Oncology Group performance status and no recent chemotherapy administration. Death within 90 days was independently associated with noncolorectal cancer histology, ascites, and nonsurgical treatment. CONCLUSIONS: Observational outcome measures can provide follow-up data and the identification of variables associated with outcome for patients who are unable to respond to outpatient surveys. PMID- 24341325 TI - Wiedemann-Franz relation and thermal-transistor effect in suspended graphene. AB - We extract experimentally the electronic thermal conductivity, Ke, in suspended graphene that we dope using a back-gate electrode. We make use of two-point dc electron transport at low bias voltages and intermediate temperatures (50-160 K), where the electron and lattice temperatures are decoupled. The thermal conductivity is proportional to the charge conductivity times the temperature, confirming that the Wiedemann-Franz relation is obeyed in suspended graphene. We extract an estimate of the Lorenz coefficient as 1.1-1.7 * 10(-8) W OmegaK(-2). Ke shows a transistor effect and can be tuned with the back-gate by more than a factor of 2 as the charge carrier density ranges from ~0.5 to 1.8 * 10(11) cm( 2). PMID- 24341324 TI - Thoracic paravertebral block for nephrectomy: a randomized, controlled, observer blinded study. AB - OBJECTIVE: This study evaluated whether adding a preoperative single thoracic paravertebral block (TPVB) to intravenous patient-controlled analgesia (IV PCA) would improve postoperative analgesia compared with using IV PCA alone in patients undergoing nephrectomy. DESIGN: Prospective, randomized, controlled, observer-blinded trial. SETTING: University hospital. SUBJECTS: Thirty-four adult patients undergoing elective open nephrectomy. METHODS: The patients were randomized to receive a TPVB plus IV PCA (group T) or IV PCA alone (group C). A single 18-mL injection of 0.75% ropivacaine was administered preoperatively under ultrasound guidance; fentanyl was used for IV PCA. Each patient's postoperative pain score based on a verbal numerical rating scale, postoperative fentanyl consumption, inspiratory volume by incentive spirometry, and complications were evaluated at 1, 3, 6, 12, and 24 hours after surgery. Changes in heart rate (HR), systolic arterial pressure (SAP), and mean arterial pressure (MAP) were evaluated following skin incision. RESULTS: The postoperative pain score and fentanyl consumption were significantly lower in group T than in group C at all time points up to 24 hours after surgery. The postoperative inspiratory volumes were not significantly different. The changes in HR were similar, while the increases in SAP and MAP after skin incision were lower in group T than in group C. CONCLUSIONS: A preoperative single TPVB improved postoperative analgesia by reducing the postoperative pain score and fentanyl consumption in patients undergoing nephrectomy. PMID- 24341326 TI - A case of adult dermatomyositis associated with parainfluenza virus infection and Jo-1 antibody. PMID- 24341327 TI - Effects of 1,8-cineole on hypertension induced by chronic exposure to nicotine in rats. AB - OBJECTIVES: The monoterpenic oxide 1,8-cineole is a major component of many essential oils. We investigated its effects on systolic blood pressure (SBP) and oxidative stress in rats chronically exposed to nicotine. METHODS: Male Sprague Dawley rats (100-120 g) were intraperitoneally injected with 0.8 mg/kg/day nicotine for 21 days, followed by 3 mg/kg nicotine the next day. Rats were subsequently injected intraperitoneally with 0.01, 0.1 and 1 mg/kg 1,8-cineole, or 10 mg/kg nifedipine. SBP was measured using a tail cuff transducer, plasma nitrite concentration was measured colorimetrically, and plasma corticosterone concentration was measured by enzyme immunoassay. KEY FINDINGS: We found that 0.1 mg/kg 1,8-cineole significantly reduced SBP, and that 1.0 mg/kg 1,8-cineole significantly increased plasma nitrite concentrations, compared with rats chronically exposed to nicotine alone. Rats chronically exposed to nicotine showed a significant increase in lipid peroxidation levels, an elevation significantly antagonized by treatment with 0.01 mg/kg and 0.1 mg/kg 1,8-cineole. Chronic exposure to nicotine also significantly increased plasma corticosterone levels, but this effect was not diminished by treatment with 1,8-cineole. CONCLUSIONS: These results indicate that 1,8-cineole may lower blood pressure, and that this antihypertensive effect may be associated with the regulation of nitric oxide and oxidative stress in rats chronically exposed to nicotine. PMID- 24341328 TI - Phylogenetic relationship and virulence inference of Streptococcus Anginosus Group: curated annotation and whole-genome comparative analysis support distinct species designation. AB - BACKGROUND: The Streptococcus Anginosus Group (SAG) represents three closely related species of the viridans group streptococci recognized as commensal bacteria of the oral, gastrointestinal and urogenital tracts. The SAG also cause severe invasive infections, and are pathogens during cystic fibrosis (CF) pulmonary exacerbation. Little genomic information or description of virulence mechanisms is currently available for SAG. We conducted intra and inter species whole-genome comparative analyses with 59 publically available Streptococcus genomes and seven in-house closed high quality finished SAG genomes; S. constellatus (3), S. intermedius (2), and S. anginosus (2). For each SAG species, we sequenced at least one numerically dominant strain from CF airways recovered during acute exacerbation and an invasive, non-lung isolate. We also evaluated microevolution that occurred within two isolates that were cultured from one individual one year apart. RESULTS: The SAG genomes were most closely related to S. gordonii and S. sanguinis, based on shared orthologs and harbor a similar number of proteins within each COG category as other Streptococcus species. Numerous characterized streptococcus virulence factor homologs were identified within the SAG genomes including; adherence, invasion, spreading factors, LPxTG cell wall proteins, and two component histidine kinases known to be involved in virulence gene regulation. Mobile elements, primarily integrative conjugative elements and bacteriophage, account for greater than 10% of the SAG genomes. S. anginosus was the most variable species sequenced in this study, yielding both the smallest and the largest SAG genomes containing multiple genomic rearrangements, insertions and deletions. In contrast, within the S. constellatus and S. intermedius species, there was extensive continuous synteny, with only slight differences in genome size between strains. Within S. constellatus we were able to determine important SNPs and changes in VNTR numbers that occurred over the course of one year. CONCLUSIONS: The comparative genomic analysis of the SAG clarifies the phylogenetics of these bacteria and supports the distinct species classification. Numerous potential virulence determinants were identified and provide a foundation for further studies into SAG pathogenesis. Furthermore, the data may be used to enable the development of rapid diagnostic assays and therapeutics for these pathogens. PMID- 24341330 TI - Sodium glucose co-transport 2 inhibitors in the treatment of type 2 diabetes mellitus: a meta-analysis of randomized double-blind controlled trials. AB - BACKGROUND: The discovery of sodium-glucose co-transporter 2 (SGLT2) inhibitors, with a novel mechanism independent of insulin secretion or sensitization, bring about a new therapeutic approach to the management of type 2 diabetes mellitus. The aim of this meta-analysis was to evaluate the safety and efficacy of SGLT2 inhibitors at different doses in randomized double blind clinical trials. METHODS: This meta-analysis was conducted by including randomized double-blind controlled trials of SGLT2 inhibitors in patients with type 2 diabetes irrespective of their antidiabetic drug exposure history but with an inadequate glycemic control. All the effect sizes were computed using the random effects model. Standardized mean differences (SMDs) and odds ratios (OR) were computed for continuous and dichotomous variables, respectively. Additional analyses like sensitivity analysis, subgroup analysis and meta-regression were also performed. RESULTS: The pooled analyses demonstrated a significant reduction in mean changes in Hemoglobin A1c (HbA1c) (SMD = -0.78%, 95% CI, -0.87 to -0.69), fasting plasma glucose (FPG) (SMD = -0.70 mg/dl, 95% CI, -0.79 to -0.61), body weight (overall SMD = -0.59 kg, 95% CI, -0.65 to -0.52) and blood pressure from baseline with SGLT2 inhibitors based therapy. Consistently a significant number of patients treated with SGLT2 inhibitors achieved HbA1c < 7% (OR = 2.09, 95% CI, 1.77 to 2.46). SGLT2 inhibitors based therapy was associated with adverse events like genital and urinary tract infections. CONCLUSION: All studied doses of SGLT2 inhibitors, either as monotherapy or in combination with other antidiabetic agents, consistently improved glycemic control in patients with type 2 diabetes. However, a small percentage of patients suffer from genital and urinary tract infections. PMID- 24341329 TI - A structured review and exploration of the healthcare costs associated with stillbirth and a subsequent pregnancy in England and Wales. AB - BACKGROUND: In contrast to other pregnancy complications the economic impact of stillbirth is poorly understood. We aimed to carry out a preliminary exploration of the healthcare costs of stillbirth from the time of pregnancy loss and the period afterwards; also to explore and include the impact of a previous stillbirth on the healthcare costs of the next pregnancy. METHODS: A structured review of the literature including cost studies and description of costs to health-care providers for care provided at the time of stillbirth and in a subsequent pregnancy. Costs in a subsequent pregnancy were compared in three alternative models of care for multiparous women developed from national guidelines and expert opinion: i) "low risk" women who had a live birth, ii) "high risk" women who had a live birth and iii) women with a previous stillbirth. RESULTS: The costs to the National Health Service (NHS) for investigation immediately following stillbirth ranged from L1,242 (core recommended investigations) to L1,804 (comprehensive investigation). The costs in the next pregnancy following a stillbirth ranged from L2,147 (low-risk woman with a previous healthy child) to L3,751 (Woman with a previous stillbirth of unknown cause). The cost in the next pregnancy following a stillbirth due to a known recurrent or an unknown cause is almost L500 greater than the pregnancy following a stillbirth due to a known non-recurrent cause. CONCLUSIONS: The study has highlighted the paucity of evidence regarding economic issues surrounding stillbirth. Women who have experienced a previous stillbirth are likely to utilise more health care services in their next pregnancy particularly where no cause is found. Every effort should be made to determine the cause of stillbirth to reduce the overall cost to the NHS. The cost associated with identifying the cause of stillbirth could offset the costs of care in the next pregnancy. Future research should concentrate on robust studies looking into the wider economic impact of stillbirth. PMID- 24341331 TI - A synthetic biology approach for evaluating the functional contribution of designer cellulosome components to deconstruction of cellulosic substrates. AB - BACKGROUND: Select cellulolytic bacteria produce multi-enzymatic cellulosome complexes that bind to the plant cell wall and catalyze its efficient degradation. The multi-modular interconnecting cellulosomal subunits comprise dockerin-containing enzymes that bind cohesively to cohesin-containing scaffoldins. The organization of the modules into functional polypeptides is achieved by intermodular linkers of different lengths and composition, which provide flexibility to the complex and determine its overall architecture. RESULTS: Using a synthetic biology approach, we systematically investigated the spatial organization of the scaffoldin subunit and its effect on cellulose hydrolysis by designing a combinatorial library of recombinant trivalent designer scaffoldins, which contain a carbohydrate-binding module (CBM) and 3 divergent cohesin modules. The positions of the individual modules were shuffled into 24 different arrangements of chimaeric scaffoldins. This basic set was further extended into three sub-sets for each arrangement with intermodular linkers ranging from zero (no linkers), 5 (short linkers) and native linkers of 27-35 amino acids (long linkers). Of the 72 possible scaffoldins, 56 were successfully cloned and 45 of them expressed, representing 14 full sets of chimaeric scaffoldins. The resultant 42-component scaffoldin library was used to assemble designer cellulosomes, comprising three model C. thermocellum cellulases. Activities were examined using Avicel as a pure microcrystalline cellulose substrate and pretreated cellulose-enriched wheat straw as a model substrate derived from a native source. All scaffoldin combinations yielded active trivalent designer cellulosome assemblies on both substrates that exceeded the levels of the free enzyme systems. A preferred modular arrangement for the trivalent designer scaffoldin was not observed for the three enzymes used in this study, indicating that they could be integrated at any position in the designer cellulosome without significant effect on cellulose-degrading activity. Designer cellulosomes assembled with the long-linker scaffoldins achieved higher levels of activity, compared to those assembled with short-and no-linker scaffoldins. CONCLUSIONS: The results demonstrate the robustness of the cellulosome system. Long intermodular scaffoldin linkers are preferable, thus leading to enhanced degradation of cellulosic substrates, presumably due to the increased flexibility and spatial positioning of the attached enzymes in the complex. These findings provide a general basis for improved designer cellulosome systems as a platform for bioethanol production. PMID- 24341332 TI - Rivaroxaban for the treatment of symptomatic deep-vein thrombosis and pulmonary embolism in Chinese patients: a subgroup analysis of the EINSTEIN DVT and PE studies. AB - BACKGROUND: The worldwide EINSTEIN DVT and EINSTEIN PE studies randomized 8282 patients with acute symptomatic deep-vein thrombosis (DVT) and/or pulmonary embolism (PE) and, for the first time in trials in this setting, included patients in China. This analysis evaluates the results of these studies in this subgroup of patients. METHODS: A total of 439 Chinese patients who had acute symptomatic DVT (n=211), or PE with or without DVT (n=228), were randomized to receive rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily) or standard therapy of enoxaparin overlapping with and followed by an adjusted dose vitamin K antagonist, for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or non-major clinically relevant bleeding. RESULTS: The primary efficacy outcome occurred in seven (3.2%) of the 220 patients in the rivaroxaban group and in seven (3.2%) of the 219 patients in the standard-therapy group (hazard ratio, 1.04; 95% confidence interval 0.36-3.0; p=0.94). The principal safety outcome occurred in 13 (5.9%) patients in the rivaroxaban group and in 20 (9.2%) patients in the standard-therapy group (hazard ratio, 0.63; 95% confidence interval 0.31-1.26; p=0.19). Major bleeding was observed in no patients in the rivaroxaban group and in five (2.3%) patients in the standard-therapy group. In fragile patients (defined as age >75 years, creatinine clearance <50 mL/min, and/or body weight <=50 kg), the principal safety outcome occurred in four (8.9%) of the 45 patients who received rivaroxaban compared with seven (15.2%) of the 46 patients who received standard therapy. CONCLUSIONS: In Chinese patients with acute symptomatic DVT and/or PE, rivaroxaban was as efficacious as enoxaparin followed by vitamin K antagonist therapy, with a similar safety profile. The relative efficacy and safety of rivaroxaban compared with enoxaparin/vitamin K antagonist were consistent with that found in the rest of the world. TRIAL REGISTRATION NUMBER: EINSTEIN PE, ClinicalTrials.gov NCT00439777; EINSTEIN DVT, ClinicalTrials.gov NCT00440193. PMID- 24341333 TI - The use of mindfulness-based cognitive therapy for improving quality of life for inflammatory bowel disease patients: study protocol for a pilot randomised controlled trial with embedded process evaluation. AB - BACKGROUND: Inflammatory bowel disease (IBD) is a chronic condition with an unpredictable disease course. Rates of anxiety and depression among IBD patients in relapse (active disease symptoms) as well as in remission are higher than in the general population. Previous studies suggest that the prolonged effect of pain, anxiety, distress and depression have a detrimental effect on patients'quality of life (QoL). Poor QoL in itself is associated with further symptom relapse. Mindfulness based cognitive therapy (MBCT) is a psychological group intervention that has the potential to improve QoL. When used in other chronic conditions, it demonstrated reduced negative effect from pain and psychological factors at completion of an 8-week MBCT course. The effect of MBCT has never been researched in IBD. The aim of this study is to obtain the information required to design a full scale randomised controlled trial (RCT) that will examine the effectiveness of MBCT in improving quality of life for IBD patients. METHODS/DESIGN: This is an exploratory RCT with embedded process evaluation. Forty IBD patients will be recruited from NHS outpatient gastroenterology clinics and will be randomised to either a MBCT (intervention) group or to a wait-list (control) group. All participants will undergo 16 h of structured group training over an 8-week period, with the control group starting 6 months later than the intervention group. Primary outcomes are recruitment, completion/retention rates and adherence and adaptation to the MBCT manual for IBD patients. The secondary outcome is to assess the feasibility of collecting reliable and valid data on proposed outcome measures such as quality of life, anxiety, depression, disease activity and mindful awareness. The process evaluation will use a survey and focus groups to assess the acceptability of the intervention and trial procedures for IBD patients. DISCUSSION: The outcomes of this study will help define the barriers, uptake and perceived benefits of MBCT program for IBD patients. This information will enable the design of a full-scale study assessing the effect of MBCT on quality of life for IBD patients. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN27934462. PMID- 24341334 TI - Assessment of hematopoietic failure due to Rpl11 deficiency in a zebrafish model of Diamond-Blackfan anemia by deep sequencing. AB - BACKGROUND: Diamond-Blackfan anemia is a rare congenital red blood cell dysplasia that develops soon after birth. RPL11 mutations account for approximately 4.8% of human DBA cases with defective hematopoietic phenotypes. However, the mechanisms by which RPL11 regulates hematopoiesis in DBA remain elusive. In this study, we analyzed the transcriptome using deep sequencing data from an Rpl11-deficient zebrafish model to identify Rpl11-mediated hematopoietic failure and investigate the underlying mechanisms. RESULTS: We characterized hematological defects in Rpl11-deficient zebrafish embryos by identifying affected hematological genes, hematopoiesis-associated pathways, and regulatory networks. We found that hemoglobin biosynthetic and hematological defects in Rpl11-deficient zebrafish were related to dysregulation of iron metabolism-related genes, including tfa, tfr1b, alas2 and slc25a37, which are involved in heme and hemoglobin biosynthesis. In addition, we found reduced expression of the hematopoietic stem cells (HSC) marker cmyb and HSC transcription factors tal1 and hoxb4a in Rpl11 deficient zebrafish embryos, indicating that the hematopoietic defects may be related to impaired HSC formation, differentiation, and proliferation. However, Rpl11 deficiency did not affect the development of other blood cell lineages such as granulocytes and myelocytes. CONCLUSION: We identified hematopoietic failure of Rpl11-deficient zebrafish embryos using transcriptome deep sequencing and elucidated potential underlying mechanisms. The present analyses demonstrate that Rpl11-deficient zebrafish may serve as a model of DBA and may provide insights into the pathogenesis of mutant RPL11-mediated human DBA disease. PMID- 24341341 TI - Nutritional manipulation as mind-body therapy for cancer. PMID- 24341335 TI - PIK3CA, HRAS and PTEN in human papillomavirus positive oropharyngeal squamous cell carcinoma. AB - BACKGROUND: Recent genomic evidence suggests frequent phosphatidylinositide 3 kinase (PI3K) pathway activation in human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma. Mutations/amplification of the gene encoding p110alpha catalytic subunit of phosphoinositide 3-kinase (PIK3CA), loss of phosphatase and tensin homolog (PTEN) and HRAS mutations are known to activate PI3K pathway. METHODS AND RESULTS: PIK3CA mutations were identified by Sanger sequencing in 23 of 75 (31%) HPV-positive oropharyngeal carcinomas, including exon 9 (p.E545K [n = 10] and p.E542K [n = 5]) or exon 20 (p.H1047Y, n = 2) mutations. Five rare and one novel (p.R537Q) PIK3CA mutations were identified. HRAS mutation (p.Q61L) was detected in 1 of 62 tested cases. PIK3CA amplification by fluorescence in situ hybridization (FISH) was identified in 4 cases (4/21, 20%), while PTEN loss was seen in 7 (7/21, 33%) cases (chromosome 10 monosomy [n = 4], homozygous deletion [n = 3]). CONCLUSIONS: Overall, genetic alterations that likely lead to PI3K pathway activation were identified in 34 of 75 cases (45%) and did not correlate with disease specific survival. These findings offer a molecular rationale for therapeutic targeting of PI3K pathway in patients with HPV-positive oropharyngeal carcinoma. PMID- 24341342 TI - Correlating traditional Ayurvedic and modern medical perspectives on cancer: results of a qualitative study. AB - OBJECTIVE: To characterize Ayurvedic perspectives on the etiopathogenesis and supportive treatments for a biomedical diagnosis of cancer. METHODS: Hour-long, digitally recorded interviews were conducted with 10 experienced Ayurvedic clinicians, transcribed verbatim, and analyzed using techniques of qualitative thematic analysis. RESULTS: Four major themes were identified. The Ayurvedic description of the pathophysiology of cancer uses traditional concepts translated into a modern context. Although the biomedical treatment of cancer is considered valuable, from an Ayurvedic perspective it results in degeneration and depletion. In cases where biomedical treatment of cancer is not feasible, an Ayurvedic approach focusing on strengthening digestion, eliminating toxins, reducing tumor growth, and improving tissue metabolism is useful. An Ayurvedic approach to cancer supportive care focuses on restoring equilibrium, building strength, and rejuvenation. CONCLUSION: Ayurvedic medicine offers a unique perspective on the biomedical diagnosis of cancer that emphasizes restoring wholeness, uses natural remedies, includes a focus on emotional health, and emphasizes prevention strategies. PMID- 24341343 TI - High-pressure structural transformations in semiconductor nanocrystals. AB - Pressure-induced structural transformations in semiconductor nanocrystals are examined. High-pressure Raman spectroscopy, EXAFS, X-ray diffraction, and optical absorption are discussed as methods for studying these transformations in CdSe, CdS, and Si nanocrystals. In these nanocrystal systems, each technique shows an elevation in solid-solid structural transformation pressure as crystallite size decreases. By analogy with melting in nanocrystals, this elevation in transformation pressure is explained in terms of an increase in surface energy in the newly formed high-pressure phase crystallites. The increase in surface energy is in turn the result of transition path-induced changes in the shape of the nanocrystals. These changes convert spherical nanocrystals with low-index, low energy surfaces into oblate or prolate crystallites with higher-index, higher energy surfaces. The elevation in structural transformation pressure in nanocrystals is thus a kinetic rather than a thermodynamic phenomenon. PMID- 24341344 TI - Alternative therapeutic approach to renal-cell carcinoma: induction of apoptosis with combination of vitamin K3 and D-fraction. AB - PURPOSE: Because of a dismal prognosis for advanced renal-cell carcinoma (RCC), an alternative therapeutic approach, using vitamin K3 (VK3) and D-fraction (DF) was investigated. VK3 is a synthetic VK derivative and DF is a bioactive mushroom extract, and they have been shown to have antitumor activity. We examined if the combination of VK3 and DF would exhibit the improved anticancer effect on RCC in vitro. MATERIALS AND METHODS: Human RCC, ACHN cell line, were treated with varying concentrations of VK3, DF, or a combination of the two. Cell viability was assessed at 72 hours by MTT assay. To explore the possible anticancer mechanism, studies on cell cycle, chromatin modifications, and apoptosis were conducted. RESULTS: VK3 alone led to a ~20% reduction in cell viability at 4 MUM, while DF alone induced a 20% to 45% viability reduction at >= 500 MUg/mL. A combination of VK3 (4 MUM) and DF (300 MUg/mL) led to a drastic >90% viability reduction, however. Cell cycle analysis indicated that VK3/DF treatment induced a G1 cell cycle arrest, accompanied by the up-regulation of p21(WAF1) and p27(Kip1). Histone deacetylase (HDAC) was also significantly (~60%) inactivated, indicating chromatin modifications. In addition, Western blot analysis revealed that the up-regulation of Bax and activation of poly-(ADP-ribose)-polymerase (PARP) were seen in VK3/DF-treated cells, indicating induction of apoptosis. CONCLUSIONS: The combination of VK3 and DF can lead to a profound reduction in ACHN cell viability, through a p21(WAF1)-mediated G1 cell cycle arrest, and ultimately induces apoptosis. Therefore, the combination of VK3/DF may have clinical implications as an alternative, improved therapeutic modality for advanced RCC. PMID- 24341347 TI - Organising health research systems as a key to improving health: the World Health Report 2013 and how to make further progress. AB - The World Health Report 2013 provides a major boost to the health research community and, in particular, to those who believe that health research will make its greatest impact on improving health when it is organised through a systems approach. The World Health Report 2013, Research for Universal Health Coverage, starts with three key messages. Firstly, that universal health coverage, with full access to high-quality services, needs research evidence if it is to be achieved; second, all nations should conduct and use research; and finally, the report states that systems are needed to develop national research agendas, to raise funds, to strengthen research capacity, and to make effective use of research findings. Each of these themes is elaborated in the report and supported by extensive references.In this editorial, we first outline the key messages from the World Health Report 2013 and highlight the contributions made by papers from our journal, Health Research Policy and Systems. In addition, we discuss very recent papers that advance some issues even further. In particular, we consider new evidence both on how to achieve financial protection for those who use health services, and on whether healthcare professionals and organisations who engage in research provide an improved healthcare performance. Finally, we propose additional perspectives that add to the impressive body of evidence and analyses presented in the report. Specifically, we suggest that considering the needs of various stakeholders, as attempted in the UK, in parallel with analysing how to fulfil essential functions, should boost the prospects of successfully building and strengthening health research systems. This is important because research is vital for achieving universal health coverage, and consequently for improving the health of millions of people. PMID- 24341348 TI - Hospital Inpatient versus HOme-based rehabilitation after knee arthroplasty (The HIHO study): study protocol for a randomized controlled trial. AB - BACKGROUND: Formal rehabilitation programs are often assumed to be required after total knee arthroplasty to optimize patient recovery. Inpatient rehabilitation is a costly rehabilitation option after total knee arthroplasty and, in Australia, is utilized most frequently for privately insured patients. With the exception of comparisons with domiciliary services, no randomized trial has compared inpatient rehabilitation to any outpatient based program. The Hospital Inpatient versus HOme (HIHO) study primarily aims to determine whether 10 days of post-acute inpatient rehabilitation followed by a hybrid home program provides superior recovery of functional mobility on the 6-minute walk test (6MWT) compared to a hybrid home program alone following total knee arthroplasty. Secondarily, the trial aims to determine whether inpatient rehabilitation yields superior recovery in patient-reported function. METHODS/DESIGN: This is a two-arm parallel randomized controlled trial (RCT), with a third, non-randomized, observational group. One hundred and forty eligible, consenting participants who have undergone a primary total knee arthroplasty at a high-volume joint replacement center will be randomly allocated when cleared for discharge from acute care to either 10 days of inpatient rehabilitation followed by usual care (a 6-week hybrid home program) or to usual care. Seventy participants in each group (140 in total) will provide 80% power at a significance level of 5% to detect an increase in walking capacity from 400 m to 460 m between the Home and Inpatient groups, respectively, in the 6MWT at 6 months post-surgery, assuming a SD of 120 m and a drop-out rate of <10%.The outcome assessor will assess participants at 10, 26 and 52 weeks post operatively, and will remain blind to group allocation for the duration of the study, as will the statistician. Participant preference for rehabilitation mode stated prior to randomization will be accounted for in the analysis together with any baseline differences in potentially confounding characteristics as required. DISCUSSION: The HIHO Trial will be the first RCT to investigate the efficacy of inpatient rehabilitation compared to any outpatient alternative following total knee arthroplasty. TRIAL REGISTRATION: U.S. National Institutes of Health Clinical Trials Registry (http://clinicaltrials.gov) ref: NCT01583153. PMID- 24341349 TI - Biomass digestibility is predominantly affected by three factors of wall polymer features distinctive in wheat accessions and rice mutants. AB - BACKGROUND: Wheat and rice are important food crops with enormous biomass residues for biofuels. However, lignocellulosic recalcitrance becomes a crucial factor on biomass process. Plant cell walls greatly determine biomass recalcitrance, thus it is essential to identify their key factors on lignocellulose saccharification. Despite it has been reported about cell wall factors on biomass digestions, little is known in wheat and rice. In this study, we analyzed nine typical pairs of wheat and rice samples that exhibited distinct cell wall compositions, and identified three major factors of wall polymer features that affected biomass digestibility. RESULTS: Based on cell wall compositions, ten wheat accessions and three rice mutants were classified into three distinct groups each with three typical pairs. In terms of group I that displayed single wall polymer alternations in wheat, we found that three wall polymer levels (cellulose, hemicelluloses and lignin) each had a negative effect on biomass digestibility at similar rates under pretreatments of NaOH and H2SO4 with three concentrations. However, analysis of six pairs of wheat and rice samples in groups II and III that each exhibited a similar cell wall composition, indicated that three wall polymer levels were not the major factors on biomass saccharification. Furthermore, in-depth detection of the wall polymer features distinctive in rice mutants, demonstrated that biomass digestibility was remarkably affected either negatively by cellulose crystallinity (CrI) of raw biomass materials, or positively by both Ara substitution degree of non-KOH extractable hemicelluloses (reverse Xyl/Ara) and p-coumaryl alcohol relative proportion of KOH-extractable lignin (H/G). Correlation analysis indicated that Ara substitution degree and H/G ratio negatively affected cellulose crystallinity for high biomass enzymatic digestion. It was also suggested to determine whether Ara and H monomer have an interlinking with cellulose chains in the future. CONCLUSIONS: Using nine typical pairs of wheat and rice samples having distinct cell wall compositions and wide biomass saccharification, Ara substitution degree and monolignin H proportion have been revealed to be the dominant factors positively determining biomass digestibility upon various chemical pretreatments. The results demonstrated the potential of genetic modification of plant cell walls for high biomass saccharification in bioenergy crops. PMID- 24341350 TI - Peracetic acid: a practical agent for sterilizing heat-labile polymeric tissue engineering scaffolds. AB - Advanced biomaterials and sophisticated processing technologies aim at fabricating tissue-engineering scaffolds that can predictably interact within a biological environment at the cellular level. Sterilization of such scaffolds is at the core of patient safety and is an important regulatory issue that needs to be addressed before clinical translation. In addition, it is crucial that meticulously engineered micro- and nano- structures are preserved after sterilization. Conventional sterilization methods involving heat, steam, and radiation are not compatible with engineered polymeric systems because of scaffold degradation and loss of architecture. Using electrospun scaffolds made from polycaprolactone, a low melting polymer, and employing spores of Bacillus atrophaeus as biological indicators, we compared ethylene oxide, autoclaving and 80% ethanol to a known chemical sterilant, peracetic acid (PAA), for their ability to sterilize as well as their effects on scaffold properties. PAA diluted in 20% ethanol to 1000 ppm or above sterilized electrospun scaffolds in 15 min at room temperature while maintaining nano-architecture and mechanical properties. Scaffolds treated with PAA at 5000 ppm were rendered hydrophilic, with contact angles reduced to 0 degrees . Therefore, PAA can provide economical, rapid, and effective sterilization of heat-sensitive polymeric electrospun scaffolds that are used in tissue engineering. PMID- 24341351 TI - Change in body mass index, weight, and hot flashes: a longitudinal analysis from the midlife women's health study. AB - BACKGROUND: The goals of this study were to examine the associations between body mass index (BMI), as well as BMI change and weight change, with midlife hot flashes. METHODS: Data were analyzed from an ongoing 5-year cohort study of 631 midlife women (ages 45-54 years) recruited from Baltimore, Maryland, and its surrounding counties. Height and weight were measured at clinic visits conducted annually. Questionnaires administered at each clinic visit collected detailed data on hot flashes, including the severity and frequency, and other covariates. Data were analyzed using logistic regression and generalized estimated equation models, adjusting for potential confounders. RESULTS: Among women enrolled in the study, 45.2% reported hot flashes and 32.0% were categorized as being obese (BMI >=30 kg/m(2)) at baseline. At baseline, BMI was not significantly associated with ever experiencing hot flashes (BMI >=30 versus <25 kg/m(2): odds ratio [OR] 0.92; 95% confidence interval [CI]: 0.58, 1.15) or any of the other hot flashes outcomes (recent, frequent, or severe). In addition, no statistically significant associations between BMI, BMI change, or weight change, and the hot flash outcomes were observed in the longitudinal models (for example, any hot flashes: BMI >=30 versus <25 kg/m(2): OR 0.81; 95% CI: 0.56, 1.17). CONCLUSION: BMI, BMI change, and weight change during midlife were not related to hot flashes in this study. The data suggest that other factors, such as smoking habits, are more important in determining hot flashes risk during midlife. PMID- 24341352 TI - Genome wide association studies for body conformation traits in the Chinese Holstein cattle population. AB - BACKGROUND: Genome-wide association study (GWAS) is a powerful tool for revealing the genetic basis of quantitative traits. However, studies using GWAS for conformation traits of cattle is comparatively less. This study aims to use GWAS to find the candidates genes for body conformation traits. RESULTS: The Illumina BovineSNP50 BeadChip was used to identify single nucleotide polymorphisms (SNPs) that are associated with body conformation traits. A least absolute shrinkage and selection operator (LASSO) was applied to detect multiple SNPs simultaneously for 29 body conformation traits with 1,314 Chinese Holstein cattle and 52,166 SNPs. Totally, 59 genome-wide significant SNPs associated with 26 conformation traits were detected by genome-wide association analysis; five SNPs were within previously reported QTL regions (Animal Quantitative Trait Loci (QTL) database) and 11 were very close to the reported SNPs. Twenty-two SNPs were located within annotated gene regions, while the remainder were 0.6-826 kb away from known genes. Some of the genes had clear biological functions related to conformation traits. By combining information about the previously reported QTL regions and the biological functions of the genes, we identified DARC, GAS1, MTPN, HTR2A, ZNF521, PDIA6, and TMEM130 as the most promising candidate genes for capacity and body depth, chest width, foot angle, angularity, rear leg side view, teat length, and animal size traits, respectively. We also found four SNPs that affected four pairs of traits, and the genetic correlation between each pair of traits ranged from 0.35 to 0.86, suggesting that these SNPs may have a pleiotropic effect on each pair of traits. CONCLUSIONS: A total of 59 significant SNPs associated with 26 conformation traits were identified in the Chinese Holstein population. Six promising candidate genes were suggested, and four SNPs showed genetic correlation for four pairs of traits. PMID- 24341353 TI - High-energy-surface engineered metal oxide micro- and nanocrystallites and their applications. AB - Because many physical and chemical processes occur at surfaces, surface atomic structure is a critical factor affecting the properties of materials. Due to the presence of high-density atomic steps and edges and abundant unsaturated coordination sites, micro- and nanocrystallites with high-energy surfaces usually exhibit greater reactivity than those with low-energy surfaces. However, high energy crystal surfaces are usually lost during crystal growth as the total surface energy is minimized. Therefore, the selective exposure of high-energy facets at the surface of micro- and nanocrystallites is an important and challenging research topic. Metal oxides play important roles in surface associated applications, including catalysis, gas sensing, luminescence, and antibiosis. The synthesis of metal oxide micro- and nanocrystallites with specific surfaces, particularly those with high surface energies, is more challenging than the synthesis of metal crystals due to the presence of strong metal-oxygen bonds and diverse crystal structures. In this Account, we briefly summarize recent progress in the surface-structure-controlled synthesis of several typical metal oxide micro- and nanocrystallites, including wurtzite ZnO, anatase TiO2, rutile SnO2, and rocksalt-type metal oxides. We also discuss the improvement of surface properties, focusing on high-energy surfaces. Because of the huge quantity and diverse structure of metal oxides, this Account is not intended to be comprehensive. Instead, we discuss salient features of metal oxide micro- and nanocrystallites using examples primarily from our group. We first discuss general strategies for tuning the surface structure of metal oxide micro- and nanocrystallites, presenting several typical examples. For each example, we describe the basic crystallographic characteristics as well as the thermodynamic (i.e., tuning surface energy) or kinetic (i.e., tuning reaction rates) strategies we have used to synthesize micro- and nanocrystallites with high surface energies. We discuss the structural features of the specific facets and analyze the basis for the enhanced performance of the metal oxide micro- and nanocrystallites in water splitting, the degradation of organic pollutants, gas sensing, catalysis, luminescence, and antibiosis. Finally, we note the future trends in high-energy-facet metal oxide micro- and nanocrystallite research. A comprehensive understanding of the properties of metal oxide micro- and nanocrystallites with high-energy crystal surfaces and related synthetic strategies will facilitate the rational design of functional nanomaterials with desired characteristics. PMID- 24341354 TI - Comparison of the shaping ability of GT(r) Series X, Twisted Files and AlphaKite rotary nickel-titanium systems in simulated canals. AB - BACKGROUND: Efforts to improve the performance of rotary NiTi instruments by enhancing the properties of NiTi alloy, or their manufacturing processes rather than changes in instrument geometries have been reported. The aim of this study was to compare in-vitro the shaping ability of three different rotary nickel titanium instruments produced by different manufacturing methods. METHODS: Thirty simulated root canals with a curvature of 35 in resin blocks were prepared with three different rotary NiTi systems: AK- AlphaKite (Gebr. Brasseler, Germany), GTX- GT(r) Series X (Dentsply, Germany) and TF- Twisted Files (SybronEndo, USA).The canals were prepared according to the manufacturers' instructions. Pre- and post-instrumentation images were recorded and assessment of canal curvature modifications was carried out with an image analysis program (GSA, Germany).The preparation time and incidence of procedural errors were recorded. Instruments were evaluated under a microscope with 15 * magnifications (Carl Zeiss OPMI Pro Ergo, Germany) for signs of deformation. The Data were statistically analyzed using SPSS (Wilcoxon and Mann-Whitney U-tests, at a confidence interval of 95%). RESULTS: Less canal transportation was produced by TF apically, although the difference among the groups was not statistically significant. GTX removed the greatest amount of resin from the middle and coronal parts of the canal and the difference among the groups was statistically significant (p < 0.05). The shortest preparation time was registered with TF (444 s) and the longest with GTX (714 s), the difference among the groups was statistically significant (p < 0.05). During the preparation of the canals no instrument fractured. Eleven instruments of TF and one of AK were deformed. CONCLUSION: Under the conditions of this study, all rotary NiTi instruments maintained the working length and prepared a well-shaped root canal. The least canal transportation was produced by AK. GTX displayed the greatest cutting efficiency. TF prepared the canals faster than the other two systems. PMID- 24341355 TI - Aqueous phase synthesis of Au-Ag core-shell nanocrystals with tunable shapes and their optical and catalytic properties. AB - In this study, rhombic dodecahedral gold nanocrystals were used as cores for the generation of Au-Ag core-shell nanocrystals with cubic, truncated cubic, cuboctahedral, truncated octahedral, and octahedral structures. Gold nanocrystals were added to an aqueous mixture of cetyltrimethylammonium chloride (CTAC) surfactant, AgNO3, ascorbic acid, and NaOH to form the core-shell nanocrystals. The nanocrystals are highly uniform in size and shape, and can readily self assemble into ordered packing structures on substrates. Results from observation of solution color changes and variation in the reaction temperature suggest octahedra are produced at a higher growth rate, while slower growth favors cube formation. The major localized surface plasmon resonance (LSPR) band positions for these nanocrystals are red-shifted compared to those for pristine silver particles with similar dimensions due to the LSPR effect from the gold cores. By increasing the concentrations of reagents, Au-Ag core-shell cubes and octahedra with tunable sizes were obtained. Au-Ag cubes with body diagonals of 130, 144, and 161 nm and octahedra with body diagonals of 113, 126, and 143 nm have been prepared, allowing the investigation of size effect on their optical properties. Au-Ag octahedra with thinner Ag shells (12-16.5 nm) exhibit a blue-shifted major LSPR band relative to the LSPR band at 538 nm for the gold cores. For Au-Ag octahedra and cubes with thicker shells (22.5-37 nm), the major LSPR band is progressively red-shifted from that of the gold cores with increasing shell thickness and particle size. The Au-Ag octahedra show higher catalytic activity than cubes toward reduction of 2-amino-5-nitrophenol by NaBH4 at 30 degrees C, but both particle shapes display significantly enhanced catalytic efficiency at 40 degrees C. PMID- 24341356 TI - Synthesis and cytostatic evaluation of 4-N-alkanoyl and 4-N-alkyl gemcitabine analogues. AB - The coupling of gemcitabine with functionalized carboxylic acids (C9-C13) or reactions of 4-N-tosylgemcitabine with the corresponding alkyl amines afforded 4 N-alkanoyl and 4-N-alkyl gemcitabine derivatives. The analogues with a terminal hydroxyl group on the alkyl chain were efficiently fluorinated under conditions that are compatible with protocols for (18)F labeling. The 4-N alkanoylgemcitabines showed potent cytostatic activities in the low nanomolar range against a panel of tumor cell lines, whereas cytotoxicity of the 4-N alkylgemcitabines were in the low micromolar range. The cytotoxicity for the 4-N alkanoylgemcitabine analogues was reduced approximately by 2 orders of magnitude in the 2'-deoxycytidine kinase (dCK)-deficient CEM/dCK(-) cell line, whereas cytotoxicity of the 4-N-alkylgemcitabines was only 2-5 times lower. None of the compounds acted as efficient substrates for cytosolic dCK; therefore, the 4-N alkanoyl analogues need to be converted first to gemcitabine to display a significant cytostatic potential, whereas 4-N-alkyl derivatives attain modest activity without measurable conversion to gemcitabine. PMID- 24341357 TI - Survey of policy for MRSA screening in English cataract surgical units and changes to practice after updated National guidelines. AB - BACKGROUND: National guidelines on MRSA (methicillin-resistant Staphylococcus aureus) screening policy in England have changed on a number of occasions, but there is limited data on its influence at a local level. The aim of this study was to determine if changes in National policy influenced preoperative screening of cataract patients for MRSA. METHODS: A structured telephone survey was conducted on all 133 ophthalmology units in England in 2004 and again in 2007 for the initial responders, after a change in national policy. RESULTS: A total of 74 units (56%) responded in 2004 and 71 units (96% of initial respondents) in 2007. In 2004, 57% of units screened for MRSA. They screened groups at high risk of carriage, including patients with previous MRSA (93%) and patients from Nursing homes (21%). Swab sites included the nose (100%), eyes (31%) and perineum (62%). In 2007, there was no significant change in the number of units that screened for MRSA (57% vs 66%; p = 0.118; McNemar test). However, more units screened for MRSA in patients from nursing/residential homes (21% vs 51%; p = 0.004, McNemar test), and in patients who had recent admission to hospital (12% vs 36%; p = 0.003). In the second survey, 3 units (6%) now screened patients who were close relatives of MRSA carriers. CONCLUSION: This survey has highlighted inconsistences in MRSA screening practice of day-case cataract surgery patients across England after 2 major national policy changes. A change in DoH policy only led to more units screening patients for MRSA from high risk groups. PMID- 24341358 TI - Ruthmycin, a new tetracyclic polyketide from Streptomyces sp. RM-4-15. AB - The isolation and structural elucidation of a new tetracyclic polyketide (ruthmycin) from Streptomyces sp. RM-4-15, a bacteria isolated near thermal vents from the Ruth Mullins underground coal mine fire in eastern Kentucky, is reported. In comparison to the well-established frenolicin core scaffold, ruthmycin possesses an unprecedented signature C3 bridge and a corresponding fused six member ring. Preliminary in vitro antibacterial, anticancer, and antifungal assays revealed ruthmycin to display moderate antifungal activity. PMID- 24341359 TI - Lessons learned from a Maryland citizen advocacy group's experience in impacting health reform: the seven Cs of effective citizen advocacy. AB - The Affordable Care Act and the Mental Health Parity and Addiction Equity Act, in conjunction with state reform efforts, provide opportunities for increased access to mental health care, but advocates must engage throughout the process to ensure consumers' needs are met. This article describes the advocacy experiences of the Mental Health Association of Maryland (MHAMD) and provides a historical perspective for current advocacy efforts. It discusses current health care reform initiatives in Maryland, similar to other states' efforts, and highlights critical issues of concern for advocates. Using examples from MHAMD's recent experience, 7 effective advocacy strategies are illustrated. PMID- 24341360 TI - Polystyrene plastic: a source and sink for polycyclic aromatic hydrocarbons in the marine environment. AB - Polycyclic aromatic hydrocarbons (PAHs) on virgin polystyrene (PS) and PS marine debris led us to examine PS as a source and sink for PAHs in the marine environment. At two locations in San Diego Bay, we measured sorption of PAHs to PS pellets, sampling at 0, 1, 3, 6, 9, and 12 months. We detected 25 PAHs using a new analytical method with comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry. Several congeners were detected on samples before deployment. After deployment, some concentrations decreased (1,3 dimethylnaphthalene and 2,6-methylnaphthalene), while most increased [2 methylanthracene and all parent PAHs (PPAHs), except fluorene and fluoranthene], suggesting that PS debris is a source and sink for PAHs. When sorbed concentrations of PPAHs on PS are compared to the five most common polymers [polyethylene terephthalate (PET), high-density polyethylene (HDPE), polyvinyl chloride (PVC), low-density polyethylene (LDPE), and polypropylene (PP)], PS sorbed greater concentrations than PP, PET, and PVC, similar to HDPE and LDPE. Most strikingly, at 0 months, PPAHs on PS ranged from 8 to 200 times greater than on PET, HDPE, PVC, LDPE, and PP. The combination of greater PAHs in virgin pellets and large sorption suggests that PS may pose a greater risk of exposure to PAHs upon ingestion. PMID- 24341361 TI - Advanced glycation end-products impair Na+/K+-ATPase activity in diabetic cardiomyopathy: role of the adenosine monophosphate-activated protein kinase/sirtuin 1 pathway. AB - Decreased Na(+) /K(+) -ATPase activity, and both sirtuin 1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK) have been reported to be involved in the development of diabetic cardiomyopathy (DCM). The present study aimed to investigate the advanced glycation end-products (AGE) that impair Na(+) /K(+) ATPase stability by regulating the AMPK/SIRT1 pathway during progression of DCM. To study type 1 diabetic mellitus (T1DM), a disease model in rats was established by a single intraperitoneal injection of streptozotocin (STZ; 65 mg/kg), and neonatal rat cardiomyocytes were also cultured. Heart function was detected by Doppler, and SIRT1 and AMPK protein expression were detected by immunohistochemistry and western blotting. Na(+) /K(+) -ATPase activity was also monitored. Using in vivo rat models of DCM, we showed that Na(+) /K(+) -ATPase activity decreased when both AMPK and SIRT1 expression were downregulated. In vitro, AGE impaired Na(+) /K(+) -ATPase activity and decreased the AMPK and SIRT1 expression. Sirtuin 1 overexpression increased Na(+) /K(+) -ATPase activity. 5 aminoimidazole-4-carboxamide-3-ribonucleoside (AICAR) upregulated SIRT1 expression and increased Na(+) /K(+) -ATPase activity, which could be partially abolished by splitomicin. Our results suggest that the dysfunction of DCM is related to AGE-induced Na(+) /K(+) -ATPase activity impairment through a mechanism involving the AMPK/SIRT1 pathway. PMID- 24341362 TI - Crawling and walking infants see the world differently. AB - How does visual experience change over development? To investigate changes in visual input over the developmental transition from crawling to walking, thirty 13-month-olds crawled or walked down a straight path wearing a head-mounted eye tracker that recorded gaze direction and head-centered field of view. Thirteen additional infants wore a motion tracker that recorded head orientation. Compared to walkers, crawlers' field of view contained less walls and more floor. Walkers directed gaze straight ahead at caregivers, whereas crawlers looked down at the floor. Crawlers obtained visual information about targets at higher elevations caregivers and toys-by craning their heads upward and sitting up to bring the room into view. Findings indicate that visual experiences are intimately tied to infants' posture. PMID- 24341363 TI - Real-Time PCR of cytomegalovirus and Epstein-Barr virus in adult Egyptian patients with systemic lupus erythematosus. AB - OBJECTIVE: Infections may act as environmental triggers for induction of systemic lupus erythematosus (SLE). We sought to explore the relative frequencies of Epstein-Barr virus (EBV) and human cytomegalovirus (CMV) in adult Egyptian patients with SLE and their correlation with disease activity and damage. METHODS: Thirty-three consecutive adult patients satisfying the 1997 American College of Rheumatology (ACR) Classification Criteria for SLE and 30 healthy controls were included in this case-control study. All patients were subjected to complete clinical and laboratory evaluation to determine the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR). Sera from both groups were analyzed for immunoglobulin M (IgM) and IgG antibodies against CMV and EBV. Qualitative real time polymerase chain reaction (PCR) for both viruses was performed for all SLE patients. RESULTS: Almost all SLE patients 32/33 (96.9%) were positive for IgG anti-CMV antibodies versus 20/30 in the control group (66.6%) (P = 0.002). All SLE patients were positive for IgG anti-EBV antibodies compared to 25 in the control group (100% vs. 83.3%, P = 0.02). CMV and EBV DNA were detected by PCR in 30.3% and 51.5% of SLE patients, respectively. A statistically significant lower SLEDAI was found in PCR positive patients for EBV compared to negative patients (9.6 +/- 5.2 vs. 13.1 +/- 3.1, respectively P = 0.041). CONCLUSIONS: Adult Egyptian patients with SLE had higher frequencies of anti-CMV and EBV IgG compared to healthy controls. Furthermore, our single point assessment of SLEDAI suggested that exposure to EBV infection might be associated with a lower disease activity. PMID- 24341364 TI - Natural selection and glucocorticoid physiology. AB - Glucocorticoid hormones are considered potent modulators of trade-offs between reproduction and survival. As such, selection should affect glucocorticoid physiology, although relatively little is known about how selection may act on glucocorticoid profiles. In general, the evolution of physiology is less studied and less well understood than morphological or life history traits. Here, we used a long-term data set from a population of mountain white-crowned sparrows to estimate natural selection on glucocorticoid profiles. Our study suggests that survival selection favours higher hormone concentrations for multiple components of glucocorticoid physiology (both baseline and stress-induced glucocorticoid levels). Fecundity selection varies depending on the component of hypothalamic pituitary-adrenal physiology; greater reproductive output was associated with higher baseline glucocorticoid levels, but lower stress-induced glucocorticoid levels. Additionally, the selection gradient was greater for glucocorticoids than for a morphological trait (wing length). These results support the hypothesis that stress-induced glucocorticoids increase survival over reproduction within a wild population (the CORT-trade-off hypothesis). Taken together, these results add to our knowledge of how selection operates on physiological traits and also provide an evolutionary and ecological perspective on several key open issues in the field of glucocorticoid physiology. PMID- 24341365 TI - Flow cytometric evaluation of ki67 for the determination of malignancy grade in canine lymphoma. AB - Ki67 is a nuclear antigen significantly correlated with degree of malignancy in human non-Hodgkin lymphomas. We wanted to assess the ability of flow cytometric evaluation of Ki67 index (Ki67I) in differentiating the grade of malignancy in canine lymphomas. Ki67I was determined on lymph node aspirates of 90 immunophenotyped lymphomas classified according to the updated Kiel classification: 80 high grade (HG, 62 B cell and 18 T cell) and 10 low grade (LG, 3 B cell and 7 T cell) lymphomas. HG lymphomas showed significantly higher Ki67I compared with LG lymphomas (P < 0.0001). A significant difference in HG lymphomas was detected between B- and T-immunophenotypes. Receiver operating characteristic (ROC) curve highlighted a high accuracy of Ki67I in recognizing HG lymphomas [area under the curve (AUC) = 99.4] and a cut-off value of 12.2% was established (sensitivity = 96.3% and specificity = 100%). Thus, we suggest the combination of Ki67I flow cytometric determination and immunophenotype as a reliable tool to classify canine lymphomas. PMID- 24341366 TI - Assessment of two-component ventricular septum: functional differences in systolic deformation and rotation assessed by speckle tracking imaging. AB - BACKGROUND: The purpose of this study was to elucidate functional differences in the right and left components of the ventricular septum (Rt and Lt, respectively). METHODS: Strain, strain rate, rotation, and rotation rate profile curves of Rt and Lt were obtained using speckle tracking echocardiography in 38 normal children and adolescents. RESULTS: The echogenic bright line serving as the boundary separating Rt from Lt was consistently visible in the middle of the ventricular septum. There was no significant difference in peak strain or peak strain rate during systole between Rt and Lt. However, the time interval from the onset of QRS-wave to peak strain and peak strain rate were significantly lower in Lt than in Rt in terms of radial and circumferential deformation (P < 0.005, all), whereas there was no significant difference in longitudinal deformation in the time to peak strain or peak strain rate between Rt and Lt. Lt showed counterclockwise rotation, whereas Rt showed clockwise rotation (10.4 +/- 2.9 degrees vs. -10.2 +/- 2.6 degrees , P < 0.0001). Time to peak rotation was significantly lower in Lt than in Rt (201.7 +/- 32.7 msec vs. 370.4 +/- 31.2 msec, P < 0.0001). CONCLUSION: Morphologically and functionally the ventricular septum is a two-component structure. Evaluation of deformation and rotation of the 2 components would help in evaluating septal performance. PMID- 24341367 TI - Fractional erbium: YAG laser-assisted photodynamic therapy for facial actinic keratoses: a randomized, comparative, prospective study. AB - BACKGROUND: Photodynamic therapy (PDT) with methyl aminolevulinate (MAL) is effective for treating multiple actinic keratoses (AKs). Ablative fractional laser (FL) creates vertical channels that may facilitate MAL delivery and improve PDT response. OBJECTIVE: To evaluate the efficacy of FL-assisted PDT (FL-PDT) in treating facial AKs in Korean patients. METHODS: A prospective randomized non blinded trial initially evaluated 271 facial AKs in 45 patients. All patients underwent one session of MAL-PDT using a red light-emitting diode lamp at 37 J/cm(2) , and 23 patients with 135 AK lesions were randomly assigned to pre treatment with a 2940-nm ablative fractional erbium:Yag laser. Patients were followed up at 1, 2 and 4 weeks and every month until 6 and 12 months post treatment. Response, adverse events, cosmetic outcome and patient satisfaction were documented. Finally, a total of 236 facial AKs in 40 patients were enrolled and analysed in this study. RESULTS: FL-PDT was significantly more effective than MAL-PDT at treating all AK grades (86.9% vs. 61.2%; P < 0.001). The efficacy of FL-PDT was most pronounced in treating Olsen grade III AKs (69.4% vs. 32.5%; P = 0.001). FL-PDT also showed a lower lesion recurrence rate than MAL-PDT (9.7% vs. 26.6%; P = 0.004). Excellent or good cosmetic outcome was reported in >90% cases. Erythema and hyperpigmentation intensities were higher in the FL-PDT group (P > 0.05). Side-effects were more frequent in the FL-PDT group, but these were mild and well tolerated (P > 0.05). CONCLUSION: FL-PDT is effective for treating AKs, especially moderate-to-thick lesions. PMID- 24341368 TI - Effectiveness of a tailored intervention to improve cardiovascular risk management in primary care: study protocol for a randomised controlled trial. AB - BACKGROUND: Cardiovascular disease (CVD) is an important worldwide cause of mortality. In The Netherlands, CVD is the leading cause of death for women and the second cause of death for men. Recommendations for diagnosis and treatment of CVD are not well implemented in primary care. In this study, we aim to examine the effectiveness of a tailored implementation program targeted at practice nurses to improve healthcare for patients with (high risk for) CVD. METHODS/DESIGN: A two-arm cluster randomized trial is planned. We offer practice nurses a tailored program to improve adherence to six specific recommendations related to blood pressure and cholesterol target values, risk profiling and lifestyle advice. Practice nurses are offered training and feedback on their motivational interviewing technique and an e-learning program on cardiovascular risk management (CVRM). They are also advised to screen for the presence and severity of depressive symptoms in patients. We also advise practice nurses to use selected E-health options (selected websites and Twitter-consult) in patients without symptoms of depression. Patients with mild depressive symptoms are referred to a physical exercise group. We recommend referring patients with major depressive symptoms for assessment and treatment of depressive symptoms if appropriate before starting CVRM. Data from 900 patients at high risk of CVD or with established CVD will be collected in 30 general practices in several geographical areas in The Netherlands. The primary outcome measure is performance of practice nurses in CVRM and reflects application of recommendations for personalized counselling and education of CVRM patients. Patients' health-related lifestyles (physical exercise, diet and smoking status) will be measured with validated questionnaires and medical record audit will be performed to document estimated CVD risk. Additionally, we will survey and interview participating healthcare professionals for exploration of processes of change. The control practices will provide usual care. DISCUSSION: Tailored interventions can improve healthcare. An understanding of the methods to reach the improved healthcare can be improved. This research contributes a share of it. Identification of the determinants of practice and developing implementation interventions were two steps which were completed. The subsequent step was implementation of the tailored intervention program. TRIAL REGISTRATION: Name trial register: Nederlands trial register. Web address of trial register: http://www.trialregister.nl. Data of registration: 11 July 2013. Number of registration: NTR4069. PMID- 24341369 TI - Prophylaxis against hepatitis B reactivation among patients with lymphoma receiving rituximab. AB - Hepatitis B virus (HBV) reactivation occurs commonly in patients with non-Hodgkin lymphoma, receiving rituximab-based therapeutic regimen. Guidelines from different organizations are not all in agreement with regard to screening and antiviral prophylaxis, given the limited evidence. Antiviral prophylaxis has been recommended for all HBV surface antigen-positive patients. Evidence for benefit from prophylaxis has recently been recognized among HBV surface antigen negative/HBV core antibody-positive patients. Incidence of HBV reactivation varies in different geographical locations and the decision to start antiviral prophylaxis should consider local incidence data. Given the increased rates of rituximab-associated HBV reactivation and potentially fatal outcome, it is prudent that all patients who receive rituximab should be screened for HBV markers. PMID- 24341370 TI - Femtosecond pulse shaping, multiple-pulse spectroscopy, and optical control. AB - A review is presented of femtosecond pulse-shaping methods and their application to spectroscopy of atoms, molecules, and condensed materials. Pulse shaping can be used to generate femtosecond pulse sequences and other optical waveforms whose time-dependent amplitude, phase, frequency, and polarization profiles are all specified precisely. The light-matter interaction mechanisms through which such waveforms can be used for optical control over molecular and material responses are discussed. Most of the spectroscopic experiments conducted to date that involve shaped femtosecond waveforms are reviewed. These have involved control over coherent electronic responses of atoms, small molecules, and multiple quantum wells and control over coherent molecular and lattice vibrations. A selective review is presented of theoretical predictions and qualitative discussions of optical control possibilities involving complex ultrafast waveforms. PMID- 24341371 TI - The private life of environmental bacteria: pollutant biodegradation at the single cell level. AB - Bacteria display considerable cell-to-cell heterogeneity in a number of genetic and physiological traits. Stochastic differences in regulatory patterns (e.g. at the transcriptional level) propagate into the metabolic and physiological status of otherwise isogenic cells, which ultimately results in appearance of sub populations within the community. As new technologies emerge and because novel single cell strategies are constantly being refined, our knowledge on microbial individuality is in burgeoning and constant expansion. These approaches encompass not only molecular biology tools (e.g. fluorescent-protein based reporters) but also a suite of sophisticated, non-invasive technologies to gain insight into the metabolic state of individual cells. Defining the role of individual heterogeneities is thus instrumental for the population-level understanding of macroscopic processes in both environmental and industrial set-ups. The present article reviews the state-of-the-art methodologies for the investigation of single bacteria at both the genetic and metabolic level, and places the application of currently available tools in the context of microbial ecology and environmental microbiology. As a case example, we examine the stochastic and multi-stable behaviour of the TOL-encoded pathway of Pseudomonas putida mt-2 for the biodegradation of aromatic compounds. Bet-hedging strategies and division of labour are considered as factors pushing forward the evolution of environmental microorganisms. PMID- 24341372 TI - Hope against hope: exploring the hopes and challenges of rural female caregivers of persons with advanced cancer. AB - BACKGROUND: This paper focuses on the qualitative component of a study evaluating a hope intervention, entitled Living with Hope Program (LWHP), designed to foster hope in female caregivers of family members living with advanced cancer. The purpose of this research is to share, in the form of a story, the experiences of rural female caregivers caring for family members with advanced cancer, focusing on what fosters their hope. Hope is a psychosocial and spiritual resource that has been found to help family caregivers live through difficult transitions and challenges. METHODS: Twenty-three participants from rural Western Canada completed daily journal entries documenting their hopes and challenges. Cortazzi's (2001) method of narrative analysis was used to analyze the data, which was then transcribed into a narrative entitled 'hope against hope.' RESULTS: The journal entries highlighted: the caregivers' hopes and what fostered their hope; the various challenges of caregiving; self-care strategies, and; their emotional journey. Hope was integrated throughout their entire experience, and 'hope against hope' describes how hope persists even when there is no hope for a cure. CONCLUSIONS: This research contributes to the assessment of caregiver interventions that impact hope and quality of life, while illustrating the value of a narrative approach to both research and practice. Journaling may be particularly valuable for rural caregivers who are isolated, and may lack direct professional and peer support. There is an opportunity for health professionals and other providers to foster a relationship of trust with family caregivers, in which their story can be told openly and where practitioners pay closer attention to the psychosocial needs of caregivers. PMID- 24341373 TI - Safety evaluation of mechanical recycling processes used to produce polyethylene terephthalate (PET) intended for food contact applications. AB - The development of a scheme for the safety evaluation of mechanical recycling processes for polyethylene terephthalate (PET) is described. The starting point is the adoption of a threshold of toxicological concern such that migration from the recycled PET should not give rise to a dietary exposure exceeding 0.0025 MUg kg(-1) bw day(-1), the exposure threshold value for chemicals with structural alerts raising concern for potential genotoxicity, below which the risk to human health would be negligible. It is practically impossible to test every batch of incoming recovered PET and every production batch of recycled PET for all the different chemical contaminants that could theoretically arise. Consequently, the principle of the safety evaluation is to measure the cleaning efficiency of a recycling process by using a challenge test with surrogate contaminants. This cleaning efficiency is then applied to reduce a reference contamination level for post-consumer PET, conservatively set at 3 mg kg(-1) PET for a contaminant resulting from possible misuse by consumers. The resulting residual concentration of each contaminant in recycled PET is used in conservative migration models to calculate migration levels, which are then used along with food consumption data to give estimates of potential dietary exposure. The default scenario, when the recycled PET is intended for general use, is that of an infant weighing 5 kg and consuming every day powdered infant formula reconstituted with 0.75 L of water coming from water bottles manufactured with 100% recycled PET. According to this scenario, it can be derived that the highest concentration of a substance in water that would ensure that the dietary exposure of 0.0025 ug kg(-1) bw day(-1) is not exceeded, is 0.017 MUg kg(-1) food. The maximum residual content that would comply with this migration limit depends on molecular weight and is in the range 0.09-0.32 mg kg(-1) PET for the typical surrogate contaminants. PMID- 24341374 TI - First detailed reconstruction of the karyotype of Trachypithecus cristatus (Mammalia: Cercopithecidae). AB - BACKGROUND: The chromosomal homologies of human (Homo sapiens = HSA) and silvered leaf monkey (Trachypithecus cristatus = TCR) have been previously studied by classical chromosome staining and by fluorescence in situ hybridization (FISH) applying chromosome-specific DNA probes of all human chromosomes in the 1980s and 1990s, respectively. RESULTS: However, as the resolution of these techniques is limited we used multicolor banding (MCB) at an ~250-band level, and other selected human DNA probes to establish a detailed chromosomal map of TCR. Therefore it was possible to precisely determine evolutionary conserved breakpoints, orientation of segments and distribution of specific regions in TCR compared to HSA. Overall, 69 evolutionary conserved breakpoints including chromosomal segments, which failed to be resolved in previous reports, were exactly identified and characterized. CONCLUSIONS: This work also represents the first molecular cytogenetic one characterizing a multiple sex chromosome system with a male karyotype 44,XY1Y2. The obtained results are compared to other available data for old world monkeys and drawbacks in hominoid evolution are discussed. PMID- 24341375 TI - Parents' experiences of living with a child with hydrocephalus: a cross-sectional interview-based study. AB - BACKGROUND: Shunts, the main treatment for hydrocephalus, are problematic because they frequently malfunction. Detecting shunt malfunction is challenging because symptoms are similar to those of common childhood illnesses, particularly viral infections. Parents are responsible for identifying shunt malfunction and responding accordingly. Understanding parents' experiences has the potential to improve parent-professional collaboration and the management of the child's condition. AIM: To explore parents' experiences of living with a child with hydrocephalus and their decisions when they suspect shunt malfunction. DESIGN AND METHODS: A cross-sectional interview-based survey using qualitative methods was undertaken. Twenty-five parents participated in the interviews. Framework approach underpinned data analysis. FINDINGS: Three concepts, 'uncertainty', 'developing expertise', and 'a normal life', were identified. These concepts were dynamic in nature as parents learned through experience, adapted to changes in their child's health status and made decisions about their needs. Uncertainty because of the unpredictability and life-threatening nature of shunt malfunction dominated parents' accounts. Through experience, parents learned to differentiate between symptoms that suggested a shunt problem and those of other childhood illnesses, but perceived their expertise was not always valued by health professionals or used to inform clinical decisions. Decisions about where or when to seek advice related to prior experiences of health-care services and minimizing disruption for the whole family. CONCLUSION: Parents can recognize illness symptoms suggestive of shunt malfunction and want to collaborate with health professionals about the management of their child's condition. Collaboration with parents requires health professionals to listen to parents' concerns and value their experiences. PMID- 24341376 TI - Increased polysedative use in veterans with posttraumatic stress disorder. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) treatment is often complicated in veterans by co-occurring conditions including pain, insomnia, brain injury, and other mental disorders. Pharmacologic approaches to these conditions can produce an accumulation of sedating medications with potential for safety concerns. OBJECTIVE: The objective of this study was to characterize polysedative prescribing among veterans with PTSD over an 8-year period. DESIGN: National Department of Veterans Affairs (VA) data were used to identify veterans with PTSD using International Classification of Diseases, Ninth Revision codes among regular medication users. Prescribing of benzodiazepines, hypnotics, atypical antipsychotics, opioids, and muscle relaxants was determined annually. Prevalence and incidence rates were determined for each medication class from 2004 through 2011. Polysedative use was determined from longitudinal refill patterns that indicated concurrent use across sedative classes. RESULTS: In 2004, 9.8% of veterans with PTSD concurrently received medications from three or more sedative classes. By 2011, the prevalence of concurrent use involving three or more classes increased to 12.1%. Polysedative use varied across demographic subgroups, with higher rates observed among women, rural residents, younger adults, Native Americans and Whites. The most common combination was an opioid plus a benzodiazepine, taken concurrently by 15.9% of veterans with PTSD. CONCLUSIONS: Important trends in polysedative use among veterans with PTSD illustrate the complexity of treating an intersecting cluster of symptoms managed by sedative medications. As the VA seeks to improve care by focusing on non-pharmacologic options, our findings emphasize the need for a comprehensive approach that encompasses overlapping conditions of relevance to veterans with PTSD. PMID- 24341377 TI - Transport across membranes. PMID- 24341378 TI - Enhancing the patient involvement in outcomes: a study protocol of personalised outcome measurement in the treatment of substance misuse. AB - BACKGROUND: Involving patients in treatment is becoming increasingly popular in mental health [Sales & Alves: Personalized evaluation of psychological treatments: A review of tools and research designs, submitted]. However, in substance misuse treatment settings, the patient perspective about treatment tends to be overlooked. This has been cited as a key priority by Orford et al. [Addiction, 103: 875-885, 2008] who included patient feedback about treatment as one of ten areas requiring an urgent paradigm shift in addiction research and practice.This project will apply an innovative method to involve substance misuse patients in psychological therapies, by asking them to suggest topics to evaluate their treatment. These topics suggested by patients can be written as a list of personalised items, so-called as patient-generated outcome measures (PGOM). Despite its patient-friendly features, PGOM's have never been used in this population, which is what this project aims to overcome. METHODS/DESIGN: This project is part of an International Exchange Platform on Personalising Addiction Treatment. Data will be collected in two phases (pre-post study and focus groups with patients) to explore the following: (1). How reliable and sensitive to change are PGOM's and standardised measures in substance misuse treatment? (2). Do PGOM's add relevant information to standardised measures? (3). What are the views of substance misuse patients about personalised outcome assessment? (4). Development of guidelines on using PGOM's in this population DISCUSSION: This research will potentially demonstrate the diversity of personal problems among patients seeking substance misuse treatment, suggesting the relevance of PGOM as a method to personalise outcome measurement and, ultimately, guiding treatment provision. It is expected that, as in previous studies, PGOM's will be perceived as helpful and patient-friendly tools, where patients may express their own concerns in a semi-structured setting. Similarly to other populations, we also expect PGOM's to be reliable, valid and sensitive to clinical changes in substance misuse treatment, as well as more content informative than their standardised counterparts. If these results are achieved, we might hypothesize that PGOM's are a potentially valid supplement to traditional standardised scales, by providing a closer insight to what motivates patients to participate in substance misuse treatment programmes. PMID- 24341379 TI - Surrogate outcomes: experiences at the Common Drug Review. AB - BACKGROUND: Surrogate outcomes are a significant challenge in drug evaluation for health technology assessment (HTA) agencies. The research objectives were to: identify factors associated with surrogate use and acceptability in Canada's Common Drug Review (CDR) recommendations, and compare the CDR with other HTA or regulatory agencies regarding surrogate concerns. METHODS: Final recommendations were identified from CDR inception (September 2003) to December 31, 2010. Recommendations were classified by type of outcome (surrogate, final, other) and acceptability of surrogates (determined by the presence/absence of statements of concern regarding surrogates). Descriptive and statistical analyses examined factors related to surrogate use and acceptability. For thirteen surrogate-based submissions, recommendations from international HTA and regulatory agencies were reviewed for statements about surrogate acceptability. RESULTS: Of 156 final recommendations, 68 (44%) involved surrogates. The overall 'do not list' (DNL) rate was 48%; the DNL rate for surrogates was 41% (p = 0.175). The DNL rate was 64% for non-accepted surrogates (n = 28) versus 25% for accepted surrogates (odds ratio 5.4, p = 0.002). Clinical uncertainty, use of economic evidence over price alone, and a premium price were significantly associated with non-accepted surrogates. Surrogates were used most commonly for HIV, diabetes, rare diseases, cardiovascular disease and cancer. For the subset of drugs studied, other HTA agencies did not express concerns for most recommendations, while regulatory agencies frequently stated surrogate acceptance. CONCLUSIONS: The majority of surrogates were accepted at the CDR. Non-accepted surrogates were significantly associated with clinical uncertainty and a DNL recommendation. There was inconsistency of surrogate acceptability across several international agencies. Stakeholders should consider collaboratively establishing guidelines on the use, validation, and acceptability of surrogates. PMID- 24341380 TI - Semantic integration of gene expression analysis tools and data sources using software connectors. AB - BACKGROUND: The study and analysis of gene expression measurements is the primary focus of functional genomics. Once expression data is available, biologists are faced with the task of extracting (new) knowledge associated to the underlying biological phenomenon. Most often, in order to perform this task, biologists execute a number of analysis activities on the available gene expression dataset rather than a single analysis activity. The integration of heterogeneous tools and data sources to create an integrated analysis environment represents a challenging and error-prone task. Semantic integration enables the assignment of unambiguous meanings to data shared among different applications in an integrated environment, allowing the exchange of data in a semantically consistent and meaningful way. This work aims at developing an ontology-based methodology for the semantic integration of gene expression analysis tools and data sources. The proposed methodology relies on software connectors to support not only the access to heterogeneous data sources but also the definition of transformation rules on exchanged data. RESULTS: We have studied the different challenges involved in the integration of computer systems and the role software connectors play in this task. We have also studied a number of gene expression technologies, analysis tools and related ontologies in order to devise basic integration scenarios and propose a reference ontology for the gene expression domain. Then, we have defined a number of activities and associated guidelines to prescribe how the development of connectors should be carried out. Finally, we have applied the proposed methodology in the construction of three different integration scenarios involving the use of different tools for the analysis of different types of gene expression data. CONCLUSIONS: The proposed methodology facilitates the development of connectors capable of semantically integrating different gene expression analysis tools and data sources. The methodology can be used in the development of connectors supporting both simple and nontrivial processing requirements, thus assuring accurate data exchange and information interpretation from exchanged data. PMID- 24341381 TI - Design of an amide N-glycoside derivative of beta-glucogallin: a stable, potent, and specific inhibitor of aldose reductase. AB - beta-Glucogallin (BGG), a major component of the Emblica officinalis medicinal plant, is a potent and selective inhibitor of aldose reductase (AKR1B1). New linkages (ether/triazole/amide) were introduced via high yielding, efficient syntheses to replace the labile ester, and an original two-step (90%) preparation of BGG was developed. Inhibition of AKR1B1was assessed in vitro and using transgenic lens organ cultures, which identified the amide linked glucoside (BGA) as a stable, potent, and selective therapeutic lead toward the treatment of diabetic eye disease. PMID- 24341383 TI - Selection of trait combinations through bee and fly visitation to flowers of Polemonium foliosissimum. AB - Pollinators are known to exert natural selection on floral traits, but the extent to which combinations of floral traits are subject to correlational selection (nonadditive effects of two traits on fitness) is not well understood. Over two years, we used phenotypic manipulations of plant traits to test for effects of flower colour, flower shape and their interaction on rates of pollinator visitation to Polemonium foliosissimum. We also tested for correlational selection based on weighting visitation by the amount of conspecific pollen delivered per visit by each category of insect visitor. Although bumblebees were the presumed pollinators, solitary bees and flies contributed substantially (42%) to pollination. In manipulations of one trait at a time, insects visited flowers presenting the natural colour and shape over flowers manipulated to present artificial mutants with either paler colour or a more open or more tubular flower. When both colour and shape were manipulated in combination, selection on both traits arose, with bumblebees responding mainly to colour and flies responding mainly to shape. Despite selection on both floral traits, in a year with many bumblebees, we saw no evidence for correlational selection of these traits. In a year when flies predominated, fly visitation showed a pattern of correlational selection, but not favouring the natural phenotype, and correlational selection was still not detected for expected pollen receipt. These results show that flower colour and shape are subject to pollinator-mediated selection and that correlational selection can be generated based on pollinator visitation alone, but provide no evidence for correlational selection specifically for the current phenotype. PMID- 24341384 TI - Functioning and disability after stroke in children: using the ICF-CY to classify health outcome and inform future clinical research priorities. AB - AIM: The International Classification of Functioning Disability and Health, Child Youth version (ICF-CY) provides a framework for describing and evaluating health, intervention outcomes, and needs assessment. It can, however, also serve as a system for classifying the focus of outcome studies and identification of gaps in current knowledge. METHOD: The paediatric arterial ischaemic stroke (AIS) population was targeted. Multiple databases were systematically searched for AIS outcome studies focussing on functioning or disability. Findings were rated using the ICF-CY framework. RESULTS: Twenty-eight studies were identified. Most were cross-sectional and age range at assessment varied widely. Sixty-seven different standardized measures were used, predominantly evaluating body functions. The most common domains of activity and participation reported were learning and applying knowledge, general tasks and demands, and self-care skills. Health related quality of life was measured in nine papers. Environmental factors were rarely evaluated. INTERPRETATION: AIS outcome studies addressing the relationship between body structures and functions (e.g. brain lesion characteristics, neurological examination findings) and activities, participation, and quality of life have emerged in recent years. Comparison of findings across studies is complicated by design and tool selection. The relationship between components of activity limitation and participation restriction is rarely explored. PMID- 24341382 TI - Inhibition of LPS-induced airway neutrophilic inflammation in healthy volunteers with an oral CXCR2 antagonist. AB - BACKGROUND: Inhaled lipopolysaccharide (LPS) induces a dose-dependent, acute neutrophilic response in the airways of healthy volunteers that can be quantified in induced sputum. Chemokines, such as CXCL1 and CXCL8, play an important role in neutrophilic inflammation in the lung through the activation of CXCR2 and small molecule antagonists of these receptors have now been developed. We investigated the effect of AZD8309, a CXCR2 antagonist, compared with placebo on LPS-induced inflammation measured in sputum of healthy volunteers. METHODS: Twenty healthy subjects were randomized in a double-blind placebo-controlled, cross-over study. AZD8309 (300 mg) or placebo was dosed twice daily orally for 3 days prior to challenge with inhaled LPS and induced sputum was collected 6 h later. RESULTS: Treatment with AZD8309 showed a mean 77% reduction in total sputum cells (p < 0.001) and 79% reduction in sputum neutrophils (p < 0.05) compared with placebo after LPS challenge. There was also a reduction in neutrophil elastase activity (p < 0.05) and CXCL1 (p < 0.05) and trends for reductions in sputum macrophages (47%), leukotriene B4 (39%) and CXCL8 (52%). CONCLUSIONS: AZD8309 inhibited LPS induced inflammation measured in induced sputum of normal volunteers, indicating that this treatment may be useful in the treatment of neutrophilic diseases of the airways, such as COPD, severe asthma and cystic fibrosis. TRIAL REGISTRATION: NCT00860821. PMID- 24341385 TI - Structural impact of cations on lipid bilayer models: nanomechanical properties by AFM-force spectroscopy. AB - Atomic Force Microscopy (AFM) has become an invaluable tool for studying the micro- and nanoworlds. As a stand-alone, high-resolution imaging technique and force transducer, it defies most other surface instrumentation in ease of use, sensitivity and versatility. The main strength of AFM relies on the possibility to operate in an aqueous environment on a wide variety of biological samples, from single molecules - DNA or proteins - to macromolecular assemblies like biological membranes. Understanding the effect of mechanical stress on membranes is of primary importance in biophysics, since cells are known to perform their function under a complex combination of forces. In the later years, AFM-based Force-Spectroscopy (AFM-FS) has provided a new vista on membrane mechanics in a confined area within the nanometer realm, where most of the specific molecular interactions take place. Lipid membranes are electrostatically charged entities that physiologically coexist with electrolyte solutions. Thus, specific interactions with ions are a matter of considerable interest. The distribution of ions in the solution and their interaction with the membranes are factors that substantially modify the structure and dynamics of the cell membranes. Furthermore, signaling processes are modified by the membrane capability of retaining ions. Supported Lipid Bilayers (SLBs) are a versatile tool to investigate phospholipid membranes mimicking biological surfaces. In the present contribution, we review selected experiments on the mechanical stability of SLBs as models of lipid membranes by means of AFM-FS, with special focus on the effect of cations and ionic strength in the overall nanomechanical stability. PMID- 24341386 TI - Triamidetriamine bearing macrobicyclic and macrotricyclic ligands: potential applications in the development of copper-64 radiopharmaceuticals. AB - A versatile and straightforward synthetic approach is described for the preparation of triamide bearing analogues of sarcophagine hexaazamacrobicyclic cage ligands without the need for a templating metal ion. Reaction of 1,1,1 tris(aminoethyl)ethane (tame) with 3 equiv of 2-chloroacetyl chloride, yields the tris(alpha-chloroamide) synthetic intermediate 6, which when treated with either 1,1,1-tris(aminoethyl)ethane or 1,4,7-triazacyclononane furnished two novel triamidetriamine cryptand ligands (7 and 8 respectively). The Co(III) and Cu(II) complexes of cryptand 7 were prepared; however, cryptand 8 could not be metalated. The cryptands and the Co(III) complex 9 have been characterized by elemental analysis, (1)H and (13)C NMR spectroscopy, and X-ray crystallography. These studies confirm that the Co(III) complex 9 adopts an octahedral geometry with three facial deprotonated amido-donors and three facial amine donor groups. The Cu(II) complex 10 was characterized by elemental analysis, single crystal X ray crystallography, cyclic voltammetry, and UV-visible absorption spectroscopy. In contrast to the Co(III) complex (9), the Cu(II) center adopts a square planar coordination geometry, with two amine and two deprotonated amido donor groups. Compound 10 exhibited a quasi-reversible, one-electron oxidation, which is assigned to the Cu(2+/3+) redox couple. These cryptands represent interesting ligands for radiopharmaceutical applications, and 7 has been labeled with (64)Cu to give (64)Cu-10. This complex showed good stability when subjected to L cysteine challenge whereas low levels of decomplexation were evident in the presence of L-histidine. PMID- 24341387 TI - Monte Carlo simulation analysis of ceftobiprole, dalbavancin, daptomycin, tigecycline, linezolid and vancomycin pharmacodynamics against intensive care unit-isolated methicillin-resistant Staphylococcus aureus. AB - The aim of the present study was to compare the potential of ceftobiprole, dalbavancin, daptomycin, tigecycline, linezolid and vancomycin to achieve their requisite pharmacokinetic/pharmacodynamic (PK/PD) targets against methicillin resistant Staphylococcus aureus isolates collected from intensive care unit (ICU) settings. Monte Carlo simulations were carried out to simulate the PK/PD indices of the investigated antimicrobials. The probability of target attainment (PTA) was estimated at minimum inhibitory concentration values ranging from 0.03 to 32 MUg/mL to define the PK/PD susceptibility breakpoints. The cumulative fraction of response (CFR) was computed using minimum inhibitory concentration data from the Canadian National Intensive Care Unit study. Analysis of the simulation results suggested the breakpoints of 4 MUg/mL for ceftobiprole (500 mg/2 h t.i.d.), 0.25 MUg/mL for dalbavancin (1000 mg), 0.12 MUg/mL for daptomycin (4 mg/kg q.d. and 6 mg/kg q.d.) and tigecycline (50 mg b.i.d.), and 2 MUg/mL for linezolid (600 mg b.i.d.) and vancomycin (1 g b.i.d. and 1.5 g b.i.d.). The estimated CFR were 100, 100, 70.6, 88.8, 96.5, 82.4, 89.4, and 98.3% for ceftobiprole, dalbavancin, daptomycin (4 mg/kg/day), daptomycin (6 mg/kg/day), linezolid, tigecycline, vancomycin (1 g b.i.d.) and vancomycin (1.5 g b.i.d.), respectively. In conclusion, ceftobiprole and dalbavancin have the highest probability of achieving their requisite PK/PD targets against methicillin-resistant Staphylococcus aureus isolated from ICU settings. The susceptibility predictions suggested a reduction of the vancomycin breakpoint to 1 MUg/mL. PMID- 24341388 TI - Organocatalytic enantioselective vinylogous Michael reaction of vinylketene silyl N,O-acetals. AB - The enantioselective vinylogous Michael reaction of vinylketene silyl N,O-acetals derived from alpha,beta-unsaturated N-acyl pyrroles and a broad range of alpha,beta-unsaturated aldehydes proceeds with good regio-, diastereo-, and enantioselectivity when the Hayashi-Jorgensen diphenylprolinolsilylether was employed as a chiral organocatalyst. Products were obtained in generally good yields and as single stereoisomers after chromatographic purification with very high optical purity. They were easily derivatized into a set of useful synthetic building blocks. PMID- 24341389 TI - Plant derived secondary metabolites as anti-cancer agents. PMID- 24341390 TI - Proteomic comparison between maturation drying and prematurely imposed drying of Zea mays seeds reveals a potential role of maturation drying in preparing proteins for seed germination, seedling vigor, and pathogen resistance. AB - We have studied the role(s) of maturation drying in the acquisition of germinability, seedling vigor and pathogen resistance by comparing the proteome changes in maize embryo and endosperm during mature and prematurely imposed drying. Prematurely imposed dried seeds at 40 days after pollination (DAP) germinated almost as well as mature seeds (at 65 DAP), but their seedling growth was slower and they were seriously infected by fungi. A total of 80 and 114 proteins were identified to change at least two-fold (p < 0.05) in abundance during maturation drying in embryo and endosperm, respectively. Fewer proteins (48 and 59 in embryo and endosperm, respectively) changed in abundance during prematurely imposed drying. A number of proteins, 33 and 38 in embryo and endosperm, respectively, changed similarly in abundance during both maturation and prematurely imposed drying. Storage proteins were abundant in this group and may contribute to the acquisition of seed germinability. However, a relatively large number of proteins changed in the embryo (47 spots) and endosperm (76 spots) specifically during maturation drying. Among these proteins, storage proteins in the embryo and defense proteins in the endosperm may be particularly important for seedling vigor and resistance to fungal infection, respectively. PMID- 24341391 TI - Occupational accidents in professional dance with focus on gender differences. AB - BACKGROUND: Classical dance comprises gender specific movement tasks. There is a lack of studies which investigate work related traumatic injuries in terms of gender specific differences in detail. OBJECTIVE: To define gender related differences of occupational accidents. METHODS: Basis for the evaluation were occupational injuries of professional dancers from three (n = 785; f: n = 358, m: n = 427) state theatres. RESULTS: The incidence rate (0.36 per year) was higher in males (m: 0.45, f: 0.29). There were gender specific differences as to the localizations of injuries, particularly the spine region (m: 17.3%, f: 9.8%, p = 0.05) and ankle joint (m: 23.7%, f: 35.5%, p = 0.003). Compared to male dancers, females sustained more injuries resulting from extrinsic factors. Significant differences could specifically be observed with dance floors (m: 8.8%, f: 15.1%, p = 0.02). There were also significant gender differences observed with movement vocabulary. CONCLUSION: The clearly defined gender specific movement activities in classical dance are reflected in occupational accidents sustained. Organisational structures as well as work environment represent a burden likewise to male and female dancers. The presented differences support the development of gender specific injury prevention measures. PMID- 24341392 TI - Treatment of recalcitrant facial verrucae vulgares with sinecatechins (greentea catechins) ointment. AB - BACKGROUND: Facial verrucae vulgares are benign, but disfiguring skin manifestations of human papilloma virus infection. They are found as verrucae planae juveniles in young adults, but also as common warts in immunocompromised or atopic patients. OBJECTIVE: To find an alternative, non-surgical treatment for a young man with atopic dermatitis and facial warts, who had not responded to 5 FU ointment, waterfiltered infrared A (wIRA) irradiation and topical retinoids. METHODS: Topical treatment with a sinecatechins 10% ointment (Veregen(TM) ) as approved for genital warts thrice daily for 3 weeks in a 34-year-old man with atopic dermatitis RESULTS: Complete remission of all facial warts was achieved within 20 days. Few side-effects were observed (initially some light skin irritation only). CONCLUSION: In this case, topical sinecatechins proved to be a well-tolerated and effective alternative to treat recalcitrant facial warts without surgery. PMID- 24341393 TI - Density-functional theory of the electronic structure of molecules. AB - Recent fundamental advances in the density-functional theory of electronic structure are summarized. Emphasis is given to four aspects of the subject: (a) tests of functionals, (b) new methods for determining accurate exchange correlation functionals, (c) linear scaling methods, and (d) developments in the description of chemical reactivity. PMID- 24341394 TI - Comparison of three-dimensional speckle tracking echocardiography and two dimensional echocardiography for evaluation of left atrial size and function in healthy volunteers (results from the MAGYAR-Healthy study). AB - OBJECTIVE: Noninvasive accurate assessment of left atrial (LA) size and function is an essential requirement in daily clinical practice. Real time three dimensional (3D) echocardiography (RT3DE) with direct volumetric method has been found to be a highly accurate and reproducible noninvasive tool for the evaluation of LA dimensions and functional properties. Three-dimensional speckle tracking echocardiography (3DSTE) has just been introduced for volumetric assessments, which uses different, as called "block-matching" algorithm by strain analysis. This study was designed to compare two-dimensional (2D) echocardiography with 3DSTE for calculation of LA volumes and assessment of LA functional properties in healthy subjects. METHODS: This study comprised of randomly selected 35 healthy subjects (40.9 +/- 10.9 years, 20 men) in sinus rhythm, they all had undergone standard transthoracic 2D echocardiographic Doppler study extended with 3DSTE. RESULTS: Two-dimensional echocardiography- and 3DSTE-derived minimum (Vmin ) and maximum (Vmax ) LA volumes and LA volume before atrial contraction (Vpre A ) did not differ significantly. Calculated functional LA properties were also compared. Good correlations were found between both techniques for Vmax (r = 0.93, P < 0.0001), Vmin (r = 0.62, P < 0.0001), and Vpre A (r = 0.74, P < 0.0001). CONCLUSIONS: It may be stated that 3DSTE seems to be feasible in detection of cyclic changes in LA volumes and calculation of its functional properties is comparable to 2D echocardiography. PMID- 24341395 TI - Quantification of cytomegalovirus viral load. AB - Cytomegalovirus (CMV), a member of the Herpesviridae family, is worldwide distributed. After the primary infection, CMV induces a latent infection with possible reactivation(s). It is responsible for severe to life-threatening diseases in immunocompromised patients and in foetuses and newborns of infected mothers. For monitoring CMV load, classical techniques based on rapid culture or pp65 antigenemia are progressively replaced by quantitative nuclear acid tests (QNAT), easier to implement and standardize. A large variety of QNAT are available from laboratory-developed assays to fully-automated commercial tests. The indications of CMV quantification include CMV infection during pregnancy and in newborns, and viral surveillance of grafted and non-grafted immunocompromised patients, patients with bowel inflammatory diseases and those hospitalised in intensive care unit. A close cooperation between virologists and clinicians is essential for optimizing the benefit of CMV DNA monitoring. PMID- 24341396 TI - A second chromosomal copy of the catA gene endows Pseudomonas putida mt-2 with an enzymatic safety valve for excess of catechol. AB - Pseudomonas putida mt-2 harbours two different routes for catabolism of catechol, namely one meta pathway encoded by the xyl genes of the TOL plasmid pWW0 and one ortho pathway determined by the chromosomal ben and cat genes. P. putida mt-2 has a second chromosomal copy of the catA gene (named catA2) located downstream of the ben operon that encodes an additional catechol-1,2-dioxygenase. The metabolic and regulatory phenotypes of strains lacking one enzyme, the other and both of them in cells with and without the TOL plasmid were evaluated. The data consistently indicated that induction of the ortho pathway by benzoate plasmid less strain P. putida KT2440 led to catechol surplus, the toxicity of which at high concentrations being counteracted by CatA2. Cells carrying pWW0 but lacking catA2 experienced both a rapid loss of the plasmid when grown on benzoate (a substrate of the lower pathway) and a slowdown of their growth rate when cultured with benzylalcohol (a substrate converted to benzoate by the upper pathway). These data reveal the role of CatA2 as a type of metabolic safety valve for excess catechol that alleviates the metabolic conflict generated by simultaneous expression of the meta and ortho pathways, thereby facilitating their co existence. PMID- 24341397 TI - Do community pharmacists actively engage elderly patients in the dialogue? Results from pharmaceutical care consultations. AB - BACKGROUND: Little is known about community pharmacist-patient interaction within a consultation room, particularly in terms of patient activation and engagement. OBJECTIVE: To explore pharmacists' communication and attitudes while providing advanced medication-related services. METHODS: A cross-sectional descriptive study, using the Roter Interaction Analysis System (RIAS) framework, to analyse a sample of audio-recorded pharmaceutical care consultations with elderly patients. RESULTS: Around 15.0 per cent of pharmacists' utterances and 3.6 per cent of patients' were related to engagement with the latter during the exchange. To improve health outcomes, such as adherence to a therapeutic regime, pharmacists should augment patients' participation in the dialogue, facilitating concerns and disclosure of doubts, thus improving correct medication use behaviour. PMID- 24341398 TI - A qualitative investigation of the impact of peer to peer online support for women living with polycystic ovary syndrome. AB - BACKGROUND: Polycystic Ovary Syndrome is a common, chronic condition which affects women living with the condition both physically and psychologically. Social support may be beneficial to sufferers in coping with chronic conditions and the Internet is becoming a common place for accessing social support and information. The aim of this study was to consider the experiences of women living with Polycystic Ovary Syndrome who access and participate in an online support group discussion forum dedicated to issues surrounding this condition. METHODS: Fifty participants responded to a series of open-ended questions via an online survey. RESULTS: Thematic analysis revealed a number of empowering and disempowering experiences associated with online support group participation. The empowering processes reported by members of the group included: Connecting with others who understand; Access to information and advice; Interaction with healthcare professionals; Treatment-related decision making; Improved adjustment and management. In terms disempowering processes, only two were described by group participants: Reading about the negative experiences of others and Feeling like an outsider. CONCLUSIONS: For women living with Polycystic Ovary Syndrome, participation within an online support group may help to empower them in a range of important ways however, there may be some disempowering consequences. PMID- 24341401 TI - Polyploidy in myelofibrosis: analysis by cytogenetic and SNP array indicates association with advancing disease. AB - BACKGROUND: Myelofibrosis occurs as primary myelofibrosis or as a late occurrence in the evolution of essential thrombocythaemia and polycythaemia vera. It is the rarest of the three classic myeloproliferative neoplasms (MPN). Polyploidy has only rarely been reported in MPN despite the prominent involvement of abnormal megakaryocytes. The use of peripheral blood samples containing increased numbers of haematopoietic progenitors has improved the output from cytogenetic studies in myelofibrosis and together with the use of single nucleotide polymorphism arrays (SNPa) has contributed to an improved knowledge regarding the diverse genetic landscape of this rare disease. RESULTS: Cytogenetic studies performed on a consecutive cohort of 42 patients with primary or post ET/PV myelofibrosis showed an abnormal karyotype in 24 cases and of these, nine showed a polyploid clone. Six of the nine cases showed a tetraploid (4n) subclone, whereas three showed mixed polyploid subclones with both tetraploid and octoploid (4n/8n) cell lines. The abnormal clone evolved from a near diploid karyotype at the initial investigation to a tetraploid karyotype in follow-up cytogenetic analysis in four cases. In total, six of the nine polyploid cases showed gain of 1q material. The remaining three cases showed polyploid metaphases, but with no detectable structural karyotypic rearrangements. Three of the nine cases showed chromosome abnormalities of 6p, either at diagnosis or later acquired. SNPa analysis on eight polyploid cases showed additional changes not previously recognised by karyotype analysis alone, including recurring changes involving 9p, 14q, 17q and 22q. Except for gain of 1q, SNPa findings from the polyploid group compared to eight non-polyploid cases with myelofibrosis found no significant differences in the type of abnormality detected. CONCLUSIONS: The study showed the use of peripheral blood samples to be suitable for standard karyotyping evaluation and DNA based studies. The overall profile of abnormalities found were comparable with that of post-MPN acute myeloid leukaemia or secondary myelodysplastic syndrome and cases in the polyploidy group were associated with features of high risk disease. The above represents the first documented series of polyploid karyotypes in myelofibrosis and shows a high representation of gain of 1q. PMID- 24341402 TI - The physical activity profile of active children in England. AB - BACKGROUND: In line with WHO guidelines, the UK government currently recommends that school-aged children participate in at least 60 minutes, and up to several hours, of at least moderate physical activity on a daily basis. A recent health survey indicates that the amount of reported physical activity varies by age, gender and socioeconomic status. The objective of this study is to identify what types of activity contribute most towards overall physical activity in children who achieve the UK physical activity recommendations; and how this varies according to age, gender and socioeconomic status. METHODS: Self-reported physical activity was captured through the Health Survey for England 2008, a nationally representative, cross-sectional survey. We analysed data from 1,110 children aged 5-15 years who reported meeting the UK physical activity recommendations. The proportions of total physical activity achieved in various domains of activity were calculated and associations with age, gender and socioeconomic status were examined. RESULTS: Active play was the largest contributor to overall physical activity (boys = 48%, girls = 53%), followed by walking (boys = 17%, girls = 23%). Active school travel contributed only a small proportion (6% for boys and girls). With increasing age, the contribution from active play decreased (rho = -0.417; p < 0.001) and the contribution of walking (rho = 0.257; p < 0.001) and formal sport (rho = 0.219; p < 0.001) increased. At all ages, sport contributed more among boys than girls. Sport contributed proportionately less with increasing deprivation (rho = -0.191; p < 0.001). CONCLUSIONS: The contributors to overall physical activity among active children varies with age, socioeconomic status and gender. This knowledge can be used to target interventions appropriately to increase physical activity in children at a population level. PMID- 24341403 TI - Misrepresentation in multidisciplinary pain medicine fellowship applications to a single academic program. AB - BACKGROUND AND OBJECTIVES: Publication misrepresentation by residency applicants has been well documented, but fewer studies have investigated it in fellowship applicants, specifically in pain medicine. We therefore sought to evaluate the demographics of pain medicine fellowship applicants and the type, number, and accuracy of referenced publications they reported. METHODS: Applications to the Multidisciplinary Pain Medicine fellowship program in the Mayo School of Graduate Medical Education, Rochester, Minnesota were reviewed for three consecutive academic years (2009-2012). Demographic information and publications claimed by applicants were compiled, and publications were scrutinized by a medical librarian for accuracy. RESULTS: Over a 3-year period, 179 fellowship applications were received. Of the 179 applicants, more than half (106 [59%]) listed at least one publication. Of 324 listed publications, 263 were verifiable; of these, 14 (5.3%) were deemed fraudulent, and six (2.3%) contained an inaccuracy possibly conferring a competitive advantage. In our small sample size, we found no difference in the rate of publications or in the accuracy of listed publications across subspecialties, or between US medical graduates and international medical graduates. CONCLUSIONS: The lack of national data, specifically on applicant misrepresentation, due to the heretofore absence of a universal application process or match, impedes assessment of the extent to which these findings are representative of the national applicant pool. We observed notable trends (few female applicants; numerous international medical graduate applicants) different from those reported by other specialties. Despite the low rate (5.3%) of fraudulent publications, fellowship program directors and selection committees should be aware of this possibility to ensure selection of fellows with the highest degree of professional and ethical integrity. PMID- 24341405 TI - Interspecies and intraspecies interactions in social amoebae. AB - The stable co-existence of individuals of different genotypes and reproductive division of labour within heterogeneous groups are issues of fundamental interest from the viewpoint of evolution. Cellular slime moulds are convenient organisms in which to address both issues. Strains of a species co-occur, as do different species; social groups are often genetically heterogeneous. Intra- and interspecies 1 : 1 mixes of wild isolates of Dictyostelium giganteum and D. purpureum form chimaeric aggregates, following which they segregate to varying extents. Intraspecies aggregates develop in concert and give rise to chimaeric fruiting bodies that usually contain more spores (reproductives) of one component than the other. Reproductive skew and variance in the proportion of reproductives are positively correlated. Interspecies aggregates exhibit almost complete sorting; most spores in a fruiting body come from a single species. Between strains, somatic compatibility correlates weakly with sexual compatibility. It is highest within clones, lower between strains of a species and lowest between strains of different species. Trade-offs among fitness-related traits (between compatible strains), sorting out (between incompatible strains) and avoidance (between species) appear to lie behind coexistence. PMID- 24341404 TI - A flexible statistical model for alignment of label-free proteomics data- incorporating ion mobility and product ion information. AB - BACKGROUND: The goal of many proteomics experiments is to determine the abundance of proteins in biological samples, and the variation thereof in various physiological conditions. High-throughput quantitative proteomics, specifically label-free LC-MS/MS, allows rapid measurement of thousands of proteins, enabling large-scale studies of various biological systems. Prior to analyzing these information-rich datasets, raw data must undergo several computational processing steps. We present a method to address one of the essential steps in proteomics data processing--the matching of peptide measurements across samples. RESULTS: We describe a novel method for label-free proteomics data alignment with the ability to incorporate previously unused aspects of the data, particularly ion mobility drift times and product ion information. We compare the results of our alignment method to PEPPeR and OpenMS, and compare alignment accuracy achieved by different versions of our method utilizing various data characteristics. Our method results in increased match recall rates and similar or improved mismatch rates compared to PEPPeR and OpenMS feature-based alignment. We also show that the inclusion of drift time and product ion information results in higher recall rates and more confident matches, without increases in error rates. CONCLUSIONS: Based on the results presented here, we argue that the incorporation of ion mobility drift time and product ion information are worthy pursuits. Alignment methods should be flexible enough to utilize all available data, particularly with recent advancements in experimental separation methods. PMID- 24341406 TI - Why parents refuse childhood vaccination: a qualitative study using online focus groups. AB - BACKGROUND: In high income countries, vaccine-preventable diseases have been greatly reduced through routine vaccination programs. Despite this success, many parents question, and a small proportion even refuse vaccination for their children. As no qualitative studies have explored the factors behind these decisions among Dutch parents, we performed a study using online focus groups. METHODS: In total, eight online focus groups (n = 60) which included Dutch parents with at least one child, aged 0-4 years, for whom they refused all or part of the vaccinations within the National Immunization Program (NIP). A thematic analysis was performed to explore factors that influenced the parents' decisions to refuse vaccination. RESULTS: Refusal of vaccination was found to reflect multiple factors including family lifestyle; perceptions about the child's body and immune system; perceived risks of disease, vaccine efficacy, and side effects; perceived advantages of experiencing the disease; prior negative experience with vaccination; and social environment. The use of online focus groups proved to be an effective qualitative research method providing meaningful data. CONCLUSION: Information provided by the NIP turned out to be insufficient for this group of parents. More trust in the NIP and deliberate decisions might result from increased parental understanding of lifestyle and disease susceptibility, the impact of vaccinations on the immune system, and the relative risks of diseases and their vaccines. The public health institute should also inform parents that the NIP is recommended but non-mandatory. PMID- 24341407 TI - C?N-containing azaarenes as activating groups in enantioselective catalysis. AB - Nitrogen-containing aromatic heterocycles (azaarenes) are of widespread chemical significance, and chiral compounds containing azaarenes feature prominently in pharmaceuticals, agrochemicals, and natural products. This Perspective highlights the use of a relatively underdeveloped strategy to prepare chiral azaarene containing compounds: exploitation of the C?N bond embedded within certain azaarenes to activate adjacent functionality in catalytic asymmetric reactions. Work in this area has resulted in the development of several different types of catalytic enantioselective processes, including reductions, nucleophilic additions, and reductive couplings. It is hoped that this Perspective will encourage more researchers to work in this promising area. PMID- 24341408 TI - Is outcome of constraint-induced movement therapy in unilateral cerebral palsy dependent on corticomotor projection pattern and brain lesion characteristics? AB - AIM: The aim of the study was to explore individual variations in outcome of hand function after constraint-induced movement therapy (CIMT) in relation to the organization of corticomotor projection and brain lesion characteristics in participants with unilateral cerebral palsy (CP). METHOD: Sixteen participants (eight males, eight females; mean age 13 y, [SD 2 y] range 10-16 y) with unilateral CP (nine right-sided; Manual Ability Classification System [MACS] level I, n=1; level II, n=15) who participated in a 2-week CIMT day camp (63 h) were included in the study. Various aspects of hand function were measured by the Jebsen-Taylor Hand Function Test (JTHFT), the Assisting Hand Assessment (AHA), and the Melbourne Assessment, both before and after the day camp. Transcranial magnetic stimulation was used to explore the corticomotor organization, and brain lesion characteristics were described by visual assessment of conventional structural magnetic resonance images. RESULTS: At a group level, the training was associated with significant improvements in JTHFT (p=0.003) and AHA (p=0.046), but not in Melbourne Assessment scores. Improvements were found in all types of corticomotor projection patterns, i.e. contralateral, mixed, and ipsilateral. There was no relationship between functional improvement and brain lesion characteristics. INTERPRETATION: Individuals with CP experience improved motor outcomes after CIMT, independent of corticomotor projection pattern and lesion characteristics. PMID- 24341409 TI - Novel faces of heme oxygenase-1: mechanisms and therapeutic potentials. AB - Not only double, Janus face, but numerous appearances characterize heme oxygenase 1 (HO-1), an inducible enzyme which main role is to degrade heme. Recently, the noncanonical functions of HO-1 have particularly attracted researchers' attention. Indeed, understanding the enzyme-independent activities of HO-1 can provide additional chances for translational application of research on HO-1. In this Forum, eight reviews and two original articles describe a plethora of mechanisms in which this pleiotropic protein is involved. Further understanding of HO-1 functions is of particular significance for elucidating the pathology of various human diseases and providing rationale for novel therapies. PMID- 24341411 TI - Infection- and procedure-dependent effects on pulmonary gene expression in the early phase of influenza A virus infection in mice. AB - BACKGROUND: Investigating the host response in the early stage of influenza A virus (IAV) infection is of considerable interest. However, it is conceivable that effects due to the anesthesia and/or intranasal infection procedure might introduce artifacts. We therefore aimed to evaluate the effects of anesthesia and/or intranasal infection on transcription of selected pulmonary mRNAs in two inbred mouse strains with differential susceptibility to IAV infection. RESULTS: DBA/2J and C57BL/6J mice were evaluated in a time course experiment in which lung tissue was sampled after 6, 12, 18, 24, 48 and 120 h. After anesthesia with ketamine and xylazine, a suspension of mouse-adapted IAV strain PR8_Mun in 20 MUl sterile buffer, or 20 MUl sterile buffer only, was instilled intranasally. The mice receiving anesthesia and PBS only were designated the "mock treatment" group. Pulmonary expression of 10 host mRNAs (Fos, Retnla, Irg1, Il6, Il1b, Cxcl10, Stat1, Ifng, Ifnl2, and Mx1) and viral hemagglutinin (HA) mRNA were determined at the designated time points. As expected, weight loss and viral replication were greater in the DBA/2J strain (which is more susceptible to IAV infection). Four mRNAs (Retnla, Irg1, Il6, and Cxcl10) were procedure-dependently regulated in DBA/2J mice between 6 and 24 h, and two (Retnla and Il6) in C57BL/6J mice, although to a lesser extent. All 10 mRNAs rose after infection, but one (Fos) only in DBA/2J mice. These infection-dependent effects could be separated from procedure-dependent effects beginning around 12 h in DBA/2J and 18 h in C57BL/6J mice. The interferon-related mRNAs Stat1, Ifng, Infl2, and Mx1 were unaffected by mock treatment in either mouse strain. Mx1 and Infl2 correlated best with HA mRNA expression (r = 0.97 and 0.93, respectively, in DBA/2J). CONCLUSIONS: These results demonstrate effects of the anesthesia and/or intranasal infection procedure on pulmonary gene expression, which are detectable between approximately 6 and 24 h post procedure and vary in intensity and temporal evolution depending on the mouse strain used. Mock infection controls should be included in all studies on pulmonary gene expression in the early phase of infection with IAV and, likely, other respiratory pathogens. PMID- 24341413 TI - Functional architecture of the CFTR chloride channel. AB - Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a member of the ATP-binding cassette (ABC) family of membrane transport proteins. CFTR is unique among ABC proteins in that it functions not as an active transporter but as an ATP-gated Cl(-) channel. As an ion channel, the function of the CFTR transmembrane channel pore that mediates Cl(-) movement has been studied in great detail. On the other hand, only low resolution structural data is available on the transmembrane parts of the protein. The structure of the channel pore has, however, been modeled on the known structure of active transporter ABC proteins. Currently, significant barriers exist to building a unified view of CFTR pore structure and function. Reconciling functional data on the channel with indirect structural data based on other proteins with very different transport functions and substrates has proven problematic. This review summarizes current structural and functional models of the CFTR Cl(-) channel pore, including a comprehensive review of previous electrophysiological investigations of channel structure and function. In addition, functional data on the three-dimensional arrangement of pore-lining helices, as well as contemporary hypotheses concerning conformational changes in the pore that occur during channel opening and closing, are discussed. Important similarities and differences between different models of the pore highlight current gaps in our knowledge of CFTR structure and function. In order to fill these gaps, structural and functional models of the membrane-spanning pore need to become better integrated. PMID- 24341412 TI - Impaired immune defense in hemodialysis patients: role of alpha-defensins? AB - The mechanisms underlying the impaired immune response in hemodialysis (HD) patients are not completely understood. The alpha-defensins human neutrophil peptides-1, 2, and 3 are low molecular weight peptides with antimicrobial activity and important effector molecules of innate immune responses. We now examined the expression of these peptides in HD patients. Seventy-six patients on chronic HD treatment (mean time on HD 5.8 years; mean age 70 years) were studied and compared with 38 healthy volunteers and 20 patients with infections and normal renal function. Expression of alpha-defensins was analyzed semiquantitatively in leukocytes on the messenger RNA (mRNA) level by reverse transcriptase polymerase chain reaction; the alpha-defensin protein levels in serum were detected by enzyme-linked immunosorbent assay. alpha-Defensin concentrations (140 +/- 10.5 ng/mL; mean +/- standard error of the mean) as well as mRNA levels in leukocytes (82.9 +/- 7.9 arbitrary units [a.u.]) in HD patients were not significantly different from those in healthy volunteers (156 +/- 15.2 ng/mL; 81.4 +/- 11.3 a.u.). Defensin levels were independent of the time of the patient on HD and their age. During infection periods (mean increase of the C reactive protein to 161 +/- 17.3 mg/L), defensin serum levels increased to 321 +/ 65 ng/mL (P < 0.005) and mRNA expression in leukocytes to 159 +/- 19.2 a.u. (P < 0.05). These increases were not significantly different from those in patients with normal renal function (298 +/- 46.8 ng/mL and 128 +/- 9.1 a.u., respectively) suffering from infections (C-reactive protein 222 +/- 26.6 mg/L). Our results suggest that the impaired immune defense in dialysis patients is not due to a deficiency in alpha-defensins in these patients as neither basal levels nor expression during infections were reduced compared with subjects with normal renal function. PMID- 24341410 TI - The prevention and management of infections due to multidrug resistant organisms in haematology patients. AB - Infections due to resistant and multidrug resistant (MDR) organisms in haematology patients and haematopoietic stem cell transplant recipients are an increasingly complex problem of global concern. We outline the burden of illness and epidemiology of resistant organisms such as gram-negative pathogens, vancomycin-resistant Enterococcus faecium (VRE), and Clostridium difficile in haematology cohorts. Intervention strategies aimed at reducing the impact of these organisms are reviewed: infection prevention programmes, screening and fluoroquinolone prophylaxis. The role of newer therapies (e.g. linezolid, daptomycin and tigecycline) for treatment of resistant and MDR organisms in haematology populations is evaluated, in addition to the mobilization of older agents (e.g. colistin, pristinamycin and fosfomycin) and the potential benefit of combination regimens. PMID- 24341414 TI - An efficient immunodetection method for histone modifications in plants. AB - BACKGROUND: Epigenetic mechanisms can be highly dynamic, but the cross-talk among them and with the genome is still poorly understood. Many of these mechanisms work at different places in the cell and at different times of organism development. Covalent histone modifications are one of the most complex and studied epigenetic mechanisms involved in cellular reprogramming and development in plants. Therefore, the knowledge of the spatial distribution of histone methylation in different tissues is important to understand their behavior on specific cells. RESULTS: Based on the importance of epigenetic marks for biology, we present a simplified, inexpensive and efficient protocol for in situ immunolocalization on different tissues such as flowers, buds, callus, somatic embryo and meristematic tissue from several plants of agronomical and biological importance. Here, we fully describe all the steps to perform the localization of histone modifications. Using this method, we were able to visualize the distribution of H3K4me3 and H3K9me2 without loss of histological integrity of tissues from several plants, including Agave tequilana, Capsicum chinense, Coffea canephora and Cedrela odorata, as well as Arabidopsis thaliana. CONCLUSIONS: There are many protocols to study chromatin modifications; however, most of them are expensive, difficult and require sophisticated equipment. Here, we provide an efficient protocol for in situ localization of histone methylation that dispenses with the use of expensive and sensitive enzymes. The present method can be used to investigate the cellular distribution and localization of a wide array of proteins, which could help to clarify the biological role that they play at specific times and places in different tissues of various plant species. PMID- 24341415 TI - Synthesis and photochemical properties of pH responsive tris-cyclometalated iridium(III) complexes that contain a pyridine ring on the 2-phenylpyridine ligand. AB - In our previous publication, it was reported that fac-Ir(atpy)3 3 (atpy = 2-(5' amino-4'-tolyl)pyridine), which contains three amino groups at the 5'-position of the atpy ligands, exhibits a pH-dependent change in the color of the emitted radiation. Aqueous solution of 3 shows a weak red emission (at around 613 nm) under neutral or basic conditions, but the emission color changes to green (at around 530 nm) under acidic conditions, where the NH2 group is protonated to become an electron-withdrawing (NH3)(+) group. In this manuscript, we report on the preparation of some new pH-responsive Ir(III) complexes; fac-Ir(4Pyppy)3 5 and fac-Ir(3Pyppy)3 6 that contain three pyridyl groups at the 5'-position of the 2-phenylpyridine (ppy) ligand, and Ir(4Pyppym)3 7 and Ir(3Pyppym)3 8 that contain a pyridyl group at the same position of the 2-phenylpyrimidine (ppym) ligand. The introduction of three pyridyl groups on iodinated Ir(ppy)3 and Ir(ppym)3 was achieved via Suzuki-Miyaura cross-coupling reaction assisted by microwave irradiation. Solutions of the acid-free Ir(III) complexes 5, 6, 7, and 8 showed a strong green emission (at around 500 nm) in dimethylsulfoxide (DMSO). Protonation of three pyridyl groups of 5 and 7 causes a significant red-shift in the emission wavelength (at around 600 nm) with a decrease in emission intensity. The pH dependent emission change of these complexes is also discussed. The generation of singlet oxygen ((1)O2) by the photoirradiation of the Ir complexes 5 and 6 was evidenced by the decomposition of 1,3-diphenylisobenzofuran (DPBF), the oxidation of thioanisole, and the oxidation of 2,2,5,5-tetramethyl-3-pyrroline-3 carboxamide (TPC). The induction of necrosis-like cell death of HeLa-S3 cells upon photoirradiation of 5 at 465 nm is also reported. PMID- 24341416 TI - Iminium ion-enamine cascade cyclizations: facile access to structurally diverse azacyclic compounds and natural products. AB - A one-pot, mild, two-component iminium ion-enamine cascade reaction to construct structurally diverse azacyclic frameworks from l-proline and l-pipecolic acid, and its application to indolizidine and quinolizidine alkaloids and azasteroids, is reported. PMID- 24341417 TI - Cyclooxygenase 2 expression and apoptosis in normal and psoriatic epidermis models exposed to salt water soaks and narrowband ultraviolet B radiation. AB - BACKGROUND: Combined treatment using salt water baths and artificial ultraviolet (UV) radiation (balneophototherapy, BPT) is a common therapeutic option for conditions such as psoriasis. However, it remains unknown whether pre-treatment with salt water soaks alter inflammatory and/or carcinogenic effects of UVB phototherapy. OBJECTIVES: We aimed to investigate the impact of BPT on COX-2 gene expression and apoptosis in normal and psoriatic keratinocytes. METHODS: Normal epidermis models (NEM) and psoriatic epidermis models (PEM) were treated using different salt water soaks (3% NaCl, 30% NaCl, 30% Dead Sea salt; DSS) and subsequent narrowband ultraviolet B (NB-UVB) for three consecutive days. RT-PCR was performed for cyclooxygenase 2 (COX-2), survivin, and caspase-3. RESULTS: Compared with untreated controls COX-2 mRNA was significantly increased in NB-UVB irradiated NEM and PEM. NB-UVB-exposed and non-exposed 30% NaCl and 30% DSS treated NEM and PEM (except for NB-UVB-exposed and non-irradiated 30% DSS) showed significantly higher COX-2 mRNA when compared with controls and 3% NaCl. In NB UVB-exposed 30% NaCl and 30% DSS-treated NEM and PEM survivin mRNA was significantly decreased when compared with controls and 3% NaCl. Compared with NB UVB-exposed controls mRNA of caspase-3 was significantly increased in NB-UVB exposed 30% NaCl and 30% DSS-treated PEM. CONCLUSION: Although BPT using high concentrated salt water solutions is associated with increased epidermal COX-2 mRNA expression, apoptosis of keratinocytes is enhanced possibly due to the down regulation of survivin mRNA expression. If confirmed in larger studies these observations have important implications for BPT efficacy as well as safety, particularly with regard to the risk of early carcinogenesis. PMID- 24341418 TI - Fluidity in autobiographical memories: relationship memories sampled on two occasions. AB - We investigated consistency of relationship memories. College undergraduates described five events (first meeting, first date, first fight, most embarrassing event, and favourite memory) from their current relationship or, if not currently dating, most recent relationship. Three months later, they were asked to describe the same events again. We scored the consistency of these narratives at three levels of analysis: event, basic information and propositions. The participants demonstrated low consistency in their descriptions, particularly at more detailed levels of analysis. Consistency depended somewhat on the events being recalled, with participants being more consistent for commonly retrieved relationship memories such as first dates. We also found that those individuals who continued in a relationship were less consistent than those describing a previous relationship. These still dating couples had increased opportunities to narrate event stories together and to update knowledge about the relationship through new episodes. In this fashion, updating of experiences may have led to more inconsistencies in recall over time. When considered with research on flashbulb memories, our findings indicate that updating and revisions may be general features of autobiographical memory. PMID- 24341419 TI - Trying to understand gestational diabetes. AB - Women with normal glucose tolerance pre-gravid and developing gestational diabetes in late gestation have subclinical metabolic dysfunction prior to conception compared with women with normal glucose tolerance. Because of the 60% decrease in insulin sensitivity with normal pregnancy, these women develop clinical hyperglycaemia/gestational diabetes in late gestation. The metabolic dysfunction includes impaired insulin response, decreased hepatic suppression of glucose production during insulin infusion and decreased insulin-stimulated glucose uptake in skeletal muscle, i.e. peripheral insulin resistance. The insulin resistance in normal glucose tolerance pregnancy is related to a decrease in the post-receptor insulin signalling cascade, specifically decreased insulin receptor substrate 1 tyrosine phosphorylation. In women with normal glucose tolerance this is reversed post-partum. In contrast, in gestational diabetes, in addition to the decrease in insulin receptor substrate 1 tyrosine phosphorylation, there is an additional decrease in tyrosine phosphorylation of the intracellular portion of the insulin receptor that is not related to the insulin receptor protein content. Post-partum women with gestational diabetes, who had retention of gestational weight gain, had no significant improvement in insulin sensitivity and increased inflammation expressed as increased plasma and skeletal muscle tumour necrosis factor alpha. The increased inflammation or meta inflammation is a hallmark of obesity and during pregnancy develops in both white adipose tissue and placenta. Last gene array studies of placenta were associated with alterations in gene expression relating primarily to lipid in contrast to glucose metabolic pathways in gestational diabetes compared with Type 1 diabetes. Future studies are directed at decreasing inflammation prior to and during pregnancy using various lifestyle and nutritional interventions. PMID- 24341420 TI - Inhibitory effects of grape skin extract and resveratrol on fatty acid synthase. AB - BACKGROUND: Grape skin, a rich source of phytochemicals, has been reported to possess remarkable anti-obesity activity. Fatty acid synthase (FAS) is a key enzyme catalyzing the synthesis of fatty acid de novo, and has been considered as an anti-obesity target. To elucidate the anti-obesity mechanism of grape skin, we investigated the effects of grape skin extract (GSE) and resveratrol, one of the phytochemicals in GSE, on FAS and FAS over-expressed 3 T3-L1 preadipocyte. METHODS: Purified FAS was obtained from chicken liver. Dried grape skin was extracted by 50% ethanol and partitioned by ethyl acetate. Inhibitory effects of GSE and resveratrol on FAS including fast-binding inhibition, time-dependent inhibition, and enzyme kinetics were determined. Inhibitory effects of GSE and resveratrol on 3T3-L1 preadipocyte were also measured. RESULTS: GSE inhibited the overall reaction and beta-ketoacyl reductase (KR) reaction of FAS with IC50 values of 4.61 MUg/ml and 20.3 MUg/ml. For inhibition by resveratrol, the relevant IC50 values were 11.1 MUg/ml and 21.9 MUg/ml, respectively. And both GSE and resveratrol showed time-dependent inhibition for FAS, with the kobs values of 0.028 min-1, and 0.040 min-1 respectively. They inhibited the overall reaction of FAS competitively with acetyl-CoA, noncompetitively with malonyl-CoA and in a mixed manner with NADPH. Moreover, the inhibition on KR domain by resveratrol was time-dependent with kobs value of 0.106 min-1. In 3 T3-L1 preadipocytes, resveratrol reduced lipid accumulation remarkably. CONCLUSIONS: GSE and resveratrol are potent FAS inhibitors and they bound reversibly to the KR domain of FAS to inhibit the reduction of the saturated acyl groups in fatty acid synthesis. Based on the valid data and deliberate analysis, we proposed that GSE and resveratrol have great medical potential and officinal value in treating obesity and related diseases. PMID- 24341421 TI - Using cumulative toxicity to identify the optimal second-line targeted therapy in patients with metastatic renal cell carcinoma: what's new? AB - The life expectancy in metastatic renal cell carcinoma patients treated with targeted therapies can be influenced by the time spent on treatment, and the current focus of clinical research in this field appears to be on extending the time on treatment while limiting toxicities. It has been proposed that a strategy based on the sequential administration of two tyrosine kinase inhibitors could result in unacceptable cumulative toxicity for many metastatic renal cell carcinoma patients, while switching to a mTOR inhibitor does not. However, a definite consensus on this issue has not been reached. As very little information from head-to-head studies is available, clinicians have to base their treatment decisions on existing evidence, with an obvious preference for high-quality studies. Some recent studies have provided new insights into the issue of cumulative toxicity of second-line targeted therapies in metastatic renal cell carcinoma patients. In this article, we discuss the evidence emerging from the randomized AXIS and RECORD-3 trials. PMID- 24341422 TI - Cancer patient experience, hospital performance and case mix: evidence from England. AB - AIMS: This study aims to explore differences between crude and case mix adjusted estimates of hospital performance with respect to the experience of cancer patients. MATERIALS & METHODS: This study analyzed the English 2011/2012 Cancer Patient Experience Survey covering all English National Health Service hospitals providing cancer treatment (n = 160). Logistic regression analysis was used to predict hospital performance for each of the 64 evaluative questions, adjusting for age, gender, ethnic group and cancer diagnosis. The degree of reclassification was explored across three categories (bottom 20%, middle 60% and top 20% of hospitals). RESULTS: There was high concordance between crude and adjusted ranks of hospitals (median Kendall's tau = 0.84; interquartile range: 0.82-0.88). Across all questions, a median of 5.0% (eight) of hospitals (interquartile range: 3.8-6.4%; six to ten hospitals) moved out of the extreme performance categories after case mix adjustment. CONCLUSION: In this context, patient case mix has only a small impact on measured hospital performance for cancer patient experience. PMID- 24341423 TI - Novel telemedicine technologies in geriatric chronic non-cancer pain: primary care providers' perspectives. AB - OBJECTIVE: We sought to identify primary care providers' interest in, as well as perceived barriers and facilitators to, using novel telemedicine technologies (e.g., smartphones) for managing chronic non-cancer pain (CNCP) in older adults. DESIGN: Six focus groups were conducted with 25 primary care providers. SETTING: Two academically affiliated primary care practices serving older adults with CNCP in New York City. METHODS: The investigators used content analysis to analyze transcribed focus group data and identify specific themes. RESULTS: While most providers reported limited use of telemedicine, they expressed substantial interest in trying devices such as smartphones in the management of older patients with CNCP. Perceived barriers to implementation of telemedicine tools included information overload, lack of mobile device usability among patients and clinicians, liability issues, and cost. To overcome these barriers, participants suggested implementing electronic or human-based pre-analysis of data (e.g., a computer or a person that triages patient data), creating a low-cost and user friendly mobile device design, and targeting appropriate user populations. CONCLUSIONS: Primary care providers are interested in applying telemedicine when caring for older adults with CNCP. Although they perceived multiple barriers to device implementation, they offered innovative solutions to address these barriers. Providers felt that novel telemedicine technologies may improve the management of CNCP but wanted evidence that the devices were both cost- and time efficient, and led to improved patient outcomes before adopting their use in practice. PMID- 24341424 TI - Applications of docking and molecular dynamic studies on the search for new drugs against the biological warfare agents Bacillus anthracis and Yersinia pestis. AB - The fear of biological warfare agents (BWA) use by terrorists is the major concern of the security agencies and health authorities worldwide today. The non existence of vaccines or drugs against most BWA and the possibility of genetic modified strains has turned the search for new drugs to a state of urgency. Fast in silico techniques are, therefore, perfect tools for this task once they can quickly provide structures of several new lead compounds for further experimental work. Here we try to present a mini-review on docking and molecular dynamics simulations studies applied to the drug design against the BWA Bacillus anthracis and Yersinia pestis. PMID- 24341425 TI - Serum thyroglobulin improves the sensitivity of the McGill Thyroid Nodule Score for well-differentiated thyroid cancer. AB - BACKGROUND: The McGill Thyroid Nodule Score (MTNS) is a scoring system devised to help physicians to assess the preoperative risk that a thyroid nodule is malignant. It uses 22 different known risk factors for thyroid cancer (radiation exposure, microcalcifications on ultrasound, positive HBME-1 stain on biopsy, etc.) and attributes a percentage risk that the nodule is malignant. Recently, preoperative thyroglobulin (Tg) levels have been shown to correlate with the risk of malignancy. The aim of this study was to incorporate Tg levels into the already established MTNS. METHODS: This is a retrospective analysis of 184 thyroidectomy patients at the McGill University Thyroid Cancer Center. Patients with preoperative Tg levels were included in the study, and patients with incidental papillary microcarcinoma without extrathyroidal extent on final pathology were excluded. MTNS scores were calculated for all patients. Preoperative Tg levels of 75 ng/mL added one point to the MTNS, and levels of 187.5 ng/mL added two points. The new system is named MTNS+. RESULTS: Malignancy rates were calculated for each MTNS+ score. Patients with a score of 0-1 were <5% at risk of malignancy. The malignancy rate for scores of 2-3 was 14.29%, followed by 28.95% for scores of 4-6, 32.65% for scores of 7-8, 64.86% for scores of 9-11, 71.43% for scores of 12-14, 78.57% for scores of 15-18, and 92.31% for scores of 19-22. All patients (five of five) with an MTNS+ score of 23 or more had a malignant final pathology result. Patients with scores greater than eight had a relative risk of 2.5 [CI 1.79-3.49] of malignancy compared to patients with lower scores. MTNS+ showed good specificity at higher scores, with 89%, 96%, and 100% at scores above 11, 14, and 20 respectively. Compared to MTNS, adding Tg levels did not improve positive predictive values (PPV) or specificity, but improved sensitivity by 7.89% for scores greater than eight, and by up to 10.48% for scores greater than seven. CONCLUSION: This study shows that adding Tg to the MTNS increases the sensitivity of this scoring system. Moreover, it suggests that a combined scoring system such as the MTNS+ can accurately stratify the risk of well-differentiated malignancy in patients with thyroid nodules. PMID- 24341427 TI - Blood donation within the family: the transmission of values and practices. AB - BACKGROUND: This article presents the results of our study, which aimed to examine the role of family in the transmission of practices and values associated with blood donation. STUDY DESIGN AND METHODS: Fifty-two qualitative semi structured interviews were conducted in the province of Quebec, Canada. They were categorized into three distinct dyads (one parent and one child interviewed per dyad): 1) parent donor/child donor (10 dyads); 2) parent nondonor/child donor (8 dyads); and 3) parent donor/child nondonor (8 dyads). RESULTS AND CONCLUSION: Our results point to two kinds of families: in the first type, blood donation has been an integral "part of life" for generations and we can observe a process of transmission--a set of practices that encompasses imitation or modeling. In the second type of family, the act of donating blood was perceived and defined as an individual one, in the sense of personal, and sometimes even as a private gesture: a majority of young donors started giving at their colleges' blood drives without discussing it with their families. PMID- 24341426 TI - Bedroom media, sedentary time and screen-time in children: a longitudinal analysis. AB - BACKGROUND: Having electronic media in the bedroom is cross-sectionally associated with greater screen-time in children, but few longitudinal studies exist. The aim of this study was to describe longitudinal patterns of ownership and examine cross-sectional and longitudinal associations of bedroom media with children's sedentary behaviour. METHODS: Data are from the Sport, Physical activity and Eating behaviour: Environmental Determinants in Young people (SPEEDY) study, collected at 3 time-points: baseline (2007, T0; age 10.3 +/- 0.3 years), 1-year (T1y) and 4-year (T4y) follow-up. For each assessment, 1512 (44.9% male), 715 (41.0% male), and 319 (48.3% male) participants provided valid accelerometer data. Outcome variables were accelerometer-assessed sedentary time and self-reported screen-time. The presence of a television or computer in the bedroom was self-reported by participants and a combined bedroom media score calculated as the sum of such items. Cross-sectional and longitudinal associations between bedroom media and each outcome were examined using multi level linear regression. RESULTS: Bedroom TV ownership fell from 70.9% at T0 to 42.5% at T4y. Having a TV in the bedroom (beta; 95% CI*100, T0: -1.17; -1.88, 0.46. T1y: -1.68; -2.67, -0.70) and combined bedroom media (T0: -0.76; -1.26, 0.27. T1y: -0.79; -1.51, -0.07) were negatively associated with objectively measured weekly sedentary time at T0 and T1y. Having a computer in the bedroom (beta; 95% CI, T0: 0.15; 0.02, 0.29. T4y: 0.35; 0.10, 0.60) and combined bedroom media (T0: 0.09: 0.01, 0.18. T4y: 0.20; 0.05, 0.34) were positively associated with screen-time at T0 and T4y. Relative to participants without a computer throughout the study, children that had a computer in their bedroom at T0 but not at T4y (beta; 95% CI for change in screen-time: -8.02; -12.75, -3.29) reported smaller increases in screen-time. CONCLUSIONS: The bedroom media environment changes with age and exhibits a complex relationship with children's sedentary behaviour. Modifying children's bedroom media environment may impact upon screen time but appears unlikely to influence overall sedentary time. PMID- 24341428 TI - Predicting first lifetime plasma donation among whole blood donors. AB - BACKGROUND: The aim of the study was to predict a first lifetime plasma donation among whole blood donors. STUDY DESIGN AND METHODS: A sample of 252 whole blood donors, who never donated plasma, completed the study questionnaire assessing intention, attitudes, subjective norm, and perceived behavioral control toward giving plasma. The dependent variables were intention to give plasma and first lifetime plasma donation within 6 months. RESULTS: At 6 months, 57 individuals had made 98 plasma donations. First lifetime plasma donation was predicted by intention (p < 0.05) and age (50+ years, p < 0.05). Intention was determined by attitudes (p < 0.001) and perceived behavioral control (p < 0.001). CONCLUSION: Promotional strategies to recruit new plasma donors should target individuals aged 50 years and more. Such strategies should be coupled with actions to lower the perceived barriers and highlight the perceived advantages of becoming a plasma donor. PMID- 24341429 TI - The influence of acculturation, medical mistrust, and perceived discrimination on knowledge about blood donation and blood donation status. AB - AIM: The aim of this research was to assess whether perceived discrimination, the level of acculturation, and medical mistrust are associated with knowledge about blood donation processes and blood donation status. METHODS: This cross-sectional study involved 425 African migrants recruited in Melbourne and Adelaide, Australia. Participants were surveyed face-to-face using bilingual workers to maximize the inclusion across different levels of literacy in the community. RESULTS: In the adjusted model, the scores for knowledge about blood donation were positively associated with a longer stay in Australia (beta = 0.12, p = 0.001), significantly higher among those with a tertiary education (beta = 0.75; p = 0.049), those who came from rural areas (beta = 1.54, p = 0.015), and Christians (beta = 1.83, p < 0.01) but significantly lower among those from the western African region (beta = -1.10, p = 0.032). Scores for knowledge about blood donation were lower among those who were marginalized (beta = -1.01, p = 0.026). Medical mistrust and perceived discrimination were not associated with knowledge about blood donation. Participants who were traditionally orientated were 69% less likely to have ever given blood than those who were bicultural or integrated (odds ratio [OR]: 0.31, p = 0.044), whereas the effects of perceived discrimination and medical mistrust were not significant. We also examined whether to restrict the analysis to those who had given blood in Australia postmigration and found that the level of acculturation and medical mistrust were not significant but that perceived discrimination, especially personal discrimination, mattered (OR = 0.63, p = 0.005). CONCLUSION: Efforts to increase blood donation among African migrants need to address the issues related to perceived personal discrimination as an important intervention target. PMID- 24341430 TI - The symbolic roots of blood donation. AB - BACKGROUND: Throughout history, blood has been embedded with powerful and paradoxical connotations. In the last decades, a more rational conception based on scientific knowledge has emerged, portraying blood as a "disenchanted" and utilitarian object, hence more apt for donation between strangers. This study aims to examine blood's representations in Quebec, Canada. STUDY DESIGN AND METHODS: Data were collected in four separate studies carried out between 2009 and 2011 in Quebec. A total of 234 1 to 11/2 hour-long semi-structured qualitative interviews were conducted with: 184 donors (including lapsed donors) and 50 nondonors; 106 women and 128 men from a variety of age groups eligible to donate; 76 minority informants from Asian, Middle-Eastern, Latin American, African, and Caribbean origins; and 158 informants from the majority society. RESULTS: Many respondents donated blood because it was a "useful" substance. Others associated blood donation with a gift of vitality, strength, and energy. Some stressed the irreplaceable nature of blood, its rarity, and preciousness. It can also be associated with worrisome representations and seen as "bad" or carry infections: as a fluid, it has the ability to cross troublesome body boundaries. CONCLUSION: This overview of contemporary representations of blood in relation to blood donation in Quebec illustrates that though this substance might be disenchanted for many, it still maintains its mysteriousness for others, which underpins the importance of its social, cultural, and religious representations that can potentially lead to useful avenues in improving donor recruitment and retention. PMID- 24341431 TI - Recruitment and retention of blood donors in four Canadian cities: an analysis of the role of community and social networks. AB - BACKGROUND: This study approaches the decision to donate blood as a dynamic process involving interplay between blood donors' personal motives, donors' social contexts, and the donor recruitment and retention activities of blood collection agencies. STUDY DESIGN AND METHODS: Data were gathered from four blood donation clinics using in-depth interviews with Canadian Blood Services employees, donors, and nondonors in 25 organizations participating in Life Link, a donor recruitment program that supports organizations to educate employees about the benefits of blood donation. Further data were obtained from ethnographic observations of blood collection and donor recruitment activities. RESULTS: Thematic analysis resulted in three umbrella themes: leveraging social networks, embedding the clinic in the community, and donating blood and social reciprocity. Donor recruitment activities at all four clinics enhanced awareness of blood donation in the workplace by using experienced donors to motivate their coworkers in making a first-time donation. Clinic employees reported varying success in improving awareness of blood donation in the broader community, in part because of varying employee engagement in community-wide activities and celebrations. Altruistic motives were mentioned by experienced donors, who also identified a desire to reciprocate to their community as another strong motive. CONCLUSION: This study contextualizes donor recruitment and retention as involving activities that tie blood donation to meaningful aspects of donors' social networks and community. The findings point to the need for further analyses of the institutional dimensions of blood donation to develop effective strategies beyond appeals to altruism. PMID- 24341435 TI - Sulfamic acid and its N- and O-substituted derivatives. PMID- 24341432 TI - Network-based differential gene expression analysis suggests cell cycle related genes regulated by E2F1 underlie the molecular difference between smoker and non smoker lung adenocarcinoma. AB - BACKGROUND: Differential gene expression (DGE) analysis is commonly used to reveal the deregulated molecular mechanisms of complex diseases. However, traditional DGE analysis (e.g., the t test or the rank sum test) tests each gene independently without considering interactions between them. Top-ranked differentially regulated genes prioritized by the analysis may not directly relate to the coherent molecular changes underlying complex diseases. Joint analyses of co-expression and DGE have been applied to reveal the deregulated molecular modules underlying complex diseases. Most of these methods consist of separate steps: first to identify gene-gene relationships under the studied phenotype then to integrate them with gene expression changes for prioritizing signature genes, or vice versa. It is warrant a method that can simultaneously consider gene-gene co-expression strength and corresponding expression level changes so that both types of information can be leveraged optimally. RESULTS: In this paper, we develop a gene module based method for differential gene expression analysis, named network-based differential gene expression (nDGE) analysis, a one-step integrative process for prioritizing deregulated genes and grouping them into gene modules. We demonstrate that nDGE outperforms existing methods in prioritizing deregulated genes and discovering deregulated gene modules using simulated data sets. When tested on a series of smoker and non smoker lung adenocarcinoma data sets, we show that top differentially regulated genes identified by the rank sum test in different sets are not consistent while top ranked genes defined by nDGE in different data sets significantly overlap. nDGE results suggest that a differentially regulated gene module, which is enriched for cell cycle related genes and E2F1 targeted genes, plays a role in the molecular differences between smoker and non-smoker lung adenocarcinoma. CONCLUSIONS: In this paper, we develop nDGE to prioritize deregulated genes and group them into gene modules by simultaneously considering gene expression level changes and gene-gene co-regulations. When applied to both simulated and empirical data, nDGE outperforms the traditional DGE method. More specifically, when applied to smoker and non-smoker lung cancer sets, nDGE results illustrate the molecular differences between smoker and non-smoker lung cancer. PMID- 24341436 TI - Autonomic function in a prevalent Tanzanian population with Parkinson's disease and its relationship to disease duration and 5-year mortality. AB - BACKGROUND: Autonomic dysfunction is common in patients with Parkinson's disease (PD). We report autonomic function test results in a prevalent, largely untreated, Tanzanian population of PD patients, at different disease stages and investigate the relationship between autonomic dysfunction and mortality. METHODS: Ewing's battery of autonomic tests was carried out on a prevalent population of PD patients living in the rural Hai district of Tanzania. Where possible, all four tests were performed in the patient's home. The main outcome of interest was the presence of abnormalities of sympathetic or parasympathetic function. Information on medications used and other co-morbidities was recorded. RESULTS: Autonomic function tests were recorded for 29 subjects, of whom 3 were on medication at the time of assessment. Of the 26 unmedicated patients, 14 (53.8%) had at least one abnormal test result for autonomic function, of whom only 3 (21.4%) were in late stage disease (Hoehn and Yahr stage IV or V), compared to 7 (58.3%) of 12 with normal autonomic function tests in late stage disease. Ten subjects had died at 5-year follow-up, but there was no association between mortality and autonomic function test abnormalities. CONCLUSIONS: In unmedicated subjects, many patients in late stage disease had relatively preserved autonomic function, compared to those in early stage disease. In people with PD who are taking medication, it may be that when autonomic dysfunction presents in late stage disease it is often due to side effects of medication rather than the disease itself. PMID- 24341437 TI - Mastery motivation in children with congenital hemiplegia: individual and environmental associations. AB - AIM: The aim of this study was to examine the relationship between mastery motivation and individual and environmental characteristics in school-aged children with congenital hemiplegia. METHOD: Forty-eight child-caregiver dyads (children's mean age 7y 11mo, SD 2y 4mo; 33 males, 15 females; Manual Ability Classification System [MACS] level I, n=25, and level II, n=23; predominant motor type spastic hemiplegia, n=47) were recruited to this cross-sectional study. Children were assessed using the Melbourne Assessment of Unilateral Upper Limb Function (MUUL) and the Assisting Hand Assessment. Caregivers completed the Dimensions of Mastery Questionnaire, the Parenting Scale, and a demographic questionnaire. RESULTS: Consistent and positive parental disciplinary practices were associated with higher total motivation (p=0.006) and instrumental aspect scores (p=0.009). Children with siblings and from single-parent families experienced greater negative reactions to failure (p=0.006). Children from two parent families (p=0.018) and with better bimanual performance (p=0.015) demonstrated greater object-oriented persistence. Age, sex, limitations in manual ability (MACS), and movement and body function of the impaired limb (MUUL) did not contribute significantly to mastery motivation. INTERPRETATION: Inconsistent, excessively lax, and verbose parenting practices may discourage children from persevering with challenging tasks. Functional parenting styles, positive discipline practices, and autonomy-supportive strategies for task engagement should be encouraged when intervening with children with cerebral palsy. Parents should be supported to engage in these practices in all aspects of daily activities. PMID- 24341438 TI - Differential regulation of the rainbow trout (Oncorhynchus mykiss) MT-A gene by nuclear factor interleukin-6 and activator protein-1. AB - BACKGROUND: Previously we have identified a distal region of the rainbow trout (Oncorhynchus mykiss) metallothionein-A (rtMT-A) enhancer region, being essential for free radical activation of the rtMT-A gene. The distal promoter region included four activator protein 1 (AP1) cis-acting elements and a single nuclear factor interleukin-6 (NF-IL6) element. In the present study we used the rainbow trout hepatoma (RTH-149) cell line to further examine the involvement of NF-IL6 and AP1 in rtMT-A gene expression following exposure to oxidative stress and tumour promotion. RESULTS: Using enhancer deletion studies we observed strong paraquat (PQ)-induced rtMT-A activation via NF-IL6 while the AP1 cis-elements showed a weak but significant activation. In contrast to mammals the metal responsive elements were not activated by oxidative stress. Electrophoretic mobility shift assay (EMSA) mutation analysis revealed that the two most proximal AP1 elements, AP11,2, exhibited strong binding to the AP1 consensus sequence, while the more distal AP1 elements, AP13,4 were ineffective. Phorbol-12-myristate 13-acetate (PMA), a known tumor promoter, resulted in a robust induction of rtMT A via the AP1 elements alone. To determine the conservation of regulatory functions we transfected human Hep G2 cells with the rtMT-A enhancer constructs and were able to demonstrate that the cis-elements were functionally conserved. The importance of NF-IL6 in regulation of teleost MT is supported by the conservation of these elements in MT genes from different teleosts. In addition, PMA and PQ injection of rainbow trout resulted in increased hepatic rtMT-A mRNA levels. CONCLUSIONS: These studies suggest that AP1 primarily is involved in PMA regulation of the rtMT-A gene while NF-IL6 is involved in free radical regulation. Taken together this study demonstrates the functionality of the NF IL6 and AP-1 elements and suggests an involvement of MT in protection during pathological processes such as inflammation and cancer. PMID- 24341439 TI - Patient participation in medication safety during an acute care admission. AB - BACKGROUND: Patient participation in medication management during hospitalization is thought to reduce medication errors and, following discharge, improve adherence and therapeutic use of medications. There is, however, limited understanding of how patients participate in their medication management while hospitalized. OBJECTIVE: To explore patient participation in the context of medication management during a hospital admission for a cardiac surgical intervention of patients with cardiovascular disease. DESIGN: Single institution, case study design. The unit of analysis was a cardiothoracic ward of a major metropolitan, tertiary referral hospital in Melbourne, Australia. Multiple methods of data collection were used including pre-admission and pre-discharge patient interviews (n = 98), naturalistic observations (n = 48) and focus group interviews (n = 2). RESULTS: All patients had changes made to their pre-operative cardiovascular medications as a consequence of surgery. More patients were able to list and state the purpose and side-effects of their cardiovascular medications at pre-admission than prior to discharge from hospital. There was very little evidence that nurses used opportunities such as medication administration times to engage patients in medication management during hospital admission. DISCUSSION AND CONCLUSIONS: Failure to engage patients in medication management and provide opportunities for patients to learn about changes to their medications has implications for the quality and safety of care patients receive in hospital and when managing their medications once discharged. To increase the opportunity for patients to participate in medication management, a fundamental shift in the way nurses currently provide care is required. PMID- 24341440 TI - Significance of metacognitive skills in laparoscopic surgery assessed by essential task simulation. AB - BACKGROUND: Metacognition is the knowledge about one's own methods of perceiving, remembering, thinking, and acting. This study determined the significance of metacognitive skills in laparoscopic surgery with the aim of applying the findings in a laparoscopic surgery training program. MATERIAL AND METHODS: Eighteen medical students with no experience in laparoscopic surgery (novice group) and eight expert surgeons who had each performed >100 laparoscopic surgeries (expert group) were enrolled. The examinees in each group performed an evaluation task using a virtual reality simulator and answered questions about the task. RESULTS: The longest performance times, longest path lengths, and most frequent tissue damage occurred at 135 degrees in the novice group and at 180 degrees in the expert group. The greatest recognition of task difficulties, impatience, and irritation occurred at 135 degrees in the novice group and at 180 degrees in the expert group. There were statistically significant correlation coefficients between the instrument path length and task difficulty (metacognition) at 135 degrees (R = 0.74, p = 0.03) and 180 degrees (R = 0.79, p = 0.02) in the expert group, but there were no significant correlations in the novice group. CONCLUSION: We elucidated the significance of metacognitive skills in laparoscopic surgery. A training program should include recognition feedback systems. PMID- 24341441 TI - A tool to analyze the transferability of health promotion interventions. AB - BACKGROUND: Health promotion interventions are often complex and not easily transferable from one setting to another. The objective of this article is to present the development of a tool to analyze the transferability of these interventions and to support their development and adaptation to new settings. METHODS: The concept mapping (CM) method was used. CM is helpful for generating a list of ideas associated with a concept and grouping them statistically. Researchers and stakeholders in the health promotion field were mobilized to participate in CM and generated a first list of transferability criteria. Duplicates were eliminated, and the shortened list was returned to the experts, scored for relevance and grouped into categories. Concept maps were created, then the project team selected the definitive map. From the final list of criteria thus structured, a tool to analyze transferability was created. This tool was subsequently tested by 15 project leaders and nine experts. RESULTS: In all, 18 experts participated in CM. After testing, a tool, named ASTAIRE, contained 23 criteria structured into four categories: population, environment, implementation, and support for transfer. It consists of two tools--one for reporting data from primary interventions and one for analyzing interventions' transferability and supporting their adaptation to new settings. CONCLUSION: The tool is helpful for selecting the intervention to transfer into the setting being considered and for supporting its adaptation. It also facilitates new interventions to be produced with more explicit transferability criteria. PMID- 24341442 TI - Bioactive and biomimetic restorative materials: a comprehensive review. Part II. AB - This second part (Part II) of a two-part comprehensive review of bioactive and biomimetic restorative materials reviews the calcium aluminate-based restorative dental materials. Part II explores the development, composition, properties, and application of the bioactive calcium aluminate-based materials that have been developed for several indications in restorative dentistry. CLINICAL SIGNIFICANCE: Bioactive materials have evolved over the past three decades from relatively specialized, highly biocompatible, but low-strength dental materials to now emerge in product compositions for expanded clinical uses in restorative dentistry. Further developments to meet additional restorative clinical needs are anticipated in the newly emerging category of dental materials. PMID- 24341444 TI - Efficient and reproducible identification of mismatch repair deficient colon cancer: validation of the MMR index and comparison with other predictive models. AB - BACKGROUND: The identification of mismatch-repair (MMR) defective colon cancer is clinically relevant for diagnostic, prognostic and potentially also for treatment predictive purposes. Preselection of tumors for MMR analysis can be obtained with predictive models, which need to demonstrate ease of application and favorable reproducibility. METHODS: We validated the MMR index for the identification of prognostically favorable MMR deficient colon cancers and compared performance to 5 other prediction models. In total, 474 colon cancers diagnosed >= age 50 were evaluated with correlation between clinicopathologic variables and immunohistochemical MMR protein expression. RESULTS: Female sex, age >=60 years, proximal tumor location, expanding growth pattern, lack of dirty necrosis, mucinous differentiation and presence of tumor-infiltrating lymphocytes significantly correlated with MMR deficiency. Presence of at least 4 of the MMR index factors identified MMR deficient tumors with 93% sensitivity and 76% specificity and showed favorable reproducibility with a kappa value of 0.88. The MMR index also performed favorably when compared to 5 other predictive models. CONCLUSIONS: The MMR index is easy to apply and efficiently identifies MMR defective colon cancers with high sensitivity and specificity. The model shows stable performance with low inter-observer variability and favorable performance when compared to other MMR predictive models. PMID- 24341445 TI - Synthesis of angiolam A. AB - The first total synthesis of angiolam A has been accomplished in 18 steps. Key steps include vinylogous Mukaiyama aldol reactions of aldehyde-derived dienol ethers, conjugate reduction of the resulting double bond followed by diastereoselective protonation and the Witzeman protocol for macrolactamization. Comparison of the optical rotation of the synthesized material with the isolation data established that the absolute configuration of angiolam A is opposite from the proposed structure. PMID- 24341443 TI - Maternal outcomes and follow-up after gestational diabetes mellitus. AB - Gestational diabetes mellitus reflects impaired maternal insulin secretion relative to demand prior to pregnancy, as well as temporary metabolic stressors imposed by the placenta and fetus. Thus, after delivery, women with gestational diabetes have increased risk of diabetes and recurrent gestational diabetes because of their underlying impairment, which may be further exacerbated by fat accretion during pregnancy and post-partum deterioration in lifestyle behaviours. This hypothetical model is discussed in greater detail, particularly the uncertainty regarding pregnancy as an accelerator of beta-cell decline and the role of gestational weight gain. This report also presents risk estimates for future glucose intolerance and diabetes and reviews modifiable risk factors, particularly body mass and lifestyle alterations, including weight loss and breastfeeding. Non-modifiable risk factors such as race/ethnicity and insulin use during pregnancy are also discussed. The review concludes with current literature on lifestyle modification, recommendations for post-partum glucose screening, and future directions for research to prevent maternal disease. PMID- 24341446 TI - Probing hydrogen bond networks in half-sandwich Ru(II) building blocks by a combined 1H DQ CRAMPS solid-state NMR, XRPD, and DFT approach. AB - The hydrogen bond network of three polymorphs (1alpha, 1beta, and 1gamma) and one solvate form (1.H2O) arising from the hydration-dehydration process of the Ru(II) complex [(p-cymene)Ru(kappaN-INA)Cl2] (where INA is isonicotinic acid), has been ascertained by means of one-dimensional (1D) and two-dimensional (2D) double quantum (1)H CRAMPS (Combined Rotation and Multiple Pulses Sequences) and (13)C CPMAS solid-state NMR experiments. The resolution improvement provided by homonuclear decoupling pulse sequences, with respect to fast MAS experiments, has been highlighted. The solid-state structure of 1gamma has been fully characterized by combining X-ray powder diffraction (XRPD), solid-state NMR, and periodic plane-wave first-principles calculations. None of the forms show the expected supramolecular cyclic dimerization of the carboxylic functions of INA, because of the presence of Cl atoms as strong hydrogen bond (HB) acceptors. The hydration-dehydration process of the complex has been discussed in terms of structure and HB rearrangements. PMID- 24341451 TI - Comprehensive imaging of porcine adrenal gland lipids by MALDI-FTMS using quercetin as a matrix. AB - Adrenal glands synthesize and release functional zone-specific steroid and catecholamine hormones to regulate mammalian stress responses. Lipids such as sphingolipids have been shown to control the steroid hormone biosynthesis in adrenal glands, indicating their important roles in endocrine organs. Molecular imaging by matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) is a well-established analytical technique for determining both the spatial location and the relative abundances of various lipids on tissue. To better understand the overall roles of different lipid classes that play in the mammalian adrenal glands, it is necessary to comprehensively determine the spatial distributions of various lipids in the different functional zones of adrenal glands. However, the potential of this technique has not been fully reached, considering there are thousands of lipid species in a cell or tissue. To achieve this, we used quercetin as a MALDI matrix for negative ion detection of endogenous lipids on tissue sections of porcine adrenal glands by MALDI-Fourier transform ion cyclotron resonance (FTICR) MS. As a result of these experiments, 409 endogenous compounds were detected in the negative ion mode. Combining both the positive and negative ion detection led to successful determination of the spatial distribution patterns of 555 unique endogenous compounds that were identified as 544 lipid entities and 11 nonlipid metabolites. Many classes of these lipids showed distinct distribution patterns in different functional zones of the adrenal gland. To the best of our knowledge, this work presents the largest group of lipid entities that have been analyzed in a single MS imaging study so far, and comprehensive profiles of the spatial distributions of lipids in porcine adrenal glands are shown here for the first time. PMID- 24341448 TI - Association between nonsteroidal anti-inflammatory drug use and brain tumour risk: a meta-analysis. AB - AIMS: Several epidemiological studies have evaluated the association between nonsteroidal anti-inflammatory drugs (NSAIDs) and brain tumour risk. However, results from these studies have been inconsistent. The aim of this detailed meta analysis is to review and summarize the evidence on this association. METHODS: A comprehensive search for articles published up to September 2013 was performed. Studies evaluating the association between exposure to NSAIDs and risk of brain tumours were included. Random-effects meta-analytical models were used to calculate the relative risk (RR) and corresponding 95% confidence intervals (CIs). Sensitivity analyses, Galbraith plots and subgroup analyses were also performed. RESULTS: Ten studies (six case-control studies, three cohort studies and one randomized controlled trial), published between 2003 and 2013, were included in this analysis. Compared with non-use, overall use of NSAIDs was not statistically significantly associated with brain tumour risk based on the random effects models (RR = 1.01; 95% CI = 0.89, 1.15). No differences were observed when analyses were stratified by gender and brain tumour subtype. Specific analysis for aspirin and non-aspirin NSAIDs yielded similar results. However, a slightly increased risk of brain tumour in NSAID users was observed in cohort studies (RR = 1.32; 95% CI = 1.06, 1.64; P = 0.014). Furthermore, our analysis did not show a significant association between frequency and dose of aspirin use and brain tumour risk. CONCLUSIONS: Use of NSAIDs (aspirin and non-aspirin NSAIDs) does not appear to be associated with brain tumour risk, but larger studies are needed to substantiate this relationship. PMID- 24341447 TI - Effects of some anesthetic agents on skin microcirculation evaluated by laser Doppler perfusion imaging in mice. AB - BACKGROUND: Anesthetic agents alter microcirculation, influencing tissue oxygenation and delivery of vital substrates. Laser Doppler perfusion imaging is a widespread technique in the field of microvascular research that can evaluate noninvasively and in real time the effects of environmental conditions, physical manipulations, diseases and treatments on peripheral perfusion. This study aims to evaluate laser Doppler perfusion imaging as a means to detect changes in skin microcirculation induced by some popular anesthetic agents in a murine model. Twenty-four age- and gender-matched healthy CD1 mice were examined by laser Doppler perfusion imaging. The skin microcirculatory response was measured at the level of plantar surfaces during isoflurane anesthesia with or without subsequent dexmedetomidine or acepromazine. At the end of the procedure, dexmedetomidine was reversed by atipamezole administration. RESULTS: In all mice, skin blood flow under isoflurane anesthesia did not show significant differences over time (P = 0.1). The serial perfusion pattern and values following acepromazine or dexmedetomidine administration differed significantly (P < 0.05). CONCLUSIONS: We standardized a reliable laser Doppler perfusion imaging protocol to non invasively assess changes in skin microcirculation induced by anesthesia in mice, considering the advantages and drawbacks of this technique and its translational value. PMID- 24341452 TI - Nummular headache in a patient with craniosynostosis: one more evidence for a peripheral mechanism. PMID- 24341453 TI - Pemphigus vulgaris-associated Kaposi's sarcoma: response to paclitaxel and review of the literature. AB - Systemic corticosteroids have long been the mainstay of treatment for pemphigus patients. However, the necessity of their high-dose and long-term administration has brought about a number of complications, sometimes causing significant morbidities. Maintaining a balance between therapeutic and undesirable effects of medications is not always easily achievable. Therefore, additional treatment modalities are frequently needed to control side-effects. Kaposi's sarcoma (KS) is a rare, potentially life-threatening complication in this setting. Due to the rarity of data on pemphigus-associated KS treatment, the best therapeutic approach is still undecided. Here, we report two cases of pemphigus patients who had developed extensive KS as a result of severe immunosuppressive therapy and were successfully treated with paclitaxel. In addition, we performed a review of literature to assess the results of the previously employed treatment modalities in this setting. PMID- 24341456 TI - Evidence to practice commentary: upper limb constraint in infants: important perspectives on measurement and the potential for activity-dependent withdrawal of corticospinal projections. PMID- 24341454 TI - Genetic mutations in nonsyndromic deafness patients of Chinese minority and Han ethnicities in Yunnan, China. AB - BACKGROUND: Each year in China, 30,000 babies are born with congenital hearing impairment. However, the molecular etiology of hearing impairment in the Yunnan Province population where more than 52 minorities live has not been thoroughly investigated. To provide appropriate genetic testing and counseling to these families, we investigated the molecular etiology of nonsyndromic deafness in this population. METHODS: Unrelated students with hearing loss (n = 235) who attended Kunming Huaxia secondary specialized school in Yunnan enrolled in this study. Three prominent deafness-related genes, GJB2, SLC26A4 and mtDNA 12S rRNA, were analyzed. High-resolution temporal bone computed tomography (CT) scan examinations were performed in 100 cases, including 16 cases with SLC26A4 gene variants, and 37 minorities and 47 Han cases without any SLC26A4 gene mutation. RESULTS: The GJB2 mutation was detected in 16.67% (7/42) of minority patients and 17.62% (34/193) of Chinese Han patients (P > 0.05). 235delC was the hotspot mutation in nonsyndromic hearing loss (NSHL) patients, whereas 35delG was not found. The 431_450del19 mutation was detected for the first time in Han NSHL patients, which resulted in a premature stop codon and changed the protein. The SLC26A4 mutation was found in 9.52% (4/42) of minority patients and 9.84% (19/193) of Han Chinese patients (P > 0.05). The frequencies of mtDNA 12S rRNA mutation in minority and Han Chinese patients were 11.90% (5/42) and 7.77% (15/193; P > 0.05), respectively. Sixteen (16/23, 69.57%) patients with SLC26A4 mutations received temporal bone CT scan, and 14 patients were diagnosed with enlarged vestibular aqueducts (EVAs); the other 2 patients had normal inner ear development. The ratio of EVA in the minorities was 14.63% (6/41). CONCLUSIONS: In this study, a total of 35.74% deaf patients showed evidence of genetic involvement, based on either genetic screening or family history; 17.45%, 9.79%, and 8.51% of the patients were determined to have inherited hearing impairment caused by GJB2, SLC26A4, and mtDNA 1555A > G mutations. There was no significant difference in deafness associated gene mutational spectrum and frequency between the Yunnan minority and Han patients. PMID- 24341455 TI - Efficacy and acceptability of reduced intensity constraint-induced movement therapy for children aged 9-11 years with hemiplegic cerebral palsy: a pilot study. AB - OBJECTIVE: Assess efficacy and acceptability of reduced intensity constraint induced movement therapy (CIMT) in children with cerebral palsy (CP). METHODS: Single-subject research design and semi-structured interviews. Children (9-11y) with hemiplegia underwent five baseline assessments followed by two weeks CIMT. Six further assessments were performed during treatment and follow-up phases. The primary outcome was the Melbourne Assessment of Unilateral Upper Limb Function (MUUL). Quantitative data were analysed using standard single-subject methods and qualitative data by thematic analysis. RESULTS: Four of the seven participants demonstrated statistically significant improvements in MUUL (3-11%, p < .05). Two participants achieved significant improvements in active range of motion but strength and tone remained largely unchanged. Qualitative interviews highlighted limitations of the restraint, importance of family involvement, and coordination of treatment with education. CONCLUSIONS: Reduced intensity CIMT may be effective for some children in this population; however it is not suitable for all children with hemiplegia. PMID- 24341458 TI - Insights into the microbial diversity and bioburden in a South American spacecraft assembly clean room. AB - In this study, samples from the spacecraft assembly clean room BAF (final assembly building), located at Centre Spatial Guyanais in Kourou, French Guiana, were characterized by qualitative and quantitative methods to determine the bioburden and biodiversity. The cultivation assays mainly focused on extremotolerant microorganisms that have special metabolic skills, such as the ability to grow without oxygen, fix nitrogen, grow autotrophically, or reduce sulfate. A broad range of media and growth conditions were used to simulate possible extraterrestrial environments and clean room buildings. In addition to these alternative cultivation assays, the ESA standard protocol for bioburden estimation was also applied. The phylogenetic analysis of the isolates (mainly facultative anaerobes) showed an extraordinarily broad cultivable biodiversity. Overall, 49 species were isolated and identified as members of the bacterial phyla Actinobacteria, Firmicutes, alpha-, beta-, gamma-Proteobacteria, and Bacteroidetes/Chlorobi. In addition to cultivation-based analyses, molecular techniques were also applied, including construction of a 16S rRNA gene clone library. The results indicate a wide-ranging microbial diversity (12 bacterial phyla, 34 families) that not only confirms the results of the cultivation efforts but also deepens our understanding of the noncultivable variety. Our investigations hint at a very broad, mainly uncultivated microbial diversity. PMID- 24341457 TI - The Caenorhabditis elegans interneuron ALA is (also) a high-threshold mechanosensor. AB - BACKGROUND: To survive dynamic environments, it is essential for all animals to appropriately modulate their behavior in response to various stimulus intensities. For instance, the nematode Caenorhabditis elegans suppresses the rate of egg-laying in response to intense mechanical stimuli, in a manner dependent on the mechanosensory neurons FLP and PVD. We have found that the unilaterally placed single interneuron ALA acted as a high-threshold mechanosensor, and that it was required for this protective behavioral response. RESULTS: ALA was required for the inhibition of egg-laying in response to a strong (picking-like) mechanical stimulus, characteristic of routine handling of the animals. Moreover, ALA did not respond physiologically to less intense touch stimuli, but exhibited distinct physiological responses to anterior and posterior picking-like touch, suggesting that it could distinguish between spatially separated stimuli. These responses required neither neurotransmitter nor neuropeptide release from potential upstream neurons. In contrast, the long, bilaterally symmetric processes of ALA itself were required for producing its physiological responses; when they were severed, responses to stimuli administered between the cut and the cell body were unaffected, while responses to stimuli administered posterior to the cut were abolished. CONCLUSION: C. elegans neurons are typically classified into three major groups: sensory neurons with specialized sensory dendrites, interneurons, and motoneurons with neuromuscular junctions. Our findings suggest that ALA can autonomously sense intense touch and is thus a dual-function neuron, i.e., an interneuron as well as a novel high-threshold mechanosensor. PMID- 24341459 TI - Seeding life on the moons of the outer planets via lithopanspermia. AB - Material from the surface of a planet can be ejected into space by a large impact and could carry primitive life-forms with it. We performed n-body simulations of such ejecta to determine where in the Solar System rock from Earth and Mars may end up. We found that, in addition to frequent transfer of material among the terrestrial planets, transfer of material from Earth and Mars to the moons of Jupiter and Saturn is also possible, but rare. We expect that such transfers were most likely to occur during the Late Heavy Bombardment or during the ensuing 1-2 billion years. At this time, the icy moons were warmer and likely had little or no ice shell to prevent meteorites from reaching their liquid interiors. We also note significant rates of re-impact in the first million years after ejection. This could re-seed life on a planet after partial or complete sterilization by a large impact, which would aid the survival of early life during the Late Heavy Bombardment. PMID- 24341461 TI - Carl R. Woese, 1928-2012. PMID- 24341462 TI - Malignancy rate in thyroid nodules classified as Bethesda category III (AUS/FLUS). AB - BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology is the standard for interpreting fine needle aspiration (FNA) specimens. The "atypia of undetermined significance/follicular lesion of undetermined significance" (AUS/FLUS) category, known as Bethesda Category III, has been ascribed a malignancy risk of 5-15%, but the probability of malignancy in AUS/FLUS specimens remains unclear. Our objective was to determine the risk of malignancy in thyroid FNAs categorized as AUS/FLUS at a comprehensive cancer center. METHODS: The management of 541 AUS/FLUS thyroid nodule patients treated at Memorial Sloan Kettering Cancer Center between 2008 and 2011 was analyzed. Clinical and radiologic features were examined as predictors for surgery. Target AUS/FLUS nodules were correlated with surgical pathology. RESULTS: Of patients with an FNA initially categorized as AUS/FLUS, 64.7% (350/541) underwent immediate surgery, 17.7% (96/541) had repeat FNA, and 17.6% (95/541) were observed. Repeat FNA cytology was unsatisfactory in 5.2% (5/96), benign in 42.7% (41/96), AUS/FLUS in 38.5% (37/96), suspicious for follicular neoplasm in 5.2% (5/96), suspicious for malignancy in 4.2% (4/96), and malignant in 4.2% (4/96). Of nodules with two consecutive AUS/FLUS diagnoses that were resected, 26.3% (5/19) were malignant. Among all index AUS/FLUS nodules (triaged to surgery, repeat FNA, or observation), malignancy was confirmed on surgical pathology in 26.6% [CI 22.4 31.3]. Among AUS/FLUS nodules triaged to surgery, the malignancy rate was 37.8% [CI 33.1-42.8]. Incidental cancers were found in 22.3% of patients. On univariate logistic regression analysis, factors associated with triage to surgery were younger patient age (p<0.0001), increasing nodule size (p<0.0001), and nodule hypervascularity (p=0.032). CONCLUSIONS: In patients presenting to a comprehensive cancer center, malignancy rates in nodules with AUS/FLUS cytology are higher than previously estimated, with 26.6-37.8% of AUS/FLUS nodules harboring cancer. These data imply that Bethesda Category III nodules in some practice settings may have a higher risk of malignancy than traditionally believed, and that guidelines recommending repeat FNA or observation merit reconsideration. PMID- 24341463 TI - Dilated cardiomyopathy secondary to chronic cocaine abuse: a case report. AB - BACKGROUND: Cocaine is a potent sympathomimetic agent associated with the development of possible fatal cardiovascular complications. Dysrhythmias, acute myocardial infarction, hypertension and dilated cardiomyopathy are just some of many cardiovascular effects related to the abuse of cocaine. CASE PRESENTATION: A 38-year-old Hispanic male with a past medical history of hypertension presented with a chief complaint of progressive shortness of breath. The patient confessed to the use of cocaine for almost 18 years once per week. On examination he was hypertensive and tachycardic with a systolic murmur over the 5th intercostal space at the level of the left mid-clavicular line. Laboratory workup revealed an elevated Brain natriuretic peptide; urine toxicology was positive for cocaine. 2D echocardiogram showed dilated cardiomyopathy. Cardiac catheterization excluded angioischemic cause. He was managed medically and subsequently discharged with drug rehabilitation. On follow-up diagnostic evaluation after 5 months of cocaine cessation, his ejection function improved significantly. CONCLUSION: The exact incidence of cocaine related cardiomyopathy is unknown and likely underreported. The clinical course is abrupt and comparatively similar to other types of cardiomyopathy. The management is like other forms of cardiomyopathy; however beta-blockers should be avoided. The myocardial dysfunction is reversible with abstaining from additional cocaine ingestion. Non-invasive testing should be performed after several months to re-evaluate the treatment response. PMID- 24341464 TI - Explosive diversification following a benthic to pelagic shift in freshwater fishes. AB - BACKGROUND: Interspecific divergence along a benthic to pelagic habitat axis is ubiquitous in freshwater fishes inhabiting lentic environments. In this study, we examined the influence of this habitat axis on the macroevolution of a diverse, lotic radiation using mtDNA and nDNA phylogenies for eastern North America's most species-rich freshwater fish clade, the open posterior myodome (OPM) cyprinids. We used ancestral state reconstruction to identify the earliest benthic to pelagic transition in this group and generated fossil-calibrated estimates of when this shift occurred. This transition could have represented evolution into a novel adaptive zone, and therefore, we tested for a period of accelerated lineage accumulation after this historical habitat shift. RESULTS: Ancestral state reconstructions inferred a similar and concordant region of our mtDNA and nDNA based gene trees as representing the shift from benthic to pelagic habitats in the OPM clade. Two independent tests conducted on each gene tree suggested an increased diversification rate after this inferred habitat transition. Furthermore, lineage through time analyses indicated rapid early cladogenesis in the clade arising after the benthic to pelagic shift. CONCLUSIONS: A burst of diversification followed the earliest benthic to pelagic transition during the radiation of OPM cyprinids in eastern North America. As such, the benthic/pelagic habitat axis has likely influenced the generation of biodiversity across disparate freshwater ecosystems. PMID- 24341466 TI - Real-time continuous glucose monitoring as a tool to prevent severe hypoglycaemia in selected pregnant women with Type 1 diabetes - an observational study. AB - AIMS: Among women with Type 1 diabetes who have had severe hypoglycaemia the year before pregnancy, 70% also experience this complication in pregnancy, and particularly in the first half of pregnancy. We evaluated whether routine use of real-time continuous glucose monitoring from early pregnancy onwards could prevent severe hypoglycaemia in these women. METHODS: All 136 consecutive pregnant women with Type 1 diabetes referred to our centre were asked about severe hypoglycaemic events in the year before pregnancy and early in pregnancy at their first antenatal visit. Women with a relevant recent history were informed about their additional high risk of severe hypoglycaemia, their treatment was focused on restricted insulin doses during the first 16 gestational weeks, and they were offered real-time continuous glucose monitoring on top of self-monitored plasma glucose measurements. RESULTS: Among 28 women with a recent history of severe hypoglycaemia, 12 (43%) used real-time continuous glucose monitoring from a median (range) of 10 (7-13) gestational weeks for 10 (1-32) weeks. Among these 12 women, eight had experienced a total of 34 (range 1-11) severe hypoglycaemic events in the year before pregnancy and nine had experienced 23 (range 1-10) events early in pregnancy. After initiation of real-time continuous glucose monitoring, two (17%) women experienced one event each. The incidence rates of severe hypoglycaemia were 2.8,17.5 and 0.3 events/patient year. Among the 16 women in the high risk group not using real-time continuous glucose monitoring, the corresponding figures were 1.6, 5.0 and 0.1 events/patient-year. CONCLUSIONS: Further evaluation is required to determine whether continuous real-time continuous glucose monitoring from early pregnancy onwards in highly selected women may reduce the risk of severe hypoglycaemia. Other elements of focused intervention probably also contribute to the risk reduction. PMID- 24341465 TI - Improving mental health of adolescents with Type 1 diabetes: protocol for a randomized controlled trial of the Nothing Ventured Nothing Gained online adolescent and parenting support intervention. AB - BACKGROUND: Management of Type 1 diabetes comes with substantial personal and psychological demands particularly during adolescence, placing young people at significant risk for mental health problems. Supportive parenting can mitigate these risks, however the challenges associated with parenting a child with a chronic illness can interfere with a parent's capacity to parent effectively. Interventions that provide support for both the adolescent and their parents are needed to prevent mental health problems in adolescents; to support positive parent-adolescent relationships; and to empower young people to better self manage their illness. This paper presents the research protocol for a study evaluating the efficacy of the Nothing Ventured Nothing Gained online adolescent and parenting intervention which aims to improve the mental health outcomes of adolescents with Type 1 diabetes. METHOD/DESIGN: A randomized controlled trial using repeated measures with two arms (intervention and wait-list control) will be used to evaluate the efficacy and acceptability of the online intervention. Approximately 120 adolescents with Type 1 diabetes, aged 13-18 years and one of their parents/guardians will be recruited from pediatric diabetes clinics across Victoria, Australia. Participants will be randomized to receive the intervention immediately or to wait 6 months before accessing the intervention. Adolescent, parent and family outcomes will be assessed via self-report questionnaires at three time points (baseline, 6 weeks and 6 months). The primary outcome is improved adolescent mental health (depression and anxiety). Secondary outcomes include adolescent behavioral (diabetes self-management and risk taking behavior), psychosocial (diabetes relevant quality of life, parent reported child well-being, self-efficacy, resilience, and perceived illness benefits and burdens); metabolic (HbA1c) outcomes; parent psychosocial outcomes (negative affect and fatigue, self-efficacy, and parent experience of child illness); and family outcomes (parent and adolescent reported parent-adolescent communication, responsibility for diabetes care, diabetes related conflict). Process variables including recruitment, retention, intervention completion and intervention satisfaction will also be assessed. DISCUSSION: The results of this study will provide valuable information about the efficacy, acceptability and therefore the viability of delivering online interventions to families affected by chronic illnesses such as Type 1 diabetes. TRIAL REGISTRATION: Australian New Zealand clinical trials registry (ANZCTR); ACTRN12610000170022. PMID- 24341467 TI - Hexavalent chromium in leather is now regulated in European Union member states to limit chromium allergy and dermatitis. PMID- 24341468 TI - Occupational airborne contact dermatitis caused by trifluoroacetic acid in an organic chemistry laboratory. PMID- 24341469 TI - Protein contact dermatitis caused by worms and insects used to feed exotic birds. PMID- 24341470 TI - Impact of a mandatory geriatric medicine clerkship on the care of older acute medical patients: a retrospective cohort study. AB - BACKGROUND: The impact of geriatric medicine educational programs on patient level outcomes, as opposed to educational measures, is not well studied. We aimed to determine whether completion of a mandatory geriatrics rotation changed the clinical behaviors of clerks caring for older patients admitted to a medical clinical teaching unit. METHODS: We reviewed the charts of 132 older (>70y) patients, admitted to one medical clinical teaching unit (CTU) during 2005, and cared for by a clinical clerk, for documented functional assessment, cognitive assessment, recognition of medications that cause confusion, and early removal of indwelling urinary catheters. Performance of these outcomes was compared between clerks who had completed a mandatory 2-week geriatrics rotation immediately before the medical CTU rotation (n = 62) and those who completed geriatrics immediately after (n = 74). Patient outcomes were also measured and compared between groups. RESULTS: Compared to clerks without prior geriatric exposure, clerks with geriatrics exposure were almost 3 times as likely to assess function of their older patients within two days of assuming care (27% vs. 12%, OR: 2.73, 95% CI: 1.12 to 6.66). There were no significant differences in the other clinical behaviors. Patients cared for by geriatrics-exposed clerks were less likely to die or be institutionalized (10% vs. 31%, OR: 0.24, 95% CI: 0.09 to 0.63), and they had shorter lengths of stay by an average of -7.14 days (95% CI: 12.2 to -2.07). Adjustment for baseline differences in age and cognitive impairment did not alter the results. CONCLUSIONS: Clinical clerks who had completed a mandatory geriatrics rotation were more likely to document functional status upon assuming care of their older medical CTU patients, and there was also an association with better clinical outcomes. This highlights the value of including a geriatric medicine rotation as part of the core clerkship curriculum. PMID- 24341471 TI - Preliminary investigation of the Kitchen Picture Test (KPT): a new screening test of practical judgment for older adults. AB - Judgment is widely recognized as an important executive function, and deficits in judgment can lead to health risks, safety concerns, and hospitalizations. Surprisingly, relatively few tests of judgment have been developed specifically for older adults--a population particularly vulnerable to executive and functional declines. The Kitchen Picture Test (KPT) is a new screening measure of practical judgment. In two independent studies (Study 1, N = 99 nursing home patients; Study 2, N = 163 nursing home and assisted living patients), psychometric analyses confirmed strong evidence for reliability, construct validity, and predictive validity. A receiver operating characteristic (ROC) curve was calculated from sensitivity and 1-specificity values for diagnoses of dementia versus no dementia. A KPT cut score can be used for identifying persons to be referred to appropriate health-care professionals who have specific expertise in the evaluation and treatment of cognitive impairment. PMID- 24341472 TI - Semidirect composite onlay with cavity sealing: a review of clinical procedures. AB - The evolution in adhesive dentistry has broadened the indication of esthetic restorative procedures especially with the use of resin composite material. Depending on the clinical situation, some restorative techniques are best indicated. As an example, indirect adhesive restorations offer many advantages over direct techniques in extended cavities. In general, the indirect technique requires two appointments and a laboratory involvement, or it can be prepared chairside in a single visit either conventionally or by the use of computer-aided design/computer-aided manufacturing systems. In both cases, there will be an extra cost as well as the need of specific materials. This paper describes the clinical procedures for the chairside semidirect technique for composite onlay fabrication without the use of special equipments. The use of this technique combines the advantages of the direct and the indirect restoration. CLINICAL SIGNIFICANCE: The semidirect technique for composite onlays offers the advantages of an indirect restoration and low cost, and can be the ideal treatment option for extended cavities in case of financial limitations. PMID- 24341473 TI - Bifunctional Zn(II)Ln(III) dinuclear complexes combining field induced SMM behavior and luminescence: enhanced NIR lanthanide emission by 9-anthracene carboxylate bridging ligands. AB - There were new dinuclear Zn(II)-Ln(III) complexes of general formulas [Zn(MU L)(MU-OAc)Ln(NO3)2] (Ln(III) = Tb (1), Dy (2), Er (3), and Yb (4)), [Zn(MU-L)(MU NO3)Er(NO3)2] (5), [Zn(H2O)(MU-L)Nd(NO3)3].2CH3OH (6), [Zn(MU-L)(MU-9 An)Ln(NO3)2].2CH3CN (Ln(III) = Tb (7), Dy (8), Er (9), Yb(10)), [Zn(MU-L)(MU-9 An)Yb(9-An)(NO3)3].3CH3CN (11), [Zn(MU-L)(MU-9-An)Nd(9-An)(NO3)3].2CH3CN.3H2O (12), and [Zn(MU-L)(MU-9-An)Nd(CH3OH)2(NO3)]ClO4.2CH3OH (13) prepared from the reaction of the compartmental ligand N,N',N"-trimethyl-N,N"-bis(2-hydroxy-3 methoxy-5-methylbenzyl)diethylenetriamine (H2L), with ZnX2.nH2O (X = NO3(-) or OAc(-)) salts, Ln(NO3)3.nH2O, and, in some instances, 9-anthracenecarboxylate anion (9-An). In all these complexes, the Zn(II) ions invariably occupy the internal N3O2 site whereas the Ln(III) ions show preference for the O4 external site, giving rise to a Zn(MU-diphenoxo)Ln bridging fragment. Depending on the Zn(II) salt and solvent used in the reaction, a third bridge can connect the Zn(II) and Ln(III) metal ions, giving rise to triple-bridged diphenoxoacetate in complexes 1-4, diphenoxonitrate in complex 5, and diphenoxo(9 anthracenecarboxylate) in complexes 8-13. Dy(III) and Er(III) complexes 2, 8 and 3, 5, respectively, exhibit field induced single molecule magnet (SMM) behavior, with Ueff values ranging from 11.7 (3) to 41(2) K. Additionally, the solid-state photophysical properties of these complexes are presented showing that ligand L(2 ) is able to sensitize Tb(III)- and Dy(III)-based luminescence in the visible region through an energy transfer process (antenna effect). The efficiency of this process is much lower when NIR emitters such as Er(III), Nd(III), and Yb(III) are considered. When the luminophore 9-anthracene carboxylate is incorporated into these complexes, the NIR luminescence is enhanced which proves the efficiency of this bridging ligand to act as antenna group. Complexes 2, 3, 5, and 8 can be considered as dual materials as they combine SMM behavior and luminescent properties. PMID- 24341474 TI - Naevus sebaceus: a mosaic RASopathy. AB - Epidermal naevi are common cutaneous mosaic disorders that occur in 0.1-0.3% of live births. They are subdivided into keratinocytic and organoid naevi, the latter including naevus sebaceus (NS). Typically, NS develops as a yellowish orange plaque on the scalp, and represents a hamartoma containing epidermal, sebaceous and apocrine elements. The histological features of NS sampled in childhood include hyperkeratosis, acanthosis, increased sebaceous lobules, and primitive hair follicles. During puberty, most lesions develop more prominent sebaceous and apocrine components. Subsequently, secondary tumours may occur in around 25% of NS; most lesions are benign (e.g. trichoblastomas, syringocystadenoma papilliferum or other basaloid proliferations), although malignant tumours arising within NS can occur (< 1%). Recently, somatic mosaicism has been shown, with activating Ras mutations in HRAS or KRAS in NS lesional keratinocytes (but not in adjacent nonlesional skin or dermal fibroblasts). These mutations lead to constitutive activation of the RAF-MEK-ERK and phosphoinositide 3-kinase signalling pathways, and result in increased cellular proliferation. Similar but more extensive mosaicism underlies Schimmelpenning-Feuerstein-Mims syndrome. The most common mutation is c.37G>C (p.Gly13Arg) in HRAS, which is present in > 90% of NS. This mutation also seems to be present in NS cases that develop secondary tumours, although no additional mutations (second hit) or other genetic events have yet been identified. Treatment of NS often involves prophylactic surgical excision, but the recent identification of key epidermal signalling abnormalities underlying the cell proliferation means that future development of new medical treatments for NS that target the aberrant signalling pathways may also be feasible. PMID- 24341475 TI - A study of service provision in psychocutaneous medicine. AB - BACKGROUND: Psychocutaneous medicine concerns the recognition and treatment of psychological distress and psychiatric morbidity associated with dermatological diseases. A study in 2004 examining resources in the UK highlighted a number of deficiencies, and recommended that psychodermatology services be available, at least regionally, in the UK. Although there is now increased recognition of psychodermatology, this study of the availability of these services shows that provision has deteriorated since 2004. AIM: To study the service provision of psychocutaneous medicine in the UK. METHODS: Consultants in dermatology units across the UK were asked to take part in an online survey, accessible via an emailed link. This consisted of 10 questions concerning availability of psychodermatology services and psychological support for patients within their local trusts, both in adult and in child and adolescent medicine. Basic percentages were used to analyse quantitative data and content analysis for qualitative data. RESULTS: From 154 surveys, 127 responses were returned. The data indicated that despite frequently encountering patients who required psychological and psychiatric input, a large majority of UK dermatologists have inadequate access to appropriate support in their department. Importantly, this included the child and adolescent medicine and skin cancer departments, despite there being clear objectives for these services to be routinely available. CONCLUSIONS: A lack of resources in psychocutaneous medicine was highlighted in 2004, and the situation has not improved, or is, if anything, worse. Essential access to psychiatric and psychological support for patients is not currently available in most dermatology departments across the country. PMID- 24341476 TI - Psoriasis is associated with decreased plasma adiponectin levels independently of cardiometabolic risk factors. AB - BACKGROUND: Psoriasis is an inflammatory skin disease that may be associated with an adverse cardiometabolic profile including modulated plasma adiponectin and leptin levels. Whether these levels are independent of cardiometabolic risk factors, which are also prevalent in psoriasis, is not known. METHODS: A consecutive sample of 122 participants with varying degrees of psoriasis severity, and a random sample of 134 participants without psoriasis, were recruited for this case-control study. Cardiometabolic risk factors including traditional cardiovascular risk factors, waist circumference, insulin resistance, and total plasma adiponectin and leptin were measured. Total plasma adiponectin and leptin levels were compared in unadjusted and adjusted analyses by psoriasis status. RESULTS: Participants with psoriasis had mostly mild disease and were mainly on topical therapies, but still had a more adverse cardiometabolic profile compared with those without psoriasis. Furthermore, plasma adiponectin levels were significantly lower in participants with psoriasis than those without {7.13 MUg/mL [interquartile range (IQR) 4.9-11.3) vs. 14.5 MUg/mL (IQR 8.4-24.1); P < 0.001]}. Plasma leptin (ng/mL) levels were higher in the psoriasis group but this did not reach statistical significance [11.3 (IQR 6.4-21.8) vs. 9.8 (IQR 4.9 20.5); P = 0.07]. In multivariable modelling, plasma adiponectin levels were still negatively associated with psoriasis status after adjusting for waist size (% difference = -41.2%, P < 0.001), insulin resistance (% difference = -39.5%, P < 0.001), and both waist size and insulin resistance (% difference = -38.5%, P < 0.001). CONCLUSIONS: Plasma levels of adiponectin were lower in psoriasis, and this relationship persisted after adjusting for cardiometabolic risk factors known to decrease adiponectin levels. These findings suggest that inflammation present in psoriasis may be associated with adipose tissue dysfunction; however, direct studies of adipose tissue are needed to confirm this. PMID- 24341477 TI - An epidemiological study of androgenic alopecia in 3114 Korean patients. AB - BACKGROUND: Androgenetic alopecia (AGA) is the most common type of hair loss, and is characterized by the transformation of terminal scalp hair into vellus hair. The epidemiology of AGA is not fully understood. A strong genetic basis has long been identified, although little is known of its nongenetic causes. AIM: To evaluate the association of AGA with a number of environmental factors, including smoking, drinking and sleeping habit. METHODS: In total, 3114 Korean individuals with AGA who attended any one of 17 dermatology clinics in 6 cities in South Korea between March 2011 and February 2012 were enrolled in the study. Epidemiologic a data were collected using a standard questionnaire. RESULTS: No association was seen between eating or sleeping habits and severity of hair loss. However, drinking and smoking were associated with the severity of AGA in male patients. We also found that patients of both genders with a family history had more advanced types of hair loss, and the age of onset of AGA in male patients with a family history was earlier than that in male patients without a family history. CONCLUSIONS: Although the evidence for an environmental influence on AGA remains very weak, we did find an association between hair loss severity and certain environmental factors, such as smoking and drinking. Family history with more severe hair loss and an earlier age of onset. PMID- 24341478 TI - A Scandinavian case of skin fragility, alopecia and cardiomyopathy caused by DSP mutations. AB - Congenital skin fragility is a heterogeneous disorder with epidermolysis bullosa and various skin infections as the leading causes. However, even rare diseases must be considered in the differential diagnosis of neonatal skin blistering, including some genetic syndromes with extracutaneous involvement. One such syndrome is ectodermal dysplasia due to deficiency of desmoplakin, a desmosomal protein essential for cellular cohesion in both epithelia and cardiac tissues. Desmoplakin is encoded by the DSP gene, which is localized on chromosome 6p24. Both dominant and recessive mutations in this gene have been reported to cause skin fragility and keratinization defects. We report a child born with a fragile epidermis, alopecia, thick nails, and focal hyperkeratoses on the digits and knees. She was found to have a deficiency of desmoplakin caused by compound heterozygous DSP mutations. She has gradually developed signs of a left ventricular cardiomyopathy. PMID- 24341479 TI - Promoter demethylation contributes to TSLP overexpression in skin lesions of patients with atopic dermatitis. AB - BACKGROUND: Thymic stromal lymphopoietin (TSLP) plays an important role in promoting T-cell homeostasis, and appears to be a central player in the development of allergic symptoms, especially in asthma and atopic dermatitis (AD). Human TSLP is overexpressed in keratinocytes of patients with acute and chronic AD. However, the mechanism of TSLP overexpression remains unclear. AIM: To investigate whether TSLP expression is regulated by aberrant DNA methylation modification of the TSLP promoter in keratinocytes of patients with AD. METHODS: mRNA and protein levels of TSLP in lesional skin samples from 10 children with AD and 10 healthy controls were measured by real-time quantitative reverse transcriptase-PCR and immunohistochemistry. Bisulfite sequencing was performed to determine the methylation status of the TSLP promoter, and 5-azacytidine (5-aza), a DNA methyltransferase inhibitor, was used to determine the influence of DNA methylation on TSLP expression. RESULTS: TSLP mRNA and protein expression levels were increased in skin lesions from patients with AD compared with healthy controls. Moreover, promoter hypomethylation of the TSLP gene was identified in skin lesions from patients with AD, and treating keratinocytes with 5-aza reduced the methylation level of the TSLP promoter and increased TSLP transcription. CONCLUSIONS: DNA demethylation of a specific regulatory region of the TSLP gene may contribute to TSLP overexpression in skin lesions in patients with AD. PMID- 24341480 TI - Measles in a previously vaccinated human immunodeficiency virus-positive adult. PMID- 24341482 TI - Quinoline-based two-photon fluorescent probe for nitric oxide in live cells and tissues. AB - A two-photon fluorescent probe (QNO) for nitric oxide is reported. The probe is designed with a photoinduced electron transfer (PeT) mechanism and shows 12-fold fluorescence enhancement toward NO. Adopting a quinoline derivative as the fluorophore, QNO has a large two-photon action cross section value of 52 GM and long-wavelength emission. It also features high selectivity, low cytotoxicity, and pH insensitivity. By utilizing two-photon microscopy (TPM), QNO can detect NO in live cells and live tissues at a depth of 90-180 MUm. PMID- 24341483 TI - Chemoselective reductions of nitroaromatics in water at room temperature. AB - A robust and green protocol for the reduction of functionalized nitroarenes to the corresponding primary amines has been developed. It relies on inexpensive zinc dust in water containing nanomicelles derived from the commercially available designer surfactant TPGS-750-M. This mild process takes place at room temperature and tolerates a wide range of functionalities. Highly selective reductions can also be achieved in the presence of common protecting groups. PMID- 24341484 TI - Effect of combined mutations in the enhancer II and basal core promoter of hepatitis B virus on development of hepatocellular carcinoma in Qidong, China. AB - AIM: To investigate the roles of mutations in enhancer II (Enh II), basal core promoter (BCP) and precore (PC) regions of hepatitis B virus (HBV) in the progression of hepatocellular carcinoma (HCC) in Qidong, China. METHODS: We conducted a case-control study within a cohort of 2387 male HBV carriers who were recruited between August and September 1996. The HBV DNA sequence was determined in 152 HCC and 131 chronic hepatitis patients. Mutation exchanges during follow up in 115 cases were compared with 108 controls with serum samples taken during a similar length of follow up. In addition, a longitudinal study was conducted in 22 cases in which serial serum samples were available before HCC. RESULTS: After adjustment for age, history of cigarette smoking and alcohol consumption, hepatitis B e-antigen positivity, T1653, V1753 and T1762/A1764 double mutations were associated with risk of HCC. Multivariate analysis showed that T1653, V1753 and T1762/A1764 double mutations were independent risk factors of HCC. Moreover, a significant biological gradient of HCC risk by number of mutations in Enh II/BCP regions was observed. Paired samples analysis indicated that the increased HCC risk for at-risk sequence mutations were attributable to the persistence of these mutations, but not a single time point mutation. The longitudinal observation demonstrated a gradual combination of mutations in Enh II/BCP regions accumulated during the development of HCC. CONCLUSION: T1653, V1753 and T1762/A1764 double mutations were independent risk factors of HCC. The effect of combined mutations in Enh II/BCP regions increased the risk and persistence of at risk sequence mutations and was critical for HCC development. PMID- 24341485 TI - Use of ethanol extract of Mycobacterium bovis for detection of specific antibodies in sera of farmed red deer (Cervus elaphus) with bovine tuberculosis. AB - BACKGROUND: Bovine tuberculosis (bTB) in wildlife species poses a threat to domestic livestock in many situations. Control programs for bTB in livestock depend on testing and slaughtering the positive animals; however, the currently available diagnostic tests often have poor specificity. In our previous study, we developed a specific and sensitive enzyme linked immunosorbent assay (ELISA) for another mycobacterial disease - Johne's disease, using surface antigens of Mycobacterium avium ssp. paratuberculosis (MAP) extracted by briefly agitating the bacilli in 80% ethanol solution. The ELISA test was named ethanol vortex ELISA (EVELISA). The objective of this study is to examine whether EVELISA technique could be used to specifically detect anti-Mycobacterium bovis (M. bovis) antibodies in the serum of M. bovis-infected farmed red deer (Cervus elaphus). We tested a total of 45 red deer serum samples, divided in 3 groups - uninfected animals (n = 15), experimentally infected with M. bovis (n = 15) and experimentally infected with MAP (n = 15). RESULTS: The presence of anti-M. bovis antibodies was tested using an ethanol extract of M. bovis. Without absorption of anti-MAP cross reactive antibodies, it was found that 13 out of the 15 MAP infected animals showed high antibody binding. Using heat killed MAP as an absorbent of cross reactive antibodies, anti-M. bovis antibodies were detected in 86.7% of M. bovis-infected animals with minor false positive results caused by MAP infection. CONCLUSIONS: The results from this study suggest that EVELISA may form a basis for a sensitive and specific test for the diagnosis of bTB in farmed red deer. PMID- 24341486 TI - Role of fluorodeoxyglucose positron emission tomography (FDG PET)-computed tomography (CT) in the staging of bladder cancer. AB - OBJECTIVE: To determine whether to use (18) F-fluorodeoxyglucose positron emission tomography (FDG PET) scans in the preoperative staging of bladder cancer (BC). PATIENTS AND METHODS: In all, 233 patients with muscle-invasive BC (MIBC) or high-risk non-MIBC being considered for radical cystectomy (RC) between 2005 and 2011 had FDG-PET and computed tomography (CT) of the chest, abdomen and pelvis to assess for pelvic lymph node (LN) involvement or distant metastases. Sensitivity and specificity for detecting pelvic LN involvement was determined by comparing the results of the scans to the histopathology reports in patients undergoing RC. These parameters for distant metastases were determined from biopsy results or follow-up imaging. In patients who did not undergo RC, follow up imaging was used to evaluate the sensitivity and specificity. Patients were excluded from analysis if they either had neoadjuvant chemotherapy or had <10 LNs removed at lymphadenectomy. RESULTS: The PET scan was able to detect metastatic disease outside of the pelvis with a sensitivity of 54% compared with 41% for the staging CT (N = 207). Both scans had similar specificities of 97% and 98%. There were 13 PET avid lesions not visualised on the corresponding staging CT scans. These proved to be metastatic BC (six patients), a synchronous primary colonic cancer (one), colonic adenomas (one), basal cell tumour of the parotid gland (one) and inflammatory lesions (four). The sensitivity and specificity of the CT scans for pelvic LN involvement was 45% and 98%, respectively (N = 93). Using a combination of the PET and CT scan, the sensitivity for detecting metastatic disease in LNs increased to 69% with a 3% reduction in specificity to 95%. CONCLUSIONS: PET when used in conjunction with a standard CT scan provides a small improvement in preoperative staging of BC. However, this advantage is not significant enough to justify the additional cost. Hence we recommend use of dual imaging only in highly selected patients. PMID- 24341488 TI - Self-assembly and chemical modifications of bisphenol a on Cu(111): interplay between ordering and thermally activated stepwise deprotonation. AB - Bisphenol A (BPA) is a chemical widely used in the synthesis pathway of polycarbonates for the production of many daily used products. Besides other adverse health effects, medical studies have shown that BPA can cause DNA hypomethylation and therefore alters the epigenetic code. In the present work, the reactivity and self-assembly of the molecule was investigated under ultra high-vacuum conditions on a Cu(111) surface. We show that the surface-confined molecule goes through a series of thermally activated chemical transitions. Scanning tunneling microscopy investigations showed multiple distinct molecular arrangements dependent on the temperature treatment and the formation of polymer like molecular strings for temperatures above 470 K. X-ray photoelectron spectroscopy measurements revealed the stepwise deprotonation of the hydroxy groups, which allows the molecules to interact strongly with the underlying substrate as well as their neighboring molecules and therefore drive the organization into distinct structural arrangements. On the basis of the combined experimental evidence in conjunction with density functional theory calculations, structural models for the self-assemblies after the thermal treatment were elaborated. PMID- 24341487 TI - TPX2 is a novel prognostic marker for the growth and metastasis of colon cancer. AB - BACKGROUND: We have previously demonstrated an aberrant overexpression of the microtubule-associated protein TPX2 in colon cancer using a genome-wide gene expression profiling analysis. Here, we aim to investigate its expression pattern, clinical significance, and biological function in colon cancer. METHODS: TPX2 expression was analyzed in human colon cancer cell lines and tumor samples. The effect of TPX2 on cell proliferation, tumorigenesis, and metastasis was examined in vitro and in vivo. RESULTS: TPX2 was overexpressed in 129 of the 203 (60.8%) colon cancer metastatic lesions, with the expression being significantly higher than that in primary cancerous tissue and normal colon mucosa. Overexpression of TPX2 was significantly associated with clinical staging, vessel invasion, and metastasis. In survival analyses, patients with TPX2 overexpression had worse overall survival and metastasis free survival, suggesting that deregulation of TPX2 may contribute to the metastasis of colon cancer. Consistent with this, suppression of TPX2 expression inhibited proliferation and tumorigenicity of colon cancer cells both in vitro and in vivo. Strikingly, we found that TPX2 knockdown significantly attenuated the migration and invasion ability of colon cancer cells, which was further shown to be mechanistically associated with AKT-mediated MMP2 activity. CONCLUSIONS: These findings suggest that TPX2 plays an important role in promoting tumorigenesis and metastasis of human colon cancer, and may represent a novel prognostic biomarker and therapeutic target for the disease. PMID- 24341489 TI - Hair analysis for forensic applications: is the future bright? PMID- 24341490 TI - Microfluidics for detection of airborne pathogens: what challenges remain? PMID- 24341492 TI - PK of immunoconjugate anticancer agent CMD-193 in rats: ligand-binding assay approach to determine in vivo immunoconjugate stability. AB - BACKGROUND: Antibody-drug conjugates (ADCs) are a new generation of anticancer therapeutics. The objective of this manuscript is to propose a methodology that can be used to assess the stability of the ADCs by using the PK data obtained by ligand-binding assays that measure various components of ADCs. RESULTS: The ligand-binding assays format of different components of ADCs provided unique valuable PK information. The mathematical manipulation of the bioanalytical data provided an insight into the in vivo integrity, indicating that the loading of the calicheamicin on the G193 antibody declines in an apparent slow first-order process. CONCLUSION: This report demonstrates the value of analyzing various components of the ADC and their PK profiles to better understand the disposition and in vivo stability of ADCs. PMID- 24341493 TI - An ultrasensitive method for the quantitation of active and inactive GLP-1 in human plasma via immunoaffinity LC-MS/MS. AB - BACKGROUND: Measuring endogenous levels of incretin hormones, like GLP-1, is critical in the development of antidiabetic compounds. However, the assays used to measure these molecules often have analytical issues. RESULTS: We have developed an ultrasensitive, highly-selective immunoaffinity LC-MS/MS (IA LC MS/MS) assay capable of quantitating endogenous levels of active (7-36 amide) and inactive (9-36 amide) GLP-1 in human plasma. We performed fit-for-purpose validation of the assay by assessing the following assay performance characteristics: inter-assay precision, sensitivity, spike recovery, dilution linearity, absolute recovery, matrix effect, immunoprecipitation efficiency, and food effect. CONCLUSION: We have developed a robust analytical method for the quantitation of endogenous active and inactive GLP-1 in human plasma. In addition, we employed this method to measure the typical changes in GLP-1 levels after food intake. The sensitivity of this assay is better than another LC-MS/MS GLP-1 assay previously reported and many commercially available immunoassays. This important analytical tool could be used to qualify and/or harmonize the different immunoassays used for the quantitation of GLP-1. PMID- 24341494 TI - LC-MS/MS in endocrinology: what is the profit of the last 5 years? AB - Currently, chromatography (GC but more commonly HPLC) is the analytical method of choice for several hormones, either because the immunoassays suffer from extensive crossreactivity or because chromatography permits simultaneous measurements of hormones. However, sometimes the conventional detection systems with HPLC methods do not meet desired specificity. With the increase of robust and affordable LC-MS/MS systems, the next step forward in specificity was taken. LC-MS/MS is rapidly being incorporated in the endocrine laboratories. To be useful in the clinical diagnostic practice, it is of utmost importance that methods are both analytically and clinically vaidated, as until now, the majority of applications of LC-MS/MS in the clinical laboratories are 'home-made' methods, therefore special case must be taken. This review aims to focus on Clinical and Laboratory Standards Institute or comparable validated LC-MS/MS methods for targeted hormone analysis used for diagnostic purposes in human samples, published in the last 5 years. PMID- 24341495 TI - Global metabolic profiling for the study of alcohol-related disorders. AB - Alcohol-related disorders are multifaceted since ethanol can induce profound metabolic perturbations when taken in excess. Global metabolic profiling strategies may aid the understanding of ethanol-related effects by shedding light on these metabolic changes and potentially revealing unknown mechanisms of ethanol toxicity. Here an overview of studies designed to explore the effects of alcohol (ethanol) consumption using holistic metabolite profiling approaches (metabonomics/metabolomics) is presented, demonstrating the potential of this methodology. The analytical technologies used (NMR, GC-MS and LC-MS), have been applied to the profiling of serum, plasma, urine and tissues, obtained from animal models or humans, after exposure to alcohol. From the metabolic profiling data of a range of biological samples, a number of endogenous metabolites have been proposed as potential ethanol consumption-related biomarkers. The biomarkers suggested by these studies, and the biochemical insights that they provide for understanding the effects of ethanol mechanisms of toxicity, are discussed. PMID- 24341496 TI - Immunogenicity and PK/PD evaluation in biotherapeutic drug development: scientific considerations for bioanalytical methods and data analysis. AB - With the advent of novel technologies, considerable advances have been made in the evaluation of the relationship between PK and PD. Ligand-binding assays have been the primary assay format supporting PK and immunogenicity assessments. Critical and in-depth characterizations of the ligand-binding assay of interest can provide valuable understanding of the limitations, for interpreting PK/PD and immunogenicity results. This review illustrates key challenges with regard to understanding the relationship between anti-drug antibody and PK/PD, including confounding factors associated with the development and validation of ligand binding assays, mechanisms by which anti-drug antibody impacts PK/PD, factors to consider during data analyses and interpretation, and a perspective on integrating immunogenicity data into the well-established quantitative modeling approach. Through recognizing these challenges, we propose some opportunities for improvements in the development and validation of fit-for-purpose bioanalytical methods. PMID- 24341497 TI - Microfluidic paper-based devices for bioanalytical applications. AB - Paper has become increasingly recognized as a very interesting substrate for the construction of microfluidic devices, with potential application in a variety of areas, including health diagnosis, environmental monitoring, immunoassays and food safety. The aim of this review is to present a short history of analytical systems constructed from paper, summarize the main advantages and disadvantages of fabrication techniques, exploit alternative methods of detection such as colorimetric, electrochemical, photoelectrochemical, chemiluminescence and electrochemiluminescence, as well as to take a closer look at the novel achievements in the field of bioanalysis published during the last 2 years. Finally, the future trends for production of such devices are discussed. PMID- 24341498 TI - Follicular variant of papillary thyroid carcinoma: distinct biologic behavior based on ultrasonographic features. AB - BACKGROUND: Follicular variants of papillary thyroid carcinoma (FVPTCs) have dichotomous ultrasonographic (US) features. We investigated the differences in the biologic behavior of FVPTC according to US features. METHODS: We reviewed the US findings, pathologic reports, and medical charts of 75 consecutive patients with FVPTC who underwent surgery at our institution from January 2006 to December 2008. FVPTCs were divided into PTC-like and follicular neoplasm (FN)-like based on US findings. PTC-like nodules were defined as having at least one accepted malignant feature (a taller-than-wide shape, an infiltrative margin, marked hypoechogenicity, and micro- or macrocalcifications), whereas FN-like nodules showed oval solid features without malignant features. The prognostic factors were compared. RESULTS: Of the 75 FVPTCs, 42 (56%) were PTC-like and 33 (44%) were FN-like. The mean tumor size of PTC-like FVPTC was significantly smaller than that of FN-like FVPTC (p=0.0483). PTC-like FVPTC showed a significantly higher rate of multifocality than FN-like FVPTC (48% and 15% respectively; p=0.0031). Extrathyroidal extension occurred in 55% of PTC-like FVPTCs compared to 12% of FN-like FVPTCs (p=0.0001). Lymph node metastasis was more frequent in PTC-like FVPTC than in FN-like FVPTC (36% vs. 12%; p=0.0197). PTC-like FVPTC had a higher stage than FN-like FVPTC (p=0.0001). These significant factors persisted in multivariate analysis. Only one recurrence and one distant metastasis were identified, and both occurred in PTC-like FVPTC. CONCLUSIONS: FVPTC with malignant US features seems to behave in a more aggressive fashion than FVPTC without malignant US features. US can help predict the behavior of FVPTC. PMID- 24341499 TI - Expression of FcFT1, a FLOWERING LOCUS T-like gene, is regulated by light and associated with inflorescence differentiation in fig (Ficus carica L.). AB - BACKGROUND: Because the floral induction occurs in many plants when specific environmental conditions are satisfied, most plants bloom and bear fruit during the same season each year. In fig, by contrast, the time interval during which inflorescence (flower bud, fruit) differentiation occurs corresponds to the shoot elongation period. Fig trees thus differ from many species in their reproductive growth characteristics. To date, however, the molecular mechanisms underlying this unorthodox physiology of floral induction and fruit setting in fig trees have not been elucidated. RESULTS: We isolated a FLOWERING LOCUS T (FT)-like gene from fig and examined its function, characteristics, and expression patterns. The isolated gene, F. carica FT (FcFT1), is single copy in fig and shows the highest similarity at the amino acid level (93.1%) to apple MdFT2. We sequenced its upstream region (1,644 bp) and identified many light-responsive elements. FcFT1 was mainly expressed in leaves and induced early flowering in transgenic tobacco, suggesting that FcFT1 is a fig FT ortholog. Real-time reverse-transcription PCR analysis revealed that FcFT1 mRNA expression occurred only in leaves at the lower nodes, the early fruit setting positions. mRNA levels remained a constant for approximately 5 months from spring to autumn, corresponding almost exactly to the inflorescence differentiation season. Diurnal variation analysis revealed that FcFT1 mRNA expression increased under relative long-day and short-day conditions, but not under continuous darkness. CONCLUSION: These results suggest that FcFT1 activation is regulated by light conditions and may contribute to fig's unique fruit-setting characteristics. PMID- 24341500 TI - First evidence of Candidatus Neoehrlichia mikurensis in Hungary. AB - Altogether 2004 Ixodes ricinus ticks, from 37 places in Hungary, were analysed in pools with a recently developed multiplex real-time PCR for the presence of Candidatus Neoehrlichia mikurensis and for other representatives of the genus. Ca. Neoehrlichia mikurensis was identified in nine sampling sites, indicating three separated endemic regions along the borders of Hungary. In addition, results of samples from seven places (except for the western part of the country) were positive in the genus-specific (Ca. Neoehrlichia sp.) PCR, but were negative for Ca. Neoehrlichia mikurensis. PMID- 24341502 TI - Adopting a blended learning approach to teaching evidence based medicine: a mixed methods study. AB - BACKGROUND: Evidence Based Medicine (EBM) is a core unit delivered across many medical schools. Few studies have investigated the most effective method of teaching a course in EBM to medical students. The objective of this study was to identify whether a blended-learning approach to teaching EBM is more effective a didactic-based approach at increasing medical student competency in EBM. METHODS: A mixed-methods study was conducted consisting of a controlled trial and focus groups with second year graduate medical students. Students received the EBM course delivered using either a didactic approach (DID) to learning EBM or a blended-learning approach (BL). Student competency in EBM was assessed using the Berlin tool and a criterion-based assessment task, with student perceptions on the interventions assessed qualitatively. RESULTS: A total of 61 students (85.9%) participated in the study. Competency in EBM did not differ between the groups when assessed using the Berlin tool (p = 0.29). Students using the BL approach performed significantly better in one of the criterion-based assessment tasks (p = 0.01) and reported significantly higher self-perceived competence in critical appraisal skills. Qualitative analysis identified that students had a preference for the EBM course to be delivered using the BL approach. CONCLUSIONS: Implementing a blended-learning approach to EBM teaching promotes greater student appreciation of EBM principles within the clinical setting. Integrating a variety of teaching modalities and approaches can increase student self-confidence and assist in bridging the gap between the theory and practice of EBM. PMID- 24341503 TI - The transtheoretical model (TTM) questionnaire for smoking cessation: psychometric properties of the Iranian version. AB - BACKGROUND: The transtheoretical model (TTM) is a common framework for studies of smoking cessation. Using the TTM, several instruments were developed to measure to what extent interventions could make changes in people's behavior. The current study aimed to test the validity and reliability of the Persian version of a TTM based questionnaire for smoking cessation in Iran. METHODS: This was a cross sectional validation study among adult male smokers using the TTM Questionnaire. Backward-forward procedure was applied to translate the questionnaire from English into Persian (the Iranian language). The confirmatory factor analyses were performed to test validity. The internal consistency and stability of the questionnaire was examined using Cronbach's alpha coefficient and Intraclass Correlation Coefficient (ICC). RESULTS: In all 150 male smokers were entered into the study. The mean age of participants was 36.51 +/- 7.94 years. The results obtained from confirmatory factor analysis revealed that the data was fit to the model: the goodness of fit index (GFI) = 0.92; the comparative fit index (CFI) = 0.91; the root mean square error of approximation (RMSEA) = 0.065 (95% CI = 0.063 0.067), and the relative chi-square (x2/df) = 1.87, p < 0.001. The Cronbach's alpha ranged from 0.60 to 0.84 indicating an acceptable result. Also Intraclass Correlation of Coefficient (ICC) ranged from 0.61 to 0.83 corresponding to a satisfactory finding. CONCLUSION: The current study provided psychometric evidence for an appropriate, reliable, and valid tool to determine smoking behaviors among Iranian adult smokers. Indeed the findings from this study could be applied in designing smoking cessation interventions in Iran. PMID- 24341504 TI - Associations between perceptions of evidence and adoption of H1N1 influenza infection prevention strategies among healthcare workers providing care to persons with spinal cord injury. AB - AIM: To examine associations between perceptions of evidence (research evidence, clinical expertise, patient preferences) and outcomes of a nationwide programme to implement H1N1 influenza prevention guidelines. BACKGROUND: Healthcare workers do not consistently adhere to recommended infection control practices and this may be associated with their perceptions of evidence sources. DESIGN: Cross sectional mailed survey. METHOD: A survey of healthcare workers was administered in August 2010 after implementation of H1N1 prevention guidelines. Outcomes of interest were ratings of adherence to H1N1 prevention guidelines. FINDINGS: Respondents with complete data (N = 283) were included in analyses. Facility level adherence to guidelines was associated with opinions of clinical experts. Healthcare workers who rated clinical expertise as aligning with recommendations also rated their facilities as being more adherent to guidelines. Perceptions of research evidence and patient preferences were not associated with facility adherence. Personal adherence was not associated with perceptions of evidence, except among those healthcare workers who rated both clinical experts and patients as unsupportive of guidelines; these practitioners were less likely to adhere to recommended personal hygiene practices. CONCLUSION: Efforts to implement guidelines might be most effective when capitalizing on the influence of clinical experts. To better explain variability in guideline adherence, inclusion of a broader array of variables is recommended for future studies. PMID- 24341505 TI - Dr. Rodney Wootten (1946 - 2013). PMID- 24341506 TI - Updated morphology, histopathology and molecular phylogeny of Myxobolus hearti, cardiac myxosporea in gibel carp, Carassius gibelio (Bloch). AB - The original description of Myxobolus hearti is supplemented with new data on spore morphology, histopathology and molecular phylogeny. Myxobolus hearti are found in the heart ventricle of the gibel carp, Carassius gibelio (Bloch), where they form whitish oval or irregularly shaped plasmodia. Mature spores are oval or shortly ellipsoidal in frontal view, lemon-shaped in sutural view and eye-shaped in apical view. The spores are 14.12 +/- 0.35 (13.6-15) MUm long (mean +/- SD), 11.85 +/- 0.34 +/- 0.36 (11-12) MUm wide and 7.32 +/- 0.36 (7-8) MUm thick. The two polar capsules are equal in size, 6.11 +/- 0.29 (6-7) MUm long and 3.89 +/- 0.31(3-4) MUm wide, and are long pyriform in shape. Polar filaments have six or seven coils situated perpendicular to the longitudinal axis of the polar capsules. Histopathology indicates that the plasmodia are encased by the host connective tissue, and no inflammatory responses are found in the heart ventricles. Phylogenetic analysis based on the 18S small-subunit ribosomal DNA sequences indicates that M. hearti is, genetically, most similar to Henneguya doneci, a gill-infecting species. PMID- 24341507 TI - A high-throughput Sanger strategy for human mitochondrial genome sequencing. AB - BACKGROUND: A population reference database of complete human mitochondrial genome (mtGenome) sequences is needed to enable the use of mitochondrial DNA (mtDNA) coding region data in forensic casework applications. However, the development of entire mtGenome haplotypes to forensic data quality standards is difficult and laborious. A Sanger-based amplification and sequencing strategy that is designed for automated processing, yet routinely produces high quality sequences, is needed to facilitate high-volume production of these mtGenome data sets. RESULTS: We developed a robust 8-amplicon Sanger sequencing strategy that regularly produces complete, forensic-quality mtGenome haplotypes in the first pass of data generation. The protocol works equally well on samples representing diverse mtDNA haplogroups and DNA input quantities ranging from 50 pg to 1 ng, and can be applied to specimens of varying DNA quality. The complete workflow was specifically designed for implementation on robotic instrumentation, which increases throughput and reduces both the opportunities for error inherent to manual processing and the cost of generating full mtGenome sequences. CONCLUSIONS: The described strategy will assist efforts to generate complete mtGenome haplotypes which meet the highest data quality expectations for forensic genetic and other applications. Additionally, high-quality data produced using this protocol can be used to assess mtDNA data developed using newer technologies and chemistries. Further, the amplification strategy can be used to enrich for mtDNA as a first step in sample preparation for targeted next-generation sequencing. PMID- 24341508 TI - Light-induced organic monolayer modification of iodinated carbon electrodes. AB - We report the modification of carbon electrodes formed from pyrolyzed photoresist films (PPF) via plasma iodination followed by the organic monolayer modification of these surfaces. The iodinated surfaces were characterized using cyclic voltammetry, atomic force microscopy, and X-ray photoelectron spectroscopy to enable the optimization of the iodination while preserving the stability and smoothness of the carbon surface. Subsequently, the C-I surface was further modified with molecules that possess an alkene or alkyne at one end through light activation with low energy (visible range lambda 514 nm). The versatility of the modification reaction of the C-I surfaces is shown by reactions with undecylenic acid, 1,8-nonadiyne, and S-undec-10-enyl-2,2,2-trifluoroethanethioate (C11-S TFA). Modification with 1,8-nonadiyne allows further modification via "click" chemistry with azido-terminated oligo(ethylene oxide) molecules demonstrated briefly to alter the hydrophilicity of the surface after attachment of ethylene oxide moieties. Furthermore, patterning of C11-S-TFA was demonstrated using a simple photolithography technique. Deprotection of the C11-S-TFA gave a free thiol allowed patterning of gold nanoparticles on the surface as verified using scanning electron microscopy (SEM). These results demonstrate that plasma iodination to form C-I is a versatile, simple, and modular approach to functionalize the carbon surface. PMID- 24341509 TI - Food rewards modulate the activity of song neurons in Bengalese finches. AB - Vocal learning, a critical component of speech acquisition, is a rare trait in animals. Songbirds are a well-established animal model in vocal learning research; male birds acquire novel vocal patterns and have a well-developed 'song system' in the brain. Although this system is unique to songbirds, anatomical and physiological studies have reported similarities between the song system and the thalamo-cortico-basal ganglia circuit that is conserved among reptiles, birds, and mammals. Here, we focused on the similarity of the neural response between these two systems while animals were engaging in operant tasks. Neurons in the basal ganglia of vertebrates are activated in response to food rewards and reward predictions in behavioral tasks. A striatal nucleus in the avian song system, Area X, is necessary for vocal learning and is considered specialized for singing. We found that the spiking activity of singing-related Area X neurons was modulated by food rewards and reward signals in an operant task. As previous studies showed that Area X is not critical for general cognitive tasks, the role of Area X in general learning might be limited and vestigial. However, our results provide a new viewpoint to investigate the independence of the vocal learning system from neural systems involved in other cognitive tasks. PMID- 24341511 TI - Feedback GAP: pragmatic, cluster-randomized trial of goal setting and action plans to increase the effectiveness of audit and feedback interventions in primary care. AB - BACKGROUND: Audit and feedback to physicians is a commonly used quality improvement strategy, but its optimal design is unknown. This trial tested the effects of a theory-informed worksheet to facilitate goal setting and action planning, appended to feedback reports on chronic disease management, compared to feedback reports provided without these worksheets. METHODS: A two-arm pragmatic cluster randomized trial was conducted, with allocation at the level of primary care clinics. Participants were family physicians who contributed data from their electronic medical records. The 'usual feedback' arm received feedback every six months for two years regarding the proportion of their patients meeting quality targets for diabetes and/or ischemic heart disease. The intervention arm received these same reports plus a worksheet designed to facilitate goal setting and action plan development in response to the feedback reports. Blood pressure (BP) and low-density lipoprotein cholesterol (LDL) values were compared after two years as the primary outcomes. Process outcomes measured the proportion of guideline-recommended actions (e.g., testing and prescribing) conducted within the appropriate timeframe. Intention-to-treat analysis was performed. RESULTS: Outcomes were similar across groups at baseline. Final analysis included 20 physicians from seven clinics and 1,832 patients in the intervention arm (15% loss to follow up) and 29 physicians from seven clinics and 2,223 patients in the usual feedback arm (10% loss to follow up). Ten of 20 physicians completed the worksheet at least once during the study. Mean BP was 128/72 in the feedback plus worksheet arm and 128/73 in the feedback alone arm, while LDL was 2.1 and 2.0, respectively. Thus, no significant differences were observed across groups in the primary outcomes, but mean haemoglobin A1c was lower in the feedback plus worksheet arm (7.2% versus 7.4%, p<0.001). Improvements in both arms were noted over time for one-half of the process outcomes. DISCUSSION: Appending a theory informed goal setting and action planning worksheet to an externally produced audit and feedback intervention did not lead to improvements in patient outcomes. The results may be explained in part by passive dissemination of the worksheet leading to inadequate engagement with the intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT00996645. PMID- 24341513 TI - Total synthesis of sandramycin and its analogues via a multicomponent assemblage. AB - The total synthesis of sandramycin has been accomplished by using a Staudinger/aza-Wittig/diastereoselective Ugi three-component reaction sequence as a key step to obtain a linear pentadepsipeptide. Subsequent [5 + 5] coupling of the penptapeptide, macrolactamization, and introduction of the quinaldin chromophores afforded sandramycin. Dihydroxy and diacetoxy analogues were also prepared, and the cytotoxic activity of these analogues against a range of human cancer cell lines was evaluated. PMID- 24341512 TI - Pancreatic-carcinoma-cell-derived pro-angiogenic factors can induce endothelial cell differentiation of a subset of circulating CD34+ progenitors. AB - BACKGROUND: CD34+ progenitor cells comprise both hematopoietic and endothelial progenitor cells. Recent studies suggest that circulating endothelial progenitor cells are recruited into the angiogenic vascular system of several cancers, including pancreatic carcinoma, and that they correlate with clinical progress. However, whether endothelial progenitor cell mobilization occurs in response to cytokine release by tumor cells is still unclear. METHODS: The chemotactic- and/or differentiating-activities of the poorly-differentiated pancreatic carcinoma cell line PT45, and of the immortal H6c7 cell line, a line of near normal pancreatic duct epithelial cells, on endothelial progenitor cells were investigated in vitro using circulating CD34+ as model. RESULTS: The study showed that Vascular Endothelial Growth Factor produced by PT45 cells and, at lesser extent, by H6c7 cells, predominantly chemoattract peripheral blood CD34+ expressing the type 2 relative receptor. Addition of PT45-conditioned medium to CD34+ cells, cultured under conditions supporting myeloid cell development, diverted the differentiation of a subset of these progenitor cells into cells expressing endothelial cell markers, such as CD146, CD105, VE-cadherin and von Willebrand Factor-related antigen. Moreover, these endothelial-like cells formed capillary networks in vitro, chiefly through the release of Angiopoietin-1 by PT45 cells. CONCLUSIONS: The results demonstrate that pancreatic-carcinoma cells potentially attract circulating endothelial progenitor cells to the tumor site, by releasing high levels of pro-angiogenic factors such as Vascular Endothelial Growth Factor and Angiopoietin-1, and may direct the differentiation of these cell subsets of the CD34+ cell population into endothelial cells; the latter cells may become a component of the newly-formed vessels, contributing to angiogenesis-mediated tumor growth and metastasis. PMID- 24341514 TI - Microscale modelling in biomechanics and mechanobiology. PMID- 24341515 TI - Geometrical spin frustration and ferromagnetic ordering in (MnxPb2-x)Pb2Sb4Se10. AB - Engineering the atomic structure of an inorganic semiconductor to create isolated one-dimensional (1D) magnetic subunits that are embedded within the semiconducting crystal lattice can enable chemical and electronic manipulation of magnetic ordering within the magnetic domains, paving the way for (1) the investigation of new physical phenomena such as the interactions between electron transport and localized magnetic moments at the atomic scale and (2) the design and fabrication of geometrically frustrated magnetic materials featuring cooperative long-range ordering with large magnetic moments. We report the design, synthesis, crystal structure and magnetic behavior of (MnxPb2 x)Pb2Sb4Se10, a family of three-dimensional manganese-bearing main-group metal selenides featuring quasi-isolated [(MnxPb2-x)3Se30]infinity hexanuclear magnetic ladders coherently embedded and uniformly distributed within a purely inorganic semiconducting framework, [Pb2Sb4Se10]. Careful structural analysis of the magnetic subunit, [(MnxPb2-x)3Se30]infinity and the temperature dependent magnetic susceptibility of (MnxPb2-x)Pb2Sb4Se10, indicate that the compounds are geometrically frustrated 1D ferromagnets. Interestingly, the degree of geometrical spin frustration (f) within the magnetic ladders and the strength of the intrachain antiferromagnetic (AFM) interactions strongly depend on the concentration (x value) and the distribution of the Mn atom within the magnetic substructure. The combination of strong intrachain AFM interactions and geometrical spin frustration in the [(MnxPb2-x)3Se30]infinity ladders results in a cooperative ferromagnetic order with exceptionally high magnetic moment at around 125 K. Magnetotransport study of the Mn2Pb2Sb4Se10 composition over the temperature range from 100 to 200 K revealed negative magnetoresistance (NMR) values and also suggested a strong contribution of magnetic polarons to the observed large effective magnetic moments. PMID- 24341516 TI - Families and well-being in East Asia: a special section. PMID- 24341517 TI - Transferring the emergence profile from the provisional to the final restoration. AB - In implant restorations, the ability to manage the response of soft tissue properly and achieve a proper emergence profile is a primary goal for the clinician. The desirable emergence profile can be formed by the use of the provisional restorations. Once this task is achieved, the soft tissue contour must be transferred accurately to the final restoration. In this technique article, four different methods are presented for transferring the emergence profile: the modification of the impression post by adding composite resin intraorally or extraorally, the fabrication of a working cast mimicking the soft tissue contour, and the use of CAD/CAM technology. Each technique presents certain advantages and disadvantages. The choice, therefore, relies on the clinician's judgment depending on the available materials, time, and familiarization with the necessary steps. The aim of this technique article is to describe, evaluate, and compare with the use of clinical examples these four techniques presented for the transfer of the emergence profile from the provisional to the final restoration. CLINICAL SIGNIFICANCE: The application of these simple, yet important, techniques can not only help achieve optimal esthetics but also contribute to the maintenance of peri-implant health. Especially in esthetically demanding cases-such as in implant restorations in the anterior area or in cases with high lip line-their application can lead to a more predictable final result. PMID- 24341518 TI - Substitutional photoluminescence modulation in adducts of a europium chelate with a range of alkali metal cations: a gas-phase study. AB - We present gas-phase dispersed photoluminescence spectra of europium(III) 9 hydroxyphenalen-1-one (HPLN) complexes forming adducts with alkali metal ions ([Eu(PLN)3M](+) with M = Li, Na, K, Rb, and Cs) confined in a quadrupole ion trap for study. The mass selected alkali metal cation adducts display a split hypersensitive (5)D0 -> (7)F2 Eu(3+) emission band. One of the two emission components shows a linear dependence on the radius of the alkali metal cation whereas the other component displays a quadratic dependence thereon. In addition, the relative intensities of both components invert in the same order. The experimental results are interpreted with the support of density functional calculations and Judd-Ofelt theory, yielding also structural information on the isolated [Eu(PLN)3M](+) chromophores. PMID- 24341521 TI - Case of presymptomatic aceruloplasminemia treated with deferasirox. AB - Aceruloplasminemia is an autosomal recessive disease characterized by an abnormal iron metabolism. The absence of ferroxidase activity caused by mutation of ceruloplasmin leads to iron overload in the brain, liver and other organs. We report a 35-year-old man who was diagnosed with aceruloplasminemia without neurological manifestation despite the accumulation of iron in the brain and liver. To prevent the development of neurodegenerative disorder related to iron toxicity, iron depletion therapy was performed. Iron chelator deferasirox was effective in reducing serum ferritin level and to prevent the progression of the disease. PMID- 24341522 TI - Cancer-related genes in the transcription signature of facioscapulohumeral dystrophy myoblasts and myotubes. AB - Muscular dystrophy is a condition potentially predisposing for cancer; however, currently, only Myotonic dystrophy patients are known to have a higher risk of cancer. Here, we have searched for a link between facioscapulohumeral dystrophy (FSHD) and cancer by comparing published transcriptome signatures of FSHD and various malignant tumours and have found a significant enrichment of cancer related genes among the genes differentially expressed in FSHD. The analysis has shown that gene expression profiles of FSHD myoblasts and myotubes resemble that of Ewing's sarcoma more than that of other cancer types tested. This is the first study demonstrating a similarity between FSHD and cancer cell expression profiles, a finding that might indicate the existence of a common step in the pathogenesis of these two diseases. PMID- 24341524 TI - The haustorial transcriptomes of Uromyces appendiculatus and Phakopsora pachyrhizi and their candidate effector families. AB - Haustoria of biotrophic rust fungi are responsible for the uptake of nutrients from their hosts and for the production of secreted proteins, known as effectors, which modulate the host immune system. The identification of the transcriptome of haustoria and an understanding of the functions of expressed genes therefore hold essential keys for the elucidation of fungus-plant interactions and the development of novel fungal control strategies. Here, we purified haustoria from infected leaves and used 454 sequencing to examine the haustorial transcriptomes of Phakopsora pachyrhizi and Uromyces appendiculatus, the causal agents of soybean rust and common bean rust, respectively. These pathogens cause extensive yield losses in their respective legume crop hosts. A series of analyses were used to annotate expressed sequences, including transposable elements and viruses, to predict secreted proteins from the assembled sequences and to identify families of candidate effectors. This work provides a foundation for the comparative analysis of haustorial gene expression with further insights into physiology and effector evolution. PMID- 24341523 TI - A general strategy for organocatalytic activation of C-H bonds via photoredox catalysis: direct arylation of benzylic ethers. AB - Direct C-H functionalization and arylation of benzyl ethers has been accomplished via photoredox organocatalysis. The productive merger of a thiol catalyst and a commercially available iridium photoredox catalyst in the presence of household light directly affords benzylic arylation products in good to excellent yield. The utility of this methodology is further demonstrated in direct arylation of 2,5-dihydrofuran to form a single regioisomer. PMID- 24341525 TI - STAT3-dependent transactivation of miRNA genes following Toxoplasma gondii infection in macrophage. AB - BACKGROUND: The apicomplexan parasite Toxoplasma gondii can infect and replicate in virtually any nucleated cell in many species of warm-blooded animals; T. gondii has elaborate mechanisms to counteract host-cell apoptosis in order to maintain survival and breed in the host cells. METHODS: Using microarray profiling and a combination of conventional molecular approaches, we investigated the levels of microRNAs (miRNAs ) in human macrophage during T. gondii infection. We used molecular tools to examine Toxoplasma-upregualted miRNAs to revealed potential signal transducers and activators of transcription 3(STAT3) binding sites in the promoter elements of a subset of miRNA genes. We analysed the apoptosis of human macrophage with the functional inhibition of the STAT3-binding miRNAs by flow cytometry. RESULTS: Our results demonstrated differential alterations in the mature miRNA expression profile in human macrophage following T. gondii infection. Database analysis of Toxoplasma-upregulated miRNAs revealed potential STAT3 binding sites in the promoter elements of a subset of miRNA genes. We demonstrated that miR-30c-1, miR-125b-2, miR-23b-27b-24-1 and miR-17 ~ 92 cluster genes were transactivated through promoter binding of the STAT3 following T. gondii infection. Importantly, functional inhibition of selected STAT3-binding miRNAs in human macropahges increased apoptosis of host cells. CONCLUSIONS: A panel of miRNAs is regulated through promoter binding of the STAT3 in human macrophage and these miRNAs are involved in anti-apoptosis in response to T. gondii infection. PMID- 24341526 TI - A cross-sectional pilot study of the Scottish early development instrument: a tool for addressing inequality. AB - BACKGROUND: Early childhood is recognised as a key developmental phase with implications for social, academic, health and wellbeing outcomes in later childhood and indeed throughout the adult lifespan. Community level data on inequalities in early child development are therefore required to establish the impact of government early years' policies and programmes on children's strengths and vulnerabilities at local and national level. This would allow local leaders to target tailored interventions according to community needs to improve children's readiness for the transition to school. The challenge is collecting valid data on sufficient samples of children entering school to derive robust inferences about each local birth cohort's developmental status. This information needs to be presented in a way that allows community stakeholders to understand the results, expediting the improvement of preschool programming to improve future cohorts' development in the early years. The aim of the study was to carry out a pilot to test the feasibility and ease of use in Scotland of the 104-item teacher-administered Early Development Instrument, an internationally validated measure of children's global development at school entry developed in Canada. METHODS: Phase 1 was piloted in an education district with 14 Primary 1 teachers assessing a cohort of 154 children, following which the instrument was adapted for the Scottish context (Scottish Early Development Instrument: SEDI). Phase 2 was then carried out using the SEDI. Data were analysed from a larger sample of 1090 participants, comprising all Primary 1 children within this school district, evaluated by 68 teachers. RESULTS: The SEDI displayed adequate psychometric and discriminatory properties and is appropriate for use across Scotland without any further modifications. Children in the lowest socioeconomic status quintiles were 2-3 times more likely than children in the most affluent quintile to score low in at least one developmental domain. Even in the most affluent quintile though, 17% of children were 'developmentally vulnerable', suggesting that those in need cannot be identified by socioeconomic status alone. CONCLUSIONS: The SEDI offers a feasible means of providing communities with a holistic overview of school readiness for targeting early years' interventions. PMID- 24341528 TI - Arginine vasotocin treatment induces a stress response and exerts a potent anorexigenic effect in rainbow trout, Oncorhynchus mykiss. AB - The peptide arginine vasotocin (AVT), homologous to mammalian arginine vasopressin, is involved in many aspects of fish physiology, such as osmoregulation, regulation of biological rhythms, reproduction, metabolism or responses to stress, and the modulation of social behaviours. Because a decrease in appetite is a general response to stress in fish and other vertebrates, we investigated the role of AVT as a possible food intake regulator in fish. We used i.c.v. injections for central administration of AVT to rainbow trout (Oncorhynchus mykiss). In a first experiment, we evaluated the temporal response of food intake after AVT treatment. In a second experiment, we investigated the effects of central AVT administration on the response of typical stress markers (plasma cortisol, glucose and lactate), as well as brain serotonergic, noradrenergic and dopaminergic activity. In addition, the mRNA levels of genes involved in food intake regulation [neuropetide Y, pro-opiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART) and corticotrophin-releasing factor (CRF)] and in CRF- (CRF-binding protein) and AVT-signalling (pro-VT and AVT receptor), were also assessed after AVT treatment. Our results showed that AVT is a potent anorexigenic factor in fish. Increases of plasma cortisol and glucose after AVT treatment strongly suggest that AVT administration induced a stress response and that AVT action was mediated by hypothalamic-pituitary interrenal axis activation, which was also supported by the increase of the serotonergic activity in trout telencephalon and hypothalamus. The increased hypothalamic levels of POMC and CART suggest that these peptides might have a role in the anorexigenic action of AVT, whereas the involvement of CRF signalling is unclear. PMID- 24341527 TI - Long-term efficacy of modified-release recombinant human thyrotropin augmented radioiodine therapy for benign multinodular goiter: results from a multicenter, international, randomized, placebo-controlled, dose-selection study. AB - BACKGROUND: Enhanced reduction of multinodular goiter (MNG) can be achieved by stimulation with recombinant human thyrotropin (rhTSH) before radioiodine ((131)I) therapy. The objective was to compare the long-term efficacy and safety of two low doses of modified release rhTSH (MRrhTSH) in combination with (131)I therapy. METHODS: In this phase II, single-blinded, placebo-controlled study, 95 patients (57.2 +/- 9.6 years old, 85% women, 83% Caucasians) with MNG (median size 96.0 mL; range 31.9-242.2 mL) were randomized to receive placebo (n=32), 0.01 mg MRrhTSH (n=30), or 0.03 mg MRrhTSH (n=33) 24 hours before a calculated (131)I activity. Thyroid volume (TV) and smallest cross-sectional area of trachea (SCAT) were measured (by computed tomography scan) at baseline, six months, and 36 months. Thyroid function and quality of life (QoL) was evaluated at three month and yearly intervals respectively. RESULTS: At six months, TV reduction was enhanced in the 0.03 mg MRrhTSH group (32.9% vs. 23.1% in the placebo group; p=0.03) but not in the 0.01 mg MRrhTSH group. At 36 months, the mean percent TV reduction from baseline was 44 +/- 12.7% (SD) in the placebo group, 41 +/- 21.0% in the 0.01 mg MRrhTSH group, and 53 +/- 18.6% in the 0.03 mg MRrhTSH group, with no statistically significant differences among the groups, p=0.105. In the 0.03 mg MRrhTSH group, the subset of patients with basal (131)I uptake <20% had a 24% greater TV reduction at 36 months than the corresponding subset of patients in the placebo group (p=0.01). At 36 months, the largest relative increase in SCAT was observed in the 0.03 mg MRrhTSH group (13.4 +/- 23.2%), but this was not statistically different from the increases observed in the placebo or the 0.01 mg MRrhTSH group (p=0.15). Goiter-related symptoms were reduced and QoL improved, without any enhanced benefit from using MRrhTSH. At three years, the prevalence of permanent hypothyroidism was 13%, 33%, and 45% in the placebo, 0.01 mg, and 0.03 mg MRrhTSH groups respectively. The overall safety profile of the study was favorable. CONCLUSIONS: When used as adjuvant to (131)I, enhanced MNG reduction could not be demonstrated with MRrhTSH doses <= 0.03 mg, indicating that the lower threshold for efficacy is around this level. PMID- 24341529 TI - New estimates of the burden of acute community-acquired infections among older people with diabetes mellitus: a retrospective cohort study using linked electronic health records. AB - AIM: To describe the incidence of acute community-acquired infections (lower respiratory tract infections, urinary tract infections and sepsis) among the UK population aged >=65 years with diabetes mellitus, and all-cause 28-day hospital admission rates and mortality. METHODS: We used electronic primary care records from the Clinical Practice Research Datalink, linked to death certificates and Hospital Episode Statistics admission data, to conduct a retrospective cohort study from 1997 to 2011. RESULTS: Among the 218 805 older people with diabetes there was a high burden of community-acquired infection, lower respiratory tract infections having the highest incidence (crude rate: 152.7/1000 person-years) followed by urinary tract infections (crude rates 51.4 and 147.9/1000 person years for men and women, respectively). The incidence of all infections increased over time, which appeared to be driven by the population's changing age structure. Most patients diagnosed with pneumonia and sepsis were hospitalized on the same day (77.8 and 75.1%, respectively). For lower respiratory tract infections and urinary tract infections, a large proportion of 28-day hospitalizations were after the day of diagnosis (39.1 and 44.3%, respectively), and a notable proportion of patients (7.1 and 5.1%, respectively) were admitted for a cardiovascular condition. In the 4 weeks after onset, all-cause mortality was 32.1% for pneumonia (3115/9697), 31.7% for sepsis (780/2461), 4.1% for lower respiratory tract infections (5685/139 301) and 1.6% for urinary tract infections (1472/91 574). CONCLUSIONS: The present large cohort study provides up-to-date detailed infection incidence estimates among older people with diabetes in the community, with variation by age, sex and region and over time. This should be of use for patient communication of risk and future healthcare planning. PMID- 24341530 TI - Delivery of primary health care to persons who are socio-economically disadvantaged: does the organizational delivery model matter? AB - BACKGROUND: As health systems evolve, it is essential to evaluate their impact on the delivery of health services to socially disadvantaged populations. We evaluated the delivery of primary health services for different socio-economic groups and assessed the performance of different organizational models in terms of equality of health care delivery in Ontario, Canada. METHODS: Cross sectional study of 5,361 patients receiving care from primary care practices using Capitation, Salaried or Fee-For-Service remuneration models. We assessed self reported health status of patients, visit duration, number of visits per year, quality of health service delivery, and quality of health promotion. We used multi-level regressions to study service delivery across socio-economic groups and within each delivery model. Identified disparities were further analysed using a t-test to determine the impact of service delivery model on equity. RESULTS: Low income individuals were more likely to be women, unemployed, recent immigrants, and in poorer health. These individuals were overrepresented in the Salaried model, reported more visits/year across all models, and tended to report longer visits in the Salaried model. Measures of primary care services generally did not differ significantly between low and higher income/education individuals; when they did, the difference favoured better service delivery for at-risk groups. At-risk patients in the Salaried model were somewhat more likely to report health promotion activities than patients from Capitation and Fee-For Service models. At-risk patients from Capitation models reported a smaller increase in the number of additional clinic visits/year than Fee-For-Service and Salaried models. At-risk patients reported better first contact accessibility than their non-at-risk counterparts in the Fee-For-Service model only. CONCLUSIONS: Primary care service measures did not differ significantly across socio-economic status or primary care delivery models. In Ontario, capitation based remuneration is age and sex adjusted only. Patients of low socio-economic status had fewer additional visits compared to those with high socio-economic status under the Capitation model. This raises the concern that Capitation may not support the provision of additional care for more vulnerable groups. Regions undertaking primary care model reforms need to consider the potential impact of the changes on the more vulnerable populations. PMID- 24341531 TI - Ankle-brachial index and the incidence of cardiovascular events in the Mediterranean low cardiovascular risk population ARTPER cohort. AB - BACKGROUND: Peripheral arterial disease (PAD) of the lower limbs is a cardiovascular disease highly prevalent particularly in the asymptomatic form. Its prevalence starts to be a concern in low coronary risk countries like Spain. Few studies have analyzed the relationship between ankle-brachial index (ABI) and cardiovascular morbi-mortality in low cardiovascular risk countries like Spain where we observe significant low incidence of ischemic heart diseases together with high prevalence of cardiovascular risk factors. The objective of this study is to determine the relationship between pathological ABI and incidence of cardiovascular events (coronary disease, cerebrovascular disease, symptomatic aneurism of abdominal aorta, vascular surgery) and death in the >49 year population-based cohort in Spain (ARTPER). METHODS: Baseline ABI was measured in 3,786 randomly selected patients from 28 Primary Health Centers in Barcelona, distributed as: ABI<0.9 peripheral arterial disease (PAD), ABI >=1.4 arterial calcification (AC), ABI 0.9-1.4 healthy; and followed during 4 years. RESULTS: 3,307 subjects were included after excluding those with previous vascular events. Subjects with abnormal ABI were older with higher proportion of men, smokers and diabetics. 260 people presented cardiovascular events (incidence 2,117/100,000 person-years) and 124 died from any cause (incidence 978/100,000 person-years). PAD had two-fold greater risk of coronary disease (adjusted hazard ratio (HR) = 2.0, 95% confidence interval (CI) 1.3-3.2) and increased risk of vascular surgery (HR = 5.6, 95%CI 2.8-11.5) and mortality (HR = 1.8, 95%CI 1.4-2.5). AC increased twice risk of cerebrovascular events (HR = 1.9, 95%CI 1.0-3.5) with no relationship with ischemic heart disease. CONCLUSIONS: PAD increases coronary disease risk and AC cerebrovascular disease risk in low cardiovascular risk Mediterranean population. ABI could be a useful tool to detect patients at risk in Primary Health Care. PMID- 24341532 TI - Effects of alternative splicing on the function of bestrophin-1 calcium-activated chloride channels. AB - The proposed Ca2+-activated Cl- channel protein Best1 (bestrophin 1) is expressed and functionally important in the retina and in the brain. Human BEST1 has two known splice variants, Best1V1 and Best1V2, which arise from alternative splicing of two exons: exon 2 splicing results in a unique N-terminal domain, whereas alternative splicing of exon 11 produces two mutually exclusive C-termini. Prior studies were limited to Best1V1 and its clinically relevant mutations. In the present work, we cloned a novel splice variant of Best1V1 missing exon 2 (Best1V1Deltaex2) and differing from each of the two previously identified isoforms by one alternatively spliced domain. This finding allowed us to determine the role for alternative splicing of the Best1 N- and C-termini. We heteroexpressed Best1V1Deltaex2 in HEK (human embryonic kidney)-293 cells, and compared its properties with Best1V1 and Best1V2. Western blot analysis confirmed protein expression from all three splice variants. Both Best1V1 and Best1V1Deltaex2 successfully formed Ca2+-activated Cl- channels, demonstrating that the N-terminus encoded by exon 2 is not essential for channel function. In contrast, Best1V2-expressing cells had no detectable Ca2+-activated Cl- currents, pointing to a critical role for splicing of the C-terminus. Surface protein biotinylation demonstrated that Best1V1 and Best1V1Deltaex2 are trafficked to the plasma membrane, whereas Best1V2 is not. These results define the impact of alternative splicing on Best1 function, and should be taken into consideration in future modelling of the Best1 protein structure. PMID- 24341533 TI - Facile directed assembly of hollow polymer nanocapsules within spontaneously formed catanionic surfactant vesicles. AB - Surfactant vesicles containing monomers in the interior of the bilayer were used to template hollow polymer nanocapsules. This study investigated the formation of surfactant/monomer assemblies by two loading methods, concurrent loading and diffusion loading. The assembly process and the resulting aggregates were investigated with dynamic light scattering, small angle neutron scattering, and small-angle X-ray scattering. Acrylic monomers formed vesicles with a mixture of cationic and anionic surfactants in a broad range of surfactant ratios. Regions with predominant formation of vesicles were broader for compositions containing acrylic monomers compared with blank surfactants. This observation supports the stabilization of the vesicular structure by acrylic monomers. Diffusion loading produced monomer-loaded vesicles unless vesicles were composed from surfactants at the ratios close to the boundary of a vesicular phase region on a phase diagram. Both concurrent-loaded and diffusion-loaded surfactant/monomer vesicles produced hollow polymer nanocapsules upon the polymerization of monomers in the bilayer followed by removal of surfactant scaffolds. PMID- 24341534 TI - Age- and gender-adjusted normative data for the German version of Rey's Auditory Verbal Learning Test from healthy subjects aged between 50 and 70 years. AB - Rey's Auditory Verbal Learning Test (AVLT) is widely used to evaluate dysfunctional episodic memory. The current study aimed to provide extended age- and gender-specific norms for the German AVLT for individuals older than 50 years. In 690 subjects, a comprehensive medical examination including a structural 3.0-tesla magnetic resonance imaging scan was administered, as well as extensive neuropsychological tests. After controlling for exclusion criteria, 407 subjects were included in the analysis. AVLT performance decreased with age, and women outperformed men. We present age- and gender-specific normative data for the German AVLT from subjects aged between 50 and 70 years. PMID- 24341536 TI - Clonal complexes of Staphylococcus aureus: all mixed and together. AB - In this manuscript, we show that the most important clonal complexes of Staphylococcus aureus, CC1, CC5, CC8, CC15 and CC97, are now all connected by eburst when run on the Multi-locus sequence typing (mlst) database. The seven loci suggested for the mlst scheme of S. aureus are not enough to separate the most important clones such as New York/Japan and Brazilian Epidemic Clone (BEC). They now all belong to the same clonal complex and this may be the time to think about a new way to discriminate them. PMID- 24341535 TI - VTCdb: a gene co-expression database for the crop species Vitis vinifera (grapevine). AB - BACKGROUND: Gene expression datasets in model plants such as Arabidopsis have contributed to our understanding of gene function and how a single underlying biological process can be governed by a diverse network of genes. The accumulation of publicly available microarray data encompassing a wide range of biological and environmental conditions has enabled the development of additional capabilities including gene co-expression analysis (GCA). GCA is based on the understanding that genes encoding proteins involved in similar and/or related biological processes may exhibit comparable expression patterns over a range of experimental conditions, developmental stages and tissues. We present an open access database for the investigation of gene co-expression networks within the cultivated grapevine, Vitis vinifera. DESCRIPTION: The new gene co-expression database, VTCdb (http://vtcdb.adelaide.edu.au/Home.aspx), offers an online platform for transcriptional regulatory inference in the cultivated grapevine. Using condition-independent and condition-dependent approaches, grapevine co expression networks were constructed using the latest publicly available microarray datasets from diverse experimental series, utilising the Affymetrix Vitis vinifera GeneChip (16 K) and the NimbleGen Grape Whole-genome microarray chip (29 K), thus making it possible to profile approximately 29,000 genes (95% of the predicted grapevine transcriptome). Applications available with the online platform include the use of gene names, probesets, modules or biological processes to query the co-expression networks, with the option to choose between Affymetrix or Nimblegen datasets and between multiple co-expression measures. Alternatively, the user can browse existing network modules using interactive network visualisation and analysis via CytoscapeWeb. To demonstrate the utility of the database, we present examples from three fundamental biological processes (berry development, photosynthesis and flavonoid biosynthesis) whereby the recovered sub-networks reconfirm established plant gene functions and also identify novel associations. CONCLUSIONS: Together, we present valuable insights into grapevine transcriptional regulation by developing network models applicable to researchers in their prioritisation of gene candidates, for on-going study of biological processes related to grapevine development, metabolism and stress responses. PMID- 24341537 TI - Nonlinear optical pulse suppression via ultrafast photoinduced electron transfer in an aggregated perylene diimide/oligothiophene molecular triad. AB - A donor-acceptor-donor triad material in which two quinquethiophene moieties are attached via nonconjugated, flexible bridges to the 1,7-positions (80% isomer) and 1,6-positions (20% isomer) of a perylene diimide (PDI-5T) has been synthesized, and its nonlinear suppression of nanosecond laser pulses in the 680 750 nm range has been studied. The kinetics of the photoinduced charge separation processes have been characterized using femtosecond transient pump-probe spectroscopy. Excitation of either the quinquethiophene donor or perylene diimide acceptor leads to ultrafast (<700 fs) photoinduced charge separation, yielding quinquethiophene and perylene diimide radical ions that are strongly absorbing in the red-near-IR region. Despite the short lifetime (52 ps) of the charge separated state, reasonably strong nonlinear suppression of nanosecond pulses, with figures-of-merit up to 14, has been realized with 4 mM solutions of PDI-5T. Although the radical ion absorption (RIA) is much stronger at 750 nm than that at 680 or 700 nm, the best optical suppression figures-of-merit were observed at 680 and 700 nm. Comparison of the optical parameters at these wavelengths suggests that the stronger ground-state absorption, due to aggregates of PDI-5T, is responsible for the enhanced figure-of-merit at the shorter wavelength. PMID- 24341538 TI - Palladium-catalyzed unactivated C(sp3)-H bond activation and intramolecular amination of carboxamides: a new approach to beta-lactams. AB - An efficient method to synthesize the beta-lactams with high regioselectivity via Pd-catalyzed C(sp(3))-H bond activation and intramolecular amination of simple and readily available aminoquinoline carboxamides was demonstrated. C6F5I plays a significant role in the formation of the C-N bond of the four-membered ring beta lactams. High yield along with wide substrate scope and functional group tolerance makes this reaction applicable to build natural-product-derived beta lactams. This method has been applied to the efficient synthesis of the beta lactamase inhibitor MK-8712. PMID- 24341540 TI - In situ scanning electron microscope peeling to quantify surface energy between multiwalled carbon nanotubes and graphene. AB - Understanding atomic interactions between constituents is critical to the design of high-performance nanocomposites. Here, we report an experimental-computational approach to investigate the adhesion energy between as-produced arc discharge multiwalled carbon nanotubes (MWCNTs) and graphene. An in situ scanning electron microscope (SEM) experiment is used to peel MWCNTs from graphene grown on copper foils. The force during peeling is obtained by monitoring the deflection of a cantilever. Finite element and molecular mechanics simulations are performed to assist the data analysis and interpretation of the results. A finite element analysis of the experimental configuration is employed to confirm the applicability of Kendall's peeling model to obtain the adhesion energy. Molecular mechanics simulations are used to estimate the effective contact width at the MWCNT-graphene interface. The measured surface energy is gamma = 0.20 +/- 0.09 J.m(-2) or gamma = 0.36 +/- 0.16 J.m(-2), depending on the assumed conformation of the tube cross section during peeling. The scatter in the data is believed to result from an amorphous carbon coating on the MWCNTs, observed using transmission electron microscopy (TEM), and the surface roughness of graphene as characterized by atomic force microscopy (AFM). PMID- 24341541 TI - Distinct effects of self-construal priming on empathic neural responses in Chinese and Westerners. AB - The present study investigated whether and how self-construal priming influences empathic neural responses to others' emotional states. We recorded event-related brain potentials to stimuli depicting the hands of unknown others experiencing painful or non-painful events from Chinese and Western participants after they had been primed in three conditions (independent self-construal priming, interdependent self-construal priming, and a control condition). Stimuli depicting painful events (as opposed to non-painful ones) elicited a positive shift of the fronto-central activity at 232-332 ms and of the central-parietal activity at 440-740 ms in the control condition. Moreover, neural responses to stimuli depicting painful (vs. non-painful) situations at 232-332 ms were decreased by interdependent self-construal priming among Chinese and by independent self-construal priming among Westerners. Our findings suggest that self-construal priming modulates sensitivity to perceived pain in unknown others and that this effect varies with culture. PMID- 24341542 TI - Bioactive and biomimetic restorative materials: a comprehensive review. Part I. AB - The objective of this two-part review article is to compare and contrast the composition, properties, and performance of the calcium silicate- and calcium aluminate-based, bioactive dental materials, with an emphasis on the restorative applications of this evolving class of materials. Part I examines the development and application of the calcium silicate-based materials ranging from dental materials derived from Portland cement to more recent materials based on further modifications of calcium silicate cement chemistry. Part II will consider the development, composition, properties, and application of the bioactive calcium aluminate-based materials that have recently been developed for several indications in restorative dentistry. CLINICAL SIGNIFICANCE: Bioactive materials have evolved over the past three decades from relatively specialized, highly biocompatible, but low-strength dental materials to now emerge in product compositions for expanded clinical uses in restorative dentistry. Further developments to meet additional restorative clinical needs are anticipated in this newly emerging category of dental materials. PMID- 24341543 TI - Pharmacokinetic-pharmacodynamic integration and modelling of florfenicol in calves. AB - Florfenicol was administered subcutaneously to 10 calves at a dose of 40 mg/kg. Pharmacokinetic-pharmacodynamic (PK-PD) integration and modelling of the data were undertaken using a tissue cage model, which allowed comparison of microbial growth inhibition profiles in three fluids, serum, exudate and transudate. Terminal half-lives were relatively long, so that florfenicol concentrations were well maintained in all three fluids. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration were determined in vitro for six strains each of the calf pneumonia pathogens, Mannhemia haemolytica and Pasteurella multocida. An PK-PD integration for three serum indices provided mean values for P. multocida and M. haemolytica, respectively, of 12.6 and 10.4 for Cmax /MIC, 183 and 152 h for AUC0-24 h /MIC and 78 and 76 h for T>MIC. Average florfenicol concentrations in serum exceeded 4 * MIC and 1.5 * MIC for the periods 0-24 and 48-72 h, respectively. Ex vivo growth inhibition curves for M. haemolytica and P. multocida demonstrated a rapid (with 8 h of exposure) and marked (6 log10 reduction in bacterial count or greater) killing response, suggesting a concentration-dependent killing action. During 24-h incubation periods, inhibition of growth to a bacteriostatic level or greater was maintained in serum samples collected up to 96 h and in transudate and exudate samples harvested up to 120 h. Based on the sigmoidal Emax relationship, PK-PD modelling of the ex vivo time-kill data provided AUC0-24 h /MIC serum values for three levels of growth inhibition, bacteriostatic, bactericidal and 4 log10 decrease in bacterial count; mean values were, respectively, 8.2, 26.6 and 39.0 h for M. haemolytica and 7.6, 18.1 and 25.0 h for P. multocida. Similar values were obtained for transudate and exudate. Based on pharmacokinetic and PK-PD modelled data obtained in this study and scientific literature values for MIC distributions, Monte Carlo simulations over 100 000 trials were undertaken to predict once daily dosages of florfenicol required to provide 50% and 90% target attainment rates for three levels of growth inhibition, namely, bacteriostasis, bactericidal action and 4 log10 reduction in bacterial count. PMID- 24341544 TI - Self-compliance-improved resistive switching using Ir/TaOx/W cross-point memory. AB - Resistive switching properties of a self-compliance resistive random access memory device in cross-point architecture with a simple stack structure of Ir/TaOx/W have been investigated. A transmission electron microscope and atomic force microscope were used to observe the film properties and morphology of the stack. The device has shown excellent switching cycle uniformity with a small operation of +/-2.5 V and a resistance ratio of >100. The device requires neither any frorming-process nor current compliance limit for repeatable operation in contrast to conventional resistive random access memory devices. The effect of bottom electrode morphology and surface roughness is also studied. The improvement is due to the enhanced electric field at the nanotips in the bottom electrode and the defective TaOx switching layer which enable controlled filament formation/rupture. The device area dependence of the low resistance state indicates multifilament formation. The device has shown a robust alternating current endurance of >105 cycles and a data retention of >104 s. PMID- 24341545 TI - The effectiveness of health impact assessment in influencing decision-making in Australia and New Zealand 2005-2009. AB - BACKGROUND: Health Impact Assessment (HIA) involves assessing how proposals may alter the determinants of health prior to implementation and recommends changes to enhance positive and mitigate negative impacts. HIAs growing use needs to be supported by a strong evidence base, both to validate the value of its application and to make its application more robust. We have carried out the first systematic empirical study of the influence of HIA on decision-making and implementation of proposals in Australia and New Zealand. This paper focuses on identifying whether and how HIAs changed decision-making and implementation and impacts that participants report following involvement in HIAs. METHODS: We used a two-step process first surveying 55 HIAs followed by 11 in-depth case studies. Data gathering methods included questionnaires with follow-up interview, semi structured interviews and document collation. We carried out deductive and inductive qualitative content analyses of interview transcripts and documents as well as simple descriptive statistics. RESULTS: We found that most HIAs are effective in some way. HIAs are often directly effective in changing, influencing, broadening areas considered and in some cases having immediate impact on decisions. Even when HIAs are reported to have no direct effect on a decision they are often still effective in influencing decision-making processes and the stakeholders involved in them. HIA participants identify changes in relationships, improved understanding of the determinants of health and positive working relationships as major and sustainable impacts of their involvement. CONCLUSIONS: This study clearly demonstrates direct and indirect effectiveness of HIA influencing decision making in Australia and New Zealand. We recommend that public health leaders and policy makers should be confident in promoting the use of HIA and investing in building capacity to undertake high quality HIAs. New findings about the value HIA stakeholders put on indirect impacts such as learning and relationship building suggest HIA has a role both as a technical tool that makes predictions of potential impacts of a policy, program or project and as a mechanism for developing relationships with and influencing other sectors. Accordingly when evaluating the effectiveness of HIAs we need to look beyond the direct impacts on decisions. PMID- 24341546 TI - Ethnicity and health in context. PMID- 24341548 TI - Comparison between preoperative and real-time intraoperative planning 125I permanent prostate brachytherapy: long-term clinical biochemical outcome. AB - BACKGROUND: The purpose of the study is to evaluate the long-term clinical outcome through biochemical no evidence of disease (bNED) rates among men with low to intermediate risk prostate cancer treated with two different brachytherapy implant techniques: preoperative planning (PP) and real-time planning (IoP). METHODS: From June 1998 to July 2011, 1176 men with median age of 67 years and median follow-up of 47 months underwent transperineal ultrasound-guided prostate 125I-brachytherapy using either PP (132) or IoP (1044) for clinical T1c-T2b prostate adenocarcinoma Gleason <8 and prostate-specific antigen (PSA) <20 ng/ml. Men with Gleason 7 received combination of brachytherapy, external beam radiation and 6-month androgen deprivation therapy (ADT). Biological effective dose (BED) was calculated using computerized tomography (CT)-based dosimetry 1-month postimplant. Failure was determined according to the Phoenix definition. RESULTS: The 5- and 7-year actuarial bNED rate was 95% and 90% respectively. The 7-year actuarial bNED was 67% for the PP group and 95% for the IoP group (P < 0.001). Multivariate Cox regression analyses identified implant technique or BED, ADT and PSA as independent prognostic factors for biochemical failure. CONCLUSIONS: Following our previous published results addressing the limited and disappointing outcomes of PP method when compared to IoP based on CT dosimetry and PSA kinetics, we now confirm the long-term clinical, bNED rates clear cut superiority of IoP implant methodology. PMID- 24341550 TI - Synthesis and characterization of a high-symmetry ferrous polypyridyl complex: approaching the 5T2/3T1 crossing point for Fe(II.). AB - Electronic structure theory predicts that, depending on the strength of the ligand field, either the quintet ((5)T2) or triplet ((3)T1) term states can be stabilized as the lowest-energy ligand-field excited state of low-spin octahedral d(6) transition-metal complexes. The (3)T1 state is anticipated for second- and third-row metal complexes and has been established for certain first-row compounds such as [Co(CN)6](3-), but in the case of the widely studied Fe(II) ion, only the (5)T2 state has ever been documented. Herein we report that 2,6 bis(2-carboxypyridyl)pyridine (dcpp), when bound to Fe(II), presents a sufficiently strong ligand field to Fe(II) such that the (5)T2/(3)T1 crossing point of the d(6) configuration is approached if not exceeded. The electrochemical and photophysical properties of [Fe(dcpp)2](2+), in addition to being of fundamental interest, may also have important implications for solar energy conversion strategies that seek to utilize earth-abundant components. PMID- 24341549 TI - Maternal circulating dendritic cell subtypes at delivery and during the 1-year postpartum period. AB - PROBLEM: Dendritic cells (DCs) play an important role in maintaining pregnancy by inducing tolerance toward the fetus. Such an immunologic change in the mother should be restored to normal after delivery, but few studies have reported postpartum maternal immune recovery, in terms of the types circulating DCs. METHOD OF STUDY: The level of each DC subtype and HLA-DR-positive immunoreactivity of the blood from 29 pregnant women with uncomplicated labor was serially analyzed by flowcytometry at delivery and at 1.5, 6, and 12 months after delivery. DC subtypes were characterized as myeloid, lymphoid, and less differentiated (ldDC). Mean fluorescence intensity (MFI) was evaluated for HLA-DR expression for each DC subtype. RESULTS: The total number and the percentage of DCs at delivery were lower than those at 12 months postpartum. The ldDC fractions were significantly higher at delivery and at 1.5 months than at 12 months postpartum. The MFI of HLA-DR expression on ldDCs at delivery was lower than that at 12 months postpartum. The myeloid-to-lymphoid DC ratio did not differ over the 1-year postpartum period. CONCLUSION: The maternal alteration in DCs rapidly normalized within 1.5 months, except for the ldDC fraction, which persisted between 1.5 and 6 months after delivery. PMID- 24341551 TI - Conformational analysis of single perfluoroalkyl chains by single-molecule real time transmission electron microscopic imaging. AB - Whereas a statistical average of molecular ensembles has been the conventional source of information on molecular structures, atomic resolution movies of single organic molecules obtained by single-molecule real-time transmission electron microscopy have recently emerged as a new tool to study the time evolution of the structures of individual molecules. The present work describes a proof-of principle study of the determination of the conformation of each C-C bond in single perfluoroalkyl fullerene molecules encapsulated in a single-walled carbon nanotube (CNT) as well as those attached to the outer surface of a carbon nanohorn (CNH). Analysis of 82 individual molecules in CNTs under a 120 kV electron beam indicated that 6% of the CF2-CF2 bonds and about 20% of the CH2-CH2 bonds in the corresponding hydrocarbon analogue are in the gauche conformation. This comparison qualitatively matches the known conformational data based on time and molecular-average as determined for ensembles. The transmission electron microscopy images also showed that the molecules entered the CNTs predominantly in one orientation. The molecules attached on a CNH surface moved more freely and exhibited more diverse conformation than those in a CNT, suggesting the potential applicability of this method for the determination of the dynamic shape of flexible molecules and of detailed conformations. We observed little sign of any decomposition of the specimen molecules, at least up to 10(7) e.nm(-2) (electrons/nm(2)) at 120 kV acceleration voltage. Decomposition of CNHs under irradiation with a 300 kV electron beam was suppressed by cooling to 77 K, suggesting that the decomposition is a chemical process. Several lines of evidence suggest that the graphitic substrate and the attached molecules are very cold. PMID- 24341552 TI - Rejection is less common in children undergoing liver transplantation for hepatoblastoma. AB - To compare the incidence of acute histologically proven rejection in children who have had a liver transplant for hepatoblastoma with a control group of children transplanted for biliary atresia (EHBA). A retrospective case notes based study was performed. Twenty patients were identified with hepatoblastoma who were transplanted at a single unit between 1991 and 2008. These were matched as closely as possible for age, gender, year of transplant and type of immunosuppression used to the control group transplanted for biliary atresia (n = 60). There was a significant decrease in rate of acute rejection as assessed by the rejection activity index (RAI) in the hepatoblastoma group (75% vs. 50%, respectively, p < 0.04). Chronic rejection was rare in both groups, but twice as common in the biliary atresia group. Equal levels of immunosuppression were achieved in both groups. Renal function was noted to be reduced one yr post transplant in both groups, as previously reported. A modified immunosuppression regimen could be considered in children with hepatoblastoma undergoing liver transplantation. PMID- 24341553 TI - Is the strength of association between indicators of dietary quality and the nutritional status of children being underestimated? PMID- 24341554 TI - Reply to correspondence: is the strength of association between indicators of dietary quality and the nutritional status of children being underestimated? PMID- 24341555 TI - Impact of climate variability on Plasmodium vivax and Plasmodium falciparum malaria in Yunnan Province, China. AB - BACKGROUND: Malaria remains a public health problem in the remote and poor area of Yunnan Province, China. Yunnan faces an increasing risk of imported malaria infections from Mekong river neighboring countries. This study aimed to identify the high risk area of malaria transmission in Yunnan Province, and to estimate the effects of climatic variability on the transmission of Plasmodium vivax and Plasmodium falciparum in the identified area. METHODS: We identified spatial clusters of malaria cases using spatial cluster analysis at a county level in Yunnan Province, 2005-2010, and estimated the weekly effects of climatic factors on P. vivax and P. falciparum based on a dataset of daily malaria cases and climatic variables. A distributed lag nonlinear model was used to estimate the impact of temperature, relative humidity and rainfall up to 10-week lags on both types of malaria parasite after adjusting for seasonal and long-term effects. RESULTS: The primary cluster area was identified along the China-Myanmar border in western Yunnan. A 1 degrees C increase in minimum temperature was associated with a lag 4 to 9 weeks relative risk (RR), with the highest effect at lag 7 weeks for P. vivax (RR = 1.03; 95% CI, 1.01, 1.05) and 6 weeks for P. falciparum (RR = 1.07; 95% CI, 1.04, 1.11); a 10-mm increment in rainfall was associated with RRs of lags 2-4 weeks and 9-10 weeks, with the highest effect at 3 weeks for both P. vivax (RR = 1.03; 95% CI, 1.01, 1.04) and P. falciparum (RR = 1.04; 95% CI, 1.01, 1.06); and the RRs with a 10% rise in relative humidity were significant from lag 3 to 8 weeks with the highest RR of 1.24 (95% CI, 1.10, 1.41) for P. vivax at 5-week lag. CONCLUSIONS: Our findings suggest that the China-Myanmar border is a high risk area for malaria transmission. Climatic factors appeared to be among major determinants of malaria transmission in this area. The estimated lag effects for the association between temperature and malaria are consistent with the life cycles of both mosquito vector and malaria parasite. These findings will be useful for malaria surveillance-response systems in the Mekong river region. PMID- 24341556 TI - Biological and molecular events associated with simultaneous transmission of plant viruses by invertebrate and fungal vectors. AB - Viruses are likely to be the most dangerous parasites of living organisms because of their widespread occurrence, possible deleterious effects on their hosts and high rates of evolution. Virus host-to-host transmission is a critical step in the virus life cycle, because it enables survival in a given environment and efficient dissemination. As hosts of plant viruses are not mobile, these pathogens have adopted diverse transmission strategies involving various vector organisms, mainly arthropods, nematodes, fungi and protists. In nature, plants are often infected with more than one virus at a time, thereby creating potential sources for vectors to acquire and transmit simultaneously two or more viruses. Simultaneous transmission can result in multiple infections of new host plants, which become subsequent potential sources of the viruses, thus enhancing the spread of the diseases caused by these pathogens. Moreover, it can contribute to the maintenance of viral genetic diversity in the host communities. However, despite its possible significance, the problem of the simultaneous transmission of plant viruses by vectors has not been investigated in detail. In this review, the current knowledge on multiple viral transmissions by aphids, whiteflies, leafhoppers, planthoppers, nematodes and fungi is outlined. PMID- 24341558 TI - GPI (glycosylphosphatidylinositol)-linked aspartyl proteases regulate vacuole homoeostasis in Candida glabrata. AB - A family of 11 GPI (glycosylphosphatidylinositol)-linked cell surface-associated aspartyl proteases (yapsins) in the human opportunistic fungal pathogen Candida glabrata is required for cell wall remodelling, pH homoeostasis, survival in macrophages and virulence in a murine model of disseminated candidiasis. In the present paper, we report new roles for yapsins in C. glabrata physiology and implicate them for the first time in the regulation of vacuole homoeostasis. In the present study we show that a C. glabrata mutant lacking all 11 yapsins, Cgyps1-11?, possesses an enlarged vacuole and displays vma- (vacuolar membrane ATPase)-like phenotypes with elevated metal ion susceptibility in an alkaline pH medium and diminished Vma activity. The results of the present study also demonstrate a singular role for CgYps1 (C. glabrata yapsin 1) in the maintenance of ion homoeostasis under normal and calcineurin-inhibited conditions. Elevated polyphosphate levels and diminished cellular CPY (carboxypeptidase Y) activity in the Cgyps1-11? mutant highlight the yapsin requirement for a properly functioning vacuole. Lastly, a gross perturbation of cellular homoeostasis in the Cgyps1-11? mutant, even in the absence of external stressors, characterized by reduced levels of ATP and stress metabolites, elevated ROS (reactive oxygen species) levels, cell surface abnormalities, and a constitutively activated PKC (protein kinase C) signalling pathway underscore diverse physiological functions of yapsins in C. glabrata. PMID- 24341557 TI - SACE_5599, a putative regulatory protein, is involved in morphological differentiation and erythromycin production in Saccharopolyspora erythraea. AB - BACKGROUND: Erythromycin is a medically important antibiotic, biosynthesized by the actinomycete Saccharopolyspora erythraea. Genes encoding erythromycin biosynthesis are organized in a gene cluster, spanning over 60 kbp of DNA. Most often, gene clusters encoding biosynthesis of secondary metabolites contain regulatory genes. In contrast, the erythromycin gene cluster does not contain regulatory genes and regulation of its biosynthesis has therefore remained poorly understood, which has for a long time limited genetic engineering approaches for erythromycin yield improvement. RESULTS: We used a comparative proteomic approach to screen for potential regulatory proteins involved in erythromycin biosynthesis. We have identified a putative regulatory protein SACE_5599 which shows significantly higher levels of expression in an erythromycin high-producing strain, compared to the wild type S. erythraea strain. SACE_5599 is a member of an uncharacterized family of putative regulatory genes, located in several actinomycete biosynthetic gene clusters. Importantly, increased expression of SACE_5599 was observed in the complex fermentation medium and at controlled bioprocess conditions, simulating a high-yield industrial fermentation process in the bioreactor. Inactivation of SACE_5599 in the high-producing strain significantly reduced erythromycin yield, in addition to drastically decreasing sporulation intensity of the SACE_5599-inactivated strains when cultivated on ABSM4 agar medium. In contrast, constitutive overexpression of SACE_5599 in the wild type NRRL23338 strain resulted in an increase of erythromycin yield by 32%. Similar yield increase was also observed when we overexpressed the bldD gene, a previously identified regulator of erythromycin biosynthesis, thereby for the first time revealing its potential for improving erythromycin biosynthesis. CONCLUSIONS: SACE_5599 is the second putative regulatory gene to be identified in S. erythraea which has positive influence on erythromycin yield. Like bldD, SACE_5599 is involved in morphological development of S. erythraea, suggesting a very close relationship between secondary metabolite biosynthesis and morphological differentiation in this organism. While the mode of action of SACE_5599 remains to be elucidated, the manipulation of this gene clearly shows potential for improvement of erythromycin production in S. erythraea in industrial setting. We have also demonstrated the applicability of the comparative proteomics approach for identifying new regulatory elements involved in biosynthesis of secondary metabolites in industrial conditions. PMID- 24341559 TI - Electrophysiological effects of kainic acid on vasopressin-enhanced green fluorescent protein and oxytocin-monomeric red fluorescent protein 1 neurones isolated from the supraoptic nucleus in transgenic rats. AB - The supraoptic nucleus (SON) contains two types of magnocellular neurosecretory cells: arginine vasopressin (AVP)-producing and oxytocin (OXT)-producing cells. We recently generated and characterised two transgenic rat lines: one expressing an AVP-enhanced green fluorescent protein (eGFP) and the other expressing an OXT monomeric red fluorescent protein 1 (mRFP1). These transgenic rats enable the visualisation of AVP or OXT neurones in the SON. In the present study, we compared the electrophysiological responses of AVP-eGFP and OXT-mRFP1 neurones to glutamic acid in SON primary cultures. Glutamate mediates fast synaptic transmission through three classes of ionotrophic receptors: the NMDA, AMPA and kainate receptors. We investigated the contributions of the three classes of ionotrophic receptors in glutamate-induced currents. Three different antagonists were used, each predominantly selective for one of the classes of ionotrophic receptor. Next, we focused on the kainate receptors (KARs). We examined the electrophysiological effects of kainic acid (KA) on AVP-eGFP and OXT-mRFP1 neurones. In current clamp mode, KA induced depolarisation and increased firing rates. These KA-induced responses were inhibited by the non-NMDA ionotrophic receptor antagonist 6-cyano-7-nitroquinoxaline-2,3(1H4H)-dione in both AVP-eGFP and OXT-mRFP1 neurones. In voltage clamp mode, the application of KA evoked inward currents in a dose-dependent manner. The KA-induced currents were significantly larger in OXT-mRFP1 neurones than in AVP-eGFP neurones. This significant difference in KA-induced currents was abolished by the GluK1 containing KAR antagonist UBP302. At high concentrations (250-500 MUm), the specific GluK1-containing KAR agonist (RS)-2-amino-3-(3-hydroxy-5-tert butylisoxazol-4-yl) propanoic acid (ATPA) induced significantly larger currents in OXT-mRFP1 neurones than in AVP-eGFP neurones. Furthermore, the difference between the AVP-eGFP and OXT-mRFP1 neurones in the ATPA currents was approximately equal to the difference in the KA currents. These findings suggest that the GluK1-containing KARs may be more highly expressed in OXT neurones than in AVP neurones. These results may provide new insight into the physiology and synaptic plasticity of SON neurones. PMID- 24341560 TI - Efficient selection of biomineralizing DNA aptamers using deep sequencing and population clustering. AB - DNA-based information systems drive the combinatorial optimization processes of natural evolution, including the evolution of biominerals. Advances in high throughput DNA sequencing expand the power of DNA as a potential information platform for combinatorial engineering, but many applications remain to be developed due in part to the challenge of handling large amounts of sequence data. Here we employ high-throughput sequencing and a recently developed clustering method (AutoSOME) to identify single-stranded DNA sequence families that bind specifically to ZnO semiconductor mineral surfaces. These sequences were enriched from a diverse DNA library after a single round of screening, whereas previous screening approaches typically require 5-15 rounds of enrichment for effective sequence identification. The consensus sequence of the largest cluster was poly d(T)30. This consensus sequence exhibited clear aptamer behavior and was shown to promote the synthesis of crystalline ZnO from aqueous solution at near-neutral pH. This activity is significant, as the crystalline form of this wide-bandgap semiconductor is not typically amenable to solution synthesis in this pH range. High-resolution TEM revealed that this DNA synthesis route yields ZnO nanoparticles with an amorphous-crystalline core-shell structure, suggesting that the mechanism of mineralization involves nanoscale coacervation around the DNA template. We thus demonstrate that our new method, termed Single round Enrichment of Ligands by deep Sequencing (SEL-Seq), can facilitate biomimetic synthesis of technological nanomaterials by accelerating combinatorial selection of biomolecular-mineral interactions. Moreover, by enabling direct characterization of sequence family demographics, we anticipate that SEL-Seq will enhance aptamer discovery in applications employing additional rounds of screening. PMID- 24341562 TI - An association between systolic blood pressure and stroke among patients with impaired consciousness in out-of-hospital emergency settings. AB - BACKGROUND: Stroke is difficult to diagnose when consciousness is disturbed. However few reports have discussed the clinical predictors of stroke in out-of hospital emergency settings. This study aims to evaluate the association between initial systolic blood pressure (SBP) value measured by emergency medical service (EMS) and diagnosis of stroke among impaired consciousness patients. METHODS: We included all patients aged 18 years or older who were treated and transported by EMS, and had impaired consciousness (Japan Coma Scale ? 1) in Osaka City (2.7 million), Japan from January 1, 1998 through December 31, 2007. Data were prospectively collected by EMS personnel using a study-specific case report form. Multiple logistic regressions assessed the relationship between initial SBP and stroke and its subtypes adjusted for possible confounding factors. RESULTS: During these 10 years, a total of 1,840,784 emergency patients who were treated and transported by EMS were documented during the study period in Osaka City. Out of 128,678 with impaired consciousness, 106,706 who had prehospital SBP measurements in the field were eligible for our analyses. The proportion of patients with severe impaired consciousness significantly increased from 14.5% in the <100 mmHg SBP group to 27.6% in the > =200 mmHg SBP group (P for trend <0.001). The occurrence of stroke significantly increased with increasing SBP (adjusted odd ratio [AOR] 1.34, 95% confidence interval [CI] 1.33 to 1.35), and the AOR of the SBP > =200 mmHg group versus the SBP 101-120 mmHg group was 5.26 (95% CI 4.93 to 5.60). The AOR of the SBP > =200 mmHg group versus the SBP 101 120 mmHg group was 9.76 in subarachnoid hemorrhage (SAH), 16.16 in intracranial hemorrhage (ICH), and 1.52 in ischemic stroke (IS), and the AOR of SAH and ICH was greater than that of IS. CONCLUSIONS: Elevated SBP among emergency patients with impaired consciousness in the field was associated with increased diagnosis of stroke. PMID- 24341564 TI - Characteristics of agranulocytosis as an adverse effect of antithyroid drugs in the second or later course of treatment. AB - BACKGROUND: Agranulocytosis is a serious adverse effect of antithyroid drugs (ATDs) and mainly develops within three months after the start of uninterrupted ATD treatment. Agranulocytosis can also develop for the first time after interruption and subsequent resumption of the same ATD treatment. However, little is known with regard to agranulocytosis that develops after resumption of the same ATD treatment. OBJECTIVES: We investigated the characteristics of patients who developed agranulocytosis during their second or later course of ATD treatment. METHODS: A total of 81 patients at our hospital were diagnosed with ATD-induced agranulocytosis. In 14 of the cases (methimazole (MMI), n=10; propylthiouracil (PTU), n=4), the agranulocytosis developed for the first time in the context of the second or later course of treatment with the same ATD; those patients were designated the "resumed group." The 35 patients (MMI, n=28; PTU, n=7) who developed agranulocytosis during their first uninterrupted course of ATD therapy were designated the "first group." RESULTS: The median total duration of ATD treatment before the diagnosis of agranulocytosis was 559 days (range 86-1775 days), and the median interval between the final day of the previous course and the first day of the course in which agranulocytosis was diagnosed was 916.5 days (range 153-8110 days). There were no cases in which agranulocytosis developed when treatment with the same ATD was resumed after discontinuation for less than five months. The difference between the start of ATD treatment in the course in which agranulocytosis was diagnosed and the time interval at which agranulocytosis was diagnosed was similar when comparing the first group and the resumed group (39 (20-98) days in the first group vs. 32.5 (21-95) days in the resumed group; n.s.). There were no significant differences between the groups in terms of granulocyte count at the time agranulocytosis was diagnosed, mortality rate, or the interval between the diagnosis of agranulocytosis and recovery. CONCLUSIONS: When ATD treatment is resumed, patient follow-up is essential in order to monitor for the development of agranulocytosis. PMID- 24341565 TI - Morphine protects SH-SY5Y human neuroblastoma cells against 6-hydroxydopamine induced cell damage: involvement of anti-oxidant, calcium blocking, and anti apoptotic properties. AB - Parkinson's disease is a neurodegenerative disorder characterized by progressive and selective death of dopaminergic neurons. Understanding the neuroprotective effects of chemical reagents has attracted increasing attention. The MU opioid agonist morphine exerts both toxic and protective effects. However, until recently, the neuroprotective role of morphine against 6-hydroxydopamine (6-OHDA) induced cell death has not been studied. Here, we investigated the effects of morphine on 6-OHDA-induced neurotoxicity in human neuroblastoma SH-SY5Y cell line as an in vitro model of Parkinson's disease. Cell damage was induced by 150 MUM 6 OHDA, and the cells' viability was examined by MTT assay. Intracellular calcium, reactive oxygen species (ROS), and mitochondrial membrane potential were determined by the fluorescence spectrophotometry method. Fragmented DNA and biochemical markers of apoptosis were also determined by gel electrophoresis and immunoblotting, respectively. The data showed that 6-OHDA caused a loss of cell viability and mitochondrial membrane potential. In addition, intracellular ROS and calcium levels, activated caspase-3, Bax:Bcl-2 ratio, cytochrome c release, as well as DNA fragmentation were significantly increased in 6-OHDA-treated cells. Incubation of SH-SY5Y cells with morphine (100 MUM) elicited a protective effect and reduced biochemical markers of cell damage and death. These results suggest that morphine has neuroprotective effects against 6-OHDA-induced neurotoxicity, and such effects are accompanied by its anti-oxidant, calcium blocking, and anti-apoptotic properties. PMID- 24341566 TI - Serum S100A12 concentrations are correlated with angiographic coronary lesion complexity in patients with coronary artery disease. AB - The neutrophil activation marker S100A12 is an important pro-inflammatory cytokine and a potential biomarker for a range of inflammatory diseases. This study aims to investigate whether serum S100A12 concentrations are associated with angiographic coronary lesion complexity in patients with coronary artery disease (CAD). We enrolled 240 CAD and 68 healthy controls. Coronary lesion complexity was assessed by coronary angiography (CAG). Serum S100A12 concentrations were detected by enzyme-linked immunosorbent assay (ELISA). We demonstrated that serum S100A12 concentrations were independently associated with the presence of complex lesion in patients with stable angina pectoris (SAP) (Odds ratio 1.02, 95% CI 1.01-1.04; p < 0.01). In addition, among patients with acute coronary syndrome (ACS) who had significantly higher serum S100A12 concentrations than SAP patients (140.8 [interval 109.4-208.6] vs. 120.8 [interval 96.1-145.9] MUg/L, respectively, p < 0.01), those with multi-complex lesions had significantly higher serum S100A12 concentrations than those with no or one complex lesion (156.3 [interval 116.2-247.4] vs. 129.2 [interval 99.8 165.2] MUg/L, respectively, p < 0.01). These findings suggest that S100A12 in serum might be a potential biomarker for providing valuable information regarding coronary plaque vulnerability in patients with CAD. PMID- 24341563 TI - Traumatic brain injury in vivo and in vitro contributes to cerebral vascular dysfunction through impaired gap junction communication between vascular smooth muscle cells. AB - Gap junctions (GJs) contribute to cerebral vasodilation, vasoconstriction, and, perhaps, to vascular compensatory mechanisms, such as autoregulation. To explore the effects of traumatic brain injury (TBI) on vascular GJ communication, we assessed GJ coupling in A7r5 vascular smooth muscle (VSM) cells subjected to rapid stretch injury (RSI) in vitro and VSM in middle cerebral arteries (MCAs) harvested from rats subjected to fluid percussion TBI in vivo. Intercellular communication was evaluated by measuring fluorescence recovery after photobleaching (FRAP). In VSM cells in vitro, FRAP increased significantly (p<0.05 vs. sham RSI) after mild RSI, but decreased significantly (p<0.05 vs. sham RSI) after moderate or severe RSI. FRAP decreased significantly (p<0.05 vs. sham RSI) 30 min and 2 h, but increased significantly (p<0.05 vs. sham RSI) 24 h after RSI. In MCAs harvested from rats 30 min after moderate TBI in vivo, FRAP was reduced significantly (p<0.05), compared to MCAs from rats after sham TBI. In VSM cells in vitro, pretreatment with the peroxynitrite (ONOO(-)) scavenger, 5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron[III], prevented RSI induced reductions in FRAP. In isolated MCAs from rats treated with the ONOO(-) scavenger, penicillamine, GJ coupling was not impaired by fluid percussion TBI. In addition, penicillamine treatment improved vasodilatory responses to reduced intravascular pressure in MCAs harvested from rats subjected to moderate fluid percussion TBI. These results indicate that TBI reduced GJ coupling in VSM cells in vitro and in vivo through mechanisms related to generation of the potent oxidant, ONOO(-). PMID- 24341567 TI - Chiroptical inversion induced by rotation of a carbon-carbon single bond: an experimental and theoretical study. AB - We propose a new strategy to construct chiral molecular switches with highly reversible and sensitive chiroptical responses to variations in the external environment. Its fundamental concept involves a stimuli-triggered exchange of two conformations presenting significantly different chiroptical properties through the rotation of a carbon-carbon single bond, as demonstrated by chiral Schiff bases s-1, s-2, and a salicylamide analogue s-3. Upon addition of base in solution, the circular dichroism (CD) spectra of these molecular switches displayed unique changes featuring an inversion of the Cotton effect's signs, and the original CD profiles can be recoverd by acidification. Various spectroscopic studies as well as the conformational analysis combining with TDDFT computations allowed clear elucidation of the chiroptical inversion mechanism. It is expected that this kind of chiroptical switches is of great interest for molecular recognition, chemosensing, and the construction of molecular-scale devices. Furthermore, the present study indicates that the use of the conformational transition about a single bond may serve as the basis for designing chiroptical inversion systems. PMID- 24341568 TI - Group involvement and self-rated health among the Japanese elderly: an examination of bonding and bridging social capital. AB - BACKGROUND: To date, only a small amount of research on bonding/bridging social capital has separately examined their effects on health though they have been thought to have differential effects on health outcomes. By using a large population-based sample of elderly Japanese people, we sought to investigate the association between bonding and bridging social capital and self-rated health for men and women separately. METHODS: In August 2010, questionnaires were sent to all residents aged >= 65 years in three municipalities in Okayama prefecture (n = 21232), and 13929 questionnaires were returned (response rate: 65.6%). Social capital was measured from survey responses to questions on participation in six different types of groups: a) the elderly club or sports/hobby/culture circle; b) alumni association; c) political campaign club; d) citizen's group or environmental preservation activity; e) community association; and f) religious organization. Participant perception of group homogeneity (gender, age, and previous occupation) was used to divide social capital into bonding or bridging. Odds ratios (ORs) and 95% confidence intervals (CIs) for poor self-rated health were calculated. RESULTS: A total of 11146 subjects (4441 men and 6705 women) were available for the analysis. Among men, bonding and bridging social capital were inversely associated with poor self-rated health (high bonding social capital; OR: 0.55, 95% CI: 0.31-0.99; high bridging social capital; OR: 0.62, 95% CI: 0.48-0.81) after adjusting for age, educational attainment, smoking status, frequency of alcohol consumption, overweight, living arrangements, and type-D personality. The beneficial effect among women was more likely limited to bonding social capital (high bonding social capital; OR: 0.34, 95% CI: 0.12-1.00), and the association between bridging social capital and self-rated health was less clear (high bridging social capital; OR: 0.69, 95% CI: 0.44-1.07). CONCLUSIONS: Bonding/bridging social capital could have differential associations with self rated health among the Japanese elderly depending on the individual's sex. Considering the lack of consensus on how to measure bonding and bridging social capital, however, we need to carefully assess the generalizability of our findings. Further research is warranted to identify health-relevant dimensions of social capital in different cultural or economic settings. PMID- 24341569 TI - Hydrogen evolution reaction measurements of dealloyed porous NiCu. AB - : Porous metals are of interest for their high surface area and potential for enhanced catalytic behavior. Electrodeposited NiCu thin films with a range of compositions were electrochemically dealloyed to selectively remove the Cu component. The film structure, composition, and reactivity of these samples were characterized both before and after the dealloying step using scanning electron microscopy, energy-dispersive spectroscopy, and electrochemical measurements. The catalytic behavior of the dealloyed porous Ni samples towards the hydrogen evolution reaction was measured and compared to that of the as-deposited samples. The dealloyed samples were generally more reactive than their as-deposited counterparts at low overpotentials, making the dealloying procedure a promising area of exploration for improved hydrogen evolution catalysts. PMID- 24341570 TI - Atrial tachyarrhythmias temporally precede fluid accumulation in implantable device patients. AB - BACKGROUND: The complex relationship between heart failure and atrial tachyarrhythmias (AT/atrial fibrillation [AF]) is not well understood. We examined the temporal association between changes in intrathoracic impedance, suggesting thoracic fluid accumulation, and AT/AF occurrence in cardiac resynchronization therapy-defibrillator and implantable cardioverter defibrillator (ICD) patients. METHODS: A retrospective analysis was conducted on stored implantable device data to identify patients with automatic monitoring of daily AT/AF burden and intrathoracic impedance. Daily population trends in AT/AF burden before and after a fluid index threshold crossing (FIC) were determined. RESULTS: A total of 73,018 patients (68 +/- 12 years, 51% ICD, 75% male) were evaluated over 18.6 +/- 11.5 months. Kaplan-Meier analysis indicated a significantly higher probability of FIC events in the first month following the onset of persistent AT/AF when compared to a matched group without persistent AT/AF (hazard ratio [HR] 1.65, 95% confidence interval [CI] [1.58, 1.72], P < 0.001). Conversely, patients were significantly more likely to experience an episode of persistent AF in the first month after the FIC event (HR 1.32, 95% CI [1.08, 1.63], P = 0.008). The probability of a fluid index crossing within 30 days of the onset of persistent AT/AF was significantly lower in a subgroup of patients with adequate rate control (35.8% [34.3-37.4%] vs 42.0% [39.6-44.6%]; HR 1.24 [1.13-1.36]). CONCLUSION: Thoracic fluid accumulation, as indicated by decreasing intrathoracic impedance, was more likely to occur immediately after the onset of persistent AT/AF, especially in the presence of inadequate rate control. Likewise, the onset of persistent AT/AF was more likely following a decrease in intrathoracic impedance. PMID- 24341571 TI - Early protocol biopsies in pediatric renal transplantation: interest for the adaptation of immunosuppression. AB - GPB are often performed in PRT to detect subclinical acute rejection or IF/TA. Reducing immunosuppression side effects without increasing rejection is a major concern in PRT. We report the results of GPB in children transplanted with a steroid-sparing protocol adapted to immunological risk. Children under 18 yr who received a renal transplantation between April 1, 2009 and May 31, 2012 were included. Immunosuppression consisted of an antibody induction therapy, tacrolimus, and MMF for all recipients. CSs were administered to children under five yr old, or receiving a second allograft. Twenty-eight children were included, 50% were CSs free. GPB were performed between three and six months. IF/TA was documented in seven biopsies; four of these seven children were CS free. One child, with CSs, presented a borderline rejection, and another child, steroid free, with significant inflammatory interstitial infiltrate, considered as a subclinical rejection, was treated with CSs pulses. The median eGFR was stable (74, 67.5, and 82 mL/min/1.73 m2 at, respectively, seven days, three months, and one yr). Patient and graft survival were 100%. These results have to be confirmed in a larger cohort, with long-term follow-up. PMID- 24341572 TI - VOC emission of various Serratia species and isolates and genome analysis of Serratia plymuthica 4Rx13. AB - Bacteria emit a wealth of volatile organic compounds. Gas chromatography coupled to mass spectrometry analysis of five Serratia strains revealed ketones, dimethyl di- and trisulfide and 2-phenylethanol commonly released in this genus. The polymethylated bicyclic hydrocarbon sodorifen was uniquely released by the rhizobacterium Serratia plymuthica 4Rx13. Of 10 Serratia strains, only S. plymuthica isolates originating from plants grown on fields near Rostock (Germany) released this new and unusual compound. Since the biosynthetic pathway of sodorifen was unknown, the genome sequence of S. plymuthica 4Rx13 was determined and annotated. Genome comparison of S. plymuthica 4Rx13 with sodorifen non-producing Serratia species highlighted 246 unique candidate open reading frames. PMID- 24341573 TI - Hypodontia prevalence over four decades in a Slovenian population. AB - AIM: This study was performed to determine the prevalence of hypodontia of permanent teeth in the Slovenian population and whether such prevalence is associated with the year of birth. MATERIAL AND METHODS: The prevalence of hypodontia in the Slovenian population, both male and female, and the association between tooth types, the upper or lower arch, the associated dental anomalies, and orthodontic treatment were studied using interviews and oral and panoramic radiographic examinations of 2,546 Slovenians born in years 1966, 1976, 1986, and 1996. The data were processed using Chi-square test. RESULTS: Among the 2,546 subjects studied, 307 teeth were missing in 175 subjects. The overall prevalence of hypodontia, excluding the third molars, was 6.9%; and there was no statistically significant difference with the year of birth. The most commonly missing teeth were the mandibular second premolar (38.8%), followed by the maxillary lateral incisors (32.6%). The majority (86.9%) of patients with hypodontia were missing only one or two teeth. Subjects with hypodontia (54.9%) were more often involved in orthodontic treatment than subjects without hypodontia (20.5%). CONCLUSIONS: The relatively high prevalence of hypodontia and its frequent association with other dental anomalies emphasizes the importance of dental examination in early childhood with radiographic screening for hypodontia as standard public oral health policy. CLINICAL SIGNIFICANCE: The relatively high prevalence of hypodontia in Slovenians and its frequent association with other dental anomalies emphasizes the importance of dental examination with radiographic screening of hypodontia in childhood as part of public oral health policy. PMID- 24341574 TI - Crack-free and scalable transfer of carbon nanotube arrays into flexible and highly thermal conductive composite film. AB - Carbon nanotube (CNT) arrays show great promise in developing anisotropic thermal conductive composites for efficiently dissipating heat from high-power devices along thickness direction. However, CNT arrays are always grown on some substrates and liable to be deformed and broken into pieces during transfer and solution treatment. In the present study, we intentionally synthesized well crystallized and large-diameter (~80 nm) multiwalled CNT (MWCNT) arrays by floating catalyst chemical vapor deposition (FCCVD) method. Such arrays provided high packing density and robust structure from collapse and crack formation during post solution treatment and therefore favored to maintain original thermal and electrical conductive paths. Under optimized condition, the CNT arrays can be transferred into flexible composite films. Furthermore, the composite film also exhibited excellent thermal conductivity at 8.2 W/(m.K) along thickness direction. Such robust, flexible, and highly thermal conductive composite film may enable some prospective applications in advanced thermal management. PMID- 24341575 TI - Executive summary: global health and emergency care-what do we need to know to address the burden of illness and injury? AB - Emergency physicians are uniquely poised to address challenges in health services, health care systems development and management, and emerging global disease burdens (both communicable and noncommunicable). This special issue of Academic Emergency Medicine reports the results of the 2013 consensus conference, which included eight focus areas that are intended to advance emergency care research. Advancing our understanding of cardiac and injury resuscitation, ethics of research, health systems development, and the education of our future leaders in global health will ultimately affect the populations of all nations across the globe. PMID- 24341576 TI - The role of graduate medical education in global health: proceedings from the 2013 Academic Emergency Medicine consensus conference. AB - The past 40 years have seen expanded development of emergency medicine (EM) postgraduate residency training programs worldwide. An important part of this educational experience is the ability of resident trainees to participate in experiences abroad. However, little is known about how these experiences shape trainees and the populations they serve. During the 2013 Academic Emergency Medicine consensus conference, a group of educators met to define and outline current trends in graduate medical education (GME) emergency care research. The authors discuss future research questions bridging the gap of GME and global health. PMID- 24341577 TI - Global health and emergency care: an undergraduate medical education consensus based research agenda. AB - Global emergency medicine (EM) is a rapidly growing field within EM, as evidenced by the increasing number of medical students desiring global health and emergency care experiences. Despite this growing popularity, little is known of the effect of undergraduate medical education in global health on learners and patients in the United States and abroad. During the 2013 Academic Emergency Medicine consensus conference, a group of leading medical school educators convened to generate a research agenda on priority questions to be answered in this arena. This consensus-based research agenda is presented in this article. PMID- 24341578 TI - Global health and emergency care: a postgraduate medical education consensus based research agenda. AB - Global emergency medicine (EM) is a rapidly growing field within EM, as evidenced by the increasing number of trainees and clinicians pursuing additional experiences in global health and emergency care. In particular, many trainees now desire opportunities at the postgraduate level by way of global EM fellowship programs. Despite this growing popularity, little is known of the effects of postgraduate training in global health and emergency care on learners and patients in the United States and abroad. During the 2013 Academic Emergency Medicine consensus conference on global health and emergency care, a group of leading educators at the postgraduate medical education level convened to generate a research agenda of pressing questions to be answered in this area. The consensus-based research agenda is presented in this article. PMID- 24341579 TI - Research priorities for data collection and management within global acute and emergency care systems. AB - Barriers to global emergency care development include a critical lack of data in several areas, including limited documentation of the acute disease burden, lack of agreement on essential components of acute care systems, and a lack of consensus on key analytic elements, such as diagnostic classification schemes and regionally appropriate metrics for impact evaluation. These data gaps obscure the profound health effects of lack of emergency care access in low- and middle income countries (LMICs). As part of the Academic Emergency Medicine consensus conference "Global Health and Emergency Care: A Research Agenda," a breakout group sought to develop a priority research agenda for data collection and management within global emergency care systems. PMID- 24341580 TI - Ethics in acute care research: a global perspective and research agenda. AB - The 2013 Academic Emergency Medicine consensus conference focused on global health and emergency care research. One conference breakout session discussed research ethics and developed a research agenda concerning global acute care research ethics. This article represents the proceedings from that session, particularly focusing on ethical issues related to protecting human subjects while conducting acute care research. Protecting human research subjects from unnecessary risk is an important component of conducting ethical research, regardless of the research site. There are widely accepted ethical principles related to human subjects research; however, the interpretation of these principles requires specific local knowledge and expertise to ensure that research is conducted ethically within the societal and cultural norms. There is an obligation to conduct research ethically while recognizing the roles and responsibilities of all participants. This article discusses the complexities of determining and applying socially and culturally appropriate ethical principles during the conduct of global acute care research. Using case studies, it focuses both on the procedural components of ethical research conducted outside of "Western" culture and on basic ethical principles that are applicable to all human subjects research. This article also proposes specific research topics to stimulate future thought and the study of ethics in these complex circumstances. PMID- 24341581 TI - Emergency care research funding in the global health context: trends, priorities, and future directions. AB - Over the past few decades there has been a steady growth in funding for global health, yet generally little is known about funding for global health research. As part of the 2013 Academic Emergency Medicine consensus conference, a session was convened to discuss emergency care research funding in the global health context. Overall, the authors found a lack of evidence available to determine funding priorities or quantify current funding for acute care research in global health. This article summarizes the initial preparatory research and reports on the results of the consensus conference focused on identifying challenges and strategies to improve funding for global emergency care research. The consensus conference meeting led to the creation of near- and long-term goals to strengthen global emergency care research funding and the development of important research questions. The research questions represent a consensus view of important outstanding questions that will assist emergency care researchers to better understand the current funding landscape and bring evidence to the debate on funding priorities of global health and emergency care. The four key areas of focus for researchers are: 1) quantifying funding for global health and emergency care research, 2) understanding current research funding priorities, 3) identifying barriers to emergency care research funding, and 4) using existing data to quantify the need for emergency services and acute care research. This research agenda will enable emergency health care scientists to use evidence when advocating for more funding for emergency care research. PMID- 24341582 TI - Clinical and translational research in global health and emergency care: a research agenda. AB - As policy-makers increasingly recognize emergency care to be a global health priority, the need for high-quality clinical and translational research in this area continues to grow. As part of the proceedings of the 2013 Academic Emergency Medicine consensus conference, this article discusses the importance of: 1) including clinical and translational research in the initial emergency care development plan, 2) defining the burden of acute disease and the barriers to conducting research in resource-limited settings, 3) assessing the appropriateness and effectiveness of local and global acute care guidelines within the local context, 4) studying the local research infrastructure needs to understand the best methods to build a sustainable research infrastructure, and 5) studying the long-term effects of clinical research programs on health care systems. PMID- 24341583 TI - Emergency care and health systems: consensus-based recommendations and future research priorities. AB - The theme of the 14th annual Academic Emergency Medicine consensus conference was "Global Health and Emergency Care: A Research Agenda." The goal of the conference was to create a robust and measurable research agenda for evaluating emergency health care delivery systems. The concept of health systems includes the organizations, institutions, and resources whose primary purpose is to promote, restore, and/or maintain health. This article further conceptualizes the vertical and horizontal delivery of acute and emergency care in low-resource settings by defining specific terminology for emergency care platforms and discussing how they fit into broader health systems models. This was accomplished through discussion surrounding four principal questions touching upon the interplay between health systems and acute and emergency care. This research agenda is intended to assist countries that are in the early stages of integrating emergency services into their health systems and are looking for guidance to maximize their development and health systems planning efforts. PMID- 24341584 TI - Global health and emergency care: a resuscitation research agenda--part 1. AB - At the 2013 Academic Emergency Medicine global health consensus conference, a breakout session on a resuscitation research agenda was held. Two articles focusing on cardiac arrest and trauma resuscitation are the result of that discussion. This article describes the burden of disease and outcomes, issues in resuscitation research, and global trends in resuscitation research funding priorities. Globally, cardiovascular disease and trauma cause a high burden of disease that receives a disproportionately smaller research investment. International resuscitation research faces unique ethical challenges. It needs reliable baseline statistics regarding quality of care and outcomes; data linkages between providers; reliable and comparable national databases; and an effective, efficient, and sustainable resuscitation research infrastructure to advance the field. Research in resuscitation in low- and middle-income countries is needed to understand the epidemiology, infrastructure and systems context, level of training needed, and potential for cost-effective care to improve outcomes. Research is needed on low-cost models of population-based research, ways to disseminate information to the developing world, and finding the most cost-effective strategies to improve outcomes. PMID- 24341585 TI - Global health and emergency care: a resuscitation research agenda--part 2. AB - At the 2013 Academic Emergency Medicine global health consensus conference, a breakout session to develop a research agenda for resuscitation was held. Two articles are the result of that discussion. This second article addresses data collection, management, and analysis and regionalization of postresuscitation care, resuscitation programs, and research examples around the world and proposes a strategy to strengthen resuscitation research globally. There is a need for reliable global statistics on resuscitation, international standardization of data, and development of an electronic standard for reporting data. Regionalization of postresuscitation care is a priority area for future research. Large resuscitation clinical research networks are feasible and can give valuable data for improvement of service and outcomes. Low-cost models of population-based research, and emphasis on interventional and implementation studies that assess the clinical effects of programs and interventions, are needed to determine the most cost-effective strategies to improve outcomes. The global challenge is how to adapt research findings to a developing world situation to have an effect internationally. PMID- 24341586 TI - Prehospital research in sub-saharan Africa: establishing research tenets. AB - Prehospital care constitutes an important link in the continuum of emergency care and confers a survival benefit to injured and ill persons. As development of acute and emergency care in sub-Saharan Africa expands, there is a strong need to improve the delivery of prehospital care to help relieve the overwhelming regional morbidity and mortality attributable to time-sensitive, life-threatening conditions. Effective research is integral to prehospital care development, as it helps quantify the need for prehospital care and tests effective solutions. Unfortunately, there is limited consensus guiding such research in the low resource nations of sub-Saharan Africa that face unique challenges. This article aims to assimilate the current pertinent literature to demonstrate research success stories and challenges, and ultimately to build on previous efforts to establish prehospital research priorities for sub-Saharan Africa. Region-specific obstacles hindering prehospital research include the lack of epidemiologic data on emergency conditions, the underdevelopment of in-hospital emergency care, confusing prehospital terminology, poorly defined prehospital research priorities, the lack of qualified local prehospital researchers, and a poor understanding of local prehospital care systems. Solutions are offered to overcome each challenge by building on previous recommendations, by proposing new guiding principles, and by identifying areas where further consensus-building is needed. These guiding principles and suggestions are designed to steer discussions and output from future global health meetings targeted at improving prehospital research and development in sub-Saharan Africa. PMID- 24341587 TI - Creating change through collaboration: a twinning partnership to strengthen emergency medicine at Addis Ababa University/Tikur Anbessa Specialized Hospital- a model for international medical education partnerships. AB - BACKGROUND: Morbidity and mortality due to the lack of an organized emergency medical care system are currently high in Ethiopia. Doctors, nurses, and other medical staff often have limited or no formal training on how to handle emergencies. Because of insufficient human and resource capacity needed to assess and treat acutely ill patients, many who are injured may die unnecessarily, at the site of injury, during transport, or at the hospital. OBJECTIVES: This article describes the development of a twinning partnership between Addis Ababa University (AAU), the University of Wisconsin-Madison (UW), and the nonprofit organization People to People (P2P), to strengthen emergency care at Tikur Anbessa Specialized Hospital (TASH) and increase the number of trained emergency medical professionals. METHODS: The partnership applied the six-phase twinning partnership model, with the overall goal of enhancing and strengthening emergency and trauma care by building institutional and human resource capacity. This was achieved by 1) developing local leaders in emergency medicine (EM), 2) creating training modules adapted to the Ethiopian context, 3) launching an emergency training center, and 4) supporting academic program development. The authors evaluated the program's effectiveness based on our achievements toward these goals. RESULTS: Results include: 1) eight Ethiopian faculty completed a condensed EM fellowship in the United States. Now six Ethiopian physicians serve as EM faculty and two as pediatric EM faculty. 2) Nine emergency training modules were adapted to the Ethiopian context. 3) An emergency training center was opened in 2010 and to date has trained over 4,000 Ethiopian medical professionals. 4) Two academic training programs (EM residency and masters nursing programs) were initiated. CONCLUSIONS: With many complex factors affecting the burden of emergency care, innovative and interdisciplinary collaborations are needed in Ethiopia to train medical workers, build local leadership capacity, strengthen infrastructure, and inform policies. The short-term achievements of this twinning model could suggest that long-term, institution-to-institution collaborations that are driven by local stakeholders are an effective strategy to create equitable relationships and build sustainable health systems and may serve as a model for other global health partnerships. PMID- 24341588 TI - Society for Academic Emergency Medicine's Global Emergency Medicine Academy: global health elective code of conduct. PMID- 24341591 TI - Investigation of effects of levobupivacaine injection to rabbit knee joint on histopathologic changes of joint cartilage tissue and changes of serum biochemical parameters. AB - The aim of this study is to evaluate the effects of intra-articular levobupivacaine on rabbit knee articular cartilage and certain biochemical parameters in the blood. A total of 24 New Zealand rabbits were included to study. Blood sampling was carried out in all animals on the first day, then the subjects were randomly allocated either to the control group (Group C, n = 9) or to the levobupivacaine group (Group L, n = 15). Group C underwent each two intra articular injections of saline, 0.25 mL into the right knee and 0.50 mL into the left one. Group L was injected 0.25 mL (1.25 mg) of levobupivacaine into the right knee and 0.50 mL (2.5 mg) into the left one. The groups were divided randomly into three. Tissue and blood samples for histologic and biochemical examination were collected from Groups C1 and L1 on the first, C2 and L2 on the second, and C3 and L3 on the tenth day of the study. Interleukin-1beta (IL-1 beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C reactive protein (CRP) levels were analyzed. No statistically significant differences could be detected when comparing either left or right joints within the same groups and with Group C and L (P > 0.05). Significant elevations of biochemical parameters were found in Group C. It is concluded that levobupivacaine does not lead to significant histologic changes in rabbit articular cartilage. Significant elevations of biochemical parameters being generally found in the C Group, it is thought that such elevations are not linked to levobupivacaine. Intra-articular levobupivacaine may be a safe alternative for use in post-operative analgesia. PMID- 24341592 TI - The reprogramming factor nuclear receptor subfamily 5, group A, member 2 cannot replace octamer-binding transcription factor 4 function in the self-renewal of embryonic stem cells. AB - Although octamer-binding transcription factor 4 (Oct-4) is one of the most intensively studied factors in mammalian development, no cellular genes capable of replacing Oct-4 function in embryonic stem (ES) cells have been found. Recent data show that nuclear receptor subfamily 5, group A, member 2 (Nr5a2) is able to replace Oct-4 function in the reprogramming process; however, it is unclear whether Nr5a2 can replace Oct-4 function in ES cells. In this study, the ability of Nr5a2 to maintain self-renewal and pluripotency in ES cells was investigated. Nr5a2 localized to the nucleus in ES cells, similarly to Oct-4. However, expression of Nr5a2 failed to rescue the stem cell phenotype or to maintain the self-renewal ability of ES cells. Furthermore, as compared with Oct-4-expressing ES cells, Nr5a2-expressing ES cells showed a reduced number of cells in S-phase, did not expand normally, and did not remain in an undifferentiated state. Ectopic expression of Nr5a2 in ES cells was not able to activate transcription of ES cell specific genes, and gene expression profiling demonstrated differences between Nr5a2-expressing and Oct-4-expressing ES cells. In addition, Nr5a2-expressing ES cells were not able to form teratomas in nude mice. Taken together, these results strongly suggest that the gene regulation properties of Nr5a2 and Oct-4 and their abilities to confer self-renewal and pluripotency of ES cells differ. The present study provides strong evidence that Nr5a2 cannot replace Oct-4 function in ES cells. PMID- 24341593 TI - Molecular characterization and functional analyses of ZtWor1, a transcriptional regulator of the fungal wheat pathogen Zymoseptoria tritici. AB - Zymoseptoria tritici causes the major fungal wheat disease septoria tritici blotch, and is increasingly being used as a model for transmission and population genetics, as well as host-pathogen interactions. Here, we study the biological function of ZtWor1, the orthologue of Wor1 in the fungal human pathogen Candida albicans, as a representative of a superfamily of regulatory proteins involved in dimorphic switching. In Z. tritici, this gene is pivotal for pathogenesis, as ZtWor1 mutants were nonpathogenic and complementation restored the wild-type phenotypes. In planta expression analyses showed that ZtWor1 is up-regulated during the initiation of colonization and fructification, and regulates candidate effector genes, including one that was discovered after comparative proteome analysis of the Z. tritici wild-type strain and the ZtWor1 mutant, which was particularly expressed in planta. Cell fusion and anastomosis occur frequently in ZtWor1 mutants, reminiscent of mutants of MgGpb1, the beta-subunit of the heterotrimeric G protein. Comparative expression of ZtWor1 in knock-out strains of MgGpb1 and MgTpk2, the catalytic subunit of protein kinase A, suggests that ZtWor1 is downstream of the cyclic adenosine monophosphate (cAMP) pathway that is crucial for pathogenesis in many fungal plant pathogens. PMID- 24341594 TI - Tick infestation risk for dogs in a peri-urban park. AB - BACKGROUND: Increases in the abundance and distribution of ticks and tick borne disease (TBD) within Europe have been reported extensively over the last 10-20 years. Changes in climate, habitat management, economic patterns and changes in the abundance of hosts, particularly deer, may all have influenced this change to varying extents. Increasing abundances of tick populations in urban and peri urban environments, such as parks, are of particular concern. In these sites, suitable habitat, wildlife hosts, tick populations, people and their pets may be brought into close proximity and hence may provide foci for tick infestation and, ultimately, disease transmission. METHODS: The distribution and abundance of ticks were examined in an intensively used, peri-urban park. First the seasonal and spatial distribution and abundance of ticks in various habitat types were quantified by blanket dragging. Then the pattern of pet dog movement in the park was mapped by attaching GPS recorders to the collars of dogs brought to the park for exercise, allowing their walking routes to be tracked. Information about the dog, its park use and its history of tick attachment were obtained from the dog owners. RESULTS: Ticks were found predominantly in woodland, woodland edge and deer park areas and were least abundant in mown grassland. Tick infestation of dogs was a relatively frequent occurrence with, on average, one case of tick attachment reported per year for a dog walked once per week, but for some dogs walked daily, infestation 4-5 times per week was reported. All dogs appeared to be at equal risk, regardless of walk route or duration and infestation was primarily influenced by the frequency of exposure. CONCLUSIONS: In peri-urban green spaces, tick-biting risk for dogs may be high and here was shown to be related primarily to exposure frequency. While tick-biting is of direct veterinary importance for dogs, dogs also represent useful sentinels for human tick-exposure. PMID- 24341595 TI - Screening glycosynthase libraries with a fluoride chemosensor assay independently of enzyme specificity: identification of a transitional hydrolase to synthase mutant. AB - Glycosynthases have become efficient tools for the enzymatic synthesis of oligosaccharides, glycoconjugates and polysaccharides. Enzyme-directed evolution approaches are applied to improve the performance of current glycosynthases and engineer specificity for non-natural substrates. However, simple and general screening methods are required since most of the reported assays are specific for each particular enzyme. In the present paper, we report a general screening assay that is independent of enzyme specificity, and implemented in an HTS (high throughput screening) format for the screening of cell extracts in directed evolution experiments. Fluoride ion is a general by-product released in all glycosynthase reactions with glycosyl fluoride donors. The new assay is based on the use of a specific chemical sensor (a silyl ether of a fluorogenic methylumbelliferone) to transduce fluoride concentration into a fluorescence signal. As a proof-of-concept, it has been applied to a nucleophile saturation mutant library of Bacillus licheniformis 1,3-1,4-beta-glucanase. Beyond the expected mutations at the glutamic acid (catalytic) nucleophile, other variants have been shown to acquire glycosynthase activity. Surprisingly, an aspartic acid for glutamic acid replacement renders a highly active glycosynthase, but still retains low hydrolase activity. It appears as an intermediate state between glycosyl hydrolase and glycosynthase. PMID- 24341596 TI - Global reaction route mapping of isomerization pathways of exotic C6H molecular species. AB - C6H radical is known to exist in the astrophysical environment in linear form; however, it may originate from nonlinear isomeric forms. Potential energy surface of C6H is explored to search isomers of C6H and transition states connecting them. This work reports first-ever identification of reaction pathways for isomerization of C6H. The reaction route search is performed through global reaction route mapping method, which utilizes an uphill walking technique based on an anharmonic downward distortion following approach to search intermediates and transition states. The computations performed at the CASSCF/aug-cc-pVTZ, CCSD(T)/6-311++G(d,p)//DFT/B3LYP/6-311++G(d,p), and DFT/B3LYP/aug-cc-pVTZ levels of the theory identified 14 isomers (including 8 new isomeric forms of C6H) and 28 transition states. Most of the identified isomers are found to have significant multireference character. The kinetic stability and natural bond orbital analysis of the identified isomers is also investigated. The isomeric forms are further characterized using spectral analysis involving rotational constants, vibrational frequencies, and Raman scattering activities as well as analyzing the effect of isotopic substitution of hydrogen on the spectral features. This study proposes that the linear-C6H can readily isomerize to a six member ring isomer. PMID- 24341597 TI - Impedance spectroscopic analysis of lead iodide perovskite-sensitized solid-state solar cells. AB - Mesoscopic solid-state solar cells based on the inorganic-organic hybrid perovskite CH3NH3PbI3 in conjunction with the amorphous organic semiconductor spiro-MeOTAD as a hole transport material (HTM) are investigated using impedance spectroscopy (IS). A model to interpret the frequency response of these devices is established by expanding and elaborating on the existing models used for the liquid and solid-state dye-sensitized solar cells. Furthermore, the influence of changing the additive concentrations of tert-butylpyridine and LiTFSI in the HTM and varying the HTM overlayer thickness on top of the sub-micrometer thick TiO2 on the extracted IS parameters is investigated. The internal electrical processes of such devices are studied and correlated with the overall device performance. In particular, the features in the IS responses that are attributed to the ionic and electronic transport properties of the perovskite material and manifest as a slow response at low frequency and an additional RC element at intermediate frequency, respectively, are explored. PMID- 24341598 TI - Comparison of effects of isotonic sodium chloride with diltiazem in prevention of contrast-induced nephropathy. AB - INTRODUCTION AND OBJECTIVE: Contrast-induced nephropathy (CIN) significantly increases the morbidity and mortality of patients. The aim of this study is to investigate and compare the protective effects of isotonic sodium chloride with sodium bicarbonate infusion and isotonic sodium chloride infusion with diltiazem, a calcium channel blocker, in preventing CIN. MATERIALS AND METHODS: Our study included patients who were administered 30-60 mL of iodinated contrast agent for percutaneous coronary angiography (PCAG), all with creatinine values between 1.1 and 3.1 mg/dL. Patients were divided into three groups and each group had 20 patients. The first group of patients was administered isotonic sodium chloride; the second group was administered a solution that of 5% dextrose and sodium bicarbonate, while the third group was administered isotonic sodium chloride before and after the contrast injection. The third group received an additional injection of diltiazem the day before and first 2 days after the contrast injection. All of the patients' plasma blood urea nitrogen (BUN) and creatinine levels were measured on the second and seventh day after the administration of intravenous contrast material. RESULTS: The basal creatinine levels were similar for all three groups (p > 0.05). Among a total of 60 patients included in the study, 16 patients developed acute renal failure (ARF) on the second day after contrast material was injected (26.6%). The number of patients who developed ARF on the second day after the injection in the first group was five (25%), in the second group was six (30%) and the third group was five (25%) (p > 0.05). CONCLUSION: There was no significant difference between isotonic sodium chloride, sodium bicarbonate and isotonic sodium chloride with diltiazem application in prevention of CIN. PMID- 24341599 TI - The influence of type-I and type-II triplet multiple quantum well structure on white organic light-emitting diodes. AB - We demonstrate high-efficient white organic light-emitting diodes (WOLEDs) based on triplet multiple quantum well (MQW) structure and focus on the influence on WOLEDs through employing different potential barrier materials to form type-I and type-II MQWs, respectively. It is found that type-I MQW structure WOLEDs based on 1,3,5-tris(N-phenyl-benzimidazol-2-yl)benzene as potential barrier layer (PBL) offers high electroluminescent (EL) performance. That is to say, maximum current efficiency and power efficiency are achieved at about 1,000 cd/m2 with 16.4 cd/A and 8.3 lm/W, which increase by 53.3% and 50.9% over traditional three-layer structure WOLEDs, respectively, and a maximum luminance of 17,700 cd/m2 is earned simultaneously. The achievement of high EL performance would be attributed to uniform distribution and better confinement of carriers within the emitting layer (EML). However, when 4,7-diphenyl-1,10-phenanthroline or 2,9-dimethyl-4,7 diphenyl-1,10-phenanthroline is used as PBL to form type-II MQW structure, poor EL performance is obtained. We attribute that to improper energy level alignment between the interface of EML/PBL, which leads to incomplete confinement and low recombination efficiency of carriers, a more detailed mechanism was argued. PMID- 24341590 TI - A BAC based physical map and genome survey of the rice false smut fungus Villosiclava virens. AB - BACKGROUND: Rice false smut caused by Villosiclava virens is a devastating fungal disease that spreads in major rice-growing regions throughout the world. However, the genomic information for this fungal pathogen is limited and the pathogenic mechanism of this disease is still not clear. To facilitate genetic, molecular and genomic studies of this fungal pathogen, we constructed the first BAC-based physical map and performed the first genome survey for this species. RESULTS: High molecular weight genomic DNA was isolated from young mycelia of the Villosiclava virens strain UV-8b and a high-quality, large-insert and deep coverage Bacterial Artificial Chromosome (BAC) library was constructed with the restriction enzyme HindIII. The BAC library consisted of 5,760 clones, which covers 22.7-fold of the UV-8b genome, with an average insert size of 140 kb and an empty clone rate of lower than 1%. BAC fingerprinting generated successful fingerprints for 2,290 BAC clones. Using the fingerprints, a whole genome-wide BAC physical map was constructed that contained 194 contigs (2,035 clones) spanning 51.2 Mb in physical length. Bidirectional-end sequencing of 4,512 BAC clones generated 6,560 high quality BAC end sequences (BESs), with a total length of 3,030,658 bp, representing 8.54% of the genome sequence. Analysis of the BESs revealed general genome information, including 51.52% GC content, 22.51% repetitive sequences, 376.12/Mb simple sequence repeat (SSR) density and approximately 36.01% coding regions. Sequence comparisons to other available fungal genome sequences through BESs showed high similarities to Metarhizium anisopliae, Trichoderma reesei, Nectria haematococca and Cordyceps militaris, which were generally in agreement with the 18S rRNA gene analysis results. CONCLUSION: This study provides the first BAC-based physical map and genome information for the important rice fungal pathogen Villosiclava virens. The BAC clones, physical map and genome information will serve as fundamental resources to accelerate the genetic, molecular and genomic studies of this pathogen, including positional cloning, comparative genomic analysis and whole genome sequencing. The BAC library and physical map have been opened to researchers as public genomic resources (http://gresource.hzau.edu.cn/resource/resource.html). PMID- 24341600 TI - Clinical significance of small airway obstruction markers in patients with asthma. AB - BACKGROUND: The role of small airway obstruction in the clinical expression of asthma is incompletely understood. OBJECTIVE: We tested the hypotheses that markers of small airway obstruction are associated with (i) increased asthma severity, (ii) impaired asthma control and quality of life and (iii) frequent exacerbations. METHODS: Seventy-four adults with asthma and 18 healthy control subjects underwent impulse oscillometry (IOS), multiple breath inert gas washout (MBW), body plethysmography, single-breath determination of carbon monoxide uptake and spirometry. Patients completed the six-point Asthma Control Questionnaire (ACQ-6) and standardized Asthma Quality of Life Questionnaire [AQLQ(S)]. Asthma severity was classified according to the Global Initiative for Asthma (GINA) treatment steps. RESULTS: The putative small airway obstruction markers Sacin , resistance at 5 Hz minus resistance at 20 Hz (R5-R20) and reactance area (AX) were not independently associated with asthma severity, control, quality of life or exacerbations. In contrast, markers of total (R5) and mean airway resistance of large and small airways (R20) were significantly higher in the severe asthma group compared with the mild-moderate group (0.47 vs. 0.37, P < 0.05 for R5; 0.39 vs. 0.31, P < 0.01 for R20). The strongest independent contributors to ACQ-6 score were R20 and forced expiratory volume in one second (% pred.), and the strongest independent contributors to AQLQ(S) score were R20 and forced vital capacity (% pred.). A history of one or more exacerbations within the previous year was independently associated with R20. CONCLUSIONS AND CLINICAL RELEVANCE: Previously reported markers of small airway obstruction do not appear to be independently associated with asthma disease expression. In contrast, the IOS parameter R20, a marker of mean airway resistance of both large and small airways, appears to have independent clinical significance. These observations require confirmation in prospective longitudinal studies. PMID- 24341601 TI - Mind the gaps: a qualitative study of perceptions of healthcare professionals on challenges and proposed remedies for cervical cancer help-seeking in post conflict northern Uganda. AB - BACKGROUND: There are limited data on perceptions of health professionals on challenges faced by cervical cancer patients seeking healthcare in the developing countries. We explored the views of operational level health professionals on perceived barriers to cervical screening and early help-seeking for symptomatic cervical cancer and the proposed remedies to the challenges. METHODS: Fifteen key informant interviews were held with health professionals including medical directors, gynecologists, medical officers, nurses and midwives in the gynecology and obstetrics departments of two hospitals in northern Uganda during August 2012 to April 2013. We used content analysis techniques to analyze the data. RESULTS: Health professionals' perceived barriers to cervical cancer care included: (i) patients and community related barriers e.g. lack of awareness on cervical cancer and available services, discomfort with exposure of women's genitals and perceived pain during pelvic examinations, and men's lack of emotional support to women (ii) individual healthcare professional's challenges e.g. inadequate knowledge and skills about cervical cancer management; (iii) health facility related barriers e.g. long distances and lack of transport to cervical cancer screening and care centers, few gynecologists and lack of pathologists, delayed histology results, lack of established palliative care services and inadequate pain control; and (iv) health policy challenges e.g. lack of specialized cancer treatment services, and lack of vaccination for human papilloma virus. Other challenges included increased number of cervical cancer patients and late stage of cervical cancer at presentations. CONCLUSIONS: Operational level healthcare professionals in northern Uganda reported several practical challenges facing cervical cancer care that influence their decisions, management goals and practices. The challenges and proposed remedies can inform targeted interventions for early detection, management, and control of cervical cancer in Uganda. PMID- 24341602 TI - Abdominal damage control surgery and reconstruction: world society of emergency surgery position paper. AB - Damage control laparotomy was first described by Dr. Harlan Stone in 1983 when he suggested that patients with severe trauma should have their primary procedures abbreviated when coagulopathy was encountered. He recommended temporizing patients with abdominal packing and temporary closure to allow restoration of normal physiology prior to returning to the operating room for definitive repair. The term damage control in the trauma setting was coined by Rotondo et al., in 1993. Studies in subsequent years have validated this technique by demonstrating decreased mortality and immediate post-operative complications. The indications for damage control laparotomy have evolved to encompass abdominal compartment syndrome, abdominal sepsis, vascular and acute care surgery cases. The perioperative critical care provided to these patients, including sedation, paralysis, nutrition, and fluid management strategies may improve closure rates and recovery. In the rare cases of inability to primarily close the abdomen, there are a number of reconstructive strategies that may be used in the acute and chronic phases of abdominal closure. PMID- 24341604 TI - A SYBR Green 1-based in vitro test of susceptibility of Ghanaian Plasmodium falciparum clinical isolates to a panel of anti-malarial drugs. AB - BACKGROUND: Based on report of declining efficacy of chloroquine, Ghana shifted to the use of artemisinin-based combination therapy (ACT) in 2005 as the first line anti-malarial drug. Since then, there has not been any major evaluation of the efficacy of anti-malarial drugs in Ghana in vitro. The sensitivity of Ghanaian Plasmodium falciparum isolates to anti-malarial drugs was, therefore, assessed and the data compared with that obtained prior to the change in the malaria treatment policy. METHODS: A SYBR Green 1 fluorescent-based in vitro drug sensitivity assay was used to assess the susceptibility of clinical isolates of P. falciparum to a panel of 12 anti-malarial drugs in three distinct eco epidemiological zones in Ghana. The isolates were obtained from children visiting health facilities in sentinel sites located in Hohoe, Navrongo and Cape Coast municipalities. The concentration of anti-malarial drug inhibiting parasite growth by 50% (IC50) for each drug was estimated using the online program, ICEstimator. RESULTS: Pooled results from all the sentinel sites indicated geometric mean IC50 values of 1.60, 3.80, 4.00, 4.56, 5.20, 6.11, 10.12, 28.32, 31.56, 93.60, 107.20, and 8952.50 nM for atovaquone, artesunate, dihydroartemisin, artemether, lumefantrine, amodiaquine, mefloquine, piperaquine, chloroquine, tafenoquine, quinine, and doxycycline, respectively. With reference to the literature threshold value indicative of resistance, the parasites showed resistance to all the test drugs except the artemisinin derivatives, atovaquone and to a lesser extent, lumefantrine. There was nearly a two-fold decrease in the IC50 value determined for chloroquine in this study compared to that determined in 2004 (57.56 nM). This observation is important, since it suggests a significant improvement in the efficacy of chloroquine, probably as a direct consequence of reduced drug pressure after cessation of its use. Compared to that measured prior to the change in treatment policy, significant elevation of artesunate IC50 value was observed. The results also suggest the existence of possible cross-resistance among some of the test drugs. CONCLUSION: Ghanaian P. falciparum isolates, to some extent, have become susceptible to chloroquine in vitro, however the increasing trend in artesunate IC50 value observed should be of concern. Continuous monitoring of ACT in Ghana is recommended. PMID- 24341606 TI - Rapid molecular diagnosis of genetic diseases by high resolution melting analysis: fabry and glycogen storage 1A diseases. AB - For inborn errors of metabolism, high resolution melting analysis (HRMA) is a rapid, efficient, simple, and inexpensive method for mutation/rare variant screening. HRMA is a recent molecular technique for genotyping single-nucleotide polymorphisms without using probes. Here we apply HRMA to the alpha-galactosidase a (GLA) and glucose-6-phosphatase-alpha (G6PC) genes for mutation detection of patients with Fabry disease (MIM 301500) and glycogen storage disease type 1A (GSD1A; MIM 232200), respectively. To evaluate the procedure, genomic DNAs were blindly tested for known GLA mutations (c.658C>T, c. 679C>T, c.772G>A, c.796G>A, or c.718-719delAA) in three affected males and two obligate heterozygotes with Fabry disease, a G6PC mutation (c.247C>T) in a patient homozygous for that lesion, and 10 healthy control Turkish individuals. HRMA clearly detected the mutant amplicons and discriminated them from all wild-type GLA or G6PC amplicons. HRMA proved to be a sensitive, specific, and cost-effective mutation screening method for the rapid molecular diagnosis of these inborn errors of metabolism, indicating that the technique can be readily adapted to other genetic diseases. PMID- 24341605 TI - What is actually measured in process evaluations for worksite health promotion programs: a systematic review. AB - BACKGROUND: Numerous worksite health promotion program (WHPPs) have been implemented the past years to improve employees' health and lifestyle (i.e., physical activity, nutrition, smoking, alcohol use and relaxation). Research primarily focused on the effectiveness of these WHPPs. Whereas process evaluations provide essential information necessary to improve large scale implementation across other settings. Therefore, this review aims to: (1) further our understanding of the quality of process evaluations alongside effect evaluations for WHPPs, (2) identify barriers/facilitators affecting implementation, and (3) explore the relationship between effectiveness and the implementation process. METHODS: Pubmed, EMBASE, PsycINFO, and Cochrane (controlled trials) were searched from 2000 to July 2012 for peer-reviewed (randomized) controlled trials published in English reporting on both the effectiveness and the implementation process of a WHPP focusing on physical activity, smoking cessation, alcohol use, healthy diet and/or relaxation at work, targeting employees aged 18-65 years. RESULTS: Of the 307 effect evaluations identified, twenty-two (7.2%) published an additional process evaluation and were included in this review. The results showed that eight of those studies based their process evaluation on a theoretical framework. The methodological quality of nine process evaluations was good. The most frequently reported process components were dose delivered and dose received. Over 50 different implementation barriers/facilitators were identified. The most frequently reported facilitator was strong management support. Lack of resources was the most frequently reported barrier. Seven studies examined the link between implementation and effectiveness. In general a positive association was found between fidelity, dose and the primary outcome of the program. CONCLUSIONS: Process evaluations are not systematically performed alongside effectiveness studies for WHPPs. The quality of the process evaluations is mostly poor to average, resulting in a lack of systematically measured barriers/facilitators. The narrow focus on implementation makes it difficult to explore the relationship between effectiveness and implementation. Furthermore, the operationalisation of process components varied between studies, indicating a need for consensus about defining and operationalising process components. PMID- 24341607 TI - Evidence for the therapeutic efficacy of either mild hypothermia or oxygen radical scavengers after repetitive mild traumatic brain injury. AB - Repetitive brain injury, particularly that occurring with sporting-related injuries, has recently garnered increased attention in both the clinical and public settings. In the laboratory, we have demonstrated the adverse axonal and vascular consequences of repetitive brain injury and have demonstrated that moderate hypothermia and/or FK506 exerted protective effects after repetitive mild traumatic brain injury (mTBI) when administered within a specific time frame, suggesting a range of therapeutic modalities to prevent a dramatic exacerbation. In this communication, we revisit the utility of targeted therapeutic intervention to seek the minimal level of hypothermia needed to achieve protection while probing the role of oxygen radicals and their therapeutic targeting. Male Sprague-Dawley rats were subjected to repetitive mTBI by impact acceleration injury. Mild hypothermia (35 degrees C, group 2), superoxide dismutase (group 3), and Tempol (group 4) were employed as therapeutic interventions administered 1 h after the repetitive mTBI. To assess vascular function, cerebral vascular reactivity to acetylcholine was evaluated 3 and 4 h after the repetitive mTBI, whereas to detect the burden of axonal damage, amyloid precursor protein (APP) density in the medullospinal junction was measured. Whereas complete impairment of vascular reactivity was observed in group 1 (without intervention), significant preservation of vascular reactivity was found in the other groups. Similarly, whereas remarkable increase in the APP-positive axon was observed in group 1, there were no significant increases in the other groups. Collectively, these findings indicate that even mild hypothermia or the blunting free radical damage, even when performed in a delayed period, is protective in repetitive mTBI. PMID- 24341608 TI - Current status of skeletal anchorage dental applications in orthodontics, part I. PMID- 24341609 TI - Genomic amplification and high expression of EGFR are key targetable oncogenic events in malignant peripheral nerve sheath tumor. AB - BACKGROUND: The dismal outcome of malignant peripheral nerve sheath tumor (MPNST) highlights the necessity of finding new therapeutic methods to benefit patients with this aggressive sarcoma. Our purpose was to investigate epidermal growth factor receptor (EGFR) as a potential therapeutic target in MPNSTs. PATIENTS AND METHODS: We performed a microarray based-comparative genomic hybridization (aCGH) profiling of two cohorts of primary MPNST tissue samples including 25 patients treated at The University of Texas MD Anderson Cancer Center (MD Anderson) and 26 patients from Tianjin Medical University Cancer Institute & Hospital (TMUCIH). Fluorescence in situ hybridization (FISH) method was used to validate the gene amplification detected by aCGH analysis. Another independent cohort of 56 formalin fixed paraffin embedded (FFPE) MPNST samples was obtained to explore EGFR protein expression by immunohistochemical analysis. Cell biology detection and validation were performed on human MPNST cell lines ST88-14 and STS26T. RESULTS: aCGH and pathway analysis of the 51 MPNSTs identified significant gene amplification events in EGFR pathway, including frequent amplifications of EGFR gene itself, which was subsequently validated by FISH assay. High expression of EGFR protein was associated with poor disease-free and overall survival of human MPNST patients. In human MPNST cell lines ST88-14 and STS26T, inhibition of EGFR by siRNA or Gefitinib led to decreased cell proliferation, migration, and invasion accompanied by attenuation of PI3K/AKT and MAPK pathways. CONCLUSION: These results suggest that EGFR is a potential therapeutic target for MPNST. PMID- 24341610 TI - The effect of triple glutamic mutations E9Q/E194Q/E204Q on the structural stability of bacteriorhodopsin. AB - In the present study, we report on the structural features of the bacteriorhodopsin triple mutant E9Q/E194Q/E204Q (3Glu) of bacteriorhodopsin by combining experimental and molecular dynamics (MD) approaches. In 3Glu mutant, Glu9, Glu194 and Glu204 residues located at the extracellular side of the protein were mutated altogether to glutamines. UV-visible and differential scanning calorimetry experiments served as diagnostic tools for monitoring the resistance against thermal stress of the active site and the tertiary structures of the 3Glu. The analyses of the UV-visible thermal difference spectra demonstrate that the spectral forms at room temperature and the thermal unfolding path differ in the wild-type bacteriorhodopsin and the 3Glu. Even with these spectral differences, the thermal unfolding of the active site occurs at rather similar melting temperatures in both proteins. A noteworthy consequence of the mutations is the altered two-dimensional packing revealed by the lack of the pre-transition peak in differential scanning calorimetry traces of 3Glu mutant, as previously detected in wild-type and the corresponding single mutants. The infrared spectroscopy data agree with the loss of paracrystalinity, illustrating a substantial conversion of alphaII to alphaI helical conformation in the 3Glu mutant. Molecular dynamics simulations show higher dynamics flexibility of most of the extracellular regions of 3Glu, which may account for the somewhat lower tertiary structural stability of the mutated protein. Finally, hydrogen bond analysis reveals that the mutated Glu194 and Glu204 residues create ~ 50% less hydrogen bonds with water molecules compared to wild-type bacteriorhodopsin. These results exemplify the role of the water hydrogen-bonding network for structural integrity and conformational flexibility of bacteriorhodopsin. PMID- 24341612 TI - Premature ovarian insufficiency: how to improve reproductive outcome? AB - Premature ovarian insufficiency (POI) is a life-changing condition that affects women in their reproductive age. The condition is not necessarily permanent but is associated with intermittent and unpredictable ovarian activity. Hence, spontaneous pregnancies have been reported to be 5-10%. However, pregnancy in patients with POI is still unlikely and rare. Although, there are reviews on POI in the literature, there is a lack of reports which focus on how to improve the reproductive outcome of these women who wish to conceive spontaneously or use assisted conception with their own oocytes. We found that there is no conclusive evidence of which treatment is optimal for women with POI who wish to conceive using their own gametes. However, one could surmise that it is important to lower gonadotropin levels into the physiological range before embarking on any treatment, even if natural conception is the only choice for the woman/couple. In the future, multi-center, randomized, double-blind, placebo-controlled trials should be carried out, which may entail recruitment of patients from various centers nationally and internationally to increase the sample size and therefore achieve a powered study. This may standardize the treatment of women with POI who wish to conceive and ultimately have their biological child. PMID- 24341613 TI - Fabrication of gold nanoparticles by laser ablation in liquid and their application for simultaneous electrochemical detection of Cd2+, Pb2+, Cu2+, Hg2+. AB - In this paper, we demonstrated the fabrication of high active and high sensitive Au nanoparticles by laser ablation in liquid (LAL) method, and their application in electrochemical detection of heavy metal ions. First, LAL method are used to fabricate Au nanoparticles in water in a clean way. Second, the Au nanoparticles were assembled onto the surface of the glassy carbon (GC) electrode by an electrophoretic deposition method to form an AuNPs/GC electrode for electrochemical characterization and detection. Through differential pulse anodic stripping voltammetry method, it shows that the AuNPs/GC electrode could be used for the simultaneous and selective electrochemical detection of Cd(2+), Pb(2+), Cu(2+), and Hg(2+). By studying the influence of test conditions to optimize the electrochemical detection, we can detect Cd(2+), Pb(2+), Cu(2+), and Hg(2+) simultaneously with a low concentration of 3 * 10(-7) M in the experiments. PMID- 24341611 TI - Nanomedicines for inflammatory arthritis: head-to-head comparison of glucocorticoid-containing polymers, micelles, and liposomes. AB - As an emerging research direction, nanomedicine has been increasingly utilized to treat inflammatory diseases. In this head-to-head comparison study, four established nanomedicine formulations of dexamethasone, including liposomes (L Dex), core-cross-linked micelles (M-Dex), slow releasing polymeric prodrugs (P Dex-slow), and fast releasing polymeric prodrugs (P-Dex-fast), were evaluated in an adjuvant-induced arthritis rat model with an equivalent dose treatment design. It was found that after a single i.v. injection, the formulations with the slower drug release kinetics (i.e., M-Dex and P-Dex-slow) maintained longer duration of therapeutic activity than those with relatively faster drug release kinetics, resulting in better joint protection. This finding will be instructional in the future development and optimization of nanomedicines for the clinical management of rheumatoid arthritis. The outcome of this study also illustrates the value of such head-to-head comparison studies in translational nanomedicine research. PMID- 24341614 TI - Influence of defective complete dentures renewal on TMD; an MRI and clinical controlled prospective study. AB - BACKGROUND: The influence of complete denture occlusion on temporomandibular disorder (TMD) is controversial. Some studies found that defective occlusion contributes to the development of TMD, while others found no correlation. OBJECTIVE: This prospective controlled study evaluated the relationship between renewal of old defective complete dentures and TMD as evidenced both by clinical examination and magnetic resonance imaging (MRI) findings. MATERIALS AND METHODS: The study included 25 complete denture patients with signs and symptoms of TMD and 21 asymptomatic controls. Clicking was a common finding in all symptomatic joints. All selected participants needed complete denture renewal. MRI and clinical assessment following research diagnostic criteria for TMD guidelines (RDC/TMD) were carried out at baseline and 2 years after new complete denture insertion. Temporomandibular joint (TMJ) pain, muscle pain, clicking and movement limitation were the assessed signs and symptoms. MRIs were conducted to evaluate the TMJs for disc displacement, disc morphology and joint effusion. RESULTS: Complete denture renewal significantly improved the signs and symptoms of TMD in symptomatic group (p < 0.01). Only in the symptomatic group, treatment resulted in a significant increase in joints displaying superior (normal) disc position (symptomatic p < 0.001; asymptomatic p = 0.157). New dentures did not affect disc morphology in both groups (p = 0.5 for both groups) but significantly reduced joint effusion in the symptomatic group (symptomatic p < 0.001; asymptomatic p = 0.5). Relationship between clinical and MRI findings was not one to one. CONCLUSIONS: New complete dentures had a positive impact on TMD signs and symptoms, disc position and joint effusion but not on disc morphology. PMID- 24341615 TI - Transcriptome analysis of Pinus monticola primary needles by RNA-seq provides novel insight into host resistance to Cronartium ribicola. AB - BACKGROUND: Five-needle pines are important forest species that have been devastated by white pine blister rust (WPBR, caused by Cronartium ribicola) across North America. Currently little transcriptomic and genomic data are available to understand molecular interactions in the WPBR pathosystem. RESULTS: We report here RNA-seq analysis results using Illumina deep sequencing of primary needles of western white pine (Pinus monticola) infected with WPBR. De novo gene assembly was used to generate the first P. monticola consensus transcriptome, which contained 39,439 unique transcripts with an average length of 1,303 bp and a total length of 51.4 Mb. About 23,000 P. monticola unigenes produced orthologous hits in the Pinus gene index (PGI) database (BLASTn with E values < e 100) and 6,300 genes were expressed actively (at RPKM >= 10) in the healthy tissues. Comparison of transcriptomes from WPBR-susceptible and -resistant genotypes revealed a total of 979 differentially expressed genes (DEGs) with a significant fold change > 1.5 during P. monticola- C. ribicola interactions. Three hundred and ten DEGs were regulated similarly in both susceptible and resistant seedlings and 275 DEGs showed regulatory differences between susceptible and resistant seedlings post infection by C. ribicola. The DEGs up regulated in resistant seedlings included a set of putative signal receptor genes encoding disease resistance protein homologs, calcineurin B-like (CBL) interacting protein kinases (CIPK), F-box family proteins (FBP), and abscisic acid (ABA) receptor; transcriptional factor (TF) genes of multiple families; genes homologous to apoptosis-inducing factor (AIF), flowering locus T-like protein (FT), and subtilisin-like protease. DEGs up-regulated in resistant seedlings also included a wide diversity of down-stream genes (encoding enzymes involved in different metabolic pathways, pathogenesis-related -PR proteins of multiple families, and anti-microbial proteins). A large proportion of the down regulated DEGs were related to photosystems, the metabolic pathways of carbon fixation and flavonoid biosynthesis. CONCLUSIONS: The novel P. monticola transcriptome data provide a basis for future studies of genetic resistance in a non-model, coniferous species. Our global gene expression profiling presents a comprehensive view of transcriptomic regulation in the WPBR pathosystem and yields novel insights on molecular and biochemical mechanisms of disease resistance in conifers. PMID- 24341617 TI - Busulfan and melphalan as consolidation therapy with autologous peripheral blood stem cell transplantation following Children's Oncology Group (COG) induction platform for high-risk neuroblastoma: early results from a single institution. AB - Bu-Mel as preparative therapy prior to autologous stem cell rescue was recently shown to be superior to the conventional CEM regimen for HR NBL in Europe. There are no data available on the feasibility and toxicity of Bu-Mel as consolidation therapy following the COG-type induction regimens used in North America. We report early complications and outcomes of patients with HR NBL who received Bu Mel for consolidation following COG-based induction. Retrospective analysis of all patients who had received Bu-Mel as preparative regimen prior to stem cell rescue for HR NBL was carried out. Toxicity, outcomes, and any delays to receiving radiation or anti-GD2 antibody therapy were analyzed. Six patients undergoing PBSCT had received Bu-Mel. The treatment was well tolerated. Mucositis was the main toxicity; three patients had developed neutropenia fever and none developed pulmonary toxicity. One patient had developed moderate SOS that responded to conservative management. All patients were able to receive and tolerate post-transplant local radiotherapy and ch.14.18 anti-GD2 antibody therapy without any delays. All patients are alive with no disease recurrence. The Bu-Mel regimen is well tolerated and is feasible post-COG-type induction platform. PMID- 24341616 TI - Primary care and youth mental health in Ireland: qualitative study in deprived urban areas. AB - BACKGROUND: Mental disorders account for six of the 20 leading causes of disability worldwide with a very high prevalence of psychiatric morbidity in youth aged 15-24 years. However, healthcare professionals are faced with many challenges in the identification and treatment of mental and substance use disorders in young people (e.g. young people's unwillingness to seek help from healthcare professionals, lack of training, limited resources etc.) The challenge of youth mental health for primary care is especially evident in urban deprived areas, where rates of and risk factors for mental health problems are especially common. There is an emerging consensus that primary care is well placed to address mental and substance use disorders in young people especially in deprived urban areas. This study aims to describe healthcare professionals' experience and attitudes towards screening and early intervention for mental and substance use disorders among young people (16-25 years) in primary care in deprived urban settings in Ireland. METHODS: The chosen method for this qualitative study was inductive thematic analysis which involved semi-structured interviews with 37 healthcare professionals from primary care, secondary care and community agencies at two deprived urban centres. RESULTS: We identified three themes in respect of interventions to increase screening and treatment: (1) Identification is optimised by a range of strategies, including raising awareness, training, more systematic and formalised assessment, and youth-friendly practices (e.g. communication skills, ensuring confidentiality); (2) Treatment is enhanced by closer inter-agency collaboration and training for all healthcare professionals working in primary care; (3) Ongoing engagement is enhanced by motivational work with young people, setting achievable treatment goals, supporting transition between child and adult mental health services and recognising primary care's longitudinal nature as a key asset in promoting treatment engagement. CONCLUSIONS: Especially in deprived areas, primary care is central to early intervention for youth mental health. Identification, treatment and continuing engagement are likely to be enhanced by a range of strategies with young people, healthcare professionals and systems. Further research on youth mental health and primary care, including qualitative accounts of young people's experience and developing complex interventions that promote early intervention are priorities. PMID- 24341618 TI - A daily process examination of the temporal association between alcohol use and verbal and physical aggression in community couples. AB - Alcohol use has been associated with intimate partner aggression perpetration and victimization; however, much of the evidence is based on survey research. Few studies have addressed the proximal effects of drinking episodes on the subsequent occurrence of partner aggression. The current study used daily diary methodology to consider the daily and temporal association between drinking episodes and episodes of partner verbal and physical aggression among a community sample of married and cohabiting couples (N = 118). Male and female partners each provided 56 days of independent daily reports of drinking and partner conflict episodes, including verbal and physical aggression, using interactive voice response technology. Dyadic data analyses, guided by the actor-partner interdependence model, were conducted using hierarchical generalized linear modeling with multivariate outcomes. Daily analyses revealed that alcohol consumption was associated with perpetration of verbal and physical aggression the same day, but not with victimization. Temporal analyses revealed that the likelihood of perpetrating verbal and physical aggression, and the likelihood of being verbally and physically victimized, increased significantly when alcohol was consumed in the previous four hours. Findings did not differ according to gender of perpetrator or victim, and the interaction between perpetrator and victim's alcohol use was not significant in any analysis. The study provides clear evidence that, within a sample of community couples without substance-use disorders or other psychopathology, alcohol consumption by men and women contributes to the occurrence of partner aggression episodes. PMID- 24341619 TI - Statins stabilize the renal function of IgA nephropathy. AB - BACKGROUND: The renoprotective pleiotropic effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has recently been reported by several investigators. However, the effect of statins on IgA nephropathy (IgAN) is still unknown. METHODS: We selected 24 IgAN patients who had newly started statin therapy and were not treated with steroids and immunosuppressive agents during the observation period. We analyzed and compared clinical findings 1 year before and after treatment. RESULTS: Mean age was 50.5 +/- 9.91 years and mean blood pressure was 90.9 +/- 10.8 mmHg. Renal function was slightly deteriorated, serum creatinine was 1.03 (0.71-1.24) mg/dL and estimated glomerular filtration rate (eGFR) was 55.8 +/- 22.8 mL/min. Lipid metabolism was poorly controlled [total cholesterol 247.7 +/- 35.7 mg/dL, low-density lipoprotein cholesterol 151.5 (140.8-172.8) mg/dL, and triglyceride 163.0 (126.3-243.8) mg/dL]. Mild urinary abnormality was observed [proteinuria: 0.50 (0.22-1.29) g/g creatinine, urinary red blood cells 1.0 (0.2-5.0) per high power field]. After 1 year of statin treatment, lipid control was significantly better than at baseline. Proteinuria was not significantly decreased but renal function was improved. eGFR changed from a -5.9% decrease to a 2.4% increase (p = 0.0098). CONCLUSION: Our results indicated that statins stabilized the renal function of IgAN patients independent of their reduction of proteinuria. PMID- 24341621 TI - Porous silicon-cell penetrating peptide hybrid nanocarrier for intracellular delivery of oligonucleotides. AB - The largest obstacle to the use of oligonucleotides as therapeutic agents is the delivery of these large and negatively charged biomolecules through cell membranes into intracellular space. Mesoporous silicon (PSi) is widely recognized as a potential material for drug delivery purposes due to its several beneficial features like large surface area and pore volume, high loading capacity, biocompatibility, and biodegradability. In the present study, PSi nanoparticles stabilized by thermal oxidation or thermal carbonization and subsequently modified by grafting aminosilanes on the surface are utilized as an oligonucleotide carrier. Splice correcting oligonucleotides (SCOs), a model oligonucleotide drug, were loaded into the positively charged PSi nanoparticles with a loading degree as high as 14.3% (w/w). Rapid loading was achieved by electrostatic interactions, with the loading efficiencies reaching 100% within 5 min. The nanoparticles were shown to deliver and release SCOs, in its biologically active form, inside cells when formulated together with cell penetrating peptides (CPP). The biological effect was monitored with splice correction assay and confocal microscopy utilizing HeLa pLuc 705 cells. Furthermore, the use of PSi carrier platform in oligonucleotide delivery did not reduce the cell viability. Additionally, the SCO-CPP complexes formed in the pores of the carrier were stabilized against proteolytic digestion. The advantageous properties of protecting and releasing the cargo and the possibility to further functionalize the carrier surface make the hybrid nanoparticles a potential system for oligonucleotide delivery. PMID- 24341622 TI - Blood flow in hemodialysis catheters: a numerical simulation and microscopic analysis of in vivo-formed fibrin. AB - Although catheters with side holes allow high flow rate during hemodialysis, they also induce flow disturbances and create a critical hemodynamic environment that can favor fibrin deposition and thrombus formation. This study compared the blood flow and analyzed the influence of shear stress and shear rate in fibrin deposition and thrombus formation in nontunneled hemodialysis catheters with unobstructed side holes (unobstructed device) or with some side holes obstructed by blood thrombi (obstructed device). Computational fluid dynamics (CFD) was performed to simulate realistic blood flow under laminar and turbulent conditions. The results from the numerical simulations were compared with the fibrin distribution and thrombus architecture data obtained from scanning electron microscopy (SEM) and two photons laser scanning microscopy (TPLSM) on human thrombus formed in catheters removed from patients. CFD showed that regions of flow eddies and separation were mainly found in the venous holes region. TPLSM characterization of thrombi and fibrin structure in patient samples showed fibrin formations in accordance with simulated flux dynamics. Under laminar flow conditions, the wall shear stress close to border holes increased from 87.3+/-0.2 Pa in the unobstructed device to 176.2+/-0.5 Pa in the obstructed one. Under turbulent flow conditions, the shear stress increased by 47% when comparing the obstructed to the unobstructed catheter. The shear rates were generally higher than 5000/s and therefore sufficient to induce fibrin deposition. This findings were supported by SEM data documenting a preferential fibrin arrangement on side hole walls. PMID- 24341620 TI - An exploratory spatial analysis to assess the relationship between deprivation, noise and infant mortality: an ecological study. AB - BACKGROUND: Few studies have explored how noise might contribute to social health inequalities, and even fewer have considered infant mortality or its risk factors as the health event of interest.In this paper, we investigate the impact of neighbourhood characteristics - both socio-economic status and ambient noise levels - on the spatial distribution of infant mortality in the Lyon metropolitan area, in France. METHODS: All infant deaths (n = 715) occurring between 2000 and 2009 were geocoded at census block level. Each census block was assigned multi component socio-economic characteristics and Lden levels, which measure exposure to noise. Using a spatial-scan statistic, we examined whether there were significant clusters of high risk of infant mortality according to neighbourhood characteristics. RESULTS: Our results highlight the fact that infant mortality is non-randomly distributed spatially, with clusters of high risk in the south-east of the Lyon metropolitan area (RR = 1.44; p = 0.09). After adjustments for socio economic characteristics and noise levels, this cluster disappears or shifts according to in line with different scenarios, suggesting that noise and socio economic characteristics can partially explain the spatial distribution of infant mortality. CONCLUSION: Our findings show that noise does have an impact on the spatial distribution of mortality after adjustments for socio-economic characteristics. A link between noise and infant mortality seems plausible in view of the three hypothetical, non-exclusive, pathways we propose in our conceptual framework: (i) a psychological pathway, (ii) a physiological disruption process and (iii) an unhealthy behaviours pathway. The lack of studies makes it is difficult to compare our findings with others. They require further research for confirmation and interpretation. PMID- 24341624 TI - Analysis and therapeutic schedule of the postoperative recurrence of bone tuberculosis. AB - OBJECTIVE: The present study aims to analyze the main reasons that lead to the failure of bone tuberculosis (TB) surgery and the efficacy of reoperation. METHODS: A total of 3,000 cases of bone TB patients were examined retrospectively. Of these, 180 cases had recurrence, including 135 cases of spinal TB and 45 cases of limb TB. Preoperative indicators of duration of anti-TB chemotherapy, nutritional conditions, temperature conditions and erythrocyte sedimentation rate, and medication time of postoperative and recurrence were statistically analyzed. RESULTS: Of all 180 cases with reoperation, 176 cases were cured, and four paralyzed patients were symptomatically improved. The causes of postoperative recurrence of bone TB were relatively complex. Efficacy of reoperation was evaluated. Shorter chemotherapy duration, long-term illness, poor health, a higher body temperature, and an accelerated ESR are likely to increase the risk of recurrence. CONCLUSIONS: Given the operation failure, careful analysis of the failure reasons and the targeted reoperation can obtain satisfactory results, thereby avoiding the failure of the initial surgery. PMID- 24341625 TI - Cathepsin B/X is secreted by Echinometra lucunter sea urchin spines, a structure rich in granular cells and toxins. AB - BACKGROUND: Echinometra lucunter is a common American sea urchin responsible for the majority of the marine accidents in Brazil. Although not lethal, these accidents are reported to be extremely painful. Recently, our group described the presence of toxins in its spines that contribute to the pathological reactions. Additionally, we have observed that the E. lucunter spines can regenerate when broken. In the present work we evaluated the enzymatic activities of sea urchin spine extracts in order to identify an enzyme that could contribute not only to the toxicity, but also participate in the spine growth and regeneration. RESULTS: The spine aqueous extract was tested for peptidase activity, with synthetic substrates, in the presence and absence of inhibitors and activators. For proper enzyme classification, the FRET-substrate cleavage pattern, pH-dependency activity and Western-blot analyses were performed. The spine extract was able to cleave Z-R-MCA and Abz-GIVRAK(Dnp)-OH following pre-incubation with DTT, and was inhibited by E-64. Furthermore, the double-peaked pH curve (5 and 7) and the cleavage site proportion (4:6, R?A:A?K) indicate the presence of both mono and dicarboxypeptidase activities. Moreover, in Western-blot analysis, the spine extract was positive for anti-cathepsin B antibody. CONCLUSIONS: E. lucunter spines extracts presented a cysteine peptidase activity that was identified as cathepsin B/X that would participate in the remodeling and growth processes of the spine, as well as in the inflammatory response to the accident. PMID- 24341627 TI - Descriptive and temporal analysis of post-mortem lesions recorded in slaughtered pigs in New Zealand from 2000 to 2010. AB - AIMS: To complete a retrospective analysis of data from a national abattoir-based lesion recording system (PigCheck) in the New Zealand pig industry, in order to establish the prevalence of 20 post-mortem disease lesions, describe long-term trends in the prevalence of these lesions, and identify the proportion of the monthly variation in lesion prevalence that could be attributed to individual farms or abattoirs. METHODS: Slaughter lesion data were collected and reported at the lot level (a cohort of pigs delivered from one farm, at one time). Data on the prevalence of lesions between January 2000 and December 2010 was aggregated by month, and time-series analysis of the data for each lesion was conducted. The time series pattern for each lesion was described with an auto-regressive integrated moving average (ARIMA) model; seasonality of lesion occurrence was assessed separately. To determine the proportion of variance in lesion prevalence that could be attributed to farms relative to that attributed to abattoirs, a hierarchical binomial generalised linear mixed model was created incorporating two random effect levels, at the farm (within abattoir) and abattoir levels. RESULTS: A dataset comprised of 124,407 lots (6,220,664 pigs, 279 farms, five abattoirs) was compiled for analysis. The most prevalent conditions across the 11 year time series were antero-ventral pneumonia (7.6%), pleuropneumonia (11.4%), and milk spots (9.2%). Of the 15 lesions shown to have a significant annual change in prevalence, 10 decreased over time and five increased. The variance in prevalence that was observed for pyogenic lesion (92%), mange (73%), and ileitis (62%) was attributed primarily to variation between abattoirs. By contrast, the farm of origin explained the greatest percentage of variance in prevalence for rectal prolapse (98%), pneumonia (97%), and antero-ventral pneumonia (96%). CONCLUSIONS: The overall prevalence of most lesions recorded in PigCheck for the period was low relative to published data from other countries. Common lung pathologies contributing to lesions such as antero-ventral pneumonia and pleuropneumonia were primarily a function of farm management and were not likely due to variability in lesion recording at different abattoirs. CLINICAL RELEVANCE: Based on the low frequency of lesions in pigs at commercial abattoirs, the health status of pigs in the New Zealand pig industry is considered to be very good. Pneumonia, pleurisy, and ascariasis are some of the most prevalent conditions that should be focussed on through development of herd health management plans. PMID- 24341628 TI - Relations between the school physical environment and school social capital with student physical activity levels. AB - BACKGROUND: The physical and social environments at schools are related to students' moderate-to-vigorous physical activity (MVPA) levels. The purpose of this study was to explore the interactive effects of the school physical environment and school social capital on the MVPA of students while at school. METHODS: Data from 18,875 grade 6-10 students from 331 schools who participated in the 2009/10 Canadian Health Behaviour in School-Aged Children survey were analyzed using multi-level regression. Students answered questions on the amount of time they spend in MVPA at school and on their school's social capital. Administrator reports were used to create a physical activity related physical environment score. RESULTS: The school physical environment score was positively associated with student MVPA at school (beta = 0.040, p < .005). The association between the school social capital and MVPA was also positive (beta = 0.074, p < .001). The difference in physical environments equated to about 20 minutes/week of MVPA for students attending schools with the lowest number of physical environment features and about 40 minutes/week for students attending schools with the lowest school social capital scores by comparison to students attending schools with the highest scores. CONCLUSIONS: The findings suggest that school social capital may be a more important factor in increasing students MVPA than the school physical environment. The results of this study may help inform interventions aimed at increasing student physical activity levels. PMID- 24341629 TI - Scaling dermatosis in three dogs associated with abnormal sebaceous gland differentiation. AB - BACKGROUND: Abnormal sebaceous gland differentiation, so-called 'sebaceous gland dysplasia', is a rare condition described in the dog and the cat. Although little is known about this condition, it is thought that a genetic defect causes abnormal sebaceous gland development. Clinically, this condition occurs in young cats and dogs and is characterized by variable degrees of adherent scale, hair casts, poor coat quality and hypotrichosis. HYPOTHESIS/OBJECTIVE: Here, we describe the clinical presentation and treatment of three adult dogs with abnormal sebaceous gland differentiation. ANIMALS: Three adult dogs presented with a keratinization defect characterized by progressive scaling, hair casts, dull, dry, brittle hair coat and hypotrichosis beginning in puppyhood to early adulthood. METHODS: Multiple 6 mm punch skin biopsy samples were obtained from each dog. Treatments included various topical keratomodulatory agents, oral essential fatty acids and oral vitamin A. RESULTS: Histologically, all sebaceous glands were small and composed of a mixture of irregularly clustered basal reserve cells and mature sebocytes. With therapy, two of the dogs showed moderate to marked clinical improvement in scaling, hair casts and hair coat quality. CONCLUSIONS AND CLINICAL IMPORTANCE: Although rare, 'sebaceous gland dysplasia' should be considered in cases where a primary keratinization defect is suspected. Given that abnormal sebaceous differentiation is a structural defect of the skin, treatment must be maintained and is aimed at ameliorating the clinical signs rather than curing the disease. PMID- 24341631 TI - Management of late-onset portal vein complications in pediatric living-donor liver transplantation. AB - The purpose of this study was to evaluate retrospectively the results of PTA for late-onset PV complications after pediatric LDLT and to assess whether a meso-Rex shunt is a viable option for treating restenosis of the PV after PTA in selected cases. Seventy-five children who underwent adult-to-child LDLT were included in this study, and there were six late-onset PV complications (8.0%). The initial therapeutic approach was PTA, with or without stent: PTA with balloon dilation for three children, PTA with stent placement for one child, and failure to cannulate the occluded PV for two children. A meso-Rex shunt was performed in the two children after failed PTA: One suffered complete obstruction of the main PV, and the other, restenosis with total thrombosis after PTA with stent. The PTA was a technical and clinical success in four with PV stenosis of the six patients (66.7%), and successful application of a meso-Rex shunt in the other two children resulted in restoration of PV flow. In conclusion, PTA is a safe and effective procedure for treating late-onset PV stenosis after pediatric LDLT. However, in growing pediatric recipients with restenosis of the PV after PTA or chronic PV thrombosis, a meso-Rex shunt may be a better choice for late-onset PV complications. PMID- 24341632 TI - Three-dimensional hydrodynamic focusing method for polyplex synthesis. AB - Successful intracellular delivery of nucleic acid therapeutics relies on multiaspect optimization, one of which is formulation. While there has been ample innovation on chemical design of polymeric gene carriers, the same cannot be said for physical processing of polymer-DNA nanocomplexes (polyplexes). Conventional synthesis of polyplexes by bulk mixing depends on the operators' experience. The poorly controlled bulk mixing process may also lead to batch-to-batch variation and consequent irreproducibility. Here, we synthesize polyplexes by using a three dimensional hydrodynamic focusing (3D-HF) technique in a single-layered, planar microfluidic device. Without any additional chemical treatment or postprocessing, the polyplexes prepared by the 3D-HF method show smaller size, slower aggregation rate, and higher transfection efficiency, while exhibiting reduced cytotoxicity compared to the ones synthesized by conventional bulk mixing. In addition, by introducing external acoustic perturbation, mixing can be further enhanced, leading to even smaller nanocomplexes. The 3D-HF method provides a simple and reproducible process for synthesizing high-quality polyplexes, addressing a critical barrier in the eventual translation of nucleic acid therapeutics. PMID- 24341633 TI - Comparison of one-level microendoscopy laminoforaminotomy and cervical arthroplasty in cervical spondylotic radiculopathy: a minimum 2-year follow-up study. AB - BACKGROUND: This study aims to compare the perioperative parameters and clinical results between microendoscopy laminoforaminotomy (MELF) and cervical arthroplasty (CA) in the treatment of one-level cervical spondylotic radiculopathy in a retrospective study. METHODS: From 2003 to 2007, a total of 97 patients with one-level cervical spondylotic radiculopathy were treated. Forty five patients underwent CA. Fifty-two patients underwent MELF. Patient demographics and operative data were collected with a minimum 2-year follow-up. Perioperative parameters were compared. Clinical assessment in terms of neck disability index (NDI), short form (SF)-36, and visual analogue scale (VAS) of arm pain and neck pain was performed prior to surgery and at 1.5, 3, 6, 12, and 24 months after surgery. RESULTS: Fluoroscopy time (CA, 60.3 s; MELF, 12.1 s; P < 0.01) and surgical time (CA, 95.1 min; MELF, 24.0 min; P < 0.01) were significantly longer in the CA cases. Shorter hospitalized days (CA, 1.1 days; MELF, 0.13 days; P < 0.01) and less estimated blood loss (EBL; CA, 75.8 ml; MELF, 31.9 ml; P < 0.01) were observed in the MELF group. Both CA and MELF groups showed significant improvement in NDI, VAS of neck pain and arm pain, and SF-36 (P < 0.05 for each) at 1.5, 3, 6, 12, and 24 months after surgery, but there was no significant difference between them (P > 0.05). CONCLUSIONS: As alternatives of anterior cervical decompression and fusion (ACDF), both CA and MELF can produce satisfactory clinical outcomes. MELF has the additional benefits of less blood loss, less surgical time, less X-ray time, and shorter hospital stay. PMID- 24341630 TI - Diagnosis and treatment of viral diseases in recipients of allogeneic hematopoietic stem cell transplantation. AB - Viral infections are important causes of morbidity and mortality after allogeneic stem cell hematopoietic transplantation (allo-HSCT). Although most viral infections present with asymptomatic or subclinical manifestations, viruses may result in fatal complications in severe immunocompromised recipients. Reactivation of latent viruses, such as herpesviruses, is frequent during the immunosuppression that occurs with allo-HSCT. Viruses acquired from community, such as the respiratory and gastrointestinal viruses, are also important pathogens of post-transplant viral diseases. Currently, molecular diagnostic methods have replaced or supplemented traditional methods, such as viral culture and antigen detection, in diagnosis of viral infections. The utilization of polymerase chain reaction facilitates the early diagnosis. In view of lacking efficacious agents for treatment of viral diseases, prevention of viral infections is extremely valuable. Application of prophylactic strategies including preemptive therapy reduces viral infections and diseases. Adoptive cellular therapy for restoring virus-specific immunity is a promising method in the treatment of viral diseases. PMID- 24341634 TI - Identification and genetic effect of a variable duplication in the promoter region of the cattle ADIPOQ gene. AB - In cattle, the ADIPOQ gene is located in the vicinity of the quantitative trait locus (QTL) affecting marbling, the ribeye muscle area and fat thickness on BTA1. In our study, a novel variable duplication (NW_003103812.1:g.9232067_9232133dup) in the bovine ADIPOQ promoter region was identified and genotyped in seven Chinese cattle breeds. Using a reporter assay, we demonstrated that g.9232067_9232133dup decreased the basal transcriptional activity of the ADIPOQ gene in the 3T3-L1 and C2C12 cells. Furthermore, g.9232067_9232133dup suppressed the mRNA expression of the gene in adipose and muscle tissues. An association analysis indicated that the incremental variable duplication was associated with body measurements. PMID- 24341636 TI - Electrospun cellulose acetate-garnet nanocomposite magnetic fibers for bioseparations. AB - Cellulose acetate fibers with magnetic properties have recently attracted much attention because of their potential novel applications in biomedicine such as for cell and protein separations, magnetic resonance imaging contrast agents, and magnetic filters. In this work, as synthesized yttrium iron garnet and gadolinium substituted yttrium iron garnet nanoparticles have been used to generate magnetic filter paper. Garnet nanoparticles dispersed in cellulose acetate polymer solutions were electrospun as free-standing nonwoven fiber mats as well as on cellulose filter paper substrates resulting in magnetic filter papers. The magnetic fibers were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), powder X-ray diffraction (PXRD), and superconducting quantum interference device (SQUID) magnetic property measurements. The resulting magnetic polymer nanocomposites can be easily picked up by an external magnet from a liquid medium. Fluorescein isothiocyanate (FITC) labeled bovine serum albumin (BSA) was separated from solution by using the magnetic filter paper. PMID- 24341637 TI - Mucoceles of the oral cavity in neonates and infants--report of a case and literature review. AB - Oral mucoceles are common lesions that normally appear in the second decade of life. They are uncommon in neonates and infants. We present a case of a mucocele in a 10-month-old infant and review the literature regarding the epidemiology and treatment in this age group. PMID- 24341635 TI - Characterization of cytokinin signaling and homeostasis gene families in two hardwood tree species: Populus trichocarpa and Prunus persica. AB - BACKGROUND: Through the diversity of cytokinin regulated processes, this phytohormone has a profound impact on plant growth and development. Cytokinin signaling is involved in the control of apical and lateral meristem activity, branching pattern of the shoot, and leaf senescence. These processes influence several traits, including the stem diameter, shoot architecture, and perennial life cycle, which define the development of woody plants. To facilitate research about the role of cytokinin in regulation of woody plant development, we have identified genes associated with cytokinin signaling and homeostasis pathways from two hardwood tree species. RESULTS: Taking advantage of the sequenced black cottonwood (Populus trichocarpa) and peach (Prunus persica) genomes, we have compiled a comprehensive list of genes involved in these pathways. We identified genes belonging to the six families of cytokinin oxidases (CKXs), isopentenyl transferases (IPTs), LONELY GUY genes (LOGs), two-component receptors, histidine containing phosphotransmitters (HPts), and response regulators (RRs). All together 85 Populus and 45 Prunus genes were identified, and compared to their Arabidopsis orthologs through phylogenetic analyses. CONCLUSIONS: In general, when compared to Arabidopsis, differences in gene family structure were often seen in only one of the two tree species. However, one class of genes associated with cytokinin signal transduction, the CKI1-like family of two-component histidine kinases, was larger in both Populus and Prunus than in Arabidopsis. PMID- 24341638 TI - 7-chloroquinoline-isatin conjugates: antimalarial, antitubercular, and cytotoxic evaluation. AB - A series of twenty piperazine-tethered 7-chloroquinoline-isatin hybrids have been synthesized via either direct nucleophilic substitution or Cu(Iota)Cl-mediated Mannich reaction. These new conjugates were evaluated for their antimalarial and antitubercular efficacy against a chloroquine-resistant strain of Plasmodium falciparum and Mycobacterium tuberculosis, respectively, while the cytotoxic profiles were evaluated against 3T6 cell line, a permanent mouse embryonic fibroblast cell line. The most potent of the test compound with IC50 of 0.22 MUm against W2 strain of P. falciparum and 31.62 MUm against the embryonic fibroblast cell line (cytotoxicity) displayed a high selective index of 143.73. PMID- 24341640 TI - Monitor lizard bite-induced acute kidney injury--a case report. AB - Envenomations by venomous lizards are rare. Monitor lizard bite-induced acute kidney injury (AKI) is a previously unreported complication in humans. A 55-year old female was bitten on her right leg during farming activity by a monitor lizard (Varanus bengalensis). The patient experienced severe local pain and bleeding from the wound, coagulopathy, hemolysis, rhabdomyolysis, sepsis, and AKI. Patient was treated with supportive care and peritoneal dialysis but succumbed to a sudden cardiac arrest. Post mortem kidney biopsy revealed pigment induced-acute tubular injury. AKI after monitor lizard envenomation is caused by acute tubular injury in the setting of intravascular hemolysis, rhabdomyolysis and sepsis. Coagulopathy and direct nephrotoxicity may be the other contributory factors in causing AKI. PMID- 24341639 TI - Identification of PDE5A:E90K: a polymorphism in the canine phosphodiesterase 5A gene affecting basal cGMP concentrations of healthy dogs. AB - BACKGROUND: Cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE5A) is the target of phosphodiesterase inhibitors such as sildenafil. Polymorphisms in the PDE5A gene that may predict response to therapy with sildenafil and nitric oxide, be linked to disease progression, and aid in risk assessment have been identified in human beings. Identification of polymorphisms in PDE5A could affect the physiologic actions of PDE5A and the effects of phosphodiestrase type 5 inhibitor drugs. HYPOTHESIS/OBJECTIVE: Functional polymorphisms exist in the canine PDE5A gene. Specific objectives were to identify PDE5A polymorphisms and evaluate their functional relevance. ANIMALS: Seventy healthy dogs. METHODS: The exonic, splice-site, 3' and 5' untranslated regions of the canine PDE5A gene were sequenced in 15 dogs and aligned with the canine reference sequence. Identified polymorphisms were evaluated in 55 additional, healthy, unrelated dogs of 20 breeds. Plasma was collected from 51 of these dogs and cGMP was measured. An unpaired t-test and one-way ANOVA with Dunnett's test of multiple comparisons were used to evaluate the effect of genotype on cGMP. RESULTS: A common exonic polymorphism was identified that changed glutamic acid to lysine and resulted in significantly lower cGMP concentrations in the group with polymorphism versus the wild type group (P = .014). Additionally, 6 linked single nucleotide polymorphisms in the 3' untranslated region were identified that did not alter cGMP concentrations. CONCLUSIONS AND CLINICAL IMPORTANCE: A polymorphism exists in the canine PDE5A gene that is associated with variable circulating cGMP concentrations in healthy dogs and warrants investigation in diseases such as pulmonary hypertension. PMID- 24341641 TI - Esthetic evaluation of implants placed after orthodontic treatment in patients with congenitally missing lateral incisors. AB - OBJECTIVE: The aim of this retrospective study was to evaluate the esthetic outcome of single tooth Morse taper connection implants used to replace congenitally missing lateral incisors after orthodontic treatment by means of the pink esthetic score (PES) and white esthetic score (WES) index. MATERIALS AND METHODS: Twenty consecutive patients who were treated with a single tooth Morse taper connection implants (Leone Implant System(r), Florence, Italy) were enrolled in this study. An independent calibrated examiner applied the PES/WES index to 20 implant-supported restorations 3 months and 3 years after implant placement. RESULTS: No implants were lost. All 20 implants fulfilled the established success criteria for dental implants with regard to osseointegration and prosthetic complications, with an overall implant-crown success of 100.0%. At the 3 year examination, the mean distance between the implant shoulder and the first visible bone-implant contact was of 0.49 +/- 0.18 mm (95% confidence interval 0.41-0.57); the mean PES was 8.15 +/- 1.69, and the mean WES was 8.70 +/ 0.92. CONCLUSIONS: The placement of single-tooth Morse taper connection implants for rehabilitation of congenitally missing lateral incisors after orthodontic treatment represents a successful procedure in the medium term. Further studies are necessary in order to assess the long-term esthetic score. CLINICAL SIGNIFICANCE: This paper evaluates the esthetic outcome of Morse taper connection implants placed to restore congenitally missing lateral incisors after orthodontic treatment. PMID- 24341643 TI - Guidelines for the practice of telepsychology. PMID- 24341642 TI - IL-4 analogues with site-specific chemical modification at position 121 inhibit IL-4 and IL-13 biological activities. AB - IL-4 signaling into a cell occurs via assembly of a receptor complex that consists of a high-affinity IL-4Ralpha chain and a low affinity chain, where the low-affinity chain is either gammac or IL-13Ralpha1. It has been previously shown that mutational disruption of the low affinity interface in the IL-4DM (double mutein) yields an antagonist that inhibits IL-4 as well as IL-13-dependent responses. The present study reveals that new types of IL-4 antagonists can be generated by site-specific chemical modification. The chemically modified IL-4 analogues consist of (1) mixed disulfides created by refolding IL-4 cysteine muteins in the presence of different thiol compounds or (2) maleimide conjugates created by modifying cysteine muteins with maleimide derivatives. IL-4 analogues chemically modified at position 121 retain marginal binding affinity to gammac or IL-13Ralpha1 receptor ectodomains during SPR interaction analysis. The biological activity of the analogues is strongly reduced in HEK-Blue IL-4/IL-13 cells as well as in Jurkat cells. Since the IL-4 analogues modified at position 121 have the ability to inhibit gammac (IL-4)- and IL13Ralpha1 (IL-4/IL-13)-dependent responses in Jurkat and HEK-Blue cell lines, they effectively act as IL-4 antagonists. The results of our IL-4 study provide the first example of a cytokine that is transformed into a competitive inhibitor by site-specific chemical modification. PMID- 24341644 TI - 2013 reports of the regional associations. PMID- 24341649 TI - Robert Perloff (1921-2013). PMID- 24341650 TI - Rogers H. Wright (1927-2013). PMID- 24341651 TI - Nathan H. Azrin (1930-2013). PMID- 24341652 TI - Vytautas J. Bieliauskas (1920-2013). PMID- 24341655 TI - Can computer-mediated communication increase adolescents' sexually risky behaviors? PMID- 24341656 TI - The online space presents a unique opportunity for psychological sciences to improve the health of youth. PMID- 24341657 TI - Comparison of anaesthetic and analgesic effects of emulsified isoflurane used alone or combined with lidocaine and fentanyl in dogs. AB - AIM: The objective of this study was to investigate the effects of a combination of emulsified isoflurane, lidocaine, and fentanyl (EI-L-F) compared with the efficacy of emulsified isoflurane alone (EI), a combination of emulsified isoflurane and lidocaine (EI-L) or emulsified isoflurane and fentanyl (EI-F) for anaesthetising dogs. METHODS: Eight mongrel dogs were anesthetised with EI (8 mL/kg/hour), EI-L (3 mg/kg/hour lidocaine and 6 mL/kg/hour of emulsified isoflurane), EI-F (1.5 MUg/kg/hour fentanyl and 6 mL/kg/hour of emulsified isoflurane), and EI-L-F (5 mL/kg/hour of emulsified isoflurane, 1 MUg/kg/hour of fentanyl and 2.4 mg/kg/hour of lidocaine). Each dog received all four treatments and there was a 15-day washout period between the treatments. The dogs' anaesthesia and analgesia scores and physiological parameters were determined before and 5, 10, 20, 30, 40, 50, 60, 70 and 80 minutes after the administration of anaesthetic agents. RESULTS: The dogs in each of the four groups became laterally recumbent within 1 minute. Respiration rate and heart rate increased (p<0.05) during the first 5 minutes of anaesthesia in all groups. Respiration rate in the EI-F-L group was higher (p=0.037) than other groups from 30 to 50 minutes. Heart rate was higher in the EI than EI-F-L group (p=0.018) from 10 to 20 minutes, then returned to near baseline. Arterial oxygen saturation decreased during the period of anaesthesia but was higher (p=0.032) from 10 to 50 minutes in EI-F-L group than in other groups. The total anaesthesia scores in the EI-L-F group were higher than the EI and EI-L groups (p<0.05). The mean time to body movement was 5 (SD 2), 5 (SD 2), 7 (SD 2) and 8 (SD 2) minutes for the EI, EI-L, EI-F and EI-F-L groups, respectively. The mean time to standing was 8 (SD 2), 9 (SD 2), 10 (SD 2) and 13 (SD 3) minutes for the EI, EI-L, EI-F and EI-F-L groups, respectively. No excitement was observed during recovery after anaesthesia. CONCLUSIONS: The EI-F-L combination that was used in this study provided an adequate anaesthesia effect in dogs, which was characterised by adequate analgesia and muscle relaxation without any complications. PMID- 24341658 TI - Leflunomide in idiopathic membranous nephropathy: a new immunosuppressive with promising treatment potential. PMID- 24341659 TI - Effect of levamisole supplementation on tetanus vaccination response rates in haemodialysis patients: a randomized double-blind placebo-controlled trial. AB - Levamisole as an immunomodulator drug has been demonstrated to improve the immune response to hepatitis B virus vaccination in haemodialysis patients. The aim of this randomized double-blind placebo-controlled trial was to evaluate the effect of levamisole supplementation on tetanus-diphtheria (Td) vaccine response rates in haemodialysis patients. Forty haemodialysis patients who had not received tetanus vaccination in a year before investigation and had unprotective anti tetanus immunoglobulin G (IgG) levels (<0.1 international unit/mL) were enrolled and randomized into two equal groups to receive one dose of intramuscular Td vaccine supplemented with either levamisole (100 mg) or placebo daily, for 6 days before and 6 days after vaccination. The anti-tetanus IgG levels were measured 1 and 6 months after vaccination. One month post-vaccination, four patients were excluded from the levamisole group and two from the placebo group because of either death or renal transplantation. At 1 month, 13 out of 16 (81%) patients in the levamisole group as compared with six out of 18 (33%) patients in the placebo group developed protective anti-tetanus IgG levels (relative risk = 2.44, 95% confidence interval (CI) = 1.21, 4.88). From 1 to 6 months post-vaccination, one more patient in the levamisole group and two more patients in the placebo group were excluded because of renal transplantation. At 6 months, 11 out of 15 (73%) patients in the levamisole group as compared with four out of 16 (25%) patients in the placebo group still had protective anti-tetanus IgG levels (relative risk = 2.93, 95% CI = 1.19, 7.23). Supplementation of Td vaccination with levamisole may enhance seroconversion against tetanus in haemodialysis patients. PMID- 24341660 TI - Commentary on the KDIGO Clinical Practice Guideline for the management of blood pressure in chronic kidney disease. PMID- 24341661 TI - Is lead chelation therapy effective for chronic kidney disease? A meta-analysis. AB - The heavy metal lead (Pb) is a major environmental and occupational hazard. Epidemiological studies have demonstrated a strong association between lead exposure and the presence of chronic kidney injury. Some studies have suggested that chelation therapy with calcium disodium ethylenediaminetetraacetic acid (calcium disodium EDTA) might help decrease the progression of chronic kidney disease among patients with measurable body lead burdens. However, calcium disodium EDTA chelation in lead exposure is controversial due to the potential for adverse effects such as acute tubular necrosis. Therefore, we investigated the available randomized controlled trials assessing the renoprotective effects of calcium disodium EDTA chelation therapy. Our meta-analysis shows that calcium disodium EDTA chelation therapy can effectively delay the progression of chronic kidney disease in patients with measurable body lead burdens reflected by increasing the levels of estimated glomerular filtration rate (eGFR) and creatinine clearance rate (Ccr). There appears to be no conclusive evidence that calcium disodium EDTA can decrease proteinuria. PMID- 24341662 TI - New onset psoriasis after rituximab for treatment of idiopathic membranous nephropathy. PMID- 24341663 TI - Fractured catheter guide wire in the right ventricle of a dialysis patient. PMID- 24341664 TI - An unusual case of severe acute tubular necrosis. PMID- 24341665 TI - Inhibition of the mutagenic effects of N-methyl-N'-nitro-N-nitrosoguanidine and 9 aminoacridine by indenopyridines in the Salmonella typhimurium tester strain 1537 and E. coli. AB - The goal of the present research was to determine the protective potential of five newly synthesized indenopyridine derivatives against N-methyl-N'-nitro-N nitrosoguanidine (MNNG) and 9-aminoacridine (9-AA) induced mutagenesis. MNNG sensitive Escherichia coli WP2uvrA and 9-AA sensitive Salmonella typhimurium TA1537 were chosen as the bacterial tester strains. All of the test compounds showed significant antimutagenic activity at various tested concentrations. The inhibition rates ranged from 25.6% (Compound 2 - 1 mM/plate) to 68.2% (Compound 1 - 2.5 mM/plate) for MNNG and from 25.7% (Compound 4 - 1 mM/plate) to 76.1% (Compound 3 - 2.5 mM/plate) for 9-AA genotoxicity. Moreover, the mutagenicity of the test compounds was investigated by using the same strains. None of the test compounds has mutagenic properties on the bacterial strains at the highest concentration of 2.5 mM. Thus, the findings of the present study give valuable clues to develop new strategies for chemical prevention from MNNG and 9-AA genotoxicity by using synthetic indenopyridine derivatives. PMID- 24341667 TI - A study into blood alcohol concentration in fatal accidents among vulnerable road users in a tertiary care hospital Sri Lanka. AB - Reckless driving behaviour associated with alcohol has been well known. In Sri Lanka, research on blood alcohol concentration (BAC) in road fatalities is scares. Thus, we studied the BAC in vulnerable road users (VRUs) encountered in medico-legal autopsies. A retrospective descriptive study based on case records of VRU fatalities from 2005 to 2012 referred for a tertiary care unit for post mortem examination was conducted. A pro-forma was developed to extract data from the post-mortem blood alcohol reports. Data were analysed using percentages and p values. There were 119 cases from the 328 autopsies to investigate blood alcohol tests. A total of 51% (n = 61) out of 119 had BAC above 80 mg/100 ml and mean level was 103 mg/100 ml. 2/3 of pedestrians had a BAC above 80 mg/100 ml with a mean level of 139 mg/dl. The highest mean blood alcohol (158 mg/dl) was reported from three-wheeler users. Majority of cases with more than 80 mg/100 ml BAC was reported in the age group of 40-60 years, while 40% of the elderly too had a BAC above 80 mg/100 ml. The comparison between pedestrians having above 80 mg/100 ml of BAC with that of other VRUs (active road users) showed a significant statistical difference (p = 0.017). The study results suggest that alcohol influence among pedestrians represent a significant risk factor for fatal road traffic accidents. PMID- 24341666 TI - A single-nucleotide polymorphism in the proximal promoter region of the apolipoprotein M gene is associated with dyslipidaemia but not increased coronary artery diseases in Chinese populations. AB - BACKGROUND: It has been reported that rs940494 and rs805296 SNPs of apolipoprotein M (apoM) gene may confer the risk in the development of type 2 diabetes (T2D) and coronary artery disease (CAD) in the Han Chinese. However, a recent study demonstrated that rs805297 polymorphism is significantly associated with reduced total high density lipoprotein (HDL) levels in rheumatoid arthritis patients. But the relationship between rs805297 SNP and CAD has not been explored. The aim of the present study was to elucidate whether the rs805297 mutant allele is implicated in CAD and links to changes in blood lipid levels in these patients. METHODS: Three hundred CAD patients and three hundred and twelve non-CAD patients were subjected in the present study. All subjects were confirmed by the angiography. Plasma concentrations of apoM were semi-quantitatively determined by dot-blotting analysis, and total serum lipid levels were quantified using an automated RA-1000 (Technician, USA). The genotyping of rs805297 of apoM was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Genotype and allele frequencies were not significant (P = 0.5798 and 0.3834, respectively) between cases and controls. Compared with the wild-type C/C genotype, carriers of the C/A and A/A genotypes did not have an increased risk of CAD, as determined by multiple logistic regression analysis, after adjustment for age, sex, BMI, history of smoking, hypertension and hypercholesterolemia. (CA, odds ratio = 0.49, 95% confidence interval 0.15-1.87, P = 0.462; AA, odds ratio = 0.51, 95% confidence interval 0.13-1.68, P = 0.534). The plasma concentration levels of apoM did not differ significantly among carriers of the three genotypes between two groups. Lastly, control subjects with A/A genotypes had lower total levels of HDL cholesterol than did those with C/C genotypes. CONCLUSIONS: The results presented here suggest that the rs805297 SNP is not associated with an increased risk of developing CAD, although it does independently correlate with dyslipidaemia in Han Chinese individuals. PMID- 24341668 TI - Gene regulatory network inference by point-based Gaussian approximation filters incorporating the prior information. AB - : The extended Kalman filter (EKF) has been applied to inferring gene regulatory networks. However, it is well known that the EKF becomes less accurate when the system exhibits high nonlinearity. In addition, certain prior information about the gene regulatory network exists in practice, and no systematic approach has been developed to incorporate such prior information into the Kalman-type filter for inferring the structure of the gene regulatory network. In this paper, an inference framework based on point-based Gaussian approximation filters that can exploit the prior information is developed to solve the gene regulatory network inference problem. Different point-based Gaussian approximation filters, including the unscented Kalman filter (UKF), the third-degree cubature Kalman filter (CKF3), and the fifth-degree cubature Kalman filter (CKF5) are employed. Several types of network prior information, including the existing network structure information, sparsity assumption, and the range constraint of parameters, are considered, and the corresponding filters incorporating the prior information are developed. Experiments on a synthetic network of eight genes and the yeast protein synthesis network of five genes are carried out to demonstrate the performance of the proposed framework. The results show that the proposed methods provide more accurate inference results than existing methods, such as the EKF and the traditional UKF. PMID- 24341669 TI - Minimizing the threat of pandemic emergence from avian influenza in poultry systems. AB - BACKGROUND: Live-animal markets are a culturally important feature of meat distribution chains in many populations, yet they provide an opportunity for the maintenance and transmission of potentially emergent zoonotic pathogens. The ongoing human outbreak of avian H7N9 in China highlights the need for increased surveillance and control in these live-bird markets (LBMs). DISCUSSION: Closure of retail markets in affected areas rapidly decreased human cases to rare, sporadic occurrence, but little attention has been paid thus far to the role of upstream elements of the poultry distribution chain such as wholesale markets. This could partly explain why transmission in poultry populations has not been eliminated more broadly. We present surveillance data from both wholesale live bird markets (wLBMs) and rLBMs in Shantou, China (from 2004-2006), and call on disease-dynamic theory to illustrate why closing rLBMs has only minor effects on the overall volume of transmission. We show that the length of time birds stay in rLBMs can severely limit transmission there, but that the system-wide effect may be reduced substantially by high levels of transmission upstream of retail markets. SUMMARY: Management plans that minimize transmission throughout the entire poultry supply chain are essential for minimizing exposure to the public. These include reducing stay-time of birds in markets to 1 day, standardizing poultry supply chains to limit transmission in pre-retail settings, and monitoring strains with epidemiological traits that pose a high risk of emergence. These actions will further limit human exposure to extant viruses and reduce the likelihood of the emergence of novel strains by decreasing the overall volume of transmission. PMID- 24341670 TI - Impact of heterogeneity on oxygen transfer in a fluctuating capillary fringe. AB - We performed quasi-two-dimensional flow through laboratory experiments to study the effect of a coarse-material inclusion, located in the proximity of the water table, on flow and oxygen transfer in the capillary fringe. The experiments investigate different phases of mass transfer from the unsaturated zone to anoxic groundwater under both steady-state and transient flow conditions, the latter obtained by fluctuating the water table. Monitoring of flow and transport in the different experimental phases was performed by visual inspection of the complex flow field using a dye tracer solution, measurement of oxygen profiles across the capillary fringe, and determination of oxygen fluxes in the effluent of the flow through chamber. Our results show significant effects of the coarse-material inclusion on oxygen transfer during the different phases of the experiments. At steady state, the oxygen flux across the unsaturated/saturated interface was considerably enhanced due to flow focusing in the fully water-saturated coarse material inclusion. During drainage, a zone of higher water saturation formed in the fine material overlying the coarse lens. The entrapped oxygen-rich aqueous phase contributed to the total amount of oxygen supplied to the system when the water table was raised back to its initial level. In case of imbibition, pronounced air entrapment occurred in the coarse lens, causing oxygen to partition between the aqueous and gaseous phases. The oxygen mass supplied to the anoxic groundwater following the imbibition event was found to be remarkably higher (approximately seven times) in the heterogeneous system compared with a similar experiment performed in a homogeneous porous medium. PMID- 24341671 TI - A new HLA allele, HLA-B*08:108, described in two unrelated Spanish individuals. AB - HLA-B*08:108 shows one nucleotide difference regarding B*08:01:01 at codon 109 (CTC>TTC, L109>F109). PMID- 24341672 TI - Drug-related problems in type 2 diabetes mellitus patients with dyslipidemia. AB - BACKGROUND: Drug-Related Problems (DRPs) commonly occur among type 2 diabetes mellitus (T2DM) patients. However, few studies have been performed on T2DM patients with dyslipidemia. This purpose of this study was to assess drug-related problems (DRPs) and factors associated with its occurrence. METHODS: The retrospective study involved 208 T2DM in-patients and out-patients with dyslipidemia, and was conducted at a tertiary hospital in Malaysia from January 2009 to December 2011. The identification and assessment of DRPs were based on the Pharmaceutical Care Network Europe (PCNE) tool version 5.01. The potentially inappropriate medication use in older adults was assessed based on the American Geriatrics Society updated Beers Criteria. RESULTS: A total of 406 DRPs were identified. Among these patients, 91.8% had at least one DRP, averaging 1.94+/ 1.10 problems per patient. The majority of T2DM patients with dyslipidemia (91.8%) had at least one DRP. The most frequent types of DRP were potential drug drug interaction (18.0%), drug not taken or administered (14.3%) and insufficient awareness of health and diseases (11.8%). Anti-hypertensive, lipid-modifying and anti-diabetic agents were the drug classes that were most likely to be associated with DRPs. Male gender, renal impairment, polypharmacy and poor lipid control were factors that were significantly associated with DRP in diabetic dyslipidemia patients. CONCLUSION: Early identification of DRPs and factors associated with them are essential to prevent and resolve DRPs in T2DM patients with dyslipidemia. PMID- 24341674 TI - Unusual cause of dyspnoea: a case presentation of an echocardiographic pitfall. AB - Congenital or acquired communication between the left ventricle and the right atrium is known as the Gerbode defect, which is rarely diagnosed since the defect is very unusual and for this reason often misinterpreted as an eccentric tricuspid regurgitation jet. The entity and reason of the defect is unknown to many physicians, so that profound knowledge and a careful and meticulous echocardiogram are necessary in order to prevent misinterpretation of this defect as a pulmonary hypertension. We report the case of a 76-year-old Austrian woman who developed such a Gerbode defect after a recent bioprosthetic aortic valve replacement. PMID- 24341673 TI - Investigation of the hub genes and related mechanism in ovarian cancer via bioinformatics analysis. AB - BACKGROUND: Ovarian cancer is a cancerous growth arising from the ovary. OBJECTIVE: This study was aimed to explore the molecular mechanism of the development and progression of the ovarian cancer. METHODS: We first identified the differentially expressed genes (DEGs) between the ovarian cancer samples and the healthy controls by analyzing the GSE14407 affymetrix microarray data, and then the functional enrichments of the DEGs were investigated. Furthermore, we constructed the protein-protein interaction network of the DEGs using the STRING online tools to find the genes which might play important roles in the progression of ovarian cancer. In addition, we performed the enrichment analysis to the PPI network. RESULTS: Our study screened 659 DEGs, including 77 up- and 582 down-regulated genes. These DEGs were enriched in pathways such as Cell cycle, p53 signaling pathway, Pathways in cancer and Drug metabolism. CCNE1, CCNB2 and CYP3A5 were the significant genes identified from these pathways. Protein-protein interaction (PPI) network was constructed and network Module A was found closely associated with ovarian cancer. Hub nodes such as VEGFA, CALM1, BIRC5 and POLD1 were found in the PPI network. Module A was related to biological processes such as mitotic cell cycle, cell cycle, nuclear division, and pathways namely Cell cycle, Oocyte meiosis and p53 signaling pathway. CONCLUSIONS: It indicated that ovarian cancer was closely associated to the dysregulation of p53 signaling pathway, drug metabolism, tyrosine metabolism and cell cycle. Besides, we also predicted genes such as CCNE1, CCNB2, CYP3A5 and VEGFA might be target genes for diagnosing the ovarian cancer. PMID- 24341675 TI - High activity redox catalysts synthesized by chemical vapor impregnation. AB - The use of precious metals in heterogeneous catalysis relies on the preparation of small nanoparticles that are stable under reaction conditions. To date, most conventional routes used to prepare noble metal nanoparticles have drawbacks related to surface contamination, particle agglomeration, and reproducibility restraints. We have prepared titania-supported palladium (Pd) and platinum (Pt) catalysts using a simplified vapor deposition technique termed chemical vapor impregnation (CVI) that can be performed in any standard chemical laboratory. These materials, composed of nanoparticles typically below 3 nm in size, show remarkable activity under mild conditions for oxidation and hydrogenation reactions of industrial importance. We demonstrate the preparation of bimetallic Pd-Pt homogeneous alloy nanoparticles by this new CVI method, which show synergistic effects in toluene oxidation. The versatility of our CVI methodology to be able to tailor the composition and morphology of supported nanoparticles in an easily accessible and scalable manner is further demonstrated by the synthesis of Pdshell-Aucore nanoparticles using CVI deposition of Pd onto preformed Au nanoparticles supported on titania (prepared by sol immobilization) in addition to the presence of monometallic Au and Pd nanoparticles. PMID- 24341676 TI - Revisiting the psychometric properties of the Levenson self-report psychopathy scale. AB - A number of studies have addressed the dimensionality and the measurement invariance of the Levenson Self-Report Psychopathy scale (LSRP; Levenson, Kiehl, & Fitzpatrick, 1995). However, previous investigations exclusively relied on North American samples and mainly on statistical methods that assume data as normally and continuously distributed. The aim of this study was to further investigate dimensionality and differential item functioning for gender in the 26 item LSRP scale in a Brazilian population-based sample using analytical methods adequate for ordered categorical variables. Findings revealed strong evidence for a 2-factor model, similar to the original factor structure of the instrument. Only 3 items presented negligible differential functioning for gender. We address the implications of these results, and stress the need for expanding research on the measurement and structural invariance of the LSRP scale by means of cross cultural investigations. PMID- 24341677 TI - Interindividual variability in social insects - proximate causes and ultimate consequences. AB - Individuals within social groups often show consistent differences in behaviour across time and context. Such interindividual differences and the evolutionary challenge they present have recently generated considerable interest. Social insects provide some of the most familiar and spectacular examples of social groups with large interindividual differences. Investigating these within-group differences has a long research tradition, and behavioural variability among the workers of a colony is increasingly regarded as fundamental for a key feature of social insects: division of labour. The goal of this review is to illustrate what we know about both the proximate mechanisms underlying behavioural variability among the workers of a colony and its ultimate consequences; and to highlight the many open questions in this research field. We begin by reviewing the literature on mechanisms that potentially introduce, maintain, and adjust the behavioural differentiation among workers. We highlight the fact that so far, most studies have focused on behavioural variability based on genetic variability, provided by e.g. multiple mating of the queen, while other mechanisms that may be responsible for the behavioural differentiation among workers have been largely neglected. These include maturational, nutritional and environmental influences. We further discuss how feedback provided by the social environment and learning and experience of adult workers provides potent and little-explored sources of differentiation. In a second part, we address what is known about the potential benefits and costs of increased behavioural variability within the workers of a colony. We argue that all studies documenting a benefit of variability so far have done so by manipulating genetic variability, and that a direct test of the effect of behavioural variability on colony productivity has yet to be provided. We emphasize that the costs associated with interindividual variability have been largely overlooked, and that a better knowledge of the cost/benefit balance of behavioural variability is crucial for our understanding of the evolution of the mechanisms underlying the social organization of insect societies. We conclude by highlighting what we believe to be promising but little-explored avenues for future research on how within-colony variability has evolved and is maintained. We emphasize the need for comparative studies and point out that, so far, most studies on interindividual variability have focused on variability in individual response thresholds, while the significance of variability in other parameters of individual response, such as probability and intensity of the response, has been largely overlooked. We propose that these parameters have important consequences for the colony response. Much more research is needed to understand if and how interindividual variability is modulated in order to benefit division of labour, homeostasis and ultimately colony fitness in social insects. PMID- 24341678 TI - Pediatric dermatology training survey of United States dermatology residency programs. AB - Variability exists in pediatric dermatology education for dermatology residents. We sought to formally assess the pediatric dermatology curriculum and experience in a dermatology residency program. Three unique surveys were developed for dermatology residents, residency program directors, and pediatric dermatology fellowship program directors. The surveys consisted of questions pertaining to residency program characteristics. Sixty-three graduating third-year residents, 51 residency program directors, and 18 pediatric dermatology fellowship program directors responded. Residents in programs with one or more full-time pediatric dermatologist were more likely to feel very competent treating children and were more likely to be somewhat or extremely satisfied with their pediatric curriculums than residents in programs with no full-time pediatric dermatologist (50.0% vs 5.9%, p = 0.002, and 85.3% vs 52.9%, p < 0.001, respectively). Residents in programs with no full-time pediatric dermatologist were the only residents who were somewhat or extremely dissatisfied with their pediatric training. Residency program directors were more satisfied with their curriculums when there was one or more pediatric dermatologist on staff (p < 0.01). Residents in programs with pediatric dermatology fellowships were much more likely to report being extremely satisfied than residents in programs without a pediatric dermatology fellowship (83.3% vs 21.2%; p < 0.001). The results of this survey support the need for dermatology residency programs to continue to strengthen their pediatric dermatology curriculums, especially through the recruitment of full-time pediatric dermatologists. PMID- 24341679 TI - Uncertainty of population risk estimates for pathogens based on QMRA or epidemiology: a case study of Campylobacter in the Netherlands. AB - Epidemiology and quantitative microbiological risk assessment are disciplines in which the same public health measures are estimated, but results differ frequently. If large, these differences can confuse public health policymakers. This article aims to identify uncertainty sources that explain apparent differences in estimates for Campylobacter spp. incidence and attribution in the Netherlands, based on four previous studies (two for each discipline). An uncertainty typology was used to identify uncertainty sources and the NUSAP method was applied to characterize the uncertainty and its influence on estimates. Model outcomes were subsequently calculated for alternative scenarios that simulated very different but realistic alternatives in parameter estimates, modeling, data handling, or analysis to obtain impressions of the total uncertainty. For the epidemiological assessment, 32 uncertainty sources were identified and for QMRA 67. Definitions (e.g., of a case) and study boundaries (e.g., of the studied pathogen) were identified as important drivers for the differences between the estimates of the original studies. The range in alternatively calculated estimates usually overlapped between disciplines, showing that proper appreciation of uncertainty can explain apparent differences between the initial estimates from both disciplines. Uncertainty was not estimated in the original QMRA studies and underestimated in the epidemiological studies. We advise to give appropriate attention to uncertainty in QMRA and epidemiological studies, even if only qualitatively, so that scientists and policymakers can interpret reported outcomes more correctly. Ideally, both disciplines are joined by merging their strong respective properties, leading to unified public health measures. PMID- 24341680 TI - Anteroventral pre-optic neurones, control of breathing and H2S: physiology or toxicology? PMID- 24341681 TI - Rapid microsatellite development for tree peony and its implications. AB - BACKGROUND: Microsatellites are ubiquitous in genomes of various organisms. With the realization that they play roles in developmental and physiological processes, rather than exist as 'junk' DNA, microsatellites are receiving increasing attention. Next-generation sequencing allows acquisition of large scale microsatellite information, and is especially useful for plants without reference genome sequences. RESULTS: In this study, enriched DNA libraries of tree peony, a well-known ornamental woody shrub, were used for high-throughput microsatellite development by 454 GS-FLX Titanium pyrosequencing. We obtained 675,221 reads with an average length of 356 bp. The total size of examined sequences was 240,672,018 bp, from which 237,134 SSRs were identified. Of these sequences, 164,043 contained SSRs, with 27% featuring more than one SSR. Interestingly, a high proportion of SSRs (43%) were present in compound formation. SSRs with repeat motifs of 1-4 bp (mono-, di-, tri-, and tetra nucleotide repeats) accounted for 99.8% of SSRs. Di-nucleotide repeats were the most abundant. As in most plants, the predominant motif in tree peony was (A/T)n, with (G/C)n less common. The lengths of SSRs were classified into 11 groups. The shortest SSRs (10 bp) represented 1% of the total number, whereas SSRs 21-30 and 101-110 bp long accounted for 26% and 29%, respectively, of all SSRs. Many sequences (42,111) were mapped to CDS (coding domain sequence) regions using Arabidopsis as a reference. GO annotation analysis predicted that CDSs with SSRs performed various functions associated with cellular components, molecular functions, and biological processes. Of 100 validated primer pairs, 24 were selected for polymorphism analysis among 23 genotypes; cluster analysis of the resulting data grouped genotypes according to known relationships, confirming the usefulness of the developed SSR markers. CONCLUSIONS: The results of our large scale SSR marker development using tree peony are valuable for investigating plant genomic structural evolution and elucidating phenotypic variation in this species during its evolution and artificial selection. The newly identified SSRs should be useful for genetic linkage map construction, QTL mapping, gene location and cloning, and molecular marker-assisted breeding. In addition, the genome-wide marker resources generated in this study should aid genomic studies of tree peony and related species. PMID- 24341683 TI - Porous inorganic materials from living porogens: channel-like TiO2 from yeast assisted sol-gel process. AB - Vitality of yeast cells maintained in an aqueous sol-gel solution containing titanium tetraisopropoxide and glucose. The living cells and their metabolites acted as the porogens for a channel-like TiO2 precursor. Further processing of the precursor offered a channel-like meso/macroporous TiO2, a potential anode material for Li-ion battery. PMID- 24341682 TI - Analysis of seroreactivity against cell culture-derived Bartonella spp. antigens in dogs. AB - BACKGROUND: Little is known about the specificity of Bartonella spp. immunofluorescent antibody (IFA) assays in dogs. Bacteremia in sick dogs most often has been associated with Bartonella henselae (Bh), Bartonella vinsonii subspecies berkhoffii (Bvb), and Bartonella koehlerae (Bk). Clarification of the diagnostic utility of IFA serology when testing against these organisms is needed. OBJECTIVE: To evaluate the specificity of Bartonella IFA assays utilizing 6 cell culture-grown antigen preparations. ANIMALS: Archived sera from SPF dogs (n = 29) and from dogs experimentally infected with Bvb (n = 10) and Bh (n = 3). METHODS: Antibodies (Abs) to Bvb genotypes I, II, and III, Bh serotype I, strains H-1 and SA2, and to Bk were determined by IFA testing. RESULTS: Serum from naive SPF dogs shown to be negative for Bartonella bacteremia did not react with any of the 6 Bartonella antigens by IFA testing. Dogs experimentally infected with Bvb genotype I developed Abs against homologous antigens, with no cross-reactivity to heterologous Bvb genotypes, Bh H-1, SA2 strains, or to Bk. Dogs experimentally infected with Bh serotype I developed Abs against Bh H-1, but not to Bh SA2 strain with no cross-reactive Abs to Bvb genotypes I-III or to Bk. CONCLUSIONS AND CLINICAL IMPORTANCE: Bartonella spp. Ab responses during acute experimental infections are species and type specific. PMID- 24341684 TI - Crowding induced collective hydration of biological macromolecules over extended distances. AB - Ultrafast two-dimensional infrared (2D-IR) spectroscopy reveals picosecond protein and hydration dynamics of crowded hen egg white lysozyme (HEWL) labeled with a metal-carbonyl vibrational probe covalently attached to a solvent accessible His residue. HEWL is systematically crowded alternatively with polyethylene glycol (PEG) or excess lysozyme in order to distinguish the chemically inert polymer from the complex electrostatic profile of the protein crowder. The results are threefold: (1) A sharp dynamical jamming-like transition is observed in the picosecond protein and hydration dynamics that is attributed to an independent-to-collective hydration transition induced by macromolecular crowding that slows the hydration dynamics up to an order of magnitude relative to bulk water. (2) The interprotein distance at which the transition occurs suggests collective hydration of proteins over distances of 30-40 A. (3) Comparing the crowding effects of PEG400 to our previously reported experiments using glycerol exposes fundamental differences between small and macromolecular crowding agents. PMID- 24341686 TI - Therapeutic potential of spinal cord stimulation for gastrointestinal motility disorders: a preliminary rodent study. AB - BACKGROUND: Spinal cord electrical stimulation (SCS) has been applied for the management of chronic pain. Most of studies have revealed a decrease in sympathetic activity with SCS. The aim of this study was to investigate the effects and mechanisms of SCS on gastrointestinal (GI) motility in healthy and diabetic rats. METHODS: Male rats chronically implanted with a unipolar electrode at T9/T10 were studied. The study included four experiments to assess the effects of SCS on (1) gastric tone; (2) gastric emptying of liquids and intestinal transit; (3) gastric emptying of solids; and (4) sympathovagal balance in healthy rats and/or in Streptozotocin (STZ)-induced diabetic rat. KEY RESULTS: (1) Spinal cord stimulation intensity dependently increased gastric tone in healthy rats. The gastric volume was 0.97 +/- 0.15 mL at baseline, and decreased to 0.92 +/- 0.16 mL with SCS of the 30% motor threshold (MT; p = 0.13 vs baseline), 0.86 +/- 0.14 mL with 60% MT (p = 0.045 vs baseline), and 0.46 +/- 0.19 mL with 90% MT (p = 0.0050 vs baseline). (2) Spinal cord stimulation increased gastric emptying of liquids by about 17% and accelerated small intestinal transit by about 20% in healthy rats (p < 0.001). (3) Spinal cord stimulation accelerated gastric emptying of solids by about 24% in healthy rats and by about 78% in diabetic rats. (4) Spinal cord stimulation decreased sympathetic activity (1.13 +/- 0.18 vs 0.68 +/- 0.09, p < 0.04) and sympathovagal balance (0.51 +/- 0.036 vs 0.40 +/- 0.029, p = 0.028). CONCLUSIONS & INFERENCES: Spinal cord stimulation accelerates gastric emptying of liquids and solids, and intestinal transit, probably by inhibiting the sympathetic activity. Spinal cord stimulation may have a therapeutic potential for treating GI motility disorders. PMID- 24341685 TI - Three-dimensional spheroid-cultured mesenchymal stem cells devoid of embolism attenuate brain stroke injury after intra-arterial injection. AB - The therapeutic effect of mesenchymal stem cells (MSCs) in tissue repair/regeneration is substantially dampened by the loss of primitive properties and poor engraftment to target organs. In this study, the multipotency and cell sizes of human MSCs, which had been expanded in monolayer culture for several passages, were dramatically restored after an episode of three-dimensional (3D) spheroid culture. Unlike MSCs derived from monolayer, which caused embolism and blindness, MSCs derived from 3D spheroids did not cause vascular obstructions, after intra-carotid artery infusion in rats. Importantly, intra-carotid infusion of 1 million 3D spheroid MSCs in rats 24 h after middle cerebral artery occlusion and reperfusion resulted in engraftment of the cells into the lesion and significant (over 70%) reduction of infarct size along with restoration of neurologic function. Moreover, the enhanced effect of spheroid MSCs was coincided with significantly increased differentiation of the MSCs into neurons and markedly increased number of endogenous glial fibrillary acidic protein-positive neural progenitors in the peri-infarct boundary zone. However, the similarly administered monolayer MSCs resulted in a modest functional improvement. Our results suggest that 3D MSCs, in combination with intra-carotid delivery, may represent a novel therapeutic approach of MSCs for stroke. PMID- 24341687 TI - Predicting the final result in implant-supported fixed restorations for completely edentulous patients. AB - Predicting the final result is a very important factor in implant restorations. When a fixed implant-supported restoration is planned for the restoration of completely edentulous patients, it is important to recognize the esthetic performance of the prosthesis in the initial stages. Bone resorbtion may result in an unfavorable interarch relationship, and soft tissue support may be needed. A detailed presurgical evaluation (including tooth setup, construction of radiological and surgical guide) is needed to ensure the placement of implants in prosthetically favored positions. In this paper, a technique is presented where a detailed wax-up of the restoration is accomplished on provisional implant abutments and tried on the patient after implant placement. This setup may offer valuable information on the expected lip support and the need of gingiva-colored ceramic. In this way, the esthetic result can be evaluated at early stages before any irreversible laboratory stages are performed and needed corrections can be done accordingly. CLINICAL SIGNIFICANCE: In extended implant-supported fixed restorations, it is very important to predict the final esthetic result at an early stage. The presented technique allows a safe and accurate evaluation of the expected esthetic result before any construction stage. PMID- 24341688 TI - Towards novel anti-tumor strategies for hepatic cancer: E-viniferin in combination with vincristine displays pharmacodynamic synergy at lower doses in HepG2 cells. AB - Hepatocellular carcinoma is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. The efficacy of novel combination treatments are increasingly evaluated with use of integrative biology research and development (R&D) strategies and methodological triangulation. We investigated the anti-tumor effect of E-viniferin alone, and the putative synergy of E-viniferin with vincristine on the growth of HepG2 cells in vitro. Growth inhibition and apoptosis induction were determined by MTT assay and annexin V/propidium iodide (PI), respectively. Morphological changes and DNA fragmentation were investigated under electron microscopy and by agarose gel electrophoresis, respectively. The results collectively showed that treating cells with E-viniferin and vincristine significantly inhibited cell viability at lower doses as compared to each agent applied alone. IC(50) values for E viniferin and vincristine were determined as 98.3 and 52.5 MUM at 24 h, respectively. IC(50) value of E-viniferin in combination with vincristine was 15.8+11.25 MUM (mean/SD) at 24 h. The viability of cells treated with 17.9 MUM vincristine alone for 24 h was 79.62%; it reduced to 26.53% when 25 MUM E viniferin was added in combination with vincristine (p<0.05). We found that combination of drugs promoted the sensitivity of cells against to vincristine treatment. The effect of combined use was in support of a synergistic pharmacodynamic effect. Moreover, low doses of the combination regimen induced phosphatidyl re-localization, morphological changes, and DNA fragmentation, and therefore caused apoptotic death. This study thus suggests that low concentrations of E-viniferin and vincristine can enhance the anti-tumor effects efficiently by inducing HepG2 cell apoptosis. Further studies in other model systems are warranted with a view to potential future applications in the clinic of such combination regimens and their putative mechanism of action in the observed synergy reported here. PMID- 24341690 TI - Failure to recognise patients at the end of life in acute hospitals. PMID- 24341689 TI - Human papillomavirus proteins are found in peripheral blood and semen Cd20+ and Cd56+ cells during HPV-16 semen infection. AB - BACKGROUND: Human papillomavirus (HPV) currently represents an important risk factor for cancer development and infertility in humans. Whilst binding of HPV to spermatozoa has been associated with male infertility, an investigation about the presence of HPV-DNA in non-spermatozoal semen cells is lacking. Previous findings documented the presence of HPV in peripheral blood leukocytes. The aim of this study was to investigate the expression of HPV markers in semen and blood leukocytes during HPV-16 infection. METHODS: A total of 32 subjects, 16 patients affected by HPV-16 semen infection and 16 controls, were evaluated in our andrological centre and enrolled in the study. Semen non-spermatozoal cells from all subjects were isolated and evaluated for the expression of HPV-16 markers (DNA and L1, E6 proteins) and further characterized for their molecular phenotype. Analogue determination was performed on peripheral blood mononuclear cells. RESULTS: The presence of HPV-DNA by FISH analysis in a round cell population from semen, confirmed to be CD45+ leukocytes, was observed. These HPV DNA containing-cells also displayed HPV-16-E6 and HPV-16-L1 viral proteins and, upon further investigation, were found to be CD20+ and CD56+, likely phenotypes of B cells and natural killer cells (NK) respectively. In 25% of the patient group, a very small population of peripheral blood mononuclear cells was found to be positive for HPV-DNA via FISH. These cells displayed the CD20+ and CD56+ phenotype alike. None of the control subjects displayed HPV-DNA in either semen or peripheral blood. CONCLUSION: Considering the role of CD20+ and CD56+ cell populations in the antiviral immune response, the detection of HPV markers on leukocytes may reflect the presence of virus particles within the endosomal compartment. However, the presence of HPV markers in circulating mononuclear cells raise concerns about the risk of developing cancers to distal organs. PMID- 24341691 TI - The impact of age in intensive care. PMID- 24341692 TI - Fluid responsiveness predicted by elevation of PEEP in patients with septic shock. AB - BACKGROUND: The assessment of whether a patient is fluid responsive can be difficult in clinical practice. Invasive filling pressures are inadequate indicators of preload and fluid responsiveness in critically ill patients. Dynamic indices may be unreliable in clinical practice because of arrhythmias or spontaneous breathing efforts. Elevation of positive end-expiratory pressure (PEEP) causes cardiorespiratory interactions, which may produce signs of hypovolaemia. Our aim was to assess whether haemodynamic changes during a short elevation of PEEP would predict fluid responsiveness in patients with septic shock. METHODS: We performed a prospective observational study in 20 patients with septic shock on mechanical ventilation. We assessed the following changes in haemodynamic variables during a temporary elevation of PEEP from 10 cm H2O to 20 cm H2O during an end-expiratory pause: mean arterial pressure (MAP), systolic arterial pressure, pulse pressure, central venous pressure, pulmonary artery occlusion pressure, left ventricular end diastolic area and aortic velocity-time integral. We defined fluid responsiveness as an increase in cardiac output of 15% to a subsequent fluid challenge. RESULTS: Decrease in MAP related to elevation of PEEP predicted fluid responsiveness (P = 0.003). The best cut-off value of DeltaMAP for clinical use was -8%, with a negative predictive value for fluid responsiveness of 100%. CONCLUSION: In patients with septic shock, the absence of decrease in MAP during an elevation of PEEP may be used to identify patients who will not increase their cardiac output in response to fluid challenge. PMID- 24341693 TI - Circulating glycosaminoglycan species in septic shock. AB - BACKGROUND: Glycosaminoglycans (GAGs) are negatively charged polysaccharides present, e.g., on the luminal face of the blood vessels as heparan sulphate (HS) and hyaluronic acid (HA), in the interstitium as HA, and in neutrofils and plasma as chondroitin sulphate (CS) and HA. Total plasma levels of GAG are increased in human septic shock, but the origin and pathophysiological implications are unclear. In order to determine the source of circulating GAG in sepsis, we compared plasma levels of HS, HA, CS and keratan sulphate (KS) in patients with septic shock and controls. METHODS: HS and KS were measured with enzyme-linked immunosorbent assay, and HA and CS disaccharides with liquid chromatography tandem mass spectrometry in plasma obtained from patients admitted to intensive care fulfilling criteria for septic shock as well as from matched control patients scheduled for neurosurgery. RESULTS: Median levels of HS and HA were fourfold increased in septic shock and were higher in patients that did not survive 90 days (threefold and fivefold for HS and HA, respectively). Median CS levels were unaltered, while KS levels were slightly decreased in sepsis patients. HS and HA levels correlated with levels of interleukin-6 and interleukin-10. Except for HA, GAG levels did not correlate to liver or kidney sequential organ function score. CONCLUSION: Median plasma level of HS and HA is increased in septic shock patients, are higher in patients that do not survive, and correlates with inflammatory activation and failing circulation. The increased levels could be due to vascular damage. PMID- 24341694 TI - Pumpless extracorporeal CO(2) removal restores normocapnia and is associated with less regional perfusion in experimental acute lung injury. AB - BACKGROUND: Lung protective ventilation may lead to hypoventilation with subsequent hypercapnic acidosis (HA). If HA cannot be tolerated or occurs despite increasing respiratory rate or buffering, extracorporeal CO2-removal using a percutaneous extracorporeal lung assist (pECLA) is an option. We hypothesised that compensation of HA using pECLA impairs regional perfusion. To test this hypothesis we determined organ blood flows in a lung-injury model with combined hypercapnic and metabolic acidosis. METHODS: After induction of lung injury using hydrochloric acid (HCl) aspiration and metabolic acidosis by intravenous HCl infusion in nine pigs, an arterial-venous pECLA device was inserted. In randomised order, four treatments were tested: pECLA shunt (1) with and (2) without HA, and clamped pECLA shunt (3) with and (4) without HA. Regional blood flows were measured with the coloured microsphere technique. RESULTS: HA resulted in higher perfusion in adrenal glands, spleen and parts of splanchnic area (P < 0.05) compared with normocapnia. During CO2-removal with pECLA, regional perfusion decreased to levels comparable with those without pECLA and normocapnia. Cardiac output (CO) increased during HA without a pECLA shunt and was highest during HA with a pECLA shunt compared with normocapnia. During CO2 removal with pECLA, this variable decreased but stayed higher than during normocapnia with clamped pECLA shunt (P < 0.05). CONCLUSION: In our lung-injury model, HA was associated with increased systemic and regional blood flow in several organs. pECLA provides effective CO2 removal, requiring a higher CO for perfusion of the pECLA device without improvement of regional organ perfusion. PMID- 24341695 TI - Effects of early amiodarone administration during and immediately after cardiopulmonary resuscitation in a swine model. AB - BACKGROUND: Aim of this experimental study was to compare haemodynamic effects and outcome with early administration of amiodarone and adrenaline vs. adrenaline alone in pigs with prolonged ventricular fibrillation (VF). METHODS: After 8 min of untreated VF arrest, bolus doses were administered of adrenaline (0.02 mg/kg) and either amiodarone (5 mg/kg) or saline (n = 8 per group) after randomisation. Cardiopulmonary resuscitation (CPR) was commenced immediately after drug administration, and defibrillation was attempted 2 min later. CPR was resumed for another 2 min after each defibrillation attempt, and the same dose of adrenaline was given every 4th minute during CPR. Haemodynamic monitoring and mechanical ventilation continued for 6 h after return of spontaneous circulation (ROSC), and the pigs were euthanised at 48 h. Researchers were blinded for drug groups throughout the study. RESULTS: There was no difference in rates of ROSC and 48-h survival with amiodarone vs. saline (5/8 vs. 7/8 and 0/8 vs. 3/8, respectively). Diastolic aortic pressure and coronary perfusion pressure were significantly lower with amiodarone during CPR and 1 min after ROSC (P < 0.05). The number of electric shocks required for terminating VF, time to ROSC and adrenaline dose were significantly higher with amiodarone (P < 0.01). The incidence of post resuscitation tachyarrhythmias tended to be higher in the saline group (P = 0.081). CONCLUSION: Early administration of amiodarone did not improve ROSC or 48 h survival rates, and was associated with worse haemodynamics in this swine model of cardiac arrest. PMID- 24341696 TI - A word of warning when working in the Third World. PMID- 24341698 TI - Establishment of reporter platforms capable of detecting NF-kappaB mediated immuno-modulatory activity. AB - Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) are transcriptional targets of nuclear factor kappa B (NF-kappaB) that are involved in inflammatory responses. The aim of this study is to develop a method for efficiently detecting inflammation modulatory activities. Here we established RAW264.7 macrophage cells stably expressing a luciferase reporter gene directed by iNOS or COX-2 promoter. Lipopolysaccharide (LPS) treatment stimulated the luciferase activity which paralleled with increased iNOS and COX-2 mRNA levels determined by RT-q-PCR. The LPS-stimulated luciferase activity was blocked by NF kappaB inhibitor CAPE and by nobiletin, an anti-inflammatory natural product from citrus peels. We have applied the platforms to screen various mushroom species; analysis by scatter plot revealed a strong correlation to the results obtained by ELISA-based detection of TNF-alpha. Together we have established luciferase reporter systems sensitive to NF-kappaB-dependent iNOS and COX-2 activation, which provides an alternative screening method for identifying food components with immune-modulatory activities. PMID- 24341699 TI - BK virus nephropathy complicated with meningoencephalitis after kidney transplantation. AB - BK disease is an opportunistic infection in organ transplant recipients and patients with other cellular immunodeficiencies. To the best of our knowledge, we report the second case of BK meningoencephalitis associated with nephropathy in a kidney transplant recipient. A 15-yr-old boy underwent a cadaveric kidney transplant without complications; however, 11 wk after the transplantation, he was admitted to the hospital for graft dysfunction and cytopenia, which were confirmed by BK nephropathy (plasma viral replication and histological evidence). Four days after his hospital admission, he developed a high-grade fever and headache. CSF analysis revealed pleocytosis with a positive PCR for BK virus. Reduction in immunosuppression and supportive care conducting cycles of immunoglobulin and cidofovir were successful in treating the patient. BK meningoencephalitis should be considered in kidney transplant recipients who present with signs and symptoms of meningoencephalitis. PMID- 24341700 TI - Testicular effects of monensin, a golgi interfering agent in male rats. AB - OBJECTIVE: The present study was undertaken to explore the effects of monensin, a potent Golgi disturbing agent on male fertility. METHODS: Male Wistar rats were administered monensin at the dose levels of 2.5, 5, and 10 mg/kg b wt. Animals were sacrificed after 67 days of the treatment. The activities of lactate dehydrogenase (LDH), ATPase, acid phosphatase and thiamine pyrophosphatase (TPPase) were measured in the testis. Cytochemical assay of Golgi body marker enzyme, thiamine pyrophosphatase was also performed. Ultrastructural changes in testis were studied by Transmission electron microscopy. Sperm number and motility were also examined. RESULTS AND DISCUSSION: The alterations in the activities of above mentioned enzymes indicate the pronounced effect of the drug on the functioning of spermatogenic cells. The findings from electron microscopy such as membrane disruption, swelling and disintegration of Golgi apparatus strongly suggest the interference of monensin with the functioning of Golgi apparatus in the spermatogenic cells. Data from the sperm number and motility as well as the fertility studies and the resulted litter size further points towards the antifertility effects of monensin in male rats. CONCLUSION: The findings from the present study strongly indicated the effects of monensin on the testis, involving alterations in key enzyme activities and changes at the ultrastructural level. PMID- 24341701 TI - Prevalence of major cardiovascular risk factors and adverse risk profiles among three ethnic groups in the Xinjiang Uygur Autonomous Region, China. AB - BACKGROUND: Prevalence of cardiovascular disease (CVD) risk factors have been scarcely studied in Xinjiang, a multi-ethnic region. METHODS: Multi-ethnic, cross sectional cardiovascular risk survey study in Xinjiang, including individuals of Uygur (n = 4695), Han (n = 3717) and Kazakh (n = 3196) ethnicities, aged 35-74 years. Analyses involved 11,608 participants with complete data enrolled between October 2007 and March 2010. RESULTS: There were differences in age-standardized prevalence of CVD risk factors between the three groups (all P < 0.001). Hypertension, obesity and smoking rates were higher among Kazakh (54.6%, 24.5%, and 35.8%, respectively). Dyslipidemia prevalence was higher among Uygur (54.3%), and diabetes prevalence was higher among Hans (7.1%). Age-standardized prevalence of adverse CVD risk profiles was different across different ethnicities. Compared with the Han participants, the Uygur and Kazakh had more CVD risk factors (P < 0.001). Compared with the Han participants, the adjusted odds ratios of 1, 2, and >=3 risk factors profiles for Kazakh and Uygur participants were higher (all P < 0.001). CONCLUSIONS: The present study showed the pervasive burden of CVD risk factors in all participant groups in the Xinjiang region. Three major ethnic groups living in Xinjiang had striking differences in the prevalence of major CVD risk factors and adverse risk profiles. Ethnic-specific strategies should be developed to prevent CVD in different ethnic groups, as well as to develop strategies to prevent future development of adverse CVD risk factors at a younger age. PMID- 24341702 TI - Saponins from the roots of Platycodon grandiflorum suppresses TGFbeta1-induced epithelial-mesenchymal transition via repression of PI3K/Akt, ERK1/2 and Smad2/3 pathway in human lung carcinoma A549 cells. AB - Transforming growth factor beta (TGFbeta) is a multifunctional cytokine that induces growth arrest, tissue fibrosis, and epithelial-mesenchymal transition (EMT) through activation of Smad and non-Smad signaling pathways. EMT is the differentiation switch by which polarized epithelial cells differentiate into contractile and motile mesenchymal cells. Our previous studies have shown that saponins from the roots of Platycodon grandiflorum (CKS) have antiinflammatory, antioxidant, antimetastatic, and hepatoprotective effects. In this study, we investigated the inhibitory effect of CKS on TGFbeta1-induced alterations characteristic of EMT in human lung carcinoma A549 cells. We found that CKS treated cells displayed inhibited TGFbeta1-mediated E-cadherin downregulation and Vimentin upregulation and also retained epithelial morphology. Furthermore, TGFbeta1-increased Snail expression, a repressor of E-cadherin and an inducer of the EMT, was reduced by CKS. CKS inhibited TGFbeta1-induced phosphorylation of Akt, ERK1/2, and glycogen synthase kinase-3beta (GSK-3beta). Inhibition of PI3K/Akt and ERK1/2 also blocked TGFbeta1-induced GSK-3beta phosphorylation and Snail activation. Furthermore, TGFbeta1-increased Snail expression was reduced by selective inhibitors of Akt and ERK1/2. Moreover, CKS treatment attenuated TGFbeta1-induced Smad2/3 phosphorylation and upregulated Smad7 expression. These results indicate that pretreatment with the CKS inhibits the TGFbeta1-induced EMT through PI3K/Akt, ERK1/2, GSK-3beta and Smad2/3 in human lung carcinoma cells. PMID- 24341705 TI - Diffusion-controlled synthesis of PbS and PbSe quantum dots with in situ halide passivation for quantum dot solar cells. AB - We developed a simple non-hot-injection synthetic route that achieves in situ halide-passivated PbS and PbSe quantum dots (QDs) and simplifies the fabrication of Pb-chalcogenide QD solar cells. The synthesis mechanism follows a temperature dependent diffusion growth model leading to strategies that can achieve narrow size distributions for a range of sizes. We show that PbS QDs can be produced with a diameter as small as 2.2 nm, corresponding to a 1.7 eV band gap, while the resulting size distribution (6-7%) is comparable to that of hot-injection syntheses. The in situ chloride surface passivation is demonstrated by X-ray photoelectron spectroscopy and an improved photostability of both PbS and PbSe QDs when stored under air. Additionally, the photoluminescence quantum yield of the PbS QDs is ~30% higher compared to the traditional synthesis. We show that PbS QD solar cells with 6.5% power conversion efficiency (PCE) can be constructed. Finally, we fabricated PbSe QD solar cells in air (rather than in inert atmosphere), achieving a PCE of 2.65% using relatively large QDs with a corresponding band gap of 0.89 eV. PMID- 24341704 TI - Role of dermatomes in the determination of therapeutic characteristics of channel acupoints: a similarity-based analysis of data compiled from literature. AB - BACKGROUND: Analysis of the relationship between the nervous system anatomy and the therapeutic characteristics of all acupuncture points in the channel network may provide new insights on the physiological mechanisms underlying acupuncture stimulation for prevention, treatment, and rehabilitation purposes. This study investigates the association between the similarity of acupoints' dermatomes, traditional actions, and contemporary indications. METHODS: CHANNEL ACUPOINTS HAD THEIR CHARACTERISTICS ANNOTATED FROM A LITERATURE REVIEW OF FOUR TOPOGRAPHIC ATLASES OF CHINESE MEDICINE AND ONE ATLAS OF HUMAN ANATOMY: initials of the channel's name (n = 14), sequential number in the channel (n = 67), acupoint's name (n = 361), dermatomes related to perpendicular needle insertion (n = 31), traditional actions (n = 848), and contemporary indications (n = 1143). Jaccard's similarity coefficient quantified the similarities between dual acupoints. All dual acupoints were evaluated to generate similarity matrices for each nominal variable. Cross-tables were generated by simultaneous classification of variables into levels of similarity with respect to: dermatomes versus traditional actions, dermatomes versus contemporary indications, and traditional actions versus contemporary indications. Goodman-Kruskal gamma and Rousson gamma*(2) were calculated based on cross-tables, bootstrap and permutated samples to evaluate the association and determination coefficient between variables, respectively. RESULTS: Significant associations were observed between levels of similarities of dermatomes and traditional actions (gamma = 0.542; P < 0.001), dermatomes and contemporary indications (gamma = 0.657; P < 0.001), and traditional actions and contemporary indications (gamma = 0.716; P < 0.001). Similarities of dermatomes explained 16% of the variance of traditional actions and 25% of contemporary indications. Traditional actions explained 30% of the variance of contemporary indications. The association between traditional actions and contemporary indications was the highest one (gamma = 0.716, 95% confidence interval (95% CI) = [0.715; 0.719]), followed by the association between dermatomes and contemporary indications (gamma = 0.622, 95% CI = [0.621; 0.623]), and between dermatomes and traditional actions (gamma = 0.446, 95% CI = [0.444; 0.447]), all with P < 0.001. CONCLUSIONS: The similarity of dermatomes between dual acupoints partially determined the similarity of traditional actions and contemporary indications, therefore dermatomes partially determine the therapeutic efficacy of acupuncture. PMID- 24341706 TI - Hypogammaglobulinemia factitia- Munchausen syndrome masquerading as common variable immune deficiency. AB - BACKGROUND: We describe the first case of a patient with factitious disorder who closely simulated a primary immune deficiency disorder - Common Variable Immune Deficiency (CVID), by surreptitiously ingesting non-steroidal anti-inflammatory agents. CASE DESCRIPTION: He was treated with several expensive and potentially dangerous drugs before the diagnosis was established through collateral information. In retrospect he did not meet the proposed new criteria for CVID. These criteria may prove useful in distinguishing cases of CVID from secondary hypogammaglobulinemia. CONCLUSION: It is imperative clinicians recognise patients with factitious disorder at the earliest opportunity to prevent iatrogenic morbidity and mortality. PMID- 24341703 TI - Obese parents--obese children? Psychological-psychiatric risk factors of parental behavior and experience for the development of obesity in children aged 0-3: study protocol. AB - BACKGROUND: The incidences of childhood overweight and obesity have increased substantially and with them the prevalence of associated somatic and psychiatric health problems. Therefore, it is important to identify modifiable risk factors for early childhood overweight in order to develop effective prevention or intervention programs. Besides biological factors, familial interactions and parental behavioral patterns may influence children's weight development. Longitudinal investigation of children at overweight risk could help to detect significant risk and protective factors. We aim to describe infants' weight development over time and identify risk and protective factors for the incidence of childhood obesity. Based on our findings we will draw up a risk model that will lay the foundation for an intervention/prevention program. METHODS/DESIGN: We present the protocol of a prospective longitudinal study in which we investigate families with children aged from 6 months to 47 months. In half of the families at least one parent is obese (risk group), in the other half both parents are normal weight (control group). Based on developmental and health psychological models, we consider measurements at three levels: the child, the parents and parent-child-relationship. Three assessment points are approximately one year apart. At each assessment point we evaluate the psychological, social, and behavioral situation of the parents as well as the physical and psychosocial development of the child. Parents are interviewed, fill in questionnaires, and take part in standardized interaction tasks with their child in a feeding and in a playing context in our research laboratory. The quality of these video-taped parent-child interactions is assessed by analyzing them with standardized, validated instruments according to scientific standards. DISCUSSION: Strengths of the presented study are the prospective longitudinal design, the multi-informant approach, including the fathers, and the observation of parent-child interaction. A limitation is the variation in children's age. PMID- 24341707 TI - Dissociation of memory systems: The story unfolds. AB - In this article we describe the ideas and circumstances that led to the experiment demonstrating a triple dissociation of memory systems. We then move on to discuss the results of 20 years of investigation of those ideas. First, evidence is described from animal studies consistent with the ideas that memory for different kinds of information is stored in different brain systems, and that the hippocampus, amygdala, and dorsal striatum are each central structures in one of the systems. We then focus on the 3 tasks used in the original triple dissociation: win-stay learning, conditioned cue preference, and win-shift learning. Each of these tasks is specific to behavior resulting from the type of information stored in one of the systems, but the use of other behavioral tests that are sensitive to the types of information stored in other systems has revealed that, in each case, other types of information are acquired in parallel. Next, evidence consistent with the idea that the outputs of the systems compete for control of behavior is discussed together with alternative forms of more direct interactions among the systems. Finally, some evidence that many of these ideas about multiple parallel memory systems may apply to humans is reviewed. PMID- 24341708 TI - A triple dissociation of memory systems: Hippocampus, amygdala, and dorsal striatum. AB - This study investigated the respective roles of the hippocampus, the amygdala, and the dorsal striatum in learning and memory. A standard set of experimental conditions for studying the effects of lesions to the three brain areas using an 8-arm radial maze was used: a win-shift version, a conditioned cue preference (CCP) version, and a win-stay version. Damage to the hippocampal system impaired acquisition of the win-shift task but not the CCP or win-stay tasks. Damage to the lateral amygdala impaired acquisition of the CCP task but not the win-shift or win-stay tasks. Damage to the dorsal striatum impaired acquisition of the win stay task but not the win-shift or CCP tasks. These results are consistent with the hypothesis that the mammalian brain may be capable of acquiring different kinds of information with different, more-or-less independent neural systems. A neural system that includes the hippocampus may acquire information about the relationships among stimuli and events. A neural system that includes the amygdala may mediate the rapid acquisition of behaviors based on biologically significant events with affective properties. A neural system that includes the dorsal striatum may mediate the formation of reinforced stimulus-response associations. PMID- 24341709 TI - Immediate response strategy and shift to place strategy in submerged T-maze. AB - A considerable amount of research has demonstrated that animals can use different strategies when learning about, and navigating within, their environment. Since the influential research of Packard and McGaugh (1996), it has been widely accepted that, early in learning, rats use a flexible dorsal hippocampal dependent place strategy. As learning progresses, they switch to a less effortful and more automatic dorsolateral caudate-dependent response strategy. However, supporting literature is dominated by the use of appetitively motivated tasks, using food reward. Because motivation often plays a crucial role in guiding learning, memory, and behavior, we examined spatial learning strategies of rats in an escape-motivated submerged T-maze. In Experiment 1, we observed rapid learning and the opposite pattern as that reported in appetitively motivated tasks. Rats exhibited a response strategy early in learning before switching to a place strategy, which persisted over extensive training. In Experiment 2, we replicated Packard and McGaugh's (1996) observations, using the apparatus and procedures as in Experiment 1, but with food reward instead of water escape. Mechanisms for, and implications of, this motivational modulation of spatial learning strategy are considered. PMID- 24341710 TI - Transient inactivation of the thalamic nucleus reuniens and rhomboid nucleus produces deficits of a working-memory dependent tactile-visual conditional discrimination task. AB - Working memory depends on communication between the hippocampus and the prefrontal cortex (PFC); however, the neural circuitry that mediates interactions between these brain areas has not been well characterized. Two candidate structures are the thalamic reuniens (RE) and rhomboid (Rh) nuclei, which are reciprocally connected with both the hippocampus and PFC. These known anatomical connections suggest that RE/Rh may be involved in mediating hippocampal prefrontal communication, and therefore may be critical for working memory processing. To test the hypothesis that RE/Rh are necessary for working memory, we trained separate groups of rats to perform 1 of 2 tasks in a T-maze. The first task was a working memory-dependent conditional discrimination (CDWM) task, and the second task was a nonworking memory-dependent conditional discrimination (CD) task. These tasks took place in the same maze, featured the same number of trials, and utilized the same cue (a tactile-visual maze insert). After rats had learned either task, RE/Rh were transiently inactivated with the GABAA receptor agonist muscimol, and performance was assessed. RE/Rh inactivation caused performance deficits on the CDWM task, but not the CD task. This result suggests that RE/Rh are a necessary component of working memory task performance, which is also thought to depend on the hippocampal-prefrontal circuit. RE/Rh inactivation did not cause a performance deficit on the CD task, suggesting that RE/Rh have dissociable contributions to working memory-dependent and nonworking memory dependent tasks, independently of the known contributions of these 2 thalamic nuclei to the sensorimotor and attention-related aspects of other memory tasks. PMID- 24341711 TI - The effects of bilateral lesions to the dorsal tegmental nucleus on spatial learning in rats. AB - The head-direction (HD) signal is believed to originate in the dorsal tegmental nucleus (DTN) and lesions to this structure have been shown to disrupt HD cell firing in other areas along the HD cell circuit. To investigate the role of the DTN in spatial navigation, rats with bilateral, electrolytic (Experiment 1), or neurotoxic (Experiment 2) lesions to the DTN were compared with sham controls on two tasks that differed in difficulty and could be solved using directional heading. Rats were first trained on a direction problem in a water T maze where they learned to travel either east or west from two locations in the experimental room. DTN-lesioned rats were impaired relative to sham controls, both early in training, on the first block of eight trials, and on the total trials taken to reach criterion. In the food-foraging task, rats were trained to leave a home cage at the periphery of a circular table, find food in the center of the table and return to the home cage. Again, DTN-lesioned rats were impaired relative to sham rats, making more errors on the return component of the foraging trip. These data extend previous cell-recording studies and behavioral tests in which rats with electrolytic DTN lesions were used, and they demonstrate the importance of the direction system to spatial learning. PMID- 24341712 TI - Effective treatment of eating disorders: Results at multiple sites. AB - We report the results of a study based on 1,428 patients with eating disorders treated at 6 clinics. These patients were consecutively referred over 18 years and used inpatient and outpatient treatment. The subjects were diagnosed with anorexia nervosa, bulimia nervosa, or an eating disorder not otherwise specified. Patients practiced a normal eating pattern with computerized feedback technology, they were supplied with external heat, their physical activity was reduced, and their social habits restored to allow them to return to their normal life. The estimated rate of remission for this therapy was 75% after a median of 12.5 months of treatment. A competing event such as the termination of insurance coverage, or failure of the treatment, interfered with outcomes in 16% of the patients, and the other patients remained in treatment. Of those who went in remission, the estimated rate of relapse was 10% over 5 years of follow-up and there was no mortality. These data replicate the outcomes reported in our previous studies and they compare favorably with the poor long-term remission rates, the high rate of relapse, and the high mortality rate reported with standard treatments for eating disorders. PMID- 24341713 TI - Dissociation of thirst and sodium appetite in the furo/cap model of extracellular dehydration and a role for N-methyl-D-aspartate receptors in the sensitization of sodium appetite. AB - Depletion of extracellular fluids motivates many animals to seek out and ingest water and sodium. Animals with a history of extracellular dehydration display enhanced sodium appetite and, in some cases, thirst. The progressive increase in sodium intake induced by repeated sodium depletions is known as sensitization of sodium appetite. Administration of the diuretic and natriuretic drug, furosemide, along with a low dose of captopril (furo/cap), elicits thirst and a rapid onset of sodium appetite. In the present studies the furo/cap model was used to explore the physiological mechanisms of sensitization of sodium appetite. However, when thirst and sodium appetite were measured concurrently in the furo/cap model, individual rats exhibited sensitization of either thirst or sodium appetite. In subsequent studies, thirst and sodium appetite were dissociated by offering either water prior to sodium or sodium before water. When water and sodium intake were dissociated in time, the furo/cap model reliably produced sensitization of sodium appetite. It is likely that neuroplasticity mediates this sensitization. Glutamatergic N-methyl-d-aspartate receptor (NMDA-R) activation is critical for the development of most forms of neuroplasticity. Therefore, we hypothesized that integrity of NMDA-R function is necessary for the sensitization of sodium appetite. Pharmacological blockade of NMDA-Rs with systemic administration of MK 801 (0.15 mg/kg) prevented the sensitization of fluid intake in general when water and sodium were offered concurrently, and prevented sensitization of sodium intake specifically when water and sodium intake were dissociated. The involvement of NMDA-Rs provides support for the possibility that sensitization of sodium appetite is mediated by neuroplasticity. PMID- 24341714 TI - The discriminative stimulus effects of a nicotine-ethanol compound in rats: Extinction with the parts differs from the whole. AB - Nicotine and ethyl alcohol (EtOH) interact neurophysiologically and induce internal sensory states that contribute to their coabuse. Evaluating the combined internal sensory effects of nicotine and alcohol may be important for understanding this nexus. With rats, this investigation used an operant drug discrimination procedure to establish discriminative stimulus control with a mixture of nicotine plus EtOH (NE) at doses of nicotine (0.3 mg/kg) and EtOH (1.0 g/kg) that have previously been shown to be equally salient (Gauvin & Holloway, 1993). In Experiment (Exp) 1 the NE compound mixture continued to evoke responding despite extinction of responding with nicotine and EtOH alone. In Exp 2 the NE mixture was reliably discriminated from the nicotine and EtOH elements. Experiment 3 showed that the discriminative functions of the NE mixture emerged when the nicotine and EtOH elements were combined following their initial establishment as separate discriminative stimuli; however, nicotine evoked more control than EtOH. Extinction of responding with the NE mixture impacted rates of responding with nicotine and EtOH alone. The results of the all three studies parallel findings with exteroceptive Pavlovian literature in showing that extinction of responding with the elemental parts does not appear to impact the whole-but, extinction with the whole appears to affect its parts. The multielement discriminative function of a NE mixture appears to be a "unique cue" that differs qualitatively from nicotine or EtOH alone. Associative factors related to compound conditioning (i.e., configural learning) play an important role in mediating the discriminative functions of drug mixtures. PMID- 24341715 TI - The effects of parity and maternal behavior on gene expression in the medial preoptic area and the medial amygdala in postpartum and virgin female rats: A microarray study. AB - To determine the pattern of gene expression in brains associated with mothering during the postpartum period, in the present study we assessed gene expression through microarrays in four groups of female rats: two groups of new mothers that were experiencing the hormonal and neurochemical changes associated with pregnancy and parturition, and two groups of virgin females that were not. Within each of these parity groups we assessed one group of animals that was exposed to and responded to pups and engaged in maternal behavior, and one group left without any exposure to pups and therefore had no maternal experience. We explored the pattern of expression of genes related to the hormones, neurotransmitters, and modulatory neuropeptides associated with maternal behavior within the medial preoptic area (MPOA) and the medial amygdala (MeA) in the rat. Within the MPOA there were significant main effects of pup exposure for the dopamine-related genes (DRD4 and dopamine transporter, DAT), the glucocorticoid related gene (CYPX1B1a), the opioid receptor MU-1 gene (OPRM1) and the gamma aminobutyric acid (GABA) receptor gene (GABAbRid). OPRM1 and the serotonin related gene that regulates biosynthesis of serotonin (5HTR2A) showed a main effect of parity. For both sets of analyses, higher gene expression was associated with pup exposure and parity. Genes expressed in the MeA tended to reside in the glucocorticoid family. The microarrays were able to identify, on a transcriptional level, a list of candidate genes involved in maternal behavior and the factors that surround it. PMID- 24341716 TI - 17beta-estradiol enhances memory duration in the main olfactory bulb in CD-1 mice. AB - Rodents rely heavily on odor detection, discrimination, and memory to locate food, find mates, care for pups, and avoid predators. Estrogens have been shown to increase memory retention in rodents performing spatial memory and object placement tasks. Here we evaluate the extent to which 17beta-estradiol modulates memory formation and duration in the olfactory system. Adult CD-1 mice were gonadectomized and given either systemic 17beta-estradiol replacement, local 17beta-estradiol in the main olfactory bulb, or no replacement. Before performing the behavioral task the mice were given saline or PHTPP (an estrogen receptor beta [ER-beta] antagonist) via bilateral infusion into the main olfactory bulb. As the beta-type estrogen receptor (ER-beta) is more abundant than the alpha-type estrogen receptor in the murine main olfactory bulb, the current study focuses on 17beta-estradiol and its interactions with ERbeta. Habituation, a simple, nonassociative learning task in which an animal is exposed to the same odor over successive presentations, was used to evaluate the animals' ability to detect odors and form an olfactory memory. To evaluate memory duration, we added a final trial of intertrial interval time (30 or 60 min) in which we presented the habituated odor. Neither surgical nor drug manipulation affected the ability of mice to detect or habituate to an odor. After habituation, gonadectomized 17beta estradiol-treated mice retained memory of an odor for 30 min, whereas non estradiol-treated, 17beta-estradiol+ERbeta antagonist (PHTPP), and untreated male mice did not remember an odor 30 min after habituation. The results show that both systemic and local bulbar infusions of 17beta-estradiol enhance odor memory duration in mice. PMID- 24341717 TI - Differential facilitative effects of glucose administration on Stroop task conditions. AB - Previous research has demonstrated that glucose administration improves memory performance. These glucose facilitation effects have been most reliably demonstrated in medial temporal lobe tasks with the greatest effects found for cognitively demanding tasks. The aim of the proposed research was to first explore whether such effects might be demonstrated in a frontal lobe task. A second aim was to investigate whether any beneficial effects of glucose may arise more prominently under tasks of increasing cognitive demand. To achieve these aims, the Stroop Task was administered to participants and effects of a drink of glucose (25 g) were compared with an aspartame-sweetened control drink on performance in young adults. Results demonstrated that glucose ingestion significantly reduced RTs in the congruent and incongruent conditions. No effect on error rates was observed. Of most importance was the finding that this glucose facilitative effect was significantly greatest in the most cognitively demanding task, that is, the incongruent condition. The present results support the contention that the glucose facilitation effect is most robust under conditions of enhanced task difficulty and demonstrate that such benefits extend to frontal lobe function. PMID- 24341718 TI - Acceleration of image analyst training with transcranial direct current stimulation. AB - Humans today are routinely and increasingly presented with vast quantities of data that challenge their capacity for efficient processing. To restore the balance between man and machine, it is worthwhile to explore new methods for enhancing or accelerating this capacity. This study was designed to investigate the efficacy of transcranial DC stimulation (tDCS) to reduce training time and increase proficiency in spatial recognition using a simulated synthetic aperture radar (SAR) task. Twenty-seven Air Force active duty members volunteered to participate in the study. Each participant was assigned to 1 of 3 stimulation groups and received two, 90-min training sessions on a target search and identification task using SAR imagery followed by a test. The tDCS anode was applied to site F10 according to the 10-20 electroencephalographic electrode convention while the cathode was placed on the contralateral bicep. Group 1 received anodal tDCS at 2 mA for 30 min in the first training session and sham tDCS in the second session. Group 2 received the stimulation conditions in the opposite order. Group 3 did not receive stimulation at all. Results showed that participants receiving training plus tDCS attained visual search accuracies ~25% higher than those provided with sham stimulation or no stimulation. However, a corresponding performance improvement was not found in the first training session for the change detection portion of the task. This indicates that experience with the imagery is important in the tDCS-elicited performance improvements in change detection. PMID- 24341719 TI - Defining characteristics of early adopters of multimodality cardiovascular imaging. AB - BACKGROUND: The prototype for the cardiovascular imager has evolved to necessitate some degree of competency in multimodality imaging (MMI)-defined as expertise in at least 2 of the 4 modalities (echocardiography [ECHO], nuclear cardiology [NUC], cardiovascular computed tomography [CCT], and magnetic resonance [CMR]). Uncertainty exists about the effects of this change. METHODS: Information detailing the current totals of board-certified practitioners in MMI was collected and organized into groups of 1, 2, and 3 modalities. A randomized stratified sample of names was obtained to identify a representative 10% of each group. Those names were cross-referenced online with information from state medical boards, faculty rosters of academic medical centers, and physician tracking Websites. RESULTS: There are a total of 2209 board-certified MMI practitioners (2 modalities = 1885, 3 modalities = 324) and 6450 single-modality imagers in the United States. Of those sampled, 98.9% were cardiologists, 31.3% were at academic medical centers and mean time from medical school graduation was 17.75 years. MMI practitioners were more likely to have graduated from medical school more recently (P < 0.0001) and to be trained cardiologists (P = 0.003) than those who practice in a single modality. There was a nonsignificant trend toward MMI being practiced more commonly in an academic setting (P = 0.38). CONCLUSION: Board-certified specialists in MMI tend to be younger cardiologists than those engaged in single-modality cardiac imaging. There are few advanced (3 modality) MMI practitioners in the United States. PMID- 24341720 TI - Influence of pyrene grafting on PMMA nanosecond laser ablation at 248 nm. AB - In this work, we investigate the effects of KrF nanosecond laser ablation on poly(methyl methacrylate) (PMMA) in combination with pyrene. Three materials containing PMMA were studied: (1) one doped with pure pyrene, (2) one doped with methyl 3-(1-pyrenyl)propanoate (so called alkylpyrene derivative thereafter), and (3) one grafted with pyrene. This last new material was developed by covalently bonding pyrene molecules to PMMA side-chains. A comparative study was undertaken to determine and compare the respective properties of the PMMA dye containing pyrene during nanosecond laser ablation at 248 nm. Cavities were etched for each material with up to 20 pulses for fluences between 0.03 and 1.7 J/cm(2) in samples containing 1, 2, and 4 mol % chromophore. The threshold fluences and the effective absorption coefficients were obtained. It was observed that effective absorption coefficients increased and threshold fluences decreased with the chromophore percentages in each kind of sample. Ablation parameters were not significantly modified when the dopant was changed from pyrene to the alkylpyrene derivative. On the other hand, when pyrene molecules were grafted on the polymer, the threshold fluences decreased, whereas the effective absorption coefficients became similar at fluences above 0.6 J/cm(2). PMID- 24341721 TI - Multibubble sonoluminescence in ethylene glycol/water mixtures. AB - The multibubble sonoluminescence (MBSL) signals generated by 3.5 ms pulses of 515 kHz ultrasound in air-saturated ethylene glycol, water, and ethylene glycol/water mixtures were examined in the absence and presence of a range of solutes, including aliphatic alcohols of various chain lengths (C3-C6) and ionic and zwitterionic surfactants. In general, the alcohols quenched the SL in most solvent mixtures and the surfactants enhanced the sonoluminescence signal. However, in some solvent mixtures complex effects were observed in the presence of the solutes. The discussion presented rationalizes the varied behavior of the solutes on the MBSL observed in terms of their influence on inter- and intrabubble effects experienced by bubbles in an ultrasound field. PMID- 24341722 TI - Comparison of site-specific PEGylations of the N-terminus of interferon beta-1b: selectivity, efficiency, and in vivo/vitro activity. AB - PEGylation, including nonspecific and site-directed approaches, is a well established and validated strategy to increase the stability, in vivo plasma retention time, and efficacy of protein pharmaceutics together with a reduction in immunogenicity and hydrophobicity. Site-directed conjugation by PEG-aldehyde is the most widely used method for N-terminal modification; however, the generation of multimodified products is inevitable because of lysine chemistry, which always leads to difficulties in purification and quantification. In this study, we developed a specific PEGylation strategy through the periodation of the N-terminus of interferon beta-1b (IFN-beta-1b) followed by the coupling of PEG hydrazide. The prolonged elimination half-life and significantly diminished immunogenicity of the PEG-hydrazide-modified protein indicated the development of an effective process for improving the pharmacology and immunogenicity of IFN beta-1b. We further conducted comparisons on the selectivity, velocity, yield, and pharmacokinetics of the two methods. The results demonstrated that the hydrazide-based conjugation was a highly specific coupling reaction that only produced homogeneous N-terminal mono-PEGylated conjugate but also generated heterogeneous multimodified products in the aldehyde-based process. In addition, a better PEGylation yield was found for the hydrazide conjugation compared with that of the aldehyde strategy. These investigations supply a practical approach for the site-specific modification of proteins with an N-terminal serine or threonine to achieve improved homogeneity of the conjugates as well as enhanced pharmacological properties. PMID- 24341724 TI - Scale-up of hydrophobin-assisted recombinant protein production in tobacco BY-2 suspension cells. AB - Plant suspension cell cultures are emerging as an alternative to mammalian cells for production of complex recombinant proteins. Plant cell cultures provide low production cost, intrinsic safety and adherence to current regulations, but low yields and costly purification technology hinder their commercialization. Fungal hydrophobins have been utilized as fusion tags to improve yields and facilitate efficient low-cost purification by surfactant-based aqueous two-phase separation (ATPS) in plant, fungal and insect cells. In this work, we report the utilization of hydrophobin fusion technology in tobacco bright yellow 2 (BY-2) suspension cell platform and the establishment of pilot-scale propagation and downstream processing including first-step purification by ATPS. Green fluorescent protein hydrophobin fusion (GFP-HFBI) induced the formation of protein bodies in tobacco suspension cells, thus encapsulating the fusion protein into discrete compartments. Cultivation of the BY-2 suspension cells was scaled up in standard stirred tank bioreactors up to 600 L production volume, with no apparent change in growth kinetics. Subsequently, ATPS was applied to selectively capture the GFP HFBI product from crude cell lysate, resulting in threefold concentration, good purity and up to 60% recovery. The ATPS was scaled up to 20 L volume, without loss off efficiency. This study provides the first proof of concept for large scale hydrophobin-assisted production of recombinant proteins in tobacco BY-2 cell suspensions. PMID- 24341723 TI - Genome comparison of two Magnaporthe oryzae field isolates reveals genome variations and potential virulence effectors. AB - BACKGROUND: Rice blast caused by the fungus Magnaporthe oryzae is an important disease in virtually every rice growing region of the world, which leads to significant annual decreases of grain quality and yield. To prevent disease, resistance genes in rice have been cloned and introduced into susceptible cultivars. However, introduced resistance can often be broken within few years of release, often due to mutation of cognate avirulence genes in fungal field populations. RESULTS: To better understand the pattern of mutation of M. oryzae field isolates under natural selection forces, we used a next generation sequencing approach to analyze the genomes of two field isolates FJ81278 and HN19311, as well as the transcriptome of FJ81278. By comparing the de novo genome assemblies of the two isolates against the finished reference strain 70-15, we identified extensive polymorphisms including unique genes, SNPs (single nucleotide polymorphism) and indels, structural variations, copy number variations, and loci under strong positive selection. The 1.75 MB of isolate specific genome content carrying 118 novel genes from FJ81278, and 0.83 MB from HN19311 were also identified. By analyzing secreted proteins carrying polymorphisms, in total 256 candidate virulence effectors were found and 6 were chosen for functional characterization. CONCLUSIONS: We provide results from genome comparison analysis showing extensive genome variation, and generated a list of M. oryzae candidate virulence effectors for functional characterization. PMID- 24341725 TI - Radical prostatectomy: initial experience with robot-assisted laparoscopic procedures at a large university hospital. AB - OBJECTIVE: The aim of this study was to compare oncological and functional outcomes between robot-assisted laparoscopic radical prostatectomy (RALP) and retropubic radical prostatectomy (RRP) during the initial phase with RALP at a large university hospital. MATERIAL AND METHODS: Patient and tumour characteristics, surgeon, nerve sparing, surgical margins and blood loss were recorded prospectively in patients who underwent RRP or RALP between April 2008 and May 2012. Patients filled out the Danish Prostate Symptom Score (DAN-PSS) and International Index of Erectile Function 5 (IIEF-5) questionnaires before surgery and at follow-up and they were asked to report their use of pads/diapers. Potency was defined as an IIEF-5 score of at least 17 with or without phosphodiesterase-5 inhibitors. Patients using up to one pad daily for security reasons only were considered continent. Positive surgical margins, blood loss and functional outcomes were compared between groups. RESULTS: Overall, 453 patients were treated with RRP and 585 with RALP. On multivariate logistic regression analyses, the type of surgery did not affect surgical margins (p = 0.96) or potency at 12 months (p = 0.7). Patients who had undergone RRP had an increased chance of reporting subjective continence at 12 months (odds ratio 2.6, p = 0.014). There was no difference in the proportion of RRP and RALP patients who underwent surgical treatment for incontinence (p = 0.57). On multivariate linear regression analysis, RALP was an independent predictor of a low perioperative blood loss (RRP:RALP ratio = 2.89, p < 0.0001). CONCLUSIONS: RALP is a safe procedure with regard to perioperative and oncological results. However, it is important to be aware that functional outcomes may be compromised in the initial phase when introducing RALP. PMID- 24341726 TI - Trust-level risk evaluation and risk control guidance in the NHS East of England. AB - In recent years, the healthcare sector has adopted the use of operational risk assessment tools to help understand the systems issues that lead to patient safety incidents. But although these problem-focused tools have improved the ability of healthcare organizations to identify hazards, they have not translated into measurable improvements in patient safety. One possible reason for this is a lack of support for the solution-focused process of risk control. This article describes a content analysis of the risk management strategies, policies, and procedures at all acute (i.e., hospital), mental health, and ambulance trusts (health service organizations) in the East of England area of the British National Health Service. The primary goal was to determine what organizational level guidance exists to support risk control practice. A secondary goal was to examine the risk evaluation guidance provided by these trusts. With regard to risk control, we found an almost complete lack of useful guidance to promote good practice. With regard to risk evaluation, the trusts relied exclusively on risk matrices. A number of weaknesses were found in the use of this tool, especially related to the guidance for scoring an event's likelihood. We make a number of recommendations to address these concerns. The guidance assessed provides insufficient support for risk control and risk evaluation. This may present a significant barrier to the success of risk management approaches in improving patient safety. PMID- 24341727 TI - Characterization of focused seepage through an earthfill dam using geoelectrical methods. AB - Resistivity and self-potential tomography can be used to investigate anomalous seepage inside heterogeneous earthen dams. The self-potential (SP) signals provide a unique signature to groundwater flow because the source current density responsible for the SP signals is proportional to the Darcy velocity. The distribution of the SP signals is also influenced by the distribution of the resistivity; therefore, resistivity and SP need to be used in concert to elucidate groundwater flow pathways. In this study, a survey is conducted at a small earthen dam in Colorado where anomalous seepage is observed on the downstream face at the dam toe. The data reveal SP and direct current resistivity anomalies that are used to delineate three anomalous seepage zones within the dam and to estimate the source of the localized seepage discharge. The SP data are inverted in two dimensions using the resistivity distribution to determine the distribution of the Darcy velocity responsible for the observed seepage. The inverted Darcy velocity agrees with an estimation of the Darcy velocity from the hydraulic conductivity obtained from a slug test and the observed head gradient. PMID- 24341728 TI - Association between ghrelin gene (Leu72Met) polymorphism and ghrelin serum level with coronary artery diseases. AB - Research shows that ghrelin gene polymorphism has some association with coronary artery diseases (CAD). Due to genetic differences among nations and the high prevalence of CAD, we conducted this study to examine the possible association between the polymorphism of ghrelin gene Leu72Met and CAD among an Iranian population. This case-control study was undertaken with patients who were referred to referral heart center, in 2011, with chest pain or a positive exercise test. Patients with risk factors for heart disease or who were surgery candidates, who underwent angiography and echocardiography, were also included. DNA extractions were performed using a modified salting out method, and the ghrelin region was amplified using polymerase chain reaction. The presence of the Leu72Met polymorphism and the serum levels of ghrelin were determined using the restriction fragment length polymorphism method and the enzyme-linked immunosorbent assay, respectively. The results indicated that in CAD patients, the incidence of heart failure was significantly different between the groups with genotypes CC or AA+CA (p=0.041). Mean serum level of ghrelin in the CAD group was significantly higher than that in the control group (p<0.0001). Additionally, there was a significant relationship between the distribution of ghrelin genotypes and serum levels of ghrelin in both the CAD and control groups (p<0.0001). This study indicates that there was a significant association between heart failure in CAD patients and the presence of the polymorphism, as well as an increase in serum levels of ghrelin associated with genotype distribution such that ghrelin levels have an inverse relationship with the frequency of the CC genotype. PMID- 24341729 TI - Plasma and erythrocyte glutathione peroxidase activity, serum selenium concentration, and plasma total antioxidant capacity in cats with IRIS stages I IV chronic kidney disease. AB - BACKGROUND: Serum selenium concentrations and the activity of plasma glutathione peroxidase (GPx) decrease with the progression of chronic kidney disease (CKD) in human patients. Selenium is considered a limiting factor for plasma GPx synthesis. Plasma total antioxidant capacity (TAC) is decreased in CKD cats in comparison to healthy cats. HYPOTHESIS: Serum selenium concentrations and plasma and erythrocyte GPx activity in cats with CKD are lower than in healthy cats. Serum selenium concentrations, the activity of enzymes, and plasma TAC progressively decrease with the progression of kidney disease according to IRIS (International Renal Interest Society) classification. ANIMALS: Twenty-six client owned cats in IRIS stages I-IV of CKD were compared with 19 client-owned healthy cats. METHODS: A CBC, serum biochemical profile, urinalysis, plasma and erythrocyte GPx activity, serum selenium concentration, and plasma TAC were measured in each cat. RESULTS: Cats in IRIS stage IV CKD had a significantly higher (P = .025) activity of plasma GPx (23.44 +/- 6.28 U/mL) than cats in the control group (17.51 +/- 3.75 U/mL). There were no significant differences in erythrocyte GPx, serum selenium concentration, and plasma TAC, either among IRIS stages I-IV CKD cats or between CKD cats and healthy cats. CONCLUSIONS AND CLINICAL IMPORTANCE: Erythrocyte GPx activity, serum selenium concentration, and plasma TAC do not change in CKD cats compared with healthy cats. Selenium is not a limiting factor in feline CKD. Increased plasma GPx activity in cats with stage IV CKD suggests induction of antioxidant defense mechanisms. Antioxidant defense systems might not be exhausted in CKD in cats. PMID- 24341730 TI - Word-level intelligibility after caudal zona incerta stimulation for Parkinson's disease. AB - OBJECTIVES: To investigate the effect of caudal zona incerta-deep brain stimulation (cZi-DBS) on word-level speech intelligibility in patients with Parkinson's disease, under both an optimal listening condition and a simulated more naturalistic listening condition. MATERIALS AND METHODS: Spoken single words were extracted from read samples collected from 10 bilaterally implanted patients with PD pre- and post-cZi-DBS. Intelligibility was assessed through a transcription task performed by 32 naive listeners under two listening conditions: (i) with low-amplitude conversational speech added as background and (ii) with no added background noise. The listeners' responses were scored in terms of agreement with the intended words. RESULTS: Post-operatively, the total intelligibility score was significantly lower when cZi stimulation was switched on compared with off, for both listening conditions (with and without added background noise). Intelligibility was also significantly lower on stimulation compared with preoperative recordings, but only when assessed in the listening condition without background noise. The listening condition with added background noise resulted in significantly lower intelligibility scores compared with the no added noise condition for all stimulation conditions. CONCLUSIONS: The results of this study indicate that cZi-DBS in patients with PD can be detrimental to word level speech intelligibility. PMID- 24341731 TI - Polysaccharide from seeds of Plantago asiatica L. affects lipid metabolism and colon microbiota of mouse. AB - Polysaccharide from the seeds of Plantago asiatica L. was given via oral administration to mice (0.4 g/kg body weight, 30 days) to observe its effects on mouse nutrient metabolism and colon microbiota. It was found the polysaccharide intake could lower the apparent absorption of lipid. Total triglyceride, cholesterol, and atherogenic index in blood serum with total lipid and cholesterol levels in liver of polysaccharide group mice were all significantly lower than those of the control group (p < 0.05). Furthermore, the effect of the polysaccharide intake on mouse colon bacterial communities was investigated. Mice from the polysaccharide group showed a higher colon bacterial diversity than the control group. Bacteroides sp., Eubacterium sp., butyrate-producing bacteria Butyrivibrio sp., and probiotics Bifidobacterium bifidum , Lactobacillus fermentum , and Lactobacillus reuteri in mouse colon were all increased after polysaccharide intake. These indicated that the intake of polysaccharide from P. asiatica L. could be beneficial for lipid metabolism and colon microbiota. PMID- 24341732 TI - Systematic underreporting of the population-based incidence of pancreatic and biliary tract cancers. AB - BACKGROUND: Incidence rates of cancers of the pancreas and biliary tract, typically derived from cancer registers, have been reported to be decreasing. This study tested whether pancreatic and biliary tract cancers are underreported in the Swedish Cancer Register (CR). METHODS: The concordance of pancreatic and biliary tract cancer diagnoses in 1990-2009 between CR and the Swedish Patient Register (PR) were evaluated through record linkage. To further assess the completeness of these cancer diagnoses in both CR and PR, record linkage was also made to the Swedish Causes of Death Register (DR). RESULTS: A total of 31 067 cases of pancreatic cancer and 14 273 cases of biliary tract cancer were identified in CR or PR. Altogether, 44% of the pancreatic cancers and 44% of the biliary tract cancers were registered in PR only, and not in CR. The concordance between CR and PR declined from 63% in the years 1990-1994 to 44% in 2005-2009 for pancreatic cancer. The corresponding figures for biliary tract cancer were 60% and 37%. This decline in concordance was also observed with increasing age, e.g. the concordance between CR and PR for pancreatic cancer declined from 62% in patients<60 years to 36% among patients>=80 years. The corresponding figures for biliary tract cancer were 52% and 38%. CONCLUSION: There is an overwhelming underreporting of pancreatic and biliary tract cancers within the Swedish Cancer Register, which has increased during recent years. The reported decreasing incidence rates for pancreatic and biliary tract cancers might therefore be incorrect. PMID- 24341733 TI - A case of subacute infective endocarditis and blood access infection caused by Enterococcus durans. AB - BACKGROUND: Infection by Enterococcus durans (E. durans) is very rare; reported cases are often preceded by therapy or an immunosuppressed state, including infective endocarditis, urinary tract infection, or wound infection. A few reported cases of infective endocarditis exist, with no reports describing involvement of blood access infection. CASE PRESENTATION: The patient is an 83 year-old man who had been undergoing hemodialysis for 8 years due to renal failure caused by diabetic nephropathy. He developed infective endocarditis and blood access infection/infective aneurysm due to Enterococcus durans; these conditions were treated with the antibiotic regimen of ampicillin + gentamicin. There have been only a few reported cases of infective endocarditis caused by E. durans, and to our knowledge, this is the first report of blood access infection. CONCLUSIONS: We have experienced a case of concurrent infective endocarditis and blood access infection/infective aneurysm caused by E. durans. This is the world's first reported case of blood access infection/infective aneurysm by E. durans. PMID- 24341734 TI - Cruciferous vegetables and risk of colorectal neoplasms: a systematic review and meta-analysis. AB - Evidence shows cruciferous vegetables exhibit chemoprotective properties, commonly attributed to their rich source of isothiocyanates. However, epidemiological data examining the association between cruciferous vegetable intake and colorectal neoplasms have been inconclusive. This meta-analysis examines the epidemiological evidence to characterize the association between cruciferous vegetable intake and risk of developing colorectal neoplasms. Thirty three articles were included in the meta-analysis after a literature search of electronic databases. Subgroup analysis for individual cruciferae types (n = 8 studies) and GST polymorphism (n = 8 studies) were performed. Pooled adjusted odds ratios (ORs) comparing highest and lowest categories of dietary pattern scores were calculated. Results show a statistically significant inverse association between cruciferous vegetable intake and colon cancer [OR = 0.84; 95% confidence interval (CI): 0.72-0.98; P value heterogeneity < 0.001]. Broccoli in particular exhibited protective benefits against colorectal (CRC) neoplasms (OR = 0.80; 95% CI: 0.65-0.99; P value heterogeneity = 0.02). Stratification by GST genotype reveals that the GSTT1 null genotype confers a reduction in CRC risk (OR = 0.78; 95% CI: 0.64-0.95; P value heterogeneity = 0.32). This study provides support to the hypothesis that cruciferous vegetable intake protects against cancer of the colon. This study also demonstrates the significance of gene-diet interactions and the importance of assessing individual cruciferous vegetables. PMID- 24341735 TI - sp3-sp2 vs sp3-sp3 C-C site selectivity in Rh-catalyzed ring opening of benzocyclobutenol: a DFT study. AB - The C(sp(3))-C(sp(2)) vs C(sp(3))-C(sp(3)) site selectivity in the C-C bond activation in Rh-catalyzed ring opening of benzocyclobutenol was systematically investigated using density functional theory (DFT). The catalytic cycle includes three elementary steps: the proton transfer from the substrate to a rhodium hydroxide, the C-C cleavage, and the proton transfer from water onto a carbon forming the final product with regeneration of the rhodium hydroxide. The site selectivity is determined by the C-C cleavage step; the C(sp(3))-C(sp(2)) cleavage is favored over the C(sp(3))-C(sp(3)) cleavage because the former transition state is stabilized by an interaction between the benzene ring of the substrate and Rh. DMSO, a more polar solvent, reduces the site selectivity as the more polar C(sp(3))-C(sp(3)) transition state (TS) is stabilized more than the C(sp(3))-C(sp(2)) TS and decreases the advantage of the latter TS. DPPF ligand is bulky, and the steric repulsion on the tighter C(sp(3))-C(sp(2)) TS causes the loss of the site selectivity. For the even more crowded Rh(P(t-Bu)3)2 catalyst, one phosphine has to dissociate before the C-C cleavage reaction takes place, and the advantage of the C(sp(3))-C(sp(2)) TS is regained for the less crowded RhP(t Bu)3 active catalyst. PMID- 24341737 TI - Editorial. AB - Mewhort talks about being editor of Canadian Journal of Experimental Psychology. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 24341736 TI - Toxicity mechanisms in Escherichia coli vary for silver nanoparticles and differ from ionic silver. AB - Silver nanoparticles (Ag NPs) are commonly added to various consumer products and materials to impair bacterial growth. Recent studies suggested that the primary mechanism of antibacterial action of silver nanoparticles is release of silver ion (Ag(+)) and that particle-specific activity of silver nanoparticles is negligible. Here, we used a genome-wide library of Escherichia coli consisting of ~4000 single gene deletion mutants to elucidate which physiological pathways are involved in how E. coli responds to different Ag NPs. The nanoparticles studied herein varied in both size and surface charge. AgNO3 was used as a control for soluble silver ions. Within a series of differently sized citrate-coated Ag NPs, smaller size resulted in higher Ag ion dissolution and toxicity. Nanoparticles functionalized with cationic, branched polyethylene imine (BPEI) exhibited equal toxicity with AgNO3. When we used a genome-wide approach to investigate the pathways involved in the response of E. coli to different toxicants, we found that only one of the particles (Ag-cit10) exhibited a pattern of response that was statistically similar to that of silver ion. By contrast, the pathways involved in E. coli response to Ag-BPEI particles were more similar to those observed for another cationic nanoparticle that did not contain Ag. Overall, we found that the pathways involved in bacterial responses to Ag nanoparticles are highly dependent on physicochemical properties of the nanoparticles, particularly the surface characteristics. These results have important implications for the regulation and testing of silver nanoparticles. PMID- 24341738 TI - Human perception: a science of synergy. AB - This article is loosely based on an address given to the Canadian Society for Brain, Behaviour and Cognitive Science at their annual meeting on June 7, 2013, in honor of being named the 2013 Donald O. Hebb Distinguished Contribution Award Winner. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 24341739 TI - [Emotional perception of elemental movement. Study on a population of school age children]. AB - Our goal is to examine the emotional influence of perceived basic motions on cognitive processes in childhood. The main hypothesis of this study proposes that the perception of motion will subsequently influence cognitive processing in a specific, emotional manner. We studied 90 children aged nine to 12 years old. On a screen they were shown a black-shaped disk moving in one of three different directions associated with positive, negative and neutral valences. Furthermore, both before and after the children had seen the motion, they were asked to perform a writing speed task (numbers counting down). The results show that (1) children attribute an emotional valence to the "positive" motion and (2) the writing speed cognitive task is influenced by the "negative" motion. Thus, we suggest that basic motions can elicit changes in emotional manner in childhood to perceptive and executive processes according to their specific trajectory. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 24341740 TI - Observation and action priming in anticipative tasks implying biological movements. AB - The purpose of this study was to assess the effect of short-term priming in perceptual anticipation tasks involving point-light biological motions. After the production or the observation of a relevant or an irrelevant movement (action vs. observation priming), 11 right-handed volunteers were asked to anticipate, as quickly and accurately as possible, the end point of a pointing movement after the stimulus vanished upon completion of 60% of the total movement. Our results indicate that perceptual accuracy is significantly affected only with relevant observation priming. This suggests that perceptual anticipation tasks' involving point-light biological motions implies specific perceptual competencies. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 24341741 TI - Individual differences in working memory, secondary memory, and fluid intelligence: evidence from the levels-of-processing span task. AB - Individual differences in working memory (WM) are related to performance on secondary memory (SM), and fluid intelligence (gF) tests. However, the source of the relation remains unclear, in part because few studies have controlled for the nature of encoding; therefore, it is unclear whether individual variation is due to encoding, maintenance, or retrieval processes. In the current study, participants performed a WM task (the levels-of-processing span task; Rose, Myerson, Roediger III, & Hale, 2010) and a SM test that tested for both targets and the distracting processing words from the initial WM task. Deeper levels of processing at encoding did not benefit WM, but did benefit subsequent SM, although the amount of benefit was smaller for those with lower WM spans. This result suggests that, despite encoding cues that facilitate retrieval from SM, low spans may have engaged in shallower, maintenance-focused processing to maintain the words in WM. Low spans also recalled fewer targets, more distractors, and more extralist intrusions than high spans, although this was partially due to low spans' poorer recall of targets, which resulted in a greater number of opportunities to commit recall errors. Delayed recall of intrusions and commission of source errors (labeling targets as processing words and vice versa) were significant negative predictors of gF. These results suggest that the ability to use source information to recall relevant information and withhold recall of irrelevant information is a critical source of both individual variation in WM and the relation between WM, SM, and gF. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 24341743 TI - Microarray analysis provides new insights into the function of apolipoprotein O in HepG2 cell line. AB - BACKGROUND: Apolipoprotein O (apoO) is a new member of the apolipoprotein family. However, data on its physiological functions are limited and inconsistent. Using a microarray expression analysis, this study explored the function of apoO in liver cells. METHODS: HepG2 cells were treated either with oleic acid or tumor necrosis factor-alpha for 24 h. mRNA and protein expression of apoO were assessed by quantitative real-time PCR (qRT-PCR) and Western blot respectively. An efficient lentiviral siRNA vector targeting the human apoO gene was designed and constructed. The gene expression profile of HepG2 human hepatocellular carcinoma cells transfected with the apoO silencing vector was investigated using a whole genome oligonucleotide microarray. The expression levels of some altered genes were validated using qRT-PCR. RESULTS: ApoO expression in HepG2 cells was dramatically affected by lipid and inflammatory stimuli. A total of 282 differentially expressed genes in apoO-silenced HepG2 cells were identified by microarray analysis. These genes included those participating in fatty acid metabolism, such as ACSL4, RGS16, CROT and CYP4F11, and genes participating in the inflammatory response, such as NFKBIZ, TNFSF15, USP2, IL-17, CCL23, NOTCH2, APH-1B and N2N. The gene Uncoupling protein 2 (UCP2), which is involved in both these metabolic pathways, demonstrated significant changes in mRNA level after transfection. CONCLUSIONS: It is likely that apoO participates in fatty acid metabolism and the inflammatory response in HepG2 cells, and UCP2 may act as a mediator between lipid metabolism and inflammation in apoO-silenced HepG2 cells. PMID- 24341745 TI - BiFeO3/TiO2 nanotube arrays composite electrode: construction, characterization, and enhanced photoelectrochemical properties. AB - This work aims at the exploration of nanostructured ferroelectric-material modified semiconductor electrodes for enhanced photo-induced activity. A well aligned BiFeO3/TiO2-nanotubes (NTs) array with visible-light activity was successfully synthesized on a titanium sheet by combining anodization and an ultrasonic-immersion method followed by annealing. The structural and optical properties of the TiO2-NTs and the composite BiFeO3/TiO2-NTs were comparatively characterized. The composite BiFeO3/TiO2-NTs grown on a Ti sheet and used as an electrode exhibited a stronger absorption in the visible region and a much higher photoconversion efficiency than the pure TiO2-NTs/Ti electrode. Electrochemical impedance investigation attested to a significant improvement of the interfacial electron-transfer kinetics with enhanced separation of electron-hole pairs. The as-prepared composite electrode showed a high efficiency for photoelectrocatalytic degradation towards rhodamine B under visible-light irradiation (lambda > 400 nm). The enhanced photoelectrocatalytic activity of the composite electrode could be attributed to the synergistic effect between the lowered electron-hole recombination rate by the applied bias and the wider spectral response promoted by the BiFeO3 component. PMID- 24341744 TI - Association of a microRNA-323b polymorphism with the persistence of hepatitis B virus infection by the enhancement of viral replication. AB - Recent studies have shown that some mammalian microRNAs (miRNAs) play a role in antiviral defence. However, little is known about the role of miRNA-323b in hepatitis B virus (HBV)-host interaction. We explored whether single nucleotide polymorphism (SNP) of miRNA-323b affects HBV replication in a Korean HBV cohort. Genotyping was performed in a total of 1439 subjects composed of 404 spontaneously recovered (SR) subjects as normal controls and 1035 chronic carriers (CC) of HBV who were further classified into 313 patients with chronic hepatitis, 305 patients with liver cirrhosis and 417 patients with hepatocellular carcinoma. To confirm the effect of SNP of miRNA-323b on HBV replication in vitro, HepAD38 cells were transfected with miRNA-323b wild type or miRNA-323b SNP plasmid vectors, and HBV replication was induced for 5 days. HBV DNA was isolated and quantified using real-time PCR. The polymorphism rs56103835C>T in the pre miRNA region of miRNA-323b revealed significant minor allele frequency (0.273). rs56103835C>T SNP showed significantly affect persistence of HBV in CC group compared with SR group (OR = 1.29, P = 0.009 in a codominant model; OR = 1.29, P = 0.03 in a dominant model; and OR = 1.78, P = 0.03 in a recessive model). In vitro, the total intracellular HBV DNA content was significantly reduced by miRNA 323b wild-type plasmid vector transfection (P = 0.014). The polymorphism of miRNA 323b was significantly associated with persistence of HBV by the enhancement of HBV replication (P = 0.021). Our findings provide a novel perspective on the role SNP of miRNAs in host-virus interactions in HBV infection. PMID- 24341746 TI - The feasibility of the initial postsystolic to systolic strain rate ratio as a predictor of the viability of ischemic myocardium with acute myocardial infarction. AB - BACKGROUND: Investigations of a strain index for the viability of ischemic myocardium with acute myocardial infarction (AMI) have been challenging. Therefore, the aim of this study was to evaluate patients with AMI to determine an optimal strain index for predicting the viability of ischemic myocardium. METHODS AND RESULTS: A total of 57 patients with AMI were assessed according to two-dimensional (2D) speckle tracking imaging strain and strain rate (SR), measured during the acute phase before urgent revascularization and at a 1-year follow-up postrevascularization. During the acute phase, all the myocardial segments were classified according to the acute end-systolic strain (Ses) values as normal (Ses <= -13%), hypocontractile (-13% < Ses <= -7%), or having a severe contractile abnormality (Ses > -7%). At the 1-year follow-up, we reassessed the recovery of the segments with a severe contractile abnormality. The viability of these segments was defined as an improved Ses (<= -7%) at follow-up postrevascularization. The Ses values, postsystolic strain index (PSI), and SR values were significantly better in the viable segments than in the nonviable segments at both the acute phase and at follow-up (P < 0.001). The initial postsystolic to systolic SR ratio (SRps/SRs) had the best area under the curve (AUC = 0.897). In addition, a cutoff value of 0.6 predicted recovery from a severe contractile abnormality with a sensitivity of 75% and a specificity of 88%. CONCLUSIONS: The initial SRps/SRs ratio identified the viability of ischemic myocardium with AMI; therefore, this novel index may be clinically useful in the treatment of patients with AMI. PMID- 24341747 TI - Comparison between clinical and digital soft tissue measurements. AB - OBJECTIVE: The use of periodontal probes harbors the risk of measurement errors. The aim of this study was to investigate the accuracy of the digital determination of gingival recession and papilla height on virtual jaw models, given the hypothesis that they show lower intrarater and interrater variability than conventional linear measurements taken clinically or on cast models. MATERIALS AND METHODS: Gingival recessions and papilla heights were measured at 30 sites by five examiners using the following methods: (A) direct measurements using a periodontal probe intraorally or (B) on cast models using a caliper, (C) digital measurements on virtual models obtained by optical scans taken intraorally, or (D) made of cast models using the same software. Measurements were repeated after 1 week and intraclass, intrarater, and interrater correlations of the measurements using the four different methods were analyzed. RESULTS: The greatest disagreement between the 1st and 2nd measurement was identified for method A. Recessions were less reliably measured than papillae. The best agreement between methods was found in the digital ones (C and D). Regarding papilla height, increased values were obtained when method D was applied as compared with both clinical evaluations. For gingival recession, method A measured the highest values. CONCLUSION: In the present study, the use of digital technologies by intraoral scanning or scanning of cast models improved the reproducibility and lowered the variance of measurements within one individual and between different investigators. CLINICAL SIGNIFICANCE: Providing a more reliable and examiner-independent technique for measurements of the soft tissue architecture could improve data quality in periodontal research and in the analysis of different clinical treatment modalities. PMID- 24341748 TI - Firefly luciferase inhibitor-conjugated peptide quenches bioluminescence: a versatile tool for real time monitoring cellular uptake of biomolecules. AB - In this paper, novel firefly luciferase-specific inhibitor compounds (FLICs) are evaluated as potential tools for cellular trafficking of transporter conjugates. As a proof-of-concept, we designed FLICs that were suitable for solid phase peptide synthesis and could be covalently conjugated to peptides via an amide bond. The spacer between inhibitor and peptide was optimized to gain efficient inhibition of recombinant firefly luciferase (FLuc) without compromising the activity of the model peptides. The hypothesis of using FLICs as tools for cellular trafficking studies was ensured with U87Fluc glioblastoma cells expressing firefly luciferase. Results show that cell penetrating peptide (penetratin) FLIC conjugate 9 inhibited FLuc penetrated cells efficiently (IC50 = 1.6 MUM) and inhibited bioluminescence, without affecting the viability of the cells. Based on these results, peptide-FLIC conjugates can be used for the analysis of cellular uptake of biomolecules in a new way that can at the same time overcome some downsides seen with other methods. Thus, FLICs can be considered as versatile tools that broaden the plethora of methods that take advantage of the bioluminescence phenomena. PMID- 24341749 TI - CHARMM36 united atom chain model for lipids and surfactants. AB - Molecular simulations of lipids and surfactants require accurate parameters to reproduce and predict experimental properties. Previously, a united atom (UA) chain model was developed for the CHARMM27/27r lipids (Henin, J., et al. J. Phys. Chem. B. 2008, 112, 7008-7015) but suffers from the flaw that bilayer simulations using the model require an imposed surface area ensemble, which limits its use to pure bilayer systems. A UA-chain model has been developed based on the CHARMM36 (C36) all-atom lipid parameters, termed C36-UA, and agreed well with bulk, lipid membrane, and micelle formation of a surfactant. Molecular dynamics (MD) simulations of alkanes (heptane and pentadecane) were used to test the validity of C36-UA on density, heat of vaporization, and liquid self-diffusion constants. Then, simulations using C36-UA resulted in accurate properties (surface area per lipid, X-ray and neutron form factors, and chain order parameters) of various saturated- and unsaturated-chain bilayers. When mixed with the all-atom cholesterol model and tested with a series of 1,2-dimyristoyl-sn-glycero-3 phosphocholine (DMPC)/cholesterol mixtures, the C36-UA model performed well. Simulations of self-assembly of a surfactant (dodecylphosphocholine, DPC) using C36-UA suggest an aggregation number of 53 +/- 11 DPC molecules at 0.45 M of DPC, which agrees well with experimental estimates. Therefore, the C36-UA force field offers a useful alternative to the all-atom C36 lipid force field by requiring less computational cost while still maintaining the same level of accuracy, which may prove useful for large systems with proteins. PMID- 24341751 TI - The contribution of internal resources, external resources, and emotional distress to use of drugs and alcohol among Israeli Jewish urban adolescents. AB - The contribution of selected background variables (age, gender), internal resources (mastery, emotional maturity), external resources (parental and peer support), and emotional distress to alcohol and drug use among 160 Israeli Jewish urban high school students were examined. Analyzing the variables with hierarchical regression, emotional distress contributed most significantly to both alcohol and drug use, and the contribution of age was somewhat less significant for both of them. Emotional distress also contributed indirectly to drug use through an interaction with one's sense of mastery. Gender, internal resources, and external resources contributed differentially to alcohol and drug use. Whereas gender and internal resources contributed only to drug use, external resources contributed only to alcohol use. Specifically, peer support contributed positively to alcohol use whereas parental support contributed negatively. The discussion provides explanations for these research findings and their implications, and the research's limitations are noted. PMID- 24341750 TI - Comprehensive analysis of the Corynebacterium glutamicum transcriptome using an improved RNAseq technique. AB - BACKGROUND: The use of RNAseq to resolve the transcriptional organization of an organism was established in recent years and also showed the complexity and dynamics of bacterial transcriptomes. The aim of this study was to comprehensively investigate the transcriptome of the industrially relevant amino acid producer and model organism Corynebacterium glutamicum by RNAseq in order to improve its genome annotation and to describe important features for transcription and translation. RESULTS: RNAseq data sets were obtained by two methods, one that focuses on 5'-ends of primary transcripts and another that provides the overall transcriptome with an improved resolution of 3'-ends of transcripts. Subsequent data analysis led to the identification of more than 2,000 transcription start sites (TSSs), the definition of 5'-UTRs (untranslated regions) for annotated protein-coding genes, operon structures and many novel transcripts located between or in antisense orientation to protein-coding regions. Interestingly, a high number of mRNAs (33%) is transcribed as leaderless transcripts. From the data, consensus promoter and ribosome binding site (RBS) motifs were identified and it was shown that the majority of genes in C. glutamicum are transcribed monocistronically, but operons containing up to 16 genes are also present. CONCLUSIONS: The comprehensive transcriptome map of C. glutamicum established in this study represents a major step forward towards a complete definition of genetic elements (e.g. promoter regions, gene starts and stops, 5'-UTRs, RBSs, transcript starts and ends) and provides the ideal basis for further analyses on transcriptional regulatory networks in this organism. The methods developed are easily applicable for other bacteria and have the potential to be used also for quantification of transcriptomes, replacing microarrays in the near future. PMID- 24341752 TI - Staphylococcal enterotoxin B influences the DNA methylation pattern in nasal polyp tissue: a preliminary study. AB - Staphylococcal enterotoxins may influence the pro-inflammatory pattern of chronic sinus diseases via epigenetic events. This work intended to investigate the potential of staphylococcal enterotoxin B (SEB) to induce changes in the DNA methylation pattern. Nasal polyp tissue explants were cultured in the presence and absence of SEB; genomic DNA was then isolated and used for whole genome methylation analysis. Results showed that SEB stimulation altered the methylation pattern of gene regions when compared with non stimulated tissue. Data enrichment analysis highlighted two genes: the IKBKB and STAT-5B, both playing a crucial role in T- cell maturation/activation and immune response. PMID- 24341753 TI - The China Health and Nutrition Survey, 1989-2011. AB - The China Health and Nutrition Survey (CHNS) began in 1989 with the goal of creating a multilevel method of data collection from individuals and households and their communities to understand how the wide-ranging social and economic changes in China affect a wide array of nutrition and health-related outcomes. Initiated with a partial sample in 1989, the full survey runs from 1991 to 2011, and this issue documents the CHNS history. The CHNS cohort includes new household formation and replacement communities and households; all household members are studied. Furthermore, in-depth community data are collected. The sample began with eight provinces and added a ninth, Heilongjiang, in 1997 and three autonomous cities, Beijing, Shanghai, and Chongqing, in 2011. The in-depth community contextual measures have allowed us to create a unique measure of urbanicity that captures major dimensions of modernization across all 288 communities currently in the CHNS sample. The standardized, validated urbanicity measure captures the changes in 12 dimensions: population density; economic activity; traditional markets; modern markets; transportation infrastructure; sanitation; communications; housing; education; diversity; health infrastructure; and social services. Each is based on numerous measures applicable to each dimension. They are used jointly and separately in hundreds of studies. PMID- 24341754 TI - China in the period of transition from scarcity and extensive undernutrition to emerging nutrition-related non-communicable diseases, 1949-1992. AB - This study uses unique official data to document nutritional changes in the 1949 1992 period. In 1949, widespread famine, high mortality and low life expectancy dominated. Economic progress was uneven; however, the longer term food supply changed greatly, and hunger was conquered. Diet composition shifted greatly over this period. Cereal consumption, already high, increased from 541.2 g d(-1) (70.0% coarse grains) in 1952 to 645.9 g d(-1) (15.9% coarse grains) in 1992. Consumption of animal-source foods, half of which were pork and pork products, tripled from 30.0 to 103.0 g d(-1). The proportion of energy intake from fat tripled from 7.6% to 22.5%, and that from carbohydrates decreased from 83.0% to 65.8% over the same period. Physical activity was high in all domains, but shifts were beginning to occur (e.g. the initial mechanization of work and the expansion of biking). Nutritional improvement was uneven, including increased undernutrition in the 1959-1962 period and a remarkable rebound and continued improvement thereafter. Overweight emerged only after 1982. Shifts in diet, activity and body composition in 1949-1992 set the stage for major shifts in nutrition in the subsequent decades. PMID- 24341755 TI - Dynamics of the Chinese diet and the role of urbanicity, 1991-2011. AB - China's food consumption patterns and eating and cooking behaviours changed dramatically between 1991 and 2011. Macronutrient composition has shifted towards fats, and protein and sodium intakes remain high and potassium intake low. The rapid decline in intake of coarse grains and, later, of refined grains and increases in intake of edible oils and animal-source foods accompanied by major eating and cooking behaviour shifts are leading to what might be characterized as an unhealthy Western type of diet, often based on traditional recipes with major additions and changes. The most popular animal-source food is pork, and consumption of poultry and eggs is increasing. The changes in cooking and eating styles include a decrease in the proportion of food steamed, baked, or boiled, and an increase in snacking and eating away from home. Prior to the last decade, there was essentially no snacking in China except for hot water or green tea. Most recently, the intake of foods high in added sugar has increased. The dietary shifts are affected greatly by the country's urbanization. The future, as exemplified by the diet of the three mega cities, promises major growth in consumption of processed foods and beverages. PMID- 24341756 TI - The physical activity transition among adults in China: 1991-2011. AB - Previous studies have linked work, home production, travel activities and inactivity with weight and health outcomes. However, these focused on average physical activity (PA) over time rather than changes in PA and associated sociodemographic and economic factors and urbanicity. Using the 1991-2011 China Health and Nutrition Survey data, we estimated the metabolic equivalent of task hours per week for individuals in occupational, domestic, travel and active leisure domains and sedentary hours per week. We present the distributions among adult men and women (aged 18-60), and use quantile regression models to explore factors associated with these trends. Trend analyses on the distribution of PA show declines along the whole distribution of occupational PA for men and women and domestic PA for women in China. These patterns remain consistent after adjusting for individual- and household-level factors. Controlling for urbanicity mitigated the decrease in occupational PA, particularly for men, but not the decrease in domestic PA. Given China's rapid urbanization and its association with occupational PA declines and the strong time trend in domestic PA, there is a need to invest in interventions and policies that promote PA during leisure and travel times. PMID- 24341757 TI - Overweight dynamics in Chinese children and adults. AB - China has experienced a transition from a history of undernutrition to a rapid increase in obesity. The China Health and Nutrition Survey, an ongoing longitudinal, household-based survey of urban and rural residents of nine provinces, documents these changes using measured height and weight across 53,298 observations from 18,059 participants collected from 1991 to 2011. Adult overweight (body mass index [BMI] >= 25 kg/m(2)) prevalence nearly tripled from 1991 (11.7%) to 2009 (29.2%), with significant cohort and age-related effects (stronger in males). Among youth, quantile regression reveals changes across the BMI distribution. By 2009, approximately 12% of children and adolescents were overweight, and 3% of 7-11-year-olds and 1% of 12-17-year-olds were obese (International Obesity Taskforce BMI 25 and 30 kg/m(2) equivalents, respectively). In 1991-2000, urbanicity was strongly and positively associated with BMI, but in 2000-2011, trends were similar across rural and urban areas. Among women, the burden has shifted to lower educated women (the reverse is true for males, as overweight was higher in men of higher education). Our findings highlight the importance of preventive measures early in the life cycle to reduce weight gain. PMID- 24341758 TI - The emergence of cardiometabolic disease risk in Chinese children and adults: consequences of changes in diet, physical activity and obesity. AB - Strong secular declines in physical activity, increased fat and salt intake, and increased obesity, especially abdominal obesity, mark China's recent nutrition transition. The China Health and Nutrition 2009 Survey collected anthropometry, blood pressure and fasting blood samples from more than 9,000 individuals >= 7 years of age. We focus on elevated blood pressure and plasma markers of diabetes, inflammation and dyslipidemia. We used international definitions of cardiometabolic risk and estimated age- and sex-specific prevalence ratios for each outcome for high waist circumference or overweight. We used logistic regression to assess each risk factor's association with diet, physical activity, overweight and abdominal obesity. Cardiometabolic risk prevalence was high in all age groups Prevalence ratios for most risk factors were nearly doubled for overweight or high waist circumference groups. Prevalence ratios were higher in younger than older adults. Low physical activity consistently predicted higher cardiometabolic risk across most outcomes and age-sex groups. The co-occurrence of overweight and high waist circumference was highly predictive of dyslipidemia, elevated glycated haemoglobin and diabetes. High prevalence of cardiometabolic risk factors and their strong association with weight status and abdominal obesity in young adults portend increases in cardiometabolic morbidity and mortality. Early interventions will be required to reverse trends. PMID- 24341760 TI - Construction and manipulation of functional three-dimensional droplet networks. AB - Previously, we reported the manual assembly of lipid-coated aqueous droplets in oil to form two-dimensional (2D) networks in which the droplets are connected through single lipid bilayers. Here we assemble lipid-coated droplets in robust, freestanding 3D geometries: for example, a 14-droplet pyramidal assembly. The networks are designed, and each droplet is placed in a designated position. When protein pores are inserted in the bilayers between specific constituent droplets, electrical and chemical communication pathways are generated. We further describe an improved means to construct 3D droplet networks with defined organizations by the manipulation of aqueous droplets containing encapsulated magnetic beads. The droplets are maneuvered in a magnetic field to form simple construction modules, which are then used to form larger 2D and 3D structures including a 10-droplet pyramid. A methodology to construct freestanding, functional 3D droplet networks is an important step toward the programmed and automated manufacture of synthetic minimal tissues. PMID- 24341761 TI - Accuracy and consistency of weights provided by home bathroom scales. AB - BACKGROUND: Self-reported body weight is often used for calculation of Body Mass Index because it is easy to collect. Little is known about sources of error introduced by using bathroom scales to measure weight at home. The objective of this study was to evaluate the accuracy and consistency of digital versus dial type bathroom scales commonly used for self-reported weight. METHODS: Participants brought functioning bathroom scales (n=18 dial-type, n=43 digital type) to a central location. Trained researchers assessed accuracy and consistency using certified calibration weights at 10 kg, 25 kg, 50 kg, 75 kg, 100 kg, and 110 kg. Data also were collected on frequency of calibration, age and floor surface beneath the scale. RESULTS: All participants reported using their scale on hard surface flooring. Before calibration, all digital scales displayed 0, but dial scales displayed a mean absolute initial weight of 0.95 (1.9 SD) kg. Digital scales accurately weighed test loads whereas dial-type scale weights differed significantly (p<0.05). Imprecision of dial scales was significantly greater than that of digital scales at all weights (p<0.05). Accuracy and precision did not vary by scale age. CONCLUSIONS: Digital home bathroom scales provide sufficiently accurate and consistent weights for public health research. Reminders to zero scales before each use may further improve accuracy of self reported weight. PMID- 24341759 TI - Synthesis and implications: China's nutrition transition in the context of changes across other low- and middle-income countries. AB - The China Health and Nutrition Survey (CHNS) is important for its insights into current and future diet, physical activity, and obesity-related changes in China and for understanding underlying processes common across low- and middle-income countries (LMICs). While China modernized later than Latin American countries, many changes seen in China echo those in Latin America and in other LMICs. In general, changes in physical activity and diet behaviours in China have occurred at a faster pace relative to other LMICs. Modernization of the overall Chinese food system has lagged behind most other LMICs, yet the now-rapid changes in the Chinese food system are similar to what has been seen in other LMICs. Further, there is variation in these changes across social and geographic space. The incidence of obesity and non-communicable diseases has increased as the major health burden has shifted towards the poor. This paper examines changes in China and addresses the literature and issues that link these changes with those in other LMICs. In many ways, the detailed 20-year CHNS, with nine repeated measures, provides a remarkable window through which to understand nutrition related changes in other LMICs. PMID- 24341762 TI - Utilization of microbe-derived electricity for practical application. PMID- 24341763 TI - Acute mortality, bacterial load, and pathology of select lines of adult rainbow trout challenged with Weissella sp. NC36. AB - A challenge for improving disease resistance in fish through genetics is to understand specificity of resistance and whether selection for one pathogen alters the response to unrelated pathogenic microorganisms. Adult Rainbow Trout Oncorhynchus mykiss that had been bred for differential susceptibility to Flavobacterium psychrophilum, the causative agent of bacterial cold water disease (BCWD) and designated ARS-Fp-R (resistant), ARS-Fp-S (susceptible), and ARS-Fp-C (control line), as well as a pool of commercial-stock Rainbow Trout, were intraperitoneally challenged with Weissella sp. NC36. Clinical signs, survival, and innate mechanisms affecting disease resistance were monitored over 9 d. Acute disease signs included exophthalmia associated with retrobulbar inflammation and hemorrhage, cerebral hemorrhage, and mild to moderate granulomatous pericarditis. The ARS-Fp-R line did not demonstrate significant survival differences over a 9-d period compared with the ARS-Fp-C and ARS-Fp-S lines (P >= 0.09) indicating that during the acute phase of disease, the resistance factors that limit BCWD do not confer cross protection against Weissella sp. NC36. The linear effect of body weight at challenge was statistically significant, as each 10-g increase in body weight increased the hazard of death by 1% (P = 0.02). Bacterial loads on day 3, assessed by splenic and cerebral CFU counts, did not differ between ARS-Fp-R and ARS-Fp-S trout and there was no correlation between CFU counts and body weight. These findings help elucidate the specificity of disease resistance in selectively bred lines and contribute to our understanding of disease caused by Weissella sp., a recently described pathogen found in cultured Rainbow Trout. PMID- 24341764 TI - Infestation and pathological alterations by Ergasilus sarsi (Copepoda) on the Tanganyika Killifish from Africa. AB - A total of 204 Ergasilus sarsi, a copepod, were collected from Tanganyika Killifish Lamprichthys tanganicanus in Lake Tanganyika during March 2010. The prevalence was 86.40%, the mean intensity was 7.56, and the mean abundance was 6.38. Only 27 of the fish were infested, and the highest infestation on one fish was 29. Proliferation of mucus cells and lamellar fusion occurred. Haemorrhage due to blood vessel compression was noted. This is the first record of E. sarsi from Tanganyika Killifish. This study is also the first to provide a description of the pathological alterations caused by E. sarsi. PMID- 24341765 TI - Comparative analysis of the acute response of zebrafish Danio rerio skin to two different bacterial infections. AB - Skin is an important innate immune organ in fish; however, little is known about the skin's immune response to infectious pathogens. We conducted a comparative analysis of the acute immune response of Zebrafish Danio rerio skin against gram positive (Staphylococcus chromogenes) and gram-negative (Citrobacter freundii) bacterial infections. Gene expression profiles induced from the two different infections were identified by microarray hybridization, with many genes demonstrating an acute immune response in the skin. Differentially expressed genes were mainly involved in response to stress and stimulus, complement activation, acute-phase response, and defense and immune response. Compared with transcription patterns of skin from the two infections, a similar innate immunity (e.g., transferrin, coagulation factor, complements, and lectins) was observed but with different acute-phase genes (e.g., ceruloplasmin, alpha-1-microglobulin, vitellogenin, and heat shock protein). These results suggest that the skin of fish plays an important role in the innate immune responses to bacterial infection. PMID- 24341766 TI - Triploid grass carp susceptibility and potential for disease transfer when used to control aquatic vegetation in reservoirs with avian vacuolar myelinopathy. AB - Avian vacuolar myelinopathy (AVM) is an often-lethal neurologic disease that affects waterbirds and their avian predators (i.e., bald eagles Haliaeetus leucocephalus) in the southern United States. Feeding trials and field surveys provided evidence that AVM is caused by a toxin-producing, undescribed cyanobacterium (UCB), which grows as an epiphyte on the leaves of submerged aquatic vegetation (SAV). Reservoirs with documented AVM epornitics support dense growth of nonnative SAV. Waterbirds ingest the toxin when feeding on aquatic plants with the epiphytic UCB, and secondary intoxication occurs when raptors consume these birds. Vegetation management has been proposed as a means to reduce waterbird exposure to the putative toxin. We fed aquatic vegetation with and without the UCB to triploid Grass Carp Ctenopharyngodon idella in laboratory and field trials. Only Grass Carp that ingested aquatic vegetation with the UCB developed lesions in the central nervous system. The lesions (viewed using light microscopy) appeared similar to those in birds diagnosed with AVM. Grass Carp that received aquatic vegetation without the UCB were unaffected. Grass Carp tissues from each treatment were fed to domestic chickens Gallus domesticus (an appropriate laboratory model for AVM) in a laboratory trial; the chickens displayed no neurologic signs, and histology revealed a lack of the diagnostic lesions in brain tissues. Results from our trials suggest that (1) triploid Grass Carp are susceptible to the AVM toxin, although no fish mortalities were documented; and (2) the toxin was not accumulated in Grass Carp tissues, and the risk to piscivorous avifauna is likely low. However, a longer exposure time and analysis of sublethal effects may be prudent to further evaluate the efficacy and risk of using triploid Grass Carp to manage aquatic vegetation in a system with frequent AVM outbreaks. PMID- 24341767 TI - Assessment of the risk of White Sturgeon to become infected and potential carriers of infectious pancreatic necrosis virus. AB - Little scientific information is available to assess whether White Sturgeon Acipenser transmontanus can become infected and potential carriers of infectious pancreatic necrosis virus (IPNV). To assess this risk, monitoring results of adult and progeny White Sturgeon were examined from waters historically stocked with salmonid fish known to be IPNV carriers. From 1999 through 2004 White Sturgeon from a total of 30 separate families whose parentage came from waters historically stocked with IPNV carrier fish were tested. Duplicate groups of 25 juvenile Snake River White Sturgeon were waterborne exposed to 1.0*10(4) 50% tissue culture infective dose (TCID50)/mL of water for 1 h and an additional group was injected intraperitoneally with 1.0*10(5) TCID50/fish. A negative control group was handled similarly but was not exposed to the virus. No morbidity was detected in any of the treatment groups or the negative control. At 34, 40, 47, and 54 d postexposure to IPNV, virus reisolation was attempted on five fish from each group, and an additional five fish from each group were examined for histological changes consistent with an IPNV infection. At 34 and 40 d postinjection with IPNV, 20% (one of five) of the fish tested positive for the virus per sample interval; however, fish from groups that were waterborne-exposed to IPNV were all negative. At 47 and 54 d after exposure or injection with IPNV an additional five fish from each group were tested at each sample interval and all results were negative. Histological analysis of target tissue obtained from five fish per group at 34 and 54 d postinfection also failed to detect any consistent change associated with an IPNV infection. These results suggest that the risk of White Sturgeon to become infected and develop into potential carriers of IPNV is negligible. PMID- 24341768 TI - A cross-sectional study of the association between risk factors and hemorrhagic disease of grass carp in ponds in Southern China. AB - A cross-sectional survey of 215 Grass Carp Ctenopharyngodon idella ponds was conducted in southern China between May 2010 and November 2011. An in-depth questionnaire was developed to evaluate a series of biosecurity practices, environmental factors, and management factors at the farm level. Fish samples with clinical hemorrhagic signs were also collected from each pond to assess the clinical disease of Grass Carp reovirus by using reverse transcription (RT) PCR assay. The association between the incidence of Grass Carp hemorrhagic disease (GCHD) and risk factors was analyzed using logistic regression. Of the 215 ponds, 144 showed GCHD-positive responses to RT-PCR assay. In addition, survey results revealed that inferior environmental conditions occurred in most ponds with an incidence of GCHD; such conditions included a thick mud layer; no cleansing and restoration practices (CRPs) before culture; and poor water quality (i.e., high ammonia nitrogen and nitrite concentrations and low transparency). Logistic regression model results suggested that decreased risks were associated with fry vaccination, a safe water source, and deepening of the water level, whereas increased risk factors mainly included no CRPs, excessive rearing density, disease history, and inferior water quality. Presently, control efforts are restricted to immunization of Grass Carp as the best management option for farms. Deepening the water levels and improving water sources can also effectively reduce the incidence of GCHD by diluting the pond rearing densities. PMID- 24341769 TI - Ammocoetes of Pacific Lamprey are not susceptible to common fish rhabdoviruses of the U.S. Pacific northwest. AB - Pacific Lampreys Entosphenus tridentatus have experienced severe population declines in recent years and efforts to develop captive rearing programs are under consideration. However, there is limited knowledge of their life history, ecology, and potential to harbor or transmit pathogens that may cause infectious disease. As a measure of the possible risks associated with introducing wild lampreys into existing fish culture facilities, larval lampreys (ammocoetes) were tested for susceptibility to infection and mortality caused by experimental exposures to the fish rhabdovirus pathogens: infectious hematopoietic necrosis virus (IHNV) and viral haemorrhagic septicaemia virus (VHSV). Two IHNV isolates, representing the U and M genogroups, and one VHSV isolate from the IVa genotype were each delivered to groups of ammocoetes by immersion at moderate and high viral doses, and by intraperitoneal injection. Ammocoetes were then held in triplicate tanks with no substrate or sediment. During 41 d of observation postchallenge there was low or no mortality in all groups, and no virus was detected in the small number of fish that died. Ammocoetes sampled for incidence of infection at 6 and 12 d after immersion challenges also had no detectable virus, and no virus was detected in surviving fish from any group. A small number of ammocoetes sampled 6 d after the injection challenge had detectable virus, but at levels below the original quantity of virus injected. Overall there was no evidence of infection, replication, or persistence of any of the viruses in any of the treatment groups. Our results suggest that Pacific Lampreys are highly unlikely to serve as hosts that maintain or transmit these viruses. PMID- 24341770 TI - Predominant bacteria associated with red snapper from the Northern Gulf of Mexico. AB - Since the Deepwater Horizon oil spill in 2010, anecdotal observations of Red Snapper Lutjanus campechanus from the northern Gulf of Mexico exhibiting unusual external lesions have been reported. Two opportunistic bacterial fish pathogens, Vibrio vulnificus and Photobacterium damselae, were recovered from the fish and were deemed responsible for the abnormalities. However, the culturable microbiota of healthy Red Snapper has not yet been characterized. We analyzed the heterotrophic bacteria associated with healthy Red Snapper caught off the Louisiana coast. In total, 179 isolates from 60 fish were recovered from skin and mucus, and 43 isolates were obtained from anterior kidney. All isolates were identified by 16S ribosomal RNA gene sequencing. The Proteobacteria was the predominant phylum in both external and internal samples, followed by the Firmicutes and the Actinobacteria. Within the Proteobacteria, most isolates were members of the genera Vibrio and Photobacterium, and V. natriegens and P. damselae were the predominant species. The results of this study suggest that both Vibrio spp. and Photobacterium spp. are associated with the normal microbiota of healthy Red Snapper. Thus, the opportunistic fish pathogens recovered in previous studies cannot be deemed lesion-forming until Koch's postulates are fulfilled. PMID- 24341771 TI - Fish processing facilities: new challenge to marine biosecurity in Canada. AB - The transmission of pathogens is a common consequence of animal food production. Marine salmon farms and their processing facilities can serve as sources of virulent fish pathogens; our study is the first to confirm the broadcast of a live fish pathogen from a farmed salmon processing facility into the marine waters of Canada's Pacific coast. We found live salmon lice Lepeophtheirus salmonis, mucus, and fish tissue in effluent from the processing facility. Sea lice transmitted from this source may pose a threat to wild salmon populations, and the release of untreated offal, including blood water, is of considerable concern. Further research is needed to quantify the extent to which processing facilities release sea lice and to determine whether more virulent fish pathogens are present in effluent. These data underscore the need for fish farming nations to develop mandatory biosecurity programs to ensure that farmed salmon processing facilities will prevent the broadcast of infectious fish pathogens into wild fish habitat. PMID- 24341773 TI - Mouthwash use and the prevention of plaque, gingivitis and caries. PMID- 24341774 TI - The dynamics of methicillin-resistant Staphylococcus aureus exposure in a hospital model and the potential for environmental intervention. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of healthcare-associated infections. An important control strategy is hand hygiene; however, non-compliance has been a major problem in healthcare settings. Furthermore, modeling studies have suggested that the law of diminishing return applies to hand hygiene. Other additional control strategies such as environmental cleaning may be warranted, given that MRSA-positive individuals constantly shed contaminated desquamated skin particles to the environment. METHODS: We constructed and analyzed a deterministic environmental compartmental model of MRSA fate, transport, and exposure between two hypothetical hospital rooms: one with a colonized patient, shedding MRSA; another with an uncolonized patient, susceptible to exposure. Healthcare workers (HCWs), acting solely as vectors, spread MRSA from one patient room to the other. RESULTS: Although porous surfaces became highly contaminated, their low transfer efficiency limited the exposure dose to HCWs and the uncolonized patient. Conversely, the high transfer efficiency of nonporous surfaces allows greater MRSA transfer when touched. In the colonized patient's room, HCW exposure occurred more predominantly through the indirect (patient to surfaces to HCW) mode compared to the direct (patient to HCW) mode. In contrast, in the uncolonized patient's room, patient exposure was more predominant in the direct (HCW to patient) mode compared to the indirect (HCW to surfaces to patient) mode. Surface wiping decreased MRSA exposure to the uncolonized patient more than daily surface decontamination. This was because wiping allowed higher cleaning frequency and cleaned more total surface area per day. CONCLUSIONS: Environmental cleaning should be considered as an integral component of MRSA infection control in hospitals. Given the previously under appreciated role of surface contamination in MRSA transmission, this intervention mode can contribute to an effective multiple barrier approach in concert with hand hygiene. PMID- 24341775 TI - Metabolism, distribution, and excretion of deoxynivalenol with combined techniques of radiotracing, high-performance liquid chromatography ion trap time of-flight mass spectrometry, and online radiometric detection. AB - Dispositions of deoxynivalenol (DON) in rats and chickens were investigated, using a radiotracer method coupled with a novel gamma-accurate radioisotope counting (gamma-ARC) radio-high-performance liquid chromatography ion trap time of-flight tandem mass spectrometry (radio-HPLC-IT-TOF-MS/MS) system. 3beta-(3)H DON was chemically synthesized and orally administrated to both sexes of rats and chickens as single or multiple doses. The results showed that DON was widely distributed and quickly eliminated in all tissues. The highest concentration was found in the gastrointestinal tract at 6 h post-administration. Substantially lower levels were detected in the kidney, liver, heart, lung, spleen, and brain. Three new metabolites were identified tentatively as 10-deoxynivalenol-sulfonate, 10-deepoxy-deoxynivalenol (DOM-1)-sulfonate, and deoxynivalenol-3alpha-sulfate. Deoxynivalenol-3alpha-sulfate was a major metabolite in chickens, while the major forms in rats were DOM-1 and DON. Additionally, a higher excretion rate in urine was observed in female rats than in male rats. The differences in metabolite profiles and excretion rates, which suggested diverse ways to detoxify, may relate to the different tolerances in different genders or species. PMID- 24341776 TI - One-step production of bioactive proteins through simultaneous PEGylation and refolding. AB - Production of protein therapeutics often involves in vitro refolding from bacterial inclusion bodies and subsequent PEGylation to improve protein stability and plasma half-life. Here, we devised a novel strategy for one-step production of site-specific mono-PEGylated proteins with good bioactivity and improved biostability by integrating PEGylation and protein refolding (IPPR). Using lysozyme and recombinant human fibroblast growth factor 21 (rhFGF21) as model proteins, we showed that both PEGylation and refolding of denatured proteins have been simultaneously accomplished by IPPR with high efficiency of refolding yield and bioconjugation. PEGylated rhFGF21 by IPPR has a similar capacity as the native rhFGF21 to stimulate glucose uptake in 3T3-L1 cells, but exhibits prolonged blood glucose and triglyceride lowering activity levels in the ob/ob diabetic mouse model. Hence, IPPR will significantly facilitate the generation of protein therapeutics. PMID- 24341777 TI - Can uterine artery Doppler parameters predict copper intrauterine device-induced side effects? AB - OBJECTIVES To evaluate the predictive value of uterine artery Doppler characteristics in predicting copper intrauterine device (IUD)-induced side effects such as dysmenorrhoea and menorrhagia, and worsening of dyspareunia. METHODS One hundred and twenty regularly menstruating women were enrolled in the study. All underwent transvaginal uterine artery Doppler analysis in the early follicular phase, on two occasions: before insertion of the IUD, and six months after insertion. Pre- and post-insertion resistance (RI) and pulsatility (PI) indices of the uterine arteries were measured. Doppler parameters were compared between subjects experiencing an increase in IUD-mediated side effects and those reporting no change. RESULTs RI and PI of all participants before and after IUD insertion were not significantly different (0.75 +/- 0.06 vs. 0.74 +/- 0.09, p = 0.49; 1.81 +/- 0.55 vs. 1.83 +/- 0.70, p = 0.7, respectively). No significant difference was found in the comparison of pre- and post-insertion PI and RI values of women who had increased- and those who experienced no change in dysmenorrhoea, dyspareunia and duration/amount of menstruation. CONCLUSIONS No major changes in uterine blood flow were observed in women experiencing increased menstrual bleeding, dyspareunia or dysmenorrhoea after insertion of a copper IUD. The occurrence of these effects cannot be predicted by prior Doppler flow analysis. PMID- 24341778 TI - Evolution of MRI changes in Rasmussen's encephalitis. AB - PURPOSE: We studied the MRI findings in 16 patients with Rasmussen's encephalitis (RE), further analysed serial MRI changes in 11 of them and correlated it with clinical features. METHODOLOGY: The diagnosis of RE was based on the European consensus statement (Brain, 128, 2005, 454). Details related to demographical, clinical, MRI observations were analysed. RESULTS: Forty MRIs of brain of 16 patients were reviewed. Eleven patients had undergone serial brain MRIs ranging from two to five occasions. All the patients had unihemispheric focal cortical atrophy, predominantly in the perisylvian region (n = 13). Other features were white matter signal changes (n = 14), and ipsilateral caudate (n = 6) and putamen (n = 4) atrophy. Signal alterations in putamen and caudate were noted in four each. In all the 11 patients with serial MRI, there was progression of cerebral atrophy and a trend towards increase in MRI staging. The MRI signal changes remained same in five patients, resolved in three patients, differential change in two patients and increased in one patient. Diffusion-weighted imaging showed facilitated diffusion (n = 5), and MR spectroscopy showed reduced N-acetyl aspartate and elevated lactate (n = 2). CONCLUSIONS: Pattern recognition of MRI findings and the changes in serial MRI might serve as a surrogate marker of disease viz. unihemispheric progressive focal cortical atrophy and signal changes predominantly in the perisylvian distribution and caudate followed by putamen involvement. This might assist in understanding and monitoring of the disease progression. PMID- 24341779 TI - Effects of processing style on responsiveness to affective stimuli and processing fluency. AB - In the present study, we provide direct evidence for effects of global versus local processing on responsiveness to and reliance on affective information in judgement and decision-making. Results of Experiments 1 and 2 showed an increased responsiveness to affective stimuli among participants in a global processing mode. Experiment 3 showed similar effects for processing fluency; participants adopting a global processing style showed an increased reliance on fluency. Experiment 4 replicated our findings in a more mundane judgement task in which participants judged apartments. We discuss our findings in relation to the distinction between intuitive versus deliberative modes of thinking. PMID- 24341780 TI - Primary cardiac lymphoma presenting as an atypical type of hypertrophic cardiomyopathy. AB - Primary cardiac lymphoma (PCL) is a very rare malignancy although cardiac involvement with the disseminated disease is not uncommon. We present a case of a 43-year-old man with PCL that initially presented as marked thickening of all cardiac walls and was mistakenly diagnosed as an atypical type of hypertrophic cardiomyopathy. The diagnosis of PCL was made with a delay of 9 months after the initial presentation, when atypical lymphocytes staining positive for CD79a and CD20 were demonstrated in the rapidly growing mediastinal and neck mass. Anthracycline-based chemotherapy and anti-CD20 immunotherapy resulted in a remarkable reduction in cardiac wall thickness and mediastinal mass. The first lesson to be learnt from this case is that PCL can present as a diffuse infiltrative disease without a mass. The second lesson is that prompt exploratory thoracotomy should not be delayed when the diagnosis is elusive. PMID- 24341781 TI - Influence of periodontal biotype on buccal bone remodeling after tooth extraction using the flapless approach with a xenograft: a histomorphometric and fluorescence study in small dogs. AB - BACKGROUND: Several approaches have been used to counteract alveolar bone resorption after tooth extraction. PURPOSE: The aim of the present study was to evaluate the influence of gingival thickness and bone grafting on buccal bone remodeling in extraction sockets with thin buccal bone, using a flapless approach. MATERIALS AND METHODS: The gingiva of 8 dogs was thinned at one side of the mandible and mandibular premolars were extracted without flaps. The sockets were randomly assigned to the test group (thin gingiva) (TG), the test group with grafting material TG + GM, the control group (normal gingiva) (CG), or the control group with grafting material CG + GM. Ground sections were prepared from 12-week healing biopsies, and histomorphometry and fluorescence analysis were performed. RESULTS: In the groups with thin gingiva, numerically greater buccal bone loss was observed, while there were no differences between grafted and nongrafted sites. A numerically higher rate of mineralization was observed for the grafted sites, as compared with the nongrafted sites, at 12 weeks. CONCLUSIONS: A thin buccal bone plate leads to higher bone loss in extraction sockets, even with flapless surgery. The gingival thickness or the use of a graft material did not prevent buccal bone resorption in a naturally thin biotype, but modified the mineralization process. PMID- 24341783 TI - Pepper seed extract suppresses invasion and migration of human breast cancer cells. AB - This study was performed to determine the antimetastatic activities of chili pepper seed on human breast cancer cells. The water extract of chili pepper seeds was prepared and it contained a substantial amount of phenols (131.12 mg%) and no capsaicinoids. Pepper seed extract (PSE) suppressed the proliferation of MDA-MB 231 and MCF-7 cells at the concentration of 10, 25, and 50 MUg/ml (MDA-MB-231: IC50 = 20.1 MUg/ml, MCF-7: IC50 = 14.7 MUg/ml). PSE increased the expression level of E-cadherin up to 1.2-fold of the control in MCF-7 cells. PSE also decreased the secretion of matrix metalloproteinase (MMP)-2 and MMP-9 in MDA-MB 231 and MCF-7 cells at the concentration of 25 and 50 MUg/ml. PSE treatment significantly suppressed the invasion of MDA-MB-231 and MCF-7 cells in a dose dependent manner. The motility of cancer cells was apparently retarded in the wound healing assay by the PSE treatment. Although our data collectively demonstrate that PSE inhibits invasion and migration of breast cancer cells, further study is needed to identify specific mechanisms and bioactive components contributing to antimetastatic effects of chili pepper seed. PMID- 24341782 TI - Functional analyses of cotton (Gossypium hirsutum L.) immature fiber (im) mutant infer that fiber cell wall development is associated with stress responses. AB - BACKGROUND: Cotton fiber maturity is an important factor for determining the commercial value of cotton. How fiber cell wall development affects fiber maturity is not well understood. A comparison of fiber cross-sections showed that an immature fiber (im) mutant had lower fiber maturity than its near isogenic wild type, Texas marker-1 (TM-1). The availability of the im mutant and TM-1 provides a unique way to determine molecular mechanisms regulating cotton fiber maturity. RESULTS: Transcriptome analysis showed that the differentially expressed genes (DEGs) in the im mutant fibers grown under normal stress conditions were similar to those in wild type cotton fibers grown under severe stress conditions. The majority of these DEGs in the im mutant were related to stress responses and cellular respiration. Stress is known to reduce the activity of a classical respiration pathway responsible for energy production and reactive oxygen species (ROS) accumulation. Both energy productions and ROS levels in the im mutant fibers are expected to be reduced if the im mutant is associated with stress responses. In accord with the prediction, the transcriptome profiles of the im mutant showed the same alteration of transcriptional regulation that happened in energy deprived plants in which expressions of genes associated with cell growth processes were reduced whereas expressions of genes associated with recycling and transporting processes were elevated. We confirmed that ROS production in developing fibers from the im mutant was lower than that from the wild type. The lower production of ROS in the im mutant fibers might result from the elevated levels of alternative respiration induced by stress. CONCLUSION: The low degree of fiber cell wall thickness of the im mutant fibers is associated with deregulation of the genes involved in stress responses and cellular respiration. The reduction of ROS levels and up-regulation of the genes involved in alternative respirations suggest that energy deprivation may occur in the im mutant fibers. PMID- 24341784 TI - Pollen and stomata morphometrics and polyploidy in Eriotheca (Malvaceae Bombacoideae). AB - Approximately 70% of the angiosperm species are polyploid, an important phenomenon in the evolution of those plants. But ploidy estimates have often been hindered because of the small size and large number of chromosomes in many tropical groups. Since polyploidy affects cell size, morphometric analyses of pollen grains and stomata have been used to infer ploidy level. Polyploidy is present in many species of the Cerrado, the Neotropical savanna region in Central Brazil, and has been linked to apomixis in some taxa. Eriotheca gracilipes and Eriotheca pubescens are common tree species in this region, and present cytotypes that form reproductive mosaics. Hexaploid individuals (2n = 6x = 276) are polyembryonic and apomictic, while tetraploid and diploid individuals (2n = 2x = 92, 2n = 4x = 184) are sexual and monoembryonic. We tested whether morphometric analysis can be used to estimate ploidy levels in E. gracilipes and E. pubescens individuals. Pollen material from diploid and hexaploid individuals of E. gracilipes, and tetraploid and hexaploid individuals of E. pubescens, were fixed in 50% FAA, and expanded leaves were dried in silica gel. Pollen grains and stomata of at least five individuals from each population were measured. The results demonstrate that all measures were significantly different among cytotypes. Individuals with higher levels of ploidy (hexaploid) all presented measurements that were higher than those with lower levels (diploid and tetraploid). There was no overlap between ploidy levels in each species at 95% confidence interval. Thus, the size of the pollen grains and stomata are effective parameters for analysis of ploidy levels in E. gracilipes and E. pubescens. PMID- 24341785 TI - Nanostructured surfaces frustrate polymer semiconductor molecular orientation. AB - Nanostructured grating surfaces with groove widths less than 200 nm impose boundary conditions that frustrate the natural molecular orientational ordering within thin films of blended polymer semiconductor poly(3-hexlythiophene) and phenyl-C61-butyric acid methyl ester, as revealed by grazing incidence X-ray scattering measurements. Polymer interactions with the grating sidewall strongly inhibit the polymer lamellar alignment parallel to the substrate typically found in planar films, in favor of alignment perpendicular to this orientation, resulting in a preferred equilibrium molecular configuration difficult to achieve by other means. Grating surfaces reduce the relative population of the parallel orientation from 30% to less than 5% in a 400 nm thick film. Analysis of in-plane X-ray scattering with respect to grating orientation shows polymer backbones highly oriented to within 10 degrees of parallel to the groove direction. PMID- 24341786 TI - Emotional intelligence is a second-stratum factor of intelligence: evidence from hierarchical and bifactor models. AB - This article examines the status of emotional intelligence (EI) within the structure of human cognitive abilities. To evaluate whether EI is a 2nd-stratum factor of intelligence, data were fit to a series of structural models involving 3 indicators each for fluid intelligence, crystallized intelligence, quantitative reasoning, visual processing, and broad retrieval ability, as well as 2 indicators each for emotion perception, emotion understanding, and emotion management. Unidimensional, multidimensional, hierarchical, and bifactor solutions were estimated in a sample of 688 college and community college students. Results suggest adequate fit for 2 models: (a) an oblique 8-factor model (with 5 traditional cognitive ability factors and 3 EI factors) and (b) a hierarchical solution (with cognitive g at the highest level and EI representing a 2nd-stratum factor that loads onto g at lambda = .80). The acceptable relative fit of the hierarchical model confirms the notion that EI is a group factor of cognitive ability, marking the expression of intelligence in the emotion domain. The discussion proposes a possible expansion of Cattell-Horn-Carroll theory to include EI as a 2nd-stratum factor of similar standing to factors such as fluid intelligence and visual processing. PMID- 24341788 TI - Requirements for a minimum standard of care for phenylketonuria: the patients' perspective. AB - Phenylketonuria (PKU, ORPHA716) is an inherited disorder that affects about one in every 10,000 children born in Europe. Early and continuous application of a modified diet is largely successful in preventing the devastating brain damage associated with untreated PKU. The management of PKU is inconsistent: there are few national guidelines, and these tend to be incomplete and implemented sporadically. In this article, the first-ever pan- European patient/carer perspective on optimal PKU care, the European Society for Phenylketonuria and Allied Disorders (E.S.PKU) proposes recommendations for a minimum standard of care for PKU, to underpin the development of new pan-European guideline for the management of PKU. New standards of best practice should guarantee equal access to screening, treatment and monitoring throughout Europe. Screening protocols and interpretation of screening results should be standardised. Experienced Centres of Expertise are required, in line with current European Union policy, to guarantee a defined standard of multidisciplinary treatment and care for all medical and social aspects of PKU. Women of childbearing age require especially intensive management, due to the risk of severe risks to the foetus conferred by uncontrolled PKU. All aspects of treatment should be reimbursed to ensure uniform access across Europe to guideline-driven, evidence-based care. The E.S.PKU urges PKU healthcare professionals caring for people with PKU to take the lead in developing evidence based guidelines on PKU, while continuing to play an active role in serving as the voice of patients and their families, whose lives are affected by the condition. PMID- 24341789 TI - Ingestion of microplastic has limited impact on a marine larva. AB - There is increasing concern about the impacts of microplastics (<1 mm) on marine biota. Microplastics may be mistaken for food items and ingested by a wide variety of organisms. While the effects of ingesting microplastic have been explored for some adult organisms, there is poor understanding of the effects of microplastic ingestion on marine larvae. Here, we investigated the ingestion of polyethylene microspheres by larvae of the sea urchin, Tripneustes gratilla. Ingestion rates scaled with the concentration of microspheres. Ingestion rates were, however, reduced by biological fouling of microplastic and in the presence of phytoplankton food. T. gratilla larvae were able to egest microspheres from their stomach within hours of ingestion. A microsphere concentration far exceeding those recorded in the marine environment had a small nondose dependent effect on larval growth, but there was no significant effect on survival. In contrast, environmentally realistic concentrations appeared to have little effect. Overall, these results suggest that current levels of microplastic pollution in the oceans only pose a limited threat to T. gratilla and other marine invertebrate larvae, but further research is required on a broad range of species, trophic levels, and polymer types. PMID- 24341787 TI - Oral cyclosporine treatment in dogs: a review of the literature. AB - Cyclosporine is an immunomodulatory drug used to treat an increasing spectrum of diseases in dogs. Cyclosporine is a calcineurin inhibitor, ultimately exerting its inhibitory effects on T-lymphocytes by decreasing production of cytokines, such as interleukin-2. Although, in the United States, oral cyclosporine is approved in dogs only for treatment of atopic dermatitis, there are many other indications for its use. Cyclosporine is available in 2 oral formulations: the original oil-based formulation and the more commonly used ultramicronized emulsion that facilitates oral absorption. Ultramicronized cyclosporine is available as an approved animal product, and human proprietary and generic preparations are also available. Bioavailability of the different formulations in dogs is likely to vary among the preparations. Cyclosporine is associated with a large number of drug interactions that can also influence blood cyclosporine concentrations. Therapeutic drug monitoring (TDM) can be used to assist in attaining consistent plasma cyclosporine concentrations despite the effects of varying bioavailability and drug interactions. TDM can facilitate therapeutic success by guiding dose adjustments on an individualized basis, and is recommended in cases that do not respond to initial oral dosing, or during treatment of severe, life-threatening diseases for which a trial-and-error approach to dose adjustment is too risky. Pharmacodynamic assays that evaluate individual patient immune responses to cyclosporine can be used to augment information provided by TDM. PMID- 24341790 TI - Thermodynamics of nanoparticles: experimental protocol based on a comprehensive Ginzburg-Landau interpretation. AB - The effects of surface and interface on the thermodynamics of small particles require a deeper understanding. This step is crucial for the development of models that can be used for decision-making support to design nanomaterials with original properties. On the basis of experimental results for phase transitions in compressed ZnO nanoparticles, we show the limitations of classical thermodynamics approaches (Gibbs and Landau). We develop a new model based on the Ginzburg-Landau theory that requires the consideration of several terms, such as the interaction between nanoparticles, pressure gradients, defect density, and so on. This phenomenological approach sheds light on the discrepancies in the literature as it identifies several possible parameters that should be taken into account to properly describe the transformations. For the sake of clarity and standardization, we propose an experimental protocol that must be followed during high-pressure investigations of nanoparticles in order to obtain coherent, reliable data that can be used by the scientific community. PMID- 24341791 TI - Influence of solvent and solvent additive on the morphology of PTB7 films probed via X-ray scattering. AB - Films of the semiconducting polymer poly[[4,8-bis[(2-ethylhexyl)oxy]benzo[1,2 b:4,5-b']dithiophene-2,6-diyl][3-fluoro-2-[(2-ethylhexyl)carbonyl]thieno[3,4 b]thiophenediyl]] with 40% fluorinated monomers, denoted PTB7-F40, are spin coated out of different solvents onto PEDOT:PSS films. The influence of the used solvents chlorobenzene, 1,2-dichlorobenzene, and 1,2,4-trichlorobenzene as well as the influence of the additive 1,8-diiodooctane (DIO) is probed with grazing incidence small- and wide-angle X-ray scattering (GISAXS and GIWAXS). As seen with GISAXS, without DIO, the films are homogeneous and show roughness correlation with the PEDOT:PSS film surface. With DIO, an inner film structure with a size of 50-75 nm is found and the roughness correlations weaken. In addition, as seen in GIWAXS, the crystalline part of the films is influenced by the used solvent if DIO is added. PMID- 24341792 TI - Depression, anxiety, and suicidal ideation among Vietnamese secondary school students and proposed solutions: a cross-sectional study. AB - BACKGROUND: There is a rapidly growing public awareness of mental health problems among Vietnamese secondary school students. This study aims to determine the prevalence of anxiety, depression, and suicidal ideation, to identify related risk factors, and to explore students' own proposals for improving their mental health. METHODS: A cross-sectional study was conducted among 1161 secondary students in Can Tho City, Vietnam during September through December, 2011. A structured questionnaire was used to assess anxiety, depression, suicidal ideation and proposed solutions. Depression was measured using the Center for Epidemiology Studies Depression Scale. RESULTS: The prevalence estimates of symptoms reaching a threshold comparable to a diagnosis of anxiety and depression were 22.8% and 41.1%, respectively. Suicide had been seriously considered by 26.3% of the students, while 12.9% had made a suicide plan and 3.8% had attempted suicide. Major risk factors related to anxiety and depression were physical or emotional abuse by the family, and high educational stress. As proposed solutions, nearly 80% of students suggested that the academic workload should be reduced and that confidential counselors should be appointed at schools. About half the students stated that the attitudes of their parents and teachers needed to change. A significant majority said that they would visit a website that provided mental health support for students. CONCLUSIONS: Anxiety, depression, and suicidal ideation are common among Vietnamese secondary school students. There are strong associations with physical and emotional abuse in the family and high educational stress. Academic curricula and attitudes of parents and teachers need to be changed from a punitive to a more supportive approach to reduce the risk of poor mental health. An internet-based mental health intervention could be a feasible and effective first step to improve students' mental health. PMID- 24341793 TI - Work function modulation and thermal stability of reduced graphene oxide gate electrodes in MOS devices. AB - Work function (WF) tuning of the contact electrodes is a key requirement in several device technologies, including organic photovoltaics (OPVs), organic light-emitting diodes (OLEDs), and complementary metal oxide semiconductor (CMOS) transistors. Here, we demonstrate that the WF of the gate electrode in an MOS structure can be modulated from 4.35 eV (n-type metal) to 5.28 eV (p-type metal) by sandwiching different thicknesses of reduced graphene oxide (rGO) layers between top contact metals and gate dielectric SiO2. The WF of the gate electrode shows strong dependence on the rGO thickness and is seen to be nearly independent of the contact metals used. The observed WF modulation is attributed to the different amounts of oxygen concentrations in different thicknesses of rGO layers. Importantly, this oxygen concentration can also be varied by the reduction extent of the graphene oxide as experimentally demonstrated. The results are verified by X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy analyses. The obtained WF values are thermally stable up to 800 degrees C. At further high temperatures, diffusion of metal through the rGO sheets is the main cause for WF instability, as confirmed by cross-sectional high resolution transmission electron microscopy analysis. These findings are not limited to MOS devices, and the WF modulation technique has the potential for applications in other technologies such as OLEDs and OPVs involving graphene as conducting electrodes. PMID- 24341794 TI - A consensus surface activation marker signature is partially dependent on human immunodeficiency virus type 1 Nef expression within productively infected macrophages. AB - BACKGROUND: The high prevalence of HIV-associated comorbidities including neurocognitive disorder, high levels of residual inflammatory mediators in the plasma and cerebrospinal fluid and the resurgence of HIV replication upon interruption of antiviral treatment in HIV-1 infected individuals, strongly suggests that despite therapy HIV persists in its cellular targets which include T-lymphocytes and cells of the myeloid lineage. These reservoirs present a major barrier against eradication efforts. Knowledge of the molecular mechanisms used by HIV to modulate innate macrophage immune responses and impair viral clearance is quite limited. To explore the role of HIV in potentially modulating macrophage function through changes in protein expression, we used single-cell analyses with flow cytometry to determine whether, in unpolarized cultures, macrophage surface marker phenotype was altered by HIV infection in a manner that was independent of host genetic background. RESULTS: These analyses revealed that at several time points post-infection, GFP + HIV-infected macrophages were significantly enriched in the CD14+ fraction (3 to 5-fold, p = .0001) compared to bystander, or uninfected cells in the same culture. However, the enrichment and higher levels of CD14 on HIV expressing macrophages did not depend on the production of HIV Nef. Sixty to eighty percent of macrophages productively infected with HIV after day 28 post-infection were also enriched in the population of cells expressing the activation markers CD69 (2 to 4-fold, p < .0001) and CD86 (2 to 4-fold, p < .0001 ) but suppressed amounts of CD68 (3 to 10-fold, p < .0001) compared to bystander cells. Interestingly, there was no enrichment of CD69 on the surface of HIV producing cells that lacked Nef or expressed a variant of Nef mutated in its SH3-binding domain. CONCLUSIONS: These findings suggest that HIV actively regulates the expression of a subset of surface molecules involved in innate and inflammatory immune signaling in primary human macrophages through Nef-dependent and Nef-independent mechanisms acting within productively infected cells. PMID- 24341796 TI - The effect of keratinized mucosa width on peri-implant outcome under supportive postimplant therapy. AB - BACKGROUND: Long-ranging data on the influence of keratinized mucosa (KM) on peri implant tissue status have been scarce. PURPOSE: Retrospective evaluation of peri implant diseases and KM width in patients with versus without mucogingival surgery. MATERIALS AND METHODS: Under supportive postimplant therapy (SIT) in a private practice, 68 patients with peri-implant KM widths <1 mm were identified between 1992 and 2011 (eight dropouts). Thirty patients rejected surgery (control [C] group), and 30 patients agreed (intervention [I] group). After at least 1 year, KM width, mucositis, and peri-implant conditions were assessed. RESULTS: Sixty nonsmoking patients (n = 105 implants) were available for assessment after 12.10 +/- 4.93 years. No implants were lost (survival rate: 100%). An average of 10.69 years after surgery, the I group implants showed a mean KM gain of 3.10 +/- 1.43 mm (C group: 0 mm). The mucositis rates were as follows: I group: 38.98%; C group: 31.91%. Peri-implantitis was detected in two implants (1.87%) and two individuals (6.67%) in the I group. No significant differences between groups were found, except that the KM width values were significantly greater in the I group (p < 0.001). CONCLUSIONS: Low incidences of peri-implant diseases over long periods can be expected in patients attending SIT programs, independent of the absence or presence of KM. PMID- 24341795 TI - Antitumor activity of photodynamic therapy performed with nanospheres containing zinc-phthalocyanine. AB - BACKGROUND: The increasing incidence of cancer and the search for more effective therapies with minimal collateral effects have prompted studies to find alternative new treatments. Among these, photodynamic therapy (PDT) has been proposed as a very promising new modality in cancer treatment with the lowest rates of side effects, revealing itself to be particularly successful when the photosensitizer is associated with nanoscaled carriers. This study aimed to design and develop a new formulation based on albumin nanospheres containing zinc phthalocyanine tetrasulfonate (ZnPcS4-AN) for use in the PDT protocol and to investigate its antitumor activity in Swiss albino mice using the Ehrlich solid tumor as an experimental model for breast cancer. METHODS: Ehrlich tumor's volume, histopathology and morphometry were used to assess the efficacy of intratumoral injection of ZnPcS4-AN in containing tumor aggressiveness and promoting its regression, while the toxicity of possible treatments was assessed by animal weight, morphological analysis of the liver and kidneys, hemogram, and serum levels of total bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), alkaline phosphatase, creatinine and urea. In order to evaluate the efficacy of PDT, groups of animals treated with intratumoral injection of doxorubicin (Dox) were also investigated. RESULTS: Intratumoral injection of ZnPcS4-AN was found to be efficient in mediating PDT to refrain tumor aggressiveness and to induce its regression. Although tumor volume reduction was not significant, PDT induced a remarkable increase in the necrosis area seen in the tumor's central region, as in other experimental groups, including tumor and Dox treated groups, but also in the tumor's peripheral region. Further, PDT showed minimal adverse effects. Indeed, the use of ZnPcS4-AN in mediating PDT revealed anti-neoplastic activity similar to that obtained while using intratumoral Dox therapy. CONCLUSIONS: PDT mediated by the new formulation ZnPcS4-AN enhanced the inhibition of tumor growth while producing practically no adverse effects and thus emerges as a very promising nanotechnology-based strategy for solid cancer treatment. PMID- 24341797 TI - Soluble phenolic compounds in fresh and ensiled orchard grass (Dactylis glomerata L.), a common species in permanent pastures with potential as a biomass feedstock. AB - High-value coproducts can greatly improve the feasibility of utilizing plant feedstocks for biorefining and biofuel production. Plant polyphenolics have potential application in the pharmaceutical and cosmetic industries. Orchard grass varieties have been noted for accumulation of polyphenolic compounds, and the current study determined the soluble phenol profile and content in the orchard grass variety 'Abertop'. Hydroxycinnamates and flavonoids were monitored during the transition from vegetative to flowering stage at maximum crop yield. Caffeic acid derivatives, related to bioactives in the Asian medicinal herb Salvia miltiorrhiza , and novel hydroxycinnamate-flavone conjugates were also identified in extracts. Harvest yields of hydroxycinnamates and flavonoids ranged from 2.6 to 4.0 kg/ha and from 2.1 to 5.1 kg/ha, respectively. Abundant compounds showed high levels of antioxidant activity comparable with that of trolox. Minimal changes in soluble phenol content and composition were observed after ensiling with the exception of increases in caffeic acid, a caffeic acid derivative, and a caffeic acid breakdown product, dihydroxystyrene. PMID- 24341798 TI - Multimodality imaging of holmes heart with parachute mitral valve. PMID- 24341799 TI - The mechanism of cellulose hydrolysis by a two-step, retaining cellobiohydrolase elucidated by structural and transition path sampling studies. AB - Glycoside hydrolases (GHs) cleave glycosidic linkages in carbohydrates, typically via inverting or retaining mechanisms, the latter of which proceeds via a two step mechanism that includes formation of a glycosyl-enzyme intermediate. We present two new structures of the catalytic domain of Hypocrea jecorina GH Family 7 cellobiohydrolase Cel7A, namely a Michaelis complex with a full cellononaose ligand and a glycosyl-enzyme intermediate, that reveal details of the 'static' reaction coordinate. We also employ transition path sampling to determine the 'dynamic' reaction coordinate for the catalytic cycle. The glycosylation reaction coordinate contains components of forming and breaking bonds and a conformational change in the nucleophile. Deglycosylation proceeds via a product-assisted mechanism wherein the glycosylation product, cellobiose, positions a water molecule for nucleophilic attack on the anomeric carbon of the glycosyl-enzyme intermediate. In concert with previous structures, the present results reveal the complete hydrolytic reaction coordinate for this naturally and industrially important enzyme family. PMID- 24341800 TI - Short peptide tag for covalent protein labeling based on coiled coils. AB - To label proteins covalently, one faces a trade-off between labeling a protein specifically and using a small tag. Often one must compromise one parameter for the other or use additional components, such as an enzyme, to satisfy both requirements. Here, we report a new reaction that covalently labels proteins by using engineered coiled-coil peptides. Harnessing the concept of "proximity induced reactivity", the 21-amino-acid three-heptad peptides CCE/CCK were modified with a nucleophilic cysteine and an alpha-chloroacetyl group at selected positions. When pairs of coiled coils associated, an irreversible covalent bond spontaneously formed between the peptides. The specificity of the cross-linking reaction was characterized, the probes were improved by making them bivalent, and the system was used to label a protein in vitro and receptors on the surface of mammalian cells. PMID- 24341803 TI - Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase. AB - BACKGROUND: Synthesis and apoenzyme attachment of lipoic acid have emerged as a new complex metabolic pathway. Mutations in several genes involved in the lipoic acid de novo pathway have recently been described (i.e., LIAS, NFU1, BOLA3, IBA57), but no mutation was found so far in genes involved in the specific process of attachment of lipoic acid to apoenzymes pyruvate dehydrogenase (PDHc), alpha-ketoglutarate dehydrogenase (alpha-KGDHc) and branched chain alpha-keto acid dehydrogenase (BCKDHc) complexes. METHODS: Exome capture was performed in a boy who developed Leigh disease following a gastroenteritis and had combined PDH and alpha-KGDH deficiency with a unique amino acid profile that partly ressembled E3 subunit (dihydrolipoamide dehydrogenase / DLD) deficiency. Functional studies on patient fibroblasts were performed. Lipoic acid administration was tested on the LIPT1 ortholog lip3 deletion strain yeast and on patient fibroblasts. RESULTS: Exome sequencing identified two heterozygous mutations (c.875C > G and c.535A > G) in the LIPT1 gene that encodes a mitochondrial lipoyltransferase which is thought to catalyze the attachment of lipoic acid on PDHc, alpha-KGDHc, and BCKDHc. Anti-lipoic acid antibodies revealed absent expression of PDH E2, BCKDH E2 and alpha-KGDH E2 subunits. Accordingly, the production of 14CO2 by patient fibroblasts after incubation with 14Cglucose, 14Cbutyrate or 14C3OHbutyrate was very low compared to controls. cDNA transfection experiments on patient fibroblasts rescued PDH and alpha-KGDH activities and normalized the levels of pyruvate and 3OHbutyrate in cell supernatants. The yeast lip3 deletion strain showed improved growth on ethanol medium after lipoic acid supplementation and incubation of the patient fibroblasts with lipoic acid decreased lactate level in cell supernatants. CONCLUSION: We report here a putative case of impaired free or H protein-derived lipoic acid attachment due to LIPT1 mutations as a cause of PDH and alpha-KGDH deficiencies. Our study calls for renewed efforts to understand the mechanisms of pathology of lipoic acid-related defects and their heterogeneous biochemical expression, in order to devise efficient diagnostic procedures and possible therapies. PMID- 24341804 TI - Clinical, demographic and histopathological features of symmetrical acral keratoderma. AB - BACKGROUND: A series of cases of symmetrical acral keratoderma have been described recently in China. However, no studies about its demographic information and epidermal barrier function have been documented. OBJECTIVES: To describe the clinical manifestation, demographic information and clinicopathological features of 71 cases with symmetrical acral keratoderma. PATIENTS AND METHODS: Seventy-one cases with symmetrical acral keratoderma were retrospectively reviewed. Their demographic information, clinical manifestations, histopathology and epidermal barrier function were analysed. RESULTS: Among these patients, there were 64 males and seven females, ranging in age from 4 to 53 years with an average age at onset of 27 +/- 8.9 years. Clinical manifestation was characterized by brown hyperkeratotic patches over the dorsum of the hands, palms and feet, dorsal digits and wrists, elbows, knees and ankles. The lesions became dramatically whitish with mild swelling immediately after soaking in water and resolved spontaneously in winter. In patients, a moderate increase of transepidermal water loss (TEWL) from 16.16 +/- 6.15 to 9.9 +/- 4.21 g m(-2) h( 1) (P = 0.0054) and a moderate decrease of skin hydration from 65.9 +/- 5.06 to 42.58 +/- 10.73 (P < 0.01) in comparison with the control group were observed. Histopathological examination revealed epidermal hyperkeratosis, acanthosis and papillomatous hyperplasia as well as dermal infiltration with a few lymphocytes. CONCLUSIONS: Symmetrical acral keratoderma is characterized by symmetry, acra, keratinization and marked seasonal changes. The epidermal barrier function of the skin was negatively affected. PMID- 24341808 TI - Rough colony morphology of Mycobacterium massiliense Type II genotype is due to the deletion of glycopeptidolipid locus within its genome. AB - BACKGROUND: Recently, we introduced the complete genome sequence of Mycobacterium massiliense clinical isolates, Asan 50594 belonging to Type II genotype with rough colony morphology. Here, to address the issue of whether the rough colony morphotype of M. massiliense Type II genotype is genetically determined or not, we compared polymorphisms of the glycopeptidolipid (GPL) gene locus between M. massiliense Type II Asan 50594 and other rapidly growing mycobacteria (RGM) strains via analysis of genome databases. RESULTS: We found deletions of 10 genes (24.8 kb), in the GPL biosynthesis related gene cluster of Asan 50594 genome, but no deletions in those of other smooth RGMs. To check the presence of deletions of GPL biosynthesis related genes in Mycobacterium abscessus--complex strains, PCRs targeting 12 different GPL genes (10 genes deleted in Asan 50594 genome as well as 2 conserved genes) were applied into 76 clinical strains of the M. abscessus complex strains [54 strains (Type I: 33, and Type II: 21) of M. massiliense and 22 strains (rough morphoype: 11 and smooth morphotype: 11) of M. abscessus]. No strains of the Type II genotype produced PCR amplicons in a total of 10 deleted GPL genes, suggesting loss of GPL biosynthesis genes in the genome of M. massiliense type II genotype strains. CONCLUSIONS: Our data suggested that the rough colony morphotype of the M. massiliense Type II genotype may be acquired via deletion events at the GPL gene locus for evolutionary adaptation between the host and pathogen. PMID- 24341809 TI - Does the targeted delivery of theranostic carbon nanotubes have potential as a valid anticancer strategy? PMID- 24341810 TI - Casein-based micelles: a novel vector for delivery of the poorly soluble anticancer drug, flutamide? PMID- 24341813 TI - Multifunctional liposomes for MRI and image-guided drug delivery. AB - Liposomes are a class of nanovesicles that have been explored extensively in the biomedical arena for early diagnosis and treatment of disease. In recent years, several liposomal drug formulations have been clinically approved in oncology. In a modular approach, the properties of liposomes can be tailored for combined molecular MRI, therapy and image-guided delivery of therapeutic drugs. Over the last year, extensive research has been performed in the authors laboratory on paramagnetic liposomes as innovative imaging probes for the detection of specific molecular or cellular targets and image-guided drug delivery using multifunctional, temperature-sensitive liposomes. A number of key achievements by the authors group will be highlighted in this research spotlight. PMID- 24341814 TI - Interview with Nejat Duzgunes: liposomal carriers for gene delivery. AB - Nejat Duzgunes is professor of Microbiology in the Department of Biomedical Sciences at the University of the Pacific, Arthur A Dugoni School of Dentistry (CA, USA). He has published over 200 scientific articles and has held numerous academic positions throughout his career. Professor Duzgunes spoke to Therapeutic Delivery about his work in the field of liposomes for gene delivery, as well as discussing gene therapy methods targeting HIV and current challenges in the clinical translation of new discoveries and developments. Interview conducted by James Potticary, Assistant Commissioning Editor. PMID- 24341815 TI - Indomethacin-loaded redox nanoparticles improve oral bioavailability of indomethacin and suppress its small intestinal inflammation. AB - BACKGROUND: Continuous administration of low-dose nonsteroidal anti-inflammatory drugs such as indomethacin (IND) is associated with an increased risk of gastrointestinal damage. In this study, the authors developed IND-loaded redox nanoparticles (IND@RNP(O)) with core-shell-type polymeric micelles possessing nitroxide radicals as reactive oxygen species scavengers. RESULTS: Orally administered IND@RNP(O) significantly accumulated in the intestinal mucosa and improved blood uptake of IND. Because of the reactive oxygen species-scavenging effect, IND@RNP(O) did not cause severe inflammation in the small intestine; this effect sharply contrasted with those of orally administered free-IND and IND loaded polymeric micelles that do not possess reactive oxygen species scavengers. CONCLUSION: Oral IND@RNP(O) administration is a useful approach for improving the oral bioavailability of IND and suppressing its adverse effects. PMID- 24341816 TI - The road ahead: working towards effective clinical translation of myocardial gene therapies. AB - During the last two decades the fields of molecular and cellular cardiology, and more recently molecular cardiac surgery, have developed rapidly. The concept of delivering cDNA encoding a therapeutic gene to cardiomyocytes using a vector system with substantial cardiac tropism, allowing for long-term expression of a therapeutic protein, has moved from hypothesis to bench to clinical application. However, the clinical results to date are still disappointing. The ideal gene transfer method should be explored in clinically relevant animal models of heart disease to evaluate the relative roles of specific molecular pathways in disease pathogenesis, helping to validate the potential targets for therapeutic intervention. Successful clinical cardiovascular gene therapy also requires the use of nonimmunogenic cardiotropic vectors capable of expressing the requisite amount of therapeutic protein in vivo and in situ. Depending on the desired application either regional or global myocardial gene delivery is required. Cardiac-specific delivery techniques incorporating mapping technologies for regional delivery and highly efficient methodologies for global delivery should improve the precision and specificity of gene transfer to the areas of interest and minimize collateral organ gene expression. PMID- 24341818 TI - Dry-powder inhalers in acute asthma. AB - An updated literature search was performed to evaluate the efficacy of rapid acting beta2-agonists delivered via dry powder inhalers in the treatment of moderate-to-severe acute asthma. Databases were searched from 1985 up to December 2012. A total of 23 randomized, double-blind or open clinical studies in acute asthma comparing the efficacy of a dry powder inhaler with a pressurized metered dose inhaler or a nebulizer, and performed under controlled hospital conditions, were identified. This review found that administration of beta2-agonist bronchodilators via dry powder inhalers (formoterol, salbutamol, terbutaline and budesonide/formoterol) was effective during severe asthma worsening and acute asthma attacks, and was as effective as established therapies with a pressurized metered-dose inhaler with or without a spacer, or nebulization. These results ensure that patients can rely upon dry powder inhalers equally well as other inhaler devices during episodes of asthma worsening. PMID- 24341819 TI - A critical appraisal of microemulsions for drug delivery: part II. AB - Microemulsions are thermodynamically stable, optically transparent isotropic solutions of oil and water successfully formulated by using a combination of suitable surfactant and cosurfactant. The solubilization power of microemulsions for lipophilic, hydrophilic and amphiphilic solutes form a viable approach for enhancing the bioavailability of hydrophobic drugs and percutaneous permeation of poorly permeable drugs, mainly due to the large area per volume ratio available for mass transfer. Microemulsions have emerged as novel vehicles for drug delivery due to their versatile applications. They allow sustained release for topical, oral, nasal, intravenous, ocular, parenteral and other administration routes of drugs. They also offer a relevant application platform for improving target specificity, therapeutic activity, and reducing toxicity of drugs. PMID- 24341817 TI - Nanomicellar carriers for targeted delivery of anticancer agents. AB - Clinical application of anticancer drugs is limited by problems such as low water solubility, lack of tissue-specificity and toxicity. Formulation development represents an important approach to these problems. Among the many delivery systems studied, polymeric micelles have gained considerable attention owing to ease in preparation, small sizes (10-100 nm), and ability to solubilize water insoluble anticancer drugs and accumulate specifically at the tumors. This article provides a brief review of several promising micellar systems and their applications in tumor therapy. The emphasis is placed on the discussion of the authors' recent work on several nanomicellar systems that have both a delivery function and antitumor activity, named dual-function drug carriers. PMID- 24341820 TI - Procalcitonin guided antibiotic therapy of acute exacerbations of asthma: a randomized controlled trial. AB - BACKGROUND: This randomized controlled trial aimed to evaluate whether the serum procalcitonin (PCT) level can be utilized to guide the use of antibiotics in the treatment of acute exacerbations of asthma. METHODS: A total of 293 consecutive patients with suspected asthma attacks from February 2005 to July 2010 participated in this study. 225 patients completed the study. Serum PCT levels, and other inflammatory biomarkers of all patients were measured. In addition to the standard treatment, the control group received antibiotics according to the attending physicians' discretions, while the patients in the PCT group were treated with antibiotics according to serum PCT concentrations. Antibiotics usage was strongly discouraged when the PCT concentration was below 0.1 MUg/L; discouraged when the PCT concentration was between 0.1 MUg/L and 0.25 MUg/L; or encouraged when the PCT concentration was above 0.25 MUg/L. The primary endpoint was the determination of antibiotics usage. The second endpoints included the diagnostic accuracy of PCT and other laboratory biomarkers the effectiveness of asthma control, secondary ED visits, hospital re-admissions, repeated needs for steroids or dosage increase, needs for antibiotics, WBC count, PCT levels and FEV1%. RESULTS: At baseline, two groups were identical regarding clinical, laboratory and symptom score. Probability of the antibiotics usage in the PCT group (46.1%) was lower than that in the control group (74.8%) (chi2 = 21.97, p < 0.001. RR = 0.561, 95% CI 0.441-0.713). PCT and IL-6 showed good diagnostic significance for bacterial asthma (r = 0.705, p = 0.003). The degrees of asthma control in patients were categorized to three levels and were comparable between the two groups at the six weeks follow-up period (chi2 = 1.62, p = 0.45). There were no significant difference regarding other secondary outcomes (p > 0.05). CONCLUSIONS: The serum PCT concentration can be used to effectively determine whether the acute asthma patients have bacterial infections in the respiratory tract, and to guide the use of antibiotics in the treatment of acute asthma exacerbations, which may substantially reduce unnecessary antibiotic use without compromising the therapeutic outcomes. TRIAL REGISTRATION: ICTRP ChiCTR-TRC 12002534. PMID- 24341821 TI - Soluble receptor for advanced glycation end products as an indicator of pulmonary vascular injury after cardiac surgery. AB - BACKGROUND: Cardiac surgery is frequently complicated by an acute vascular lung injury and this may be mediated, at least in part, by the (soluble) receptor for advanced glycation end products (sRAGE). METHODS: In two university hospital intensive care units, circulating sRAGE was measured together with the 68Gallium transferrin pulmonary leak index (PLI), a measure of pulmonary vascular permeabiliy, in 60 consecutive cardiac surgery patients stratified by the amount of blood transfusion, within 3 hours of admission to the intensive care. RESULTS: Cardiac surgery resulted in elevated plasma sRAGE levels compared to baseline (315 +/- 181 vs 110 +/- 55 pg/ml, P = 0.001). In 37 patients the PLI was elevated 50% above normal. The PLI correlated with sRAGE (r2 = 0.11, P = 0.018). Plasma sRAGE discriminated well between those with an elevated PLI and those with a normal PLI (area under the operator curve 0.75; P = 0.035; 95% CI 0.55-0.95), with 91% sensitivity but low specificity of 36% at a cutoff value of 200 pg/mL. Blood transfusion did not influence sRAGE levels. CONCLUSIONS: sRAGE is elevated in plasma after cardiac surgery and indicates increased pulmonary vascular permeability. The level of sRAGE is not affected by transfusion. PMID- 24341823 TI - Using facial emotional stimuli in visual search experiments: the arousal factor explains contradictory results. AB - For more than two decades, visual search experiments using pictures of emotional faces as stimuli have generated contradictory results. Evidence of a superior detection of angry faces compared to happy faces have been mixed with an equal amount of evidence in the opposite direction. In this article, we review this literature, and examine the hypothesis that the neglected stimulus factor of emotional arousal may explain these contradictory results. Through an extensive reanalysis of results from our own laboratory as well as from other researchers, we show that the arousal factor systematically influences the outcome of the reviewed visual search experiments, and may thus provide a key to the historical contradictions within this research field. PMID- 24341822 TI - Effect of trilostane on hormone and serum electrolyte concentrations in dogs with pituitary-dependent hyperadrenocorticism. AB - BACKGROUND: The effects of trilostane on key hormones and electrolytes over 24 hours in dogs with pituitary-dependent hyperadrenocorticism (PDH) are unknown. OBJECTIVES: To determine the plasma concentration of cortisol, endogenous adrenocorticotropic hormone (ACTH), aldosterone, sodium, potassium, and ionized calcium concentrations, and plasma renin activity over a 24-hour period after administration of trilostane to dogs with well-controlled PDH. ANIMALS: Nine dogs (mean age 9.3 +/- 0.67 years, mean weight 31.9 +/- 6.4 kg) with confirmed PDH. METHODS: Prospective study. Thirty days after the first administration of trilostane, blood samples were taken at -30, 0 (baseline), 15, 30, 60, and 90 minutes, and 2, 3, 4, 6, 8, 12, 16, 20, and 24 hours after administration of trilostane and plasma concentration of cortisol, endogenous ACTH, aldosterone, sodium, potassium, ionized calcium, and renin activity were determined. RESULTS: Cortisol concentrations decreased significantly (P < .001) 2-4 hours after trilostane administration. From baseline, there was a significant (P < .001) increase in endogenous ACTH concentrations between hours 3-12, a significant increase (P < .001) in aldosterone concentration between hours 16-20, and a significant (P < .001) increase in renin activity between hours 6-20. Potassium concentration decreased significantly (P < .05) between hours 0.5-2. CONCLUSION AND CLINICAL IMPORTANCE: Treatment with trilostane did not cause clinically relevant alterations in plasma aldosterone and potassium concentration. Results suggest that in dogs with PDH, the optimal time point for an ACTH-stimulation test to be performed is 2-4 hours after trilostane dosing. Future studies are necessary to establish interpretation criteria for a 2- to 4-hour postpill ACTH stimulation test. PMID- 24341824 TI - Phytic acid in green leaves. AB - Phytic acid or phytate, the free-acid form of myo-inositolhexakiphosphate, is abundant in many seeds and fruits, where it represents the major storage form of phosphorus. Although also known from other plant tissues, available reports on the occurrence of phytic acid, e.g. in leaves, have never been compiled, nor have they been critically reviewed. We found 45 published studies with information on phytic acid content in leaves. Phytic acid was almost always detected when studies specifically tried to detect it, and accounted for up to 98% of total P. However, we argue that such extreme values, which rival findings from storage organs, are dubious and probably result from measurement errors. Excluding these high values from further quantitative analysis, foliar phytic acid-P averaged 2.3 mg.g(-1) , and represented, on average, 7.6% of total P. Remarkably, the ratio of phytic acid-P to total P did not increase with total P, we even detected a negative correlation of the two variables within one species, Manihot esculenta. This enigmatic finding warrants further attention. PMID- 24341825 TI - Minimizing the energy requirement of dewatering scenedesmus sp. by microfiltration: performance, costs, and feasibility. AB - The harvesting of the microalgae Scenedesmus species using a 200 L pilot-scale microfiltration system was investigated and critically assessed. The energy requirement was determined and correlated to the different operating parameters, such as transmembrane pressure (DeltaP), membrane area, temperature, and initial biomass concentration. A filtration model was developed and showed a strong correlation with experimental data up to 20.0 g of dry cell weight (DCW)/L. The non-optimized filtration system had an energy requirement of 2.23 kWh/m(3) with an associated cost of $0.282/kg of microalgae. The investigation into the influence of the operating parameters and scale-up effects showed that the energy requirement could be substantially reduced to 0.90 kWh/m(3) and $0.058/kg of microalgae harvested. Maintenance costs associated with cleaning were estimated to be 0.23 kWh or $0.029/batch of microalgae processed. Dependent upon the operating conditions, harvesting may represent 6-45% of the energy embedded in the microalgae with a carbon footprint of 0.74-1.67 kg of CO2/kg of microalgae. Microfiltration was demonstrated to be a feasible microalgae harvesting technology allowing for more than 99% volume reduction. The energy requirement and associated carbon footprint of microalgae harvesting reported here do not forfeit the need for an industrial-scale study; however, the information provided presents a more realistic approximation than the literature reported to date. PMID- 24341826 TI - Higher mean platelet volume level in patients with pulmonary embolism. PMID- 24341828 TI - Non-exponential kinetics and a complete folding pathway of an alpha-helical heteropeptide: direct observation and comprehensive molecular dynamics. AB - We have performed a combined experimental and computational study of the folding of a 21-residue alpha-helix-forming heteropeptide (WH21). Temperature jump kinetics with improved dynamic range at several temperatures revealed non exponential relaxation that could be well described with two time constants of 20 and 300 ns at 298 K. In the computational part, we performed multi-microsecond molecular dynamics simulations of WH21 in explicit water, using the AMBER03 and OPLS/AA potentials. The simulations were in good agreement with available experimental data on helix content and relaxation times. On the basis of 70 individual transitions, we identified the main pathways of helix unfolding. Three paths were found in both force fields, with unfolding progressing through (1) N terminus, C-terminus, and center; (2) C-terminus, N-terminus, and center; and (3) C-terminus, center, and N-terminus. An additional fourth path starting in the central region and expanding to the termini was detected only with AMBER03. Intermediate structures sampled along the pathway included a central helix with frayed termini, an off-center helix, and a helical hairpin. The simulations suggest that the short relaxation should be assigned to partly cooperative fluctuations of several neighboring hydrogen bonds. Overall, by a combination of ultrafast kinetic measurements and detailed microscopic description through comprehensive molecular dynamics, we have obtained important new insights into the helix folding process. PMID- 24341827 TI - Maize genotype and food matrix affect the provitamin A carotenoid bioefficacy from staple and carrot-fortified feeds in Mongolian gerbils (Meriones unguiculatus). AB - Biofortification to increase provitamin A carotenoids is an agronomic approach to alleviate vitamin A deficiency. Two studies compared biofortified foods using in vitro and in vivo methods. Study 1 screened maize genotypes (n = 44) using in vitro analysis, which demonstrated decreasing micellarization with increasing provitamin A. Thereafter, seven 50% biofortified maize feeds that hypothesized a one-to-one equivalency between beta-cryptoxanthin and beta-carotene were fed to Mongolian gerbils. Total liver retinol differed among the maize groups (P = 0.0043). Study 2 assessed provitamin A bioefficacy from 0.5% high-carotene carrots added to 60% staple-food feeds, followed by in vitro screening. Liver retinol was highest in the potato and banana groups, maize group retinol did not differ from baseline, and all treatments differed from control (P < 0.0001). In conclusion, beta-cryptoxanthin and beta-carotene have similar bioefficacy; meal matrix effects influence provitamin A absorption from carrot; and in vitro micellarization does not predict bioefficacy. PMID- 24341829 TI - Accuracy of Dental Implant Placement Using CBCT-Derived Mucosa-Supported Stereolithographic Template. AB - PURPOSE: The aim of the present in vivo study was to evaluate whether a difference exists between the maxilla and the mandible regarding the precision of implant placement utilizing a cone beam computed tomography (CBCT)-derived mucosa supported stereolithographic (SLA) template. MATERIALS AND METHODS: Eighty implants (44 maxilla, 36 mandible) were placed in 18 fully edentulous jaws (10 maxillas, eight mandibles) using a mucosa-supported SLA surgical template. A voxel-based registration technique was applied to match the postoperative and preoperative CBCT scans. RESULTS: Vertical deviation (p = .026) at the implant hex and angular deviation (p = .0188) were significantly lower in the maxilla than in the mandible. The global linear deviation and lateral deviation at the implant hex were not significantly different. At the implant apex, the average maximum vertical deviation was within 1 mm (0.1-4.6 mm). The average maximum lateral deviation was 1.8 mm (0.9-5.5 mm) in the maxilla and 2.3 mm (0.5-5.5 mm) in the mandible when a 15-mm-long implant was placed. CONCLUSIONS: When using CBCT-derived mucosa-supported SLA templates, clinicians should be aware of differences in the angular deviation of the implants in the mandible and maxilla. The average maximum linear deviation should be considered as a safety margin at the implant apex. PMID- 24341831 TI - Self-assembled free-standing polypyrrole nanotube membrane as an efficient FTO- and Pt-free counter electrode for dye-sensitized solar cells. AB - The construction of nanoporous conductive polymer membranes has potential applications in catalysts and energy-conversion devices. In this letter, we present a facile method to prepare free-standing polypyrrole (PPy) nanotube films by simply heating pulp-like homogeneous suspensions at a low temperature, which can be employed as a novel counter electrode (CE) to substitute for the expensive fluorine-doped tin oxide (FTO) glass and Pt used in dye-sensitized solar cells (DSSCs). The DSSCs assembled with these paper-like PPy membranes show an impressive conversion efficiency of 5.27%, which is about 84% of the cell with a conventional Pt/FTO CE (6.25%). PMID- 24341830 TI - Pulmonary infiltrates during community acquired Gram-negative bacteremia: a retrospective single centre study. AB - BACKGROUND: The primary aim of this study was to describe the frequency of pulmonary infiltrates on chest X-ray (CXR) during community acquired Gram negative bacteremia at a single centre in Denmark. METHODS: The patients were retrospectively identified from the laboratory information system and clinical and radiological data were retrieved from the electronic health records. Overall 114 patients with E.coli or K.pneumoniae bacteremia fulfilled the inclusion criteria during the period 2009-2010. RESULTS: CXR was performed in 77% of cases (80% of E.coli and 56% of K.pneumoniae) among which infiltrates were identified in 34%. The two most frequent localizations of infiltrates during E.coli bacteremia were lower lobe/basal (56%) and diffuse (22%). Furthermore, 30% of infiltrates were bilateral while 40% were present on the right lung and 30% on the left lung. CONCLUSIONS: In conclusion, the presence of infiltrates during community acquired Gram-negative bacteremia was very frequent in our population. PMID- 24341832 TI - Does the diabetes of type 2 affect the sexual functions of women? AB - This study aimed to investigate female sexual dysfunction in patients with type 2 diabetes. Using the Index of Female Sexual Function, the authors compared the sexual function of type 2 diabetic women with that of nondiabetic women. Participants were 76 sexually active women with type 2 diabetes (study group) and 100 sexually active nondiabetic women (control group); all women were 24-47 years of age and had similar backgrounds. The participants with type 2 diabetes were selected from those women who applied to the Diabetes Polyclinic of the Istanbul University. Results were analyzed using chi-square and Student's t test. The prevalence of sexual dysfunction was significantly higher among the study group than in the control group. The authors found that if HbA1c, body mass index, and duration of diabetes increase, the prevalence of sexual dysfunction also increases. The authors of this article conclude that all diabetic patients should be considered to have sexuality, and patients with sexual dysfunction should be referred to appropriate medical centers. PMID- 24341833 TI - Silicon/hematite core/shell nanowire array decorated with gold nanoparticles for unbiased solar water oxidation. AB - We report the facile fabrication of three-dimensional (3D) silicon/hematite core/shell nanowire arrays decorated with gold nanoparticles (AuNPs) and their potential application for sunlight-driven solar water splitting. The hematite and AuNPs respectively play crucial catalytic and plasmonic photosensitization roles, while silicon absorbs visible light and generates high photocurrent. Under simulated solar light illumination, solar water splitting with remarkable efficiency is achieved with no external bias applied. Such a nanocomposite photoanode design offers great promise for unassisted sunlight-driven water oxidation, and further stability and efficiency improvements to the device will lead to exciting prospects for practical solar water splitting and artificial photosynthesis. PMID- 24341834 TI - The effects of age and delay on responses to repeated questions in forensic interviews with children alleging sexual abuse. AB - We examined transcripts of forensic interviews with 115 children aged between 3 and 12 years, interviewed between 1 day and 18 months after allegedly experiencing a single incident of sexual abuse. Repeated questions were categorized with respect to the reasons why interviewers asked questions again, how interviewers asked repeated questions, and how children responded. On average, interviewers asked 3 repeated questions per interview. As age increased, the frequency of question repetition declined but there was no association between repetition and delay. Interviewers most often repeated questions for clarification (53.1%), but questions were also repeated frequently to challenge children's previous responses (23.7%), and for no apparent reason (20.1%). In response, children typically repeated (54.1%) or elaborated on (31.5%) their previous answers; they contradicted themselves less often (10.8%). Questions repeated using suggestive prompts were more likely to elicit contradictions. There was no association between age or delay and the reasons why questions were repeated, how they were repeated, and how children responded. These findings emphasize the importance of training forensic interviewers to repeat questions only when the children or interviewers seek clarification and to encourage children who are anxious or reluctant to disclose. All repeated questions should be open-ended and interviewers should explain to children why questions are being repeated. PMID- 24341835 TI - Post-identification feedback to eyewitnesses impairs evaluators' abilities to discriminate between accurate and mistaken testimony. AB - Giving confirming feedback to mistaken eyewitnesses has robust distorting effects on their retrospective judgments (e.g., how certain they were, their view, etc.). Does feedback harm evaluators' abilities to discriminate between accurate and mistaken identification testimony? Participant-witnesses to a simulated crime made accurate or mistaken identifications from a lineup and then received confirming feedback or no feedback. Each then gave videotaped testimony about their identification, and a new sample of participant-evaluators judged the accuracy and credibility of the testimonies. Among witnesses who were not given feedback, evaluators were significantly more likely to believe the testimony of accurate eyewitnesses than they were to believe the testimony of mistaken eyewitnesses, indicating significant discrimination. Among witnesses who were given confirming feedback, however, evaluators believed accurate and mistaken witnesses at nearly identical rates, indicating no ability to discriminate. Moreover, there was no evidence of overbelief in the absence of feedback whereas there was significant overbelief in the confirming feedback conditions. Results demonstrate that a simple comment following a witness' identification decision ("Good job, you got the suspect") can undermine fact-finders' abilities to discern whether the witness made an accurate or a mistaken identification. PMID- 24341836 TI - Evaluator differences in Psychopathy Checklist-Revised factor and facet scores. AB - Recent research suggests that the reliability of some measures used in forensic assessments--such as Hare's (2003) Psychopathy Checklist-Revised (PCL-R)--tends to be weaker when applied in the field, as compared with formal research studies. Specifically, some of the score variability in the field is attributable to evaluators themselves, rather than the offenders they evaluate. We studied evaluator differences in PCL-R scoring among 558 offenders (14 evaluators) and found evidence of large evaluator differences in scoring for each PCL-R factor and facet, even after controlling for offenders' self-reported antisocial traits. There was less evidence of evaluator differences when we limited analyses to the 11 evaluators who reported having completed a PCL-R training workshop. Findings provide indirect but positive support for the benefits of PCL-R training, but also suggest that evaluator differences may be evident to some extent in many field settings, even among trained evaluators. PMID- 24341837 TI - Do confessions taint perceptions of handwriting evidence? An empirical test of the forensic confirmation bias. AB - Citing classic psychological research and a smattering of recent studies, Kassin, Dror, and Kukucka (2013) proposed the operation of a forensic confirmation bias, whereby preexisting expectations guide the evaluation of forensic evidence in a self-verifying manner. In a series of studies, we tested the hypothesis that knowing that a defendant had confessed would taint people's evaluations of handwriting evidence relative to those not so informed. In Study 1, participants who read a case summary in which the defendant had previously confessed were more likely to erroneously conclude that handwriting samples from the defendant and perpetrator were authored by the same person, and were more likely to judge the defendant guilty, compared with those in a no-confession control group. Study 2 replicated and extended these findings using a within-subjects design in which participants rated the same samples both before and after reading a case summary. These findings underscore recent critiques of the forensic sciences as subject to bias, and suggest the value of insulating forensic examiners from contextual information. PMID- 24341838 TI - Involuntary civil commitment: communicating with the court regarding "danger to other". AB - Beginning in the 1990s, researchers in the field of violence risk assessment recognized that even the most accurate and valid assessment could not assist fact finders if the information was communicated in an unclear, imprecise, and/or incomplete manner (Monahan & Steadman, 1996; Schopp, 1996). The purpose of the current study was to investigate judges' opinions regarding the probative value of risk communication messages in civil commitment proceedings. Three types of risk communication messages were investigated: (1) description; (2) prediction; and (3) management. Additionally, the risk prediction model was investigated more in-depth by varying the format used to communicate the prediction: (1) categorical; (2) frequency; and (3) probabilistic. A national sample of 403 judges completed the study and via random selection, each received one of 10 risk vignettes. The vignettes described a situation in which a person underwent an evaluation for civil commitment based on the danger to other criteria; danger to self criteria was not at issue in this case. Risk messages and risk level were systematically varied. This study found that the risk models (i.e., description, prediction, and management) were viewed as equally probative. However, within the risk prediction model, categorical messages were viewed as the having the highest probative value. Results also indicated that of the three models, the risk prediction model led to rulings that are more strict than the other risk models, but no one risk prediction format resulted in higher restrictiveness. Results of this study can be used to provide mental health professionals some guidance as to how to present their data such that judges find the information easy to interpret and probative to their decisions. PMID- 24341839 TI - Auditory pre-experience modulates classification of affect intensity: evidence for the evaluation of call salience by a non-human mammal, the bat Megaderma lyra. AB - INTRODUCTION: Immediate responses towards emotional utterances in humans are determined by the acoustic structure and perceived relevance, i.e. salience, of the stimuli, and are controlled via a central feedback taking into account acoustic pre-experience. The present study explores whether the evaluation of stimulus salience in the acoustic communication of emotions is specifically human or has precursors in mammals. We created different pre-experiences by habituating bats (Megaderma lyra) to stimuli based on aggression, and response, calls from high or low intensity level agonistic interactions, respectively. Then we presented a test stimulus of opposite affect intensity of the same call type. We compared the modulation of response behaviour by affect intensity between the reciprocal experiments. RESULTS: For aggression call stimuli, the bats responded to the dishabituation stimuli independent of affect intensity, emphasising the attention-grabbing function of this call type. For response call stimuli, the bats responded to a high affect intensity test stimulus after experiencing stimuli of low affect intensity, but transferred habituation to a low affect intensity test stimulus after experiencing stimuli of high affect intensity. This transfer of habituation was not due to over-habituation as the bats responded to a frequency-shifted control stimulus. A direct comparison confirmed the asymmetric response behaviour in the reciprocal experiments. CONCLUSIONS: Thus, the present study provides not only evidence for a discrimination of affect intensity, but also for an evaluation of stimulus salience, suggesting that basic assessment mechanisms involved in the perception of emotion are an ancestral trait in mammals. PMID- 24341840 TI - Pancreaticoduodenectomy for biliary tract carcinoma with situs inversus totalis: difficulties and technical notes based on two cases. AB - Situs inversus totalis (SIT) denotes complete right-left inversion of the thoracic and abdominal viscera. Diagnosis and surgical procedures for abdominal pathology in patients with SIT are technically more complicated because of mirror image transposition of the visceral organs. Moreover, SIT is commonly associated with cardiovascular and hepatobiliary malformations, which make hepatobiliary pancreatic surgery difficult. Two cases of pancreaticoduodenectomy for biliary tract carcinoma in patients with SIT are presented. Both patients had an anomaly of the hepatic artery. Advanced diagnostic imaging techniques were very important for careful preoperative planning and to prevent misunderstanding of the arrangement of the abdominal viscera. This facilitated the surgical team's adaptation to the mirror image of the standard procedure and helped avoid intraoperative complications due to cardiovascular and hepatobiliary malformations associated with SIT. Pancreaticoduodenectomy in patients with SIT can be performed successfully with detailed preoperative assessment, use of effective techniques by the surgeon, and appropriate support by assistants. PMID- 24341841 TI - Severity of coronary artery disease and echocardiographic parameters of ventricular diastolic function. AB - OBJECTIVE: The objective of this study was to determine the relation between the severity of the coronary artery disease (CAD) and left ventricular (LV) diastolic function in patient with stable CAD and normal LV ejection fraction. METHODS: Sixty patients with stable CAD were included in the study. All angiographic variables pertinent to SYNTAX Score (SS) and Gensini score (GS) calculation were computed by two experienced interventional cardiologists. All patients underwent echocardiographic examination. RESULTS: We divided the patients into 4 groups according to median of SS and GS. It was observed that LV diastolic function was impaired in 26 patients (86.7%) in under group of SS, 23 patients (76.7%) in upper group of SS, and 27 patients (87.1%) in under group of GS, and 22 patients (75.9%) in upper group of GS. There was no significant difference between the SS, GS, clinical, and echocardiographic findings. CONCLUSION: The diastolic function did not demonstrate any impairment according to the severity of the CAD in patients which coronary angiography performed with the diagnosis of stable CAD. PMID- 24341842 TI - A comprehensive evaluation of selected components and processes used in the manufacture of cigarettes: approach and overview. AB - CONTEXT: In addition to tobacco and cigarette ingredients, there are many non tobacco components and processes used to manufacture commercial cigarettes. Proposed cigarette components and manufacturing process changes were evaluated using a tiered toxicological testing program. OBJECTIVE: The toxicological testing and evaluation of proposed changes to selected non-tobacco cigarette components and manufacturing processes are described in this special report. MATERIALS AND METHODS: Selected non-tobacco cigarette components and manufacturing processes were evaluated using experimental and control cigarettes. These experimental cigarettes were evaluated using mainstream smoke chemistry, bacterial mutagenicity and cytotoxicity assays. In some evaluations, 90-day nose only mainstream smoke inhalation studies using rats were performed. RESULTS: Some proposed design changes were not implemented, or limitations on their use were established. Most study results, however, were similar to those previously reported in the scientific literature for design changes in cigarette construction. CONCLUSION: The studies reported in the series of publication demonstrate that our testing approach is feasible for evaluation of cigarette component and manufacturing process changes. PMID- 24341843 TI - A comprehensive toxicological evaluation of three adhesives using experimental cigarettes. AB - CONTEXT: Adhesives are used in several different manufacturing operations in the production of cigarettes. The use of new, "high-speed-manufacture" adhesives (e.g. vinyl acetate based) could affect the smoke chemistry and toxicology of cigarettes, compared with older "low-speed-manufacture" adhesives (e.g. starch based). OBJECTIVE: This study was conducted to determine whether the inclusion of different levels of three adhesives (ethylene vinyl acetate, polyvinyl acetate and starch) in experimental cigarettes results in different smoke chemistry and toxicological responses in in vitro and in vivo assays. MATERIALS AND METHODS: A battery of tests (analytical chemistry, in vitro and in vivo assays) was used to compare the chemistry and toxicology of smoke from experimental cigarettes made with different combinations of the three adhesives. Varying levels of the different side-seam adhesives, as well as the transfer of adhesives from packaging materials, were tested. RESULTS: There were differences in some mainstream cigarette smoke constituents as a function of the level of adhesive added to experimental cigarettes and between the tested adhesives. None of these differences translated into statistically significant differences in the in vitro or in vivo assays. CONCLUSION: The use of newer "high-speed-manufacture" vinyl acetate-based adhesives in cigarettes does not produce toxicological profiles that prevent the adhesives from replacing the older "low-speed-manufacture" adhesives (such as starch). PMID- 24341844 TI - A comprehensive evaluation of the toxicology of experimental cigarettes manufactured with banded papers. AB - CONTEXT: To comply with state requirements, cigarette manufacturers have added low-permeability bands to the cigarette paper. These bands can extinguish the cigarette when it is no longer being puffed by a smoker. OBJECTIVE: This study was conducted to evaluate the toxicology resulting from the addition of different types of bands to experimental cigarettes. MATERIALS AND METHODS: A battery of assays that are typically used in toxicology studies with cigarette smoke, namely smoke chemistry, in vitro mutagenicity and cytotoxicity, and inhalation studies with rats, were used to evaluate different band characteristics added to cigarette paper. RESULTS: Although differences in the amount of band material was associated with an increase in some metals measured in mainstream tobacco smoke, it was not dose responsive to any band design parameter (base paper permeability, band width, band spacing, band chalk amount, or citrate). Occasional, minor differences were produced by the different types of bands; overall, there was no increased toxicity. CONCLUSION: Although there were increases and decreases in some mainstream smoke constituents, the in vitro and in vivo testing performed demonstrated that low-permeability bands on cigarettes do not modify the toxicity of smoke inhaled by smokers. PMID- 24341845 TI - A comprehensive evaluation of the toxicology of monogram inks added to experimental cigarettes. AB - CONTEXT: Cigarettes often have a small identifying mark (monogram) printed either on the cigarette paper toward the filter end of the cigarette or on the tipping paper. OBJECTIVE: A battery of tests was used to compare the toxicology of mainstream smoke from experimental cigarettes manufactured with different monogram inks. Cigarettes with different concentrations of different pigments were compared with cigarettes without ink, and with a control ink. MATERIALS AND METHODS: Smoke from each of the experimental cigarettes was evaluated using analytical chemistry and in vitro bacterial mutagenicity (Salmonella, five strains, +/- S9) and cytotoxicity (neutral red uptake) assays. RESULTS: No differences were observed between experimental cigarettes printed with three different pigment loads of iron oxide-based Black pigment and non-printed cigarettes. In general, no dose response was observed. However, increases in certain smoke constituents were found to correlate with Pigment Yellow 14 (also known as benzidine yellow) and Pigment Blue 15 (copper phthalocyanine). Increases in bacterial mutagenicity were observed for high-level print of Pigment Yellow 14 in TA98 and TA1537 and the high-level print of Pigment Blue 15 in TA98. In vitro cytotoxicity of mainstream smoke was unaffected by the presence of monogram ink on cigarettes. CONCLUSION: Statistically significant dose-responsive constituent changes and an increase in mutagenicity were observed with inclusion of Pigment Yellow 14 and Pigment Blue 15. Other pigments showed minimal toxicological activity. PMID- 24341846 TI - A comprehensive evaluation of the toxicology of different cut widths of tobacco in experimental cigarettes. AB - CONTEXT: Literature suggests that the width of tobacco strips in cigarettes may affect the smoke chemistry and toxicology of such products. OBJECTIVE: A comprehensive analysis of smoke from experimental cigarettes can be used to determine whether different cut widths of tobacco result in different toxicological activity. MATERIALS AND METHODS: A battery of tests was used to compare the chemistry and in vitro and in vivo toxicology of smoke from experimental cigarettes made with tobacco cut to different widths. RESULTS: Different cut widths of tobacco did not elicit consistent and significant differences in cigarette smoke chemistry, responses in in vitro mutagenicity or cytotoxicity assays or most endpoints in 90-d rat inhalation studies. Of note, however, were atypical in-life observations and slightly depressed body weights observed in two rat inhalation studies. CONCLUSION: Most of our data indicate that different cut widths of tobacco used in cigarettes are unlikely to change the toxicity of mainstream cigarette smoke; however, without additional investigation, the atypical in-life observations and depression in body weights cast doubt on the toxicological acceptability of cutting the tobacco into wider shreds. PMID- 24341847 TI - A comprehensive evaluation of the toxicology resulting from laser-generated ventilation holes in cigarette filters. AB - CONTEXT: Recent technological advances allow ventilation holes in (or adjacent to) cigarette filters to be produced using lasers instead of using the mechanical procedures of earlier techniques. OBJECTIVE: Analytical chemistry can be used to compare the composition of mainstream smoke from experimental cigarettes having filters with mechanically produced ventilation holes to that of cigarettes with ventilation holes that were produced using laser technology. MATERIALS AND METHODS: Established procedures were used to analyze the smoke composition of 38 constituents of mainstream smoke generated using standard conditions. RESULTS: There were no differences between the smoke composition of cigarettes with filter ventilation holes that were produced mechanically or through use of laser technology. CONCLUSION: The two methods for producing ventilation holes in cigarette filters are equivalent in terms of resulting mainstream smoke chemistry, at two quite different filter ventilation percentages. PMID- 24341848 TI - A comprehensive evaluation of the toxicology of the "Deli" cast sheet process used in experimental cigarettes. AB - CONTEXT: Manufacture of cigarettes results in tobacco by-products, some of which can be processed and added back to cigarettes. Such additions (known as reconstituted tobacco or reconstituted leaf) have been shown to reduce tar yields. A new process (termed "Deli" cast sheet) is a potential refinement of the reconstitution process. OBJECTIVE: Compare toxicity of smoke from experimental cigarettes made with reconstituted leaf with that from cigarettes made with Deli cast sheet. MATERIALS AND METHODS: Analytical chemistry, Salmonella mutagenicity and cytotoxicity assays were used to evaluate the composition biological activity of mainstream smoke from experimental cigarettes made with Deli cast sheet or with reconstituted leaf. The effect of different amounts of guar and propylene glycol in Deli cast sheet was also evaluated. RESULTS: Small increases in the amount of nitrogen oxides were found as a result of inclusion of the Deli cast sheet when compared with reconstituted leaf; no differences in cytotoxicity or mutagenicity were found. CONCLUSION: The Deli process neither significantly modified chemical composition of smoke nor affected its biological activity, as measured by the mutagenicity and cytotoxicity assays used here. PMID- 24341849 TI - A comprehensive evaluation of the toxicology of experimental, non-filtered cigarettes manufactured with different circumferences. AB - CONTEXT: Historical work indicates that cigarette circumference may affect the toxicological profile of experimental cigarettes. OBJECTIVE: Studies were conducted to examine the effect of different cigarette circumferences on (1) selected mainstream smoke constituents including concentrations of tobacco specific nitrosamines (TSNA) in smoke and (2) mutagenicity and cytotoxicity of cigarette smoke condensate. MATERIALS AND METHODS: Analytical chemistry, Salmonella mutagenicity and cytotoxicity assays were used to evaluate the composition and biological activity of mainstream smoke from experimental, non filtered cigarettes manufactured with four different circumferences (17.0-27.1 mm). RESULTS: Most smoke constituents, including TSNA, decreased with decreasing cigarette circumference; however, amounts of hydrogen cyanide increased in a non circumference dependent manner. Mutagenicity and cytotoxicity also decreased slightly with decreasing cigarette circumference. CONCLUSION: Cigarette circumference may have a minor role in the toxicological profile of experimental cigarettes, with a so-far-unidentified mechanism. PMID- 24341852 TI - Emotion recognition of static and dynamic faces in autism spectrum disorder. AB - There is substantial evidence for facial emotion recognition (FER) deficits in autism spectrum disorder (ASD). The extent of this impairment, however, remains unclear, and there is some suggestion that clinical groups might benefit from the use of dynamic rather than static images. High-functioning individuals with ASD (n = 36) and typically developing controls (n = 36) completed a computerised FER task involving static and dynamic expressions of the six basic emotions. The ASD group showed poorer overall performance in identifying anger and disgust and were disadvantaged by dynamic (relative to static) stimuli when presented with sad expressions. Among both groups, however, dynamic stimuli appeared to improve recognition of anger. This research provides further evidence of specific impairment in the recognition of negative emotions in ASD, but argues against any broad advantages associated with the use of dynamic displays. PMID- 24341850 TI - Ventriculomegaly associated with ependymal gliosis and declines in barrier integrity in the aging human and mouse brain. AB - Age-associated ventriculomegaly is typically attributed to neurodegeneration; however, additional factors might initiate or contribute to progressive ventricular expansion. By directly linking postmortem human MRI sequences with histological features of periventricular tissue, we show that substantial lateral ventricle surface gliosis is associated with ventriculomegaly. To examine whether loss of ependymal cell coverage resulting in ventricle surface glial scarring can lead directly to ventricle enlargement independent of any other injury or degenerative loss, we modeled in mice the glial scarring found along the lateral ventricle surface in aged humans. Neuraminidase, which cleaves glycosidic linkages of apical adherens junction proteins, was administered intracerebroventricularly to denude areas of ependymal cells. Substantial ependymal cell loss resulted in reactive gliosis rather than stem cell-mediated regenerative repair of the ventricle lining, and the gliotic regions showed morphologic and phenotypic characteristics similar to those found in aged humans. Increased levels of aquaporin-4, indicative of edema, observed in regions of periventricular gliosis in human tissue were also replicated in our mouse model. 3D modeling together with volume measurements revealed that mice with ventricle surface scarring developed expanded ventricles, independent of neurodegeneration. Through a comprehensive, comparative analysis of the lateral ventricles and associated periventricular tissue in aged humans and mouse, followed by modeling of surface gliosis in mice, we have demonstrated a direct link between lateral ventricle surface gliosis and ventricle enlargement. These studies highlight the importance of maintaining an intact ependymal cell lining throughout aging. PMID- 24341851 TI - The early phase transcriptome of bovine monocyte-derived macrophages infected with Staphylococcus aureus in vitro. AB - BACKGROUND: In the mammary gland, local recruitment and action of macrophages is a key immunological defence mechanism against infection. Macrophages are members of the innate immune system, serve as the first line of the defence against invading pathogens and are critical effectors and regulators of inflammation. We have examined the early phase response of bovine macrophages to infection with live Staphylococcus aureus. Genome-wide transcript profiling of blood monocyte derived macrophages from six Norwegian Red heifers infected with live S. aureus for 2 and 6 hours in vitro was performed. RESULTS: About 420 of the 17 000 genes on the ARK-Genomics bovine cDNA array were differentially regulated at 6 hours post infection. Approximately 70% of the responding genes had a known identity (Entrez Gene ID) and were used in the identification of overrepresented pathways and biological functions in the dataset.Analysis of a subset of differentially regulated genes (List eQG) obtained by comparison with data from genome-wide association mapping in Norwegian Red cattle identified anti-inflammatory cytokines interleukin 4 and interleukin 13 as putative expression quantitative trait loci, suggesting that S. aureus infection triggers alternative activation of macrophages. Moreover, several classical activation pathways were found, mainly cellular immune response and cytokine signaling pathways, i.e. triggering receptor expressed on myeloid cells 1 (TREM1) and nucleotide-binding and oligomerization domain-like receptor (NLR) pathways. Tumor necrosis factor receptor superfamily member 5 (CD40 ligand) was identified as an upstream regulator which points toward CD40 likely acting as a co-stimulatory receptor during Toll-like receptor 2(TLR2)-mediated inflammatory response of bovine macrophages to S. aureus infection. Furthermore, peptidoglycan was identified as an upstream regulator in the List eQG, which indicates that this bacterial cell wall component might be pivotal in macrophage intracellular bacterial recognition during early inflammation. CONCLUSIONS: Here we have shown that in vitro infection of bovine macrophages with live S. aureus induced both alternative and classical activation pathways. Alternative activation of macrophages may be a mechanism contributing to intracellular persistence of S. aureus in the course of inflammation such as during mastitis in dairy cattle. PMID- 24341853 TI - Postradiation cutaneous pleomorphic rhabdomyosarcoma with extracellular collagen deposits reminiscent of so-called amianthoid fibers. AB - Rhabdomyosarcoma is a malignant mesenchymal neoplasm that rarely presents as primary skin tumor. So-called amianthoid fibers are hyalinized collagen mats that have been described in myofibroblastic tumors but not in rhabdomyosarcoma. A 65 year-old male developed a submandibular nodule 9 years after an oral squamous cell carcinoma, which had been treated with chemotherapy and radiotherapy. Histological examination of the nodule revealed a pleomorphic rhabdomyosarcoma with extracellular collagen deposits reminiscent of so-called amianthoid fibers. By immunohistochemistry, the tumor cells were positive for vimentin, desmin, smooth muscle actin (SMA), muscle-specific actin (MSA), CD10, CD56, CD99, beta catenin and D2-40. However, only 15-20% of the tumor cells were positive for myoglobin, MyoD1 and myf-4/myogenin. We describe first so-called amianthoid fibers harboring blood capillaries in a rhabdomyosarcoma, suggesting that they are rigid collagen structures that lead to tumor vascularization. The low expression for myogenic regulatory proteins and strong expression for other markers may be misleading and do not contribute to the diagnosis of rhabdomyosarcoma. PMID- 24341854 TI - Facial and extrafacial eosinophilic pustular folliculitis: a clinical and histopathological comparative study. AB - BACKGROUND: Although more than 300 cases of eosinophilic pustular folliculitis (EPF) have been reported to date, differences in clinicohistopathological findings among affected sites have not yet been evaluated. OBJECTIVES: To evaluate differences in the clinical and histopathological features of facial and extrafacial EPF. METHODS: Forty-six patients diagnosed with EPF were classified into those with facial and extrafacial disease according to the affected site. Clinical and histopathological characteristics were retrospectively compared, using all data available in the patient medical records. RESULTS: There were no significant between-group differences in subject ages at presentation, but a male predominance was observed in the extrafacial group. In addition, immunosuppression-associated type EPF was more common in the extrafacial group. Eruptions of plaques with an annular appearance were more common in the facial group. Histologically, perifollicular infiltration of eosinophils occurred more frequently in the facial group, whereas perivascular patterns occurred more frequently in the extrafacial group. Follicular mucinosis and exocytosis of inflammatory cells in the hair follicles were strongly associated with facial EPF. CONCLUSIONS: The clinical and histopathological characteristics of patients with facial and extrafacial EPF differ, suggesting the involvement of different pathogenic processes in the development of EPF at different sites. PMID- 24341855 TI - Design and characterization of an injectable tendon hydrogel: a novel scaffold for guided tissue regeneration in the musculoskeletal system. AB - A biocompatible hydrogel consisting of extracellular matrix (ECM) from human tendons is described as a potential scaffold for guided tissue regeneration and tissue engineering purposes. Lyophilized decellularized tendons were milled and enzymatically digested to form an ECM solution. The ECM solution properties are assessed by proteome analysis with mass spectrometry, and the material's rheological properties are determined as a function of frequency, temperature, and time. In vivo application of the gel in a rat model is assessed for remodeling and host cell repopulation. Histology for macrophage invasion, fibroblast repopulation, and nanoscale properties of the gel is assessed. Gel interaction with multipotent adipoderived stem cells (ASCs) is also addressed in vitro to assess possible cytotoxicity and its ability to act as a delivery vehicle for cells. Proteome analysis of the ECM-solution and gel mass spectroscopy identified the most abundant 150 proteins, of which two isoforms of collagen I represented more than 55% of the sample. Rheology showed that storage (G') and loss (G") of the ECM solution were stable at room temperature but displayed sigmoidal increases after ~15 min at 37 degrees C, matching macroscopic observations of its thermo responsiveness. G' and G" of the gel at 1 rad/s were 213.1+/-19.9 and 27.1+/-2.4 Pa, respectively. Electron microscopy revealed fiber alignment and good structural porosity in the gel, as well as invasion of cells in vivo. Histology also showed early CD68(+) macrophage invasion throughout the gel, followed by increasing numbers of fibroblast cells. ASCs mixed with the gel in vitro proliferated, indicating good biocompatibility. This ECM solution can be delivered percutaneously into a zone of tendon injury. After injection, the thermoresponsive behavior of the ECM solution allows it to polymerize and form a porous gel at body temperature. A supportive nanostructure of collagen fibers is established that conforms to the three-dimensional space of the defect. This hydrogel holds the distinctive composition specific for tendon ECM, where tissue specific cues facilitate host cell infiltration and remodeling. The results presented indicate that injectable ECM materials from tendon may offer a promising alternative in the treatment of tendinopathies and acute tendon injuries. PMID- 24341856 TI - Prevention of stricture recurrence following urethral endoscopic management: what do we have? AB - OBJECTIVE: Strictures of the urethra are the most common cause of obstructed micturition in younger men and there is frequent recurrence after initial treatment. This review was performed to determine the best strategy for stricture recurrence prevention following urethral endoscopic management. METHODS: We reviewed the published literature in PubMed, the Cochrane Library, and Google Scholar focusing on this intractable problem regardless of language restrictions. Outcomes of interest included the study methods and the applied strategy's efficacy. The level of evidence and grade of recommendations of included studies were appraised with an Oxford Centre for Evidence-Based Medicine Scale. RESULTS: Currently, numerous techniques, including catheterization, repeated dilation, brachytherapy, and intraurethral use of various antifibrosis agents, have been employed to oppose the process of wound contraction or regulate the extracellular matrix. But unfortunately, none of these techniques or agents have demonstrated efficacy with enough evidence. CONCLUSIONS: Although lots of strategies are available, still, we do not have a suitable, single optimum solution for all the conditions. The clinical decision of stricture-recurrence-prevention techniques should be carefully tailored to every individual patient. As the studies are not sufficient, more efforts are warranted to address this interesting but challenging issue. PMID- 24341857 TI - Cognitive profile in patients with a first-ever lacunar infarct with and without silent lacunes: a comparative study. AB - BACKGROUND: The detection of early neuropsychological abnormalities as precursors of cognitive decline of vascular origin in patients with lacunar stroke is a subject of increasing interest. The objective of this study was to assess whether there were differences in the performance of a battery of neuropsychological tests in first-ever lacunar stroke patients with and without associated silent multiple lacunar infarctions found incidentally on the brain magnetic resonance imaging (MRI) scan. METHODS: A total of 72 consecutive patients with first-ever lacunar infarction were studied 1 month after stroke. All patients underwent a comprehensive neuropsychological evaluation, which included the California Verbal Learning Test (CVLT), Phonetic Verbal Fluency Test (PMR), Semantic Verbal Fluency Test (category "animals"), Digit Span Forward and Backward from the Wechsler Adult Intelligence Scale (WAIS-III), and Mini-Mental State Examination (MMSE). RESULTS: A total of 38 patients (52.7%) had silent multiple lacunar infarcts, with corona radiata as the most frequent topography (P < 0.023). White matter hyperintensities (leukoaraiosis) were observed in 81.1% of patients with silent multiple lacunar infarcts and in 50% with a single lacunar infarction (P < 0.007). Patients in both groups showed similar scores in the MMSE, but those with associated silent lacunar infarctions showed a poorer performance in the semantic fluency test (P < 0.008) and in short delayed verbal memory (P < 0.001). In both cases, however, leukoaraiosis was not statistically significant in multivariate linear regression models adjusted by confounding covariates. In these models, multiple silent lacunar infarctions and education were independent predictors of poor performance in the semantic fluency test and in short delayed verbal memory. CONCLUSIONS: The presence of silent multiple lacunar infarctions documented on brain MRI scans in patients with first-ever lacunar stroke was associated with mild neuropsychological abnormalities, particularly in the performance of executive functions (semantic fluency) and short delayed verbal memory. According to these findings, in the initial stages of small vessel disease, mild neuropsychological abnormalities appear to be related to lacunes rather than to leukoaraiosis or perivascular hyperintensities of vascular cause. PMID- 24341859 TI - Rheology of disentangled multiwalled carbon nanotubes dispersed in uncured epoxy fluid. AB - The rheological behaviors of clustered and disentangled multiwalled carbon nanotubes (MWCNTs) dispersed in a stable, non-reactive Newtonian epoxy fluid have been investigated. Suspensions of untreated and chemically oxidized MWCNTs in epoxy show strong rate-dependent behavior and long-time elastic response that is characteristic of a flocculated microstructure. Suspensions of disentangled MWCNTs in epoxy were prepared by a functionalization reaction with nitrobenzene, and show distinct rheological behavior that is attributed to the motion and rotation of the individual nanoparticles. Characteristic features of the disentangled MWCNTs in epoxy are a lack of low-frequency plateau in storage modulus and shear thickening behavior at high shear rate. The rheological behavior is discussed on the basis of continuum-level predictions for the motion of individual, semiflexible fibers under shearing flows. Implications of MWCNT disentanglement on fundamental study and applications of MWCNT-filled systems are discussed. PMID- 24341858 TI - Increased impulsivity in rats as a result of repeated cycles of alcohol intoxication and abstinence. AB - Impulsivity is a risk factor for alcoholism, and long-term alcohol exposure may further impair impulse control in a manner that propels problematic alcohol use. The present study employed the rat 5-choice serial reaction time task (5-CSRTT) to measure behavioral inhibition and attentional capacity during abstinence from repeated 5-day cycles of alcohol liquid diet consumption. Task performance was not disrupted following the first cycle of alcohol exposure; however, evidence of impaired behavioral inhibition emerged following the third cycle of alcohol exposure. In comparison with controls, alcoholic rats exhibited deficits in inhibitory control during cognitively challenging 5-CSRTT tests employing variable intertrial interval (varITI). This behavioral disruption was not present during early abstinence (3 days) but was evident by 7 days of abstinence and persisted for at least 34 days. Interestingly, renewed alcohol consumption ameliorated these disruptions in impulse control, although deficient behavioral inhibition re-emerged during subsequent abstinence. Indices of increased impulsivity were no longer present in tests conducted after 49 days of abstinence. Alcohol-related impairments in impulse control were not evident in sessions employing highly familiar task parameters regardless of the abstinence period, and control experiments confirmed that performance deficits during the challenge sessions were unlikely to result from alcohol-related disruption in the adaptation to repeated varITI testing. Together, the current findings demonstrate that chronic intermittent alcohol consumption results in decreased behavioral inhibition in rats that is temporally similar to clinical observations of disrupted impulsive control in abstinent alcoholics performing tasks of behavioral inhibition. PMID- 24341860 TI - Application of Ni-Ti alloy connector for the treatment of comminuted coronal plane supracondylar-condylar femoral fractures: a retrospective review of 21 patients. AB - BACKGROUND: Our preliminary retrospective study assessed outcomes after the use of Ni-Ti arched shape-memory connector (ASC) combined with partially threaded cancellous screws (PTCS) to repair coronal plane supracondylar-condylar femoral fractures. METHODS: Twenty-one patients (16 men and 5 women) with a mean age of 34.1 years (range, 28 to 44 years) with coronal plane supracondylar and condylar fractures of the distal femur were included in this study. Each patient underwent open reduction and internal fixation using the ASC and PTCS. Active functional exercises with restricted weight bearing were initiated the first postoperative day. A gradual increase in weight bearing status and range of motion was permitted and subjects progressed to full weight bearing by 8 weeks. Surgical time, blood loss, postoperative knee range of motion, American Knee Society Scores (KSS), and postoperative complications were assessed. RESULTS: The mean surgical time was 75 mins (range, 45 to 100 mins) and average blood loss was 105 ml (range, 35 to 130 ml). Mean follow-up was 65 months (range, 22 to 90 months). No subjects demonstrated evidence of osteonecrosis or arthritis at the final follow-up. The mean KSS was excellent (>=85) in 8 subjects, good (70-84) in 11 subjects, and fair (60-69) in 2 subjects. The mean active range of motion of knee flexion at final follow-up was 100 degrees (range, 85 to 110 degrees). CONCLUSIONS: ASC combined with PTCS can serve as an effective means for managing comminuted femoral fractures that extend from the condyle to the supracondylar region. However, further prospective comparative studies and biomechanical analyses are needed to evaluate long-term outcomes using these materials. PMID- 24341861 TI - The relationship between emotion regulation difficulties and psychopathic personality characteristics. AB - The factors of psychopathy assessment tools diverge in their relationships with numerous problematic behaviors and psychological disorders. Emotion dysregulation is a pathological process argued to cut across diagnoses, and may be important in better understanding these divergent associations. This study sought to clarify psychopathy's association with emotion regulation difficulties. It was predicted that the Fearless Dominance and Self-Centered Impulsivity factors of the Psychopathic Personality Inventory-Revised would demonstrate differential relationships with a multidimensional conceptualization of emotion regulation difficulties. Ninety-one male undergraduate students and 28 male court-mandated anger management participants completed self-report questionnaires measuring emotion regulation difficulties and psychopathic personality characteristics. Hierarchical regression analyses indicated that emotion regulation difficulties were negatively associated with Fearless Dominance psychopathic traits, but positively associated with Self-Centered Impulsivity and global psychopathic traits. In addition, emotion regulation difficulties explained incremental variance in psychopathic traits over and above negative affect alone. These findings may have clinical implications for the etiology and treatment of psychopathic personality disorder. PMID- 24341862 TI - Ecological risk of nonylphenol in China surface waters based on reproductive fitness. AB - It has been recognized that ecological risk assessment based on traditional endpoints of toxicity are unable to provide adequate protection because some chemicals may affect reproductive fitness of aquatic organisms at much lower concentrations. In this paper, predicted no effect concentrations (PNECs) for 4 nonylphenol (NP) were derived based either on endpoints of survival, development, and growth or on some nonlethal biomarkers of reproduction, biochemical and molecular biology data. The PNECs derived from reproductive lesion ranged from 0.12 to 0.60 MUg NP L(-1), which was significantly lower than those derived from other endpoints. An assessment of ecological risks posed by NP to aquatic organisms in surface waters of China was conducted based on concentration levels of NP in 16 surface waters of 4 major river basins and PNECs derived from reproductive fitness by a tiered ecological risk assessment (ERA). The results showed that 14.2% and 76.5% of surface waters in China may have ecological risks resulting from reproductive fitness if the thresholds of protection for aquatic organisms were set up as 5% (HC5) and 1% (HC1), respectively. The risks were significantly greatest in the Yangtze River Basin than in other major river basins. In comparison with the risks assessed based on traditional endpoints, such as lethality, for those chemicals causing adverse effects on reproduction due to modulation of endocrine function, to be protective of ecosystem structure and function, lesser PNECs, based on sublethal effects of reproduction, were appropriate. PMID- 24341863 TI - Prescribing for comorbid disease in a palliative population: focus on the use of lipid-lowering medications. AB - BACKGROUND: The balance of benefit versus burden of ongoing treatments for comorbid disease in palliative populations as death approaches needs careful consideration given their particular susceptibility to adverse drug effects. AIM: To provide descriptive data regarding the medications being prescribed to patients who have a life-limiting illness at the time of referral to a palliative care service in regional Australia, with particular focus on lipid-lowering medications. METHODS: A prospective case note review of 203 patients reporting the number of medications prescribed and, for lipid-lowering medications, the indication and level of prevention sought (primary, secondary, tertiary). Rates were compared by performance status, disease phase and comorbidity burden. RESULTS: Mean number of regular medications prescribed was 7.2, with higher rates observed in those patients with a non-malignant primary diagnosis (rate ratio 1.28, confidence interval (CI) 1.11-1.50) or poorer performance status (rate ratio 1.37, CI 1.11-1.69) and lower rates for those in the terminal phase of disease (rate ratio 0.48, CI 0.30-0.76). Over one fifth of patients were prescribed a lipid-lowering medication, and two fifths of these prescriptions were for primary prevention of cardiovascular disease. Patients in the highest quartile of Charlson Comorbidity Index score were 4.6 (CI 2.06-10.09) times more likely to be prescribed a lipid-lowering medication than those in the lowest quartile. CONCLUSIONS: Polypharmacy is prevalent for this group of patients, placing them at high risk of drug-drug and drug-host interactions. Prescribing may be driven by risk factors and disease guidelines rather than a rational, patient-centred approach. PMID- 24341864 TI - Characterization of an envelope gene VP19 from Singapore grouper iridovirus. AB - BACKGROUND: Viral envelope proteins are always proposed to exert important function during virus infection and replication. Vertebrate iridoviruses are enveloped large DNA virus, which can cause great economic losses in aquaculture and ecological destruction. Although numerous iridovirus envelope proteins have been identified using bioinformatics and proteomic methods, their roles in virus infection remained largely unknown. METHODS: Using SMART and TMHMM programs, we investigated the structural characteristics of Singapore grouper iridovirus (SGIV) VP19. A specific antibody against VP19 was generated and the expression profile of VP19 was clarified. The subcellular localization of VP19 in the absence or presence of other viral products was determined via transfection and immune fluorescence assay. In addition, Western blot assay and electron microscopy examination were performed to demonstrate whether SGIV VP19 was an envelope protein or a capsid protein. RESULTS: Here, SGIV VP19 was cloned and characterized. Among all sequenced iridoviruses, VP19 and its orthologues shared common features, including 19 invariant cysteines, a proline-rich motif and a predicted transmembrane domain. Subsequently, the protein synthesis of VP19 was only detected at the late stage of SGIV infection and inhibited obviously by treating with AraC, confirming that VP19 was a late expressed protein. Ectopic expression of EGFP-VP19 in vitro displayed a punctate pattern in the cytoplasm. In SGIV infected cells, the newly synthesized VP19 protein was initially localized in the cytoplasm in a punctate pattern, and then aggregated into the virus assembly site at the late stage of SGIV infection, suggesting that other viral protein products were essential for VP19's function during SGIV infection. In addition, Western blot assay and electron microscopy observation revealed that SGIV VP19 was associated with viral envelope, which was different from major capsid protein (MCP). CONCLUSION: Taken together, the current data suggested that VP19 represented a conserved envelope protein in iridovirus, and might contribute greatly to virus assembly during virus infection. PMID- 24341865 TI - Prevalence of detectable venous pressure drops expected with venous needle dislodgement. AB - Venous needle dislodgement (VND) is a potentially fatal complication during hemodialysis (HD) treatment and the venous pressure monitor is the most widely used device for its detection. VND can only be detected by the venous sensor if the resulting pressure drop exceeds the difference between the actual venous pressure and the lower alarm limit. In clinical practice, the lower alarm limit is usually set 30-40 mmHg below the actual venous pressure to avoid a disproportionate high number of nuisance alarms. The aim of this study was to quantify the number of fistulas and grafts in a group of HD patients where venous pressure monitoring can be expected to detect VND. We determined intra-access pressures in 99 chronic HD patients. Sixty-five (65.7%) had a fistula and 34 (34.3%) had a prosthetic graft as a vascular access. Mean intra-access pressure (Pa ) in fistulas was 32.6 +/- 23.5 mmHg, whereas in grafts mean Pa was 60.9 +/- 19.5 mmHg. Nineteen (29.2%) of the fistulas and 32 (94.1%) of the grafts exhibited an intra-access pressure above 40 mmHg. Therefore, in our study nearly all grafts but only 29% of fistulas would fulfill the requirement for venous pressure monitoring to detect VND. PMID- 24341866 TI - Features of wild-type human SOD1 limit interactions with misfolded aggregates of mouse G86R Sod1. AB - Mutations in the gene encoding superoxide dismutase 1 (SOD1) account for about 20% of the cases of familial amyotrophic lateral sclerosis (fALS). It is well established that mutations in SOD1, associated with fALS, heighten the propensity of the protein to misfold and aggregate. Although aggregation appears to be a factor in the toxicity of mutant SOD1s, the precise nature of this toxicity has not been elucidated. A number of other studies have now firmly established that raising the levels of wild-type (WT) human SOD1 (hSOD1) proteins can in some manner augment the toxicity of mutant hSOD1 proteins. However, a recent study demonstrated that raising the levels of WT-hSOD1 did not affect disease in mice that harbor a mouse Sod1 gene (mSod1) encoding a well characterized fALS mutation (G86R). In the present study, we sought a potential explanation for the differing effects with WT-hSOD1 on the toxicity of mutant hSOD1 versus mutant mSod1. In the cell culture models used here, we observe poor interactions between WT-hSOD1 and misfolded G86R-mSod1, possibly explaining why over-expression of WT-hSOD1 does not synergize with mutant mSod1 to accelerate the course of the disease in mice. PMID- 24341867 TI - Eleven nanometer alignment precision of a plasmonic nanoantenna with a self assembled GaAs quantum dot. AB - Plasmonics offers the opportunity of tailoring the interaction of light with single quantum emitters. However, the strong field localization of plasmons requires spatial fabrication accuracy far beyond what is required for other nanophotonic technologies. Furthermore, this accuracy has to be achieved across different fabrication processes to combine quantum emitters and plasmonics. We demonstrate a solution to this critical problem by controlled positioning of plasmonic nanoantennas with an accuracy of 11 nm next to single self-assembled GaAs semiconductor quantum dots, whose position can be determined with nanometer precision. These dots do not suffer from blinking or bleaching or from random orientation of the transition dipole moment as colloidal nanocrystals do. Our method introduces flexible fabrication of arbitrary nanostructures coupled to single-photon sources in a controllable and scalable fashion. PMID- 24341868 TI - Unidirectional freezing of ceramic suspensions: in situ X-ray investigation of the effects of additives. AB - Using in situ X-ray radiography, we investigated unidirectional freezing of titanium dioxide suspensions. We showed how processing additives, which are generally used for ice-templating, strongly modified freezing dynamics during the solidification process. We observed and identified different freezing regimes by varying the amount of dispersant, binder, or poly(ethylene glycol) (PEG). We demonstrated that because each regime corresponds to a given final structure understanding the particle motion and redistribution at the ice-front level was essential. We also examined the transition from a random particles-entrapment regime to a well-defined lamellar regime and proposed and discussed two mechanisms by which additives might affect the solidification process. PMID- 24341869 TI - Internet pornography use: perceived addiction, psychological distress, and the validation of a brief measure. AB - The authors aimed to validate a brief measure of perceived addiction to Internet pornography refined from the 32-item Cyber Pornography Use Inventory, report its psychometric properties, and examine how the notion of perceived addiction to Internet pornography might be related to other domains of psychological functioning. To accomplish this, 3 studies were conducted using a sample of undergraduate psychology students, a web-based adult sample, and a sample of college students seeking counseling at a university's counseling center. The authors developed and refined a short 9-item measure of perceived addiction to Internet pornography, confirmed its structure in multiple samples, examined its relatedness to hypersexuality more broadly, and demonstrated that the notion of perceived addiction to Internet pornography is very robustly related to various measures of psychological distress. Furthermore, the relation between psychological distress and the new measure persisted, even when other potential contributors (e.g., neuroticism, self-control, amount of time spent viewing pornography) were controlled for statistically, indicating the clinical relevance of assessing perceived addiction to Internet pornography. PMID- 24341870 TI - Improving structural similarity based virtual screening using background knowledge. AB - BACKGROUND: Virtual screening in the form of similarity rankings is often applied in the early drug discovery process to rank and prioritize compounds from a database. This similarity ranking can be achieved with structural similarity measures. However, their general nature can lead to insufficient performance in some application cases. In this paper, we provide a link between ranking-based virtual screening and fragment-based data mining methods. The inclusion of binding-relevant background knowledge into a structural similarity measure improves the quality of the similarity rankings. This background knowledge in the form of binding relevant substructures can either be derived by hand selection or by automated fragment-based data mining methods. RESULTS: In virtual screening experiments we show that our approach clearly improves enrichment factors with both applied variants of our approach: the extension of the structural similarity measure with background knowledge in the form of a hand-selected relevant substructure or the extension of the similarity measure with background knowledge derived with data mining methods. CONCLUSION: Our study shows that adding binding relevant background knowledge can lead to significantly improved similarity rankings in virtual screening and that even basic data mining approaches can lead to competitive results making hand-selection of the background knowledge less crucial. This is especially important in drug discovery and development projects where no receptor structure is available or more frequently no verified binding mode is known and mostly ligand based approaches can be applied to generate hit compounds. PMID- 24341871 TI - International Consortium of Rice Mutagenesis: resources and beyond. AB - Rice is one of the most important crops in the world. The rice community needs to cooperate and share efforts and resources so that we can understand the functions of rice genes, especially those with a role in important agronomical traits, for application in agricultural production. Mutation is a major source of genetic variation that can be used for studying gene function. We will present here the status of mutant collections affected in a random manner by physical/chemical and insertion mutageneses.As of early September 2013, a total of 447, 919 flanking sequence tags from rice mutant libraries with T-DNA, Ac/Ds, En/Spm, Tos17, nDART/aDART insertions have been collected and publicly available. From these, 336,262 sequences are precisely positioned on the japonica rice chromosomes, and 67.5% are in gene interval. We discuss the genome coverage and preference of the insertion, issues limiting the exchange and use of the current collections, as well as new and improved resources. We propose a call to renew all mutant populations as soon as possible. We also suggest that a common web portal should be established for ordering seeds. PMID- 24341872 TI - Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. PMID- 24341873 TI - Patient factors associated with incidents of aggression in a general inpatient setting. AB - AIMS AND OBJECTIVES: To determine patient factors associated with aggressive (code grey) events in the setting of a metropolitan hospital during a six-month period, to inform screening and prevention practices. BACKGROUND: Patient aggression continues to place nurses and patients at risk. Nurses need to be able to identify situations that are likely to escalate into aggression in order to ensure their own safety and the quality of care they can provide. Research has focussed on emergency departments and psychiatric units. Approaches that are appropriate for these settings may not fit for the general inpatient setting. DESIGN: A structured audit and epidemiological analysis of hospital population, regarding incidence of aggression. METHODS: A retrospective audit of code grey event reports and medical records of patients admitted to 16 general medical surgical wards, during a six-month period. All available records of 121 code grey events were audited. Demographic factors for patients with code grey events were compared with factors for 6472 patients admitted. Statistical tests included chi squared, bivariate and logistic regression. RESULTS: Diagnoses associated with increased risk of code grey were the following: delirium (11 times more likely) and dementia (seven times). Patients were more likely to have a code grey event if they were over 65 years of age (more than twice), were male (more than twice), were a recipient of Veterans' Affairs pension (four times), had never been married or had been admitted through the emergency department (almost twice). CONCLUSION: This study adds to the current knowledge of the distinctive profile of patients in medical-surgical settings who are associated with aggressive events. RELEVANCE TO CLINICAL PRACTICE: It is recommended that nurses increase their focus on assessment of identified risk factors and documentation of behaviours, to help predict aggressive events, and that this focus be supported by hospital safety and care policy. PMID- 24341876 TI - Targeting obesity, insulin resistance and Type 2 diabetes with immunotherapy: the challenges ahead. PMID- 24341875 TI - Biologic treatment of pediatric rheumatic diseases: are we spoilt for choice? PMID- 24341874 TI - Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer's disease transgenic mice. AB - Alzheimer's disease (AD) is the most common type of dementia. It is the only one of the top ten causes of death in the USA for which prevention strategies have not been developed. Although AD has traditionally been associated with the deposition of amyloid beta plaques and tau tangles, it is becoming increasingly clear that it involves disruptions in multiple cellular systems. Therefore, it is unlikely that hitting a single target will result in significant benefits to patients with AD. An alternative approach is to identify molecules that have multiple biological activities that are relevant to the disease. Fisetin is a small, orally active molecule which can act on many of the target pathways implicated in AD. We show here that oral administration of fisetin to APPswe/PS1dE9 double transgenic AD mice from 3 to 12 months of age prevents the development of learning and memory deficits. This correlates with an increase in ERK phosphorylation along with a decrease in protein carbonylation, a marker of oxidative stress. Importantly, fisetin also reduces the levels of the cyclin dependent kinase 5 (Cdk5) activator p35 cleavage product, p25, in both control and AD brains. Elevated levels of p25 relative to p35 cause dysregulation of Cdk5 activity leading to neuroinflammation and neurodegeneration. These fisetin dependent changes correlate with additional anti-inflammatory effects, including alterations in global eicosanoid synthesis, and the maintenance of markers of synaptic function in the AD mice. Together, these results suggest that fisetin may provide a new approach to the treatment of AD. PMID- 24341878 TI - Conference scene: New research directions in innate immunity. AB - The 2013 3R's event, chaired by Kathy Triantafilou and Martha Triantafilou (Institute of Infection & Immunity, Cardiff University School of Medicine, UK), brought together immunologists across Europe investigating multiple species and pathology. The conference heard nine speakers describe their research, and received ten highly structured in-depth posters from postgraduate students. Three promising research directions are described, demonstrating the importance of continued support for innate immunity research in common diseases affecting humans and ruminants, universally understood to have profound economic impacts on patients, health services and the agricultural industry. PMID- 24341879 TI - Requirement of NK cells for selective A2A receptor blockade to suppress CD73+ tumor metastasis. AB - Evaluation of: Beavis PA, Divisekera U, Paget C et al. Blockade of A2A receptors potently suppresses the metastasis of CD73(+) tumors. Proc. Natl Acad. Sci. USA 110(36), 14711-14716 (2013). CD73 is becoming an emerging therapeutic target for the prevention of tumor growth and metastasis. However, the mechanism by which CD73 promotes tumor metastasis is unclear. Beavis et al. evaluated the efficacy of A2A and A2B adenosine receptor antagonists in inhibiting the metastasis of tumors expressing CD73, either endogenously or ectopically. They demonstrate distinct mechanisms whereby A2A versus A2B adenosine receptors could contribute to CD73(+) tumor metastasis. As A2Areceptor (R)/A2BR antagonists have been tested in clinical trials in other disease settings, this study highlights the potential therapeutic application of an A2AR/A2BR blockade strategy for treatment of CD73(+) metastatic tumors. PMID- 24341880 TI - Partial recovery after severe immune reconstitution inflammatory syndrome in a multiple sclerosis patient with progressive multifocal leukoencephalopathy. AB - Progressive multifocal leukoencephalopathy (PML) is a rare and severe complication of natalizumab therapy in patients with multiple sclerosis and it may be accompanied by immune reconstitution inflammatory syndrome (IRIS). Here, we describe a case of abnormally severe IRIS, which occurred 2 months after natalizumab-associated PML in a 38-year-old woman affected by multiple sclerosis. The patient was John Cunningham virus-positive and was treated for 21 months when she developed PML. The subsequent IRIS diffusely afflicted the brain, producing edema and signs of intracranial hypertension, with a clinically severe form compromising the state of consciousness, requiring intensive care and high-dosage steroid treatment. Nevertheless, she survived and partially recovered. There is still difficulty in differentiating PML progression from IRIS onset and there is not a clear description in the literature about different clinical forms of IRIS, prognostic factors and guidelines to properly treat this complication in order to reduce the residual disability of the patient surviving this treatment complication. PMID- 24341881 TI - Serum-specific IgE and allergen immunotherapy in allergic children. AB - AIM: Allergen immunotherapy (AIT) is indicated in IgE-mediated respiratory allergy. Recently, it has been reported that serum-specific IgE (sIgE) levels >10 kU/l may predict AIT efficacy in adults with allergic rhinitis. The aim of the present preliminary study was to investigate whether this cut-off could also be associated with perception of effective AIT in children with allergic asthma and/or rhinitis due to house dust mites (HDM). METHODS: A total of 31 allergic children (17 males; mean age of 12.5 years) with levels of serum sIgE to HDM >10 kU/l were evaluated. Eight allergic children (five males; mean age of 13.4 years) with levels of serum sIgE to HDM <10 kU/l were considered as control. All patients were treated with sublingual immunotherapy for 3 years with HDM allergen extract. Children's perception of AIT efficacy was assessed by visual analog scale (VAS), considering both symptom severity and drug use. Responder patients were defined with >6 VAS. Severity of nasal symptoms was assessed by nasal VAS, and asthma control was evaluated by asthma control test; both were considered before and after AIT. RESULTS: All children (but one) with sIgE >10 kU/l perceived AIT efficacy, whereas only one child with sIgE <10 kU/l perceived AIT benefit (p < 0.001). There was a strong relationship between perception of AIT efficacy by VAS and serum sIgE levels (r = 0.615; p < 0.001). Also, nasal VAS and asthma control tests significantly improved only in children with sIgE >10 kU/l (p < 0.001 for both). CONCLUSION: Allergen-sIgE assessment before AIT prescription might represent a useful tool to individuate potential responders. PMID- 24341882 TI - Ovarian cancer: designing effective vaccines and specific diagnostic tools. AB - AIM: Notwithstanding a renewed interest in the application of immunotherapy as an alternative to chemotherapy and radiotherapy for the treatment of ovarian cancer (OC), and in spite of the available knowledge about ovarian tumor-associated antigens, the search for a vaccine against OC remains a scientific and clinical challenge. Likewise, immunodiagnostics can detect only a late stage of the disease. Thus, the development of new therapeutic and diagnostic options is highly desirable. METHODS: Based on the low-similarity hypothesis, which supports the concept that immunogenicity is preferentially associated to sequences with no/low-similarity to the host proteome, and using Protein Information Resource peptide match program, we searched the ovarian tumor antigen CA125 for amino acid sequences unique to CA125 and absent in the remaining human proteins. RESULTS & CONCLUSION: We identified a set of 159 pentapeptides unique to CA125 that might be used to design specific and effective immunological tools for diagnosis and treatment of OC. PMID- 24341883 TI - In vitro assessment of the effects of anti-HER2 monoclonal antibodies on proliferation of HER2-overexpressing breast cancer cells. AB - BACKGROUND: HER2 proto-oncogene is critical in the biology of breast cancer and an important therapeutic target of monoclonal antibodies (mAbs). We have recently established a panel of anti-HER2 mAbs recognizing different epitopes within the extracellular domain of HER2. MATERIALS & METHODS: In the present study the antiproliferative effect of these mAbs was investigated on HER2-overexpressing human breast cancer cell line BT474, using radioactive thymidine incorporation assay. RESULTS: Our results demonstrated that while two of the mAbs (1T0 and 2A8) inhibited cell proliferation dose dependently, similar to trastuzumab, six mAbs (1F2, 1B5, 1H9, 4C7, 1H6 and 2A9) augmented cell proliferation. Treatment of BT474 cells with different combinations of two mAbs induced either synergistic inhibitory or stimulatory effects. DISCUSSION: Our findings indicate that combination of some stimulatory mAbs could completely abolish the inhibitory effect of other mAbs against HER2. Employment of some combinations of mAbs with significant synergistic inhibitory function may improve the therapeutic efficacy of HER2-specific mAbs. PMID- 24341884 TI - Broadly neutralizing antibodies and the promise of universal vaccines: where are we now? AB - Recent research has provided strong support for the utility of broadly neutralizing antibodies generated against viruses, which inherently possess a high degree of antigenic variability (such as influenza virus or HIV) as a feasible means to prevent infection. Many of these antibodies share the ability to bind to highly conserved regions within the stem of the virus 'spike' or surface glycoprotein, in such a way that they interfere with virus entry, including membrane fusion. As a result, broadly neutralizing antibodies could be supplied to patients as a form of passive immunotherapy, as well as play a role in the design of new 'universal' vaccines and antiviral agents. The following article describes the most recent innovations in this exciting field. PMID- 24341885 TI - The adaptation model of immunity. AB - Although 'self-nonself' and 'danger' theories have improved our understanding of the immune system, successful immunotherapy of cancer and many autoimmune diseases still remain far from reach. This indicates that our knowledge of how the immune system decides to respond effectively or ineffectively is limited. Emerging evidence suggest that decision-making during the immune response is not solely determined by 'nonself' entity of the antigen or damage-associated 'danger' signals. This article provides an overview of the 'self-nonself' and 'danger' models, and suggests that 'adaptation' signals are needed to guarantee immunological tolerance that has been observed during the immune response toward 'self', 'nonself' or even 'danger'. This should be facilitated by dynamic expression of adapting receptors (ARs) and adapting ligands on cells of the immune system and other somatic cells. Any alterations in the expression of ARs on certain tissues would result in tissue-specific autoimmune diseases or spontaneous regression of cancer. Identification of such ARs and their nominal adapting ligands could lead to the discovery of currently unknown receptors and their implications in the treatment of cancer, solid organ transplantation and autoimmune diseases. PMID- 24341886 TI - Subcutaneous IgG in neurologic diseases. AB - Subcutaneous administration of IgG (SCIG) has become widely used in primary immune deficiency diseases but it has only recently been studied for maintenance therapy in autoimmune peripheral neuropathies, such as chronic idiopathic demyelinating polyneuropathy and multifocal motor neuropathy. Weekly self administration of SCIG is safe and well-tolerated, and results in steady-state serum IgG levels, as contrasted with the peaks and troughs of monthly immune globulin (human) for intravenous use. Freedom from the need for venous access or medical personnel for infusions, flexibility in scheduling, convenience of home therapy, and improved clinical stability due to the steady-state IgG levels, lead many patients to prefer SCIG to immune globulin (human) for intravenous use. Long term studies are needed to determine if the constant IgG levels and clinical stability translate into better long-term outcomes. PMID- 24341887 TI - Cancer immunotherapy using tumor cryoablation. AB - Cryoablation is increasingly being used as a primary treatment for localized cancers and as a salvage therapy for metastatic cancers. Anecdotal clinical reports and animal experiments have confirmed an induction of systemic antitumor immune response by tumor cryoablation. To capitalize on the stimulatory effects of cryoablation for cancer immunotherapy, this response must be intensified using other immunomodulatory agents. This article reviews the preclinical and clinical evidence and discusses the mechanism of the antitumor immune response generated by cryoablation. The rationale and evidence behind several immunotherapy approaches that can be combined with cryoablation to devise a cryoimmunotherapeutic strategy with a potential to impact the progression of metastatic disease are described. PMID- 24341888 TI - Immunotherapy in acute myeloid leukemia. AB - Treatment of acute myeloid leukemia (AML) with current chemotherapy regimens is still disappointing, with overall survival rates of <= 40% at 5 years. It is now well established that AML cells can evade the immune system through multiple mechanisms, including the expression of the enzyme indoleamine 2,3 dioxygenase. Immunotherapeutic strategies, including both active, such as vaccination with leukemia-associated antigens, and passive, such as adoptive transfer of allogeneic natural killer cells, may overcome leukemia escape and lead to improved cure. Allogeneic hemopoeitic stem cell transplantation, the most effective treatment of AML, is the best known model of immunotherapy. Following transplant, recipient AML cells are eradicated by donor immune cells through the graft-versus-leukemia (GVL) effect. However, GVL is clinically associated with graft-versus-host disease, the major cause of mortality after transplant. GVL is mediated by donor T cells recognizing either leukemia-associated antigens or minor as well as major histocompatibility antigens. Several innovative strategies have been devised to generate leukemia reactive T cells so as to increase GVL responses with no or little graft-versus-host disease. PMID- 24341889 TI - RNA-Seq optimization with eQTL gold standards. AB - BACKGROUND: RNA-Sequencing (RNA-Seq) experiments have been optimized for library preparation, mapping, and gene expression estimation. These methods, however, have revealed weaknesses in the next stages of analysis of differential expression, with results sensitive to systematic sample stratification or, in more extreme cases, to outliers. Further, a method to assess normalization and adjustment measures imposed on the data is lacking. RESULTS: To address these issues, we utilize previously published eQTLs as a novel gold standard at the center of a framework that integrates DNA genotypes and RNA-Seq data to optimize analysis and aid in the understanding of genetic variation and gene expression. After detecting sample contamination and sequencing outliers in RNA-Seq data, a set of previously published brain eQTLs was used to determine if sample outlier removal was appropriate. Improved replication of known eQTLs supported removal of these samples in downstream analyses. eQTL replication was further employed to assess normalization methods, covariate inclusion, and gene annotation. This method was validated in an independent RNA-Seq blood data set from the GTEx project and a tissue-appropriate set of eQTLs. eQTL replication in both data sets highlights the necessity of accounting for unknown covariates in RNA-Seq data analysis. CONCLUSION: As each RNA-Seq experiment is unique with its own experiment-specific limitations, we offer an easily-implementable method that uses the replication of known eQTLs to guide each step in one's data analysis pipeline. In the two data sets presented herein, we highlight not only the necessity of careful outlier detection but also the need to account for unknown covariates in RNA-Seq experiments. PMID- 24341890 TI - Marjolin's ulcer: a preventable malignancy arising from scars. AB - BACKGROUND: Marjolin's ulcer (MU) is a rare malignancy arising from various forms of scars. This potentially fatal complication typically occurs after a certain latency period. This article attempts to reveal the importance of the latency period in the prevention and early treatment of the malignancy. METHODS: A retrospective review of 17 MU patients who underwent surgical procedures between June of 2005 and December 2011 was conducted. Etiology of injuries, latency period, repeated ulceration, and outcomes were recorded. This observational report reveals characteristics of patients who develop MU. RESULTS: An incidence of 0.7% of MU was found amongst patients complaining of existing scars in our study; burns and trauma were the most common etiology of MU. The mean latency period was 29 years (SD = 19) and the mean post-ulceration period was 7 years (SD = 9). Statistical analysis revealed a negative correlation between the age of patients at injury and the length of latency period (r = -0.8, P <0.01), as well as the lengths of pre-ulceration and post-ulceration periods (r = -0.7, P <0.01). CONCLUSIONS: Patients experience different lengths of pre- and post-ulceration periods during the latency period. Younger patients tend to have a longer latency period. Skin breakdown on chronic scars and chronic unhealed ulcers are two main sources of MU. MU may be preventable with a close surveillance of the ulcer during the latency period. PMID- 24341891 TI - Low-dose bone morphogenetic protein-2/stromal cell-derived factor-1beta cotherapy induces bone regeneration in critical-size rat calvarial defects. AB - Increasing evidence suggests that stromal cell-derived factor-1 (SDF-1/CXCL12) is involved in bone formation, though underlying molecular mechanisms remain to be fully elucidated. Also, contributions of SDF-1beta, the second most abundant splice variant, as an osteogenic mediator remain obscure. We have shown that SDF 1beta enhances osteogenesis by regulating bone morphogenetic protein-2 (BMP-2) signaling in vitro. Here we investigate the dose-dependent contribution of SDF 1beta to suboptimal BMP-2-induced local bone formation; that is, a dose that alone would be too low to significantly induce bone formation. We utilized a critical-size rat calvarial defect model and tested the hypotheses that SDF-1beta potentiates BMP-2 osteoinduction and that blocking SDF-1 signaling reduces the osteogenic potential of BMP-2 in vivo. In preliminary studies, radiographic analysis at 4 weeks postsurgery revealed a dose-dependent relationship in BMP-2 induced new bone formation. We then found that codelivery of SDF-1beta potentiates suboptimal BMP-2 (0.5 MUg) osteoinduction in a dose-dependent order, reaching comparable levels to the optimal BMP-2 dose (5.0 MUg) without apparent adverse effects. Blocking the CXC chemokine receptor 4 (CXCR4)/SDF-1 signaling axis using AMD3100 attenuated the osteoinductive potential of the optimal BMP-2 dose, confirmed by qualitative histologic analysis. In conclusion, SDF-1beta provides potent synergistic effects that support BMP-induced local bone formation and thus appears a suitable candidate for optimization of bone augmentation using significantly lower amounts of BMP-2 in spine, orthopedic, and craniofacial settings. PMID- 24341892 TI - Nickel-catalyzed regiodivergent opening of epoxides with aryl halides: co catalysis controls regioselectivity. AB - Epoxides are versatile intermediates in organic synthesis, but have rarely been employed in cross-coupling reactions. We report that bipyridine-ligated nickel can mediate the addition of functionalized aryl halides, a vinyl halide, and a vinyl triflate to epoxides under reducing conditions. For terminal epoxides, the regioselectivity of the reaction depends upon the cocatalyst employed. Iodide cocatalysis results in opening at the less hindered position via an iodohydrin intermediate. Titanocene cocatalysis results in opening at the more hindered position, presumably via Ti(III)-mediated radical generation. 1,2-Disubstituted epoxides are opened under both conditions to form predominantly the trans product. PMID- 24341893 TI - Effects of the serotonin transporter polymorphism and history of major depression on overgeneral autobiographical memory. AB - Overgeneral autobiographical memory (OGM) is a key memory deficit in major depressive disorder (MDD). Much research has examined cognitive mechanisms underlying OGM, but little work has investigated potential neurobiological influences. There is preliminary evidence that a genetic serotonergic vulnerability coupled with depressive symptoms may be associated with other memory impairments, and experimental research suggests a role for serotonin in OGM. We investigated whether a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) was associated with OGM in interaction with a lifetime history of MDD in 370 young adults in a longitudinal study of risk for emotional disorders. There was a significant interaction between 5-HTTLPR genotype and lifetime history of MDD in predicting OGM. Among S allele homozygotes, MDD history was associated with greater OGM, whereas no significant relationship between MDD history and OGM emerged among L carriers. Furthermore, there was evidence that a greater number of S alleles were associated with greater memory specificity in individuals without a history of MDD. Implications for understanding cognitive and biological risk for depression are discussed. PMID- 24341894 TI - Resource activation in generalized anxiety--an observer-based microprocess analysis of patients' in-session outcomes. AB - Despite a long-standing need for patient-focused research on individuals with generalized anxiety disorder, there is little systematized knowledge about the in session behaviors of these patients. The primary objective of this study was to describe the timing of expression of negative emotionality (level of explication) and the patients' focus on their own resources and how these indicators are associated with posttreatment outcome. Trained coders made minute-by-minute ratings of 1,100 min of video of 20 patient-therapist dialogues during Session 5. The results indicated that a higher level of explication generally observed at a later stage during the therapy sessions and the patients' focus on competencies (usually observed at an early stage) were positively associated with treatment outcome, independent of pretreatment distress, rapid response of well-being and symptom reduction, as well as the therapists' professional experience and treatment duration. However, positive reinterpretations and mentions of personal goals were negatively associated with outcome. If replicated, these results will highlight the importance of the in-session beginning phase in patients with generalized anxiety disorder. PMID- 24341896 TI - Chemical factors that control lignin polymerization. AB - Lignin is a complex, branched polymer that reinforces plant tissue. Understanding the factors that govern lignin structure is of central importance to the development of technologies for converting lignocellulosic biomass into fuels because lignin imparts resistance to chemical, enzymatic, and mechanical deconstruction. Lignin is formed by enzymatic oxidation of phenolic monomers (monolignols) of three main types, guaiacyl (G), syringyl (S), and p hydroxyphenyl (H) subunits. It is known that increasing the relative abundance of H subunits results in lower molecular weight lignin polymers and hence more easily deconstructed biomass, but it is not known why. Here, we report an analysis of frontier molecular orbitals in mono-, di-, and trilignols, calculated using density functional theory, which points to a requirement of strong p electron density on the reacting phenolic oxygen atom of the neutral precursor for enzymatic oxidation to occur. This model is consistent with a proton-coupled electron transfer (PCET) mechanism and for the first time explains why H subunits in certain linkages (beta-beta or beta-5) react poorly and tend to "cap" the polymer. In general, beta-5 linkages with either a G or H terminus are predicted to inhibit elongation. More broadly, the model correctly accounts for the reactivity of the phenolic groups in a diverse set of dilignols comprising H and G subunits. Thus, we provide a coherent framework for understanding the propensity toward growth or termination of different terminal subunits in lignin. PMID- 24341895 TI - Structure of the myotonic dystrophy type 2 RNA and designed small molecules that reduce toxicity. AB - Myotonic dystrophy type 2 (DM2) is an incurable neuromuscular disorder caused by a r(CCUG) expansion (r(CCUG)(exp)) that folds into an extended hairpin with periodically repeating 2*2 nucleotide internal loops (5'CCUG/3'GUCC). We designed multivalent compounds that improve DM2-associated defects using information about RNA-small molecule interactions. We also report the first crystal structure of r(CCUG) repeats refined to 2.35 A. Structural analysis of the three 5'CCUG/3'GUCC repeat internal loops (L) reveals that the CU pairs in L1 are each stabilized by one hydrogen bond and a water-mediated hydrogen bond, while CU pairs in L2 and L3 are stabilized by two hydrogen bonds. Molecular dynamics (MD) simulations reveal that the CU pairs are dynamic and stabilized by Na(+) and water molecules. MD simulations of the binding of the small molecule to r(CCUG) repeats reveal that the lowest free energy binding mode occurs via the major groove, in which one C residue is unstacked and the cross-strand nucleotides are displaced. Moreover, we modeled the binding of our dimeric compound to two 5'CCUG/3'GUCC motifs, which shows that the scaffold on which the RNA-binding modules are displayed provides an optimal distance to span two adjacent loops. PMID- 24341897 TI - Polylactic acid composites incorporating casein functionalized cellulose nanowhiskers. AB - BACKGROUND: Polylactic acid (PLA) is considered to be a sustainable alternative to petroleum-based polymers for many applications. Using cellulose fiber to reinforce PLA is of great interest recently due to its complete biodegradability and potential improvement of the mechanical performance. However, the dispersion of hydrophilic cellulose fibers in the hydrophobic polymer matrix is usually poor without using hazardous surfactants. The goal of this study was to develop homogenously dispersed cellulose nanowhisker (CNW) reinforced PLA composites using whole milk casein protein, which is an environmentally compatible dispersant. RESULTS: In this study, whole milk casein was chosen as a dispersant in the PLA-CNW system because of its potential to interact with the PLA matrix and cellulose. The affinity of casein to PLA was studied by surface plasmon resonance (SPR) imaging. CNWs were functionalized with casein and used as reinforcements to make PLA composites. Fluorescent staining of CNWs in the PLA matrix was implemented as a novel and simple way to analyze the dispersion of the reinforcements. The dispersion of CNWs in PLA was improved when casein was present. The mechanical properties of the composites were studied experimentally. Compared to pure PLA, the PLA composites had higher Young's modulus. Casein (CS) functionalized CNW reinforced PLA (PLA-CS-CNW) at 2 wt% filler content maintained higher strain at break compared to normal CNW reinforced PLA (PLA-CNW). The Young's modulus of PLA-CS-CNW composites was also higher than that of PLA-CNW composites at higher filler content. However, all composites exhibited lower strain at break and tensile strength at high filler content. CONCLUSIONS: The presence of whole milk casein improved the dispersion of CNWs in the PLA matrix. The improved dispersion of CNWs provided higher modulus of the PLA composites at higher reinforcement loading and maintained the strain and stress at break of the composites at relatively low reinforcement loading. The affinity of the dispersant to PLA is important for the ultimate strength and stiffness of the composites. PMID- 24341898 TI - Naturally occurring resistance mutations to inhibitors of HCV NS5A region and NS5B polymerase in DAA treatment-naive patients. AB - BACKGROUND: Direct-acting antiviral (DAA) agents target HCV proteins; some of these have already been approved for the treatment of HCV infection, while others are in development. However, selection of DAA-resistant viral variants may hamper treatment. The aim of this study was to illustrate potential natural DAA resistance mutations in the HCV NS5A and NS5B regions of HCV genotypes 1a and 1b from DAA-naive patients. METHODS: Direct sequencing of HCV NS5A and NS5B regions was performed in 32 patients infected with HCV genotype 1a and 30 patients infected with HCV genotype 1b; all subjects were naive to DAAs. RESULTS: In genotype 1a strains, resistance mutations in NS5A (M28V, L31M and H58P) were observed in 4/32 (12.5%) patients, and resistance mutations in NS5B (V321I, M426L, Y448H, Y452H) were observed in 4/32 (12.5%) patients. In genotype 1b, resistance mutations in NS5A (L28V, L31M, Q54H, Y93H and I280V) were observed in 16/30 (53.3%) patients, while resistance mutations in NS5B (L159F, V321I, C316N, M426L, Y452H, R465G and V499A) were observed in 27/30 (90%) patients. CONCLUSIONS: Mutations conferring DAA resistance were detected in NS5A and NS5B of HCV genotypes 1a and 1b from DAA-naive patients. Although some mutations confer only a low level of resistance, the presence at baseline of mutated HCV variants should be taken into consideration in the context of DAA therapy. PMID- 24341900 TI - Feasibility and prognostic value of stress echocardiography in obese, morbidly obese, and super obese patients referred for bariatric surgery. AB - BACKGROUND: Stress echocardiography (SE) is clinically used in the risk stratification and prognosis of patients with coronary artery disease. Due to multiple comorbidities, obese patients have increased risk of adverse cardiovascular events perioperatively in noncardiac surgery. The aim of this study was to investigate the feasibility of SE in morbidly obese patients undergoing bariatric surgery. METHODS: Consecutive patients referred for SE for preoperative evaluation prior to bariatric surgery from January 2002 to July 2011 formed the study cohort. Contrast was used to define the endocardial border in patients with poor acoustic windows. All-cause mortality data were obtained from Social Security Death Index. RESULTS: Six hundred fifty-two patients (47 +/- 10 years, 84% females) with the mean follow-up of 3.0 +/- 2.7 years and mean body mass index (BMI) of 47 +/- 9 kg/m2 were included in this analysis. Dobutamine SE was performed in 65% of patients compared to exercise SE in 35%. Patients with higher BMI were more likely to undergo dobutamine SE (P < 0.0001). Similarly, incidence of poor acoustic windows and contrast use was higher in those with increased BMI (P < 0.001). Contrast use was higher in patients undergoing dobutamine SE (39%) versus exercise (25%), (P = 0.002). 19 patients (3%) had an abnormal SE and 8 patients (1.2%) died during the follow-up period. CONCLUSION: Stress echocardiography is feasible in the morbidly obese patients. Patients with higher BMI were more likely to undergo dobutamine SE and have higher incidence of poor acoustic windows and contrast use. PMID- 24341899 TI - 123I-ADAM SPET imaging of serotonin transporter in patients with epilepsy and comorbid depression. AB - BACKGROUND: Purpose of the study was to investigate alterations in midbrain serotonin transporter (SERT) binding in patients with epilepsy and symptoms of depression compared to patients with epilepsy with no symptoms of depression. METHODS: We studied 12 patients with epilepsy (7 patients had focal and 5 had generalized epilepsy syndromes). The presence of self-reported symptoms of depression was assessed using Beck Depression Inventory (BDI) and the Emotional State Questionnaire (EST-Q). The binding potential of the SERT was assessed by performing brain single photon emission tomography (SPET) using the SERT radioligand 2-((2-((dimethylamino)methyl)phenyl)thio)-5-(123)iodophenylamine (123I-ADAM). RESULTS: Seven patients had BDI and EST-Q subscale scores greater than 11 points, which was interpreted as the presence of symptoms of depression. We found that 123I-ADAM binding was not significantly different between patients with epilepsy with and without symptoms of depression. In addition, 123I-ADAM binding did not show a significant correlation to either BDI or EST-Q depression subscale scores and did not differ between patients with focal vs. generalized epilepsy. CONCLUSION: The results of our study failed to demonstrate alterations of SERT binding properties in patients with epilepsy with or without symptoms of depression. PMID- 24341901 TI - Diffuse oesophageal leiomyomatosis. PMID- 24341902 TI - Surface-enhanced infrared spectroscopy using metal oxide plasmonic antenna arrays. AB - We successfully demonstrate surface-enhanced infrared spectroscopy using arrays of indium tin oxide (ITO) plasmonic nanoantennas. The ITO antennas show a strongly reduced plasmon wavelength, which holds promise for ultracompact antenna arrays and extremely subwavelength metamaterials. The strong plasmon confinement and reduced antenna cross section allows ITO antennas to be integrated at extremely high densities with no loss in performance due to long-range transverse interactions. By further reducing the spacing of antennas in the arrays, we access the regime of plasmonic near field coupling where the response is enhanced for both Au and ITO devices. Ultracompact ITO antennas with high spatial and spectral selectivity in spectroscopic applications offer a viable new platform for infrared plasmonics, which may be combined with other functionalities of these versatile materials in devices. PMID- 24341903 TI - Comparative analysis of cellular phenotypes within the neointima from vein segments collected prior to vascular access surgery and stenotic arteriovenous dialysis accesses. AB - Venous stenosis, secondary to venous neointimal hyperplasia (VNH), at the arteriovenous anastomosis (AV) is a major etiology of vascular access failure in AV fistulas (AVF) and AV grafts (AVG). Recently, our group has reported that severe VNH also occurs prior to vascular access placement. The objective of this study was to perform a comparison of the cellular phenotypes within the neointima from veins collected from subjects at the time of new vascular access creation and stenotic veins from subjects with failed AVGs and AVFs. Vein samples, collected at the time of new access surgery, and stenotic vein segments, collected at access revision, were evaluated for expression of alpha-smooth muscle actin (SMA), vimentin, and desmin within the neointima, and quantified using semiquantitative scoring. Within the neointima, the majority of cells from vein samples collected at the time of new access surgery were contractile smooth muscle cells, and veins from stenotic AVF and AVG were predominately myofibroblasts. Our results suggest the possibility of different mechanistic pathways in response to vascular injury that occurs prior to vascular access creation vs. after access creation, and that divergent therapeutic approaches may be needed for treating vascular injury in these two settings. PMID- 24341904 TI - beta-Amyloid precursor protein staining of the brain in sudden infant and early childhood death. AB - AIMS: To develop and validate a scoring method for assessing beta-amyloid precursor protein (APP) staining in cerebral white matter and to investigate the occurrence, amount and deposition pattern based on the cause of death in infants and young children. METHODS: Archival cerebral tissue was examined from a total of 176 cases (0 to 3 years of age). Each of the APP-stained sections was graded according to a simple scoring system based on the number and type of changes in eight anatomical regions. RESULTS: Examination of the sections revealed some degree of APP staining in 95% of the cases. The highest mean APP scores were found in cases of head trauma, and the lowest scores were found in the cases of drowning. APP staining, although sometimes minimal, was found in all 48 cases of and sudden infant death syndrome (SIDS). Patterns of APP staining (the amount and distribution) were different in cases of head trauma, infection and SIDS but were similar in the SIDS and asphyxia groups. CONCLUSION: This study demonstrates the use of an integrated scoring system that was developed to assess APP staining in the brain. APP staining was seen in a high proportion of cases, including relatively sudden deaths. The amount of APP was significantly higher in cases of trauma than in nontraumatic deaths. However, APP was detected within all groups. The pattern of APP staining was similar in infants who had died of SIDS and from mechanical asphyxia. PMID- 24341906 TI - Nanoparticles meet cell membranes: probing nonspecific interactions using model membranes. AB - Nanotoxicity studies have shown that both carbon-based and inorganic engineered nanoparticles can be toxic to microorganisms. Although the pathways for cytotoxicity are diverse and dependent upon the nature of the engineered nanoparticle and the chemical environment, numerous studies have provided evidence that direct contact between nanoparticles and bacterial cell membranes is necessary for cell inactivation or damage, and may in fact be a primary mechanism for cytotoxicity. The propensities for nanoparticles to attach to and disrupt cell membranes are still not well understood due to the heterogeneous and dynamic nature of biological membranes. Model biological membranes can be employed for systematic investigations of nanoparticle-membrane interactions. In this article, current and emerging experimental approaches to identify the key parameters that control the attachment of ENPs on model membranes and the disruption of membranes by ENPs will be discussed. This critical information will help enable the "safe-by-design" production of engineered nanoparticles that are nontoxic or biocompatible, and also allow for the design of antimicrobial nanoparticles for environmental and biomedical applications. PMID- 24341905 TI - Risk factors for morphoea disease severity: a retrospective review of 114 paediatric patients. AB - BACKGROUND: Morphoea is a rare fibrosing disease of the skin and subcutaneous tissue with an unpredictable disease course, running the spectrum from mild skin involvement to severe disfigurement or extracutaneous complications. OBJECTIVES: Our objective was to describe the natural history of paediatric morphoea and determine patient variables that were associated with severe disease. PATIENTS AND METHODS: We conducted a retrospective chart review of patients with morphoea seen in one paediatric hospital system. Information about demographics, clinical characteristics, disease course and treatment were collected. Statistical analysis was performed using appropriate univariate tests and a multivariable model. RESULTS: One hundred and fourteen patients met study inclusion criteria. The female : male ratio was 2.6 : 1, and the median age of onset was 7 years old. There were 55 patients (48%) with linear morphoea, 38 patients (33%) with circumscribed morphoea, 12 patients (11%) with generalized morphoea, and nine patients (8%) with mixed morphoea. Neurological symptoms and joint involvement were present in 27 subjects (24%). Extracutaneous manifestations occurred in 38% of subjects with linear morphoea, compared with 15% with generalized morphoea and 3% with circumscribed morphoea (P = 0.0001). Thirty-six per cent of children with disease onset prior to 10 years of age and 5% of children with disease onset after 10 years of age had extracutaneous manifestations (P = 0.0002). Both linear morphoea and early-onset disease were significantly associated with extracutaneous involvement in a multivariable model. CONCLUSIONS: Children with linear morphoea and disease onset before 10 years of age should be monitored closely for extracutaneous manifestations and need early treatment with systemic medications to prevent disease complications. PMID- 24341907 TI - Transcriptome analysis of leaf and root of rice seedling to acute dehydration. AB - BACKGROUND: Water deficiency is one of the most serious worldwide problems for agriculture. Recently, it has become more serious and outspread, which urgently requires the production of drought-tolerant plants. Microarray experiments using mRNA from air-dried leaves and roots of rice were performed in an attempt to study genes involved in acute dehydration response. RESULTS: Set of 10,537 rice genes was significantly up- or down-regulated in leaves or roots under the treatment. Gene Ontology analysis highlighted gene expression during acute dehydration response depending on organ types and the duration of stress. Rice responded by down-regulating many processes which are mainly involved in inhibiting growth and development. On the other hand, phytohormones (ABA, cytokinin, brassinosteroid) and protective molecules were induced to answer to multiple stresses. Leaves induced more genes than roots but those genes were scattered in various processes, most significantly were productions of osmoprotectants and precursors for important pathways in roots. Roots up regulated fewer genes and focused on inducing antioxidants and enhancing photosynthesis. Myb, zf-C3HC4, and NAM were most strongly affected transcription factors with the dominance of leaf over root. CONCLUSIONS: Leaf and root tissues shared some common gene expression during stress, with the purpose of enhancing protective systems. However, these two tissues appeared to act differently in response to the different level of dehydration they experience. Besides, they can affect each other via the signaling and transportation system. PMID- 24341909 TI - Evaluating the automated Thermedx Fluid Management System in a ureteroscopy model. AB - INTRODUCTION: The Thermedx Fluid Management System (TFMS) is an automated pressurized irrigation system that allows concurrent temperature control. Developed for use in multiple surgical specialties, it provides settings specific to several endoscopic urologic procedures. The objective of this study was to critically appraise the functional characteristics and precision of the device regarding irrigation warming, pressurization, and flow during semirigid ureteroscopy. METHODS: Using an in vitro model, the TFMS was assessed using the proprietary urology tubing with and without a short semirigid ureteroscopy/ureteroscope (URS) (7.4F/35 cm Wolf 425612). Pressures and temperatures were measured using continuous digital sensors (Meriam m1550-gi0015, and Taylor Digital Thermometer 9842). Stepwise increases in settings were measured with and without the ureteroscope (from 100 to 200 mm Hg), and with and without the included pressure release valve (preset for 150 mm Hg). Continuous measures (60/min) were recorded and compared with values recorded by the internal unit sensors. RESULTS: At room temperature (18.1 degrees C), the starting irrigation temperature was 19.5 degrees C, increasing to 35.5 degrees C after 7.2 minutes at maximum settings (40 degrees C). Irrigation returned to baseline temperature after 6.7 minutes with the heater disabled. The irrigation temperature was not affected by changes in pressure settings and flow rates. The unit's display readings were 4 degrees C-6 degrees C higher than measured at the tip of the ureteroscope. Flow rates detected at the tip of the URS were 2%-8% less than the unit reported. Pressures were between 8%-17% higher using URS than that reported by the unit, and highest values were encountered when the physical safety pop-off valve was removed from the tubing. CONCLUSIONS: The TFMS provides a pressurized/warmed irrigation strategy for many endoscopic procedures. It is important to note that the system underestimates pressures at the tip of the endoscope, while overestimating the flow rates and temperatures delivered from the scope when utilizing the device. PMID- 24341908 TI - OnPLS integration of transcriptomic, proteomic and metabolomic data shows multi level oxidative stress responses in the cambium of transgenic hipI- superoxide dismutase Populus plants. AB - BACKGROUND: Reactive oxygen species (ROS) are involved in the regulation of diverse physiological processes in plants, including various biotic and abiotic stress responses. Thus, oxidative stress tolerance mechanisms in plants are complex, and diverse responses at multiple levels need to be characterized in order to understand them. Here we present system responses to oxidative stress in Populus by integrating data from analyses of the cambial region of wild-type controls and plants expressing high-isoelectric-point superoxide dismutase (hipI SOD) transcripts in antisense orientation showing a higher production of superoxide. The cambium, a thin cell layer, generates cells that differentiate to form either phloem or xylem and is hypothesized to be a major reason for phenotypic perturbations in the transgenic plants. Data from multiple platforms including transcriptomics (microarray analysis), proteomics (UPLC/QTOF-MS), and metabolomics (GC-TOF/MS, UPLC/MS, and UHPLC-LTQ/MS) were integrated using the most recent development of orthogonal projections to latent structures called OnPLS. OnPLS is a symmetrical multi-block method that does not depend on the order of analysis when more than two blocks are analysed. Significantly affected genes, proteins and metabolites were then visualized in painted pathway diagrams. RESULTS: The main categories that appear to be significantly influenced in the transgenic plants were pathways related to redox regulation, carbon metabolism and protein degradation, e.g. the glycolysis and pentose phosphate pathways (PPP). The results provide system-level information on ROS metabolism and responses to oxidative stress, and indicate that some initial responses to oxidative stress may share common pathways. CONCLUSION: The proposed data evaluation strategy shows an efficient way of compiling complex, multi-platform datasets to obtain significant biological information. PMID- 24341910 TI - Hypertension 101: the place to start. PMID- 24341913 TI - Fungal evolutionary genomics provides insight into the mechanisms of adaptive divergence in eukaryotes. AB - Fungi are ideal model organisms for dissecting the genomic bases of adaptive divergence in eukaryotes. They have simple morphologies and small genomes, occupy contrasting, well-identified ecological niches and tend to have short generation times, and many are amenable to experimental approaches. Fungi also display diverse lifestyles, from saprotrophs to pathogens or mutualists, and they play extremely important roles in both ecosystems and human activities, as wood decayers, mycorrhizal fungi, lichens, endophytes, plant and animal pathogens, and in fermentation or drug production. We review here recent insights into the patterns and mechanisms of adaptive divergence in fungi, including sources of divergence, genomic variation and, ultimately, speciation. We outline the various ecological sources of divergent selection and genomic changes, showing that gene loss and changes in gene expression and in genomic architecture are important adaptation processes, in addition to the more widely recognized processes of amino acid substitution and gene duplication. We also review recent findings regarding the interspecific acquisition of genomic variation and suggesting an important role for introgression, hybridization and horizontal gene transfers (HGTs). We show that transposable elements can mediate several of these genomic changes, thus constituting important factors for adaptation. Finally, we review the consequences of divergent selection in terms of speciation, arguing that genetic incompatibilities may not be as widespread as generally thought and that pleiotropy between adaptation and reproductive isolation is an important route of speciation in fungal pathogens. PMID- 24341912 TI - SNJ-1945, a calpain inhibitor, protects SH-SY5Y cells against MPP(+) and rotenone. AB - Complex pathophysiology of Parkinson's disease involves multiple CNS cell types. Degeneration in spinal cord neurons alongside brain has been shown to be involved in Parkinson's disease and evidenced in experimental parkinsonism. However, the mechanisms of these degenerative pathways are not well understood. To unravel these mechanisms SH-SY5Y neuroblastoma cells were differentiated into dopaminergic and cholinergic phenotypes, respectively, and used as cell culture model following exposure to two parkinsonian neurotoxicants MPP(+) and rotenone. SNJ-1945, a cell-permeable calpain inhibitor was tested for its neuroprotective efficacy. MPP(+) and rotenone dose-dependently elevated the levels of intracellular free Ca(2+) and induced a concomitant rise in the levels of active calpain. SNJ-1945 pre-treatment significantly protected cell viability and preserved cellular morphology following MPP(+) and rotenone exposure. The neurotoxicants elevated the levels of reactive oxygen species more profoundly in SH-SY5Y cells differentiated into dopaminergic phenotype, and this effect could be attenuated with SNJ-1945 pre-treatment. In contrast, significant levels of inflammatory mediators cyclooxygenase-2 (Cox-2 and cleaved p10 fragment of caspase-1) were up-regulated in the cholinergic phenotype, which could be dose dependently attenuated by the calpain inhibitor. Overall, SNJ-1945 was efficacious against MPP(+) or rotenone-induced reactive oxygen species generation, inflammatory mediators, and proteolysis. A post-treatment regimen of SNJ-1945 was also examined in cells and partial protection was attained with calpain inhibitor administration 1-3 h after exposure to MPP(+) or rotenone. Taken together, these results indicate that calpain inhibition is a valid target for protection against parkinsonian neurotoxicants, and SNJ-1945 is an efficacious calpain inhibitor in this context. SH-SY5Y cells, differentiated as dopaminergic (TH positive) and cholinergic (ChAT positive), were used as in vitro models for Parkinson's disease. MPP+ and rotenone induced up-regulation of calpain, expression, and activity as a common mechanism of neurodegeneration. SNJ 1945, a novel calpain inhibitor, protected both the cell phenotypes against MPP+ and rotenone. PMID- 24341914 TI - Quantification of cell co-migration occurrences during cell aggregation on fibroin substrates. AB - A quantitative analytical method was proposed for measuring cell co-migration, which was defined as two or more cells migrating together. To accurately identify and quantify this behavior, cell migration on fibroin substrates was analyzed with respect to intercellular distance. Specifically, cell size was characterized by major diameter, and then, based on these measurements and cell center data, a specific threshold distance for defining co-migration was determined after analyzing cell motion using the Voronoi diagram method. The results confirmed that co-migration occurrences of rounded cells were significantly more stable on fibroin than on ProNectin substrates under the present experimental conditions. The cell co-migration analysis method in this article was shown to be successful in evaluating the stability of cell co-migration and also suggested the presence of "critical distance" where two cells interact on fibroin substrates. With further research, the cell co-migration analysis method and "critical distance" may prove to be capable of identifying the aggregation behavior of other cells on different materials, making it a valuable tool that can be used in tissue engineering design. PMID- 24341915 TI - Dengue epidemics and adverse obstetrical outcomes in French Guiana: a semi ecological study. AB - OBJECTIVE: To determine whether dengue epidemics are associated with an increase in adverse obstetrical outcomes. METHODS: Semi-ecological study combining individual data on obstetrical events from the perinatal registry and aggregated exposure data from the epidemiologic surveillance of dengue in Cayenne, French Guiana between 2004 and 2007. RESULTS: After adjustment for individual risk factors, analysis showed that an epidemic level of dengue transmission during the first trimester was associated with an increased risk of post-partum haemorrhage and preterm birth. The associated risks seemed to depend on the epidemic level. CONCLUSIONS: Despite its limitations, this study suggests that dengue in the first trimester may be related to preterm birth and to post-partum bleeding, thus leading to specific hypotheses that should be tested in prospective studies. PMID- 24341911 TI - Humans and cattle: a review of bovine zoonoses. AB - Infectious disease prevention and control has been among the top public health objectives during the last century. However, controlling disease due to pathogens that move between animals and humans has been challenging. Such zoonotic pathogens have been responsible for the majority of new human disease threats and a number of recent international epidemics. Currently, our surveillance systems often lack the ability to monitor the human-animal interface for emergent pathogens. Identifying and ultimately addressing emergent cross-species infections will require a "One Health" approach in which resources from public veterinary, environmental, and human health function as part of an integrative system. Here we review the epidemiology of bovine zoonoses from a public health perspective. PMID- 24341916 TI - Management of chronic pain with chronic opioid therapy in patients with substance use disorders. AB - Substance use disorders (SUDs), whether active or in remission, are often encountered in patients with chronic nonmalignant pain. Clinicians are challenged when managing chronic pain while facing substance abuse issues during the course of chronic opioid therapy (COT). Further, the interrelated behavioral symptomatology of addiction and chronic pain suggests that if one disorder is untreated, effective treatment of the other in not possible. Incomplete understanding of the overlapping presentations of the two disorders, coupled with insufficient management of both conditions, leads to undertreated pain and premature discharge of SUD patients from pain treatment. In order to achieve pain relief and optimal functionality, both conditions need to be carefully managed. This paper reviews the prevalence of SUDs in chronic pain patents; the overlapping presentation of the two disorders; risk factors and stratification for addiction; identification of addiction in the chronic pain population; and suggestions for treating patients with COT, with an emphasis on relapse prevention. With appropriate assessment and treatment, COT for chronic pain patients with a history of SUD can be successful, leading to improved functionality and quality of life. PMID- 24341917 TI - IVF outcome is optimized when embryos are replaced between 5 and 15 mm from the fundal endometrial surface: a prospective analysis on 1184 IVF cycles. AB - BACKGROUND: Some data suggest that the results of human in vitro fertilization (IVF) may be affected by the site of the uterine cavity where embryos are released. It is not yet clear if there is an optimal range of embryo-fundus distance (EFD) within which embryos should be transferred to optimize IVF outcome. METHODS: The present study included 1184 patients undergoing a blind, clinical-touch ET of 1-2 fresh embryos loaded in a soft catheter with a low amount of culture medium. We measured the EFD using transvaginal US performed immediately after ET, with the aim to assess (a) if EFD affects pregnancy and implantation rates, and (b) if an optimal EFD range can be identified. RESULTS: Despite comparable patients' clinical characteristics, embryo morphological quality, and endometrial thickness, an EFD between 5 and 15 mm allowed to obtain significantly higher pregnancy and implantation rates than an EFD above 15 mm. The abortion rate was much higher (although not significantly) when EFD was below 5 mm than when it was between 5 and 15 mm. Combined together, these results produced an overall higher ongoing pregnancy rate in the group of patients whose embryos were released between 5 and 15 mm from the fundal endometrial surface. CONCLUSIONS: The site at which embryos are released affects IVF outcome and an optimal EFD range exists; this observations suggest that US-guided ET could be advantageous vs. clinical-touch ET, as it allows to be more accurate in releasing embryos within the optimal EFD range. PMID- 24341919 TI - Design and regulation of efficient photoinduced electron transfer in macromolecular and photosynthetic systems. AB - The factors that govern efficient electron transfer in the initial steps of photosynthetic charge separation are discussed. The dependence of the electron transfer rate constant on free energy, temperature, and distance are described both in theory and in numerous experiments on photosynthetic and macromolecular systems, with particular attention to those aspects of macromolecular charge transfer systems that show strong analogy to characteristics of photosynthetic charge transfer reactions. The unique features of the primary charge separation reaction in photosynthesis are emphasized in light of recent experimental data, including time-resolution of excited state vibrational motion, the electric field dependence of the quantum yield, and resonance Raman and hole-burning experiments that probe the nature of the initially formed excited state. The experimental results indicate the need for further development of electron transfer theory to include nonequilibrium vibrational populations and more explicit models of higher order electronic coupling. PMID- 24341918 TI - The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific. AB - To re-examine the correlation between mtDNA variability and longevity, we examined mtDNAs from samples obtained from over 2200 ultranonagenarians (and an equal number of controls) collected within the framework of the GEHA EU project. The samples were categorized by high-resolution classification, while about 1300 mtDNA molecules (650 ultranonagenarians and an equal number of controls) were completely sequenced. Sequences, unlike standard haplogroup analysis, made possible to evaluate for the first time the cumulative effects of specific, concomitant mtDNA mutations, including those that per se have a low, or very low, impact. In particular, the analysis of the mutations occurring in different OXPHOS complex showed a complex scenario with a different mutation burden in 90+ subjects with respect to controls. These findings suggested that mutations in subunits of the OXPHOS complex I had a beneficial effect on longevity, while the simultaneous presence of mutations in complex I and III (which also occurs in J subhaplogroups involved in LHON) and in complex I and V seemed to be detrimental, likely explaining previous contradictory results. On the whole, our study, which goes beyond haplogroup analysis, suggests that mitochondrial DNA variation does affect human longevity, but its effect is heavily influenced by the interaction between mutations concomitantly occurring on different mtDNA genes. PMID- 24341920 TI - Left ventricular and atrial functions in hypertrophic cardiomyopathy patients with very high LVOT gradient: a speckle tracking echocardiographic study. AB - BACKGROUND: Determination of myocardial deformation (strain) by two-dimensional (2D) speckle tracking echocardiography (STE) is a new method for evaluating left ventricular (LV) regional function in patients with hypertrophic cardiomyopathy (HCM). The aim of this study was to assess LV and left atrial (LA) functions with 2DSTE in HCM patients and to investigate relation between strain analysis and LV outflow tract (LVOT) gradient. METHODS: Forty consecutive HCM patients (26 male, mean age: 47.7 +/- 15.2 years), and 40 healthy volunteers (22 male, mean age: 46.6 +/- 11.2 years) were included in the study. All subjects underwent a transthoracic echocardiography for evaluation of LV and LA functions with 2DSTE. The HCM patients were divided into 2 groups according to the presence of resting LVOT gradient >100 mmHg. RESULTS: Left ventricular global longitudinal strain (GLS), global radial strain (GRS), and global circumferential strain (GCS) were significantly lower in patients with HCM compared with controls (-20.3 +/- 3.6% vs. -24.1 +/- 3.4% P < 0.001, 38.1 +/- 12.8% vs. 44.8 +/- 10.2% P = 0.012, and 22.0 +/- 4.4% vs. -23.9 +/- 4.0% P = 0.045, respectively). Although basal and apical rotation were similar between the groups, mid-rotation was significantly clockwise in HCM patients (-1.53 +/- 2.06 degrees vs. 0.05 +/- 1.7 degrees P < 0.001). Both LA reservoir functions and LA conduit functions were significantly lower in HCM patients (21.6 +/- 9.1% vs. 39.4 +/- 10.6% P < 0.001, and 10.5 +/- 4.3% vs. 15.7 +/- 5.3%, P < 0.001). Fifteen patients had a resting LVOT gradient of >100 mmHg and they had significantly decreased GLS, twist and untwist compared to the HCM patients with lower resting LVOT gradient (-18.7 +/- 2.3% vs. -21.2 +/ 3.9% P = 0.016, 19.4 +/- 4.3 degrees vs. 23.5 +/- 7.4 degrees P = 0.038 and 94.0 +/- 29.1 degrees /sec vs. -134.9 +/- 55.8 degrees /sec, 0.005, respectively). Although basal and apical rotation were similar between the 2 groups, mid-rotation was significantly clockwise in HCM patients with higher LVOT gradient (-2.52 +/- 1.76 degrees vs. -0.96 +/- 2.03 degrees , P = 0.018). Correlation analysis revealed that LVOT peak velocity was associated with GLS (r = -0.358, P = 0.023), LV mid-rotation (r = -0.366, P = 0.024), and LV untwist (r = -0.401, P = 0.013). CONCLUSIONS: Left ventricular and LA functions are impaired in patients with HCM. 2DSTE is useful in determining patients with impaired myocardial mechanics. High LVOT gradient may be one of the responsible factors that trigger deterioration of LV longitudinal strain and twist mechanics in patients with HCM. Further studies are required to clarify the preliminary results of this study. PMID- 24341921 TI - An unusual interstrand H-bond stabilizes the heteroassembly of helical alphabetagamma-chimeras with natural peptides. AB - The substitution of alpha-amino acids by homologated amino acids has a strong impact on the overall structure and topology of peptides, usually leading to a loss in thermal stability. Here, we report on the identification of an ideal core packing between an alpha-helical peptide and an alphabetagamma-chimera via phage display. Selected peptides assemble with the chimeric sequence with thermal stabilities that are comparable to that of the parent bundle consisting purely of alpha-amino acids. With the help of MD simulations and mutational analysis this stability could be explained by the formation of an interhelical H-bond between the selected cysteine and a backbone carbonyl of the beta/gamma-segment. Gained results can be directly applied in the design of biologically relevant peptides containing beta- and gamma-amino acids. PMID- 24341922 TI - Low-temperature processed electron collection layers of graphene/TiO2 nanocomposites in thin film perovskite solar cells. AB - The highest efficiencies in solution-processable perovskite-based solar cells have been achieved using an electron collection layer that requires sintering at 500 degrees C. This is unfavorable for low-cost production, applications on plastic substrates, and multijunction device architectures. Here we report a low cost, solution-based deposition procedure utilizing nanocomposites of graphene and TiO2 nanoparticles as the electron collection layers in meso-superstructured perovskite solar cells. The graphene nanoflakes provide superior charge collection in the nanocomposites, enabling the entire device to be fabricated at temperatures no higher than 150 degrees C. These solar cells show remarkable photovoltaic performance with a power conversion efficiency up to 15.6%. This work demonstrates that graphene/metal oxide nanocomposites have the potential to contribute significantly toward the development of low-cost solar cells. PMID- 24341923 TI - In vitro functional interactions of acetylcholine esterase inhibitors and muscarinic receptor antagonists in the urinary bladder of the rat. AB - Obidoxime, a weak acetylcholine-esterase (AChE) inhibitor, exerts muscarinic receptor antagonism with a significant muscarinic M2 receptor selective profile. The current examinations aimed to determine the functional significance of muscarinic M2 receptors in the state of AChE inhibition, elucidating muscarinic M2 and M3 receptor interaction. In the in vitro examinations, methacholine evoked concentration-dependent bladder contractile and atrial frequency inhibitory responses. Although atropine abolished both, methoctramine (1 MUmol/L) only affected the cholinergic response in the atrial preparations. However, in the presence of methoctramine, physostigmine, an AChE inhibitor, increased the basal tension of the bladder strip preparations (+68%), as well as the contractile responses to low concentrations of methacholine (< 5 MUmol/L; +90-290%). In contrast to physostigmine, obidoxime alone raised the basal tension (+58%) and the responses to low concentrations of methacholine (< 5 MUmol/L; +80-450%). Physostigmine concentration-dependently increased methacholine-evoked responses, similarly to obidoxime at low concentrations. However, at large concentrations (> 5 MUmol/L), obidoxime, because of its unselective muscarinic receptor antagonism, inhibited the methacholine bladder responses. In conclusion, the current results show that muscarinic M2 receptors inhibit muscarinic M3 receptor-evoked contractile responses to low concentrations of acetylcholine in the synaptic cleft. The muscarinic M2 and M3 receptor crosstalk could be a counteracting mechanism in the treatment of AChE inhibition when using reactivators, such as obidoxime. PMID- 24341924 TI - Assessment of general education teachers' Tier 1 classroom practices: contemporary science, practice, and policy. AB - Progress monitoring is a type of formative assessment. Most work on progress monitoring in elementary school settings has been focused on students. However, teachers also can benefit from frequent evaluations. Research addressing teacher progress monitoring is critically important given the recent national focus on teacher evaluation and effectiveness. This special topic section of School Psychology Quarterly is the first to showcase the current research on measuring Tier 1 instructional and behavioral management practices used by prekindergarten and elementary school teachers in general education settings. The three studies included in the special section describe the development and validation efforts of several teacher observational and self-report measures of instruction and/or behavioral management. These studies provide evidence for the utility of such assessments for documenting the use of classroom practices, and these assessment results may be leveraged in innovative coaching models to promote best practice. These articles also offer insight and ideas for the next generation of teacher practice assessment for the field. Finally, the special topic is capped by a commentary synthesizing the current work and offers "big ideas" for future measurement development, policy, and professional development initiatives. PMID- 24341925 TI - Predictive validity of the classroom strategies scale-observer form on statewide testing scores: an initial investigation. AB - The present study examined the validity of a teacher observation measure, the Classroom Strategies Scale--Observer Form (CSS), as a predictor of student performance on statewide tests of mathematics and English language arts. The CSS is a teacher practice observational measure that assesses evidence-based instructional and behavioral management practices in elementary school. A series of two-level hierarchical generalized linear models were fitted to data of a sample of 662 third- through fifth-grade students to assess whether CSS Part 2 Instructional Strategy and Behavioral Management Strategy scale discrepancy scores (i.e., ? |recommended frequency--frequency ratings|) predicted statewide mathematics and English language arts proficiency scores when percentage of minority students in schools was controlled. Results indicated that the Instructional Strategy scale discrepancy scores significantly predicted mathematics and English language arts proficiency scores: Relatively larger discrepancies on observer ratings of what teachers did versus what should have been done were associated with lower proficiency scores. Results offer initial evidence of the predictive validity of the CSS Part 2 Instructional Strategy discrepancy scores on student academic outcomes. PMID- 24341926 TI - Development and construct validity of the Classroom Strategies Scale-Observer Form. AB - Research on progress monitoring has almost exclusively focused on student behavior and not on teacher practices. This article presents the development and validation of a new teacher observational assessment (Classroom Strategies Scale) of classroom instructional and behavioral management practices. The theoretical underpinnings and empirical basis for the instructional and behavioral management scales are presented. The Classroom Strategies Scale (CSS) evidenced overall good reliability estimates including internal consistency, interrater reliability, test-retest reliability, and freedom from item bias on important teacher demographics (age, educational degree, years of teaching experience). Confirmatory factor analyses (CFAs) of CSS data from 317 classrooms were carried out to assess the level of empirical support for (a) a 4 first-order factor theory concerning teachers' instructional practices, and (b) a 4 first-order factor theory concerning teachers' behavior management practice. Several fit indices indicated acceptable fit of the (a) and (b) CFA models to the data, as well as acceptable fit of less parsimonious alternative CFA models that included 1 or 2 second-order factors. Information-theory-based indices generally suggested that the (a) and (b) CFA models fit better than some more parsimonious alternative CFA models that included constraints on relations of first-order factors. Overall, CFA first-order and higher order factor results support the CSS Observer Total, Composite, and subscales. Suggestions for future measurement development efforts are outlined. PMID- 24341927 TI - Commentary on two classroom observation systems: moving toward a shared understanding of effective teaching. AB - In this commentary, I make five points: that designing observation systems that actually predict students' outcomes is challenging; second that systems that capture the complex and dynamic nature of the classroom learning environment are more likely to be able to meet this challenge; three, that observation tools are most useful when developed to serve a particular purpose and are put to that purpose; four that technology can help; and five, there are policy implications for valid and reliable classroom observation tools. The two observation systems presented in this special issue represent an important step forward and a move toward policy that promises to make a true difference in what is defined as high quality and effective teaching, what it looks like in the classroom, and how these practices can be more widely disseminated so that all children, including those attending under-resourced schools, can experience effective instruction, academic success and the lifelong accomplishment that follows. PMID- 24341928 TI - Recurrence of abdominal large-vessel vasculitis and development of severe Sweet syndrome after a single cycle of 5-azacytidine in a patient with myelodysplastic syndrome. PMID- 24341929 TI - Capping four years of growth of Molecular Autism: impact factor coming in 2014. PMID- 24341930 TI - alpha-Melanocyte-stimulating hormone: a protective peptide against chemotherapy induced hair follicle damage? AB - BACKGROUND: Effective, safe and well-tolerated therapeutic and/or preventive regimens for chemotherapy-induced alopecia (CIA) still remain to be developed. Because alpha-melanocyte-stimulating hormone (alpha-MSH) exerts a number of cytoprotective effects and is well tolerated, we hypothesized that it may be a candidate CIA-protective agent. OBJECTIVES: To explore, using a human in vitro model for chemotherapy-induced hair follicle (HF) dystrophy that employs the key cyclophosphamide metabolite (4-hydroperoxy-cyclophosphamide, 4-HC), whether alpha MSH protects from 4-HC-induced HF dystrophy. METHODS: Microdissected human scalp HFs from four individuals were treated with 4-HC, alpha-MSH and 4-HC plus alpha MSH. Changes in HF cycling, melanin distribution and hair matrix keratinocyte proliferation/apoptosis were examined by quantitative (immune-) morphometry. Expression of the cytoprotective enzyme haem oxygenase-1 (HO-1) was determined by real-time reverse transcriptase-polymerase chain reaction in HF of two individuals. RESULTS: In 50% of the individuals alpha-MSH reduced melanin clumping as an early sign of 4-HC-induced disruption of follicular pigmentation. alpha-MSH reduced 4-HC-induced apoptosis in the HFs of one female patient. These protective effects of alpha-MSH were not associated with changes in 4-HC-induced catagen induction. alpha-MSH and 4-HC both increased HO-1 mRNA expression, while the combination of both agents had additive effects on HO-1 transcription. CONCLUSIONS: Exogenous alpha-MSH exerts moderate HF-protective effects against 4 HC-induced human scalp HF damage and upregulates the intrafollicular expression of a key cytoprotective enzyme. However, as substantial interindividual response variations were found, further studies are needed to probe alpha-MSH as a candidate CIA-protective agent. PMID- 24341931 TI - The prevalence rate and the role of the spatial extent of pain in nonspecific chronic back pain--a population-based study in the south-west of Germany. AB - OBJECTIVE: To determine the prevalence of chronic back pain in the general population and to establish an evidence-based subclassification system for chronic back pain based on pain extent. DESIGN: Representative population-based survey. SETTING: South-western Germany. SUBJECTS: Four-thousand representative residents were contacted. The corrected response rate was 61.8% (N = 2,408). Those suffering from chronic back pain (pain >=45 days/last 3 months) were invited to a clinical evaluation. OUTCOME MEASURES: Chronic back pain, spatial extent of pain, sociodemographic and clinical variables. RESULTS: Age- and sex adjusted prevalence rate for chronic back pain was 17.7%. Analyzing pain extent, we found that only 19.6% suffered strictly from chronic local back pain, while the majority indicated additional pain regions. Thus, we developed a subclassification system based on pain extent that consists of four more homogeneous groups (19.6% strict chronic local pain, 42.1% chronic regional pain, 24.3% common chronic widespread pain, 13.9% extreme chronic widespread pain). Interestingly, in this system, increasing pain extent was significantly associated with higher distress, as reflected by sociodemographic (e.g., lower education, lower social class, and higher application rate for disability pension) and clinical variables (e.g., higher pain intensity, more pain medication, more consultations, higher impairment, and lower quality of life). CONCLUSIONS: Chronic back pain is prevalent and usually involves additional pain areas outside of the back. This challenges the concept of chronic back pain as a distinct entity. To identify patients who are distressed by chronic back pain, a four-class taxonomy based on pain drawings is both feasible and clinically useful. PMID- 24341932 TI - Un-nesting DNA Russian dolls - the potential for constructing food webs using residual DNA in empty aphid mummies. AB - Constructing food-web assemblages comprising parasitoid wasps involves large field collections of hosts followed by labour-intensive rearing of the insects to evaluate the rates of parasitism along with morphological or molecular identification of the parasitoid species. This article presents research towards a new molecular method for the practical and accurate construction of aphid-based food webs. We hypothesize that parasitoid and hyperparasitoid DNA left inside aphid mummies after emergence of these third and fourth trophic-level guilds can be simultaneously detected using universal polymerase chain reaction (PCR) primers for nonspecific DNA amplification in combination with single-stranded conformation polymorphism (SSCP) analysis. Such a protocol theoretically allows food-web construction to be performed with no a priori knowledge of the species present. Moreover, the use of empty mummies circumvents rearing and minimizes labour and time in the field and laboratory. To test our hypothesis, we conducted DNA analyses on laboratory-produced parasitized aphids (mummies) from Myzus persicae and Brevicoryne brassicae (two important aphid pest species) after exposure to the parasitoid Diaeretiella rapae and the hyperparasitoid Asaphes vulgaris. DNA is amplifiable in empty aphid mummies for as long as 3 weeks after parasitoid emergence. However, the simultaneous identification of several species in a single mummy sample was rare, which hinders the accurate inference of trophic links. DNA quality and relative quantity, together with preferential amplification, are potential explanations of current results. Technical refinements are needed to ensure full reliability and detection of complex trophic links. The use of PCR-SSCP for food-web construction is novel, and its potential to include an important number of different species is yet to be fully explored. PMID- 24341933 TI - Electrostatic potential within the free volume space of imidazole-based solvents: insights into gas absorption selectivity. AB - In this work, a variety of molecular simulation tools are used to help characterize the selective absorption of CO2 and CH4 in imidazole-based solvents. We focus our efforts on a series of 1-n-alkyl-2-methyl-imidazoles and ether functionalized imidazoles, over a temperature range from 293 to 353 K, and we perform detailed analysis of the free volume. We find that the electrostatic potential within the solvent free volume cavities provides a useful indication of the selective absorption of CO2 and CH4. The electrostatic potential calculation is significantly faster than the direct calculation of the chemical potential, and tests with the 1-n-alkyl-2-methyl-imidazoles and the ether-functionalized imidazoles indicate that this may be a useful screening tool for other solvents. PMID- 24341934 TI - Chronic stress and Parkinson's disease. PMID- 24341935 TI - Delayed shortening and shifting of carotid wallstent. PMID- 24341936 TI - Successful treatment of neurological malignant atrophic papulosis in child by corticosteroid combined with intravenous immunoglobulin. PMID- 24341937 TI - Progressive hemorrhagic transformation following dual antiplatelet therapy. PMID- 24341938 TI - Humanin attenuated the change of voltage-dependent potassium currents in hippocampal neurons induced by anoxia. PMID- 24341940 TI - Ward safety checklist in the acute surgical unit. AB - BACKGROUND: Deficiencies in daily ward rounds are increasingly identified. A ward safety checklist has recently been devised to improve the fast-paced surgical ward round. METHODS: Over 2 weeks the morning post-take surgical ward round was evaluated using the ward safety checklist. In order to avoid the Hawthorne effect, doctors involved were not aware their performance was being observed. RESULTS: One hundred patient encounters were evaluated. The three phases of the card safety checklist showed statistically significant improvement but for many components compliance was below 100%. CONCLUSION: Implementing this simple checklist has provided our unit with a starting point in how to overcome some of the deficiencies of the post-take surgical ward round. PMID- 24341941 TI - Nucleation: measurements, theory, and atmospheric applications. PMID- 24341939 TI - Reductions in serum IGF-1 during aging impair health span. AB - In lower or simple species, such as worms and flies, disruption of the insulin like growth factor (IGF)-1 and the insulin signaling pathways has been shown to increase lifespan. In rodents, however, growth hormone (GH) regulates IGF-1 levels in serum and tissues and can modulate lifespan via/or independent of IGF 1. Rodent models, where the GH/IGF-1 axis was ablated congenitally, show increased lifespan. However, in contrast to rodents where serum IGF-1 levels are high throughout life, in humans, serum IGF-1 peaks during puberty and declines thereafter during aging. Thus, animal models with congenital disruption of the GH/IGF-1 axis are unable to clearly distinguish between developmental and age related effects of GH/IGF-1 on health. To overcome this caveat, we developed an inducible liver IGF-1-deficient (iLID) mouse that allows temporal control of serum IGF-1. Deletion of liver Igf-1 gene at one year of age reduced serum IGF-1 by 70% and dramatically impaired health span of the iLID mice. Reductions in serum IGF-1 were coupled with increased GH levels and increased basal STAT5B phosphorylation in livers of iLID mice. These changes were associated with increased liver weight, increased liver inflammation, increased oxidative stress in liver and muscle, and increased incidence of hepatic tumors. Lastly, despite elevations in serum GH, low levels of serum IGF-1 from 1 year of age compromised skeletal integrity and accelerated bone loss. We conclude that an intact GH/IGF-1 axis is essential to maintain health span and that elevated GH, even late in life, associates with increased pathology. PMID- 24341943 TI - Total mercury concentrations in lionfish (Pterois volitans/miles) from the Florida Keys National Marine Sanctuary, USA. AB - Strategies to control invasive lionfish in the western Atlantic and Caribbean are likely to include harvest and consumption. Until this report, total mercury concentrations had been documented only for lionfish from Jamaica, and changes in concentrations with increasing fish size had not been evaluated. In the Florida Keys, total mercury concentrations in dorsal muscle tissue from 107 lionfish ranged from 0.03 to 0.48 ppm, with all concentrations being less than the regulatory threshold for limited consumption. Mercury concentrations did not vary consistently with standard lengths or wet weights of lionfish. In 2010, lionfish from the upper Keys had mean concentrations that were 0.03-0.04 ppm higher than lionfish from the middle Keys, but mean concentrations did not differ consistently among years and locations. Overall, total mercury concentrations in lionfish were lower than those in several predatory fishes that support commercial and recreational fisheries in Florida. PMID- 24341942 TI - Treatment outcomes in a cohort of Palestine refugees with diabetes mellitus followed through use of E-Health over 3 years in Jordan. AB - OBJECTIVE: The aim of this study was to use E-Health to report on 12-month, 24 month and 36-month outcomes and late-stage complications of a cohort of Palestine refugees with diabetes mellitus (DM) registered in the second quarter of 2010 in a primary healthcare clinic in Amman, Jordan. METHOD: Retrospective cohort study with treatment outcomes censored at 12-month time points using E-Health in UNRWA's Nuzha Primary Health Care Clinic. RESULTS: Of 119 newly registered DM patients, 61% were female, 90% were aged >=40 years, 92% had type 2 DM with 73% of those having hypertension and one-third of patients were newly diagnosed. In the first 3 years of follow-up, the proportion of clinic attendees decreased from 72% to 64% and then to 61%; the proportion lost to-follow-up increased from 9% to 19% and then to 29%. At the three time points of follow-up, 71-78% had blood glucose <=180 mg/dl; 63-74% had cholesterol <200 mg/dl; and about 90% had blood pressure <140/90 mmHg. Obesity remained constant at 50%. The proportion of patients with late-stage complications increased from 1% at baseline to 7% at 1 year, 14% at 2 years and 15% at 3 years. CONCLUSION: Nuzha PHC Clinic was able to monitor a cohort of DM patients for 3 years using E-Health and the principles of cohort analysis. This further endorses the use of cohort analysis for managing patients with DM and other non-communicable diseases. PMID- 24341944 TI - Essential, trace and toxic element concentrations in the liver of the world's largest bony fish, the ocean sunfish (Mola mola). AB - No studies document essential (calcium, magnesium, phosphorus, potassium, sodium), trace (barium, boron, chromium, cobalt, copper, iron, manganese, molybdenum, selenium, zinc) or toxic element (antimony, arsenic, cadmium, lead, mercury, thallium) concentrations in any members of the family Molidae, including the world's largest bony fish, the ocean sunfish (Mola mola). Here, we analyzed 21 elements in the liver of one M. mola. These values were compared to liver concentrations in multiple species with spatial and dietary overlap. Concentrations of calcium (3339 ppm wet weight) and iron (2311 ppm wet weight) were extremely elevated in comparison to a number of other fish species, indicating that calcium and/or iron toxicity may have occurred in this animal. Concentrations of toxic elements were generally low, with the exception of cadmium (3.5 ppm). This study represents the first report of essential, trace and toxic elements in this species. PMID- 24341945 TI - The influence of pearl oyster farming on reef fish abundance and diversity in Ahe, French Polynesia. AB - Many cultured pearl farms are located in areas of the Pacific that have thriving, highly diverse fish communities but the impacts of farming on these communities are poorly understood. We studied the effects of pearl oyster farming on shore fish abundance and diversity in the lagoon of Ahe, French Polynesia by adapting roving diver census methods to the coral reef bommies of the lagoon and compared 16 sites with high pearl farming impact to others with no direct impact. Pearl farming has a slightly positive effect on reef fish abundance (N) and no significant impact on fish diversity (H) or community composition. This is important when considering the ecological sustainability of pearl farming in French Polynesia and suggests that a potential synergy between pearl farms and marine conservation should be further explored. PMID- 24341946 TI - The magnitude and spatial range of current-use urban PCB and PBDE emissions estimated using a coupled multimedia and air transport model. AB - SO-MUM, a coupled atmospheric transport and multimedia urban model, was used to estimate spatially resolved (5 * 5 km(2)) air emissions and chemical fate based on measured air concentrations and chemical mass inventories within Toronto, Canada. Approximately 95% and 70% of Sigma5PCBs (CB-28, -52, -101, -153, and 180) and Sigma5PBDEs (BDE-28, -47, -100, -154, and -183) emissions of 17 (2-36) and 18 (3-42) kg y(-1), respectively, undergo atmospheric transport from the city, which is partly over Lake Ontario. The urban air plume was found to reach about 50 km for PCBs and PBDEs, in the direction of prevailing winds which is almost twice the distance of the wind-independent plume. The distance traveled by the plume is a function of prevailing wind velocity, the geographic distribution of the chemical inventory, and gas-particle partitioning. Soil wash-off of historically accumulated Sigma5PCBs to surface water contributed ~ 0.4 kg y(-1) (of mainly higher congeners) to near-shore Lake Ontario compared with volatilization of ~ 6 kg y(-1) of mainly lighter congeners. Atmospheric emissions from primary sources followed by deposition to surface films and subsequent wash off to surface water contributed ~ 1 kg y(-1) and was the main route of Sigma5PBDE loadings to near-shore Lake Ontario which acts as a net PBDE sink. Secondary emissions of PCBs and PBDEs from at least a ~ 900,000 km(2) rural land area would be needed to produce the equivalent primary emissions as Toronto (~ 640 km(2)). These results provide clear support for reducing inventories of these POPs. PMID- 24341947 TI - The Journal of Pharmacy and Pharmacology 2013. PMID- 24341948 TI - Concentrations of metronidazole in human plasma and saliva after tablet or gel administration. AB - OBJECTIVES: The aim of this study was to determine the pharmacokinetic profile of metronidazole (Mtz) tablet and to compare Mtz gel and tablet concentrations in both blood plasma and saliva. METHODS: In this randomized cross-over study with a 1-week washout period, 13 volunteers randomly received one (a single oral dose of 750 mg Mtz (Flagyl(r)--tablet) and 2) 3 g of 15% Mtz benzoate gel (applied by using a dental tray). The HPLC with ultraviolet detection was used to quantify plasma and saliva concentrations of Mtz. The pharmacokinetic parameters (PPs) areas under the curves from 0 to 48 h (AUC0-48) and from 0 to infinity (AUC0 infinity), the maximum plasma concentration (C(max)), the time to C(max), volume of distribution and renal clearance were determined for Mtz tablet. KEY FINDINGS: Considering the Mtz tablet, plasma showed higher Mtz concentration from 6 to 24 h after drug administration and the highest values concerning AUC0-48 h and AUC0 infinity than those obtained in saliva (P < 0.05). No significant differences were observed between plasma and saliva concentrations for Mtz gel. CONCLUSIONS: The study showed that some PPs were higher in plasma (P < 0.05) than in saliva concerning Mtz tablet. Gel formulation had similar Mtz bioavailability in plasma and saliva resulting in systemic absorption. PMID- 24341949 TI - The role of 5-hydroxytryptamine receptor subtypes in the regulation of brain derived neurotrophic factor gene expression. AB - OBJECTIVES: The study aims to investigate the role of 5-hydroxytryptamine receptor subtypes in mediating the inhibitory effect of the selective serotonin reuptake inhibitor (fluoxetine on brain-derived neurotrophic factor gene (bdnf) expression in rat hippocampus. METHODS: In situ hybridization was used for regional determination of bdnf expression levels in hippocampal brain slices from normal, lesioned (5-hydroxytryptamine or noradrenaline) or adrenalectomized rats; treated with fluoxetine and/or 5-hydroxytryptamine selective ligands. KEY FINDINGS: Our study shows that the transient fluoxetine-induced down-regulation of bdnf gene expression depends on an intact 5-hydroxytryptamine but not noradrenaline system or circulating glucocorticoids. Pretreatment with the 5 hydroxytryptamine4 antagonist SB-204070 blocked the overall fluoxetine-induced inhibition of bdnf levels in hippocampus, while pretreatment with the 5 hydroxytryptamine2 antagonists ketanserin had an effect in the CA3 but not in the dentate gyrus sub-region of hippocampus. The 5-hydroxytryptamine1A antagonist WAY 100635 and the 5-hydroxytryptamine3 antagonist granisetron were both ineffective. CONCLUSIONS: Our study found strong support for a primary effect of 5 hydroxytryptamine but not noradrenaline or circulating glucocorticoids in the mediation of fluoxetine-induced down-regulation of bdnf expression. More specifically, we also show that 5-hydroxytryptamine4 receptor-stimulation seems to play a pivotal role in this effect. PMID- 24341950 TI - Synthesis, characterization and in vitro extracellular and intracellular activity against Mycobacterium tuberculosis infection of new second-line antitubercular drug-palladium complexes. AB - OBJECTIVES: The aim of this work was to characterize novel palladium (Pd) complexes with second-line antitubercular drugs, namely capreomycin (C), kanamycin (K) and ofloxacin (Ofx), and to address the in vitro extracellular and intracellular activity against Mycobacterium tuberculosis infection. METHODS: Synthesis reaction kinetics and complex properties were assessed. Kf was calculated from the transition state quasi-equilibrium approximation and Arrhenius plot. The complexes were characterized for qualitative solubility, stoichiometry, powder size and morphology, element analysis, and thermal behaviour. Structural analyses were performed by Fourier transform infrared spectroscopy and nuclear magnetic resonance. Activity was evaluated against H37Ra M. tuberculosis strain and in infected THP-1 cells, and compared with that of the parent drugs. KEY FINDINGS: The complexes showed log Kf of 6 for CPd and OfxPd, and 10 for KPd indicating good stability. Stoichiometry of 1:1, 2: 3 and 1:3 resulted for OfxPd, KPd, and CPd. OfxPd structure matched that in literature, while K and C had more complex structures with possible multiple coexisting species. The complexes had extracellular activity comparable with drugs and an improved efficacy against intracellular infection of M. tuberculosis. CONCLUSIONS: The novel anti-tuberculosis (TB) complexes had promising properties, and extracellular and intracellular activity, which makes them potential tools for intracellular targeting of pulmonary TB. PMID- 24341951 TI - Aerococcus christensenii native aortic valve subacute bacterial endocarditis (SBE) presenting as culture negative endocarditis (CNE) mimicking marantic endocarditis. AB - This is a case report of an adult who presented with apparent culture negative endocarditis (CNE) thought to be marantic endocarditis due to a B-cell lymphoproliferative disorder. This was a most perplexing case and was eventually diagnosed as subacute bacterial endocarditis (SBE) due to a rare slow growing organism. Against the diagnosis of SBE was the lack of fever, hepatomegaly, peripheral manifestations and microscopic hematuria. Also, against a diagnosis of SBE was another explanation for the patient's abnormal findings, e.g., elevated ferritin levels, elevated alpha1/alpha2 globulins on SPEP, an elevated alkaline phosphatase, flow cytometry showing B-lymphocytes expressing CD5, and a bone lesion in the right iliac. Findings compatible with both SBE and marantic endocarditis due to a B-cell lymphoproliferative disorder included an elevated ESR, and splenomegaly. Blood cultures eventually became positive during hospitalization. We report a case of native aortic valve (AV) subacute bacterial endocarditis (SBE) due to Aerococcus christensenii mimicking marantic endocarditis due to a B-cell lymphoproliferative disorder. To the best of our knowledge, this is the first reported case of native AV SBE due to A. christensenii presenting as marantic endocarditis. PMID- 24341952 TI - Examining barriers to self-reporting of elder physical abuse in community dwelling older adults. AB - One out of 10 older adults experiences elder abuse in their lifetime, though less than one third of these cases ever get reported. The purpose of this study was to describe older adults' perceptions of physical abuse (PA) as a type of elder abuse including reasons why they may or may not self-report. An author developed vignette scale was used to present three types of PA and three barriers to reporting for each of three living situations. Older adults (n = 76) rated perceptions of whether or not the situation is abusive, likelihood of reporting and likelihood of reporting when presented with each of three barriers. The study participants had a consistent perception of PA; however the barriers affected their likelihood of reporting, which varied across types and situations. The results provide further evidence that reporting abuse is multifactorial and have implications for educational interventions. PMID- 24341953 TI - Lateral neck tumour: Ectopic thyroid vs metastasis of a differentiated thyroid carcinoma. PMID- 24341955 TI - Consequences of intraspecific variation in female body size in Stagmomantis limbata (Mantodea: Mantidae): feeding ecology, male attraction, and egg production. AB - Body size is an important feature of organisms, influencing many components of life history and fitness, such as feeding success and reproductive output. Body size is considered especially salient for solitary predators, whose food intake hinges on individual predation success, which in turn is often driven by the relative sizes of predator and prey. The current study examined intraspecific variation in adult female length and its fitness consequences in a solitary predator, the praying mantid Stagmomantis limbata Hahn. Through a 5-yr integration of observational and experimental work in the field and captivity, we investigated the relationship between female pronotum length and prey size, diet breadth, male attraction, and measures of egg production (fecundity and ootheca mass). We found that longer females ate longer prey in the field and showed greater breadth of prey size than shorter females. Longer females did not necessarily feed at higher rates in the field, as measured by the rate of abdominal expansion. Female length failed to show significant effects on male attraction or on the incidence of cannibalism. Longer females had higher fecundity (mature eggs in body at death) and laid heavier oothecae than shorter females. In nature, longer females consistently emerged as adults earlier in the season than shorter females. Shorter female adults emerged when feeding rates were higher in the field, suggesting an incidental ecological benefit of shorter adult size. PMID- 24341954 TI - Role of active site residues in promoting cobalt-carbon bond homolysis in adenosylcobalamin-dependent mutases revealed through experiment and computation. AB - Adenosylcobalamin (AdoCbl) serves as a source of reactive free radicals that are generated by homolytic scission of the coenzyme's cobalt-carbon bond. AdoCbl dependent enzymes accelerate AdoCbl homolysis by ~10(12)-fold, but the mechanism by which this is accomplished remains unclear. We have combined experimental and computational approaches to gain molecular-level insight into this process for glutamate mutase. Two residues, glutamate 330 and lysine 326, form hydrogen bonds with the adenosyl group of the coenzyme. A series of mutations that impair the enzyme's ability to catalyze coenzyme homolysis and tritium exchange with the substrate by 2-4 orders of magnitude were introduced at these positions. These mutations, together with the wild-type enzyme, were also characterized in silico by molecular dynamics simulations of the enzyme-AdoCbl-substrate complex with AdoCbl modeled in the associated (Co-C bond formed) or dissociated [adenosyl radical with cob(II)alamin] state. The simulations reveal that the number of hydrogen bonds between the adenosyl group and the protein side chains increases in the homolytically dissociated state, with respect to the associated state, for both the wild-type and mutant enzymes. The mutations also cause a progressive increase in the mean distance between the 5'-carbon of the adenosyl radical and the abstractable hydrogen of the substrate. Interestingly, the distance between the 5'-carbon and substrate hydrogen, determined computationally, was found to inversely correlate with the log k for tritium exchange (r = 0.93) determined experimentally. Taken together, these results point to a dual role for these residues: they both stabilize the homolytic state through electrostatic interactions between the protein and the dissociated coenzyme and correctly position the adenosyl radical to facilitate the abstraction of hydrogen from the substrate. PMID- 24341956 TI - Re: J. Alfred Witjes. A case of abiraterone acetate withdrawal. Eur Urol 2013;64:517-8. PMID- 24341957 TI - Castration-resistant prostate cancer: adaptation or clonal selection? Insight from the EORTC 30891 trial. PMID- 24341958 TI - Assessing the response to targeted therapies in renal cell carcinoma: technical insights and practical considerations. AB - CONTEXT: The introduction of targeted agents for the treatment of renal cell carcinoma (RCC) has resulted in new challenges for assessing response to therapy, and conventional response criteria using computed tomography (CT) are limited. It is widely recognised that targeted therapies may lead to significant necrosis without significant reduction in tumour size. In addition, the vascular effects of antiangiogenic therapy may occur long before there is any reduction in tumour size. OBJECTIVE: To perform a systematic review of conventional and novel imaging methods for the assessment of response to targeted agents in RCC and to discuss their use from a clinical perspective. EVIDENCE ACQUISITION: Relevant databases covering the period January 2006 to April 2013 were searched for studies reporting on the use of anatomic and functional imaging techniques to predict response to targeted therapy in RCC. Inclusion criteria were randomised trials, nonrandomised controlled studies, retrospective case series, and cohort studies. Reviews, animal and preclinical studies, case reports, and commentaries were excluded. A narrative synthesis of the evidence is presented. EVIDENCE SYNTHESIS: A total of 331 abstracts and 76 full-text articles were assessed; 34 studies met the inclusion criteria. Current methods of response assessment in RCC include anatomic methods--based on various criteria including Choi, size and attenuation CT, and morphology, attenuation, size, and structure--and functional techniques including dynamic contrast-enhanced (DCE) CT, DCE-magnetic resonance imaging, DCE ultrasonography, positron emission tomography, and approaches utilising radiolabelled monoclonal antibodies. CONCLUSIONS: Functional imaging techniques are promising surrogate biomarkers of response in RCC and may be more appropriate than anatomic CT-based methods. By enabling quantification of tumour vascularisation, functional techniques can directly and rapidly detect the biologic effects of antiangiogenic therapies compared with the indirect detection of belated effects on tumour size by anatomic methods. However, larger prospective studies are needed to validate early results and standardise techniques. PMID- 24341959 TI - Re: Jimsgene Sanjmyatav, Sven Hauke, Mieczyslaw Gajda, et al. Establishment of a multicolour fluorescence in situ hybridisation-based assay for subtyping of renal cell tumours. Eur Urol 2013;64:689-91. PMID- 24341960 TI - Kinetic control of chirality in porphyrin J-aggregates. AB - Detailed kinetic investigations demonstrate the fundamental role of kinetic parameters in the expression and transmission of chirality in supramolecular systems. The rate of the aggregation process leading to the formation of J aggregates strongly affects the size of these nanoassemblies and the chiral induction. PMID- 24341961 TI - Clinical tests for intestinal permeability: 'sweet' transition from clinical to basic physiology. PMID- 24341962 TI - Psychological insulin resistance in geriatric patients with diabetes mellitus. AB - OBJECTIVE: To determine the extent to which geriatric patients with diabetes mellitus experience psychological insulin resistance (PIR). METHODS: A total of 67 unselected geriatric patients with diabetes (mean age 82.8+/-6.7 years, diabetes duration 12.2 [0.04-47.2] years, 70.1% female) were recruited in a geriatric care center of a university hospital. A comprehensive geriatric assessment (CGA) was performed including WHO-5, Hospital Anxiety and Depression Scale (HADS), Mini Mental State Examination (MMSE) and Barthel-Index. We assessed PIR using the Barriers of Insulin Treatment Questionnaire (BIT) and the Insulin Treatment Appraisal Scale in a face-to-face interview. RESULTS: Insulin-naive patients (INP) showed higher PIR scores than patients already on insulin therapy (BIT-sum score: 4.3+/-1.4 vs. 3.2+/-1.0; p<0.001). INP reported in the BIT increased fear of injection and self-testing (2.4+/-2.4 vs. 1.3+/-0.8; p=0.016), expect disadvantages from insulin treatment (2.7+/-1.6 vs. 1.9+/-1.4; p=0.04), and fear of stigmatization by insulin injection (5.2+/-2.3 vs. 3.6+/-2.6; p=0.008). Fear of hypoglycemia, however, did not differ significantly (6.3+/-2.8 vs. 5.1+/-3.1; p=0.11). Depression was not shown to be a barrier to insulin therapy. CONCLUSION: INP with diabetes have a significantly more negative attitude toward insulin therapy in comparison to patients already on insulin. PRACTICE IMPLICATIONS: Systematic assessment of barriers of insulin therapy, individualized diabetes treatment plans and information of patients may help to overcome such negative attitudes, leading to quicker initiation of therapy, improved adherence to treatment and a better quality of life. PMID- 24341964 TI - Editorial comment to Risk factors for the development of well leg compartment syndrome after sex reassignment surgery in patients with gender identity disorder. PMID- 24341963 TI - Effectiveness of web-based versus folder support interventions for young informal carers of persons with mental illness: a randomized controlled trial. AB - OBJECTIVE: Compare the impact of two interventions, a web-based support and a folder support, for young persons who care for people who suffer from mental illness. METHODS: This study was a randomized control trial, following the CONSORT statements, which compared the impact of two interventions. Primary outcome variable was stress, and secondary outcome variables were caring situation, general self-efficacy, well-being, health, and quality of life of young informal carers (N=241). Data were collected in June 2010 to April 2011, with self-assessment questionnaires, comparing the two interventions and also to detect changes. RESULTS: The stress levels were high in both groups at baseline, but decreased in the folder group. The folder group had improvement in their caring situation (also different from the web group), general self-efficacy, well being, and quality of life. The web group showed increase in well-being. CONCLUSION: Young informal carers who take on the responsibility for people close to them; suffer consequences on their own health. They live in a life-situation characterized by high stress and low well-being. This signals a need for support. PRACTICE IMPLICATIONS: The non-significant differences show that each intervention can be effective, and that it depends upon the individual's preferences. This highlights the importance of adopting person-centered approach, in which young persons can themselves choose support strategy. PMID- 24341965 TI - Editors' pick: re-'colon'-ization of healthy microbiota after recurrent C. difficile infection. PMID- 24341966 TI - Caudal vs transforaminal epidural steroid injections as short-term (6 months) pain relief in lumbar spinal stenosis patients with sciatica. AB - OBJECTIVE: The aim of this study is to evaluate prospectively the efficacy of caudal epidural steroid injection (CESI) and transforaminal epidural steroid injection (TFESI) in lumbar spinal stenosis patients with sciatic pain. DESIGN: Prospective clinical study. SETTING AND PATIENTS: Thirty-one patients (average age 62 years) from two hospitals, with single dermotomal distribution of sciatic pain due to spinal stenosis were included in the study. INTERVENTIONS: Patients underwent epidural steroid injections done by the same injectionist. Eleven patients from one hospital were included in the CESI group, while the TFESI group consisted of 20 comparable patients from the second site. OUTCOME MEASURES: Primary outcome measure was the complete relief or at least 50% reduction of pain (visual analog scale [VAS]) at 6 months postinjection. Secondary outcome measures were the improvement of function (of at least 15 points of Oswestry Disability Index [ODI]) at 6 months and the changes of VAS and ODI and at 2 weeks, at 3 months, and at 6 months postinjection. RESULTS: A significantly greater number of stenosis patients showed pain relief at 6 months postinjection with TFSI (90%) than with CESI (54.54%). All patients with TFSI showed improvement of function at 6 months while only three (27.27%) patients with caudal epidural improved functionally. Out of the total 31 patients, two patients from group A underwent a second CESI at 15 days postinjection and decompressive spine surgery between 3 and 6 months postinjection. CONCLUSIONS: The effectiveness of transforaminal steroid injection for the stenosis patients with sciatica was superior to caudal at 6 months postinjection. PMID- 24341967 TI - Determination of the optimum operating point for a handheld minimal erythema dose device. PMID- 24341968 TI - Assessing the efficacy of LGBT cultural competency training for aging services providers in California's central valley. AB - This study reviews the outcomes of a cultural competency training for aging services providers regarding lesbian, gay, bisexual, and transgender (LGBT) older adults. Results indicate that participants significantly increased their knowledge, skills, and positive attitudes about working with LGBT older adults, with men and non-LGBT individuals reporting the most gain. Recommendations for future research include determining which factors influence the enduring effects of this type of training and developing a standardized instrument for measuring such success. Legislative and policy changes targeted at requiring this type of cultural competency training for all direct service providers are considered. PMID- 24341969 TI - Management of short bowel syndrome. AB - Most intestinal failure in children is due to short bowel syndrome (SBS) where congenital or acquired lesions have led to an extensive loss of intestinal mass. The vast majority of morbidity and mortality of patients with SBS is due to complications secondary to their long term dependence on parenteral nutrition. In response to SBS, the intestine undergoes a process of remodeling termed adaptation. Principles guiding the medical management of SBS include providing adequate parenteral nutrition, fluids and electrolytes for growth and normal development, promoting small bowel adaptation, and preventing and treating complications related to the patient's underlying disease and their parenteral nutrition. Catheter associated blood stream infection (CABSI) is major source of morbidity and mortality in patients with intestinal failure from SBS. Intestinal failure associated liver disease (IFALD)is another major source of morbidity and mortality in patients with SBS. IFALD is the most consistent negative predictor of outcome including death and continued parenteral nutrition dependence. Enteral nutrition is critical for intestinal adaptation and preventing IFALD. Patients with SBS who develop dilated dysmotile segments may benefit from autologous intestinal reconstruction surgery (AIRS) with the goal of decreasing stasis and disordered motility through intestinal narrowing and lengthening. Patients with SBS should be referred for transplantation if they have failed intestinal rehabilitation including AIRS, have no reasonable chance for enteral feeding tolerance, develop irreversible IFALD, have recurrent sepsis, or have exhausted their central venous access sites. With improvements in medical and surgical care, overall survival of patients with SBS now exceeds 90%. PMID- 24341970 TI - Painless engorgement of the calf in a patient with ankylosing spondylitis. PMID- 24341971 TI - Low pH inactivation for xenotropic gamma retrovirus in recombinant human TNF alpha receptor immunoglobulin G and mechanism of inactivation. AB - CHO-derived recombinant proteins for human therapeutic are used commonly. There are noninfectious endogenous retroviruses in CHO cells. Validation study for inactivation process is required. Murine xenotropic gamma retrovirus (X-MulV) is a model virus in validation study. In our previous study, optimum conditions for X-MulV inactivation were sifted. In this study, we performed a further research on low pH inactivation for evaluation of X-MulV clearance in manufacturing of recombinant human TNF-alpha receptor immunoglobulin G fusion proteins (rhTNF alpha) for injection. Cell-based infectivity assay was used for the evaluation of X-MulV clearance. RhTNF-alpha were spiked with X-MulV and were inactivated at pH 3.60 ~ 3.90, 25 +/- 2 degrees C, and 0 ~ 240 min, respectively. Samples incubated at the conditions for 15 ~ 180 min were not inactivated effectively. For 4 h incubation, log10 reductions were achieved 5.0 log10. Biological activity of rhTNF-alpha incubated at pH 3.60, 25 degrees C for 4 h, which was assayed on murine L929 fibroblasts cells, was not affected by low pH. Env gene of X-MulV, which was detected by conventional PCR method for the first time, was not detected after incubation at pH 3.60, and it may be the mechanism of low pH inactivation. PMID- 24341972 TI - Here's looking at you, kid: attention to infant emotional faces in mothers and non-mothers. AB - Infant facial cues play a critical role in eliciting care and nurturance from an adult caregiver. Using an attentional capture paradigm we investigated attentional processing of adult and infant emotional facial expressions in a sample of mothers (n = 29) and non-mothers (n = 37) to determine whether infant faces were associated with greater task interference. Responses to infant target stimuli were slower than adult target stimuli in both groups. This effect was modulated by parental status, such that mothers compared to non-mothers showed longer response times to infant compared to adult faces. Both groups also responded more slowly to emotional faces, an effect that was more marked for infant emotional faces. Finally, it was found that greater levels of mothers' self-reported parental distress was associated with less task interference when processing infant faces. These findings indicate that for adult women, infant faces in general and emotional infant faces in particular, preferentially engage attention compared to adult faces. However, for mothers, infant faces appear to be more salient in general. Therefore, infant faces may constitute a special class of social stimuli. We suggest that alterations in attentional processing in motherhood may constitute an adaptive behavioural change associated with becoming a parent. PMID- 24341973 TI - Effects of anonymous peer observation on adolescents' preference for immediate rewards. AB - Research suggests that the presence of peers influences adolescent risk-taking by increasing the perceived reward value of risky decisions. While prior work has involved observation of participants by their friends, the current study examined whether observation by an anonymous peer could elicit similarly increased reward sensitivity. Late adolescent participants completed a delay discounting task either alone or under the belief that performance was being observed from a neighboring room by an unknown viewer of the same gender and age. Even in this limited social context, participants demonstrated a significantly increased preference for smaller, immediate rewards when they believed that they were being watched. This outcome challenges several intuitive accounts of the peer effect on adolescent risk-taking, and indicates that the peer influence on reward sensitivity during late adolescence is not dependent on familiarity with the observer. The findings have both theoretical and practical implications for our understanding of social influences on adolescents' risky behavior. PMID- 24341975 TI - Resting gamma power is linked to reading ability in adolescents. AB - Infants who have more power within the gamma frequency range at rest develop better language and cognitive abilities over their first 3 years of life (Benasich et al., 2008). This positive trend may reflect the gradual increase in resting gamma power that peaks at about 4 years (Takano & Ogawa, 1998): infants further along the maturational curve may exhibit both increased resting gamma power and more advanced language and cognitive function. Similar to other neural characteristics such as synaptic density, resting gamma power subsequently decreases with further development into adulthood (Tierney, Strait, O'Connell & Kraus, 2013). If previously reported relationships between resting gamma power and behavioral performance reflect variance in maturation, at least in part, negative correlations between resting gamma and behavior may predominate in later developmental stages, during which resting gamma activity is decreasing. We tested this prediction by examining resting gamma activity and language-dependent behavioral performance, reflected by a variety of reading-related tests, in adolescents between the ages of 14 and 15 years. Consistent with our predictions, resting gamma power inversely related to every aspect of reading assessed (i.e. reading fluency, rapid naming, and basic reading proficiency). Our results suggest that resting gamma power acts as an index of maturational progress in adolescents. PMID- 24341974 TI - Adolescent mice, unlike adults, consume more alcohol in the presence of peers than alone. AB - One hallmark of adolescent risk-taking is that it typically occurs when adolescents are with peers. It has been hypothesized that the presence of peers primes a reward-sensitive motivational state that overwhelms adolescents' immature capacity for inhibitory control. We examined this hypothesis using a rodent model. A sample of mice were raised in same-sex triads and were tested for alcohol consumption either as juveniles or as adults, with half in each age group tested alone and half tested with their cagemates. The presence of 'peers' increased alcohol consumption among adolescent mice, but not adults. The peer effect on human adolescent reward-seeking may reflect a hard-wired, evolutionarily conserved process through which the presence of agemates increases individuals' sensitivity to potential rewards in their immediate environment. PMID- 24341976 TI - The deficit of letter processing in developmental dyslexia: combining evidence from dyslexics, typical readers and illiterate adults. AB - To clarify the link between anomalous letter processing and developmental dyslexia, we examined the impact of surrounding contours on letter vs. pseudo letter processing by three groups of children - phonological dyslexics and two controls, one matched for chronological age, the other for reading level - and three groups of adults differing by schooling and literacy - unschooled illiterates and ex-illiterates, and schooled literates. For pseudo-letters, all groups showed congruence effects (CE: better performance for targets surrounded by a congruent than by an incongruent shape). In contrast, for letters, only dyslexics exhibited a CE, strongly related to their phonological recoding abilities even after partialling out working memory, whereas the reverse held true for the pseudo-letter CE. In illiterate adults, the higher letter knowledge, the smaller their letter CE; their letter processing was immune (to some extent) to inference from surrounding information. The absence of a letter CE in illiterates and the positive CE in dyslexics have their origin in different aspects of the same ability, i.e. phonological recoding. PMID- 24341977 TI - P44, the 'longevity-assurance' isoform of P53, regulates tau phosphorylation and is activated in an age-dependent fashion. AB - p44 is a short isoform of p53 with 'longevity-assurance' activity. Overexpression of p44 in the mouse (p44(+/+) transgenic mice) causes a progeroid phenotype that mimics an accelerated form of aging. The phenotype includes abnormal phosphorylation of the microtubule-binding protein tau, synaptic deficits, and cognitive decline. Genetic engineering demonstrated that the phosphorylation status of tau acts upstream of the synaptic deficits. Here, we provide evidence that p44 promotes the phosphorylation of tau in the mouse. Specifically, we show that p44 binds to the promoter of tau kinases Dyrk1A, GSK3beta, Cdk5, p35, and p39 and activates their transcription. The upregulation of the above kinases is followed by increased phosphorylation of tau. Finally, we show that p44 is preferentially found in the nucleus and that its levels increase with age in the mouse brain. Taken together, these results suggest that an imbalance in the p53:p44 ratio might be involved with the altered tau metabolism that characterizes aging. PMID- 24341979 TI - Ion reaction dynamics. PMID- 24341978 TI - Photoaffinity labeling the propofol binding site in GLIC. AB - Propofol, an intravenous general anesthetic, produces many of its anesthetic effects in vivo by potentiating the responses of GABA type A receptors (GABAAR), members of the superfamily of pentameric ligand-gated ion channels (pLGICs) that contain anion-selective channels. Propofol also inhibits pLGICs containing cation selective channels, including nicotinic acetylcholine receptors and GLIC, a prokaryotic proton-gated homologue from Gloeobacter violaceus . In the structure of GLIC cocrystallized with propofol at pH 4 (presumed open/desensitized states), propofol was localized to an intrasubunit pocket at the extracellular end of the transmembrane domain within the bundle of transmembrane alpha-helices (Nury, H, et al. (2011) Nature 469, 428-431). To identify propofol binding sites in GLIC in solution, we used a recently developed photoreactive propofol analogue (2 isopropyl-5-[3-(trifluoromethyl)-3H-diazirin-3-yl]phenol or AziPm) that acts as an anesthetic in vivo and potentiates GABAAR in vitro. For GLIC expressed in Xenopus oocytes, propofol and AziPm inhibited current responses at pH 5.5 (EC20) with IC50 values of 20 and 50 MUM, respectively. When [(3)H]AziPm (7 MUM) was used to photolabel detergent-solubilized, affinity-purified GLIC at pH 4.4, protein microsequencing identified propofol-inhibitable photolabeling of three residues in the GLIC transmembrane domain: Met-205, Tyr-254, and Asn-307 in the M1, M3, and M4 transmembrane helices, respectively. Thus, for GLIC in solution, propofol and AziPm bind competitively to a site in proximity to these residues, which, in the GLIC crystal structure, are in contact with the propofol bound in the intrasubunit pocket. PMID- 24341980 TI - Oxidative stress may be involved in distant organ failure in tourniquet shock model mice. AB - Crush syndrome is characterized by prolonged shock resulting from extensive muscle damage and multiple organ failure. However, the pathogenesis of multiple organ failure has not yet been completely elucidated. Therefore, we investigated the molecular biological and histopathological aspects of distant organ injury in crush syndrome by using tourniquet shock model mice. DNA microarray analysis of the soleus muscle showed an increase in the mRNA levels of Cox-2, Hsp70, c-fos, and IL-6, at 3h after ischemia/reperfusion injury at the lower extremity. In vivo staining with hematoxylin and eosin (HE) showed edema and degeneration in the soleus muscle, but no change in the distant organs. Immunohistological staining of the HSP70 protein revealed nuclear translocation in the soleus muscle, kidney, liver, and lung. The c-fos mRNA levels were elevated in the soleus muscle, kidney, and liver, displaying nuclear translocation of c-FOS protein. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) analysis suggested the involvement of apoptosis in ischemia/reperfusion injury in the soleus muscle. Apoptotic cells were not found in greater quantities in the kidney. Oxidative stress, as determined using a free radical elective evaluator (d-ROM test), markedly increased after ischemia/reperfusion injury. Therefore, examination of immunohistological changes and determination of oxidative stress are proposed to be useful in evaluating the extent of tourniquet shock, even before changes are observed by HE staining. PMID- 24341981 TI - Artificial neural networks for bilateral prediction of formulation parameters and drug release profiles from cochlear implant coatings fabricated as porous monolithic devices based on silicone rubber. AB - OBJECTIVES: The coating of cochlear implants for topical delivery of drugs, for example, corticosteroids, or antibiotics is a novel approach to manage post surgical complications associated with cochlear implantation surgery like inflammation or infections. Many variables, including formulation parameters, can be changed to modulate the amount and duration of drug release from these devices. Mathematical modeling of drug release profile from a delivery system may be helpful to accelerate formulations in a more cost-efficient way. To attain specific in vitro drug release characteristics, a model should be capable to provide good estimates on the initial formulation parameters, for example, composition, geometry and drug loading vice versa. Here, artificial neural networks (ANNs) are used to predict dexamethasone (DEX) release profile and formulation parameters, bilaterally, from cochlear implant coatings designed as porous, monolithic silicone rubber-based matrices. METHODS: The devices were fabricated as monolithic dispersions of DEX in a silicone rubber matrix containing porogens. A newly developed mathematical function was fitted on the experimental DEX release curves, and the function coefficients were fed into the network as input variables to simulate drug release profile from the porous devices. Formulation variables consisted of drug loading percentage (0.05-0.5% w/w), porogen type (dextran (dext) or sodium chloride particles) and porogen content (5-40% w/w). The ANN was also examined to determine optimal levels of the formulation parameters to provide a specifically desired drug release profile. KEY FINDINGS: The results showed that DEX release profile from porous cochlear implant devices can be modelled accurately and precisely using ANN in order to predict optimal levels for the formulation parameters to provide a specific drug release profile vice versa. CONCLUSIONS: The developed ANNs were used to achieve shorter formulation development process, and to provide tailor-made drug delivery regimens. ANNs were also successfully simulated non-linear relationships present between the initial formulation variable(s) and predict the subsequent drug release patterns. PMID- 24341983 TI - Optimal control of population recovery--the role of economic restoration threshold. AB - A variety of ecological systems around the world have been damaged in recent years, either by natural factors such as invasive species, storms and global change or by direct human activities such as overfishing and water pollution. Restoration of these systems to provide ecosystem services entails significant economic benefits. Thus, choosing how and when to restore in an optimal fashion is important, but has not been well studied. Here we examine a general model where population growth can be induced or accelerated by investing in active restoration. We show that the most cost-effective method to restore an ecosystem dictates investment until the population approaches an 'economic restoration threshold', a density above which the ecosystem should be left to recover naturally. Therefore, determining this threshold is a key general approach for guiding efficient restoration management, and we demonstrate how to calculate this threshold for both deterministic and stochastic ecosystems. PMID- 24341982 TI - Lipoprotein activators stimulate Escherichia coli penicillin-binding proteins by different mechanisms. AB - In Escherichia coli , the bifunctional penicillin-binding proteins (PBPs), PBP1A and PBP1B, play critical roles in the final stage of peptidoglycan (PG) biosynthesis. These synthetic enzymes each possess a PG glycosyltransferase (PGT) domain and a transpeptidase (TP) domain. Recent genetic experiments have shown that PBP1A and PBP1B each require an outer membrane lipoprotein, LpoA and LpoB, respectively, to function properly in vivo. Here, we use complementary assays to show that LpoA and LpoB each increase the PGT and TP activities of their cognate PBPs, albeit by different mechanisms. LpoA directly increases the rate of the PBP1A TP reaction, which also results in enhanced PGT activity; in contrast, LpoB directly affects PGT domain activity, resulting in enhanced TP activity. These studies demonstrate bidirectional coupling of PGT and TP domain function. Additionally, the transpeptidation assay described here can be applied to study other activators or inhibitors of the TP domain of PBPs, which are validated drug targets. PMID- 24341985 TI - Beyond realism in climate change experiments: gradient approaches identify thresholds and tipping points. AB - Experimental evidence for impacts of increased climatic variability and extremes on ecosystems is urgently needed. The constraint in our knowledge, however, is not caused by the uncertainty in the applied climate scenarios. We need mechanistic understanding from experiments challenging ecological thresholds coupled with ecosystem models to allow for meaningful up-scaling. PMID- 24341984 TI - Historical contingency in species interactions: towards niche-based predictions. AB - The way species affect one another in ecological communities often depends on the order of species arrival. The magnitude of such historical contingency, known as priority effects, varies across species and environments, but this variation has proven difficult to predict, presenting a major challenge in understanding species interactions and consequences for community structure and function. Here, we argue that improved predictions can be achieved by decomposing species' niches into three components: overlap, impact and requirement. Based on classic theories of community assembly, three hypotheses that emphasise related, but distinct influences of the niche components are proposed: priority effects are stronger among species with higher resource use overlap; species that impact the environment to a greater extent exert stronger priority effects; and species whose growth rate is more sensitive to changes in the environment experience stronger priority effects. Using nectar-inhabiting microorganisms as a model system, we present evidence that these hypotheses complement the conventional hypothesis that focuses on the role of environmental harshness, and show that niches can be twice as predictive when separated into components. Taken together, our hypotheses provide a basis for developing a general framework within which the magnitude of historical contingency in species interactions can be predicted. PMID- 24341986 TI - Analysis of the medical causes of death in cerebral palsy. AB - AIM: To investigate causes of death and age at death in cerebral palsy subjects compared with the general population. METHOD: Analysis of data supplied by the centre of epidemiology on the medical causes of death within the National Institute of Health and Medical Research in France was conducted. Three thousand and thirty-one death certificates indicating a diagnosis of cerebral palsy (ICD 10 code G80) were reported between 2000 and 2008. RESULTS: Median age at death was between 45-54 years and principal cause of death (24%) comprised the category "symptoms, signs, and abnormal results of clinical and laboratory tests, not classified elsewhere". Of these, 66% were related to the circulatory and respiratory systems. "Diseases of the respiratory system" were the second most common cause of death (19% compared with 6% in the French general population). The third most common cause of death was "diseases of the circulatory system" (15% compared with 29% in the French general population). While deaths caused by tumour pathologies in the general population are the most common cause of deaths, these represented only 7% of deaths in subjects with cerebral palsy. INTERPRETATION: These results concur with other published data, i.e. subjects with cerebral palsy die younger than the French general population, and the principal causes of death are respiratory and circulatory problems. This study emphasises the importance of access to epidemiological data about the French cerebral palsy population. PMID- 24341987 TI - Nutrient enrichment affects immature mosquito abundance and species composition in field-based mesocosms in the coastal plain of Georgia. AB - This study is the first to examine the relationship between nutrient enrichment and oviposition preference as measured by larval mosquito abundance using field based mesocosms adjacent to wetlands in the Gulf Coastal Plain of Georgia. Agricultural wetlands in this region are known to have higher levels of nutrients and suspended sediments compared with forested wetlands, and previous studies have shown differences in mosquito communities in agricultural and forested wetlands. The purpose of this study was to determine whether nutrient enrichment contributes to the differences in mosquito oviposition preferences as reflected by larval mosquito presence and abundance in wetlands. We predicted that adding nutrients to mesocosms similar to concentrations in agricultural wetlands would favor responses of mosquito species often associated with nutrient-rich agricultural wetlands. Results indicated vegetation height, vegetation stem density, and phosphate levels were greater in fertilized mesocosms compared with nonfertilized mesocosms. The abundance of Aedes albopictus (Skuse) and Culex restuans Theobald was greater in mesocosms treated with fertilizer compared with nonfertilized mesocosms. Nutrient enrichment influenced oviposition and larval abundance of some mosquitoes of medical concern. This study provides evidence that can be used to predict the influence of nutrient enrichment on distribution and abundance of disease vectors and other nuisance mosquito species within an agricultural landscape. PMID- 24341988 TI - High throughput screening of CO2-tolerating microalgae using GasPak bags. AB - BACKGROUND: Microalgae are diverse in terms of their speciation and function. More than 35,000 algal strains have been described, and thousands of algal cultures are maintained in different culture collection centers. The ability of CO2 uptake by microalgae varies dramatically among algal species. It becomes challenging to select suitable algal candidates that can proliferate under high CO2 concentration from a large collection of algal cultures. RESULTS: Here, we described a high throughput screening method to rapidly identify high CO2 affinity microalgae. The system integrates a CO2 mixer, GasPak bags and microplates. Microalgae on the microplates will be cultivated in GasPak bags charged with different CO2 concentrations. Using this method, we identified 17 algal strains whose growth rates were not influenced when the concentration of CO2 was increased from 2 to 20% (v/v). Most CO2 tolerant strains identified in this study were closely related to the species Scenedesmus and Chlorococcum. One of Scenedesmus strains (E7A) has been successfully tested in in the scale up photo bioreactors (500 L) bubbled with flue gas which contains 10-12% CO2. CONCLUSION: Our high throughput CO2 testing system provides a rapid and reliable way for identifying microalgal candidate strains that can grow under high CO2 condition from a large pool of culture collection species. This high throughput system can also be modified for selecting algal strains that can tolerate other gases, such as NOx, SOx, or flue gas. PMID- 24341989 TI - Editorial comment to Does mechanical bowel preparation ameliorate damage from rectal injury in radical prostatectomy? Analysis of 151 rectal injury cases. PMID- 24341991 TI - The effects of training on the ability of adults with an intellectual disability to give informed consent to medication. AB - BACKGROUND: This study had two aims: to investigate the capacity of individuals with intellectual disabilities (ID) to make decisions about their medications, and to evaluate whether the provision of training (information) sessions on medications would increase their capacity. METHOD: Twenty-eight adults (18 male and 10 female), with a mild to moderate ID were included in this study and they were taking either Epilim, Metformin or Haloperidol medications. The participants were split into groups that comprised of participants taking the same medications. Each of the groups received three training sessions on their own medications. Capacity to consent was measured by the Adapted - Assessment of Capacity Questionnaire (A-ACQ), which was specially adapted for each medication type from the original measure (ACQ). Receptive language ability was measured by the British Picture Vocabulary Scale-II (BPVS-II). RESULTS: A two-factor mixed anova analysis indicated that the provision of training had improved the capacity of the participants to give informed consent to taking their medications. Analysis using Pearson's correlations indicated that increased levels of receptive language ability correlated with greater ability to give informed consent to taking medication. CONCLUSIONS: The provision of information that is formatted in a way that individuals with ID can understand may be a useful way to increase knowledge on medications. Further research that investigates the provision of information with larger samples is warranted. PMID- 24341990 TI - A gradient of matrix-bound FGF-2 and perlecan is available to lens epithelial cells. AB - Fibroblast growth factors play a key role in regulating lens epithelial cell proliferation and differentiation via an anteroposterior gradient that exists between the aqueous and vitreous humours. FGF-2 is the most important for lens epithelial cell proliferation and differentiation. It has been proposed that the presentation of FGF-2 to the lens epithelial cells involves the lens capsule as a source of matrix-bound FGF-2. Here we used immunogold labelling to measure the matrix-bound FGF-2 gradient on the inner surface of the lens capsule in flat mounted preparations to visualize the FGF-2 available to lens epithelial cells. We also correlated FGF-2 levels with levels of its matrix-binding partner perlecan, a heparan sulphate proteoglycan (HSPG) and found the levels of both to be highest at the lens equator. These also coincided with increased levels of phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2) in lens epithelial cells that localised to condensed chromosomes of epithelial cells that were Ki-67 positive. The gradient of matrix-bound FGF-2 (anterior pole: 3.7 +/- 1.3 particles/MUm2; equator: 8.2 +/- 1.9 particles/MUm2; posterior pole: 4 +/- 0.9 particles/MUm2) and perlecan (anterior pole: 2.1 +/- 0.4 particles/MUm2; equator: 5 +/- 2 particles/MUm2; posterior pole: 1.9 +/- 0.7 particles/MUm2) available at the inner lens capsule surface was measured for the bovine lens. These data support the anteroposterior gradient hypothesis and provide the first measurement of the gradient for an important morphogen and its HSPG partner, perlecan, at the epithelial cell-lens capsule interface. PMID- 24341992 TI - Relative accuracy, specificity and sensitivity of a 5' nuclease real-time PCR assay for Salmonella detection in naturally contaminated pork cuts. AB - In the present study the relative sensitivity, specificity and accuracy of a Real Time PCR assay for Salmonella detection in naturally contaminated pork cuts were evaluated in comparison with the ISO 6579:2004 reference culture method. Meat samples were collected from packaging up to the end of shelf life from 10 different lots over a year. The PCR method included an 18 h pre-enrichment step in buffered peptone water, a DNA extraction step, and a final 5' nuclease Real Time PCR assay, including an Internal Amplification Control (IAC) and targeting the ttrRSBCA locus. Based on the analysis of 480 sub-units (three sub-units for each sample), the relative sensitivity, specificity and accuracy of the Real-Time PCR assay were 90, 78.7, and 82.9% respectively, corresponding to a Cohen's kappa value of 0.81 (very good agreement). These results suggest the PCR method as a rapid and accurate method for the quick check of meat lots before distribution. The ISO reference method might be applied only on positive Real-Time PCR samples for confirmatory and isolation purposes, mandatory in epidemiological investigations. PMID- 24341993 TI - Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. AB - Rapamycin, an inhibitor of mTOR kinase, increased median lifespan of genetically heterogeneous mice by 23% (males) to 26% (females) when tested at a dose threefold higher than that used in our previous studies; maximal longevity was also increased in both sexes. Rapamycin increased lifespan more in females than in males at each dose evaluated, perhaps reflecting sexual dimorphism in blood levels of this drug. Some of the endocrine and metabolic changes seen in diet restricted mice are not seen in mice exposed to rapamycin, and the pattern of expression of hepatic genes involved in xenobiotic metabolism is also quite distinct in rapamycin-treated and diet-restricted mice, suggesting that these two interventions for extending mouse lifespan differ in many respects. PMID- 24341995 TI - European springtime temperature synchronises ibex horn growth across the eastern Swiss Alps. AB - Direct effects of climate change on animal physiology, and indirect impacts from disruption of seasonal synchrony and breakdown of trophic interactions are particularly severe in Arctic and Alpine ecosystems. Unravelling biotic from abiotic drivers, however, remains challenging because high-resolution animal population data are often limited in space and time. Here, we show that variation in annual horn growth (an indirect proxy for individual performance) of 8043 male Alpine ibex (Capra ibex) over the past four decades is well synchronised among eight disjunct colonies in the eastern Swiss Alps. Elevated March to May temperatures, causing premature melting of Alpine snowcover, earlier plant phenology and subsequent improvement of ibex food resources, fuelled annual horn growth. These results reveal dependency of local trophic interactions on large scale climate dynamics, and provide evidence that declining herbivore performance is not a universal response to global warming even for high-altitude populations that are also harvested. PMID- 24341996 TI - Metabolic stress and cancer: is autophagy the common denominator and a feasible target? AB - OBJECTIVES: Autophagy facilitates the degradation of proteins or organelles into recyclable molecules, which are released into the cell to foster cell survival under energetic stress. Furthermore, autophagy has been associated with cancer cell survival and chemoresistance, and as such, it is an area of increasing interest. As autophagic activity and its regulation are related to metabolism and energy stress, it is critical to elucidate the exact molecular mechanisms that drive it. KEY FINDINGS: Cancer is recognised to have specific metabolic changes, which include the switch from oxidative phosphorylation to glycolysis. Although the exact rationale is yet to be determined, it is proposed to limit hypoxic stress and generate substrates for biosynthesis. The various forms of energetic stress including hypoxia, glucose and amino acid deprivation have been reviewed in relation to their effect on autophagy and certain key molecules identified to date. These key molecules, which include AMP-activated protein kinase, mammalian target of rapamycin complex 1, adenosine triphosphate and reactive oxygen species, are all implicated as key stimuli of autophagic activity, as will be discussed in this review. SUMMARY: These findings indicate that autophagic regulation could be a means to better cancer treatment. PMID- 24341994 TI - Lipids and topological rules governing membrane protein assembly. AB - Membrane protein folding and topogenesis are tuned to a given lipid profile since lipids and proteins have co-evolved to follow a set of interdependent rules governing final protein topological organization. Transmembrane domain (TMD) topology is determined via a dynamic process in which topogenic signals in the nascent protein are recognized and interpreted initially by the translocon followed by a given lipid profile in accordance with the Positive Inside Rule. The net zero charged phospholipid phosphatidylethanolamine and other neutral lipids dampen the translocation potential of negatively charged residues in favor of the cytoplasmic retention potential of positively charged residues (Charge Balance Rule). This explains why positively charged residues are more potent topological signals than negatively charged residues. Dynamic changes in orientation of TMDs during or after membrane insertion are attributed to non sequential cooperative and collective lipid-protein charge interactions as well as long-term interactions within a protein. The proportion of dual topological conformers of a membrane protein varies in a dose responsive manner with changes in the membrane lipid composition not only in vivo but also in vitro and therefore is determined by the membrane lipid composition. Switching between two opposite TMD topologies can occur in either direction in vivo and also in liposomes (designated as fliposomes) independent of any other cellular factors. Such lipid-dependent post-insertional reversibility of TMD orientation indicates a thermodynamically driven process that can occur at any time and in any cell membrane driven by changes in the lipid composition. This dynamic view of protein topological organization influenced by the lipid environment reveals previously unrecognized possibilities for cellular regulation and understanding of disease states resulting from mis-folded proteins. This article is part of a Special Issue entitled: Protein trafficking and secretion in bacteria. Guest Editors: Anastassios Economou and Ross Dalbey. PMID- 24341997 TI - Chicory (Cichorium intybus L.) and cereals differently affect gut development in broiler chickens and young pigs. AB - Dietary fiber, resistant to host-mediated digestion in the small intestine due to lack of endogenous enzymes, impacts many facets of animal health and is associated with gut development especially in young monogastrics. Furthermore, it can be used as in-feed antibiotic alternative. Chicory (Cichorium intybus L.) forage with high content of pectin (uronic acids as building blocks) is a novel class of dietary fiber that is chemically different from cereal grains (with high content of arabinoxylans). In the present study, we investigated effects of dietary inclusion of chicory forage on digestibility, gut morphology and microbiota in broilers and young pigs. In the chicken experiment, 160 1-d old broiler chicks were fed 3 nutritionally balanced diets for 30 d including a cereal-based diet and 2 diets with part of the cereals substituted with 60 and 120 g/kg chicory forage (CF60 and CF120), whereas in the pig experiment, 18 seven wk old Yorkshire pigs were fed 3 diets for 18 d including a cereal-based diet and 2 diets with 80 and 160 g/kg chicory forage inclusion (CF80 and CF160). Our results showed that young pigs were capable to utilize chicory forage well with higher total tract apparent digestibility (TTAD) of all fiber fractions, particularly uronic acid, compared with the control (P < 0.01). In contrast, a decreased TTAD of all fiber fractions was observed in chickens fed on diet CF120 (P < 0.05). Moreover, diet induced changes in gut morphology were observed in the large intestine of chickens. The alteration of cecal mucosal thickness was further positively correlated with TTAD of non-starch polysaccharides (NSP) and its constituent sugars (P < 0.05). In addition, in pigs, terminal restriction fragment length polymorphism (T-RFLP) analysis of intestinal microbiota revealed substantial dietary effects (cereal control diet vs. chicory forage inclusion) on the relative abundance of 2 dominant bacterial phylotypes (Prevotella sp. vs. Roseburia sp.) respectively (P < 0.05). In conclusion, our data showed that chicory forage (Cichorium intybus L.), a novel dietary fiber source in animal nutrition, have potential beneficial properties as fiber ingredient in diets for both pigs and chickens. PMID- 24341998 TI - Cardio-ventilatory responses to poikilocapnic hypoxia and hypercapnia in trained breath-hold divers. AB - Trained breath-hold divers (BHDs) are exposed to repeated bouts of intermittent hypoxia and hypercapnia during prolonged breath-holding. It has thus been hypothesized that their specific training may develop enhanced chemo responsiveness to hypoxia associated with reduced ventilatory response to hypercapnia. Hypercapnic ventilatory responses (HCVR) and hypoxic ventilatory responses at rest (HVRr) and exercise (HVRe) were assessed in BHDs (n=7) and a control group of non-divers (NDs=7). Cardiac output (CO), stroke volume (SV) and heart rate (HR) were also recorded. BHDs presented carbon dioxide sensitivity similar to that of NDs (2.85+/-1.41 vs. 1.85+/-0.93Lmin(-1)mmHg(-1), p>0.05, respectively). However, both HVRr (+68%) and HVRe (+31%) were increased in BHDs. CO and HR reached lower values in BHDs than NDs during the hypoxic exercise test. These results suggest that the exposure to repeated bouts of hypoxia/hypercapnia frequently experienced by trained breath-hold divers only enhances their chemo responsiveness to poikilocapnic hypoxia, without altering HCVR. PMID- 24342000 TI - Effect of dietary cadmium on the activity of glutathione S-transferase and carboxylesterase in different developmental stages of the Oxya chinensis (Orthoptera: Acridoidea). AB - Glutathione S-transferases (GSTs) and carboxylesterases (CarEs) play important roles in the detoxification of endogenous and exogenous compounds. In this study, the biochemical effects of dietary cadmium (Cd) on the activities of GST and CarE in different developmental stages of the rice grasshopper Oxya chinensis Thunberg were studied. The results showed that the effects of the Cd concentration and developmental stage on GST activity were statistically significant. GST activity in O. chinensis increased at the highest Cd concentration in most nymphs, suggesting that GST is typically inducible by Cd. However, GST activity was inhibited in adults under Cd stress owing to life-stage-specific physiological characteristics. The results showed that the substrates, developmental stage, and Cd concentration had statistically significant effects on CarE activity. In most studies of CarE activity, the interaction between any two studied factors was statistically significant, although the interaction effects of the substrates, developmental stages, and Cd concentrations were not significant, which implied that the insect physiological condition and the external environmental may affect CarE activity. The results suggest that the insect's life stage and enzyme substrates should be considered when enzyme activity under Cd stress is studied. PMID- 24341999 TI - Rapid diaphragm atrophy following cervical spinal cord hemisection. AB - A cervical (C2) hemilesion (C2Hx), which disrupts ipsilateral bulbospinal inputs to the phrenic nucleus, was used to study diaphragm plasticity after acute spinal cord injury. We hypothesized that C2Hx would result in rapid atrophy of the ipsilateral hemidiaphragm and increases in mRNA expression of proteolytic biomarkers. Diaphragm tissue was harvested from male Sprague-Dawley rats at 1 or 7 days following C2Hx. Histological analysis demonstrated reduction in cross sectional area (CSA) of type I and IIa fibers in the ipsilateral hemidiaphragm at 1 but not 7 days. Type IIb/x fibers, however, had reduced CSA at 1 and 7 days. A targeted gene array was used to screen mRNA changes for genes associated with skeletal muscle myopathy and myogenesis; this was followed by qRT-PCR validation. Changes in diaphragm gene expression suggested that profound myoplasticity is initiated immediately following C2Hx including activation of both proteolytic and myogenic pathways. We conclude that an immediate myoplastic response occurs in the diaphragm after C2Hx with atrophy occurring in ipsilateral myofibers within 1 day. PMID- 24342001 TI - Comparison of reducing effect on lung injury of dexamethasone and bosentan in acute lung injury: an experimental study. AB - BACKGROUND: Different medical therapies are employed in acute lung injury (ALI) but there is still a debate about the efficacy of these drugs. Among these therapies steroids are clinically applied and bosentan is experimentally studied. The aim of this study was to evaluate the efficacy of these two drugs to treat inflammation in ALI by histopathological comparison. METHODS: The five experimental groups (n = 5 per group) were: saline control (Group I); lipopolysaccharide (LPS) + saline (Group II); LPS + dexamethasone (Group III); LPS + 50 mg/kg bosentan (Group IV); and LPS + 100 mg/kg bosentan (Group V). Bosentan was administered orally one hour before and 12 hours after LPS treatment. Dexamethasone was administered intraperitoneally in three doses of 1 mg/kg; one dose was co-administered with LPS and the other two doses were given respectively 30 minutes before and after LPS treatment. Vasodilation-congestion, hemorrhage, polymorphonuclear leukocyte (PMN) infiltration, mononuclear leukocyte (MNL) infiltration, alveolar wall thickening, alveolar destruction/emphysematous appearance, and focal organization were the parameters used as criteria for evaluating inflammation and efficacy of treatment. RESULTS: Compared to the LPS only group (Group II), dexamethasone treatment (Group III) resulted in significant improvements in vasodilation-congestion, hemorrhage, PMN and MNL infiltration, alveolar wall thickening and emphysematous areas. Treatment with 50 mg/kg dose of bosentan (Group IV) also resulted in significant improvements in hemorrhage, PMN and MNL infiltration, alveolar wall thickening and alveolar destruction. Reducing lung injury and reparative effects of 100 mg/kg bosentan were significant in all parameters. CONCLUSIONS: Bosentan is as effective as dexamethasone for treating lung injury in ALI. Bosentan at 100 mg/kg can be recommended as a first treatment choice based on its significant reducing lung injury and reparative effects. PMID- 24342002 TI - Doppler ultrasonography and hypertensive target organ damage. PMID- 24342003 TI - Complete reverse remodeling in acute stress cardiomyopathy. Is preserved tissue contractility under stress related to reverse remodeling. AB - Acute stress cardiomyopathy is the unique disease which represents exaggerated and dysfunctional regions of the same cardiac tissue at the same episode. The impressive clinical course which involves the specific region is the stress mediated exaggerated function of LV base under acutely developed stress induction. After abolishment of stress induction, dysfunctional part of LV which is the midapical myocardium undergoes a complete tissue functional recovery. The evolution of reverse remodeling in acute stress cardiomyopathy has been described using 2 and 3-dimensional echocardiography in the literature. This is the second report regarding reverse LV remodeling in acute stress cardiomyopathy in which we rather evaluate the underlying mechanisms leading complete reverse LV remodeling of dysfunctional myocardium. Therefore, we focus on the existence of preserved and exaggerated regional tissue under stress which possibly represents the predicted myocardial tissue recovery in this acute clinical entity. We also discuss the potential contribution of short-term disease course and lack of prior disease episodes to complete reverse remodeling differently from the heavy burden of chronic diseases leading to permanent tissue jeopardy. PMID- 24342004 TI - Management of cardiac device infections according to current data. AB - The use of implantable devices in management of cardiac diseases is increasing as a result of improvements in technology of permanent pacemaker and implantable cardioverter defibrillators. Device related infections are also rising accordingly and have become an important clinical problem. Accurate diagnosis and optimal management of these infections is challenging, necessitating complete removal of the device and prolonged antibiotic therapy. In this regard, a multidisciplinary approach is required with the essential support of microbiology and imaging modalities. This paper highlights the current literature on the pathogenesis, risk factors, diagnosis and management of device related infections. PMID- 24342005 TI - Rhythm and conduction abnormalities after transcatheter closure of VSDs: a single center experience. PMID- 24342007 TI - Ingestion of a marked bacterial pathogen of cotton conclusively demonstrates feeding by first instar southern green stink bug (Hemiptera: Pentatomidae). AB - Long-held dogma dictates that first instars of Nezara viridula (L.) do not feed, yet recent observations of stylet activity within a food source suggest otherwise. As a cosmopolitan pest of cotton and other high-value cash crops, confirmation of feeding by first instars may ultimately influence the knowledge on biology and management strategies for this pest. To determine whether first instars feed, newly hatched nymphs were provided sterile green beans (control) or beans infected with a rifampicin-resistant marked bacterial pathogen (Pantoea agglomerans (Ewing and Fife)) of cotton. Insects were exposed to beans for 2 d, and feeding was confirmed based on detection of marked bacteria ingested by the insect. Normal bacterial flora was detected in all insects; however, control insects did not possess the marked bacteria. Of the first instars surviving on infected beans, ?65% possessed the marked bacteria internally. Furthermore, the frequency of insects with marked bacteria was higher in insects collected directly from the bean surface than those that were off the bean at time of collection. Densities of innate and marked bacteria were comparable (both ranging from 10(1) to 10(3)), suggesting that the marked bacteria did not exclude preexisting bacterial flora. Marked bacteria were also detected in a subset of second instars, indicating marked bacteria were retained through the molting process after ingesting bacteria as first instars. Our findings conclusively demonstrate feeding by first instars and redefine the long-held perspective of nonfeeding by first instars. These findings may necessitate changes to crop protection strategies against feeding and vectoring of plant pathogens by N. viridula. PMID- 24342006 TI - Mean platelet volume and platelet count: overlooked markers of high on-treatment platelet reactivity and worse outcome in patients with acute coronary syndrome. PMID- 24342008 TI - The impact of single nucleotide polymorphisms on patterns of non-contact musculoskeletal soft tissue injuries in a football player population according to ethnicity. AB - BACKGROUND AND OBJECTIVE: The prevention, diagnosis, and management of non contact musculoskeletal soft tissue injuries (NCMSTIs) related to participation in sports are key components of sport and exercise medicine. Epidemiological data have demonstrated the existence of interindividual differences in the severity of NCMSTIs, indicating that these injuries occur as a consequence of both extrinsic and intrinsic factors, including genetic variations. SUBJECTS AND METHODS: We have collected data on NCMSTIs suffered by 73 elite players of White, black African and Hispanic ethnicity of European football over the course of three consecutive seasons. We have also examined eight single nucleotide polymorphisms (SNPs) in genes related to tissue recovery and tissue repair in blood drawn from the players and correlated our findings with type and severity of injuries in each ethnic group. RESULTS: The frequency of the SNPs varied among the three ethnic sub-groups (p<0.0001). Among Whites, a significant relationship was observed between ligament injuries and ELN (p=0.001) and between tendinous injuries and ELN (p=0.05) and IGF2 (p=0.05). Among Hispanics, there was a significant relation between muscle injuries and ELN (p=0.032) and IGF2 (p=0.016). CONCLUSIONS: Interracial genotypic differences may be important in the study of NCMSTIs. A genetic profile based on SNPs may be useful tool to describe each individual's injuribility risk and provide specific treatment and preventive care for football players. PMID- 24342009 TI - [Influence of the duration of a former ward stay on the prognosis of patients with long Intensive Care Unit stays]. PMID- 24342011 TI - [Claims of alleged malpractice. Are there differences between male and female physicians?]. PMID- 24342010 TI - [Hirschsprung's disease, RET proto-oncogene mutation and prophylactic thyroidectomy]. PMID- 24342012 TI - [Antiplatelet therapy: resistance to traditional antiaggregation drugs and role of new antiplatelet agents]. AB - Platelet aggregation plays a key role in the development of major cardiovascular events (MACE) related to atherothrombosis. Since the appearance of coronary stenting, the importance of measuring and modulating platelet activity has considerably increased in the scientific literature during the last decade. Double antiplatelet therapy with aspirin and clopidogrel administrated to stent carriers has widely demonstrated its efficacy in the prevention of MACE compared with aspirin alone. These benefits are also present when a conservatory approach is chosen for acute coronary syndrome management. However, there are an important number of patients who develop MACE despite optimal dual antiplatelet therapy, most likely related to an incomplete platelet activity inhibition. Many studies suggest an important inter-individual variability in the response to the drugs, maybe related, at least in part, to the use of different assessment techniques of platelet aggregation. Other authors suggest an incomplete platelet inhibition as a possible explanation for the presence of MACE in patients under optimal antiplatelet therapy. Resistance to usual drugs has become a clinically relevant issue that requires an individual approach where new antiplatelet agents, such as prasugrel or ticagrelor, could play an important role as stated in current consensus documents. PMID- 24342013 TI - [Urinary schistosomiasis]. PMID- 24342014 TI - Association between polymorphism c.1-765G>C of the COX2 gene and cognitive impairment in individuals 65 years or more with diabetes from a Geriatric Service in Monterrey, Mexico. AB - BACKGROUND AND OBJECTIVE: Cognitive impairment and dementia are common geriatric syndromes in diabetic patients. Inflammation plays a crucial role in the pathophysiology of Alzheimer's disease and cognitive impairment. Cyclooxygenases (COX) 1 and 2 participate in inflammation. The polymorphism c.1-765G>C of the COX2 gene might be protective against cognitive decline in Mexicans with diabetes mellitus through its reduced promotor activity. To determine the association between polymorphism c.1-765G>C of the COX2 gene and cognitive impairment in elderly adults with diabetes. PATIENTS AND METHODS: Case-control study. We included diabetic patients from the Geriatric Clinic of General Hospital No. 17 who were over 65 years and accepted to participate. Cases were patients with a score of 24 or less on the Mini Mental Status Examination (MMSE) and with DSM IV criteria for dementia. Controls were those with MMSE scores of 25 or greater. Results We included 97 patients (50 cases and 47 controls). There were no differences regarding clinical and laboratory characteristics between cases and controls. The frequency of the C allele and the CG genotype was higher in controls than in cases and this difference remained significant in a multivariate analysis with an odds ratio of 0.012 (95% CI 0.001-0.091) and 0.009 (95% CI 0.001 0.076) in the bivariate and multivariate analysis, respectively, using the GG genotype frequency as a reference. CONCLUSION: Cognitive impairment in Mexican patients with diabetes is associated with less exposure to the CG genotype of the c.1-765G>C polymorphism of COX2. PMID- 24342015 TI - [New drugs in the treatment of multiple myeloma]. AB - Progress in the treatment of multiple myeloma in the last decade has been able to delay, but ultimately not to prevent, the development of resistances and most patients still die of the disease or its related complications. New drugs have been developed including new alkylating agents, proteasome inhibitors and immunomodulators but also monoclonal antibodies and drugs with new mechanisms of action. Hopefully, this new generation of targeted agents will improve the results of the initial therapy, avoid relapses and development of resistances and provide better and less toxic options for the relapsed and refractory patient. PMID- 24342016 TI - Seasonal variation in the occurrence and removal of pharmaceuticals and personal care products in a wastewater treatment plant in Xiamen, China. AB - The occurrence and seasonal variation of 50 pharmaceuticals and personal care products (PPCPs) in a wastewater treatment plant (WWTP) in Xiamen, China was investigated over a period of one year. Among the targets, 39 PPCPs were detected in the influent. The highest concentration was observed for acetaminophen, with the average concentration in the influent of 2963.5ng/L. The seasonal variation of PPCPs in the influent was observed. For most pharmaceuticals, highest concentrations were in March 2013, followed by December 2012, while the concentrations were lower in August 2012 and May 2013. Among the detected PPCPs, 14 targets could be removed more than 50% in the WWTP. The activated sludge treatment process contributed to most of PPCP removal, while the adsorption to the particles in the primary treatment and the transformation under UV radiation in the disinfection treatment also contributed to the PPCP removal. Among the detected PPCPs in the influent, 36 PPCPs could be detected in the final effluent of the WWTP. Significantly higher concentrations of PPCPs were observed in effluent samples collected in March 2013 compared to other seasons, suggesting higher concentrations of PPCPs could be discharged into the surrounding seawater during this period. PMID- 24342017 TI - A comparison land-water environment of maximal voluntary isometric contraction during manual muscle testing through surface electromyography. AB - BACKGROUND: The aim of this study was to compare through surface electromyographic (sEMG) recordings of the maximum voluntary contraction (MVC) on dry land and in water by manual muscle test (MMT). METHOD: Sixteen healthy right handed subjects (8 males and 8 females) participated in measurement of muscle activation of the right shoulder. The selected muscles were the cervical erector spinae, trapezius, pectoralis, anterior deltoid, middle deltoid, infraspinatus and latissimus dorsi. The MVC test conditions were random with respect to the order on the land/in water. RESULTS: For each muscle, the MVC test was performed and measured through sEMG to determine differences in muscle activation in both conditions. For all muscles except the latissimus dorsi, no significant differences were observed between land and water MVC scores (p = 0.063-0.679) and precision (%Diff = 7-10%) were observed between MVC conditions in the muscles trapezius, anterior deltoid and middle deltoid. CONCLUSIONS: If the procedure for data collection is optimal, under MMT conditions it appears that comparable MVC sEMG values were achieved on land and in water and the integrity of the EMG recordings were maintained during water immersion. PMID- 24342018 TI - Ethnic difference in myopia between Asians and non-Hispanic whites in the United States. PMID- 24342019 TI - Intravitreal anti-vascular endothelial growth factor for submacular hemorrhage from choroidal neovascularization. AB - PURPOSE: To evaluate the efficacy of intravitreal anti-vascular endothelial growth factor (VEGF) monotherapy for patients diagnosed with exudative age related macular degeneration (AMD) accompanied by submacular hemorrhage. DESIGN: Retrospective, observational case series. PARTICIPANTS: Ninety-one eyes of 91 patients who initially presented with submacular hemorrhage associated with exudative AMD from October 2009 to September 2012. Patients were followed up for at least 6 months after treatment. METHODS: Best-corrected visual acuity (BCVA) was measured at diagnosis and at 1, 3, and 6 months after treatment. The duration of symptoms was estimated. The extent of hemorrhage was estimated using fundus photography, and central foveal thickness was measured using optical coherence tomography. Change in BCVA during 6 months after treatment was estimated. The correlation of BCVA at 6 months with duration of symptoms, extent of hemorrhage, and central foveal thickness was evaluated. MAIN OUTCOME MEASURES: The BCVA, duration of symptoms, extent of hemorrhage, and central foveal thickness. RESULTS: The mean duration of symptoms was 27.6+/-39.5 days. The mean extent of hemorrhage was 7.8+/-5.6 disc areas, and the mean central foveal thickness was 610.1+/-249.6 MUm. All eyes were treated with 3.2+/-0.8 (range, 1-5) monthly intravitreal anti-VEGF injections during the 6-month follow-up period. The logarithm of the minimum angle of resolution BCVA at diagnosis and at 1, 3, and 6 months after the initial diagnosis was 1.38+/-0.53 (Snellen equivalent, 20/479), 1.27+/-0.57, 1.05+/-0.58, and 0.96+/-0.65 (Snellen equivalent, 20/182), respectively. The BCVA at 6 months significantly improved from baseline (P < 0.001). Poor BCVA at 6 months correlated with a longer duration of symptoms, greater extent of hemorrhage, and greater central foveal thickness (P = 0.008, P = 0.004, and P = 0.014, respectively). CONCLUSIONS: Anti-VEGF monotherapy was found to be a useful treatment option for exudative AMD accompanied by submacular hemorrhage. However, the limited efficacy in eyes with large hemorrhage may suggest the need for more aggressive treatment in these cases. PMID- 24342020 TI - Factors predictive of remission of new-onset anterior uveitis. AB - PURPOSE: To identify factors predictive of remission of inflammation in new-onset anterior uveitis cases treated at tertiary uveitis care facilities. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients seeking treatment at participating academic uveitis clinics within 90 days of initial diagnosis of anterior uveitis. METHODS: Retrospective cohort study based on standardized chart review. MAIN OUTCOME MEASURES: Factors predictive of remission (no disease activity without corticosteroid or immunosuppressive treatments at all visits during a 90-day period). RESULTS: Nine hundred ninety eyes (687 patients) had a first-ever diagnosis of anterior uveitis within 90 days before initial presentation and had follow-up visits thereafter. The median follow-up time was 160 days. Systemic diagnoses with juvenile idiopathic arthritis (JIA; adjusted hazard ratio [aHR], 0.38; 95% confidence interval [CI], 0.19-0.74) and Behcet's disease (aHR, 0.10; 95% CI, 0.01-0.85) were associated with a lower incidence of uveitis remission. Cases of bilateral uveitis (aHR, 0.68; 95% CI, 0.54-0.87) and those with a history of cataract surgery before presentation (aHR, 0.51; 95% CI, 0.29-0.87) also had a lower incidence of remission. Regarding clinical findings at the initial visit, a high degree of vitreous cells at initial presentation was associated with a lower incidence of remission (for 1+ or more vs. none: aHR, 0.72; 95% CI, 0.55-0.95). An initial visual acuity of 20/200 or worse, with respect to 20/40 or better, also was predictive of a lower incidence of remission (aHR, 0.52; 95% CI, 0.32-0.86). CONCLUSIONS: Factors associated with a lower incidence of remission among new-onset anterior uveitis cases included diagnosis with JIA, Behcet's disease, bilateral uveitis, history of cataract surgery, findings of 1+ or more vitreous cells at presentation, and an initial visual acuity of 20/200 or worse. Patients with these risk factors seem to be at higher risk of persistent inflammation; reciprocally, patients lacking these factors would be more likely to experience remission. Patients with risk factors for nonremission of uveitis should be managed taking into account the higher probability of a chronic inflammatory course. PMID- 24342021 TI - Association between visual field defects and quality of life in the United States. AB - PURPOSE: To investigate the association between visual field defects and quality of life in the United States population. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 5186 participants in the 2005 through 2008 National Health and Nutrition Examination Survey 40 years of age and older without a self reported history of age-related macular degeneration or prior refractive surgery who had undergone frequency doubling technology perimetric testing. METHODS: Frequency doubling technology perimetry was performed in both eyes. Results from the better eye were used to categorize subjects as normal or having mild, moderate, or severe visual field loss. Subjects completed surveys about their visual and physical functioning ability. MAIN OUTCOME MEASURES: Disability pertaining to 6 vision-related activities, 2 visual function questions, and 5 physical functioning domains. RESULTS: Eighty-one percent of subjects had normal visual fields and 10%, 7%, and 2% demonstrated mild, moderate, and severe visual field defects, respectively. Subjects with greater severity of visual field defects had greater difficulty with vision-related activities. Subjects with severe visual field defects demonstrated the greatest odds of difficulty with all 6 activities. The 2 activities impacted most adversely were daytime driving in familiar places (odds ratio [OR], 12.4; 95% confidence interval [CI], 6.1-25.1) and noticing objects off to the side when walking (OR, 7.7; 95% CI, 4.7-12.7). Subjects with severe visual field defects had greater odds of worrying about eyesight (OR, 3.4; 95% CI, 2.0-5.8) and being limited by vision in the time spent on daily activities (OR, 5.1; 95% CI, 3.0-8.5). Subjects with severe visual field defects demonstrated the greatest odds of difficulty with 3 physical function domains, including activities of daily living (OR, 2.45; 95% CI, 1.37-4.38), instrumental activities of daily living (OR, 2.45; 95% CI, 1.37-4.38), as well as leisure and social activities (OR, 3.29; 95% CI, 1.87-5.77). CONCLUSIONS: Greater severity of visual field abnormality was associated with significantly greater odds of disability with vision-related function and physical function. These findings support the necessity of routine screening to find those who may benefit from therapy to prevent progressive glaucomatous vision loss. PMID- 24342022 TI - Effect of centration and circularity of manual capsulorrhexis on cataract surgery refractive outcomes. AB - PURPOSE: To determine if postoperative refractive outcome in cataract surgery relates to centration or circularity of the capsulorrhexis. DESIGN: Prospective, observational study. PARTICIPANTS: One hundred thirteen eyes from 108 patients undergoing routine phacoemulsification cataract surgery with manual continuous curvilinear capsulorrhexis. METHODS: Patients underwent refraction, and digital retroillumination photographs were obtained 1 month and 1 year after surgery. Capsulorrhexis parameters were analyzed using computer photographic software. MAIN OUTCOME MEASURES: Postoperative spherical equivalent (SE), deviation from predicted refraction, and postoperative spectacle cylinder. RESULTS: At 1 month, mean capsulorrhexis circularity index was 0.83 +/- 0.01 mm and mean decentration was 0.30 +/- 0.14 mm. There was no significant correlation between either circularity or decentration and any of the refractive outcomes of SE, deviation from predicted refraction, or spectacle cylinder at 1 month or at 1 year. In contrast, an association between capsulorrhexis decentration and change in postoperative SE from 1 month to 1 year was observed: 56% of patients with more than 0.4 mm of decentration had a change in SE of more than 0.25 diopter (D) compared with 30% with 0.4 mm or less of decentration (P = 0.04). In eyes with incomplete capsulorrhexis-optic overlap, 60% had a change in spectacle cylinder of more than 0.50 D from 1 month to 1 year, compared with 15% of eyes with complete overlap (P = 0.004). CONCLUSIONS: Postoperative refraction at 1 year was not related to centration or circularity of the capsulorrhexis. However, decentration by more than 0.4 mm was associated with a 0.25-D change in SE and incomplete capsulorrhexis-optic overlap was associated with a 0.50-D change in spectacle cylinder from 1 month to 1 year. PMID- 24342023 TI - Retinal blood vessel positional shifts and glaucoma progression. AB - PURPOSE: To determine the characteristics and significance of retinal blood vessel (RBV) positional shifts over time in a cohort of patients with progressive glaucoma. DESIGN: Retrospective cohort study. PARTICIPANTS: Baseline and serial stereophotographs from 1 eye of 125 patients with open-angle glaucoma with >=8 reliable Swedish interactive threshold algorithm standard visual fields (VFs) were included. On the basis of global rates of threshold sensitivity change, patients with glaucoma were divided into groups of minimal (<-0.02 decibels [dB]/year), moderate (-0.02 to -0.65 dB/year), or fast (>=-0.65 dB/year) progression. To determine whether graders' assessments of RBV positional shifts were false-positives, a control group consisting of 33 patients with glaucoma with 2 sets of photographs taken on the same day was included. METHODS: Masked graders reviewed serial photographs aligned with automated alternation flicker (EyeIC, Narbeth, PA) and assessed them for the presence of any discrete RBV positional shifts (2 graders) and for traditional measures of structural progression (2 graders), including neuroretinal rim loss, parapapillary atrophy progression, and disc hemorrhage (DH). MAIN OUTCOME MEASURES: Presence or absence of RBV positional shifts, rates of VF progression, and presence or absence of traditional measures of structural progression. RESULTS: A total of 158 image sets (125 longitudinal and 33 same-day controls) from patients with glaucoma were included. Retinal blood vessel shifts were noted in 33 of 125 (26.4%) longitudinally followed glaucomatous eyes and 2 of 33 (6%) same-day control patients (P = 0.01). Agreement between graders I and II was 90.4% (kappa=0.77; P< 0.001). Eyes with RBV positional change progressed more rapidly than those without (-0.55 vs. -0.29 dB/year; 95% confidence interval [CI], 0.03-0.48); P = 0.03). Retinal blood vessel shift was present in 12.1% of minimal progressors versus 31.5% of moderate and fast progressors (P = 0.04). Rate of VF progression was statistically associated with RBV shift (odds ratio [OR], 2.2; 95% CI, 1.1 4.5; P = 0.03). Other variables significantly associated with RBV shift included neuroretinal rim loss (OR, 21.9; 95% CI, 5.7-83.6; P< 0.001) and DH (OR, 4.6; 95% CI, 1.5-15.5; P< 0.01). A multivariable model revealed that rim loss and DH, but not rate of functional change, were significantly associated with RBV shift. CONCLUSIONS: Retinal blood vessel positional shifts occurred in eyes with functionally progressive glaucoma, neuroretinal rim loss, and DH. This is a novel clinical finding that could help identify glaucoma progression or individuals at higher risk for future progression. PMID- 24342025 TI - BST1 rs11724635 interacts with environmental factors to increase the risk of Parkinson's disease in a Taiwanese population. AB - A recently published genome-wide association study in Caucasian and Asian populations showed a significant association between the bone marrow stromal cell antigen 1 (BST1) SNP rs11724635 and increased risk for Parkinson's disease (PD). To investigate whether BST1 rs11724635 increases the risk of PD, either by itself or in combination with environmental factors, we performed an association analysis of BST1 rs11724635 in a large cohort of Taiwanese patients with PD and age matched controls. The study used TaqMan genotyping, logistic regression, and haplotype methods. The genotype distribution of rs11724635 in PD patients (N = 468; p = 0.50) and control subjects (N = 487; p = 0.44) was consistent with Hardy Weinberg equilibrium. Compared with the AA genotype, the frequency of both CA and CC genotypes was not significantly different between the patient and control groups. The adjusted odd ratios (ORs) for CA and CC were not statistically significant (CA: OR = 0.962, 95% CI = 0.643-1.439, p = 0.850; CC: OR = 0.992, 95% CI = 0.654-1.503, p = 0.969). Of note, ever use of well water before the onset of PD symptoms had an impact on the occurrence of PD through interactions with BST1 rs11724635 AC (OR = 1.453, p = 0.024) and CC (OR = 1.623, p = 0.008). Our results show that the BST1 rs11724635 polymorphism alone is not associated with the development of PD, but it can interact with well water drinking to increase the risk of PD in this Taiwanese population. PMID- 24342024 TI - Alcohol and drug treatment involvement, 12-step attendance and abstinence: 9-year cross-lagged analysis of adults in an integrated health plan. AB - This study explored causal relationships between post-treatment 12-step attendance and abstinence at multiple data waves and examined indirect paths leading from treatment initiation to abstinence 9-years later. Adults (N = 1945) seeking help for alcohol or drug use disorders from integrated healthcare organization outpatient treatment programs were followed at 1-, 5-, 7- and 9 years. Path modeling with cross-lagged partial regression coefficients was used to test causal relationships. Cross-lagged paths indicated greater 12-step attendance during years 1 and 5 and were casually related to past-30-day abstinence at years 5 and 7 respectfully, suggesting 12-step attendance leads to abstinence (but not vice versa) well into the post-treatment period. Some gender differences were found in these relationships. Three significant time-lagged, indirect paths emerged linking treatment duration to year-9 abstinence. Conclusions are discussed in the context of other studies using longitudinal designs. For outpatient clients, results reinforce the value of lengthier treatment duration and 12-step attendance in year 1. PMID- 24342026 TI - The receptor binding domain of MERS-CoV: the dawn of vaccine and treatment development. AB - The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) is becoming another "SARS-like" threat to the world. It has an extremely high death rate (~50%) as there is no vaccine or efficient therapeutics. The identification of the structures of both the MERS-CoV receptor binding domain (RBD) and its complex with dipeptidyl peptidase 4 (DPP4), raises the hope of alleviating this currently severe situation. In this review, we examined the molecular basis of the RBD-receptor interaction to outline why/how could we use MERS-CoV RBD to develop vaccines and antiviral drugs. PMID- 24342027 TI - Multiple sclerosis: lessons from molecular neuropathology. AB - Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, which leads to widespread focal lesions of primary demyelination with variable axonal, neuronal and astroglia injury. The mechanisms responsible for tissue injury in the MS brain and spinal cord are only incompletely understood. In this review we discuss that the formation of confluent subpial cortical lesions is the most specific type of tissue damage, which is exclusively present in MS patients. Current data suggest that subpial demyelination is triggered by a soluble factor, which is produced in meningeal inflammatory infiltrates and diffuses into the cortical parenchyma, where it destroys myelin either directly or indirectly through microglia activation. The presence of demyelinating activity in sera and cerebrospinal fluid of MS patients is known for decades, but the molecular nature of the possibly underlying demyelinating factor is still unclear. Destruction of myelin sheaths and oligodendrocytes as well as neurodegeneration in MS are associated with massive oxidative stress and mitochondrial injury. Oxidative stress appears to be driven in early MS by activated microglia and oxidative burst and is, in the progressive stage of the disease, amplified by additional factors related to the age of patients and accumulation of pre-existing brain damage. Thus, the demyelinating factor in MS patients may either be a currently unknown cytokine or an inflammatory mediator or, alternatively, a mixture of cytokines. It may activate microglia towards uncontrolled oxygen radical production. Alternatively, the demyelinating factor may by itself trigger demyelination, which is then amplified by oxidative injury. The molecular characterization of the demyelinating factor may provide an important clue for the understanding of MS pathogenesis in the future. PMID- 24342028 TI - Breastfeeding and risk of atopic dermatitis up to the age 42 months: a birth cohort study in Japan. AB - PURPOSE: The purpose of this study was to investigate the association between breastfeeding and atopic dermatitis (AD) up to the age 42 months. METHODS: Data from a nationally representative population-based birth cohort study in Japan were used (N = 38,757). Feeding pattern and breastfeeding duration were investigated via questionnaires when infants were aged 6 months. Physician diagnosed AD during the previous 1 year was ascertained via questionnaires when the children were aged 18, 30, and 42 months. The associations between feeding patterns or breastfeeding duration and physician-diagnosed AD from the age 6 to 42 months, categorized by AD status (no history of AD, episodic AD, and persistent AD), were analyzed using ordered logistic regression adjusted for covariates. RESULTS: Breastfeeding was positively associated with AD, with dose response association (P for trend < .001). Exclusively breastfed infants were 1.26 times more likely to have AD (95% confidence interval, 1.12-1.41) than infants fed formula alone. Furthermore, children with a longer breastfeeding duration were also significantly more likely to have AD (P for trend < .001). CONCLUSIONS: Breastfeeding is associated with an increased risk of AD up to the age 42 months. Further study is needed to elucidate the mechanism underlying the association between breastfeeding and AD. PMID- 24342029 TI - Personal hair dye use and bladder cancer: a meta-analysis. AB - Despite considerable research, the issue of hair dyes and bladder cancer is still open to discussion. In January 2013, we searched in PubMed/EMBASE to identify observational studies investigating the association between personal use of hair dyes and bladder cancer incidence/mortality. Pooled relative risks (RRs) and corresponding 95% confidence intervals (CIs) were calculated using random-effects models. Fifteen case-control and two cohort studies were available for meta analysis (8504 cases/deaths, 14,102 controls, and 617,937 persons at risk). Compared with no use, the pooled RR of bladder cancer for personal use of any type of hair dyes was 0.93 (95% CI, 0.82-1.05), with moderate heterogeneity among studies (I(2) = 34.1%, P = .07). Similar RRs were found for females (RR = 0.95) and males (RR = 0.81). Based on seven studies, the pooled RR for personal use of permanent hair dyes was 0.92 (95% CI, 0.77-1.09). Compared with no use, no association was observed for the highest categories of duration of use and lifetime frequency of use of both any type of dyes and permanent dyes. The pooled RR from four studies reporting results for use of dark-colored dyes was 1.29 (95% CI, 0.98-1.71). This meta-analysis allows to definitively exclude any appreciable excess risk of bladder cancer among personal hair dye users. PMID- 24342030 TI - Body mass index and risk of head and neck cancer by race: the Carolina Head and Neck Cancer Epidemiology Study. AB - PURPOSE: Most studies, primarily conducted in populations of European ancestry, reported increased risk of head and neck cancer (HNC) associated with leanness (body mass index [BMI] <18.5 kg/m(2)) and decreased for overweight or obesity (25.0 to <30.0 and >30 kg/m(2), respectively), compared with normal weight (18.5 to <25.0 kg/m(2)). METHODS: The Carolina Head and Neck Cancer Epidemiology Study is a population-based, racially diverse case-control study of 1289 incident HNC cases (330 African Americans) and 1361 controls (261 African Americans). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for associations between BMI 1 year prediagnosis and HNC risk stratified by race and adjusted for age, sex, smoking, alcohol, and education. RESULTS: Multiplicative interaction between BMI and race was evident (Pint = .00007). Compared with normal weight, ORs for leanness were increased for African Americans (OR, 3.91; 95% CI, 0.72 21.17) and whites (OR, 1.48; 95% CI, 0.60-3.65). For overweight and obesity, ORs were decreased in African Americans (OR, 0.51; 95% CI, 0.32-0.83 and OR, 0.47; 95% CI, 0.28-0.79, respectively) but in not whites. The increased risk associated with leanness was greater for smokers than nonsmokers (Pint = .02). CONCLUSIONS: These data, which require replication, suggest that leanness is associated with increased HNC risk among African Americans to a greater extent than whites and overweight and obesity is associated with decreased HNC risk only among African Americans. PMID- 24342031 TI - Pre-chemotherapy abiraterone acetate. A proposal of a treatment algorithm in castration resistant prostate cancer. AB - CONTEXT: Prostate cancer treatment remains a challenge for the urologist. Medical control in locally advanced or metastatic prostate cancer is usually performed with LHRH analogues and/or antiandrogens. Different treatments have been proposed when there is biochemical and clinical progression of the disease and other new ones have changed the patients' perspective and life expectancy. OBJECTIVE: This review has aimed to establish the current role of Abiraterone Acetate in the treatment of castration-resistant prostate cancer and facilitate decision-making by the Urologist by means of a Treatment Algorithm. ACQUISITION OF THE EVIDENCE: A search of current evidence on Abiraterone treatment in patients with castration resistant metastatic prostate cancer was performed in PubMed, mainly analyzing those studies designed as clinical trials. In addition, we reviewed and updated the role of hormone therapy and androgen receptors in prostate cancer. EVIDENCE SYNTHESIS: There are currently basically two clinical trials that demonstrate the effectiveness of Abiraterone in metastatic prostate cancer compared to placebo. The study COU-AA 302 shows a clear benefit with Abiraterone prior to chemotherapy in patients with castration-resistant prostate cancer, this making it possible to establish an algorithm for initial treatment that facilitates decision-making by the urologist. CONCLUSION: Abiraterone is a pre-chemotherapy treatment option in selected patients with castration resistant metastatic prostate cancer, although it is necessary to improve the cost and to design more multicenter clinical trials to optimize the cost/benefit ratio. PMID- 24342032 TI - The impact of metabolic parameters on the change of pulmonary function in obese patients. AB - BACKGROUND: Ethnic differences exist in the function and distribution of adipose tissue, which influences whole body metabolism, including pulmonary function. The object of this study was to examine the relationships between serum metabolic parameters and pulmonary function in a morbidly obese Asia-Pacific population. METHODS: One-hundred thirty-seven morbidly obese Chinese patients, aged>=18 years with a body mass index (BMI)>32 kg/m(2) who were being evaluated for bariatric surgery between July 2007 and December 2008, were studied. Cross-sectional associations between serum metabolic parameters, including lipids, glucose, insulin, leptin, and adiponectin levels with forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1) assessed by spirometry, were analyzed. Multiple regression analyses also were conducted, with age, gender, smoking history, and various anthropometric measurements of obesity as confounders. RESULTS: Serum adiponectin and HDL cholesterol had a positive correlation with FVC and FEV1. In addition, insulin resistance, determined by the homeostatic model assessment method (HOMA), was negatively correlated with FVC. In the multiple linear regression analysis, only serum adiponectin was significantly correlated with FVC and FEV1, independent of obesity level. CONCLUSIONS: Serum adiponectin level was positively and independently associated with pulmonary function in morbidly obese Chinese adults. PMID- 24342033 TI - The early use of Roux limb as surgical treatment for proximal postsleeve gastrectomy leaks. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is thought to be a simpler and safer operation compared with malabsorptive operations that include an enteric anastomosis. Leakage along the staple line at the gastroesophageal junction (GEJ) is difficult to treat and is a known complication of sleeve gastrectomy. Nonsurgical treatment methods often fail to heal the leaks and patients often require conversion to other procedures for definitive treatment. We report our experience with conversion to Roux-en-Y anastomosis over the leak site as a treatment option, comparing patients who had early treatment to late intervention. The purpose of the study is to stress the medical and social benefits of early surgical reintervention with conversion to Roux-en-Y anastomosis over the leak site. METHODS: Six patients underwent Roux limb placement over the leak site. Four of the patients had delayed surgery (group A), and the other 2 had early intervention (group B). RESULTS: Patients in group A had a median increase of all medical cost by 500%, whereas the 2 patients who underwent early intervention (group B) had an increase by 200%. The mean time until complete recovery (removal of all drains, adequate oral intake, and return to normal daily activity) in group A was 131.25 days (range 99-165) versus 38 days (range 28-48) in group B. CONCLUSIONS: Roux-en-Y gastrojejunostomy over the leak site is an effective technique to treat refractory staple line leakage and can be adopted as early treatment in selected patients after stabilization, thereby reducing the cost and length of hospital stays. PMID- 24342034 TI - Venous thromboembolism after laparoscopic biliopancreatic diversion with duodenal switch: analysis of 362 patients. AB - BACKGROUND: Venous thromboembolism (VTE), which manifests as deep venous thrombosis (DVT) or pulmonary embolism (PE), is relatively uncommon after weight loss procedures but has the strong potential to affect patient morbidity and mortality. This type of complication has been studied extensively in more common weight loss procedures, such as Roux-en-Y gastric bypass (RYGB). VTE has not been studied after biliopancreatic diversion with duodenal switch (BPD-DS), a bariatric procedure performed mainly for super morbidly obese patients, who are inherently associated with a higher incidence of co-morbidity. The objective of this study was to review VTE prevalence and identify risk factors associated with the postoperative occurrence of VTE in a collected data set of patients after laparoscopic BPD-DS. METHODS: The database of all patients who underwent laparoscopic BPD-DS between 2006 and 2012 was reviewed. Preoperative clinical information, which included history of VTE, inferior vena cava (IVC) filter placement, operative variables, and postoperative course, were reviewed. All VTE related events that occurred within 90 days postoperatively were collected and analyzed. RESULTS: Of 362 patients who underwent laparoscopic BPD-DS during the study period, 12 (3.3%) experienced a VTE complication. Eight (2.2%) patients presented with DVT; 4 (1.1%) patients presented with PE. VTE complications were more common in females than males (83.3% versus 16.6%, respectively). Age, body mass index (BMI), and time interval between preoperative and postoperative doses of heparin for DVT prophylaxis did not influence the occurrence of VTE complications. However, operative time (P = .02) and length of hospital stay (P = .0005) were identified as risk factors associated with postoperative VTE complications. No related mortality occurred in this study. CONCLUSION: The prevalence of VTE after BPD-DS is relatively low and comparable to other weight loss procedures. Overall risk of postoperative VTE after laparoscopic BPD-DS appears to be associated with the length of operation and hospital stay. PMID- 24342035 TI - Obstetric outcomes after restrictive bariatric surgery: what happens after 2 consecutive pregnancies? AB - BACKGROUND: The objective of this study was to compare the outcomes of 2 consecutive pregnancies of the same women who conceived after restrictive bariatric surgeries. METHODS: A retrospective study comparing consecutive pregnancy outcomes of the same women, who conceived before and twice after a restrictive bariatric surgery, was conducted. RESULTS: This study included 109 women, and therefore, 327 paired pregnancies: 109 pregnancies preceded and 218 followed restrictive bariatric surgery (87% had laparoscopic banding, and 13% had silastic ring vertical gastroplasty). Both prepregnancy and predelivery body mass index were significantly lower after bariatric surgery (36.7+/-4.4 versus 31. 5+/ 5.5, P<.001; 40.6+/-5.5 versus 35.3+/-6.1, P<.001; respectively). This effect was preserved at the subsequent pregnancy (31.5+/-5.5 versus 31.3+/-6.3, P = .609, and 35.3+/-6.1 versus 35.1+/-5.9, P = .706, respectively). The rates of hypertensive disorders and gestational diabetes mellitus were significantly lower after the bariatric operation, for the first and the second pregnancy (21% versus 7.4% and 4.7%, P = .009, and 19% versus 5.6% and. 6.6%, P = .007, respectively). The rate of macrosomic newborn was significant lower in the second postbariatric pregnancy (11.1% before versus 1.1% after second pregnancy, P = .02). Using multiple logistic regression models controlling for maternal age, prepregnancy body mass index, and the type of surgery, the reduction in hypertensive disorders (adjusted odds ratio (OR) .3, 95% confidence interval (CI) .12-.82; P = .018 for the first postoperative pregnancy and adjusted OR .2, 95% CI .06-.64; P = .007 for the second postoperative pregnancy), and gestational diabetes mellitus (adjusted OR .2, 95% CI .06-.48; P = .001 for the first postoperative pregnancy and adjusted OR .3, 95% CI .05-.51; P = .002 for the second postoperative pregnancy) remained significant. CONCLUSIONS: A significant decrease in pregnancy complications, such as hypertensive disorders and gestational diabetes mellitus, is achieved after a restrictive bariatric surgery. This improvement is maintained at the second subsequent pregnancy. PMID- 24342036 TI - Relevance of beta-cell function for improved glycemic control after gastric bypass surgery. AB - BACKGROUND: Residual beta-cell function and gastrointestinal hormones have been suggested as relevant determinants of improved glycemic control ensuing Roux-en-Y gastric bypass (RYGB). The objective of this study was to compare the glycemic control up to 24 months after RYGB in C-peptide negative morbidly obese (MO) type 1 diabetes mellitus (T1 DM) women (n = 7) and C-peptide positive (>.6 ng/mL) MO women with type 2 diabetes mellitus (T2 DM, n = 7) on basal-bolus insulin therapy. The glucagon-like peptide 1 (GLP-1) and glucagon response to a mixed meal challenge were also compared between groups. METHODS: Percent excess weight loss (%EWL), HbA1c, and daily insulin dose (DID) after RYGB were compared between groups. The GLP-1 and glucagon response (area under the curve 0-120 minutes) after a mixed meal at last follow-up visit were also compared. RESULTS: At 24 months, marked %EWL was observed in women with T1 DM and women with T2 DM (mean+/ standard error, 82.6% +/- 11.3% and 87.4% +/- 30.5%, respectively; P = .722]. In women with T1 DM, HbA1c (4 months, P<.05) and DID improved transiently (P<.05, up to 8 months) but were comparable to baseline thereafter (HbA1c: baseline, 8.3 +/- 1.2 and 24 months, 8.2 +/- .9, P = 1.00; DID: baseline, .61 +/- .17 and 24 months .62 +/- .12 IU/kg/d, P = 1.00]. In contrast, in MO women with T2 DM, HbA1c decreased significantly throughout follow-up, with 2 patients presenting diabetes remission and all but one an HbA1c<7% at 24 months. The GLP-1 response was comparable between groups (P = .612), and was not accompanied by suppression of the glucagon response to meal intake. CONCLUSIONS: In the absence of residual beta-cell, RYGB results in no significant benefit on glycemic control, despite a marked response of GLP-1 to meal intake. PMID- 24342037 TI - Adjustable gastric banding: a comparison of models. AB - BACKGROUND: There are several models of adjustable gastric banding in use with little evidence for choosing a particular model. The objective of this study was to evaluate factors for selecting a particular type of band in terms of weight loss, complications, and co-morbidities. METHODS: From July 2006 to May 2012, 222 patients underwent laparoscopic adjustable gastric banding (LAGB) by a single surgeon. Patient demographic characteristics, weight loss, body mass index (BMI), percentage of weight loss (%EWL), complications, and co-morbidities were retrospectively reviewed. Patients were grouped according to the band model into 6 categories: 27 LAP-BAND Adjustable Gastric Banding System VG, 25 Allergan-LAGB, 20 LAP-BAND AP(M) Standard, 18 LAP-BAND AP(M) Large, 34 Realize Band, and 98 Realize-C band. RESULTS: At 60 months follow up, in the LAP-BAND VG Group, the mean %EWL was 41%, percentage of co-morbidity improvement was 66%, and percentage of complications was 14.3%; the same percentages in the Allergan-LAGB Group were 41%, 0%, and 52%, respectively; in the LAP-BAND AP Standard Group were 42%, 20%, and 40%, respectively; in the LAP-BAND AP Large group were 38% , 12.5%, and 27.8%, respectively (at 48 months); in the Realize Band Group were 37%, 60%, and 0%, respectively (at 48 months); and in the Realize-C Band Group were 48%,12.5%, and 12.2%, respectively (at 36 months). CONCLUSIONS: In terms of weight loss and co-morbidities, no differences were found supporting the choice of one model over the others. Short-term and long-term band-related complications occurred without any clear predilection. The port-related complications were significantly lower in the Realize bands. PMID- 24342038 TI - Cyclen-based lipidic oligomers as potential gene delivery vehicles. AB - A series of cyclen-based linear oligomers bearing hydrophobic long chains (lipopolymers Cy-LC, where Cy and LC represent cyclen-based linear backbone and hydrophobic long chain substituents, respectively) were designed and synthesized. The effects of type and degree of substitution (DS) of hydrophobic long chains on the transfection efficiency were systematically studied. The nitrogen atoms with relatively strong basicity on the cyclen ensure their good DNA binding ability, which was confirmed by gel retardation and ethidium bromide exclusion assays. Lipopolyplexes could be formed as nanoparticles with suitable sizes and zeta potentials for gene transfection. In vitro gene delivery experiments revealed that the linoleic acid (LIN) substituted material Cy-LIN has better transfection efficiency than 25 kDa polyethylenimine in the absence or in the presence of serum. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and hemolysis assays showed low cytotoxicity and good biocompatibility of the lipopolyplexes. Fluorescent labeled DNA was used to study the cellular uptake and intracellular distribution of transfected DNA. Flow cytometry results suggested that a long chain is necessary for efficient cellular uptake, and images from confocal laser scanning microscopy showed that after 4h transfection, most of the fluorescent labeled DNA accumulated in the perinuclear region, which was required for efficient gene expression. Moreover, it was also found that the DS of the hydrophobic moiety can adjust the balance between DNA binding ability and dissociation of polyplexes, significantly affecting the transfection efficiency. PMID- 24342039 TI - Biomaterials for orbital implants and ocular prostheses: overview and future prospects. AB - The removal of an eye is one of the most difficult and dramatic decisions that a surgeon must consider in case of severe trauma or life-threatening diseases to the patient. The philosophy behind the design of orbital implants has evolved significantly over the last 60 years, and the use of ever more appropriate biomaterials has successfully reduced the complication rate and improved the patient's clinical outcomes and satisfaction. This review provides a comprehensive picture of the main advances that have been made in the development of innovative biomaterials for orbital implants and ocular prostheses. Specifically, the advantages, limitations and performance of the existing devices are examined and critically compared, and the potential of new, smart and suitable biomaterials are described and discussed in detail to outline a forecast for future research directions. PMID- 24342040 TI - Hydroxyapatite coating affects the Wnt signaling pathway during peri-implant healing in vivo. AB - Owing to its bio- and osteoconductivity, hydroxyapatite (HA) is a widely used implant material, but its osteogenic properties are only partly evaluated in vitro and in vivo. The present study focused on bone healing adjacent to HA coated titanium (Ti) implants, with or without incorporated lithium ions (Li(+)). Special attention was given to the Wnt signaling pathway. The implants were inserted into rat tibia for 7 or 28 days and analyzed ex vivo, mainly by histomorphometry and quantitative real-time polymerase chain reaction (qPCR). HA coated implants showed, irrespective of Li(+) content, bone-implant contact (BIC) and removal torque values significantly higher than those of reference Ti. Further, the expression of OCN, CTSK, COL1A1, LRP5/6 and WISP1 was significantly higher in implant-adherent cells of HA-coated implants, with or without Li(+). Significantly higher beta-catenin expression and significantly lower COL2A1 expression were observed in peri-implant bone cells from HA with 14 ng cm(-2) released Li(+). Interestingly, Ti implants showed a significantly larger bone area (BA) in the threads than HA with 39 ng cm(-2) released Li(+), but had a lower BIC than any HA-coated implant. This study shows that HA, with or without Li(+), is a strong activator of the Wnt signaling pathway, and may to some degree explain its high bone induction capacity. PMID- 24342041 TI - Plasma membrane functionalization using highly fusogenic immune activator liposomes. AB - Cell surface functionalization and target molecule incorporation into living cell membranes without functional damage represent major biotechnological challenges. One possible way to achieve these goals is to induce cell membrane fusion with an artificial membrane containing molecules equipped with reactive groups or ligands. In this work we developed a carrier system to incorporate lipopolysaccharide (LPS), an immune cell activating molecule from Gram-negative bacteria, into mammalian membranes. LPS is not present in untreated mammalian cells which hence are not detectable by the immune system. Here, we demonstrate the successful incorporation of LPS into fusogenic liposomes (FLs) and subsequent incorporation into mammalian plasma membranes using these FLs. Additionally, the presence of LPS in cell membranes was probed by the addition of non-activated macrophages. A high concentration of LPS in the plasma membrane of immortalized fibroblasts activated the immune cells, which in turn started to eliminate LPS exhibiting cells. Our method for cellular membrane functionalization is a promising tool for biomedical applications and could provide the basis for specific cell targeting approaches. PMID- 24342042 TI - Immobilization of heparin/poly-(L)-lysine nanoparticles on dopamine-coated surface to create a heparin density gradient for selective direction of platelet and vascular cells behavior. AB - Restenosis, thrombosis formation and delayed endothelium regeneration continue to be problematic for coronary artery stent therapy. To improve the hemocompatibility of the cardiovascular implants and selectively direct vascular cell behavior, a novel kind of heparin/poly-l-lysine (Hep/PLL) nanoparticle was developed and immobilized on a dopamine-coated surface. The stability and structural characteristics of the nanoparticles changed with the Hep:PLL concentration ratio. A Hep density gradient was created on a surface by immobilizing nanoparticles with various Hep:PLL ratios on a dopamine-coated surface. Antithrombin III binding quantity was significantly enhanced, and in plasma the APTT and TT times as coagulation tests were prolonged, depending on the Hep density. A low Hep density is sufficient to prevent platelet adhesion and activation. The sensitivity of vascular cells to the Hep density is very different: high Hep density inhibits the growth of all vascular cells, while low Hep density could selectively inhibit smooth muscle cell hyperplasia but promote endothelial progenitor cells and endothelial cell proliferation. These observations provide important guidance for modification of surface heparinization. We suggest that this method will provide a potential means to construct a suitable platform on a stent surface for selective direction of vascular cell behavior with low side effects. PMID- 24342043 TI - Microcryogels as injectable 3-D cellular microniches for site-directed and augmented cell delivery. AB - The success of cell therapy for tissue repair and regeneration demands efficient and reliable cell delivery methods. Here we established a novel microengineered cryogel (microcryogel) array chip containing microcryogels with predefined size and shape as injectable cell delivery vehicles. The microscale macroporous cryogels enabled automatic and homogeneous loading of tailored cellular niches (e.g. cells, matrices, bioactive factors) and could be easily harvested from the ready-to-use array chip. In contrast to microscale hydrogels, microcryogels exhibited excellent elasticity and could retain their shape and integrity after injection through the microsyringe routinely used for cell therapy. Human mesenchymal stromal cells loaded within microcryogels could be shielded from the mechanical insult and necrosis caused by during direct cell injection. After subcutaneous injection to the mice, cell-loaded microcryogels exhibited concentrated localization and enhanced retention at the injection site compared to dissociated cells. To demonstrate the potential therapeutic application for ischemic diseases, site-directed induction of angiogenesis was achieved subcutaneously in mice 2weeks after injection of NIH/3T3 fibroblast-loaded microcryogels, indicating long-term engraftment, accumulative paracrine stimulation and augmented host tissue integration. Our results convincingly showed the great promise of microcryogels as 3-D cellular microniches and injectable cell delivery vehicles to tackle major challenges faced by cell therapy-based regenerative medicine including shear-induced damages, uncontrolled localization, poor retention, limited cellular survival and functionalities in vivo. PMID- 24342044 TI - Differential effect of hypoxia on human mesenchymal stem cell chondrogenesis and hypertrophy in hyaluronic acid hydrogels. AB - Photocrosslinked hyaluronic acid (HA) hydrogels provide a conducive 3-D environment that supports the chondrogenesis of human mesenchymal stem cells (hMSCs). The HA macromer concentration in the hydrogels has a significant impact on the chondrogenesis of the encapsulated MSCs due to changes in the physical properties of the hydrogels. Meanwhile, hypoxia has been shown to promote MSC chondrogenesis and suppress subsequent hypertrophy. This study investigates the combinatorial effect of tuning HA macromer concentration (1.5-5%w/v) and hypoxia on MSC chondrogenesis and hypertrophy. To decouple the effect of HA concentration from that of crosslinking density, the HA hydrogel crosslinking density was adjusted by varying the extent of the reaction through the light exposure time while keeping the HA concentration constant (5%w/v at 5 or 15 min). It was found that hypoxia had no significant effect on the chondrogenesis and cartilaginous matrix synthesis of hMSCs under all hydrogel conditions. In contrast, the hypoxia mediated positive or negative regulation of hMSC hypertrophy in HA hydrogels is dependent on the HA concentration but independent of the crosslinking density. Specifically, hypoxia significantly suppressed hMSC hypertrophy and neocartilage calcification in low HA concentration hydrogels, whereas hypoxia substantially enhanced hMSC hypertrophy, leading to elevated tissue calcification in high HA concentration hydrogels irrespective of their crosslinking density. In addition, at a constant high HA concentration, increasing hydrogel crosslinking density promoted hMSC hypertrophy and matrix calcification. To conclude, the findings from this study demonstrate that the effect of hypoxia on hMSC chondrogenesis and hypertrophy is differentially influenced by the encapsulating HA hydrogel properties. PMID- 24342045 TI - Immunological principles regulating immunomodulation with biomaterials. AB - The immune system has evolved to recognize and eliminate pathogens; this recognition relies on the identification of structural molecular patterns within unique tissue microenvironments. Therefore, bioengineers can harness these immunological cues to design materials that modulate innate and adaptive immunity in a controlled manner. This review acts as an immunology primer by focusing on the basic molecular and cellular immunology principles governing immunomodulation with biomaterials. PMID- 24342046 TI - AP-1 regulates sphingosine kinase 1 expression in a positive feedback manner in glomerular mesangial cells exposed to high glucose. AB - Our previous studies have confirmed that the sphingosine kinase 1 (SphK1) sphingosine 1-phosphate (S1P) signaling pathway in the kidney under diabetic conditions is closely correlated with the pathogenesis of diabetic nephropathy (DN). The activation of SphK1-S1P pathway by high glucose (HG) can increase the expression of fibronectin (FN), an important fibrotic component, in glomerular mesangial cells (GMCs) by promoting the DNA-binding activity of transcription factor AP-1. However, the mechanism responsible for the sustained activation of SphK1-S1P pathway remains unclear. Given the binding motifs for AP-1 within the first intron of the SphK1 gene, we speculated that the activated AP-1 in the kidney under HG condition possibly regulates SphK1 expression in a positive feedback manner, thereby promoting the sustained activation of SphK1-S1P pathway and mediating the pathological progression of DN. Here, we observed the effect of AP-1 on SphK1 expression in GMCs and explored the molecular mechanism involved in the sustained activation of SphK1-S1P pathway. We found two consensus binding motifs for AP-1 in the promoter sequences and non-coding region downstream of the transcriptional initiation of the rat SphK1 gene by chromatin immunoprecipitation assay. The treatment of GMCs with both HG and S1P significantly increased the protein expression of c-Jun and c-Fos, and obviously enhanced the phosphorylation of c-Jun at Ser63 and Ser73, and c-Fos at Ser32. Knockdown of c-Jun and c-Fos with siRNAs substantially inhibited the expression of SphK1 and FN, whereas overexpression of c-Jun and c-Fos significantly increased the expression of SphK1 and FN. Curcumin treatment greatly decreased the levels of c-Jun, c-Fos, SphK1, and FN in the kidney tissues of diabetic rats. SiRNAs targeting SphK1 and S1P2 receptor respectively inhibited the phosphorylation of c-Jun (ser63 and ser73) and c-Fos (ser32), as well as FN expression under both normal and HG conditions. Our data demonstrated that the activated SphK1-S1P signaling pathway in GMCs under diabetic conditions is closely associated with AP-1 to form a positive feedback loop. This positive feedback loop functions as an important molecular basis for the sustained activation of SphK1-S1P pathway and increased FN expression that lead to the initiation and progression of DN. PMID- 24342047 TI - Long-term colloidal stability and metal leaching of single wall carbon nanotubes: effect of temperature and extracellular polymeric substances. AB - Long term (90 day) stability, aggregation kinetics in the presence and absence of natural organic materials (NOM), and metal leaching of five commercial single wall carbon nanotubes (SWCNTs) in waters (e.g. freshwater, seawater, stormwater, wastewater, and groundwater) were studied, as well as the effect of temperature on SWCNT stability and metal leaching. Zeta (zeta) potential of SWCNT decreased in magnitude with increase in temperature. In wastewater, SWCNT sedimented from the water column to below detectable levels after 30 days when kept at 40 degrees C, but at 20 degrees C 19% suspension was still observed after the same exposure time. Addition of 0.1 mg-C L(-1) EPS shifted the critical coagulation concentration (CCC) of SRNOM-stabilized SWCNT from 15 mM to 54 mM NaCl via additional electrostatic and possibly steric stabilization. Attachment efficiencies (alpha) of SWCNT in waters ranged from ~0.001 in DI with 10 mg L(-1) SRNOM to 1 in seawater. However, sedimentation of SWCNT in seawater (and other high ionic strength conditions) was not as fast as expected due to improved buoyancy and/or drag. Purified forms of SWCNTs exhibited better dispersibility and stability in most waters, but as expected, the total metal leached out was higher in the raw variants. Metal leaching from CNT in these studies was controlled by metal and water chemistries, CNT pretreatment, leachable metal fraction, exposure time, and presence of NOM. PMID- 24342049 TI - Transformation of heavy metal speciation during sludge drying: mechanistic insights. AB - Speciation can fundamentally affect on the stability and toxicity of heavy metals in sludge from wastewater treatment plants. This research investigated the speciation of heavy metals in sludge from both municipal and industrial sources, and metal speciation change as a result of drying process to reduce sludge volume. The changes in sludge properties including sludge moisture content, temperature, density, and electrical conductivity were also monitored to provide insights into the mechanisms causing the change in heavy metal speciation. The results show that the drying process generally stabilized Cr, Cu, Cd, and Pb in sludge by transforming acid-soluble, reducible, and oxidizable species into structurally stable forms. Such transformation and stabilization occurred regardless of the sludge source and type, and were primarily caused by the changes in sludge properties associated with decomposition of organic matter and sulfide. The results enhanced our understanding of the geochemical behavior of heavy metals in municipal sludge, and are useful for designing a treatment system for environment-friendly disposal of sludge. PMID- 24342048 TI - Simultaneous nitrogen and phosphorus removal in the sulfur cycle-associated Enhanced Biological Phosphorus Removal (EBPR) process. AB - Hong Kong has practiced seawater toilet flushing since 1958, saving 750,000 m(3) of freshwater every day. A high sulfate-to-COD ratio (>1.25 mg SO4(2-)/mg COD) in the saline sewage resulting from this practice has enabled us to develop the Sulfate reduction, Autotrophic denitrification and Nitrification Integrated (SANI((r))) process with minimal sludge production and oxygen demand. Recently, the SANI((r)) process has been expanded to include Enhanced Biological Phosphorus Removal (EBPR) in an alternating anaerobic/limited-oxygen (LOS-EBPR) aerobic sequencing batch reactor (SBR). This paper presents further development - an anaerobic/anoxic denitrifying sulfur cycle-associated EBPR, named as DS-EBPR, bioprocess in an alternating anaerobic/anoxic SBR for simultaneous removal of organics, nitrogen and phosphorus. The 211 day SBR operation confirmed the sulfur cycle-associated biological phosphorus uptake utilizing nitrate as electron acceptor. This new bioprocess cannot only reduce operation time but also enhance volumetric loading of SBR compared with the LOS-EBPR. The DS-EBPR process performed well at high temperatures of 30 degrees C and a high salinity of 20% seawater. A synergistic relationship may exist between sulfur cycle and biological phosphorus removal as the optimal ratio of P-release to SO4(2-) reduction is close to 1.0 mg P/mg S. There were no conventional PAOs in the sludge. PMID- 24342050 TI - Development of carbon nanotubes/CoFe2O4 magnetic hybrid material for removal of tetrabromobisphenol A and Pb(II). AB - Multi-walled carbon nanotubes (MWCNTs) coated with magnetic amino-modified CoFe2O4 (CoFe2O4-NH2) nanoparticles (denoted as MNP) were prepared via a simple one-pot polyol method. The MNP composite was further modified with chitosan (CTS) to obtain a chitosan-functionalized MWCNT/CoFe2O4-NH2 hybrid material (MNP-CTS). The obtained hybrid materials were characterized by Transmission Electron Microscopy (TEM), Fourier Transform Infrared Spectrogram (FT-IR) Analysis and X ray Photoelectron Spectroscopy (XPS) Analysis, Vibrating Sample Magnetometer (VSM) Analysis and the Brunauer-Emmett-Teller (BET) surface area method, respectively. The composites were tested as adsorbents for tetrabromobisphenol A (TBBPA) and Pb(II), and were investigated using a pseudo-second-order model. The adsorption of TBBPA was well represented by the Freundlich isotherm; the Langmuir model better described Pb(II) absorption. MNP-CTS adsorbed both TBBPA and Pb(II) (maximum adsorption capacities of 42.48 and 140.1mgg(-1), respectively) better than did MNP without CTS. Magnetic composite particles with adsorbed TBBPA and Pb(II) could be regenerated using 0.2M NaOH solution and were separable from liquid media using a magnetic field. PMID- 24342051 TI - Chiral fungicide triadimefon and triadimenol: Stereoselective transformation in greenhouse crops and soil, and toxicity to Daphnia magna. AB - Various chiral pesticides are used in greenhouses to ensure high crop yields. However, detailed knowledge on the environmental behavior of such chiral contaminants with respect to enantioselectivity in the greenhouse has received little attention so far. Here, the widely used fungicide triadimefon was chosen as a "chiral probe" to investigate its enantioselective degradation and formation of triadimenol in greenhouse tomato, cucumber, and soil under different application modes. In addition, the stereoselectivity of individual isomers of triadimefon and triadimenol in aquatic toxicity were first studied. Significant differences in their acute toxicity to Daphnia magna were observed among the isomers. Under foliage application or soil irrigation application, S-(+) triadimefon was preferentially degraded, resulting in relative enrichment of the more toxic R-(-)-enantiomer in tomato, cucumber, and soil. Further enantioselective analysis of converted triadimenol showed that the compositions of the four product stereoisomers were different and closely dependent on environmental conditions: the most toxic RS-(+)-triadimenol was the most preferentially produced isomer in tomato under foliage treatment, while the RR (+)-triadimenol was proved to be the highest amount of metabolite isomer in cucumber and soil under both treatment modes and in tomato under soil treatment. PMID- 24342052 TI - Rickettsial infection in Ixodes ricinus ticks in urban and natural habitats of Slovakia. AB - A total of 1810 Ixodes ricinus ticks was collected from the vegetation from 2 different habitat types: urban and natural. Urban habitats were represented by cemeteries and public parks in the following towns: Bratislava, Malacky, and Martin at 150 m and 400 m above sea level. Natural habitats were selected in the mountain forest of the Martinske hole Mts. in Central Slovakia at 3 different altitudinal levels, i.e. 600 m, 800 m and 1000 ma.s.l. All ticks were tested for the presence of spotted fever group rickettsiae. The DNA of Rickettsia spp. was identified in 9% of all tested ticks. Rickettsia-infected ticks were present in both, urban and sylvatic sites at all studied altitudes. Four different species of Rickettsia were present in positive I. ricinus ticks. Rickettsia helvetica was identified in 77 out of 87 Rickettsia-positive I. ricinus ticks, followed by 8 samples that belonged to Rickettsia monacensis and 2 of the positive ticks were infected with different unidentified Rickettsia spp. Due to the association of R. helvetica and R. monacensis with human infections, it is essential to understand which species of Rickettsia circulate in the natural foci of Slovakia. Circulation of pathogenic rickettsiae in urban as well as natural habitats at different altitudinal levels in Slovakia emphasizes that infection risk is very common throughout this Central European country. PMID- 24342053 TI - Outsourcing medical data analyses: can technology overcome legal, privacy, and confidentiality issues? AB - BACKGROUND: Medical data are gold mines for deriving the knowledge that could change the course of a single patient's life or even the health of the entire population. A data analyst needs to have full access to relevant data, but full access may be denied by privacy and confidentiality of medical data legal regulations, especially when the data analyst is not affiliated with the data owner. OBJECTIVE: Our first objective was to analyze the privacy and confidentiality issues and the associated regulations pertaining to medical data, and to identify technologies to properly address these issues. Our second objective was to develop a procedure to protect medical data in such a way that the outsourced analyst would be capable of doing analyses on protected data and the results would be comparable, if not the same, as if they had been done on the original data. Specifically, our hypothesis was there would not be a difference between the outsourced decision trees built on encrypted data and the ones built on original data. METHODS: Using formal definitions, we developed an algorithm to protect medical data for outsourced analyses. The algorithm was applied to publicly available datasets (N=30) from the medical and life sciences fields. The analyses were performed on the original and the protected datasets and the results of the analyses were compared. Bootstrapped paired t tests for 2 dependent samples were used to test whether the mean differences in size, number of leaves, and the accuracy of the original and the encrypted decision trees were significantly different. RESULTS: The decision trees built on encrypted data were virtually the same as those built on original data. Out of 30 datasets, 100% of the trees had identical accuracy. The size of a tree and the number of leaves was different only once (1/30, 3%, P=.19). CONCLUSIONS: The proposed algorithm encrypts a file with plain text medical data into an encrypted file with the data protected in such a way that external data analyses are still possible. The results show that the results of analyses on original and on protected data are identical or comparably similar. The approach addresses the privacy and confidentiality issues that arise with medical data and is adherent to strict legal rules in the United States and Europe regarding the processing of the medical data. PMID- 24342054 TI - The patient health questionnaire-15 and its abbreviated version as screening tools for depression in Korean college and graduate students. AB - OBJECTIVE: Over half of all suicides worldwide occur in Asia. Given the close association between suicide and depression, it is quite unexpected that depression is least frequently diagnosed in Asia. This is, in part, due to the fact that Asians somatize depression. Young adults including college and graduate students are no exceptions. Therefore, a somatic symptom-focused screening tool would be useful in detecting depression in Asian college and graduate students. The purpose of this study was to evaluate the psychometric properties of the Patient Health Questionnaire-15 (PHQ-15) in screening for depression among Korean college and graduate students. In addition, we developed an abbreviated version of the PHQ-15 (aPHQ-15) and studied validity measures. METHODS: Three-hundred and fifty Korean college and graduate students were screened with the PHQ-15. Of all participants, 176 were interviewed using the Structured Clinical Interview for DSM-IV to diagnose major depressive episode, while the other 174 were evaluated with the Beck Depression Inventory-II (BDI-II) and the Inventory of Depressive Symptomatology-Self-Report (IDS-SR). Reliability and validity measures including the internal consistency, test-retest reliability, and criterion, convergent, and divergent validity were tested. Principal component analysis was used in developing the abbreviated version of the PHQ-15. RESULTS: The PHQ-15 showed good internal consistency and test-retest reliability (Cronbach's alpha 0.82, intra class correlation coefficient 0.87). The optimal cut-off point for detecting depression was estimated to be 8. There were strong correlations between the PHQ 15 total scores and self-report measures of depressive symptom severity (BDI-II: r=0.69 and p<0.001, IDS-SR: r=0.77 and p<0.001). The 5-item aPHQ-15 had comparable validity with the PHQ-15. CONCLUSIONS: The somatic symptom-focused PHQ 15 and aPHQ-15 can work as effective screening tools for depression. PMID- 24342055 TI - Mediators and moderators of functional impairment in adults with obsessive compulsive disorder. AB - The current study examined correlates, moderators, and mediators of functional impairment in 98 treatment-seeking adults with obsessive-compulsive disorder (OCD). Participants completed or were administered measures assessing obsessive compulsive symptom severity, functional impairment, resistance against symptoms, interference due to obsessive-compulsive symptoms, depressive symptoms, insight, and anxiety sensitivity. Results indicated that all factors, except insight into symptoms, were significantly correlated with functional impairment. The relationship between obsessive-compulsive symptom severity and functional impairment was not moderated by patient insight, resistance against obsessive compulsive symptoms, or anxiety sensitivity. Mediational analyses indicated that obsessive-compulsive symptom severity mediated the relationship between anxiety sensitivity and obsessive-compulsive related impairment. Indeed, anxiety sensitivity may play an important contributory role in exacerbating impairment through increases in obsessive-compulsive symptom severity. Depressive symptoms mediated the relationship between obsessive-compulsive symptom severity and obsessive-compulsive related impairment. Implications for assessment and treatment are discussed. PMID- 24342057 TI - The impact of personality on quality of life and disease activity in patients with Behcet's disease: a pilot study. AB - BACKGROUND: The aim of this study was to examine the personality characteristics of patients with Behcet's Disease (BD) using the Temperament and Character Inventory (TCI) compared with healthy control subjects and to investigate the relationship between the temperament and character properties and quality of life, disease activity, depression and anxiety in Behcet's patients. METHODS: A total of 46 BD patients and 40 healthy subjects were included in the study. All patients and controls were determined using the TCI, Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders Clinical Version for Axis I disorders (SCID-CV), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Quality of life (QOL) Instrument for Skin Disorders and Behcet Disease Current Activity Form (BDCAF). RESULTS: BD patients demonstrated significantly lower Reward Dependence than healthy controls. Among the subscales; Explarotory Excitability, Shyness with Strangers, Attachment, Spiritual Acceptance were lower and Self-Acceptance was higher in patients compared to control subjects. Decreased quality of life and increased disease activity of the patients were correlated with increased anxiety and depression. Responsibility, Self-Forgetfulness and Transpersonal Identification were associated with quality of life while Responsibility was the major factor effecting QOL. Disease activity was not found related with TCI properties. CONCLUSION: Temperament and Character traits of BD patients were different from healthy group that might be due to many factors like genetics, biological or socio-cultural differences. BD patients were demonstrated as materialistic, self-contained, self-confident, cold, detached, and reserved although they are not shy. Considering the different personality traits of BD patients in psychotherapeutic approaches, may have a positive impact on QOL and comorbid major depressive disorder. PMID- 24342056 TI - Emotion dysregulation as a maintenance factor of borderline personality disorder features. AB - We examined within-individual changes in emotion dysregulation over the course of one year as a maintenance factor of borderline personality disorder (BPD) features. We evaluated the extent to which (1) BPD symptom severity at baseline predicted within-individual changes in emotion dysregulation and (2) within individual changes in emotion dysregulation predicted four BPD features at 12 month follow-up: affective instability, identity disturbances, negative relationships, and impulsivity. The specificity of emotion dysregulation as a maintaining mechanism of BPD features was examined by controlling for a competing intervening variable, interpersonal conflict. BPD symptoms at baseline predicted overall level and increasing emotion dysregulation. Additionally, increasing emotion dysregulation predicted all four BPD features at 12-month follow-up after controlling for BPD symptoms at baseline. Further, overall level of emotion dysregulation mediated the association between BPD symptom severity at baseline and both affective instability and identity disturbance at 12-month follow-up, consistent with the notion of emotion dysregulation as a maintenance factor. Future research on the malleability of emotion dysregulation in laboratory paradigms and its effects on short-term changes in BPD features is needed to inform interventions. PMID- 24342058 TI - Vertical asymmetries and inhibition of return: effects of spatial and non-spatial cueing on behavior and visual ERPs. AB - The mechanisms underlying inhibition of return (IOR) are still under debate. Besides the probable implication of several processes in its generation, a reason for this uncertainty may be related to experimental factors affecting the presence, time course, and magnitude of IOR. Two of them may be related to the arrangement of the stimuli in the visual field that could cause possible interactions between IOR and response conflict effects (horizontal arrangements) or between IOR and perceptual asymmetries (vertical arrangement). The purpose of the present study was to explore location and color cueing effects with a vertical arrangement of stimuli, free of S-R compatibility effects. To examine this possibility, a cue-back task with stimuli in the vertical meridian was employed. Targets could randomly and equiprobably appear at cued or uncued locations, or with cued or uncued color. These cueing effects were analyzed on behavior and ERPs separately for upper and lower visual fields (UVF and LVF). Under location cueing, behavioral responses were slower (spatial IOR) in both hemifields. In the ERPs, N1 reductions were observed in both visual fields although with different modulations in their latency and scalp distribution. In the P3 rising beginning, posterior negative deflections in the LVF (Nd) and anterior positive deflections (Pd) in the UVF were observed. Under color cueing, P3 amplitude was reduced in the UVF accompanied by no behavioral effects. These results suggest that different patterns of brain activation can be obtained in upper and lower visual fields under spatial- and non-spatial cueing conditions. PMID- 24342059 TI - Evaluation of culture media for the production of secondary metabolites in a natural products screening program. AB - Variation in the growing environment can have significant impacts on the quantity and diversity of fungal secondary metabolites. In the industrial setting, optimization of growing conditions can lead to significantly increased production of a compound of interest. Such optimization becomes challenging in a drug discovery screening situation, as the ideal conditions for one organism may induce poor metabolic diversity for a different organism. Here, the impact of different media types, including six liquid media and five solid media, on the secondary metabolite production of three fungal strains was examined in the context of the drug-discovery screening process. The relative production of marker compounds was used to evaluate the usefulness and reliability of each medium for the purpose of producing secondary metabolites. PMID- 24342060 TI - Vascular Quality of Life Questionnaire-6 facilitates health-related quality of life assessment in peripheral arterial disease. AB - BACKGROUND: Most commonly used outcome measures in peripheral arterial disease (PAD) provide scarce information about achieved patient benefit. Therefore, patient-reported outcome measures have become increasingly important as complementary outcome measures. The abundance of items in most health-related quality of life instruments makes everyday clinical use difficult. This study aimed to develop a short version of the 25-item Vascular Quality of Life Questionnaire (VascuQoL-25), a PAD-specific health-related quality of life instrument. METHODS: The study recruited 129 individuals with intermittent claudication and 71 with critical limb ischemia from two university hospitals. Participants were a mean age of 70 +/- 9 years, and 57% were men. All patients completed the original VascuQoL when evaluated for treatment, and 127 also completed the questionnaire 6 months after a vascular procedure. The VascuQoL-25 was reduced based on cognitive interviews and psychometric testing. The short instrument, the VascuQoL-6, was tested using item-response theory, exploring structure, precision, item fit, and targeting. A subgroup of 21 individuals with intermittent claudication was also tested correlating the results of VascuQoL-6 to the actual walking capacity, as measured using global positioning system technology. RESULTS: On the basis of structured psychometric testing, the six most informative items were selected (VascuQoL-6) and tested vs the original VascuQoL-25. The correlation between VascuQoL-25 and VascuQoL-6 was r = 0.88 before intervention, r = 0.96 after intervention, and the difference was r = 0.91 (P < .001). The Cronbach alpha for the VascuQoL-6 was .85 before and .94 after intervention. Cognitive interviews indicated that the responders considered all six items to be relevant and comprehensible. Rasch analysis was used to reduce response options from seven (VascuQoL-25) to four (VascuQoL-6). VascuQol-6 was shown to have high precision and discriminative properties. Item fit was excellent, with both "infit" and "outfit" between 0.7 and 1.3 for all six items. The standardized response mean after intervention was 1.15, indicating good responsiveness to clinical change. VascuQoL-6 results correlated strongly (r = 0.72; P < .001) with the actual measured walking ability (n = 21). CONCLUSIONS: VascuQoL-6 is a valid and responsive instrument for the assessment of health related quality of life in PAD. The main advantage is the compact format that offers a possibility for routine use in busy clinical settings. PMID- 24342061 TI - Discussion. PMID- 24342062 TI - PECAM-1 phosphorylation and tissue factor expression in HUVECs exposed to uniform and disturbed pulsatile flow and chemical stimuli. AB - INTRODUCTION: We analyzed the relationship between platelet endothelial cell adhesion molecule-1 (PECAM-1) activation and tissue factor (TF) RNA expression in human umbilical vein endothelial cells (HUVECs) exposed to mechanical and chemical stimulation. METHODS: Fifty percent confluent and 100% confluent HUVEC cultures were exposed to pulsatile forward flow, as a model for uniform flow, or pulsatile to-and-fro flow, as a model for disturbed flow, using a parallel-plate flow chamber system for up to 4 hours in the presence or absence of 4 U/mL thrombin. Protein lysates were immunoprecipitated for PECAM-1 and then immunoblotted with anti-phospho-tyrosine antibody. TF RNA expression was determined using quantitative reverse transcription polymerase chain reaction. RESULTS: HUVECs exposed to disturbed flow induced higher TF expression at 4 hours than HUVECs exposed to uniform flow in sparse cultures (16.8 +/- 5.8 vs 5.1 +/- 1.2; P < .05). HUVECs exposed to disturbed flow and thrombin induced higher TF RNA expression at 4 hours than cultures exposed to uniform flow and thrombin in both confluent (47.0 +/- 6.0 vs 30.2 +/- 4.9; P < .05) and sparse (72.3 +/- 10.7 vs 49.8 +/- 4.7; P < .05) cultures. In confluent HUVEC cultures, PECAM-1 is minimally phosphorylated by disturbed and uniform flow, while in sparse HUVEC cultures, PECAM-1 phosphorylation at 15 minutes is greater in both disturbed and uniform flow (2.0 +/- 0.2 and 2.1 +/- 0.4 respectively; P < .05). Thrombin treatment of static HUVECs exhibited greater PECAM-1 phosphorylation at 15 minutes in confluent compared with sparse cultures (3.0 +/- 0.5 vs 2.3 +/- 0.1; P < .05). PECAM-1 phosphorylation of HUVECs exposed to both flow and thrombin is significantly higher in sparse cultures compared with either flow or thrombin stimulation alone but was suppressed in confluent cultures. CONCLUSIONS: The significantly higher TF RNA expression induced by disturbed flow and cell confluence indicates that suppression of PECAM-1 phosphorylation may be an important contributory mechanical signal pathway that promotes TF expression when HUVECs are exposed to disturbed flow. PMID- 24342063 TI - Use and durability of femoral vein for autologous reconstruction with infection of the aortoiliofemoral axis. AB - OBJECTIVE: To analyze early and late mortality, venous morbidity, reinfection, and freedom from reintervention after using the femoral vein (FV) for vascular reconstruction with infection of the aortoiliofemoral axis. METHODS: By reviewing our database, 86 patients could be identified with implantation of FV grafts in infected fields between November 1995 and July 2012. The patient records were retrospectively analyzed and follow-up information obtained from patients or their general physician. Seventy-one patients presented with prosthetic graft infection and 15 with an infected aneurysm. For data analysis, patients were divided into an aortoiliac (n = 67) and a femoral group (n = 19). Study end points assessed were early and late mortality, incidence of deep vein thrombosis of the FV donor limb, graft patency, limb salvage, reinfection, and freedom from reintervention. RESULTS: Sixty-seven aortoiliac reconstructions were performed using 84 FV grafts with an operative mortality of 9%. After a mean follow-up of 45 months, survival, patency, limb salvage, and freedom from reintervention were 45%, 97%, 94%, and 91%, respectively, at 5 years. Twenty FV grafts were employed for 19 femoral reconstructions with an operative mortality of 10.5%. Here, mean follow-up was 35 months and survival, patency, limb salvage, and freedom from reintervention were 29%, 87%, 93%, and 81%, respectively, at 5 years. Specimen culture confirmed Staphylococcus (epidermidis and aureus) as the predominant microorganism. Venous morbidity after FV harvest showed an incidence of deep venous thrombosis of 13.7% for popliteal and 10.6% for tibial level at a follow up of 24 months with only mild clinical symptoms (21% limb swelling). CONCLUSIONS: Vascular reconstruction using autologous FV in arterial and graft infection of the aortoiliofemoral axis provides durable long-term results with acceptable mortality and morbidity. PMID- 24342064 TI - Comparative effectiveness of endovascular versus open repair of ruptured abdominal aortic aneurysm in the Medicare population. AB - OBJECTIVE: Endovascular aortic repair (EVAR) for abdominal aortic aneurysm (AAA) is increasingly used for emergent treatment of ruptured AAA (rAAA). We sought to compare the perioperative and long-term mortality, procedure-related complications, and rates of reintervention of EVAR vs open aortic repair of rAAA in Medicare beneficiaries. METHODS: We examined perioperative and long-term mortality and complications after EVAR or open aortic repair performed for rAAA in all traditional Medicare beneficiaries discharged from a United States hospital from 2001 to 2008. Patients were matched by propensity score on baseline demographics, coexisting conditions, admission source, and hospital volume of rAAA repair. Sensitivity analyses were performed to evaluate the effect of bias that might have resulted from unmeasured confounders. RESULTS: Of 10,998 patients with repaired rAAA, 1126 underwent EVAR and 9872 underwent open repair. Propensity score matching yielded 1099 patient pairs. The average age was 78 years, and 72.4% were male. Perioperative mortality was 33.8% for EVAR and 47.7% for open repair (P < .001), and this difference persisted for >4 years. At 36 months, EVAR patients had higher rates of AAA-related reinterventions than open repair patients (endovascular reintervention, 10.9% vs 1.5%; P < .001), whereas open patients had more laparotomy-related complications (incisional hernia repair, 1.8% vs 6.2%; P < .001; all surgical complications, 4.4% vs 9.1%; P < .001). Use of EVAR for rAAA increased from 6% of cases in 2001 to 31% in 2008, whereas during the same interval, overall 30-day mortality for admission for rAAA, regardless of treatment, decreased from 55.8% to 50.9%. CONCLUSIONS: EVAR for rAAA is associated with lower perioperative and long-term mortality in Medicare beneficiaries. Increasing adoption of EVAR for rAAA is associated with an overall decrease in mortality of patients hospitalized for rAAA during the last decade. PMID- 24342066 TI - The effect of ballooning following carotid stent deployment on hemodynamic stability. AB - OBJECTIVE: While patient eligibility for carotid artery stenting (CAS) is well established, the intraoperative technique remains widely varied. The decision to perform poststent ballooning (PSB) is operator-dependent and often influenced by the interpretation of poststent angiography. While visually creating a greater luminal diameter, it is unclear whether PSB has immediate risks or long-term benefits. The purpose of this report is to determine whether PSB has any effects on periprocedural hemodynamic stability. METHODS: A retrospective analysis of all patients that underwent CAS between 2005 and 2012 at a tertiary care center was performed. The primary end point was hemodynamic instability, defined as bradycardia (a heart rate of <60 beats/min) or hypotension (systolic blood pressure of <90 mm Hg) during the intraoperative or postoperative period. Binary logistic regression model was performed to determine the effect of PSB on the occurrence of hemodynamic instability, adjusting for patient's age, sex, hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, recent myocardial infarction, previous carotid endarterectomy, high-risk status, and symptomatic status. RESULTS: A total of 103 (51 men and 52 women) patients underwent placement of a unilateral carotid stent between 2005 and 2012 at our institution. All patients underwent prestent dilatation. However, 70% (n = 72) underwent PSB whereas 30% (n = 31) did not. PSB was a significant predictor of hemodynamic depression (odds ratio [OR], 3.8; 95% confidence interval, 1.3-11; P < .01). Symptomatic status, recent myocardial infarction, hyperlipidemia, and coronary artery disease were associated with a length of stay exceeding 24 hours postoperatively (OR, 6.6; P < .01, OR, 6.1; P < .01, OR, 5.4; P = .04, and OR, 9.3; P < .01, respectively). At follow-up, 97% (83/86) stents were patent. Two stent stenoses occurred in the group that received PSB, while one stent stenosis occurred in the group that did not receive PSB. CONCLUSIONS: PSB increases the risk of intra- or postoperative hemodynamic depression in CAS and might increase the risk of major adverse cardiovascular events. Given the added complications and the lack of evidence supporting long term patency, PSB should be only selectively used. PMID- 24342065 TI - Natural history of grade I-II blunt traumatic aortic injury. AB - BACKGROUND: Endovascular aortic repair has revolutionized the management of traumatic blunt aortic injury (BAI). However, debate continues about the extent of injury requiring endovascular repair, particularly with regard to minimal aortic injury. Therefore, we conducted a retrospective observational analysis of our experience with these patients. METHODS: We retrospectively reviewed all BAI presenting to an academic level I trauma center over a 10-year period (2000 2010). Images were reviewed by a radiologist and graded according to Society for Vascular Surgery guidelines (grade I-IV). Demographics, injury severity, and outcomes were recorded. RESULTS: We identified 204 patients with BAI of the thoracic or abdominal aorta. Of these, 155 were deemed operative injuries at presentation, had grade III-IV injuries or aortic dissection, and were excluded from this analysis. The remaining 49 patients had 50 grade I-II injuries. We managed 46 grade I injuries (intimal tear or flap, 95%), and four grade II injuries (intramural hematoma, 5%) nonoperatively. Of these, 41 patients had follow-up imaging at a mean of 86 days postinjury and constitute our study cohort. Mean age was 41 years, and mean length of stay was 14 days. The majority (48 of 50, 96%) were thoracic aortic injuries and the remaining two (4%) were abdominal. On follow-up imaging, 23 of 43 (55%) had complete resolution of injury, 17 (40%) had no change in aortic injury, and two (5%) had progression of injury. Of the two patients with progression, one progressed from grade I to grade II and the other progressed from grade I to grade III (pseudoaneurysm). Mean time to progression was 16 days. Neither of the patients with injury progression required operative intervention or died during follow-up. CONCLUSIONS: Injury progression in grade I-II BAI is rare (~5%) and did not cause death in our study cohort. Given that progression to grade III injury is possible, follow-up with repeat aortic imaging is reasonable. PMID- 24342067 TI - The combination of surgical embolectomy and endovascular techniques may improve outcomes of patients with acute lower limb ischemia. AB - OBJECTIVE: Surgical arterial thromboembolectomy (TE) is an efficient treatment for acute arterial thromboemboli of lower limbs, especially if a single large artery is involved. Unfortunately, residual thrombus, propagation of thrombi, chronic atherosclerotic disease, and vessel injuries secondary to balloon catheter passage may limit the clinical success rate. Intraoperative angiography can identify any arterial imperfection after TE, which may be corrected simultaneously by endovascular techniques (so-called "hybrid procedures," HP). The aim of this study is to compare outcomes of surgical TE vs HP in patients with acute lower limb ischemia (ALLI). METHODS: From 2006 to 2012, 322 patients with ALLI were admitted to our department. Patients received urgent surgical treatment using only a Fogarty balloon catheter (TE group = 112) or in conjunction with endovascular completion (HP group = 210). In-hospital complications, 30-day mortality, primary and secondary patency, reintervention rate, limb salvage, and overall survival rates were calculated using the Kaplan Meier method and compared by log-rank test. RESULTS: HPs (n = 210) following surgical TE consisted of angioplasty (PTA) +/- stenting in 90 cases, catheter directed intra-arterial thrombolysis + PTA +/- stenting in 24, thrombus fragmentation and aspiration by large guiding catheter + PTA +/- stenting in 67, vacuum-based accelerated thromboaspiration by mechanical devices in 9, and primary covered stenting in 12. Estimated primary patency was 90.4% vs 70.4% at 2 year and 87.1% vs 66.3% at 5-year follow-up, respectively, for HP and TE patients (hazard ratio, 3.1; 95% confidence interval, 1.78-5.41; P < .01). A hazard ratio of 2.1 for limb salvage was noted for the HP group (95% confidence interval, 1.01 4.34; P = .03). Estimated freedom from reintervention at 1 year was 94.4% for HP vs 82.1% for TE patients, and 89% vs 73.7% at 5 years, respectively (P = .04). CONCLUSIONS: HPs for ALLI may represent the tools that, when applied to specific clinical scenarios, hold the potential to reduce the morbidity previously associated with acute arterial occlusion. PMID- 24342068 TI - Experience with a novel custom-made fenestrated stent graft in the repair of juxtarenal and type IV thoracoabdominal aneurysms. AB - OBJECTIVE: Fenestrated stent grafting has become increasingly popular as a means to manage complex aortic pathology, including juxta- and pararenal aneurysms. The design of a recently developed custom-made fenestrated stent graft, in theory, confers advantages when managing anatomically challenging aortic morphology. This study evaluated its feasibility in anatomically challenging scenarios. METHODS: Over a 12-month period, 20 patients received fenestrated stent grafts. Among those, 13 patients with juxtarenal or type IV thoracoabdominal aortic aneurysms underwent endovascular repair with the novel fenestrated stent graft at a single UK institution. Data on aneurysm morphology and immediate and short-term results were collected prospectively. RESULTS: The mean aneurysmal sac size was 7.3 cm (range, 5.5-10.0 cm). The mean infrarenal neck length was 4.4 mm (range, 0-9 mm), and in three cases was lined by a pre-existing infrarenal stent graft. Nine cases had an infrarenal neck angulation of 60( degrees ) or more in either the anteroposterior or coronal planes. Five cases had >=50% thrombus at the proximal landing zone. A total of 35 target vessels were cannulated, of which six right renal and four left renal arteries were angulated >=120( degrees ). Two-thirds of cannulated celiac trunks were angulated >=120( degrees ), and one cannulated superior mesenteric artery was angulated >= 140( degrees ). Seven of the cannulated targets were stenosed more than 60%. One patient had two right renal arteries arising 3 mm from each other. Four right and four left common iliac arteries were angulated >=90( degrees ) in relation to the infrarenal aorta. Technical success was 100%. Median time from date of procedure to most recent follow-up with computed tomography scanning was 33 weeks. There was no type I or III endoleak. One type II endoleak was observed at the time of most recent computed tomography scanning and treated expectantly. There was a single incident of left renal artery occlusion. One patient required repair of a brachial artery, fasciotomies, and temporary haemofiltration. One patient died from ischemic heart disease 77 weeks after the procedure. CONCLUSIONS: The use of the novel fenestrated stent graft system in patients with hostile aortic aneurysmal morphology is feasible with acceptable short-term outcomes. PMID- 24342070 TI - A novel approach for hybrid repair of type B aortic dissection associated with coarctation of the aorta. AB - We report the case of an acute type B aortic dissection in association with an unknown isthmic coarctation in a 53-year-old man. An intimal tear was located just distal to the coarctation, and the intimal flap extended to the level of the renal arteries. Hybrid repair was performed successfully 4 months later, without deep hypothermic circulatory arrest. An extra-anatomic bypass connected the ascending aorta to the abdominal aorta. The coarctation was occluded using a ventricular septal defect occluder. The hybrid repair was safe and effective for the patient. PMID- 24342069 TI - Flow reversal promotes intimal thickening in vein grafts. AB - OBJECTIVE: After vascular interventions, unidentified mechanisms disrupt the homeostasis of a focal narrowing to initiate an intimal thickening response. We hypothesize that perturbations in the hemodynamic microenvironment are the initiating event for this disruption of homeostasis and intimal thickening in vein bypass grafts. The objective of this study was to investigate the relation between local flow perturbations and its influence on the vein graft architecture. METHODS: An external ligature was used to create an 80% focal midgraft stenosis in bilateral rabbit carotid vein grafts. A unilateral distal ligation created a ninefold difference in flow rate between high-flow and low flow grafts. Ten vein grafts were harvested at 28 days and serially sectioned for morphologic evaluation and vein graft reconstruction. Computational fluid dynamics analyses were performed to examine the hemodynamic environment within these complex flow regions. RESULTS: The largest intimal thickening occurred exclusively within the region immediately distal to the maximum stenosis in high flow grafts, which was characterized by persistent flow separation and reversal for the entire cardiac cycle. In regions of low to moderate shear stress (<5 Pa), the typical inverse correlation between intimal thickness and wall shear was observed. CONCLUSIONS: Regions of vein bypass grafts exposed to persistent flow reversal are most at risk for intimal thickening and loss of lumen. PMID- 24342071 TI - [Cortical spreading depolarization phenomena in patients with traumatic and ischemic brain injuries. Results of a pilot study]. AB - OBJECTIVES: To determine the frequency and duration of cortical spreading depolarization (CSD) and CSD-like episodes in patients with traumatic brain injury (TBI) and malignant middle cerebral artery infarction (MMCAI) requiring craniotomy. DESIGN: A descriptive observational study was carried out during 19 months. SETTING: Neurocritical patients. PATIENTS: Sixteen patients were included: 9 with MMCAI and 7 with moderate or severe TBI, requiring surgical treatment. INTERVENTIONS: A 6-electrode subdural electrocorticographic (ECoG) strip was placed onto the perilesional cortex. MAIN VARIABLES OF INTEREST: An analysis was made of the time profile and the number and duration of CSD and CSD like episodes recorded from the ECoGs. RESULTS: Of the 16 patients enrolled, 9 presented episodes of CSD or CSD-like phenomena, of highly variable frequency and duration. CONCLUSIONS: Episodes of CSD and CSD-like phenomena are frequently detected in the ischemic penumbra and/or traumatic cortical regions of patients with MMCAI who require decompressive craniectomy or of patients with contusional TBI. PMID- 24342072 TI - The role of the specialist acute oncology nurse in the new acute oncology services. PMID- 24342073 TI - Acute oncology: a bona fide subspecialty or a distraction from the day job? PMID- 24342074 TI - Coffee and green tea consumption is associated with insulin resistance in Japanese adults. AB - OBJECTIVE: Higher coffee and green tea consumption has been suggested to decrease risk of type 2 diabetes, but their roles in insulin resistance (IR) and insulin secretion remain unclear. This study examined the association between habitual consumption of these beverages and markers of glucose metabolism in a Japanese working population. MATERIALS/METHODS: Participants were 1440 Japanese employees (1151 men and 289 women) aged 18-69years. Consumption of coffee and green tea was ascertained via a validated brief diet history questionnaire. Multilevel linear regression was used to estimate means (95% confidence intervals) of fasting insulin, fasting plasma glucose, homeostatic model assessment of IR (HOMA-IR), homeostatic model assessment of beta-cell function (HOMA-beta) and glycated hemoglobin (HbA1c) with adjustment for potential confounding variables. RESULTS: Coffee consumption was significantly, inversely associated with HOMA-IR (P for trend=0.03), and the association appeared to be confined to overweight subjects (BMI>=25kg/m(2)) (P for trend=0.01, P for interaction=0.08). Unexpectedly, green tea consumption was positively associated with HOMA-IR (P for trend=0.02), though there was no dose-response relationship among daily consumers of green tea. Neither coffee nor green tea consumption was associated with HOMA-beta and HbA1c. CONCLUSIONS: Our findings indicate that coffee consumption may be associated with decreased IR, but not with insulin secretion. The positive association between green tea consumption and IR warrants further investigation. PMID- 24342075 TI - Irisin in humans: recent advances and questions for future research. PMID- 24342077 TI - National comparison of literally homeless male and female VA service users: entry characteristics, clinical needs, and service patterns. AB - BACKGROUND: Although there are growing numbers of homeless female U.S. veterans, the U.S. Department of Veterans Affairs (VA) has traditionally served a predominantly male population; thus, it is important to examine differences between homeless female and male veterans in their service needs and the current provision of VA homeless services. METHODS: A national registry of 119,947 users of VA homeless services from 2011 to 2012 was used to 1) estimate the proportion of female veterans among VA homeless service users, 2) examine the proportion of VA homeless service users who are literally homeless by gender, and 3) report differences between female and male VA homeless service users who are literally homeless on sociodemographic and clinical characteristics, as well as on outreach, referral, and admission patterns for an array of specialized VA services. FINDINGS: Of VA homeless service users, 8% were female compared with 7% among all homeless veterans, 6% among all VA service users, and 7% among all veterans. Of female VA homeless service users, 54% were literally homeless, slightly fewer than the 59% of male VA homeless service users. Comparing literally homeless VA service users, females were younger, 21% more had dependent children, 8% more were diagnosed with non-military-related posttraumatic stress disorder, and 19% to 20% more were referred and admitted to VA's supported housing program than males. CONCLUSIONS: Female veterans use VA homeless services at a rate similar to their use of general VA services and they have unique needs, especially for child care, which may require additional specialized resources. PMID- 24342076 TI - Focal adhesion kinase antagonizes doxorubicin cardiotoxicity via p21(Cip1.). AB - Clinical application of potent anthracycline anticancer drugs, especially doxorubicin (DOX), is limited by a toxic cardiac side effect that is not fully understood and preventive strategies are yet to be established. Studies in genetically modified mice have demonstrated that focal adhesion kinase (FAK) plays a key role in regulating adaptive responses of the adult myocardium to pathological stimuli through activation of intracellular signaling cascades that facilitate cardiomyocyte growth and survival. The objective of this study was to determine if targeted myocardial FAK activation could protect the heart from DOX induced de-compensation and to characterize the underlying mechanisms. To this end, mice with myocyte-restricted FAK knock-out (MFKO) or myocyte-specific expression of an active FAK variant (termed SuperFAK) were subjected to DOX treatment. FAK depletion enhanced susceptibility to DOX-induced myocyte apoptosis and cardiac dysfunction, while elevated FAK activity provided remarkable cardioprotection. Our mec6hanistic studies reveal a heretofore unappreciated role for the protective cyclin-dependent kinase inhibitor p21 in the repression of the pro-apoptotic BH3-only protein Bim and the maintenance of mitochondrial integrity and myocyte survival. DOX treatment induced proteasomal degradation of p21, which exacerbated mitochondrial dysfunction and cardiomyocyte apoptosis. FAK was both necessary and sufficient for maintaining p21 levels following DOX treatment and depletion of p21 compromised FAK-dependent protection from DOX. These findings identify p21 as a key determinant of DOX resistance downstream of FAK in cardiomyocytes and indicate that cardiac-restricted enhancement of the FAK/p21 signaling axis might be an effective strategy to preserve myocardial function in patients receiving anthracycline chemotherapy. PMID- 24342079 TI - Disproportionately harsh treatment for GP who married a patient's widower. PMID- 24342078 TI - A new role for Hedgehogs in juxtacrine signaling. AB - The Hedgehog pathway plays important roles in embryonic development, adult stem cell maintenance and tumorigenesis. In mammals these effects are mediated by Sonic, Desert and Indian Hedgehog (Shh, Dhh and Ihh). Shh undergoes autocatalytic cleavage and dual lipidation prior to secretion and forming a response gradient. Post-translational processing and secretion of Dhh and Ihh ligands has not previously been investigated. This study reports on the synthesis, processing, secretion and signaling activities of SHH, IHH and DHH preproteins expressed in cultured cells, providing unexpected evidence that DHH does not undergo substantial autoprocessing or secretion, and does not function in paracrine signaling. Rather, DHH functions as a juxtacrine signaling ligand to activate a cell contact-mediated HH signaling response, consistent with its localised signaling in vivo. Further, the LnCAP prostate cancer cell, when induced to express endogenous DHH and SHH, is active only in juxtacrine signaling. Domain swap studies reveal that the C-terminal domain of HH regulates its processing and secretion. These findings establish a new regulatory role for HHs in cell mediated juxtacrine signaling in development and cancer. PMID- 24342080 TI - Outpatient management of biliary colic: a prospective observational study of prescribing habits and analgesia effectiveness. AB - BACKGROUND: Uncomplicated biliary colic presents a significant health and financial burden to hospitals and primary care services alike. There is little guidance on the correct analgesia to use on an outpatient basis. This study aimed to evaluate the effectiveness of oral analgesics on biliary colic pain and to explore the prescribing habits of community doctors. METHODS: Consecutive patients with ultrasound proven symptomatic gallstones completed a questionnaire recording demographics and symptomatology. Pain was assessed using a visual analogue scale (VAS) based on the Biliary Symptom Score (BSS) to evaluate the effectiveness of various analgesic agents. Local General Practitioners were also surveyed to establish prescribing practices. RESULTS: Co-Codamol had the highest mean effectiveness VAS score (6.5/10). Patients with increased BMI, short symptom duration and a BSS >70 were most likely to suffer from severe pain. Patients in a subgroup with severe pain were most likely to have their pain reduced by NSAID analgesia compared to no NSAID (OR 2.20, p = 0.027). This effect remained significant upon multivariable regression (OR 2.52, p = 0.018) in a model containing age and NSAIDs. There was wide variation in the prescribing practice of GPs and hospital doctors. CONCLUSIONS: The range of drugs prescribed for biliary colic is extensive with little evidence base. In this study NSAIDs were the most effective analgesia for patients with severe pain. In the absence of contraindications to their use, physician education or guidance emphasizing the benefits of NSAIDs may potentially reduce symptomatic hospital presentation and admissions for biliary colic. PMID- 24342081 TI - Hepatic resection of non-colorectal and non-neuroendocrine liver metastases - survival benefit for patients with non-gastrointestinal primary cancers - a case controlled study. AB - PURPOSE: Whereas resection of colorectal liver metastases is gold standard, there is an ongoing debate on benefit of resection of non-colorectal (NCRC) and non neuroendocrine (NNEC) liver metastases. METHODS: The potential survival benefit of patients undergoing resection of NCRC or NNEC liver metastases was investigated. Data from a prospectively maintained database were reviewed over a 7-year period. Kaplan-Meier method was used for the evaluation of outcome following resection. RESULTS: 101 patients underwent 116 surgical procedures for synchronous and metachronous NCRC or NNEC liver metastases with a morbidity of 23% and a mortality of ~1%. 11 patients underwent repeated liver resection procedures. Overall 5-year survival after liver resection was 30% depending on primary tumour site. Median survival was significantly increased after resection of hepatic metastases from non-gastrointestinal primaries compared to gastrointestinal primaries. Resection of hepatic metastases from non gastrointestinal primaries resulted in significantly increased median survival compared to exploration only. Patients with hepatic metastases from gastrointestinal primaries did not benefit from hepatic surgery. CONCLUSION: Hepatic resection for liver metastases from NCRC or NNEC cancers is a save treatment procedure. However, the decision to perform surgery should depend on the primary cancer. Especially patients with liver metastases from non gastrointestinal primaries profit from hepatic surgery. PMID- 24342082 TI - Expression profiles of key phenylpropanoid genes during Vanilla planifolia pod development reveal a positive correlation between PAL gene expression and vanillin biosynthesis. AB - In Vanilla planifolia pods, development of flavor precursors is dependent on the phenylpropanoid pathway. The distinctive vanilla aroma is produced by numerous phenolic compounds of which vanillin is the most important. Because of the economic importance of vanilla, vanillin biosynthetic pathways have been extensively studied but agreement has not yet been reached on the processes leading to its accumulation. In order to explore the transcriptional control exerted on these pathways, five key phenylpropanoid genes expressed during pod development were identified and their mRNA accumulation profiles were evaluated during pod development and maturation using quantitative real-time PCR. As a prerequisite for expression analysis using qRT-PCR, five potential reference genes were tested, and two genes encoding Actin and EF1 were shown to be the most stable reference genes for accurate normalization during pod development. For the first time, genes encoding a phenylalanine ammonia-lyase (VpPAL1) and a cinnamate 4-hydroxylase (VpC4H1) were identified in vanilla pods and studied during maturation. Among phenylpropanoid genes, differential regulation was observed from 3 to 8 months after pollination. VpPAL1 was gradually up-regulated, reaching the maximum expression level at maturity. In contrast, genes encoding 4HBS, C4H, OMT2 and OMT3 did not show significant increase in expression levels after the fourth month post-pollination. Expression profiling of these key phenylpropanoid genes is also discussed in light of accumulation patterns for key phenolic compounds. Interestingly, VpPAL1 gene expression was shown to be positively correlated to maturation and vanillin accumulation. PMID- 24342083 TI - Impact of brassinosteroids and ethylene on ascorbic acid accumulation in tomato leaves. AB - Plant steroid hormones brassinosteroids (BRs) and the gaseous hormone ethylene (ET) alter the ascorbic acid-glutathione (AA-GSH) levels in tomato (Solanum lycopersicum L.) plants. The interaction of these hormones in regulating antioxidant metabolism is however unknown. The combined use of genetics (BR mutants) and chemical application (BR/ET-related chemicals) shows that BRs and ET signalling pathways interact, to regulate leaf AA content and synthesis. BR deficient (d(x)) leaves display low total AA but BR-accumulating (35S:D) leaves show normal total AA content. Leaves with either BR levels lower or higher than wild type plants showed a higher oxidised AA redox state. The activity of L galactono-1,4-lactone dehydrogenase (L-GalLDH), the mitochondrial enzyme that catalyses the last step in AA synthesis is lower in d(x) and higher in 35S:D plants. BR-deficient mutants show higher ET production but it is restored to normal levels when BR content is increased in 35S:D plants. Suppression of ET signalling using 1-methylcyclopropene in d(x) and 35S:D plants restored leaf AA content and L-GalLDH activity, to the values observed in wild type. The suppression of ET action in d(x) and 35S:D leaves leads to the respective decreasing and increasing respiration, indicating an opposite response compared to AA synthesis. This inverse relationship is lacking in ET suppressed d(x) plants in response to external BRs. The modifications in the in vivo activity of L-GalLDH activity do not correlate with changes in the level of the enzyme. Taken together, these data suggest that ET suppresses and BRs promote AA synthesis and accumulation. PMID- 24342085 TI - Degradation of ciprofloxacin and sulfamethoxazole by ferrous-activated persulfate: implications for remediation of groundwater contaminated by antibiotics. AB - The wide occurrence of antibiotics in groundwater raised great scientific interest as well as public awareness in recent years due to their potential ability to spread antibiotic resistant gene and pose risk to humans. The present study investigated the ferrous ion (Fe(II)) activated decomposition of persulfate (S2O8(2-)), as a potential in situ chemical oxidation (ISCO) approach, for remediation of groundwater contaminated by antibiotics. Fe(II)-persulfate mediated ciprofloxacin (CIP) degradation was found to be more efficient than sulfamethoxazole (SMX) at near neutral pH (pH6.0), probably due to the higher electric density in CIP molecule and its ability to form complex with Fe(II) as a ligand. Hydroxyl (HO) and sulfate radical (SO4(-)) were determined to be responsible for the degradation of CIP and SMX in Fe(II)-persulfate system by molecular probes. No enhancement in the degradation of CIP was observed when citrate (CA), ethylenediaminetetraacetate (EDTA) and (S,S)-ethylenediamine-N,N' disuccinate (EDDS) were used as Fe(II) chelating agents in Fe(II)-persulfate system. For SMX, CA and EDTA accelerated the degradation by Fe(II)-persulfate. Degradation of antibiotics in river water matrix was nearly the same as that in Milli-Q water, implying the possibility of using Fe(II)-persulfate for antibiotics depletion under environmentally relevant condition. A comparison of the degradation efficiency of SMX with other sulfonamides and sulfanilic acid indicated that the heterocyclic ring has a large impact on the degradation of sulfonamides. Transformation products of CIP and SMX by Fe(II)-persulfate were analyzed by solid phase extraction-liquid chromatography-mass spectrometry (SPE LC-MS) technique. Based on the intermediate products, Fe(II)-persulfate mediated CIP degradation pathways were tentatively proposed. PMID- 24342084 TI - Ancient signals: comparative genomics of green plant CDPKs. AB - Calcium-dependent protein kinases (CDPKs) are multifunctional proteins that combine calcium-binding and signaling capabilities within a single gene product. This unique versatility enables multiple plant biological processes to be controlled, including developmental programs and stress responses. The genome of flowering plants typically encodes around 30 CDPK homologs that cluster in four conserved clades. In this review, we take advantage of the recent availability of genome sequences from green algae and early land plants to examine how well the previously described CDPK family from angiosperms compares to the broader evolutionary states associated with early diverging green plant lineages. Our analysis suggests that the current architecture of the CDPK family was shaped during the colonization of the land by plants, whereas CDPKs from ancestor green algae have continued to evolve independently. PMID- 24342086 TI - Occurrence, behavior and distribution of high levels of uranium in shallow groundwater at Datong basin, northern China. AB - Geochemical investigations of uranium (U) occurrence in the environments were conducted at Datong basin of northern China. The results suggest that U contents were generally <1mg/kg for the igneous and metamorphic rocks, typically 2-5mg/kg for the Carboniferous and Permian sedimentary rocks and around 3mg/kg for sediments and topsoil, respectively. U in the Quaternary aquifer sediments may be primarily associated with carnotite from the Carboniferous and Permian coal bearing clastic rocks around the basin. Shallow groundwater had U concentrations of <0.02-288 MUg/L (average 24 MUg/L), with 24% of the investigated boreholes above the WHO provisional guideline of 30 MUg/L for U in drinking water. Average U concentration for surface water was 5.8 MUg/L. In oxidizing waters, uranyl (UO2(2+)) species is dominant and strongly adsorbed onto iron (hydro)xides, while it would be preferentially complexed with carbonate in the alkaline groundwater, forming highly soluble uranyl-carbonate complexes at Datong. Under reducing conditions, uranous (U(IV)) species is ready to precipitate or bind to organic matter, therefore having a low mobility. At the study area, high U groundwater (>30 MUg/L) occurs at the alluvial plains due to intermediate redox and enhanced alkaline conditions. The abnormally high levels of U in groundwater (>100 MUg/L) are locally found at the west alluvial plains. By contrast, U co-precipitation with secondary carbonate minerals like Ca2UO2(CO3)3 in the dominant Ca-Mg-Na-HCO3 type groundwater may prevail at the east alluvial plains. Besides, bedrocks such as Carboniferous and Permian sedimentary rocks, especially the coal-bearing strata which have higher U contents at the west mountain areas may also account for the abnormally high levels of U in groundwater. PMID- 24342087 TI - Characterization of soluble microbial products as precursors of disinfection byproducts in drinking water supply. AB - Water pollution by wastewater discharge can cause the problem of disinfection byproducts (DBPs) in drinking water supply. In this study, DBP formation characteristics of soluble microbial products (SMPs) as the main products of wastewater organic biodegradation were investigated. The results show that SMPs can act as DBP precursors in simulated wastewater biodegradation process. Under the experimental conditions, stabilized SMPs had DBPFP (DBP formation potential) yield of around 5.6 MUmol mmol(-1)-DOC (dissolved organic carbon) and DBP speciation profile different from that of the conventional precursor, natural organic matter (NOM). SMPs contained polysaccharides, proteins, and humic-like substances, and the latter two groups can act as reactive DBP precursors. SMP fraction with molecular weight of <1 kDa accounted for 85% of the organic carbon and 65% of the DBP formation. As small SMP molecules are more difficult to remove by conventional water treatment processes, more efforts are needed to control wastewater-derived DBP problem in water resource management. PMID- 24342088 TI - Natural sources of atmospheric aerosols influencing air quality across Europe. AB - Atmospheric aerosols are emitted by natural and anthropogenic sources. Contributions from natural sources to ambient aerosols vary widely with time (inter-annual and seasonal variability) and as a function of the distance to source regions. This work aims to identify the main natural sources of atmospheric aerosols affecting air quality across Europe. The origin, frequency, magnitude, and spatial and temporal variability of natural events were assessed for the years 2008 and 2009. The main natural sources of atmospheric aerosols identified were African dust, sea spray and wildfires. Primary biological particles were not included in the present work. Volcanic eruptions did not affect air quality significantly in Europe during the study period. The impact of natural episodes on air quality was significant in Southern and Western Europe (Cyprus, Spain, France, UK, Greece, Malta, Italy and Portugal), where they contributed to surpass the PM10 daily and annual limit values. In Central and Northern Europe (Germany, Austria and Latvia) the impact of these events was lower, as it resulted in the exceedance of PM daily but not annual limit values. Contributions from natural sources to mean annual PM10 levels in 2008 and 2009 ranged between 1 and 2 MUg/m(3) in Italy, France and Portugal, between 1 and 4 MUg/m(3) in Spain (10 MUg/m(3) when including the Canary Islands), 5 MUg/m(3) in UK, between 3 and 8 MUg/m(3) in Greece, and reached up to 13 MUg/m(3) in Cyprus. The evaluation of the number of monitoring stations per country reporting natural exceedances of the daily limit value (DLV) is suggested as a potential tool for air quality monitoring networks to detect outliers in the assessment of natural contributions. It is strongly suggested that a reference methodology for the identification and quantification of African dust contributions should be adopted across Europe. PMID- 24342089 TI - Single-bilayer graphene oxide sheet impacts and underlying potential mechanism assessment in germinating faba bean (Vicia faba L.). AB - This study investigates the impact of different single-bilayer graphene oxide sheet (hereafter 'graphene oxide', GO; size: 0.5-5 MUm) concentrations (0, 100, 200, 400, 800 and 1,600 mg L(-1)) and underlying potential mechanisms in germinating faba bean (Vicia faba L.) seedlings. The study revealed both positive and negative concentration-dependent GO-effects on V. faba. Significant negative impacts of GO concentrations (ordered by magnitude of effect: 1600>200>100 mg GO L(-1)) were indicated by decreases in growth parameters and the activity of H2O2 decomposing enzymes (ascorbate peroxidase, APX; catalase, CAT), and by increases in the levels of electrolyte leakage (EL), H2O2, and lipid and protein oxidation. The positive impacts of 400 and 800 mg GO L(-1) included significant improvements in V. faba health status indicated by decreased levels of EL, H2O2, and lipid and protein oxidation, and by enhanced H2O2-decomposing APX and CAT activity, and increased proline and seed-relative water content. V. faba seedlings-polypeptide patterns strongly substantiated these GO-concentration effects. Overall, the positive effects of these two GO concentrations (800>400 mg L(-1)) on V. faba seedlings indicate their safe nature and allow to suggest further studies. PMID- 24342090 TI - Aqueous photodegradation of sethoxydim herbicide: Qtof elucidation of its by products, mechanism and degradation pathway. AB - The photochemical fate of sethoxydim herbicide in water was studied under simulated sunlight radiation (Suntest apparatus). This compound exhibited a rapid degradation rate in water with a half-life of approximately 1h, which is in accordance with the high calculated value of the quantum yield (Phi=0.26). Consequently, the photolysis of sethoxydim should be considered as an efficient route of sethoxydim removal in aqueous media. During the photodegradation studies, ten by-products were detected, and their identification was accomplished using high-performance liquid chromatography (HPLC) coupled with quadrupole time of-flight mass spectrometry (Qtof) and electrospray ionization in positive mode (ESI+). A detailed and exhaustive study of the mass spectra of the precursor ions and their MS/MS fragmentation patterns allowed for their identification. The photodegradation products resulted from the cleavage and isomerization of the NO bond of the oxime, oxidation of the sulfur atom, oxidative CS bond cleavage and Beckmann rearrangement followed by intramolecular cyclization. Additionally, the reactive species involved and a plausible mechanism for the photodegradation of sethoxydim in water are discussed. Finally, based on the identified products, a rational pathway for the photodegradation of sethoxydim in water is proposed. PMID- 24342091 TI - Analysis of sediments and plants from the system of five fishponds in the Czech Republic using culture and PCR methods. AB - Nontuberculous mycobacteria (NTM) are ubiquitous organisms that have been isolated from a variety of environmental sources. Several NTM species are responsible for diseases in humans and/or animals known as mycobacterioses. The aim of this study was to determine the levels of NTM in the sediments and plants of five fish ponds in the Czech Republic using culture and quantitative real time PCR (qPCR). Additionally, we investigated if there was any link between environmental samples from the fish ponds and the fish occupying them. A total of 8 NTM (14.0%) were cultured from the aquatic environment. qPCR analysis showed that Mycobacterium avium hominissuis was most frequently present (54.4%), followed by Mycobacterium avium paratuberculosis (42.1%). The least frequently isolated NTM was Mycobacterium avium avium (5.3%). Thus, in this study we confirm the presence of mycobacteria in sediments and aquatic plants in fishponds, which are occupied by fish intended for human consumption. We successfully isolated NTM from the tissue of one fish and confirmed a possible transmission of mycobacteria from the aquatic environment to the fish. Consequently, the consumption of such fish represents a possible risk for consumers, particularly immunocompromised individuals. PMID- 24342092 TI - Occurrence of organochlorine contaminants (PCBs, PCDDs and PCDFs) and pathologic findings in loggerhead sea turtles, Caretta caretta, from the Adriatic Sea (Mediterranean Sea). AB - Livers of 12 loggerhead sea turtles, Caretta caretta from the Eastern Mediterranean Sea (Adriatic Sea) were analyzed for the presence of polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs). Pathological and microbiological studies were also carried out in order to provide a contribution to the knowledge of causes of Mediterranean turtle death. Boat-strike injuries, entanglement in derelict fishing nets and ingestion of hooks and monofilament lines are the causes of death most frequently observed. PCBs (average: 1,399 ng g(-1) fat basis) were the dominant chemicals, followed by PCDFs (average: 61 pg g(-1) fat basic) and PCDDs (average: 16 pg g(-1) fat basis). Hexachlorobiphenyl 153 accounted for the greatest proportion of the total PCBs, followed in order by PCB 138 and PCB 180 (14.1%). Mid-chlorinated, penta-through hepta-PCBs were among the top contributors to the sum of total PCBs, while the homolog pattern of PCCD/Fs was dominated by the tetra- to hexa-substituted congeners. In general the contamination level observed here was comparable with that reported in literature for specimens from different marine areas. Average TEQPCDD/Fs+Dl-PCBs concentration was 27.02 pg g(-1) wet weight (305.1 pg g(-1) lipid weight), with dioxin like-PCBs (93.4%) contributing much more to the total than PCDFs (3.9%) and PCDDs (2.7%). The appreciable concentration of TEQ would at first suggest that there are signs of potential threats to the health of these marine reptiles. Apart from PCBs, this is the first study documenting concentrations of PCDD/Fs in marine turtles from the Mediterranean Sea. Further investigations are urgently needed to characterize their contamination level for a better future protection and conservation of this endangered animal. PMID- 24342093 TI - A snapshot of illicit drug use in Sweden acquired through sewage water analysis. AB - Analytical measurements of sewage water have been used many times to estimate the consumption of specific drugs in an area. This study measured a large number of illicit drugs and metabolites (>30) at a large number of sewage treatment plants (STPs) distributed across Sweden. Twenty-four illicit and prescription drugs, classified as narcotic substances in Sweden, and seven selected metabolites were included in the study. A 24 hour composite sample of incoming sewage water was collected from 33 different municipalities at various geographic locations across Sweden. Species were analyzed using an on-line solid-phase extraction-liquid chromatography electrospray tandem mass spectrometry method. The method proved to be rapid with minimum need for sample work up and was able to detect 13 compounds above their respective limits of quantification. The results for all compounds were presented as per capita loads. Multivariate data analysis was used to relate drug consumption to geographical location and/or population of cities. The results showed that geographical differences in drug consumption were apparent across the country. For the narcotic pharmaceuticals, the geographical differences suggested by the multivariate model were supported by prescription statistics. PMID- 24342094 TI - Differential gene expression profiling analysis in workers occupationally exposed to benzene. AB - Benzene is an important industrial chemical and an environmental contaminant, but the pathogenesis of hematotoxicity induced by chronic occupational benzene exposure remains to be elucidated. To gain an insight into the molecular mechanisms and new biomarkers, microarray analysis was used to identify the differentially expressed mRNA critical for benzene hematotoxicity. RNA was extracted from four chronic benzene poisoning patients occupationally exposed to benzene, three benzene-exposed workers without clinical symptoms and three health controls without benzene exposure and mRNA expression profiling was performed using Gene Chip Human Gene 2.0ST Arrays. Analysis of mRNA expression profiles were conducted to identify key genes, biological processes and pathways by the series test of cluster (STC), STC-Gene Ontology analysis (STC-GO), pathway analysis and Signal-net. PRINCIPAL FINDINGS: 1) 1661 differentially expressed mRNAs were identified and assigned to sixteen model profiles. 2) Profiles 14, 10, 11, 1 and 15 are the predominant expression profiles which were involved in immune response, inflammatory response, chemotaxis, defense response, anti apoptosis and signal transduction. 3) The importance of immune response at benzene hematotoxicity is highlighted by several immune-related signaling pathways such as B/T cell receptor signaling pathway, acute myeloid leukemia, hematopoietic cell lineage and natural killer cell mediated cytotoxicity. 4) Signet analysis showed that PIK3R1, PIK3CG, PIK3R2, GNAI3, KRAS, NRAS, NFKB1, HLA DMA, and HLA-DMB were key genes involved in benzene hematotoxicity. These genes might be new biomarkers for the prevention and early diagnosis of benzene poisoning. This is a preliminary study that paves the way to further functional study to understand the underlying regulatory mechanisms. PMID- 24342095 TI - Source apportionment of particulate matter and selected volatile organic compounds with multiple time resolution data. AB - Fine particulate matter (PM2.5) and volatile organic compounds (VOCs) co-exist in ambient air and contribute to adverse health effects in human populations. This study was conducted to demonstrate the feasibility of utilizing a composite data set which included PM2.5 and VOC data with multiple time resolutions for source apportionment. Hourly VOC and 12-h PM2.5 speciation data were combined into an improved source apportionment model to quantify different pollutant source contributions to PM2.5 and VOC mixtures. Five factors were retrieved, including vehicle 1, vehicle 2, industrial processing, transported regional, and secondary pollution sources. The largest contributors were vehicular emissions for VOCs (62%) and PM2.5 (35%). Nonetheless, transported regional and secondary pollution sources accounted for a noteworthy portion of PM2.5 (27% and 25%, respectively) relative to VOCs (8% and 5%, respectively). Additional sensitivity analyses showed that excluding the PM2.5 data or reducing the associated temporal resolution (12-h to 24-h) retrieved fewer source factors and increased the errors of source contribution estimates. PMID- 24342097 TI - Modelling the propagation of smoke from a tanker fire in a built-up area. AB - The paper presents the application of a Lagrangian particle model to problems connected with safety in road transport. Numerical simulations were performed for a hypothetical case of smoke emission from a tanker fire in a built-up area. Propagation of smoke was analysed for three wind directions. A diagnostic model was used to determine the air velocity field, whereas the dispersion of pollutants was analysed by means of a Lagrangian particle model (Brzozowska, 2013). The Idrisi Andes geographic information system was used to provide data on landforms and on their aerodynamic roughness. The presented results of computations and their analysis exemplify a possible application of the Lagrangian particle model: evaluation of mean (averaged over time) concentrations of pollutants and their distribution in the considered area (especially important due to the protection of people, animals and plants) and simulation of the propagation of harmful compounds in time as well as performing computations for cases of the potential effects of road incidents. PMID- 24342096 TI - The lead (Pb) isotope signature, behaviour and fate of traffic-related lead pollution in roadside soils in The Netherlands. AB - In this study the origin, behaviour and fate of anthropogenic Pb in sandy roadside soils were assessed by measuring soil characteristics, Pb isotope composition and content. In 1991 and 2003 samples were taken at different depth intervals at approximately 8 and 75 m from two highways in The Netherlands. The Pb isotope composition of the litter layer ((206)Pb/(207)Pb=1.12-1.14) differs from the deeper soil samples ((206)Pb/(207)Pb=1.20-1.21). Based on a mixing model it is concluded that the samples contain two Pb sources: natural Pb and anthropogenic Pb, the latter mainly derived from gasoline. (206)Pb/(207)Pb ratios demonstrate that the roadside soils were polluted to a depth of ~15 cm. Within this depth interval, anthropogenic Pb content is associated with organic matter. Although Pb pollution only reached a depth of ~15 cm, this does not mean that the topsoils retain all anthropogenic Pb. Due to the low pH and negligible binding capacity of soils at depths >15 cm, anthropogenic Pb migrated towards groundwater after reaching depths of >15 cm. The Pb isotope composition of the groundwater ((206)Pb/(207)Pb=1.135-1.185) establishes that groundwater is polluted with anthropogenic Pb. The contribution of anthropogenic Pb to the groundwater varies between ~30 and 100%. Based on the difference in soil Pb content and Pb isotope compositions over a period of 12 years, downward Pb migration is calculated to vary from 72 +/- 95 to 324 +/- 279 mg m(-2)y(-1). Assuming that the downward Pb flux is constant over time, it is calculated that 35-90% of the atmospherically delivered Pb has migrated to the groundwater. PMID- 24342098 TI - Distribution and fate of perfluoroalkyl substances in Mediterranean Spanish sewage treatment plants. AB - The concentrations of 21 perfluoroalkyl substances (PFASs: C4-C14, C16, C18 carboxylates, C4, C6-C8 and C10 sulfonates and C8 sulfonamide) were determined in influent, effluent and sludge from 16 different sewage treatment plants (STPs) located in the Ebro (6), Guadalquivir (5), Jucar (2) and Llobregat (3) Rivers, in two consecutive years (2010 and 2011). The analytes were extracted by solid phase extraction (SPE) and determined by Liquid Chromatography triple Quadrupole Mass Spectrometer (LC-QqQ-MS). All samples, except two sludges from Guadalquivir River STPs, were contaminated with at least one PFAS. Perfluorobutanoate (PFBA), perfluoropentanoate (PFPeA) and perfluorooctane sulfonate (L-PFOS) were the most frequently detected. The highest concentration in water was determined in 2010 in a Guadalquivir River STP (perfluorohexanoate, PFHxA: 5.60MUgL(-1)) and, in 2011, in an Ebro River STP (perfluorobutane sulfonate, L-PFBS: 0.31MUgL(-1)). In sludge samples, the maximum concentration in 2010 was 1.79MUgg(-1)dry weight (dw) (L PFOS, in a Llobregat River STP), and in 2011, 1.88MUgg(-1)dw (PFBA, in one Guadalquivir River STP). High PFAS values in sludge could be related to positive removal efficiencies, and can be attributed to their adsorption. Distribution coefficients (Kd) were determined ranging between 0.32Lkg(-1) (perfluorohexane sulfonate, L-PFHxS) and 36.6 10(3)Lkg(-1) (PFBA). The total PFAS loads discharged into the basins showed high values for the Ebro River STPs (66.9gday(-1)) while in the others, the loads were between 3.97gday(-1), in the Jucar STPs, and 32.2gday(-1), in the Guadalquivir STPs. PMID- 24342099 TI - Field and modeling study of PBDEs uptake by three tree species. AB - A quantitative model was developed to predict the contributions of various pathways of taking up polybrominated diphenyl ethers (PBDEs) into leaves of three evergreen tree species, including soil-root-leaf pathway, soil-air-leaf pathway, and gaseous deposition. The contributions of soil-root-leaf pathway were negligible for PBDE accumulation in leaves. Soil-air-leaf pathway accounted for 16.3% and 3.8% of the total BDE-28 and BDE-47 levels in leaves, respectively; but for the PBDE congeners with log KAW<=-4 and log KOA>11, this pathway was ignorable. The contributions of gaseous deposition varied widely, accounting for 10%-50% for BDE-28, 100, 153, 154, and 183, 34%-96% for BDE-47, and <5% for BDE 209 of the measured concentrations in leaves of the three tree species. Therefore, direct atmosphere deposition without the influence of soil volatilization was a significant pathway for foliar uptake of BDE-47, 99, 100, 153, 154, and 183 on a background of low contaminated soil. For BDE-209, atmospheric particulate deposition dominates its foliar uptake. PMID- 24342100 TI - Spatio-temporal analysis of remotely-sensed forest mortality associated with road de-icing salts. AB - Forest mortality along highways has long been a concern in areas where de-icing compounds are applied during winter. This study combined the spatial advantage of high-resolution remote sensing imagery and the temporal advantage of long-term archival imagery to quantify forest mortality and to detect the subtle and chronic effects of road de-icing salts for a large mountain watershed in the Sierra Nevada Mountains, USA. IKONOS-derived mortality was used in a fine-scale spatial analysis to assess road proximity and roadside topography effects on forest mortality and to compare two potential mechanisms of de-icing salt damage, i.e. aerial deposition and soil uptake. These mechanisms were modeled using spatial proxy variables that were constructed from LiDAR topographical data. The analysis revealed a clear trend of increasing mortality with increasing potential for aerial deposition of de-icing salt onto tree crowns, mainly occurring within 10 m from roads. The effect of soil uptake of salt was weaker than that of aerial deposition but had a broader potential effect zone that extended to at least 100 m from roads. Landsat TM-derived mortality from 1989 to 2010 provided a long-term time series that indicated both immediate and lagged effects of salt application on forest mortality. Immediate effects of de-icing salt were only distinct in wet years when salt application and spray generation by passing traffic and snow plowing were likely high and other damaging factors, such as bark beetles or drought mortality, were likely weak. A strong and consistent one-year lag in the effect of salt application on incidence of mortality suggested that longer-term impacts of de-icing salt on forest health likely involved more complex pathways than simply aerial deposition. Our multi-scale remote sensing approach provided convincing evidence that de-icing salt was a significant factor for roadside forest mortality and allows for efficient future monitoring at the large watershed scale. PMID- 24342101 TI - Aromatic plants play an important role in promoting soil biological activity related to nitrogen cycling in an orchard ecosystem. AB - Aromatic plants can substantially improve the diversity and structure of arthropod communities, as well as reduce the number of herbivore pests and regulate the abundance of predators and parasitoids. However, it is not clear whether aromatic plants are also effective in improving soil quality by enhancing nutrient cycling. Here, field experiments are described involving intercropping with aromatic plants to investigate their effect on soil nitrogen (N) cycling in an orchard ecosystem. The results indicate that the soil organic nitrogen and available nitrogen contents increased significantly in soils intercropped with aromatic plants. Similarly, the activities of soil protease and urease increased, together with total microbial biomass involved in N cycling, including nitrifying bacteria, denitrifying bacteria and azotobacters, as well as the total numbers of bacteria and fungi. This suggests that aromatic plants improve soil N cycling and nutrient levels by enriching the soil in organic matter through the regulation of both the abundance and community structure of microorganisms, together with associated soil enzyme activity, in orchard ecosystems. PMID- 24342103 TI - Examining shifts in Carabidae assemblages across a forest-agriculture ecotone. AB - Northeastern U.S. farms are often situated adjacent to forestland due to the heterogeneous nature of the landscape. We investigated how forested areas influence Carabidae diversity within nearby crop fields by establishing transects of pitfall traps. Trapping extended across a forest-agriculture ecotone consisting of maize, an intermediate mowed grass margin, and a forest edge. Carabidae diversity was compared among the three habitats, and community and population dynamics were assessed along the transect. We used a principal response curve to examine and visualize community change across a spatial gradient. The highest levels of richness and evenness were observed in the forest community, and carabid assemblages shifted significantly across the ecotone, especially at the forest-grass interface. Despite strong ecotone effects, population distributions showed that some species were found in all three habitats and seemed to thrive at the ecotone. Based on similarity indices, carabid assemblages collected in maize adjacent to forest differed from carabid assemblages in maize not adjacent to forest. We conclude that forest carabid assemblages exhibit high degrees of dissimilarity with those found in agricultural fields and forested areas should thus be retained in agricultural landscapes to increase biodiversity at the landscape scale. However, ecotone species found at forest edges can still noticeably influence carabid community composition within neighboring agricultural fields. Further studies should determine how these shifts in carabid assemblages influence agroecosystem services in relation to ecosystem services observed in fields embedded in an agricultural matrix. PMID- 24342102 TI - Human health risk associated with exposure to toxic elements in mainstream and sidestream cigarette smoke. AB - Toxic particulate elements present in cigarette smoke pose health threats to the life of smokers due to direct inhalation and at the same time increase health risks to non-smokers present in the vicinity of smokers because of their exposure. This study conducted a series of experiments using a controlled experimental chamber, equipped with simulated smoking conditions for characterization of particulate trace elements in mainstream and sidestream cigarette smoke. Four popular commercial cigarette brands available in Singapore market were used in this study. The target elements for extraction and analysis were Al, As, B, Ba, Be, Bi, Ca, Cd, Co, Cr, Cs, Cu, Fe, Ga, Hg, K, Li, Mg, Mn, Na, Ni, Pb, Rb, Se, Sn, Sr, Te, Tl and Zn of both water-soluble and total constituents. The human health risk assessment results showed that the sidestream smoke had higher concentrations of toxic elements than those in the mainstream smoke. However, risk assessment analysis revealed that the sidestream smoke resulted in less human health risks compared to the mainstream smoke due to the influence of dilution of particulate emissions in sidestream smoke prior to inhalation exposure experienced by non-smokers. The cumulative non-cancer and cancer risks of toxic elements varied from 2.0 to 3.1 and from 398.4*10(-6) to 626.1*10(-6) due to inhalation of cigarette smoke by an active smoker. In the case of non-smokers, the risks were estimated under three possible cases of exposure. The cumulative cancer risks under three different cases were greater than the permissible limits. Therefore, it could be concluded that the toxic particulate elements present in cigarette smoke have significant carcinogenic and non-carcinogenic health effects due to inhalation exposure in the environment. PMID- 24342104 TI - High-dose chemotherapy and autologous stem cell transplantation in multiple myeloma: a single institution experience at All India Institute of Medical Sciences, New Delhi, using non-cryopreserved peripheral blood stem cells. AB - BACKGROUND: Intravenous high-dose melphalan has a short half-life, and application of this single drug in MM transplant favors the use of stem cells without cryopreservation, for wider use in general and in resource-limited settings in particular. PATIENTS AND METHODS: Ninety-two patients with MM were given high-dose melphalan and rescued with granulocyte colony stimulating factor (G-CSF) mobilized noncryopreserved autologous PBSC, in our hospital during the past 18 years. Stem cells were mobilized with 4 days of G-CSF, harvested (median CD34 dose, 2.9 * 10(6)/kg) and then stored at 4 degrees C in a refrigerator for a median of 2 days (range, 1-5 days) before reinfusion. RESULTS: Median time to neutrophil (> 500/mm(3)) and platelet (> 20,000/mm(3)) engraftment were 10 and 14 days respectively. There was no graft failure. Mucositis grade 3/4 was seen in 66 patients (72%). Transplant-related mortality at 100 days was 3.2%. The overall response to transplant was 88% and improvement compared with pretransplant status was seen in 48%. The median overall survival (OS) and progression-free survival (PFS) were 61.7 months and 35.4 months respectively; independent predictors of survival were Eastern Cooperative Oncology Group Performance Status and hemoglobin for OS and chemosensitive disease and remission status after transplant for PFS. CONCLUSION: We conclude that high-dose chemotherapy and autologous transplant with noncryopreserved PBSC is a simple, effective, and safe method for MM with equivalent results, and that cryopreservation is not necessary. It reduces the cost of transplant and avoids dimethyl sulfoxide toxicity. PMID- 24342105 TI - Acquired Glanzmann thrombasthenia associated with Hodgkin lymphoma: rapid reversal of functional platelet defect with ABVD (adriamycin/bleomycin/vinblastine/dacarbazine) chemotherapy. PMID- 24342106 TI - Emotion recognition in Parkinson's disease after subthalamic deep brain stimulation: differential effects of microlesion and STN stimulation. AB - Deep brain stimulation of the subthalamic nucleus (STN-DBS) has acquired a relevant role in the treatment of Parkinson's disease (PD). Despite being a safe procedure, it may expose patients to an increased risk to experience cognitive and emotional difficulties. Impairments in emotion recognition, mediated both by facial and prosodic expressions, have been reported in PD patients treated with such procedure. However, it is still unclear whether the STN per se is responsible for such changes or whether others factors like the microlesion produced by the electrode implantation may also play a role. In this study we evaluated facial emotions discrimination and emotions recognition using both facial and prosodic expressions in 12 patients with PD and 13 matched controls. Patients' were tested in four conditions: before surgery, both in on and off medication, and after surgery, respectively few days after STN implantation before turning stimulator on and few months after with stimulation on. We observed that PD patients were impaired in discriminating and recognizing facial emotions, especially disgust, even before DBS implant. Microlesion caused by surgical procedure was found to influence patients' performance on the discrimination task and recognition of sad facial expression while, after a few months of STN stimulation, impaired disgust recognition was again prominent. No impairment in emotional prosody recognition was observed both before and after surgery. Our study confirms that PD patients may experience a deficit in disgust recognition and provides insight into the differential effect of microlesion and stimulation of STN on several tasks assessing emotion recognition. PMID- 24342107 TI - Direct production of organic acids from starch by cell surface-engineered Corynebacterium glutamicum in anaerobic conditions. AB - We produced organic acids, including lactate and succinate, directly from soluble starch under anaerobic conditions using high cell-density cultures of Corynebacterium glutamicum displaying alpha-amylase (AmyA) from Streptococcus bovis 148 on the cell surface. Notably, reactions performed under anaerobic conditions at 35 and 40 degrees C, which are higher than the optimal growth temperature of 30 degrees C, showed 32% and 19%, respectively, higher productivity of the organic acids lactate, succinate, and acetate compared to that at 30 degrees C. However, alpha-amylase was not stably anchored and released into the medium from the cell surface during reactions at these higher temperatures, as demonstrated by the 61% and 85% decreases in activity, respectively, from baseline, compared to the only 8% decrease at 30 degrees C. The AmyA-displaying C. glutamicum cells retained their starch-degrading capacity during five 10 h reaction cycles at 30 degrees C, producing 107.8 g/l of total organic acids, including 88.9 g/l lactate and 14.0 g/l succinate. The applicability of cell surface-engineering technology for the production of organic acids from biomass by high cell-density cultures of C. glutamicum under anaerobic conditions was demonstrated. PMID- 24342108 TI - The two-component system NisK/NisR contributes to the virulence of Streptococcus suis serotype 2. AB - Two-component signal-transduction systems (TCSTSs) may regulate some virulence factors in response to external stimuli, and thus allowing Streptococcus suis serotype 2 to interact with the host, promote survival, and cause disease. Here, a mutant of the NisKR TCSTS had attenuated virulence in vitro, as exemplified by lowered hemolytic activity, reduced adherence to epithelial cells, increased elimination by macrophages, and decreased resistance to killing by neutrophils. Results also showed that this system is important for the ability of S. suis serotype 2 to survive and proliferate in an in vivo mouse model. Thus, the NisKR system plays a significant role in pathogenesis, both in colonization and invasive disease. PMID- 24342110 TI - Methyl angolensate and mexicanolide-type limonoids from the seeds of Cipadessa baccifera. AB - Six new methyl angolensate type (1-6) and three new mexicanolide-type (7-9) limonoids, along with six known limonoids (10-15), were isolated from the seeds of Cipadessa baccifera. The structures of all these compounds were established by extensive 1D, 2D NMR, and HRESIMS experiments, and structures of 11 and 13 were further confirmed by a single crystal X-ray diffraction analysis, which are reported for the first time. The cytotoxic activities of these isolates were also studied against A549, MCF7, ME-180, HT-29, B-16, ACHN cancer cell lines using MTT assay, and results indicated that compounds 4, 10, and 14 displayed potent cytotoxic activity against B-16, ACHN cell lines with an IC50 values of 8.51 and 7.0 MUg/mL, respectively. PMID- 24342109 TI - Macroline, akuammiline, sarpagine, and ajmaline alkaloids from Alstonia macrophylla. AB - A total of seventeen alkaloids, comprising six macroline (including alstofolinine A, a macroline indole incorporating a butyrolactone ring-E), two ajmaline, one sarpagine, and eight akuammiline alkaloids, were isolated from the stem-bark and leaf extracts of the Malayan Alstonia macrophylla. The structure and relative configurations of these alkaloids were established using NMR, MS and in several instances, confirmed by X-ray diffraction analysis. Six of these alkaloids were effective in reversing multidrug-resistance (MDR) in vincristine-resistant KB cells. PMID- 24342111 TI - Using plant chemistry and insect preference to study the potential of Barbarea (Brassicaceae) as a dead-end trap crop for diamondback moth (Lepidoptera: Plutellidae). AB - Barbarea vulgaris R. Br. has been proposed as a dead-end trap crop for diamondback moth, Plutella xylostella L. (Lepidoptera: Plutellidae), because its larvae do not survive on this plant species despite being highly preferred for oviposition. We compared plants of several species, varieties, and types in the genus Barbarea (Brassicaceae) to study their potential as trap crops for P. xylostella. In terms of insect behavior, Barbarea plants were assessed based on the criteria of high oviposition preference by P. xylostella moths (compared to other Barbarea plants and to three Brassica oleracea L. crop varieties) and low survival of P. xylostella larvae. Barbarea plants were also assessed based on the criteria of high content of glucosinolates, which stimulate adult oviposition and larval feeding in P. xylostella, and high content of saponins, which are detrimental to survival of P. xylostella larvae. All Barbarea plants tested were preferred over cabbage by ovipositing P. xylostella. Among Barbarea plants, few significant differences in oviposition preference by P. xylostella were found. Ovipositing P. xylostella preferred B. vulgaris plants containing mainly 2 phenylethylglucosinolate over B. vulgaris plants containing mainly (S)-2-hydroxy 2-phenylethylglucosinolate, and P-type B. vulgaris var. arcuata plants over Barbarea rupicola and B. vulgaris var. variegata plants. Despite containing a lower content of saponins than other Barbarea plants tested, Barbarea verna did not allow survival of P. xylostella larvae. Our studies show that, except for B. rupicola and P-type B. vulgaris var. arcuata, which allowed survival of P. xylostella larvae, all Barbarea plants tested have potential as dead-end trap crops for P. xylostella. PMID- 24342112 TI - Associations between mental disorders and subsequent onset of hypertension. AB - BACKGROUND: Previous work has suggested significant associations between various psychological symptoms (e.g., depression, anxiety, anger, alcohol abuse) and hypertension. However, the presence and extent of associations between common mental disorders and subsequent adult onset of hypertension remain unclear. Further, there are few data available on how such associations vary by gender or over life course. METHODS: Data from the World Mental Health Surveys (comprising 19 countries and 52,095 adults) were used. Survival analyses estimated associations between first onset of common mental disorders and subsequent onset of hypertension, with and without psychiatric comorbidity adjustment. Variations in the strength of associations by gender and by life course stage of onset of both the mental disorder and hypertension were investigated. RESULTS: After psychiatric comorbidity adjustment, depression, panic disorder, social phobia, specific phobia, binge eating disorder, bulimia nervosa, alcohol abuse and drug abuse were significantly associated with subsequent diagnosis of hypertension (with odds ratios ranging from 1.1 to 1.6). Number of lifetime mental disorders was associated with subsequent hypertension in a dose-response fashion. For social phobia and alcohol abuse, associations with hypertension were stronger for males than females. For panic disorder, the association with hypertension was particularly apparent in earlier-onset hypertension. CONCLUSIONS: Depression, anxiety, impulsive eating disorders and substance use disorders were significantly associated with the subsequent diagnosis of hypertension. These data underscore the importance of early detection of mental disorders, and of physical health monitoring in people with these conditions. PMID- 24342113 TI - The association between depressive disorders and health care utilization: results from the Sao Paulo ageing and health study (SPAH). AB - BACKGROUND: Although depressive disorders are associated with increased health care utilization in the elderly living in high-income countries, few studies have examined this relationship in Latin America. METHOD: The present study is part of the Sao Paulo Ageing and Health Study, a population-based epidemiological study of mental disorders in 2072 low-income adults >= 65 years old living in Sao Paulo, Brazil. Depressive disorders defined as major depressive disorder (MDD) and clinically relevant depressive symptoms (CRDS) were assessed with the Geriatric Mental State and the Neuropsychiatric Inventory. We examined the association between depressive disorders/symptoms and health care utilization (outpatient visits, hospital admissions and medication use in the past 3 months) using count models. RESULTS: The prevalence of MDD and CRDS was 4.9% and 21.4%, respectively. In the fully adjusted model, older adults with MDD were 36% more likely to have one more outpatient visit (RM: 1.36, 95% CI: 1.11-1.67), while older adults with CRDS were 14% more likely to have one more outpatient visit (RM: 1.14, 95% CI: 1.02-1.28). Elderly individuals with MDD had a prevalence of hospital admissions in the previous 3 months that was twice that of those without depression (PR=2.02, 95% CI: 1.09-3.75). Significant differences were not found for medication use. CONCLUSION: Among low-income older adults living in Brazil, those with MDD are more likely to have a recent hospital admission and outpatient service use than those without depression. Future studies are needed to examine the effectiveness of depression treatments for this population in order to both decrease the burden of illness as well as to minimize health care utilization related to depression. PMID- 24342114 TI - Determinants of a hopeful attitude among family caregivers in a palliative care setting. AB - OBJECTIVE: This study investigated the determinants of a hopeful attitude among family caregivers involved with palliative care. METHOD: We investigated a broad range of factors for the patient-family dyad in a palliative care setting using a cross-sectional design. The patients' sociodemographic, clinical and psychological factors were evaluated, as well as caregiver-related sociodemographic and psychological factors, including depressive symptoms, burden, coping style and religiosity. Caregivers were divided into two groups based on a hopeful or nonhopeful attitude and assessed using the abbreviated version of the seven-item Beck Hopelessness Scale (BHS-7). RESULTS: Of 304 analyzed dyads, 210 (69.1%) caregivers showed a hopeful attitude, with a BHS-7 score of 0. The adjusted logistic regression analyses showed that caregivers' hopeful attitude was determined by only their psychological status: less depressive symptoms [odds ratio (OR), 0.86; 95% confidence interval (CI), 0.83 0.90], active coping strategy (OR, 1.12; 95% CI, 1.07-1.18) and lower burden (OR, 0.93; 95% CI, 0.88-0.99). In a subpopulation analysis (n=200), higher religiosity was a significantly associated factor. CONCLUSION: Healthcare providers need to pay attention to the psychological vulnerability of caregivers to encourage a hopeful attitude. Additional studies of longitudinal design for hopeful attitude throughout the trajectory of palliative care are necessary. PMID- 24342115 TI - Efficacy of psychotherapy on diurnal cortisol patterns and suicidal ideation in adjustment disorder with depressed mood. AB - AIMS: The aims were to examine the effects of psychotherapy on depressive and anxiety symptoms, the occurrence of suicidal ideations and diurnal cortisol patterns in patients with adjustment disorder (AD) with depressed mood. METHODS: Participants recruited from an outpatient department of psychiatry at a general hospital were randomly assigned to one of two groups: 34 in psychotherapy group and 37 in control group. The control group consisted of one-session psychoeducation. Psychotherapy included the eight-weekly body-mind-spirit (BMS) group psychotherapy. Measures included Beck Depression Inventory-II and State Trait Anxiety Inventory. Salivary cortisol samples were collected from the patients at their homes on awakening; 30 and 45 min after awakening; and at 1200, 1700 and 2100 h. Measurements were taken at baseline and at months 2 (end of intervention), 5, 8 and 14. RESULTS: There was no differential change over time between the BMS and control groups in self-reported depression or anxiety symptoms. However, suicidal ideation appeared to be reduced in the psychotherapy group. Changes in diurnal cortisol patterns were also significantly different in group * time interactions, in favor of BMS group. CONCLUSIONS: Psychotherapy likely provides improvements in psychobiological stress responses and decreases the occurrence of suicidal ideation in patients with AD. PMID- 24342116 TI - Timely digits? PMID- 24342117 TI - Understanding the conundrums of viral assembly. PMID- 24342118 TI - [Does endoscopist fatigue play a role in incomplete colonoscopies and detection of polypoid lesions?]. AB - INTRODUCTION: Nowadays, the possible effect of endoscopist fatigue on the results of colonoscopies is under discussion. We aimed to analyze possible differences in cecal intubation and the polyp and adenoma detection rate, depending on whether colonoscopies were performed at the beginning or at the end of the daily endoscopy session and to analyze the influence of the queue position on the detection rate. PATIENTS AND METHODS: A retrospective study was performed with 1,000 ambulatory and consecutive colonoscopies, divided into 2 groups: "early" and "late" procedures. A total of 95 colonoscopies were excluded due to poor colon cleansing. After confirming that patient characteristics were homogenous in the two groups, we compared the frequency of complete colonoscopies and the polyp and adenoma detection rate. Possible differences between the 2 groups in the polyp detection rate according to the colonoscopy schedule were analyzed. RESULTS: The overall polyp and adenoma detection rates were 44.2 and 30.5%, respectively, with no significant differences among 13 different endoscopists; polyps: p = 0.21; adenomas: p=0.63. No significant differences were found between the "early group" (n= 532) and the "late group" (n = 373) in the rates of complete colonoscopies [97.2 vs 99.4% (p=0.92)], the polyp detection rate [45.9 vs 41.8% (p=0.23)], the adenoma detection rate [30.8 vs 30% (p=0.80)] or the serrated adenoma rate [2.1% vs 1.6% (p=0.62)]. The lesion detection rate did not vary in relation to the "queue position": polyps [p = 0.60, and adenomas: p = 0.83. CONCLUSIONS: In our series, endoscopist fatigue at the end of the day had no influence on the complete colonoscopy rate or on the polyp and adenoma detection rate. There were no differences in the number of polypoid lesions detected according to the timing of the colonoscopy schedule. PMID- 24342119 TI - [Eosinophilic enteritis, an infrequent cause of emergency surgery]. PMID- 24342120 TI - Re "Development of a scale-down model of hydrodynamic stress to study the performance of an industrial CHO cell line under simulated production scale bioreactor conditions" [Sieck, J.B., Cordes, T., Budach, W.E., Rhiel, M.H., Suemeghy, Z., Leist, C., Villiger, T.K., Morbidelli, M., Soos, M., 2013. Journal of Biotechnology 164, 41-49]. PMID- 24342121 TI - Safety of resuscitation with Ringer's acetate solution in severe burn (VolTRAB)- an observational trial. AB - BACKGROUND: A variety of crystalloids are available during fluid resuscitation of the severely burnt patient. There is a paucity of literature evidence on the comparative influence of these with regard to clinical outcomes. Significant differences in crystalloids may be clinically relevant given the large volumes employed during shock resuscitation. METHODS: The study compared two groups of severely burnt patients (TBSA 20-70%). Prospectively 40 consecutive patients treated with Ringer's acetate (RA group) against a retrospective control group of 40 patients treated with Ringer's lactate (RL group). Outcome parameters analysed included Sequential Organ Failure Assessment (SOFA)-scores at Days 3 and 7 after injury, mortality at 28 and 60 days, electrolyte and renal function, infection rates, cumulative volume administration and duration of ventilator support. RESULTS: Groups RA and RL were comparable w.r.t. age, total body surface area burn size and ABSI. SOFA-scores on Day 1 of admission also showed no significant difference but were significantly lower in RA group between the 3rd and 6th day. By Day 7 these differences could be attributed as a group effect (P=0.019). In particular low cardiovascular organ function scores contributed to this. Total crystalloid use within the first 28 days were equal in both but differed within the RA group having lower observed volumes of colloid and incidence of blood transfusion. Furthermore group RA had distinctly higher levels of platelets throughout treatment. Elevated lactate levels were noted in RL group during the initial three days. Survival rates at 28 days and 60 days showed no significant difference. CONCLUSION: Ringer's acetate solution is a suitable medium for the initial fluid management of the acutely burnt patient. In comparison to Ringer's lactate solution the study revealed lower SOFA-scores for Ringer's acetate solution (ClinicalTrials.gov number, NCT00609700). PMID- 24342122 TI - Mortality and treatment cost estimates for 1075 consecutive patients treated by a regional adult burn service over a five year period: the Liverpool experience. AB - OBJECTIVE: To assess the clinical outcomes and treatment costs of a regional adult burn service in northwest England. METHODS: We retrospectively reviewed data on a five year cohort of 1075 patients treated by the Mersey Regional Burn Service between 2006 and 2010 to obtain age-stratified mortality estimates based on the lethal area 50 (LA50) measure. Treatment cost estimates were made for a one year cohort of 262 patients treated between April 2011 and April 2012. RESULTS: 44 (4.1%) of the five year cohort died; 36 had suffered flame burns. Our LA50 was 71.08 for the 15-44 age group, 56.64 for the 45-64 age group, and 28.82 for the 65 and over age group. Mean treatment costs associated with patients allocated to different burn-specific healthcare resource groups ranged from L2527.77 to L31,870.95. Detailed cost estimates for three patients ranged from L12,553.23 to L66,029.33. CONCLUSION: The LA50 estimates for the Mersey Regional Burn Service compare favourably with previous reports in the literature. Our treatment costs were substantially lower compared to those reported previously in the United Kingdom. This study demonstrates that high quality and cost effective care can be delivered by a service that treats relatively few major burns (>70% TBSA). PMID- 24342123 TI - Acute effects of local cold therapy in superficial burns on pain, in vivo microcirculation, edema formation and histomorphology. AB - BACKGROUND: Local cold therapy for burns is generally recommended to relief pain and limit tissue damage, however, there is limited data of its physiological benefit. This study aimed to evaluate pathophysiological effects of cold therapy in superficial burn on microcirculation, edema formation, and histomorphology. METHODS: In 12 volunteers (8f, 4m; aged 30.4+/-14.1 years) circumscribed superficial burn was induced on both hand back and either left untreated as control (control-group) or treated by local-cold-application (cold-treatment group). Prior to burn (t0), immediately (t1), 15 min (t2), and 30 min (t3) following cold therapy, following parameter was evaluated using intravital microscopy; epidermal-thickness (ET), granular-cell-size (GCS), individual-blood cell-flow (IBCF), and functional-capillary-density (FCD). RESULTS: Both ET and GCS increased significantly more in control-group and slightly in cold-treatment group in t1, while turns to insignificant t2 onwards. IBCF and FCD raised up in control-group compared to dramatically decrease in cold-treatment-group in t1. In t2 both parameter remains in control-group and increased in cold-treatment-group. Comparison of both groups for IBCF and FCD indicates significant difference in t1 and t2, however, insignificant in t0 and t3. CONCLUSIONS: Microcirculation, edema formation, and histomorphology of superficial burn has been significantly influenced through immediate cold therapy, however, this alterations are transient and turns to ineffective after 30 min. PMID- 24342124 TI - Pharmacokinetic interactions between rebamipide and selected nonsteroidal anti inflammatory drugs in rats. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal and renal side effects. Rebamipide is a mucoprotective agent that reduces gastrointenstinal side effects when administered concomitantly with NSAIDs. In this study, we investigated the pharmacokinetic drug interactions of rebamipide with two selected NSAIDs, celecoxib or diclofenac. Rats were randomly divided into five groups. Two groups received placebo and three groups were administered rebamipide (30 mg/kg) orally twice daily for two days. On day 3, the animals treated with placebo received celecoxib (40 mg/kg) or diclofenac (10mg/kg) and rats receiving rebamipide were administerd rebamipide followed by a single dose of placebo, celecoxib, or diclofenac. To investigate drug protein interactions, blank rat plasma was spiked with known concentrations of rebamipide, diclofenac plus rebamipide, or celecoxib plus rebamipide then dialyzed through a Rapid Equilibrium Dialysis device. AUC (139.70+/-24.97 MUg h/mL), Cmax (42.99+/-2.98 MUg/mL), and CLoral (0.08+/-0.02 L/h/kg) values of diclofenac in diclofenac plus rebamipide group altered when compared to those of diclofenac treated groups. Treatment with rebamipide showed no significant change in pharmacokinetic parameters of celecoxib treated rats. Cmax (7.80+/-1.22 MUg/mL), AUC (56.46+/ 7.30 MUg h/mL), Vd/F (7.55+/-1.37 L/kg), and CLoral (0.58+/-0.09 L/h/kg) of rebamipide were significantly altered when diclofenac was co-administered with rebamipide. Pharmacokinetic parameters of rebamipide plus celecoxib group were not significantly different from those of rebamipide group. Plasma protein binding was not affected by concomitant administration of another drug. These results indicate alteration of pharmacokinetic parameters of both rebamipide and diclofenac when co-administered and cannot be explained by a variation in plasma protein binding. PMID- 24342125 TI - Inhibition of human cytochrome P450 enzymes by hops (Humulus lupulus) and hop prenylphenols. AB - As hops (Humulus lupulus L.) are used in the brewing of beer and by menopausal women as estrogenic dietary supplements, the potential for hop extracts and hop constituents to cause drug-botanical interactions by inhibiting human cytochrome P450 enzymes was investigated. Inhibition of major human cytochrome P450 enzymes by a standardized hop extract and isolated hop prenylated phenols was evaluated using a fast and efficient assay based on ultrahigh pressure liquid chromatography-tandem mass spectrometry. The hop extract at 5 MUg/mL inhibited CYP2C8 (93%), CYP2C9 (88%), CYP2C19 (70%), and CYP1A2 (27%) with IC50 values of 0.8, 0.9, 3.3, and 9.4 MUg/mL, respectively, but time-dependent inactivation was observed only for CYP1A2. Isoxanthohumol from hops was the most potent inhibitor of CYP2C8 with an IC50 of 0.2 MUM, whereas 8-prenylnaringenin was the most potent inhibitor of CYP1A2, CYP2C9 and CYP2C19 with IC50 values of 1.1 MUM, 1.1 MUM and 0.4 MUM, respectively. Extracts of hops contain prenylated compounds such as the flavanones isoxanthohumol and 8-prenylnaringenin and the chalcone xanthohumol that can inhibit CYP450s, especially the CYP2C family, which may affect the efficacy and safety of some CYP2C substrate drugs when co-administered. PMID- 24342126 TI - Applicability of a high-throughput shotgun plasma protein screening approach in understanding maternal biological pathways relevant to infant birth weight outcome. AB - There are reports linking maternal nutritional status, smoking and environmental chemical exposures to adverse pregnancy outcomes. However, biological bases for association between some of these factors and birth outcomes are yet to be established. The objective of this preliminary work is to test the capability of a new high-throughput shotgun plasma proteomic screening in identifying maternal changes relevant to pregnancy outcome. A subset of third trimester plasma samples (N=12) associated with normal and low-birth weight infants were fractionated, tryptic-digested and analyzed for global proteomic changes using a MALDI-TOF-TOF MS methodology. Mass spectral data were mined for candidate biomarkers using bioinformatic and statistical tools. Maternal plasma profiles of cytokines (e.g. IL8, TNF-alpha), chemokines (e.g. MCP-1) and cardiovascular endpoints (e.g. ET-1, MMP-9) were analyzed by a targeted approach using multiplex protein array and HPLC-Fluorescence methods. Target and global plasma proteomic markers were used to identify protein interaction networks and maternal biological pathways relevant to low infant birth weight. Our results exhibited the potential to discriminate specific maternal physiologies relevant to risk of adverse birth outcomes. This proteomic approach can be valuable in understanding the impacts of maternal factors such as environmental contaminant exposures and nutrition on birth outcomes in future work. BIOLOGICAL SIGNIFICANCE: We demonstrate here the fitness of mass spectrometry-based shot-gun proteomics for surveillance of biological changes in mothers, and for adverse pathway analysis in combination with target biomarker information. This approach has potential for enabling early detection of mothers at risk for low infant birth weight and preterm birth, and thus early intervention for mitigation and prevention of adverse pregnancy outcomes. This article is part of a Special Issue entitled: Can Proteomics Fill the Gap Between Genomics and Phenotypes? PMID- 24342127 TI - Robot-assisted radical nephroureterectomy for upper urinary tract urothelial carcinoma: a promising alternative to open surgery or a future "gold standard"? PMID- 24342128 TI - Preoperative androgen deprivation therapy for localized prostate cancer: delayed biochemical recurrence in high-risk disease. AB - BACKGROUND: The role of preoperative ADT for localized prostate cancer is controversial; prospective assessments have yielded varying results. We sought to define a subset of patients with a higher likelihood of benefit from preoperative ADT. PATIENTS AND METHODS: An institutional database including consecutive patients receiving definitive surgery for localized prostate cancer was interrogated. Patients recorded as having received preoperative ADT were matched in a 1:2 fashion to patients who had not received previous ADT. Patients were matched on the basis of clinicopathologic characteristics, use of adjuvant treatment strategies, and duration of prostate-specific antigen follow-up. Time to biochemical recurrence (TTBR) was compared using the Kaplan-Meier method and log-rank test for the overall study population and in subsets defined according to D'Amico risk. RESULTS: No significant differences in clinicopathologic characteristics were noted between recipients (n = 101) and matched nonrecipients (n = 196) of preoperative ADT. Although not statistically significant, positive surgical margin rates, seminal vesicle invasion, and extracapsular extension were less frequent in patients receiving preoperative ADT. Furthermore, a lesser incidence of perioperative complications was noted in this group (7.4% vs. 18.4%). No significant differences were noted in TTBR between recipients and nonrecipients of preoperative ADT in the overall study population. However, among patients with high-risk disease, TTBR was significantly longer in patients who had received preoperative ADT (P = .004). CONCLUSION: The data presented herein suggest a potential benefit of preoperative ADT in patients with high-risk localized prostate cancer. Consideration should be given to enriching for this subset in preoperative studies of novel endocrine therapies. PMID- 24342129 TI - Effects of symmetric and asymmetric dispersal on the dynamics of heterogeneous metapopulations: two-patch systems revisited. AB - Although the effects of dispersal on the dynamics of two-patch metapopulations are well studied, potential interactions between local dynamics and asymmetric dispersal remain unexplored. We examined the dynamics of two Ricker models coupled by symmetric or asymmetric constant-fraction dispersal at different rates. Unlike previous studies, we extensively sampled the r1-r2 space and found that stability of the coupled system was markedly affected by interactions between dispersal (in terms of strength and asymmetry) and local dynamics. When both subpopulations were intrinsically chaotic, increased symmetry in the exchange of individuals had a greater stabilizing impact on the dynamics of the system. When one subpopulation showed considerably more unstable dynamics than the other, higher asymmetry in the exchange of individuals had a stabilizing or destabilizing effect on the dynamics depending on whether the net dispersal bias was from the relatively stable to the relatively unstable subpopulation, or vice versa. The sensitivity of chaotic dynamics to stabilization due to dispersal varied with r-value in the chaotic subpopulation. Under unidirectional or bidirectional symmetric dispersal, when one subpopulation was intrinsically chaotic and the other had stable dynamics, the stabilization of chaotic subpopulations with r~3.3-4.0 occurred at the lowest dispersal rates, followed by chaotic subpopulations with r~2.7-2.95 and, finally, chaotic subpopulations with r~2.95-3.3. The mechanism for this pattern is not known but might be related to the range and number of different attainable population sizes possible in different r-value zones. PMID- 24342131 TI - Construction of energy transfer pathways self-assembled from DNA-templated stacks of anthracene. AB - We describe optical properties of anthracene stacks formed from single-component self-assembly of thymidylic acid-appended anthracene 2,6-bis[5-(3'-thymidylic acid)pentyloxy] anthracene (TACT) and the binary self-assembly of TACT and complementary 20-meric oligoadenylic acid (TACT/dA20) in an aqueous buffer. UV Vis and emission spectra for the single-component self-assembly of TACT and the binary self-assembly of TACT/dA20 were very consistent with stacked acene moieties in both self-assemblies. Interestingly, time-resolved fluorescence spectra from anthracene stacks exhibited very different features of the single component and binary self-assemblies. In the single-component self-assembly of TACT, a dynamic Stokes shift (DSS) and relatively short fluorescence lifetime (tau=0.35ns) observed at around 450nm suggested that the anthracene moieties were flexible. Moreover, a broad emission at 530nm suggested the formation of an excited dimer (excimer). In the binary self-assembly of TACT/dA20, we detected a broad, red-shifted emission component at 534nm with a lifetime (tau=0.4ns) shorter than that observed in the TACT single-component self-assembly. Combining these results with the emission spectrum of the binary self-assembly of TACT/5' HEX dA20, we concluded that the energy transfer pathway was constructed by columnar anthracene stacks formed from the DNA-templated self-assembly of TACT. PMID- 24342130 TI - Fish oil improves motor function, limits blood-brain barrier disruption, and reduces Mmp9 gene expression in a rat model of juvenile traumatic brain injury. AB - The effects of an oral fish oil treatment regimen on sensorimotor, blood-brain barrier, and biochemical outcomes of traumatic brain injury (TBI) were investigated in a juvenile rat model. Seventeen-day old Long-Evans rats were given a 15mL/kg fish oil (2.01g/kg EPA, 1.34g/kg DHA) or soybean oil dose via oral gavage 30min prior to being subjected to a controlled cortical impact injury or sham surgery, followed by daily doses for seven days. Fish oil treatment resulted in less severe hindlimb deficits after TBI as assessed with the beam walk test, decreased cerebral IgG infiltration, and decreased TBI-induced expression of the Mmp9 gene one day after injury. These results indicate that fish oil improved functional outcome after TBI resulting, at least in part from decreased disruption of the blood-brain barrier through a mechanism that includes attenuation of TBI-induced expression of Mmp9. PMID- 24342132 TI - Synthesis, characterization and crystal structure of cobalt(III) complexes containing 2-acetylpyridine thiosemicarbazones: DNA/protein interaction, radical scavenging and cytotoxic activities. AB - The synthesis, structure and biological studies of cobalt(III) complexes supported by NNS-tridentate ligands are reported. Reactions of 2-acetylpyridine N substituted thiosemicarbazone (HL(1-3)) with [CoCl2(PPh3)2] resulted [Co(L(1 3))2]Cl (1-3) which were characterized by elemental analysis and various spectral studies. The molecular structure of the complex 1 has been determined by single crystal X-ray diffraction studies. In vitro DNA binding studies of complexes 1-3 carried out by fluorescence studies and the results revealed the binding of complexes to DNA via intercalation. The binding constant (Kb) values of complexes 1-3 from fluorescence experiments showed that the complex 3 has greater binding propensity for DNA. The DNA cleavage activity of the complexes 1 and 3 were ascertained by gel electrophoresis assay which revealed that the complexes are good DNA cleavage agents. Further, the interactions of the complexes with bovine serum albumin (BSA) were also investigated using fluorescence spectroscopic method, which showed that the complexes 1-3 could bind strongly with BSA. The antioxidant property of the complexes was evaluated to test their free-radical scavenging ability. Furthermore, in vitro cytotoxicity of the complexes against MCF-7 and A431 cell lines was assayed which showed higher activity and efficiently vanished the cancer cells even at low concentrations. PMID- 24342133 TI - Impact of drought on vector-borne diseases--how does one manage the risk? AB - OBJECTIVES: This article aimed to review all literature on drought and vector borne disease to enable an assessment of the possible impact of drought on the changing risk of vector-borne diseases in the UK. STUDY DESIGN: A systematic literature review was performed. METHODS: Using a search strategy developed from a combination of terms for drought and selected outcomes, the authors systematically reviewed all available literature from 1990 to 2012 on the impact of drought on vector-borne diseases. The following databases were searched: PubMed, Web of Science, and EMBASE. After reviewing the abstracts, 38 articles were found to fit the inclusion and exclusion criteria. RESULTS: Evidence found drought followed by re-wetting can have a substantial effect on water table levels, vegetation, and aquatic predators; all factors which influence mosquito populations. Several studies found an association between a drought during the previous year and West Nile virus incidence. Urban mosquito vectors of dengue virus and chikungunya virus are adaptable by nature and are able to exploit a multitude of additional aquatic habitats created as a response to drought (i.e. water storage containers). Tick populations are likely to be negatively affected by drought as they are dependent upon high levels of humidity and soil moisture. CONCLUSIONS: Further research is needed to identify public health interventions and environmental control measures for an invasive mosquito problem or arthropod borne disease outbreak in the UK. PMID- 24342135 TI - Well-being: its influence and local impact on public health. AB - OBJECTIVES: To explore the emergence of the concept of well-being and examine its influences on the modernization of the public health structure at the local level. STUDY DESIGN: The article applies a theoretical and policy orientated approach. METHODS: The article assesses the concept of well-being and applies its uses to local policy and practice. RESULTS: The concept of well-being has implications for the development of local public health structures, policy making and delivery. CONCLUSIONS: In terms of local policy making, it enables public health professionals to develop locally based concepts and uses of well-being, engage communities, make links to social capital and consider wider determinants within them. In terms of delivery, it focuses attention on the need for collaboration between local statutory and voluntary organizations in applying local concepts of well-being to public health policy; and engaging with healthcare interventions grounded within local context and needs. PMID- 24342134 TI - Solid fuel use is a major risk factor for acute coronary syndromes among rural women: a matched case control study. AB - OBJECTIVES: Almost half of the world's population uses solid fuel for cooking, exposing women to high levels of particulate pollution in indoor air. The risk of acute coronary syndrome (ACS) was assessed among rural women, according to their use of solid fuel. STUDY DESIGN: Matched case control study. METHODS: Data were collected at a public tertiary care hospital in a rural district of Pakistan. Seventy-three women with ACS were compared with controls, individually matched for sex and age (+/- 5 years), who were admitted to hospital for other reasons. Fuels used for cooking and exposures to potentially confounding variables were ascertained through a questionnaire administered at interview and measurement of height and weight. Conditional logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (95% CIs). RESULTS: After adjustment for potential confounding factors, current use of solid fuel was strongly associated with ACS (OR 4.8, 95% CI: 1.5-14.8), and risk was lowest in women who had last used solid fuel more than 15 years earlier. The population attributable fraction for ACS in relation to current use of solid fuel was 49.0% (95% CI: 41.3%-57.4%). CONCLUSIONS: These findings support the hypothesis that indoor air pollution from use of solid fuel is an important cause of ACS. Our study demonstrates the feasibility of case-control studies in rural populations of women to address this question, and is an encouragement to larger and statistically more powerful investigations. PMID- 24342136 TI - Risk factors for double primary malignancies and their clinical implications in patients with sporadic gastric cancer. AB - AIMS: We carried out a large scale study to identify the risk factors for double primary malignancy (DPM) development in gastric cancer patients and to evaluate the clinical implications for these patients. METHODS: A total of 2593 patients who underwent gastrectomy for primary gastric cancer from January 2005 to November 2010 were reviewed with regard to DPM. We compared the clinicopathological characteristics, risk factors for developing DPM, and prognosis between the DPM+ group and the DPM- group. RESULTS: Of the 2593 patients, 152 (5.9%) were diagnosed with DPM. The most common accompanying malignancies were colorectal, lung and thyroid. Multivariate analysis indicated that age (p = 0.016) and MSI status (p = 0.002) were associated with a higher frequency of DPM. 30.3% of patients were diagnosed with DPM within 1 year around perioperative period and 53.3% of patients had DPM detected during 5 years of post-operative follow up periods. Although there was no significant difference in overall survival between the DPM+ and DPM- group, DPM+ patients had a worse prognosis than DPM- patients in stage I gastric cancer. CONCLUSIONS: Gastric cancer patients over the age of 60 or with a MSI-high status had an increased risk for developing DPM. Further, in stage I gastric cancer, the presence of DPM was associated with a worse prognosis. Therefore, careful pre- and postoperative surveillance is especially important in these patients. PMID- 24342137 TI - Correction: Design and synthesis of tetrahydrophthalimide derivatives as inhibitors of HIV-1 reverse transcriptase. PMID- 24342138 TI - Response to Gallup et al.: are rich interpretations of visual self-recognition a bit too rich? PMID- 24342139 TI - Torradoviruses are transmitted in a semi-persistent and stylet-borne manner by three whitefly vectors. AB - Members of the genus Torradovirus (family Secoviridae, type species Tomato torrado virus, ToTV) are spherical plant viruses transmitted by the whitefly species Trialeurodes vaporariorum and Bemisia tabaci. Knowledge on the mode of vector transmission is lacking for torradoviruses. Here, the mode of transmission was determined for Tomato marchitez virus (ToMarV). A minimal acquisition access period (AAP) and inoculation access period (IAP) of approximately 2h each was required for its transmission by T. vaporariorum, while optimal transmission required an AAP and IAP of at least 16h and 8h, respectively. Whiteflies could retain the virus under non-feeding conditions for at least 8h without loss of transmission efficiency, but upon feeding on a non-host plant in between the AAP and IAP they retained the virus for no more than 8h. Similar conditions supported transmission of isolates of ToTV and Tomato chocolate virus (ToChV) by T. vaporariorum and B. tabaci. Additionally, similar experiments revealed the banded winged whitefly (Trialeurodes abutilonea) as a vector for all three virus species. The results are congruent with acquisition and retention periods for semi-persistent virus transmission. RT-PCR detection analysis of ToTV and ToMarV in the vector's body revealed their presence in the stylet, but not in the head where the pharynx of the foregut is located. The results altogether indicate a semi-persistent stylet-borne mode of vector transmission for torradoviruses. Additionally, this is the first group of spherical viruses transmitted by at least three different species of whiteflies. PMID- 24342140 TI - Development of a novel DNA-launched dengue virus type 2 infectious clone assembled in a bacterial artificial chromosome. AB - Major progress in Dengue virus (DENV) biology has resulted from the use of infectious clones obtained through reverse genetics. The construction of these clones is commonly based on high- or low-copy number plasmids, yeast artificial chromosomes, yeast-Escherichia coli shuttle vectors, and bacterial artificial chromosomes (BACs). Prokaryotic promoters have consistently been used for the transcription of these clones. The goal of this study was to develop a novel DENV infectious clone in a BAC under the control of the cytomegalovirus immediate early promoter and to generate a virus with the fusion envelope-green fluorescent protein in an attempt to track virus infection. The transfection of Vero cells with a plasmid encoding the DENV infectious clone facilitated the recovery of infectious particles that increased in titer after serial passages in C6/36 cells. The plaque size and syncytia phenotypes of the recombinant virus were similar to those of the parental virus. Despite the observation of autonomous replication and the detection of low levels of viral genome after two passages, the insertion of green fluorescent protein and Renilla luciferase reporter genes negatively impacted virus rescue. To the best of our knowledge, this is the first study using a DENV infectious clone under the control of the cytomegalovirus promoter to facilitate the recovery of recombinant viruses without the need for in vitro transcription. This novel molecular clone will be useful for establishing the molecular basis of replication, assembly, and pathogenesis, evaluating potential antiviral drugs, and the development of vaccine candidates for attenuated recombinant viruses. PMID- 24342141 TI - Detection of Quang Binh virus from mosquitoes in China. AB - Flaviviruses present a wide range of genetic diversity and exhibit diverse host relationships. Mosquito-borne flaviviruses have recently been isolated and characterized worldwide. Yunnan Province of China is one of the richest areas of species diversity and is the center of multi-species evolution in mainland Asia, which supports the circulation of numerous arthropod-borne viruses (arboviruses). In a screening program of arboviruses, mosquitoes were collected during the mosquito activity season in the Yunnan Province from 2007 to 2010. Eleven flavivirus strains, named Yunnan Culex flaviviruses (YNCxFVs), were obtained from Culex tritaeniorhynchus and Anopheles sinensis specimens. Sequence analyses based on partial nonstructural protein (NS) 5 gene indicated that the YNCxFVs shared 92.8-99.6% nucleotide identity with each other and were similar to the Culex related flaviviruses. The complete genome of one representative isolate, LSFlaviV A20-09, was sequenced. The genome was 10,865 nucleotides long and contained a single, long open reading frame (ORF) of 10,080 nucleotides that encoded a 3360 aa polyprotein. This genome was most closely related to the Quang Binh virus (QBV) VN180 strain, an insect-specific flavivirus isolated from Culex mosquitoes in Vietnam, but only had 83.0% nucleotide and 93.8% amino acid identities for the ORF sequence. The genome has approximately 66.3%-68.5% nucleotide sequence and 69.3-73.3% amino acid sequence identities to other Culex flaviviruses, and only has 47.9-57.9% nucleotide sequence and 38.7-55.1% amino acid sequence identities to Coquillettidia-related, Mansonia-related and Aedes-related flaviviruses. Phylogenetic analyses revealed that the LSFlaviV-A20-09 fell into the Culex related flavivirus clade. Our discoveries provide more information regarding the heterogeneity of viruses that infect mosquitoes. PMID- 24342142 TI - LncRNA profiling reveals new mechanism for VDR protection against skin cancer formation. AB - Accumulating evidence strongly suggests a protective role of vitamin D signaling against chemical and UVR-induced skin cancer formation. However, the mechanism remains largely unknown. Recently, the emerging role of long, non-coding RNA (lncRNA) as a hallmark of cancer has become better appreciated. LncRNAs are mRNA like transcripts ranging in length from 200 bases to 100kb lacking significant open reading frames, which are involved in a broad spectrum of tumorigenic/metastatic processes. In this study we profiled 90 well-annotated mouse lncRNAs from cultured mouse keratinocytes after deleting the vitamin D receptor (VDR) (~90%) vs. control cells using an lncRNA array analysis. We found that several well-known oncogenes, including H19, HOTTIP and Nespas, are significantly increased (6.3-1.8-fold), whereas tumor suppressors (Kcnq1ot1, lincRNA-p21) are decreased (up to 50-70%) in VDR deleted keratinocytes. A similar pattern of lncRNA profiling is observed in the epidermis of K14 driven, tamoxifen regulated epidermal-specific VDR null vs. wild-type control mice. Additionally there is an increase in the expression levels of other oncogenes (mHOTAIR, Malat1 and SRA) and a decrease of other tumor suppressors (Foxn2-as, Gtl2-as, H19-as). The increased expression levels of HOTTIP and H19 were further confirmed by real time PCR analysis with individually designed primer sets. The major finding of this study is a novel mechanism for protection by VDR against skin cancer formation by maintaining the balance of oncogenic to tumor suppressing lncRNAs. In keratinocytes lacking VDR this balance is disturbed with increased expression of oncogenes and decreased expression of tumor suppressors, a mechanism that predisposes the VDR deficient mice to skin cancer formation. This article is part of a Special Issue entitled "Vitamin D Workshop". PMID- 24342143 TI - Change in sexual function in men with lower urinary tract symptoms/benign prostatic hyperplasia associated with long-term treatment with doxazosin, finasteride and combined therapy. AB - PURPOSE: We examined the effects of doxazosin, finasteride and combined therapy in men with lower urinary tract symptoms associated with benign prostatic hyperplasia on sexual function, as assessed by the Brief Male Sexual Function Inventory during 4 years. MATERIALS AND METHODS: The MTOPS (Medical Therapy of Prostatic Symptoms) study was a multicenter, randomized, double-blind, placebo controlled clinical trial with a primary outcome of time to benign prostatic hyperplasia progression. Change in sexual function was a secondary outcome. We analyzed the records of 2,783 men enrolled in the study who completed the inventory at baseline and at least once during followup. RESULTS: In men enrolled in MTOPS sexual function decreased with time. Men assigned to finasteride and combined therapy experienced overall statistically significant but slight worsening of ejaculatory function compared with men on placebo. Men assigned to combined therapy also experienced significant worsening in erectile function and sexual problem assessment. There was no significant difference in changes in any inventory domain in men assigned to doxazosin alone compared to placebo. CONCLUSIONS: This study significantly extends understanding of the effects of long-term treatment with these drugs on sexual function in men with lower urinary tract symptoms associated with benign prostatic hyperplasia. Treatment with finasteride or combined therapy was associated with worsening sexual function while treatment with doxazosin alone was associated with minimal negative impact, if any. Physicians should discuss with their patients the possible long-term effects of these drugs for lower urinary tract symptoms associated with benign prostatic hyperplasia on sexual function. PMID- 24342144 TI - Alvimopan, a peripherally acting MU-opioid receptor antagonist, is associated with reduced costs after radical cystectomy: economic analysis of a phase 4 randomized, controlled trial. AB - PURPOSE: We evaluated the effect of alvimopan treatment vs placebo on health care utilization and costs related to gastrointestinal recovery in patients treated with radical cystectomy in a randomized, phase 4 clinical trial. MATERIALS AND METHODS: Resource utilization data were prospectively collected and evaluated by cost consequence analysis. Hospital costs were estimated from 2012 Medicare reimbursement rates and medication wholesale acquisition costs. Differences in base case mean costs between the study cohorts for total postoperative ileus related costs (hospital days, study drug, nasogastric tubes, postoperative ileus related concomitant medication and postoperative ileus related readmissions) and total combined costs (postoperative ileus related, laboratory, electrocardiograms, nonpostoperative ileus related concomitant medication and nonpostoperative ileus related readmission) were evaluated by probabilistic sensitivity analysis using a bootstrap approach. RESULTS: Mean hospital stay was 2.63 days shorter for alvimopan than placebo (mean+/-SD 8.44+/-3.05 vs 11.07+/ 8.23 days, p=0.005). Use of medications or interventions likely intended to diagnose or manage postoperative ileus was lower for alvimopan than for placebo, eg total parenteral nutrition 10% vs 25% (p=0.001). Postoperative ileus related health care costs were $2,340 lower for alvimopan and mean total combined costs were decreased by $2,640 per patient for alvimopan vs placebo. Analysis using a 10,000-iteration bootstrap approach showed that the mean difference in postoperative ileus related costs (p=0.04) but not total combined costs (p=0.068) was significantly lower for alvimopan than for placebo. CONCLUSIONS: In patients treated with radical cystectomy alvimopan decreased hospitalization cost by reducing the health care services associated with postoperative ileus and decreasing the hospital stay. PMID- 24342145 TI - The association of lower urinary tract symptoms, depression and suicidal ideation: data from the 2005-2006 and 2007-2008 National Health and Nutrition Examination Survey. AB - PURPOSE: We examine the association among depression, suicidal ideation and self reported lower urinary tract symptoms using a large, cross-sectional, population based study. MATERIALS AND METHODS: The study included 2,890 men from the 2005 2006 or 2007-2008 cycles of the NHANES (National Health and Nutrition Examination Survey) who were 40 years old or older. Men were asked if they experienced nocturia, urinary hesitancy and/or incomplete bladder emptying. The PHQ-9 (Patient Health Questionnaire-9) was used to determine the likelihood of clinical depression and suicidal ideation. RESULTS: The prevalence of lower urinary tract symptoms was 33.7% and 10.3% for men reporting 1 and 2 or more symptoms, respectively. Moderate to severe depression (PHQ-9 score 10 or greater) and suicidal ideation were reported by 181 (6.3%) and 105 (3.6%) men, respectively. Men reporting moderate to severe depression (compared to those reporting minimal depression) had a higher odds of reporting lower urinary tract symptoms (adjusted odds ratio [AOR] 5.09, 95% CI 3.17-8.17 for PHQ-9 score 5 to 9 and AOR 7.62, 95% CI 3.90-14.87 for PHQ-9 score 10 or greater; p trend <0.0001). More lower urinary tract symptoms were associated with a significantly higher odds of moderate to severe depression (AOR 3.09, 95% CI 1.86-5.15 for 1 symptom and AOR 8.06, 95% CI 4.18-15.53 for 2 or more symptoms, p trend <0.0001) and a higher odds of suicidal ideation (AOR 1.70, 95% CI 0.85-3.42 and AOR 2.71, 95% CI 1.40-5.25, respectively, p trend = 0.004). CONCLUSIONS: A significant relationship was observed between lower urinary tract symptoms and depression/suicidal ideation. While the pathophysiology of the relationship and its significance in clinical practice remain unclear, clinicians may consider screening men with severe lower urinary tract symptoms for depression. PMID- 24342146 TI - DNA based therapy with diphtheria toxin-A BC-819: a phase 2b marker lesion trial in patients with intermediate risk nonmuscle invasive bladder cancer. AB - PURPOSE: H19 is a paternally imprinted oncofetal gene expressed in various embryonic tissues and in 85% of bladder tumors but suppressed in the adult healthy bladder. BC-819 is a DNA plasmid that carries the gene for diphtheria toxin-A under regulation of the H19 promoter sequence. We assessed the efficacy and toxicity of intravesical BC-819 instillations to prevent tumor recurrence and ablate a marker lesion in a phase 2b trial. MATERIALS AND METHODS: A total of 47 patients with recurrent, multiple nonmuscle invasive bladder tumors in whom prior intravesical therapy had failed underwent transurethral resection of all except 1 marker tumor. Patients expressing H19 received a 6-week induction course of intravesical BC-819. Patients who achieved a complete response (absent new tumors at 3 months) were given 3 maintenance courses of 3-weekly instillations every 3 months. RESULTS: All patients were evaluable for adverse effects and 39 were evaluable for efficacy. Complete tumor ablation was achieved in 33% of patients and in 64% there were no new tumors at 3 months. Median time to recurrence was 11.3 months in all cases but significantly longer (22.1 months) when analyzed by response status at 3 months. Adverse events were mild. The study was limited by the small number of patients. CONCLUSIONS: BC-819 prevented new tumor growth in two-thirds of the patients and ablated a third of the marker lesions. Prolonged time to recurrence was observed in responding patients. These results along with the good safety profile make BC-819 a potential medication for bladder cancer. PMID- 24342147 TI - Inflammatory response to Escherichia coli urinary tract infection in the neurogenic bladder of the spinal cord injured host. AB - PURPOSE: Urinary tract infections cause significant morbidity in patients with spinal cord injury. An in vivo spinal cord injured rat model of experimental Escherichia coli urinary tract infection mimics human disease with enhanced susceptibility to urinary tract infection compared to controls. We hypothesized that a dysregulated inflammatory response contributes to enhanced susceptibility to urinary tract infection. MATERIALS AND METHODS: Spinal cord injured and sham injured rats were inoculated transurethrally with E. coli. Transcript levels of 84 inflammatory pathway genes were measured in bladder tissue of each group before infection, 24 hours after infection and after 5 days of antibiotic therapy. RESULTS: Before infection quantitative polymerase chain reaction array revealed greater than twofold up-regulation in the proinflammatory factor transcripts slc11a1, ccl4 and il1beta, and down-regulation of the antimicrobial peptides lcn2 and mpo in spinal cord injured vs control bladders. At 24 hours after infection spinal cord injured bladders showed an attenuated innate immune response with decreased expression of il6, slc11a1, il1beta and lcn2, and decreased il10 and slpi expression compared to controls. Despite clearance of bacteriuria with antibiotics spinal cord injured rats had delayed induction of il6 transcription and a delayed anti-inflammatory response with decreased il10 and slpi transcript levels relative to controls. CONCLUSIONS: Spinal cord injured bladders fail to mount a characteristic inflammatory response to E. coli infection and cannot suppress inflammation after infection is eliminated. This may lead to increased susceptibility to urinary tract infection and persistent chronic inflammation through neural mediated pathways, which to our knowledge remain to be defined. PMID- 24342149 TI - Combat veterans with PTSD after mild TBI exhibit greater ERPs from posterior medial cortical areas while appraising facial features. AB - Posttraumatic stress disorder (PTSD) worsens prognosis following mild traumatic brain injury (mTBI). Combat personnel with histories of mTBI exhibit abnormal activation of distributed brain networks-including emotion processing and default mode networks. How developing PTSD further affects these abnormalities has not been directly examined. We recorded electroencephalography in combat veterans with histories of mTBI, but without active PTSD (mTBI only, n=16) and combat veterans who developed PTSD after mTBI (mTBI+PTSD, n=16)-during the Reading the Mind in the Eyes Test (RMET), a validated test of empathy requiring emotional appraisal of facial features. Task-related event related potentials (ERPs) were identified, decomposed using independent component analysis (ICA) and localized anatomically using dipole modeling. We observed larger emotional face processing ERPs in veterans with mTBI+PTSD, including greater N300 negativity. Furthermore, greater N300 negativity correlated with greater PTSD severity, especially avoidance/numbing and hyperarousal symptom clusters. This correlation was dependent on contributions from the precuneus and posterior cingulate cortex (PCC). Our results support a model where, in combat veterans with histories of mTBI, larger ERPs from over-active posterior-medial cortical areas may be specific to PTSD, and is likely related to negative self-referential activity. PMID- 24342148 TI - The impact of recent screening recommendations on prostate cancer screening in a large health care system. AB - PURPOSE: The United States Preventive Services Task Force recently recommended against routine prostate cancer screening, stating that the risks of screening outweigh the benefits. We determined the impact of this recommendation on prostate cancer screening in a large health system. MATERIALS AND METHODS: We obtained data on all screening prostate specific antigen tests performed at University Hospitals Case Medical Center and affiliated hospitals in northeastern Ohio from January 2008 to December 2012. We examined the total number of prostate specific antigen tests ordered with time and adjusted for patient volume by fitting a regression line. The overall trend was examined and stratified by location (urban, suburban or rural), patient age and provider type (primary care or urology). RESULTS: A total of 43,498 screening prostate specific antigen tests were performed from January 2008 to December 2012. Most tests were ordered by specialists in internal medicine (64.9%), followed by family medicine (23.7%), urology (6.1%) and hematology/oncology (1.3%). Prostate specific antigen screening increased with time until March 2009, when initial screening trials were published. Prostate specific antigen testing then decreased significantly and continued to decrease after the task force recommendations. Similar patterns were noted in almost all subgroups. The greatest decrease in screening was observed by urologists and in patients in the intermediate age group (50 to 59 years). CONCLUSIONS: United States Preventive Services Task Force recommendations appeared to have decreased prostate cancer screening. The greatest impact was seen for urologists and patients in the intermediate age group. Further study is needed to determine the long-term effects of these recommendations on the screening, diagnosis, treatment and prognosis of this prevalent malignancy. PMID- 24342150 TI - The effect of traffic tickets on road traffic crashes. AB - Road traffic crashes are globally a leading cause of death. The current study tests the effect of traffic tickets issued to drivers on subsequent crashes, using a unique dataset that overcomes some shortcomings of previous studies. The study takes advantage of a national longitudinal dataset at the individual level that merges Israeli census data with data on traffic tickets issued by the police and official data on involvement in road traffic crashes over seven years. The results show that the estimated probability of involvement in a subsequent fatal or severe crash was more than eleven times higher for drivers with six traffic tickets per year compared to those with one ticket per year, while controlling for various confounders. However, the majority of fatal and severe crashes involved the larger population of drivers who received up to one ticket on average per year. The current findings indicate that reducing traffic violations may contribute significantly to crash and injury reduction. In addition, mass random enforcement programs may be more effective in reducing fatal and severe crashes than targeting high-risk recidivist drivers. PMID- 24342151 TI - Structural brain differences in school-age children with residual speech sound errors. AB - The purpose of the study was to identify structural brain differences in school age children with residual speech sound errors. Voxel based morphometry was used to compare gray and white matter volumes for 23 children with speech sound errors, ages 8;6-11;11, and 54 typically speaking children matched on age, oral language, and IQ. We hypothesized that regions associated with production and perception of speech sounds would differ between groups. Results indicated greater gray matter volumes for the speech sound error group relative to typically speaking controls in bilateral superior temporal gyrus. There was greater white matter volume in the corpus callosum for the speech sound error group, but less white matter volume in right lateral occipital gyrus. Results may indicate delays in neuronal pruning in critical speech regions or differences in the development of networks for speech perception and production. PMID- 24342152 TI - Individualized heparin and protamine management improves rotational thromboelastometric parameters and postoperative hemostasis in valve surgery. AB - OBJECTIVES: This study investigated whether a tailored approach to heparin and protamine management improved thromboelastometric parameters after cardiopulmonary bypass and reduced postoperative blood loss compared with activated coagulation time (ACT)-based fixed target heparin and protamine management. DESIGN: Randomized controlled study. SETTING: Tertiary university hospital. PARTICIPANTS: Patients undergoing elective valve surgery (n = 38). INTERVENTIONS: Heparin and protamine management were based either on the ACT (n = 19) or hemostasis management system (HMS) measurements (n = 19; HMS Plus; Medtronic, Minneapolis, MN). MEASUREMENTS AND MAIN RESULTS: The target ACT for initiation of cardiopulmonary bypass was 480 seconds. Study variables included rotational thromboelastometry EXTEM (extrinsic coagulation), HEPTEM (intrinsic coagulation with heparinase), and FIBTEM (fibrin part of clot formation) tests and 24-hour blood loss. The use of HMS reduced the median protamine-to-heparin ratio from 1.00 (1.00-1.00) to 0.62 (0.56-0.66; p<0.001). The ACT group showed a prolonged postbypass clotting time for both EXTEM (86 +/- 13 seconds v 78 +/- 10 seconds; p = 0.05) and HEPTEM (217 +/- 58 seconds v 183 +/- 24 seconds; p = 0.03) tests. There was a moderate correlation between protamine dosing with the EXTEM and HEPTEM clotting time (r = 0.42; p = 0.009 and r = 0.38; p = 0.02, respectively). The number of patients with more than 450 mL/24 hours was higher in the ACT than in the HMS group (42% v 12%; p = 0.04). CONCLUSIONS: Individualized heparin and protamine management decreased the protamine-to heparin ratio, improved postbypass thromboelastometric hemostatic parameters, and reduced the incidence of severe blood loss compared with an ACT-based strategy, supporting the added value of this approach for hemostatic optimization during cardiac surgery. PMID- 24342153 TI - [Quality of care indicators for benign prostatic hyperplasia. A qualitative study]. AB - OBJECTIVE: To assess quality of care indicators for benign prostatic hyperplasia (BPH), and to evaluate their strengths and weaknesses for incorporation into health information systems. DESIGN: Structured expert meeting, using procedures adapted from the nominal group techniques and the Rand consensus method. SETTING: Valencian School of Health Studies. PARTICIPANTS AND/OR CONTEXTS: Forty panellists (74% doctors, 70% from primary care settings) with experience in the management of BPH from 15 departments of the Valencia Health Agency. METHOD: Three workshops were held simultaneously (examination and diagnosis, drug therapy, and appropriateness and results), and the 15 quality indicators selected by the coordination group were assessed. RESULTS: Eleven of the 15 indicators scored in the range of high relevance. The 5 best rated were: the use of alpha blockers + 5-alpha reductase inhibitor from certain severity level, digital rectal examination in the initial assessment, follow-up with the International Prostate Symptoms Score (IPSS), the rate of urgent catheterization in Hospital Accident & Emergency Units, initial assessment with the IPSS and the use of alpha blockers prior to catheter removal for acute retention of urine. CONCLUSIONS: Some of the assessed indicators can be useful for incorporation into health information systems. PMID- 24342154 TI - The pull-through: back to the future. AB - BACKGROUND: Historically, colo-anal pull-through (P-T) has been the first surgical procedure adopted to facilitate a handmade lower anastomosis. Very popular around mid twentieth century, P-T has had poor diffusion, mainly as a consequence of the technical simplifications brought by staplers. Recent literature seems poor on this specific topic, despite description of P-T appears in published series during the reconstructive phase of total laparoscopic protectomies. A comeback of P-T has also been observed as an option with deferred anastomosis, to allow and protect a colo-anal anastomosis in situations at greater risk of dehiscence, avoiding a temporary faecal diversion. After reviewing the most significant aspects of classic techniques of P-T, we report our experience with transanal laparoscopic P-T for distal rectal cancer, presenting a new, modified P-T with deferred anastomosis aimed at improving defecatory compliance. PATIENTS AND METHODS: Between January 2008 and June 2011 we operated in 258 rectal cancers (0-14 cm from the anal verge), 62.79% of which by laparoscopic access (VL), with 218 restorative procedures (84.49%). The colo anal anastomoses (CAA) were globally 68 (26.35%), of which 48 in VL procedures (70.58%). In 27 of these CAAs we utilised the P-T procedure, with immediate CAA (I-CAA) in 11 cases (all VL) and delayed CAA (D-CAA) in 16 (2 VL), by selective indications. All CAAs were manually fashioned; 6 D-CAA had the addition of a transverse coloplasty. Site of tumor was the lower rectum in 24 patients, with 21 patients receiving preoperative chemoradiation. RESULTS: There was no operative mortality. Early morbidity: DCAA: 3 pelvic abscesses with stoma formation. I-CAA: 1 intraoperative re-resection and colo-anal anastomosis with stoma formation for defective distal vascular supply. Late morbidity: anastomotic stenosis in 5/12 I CAA and 4/14 D-CAA controlled by mechanical dilation. Function: 4/7 D-CAA and 4/6 I-CAA nearly complete functional recovery (Kirwan's 1 or 2). CONCLUSION: There are selective indications to P-T, when resection and anastomosis is not feasible in one step, or also as a primary restorative option in elective cases when a covering stoma is refused or dangerous. PMID- 24342155 TI - Radiologically innocuous breast reduction specimens. Should we send them to pathology lab anyway? AB - Breast Reduction (BR) is a common procedure around the world. Patients are screened for incidental carcinoma preoperatively by mammography or ultrasonography and BR specimens are sent for pathologic examination postoperatively. Since the incidence of incidental carcinoma is very low, no consensus exist regarding efficiency of pathologic examination. To assess the value of pathologic examination, we examined mammographically and ultrasonographically negative eighty BR specimens from 40 women. Twenty seven women had pathological lesions in their specimens (67,5%). This indicates that, even mammographically and ultrasonographically innocuous, BR specimens may reveal important pathological diagnosis that alters patient management. PMID- 24342156 TI - Micro HTA as a tool for clinical governance: the experience of the Breast Unit in "Santa Maria" Terni Hospital. AB - The last decade has witnessed the affirmation of the paradigm Health Technology Assessment (HTA) as a tool for government innovation technology in health care. As is known, this is an approach of evaluation oriented policy making that, in addition to provide for the disclosure of its results, it is proposed to consider simultaneously the clinical, economic, organizational, ethical and social issues arising from the introduction or disposal of a health technology, understood in the broadest sense of the term. In order to reconstruct a realistic picture of its level of implementation we have reproduced a micro HTA which served to assess the Harmonic Focus(r) device usefulness in breast surgery. PMID- 24342157 TI - Outpatient surgical procedures: which is the ideal teaching procedure for a resident surgeon? AB - AIM: The aim of our study is to evaluate which surgical procedures can be considered the ideal teaching procedure for a resident surgeon. MATERIALS AND METHODS: This is a retrospective study. A chart review was performed on all patients who underwent inguinal hernia repair, saphenectomy, excision of pilonidal sinus and hemorrhoidectomy at our institution, between September 2000 and July 2011, and have at least 1 year of follow-up. We evaluated operative time and complications comparing the results obtained by resident or attending surgeon. RESULTS: We obtained a higher operative time among the procedures performed by resident surgeons for all evaluated interventions. Whereas the occurrence of complications after hernia repair and excision and primary closure of pilonidal sinus were similar in case and control subjects (p = 0,1 and p = 0,1), the occurrence of complications after hemorrhoidectomy and saphenectomy was significantly higher in the case group (p = 0,08 and p = 0,1). CONCLUSION: Hernia repair and excision and primary closure of pilonidal sinus have to be considered the ideal teaching procedure in a residency program, giving to the young surgeon the opportunity of reach several skills that he needs to master most difficult surgical procedures. Saphenectomy and hemorrhoidectomy should be considered safe only if performed by a senior resident surgeon. PMID- 24342158 TI - Additional applications of the Foley catheter in cardiac surgery. AB - We describe an additional use of the Foley catheter for preoperative and postoperative evaluation of the regurgitant mitral valve. PMID- 24342159 TI - Safety and efficacy of saphenectomy in elderly patients. AB - AIM: The aim of this study is to evaluate safety and efficacy of saphenactomy in elderly patients. PATIENTS AND METHODS: A total of 358 patients with varicose veins of the lower limbs treated between January 2001 and December 2011. 213 of these were patients under 65 years old and 145 patients were over this age. We have evaluated short- and long-term complications to compare the results among young and elderly patients. RESULTS: Postoperative complications that occurred were: infection, haematoma, nerve injury (paresthesia and pain) and deep vein thrombosis. Although a trend towards better results was observed among the young patients, no significant differences were shown in our experience. CONCLUSION: Elective saphenectomy has a good outcome also in the elderly patients. The slightly higher rate of complications that occurred in older patients is not significant and does not support advising against the use of this surgical approach in the elderly. So in our opinion saphenectomy is quite safe and feasible also in patients over 65 years. PMID- 24342160 TI - Spontaneous rupture of a hepatic epithelioid angiomyolipoma: damage control surgery. A case report. AB - BACKGROUND: Angiomyolipoma (AML) is a rare mesenchymal tumor composed by blood vessels, adipose tissue and smooth muscle cells in variable proportions. Although it is most often diagnosed in the kidney, this tumor may originate from any part of the liver. It is often misdiagnosed as hepatocellular carcinoma (HCC) or other benign liver tumor. We describe a case of spontaneous rupture of hepatic angiomyolipoma in a young woman, with evidence of internal hemorrhage and hemoperitoneum. CASE REPORT: Liver tumor rupture is a rare but real surgical emergency. In our case it has been managed according to the trauma principles of the damage control surgery. At the time of the observation, the patient presented an instable condition, so the decision-making was oriented toward a less invasive first step of liver packing instead of a more aggressive intervention such as one shot hepatic resection. CONCLUSION: Damage control surgery with deep parenchymal sutures of the liver and pro-coagulant tissue adhesives packing abbreviates surgical time before the development of critical and irreversible physiological endpoints and permits a more confident second time surgery. This surgical management concept helps to reduce the mortality rate and the incidence of complications not only in traumatic liver damages, it works very well in spontaneous liver ruptures as well. PMID- 24342161 TI - Laparoscopic removal of a giant paratubal cyst complicated by hydronephrosis. AB - Paratubal cysts represent approximately 10% of all adnexal masses. In most cases they are very small, but very few cases are reported in the literature where they exceed 15 cm of diameter. Furthermore, giant paratubal cysts complicated by bilateral hydronephrosis are unique. The Authors describe a case of a huge paratubal cyst (30 cm in diameter), in a 14 year old obese girl, treated by complete laparoscopic enucleation. PMID- 24342162 TI - Treatment of renal angiomyolipoma: surgery versus angioembolization. AB - Renal angiomyolipoma (AML) is a benign mesenchymal tumour. AML often leads to haemorrhagic complications such as retroperitoneal haematoma. Treatment varies from case to case, ranging from minimally invasive approaches such as selective embolization of the renal artery to invasive wedge resection, partial nephrectomy or, in more severe cases, radical nephrectomy. Here we report a case of retroperitoneal haematoma secondary to AML, treated with conservative approach by super-selective embolization of the lower-pole segmental renal artery. PMID- 24342163 TI - Surgical repair of rectocele. Comparison of transvaginal and transanal approach and personal technique. AB - Rectocele is defined as a herniation of the rectal wall inside the vagina due to a defect of the recto-vaginal septum. It is traditionally considered a posterior compartment damage with weakness of posterior vaginal wall support resulting in a bulging of the rectum into the vaginal cavity. One of the main causes of rectal prolapse is the operative vaginal birth, although the evidence of the defect may occur after many years The treatment of rectocele is surgical, and the approach can be transperineal, transvaginal, and transanal or, in selected cases, transperitoneal through open or laparoscopic techniques. In this study we compare two transvaginal surgical techniques - i.e. the perineal body anchorage to the posterior septum and the traditional Denonvilliers' transversal suture after removing of the vaginal skin, with the mostly performed transanal procedure, the STARR - comparing the data from the literature on their results. Mean hospital stay, rectal symptoms, dyspareunia, quality of life, recurrence rate and postoperative complications have been considered. Both transvaginal and transrectal surgical techniques are effective to solve posterior compartment defect and to improve the quality of life. Vaginal approach may interfere with the sexual activity; furthermore it is associated with minimal postoperative pain than the transanal approach. Better anatomic results are assured after endovaginal surgery, while better rectal function prevail after the transanal approach. Vaginal techniques are more suitable to gynecologists, whereas the transrectal ones are usually performed by colo-proctologists or general surgeons. PMID- 24342164 TI - Intramuscular electroporation of a P1A-encoding plasmid vaccine delays P815 mastocytoma growth. AB - This study aimed to construct DNA vaccines encoding the mouse P1A tumor antigen and to generate a protective immune response against the P815 mastocytoma, as a model for vaccines against human MAGE-type tumor antigens. DNA vaccines were constructed and delivered to mice by intramuscular electroporation before tumor challenge. Immunization with a plasmid coding for the full-length P1A significantly delayed tumor growth and mice survived at least 10 days longer than untreated controls. 10% of the mice completely rejected the P815 tumors while 50% of them showed a regression phase followed by tumor regrowth. Mice immunized by electroporation of a P1A(35-43) minigene-encoding plasmid failed to reject tumor and even delay tumor growth. The P1A(35-43)-encoding plasmid was modified and helper epitope sequences were inserted. However, these modified plasmids were not able to improve the response against P815 mastocytoma. Consistent with these results, a 12-fold higher CTL activity was observed when the plasmid coding for full-length P1A was delivered as compared to the plasmid encoding the P1A(35-43) epitope. Our results demonstrated that electroporation is an efficient method to deliver DNA vaccines against P815 and suggested the superiority of full-length as compared to minigene constructs for DNA vaccines. PMID- 24342165 TI - Another case suggesting that the GMC is not fit for purpose. PMID- 24342166 TI - A dosimetric evaluation of the Eclipse AAA algorithm and Millennium 120 MLC for cranial intensity-modulated radiosurgery. AB - The aim of this study is to assess the accuracy of a convolution-based algorithm (anisotropic analytical algorithm [AAA]) implemented in the Eclipse planning system for intensity-modulated radiosurgery (IMRS) planning of small cranial targets by using a 5-mm leaf-width multileaf collimator (MLC). Overall, 24 patient-based IMRS plans for cranial lesions of variable size (0.3 to 15.1cc) were planned (Eclipse, AAA, version 10.0.28) using fixed field-based IMRS produced by a Varian linear accelerator equipped with a 120 MLC (5-mm width on central leaves). Plan accuracy was evaluated according to phantom-based measurements performed with radiochromic film (EBT2, ISP, Wayne, NJ). Film 2D dose distributions were performed with the FilmQA Pro software (version 2011, Ashland, OH) by using the triple-channel dosimetry method. Comparison between computed and measured 2D dose distributions was performed using the gamma method (3%/1mm). Performance of the MLC was checked by inspection of the DynaLog files created by the linear accelerator during the delivery of each dynamic field. The absolute difference between the calculated and measured isocenter doses for all the IMRS plans was 2.5% +/- 2.1%. The gamma evaluation method resulted in high average passing rates of 98.9% +/- 1.4% (red channel) and 98.9% +/- 1.5% (blue and green channels). DynaLog file analysis revealed a maximum root mean square error of 0.46mm. According to our results, we conclude that the Eclipse/AAA algorithm provides accurate cranial IMRS dose distributions that may be accurately delivered by a Varian linac equipped with a Millennium 120 MLC. PMID- 24342167 TI - Assessing the feasibility of volumetric-modulated arc therapy using simultaneous integrated boost (SIB-VMAT): An analysis for complex head-neck, high-risk prostate and rectal cancer cases. AB - Intensity-modulated radiotherapy (IMRT) allowed the simultaneous delivery of different doses to different target volumes within a single fraction, an approach called simultaneous integrated boost (SIB). As consequence, the fraction dose to the boost volume can be increased while keeping low doses to the elective volumes, and the number of fractions and overall treatment time will be reduced, translating into better radiobiological effectiveness. In recent years, volumetric-modulated arc therapy (VMAT) has been shown to provide similar plan quality with respect to fixed-field IMRT but with large reduction in treatment time and monitor units (MUs) number. However, the feasibility of VMAT when used with SIB strategy has few investigations to date. We explored the potential of VMAT in a SIB strategy for complex cancer sites. A total of 15 patients were selected, including 5 head-and-neck, 5 high-risk prostate, and 5 rectal cancer cases. Both a double-arc VMAT and a 7-field IMRT plan were generated for each case using Oncentra MasterPlan treatment planning system for an Elekta Precise linac. Dosimetric indexes for targets and organs at risk (OARs) were compared based on dose-volume histograms. Conformity index, homogeneity index, and dose contrast index were used for target analyses. The equivalent uniform doses and the normal tissue complication probabilities were calculated for main OARs. MUs number and treatment time were analyzed to score treatment efficiency. Pretreatment dosimetry was performed using 2-dimensional (2D)-array dosimeter. SIB-VMAT plans showed a high level of fluence modulation needed for SIB treatments, high conformal dose distribution, similar target coverage, and a tendency to improve OARs sparing compared with the benchmark SIB-IMRT plans. The median treatment times reduced from 13 to 20 minutes to approximately 5 minutes for all cases with SIB-VMAT, with a MUs reduction up to 22.5%. The 2D-array ion chambers' measurements reported an agreement of more than 95% for a criterion of 3% to 3mm. SIB-VMAT was able to combine the advantages of conventional SIB-IMRT with its highly conformal dose distribution and OARs sparing and the advantages of 3D-conformal radiotherapy with its fast delivery. PMID- 24342168 TI - "Gain more working space at a low intraperitoneal pressure" may be a difficult, but worthy anesthesiologic challenge. PMID- 24342169 TI - [Obstructive laryngeal disease and obstructive sleep apnoea syndrome, a combination with serious peri-operative risk]. AB - We present the case of a patient who was diagnosed with chronic bronchitis, obstructive sleep apnoea syndrome, and large Reinke laryngeal oedemas that were removed by transoral laser microsurgery. In the immediate post-operative period acute respiratory insufficiency occurred due to pharyngeal collapse that required emergency re-intubation, after which the patient was transferred to the ICU where mechanical ventilation was given for 18h. Subsequent progress was normal. We describe the combination of various risk-factors related to anaesthetic management and the importance of considering each one of them, especially the preoperative detection of the severity of obstructive sleep apnoea syndrome. PMID- 24342170 TI - [Myasis in a case of a scalp electrical burn]. PMID- 24342171 TI - Bio-augmentation as a tool for improving the modified sequencing batch biofilm reactor. AB - Biological treatment of domestic sewage was accomplished in a pilot-scale modified sequencing batch biofilm reactor (SBBR) bio-augmented with consortium of 5 strains of indigenous bacteria (genus Pseudomonas and Bacillus). The reactor consisted of fibrous filler in the upper and ceramsite filter media in the bottom. It demonstrated to have a short hydraulic residence time (HRT) for 10 h and good quality effluent to cope with low C/N ratio domestic wastewater. The biofilm attached fibrous fillers mainly contributed to contaminants removal. Bio augmentation dramatically enhanced the removal efficiency of chemical oxygen demand (COD), total phosphorus (TP), and especially total nitrogen (TN), which increased respectively from 80.3%, 58.1% and 41.3% to 83.7%, 67.8% and 58.7%. Polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE) technique indicated the 5 strains' survival in the reactor and that Bacillus cereus strain ZQN2 was the most dominant bacteria. PMID- 24342172 TI - Expression levels of domestic cDNA cassettes integrated in the nuclear genomes of various Chlamydomonas reinhardtii strains. AB - We attempted to overexpress three types of expression cassettes, each of which contained a different open reading frame (ORF) of domestic Chlamydomonas cDNAs. Each ORF was strongly driven by an artificial hybrid promoter. We used two wild type Chlamydomonas strains (i.e., CC-124 and CC-125) and two mutant strains [i.e., UV-mutated (UVM) 4 and UVM11] that have been reported to have a high potency for expressing nondomestic nuclear transgenes. We found that the 1-deoxy d-xylulose-5-phosphatesynthase (DXS1), 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR1), and squalene synthase (SQS) cassettes were not readily overexpressed in the wild-type strains at levels where the products were clearly detectable by Western blotting using a monoclonal antibody. In contrast, Western blot-positive SQS cassette transformants were frequently detected in the UVM4 and UVM11 strains, i.e., at an approximately 4.5 times higher frequency than that in the CC-124 wild-type strain. Moreover, transformants that accumulated large amounts of the SQS protein were obtained frequently in the UVM4 and UVM11 strains, i.e., the frequency was approximately 2.2 times higher than that in the CC-124 strain. However, a position effect of the integrated expression cassette was obviously detected not only in the wild-type but also in UVM strains. This suggests that the epigenetic repression mechanism of transgenic genes was not completely knocked out, even in the UVM strains. Further improved Chlamydomonas strains are essential to facilitate high-throughput screening of transformants that express nuclear transgenes at a high level. PMID- 24342173 TI - Purification and basic biochemical characterization of 19 recombinant plant peroxidase isoenzymes produced in Pichia pastoris. AB - The plant enzyme horseradish peroxidase (HRP) is used in several important industrial and medical applications, of which especially biosensors and diagnostic kits describe an emerging field. Although there is an increasing demand for high amounts of pure enzyme preparations, HRP is still isolated from the plant as a mixture of different isoenzymes with different biochemical properties. Based on a recent next generation sequencing approach of the horseradish transcriptome, we produced 19 individual HRP isoenzymes recombinantly in the yeast Pichia pastoris. After optimizing a previously reported 2-step purification strategy for the recombinant isoenzyme HRP C1A by substituting an unfavorable size exclusion chromatography step with an anion exchange step using a monolithic column, we purified the 19 HRP isoenzymes with varying success. Subsequent basic biochemical characterization revealed differences in catalytic activity, substrate specificity and thermal stability of the purified HRP preparations. The preparations of the isoenzymes HRP A2A and HRP A2B were found to be highly interesting candidates for future applications in diagnostic kits with increased sensitivity. PMID- 24342174 TI - Heroin and amphetamine users display opposite relationships between trait and neurobehavioral dimensions of impulsivity. AB - The multidimensional construct of impulsivity is implicated in all phases of the addiction cycle. Substance dependent individuals (SDIs) demonstrate elevated impulsivity on both trait and laboratory tests of neurobehavioral impulsivity; however our understanding of the relationship between these different aspects of impulsivity in users of different classes of drugs remains rudimentary. The goal of this study was to assess for commonalities and differences in the relationships between trait and neurobehavioral impulsivity in heroin and amphetamine addicts. Participants included 58 amphetamine dependent (ADIs) and 74 heroin dependent individuals (HDIs) in protracted abstinence. We conducted Principal Component Analyses (PCA) on two self-report trait and six neurobehavioral measures of impulsivity, which resulted in two trait impulsivity (action, planning) and four neurobehavioral impulsivity composites (discriminability, response inhibition efficiency, decision-making efficiency, quality of decision-making). Multiple regression analyses were used to determine whether neurobehavioral impulsivity is predicted by trait impulsivity and drug type. The analyses revealed a significant interaction between drug type and trait action impulsivity on response inhibition efficiency, which showed opposite relationships for ADIs and HDIs. Specifically, increased trait action impulsivity was associated with worse response inhibition efficiency in ADIs, but with better efficiency in HDIs. These results challenge the unitary account of drug addiction and contribute to a growing body of literature that reveals important behavioral, cognitive, and neurobiological differences between users of different classes of drugs. PMID- 24342175 TI - Gender differences in prevalence and correlates of antisocial personality disorder among heroin dependent users in compulsory isolation treatment in China. AB - BACKGROUND: Little is known about gender difference in correlates of antisocial personality disorder (ASPD) among drug users. OBJECTIVE: To detect gender difference in correlates of ASPD in a Chinese heroin dependent sample. METHODS: Structured interviews were conducted among 882 heroin dependent users in two compulsory isolation settings in Changsha, China. Descriptive statistics were employed to report sample characteristics by gender. Bivariate relationships were examined between co-occurring ASPD and variables measuring demographic, drug use, and psychiatric co-morbidities. Multivariate logistic regressions with stepwise forward method were conducted to determine independent predictors for co occurring ASPD. All analyses examining correlates of co-occurring ASPD were conducted for the total, the male and the female participants respectively to detect both the common and the unique correlates of ASPD by gender. RESULTS: Of the total participants, 41.4% (54.2% of males and 15.4% of females) met the DSM IV criteria of ASPD. For male participants, lower educational level, unemployment, unmarried, younger age at first heroin use, previous history of compulsory treatment, larger amounts of heroin used per day and poly-drug abuse during past month before admission, as well as psychiatric co-morbidities of lifetime major depressive disorder and borderline personality disorder were independent predictors for co-occurring ASPD; while for female participants, only three variables: younger age at first heroin use, paranoid personality disorder and borderline personality disorder were independent predictors for co-occurring ASPD. CONCLUSIONS: Gender differences in prevalence and correlates of ASPD among heroin dependent users were detected. The findings highlight a need for gender specific interventions. PMID- 24342176 TI - Analyses of meal patterns across dietary shifts. AB - The direct controls of meal size can be categorized into positive signals such as those from the oral cavity and negative signals such as postoral inhibitory cues. It follows that the relative contribution of these signals, and in turn meal pattern parameters, change across periods of high-energy diet exposure. Here, we compared daily intake and meal pattern analysis in male Sprague-Dawley rats presented a high-energy diet for 6weeks then standard chow for ~1week (HE), with those of standard chow fed controls (CHOW). These measures allow for evaluation of (1) whether there are distinct dynamic and static phases of DIO and if so, how they are characterized, (2) how meal patterns change across short and long term HE experience, and (3) ingestive behavioral changes when HE-fed animals are returned to standard chow. The HE animals showed significantly higher intake primarily driven by an increase in meal size compared to CHOW controls. This was most pronounced during the first several days of high-energy diet exposure thus characterizing the dynamic phase. Intake and meal size decreased with longer exposure to the diet but remained significantly higher than those of CHOW. Increased meal size could be driven by enhanced orosensory stimulation and/or reduced sensitivity to postoral inhibitory feedback. Distribution curves derived from histogram plots of meal size revealed both larger average meal size (right shift) and spread (standard deviation) thus it is tempting to speculate that more than one type of mechanism influences increased meal size. Meal number decreased suggesting post meal inhibitory signaling is relatively intact. However, this increase was insufficient to compensate for the increased meal size. When HE animals were switched to standard chow, daily intake and meal size decreased and eventually returned to values comparable to those of the CHOW rats. Meal number remained lower suggesting altered physiological mechanism(s) that underlie the control of ingestive behavior as a function of previous high-energy diet exposure. PMID- 24342177 TI - [Biomarkers in endocrinology]. AB - TSH assay is the best parameter of the thyroid function. For adults, the normal interval of TSH concentrations range from 0.4 to 4 mUI/L. At the first trimester of pregnancy, TSH levels must be <2.5 mUI/L. Normal TSH levels increase with aging and obesity. The biological diagnosis relies on the identification of excessive secretion of the metanephrines which are more sensitive and specific than those of catecholamines. The concentrations of the free plasmatic metanephrines reflect the ongoing production of tumor. Plasma methoxytyramine is a novel biomarker of metastatic pheochromocytomas and paragangliomas. Serum IGF1 is a reliable measure of integrated GH concentrations in patients with acromegaly. Accurate assessment of IGF1 concentrations requires age and sex matched control values. IGF1 is a sensitive tool for the diagnosis of acromegaly and efficacy of therapies. Serum AMH assay is more sensitive, more specific and more reproducible that counting of ovarian follicles by ultrasound. AMH level above 5 ng/mL (35 pmol/L) could be chosen as one of the diagnostic criteria for the polycystic ovary syndrome. In early or "incipiens" ovarian failure, the decrease in serum AMH is far ahead of the increase in FSH. Thyroglobulin (TG) and calcitonin (CT) are the sensitive and specific markers of respectively well differentiated thyroid cancers of follicular origin and of the medullary thyroid cancers. The same tumour marker assay should be used to monitor a given patient. Chromogranin A (CgA) is a highly efficient biomarker for diagnosis and follow-up of various endocrine tumours. Despite the lack of international standardisation, some CgA assays are reliable. PMID- 24342179 TI - Exercise addiction: a study of eating disorder symptoms, quality of life, personality traits and attachment styles. AB - Exercise addiction is characterized by excessive exercise patterns with potential negative consequences such as overuse injuries. The aim of this study was to compare eating disorder symptoms, quality of life, personality traits and attachments styles in exercisers with and without indications of exercise addiction. A case-control study with 121 exercisers was conducted. The exercisers were categorized into an addiction group (n=41) or a control group (n=80) on the basis of their responses to the Exercise Addiction Inventory. The participants completed the Eating Disorder Inventory 2, the Short-Form 36, the NEO Personality Inventory Revised and the Adult Attachment Scale. The addiction group scored higher on eating disorder symptoms, especially on perfectionism but not as high as eating disorder populations. The characteristic personality traits in the addiction group were high levels of excitement-seeking and achievement striving whereas scores on straightforwardness and compliance were lower than in the exercise control group. The addiction group reported more bodily pain and injuries. This study supports the hypothesis that exercise addiction is separate to an eating disorder, but shares some of the concerns of body and performance. It is driven by a striving for high goals and excitement which results in pain and injuries from overuse. PMID- 24342180 TI - Low-fat meat sausages with fish oil: optimization of milk proteins and carrageenan contents using response surface methodology. AB - Response surface methodology was used to analyze the effect of milk proteins and 2:1 kappa:iota-carrageenans on cooking loss (CL), weight lost by centrifugation (WLC) and texture attributes of low-fat meat sausages with pre-emulsified fish oil. A central-composite design was used to develop models for the objective responses. Changes in carrageenans affected more the responses than milk proteins levels. Convenience functions were calculated for CL, WLC, hardness, and springiness of the product. Responses were optimized simultaneously minimizing CL and WLC; ranges for hardness and springiness corresponded to commercial products (20 g of pork fat/100 g). The optimum corresponded to 0.593 g of carrageenans/100 g and 0.320 g of milk proteins and its total lipid content was 6.3 g/100 g. This formulation was prepared and evaluated showing a good agreement between predicted and experimental responses. These additives could produce low-fat meat sausages with pre-emulsified fish oil with good nutritional quality and similar characteristics than traditional ones. PMID- 24342178 TI - A bioimage informatics based reconstruction of breast tumor microvasculature with computational blood flow predictions. AB - Induction of tumor angiogenesis is among the hallmarks of cancer and a driver of metastatic cascade initiation. Recent advances in high-resolution imaging enable highly detailed three-dimensional geometrical representation of the whole-tumor microvascular architecture. This enormous increase in complexity of image-based data necessitates the application of informatics methods for the analysis, mining and reconstruction of these spatial graph data structures. We present a novel methodology that combines ex-vivo high-resolution micro-computed tomography imaging data with a bioimage informatics algorithm to track and reconstruct the whole-tumor vasculature of a human breast cancer model. The reconstructed tumor vascular network is used as an input of a computational model that estimates blood flow in each segment of the tumor microvascular network. This formulation involves a well-established biophysical model and an optimization algorithm that ensures mass balance and detailed monitoring of all the vessels that feed and drain blood from the tumor microvascular network. Perfusion maps for the whole tumor microvascular network are computed. Morphological and hemodynamic indices from different regions are compared to infer their role in overall tumor perfusion. PMID- 24342181 TI - Heat shock and structural proteins associated with meat tenderness in Nellore beef cattle, a Bos indicus breed. AB - Nellore beef cattle, a Bos indicus (Zebu) breed, is well adapted to tropical conditions and has allowed Brazil to become one of the largest producers of red meat. Nevertheless, B. indicus breeds are reported to have less tender meat than Bos taurus. This study was designed to identify genes associated with meat tenderness and thus provides important information for breeding programs. A group of 138 animals was evaluated for longissimus thoracis muscle shear force (SF). Animals with the highest and lowest SF values (six animals each) were then selected for protein abundance studies. Samples were subjected to two-dimensional gel electrophoresis (2-DE) followed by peptide sequencing through mass spectrometry (MS) to identify differentially expressed proteins associated with SF values. Seventeen differentially expressed spots were observed (p<0.05) between the two groups. The 13 proteins identified included structural proteins (alpha actin-1, MLC1, MLC3, MLC2F and tropomyosin), related to cell organization (HSPB1 and HSP70), metabolism (beta-LG, ACBD6 and Complex III subunit I) and some uncharacterized proteins. Results confirm the existence of differentially expressed proteins associated with SF, which can lead to a better understanding of mechanisms involved in meat tenderness. PMID- 24342182 TI - Proteolysis and sensory properties of dry-cured bacon as affected by the partial substitution of sodium chloride with potassium chloride. AB - Quadriceps femoris muscle samples (48) from 24 pigs were processed into dry-cured bacon. This study investigated the influence of partial substitution of sodium chloride (NaCl) with potassium chloride (KCl) on proteolysis and sensory properties of dry-cured bacon. Three salt treatments were considered, namely, I (100% NaCl), II (60% NaCl, 40% KCl), and III (30% NaCl, 70% KCl). No significant differences were observed among treatments in the proteolysis, which was reflected by SDS-PAGE, proteolysis index, amino acid nitrogen, and peptide nitrogen contents. Furthermore, there were no significant differences in the moisture content between control and treatment II, whereas the moisture content in treatment III was significantly higher (p<0.05) in comparison with control (treatment I). The sensory analysis indicated that it was possible to reduce NaCl by 40% without adverse effects on sensory properties, but 70% replacement of NaCl with KCl resulted in bacon with less hardness and saltiness and higher (p<0.05) juiciness and bitterness. PMID- 24342183 TI - Determination of tetracyclines in pig and other meat samples using liquid chromatography coupled with diode array and tandem mass spectrometric detectors. AB - Two high performance liquid chromatographic methods (HPLC-DAD and LC-MS/MS) were developed to analyze tetracycline (TC) residues in pig meat (pork) samples. The method involved a sample preparation using a solid-liquid extraction (SLE) by McIlvaine buffer, followed by a solid-phase extraction (SPE) clean-up using Strata-XL cartridges. The developed sample clean-up resulted in a selective chromatogram in the HPLC-DAD separation and a reduced matrix effect (ME) in LC MS/MS analysis. Moreover, HPLC columns packed with core-shell particles were tested for separation, which further enhanced the sensitivity and the selectivity of determinations. The validation of the methods for pig samples was carried out according to European Union 2002/657/EC decision. In addition, validation was also performed for bovine, chicken, and turkey meat samples using HPLC-DAD method. The performance characteristics of determinations were evaluated with both spiked and incurred samples, and were systematically compared. LC-MS/MS technique was found to be more accurate for spiked samples; however, HPLC-DAD method resulted in more reliable concentrations for incurred samples. PMID- 24342184 TI - Carcass and meat quality characteristics of Brahman cross bulls and steers finished on tropical pastures in Costa Rica. AB - Forty-eight male calves (3/4 Brahman*1/4 Charolais) were used to determine carcass cutability and meat tenderness of Longissimus lumborum (LL), Gluteus medius (GM), Semitendinosus (ST) and Psoas major (PM) steaks from lighter weight carcasses of bulls and steers castrated at 3, 7, or 12 mo of age grown under tropical pasture conditions. Steaks from steers had lower (more tender) LL Warner Bratzler shear force (WBSF) values than those from bulls. Steaks from steers castrated at 3 mo had lower GM WBSF than those from bulls. For PM steaks, those aged 28 d had lower WBSF than those aged 2d. Steaks aged 28 d had the lowest LL and GM WBSF and steaks aged 2d had the highest LL, GM, and ST WBSF. Castration at younger ages is recommended because it provides improvement in LL and GM tenderness over bulls with no differences in carcass traits or subprimal yields. PMID- 24342185 TI - Effects of process variables on some quality properties of meatballs semi-cooked in a continuous type ohmic cooking system. AB - Ohmic cooking of meatballs was conducted in a continuous type ohmic cooker using different voltage gradients (15, 20 and 25 V/cm) and holding times (0, 15 and 30 s). The color and textural properties and log reductions in total microbial count of the meatballs were assessed. The effects of process variables on these responses were evaluated by linear and quadratic mathematical models. Desirability function was used to determine the optimum ohmic pre-cooking condition by considering the criteria of minimizing hardness ratio, and maximizing chewiness ratio, resilience ratio, log reduction in microbial load, outside chroma ratio, inside chroma ratio and in range of springiness, gumminess and inside L ratios. The optimum ohmic pre-cooking condition was found to be a 15.26 V/cm voltage gradient with no holding time. It is concluded that application of the optimum condition in the related ohmic system offers potential for the production of high quality and safe semi-cooked meat products. PMID- 24342186 TI - Satureja horvatii essential oil: in vitro antimicrobial and antiradical properties and in situ control of Listeria monocytogenes in pork meat. AB - The dominant compounds in Satureja horvatii oil were p-cymene (33.14%), thymol (26.11%) and thymol methyl ether (15.08%). The minimum inhibitory concentration (MIC) varied from 0.03 to 0.57 mg/mL for bacteria, and from 0.56 to 2.23 mg/mL for yeast strains, while minimum bactericidal/yeast-cidal concentration (MBC/MYC) varied from 0.07 to 1.15 mg/mL and 1.11 to 5.57 mg/mL for bacteria and yeasts, respectively. The antiradical potential of the essential oil was evaluated using hydroxyl radical (*OH) generated in Fenton reaction. The meat preserving potential of essential oil from Satureja horvatii was investigated against L. monocytogenes. Essential oil successfully inhibited development of L. monocytogenes in pork meat. Sensorial evaluation on flavor and color of meat was performed. The color and flavor of meat treated with essential oil improved after 4 days of storage. S. horvatii essential oil can act as a potent inhibitor of food spoiling microorganisms, in meat products and also can be a useful source of natural antioxidants. PMID- 24342187 TI - Effectiveness of oxygen barrier oven bags in low temperature cooking on reduction of warmed-over flavor in beef roasts. AB - A 3*3*2 factorial was utilized to determine if roast size (small, medium, large), cooking method (open-pan, oven bag, vacuum bag), and heating process (fresh, reheated) prevented warmed-over flavor (WOF) in beef clod roasts. Fresh vacuum bag and reheated open-pan roasts had higher cardboardy flavor scores compared with fresh open-pan roast scores. Reheated roasts in oven and vacuum bags did not differ from fresh roasts for cardboardy flavor. Brothy and fat intensity were increased in reheated roasts in oven and vacuum bags compared with fresh roasts in oven and vacuum bags. Differences in TBARS were found in the interaction of heating process and roast size with the fresh and reheated large, and reheated medium roasts having the lowest values. Based on TBARS data, to prevent WOF in reheated beef roasts, a larger size roast in a cooking bag is the most effective method. PMID- 24342188 TI - Prediction of carcass composition and individual carcass cuts of Japanese Black steers. AB - The objective of this study was to develop equations to predict carcass tissue weights and percentages and boneless carcass non-trimmed cut weights by using the cold carcass weight (CCW) and three other traits at the 6-7th rib section, which are routinely collected in carcass markets in Japan. Carcasses from 94 Japanese Black steers were used for the multiple regression analysis with a stepwise procedure and a novel Least Absolute Shrinkage and Selection Operator (LASSO). The accuracies of prediction (R(2)) and RMSEs for the carcass tissue and cut weights were similar between the two procedures. In contrast, LASSO appeared to be the better procedure for predicting carcass tissue percentages. The longissimus muscle area and subcutaneous fat thickness were the important predictors for the lean percentage in the stepwise procedure, and CCW was additionally selected when the LASSO procedure was used. PMID- 24342189 TI - Severe visual field alterations in patients with optic nerve drusen. PMID- 24342191 TI - The contribution of Nth and Nei DNA glycosylases to mutagenesis in Mycobacterium smegmatis. AB - The increased prevalence of drug resistant strains of Mycobacterium tuberculosis (Mtb) indicates that significant mutagenesis occurs during tuberculosis disease in humans. DNA damage by host-derived reactive oxygen/nitrogen species is hypothesized to be critical for the mutagenic process in Mtb thus, highlighting an important role for DNA repair enzymes in maintenance of genome fidelity. Formamidopyrimidine (Fpg/MutM/Fapy) and EndonucleaseVIII (Nei) constitute the Fpg/Nei family of DNA glycosylases and together with EndonucleaseIII (Nth) are central to the base excision repair pathway in bacteria. In this study we assess the contribution of Nei and Nth DNA repair enzymes in Mycobacterium smegmatis (Msm), which retains a single nth homologue and duplications of the Fpg (fpg1 and fpg2) and Nei (nei1 and nei2) homologues. Using an Escherichia coli nth deletion mutant, we confirm the functionality of the mycobacterial nth gene in the base excision repair pathway. Msm mutants lacking nei1, nei2 and nth individually or in combination did not display aberrant growth in broth culture. Deletion of nth individually results in increased UV-induced mutagenesis and combinatorial deletion with the nei homologues results in reduced survival under oxidative stress conditions and an increase in spontaneous mutagenesis to rifampicin. Deletion of nth together with the fpg homolgues did not result in any growth/survival defects or changes in mutation rate. Furthermore, no differential emergence of the common rifampicin resistance conferring genotypes were noted. Collectively, these data confirm a role for Nth in base excision repair in mycobacteria and further highlight a novel interplay between the Nth and Nei homologues in spontaneous mutagenesis. PMID- 24342192 TI - Late preterm infant - Nature's unfinished master piece. AB - Late preterm infants (LPI) are preterm infants born at a gestational age between 34 and 0/7 weeks to 36 6/7 weeks. Because of their physiologic and metabolic immaturities, they are at increased risk for a spectrum of morbidities and mortality when compared to the term infants. LPI are "great pretenders and masqueraders", as they pretend to be and masquerading as term infants. Because of their size, frequently they are treated as term infants with potential for bad consequences. In this review, the incidence and high risk factors for late preterm deliveries, early morbidities, late complications and management are described. Computerized data bases such as PubMed, OVID and Embase were searched between January 2005 and March 2012, by using the search terms, Late Preterm Infants and Near Term Infants. From this detailed search available, evidence based guidelines were incorporated in the care of these LPI. PMID- 24342190 TI - Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia. AB - Ataxia Telangiectasia (A-T) is a progressive childhood disorder characterized most notably by cerebellar degeneration and predisposition to cancer. A-T is caused by mutations in the kinase ATM, a master regulator of the DNA double strand break response. In addition to DNA-damage signaling defects, A-T cells display mitochondrial dysfunction that is thought to contribute to A-T pathogenesis. However, the molecular mechanism leading to mitochondrial dysfunction in A-T remains unclear. Here, we show that lack of ATM leads to reduced mitochondrial DNA (mtDNA) integrity and mitochondrial dysfunction, which are associated to defective mtDNA repair. While protein levels of mtDNA repair proteins are essentially normal, in the absence of ATM levels specifically of DNA ligase III (Lig3), the only DNA ligase working in mitochondria is reduced. The reduction of Lig3 is observed in different A-T patient cells, in brain and pre-B cells derived from ATM knockout mice as well as upon transient or stable knockdown of ATM. Furthermore, pharmacological inhibition of Lig3 in wild type cells phenocopies the mtDNA repair defects observed in A-T patient cells. As targeted deletion of LIG3 in the central nervous system causes debilitating ataxia in mice, reduced Lig3 protein levels and the consequent mtDNA repair defect may contribute to A-T neurodegeneration. A-T is thus the first disease characterized by diminished Lig3. PMID- 24342193 TI - [Clinical features of preterm infants born to mothers with systemic lupus erythematosus: a retrospective analysis]. AB - OBJECTIVE: To retrospectively characterize clinical features of preterm infants born to mothers with systemic lupus erythematosus (SLE). METHODS: Clinical data of preterm infants born to mothers with SLE in Peking Union Medical College Hospital over a period of more than 10 years (2000-2012) and preterm babies born to mothers without SLE in the same hospital and during the same time period were collected. Preterm-associated complications in the two groups of babies were comparatively analyzed. RESULTS: During the time period studied, 128 women with SLE delivered a total of 134 babies, 86 at full-term and 42 at preterm. Of the 42 preterm infants, 4 were diagnosed with neonatal lupus syndrome. Neonatal infection was the most common complication in preterm infants born to SLE mothers, which occurred in 20 cases (47.62%), followed by small for gestational age (28.57%), neonatal respiratory distress syndrome (26.19%), congenital heart disease (14.29%), and neonatal pulmonary hemorrhage (4.76%). In the same time period, 2 308 preterm babies were born to mothers without SLE. In these preemies, 16.81% experienced neonatal infection, 13.21% were small for gestational age, and 5.16% had congenital heart disease. All these parameters were significantly lower than in preterm babies born to mothers with SLE (P<0.05). CONCLUSIONS: SLE preterm offspring seem to be more prone to neonatal infection, small for gestational age and at a higher risk of congenital heart disease as compared to preterm babies from women without SLE. PMID- 24342194 TI - [Investigation of risk factors for hearing impairment in premature infants]. AB - OBJECTIVE: To investigate the risk factors for hearing impairment in premature infants. METHODS: A total of 895 premature infants who were admitted to the neonatal intensive care unit from January to December 2010 were evaluated using distortion product otoacoustic emission to detect hearing impairment. The failure rates in initial screening and secondary screening were recorded. The risk factors for failure to pass hearing screenings were elucidate using multivariate logistic regression analysis. RESULTS: The failure rate in initial screening was 38.4%, and the failure rate in secondary screening was 18.3%. In the auditory brainstem response test conducted at three months after birth, the failure rate was 22.2%. In premature infants with a gestational age of 28-29(+6) weeks, 60.5% did not pass the initial screening; 48.1% of the premature infants with a birth weight of 1 001-1 499 g failed the initial screening; 70.0% of the premature infants with a birth weight of <=1 000 g failed the initial screening; 53.8% of the premature infants who had severe asphyxia failed the initial screening; 45.0% of the premature infants who used invasive ventilation failed the initial screening; 47.9% of the premature infants with a total bilirubin of >=340 umol/L failed the initial screening; 54.6% of the premature infants with septicemia failed the initial screenings. The multivariate logistic regression analysis revealed the following independent risk factors for failing the initial and secondary hearing screenings: gestational age, birth weight, hyperbilirubinemia and septicemia. CONCLUSIONS: Premature infants are susceptible to hearing impairment because they have immature organs and tissues and incomplete blood brain barrier function and are sensitive to such factors as hyperbilirubinemia and infection. Early hearing screening and follow-up are necessary for premature infants to ensure timely interventions. PMID- 24342195 TI - [Effect of positive nutritional support strategy on extrauterine growth restriction in preterm infants]. AB - OBJECTIVE: To investigate the effects of positive nutritional support in the early stage after birth on the nutritional status during hospitalization and extrauterine growth restriction (EUGR) in preterm infants. METHODS: There were two groups of preterm infants. Group A (n=99) was given the previous nutritional program, while group B (n=101) was given positive nutritional support. The nutritional intake, growth rate and EUGR incidence were compared between the two groups. RESULTS: Compared with group A, group B had significantly higher enteral calorie intake and total calorie intake within one week after birth. Additionally, the age of first feeding, time of regaining birth weight, duration of intravenous nutrition, time to full enteral feeding, and length of hospital stay in group B were all shorter than in group A. Group B also had less physiological weight loss than group A. Among the preterm infants with a gestational age less than 32 weeks, group B had faster increases in body weight, head circumference, and body length and a lower incidence of EUGR compared with group A. Among the preterm infants with a gestational age not less than 32 weeks, group B had faster increases in body weight and a lower incidence of EUGR (evaluated based on body weight and head circumference) compared with group A. During hospitalization, group B had significantly lower incidence of feeding intolerance, necrotizing enterocolitis, and sepsis than group A. CONCLUSIONS: Positive nutritional support strategy, applied in preterm infants early after birth, can effectively improve their nutritional status during hospitalization and reduce the incidence of EUGR without increasing the incidence of related complications during hospitalization. PMID- 24342196 TI - [Clinical study of iron protein succinylate oral solution for preventing and treating anemia of prematurity]. AB - OBJECTIVE: To evaluate the efficacy and safety of iron protein succinylate (IPS) oral solution in preventing and treating anemia of prematurity (AOP). METHODS: Sixty premature infants less than 35 weeks of gestation were randomly divided into IPS (n=30) and polysaccharide iron complex (PIC) groups(n=30). Treatment began at two weeks after birth. The infants received IPS or PIC in addition to recombinant human erythropoietin. On days 14, 28, 42, and 60 after treatment, hemoglobin (Hb), red blood cell count(RBC), hematocrit (HCT), percentage of reticulocytes, serum iron, and serum ferritin were determined. Liver and renal functions were evaluated before and after treatment. RESULTS: There were significant differences in the changing trends of RBC and HCT between the two groups (P<0.05). In the IPS group, RBC and HCT gradually decreased after birth, but began to rise gradually on days 28 and 42 of treatment; in the PIC group, RBC and HCT kept decreasing from birth to day 60 of treatment. On day 60 of treatment, the IPS group had significantly higher levels of Hb, RBC, HCT, serum iron, and serum ferritin than the PIC group (P<0.05). No notable adverse events occurred in either group. CONCLUSIONS: IPS oral solution has good efficacy and tolerability in preventing and treating AOP. PMID- 24342197 TI - [Effects of recombinant human erythropoietin on neurointelligence development in very low birth weight infants]. AB - OBJECTIVE: To evaluate the clinical effects of the early use of recombinant human erythropoietin (rhEPO) on the neurointelligence development in very low birth weight infants (VLBWI). METHODS: Seventy-eight VLBWI were divided into rhEPO treatment group (n=35) and control group (n=43) according to the choice of their parents. Neonatal behavioral neurological assessment (NBNA) was performed at 40 weeks of corrected gestational age. The Gesell Developmental Schedules were used for neurodevelopmental evaluation at 3, 6, and 12 months of corrected age. The abnormal rates of auditory brainstem response (ABR) and cranial ultrasound were evaluated at 6 months of corrected age. RESULTS: The rhEPO treatment group had significantly higher NBNA scores at 40 weeks of corrected gestational age than the control group (P<0.05). The adaptability at 3 months of corrected age, the gross motor, adaptability, and sociability at 6 months, and the gross motor, adaptability, fine motor, sociability, and language at 12 months were significantly better in the rhEPO treatment group than in the control group (P<0.05). The abnormal rates of ABR and cranial ultrasound in the rhEPO treatment group were significantly lower than in the control group at 6 months of corrected age (P<0.05). CONCLUSIONS: Early use of rhEPO can promote the early recovery of neurological symptoms and improve the cognitive, motor, and language abilities in VLBWI due to its protective effects on the nervous system. PMID- 24342198 TI - [Clinical effect of combination therapy with high-frequency oscillation ventilation, pulmonary surfactant and inhaled nitric oxide in the treatment of neonatal hypoxemic respiratory failure]. AB - OBJECTIVE: To investigate the clinical effect of combination therapy with high frequency oscillation ventilation (HFOV), pulmonary surfactant (PS) and inhaled nitric oxide (iNO) in the treatment of neonatal hypoxemic respiratory failure (HRF). METHODS: A total of 116 neonates with HRF were studied, and they were randomly divided into two groups: triple therapy (n=58) and dual therapy (n=58). The triple therapy group received HFOV, PS, and iNO, while the dual therapy group received HFOV and iNO. Blood gas values, PaO2/FiO2 (P/F), oxygenation index (OI), and pulmonary arterial pressure (PA) were determined before treatment and after 24 and 48 hours of treatment. Among the neonates with different P/F ratios and OI values and with or without persistent pulmonary hypertension of the newborn (PPHN), the treatment outcomes of two groups were compared. RESULTS: The durations of mechanical ventilation and iNO therapy in the triple therapy group were significantly shorter than in the dual therapy group (P<0.01). After 24 and 48 hours of treatment, the triple therapy group had significantly improve PaO2 and PaCO2 compared with the dual therapy group (P<0.01). After 24 and 48 hours of treatment, the neonates with PPHN in the triple therapy group had significantly decreased PA compared with the dual therapy group (P<0.01). In the cases with a P/F ratio of <=50, the triple group had a significantly higher cure rate than the dual therapy group (P<0.05). In both groups, the P/F ratios of the neonates who died were significantly lower than those of survivors (P<0.01). In the cases with an OI of >=40, the triple group had a significantly higher cure rate than the dual therapy group (P<0.05). In both groups, the OI values of the neonates who died were significantly higher than those of survivors (P<0.01). In neonates with PPHN, the triple group had a significantly higher cure rate than the dual therapy group (P<0.05). The triple therapy group had a significantly shorter length of hospital stay (P<0.01) and a significantly higher cure rate (P<0.05) compared with the dual therapy group. There were no significant differences in complications between the two groups (P>0.05). No severe side effect was found during the treatment in either group. CONCLUSIONS: Triple therapy with HFOV, PS and iNO is a more effective treatment for neonatal HRF compared with the dual therapy with HFOV and iNO. The triple therapy can significantly improve oxygenation and survival rate, providing a new treatment for the neonates with HRF, especially the critical cases who suffer severe lung disease with PPHN and have a P/F ratio of <=50 or an OI of >=40. PMID- 24342199 TI - [Clinical characteristics of abdominal distention in early newborns]. AB - OBJECTIVE: Abdominal distention is a common disorder in newborns, which can be life-threatening in severe cases. Currently, little literature is available regarding early identification of the etiology of this disorder in newborn babies, which is imperative to reducing the likelihood of serious consequences. This retrospective study was conducted to analyze the clinical characteristics of early newborns with abdominal distention, aiming at identifying the underlying etiologic factors. METHODS: Medical records of 201 (65 premature and 136 full term) early newborns with abdominal distention between January 2011 and December 2012 were retrieved. RESULTS: Congenital malformations (including congenital megacolon, anal atresia, malrotation, intestinal atresia, intestinal duplication and posterior urethral valves) occurred in 44.6% of the premature newborns with abdominal distention and 61.8% of the full-term newborns with the disorder. Congenital megacolon was the number one cause of abdominal distention in the full term group (33.8%) and the number two cause in the preterm group (13.8%). As far as other individual abnormalities were concerned, sepsis was the number one cause of abdominal distention in the preterm group (35.4%) and the number two cause in the full-term group (21.3%). Vomiting was a main symptom associated with abdominal distension, occurring in 64.0% of the full-term newborns and 44.6% of the preterm newborns. The most pronounced X-ray manifestation was bowel distention with an air-fluid level in the preterm group (47.7%) but was bowel distention without a fluid level in the full-term group (57.3%). Eliological and symptomatic treatment was effective in 86.2% of the premature cases and 88.2% in the full-term cases (P>0.05). CONCLUSIONS: Congenital malformations may be the major cause of abdominal distension in early newborns. Sepsis and congenital megacolon are the single disease most frequently associated with abdominal distention in preterm and full-term newborns respectively. Vomiting is a main accompanying symptom in early newborns with abdominal distention. X-ray manifestations seem to be more severe in preterm newborns than in full term newborns. A satisfactory outcome can be achieved after treatment in both preterm and full-term newborns with this disorder. PMID- 24342200 TI - [Changes in epidermal growth factor concentrations in neonates with late-onset breast milk jaundice after stopping breast feeding]. AB - OBJECTIVE: To investigate the changes in epidermal growth factor (EGF) concentrations in infants' serum and breast milk in neonates with late-onset breast milk jaundice after stopping breast feeding. METHODS: Thirty full-term infants with late-onset breast milk jaundice were included in the study. Infants' serum and breast milk were collected before and 72 hours after stopping breast feeding, and the total bilirubin and EGF concentrations in infants' serum and EGF concentration in breast milk were measured respectively. RESULTS: At 72 hours after stopping breast feeding, the total bilirubin and EGF concentrations in infants' serum were significantly decreased (P<0.05), but the EGF concentration in breast milk did not show significant change (P>0.05). CONCLUSIONS: After stopping breast feeding, the neonates with late-onset breast milk jaundice show significant decreases in serum EGF concentration, but the EGF concentration in breast milk shows no significant change. The role and action mechanism of EGF in late-onset breast milk jaundice need further study. PMID- 24342201 TI - [Risk factors for prognosis of neonatal necrotizing enterocolitis: an analysis of 82 cases]. AB - OBJECTIVE: To study the risk factors for prognosis of neonatal necrotizing enterocolitis (NEC). METHODS: A retrospective analysis was performed on the clinical data of 82 neonates with NEC confirmed between January 2008 and October 2012. The possible prognostic factors in NEC were investigated by logistic regression analysis. RESULTS: In the 82 cases of NEC, the cure rate decreased with the aggravation of condition (P<0.05). The preterm infants had a significantly higher incidence of NEC than the full-term infants at three or more weeks after birth (P=0.004). The univariate analysis showed that the prognosis of NEC was related to the factors such as sepsis, congenital heart disease, scleredema, peritonitis, metabolic acidosis, hyponatremia, leukocyte disorder, thrombocytopenia, elevated C-reactive protein, and severe abdominal X-ray abnormalities (P<0.05), and the further logistic regression analysis revealed that congenital heart disease, scleredema, and metabolic acidosis were main risk factors for the clinical outcome of NEC (P<0.05). CONCLUSIONS: The onset time of NEC is correlated with gestational age in neonates. There are multiple prognostic factors in NEC; special attention should be paid to the patients with congenital heart disease, scleredema, and metabolic acidosis so that early intervention is performed to reduce mortality. PMID- 24342202 TI - [Application of throat swab nested PCR in the diagnosis of congenital human cytomegalovirus infection in neonates]. AB - OBJECTIVE: To evaluate the clinical application value of throat swab nested PCR for detecting active congenital human cytomegalovirus (HCMV) infection in neonates. METHODS: The throat swabs and umbilical cord blood specimens from 51 neonates were collected for nested PCR assay for HCMV glycoprotein B (gB) gene. Moreover, 18 of them were subjected to a pp65 antigen test. RESULTS: The sensitivity and specificity of throat swab nested PCR for HCMV gB gene were 67% and 75%, respectively, and the positive and negative predictive values were 57% and 82%, respectively. CONCLUSIONS: Throat swab nested PCR assay for HCMV gB gene is non-invasive, rapid, and highly sensitive for HCMV detection and holds promise as an excellent screening technology for detecting active congenital HCMV infection in neonates. PMID- 24342203 TI - [Influence of different antibiotic strategies on outcomes of hospitalized neonates]. AB - OBJECTIVE: To observe the outcomes of hospitalized neonates who were managed with two different antibiotics strategies, namely, the risk factor based antibiotic strategy and the combination antibiotic strategy that is based on risk factors, infection screening and monitoring. METHODS: A cohort study was performed on a control group of 4 406 cases of neonates hospitalized between January 2010 and May 2011 and an observed group of 4 476 neonates hospitalized between July 2011 and October 2012. The control group adopted the risk factor based antibiotic strategy and the observed group received a combination antibiotic strategy based on risk factors, infection screening and monitoring. The rate of antibiotic use, average length of stay, readmission rate and mortality rate were compared between the two groups. RESULTS: With the change from the risk factor based antibiotic strategy to the combination antibiotic strategy, the total rate of antibiotic use decreased from 79.6% to 50.5% (P<0.01). There were no differences in the average length of stay, readmission rate, and mortality rate between the two groups. CONCLUSIONS: The combination antibiotic strategy based on risk factors, infection screening and monitoring can reduce antibiotic use substantially and has no adverse effects on treatment outcomes in hospitalized neonates. PMID- 24342204 TI - [Octreotide as a treatment of congenital chylothorax]. PMID- 24342205 TI - [Enterococcus gallinarum meningitis: a case report]. PMID- 24342206 TI - [Multiple acyl-CoA dehydrogenase deficiency in a neonate]. PMID- 24342207 TI - [Clinical application of inhaled nitric oxide in hypoxic respiratory failure of preterm infants]. AB - Inhaled NO (iNO) has been shown to have beneficial effects on decreasing pulmonary inflammation, increasing function of surfactant and improving lung growth in prematurely born animal models. iNO has been gradually applied in the neonatal intensive care unit since its first use for persistent pulmonary hypertension (PPHN) in the early 1990's. Although many research findings have shown the benefits of iNO for hypoxic respiratory failure (HRF) of preterm infants, there is no certain evidence to support the routine use of iNO in premature infants. According to recent literature, the mechanism of iNO therapy, treatment scheme, iNO effectiveness and safety in premature infants were reviewed in this article, so as to provide bases for the clinical use of this treatment. PMID- 24342208 TI - [Circulating microRNA expression in children with idiopathic short stature]. AB - OBJECTIVE: To study the role of circulating microRNAs (miRNA) in the pathogenesis of idiopathic short stature (ISS) through detecting miRNA expression profile in plasma of children with ISS. METHODS: Plasma miRNA expression was determined by microarray in 20 children with ISS and 20 healthy children. Altered microRNAs were verified by real-time PCR. The online miRNA target gene prediction software was used to predict and screen miRNA differentially expressed target genes. RESULTS: According to the microarray, there were 40 differentially expressed miRNAs in the ISS group compared with the control group, including 24 up regulated miRNAs and 16 down-regulated miRNAs. Real-time PCR verified two up regulated (miR-185and miR-574-5p) and two down-regulated miRNAs (miR-497and miR 15a) and confirmed that plasma miR-185 expression was significantly up-regulated (P<0.05) and miR-497 expression was significantly down-regulated (P<0.05) in children with ISS. CONCLUSIONS: Plasma miRNA expression levels in children with ISS are significantly different from healthy controls, suggesting that plasma miRNA is associated with the pathogenesis of ISS. PMID- 24342209 TI - [Expression of sICAM-1 in children with intravenous immunoglobulin-resistant Kawasaki disease]. AB - OBJECTIVE: To investigate the expression of soluble intercellular adhesion molecule-1 (sICAM-1) and itd significance in children with intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD). METHODS: A total of 271 children with KD who received IVIG treatment (including 252 IVIG-sensitive cases and 19 IVIG-resistant cases) were selected in the study; 78 of the 271 children had coronary artery dilation. Thirty-six age-matched healthy children were selected as the control group. Plasma sICAM-1 levels were measured using enzyme linked immunosorbent assay. White blood cell count (WBC), neutrophil count, C relative protein (CRP), aspartate aminotransferase(AST), serum sodium, and serum potassium were measured by laboratory tests. RESULTS: Before IVIG treatment, the IVIG-sensitive cases and IVIG-resistant cases had significantly higher sICAM-1 levels than the control group (P<0.05), and the IVIG-resistant cases had significantly higher sICAM-1 levels than the IVIG-sensitive cases (P<0.05). After 24-48 hours of IVIG treatment, the IVIG-resistant cases had significantly higher sICAM-1 levels than the IVIG-sensitive cases (P<0.05). Before IVIG treatment, among the IVIG-sensitive cases, the sICAM-1 level was significantly higher in those with coronary artery dilation than in those without coronary artery dilation (P<0.05); among the IVIG-resistant cases, the sICAM-1 level was significantly higher in those with coronary artery dilation than in those without coronary artery dilation (P<0.05). In the IVIG-resistant cases, sICAM-1 level was positively correlated with WBC (before and after treatment) (r=0.7562, P<0.01; r=0.8435, P<0.01) and CRP (after treatment) (r=0.8936, P<0.01). CONCLUSIONS: High sICAM-1 level may be used as a risk factor for resistance to IVIG and coronary artery dilation in children with KD. PMID- 24342210 TI - [Changes in Th17 and CD4+CD25+ Treg cells and their significance among children with hand, foot and mouth disease]. AB - OBJECTIVE: To investigate the changes in peripheral blood Th17 and CD4(+)CD25(+) regulatory T (Treg) cells and their significance among children with hand, foot and mouth disease (HFMD). METHODS: Eighty-nine children with HFMD, including 55 cases of common HFMD and 34 cases of severe HFMD, were included in the study; and 30 healthy children were selected as the control group. The percentages of Th17 and CD4(+)CD25(+) Treg cells in CD4(+) T cells in peripheral blood were determined by flow cytometry. The expression levels of interleukin (IL)-10, transforming growth factor-beta (TGF-beta), and IL-17 were measured by enzyme linked immunosorbent assay. RESULTS: Compared with the control group, the cases of common HFMD and severe HFMD had significantly increased levels of Th17 cells and IL-17 (P<0.05) but significantly decreased levels of CD4(+)CD25(+) Treg cells, IL-10, and TGF-beta (P<0.05). The severity of the HFMD was positively correlated with the levels of Th17 cells and IL-17 in peripheral blood but negatively correlated with the levels of CD4(+)CD25(+) Treg cells, IL-10, and TGF beta. CONCLUSIONS: Children with HFMD have increased response of Th17 cells but decreased response of CD4(+)CD25(+) Treg cells in peripheral blood. Th17/CD4(+)CD25(+) Treg cell imbalance may play an important role in the pathogenesis of HFMD. PMID- 24342211 TI - [Levels of myeloid-derived suppressor cells in peripheral blood of infants with recurrent wheezing]. AB - OBJECTIVE: To study myeloid-derived suppressor cells (MDSC) levels in peripheral blood of infants with recurrent wheezing, and the role of MDSC in the development of recurrent wheezing. METHODS: Thirty-one infants with recurrent wheezing at wheezing attacks were randomly enrolled in the study. Twenty-seven infants with bronchopneumonia and 27 preoperative infants (hernia or renal calculus), without infectious or neoplastic diseases, were selected as controls. The proportion of MDSC in peripheral blood mononuclear cells (PBMC) was measured by flow cytometry. RESULTS: The proportion of MDSC in PBMC in infants with wheezing was significantly higher than in those with bronchopneumonia and preoperative infants (P<0.05). CONCLUSIONS: MDSC levels increase in infants with recurrent wheezing, suggesting that MDSC may play a crucial role in the development of this disorder. PMID- 24342212 TI - [Dynamic changes in plasma D-dimer level and its prognostic value in children with severe hand-foot- mouth disease]. AB - OBJECTIVE: To study the dynamic changes in plasma D-dimer and its prognostic value in children with severe hand-foot-mouth disease (HFMD). METHODS: A total of 95 children who suffered from HFMD between May 2010 and September 2012, including 65 cases of severe HFMD (observation group) and 30 cases of non-severe HFMD (control group), were enrolled in the study. Plasma D-dimer levels of the observation group on days 1, 2, 3, 4 and 5 were compared with plasma D-dimer levels of the control group on day 1 after admission. In the observation group, plasma D-dimer levels on days 1, 2, 3, 4 and 5 were compared. The prognostic value of plasma D-dimer was analyzed using the receiver operating characteristic (ROC) curve. RESULTS: Of the 65 cases in the observation group, 15 died, and 50 survived. All the 30 cases in the control group survived. Plasma D-dimer levels in the observation group on days 1, 2, 3, 4 and 5 were significantly higher than in the control group on day 1 after admission (P<0.05). In the observation group, there were significant differences between plasma D-dimer levels on days 1, 2, 3, 4 and 5 (P<0.01), and plasma D-dimer level was the highest on day 1 after admission and second highest on the next day. Of the patients in the observation group, those who died had significantly higher plasma D-dimer levels on day 1 after admission than those who survived (P<0.05). In the observation group, plasma D-dimer levels on day 1 after onset had an area under the ROC curve of 0.877 (95% confidence interval: 0.785-0.969) and an optimal cut-off value of 582.10 MUg/L (80% sensitivity and 78% specificity) for predicting mortality. CONCLUSIONS: Children with severe HFMD have significantly increased plasma D dimer levels, and the severer the condition, the higher the value. Plasma D-dimer levels can be used as one of the important indices for assessing the severity and prognosis of severe HFMD. PMID- 24342213 TI - [Probiotics improve obesity-associated dyslipidemia and insulin resistance in high-fat diet-fed rats]. AB - OBJECTIVE: To evaluate the effect of probiotics (bifidobacterium breve and lactobacillus acidophilus) on serum lipid, serum insulin and insulin resistance in high-fat diet (HFD)-induced obese rats. METHODS: Fifty male Sprague-Dawley rats were randomly assigned to a control (n=10) and a high fat diet groups (n=40) and were fed with standard diet and HFD respectively. Four weeks later, thirty six HFD-induced obese rats were randomly administered with normal saline (NS), bifidobacterium breve and lactobacillus acidophilus daily (n=12 each). Four weeks later, body lengths, body weights and abdomen circumference of rats were measured, blood lipid, glucose and insulin levels were measured, and Lee's index and insulin resistance index were calculated. RESULTS: Body weight, abdomen circumference, Lee's index, fasting glucose, triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL) in the NS-treated HFD group were significantly higher than the control group (P<0.05). The bifidobacterium breve and lactobacillus acidophilus-treated groups had significantly lower levels of body weight, abdomen circumference, Lee's index, fasting glucose, TC, TG and LDL than the NS-treated HFD group (P<0.05), but the levels of the parameters in the bifidobacterium breve and lactobacillus acidophilus-treated groups were significantly higher than the control group (P<0.05). High density lipoprotein (HDL) and insulin sensitivity index in the NS-treated HFD group were significantly lower than the control group (P<0.05). Bifidobacterium breve and lactobacillus acidophilus treatment dramatically increased HDL levels and insulin sensitivity index compared with the NS-treated HFD group (P<0.05), although the levels of the two parameters did not reach to the levels of the control group. There were significant differences in the levels of fasting insulin, insulin resistance index and insulin secretion index between the bifidobacterium breve and lactobacillus acidophilus groups (P<0.05). CONCLUSIONS: Lactobacillus acidophilus and bifidobacterium breve can decrease serum levels of lipid and glucose and improve insulin resistance in obese rats. Bifidobacterium breve seems to be more effective on attenuating insulin resistance than lactobacillus acidophilus. PMID- 24342214 TI - [Effect of astragalus injection on U937 leukemia cells proliferation and apoptosis and relevant molecular mechanisms]. AB - OBJECTIVE: To study the effect of astragalus injection on U937 leukemia cells proliferation and apoptosis and relevant molecular mechanisms. METHODS: Leukemia cell line U937 cells were treated with different concentrations of astragalus (62.5, 125, 250, 500, 1 000 MUg/mL). The U937 cells without astragalus treatment were used as the control group. The ability of cell proliferation was measured by MTT method. Flow cytometry was used to explore cell apoptosis. The cell morphology changes were observed under a fluorescent microscope by dyeing Hoechst33258. mRNA expression of c-myc and p27 in U937 cells which was exposed in 1 000 MUg/mL astragalus after 0, 12, 24 and 48 hours was detected by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Various concentrations of astragalus injection inhibited U937 cell proliferation effectively compared with the control group (P<0.05). They also induced U937 cells apoptosis and the apoptosis rate reached to (63 +/- 4)% in the 1 000 MUg/mL astragalus treatment group. mRNA expression level of c-myc was gradually declined and p27 mRNA expression was gradually increased with astragalus treatment time (P<0.01). CONCLUSIONS: Astragalus injection may inhibit proliferation and induce apoptosis of leukemia cell line U937 in vitro. This contributes to down-regulation of c-myc expression and up-regulation of p27 expression. PMID- 24342215 TI - [Effect of IL-18BP on Fractalkine chemokine expression in the kidney tissue of rats with renal fibrosis]. AB - OBJECTIVE: To study the expression of Fractalkine (FKN) in the kidney tissue of rats with renal fibrosis and the effect of IL-18BP on FKN. METHODS: Male Wister rats were randomly assigned to sham-operation (n=24), unilatral ureteral obstruction (UUO, n=22), and IL-18 binding protein (IL-18BP) treatment groups (n=23). The UUO model was prepared by unilateral ureteral ligation in the later two groups. The IL-18BP treatment group received an intraperitoneal injection of IL-18BP (0.1 mg/kg) every other day after UUO inducement, for 7 times, while normal saline was administered in the other two groups. Seven or eight rats of every group were sacrificed at 3, 7 or 14 days after IL-18BP or normal saline injections. FKN levels at various times were detected by immunohistochemistry and Western blot. RESULTS: Compared with the sham-operation group, FKN levels in the kidney tissue of the untreated UUO group increased significantly at all time points (P<0.01). IL-18BP treatment decreased significantly FKN levels in the kidney tissue at all time points compared with the untreated UUO group (P<0.01). CONCLUSIONS: IL-18BP treatment may down-regulate the increased FKN levels of the rat kidney tissue caused by UUO, possibly thus delays the occurrence and development of renal fibrosis. PMID- 24342216 TI - [Clinical analysis of chemotherapy-related neutropenic enterocolitis in children with acute leukemia]. PMID- 24342217 TI - [Clinical analysis of 24 cases of childhood thromboembolism]. PMID- 24342218 TI - [Clinical features of 37 cases of Panayiotopoulos syndrome]. PMID- 24342219 TI - [Epilepsy as the first presentation in a child with type 1 diabetes mellitus]. PMID- 24342220 TI - [Listeria monocytogenes meningitis in infants: report of two cases]. PMID- 24342221 TI - New advice on switching antiepileptic drugs might be a false economy. PMID- 24342222 TI - Major obstetric haemorrhage: monitoring with thromboelastography, laboratory analyses or both? AB - BACKGROUND: Haemorrhage is a common cause of morbidity and mortality in the obstetric population. The aim of this study was to compare the use of thromboelastography and laboratory analyses to evaluate haemostasis during major obstetric haemorrhage. A secondary aim was to evaluate correlations between the results of thromboelastography, laboratory analyses and estimated blood loss. METHODS: Forty-five women with major obstetric haemorrhage and 49 women with blood loss <600 mL were included. The following thromboelastography analyses were performed: time to start of clotting (TEG-R), time to 20 mm of clot firmness (TEG K), rate of clot growth (TEG-Angle), maximum amplitude of clot (TEG-MA) and lysis after 30 min (TEG-LY30). In addition, platelet count, activated partial thromboplastin time, prothrombin time, fibrinogen, antithrombin and D-dimer were measured. RESULTS: Thromboelastography variables reflecting clot stability and fibrinolysis were decreased in women with massive obstetric haemorrhage compared to women with normal bleeding, while clot initiation was accelerated. Laboratory analyses also showed impaired haemostasis with the most pronounced differences in platelet count, fibrinogen concentration and antithrombin activity. The strongest correlations existed between fibrinogen and TEG-MA and between estimated blood loss and TEG-MA, fibrinogen and antithrombin, respectively. CONCLUSIONS: Impaired haemostasis, demonstrated by thromboelastography and laboratory analyses, was found after an estimated blood loss of 2000 mL. Thromboelastography provides faster results than standard laboratory testing which is advantageous in the setting of on-going obstetric haemorrhage. However, laboratory analyses found greater differences in coagulation variables, which correlated better with estimated blood loss. PMID- 24342223 TI - An observational assessment of the sublingual microcirculation of pregnant and non-pregnant women. AB - BACKGROUND: The microcirculation is responsible for distribution of blood within tissues, delivery of oxygen and other nutrients, and regulation of blood pressure. The objective of this study was to compare the sublingual microcirculation of pregnant participants to that of comparable non-pregnant volunteers. METHODS: Two groups of participants were recruited: a group of pregnant, non-laboring women with singleton pregnancies at term gestation and a control group of age-comparable non-pregnant volunteers. A sidestream dark field imaging device was applied to the sublingual mucosal surface obtaining a steady image for at least 20 s duration, in five visual fields. The resultant five video clips per participant were analyzed blindly and at random to prevent coupling between images. The mean microvascular flow index values for each group were compared using a paired t-test. RESULTS: Thirty-seven participants were recruited (19 pregnant, 18 non-pregnant); a single pregnant participant was withdrawn because of technical issues. Baseline characteristics were similar with the exception of weight and body mass index. The mean microvascular flow index was significantly higher in the pregnant group 2.7 +/- 0.2 compared to the non pregnant group 2.5 +/- 0.3 (P = 0.021), while the perfused vessel density and proportion of perfused vessels were not significantly different (P = 0.707 and 0.403, respectively). CONCLUSION: The microvascular flow index of pregnant women is higher than a comparable non-pregnant group, which appears to correlate with the physiological changes of pregnancy. PMID- 24342224 TI - Greenwood frequency-position relationship in the primary auditory cortex in guinea pigs. AB - Although orderly representation of sound frequency over space is a hallmark feature of the primary auditory cortex (A1), the quantitative relationship between sound frequency and cortical position is unclear. We examined this relationship in the guinea pig A1 by presenting a series of stimulus tones with a wide frequency range, and recording the evoked cortical responses using an optical imaging technique with high spatial resolution. We identified the cortical positions of three best-frequency indices for each tone: the onset response position, the peak amplitude position, and the maximum rise rate position of the response. We found a nonlinear log frequency-position relationship for each of the three indices, and the frequency-position relationship was always well described by a Greenwood equation, with correlation coefficients greater than 0.98. The cortical magnification factor, measured in octave/mm, was found to be a function of frequency, i.e. not a constant. Our results are novel in that they demonstrate a quantitative relationship between sound frequency and cortical position in the guinea pig A1, as described by the Greenwood equation. PMID- 24342225 TI - Why diffusion tensor MRI does well only some of the time: variance and covariance of white matter tissue microstructure attributes in the living human brain. AB - Fundamental to increasing our understanding of the role of white matter microstructure in normal/abnormal function in the living human is the development of MR-based metrics that provide increased specificity to distinct attributes of the white matter (e.g., local fibre architecture, axon morphology, and myelin content). In recent years, different approaches have been developed to enhance this specificity, and the Tractometry framework was introduced to combine the resulting multi-parametric data for a comprehensive assessment of white matter properties. The present work exploits that framework to characterise the statistical properties, specifically the variance and covariance, of these advanced microstructural indices across the major white matter pathways, with the aim of giving clear indications on the preferred metric(s) given the specific research question. A cohort of healthy subjects was scanned with a protocol that combined multi-component relaxometry with conventional and advanced diffusion MRI acquisitions to build the first comprehensive MRI atlas of white matter microstructure. The mean and standard deviation of the different metrics were analysed in order to understand how they vary across different brain regions/individuals and the correlation between them. Characterising the fibre architectural complexity (in terms of number of fibre populations in a voxel) provides clear insights into correlation/lack of correlation between the different metrics and explains why DT-MRI is a good model for white matter only some of the time. The study also identifies the metrics that account for the largest inter-subject variability and reports the minimal sample size required to detect differences in means, showing that, on the other hand, conventional DT-MRI indices might still be the safest choice in many contexts. PMID- 24342226 TI - Looking for a face in the crowd: fixation-related potentials in an eye-movement visual search task. AB - Despite the compelling contribution of the study of event related potentials (ERPs) and eye movements to cognitive neuroscience, these two approaches have largely evolved independently. We designed an eye-movement visual search paradigm that allowed us to concurrently record EEG and eye movements while subjects were asked to find a hidden target face in a crowded scene with distractor faces. Fixation event-related potentials (fERPs) to target and distractor stimuli showed the emergence of robust sensory components associated with the perception of stimuli and cognitive components associated with the detection of target faces. We compared those components with the ones obtained in a control task at fixation: qualitative similarities as well as differences in terms of scalp topography and latency emerged between the two. By using single trial analyses, fixations to target and distractors could be decoded from the EEG signals above chance level in 11 out of 12 subjects. Our results show that EEG signatures related to cognitive behavior develop across spatially unconstrained exploration of natural scenes and provide a first step towards understanding the mechanisms of target detection during natural search. PMID- 24342227 TI - Estimation of parasympathetic nerve function during sleep in patients with obstructive sleep apnea by instantaneous time-frequency analysis. AB - BACKGROUND AND OBJECTIVES: The pathophysiologic aspects of parasympathetic nerve (PN) function during sleep in patients with obstructive sleep apnea (OSA) studied by classical power spectrum analysis on heart rate variability (HRV) are highly controversial. The controversy is attributed to methodologic concerns, such as poor time resolution involved in power spectrum analysis. We aimed to establish the appropriate method for the investigation of PN function in OSA patients with apneas and hypopneas using instantaneous time-frequency analysis with complex demodulation (CD) and sufficient time resolution. METHODS: A total of 30 patients with PSG-confirmed mild to severe OSA were recruited for the analysis of frequency spectra contained in R-R intervals (RRI) of overnight electrocardiograph (ECG) tracings. High-frequency (HF) domains ranging between 0.15 and 0.40 Hz were selected for analysis. Among these domains, the HF domain with the maximum instantaneous amplitude was defined as the main HF peak and was used as the surrogate marker of PN discharge. Based on density spectrum array (DSA) map for main HF peak constructed with a time scale of 1s and a frequency resolution of 0.002 Hz (HF-DSA map), the shift in central frequency (CF) of main HF peak over time was continuously monitored. When the main HF peak with the same CF lasted for more than 20 s or 5 min on HF-DSA map, the PN function was considered to be stable or very stable. The measurements were then repeated after continuous positive airway pressure (CPAP) treatment. RESULTS: The extent of PN evoked modulation of RRI was enhanced in nonrapid eye movement (NREM) sleep, though the stability was reduced in both NREM and rapid eye movement (REM) sleep. These peculiar behaviors of PN function were reversed by CPAP treatment. CONCLUSION: We found that instantaneous time-frequency analysis allowed estimation of transitional changes in PN function during sleep in OSA patients. PMID- 24342228 TI - Video-mediastinoscopy is still the gold standard. PMID- 24342229 TI - Obstructive sleep apnea prevalence and adverse respiratory events in surgical patients. PMID- 24342230 TI - Comments on CSF kappaFLC assay evaluation in assessing intrathecal synthesis. PMID- 24342231 TI - CSF neurofilament light chain is elevated in OMS (decreasing with immunotherapy) and other pediatric neuroinflammatory disorders. AB - Using a panel of seven brain cell-specific biomarkers in cerebrospinal fluid (CSF), pediatric opsoclonus-myoclonus syndrome (OMS) (n=234) was compared to pediatric non-inflammatory neurological controls (n=84) and other inflammatory neurological disorders (OIND) (n=44). Only CSF NFL was elevated in untreated OMS versus controls (+83%). It was 87% higher in OIND than in OMS. On combination treatment with front-loaded ACTH, IVIg, rituximab, median CSF NFL decreased by 60% to control levels. These biochemical data suggest neuronal/axonal injury in some children with OMS without indicators of astrogliosis, and reduction on sufficient immunotherapy. PMID- 24342232 TI - Dermal toxicity, eye and dermal irritation and skin sensitization evaluation of a new formulation of Bacillus thuringiensis var israelensis SH-14. AB - Bacillus thuringiensis (Bt) is the best known and most widely used of all pesticidal microbes. The aim of this study was to assess the toxicity of a new formulation of Bacillus thuringiensis var israelensis SH-14 in rats through acute dermal toxicity, dermal and eye irritation experiments. The acute dermal toxicity and dermal and eye irritation studies were performed using rabbits according to the United States Environmental Protection Agency guidelines 885.3100, 870.2500 and 870.2500, respectively. The skin sensitization study was carried out in accordance to the EPA OPPTS 870.2600 using guinea pigs. There was no mortality and no evidence of treatment-related toxicity in acute dermal toxicity test. No dermal responses, including erythema/eschar or edema, were found in rabbits treated with the new formulation of Bti SH-14. Minimum response was observed after eye application of test substance. No skin sensitization reactions were observed after the challenge with the new formulation of Bti SH-14 in the Bti SH 14-treated guinea pigs. In summary, the present study demonstrated that the new formulation of Bti SH-14 is not acutely toxic via dermal route, has low eye irritation and would not cause dermal irritation or hypersensitivity to tested animals. PMID- 24342233 TI - Strengthening the foundation of next generation risk assessment. AB - In a recent draft report, Next Generation Risk Assessment: Incorporation of Recent Advances in Molecular, Computational, and Systems Biology, the US Environmental Protection Agency presents valuable contributions to understanding the roles that evolving toxicity testing methods and associated interpretative techniques can play in assessing the risks associated with chemical exposures. However, the evaluations presented in the NexGen report would benefit from more thorough consideration of several essential components of a critical review of toxicity data, e.g., data quality, data relevance, and the extent to which the test endpoints reflect adverse effects. Such considerations are necessary to ensure that the NexGen report evaluations--and the resulting conclusions and recommendations--are grounded in scientifically sound, representative data reviews. We illustrate these concerns with a critique of the report's prototype ozone evaluation. Although substantial additional research is needed before new toxicity data types can be used reliably in rigorous risk assessment applications, they clearly offer exciting opportunities for advancing toxicological science and risk assessment. By explicitly identifying limitations still to be addressed and providing stronger guideposts for future research needs, the NexGen report could serve an influential role in achieving the promise of these new research approaches. PMID- 24342234 TI - Estrogen and the cystic fibrosis gender gap. AB - Cystic fibrosis (CF) is the most frequent inherited disease in Caucasian populations and is due to a defect in the expression or activity of a chloride channel encoded by the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Mutations in this gene affect organs with exocrine functions and the main cause of morbidity and mortality for CF patients is the lung pathology in which the defect in CFTR decreases chloride secretion, lowering the airway surface liquid height and increasing mucus viscosity. The compromised ASL dynamics leads to a favorable environment for bacterial proliferation and sustained inflammation resulting in epithelial lung tissue injury, fibrosis and remodeling. In CF, there exist a difference in lung pathology between men and women that is termed the "CF gender gap". Recent studies have shown the prominent role of the most potent form of estrogen, 17beta-estradiol in exacerbating lung function in CF females and here, we review the role of this hormone in the CF gender dichotomy. PMID- 24342235 TI - Combined group and individual schema therapy for borderline personality disorder: a pilot study. AB - BACKGROUND AND OBJECTIVES: Schema Therapy (ST) is a highly effective treatment for Borderline Personality Disorder (BPD). In a group format, delivery costs could be reduced and recovery processes catalyzed by specific use of group processes. As patients may also need individual attention, we piloted the combination of individual and group-ST. METHODS: Two cohorts of BPD patients (N = 8, N = 10) received a combination of weekly group-ST and individual ST for 2 years, with 6 months extra individual ST if indicated. Therapists were experienced in individual ST but not in group-ST. The second cohort of therapists was trained in group-ST by specialists. This made it possible to explore the training effects. Assessments of BPD manifestations and secondary measures took place every 6 months up to 2.5 years. Change over time and differences between cohorts were analyzed with mixed regression. RESULTS: Dropout from treatment was 33.3% in Year 1, and 5.6% in Year 2, without cohort differences. BPD manifestations reduced significantly, with large effect sizes, and 77% recovery at 30 months. Large improvements were also found on general psychopathological symptoms, schema (mode) measures, quality of life, and happiness. Cohort-2 tended to improve faster, but there were no differences between cohorts in the long term. LIMITATIONS: The study was uncontrolled, training effects might have been non-specific, and the sample size was relatively small. CONCLUSIONS: Combined group-individual ST can be an effective treatment, but dropout might be higher than from individual ST. Addition of specialized group-ST seems to speed up recovery compared to only individual ST. PMID- 24342236 TI - Response to: Naming a novel hemoglobin variant. PMID- 24342238 TI - Design, synthesis and anti-Alzheimer properties of dimethylaminomethyl substituted curcumin derivatives. AB - Eight dimethylaminomethyl-substituted curcumin derivatives were designed and synthesized. The antioxidant test revealed that the synthesized compounds had higher free radical scavenging activity towards both 2,2-diphenyl-1 picrylhydrazyl free radicals (DPPH) (IC50 1.5-29.9MUM) and galvinoxyl radicals (IC50 4.9-41.1MUM) than the lead compound curcumin. Besides, compound 3a could effectively inhibit the Abeta self-aggregation in vitro. Investigated in phosphate-buffered solutions (pH=7.4) in the presence or absence of 0.1% FBS 3a showed a good stability while curcumin did not. Furthermore, 3a showed a good lipophilicity (logP=3.48), suggesting a potential ability to penetrate the blood brain-barrier. The aqueous solubility of the hydrochloride salt of 3a (16.7mg/mL) has also been significantly improved as compared with curcumin (<0.1mg/mL). PMID- 24342237 TI - Fluorescent probes of the isoxazole-dihydropyridine scaffold: MDR-1 binding and homology model. AB - Isoxazole-1,4-dihydropyridines (IDHPs) were tethered to fluorescent moieties using double activation via a lanthanide assisted Weinreb amidation. IDHP fluorophore conjugate 3c exhibits the highest binding to date for IDHPs at the multidrug-resistance transporter (MDR-1), and IDHP-fluorophore conjugates 3c and 7 distribute selectively in SH-SY5Y cells. A homology model for IDHP binding at MDR-1 is presented which represents our current working hypothesis. PMID- 24342239 TI - pH-rate profiles of L-arabinitol 4-dehydrogenase from Hypocrea jecorina and its application in L-xylulose production. AB - l-Arabinitol 4-dehydrogenase (LAD) from Hypocrea jecorina (HjLAD) was cloned and overexpressed in Escherichia coli BL21 (DE3). The kinetics of l-arabinitol oxidation by NAD(+), catalyzed by HjLAD, was studied within the pH range of 7.0 9.5 at 25 degrees C. The turnover number (kcat) and the catalytic efficiency (kcat/Km) were 4200min(-1) and 290mM(-1)min(-1), respectively. HjLAD showed the highest turnover number and catalytic efficiency among all previously characterized LADs. In further application of HjLAD, rare l-sugar l-xylulose was produced by the enzymatic oxidation of arabinitol to give a yield of approximately 86%. PMID- 24342240 TI - A tetradecapeptide somatostatin dicarba-analog: Synthesis, structural impact and biological activity. AB - We described here the first tetradecapeptide somatostatin-analogue where the disulfide bridge has been replaced by a carbon-carbon double bond. This analogue was prepared using microwave assisted ring closing metathesis (RCM) using the 2nd generation Grubbs as catalyst. Under our optimized conditions the cyclization between allylGly 3 and 14 proceeded in moderate yield, excellent cyclic/linear ratio and very high Z-double bond selectivity. NMR studies also demonstrated that the conformational flexibility of this peptide is increased in comparison to that of the natural hormone. Remarkably, this alkene-bridged somatostatin analog is highly selective against somatostatin receptors 1 and 5, suggesting that conformational rigidity is not required for the efficient interaction of somatostatin analogues with these two receptors. PMID- 24342241 TI - Effect of variation in signal amplitude and transit time on reliability analysis of ultrasonic time of flight diffraction characterization of vertical and inclined cracks. AB - The variation of amplitude and transit time of the diffracted signal from the crack-tip in complex geometry components and their resulting effect on the probability of detection (POD) and probability of sizing (POS) was studied. The diffracted signal amplitude has been evaluated from the standard expressions for diffraction coefficient, spatial attenuation and the transit time from the respective mathematical models for both vertical and inclined cracks. The same parameters namely the signal amplitude and the transit time have been measured through experiments conducted on simulated test specimens. It has been observed that the analytical and experimental results compare well with each other. Based on this result the trend and shape (width of the transition zone) of the POD/POS curves can be predicted. PMID- 24342242 TI - [Celiac disease in Mexico: describing the tip of the iceberg?]. PMID- 24342243 TI - The ethanol extract of Zingiber zerumbet Smith attenuates non-alcoholic fatty liver disease in hamsters fed on high-fat diet. AB - The beneficial effects of the ethanol extract of Zingiber zerumbet rhizome (EEZZR) for use in the treatment of non-alcoholic fatty liver disease (NAFLD) were investigated. Syrian golden hamsters were fed a high-fat diet to induce NAFLD. EEZZR (100, 200, or 300mg/kg) were orally administered by gavage once daily for 8weeks. The higher plasma levels of total cholesterol, triglycerides, free fatty acids, and hepatic lipids, as well as the degree of insulin resistance were lowered by EEZZR. Histological evaluation of liver specimens demonstrated that the hepatic steatosis of EEZZR-treated groups was improved. EEZZR decreased hepatic mRNA levels of sterol regulatory element-binding protein-1c and its lipogenic target genes. The hepatic mRNA expression of peroxisome proliferator activated receptor alpha, together with its target genes responsible for beta oxidation of fatty acids were also upregulated by EEZZR. In conclusion, these findings suggest that EEZZR has the promising potential to ameliorate NAFLD. PMID- 24342244 TI - [A prospective multicenter clinical trial of medical and surgical treatment for chronic rhinosinusitis]. AB - OBJECTIVE: To demonstrate the clinical outcomes of maximal medical therapy(MMT) and functional endoscopic sinus surgery+ maximal medical therapy (FESS+MMT) for moderate to severe chronic rhinosinusitis without nasal polyps (CRSsNP) in China, to provide clinical evidence for treatment recommendation. METHODS: A prospective multicenter case control study consisting of 90 strictly selected CRSsNP patients were carried out by ENT Hospital of SUN Yet-sen university and 7 other university affiliated hospitals across China from March 2011 to October 2012. All patients were selected to MMT group or FESS+MMT group followed by 3 months treatment and 6 months follow up. Treatment efficacy evaluation indicators included improvement of visual analogue scale (VAS) score, quality of life, CT score and post operative nasal endoscopic evaluations. SPSS16.0 software was used to analyze the data. RESULTS: All patients enrolled complied with moderate to severe CRSsNP evaluation criteria. There were no significant differences found in the baseline data between two groups (P > 0.05). (1) At the 3 time points (pre-treatment, 3 months and 6 mongths after treatment) , VAS overall symptom score in MMT group were 6.52 +/- 2.61, 2.66 +/- 2.10, 2.40 +/- 1.56, significant differences were found among them (t value were 2.083 and 2.295, both P < 0.05); in FESS+MMT group the values were 6.99 +/- 2.70, 0.95 +/- 0.84, 0.60 +/- 0.81, significant differences were found among them (t value were 3.582 and 5.196, both P < 0.05); SNOT-20 score in MMT group were 38.61 +/- 17.36, 18.59 +/- 14.04, 18.40 +/- 8.91, significant differences were found among them (t value were 2.737 and 2.657, both P < 0.05); in FESS+MMT group the values were 38.21 +/- 19.61, 5.94 +/- 5.01, 2.65 +/- 2.31, significant differences were found among them (t value were 3.247, 3.319, both P < 0.05). (2) FESS+MMT group relative to the MMT group in VAS overall symptom score and quality of life improvements appeared earlier and were more pronounced. (3) Overall treatment efficacy showed that in MMT group: complete control 14 cases (30.4%), partially control 31 cases (67.4%), uncontrolled 1 cases (2.2%); In FESS+MMT group: complete control 17 cases (38.6%), partially control 26 cases (59.1%), uncontrolled 1 cases (2.3%). (4) Patients' satisfaction survey showed that the number of the patients who were very satisfied with the efficacy in the FESS+MMT group were 2 times higher than the MMT group. CONCLUSIONS: (1) For moderate to severe CRSsNP, both MMT and FESS+MMT treatment can effectively control the overall symptoms and classified symptoms, reduce CT scores and significantly improve the quality of life, the ineffective rate is less than 5%. (2) FESS+MMT group in terms of improving symptoms and the onset time are better than MMT group, especially in improving the stuffy nose, head and face fullness, and mental and physical symptoms are better than MMT group. (3) FESS+MMT group showed better results in patient satisfaction survey compared to the MMT group. Therefore for moderate to severe CRSsNP patients, FESS+MMT therapy could be recommended as the preferred treatment. PMID- 24342245 TI - Gamma ray sterilization of delta inulin adjuvant particles (AdvaxTM) makes minor, partly reversible structural changes without affecting adjuvant activity. AB - We earlier identified a developmental series of seven isoforms/polymorphs of microparticulate inulin by comparing non-covalent bonding strengths. Their pharmaceutical utility lies in the modulation of cellular immunity, exploited as vaccine adjuvants (AdvaxTM) especially for delta inulin (DI). As such particles cannot be sterilized by filtration we explore the effect of (60)Co gamma radiation (GR) on inulin isoforms, particularly DI. Its adjuvant activity and overt physical properties were unaffected by normal GR sterilizing doses (up to 25kGy). Heating irradiated isoform suspensions near their critical dissolution temperature revealed increased solubility deduced to reflect a single lethal event in one component of a multi-component structure. Local oxidative effects of GR on DI were not found. The observed DI loss was almost halved by re-annealing at the critical temperature: surviving inulin chains apparently reassemble into smaller amounts of the original type of structure. Colorimetric tetrazolium assay revealed increases in reducing activity after GR of raw inulin powder, which yielded DI with normal physical properties but only 25% normal recovery yet 4* normal reducing ability, implying final retention of some GR-changed inulin chains. These findings suggest minimal inulin chain cleavage and confirm that GR may be a viable strategy for terminal sterilization of microparticulate inulin adjuvants. PMID- 24342246 TI - Cross-reactive immune response elicited by parenteral Vi polysaccharide typhoid vaccine against non-typhoid Salmonellae. AB - BACKGROUND: Despite 155000 deaths and over 90 million cases - and the current emergence of antimicrobial resistance - no vaccines are available against non typhoid Salmonellae (NTS). We recently presented immunological arguments for using the oral Salmonella Typhi Ty21a as surrogate vaccine against NTS strains: Ty21a elicits intestinal antibodies against typhoidal O-9,12 antigen, and numerous NTS strains share one or both of these structures with S. Typhi. The Vi polysaccharide vaccine can, presumably because of contaminating typhoidal lipopolysaccharide, also elicit a humoral response to O-9,12, although a lower one in magnitude than the Ty21a. In this study, the Vi vaccine was explored for cross-reactive immune response to various NTS strains, and compared to that elicited by the Ty21a vaccine. MATERIALS AND METHODS: Volunteers immunized with the Vi polysaccharide (Typherix((r)); n=25) were investigated for circulating plasmablasts secreting antibodies reactive with six NTS serotypes. The results were compared to those for 25 age- and gender-matched volunteers vaccinated with Ty21a (Vivotif((r))), as partly presented in our previous study. The cross reactive plasmablasts elicited by the Vi vaccine were also analyzed for homing receptor expressions. RESULTS: 49 out of 50 vaccinees showed a cross-reactive plasmablast response against S. Enteritidis sharing both O-9 and O-12 antigens with S. Typhi (mean: 95%CI 37: 19-55 and 363: 234-493 plasmablasts/10(6) PBMC in the Vi and the Ty21a group, respectively). The response against strains only sharing O-12 was weaker (22: 8-38 and 222: 105-338 against S. Typhimurium). Strains without typhoidal O-antigens generated no significant reactivity. The cross-reactive plasmablasts elicited by the Vi vaccine had systemic homing properties. CONCLUSIONS: The Vi vaccine elicited an immune response cross reactive with several NTS strains. This response was lower than that in Ty21a vaccinated volunteers. The clinical significance of these responses deserves further research with respect to both gastrointestinal and invasive NTS (iNTS) disease. PMID- 24342247 TI - BacMam virus-based surface display of the infectious bronchitis virus (IBV) S1 glycoprotein confers strong protection against virulent IBV challenge in chickens. AB - Avian infectious bronchitis virus (IBV) is associated with production inefficiencies in domestic fowl, and causes massive economic losses to the poultry industry worldwide. Progress has been made in designing novel and efficient candidate vaccines to control IBV infection. BacMam virus, a modified baculovirus mediating transgene expression under the control of a mammalian promoter, has emerged as a versatile and safe vector during vaccine development. In previous work, we generated the BacMam virus Ac-CMV-S1, which expressed the S1 glycoprotein of IBV-M41. We showed that Ac-CMV-S1 induced excellent cellular immunity, but did not confer adequate protection in chickens compared with the conventional inactivated vaccine. In the current study, we generated an improved BacMam virus, BV-Dual-S1. This virus displayed the S1 glycoprotein on the baculovirus envelope, and was capable of expressing it in mammalian cells. BV Dual-S1 elicited stronger humoral and cell-mediated immune responses, and showed greater capacity for induction of cytotoxic T lymphocyte responses, compared with Ac-CMV-S1 in specific pathogen-free chickens. A significant difference was not observed for protection rates between chickens immunized with BV-Dual-S1 (83%) or inactivated vaccine (89%) following challenge with virulent IBV-M41. Our findings show that the protective efficacy of BV-Dual-S1 could be significantly enhanced by baculovirus display technology. BacMam virus-based surface display strategies could serve as effective tools in designing vaccines against IB and other infectious diseases. PMID- 24342248 TI - Protective efficacy in mice of monovalent and trivalent live attenuated influenza vaccines in the background of cold-adapted A/X-31 and B/Lee/40 donor strains. AB - Influenza virus continues to take a heavy toll on human health and vaccination remains the mainstay of efforts to reduce the clinical impact imposed by viral infections. Proven successful for establishing live attenuated vaccine donor strains, cold-adapted live attenuated influenza vaccines (CAIVs) have become an attractive modality for controlling the virus infection. Previously, we developed the cold-adapted strains A/X-31 and B/Lee/40 as novel donor strains of CAIVs against influenza A and B viruses. In this study, we investigated the protective immune responses of both mono- and trivalent vaccine formulations in the mouse model. Two type A vaccines and one type B vaccine against A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), and B/Shangdong/7/97 in the background of the A/X-31 ca or B/Lee/40 ca were generated by a reassortment procedure and evaluated for their immunogenicity and protective efficacy. Each monovalent vaccine elicited high levels of serum antibodies and conferred complete protection against homologous wild type virus infection. As compared to the monovalent vaccines, trivalent formulation induced higher levels of type A-specific serum antibodies and slightly lower levels of type B-specific antibodies, suggesting an immunological synergism within type A viruses and an interference in the replication of type B virus. Relatively lower type B-specific immunogenicity in trivalent vaccine formulation could be effectively implemented by increasing the vaccine dose of influenza B virus. These results of immunogenicity, protection efficacy, and immunological synergism between type A vaccines provide an experimental basis for optimal composition of trivalent vaccines for subsequent developments of multivalent CAIVs against seasonal and pandemic influenza viruses. PMID- 24342249 TI - Serotype distribution and antimicrobial susceptibilities of nasopharyngeal isolates of Streptococcus pneumoniae from healthy children in the 13-valent pneumococcal conjugate vaccine era. AB - Few epidemiological data are available since the introduction of 13-valent pneumococcal vaccine (PCV13) in 2010. We conducted a cross-sectional study to estimate the prevalence of Streptococcus pneumoniae (SP) nasopharyngeal carriage in healthy Italian infants and young children and to evaluate the impact of PCV13 on pneumococcal colonization. In the trimester September-December 2011 nasopharyngeal swabs were collected from healthy children aged 3-59 months presenting for routine well careat 16 primary care pediatricians in Milan. SP carriage isolates were serotyped and tested for antimicrobial resistance using EUCAST breakpoints. Among 1250 enrolled children, 618 had received at least 1 dose of PCV13, 292 at least 1 dose of PCV7, 94 a combination of the two vaccines and 246 were not vaccinated. The prevalence of SP carriage was 27% (95% confidence interval [CI] 25-30). At multivariable analysis, age>=25 months (prevalence ratio [PR]=0.74) and use of antibiotics in the previous 3 months (PR=0.67) were associated with lower SP carriage prevalence. Having siblings (PR=1.79 for 1 sibling and PR=2.23 for >=2 siblings), day-care attendance (PR=2.27) and respiratory tract infections in the previous 3 months (PR=1.39) were associated with higher SP carriage prevalence. The immunization status for SP was not associated with SP carriage at univariable or at multivariable analysis. The most common carriage isolates were 6C, 19A and 23A. The prevalence of the six additional PCV13 serotypes carriage in children appropriately vaccinated with PCV13 was lower than in children appropriately vaccinated with PCV7 (0 vs. 0.060); the greater reduction in prevalence of carriage was observed for serotype 19A (0 vs. 0.041). Serotype 6C was the most common drug-resistant serotype (17.2%). Further epidemiological studies are needed to assess changes in circulating SP serotypes following the large-scale introduction of PCV13. PMID- 24342250 TI - The relationship between concentration of specific antibody at birth and subsequent response to primary immunization. AB - BACKGROUND AND AIMS: Trans-placentally acquired antibodies can protect infants from infection in the first months of life. However, high concentrations of antibody at birth may impact the infant's own immune response to primary immunization. We examine the relationship between concentration of specific antibody to Bordetella pertussis, Haemophilus influenzae type b (Hib), tetanus toxoid and pneumococcal antigens at birth and following primary immunization. METHODS: Healthy mother-infant pairs were recruited from a UK maternity unit. Peripheral blood samples were obtained at birth and 4 weeks after primary immunization. Specific antibody concentrations were determined using enzyme linked immunosorbent assays. Pertussis antibody concentrations >50 IU/ml, Tetanus antibody levels >0.1 IU/ml and Hib antibody levels >0.15 mg/l were regarded as protective. RESULTS: Following primary immunization, 35/36 (97%) infants had specific antibody concentrations associated with protection against Hib, 32/36 (89%) against pertussis and 36/36 (100%) against tetanus. Concentrations of all specific antibodies were significantly higher than at birth (p<0.0001), except anti-tetanus toxoid, p=0.41. However, there was an inverse correlation between infant antibody concentration at birth and fold-increase in antibody concentration post-immunization for tetanus: rs -0.86 (95%CI -0.93 to -0.74), p<0.0001; pneumococcus: rs -0.82 (95% CI -0.91 to -0.67), p<0.0001; pertussis: rs -0.77 (95% CI -0.89 to -0.58), p<0.0001 and Hib: rs -0.66 (95%CI -0.82 to -0.42), p<0.0001. The highest concentrations of specific IgG at birth were associated with lower concentrations post-immunization for tetanus (p=0.009) and pneumococcus (p=0.03). This association was not observed for Hib (p=0.88) or pertussis (p=0.14). CONCLUSION: Higher antibody concentration at birth appeared to inhibit the response to infant immunization for tetanus and pneumococcus; the effect was less marked for Hib and pertussis. However, the majority of infants achieved high antibody levels post-immunization. This supports maternal immunization, as high levels of maternally derived antibody at birth may not inhibit infants' immunization responses in a clinically relevant manner. PMID- 24342251 TI - Recombinant antigens based on toxins A and B of Clostridium difficile that evoke a potent toxin-neutralising immune response. AB - Infection with the bacterium Clostridium difficile causes symptoms ranging from mild to severe diarrhoea with life-threatening complications and remains a significant burden to healthcare systems throughout the developed world. Two potent cytotoxins, TcdA and TcdB are the prime mediators of the syndrome and rapid neutralisation of these would afford significant benefits in disease management. In the present study, a broad range of non-toxic, recombinant fragments derived from TcdA and TcdB were designed for soluble expression in E. coli and assessed for their capacity to generate a potent toxin-neutralising immune response as assessed by cell-based assays. Significant differences between the efficacies of isolated TcdA and TcdB regions with respect to inducing a neutralising immune response were observed. While the C-terminal repeat regions played the principal role in generating neutralising antibodies to TcdA, in the case of TcdB, the central region domains dominated the neutralising immune response. For both TcdA and TcdB, fragments which comprised domains from both the central and C-terminal repeat region of the toxins were found to induce the most potent neutralising immune responses. Generated antibodies neutralised toxins produced by a range of C. difficile isolates including ribotype 027 and 078 strains. Passive immunisation of hamsters with a combination of antibodies to TcdA and TcdB fragments afforded complete protection from severe CDI induced by a challenge of bacterial spores. The results of the study are discussed with respect to the development of a cost effective immunotherapeutic approach for the management of C. difficile infection. PMID- 24342252 TI - Randomized controlled trial of two dosing schedules for human papillomavirus vaccination among college age males. AB - BACKGROUND: Quadrivalent human papillomavirus (HPV) vaccine, for protection against sexually transmitted HPV infection, is licensed for females and males 9 26 years on a 3-dose schedule (0, 2, and 6 months; Standard schedule). Vaccine uptake has been low and catch-up vaccination of older adolescents using an alternate dosing schedule may increase coverage. This study tested the non inferiority of the immunogenicity of an alternate dosing schedule (0, 2, 12 months) among college age males. METHODS: 220 18-25 year old males were randomly assigned to Standard or Alternate schedules. Blood samples were drawn immediately before Dose 1 and 2-6 weeks after Dose 3 and analyzed for antibody titers using a Luminex immunoassay. A value <1.5 for the upper 95% confidence interval (CI) bound of the Standard to Alternate schedule geometric mean titer (GMT) ratio was deemed non-inferior. RESULTS: Participants averaged 21.3 years old; 19.1% were non-white; completion rate was 93%. The anti-HPV titers for the Alternate schedule group were non-inferior to those of Standard schedule group for all four HPV vaccine virus types. Our results also demonstrated superiority of the Alternate schedule group for all four HPV vaccine virus types. CONCLUSION: A delayed third dose at 12 months is immunologically non-inferior and superior for four HPV virus types. Using an alternate dosing schedule offers more flexibility to receive the 3-dose HPV vaccine and may result in higher vaccination rates among college-age males. PMID- 24342253 TI - Accuracy of traditional and novel serology tests for predicting cross-protection in foot-and-mouth disease vaccinated cattle. AB - Foot-and-mouth disease virus (FMDV) antigenic-match between vaccine and field viruses has traditionally been estimated in vitro by computing the r1 value using virus neutralization test (VNT) or ELISA titers. In this study we compared the accuracy in predicting cross-protection between the r1 value estimated by VNT and two recently developed tests that measure IgG subtypes and avidity. Data analyzed consisted of 64 serum samples from FMDV A24/Cruzeiro vaccinated bovines challenged with the heterologous A/Argentina/2001 strain and evaluated for podal generalization. We computed the tests sensitivity (Se), specificity (Sp), and receiving operating characteristics (ROC) curve. The heterologous IgG1/IgG2 ratio was the most accurate test (Se=0.71, Sp=0.98), followed by heterologous IgG1 (Se=0.53, Sp=0.96), VNT (Se=0.47, Sp=1.00), whereas r1 accuracy was substantially low (Se=0.41, Sp=0.81). Because sensitivity of individual tests was limited, we argue that two or more of the tests should be used in combination to produce accurate estimates of protection. PMID- 24342254 TI - Development of a whole cell pneumococcal vaccine: BPL inactivation, cGMP production, and stability. AB - Pneumococcal infections impose a large burden of disease on the human population, mainly in developing countries, and the current pneumococcal vaccines offer serotype-specific protection, but do not cover all pathogenic strains, leaving populations vulnerable to disease caused by non-vaccine serotypes. The pneumococcal whole cell vaccine is a low-cost strategy based on non-capsular antigens common to all strains, inducing serotype-independent immunity. Therefore, we developed the process for the cGMP production of this cellular vaccine. Initially, three engineering runs and two cGMP runs were performed in 60 L bioreactors, demonstrating the consistency of the production process, as evaluated by the growth curves, glucose consumption and metabolite formation (lactate and acetate). Cell recovery by tangential filtration was 92 +/- 13 %. We optimized the conditions for beta-propiolactone (BPL) inactivation of the bacterial suspensions, establishing a maximum cell density of OD600 between 27 and 30, with a BPL concentration of 1:4000 (v/v) at 150 rpm and 4 degrees C for 30 h. BPL was hydrolyzed by heating for 2h at 37 degrees C. The criteria and methods for quality control were defined using the engineering runs and the cGMP Lots passed all specifications. cGMP vaccine Lots displayed high potency, inducing between 80 and 90% survival in immunized mice when challenged with virulent pneumococci. Sera from mice immunized with the cGMP Lots recognized several pneumococcal proteins in the extract of encapsulated strains by Western blot. The cGMP whole cell antigen bulk and whole cell vaccine product lots were shown to be stable for up to 12 and 18 months, respectively, based upon survival assays following i.p. challenge. Our results show the consistency and stability of the cGMP whole cell pneumococcal vaccine lots and demonstrate the feasibility of production in a developing country setting. PMID- 24342255 TI - Glutathione s-transferase Pi-1: a novel approach to mitigating adverse cardiac remodeling after myocardial infarction. PMID- 24342256 TI - Diagnostic utility of cardiac biomarkers in discriminating Takotsubo cardiomyopathy from acute myocardial infarction. AB - BACKGROUND: Takotsubo cardiomyopathy (TC) mimics acute myocardial infarction (AMI). We postulated that ventricular dysfunction in TC in the absence of significant myocardial necrosis would produce higher B-type natriuretic peptide (BNP)/troponin T (TnT) and BNP/creatine kinase MB fraction (CKMB) ratios than in AMI. METHODS AND RESULTS: We studied 58 consecutive TC (age 65.8 +/- 82.9) and 97 AMI patients (age 59.8 +/- 83.4). The ratios of BNP/TnT and BNP/CKMB were calculated with the use of first simultaneously drawn laboratory values. Receiver operating characteristic curves were used to distinguish TC from AMI with 95% specificity based on cardiac biomarker ratios. Median BNP/TnT and BNP/CKMB ratios were, respectively, 1,292 [interquartile range 443.4-2,657.9] and 28.44 [13.7 94.8] in the TC group and 226.9 [69.91-426.32] and 3.63 [1.07-10.02] in the AMI group (P < .001). TC can be distinguished from AMI with 95% specificity with the use of BNP/TnT ratio >= 1,272 (sensitivity 52%) and BNP/CKMB ratio >= 29.9 (sensitivity 50%). CONCLUSIONS: The value of BNP is significantly higher in TC than in AMI. Early BNP/TnT and BNP/CKMB ratios help to differentiate TC from AMI with greater accuracy than BNP alone. PMID- 24342257 TI - Heart failure notwithstanding ejection fraction (HFnEF)--a possible unifying hypothesis? PMID- 24342258 TI - Patient needs and research priorities in the enteral nutrition market - a quantitative prioritization analysis. AB - BACKGROUND & AIMS: A quantitative systematic identification and prioritization of unmet needs and research opportunities in relation to enteral nutrition was conducted by means of a tailor-made health research prioritization process. METHODS: The research objectives were reached by conducting qualitative interviews followed by quantitative questionnaires targeting enteral nutrition key opinion leaders (KOLs). (1) Define disease areas that deserve more research attention; (2) Rank importance of product characteristics of tube feeding (TF) and oral nutritional supplements (ONS); (3) Assess involvement of KOLs in enteral nutrition R&D process. KOLs ranked three product characteristics and three disease areas that deserve additional research attention. From these, overall priority scores were calculated by multiplying ranks for both product characteristics and disease areas. RESULTS: 17 qualitative interviews were conducted and 77 questionnaires (response rate 35%) were completed and returned. (1) Disease areas in ONS and TF with highest priorities are: ONS: general malnutrition & geriatrics, TF: intensive care. (2) TF product characteristics with highest priorities are: composition and clinical evidence from a KOL perspective; tolerance and ease of use from a patient perspective. ONS product characteristics with highest priorities are: composition, clinical evidence and taste from a KOL perspective; taste from a patient perspective. We find a high discrepancy between product characteristic prioritization from a KOL and patient perspective. (3) Although 62% of all KOLs give advice to enteral nutrition companies on patient needs, they under-influence the setting of research priorities by enteral nutrition companies. CONCLUSIONS: This study provides a systematic approach to achieve research prioritization in enteral nutrition. In addition to providing new directions for enteral nutrition research and development, this study highlights the relevance of involving KOLs in the identification of research priorities as they have the ability to provide a balanced view of the unmet patient needs. PMID- 24342259 TI - The effect of vascular pedicle preservation on blood flow and clinical outcome following ulnar nerve transposition. AB - PURPOSE: To evaluate the efficacy of a technique to preserve the extrinsic vascular supply to the ulnar nerve after transposition and its effect on blood flow and clinical outcome. METHODS: We included 36 patients with cubital tunnel syndrome. The patients were randomly selected to undergo vascular pedicles sparing surgery for anterior ulnar nerve transposition (VP group) or nerve transposition and artery ligation (non-VP group). Blood flow to the ulnar nerve was estimated intraoperatively at 3 locations in the cubital tunnel before and after transposition using a laser Doppler flowmeter. Clinical results at 3, 6, and 12 months after surgery were also compared between the 2 groups. RESULTS: The blood flow before ulnar nerve transposition was not significantly different between the groups. Blood flow at all 3 locations after the ulnar nerve transposition was significantly higher in the VP group than in the non-VP group. Blood flow in the non-VP group reduced to values between 28% and 52% from the pre transposition baseline values. After surgery, no significant differences were observed in the clinical results between the groups, except for the Disabilities of the Arm, Shoulder and Hand scores at 12 months after surgery, which was greater in the non-VP group. CONCLUSIONS: The procedure of preserving the extrinsic vascular pedicles can prevent compromise of blood flow to the ulnar nerve immediately after nerve transposition. However, this procedure had no correlation to improved recovery of ulnar nerve function after surgery. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 24342260 TI - Computational sensitivity analysis to identify muscles that can mechanically contribute to shoulder deformity following brachial plexus birth palsy. AB - PURPOSE: Two mechanisms, strength imbalance or impaired longitudinal muscle growth, potentially cause osseous and postural shoulder deformity in children with brachial plexus birth palsy. Our objective was to determine which muscles, via either deformity mechanism, were mechanically capable of producing forces that could promote shoulder deformity. METHODS: In an upper limb computational musculoskeletal model, we simulated strength imbalance by allowing each muscle crossing the shoulder to produce 30% of its maximum force. To simulate impaired longitudinal muscle growth, the functional length of each muscle crossing the shoulder was reduced by 30%. We performed a sensitivity analysis to identify muscles that, through either simulated deformity mechanism, increased the posteriorly directed, compressive glenohumeral joint force consistent with osseous deformity or reduced the shoulder external rotation or abduction range of motion consistent with postural deformity. RESULTS: Most of the increase in the posterior glenohumeral joint force by the strength imbalance mechanism was caused by the subscapularis, latissimus dorsi, and infraspinatus. Posterior glenohumeral joint force increased the most owing to impaired growth of the infraspinatus, subscapularis, and long head of biceps. Through the strength imbalance mechanism, the subscapularis, anterior deltoid, and pectoralis major muscles reduced external shoulder rotation by 28 degrees , 17 degrees , and 10 degrees , respectively. Shoulder motion was reduced by 40 degrees to 56 degrees owing to impaired growth of the anterior deltoid, subscapularis, and long head of triceps. CONCLUSIONS: The infraspinatus, subscapularis, latissimus dorsi, long head of biceps, anterior deltoid, pectoralis major, and long head of triceps were identified in this computational study as being the most capable of producing shoulder forces that may contribute to shoulder deformity following brachial plexus birth palsy. CLINICAL RELEVANCE: The muscles mechanically capable of producing deforming shoulder forces should be the focus of experimental studies investigating the musculoskeletal consequences of brachial plexus birth palsy and are potentially critical targets for treating shoulder deformity. PMID- 24342261 TI - The effect of suture caliber and number of core suture strands on zone II flexor tendon repair: a study in human cadavers. AB - PURPOSE: To compare the tensile properties of a 3-0, 4-strand flexor tendon repair with a 4-0, 4-strand repair and a 4-0, 8-strand repair. METHODS: Following evaluation of the intrinsic material properties of the 2 core suture calibers most commonly used in tendon repair (3-0 and 4-0), we tested the mechanical properties of 40 cadaver flexor digitorum profundus tendons after zone II repair with 1 of 3 techniques: a 3-0, 4-strand core repair, a 4-0, 8-strand repair, or a 4-0, 4-strand repair. We compared results across suture caliber for the 2 sutures and across tendon repair methods. RESULTS: Maximum load to failure of 3-0 polyfilament caprolactam suture was 49% greater than that of 4-0 polyfilament caprolactam suture. The cross-sectional area of 3-0 polyfilament caprolactam was 42% greater than that of 4-0 polyfilament caprolactam. The 4-0, 8-strand repair produced greater maximum load to failure when compared with the 2 4-strand techniques. Load at 2-mm gap, stiffness, and work to yield were significantly greater in the 4-0, 8-strand repair than in the 3-0, 4-strand repair. CONCLUSIONS: In an ex vivo model, an 8-strand repair using 4-0 suture was 43% stronger than a 4-strand repair using 3-0 suture, despite the finding that 3-0 polyfilament caprolactam was 49% stronger than 4-0 polyfilament caprolactam. These results suggest that, although larger-caliber suture has superior tensile properties, the number of core suture strands across a repair site has an important effect on time zero, ex vivo flexor tendon repair strength. CLINICAL RELEVANCE: Surgeons should consider using techniques that prioritize multistrand core suture repair over an increase in suture caliber. PMID- 24342262 TI - An American Society for Surgery of the Hand (ASSH) task force report on hand surgery subspecialty certification and ASSH membership. AB - A task force for the American Society for Surgery of the Hand (ASSH) recently investigated the practice patterns, board certification, subspecialty certification status, and ASSH membership of hand surgeons after completion of fellowship training. A total of 37% of the fellowship graduates from 2000 to 2006 had not attained subspecialty certification for a variety of reasons. A smaller group of fellowship graduates obtained the subspecialty certification but had not become Active Members of the ASSH. Efforts to strengthen the hand surgeon community and best serve our patients should focus on evolving patterns in post fellowship choices that reflect practice type choices and generational changes. PMID- 24342263 TI - Reducing overdiagnosis and disease mongering in ADHD in Lombardy. PMID- 24342264 TI - Date of birth and hay fever risk in children and adolescents of Kazakhstan. AB - Introduction the first months of life are the most vulnerable period in allergic disease development and it is not clear enough whether inhalant pollen allergen exposure predisposes the risk of consequent allergic reactions. OBJECTIVE: To study the clinical and epidemiological criteria of hay fever with special emphasis on investigation of the relationship between the date of birth and seasonal allergic rhinitis development in children and adolescents in Kazakhstan. METHODS: The prospective hospital based study was conducted during pollen season from the beginning of May to the end of October in two consequent years 2010 and 2011. 184 children and adolescents at the age of 1--17 years underwent consultations and skin prick tests in the allergological center "Umit" (Astana, Kazakhstan). Special allergological questionnaires were developed and adapted for local residents. The assessment of symptoms severity was performed using a scoring system. Skin prick tests were performed in 112 patients. The number of patients was explained by the age limitations. Correlation analysis between skin prick test results and the month of birth were performed. RESULTS: It was found that in summer months there were the highest number of patients with seasonal allergic rhinitis 68 (36.9%), followed by spring 44 (23.9%), then autumn 37 (20.1%) and the lowest percent of patients 35 (19.1%) was born in winter. Rhinoconjunctival syndrome was diagnosed in 180 (97.8%) patients, pollen induced bronchial asthma in 76 (41.3%) and pollen induced urticaria in 35 (19.0%) patients. Mono sensitization among Kazakhstan children and adolescents was determined only to several species of the plants, mainly to Artemisia Absinthium (68.2%) and Sunflower (25.7%), whereas multiple sensitization to the mix of weeds was determined in 75 (66.9%) patients, to the mix of meadow grass in 33 (29.4%), mix of meadow grass+mix of weeds in 25 (22.3%) and mix of trees in 9 (7.1%) patients. The mean of symptoms severity of total scoring (24) was 15.5. The mean of IgE level in blood tests was 323.2IU/ml. CONCLUSIONS: Our results proved that first months of life are the crucial period and inhalant pollen allergen exposure, particularly to the weeds pollen, predisposes the risk of consequent allergic reactions development in children and adolescents in Kazakhstan. This fact may predetermine the risk of consequent allergic reactions development and the awareness of patients about it helps to prevent following severe clinical manifestations. PMID- 24342265 TI - Depression as a moderator of benefit from Media Smart: a school-based eating disorder prevention program. AB - OBJECTIVE: To investigate if baseline depression moderated response to Media Smart, an 8-lesson school-based program previously found to achieve a long-term risk reduction effect in young adolescents. METHOD: 540 Grade 8 students (M age = 13.62 years, SD = .37) from 4 schools participated with 11 classes receiving the Media Smart program (126 girls; 107 boys) and 13 comparison classes receiving their normal lessons (147 girls; 160 boys). Shape and weight concern, media internalization, body dissatisfaction, dieting, ineffectiveness, and perceived pressure were the outcome variables. RESULTS: Moderation was indicated by significant interaction effects for group (Media Smart; Control) * moderator (high depression; low depression) * time (post-program; 6-month follow-up; 2.5 year follow-up), with baseline entered as a covariate. Such effects were found for shape and weight concern, media internalization, body dissatisfaction, ineffectiveness and perceived pressure. Post-hoc testing found high depression Media Smart participants scored significantly lower than their control counterparts at post-program on shape and weight concern, media internalization and dieting, whereas low depression Media Smart participants scored significantly lower on shape and weight concern at 2.5-year follow-up. DISCUSSION: Media Smart achieved a reduction in eating disorder risk factors for high-depression participants and a reduced rate of growth in risk factor scores for low depression participants. Trial registry name: Australian New Zealand Clinical Trials Registry. URL: http://www.anzctr.org.au. Registration identification number: ACTRN12608000545369. PMID- 24342266 TI - Diazinon and diazoxon impair the ability of astrocytes to foster neurite outgrowth in primary hippocampal neurons. AB - Evidence from in vivo and epidemiological studies suggests that organophosphorus insecticides (OPs) are developmental neurotoxicants, but possible underlying mechanisms are still unclear. Astrocytes are increasingly recognized for their active role in normal neuronal development. This study sought to investigate whether the widely-used OP diazinon (DZ), and its oxygen metabolite diazoxon (DZO), would affect glial-neuronal interactions as a potential mechanism of developmental neurotoxicity. Specifically, we investigated the effects of DZ and DZO on the ability of astrocytes to foster neurite outgrowth in primary hippocampal neurons. The results show that both DZ and DZO adversely affect astrocyte function, resulting in inhibited neurite outgrowth in hippocampal neurons. This effect appears to be mediated by oxidative stress, as indicated by OP-induced increased reactive oxygen species production in astrocytes and prevention of neurite outgrowth inhibition by antioxidants. The concentrations of OPs were devoid of cytotoxicity, and cause limited acetylcholinesterase inhibition in astrocytes (18 and 25% for DZ and DZO, respectively). Among astrocytic neuritogenic factors, the most important one is the extracellular matrix protein fibronectin. DZ and DZO decreased levels of fibronectin in astrocytes, and this effect was also attenuated by antioxidants. Underscoring the importance of fibronectin in this context, adding exogenous fibronectin to the co culture system successfully prevented inhibition of neurite outgrowth caused by DZ and DZO. These results indicate that DZ and DZO increase oxidative stress in astrocytes, and this in turn modulates astrocytic fibronectin, leading to impaired neurite outgrowth in hippocampal neurons. PMID- 24342268 TI - Approaching pre-diabetes. AB - As the global epidemic of type 2 diabetes continues to rise, the time has come to revisit our approach to pre-diabetes. Recently, much ado has been made about screening, diagnosis, pathophysiology and clinical interventions in pre-diabetes, and all for good reason as the key to reversing the diabetes epidemic likely lies therein. The somewhat controversial term "pre-diabetes" represents collective dysglycemic states intermediate between normal glucose regulation (NGR) and diabetes. Not all people with pre-diabetes will develop diabetes, but the majority will. In fact, up to 70% of those with pre-diabetes may acquire the disease over their lifetime. Furthermore, even when overt diabetes is delayed or prevented, both micro- and macrovascular disease appears more prevalent in those with pre-diabetes compared to their normoglycemic peers. Hence, there is growing consensus that NGR should be the goal for people with pre-diabetes. Nevertheless, there is much to consider in that pursuit. Herein, we provide an update on the global burden of pre-diabetes, its underlying pathophysiology and discuss clinical considerations in these individuals at high risk of developing diabetes. PMID- 24342267 TI - Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines. AB - The renin-angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5MUg/h) or vehicle for 4weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1beta and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy. PMID- 24342269 TI - Targeting relaxase genes for classification of the predominant plasmids in Enterobacteriaceae. AB - Plasmids are the main vectors of antimicrobial drug resistance and virulence genes, especially in Enterobacteriaceae. Identification and classification of plasmids is essential for analysis of their distribution. The most widely used typing method is PCR-based replicon typing (PBRT). A new classification scheme based on relaxase gene typing has been described recently. We propose a practical application of this method, with the development of a multiplex PCR set targeting relaxase genes found on plasmids most frequently encountered in Enterobacteriaceae. This method, here called "plasmid relaxase gene typing" (PRaseT), was validated with 60 transconjugants and transformants harboring various replicon types. The method was tested with 39 multidrug-resistant clinical isolates including Escherichia coli, Klebsiella pneumoniae and Salmonella enterica subsp. enterica carrying 1-7 replicons as well as with 17 plasmids non-typeable using PBRT; all replicons were tested in parallel with PBRT for comparison. Six multiplex PCRs and one simplex PCR, including 24 pairs of primers, recognized plasmids of groups A/C, B/O, colE, FIA, FIB, FIC, FV, FIIk, HI1, HI2, I1, K, L/M, N, P1alpha, Q1, U, W, X1, X2, X3 and X4. There was perfect correlation between PRaseT and PBRT results in 31/39 (79.5%) clinical isolates. Moreover, 11/17 (64.7%) plasmids non-typeable by PBRT could be typed by PRaseT. Our set of multiplex PCRs showed high sensitivity and specificity for the classification of resistance plasmids. It has proved complementary to the widely used PBRT and will improve the monitoring of plasmid distribution in every-day practice. PMID- 24342271 TI - Robust stability and stabilization of fractional order linear systems with positive real uncertainty. AB - This paper investigates the robust stability and stabilization of fractional order linear systems with positive real uncertainty. Firstly, sufficient conditions for the asymptotical stability of such uncertain fractional order systems are presented. Secondly, the existence conditions and design methods of the state feedback controller, static output feedback controller and observer based controller for asymptotically stabilizing such uncertain fractional order systems are derived. The results are obtained in terms of linear matrix inequalities. Finally, some numerical examples are given to validate the proposed theoretical results. PMID- 24342270 TI - Cascaded Kalman and particle filters for photogrammetry based gyroscope drift and robot attitude estimation. AB - Based on a cascaded Kalman-Particle Filtering, gyroscope drift and robot attitude estimation method is proposed in this paper. Due to noisy and erroneous measurements of MEMS gyroscope, it is combined with Photogrammetry based vision navigation scenario. Quaternions kinematics and robot angular velocity dynamics with augmented drift dynamics of gyroscope are employed as system state space model. Nonlinear attitude kinematics, drift and robot angular movement dynamics each in 3 dimensions result in a nonlinear high dimensional system. To reduce the complexity, we propose a decomposition of system to cascaded subsystems and then design separate cascaded observers. This design leads to an easier tuning and more precise debugging from the perspective of programming and such a setting is well suited for a cooperative modular system with noticeably reduced computation time. Kalman Filtering (KF) is employed for the linear and Gaussian subsystem consisting of angular velocity and drift dynamics together with gyroscope measurement. The estimated angular velocity is utilized as input of the second Particle Filtering (PF) based observer in two scenarios of stochastic and deterministic inputs. Simulation results are provided to show the efficiency of the proposed method. Moreover, the experimental results based on data from a 3D MEMS IMU and a 3D camera system are used to demonstrate the efficiency of the method. PMID- 24342272 TI - A novel disturbance-observer based friction compensation scheme for ball and plate system. AB - Friction is often ignored when designing a controller for the ball and plate system, which can lead to steady-error and stick-slip phenomena, especially for the small amplitude command. It is difficult to achieve high-precision control performance for the ball and plate system because of its friction. A novel reference compensation strategy is presented to attenuate the aftereffects caused by the friction. To realize this strategy, a linear control law is proposed based on a reduced-order observer. Neither the accurate friction model nor the estimation of specific characteristic parameters is needed in this design. Moreover, the describing function method illustrates that the limit cycle can be avoided. Finally, the comparative mathematical simulations and the practical experiments are used to validate the effectiveness of the proposed method. PMID- 24342273 TI - Identification of IPMC nonlinear model via single and multi-objective optimization algorithms. AB - Ionic Polymer-Metal Composites (IPMCs) are electro-active polymers transforming mechanical forces into electric signals and vice versa. This paper proposes an improved electro-mechanical grey-box model for IPMC membrane working as actuator. In particular the IPMC nonlinearity has been characterized through experimentation and included within the electric model. Moreover identification of the model parameters has been performed via optimization algorithms using both single- and multi-objective formulation. Minimization was attained via the Nelder Mead simplex and the Genetic Algorithms considering as cost functions the error between the experimental and modeled absorbed current and the error between experimental and modeled displacement. The obtained results for the different formulations have been then compared. PMID- 24342274 TI - Operative environment. PMID- 24342275 TI - Diagnosis of periprosthetic joint infection. PMID- 24342276 TI - Wound management. PMID- 24342277 TI - Perioperative skin preparation. PMID- 24342278 TI - Effectiveness of telemedical applications in postoperative follow-up after total joint arthroplasty. AB - We hypothesized that a postoperative clinical telemedicine tool will be effective in reducing the total number of unscheduled postoperative clinic visits and calls while increasing patient satisfaction. The medical charts of 34 patients who underwent telemedicine follow-up during their postoperative care were compared to that of 44 patients who did undergo telemedicine follow-up. There were 14 unscheduled clinic visits in the non-telemedicine follow-up group compared to only 3 in the telemedicine follow-up group (P = 0.01). There were 40 in-clinic calls made by patients in the non-telemedicine follow-up group compared to only 6 made by patients in the telemedicine group (P < 0.01). In addition, patients who underwent telemedicine follow-up rated their postoperative satisfaction higher than those who did not undergo telemedicine follow-up. PMID- 24342279 TI - Spacers. PMID- 24342280 TI - Determining optimal compression to ventilation ratio in neonatal resuscitation. PMID- 24342281 TI - The 2-min walk test is sufficient for evaluating walking abilities in sporadic inclusion body myositis. AB - Sporadic inclusion body myositis causes progressive functional loss due to declining muscle strength. Although the underlying cause is unknown, clinical trials are underway to improve strength and function. Selection of appropriate outcome measures is critical for the success of these trials. The 6-min walk test has been the de facto standard for assessing function in neuromuscular disease; however, the optimal walking test has not been determined in this disease. In this study, 67 individuals with sporadic inclusion body myositis completed a battery of quantitative strength and functional tests including timed walking tests, patient-reported outcomes, and other tasks. The 2-min and 6-min walk tests are highly correlated to each other (r=0.97, p<0.001) and to all lower extremity strength, patient-reported, and functional measures in this population. All subjects completed the 2-min walk test, but 7% of subjects were unable to walk the full 6-min of the 6-min walk test due to fatigue. The 2-min walk test demonstrates similar correlation to all outcomes compared to the 6-min walk test, is less fatiguing and better tolerated. Results suggest that the 2-min walk test is a better alternative to tests of longer duration. Further research is needed to determine longitudinal changes on this outcome. PMID- 24342282 TI - Early infantile sensory-motor neuropathy with late onset respiratory distress. AB - Children with spinal muscular atrophy with respiratory distress (SMARD1) usually present within their first year of life, with respiratory failure due to diaphragmatic paralysis and progressive distal limb weakness. We present a child with a confirmed compound heterozygous IGHMBP2 mutation c.[676G>T];[2083A>T] in whom severe sensory-motor neuropathy preceded diaphragmatic paralysis by almost 3years. Autonomic system involvement with neurogenic bladder and urine retention were found at 3years. In summary, our patient highlights the broad spectrum of phenotypes observed in SMARD1. Currently, no prediction of phenotype according to genotype is possible, suggesting that yet unknown factors cause the observed phenotypic variation. Even in the absence of obvious diaphragmatic weakness, SMARD1 should be considered in severe infantile onset neuropathies. High throughput techniques, such as next generation sequencing, will possibly offer a useful approach in the heterogeneous group of inherited neuropathies. PMID- 24342283 TI - Adenovirus-mediated expression of myogenic differentiation factor 1 (MyoD) in equine and human dermal fibroblasts enables their conversion to caffeine sensitive myotubes. AB - Several human and animal myopathies, such as malignant hyperthermia (MH), central core disease and equine recurrent exertional rhabdomyolysis (RER) are confirmed or thought to be associated with dysfunction of skeletal muscle calcium regulation. For some patients in whom the genetic cause is unknown, or when mutational analysis reveals genetic variants with unclear pathogenicity, defects are further studied through use of muscle histopathology and in vitro contraction tests, the latter in particular, when assessing responses to ryanodine receptor agonists, such as caffeine. However, since muscle biopsy is not always suitable, researchers have used cultured cells to model these diseases, by examining calcium regulation in myotubes derived from skin, following forced expression of muscle-specific transcription factors. Here we describe a novel adenoviral vector that we used to express equine MyoD in dermal fibroblasts. In permissive conditions, transduced equine and human fibroblasts differentiated into multinucleated myotubes. We demonstrate that these cells have a functional excitation-calcium release mechanism and, similarly to primary muscle-derived myotubes, respond in a dose-dependent manner to increasing concentrations of caffeine. MyoD-induced conversion of equine skin-derived fibroblasts offers an attractive method for evaluating calcium homeostasis defects in vitro without the need for invasive muscle biopsy. PMID- 24342284 TI - Molecular techniques in anatomic pathology: an overview. PMID- 24342285 TI - Applications and limitations of oncogene mutation testing in clinical cytopathology. AB - In an increased number of settings, cytology represents the only source of sampling and it often substitutes histology as an independent diagnostic modality. Thus, DNA molecular targets to stratify patients for targeted therapy are often evaluated on cytology. In addition, DNA mutational tests may refine indeterminate thyroid and pancreas cytology. This review discusses the applications and limitations of DNA mutational testing on cytology. With respect to histology, most cytological samples have the advantages of a purer population of tumor cells, with low stromal component, a better preserved DNA, and assessing at the same time of sample collection cellular adequacy for DNA testing. However, since in vitro diagnostic tests are licensed only for paraffin-tissue, all mutational assays on cytology are "home brew," requiring a rigorous validation process. This should take into account not only the performance characteristics of the molecular assay but also features inherent to any given cytological samples, such as its source, preparation type, fixation and staining modalities, and the most effective tumor cell enrichment methods. This calls for a change of cytotechnologists and cytopathologists mentality to collect and process the cytological samples not only for microscopy but also to assess clinically relevant molecular markers. PMID- 24342286 TI - The role of molecular analyses in the diagnosis and treatment of non-small-cell lung carcinomas. AB - Non-small-cell lung cancer (NSCLC) subtyping has recently been a key factor in determining patient management with novel drugs. In addition, the identification of distinct oncogenic driver mutations frequently associated with NSCLC histotype and coupled to the clinical responses to targeted therapies have revolutionized the impact of histologic type and molecular biomarkers in lung cancer. Several molecular alterations involving different genes (EGFR, KRAS, ALK, BRAF, and HER2) seem to have a remarkable predilection for adenocarcinoma and specific inhibitors of EGFR and ALK are now available for patients with adenocarcinoma harboring the relevant gene alterations. The efficacy of histology-based and molecular-targeted therapies had a deep impact in (1) re-defining classification of lung cancer (particularly adenocarcinomas) and (2) routine clinical practice of pathologists involved in optimization of handling of tissue samples in order to guarantee NSCLC subtyping with the help of immunohistochemistry and adequately preserve tumor cells for molecular analysis. In agreement with the modern multidisciplinary approach to lung cancer, we reviewed here the diagnostic and predictive value of molecular biomarkers according to the clinical, pathologic, and molecular biologist viewpoints. PMID- 24342287 TI - Molecular genetics and genomics progress in urothelial bladder cancer. AB - The clinical management of solid tumor patients has recently undergone a paradigm shift as the result of the accelerated advances in cancer genetics and genomics. Molecular diagnostics is now an integral part of routine clinical management in lung, colon, and breast cancer patients. In a disappointing contrast, molecular biomarkers remain largely excluded from current management algorithms of urologic malignancies. The need for new treatment alternatives and validated prognostic molecular biomarkers that can help clinicians identify patients in need of early aggressive management is pressing. Identifying robust predictive biomarkers that can stratify response to newly introduced targeted therapeutics is another crucially needed development. The following is a brief discussion of some promising candidate biomarkers that may soon become a part of clinical management of bladder cancers. PMID- 24342289 TI - Contributions of molecular analysis to the diagnosis and treatment of gastrointestinal neoplasms. AB - This review discusses the role of molecular analysis in the diagnosis and treatment of gastrointestinal (GI) neoplasms. It is divided into 3 sections. The first section describes clinical applications of 11 immunohistochemical stains (p53, HER2, KIT, SDHB, SMAD4, beta-catenin, L-FABP, MLH1, PMS2, MSH2, and MSH6), the results of which directly reflect underlying genetic or epigenetic events. These applications are mainly diagnostic but in a few instances are predictive. Germline mutation testing is a diagnostic cornerstone in the hereditary cancer predisposition syndromes (HCPSs). Section two will describe the genotype and phenotype of 8 HCPSs presenting in the GI tract. Where available, guidelines based on evidence and/or expert opinion as to whom to test are presented. With our ever-expanding knowledge of the molecular genetic basis of cancer and an increasingly "biologic-oriented" therapeutic armamentarium, pathologists play a vital role in directing molecular-based predictive testing. The final section will discuss the 4 most mature examples in the GI tract: (1) HER2 testing to select patients with advanced gastroesophageal adenocarcinoma for anti-HER2 therapy, (2) KIT and PDGFRA mutation analysis to direct tyrosine kinase inhibitor therapy in gastrointestinal stromal tumor, (3) DNA mismatch repair function testing to determine the applicability of adjuvant chemotherapy in patients with stage II colorectal cancer (CRC), and (4) KRAS mutation analysis and related testing to determine the appropriateness of anti-EGFR monoclonal antibody therapy in patients with metastatic CRC. PMID- 24342288 TI - Breast carcinoma: is molecular evaluation a necessary part of current pathological analysis? AB - Breast cancer is the most common women cancer and is the second leading cause of cancer-related mortality in women. While the last two decades revolutionized breast cancer treatment with the development and use of therapies targeting steroid receptors and HER2/neu, there are limits to the risk estimation provided by traditional clinicopathologic parameters and IHC. Therefore, there is continued potential for inaccurate risk stratification of breast cancer patients which may lead to over- or under-treatment. In this review, we discuss the latest developments in the area of breast cancer research which have lead to better understanding of the breast cancer mechanisms, provided more accurate risk stratification, and identified potential new treatment targets. Specifically, we review the new dualistic model of breast carcinogenesis, which can inform pathologic diagnosis and tumor grading; we also discuss the intrinsic molecular classification of breast cancer and its impact on diagnosis and treatment; lastly, we compare the most common commercial molecular prognostic and predictive assays, with their respective strengths and weaknesses, and their clinical utility. PMID- 24342290 TI - Molecular pathology of melanocytic tumors. AB - Genetic and genomic analyses of melanocytic tumors have yielded new opportunities for improvements in diagnostic accuracy for the distinction of nevus from melanoma and better selection of patients affected by melanoma for targeted treatment. Since chromosomal copy number changes are commonly found in malignant melanoma, but rare in melanocytic nevi, cytogenetic assays have emerged as a promising ancillary study for the workup of melanocytic tumors with ambiguous light microscopic features. Comparative genomic hybridization (CGH) permits assessment of the full set of chromosomes, but requires a significant amount of lesional tissue, and may fail to detect aberrations in a minor subpopulation of tumor cells. Fluorescence in situ hybridization (FISH) is the cytogenetic assay of choice for limited amounts of tissue. FISH targets only specific chromosomes, with inherent limitations in test sensitivity and specificity. FISH analysis is also heavily dependent on individual experience. Molecular studies have identified distinct sets of mutations in melanoma and/or nevi. These mutations have become clinically relevant for targeted therapy of patients with advanced disease, especially for the treatment of patients with metastatic melanoma carrying the BRAF(V600) or KIT mutations. However, mutation analysis can on occasion also be used for diagnostic purposes. PMID- 24342291 TI - A current perspective on the role for molecular studies in soft tissue tumor pathology. AB - Soft tissue sarcomas represent an heterogenous group of malignancies. They represent a diagnostic challenge, and their accurate classification impact over treatment options. Sarcomas, similarly to hematologic neoplasm, often harbor relatively specific genetic aberrations, the recognition of which can be used to improved diagnostic accuracy. This review will focus on the clinical relevance of molecular analysis in soft tissue sarcomas, trying to elucidate its role as a diagnostic tool as well as a potential prognostic/predictive marker. PMID- 24342292 TI - Hematological diseases: prototypical conditions requiring the diagnostic and prognostic use of molecular data. AB - The field of diagnostic hematopathology is dynamic and evolving given the ongoing accumulation of molecular information and demand for integration of this information into routine clinical practice. In light of this molecular revolution, the appropriate and effective utilization of molecular studies by clinicians/pathologists is of paramount importance to the current diagnosis, prognosis, and monitoring of nearly all hematologic diseases. In the routine workup of certain hematologic neoplasms, it is more pertinent and practical to understand the purpose of these analyses and how to generally apply them to particular diseases rather than trying to remember a likely outdated list of genes. We will see advances in the treatment of hematologic malignancies as drug development catches up to our molecular understanding of diseases. PMID- 24342293 TI - FT IR, FT-Raman spectra and chemical computations of herbicide 2-phenoxy propionic acid--a DFT approach. AB - FT IR and FT Raman spectra of herbicidal molecule 2-phenoxy propionic acid have been recorded and analyzed with the aid of normal coordinate analysis and DFT methods. Stability of the molecule arising from hyperconjugative interactions has been probed using NBO analysis. Predicted electronic absorption spectrum from TD DFT calculation has been compared with the UV-vis spectrum. HOMO-LUMO, Mulliken population analysis and atomic charges, thermodynamic calculation and aromaticity were also calculated. From the PES scan the most stable geometry has been determined. ESP has been mapped over the electron density to obtain information about the size, shape, charge density distribution and chemical reactivity of the molecule. PMID- 24342294 TI - Intermolecular interactions in binary and ternary solutions of two cycloimmonium carboethoxy-anilido-methylids. AB - Two cycloimmonium ylids with pyridinium and iso-quinolinium as heterocycle and having common carbanion were studied from the point of view of the solvent influence on electronic absorption spectra in binary and ternary solutions. The supplies of the universal and specific interactions to the spectral shifts in the electronic absorption spectra of hydroxyl solutions were separated. The strength of the specific interactions of the ylid molecules with octanol was estimated by using ternary solutions in binary solvent Octanol+Dichloroethane, in which the universal interactions have similar strengths. Quantum mechanical calculations and also the solvatochromic effect allowed us estimating the values of the molecular dipole moments in the excited state of the studied ylids. The conclusions showed that by excitation the molecular dipole moment of the studied ylids decreases or changes its sense, due to the electronic charge transport from the carbanion towards the heterocycle. PMID- 24342295 TI - Synthesis, characterization, and thermodynamics of some new unsymmetrical Schiff bases of salicylaldehyde with 3,4-diaminopyridine and their cobalt(III) complexes. AB - Some new Schiff bases derived from 3,4-diaminopyridine (3,4-DAP) and their new unsymmetrical Co(III) five coordinate complexes described as [Co(Chel)(L)]ClO4?H2O where (Chel) is the deprotonated form of a series of unsymmetric ligands containing 3,4-diaminopyridine (3,4-DAP) and substituted salicylaldehyde moieties and a new Co(III) six coordinate Co(III) complex, were synthesized and characterized by (1)H NMR, IR, UV-Vis, and elemental analysis. For the new synthesized five coordinate complexes, the formation constants of the interaction of the Co(III) Schiff bases with various donors were measured spectrophotometrically. The trend of the formation constants of the five coordinate Co(III) Schiff base complexes toward a given phosphine is as follow: 5 H>5-Br and the formation constants trend of these donors are as follow: PBu3>PPh2Me. Furthermore the adduct formation of the five coordinate [Co(3,4 Salpyr)(PBu3)] ClO4?H2O, with aromatic amines shows the following binding trend: Im>2-MeIm>2-EtIm>BzIm. The trend of the formation constants of Co(III) Schiff base complexes toward a given donor according to the phosphine axial ligand is as follow: PBu3>PPh2Me. PMID- 24342296 TI - Correlation of tumor necrosis factor-beta and interleukin-1 gene cluster polymorphism with susceptibility to bacteremia in patients undergoing kidney transplantation. AB - BACKGROUND: Bacteremia remains a significant cause of morbidity and mortality after kidney transplantation. This study was conducted to investigate whether the polymorphisms of tumor necrosis factor (TNF)-beta, interleukin (IL)-1beta, and IL 1 receptor antagonist (IL-1ra) gene predicted the susceptibility to bacteremia within the first 6 months after kidney transplantation. METHODS: Subjects comprised 82 infected kidney transplant recipients and 60 non-infected kidney transplant recipients. Bacteremia was diagnosed in 16 of the 82 infected recipients. Genomic DNA from these 142 kidney transplant recipients was extracted from peripheral blood leukocytes. Regions containing the NcoI polymorphic site at position +252 of TNF-beta gene and the AvaI polymorphic site at position -511 of IL-1beta gene were amplified by polymerase chain reaction (PCR) and subsequently digested with NcoI and AvaI restriction enzymes, respectively. The polymorphic regions within intron 2 of IL-1ra gene containing variable numbers of a tandem repeat (VNTR) of 86 base pairs were amplified by PCR. RESULTS: Genotypic and allelic frequencies were similar between infected recipients and non-infected ones. Individual locus analysis showed that recipient TNF-beta and IL-1ra gene polymorphisms were not associated with the presence of bacteremia (P = 0.684 and P = 0.567, respectively). However, genotype analysis revealed that recipient IL 1beta-511CC genotype was strongly associated with susceptibility to develop bacteremia (P = 0.003). Recipient IL-1beta-511CC genotype (odds ratio 5.242, 95% confidence intervals 1.645-16.706, P = 0.005) independently predicted the risk for bacteremia within the first 6 months after kidney transplantation. CONCLUSIONS: These findings indicate a critical role of IL-1beta gene polymorphisms in susceptibility to bacteremia after kidney transplantation, which may be useful to screen for patients at higher risk for post-transplant bacteremias. Thus, the identified individuals can benefit from preventive treatment and a less potent immunosuppressive regimen. PMID- 24342297 TI - Polymorphisms of angiotensin-converting enzyme 2 gene confer a risk to lone atrial fibrillation in Chinese male patients. AB - BACKGROUND: Growing epidemiologic evidence has indicated that genetics can predispose individuals to the occurrence of lone atrial fibrillation (AF). The angiotensin-converting enzyme 2 (ACE2) gene has been established to be associated with hypertension and left ventricular hypertrophy. The objective of our study was to investigate the association of ACE2 gene polymorphisms with lone AF. METHODS: A total of 265 consecutive lone AF patients and 289 healthy controls were successfully investigated. The polymorphisms rs2106809 and rs2285666 were genotyped by polymerase chain reaction (PCR) and direct sequencing. A Logistic regression model was used to determine the odds ratio (OR) and 95% confidence intervals (CI) of variations of ACE2 for lone AF. RESULTS: The T allele of rs2106809 conferred an increased risk for lone AF (OR 1.24, 95% CI 1.01-1.52, P = 0.03) in males after adjustment for conventional risk factors. SNP at rs2285666 in males was not significantly different between AF patients and controls. No association was found between the two polymorphisms in the female population with lone AF. After (36.3 +/- 4.5) months of follow-up, the end point data were obtained: death (cardiac and noncardiac), ischemic stroke, and heart failure. In the male subgroup, the associations between rs2106809 T male carriers and combined end points including ischemic stroke, heart failure, and death in our study were of significance (OR 3.6, 95% CI 1.0-13.1, P = 0.04). CONCLUSIONS: The results indicate that polymorphism at ACE2 gene is associated with male lone AF in a Chinese Han population. Lone AF males who carry the rs2106809 T allele are associated with adverse cardiac events. PMID- 24342298 TI - Muscle mass loss and intermuscular lipid accumulation were associated with insulin resistance in patients receiving hemodialysis. AB - BACKGROUND: An accelerated muscle wasting was the pivotal factor for protein energy wasting in end stage renal disease. However, very few researches have examined the skeletal muscle quantity and quality in clinical patients. This study investigated the muscle morphologic changes by magnetic resonance imaging (MRI) and analyzed the related factors in hemodialysis patients. METHODS: Fifty eight patients receiving maintenance hemodialysis (HD) were investigated and 28 healthy adults with gender and age matched were used as controls (Control). Anthropometry, cytokine factors, and laboratory data were measured. The muscle and intermuscular adipose tissues (IMAT) were analyzed via a Thigh MRI. The bicep samples were observed after HE staining. Homeostatic model assessment of insulin resistance (HOMA-IR) was measured and their association with muscle wasting was analyzed. RESULTS: HD patients tended to have a lower protein diet, anthropometry data, and serum albumin, but the C reactive protein and interleukin-6 increased significantly. The MRI showed that HD patients had less muscle mass and a lower muscle/total ratio, but the fat/muscle and IMAT was higher when compared to the Control group. The muscle fiber showed atrophy and fat accumulation in the biceps samples come from the HD patients. Moreover, we found that the HD patients presented with a high level of plasma fasting insulin and increased HOMA-IR which negatively correlated with the muscle/total ratio, but positively with the fat/muscle ratio. CONCLUSIONS: Muscle wasting presented early before an obvious malnutrition condition emerged in HD patients. The main morphological change was muscle atrophy along with intermuscular lipid accumulation. Insulin resistance was associated with muscle wasting in dialysis patients. PMID- 24342299 TI - Metabolic syndrome and coronary artery calcification: a community-based natural population study. AB - BACKGROUND: Little is known about the influence of metabolic syndrome (MetS) on coronary artery calcification (CAC) in China. In this article, we aimed to explore the distribution of CAC in populations with and without MetS, and estimate the influence of MetS and its components on CAC in a community-based population of Beijing. METHODS: A total of 1647 local residents of Beijing, age 40-77 years, were recruited for a cardiovascular risk factors survey and were determined fasting plasma glucose (FPG), blood lipids, and 64 multi-detector computed tomography (64-MDCT) coronary artery calcium score (CACS) measurement (Agatston scoring). The distribution of CAC was described, and the influence of MetS components on CAC was evaluated. RESULTS: In this population, the prevalence and extent of CAC increased with increasing age and both were higher in MetS subjects compared to nonMetS subjects (all P < 0.05), with the exception of those older than 65 years old. The risk of CAC increased with increasing numbers of MetS components, and the odds ratios for predicting positive CAC in subjects with 1, 2, 3, and = 4 MetS components were 1.60, 1.84, 2.12, and 3.12, respectively (all P < 0.05). Elevated blood pressure, elevated FPG, elevated triglycerides, and overweight increased the risk of CAC, yielding odds ratios of 2.64, 1.67, 1.32, and 1.37, respectively (all P < 0.05). CONCLUSIONS: In the Beijing community-based population, MetS increases the risk of CAC. The risk of CAC increases with increasing numbers of MetS components. Not only the number, but also the variety of risk factors for MetS is correlated with the risk of CAC. Elevated blood pressure, hyperglycemia, hypertriglyceridemia and overweight increase the risk of CAC. PMID- 24342300 TI - Survival without common toxicity criteria grade 3/4 toxicity following second line treatment with pemetrexed for nonsquamous non-small cell lung cancer in Chinese patients. AB - BACKGROUND: The efficacy of pemetrexed in the second-line treatment of Chinese patients with advanced non-small cell lung cancer (NSCLC) has been shown to be similar to that of docetaxel in a recent study; additionally, pemetrexed was associated with much better safety and toxicity profiles. Here, the survival without common toxicity criteria grade 3/4 toxicity (SWT) data from a post hoc analysis of this recent prospective NSCLC study in Chinese patients is reported. This post hoc analysis differs from the main study; it focuses on the nonsquamous population to align with the current approval for pemetrexed in China. METHODS: A total of 154 patients with nonsquamous NSCLC received either pemetrexed (500 mg/m(2) intravenously (IV)) or docetaxel (75 mg/m(2) IV) on day 1 of 21-day cycles. SWT was analyzed using Kaplan-Meier and univariate Cox methods. RESULTS: Patients treated with pemetrexed had a longer median SWT than patients treated with docetaxel (7.4 months versus 1.2 months; unadjusted hazard ratio = 0.59, 95% confidence interval (CI): 0.41-0.84; P = 0.003). At 12 and 18 months, the SWT event-free probability for pemetrexed patients (18 months: 24.5%, 95%CI 13.9% 36.6%, vs. 12.3%, 95% CI 4.8%-23.6%) was greater than that for docexatel patients (12 months: 37.3%, 95% CI 26.5%-48.0%, vs. 23.3%, 95% CI 14.4-33.4). The progression-free survival without common toxicity criteria grade 3/4 toxicity (PFS-WT) was also statistically significantly longer for patients treated with pemetrexed than patients treated with docetaxel (1.9 months vs. 1.1 months, P = 0.002). CONCLUSIONS: Chinese patients with nonsquamous NSCLC disease treated with pemetrexed had improved SWT beyond 6 months than those receiving docetaxel. This analysis supports a benefit-to-risk profile that favors pemetrexed over docetaxel in the second-line treatment of Chinese nonsquamous NSCLC patients. PMID- 24342301 TI - Comparison of two different renorrhaphy techniques in retroperitoneal laparoscopic partial nephrectomy for complex tumor. AB - BACKGROUND: Partial nephrectomy is currently the standard treatment for clinical T1 renal neoplasms, as it can provide oncologic outcomes equivalent to radical nephrectomy. The aim was to evaluate the efficacy of self-retaining suture (SRS) in renorrhaphy technique in retroperitoneal laparoscopic partial nephrectomy (LPN) for a single renal mass of moderate or high complexity by assessing peri operative outcomes. METHODS: A retrospective analysis was done of 64 patients between 2010 and 2012 for complex renal mass (RENAL score >= 7) in whom retroperitoneal LPN was performed with two layers using continuous knotless barbed suture (Quill PDO SRS group; n = 34) and absorbable vicryl (non-SRS group; n = 30), respectively. Cases were matched for RENAL score. All the surgical procedures were performed by the same surgeon with experience of more than 500 cases of LPN. Comparisons were made in patients and preoperative outcomes and peri-operative complications between SRS group and non-SRS group. RESULTS: Mean warm ischemia time (WIT) in SRS group was less than non-SRS group (18.0 vs. 24.8 minutes, P = 0.021). Renorrhaphy suture cost in SRS group was lower than non-SRS group ($269.6 vs. $335.8, P = 0.001). There were no significant differences between the two groups for postoperative changes in creatinine and estimated glomerular filtration rate and the rate of peri-operative complications. CONCLUSION: SRS was safe for complex renal tumor with two layers, continuous and unknot suture, during LPN and would reduce the WIT and renorrhaphy suture cost significantly. PMID- 24342302 TI - A new anastomosis method for choledochojejunostomy by the way behind antrue pyloricum. AB - BACKGROUND: Reflux cholangitis has been the most common complication after Roux en-Y choledochojejunostomy. In this study we intended to evaluate the perioperative and long-term efficacy of a new anastomosis method for choledochojejunostomy. METHODS: Clinical data of 143 eligible patients who underwent choledochojejunostomy in the Eastern Hepatobiliary Surgery Hospital affiliated to the Second Military Medical University, China between January 2007 and December 2010 were retrospectively analyzed. Among the patients, 38 consecutive cases underwent this new anastomosis method for choledochojejunostomy (improved group, IG) and 105 underwent standard Roux-en-Y choledochojejunostomy (control group, CG). Changes in the incidence of cholangitis, the time of beginning to eat liquid meals, post-operative delayed gastric emptying and liver function between the two groups were compared. RESULTS: There was no statistical difference in the levels of alanine transaminase, alkaline phosphomonoesterase and gamma-glutamy transferase between the two groups. The time of beginning to eat liquid meals was significantly shorter in IG than CG (P < 0.05). The incidence of delayed gastric emptying was lower in IG than CG, with statistical tendency between the two groups (P = 0.052). Among nine patients with different degrees of acute cholangitis in the two groups, one patient (2.6%) in IG and eight (7.6%) in CG suffered from acute cholangitis within six months of follow-up after discharge, but with no statistical difference between the two groups (P > 0.05). Of the nine patients with acute cholangitis, none in IG and four in CG were hospitalized for further treatment (P > 0.05). CONCLUSIONS: Patients in IG had satisfactory perioperative and long-term prognosis with shorter time of beginning to eat liquid meals and lower incidence of delayed gastric emptying. This new procedure of choledochojejunostomy by the way behind antrue pyloricum was easy and safe to perform with no mortality and low complication rates. PMID- 24342303 TI - Usefulness of radial extracorporeal shock wave therapy for the spasticity of the subscapularis in patients with stroke: a pilot study. AB - BACKGROUND: There are not many studies about treatment of shoulder spasticity. Although botulinum toxin injection has been reported to be effective for shoulder spasticity, the effectiveness was judged by pain and limited motion change, but not the spasticity itself. Shoulder spasticity is considered to play an important role in hemiplegic frozen shoulder. However, the subscapularis muscle, unlike the pectoralis major muscle, is located deep beneath scapula, where conventional injection is difficult to perform. As extracorporeal shock wave therapy (ESWT) has been reported to be effective for spasticity relief, and we thought spasticity of subscapularis muscle located deep beneath the scapula would be a good candidate for ESWT treatment. This study was to evaluate the beneficial effects of radial ESWT (rESWT) on spastic subscapularis muscle in stroke patients. METHODS: This is an uncontrolled, prospective, unicenter, clinical pilot study. Stroke patients (n = 57; mean age 55.4 years) with spastic shoulders were recruited between June 2011 and February 2012 at the University Rehabilitation Hospital. rESWT was administered to each patient every two or three days for two weeks (five total treatments). Evaluation consisted of 11 measurements for each patient; at the start of each of the five treatments and once per week during the following six weeks. Spasticity was measured at external rotator muscles of the shoulder using the modified Ashworth scale (MAS), and passive range of motion (ROM) of the shoulder in external rotation was recorded. Pain was measured using a visual analogue scale (VAS) during passive ROM of the shoulder in external rotation, and was additionally recorded for patients who preserved cognitive and communicative ability (Pain group). RESULTS: Reduction in MAS and VAS and improvement of ROM during and after rESWT treatments were prominent compared to baseline. The reduction in MAS and VAS and improvement of ROM continued four weeks after the last treatment and the effects of the treatment decreased afterward. CONCLUSION: rESWT will be able to provide stroke patients with an effective and safe procedure for the reduction of spasticity and pain as well as for the improvement of ROM of spastic shoulders. PMID- 24342304 TI - Efficacy and feasibility of gemcitabine and carboplatin as first-line chemotherapy in elderly patients with advanced non-small cell lung cancer. AB - BACKGROUND: Although platinum-based chemotherapy is a standard first-line treatment in advanced non-small cell lung cancer (NSCLC), further research for the safety and efficacy of combination chemotherapy in elderly patients has been required. The purpose of this study was to evaluate the efficacy and safety of gemcitabine and carboplatin as first-line treatment in elderly patients with advanced NSCLC and to evaluate the prognostic factors. METHODS: Eligibility included: (1) age of 70 years or more, (2) histologically confirmed NSCLC, (3) chemotherapy-naive, (4) advanced disease with stage IIIB or IV, (5) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2, (6) adequate organ function. Patients received intravenous carboplatin (area under curve (AUC) = 5) on day 1 and gemcitabine (1000 mg/m2) on days 1 and 8, every 3 weeks. RESULTS: The medical records of forty patients were reviewed retrospectively. Median age was 73.9 years (range, 70-84.6), and there were 27 men (67.5%). Thirty-seven patients (92.5%) had ECOG PS 0-1. Adenocarcinoma was found in 57.5%. Median cycles were administrated with 4.5 per person (range: 1-6). Best responses were partial response in 22 (55.0%) patients and stable disease (SD) in 13 (32.5%). The median progression free survival (PFS) and overall survival (OS) were 5.9 months (95% CI: 4.5-7.3 months) and 9.6 months (95% CI: 8.2-11.0 months), respectively. Grade 4 hematologic toxicities for neutropenia (7.5%), thrombocytopenia (7.5%) and anemia (5.0%) were observed. Histology was significant prognostic factor for PFS (P = 0.024). CONCLUSION: Gemcitabine and carboplatin combination chemotherapy is an effective and manageable treatment option in elderly advanced NSCLC patients with good performance status. PMID- 24342305 TI - What is the real practice of exercise echocardiographic testing in asymptomatic patients with severe aortic stenosis? AB - BACKGROUND: Although exercise testing has been suggested to help predict clinical outcome, limited data are available to guide how exercise Doppler echocardiography (ECG) can be used clinically in asymptomatic patients with aortic stenosis (AS). The aim of this study was to assess the clinical value of exercise echocardiographic testing in asymptomatic patients with severe AS. METHODS: Symptom-limited treadmill exercise testing using the modified Bruce protocol was performed in 31 asymptomatic patients (mean age (62 +/- 11) years) with severe AS (aortic valve area <1 cm(2), peak aortic velocity (AV Vmax) >4 m/sec, or a mean transaortic pressure gradient (AV mean PG) >40 mmHg (1 mmHg = 0.133 kPa)) with normal left ventricular (LV) systolic function (LV ejection fraction (EF) >50%). Clinical symptoms, vital signs, ECG, and Doppler hemodynamics were obtained during and/or immediately after exercise. RESULTS: Aortic valve replacement (AVR) was performed in 18 patients during follow-up. The patients who had AVR exhibited higher baseline AV mean PG (51 (35-84) vs. 44 (25.2-57.0) mmHg; P = 0.031). There were no significant differences between the AVR group and non-AVR group including exercise duration (7.47 (2.32-11.59) vs. 7.25 (4.06-10.52) minutes, P = 0.917), exercise capacity (10.1 (4.6-12.8) vs. 10.1 (7.0-12.8) metabolic equivalents, P = 0.675), and an increment in AV mean PG by exercise (18.5 (3.2-48.0) vs. 12.6 (4.4-32.1) mmHg, P = 0.366). Univariate regression analysis revealed that independent determinant of AVR was the baseline AV mean PG (P = 0.031). CONCLUSIONS: Although additional value of exercise ECG was demonstrated, baseline transaortic mean pressure gradient is the major determinant of AVR. Further large-scale prospective studies are required to determine whether surgery should be recommended in the presence of an abnormal exercise ECG in asymptomatic severe AS. PMID- 24342306 TI - Effect of long intermittent hemodialysis on improving dialysis adequacy of maintenance hemodialysis patients. AB - BACKGROUND: With the increase in hemodialysis (HD) patients, the blood dialysis patient's quality of life (QoL) and long-term survival are still a challenge for clinicians. Recent studies have found that most of the HD patients have sleep disorders, which have a certain correlation with long-term survival and QoL. But there are few studies of Chinese in this field. This study aimed to investigate whether increasing the dialysis dose can improve sleep quality, so we treated HD patients on long intermittent hemodialysis (LIHD). METHODS: Forty patients who were treated by conventional HD at the Beijing Friendship Hospital Blood Purification Center were offered the option of LIHD. The patients' laboratory data, medication use, and questionnaire answers were analyzed. Conventional HD was delivered thrice weekly with 4 hours per treatment, and LIHD was delivered thrice weekly with 8 hours per treatment. The study lasted 6 months. Questionnaires included sleep quality survey and QoL SF-36; the former includes the Athens Insomnia Scale, Pittsburgh Sleep Quality Index (PSQI), and Epworth Sleepiness Scale (ESS). RESULTS: After conversion to LIHD the dialysis efficiency (Kt/V) significantly increased than before (P < 0.05) and clearance rate of urea nitrogen also increased from 67 to 78% (P < 0.01). After conversion, median values for Hb increased from 108.95 to 126.55 g/L (P < 0.01); albumin increased from 38.85 to 40.05 g/L (P < 0.01). Phosphorus decreased from 2.69 to 1.54 mmol/L (P < 0.01), but there was no alteration in blood calcium; phosphorus and calcium phosphate product levels were under more control, but parathyroid hormone (iPTH) level did not change after conversion to LIHD. After conversion, blood pressure (BP) was better controlled than before and the mean number of antihypertensive drugs prescribed declined from 2.9 to 0.5 (P < 0.01). There was a significant reduction in the use of erythropoietin-stimulating agent of 5250 U/w (P < 0.01). Sleep quality significantly improved in the 2 months after conversion to LIHD, and the PSQI score decreased from 10.80 to 5.45 and the ESS score decreased from 12.05 to 5.30 (P < 0.01). However, sleep quality started to decline after 2 months on LIHD. QoL SF-36 score increased from 410.92 to 592.53 (P < 0.01). CONCLUSION: LIHD offers an effective improvement in dialysis adequacy for Chinese maintenance HD patients, but it improves sleep quality only briefly which may be related to loss of serum calcium and parathyroid dysfunction. PMID- 24342307 TI - Upregulation of glucosylceramide synthase protein in papillary thyroid carcinoma. AB - BACKGROUND: Glucosylceramide synthase (GCS) can reduce ceramide levels and help cells escape ceramide-induced apoptosis, thus leading to multidrug resistance (MDR). However, its expression and clinical significance in thyroid neoplasms still remain unclear. We aimed to elucidate the expression of GCS and explore its correlation with the clinicopathological characteristics in papillary thyroid carcinomas (PTCs). METHODS: We retrospectively investigated GCS protein expression level in tissue specimens obtained from 108 consecutive PTC patients by immunohistochemistry and Western blotting. RESULTS: GCS was weakly positive or negative in normal follicular cells, but it was frequently overexpressed in PTC cells. GCS overexpression was associated with primary tumor size, local infiltration, lymph node metastasis, and local recurrence, but not associated with gender, age, pathological variants, tumor multifocality, tumor stage or distant metastasis. Western blotting also showed that GCS protein levels were much higher in PTCs' tissues than in normal thyroid tissues. CONCLUSION: GCS was upregulated in PTCs and might be an independent factor affecting prognosis. PMID- 24342308 TI - Evaluation of the therapeutic efficiency of mandibular anterior implant-supported fixed bridges with cantilevers. AB - BACKGROUND: Dental implant technology has developed rapidly in recent years. However, the use of implant-supported fixed bridges with cantilevers has been controversial. The purpose of this study was to evaluate the clinical results of the mandibular anterior implant-supported fixed bridges with a cantilever. Method Thirty-three patients (15 males, 18 females; mean age, 42.6 years; range 20-54 years) with two missing anterior mandibular teeth had single implant-supported fixed bridges with a cantilever. Clinical examination was recorded and radiographs were taken. The mean duration of follow-up was 30 months (15-44 months). RESULTS: All implants survived. Loosening or fracture of the prosthesis was not observed. All patients were satisfied with the treatment. The mean bone resorption values after 12, 24, and 36 months of implant loading were 0.94, 1.18 and 1.35 mm respectively. The changes of gingival papilla height ranged from 0 to 0.5 mm. There was significant difference between 1-year and 2 or 3 years restoration groups regarding the average gingival height changes (P < 0.05). CONCLUSION: After careful and precise selection of patients, restoration with a single implant-supported fixed bridge with a cantilever can be recommended if two anterior mandibular teeth are missing. PMID- 24342309 TI - Microsurgical transverse 2-suture intussusception vasoepididymostomy: effectiveness and rationality. AB - BACKGROUND: 2-Suture longitudinal vasoepididymostomy shows superiority to transverse technique in an animal study; to date, this has not been consistently confirmed in human body. In the present study, we evaluated the effectiveness of 2-suture transverse intussusception vasoepididymostomy and compared the rationality between transverse and longitudinal techniques. METHODS: From May 2007 to December 2008, we performed 2-suture transverse vasoepididymostomy in 19 consecutive patients, as described by Marmar with modification. Between March 2009 and January 2010, the internal diameter of the vas lumen and the outer diameter of the epididymal tube were measured using microruler (21 patients and 37 sides). RESULTS: Three patients lost to follow-up. At the first follow-up period (ranged from 10 to 24 months), the patency rate was 56.3% (9/16) and the natural pregnancy rate was 25% (4/16). At the second follow-up period (ranged from 46 to 63 months), the patency rate was 68.8% (11/16), the natural pregnancy rate was 37.5% (6/16), respectively, and the take-home baby rate was 31.3% (5/16). The diameter of the vas lumen and the outer diameter of the epididymal tubule were (0.512 +/- 0.046) mm and (0.572 +/- 0.051) mm (P < 0.001), respectively. CONCLUSION: Transverse 2-suture intussusception vasoepididymostomy is still an effective technique in treating obstructive azoospermia. PMID- 24342310 TI - Outcomes of upper airway reconstructive surgery for obstructive sleep apnea syndrome based on polysomnography after nasopharyngeal tube insertion. AB - BACKGROUND: The most common obstruction sites for obstructive sleep apnea hypopnea syndrome (OSAHS) are the oropharynx and the glossopharyx. The diagnosis of glossopharyngeal airway obstruction is difficult. The study aimed to assess the effect of upper airway reconstructive surgery for OSAHS based on polysomnography (PSG) after nasopharyngeal tube insertion (NPT-PSG), and to evaluate the clinical value of NPT-PSG in localizing the obstructive sites. METHODS: Seventy-nine OSAHS patients diagnosed with PSG were included in the study. PSG was repeated with a nasopharyngeal tube in place (NPT-PSG). RESULTS: of the two PSGs were compared. A NPT-PSG apnea hypopnea index (AHI) greater than 15 times per hour was used as a threshold for glossopharyngeal surgery. The cause of glossopharyngeal airway obstruction was taken into consideration in planning glossopharyngeal surgery. Assessment of efficacy was followed-up. RESULTS: After NPT-PSG, patients' AHI significantly decreased and lowest oxygen saturation (LaSO2) significantly increased. Of the 79 patients, 47 were treated with uvulopalatopharyngoplasty (UPPP) alone and 32 with UPPP + glossopharyngeal surgery. Thirty-two patients were considered cured, 33 markedly improved, and 14 failed. The overall surgery success rate was 82.3%. CONCLUSIONS: NPT-PSG can be used as a diagnosis tool for localizing airway obstruction in OSAHS patients. Surgical treatment based on NPT-PSG results in good treatment efficacy. PMID- 24342311 TI - Association of beta-adrenergic receptor genes polymorphisms with incidence of subsequent cardiovascular events in Han Chinese patients with coronary artery disease. AB - BACKGROUND: Sequence variants in the beta-adrenergic receptor (ADRB) genes have a close relationship with the development of coronary artery disease (CAD) and the patient's prognosis. However, there is a lack of data on the role of the variants in ADRBs genes in Han Chinese patients with CAD. We aimed to investigate the association of genetic variants in the ADRB1 and ADRB2 genes with the incidence of major adverse cardiac event (MACE) in Han Chinese patients with CAD. METHODS: A total of 545 Han Chinese patients with CAD undergoing percutaneous coronary intervention (PCI) were recruited to the study and followed for one year. Three variant sites in ADRB1 (rs1801253) and ADRB2 (rs1042713 and rs1042714) were genotyped. The effect of the ADRB1 and ADRB2 genotypes on MACE within one year was assessed. RESULTS: There were 47 cases of MACE during follow-up. There was no significant difference in the incidence of MACE among patients carrying different genotypes of the three variants in ADRB1 and ADRB2 (Log-rank, all P > 0.05). Cox regression analysis showed no association between three variants in ADRB1 and ADRB2 genes and the incidence of MACE during one-year follow-up, the adjusted hazard ratios (95% confidence interval) for rs1801253, rs1042713 and rs1042714 were 1.05 (0.54-2.02), 1.24 (0.58-2.64) and 1.66 (0.81-3.42), respectively. CONCLUSION: Our data did not support a relationship between the three polymorphisms of ADRB1 (rs1801253) and ADRB2 (rs1042713 and rs1042714) genes and risk of subsequent cardiovascular events after PCI in Han Chinese patients with CAD. PMID- 24342312 TI - Factors influencing clinical outcomes of acute ischemic stroke treated with intravenous recombinant tissue plasminogen activator. AB - BACKGROUND: Thrombolysis with recombinant tissue plasminogen activator (rt-PA) has gained international recognition, clinical outcomes following this thrombolytic therapy varied from patient to patient. Factors affecting clinical outcomes have not been well understood yet, so this retrospective case-control study aimed to investigate factors that may influence clinical outcomes of acute ischemic stroke treated with intravenous rt-PA. METHODS: One hundred and one patients with acute ischemic stroke who received intravenous rt-PA thrombolysis within 4.5 hours from disease onset were included. Patients were divided into good or poor outcome group according to modified Rankin Scale (mRS) score, good outcome group: mRS score of 0-1; poor outcome group: mRS of 2-6. Stroke characteristics were compared between the two groups. Factors for stroke outcomes were analyzed via univariate analysis and Logistic regression. RESULTS: Of the 101 patients studied, patients in good outcome group (n = 55) were significantly younger than patients in poor outcome group (n = 46, (62.82 +/- 14.25) vs. (68.81 +/- 9.85) years, P = 0.029). Good outcome group had fewer patients with diabetic history (9.09% vs. 28.26%, P = 0.012), fewer patients with leukoaraiosis (7.27% vs. 28.26%, P = 0.005) and presented with lower blood glucose level ((5.72 +/- 1.76) vs. (6.72 +/- 1.32) mmol/L, P = 0.012), lower systolic blood pressure level ((135.45 +/- 19.36) vs. (148.78 +/- 19.39) mmHg, P = 0.003), lower baseline NIHSS score (12.02 +/- 5.26 vs. 15.78 +/- 4.98, P = 0.002) and shorter onset-to treatment time (OTT) ((2.38 +/- 1.21) vs. (2.57 +/- 1.03) hours, P = 0.044) than poor outcome group. Logistic regression analysis showed that absence of diabetic history (odds ratio (OR) 0.968 (95% CI 0.941-0.996)), absence of leukoaraiosis (OR 0.835 (95% CI 0.712-0.980)), lower baseline NIHSS score (OR 0.885 (95% CI 0.793-0.989)), lower pre-thrombolysis systolic blood pressure (OR 0.962 (95% CI 0.929-0.997)), and lower blood glucose level (OR 0.699 (95% CI 0.491-0.994)) before thrombolysis were significantly associated with better outcome. CONCLUSION: Patients with no history of diabetes, no leukoaraiosis, low blood glucose level, low systolic blood pressure level and low baseline NIHSS score before thrombolysis have a better outcome. PMID- 24342313 TI - Anterior herniation of lumbar disc induces persistent visceral pain: discogenic visceral pain: discogenic visceral pain. AB - BACKGROUND: Visceral pain is a common cause for seeking medical attention. Afferent fibers innervating viscera project to the central nervous system via sympathetic nerves. The lumbar sympathetic nerve trunk lies in front of the lumbar spine. Thus, it is possible for patients to suffer visceral pain originating from sympathetic nerve irritation induced by anterior herniation of the lumbar disc. This study aimed to evaluate lumbar discogenic visceral pain and its treatment. METHODS: Twelve consecutive patients with a median age of 56.4 years were enrolled for investigation between June 2012 and December 2012. These patients suffered from long-term abdominal pain unresponsive to current treatment options. Apart from obvious anterior herniation of the lumbar discs and high signal intensity anterior to the herniated disc on magnetic resonance imaging, no significant pathology was noted on gastroscopy, vascular ultrasound, or abdominal computed tomography (CT). To prove that their visceral pain originated from the anteriorly protruding disc, we evaluated whether pain was relieved by sympathetic block at the level of the anteriorly protruding disc. If the block was effective, CT-guided continuous lumbar sympathetic nerve block was finally performed. RESULTS: All patients were positive for pain relief by sympathetic block. Furthermore, the average Visual Analog Scale of visceral pain significantly improved after treatment in all patients (P < 0.05). Up to 11/12 patients had satisfactory pain relief at 1 week after discharge, 8/12 at 4 weeks, 7/12 at 8 weeks, 6/12 at 12 weeks, and 5/12 at 24 weeks. CONCLUSIONS: It is important to consider the possibility of discogenic visceral pain secondary to anterior herniation of the lumbar disc when forming a differential diagnosis for seemingly idiopathic abdominal pain. Continuous lumbar sympathetic nerve block is an effective and safe therapy for patients with discogenic visceral pain. PMID- 24342314 TI - Immune mechanism and clinical significance of macrophage to medullary hematopoietic injury of immune-related hematocytopenia patients. AB - BACKGROUND: Immune-related hematocytopenia (IRH) is considered to be related with the production of autoantibody, as well as the activation of humoral immunity which is stimulated by B lymphocyte. This study aimed to observe the levels of various cytokines in the blood serum and the in situ active state of macrophage (Mphi) in the medullary hematopoietic microenvironment of IRH patients, and to probe into the immune mechanism and clinical significance of Mphi in hematopoietic cell injury. METHODS: ELISA is used to detect the IL-4, IL-6, IL 12, IL-17, and IFN-gamma levels in the peripheral blood serum of 376 patients in pre- and post-therapy. Cytochemistry and cell immunochemistry methods are used to observe the peroxidase (POX), nonspecific esterase (NSE), hemosiderin granules, and HLA-DR activity of Mphi in the bone marrow of patients. Immunofluorescence is used to observe the expression of hemocyte antihuman globulin IgG antibody, lymphocytes CD4 molecule, Mphi membrane FcgammaIIreceptor (FcgammaIIR), mannitose receptor (MR), IFN-gamma, ICAM-1, IL-12, and IL-17A and the formation mechanism of antibody-dependent cell-mediated cytotoxicity (ADCC) hematopoietic cell islands (HI) in the medullary hematopoietic microenvironment of patients. Glucocorticoid is used for treatment on the basis of anti-infection therapy, and gamma globulin stoss therapy is used for the appearance of ADCC-type HI or serious Mphi bloodthirsty phenomenon; if necessary, association of Cyclosporine A (CsA) should be used and chalybeate should be supplemented. RESULTS: In the patient group, the levels of IL-4, IL-6, IL-12, IL-17, and IFN-gamma were increased. After treatment, the cytokine levels gradually became normal. The activated Mphi in the marrow highly expressed NSE and POX, and Mphi swallowed more hemosiderin particles, but the iron in the cytoplasm of immature erythrocytes decreased. The activated Mphi expressed HLA-DR, MR, ICAM-1, IFN gamma, and IL-12. For patients with humoral immunity activation and bacterial infection, Mphi weakly expressed IL-17A but highly expressed FcgammaIIR, and the phenomenon that ADCC-type HI broke pathological blood corpuscles often occurred; for the cellular immune activation along with virus infection, the white blood count (WBC) significantly reduced, Mphi weakly expressed FcgammaIIR, secretory highly expressed IL-17A, and the phenomena that Mphi adhered to, captured and swallowed blood cell often occurred. After four weeks of anti-infective and immunosuppressive therapy, nuclear apoptosis of Mphi occurred in the bone marrow of patients, HI and bloodthirsty phenomenon disappeared, and the peripheral blood picture started to improve. CONCLUSIONS: Mphi is an important antigen presenting cell in the IRH marrow for hematopoiesis destruction and an immune effector cell of hematopoietic injury; infection can promote the activation of Mphi, upregulate the impression of immune molecule and receptors, form ADCC HI, aggravate hematopoietic injury, and accelerate the destruction on hematopoietic cell. PMID- 24342315 TI - Results of transvenous lead extraction of coronary sinus leads in patients with cardiac 4,703 resynchronization therapy. AB - BACKGROUND: The need for transvenous lead extraction procedures of coronary sinus (CS) leads is increasing due to rising numbers of implanted cardiac resynchronization therapy devices during the past decade. METHODS: From January 2009 to June 2013, 27 CS leads were scheduled for extraction in 27 patients (mean age (63.1 +/- 14.6) years). Indications for lead extraction were infection in 13 and lead dysfunction in 14 cases. Isolated extraction of CS leads was performed in eight, extraction of multiple leads in 19 cases. Among leads with an implant time of >= 12 months (n = 19) mean implant duration (MID) was (46.4 +/- 15.2) (12 76) months. Groups were formed depending on infectious or non-infectious indications (INF vs. Non-INF), and the use or non-use of extraction tools (ET1 vs. ET0). RESULTS: Among patients with an implant duration of >= 12 months, complete procedural success was 94.7% and clinical success 100%. Operative mortality was zero. In the INF versus NON-INF groups complete procedural success (100% vs. 91.7%, P = 0.43), mean number of required extraction tools (0.7 (0-2) vs. 0.9 (0-3), P = 0.65) and MID (49.1 +/- 15.0 vs. 44.7 +/- 15.8, P = 0.83) did not differ significantly. Comparing the groups ET1 and ET0 showed no significant differences in complications (n = 1 vs. n = 1, P = 0.81) and MID (47.0 +/- 17.5 vs. 45.5 +/- 12.6, P = 0.71). CONCLUSIONS: In specialized centers transvenous lead extraction of coronary sinus leads with a mean implant duration of almost four years can be performed safely and effectively. Neither non-infectious indications nor the use of extraction tools negatively affected the outcome of the procedure. PMID- 24342316 TI - Aliskiren ameliorates sympathetic nerve sprouting and suppresses the inducibility of ventricular tachyarrhythmia in postinfarcted rat heart. AB - BACKGROUND: Aliskiren is an oral renin inhibitor, which inhibits the first rate limiting step in the renin angiotensin aldosterone system. In this study, sympathetic nerve sprouting and the inducibility of ventricular fibrillation after aliskiren treatment in myocardial infarction were investigated. METHODS: Male Sprague Dawley rats after coronary artery ligation were randomly allocated to four groups: angiotensin converting enzyme inhibitor enalapril, angiotensin receptor blocker valsartan, beta adrenergic receptor blocker carvedilol and rennin inhibitor aliskiren treatment for six weeks. Electrophysiological study, histological examination and Western blotting were performed. RESULTS: The plasma norepinephrine level and sympathetic nerve innervation significantly increased in treated infarcted rats compared to untreated rats. Aliskiren treatment reduced the sympathetic nerve innervations after myocardial infarction. There is no significant difference in sympathetic nerve innervations after myocardial infarction among the enalapril, valsartan, carvediloand or aliskiren treated groups. Programmed electrical stimulation study showed that inducible ventricular arrhythmia was reduced, ventricular fibrillation threshold was increased and ventricular effective refractory period was prolonged in enalapril, valsartan, carvedilol and aliskiren treated infarcted rats compared to untreated infarcted rats. Cardiomyocytic apoptosis in infarcted region was significantly decreased in enalapril, valsartan, carvedilol and aliskiren treated infarcted rats. CONCLUSIONS: Aliskiren ameliorated cardiomyocytic apoptosis, attenuated the sympathetic nerve innervations and reduced the vulnerability of ventricular arrhythmias after myocardial infarction. Enalapril, valsartan and carvedilol have similar effects as aliskiren on cardiomyocytic apoptosis, sympathetic nerve innervations and vulnerability of ventricular arrhythmias after myocardial infarction. PMID- 24342317 TI - A novel, recovery, and reproducible minimally invasive cardiopulmonary bypass model with lung injury in rats. AB - BACKGROUND: Cardiopulmonary bypass (CPB) has been shown to be associated with a systemic inflammatory response leading to postoperative organ dysfunction. Elucidating the underlying mechanisms and developing protective strategies for the pathophysiological consequences of CPB have been hampered due to the absence of a satisfactory recovery animal model. The purpose of this study was to establish a good rat model of CPB to study the pathophysiology of potential complications. METHODS: Twenty adult male Sprague-Dawley rats weighing 450-560 g were randomly divided into a CPB group (n = 10) and a control group (n = 10). All rats were anaesthetized and mechanically ventilated. The carotid artery and jugular vein were cannulated. The blood was drained from the right atrium via the right jugular and transferred by a miniaturized roller pump to a hollow fiber oxygenator and back to the rat via the left carotid artery. Priming consisted of 8 ml of homologous blood and 8 ml of colloid. The surface of the hollow fiber oxygenator was 0.075 m(2). CPB was conducted for 60 minutes at a flow rate of 100 120 ml* kg(-1)*min(-1) in the CPB group. Oxygen flow/perfusion flow was 0.8 to 1.0, and the mean arterial pressure remained 60-80 mmHg. Blood gas analysis, hemodynamic investigations, and lung histology were subsequently examined. RESULTS: All CPB rats recovered from the operative process without incident. Normal cardiac function after successful weaning was confirmed by electrocardiography and blood pressure measurements. Mean arterial pressure remained stable. The results of blood gas analysis at different times were within the normal range. Levels of IL-1beta and TNF-alpha were higher in the lung tissue in the CPB group (P < 0.005). Histological examination revealed marked increases in interstitial congestion, edema, and inflammation in the CPB group. CONCLUSION: This novel, recovery, and reproducible minimally invasive CPB model may open the field for various studies on the pathophysiological process of CPB and systemic ischemia-reperfusion injury in vivo. PMID- 24342318 TI - Influence of extract of Ginkgo biloba leaves tablets on the aquaporin-1 expression in isolated lung ischemia reperfusion. AB - BACKGROUND: The extract of Ginkgo biloba leaves tablets, ginaton, is widely used in treating ischemic cerebrovascular disease in the clinic. This study aimed to investigate the expression of aquaporin-1 (AQP-1) in rat lung with ischemia/reperfusion injury after pretreatment with ginaton, and whether the pretreatment with ginaton reduces the acute lung injury caused by ischemia/reperfusion injury. METHODS: Adult Wistar rats were divided into two groups. Some rats were used as donors (n = 20), the others as recipients (n = 20). Left lungs of donor rats were used for the isolated lung reperfusion model, which perfused only with low potassium dextran (LPD) solution as group A (n = 10); the others were pretreated with ginaton before reperfusion as group C (n = 10). Right lung of donor rat without any treatment was used as a control group (group B and group D, n = 10 for each group). After the model was established, the expression of AQP-1 in the lung tissues was examined by immunohistochemistry, Western blotting, and reverse transcriptase-polymerase chain reaction. RESULTS: Immunohistochemical examination revealed that AQP-1 was expressed in endothelia. Immunoblotting demonstrated that the relative gray values of AQP-1 protein in groups A and C were 0.65+/-0.06, 0.88+/-0.11, respectively. The relative gray values of the mRNA expression in groups A and C were 0.30+/-0.08, 0.49+/-0.11, respectively. The expression of AQP-1 protein and mRNA in group C was significantly higher than in group A (P < 0. 05). CONCLUSION: The pretreatment with ginaton can reduce the acute lung injury caused by ischemia/reperfusion. PMID- 24342319 TI - Elevated levels of mitochonrial respiratory complexes activities and ATP production in 17-beta-estradiol-induced prolactin-secretory tumor cells in male rats are inhibited by melatonin in vivo and in vitro. AB - BACKGROUND: Our earlier studies indicate that melatonin inhibits the proliferation of prolactinoma and induces apoptosis of pituitary prolactin secreting tumor in rats. Melatonin has also been shown to induce apoptosis and to reduce the production of ATP in breast tumor cells. This study analyzed the levels of the four mitochondrial respiratory complexes and the production of ATP and also the effects of melatonin treatment of prolactinoma. METHODS: In the in vivo study, mitochondria were harvested from control pituitaries or prolactinoma collected from the pituitaries of melatonin- and 17-beta-estradiol (E2)-treated male rats. In the in vitro study, prolactinoma cells mitochondria were harvested. Activities of the four mitochondrial respiratory complexes were assayed using fluorometer. ATP production of prolactinoma cells was estimated using bioluminescent methods. RESULTS: Elevated levels of four mitochondrial respiratory complexes activities and ATP production were recorded in prolactinoma cells. Moreover, in both in vivo and in vitro studies, melatonin inhibited the activities of mitochondrial respiratory complexes and the production of ATP in prolactinoma cells. CONCLUSIONS: There is a link between mitochondrial function increase and tumorigenesis. Melatonin induces apoptosis of pituitary prolactin secreting tumor of rats via the induction of mitochondrial dysfunction and inhibition of energy metabolism. PMID- 24342320 TI - Efficacy and safety of a novel nano-porous polymer-free sirolimus-eluting stent in pigs. AB - BACKGROUND: Drug-eluting stents represent a major advance in interventional cardiology. However, the current drug-eluting stents have significant limitations. One of the major problems is very late stent thrombosis, which is likely caused by inflammation and a hypersensitivity reaction related to a polymer on the stent. A polymer-free sirolimus-eluting stent with a unique nano porous surface has been developed. This study aimed to evaluate this novel polymer-free sirolimus-eluting stent for its efficacy and safety in a pig model. METHODS: Stents were directly coated with sirolimus (a drug concentration of 2.2 ug/mm(2) on the stent surface). The polymer-free sirolimus-eluting stents (PFSES) were compared to standard polymer-coated sirolimus-eluting stents (PCSES) and bare-metal stents (BMS) in 18 pigs. RESULTS: At one month the degree of neointimal hyperplasia was similar between the two sirolimus-eluting stent groups and was significantly less compared to BMS ((1.93 +/- 0.51) mm(2), (1.57 +/- 0.69) mm(2) vs. (4.45 +/- 1.05) mm(2), P < 0.05) At three months, PFSES maintained the low level of neointima ((2.41 +/- 0.99) mm(2) vs. (4.32 +/- 1.16) mm(2), P < 0.05), whereas PCSES had developed significant neointimal proliferation similar to BMS. The inflammation level was significantly higher in PCSES when compared with BMS three months post-implantation (2.50 +/- 0.55 vs. 0.83 +/- 0.75, P < 0.05) whereas PFSES showed a low level of inflammation comparable to PCSES (1.33 +/- 0.52 vs. 2.50 +/- 0.55, P < 0.05). CONCLUSION: The PFSES is effective and safe, and appears to be superior to standard PCSEs. PMID- 24342321 TI - Human decorin regulates proliferation and migration of human lung cancer A549 cells. AB - BACKGROUND: Decorin is a small leucine-rich proteoglycan and it plays an important role in regulation of cell growth and migration in various tumor cell lines. Decorin was found down-regulated in non-small cell lung cancer tissue and may be involved in regulation of lung cancer development. METHODS: In this study, lentivirus-mediated RNA interference and over expression were employed to change the expression levels of decorin in lung cancer A549 cells. We tested the cell cycle of A549 cells and the expression of transforming growth factor (TGF)-beta, cyclin D1, epidermal growth factor receptor (EGFR), P53, and P21. RESULTS: We found that up-regulation of decorin could inhibit proliferation, block cell cycle at G1 and decrease invasive activity of A549 cells. Moreover, we also show that up-regulation of decorin induced significant decreases of TGF-beta1, cyclin D1 expression, phosphorylation of EGFR, and increases of P53 and P21 expression. Opposite results were observed in A549 cells with down-regulation of decorin. CONCLUSION: Our results suggest that decorin is a key regulator involved in proliferation and migration of A549 cells. PMID- 24342322 TI - Investigation on the optical scan condition for imaging of multi-slice spiral CT liver perfusion in rats. AB - BACKGROUND: Multi-slice CT liver perfusion has been widely used in experimental studies of hemodynamic changes in liver lesions, and is usually performed as an adjunct to a conventional CT examination because of its high temporal and spatial resolution, simple protocol, good reproducibility, and ability to measure hemodynamic changes of liver tissues at the capillary level. Experimental rat models, especially those of induced liver cancer, are often used in studies of hemodynamic changes in liver cancer. Carcinogenesis in rats has a similar pathological progression and characteristics resembling those in human liver cancer; as a result, rat models are often used as ideal animal models in the study of human liver cancer. However, liver perfusion imaging in rats is difficult to perform, because rats' livers are so small that different concentrations, flow rates, and dose of contrast agents during the CT perfusion scanning can influence the quality of liver perfusion images in rats. The purpose of this study, therefore, was to investigate the optimal scan protocol for the imaging of hepatic perfusion using a deconvolution mathematical method in rats by comparing the results of rats in different injection conditions of the contrast agent, including concentration, rate and time. METHODS: Plain CT scan conditions in eighty 2-month-old male Wistar rats were 5.0 mm slice thickness, 5.0 mm interval, 1.0 pitch, 120 kV tube voltage, 60 mA tube current, 512 * 512 matrix, and FOV 9.6 cm. Perfusion scanning was carried out with different concentrations of diatrizoate (19%, 38%, 57%, and 76%), different injection rates (0.3 and 0.5 ml/s), and different injection times (1, 2-3, 4-5, and 6 seconds). The above conditions were randomly matched and adjusted to determine the best perfusion scan protocol. Three-phase contrast-enhanced scanning was performed after CT perfusion. Histological examination of the liver tissues with hematoxylin and eosin stains was done after CT scanning. RESULTS: When the concentration of the contrast agent was 19% or 38%, no pseudo-color map was created. The viscosity increased when the concentration of the contrast agent was 76%; so it is difficult to inject the contrast agent at such a high concentration. Also no pseudo-color map was generated when the injection time was short (1, 2-3, and 4-5 seconds) or the injection rate was low (0.3 ml/s). The best perfusion images and perfusion parameters were obtained during 50 seconds scanning. Each rat was given an injection of 57% diatrizoate at 0.5 ml/s via the tail vein using a high pressure syringe for 6 seconds. The perfusion parameters included hepatic blood flow (HBF), hepatic blood volume (HBV), mean transit time (MTT) of the contrast agent, capillary permeability-surface area product (PS), hepatic arterial index (HAI), hepatic artery perfusion (HAP), and hepatic portal perfusion (HPP). All these parameters reflected the perfusion status of liver parenchyma in normal rats. Three phases of enhancement were modified according to the time-density curves (TDCs) of the perfusion imaging: hepatic arterial phase (7 seconds), hepatic portal venous phase (15 seconds), and a delayed phase (23-31 seconds). On examination by microscopy, the liver tissues were pathologically normal. CONCLUSIONS: The appropriate protocol with multi-slice spiral CT liver perfusion reflected normal liver hemodynamics in rats. This study laid a solid foundation for further investigation of the physiological characteristics of liver cancer in a rat model, and was an important supplement to and reference for conventional contrast-enhanced CT scans. PMID- 24342323 TI - Effect of CO2 pneumoperitoneum on the expression of the chemokine receptors CXCR4 and CCR7 in colorectal carcinoma cells in vitro. AB - BACKGROUND: The ability of pneumoperitoneum in laparoscopic surgery to promote proliferation and metastasis of colorectal cancer has become a focus of research in the field of minimally invasive surgery. The aim of this research was to investigate the effect of CO2 pneumoperitoneum under different pressures and exposed times on the expression of chemokine receptors in colorectal carcinoma cells. METHODS: We constructed an in vitro pneumoperitoneum model. SW480 colon carcinoma cells were exposed to CO2 pneumoperitoneum under different pressures (6, 9, 12, and 15 mmHg) for 1, 2, and 4 hours. These cells were then cultivated under the same conditions as normal SW480 colon carcinoma cells without CO2 pneumoperitoneum (control group), treated at 37 degrees C, and 5% CO2. The expression of the chemokine receptors CXC receptor 4 (CXCR4) and chemokine C receptor 7 (CCR7) was detected by immunocytochemistry and reverse transcriptase polymerase chain reaction after being cultivated for 0, 24, 48, and 72 hours. RESULTS: Immunocytochemistry showed that CXCR4 expression in SW480 cells was significantly decreased in the 6, 9, 12, and 15 mmHg CO2 pneumoperitoneum-treated groups for the same exposure times compared with controls (P < 0.05). CCR7 expression in SW480 cells was significantly decreased in the 12 and 15 mmHg CO2 pneumoperitoneum-treated groups compared with controls (P < 0.05). CXCR4 and CCR7 expression increased up to the level of the control group after 24 and 48 hours (P > 0.05). If the CO2 pneumoperitoneum pressure increased, CXCR4 and CCR7 expression decreased at all exposure times. If the CO2 pneumoperitoneum exposure time prolonged, there were no significant differences in CXCR4 and CCR7 expression under the same pressure. Under all exposure times, CXCR4 and CCR7 mRNA expression was significantly decreased in the 6, 9, 12, and 15 mmHg CO2 pneumoperitoneum-treated groups (P < 0.05) compared with controls, and it increased up to the level of controls after being cultivated for 48 hours (P > 0.05). If the CO2 pneumoperitoneum pressure increased (with all exposure times) and exposure time prolonged (under the same pressure), there were no significant differences in CXCR4 and CCR7 expression. CONCLUSIONS: CXCR4 and CCR7 expression is temporarily affected after continuous CO2 pneumoperitoneum treatment. The high pressure of CO2 pneumoperitoneum plays an important role in suppressing the expression of these chemokine receptors. Different lengths of time of exposure to a CO2 pneumoperitoneum-like environment do not change CXCR4 and CCR7 expression. PMID- 24342324 TI - Short-term safety and efficacy of the biodegradable iron stent in mini-swine coronary arteries. AB - BACKGROUND: To overcome the drawbacks of permanent stents, biodegradable stents have been studied in recent years. The bioabsorbable polymer vascular scaffold (BVS) was the first bioabsorbable stent to undergo clinical trials, demonstrating safety and feasibility in the ABSORB studies. Iron can potentially serve as the biomaterial for biodegradable stents. This study aimed to assess the short-term safety and efficacy of a biodegradable iron stent in mini-swine coronary arteries. METHODS: Eight iron stents and eight cobalt chromium alloy (VISION) control stents were randomly implanted into the LAD and RCA of eight healthy mini swine, respectively. Two stents of the same metal base were implanted into one animal. At 28 days the animals were sacrificed after coronary angiography, and histopathological examinations were performed. RESULTS: Histomorphometric measurements showed that mean neointimal thickness ((0.46 +/- 0.17) mm vs. (0.45 +/- 0.18) mm, P = 0.878), neointimal area ((2.55 +/- 0.91) mm(2) vs. (3.04 +/- 1.15) mm(2), P = 0.360) and percentage of area stenosis ((44.50 +/- 11.40)% vs. (46.00 +/- 17.95)%, P = 0.845) were not significantly different between the iron stents and VISION stents. There was no inflammation, thrombosis or necrosis in either group. The scanning electron microscopy (SEM) intimal injury scores (0.75 +/- 1.04 vs. 0.88 +/- 0.99, P = 0.809) and number of proliferating cell nuclear antigen (PCNA) positive staining cells were not significantly different between the two groups. The percentage of neointimal coverage by SEM examination was numerically higher in iron stents than in VISION stents ((84.38 +/- 14.50)% vs. (65.00 +/- 22.04)%, P = 0.057), but the difference was not statistically significant. Iron staining in the tissue surrounding the iron stents at 28 days was positive and the vascular wall adjacent to the iron stent had a brownish tinge, consistent with iron degradation. No abnormal histopathological changes were detected in coronary arteries or major organs. CONCLUSIONS: The biodegradable iron stent has good biocompatibility and short-term safety and efficacy in the miniswine coronary artery. Corrosion of iron stents is observed at four weeks and no signs of organ toxicity related to iron degradation were noted. PMID- 24342325 TI - Wnt3a enhances bone morphogenetic protein 9-induced osteogenic differentiation of C3H10T1/2 cells. AB - BACKGROUND: Bone morphogenetic protein 9 (BMP9) and Wnt/beta-catenin signaling pathways are able to induce osteogenic differentiation of mesenchymal stem cells (MSCs), but the role of Wnt/beta-catenin signaling pathway in BMP9-induced osteogenic differentiation is not well understood. Thus, our experiment was undertaken to investigate the interaction between BMP9 and Wnt/beta-catenin pathway in inducing osteogenic differentiation of MSCs. METHODS: C3H10T1/2 cells were infected with recombinant adenovirus expressing BMP9, Wnt3a, and BMP9+Wnt3a. ALP, the early osteogenic marker, was detected by quantitative and staining assay. Later osteogenic marker, mineral calcium deposition, was determined by Alizarin Red S staining. The expression of osteopotin (OPN), osteocalcin (OC), and Runx2 was analyzed by Real time PCR and Western blotting. In vivo animal experiment was carried out to further confirm the role of Wnt3a in ectopic bone formation induced by BMP9. RESULTS: The results showed that Wnt3a enhanced the ALP activity induced by BMP9 and increased the expressions of OC and OPN, with increase of mineral calcium deposition in vitro and ectopic bone formation in vivo. Furthermore, we also found that Wnt3a increased the level of Runx2, an important nuclear transcription factor of BMP9. CONCLUSION: Canonical Wnt/beta catenin signal pathway may play an important role in BMP9-induced osteogenic differentiation of MSCs, and Runx2 may be a linkage between the two signal pathways. PMID- 24342326 TI - Protective effects of penehyclidine hydrochloride on acute lung injury caused by severe dichlorvos poisoning in swine. AB - BACKGROUND: Organophosphate poisoning is an important health problem in developing countries which causes death mainly by inducing acute lung injury. In this study, we examined the effects of penehyclidine hydrochloride (PHC), a selective M-receptor inhibitor, on dichlorvos-induced acute lung injury in swine. METHODS: Twenty-two female swines were randomly divided into control (n = 5), dichlorvos (n = 6), atropine (n = 6), and PHC (n = 5) groups. Hemodynamic data, extravascular lung water index (EVLWI), and pulmonary vascular permeability index (PVPI) were monitored; blood gas analysis and acetylcholinesterase (AchE) levels were measured. PaO2/FiO2, cardiac index (CI), and pulmonary vascular resistance indices (PVRI) were calculated. At termination of the study, pulmonary tissue was collected for ATPase activity determination and wet to dry weight ratio (W/D) testing 6 hours post-poisoning. TUNEL assay, and Bax, Bcl-2, and caspase-3 expression were applied to pulmonary tissue, and histopathology was observed. RESULTS: After poisoning, PHC markedly decreased PVRI, increased CI more effectively than atropine. Anticholinergic treatment reduced W/D, apoptosis index (AI), and mitigated injury to the structure of lung; however, PHC reduced AI and caspase-3 expression and improved Bcl-2/Bax more effectively than atropine. Atropine and PHC improved ATPase activities; a significant difference between groups was observed in Ca(2+)-ATPase activity, but not Na(+)-K(+)-ATPase activity. CONCLUSIONS: The PHC group showed mild impairment in pathology, less apoptotic cells, and little impact on cardiac function compared with the atropine group in dichlorvos-induced acute lung injury. PMID- 24342327 TI - A comparative study on the medium-long term results of endovascular repair and open surgical repair in the management of ruptured abdominal aortic aneurysms. AB - BACKGROUND: Although it is generally acknowledged that patients with ruptured abdominal aortic aneurysm (rAAA) obtain the greatest benefit from endovascular repair (EVAR), convincing evidence on the medium-long term effect is lacking. The aim of this study was to compare and summarize published results of rAAA that underwent EVAR with open surgical repair (OSR). METHODS: A search of publicly published literature was performed. Based on an inclusion and exclusion criteria, a systematic meta-analysis was undertaken to compare patient characteristics, complications, short term mortality and medium-long term outcomes. A random effects model was used to pool the data and calculate pooled odds ratios and weighted mean differences. A quantitative method was used to analyze the differences between these two methods. RESULTS: A search of the published literature showed that fourteen English language papers comprising totally 1213 patients with rAAA (435 EVAR and 778 OSR) would be suitable for this study. Furthermore, 13 Chinese studies were included, including 267 patients with rAAA totally, among which 238 patients received operation. The endovascular method was associated with more respiratory diseases before treatment (OR = 1.81, P = 0.01), while there are more patients with hemodynamic instability before treatment in OSR group (OR = 1.53, P = 0.031). Mean blood transfusion was 1328 ml for EVAR and 2809 ml for OSR (weighted mean difference (WMD) 1500 ml, P = 0.014). The endovascular method was associated with a shorter stay in intensive care (WMD 2.34 days, P < 0.001) and a shorter total postoperative stay (WMD 6.27 days, P < 0.001). The pooled post-operative complication rate of respiratory system and visceral ischemia seldom occurred in the EVAR group (OR = 0.48, P < 0.001 and OR = 0.28, P = 0.043, respectively). The pooled 30-day mortality was 25.7% for EVAR and 39.6% for OSR, and the odds ratio was 0.53 (95% confidence interval (CI) 0.41 0.70, P < 0.001). There was not, however, any significant reduction in the medium long all-cause mortality rate (HR = 1.13, P = 0.381) and re-intervention rate (OR = 2.19, P = 0.243) following EVAR. In EVAR group, nevertheless, incidence of type I endoleak was significantly lower than type II endoleak (OR = 0.33, P = 0.039) at late follow-up period. CONCLUSIONS: On the basis of this systematic review, rAAA EVAR results in less blood use for transfusion, shorter operation time, shorter intensive care unit and hospital stays, and lower 30-day mortality. However, in the medium-long term, it is not associated with a reduction in all cause mortality. PMID- 24342329 TI - Criteria and practical guidance for determination of brain death in adults (BQCC version). PMID- 24342328 TI - Association between C-reactive protein gene +1059 G/C polymorphism and the risk of coronary heart disease: a meta-analysis. AB - BACKGROUND: C-reactive protein (CRP) gene +1059 G/C polymorphism has been reported to be associated with coronary heart disease (CHD) risk, but the results remain inconclusive. This meta-analysis was therefore conducted to clarify these controversies. METHODS: A comprehensive search was conducted to identify all case control studies on the association between CRP gene +1059 G/C polymorphism and CHD risk. All the related studies were further strictly selected according to the inclusion criteria. Meta-analysis was performed with STATA 10.1 (StataCorp, USA). The association was assessed by odds ratio (OR) and 95% confidence interval (CI); both Begg's funnel plot and Egger's regression test were used to assess the publication bias. RESULTS: This meta-analysis on a total of 13 studies comprising 6316 CHD cases and 4467 controls showed no significant association between CRP gene +1059 G/C polymorphism and CHD risk in the overall study (for C/C+C/G vs. G/G: OR = 1.01, 95% CI = 0.81-1.25, P = 0.96; for C/C vs. C/G+G/G: OR = 1.17, 95% CI = 0.77-1.77, P = 0.47; for C/C vs. G/G: OR = 1.17, 95% CI = 0.77-1.77, P = 0.47; for C allele vs. G allele: OR = 1.01, 95% CI = 0.81-1.24, P = 0.96). However, in the subgroup analysis by ethnicity, the results showed significant association between CRP gene +1059 G/C polymorphism and CHD risk among Caucasians (for C/C vs. G/G: OR = 2.54, 95% CI = 1.13-5.72, P = 0.02; C/C vs. C/G+G/G: OR = 2.45, 95% CI = 1.09-5.51, P = 0.03), but not among Asians and Africans (P > 0.05). CONCLUSION: CRP gene +1059 G/C polymorphism may be associated with increased CHD risk among Caucasians and more evidences need to validate the conclusion. PMID- 24342330 TI - Transcranial Doppler for detection of changes in ophthalmic artery blood flow. PMID- 24342331 TI - Mechanism of improved speech production by voice cues in nonfluent aphasia patients. PMID- 24342332 TI - Diagnosis and treatment of autoimmune pancreatitis: analysis of six cases. PMID- 24342333 TI - Management of the occlusion and stenosis of the aortic arch branches in the course of Takayasu's arteritis. PMID- 24342334 TI - Clinical signs and genetic sequencing of benign recurrent intrahepatic cholestasis. PMID- 24342335 TI - Surgical treatment of multivessel lesions in Takayasu arteritis. PMID- 24342336 TI - Hepatic ectopic pregnancy treated successfully by hepatectomy. PMID- 24342337 TI - Off-pump surgery for coronary artery disease combined with mitral stenosis. PMID- 24342338 TI - How to interpret low human chorionic gonadotropin levels in cerebrospinal fluid of patients with intracranial germinoma? PMID- 24342339 TI - Assessing risk factors of perioperative major cardiac events in elderly patients with coronary heart disease undergoing noncardiac surgery. PMID- 24342340 TI - Structural concept of intracranial cavernous angioma for the surgical treatment. PMID- 24342341 TI - H7N9 viral pneumonia: asymmetric and irregular changes on computed tomography. PMID- 24342342 TI - Propylthiouracil induced antineutrophil cytoplasmic antibodies-associated vasculitis. PMID- 24342343 TI - Support or not to support the left ventricle in patients with acute myocardial infarction complicated by cardiogenic shock? PMID- 24342344 TI - Transition of hospital accreditation management in China. PMID- 24342345 TI - Cardiac resynchronization therapy arrhythmogenic mechanism in a canine heart failure model. PMID- 24342346 TI - Dynamics of biofilm formation during anaerobic digestion of organic waste. AB - Biofilm-based reactors are effectively used for wastewater treatment but are not common in biogas production. This study investigated biofilm dynamics on biofilm carriers incubated in batch biogas reactors at high and low organic loading rates for sludge from meat industry dissolved air flotation units. Biofilm formation and dynamics were studied using various microscopic techniques. Resulting micrographs were analysed for total cell numbers, thickness of biofilms, biofilm covered surface area, and the area covered by extracellular polymeric substances (EPS). Cell numbers within biofilms (10(11) cells ml(-1)) were up to one order of magnitude higher compared to the numbers of cells in the fluid reactor content. Further, biofilm formation and structure mainly correlated with the numbers of microorganisms present in the fluid reactor content and the organic loading. At high organic loading (45 kg VS m(-3)), the thickness of the continuous biofilm layer ranged from 5 to 160 MUm with an average of 51 MUm and a median of 26 MUm. Conversely, at lower organic loading (15 kg VS m(-3)), only microcolonies were detectable. Those microcolonies increased in their frequency of occurrence during ongoing fermentation. Independently from the organic loading rate, biofilms were embedded completely in EPS within seven days. The maturation and maintenance of biofilms changed during the batch fermentation due to decreasing substrate availability. Concomitant, detachment of microorganisms within biofilms was observed simultaneously with the decrease of biogas formation. This study demonstrates that biofilms of high cell densities can enhance digestion of organic waste and have positive effects on biogas production. PMID- 24342347 TI - Conformational studies of gas-phase ribose and 2-deoxyribose by density functional, second order PT and multi-level method calculations: the pyranoses, furanoses, and open-chain structures. AB - We present an extensive computational study of a complex conformational isomerism of two gas phase pentoses of biological and potential astrobiological importance, d-ribose and 2-deoxy-d-ribose. Both cyclic (alpha- and beta-pyranoses, alpha- and beta-furanoses) and open-chain isomers have been probed using second order Moller Plesset perturbation theory (MP2), M06-2X density functional, and multi-level G4 methods. This study revealed a multitude of existing minima structures. Numerous furanose conformers found are described with the Altona and Sundaralingam pseudorotation parameters. In agreement with the recent gas-phase microwave (MW) investigation of Cocinero et al., the calculated free ribose isomers of lowest energy are the two beta-pyranoses with the (1)C4 and (4)C1 ring chair conformations. Both beta-pyranoses lie within 0.9kJ/mol in terms of DeltaG(298K) (G4), thus challenge the computational methods used to predict the ribose global minimum. The calculated most favoured ribofuranose is the alpha-anomer having the twist (2)T1 ring conformation, put 10.4kJ/mol higher in DeltaG than the global minimum. By contrast with d-ribose, the lowest energy 2-deoxy-d-ribose is the alpha-pyranose, with the most stable 2-deoxy-d-furanose (the alpha-anomer) being only 6.2kJ/mol higher in free energy. For both pentoses, the most favoured open chain isomers are significantly higher in energy than the low-lying cyclic forms. A good overall agreement is observed between the M06-2X and MP2 results in terms of both the existing low-energy minima structures and intramolecular H-bonding geometrical parameters. The natural orbital analysis confirms the occuring of the endo- and exo-anomeric effects and maximization of intramolecular H-bonding in the lowest-lying pyranoses and furanoses of both sugars. PMID- 24342348 TI - Examination of the influence of C5-hydroxymethyl group and configurations of hydroxyl groups at C2, C3, and C4 stereocentres on the N-glycosidic torsion: synthesis and X-ray crystallographic investigation of N-(D ribopyranosyl)alkanamides as N-glycoprotein linkage region analogs. AB - N-Linked glycosylation is not only present in eukaryotes but also occurs in archaea and bacteria and is mainly characterized by the beta-glucosylamine linkage to the asparagine (GlcNAcbetaAsn). Earlier crystallographic studies aimed at understanding the structural significance of the linkage region constituents revealed that N-glycosidic torsion, phiN is influenced considerably by variation in the glycan part as compared to the aglycon moiety. The phiN value observed for XylbetaNHAc deviated maximum as compared to that of the model compound, GlcNAcbetaNHAc. The present work was undertaken to assess the influence of ribose on the N-glycosidic torsions and molecular assembly. Several ribopyranosyl alkanamides have been synthesized and crystal structures of three of them have been solved. A comprehensive crystal structure analysis of ribosyl alkanamides along with xylosyl and arabinosyl alkanamides showed the wide range of deviations in their phiN values as compared to the negligible deviation shown by hexopyranosyl alkanamides. This study revealed the importance of C5-hydroxymethyl group and hydroxyl group configurations at C2, C3, and C4 stereocentres in controlling the N-glycosidic torsions. PMID- 24342349 TI - Response to commentary on "are some invertebrates exquisitely sensitive to the human pharmaceutical fluoxetine?". PMID- 24342351 TI - Response to commentary on "are some invertebrates exquisitely sensitive to the human pharmaceutical fluoxetine?". PMID- 24342350 TI - Interactive effects of n-TiO2 and 2,3,7,8-TCDD on the marine bivalve Mytilus galloprovincialis. AB - Despite the growing concern over the potential biological impact of nanoparticles (NPs) in the aquatic environment, little is known about their interactions with other pollutants. The bivalve Mytilus sp, largely utilized as a sentinel for marine contamination, has been shown to represent a significant target for different types of NP, including n-TiO2, one of the most widespread in use. In this work, the possible interactive effects of n-TiO2 and 2,3,7,8-TCDD, chosen as models of NP and organic contaminant, respectively, were investigated in Mytilus galloprovincialis. In vitro experiments with n-TiO2 and TCDD, alone and in combination, were carried out in different conditions (concentrations and times of exposure), depending on the target (hemocytes, gill cells and biopsies) and the endpoint measured. Mussels were also exposed in vivo to n-TiO2 (100 MUg L( 1)) or to TCDD (0.25 MUg L(-1)), alone and in combination, for 96 h. A wide range of biomarkers, from molecular to tissue level, were measured: lysosomal membrane stability and phagocytosis in hemocytes, ATP-binding cassette efflux transporters in gills (gene transcription and efflux activity), several biomarkers of genotoxicity in gill and digestive cells (DNA damage, random amplified polymorphic DNA-RAPD changes), lysosomal biomarkers and transcription of selected genes in the digestive gland. The results demonstrate that n-TiO2 and TCDD can exert synergistic or antagonistic effects, depending on experimental condition, cell/tissue and type of measured response. Some of these interactions may result from a significant increase in TCDD accumulation in whole mussel organisms in the presence of n-TiO2, indicating a Trojan horse effect. The results represent the most extensive data obtained so far on the sub-lethal effects of NPs and organic contaminants in aquatic organisms. Moreover, these data extend the knowledge on the molecular and cellular targets of NPs in bivalves. PMID- 24342352 TI - Vitellogenin is not an appropriate biomarker of feminisation in a crustacean. AB - The expression of the yolk protein vitellogenin (Vtg) has been used as a biomarker of feminisation in multiple fish species throughout the world. Since the late 1990s, researchers have attempted to develop similar biomarkers to address whether reproductive endocrine disruption also occurs in the males of invertebrate groups such as the Crustacea. To date, the vast majority of studies investigating Vtg induction in male Crustacea have resulted in negative or inconclusive results, leading researchers to question the utility of Vtg expression as a biomarker in this taxon. This study measured the expression of Vtg genes in two intersex phenotypes (termed internal and external) found in the male amphipod, Echinogammarus marinus, and compared them with those of normal males and females. Males presenting the external intersex phenotype are infected with known feminising parasites and display a variety of feminised traits including oviduct structures on their testes and external female brood plates (oostegites). The internal intersex male phenotype, that displays a pronounced oviduct structure on the testes without the external intersex characteristics, is not parasite infected and it is thought to be a result of environmental contamination. Given their morphology, these phenotypes might be considered highly 'feminised' or 'de-masculinised' and can be utilised to test the suitability of feminisation biomarkers. The E. marinus transcriptome was searched for genes resembling Vtg and two sequences were revealed, that we subsequently refer to as Vtg1 and Vtg2. Results from a high-throughput transcriptomic sequencing screen of gonadal cDNA libraries suggested that very low expression (in this manuscript gene transcription is taken to represent gene expression, although it is acknowledged that in addition to transcription, translation, transcript processing, mRNA stability and protein stability can regulate gene expression) of Vtg1 and Vtg2 in normal males (ESTs=1 and 0 for Vtg1 and Vtg2, respectively), internal intersex males (ESTs=0 for both Vtg sequences) and external intersex males (ESTs=5 and 0 for Vtg1 and Vtg2, respectively). In contrast, the sequencing suggested notable levels of expression of both Vtg genes in females (ESTs=1133 and 84 for Vtg1 and Vtg2, respectively). Subsequent qPCR analysis validates these expression levels, with the signal for Vtg1 and Vtg2 transcripts in all male phenotypes being indistinguishable from that caused by contamination of trace levels of genomic DNA or the low-level amplification non target sequences. These findings suggest that Vtg expression is not notably induced in highly feminised amphipods and is therefore not an appropriate biomarker of feminisation/de-masculination in crustaceans. We discuss our findings in the context of previous attempts to measure Vtg in male crustaceans and suggest a requirement for more appropriate taxon-specific biomarkers to monitor feminisation in these groups. PMID- 24342353 TI - Prioritising ward rounds would improve junior doctors' experience and patient care. PMID- 24342354 TI - Combating inflammaging through a Mediterranean whole diet approach: the NU-AGE project's conceptual framework and design. AB - The development of a chronic, low grade, inflammatory status named "inflammaging" is a major characteristic of ageing, which plays a critical role in the pathogenesis of age-related diseases. Inflammaging is both local and systemic, and a variety of organs and systems contribute inflammatory stimuli that accumulate lifelong. The NU-AGE rationale is that a one year Mediterranean whole diet (considered by UNESCO a heritage of humanity), newly designed to meet the nutritional needs of the elderly, will reduce inflammaging in fully characterized subjects aged 65-79 years of age, and will have systemic beneficial effects on health status (physical and cognitive). Before and after the dietary intervention a comprehensive set of analyses, including omics (transcriptomics, epigenetics, metabolomics and metagenomics) will be performed to identify the underpinning molecular mechanisms. NU-AGE will set up a comprehensive database as a tool for a systems biology approach to inflammaging and nutrition. NU-AGE is highly interdisciplinary, includes leading research centres in Europe on nutrition and ageing, and is complemented by EU multinational food industries and SMEs, interested in the production of functional and enriched/advanced traditional food tailored for the elderly market, and European Federations targeting policy makers and major stakeholders, from consumers to EU Food & Drink Industries. PMID- 24342355 TI - pERK 1/2 inhibit Caspase-8 induced apoptosis in cancer cells by phosphorylating it in a cell cycle specific manner. AB - ERK 1/2 are found to be hyperactive in many cancers. Active ERK 1/2 (pERK 1/2) are known to protect cancer cells from undergoing death receptor-mediated apoptosis, although the mechanism(s) behind this is poorly understood. Through in vitro kinase assays and mass-spectrometry we demonstrate that pERK 1/2 can phosphorylate pro-Caspase-8 at S387. Also, in EGFR-overexpressing Type I and II ovarian and breast cancer cell lines respectively, ERK 1/2 remain active only during the interphase. During this period, pERK 1/2 could inhibit Trail-induced apoptosis, most effectively during the G1/S phase. By knocking-down the endogenous pro-Caspase-8 using RNAi and replacing it with its non phosphorylatable counterpart (S387A), a significant increase in Caspase-8 activity upon Trail stimulation was observed, even in the presence of pERK 1/2. Taken together, we propose that a combination of Trail and an inhibitor of ERK 1/2 activities could potentially enhance of Trail's effectiveness as an anti cancer agent in ERK 1/2 hyperactive cancer cells. PMID- 24342357 TI - Soluble organic carbon and pH of organic amendments affect metal mobility and chemical speciation in mine soils. AB - We evaluated the effects of pH and soluble organic carbon affected by organic amendments on metal mobility to find out the optimal conditions for their application in the stabilization of metals in mine soils. Soil samples (pH 5.5 6.2) were mixed with 0, 30 and 60 th a(-1) of sheep-horse manure (pH 9.4) and pine bark compost (pH 5.7). A single-step extraction procedure was performed using 0.005 M CaCl2 adjusted to pH 4.0-7.0 and metal speciation in soil solution was simulated using NICA-Donnan model. Sheep-horse manure reduced exchangeable metal concentrations (up to 71% Cu, 75% Zn) due to its high pH and degree of maturity, whereas pine bark increased them (32% Cu, 33% Zn). However, at increasing dose and hence pH, sheep-horse manure increased soluble Cu because of higher soluble organic carbon, whereas soluble Cu and organic carbon increased at increasing dose and correspondingly decreasing pH in pine bark and non-amended treatments. Near the native pH of these soils (at pH 5.8-6.3), with small doses of amendments, there was minimum soluble Cu and organic carbon. Pine bark also increased Zn solubility, whereas sheep-horse manure reduced it as soluble Zn always decreased with increasing pH. Sheep-horse manure also reduced the proportion of free metals in soil solution (from 41% to 4% Cu, from 97% to 94% Zn), which are considered to be more bioavailable than organic species. Sheep horse manure amendment could be efficiently used for the stabilization of metals with low risk of leaching to groundwater at low doses and at relatively low pH, such as the native pH of mine soils. PMID- 24342358 TI - Effects of exogenous rare earth elements on phosphorus adsorption and desorption in different types of soils. AB - Phosphorus (P) is an important biogeochemical element and the environmental fate of P receives increasing attention. Through batch equilibration experiments, the adsorption and desorption of P in the absence and presence of exogeneous rare earth elements (REEs) were investigated in five types of agricultural soil samples collected from China. The results showed that the addition of different doses of REEs had influences on P adsorption processes in the soils, and there were differences in different soil types and different P concentrations of the P solutions. The amount of P adsorption tended to decline when the five types of soils were amended with low concentrations of REEs. The characteristics of P adsorption were more complicated when high concentrations of REEs were added to the different soils. Affected by the high concentrations of REEs, when the P concentration of the P solution added to soils was less than 20 mg L(-1), the rate of P adsorption tended to increase in all the five types of soils. However, when the P concentration of the P solution added to soil was greater than 30 mg L(-1), the rate of P adsorption tended to decrease. The Langmuir equation fitted P adsorption in all the five types of soils well. Compared with the control, when soil samples were amended with REEs, the P desorption rates of the five types of soils increased. PMID- 24342356 TI - SUMOylation of RhoGDIalpha is required for its repression of cyclin D1 expression and anchorage-independent growth of cancer cells. AB - Selective activation of Rho GTPase cascade requires the release of Rho from RhoGDI (GDP-dissociation inhibitors) complexes. Our previous studies identified RhoGDIalpha SUMOylation at Lys-138 and its function in the regulation of cancer cell invasion. In the current study, we demonstrate that RhoGDIalpha SUMOylation has a crucial role in the suppression of cancer cell anchorage-independent growth as well as the molecular mechanisms underlying this suppression. We found that ectopic expression of RhoGDIalpha resulted in marked inhibition of an anchorage independent growth with induction of G0/G1 cell cycle arrest, while point mutation of RhoGDIalpha SUMOylation at residue Lys-138 (K138R) abrogated this growth suppression and G0/G1 cell cycle arrest in cancer cells. Further studies showed that SUMOylation at Lys-138 was critical for RhoGDIalpha down-regulation of cyclin D1 protein expression and that MEK1/2-Erk was a specific downstream target of SUMOylated RhoGDIalpha for its inhibition of C-Jun/AP-1 cascade, cyclin d1 transcription, and cell cycle progression. These results strongly demonstrate that SUMOylated RhoGDIalpha suppressed C-Jun/AP-1-dependent transactivation specifically via targeting MEK1/2-Erk, subsequently leading to the down regulation of cyclin D1 expression and anti-cancer activity. Our results provide new mechanistic insights into the understanding of essential role of SUMOylation at Lys-138 in RhoGDIalpha's biological function. PMID- 24342359 TI - Birnessite-induced mechanochemical degradation of 2,4-dichlorophenol. AB - DCP (2,4-dichlorophenol) is the key-intermediate in the synthesis of some widely used pesticides and is an EPA priority pollutant. The mechanochemical breakdown of DCP loaded on birnessite (delta-MnO2), montmorillonite saturated with Na(+) or Cu(2+) and hematite was investigated. Mechanical force was applied by grinding of mixtures of DCP and the minerals, using mortar and pestle. Grinding of DCP for 5 min with the montmorillonites or with hematite resulted in negligible degradation during grinding, while grinding with birnessite induced the immediate degradation of 90% of the loaded DCP. Incubation for 24h after grinding did result in up to 30% degradation of the DCP loaded on the other minerals tested. HPLC and LC-MS analysis revealed that the transformation of DCP yielded oligomerization products as well as partial dechlorination. DCP degradation on birnessite was accompanied with a substantial increase in the extractability of manganese from the mineral into an acidic aqueous solution, indicating that Mn(IV) in the mineral transformed into Mn(II) and that birnessite served as an electron acceptor in the transformation. The oligomerization and partial dechlorination brought about by grinding, suggest a reduction in bioavailability and toxicity. PMID- 24342360 TI - Cu-doped zinc oxide and its polythiophene composites: preparation and antibacterial properties. AB - Cu-doped zinc oxide and its polythiophene nanocomposites were prepared by the Sol Gel and in situ polymerization methods, respectively. The structures, morphologies and compositions of the samples were characterized. The antibacterial properties of the samples on three kinds of strains were determined by using powder inhibition zones, minimum inhibitory concentrations and minimal bactericidal concentrations. The study confirmed that the antibacterial activities of the composites were better than those of their each component. The antibacterial mechanisms of the samples were discussed further. PMID- 24342361 TI - Fluoride and arsenic exposure through water and grain crops in Nagarparkar, Pakistan. AB - The aim of present study was to simultaneously estimate the arsenic (As) and fluoride (F(-)) concentrations in irrigated surface water, soil and grain crops of Nagarparkar, Pakistan during 2010-2012. The As and F(-) were analyzed by hydride generation atomic absorption spectrometer and ion selective electrode, respectively. Total arsenic (As(T)) and F(-) in irrigated surface water samples were found in the range of 360-683 MUg L(-1) and 18.5-35.4 mg L(-1), respectively. While As(T) and F(-) concentrations in agriculture soil samples were observed in the range of 110-266 and 125-566 mg kg(-1), respectively. The water extractable As and F(-) were found 3-4% of total concentration of these in soils. The As(T) concentration was higher in kidney been (KB) as compared to pearl millet (PM) and green gram (GG), whereas GG had higher F(-) levels as compared to other two grain crops (p<0.05). The KB samples grown in nine sites shows BCF of As in the range of 0.018-0.038. The GG has higher BCF of F(-) as compared to KB and PM (p<0.05) grown in all sites. The exposure dose and risk factor of As and F(-) were obtained by estimated daily intake (EDI) and hazardous index (HI). It was found that all understudy age groups were at the severe risk of arsenicosis and fluorosis, but the severity is higher in younger age group (7 15 years) as compared to elder groups (p<0.05). PMID- 24342362 TI - The first demonstration of CYP1A and the ABC protein(s) gene expression and activity in European seabass (Dicentrarchus labrax) primary hepatocytes. AB - Primary hepatocytes are a model for studying various effects of different xenobiotics, including detoxification strategies. In this study we have isolated and cultured European seabass (Dicentrarchus labrax) primary hepatocytes and assessed gene transcription and activity of CYP1A (phase I of cellular detoxification) and ABCC1 and ABCC2 (phase III) transport proteins after exposure to benzo(a)pyrene (BaP). A dose dependent increase in Abcc2 and Cyp1a mRNA transcripts was observed in seabass primary hepatocytes upon exposure to BaP. The activity of ABC proteins, as key mediators of the multixenobiotic resistance (MXR), was further confirmed by assessing the accumulation of the model fluorescence substrate rhodamine 123 in the absence and presence of model inhibitors. A weak interaction between BaP and ABC proteins was observed. CYP1A dependent ethoxyresorufin-O-deeethylase (EROD) activity was significantly induced by the presence of BaP. After the 24h exposure period only 10% of the initial BaP was present in the incubation medium, clearly demonstrating biotransformation potential of primary seabass hepatocytes. Furthermore, the presence of the 3 hydroxybenzo(a)pyrene, a BaP metabolite, in the medium implies its active efflux. In conclusion, we showed that seabass primary hepatocytes do express important elements of the cellular detoxification machinery and may be a useful in vitro model for studying basic cellular detoxification mechanisms and their interaction with environmental contaminants. PMID- 24342363 TI - Fixed charges in the gel matrix of sensor chips and dissociation in diffusion gradients influence the detection of fast protein-protein interactions. AB - In molecular interaction studies based on surface plasmon resonance (SPR) measurements, the ligand is often immobilized in a thin carboxydextran gel matrix. Here we investigated the influence of the charged gel on the results of such SPR measurements. At physiological ionic strength, analytes with a net charge of more than about 5 are considerably enriched or depleted due to the Donnan potential under commonly applied experimental conditions. Below physiological ionic strength, enrichment was found to be even stronger than predicted by Donnan theory. The influence of the gel matrix on the apparent binding is prevented in competition experiments, in which SPR measurements are only used to discriminate between free and complexed analyte while the interaction between analyte and ligand is studied in solution. However, if the analyte-ligand interaction is very fast, thermodynamic equilibrium is disturbed near the interface where free analyte binds to the immobilized ligand due to mass transport limitation. Consequently, the soluble analyte-ligand complex dissociates, which results in an overestimation of free analyte. In experiments of calmodulin binding to fragments of the KCNH1 ion channel protein this mass transport-induced dissociation led to a systematic underestimation of the affinity. We conclude that the insufficient discrimination between the true analyte-ligand binding and the complex interactions of the analyte with the gel phase may result in systematic errors. The theoretical framework for recognizing and avoiding such errors is provided. PMID- 24342364 TI - [This is not a karyotype... For a sound and validated approach of advanced non invasive screening of fetal trisomy 21 in maternal blood]. PMID- 24342365 TI - [Group G streptococcal bacteremia in the post-partum period. A case report]. AB - Bacteremia with streptococcus group G is a rare infection, particularly in the post-partum, but of which the incidence has been increasing since the end of the 20th century. The objective of our work is to report the clinical and the bacteriologic aspects, as well as the therapeutic modalities of an exceptional case of bacteremia with streptococcus group G, after a normal vaginal delivery, in a 26-year-old woman. Streptococcus group G being a part of the normal flora of the female genital tract, the endogenous contamination probably took place by passage in the blood circulation during the episiotomy. PMID- 24342366 TI - [Interpretation of atypical values of maternal serum markers]. AB - OBJECTIVES: Prenatal screening was set up to identify patients at high-risk of chromosome 21 trisomy based on maternal serum markers measurement. However, the risk of trisomy 21 should not be the only result considered by obstetricians. In fact, abnormal marker values can be associated with other fetal diseases and used to improve maternal and fetal follow-up. Our objective was therefore to study other predictive values of maternal serum markers. MEANS AND METHODS: A search through publications was conducted using the PubMed(r) or Cochrane(r) databases. RESULT: In case of high PAPP-A there is no link with any complications. Second trimester high hCG or first trimester low hCG are associated with an increased vascular risk. High alpha-fetoprotein level is a marker of neural tube defects or abdominal wall defect. Persistence of high alpha-fetoprotein with normal echography can suggest other rare fetal diseases. Low maternal serum markers suggests 18 trisomy. Oestriol reflects the fetal hypothalamo-hypophyseal axis and can be used as a diagnosis tool. CONCLUSION: Serum markers could be interesting tools for the identification of high-risk pregnancy and the prevention of neonatal complications. They also appear as a potential help to diagnose certain congenital malformations. PMID- 24342367 TI - [Pronostic risk assessment of delivery, in patients admitted for threatened preterm birth, in a tertiary care maternity center]. AB - OBJECTIVES: To assess preterm birth rate, in patients admitted for threatened preterm birth (TPB) in a tertiary care maternity center and evaluate our diagnostic and therapeutic tools. MATERIALS AND METHODS: A retrospective cohort study, in a tertiary care maternity center (Marseille, France), reviewed all admissions for TPB from January 1 to December 31, 2009. RESULTS: We recorded 224 admissions for TPB (181 single pregnancies and 43 twin pregnancies), 43.8% of TPB admissions were from materno-fetal transfer. Preterm birth rate was 44.9% (n=89), 39% (n=66) for single pregnancy and 76.6% (n=23) for twins. The 15 mm threshold for transvaginal sonography cervical length (CL) was the most relevant to predict the risk of preterm delivery, 77.3% (85/110) of patients with CL>15 mm having full term delivery. CONCLUSION: For single pregnancy, most of the patients with cervical length>15 mm have full term delivery. It seems important to us to develop the use of more efficient predictive markers of risk-premature labor in order to improve the diagnosis and management of TPB. PMID- 24342368 TI - Management of nonunion of lower-extremity long bones using mono-lateral external fixator--report of 37 cases. AB - INTRODUCTION: The management of nonunion has remained a constant challenge. The associated bone defect, shortening, deformity and infection complicate the management. A mono-lateral external fixator may minimise some of the problems frequently encountered in these patients. We report our results of prospectively evaluated 37 consecutive patients regarding nonunion of lower-extremity long bones managed using a mono-lateral external fixator. PATIENTS AND METHODS: A total of 37 patients (7 femurs and 30 tibias), mean age 36 years, were stabilised using a mono-lateral fixator for nonunion of long bones. The mean time since injury was 8 months. Fifteen cases were infected and they received debridement and antibiotic treatment as per culture and sensitivity reports. In cases where the bone gap or shortening was >3 cm in the tibia and >5 cm in the femur, corticotomy and bone transport (bifocal procedure) was done and in the remaining cases, only compression-distraction (monofocal procedure) was done. The bone and functional results were assessed at the end of treatment according to the criteria described by Paley et al. RESULTS: Union was achieved in 34 cases (91.9%). The average time for union was 5 months. Five cases were treated with the bifocal method and 32 cases were treated with the monofocal method. The average length gain in the bifocal method was 5.7 cm, mean duration of treatment was 8.2 months and bone healing index (BHI) was 1.44 months cm(-1). In six cases, the monofocal treatment was used for limb lengthening. The average length gain was 1.9 cm, mean duration of treatment was 4.83 months and BHI was 2.5 months cm( 1). Bone grafting was required in two cases at the docking site. The bone results were excellent in 24 cases, good in nine cases, fair in one case and poor in three cases. The functional results were excellent in 27 cases, good in six cases, fair in one case and poor in three cases. The most common complication in this series was pin-tract infection (11.5%). CONCLUSIONS: A mono-lateral external fixator is an effective method for treating nonunion in the lower extremity with or without bone loss. The nonunion site can be carefully controlled with simultaneous correction of angulation and length. PMID- 24342369 TI - Analysis of strategies to increase external fixator stiffness: is double stacking worth the cost? AB - We compared the mechanical benefits and costs of 3 strategies that are commonly used to increase knee-spanning external fixator stiffness (resistance to deformation): double stacking, cross-linking, and use of an oblique pin. At our academic trauma centre and biomechanical testing laboratory, we used ultra-high molecular-weight polyethylene bone models and commercially available external fixator components to simulate knee-spanning external fixation. The models were tested in anterior-posterior bending, medial-lateral bending, axial compression, and torsion. We recorded the construct stiffness for each strategy in all loading modes and assessed a secondary outcome of cost per 10% increase in stiffness. Double stacking significantly increased construct stiffness under anterior posterior bending (109%), medial-lateral bending (22%), axial compression (150%), and torsion (41%) (p<0.05). Use of an oblique pin significantly increased stiffness under torsion (25%) (p<0.006). Cross-linking significantly increased stiffness only under torsion (29%) (p<0.002). Double stacking increased costs by 84%, cross-linking by 28%, and use of an oblique pin by 15% relative to a standard fixator. All 3 strategies increased stiffness under torsion to varying degrees, but only double stacking increased stiffness in all 4 testing modalities (p<0.05). Double stacking is most effective in increasing resistance to bending, particularly under anterior-posterior bending and axial compression, but requires a relatively high cost increase. Clinicians can use these data to help guide the most cost-effective strategy to increase construct stiffness based on the plane in which stiffness is needed. PMID- 24342370 TI - The factor in the license: in reference to "use of prothrombin complex concentrates and fibrinogen concentrates in the perioperative setting: a systematic review". PMID- 24342371 TI - Evaluation of the muscle volumes of the transverse rotator cuff force couple in nonpathologic shoulders. AB - BACKGROUND: The balance between the subscapularis muscle and the infraspinatus/teres minor muscles, often referred to as the rotator cuff transverse force couple (TFC), has been proposed to be a critical component for normal shoulder function. The relationship between the muscle volume and the power means that TFC can be evaluated with the measurement of the muscle volume of the subscapularis muscle and the infraspinatus/teres minor. The aim of this study is to evaluate an innovative computed tomography (CT)-based technique to measure the muscle volume and to evaluate if there is a significant difference between muscle volumes of both the subscapularis muscle and the infraspinatus/teres minor in nonpathologic shoulders. MATERIALS AND METHODS: CT images of 27 shoulders (21 patients) with a full scapula and a proximal humeral head were evaluated. Two volume masks (subscapularis and infraspinatus/teres minor) were calculated on the basis of the assigned muscle contours on the transverse slices. The intraobserver and interobserver correlation coefficient was calculated. RESULTS: The intraobserver and interobserver correlation coefficient was excellent. The correlation between the anterior and posterior part of the TFC was strong. There was no significant difference between the volume masks. CONCLUSIONS: Muscle volume of the TCF can be quantified using CT images. In nonpathologic shoulders, there is no significant difference between the muscle volume of the anterior (subscapularis) and posterior part (teres minor/infraspinatus) of the TFC. PMID- 24342372 TI - Three-dimensional quantitative evaluation of facial morphology in adults with unilateral cleft lip and palate, and patients without clefts. AB - The aims of this study were to assess the quantitative values of measurements using proportion indices in the craniofacial region in patients with repaired, non-syndromic, complete unilateral cleft lip and palate (UCLP), and compare them with a control group who did not have clefts using the non-invasive systems of 3 dimensional technology. Three-dimensional measurements of the facial surfaces of 15 Malay patients who had UCLP repaired and 100 Malay control patients aged 18-25 years were analysed. The 3-dimensional images of the respondents' faces were captured using the VECTRA-3D Stereophotogrammetry System. Eleven craniofacial proportions were assessed using a combination of 18 linear measurements obtained from 21 anthropometric soft tissue landmarks. These measurements were used to produce proportion indices to find the differences in the morphological features between the groups, and assessed using the independent sample t test and z scores. There were significant differences between the groups in 7 out of 11 craniofacial proportion indices (p=0.001-0.044). Z scores of 2 indices were disproportionate. They were nasal index (which was severely supernormal) and upper lip index (which was moderately supernormal). Patients with UCLP had higher mean z scores, indicating that patients with UCLP tended to have larger faces than the control group. There were clinically important differences mainly in the nasolabial area, where the nose and the upper lip were wider, larger, or flatter in patients with UCLP. PMID- 24342373 TI - Young children's motor skill performance: relationships with activity types and parent perception of athletic competence. AB - OBJECTIVES: The aims were to examine the relationship between children's motor skill levels and types of physical activities performed during preschool attendance, and to examine the relationship between motor skill performance and parent perception of athletic competence. DESIGN: Cross-sectional. METHODS: Participants were 264, 3-, 4-, and 5-year-old children from 22 preschools. Locomotor and object control skills were assessed with a standardized motor skill protocol. Direct observation (OSRAC-P) was used to record activity types: walk, run, jump/skip, dance, and throw. Parents rated their child's athletic competence. Children were categorized into tertiles for locomotor and object control scores. Mixed models were used to test for differences across motor skill tertiles for each aim. Models controlled for sex, age, race/ethnicity, body mass index, and parent education, with preschool as a random variable. RESULTS: Children in the highest locomotor tertile engaged in more dancing than children in the lowest tertile (p = 0.04). Children in the highest object control tertile engaged in throwing more frequently than children in lower tertiles (p < 0.05). Parents of children in the highest locomotor tertile perceived their children's competence as higher than parents of children in lower tertiles (p < 0.05). Parents of children in the lowest object control tertile perceived their children's competence as significantly lower than parents of children in higher tertiles (p < 0.05). CONCLUSIONS: These findings point to the need for policy and practice research to help parents and child care professionals provide opportunities for young children to learn and practice motor skills. PMID- 24342374 TI - Communication skills training for breast cancer teams talking about trials. AB - OBJECTIVES: We modified an educational intervention developed to improve communication about clinical trials and enhance multidisciplinary team (MDT) working for specialist breast cancer MDTs. We assessed the effect of one day MDT training on team members' awareness & clarity about trials in their portfolio, and individuals' confidence & communication about clinical trials. MATERIALS AND METHODS: Six MDTs in England participated between May 2012 and January 2013. Teams identified a breast trial from their portfolio that was about to start or one for which recruitment was proving difficult. Participants completed questionnaires identifying their roles and awareness of trial activity. The interactive workshop contained several generic elements: including PPT presentations, relevant exercises, and practical sessions but were also customised to fit the individual MDT requirements. Participants completed post course questionnaires and the team leaders completed a 6-month review. RESULTS: Eighty healthcare professionals participated. There were significant positive changes (P < 0.001) post-workshop for all 15 key areas probed concerning awareness and clarity about the trial(s) discussed during the training intervention. Six month questionnaire data revealed 5/6 teams had greater awareness of actual roles played by their colleagues and that more team members were willing and able to discuss trial(s) with patients. Additionally, 5/6 team leaders said that dynamics had changed for the better and enthusiasm for trials improved. CONCLUSION: Workshops focussed on clinical trials can be conducted in one day and produce improvements in team awareness, knowledge of teams' trials portfolios and communication skills. PMID- 24342375 TI - Neuroendocrine breast tumours: breast cancer or neuroendocrine cancer presenting in the breast? AB - Neuroendocrine tumours (NET) of the breast are rare. Diagnosis depends on close scrutiny of core- or excisional-biopsy specimens for characteristic growth patterns (papillary, nesting or mixed), which should trigger immunohistochemical staining for neuroendocrine markers (in particular chromogranin and synaptophysin). The diagnosis is confirmed if a) >50% of the tissue specimen demonstrate neuroendocrine markers and b) in-situ ductal carcinoma is identified and/or imaging modalities exclude extra-mammary sites. Our literature search including the non-English literature identified 66 articles with data on 123 cases, including our own. Oestrogen receptors are not diagnostic for NET's of the breast as they are found in tumours of non-mammary origin, too. Half of reported cases of neuroendocrine tumours have axillary lymph node involvement. Breast conserving surgery (wide local excision +/- axillary clearance) is commonly performed for suitable tumours. Chemotherapy regimens utilised are commonly either platinum- (as for small-cell cancers) or anthracycline-based (as for primary breast cancers). Best management remains unknown. PMID- 24342376 TI - Sudden unexpected death in children with epilepsy: Hearing from parents. PMID- 24342377 TI - Multi-level and multi-scale integrative approach to the understanding of human blastocyst implantation. AB - Implantation is a complex process which results in fixation of zona pellucida free blastocyst to the maternal uterine endometrium. In the human, it involves progesterone mediated preparation of endometrium, age- and stage-matched development of pre-implantation embryo, and interaction between embryo and endometrium. In the present essay, we present the case to explain why there is a necessity of undertaking multi-level, multi-scale integrative approach to deconstruct the succession process of endometrial development to the climax of implantation. PMID- 24342378 TI - Here/In this issue and there/abstract thinking: how do we know what we know? Cautionary tales in medical publishing. PMID- 24342379 TI - Presidential address: partnering for the world's children. PMID- 24342380 TI - Transforming trajectories for traumatized children. PMID- 24342381 TI - Beyond rising rates: personalized medicine and public health approaches to the diagnosis and treatment of attention-deficit/hyperactivity disorder. PMID- 24342382 TI - Not just another antipsychotic-for-conduct-problems trial. PMID- 24342383 TI - Longitudinal patterns of anxiety from childhood to adulthood: the Great Smoky Mountains Study. AB - OBJECTIVE: The aims of this study were 2-fold: to provide a brief introduction to the prospective longitudinal Great Smoky Mountains Study and review recent findings; and to use this sample to conduct an epidemiologic analysis of common childhood anxiety disorders. METHOD: The population-based Great Smoky Mountains Study assessed 1,420 participants from 11 counties in the southeastern United States up to 11 times between ages 9 and 26 years with the structured Child and Adolescent Psychiatric Assessment and its upward extension, the Young Adult Psychiatric Assessment. RESULTS: The U-shaped age prevalence curve for any anxiety disorder was the product of high levels of childhood separation anxiety and adult panic, agoraphobia, and generalized anxiety. More than 1 in 5 subjects met criteria for an anxiety disorder by early adulthood. In terms of cumulative comorbidity, there was evidence of overlap between anxiety disorders, but the level of overlap was generally consistent with what is seen among other common childhood disorders. All childhood anxiety disorders were associated with adverse functioning in at least 1 young adult functional domain, with the poorest outcomes for childhood generalized anxiety and DSM-III-R overanxious disorder. CONCLUSION: Clinically significant anxiety is a common mental health problem to have had by adulthood. There was little evidence to support the consolidation of anxiety disorders, and some evidence to justify reintroduction of DSM-III-R overanxious disorder. The transition to young adulthood appears to be a key period for understanding the development of common adult anxiety disorders such as panic and agoraphobia. PMID- 24342384 TI - Trends in the parent-report of health care provider-diagnosed and medicated attention-deficit/hyperactivity disorder: United States, 2003-2011. AB - OBJECTIVE: Data from the 2003 and 2007 National Survey of Children's Health (NSCH) reflect the increasing prevalence of parent-reported attention deficit/hyperactivity disorder (ADHD) diagnosis and treatment by health care providers. This report updates these prevalence estimates for 2011 and describes temporal trends. METHOD: Weighted analyses were conducted with 2011 NSCH data to estimate prevalence of parent-reported ADHD diagnosis, current ADHD, current medication treatment, ADHD severity, and mean age of diagnosis for U.S. children/adolescents aged 4 to 17 years and among demographic subgroups. A history of ADHD diagnosis (2003-2011), as well as current ADHD and medication treatment prevalence (2007-2011), were compared using prevalence ratios and 95% confidence intervals. RESULTS: In 2011, 11% of children/adolescents aged 4 to 17 years had ever received an ADHD diagnosis (6.4 million children). Among those with a history of ADHD diagnosis, 83% were reported as currently having ADHD (8.8%); 69% of children with current ADHD were taking medication for ADHD (6.1%, 3.5 million children). A parent-reported history of ADHD increased by 42% from 2003 to 2011. Prevalence of a history of ADHD, current ADHD, medicated ADHD, and moderate/severe ADHD increased significantly from 2007 estimates. Prevalence of medicated ADHD increased by 28% from 2007 to 2011. CONCLUSIONS: Approximately 2 million more U.S. children/adolescents aged 4 to 17 years had been diagnosed with ADHD in 2011, compared to 2003. More than two-thirds of those with current ADHD were taking medication for treatment in 2011. This suggests an increasing burden of ADHD on the U.S. health care system. Efforts to further understand ADHD diagnostic and treatment patterns are warranted. PMID- 24342385 TI - What does risperidone add to parent training and stimulant for severe aggression in child attention-deficit/hyperactivity disorder? AB - OBJECTIVE: Although combination pharmacotherapy is common in child and adolescent psychiatry, there has been little research evaluating it. The value of adding risperidone to concurrent psychostimulant and parent training (PT) in behavior management for children with severe aggression was tested. METHOD: One hundred sixty-eight children 6 to 12 years old (mean age 8.89 +/- 2.01 years) with severe physical aggression were randomized to a 9-week trial of PT, stimulant (STIM), and placebo (Basic treatment; n = 84) or PT, STIM, and risperidone (Augmented treatment; n = 84). All had diagnoses of attention-deficit/hyperactivity disorder and oppositional-defiant disorder (n = 124) or conduct disorder (n = 44). Children received psychostimulant (usually Osmotic Release Oral System methylphenidate) for 3 weeks, titrated for optimal effect, while parents received PT. If there was room for improvement at the end of week 3, placebo or risperidone was added. Assessments included parent ratings on the Nisonger Child Behavior Rating Form (Disruptive-Total subscale was the primary outcome) and Antisocial Behavior Scale; blinded clinicians rated change on the Clinical Global Impressions scale. RESULTS: Compared with Basic treatment (PT + STIM [44.8 +/- 14.6 mg/day] + placebo [1.88 mg/day +/- 0.72]), Augmented treatment (PT + STIM [46.1 +/- 16.8 mg/day] + risperidone [1.65 mg/day +/- 0.75]) showed statistically significant improvement on the Nisonger Child Behavior Rating Form Disruptive Total subscale (treatment-by-time interaction, p = .0016), the Nisonger Child Behavior Rating Form Social Competence subscale (p = .0049), and Antisocial Behavior Scale Reactive Aggression subscale (p = .01). Clinical Global Impressions scores were substantially improved for the 2 groups but did not discriminate between treatments (Clinical Global Impressions-Improvement score <=2, 70% for Basic treatment versus 79% for Augmented treatment). Prolactin elevations and gastrointestinal upset occurred more with Augmented treatment; other adverse events differed modestly from Basic treatment; weight gain in the Augmented treatment group was minor. CONCLUSIONS: Risperidone provided moderate but variable improvement in aggressive and other seriously disruptive child behaviors when added to PT and optimized stimulant treatment. Clinical trial registration information-Treatment of Severe Childhood Aggression (The TOSCA Study), URL: http://clinicaltrials.gov, unique identifier: NCT00796302. PMID- 24342386 TI - Attention bias modification treatment augmenting effects on cognitive behavioral therapy in children with anxiety: randomized controlled trial. AB - OBJECTIVE: Attention bias modification treatment (ABMT) is a promising novel treatment for anxiety disorders, but clinical trials have focused largely on stand-alone formats among adults. This randomized controlled trial examined the augmenting effects of threat-based ABMT on cognitive behavioral therapy (CBT) in clinically anxious youth. METHOD: Sixty-three treatment-seeking children with anxiety disorder were randomly assigned to 1 of the following 3 treatment groups: ABMT + CBT; ABMT placebo + CBT; and CBT-alone. Participants in the 2 ABMT conditions received repeated training on dot-probe tasks either designed to shift attention away from threats (active) or designed to induce no changes in attention patterns (placebo). Primary outcome measures were frequency and severity of anxiety symptoms as determined by a clinician using a semi-structured interview. Self- and parent-rated anxiety measures and threat-related attention bias scores were also measured before and after treatment. RESULTS: Both the active and placebo ABMT groups showed greater reductions in clinician-rated anxiety symptoms than the CBT-alone group. Furthermore, only the active ABMT group showed significant reduction in self- or parent-rated anxiety symptoms. Finally, all groups showed a shift in attention patterns across the study, starting with a bias toward threat at baseline and shifting attention away from threat after treatment. CONCLUSIONS: Active and placebo ABMT might augment the clinical response to CBT for anxiety. This effect could arise from benefits associated with performing computer-based paradigms such as the dot-probe task. Given the absence of group differences in attention-bias changes during treatment, possible mechanisms and methodological issues underlying the observed findings are discussed. Clinical trial registration information-Augmenting Effects of ABMT on CBT in Anxious Children: A Randomized Clinical Trial; http://clinicaltrials.gov/; NCT01730625. PMID- 24342387 TI - Effects of comorbid anxiety disorders on the longitudinal course of pediatric bipolar disorders. AB - OBJECTIVE: To examine the longitudinal effects of comorbid anxiety disorders in youth with bipolar spectrum disorder (BP). METHOD: As part of the Course and Outcome of Bipolar Youth study, 413 youth, who were 7 through 17 years or age and who met criteria for DSM-IV BP-I (n = 244), BP-II (n = 28), and operationally defined bipolar disorder not otherwise specified (BP-NOS) (n = 141) were included. Subjects were followed on average 5 years using the Longitudinal Interval Follow-up Evaluation. Effects of anxiety on the time to mood recovery and recurrence and percentage of time with syndromal and subsyndromal mood symptomatology during the follow-up period were analyzed. RESULTS: At intake and during the follow-up, 62% of youth with BP met criteria for at least 1 anxiety disorder. About 50% of the BP youth with anxiety had >=2 anxiety disorders. Compared to BP youth without anxiety, those with anxiety had significantly more depressive recurrences and significantly longer median time to recovery. The effects of anxiety on recovery disappeared when the severity of depression at intake was taken into account. After adjusting for confounding factors, BP youth with anxiety, particularly those with >=2 anxiety disorders, spent significantly less follow-up time asymptomatic and more time with syndromal mixed/cycling and subsyndromal depressive symptomatology compared to those without anxiety. CONCLUSIONS: Anxiety disorders are common and adversely affect the course of BP in youth, as characterized by more mood recurrences, longer time to recovery, less time euthymic, and more time in mixed/cycling and depressive episodes. Prompt recognition and the development of treatments for BP youth with anxiety are warranted. PMID- 24342388 TI - Advancing a multidimensional, developmental spectrum approach to preschool disruptive behavior. AB - OBJECTIVE: Dimensional approaches are gaining scientific traction. However, their potential for elucidating developmental aspects of psychopathology has not been fully realized. The goal of this article is to apply a multidimensional, developmental framework to model the normal-abnormal spectrum of preschool disruptive behavior. The Multidimensional Assessment of Preschool Disruptive Behavior (MAP-DB), a novel measure, was used to model dimensional severity across developmental parameters theorized to distinguish the normative misbehavior of early childhood from clinically salient disruptive behavior. The 4 MAP-DB dimensions are Temper Loss, Noncompliance, Aggression, and Low Concern for Others. METHOD: Parents of a diverse sample of 1,488 preschoolers completed the MAP-DB. Multidimensional item response theory (IRT) was used for dimensional modeling. RESULTS: The 4-dimensional, developmentally informed model demonstrated excellent fit. Its factor loadings did not differ across demographic subgroups. All dimensions provided good coverage of the abnormal end of the severity continuum, but only Temper Loss and Noncompliance provided good coverage of milder, normatively occurring behaviors. The developmental expectability and quality of behaviors distinguished normative from atypical behaviors. The point at which frequency of behaviors was atypical varied based on dimensional location for Temper Loss, Noncompliance, and Aggression. CONCLUSION: The MAP-DB provides an innovative method for operationalizing developmentally specified, dimensional phenotypes in early childhood. Establishing the validity of these dimensional phenotypes in relation to clinical outcomes, neurocognitive substrates, and etiologic pathways will be a crucial test of their clinical utility. PMID- 24342389 TI - Children's Yale-Brown obsessive compulsive scale in autism spectrum disorder: component structure and correlates of symptom checklist. AB - OBJECTIVE: Repetitive behaviors in autism spectrum disorders (ASD) range from motor stereotypy to immersion in restricted interests. The modified Children's Yale-Brown Obsessive Compulsive Scale for children with autism spectrum disorder (CYBOCS-ASD) includes a Symptom Checklist (behavior present or absent) and 5 severity scales (Time Spent, Interference, Distress, Resistance and Control). METHOD: We assembled CYBOCS-ASD data from 3 Research Units on Pediatric Psychopharmacology Autism Network trials to explore the component structure of repetitive behaviors in children with ASD. Raters trained to reliability conducted the CYBOCS-ASD in 272 medication-free subjects. Fifteen Symptom Checklist items were endorsed for less than 5% of the sample and were dropped. Principal component analysis was used to explore the clustering of 23 checklist items. Component scores computed for each subject were correlated with other measures. We also examined the distribution of severity scales. RESULTS: The subjects (229 boys and 43 girls; mean age = 7.8 +/- 2.6 years) met criteria for an ASD; half were intellectually disabled. The PCA resulted in a 5-component solution to classify repetitive behaviors (34.4% of the variance): hoarding and ritualistic behavior; sensory and arranging behavior; sameness and self-injurious behavior; stereotypy; restricted interests. Sensory and arranging and stereotypy components were associated with lower adaptive functioning (Pearson r = 0.2-0.3; p < .003). The resistance scale showed little variation, with more than 60% of the sample with the highest score. CONCLUSIONS: Rarely endorsed items can be dropped from the Checklist. The resistance item does not appear to be relevant for children with ASD. PMID- 24342390 TI - Maternal depression and warmth during childhood predict age 20 neural response to reward. AB - OBJECTIVE: Early parenting experiences likely shape children's brain development, with consequences potentially extending into adulthood. Parents' affective disorders and expressions of positive affect could exert an influence on affect related circuitry. The current study evaluated how maternal depression and maternal warmth assessed in early childhood and early adolescence were related to boys' reward function during early adulthood. METHOD: Participants were 120 boys at socioeconomic risk for emotional problems. Mothers' history of depression during the child's lifetime was measured when boys were 42 months old and 10 and 11 years old. Maternal warmth was observed during mother-child interactions at 18 and 24 months and at 10 and 11 years. RESULTS: Maternal warmth during early childhood was associated with less activation in the medial prefrontal cortex (mPFC) when anticipating and experiencing reward loss. Maternal warmth during early adolescence was associated with less activation in the mPFC when winning rewards and greater activation in the caudate when experiencing loss. The association between maternal warmth during early childhood and early adolescence and reward function in the striatum and mPFC was stronger for boys exposed to maternal depression relative to boys who were not. CONCLUSIONS: The experience of warmth and affection from mothers may be a protective factor for reward function in boys exposed to maternal depression, possibly by engaging vulnerable neural reward systems through affiliation. PMID- 24342392 TI - Dynamic changes in nuclear import of a nuclear localisation signal-bearing substrate in 8-cell stage porcine embryos. AB - Coordinated intracellular trafficking is critically important for proper timing of major cellular events during embryogenesis. Nuclear import mediated by the karyopherin alpha/beta (importin alpha/beta) heterodimer is perhaps the best characterised nuclear trafficking system in eukaryotic cells. Seven karyopherin alpha subtypes have been identified in the domestic pig, and although each karyopherin alpha subtype transports proteins bearing classical nuclear localisation signals (NLSs), individual karyopherin alpha subtypes have been shown to preferentially transport specific cargoes. The aim of the present study was to determine the mechanism by which BRN2, a transcription factor previously reported to be transported by the karyopherin alpha/beta heterodimer, gains access to the nucleus in porcine oocytes and embryos. Using a combination of in vivo and in vitro assays, we tested the hypothesis that discrete karyopherin alpha subtypes transport BRN2 into the nuclei of porcine oocytes and cleavage stage embryos. Our results show that ectopically expressed BRN2 adopts a nuclear localisation in all nuclei through the 4-cell stage of development, whereas only a subset of blastomeres in 8-cell stage embryos possess nuclear BRN2. This pattern is unique to BRN2 because another ectopically expressed NLS-containing protein is able to adopt a nuclear localisation in all blastomeres of 8-cell stage embryos. PMID- 24342393 TI - Human white adipocytes express the cold receptor TRPM8 which activation induces UCP1 expression, mitochondrial activation and heat production. AB - Mammals possess two types of adipose tissue, white (WAT) and brown (BAT). The uncoupling protein 1 (UCP1) is a hallmark of BAT, being the pivotal player for cold-induced thermogenesis. WAT can acquire BAT characteristics with up regulation of UCP1 after cold exposure or adrenergic stimulation. In the present study we demonstrated that human white adipocytes express the cold-sensing receptor TRPM8 which activation by menthol and icilin induced a rise in [Ca2+](i) and UCP1 expression, increased mitochondrial membrane potential, glucose uptake and heat production. The induction of "brown-like" phenotype in human white adipocytes after TRPM8 activation was supported by ultrastructural morphological changes of mitochondrial morphology and of their intracellular localization, with no modifications of the genes regulating mitochondrial biogenesis. In conclusion human white adipocytes express the cold receptor TRPM8 which activation induces their "browning" supporting a possible role of this receptor in the control of adipose tissue metabolism and body energy balance. PMID- 24342395 TI - Is timing everything? PMID- 24342394 TI - Hematopoietic cell transplant comorbidity index is predictive of survival after autologous hematopoietic cell transplantation in multiple myeloma. AB - Autologous hematopoietic stem cell transplantation (AHCT) improves survival in patients with multiple myeloma (MM) but is associated with morbidity and nonrelapse mortality (NRM). Hematopoietic cell transplant comorbidity index (HCT CI) was shown to predict risk of NRM and survival after allogeneic transplantation. We tested the utility of HCT-CI as a predictor of NRM and survival in patients with MM undergoing AHCT. We analyzed outcomes of 1156 patients of AHCT after high-dose melphalan reported to the Center for International Blood and Marrow Transplant Research. Individual comorbidities were prospectively collected at the time of AHCT. The impact of HCT-CI and other potential prognostic factors, including Karnofsky performance score (KPS), on NRM and survival were studied in multivariate Cox regression models. HCT-CI score was 0, 1, 2, 3, and >3 in 42%, 18%, 13%, 13%, and 14% of the study cohort, respectively. Subjects were stratified into 3 risk groups: HCT-CI score of 0 (42%) versus HCT-CI score of 1 to 2 (32%) versus HCT-CI score > 2 (26%). Higher HCT-CI was associated with lower KPS < 90 (33% of subjects score of 0 versus 50% in HCT-CI score > 2). HCT-CI score > 2 was associated with melphalan dose reduction (22% versus 10% in score 0 cohort). One-year NRM was low at 2% (95% confidence interval, 1% to 4%) and did not correlate with HCT-CI score (P = .9). On multivariate analysis, overall survival was inferior in groups with HCT-CI score of 1 to 2 (relative risk, 1.37, [95% confidence interval, 1.01 to 1.87], P = .04) and HCT-CI score > 2 (relative risk, 1.5 [95% confidence interval, 1.09 to 2.08], P = .01). Overall survival was also inferior with KPS < 90 (P < .001), IgA subtype (P <= .001), those receiving >1 pretransplant induction regimen (P = .007), and those with resistant disease at the time of AHCT (P < .001). AHCT for MM is associated with low NRM, and death is predominantly related to disease progression. Although a higher HCT-CI score did not predict NRM, it was associated with inferior survival. PMID- 24342396 TI - Effect of lifetime endurance training on left atrial mechanical function and on the risk of atrial fibrillation. AB - BACKGROUND: Left atrium (LA) dilation and P-wave duration are linked to the amount of endurance training and are risk factors for atrial fibrillation (AF). The aim of this study was to evaluate the impact of LA anatomical and electrical remodeling on its conduit and pump function measured by two-dimensional speckle tracking echocardiography (STE). METHOD: Amateur male runners >30 years were recruited. Study participants (n=95) were stratified in 3 groups according to lifetime training hours: low (<1500 h, n=33), intermediate (1500 to 4500 h, n=32) and high training group (>4500 h, n=30). RESULTS: No differences were found, between the groups, in terms of age, blood pressure, and diastolic function. LA maximal volume (30+/-5, 33+/-5 vs. 37+/-6 ml/m(2), p<0.001), and conduit volume index (9+/-3, 11+/-3 vs. 12+/-3 ml/m(2), p<0.001) increased significantly from the low to the high training group, unlike the STE parameters: pump strain 15.0+/-2.8, -14.7+/-2.7 vs. -14.9+/-2.6%, p=0.927; conduit strain 23.3+/-3.9, 22.1+/-5.3 vs. 23.7+/-5.7%, p=0.455. Independent predictors of LA strain conduit function were age, maximal early diastolic velocity of the mitral annulus, heart rate and peak early diastolic filling velocity. The signal-averaged P-wave (135+/ 11, 139+/-10 vs. 148+/-14 ms, p<0.001) increased from the low to the high training group. Four episodes of non-sustained AF were recorded in one runner of the high training group. CONCLUSION: The LA anatomical and electrical remodeling does not have a negative impact on atrial mechanical function. Hence, a possible link between these risk factors for AF and its actual, rare occurrence in this athlete population, could not be uncovered in the present study. PMID- 24342397 TI - Predictive power of the fractalkine receptor CX3CR1 on CD4 T cells in patients with chronic heart failure. PMID- 24342398 TI - Mitral valve in valve: a new choice to be still cautious. PMID- 24342399 TI - Impact of new task force criteria in the diagnosis of arrhythmogenic right ventricular cardiomyopathy. AB - BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy that can lead to sudden cardiac death. The diagnostic criterion has recently been revised and through the use of cardiac magnetic resonance (CMR) imaging this study aimed to assess the clinical impact of comparing the original 1994 task force (TF) criterion to the revised 2010 criterion. METHODS: We evaluated 173 consecutive CMR scans of patients referred with clinical suspicion of ARVC between 2008 and 2011. We then compared the prevalence of major and minor CMR criteria by applying the two criteria. RESULTS: Using the 1994 TF criterion, 13 (7.5%) patients had definite, 11 (6.4%) had borderline, and 39 (22.5%) had possible ARVC. Using the 2010 TF criterion, 10 (5.8%) patients had definite, 1 had borderline, and 7 had (0.04%) possible ARVC. With the 1994 criterion, 81 patients satisfied CMR criterion, of which 36 (44%) had major and 45 (56%) had minor criteria. Upon reclassification with the revised criterion, 61 of the 81 patients were not assigned any criteria, even though many patients had significant risk factors. The negative predictive values (NPV) for both CMR criteria were 100% but the positive predictive values (PPV) for combined CMR major or minor criteria improved from 23% to 55%. CONCLUSIONS: Revision of the criterion has enhanced the diagnostic capabilities of CMR but has resulted in a large cohort of patients not classified. In these patients, there is presently no official consensus on imaging or clinical strategy for surveillance of the evolution of pathology over time. PMID- 24342400 TI - Open-access.com. PMID- 24342401 TI - A simple approach for the reduction of knotted coronary catheters during transradial coronary angiography. PMID- 24342402 TI - Haptoglobin genotype does not predict extent of coronary artery calcification in a prospective cohort of patients with type 2 diabetes. PMID- 24342403 TI - Is it possible to separate ischemic and bleeding risk in patients with non-ST segment elevation acute coronary syndromes? PMID- 24342404 TI - The QRS narrowing index for easy and early identification of responder to cardiac resynchronization therapy. PMID- 24342406 TI - Repeated pacemaker dysfunction in a patient with recurrent Takotsubo cardiomyopathy precipitated by hyponatremia. PMID- 24342407 TI - Performance-enhancing effects of non-selective endothelin receptor antagonist. PMID- 24342408 TI - Shoulder technique: a modified sleeve technique devised for treating isolated coronary stenosis at side branch ostium. PMID- 24342405 TI - Low admission heart rate is a marker rather than a mediator of increased in hospital mortality for patients with acute heart failure syndromes in sinus rhythm. PMID- 24342409 TI - Calibration of intravascular optical coherence tomography as presented in peer reviewed publications. PMID- 24342410 TI - Treatment failure of low molecular weight heparin bridging therapy in atrial fibrillation after acute coronary syndrome. PMID- 24342411 TI - Prognostic role of glucose abnormalities in patients with ST-elevation myocardial infarction and mild renal impairment. PMID- 24342412 TI - Various morphological-types of all and fragmented ventricular premature beats on a 12-lead Holter-ECG had positive-relationship with occurrence of LV fibrosis on CT in HCM subjects. PMID- 24342413 TI - Comment on: idiopathic pericarditis presenting large hemorrhagic pericardial effusion. PMID- 24342414 TI - Coronary microvascular dysfunction portends poor prognosis in the setting of chronic renal failure: harnessing dual marker strategy for better risk stratification? PMID- 24342415 TI - Successful treatment of a patient with symptomatic long QT syndrome type 3 using ranolazine combined with a beta-blocker. PMID- 24342416 TI - Dobutamine stress cardiac magnetic resonance versus echocardiography for the assessment of outcome in patients with suspected or known coronary artery disease. Are the two imaging modalities comparable? AB - PURPOSE: To compare the value of Dobutamine stress echocardiography (DSE) with that provided by Dobutamine Cardiac Magnetic Resonance (DCMR) for the non invasive risk stratification of patients with suspected or known coronary artery disease (CAD). METHODS: Patients with suspected or known CAD underwent either DSE or DCMR using the same standardized protocol. Patient matching was then performed retrospectively for age, gender and risk factors. Outcome data including cardiac death and non-fatal myocardial infarction (defined as hard cardiac events) and 'late' revascularization performed >90days after the diagnostic procedures were collected during at least 6months. RESULTS: Follow-up data were available in 1852 patients who completed either DSE (n=884) or DCMR (n=884) during a mean follow-up duration of 4.1+/-2.4 and 3.9+/-1.9years, respectively (p=NS). Matched patients exhibited an overall high risk profile (69+/-9years; 69% male, 70% history of CAD and 26% diabetes mellitus in both groups). Using multivariable analysis, both modalities successfully identified patients with inducible ischemia at higher risk for subsequent hard cardiac events, surpassing the value of conventional risk factors like age, male gender and diabetes (HR=9.2; 95%CI=5.6-14.9 for DCMR versus 2.5; 95%CI=1.7-3.7 for DSE). By testing for interaction the predictive capacity of DCMR was higher than that provided by DSE (p=0.02). Patients with negative DCMR exhibited lower event rates compared to those with negative DSE (annual hard cardiac event rate of 0.8% versus 3.2%, p=0.002). CONCLUSIONS: DSE & DCMR aid the risk stratification of CAD patients. However, inducible WMA during DCMR are associated with a higher risk for subsequent cardiac events. Patients with negative DCMR on the other hand, exhibited a lower event rate compared to those with negative DSE. PMID- 24342417 TI - Transvenous lead implantation in a patient with mechanical prosthesis in the tricuspid position: transvenous route should be the first choice. PMID- 24342418 TI - Acute aortic regurgitation and hemodynamic collapse after balloon aortic valvuloplasty. PMID- 24342419 TI - Efficacy of dual focus mutual aid for persons with mental illness and substance misuse. AB - BACKGROUND: Previous studies have indicated that persons with co-occurring mental health and substance use problems can benefit by attending dual-focus mutual aid groups. However, to date, a trial to test the efficacy of these groups has not been published. METHOD: This study randomly assigned 203 substance misusing clients attending a mental health or dual-diagnosis facility to either a dual focus 12-step group (Double Trouble in Recovery; DTR) or a waiting list control group. Participants were followed for 3-6 months. The primary outcome was substance use (days used in the past 30 with saliva testing to detect under reporting); secondary outcomes included psychiatric medication adherence, attendance at traditional (single-focus) 12-step meetings (e.g., AA/NA); and improvement in mental health and substance use problems (quality of life). Multilevel model (MLM) regression was used to analyze the nested effect of participants within 8 facilities (7 in New York City and 1 in Michigan). Regression imputation was used to adjust for drug use under-reporting. RESULTS: At follow-up 79% of the subjects were interviewed. In intent to treat analysis, DTR subjects compared with control subjects used alcohol (p=.03) and any substances (p=.02) on fewer days. DTR compared with control subjects were also more likely to rate themselves as experiencing better mental health and fewer substance use problems (p=.001). There were no effects for DTR on drug use only, medication adherence or NA/AA attendance. CONCLUSION: Findings reported in previous studies on the association between exposure to DTR and reductions in substance use were partially supported in this efficacy trial. PMID- 24342421 TI - Regression to the mean and alcohol consumption: a cohort study exploring implications for the interpretation of change in control groups in brief intervention trials. AB - BACKGROUND: Reductions in drinking among individuals randomised to control groups in brief alcohol intervention trials are common and suggest that asking study participants about their drinking may itself cause them to reduce their consumption. We sought to test the hypothesis that the statistical artefact regression to the mean (RTM) explains part of the reduction in such studies. METHODS: 967 participants in a cohort study of alcohol consumption in New Zealand provided data at baseline and again six months later. We use graphical methods and apply thresholds of 8, 12, 16 and 20 in AUDIT scores to explore RTM. RESULTS: There was a negative association between baseline AUDIT scores and change in AUDIT scores from baseline to six months, which in the absence of bias and confounding, is RTM. Students with lower baseline scores tended to have higher follow-up scores and conversely, those with higher baseline scores tended to have lower follow-up scores. When a threshold score of 8 was used to select a subgroup, the observed mean change was approximately half of that observed without a threshold. The application of higher thresholds produced greater apparent reductions in alcohol consumption. CONCLUSIONS: Part of the reduction seen in the control groups of brief alcohol intervention trials is likely to be due to RTM and the amount of change is likely to be greater as the threshold for entry to the trial increases. Quantification of RTM warrants further study and should assist understanding assessment and other research participation effects. PMID- 24342420 TI - A voxel-based morphometry study of young occasional users of amphetamine-type stimulants and cocaine. AB - BACKGROUND: Although the interaction of brain volume with amphetamine-type stimulants (ATS) and cocaine has been investigated in chronically dependent individuals, little is known about structural differences that might exist in individuals who consume ATS and cocaine occasionally but are not dependent on these drugs. METHODS: Regional brain volumes in 165 college aged occasional users of ATS (namely: amphetamine, methamphetamine, methylphenidate, and 3,4 methylenedioxymethamphetamine; MDMA) and cocaine were compared by voxel-based morphometry with 48 ATS/cocaine-naive controls. RESULTS: Grey matter volume was significantly higher in the left ventral anterior putamen of occasional users, and lower in the right dorsolateral cerebellum and right inferior parietal cortex. A regression in users alone on lifetime consumption of combined ATS (namely: amphetamine, methamphetamine, methylphenidate and MDMA) and cocaine use revealed that individuals who used more ATS/cocaine had greater volume in the right ventromedial frontal cortex. A second regression on lifetime consumption of ATS with cocaine as a covariate revealed that individuals with a greater history of ATS use alone had more grey matter volume in the left mid-insula. Interestingly, structural changes in the ventromedial prefrontal cortex, insula and striatum have been consistently observed in volumetric studies of chronic ATS and cocaine dependence. CONCLUSION: The present results suggest that these three brain regions may play a role in stimulant use even in early occasional users. PMID- 24342423 TI - Longitudinal study of perinatal maternal stress, depressive symptoms and anxiety. AB - OBJECTIVES: to understand the trends in, and relationships between, maternal stress, depressive symptoms and anxiety in pregnancy and post partum. DESIGN: a prospective longitudinal survey study was undertaken to explore maternal psychological distress throughout the perinatal period. The participants were recruited after 24 completed weeks of gestation, and were followed-up monthly until one month post partum (four surveys in total). SETTING: participants were recruited from a single hospital in southern Taiwan, and asked to complete questionnaires in the hospital waiting area. PARTICIPANTS: inclusion criteria were: age >=18 years, able to read and write Chinese, >=24 weeks of gestation, singleton pregnancy and no pregnancy complications (including a diagnosis of antenatal depression or anxiety disorder). In total, 197 women completed all four surveys (response rate 74.62%). MEASUREMENTS AND FINDINGS: stress was measured with the 10-item Perceived Stress Scale, depressive symptoms were measured with the Center for Epidemiologic Studies' Depression scale, and anxiety was measured with the Zung Self-reported Anxiety Scale. Participants were followed-up at four time points: T1 (25-29 gestational weeks), T2 (30-34 gestational weeks), T3 (>34 gestational weeks) and T4 (4-6 weeks post partum). Appointments for data collection were made in accordance with the participants' antenatal and postnatal check-ups. The three types of maternal distress had different courses of change throughout the perinatal period, as levels of depressive symptoms remained unchanged, anxiety levels increased as gestation advanced but declined after birth, and stress decreased gradually during pregnancy but returned to the T1 level after birth. There was a low to high degree of correlation in maternal stress, depressive symptoms and anxiety in pregnancy and post partum. KEY CONCLUSIONS: around one-quarter of the study participants had depressive symptoms during pregnancy and post partum. Stress and anxiety showed opposing courses during the perinatal period. Regardless of the trend, maternal mental distress returned to the T1 level after birth. IMPLICATIONS FOR PRACTICE: effective survey questionnaires are suggested for use as primary screening for possible psychological distress among pregnant and post partum women. It is suggested that health care professionals involved in obstetrics and midwifery should pay attention to the psychological needs of pre- and postnatal women, provide women with sufficient information about their mental well-being, and make appropriate and timely referrals to psychiatric or psychological care. PMID- 24342422 TI - Selective CB2 receptor activation ameliorates EAE by reducing Th17 differentiation and immune cell accumulation in the CNS. AB - CB2, the cannabinoid receptor expressed primarily on hematopoietic cells and activated microglia, mediates the immunoregulatory functions of cannabinoids. The involvement of CB2 in EAE has been demonstrated by using both endogenous and exogenous ligands. We showed previously that CB2 selective agonists inhibit leukocyte rolling and adhesion to CNS microvasculature and ameliorate clinical symptom in both chronic and remitting-relapsing EAE models. Here we showed that Gp1a, a highly selective CB2 agonist, with a four log higher affinity for CB2 than CB1, reduced clinical scores and facilitated recovery in EAE in conjunction with long term reduction in demyelination and axonal loss. We also established that Gp1a affected EAE through at least two different mechanisms, i.e. an early effect on Th1/Th17 differentiation in peripheral immune organs, and a later effect on the accumulation of pathogenic immune cells in the CNS, associated with reductions in the expression of CNS and T cell chemokine receptors, chemokines and adhesion molecules. This is the first report on the in vivo CB2-mediated Gp1a inhibition of Th17/Th1 differentiation. We also confirmed the Gp1a-induced inhibition of Th17/Th1 differentiation in vitro, both in non-polarizing and polarizing conditions. The CB2-induced inhibition of Th17 differentiation is highly relevant in view of recent studies emphasizing the importance of pathogenic self-reactive Th17 cells in EAE/MS. In addition, the combined effect on Th17 differentiation and immune cell accumulation into the CNS, emphasize the relevance of CB2 selective ligands as potential therapeutic agents in neuroinflammation. PMID- 24342424 TI - A profile of midwifery in Paraguay. AB - OBJECTIVE: The goal of this study was to provide a descriptive profile of midwifery in Paraguay. DESIGN: The study involved three components: background research from official documents and key informant interviews to complete questionnaires, qualitative interviews with Paraguayan midwives and obstetricians, and participant observation. Data from official documents and questionnaires were tabulated using descriptive statistics. Individual interviews and small-group interviews of midwives, student midwives, and obstetricians were conducted in five health departments of Paraguay. SETTING: The research took place in the capital of Paraguay, Asuncion, and four additional health departments: Central, Cordillera, Guira, and Misiones. PARTICIPANTS: Twenty-two midwives, nine student midwives, nine obstetricians, and five leaders of professional health organisations in Paraguay participated in this study. FINDINGS: Three salient themes were identified throughout the interviews. First was the understanding of the changing role of the midwife in the health system, particularly in and around the capital city of Asuncion. Second, midwives and obstetricians both reported that women were not sufficiently prepared for labour and birth during the antenatal period. Limited antenatal education and childbirth classes existed and midwives felt that this was a major barrier to vaginal birth. Finally, access to midwife-provided antenatal care is perceived to be limited. A major barrier to accessing midwifery care for women in the capital is related to the midwives' changing role in practice. Obstetricians are now providing antenatal care more often than they used to, and in some public hospitals they also attend vaginal deliveries. KEY CONCLUSIONS AND IMPLICATIONS: Limiting the utilisation of midwives may well be a major contributor to the rising rates of caesarean sections. Women are not prepared for labour and birth in the antenatal period, or are scheduled for elective caesarean sections antenatal ly. Midwives are not fulfilling their potential to prepare women for labour and birth, despite their high-level professional training. Midwives have the potential to improve antenatal preparation for low-intervention birth. This transition in care provision would be a more effective use of human resources for both obstetricians and midwives. PMID- 24342425 TI - Prevalence of abnormal Pap smears in a consecutive and previously unscreened population in Romania. AB - OBJECTIVE: To determine the prevalence of abnormal cervical smears in a previously unscreened and asymptomatic population in Romania and to compare the data with those from other countries in Europe. METHODS: In a retrospective study, data were reviewed from smears obtained from women in Romania who had been referred to the gynecologist between January 2006 and December 2011. The smears were collected through 3 regional opportunistic programs of cervical screening and were classified according to the Bethesda system. RESULTS: During the study period, 50536 smear tests were carried out. Of these, 100 smears (0.2%) were unsatisfactory and excluded from the study. Among the remaining 50436 smears, 2965 patients (5.9%) had abnormal epithelial changes. Most of the abnormal smears were represented by atypical squamous cells of undetermined significance (2.6% of all smears). The data confirmed that there is a high prevalence of high-grade intraepithelial squamous-type lesions (0.9% of all smears) in Romania, and of abnormal smears in women younger than 25years of age (14.0% of all abnormal smears). CONCLUSION: The data show that there is a high prevalence of epithelial abnormalities among cervical smears in Romania compared with other European countries that run a national screening program. PMID- 24342426 TI - Thyroglossal cyst as primary site of papillary thyroid carcinoma metastatic to jugular lymph node chain. PMID- 24342427 TI - Validity of subjective global assessment as a screening method for hospital malnutrition. Prevalence of malnutrition in a tertiary hospital. AB - INTRODUCTION: Hospital malnutrition is a highly prevalent problem that affects patient morbidity and mortality resulting in longer hospital stays and increased healthcare costs. Although there is no single nutritional screening method, subjective global assessment (SGA) may be a useful, inexpensive, and easily reproducible tool. METHODS: A cross-sectional, observational, randomized study was conducted in 197 patients in a tertiary hospital. SGA, anthropometric data, and biochemical parameters were used to assess the nutritional status of study patients. RESULTS: Fifty percent of subjects were malnourished according to SGA. A higher prevalence of malnutrition was found in medical (53%) as compared to surgical departments (47%). Half the subjects (50%) had malnutrition by SGA, but only 37.8% received nutritional treatment during their hospital stay. Mean hospital stay was longer for patients malnourished (13.5 days) or at risk of malnutrition (12.1 days) as compared to well nourished subjects (6.97 days). SGA significantly correlated (P<.012) with anthropometric and biochemical malnutrition parameters. CONCLUSIONS: Prevalence of hospital malnutrition is very high in both medical and surgical departments and is inadequately treated. SGA is a useful tool for screening hospital malnutrition because of its high degree of correlation with anthropometric and biochemical parameters. PMID- 24342428 TI - Measurement of waist circumference for retrospective studies - prospective validation of use of CT images to assess abdominal circumference. AB - INTRODUCTION: To validate the use of supine position and CT images for assessing abdominal circumference (AC). METHOD: A prospective study in consecutive patients undergoing scheduled abdominal CT at our center between 17 and 25 September 2012. AC was measured four times: Measurements 1 and 2 were sequentially done by the same trained nurse before abdominal CT just above the iliac crest, while measurements 3 and 4 were done on the last abdominal CT slice not showing the iliac bone. Student's t tests and Q-Q and Bland-Altman plots were used for statistical analysis. RESULTS: A total of 102 patients were recruited. Mean age, 60 (35-78) years. Mean BMI, 25 (18-39) kg/m(2). Mean AC, 93.2 (73-135) cm. No significant differences were found between the four ACs measured (Student's t test, P=0.83). Q-Q and Bland-Altman plots showed good overlapping for the low and central values (73-110 cm) with a greater scatter for extremely high values. For the ellipse estimation, R(2) was 0.987 with a mean error of 0.4 cm and a stretch dispersion between 1.1 and -0.3 cm. CONCLUSION: Supine (either measured or estimated on CT images by free hand elliptical ROI or ellipse formula) and standing measurements appear to be equivalent for abdominal circumferences <110 cm. PMID- 24342429 TI - Calling "time" on the GMC's investigations into complaints against doctors. PMID- 24342430 TI - Cutaneous and mammary apocrine carcinomas have different immunoprofiles. AB - Often the distinction of cutaneous apocrine carcinoma from metastatic mammary apocrine carcinoma to the skin can be a diagnostic dilemma because both tumors share similar histologic features and have overlapping immunohistochemical profile. We compared the expression of adipophilin, cytokeratin 5/6, p63, GATA3, mammaglobin, androgen receptor, estrogen receptor, progesterone receptor, and HER2 by immunohistochemistry in 14 cutaneous apocrine carcinomas (11 primary tumors, 3 metastases) and 26 primary apocrine carcinomas of the breast. Whereas focal adipophilin staining was seen in 36% (5/14) of cutaneous apocrine carcinoma, strong and diffuse adipophilin staining was seen in 88% (22/25) of mammary apocrine carcinoma (P = .0013). Differences in estrogen receptor and progesterone receptor expression were also statistically significant (P = .018 and .043). Androgen receptor was strongly positive in all cutaneous and mammary cases. Although there was no significant difference in the frequency of expression of cytokeratin 5/6, p63, HER2, GATA3, and mammaglobin in cutaneous apocrine carcinoma versus mammary apocrine carcinoma, strong and diffuse cytokeratin 5/6 and/or mammaglobin expression were seen only in cutaneous apocrine carcinoma. In conclusion, cutaneous apocrine carcinoma is likely adipophilin- ER+ PR+/- HER2- and can exhibit strong and diffuse cytokeratin 5/6 and/or mammaglobin expression. On the contrary, a mammary apocrine carcinoma is likely adipophilin+ ER- PR- and often exhibit 3+ HER2 with corresponding HER2 gene amplification. A panel of adipophilin, ER, PR, HER2, cytokeratin 5/6, and mammaglobin may be helpful in distinguishing cutaneous apocrine carcinoma from mammary apocrine carcinoma. PMID- 24342431 TI - Signet ring stromal cell tumor revisited and related signet ring cell lesions of the ovary. AB - In this article, we revisit the first reported case of ovarian signet ring stromal cell tumor (SRSCT) using modern immunohistochemical techniques and compare it to a case of signet ring cell transformation of lutein cells in an ovarian stromal tumor having components of luteinized thecoma and sclerosing stromal tumor. We introduce a new classification of signet ring stromal cell lesions of the ovary that serves as a framework to distinguish pathogenetically distinct ovarian stromal lesions that may be confused with cases of true SRSCT. The SRSCT in our first case most likely arose directly from the ovarian stroma without an identifiable precursor neoplasm. In our second case, the association of the signet ring cells with lutein cells and the positive staining of the signet ring cells for inhibin and steroidogenic factor 1 confirm that in some instances signet ring cells are derived from lutein cells. PMID- 24342432 TI - Clinicopathologic features associated with relapse in cryptogenic organizing pneumonia. AB - Organizing pneumonia (OP) is a histopathologic pattern of response to lung injury. Fibrin is a marker of acute microvascular injury, and variable amounts of intraalveolar fibrin are seen in OP; however, its relevance to clinical outcomes is unclear. We examined lung wedge biopsies of 26 patients with cryptogenic organizing pneumonia (COP), assessed the amount of fibrin associated with airspace organization, and correlated fibrin levels with other histologic, clinical, and radiographic findings. Seven patients with COP had disease relapse. Patients with multifocal fibrin deposits or acute fibrinous and organizing pneumonia (collectively, "high fibrin") showed a higher rate of OP relapse compared to those with no or focal fibrin (60% versus 6%, P < .05). Patients with radiographic evidence of disease involving all three lung zones (upper, middle, and lower) also showed higher rates of relapse compared to those in whom disease was limited to one or two zones (41% versus 0%, P = .055). In patients with both pathologic evidence of high fibrin and radiographic evidence of three-zone disease, OP relapse could be predicted with a sensitivity of 86% and specificity of 84% (positive predictive value of 67% and negative predictive value of 94%). The presence of high levels of intraalveolar fibrin in lung biopsies and radiographic evidence of disease involving all three lung zones is associated with increased risk of relapse in patients with COP, and these features may help identify patients who may benefit from more intensive steroid therapy. PMID- 24342433 TI - Acute myeloid leukemia with t(16;16) (p13;q22) showing a new CBFB-MYH11 fusion transcript associated with an atypical leukemic blasts morphology. AB - Acute myeloid leukemia (AML) cases with inv(16)(p13q22) or t(16;16)(p13;q22) are characterized by multiple CBFB-MYH11 fusion transcripts, type A being the most frequent. Rare fusion variants are frequently correlated with an atypical cytomorphology, but their biologic and prognostic significance is unclear. We report a case of acute myeloid leukemia with a balanced t(16;16)(p13;q22) and additional monosomy 13 showing a new CBFB-MYH11 fusion transcript variant. The patient also showed an atypical morphology of bone marrow blasts, since about 15% of all blasts showed bilobed nuclei but there was no pathologic eosinophilia. The biologic and prognostic implications of this rare association are discussed. PMID- 24342434 TI - gamma-Glutamylcyclotransferase as a novel immunohistochemical biomarker for the malignancy of esophageal squamous tumors. AB - Recently, overexpression of gamma-glutamylcyclotransferase (GGCT) has been reported in various cancer tissues suggesting that it has significant potential as a diagnostic marker. The aim of this study was to examine the suitability of GGCT for the detection of high-risk lesions at an early stage of esophageal squamous cell carcinoma (ESCC). A total of 200 lesions, including 120 invasive ESCC, 80 esophageal squamous intraepithelial neoplasia consisting of 40 low-grade intraepithelial neoplasia (LGIEN) and 40 high-grade intraepithelial neoplasia (HGIEN), as well as 20 confounding lesions, were examined by immunohistochemical (IHC) staining for GGCT. IHC staining for Ki-67 and p53 was also performed in esophageal squamous intraepithelial neoplasia to compare the diagnostic power of GGCT. Increased expression of GGCT was common in invasive ESCC and HGIEN (87.5% and 85.0%, respectively), but was much less frequently observed in LGIEN (17.5%). GGCT expression significantly correlated with the presence of lymph node metastasis and the degree of differentiation. In the differential diagnosis of LGIEN and HGIEN, GGCT possessed both high sensitivity and high specificity, while Ki-67 and p53 only possessed either high sensitivity or high specificity. Additionally, GGCT expression was higher in 7 out of 8 ESCC cell lines (KYSE series) than in a normal esophageal squamous cell line (Het-1A). The expression levels strongly correlated with enzymatic activity (r=.92; P<.001). These results indicate that overexpressed GGCT retains its enzymatic activity and can become a valuable biomarker for the diagnosis of HGIEN that is likely to progress to subepithelial invasion. PMID- 24342435 TI - The computational sperm cell. AB - Sperm are guided to the egg by a gradient of chemical attractants - a process called chemotaxis. The binding of the chemoattractant to receptors on the surface of the flagellum triggers a cascade of signaling events that eventually lead to an influx of Ca(2+) ions. Based on these Ca(2+) surges, which control the waveform of the flagellar beat, sperm adjust their swimming path toward the egg. In past years, many components of chemotactic signaling have been identified. Moreover, kinetic spectroscopy and imaging techniques unraveled the sequence of cellular events controlling swimming behavior. During navigation in a chemical gradient, sperm perform a surprising variety of computational operations. Here we discuss theoretical concepts of navigation strategies and the cellular underpinnings. PMID- 24342436 TI - Next generation sequencing-based expression profiling identifies signatures from benign stromal proliferations that define stromal components of breast cancer. AB - INTRODUCTION: Multiple studies have shown that the tumor microenvironment (TME) of carcinomas can play an important role in the initiation, progression, and metastasis of cancer. Here we test the hypothesis that specific benign fibrous soft tissue tumor gene expression profiles may represent distinct stromal fibroblastic reaction types that occur in different breast cancers. The discovered stromal profiles could classify breast cancer based on the type of stromal reaction patterns in the TME. METHODS: Next generation sequencing-based gene expression profiling (3SEQ) was performed on formalin fixed, paraffin embedded (FFPE) samples of 10 types of fibrous soft tissue tumors. We determined the extent to which these signatures could identify distinct subsets of breast cancers in four publicly available breast cancer datasets. RESULTS: A total of 53 fibrous tumors were sequenced by 3SEQ with an average of 29 million reads per sample. Both the gene signatures derived from elastofibroma (EF) and fibroma of tendon sheath (FOTS) demonstrated robust outcome results for survival in the four breast cancer datasets. The breast cancers positive for the EF signature (20-33% of the cohort) demonstrated significantly better outcome for survival. In contrast, the FOTS signature-positive breast cancers (11-35% of the cohort) had a worse outcome. CONCLUSIONS: We defined and validated two new stromal signatures in breast cancer (EF and FOTS), which are significantly associated with prognosis. Our group has previously identified novel cancer stromal gene expression signatures associated with outcome differences in breast cancer by gene expression profiling of three soft tissue tumors, desmoid-type fibromatosis (DTF), solitary fibrous tumor (SFT), and tenosynovial giant cell tumor (TGCT/CSF1), as surrogates for stromal expression patterns. By combining the stromal signatures of EF and FOTS, with our previously identified DTF and TGCT/CSF1 signatures we can now characterize clinically relevant stromal expression profiles in the TME for between 74% to 90% of all breast cancers. PMID- 24342437 TI - The role of FOXL2 in the pathogenesis of adult ovarian granulosa cell tumours. AB - OBJECTIVE: It has been four years since the discovery of the FOXL2 402C>G mutation in adult ovarian granulosa cell tumours. Yet to date, there have been few studies which have investigated the precise role of the mutation in tumour pathogenesis. This review aims to summarise the research in this area, proposes a mechanism of action for the mutation, and explores the implications for clinical practice and future therapeutics. METHODS: A literature search was performed with the keywords 'granulosa cell tumour' and 'FOXL2' on PubMed. RESULTS: Although the search returned 52 articles, of these only nine publications investigate the pathogenic effect of the mutant FOXL2 allele. Mutant FOXL2 maintains some of the transcriptional activity of the wildtype allele, but there is a subtle alteration of the expression in a unique suite of cancer-related genes. The mutation appears to deregulate the anti-proliferative transforming growth factor beta (TGF-beta) pathway and this may contribute to the pathogenesis of adult GCTs. The inability of mutant FOXL2 to elicit an effective apoptotic signalling cascade may also be important in GCT pathogenesis. CONCLUSION: The 402C>G mutation in FOXL2 is central to the development of adult granulosa cell tumours. Based on the evidence, we suggest that FOXL2 is an oncogene or tumour suppressor depending on the genetic context that is the GCT subtype. PMID- 24342438 TI - Prior appendectomy does not protect against subsequent development of malignant or borderline mucinous ovarian neoplasms. AB - BACKGROUND: Due to concern that mucinous malignant or borderline ovarian neoplasms (MON) may represent metastatic deposits from appendiceal primaries, gynecologic oncologists routinely perform appendectomy in these cases. However, a multidisciplinary critique of this practice is lacking. METHODS: The New England Case-Control study database was utilized to compare the effect of prior appendectomy against known risk factors for MON. Pathology and operative reports of local cases of MON were reviewed to estimate the frequency of microscopic mucinous lesions in the appendix. Protein expression patterns among mucinous ovarian, colorectal, and appendiceal cancers were compared by immunohistochemistry. RESULTS: From the New England Case-Control study, 287 cases of MON were compared against 2339 age-matched controls. Prior appendectomy did not reduce the risk of MON (OR 1.28, 95% CI 0.83-1.92, p = 0.23), while prior tubal ligation, parity, and breastfeeding were each protective against MON. Active smoking (OR 2.04, 95% CI 1.48-2.80, p < 0.001) was associated with an increased risk of MON. Among 196 mucinous adnexal tumors, appendectomy did not reclassify any MON as appendiceal in origin. By immunohistochemistry, mucinous ovarian carcinomas tended to be CK7+/CK20-/MUC2-/CDX2-, whereas mucinous colorectal and appendiceal adenocarcinomas were typically CK7-/CK20+/MUC2+/CDX2+, although with some overlap in immunophenotype. Additionally, PAX8 was positive in a subset of MOC and negative in all appendiceal carcinomas. CONCLUSION: Prior appendectomy is not protective against development of malignant or borderline MON. Routine appendectomy during surgery for MON seldom reveals an unsuspected GI primary in early stage tumors but may aid in final diagnosis in advanced stage cases. FUNDING: National Cancer Institute grants P50-CA105009 and R21 CA-156021; The Honorable Tina Brozman 'Tina's Wish' Foundation; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF); Dana-Farber Cancer Institute - Susan Smith Center for Women's Cancers; Robert and Deborah First Fund; The Gamel Family Fund; Mary Kay Foundation; Sandy Rollman Ovarian Cancer Foundation; Arthur Sachs/Fulbright/Harvard; La Fondation Philippe; La Fondation de France. PMID- 24342439 TI - Is there a role for postoperative treatment in patients with stage Ib2-IIb cervical cancer treated with neo-adjuvant chemotherapy and radical surgery? An Italian multicenter retrospective study. AB - PURPOSE: Neoadjuvant chemotherapy [NACT] followed by radical hysterectomy is an alternative therapeutic option to concurrent chemotherapy-radiotherapy for locally advanced cervical cancer. However there are very few data about the effectiveness of any post-operative treatment in this clinical setting. The purpose of this study was to correlate the patterns of recurrence and the clinical outcomes of cervical cancer patients who received NACT, with postoperative adjuvant treatment. PATIENTS AND METHODS: This retrospective multicenter study included 333 patients with FIGO stage Ib2-IIb cervical cancer who underwent platinum-based NACT followed by radical surgery. Pathological responses were retrospectively assessed as complete; optimal partial; and suboptimal response. Overall optimal response rate was the sum of complete and optimal partial response rates. RESULTS: On the whole series, recurrence-free survival was significantly longer in patients who achieved an overall optimal response than in those who did not (p<0.0001), and in patients who received adjuvant chemotherapy compared to those who did not (p=0.0001). On multivariate analysis, consolidation therapy (p=0.0012) was the only independent prognostic variable for recurrence-free survival; whereas FIGO stage (p=0.0169) and consolidation therapy (p=0.0016) were independent prognostic variables for overall survival. CONCLUSION: Optimal responders after chemo-surgical treatment for FIGO stage Ib2-IIb cervical cancer do not need any further treatment. Additional cycles of chemotherapy could be of benefit for patients with suboptimal response and intra-cervical residual disease. Both adjuvant chemotherapy and adjuvant radiation treatments do not seem to improve the clinical outcome of patients with extra-cervical residual disease compared to no further treatment. PMID- 24342440 TI - Ventral midbrain neural stem cells have delayed neurogenic potential in vitro. AB - Neural stem cells (NSCs) have been the focus of an intensive effort to direct their differentiation in vitro towards desired neuronal phenotypes for cell replacement therapies. It is thought that NSCs derived from older embryos have limited neurogenic capacity and are restricted towards an astroglial fate. This idea is largely based on studies that typically analysed NSC-derived progeny following one week of in vitro differentiation. In this report, the neurogenic capacity of older ventral midbrain (VM) NSCs was assessed. When the older NSCs were differentiated for three weeks, there were significant increases in the numbers of newly born neurons at 14 and 21 days, as assessed by 5-bromo-2' deoxyuridine (BrdU) incorporation. Therefore this study demonstrates that older NSCs retain significantly more neurogenic potential than was previously thought. These data have implications for NSC preparatory protocols and the choice of donor age for cell transplantation studies, and contributes to the understanding of NSC behaviour in vitro. PMID- 24342441 TI - Modification of cell volume and proliferative capacity of Pseudokirchneriella subcapitata cells exposed to metal stress. AB - The impact of metals (Cd, Cr, Cu and Zn) on growth, cell volume and cell division of the freshwater alga Pseudokirchneriella subcapitata exposed over a period of 72 h was investigated. The algal cells were exposed to three nominal concentrations of each metal: low (closed to 72 h-EC10 values), intermediate (closed to 72 h-EC50 values) and high (upper than 72 h-EC90 values). The exposure to low metal concentrations resulted in a decrease of cell volume. On the contrary, for the highest metal concentrations an increase of cell volume was observed; this effect was particularly notorious for Cd and less pronounced for Zn. Two behaviours were found when algal cells were exposed to intermediate concentrations of metals: Cu(II) and Cr(VI) induced a reduction of cell volume, while Cd(II) and Zn(II) provoked an opposite effect. The simultaneous nucleus staining and cell image analysis, allowed distinguishing three phases in P. subcapitata cell cycle: growth of mother cell; cell division, which includes two divisions of the nucleus; and, release of four autospores. The exposure of P. subcapitata cells to the highest metal concentrations resulted in the arrest of cell growth before the first nucleus division [for Cr(VI) and Cu(II)] or after the second nucleus division but before the cytokinesis (release of autospores) when exposed to Cd(II). The different impact of metals on algal cell volume and cell-cycle progression, suggests that different toxicity mechanisms underlie the action of different metals studied. The simultaneous nucleus staining and cell image analysis, used in the present work, can be a useful tool in the analysis of the toxicity of the pollutants, in P. subcapitata, and help in the elucidation of their different modes of action. PMID- 24342443 TI - Endovascular treatment of penetrating ulcers of the paraceliac aorta using fenestrated endografts. AB - Penetrating atherosclerotic ulcers (PAUs) are usually focal aortic lesions found in patients with significant comorbidities. They are ideal targets for an endovascular approach if localized in the descending thoracic or infrarenal aorta, but when an origin in the visceral vessels is involved, a standard endovascular approach might not be feasible or effective. We report 2 cases of endovascular treatment of PAUs involving the paraceliac abdominal aorta, using a custom-made tube fenestrated endograft with 4 fenestrations for the abdominal visceral vessels (i.e., celiac-trunk, superior mesenteric artery, and renal arteries). There were no intra- or perioperative complications. At 1 year of follow-up, patients were asymptomatic and computed tomography angiography revealed total lesion exclusion and patency of the visceral vessels. The use of a fenestrated endograft is a safe and effective option to treat paraceliac PAUs. PMID- 24342444 TI - A novel finding: the effect of nurse practitioners on the relation to quality of life, anxiety, and depressive symptoms in vascular surgery. AB - BACKGROUND: An increasing number of vascular surgery units expand their team with nurse practitioners (NPs) to optimize patient care. There are no previously performed studies which assessed the influence of NPs on patients' quality of life (QoL), anxiety, and depressive symptom levels. The transition in care from surgeon to NP in the vascular surgery unit of our hospital facilitated the comparison of both groups. METHODS: A prospective study was undertaken to analyze the effect of NPs on QoL, anxiety, and depressive symptom scores. Two groups were analyzed: a group of patients treated by a vascular surgeon alone (surgeon group) and a group of patients treated by a NP supervised by a vascular surgeon (NP group). Patients completed the short version of the World Health Organization Quality of Life Assessment (WHOQOL-BREF), the State-Trait Anxiety Inventory (STAI), and the Center for Epidemiologic Studies Depression Scale (CES-D) questionnaires both before and after intervention. RESULTS: Two hundred fourteen patients were included in our study. Within groups, there was a significant increase in physical QoL, with 5.2 points in the surgeon group and 4.4 points in the NP group. There was a significant decrease in anxiety scores (-3.8 points in the surgeon group and -5.4 points in the NP group). No differences were found for depressive symptoms. Between groups, no differences were found. CONCLUSIONS: The same improvements were found for QoL and anxiety scores in both groups. Vascular NPs are therefore competent to explain procedures and guide patients through vascular interventions. PMID- 24342445 TI - Management of postbiopsy arteriovenous fistulas in transplanted kidneys and effectiveness of endovascular treatment: a single-center experience. AB - BACKGROUND: We sought to evaluate the best therapeutic management of postbiopsy arteriovenous fistulas (AVFs) in transplanted kidneys. METHODS: Between January 2005 and December 2011, we observed 17 cases of postbiopsy AVF in transplanted kidneys (9 asymptomatic; 8 symptomatic). Asymptomatic cases were managed conservatively, while patients with symptomatic AVF underwent endovascular treatment. We used a technique that consisted in a superselective transcatheter embolization of the afferent branch. We evaluated the technical success (postoperative closure of AVF), the immediate clinical efficacy (cessation of symptoms), and clinical efficacy at follow-up (measurement of serum creatinine at 7 days and 6 and 12 months compared with preoperative levels using t-tests). RESULTS: Asymptomatic AVFs resolved spontaneously, while the endovascular treatment in symptomatic AVFs showed a complete technical and clinical success with prompt remission of the presented symptoms. We observed a statistically significant reduction in serum creatinine at 7 days and 6 and 12 months postoperatively (mean creatinine--preoperative: 3.23 +/- 1.4 mg/dL; 7 days: 2.25 +/- 0.8 mg/dL; 6 months: 1.65 +/- 0.28 mg/dL; 12 months: 1.4 +/- 0.26 mg/dL; in all cases P < 0.05). CONCLUSIONS: In our experience, asymptomatic AVFs could be managed conservatively with close follow-up while the endovascular treatment for symptomatic AVFs is both safe and effective in the short- and long-term. PMID- 24342446 TI - A novel hybrid approach using antegrade visceral debranching from both axillary arteries for thoracoabdominal aneurysm repair. AB - Hybrid aortic surgery combining visceral debranching and stent grafting is an alternative to conventional open surgery and branched stent grafting for thoracoabdominal aneurysm repair. Visceral aortic branch bypasses are usually performed from the iliac arteries or the infrarenal or ascending aorta. Herein, we describe a new debranching technique to treat a painful Crawford type III thoracoabdominal aneurysm in a high-risk patient who was deemed unsuitable for open, endovascular, or traditional hybrid repair. The superior mesenteric artery and the right renal arteries were exposed via a right retroperitoneal approach and revascularized from the right axillary artery. Splenic and left renal arteries were exposed via a left retroperitoneal approach and revascularized from the left axillary artery. PMID- 24342447 TI - Predictors of improved quality of life and claudication in patients undergoing spinal cord stimulation for critical lower limb ischemia. AB - BACKGROUND: The aim of this study was to determine predictors of improved quality of life and claudication in patients undergoing spinal cord stimulation (SCS) for critical lower limb ischemia. METHODS: We retrospectively analyzed 101 consecutive patients with few meter claudication and nonhealing ulcer who underwent definitive SCS. These patients were selected among 274 SCS patients treated at our center from 1995 to 2012. All presented with non-reconstructable critical leg ischemia (NR-CLI) and underwent supervised exercise therapy, best medical care and regular ulcers standard or advanced medications for at least 1 month before SCS implantation. We measured self-perceived quality of life using the SF-36 questionnaire. Patients with an improved walking distance of at least 30 meters after SCS had significant improvement on SF-36 questionnaire scores. We considered 30 meters as the cut-off for clinically significant improvement in pain-free walking distance, and we defined this value as functional success. Logistic regression was applied to assess baseline and other patient variables as possible predictors of functional success. RESULTS: Neither perioperative mortality nor significant complications were found. At a median follow-up of 69 months (range 1-202 months), mortality, major amputation, and minor amputation were 8.9%, 5.9%, and 6.9%, respectively. Functional clinical success was reported in 25.7% of cases. Independent predictors of functional success at univariate analysis included delay between the onset of the ulcer and SCS (P < 0.001) and the pain-free walking distance before SCS (P < 0.002). The only predictive factor of functional success at multivariate analysis was the delay between the onset of ulcer and SCS (median delay in patients with and without functional success was 3 and 15 months, respectively). In particular, comparable to pain-free walking distance before SCS, the success rate decreased by 40% for each month elapsed from onset of ulcer to SCS. CONCLUSIONS: In our series of patients who underwent SCS, reduced delay between the onset of ulcer and SCS was associated with improved quality of life and walking distance. Larger series are required to confirm these data and to assess clinical implications. PMID- 24342448 TI - Subunit-specific trafficking mechanisms regulating the synaptic expression of Ca(2+)-permeable AMPA receptors. AB - AMPA receptors are the main excitatory neurotransmitter receptor in the brain, and hence regulating the number or properties of synaptic AMPA receptors brings about critical changes in synaptic transmission. Synaptic plasticity is thought to underlie learning and memory, and can be brought about by decreasing or increasing the number of AMPA receptors localised to synaptic sites by precisely regulating AMPA receptor trafficking. AMPA receptors are tetrameric assemblies of subunits GluA1-4, and the vast majority are GluA1/2 and GluA2/3 heteromers. The inclusion of GluA2 subunit is critical because it renders the AMPA receptor channel impermeable to Ca(2+) ions. The vast majority of synaptic AMPA receptors in the brain contain GluA2, but relatively recent discoveries indicate that an increasing number of specific forms of synaptic plasticity involve not only an alteration of the number of synaptic AMPA receptors, but also changes to their GluA2 content. The resulting change in AMPA receptor Ca(2+) permeability clearly has profound consequences for synaptic transmission and intracellular signalling events. The subunit-specific trafficking mechanisms that cause such changes represent an emerging field of research with implications for an increasing number of physiological or pathological situations, and are the topic of this review. PMID- 24342449 TI - Are online support groups always beneficial? A qualitative exploration of the empowering and disempowering processes of participation within HIV/AIDS-related online support groups. AB - BACKGROUND: Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) is one of the leading concerns in healthcare. Individuals living with HIV/AIDS are often confronted with tremendous physical and psychosocial challenges. Online support groups can provide a valuable source of information, advice and support, and a medium through which individuals living with HIV/AIDS can interact with each other and share their experiences. However, very little is known about how online support group might promote empowerment and the potential disadvantages associated with online support group use among individuals living with HIV/AIDS. OBJECTIVES: The present study explored the potential empowering and disempowering processes, and empowering outcomes of online support group use among individuals with HIV/AIDS. DESIGN, SETTINGS, PARTICIPANTS: A total of 115 HIV-positive online support group members were recruited from HIV-related online support groups. They completed an online survey exploring their experiences of online support group use. RESULTS: Thematic analysis revealed six empowering processes arising from use of online support groups: exchanging information, sharing experiences, connecting to others, encountering emotional support, finding recognition and understanding, and helping others. Six empowering outcomes were identified: increased optimism, emotional well-being, social well being, being better informed, improved disease management, and feeling confident in the relationship with physicians. Potentially disempowering processes were also identified which included: being unable to connect physically, inappropriate behaviour online, declining real life relationships, and information overload and misinformation. CONCLUSION: Findings suggest ways through which individuals with HIV/AIDS may be empowered although some problematic features specific to the online context may also be present. PMID- 24342450 TI - Sensory loss and walking speed related factors for gait alterations in patients with peripheral neuropathy. AB - BACKGROUND: Walking instability and a higher risk of falls are common in patients with peripheral neuropathy. However, it remains uncertain as to whether alterations in neuropathic gait are directly related to deficient sensory locomotion control or due to a slowing of walking speed. By means of a multi speed gait assessment we determined factors related to sensory loss and walking speed that cause changes in the gait pattern of neuropathic patients. METHODS: Walking patterns of 18 neuropathic patients (70.7+/-2.4 years, 6 females) and 18 age- and gender-matched healthy subjects (70.4+/-2.4 years, 6 females) were recorded on a pressure-sensitive gait carpet for three different locomotion speeds (i.e. slow, preferred and fast) and while walking with eyes closed. Mean temporospatial gait parameters and gait variability were analyzed. The relationship between gait alterations and the history of falls in patients was evaluated. RESULTS: Alterations in the mean locomotion pattern of neuropathic patients were mainly related to reduced walking speed. However, prolonged double support times (p<0.001), widened base widths (p=0.001) and increased gait variability (p<0.001) during slow walking or with eyes closed appeared to be directly linked to peripheral sensory loss in patients. Increased gait variability was predictive for the presence of self-reported falls in the past (p=0.029). CONCLUSIONS: Sensory-loss-related prolongation of double support phases in neuropathic patients suggests a compensatory strategy to improve restabilization during locomotion. Moreover, widened base widths and increased gait variability point to an increased risk of falls. They occur primarily when patients are forced to reduce their walking speed or when visual feedback is disturbed. PMID- 24342451 TI - First joint record of Mesopithecus and cf. Macaca in the Miocene of Europe. AB - Cercopithecid fossil remains from the post-evaporitic Messinian (5.40-5.33 Ma, MN13, latest Turolian, latest Miocene) locality of Moncucco Torinese (Tertiary Piedmont Basin, NW Italy) are described. A talus is assigned to the fossil colobine Mesopithecus pentelicus, while a proximal fragment of ulna and a male lower canine are attributed to cf. Me. pentelicus. An isolated I(2) and M3 are assigned to the papionin cf. Macaca sp., and two cercopithecid phalanges are left unassigned even to the subfamily level. The record of Mesopithecus at Moncucco Torinese agrees well with the previously-known range of this species in Italy and elsewhere in Europe, whereas that of cf. Macaca constitutes only the second occurrence of macaques in the Miocene of Eurasia. Although the co-occurrence of these two genera in a single locality had been previously reported in the Pliocene, this is the first instance in which macaques are associated with the Late Miocene M. pentelicus instead of Mesopithecus monspessulanus. The record of cf. Macaca and Mesopithecus-and especially the latter's talar morphology, similar to that of extant arboreal colobines-fits well with paleoenvironmental reconstructions of Moncucco Torinese based on the associated fauna, which indicate a humid and densely-forested environment, probably with more open and drier habitats nearby. From a paleobiogeographic viewpoint, the record of Macaca at Moncucco Torinese, together with the previously reported occurrence at Almenara-Casablanca M (Spain), supports the contention that macaques dispersed from Africa into Europe during the latest Miocene (ca. 5.9-5.3 Ma) at the same time as the sea level drop associated with the Messinian Salinity Crisis. PMID- 24342452 TI - Modifying a shrug exercise can facilitate the upward rotator muscles of the scapula. AB - BACKGROUND: Scapular dyskinesis, characterised by drooping scapulae and reduced upward rotation, has been implicated in the presentation of a number of shoulder disorders. Traditionally, in shoulder rehabilitation programmes, the shrug exercise has been prescribed to facilitate upward rotation of the scapula by strengthening the upper trapezius muscle. The aim of this research was to compare muscle activation levels during the standard shrug and the upward rotation shrug in a normal and pathological population. METHODS: Surface electrodes recorded electromyographical activity from upper trapezius, middle trapezius, lower trapezius and serratus anterior muscles in 23 normal participants and 14 participants with multi-directional shoulder instability. Participants completed 10 trials of the standard shrug exercise at 0 degrees of shoulder abduction and the upward rotation shrug exercise at 30 degrees of shoulder abduction in the coronal plane. Muscle activity was expressed as a percentage of maximum voluntary isometric contraction. FINDINGS: The four muscles tested performed at a higher intensity during the modified shrug than the standard shrug. Upper trapezius and lower trapezius activity was significantly greater (P < 0.05) in both populations. Though for middle trapezius and serratus anterior muscles, the modified shrug was statistically significant only in the normal population, P = 0.031 and P = <0.001 respectively. INTERPRETATION: The upward rotation shrug is a more effective exercise for eliciting muscle activity of the upper and lower trapezius than the standard shrug in a normal and multi-directional instability population. Clinically, the upward rotation shrug might be useful to address scapular dyskinesis involving drooping shoulders and reduced scapula upward rotation. PMID- 24342453 TI - Quadriceps force during knee extension in different replacement scenarios with a modular partial prosthesis. AB - BACKGROUND: Previous biomechanical studies have shown that bi-cruciate retaining knee replacement does not significantly alter normal knee kinematics, however, there are no data on the influence of a combined medial and patellofemoral bi compartimental arthroplasty. The purpose of this in vitro study was to evaluate the effect of different replacement scenarios with a modular partial knee replacement system on the amount of quadriceps force required to extend the knee during an isokinetic extension cycle. METHODS: Ten human knee specimens were tested in a kinematic knee simulator under (1) physiologic condition and after subsequent implantation of (2) a medial unicondylar and (3) a trochlear replacement. An isokinetic extension cycle of the knee with a constant extension moment of 31 Nm was simulated. The resulting quadriceps extension force was measured from 120 degrees to full knee extension. FINDINGS: The quadriceps force curve described a typically sinusoidal characteristic before and after each replacement scenario. The isolated medial replacement resulted in a slightly, but significantly higher maximum quadriceps force (1510 N vs. 1585 N, P = 0.006) as well as the subsequent trochlear replacement showed an additional increase (1801 N, P = 0.008). However, for both replacements no significant difference to the untreated condition could be detected in mid-flexion (10-50 degrees ). INTERPRETATION: When considering a bi-compartimental replacement an increase of required maximum quadriceps force needed to extend the knee has to keep in mind. However, the close to physiological movement in mid-flexion suggests that patients with a bi-crutiate retaining arthroplasty might have an advantage in knee stability compared to total knee arthroplasty. PMID- 24342454 TI - Maintenance of longitudinal foot arch after different mid/hind-foot arthrodesis procedures in a cadaveric model. AB - BACKGROUND: Currently, the optimal treatment of flatfoot remains inconclusive. Our objectives were to understand the effect of different arthrodeses on maintenance of foot arch and provide experimental basis for rational selection in treatment of flatfoot. METHODS: Sixteen fresh-frozen cadaver feet amputated above the ankle along with a section of leg were studied from ten males and six females. We used standard clinical techniques and hardware for making the arthrodeses. Plantar pressure in the medial and lateral longitudinal arch distribution was measured with a plantar pressure mapping system under different loading conditions. FINDINGS: Values of plantar pressure reaction, mean and maximum dynamic peak pressure between all group pairs were statistically significant (P<0.05). The plantar pressure reaction appeared at the load of 960 N in the medial arch of the unoperated foot, compared with 1080 N after subtalar arthrodesis, 1200 N after talonavicular arthrodesis, 1080 N after calcaneocuboid arthrodesis, 1320 N after double arthrodesis, and 1560 N after triple arthrodesis. The plantar pressure reaction appeared at the load of 360 N in the lateral arch of the unoperated foot, compared with 600 N after subtalar arthrodesis, 600 N after talonavicular arthrodesis, 840 N after calcaneocuboid arthrodesis, 960 N after double arthrodesis, and 1440 N after triple arthrodesis. INTERPRETATION: The triple arthrodesis provided the highest support to both arches; the double arthrodesis appeared to be similar to talonavicular arthrodesis in supporting the medial arch and similar to calcaneocuboid arthrodesis in supporting the lateral arch; subtalar arthrodesis was less effective in supporting both arches. PMID- 24342455 TI - Impact of foot progression angle on the distribution of plantar pressure in normal children. AB - BACKGROUND: Plantar pressure distribution during walking is affected by several gait factors, most especially the foot progression angle which has been studied in children with neuromuscular diseases. However, this relationship in normal children has only been reported in limited studies. The purpose of this study is to clarify the correlation between foot progression angle and plantar pressure distribution in normal children, as well as the impacts of age and sex on this correlation. METHODS: This study retrospectively reviewed dynamic pedobarographic data that were included in the gait laboratory database of our institution. In total, 77 normally developed children aged 5-16 years who were treated between 2004 and 2009 were included. Each child's footprint was divided into 5 segments: lateral forefoot, medial forefoot, lateral midfoot, medial midfoot, and heel. The percentages of impulse exerted at the medial foot, forefoot, midfoot, and heel were calculated. FINDINGS: The average foot progression angle was 5.03 degrees toe-out. Most of the total impulse was exerted on the forefoot (52.0%). Toe-out gait was positively correlated with high medial (r = 0.274; P < 0.001) and forefoot impulses (r = 0.158; P = 0.012) but negatively correlated with midfoot impulse (r = -0.273; P<0.001). The moderating effects of age and sex on these correlations were insignificant. INTERPRETATION: Foot progression angle demonstrates significant impact on the distribution of foot pressure, regardless of age or sex. Foot progression angle should be taken into consideration when conducting pedobarographic examinations and balancing plantar pressure as part of the treatment of various foot pathologies. PMID- 24342456 TI - Whole breast radiotherapy in the lateral decubitus position: a dosimetric and clinical solution to decrease the doses to the organs at risk (OAR). AB - PURPOSE: To evaluate whole breast 3D-conformal radiotherapy (RT) delivered in the lateral decubitus position (isocentric lateral decubitus [ILD]) and to report the acute toxicity of a series of consecutive patients treated with ILD. MATERIALS AND METHODS: From January to December 2010, 56 consecutive patients with large breasts and early-stage breast cancer treated by breast conserving surgery underwent 3D-conformal whole breast RT in the lateral decubitus position. A dose of 50 Gy in 25 fractions via two opposed isocentric beams was prescribed to whole breast, with or without a 16 Gy photon tumor bed boost. Dosimetry of all patients was reviewed, and the acute toxicity of treatment, evaluated weekly using the NCI CTC v3.0 scale, was analyzed. RESULTS: Median age was 57 years (range: 33-71). 85% of patients had a breast circumference of at least 95 cm and 80% had at least a C cup size. Average breast volume was 991 cm(3) (range: 225-2791 cm(3)). Median dose to the breast was 50 Gy, while median dose to the tumor bed was 16 Gy. Grade 1, 2 and 3 dermatitis developed in 37.5%, 58.9% and 1.8% of patients, respectively. From a dosimetric point of view, doses to the ipsilateral lung were extremely low: average V(1Gy), V(2Gy) and V(5Gy) were 26.6%, 9.3% and 0.7%, respectively. Average mean lung dose was 0.96 Gy. For the 26 patients with left sided tumors, heart doses were also extremely low: average V(1Gy), V(2Gy) and V(5Gy) were 58.8%, 14.2% and 0.7%, respectively. Average mean heart dose was 1.35 Gy. CONCLUSION: Whole breast radiotherapy in the lateral decubitus position for patients with large breasts and early-stage breast cancer provides an excellent dosimetric profile, with low doses to the heart and ipsilateral lung. It is also very well tolerated, with a good acute toxicity profile. PMID- 24342457 TI - Characteristics of smokers with type 2 diabetes. AB - AIM: The purpose of this secondary analysis was to identify the characteristics of smokers with type 2 diabetes, enrolled in a smoking cessation program. BACKGROUND: The health consequences of smoking are particularly severe for individuals with diabetes who smoke. METHODS: The characteristics of 227 smokers with type 2 diabetes were analyzed to determine which traits were more likely to be associated with quit success. RESULTS: Results of the data analysis indicate that smokers with type 2 diabetes were more likely to be abstinent 30 days and 6 months after the quit date if they attended a majority of the program classes and support groups; and used cessation medications. Expressing concerns about the expense of cigarettes was also associated with quit success at 6 months. CONCLUSIONS: Although studies have examined compliance with other diabetes care recommendations, few have evaluated the characteristics of individuals with diabetes who smoke. PMID- 24342458 TI - The effect of gradual increment in rhG-CSF dose on stem cell yields in patients with multiple myeloma mobilized with intermediate dose cyclophosphamide plus rhG CSF. AB - Cyclophosphamide along with recombinant human granulocyte-colony stimulating factor (rhG-CSF) is a commonly used strategy for mobilization. However, the optimal timing for rhG-CSF initiation after cyclophosphamide has not been determined as conclusively as has the G-CSF dose. In this paper, we aimed to present gradual dose increment of rhG-CSF between the third day of mobilization and time to apheresis that is started with 5 MUg/kg (from day 3 to day 7) and continued with 10 MUg/kg (from day 8 to time to apheresis) for peripheral blood stem cell (PBSC) mobilization in multiple myeloma (MM) patients and its effect on stem cell yield and mobilization success. Data from 30 consecutive patients with MM who underwent PBSC mobilization between October 2011 and June 2013, were retrospectively reviewed. While twenty-eight of 30 patients (93.3%) were successfully mobilized, 2 patients (6.7%) had mobilization failure. The final median CD34+ cell dose harvested from the patients was 9.5*10(6)/kg. The median number of apheresis was 2.5 (range, 0-3). Twenty-four patients (80%) yielded >2*10(6) CD34+ cells/kg in one apheresis procedure. In conclusion, our regimen might be used to decrease the mobilization failure regarding the low dose rhG-CSF use and provide a cost effective strategy. PMID- 24342459 TI - Berberine rescues D-galactose-induced synaptic/memory impairment by regulating the levels of Arc. AB - Synaptic communication forms the basis of learning and memory. Disruptions of synaptic function and memory have been widely reported in many neurological diseases, such as dementia. Thus, restoration of impaired synaptic communication is a potential therapeutic approach for these diseases. In this study, we demonstrated that supplementation with berberine, a plant alkaloid with a long history of medicinal usage in Chinese medicine, effectively reverses the synaptic deficits induced by D-galactose. We also found that berberine rescued D-galactose induced memory impairment and additionally rescued the mRNA and protein levels of Arc/Arg3.1, an important immediate early gene that is crucial for maintaining normal synaptic plasticity. Our study provides the first piece of evidence supporting the potential use of berberine in the treatment of neural diseases with synaptic/memory impairments. PMID- 24342461 TI - The real reasons for measuring patient reported outcomes. PMID- 24342460 TI - High-mobility group box 1 and the receptor for advanced glycation end products contribute to lung injury during Staphylococcus aureus pneumonia. AB - INTRODUCTION: Staphylococcus (S.) aureus has emerged as an important cause of necrotizing pneumonia. Lung injury during S. aureus pneumonia may be enhanced by local release of damage associated molecular patterns such as high-mobility group box 1 (HMGB1). In the current study we sought to determine the functional role of HMGB1 and its receptors, toll-like receptor 4 (TLR4) and the receptor for advanced glycation end products (RAGE), in the injurious host response to S. aureus pneumonia. METHODS: Pneumonia was induced in wild type (Wt), TLR4 deficient (tlr4-/-) and RAGE deficient (rage-/-) mice by intranasal inoculation of 1 * 107 colony-forming units (CFU) of a USA300 S. aureus. In a separate set of experiments, Wt mice were injected intraperitoneally with a monoclonal anti-HMGB1 antibody or an isotype matched control antibody immediately before and every 24 hours after intranasal infection of S. aureus. Mice were sacrificed at 6, 24, 48 or 72 hours after infection for harvesting of blood and organs. RESULTS: S. aureus pneumonia was associated with HMGB1 release in the bronchoalveolar compartment peaking after 24 hours. Anti-HMGB1 attenuated lung pathology and protein leak and reduced interleukin-1beta release 6 hours after infection, but not at later time points. RAGE deficiency more modestly attenuated lung pathology without influencing protein leak, while TLR4 deficiency did not impact on lung injury. CONCLUSION: These data suggest that HMGB1 and RAGE, but not TLR4, contribute to lung injury accompanying the early phase of S. aureus pneumonia. PMID- 24342462 TI - Repetitive transcranial magnetic stimulation induced analgesia depends on N methyl-D-aspartate glutamate receptors. AB - We investigated the role of glutamate N-methyl-d-aspartate (NMDA) receptors in the analgesic effects induced by repetitive transcranial magnetic stimulation (rTMS). In a randomized, double-blind, crossover study, we compared the effects of ketamine and placebo on the analgesic effects of motor cortex (M1) or dorsolateral prefrontal cortex/premotor cortex (DLPFC/PMC) stimulation. Three groups of 12 healthy volunteers underwent active rTMS (10Hz, 80% resting motor threshold, 1,500 pulses per session) of the right M1, active stimulation of the right DLPFC/PMC, or sham stimulation during 2 experimental sessions 2 weeks apart. Cold pain thresholds were measured on the left thenar eminence before and 1 hour after cortical stimulation, to evaluate the analgesic effects of rTMS. Ketamine (0.15 mg/kg in a 10-minute bolus followed by continuous infusion of 6 MUg/kg per minute until the end of rTMS) or placebo (saline) were administered intravenously during cortical stimulation. We also systematically measured cortical excitability parameters (resting motor threshold, suprathreshold motor evoked potentials, short intracortical inhibition, and intracortical facilitation) before and after treatment, to investigate the possible relationship between changes in cortical excitability and rTMS-induced analgesia. Ketamine injection significantly decreased the analgesic effects of both M1 and DLPFC/PMC stimulation. The decrease in the analgesic effect of rTMS was not associated with changes in cortical excitability parameters, which were not influenced by rTMS following the administration of either saline or ketamine. Thus, rTMS-induced analgesia depends on glutamate NMDA receptors and may involve long-term potentiation-like mechanisms. PMID- 24342463 TI - Attentional biases in pain: more complex than originally thought? PMID- 24342464 TI - Upregulation of alpha1-adrenoceptors on cutaneous nerve fibres after partial sciatic nerve ligation and in complex regional pain syndrome type II. AB - After peripheral nerve injury, nociceptive afferents acquire an abnormal excitability to adrenergic agents, possibly due to an enhanced expression of alpha1-adrenoceptors (alpha1-ARs) on these nerve fibres. To investigate this in the present study, changes in alpha1-AR expression on nerve fibres in the skin and sciatic nerve trunk were assessed using immunohistochemistry in an animal model of neuropathic pain involving partial ligation of the sciatic nerve. In addition, alpha1-AR expression on nerve fibres was examined in painful and unaffected skin of patients who developed complex regional pain syndrome (CRPS) after a peripheral nerve injury (CRPS type II). Four days after partial ligation of the sciatic nerve, alpha1-AR expression was greater on dermal nerve fibres that survived the injury than on dermal nerve fibres after sham surgery. This heightened alpha1-AR expression was observed on nonpeptidergic nociceptive afferents in the injured sciatic nerve, dermal nerve bundles, and the papillary dermis. Heightened expression of alpha1-AR in dermal nerve bundles after peripheral nerve injury also colocalized with neurofilament 200, a marker of myelinated nerve fibres. In each patient examined, alpha1-AR expression was greater on nerve fibres in skin affected by CRPS than in unaffected skin from the same patient or from pain-free controls. Together, these findings provide compelling evidence for an upregulation of alpha1-ARs on cutaneous nociceptive afferents after peripheral nerve injury. Activation of these receptors by circulating or locally secreted catecholamines might contribute to chronic pain in CRPS type II. PMID- 24342465 TI - Health-related quality of life in 975 patients with complex regional pain syndrome type 1. AB - There are limited data available on health-related quality of life (QoL) in patients with complex regional pain syndrome (CRPS). In the present study we examined QoL in 975 CRPS patients attending 6 different clinics in the Netherlands. QoL was assessed using the MOS 36-Item Short-Form Health Survey (SF 36) with the Mental Health Summary Score (MHS) and the Physical Health Summary Score (PHS) as dependent variables. The influences of gender, type of affected limb, disease duration, pain scores, CRPS severity and set of diagnostic criteria used were investigated. We found the lowest scores of QoL in the physical domains of the SF-36, with lower-limb CRPS patients reporting poorer results than patients with an affected upper limb. Influence of gender on QoL was not observed, and correlations of QoL with disease duration and the CRPS severity score were weak. Pain correlated moderately with QoL. In addition, patients fulfilling stricter diagnostic criteria (ie, the Budapest criteria) had lower QoL scores than patients fulfilling less strict criteria (ie, the Orlando criteria). We conclude that loss of QoL in CRPS patients is due mainly to reduced physical health. A comparison with data available from the literature shows that CRPS patients generally report poorer QoL than patients with other chronic pain conditions, particularly in the physical domains. Pain correlated moderately with QoL and therefore deserves ongoing attention by physicians. Finally, patients meeting the diagnostic Budapest criteria have lower QoL scores than patients meeting the Orlando criteria, highlighting the impact of different sets of criteria on population characteristics. PMID- 24342466 TI - Introducing Pain Classics: a special review series for PAIN(r). PMID- 24342467 TI - Introduction to 2013 Journal of Clinical Virology supplement on HIV testing algorithms. PMID- 24342468 TI - Clinical performance of the Multispot HIV-1/HIV-2 rapid test to correctly differentiate HIV-2 from HIV-1 infection in screening algorithms using third and fourth generation assays and to identify cross reactivity with the HIV-1 Western Blot. AB - BACKGROUND: An accurate and rapid serologic method to differentiate HIV-2 from HIV-1 infection is required since the confirmatory HIV-1 Western Blot (WB) may demonstrate cross-reactivity with HIV-2 antibodies. OBJECTIVES: To evaluate the performance of the Bio-Rad Multispot HIV-1/HIV-2 rapid assay as a supplemental test to correctly identify HIV-2 infection and identify HIV-1 WB cross-reactivity with HIV-2 in clinical samples tested at an academic medical center. STUDY DESIGN: Between August 2008 and July 2012, clinical samples were screened for HIV using either 3rd- or 4th-generation HIV-1/2 antibody or combination antibody and HIV-1 p24 antigen assays, respectively. All repeatedly reactive samples were reflexed for Multispot rapid testing. Multispot HIV-2 and HIV-1 and HIV-2 reactive samples were further tested using an HIV-2 immunoblot assay and HIV-1 or HIV-2 RNA assays when possible. The HIV-1 WB was performed routinely for additional confirmation and to assess for HIV-2 antibody cross-reactivity. RESULTS: Of 46,061 samples screened, 890 (89.6%) of 993 repeatedly reactive samples were also Multispot-reactive: 882 for HIV-1; three for only HIV-2; and five for both HIV-1 and HIV-2. All three HIV-2-only Multispot-positives along with a single dually reactive HIV-1/2 Multispot-positive were also HIV-2 immunoblot-positive; the latter was HIV-1 RNA negative and HIV-2 RNA positive. CONCLUSIONS: The Multispot rapid test performed well as a supplemental test for HIV-1/2 diagnostic testing. Four new HIV-2 infections (0.45%) were identified from among 890 Multispot-reactive tests. The use of HIV-1 WB alone to confirm HIV 1/2 screening assays may underestimate the true prevalence of HIV-2 infection in the United States. PMID- 24342469 TI - Evaluation of supplemental testing with the Multispot HIV-1/HIV-2 Rapid Test and APTIMA HIV-1 RNA Qualitative Assay to resolve specimens with indeterminate or negative HIV-1 Western blots. AB - BACKGROUND: The use of Western blot (WB) as a supplemental test after reactive sensitive initial assays can lead to inconclusive or misclassified HIV test results, delaying diagnosis. OBJECTIVE: To determine the proportion of specimens reactive by immunoassay (IA) but indeterminate or negative by WB that could be resolved by alternative supplemental tests recommended under a new HIV diagnostic testing algorithm. STUDY DESIGN: Remnant HIV diagnostic specimens that were reactive on 3rd generation HIV-1/2 IA and either negative or indeterminate by HIV 1 WB from 11 health departments were tested with the Bio-Rad Multispot HIV-1/HIV 2 Rapid Test (Multispot) and the Gen-Probe APTIMA HIV-1 RNA Qualitative Assay (APTIMA). RESULTS: According to the new testing algorithm, 512 (89.8%) specimens were HIV-negative, 55 (9.6%) were HIV-1 positive (including 19 [3.3%] that were acute HIV-1 and 9 [1.6%] that were positive for HIV-1 by Multispot but APTIMA negative), 2 (0.4%) were HIV-2 positive, and 1 (0.2%) was HIV-positive, type undifferentiated. 47 (21.4%) of the 220 WB-indeterminate and 8 (2.3%) of the 350 WB-negative specimens were HIV-1 positive. CONCLUSION: Applying the new HIV diagnostic algorithm retrospectively to WB-negative and indeterminate specimens, the HIV infection status could be established for nearly all of the specimens. IA reactive HIV-infected persons with WB-negative results had been previously misclassified as uninfected, and HIV diagnosis was delayed for those with WB indeterminate specimens. These findings underscore the limitations of the WB to confirm HIV infection after reactive results from contemporary 3rd or 4th generation IAs that can detect HIV antibodies several weeks sooner than the WB. PMID- 24342470 TI - Comparison of HIV oral fluid and plasma antibody results during early infection in a longitudinal Nigerian cohort. AB - BACKGROUND: Oral fluid (OF) testing is a less-invasive alternative to blood-based testing for HIV. The performance of HIV OF tests has not been extensively evaluated in serially collected paired specimens from seroconverters. OBJECTIVE: To compare paired OF and plasma test performance in a cohort of HIV-1 seroconverters from Nigeria. STUDY DESIGN: Paired plasma and OF specimens from 14 seroconverters collected during 24 months of longitudinal follow up were included in the study. Plasma and OF were tested using Avioq HIV-1 Microelisa System, and first reactivity in plasma and OF specimens was compared. OF specimens reactive by Avioq were subsequently tested by OraSure HIV-1 Western blot. Genetic Systems HIV-1 Western blot was also performed on the corresponding plasma of the first 2 Avioq-OF positive time-points. RESULTS: Of the 14 seroconverters, 5 (35.7%) had concordant results between plasma and OF for all time points tested, whereas 9 (64.3%) showed reactivity on plasma before OF specimens early in infection. The median delay between plasma and OF reactivity was 29 days (range: 0 day-20 months) (p<0.0039); the median overall delay for OF compared to RNA testing was 69.5 days. Delayed antibody response with OF was observed in both males and females regardless of viral load or HIV subtypes. CONCLUSIONS: Results demonstrate decreased sensitivity of OF testing compared to blood-based testing with specimens obtained early after HIV infection. Programs that utilize OF testing in populations with increased risk of incident HIV infection should understand these limitations of OF testing. PMID- 24342471 TI - Relative accuracy of serum, whole blood, and oral fluid HIV tests among Seattle men who have sex with men. AB - BACKGROUND: Point-of-care (POC) rapid HIV tests have sensitivity during the "window period" comparable only to earliest generation EIAs. To date, it is unclear whether any POC test performs significantly better than others. OBJECTIVE: Compare abilities of POC tests to detect early infection in real time. STUDY DESIGN: Men who have sex with men (MSM) were recruited into a prospective, cross-sectional study at two HIV testing sites and a research clinic. Procedures compared four POC tests: one performed on oral fluids and three on fingerstick whole blood specimens. Specimens from participants with negative POC results were tested by EIA and pooled nucleic acid amplification testing (NAAT). McNemar's exact tests compared numbers of HIV-infected participants detected. RESULTS: Between February 2010 and May 2013, 104 men tested HIV-positive during 2479 visits. Eighty-two participants had concordant reactive POC results, 3 participants had concordant non-reactive POC tests but reactive EIAs, and 8 participants had acute infection. Of 12 participants with discordant POC results, OraQuick ADVANCE Rapid HIV-1/2 Antibody Test performed on oral fluids identified fewer infections than OraQuick performed on fingerstick (p = .005), Uni-Gold Recombigen HIV test (p = .01), and determine HIV-1/2 Ag/Ab combo (p = .005). CONCLUSIONS: These data confirm that oral fluid POC testing detects fewer infections than other methods and is best reserved for circumstances precluding fingerstick or venipuncture. Regardless of specimen type, POC tests failed to identify many HIV-infected MSM in Seattle. In populations with high HIV incidence, the currently approved POC antibody tests are inadequate unless supplemented with p24 antigen tests or NAAT. PMID- 24342472 TI - Validation and clinical use of a sensitive HIV-2 viral load assay that uses a whole virus internal control. AB - BACKGROUND: Human immunodeficiency virus type 2 (HIV-2) is distantly related to the more widespread HIV-1. Although HIV-2 infection is rare in the U.S., cases are concentrated in the Northeast. No FDA-approved HIV-2 viral load assays exist. A clinically validated laboratory-developed assay is currently available in the U.S., however it is not currently approved for use on New York State patients. OBJECTIVE: To develop a sensitive viral load assay to quantify HIV-2 RNA in plasma and to validate it for clinical use. METHODS: The real-time RT-PCR assay simultaneously amplifies HIV-2 and a whole virus internal control, added during the lysis step. Two extraction volumes can be used. Results are reported in HIV-2 RNA International Units (IU). RESULTS: The assay has a limit of detection of 7 IU/mL and a lower limit of quantification of 29 IU/mL. The assay detects multiple strains of HIV-2 group A and B and generates reproducible results. Samples exchanged with a comparator laboratory produced similar viral load results, with 74% of positives differing by <0.5 log10 IU/mL. To date, we have tested 52 clinical specimens from 25 individuals. Twenty-eight (54%) specimens had measurable HIV-2 viral loads (range: 1.63-5.14 log10 IU/mL), 10 (19%) were positive but not quantifiable, and 14 were negative. HIV-2 RNA was detected in at least one specimen from 19 of 25 (76%) individuals tested. CONCLUSIONS: We developed a sensitive and accurate HIV-2 viral load assay. Validation data indicate the assay is suitable for clinical use and its availability in New York State will improve clinical monitoring of HIV-2 infected patients. PMID- 24342473 TI - 4th generation HIV screening in Massachusetts: a partnership between laboratory and program. AB - BACKGROUND: The Massachusetts Department of Public Health's (MDPH) Office of HIV/AIDS (OHA) and Hinton State Laboratory Institute (HSLI) have offered HIV screening since 1985. Point-of-care screening and serum collection for laboratory based testing is conducted at clinic and non-clinic-based sites across Massachusetts as part of an integrated communicable disease screening intervention. OBJECTIVES AND PROJECT DESIGN: MDPH aimed to transition to a 4th generation HIV screening-based algorithm for testing all serum specimens collected at OHA-funded programs and submitted to the HSLI to detect acute HIV infections, detect and differentiate HIV-1 and HIV-2 infections, eliminate indeterminate results, reduce cost and turnaround time, and link newly diagnosed HIV+ individuals to care. The HSLI and OHA created a joint project management team to plan and lead the transition. RESULTS: The laboratory transitioned successfully to a 4th generation screening assay as part of a revised diagnostic algorithm. In the 12 months since implementation, a total of 7984 serum specimens were tested with 258 (3.2%) positive for HIV-1 and one positive for HIV-2. Eight were reported as acute HIV-1 infections. These individuals were linked to medical care and partner services in a timely manner. Turnaround time was reduced and the laboratory realized an overall cost savings of approximately 15%. CONCLUSIONS: The identification of eight acute HIV infections in the first year underscores the importance of using the most sensitive screening tests available. A multi disciplinary program and laboratory team was critical to the success of the transition, and the lessons learned may be useful for other jurisdictions. PMID- 24342474 TI - An anonymous unlinked sero-prevalence survey of HIVHCV in an urban Emergency Department. AB - BACKGROUND: In 2002, the sero-prevalence of human immunodeficiency virus-1 (HIV) in the Emergency Department (ED), University Hospital, Newark, New Jersey was 10.4%. Both HIV and hepatitis C virus (HCV) are transmitted by injection drug use (IDU) or sexual contact. However, the degree of concurrent positive HCV antibody status in HIV-infected ED patients is unknown. OBJECTIVES: In this study we determined the sero-prevalence of HIV and HIVHCV in HIV-positive patients in the ED. STUDY DESIGN: A cross-sectional study using an anonymous sero-prevalence survey was conducted from 7/1/2008 to 8/23/2008. Medical records were reviewed and de-identified; remnant blood specimens were also de-identified and tested for HIV antibody, and if positive, HCV antibody. RESULTS: Of 3488 specimens, 225 (6.5%, 95% CI: 5.7-7.3%) were positive for HIV antibody. Seventy-four patients 74/225 (32.9%, 95% CI: 33.8-46.5%) were unaware of their sero-positivity. Forty percent of HIV positive patients (90/225, 95% CI: 33.8-46.5%) were HCV antibody positive. The highest seroprevalence of HIVHCV antibody was among older patients (>= 45 years), and patients with positive urine toxicology and elevated liver function tests. DISCUSSION: Given the high prevalence of HIV and HIVHCV antibody in the ED, routine testing is important for patients >= 45 years with positive urine toxicology and elevated liver function tests. PMID- 24342475 TI - Costs and outcomes of laboratory diagnostic algorithms for the detection of HIV. AB - BACKGROUND: An alternative HIV testing algorithm, designed to improve the detection of acute and early infections and differentiate between HIV-1 and HIV-2 antibodies, has been developed by the Centers for Disease Control and Prevention and the Association of Public Health Laboratories. While it promises greater sensitivity, it also raises concerns about costs. OBJECTIVE: We sought to compare the most commonly used algorithm which was developed in 1989, a third-generation (3G) immunoassay (IA) and Western blot confirmatory test, to a newer algorithm. The new algorithm includes either a 3G or a fourth-generation (4G) initial IA, followed by confirmatory testing with a HIV-1/HIV-2 differentiation IA and, if needed, a nucleic acid amplification test (NAT). STUDY DESIGN: We conducted an analysis of HIV testing costs from the perspective of the laboratory, and classified costs according to IA testing volume. We developed a decision analytic model, populated with cost data from 17 laboratories and published assay performance data, to compare the cost-effectiveness of the testing algorithms for a cohort of 30,000 specimens with a 1% HIV prevalence and 0.1% acute HIV infection prevalence. RESULTS: Costs were lower in high-volume laboratories regardless of testing algorithm. For specimens confirmed positive for HIV antibody, the alternative algorithm (IA, Multispot) was less costly than the current algorithm (IA, WB); however, there was wide variation in reported testing costs. For our cohort, the alternative algorithm initiated with a 3G IA and 4G IA identified 15 and 25 more HIV infections, respectively, than the 1989 algorithm. In medium-volume laboratories, the 1989 algorithm was more costly and less effective than the alternative algorithm with a 3G IA; in high-volume laboratories, the alternative algorithm with 3G IA costs $162 more per infection detected. The alternative algorithm with 4G instead of 3G incurred an additional cost of $14,400 and $4865 in medium- and high-volume labs, respectively. DISCUSSION: HIV testing costs varied with IA testing volumes. The additional cost of 4G over 3G IA might be justified by the additional cases of HIV detected and transmissions averted due to earlier detection. CONCLUSION: The alternative HIV testing algorithm compares favorably to the 1989 algorithm in terms of cost and effectiveness. PMID- 24342476 TI - Performance of the new HIV-1/2 diagnostic algorithm in Florida's public health testing population: a review of the first five months of utilization. AB - OBJECTIVE: The Centers for Disease Control and Prevention and the Association of Public Health Laboratories have proposed a new HIV-1/2 Diagnostic Algorithm: a fourth-generation HIV-1/2 Ag/Ab immunoassay (IA) followed, when repeatedly reactive, by an HIV-1/HIV-2 antibody differentiation test, and if that is non reactive, HIV-1 nucleic acid amplification testing (NAT). The objective of the study was to evaluate performance of the new algorithm after five months of utilization in our high volume, high HIV-1 seroprevalence public health population. METHODS: Algorithm sensitivity and specificity was evaluated on 51,953 prospective serum or plasma specimens from individuals self-referring for HIV serostatus determination. Specimens were tested on the day of receipt or maintained at 4 degrees C until the next testing opportunity. If the initial HIV 1/2 Ag/Ab IA (Abbott Combo) was nonreactive, a negative lab interpretation report would follow. If the initial IA was reactive, repeat screening in duplicate was immediately performed. Repeatedly reactive specimens were tested with an HIV 1/HIV-2 differentiation assay (Multispot [MS] HIV-1/HIV-2 Rapid Test) on the same or next workday. If the Abbott Combo-MS assays were discordant, HIV-1 NAT (APTIMA((r)) HIV-1 RNA) was performed. In addition to the algorithm performance, we also evaluated the laboratory "specimen receipt to reporting" turnaround time (TAT). RESULTS: The sensitivity and specificity of the new HIV Diagnostic Algorithm with serum and plasma specimens over the initial 5 month period was 100% (922/922) and 99.99% (51,030/51,031), respectively. Two algorithm-defined acute HIV-1 infections (AHI) were detected. In addition only 3 of the 992 MS secondary tests performed were interpreted as HIV-1 Indeterminate (HIV-1 recombinant gp41 reactivity only). Of these, 2 were HIV-1 NAT reactive, defined in-house as an early HIV infection (EHI) and one was HIV-1 NAT nonreactive, indicating a false positive initial screening result. Laboratory TAT for reporting concordant reactive Abbott Combo-MS results in <= 2 workdays was 96%, compared to 22% for reporting concordant reactive 3rd generation IA-Western blot results. CONCLUSIONS: In our public health testing population, results from the new HIV Diagnostic Algorithm exceeded those of the 3rd generation IA-WB algorithm with respect to HIV-1 sensitivity. The identification of two algorithm-defined AHIs provided the opportunity to inform these individuals of their HIV status and link them to medical care earlier than the scheduled posttest counseling appointment. PMID- 24342477 TI - Identification of early HIV infections using the fourth generation Abbott ARCHITECT HIV Ag/Ab Combo chemiluminescent microparticle immunoassay (CIA) in San Diego County. AB - BACKGROUND: HIV screening assays have gone through several generations of development in an effort to narrow the "window period" of detection. Utilizing a fourth generation HIV screening assay has the potential to detect earlier HIV infection, thus reducing HIV-1 transmission. OBJECTIVE: To identify acute infections to decrease HIV transmission in San Diego County. STUDY DESIGN: Serum specimens were collected from clients seen by multiple submitters in San Diego County. All acceptable specimens were screened using the 4th Gen Combo Assay. Initially reactive specimens were repeated in duplicate and if repeatedly reactive, were confirmed by HIV-1 Immunofluorescent Antibody Assay (IFA). IFA negative/inconclusive specimens were sent for HIV-1 NAT and HIV-2 antibody testing to referral laboratories. BioRad Multispot HIV-1/HIV-2 Rapid Test was also performed on a subset of specimens. RESULTS: Of 14,559 specimens received in 20 months, 14,517 specimens were tested. Of the 14,517 specimens that were tested, a total of 279 (1.9%) specimens were CIA repeatedly reactive and 240 of the 279 confirmed by HIV-1 IFA. Thirty-nine gave IFA negative/inconclusive result and 30 were further tested for HIV-1 NAT and 36 for HIV-2 antibody. Thirteen specimens were considered false positives by CIA and 17 specimens were classified as acute infections. Eleven of 39 IFA negative/inconclusive specimens were further tested by Multispot. Five of the 11 were positive by Multispot. CONCLUSION: The fourth generation Abbott ARCHITECT HIV Ag/Ab Combo Assay identified 17 patients who may have been missed by the prior HIV-1 screening assay used at San Diego County Public Health Laboratory. PMID- 24342478 TI - A multicenter performance evaluation of the DPP((r)) HIV-1/2 assay for the detection of HIV antibodies in various HIV testing algorithms. AB - BACKGROUND: Multicenter studies were conducted to evaluate the DPP((r)) HIV 1/2 Assay using oral fluid (OF) and fingerstick (FS) specimens in two different countries at the point of care (POC). OBJECTIVE: To evaluate the DPP((r)) HIV 1/2 Assay using OF and FS specimens when compared to various worldwide algorithms for the detection of HIV. METHODS: At each testing center, each participant was tested using the DPP HIV 1/2 Assay using OF and FS specimens. Each sample was dispersed into a premeasured buffer in a dropper bottle (DPP((r)) SampleTainerTM bottle) and added to the sample well of the device followed by the addition of running buffer to the buffer well of the device. Reference testing was performed according to the National testing algorithm of each Country. RESULTS: Assay sensitivity resulted in ranges of 98.9-100% for OF specimens and 99.8-100% for FS specimens. Assay specificity resulted in ranges of 99.9-100% for OF specimens and 99.5-100% for FS specimens. CONCLUSIONS: Assay sensitivity and specificity obtained for both FS and OF were similar. The DPP HIV 1/2 Assay is highly accurate in detecting antibodies to HIV-1/2 with OF and FS specimens when compared to nationally accepted algorithms. The assay is especially advantageous in that the original sample is collected in a closed vial, eliminating the need for recollection of samples at the POC in the event of an invalid result or assay error upon testing. PMID- 24342479 TI - Evaluation of the accuracy and ease of use of a rapid HIV-1 Antibody Test performed by untrained operators at the point of care. AB - BACKGROUND: For broader utilization of rapid HIV antibody assays in point-of-care (POC) settings, methods should be simple enough to be performed with accuracy by untrained test providers, using only the test manufacturer's written instructions. OBJECTIVE: To demonstrate that the INSTI HIV-1 Antibody Test is simple and accurate enough to be successfully run by untrained operators in a POC setting. STUDY DESIGN: A prospective study was conducted to compare the results of the FDA-cleared, INSTI HIV-1 Antibody Test (INSTI, bioLytical Laboratories Inc., Richmond, BC, Canada) used by untrained operators on finger-stick whole blood to results obtained by trained laboratory professionals using FDA-cleared comparator methods (CM) on matching venous blood. A total of 1388 subjects were recruited into the study in three diverse US POC sites. One central laboratory was used for CM testing. Untrained operators and experienced laboratory professionals also conducted a study on prepared plasma specimens to compare limit of detection (LoD) abilities. RESULTS: Of the 517 HIV positive subjects (34 new positives and 483 known positives) the concordance between INSTI performed by untrained operators and CM performed by trained laboratory professionals was 100% (95% CI=99.3-100%). Concordance for HIV negative results (n=871) was 99.8% (95% CI=99.2-99.9%). There were no significant differences in INSTI limit of detection between untrained operators and laboratory professionals. CONCLUSIONS: Untrained operators with no laboratory background were able to perform and interpret the results of INSTI on finger-stick blood and LoD specimens with a high degree of accuracy by following only the manufacturer's written instructions. PMID- 24342480 TI - Field evaluation of the Abbott ARCHITECT HIV Ag/Ab Combo immunoassay. AB - BACKGROUND: Fourth generation assays for HIV diagnosis are progressively being introduced into routine services, due to their improvement of diagnosis. In spite of this, HIV diagnosis remains a challenge in sub-Saharan Africa, due to false positive reactivity. There is a continuous need for field evaluations and routine validations of fourth generation HIV tests in African populations. OBJECTIVES: Evaluate the performances of the ARCHITECT HIV Ag/Ab kit (Abbott) in a population living in an African setting-Cameroon compared to a population living in a European setting-France. STUDY DESIGN: 645 HIV samples from both France and Cameroon were evaluated. The positive panel (378 samples) included a diverse series of HIV-1 variants (groups M, N, O, and P) as well as HIV-2 samples. Results were compared to original diagnosis done with other 4th generation assays (AxSYM HIV Ag/Ab (Abbott) and Vidas HIV DUO QUICK) (bioMerieux). RESULTS: Sensitivity of the ARCHITECT was 100% in both sites. It diagnosed all variants of the panel with different reactivity profiles following strain diversity. A wider range of reactivity was observed for group O. Specificity was slightly lower (97.6%) in Cameroon than in France (98.6%), probably due to a higher rate of false positive reactivity. ARCHITECT HIV Ag/Ab assay had high performances in clinical sensitivity and specificity and is adapted to the wide genetic diversity of viruses circulating in West Central Africa. CONCLUSION: Our results further highlight the need to evaluate HIV diagnostic tests before introduction into routine diagnostic services both in the North and in the South. PMID- 24342481 TI - Use of the Abbott Architect HIV antigen/antibody assay in a low incidence population. AB - BACKGROUND: With the availability of 4th generation HIV diagnostic tests which are capable of detecting acute infection, Iowa evaluated the 3rd and 4th generation HIV test and compared the performance of these products in a low incidence population. OBJECTIVE: This study was conducted to evaluate the performance of an HIV antigen/antibody combination (4th generation) assay compared to an EIA 3rd generation assay. STUDY DESIGN: Over a 4 month period, 2037 specimens submitted for HIV screening were tested by Bio-Rad GS HIV-1/HIV-2 Plus O EIA and the Abbott Architect i1000SR HIV Ag/Ab Combo. The performance characteristics of sensitivity, specificity, positive predictive value and negative predictive value were determined. RESULTS: Of the 2037 specimens tested, there were 13 (0.64%) true positives detected. None of the positive specimens were from patients in the acute phase of infection. The Abbott antigen/antibody combo assay had a sensitivity, specificity, positive-predictive value and negative predictive value of 100%, 99.85%, 81.25%, and 100% respectively. The Bio Rad EIA assay had a sensitivity, specificity, positive-predictive value and negative predictive value of 100%, 99.80%, 76.47% and 100%, respectively. The EIA had four false positive results which tested negative by the antigen/antibody assay and western blot. CONCLUSION: In a low-incidence state where early infections are less commonly encountered, the EIA assay and the antigen/antibody assay performed with near equivalency. The antigen/antibody assay had one less false positive result. While no patients were detected in the acute stage of infection, the use of the antigen/antibody assay presents the opportunity to detect an infected patient sooner and prevent transmission to others. PMID- 24342482 TI - Performance comparison of the 4th generation Bio-Rad Laboratories GS HIV Combo Ag/Ab EIA on the EVOLISTM automated system versus Abbott ARCHITECT HIV Ag/Ab Combo, Ortho Anti-HIV 1+2 EIA on Vitros ECi and Siemens HIV-1/O/2 enhanced on Advia Centaur. AB - BACKGROUND: A multisite study was conducted to evaluate the performance of the Bio-Rad 4th generation GS HIV Combo Ag/Ab EIA versus Abbott 4th generation ARCHITECT HIV Ag/Ab Combo. The performance of two 3rd generation EIAs, Ortho Diagnostics Anti-HIV 1+2 EIA and Siemens HIV 1/O/2 was also evaluated. OBJECTIVE: Study objective was comparison of analytical HIV-1 p24 antigen detection, sensitivity in HIV-1 seroconversion panels, specificity in blood donors and two HIV false reactive panels. STUDY DESIGN: Analytical sensitivity was evaluated with International HIV-1 p24 antigen standards, the AFFSAPS (pg/mL) and WHO 90/636 (IU/mL) standards; sensitivity in acute infection was compared on 55 seroconversion samples, and specificity was evaluated on 1000 negative blood donors and two false reactive panels. RESULTS: GS HIV Combo Ag/Ab demonstrated better analytical HIV antigen sensitivity compared to ARCHITECT HIV Ag/Ab Combo: 0.41 IU/mL versus 1.2 IU/mL (WHO) and 12.7 pg/mL versus 20.1 pg/mL (AFSSAPS); GS HIV Combo Ag/Ab EIA also demonstrated slightly better specificity compared to ARCHITECT HIV Ag/Ab Combo (100% versus 99.7%). The 4th generation HIV Combo tests detected seroconversion 7-11 days earlier than the 3rd generation HIV antibody only EIAs. CONCLUSION: Both 4th generation immunoassays demonstrated excellent performance in sensitivity, with the reduction of the serological window period (7-11 days earlier detection than the 3rd generation HIV tests). However, GS HIV Combo Ag/Ab demonstrated improved HIV antigen analytical sensitivity and slightly better specificity when compared to ARCHITECT HIV Ag/Ab Combo assay, with higher positive predictive values (PPV) for low prevalence populations. PMID- 24342483 TI - Evaluation of the CDC proposed laboratory HIV testing algorithm among men who have sex with men (MSM) from five US metropolitan statistical areas using specimens collected in 2011. AB - BACKGROUND: Until recently most testing algorithms in the United States (US) utilized Western blot (WB) as the supplemental test. CDC has proposed an algorithm for HIV diagnosis which includes an initial screen with a Combo Antigen/Antibody 4th generation-immunoassay (IA), followed by an HIV-1/2 discriminatory IA of initially reactive-IA specimens. Discordant results in the proposed algorithm are resolved by nucleic acid-amplification testing (NAAT). OBJECTIVES: Evaluate the results obtained with the CDC proposed laboratory-based algorithm using specimens from men who have sex with men (MSM) obtained in five metropolitan statistical areas (MSAs). STUDY DESIGN: Specimens from 992 MSM from five MSAs participating in the CDC's National HIV Behavioral Surveillance System in 2011 were tested at local facilities and CDC. The five MSAs utilized algorithms of various screening assays and specimen types, and WB as the supplemental test. At the CDC, serum/plasma specimens were screened with 4th generation-IA and the Multispot HIV-1/HIV-2 discriminatory assay was used as the supplemental test. NAAT was used to resolve discordant results and to further identify acute HIV infections from all screened-non-reactive missed by the proposed algorithm. Performance of the proposed algorithm was compared to site specific WB-based algorithms. RESULTS: The proposed algorithm detected 254 infections. The WB-based algorithms detected 19 fewer infections; 4 by oral fluid (OF) rapid testing and 15 by WB supplemental testing (12 OF and 3 blood). One acute infection was identified by NAAT from all screened-non-reactive specimens. CONCLUSIONS: The proposed algorithm identified more infections than the WB-based algorithms in a high-risk MSM population. OF testing was associated with most of the discordant results between algorithms. HIV testing with the proposed algorithm can increase diagnosis of infected individuals, including early infections. PMID- 24342484 TI - Comparative evaluation of the Bio-Rad Geenius HIV-1/2 Confirmatory Assay and the Bio-Rad Multispot HIV-1/2 Rapid Test as an alternative differentiation assay for CLSI M53 algorithm-I. AB - INTRODUCTION: The CLSI-M53-A, Criteria for Laboratory Testing and Diagnosis of Human Immunodeficiency Virus (HIV) Infection; Approved Guideline includes an algorithm in which samples that are reactive on a 4th generation EIA screen proceed to a supplemental assay that is able to confirm and differentiate between antibodies to HIV-1 and HIV-2. The recently CE-marked Bio-Rad Geenius HIV-1/2 Confirmatory Assay was evaluated as an alternative to the FDA-approved Bio-Rad Multispot HIV-1/HIV-2 Rapid Test which has been previously validated for use in this new algorithm. METHODS: This study used reference samples submitted to the Canadian - NLHRS and samples from commercial sources. Data was tabulated in 2*2 tables for statistical analysis; sensitivity, specificity, predictive values, kappa and likelihood ratios. RESULTS: The overall performance of the Geenius and Multispot was very high; sensitivity (100%, 100%), specificity (96.3%, 99.1%), positive (45.3, 181) and negative (0, 0) likelihood ratios respectively, high kappa (0.96) and low bias index (0.0068). The ability to differentiate HIV-1 (99.2%, 100%) and HIV-2 (98.1%, 98.1%) Ab was also very high. CONCLUSION: The Bio Rad Geenius HIV-1/2 Confirmatory Assay is a suitable alternative to the validated Multispot for use in the second stage of CLSI M53 algorithm-I. The Geenius has additional features including traceability and sample and cassette barcoding that improve the quality management/assurance of HIV testing. It is anticipated that the CLSI M53 guideline and assays such as the Geenius will reduce the number of indeterminate test results previously associated with the HIV-1 WB and improve the ability to differentiate HIV-2 infections. PMID- 24342485 TI - The Multispot rapid HIV-1/HIV-2 differentiation assay is comparable with the Western blot and an immunofluorescence assay at confirming HIV infection in a prospective study in three regions of the United States. AB - BACKGROUND: A new HIV diagnostic algorithm has been proposed which replaces the use of the HIV-1 Western blot and HIV-1 immunofluorescence assays (IFA) as the supplemental test with an HIV-1/HIV-2 antibody differentiation assay. OBJECTIVES: To compare an FDA-approved HIV-1/HIV-2 antibody differentiation test (Multispot) as a confirmatory test with the HIV-1 Western blot and IFA. STUDY DESIGN: Participants were screened with an HIV-1/HIV-2 combination Antigen/Antibody (Ag/Ab) screening assay. Specimens with repeatedly reactive results were tested with Multispot and either Western blot or IFA. Specimens with discordant screening and confirmatory results were resolved with HIV-1 RNA testing. RESULTS: Individuals (37,876) were screened for HIV infection and 654 (1.7%) had a repeatedly reactive Ag/Ab assay result. On Multispot, 554 (84.7%) were HIV-1 reactive, 0 (0%) were HIV-2 reactive, 1 (0.2%) was reactive for both HIV-1 and HIV-2 (undifferentiated), 9 (1.4%) were HIV-1 indeterminate, and 90 (13.8%) were non-reactive. HIV-1 RNA was detected in 47/90 Multispot non-reactive (52.2%) specimens. Among specimens confirmed to have HIV infection (true positives), Multispot and Western blot detected HIV-1 antibody in a similar proportion of cases (93.7% vs. 94.4% respectively) while Multispot and IFA also detected HIV-1 antibody in a similar proportion of cases (84.5% vs. 83.4% respectively). CONCLUSIONS: In this study, Multispot confirmed HIV infections at a similar proportion to Western blot and IFA. Multispot, Western blot, and IFA, however, did not confirm all of the reactive Ag/Ab assay results and underscores the importance of HIV NAT testing to resolve discordant screening and confirmatory results. PMID- 24342486 TI - Digestive flexibility during fasting in fish: a review. AB - Digestive flexibility is important because it allows an animal to maximize energy and nutrient return from the diet consumed, and also to reduce the maintenance costs associated with one of the body's most expensive systems in terms of energy and protein requirements. Two different patterns of digestive flexibility have been described for vertebrates, one for species in which metabolic costs of homeostasis are relatively high and the gut is rarely empty (e.g., mammals and birds), and one for species in which metabolic costs of homeostasis are relatively low and the gut usually spends long periods of time empty (e.g., amphibians and reptiles). In this review we analyze the information on digestive tract down-regulation during fasting in fish, in order to evaluate the extent to which digestive flexibility in fish conforms to that in other species. We found that: (1) gut size decay during long-term fasting in fish appears to be almost linear with time, even for very long fasting periods. Thus, gut size temporal dynamics in fish during long-term fasting resemble those observed in some mammals species; (2) by contrast, histological changes during fasting in fish are more similar to those described for amphibians and reptiles; and (3) data on enterocyte turnover rates indicate that cell turnover times in fish are relatively short, and although longer than those observed in mammals, they are not very different from those reported for birds. In conclusion, current data suggest that both mechanisms, cell turnover rates and change in epithelial configuration, probably are involved in digestive tract regulation in fish. PMID- 24342487 TI - Spatiotemporal organization of microbial cells by protein concentration gradients. AB - The formation of protein concentration gradients is an effective means to restrict the activity of regulatory factors in space, thereby critically contributing to the spatiotemporal organization of biological systems. Although widely observed for extracellular proteins involved in tissue patterning, the implementation of this regulatory strategy was thought to be impossible in single, micron-sized cells. Recently, however, several intracellular proteins were shown to establish gradient-like distribution patterns, thereby relaying positional information to their downstream targets. In this review, we discuss gradient-forming systems from different microbial species, with an emphasis on their mode of action and the common principles that underlie their function. PMID- 24342488 TI - Renal aquaporins and water balance disorders. AB - BACKGROUND: Aquaporins (AQPs) are a family of proteins that can act as water channels. Regulation of AQPs is critical to osmoregulation and the maintenance of body water homeostasis. Eight AQPs are expressed in the kidney of which five have been shown to play a role in body water balance; AQP1, AQP2, AQP3, AQP4 and AQP7. AQP2 in particular is regulated by vasopressin. SCOPE OF REVIEW: This review summarizes our current knowledge of the underlying mechanisms of various water balance disorders and their treatment strategies. MAJOR CONCLUSIONS: Dysfunctions of AQPs are involved in disorders associated with disturbed water homeostasis. Hyponatremia with increased AQP levels can be caused by diseases with low effective circulating blood volume, such as congestive heart failure, or osmoregulation disorders such as the syndrome of inappropriate secretion of antidiuretic hormone. Treatment consists of fluid restriction, demeclocycline and vasopressin type-2 receptor antagonists. Decreased AQP levels can lead to diabetes insipidus (DI), characterized by polyuria and polydipsia. In central DI, vasopressin production is impaired, while in gestational DI, levels of the vasopressin-degrading enzyme vasopressinase are abnormally increased. Treatment consists of the vasopressin analogue dDAVP. Nephrogenic DI is caused by the inability of the kidney to respond to vasopressin and can be congenital, but is most commonly acquired, usually due to lithium therapy. Treatment consists of sufficient fluid supply, low-solute diet and diuretics. GENERAL SIGNIFICANCE: In recent years, our understanding of the underlying mechanisms of water balance disorders has increased enormously, which has opened up several possible new treatment strategies. This article is part of a Special Issue entitled Aquaporins. PMID- 24342489 TI - Calcium electroporation in three cell lines: a comparison of bleomycin and calcium, calcium compounds, and pulsing conditions. AB - BACKGROUND: Electroporation with calcium (calcium electroporation) can induce ATP depletion-associated cellular death. In the clinical setting, the cytotoxic drug bleomycin is currently used with electroporation (electrochemotherapy) for palliative treatment of tumors. Calcium electroporation offers several advantages over standard treatment options: calcium is inexpensive and may readily be applied without special precautions, as is the case with cytostatic drugs. Therefore, details on the use of calcium electroporation are essential for carrying out clinical trials comparing calcium electroporation and electrochemotherapy. METHODS: The effects of calcium electroporation and bleomycin electroporation (alone or in combination) were compared in three different cell lines (DC-3F, transformed Chinese hamster lung fibroblast; K-562, human leukemia; and murine Lewis Lung Carcinoma). Furthermore, the effects of electrical pulsing parameters and calcium compound on treatment efficacy were determined. RESULTS: Electroporation with either calcium or bleomycin significantly reduced cell survival (p<0.0001), without evidence of a synergistic effect. Cellular death following calcium or bleomycin treatment occurred at similar applied voltages, suggesting that similar parameters should be applied. At equimolar concentrations, calcium chloride and calcium glubionate resulted in comparable decreases in cell viability. CONCLUSIONS: Calcium electroporation and bleomycin electroporation significantly reduce cell survival at similar applied voltage parameters. The effect of calcium electroporation is independent of calcium compound. GENERAL SIGNIFICANCE: This study strongly supports the use of calcium electroporation as a potential cancer therapy and the results may aid in future clinical trials. PMID- 24342491 TI - Occurrence and behavior of illicit drugs and metabolites in sewage water from the Spanish Mediterranean coast (Valencia region). AB - In this work, a study on the occurrence and behavior of illicit drugs and metabolites in sewage water systems has been made. A comprehensive dataset was obtained by analyzing illicit drugs daily in influent and effluent waters from three sewage treatment plants (STPs), over three different weeks. To complete this dataset, monitoring was conducted during an international pop/rock festival, an interesting facet within this study. The STPs selected were sited along the Spanish Mediterranean coast (Castellon province, Valencia region) and represent towns of different sizes, with appreciable variations in the population in the summer period. Illicit drug concentrations in the influents were low, except during the celebration of the music festival, when the levels of cocaine, benzoylecgonine, amphetamine, MDA and MDMA increased. Comparing the influent and effluent concentration data allowed the rough estimation of the removal of illicit drugs and metabolites by each STP. Removal efficiencies were estimated between 75 and 100% for most of the analytes under investigation. The loads discharged into the aquatic ecosystem were also calculated from effluent data. Weekly discharges of drugs and metabolites via effluent sewage waters presented values commonly below 10 g for each individual drug, with the exception of benzoylecgonine, which usually exceeded this level. The increase in population and drug consumption during the music event led to a notable increase in the weekly discharges, reaching values up to 406 g of MDMA and 122 g of benzoylecgonine. PMID- 24342490 TI - Water quality assessment of rivers using diatom metrics across Mediterranean Europe: a methods intercalibration exercise. AB - The European Water Framework Directive establishes a framework for the protection of water resources. However, common water management tools demand common understanding of assessment methods, so quality goals are equally met. Intercalibration of methods ensures the comparability of biological elements across similar geographical areas. Many aspects can influence the outcome of intercalibration: data sampling, treatment methods, taxonomic reliability of databases, choice of metrics for ecological quality status classification, and criteria for selecting reference sites. This study describes the potentials and constraints of the intercalibration of indices using diatoms for assessment of Mediterranean rivers. Harmonisation of diatom taxonomy and nomenclature was based on a previous ring test which took place at the European level. Four diatom indices (Indice de Polluosensibilite Specifique-IPS, Indice Biologique Diatomees IBD 2007, Intercalibration Common Metric Italy-ICMi and Slovenian Ecological Status assessment system) were intercalibrated using data from six European Mediterranean countries (Cyprus, France, Italy, Portugal, Slovenia and Spain). Boundaries between High/Good and Good/Moderate quality classes were harmonised by means of the Intercalibration Common Metric (ICM). Comparability between countries was assured through boundary bias and class agreement. The national boundaries were adjusted when they deviated more than a quarter of a class equivalent (0.25) from the global mean. All national methods correlated well with the ICM, which was sensitive to water quality (negatively correlated to nutrients). Achnanthidium minutissimum sensu lato was the most discriminative species of Good ecological status class. Planothidium frequentissimum, Gomphonema parvulum and Nitzschia palea were the most contributive to Moderate ecological status class. Some taxa were discriminative for both Good and Moderate ecological status classes due to low indication and ecological discriminative power but also due to differences in taxonomy between countries. This intercalibration exercise allowed establishment of common water quality goals across Mediterranean Europe, which is substantiated with the ICM. PMID- 24342492 TI - Toxicity evaluation and source apportionment of Polycyclic Aromatic Hydrocarbons (PAHs) at three stations in Istanbul, Turkey. AB - This paper focuses on the toxicity evaluation and source apportionment of Polycyclic Aromatic Hydrocarbons (PAHs) in three monitoring stations in Istanbul, Turkey. A total of 326 airborne samples were collected and analyzed for 16 PAHs and Total Suspended Particles (TSP) for the period of September 2006-December 2007. The total average PAH concentrations were 100.7+/-61.3, 84.6+/-46.7 and 25.1+/-13.3 ng m(-3) and the TSP concentrations were 101.2+/-53.2, 152.3+/-99.1, 49.8+/-18.6 MUg m(-3) for URB1, URB2 and RUR stations, respectively. Benzo(a)Pyren (BaP) toxic equivalency factors to PAH concentration values were calculated indicating that the health risk of BaP and DiBenz(a,h)Anthracene (markers of traffic emissions) have the highest contribution compared to all of the other species measured at the sampling sites. In order to determine PAH sources, two different source apportionment techniques were applied to the measurements; diagnostic ratios (DR) and Positive Matrix Factorization (PMF). The results of the two applications were compatible indicating the vehicle emissions especially diesel engines - as the major source for urban stations. PMID- 24342493 TI - Effect of EDTA washing of metal polluted garden soils. Part II: Can remediated soil be used as a plant substrate? AB - In a field experiment on metal contaminated and EDTA-remediated soil we studied plant performance, mycorrhizal associations and prospects of potential re-use of remediated soil as a garden substrate. Two experimental plots of 4 * 1 * 0.3 m were filled, one with remediated and the other with original contaminated soil. Selected cultivars were rotated over the course of 16months. Pb, Zn, Cd and micronutrient plant uptake was measured and their phytoaccessibility was analyzed by the DTPA method. Plant fitness was assessed by chlorophyll fluorescence and gas exchange measurements and evaluation of root colonization were analyzed with mycorrhizal fungi. Remediation reduced Pb and Cd concentrations in roots, green parts and fruits in most of the plants. Phytoaccumulation of Zn was reduced in one half of the cultivars. Some plants suffered from Mn deficiency as total soil Mn was reduced 4-fold and phytoaccessibility of micronutrients Cu, Fe and Mn for 54, 26 and 79%, respectively. Plant biomass was reduced. Photosynthetic parameters of plants grown in original and remediated soil were similar, except for the reduction in Spinacia oleracea. The frequency of mycorrhizal colonization in the roots of Pisum sativum was reduced five-fold and no significant changes were found in Allium cepa roots. Remediation reduced plant uptake of Pb below the concentration stipulated by legislation. Measures to reduce plant accumulation of other toxic metals and to revitalize remediated soil are needed. PMID- 24342494 TI - Analysis of the slaughterhouses in Galicia (NW Spain). AB - In the last five years, slaughterhouses in Galicia have been producing more than 350,000 tonnes of carcass per year (Ministry of Environmental and Marine and Rural Media (MARM), 2013). The main environmental problems derived from this economic activity are the high consumption of water, the generation of waste water with a high organic load and the intensive use of energy (electricity and fuel) (European Commission, 2005). In this region of Spain, there are seventy-one slaughterhouses but only 10 to 15% of them have a carcass production capacity exceeding 50 tonnes per day (Casares et al., 2006), consequently needing an environmental permit according to the requirements set by the IPPC (Integrated Pollution Prevention and Control) Directive (European Commission, 2008). The slaughterhouses can be specialized in one livestock type, such as pigs, cattle, sheep, goats or rabbits, or they can be polyvalent. In 2009, the most important meat productions were from porcine, poultry and bovine, as they represented 96% of total production in Spain (AICE, 2011). This paper presents a general view of this important sub-sector (according to the Spanish CNAE, National Classification of Economical Activities) of the food and drinking industry in Galicia. The work considers general information about the activity, an exhaustive description of the industrial process (including preliminary operations, processing, final and auxiliary operations), environmental aspects about consumption and emission levels, and finally a proposal of technique candidates to be BAT (best available techniques) for each process stage. This structure has permitted to obtain an inventory of pollution prevention and control techniques, as well as qualitative data of incomes and outcomes of consumptions and emissions respectively. The methodology, which has already been used in previous works (Barros et al., 2008), has been proved to be appropriate to optimize the process considering environmental factors as well as the pollution prevention and control philosophy. PMID- 24342495 TI - A randomized, controlled, multicenter trial of the effects of antithrombin on disseminated intravascular coagulation in patients with sepsis. AB - INTRODUCTION: To test the hypothesis that the administration of antithrombin concentrate improves disseminated intravascular coagulation (DIC), resulting in recovery from DIC and better outcomes in patients with sepsis, we conducted a prospective, randomized controlled multicenter trial at 13 critical care centers in tertiary care hospitals. METHODS: We enrolled 60 DIC patients with sepsis and antithrombin levels of 50 to 80% in this study. The participating patients were randomly assigned to an antithrombin arm receiving antithrombin at a dose of 30 IU/kg per day for three days or a control arm treated with no intervention. The primary efficacy end point was recovery from DIC on day 3. The analysis was conducted with an intention-to-treat approach. DIC was diagnosed according to the Japanese Association for Acute Medicine (JAAM) scoring system. The systemic inflammatory response syndrome (SIRS) score, platelet count and global markers of coagulation and fibrinolysis were measured on day 0 and day 3. RESULTS: Antithrombin treatment resulted in significantly decreased DIC scores and better recovery rates from DIC compared with those observed in the control group on day 3. The incidence of minor bleeding complications did not increase, and no major bleeding related to antithrombin treatment was observed. The platelet count significantly increased; however, antithrombin did not influence the sequential organ failure assessment (SOFA) score or markers of coagulation and fibrinolysis on day 3. CONCLUSIONS: Moderate doses of antithrombin improve DIC scores, thereby increasing the recovery rate from DIC without any risk of bleeding in DIC patients with sepsis. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN CTR) UMIN000000882. PMID- 24342496 TI - The usefulness of the sum of relative enhancement ratio in making a differential diagnosis of hepatocellular carcinoma from cirrhosis-related nodules. AB - OBJECTIVE: To estimate the diagnostic accuracy of the sum of relative enhancement ratio (sRER) in making a differential diagnosis of hepatocellular carcinoma (HCC) from benign cirrhosis-related nodules. MATERIALS AND METHODS: Eighteen benign cirrhosis-related nodules and 18 HCCs were evaluated. Three radiologists independently reviewed computed tomography images using visual assessment and sRER. sRER was estimated by adding region-of-interest measurement in the arterial phase and the delayed phase. Diagnostic performance and accuracy were evaluated. RESULTS: The mean values of sRER were significantly higher in HCCs than in benign cirrhosis-related nodules. CONCLUSION: The sRER method improved diagnostic accuracy of differentiating HCCs from benign cirrhosis-related nodules. PMID- 24342497 TI - Dynamic contact stress patterns on the tibial plateaus during simulated gait: a novel application of normalized cross correlation. AB - The spatial distribution and pattern of local contact stresses within the knee joint during activities of daily living have not been fully investigated. The objective of this study was to determine if common contact stress patterns exist on the tibial plateaus of human knees during simulated gait. To test this hypothesis, we developed a novel normalized cross-correlation (NCC) algorithm and applied it to the contact stresses on the tibial plateaus of 12 human cadaveric knees subjected to multi-directional loads mimicking gait. The contact stress profiles at different locations on the tibial plateaus were compared, where regions with similar contact stress patterns were identified across specimens. Three consistent regional patterns were found, among them two most prominent contact stress patterns were shared by 9-12 of all the knees and the third pattern was shared by 6-8 knees. The first pattern was located at the posterior aspect of the medial tibial plateau and had a single peak stress that occurred during the early stance phase. The second pattern was located at the central posterior aspects of the lateral plateau and consisted of two peak stresses coincident with the timing of peak axial force at early and late stance. The third pattern was found on the anterior aspect of cartilage-to-cartilage contact region on the medial plateau consisted of double peak stresses. The differences in the location and profile of the contact stress patterns suggest that the medial and lateral menisci function to carry load at different points in the gait cycle: with the posterior aspect of the medial meniscus consistently distributing load only during the early phase of stance, and the posterior aspect of the lateral meniscus consistently distributing load during both the early and late phases of stance. This novel approach can help identify abnormalities in knee contact mechanics and provide a better understanding of the mechanical pathways leading to post-traumatic osteoarthritis. PMID- 24342498 TI - Passive biomechanical properties of human cadaveric levator ani muscle at low strains. AB - The objective of this study was to measure and model the passive biomechanics of cadaveric levator ani muscle in the fiber direction at low strains with a moderately slow deformation rate. Nine levator ani samples, extracted from female cadavers aged 64 to 96 years, underwent preconditioning and uniaxial biomechanical analysis on a tensile testing apparatus after the original width, thickness, and length were measured. The load extension data and measured dimensions were used to calculate stress-strain curves for each sample. The resulting stress-strain curves up to 10% strain were fit to four different constitutive models to determine which model was most appropriate for the data. A power-law model with two parameters was found to fit the data most accurately. Constitutive parameters did not correlate significantly with age in this study; this may be because all of the cadavers were postmenopausal. PMID- 24342499 TI - Can axes conventions of the trunk reference frame influence breast displacement calculation during running? AB - To obtain breast motion relative to the trunk, skin markers are used to define a local coordinate system (trunk), with respect to the global reference frame. This study aimed to quantify any differences in multiplanar breast displacement relative to the trunk using the first axis of rotation as either the mediolateral or longitudinal axis. Ten female participants ran on a treadmill (10 kph) in three different breast supports (no bra, everyday bra, sports bra). Four reflective markers placed on the trunk and right nipple were tracked using eight infrared cameras (200 Hz) during five running gait cycles in each breast support condition. Following marker identification, right breast multiplanar displacements were calculated relative to the trunk using either the mediolateral axis or the longitudinal axis as the first rotational axis to define the orthogonal local coordinate system. Results showed that there was a significant difference (8.2%) in superioinferior breast displacement in the sports bra condition when calculated using different axes conventions for the trunk segment. Furthermore, the greatest magnitude of breast displacement occurred in a different direction depending upon the selection of the first rotational axis. The definition of the primary reference axis of the trunk significantly alters the magnitude of superioinferior breast displacement and therefore it is recommended that the previously reported 'stable' longitudinal axis should be defined as the first rotational axis during running. Caution should also be used as the axes convention influences the magnitude and direction of breast support requirements, which has important implications for bra design. PMID- 24342500 TI - Altered biomechanical strategies and medio-lateral control of the knee represent incomplete recovery of individuals with injury during single leg hop. AB - Anterior cruciate ligament (ACL) injury can result in failure to return to pre injury activity levels and future osteoarthritis predisposition. Single leg hop is used in late rehabilitation to evaluate recovery and inform treatment but biomechanical understanding of this activity is insufficient. This study investigated single leg hop for distance aiming to evaluate if ACL patients had recovered: (1) landing strategies and (2) medio-lateral knee control. We hypothesized that patients with reconstructive surgery (ACLR) would have more similar landing strategies and knee control to healthy controls than patients treated conservatively (ACLD). 16 ACLD and 23 ACLR subjects were compared to 20 healthy controls (CONT). Kinematic and ground reaction force data were collected while subjects hopped their maximum distance. The main output parameters were hop distance, peak knee flexor angles and extensor moments and Fluency (a measure introduced to represent medio-lateral knee control). Statistical differences between ACL and control groups were analyzed using a general linear model univariate analysis, with COM velocity prior to landing as covariate. Hop distance was the smallest for ACLD and largest for CONT (p<0.001; ACLD 57.1+/ 14.1; ACLR 75.1+/-17.8; CONT 77.7+/-14.07% height). ACLR used a similar kinematic strategy to CONT, but had a reduced peak knee extensor moment (p<0.001; ACLD 0.32+/-0.14; ACLR 0.31+/-0.16; CONT 0.42+/-0.13 BW.height). Fluency was reduced in both ACLD and ACLR (p=0.006; ACLD 0.13+/-0.34; ACLR 0.14+/-0.34; CONT 0.17+/ 0.41s). Clinical practice uses hopping distance to evaluate ACL patients' recovery. This study demonstrated that aspects such as movement strategies and knee control need to be evaluated. PMID- 24342501 TI - Good research is essential for service improvement. PMID- 24342502 TI - Effects of vitamin K in postmenopausal women: mini review. AB - Possible benefits of vitamin K on bone health, fracture risk, markers of bone formation and resorption, cardiovascular health, and cancer risk in postmenopausal women have been investigated for over three decades; yet there is no clear evidence-based universal recommendation for its use. Interventional studies showed that vitamin K1 provided significant improvement in undercarboxylated osteocalcin (ucOC) levels in postmenopausal women with normal bone mineral density (BMD); however, there are inconsistent results in women with low BMD. There is no study showing any improvement in bone-alkaline-phosphatase (BAP), n-telopeptide of type-1 collagen (NTX), 25-hydroxy-vitamin D, and urinary markers. Improvement in BMD could not be shown in the majority of the studies; there is no interventional study evaluating the fracture risk. Studies evaluating the isolated effects of menatetrenone (MK-4) showed significant improvement in osteocalcin (OC); however, there are inconsistent results on BAP, NTX, and urinary markers. BMD was found to be significantly increased in the majority of studies. The fracture risk was assessed in three studies, which showed decreased fracture risk to some extent. Although there are proven beneficial effects on some of the bone formation markers, there is not enough evidence-based data to support a role for vitamin K supplementation in osteoporosis prevention among healthy, postmenopausal women receiving vitamin D and calcium supplementation. Interventional studies investigating the isolated role of vitamin K on cardiovascular health are required. Longterm clinical trials are required to evaluate the effect of vitamin K on gynecological cancers. MK-4 seems safe even at doses as high as 45 mg/day. PMID- 24342503 TI - The influence of weather conditions on urolithiasis. PMID- 24342504 TI - Associations of proteinuria and the estimated glomerular filtration rate with incident hypertension in young to middle-aged Japanese males. AB - OBJECTIVE: To investigate the independent associations of proteinuria and the estimated glomerular filtration rate (eGFR) with incident hypertension. METHODS: We investigated 29,181 Japanese males 18-59years old without hypertension in 2000 and examined whether proteinuria and the eGFR predicted incident hypertension independently over 10years. Incident hypertension was defined as a newly detected blood pressure of >=140/90mmHg and/or the initiation of antihypertensive drugs. Proteinuria and the eGFR were categorized as dipstick negative (reference), trace or >=1+ and >=60 (reference), 50-59.9 or <50ml/min/1.73m(2), respectively. Cox proportional hazards models were used to estimate the hazard ratios (HRs) of incident hypertension. RESULTS: At baseline, 236 (0.8%) and 477 (1.6%) participants had trace and >=1+ dipstick proteinuria, while 1416 (4.9%) and 129 (0.4%) participants had an eGFR of 50-59.9 and <50ml/min/1.73m(2), respectively. The adjusted HRs were significant for proteinuria >=1+ (HRs 1.20, 95% CI: 1.06 1.35) and an eGFR of <50ml/min/1.73m(2) (1.29, 1.03-1.61). When two non-referent categories were combined (dipstick>=trace vs. negative and eGFR<60 vs. >=60ml/min/1.73m(2)), the association was more significant for proteinuria (1.15, 1.04-1.27) than for eGFR (0.99, 0.92-1.07). CONCLUSIONS: Proteinuria and a reduced eGFR are independently associated with future hypertension in young to middle-aged Japanese males. PMID- 24342505 TI - Active school travel: an evaluation of the Canadian school travel planning intervention. AB - OBJECTIVE: Active school travel (AST) may provide a significant source of physical activity for children although rates of AST are declining in many countries. The objective of this study was to evaluate the Canadian School Travel Planning (STP) intervention by examining changes in school travel mode and predictors of mode change. METHODS: Schools (n=106) across Canada participated between January 2010 and March 2012. STP committees implemented school-specific strategies to increase active school transport (AST) which included educational strategies, activities and events, capital improvement projects and enforcement initiatives. Travel mode at each school was assessed by a hands-up survey and school travel plans were reviewed for content. RESULTS: Complete data were available for 53 schools. There was no increase in AST at follow-up after one year. There was variation in mode change between schools. Only season of data collection predicted a decrease in AST in the morning (B=-5.36, p<.05). CONCLUSION: This Canadian STP evaluation showed no change in AST after one year. There was evidence of some localized success at nearly half of the participating schools. More robust monitoring and evaluation are needed to examine STP effectiveness. PMID- 24342506 TI - Spatial analysis for identification of priority areas for surveillance and control in a visceral leishmaniasis endemic area in Brazil. AB - Spatial analysis of epidemiological data may be used to assist in the implementation of surveillance and control measures against visceral leishmaniasis (VL) in endemic areas. This ecological study aimed to identify priority areas for surveillance and control of VL in Sao Luis, the capital of the state of Maranhao in northeast Brazil, a highly endemic area for the disease. We evaluated the spatial structure of the incidence rates of human VL and of the mean number of human and canine cases occurring between 2005 and 2007 in 355 neighborhoods (aggregated into 203 geographical analytical units) within the municipality. The presence of spatial autocorrelation was explored using global and local Moran's I statistics. A local indicator of spatial autocorrelation was used to generate maps for the identification of VL clusters. The global Moran's I index revealed a weak, but statistically significant spatial autocorrelation for human VL incidence rates (I=0.138). A total of 43 geographical analytical units, encompassing 121 neighborhoods, were identified as priority areas for implementing surveillance and control actions. For the purpose of defining an action plan for the delivery of these measures, those 16 geographical analytical units (encompassing 54 neighborhoods) identified as clusters with high incidence rates of human VL should receive the highest priority. An additional nine geographical analytical units (comprising 28 neighborhoods) showed non significant clustering of high rates of human, and might be considered as the next priority for VL management. Finally, a further 18 geographical analytical units (covering 39 neighborhoods) had records of coexisting human and canine VL cases during the study period, and these should receive priority attention when resources become available. Spatial data analysis is a valuable tool for defining priority areas for VL surveillance in high transmission areas contributing to a more effective management of financial and technical resources, increasing the sustainability and efficiency of control efforts. PMID- 24342507 TI - Simultaneous detection of green tea catechins and gallic acid in human serum after ingestion of green tea tablets using ion-pair high-performance liquid chromatography with electrochemical detection. AB - We developed an analytical method for the simultaneous determination of tea catechins and gallic acid (GA) in human serum using ion-pair high-performance liquid chromatography (HPLC) with electrochemical detection. GA was measured to estimate the amount of gallate moiety produced by degradation of gallated catechins ((-)-epicatechin-3-gallate, ECG; (-)-epigallocatechin-3-gallate, EGCG). Ethyl gallate was adopted as an internal standard to correct for the extraction efficiency. To maximize extraction efficiency, a hydrophobic polytetrafluoroethylene (PTFE) filter was selected for pre-treatment prior to separation. HPLC separation was performed using a C18 reversed-phase column with a gradient mobile phase of phosphate buffer (pH 2.5) containing tetrahexylammonium hydrogensulfate as an ion-pair reagent. Using this method, (-) epicatechin (EC), (-)-epigallocatechin (EGC), ECG, EGCG, ethyl gallate, and GA were detected as single peaks. The resolution values for target analytes were 4.0 13.0 and the mean values of the absolute recoveries of catechins and GA were 77.3 93.9%. The detection limits for catechins and GA in serum were 0.4-3.1ng/mL. The serum catechin levels of eight healthy volunteers after ingestion of a single dose of green tea tablets were measured using this method. The concentration of total catechins (free+conjugated forms) in serum peaked 60min after ingestion. From these results, this method is thought to enable the simultaneous quantification of GA, the hydrolysis product of gallated catechins, and target catechins, and to be sufficiently sensitive for pharmacokinetic studies of catechins following oral administration of green tea. PMID- 24342508 TI - Pharmacokinetics and excretion study of sophoricoside and its metabolite in rats by liquid chromatography tandem mass spectrometry. AB - In this study, a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the determination of sophoricoside and its metabolite genistein in rat plasma, bile, urine and feces after oral administration of sophoricoside, using sulfamethalazole as internal standard (IS). The separation was performed on a reverse phase C18 column with gradient elution consisting of 0.20/00 aqueous formic acid and methanol (containing 0.20/00 formic acid). The detection was accomplished by multiple-reaction monitoring (MRM) scanning after electrospray ionization (ESI) source operating in the negative ionization mode. The optimized mass transition ion pairs (m/z) for quantitation were 431.2/268.2 for sophoricoside, 268.7/133.0 for genistein and 252.0/156.0 for IS. This developed method provides good linearity (r>0.9983), intra- and inter-day precisions (RSD<8.31%) with accuracies (RE, -6.91 to 6.66%), stability (RE, -7.45 to 6.59%), extract recovery (76.24 to 93.30%) and matrix effect (81.06-106.2%) of the analytes in plasma, bile, urine and feces. The mean elimination half-life (t1/2) of sophoricoside and genistein were 59.78+/-7.19 and 103.14+/-16.97min, respectively. The results showed that sophoricoside was rapidly absorbed and then eliminated from rat plasma. The total recoveries of sophoricoside in bile, urine and feces were about 0.0111%, 1.76% and 11.13%. The amounts excreted of genistein were 0.42+/-0.02MUg in bile, 10.15+/-0.22MUg in urine and 2.92+/-0.13MUg in feces. This is the first report to evaluate the pharmacokinetics and excretion of sophoricoside and its metabolite in rats after oral administration of sophoricoside monomer. The results provided a meaningful basis for the clinical application of sophoricoside. PMID- 24342509 TI - Selective fishing and analysis of xanthine oxidase binders from two Fabaceae species by coupling enzyme functionalized core-shell magnetic nanoparticles with HPLC-MS. AB - Xanthine oxidase (XOD) immobilized core-shell magnetic silica (Fe3O4@SiO2-XOD) nanoparticles coupled with high performance liquid chromatography-mass spectrometry (HPLC-MS) was developed to fish out and analyze XOD binders from two Fabaceae species, Puerariae lobata flower and Glycyrrhiza uralensis root. The prepared Fe3O4@SiO2-XOD nanoparticles exhibited good specificity for XOD binders, better dispersion in aqueous solution and reusability than those of Fe3O4-XOD nanoparticles. The amount of XOD immobilized onto Fe3O4@SiO2 nanoparticles was 339.9MUg/mg and the activity of Fe3O4@SiO2-XOD nanoparticles remained 95% after ten times usage. The optimum conditions of selective fishing were optimized, and finally incubating pH was set at 7, incubating temperature at 25 degrees C and adsorption time at 30min. Twelve XOD binders were successfully identified from ethyl acetate extract of P. lobata flower and G. uralensis root. The developed method provides a rapid, purposeful and effective way to identify active compounds from natural complex mixtures. PMID- 24342510 TI - Validation of an LC-MS/MS method for the quantification of mycophenolic acid in human kidney transplant biopsies. AB - Mycophenolic acid (MPA) has a low therapeutic index and large inter-individual pharmacokinetic variability necessitating therapeutic drug monitoring to individualise dosing after transplantation. There is an ongoing discrepancy as to whether plasma MPA concentrations sufficiently predict kidney rejection or toxicity and whether immunosuppressant concentrations within the graft tissue may better predict transplant outcomes. The aim of the study was to develop an LC MS/MS method for the quantification of MPA concentrations in human kidney biopsies taken as part of routine clinical procedures. A total of 4 surplus human kidney biopsies obtained from 4 different kidney transplant recipients were available to use for this study. MPA was also quantified in 2 kidney samples from rats administered MPA to assess tissue extraction reproducibility. Human kidney biopsies and rat kidneys were homogenised mechanically and underwent liquid liquid extraction before analysis by LC-MS/MS. MPA-free human kidney tissue was used in calibrators and quality control samples. Analyte detection was achieved from multiple reaction monitoring of the ammonium adducts of both MPA (m/z 321.1 >207.3) and N-phthaloyl-l-phenylalanine (PPA, internal standard, m/z 296.2 >250.2) using positive electrospray ionisation. The method was linear (calibration curves R(2)>0.99, n=10), precise, and accurate with coefficients of variation and bias less than 15%. Extraction efficiencies for MPA and PPA were approximately 97% and 86%, respectively, and matrix effects were minimal. In 4 kidney transplant recipients, tissue MPA concentrations ranged from 1.3 to 7.7ng/mg of tissue, however, the correlation between blood (C0) and tissue MPA concentrations could not be established. The method was successfully applied to the quantification of MPA in human kidney biopsies without the need to alter current clinical protocols. PMID- 24342511 TI - Development of an immunoaffinity chromatography column for selective extraction of a new agonist phenylethylamine A from feed, meat and liver samples. AB - Phenylethanolamine A (PA) is a new emerged beta-adrenergic agonist that has been illegally used as an animal feed additive for growth promotion in China. In this study, an immunoaffinity chromatography (IAC) column for selective extraction of PA from swine feed, meat and liver samples was developed. The IAC column was constructed by covalently coupling specific polyclonal antibody (Ab) against PA to CNBr-activated Sepharose 4B and packed into a common solid phase extraction (SPE) cartridge. The extraction conditions including loading, washing and eluting solutions were carefully optimized. Under optimal conditions, the IAC column was characterized in terms of maximum capacity, selectivity, extraction recovery and stability. The maximum capacity of the ICA for PA extraction was found to be 239.4ng. For selectivity testing, 100ng of other three beta-adrenergic agonists (clenbuterol, ractopamine and salbutamol) was separately loaded onto the column, and it was observed that the tested compounds could not be captured on the column, e.g. the column could only selectively recognize PA. The recovery of the IAC for PA extraction was found within 96.47-101.98% when 10, 50 and 100ng PA were separately loaded onto IAC column. The IAC column was also applied to real sample extraction. Swine feed, meat and liver samples were collected and spiked with PA in range of 1.0-20ngg(-1). The spiked and unspiked samples were extracted by IAC column and measured by high performance liquid chromatography (HPLC). It was found that there was no detectable PA in the blank samples, and the extraction recoveries of the IAC for PA from the spiked samples were within 89.48 104.89%. The stability of the column was also tested. It was showed that after 35 times repeated usage, 60% of the maximum capacity was still remained. The proposed IAC was proven to be a feasible extraction method for PA from different matrices with the properties of high maximum capacity, selectivity, extraction efficiency and stability. PMID- 24342512 TI - Simultaneous determination of imperatorin and its metabolite xanthotoxol in rat plasma by using HPLC-ESI-MS coupled with hollow fiber liquid phase microextraction. AB - The objective of the present study was to develop a new method for the simultaneous quantitation of imperatorin and its metabolite xanthotoxol in rat plasma. The samples were prepared with hollow fiber liquid phase microextraction (HF-LPME). The optimized extraction procedure was acquired by assessing extraction solvent, length of the fiber, agitation rate, extraction temperature and time. A comparison of sample pretreatment ways between HF-LPME and deproteinization with methanol was performed, which demonstrated less ion suppression and better sensitivity of HF-LPME. Analytes were separated on a C18 column with a gradient elution consisted of methanol and water containing 1mmol/L ammonium acetate. The detection was accomplished by electrospray ionization (ESI) source operating in the positive ionization mode. Selected-multiple-reaction monitoring (SMRM) scanning was employed, which guaranteed a higher sensitivity compared with MRM mode. Calibration curves were linear over investigated ranges with correlation coefficients greater than 0.9979. Precision varied from 0.26% to 14%, and the accuracy varied within +/-5.5%. The developed method was successfully applied to the pharmacokinetic research of imperatorin and its metabolite xanthotoxol after oral administration of imperatorin to rats. PMID- 24342513 TI - Note from the editors: MERS-CoV - the quest for the reservoir continues. PMID- 24342514 TI - Autochthonous case of dengue in France, October 2013. AB - In October 2013, autochthonous dengue fever was diagnosed in a laboratory technician in Bouches-du-Rhone, southern France, a department colonised by Aedes albopictus since 2010. After ruling out occupational contamination, we identified the likely chain of local vector-borne transmission from which the autochthonous case arose. Though limited, this second occurrence of autochthonous dengue transmission in France highlights that efforts should be continued to rapidly detect dengue virus introduction and prevent its further dissemination in France. PMID- 24342515 TI - Cluster of Legionnaires disease cases caused by Legionella longbeachae serogroup 1, Scotland, August to September 2013. AB - We report six confirmed cases of Legionnaires' disease in Scotland caused by Legionella longbeachae serogroup 1, identified over a four-week period in August September 2013. All cases required admission to hospital intensive care facilities. All cases were amateur gardeners with frequent exposure to horticultural growing media throughout their incubation period. L. longbeachae was identified in five samples of growing media linked to five cases. Product tracing did not identify a common product or manufacturer. PMID- 24342516 TI - Middle East Respiratory Syndrome coronavirus (MERS-CoV) serology in major livestock species in an affected region in Jordan, June to September 2013. AB - Between June and September 2013, sera from 11 dromedary camels, 150 goats, 126 sheep and 91 cows were collected in Jordan, where the first human Middle-East respiratory syndrome (MERS) cluster appeared in 2012. All sera were tested for MERS-coronavirus (MERS-CoV) specific antibodies by protein microarray with confirmation by virus neutralisation. Neutralising antibodies were found in all camel sera while sera from goats and cattle tested negative. Although six sheep sera reacted with MERS-CoV antigen, neutralising antibodies were not detected. PMID- 24342517 TI - Middle East Respiratory Syndrome (MERS) coronavirus seroprevalence in domestic livestock in Saudi Arabia, 2010 to 2013. AB - In Saudi Arabia, including regions of Riyadh and Al Ahsa, pseudoparticle neutralisation (ppNT) and microneutralisation (MNT) tests detected no antibodies to Middle East Respiratory Syndrome coronavirus (MERS-CoV) in sheep (n= 100), goats (n= 45), cattle (n= 50) and chickens (n= 240). Dromedary camels however, had a high prevalence of MERS-CoV antibodies. Bovine coronavirus (BCoV) infected sera from cattle had no cross-reactivity in MERS-CoV ppNT or MNT, while many dromedary camels' sera reacted to both BCoV and MERS-CoV. Some nevertheless displayed specific serologic reaction profiles to MERS-CoV. PMID- 24342518 TI - Transmission and molecular characterisation of wild measles virus in Romania, 2008 to 2012. AB - Molecular characterisation of measles virus is a powerful tool for tracing transmission. Genotyping may prove the absence of endemic circulation of measles virus, i.e. transmission for more than 12 months, which is one of the criteria for verifying elimination of the disease. We have genetically characterised measles viruses detected in Romania from 2008 to 2012, focusing on the recent outbreaks from 2010 to 2012 that affected mainly groups with limited access to healthcare and schools. The findings emphasise the importance of genotyping during the different phases of an outbreak. A total of 8,170 cases were notified, and 5,093 (62%) of the 7,559 possible cases were serologically confirmed. RT-PCR was performed for 104 samples: from the 101 positive samples obtained from sporadic measles cases or clusters from different counties, 73 were genotyped. Sporadic measles cases associated with D4 and D5 viruses were observed from2008 to 2009. Genotype D4-Manchester was predominant in 2011 and 2012. In addition, the related variant D4-Maramures and MVs/Limoges.FRA/17.10[D4] and a few D4 Hamburg strains were detected. The detection of several distinct MV-D4 genotypes suggests multiple virus importations to Romania. The outbreak associated with D4 genotype is the second largest outbreak in Romania in less than 10 years. PMID- 24342519 TI - Kinetics of serological responses in influenza A(H7N9)-infected patients correlate with clinical outcome in China, 2013. AB - The novel avian influenza A(H7N9) infection has recently emerged to cause severe respiratory illness in China. The objectives of this study were to define the kinetics of the antibody responses in patients with influenza A(H7N9) disease and to correlate these kinetics with clinical outcome. Serial serum samples were obtained at intervals of three to four days from 18 patients with virologically confirmed A(H7N9) disease in Shanghai. We determined the kinetics of the haemagglutination inhibition (HI) and A(H7H9) pseudotype neutralisation antibody (Nab) responses and correlated these with clinical outcomes. Most patients had robust serological responses by both HI and Nab tests. Taking into account censoring due to time of testing and death, the median time from onset of illness to Nab titre >=1:40 was 14 days (95% confidence interval (CI): 11-18 days) in the fatal cases and 10.5 days (95% CI: 7-12) in the survivors (p=0.003). The two groups did not differ in initial Nab titres, but the rate of increase in Nab titres was significantly faster for survivors by approximately 10-fold per 15 days (p=0.007). Early and rapid induction of Nab was correlated significantly with better clinical outcome. PMID- 24342520 TI - Seroprevalence of hantavirus infections in Switzerland in 2009: difficulties in determining prevalence in a country with low endemicity. PMID- 24342521 TI - Salivoma after carotid endarterectomy. AB - Although the diagnosis and management of postoperative or traumatic fluid collections have been documented extensively in the literature, to our knowledge the occurrence of a salivoma after carotid endarterectomy has not been reported. We report an extra salivary glandular collection of saliva - a "salivoma" - in a 79-year-old patient who underwent a carotid endarterectomy with a high carotid bifurcation. He presented with serous watery drainage from the incision site that had started spontaneously 4 days after surgery. The patient was taken to the operating room for exploration and washout of the wound with presumption of an infectious source. As self-retaining retractors were placed under the platysma, a large release of serous fluid occurred. Copious irrigation allowed complete washout of the wound. On postoperative day 2, the patient re-exhibited neck wound fullness and a Penrose drain was placed in the incision with clear serous fluid flowing through the drain. The patient was given a scopolamine patch to decrease salivary secretions. Within 5 days, the drainage significantly decreased and the drain was removed. This diagnosis should be included in the differential diagnosis of an expanding neck mass following carotid endarterectomy to properly treat this complication. PMID- 24342523 TI - Population genomics of the endangered giant Galapagos tortoise. AB - BACKGROUND: The giant Galapagos tortoise, Chelonoidis nigra, is a large-sized terrestrial chelonian of high patrimonial interest. The species recently colonized a small continental archipelago, the Galapagos Islands, where it has been facing novel environmental conditions and limited resource availability. To explore the genomic consequences of this ecological shift, we analyze the transcriptomic variability of five individuals of C. nigra, and compare it to similar data obtained from several continental species of turtles. RESULTS: Having clarified the timing of divergence in the Chelonoidis genus, we report in C. nigra a very low level of genetic polymorphism, signatures of a weakened efficacy of purifying selection, and an elevated mutation load in coding and regulatory sequences. These results are consistent with the hypothesis of an extremely low long-term effective population size in this insular species. Functional evolutionary analyses reveal a reduced diversity of immunity genes in C. nigra, in line with the hypothesis of attenuated pathogen diversity in islands, and an increased selective pressure on genes involved in response to stress, potentially related to the climatic instability of its environment and its elongated lifespan. Finally, we detect no population structure or homozygosity excess in our five-individual sample. CONCLUSIONS: These results enlighten the molecular evolution of an endangered taxon in a stressful environment and point to island endemic species as a promising model for the study of the deleterious effects on genome evolution of a reduced long-term population size. PMID- 24342524 TI - Metabolic characterization of (+/-)-praeruptorin A in vitro and in vivo by high performance liquid chromatography coupled with hybrid triple quadrupole-linear ion trap mass spectrometry and time-of-flight mass spectrometry. AB - (+/-)-Praeruptorin A (PA) is the major bioactive component in Peucedani Radix (Chinese name: Qian-hu), and exhibits dramatically anti-hypertensive effect typically through acting as a calcium channel blocker. The current study aims on the characterization of the metabolic profiles of PA in vitro and in vivo using high performance liquid chromatography (HPLC) coupled with hybrid triple quadrupole-linear ion trap mass spectrometry (Q-trap-MS) and time-of-flight mass spectrometry (TOF-MS). A total of 12 phase I metabolites (M1-12) in rat liver microsomes (RLMs), 9 phase I metabolites (M1-3, M5-6 and M9-12) in human liver microsomes (HLMs), 2 hydrolyzed products in rat plasma (M11 and M12), none metabolite in human plasma, none metabolite in rat intestinal bacteria, 7 metabolites (M1, M4-7, M13 and M15) in PA-treated rat urine and 6 metabolites (M1, M4-7 and M15) in PA-treated feces were detected and tentatively identified using predictive multiple reaction monitoring-information dependent acquisition enhanced product ion (predictive MRM-IDA-EPI) mode in combination with enhanced mass spectrum-information dependent acquisition-enhanced product ion (EMS-IDA EPI) mode in the mass spectrometer domain, respectively, while TOF-MS was adopted to confirm the identification. Further, 2 glucuronidated metabolites (M13-14) in RLMs and none metabolite in HLMs of cis-khellactone (CKL), which was the main actual form of PA in vivo, were generated, while its sulfated product was not observed in either rat liver S9 fractions (RS9) or human liver S9 fractions (HS9). Oxidation, hydrolysis, intra-molecular acyl migration and glucuronidation were demonstrated to be the predominant metabolic types for PA in vitro and in vivo. Judging from the decrement of peak areas, PA was metabolized quickly in both RLMs and HLMs, indicating extensively hepatic first-pass elimination. Taken together, the metabolic fates of (+/-)-praeruptorin A in vitro and in vivo were elucidated in current study, and Q-trap-MS coupled with LightSightTM software can be adopted as a useful tool for quick detection and identification of metabolites in complex biological matrices. PMID- 24342522 TI - Rationale and design of the DIPAK 1 study: a randomized controlled clinical trial assessing the efficacy of lanreotide to Halt disease progression in autosomal dominant polycystic kidney disease. AB - BACKGROUND: There are limited therapeutic options to slow the progression of autosomal dominant polycystic kidney disease (ADPKD). Recent clinical studies indicate that somatostatin analogues are promising for treating polycystic liver disease and potentially also for the kidney phenotype. We report on the design of the DIPAK 1 (Developing Interventions to Halt Progression of ADPKD 1) Study, which will examine the efficacy of the somatostatin analogue lanreotide on preservation of kidney function in ADPKD. STUDY DESIGN: The DIPAK 1 Study is an investigator-driven, randomized, multicenter, controlled, clinical trial. SETTING & PARTICIPANTS: We plan to enroll 300 individuals with ADPKD and estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m(2) who are aged 18-60 years. INTERVENTION: Patients will be randomly assigned (1:1) to standard care or lanreotide, 120 mg, subcutaneously every 28 days for 120 weeks, in addition to standard care. OUTCOMES: Main study outcome is the slope through serial eGFR measurements starting at week 12 until end of treatment for lanreotide versus standard care. Secondary outcome parameters include change in eGFR from pretreatment versus 12 weeks after treatment cessation, change in kidney volume, change in liver volume, and change in quality of life. MEASUREMENTS: Blood and urine will be collected and questionnaires will be filled in following a fixed scheme. Magnetic resonance imaging will be performed for assessment of kidney and liver volume. RESULTS: Assuming an average change in eGFR of 5.2 +/- 4.3 (SD) mL/min/1.73 m(2) per year in untreated patients, 150 patients are needed in each group to detect a 30% reduction in the rate of kidney function loss between treatment groups with 80% power, 2-sided alpha = 0.05, and 20% protocol violators and/or dropouts. LIMITATIONS: The design is an open randomized controlled trial and measurement of our primary end point does not begin at randomization. CONCLUSIONS: The DIPAK 1 Study will show whether subcutaneous administration of lanreotide every 4 weeks attenuates disease progression in patients with ADPKD. PMID- 24342525 TI - Dietary influences on the hydration and acid-base status of experimentally dehydrated dairy calves. AB - The incorporation of oral rehydration solutions (ORS) into 'milk meals' is potentially an effective, time-saving method of treating diarrhoeic calves. Although milk-based ORS are effective in improving the hydration and acid-base status of healthy calves, this effect remains to be confirmed in dehydrated/diarrhoeic animals. In this study, six experimentally-dehydrated calves were fed with either milk replacer (MR) or an ORS prepared in either water (WORS) or MR (MORS). In one experiment, calves were not treated and blood samples were taken before and after feeding. Parameters of hydration status were determined and blood gas analysis was performed. Plasma volumes increased significantly following the intake of a 'fluid meal' whereas they remained constant in the absence of treatment. The rate of plasma volume expansion was reduced by the feeding of MR relative to WORS or MORS. In dehydrated calves, the expansion of plasma volume was more pronounced following the intake of WORS but the increase was less and plasma osmolality increased significantly following the ingestion of MORS. The acid-base status of animals improved as a result of fluid absorption, but this effect was less obvious as the experimental protocol resulted in severe dehydration and moderate acidosis. Feeding hypertonic MORS raised the plasma osmolality in dehydrated calves, and may increase the risk of hypernatraemia in diarrhoeic calves, which should therefore have ad libitum access to water when undergoing treatment with hypertonic ORS. Further research is planned to assess whether feeding ORS reconstituted in milk or MR combined with ad libitum access to water offers a practical treatment for diarrhoeic calves. PMID- 24342526 TI - Myostatin signaling regulates Akt activity via the regulation of miR-486 expression. AB - Myostatin, also known as growth and differentiation factor-8, is a pivotal negative regulator of skeletal muscle mass and reduces muscle protein synthesis by inhibiting the insulin-like growth factor-1 (IGF-1)/Akt/mammalian target of rapamycin (mTOR) pathway. However, the precise mechanism by which myostatin inhibits the IGF-1/Akt/mTOR pathway remains unclear. In this study, we investigated the global microRNA expression profile in myostatin knockout mice and identified miR-486, a positive regulator of the IGF-1/Akt pathway, as a novel target of myostatin signaling. In myostatin knockout mice, the expression level of miR-486 in skeletal muscle was significantly increased. In addition, we observed increased expression of the primary transcript of miR-486 (pri-miR-486) and Ankyrin 1.5 (Ank1.5), the host gene of miR-486, in myostatin knockout mice. In C2C12 cells, myostatin negatively regulated the expression of Ank1.5. Moreover, canonical myostatin signaling repressed the skeletal muscle-specific promoter activity of miR-486/Ank1.5. This repression was partially mediated by the E-box elements in the proximal region of the promoter. We also show that overexpression of miR-486 induced myotube hypertrophy in vitro and that miR-486 was essential to maintain skeletal muscle size both in vitro and in vivo. In addition, inhibition of miR-486 led to a decrease in Akt activity in C2C12 myotubes. Our findings indicate that miR-486 is one of the intermediary molecules connecting myostatin signaling and the IGF-1/Akt/mTOR pathway in the regulation of skeletal muscle size. PMID- 24342527 TI - Involvement of Mediator complex in malignancy. AB - Mediator complex (MED) is an evolutionarily conserved multiprotein, fundamental for growth and survival of all cells. In eukaryotes, the mRNA transcription is dependent on RNA polymerase II that is associated to various molecules like general transcription factors, MED subunits and chromatin regulators. To date, transcriptional machinery dysfunction has been shown to elicit broad effects on cell proliferation, development, differentiation, and pathologic disease induction, including cancer. Indeed, in malignant cells, the improper activation of specific genes is usually ascribed to aberrant transcription machinery. Here, we focus our attention on the correlation of MED subunits with carcinogenesis. To date, many subunits are mutated or display altered expression in human cancers. Particularly, the role of MED1, MED28, MED12, CDK8 and Cyclin C in cancer is well documented, although several studies have recently reported a possible association of other subunits with malignancy. Definitely, a major comprehension of the involvement of the whole complex in cancer may lead to the identification of MED subunits as novel diagnostic/prognostic tumour markers to be used in combination with imaging technique in clinical oncology, and to develop novel anti-cancer targets for molecular-targeted therapy. PMID- 24342528 TI - Practice-owned pathology services: controversies and pitfalls--the use of special stains. PMID- 24342529 TI - Flavonol intake and stroke risk: a meta-analysis of cohort studies. AB - OBJECTIVE: Epidemiologic findings are inconsistent regarding the association between flavonol intake and the risk for stroke. The aim of this study was to determine whether an association exists between them in observational studies. METHODS: We searched the PubMed and EMBASE databases for studies conducted from 1966 to August 2013. Prospective cohort studies that provided relative risk (RR) estimates with 95% confidence intervals (CIs) for the association between flavonol intake and risk for stroke were included. A random effects model was used to combine study-specific risk estimates. RESULTS: The meta-analysis included eight studies, with 5228 stroke cases among 280 174 participants. The summary RR indicated a significant association between highest flavonol intake and reduced risk for stroke (summary RR, 0.86; 95% CI, 0.75-0.99). Furthermore, an increase in flavonol intake of 20 mg/d was associated with a 14% decrease in the risk for developing stroke (summary RR, 0.86; 95% CI, 0.77-0.96). Subgroup analyses suggested a significant inverse association between highest flavonol intake and stroke risk among men (summary RR, 0.74; 95% CI, 0.56-0.97) but not women (summary RR, 0.99; 95% CI, 0.85-1.16). CONCLUSIONS: Higher dietary flavonol intake is associated with a reduced risk for stroke, especially among men. Our results support recommendations for higher consumption of flavonol-rich foods to prevent stroke. PMID- 24342530 TI - Telomere shortening in elderly individuals with mild cognitive impairment may be attenuated with omega-3 fatty acid supplementation: a randomized controlled pilot study. AB - OBJECTIVES: Excessive shortening of the telomeric ends of chromosomes is a marker of accelerated aging. Oxidative stress and nutritional deficiency may influence this process. The aim of this study was to investigate the effect of omega-3 polyunsaturated fatty acid (omega-3 PUFA) supplementation on telomeric shortening in elderly individuals with mild cognitive impairment (MCI). METHODS: Thirty three adults ages > 65 y with MCI were randomized to receive a supplement rich in the long-chain omega-3 PUFAs eicosapentaenoic acid (EPA; 1.67 g EPA + 0.16 g docosahexaenoic acid DHA/d; n = 12) or DHA (1.55 g DHA + 0.40 g EPA/d; n = 12), versus omega-6 PUFA linoleic acid (LA; 2.2 g/d; n = 9) for 6 mo. RESULTS: The intervention did not show an increase in telomere length with treatment and there was a trend toward telomere shortening during the intervention period. Linear mixed modeling produced a robust model although statistically underpowered. Telomere shortening was greatest in the LA group (d = 0.21) than in the DHA (d = 0.12) and EPA groups (d = 0.06). Increased erythrocyte DHA levels were associated with reduced telomere shortening (r = -0.67; P = 0.02) in the DHA group. CONCLUSION: Telomeric shortening may be attenuated by omega-3 PUFA supplementation, requiring further investigation in larger samples. PMID- 24342531 TI - Direct analysis of the mushroom poisons alpha- and beta-amanitin in human urine using a novel on-line turbulent flow chromatography mode coupled to liquid chromatography-high resolution-mass spectrometry/mass spectrometry. AB - Poisonings with Amanita phalloides toxins require fast diagnosis in order to avoid expensive and unnecessary therapies. Initial clinical assessment in combination with urinary amanitin analysis is necessary for a definite diagnosis. Therefore, a simple, fast, and robust method was developed for reliable detection of alpha- and beta-amanitin as well as for fully validated quantification of alpha-amanitin in human urine. After simple dilution and centrifugation of the urine sample, a fast on-line extraction using a Transcend TLX-II system based on turbulent flow chromatography (TurboFlow) was established. A new TurboFlow mode was introduced, the pseudo quick elute mode (PQEM), which had more options for method optimization than the generic quick elute mode (QEM). It allowed running several modes in one valve arrangement. The PQEM showed better practicability in routine and emergency analysis than the previously used methods. After extraction, the fast 15min LC-high resolution (HR)-MS/MS analysis allowed reliable identification of alpha- and beta-amanitin based on fragments identified using so-called HR pseudo MS(3) experiments. According to international recommendations, the requirements for full validation including the parameters selectivity, calibration, accuracy, precision, recovery, matrix effects, and stability were fulfilled for alpha-amanitin. The method was successfully applied to the analysis of authentic urine samples containing amatoxins. In conclusion, this method allowed the determination of amatoxins using the novel PQEM in a faster, robust, and more reliable way than existing methods, making it suitable for daily routine and especially emergency toxicological analysis. PMID- 24342532 TI - Solid phase extraction of magnetic carbon doped Fe3O4 nanoparticles. AB - Carbon decorated Fe3O4 nanoparticles (Fe3O4/C) are promising magnetic solid-phase extraction (MSPE) sorbents in environmental and biological analysis. Fe3O4/C based MSPE method shows advantages of easy operation, rapidness, high sensitivity, and environmental friendliness. In this paper, the MSPE mechanism of Fe3O4/C nanoparticles has been comprehensively investigated, for the first time, through the following three efforts: (1) the comparison of extraction efficiency for polycyclic aromatic hydrocarbons (PAHs) between the Fe3O4/C sorbents and activated carbon; (2) the chromatographic retention behaviors of hydrophobic and hydrophilic compounds on Fe3O4/C nanoparticles as stationary phase; (3) related MSPE experiments for several typical compounds such as pyrene, naphthalene, benzene, phenol, resorcinol, anisole and thioanisole. It can be concluded that there are hybrid hydrophobic interaction and hydrogen bonding interaction or dipole-dipole attraction between Fe3O4/C sorbents and analytes. It is the existence of carbon and oxygen-containing functional groups coated on the surface of Fe3O4/C nanoparticles that is responsible for the effective extraction process. PMID- 24342533 TI - Selenium speciation in bay scallops by high performance liquid chromatography separation and inductively coupled plasma mass spectrometry detection after complete enzymatic extraction. AB - Selenium (Se) species, Se-methyl-seleno-cysteine (MeSeCys), seleno-cystine (SeCys2), seleno-methionine (SeMet), selenite (SeO3(2-)) and selenate (SeO4(2-)), in the three main anatomical tissues of bay scallops (Argopecten irradians), the adductor muscle, the mantle and the visceral mass, were completely released by enzymatic hydrolysis and detected by high performance liquid chromatography (HPLC) in combination with inductively coupled plasma mass spectrometry (ICP-MS). For the thorough hydrolysis of the proteins to free the Se species, bay scallop tissues were pre-treated (pre-hydrolyzed) with papain in a 1molL(-1) sodium bicarbonate solution containing 5mmolL(-1) sodium thiosulfate at 30-40 degrees C for 24h, then hydrolyzed by the combination of Flavourzyme((r)) 500 L, carboxypeptidase Y and trypsin (3+1+1) at 45 degrees C, at a constant pH of 8.00 for 6h. Under the optimized conditions, the quantification limits of MeSeCys, SeCys2, SeMet, SeO3(2-) and SeO4(2-) were 0.69, 0.48, 0.93 0.53 and 1.22MUgL(-1), respectively (equivalent to 0.14, 0.097, 0.19, 0.11 and 0.24MUgg(-1) for real samples). The working curves in the concentration ranges of 2 to 500MUgL(-1) were linear with all the RSD (n=5) smaller than 15% and regression coefficients greater than 0.999. The recoveries of the species for spiked samples at 4MUgg(-1) (equivalent to 20MUgL(-1) in the final hydrolyzates) levels all exceeded 90%. The developed method was validated by the determination of SeMet in SELM-1, a Se enriched yeast certified reference material (CRM). Selenate was the only absent species, whereas the other four species did exist in bay scallops. PMID- 24342534 TI - Detailed characterization of the kinetic performance of first and second generation silica monolithic columns for reversed-phase chromatography separations. AB - The kinetic performance of commercially available first generation and prototype second generation silica monoliths has been investigated for 2.0mm and 3.0-3.2mm inner diameter columns. It is demonstrated that the altered sol-gel process employed for the production of second generation monoliths results in structures with a smaller characteristic size leading to an improved peak shape and higher efficiencies. The permeability of the columns however, decreases significantly due to the smaller throughpore and skeleton sizes. Scanning electron microscopy pictures suggest the first generation monoliths have cylindrical skeleton branches, whereas the second generation monoliths rather have skeleton branches that resemble a single chain of spherical globules. Using recently established correlations for the flow resistance of cylindrical and globule chain type monolithic structures, it is demonstrated that the higher flow resistance of the second generation monoliths can be entirely attributed to their smaller skeleton sizes, which is also evident from the external porosity that is largely the same for both monolith generations (Ee~0.65). The recorded van Deemter plots show a clear improvement in efficiency for the second generation monoliths (minimal plate heights of 13.6-14.1MUm for the first and 6.5-8.2MUm for the second generation, when assessing the plate count using the Foley-Dorsey method). The corresponding kinetic plots, however, indicate that the much reduced permeability of the second generation monoliths results in kinetic performances (time needed to achieve a given efficiency) which are only better than those of the first generation for plate counts up to N~45,000. For more complex samples (N>=50,000), the first generation monoliths can intrinsically still provide faster analysis due to their high permeability. It is also demonstrated that - despite the improved efficiency of the second generation monoliths in the practical range of separations (N=10,000-50,000) - these columns can still not compete with state-of the-art core-shell particle columns when all columns are evaluated at their own maximum operating pressure (200bar for the monolithic columns, 600bar for core shell columns). It is suggested that monolithic columns will only become competitive with these high efficiency particle columns when further improvements to their production process are made and their pressure resistance is raised. PMID- 24342535 TI - Performance of the Wells score in patients with suspected pulmonary embolism during hospitalization: a delayed-type cross sectional study in a community hospital. AB - INTRODUCTION: The role of the Wells score for patients who develop signs and symptoms of pulmonary embolism (PE) during hospitalization has not been sufficiently validated. The aim of this study is to evaluate the performance of the Wells score for inpatients with suspected PE and to evaluate the prevalence of pulmonary embolism. MATERIALS AND METHODS: We conducted a cross sectional study nested in the prospective Institutional Registry of Thromboembolic Disease at Hospital Italiano de Buenos Aires from June 2006 to March 2011. We included patients who developed symptoms of pulmonary embolism during hospitalization. Patients were stratified based on the Wells score as PE likely (>4 points) or PE unlikely (<=4 points). The presence of pulmonary embolism was defined by pre specified criteria. RESULTS: Six hundred and thirteen patients met the inclusion criteria, with an overall prevalence of PE of 36%. Two hundred and nineteen (34%) were classified as PE likely and 394 (66%) as PE unlikely with a prevalence of PE of 66% and 20%, respectively. The Wells score showed a sensitivity of 65 (95% CI 59-72), specificity 81 (95% CI 77-85), positive predictive value 66 (95% CI 60 72) and negative predictive value 80 (95% CI 77-84). CONCLUSIONS: The Wells Score is accurate to predict the probability of PE in hospitalized patients and this population had a higher prevalence of PE than other cohorts. However, the score is not sufficiently predictive to rule out a potentially fatal disorder. PMID- 24342536 TI - Significance of platelet and monocyte activation for therapeutic immunoglobulin induced thromboembolism. AB - OBJECTIVES: Thromboembolic events (TEE) in patients receiving infusions of intravenous immunoglobulin (IVIG) products have recently been associated with contaminating factor XIa. We studied whether platelet and monocyte activation could also be involved. METHODS: Twenty IVIG samples from five manufacturers were tested for the induction of visible whole blood clot formation. A selection of TEE-associated and not associated lots was further analyzed for effects on thromboelastometry, platelet activation and adhesion, as well as monocyte tissue factor surface expression. Pure factor XIa was included for comparison. Western blotting was applied to analyze anti-CD154-reactive proteins in IVIG. RESULTS: In whole blood, IVIG enhanced macroscopic clotting additively with factor XIa. In monocytes, all IVIG products induced the FcgammaRII-dependent tissue factor expression to a similar extent, which was not affected by addition of factor XIa. Testing platelet aggregation, IVIG strengthened the ADP and TRAP-6-elicited response. Furthermore, IVIG increased platelet-monocyte adhesion and annexin V binding to platelet microvesicles, and promoted platelet adhesion to IVIG-coated surfaces. The strongest effects were observed with TEE-associated lots. CD154 related proteins were detected in all IVIG products. CD154-related high molecular weight complexes were particularly found in the TEE-associated IVIG. In platelet aggregation, recombinant soluble CD154 enhanced aggregate formation and stability. CONCLUSION: Our data demonstrate that IVIG modulate platelet and monocyte activation and can thereby affect the hemostatic balance. These effects are either additive to or independent from factor XIa. CD154-related proteins are assumed to be involved in these interactions, the mechanism of which needs to be elucidated in further studies. PMID- 24342537 TI - Validation of a commercially available kit to detect anti phosphatidylserine/prothrombin antibodies in a cohort of systemic lupus erythematosus patients. AB - BACKGROUND: Antiprothrombin antibodies detection comprises two different ELISAs: prothrombin coated on irradiated plates (aPT) or phosphatidylserine/prothrombin (aPS/PT) as the antigen. While several commercial kits are available for the detection of aPT, aPS/PT are usually detected by in-house assays. Recently, a new commercially available kit was launched and, therefore, we decided to test its efficiency by comparing it to our in-house assay. METHODS: aPS/PT were tested by our in-house assay (aPS/PT(ih)) in 75 SLE patients, using Immulon 1 plates coated with phosphatidylserine, purified human prothrombin and 1%BSA-TBS-CaCl as blocking and diluents. Data from this assay were compared to those obtained by the QUANTA Lite aPS/PT screen, IgG and IgM Elisa (INOVA Diagnostics, Inc, San Diego, USA) commercial kits (aPS/PT(c)). RESULTS: aPS/PT were found in 41.3% and 46.7% of SLE patients by the aPS/PT(ih) and the aPS/PT(c), respectively. There was a positive correlation between IgG aPS/PT(ih) and aPS/PT(c) assays (R(2)=0. 861 by Spearman test, p=0.0027). Sensitivity and specificity for APS were 62.2% and 97.4% (AUC 0.780) for the aPS/PT(ih) assay and 70.3% and 84.2% (AUC 0.858) for the aPS/PT(C). Shorter running times were also seen when comparing the aPS/PT(ih) vs. aPS/PT(c) (7hours vs. 3hours, respectively). CONCLUSION: The aPS/PT(C) is a reproducible and accurate test for the detection of aPS/PT, bringing also the advantage of shorter running times. PMID- 24342538 TI - Travel, syphilis and HIV. PMID- 24342539 TI - Cost effective production of pullulan from agri-industrial residues using response surface methodology. AB - Response surface methodology was used to develop an economically feasible process for the fermentative production of pullulan using agri-industrial residues, jaggery, de-oiled jatropha seed cake (DOJSC) and corn steep liquor (CSL), as sole media components. A second order polynomial model was obtained using central composite design to understand the effects of interactions among these substrates on pullulan biosynthesis. Results indicated that, lower concentrations of CSL and DOJSC and higher concentrations of jaggery favoured pullulan production. The optimal nutrient composition (18% jaggery, 3% DOJSC and 0.97% CSL) as suggested by the model resulted in production of 66.25 g/L pullulan with a productivity of 0.92 g/Lh. Analysis of raw material cost component for pullulan production suggested that sole utilization of agri-residues may lead to development of cost effective process for pullulan production. PMID- 24342540 TI - Inhibition of methemoglobin formation in aqueous solutions under aerobic conditions by the addition of amino acids. AB - Hemoglobin (Hb) as an important iron-containing oxygen-transport protein is easily oxidized to the ferric met-form, methemoglobin (metHb), and loses the capacity of binding oxygen during storage. In this study, the experimental data indicate that the presence of Tyr and Glu significantly suppress the metHb formation in the Hb solutions in aqueous environment under aerobic conditions at the temperature of 25 and 37 degrees C, respectively. At pO2 of 144Torr the metHb percentage in the Hb solutions was the lowest with less than 10% at day 7 after incubation with Tyr at the ratio of 24 at pH 9.5 at 25 degrees C. At 37 degrees C, the metHb percentage did not reach 5% after 12h of incubation with Glu at the ratio of 24 at pH 9. Molecular simulation analysis suggest that the presence of Tyr or Glu may contribute to the formation of the breakwater network, the stabilization of distal histidine, the changes in the size of heme pocket, and eventually result in the inhibition of metHb formation. This study provides insight into a new design for Hb-oxygen based carriers with strongly inhibition of metHb formation in aqueous environment under aerobic conditions, even at physiological temperature in vitro. PMID- 24342541 TI - Whether noise exposure causes stroke or hypertension is still not known. PMID- 24342542 TI - Lung involvement in primary Sjogren's syndrome: Correlation between high resolution computed tomography score and mortality. AB - BACKGROUND: Lung involvement is one of the major systemic manifestations of primary Sjogren's syndrome (pSS). This study aims to demonstrate the correlation between high-resolution computed tomography (HRCT), pulmonary function test (PFT) results, and outcome in these patients. METHODS: Forty-four pSS patients were enrolled and their PFT results and HRCT findings/scores were retrospectively investigated. RESULTS: All patients had reduced carbon monoxide-diffusing capacity (DLCO; <75% of the predicted value); <60% of the predicted value of peak expiratory flow (PEF), of forced vital capacity (FVC), and of forced expiratory volume in the 1st second (FEV1) were noted in 15 (34.1%) patients, 13 (29.5%) patients, and 12 (27.3%) patients, respectively. HRCT scores had a negative correlation with DLCO (r = -0.376, p = 0.012), but not with other PFT results. Twelve patients (27.3%) expired during a mean follow-up of 3.7 years; 11 (91.7%) patients died of respiratory failure in the lung-involved patients, of which three were present with pneumonia. The expired patients had lower predicted values of FEV1 (63.1 +/- 19.4% vs. 79.0 +/- 22.7%, p = 0.017), FVC (58.7 +/- 20.4% vs. 77.1 +/- 17.5%, p = 0.005), and PEF (54.3 +/- 20.5% vs. 72.0 +/- 24.8%, p = 0.035), and higher HRCT scores (9.2 +/- 5.7 vs. 5.2 +/- 3.5, p = 0.033) than those patients who survived. Patients with FEV1, FVC, PEF < 60% of the predicted value, or high HRCT score (13-18) presented shorter median overall survival (p = 0.005, p < 0.001, p = 0.021, p < 0.001, respectively). Multivariate analysis adjusted for PFT results showed that HRCT >=13 was an independent risk factor for mortality (p = 0.007). CONCLUSION: The clinical outcome of pSS patients with lung involvement in Taiwan is not very favorable. Although HRCT score was poorly correlated with PFT, high HRCT score was significantly associated with higher mortality. PMID- 24342543 TI - Continuous monitoring in an inpatient medical-surgical unit: a controlled clinical trial. AB - BACKGROUND: For hospitalized patients with unexpected clinical deterioration, delayed or suboptimal intervention is associated with increased morbidity and mortality. Lack of continuous monitoring for average-risk patients has been suggested as a contributing factor for unexpected in-hospital mortality. Our objective was to assess the effects of continuous heart rate and respiration rate monitoring in a medical-surgical unit on unplanned transfers and length of stay in the intensive care unit and length of stay in the medical-surgical unit. METHODS: In a controlled study, we have compared a 33-bed medical-surgical unit (intervention unit) to a "sister" control unit for a 9-month preimplementation and a 9-month postimplementation period. Following the intervention, all beds in the intervention unit were equipped with monitors that allowed for continuous assessment of heart and respiration rate. RESULTS: We reviewed 7643 patient charts: 2314 that were continuously monitored in the intervention arm and 5329 in the control arms. Comparing the average length of stay of patients hospitalized in the intervention unit following the implementation of the monitors to that before the implementation and to that in the control unit, we observed a significant decrease (from 4.0 to 3.6 and 3.6 days, respectively; P <.05). Total intensive care unit days were significantly lower in the intervention unit postimplementation (63.5 vs 120.1 and 85.36 days/1000 patients, respectively; P = .04). The rate of transfer to the intensive care unit did not change, comparing before and after implementation and to the control unit (P = .19). Rate of code blue events decreased following the intervention from 6.3 to 0.9 and 2.1, respectively, per 1000 patients (P = .02). CONCLUSIONS: Continuous monitoring on a medical-surgical unit was associated with a significant decrease in total length of stay in the hospital and in intensive care unit days for transferred patients, as well as lower code blue rates. PMID- 24342544 TI - Unicompartmental knee arthroplasties: robot vs. patient specific instrumentation. AB - BACKGROUND: The technical reliability demonstrated by semi active robots in implant placement could render unicompartmental knee arthroplasties (UKAs) more favourable than they are currently. The relatively untested method using patient specific instrumentation (PSI), however, has the potential to match the accuracy produced by robots but without the barriers that have prevented them from being used more widely in clinical practice, namely operative time. Therefore this study took a step towards comparing the accuracy and time taken between the two technologies. METHODS: Thirty-six UKAs were carried out on identical knee models, 12 with the Sculptor, 12 with PSI and 12 conventionally under timed conditions. Implant placement in these knees was then judged against that in a pre-operative plan. RESULTS: Tibial implant orientations and femoral implant positions and orientations were significantly more accurate in the PSI group with mean errors of 6 degrees , 2 mm and 4 degrees respectively, than the conventional group which had means of 9 degrees , 4 mm and 10 degrees . There was no significant difference between the robot and PSI generally except in tibial implant orientation (mean robotic error 3 degrees ) and tibial implant position did not vary significantly across all three groups. It was also found that use of PSI and conventional methods took half the time taken by the robot (p<0.001). CONCLUSIONS: With further development, PSI can match and possibly surpass the accuracy of the robot, as it does with the conventional method, and achieve planned surgery in less time. CLINICAL RELEVANCE: This work sets the foundation for clinical trials involving PSI. PMID- 24342545 TI - Enhancing the public impact of ethnography. PMID- 24342546 TI - Atopy and allergic respiratory disease in rural Poland before and after accession to the European Union. AB - BACKGROUND: In 2003, we recorded a striking difference in the prevalence of atopy between village and small-town populations in southwest Poland. Nine years later, we undertook a second survey of the same area. OBJECTIVE: We sought to assess whether rapid changes in farming practices, driven by accession to the European Union in 2004, were accompanied by an increase in atopy, asthma, and hay fever in these villages. METHODS: In 2012, we surveyed 1730 inhabitants older than 5 years (response rate, 85%); 560 villagers and 348 town inhabitants who had taken part in the earlier survey. Participants completed a questionnaire on farm-related exposures and symptoms of asthma and hay fever. Atopy was assessed by using skin prick tests. RESULTS: In 2012, far fewer villagers had contact with cows (4% vs 24.3% in 2003) or pigs (14% vs 33.5%), milked cows (2.7% vs 12.7%), or drank unpasteurized milk (9% vs 35%). Among the villagers, there was a significant increase at all ages in the prevalence of atopy between 2003 and 2012 both in the total population (7.3% vs 19.6%, P < .0001) and among those who took part in both surveys (7.9% vs 17.8%, P < .0001). Among the townspeople, the prevalence of atopy did not change substantially (20% vs 19.9% and 21.7% vs 18.5%, respectively). Hay fever increased 2-fold in the villages (3.0% vs 7.7%) but not in the town (7.1% vs 7.2%); there was little or no change in asthma prevalence in the villages (5.0% vs 4.3%) or town (4.3% vs 5.0%). CONCLUSIONS: We report a substantial increase in atopy at all ages and in a remarkably short period of time in a Polish population whose farm-related exposures were dramatically reduced after their country's accession to the European Union. PMID- 24342547 TI - Prevalence and characteristics of eosinophilic esophagitis in 2 ethnically distinct pediatric populations. PMID- 24342548 TI - The antimicrobial protein short palate, lung, and nasal epithelium clone 1 (SPLUNC1) is differentially modulated in eosinophilic and noneosinophilic chronic rhinosinusitis with nasal polyps. AB - BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly heterogeneous disease with aberrant host defense responses. However, whether innate immunity is similarly impaired in patients with eosinophilic and those with noneosinophilic CRSwNP remains unclear. OBJECTIVES: We sought to evaluate the expression and possible modulation of short palate, lung, and nasal epithelium clone 1 (SPLUNC1), an innate immune molecule, in the 2 CRSwNP subsets. METHODS: Polyp tissue and uncinate processes were collected from 40 patients with CRSwNP, 27 patients with chronic rhinosinusitis without nasal polyps (CRSsNP), and 22 control subjects. Expression of SPLUNC1; Toll-like receptor (TLR) 2, TLR3, and TLR4; and the proinflammatory cytokines IL-1alpha, IL-4, IL-13, IL-17A, and IFN-gamma was examined in nasal tissues. Additionally, SPLUNC1 expression in response to specific inflammatory stimulation was measured in cultured polyp epithelial cells and A549 cells. RESULTS: Polyp tissues exhibited significantly decreased expression of SPLUNC1 and other innate immune molecules compared with uncinate process tissues from patients with CRSwNP (P < .05), patients with CRSsNP, and healthy control subjects. Moreover, the eosinophilic CRSwNP subset exhibited significantly decreased SPLUNC1 expression and numbers of submucosal glands, as well as significantly increased IL-4 and IL-13 mRNA levels, compared with the noneosinophilic subset (P < .05). Accordingly, SPLUNC1 expression in polyp epithelial cells was significantly inhibited by IL-4 and IL-13 stimulation in vitro but was significantly upregulated after stimulation with TLR agonists and glucocorticoids (P < .05). CONCLUSION: Differential SPLUNC1 suppression between the eosinophilic and noneosinophilic CRSwNP subsets suggests that they possess distinct pathogenic mechanisms. This finding might benefit the design of appropriate therapeutic interventions targeted to each subset. PMID- 24342549 TI - Kindlin-3-independent adhesion of neutrophils from patients with leukocyte adhesion deficiency type III. PMID- 24342551 TI - Oncology scan--the role of intensity modulated radiation therapy as treatment for gynecologic cancers. PMID- 24342550 TI - Does family always matter? Public genomes and their effect on relatives. PMID- 24342553 TI - Impaired protection against Trichinella spiralis in mice with high levels of IgE. AB - Helminth infection induces production of a large amount of immunoglobulin E (IgE) to nonhelminth antigens. Although such "irrelevant" IgE is a major proportion of total IgE in the host, its biological significance remains unclear. Therefore, I examined protective activity against Trichinella spiralis in mice with high levels of IgE by repeated injections of anti-dansyl IgE monoclonal antibody or Nippostrongylus brasiliensis infection. Injected anti-dansyl IgE occupied IgE receptors on mast cells in naive mice. Protective activity against T. spiralis, determined with number of muscle larvae 5weeks after infection, was impaired in mice treated with anti-dansyl IgE. The impaired protection was found in mice treated with anti-dansy IgE 7 and 14days after infection, but not 21 and 28days after infection, indicating that IgE-dependent protection operates at an early stage after infection. In the next experiments, mice were infected with N. brasiliensis 4weeks before T. spiralis infection to obtain high levels of IgE. The protective activity against T. spiralis was decreased by N. brasiliensis infection. On the other hand, protection against T. spiralis was comparable in IgE-deficient SJA/9 mice and in anti-IgE-treated BALB/c mice with or without N. brasiliensis infection, suggesting that impairment of protection is dependent on IgE. These results indicate that the high levels of irrelevant IgE are beneficial for helminths and, alternatively, that anti-helminth IgE antibodies are protective for hosts. In addition, the impaired protection was found in IgE high responder mice but not in low-responder mice, suggesting that protection against T. spiralis is controlled by IgE responsiveness in the host. PMID- 24342552 TI - Effect of overground training augmented by mental practice on gait velocity in chronic, incomplete spinal cord injury. AB - OBJECTIVE: To compare the efficacy of a regimen combining mental practice (MP) with overground training (OT) with the efficacy of a regimen consisting of OT only on gait velocity and lower extremity motor outcomes in individuals with chronic (>12mo postinjury), incomplete spinal cord injury (SCI). DESIGN: Randomized, controlled, single-blinded study. SETTING: Outpatient rehabilitation laboratories. PARTICIPANTS: Subjects with chronic, incomplete SCI (N=18). INTERVENTIONS: Subjects were randomly assigned to receive (1) OT only, occurring 3d/wk for 8 weeks; or (2) OT augmented by MP (MP + OT), during which randomly assigned subjects listened to an MP audio recording directly after OT sessions. MAIN OUTCOME MEASURES: Subjects were administered a test of gait velocity as well as the Tinetti Performance Oriented Mobility Assessment, Spinal Cord Injury Independence Measure, and Satisfaction With Life Scale on 2 occasions before intervention, 1 week after intervention, and 12 weeks after intervention. RESULTS: A significant increase in gait velocity was exhibited across subjects at both 1 week posttherapy (P=.005) and at 12 weeks posttherapy (P=.006). However, no differences were seen in intervention response at either 1 or 12 weeks postintervention among subjects in the MP + OT group versus the OT-only group. CONCLUSIONS: OT was associated with significant gains in gait velocity, and these gains were not augmented by further addition of MP. PMID- 24342554 TI - Field survey focused on Opisthorchis viverrini infection in five provinces of Cambodia. AB - BACKGROUND: Opisthorchiasis is endemic in Thailand and Lao People's Democratic Republic and constitutes a major public health problem throughout the Mekong Basin. Although Cambodia is located in the Mekong Basin, the status of O. viverrini infection in that country was not previously clarified. This research was conducted to document the extent and distribution of O. viverrini infection in Cambodia. METHODS: Surveillance was conducted in 55 villages in five Cambodian provinces. Research tools included stool examination using the Kato-Katz thick smear technique, identification of intermediate hosts, and interviews covering factors related to O. viverrini infection. Some larvae and egg-positive stool samples were examined using PCR to detect O. viverrini DNA. RESULTS: A total of 16,082 stool samples from the 55 villages were examined, of which 1232 were egg positive. In 15 villages with egg-positive rates of greater than 10%, eggs were found in 998 of 3585 stool samples, for an egg-positive rate of 27.8%. PCR analysis showed that 30 of 33 samples were positive for O. viverrini DNA from five villages in Kampong Cham and Kampong Thom provinces. The first intermediate host Bithynia siamensis siamensis was identified in the target areas of Takaev, Kandal, and Kampong Cham provinces. Cercariae were identified morphologically as O. viverrini and some were confirmed using PCR. Metacercariae of O. viverrini were identified by morphologic observations, animal experiments, or PCR in six species of fish in the target areas. DISCUSSION AND CONCLUSIONS: Four Cambodian provinces were identified as endemic areas of O. viverrini infection. Careful planning is necessary for effective field surveys, because complex environmental factors might be involved in the distribution of O. viverrini infection-endemic areas in Cambodia. Many problems remain to be resolved regarding the status of O. viverrini infection in Cambodia, and a nationwide baseline survey is necessary. PMID- 24342555 TI - Timing of birth in multiple pregnancy. AB - Timing of delivery of twins should be decided when the benefit of prolonging the pregnancy outweighs the risk of stillbirth. Perinatal mortality of singletons is increased significantly after 42 weeks, whereas perinatal mortality in twins starts to increase significantly after 37 weeks. Recent, large cohort studies have showed significantly higher stillbirth rates near term even in apparently low-risk monochorionic twin pregnancies. Stillbirth risk in monochorionic twins is three-fold higher than in dichorionic twins, and this risk remains high throughout the pregnancy. In uncomplicated monochorionic twins between 32 and 37 weeks, no statistically significant increase of stillbirth occurs between 32 and 37 weeks; these pregnancies are usually monitored until delivery at 37 weeks. The risk of stillbirth in dichorionic twins does not seem to be different between 28 and 38 weeks, justifying a differential policy for the timing of delivery in monochorionic compared with dichorionic twin pregnancies. Therefore, uncomplicated dichorionic twins should be managed expectantly, and delivery can be arranged from 38 weeks. In cases of discordant fetal wellbeing at preterm gestations, timing of delivery should be based mainly on parameters and outlook for the healthy twin balanced against the condition of the compromised fetus. The threshold for early delivery may be lower in monochorionic twins because of the high mortality and morbidity in surviving twins with co-twin death. PMID- 24342556 TI - Fetal abdominal wall defects. AB - The most common fetal abdominal wall defects are gastroschisis and omphalocele, both with a prevalence of about three in 10,000 births. Prenatal ultrasound has a high sensitivity for these abnormalities already at the time of the first trimester nuchal scan. Major unrelated defects are associated with gastroschisis in about 10% of cases, whereas omphalocele is associated with chromosomal or genetic abnormalities in a much higher proportion of cases. Challenges in management of gastroschisis are related to the prevention of late intrauterine death, and the prediction and treatment of complex forms. With omphalocele, the main difficulty is the exclusion of associated conditions, not all diagnosed prenatally. An outline of the postnatal treatment of abdominal wall defects is given. Other rarer forms of abdominal wall defects are pentalogy of Cantrell, omphalocele, bladder exstrophy, imperforate anus, spina bifida complex, prune belly syndrome, body stalk anomaly, and bladder and cloacal exstrophy; they deserve multidisciplinary counselling and management. PMID- 24342557 TI - Measurement of the half-life of 68Ga. AB - The half-life of the positron-emitter (68)Ga has been measured by following the decay rate with two systems based on ionization chamber and Ge detectors. The decay rate was measured for periods of time up to 10 half-lives. The combination of the 6 results obtained with both systems gives a value of T1/2=67.845(18) min, in good agreement with recommended data and with an uncertainty lower than any other previously reported value. PMID- 24342558 TI - Measurement and calibration of metal and non-metal wastes produced from decommissioning. AB - This report described a radioactive waste reference drum which was established with large-area sources and metal slices. This reference drum could be applied in calibration or testing of drum counting systems having 4pi counting geometry and being made with plastic scintillators. This metal reference drum has the advantages of easy operation, low natural background and it also has agreeable measurement efficiency calibration curves for the drum counting system as the non metal reference drum studied previously. On the other hand, this study explored the counting efficiency variations of the drum counting system by simulations of the metal reference drum being filled with wastes up to different heights within the drum. With the exploration, it is feasible to correct the measurement errors caused by different quantities of waste filling. PMID- 24342559 TI - Comparison of properties of digital spectrometer systems. AB - We have tested two digital spectrometer systems, the DSP 9660 and Lynx((r)) modules, connected to a HPGe detector. Lynx((r)) is a fully integrated 32K channel signal analyzer based on digital signal processing techniques, which offers advanced digital stabilization. The model DSP 9660 digitalizes the signal directly at a very high sampling rate. The evaluated properties were integral nonlinearity, differential linearity, channel profiles, resolution and throughput. We found that the DSP system has slightly inferior resolution and throughput in comparison with the Lynx((r)) system. PMID- 24342560 TI - Micelle size effect on Fe-55 liquid scintillation efficiency. AB - We used efficiency tracing techniques to study the micelle size effect on liquid scintillation counting of the electron capture nuclide, (55)Fe. We determined micelle hydrodynamic diameters for specific LS cocktails via dynamic light scattering, and sought trends in efficiencies as a function of micelle size. The presence of Fe(3+) or Mn(2+) ions in the cocktails did not significantly affect micelle sizes or fluorescence quenching. We did not detect any reductions in counting efficiencies due to the micelle size effect. PMID- 24342561 TI - Characterization of brown rice as a certified reference material for Fukushima accident-related radioactivity measurements. AB - We developed a certified reference material of brown rice to measure radioactivity from the Fukushima Daiichi Nuclear Power Plant accident. The rice was planted in the spring of 2011, just after the Fukushima accident occurred, and it was harvested in the autumn of 2011. The certified value of radioactivity concentration in the rice was 33.6 Bq kg(-1) of Cs-134 and 51.8 Bq kg(-1) of Cs 137 on August 1, 2012. The reference material is being widely distributed by the National Metrology Institute of Japan. To determine the radioactivity and its uncertainties in the brown rice, we employed gamma-ray spectrometry with a high purity germanium detector and Monte Carlo simulation. PMID- 24342562 TI - A miniature TDCR system dedicated to in-situ activity assay. AB - In the framework of the European Metrology Research Programme (EMRP), the Joint Research Project MetroFission has a dedicated work package for the development of a portable Triple-to-Double-Coincidence-Ratio (TDCR) system dedicated to in-situ activity measurements of low-energy beta emitters arising from the operation of the next generation of nuclear power plants. In the design phase of the NPL version of the mini-TDCR, a wide range of metrological aspects and detector types was considered. This paper summarizes these aspects of design, in the light of previous experience with the primary TDCR system at NPL. For example, in this miniature version of the TDCR, the optical chamber was simplified and cylindrical geometry was deemed sufficient. The reflectivity of the surface was increased by painted layers of Spectraflect((r)), a specially formulated barium sulphate coating with high reflectivity across a wide range of wave lengths including UV. This option was chosen rather than the high performing and more expensive Spectralon((r)) material used for the primary NPL TDCR. The miniature TDCR system is intended for on-site monitoring and will not require as high a performance as the primary system. Other factors that were considered included sample changing, light tightness, type of photo detector, method for varying the detection efficiency, shielding and the possible addition of an internal gamma-ray source for determination of the quench parameter of the source. In this version, the sample changing is performed using a piston and an automatic shutter. Significant design effort has been applied to ensure minimal ingress of light from the piston. Efficiency variation is accomplished by increasing the vertical displacement of the vial. Provision has been made to automate this at a later stage. Maximum light transmission to the photo-multiplier tubes is obtained at the "zero" reference height. Validation measurements were successfully performed using four different radionuclides: (3)H, (241)Pu, (63)Ni, and (99)Tc. PMID- 24342563 TI - Attenuation of mania-like behavior in Na(+),K(+)-ATPase alpha3 mutant mice by prospective therapies for bipolar disorder: melatonin and exercise. AB - Bipolar disorder is a neuropsychiatric disease characterized by states of mania with or without depression. Pharmacological treatments can be inadequate at regulating mood for many individuals. Melatonin therapy and aerobic exercise are independent prospective therapies for bipolar disorder that have shown potential as mood stabilizers in humans. Myshkin mice (Myk/+) carry a heterozygous missense mutation in the neuronal Na(+),K(+)-ATPase alpha3 and model mania-related symptoms of bipolar disorder including increased activity, risk-taking behavior and reductions in sleep. One cohort of Myk/+ and wild-type littermates (+/+) was treated with melatonin and a separate cohort was treated with voluntary exercise. Mania-related behavior was assessed in both cohorts. The effect of melatonin on sleep and the effect of exercise on brain-derived neurotrophic factor (BDNF) expression in the hippocampus were assayed. Melatonin and voluntary wheel running were both effective at reducing mania-related behavior in Myk/+ but did not affect behavior in +/+. Melatonin increased sleep in Myk/+ and did not change sleep in +/+. Myk/+ showed higher baseline levels of BDNF protein in the hippocampus than +/+. Exercise increased BDNF protein in +/+ hippocampus, while it did not significantly affect BDNF levels in Myk/+ hippocampus. These findings support initial studies in humans indicating that melatonin and exercise are useful independent adjunct therapies for bipolar disorder. Their effects on mood regulation should be further examined in randomized clinical trials. Our results also suggest that hippocampal BDNF may not mediate the effects of exercise on mania-related behavior in the Myk/+ model of mania. PMID- 24342565 TI - Generalization of vestibular learning to earth-fixed targets is possible but limited when the polarity of afferent vestibular information is changed. AB - To maintain perception of the world around us during body motion, the brain must update the spatial presentation of visual stimuli, known as space updating. Previous studies have demonstrated that vestibular signals contribute to space updating. Nonetheless, when being passively rotated in the dark, the ability to keep track of a memorized earth-fixed target (EFT) involves learning mechanism(s). We tested whether such learning generalizes across different EFT eccentricities. Furthermore, we ascertained whether learning transfers to similar target eccentricities but in the opposite direction. Participants were trained to predict the position of an EFT (located at 45 degrees to their left) while being rotated counterclockwise (i.e., they press a push button when they perceived that their body midline have cross the position of the target). Overall, the results indicated that learning transferred to other target eccentricity (30 degrees and 60 degrees ) for identical body rotation direction. In contrast, vestibular learning partly transferred to target location's matching body rotation but in the opposite rotation direction. Generalization of learning implies that participants do not adopt cognitive strategies to improve their performance during training. We argue that the brain learned to use vestibular signals for space updating. Generalization of learning while being rotated in the opposite direction implies that some parts of the neural networks involved in space updating is shared between trained and untrained direction. PMID- 24342564 TI - Emerging epigenetic mechanisms of long non-coding RNAs. AB - Long non-coding RNAs (lncRNAs) have been increasingly appreciated as an integral component of gene regulatory networks. Genome-wide features of their origin and expression patterns ascribed a prominent role for lncRNAs to the regulation of protein-coding genes, and also suggest a potential link to many human diseases. Recent studies have begun to unravel the intricate regulatory mechanism of lncRNAs occurring at multiple levels. The brain is one of the richest sources of lncRNAs, many of which have already shown a close relationship with genes or genetic loci implicated in a wide range of neurological disorders. This review describes recently emerging mechanistic principles of lncRNA functions to provide neuroscientists with molecular insights that will help future research on lncRNAs in the brain. PMID- 24342567 TI - Colocalization pattern of calbindin and cocaine- and amphetamine-regulated transcript in the mammillary body-anterior thalamic nuclei axis of the guinea pig. AB - The study describes for the first time the colocalization pattern of calbindin (CB) and cocaine- and amphetamine-regulated transcript (CART) in the mammillary body (MB) and anterior thalamic nuclei (ATN) - structures connected in a topographically organized manner by the mammillothalamic tract (mtt). Immunohistochemical study was performed on fetal (E40, E50, E60), newborn (P0) and postnatal (P20, P80) brains of the guinea pig, but the coexistence pattern of the substances was invariable throughout the examined developmental stages. CB and CART colocalized in the perikarya of the lateral part of the medial mammillary nucleus (MMl), whereas in its medial part (MMm) only CB was detected. In the mtt, which originates from the MB, both the substances were present and colocalized in single fibers. Next, fibers from the mtt spread toward the ATN in a particular way: fibers containing CB ran to both the anteromedial thalamic nucleus (AM) and anteroventral thalamic nucleus (AV), while fibers containing CART ran mostly to the latter one. In the ventral part of AV, CB and CART colocalized vastly in the neuropil. The lateral mammillary nucleus and anterodorsal thalamic nucleus were virtually devoid of CB- and CART-positive structures. Based on the known connections between the MB and ATN, we conclude that the studied substances may cooperate in the MMl-AV part of the axis and CB plays a significant role in the MMm-AM part. PMID- 24342566 TI - Vitamin E is essential for Purkinje neuron integrity. AB - alpha-Tocopherol (vitamin E) is an essential dietary antioxidant with important neuroprotective functions. alpha-Tocopherol deficiency manifests primarily in neurological pathologies, notably cerebellar dysfunctions such as spinocerebellar ataxia. To study the roles of alpha-tocopherol in the cerebellum, we used the alpha-tocopherol transfer protein for the murine version (Ttpa(-/)(-)) mice which lack the alpha-tocopherol transfer protein (TTP) and are a faithful model of vitamin E deficiency and oxidative stress. When fed vitamin E-deficient diet, Ttpa(-/)(-) mice had un-detectable levels of alpha-tocopherol in plasma and several brain regions. Dietary supplementation with alpha-tocopherol normalized plasma levels of the vitamin, but only modestly increased its levels in the cerebellum and prefrontal cortex, indicating a critical function of brain TTP. Vitamin E deficiency caused an increase in cerebellar oxidative stress evidenced by increased protein nitrosylation, which was prevented by dietary supplementation with the vitamin. Concomitantly, vitamin E deficiency precipitated cellular atrophy and diminished dendritic branching of Purkinje neurons, the predominant output regulator of the cerebellar cortex. The anatomic decline induced by vitamin E deficiency was paralleled by behavioral deficits in motor coordination and cognitive functions that were normalized upon vitamin E supplementation. These observations underscore the essential role of vitamin E and TTP in maintaining CNS function, and support the notion that alpha-tocopherol supplementation may comprise an effective intervention in oxidative stress related neurological disorders. PMID- 24342568 TI - Fear response failed to return in AAB extinction paradigm accompanied with increased NR2B and GluR1 per845 in hippocampal CA1. AB - Extinction is a well-known and important behavioral phenomenon that allows an organism to adapt its behavior to its environment. Previous studies have shown that the expression of extinction is highly context dependent, meanwhile, conditioning context, as part of fear memory, might have influence on extinction formation. To this end, we have conducted four different extinction paradigms in this study: extinction conducted in the conditioning context but tested in another, novel context (AAB); conditioning in one context and extinction and testing in the second (ABB); conditioning in context A, extinction training in context B, but test back to context A (ABA); and extinction training in a third context, context C (ACB). Additionally, a low dose of the GABAA agonist muscimol was used to temporarily inactivate CA1 to observe its effect in extinction. Our results showed that rats under the AAB, but not the ACB or ABA condition, showed a similar level of freezing compared with the typical ABB extinction paradigm. Moreover, muscimol infused into CA1 before extinction training resulted in impaired extinction and down-regulation of NR2B activity and phosphorylated GluR1 (at Ser845) in CA1, and the expression levels of NR2B and GluR1 were decreased significantly in the basolateral amygdala (BLA). Thus, CA1 may play an important role in the context-specific expression of fear extinction, and Ser845 may be a phosphorylation site in GluR1 in CA1, triggering the context-specific response of extinction memory. PMID- 24342569 TI - Mu opioid receptor antagonism in the nucleus accumbens shell blocks consumption of a preferred sucrose solution in an anticipatory contrast paradigm. AB - Binge eating, a central feature of multiple eating disorders, is characterized by excessive consumption occurring during discrete, often brief, intervals. Highly palatable foods play an important role in these binge episodes - foods chosen during bingeing are typically higher in fat or sugar than those normally consumed. Multiple lines of evidence suggest a central role for signaling by endogenous opioids in promoting palatability-driven eating. This role extends to binge-like feeding studied in animal models, which is reduced by administration of opioid antagonists. However, the neural circuits and specific opioid receptors mediating these effects are not fully understood. In the present experiments, we tested the hypothesis that endogenous opioid signaling in the nucleus accumbens promotes consumption in a model of binge eating. We used an anticipatory contrast paradigm in which separate groups of rats were presented sequentially with 4% sucrose and then either 20% or 0% sucrose solutions. In rats presented with 4% and then 20% sucrose, daily training in this paradigm produced robust intake of 20% sucrose, preceded by learned hypophagia during access to 4% sucrose. We tested the effects of site-specific infusions of naltrexone (a nonspecific opioid receptor antagonist: 0, 1, 10, and 50MUg/side in the nucleus accumbens core and shell), naltrindole (a delta opioid receptor antagonist: 0, 0.5, 5, and 10MUg/side in the nucleus accumbens shell) and beta-funaltrexamine (a mu opioid receptor antagonist: 0 and 2.5MUg/side in the nucleus accumbens shell) on consumption in this contrast paradigm. Our results show that signaling through the mu opioid receptor in the nucleus accumbens shell is dynamically modulated during formation of learned food preferences, and promotes binge-like consumption of palatable foods based on these learned preferences. PMID- 24342571 TI - Helper function of CD4+ lymphocytes in antiviral immunity in ginbuna crucian carp, Carassius auratus langsdorfii. AB - Although many recent studies have suggested that CD4(+) helper T cell (Th-cell) functions are well conserved among teleost fishes and mammals, there is little evidence that CD4(+) Th-cells in fish are actually involved in both humoral and cell-mediated immunity during a secondary immune response. In the present study, adoptive transfer using clonal ginbuna crucian carp and crucian carp hematopoietic necrosis virus (CHNV) was used to investigate the functions of CD4(+) cells during humoral and cell-mediated immunity. With regard to humoral immunity, transplanting CHNV-sensitized donor cells, containing CD4(+) cells, into naive fish induced more rapid and stronger antibody production than by transplanting non-sensitized donor cells or sensitized donor cells lacking CD4(+) cells. During cell-mediated immunity, no significant differences were found in recipients that received sensitized cells regardless of whether the donor cells contained CD4(+) cells, although recipients that received both sensitized donor cells (with and without CD4(+) cells) exhibited more efficient cell-mediated cytotoxicity than those that received non-sensitized donor cells. These findings suggest that inducing a secondary antibody response requires CD4(+) cell help, and secondary cell-mediated immunity can be induced both by CD4(+) cells and leukocytes other than CD4(+) cells. PMID- 24342570 TI - Response to Commentary on "The influence of lung airways branching structure and diffusion time on measurements and models of short-range 3He gas MR diffusion". AB - Our extensive investigation of the cylinder model theory through numerical modelling and purpose-designed experiments has demonstrated that it does produce inaccurate estimates of airway dimensions at all diffusion times currently used. This is due to a variety of effects: incomplete treatment of non-Gaussian effects, finite airway size, branching geometry, background susceptibility gradients and diffusion time dependence of the (3)He MR diffusion behaviour in acinar airways. The cylinder model is a good starting point for the development of a lung morphometry technique from (3)He diffusion MR but its limitations need to be understood and documented in the interest of reliable clinical interpretation. PMID- 24342572 TI - Transfer of serum and cells from Yersinia ruckeri vaccinated doubled-haploid hot creek rainbow trout into outcross F1 progeny elucidates mechanisms of vaccine induced protection. AB - Yersinia ruckeri is a well-established bacterial pathogen for many salmonid species, against which a formalin-killed bacterin vaccine has been effective in reducing disease outbreaks. Previous studies have reported conflicting results about the protective value of the systemic humoral response to Y. ruckeri vaccination. Here we directly demonstrate that plasma contains the long-term protective component elicited by both immersion and intraperitoneal injection vaccination of rainbow trout. A total of 0.5 MUL of plasma from vaccinated fish provided almost complete protection against experimental challenge. Conversely, the cells obtained from peripheral blood conferred little or no protection in naive recipients. The protective component of immune sera was IgM based on size exclusion chromatography and recognition by monoclonal antibody Warr 1-14. Immune plasma generated against a Y. ruckeri biotype 1 strain protected equally against challenges with Y. ruckeri biotype 1 and 2 strains. These results illustrate the importance of the humoral IgM response against Y. ruckeri and the use of doubled haploid rainbow trout (Oncorhynchus mykiss) and transfer of plasma/serum and cells into F1 outcross progeny as a model system for dissection of the mechanism(s) of vaccine-induced protection. PMID- 24342573 TI - Immediate total temporomandibular joint replacement with TMJ concepts prosthesis as an alternative for ameloblastoma cases. AB - Ameloblastoma is a common epithelial odontogenic tumor, representing 1 to 3% of all cysts and tumors of the oral and maxillomandibular region. It has been more commonly found in the mandible than in the maxilla. Treatment of ameloblastoma is essentially surgical, ranging from conservative therapy such as enucleation, marsupialization, and curettage, to more radical approaches, including marginal, segmental, or composite resection. It has a high tendency to recur and, in some instances, has shown malignant development when treated inadequately. When resection is indicated, reconstructive measures must be considered. The aim of the present study is to report on 2 cases of large ameloblastomas of the solid/multicystic type that were treated by hemimandibulectomy and reconstructed with a novel technique consisting of a custom-made TMJ Concepts prosthesis (TMJ Concepts, Ventura, CA). The role and outcomes of custom-made temporomandibular joint prostheses in these circumstances are discussed. PMID- 24342574 TI - A new clinical manifestation for cheek alveolar soft-part sarcoma: a case report and review of the literature. AB - Alveolar soft part sarcoma (ASPS) is a rare, histologically distinct, soft tissue malignancy with nonspecific clinical features usually described as a nonulcerated, painless, expanding mass. It has a pseudoalveolar appearance with clustered polygonal cells lacking central cohesion. It accounts for approximately 0.5 to 1% of all soft tissue sarcomas. It has a strong predilection for adolescents and young adults 15 to 35 years old, with a female predominance. In general, ASPS grows slowly, with a predilection for the trunk and extremities and rarely in the head and neck region. A literature review found only 11 cases of cheek ASPS that have been reported since 1952. This report describes the case of an unusually rapidly growing mass in the cheek of a 36-year-old woman. The superficial location of the mass led to early detection and treatment. PMID- 24342575 TI - Self-perception of the facial profile: an aid in treatment planning for orthognathic surgery. AB - PURPOSE: To investigate the difference between the self-perception of the facial profile and analogous measurements of profile photographs in 2 age groups, adolescents and young adults, and adults. PATIENTS AND METHODS: A prototypical Caucasian profile was constructed for each gender by averaging the profiles of 28 subjects with normal occlusion. Each prototypical profile was manipulated by protruding and retruding the lips in 1-mm increments to construct a series of 13 silhouettes. Next, 85 laypeople were divided into 2 groups: adolescents and young adults (age, 15 to 25 years) and adults (age, 26 to 55 years). They were asked to complete a questionnaire that included choosing the facial profile in the constructed series they thought most resembled their own profile photograph. For each group, the difference between the chosen and actual profile was compared using a 1-sample t test. The differences between the 2 groups in identifying their own profile were compared using a 2-sample t test. RESULTS: The 2 groups were different in their ability to recognize their own profile (P = .040 for the upper lip and P = .006 for the lower lip). The adolescent and young adult group was most accurate, showing no significant difference from 0 for the chosen and actual profiles. However, the adult group was significantly different for both the upper (P = .040) and lower (P = .003) lips. CONCLUSIONS: From our study results, most laypeople aged 15 to 25 years could accurately evaluate the fullness of their own facial profile, although adults aged 26 to 55 years had more difficulty in this evaluation and tended to overestimate the protrusion of their lips. PMID- 24342576 TI - In vitro effect of bisphosphonates on oral keratinocytes and fibroblasts. AB - PURPOSE: Osteonecrosis of the jaws is a potential complication of bisphosphonate (BP) therapy. The underlying mechanisms remain unclear. Although most research has concentrated on the effects of BPs on osteoclast and osteoblast functions, the disease is diagnosed and classified based on of mucosal breakdown, suggesting that oral soft tissues may be involved in its pathogenesis. The aim of this study was to determine the effect of 3 different BP drugs (alendronate, zoledronate, and clodronate) on the function of oral keratinocytes and fibroblasts. MATERIALS AND METHODS: Human oral keratinocytes (OKF6) and fetal foreskin fibroblasts (HFFF2) were exposed to each drug at several concentrations and the effect on cell proliferation was assessed by counting the viable cells after different lengths of treatment. The effect on cell migration was examined using Transwell migration assays. An organotypic coculture model using keratinocytes and fibroblasts, which recapitulated the morphology of the oral mucosa, was used to assess the effect of the drugs on epithelial stratification and differentiation. RESULTS: The 3 BPs affected the viability and proliferation of OKF6 and HFFF2 cells at concentrations in keeping with their known relative in vitro potencies. There was no effect on cell migration or tissue architecture in organotypic cultures at subtoxic concentrations. CONCLUSION: The lack of effect of these drugs on cell migration below concentrations known to affect cell viability suggests that BP-related osteonecrosis is not caused through suppression of keratinocyte or fibroblast motility. PMID- 24342577 TI - Lymphoepithelial carcinoma--review of the treatment modalities and report of a rare case in the sublingual gland. AB - Controversies exist in the current literature regarding the treatment of lymphoepithelial carcinoma (LEC). The presented study summaries the literature controversies in the treatment of LEC and present a case of a rare LEC diagnosed in the sublingual gland of an otherwise healthy 21-year-old Arab woman. The patient was admitted for swelling in the sublingual area. A biopsy indicated a diagnosis of LEC of the sublingual gland. Treatment included a wide resection with safe margins, marginal mandibulectomy, functional neck dissection, and a radial forearm free flap for reconstruction. The patient received concomitant radiotherapy and has remained disease free since her last follow-up. The recommended primary treatment, based on the literature review, is primary surgical excision with neck dissection and optional adjuvant radiotherapy to the gland area. Chemotherapy was not found to be beneficial according to the literature. PMID- 24342578 TI - The treatment of large sialoliths by sialendoscopic combined approach. AB - PURPOSE: To investigate the advantages, disadvantages, and complications of the combined surgical technique for removing large sialoliths from the salivary glands. MATERIALS AND METHODS: This retrospective study analyzed 37 patients with obstructive sialadenitis caused by sialolithiasis who could not undergo surgery using a purely sialendoscopic technique because of the stone size or because of a tight distal stricture obstructing the passage of stone removal by an endoscope. RESULTS: Six patients had parotid gland obstruction, and the other 31 patients had submandibular gland obstruction. The calculi varied in size from 5 to 45 mm (average, 10.4 mm). Twenty-three stones were located at the hilar part of the gland or in the proximal part of the duct close to the hilum. The other 14 stones were located in the middle third of the duct. Thirty patients had no complications and were free of symptoms, with normal saliva secretion checked by milking the gland. Five patients developed minor complications that were treated under local anesthesia. Only 2 patients developed severe ductal restenosis and required further sialadenectomy. CONCLUSIONS: The combined technique showed good results for removing large sialoliths or proximally located sialoliths that could not have been removed by sialendoscopy alone. The use of an endoscope enables further exploration of the remaining duct, allowing for the removal of further sialolith and reconstruction of the duct after sialolith removal. The technique is not limited to stone size or location along the duct. PMID- 24342579 TI - Is the frequency of temporomandibular dysfunction different in various mandibular fractures? AB - PURPOSE: Trauma has been considered an important factor of temporomandibular dysfunction (TMD) etiology. The aim of the present study was to compare the frequency of TMDs in various mandibular fractures. MATERIALS AND METHODS: This was a retrospective cohort study. Mandibular fractures were subcategorized into 3 groups: group 1 had a unilateral condylar fracture, group 2 had a unilateral condylar fracture with a fracture of the contralateral body or angle of the mandible, and group 3 had a unilateral fracture of the body or angle of the mandible. TMD signs (click, pain) and maximum mouth opening (MMO) were the outcomes of the study, and fracture pattern was considered a predictor factor. Age, gender, and fixation methods were study variables. A chi(2) test was applied to compare TMD signs among groups. One-way analysis of variance was applied to compare MMO and age among groups. RESULTS: Ninety-nine patients in the 3 groups were examined for TMD signs. Results showed that 54.54% of patients in group 1, 69.69% of patients in group 2, and 24.24% of patients in group 3 had click in the temporomandibular joint (TMJ; unilaterally or bilaterally). Analysis of the data showed a significant difference among groups (P < .05). According to the results, 24.24% of patients in group 1, 73.91% of patients in group 2, and 12.12% of patients in group 3 had pain at the TMJ (unilaterally or bilaterally). There was a significant difference among groups for pain (P < .05). Analysis of the data did not show any difference for MMO among groups (P > .05). CONCLUSION: Patients who had a condylar fracture and a contralateral angle or body fracture seemed to have more TMD signs than those with a unilateral fracture. PMID- 24342580 TI - Amifostine preserves osteocyte number and osteoid formation in fracture healing following radiotherapy. AB - PURPOSE: Radiation is known to decrease osteocyte count and function, leading to bone weakening. A treatment strategy to mitigate these consequences could have immense therapeutic ramifications. The authors previously reported significantly decreased osteocyte count and mineralization capacity in a rat model of fracture healing after radiotherapy. They hypothesized that amifostine (AMF) would preserve osteocyte number and function in this model. MATERIALS AND METHODS: Thirty-six rats were divided into 3 groups: fracture, radiated fracture, and radiated fracture with AMF. Radiated groups underwent human-equivalent radiotherapy to the mandible before fixator placement and mandibular osteotomy. The AMF group received a subcutaneous injection before each dose of radiotherapy. After 40 days, mandibles were harvested for histologic processing. Quantification of osteocyte count (Oc), empty lacunae (EL), and osteoid ratio (osteoid volume [OV] to tissue volume [TV]) was performed and the results were compared using analysis of variance (P < .05). RESULTS: Radiated fractures showed significantly decreased Oc, increased EL, and a decreased capacity to produce new osteoid at the fracture site as measured with OV/TV compared with nonradiated fractures. In mandibles treated with AMF, these metrics were not statistically different than the control, indicating a preservation of osteocyte number and function. CONCLUSIONS: These results support the hypothesis that AMF preserves osteocyte number and function, thereby preventing the pernicious effects of radiotherapy on the cellular environment of fracture healing. Based on these findings, the authors encourage future investigation of this promising therapy for use in the prevention of pathologic fractures and osteoradionecrosis. PMID- 24342581 TI - Efficacy of plasma-rich growth factor in the healing of postextraction sockets in patients affected by insulin-dependent diabetes mellitus. AB - PURPOSE: To evaluate the efficacy of plasma-rich growth factor (PRGF) in improving socket healing after tooth extraction in diabetic patients. MATERIALS AND METHODS: This was a split-mouth study in which each patient also served as the control: the study socket was treated with PRGF, whereas the control socket underwent natural healing. The outcome variables were the Healing Index, residual socket volume, visual analog scale score, postsurgical complications, and outcome of a patient questionnaire. The investigation considered the impact of hyperglycemia, glycated hemoglobin, End Organ Disease Score, and smoking habits. Follow-up included 4 postextraction checkups over a 21-day period. Pairs of correlated continuous variables were analyzed with the Wilcoxon test, independent continuous variables with the Mann-Whitney test, and categorical variables with the chi(2) test or Fisher test. RESULTS: From January 2012 to December 2012, 34 patients affected by insulin-dependent diabetes mellitus underwent contemporary bilateral extractions of homologous teeth. The treatment-versus-control postoperative comparison showed that PRGF resulted in significantly smaller residual socket volumes and better Healing Indices from days 3 to 14. The patients' questionnaire outcomes were unanimously in favor of PRGF treatment. The small sample of patients with glycemia values of at least 240 mg/dL showed worse Healing Index and minor socket decreases. CONCLUSION: PRGF application after extraction improved the healing process in diabetic patients by accelerating socket closure (epithelialization) and tissue maturation, proving the association between PRGF use and improved wound healing in diabetic patients. PMID- 24342582 TI - Is autogenous abdominal fat transplantation into a large temporomandibular joint defect following removal of failed alloplastic prosthesis a definitive treatment? AB - PURPOSE: To evaluate the long-term clinical outcome after the removal of failed major alloplastic temporomandibular joint (TMJ) implants and the placement of an autologous abdominal fat graft. MATERIALS AND METHODS: A long-term clinical follow-up was performed in 4 patients who underwent removal of a failed alloplastic implant and insertion of an autologous abdominal fat graft under 1 stage surgical management. Postsurgical use of pain medication was documented and the vertical interincisal opening measurement was obtained at the follow-up visit. Long-term computed tomographic (CT) scans were available for 3 of 4 patients and evaluated for fat graft retention by a radiologist. Hounsfield units were used. RESULTS: The study showed long-term (average, 4.7 years) clinical success, including normal jaw function (>=30-mm vertical opening) and freedom from the use of pain-relieving medication. Long-term CT scans (average, 5 years after surgery) documented fat graft retention in 3 patients (-80 HU). CONCLUSION: Autogenous fat graft placement alone, after major TMJ alloplastic removal, provides excellent long-term clinical success. PMID- 24342583 TI - Sequential therapy of advanced buccal mucosa squamous cell carcinoma: three-year outcome. AB - PURPOSE: Squamous cell carcinoma (SCC) of the buccal mucosa is aggressive and requires multimodal treatment. The objective of this study was to evaluate the outcome of sequential therapy (neoadjuvant therapy plus surgery plus radiotherapy) in advanced buccal SCC and explore the prognostic factors. PATIENTS AND METHODS: In this retrospective cohort study, patients with advanced buccal cancer who received neoadjuvant chemotherapy (cisplatin, docetaxel, and 5 fluorouracil) followed by surgery and radiotherapy in the authors' department were reviewed. The outcomes of chemotherapy and surgery were analyzed. Overall survival (OS) and disease-free survival (DFS) were calculated using the Kaplan Meier method. The prognostic values of age, gender, histologic grade, lymph node status, tumor stage, pathologic response, and adverse pathologic features were explored using the log-rank test and the Cox regression model. RESULTS: From 2008 to 2011, data from 22 patients were analyzed. The overall response rate of chemotherapy was 72.7%. The pathologic complete or partial response rate was 40.9%. The median follow-up was 36 months. The 2-year DFS and OS rates were 63.3% and 67.2%, respectively. Male and younger patients showed an association with poor outcome. Multivariate analysis showed that gender was a predictive factor with respect to DFS and OS (P = .023 and .014, respectively). CONCLUSION: Sequential therapy (neoadjuvant therapy plus surgery plus radiotherapy) tends to be effective for advanced buccal cancer. Female patients have better survival. PMID- 24342584 TI - Influence of polymorphisms in the prion protein gene on the pathogenesis and neuropathological phenotype of sheep scrapie after oral infection. AB - The prion protein gene (Prnp) plays a crucial role in the susceptibility of sheep to scrapie in terms of attack rate and/or incubation period. However, the influence of Prnp on the pathogenesis of the disease, specifically the involvement of tissues of the lymphoreticular system (LRS), pathways of neuroinvasion and neuropathological phenotypes, remains controversial. This study reports the onset and progression of disease-associated prion protein (PrP(d)) accumulation in the LRS and nervous tissues of sheep of six different Prnp genotypes infected by oral administration of the same mixed scrapie brain homogenate. Sheep homozygous for glutamine (Q) at codon 171 of PrP, with either valine (V) or alanine (A) at codon 136 (i.e. VRQ/VRQ, VRQ/ARQ and ARQ/ARQ), showed early and consistent PrP(d) accumulation in LRS tissues of the pharynx and gut. In contrast, LRS involvement was minimal, inconsistent and occurred late in the incubation period in sheep heterozygous for arginine (R) at codon 171 (i.e. VRQ/ARR and ARQ/ARR). Despite this difference, all five groups were susceptible to infection and developed clinical disease, albeit with significantly different incubation periods (shortest in VRQ/VRQ and longest in ARQ/ARR sheep). The remaining group of ARR/ARR homozygous sheep did not show evidence of infection at the end of the experiment or at previous predetermined time points. As for LRS tissues, the sites of initial PrP(d) accumulation in the brain were determined immunohistochemically. These were the same in all susceptible sheep (except for ARR/ARR sheep), regardless of their Prnp genotype which, together with an early and consistent accumulation of PrP(d) in circumventricular organs and a late or inconsistent involvement of the enteric and autonomic nervous system and of the spinal cord, suggests neuroinvasion occurring via the blood. The neuropathological phenotype (PrP(d) profile in the central nervous system) of clinically affected sheep was similar in the three V136 carrier groups, but showed some differences in the two A136 homozygous groups, suggesting a codon 136 driven selection of different strains from the mixture contained in the inoculum. ARQ/ARR sheep showed an irregular distribution of brain PrP(d), contrasting with the more widespread distribution of the other four groups. The results indicate that (1) ARQ/ARR sheep are more susceptible to oral scrapie infection than would be predicted from incidence figures in natural disease, (2) amplification and accumulation of PrP(d) in LRS tissues is host genotype dependent, but does not necessarily have a marked effect on the outcome of the infection and (3) the neuropathological phenotype of scrapie is related to the host genotype, but possibly in combination with the infecting source. PMID- 24342585 TI - Neighbourhood-level socio-environmental factors and incidence of first episode psychosis by place at onset in rural Ireland: the Cavan-Monaghan First Episode Psychosis Study [CAMFEPS]. AB - BACKGROUND: Little is known about associations between the social environment and risk for psychosis within rural settings. This study sought to investigate whether such associations exist within a rural context using a prospective dataset of unusual epidemiological completeness. METHOD: Using the Cavan-Monaghan First Episode Psychosis Study database of people aged 16 years and older, both ecological analyses and multilevel modelling were applied to investigate associations between incidence of psychosis by place at onset and socio environmental risk factors of material deprivation, social fragmentation and urban-rural classification across electoral divisions. RESULTS: The primary finding was an association between more deprived social contexts and higher rates of psychotic disorder, after adjustment for age and sex [all psychoses: incidence rate ratio (IRR)=1.12, 95% CI (1.03-1.23)]. CONCLUSIONS: These findings support an association between adverse socio-environmental factors and increase in risk for psychosis by place at onset within a predominantly rural environment. This study suggests that social environmental characteristics may have an impact on risk across the urban-rural gradient. PMID- 24342587 TI - The optical biopsy of small gastric lesions. PMID- 24342586 TI - Abnormalities in the processing of emotional prosody from single words in schizophrenia. AB - BACKGROUND: Abnormalities in emotional prosody processing have been consistently reported in schizophrenia and are related to poor social outcomes. However, the role of stimulus complexity in abnormal emotional prosody processing is still unclear. METHOD: We recorded event-related potentials in 16 patients with chronic schizophrenia and 16 healthy controls to investigate: 1) the temporal course of emotional prosody processing; and 2) the relative contribution of prosodic and semantic cues in emotional prosody processing. Stimuli were prosodic single words presented in two conditions: with intelligible (semantic content condition-SCC) and unintelligible semantic content (pure prosody condition-PPC). RESULTS: Relative to healthy controls, schizophrenia patients showed reduced P50 for happy PPC words, and reduced N100 for both neutral and emotional SCC words and for neutral PPC stimuli. Also, increased P200 was observed in schizophrenia for happy prosody in SCC only. Behavioral results revealed higher error rates in schizophrenia for angry prosody in SCC and for happy prosody in PPC. CONCLUSIONS: Together, these data further demonstrate the interactions between abnormal sensory processes and higher-order processes in bringing about emotional prosody processing dysfunction in schizophrenia. They further suggest that impaired emotional prosody processing is dependent on stimulus complexity. PMID- 24342588 TI - Palliative treatment of gastric outlet obstruction in terminal patients: SEMS. Stent every malignant stricture! PMID- 24342589 TI - From gastroenterologist to surgeon to gastroenterologist for management of large sessile colonic polyps: something new under the sun? PMID- 24342590 TI - Peroral endoscopic myotomy as a platform for the treatment of spastic esophageal disorders refractory to medical therapy (with video). PMID- 24342591 TI - Direct peroral cholangioscopy using ultraslim gastroscopes: high technical performance with important diagnostic yield. PMID- 24342592 TI - A "resect and watch" strategy with endoscopic resection for pharyngeal cancer with massive subepithelial invasion would not be rational. PMID- 24342593 TI - Response. PMID- 24342594 TI - Gastroesophageal acid reflux mainly occurs on the right side of the esophagus. PMID- 24342595 TI - Response. PMID- 24342596 TI - Response. PMID- 24342597 TI - Controlled trial of TIPS versus cyanoacrylate glue for gastric variceal bleeding. PMID- 24342598 TI - Novel irregular vascular pattern features of serrated adenoma detected by high definition iScan endoscopic technique. PMID- 24342599 TI - Response. PMID- 24342600 TI - Using a stent extractor for a case of pill impaction: a novel approach. PMID- 24342601 TI - Compensation and benefits: positive trends. PMID- 24342602 TI - Nutrition apps: opportunities to guide patients and grow your career. PMID- 24342603 TI - Compensation and benefits survey 2013: education and job responsibility key to increased compensation. PMID- 24342604 TI - Research in nutrition and dietetics--what can the academy do for you? PMID- 24342605 TI - Position of the academy of nutrition and dietetics: dietary fatty acids for healthy adults. AB - It is the position of the Academy of Nutrition and Dietetics (the Academy) that dietary fat for the healthy adult population should provide 20% to 35% of energy, with an increased consumption of n-3 polyunsaturated fatty acids and limited intake of saturated and trans fats. The Academy recommends a food-based approach through a diet that includes regular consumption of fatty fish, nuts and seeds, lean meats and poultry, low-fat dairy products, vegetables, fruits, whole grains, and legumes. These recommendations are made within the context of rapidly evolving science delineating the influence of dietary fat and specific fatty acids on human health. In addition to fat as a valuable and calorically dense macronutrient with a central role in supplying essential nutrition and supporting healthy body weight, evidence on individual fatty acids and fatty acid groups is emerging as a key factor in nutrition and health. Small variations in the structure of fatty acids within broader categories of fatty acids, such as polyunsaturated and saturated, appear to elicit different physiological functions. The Academy recognizes that scientific knowledge about the effects of dietary fats on human health is young and takes a prudent approach in recommending an increase in fatty acids that benefit health and a reduction in fatty acids shown to increase risk of disease. Registered dietitian nutritionists are uniquely positioned to translate fat and fatty acid research into practical and effective dietary recommendations. PMID- 24342606 TI - How can I support my clients in setting realistic weight loss goals? PMID- 24342607 TI - Effect of methionine sulfoxide reductase B1 (SelR) gene silencing on peroxynitrite-induced F-actin disruption in human lens epithelial cells. AB - F-actin plays a crucial role in fundamental cellular processes, and is extremely susceptible to peroxynitrite attack due to the high abundance of tyrosine in the peptide. Methionine sulfoxide reductase (Msr) B1 is a selenium-dependent enzyme (selenoprotein R) that may act as a reactive oxygen species (ROS) scavenger. However, its function in coping with reactive nitrogen species (RNS)-mediated stress and the physiological significance remain unclear. Thus, the present study was conducted to elucidate the role and mechanism of MsrB1 in protecting human lens epithelial (hLE) cells against peroxynitrite-induced F-actin disruption. While exposure to high concentrations of peroxynitrite and gene silencing of MsrB1 by siRNA alone caused disassembly of F-actin via inactivation of extracellular signal-regulated kinase (ERK) in hLE cells, the latter substantially aggravated the disassembly of F-actin triggered by the former. This aggravation concurred with elevated nitration of F-actin and inactivation of ERK compared with that induced by the peroxynitrite treatment alone. In conclusion, MsrB1 protected hLE cells against the peroxynitrite-induced F-actin disruption, and the protection was mediated by inhibiting the resultant nitration of F-actin and inactivation of ERKs. PMID- 24342608 TI - A mitochondrial thioredoxin-sensitive mechanism regulates TGF-beta-mediated gene expression associated with epithelial-mesenchymal transition. AB - Transforming growth factor (TGF)-beta is a pro-oncogenic cytokine that induces the epithelial-mesenchymal transition (EMT), a crucial event in tumor progression. During TGF-beta-mediated EMT in NMuMG mouse mammary epithelial cells, we observed sustained increases in reactive oxygen species (ROS) levels in the cytoplasm and mitochondria with a concomitant decrease in mitochondrial membrane potential and intracellular glutathione levels. In pseudo rho0 cells, whose respiratory chain function was impaired, the increase in intracellular ROS levels was abrogated, suggesting an important role of mitochondrial activity as a trigger for TGF-beta-stimulated ROS generation. In line with this, TGF-beta mediated expression of the EMT marker fibronectin was inhibited not only by chemicals that interfere with ROS signaling but also by exogenously expressed mitochondrial thioredoxin (TXN2) independent of Smad signaling. Of note, TGF-beta mediated induction of HMGA2, a central mediator of EMT and metastatic progression, was similarly impaired by TXN2 expression, revealing a novel mechanism involving a thiol oxidation reaction in mitochondria, which regulates TGF-beta-mediated gene expression associated with EMT. PMID- 24342609 TI - Generation of stable 3'-mRNA cleavage fragments induced by siRNA in cells with high-levels of duck hepatitis B virus replication. AB - Therapeutic small interfering RNAs (siRNAs) have attracted a lot of interest both in basic biomedical sciences as well as in translational medicine. Apart from their therapeutic efficacy adverse effects of siRNAs must be addressed. The generation of stable mRNA cleavage fragments and the translation of N-truncated proteins induced by antisense oligodeoxynucleotides (ASOs) have been reported. Similar to ASOs, siRNAs are considered to function via an antisense mechanism that promotes the cleavage of the target mRNA. To further investigate whether the stable mRNA cleavage fragments also occur in siRNA we constructed a short hairpin RNA (shRNA) expression plasmid, pshRNA794, containing the same sequence reported in experiments using ASOs which directly targeted the overlapping region of the pre-genomic mRNA (pgmRNA) and sub-genomic mRNA (sgmRNA) of duck hepatitis B virus (DHBV). The shRNA resulted in a 70.9% and 69.9% reduction of the DHBV mRNAs in LMH and HuH-7 cells, respectively. In addition a 70% inhibition of the DHBV DNA level was observed. Interestingly, 3'-mRNA cleavage fragments were detected in LMH but not in HuH-7 cells. Taken together, our findings demonstrate that the ASO sequence was also effective in siRNA. Importantly, our results provide direct evidence that stable 3'-mRNA fragments were generated by siRNA in cells with high levels of DHBV replication. Whether these can cause adverse RNAi effects needs to be explored further. PMID- 24342610 TI - MicroRNA-21 accelerates hepatocyte proliferation in vitro via PI3K/Akt signaling by targeting PTEN. AB - MicroRNAs (miRNAs) are involved in controlling hepatocyte proliferation during liver regeneration. In this study, we established the miRNAs-expression patterns of primary hepatocytes in vitro under stimulation of epidermal growth factor (EGF), and found that microRNA-21 (miR-21) was appreciably up-regulated and peaked at 12h. In addition, we further presented evidences indicating that miR-21 promotes primary hepatocyte proliferation through in vitro transfecting with miR 21 mimics or inhibitor. We further demonstrated that phosphatidylinositol 3'-OH kinase (PI3K)/Akt signaling was altered accordingly, it is, by targeting phosphatase and tensin homologue deleted on chromosome 10, PI3K/Akt signaling is activated by miR-21 to accelerate hepatocyte rapid S-phase entry and proliferation in vitro. PMID- 24342611 TI - Activation of double-stranded RNA-dependent protein kinase inhibits proliferation of pancreatic beta-cells. AB - Double-stranded RNA-dependent protein kinase (PKR) is revealed to participate in the development of insulin resistance in peripheral tissues in type 2 diabetes (T2DM). Meanwhile, PKR is also characterized as a critical regulator of cell proliferation. To date, no study has focused on the impact of PKR on the proliferation of pancreatic beta-cells. Here, we adopted insulinoma cell lines and mice islet beta-cells to investigate: (1) the effects of glucolipotoxicity and pro-inflammatory cytokines on PKR activation; (2) the effects of PKR on proliferation of pancreatic beta-cells and its underlying mechanisms; (3) the actions of PKR on pro-proliferative effects of IGF-I and its underlying pathway. Our results provided the first evidence that PKR can be activated by glucolipitoxicity and pro-inflammatory cytokines in pancreatic beta-cells, and activated PKR significantly inhibited cell proliferation by arresting cell cycle at G1 phase. Reductions in cyclin D1 and D2 as well as increases in p27 and p53 were associated with the anti-proliferative effects of PKR, and proteasome dependent degradation took part in the reduction of cyclin D1 and D2. Besides, PKR activation abrogated the pro-proliferative effects of IGF-I by activating JNK and disrupting IRS1/PI3K/Akt signaling pathway. These findings indicate that the anti-proliferative actions of PKR on pancreatic beta-cells may contribute to the pathogenesis of T2DM. PMID- 24342612 TI - Evaluation and identification of hepatitis B virus entry inhibitors using HepG2 cells overexpressing a membrane transporter NTCP. AB - Hepatitis B virus (HBV) entry has been analyzed using infection-susceptible cells, including primary human hepatocytes, primary tupaia hepatocytes, and HepaRG cells. Recently, the sodium taurocholate cotransporting polypeptide (NTCP) membrane transporter was reported as an HBV entry receptor. In this study, we established a strain of HepG2 cells engineered to overexpress the human NTCP gene (HepG2-hNTCP-C4 cells). HepG2-hNTCP-C4 cells were shown to be susceptible to infection by blood-borne and cell culture-derived HBV. HBV infection was facilitated by pretreating cells with 3% dimethyl sulfoxide permitting nearly 50% of the cells to be infected with HBV. Knockdown analysis suggested that HBV infection of HepG2-hNTCP-C4 cells was mediated by NTCP. HBV infection was blocked by an anti-HBV surface protein neutralizing antibody, by compounds known to inhibit NTCP transporter activity, and by cyclosporin A and its derivatives. The infection assay suggested that cyclosporin B was a more potent inhibitor of HBV entry than was cyclosporin A. Further chemical screening identified oxysterols, oxidized derivatives of cholesterol, as inhibitors of HBV infection. Thus, the HepG2-hNTCP-C4 cell line established in this study is a useful tool for the identification of inhibitors of HBV infection as well as for the analysis of the molecular mechanisms of HBV infection. PMID- 24342613 TI - Hes1 promotes the IL-22-mediated antimicrobial response by enhancing STAT3 dependent transcription in human intestinal epithelial cells. AB - Notch signaling plays an essential role in the proliferation and differentiation of intestinal epithelial cells (IECs). We have previously shown that Notch signaling is up-regulated in the inflamed mucosa of ulcerative colitis (UC) and thereby plays an indispensable role in tissue regeneration. Here we show that in addition to Notch signaling, STAT3 signaling is highly activated in the inflamed mucosa of UC. Forced expression of the Notch target gene Hes1 dramatically enhanced the IL-22-mediated STAT3-dependent transcription in human IECs. This enhancement of STAT3-dependent transcription was achieved by the extended phosphorylation of STAT3 by Hes1. Microarray analysis revealed that Hes1-mediated enhancement of IL-22-STAT3 signaling significantly increased the induction of genes encoding antimicrobial peptides, such as REG1A, REG3A and REG3G, in human IECs. Conversely, the reduction of Hes1 protein levels with a gamma-secretase inhibitor significantly down-regulated the induction of those genes in IECs, resulting in a markedly poor response to IL-22. Our present findings identify a new role for the molecular function of Hes1 in which the protein can interact with cytokine signals and regulate the immune response of IECs. PMID- 24342614 TI - AKT is critically involved in cooperation between obesity and the dietary carcinogen amino-1-methyl-6-phenylimidazo [4,5-b] (PhIP) toward colon carcinogenesis in rats. AB - Obesity is highly associated with colon cancer development. Whereas it is generally attributed to pro-tumorigenic effects of high fat diet (HFD), we here show that a common genetic basis for predisposition to obesity and colon cancer might also underlie the close association. Comparison across multiple rat strains revealed that strains prone to colon tumorigenesis initiated by a dietary carcinogen amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) tended to develop obesity. Through transcriptome and extensive immunoblotting analyses, we identified the basal level of activated AKT in colonic crypts as a biomarker for the common predisposition. Notably, PhIP induced activation of AKT, which could persist for several weeks under a low fat diet (LFD), but not under HFD. On the other hand, PhIP and HFD independently induced Wnt pathway activation and inhibited apoptosis, through distinct mechanisms involving GSK-3beta, caspase 3 and poly-ADP ribose polymerase (PARP). Taken together, these observations provide mechanistic insights into how PhIP-induced activation of AKT might cooperate with HFD at multiple levels toward development of colon cancer. PMID- 24342615 TI - CD8(+)CD25(+) T cells reduce atherosclerosis in apoE(-/-) mice. AB - BACKGROUND: It is increasingly evident that CD8(+) T cells are involved in atherosclerosis but the specific subtypes have yet to be defined. CD8(+)CD25(+) T cells exert suppressive effects on immune signaling and modulate experimental autoimmune disorders but their role in atherosclerosis remains to be determined. The phenotype and functional role of CD8(+)CD25(+) T cells in experimental atherosclerosis were investigated in this study. METHODS AND RESULTS: CD8(+)CD25(+) T cells were observed in atherosclerotic plaques of apoE(-/-) mice fed hypercholesterolemic diet. Characterization by flow cytometric analysis and functional evaluation using a CFSE-based proliferation assays revealed a suppressive phenotype and function of splenic CD8(+)CD25(+) T cells from apoE(-/ ) mice. Depletion of CD8(+)CD25(+) from total CD8(+) T cells rendered higher cytolytic activity of the remaining CD8(+)CD25(-) T cells. Adoptive transfer of CD8(+)CD25(+) T cells into apoE(-/-) mice suppressed the proliferation of splenic CD4(+) T cells and significantly reduced atherosclerosis in recipient mice. CONCLUSIONS: Our study has identified an athero-protective role for CD8(+)CD25(+) T cells in experimental atherosclerosis. PMID- 24342617 TI - Cell adhesion and invasion inhibitory effect of an ovarian cancer targeting peptide selected via phage display in vivo. AB - Organ-specific metastasis is of great importance since most of the cancer deaths are caused by spread of the primary cancer to distant sites. Therefore, targeted anti-metastases therapies are needed to prevent cancer cells from metastasizing to different organs. The phage clone pc3-1 displaying peptide WSGPGVWGASVK selected by phage display had been identified which have high binding efficiency and remarkable cell specificity to SK-OV-3 cells. In the present work, the effects of selected cell-binding phage and cognate peptide on the cell adhesion and invasion of targeted cells were investigated. Results showed that the adhesive ability of SK-OV-3 to extracellular matrix was inhibited by pc3-1 and peptide WSGPGVWGASVK, and pc3-1 blocked SK-OV-3 cells attachment more effective than the cognate peptide. The peptide WSGPGVWGASVK suppressed the cell number of SK-OV-3 that attached to HUVECs monolayer up to 24% and could block the spreading of the attaching cells. Forthermore, the cognate peptide could inhibit the invasion of SK-OV-3 significantly. The number of invaded SK-OV-3 cells and invaded SK-OV-3-activated HUVECs pretreated with peptide WSGPGVWGASVK was decreased by 24.3% and 36.6%, respectively. All these results suggested that peptide WSGPGVWGASVK might possess anti-metastasis against SK-OV-3 cells. PMID- 24342616 TI - HUWE1 interacts with BRCA1 and promotes its degradation in the ubiquitin proteasome pathway. AB - The cellular BRCA1 protein level is essential for its tumor suppression activity and is tightly regulated through multiple mechanisms including ubiquitn proteasome system. E3 ligases are involved to promote BRCA1 for ubiquitination and degradation. Here, we identified HUWE1/Mule/ARF-BP1 as a novel BRCA1 interacting protein involved in the control of BRCA1 protein level. HUWE1binds BRCA1 through its N-terminus degron domain. Depletion of HUWE1 by siRNA-mediated interference significantly increases BRCA1 protein levels and prolongs the half life of BRCA1. Moreover, exogenous expression of HUWE1 promotes BRCA1 degradation through the ubiquitin-proteasome pathway, which could explain an inverse correlation between HUWE1 and BRCA1 levels in MCF10F, MCF7 and MDA-MB-231 breast cancer cells. Consistent with a functional role for HUWE1 in regulating BRCA1 mediated cellular response to DNA damage, depletion of HUWE1 by siRNA confers increased resistance to ionizing radiation and mitomycin. These data indicate that HUWE1 is a critical negative regulator of BRCA1 and suggest a new molecular mechanism for breast cancer pathogenesis. PMID- 24342618 TI - Laminin receptor mediates anti-inflammatory and anti-thrombogenic effects of pigment epithelium-derived factor in myeloma cells. AB - Pigment epithelium-derived factor (PEDF) has anti-inflammatory and anti thrombogenic properties both in cell culture and animal models. Although adipose triglyceride lipase (ATGL) and laminin receptor (LR) are two putative receptors for PEDF, which receptor mainly mediates the beneficial effects of PEDF is largely unknown. In this study, we addressed the issue. siRNA raised against LR (siLR) and siATGL transfection dramatically decreased LR and ATGL levels in human cultured myeloma cells, respectively. Ten nM PEDF significantly reduced vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), intercellular cell adhesion molecule-1 (ICAM-1) and plasminogen activator inhibitor-1 (PAI-1) mRNA levels in siCon- or siATGL-transfected myeloma cells, whereas PEDF increased rather than decreased these gene expressions in siLR transfected cells. Neutralizing antibody directed against LR (LR-Ab) or LR antagonist actually bound to LR and reduced mRNA levels of VEGF, MCP-1, ICAM-1 and PAI-1 in myeloma cells. Further, pre-treatment of LR-Ab or LR antagonist suppressed the binding of PEDF to LR and resultantly blocked the effects of PEDF in myeloma cells. In addition, high concentration of LR agonist mimicked the actions of PEDF on these gene expressions in myeloma cells. This study indicates that PEDF causes anti-angiogenic, anti-inflammatory and anti-thrombogenic reactions in myeloma cells through the interaction with LR. Target domain of LR agonist and antagonist might be involved in the PEDF-signaling to gene suppression in myeloma cells. PMID- 24342621 TI - Methylcobalamin promotes proliferation and migration and inhibits apoptosis of C2C12 cells via the Erk1/2 signaling pathway. AB - Methylcobalamin (MeCbl) is a vitamin B12 analog that has some positive effects on peripheral nervous disorders. Although some previous studies revealed the effects of MeCbl on neurons, its effect on the muscle, which is the final target of motoneuron axons, remains to be elucidated. This study aimed to determine the effect of MeCbl on the muscle. We found that MeCbl promoted the proliferation and migration of C2C12 myoblasts in vitro and that these effects are mediated by the Erk1/2 signaling pathway without affecting the activity of the Akt signaling pathway. We also demonstrated that MeCbl inhibits C2C12 cell apoptosis during differentiation. Our results suggest that MeCbl has beneficial effects on the muscle in vitro. MeCbl administration may provide a novel therapeutic approach for muscle injury or degenerating muscle after denervation. PMID- 24342619 TI - Dipeptidyl peptidase-4 inhibitor ameliorates early renal injury through its anti inflammatory action in a rat model of type 1 diabetes. AB - INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors are incretin-based drugs in patients with type 2 diabetes. In our previous study, we showed that glucagon like peptide-1 (GLP-1) receptor agonist has reno-protective effects through anti inflammatory action. The mechanism of action of DPP-4 inhibitor is different from that of GLP-1 receptor agonists. It is not obvious whether DPP-4 inhibitor prevents the exacerbation of diabetic nephropathy through anti-inflammatory effects besides lowering blood glucose or not. The purpose of this study is to clarify the reno-protective effects of DPP-4 inhibitor through anti-inflammatory actions in the early diabetic nephropathy. MATERIALS AND METHODS: Five-week-old male Sprague-Dawley (SD) rats were divided into three groups; non-diabetes, diabetes and diabetes treated with DPP-4 inhibitor (PKF275-055; 3 mg/kg/day). PKF275-055 was administered orally for 8 weeks. RESULTS: PKF275-055 increased the serum active GLP-1 concentration and the production of urinary cyclic AMP. PKF275 055 decreased urinary albumin excretion and ameliorated histological change of diabetic nephropathy. Macrophage infiltration was inhibited, and inflammatory molecules were down-regulated by PKF275-055 in the glomeruli. In addition, nuclear factor-kappaB (NF-kappaB) activity was suppressed in the kidney. CONCLUSIONS: These results indicate that DPP-4 inhibitor, PKF275-055, have reno protective effects through anti-inflammatory action in the early stage of diabetic nephropathy. The endogenous biological active GLP-1 might be beneficial on diabetic nephropathy besides lowering blood glucose. PMID- 24342622 TI - Targeting of p53 peptide analogues to anti-apoptotic Bcl-2 family proteins as revealed by NMR spectroscopy. AB - Inhibition of the interaction between the p53 tumor suppressor and its negative regulator MDM2 is of great importance to cancer therapy. The anti-apoptotic Bcl-2 family proteins are also attractive anti-cancer molecular targets, as they are key regulators of apoptotic cell death. Previously, we reported the interactions between the p53 transactivation domain (p53TAD) and diverse members of the anti apoptotic Bcl-2 family proteins. In this study, we investigated the binding of MDM2-inhibiting p53TAD peptide analogues, p53-MDM2/MDMX inhibitor (PMI) and pDI, with anti-apoptotic Bcl-2 family proteins, Bcl-XL and Bcl-2, by using NMR spectroscopy. The NMR chemical shift perturbation data demonstrated the direct binding of the p53 peptide analogues to Bcl-XL and Bcl-2 and showed that the PMI and pDI peptides bind to a conserved hydrophobic groove of the anti-apoptotic Bcl 2 family proteins. Furthermore, the structural model of the Bcl-XL/PMI peptide complex showed that the binding mode of the PMI peptide is highly similar to that of pro-apoptotic Bcl-2 homology 3 (BH3) peptides. Finally, our structural comparison provided a molecular basis for how the same PMI peptide can bind to two distinct anti-cancer target proteins Bcl-XL and MDM2, which may have potential applications for multi-targeting cancer therapy. PMID- 24342620 TI - TLR4-dependent metabolic changes are associated with cognitive impairment in an animal model of type 1 diabetes. AB - We investigated the role of Toll-like receptor 4 (TLR4), a major mediator of innate immune responses, on cognitive performance in a type 1 diabetes model (T1D). After administration of streptozotocin, both TLR4 knockout (TLR4 KO) and wild type (WT) diabetic mice displayed metabolic alterations similar to those observed in T1D patients, including increased levels of glucose, cholesterol, triglycerides and ketones. T1D mice exhibited cognitive impairment which was less severe in TLR4 KO mice compared to WT mice. WT mice with higher glucose and those with higher triglyceride levels exhibited significantly more anxiety and impaired memory compared to those with lower levels of glucose and triglycerides; these correlations were absent in TLR4 KO mice. Additional findings suggest roles for TLR4 signaling in modifying the expression of enzymes involved in energy metabolism in brain cells in the setting of T1D. Our data show that TLR4 contributes to the negative impact of T1D on anxiety and cognition. PMID- 24342623 TI - Coordinated transcriptional regulation of isopentenyl diphosphate biosynthetic pathway enzymes in plastids by phytochrome-interacting factor 5. AB - All isoprenoids are derived from a common C5 unit, isopentenyl diphosphate (IPP). In plants, IPP is synthesized via two distinct pathways; the cytosolic mevalonate pathway and the plastidial non-mevalonate (MEP) pathway. In this study, we used a co-expression analysis to identify transcription factors that coordinately regulate the expression of multiple genes encoding enzymes in the IPP biosynthetic pathway. Some candidates showed especially strong correlations with multiple genes encoding MEP-pathway enzymes. We report here that phytochrome interacting factor 5 (PIF5), a basic-helix-loop-helix type transcription factor, functions as a positive regulator of the MEP pathway. Its overexpression in T87 suspension cultured cells resulted in increased accumulation of chlorophylls and carotenoids. Detailed analyses of carotenoids by HPLC indicated that some carotenoid biosynthetic pathways were concomitantly up-regulated, possibly as a result of enhanced IPP metabolic flow. Our results also revealed other PIF family proteins that play different roles from that of PIF5 in IPP metabolism. PMID- 24342624 TI - Role of subject-specific musculoskeletal loading on the prediction of bone density distribution in the proximal femur. AB - The typical bone density patterns in the proximal femur can be explained using bone remodeling simulations incorporating a load-adaptive response. Yet, subject specific variations in bone density have not received much attention. Therefore, the objective of this study was to quantify to what extent subject-specific bone geometry and subject-specific musculoskeletal loading affect the predicted bone density distribution. To accomplish this goal, a computational bone remodeling scheme was combined with gait analysis and a subject-specific musculoskeletal model. Finite element models incorporating the subject-specific geometry as well as the subject-specific hip contact forces and associated muscle forces were used to predict the density distribution in the proximal femur of three individuals. Next, the subject-specific musculoskeletal loads were interchanged between the subjects and the resulting changes in bone remodeling of the proximal femur were analyzed. Simulations results were compared to computed tomography (CT) image based density profiles. The results confirm that the predicted bone density distribution in the proximal femur is drastically influenced by the inclusion of subject-specific loading, i.e. hip contact forces and muscle forces calculated based on gait analysis data and musculoskeletal modeling. This factor dominated the effect of individualized geometry. We conclude that when predicting femoral density distribution in patients, the effect of subject-specific differences in loading conditions of the hip joint and the associated difference in muscle forces needs to be accounted for. PMID- 24342625 TI - Characterization of uniaxial stiffness of extracellular matrix embedded with magnetic beads via bio-conjugation and under the influence of an external magnetic field. AB - In this paper, we study the deformation, and experimentally quantify the change in stiffness, of an extracellular matrix (ECM) embedded with magnetic beads that are bio-conjugated with the collagen fibers and under the influence of an external magnetic field. We develop an analytical model of the viscoelastic behavior of this modified ECM, and design and implement a stretch test to quantify (based on statistically meaningful experiment data) the resulting changes in its stiffness induced by the external magnetic field. The analytical results are in close agreement with that obtained from the experiments. We discuss the implication of these results that point to the possibility of creating desired stiffness gradients in an ECM in vitro to influence cell behavior. PMID- 24342627 TI - A letter from the editors. PMID- 24342626 TI - Clinical significance of heterogeneity in response to retreatment with epidermal growth factor receptor tyrosine kinase inhibitors in patients with lung cancer acquiring secondary resistance to the drug. AB - BACKGROUND: In patients with lung cancer acquiring resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), an intrapatient heterogeneity in response to retreatment with EGFR-TKIs remains to be elucidated. PATIENTS AND METHODS: Records were retrospectively reviewed for 68 patients with advanced non-small-cell lung cancer who received second EGFR-TKIs after systemic progression that followed durable response to the first EGFR-TKIs. All tumor lesions identified on radiologic images before second EGFR-TKIs were categorized into organs. Tumor response to EGFR-TKIs was assessed per patient and per organ. Mixed response (MR) was defined as the coexistence of at least 2 responsive and progressive organs. RESULTS: Tumor lesions were detected in 244 organs. The response rate (RR) and median time to progression (TTP) to second EGFR-TKIs for patients were 26.5% and 11.6 weeks (95% CI, 8.5-14.7 weeks), and the RR and median TTP for organs were 38.8% and 17.3 weeks (95% CI, 14.8-19.8 weeks). Of 35 patients categorized to progressive disease, 22 (62.8%) showed MR. Among organs, the RR was highest for the central nervous system (CNS) and lowest for the liver (CNS vs. others vs. liver: 77.8%, 36.9%, 17.6%; P < .001). Multivariate analysis confirmed the organ type and prior drug sensitivity at the time of stopping first EGFR-TKIs as predictors for the risk of progression to second EGFR-TKIs in organs. CONCLUSIONS: Intrapatient heterogeneity in response to second EGFR-TKIs is not a rare event. The organ type and prior drug sensitivity at the failure time of first EGFR-TKIs may predict the efficacy of second EGFR-TKIs in individual organs. PMID- 24342628 TI - Overall health of Americans seems to be improving, report finds. PMID- 24342630 TI - Deciding authorship order. PMID- 24342629 TI - Neocentromeres: a place for everything and everything in its place. AB - Centromeres are essential for chromosome inheritance and genome stability. Centromeric proteins, including the centromeric histone centromere protein A (CENP-A), define the site of centromeric chromatin and kinetochore assembly. In many organisms, centromeres are located in or near regions of repetitive DNA. However, some atypical centromeres spontaneously form on unique sequences. These neocentromeres, or new centromeres, were first identified in humans, but have since been described in other organisms. Neocentromeres are functionally and structurally similar to endogenous centromeres, but lack the added complication of underlying repetitive sequences. Here, we discuss recent studies in chicken and fungal systems where genomic engineering can promote neocentromere formation. These studies reveal key genomic and epigenetic factors that support de novo centromere formation in eukaryotes. PMID- 24342631 TI - vanO, a new glycopeptide resistance operon in environmental Rhodococcus equi isolates. AB - We describe here the sequence and gene organization of a new glycopeptide resistance operon (vanO) in Rhodococcus equi from soil. The vanO operon has low homology to enterococcal van operons and harbors a vanHOX cluster transcribed in the direction opposite that of the vanS-vanR regulatory system and composed of three open reading frames with unknown function. This finding has clinical interest, since glycopeptides are used to treat R. equi infections and resistance has been reported in clinical isolates. PMID- 24342632 TI - Novel composite efficacy measure to demonstrate the rationale and efficacy of combination antiviral-anti-inflammatory treatment for recurrent herpes simplex labialis. AB - Historically, the primary target for research and treatment of recurrent herpes simplex labialis (HSL) has been limited to inhibiting herpes simplex virus (HSV) replication. Antiviral monotherapy, however, has proven only marginally effective in curtailing the duration and severity of recurrent lesions. Recently, the role of inflammation in the progression and resolution of recurrences has been identified as an additional target. This was evaluated in a randomized study comparing combination topical 5% acyclovir-1% hydrocortisone cream (AHC) with 5% acyclovir alone (AC; in the AHC vehicle) and the vehicle. The efficacy of each topical therapy was evaluated for cumulative lesion size--a novel composite efficacy endpoint incorporating episode duration, lesion area, and proportion of nonulcerative lesions. In that study, cumulative lesion area was significantly decreased with AHC compared with AC (25% decrease; P<0.05) and the vehicle (50% decrease; P<0.0001). As research continues in this arena, cumulative lesion area should be included as a measure of efficacy in clinical trials of recurrent HSL therapies. PMID- 24342633 TI - Double recombinant Mycobacterium bovis BCG strain for screening of primary and rationale-based antimycobacterial compounds. AB - Conventional antimycobacterial screening involves CFU analysis, which poses a great challenge due to slow growth of mycobacteria. Recombinant strains carrying reporter genes under the influence of constitutive promoters allow rapid and wide screening of compounds but without revealing their modes of action. Reporter strains using pathway-specific promoters provide a better alternative but allow a limited screening of compounds interfering with only a particular metabolic pathway. This reduces these strains to merely a second-line screening system, as they fail to identify even the more potent compounds if they are not inhibiting the pathway of interest. In this study, we have generated a double recombinant Mycobacterium bovis BCG strain carrying firefly and Renilla luciferase genes as two reporters under the control of a constitutive and an inducible mycobacterial promoter. The presence of dual reporters allows simultaneous expression and analysis of two reporter enzymes within a single system. The expression profile of the firefly luciferase gene, rendered by a constitutive mycobacterial promoter, coincides with the decline in bacterial growth in response to a wide range of antimycobacterial drugs, while the enhanced expression of Renilla luciferase mirrors the selective induction of the reporter gene expression as a result of pathway-specific inhibition. Thus, the double recombinant strain allows the screening of both primary and rationally synthesized antimycobacterial compounds in a single assay. The inhibiting response of drugs was monitored with a dual-luciferase reporter assay which can be easily adapted in high-throughput mode. PMID- 24342634 TI - Validation of a novel murine wound model of Acinetobacter baumannii infection. AB - Patients recovering from traumatic injuries or surgery often require weeks to months of hospitalization, increasing the risk for wound and surgical site infections caused by ESKAPE pathogens, which include A. baumannii (the ESKAPE pathogens are Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). As new therapies are being developed to counter A. baumannii infections, animal models are also needed to evaluate potential treatments. Here, we present an excisional, murine wound model in which a diminutive inoculum of a clinically relevant, multidrug-resistant A. baumannii isolate can proliferate, form biofilms, and be effectively treated with antibiotics. The model requires a temporary, cyclophosphamide-induced neutropenia to establish an infection that can persist. A 6-mm-diameter, full-thickness wound was created in the skin overlying the thoracic spine, and after the wound bed was inoculated, it was covered with a dressing for 7 days. Uninoculated control wounds healed within 13 days, whereas infected, placebo-treated wounds remained unclosed beyond 21 days. Treated and untreated wounds were assessed with multiple quantitative and qualitative techniques that included gross pathology, weight loss and recovery, wound closure, bacterial burden, 16S rRNA community profiling, histopathology, peptide nucleic acid-fluorescence in situ hybridization, and scanning electron microscopy assessment of biofilms. The range of differences that we are able to identify with these measures in antibiotic- versus placebo-treated animals provides a clear window within which novel antimicrobial therapies can be assessed. The model can be used to evaluate antimicrobials for their ability to reduce specific pathogen loads in wounded tissues and clear biofilms. Ultimately, the mouse model approach allows for highly powered studies and serves as an initial multifaceted in vivo assessment prior to testing in larger animals. PMID- 24342635 TI - Antibiotic activity against naive and induced Streptococcus pneumoniae biofilms in an in vitro pharmacodynamic model. AB - Biofilms play a role in the pathogenicity of pneumococcal infections. A pharmacodynamic in vitro model of biofilm was developed that allows characterization of the activity of antibiotics against viability and biomass by using in parallel capsulated (ATCC 49619) and noncapsulated (R6) reference strains. Naive biofilms were obtained by incubating fresh planktonic cultures for 2 to 11 days in 96-well polystyrene plates. Induced biofilms were obtained using planktonic bacteria collected from the supernatant of 6-day-old naive biofilms. Biomass production was more rapid and intense in the induced model, but the levels were similar for both strains. Full concentration responses fitting sigmoidal regressions allowed calculation of maximal efficacies and relative potencies of drugs. All antibiotics tested (amoxicillin, clarithromycin, solithromycin, levofloxacin, and moxifloxacin) were more effective against young naive biofilms than against old or induced biofilms, except macrolides/ketolides, which were as effective at reducing viability in 2-day-old naive biofilms and in 11-day-old induced biofilms of R6. Macrolides/ketolides, however, were less potent than fluoroquinolones against R6 (approximately 5- to 20-fold-higher concentrations needed to reduction viability of 20%). However, at concentrations obtainable in epithelial lining fluid, the viabilities of mature or induced biofilms were reduced 15 to 45% (amoxicillin), 17 to 44% (macrolides/ketolides), and 12 to 64% (fluoroquinolones), and biomasses were reduced 5 to 45% (amoxicillin), 5 to 60% (macrolides/ketolides), and 10 to 76% (fluoroquinolones), with solithromycin and moxifloxacin being the most effective and the most potent agents (due to lower MICs) in their respective classes. This study allowed the ranking of antibiotics with respect to their potential effectiveness in biofilm related infections, underlining the need to search for still more effective options. PMID- 24342636 TI - New dosing strategies for an old antibiotic: pharmacodynamics of front-loaded regimens of colistin at simulated pharmacokinetics in patients with kidney or liver disease. AB - Increasing evidence suggests that colistin monotherapy is suboptimal at currently recommended doses. We hypothesized that front-loading provides an improved dosing strategy for polymyxin antibiotics to maximize killing and minimize total exposure. Here, we utilized an in vitro pharmacodynamic model to examine the impact of front-loaded colistin regimens against a high bacterial density (10(8) CFU/ml) of Pseudomonas aeruginosa. The pharmacokinetics were simulated for patients with hepatic (half-life [t1/2] of 3.2 h) or renal (t1/2 of 14.8 h) disease. Front-loaded regimens (n=5) demonstrated improvement in bacterial killing, with reduced overall free drug areas under the concentration-time curve (fAUC) compared to those with traditional dosing regimens (n=14) with various dosing frequencies (every 12 h [q12h] and q24h). In the renal failure simulations, front-loaded regimens at lower exposures (fAUC of 143 mg . h/liter) obtained killing activity similar to that of traditional regimens (fAUC of 268 mg . h/liter), with an ~97% reduction in the area under the viable count curve over 48 h. In hepatic failure simulations, front-loaded regimens yielded rapid initial killing by up to 7 log10 within 2 h, but considerable regrowth occurred for both front-loaded and traditional regimens. No regimen eradicated the high bacterial inoculum of P. aeruginosa. The current study, which utilizes an in vitro pharmacodynamic infection model, demonstrates the potential benefits of front loading strategies for polymyxins simulating differential pharmacokinetics in patients with hepatic and renal failure at a range of doses. Our findings may have important clinical implications, as front-loading polymyxins as a part of a combination regimen may be a viable strategy for aggressive treatment of high bacterial-burden infections. PMID- 24342637 TI - Clinical pharmacodynamics of antipseudomonal cephalosporins in patients with ventilator-associated pneumonia. AB - Advanced-generation cephalosporins are frequently used for empirical coverage of ventilator-associated pneumonia (VAP) due to their activity against a broad spectrum of Gram-positive and Gram-negative aerobic bacteria, including Pseudomonas aeruginosa and Enterobacteriaceae. Providing optimal antibiotic exposure is essential to achieving successful response in patients with VAP. We evaluated exposures of two antipseudomonal cephalosporins, ceftazidime and cefepime, in patients with VAP due to Gram-negative bacilli to identify the pharmacodynamic parameter predictive of microbiological success. Population pharmacokinetic models were used to estimate individual free drug exposures. Pharmacodynamic indices were determined for each patient using the baseline Gram negative bacilli with the highest drug MIC. Classification and regression tree analysis was utilized to partition exposure breakpoints, and multivariate logistic regression was conducted to identify predictors of microbiological success. A total of 73 patients (18 receiving ceftazidime therapy and 55 receiving cefepime therapy) were included. MICs ranged widely from 0.047 to 96 MUg/ml. The microbiological success rate was 58.9%. Predictive breakpoints were identified for all pharmacodynamic parameters, including a serum fT>MIC greater than 53% (P=0.02). When controlling for APACHE II (odds ratio [OR], 1.01; 95% confidence interval, 0.93 to 1.09; P=0.85) and combination therapy (OR, 0.74; 95% confidence interval, 0.25 to 2.19; P=0.59), achieving a greater than 53% fT>MIC remained a significant predictor of success (OR, 10.3; 95% confidence interval, 1.1 to 92.3; P=0.04). In patients with VAP due to Gram-negative bacilli, serum exposure of greater than 53% fT>MIC was found to be a significant predictor of favorable microbiological response for antipseudomonal cephalosporins. These data are useful when determining dosing regimens for cephalosporin agents under development for pneumonia. PMID- 24342638 TI - Imipenem, meropenem, or doripenem to treat patients with Pseudomonas aeruginosa ventilator-associated pneumonia. AB - Only limited data exist on Pseudomonas aeruginosa ventilator-associated pneumonia (VAP) treated with imipenem, meropenem, or doripenem. Therefore, we conducted a prospective observational study in 169 patients who developed Pseudomonas aeruginosa VAP. Imipenem, meropenem, and doripenem MICs for Pseudomonas aeruginosa isolates were determined using Etests and compared according to the carbapenem received. Among the 169 isolates responsible for the first VAP episode, doripenem MICs were lower (P<0.0001) than those of imipenem and meropenem (MIC50s, 0.25, 2, and 0.38, respectively); 61%, 64%, and 70% were susceptible to imipenem, meropenem, and doripenem, respectively (P was not statistically significant). Factors independently associated with carbapenem resistance were previous carbapenem use (within 15 days) and mechanical ventilation duration before VAP onset. Fifty-six (33%) patients had at least one VAP recurrence, and 56 (33%) died. Factors independently associated with an unfavorable outcome (recurrence or death) were a high day 7 sequential organ failure assessment score and mechanical ventilation dependency on day 7. Physicians freely prescribed a carbapenem to 88 patients: imipenem for 32, meropenem for 24, and doripenem for 32. The remaining 81 patients were treated with various antibiotics. Imipenem-, meropenem-, and doripenem-treated patients had similar VAP recurrence rates (41%, 25%, and 22%, respectively; P=0.15) and mortality rates (47%, 25%, and 22%, respectively; P=0.07). Carbapenem resistance emerged similarly among patients treated with any carbapenem. No carbapenem was superior to another for preventing carbapenem resistance emergence. PMID- 24342639 TI - In vitro activities of ceftazidime-avibactam and aztreonam-avibactam against 372 Gram-negative bacilli collected in 2011 and 2012 from 11 teaching hospitals in China. AB - Ceftazidime-avibactam, aztreonam-avibactam, and comparators were tested by reference broth microdilution against 372 nonrepetitive Gram-negative bacilli (346 unselected plus 26 selected meropenem-nonsusceptible Enterobacteriaceae isolates) collected from 11 teaching hospitals in China in 2011 and 2012. Meropenem-nonsusceptible isolates produced extended-spectrum beta-lactamases (ESBLs; e.g., CTX-M-14/3), AmpCs (e.g., CMY-2), and/or carbapenemases (e.g., KPC 2 and NDM-1). Avibactam potentiated the activity of ceftazidime against organisms with combinations of ESBLs, AmpCs, and KPC-2. Aztreonam-avibactam was active against all beta-lactamase producers (including producers of NDM-1 and IMP-4/8) except blaOXA-containing Acinetobacter baumannii and some Pseudomonas aeruginosa isolates. PMID- 24342640 TI - Role of Acinetobacter baumannii UmuD homologs in antibiotic resistance acquired through DNA damage-induced mutagenesis. AB - The role of Acinetobacter baumannii ATCC 17978 UmuDC homologs A1S_0636-A1S_0637, A1S_1174-A1S_1173, and A1S_1389 (UmuDAb) in antibiotic resistance acquired through UV-induced mutagenesis was evaluated. Neither the growth rate nor the UV related survival of any of the three mutants was significantly different from that of the wild-type parental strain. However, all mutants, and especially the umuDAb mutant, were less able to acquire resistance to rifampin and streptomycin through the activities of their error-prone DNA polymerases. Furthermore, in the A. baumannii mutant defective in the umuDAb gene, the spectrum of mutations included a dramatic reduction in the frequency of transition mutations, the mutagenic signature of the DNA polymerase V encoded by umuDC. PMID- 24342641 TI - Efficacies of ceftazidime-avibactam and ceftazidime against Pseudomonas aeruginosa in a murine lung infection model. AB - This study aimed to determine the efficacy of human-simulated plasma exposures of 2 g ceftazidime plus 0.5 g avibactam every 8 h administered as a 2-h infusion or a ceftazidime regimen that produced a specific epithelial lining fluid (ELF) percentage of the dosing interval in which serum free drug concentrations remain above the MIC (fT>MIC) against 28 Pseudomonas aeruginosa isolates within a neutropenic murine pneumonia model and to assess the impact of host infection on pulmonary pharmacokinetics. The fT>MIC was calculated as the mean and upper end of the 95% confidence limit. Against the 28 P. aeruginosa strains used, the ceftazidime-avibactam MICs were 4 to 64 MUg/ml, and those of ceftazidime were 8 to >128 MUg/ml. The change in log10 CFU after 24 h of treatment was analyzed relative to that of 0-h controls. Pharmacokinetic studies in serum and ELF were conducted using ceftazidime-avibactam in infected and uninfected mice. Humanized ceftazidime-avibactam doses resulted in significant exposures in the lung, producing reductions of >1 log10 CFU against P. aeruginosa with ceftazidime avibactam MICs of <=32 MUg/ml (ELF upper 95% confidence limit for fT>MIC [ELF fT>MIC] of >=19%), except for one isolate with a ceftazidime-avibactam MIC of 16 MUg/ml. No efficacy was observed against the isolate with a ceftazidime-avibactam MIC of 64 MUg/ml (ELF fT>MIC of 0%). Bacterial reductions were observed with ceftazidime against isolates with ceftazidime MICs of 32 MUg/ml (ELF fT>MIC of >=12%), variable efficacy at ceftazidime MICs of 64 MUg/ml (ELF fT>MIC of >=0%), and no activity at a ceftazidime MIC of 128 MUg/ml, where the ELF fT>MIC was 0%. ELF fT>MICs were similar between infected and uninfected mice. Ceftazidime avibactam was effective against P. aeruginosa, with MICs of up to 32 MUg/ml with an ELF fT>MIC of >=19%. The data suggest the potential utility of ceftazidime avibactam for treatment of lung infections caused by P. aeruginosa. PMID- 24342642 TI - Population analysis of Escherichia coli isolates with discordant resistance levels by piperacillin-tazobactam broth microdilution and agar dilution testing. AB - Population analysis was performed for 42 Escherichia coli isolates to determine whether heterogeneity of resistance was a factor in piperacillin-tazobactam category differences between agar dilution and broth microdilution. Of 20 isolates discordant between methods, 80% were heterogeneous. Of 22 isolates in agreement, 59% were homogeneous. Heterogeneity and homogeneity rates for those in agreement were significantly different from those that were discordant (P value, 0.010). Heterogeneity of resistance expression appears to be an important factor in category differences observed between broth microdilution and agar dilution for piperacillin-tazobactam. PMID- 24342643 TI - Genomic analyses of DNA transformation and penicillin resistance in Streptococcus pneumoniae clinical isolates. AB - Alterations in penicillin-binding proteins, the target enzymes for beta-lactam antibiotics, are recognized as primary penicillin resistance mechanisms in Streptococcus pneumoniae. Few studies have analyzed penicillin resistance at the genome scale, however, and we report the sequencing of S. pneumoniae R6 transformants generated while reconstructing the penicillin resistance phenotypes from three penicillin-resistant clinical isolates by serial genome transformation. The genome sequences of the three last-level transformants T2 18209, T5-1983, and T3-55938 revealed that 16.2 kb, 82.7 kb, and 137.2 kb of their genomes had been replaced with 5, 20, and 37 recombinant sequence segments derived from their respective parental clinical isolates, documenting the extent of DNA transformation between strains. A role in penicillin resistance was confirmed for some of the mutations identified in the transformants. Several multiple recombination events were also found to have happened at single loci coding for penicillin-binding proteins (PBPs) that increase resistance. Sequencing of the transformants with MICs for penicillin similar to those of the parent clinical strains confirmed the importance of mosaic PBP2x, -2b, and -1a as a driving force in penicillin resistance. A role in resistance for mosaic PBP2a was also observed for two of the resistant clinical isolates. PMID- 24342644 TI - A screen for and validation of prodrug antimicrobials. AB - The rise of resistant pathogens and chronic infections tolerant to antibiotics presents an unmet need for novel antimicrobial compounds. Identifying broad spectrum leads is challenging due to the effective penetration barrier of Gram negative bacteria, formed by an outer membrane restricting amphipathic compounds, and multidrug resistance (MDR) pumps. In chronic infections, pathogens are shielded from the immune system by biofilms or host cells, and dormant persisters tolerant to antibiotics are responsible for recalcitrance to chemotherapy with conventional antibiotics. We reasoned that the dual need for broad-spectrum and sterilizing compounds could be met by developing prodrugs that are activated by bacterium-specific enzymes and that these generally reactive compounds could kill persisters and accumulate over time due to irreversible binding to targets. We report the development of a screen for prodrugs, based on identifying compounds that nonspecifically inhibit reduction of the viability dye alamarBlue, and then eliminate generally toxic compounds by testing for cytotoxicity. A large pilot of 55,000 compounds against Escherichia coli produced 20 hits, 3 of which were further examined. One compound, ADC111, is an analog of a known nitrofuran prodrug nitrofurantoin, and its activity depends on the presence of activating enzymes nitroreductases. ADC112 is an analog of another known antimicrobial tilbroquinol with unknown mechanism of action, and ADC113 does not belong to an approved class. All three compounds had a good spectrum and showed good to excellent activity against persister cells in biofilm and stationary cultures. These results suggest that screening for overlooked prodrugs may present a viable platform for antimicrobial discovery. PMID- 24342645 TI - Antibiotic streptolydigin requires noncatalytic Mg2+ for binding to RNA polymerase. AB - Multisubunit RNA polymerase, an enzyme that accomplishes transcription in all living organisms, is a potent target for antibiotics. The antibiotic streptolydigin inhibits RNA polymerase by sequestering the active center in a catalytically inactive conformation. Here, we show that binding of streptolydigin to RNA polymerase strictly depends on a noncatalytic magnesium ion which is likely chelated by the aspartate of the bridge helix of the active center. Substitutions of this aspartate may explain different sensitivities of bacterial RNA polymerases to streptolydigin. These results provide the first evidence for the role of noncatalytic magnesium ions in the functioning of RNA polymerase and suggest new routes for the modification of existing and the design of new inhibitors of transcription. PMID- 24342646 TI - Trends in antibiotic resistance in coagulase-negative staphylococci in the United States, 1999 to 2012. AB - Coagulase-negative staphylococci (CoNS) are important bloodstream pathogens that are typically resistant to multiple antibiotics. Despite the concern about increasing resistance, there have been no recent studies describing the national prevalence of CoNS pathogens. We used national resistance data over a period of 13 years (1999 to 2012) from The Surveillance Network (TSN) to determine the prevalence of and assess the trends in resistance for Staphylococcus epidermidis, the most common CoNS pathogen, and all other CoNS pathogens. Over the course of the study period, S. epidermidis resistance to ciprofloxacin and clindamycin increased steadily from 58.3% to 68.4% and from 43.4% to 48.5%, respectively. Resistance to levofloxacin increased rapidly from 57.1% in 1999 to a high of 78.6% in 2005, followed by a decrease to 68.1% in 2012. Multidrug resistance for CoNS followed a similar pattern, and this rise and small decline in resistance were found to be strongly correlated with levofloxacin prescribing patterns. The resistance patterns were similar for the aggregate of CoNS pathogens. The results from our study demonstrate that the antibiotic resistance in CoNS pathogens has increased significantly over the past 13 years. These results are important, as CoNS can serve as sentinels for monitoring resistance, and they play a role as reservoirs of resistance genes that can be transmitted to other pathogens. The link between the levofloxacin prescription rate and resistance levels suggests a critical role for reducing the inappropriate use of fluoroquinolones and other broad-spectrum antibiotics in health care settings and in the community to help curb the reservoir of resistance in these colonizing pathogens. PMID- 24342647 TI - Retrospective analysis of the efficacies of two different regimens of aqueous penicillin G administered to children with pneumonia. AB - Community-acquired pneumonia (CAP) is an important childhood health problem. Penicillin remains appropriate for treating children with CAP. Clinical data are lacking on disease evolution in children treated with different posologic schemes of aqueous penicillin G. To assess if there were differences in disease evolution between children with CAP treated with 6 or 4 daily doses of aqueous penicillin G, we reviewed the medical charts of hospitalized patients 2 months to 11.5 years of age. Pneumonia was radiologically confirmed based on the detection of pulmonary infiltrate or pleural effusion on the chest radiograph taken on admission and read by a pediatric radiologist blinded to the clinical data. The total daily dose of aqueous penicillin G was 200,000 IU/kg of body weight. Data were recorded on admission, during disease evolution up to the 7th day of treatment, and at the final outcome. The results of hospitalization and the daily frequency of physical signs suggestive of pneumonia were assessed. The subgroups comprised 120 and 144 children who received aqueous penicillin G in 6 or 4 daily doses, respectively. Children>=5 years of age were more frequent in the 4-daily doses subgroup (16.0% versus 4.2%; respectively, P=0.02). There were no differences between the compared subgroups in terms of final outcomes, lengths of hospitalization, durations of aqueous penicillin G use, frequencies of aqueous penicillin G substitution, or daily frequencies of tachypnea, fever, chest retraction, lower chest recession, nasal flaring, and cyanosis up to the 7th day of treatment. The studied posologic regimens were similarly effective in treating children hospitalized with a radiologically confirmed CAP diagnosis. Aqueous penicillin G (200,000 IU/kg/day) may be given in 4 daily doses to children with CAP. PMID- 24342648 TI - Identification and characterization of a bacitracin resistance network in Enterococcus faecalis. AB - Resistance of Enterococcus faecalis against antimicrobial peptides, both of host origin and produced by other bacteria of the gut microflora, is likely to be an important factor in the bacterium's success as an intestinal commensal. The aim of this study was to identify proteins with a role in resistance against the model antimicrobial peptide bacitracin. Proteome analysis of bacitracin-treated and untreated cells showed that bacitracin stress induced the expression of cell wall-biosynthetic proteins and caused metabolic rearrangements. Among the proteins with increased production, an ATP-binding cassette (ABC) transporter with similarity to known peptide antibiotic resistance systems was identified and shown to mediate resistance against bacitracin. Expression of the transporter was dependent on a two-component regulatory system and a second ABC transporter, which were identified by genome analysis. Both resistance and the regulatory pathway could be functionally transferred to Bacillus subtilis, proving the function and sufficiency of these components for bacitracin resistance. Our data therefore show that the two ABC transporters and the two-component system form a resistance network against antimicrobial peptides in E. faecalis, where one transporter acts as the sensor that activates the TCS to induce production of the second transporter, which mediates the actual resistance. PMID- 24342649 TI - In vitro analyses of mild heat stress in combination with antifungal agents against Aspergillus fumigatus biofilm. AB - Aspergillus fumigatus biofilms still present a challenge for effective treatment in clinical settings. While mild heat stress has been introduced as a treatment for infectious diseases, the effectiveness of mild heat stress on A. fumigatus biofilm formation and antifungal susceptibility is still unknown. In the present study, confocal laser scanning microscopy (CLSM) was used to image and quantify Aspergillus fumigatus biofilm formation under three different regimens of continuous mild heat stress: at 37, 39, and 41 degrees C. Furthermore, fungal growth has been investigated under the above conditions in combination with antifungal drugs (amphotericin B [AMB], micafungin [MCF], and voriconazole [VOC]) at early and late stages. CLSM analysis showed that higher temperatures induce earlier germination and greater hyphal elongation but poorer polar growth and reduced biofilm thickness. In the early stage of biofilm formation, the combination of treatment at 39 or 41 degrees C with MCF or VOC produced no visible difference in biomass formation from similar treatments at 37 degrees C with the same drug. Interestingly, AMB treatment at 37 degrees C inhibited early stage biofilm formation to a much greater extent than at 39 and 41 degrees C. At the late stage of biofilm formation, the mild heat treatments at 39 and 41 degrees C with AMB, MCF, and VOC inhibited biomass formation compared to that at 37 degrees C. The present data show that mild heat stress has a negative regulatory effect on biofilm formation in vitro, and antifungal drug improvement with mild heat treatment at late-stage biofilm formation provides useful indications of possible effective strategies for clinical management of aspergillosis. PMID- 24342650 TI - Transcription factor CCG-8 as a new regulator in the adaptation to antifungal azole stress. AB - Antifungal azoles are widely used for controlling fungal infections. Fungi are able to change the expression of many genes when they adapt to azole stress, and increased expression of some of these genes can elevate resistance to azoles. However, the regulatory mechanisms behind transcriptional adaption to azoles in filamentous fungi are poorly understood. In this study, we found that deletion of the transcription factor gene ccg-8, which is known to be a clock-controlled gene, made Neurospora crassa hypersensitive to azoles. A comparative genome-wide analysis of the responses to ketoconazole of the wild type and the ccg-8 mutant revealed that the transcriptional responses to ketoconazole of 78 of the 488 transcriptionally ketoconazole-upregulated genes and the 427 transcriptionally ketoconazole-downregulated genes in the wild type were regulated by CCG-8. Ketoconazole sensitivity testing of all available knockout mutants for CCG-8 regulated genes revealed that CCG-8 contributed to azole adaption by regulating the ketoconazole responses of many genes, including the target gene (erg11), an azole transporter gene (cdr4), a hexose transporter gene (hxt13), a stress response gene (locus number NCU06317, named kts-1), two transcription factor genes (NCU01386 [named kts-2] and fsd-1/ndt80), four enzyme-encoding genes, and six unknown-function genes. CCG-8 also regulated phospholipid synthesis in N. crassa in a manner similar to that of its homolog in Saccharomyces cerevisiae, Opi1p. However, there was no cross talk between phospholipid synthesis and azole resistance in N. crassa. CCG-8 homologs are conserved and are common in filamentous fungi. Deletion of the CCG-8 homolog-encoding gene in Fusarium verticillioides (Fvccg-8) also made this fungus hypersensitive to antifungal azoles. PMID- 24342651 TI - Phase 2, randomized, double-blind study of the efficacy and safety of two dose regimens of eravacycline versus ertapenem for adult community-acquired complicated intra-abdominal infections. AB - Eravacycline is a novel fluorocycline, highly active against Gram-positive and Gram-negative pathogens in vitro, including those with tetracycline and multidrug resistance. This phase 2, randomized, double-blind study was conducted to evaluate the efficacy and safety of two dose regimens of eravacycline compared with ertapenem in adult hospitalized patients with complicated intra-abdominal infections (cIAIs). Patients with confirmed cIAI requiring surgical or percutaneous intervention and antibacterial therapy were randomized (2:2:1) to receive eravacycline at 1.5 mg/kg of body weight every 24 h (q24h), eravacycline at 1.0 mg/kg every 12 h (q12h), or ertapenem at 1 g (q24h) for a minimum of 4 days and a maximum of 14 days. The primary efficacy endpoint was the clinical response in microbiologically evaluable (ME) patients at the test-of-cure (TOC) visit 10 to 14 days after the last dose of study drug therapy. Overall, 53 patients received eravacycline at 1.5 mg/kg q24h, 56 received eravacycline at 1.0 mg/kg q12h, and 30 received ertapenem. For the ME population, the clinical success rate at the TOC visit was 92.9% (39/42) in the group receiving eravacycline at 1.5 mg/kg q24h, 100% (41/41) in the group receiving eravacycline at 1.0 mg/kg q12h, and 92.3% (24/26) in the ertapenem group. The incidences of treatment-emergent adverse events were 35.8%, 28.6%, and 26.7%, respectively. Incidence rates of nausea and vomiting were low in both eravacycline groups. Both dose regimens of eravacycline were as efficacious as the comparator, ertapenem, in patients with cIAI and were well tolerated. These results support the continued development of eravacycline for the treatment of serious infections, including those caused by drug-resistant Gram-negative pathogens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01265784.). PMID- 24342652 TI - Antibiotic utilization for acute respiratory tract infections in U.S. emergency departments. AB - Inappropriate use of antibiotics for acute respiratory tract infections (ARTIs) has decreased in many outpatient settings. For patients presenting to U.S. emergency departments (EDs) with ARTIs, antibiotic utilization patterns are unclear. We conducted a retrospective cohort study of ED patients from 2001 to 2010 using data from the National Hospital Ambulatory Medical Care Survey (NHAMCS). We identified patients presenting to U.S. EDs with ARTIs and calculated rates of antibiotic utilization. Diagnoses were classified as antibiotic appropriate (otitis media, sinusitis, pharyngitis, tonsillitis, and nonviral pneumonia) or antibiotic inappropriate (nasopharyngitis, unspecified upper respiratory tract infection, bronchitis or bronchiolitis, viral pneumonia, and influenza).There were 126 million ED visits with a diagnosis of ARTI, and antibiotics were prescribed in 61%. Between 2001 and 2010, antibiotic utilization decreased for patients aged<5 presenting with antibiotic-inappropriate ARTI (rate ratio [RR], 0.94; confidence interval [CI], 0.88 to 1.00). Utilization also decreased significantly for antibiotic-inappropriate ARTI patients aged 5 to 19 years (RR, 0.89; CI, 0.85 to 0.94). Utilization remained stable for antibiotic inappropriate ARTI among adult patients aged 20 to 64 years (RR, 0.99; CI, 0.97 to 1.01). Among adults, rates of quinolone use for ARTI increased significantly from 83 per 1,000 visits in 2001 to 2002 to 105 per 1,000 in 2009 to 2010 (RR, 1.08; CI, 1.03 to 1.14). Although significant progress has been made toward reduction of antibiotic utilization for pediatric patients with ARTI, the proportion of adult ARTI patients receiving antibiotics in U.S. EDs is inappropriately high. Institution of measures to reduce inappropriate antibiotic use in the ED setting is warranted. PMID- 24342653 TI - Induction of the Chlamydia muridarum stress/persistence response increases azithromycin treatment failure in a murine model of infection. AB - Viable but noninfectious (stressed/persistent) chlamydiae are more resistant to azithromycin (AZM) in culture than are organisms in the normal developmental cycle. Chlamydia muridarum-infected mice were exposed to amoxicillin to induce the organisms to enter the persistent/stressed state and subsequently treated with AZM. AZM treatment failure was observed in 22% of persistently infected mice, with an average of 321,667 inclusion-forming units (IFU) shed after AZM treatment. Productively infected mice had a 9% rate of AZM treatment failure and shed an average of 12,083 IFU. These data suggest that stressed chlamydiaeare more resistant to frontline antichlamydial drugs in vivo. PMID- 24342654 TI - Copper toxicity induced hepatocerebral and neurodegenerative diseases: an urgent need for prognostic biomarkers. AB - Copper (Cu) has been the subject of intensive research over several decades as numerous evidence robustly support the involvement of excess Cu induced neurotoxicity in hepatocerebral (Wilson's disease) and neurodegenerative disorders (especially Alzheimer's disease and Parkinson's disease); notwithstanding, the ideal Cu neurotoxicity biomarker/s for early prognosis remains elusive. Non-ceruloplasmin bound Cu is a biological marker of Wilson's disease and recent studies have shown that its levels are also increased in Alzheimer's disease. Copper chaperone for superoxide dismutase seems to be the other most promising biomarker of Cu toxicity (subject to its validation). Serum/plasma Cu, urine Cu and ceruloplasmin concentrations, most widely used laboratory indicators to diagnose Wilson's disease, are not specific for Cu excess milieu as these are also influenced by age, sex, inflammation and hormonal status. High inter-individual variability, nonexistence of standardized assays and non-specificity limit the use of other cuproenzymes as biomarkers of Cu neurotoxicity. The majority of Cu neurotoxicity biomarker research has focused in plasma/serum where other factors including inflammation, oxidative stress, dietary and environmental factors influence the Cu condition being studied. Proteomics study of cerebrospinal fluid, due to its high specificity and sensitivity represents an alternative approach to study early peripheral Cu neurotoxicity biomarker/s in experimental animals. In addition, network biology, transcriptomics in conjunction with novel in vivo Cu imaging techniques allow us to explore other potential candidates and propose new targets to be studied for chronic Cu neurotoxicity biomarker/s, and for possible therapeutic interventions. PMID- 24342655 TI - Measurements of (186)Re production cross section induced by deuterons on (nat)W target at ARRONAX facility. AB - INTRODUCTION: The ARRONAX cyclotron, acronym for "Accelerator for Research in Radiochemistry and Oncology at Nantes Atlantique" is a new facility installed in Nantes, France. A dedicated program has been launched on production of innovative radioisotopes for PET imaging and for beta- and alpha targeted radiotherapy using protons or alpha particles. Since the accelerator is also able to deliver deuteron beams up to 35 MeV, we have reconsidered the possibility of using them to produce medical isotopes. Indeed, in some cases, the use of deuterons allows higher production yield than protons. METHODS: (186)Re is a beta- emitter which has chemical properties close to the widely used (99m)Tc and has been used in clinical trials for palliation of painful bone metastases resulting from prostate and breast cancer. (186)Re production cross section has been measured between 9 and 23 MeV using the ARRONAX deuteron beam and the stacked-foil technique. A novelty in our work is the use of a monitor foil behind each (nat)W target foil in order to record efficiently the deuteron incident flux and energies all over the stack relying on the International Atomic Energy Agency (IAEA) recommended cross section of the (nat)Ti(d,x)(48)V reaction. Since a good optimization process is supposed to find the best compromise between production yield and purity of the final product, isotope of interest and contaminants created during irradiation are measured using gamma spectrometry. RESULTS: Our new sets of data are presented and compared with the existing ones and with results given by the TALYS code calculations. The thick target yield (TTY) has been calculated after the fit of our experimental values and compared with the IAEA recommended ones. CONCLUSIONS: Presented values are in good agreement with existing data. The deuteron production route is clearly the best choice with a TTY of 7.8 MB/MUAh at 30 MeV compared to 2.4 MBq/MUAh for proton as projectile at the same energy. The TALYS code gives satisfactory results for (183,186)Re isotopes. PMID- 24342657 TI - The American cranberry mitochondrial genome reveals the presence of selenocysteine (tRNA-Sec and SECIS) insertion machinery in land plants. AB - This is the first de novo assembly and annotation of a complete mitochondrial genome in the Ericales order from the American cranberry (Vaccinium macrocarpon Ait.). Moreover, only four complete Asterid mitochondrial genomes have been made publicly available. The cranberry mitochondrial genome was assembled and reconstructed from whole genome 454 Roche GS-FLX and Illumina shotgun sequences. Compared with other Asterids, the reconstruction of the genome revealed an average size mitochondrion (459,678 nt) with relatively little repetitive sequences and DNA of plastid origin. The complete mitochondrial genome of cranberry was annotated obtaining a total of 34 genes classified based on their putative function, plus three ribosomal RNAs, and 17 transfer RNAs. Maternal organellar cranberry inheritance was inferred by analyzing gene variation in the cranberry mitochondria and plastid genomes. The annotation of cranberry mitochondrial genome revealed the presence of two copies of tRNA-Sec and a selenocysteine insertion sequence (SECIS) element which were lost in plants during evolution. This is the first report of a land plant possessing selenocysteine insertion machinery at the sequence level. PMID- 24342656 TI - tRNA gene copy number variation in humans. AB - The human tRNAome consists of more than 500 interspersed tRNA genes comprising 51 anticodon families of largely unequal copy number. We examined tRNA gene copy number variation (tgCNV) in six individuals; two kindreds of two parents and a child, using high coverage whole genome sequence data. Such differences may be important because translation of some mRNAs is sensitive to the relative amounts of tRNAs and because tRNA competition determines translational efficiency vs. fidelity and production of native vs. misfolded proteins. We identified several tRNA gene clusters with CNV, which in some cases were part of larger iterations. In addition there was an isolated tRNALysCUU gene that was absent as a homozygous deletion in one of the parents. When assessed by semiquantitative PCR in 98 DNA samples representing a wide variety of ethnicities, this allele was found deleted in hetero- or homozygosity in all groups at ~50% frequency. This is the first report of copy number variation of human tRNA genes. We conclude that tgCNV exists at significant levels among individual humans and discuss the results in terms of genetic diversity and prior genome wide association studies (GWAS) that suggest the importance of the ratio of tRNALys isoacceptors in Type-2 diabetes. PMID- 24342658 TI - Determination of the lysosomal hydrolase activity in blood collected on filter paper, an alternative to screen high risk populations. AB - This study aimed to determine the enzymatic activity in dried blood samples collected on filter paper (DBS) for the diagnosis of the following diseases: Fabry, Pompe, Mucopolysaccharidosis type I (MPS I) and Mucopolysaccharosis type VI (MPS VI). DBS was used for high risk patientscreening, according to clinical suspicion. Plasma, leukocytes and cultured fibroblasts were used to confirm the diagnosis when necessary. Among the 529 DBS samples sent to the laboratory, 164 had abnormal results. Confirmatory materials of 73 individuals were rerouted. The frequency of diagnosis for lysosomal storage disorders was 5.9%. DBS is an alternative screening technique used in high risk populations, which should lead to earlier diagnosis for lysosomal storage disorders (LSDs), help patients get treatment sooner and improve the outcome of the disease. PMID- 24342659 TI - Expression and genomic imprinting of the porcine Rasgrf1 gene. AB - Imprinted genes play important roles in mammalian growth, development and behavior. The Rasgrf1 (Ras protein-specific guanine nucleotide exchange factor 1) gene has been identified as an imprinted gene in mouse and rat. In the present study, we detected its sequence, imprinting status and expression pattern in the domestic pigs. A 228 bp partial sequence located in exon 14 and a 193 bp partial sequence located in exon 1 of the Rasgrf1 gene in domestic pigs were obtained. A G/A transition, was identified in Rasgrf1 exon 14, and then, the reciprocal Berkshire * Wannan black F1 hybrid model and the RT-PCR-RFLP method were used to detect the imprinting status of porcine Rasgrf1 gene at the developmental stage of 1-day-old. The expression profile results indicated that the porcine Rasgrf1 mRNA was highly expressed in brain, pituitary and pancreas, followed by kidney, stomach, lung, testis, small intestine, ovary, spleen and liver, and at low levels of expression in longissimus dorsi, heart, and backfat. The expression levels of Rasgrf1 gene in brain, pituitary and pancreas tissues were significantly different between the two reciprocal F1 hybrids. Imprinting analysis showed that porcine Rasgrf1 gene was maternally expressed in the liver, small intestine, paternally expressed in the lung, but biallelically expressed in brain, heart, spleen, kidney, stomach, pancreas, backfat, testis, ovary, longissimus dorsi and pituitary tissues. PMID- 24342660 TI - Association of BANK1 and cytokine gene polymorphisms with type 1 diabetes in Tunisia. AB - Type 1 diabetes (T1D) is an autoimmune disease (AID) with both genetic and environmental components. We aimed to investigate the genetic association of polymorphisms in genes previously linked with other AIDs, namely BANK1, IL15 and IL2/IL21 region. A total of 76 T1D patients and 162 controls from Southern Tunisia were recruited for a case-control association study investigating the relationship between sixteen SNPs of the BANK1, IL15 and IL2/IL21 gene region and T1D. In the BANK1 gene, G allele and GG genotype of rs3733197 were significantly increased in the group of T1D patients compared to controls. In addition, in the IL15 gene, the minor allele A of rs10519613 polymorphism was significantly higher in patients than in controls. No significant association was found for SNPS in IL2/IL21 gene region. The analysis of the haplotype structure revealed the G-C-A C-T haplotype of the IL15 gene as associated with a reduction in the risk of developing T1D, while A-T-A-C-T haplotype increased the risk of developing the disease. Furthermore, in the IL2/IL21 region, only one haplotype consisting of eight SNPs was markedly associated with T1D susceptibility. Moreover, G-C combination of the BANK1/IL15 was significantly increased in T1D patients, compared to controls. Our results establish BANK1 and IL15 as new T1D genetic susceptibility factors and replicate the association of the 4q27 region with T1D. Our data agree with the effect previously observed for other autoimmune conditions and delineate a shared underlying mechanism. PMID- 24342661 TI - The largest unassigned regions of the male- and female-transmitted mitochondrial DNAs in Musculista senhousia (Bivalvia Mytilidae). AB - Musculista senhousia is a marine mussel with doubly uniparental inheritance (DUI) of mitochondria. In this study we analyzed the largest unassigned region (LUR) of its female- and male-transmitted mitochondrial genomes, described their fine characteristics and searched for shared features. Our results suggest that both LURs contain the control region of their respective mitochondrial genomes. The female-transmitted control region is duplicated in tandem, with the two copies evolving in concert. This makes the F-mtDNA of M. senhousia the first Bivalve mitochondrial genome with this feature. We also compared M. senhousia control regions to that of other Mytilidae, and demonstrated that signals for basic mtDNA functions are retained over evolutionary times even among the fast-evolving mitochondrial genomes of DUI species. Finally, we discussed how similarities between female and male LURs may be explained in the context of DUI evolution and if the duplicated female control region might have influenced the DUI system in this species. PMID- 24342662 TI - Genome-wide identification and analysis of FK506-binding protein gene family in peach (Prunus persica). AB - The FKBP protein family has prolyl isomerase activity and is related in function to cyclophilins. FKBPs are known to be involved in many biological processes including hormone signaling, plant growth, and stress responses through a chaperone or an isomerization of proline residues during protein folding. The availability of complete peach genome sequences allowed the identification of 21 FKBP genes by HMMER and BLAST analyses. Scaffold locations of these FKBP genes in the peach genome were determined and the protein domain and motif organization of peach FKBPs were analyzed. The phylogenetic relationships between peach FKBPs were also assessed. The expression profiles of peach FKBP gene results revealed that most peach FKBPs were expressed in all tissues, while a few peach FKBPs were specifically expressed in some of the tissues. This data could contribute to better understanding of the complex regulation of the peach FKBP gene family, and also provide valuable information for further research in peach functional genomics. PMID- 24342663 TI - Transcriptome analysis of the couch potato (CPO) protein reveals an expression pattern associated with early development in the salmon louse Caligus rogercresseyi. AB - The couch potato (CPO) protein is a key biomolecule involved in regulating diapause through the RNA-binding process of the peripheral and central nervous systems in insects and also recently discovered in a few crustacean species. As such, ectoparasitic copepods are interesting model species that have no evidence of developmental arrest. The present study is the first to report on the cloning of a putative CPO gene from the salmon louse Caligus rogercresseyi (CrCPO), as identified by high-throughput transcriptome sequencing. In addition, the transcription expression in larvae and adults was evaluated using quantitative real-time PCR. The CrCPO cDNA sequence showed 3261 base pairs (bp), consisting of 713bp of 5' UTR, 1741bp of 3' UTR, and an open reading frame of 807bp encoding for 268 amino acids. The highly conserved RNA binding regions RNP2 (LFVSGL) and RNP1 (SPVGFVTF), as well the dimerization site (LEF), were also found. Furthermore, eight single nucleotide polymorphisms located in the untranslated regions and one located in the coding region were detected. Gene transcription analysis revealed that CrCPO has ubiquitous expression across larval stages and in adult individuals, with the highest expression from nauplius to copepodid stages. The present study suggests a putative biological function of CrCPO associated with the development of the nervous system in salmon lice and contributes molecular evidence for candidate genes related to host-parasite interactions. PMID- 24342664 TI - Unusual benign polypoid and papular neoplasms and tumor-like lesions of the vulva. AB - We aimed to investigate the prevalence and spectrum of unusual benign neoplasms and tumor-like lesions presenting as vulvar polyps and papules, to study their clinical, pathologic, hormonal, and developmental features and whether they have important associations with other pathologic lesions or clinical diseases. We conducted a retrospective review study of 115 vulvar specimens over 7 years. Common lesions, for example, fibroepithelial polyps, skin tags, papillomas, abscesses, viral warts and common cysts, were excluded. We found 21 cases (18%) with uncommon benign vulvar lesions. They included 7 epithelial cysts, 3 vascular lesions, 3 glandular neoplasms, 3 endometrioses, 1 caruncle, 1 pilonidal sinus, 1 prolapsed urethra, 1 seborrheic keratosis, and 1 granular cell tumor. The age range was between 1 and 64 years with a mean age of 33 years. Most (86%) were 2.5 cm or less. Many were asymptomatic incidental pathologic findings that can be missed clinically. Nine cases have important clinical associations or coexisting incidental pathologic lesions. Some lesions demonstrated hormone receptors. Some were clinically confused with fibroepithelial polyps, abscesses, warts, melanocytic lesions, and tumors. In conclusion, although the vulva is a small compartment, its developmental and histologic complexity can result in a variety of unusual and rare benign polypoid and papular lesions, some unique to the vulva, which might present diagnostic challenges to the clinicians and pathologists. In addition, many bear controversy regarding their histogenesis and origin of development in the vulva. PMID- 24342665 TI - Immunohistochemical expression and prognostic relevance of Bmi-1, a stem cell factor, in epithelial ovarian cancer. AB - Ovarian cancer is the fourth most common cause of cancer-related death in women. Bmi-1 is a stem cell factor implicated in many human malignancies with poor outcome. Few published reports on the expression of Bmi-1 in epithelial ovarian cancer were either experimental or performed on cell lines. This study evaluates the immunohistochemical expression of Bmi-1 protein in epithelial ovarian cancer tissue specimens and its relevance to the clinicopathologic prognostic variables and patient survival. Forty cases of epithelial ovarian cancer were selected according to the availability of paraffin-embedded tissue and the clinicopathologic and survival data. Immunohistochemistry was performed for anti Bmi-1 antibody. Low and high Bmi-1 expression groups were compared with age, tumor stage, laterality, grade, histology, and patient survival. Bmi-1 expression was detected in 72.5% of cases, of which 42.5% had high expression. High Bmi-1 expression strongly associated with advanced International Federation of Gynecology and Obstetrics stages (P = .007), bilaterality (P = .01), and higher Gynecologic Oncology Group grades (P = .031) and carcinomas of serous histology (P = .027). It had no association with patient age. Bmi-1 expression displayed a significant inverse association with patient overall and mean survival (P = .006, P < .001). These observations suggested correlation between increased Bmi-1 expression and clinical progression in ovarian epithelial cancer. PMID- 24342666 TI - Long-term follow-up of the lung transplant patient. AB - Since the outcomes of lung transplants are still poorer than those obtained with others, such as heart, kidney or liver transplants, the challenge for medicine remains focused on prolonging functional graft survival. The procedure triggers significant post-surgical physiopathological changes in the lung parenchyma, the rib cage, the airways and pulmonary circulation. The patient is exposed to risks that must be identified and controlled, such as complications fully or partially attributable to immunosuppressive treatment, including cardiovascular disease, tumors and infections and, of course, chronic graft dysfunction. The patient's prognosis will depend largely on the degree of efficacy in the prevention, early diagnosis and appropriate treatment of possible complications. Accordingly, regardless of how long it is since the transplantation, graft recipients undergo close functional and clinical monitoring. In this article, we will review the functional changes that characterize a lung transplant recipient and the usefulness of the various diagnostic techniques for patient follow-up. PMID- 24342667 TI - Synthesis, characterization, cytotoxicity and antibacterial activity of an anthracenyl-linked bis(pyrazolyl)methane ligand and its zinc(II) complexes. AB - Three novel Zn(II) complexes (1-3) with 1,1'-(anthracen-9-ylmethylene)bis(1H pyrazole) (L(2)) have been prepared and structurally characterized by X-ray crystallography. Among them, 1 is a binuclear Zn(II) complex while 2 and 3 are mononuclear. The in vitro cytotoxic and antibacterial activities of these complexes were also evaluated. The three complexes exhibit cytotoxic specificity and significant antitumor activity. The MIC50 value of complex 1 against Pseudomonas putida reaching 0.011 MUg/mL much lower than that the positive control chloromycin (0.182 MUg/mL), indicates that complex 1 is a potent antibacterial agent. PMID- 24342669 TI - Letter from the editor: brain activity mapping. PMID- 24342668 TI - CUDC-101, a histone deacetylase inhibitor, improves the in vitro and in vivo developmental competence of somatic cell nuclear transfer pig embryos. AB - The aim of the present study was to examine the effects of CUDC-101, a novel histone deacetylase inhibitor, on the in vitro development and expression of the epigenetic marker histone H3 at lysine 9 (AcH3K9) in pig SCNT embryos. We found that treatment with 1 MUmol/L CUDC-101 for 24 hours significantly improved the development of pig SCNT embryos. Compared with the control group, the blastocyst rate was higher (18.5% vs. 10.3%; P < 0.05). To assess in vivo developmental potency, CUDC-101-treated SCNT embryos were transferred into two surrogate mothers, resulting in one pregnancy with six fetuses. We then investigated the acetylation level of histone H3K9 in SCNT embryos treated with CUDC-101 and compared them only against untreated embryos. The acetylation level of control SCNT embryos was lower than that of CUDC-101-treated embryos at pseudo-pronuclear stages, and immunofluorescent signal for H3K9ac in CUDC-101-treated embryos in a pattern similar to that of control group. In conclusion, we demonstrated that CUDC-101 can significantly improve in vitro and in vivo developmental competence and enhance the nuclear reprogramming of pig SCNT embryos. PMID- 24342670 TI - Letter from the guest editor: brain imaging. PMID- 24342671 TI - Case of the season: dural arteriovenous fistula mimicking a bithalamic neoplasm or viral encephalitis. PMID- 24342672 TI - Aneurysms, arteriovenous malformations, and dural arteriovenous fistulas: diagnosis and treatment. PMID- 24342673 TI - Stroke and stroke mimics: a pattern-based approach. PMID- 24342674 TI - Adult brain tumor imaging: state of the art. PMID- 24342676 TI - Neuroimaging of acute traumatic brain injury: emphasis on magnetic resonance imaging and prognostic factors. PMID- 24342675 TI - Advances in dementia imaging. PMID- 24342677 TI - Neuroimaging of multiple sclerosis, acute disseminated encephalomyelitis, and other demyelinating diseases. PMID- 24342678 TI - Intracranial infections: key neuroimaging findings. PMID- 24342679 TI - Imaging spectrum of cortical dysplasia in children. PMID- 24342680 TI - Nontraumatic acute intraparenchymal hemorrhage: algorithm for workup and differential diagnosis. PMID- 24342681 TI - Effect of method of delivery of sodium butyrate on maturation of the small intestine in newborn calves. AB - The effect of sodium butyrate (SB) supplementation in milk replacer (MR), starter mixture (SM), or both on small intestine maturation in newborn calves was investigated. Twenty-eight male calves with a mean age of 5 (+/- 1) d were randomly allocated into 1 of 4 groups (7 animals per group) and fed (1) MR and SM, without SB (MR(-) and SM(-), respectively; MR(-)/SM(-)); (2) MR(-) and SM supplemented with SB encapsulated within triglyceride matrix (SM(+), 0.6% as fed; MR(-)/SM(+)); (3) MR supplemented with crystalline SB (MR(+), 0.3% as fed) and SM(-) (MR(+)/SM(-)); or (4) MR(+) and SM(+) (MR(+)/SM(+)). The MR was offered in amounts equal to 10% of initial body weight of the calf. The SM was blended with whole corn grain (50/50; wt/wt) and offered ad libitum as a starter diet. Calves were slaughtered at 26 d (+/- 1) of age and small intestine development was investigated. Treatment with MR(+) decreased villus height in the proximal jejunum and decreased villus height, crypt depth, and tunica mucosa thickness in the middle jejunum, whereas treatment with SM(+) tended to increase small intestine weight and crypt depth in the proximal jejunum, and increased villus height in the distal jejunum. In the duodenum, crypt depth and tunica mucosa thickness were greater for the MR(-)/SM(+) group compared with MR(-)/SM(-), MR(+)/SM(-), and MR(+)/SM(+) groups. In the ileum, crypt depth was less for MR( )/SM(+) compared with MR(-)/SM(-). Supplementation with SB in both MR and SM enhanced cell proliferation and decreased apoptosis in the middle jejunum mucosa. Regarding brush border enzyme activities, addition of SB to MR increased lactase activity in the middle jejunum and maltase activity in the distal jejunum, and tended to increase lactase activity in the distal jejunum, aminopeptidase A activity in the middle jejunum and ileum, and aminopeptidase N activity in the ileum. In contrast, SM(+) increased dipeptidylpeptidase IV activity in the distal jejunum and tended to increase aminopeptidase N in the distal jejunum. In conclusion, both MR(+) and SM(+) affected small intestine development in newborn calves. This effect depended on the method of SB delivery but MR(+) generally had a more pronounced effect. No synergistic effect of SB supplementation into MR and SM was found. PMID- 24342682 TI - Effects of milk replacer feeding strategies on performance, ruminal development, and metabolism of dairy calves. AB - Performance, rumen development, and metabolism of male Holstein calves (n=54) were evaluated according to 1 of 3 liquid feeding strategies: 4 L of milk replacer (MR)/d until 60 d old (4 L-60 d), 6L of MR/d until 29 d old and 4 L/d from 30 to 60 d (6L-29 d/4 L-60 d), or 6L of MR/day until 60 d old (60 d-6L). Water and starter were provided ad libitum. Intakes of MR and starter were monitored daily and body weight (BW) weekly. Blood samples for glucose and insulin concentrations and ruminal content samples for volatile fatty acids and ruminal ammonia concentrations were collected at 15, 30, 45, 60, 75, and 90 d of age. Six calves on each treatment were euthanized at 30, 60, and 90 d of age. Empty weights of forestomach and abomasum, papillae length, and mitotic index were measured. Average MR intake/d (expressed as a percent of BW) was greater for calves receiving 6L/d than for those receiving 4 L/d until 30 d of age. Calves on the 6 L-29 d/4 L-60 d had the smallest MR intake from 30 to 60 d old, followed by the 4 L-60 d and 6L-60 d treatments. Starter intake (kg of dry matter/day) did not differ between groups. It increased from 0.065 kg/d in the first month to 0.386 kg/d in the second month, and to 2.065 kg/d after weaning. Weight gain was greater for calves fed more MR in the first month, but no difference was observed during the second month. After weaning, 6L-60 d calves had greater rate of weight gain than others and were heavier at 30, 60, and 90 d of age. Weight of empty forestomachs, ruminal pH, and ammoniac nitrogen concentration were not different among groups. Propionate concentration was lower for 6 L-60 d calves, but acetate and butyrate concentrations were not influenced by MR feeding strategy. Calves fed more MR until d 30 had greater ruminal epithelium mitotic index. The different MR feeding strategies did not influence papillae length or ruminal epithelium thickness. Lesions such as ruminal parakeratosis or hyperkeratosis were not observed. The MR feeding strategy did not affect glucose concentration, but insulin was higher in 6L-60 d calves than in the other groups. Glucose concentration increased with age, whereas insulin decreased until 45 d old, and then started to increase until 90 d. In conclusion, MR feeding strategy did not influence ruminal development. Feeding calves 6 L of MR/d over 60 d resulted in greater rate of weight gain without negative effects on starter intake or forestomach development. The weight advantage that 6L-60 d calves obtained preweaning was maintained until 90 d of age. PMID- 24342683 TI - Using the unified relationship matrix adjusted by breed-wise allele frequencies in genomic evaluation of a multibreed population. AB - The observed low accuracy of genomic selection in multibreed and admixed populations results from insufficient linkage disequilibrium between markers and trait loci. Failure to remove variation due to the population structure may also hamper the prediction accuracy. We verified if accounting for breed origin of alleles in the calculation of genomic relationships would improve the prediction accuracy in an admixed population. Individual breed proportions derived from the pedigree were used to estimate breed-wise allele frequencies (AF). Breed-wise and across-breed AF were estimated from the currently genotyped population and also in the base population. Genomic relationship matrices (G) were subsequently calculated using across-breed (GAB) and breed-wise (GBW) AF estimated in the currently genotyped and also in the base population. Unified relationship matrices were derived by combining different G with pedigree relationships in the evaluation of genomic estimated breeding values (GEBV) for genotyped and ungenotyped animals. The validation reliabilities and inflation of GEBV were assessed by a linear regression of deregressed breeding value (deregressed proofs) on GEBV, weighted by the reliability of deregressed proofs. The regression coefficients (b1) from GAB ranged from 0.76 for milk to 0.90 for protein. Corresponding b1 terms from GBW ranged from 0.72 to 0.88. The validation reliabilities across 4 evaluations with different G were generally 36, 40, and 46% for milk, protein, and fat, respectively. Unexpectedly, validation reliabilities were generally similar across different evaluations, irrespective of AF used to compute G. Thus, although accounting for the population structure in GBW tends to simplify the blending of genomic- and pedigree-based relationships, it appeared to have little effect on the validation reliabilities. PMID- 24342684 TI - Thermal inactivation kinetics of Shiga toxin-producing Escherichia coli in buffalo Mozzarella curd. AB - The use of raw milk in the processing of buffalo Mozzarella cheese is permitted, but the heat treatment used for stretching the curd must ensure that the final product does not contain pathogens such as Shiga toxin-producing Escherichia coli (STEC) that may be present on buffalo dairy farms. This study carried out challenge tests at temperatures between 68 degrees C and 80 degrees C for 2 to 10 min to simulate curd temperatures during the stretching phase. Curd samples were inoculated with 2 STEC strains (serotypes O157 and O26), and their inactivation rates were assessed in the different challenge tests. The curd samples were digested with papain to ensure a homogeneous dispersion of bacteria. The STEC cells were counted after inoculation (range 7.1-8.7 log cfu/g) and after heat treatments using the most probable number (MPN) technique. A plot of log MPN/g versus time was created for each separate experiment. The log linear model with tail was used to provide a reasonable fit to observed data. Maximum inactivation rate (k(max), min(-1)), residual population (log MPN/g), decimal reduction time (min), and time for a 4D (4-log10) reduction (min) were estimated at each temperature tested. A 4D reduction of the O26 STEC strain was achieved when curd was heated at 68 degrees C for 2.6 to 6.3 min or at 80 degrees C for 2.1 to 2.3 min. Greater resistance was observed for the O157 strain at 68 degrees C because k(max) was 1.48 min(-1). The model estimates can support cheesemakers in defining appropriate process criteria needed to control possible STEC contamination in raw milk intended for the production of Mozzarella. PMID- 24342685 TI - Effect of monensin in lactating dairy cow diets at 2 starch concentrations. AB - The objective of this study was to determine the effects of monensin (M) supplementation on lactation performance of dairy cows fed diets of either reduced (RS) or normal (NS) starch concentrations as total mixed rations. One hundred twenty-eight Holstein and Holstein * Jersey cows (90 +/- 33 d in milk) were stratified by breed and parity and randomly assigned to 16 pens of 8 cows each in a randomized controlled trial. Pens were then randomly assigned to 1 of 4 treatments in a 2 * 2 factorial arrangement of treatments. A 4-wk covariate adjustment period preceded the treatment period, with all pens receiving NS supplemented with 18 g of monensin/t of dry matter (DM). Following the 4-wk covariate adjustment period, cows were fed their assigned treatment diets of NS with M (18 g of monensin/t), NS with 0 g of monensin/t (C), RS with M, or RS with C for 12 wk. Actual starch concentrations for the RS and NS diets were 20.4 and 26.9% (DM basis), respectively. Mean dry matter intake (DMI; 27.0 kg/d) was unaffected by the treatments. Feeding M compared with C and NS compared with RS increased milk yield by 1.3 and 1.5 kg/d per cow, respectively. Milk protein percentage and yield and lactose yield were increased and milk urea nitrogen was decreased for NS compared with RS. Feeding M increased actual and component corrected milk feed efficiencies (component-corrected milk yield/DMI) and lactose yield and tended to increase milk urea nitrogen compared with C. Milk protein percentage was decreased for M compared with C, but milk fat percentage and yield, protein yield, and lactose percentage were unaffected by M. We observed a tendency for a starch * monensin interaction for milk feed efficiency (actual milk yield/DMI); M tended to increase efficiency more for NS than for RS. Starch and monensin had minimal effects on milk fatty acid composition and yields. Feeding RS decreased milk and protein yields, but component-corrected milk yields and feed efficiencies were similar for RS and NS. Monensin increased feed efficiency and lactation performance for both dietary starch concentrations. PMID- 24342686 TI - Effect of colostrum on gravity separation of milk somatic cells in skim milk. AB - Our objective was to determine if immunoglobulins play a role in the gravity separation (rising to the top) of somatic cells (SC) in skim milk. Other researchers have shown that gravity separation of milk fat globules is enhanced by IgM. Our recent research found that bacteria and SC gravity separate in both raw whole and skim milk and that heating milk to >76.9 degrees C for 25s stopped gravity separation of milk fat, SC, and bacteria. Bovine colostrum is a good natural source of immunoglobulins. An experiment was designed where skim milk was heated at high temperatures (76 degrees C for 7 min) to stop the gravity separation of SC and then colostrum was added back to try to restore the gravity separation of SC in increments to achieve 0, 0.4, 0.8, 2.0, and 4.0 g/L of added immunoglobulins. The milk was allowed to gravity separate for 22 h at 4 degrees C. The heat treatment of skim milk was sufficient to stop the gravity separation of SC. The treatment of 4.0 g/L of added immunoglobulins was successful in restoring the gravity separation of SC as compared with raw skim milk. Preliminary spore data on the third replicate suggested that bacterial spores gravity separate the same way as the SC in heated skim milk and heated skim milk with 4.0 g/L of added immunoglobulins. Strong evidence exists that immunoglobulins are at least one of the factors necessary for the gravity separation of SC and bacterial spores. It is uncertain at this time whether SC are a necessary component for gravity separation of fat, bacteria, and spores to occur. Further research is needed to determine separately the role of immunoglobulins and SC in gravity separation of bacteria and spores. Understanding the mechanism of gravity separation may allow the development of a continuous flow technology to remove SC, bacteria, and spores from milk. PMID- 24342687 TI - Effects of intramammary infusions of casein hydrolysate, ethylene glycol-bis(beta aminoethyl ether)-N,N,N',N'-tetraacetic acid, and lactose at drying-off on mammary gland involution. AB - The transition from the lactation to the dry period in dairy cows is a period of high risk for acquiring new intramammary infections. This risk is reduced when involution of mammary glands is completed. Consequently, strategies that accelerate the involution process after drying-off could reduce the incidence of mastitis. The objective of this study was to assess the effect of 3 different treatments on mammary gland involution. Each quarter of 8 Holstein cows in late lactation was randomly assigned at drying-off to an intramammary infusion of casein hydrolysate (CNH; 70 mg), ethylene glycol-bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA; 5.7 g), lactose (5.1g), or saline 0.9% (control) solutions. Milk samples were collected on the last 2 d before and 1, 3, 5, 7, 10, and 14 d after the last milking for determining concentrations of mammary gland involution markers. Lactoferrin, somatic cell counts (SCC), BSA, and Na(+) concentrations, as well as matrix metalloproteinase-2 and matrix metalloproteinase-9 activities gradually increased in mammary secretions during the first 2 wk following the last milking, whereas milk citrate and K(+) concentrations decreased. As involution advanced, the Na(+):K(+) ratio increased, whereas the citrate:lactoferrin ratio decreased. Compared with mammary secretions from control quarters, mammary secretions of quarters infused with CNH had higher SCC on d 1, 3, 5, and 7, and greater BSA concentrations on d 1, 3, and 5. Similarly, the CNH treatment induced a faster increase in lactoferrin concentrations, which were greater than in milk from control quarters on d 3, 5, and 7 after drying-off. Milk citrate concentrations were unaffected by CNH but the citrate:lactoferrin ratio was lower in CNH-treated quarters on d 3 and 5 than in control quarters. Moreover, CNH treatment hastened the increase in Na(+) concentration and in the Na(+):K(+) ratio on d 1. Infusion of CNH also led to an increase in proteolytic activities, with greater matrix metalloproteinase 9 activities on d 1 and 3. The EGTA infusion increased SCC above that of control quarters on d 1 and 3 but it had no effect on the other parameters. Lactose infusion had no effect on any of the involution markers. In this study, intramammary infusions of CNH were the most efficient treatment to accelerate mammary gland involution, suggesting a potential role of CNH as a local milk secretion inhibitor during milk stasis. PMID- 24342688 TI - Effect of substituting brown rice for corn on lactation and digestion in dairy cows fed diets with a high proportion of grain. AB - The effects of the substitution of brown rice (Oryza sativa L.; BR) for corn (Zea mays L.) in ensiled total mixed ration (TMR) that had a high proportion of grain on feed intake, lactation performance, ruminal fermentation, digestion, and N utilization were evaluated. Nine multiparous Holstein cows (51 +/- 9 d in milk) were used in a replicated 3 * 3 Latin square design with 3 dietary treatments: a diet containing 0, 20, or 40% steam-flaked BR and 40, 20, or 0% steam-flaked corn (dry matter basis). Cows were fed ad libitum an ensiled TMR consisting of 40.7% alfalfa silage, 11.8% grass silage, 7.1% soybean meal, and 40.0% steam-flaked grain (dry matter basis). The ensiled TMR was prepared by baling fresh TMR, and then sealed by a bale wrapper and stored outdoors at 5 to 30 degrees C for over 6 mo. Dry matter intake and milk yield were lower for cows fed 40% BR than for cows fed 40% corn. The ruminal pH and total volatile fatty acid concentrations were not affected by dietary treatment. The ruminal ammonia-N concentration decreased as the percentage of BR in the diets was elevated. The proportion of acetate decreased, and that of propionate and butyrate increased with the increasing levels of BR. Plasma urea-N concentrations was lower and glucose and insulin concentrations were higher for cows fed 40% BR than for cows fed 40% corn. The whole-tract apparent digestibility of dry matter, organic matter, and starch increased, and the digestibility of neutral detergent fiber and acid detergent fiber decreased with the increasing BR level in the diet, with no dietary effect on crude protein digestion. As a proportion of N intake, the urinary N excretion was lower and the retention of N was higher for cows fed 40% BR than for cows fed 40% corn, with no dietary effect observed on N secretion in milk and fecal N excretion. These results show that substituting BR for corn decreases urinary N losses and improves N utilization, but causes adverse effects on milk production when cows are fed high-grain diets at 40% of dietary dry matter. PMID- 24342690 TI - Effect of moderate inlet temperatures in ultra-high-pressure homogenization treatments on physicochemical and sensory characteristics of milk. AB - The effect of ultra-high-pressure homogenization (UHPH) on raw whole milk (3.5% fat) was evaluated to obtain processing conditions for the sterilization of milk. Ultra-high-pressure homogenization treatments of 200 and 300 MPa at inlet temperatures (Ti) of 55, 65, 75, and 85 degrees C were compared with a UHT treatment (138 degrees C for 4s) in terms of microbial inactivation, particle size and microstructure, viscosity, color, buffering capacity, ethanol stability, propensity to proteolysis, and sensory evaluation. The UHPH-treated milks presented a high level of microbial reduction, under the detection limit, for treatments at 300 MPa with Ti of 55, 65, 75, and 85 degrees C, and at 200 MPa with Ti = 85 degrees C, and few survivors in milks treated at 200 MPa with Ti of 55, 65, and 75 degrees C. Furthermore, UHPH treatments performed at 300 MPa with Ti = 75 and 85 degrees C produced sterile milk after sample incubation (30 and 45 degrees C), obtaining similar or better characteristics than UHT milk in color, particle size, viscosity, buffer capacity, ethanol stability, propensity to protein hydrolysis, and lower scores in sensory evaluation for cooked flavor. PMID- 24342689 TI - Compared with stearic acid, palmitic acid increased the yield of milk fat and improved feed efficiency across production level of cows. AB - The effects of dietary palmitic and stearic acids on feed intake, yields of milk and milk components, and feed efficiency of dairy cows were evaluated in an experiment with a crossover arrangement of treatments with a covariate period. Cows with a wide range of milk production (38 to 65 kg/d) were used to determine if response to fat supplementation varied according to production level. Thirty two Holstein cows (143 +/- 61 d in milk) were assigned randomly to a treatment sequence within level of milk production. Treatments were diets supplemented (2% of diet dry matter) with palmitic acid (PA; 97.9% C16:0) or stearic acid (SA; 97.4% C18:0). Treatment periods were 21 d and cows were fed a nonfat supplemented diet for 14 d immediately before the first treatment period. The final 4d of each period were used for sample and data collection. Milk production measured during the covariate period (preliminary milk yield) was used as the covariate. No interactions were detected between treatment and preliminary milk yield for the production response variables measured. Compared with SA, the PA treatment increased milk fat concentration (3.66 vs. 3.55%) and yield (1.68 vs. 1.59 kg/d), and 3.5% fat-corrected milk yield (47.5 vs. 45.6 kg/d). Treatment did not affect dry matter intake, milk yield, milk protein yield, body weight, or body condition score. Milk protein concentration was lower for PA compared with SA treatment (3.24 vs. 3.29%). The PA treatment increased feed efficiency (3.5% fat-corrected milk yield/dry matter intake) compared with SA (1.48 vs. 1.40). The increase in milk fat yield by PA was entirely accounted for by a 24% increase in 16-carbon fatty acid output into milk. Yields of de novo (3.2%) and preformed fatty acids (2.9%) were only slightly decreased by PA relative to SA. The PA treatment increased plasma concentration of nonesterified fatty acids (96.3 vs. 88.2 MUEq/L) and glucose (56.6 vs. 55.7 mg/dL) compared with SA, but insulin and beta hydroxybutyrate were not altered by the treatments. Results demonstrate that palmitic acid is more effective than stearic acid in improving milk fat concentration and yield as well as efficiency of feed conversion to milk. Responses were independent of production level and without changes in body condition score or body weight. Further studies are required to test the consistency of these responses across different types of diets. PMID- 24342691 TI - Short communication: Effect of antioxidant supplementation on milk production, milk fat synthesis, and milk fatty acids in dairy cows when fed a diet designed to cause milk fat depression. AB - This study evaluated the effect of a blend of synthetic antioxidants on the yield of milk and milk components and milk fatty acid composition in dairy cows fed a diet designed to cause milk fat depression (MFD). We hypothesized that supplementing a synthetic antioxidant to diets with a high rumen unsaturated fatty acid load (RUFAL) would decrease the severity of MFD. Sixteen lactating Holstein cows (163 +/- 47 d in milk), in a crossover design with two 21-d periods, were fed a corn silage and grass silage-based diet containing 15% distillers grains. The diet contained 34% neutral detergent fiber, 18% crude protein, 26% starch, and 4.3% total fatty acids (dry matter basis). Cows were fed the diet without supplementation (control; CON) or supplemented with 0.02% (dry matter basis) of a synthetic antioxidant (AOX; Agrado Plus, Novus International Inc., St. Charles, MO). Dry matter intake and milk yields were recorded daily. Milk samples were collected at the start of the study for baseline values and the end of each period (d 20-21) and analyzed for milk components and fatty acid composition. Dry matter intake and milk yield were unaffected by treatment and averaged 25.9 and 50.2 kg/d, respectively. Similarly, we observed no effect of treatment on yields of fat, protein, lactose, 3.5% fat-corrected milk, energy corrected milk, feed efficiency, body weight, or body condition score. Milk fat concentration and yield were both reduced by the high RUFAL diets. We observed a tendency for AOX to increase the concentration of milk fat and decrease the concentration of milk protein. Yields of de novo and preformed fatty acids were not affected by treatment, although we detected a trend for a slight increase in the yield of 16-carbon fatty acid for AOX compared with CON. Treatment had only minor effects on individual milk fatty acids, except for the concentration and yield of linoleic acid, which were over 90% higher for AOX compared with CON. In conclusion, milk fat concentration and yield were reduced by a high RUFAL diet containing 15% distillers grains; however, supplementation with AOX did not overcome the MFD induced by this diet. PMID- 24342692 TI - Economic values of production and functional traits, including residual feed intake, in Finnish milk production. AB - Improving the feed efficiency of dairy cattle has a substantial effect on the economic efficiency and on the reduction of harmful environmental effects of dairy production through lower feeding costs and emissions from dairy farming. To assess the economic importance of feed efficiency in the breeding goal for dairy cattle, the economic values for the current breeding goal traits and the additional feed efficiency traits for Finnish Ayrshire cattle under production circumstances in 2011 were determined. The derivation of economic values was based on a bioeconomic model in which the profit of the production system was calculated, using the generated steady state herd structure. Considering beef production from dairy farms, 2 marketing strategies for surplus calves were investigated: (A) surplus calves were sold at a young age and (B) surplus calves were fattened on dairy farms. Both marketing strategies were unprofitable when subsidies were not included in the revenues. When subsidies were taken into account, a positive profitability was observed in both marketing strategies. The marginal economic values for residual feed intake (RFI) of breeding heifers and cows were -25.5 and -55.8 ?/kg of dry matter per day per cow and year, respectively. The marginal economic value for RFI of animals in fattening was 29.5 ?/kg of dry matter per day per cow and year. To compare the economic importance among traits, the standardized economic weight of each trait was calculated as the product of the marginal economic value and the genetic standard deviation; the standardized economic weight expressed as a percentage of the sum of all standardized economic weights was called relative economic weight. When not accounting for subsidies, the highest relative economic weight was found for 305-d milk yield (34% in strategy A and 29% in strategy B), which was followed by protein percentage (13% in strategy A and 11% in strategy B). The third most important traits were calving interval (9%) and mature weight of cows (11%) in strategy A and B, respectively. The sums of the relative economic weights over categories for RFI were 6 and 7% in strategy A and B, respectively. Under production conditions in 2011, the relative economic weights for the studied feed efficiency traits were low. However, it is possible that the relative importance of feed efficiency traits in the breeding goal will increase in the future due to increasing requirements to mitigate the environmental impact of milk production. PMID- 24342693 TI - Technical note: Selection of suitable reference genes for studying gene expression in milk somatic cell of yak (Bos grunniens) during the lactation cycle. AB - Quantitative real-time PCR is the most sensitive technique for gene expression analysis. Data normalization is essential to correct for potential errors incurred in all steps from RNA isolation to PCR amplification. The commonly accepted approach for normalization is the use of reference gene. Until now, no suitable reference genes have been available for data normalization of gene expression in milk somatic cells of lactating yaks across lactation. In the present study, we evaluated the transcriptional stability of 10 candidate reference genes in milk somatic cells of lactating yak, including ACTB, B2M, GAPDH, GTP, MRPL39, PPP1R11, RPS9, RPS15, UXT, and RN18S1. Four genes, RPS9, PPP1R11, UXT, and MRPL39, were identified as being the most stable genes in milk somatic cells of lactating yak. Using the combination of RPS9, PPP1R11, UXT, and MRPL39 as reference genes, we further assessed the relative expression of 4 genes of interest in milk somatic cells of yak across lactation, including ELF5, ABCG2, SREBF2, and DGAT1. Compared with expression in colostrum, the overall transcription levels of ELF5, ABCG2, and SREBF2 in milk were found to be significantly upregulated in early, peak, and late lactation, and significantly downregulated thereafter, before the dry period. A similar pattern was observed in the relative expression of DGAT1, but no significant difference was revealed in its expression in milk from late lactation compared with colostrum. Based on these results, we suggest that the geometric mean of RPS9, PPP1R11, UXT, and MRPL39 can be used for normalization of real-time PCR data in milk somatic cells of lactating yak, if similar experiments are performed. PMID- 24342694 TI - Short communication: Effect of blackberry and pomegranate oils on vaccenic acid formation in a single-flow continuous culture fermentation system. AB - A single-flow continuous culture fermenter system was used to study the effect of blackberry and pomegranate oils on vaccenic acid (trans-11 C18:1; VA) formation. Four continuous culture fermenters were used in a 4 * 4 Latin square design with 4 periods of 10d each. Diets were (1) control (CON), (2) control plus soybean oil (SBO), (3) control plus blackberry oil (BBO), and (4) control plus pomegranate oil (PMO). Oil supplements were added at 30 g/kg of diet dry matter. Effluents were collected from each fermenter during the last 3d of each period and analyzed for nutrient and fatty acid composition. The concentration of VA in effluents increased with oil supplements and was greatest with the BBO diet. The concentration of stearic acid (C18:0) increased with the addition of soybean oil but decreased with the addition of pomegranate oil compared with the CON diet. The concentration of cis-9,trans-11 conjugated linoleic acid increased with oil supplements and was greatest with the PMO diet. In conclusion, all 3 oil sources were effective in increasing the production of VA. The effect of PMO and BBO on VA may have resulted in part from inhibition of the final step in the biohydrogenation of VA to stearic acid. PMID- 24342695 TI - Dairy cow handling facilities and the perception of Beef Quality Assurance on Colorado dairies. AB - A survey was conducted on Colorado dairies to assess attitudes and practices regarding Dairy Beef Quality Assurance (DBQA). The objectives were to (1) assess the need for a new handling facility that would allow all injections to be administered via DBQA standards; (2) establish if Colorado dairy producers are concerned with DBQA; and (3) assess differences in responses between dairy owners and herdsmen. Of the 95 dairies contacted, 20 (21%) agreed to participate, with a median herd size of 1,178. When asked to rank the following 7 traits--efficiency, animal safety, human safety, ease of animal handling, ease of operation, inject per Beef Quality Assurance (BQA) procedures, and cost--in order of priority when designing a new handling facility, human and animal safety were ranked highest in priority (first or second) by the majority of participants, with ease of animal handling and efficiency ranked next. Interestingly, the administration of injections per BQA standards was ranked sixth or seventh by most participants. Respondents estimated the average annual income from the sale of cull cows to be 4.6% of all dairy income, with 50% receiving at least one carcass discount or condemnation in the past 12 mo. Although almost all of the participating dairy farmers stated that the preferred injection site for medications was the neck region, a significant number admitted to using alternate injection sites. In contrast, no difference was found between responses regarding the preferred and actual location for intravenous injections. Although most participating producers are aware of BQA injection guidelines, they perceive efficiency as more important, which could result in injections being administered in locations not promoted by BQA. Dairy owners and herdsmen disagreed in whether or not workers had been injured in the animal handling area in the last 12 mo. Handling facilities that allow for an efficient and safe way to administer drugs according to BQA guidelines and educational opportunities that highlight the effect of improved DBQA on profitability could prove useful. Dairy producers play a key role in ensuring that dairy beef is safe and high quality, and just as they are committed to producing safe and nutritious milk for their customers, they should be committed to producing the best quality beef. PMID- 24342696 TI - The expression of genes involved in hepatic metabolism is altered by temporary changes to milking frequency. AB - Changes to milking frequency (MF) affect the metabolic and energetic status of dairy cows. However, the duration of altered MF necessary to modify hepatic transcription during early lactation is less clear. Additionally, long-term responses to short-term alterations in MF have not been established. Holstein Friesian dairy cows (n = 120) were allocated to 3 or 6 wk of either once-daily (1 *) or thrice-daily (3 *) milking, immediately postpartum. Following treatment, cows were switched to twice-daily (2 *) milking. These 4 treatment groups were compared with cows milked 2 * (n = 30) for the whole lactation. Liver tissue was collected by biopsy at 1, 3, 6, and 9 wk postpartum from 12 cows per treatment, RNA was extracted, and transcript abundance of genes involved in hepatic metabolism was quantified. Milking frequency altered the expression of most of the genes measured; however, we observed no effects caused by the length of time on the alternative milking frequency and no interactions between MF and length. During the MF treatment, mRNA expression of some, but not all, genes involved in gluconeogenesis (G6PC, PCK1), fatty acid beta-oxidation (CPT1A, CPT2), ketogenesis (HMGCS2), lipid transport (APOA1), and lipolysis (PNPLA2) were lower for cows milked 1 * and plasma glucose and insulin concentrations were greater. Cows milked 3 * had reduced mRNA expression for some of the genes involved in fatty acid synthesis (ACACA) and lipid transport (APOB) and had greater plasma NEFA concentrations at wk 1. At 9 wk postpartum, expression data indicated that cows previously milked 3 * had a greater capacity for gluconeogenesis (PCK1), ketogenesis (HMGCS2), and urea cycling (ASL, CPS1) and lower glucose concentrations than cows previously milked 1 *, because some of the genes involved in these processes were still altered. Milking cows 1 * relative to 2 *, however, did not result in significant carryover effects on the expression of the genes measured in this study, indicating that metabolic changes are not sustained beyond the period of reduced MF. Changes to MF altered the hepatic response during early lactation; however, this was not dependent on the duration of MF change. Although we observed only minimal carryover effects on hepatic metabolism from short periods of reduced MF postpartum, there may be long-term effects on urea cycling (ASL, CPS1) and ketogenesis (HMGCS2) when 3 * milking occurs immediately postpartum. PMID- 24342697 TI - [Multiple ganglioneuroma with cervical involvement]. PMID- 24342698 TI - [Free radial forearm flap in head and neck: our experience]. AB - INTRODUCTION: Oncologic surgery leads to important defects and sequelae, as well as notable cosmetic and functional alterations. In this aspect reconstructive surgery has an essential role, allowing more radical excision and lower associated functional and cosmetic morbidities. The aim of this study was to present and evaluate the experience and results of the reconstructive microsurgery unit in our centre's ENT department. METHODS: Retrospective study of procedures performed between 2006 and 2012. RESULTS: A total of 36 cases were reviewed. The primary tumour was found in the oropharynx (58%) in the majority of cases. In 5 cases the procedure was performed for reconstruction and fistula closure (4 pharyngostoma and 1 tracheoesophageal fistula). Failure from total necrosis was 16% (6/36). No associated mortality has been reported. The most common postoperative complications were wound dehiscence in 5 patients and pharyngostoma (fistula) in 5 cases. Prior radiotherapy significantly influenced the increase in the overall incidence of complications (P<05). CONCLUSIONS: Reconstructive surgery currently plays an important role in surgery for head and neck cancer. The radial forearm flap is a safe, reliable method for reconstruction of most defects in the ENT field. This type of intervention provides greater autonomy and safety in surgical oncology. PMID- 24342699 TI - [Explanations for the non-use of hearing aids in a group of older adults. A qualitative study]. AB - INTRODUCTION: Hearing loss is a condition that affects communication and social insertion, increasing in frequency with increasing age. Explicit Health Guarantees (GES) have placed hearing loss in adults over 65 years old as a health priority in Chile, guaranteeing access to hearing aids to those who need it. However, it has been seen that adherence to their use is hampered by several factors. METHODS: This was a qualitative study to find items related to the adherence to use of hearing aids. We performed individual and focus group interviews in the Department of Otolaryngology at a hospital in Santiago (Chile) from June to September 2012. RESULTS: Using hearing aids was positive for patients, perceiving an improvement in their relationship with the environment. The severity of hearing loss and the patient's own social life was relevant. For otolaryngologists and audiologists the study highlights the low patient perception of the need for hearing help. Discordance between expectations and the reality of patient adaptation is generated. Another relevant factor identified was the lack of a rehabilitation programme. CONCLUSIONS: The elements that influence adherence are associated with 3 groups: patient factors, audiological factors and factors dependent on the health programme. The most important, from the perspective of patients, would be the fear of improper handling; for otolaryngologists, the socio-cultural perception of the hearing aid user as a disabled individual; for audiologists, inadequate prosthetic fitting and the lack of an appropriate rehabilitation program. PMID- 24342700 TI - Petromastoid canal. PMID- 24342701 TI - A late cutaneous complication of Trilucent breast implants. PMID- 24342702 TI - 2-Methoxystypandrone ameliorates brain function through preserving BBB integrity and promoting neurogenesis in mice with acute ischemic stroke. AB - 2-Methoxystypandrone (2-MS), a naphthoquinone, has been shown to display an immunomodulatory effect in a cellular model. To explore whether 2-MS could protect mice against cerebral ischemic/reperfusion (I/R)-induced brain injury, we evaluated 2-MS's protective effects on an acute ischemic stroke by inducing a middle cerebral artery occlusion/reperfusion (MCAO) injury in murine model. Treatment of mice that have undergone I/R injury with 2-MS (10-100 MUg/kg, i.v.) at 2 h after MCAO enhanced survival rate and ameliorated neurological deficits, brain infarction, neural dysfunction and massive oxidative stress, due to an enormous production of free radicals and breakdown of blood-brain barrier (BBB) by I/R injury; this primarily occurred with extensive infiltration of CD11b positive inflammatory cells and upexpression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 and p65 nuclear factor-kappa B (NF-kappaB). All of these pathological changes were diminished by 2-MS; 2-MS also intensively limited cortical infarction and promoted upexpression of neurodevelopmental genes near peri-infarct cortex and endogenous neurogenesis near subgranular zone of hippocampal dentate gyrus and the subventricular zone, most possibly by inactivation of GSK3beta which in turn upregulating beta-catenin, Bcl-2 adam11 and adamts20. We conclude that 2-MS blocks inflammatory responses by impairing NF kappaB signaling to limit the inflammation and oxidative stress for preservation of BBB integrity; 2-MS also concomitantly promotes neurodevelopmental protein expression and endogenous neurogenesis through inactivation of GSK3beta to enhance beta-catenin signaling for upexpression of neuroprotective genes and proteins. PMID- 24342703 TI - Induction of dental epithelial cell differentiation marker gene expression in non odontogenic human keratinocytes by transfection with thymosin beta 4. AB - Previous studies have shown that the recombination of cells liberated from developing tooth germs develop into teeth. However, it is difficult to use human developing tooth germ as a source of cells because of ethical issues. Previous studies have reported that thymosin beta 4 (Tmsb4x) is closely related to the initiation and development of the tooth germ. We herein attempted to establish odontogenic epithelial cells from non-odontogenic HaCaT cells by transfection with TMSB4X. TMSB4X-transfected cells formed nodules that were positive for Alizarin-red S (ALZ) and von Kossa staining (calcium phosphate deposits) when cultured in calcification-inducing medium. Three selected clones showing larger amounts of calcium deposits than the other clones, expressed PITX2, Cytokeratin 14, and Sonic Hedgehog. The upregulation of odontogenesis-related genes, such as runt-related transcription factor 2 (RUNX2), Amelogenin (AMELX), Ameloblastin (AMBN) and Enamelin (ENAM) was also detected. These proteins were immunohistochemically observed in nodules positive for the ALZ and von Kossa staining. RUNX2-positive selected TMSB4X-transfected cells implanted into the dorsal subcutaneous tissue of nude mice formed matrix deposits. Immunohistochemically, AMELX, AMBN and ENAM were observed in the matrix deposits. This study demonstrated the possibility of induction of dental epithelial cell differentiation marker gene expression in non-odontogenic HaCaT cells by TMSB4X. PMID- 24342704 TI - Postmarketing safety of biologics and biological devices. AB - BACKGROUND CONTEXT: Regardless of study design, the approval process of biologics and biological devices cannot identify every possible safety concern. Postmarketing safety surveillance can provide information based on real-world use of medical products in heterogeneous populations and is critical for identifying potentially serious adverse events, events that are too rare to be detected during premarketing studies, late complications, and events involving individuals or uses that were not evaluated in clinical trials. PURPOSE: To review why adverse event reporting is important and how the information is used, with emphasis on the points that are most applicable for surgeons and other spine professionals. METHODS: This is an overview of postmarketing safety surveillance. RESULTS: Review of adverse event reports has resulted in safety notifications, label changes, and publications regarding the safety of biologics and biological devices, such as the risk of airway compromise after the use of recombinant human bone morphogenetic protein in cervical spine fusion, the occurrence of a fatal air embolism after the use of a fibrin sealant that had been applied with a spray device, and infections after allograft transplantation of human tissues. CONCLUSIONS: In light of the rapid development of new biologics, postmarketing surveillance is imperative for ensuring that these products are as safe as possible. By reporting adverse events, surgeons and other health care professionals play a key role in improving and refining our understanding of the safety of biologics. PMID- 24342705 TI - Cystic lung disease: achieving a radiologic diagnosis. AB - Diffuse cystic lung disease represents a diverse group of uncommon disorders with characteristic appearance on high resolution CT imaging. The combination of imaging appearance with clinical features and genetic testing where appropriate permits a confident and accurate diagnosis in the majority of the diseases without recourse for open lung biopsy. The mechanism of cyst development disease is unclear but in some disorders appears to be related to small airways obstruction. These diseases are incurable, with the exception of Langerhans cell histiocytosis which may spontaneously remit or resolve on smoking cessation. Disease progression is unpredictable; in general older patients have a more benign disease, while young patients may progress rapidly to respiratory failure. An understanding of the complications of cystic lung disease and the appearance of disease progression is essential for the management of these patients. A number of these disorders are associated with malignancy, recognition of the potential tumors permits appropriate imaging surveillance. Due to the widespread use of CT, pulmonary cysts are increasingly discovered incidentally in an asymptomatic individual. The diagnostic challenge is to determine whether these cysts represent an early feature of a progressive disease or have no clinical significance. In the elderly population the cysts are unlikely to represent a progressive disease. In individuals <50 years further evaluation is recommended. PMID- 24342706 TI - Use of S-LANSS, a tool for screening neuropathic pain, for predicting postherpetic neuralgia in patients after acute herpes zoster events: a single center, 12-month, prospective cohort study. AB - Postherpetic neuralgia (PHN) is one of the most severe sequelae of herpes zoster events. Several risk factors have been reported for PHN, including old age, severe skin rash, and intense pain. This study therefore aims to evaluate the usefulness of the Self-completed Leeds Assessment of Neuropathic Symptoms and Signs pain scale (S-LANSS) in conjunction with previously reported risk factors for predicting PHN. A group of herpes zoster patients (N = 305) were included in the cohort study. Subjects were asked for their demographic information, clinical symptoms and signs, intensity of pain by visual analog scale (VAS), and S-LANSS. They were followed up in clinical visits or via telephone for 12 months. Nineteen patients (6.2%) suffered from PHN in this study. Using logistic regression, 3 risk factors for PHN were identified: age >=70 years, high VAS scores, and high S LANSS scores. Prediction of PHN using VAS (>=8) and S-LANSS (>=15) criteria achieved a sensitivity of 78.9% and specificity of 78.0%. Prediction of PHN in elderly patients (>=70 years), using the criteria of VAS (>=6) and S-LANSS (>=15) as well, achieved 100% sensitivity and 57.1% specificity. S-LANSS could be a useful prediction tool for PHN, particularly if combined with previously well known risk factors and VAS. PERSPECTIVE: Among acute herpes zoster patients, subjects with characteristics of neuropathic pain showed high frequency of PHN. The tools for screening neuropathic pain like S-LANSS could be helpful for predicting PHN and enabling early intervention of pain management. PMID- 24342707 TI - Central pain sensitization, COMT Val158Met polymorphism, and emotional factors in fibromyalgia. AB - Neurobiological evidence points to altered central nervous system processing of nociceptive stimuli in fibromyalgia. Enzymes like catechol-O-methyl-transferase (COMT) are involved in the elimination of catecholamines playing a possible role in central sensitization and pain. We used quantitative sensory testing to evidence central sensitization in fibromyalgia patients and test whether COMTVal158Met polymorphism, associated with a reduction in enzyme activity, plays a role in sensitized patients. Pain evaluation and quantitative sensory testing were performed including the spinal nociceptive flexion reflex, a physiologic correlate for the evaluation of central nociceptive pathways. Quality of life and distress questionnaires were used. A total of 137 fibromyalgia patients were assessed and compared to 99 matched controls. Central sensitization (nociceptive flexion reflex <27 mA) was present in 95/134 (71%) patients. Among them, COMT p.Val158Met polymorphism displayed a significant linear "genotype effect" (P = .033), with the Met/Met (mean = 17.8 +/- 4.8 mA) and Val/Val (mean = 21.4 +/- 4.6 mA) subgroups at the opposite ends of the nociceptive flexion reflex threshold (Met/Met vs Val/Val P = .015) and the Val/Met subgroup (mean = 19 +/- 4.9 mA) in between (Val/Met vs Val/Val P = .041). Spontaneous moderate to severe pain was more likely to be associated with COMT Met/Met genotype. Patients showed important emotional distress compared to controls. In sensitized patients, the COMT Met/Met subgroup showed systematically-though not significantly-worse scores for all psychological variables. PERSPECTIVE: The association between COMT p.Val158Met polymorphism and central sensitization in fibromyalgia is essential as it refers to the severity of central sensitization and may be a risk factor for treatment outcome. PMID- 24342708 TI - Arabidopsis mutants affecting oxylipin signaling in photo-oxidative stress responses. AB - Plant oxylipins derive from oxygenation of polyunsaturated fatty acids in thylakoid membranes and oxylipins such as jasmonic acid (JA) and 12-oxo phytodienoic acid (OPDA) play important roles in adaptation to photo-oxidative stress. OPDA functions both as a JA precursor and as a biologically active signaling molecule that induces expression of a specific set of genes. These genes can be induced by OPDA in the JA-insensitive coronatine insensitive1 (coi1) mutant, suggesting that there is an alternative pathway for OPDA signaling, independent of COI1-dependent JA signaling. However, little is known about OPDA signaling in photo-oxidative stress responses. In this study, we isolated Arabidopsis mutants with constitutively enhanced expression from the OPDA responsive HsfA2 promoter. We used deletion mapping and complementation analysis to identify one responsible gene as CATALASE2. Our results thus indicate that ROS producing cellular metabolism links to OPDA signaling. PMID- 24342709 TI - Design and synthesis of novel distamycin-modified nucleoside analogues as HIV-1 reverse transcriptase inhibitors. AB - Design and synthesis of nucleoside analogues have persistently attracted extensive interest because of their potential application in the field of antiviral therapy, and its study also receives additional impetus for improvement in the ProTide technology. Previous studies have made great strides in the design and discovery of monophosphorylated nucleoside analogues as potential kinase independent antiretrovirals. In this work, a series of nucleoside phosphoramidates modified by distamycin analogues was synthesized and evaluated as nucleoside reverse transcriptase inhibitors (NRTIs) in HIV-1-infected MT-4 and CEM cells, including variations in nucleoside, alkyl moiety, and the structure of distamycin analogues. These compounds exhibited modest potency with the EC50 value in the range of 1.3- to 6.5-fold lower than their corresponding parent drugs in MT-4 cells, which may be attributed to increasing intracellular availability due to the existence of distamycin analogue with favorable hydrophilic-lipophilic equilibrium. Meanwhile, the length of distamycin analogue was considered and assessed as an important factor that could affect antiviral activity and cytotoxicity. Enzymatic and metabolic stability studies have been performed in order to better understand the antiviral behavior of these compounds. The present work revealed the compounds to have a favorable and selective anti-HIV-1 activity in MT-4 and CEM cells, and helped to develop strategies for design and synthesis of effective monophosphorylated nucleoside analogues, which may be applied to antiretroviral research as NRTIs. PMID- 24342710 TI - Cyclodextrin containing biodegradable particles: from preparation to drug delivery applications. AB - Cyclodextrins (CDs) offer a very broad spectrum of applications in diverse fields of drug delivery. They are a family of cyclic alpha-(1-4)-linked oligosaccharides of alpha-d-glucopyranose subunits forming a more hydrophobic central cavity and a hydrophilic outer shell. CDs bear cage like supramolecular structures, similar to calixarenes, cyclophanes and crown ethers. No covalent bonds are required to host a guest molecule in the central cavity. The aim of this review is to throw light on some of the applications and formulation techniques for the novel multifunctional CD based nanocarriers used in diverse areas of drug delivery. Furthermore, this article highlights the molecular structure, chemical, complexation properties and the use of CDs in nanosystems like liposomes, magnetic nanoparticles, biodegradable polymers, micro and nanospheres and capsules. PMID- 24342711 TI - Interaction between fed gastric media (Ensure Plus(r)) and different hypromellose based caffeine controlled release tablets: comparison and mechanistic study of caffeine release in fed and fasted media versus water using the USP dissolution apparatus 3. AB - The aim of the study was to investigate caffeine release in fed and fasted state media from three controlled release matrix tablets containing different HPMC viscosity grades. The biorelevant in vitro dissolution methods utilize the USP 3 dissolution apparatus and biorelevant media to simulate fed and fasted gastro intestinal dissolution conditions. The effect of tablet reciprocation rate (dip speed) in dissolution media (10 and 15 dips per minute) and media (water, fed and fasted) on caffeine release rate from - and erosion rate of - 100, 4000 and 15,000 mPa s HPMC viscosity tablets was investigated using factorial designed experiments. Furthermore, the mechanism of release in Ensure Plus((r)), a nutrition drink similar in composition to the FDA standard meal, was investigated by studying tablet swelling using texture analysis. Altering dip speed has negligible effect on release and erosion rates. Using fasted media instead of water slightly decreases caffeine release from 100 and 4000 mPa s HPMC viscosity tablets as well as erosion rates, while 15,000 mPa s tablets remain unaffected. Fed compared to fasted media decreases caffeine release rate, and the food effect is greater for the 100 mPa s viscosity tablets compared to the 4000 and 15,000 mPa s viscosity tablets. The investigation using texture analysis indicates that Ensure Plus((r)) becomes rate-limiting for caffeine release from HPMC tablets by forming a hydrophobic barrier around the tablets. The barrier decreases tablet water permeation, which decreases erosion rate in 100 mPa s viscosity tablets, swelling in 15,000 mPa s viscosity tablets and caffeine release from both tablets. This observed interaction between Ensure Plus((r)) and the HPMC tablets may translate into decreased drug release rate in the fed stomach, which may decrease the amount of drug available for absorption in the small intestine and thus reduce systemic drug exposure and maximum plasma concentration. PMID- 24342712 TI - Doubling of spending on dementia research by 2025 is inadequate, say experts. PMID- 24342713 TI - Association between regression and self injury among children with autism. AB - Self injurious behaviors (SIBs) are challenging clinical problems in individuals with autism spectrum disorders (ASDs). This study is one of the first and largest to utilize inpatient data to examine the associations between autism, developmental regression, and SIBs. Medical records of 125 neurobehavioral hospitalized patients with diagnoses of ASDs and SIBs between 4 and 17 years of age were reviewed. Data were collected from medical records on the type and frequency of SIBs and a history of language, social, or behavioral regression during development. The children with a history of any type of developmental regression (social, behavioral, or language) were more likely to have a diagnosis of autistic disorder than other ASD diagnoses. There were no significant differences in the occurrence of self injurious or other problem behaviors (such as aggression or disruption) between children with and without regression. Regression may influence the diagnostic considerations in ASDs but does not seem to influence the clinical phenotype with regard to behavioral issues. Additional data analyses explored the frequencies and subtypes of SIBs and other medical diagnoses in ASDs, with intellectual disability and disruptive behavior disorder found most commonly. PMID- 24342714 TI - We must unite against health law that threatens medical neutrality in Turkey. PMID- 24342715 TI - Randomised clinical trial of five ear acupuncture points for the treatment of overweight people. AB - OBJECTIVE: To evaluate the efficacy of the five ear acupuncture points (Shen-men, Spleen, Stomach, Hunger, Endocrine), generally used in Korean clinics for treating obesity, and compare them with the Hunger acupuncture point. METHODS: A randomised controlled clinical trial was conducted in 91 Koreans (16 male and 75 female, body mass index (BMI)>=23), who had not received any other weight control treatment within the past 6 months. Subjects were divided randomly into treatment I, treatment II or sham control groups and received unilateral auricular acupuncture with indwelling needles replaced weekly for 8 weeks. Treatment I group received acupuncture at the five ear acupuncture points, treatment II group at the Hunger acupuncture point only and the sham control group received acupuncture at the five ear acupuncture points used in treatment I, but the needles were removed immediately after insertion. BMI, waist circumference, weight, body fat mass (BFM), percentage body fat and blood pressure were measured at baseline and at 4 and 8 weeks after treatment. RESULTS: For the 58 participants who provided data at 8 weeks, significant differences in BMI, weight and BFM were found between the treatment and control groups. Treatment groups I and II showed 6.1% and 5.7% reduction in BMI, respectively (p<0.004). There were no significant differences between the two treatment groups. CONCLUSIONS: This finding suggests that the five ear acupuncture points, generally used in Korean clinics, and the Hunger point alone treatment are both effective for treating overweight people. PMID- 24342716 TI - Tafazzin splice variants and mutations in Barth syndrome. AB - Barth syndrome is caused by mutations in the TAZ (tafazzin) gene on human chromosome Xq28. The human tafazzin gene produces four major mRNA splice variants; two of which have been shown to be functional (TAZ lacking exon 5 and full-length) in complementation studies with yeast and Drosophila. This study characterizes the multiple alternative splice variants of TAZ mRNA and their proportions in blood samples from a cohort of individuals with Barth syndrome (BTHS). Because it has been reported that collection and processing methods can affect the expression of various genes, we tested and chose a stabilizing medium for collecting, shipping and processing of the blood samples of these individuals. In both healthy controls and in BTHS individuals, we found a greater variety of alternatively spliced forms than previously described, with a sizeable proportion of minor splice variants besides the four dominant isoforms. Individuals with certain exonic and intronic splice mutations produce additional mutant mRNAs that could be translated into two or more proteins with different amino acid substitutions in a single individual. A fraction of the minor splice variants is predicted to be non-productive. PMID- 24342717 TI - Ceftaroline activity tested against uncommonly isolated Gram-positive pathogens: report from the SENTRY Antimicrobial Surveillance Program (2008-2011). AB - Ceftaroline was tested against 1859 clinically significant Gram-positive organisms from uncommonly isolated species. The organisms (31 species/groups) were collected from 133 medical centres worldwide over a 4-year period (2008 2011). Coagulase-negative staphylococci were generally susceptible to ceftaroline, with MIC50 values (minimum inhibitory concentration required to inhibit 50% of the isolates) of 0.06-0.5mg/L. Ceftaroline was active against Micrococcus spp. [minimum inhibitory concentration required to inhibit 90% of the isolates (MIC90)=0.06 mg/L], but showed more limited potency versus some Corynebacterium spp. and Listeria monocytogenes isolates. Ceftaroline was active against all beta-haemolytic streptococci and viridans group streptococcal species/groups listed, with MIC50 and MIC90 values ranging from <= 0.015 mg/L to 0.03 mg/L and from <= 0.015 mg/L to 0.5mg/L, respectively. Based on these in vitro findings, ceftaroline may have a potential role in the treatment of infections caused by these rarer species as guided by reference MIC test results. PMID- 24342718 TI - Pioneers in CNS inhibition: 1. Ivan M. Sechenov, the first to clearly demonstrate inhibition arising in the brain. AB - This article reviews the contributions of Ivan Michailovich Sechenov [1829-1905] to the neurophysiological concept of central inhibition. He first studied this concept in the frog and on himself. Later his trainees extended the study of central inhibition to other mammalian species. Outside his own country, Sechenov is better known for his prescient contributions to physiological psychology. In Russia, however, he is also revered as "the father of Russian physiology," because of his contributions to neurophysiology and other aspects of physiology including blood gases and respiration, the physiology and biomechanics of movement, and general physiology concepts that appeared in his textbooks and later works he helped translate from largely German sources. After graduation from Moscow University Medical School in 1856 he spent 31/2 years in Germany and Austria where he attended lectures and conducted research under the direction of several prominent physiologists and biochemists. In his subsequent academic career he held positions at universities in St. Petersburg (1860-1870; 1876 1888), Odessa (1871-1876) and Moscow (1890-1905). From 1860 onwards he was acclaimed as a physiologist in academic circles. He was also well known in Russian society for his public lectures on physiology and his views on physiological psychology. The latter resulted in him being branded "politically unreliable" by the tsarist bureaucracy from 1863 onwards. Sechenov's first (1862) study on central inhibition remains his most memorable. He delayed the withdrawal of a frog's foot from a weak acid solution by chemical or electrical stimulation of selected parts of the central nervous system. He also noted similar effects on his own hand during co-activation of other sensory inputs by tickling or teeth gnashing. PMID- 24342719 TI - Oxidative stress in melanocyte senescence and melanoma transformation. AB - Melanoma is a severe type of skin cancer with a high metastasis potential and poor survival rates once metastasized. The causes of melanoma formation are multifactorial and not fully understood. Several signaling cascades such as the RAS/RAF/ERK1/2 pathway, the PI3K/AKT pathway, RAC1 and NF-kappaB are involved in melanoma initiation and progression. Reactive oxygen species (ROS) are induced by these signal transduction cascades, and they play a fundamental role in melanomagenic processes. Cells derived from the melanocytic lineage are particularly sensitive to an increase in ROS, and thus, melanoma cells rely on efficient antioxidant measures. This review summarizes the causes and consequences of ROS generation in melanocytes and melanoma and discusses the potential of pro-oxidant therapy in melanoma treatment. PMID- 24342720 TI - A formin-g role during development and disease. AB - Several different protein families were shown to be involved in the regulation of actin filament formation and have been studied extensively in processes such as cell migration. Among them are members of the formin family, which tend to promote the formation of linear actin filaments. Studies in recent years, often using loss of function animal models, have indicated that formin family members play roles beyond cell motility in vitro and are involved in processes ranging from tissue morphogenesis and cell differentiation to diseases such as cancer and cardiomyopathy. Therefore the aim of this review is to discuss these findings and to start putting them into a subcellular context. PMID- 24342721 TI - Human relevance of NRAS/BRAF mouse melanoma models. AB - Melanoma is a major problem for many individuals worldwide. Although no effective treatment is available, promising new strategies are being developed. A better understanding of the inner workings of the disease would undoubtedly lead to improved treatments. Mouse melanoma models have been used to elucidate many key regulatory pathways involved in melanoma initiation and progression, and models with mutations in the oncogenes RAF and RAS have been particularly informative. Here, we summarize and evaluate the human relevance of various RAF and RAS mouse melanoma models and their contribution to our understanding of melanoma. PMID- 24342723 TI - Tumor cells and neovasculature dual targeting delivery for glioblastoma treatment. AB - Glioblastoma multiforme (GBM), one of the most common primary malignant brain tumors, was characterized by angiogenesis and tumor cells proliferation. Antiangiogenesis and antitumor combination treatment gained much attention because of the potency in dual inhibition of both the tumor proliferation and the tumor invasion. In this study, a neovasculature and tumor cell dual targeting delivery system was developed through modification of nanoparticles with interleukin-13 peptide and RGD (IRNPs), in which interleukin-13 peptide was targeting GBM cells and RGD was targeting neovasculature. To evaluate the potency in GBM treatment, docetaxel was loaded into IRNPs. In vitro, interleukin-13 peptide and RGD could enhance the corresponding cells (C6 and human umbilical vein endothelial cells) uptake and cytotoxicity. In combination, IRNPs showed high uptake in both cells and increased the cytotoxicity on both cells. In vivo, IRNPs could effectively deliver cargoes to GBM with higher intensity than mono modified nanoparticles. Correspondingly, docetaxel-IRNPs displayed best anti tumor effect with a median survival time of 35 days, which was significantly longer than that of mono-modified and unmodified nanoparticles. Importantly, treatment with docetaxel-IRNPs could avoid the accumulation of HIF1alpha in GBM site, which was crucial for the tumor invasion. After the treatment, there was no obvious change in normal organs of mice. PMID- 24342722 TI - Targeted oral delivery of BmpB vaccine using porous PLGA microparticles coated with M cell homing peptide-coupled chitosan. AB - M cells, the key players of the mucosal immunity induction, are one of the intestinal barriers for the efficient delivery of vaccines to mucosal immune tissues. To overcome the barrier, we have developed an efficient oral vaccine carrier that constitutes poly (lactic-co-glycolic acid) (PLGA) microparticle coated with M cell targeting peptide. In this study, a membrane protein B of Brachyspira hyodysenteriae (BmpB) as a model vaccine against swine dysentery was loaded into porous PLGA microparticles (MPs). The PLGA MPs were further coated with the water-soluble chitosan (WSC) conjugated with M cell homing peptide (CKS9) to prepare BmpB-CKS9-WSC-PLGA MPs. Oral immunization of BmpB vaccine with CKS9-WSC-PLGA MPs in mice showed elevated secretory IgA responses in the mucosal tissues and systemic IgG antibody responses, providing a complete immune response. Specifically, the immunization with these MPs demonstrated to induce both Th1- and Th2-type responses based on elevated IgG1 and IgG2a titers. The elevated immune responses were attributed to the enhanced M cell targeting and transcytosis ability of CKS9-WSC-PLGA MPs to Peyer's patch regions. The high binding affinity of CKS9-WSC-PLGA MPs with the M cells to enter into the Peyer's patch regions of mouse small intestine was investigated by closed ileal loop assay and it was further confirmed by confocal laser scanning microscopy. These results suggest that the M cell targeting approach used in this study is a promising tool for targeted oral vaccine delivery. PMID- 24342724 TI - Micropit surfaces designed for accelerating osteogenic differentiation of murine mesenchymal stem cells via enhancing focal adhesion and actin polymerization. AB - Recent reports demonstrate that enhanced focal adhesion (FA) between cells and the extracellular matrix (ECM) and intracellular actin polymerization (AP) upregulates cellular functions such as proliferation, stem-cell fate and differentiation. Purposed to accelerate osteogenic differentiation, enhancement of FAs and AP of cells was induced by adding a tailor-made micropit (tMP, 3 * 3 MUm(2)) with different heights (2 or 4 MUm). The tMP surface was examined for its differentiation efficiency using mouse mesenchymal stem cells, C3H10T1/2. Though the cell spreading area was not affected by the surface topography, cells on the tMP substrates had enhanced FAs which were significantly confined inside the micropits, increased actin polymerization and traction forces, and osteogenic differentiation. Further experiments with Y-27632 and Blebbistatin, which specifically regulate FA or AP functions, demonstrated that the tMP-induced acceleration of osteogenic differentiation was caused by the rho-associated, coiled-coil containing protein kinase (ROCK) and nonmuscle myosin II (NM II), which are key molecules of the RhoA/ROCK signaling pathway. The tMP is applicable as an osteo-active substrate for the instructive bone cell differentiation and population. PMID- 24342725 TI - Bioorthogonal, two-component delivery systems based on antibody and drug-loaded nanocarriers for enhanced internalization of nanotherapeutics. AB - Nanocarriers play an important role in targeted cancer chemotherapy. The optimal nanocarrier delivery system should provide efficient and highly specific recognition of the target cells and rapid internalization of the therapeutic cargo to reduce systemic toxicity as well as to increase the cytotoxicity to cancer cells. To this end, we developed a two-step, two-component targeted delivery system based on antibody and drug-loaded nanocarrier that uses bioorthogonal click reactions for specific internalization of nanotherapeutics. The pretargeting component, anti-HER2 humanized monoclonal antibody, trastuzumab, functionalized with azide groups labels cancer cells that overexpress HER2 surface receptors. The drug carrier component, dibenzylcyclooctyne substituted albumin conjugated with paclitaxel, reacts specifically with the pretargeting component. These two components form cross-linked clusters on the cell surface, which facilitates the internalization of the complex. This strategy demonstrated substantial cellular internalization of clusters consisted of HER2 receptors, modified trastuzumab and paclitaxel-loaded albumin nanocarriers, and subsequent significant cytotoxicity in HER2-positive BT-474 breast cancer cells. Our results show high efficacy of this strategy for targeted nanotherapeutics. We foresee to broaden the applications of this strategy using agents such as radionuclides, toxins, and interfering RNA. PMID- 24342726 TI - Optical imaging of fibrin deposition to elucidate participation of mast cells in foreign body responses. AB - Mast cell activation has been shown to be an initiator and a key determinant of foreign body reactions. However, there is no non-invasive method that can quantify the degree of implant-associated mast cell activation. Taking advantage of the fact that fibrin deposition is a hallmark of mast cell activation around biomaterial implants, a near infrared probe was fabricated to have high affinity to fibrin. Subsequent in vitro testing confirmed that this probe has high affinity to fibrin. Using a subcutaneous particle implantation model, we found significant accumulation of fibrin-affinity probes at the implant sites as early as 15 min following particle implantation. The accumulation of fibrin-affinity probes at the implantation sites could also be substantially reduced if anti coagulant - heparin was administered at the implant sites. Further studies have shown that subcutaneous administration of mast cell activator - compound 48/80 - prompted the accumulation of fibrin-affinity probes. However, implant-associated fibrin-affinity probe accumulation was substantially reduced in mice with mast cell deficiency. The results show that our fibrin-affinity probes may serve as a powerful tool to monitor and measure the extent of biomaterial-mediated fibrin deposition and mast cell activation in vivo. PMID- 24342727 TI - A theranostic agent to enhance osteogenic and magnetic resonance imaging properties of calcium phosphate cements. AB - With biomimetic biomaterials, like calcium phosphate cements (CPCs), non-invasive assessment of tissue regeneration is challenging. This study describes a theranostic agent (TA) to simultaneously enhance both imaging and osteogenic properties of such a bone substitute material. For this purpose, mesoporous silica beads were produced containing an iron oxide core to enhance bone magnetic resonance (MR) contrast. The same beads were functionalized with silane linkers to immobilize the osteoinductive protein BMP-2, and finally received a calcium phosphate coating, before being embedded in the CPC. Both in vitro and in vivo tests were performed. In vitro testing showed that the TA beads did not interfere with essential material properties like cement setting. Furthermore, bioactive BMP-2 could be efficiently released from the carrier-beads. In vivo testing in a femoral condyle defect rat model showed long-term MR contrast enhancement, as well as improved osteogenic capacity. Moreover, the TA was released during CPC degradation and was not incorporated into the newly formed bone. In conclusion, the described TA was shown to be suitable for longitudinal material degradation and bone healing studies. PMID- 24342728 TI - Drug-loaded gold plasmonic nanoparticles for treatment of multidrug resistance in cancer. AB - To investigate the possibility of treating multidrug-resistant tumors with targeted chemo-photothermal treatment, we conducted in vitro and in vivo studies using a doxorubicin (DOX)-resistant DLD-1 cell line (DLD-1/DOX) and nude mice with human xenograft tumors, respectively. The chemo-photothermal treatment consisted of DOX-loaded-poly(lactic-co-glycolic acid)-Au half-shell nanoparticles with targeting moieties of anti-death receptor-4 monoclonal antibody conjugated to the Au surface. The cells or xenografted tumors treated with nanoparticles were exposed to near infrared light for 10 min, which caused an increase in temperature to 45 degrees C. Chemo-photothermal treatment resulted in a large reduction in the rate of tumor xenograft growth on DLD-1/DOX tumor-bearing mice with a much smaller dose of DOX than conventional DOX chemotherapy. These results demonstrate that targeted chemo-photothermal treatment can provide high therapeutic efficacy and low toxicity in the treatment of multidrug-resistant tumors. PMID- 24342729 TI - Intermittent letrozole therapy for metastatic breast cancer: case reports and literature review. PMID- 24342730 TI - Feasibility of 4 cycles of docetaxel and cyclophosphamide every 14 days as an adjuvant regimen for breast cancer: a Wisconsin Oncology Network study. AB - INTRODUCTION: Dose-dense therapies have had a major effect on reducing toxicity and improving outcomes in breast cancer. A combination of TC every 3 weeks has emerged as a common chemotherapy regimen used for treatment of node-negative or lower-risk node-positive breast cancer. We tested whether it is feasible to deliver TC on a dose-dense schedule, with therapy completed within 10 weeks. PATIENTS AND METHODS: We enrolled women with early stage breast cancer on a single-arm phase II study of adjuvant dose-dense TC through a regional oncology network. All women completed primary surgery before accrual, and subsequent therapy with TC was deemed appropriate by the treating physician. Planned treatment was docetaxel 75 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 2 weeks for 4 cycles with subcutaneous pegfilgrastim 6 mg administered 24 to 48 hours after the administration of each chemotherapy cycle. RESULTS: Of 42 women enrolled, 41 were evaluable using prespecified criteria. Of these, 37 (90.2%) completed therapy within 10 weeks and 34 (83%) completed therapy at 8 weeks without dose modification. Rates of neuropathy were similar to that reported previously. The rate of neutropenic fever was low (2.5%). Rash and plantar-palmar erythrodythesia were common and reached grade 3 in 4 subjects (9.8%). CONCLUSION: Dose-dense TC is feasible with tolerability profiles similar to standard TC and a low likelihood of neutropenic fever. This study supports further clinical development of this 8-week adjuvant chemotherapy regimen. PMID- 24342731 TI - One vs. two piece customized implants to reconstruct mandibular continuity defects: a preliminary study in pig cadavers. AB - OBJECTIVES: The reconstruction of mandibular continuity defects by bridging plates often leads to complications. Customized mandibular implants might be an alternative option. In the present study, the stability at the bone-implant interface of customized two-piece implants was compared to one-piece implants. METHODS: Thirty pig mandibles were randomly divided into three groups. One group (A) was left untreated and served as reference. In groups B and C, a continuity defect was created in the left mandibular side. The defects were reconstructed by customized pure titanium implants, manufactured using the LaserCUSING((r)) technology. Group B received a one-piece implant; in group C a two-piece implant was inserted to reconstruct the continuity defect. The bonding strength was examined statically and dynamically under standardized conditions. Digital Image Correlation was used for distortion measurement. Different dynamic measurements were performed for orientation purposes. RESULTS: The highest bonding strength was measured for the reference group. The two-piece implant showed an increased bonding strength when compared to the one-piece design. In all pig mandibles treated with individual implants a fracture occurred on the non-operated side. This indicates a high primary stability of the bone-implant-interface. CONCLUSION: The two-piece individual mandibular implant manufactured by LaserCUSING((r)) technology should be further analyzed in future studies. PMID- 24342732 TI - Peripheral nerve regeneration following transection injury to rat sciatic nerve by local application of adrenocorticotropic hormone. AB - The objective of this study was to assess local effect of adrenocorticotropic hormone (ACTH) on the functional recovery of the sciatic nerve in a transection model. Sixty male healthy white Wistar rats were randomized into four experimental groups of 15 animals each: In the sham-operated group (SHAM), the sciatic nerve was exposed and manipulated. In the transected group (TC), the left sciatic nerve was transected and the cut nerve ends were fixed in the adjacent muscle. In the silicone graft group (SIL) a 10-mm defect was made and bridged using a silicone tube. The graft was filled with phosphated-buffer saline alone. In the treatment group a silicone tube (SIL/ACTH) was filled with 10 MUL ACTH (0.1 mg/mL). Each group was subdivided into three subgroups of five animals each and regenerated nerve fibres were studied at 4, 8 and 12 weeks post operation. Behavioral testing, functional, gastrocnemius muscle mass and morphometric indices showed earlier regeneration of axons in SIL/ACTH than in SIL group (p < 0.05). Immunohistochemistry clearly showed more positive location of reactions to S-100 in SIL/ACTH than in SIL group. ACTH improved functional recovery and morphometric indices of sciatic nerve. This finding supports role of ACTH after peripheral nerve repair and may have clinical implications for the surgical management of patients after nerve transection. PMID- 24342734 TI - Metastasizing Ameloblastoma - a perennial pathological enigma? Report of a case and review of literature. AB - The Ameloblastoma is a slow growing locally invasive odontogenic epithelial neoplasm with a high recurrence rate and a low tendency to metastasize. Metastasis in Ameloblastoma was first described by Simmons and Emura in the 1920s. Slootweg and Muller proposed the term Malignant Ameloblastoma to describe a well-differentiated ameloblastoma that metastasizes but maintains the characteristic cytologic features of the original tumour and the term Ameloblastic Carcinoma to an ameloblastoma with malignant cytological features. About 2% of ameloblastomas undergo metastasis. So far there have only been two cases of Metastasizing Ameloblastoma reported from the Indian Subcontinent. We present the case of a 22-year-old male Indian patient, who presented with a diffuse swelling in the left posterior mandible. Radiographs revealed a multilocular radiolucency in the left mandible. On histopathological examination, the lesion was diagnosed as follicular ameloblastoma. Four years later the patient presented with a swelling in the left submandibular region. Histological examination revealed metastatic ameloblastoma within the cervical lymph node. PMID- 24342733 TI - Zoledronic acid - related osteonecrosis of the jaws. Experimental model with dental extractions in rats. AB - INTRODUCTION: Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a pathologic condition of increasing frequency, with a poorly understood pathophysiology and which can be difficult to manage. The aim of this study was to find a reproducible experimental model that directly relates chronic bisphosphonate administration with the development of osteonecrosis with or without tooth extraction, with no other drug involved. MATERIAL AND METHODS: Twenty male Wistar rats were divided into 4 groups (n = 5/group). Animals were injected over 9 weeks with zoledronic acid (0.1 mg/kg). In groups 1 and 2 three times a week intraperitoneally, and in group 3 once a week intravenously. A control group (group 4) received intraperitoneal injections of saline solution three times a week. After 8 weeks of treatment, 3 right upper jaw molars were extracted in groups 1, 3 and 4 and all rats were sacrificed 1 week later. The maxillae were histologically analyzed for presence of osteonecrosis foci, number of osteoclasts, vascularity, bone resorption status and presence of abscess. Radiographic examination was performed with a plain radiograph of each hemi-head. RESULTS: We found that group 1 (dental extractions and highest cumulative dose of zoledronic acid) had the highest incidence of osteonecrosis (80%), absence of bone resorption (100%) and lowest number of osteoclasts (mean 7.9/field at 40*). Zoledronic acid-treated groups showed variable degrees of osteosclerosis and trabecular disorganization on X-ray study. CONCLUSIONS: We offer a new animal model of BRONJ after zoledronic acid administration and dental extractions, achieving bone changes similar or superior to previous studies, highlighting the dental extraction as an important trigger factor. PMID- 24342735 TI - Unusually stable liquid foams. AB - Obtaining stable liquid foams is an important issue in view of their numerous applications. In some of these, the liquid foam in itself is of interest, in others, the liquid foam acts as a precursor for the generation of solid foam. In this short review, we will make a survey of the existing results in the area. This will include foams stabilised by surfactants, proteins and particles. The origin of the stability is related to the slowing down of coarsening, drainage or coalescence, and eventually to their arrest. The three effects are frequently coupled and in many cases, they act simultaneously and enhance one another. Drainage can be arrested if the liquid of the foam either gels or solidifies. Coalescence is slowed down by gelified foam films, and it can be arrested if the films become very thick and/or rigid. These mechanisms are thus qualitatively easy to identify, but they are less easy to model in order to obtain quantitative predictions. The slowing down of coarsening requests either very thick or small films, and its arrest was observed in cases where the surface compression modulus was large. The detail of the mechanisms at play remains unclear. PMID- 24342736 TI - Success and failure of colloidal approaches in adhesion of microorganisms to surfaces. AB - Biofilms are communities of cells attached to surfaces, their contributions to biological process may be either a benefit or a threat depending on the microorganism involved and on the type of substrate and environment. Biofilm formation is a complex series of steps; due to the size of microorganisms, the initial phase of biofilm formation, the bacterial adhesion to the surface, has been studied and modeled using theories developed in colloidal science. In this review the application of approaches such as Derjaguin, Landau, Verwey, Overbeek (DLVO) theory and its extended version (xDLVO), to bacterial adhesion is described along with the suitability and applicability of such approaches to the investigation of the interface phenomena regulating cells adhesion. A further refinement of the xDLVO theory encompassing the brush model is also discussed. Finally, the evidences of phenomena neglected in colloidal approaches, such as surface heterogeneity and fluid flow, likely to be the source of failure are defined. PMID- 24342737 TI - Causes and patterns of readmissions in patients with common comorbidities: retrospective cohort study. AB - OBJECTIVE: To evaluate the primary diagnoses and patterns of 30 day readmissions and potentially avoidable readmissions in medical patients with each of the most common comorbidities. DESIGN: Retrospective cohort study. SETTING: Academic tertiary medical centre in Boston, 2009-10. PARTICIPANTS: 10,731 consecutive adult discharges from a medical department. MAIN OUTCOME MEASURES: Primary readmission diagnoses of readmissions within 30 days of discharge and potentially avoidable 30 day readmissions to the index hospital or two other hospitals in its network. RESULTS: Among 10,731 discharges, 2398 (22.3%) were followed by a 30 day readmission, of which 858 (8.0%) were identified as potentially avoidable. Overall, infection, neoplasm, heart failure, gastrointestinal disorder, and liver disorder were the most frequent primary diagnoses of potentially avoidable readmissions. Almost all of the top five diagnoses of potentially avoidable readmissions for each comorbidity were possible direct or indirect complications of that comorbidity. In patients with a comorbidity of heart failure, diabetes, ischemic heart disease, atrial fibrillation, or chronic kidney disease, the most common diagnosis of potentially avoidable readmission was acute heart failure. Patients with neoplasm, heart failure, and chronic kidney disease had a higher risk of potentially avoidable readmissions than did those without those comorbidities. CONCLUSIONS: The five most common primary diagnoses of potentially avoidable readmissions were usually possible complications of an underlying comorbidity. Post-discharge care should focus attention not just on the primary index admission diagnosis but also on the comorbidities patients have. PMID- 24342738 TI - [Non-pharmacological steps for the treatment of acute confusional syndrome in the intensive care unit]. AB - The incidence of delirium in intensive care units is high and it has been under diagnosed and under-treated. OBJECTIVE: To describe the experiences of ICU nurses in the identification and application of non-pharmacological treatments. METHOD: A qualitative phenomenological research study was performed, based on focus groups. INCLUSION CRITERIA: ICU nurses with one year of more of experience were included. Sample Purpose and snowball technique. DATA COLLECTION: Data from the focus groups were transcribed for analysis and a thematic analysis of the texts was performed. RESULTS: Four themes were identified: a) the physical and social structure of the ICU b) family involvement, c) need for training of health professionals, and d) encouraging the sleep-wake cycle. CONCLUSIONS: It is necessary to control the ICU environment to make it more friendly, to change the routine work to promote relaxation, implement training activities and to make visiting hours flexible. PMID- 24342739 TI - Associations between brain morphology and outcome in schizophrenia in a general population sample. AB - OBJECTIVE: To analyse associations between brain morphology and longitudinal and cross-sectional measures of outcomes in schizophrenia in a general population sample. METHODS: The sample was the Northern Finland 1966 Birth Cohort. In 1999 2001, structural brain MRI and measures of clinical and functional outcomes were analysed for 54 individuals with schizophrenia around the age of 34. Sex, total grey matter, duration of illness and the use of antipsychotic medication were used as covariates. RESULTS: After controlling for multiple covariates, increased density of the left limbic area was associated with less hospitalisations and increased total white matter volume with being in remission. Higher density of left frontal grey matter was associated with not being on a disability pension and higher density of the left frontal lobe and left limbic area were related to better functioning. Higher density of the left limbic area was associated with better longitudinal course of illness. CONCLUSIONS: This study, based on unselected general population data, long follow-up and an extensive database, confirms findings of previous studies, that morphological abnormalities in several brain structures are associated with outcome. The difference in brain morphology in patients with good and poor outcomes may reflect separable aetiologies and developmental trajectories in schizophrenia. PMID- 24342741 TI - HIV/AIDS policy-making in Kyrgyzstan: a stakeholder analysis. AB - Kyrgyzstan has adopted a number of policy initiatives to deal with an accelerating HIV/AIDS epidemic. This article explores the main actors in HIV/AIDS policy-making, their interests, support and involvement and their current ability to set the agenda and influence the policy-making process. Fifty-four semi structured interviews were conducted in the autumn of 2011, complemented by a review of policy documents and secondary sources on HIV/AIDS in Kyrgyzstan. We found that most stakeholders were supportive of progressive HIV/AIDS policies, but that their influence levels varied considerably. Worryingly, several major state agencies exhibited some resistance or lack of initiative towards HIV/AIDS policies, often prompting international agencies and local NGOs to conceptualize and drive appropriate policies. We conclude that, without clear vision and leadership by the state, the sustainability of the national response will be in question. PMID- 24342740 TI - Auditory cortex activation to natural speech and simulated cochlear implant speech measured with functional near-infrared spectroscopy. AB - The primary goal of most cochlear implant procedures is to improve a patient's ability to discriminate speech. To accomplish this, cochlear implants are programmed so as to maximize speech understanding. However, programming a cochlear implant can be an iterative, labor-intensive process that takes place over months. In this study, we sought to determine whether functional near infrared spectroscopy (fNIRS), a non-invasive neuroimaging method which is safe to use repeatedly and for extended periods of time, can provide an objective measure of whether a subject is hearing normal speech or distorted speech. We used a 140 channel fNIRS system to measure activation within the auditory cortex in 19 normal hearing subjects while they listed to speech with different levels of intelligibility. Custom software was developed to analyze the data and compute topographic maps from the measured changes in oxyhemoglobin and deoxyhemoglobin concentration. Normal speech reliably evoked the strongest responses within the auditory cortex. Distorted speech produced less region-specific cortical activation. Environmental sounds were used as a control, and they produced the least cortical activation. These data collected using fNIRS are consistent with the fMRI literature and thus demonstrate the feasibility of using this technique to objectively detect differences in cortical responses to speech of different intelligibility. PMID- 24342742 TI - What explains regulatory failure? Analysing the architecture of health care regulation in two Indian states. AB - Regulating health care is a pre-eminent policy challenge in many low- and middle income countries (LMIC), particularly those with a strong private health sector. Yet, the regulatory approaches instituted in these countries have often been reported to be ineffective-India being exemplary. There is limited empirical research on the architecture and processes of health care regulation in LMIC that would explain these regulatory failures. We undertook a research study in two Indian states, with the aims of (1) mapping the organizations engaged with, and the written policies focused on health care regulation, (2) identifying gaps in the design and implementation of policies for health care regulation and (3) investigating underlying reasons for the identified gaps. We adopted a stepped research approach and applied a framework of basic regulatory functions for health care, to assess prevailing gaps in policy design and implementation. Qualitative research methods were employed including in-depth interviews with 32 representatives of regulatory organizations and document review. Several gaps in policy design were observed across both states, with a number of basic regulatory functions not underwritten in law, nor assigned to a regulatory organization to enact. In some instances the contents of regulatory policies had been weakened or diluted, rendering them less effective. Implementation gaps were also extensively reported in both states. Regulatory gaps were underpinned by human resource constraints, ambivalence in the roles of regulatory organizations, ineffective co ordination between regulatory groups and extensive contestation of regulatory policies by private stakeholders. The findings are instructive that prevailing arrangements for health care regulation are ill equipped to enact several basic functions, and further that the performance of regulatory organizations is subject to pressures and distortions similar to those characterizing the wider health system. This suggests that attempts to strengthen health care regulation will be ineffectual unless underlying governance failures are addressed. PMID- 24342743 TI - Authors' reply to McMinn and colleagues and Caan. PMID- 24342744 TI - Mutations in HBV DNA polymerase associated with nucleos(t)ide resistance are rare in treatment-naive patients. AB - BACKGROUND & AIMS: Prior studies have detected hepatitis B virus (HBV) DNA polymerase mutations in treatment-naive patients. However, most of these studies used either direct polymerase chain reaction sequencing, which detects these mutations with low levels of sensitivity, or patient cohorts that were not well characterized. We investigated the prevalence of HBV mutations in DNA polymerase by using a line probe assay. METHODS: In a prospective, cross-sectional study, we enrolled 198 treatment-naive patients with chronic hepatitis B (52.5% male; mean age, 41 years) from February 2009 to May 2011 from 3 gastroenterology and liver clinics in Northern California. Exclusion criteria included infection with hepatitis C or D viruses or human immunodeficiency virus. All patients completed a questionnaire (to determine demographics, history of liver disease, prior treatments, family medical history, drug and alcohol use, and environmental risk factors for hepatitis) that was administered by a research coordinator; mutations in HBV DNA polymerase were detected by using the INNO-LiPA HBV DR v.3 assay. RESULTS: Most patients were Vietnamese (48.5%) or Chinese (36.4%) and were infected with HBV genotypes B (67.5%) or C (24.2%). Mutations in HBV DNA polymerase were found in 2 patients (1%), rtI233V (n = 1) and rtM250M/L (n = 1). CONCLUSIONS: In a multicenter prospective study of treatment-naive patients with chronic hepatitis B, we detected mutations in HBV DNA polymerase in only 1%. Because of the low prevalence of these mutations and the uncertain clinical significance of such quasispecies, routine HBV DNA polymerase mutation analysis cannot be recommended before initiation of antiviral therapy for treatment-naive patients with chronic hepatitis B. The analysis requires further molecular and clinical studies. PMID- 24342746 TI - Efficacy and safety of a magnesium sulfate-rich natural mineral water for patients with functional constipation. AB - BACKGROUND & AIMS: Little is known about the effects of natural mineral water on constipation in adults. We assessed the effect of a magnesium sulfate-rich natural mineral water (Hepar; Nestle Waters, Issy-les-Moulineaux, France) on gastrointestinal transit in constipated women. METHODS: We performed a randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of Hepar in outpatients with functional constipation (based on the Rome III criteria). The study included 244 female patients, age 18 to 60 years, identified by 62 general practitioners throughout France. After a washout period, subjects drank 1.5 L natural low-mineral water daily (control, n = 77), 0.5 L Hepar and 1 L natural low-mineral water daily (Hepar 0.5 group, n = 85), or 1 L Hepar and 0.5 L natural low-mineral water daily (Hepar 1 group, n = 82) for 4 weeks. We collected information on the number and types of stools, abdominal pain, rescue medications, adverse events, and volume of water consumed. RESULTS: We observed no significant effect at week 1. At week 2, constipation was reduced in 21.1% of patients in the control group, in 30.9% in the Hepar 0.5 group (P = .099 vs controls), and in 37.5% in the Hepar 1 group (P = .013 vs controls). The Hepar 1 group also had a decreased number of hard or lumpy stools (Bristol scale, P = .030 vs baseline) and a substantial decrease in the use of rescue medication (P = .034 vs controls). Patient responses correlated with magnesium sulfate concentrations. Safety was very good; there were no serious adverse events among patients who drank Hepar. CONCLUSIONS: In a controlled trial, daily consumption of 1 L Hepar reduced constipation and hard or lumpy stools in a greater percentage of women with functional constipation than natural low-mineral water, as early as the second week of treatment. PMID- 24342745 TI - Serum ferritin levels lack diagnostic accuracy for liver fibrosis in patients with nonalcoholic fatty liver disease. AB - BACKGROUND & AIMS: Series studies have associated increased serum levels of ferritin with liver fibrosis in patients with nonalcoholic fatty liver disease. We aimed to determine the accuracy with which measurements of serum ferritin determine the presence and severity of liver fibrosis, and whether combining noninvasive scoring systems with serum ferritin analysis increases the accuracy of diagnosis of advanced liver fibrosis. METHODS: We performed a retrospective analysis of data from 1014 patients with liver biopsy-confirmed nonalcoholic fatty liver disease. Three cut points of serum ferritin level, adjusted for sex, were established based on receiver operating characteristic curve analysis: 1.0-, 1.5-, and 2.0-fold the upper limit of normal. Three multiple logistic regression models were created to determine the association of these cutoff values with liver fibrosis, adjusting for age, sex, race, diabetes, body mass index, and level of alanine aminotransferase. RESULTS: A greater proportion of patients with increased serum levels of ferritin had definitive nonalcoholic steatohepatitis and more-advanced fibrosis than patients without increased levels. In all models, serum level of ferritin was significantly associated with the presence and severity of liver fibrosis. However, for all 3 cutoff values, area under the receiver operating characteristic curve values were low (less than 0.60) for the presence of fibrosis or any stage of liver fibrosis; ferritin level identified patients with fibrosis with 16%-41% sensitivity and 70%-92% specificity. The accuracy with which noninvasive scoring systems identified patients with advanced fibrosis did not change with inclusion of serum ferritin values. CONCLUSIONS: Although serum levels of ferritin correlate with more-severe liver fibrosis, based on adjusted multiple logistic regression analysis, serum ferritin levels alone have a low level of diagnostic accuracy for the presence or severity of liver fibrosis in patients with nonalcoholic fatty liver disease. PMID- 24342747 TI - Infliximab vs adalimumab for Crohn's disease: perhaps too early to call it a tie. PMID- 24342749 TI - Adult hemiparkinsonian rats do not benefit from tactile stimulation. AB - Tactile stimulation (TS) applied to adult rats after cortical injury (medial frontal cortex aspiration or sensorimotor pial stripping stroke model) has been previously shown to ameliorate behavioral impairments and to improve morphological parameters like dendritic length of prefrontal cortical neurons (Gibb et al., 2010). The purpose of this study was to examine the effect of TS on healthy and hemiparkinsonian adult rats. Therefore, the animals received TS for 14 days and 15 min three times daily. At different time points rats were tested in various behavioral tests (amphetamine-induced rotation, cylinder test, staircase test). Finally, rats were sacrificed, their brains removed, and processed for Golgi-Cox analyses, tyrosine hydroxylase immunohistochemistry and quantitative RT-PCR. We found that the striatal 6-OHDA lesion itself induced a long-term increase of astroglial Fgf2 transcript levels, but was not further increased by TS. In contrast TS applied to healthy rats elicited a transient short-term increase of Fgf2 in the striatum and Bdnf, Grin1, and Fgf2 in the hippocampus. Moreover, behavioral and histological analyses do not support a beneficial effect of TS for hemiparkinsonian rats, applied for two weeks starting one day after partial striatal 6-OHDA lesion. PMID- 24342748 TI - Chronic wheel running affects cocaine-induced c-Fos expression in brain reward areas in rats. AB - Emerging evidence from human and animal studies suggests that exercise is a highly effective treatment for drug addiction. However, most work has been done in behavioral models, and the effects of exercise on the neurobiological substrates of addiction have not been identified. Specifically, it is unknown whether prior exercise exposure alters neuronal activation of brain reward circuitry in response to drugs of abuse. To investigate this hypothesis, rats were given 21 days of daily access to voluntary wheel running in a locked or unlocked running wheel. Subsequently, they were challenged with a saline or cocaine (15 mg/kg, i.p.) injection and sacrificed for c-Fos immunohistochemistry. The c-Fos transcription factor is a measure of cellular activity and was used to quantify cocaine-induced activation of reward-processing areas of the brain: nucleus accumbens (NAc), caudate putamen (CPu), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). The mean fold change in cocaine-induced c-Fos cell counts relative to saline-induced c-Fos cell counts was significantly higher in exercising compared to control rats in the NAc core, dorsomedial and dorsolateral CPu, the prelimbic area, and the OFC, indicating differential cocaine-specific cellular activation of brain reward circuitry between exercising and control animals. These results suggest neurobiological mechanisms by which voluntary wheel running attenuates cocaine-motivated behaviors and provide support for exercise as a novel treatment for drug addiction. PMID- 24342750 TI - The demise of the Liverpool Care Pathway: should we ban the highway code because of bad drivers? AB - The Neuberger report failed to show that the Liverpool Care Pathway was the cause of poor end-of-life care and made it the scapegoat for poor communication and faulty decision-making. The report's discrediting of a quality assurance mechanism that had the potential for improvement is a disservice to dying patients. Several of the report's recommendations are puzzling, but two consequences of the report, an excellent review of care pathways and a recommendation to establish a national end-of-life coalition, have the potential to improve care of the dying individual. PMID- 24342751 TI - The limited effect of omega-3 polyunsaturated fatty acids on cardiovascular risk in patients with impaired glucose metabolism: a meta-analysis. AB - OBJECTIVES: The impacts of marine-derived n-3 polyunsaturated fatty acids (n-3 PUFAs) on cardiovascular risk are not well known. We conducted this meta-analysis to determine the effects of n-3 PUFAs on cardiovascular outcomes and cardiovascular risk markers in patients with impaired glucose metabolism (IGM). DESIGN AND METHODS: We searched PUBMED, EMBASE, The Cochrane Library and reference lists of relevant papers for high quality randomized controlled trials comparing dietary intake of n-3 PUFAs with placebo in IGM patients. Data was extracted and quality assessed independently by two reviewers. Authors were contacted for missing information. Overall estimates were calculated using a random-effects model or a fixed-effects model, and the possibility of publication bias was examined using a funnel plot. Subgroup analyses were conducted to explore the association between the risk markers and study characteristics. RESULTS: Our meta-analysis included 19 studies, 24,788 patients. Compared with placebo, n-3 PUFAs had no statistically significant reduce effect on cardiovascular mortality, major cardiovascular events, all-cause mortality or composite endpoint of all-cause mortality or hospitalization for cardiovascular cause, however it can significantly reduce the level of triglycerides (weighted mean difference [WMD] -0.25mmol/L; 95% CI -0.37 to -0.13: p<0.001; 12 trials, 13,921 patients). CONCLUSION: Marine-derived n-3 polyunsaturated fatty acids have no protective effect on cardiovascular mortality, major cardiovascular events, all-cause mortality and composite endpoint of all-cause mortality or hospitalization for cardiovascular cause in IGM patients, but can reduce triglyceride level. PMID- 24342752 TI - Investigation of the silicone structure in breast implants using 1H NMR. AB - Against the background of the scandal about low-grade silicone breast implants of the French manufacturer Poly Implant Prothese (PIP), several types of implants were examined using (1)H NMR spectroscopy. The intention was to classify an implant according to its silicone structure. Therefore, the certificated raw material of the American silicone producer Nusil Technology was analyzed and used as a reference. The list of tested implants consists of implants by PFM medical, PIP, Silimed, Rofil, Eurosilicone, Mentor, Perouse Plastie, Polytech, Nagor, CUI, and McGhan. In the (1)H NMR spectrum the signal of the vinyl group, which is used to cross link silicone rubbers, is visible. It is possible to differentiate between silicones which have a vinyl terminated end group and silicones whose vinyl group is located within the chain of the polymer. The two different types of the vinyl group are one mean to classify the implants. Other categories besides the type of vinyl include the relative amount of the remaining vinyl in the implant and the chemical structure of the material used for the production of the envelope. With these characteristics the examined implants could be grouped into four types. PMID- 24342753 TI - Single point mutations of aromatic residues in transmembrane helices 5 and -6 differentially affect TRPV4 activation by 4alpha-PDD and hypotonicity: implications for the role of the pore region in regulating TRPV4 activity. AB - The importance of the TRPV4 channel for human physiology has been highlighted in recent years with the identification of an increasing number of hereditary diseases associated with mutations of this channel. However, the functional understanding of TRPV4 associated pathologies remains a puzzle due to incomplete understanding of the polymodal regulation of TRPV4 channels and lack of insight into the structure-function relationship of the channel. In this work, we identified a series of highly conserved aromatic residues in transmembrane (TM) helices 5-6 with profound importance for TRPV4 activity. Substituting F617, Y621 or F624 in TM5 with leucine reduced channel sensitivity to the agonist 4alpha-PDD and heat, yet two of these mutants - F617L and Y621L - showed increased activation in response to cell swelling. In TM6, a Y702L mutation significantly reduced sensitivity to all of the above stimuli. In conclusion, we have identified residues in TM5-6 which differentially affect heat and agonist activation, and we have demonstrated distinct activation pathways for 4alpha-PDD and osmolarity. PMID- 24342754 TI - Atopic keratoconjunctivitis: A review. AB - Atopic keratoconjunctivitis is a chronic noninfectious inflammatory condition and is one of the most severe ophthalmic complications associated with atopic dermatitis. It requires prompt and effective treatment to prevent permanent vision loss. Complications of atopic keratoconjunctivitis include cataracts, keratoconus, infectious keratitis, blepharitis, tear dysfunction, and steroid induced glaucoma. All treatment for atopic keratoconjunctivitis should be managed in conjunction with an ophthalmologist, and immediate referral is indicated when there is moderate to severe irritation, increased redness, discharge, or any visual symptoms. Treatment options include a combination of mast cell inhibitors, antihistamines, corticosteroids, and calcineurin inhibitors. PMID- 24342755 TI - Hyperpigmented macules on the face of young children: a series of 25 cases. AB - BACKGROUND: Acquired hyperpigmented lesions in early childhood can be the presenting sign of serious diseases or benign conditions and often cause significant parental anxiety. OBJECTIVE: We sought to report a series of 25 young children with hyperpigmented macules on the forehead and temples without preceding erythema, edema, or desquamation. METHODS: We conducted a retrospective review of 25 children with similar clinical findings, seen from 2009 to 2013, from 5 medical centers in 3 countries. RESULTS: There were 13 boys and 12 girls of many races. Their ages ranged from 2 to 24 months (mean 12.2 months, median 6 months). The hyperpigmentation presented abruptly in the summer (12 cases), spring (5 cases), winter (5), and fall (2), and was not clearly specified in 1 case. Histopathologic analysis in 3 cases was consistent with postinflammatory hyperpigmentation. After a follow-up period ranging from 3 months to 4.5 years, the lesions persist to a variable degree in 19 cases in which follow-up was possible. LIMITATIONS: The age of our patients precluded patch testing and/or invasive diagnostic methods. CONCLUSIONS: The clinical features and prolonged clinical course over years do not correspond with any known or previously described cause of acquired facial hyperpigmented macules in young children. PMID- 24342756 TI - Incidence of primary skin cancer after organ transplantation: An 18-year single center experience in Korea. AB - BACKGROUND: Skin cancer is the most common malignancy to arise after organ transplantation in Caucasians, but limited data are available on its incidence in Asian transplant recipients. OBJECTIVE: We sought to assess the incidence of skin cancer after organ transplantation in a Korean cohort. METHODS: A cohort study was conducted to determine the incidence and risk factors for skin cancers among kidney, liver, heart, or pancreas transplant recipients, treated at the Asan Medical Center in Seoul, Korea. RESULTS: The cumulative incidences of skin cancer were 0.70% at 5 years, 1.66% at 10 years, and 2.31% at 15 years. For all skin cancers, squamous cell carcinoma, basal cell carcinoma, and Kaposi sarcoma, the standardized incidence ratios between the recipients and the Korean general population were 30.9 (95% confidence interval, 12.4-63.6), 61.9 (12.8-180.8), 11.9 (0.3-66.1), and 565.2 (68.4-2041.6) after the end of the fifth posttransplantation year, respectively. LIMITATIONS: We cannot exclude the possibility of both the underestimation because of potential missing cases and the overestimation because of the ascertainment bias. CONCLUSION: The incidence of posttransplantation skin cancer is very low in Korean patients. However, the risk of skin cancer in organ transplant recipients may be considerably higher than that in the Korean general population. PMID- 24342757 TI - Prevalence of and risk factors of renal artery stenosis in patients with resistant hypertension. AB - Renal artery stenosis (RAS) is a common cause of secondary hypertension. Renal artery angiography is the gold standard for diagnosing RAS. The aim of this study is to report (1) the prevalence of RAS in patients with resistant hypertension and (2) the association of RAS with peripheral vascular disease (PVD) and diabetes mellitus (DM). We studied 285 consecutive patients (mean age: 72.5 years) with resistant hypertension (systolic blood pressure >140 mm Hg despite administration of at least 3 antihypertensive drugs) who underwent renal artery angiography at Baylor Heart and Vascular Hospital from January 2006 to December 2010. Sixty-nine cases of RAS were identified (incidence: 24.2%). The propensity adjusted analysis (controlling for clinical and nonclinical risk factors) showed a strong and significant association between RAS and PVD (odds ratio 5.15, 95% confidence interval 2.68 to 9.89, p <0.0001). However, the association between RAS and DM, a previously defined risk factor for RAS, was not significant in this cohort (odds ratio 0.63, 95% confidence interval 0.34 to 1.19, p = 0.16). In conclusion, results from this study define the prevalence of RAS in patients with resistant hypertension. Patients with PVD were found to be 5 times more likely to experience RAS than patients without PVD, whereas DM did not confer any increased risk. PMID- 24342758 TI - Comparison of the effectiveness of transcatheter aortic valve implantation in patients with stenotic bicuspid versus tricuspid aortic valves (from the German TAVI Registry). AB - Patients with bicuspid aortic valves (BAVs) are considered a relative contraindication to transcatheter aortic valve implantation (TAVI). One of the main reasons is the presumed risk for residual aortic regurgitation (AR). However, case reports and small case series have suggested that TAVI can be successfully performed with acceptable clinical outcomes in high-risk patients with BAV. Within the large German TAVI Registry, we sought to evaluate TAVI in older high-risk patients with BAV. From January 2009 to June 2010, a total of 1,424 patients with severe aortic stenosis undergoing TAVI were prospectively enrolled into the German TAVI Registry. For the present analysis, patients with valve-in-valve procedures were excluded and those with BAV (n = 38, 3%) were compared with those with tricuspid aortic valve (TAV; n = 1357, 97%). Patient characteristics did not markedly differ and procedural success was very high in both groups. There was a higher rate of relevant AR (>=II) after TAVI among patients with BAV (25 vs 15%, p = 0.05), whereas pacemakers were more often implanted in patients with TAV (17% vs 35%, p = 0.02). Thirty-day mortality rate was similar in both cohorts (11% vs 11%). In a Cox proportional regression analysis, BAV was not associated with higher 1-year mortality rate (hazard ratio 0.64, 95% confidence interval 0.29 to 1.41). In selected patients with BAV, TAVI can be performed with a satisfactory clinical result. Although the risk for relevant AR seems to be greater among patients with BAV, 30-day and 1-year mortality rates were not elevated compared with patients with TAV. PMID- 24342759 TI - Impact of predischarge nocturnal pulse oximetry (sleep-disordered breathing) on postdischarge clinical outcomes in hospitalized patients with left ventricular systolic dysfunction after acute decompensated heart failure. AB - Stratifying patients at a high risk for readmission and mortality before their discharge after acute decompensated heart failure (ADHF) is important. Although sleep-disordered breathing (SDB) is prevalent in patients with chronic heart failure, only few studies have investigated the impact of SDB on hospitalized patients with left ventricular (LV) systolic dysfunction after ADHF. Thus, we assessed the prevalence of SDB using nocturnal pulse oximetry and the relation between SDB and clinical events in this patient group. One hundred consecutive patients with LV systolic dysfunction who were hospitalized for ADHF were enrolled in the study. Predischarge nocturnal oximetry was performed to determine if they had SDB (defined as an oxygen desaturation index of >=5 events/hour with >=4% decrease in saturation level). Data on death and readmission for ADHF were collected. Forty-one patients had SDB. Complete outcome data were collected in the mean follow-up period of 14.2 months during which 33 events occurred. On multivariate Cox proportional hazards regression analysis, the presence of SDB was a significant independent predictor of postdischarge readmission and mortality (hazard ratio 2.93, p = 0.006). In conclusion, SDB, as determined by predischarge nocturnal oximetry, is prevalent and is an independent predictor of the combined end point of readmission and mortality in hospitalized patients with LV systolic dysfunction after ADHF. PMID- 24342760 TI - Meta-analysis of same versus different stent for drug-eluting stent restenosis. AB - Drug-eluting stent (DES) in-stent restenosis (ISR) can be treated by restenting using the same DES as previously placed (same stent strategy), versus switching to a stent that elutes a different drug (different stent strategy). To compare the efficacy of these strategies, a meta-analysis of controlled trials and observational studies evaluating patients with DES ISR was performed. The primary outcome was target lesion revascularization or target vessel revascularization, and secondary outcomes were major adverse cardiovascular events, death, and myocardial infarction. Pooled odds ratios (ORs) were calculated with the generic inverse variance method using a random-effects model. The chi-square test was used to evaluate heterogeneity. Ten studies (1,680 patients) were included. There was no significant heterogeneity among the studies for any end point. The different stent strategy was found to reduce the odds of target lesion revascularization or target vessel revascularization (OR 0.73, 95% confidence interval [CI] 0.55 to 0.96) and major adverse cardiovascular events (OR 0.72, 95% CI 0.54 to 0.96). There was no difference between the 2 strategies in rates of death (OR 1.03, 95% CI 0.49 to 2.16) or myocardial infarction (OR 0.59, 95% CI 0.24 to 1.41). In conclusion, this study demonstrates that treatment of DES ISR by restenting with a different DES than previously placed may lead to improved outcomes compared with the use of the same DES. Further large-scale trials are needed to confirm this effect. PMID- 24342761 TI - Factors affecting survival in men versus women following transcatheter aortic valve implantation. AB - Although transcatheter aortic valve implantation (TAVI) for severe aortic stenosis is becoming an established technique, the impact of gender-related differences remains unclear. Two hundred twenty-four consecutive patients undergoing TAVI were prospectively followed up in a tertiary medical center. The primary end point of the present study was all-cause mortality at 2 years of follow-up. Interaction-term analysis was used to identify gender-specific predictors of mortality after TAVI. Fifty-seven percent of the study patients were women. Age was similar (82 +/- 7 years). Compared with men, women had a lower frequency of coronary artery disease (CAD) and a higher baseline left ventricular ejection fraction (LVEF). The cumulative probability of all-cause mortality was significantly lower among women (8.6%) compared with men (26.8%; log-rank p value <0.001). A lower baseline LVEF (<45%) was associated with a significant, more than fourfold (p = 0.0019 and 0.048, respectively), increase in mortality risk among both men and women (p value for gender-by-LVEF interaction = 0.87). In contrast, the risk associated with the presence of previous CAD was shown to be gender related. Thus, in women, CAD was associated with a pronounced >14-fold increase in mortality risk, whereas in men, CAD was not associated with a significant mortality risk (p value for gender-by-LVEF interaction = 0.01). In conclusion, our findings suggest that risk assessment before TAVI should consider gender-specific differences in survival and risk factors. PMID- 24342762 TI - Statin therapy in patients with chronic kidney disease undergoing percutaneous coronary intervention (from the Evaluation of Drug Eluting Stents and Ischemic Events Registry). AB - Secondary prevention trials have demonstrated the efficacy of statins in reducing cardiovascular morbidity and mortality in patients with coronary artery disease and events after percutaneous coronary intervention (PCI). However, there are few data describing the clinical value of statins in patients with coronary artery disease and chronic kidney disease (CKD) undergoing PCI. Of 10,148 patients who entered into Evaluation of Drug Eluting Stents and Ischemic Events, a multicenter registry of unselected patients undergoing PCI from July 2004 to December 2007, we studied 2,306 patients with CKD (estimated glomerular filtration rate <=60 ml/min based on the Modified Diet in Renal Disease calculation). Patients were stratified into those receiving statins at discharge (n = 1,833, 79%) or not (n = 473, 21%). Patients in the statin group had a greater prevalence of hypertension, recent myocardial infarction (MI), and use of beta blockers and angiotensin converting enzyme inhibitors. Outcomes were assessed from discharge through 1 year follow-up. One-year all-cause mortality was 5.7% in statin group versus 8.7% in the no statin group (adjusted hazard ratio 0.55, 95% confidence interval 0.34 to 0.88). The composite of death, MI, and repeat revascularization was lower in statin group (adjusted hazard ratio 0.71, 95% confidence interval 0.51 to 0.99). In conclusion, among patients with CKD undergoing PCI, the prescription of statins at hospital discharge was associated with a significant improvement in subsequent outcomes including mortality and composite end point of death, MI, and repeat revascularization. PMID- 24342764 TI - Nocardia pneumonia in a patient with Crohn's disease receiving 6-mercaptopurine and infliximab. PMID- 24342765 TI - The debated role for thiopurines in Crohn's disease. AB - There is a new debate on the role of thiopurines in Crohn's disease. This viewpoint discusses the current evidence and balances thiopurines against other treatment options in the therapeutic algorithm of Crohn's disease. PMID- 24342763 TI - Incidence and survival of hospitalized acute decompensated heart failure in four US communities (from the Atherosclerosis Risk in Communities Study). AB - Most population-based estimates of incident hospitalized heart failure (HF) have not differentiated acute decompensated heart failure (ADHF) from chronic stable HF nor included racially diverse populations. The Atherosclerosis Risk in Communities Study conducted surveillance of hospitalized HF events (age >=55 years) in 4 US communities. We estimated hospitalized ADHF incidence and survival by race and gender. Potential 2005 to 2009 HF hospitalizations were identified by International Classification of Diseases, Ninth Revision, Clinical Modification, codes; 6,168 records were reviewed to validate ADHF cases. Population estimates were derived from US Census data; 50% of eligible hospitalizations were classified as ADHF, of which 63.6% were incident ADHF and 36.4% were recurrent ADHF. The average incidence of hospitalized ADHF was 11.6 per 1,000 persons, aged >=55 years, per year, and recurrent hospitalized ADHF was 6.6 per 1,000 persons/yr. Age-adjusted annual ADHF incidence was highest for black men (15.7 per 1,000), followed by black women (13.3 per 1,000), white men (12.3 per 1,000), and white women (9.9 per 1,000). Of incident ADHF events with heart function assessment (89%), 53% had reduced the ejection fraction (heart failure with reduced ejection fraction [HFrEF]) and 47% had preserved ejection fraction (heart failure with preserved ejection fraction [HFpEF]). Black men had the highest proportion of acute HFrEF events (70%); white women had the highest proportion of acute HFpEF (59%). Age-adjusted 28-day and 1-year case fatality after an incident ADHF was 10.4% and 29.5%, respectively. Survival did not differ by race or gender. In conclusion, ADHF hospitalization and HF type varied by both race and gender, but case fatality rates did not. Further studies are needed to explain why black men are at higher risk of hospitalized ADHF and HFrEF. PMID- 24342766 TI - Validation of the IMPACT-III quality of life questionnaire in Swiss children with inflammatory bowel disease. AB - BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) frequently manifests during childhood and adolescence. For providing and understanding a comprehensive picture of a patients' health status, health-related quality of life (HRQoL) instruments are an essential complement to clinical symptoms and functional limitations. Currently, the IMPACT-III questionnaire is one of the most frequently used disease-specific HRQoL instrument among patients with IBD. However, there is a lack of studies examining the validation and reliability of this instrument. METHODS: 146 paediatric IBD patients from the multicenter Swiss IBD paediatric cohort study database were included in the study. Medical and laboratory data were extracted from the hospital records. HRQoL data were assessed by means of standardized questionnaires filled out by the patients in a face-to-face interview. RESULTS: The original six IMPACT-III domain scales could not be replicated in the current sample. A principal component analysis with the extraction of four factor scores revealed the most robust solution. The four factors indicated good internal reliability (Cronbach's alpha=.64-.86), good concurrent validity measured by correlations with the generic KIDSCREEN-27 scales and excellent discriminant validity for the dimension of physical functioning measured by HRQoL differences for active and inactive severity groups (p<.001, d=1.04). CONCLUSIONS: This study with Swiss children with IBD indicates good validity and reliability for the IMPACT-III questionnaire. However, our findings suggest a slightly different factor structure than originally proposed. The IMPACT-III questionnaire can be recommended for its use in clinical practice. The factor structure should be further examined in other samples. PMID- 24342767 TI - Cannabis use disorders are comparatively prevalent among nonwhite racial/ethnic groups and adolescents: a national study. AB - The racial/ethnic composition of the US population is shifting, with the nonwhite population growing faster than whites. We examined cannabis use disorder (CUD) prevalences and correlates in seven racial/ethnic groups. We included cannabis use (CU) prevalence as a comparison. Data were from the 2005-2011 National Surveys on Drug Use and Health (N = 394,400). Substance use among respondents aged >=12 years was assessed by computer-assisted, self-interviewing methods. The following were included as control variables: age, sex, family income, government assistance, county type, residential stability, major depressive episode history, arrest history, nicotine dependence, alcohol disorder, and survey year. Past-year CU prevalence increased significantly from 10.45% in 2005 to 11.41-11.54% during 2009-2011. Compared with whites, mixed-race individuals had higher odds of CU; Asian Americans and Hispanics had lower odds of CU. There were no significant yearly changes in CUD prevalence in the sample during 2005-2011 (1.58-1.73%). Compared with whites, individuals who were mixed-race, black, and Native American had higher odds of CUD; Asian Americans had lower odds. In aggregate, 15.35% of past-year cannabis users met criteria for a CUD in the 12-month period. Past-year cannabis users who were black, Native American, Hispanic, or Asian American had higher odds of CUD than white users. In each racial/ethnic group, adolescent cannabis users generally showed greater odds of CUD than adult users. Behavioral health indicators (major depressive episode, arrest history, nicotine dependence, alcohol disorder) were associated with CU and CUD. In conclusion, CUD disproportionally affects nonwhite groups and youth. PMID- 24342768 TI - The 5-HTTLPR genotype modulates heart rate variability and its adjustment by pharmacological panic challenge in healthy men. AB - Abnormal serotonin transporter (5-HTT) function and autonomic nervous system (ANS) dysregulation has been proposed in panic disorder. However, in contrast to hypothalamo-pituitary-adrenocortical (HPA) functioning, ANS reactivity during panic response has yet not been investigated in humans with respect to the 5-HTT genotype. The present study assessed the influence of challenging by cholecystokinin tetrapeptide (CCK-4) on heart rate variability (HRV) measures, to monitor autonomic reactivity and its relationship to 5-HTT-linked polymorphic region (5-HTTLPR) genotypes. We hypothesized substantial effects of the 5-HTTLPR genotype on autonomic reactivity. We studied 30 healthy young men, 15 of each with the long/long (l/l) or short/short (s/s) genotype for the 5-HTTLPR. All participants received an intravenous application of 50 MUg CCK-4. HRV measures were assessed in both groups at baseline and immediately after CCK-4 application. Our results indicated lower parasympathetic activity in s/s carriers during baseline, time and frequency domain measures. CCK-4 application significantly enhanced the sympathetic tone in both groups, leading to diminished group differences. A significant treatment by genotype effect indicated reduced autonomic reactivity to CCK-4 challenge in the s/s compared to l/l carriers. Our findings show enhanced sympathetic and/or diminished cardiac vagal activity under basal conditions and blunted autonomic reactivity in s/s vs. l/l carriers. Our study provides novel data supporting claims that the s/s genotype represents a genetic vulnerability factor associated with inadequate hyporeactivity to stress and extends current knowledge on the impact of the central serotonergic activity on the sympathoadrenal pathway. PMID- 24342769 TI - [Deep vein thrombosis after tennis leg. Role of ultrasound in primary care]. PMID- 24342770 TI - [Research and the interests of the administration]. PMID- 24342771 TI - Recovery of current through mutated TASK3 potassium channels underlying Birk Barel syndrome. AB - TASK3 (TWIK-related acid-sensitive K(+) channel 3) potassium channels are members of the two-pore-domain potassium channel family. They are responsible for background leak potassium currents found in many cell types. TASK3 channels are genetically imprinted, and a mutation in TASK3 (G236R) is responsible for Birk Barel mental retardation dysmorphism syndrome, a maternally transmitted developmental disorder. This syndrome may arise from a neuronal migration defect during development caused by dysfunctional TASK3 channels. Through the use of whole-cell electrophysiologic recordings, we have found that, although G236R mutated TASK3 channels give rise to a functional current, this current is significantly smaller in an outward direction when compared with wild-type (WT) TASK3 channels. In contrast to WT TASK3 channels, the current is inwardly rectifying. Furthermore, the current through mutated channels is differentially sensitive to a number of regulators, such as extracellular acidification, extracellular zinc, and activation of Galphaq-coupled muscarinic (M3) receptors, compared with WT TASK3 channels. The reduced outward current through mutated TASK3_G236R channels can be overcome, at least in part, by both a gain-of function additional mutation of TASK3 channels (A237T) or by application of the nonsteroidal anti-inflammatory drug flufenamic acid (FFA; 2-{[3 (trifluoromethyl)phenyl]amino}benzoic acid). FFA produces a significantly greater enhancement of current through mutated channels than through WT TASK3 channels. We propose that pharmacologic enhancement of mutated TASK3 channel current during development may, therefore, provide a potentially useful therapeutic strategy in the treatment of Birk Barel syndrome. PMID- 24342772 TI - Novel small molecule inhibitors of TLR7 and TLR9: mechanism of action and efficacy in vivo. AB - The discovery that circulating nucleic acid-containing complexes in the serum of autoimmune lupus patients can stimulate B cells and plasmacytoid dendritic cells via Toll-like receptors 7 and 9 suggested that agents that block these receptors might be useful therapeutics. We identified two compounds, AT791 {3-[4-(6-(3 (dimethylamino)propoxy)benzo[d]oxazol-2-yl)phenoxy]-N,N-dimethylpropan-1-amine} and E6446 {6-[3-(pyrrolidin-1-yl)propoxy)-2-(4-(3-(pyrrolidin-1 yl)propoxy)phenyl]benzo[d]oxazole}, that inhibit Toll-like receptor (TLR)7 and 9 signaling in a variety of human and mouse cell types and inhibit DNA-TLR9 interaction in vitro. When administered to mice, these compounds suppress responses to challenge doses of cytidine-phosphate-guanidine (CpG)-containing DNA, which stimulates TLR9. When given chronically in spontaneous mouse lupus models, E6446 slowed development of circulating antinuclear antibodies and had a modest effect on anti-double-stranded DNA titers but showed no observable impact on proteinuria or mortality. We discovered that the ability of AT791 and E6446 to inhibit TLR7 and 9 signaling depends on two properties: weak interaction with nucleic acids and high accumulation in the intracellular acidic compartments where TLR7 and 9 reside. Binding of the compounds to DNA prevents DNA-TLR9 interaction in vitro and modulates signaling in vivo. Our data also confirm an earlier report that this same mechanism may explain inhibition of TLR7 and 9 signaling by hydroxychloroquine (Plaquenil; Sanofi-Aventis, Bridgewater, NJ), a drug commonly prescribed to treat lupus. Thus, very different structural classes of molecules can inhibit endosomal TLRs by essentially identical mechanisms of action, suggesting a general mechanism for targeting this group of TLRs. PMID- 24342773 TI - Bullying in elementary school and psychotic experiences at 18 years: a longitudinal, population-based cohort study. AB - BACKGROUND: Victims of bullying are at risk for psychotic experiences in early adolescence. It is unclear if this elevated risk extends into late adolescence. The aim of this study was to test whether bullying perpetration and victimization in elementary school predict psychotic experiences in late adolescence. METHOD: The current study is based on the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective community-based study. A total of 4720 subjects with bullying perpetration and victimization were repeatedly assessed between the ages of 8 and 11 years by child and mother reports. Suspected or definite psychotic experiences were assessed with the Psychosis-Like Symptoms semi-structured interview at age 18 years. RESULTS: Controlling for child's gender, intelligence quotient at age 8 years, childhood behavioural and emotional problems, and also depression symptoms and psychotic experiences in early adolescence, victims [child report at 10 years: odds ratio (OR) 2.4, 95% confidence interval (CI) 1.6 3.4; mother report: OR 1.6, 95% CI 1.1-2.3], bully/victims (child report at 10 years: OR 3.1, 95% CI 1.7-5.8; mother: OR 2.9, 95% CI 1.7-5.0) and bullies (child report at 10 years: OR 4.9, 95% CI 1.3-17.7; mother: OR 1.2, 95% CI 0.46-3.1, n.s.) had a higher prevalence of psychotic experiences at age 18 years. Path analysis revealed that the association between peer victimization in childhood and psychotic experiences at age 18 years was only partially mediated by psychotic or depression symptoms in early adolescence. CONCLUSIONS: Involvement in bullying, whether as victim, bully/victim or bully, may increase the risk of developing psychotic experiences in adolescence. Health professionals should ask routinely during consultations with children about their bullying of and by peers. PMID- 24342776 TI - Fasten your seatbelts for integrated care. PMID- 24342775 TI - Effects of raloxifene on cognition in postmenopausal women with schizophrenia: a double-blind, randomized, placebo-controlled trial. AB - Studies of estrogen therapy in postmenopausal women provide evidence of an effect of sex hormones on cognitive function. Estrogen has demonstrated some utility in the prevention of normal, age-related decline in cognitive functions, especially in memory. The potential therapeutic utility of estrogens in schizophrenia is increasingly being recognized. Raloxifene, a selective estrogen receptor modulator (SERM), appears to act similarly to conjugated estrogens on dopamine and serotonin brain systems, and may be a better option since it lacks the possible negative effects of estrogen on breast and uterine tissue. We assessed the utility of raloxifene as an adjuvant treatment for cognitive symptoms in postmenopausal women with schizophrenia in a 12-week, double-blind, randomized, placebo-controlled study. Patients were recruited from both the inpatient and outpatient departments. Thirty-three postmenopausal women with schizophrenia (DSM IV) were randomized to receive either adjuvant raloxifene (16 women) or adjuvant placebo (17 women) for three months. The main outcome measures were: Memory, attention and executive functions. Assessment was conducted at baseline and week 12. The total sample is homogenous with respect to: age, years of schooling, illness duration, baseline symptomatology and pharmacological treatment. The addition of raloxifene (60 mg) to regular antipsychotic treatment showed: we found significant differences in some aspects of memory and executive function in patients treated with raloxifene. This improvement does not correlate with clinical improvement. The use of raloxifene as an adjuvant treatment in postmenopausal women with schizophrenia seems to be useful in improving cognitive symptoms. PMID- 24342774 TI - Social interaction and social withdrawal in rodents as readouts for investigating the negative symptoms of schizophrenia. AB - Negative symptoms (e.g., asociality and anhedonia) are a distinct symptomatic domain that has been found to significantly affect the quality of life in patients diagnosed with schizophrenia. Additionally, the primary negative symptom of asociality (i.e., withdrawal from social contact that derives from indifference or lack of desire to have social contact) is a major contributor to poor psychosocial functioning and has been found to play an important role in the course of the disorder. Nonetheless, the pathophysiology underlying these symptoms is unknown and currently available treatment options (e.g., antipsychotics and cognitive-behavioral therapy) fail to reliably produce efficacious benefits. Utilizing rodent paradigms that measure social behaviors (e.g., social withdrawal) to elucidate the neurobiological substrates that underlie social dysfunction and to identify novel therapeutic targets may be highly informative and useful to understand more about the negative symptoms of schizophrenia. Accordingly, the purpose of this review is to provide an overview of the behavioral tasks for assessing social functioning that may be translationally relevant for investigating negative symptoms associated with schizophrenia. PMID- 24342777 TI - Syk and Src are major pharmacological targets of a Cerbera manghas methanol extract with kaempferol-based anti-inflammatory activity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cerbera manghas L. (Apocynaceae), a semi-mangrove medicinal plant distributed throughout tropical and subtropical countries, is traditionally known to possess analgesic, anti-inflammatory, anti-convulsant, cardiotonic, and hypotensive activity. In vitro and in vivo anti-inflammatory activities of a methanol extract of the leaves of Cerbera manghas and the underlying molecular mechanisms were investigated to validate the ethnopharmacological use of this plant. MATERIALS AND METHODS: The effect of Cerbera manghas methanol extract (Cm-ME) on the production of inflammatory mediators and the induction of HCl/EtOH-treated gastritis was explored using macrophages, HEK293 cells, and ICR mice. The molecular targets of this extract and potential active components in Cm-ME were also investigated. RESULTS: Cm-ME inhibited the production of nitric oxide (NO) in lipopolysaccharide (LPS)-treated RAW264.7 cells and peritoneal macrophages in a dose-dependent manner. This extract also suppressed the expression of NO synthase (iNOS) and cyclooxygenase (COX)-2. NF-kappaB-mediated enhancement of luciferase activity, nuclear translocation of p50 and p65, and phosphorylation of IkappaBalpha were markedly reduced by Cm-ME treatment. Direct enzyme assays, reporter gene assays, and immunoprecipitation analysis of kinases revealed Syk and Src as immunopharmacological targets of Cm-ME. Moreover, this extract strongly ameliorated the gastric symptoms induced by HCl/EtOH treatment of mice. Finally, HPLC analysis and pharmacological tests identified kaempferol as an active component of the extract with Src/Syk inhibitory activities. CONCLUSION: Inhibition of Syk/Src and the NF-kappaB pathway by kaempferol could play a key role in the anti-inflammatory pharmacological action of Cerbera manghas. PMID- 24342778 TI - An ethnobotanical study of medicinal plants used by tribal and native people of Madhupur forest area, Bangladesh. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Madhupur forest area, Tangail is one of early human settlements in Bangladesh. Having abode in the vicinity of the forest, a strong ethnobotanical practice has prevailed in this area since ancient time. Due to the rapid deforestation during the last few decades, many plants have already disappeared or are facing extinction. Thus we attempted to document the medicinal plant use of Madhupur forest area with a view to preserve the ethnobotanical knowledge and in order to protect the biodiversity of this area. MATERIALS AND METHODS: The fieldwork was conducted during a period of 1 year. Data was collected by interview, questionnaire, and group discussion with randomly selected informants including indigenous, tribal people, and Traditional Health Practitioners (THPs) living in the study area. Recorded plants are listed along with their indication, part used, form of preparation and use value (UV). Results were also analysed to determine informant consensus factor (ICF) and fidelity level (FL) of the plants on the basis of their use under various ailment categories. RESULTS: The present study has documented 78 medicinal plant species from 45 families used for the treatment of at least 77 different major and minor ailments and conditions. Medicinal plant species were categorised as tree, shrub, tuber, herb, and climber. Leaves were found to be the most frequently used plant part while decoction is the major form of preparation. In most cases preparations are either administered orally or applied topically. CONCLUSION: The present study revealed that some of the well-known medicinal plants are used extensively demonstrating an effective ethnobotanical practice in the study area. Plants with high ICF and FL values can be subjected to bioassay guided investigation while plants which scored low UVs require bioactivity screening to justify their use for the reported ailment. PMID- 24342779 TI - Anti-inflammatory and anti-hypersensitive effects of the crude extract, fractions and triterpenes obtained from Chrysophyllum cainito leaves in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Chrysophyllum cainito, popularly known as "star apple", caimito, "abiu-roxo" or "abiu-do-Para", is a tree of about 25m in height. Besides its culinary use, it is also used in folk medicine for the treatment of diabetes mellitus and several inflammatory diseases. MATERIALS AND METHODS: The crude methanolic extract (CME) was submitted to phytochemical studies for obtaining fractions and isolated compounds. They were monitored by thin-layer chromatography (TLC). The biological activity was evaluated in mice using the carrageenan-induced mechanical hypersensitivity and paw oedema. Biochemical assays, such as myeloperoxidase (MPO) and activity and cytokines levels quantification, were carried out to analyse the involvement of neutrophil migration and IL-1beta and TNFalpha production. Some adverse effects were investigated using the open-field and rota-rod tests, and it was also measured the rectal temperature. RESULTS: This study demonstrates, for the first time, the anti-hypersensitivity and anti-inflammatory effects of CME, fractions and two isolated triterpenes obtained from the leaves of Chrysophyllum cainito on carrageenan-induced hypersensitivity and paw-oedema. The mice treated with CME or chloroform fraction (CHCl3) presented reduction in mechanical hypersensitivity. The effect of the CME seemed to be partially related to the anti-inflammatory activity, as the paw-oedema and MPO activity were also significantly inhibited. The isolated compound Lup-20(29)-en-3beta-O-hexanoate demonstrated more reduction of the hypersensitivity than 3beta-Lup-20(29)-en-3-yl acetate, suggesting that this molecule might be partially responsible for the biological effects obtained with CME and CHCl3 fractions. Finally, animals treated with CME and CHCl3 did not present changes in locomotor activity, motor performance or body temperature. CONCLUSIONS: Our data demonstrates, for the first time, that the crude extract, fractions and pure compounds obtained from the Chrysophyllum cainito leaves possess important anti-hypersensitive properties against inflammatory pain in mice. The mechanisms through which Chrysophyllum cainito exerts its anti hypersensitive actions are still unclear, and require further investigation; however, this could well constitute a new and attractive alternative for the management of persistent inflammatory and neuropathic pain in humans. PMID- 24342780 TI - Effect of Cydonia oblonga Mill. leaf extract on serum lipids and liver function in a rat model of hyperlipidaemia. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cydonia oblonga Mill. leaves are traditionally used in Uyghur medicine to treat or prevent cardiovascular disease. Beyond a demonstrated effect on thrombosis, we tested it for an effect on dyslipidemia, in a rat model of hyperlipidemia. METHODS: Seventy healthy Sprague Dawley rats were randomly divided into 6 groups: normal controls, model controls, simvastatin, and low-, medium- and high-dose Cydonia oblonga Mill. leaf extracts (COM), orally for 56 days. The normal controls were fed a normal diet, all other groups a high fat diet. Rat weights were recorded over time. Total cholesterol (TC), triglycerides (TG), low and high-density lipoproteins (LDL, HDL), as well as AST, ALT and total protein (TP) were measured in serum at the end of the study. The antioxidant capacity of glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), malondialdehyde (MDA) was measured in liver samples, along with lipoprotein lipase (LPL), and hepatic lipase (HL). Liver pathology was described. RESULTS: COM dose-dependently reduced TC, TG, LDL-C and MDA, inhibited the activity of ALT, AST and LPS, increased HDL-C content, increased the activity of SOD, GSH-PX, LPL and HL, and reduced liver steatosis in hyperlipidaemia rats, which was significant at medium and high doses. The effect of COM was similar to that of simvastatin except for increased LPL and HL which were reduced by COM but not by simvastatin. CONCLUSION: Cydonia oblonga Mill. leaf extracts have hypolipidaemic and hepatoprotective effects, probably related to increasing antioxidant capacity and lipoprotein metabolism in the liver, and inhibition of lipogenesis. PMID- 24342781 TI - Evaluation of the antidiarrhoeal activity of the hydroethanolic leaf extract of Pupalia lappacea Linn. Juss. (Amaranthaceae). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pupalia lappacea is a medicinal plant found in savannah and woodland localities and forest path sides from Senegal to Southern Nigeria. It has been used in the management of diarrhoea in Nigerian traditional medicine. This study was designed to evaluate the antidiarrhoeal activity of the hydroethanolic leaf extract of Pupalia lappacea (PL). MATERIALS AND METHODS: The antidiarrhoeal activity of PL was evaluated using the normal and castor oil induced intestinal transit, castor oil-induced diarrhoea, gastric emptying and intestinal fluid accumulation tests in rodents. RESULTS: PL (100-400mg/kg, p.o.) produced a significant dose-dependent decrease in normal and castor oil-induced intestinal transit compared with the control group (distilled water 10ml/kg, p.o.). This effect was significantly (P<0.05) inhibited by pilocarpine (1mg/kg, s.c.) but not by yohimbine (10mg/kg, s.c.), prazosin (1mg/kg, s.c.), or propranolol (1mg/kg, i.p.). The extract produced a dose-dependent and significant increase in the onset of diarrhoea. PL (100-400mg/kg) also reduced the diarrhoea score, number and weight of wet stools. The in-vivo antidiarrhoeal index (ADIin vivo) of 56.95% produced by the extract at the dose of 400mg/kg was lower compared to that produced by loperamide 5mg/kg (77.75%). However, PL (400mg/kg) significantly increased gastric emptying in rats but significantly reduced the volume of intestinal content in the intestinal fluid accumulation test. Phytochemical analysis of the extract revealed the presence of alkaloids, saponins, and fixed oils and fats. The acute toxicity studies revealed that the extract is relatively safe when given orally; no death was recorded at a dose of 10g/kg. CONCLUSION: Results showed that the hydroethanolic leaf extract of Pupalia lappacea possesses antidiarrhoeal activity possibly mediated by antimuscarinic receptor activity. PMID- 24342782 TI - Evidence of the anti-Helicobacter pylori, gastroprotective and anti-inflammatory activities of Cuphea aequipetala infusion. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cuphea aequipetala (Lythraceae) is a medicinal plant highly appreciated in Mexico to treat stomach ailments such as pain and burning sensation, stomach infections, ulcers, diarrhea, dysentery, and different types of tumors and bruises. In this work, the infusion of aerial parts of this plant (CAI) was investigated for its polypharmacological potential. MATERIALS AND METHODS: In vitro anti-Helicobacter pylori activity was assessed by broth dilution method. Pharmacological studies included acute toxicity in mice using Lorke's model, anti-inflammatory activity by xylene and TPA induced ear edema assay, as well as gastroprotection with ethanol-induced gastric ulcer model. DPPH and ABTS assays were used to determine antioxidant capacity. Polyphenols and flavonoid contents were determined by Folin-Ciocalteu method and AlCl3 reaction, respectively. RESULTS: CAI showed good anti-Helicobacter pylori activity with a MIC of 125MUg/mL. The infusion was not toxic according to Lorke's model with a LD50 greater than 5g/kg. CAI exhibited low anti-edematogenic action in the models assayed. Oral administration of 300mg/kg CAI significantly reduced gastric lesions by 87.9%. The effect was reversed only by indomethacin and N ethylmaleimide demonstrating the role of endogenous prostaglandins and sulfhydryl compounds in gastroprotection. Total phenolic and flavonoid contents of CAI were 109.9mg GAE/g DW and 28.1mg QE/g DW, respectively, and the infusion exhibited a good antioxidant activity that is thought to play a role in its biological activity. The analysis of a preliminary fractionation of the infusion indicates that the complete extract conserves all its pharmacological activities in contrast to fractionated extracts. CONCLUSIONS: Cuphea aequipetala is a promising native herb in an integral therapy for the treatment of bacterial or non bacterial gastric ulcer because it possesses some anti-inflammatory properties, as well as exhibits good gastroprotective and antibacterial effects. It represents an important source for the isolation of anti-Helicobacter pylori compounds. This work provides ethnopharmacological evidence that supports the traditional use of this species. PMID- 24342783 TI - [Last updates about amniotic fluid embolism and a case report]. AB - Amniotic fluid embolism (AFE) is a rare complication of pregnancy, which, in France, is the second leading cause of maternal mortality. It results from the passage of amniotic fluid into the maternal circulation, but mechanisms leading to clinical signs are not yet clearly identified. After a literature review, we report on the case of a 34 years old patient occurred during labor. Laboratory tests were performed during acute phase to diagnose coagulopathy and to monitor vital parameters. Further laboratory tests were conducted to support the diagnosis: cytology, study of insulin-like growth factor-binding protein 1, tryptase and alpha-foetoprotein. Performances and place of these laboratory tests must be precised as no specific test can attest the diagnosis. PMID- 24342784 TI - [Utility of hCG dosage in the management of gestational trophoblastic diseases]. AB - Measurement of hCG remains today central for diagnosis, treatment and follow-up of gestational trophoblastic diseases (GTD). In order to evaluate this contribution, we conducted a prospective cohort study in the Service of high-risk pregnancy of Rabat Maternity Les Orangers and the Laboratory of Rabat Military Teaching Hospital Mohammed V over a period of eighteen months. 35 patients were included. The hCG assay was determined by electrochemiluminescence. The general frequency of the GTD is of 0.33/100 childbirth. The average age of our patients was 30.5 years. 26 patients had hCG level abnormal and higher than 200 000 UI/mL when diagnosed with GTD; 34 patients had simple endo-uterine aspiration and 1 a chemotherapy. Among 34 patients, 25 (73.5%) had a favourable evolution characterized by normal hCG level within 3 to 13 weeks and complete remission. Serum hCG remained stable and negative in all these patients with a follow-up of 18 months. 9 patients had unfavourable evolution characterized by reaxent after negativation or stagnation of hCG levels. A rigorous monitoring of hCG levels during treatment and follow-up is essential to improve forecast of these diseases. PMID- 24342785 TI - [Clinical characterization of the Stargardt disease and molecular exploration of the c.2041C>T mutation (ABCA4 gene) in Tunisian patients]. AB - In order to charaterize the Stargardt disease, the molecular exploration of the c.2041C>T mutation (ABCA4 gene) and genotype phenotype correlation in Tunisian patients, seven unrelated propositi underwent a complete ophthalmological examination. The search for the mutation was performed by a direct sequencing after a specific amplification of exon 14 of the ABCA4 gene. Baseline, the average age of propositi was 20.7 +/- 15 years and the sex-ratio was 1.3. The age of the visual impairment perception was 8.1 +/- 3.2 years. In all patients, the loss of visual acuity was bilateral and ranged from "counting fingers" to 3.2/10. Fundus and retinal fluorescein angiography examination showed advanced stages of the disease. The allele frequency of the c.2041C>T was 28.5% (4/14). We have reported this mutation in two patients. Their average age at onset was 5 and a half years and the disease progression was rapid with a severe visual loss after 1 and 5 years. All patients had a juvenile macular dystrophy with flavimaculatus flecks. To our knowledge, we reported for the first time the homozygous state of the c.2041C>T mutation. Among homozygous patients, the age at onset was early, the loss of visual acuity was important and the prognosis was severe. Due to the severity of the phenotype and the high rate of inbreeding, genetic counseling for healthy heterozygotes is essential. PMID- 24342786 TI - [Morphologic features of the binucleated lymphocytes for the assesment of persistent B-cell polyclonal lymphocytosis]. AB - Observation of binucleated lymphocytes on a blood film is a cornerstone event to assess persistent polyclonal B-cell lymphocytosis diagnosis (PPBL). But seldom case reports mentioned their finding in other contexts, mainly B-cell lymphoproliferative neoplasms such chronic lymphocytic leukemia or in reactive circumstances as multiple sclerosis undergoing natalizumab treatment. We aimed to check if some particular morphologic features were more specificaly linked to PPBL, reviewing blood films of series of patients affected by PPBL or harbouring binucleated lymphocytes whatever the diagnosis was. We found that binucleated cells in PPBL were heterogeneous but mostly midde-sized cells, asymetricaly bilobed with nucleoli, and with a moderately basophilic cytoplasm. Though mainly observed in PPBL patients, all that criteria remained unspecific. Conversely, the morphologic features of the other lymphoid cells were of good clinical value to affirm PPBL, either monocytoid or hyperbasophilic cells being systematically found. We think that a substantial percentage of binucleated lymphocytes, harbouring morphologic features such as described, and in a context of monocytoid and/or hyperbasophilic lymphocytes is predictive of PPBL diagnosis. PMID- 24342787 TI - [Comparison of two techniques for serological diagnosis of chlamydial infections: MIF and immunoblotting]. AB - Sera from a population of 58 patients were used for comparison of two techniques for serodiagnosis of Chlamydia species: the MIF (micro-immunofluorescence) and immunoblotting. The MIF uses elementary bodies (EC) of Chlamydia while immunoblotting using recombinant proteins specific synthetic species of chlamydia. The objective of this study was to determine the sensitivity and specificity of serological techniques evaluated on a population control but also ill, by a comparative study between MIF which is the reference technique and immunoblotting (Chlamycheck). The technique Chlamycheck showed very good agreement with the MIF regarding Chlamydia trachomatis, but is a less good agreement with the MIF Chlamydia pneumoniae. The excellent specificity was observed with the technique Chlamycheck in the detection of anti-C. trachomatis, the useful sign of its use in the diagnosis of acute infections of Chlamydia trachomatis. PMID- 24342788 TI - [Urinary protein electrophoresis, which analysis to select? A simplified interpretation]. AB - Permanent proteinuria is an early marker of the kidney dysfunction. Tracking by urinary strip, imposes a precise quantification by the laboratory. In front of the difficulties of urine collection during 24 hours, protein determination can be carried out on the urine of a miction and can be expressed as g per g of creatinine (uPCR). We analysed the impact of the expression of the proteinuria in g/L (uP) as compared to uPCR on the urinary electrophoretic profiles. A revision and a simplification of this in practice clinical interpretation is proposed. The proteinuria of 696 in-patients was quantified on an Olympus AU2700. The urinary electophoretic profiles (SDS-AGE) were interpreted by two biologists. uP and uPCR are well correlated (r=0.847, p< 0.0001). Data agreed for proteinuria > 1 g/L but concordance was obtained only in 74% of the subjects and 55% of the pathological patients. A repetition of the analyses is suggested. The interpretative diagram suggested with simplified comments improved interpretation. We advise an interpretation by two biologists. In conclusion, interpretation of the urinary electrophoretic profile rests on the rate of total proteinuria. Expression of the proteinuria as g/g of creatinine must be associated with the expression in g/L because of the analytical conditions. The SDS-AGE Technique does not allow the identification of the monoclonal compound but allows a quantitative follow-up under treatment and especially an early tracking of the type of renal dysfunction. PMID- 24342789 TI - [Evaluation of an haematological analyser (Siemens Advia((r)) 2120i) and improving quality of daily practice]. AB - A risk analysis, with method validation, and a study of the relevance of morphological alarms triggered by the automat have been made to the automat Advia((r)) 2120i (Siemens). The analytical performance of the systems: repeatability, fidelity, contamination, linearity, correlation, the accuracy and approach to uncertainty, are compliant with the expected results (Ricos). Thanks to the retrospective study of morphological alarms triggered by the automat and based on the recommendations of the ISLH, a new attitude about blood smear was introduced. For platelets in citrate, a slight underestimation of the number compared to those collected in EDTA was observed probably need to redefine normal platelet values citrate. PMID- 24342790 TI - [Immunophenotyping of B chronic lymphoproliferative syndromes (CLL excluded): confrontation with the histology]. AB - Immunophenotyping is a major tool for the diagnosis of the chronic lymphoid leukaemia (CLL). Its interest remains limited in the classification of the other B chronic lymphoproliferative syndromes (B-CLPS). We evaluate the place of the flow cytometry (CMF) in the diagnosis and classification of the non CLL B-CLPS. The cases with Matutes score of 4 or more are excluded. A confrontation of the results to the histology is made. 28 cases of non CLL B-CLPS are diagnosed. CMF shows a kappa monoclonal population in 15 cases and lambda in 13 cases. A co expression CD19+CD5 + is found in 11 cases concording with an atypic CLL or a mantel cell lymphoma in 6 cases with Matutes score of 3. In 5 cases, we concluded to non CLL B-CLPS (Matutes<3). The histology retained the diagnosis of a mantel cell lymphoma (4 cases), a SLVL (1 case) and an atypical LLC (1 case). CD5 is negative in 17 cases. In 5 cases, the diagnosis of hairy cell leukemia (HCL) is retained (CD 11c+ CD103+) and confirmed by the histology. The diagnosis of a marginal zone lymphoma is retained in 2 cases, a SLVL in 2 cases, a follicular lymphoma in 3 cases and prolymphocytes leukaemia in 1 case. Nine cases of non CLL B-CLPS were difficult to classify by histology. CMF is insufficient for the classification of most of the non CLL B-CLPS. Only the phenotype of the HCL is characteristic. The confrontation of the histology results remains essential. PMID- 24342791 TI - [Plasma cell leukemia: three case-reports and review of literature]. AB - Plasma cell leukemia (LP) is a rare hematologic malignancy. Its prognosis is very derogatory. It is defined by the presence in circulating blood of more than 2 G/L plasmocytes or greater than 20% of the total leukocytes. It comes in two forms: secondary plasma cell leukemia complicating multiple myeloma (MM) and primary setting. Its incidence is estimated at 0.9% of patients with acute leukemia and 2 4% of patients with MM. We report, through three observations, the clinical presentation of the plasma cell leukemia, its cytological features, immunophenotypic, physiopathological and therapeutic care. PMID- 24342792 TI - [Propionibacterium avidum cutaneous abscess in a young immunocompetent]. AB - Severe infections by Propionibacterium avidum are rare, we report a case of abscess of the root of the thigh in a young immunocompetent adult with no risk factor for infection with Propionibacterium sp. The liquid of abscess pus was inoculated immediately on culture media enriched and incubated under an atmosphere 5 to 10% CO2. The isolated strain was identified by API Coryne gallery (bioMerieux, Marcy l'etoile, France). An MIC of ciprofloxacin was performed by E test (bioMerieux Marcy l'etoile). Cultivation led to the isolation after 3 days of incubation of pure and abundant culture of Propionibacterium avidum. To our knowledge, this is only the third documented case of infection by this organism in immunocompetent patient without iatrogenic risk. Thus, further studies on the pathogenicity of P. avidum are more than necessary. PMID- 24342793 TI - [Heterogeneity in the handling of vitamin-K-antagonists and of INR: the example of Quercy-Rouergue]. AB - Using a questionnaire, we have evaluated how VKA and INR are handled by medical doctors in Quercy-Rouergue. This evaluation is part of an international post analytical quality assessment survey in laboratory medicine supervised by Noklus (http://www.noklus.no/). The original questionnaire designed by Noklus has been adapted to our local practices in replacing warfarin by fluindione. The " Centre de reference et d'education aux antithrombotiques d'Ile de France " (Creatif) also participated. Of 282 medical doctors who were sent the questionnaire 109 filled it in, 62% of them being general practitioners. For a target INR at 2.5, the thresholds used to change the dose of VKA range between 1.3 and 2.3 for low values, and between 2.8 and 4 for high values. The bleeding or ischemic risks of being under VKA, versus of not being under VKA, are largely overestimated. INR measurements also tend to be too frequent in stable, and even more so in overdosed, patients. In case of INR at 4.8 only 59% of the participants implement the recommendation of la Haute autorite de sante (HAS) and le Groupe d'etude sur l'hemostase et la thrombose (GEHT) which consists of skipping one dose of VKA, and the attitudes also diverge regarding the importance of the VKA dose reduction, and the number of days under reduced dose before the next INR measurement, the attitude of the Creatif being barely predominant among the participants, and slightly different from that recommended by the HAS and the GEHT. In conclusion, despite the limitations of our methods (the analysis of a questionnaire being less close to the truth than an analysis of actual practices), our evaluation points to the heterogeneity in the knowledge about, and in handling, VKA and INR regarding more particularly management of overdosing, and the estimation of bleeding or ischemic risks, despite the availability of supposedly clear and simple practice guidelines. PMID- 24342794 TI - [Accreditation of automated complete blood count by the LH750 Analyzer (Beckman Coulter) in Georges Pompidou Hospital (Paris, France)]. AB - Preliminary evaluation of quantitative clinical laboratory measurements is a prerequisite for the accreditation of clinical laboratories, according to the French Committee of Accreditation guidelines following the European reference Standard EN ISO 15189. Numerous papers have been published regarding biochemistry and immunology. However, data are lacking for automated complete blood count accreditation. We report here our experience at Hopital europeen Georges Pompidou hematology laboratory and present the performance characteristics of two mirrored LH750 Beckman-Coulter analysers, including precision, accuracy and uncertainty of measurement. PMID- 24342795 TI - Pulmonary vein isolation: the impact of pulmonary venous anatomy on long-term outcome of catheter ablation for paroxysmal atrial fibrillation. AB - BACKGROUND: Circumferential pulmonary vein (PV) isolation is the cornerstone of catheter ablation for atrial fibrillation (AF); however, PV reconnection remains problematic. OBJECTIVE: To assess the impact of PV anatomy on outcome after AF ablation. METHODS: One hundred two patients with paroxysmal AF underwent cardiac magnetic resonance (60%) or computed tomography (40%) before AF ablation. PV anatomy was classified according to the presence of common PVs, accessory PVs, PV branching pattern, and the dimensions of the PV ostia, intervenous ridges (IVRs), and the left PV-left atrial appendage ridge. RESULTS: Four discrete PVs were present in 48(47%) of the patients: a left common PV in 38(37%), a right common PV in 2(2%), an accessory right PV in 20(20%), and left PV in 4(4%). At a mean follow-up of 12 +/- 4 months, 75 of 102 (74%) patients were free of recurrent AF. A LCPV was associated with an increase in freedom from AF (87% vs 66% for 4 PV anatomy; P = .03). Greater left IVR length (16.9 +/- 3.5 mm vs 14.0 +/- 3.0 mm; P <= .001) and width (1.4 +/- 0.6 mm vs 1.1 +/- 0.6 mm; P = .02) were associated with increased AF recurrence. After multivariate analysis, abnormal anatomy (LCPV or accessory PV) and left IVR length were found to be the only independent predictors of freedom from AF. CONCLUSIONS: Four discrete PVs are present in the minority of patients with paroxysmal AF undergoing PV isolation. The presence of a LCPV is associated with an increased freedom from AF after catheter ablation. PV anatomy may in part explain the variable outcome to electrical isolation in patients with paroxysmal AF. PMID- 24342796 TI - Explaining selected health behaviors in a national sample of Taiwanese adults. AB - Extant research provides little evidence about how health literacy, self-efficacy and health locus of control are related to each other in affecting health behaviors. The purposes of this study were to examine the associations among health literacy, self-efficacy and health locus of control and how the three factors are related to health behaviors using data from a national survey of Taiwanese adults. The analysis showed moderate correlations among health literacy, self-efficacy and locus of control, suggesting that they were independent, albeit correlated, factors. Moreover, we found in most cases that health literacy, self-efficacy and locus of control had independent associations with health behaviors. Of the three factors, self-efficacy had the most consistent and positive associations with health behaviors. Our findings suggest that efforts to promote and sustain health behaviors need to focus on improving individuals' emotional states and correcting their faulty self-beliefs and habits of thinking. Health education campaigns and enhancement of literacy skills alone may not achieve the desirable goal of behavioral change. PMID- 24342798 TI - To boldly go "brain training". PMID- 24342799 TI - Pattern recognition for identification of lysozyme droplet solution chemistry. AB - Pattern formation during evaporation of a colloidal sessile droplet is a phenomenon relevant to a wide variety of scientific disciplines. The patterns remaining on the substrate are indicative of the transport mechanisms and phase transitions occurring during evaporation and may reflect the solution chemistry of the fluid [1-18]. Pattern formation during evaporation of droplets of biofluids has also been examined and these complex patterns may reflect the health of the patient [23-31]. Automatic detection of variations in the fluid composition based on these deposit patterns could lead to rapid screening for diagnostic or quality control purposes. In this study, a pattern recognition algorithm is presented to differentiate between deposits containing various solution compositions. The deposits studied are from droplets of simplified, model biological fluids of aqueous lysozyme and NaCl solutions. For the solution concentrations examined here, the deposit patterns are dependent upon the initial solution composition. Deposit images are represented by extracting features using the Gabor wavelet, similar to the method used for iris recognition. Two popular pattern recognition algorithms are used to classify the deposits. The k-means clustering algorithm is used to test if incremental changes in solution concentration result in reproducible and statistically interpretable variations in the deposit patterns. The k-nearest neighbor algorithm is also used to classify the deposit images by solution concentration based on a set of training images for each class. Here, we demonstrate that the deposit patterns may act as a "fingerprint" for identification of solution chemistry. The results of this study are very promising, with classification accuracies of 90-97.5%. PMID- 24342797 TI - Opposite regulation of hepatic breast cancer resistance protein in type 1 and 2 diabetes mellitus. AB - Previous studies on diabetes have reported controversial results with regard to transporters in liver. The present study aimed to explore changes in hepatic breast cancer resistance protein (BCRP) expression and functions, as well as the possible underlying mechanisms, in type 2 diabetic patients, type 1 (streptozotocin-induced), and type 2 (Goto Kakizaki) diabetic rats. Protein and mRNA levels of human (h) and rat (r) BCRP were investigated using Western blot and quantitative polymerase chain reaction analyses. Functions of liver rBCRP were evaluated using rosuvastatin. Sandwich cultured rat hepatocytes (SCRH) were cultured with d-glucose, insulin, or oleic acid for 72 h, and rBCRP mRNA was detected. The effect of oleic acid on rBCRP function in SCRH was also investigated using rosuvastatin. Results showed that liver rBCRP mRNA levels decreased to 20% in type 1 diabetic rats, whereas that in diabetic patients and GK rats significantly increased threefold and twentyfold, respectively. No changes were observed in h/rBCRP protein levels of type 2 diabetic patients and GK rats. The functions of rBCRP significantly declined in type 1 diabetic rats but showed no significant changes in GK rats. The data from SCRH indicated that d glucose decreased rBCRP mRNA level to 60%. Oleic acid increased rBCRP mRNA in SCRH by approximately eightfold but decreased rBCRP function to 50%. Therefore, h/rBCRP expression and functions were oppositely regulated in type 1 and type 2 diabetes mellitus subjects. Alternations in d-glucose, insulin, and free fatty acid levels in plasma might contribute to the changes in h/rBCRP expression and functions. PMID- 24342800 TI - Biomimetic nanocomposites of carboxymethyl cellulose-hydroxyapatite: novel three dimensional load bearing bone grafts. AB - An innovative biomimetic synthesis of novel three dimensional micro/macro porous carboxymethyl cellulose (CMC)-hydroxyapatite (HA) nanocomposites having four systematically different compositions has been established for its possible application as a load bearing synthetic bone graft. Our process, being in situ, involves a simple and cost effective route akin to a matrix mediated biomineralization process. Developed synthesis route not only controls the size of HA particles in the range of 15-50 nm, embedded in CMC matrix, but also assists in the formation of a mechanically strong three dimensional nanocomposite structures due to physical cross linking of HA impregnated CMC matrix. The process does not involve any toxic cross linker and works at near ambient conditions. The nanocomposites are systematically structurally and mechanically characterized using various techniques like scanning electron microscopy (SEM), atomic force microscopy (AFM), transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform IR (FTIR), solid state (13)C nuclear magnetic resonance ((13)C NMR), thermo-gravimetric analysis (TGA) and Universal mechanical test. It reveals that the ionic/polar or electrostatic interactions are the main driving force for formation of load bearing three dimensional nanocomposites via a process similar to matrix mediated biomineralization. Compressive strength and compressive modulus of nanocomposites, being in the range of 1.74-12 MPa and 157-330 MPa, respectively, meet the desired range of compressive strength for the synthetic grafts used in cancellous bone. An increase in the compressive strength with increase in the porosity has been an interesting observation in the present study. In vitro cytotoxicity of the synthesized nanocomposites has been evaluated using bone marrow mesenchymal stem cells (BMSC) isolated from Wistar rat. PMID- 24342801 TI - Detection of hepatitis B virus infection markers in dried plasma spots among patients in Congo-Brazzaville. AB - The detection of hepatitis B virus (HBV) infection markers by using dried plasma spots from 32 patients living in Congo has been assessed. Considering frozen plasma samples as gold standard, the sensitivity and specificity of HBV serologic markers detection in dried plasma eluted from filter paper were 100%. The sensitivity and the specificity of HBV DNA detection reached 96% and 100%, respectively, with plasma samples dried on filter paper compared to standard samples. Dried plasma samples can represent an alternative to conventional sampling for HBV detection and management of the infection in developing countries. PMID- 24342802 TI - The inhibitory effect of anandamide on oxytocin and vasopressin secretion from neurohypophysis is mediated by nitric oxide. AB - The neurohypophyseal hormones oxytocin (OT) and vasopressin (VP) are involved in behavioral, autonomic and neuroendocrine functions. Both peptides are synthesized in magnocellular neurons of paraventricular and supraoptic nuclei at hypothalamic level whose axons terminate in the neurohypophysis (NH), from where OT and VP are released into the systemic circulation. NH contains abundant nitric oxide (NO) synthase suggesting that NO plays a role in the release of these neuropeptides. The endocannabinoid system is present in magnocellular neurons of the hypothalamic neurohypophyseal system, and we have previously demonstrated that endocannabinoids modulate OT secretion at hypothalamic level. In the present work, we investigated the in vitro effect of the endocannabinoid anandamide (AEA) on OT and VP release from NH of untreated adult male rats and the involvement of NO in this action. Our results showed that AEA decreased OT and VP secretion from NH. AEA action was mediated by NO, since the inhibition of NO synthesis completely blocked this inhibitory effect. We found that cannabinoid receptor type 2 (CB2) and transient receptor potential cation channel subfamily V member 1 (TRPV1) are involved in the inhibitory effect of AEA because AM630 and capsazepine, CB2 and TRPV1 antagonists respectively, but not AM251, a CB1 antagonist, blocked AEA effect at neurohypophyseal level. These findings revealed an interaction between endocannabinoid, nitric oxide and oxytocin/vasopressin systems that could be involved in the modulation of homeostatic, behavioral and reproductive processes. PMID- 24342803 TI - Smooth muscle cells relay acute pulmonary inflammation via distinct ADAM17/ErbB axes. AB - In acute pulmonary inflammation, danger is first recognized by epithelial cells lining the alveolar lumen and relayed to vascular responses, including leukocyte recruitment and increased endothelial permeability. We supposed that this inflammatory relay critically depends on the immunological function of lung interstitial cells such as smooth muscle cells (SMC). Mice with smooth muscle protein-22alpha promotor-driven deficiency of the disintegrin and metalloproteinase (ADAM) 17 (SM22-Adam17(-/-)) were investigated in models of acute pulmonary inflammation (LPS, cytokine, and acid instillation). Underlying signaling mechanisms were identified in cultured tracheal SMC and verified by in vivo reconstitution experiments. SM22-Adam17(-/-) mice showed considerably decreased cytokine production and vascular responses in LPS- or acid-induced pulmonary inflammation. In vitro, ADAM17 deficiency abrogated cytokine release of primary SMC stimulated with LPS or supernatant of acid-exposed epithelial cells. This was explained by a loss of ADAM17-mediated growth factor shedding. LPS responses required ErbB1/epidermal growth factor receptor transactivation by TGFalpha, whereas acid responses required ErbB4 transactivation by neuregulins. Finally, LPS-induced pulmonary inflammation in SM22-Adam17(-/-) mice was restored by exogenous TGFalpha application, confirming the involvement of transactivation pathways in vivo. This highlights a new decisive immunological role of lung interstitial cells such as SMC in promoting acute pulmonary inflammation by ADAM17-dependent transactivation. PMID- 24342804 TI - HLA micropolymorphisms strongly affect peptide-MHC multimer-based monitoring of antigen-specific CD8+ T cell responses. AB - Peptide-MHC (pMHC) multimers have become one of the most widely used tools to measure Ag-specific T cell responses in humans. With the aim of understanding the requirements for pMHC-based personalized immunomonitoring, in which individuals expressing subtypes of the commonly studied HLA alleles are encountered, we assessed how the ability to detect Ag-specific T cells for a given peptide is affected by micropolymorphic differences between HLA subtypes. First, analysis of a set of 10 HLA-A*02:01-restricted T cell clones demonstrated that staining with pMHC multimers of seven distinct subtypes of the HLA-A*02 allele group was highly variable and not predicted by sequence homology. Second, to analyze the effect of minor sequence variation in a clinical setting, we screened tumor-infiltrating lymphocytes of an HLA-A*02:06 melanoma patient with either subtype-matched or HLA A*02:01 multimers loaded with 145 different melanoma-associated Ags. This revealed that of the four HLA-A*02:06-restricted melanoma-associated T cell responses observed in this patient, two responses were underestimated and one was overlooked when using subtype-mismatched pMHC multimer collections. To our knowledge, these data provide the first demonstration of the strong effect of minor sequence variation on pMHC-based personalized immunomonitoring, and they provide tools to prevent this issue for common variants within the HLA-A*02 allele group. PMID- 24342805 TI - Polymorphisms and interspecies differences of the activating and inhibitory FcgammaRII of Macaca nemestrina influence the binding of human IgG subclasses. AB - Little is known of the impact of Fc receptor (FcR) polymorphism in macaques on the binding of human (hu)IgG, and nothing is known of this interaction in the pig tailed macaque (Macaca nemestrina), which is used in preclinical evaluation of vaccines and therapeutic Abs. We defined the sequence and huIgG binding characteristics of the M. nemestrina activating FcgammaRIIa (mnFcgammaRIIa) and inhibitory FcgammaRIIb (mnFcgammaRIIb) and predicted their structures using the huIgGFc/huFcgammaRIIa crystal structure. Large differences were observed in the binding of huIgG by mnFcgammaRIIa and mnFcgammaRIIb compared with their human FcR counterparts. MnFcgammaRIIa has markedly impaired binding of huIgG1 and huIgG2 immune complexes compared with huFcgammaRIIa (His(131)). In contrast, mnFcgammaRIIb has enhanced binding of huIgG1 and broader specificity, as, unlike huFcgammaRIIb, it avidly binds IgG2. Mutagenesis and molecular modeling of mnFcgammaRIIa showed that Pro(159) and Tyr(160) impair the critical FG loop interaction with huIgG. The enhanced binding of huIgG1 and huIgG2 by mnFcgammaRIIb was shown to be dependent on His(131) and Met(132). Significantly, both His(131) and Met(132) are conserved across FcgammaRIIb of rhesus and cynomolgus macaques. We identified functionally significant polymorphism of mnFcgammaRIIa wherein proline at position 131, also an important polymorphic site in huFcgammaRIIa, almost abolished binding of huIgG2 and huIgG1 and reduced binding of huIgG3 compared with mnFcgammaRIIa His(131). These marked interspecies differences in IgG binding between human and macaque FcRs and polymorphisms within species have implications for preclinical evaluation of Abs and vaccines in macaques. PMID- 24342806 TI - Prostaglandin E2-EP3 signaling induces inflammatory swelling by mast cell activation. AB - PGE2 has long been known as a potentiator of acute inflammation, but its mechanisms of action still remain to be defined. In this study, we employed inflammatory swelling induced in mice by arachidonate and PGE2 as models and dissected the role and mechanisms of action of each EP receptor at the molecular level. Arachidonate- or PGE2-induced vascular permeability was significantly reduced in EP3-deficient mice. Intriguingly, the PGE2-induced response was suppressed by histamine H1 antagonist treatment, histidine decarboxylase deficiency, and mast cell deficiency. The impaired PGE2-induced response in mast cell-deficient mice was rescued upon reconstitution with wild-type mast cells but not with EP3-deficient mast cells. Although the number of mast cells, protease activity, and histamine contents in ear tissues in EP3-deficient mice were comparable to those in wild-type mice, the histamine contents in ear tissues were attenuated upon PGE2 treatment in wild-type but not in EP3-deficient mice. Consistently, PGE2-EP3 signaling elicited histamine release in mouse peritoneal and bone marrow-derived mast cells, and it exerted degranulation and IL-6 production in a manner sensitive to pertussis toxin and a PI3K inhibitor and dependent on extracellular Ca(2+) ions. These results demonstrate that PGE2 triggers mast cell activation via an EP3-Gi/o-Ca(2+) influx/PI3K pathway, and this mechanism underlies PGE2-induced vascular permeability and consequent edema formation. PMID- 24342807 TI - Cytogenetic and clinical risk factors for assessment of ultra high-risk multiple myeloma. AB - BACKGROUND: Cytogenetic assessments can improve conventional clinical risk assessment for ultra-high risk (UHR) multiple myeloma (MM) patients. OBJECTIVE: Cytogenetic and clinical risk factors were examined in UHR MM patients. METHODS: Consecutive MM patients (n = 168) were retrospectively screened for untreated, symptomatic MM between July 2008 and March 2011, including UHR (n = 35) and control (n = 60) patients with <= 12 or >12 month survival, respectively. Treatment outcomes; clinical, radiological, histological factors; and fluorescence in situ hybridization (FISH)-indicated cytogenetic abnormalities (CAs) were compared. RESULTS: Included UHR patients exhibited lower median overall survival (OS) (5 vs. >24 months); overall response rates (ORRs) (31.4% vs. 83.3%); complete response (CR), near CR (nCR), or very good partial response (VGPR) (8.6% vs. 51.7%) (all P<0.001); and partial response (PR) (22.9% vs. 31.7%, P = 0.358). UHR patients exhibited more renal failure (54.3% vs. 28.3%), hypercalcemia (11.4% vs. 0), elevated lactate dehydrogenase (LDH) (25.7% vs. 5%), secondary plasma cell leukemia (14.3% vs. 0), International Staging System (ISS) stage III (77.1% vs. 45%), and 1q21+ and 17p- (42.9% vs. 18.3%; 17.1% vs. 3.3%) (all P<0.05). >= 3 CAs indicated poor survival (36.7% vs. 16.1%, P = 0.035). Multivariate analysis showed ISS stage and LDH correlated with UHR (P = 0.05 and P =0.01, respectively), and 1q21+ and 17p- were increased but non-significantly correlated with UHR (P = 0.15 and P = 0.2, respectively). CONCLUSIONS: Combined clinical and cytogenetic assessments optimally indicate UHR MM patients' prognosis, allowing earlier risk-adapted interventions. PMID- 24342808 TI - Now you see it, now you don't: an unusual cause of the "double duct sign". PMID- 24342809 TI - Chronic diarrhea and weight loss. PMID- 24342810 TI - Immunosuppressed solid organ transplant recipient. PMID- 24342811 TI - Dysphagia in a patient with a Zenker's Diverticulum: there is more to it than meets the eye. PMID- 24342812 TI - Measuring the value of a senior emergency department: making sense of health outcomes and health costs. PMID- 24342813 TI - Does advanced airway management improve outcomes in adult out-of-hospital cardiac arrest? PMID- 24342814 TI - Emergency department avoidance by transgender persons: another broken thread in the "safety net" of emergency medicine care. PMID- 24342815 TI - Admit or transfer? The role of insurance in high-transfer-rate medical conditions in the emergency department. AB - STUDY OBJECTIVE: We study the association of payer status with odds of transfer compared with admission from the emergency department (ED) for multiple diagnoses with a high percentage of transfers. METHODS: This was a retrospective study of adult ED encounters using the Healthcare Cost and Utilization Project 2010 Nationwide Emergency Department Sample. We used the Clinical Classification Software to identify disease categories with 5% or more encounters resulting in transfer (27 categories; 3.7 million encounters based on survey weights). We sorted encounters by condition into 12 groups according to expected medical or surgical specialist needs. We used logistic regression to assess the role of payer status on odds of transfer compared with admission and report adjusted odds ratios (ORs). RESULTS: Among high-transfer conditions in 2010, uninsured patients had double the odds of transfer compared with privately insured patients (OR 2.12; 95% confidence interval [CI] 1.72 to 2.62). Medicaid patients were also more likely to be transferred (OR 1.2; 95% CI 1.04 to 1.38). Uninsured patients had higher odds of transfer in all specialist categories (significant in 9 of 12). The categories with the highest odds of transfer for the uninsured included nephrology (OR 2.44; 95% CI 1.07 to 5.55), psychiatry (OR 2.26; 95% CI 1.65 to 3.25), and hematology-oncology (OR 2.21; 95% CI 1.50 to 3.25); the highest for Medicaid were general surgery (OR 1.61; 95% CI 1.09 to 1.83), hematology-oncology (OR 1.55; 95% CI 1.05 to 2.30), and vascular surgery (OR 1.55; 95% CI 1.02 to 2.28). CONCLUSION: Insurance status appears to play a role in ED disposition (transfer versus admission) for many high-transfer conditions. PMID- 24342816 TI - Medical clearance: time for this dinosaur to go extinct. PMID- 24342817 TI - Impact of a new senior emergency department on emergency department recidivism, rate of hospital admission, and hospital length of stay. AB - STUDY OBJECTIVE: Senior (geriatric) emergency departments (EDs) are an emerging phenomenon across the United States, designed to provide greater comfort for elders, screening for common morbidities, and selective contact with social workers. We hypothesize that the senior ED will reduce recidivism, rate of admission, and hospital length of stay. METHODS: This was a pre/postintervention observational study of seniors (>=65 years) before and after opening of a new senior ED in a large community hospital. Older nonseniors treated during the same periods were included to detect temporal trend bias. Outcomes included admission to the hospital, hospital length of stay, and ED return visits. Cox proportional hazards models, controlling for patient age, sex, triage level, insurance type, admission on the index visit, and hospital length of stay, were used to test association with time to return within 30 and 180 days. Multivariable regression modeling was used to determine whether the intervention was associated with admission on the index visit, and hospital length of stay. RESULTS: There was no significant difference in time to return within 30 days (HR=1.09; 95% confidence interval [CI] 0.95 to 1.23), 180 days (HR=0.99; 95% CI 0.91 to 1.08), or average hospital length of stay. Risk of being admitted on the index visit was lower for seniors treated in the senior ED compared with the regular ED (Relative Risk=0.93; 95% CI 0.89 to 0.98). CONCLUSION: A new senior ED was not associated with reduced ED recidivism or hospital length of stay, but was associated with decreased rate of admission. PMID- 24342818 TI - Pretreatment with intravenous lipid emulsion reduces mortality from cocaine toxicity in a rat model. AB - STUDY OBJECTIVE: We compare the effects of intravenous lipid emulsion and normal saline solution pretreatment on mortality and hemodynamic changes in a rat model of cocaine toxicity. We hypothesize that intravenous lipid emulsion will decrease mortality and hemodynamic changes caused by cocaine administration compared with saline solution. METHODS: Twenty male Sprague-Dawley rats were sedated and randomized to receive intravenous lipid emulsion or normal saline solution, followed by a 10 mg/kg bolus of intravenous cocaine. Continuous monitoring included intra-arterial blood pressure, pulse rate and ECG tracing. Endpoints included a sustained undetectable mean arterial pressure (MAP) or return to baseline MAP for 5 minutes. The log-rank test was used to compare mortality. A mixed-effect repeated-measures ANOVA was used to estimate the effects of group (intravenous lipid emulsion versus saline solution), time, and survival on change in MAP, pulse rate, or pulse pressure. RESULTS: In the normal saline solution group, 7 of 10 animals died compared with 2 of 10 in the intravenous lipid emulsion group. The survival rate of 80% (95% confidence interval 55% to 100%) for the intravenous lipid emulsion rats and 30% (95% confidence interval 0.2% to 58%) for the normal saline solution group was statistically significant (P=.045). CONCLUSION: Intravenous lipid emulsion pretreatment decreased cocaine-induced cardiovascular collapse and blunted hypotensive effects compared with normal saline solution in this rat model of acute lethal cocaine intoxication. Intravenous lipid emulsion should be investigated further as a potential adjunct in the treatment of severe cocaine toxicity. PMID- 24342819 TI - Effect of out-of-hospital noninvasive positive-pressure support ventilation in adult patients with severe respiratory distress: a systematic review and meta analysis. AB - STUDY OBJECTIVE: Noninvasive positive-pressure ventilation (NIPPV) is increasingly being used by emergency medical services (EMS) for treatment of patients in respiratory distress. The primary objective of this systematic review is to determine whether out-of-hospital NIPPV for treatment of adults with severe respiratory distress reduces inhospital mortality compared with "standard" therapy. Secondary objectives are to examine the need for invasive ventilation, hospital and ICU length of stay, and complications. METHODS: Electronic searches of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature were conducted and reference lists of relevant articles hand searched. Randomized controlled trials comparing out-of-hospital NIPPV with standard therapy in adults (aged >=16 years) with severe respiratory distress published in English were included. Two reviewers independently screened abstracts, assessed quality of the studies, and extracted data. Data were pooled with random-effects models and reported as risk ratios (RRs) with 95% confidence intervals (CIs) and number needed to treat (NNT). RESULTS: Seven randomized controlled trials were included, with a combined total of 632 patients; 313 in the standard therapy group and 319 in the NIPPV group. In patients treated with NIPPV, the pooled estimate showed a reduction in both inhospital mortality (RR 0.58; 95% CI 0.35 to 0.95; NNT=18) and need for invasive ventilation (RR 0.37; 95% CI 0.24 to 0.58; NNT=8). There was no difference in ICU or hospital length of stay. CONCLUSION: Out-of-hospital administration of NIPPV appears to be an effective therapy for adult patients with severe respiratory distress. PMID- 24342820 TI - A two-stage patient enrichment adaptive design in phase II oncology trials. AB - Illustrated is the use of a patient enrichment adaptive design in a randomized phase II trial which allows the evaluation of treatment benefits by the biomarker expression level and makes interim adjustment according to the pre-specified rules. The design was applied to an actual phase II metastatic hepatocellular carcinoma (HCC) trial in which progression-free survival (PFS) in two biomarker defined populations is evaluated at both interim and final analyses. As an extension, a short-term biomarker is used to predict the long-term PFS in a Bayesian model in order to improve the precision of hazard ratio (HR) estimate at the interim analysis. The characteristics of the extended design are examined in a number of scenarios via simulations. The recommended adaptive design is shown to be useful in a phase II setting. When a short-term maker which correlates with the long-term PFS is available, the design can be applied in smaller early phase trials in which PFS requires longer follow-up. In summary, the adaptive design offers flexibility in randomized phase II patient enrichment trials and should be considered in an overall personalized healthcare (PHC) strategy. PMID- 24342822 TI - Atypical metastatic presentations in colorectal cancer: a case series. PMID- 24342821 TI - Cannabis-related working memory deficits and associated subcortical morphological differences in healthy individuals and schizophrenia subjects. AB - Cannabis use is associated with working memory (WM) impairments; however, the relationship between cannabis use and WM neural circuitry is unclear. We examined whether a cannabis use disorder (CUD) was associated with differences in brain morphology between control subjects with and without a CUD and between schizophrenia subjects with and without a CUD, and whether these differences related to WM and CUD history. Subjects group-matched on demographics included 44 healthy controls, 10 subjects with a CUD history, 28 schizophrenia subjects with no history of substance use disorders, and 15 schizophrenia subjects with a CUD history. Large-deformation high-dimensional brain mapping with magnetic resonance imaging was used to obtain surface-based representations of the striatum, globus pallidus, and thalamus, compared across groups, and correlated with WM and CUD history. Surface maps were generated to visualize morphological differences. There were significant cannabis-related parametric decreases in WM across groups. Similar cannabis-related shape differences were observed in the striatum, globus pallidus, and thalamus in controls and schizophrenia subjects. Cannabis-related striatal and thalamic shape differences correlated with poorer WM and younger age of CUD onset in both groups. Schizophrenia subjects demonstrated cannabis-related neuroanatomical differences that were consistent and exaggerated compared with cannabis-related differences found in controls. The cross-sectional results suggest that both CUD groups were characterized by WM deficits and subcortical neuroanatomical differences. Future longitudinal studies could help determine whether cannabis use contributes to these observed shape differences or whether they are biomarkers of a vulnerability to the effects of cannabis that predate its misuse. PMID- 24342823 TI - Colorectal cancer: Histopathologic differences in tumor characteristics between patients with and without diabetes. AB - BACKGROUND: Current literature suggests that diabetes is a possible predictor of risk and worse outcome in colorectal cancer (CRC). The objective of this study was to explore if there are histopathologic differences in CRC between populations with and without diabetes. PATIENTS AND METHODS: Retrospective analysis was done on 534 patients with CRC. Patients were divided into diabetic and nondiabetic subgroups. Data were collected for lymphovascular invasion, tumor location, depth invasion, staging, level of differentiation, histologic type, and presence of tumor components (mucinous, signet ring, or neuroendocrine). RESULTS: Univariately, patients with diabetes had deeper tumor invasion, greater lymphovascular invasion, and higher TNM staging (OR and 95% CI, 2.06 [1.37, 3.10], 2.52 [1.74, 3.63], and 2.45 [1.70, 3.52], respectively; P < .001). Covariate adjustment retained the significant effect of diabetes on tumor characteristics (P < .005). Multivariable adjustment significantly linked diabetes with signet ring cell carcinoma (log odds, 11.40 +/- 5.28; P = .03) and tumor components (log odds, 0.58 +/- 0.25; P = .02). Patients with diabetes with hyperlipidemia had more well-differentiated tumors (log odds, -0.96 +/- 0.47; P = .04). Transverse tumors were more common in patients with diabetes (log odds, 1.74 +/- 0.72; P = .02). CONCLUSION: Patients with diabetes had worse histopathologic CRC features. Hyperinsulinemia, insulinlike growth factor receptor activation, and hyperglycemia in diabetes can activate mitogenic pathways stimulating proliferation, invasion, angiogenesis, and metastasis. Future research is needed to identify responsible pathways for targeted therapy and to examine the role of better glycemic control and treatment in patients with CRC and diabetes. PMID- 24342824 TI - Late complication of a femoral monitoring catheter: a case of femoral false aneurysm treated surgically. AB - Femoral false aneurysms are rare. They are one of the main complications of femoral catheterization, trauma of this area, or the use of intravenous drugs. They usually occur in the days after femoral puncture, and only rarely occur years after the procedure or incident. Treatment often requires complex surgical methods. We report the management of a patient with a ruptured infected femoral false aneurysm that was diagnosed 4 years after a femoral puncture performed in intensive care unit to perform peripheral arterial catheter hemodynamic monitoring. The patient was operated with exclusion of the aneurysm and prosthetic bypass, associated with intravenous antibiotics adapted to the bacterial strain grown from the operative site, which resulted in a favorable outcome. PMID- 24342825 TI - Abdominal aortic rupture and spondylodiscitis: emergent EVAR and staged spinal fixation. AB - Concomitant aortic aneurismal pathology and vertebral erosion are seldom reported in literature. The differential diagnosis between a primary vertebral disease affecting the aortic wall and a primary aortic pathology causing a vertebral disruption is quite difficult. We report on a patient presenting with increasing lumbar pain and neurologic lower limbs deficit due to a vertebral erosion accompanied by aortic rupture treated by emergent endovascular aortic repair procedure and then staged vertebral fixation. Microbiological tests on intraoperative periaortic fluid collection samples showed no clear sign of infection and clinical conditions progressively improved. At 12-month follow-up, the patient is in good clinical condition, with a small residual walking impairment and no clinical, laboratory, or imaging sign of aortic endograft infection. PMID- 24342826 TI - Hybrid approach in a case of persistent sciatic artery aneurysm. AB - Persistent sciatic artery is a rare congenital vascular malformation with a reported incidence between 0.03% and 0.06%. An 82-yr-old woman presented to our institution with right acute lower limb ischemia compatible with a cardioembolic etiology. A popliteal embolectomy was performed to the patient, and at the end of the procedure, she had bilateral lower limb distal pulses. Six months after the procedure, the patient complained with right lower limb rest pain, an angiography and a computed tomography angiography were performed showing a sciatic artery aneurysm with 4.6 cm of diameter and patency of the sciatic artery to the popliteal artery. A femoropopliteal bypass and retrograde coil embolization of the sciatic aneurysm through the popliteal artery and distal sciatic artery ligation were performed. The patient was discharged 7 days after the procedure, and she remains asymptomatic. Our patient had a complete type of persistent sciatic artery with aneurysmatic degeneration. Correction of the distal ischemia with aneurysm exclusion was achieved with a simple noncomplicated hybrid procedure. PMID- 24342827 TI - Dissecting aneurysm of the celiac trunk: a case report. AB - Aneurysms of visceral arteries are relatively rare entities. Spontaneous isolated celiac artery dissection is an uncommon diagnosis, with only a few reported cases. We report the case of 52-year-old man who had an asymptomatic celiac trunk dissecting aneurysm detected by tomographic angiography. Because of the combined risk of rupture and ischemia, we decided to treat this lesion by a conventional bypass. PMID- 24342828 TI - Impact of regional versus general anesthesia on the clinical outcomes of patients undergoing major lower extremity amputation. AB - BACKGROUND: Patients undergoing major lower extremity amputation (MLEA) for peripheral arterial disease are often elderly, debilitated, and fraught with medical comorbid conditions that place them at high risk for surgical intervention. Data from lower extremity revascularization surgeries are often extrapolated to determine which anesthetic modality to use for amputations, with preference given to regional anesthesia. However, there is little evidence to support the use of one mode of anesthesia over another. We conducted this study to determine the effect of anesthetic modality on the clinical outcomes of patients undergoing above- or below-knee amputations. METHODS: This study is a retrospective review of consecutive patients who underwent MLEA at a single center between 2002-2011. The study population was divided into 2 groups based on anesthetic modality (i.e., regional vs. general anesthesia). These groups were compared based on demographics and comorbidities. Major outcomes analyzed included death, myocardial infarction (MI), and pulmonary complications. Secondary outcome measures included cardiac arrhythmias, venous thromboembolism (VTE), and duration of stay in the intensive care unit and hospital. RESULTS: Four hundred sixty-three patients were identified; 56 patients were excluded for incomplete data, leaving 407 patients in the 2 groups combined. Of these, 259 patients underwent amputation under regional anesthesia; 148 underwent amputation under general anesthesia. Patients in the regional anesthesia group were older (76.6 vs. 71.6 years; P=0.001) and had a lower body mass index (25.2 vs. 26.9 kg/m2; P=0.013). They were also less likely to be on preoperative antiplatelet therapy (aspirin or clopidogrel) or anticoagulation (27% vs. 45%; P<0.001). Regional anesthesia was associated with a lower incidence of overall postoperative pulmonary complications (15% vs. 24%; P=0.02) and postoperative arrhythmia (14% vs. 25%; P=0.001). Duration of stay in the intensive care unit (1.92 vs. 3.85 days; P=0.001) and hospital (19.4 vs 23.1 days; P=0.037) were significantly longer in the group receiving general anesthesia. No significant differences in postoperative MI (12% vs. 9%; P=not significant [NS]), VTE (5% vs. 7%; P=NS) or mortality (10% vs. 13%; P=NS) was seen between groups. Controlling for procedure, above- versus below-knee amputation did not significantly alter these results. CONCLUSIONS: Regional anesthesia for patients undergoing MLEA is associated with a lower incidence of postoperative pulmonary complications and cardiac arrhythmias. It is also associated with lower resource use. As such, regional anesthesia should likely be the favored anesthetic modality for patients undergoing MLEA. PMID- 24342829 TI - Morphometric analysis of thoracic ganglion neurons in subjects with and without primary palmar hyperhidrosis. AB - BACKGROUND: Hyperhidrosis (HH) is a disease whose physiopathology remains poorly understood and that adversely affects quality of life. There is no morphologic study that includes an adequate control group that allows for comparison of the ganglion of HH to those of normal individuals. The purpose of study was to analyze morphologic and morphometric characteristics of the ganglion from patients with HH and normal individuals (organ donators). METHODS: This was a transversal study. The sympathetic thoracic ganglia were obtained from 2 groups of patients. Group PH (palmar hyperhidrosis), 40 patients with palmar HH submitted to surgery by video-assisted thoracoscopy, and group C (control group), 14 deceased individuals (control group of organ donators) without any history of HH. The third left sympathetic thoracic ganglion was resected in all patients. RESULTS: We observed higher number of cells in the PH group than in the control group (14.25 + 3.81 vs. 10.65 + 4.93) with P = 0.007; the mean percentage of ganglion cells stained by caspases-3 in the PH group was significantly greater than that of the C group (2.37 + 0.79 vs. 0.77 + 0.28) with P < 0.001; the mean value of area of collagen in the PH group was 0.80 IQ (0.08-1.87), and in the control group it was 2.36 IQ (0.49-5.98) with P = 0.061. CONCLUSIONS: Subjects with primary palmar HH have a higher number of ganglion cells within the ganglion and a higher number of cells in apoptosis. Also, the subjects of PH group have less collagen in the sympathetic ganglion when compared with the control group, but not statistically significant. PMID- 24342830 TI - Endovascular treatment for intermittent claudication in patients with peripheral arterial disease: a systematic review. AB - BACKGROUND: We performed a systematic review and meta-analysis to examine whether patients with intermittent claudication can benefit from endovascular treatment (EVT). METHODS: A prespecified search strategy was used to identify relevant studies in the MEDLINE, Embase, and Cochrane databases. A total of 10 different randomized, controlled trials were reviewed. Random effects meta-analysis was performed between the EVT plus conservative treatment (CT) group and the CT group alone. Also, random effects meta-analysis was performed between the EVT group and the supervised exercise therapy (SET) group. RESULTS: The independent effect of EVT could directly improve the ankle-brachial index (ABI) and walking performance over the short term, but not over the long term. Moreover, compared to SET, EVT had the superiority in improving the ABI, while SET could improve walking performance more efficiently. CONCLUSIONS: Patients with intermittent claudication may benefit from endovascular treatment over the short term (within 12 months), with improvements in ABI, intermittent claudication distance, and maximum walking distance. However, considering improvements on walking performance (especially over the long term), SET is recommended. PMID- 24342831 TI - Mucormycosis: a rare complication of an amputation. AB - Mucormycosis is a rare but serious opportunistic fungal infection. Several clinical forms have been described, including cutaneous localization that is frequently associated with soft tissue trauma or burns. We report a case of cutaneous mucormycosis in a diabetic patient with severe occlusive arterial disease. The diagnosis was made early with mold growth on an amputation wound and the presence of nonseptate hyphae on direct microscopic examination, later identified on culture as Lichtheimia ramosa. Aggressive treatment, including the control of underlying diseases, systemic and local amphotericin B, and extensive surgical debridement permitted successful outcomes. PMID- 24342832 TI - Dichloroacetate attenuates hypoxia-induced resistance to 5-fluorouracil in gastric cancer through the regulation of glucose metabolism. AB - In this study, we investigated whether gastric cancer with hypoxia-induced resistance to 5-fluorouracil (5-FU) could be re-sensitized following treatment with low-dose dichloroacetate (DCA), an inhibitor of the glycolytic pathway. The expression profiles of hypoxia-inducible factor-1alpha (HIF-1alpha) and pyruvate dehydrogenase kinase-1 (PDK-1) were analyzed in tissues from 10 patients with gastric cancer who had different responses to adjuvant 5-FU treatment. For the in vitro assays, cell viability and apoptosis were evaluated with and without treatment with 20mM DCA in the AGS and MKN45 cell lines, as well as in PDK1 knockdown cell lines. The expression levels of HIF-1alpha and PDK-1 were both elevated in the tumor tissues relative to the normal gastric tissues of most patients who showed recurrence after adjuvant 5-FU treatment. Cellular viability tests showed that these cell lines had a lower sensitivity to 5-FU under hypoxic conditions compared to normoxic conditions. Moreover, the addition of 20mM DCA only increased the sensitivity of these cells to 5-FU under hypoxic conditions, and the resistance to 5-FU under hypoxia was also attenuated in PDK1 knockdown cell lines. In conclusion, DCA treatment was able to re-sensitize gastric cancer cells with hypoxia-induced resistance to 5-FU through the alteration of glucose metabolism. PMID- 24342833 TI - beta-catenin is O-GlcNAc glycosylated at Serine 23: implications for beta catenin's subcellular localization and transactivator function. AB - BACKGROUND: We have previously reported that beta-catenin is post-translationally modified with a single O-linked attachment of beta-N-acetyl-glucosamine (O GlcNAc). We showed that O-GlcNAc regulated beta-catenin's subcellular localization and transcriptional activity. OBJECTIVE: The objectives of this investigation were to identify the putative O-GlcNAc sites of beta-catenin and the relevance of identified sites in the regulation of beta-catenin's localization and transcriptional activity. METHOD: Missense mutations were introduced to potential O-GlcNAc sites of pEGFP-C2-N-Terminal- or pEGFP-C2-Wild Type-beta-catenin by site-directed mutagenesis. We determined the levels of O GlcNAc-beta-catenin, subcellular localization, interaction with binding partners and transcriptional activity of the various constructs. RESULTS: Serine 23 of beta-catenin was determined as a site for O-GlcNAc modification which regulated its subcellular distribution, its interactions with cellular partners and consequently its transcriptional activity. SIGNIFICANCE: O-GlcNAcylation of Serine 23 is a novel regulatory modification for beta-catenin's subcellular localization and transcriptional activity. This study is the first report to characterize site specific regulation of beta-catenin by the O-GlcNAc modification. PMID- 24342834 TI - The legacy of development and psychopathology. PMID- 24342835 TI - Developmental psychopathology: a paradigm shift or just a relabeling? AB - Developmental psychopathology is described as a conceptual approach that involves a set of research methods that capitalize on developmental and psychopathological variations to ask questions about mechanisms and processes. Achievements are described in relation to attachment and attachment disorders, autism, schizophrenia, childhood antecedents of adult psychopathology, testing for environmental mediation of risk effects, gene-environment interplay, intellectual and language functioning, effects of mentally ill parents on the children, stress and vulnerability to depression, ethnicity and schizophrenia, and drug response. Continuities and discontinuities over the course of development are discussed in relation to attention-deficit/hyperactivity disorder, antisocial behavior, eating disorders, substance abuse and dependency, pharmacological and behavioral addictions, and a range of other disorders. Research challenges are considered in relation to spectrum concepts, the adolescent development of a female preponderance for depression, the mechanisms involved in age differences in response to drugs and to lateralized brain injury, the processing of experiences, the biological embedding of experiences, individual differences in response to environmental hazards, nature-nurture integration, and brain plasticity. PMID- 24342836 TI - The promise of developmental psychopathology: past and present. AB - Progress in the field of developmental psychopathology is appraised in general and with regard to the particular lens of our understanding of the development of disorder. In general, the outpouring of research on various features of disorder and underlying processes could not have even been imagined 25 years ago. The progress is dazzling. At the same time, work on the development of disorders, beginning with antecedent patterns of adaptation, pales in comparison with work on the correlates of disorder. However, progress has been made. It is well established that the brain develops in the context of experience and that organism and environment continually interact over time. Something is now known about pathways leading to certain disorders and what initiates and impels individuals along them. If developmental psychopathology is to completely fulfill its promise of offering new ways of conceptualizing disorder and new guidance for prevention and intervention, much more work on developmental processes and a new way of exploring the development of disorder will be needed. Such a path is suggested. PMID- 24342837 TI - Behavior genetics: past, present, future. AB - The disciplines of developmental psychopathology and behavior genetics are concerned with many of the same questions about the etiology and course of normal and abnormal behavior and about the factors that promote typical development despite the presence of risk. The goal of this paper is to summarize how research in behavior genetics has shed light on questions that are central to developmental psychopathology. We briefly review the origins of behavior genetics, summarize the findings that have been gleaned from several decades of quantitative and molecular genetics research, and describe future directions for research that will delineate gene function as well as pathways from genes to brain to behavior. The importance of environmental contributions, at both genetic and epigenetic levels, will be discussed. We conclude that behavior genetics has made significant contributions to developmental psychopathology by documenting the interplay among risk and protective factors at multiple levels of the organism, by clarifying the causal status of risk exposures, and by identifying factors that account for change and stability in psychopathology. As the tools to identify gene function become increasingly sophisticated, and as behavioral geneticists become increasingly interdisciplinary in their scope, the field is poised to make ever greater contributions to our understanding of typical and atypical development. PMID- 24342838 TI - Beyond risk, resilience, and dysregulation: phenotypic plasticity and human development. AB - We provide a theoretical and empirical basis for the claim that individual differences exist in developmental plasticity and that phenotypic plasticity should be a subject of study in its own right. To advance this argument, we begin by highlighting challenges that evolutionary thinking poses for a science of development and psychopathology, including for the diathesis-stress framework that has (fruitfully) guided so much empirical inquiry on developmental risk, resilience, and dysregulation. With this foundation laid, we raise a series of issues that the differential-susceptibility hypothesis calls attention to, while highlighting findings that have emerged over just the past several years and are pertinent to some of the questions posed. Even though it is clear that this new perspective on Person * Environment interaction is stimulating research and influencing how hypotheses are framed and data interpreted, a great many topics remain that need empirical attention. Our intention is to encourage students of development and psychopathology to treat phenotypic plasticity as an individual difference construct while exploring unknowns in the differential-susceptibility equation. PMID- 24342841 TI - A translational neuroscience framework for the development of socioemotional functioning in health and psychopathology. AB - The development of socioemotional functioning is a complex process that occurs over a protracted time period and requires coordinating affective, cognitive, and social faculties. At many points in development, the trajectory of socioemotional development can be deleteriously altered due to a combination of environmental insults and individual vulnerabilities. The result can be psychopathology. However, researchers are just beginning to understand the neural and genetic mechanisms involved in the development of healthy and disordered socioemotional functioning. We propose a translational developmental neuroscience framework to understand the transactional process that results in socioemotional functioning in both healthy and disordered populations. We then apply this framework to healthy socioemotional development, pediatric anxiety, pediatric depression, and autism spectrum disorder, selectively reviewing current literature in light of the framework. Finally, we examine ways that the framework can help to frame future directions of research on socioemotional development and translational implications for intervention. PMID- 24342839 TI - The future of genomics for developmentalists. AB - The momentum of genomic science will carry it far into the future and into the heart of research on typical and atypical behavioral development. The purpose of this paper is to focus on a few implications and applications of these advances for understanding behavioral development. Quantitative genetics is genomic and will chart the course for molecular genomic research now that these two worlds of genetics are merging in the search for many genes of small effect. Although current attempts to identify specific genes have had limited success, known as the missing heritability problem, whole-genome sequencing will improve this situation by identifying all DNA sequence variations, including rare variants. Because the heritability of complex traits is caused by many DNA variants of small effect in the population, polygenic scores that are composites of hundreds or thousands of DNA variants will be used by developmentalists to predict children's genetic risk and resilience. The most far-reaching advance will be the widespread availability of whole-genome sequence for children, which means that developmentalists would no longer need to obtain DNA or to genotype children in order to use genomic information in research or in the clinic. PMID- 24342840 TI - Epigenetic mechanisms in the development of behavior: advances, challenges, and future promises of a new field. AB - In the past decade, there have been exciting advances in the field of behavioral epigenetics that have provided new insights into a biological basis of neural and behavioral effects of gene-environment interactions. It is now understood that changes in the activity of genes established through epigenetic alterations occur as a consequence of exposure to environmental adversity, social stress, and traumatic experiences. DNA methylation in particular has thus emerged as a leading candidate biological pathway linking gene-environment interactions to long-term and even multigenerational trajectories in behavioral development, including the vulnerability and resilience to psychopathology. This paper discusses what we have learned from research using animal models and from studies in which the translation of these findings has been made to humans. Studies concerning the significance of DNA methylation alterations in outcomes associated with stress exposure later in life and dysfunction in the form of neuropsychiatric disorders are highlighted, and several avenues of future research are suggested that promise to advance our understanding of epigenetics both as a mechanism by which the environment can contribute to the development of psychiatric disorders and as an avenue for more effective intervention and treatment strategies. PMID- 24342842 TI - Coping with complexity: developmental systems and multilevel analyses in developmental psychopathology. AB - Developmental psychopathology is not characterized by adherence to one specific theory but instead serves as an organizational framework in which research is driven by a number of key assumptions. In the developmental psychopathology approach, two primary assumptions emphasize the importance of systems thinking and the utility of multilevel analyses. As will be illustrated here, these emphases are inextricably linked: a systems approach necessitates a multilevel approach, such that a level of organization must bring coherence to a level of mechanisms. Given this assumption, coming to an integrative understanding of the relation between levels is of central importance. One broad framework for this endeavor is relational developmental systems, which has been proposed by certain theorists as a new paradigm for developmental science. The implications of embracing this framework include the potential to connect developmental psychopathology with other approaches that emphasize systems thinking and that take an integrative perspective on the problem of levels of analysis. PMID- 24342844 TI - Thinking clearly about the endophenotype-intermediate phenotype-biomarker distinctions in developmental psychopathology research. AB - The endophenotype is central to modern developmental psychopathology studies. It is used in studies seeking to connect the genetic substrates of the panoply of major mental disorders with processes, tapped by laboratory and other assessment measures, in the genotype to a behavior/psychopathology pathway. Proposed originally by Gottesman and Shields (1972; Shields & Gottesman, 1973) 41 years ago, the endophenotype concept has gained widespread traction in psychopathology research since the Gottesman and Gould (2003) review. Other concepts broadly related to the endophenotype notion have also generated discussion in experimental and developmental psychopathology research. One is the intermediate phenotype, a concept proffered as a putative alternative formulation to the endophenotype. Another concept in this intellectual vein is biomarker. The terms endophenotype, intermediate phenotype, and biomarker have often been used interchangeably in the psychiatric literature, yielding conceptual confusion. However, these three terms are not fungible. The recent Research Domain Criteria proposal from the National Institute of Mental Health has emphasized selected underlying processes thought to be of developmental etiologic significance to psychopathology. These selected processes will be the focus of energetic future research efforts, many of which will make use of the endophenotype and biomarker research paradigms. In this context, the concepts of endophenotype, intermediate phenotype, and biomarker are examined critically and contrasted in terms of meaning, intention, clarity, and intellectual history. This analysis favors use of the endophenotype concept in genetically informed laboratory and neuroscience studies of psychopathology. The term intermediate phenotype is perhaps best restricted to its originally defined meaning in genetics. Biomarker is used to denote objectively measured biological antecedents or consequences of normal or pathogenic processes or a physiologic response to a therapeutic intervention. PMID- 24342846 TI - A roadmap for the integration of culture into developmental psychopathology. AB - In this paper, I propose a roadmap for the integration of culture in developmental psychopathology. This integration is pressing because culture continues to be somewhat disconnected from theory, research, training, and interventions in developmental psychopathology, thus limiting our understanding of the epigenesis of mental health. I argue that in order to successfully integrate culture into developmental psychopathology, it is crucial to (a) study cultural development, (b) consider both individual-level and social-level cultural processes, (c) examine the interplay between culture and biology, and (d) promote improved and direct cultural assessment. I provide evidence in support of each of these guidelines, present alternative conceptual frameworks, and suggest new lines of research. Hopefully, that these directions will contribute to the emerging field of cultural development and psychopathology, which focuses on the elucidation of the cultural processes that initiate, maintain, or derail trajectories of normal and abnormal behavior. PMID- 24342843 TI - Adolescent brain development in normality and psychopathology. AB - Since this journal's inception, the field of adolescent brain development has flourished, as researchers have investigated the underpinnings of adolescent risk taking behaviors. Explanations based on translational models initially attributed such behaviors to executive control deficiencies and poor frontal lobe function. This conclusion was bolstered by evidence that the prefrontal cortex and its interconnections are among the last brain regions to structurally and functionally mature. As substantial heterogeneity of prefrontal function was revealed, applications of neuroeconomic theory to adolescent development led to dual systems models of behavior. Current epidemiological trends, behavioral observations, and functional magnetic resonance imaging based brain activity patterns suggest a quadratic increase in limbically mediated incentive motivation from childhood to adolescence and a decline thereafter. This elevation occurs in the context of immature prefrontal function, so motivational strivings may be difficult to regulate. Theoretical models explain this patterning through brain based accounts of subcortical-cortical integration, puberty-based models of adolescent sensation seeking, and neurochemical dynamics. Empirically sound tests of these mechanisms, as well as investigations of biology-context interactions, represent the field's most challenging future goals, so that applications to psychopathology can be refined and so that developmental cascades that incorporate neurobiological variables can be modeled. PMID- 24342845 TI - Stress physiology and developmental psychopathology: past, present, and future. AB - Research on the hypothalamic-pituitary-adrenocortical (HPA) axis has emerged as a vital area within the field of developmental psychopathology in the past 25 years. Extensive animal research has provided knowledge of the substrates and physiological mechanisms that guide development of stress reactivity and regulation using methods that are not feasible in humans. Recent advances in understanding the anatomy and physiology of the HPA axis in humans and its interactions with other stress-mediating systems, including accurate assessment of salivary cortisol, more sophisticated neuroimaging methods, and a variety of genetic analyses, have led to greater knowledge of how psychological and biological processes impact functioning. A growing body of research on HPA axis regulation and reactivity in relation to psychopathology has drawn increased focus on the prenatal period, infancy, and the pubertal transition as potentially sensitive periods of stress system development in children. Theories such as the allostatic load model have guided research by integrating multiple physiological systems and mechanisms by which stress can affect mental and physical health. However, almost none of the prominent theoretical models in stress physiology are truly developmental, and future work must incorporate how systems interact with the environment across the life span in normal and atypical development. Our theoretical advancement will depend on our ability to integrate biological and psychological models. Researchers are increasingly realizing the importance of communication across disciplinary boundaries in order to understand how experiences influence neurobehavioral development. It is important that knowledge gained over the past 25 years has been translated to prevention and treatment interventions, and we look forward to the dissemination of interventions that promote recovery from adversity. PMID- 24342847 TI - A biopsychosocial perspective on parenting and developmental psychopathology. AB - Although considerable research has examined the relations between parental behavior and a range of child developmental outcomes, much of this work has been conducted at a very broad level of behavioral analysis. A developmental psychopathology framework and recent research conducted within this framework point to the need for models of parenting and child psychopathology that offer greater specificity regarding processes that may be implicated in the effects of these relationships. In addition, recent animal work and some human work has focused more on the proximal biological and social mechanisms through which parenting affects child outcomes. Our conceptualization of parenting effects acknowledges that family and child factors are embedded in a dynamic biological and social context that is key to understanding developmental trajectories of child adjustment. In this paper, we review two areas of research that are illuminating the biological processes underlying links between parenting and child psychopathology: molecular genetics and psychophysiology. We adopt a biopsychosocial perspective on developmental psychopathology that implies that a set of hierarchically organized, but reciprocally interacting, processes, from the genetic to the environmental, provide the essential elements of both normative and nonnormative development (Gottlieb, 2007). New directions stimulated by this general approach are discussed, with an emphasis on the contextual and developmental issues and applications implied by such a perspective. PMID- 24342849 TI - The reformulation of emotional security theory: the role of children's social defense in developmental psychopathology. AB - Although children's security in the context of the interparental relationship has been identified as a key explanatory mechanism in pathways between family discord and child psychopathology, little is known about the inner workings of emotional security as a goal system. Thus, the objective of this paper is to describe how our reformulation of emotional security theory within an ethological and evolutionary framework may advance the characterization of the architecture and operation of emotional security and, in the process, cultivate sustainable growing points in developmental psychopathology. The first section of the paper describes how children's security in the interparental relationship is organized around a distinctive behavioral system designed to defend against interpersonal threat. Building on this evolutionary foundation for emotional security, the paper offers an innovative taxonomy for identifying qualitatively different ways children try to preserve their security and its innovative implications for more precisely informing understanding of the mechanisms in pathways between family and developmental precursors and children's trajectories of mental health. In the final section, the paper highlights the potential of the reformulation of emotional security theory to stimulate new generations of research on understanding how children defend against social threats in ecologies beyond the interparental dyad, including both familial and extrafamilial settings. PMID- 24342848 TI - Contributions of attachment theory and research: a framework for future research, translation, and policy. AB - Attachment theory has been generating creative and impactful research for almost half a century. In this article we focus on the documented antecedents and consequences of individual differences in infant attachment patterns, suggesting topics for further theoretical clarification, research, clinical interventions, and policy applications. We pay particular attention to the concept of cognitive "working models" and to neural and physiological mechanisms through which early attachment experiences contribute to later functioning. We consider adult caregiving behavior that predicts infant attachment patterns, and the still mysterious "transmission gap" between parental Adult Attachment Interview classifications and infant Strange Situation classifications. We also review connections between attachment and (a) child psychopathology; (b) neurobiology; (c) health and immune function; (d) empathy, compassion, and altruism; (e) school readiness; and (f) culture. We conclude with clinical-translational and public policy applications of attachment research that could reduce the occurrence and maintenance of insecure attachment during infancy and beyond. Our goal is to inspire researchers to continue advancing the field by finding new ways to tackle long-standing questions and by generating and testing novel hypotheses. PMID- 24342850 TI - A quarter century of progress on the early detection and treatment of autism spectrum disorder. AB - The last 25 years have witnessed tremendous changes in our ability to detect autism very early in life and provide interventions that can significantly influence children's outcomes. It was once questioned whether autism could be recognized before children had developed language and symbolic play skills; now changes in early behaviors, as well as structural brain changes, have been documented in infants 6-12 months of age who later develop autism. Advances in brain imaging and genetics offer the possibility of detecting autism before the syndrome is fully manifest, thereby reducing or preventing symptoms from developing. Whereas the primary mode of behavioral intervention a few decades ago relied on operant conditioning, recent approaches integrate the methods of applied behavioral analysis within a developmental, relationship-focused intervention model that are implemented by both parents and clinicians. These interventions have been found to have positive effects on children's developmental trajectory, as measured by both behavioral and neurophysiological assessments. Future approaches will likely combine both behavioral and pharmacological treatments for children who have less robust responses to behavioral interventions. There has been a paradigm shift in the way that autism is viewed, evolving from a lifelong condition with a very poor prognosis to one in which significant gains and neuroplasticity is expected, especially when the condition is detected early and appropriate interventions are provided. The grand challenge for the future is to bridge the tremendous gap between research and the implementation of evidence-based practices in the broader community, both in the United States and worldwide. Significant disparities in access to appropriate health care for children with autism exist that urgently require advocacy and more resources. PMID- 24342851 TI - The developmental psychopathology of irritability. AB - Chronic, severe irritability is common in childhood and is very impairing. Furthermore, childhood irritability predicts suicidality, social impairment, and depressive and anxiety disorders in adulthood. Focusing on both normative and pathologic development, we review the construct of irritability from its origins in aggression and disruptive behavior research to its contemporary relevance for affective psychopathology. We then describe two broad neurocognitive systems that show promise in differentiating irritable from nonirritable youths: aberrant processing of emotional stimuli and impaired context-sensitive regulation. We suggest behavioral, neurocognitive, and physiologic measures that may aid in studying severe irritability and assessing its therapeutics. Finally, we argue for therapeutic trials targeting severe irritability that address emotional aspects of irritability in addition to the associated disruptive behavior. PMID- 24342852 TI - Attention deficits and hyperactivity-impulsivity: what have we learned, what next? AB - The domains of self-regulation, self-control, executive function, inattention, and impulsivity cut across broad swathes of normal and abnormal development. Attention-deficit/hyperactivity disorder is a common syndrome that encompasses a portion of these domains. In the past 25 years research on attention deficit/hyperactivity disorder has been characterized by dramatic advances in genetic, neural, and neuropsychological description of the syndrome as well as clarification of its multidimensional phenotypic structure. The limited clinical applicability of these research findings poses the primary challenge for the next generation. It is likely that clinical breakthroughs will require further refinement in describing heterogeneity or clinical/biological subgroups, renewed focus on the environment in the form of etiological events as well as psychosocial contexts of development, and integration of both with biological understanding. PMID- 24342854 TI - "I can, therefore I must": fragility in the upper-middle classes. AB - We review evidence on a group recently identified as "at risk," that is, youth in upwardly mobile, upper-middle class community contexts. These youngsters are statistically more likely than normative samples to show serious disturbance across several domains including drug and alcohol use, as well as internalizing and externalizing problems. Extant data on these problems are reviewed with attention to gender-specific patterns, presenting quantitative developmental research findings along with relevant evidence across other disciplines. In considering possible reasons for elevated maladjustment, we appraise multiple pathways, including aspects of family dynamics, peer norms, pressures at schools, and policies in higher education. All of these pathways are considered within the context of broad, exosystemic mores: the pervasive emphasis, in contemporary American culture, on maximizing personal status, and how this can threaten the well-being of individuals and of communities. We then discuss issues that warrant attention in future research. The paper concludes with suggestions for interventions at multiple levels, targeting youth, parents, educators, as well as policymakers, toward reducing pressures and maximizing positive adaptation among "privileged but pressured" youth and their families. PMID- 24342855 TI - Opportunities and challenges to the development of healthy children and youth living in diverse communities. AB - The field of developmental psychopathology has seen growth in research focusing on interdisciplinarity and normative developmental processes, including context linked coping and adaptations. However, there continues to be an uncomfortable and unarticulated perspective to view others as having culture and "the self" as representing the standard. A call for explicit cultural considerations in research is needed to augment the impact of these new and other significant conceptual contributions noted. Sociopolitical influences on social contexts relevant to the different trajectories associated with youths' opportunities and challenges are presented. We focus on macrolevel factors that frame contexts in which individual development occurs. A federal and educational policy is used to illustrate how unexamined cultural traditions and patterns embedded in research and policy impact development. These examples provide insight in presenting issues of vulnerability, particularly for youth, and afford opportunities to present advances and challenges paralleled in the developmental psychopathology field. PMID- 24342853 TI - Comorbidities and continuities as ontogenic processes: toward a developmental spectrum model of externalizing psychopathology. AB - Research on child and adolescent mental health problems has burgeoned since the inaugural issue of Development and Psychopathology was published in 1989. In the quarter century since, static models of psychopathology have been abandoned in favor of transactional models, following the agenda set by editor Dante Cicchetti and other proponents of the discipline. The transactional approach, which has been applied to autism, depression, self-injury, and delinquency, (a) specifies vulnerabilities and risk factors across multiple levels of analysis spanning genes to cultures, (b) identifies multifinal and equifinal pathways to psychopathology, and (c) transcends traditional disciplinary boundaries. However, as noted by Rutter and Sroufe (2000), specific mechanisms of continuity, discontinuity, and comorbidity of psychopathology must be identified if we wish to understand etiology fully. In this article, we present a model of early-onset externalizing behavior in which comorbidities and continuities are viewed as ontogenic processes: products of complex longitudinal transactions between interdependent individual-level vulnerabilities (e.g., genetic, epigenetic, allostatic) and equally interdependent contextual risk factors (e.g., coercive parenting, deviant peer group affiliations, neighborhood criminality). Through interactions across levels of analysis, some individuals traverse along the externalizing spectrum, beginning with heritable trait impulsivity in preschool and ending in antisociality in adulthood. In describing our model, we note that (a) the approach outlined in the DSM to subtyping externalizing disorders continues to obscure developmental pathways to antisociality, (b) molecular genetics studies will likely not identify meaningful subtypes of externalizing disorder, and (c) ontogenic trait approaches to psychopathology are much more likely to advance the discipline in upcoming years. PMID- 24342856 TI - The developmental psychopathology of alcohol use and alcohol disorders: research achievements and future directions. AB - The last 25 years have seen significant advances in our conceptualization of alcohol use and alcohol use disorders within a developmental framework, along with advances in our empirical understanding that have been potentiated by advances in quantitative methods. These include advances in understanding the heterogeneity of trajectories of alcohol outcomes; new insights about early childhood antecedents, and adolescence and emerging adulthood as important developmental periods for alcohol outcomes; a more nuanced understanding of the influences of developmental transitions, and their timing and contexts; a greater appreciation for the importance of considering multiple levels of analysis (including an increasing number of genetically informative studies); a continuing focus on studying multiple pathways underlying alcohol outcomes; and an increasing focus on studying the effects of alcohol exposure on future development. The current paper reviews these advances and suggests directions for future study. PMID- 24342857 TI - Developmental mechanisms in the prodrome to psychosis. AB - Psychotic disorders continue to be among the most disabling and scientifically challenging of all mental illnesses. Accumulating research findings suggest that the etiologic processes underlying the development of these disorders are more complex than had previously been assumed. At the same time, this complexity has revealed a wider range of potential options for preventive intervention, both psychosocial and biological. In part, these opportunities result from our increased understanding of the dynamic and multifaceted nature of the neurodevelopmental mechanisms involved in the disease process, as well as the evidence that many of these entail processes that are malleable. In this article, we review the burgeoning research literature on the prodrome to psychosis, based on studies of individuals who meet clinical high risk criteria. This literature has examined a range of factors, including cognitive, genetic, psychosocial, and neurobiological. We then turn to a discussion of some contemporary models of the etiology of psychosis that emphasize the prodromal period. These models encompass the origins of vulnerability in fetal development, as well as postnatal stress, the immune response, and neuromaturational processes in adolescent brain development that appear to go awry during the prodrome to psychosis. Then, informed by these neurodevelopmental models of etiology, we turn to the application of new research paradigms that will address critical issues in future investigations. It is expected that these studies will play a major role in setting the stage for clinical trials aimed at preventive intervention. PMID- 24342858 TI - Relational interventions for child maltreatment: past, present, and future perspectives. AB - It is well established that child maltreatment has significant deleterious effects for the individual as well as for society. We briefly review research regarding the impact of child maltreatment on the attachment relationship, highlighting the need for relational interventions for maltreated children and their families to effectively thwart negative developmental cascades that are so often observed in the context of child maltreatment. Next, historical and contemporaneous perspectives on relational interventions for individuals with histories of child maltreatment are discussed, with attention to the empirical evidence for and the current evidence-based status of several relationally based interventions for child maltreatment. Differential sensitivity to the environment is then discussed as a theoretical framework with important implications for interventions for individuals who have been reared in maltreating environments. Current research on neurobiology and maltreatment is then reviewed, with an emphasis on the need for future investigations on genetic variants, epigenetics, and the efficacy of relational interventions for maltreated children. We conclude with a discussion of the tenets of developmental psychopathology, their implications for relational interventions for child maltreatment, and recommendations for advancing the development, provision, and evaluation of relational interventions for individuals with histories of child maltreatment. PMID- 24342861 TI - Neonatal epilepsy and underlying aetiology: to what extent do seizures and EEG abnormalities influence outcome? AB - Neonatal seizures constitute the most common and distinctive sign of neurological dysfunction in the first weeks of life and reflect a wide variety of underlying central nervous system disorders. Acute symptomatic seizures occur more often during the neonatal period than at any period of life and are associated with adverse long-term neurodevelopmental sequelae and an increased risk of post neonatal epilepsy. The improvements of neonatal care in the last decades have changed the spectrum of insults to which the immature brain is exposed and facilitated a decrease in mortality of newborns with seizures. However, the prevalence of long-term morbidity in survivors remains unchanged. Whereas aetiology is presumed to be the main predictor of long-term outcome in neonates with seizures, there is converging evidence that specific electroencephalographic (EEG) abnormalities are related to unfavourable outcomes. Interictal EEG abnormalities, especially concerning background activity patterns, thus constitute a major indicator of disease severity and predictor of outcome, while the added value of sequential EEG assessments is so far controversial. Moreover, experimental as well as clinical studies of hypoxic-ischaemic encephalopathy support the notion that recurrent seizures may amplify injury to the developing brain beyond that associated with the underlying aetiology, thus justifying antiepileptic drug treatment. To date, unresolved issues in seizure detection and classification, in addition to the significant variation in gestational ages and brain insults of neonates, still impede clinical research of neonatal seizures. The wider use of long-term EEG or amplitude integrated EEG monitoring may prove crucial for timely neonatal seizure identification and treatment initiation, and thus ultimately improve outcome. PMID- 24342860 TI - Rethinking evidence-based practice and two-generation programs to create the future of early childhood policy. AB - Half a century of research and program evaluation has fueled a diverse landscape of early childhood policies and practices that produce a range of positive effects on the life prospects of children who face the burdens of significant adversity. Drawing on advances in neurobiology, developmental psychology, developmental psychopathology, and prevention science, this paper presents a framework for elucidating underlying causal mechanisms that explain differences in outcomes, formulating enhanced theories of change about how to shift developmental trajectories, designing creative interventions and rethinking the concept of a two-generation strategy to produce breakthrough impacts, and launching a new era of investment in young children and their families that will achieve greater reductions in intergenerational disparities in learning, behavior, and health than those produced by current best practices. Particular attention is focused on the hypothesis that substantially better outcomes for vulnerable, young children could be achieved by greater attention to strengthening the resources and capabilities of the adults who care for them rather than by continuing to focus primarily on the provision of child-focused enrichment, parenting education, and informal support. Central to achieving this goal is the need to establish an innovation-friendly environment that embraces fast-cycle sharing, supports risk taking, and celebrates learning from failure. PMID- 24342862 TI - Predictive factors of ictal SPECT findings in paediatric patients with focal cortical dysplasia. AB - AIMS: To identify variables that influence the extent of ictal single-photon emission computed tomography (SPECT) findings in paediatric patients with focal cortical dysplasia (FCD). METHODS: We visually evaluated 98 ictal SPECT studies from 67 children treated surgically for intractable epilepsy caused by FCD. SPECT findings were classified as "non-localised", "well-localised", and "extensive" and compared with parameters of injected seizures (seizure type and duration, injection time, and scalp EEG ictal pattern), presence of structural pathology on MRI, type of surgery performed after SPECT study, and histological findings. RESULTS: A shorter injection time and duration of injected seizure was associated with more localised SPECT hyperperfusion. SPECT findings were not significantly influenced by type of injected seizure. Widespread ictal scalp EEG patterns were associated with extensive SPECT findings. Larger zones of hyperperfusion were more common in patients with lesional MRI and patients undergoing multilobar resections. SPECT studies demonstrating good localisation were more common in patients with mild malformations of cortical development. CONCLUSION: Early ictal SPECT radiotracer injection is crucial for successful localisation of the epileptogenic zone. Seizure duration, type of scalp EEG findings, and presence of structural pathology on MRI may influence the extent of ictal SPECT hyperperfusion, which was associated with certain types of epilepsy surgery as well as histopathological findings. PMID- 24342863 TI - Posterior reversible encephalopathy syndrome as the first presentation of chronic kidney disease. AB - Posterior reversible encephalopathy syndrome is a clinicoradiologic syndrome characterized by seizure, headache, nausea, vomiting, altered mental status, visual disturbance, or visual loss, together with radiologic findings. Herein we reported a patient who was a 27-year-old foreign workman brought to the emergency ward with blurred vision in both eyes, neck pain, somnolence, and altered mental status. He had no known medical or family history. On his physical examination, his blood pressure was 190/100 mmHg and visual acuity of both eyes was decreased (visual acuity = 20/40 for both eyes). Although blood pressure was controlled by intravenous labetalol bolus, his symptoms did not improve. The result of his brain computed tomographic scan was normal, but in the brain magnetic resonance imaging, there were hyperintensities in the occipital lobe and right cerebellar hemisphere, suggesting posterior reversible encephalopathy syndrome. The findings from a complete blood count, biochemical testing, and renal, pelvic and abdominal ultrasound and also the calculated glomerular filtration rate values revealed that all were in favor of chronic kidney disease (hemoglobin level, 10.3 mg/dL; blood urea nitrogen, 90 mg/dL; Cr, 6.8 mg/dL; potassium, 5 mEq/L; sodium, 140 mEq/L; Cockcroft-Gault glomerular filtration rate, 15; weight, 65 kg). The hemodialysis was performed by which the sign and symptoms and radiologic findings resolved within 24 hours. Although PRES is described to be in association with many medical conditions, as mentioned in many available articles, we came to a conclusion that PRES could be the first presentation of a condition such as chronic kidney disease in our case. PMID- 24342864 TI - The evaluation of acute vision loss: central serous chorioretinopathy. AB - Acute vision loss is frightening to patients and may represent serious pathology that is irreversible if not intervened upon quickly. We present a case of a 36 year-old man with sudden onset of unilateral painless central visual disturbance described as flashes of light. His emergency department examination was normal, and an ophthalmologic consult found fluid accumulation in the subretinal space on optical coherence tomography, confirming a diagnosis of central serous chorioretinopathy. Central serous chorioretinopathy is a poorly understood disease associated with type A personality and elevated glucocorticoids. Although there is no proven treatment regimen for acute disease, vision problems usually resolve. Some patients have recurrent episodes that can lead to permanent visual loss PMID- 24342859 TI - Childhood exposure to violence and lifelong health: clinical intervention science and stress-biology research join forces. AB - Many young people who are mistreated by an adult, victimized by bullies, criminally assaulted, or who witness domestic violence react to this violence exposure by developing behavioral, emotional, or learning problems. What is less well known is that adverse experiences like violence exposure can lead to hidden physical alterations inside a child's body, alterations that may have adverse effects on life-long health. We discuss why this is important for the field of developmental psychopathology and for society, and we recommend that stress biology research and intervention science join forces to tackle the problem. We examine the evidence base in relation to stress-sensitive measures for the body (inflammatory reactions, telomere erosion, epigenetic methylation, and gene expression) and brain (mental disorders, neuroimaging, and neuropsychological testing). We also review promising interventions for families, couples, and children that have been designed to reduce the effects of childhood violence exposure. We invite intervention scientists and stress-biology researchers to collaborate in adding stress-biology measures to randomized clinical trials of interventions intended to reduce effects of violence exposure and other traumas on young people. PMID- 24342865 TI - Pitfalls in cervical ectopic pregnancy diagnosis by emergency physicians using bedside ultrasonography. AB - Pelvic pain and vaginal bleeding are common complaints in pregnant women presenting to emergency department. Cervical ectopic pregnancy (EP) is a rare type of EP, with a higher likelihood of complications if missed. Its sonographic findings can be difficult to distinguish from normal pregnancy or an abortion in progress. In this report, we present a rare case of a cervical EP, diagnosed using bedside ultrasonography, and characterize the pitfalls associated with its diagnosis. PMID- 24342866 TI - Acute coronary syndrome presenting with earache and sore throat. AB - Chest pain and discomfort are regarded as the hallmark symptoms of acute coronary syndrome, and the absence of these symptoms are described as "atypical" presentation. In this case, we aimed to report an acute coronary syndrome diagnosed patient who was admitted to our emergency service with unilateral earache. PMID- 24342867 TI - Comment on: "Atypical presentations of dengue disease in the elderly visiting the ED". PMID- 24342868 TI - Fourth-generation troponin I and infarct size in patients without ST-elevation myocardial infarction? PMID- 24342869 TI - Managing combined critical hypothermia, diabetic ketoacidosis and cocaine intoxication noninvasively. AB - Severe hypothermia with a core temperature below 28 degrees C is critical especially in patients with diabetic ketoacidosis (DKA) and carries a high risk of mortality. Our case of a 52-year-old woman presenting with DKA, pH of 6.9, potassium of 7.6 mEq/L, and body temperature of 26 degrees C demonstrates that conservative management can be safe and successful. We used an established cardiac arrest rewarming phase protocol modified to active warming with the Meditherm 3 Machine and the facility-used rigorous DKA protocol to successfully and safely achieve rewarming without hemodialysis or extracorporeal maneuvers. Our patient arrived even more hypothermic than all previously described cases and regained normothermia and an equalized acid-base and electrolyte balance within 12 hours after admission. Eventually, no new neurologic deficit was present on discharge. PMID- 24342870 TI - B-type natriuretic peptide is associated with complex coronary lesions in patients with non-ST-elevation myocardial infarction. PMID- 24342871 TI - The accuracy of bedside ultrasonography as a diagnostic tool for the fifth metatarsal fractures. AB - OBJECTIVES: Musculoskeletal ultrasonography is a technique that is becoming more popular in diagnosing injuries of emergency department (ED) patients especially for the diagnosis of fractures. In this study, we determined the reliability of ultrasonography for the diagnosis of fractures of the fifth metatarsal. METHOD: This is a prospective blind study. Patients over 14 years old who were admitted to the ED with acute foot injury and who had tenderness on the fifth metatarsal were consecutively enrolled into the study. A bedside ultrasonography exam was performed by an emergency physician, and antero-posterior and oblique views were obtained. X-rays were blindly evaluated by an orthopedic surgeon and were considered to be the gold-standard for diagnosing fractures. In patients with noncomminuted fractures, bone displacement was measured by both radiologically and sonographically. RESULTS: Eighty-four patients were included in this study. Their mean age was 36.0, and 42.9% were male. Fractures were diagnosed by both x ray and ultrasonography in 33 patients. In one patient, the x-ray was positive for fracture, while ultrasonography yielded a negative result. For the fractures of fifth metatarsal, the diagnostic sensitivity of ultrasonography was 97.1%, the specificity was 100%, the positive likelihood ratio was infinity, the negative likelihood ratio was 0.03. Mean displacement was 1.2 +/- 0.7 mm with x-ray and 1.8 +/- 1.5 mm with ultrasonography. The intraclass correlation coefficient of displacement measured by x-ray and ultrasonography was kappa: 0.388. CONCLUSION: Ultrasonography is a reliable diagnostic tool for acute fifth metatarsal fractures. PMID- 24342872 TI - Small animal magnetic resonance imaging: an efficient tool to assess liver volume and intrahepatic vascular anatomy. AB - BACKGROUND: To develop a noninvasive technique to assess liver volumetry and intrahepatic portal vein anatomy in a mouse model of liver regeneration. MATERIALS AND METHODS: Fifty-two C57BL/6 male mice underwent magnetic resonance imaging (MRI) of the liver using a 4.7 T small animal MRI system after no treatment, 70% partial hepatectomy (PH), or selective portal vein embolization. The protocol consisted of the following sequences: three-dimensional-encoded spoiled gradient-echo sequence (repetition time per echo time 15 per 2.7 ms, flip angle 20 degrees ) for volumetry, and two-dimensional-encoded time-of-flight angiography sequence (repetition time per echo time 18 per 6.4 ms, flip angle 80 degrees ) for vessel visualization. Liver volume and portal vein segmentation was performed using a dedicated postprocessing software. In animals with portal vein embolization, portography served as reference standard. True liver volume was measured after sacrificing the animals. Measurements were carried out by two independent observers with subsequent analysis by the Cohen kappa-test for interobserver agreement. RESULTS: MRI liver volumetry highly correlated with the true liver volume measurement using a conventional method in both the untreated liver and the liver remnant after 70% PH with a high interobserver correlation coefficient of 0.94 (95% confidence interval, 0.80-0.98 for untreated liver [P < 0.001] and 0.90-0.97 after 70% PH [P < 0.001]). The diagnostic accuracy of magnetic resonance angiography for the occlusion of one branch of the portal vein was 0.95 (95% confidence interval, 0.84-1). The level of agreement between the two observers for the description of intrahepatic vascular anatomy was excellent (Cohen kappa value = 0.925). CONCLUSIONS: This protocol may be used for noninvasive liver volumetry and visualization of portal vein anatomy in mice. It will serve the dynamic study of new strategies to enhance liver regeneration in vivo. PMID- 24342873 TI - Readmission rates. PMID- 24342874 TI - Single molecule insights on conformational selection and induced fit mechanism. AB - Biomolecular interactions regulate a plethora of vital cellular processes, including signal transduction, metabolism, catalysis and gene regulation. Regulation is encoded in the molecular properties of the constituent proteins; distinct conformations correspond to different functional outcomes. To describe the molecular basis of this behavior, two main mechanisms have been advanced: 'induced fit' and 'conformational selection'. Our understanding of these models relies primarily on NMR, computational studies and kinetic measurements. These techniques report the average behavior of a large ensemble of unsynchronized molecules, often masking intrinsic dynamic behavior of proteins and biologically significant transient intermediates. Single molecule measurements are emerging as a powerful tool for characterizing protein function. They offer the direct observation and quantification of the activity, abundance and lifetime of multiple states and transient intermediates in the energy landscape, that are typically averaged out in non-synchronized ensemble measurements. Here we survey new insights from single molecule studies that advance our understanding of the molecular mechanisms underlying biomolecular recognition. PMID- 24342875 TI - Effects of changing hydraulic and organic loading rates on pollutant reduction in bark, charcoal and sand filters treating greywater. AB - Greywater flows and concentrations vary greatly, thus evaluation and prediction of the response of on-site treatment filters to variable loading regimes is challenging. The performance of 0.6 m * 0.2 m (height * diameter) filters of bark, activated charcoal and sand in reduction of biochemical oxygen demand (BOD5), chemical oxygen demand (COD), total nitrogen (Tot-N) and total phosphorus (Tot-P) under variable loading regimes was investigated and modelled. During seven runs, the filters were fed with synthetic greywater at hydraulic loading rates (HLR) of 32-128 L m(-2) day(-1) and organic loading rates (OLR) of 13-76 g BOD5 m(-2) day(-1). Based on the changes in HLR and OLR, the reduction in pollutants was modelled using multiple linear regression. The models showed that increasing the HLR from 32 to 128 L m(-2) day(-1) decreased COD reduction in the bark filters from 74 to 40%, but increased COD reduction in the charcoal and sand filters from 76 to 90% and 65 to 83%, respectively. Moreover, the models showed that increasing the OLR from 13 to 76 g BOD5 m(-2) day(-1) enhanced the pollutant reduction in all filters except for Tot-P in the bark filters, which decreased slightly from 81 to 73%. Decreasing the HLR from 128 to 32 L m(-2) day(-1) enhanced the pollutant reduction in all filters, but decreasing the OLR from 76 to 14 g BOD5 m(-2) day(-1) detached biofilm and decreased the Tot-N and Tot-P reduction in the bark and sand filters. Overall, the bark filters had the capacity to treat high OLR, while the charcoal filters had the capacity to treat high HLR and high OLR. Both bark and charcoal filters had higher capacity than sand filters in dealing with high and variable loads. Bark seems to be an attractive substitute for sand filters in settings short in water and its effluent would be valuable for irrigation, while charcoal filters should be an attractive alternative for settings both rich and short in water supply and when environmental eutrophication has to be considered. PMID- 24342876 TI - Executive functioning affects health behaviour in older people too. PMID- 24342877 TI - Real-time RT-PCR assays to differentiate wild-type group A rotavirus strains from Rotarix((r)) and RotaTeq((r)) vaccine strains in stool samples. AB - Group A rotaviruses (RVA) are the leading cause of severe diarrhea in young children worldwide. Two live-attenuated RVA vaccines, Rotarix((r)) and RotaTeq((r)) are recommended by World Health Organization (WHO) for routine immunization of all infants. Rotarix((r)) and RotaTeq((r)) vaccines have substantially reduced RVA associated mortality but occasionally have been associated with acute gastroenteritis (AGE) cases identified in vaccinees and their contacts. High-throughput assays are needed to monitor the prevalence of vaccine strains in AGE cases and emergence of new vaccine-derived strains following RVA vaccine introduction. In this study, we have developed quantitative real-time RT-PCR (qRT-PCR) assays for detection of Rotarix((r)) and RotaTeq((r)) vaccine components in stool samples. Real-time RT-PCR assays were designed for vaccine specific targets in the genomes of Rotarix((r)) (NSP2, VP4) and RotaTeq((r)) (VP6, VP3-WC3, VP3-human) and validated on sequence confirmed stool samples containing vaccine strains, wild-type RVA strains, and RVA-negative stools. For quantification, standard curves were generated using dsRNA transcripts derived from RVA gene segments. Rotarix((r)) NSP2 and VP4 qRT-PCR assays exhibited 92-100% sensitivity, 99-100% specificity, 94-105% efficiency, and a limit of detection of 2-3 copies per reaction. RotaTeq((r)) VP6, VP3-WC3, and VP3-human qRT-PCR assays displayed 100% sensitivity, 94-100% specificity, 91 102% efficiency and limits of detection of 1 copy, 2 copies, and 140 copies, respectively. These assays permit rapid identification of Rotarix((r)) and RotaTeq((r)) vaccine components in stool samples from clinical and surveillance studies and will be helpful in determining the frequency of vaccine strain associated AGE. PMID- 24342879 TI - Genotypic characterization of Streptococcus pneumoniae serotype 19F in Malaysia. AB - Streptococcus pneumoniae is an epidemiologically important bacterial pathogen. Recently, we reported the antibiotic susceptibility patterns of a limited collection of pneumococcal isolates in Malaysia with a high prevalence of erythromycin resistant strains. In the present study, 55 of the pneumococcal isolates of serotype 19F were further analysed by pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). The generated genotypic patterns were then correlated with the antibiograms previously reported. Forty-seven different PFGE profiles (PTs) were obtained, showing that the isolates were genetically diverse. MLST identified 16 sequence types (STs) with ST-236 being predominant (58.2%), followed by ST-81 (10.3%). Among the ST 236 isolates, 22 were erythromycin resistant S. pneumoniae (ERSP) and 15 were trimethoprim/sulfamethoxazole (TMP/SMX) resistant, while among ST-81, four isolates were ERSP and two were TMP/SMX resistant. The high prevalence of erythromycin resistant serotype 19F isolates of ST-236 in this study has also been reported in other North and South East Asian countries. PMID- 24342880 TI - Evolutionizing grief: viewing photographs of the deceased predicts misattribution of ambiguous stimuli by the bereaved. AB - We propose a cognitive-evolutionary model of grief where the function of grief is to reunite a person with an absent partner where this is possible, and where it is not, to disengage and reorientate the individual from the lost agent. The present study investigates the potential factors that affect reunion-promoting symptoms by focusing on the misattribution of external stimuli to the deceased by the bereaved--which we term 'false recognitions'. We propose three factors that relate to false recognitions: First, we propose that strong attachment to the deceased predisposes one to false recognitions; second, we predict that viewing photographs of the deceased (that were taken when the individual was alive) perpetuates false recognitions; and third, we propose that time elapsing since the death diminishes the frequency of false recognitions. In a survey of 164 recently bereaved (<25 months) pet owners in the U.S. and U.K., predictions concerning the association of the predictor and outcome variables were confirmed. The strongest predictor was the frequency of viewing photographic images of the deceased, a pattern consonant with our premise that, being evolutionarily novel, realistic photographs are treated as reliable cues that the agent remains a viable relationship partner. This research demonstrates the potential of evolutionary theory to inform mainstream bereavement research. PMID- 24342878 TI - Anti-oxidative stress response genes: bioinformatic analysis of their expression and relevance in multiple cancers. AB - Cells mount a transcriptional anti-oxidative stress (AOS) response program to scavenge reactive oxygen species (ROS) that arise from chemical, physical, and metabolic challenges. This protective program has been shown to reduce carcinogenesis triggered by chemical and physical insults. However, it is also hijacked by established cancers to thrive and proliferate within the hostile tumor microenvironment and to gain resistance against chemo- and radiotherapies. Therefore, targeting the AOS response proteins that are exploited by cancer cells is an attractive therapeutic strategy. In order to identify the AOS genes that are suspected to support cancer progression and resistance, we analyzed the expression patterns of 285 genes annotated for being involved in oxidative stress in 994 tumors and 353 normal tissues. Thereby we identified a signature of 116 genes that are highly overexpressed in multiple carcinomas while being only minimally expressed in normal tissues. To establish which of these genes are more likely to functionally drive cancer resistance and progression, we further identified those whose overexpression correlates with negative patient outcome in breast and lung carcinoma. Gene-set enrichment, GO, network, and pathway analyses revealed that members of the thioredoxin and glutathione pathways are prominent components of this oncogenic signature and that activation of these pathways is common feature of many cancer entities. Interestingly, a large fraction of these AOS genes are downstream targets of the transcription factors NRF2, NF-kappaB and FOXM1, and relay on NADPH for their enzymatic activities highlighting promising drug targets. We discuss these findings and propose therapeutic strategies that may be applied to overcome cancer resistance. PMID- 24342881 TI - Above and beyond short-term mating, long-term mating is uniquely tied to human personality. AB - To what extent are personality traits and sexual strategies linked? The literature does not provide a clear answer, as it is based on the Sociosexuality model, a one-dimensional model that fails to measure long-term mating (LTM). An improved two-dimensional model separately assesses long-term and short-term mating (STM; Jackson and Kirkpatrick, 2007). In this paper, we link this two dimensional model to an array of personality traits (Big 5, Dark Triad, and Schizoid Personality). We collected data from different sources (targets and peers; Study 1), and from different nations (United States, Study 1; India, Study 2). We demonstrate for the first time that, above and beyond STM, LTM captures variation in personality. PMID- 24342883 TI - Adrenal function: Bilateral macronodular adrenal hyperplasia-new genetic and pathophysiological insights. PMID- 24342882 TI - Consequences of excess iodine. AB - Iodine is a micronutrient that is essential for the production of thyroid hormones. The primary source of iodine is the diet via consumption of foods that have been fortified with iodine, including salt, dairy products and bread, or that are naturally abundant in the micronutrient, such as seafood. Recommended daily iodine intake is 150 ug in adults who are not pregnant or lactating. Ingestion of iodine or exposure above this threshold is generally well-tolerated. However, in certain susceptible individuals, including those with pre-existing thyroid disease, the elderly, fetuses and neonates, or patients with other risk factors, the risk of developing iodine-induced thyroid dysfunction might be increased. Hypothyroidism or hyperthyroidism as a result of supraphysiologic iodine exposure might be either subclinical or overt, and the source of the excess iodine might not be readily apparent. PMID- 24342884 TI - Thyroid function: Hyperthyroidism-psychiatric issues. PMID- 24342886 TI - Lipids: Cholesterol metabolite unmasked as a key player in breast cancer. PMID- 24342885 TI - Treatment and health outcomes in adults with congenital adrenal hyperplasia. AB - Congenital adrenal hyperplasia (CAH) is a genetic disorder caused by defective steroidogenesis that results in glucocorticoid deficiency; the most common underlying mutation is in the gene that encodes 21-hydroxylase. Life-saving glucocorticoid treatment was introduced in the 1950s, and the number of adult patients is now growing; however, no consensus has been reached on the management of CAH beyond childhood. Adult patients are prescribed a variety of glucocorticoids, including hydrocortisone, prednisone, prednisolone, dexamethasone and combinations of these drugs taken in either a circadian or reverse circadian regimen. Despite these personalized treatments, biochemical control of CAH is only achieved in approximately one-third of patients. Some patients have a poor health status, with an increased incidence of obesity and osteoporosis, and impaired fertility and quality of life. The majority of poor health outcomes seem to relate to inadequate treatment rather than the genotype of the patient. Patients receiving high doses of glucocorticoids and the more potent synthetic long-acting glucocorticoids are at an increased risk of obesity, insulin resistance and a reduced quality of life. Further research is required to optimize the treatment of adult patients with CAH and improve health outcomes. PMID- 24342887 TI - Effects of topical Janus kinase inhibition on ocular surface inflammation and immunity. AB - PURPOSE: To determine the effects of topical Janus kinase inhibition on ocular surface inflammation and immunity. METHODS: Ophthalmic 0.003% tofacitinib (CP 690,550) was administered topically to inhibit Janus kinase activation at the ocular surface. Male BALB/c mice 6 to 8 weeks of age were subjected to corneal thermocautery and randomized to receive tofacitinib, vehicle, or no treatment. Corneas were subsequently excised for fluorescence-activated cell sorting and quantitative real-time reverse transcription polymerase chain reaction. Female C57BL/6 mice 6 to 8 weeks of age were exposed to desiccating stress to induce experimental dry eye disease and randomized to receive tofacitinib, tofacitinib and vehicle, vehicle, or no treatment. Corneal fluorescein staining was performed to evaluate clinical disease severity. The corneas and conjunctivae were harvested for immunohistochemical staining and quantitative real-time reverse transcription polymerase chain reaction. RESULTS: After corneal thermocautery, it was found that tofacitinib treatment decreased the corneal infiltration of CD45+, Gr-1+, and CD11b+ cells on days 1 and 3. Transcripts encoding interleukin (IL) 1beta and IL-6 were significantly decreased by tofacitinib treatment at post thermocautery day 3. In experimental dry eye disease, tofacitinib treatment twice per day significantly decreased corneal fluorescein staining on days 12 and 15. The corneal infiltration of CD11b+ cells was significantly decreased by tofacitinib treatment twice per day. Tofacitinib treatment twice per day significantly increased the corneal expression of IL-1RA, and significantly decreased the corneal expression of tumor necrosis factor and IL-23. Further, tofacitinib treatment twice per day significantly decreased the conjunctival expression of IL-17A and significantly increased the conjunctival expression of FoxP3. CONCLUSIONS: Topical ophthalmic tofacitinib, a Janus kinase inhibitor, suppressed ocular surface inflammation and immunity in experimental corneal thermocautery and dry eye disease. PMID- 24342888 TI - Very early endothelial cell loss after simultaneous corneal autograft and allograft. AB - PURPOSE: For a better understanding of the very early endothelial cell (EC) loss universally described after all types of keratoplasty, we compared the EC decrease after performing a simultaneous autograft and organ-cultured allograft. METHODS: A 71-year-old woman presented with a central corneal opacity in her left eye and a profoundly amblyopic right eye with a transparent cornea. Both corneas had a normal EC density (ECD). She underwent a left autograft and a right allograft procedure with an organ-cultured cornea, in which the ECD was determined using a calibrated light microscope with image analysis 48 hours before the surgery, that is, just before the final deswelling step with dextran. The postoperative central ECD was determined using specular microscopy on days (D) 1, 2, 3, 4, 5, 15, 20, 30, 60, 90, 120, and 180. RESULTS: Both grafts were uneventful. For the autograft, the pregraft ECD was 2303 cells per square millimeter, and the cell loss was very low, from 4% (D1) to 3% (D180). For the allograft, the pregraft eye bank ECD was 2787, and this decreased by 32% on D5. On D180, the ECD decrease was almost stabilized at 38%. CONCLUSIONS: This difference between the autograft and allograft, both performed in corneas with a normal peripheral endothelial reserve, indicates that the typical very early postoperative decrease in the EC is not caused mainly by surgery-dependent overmortality. It may be mostly artificial, revealing the overestimation of eye bank ECD caused by the technical unfeasibility of strictly considering living ECs and by measuring the ECD several days before grafting. This exceptional case suggests a new paradigm: surgeons graft fewer ECs than they think. PMID- 24342889 TI - Collagen crosslinking after radial keratotomy. AB - PURPOSE: The aim of this study was to report the outcomes of corneal collagen crosslinking (CXL) after previous radial keratotomy (RK) in patients with decreasing visual acuity and/or diurnal visual fluctuations. METHODS: The charts of all patients who had undergone CXL because of a worsening corrected distance visual acuity (CDVA) and/or diurnal visual fluctuations after RK were reviewed retrospectively. Uncorrected distance visual acuity, CDVA, manifest refraction, and corneal topography were recorded preoperatively and at 1, 3, 6, and 12 months after the procedure. RESULTS: Nine eyes of 6 patients that had undergone an RK 15 to 23 years before the CXL were included in the study. In 5 patients (8 out of 9 eyes), discontinuation of diurnal visual fluctuation was reported between 6 and 12 months after the CXL. The mean uncorrected distance visual acuities pre and 12 months after the CXL were 0.7 logarithm of the minimum angle of resolution (logMAR) and 0.6 logMAR, respectively (P = 0.3). The mean CDVAs pre and 12 months after the CXL were 0.2 logMAR and 0.1 logMAR (P = 0.5), respectively. The mean average keratometry pre and 12 months after the CXL were 40.1 and 39.1 diopters (P = 0.06), respectively. The mean corneal astigmatism values pre and 12 months after the CXL were 2.3 and 1.9 diopters (P = 0.06), respectively. The mean manifest refraction spherical equivalents (MRSEs) before and 12 months after the CXL were +1.4 and +2.5 (P = 0.1), respectively. CONCLUSIONS: CXL is a safe and effective method to restore corneal stability in eyes with a history of RK. However, some of the effect that was achieved at the 6-month visit was blunted at the 12-month visit. Therefore, a longer follow-up is necessary to validate these findings. PMID- 24342890 TI - Vision-related impact on quality of life in an elderly patient population after corneal transplantation. AB - PURPOSE: The aim of this study was to assess the vision-related quality of life (QOL) and satisfaction of elderly patients who underwent corneal transplantations. METHODS: Survey data using a modified version of the Visual Function Index were collected in February-March 2013 from 175 patients (age >=65 years) of 414 eligible patients who underwent corneal transplantation between 2008 and 2010 at the Wilmer Eye Institute. The survey assessed visual functionality, independence, and satisfaction. Transplant surgeries were limited to penetrating keratoplasty, Descemet stripping automated endothelial keratoplasty (DSAEK), and keratoprosthesis. Sociodemographic and clinical data, including age, sex, initial and follow-up visual acuities, were collected. QOL survey measures were compared with patients' clinical findings to assess the differences between objective and subjective visual functioning. RESULTS: One hundred seventy-two patients were reviewed for surgery type. Eighty-six of 172 (50%) patients had follow-up data. Controlling for age, procedure, and baseline logarithm of the minimum angle of resolution (logMAR) visual acuity, patients treated by penetrating keratoplasty (P = 0.002) or keratoprosthesis (P = 0.019) were found to have poorer QOL scores than those treated with DSAEK. Age was positively associated with QOL improvement (P = 0.005). A relatively lower baseline vision (higher logMAR) was associated with a worse QOL (P < 0.001). When asked directly about their QOL, patients with relatively higher baseline vision (lower logMAR) reported no change in their QOL (P = 0.046). CONCLUSIONS: Type of surgery (DSAEK), older recipient age, and better baseline vision seem to be associated with an improved QOL in this study. Vision at follow-up is not associated with a QOL decline. Based on these findings, it is suggested that transplant surgery should be considered for elderly patients. PMID- 24342891 TI - Focal limbal stem cell deficiency in Turner syndrome: report of two patients and review of the literature. AB - PURPOSE: The aim of this study was to report the presence of focal limbal stem cell deficiency (LSCD) in 2 cases of Turner syndrome. METHODS: This is a case review. RESULTS: A 25-year-old woman with a history of Turner syndrome diagnosed at 15 years of age was referred for "advanced chronic bilateral phlyctenular disease." The patient's visual acuity at presentation was 20/25-2 in the right eye and 20/30-2 in the left eye. Slit-lamp examination of both eyes showed inferior conjunctivalization of the corneal epithelium consistent with LSCD. The patient was started on topical cyclosporine 0.05%. A 23-year-old woman with the Turner syndrome was referred for rosacea keratitis. An ocular assessment revealed the visual acuity at presentation to be 20/25 in the right eye and 20/30 in the left eye. Slit-lamp examination of both eyes showed significant conjunctivalization with epithelial scarring and opacity. The patient was started on erythromycin ointment before bedtime, artificial tears, and warm compresses. CONCLUSIONS: This study reports the first cases in the literature describing the coexistence of LSCD and Turner syndrome. Management of any ocular surface inflammation is important to prevent the progression of LSCD. PMID- 24342892 TI - A small molecule chemical chaperone optimizes its unfolded state contraction and denaturant like properties. AB - Protein aggregation is believed to occur through the formation of misfolded conformations. It is expected that, in order to minimize aggregation, an effective small molecule chaperone would destabilize these intermediates. To study the mechanism of a chemical chaperone, we have designed a series of mutant proteins in which a tryptophan residue experiences different local environments and solvent exposures. We show that these mutants correspond to a series of conformationally altered proteins with varying degree of misfolding stress and aggregation propensities. Using arginine as a model small molecule, we show that a combination of unfolded state contraction and denaturant like properties results in selective targeting and destabilization of the partially folded proteins. In comparison, the effect of arginine towards the folded like control mutant, which is not aggregation prone, is significantly less. Other small molecules, lacking either of the above two properties, do not offer any specificity towards the misfolded proteins. PMID- 24342894 TI - Slow carbamazepine clearance in a nonadherent Malay woman with epilepsy and thyrotoxicosis. AB - The authors describe a case of a 37-year-old Malay lady with an unusually slow carbamazepine clearance, which may be related to genetic polymorphisms of drug metabolizing enzymes and transporters. When given a small daily dose of 200 mg immediate-release carbamazepine, this patient experienced drowsiness. Subsequently, she reduced her carbamazepine dose to 200 mg twice a week (on Mondays and Fridays), resulting in poor seizure control. At the same time, the patient was diagnosed with hyperthyroidism and was given carbimazole and propranolol. Hyperthyroidism and the concurrent use of these antihyperthyroid agents may have further slowed down the metabolism of carbamazepine. Therapeutic drug monitoring of carbamazepine was carried out, and a slow carbamazepine clearance of 1.45 L.h-1 per 70 kg was observed. Genotyping of selected genetic variants in CYP3A4, CYP3A5, EPHX1, ABCB1, and ABCC2 revealed that she has CYP3A5*3/*3 and ABCB1 3435-CC genotypes. Both genotypes have been shown to be associated with higher adjusted mean serum carbamazepine concentration in Chinese and Korean patients with epilepsy. Physicians should be vigilant about the risk of adverse effects among patients with a slow carbamazepine clearance, especially in Malays. Simulations of carbamazepine dosing regimen based on the pharmacokinetic parameters of this patient were performed to allow individualization of drug therapy. PMID- 24342895 TI - Plasma and intracellular imatinib concentrations in patients with chronic myeloid leukemia. AB - BACKGROUND: Imatinib (Gleevec, STI-571), a 2-phenylaminopyrimidine-type competitive inhibitor of Bcr-Abl kinase, is the current frontline therapy for patients with chronic myeloid leukemia, and it induces durable responses and prolonging event-free and progression-free survival. Monitoring imatinib trough plasma concentration is a simple and rapid way to determine if the drug exposure exceeds the clinical efficacy threshold (1 mcg/mL). Because the target enzyme is located within cells, adequate drug intracellular concentrations are needed to inhibit its function. METHODS: Chromatographic methods were used to quantify imatinib concentrations in both plasma and peripheral blood mononuclear cells collected from adult patients with chronic myeloid leukemia at the Department of Hematology. Samples were collected at steady state, and trough concentrations (24 +/- 2 hours after last drug intake) were evaluated. Associations between variables were tested using the Pearson test; results are presented as mean (+/ SD). RESULTS: Thirty-five samples from 24 patients were collected; patients were mainly men (16, 66.7%), aged 60 years old (+/-13.1) and with a body mass index of 24.8 (+/-4.4). A positive and significant correlation (r = 0.203; P = 0.027) was found between imatinib plasma and intracellular concentrations. CONCLUSIONS: The observed correlation between plasma and intracellular imatinib concentrations suggests that they may be used to monitor drug exposure and treatment efficacy. PMID- 24342893 TI - Role of miRNAs and epigenetics in neural stem cell fate determination. AB - The regulation of gene expression that determines stem cell fate determination is tightly controlled by both epigenetic and posttranscriptional mechanisms. Indeed, small non-coding RNAs such as microRNAs (miRNAs) are able to regulate neural stem cell fate by targeting chromatin-remodeling pathways. Here, we aim to summarize the latest findings regarding the feedback network of epigenetics and miRNAs during embryonic and adult neurogenesis. PMID- 24342896 TI - Population pharmacokinetic/pharmacodynamic model of clozapine for characterizing the relationship between accumulated exposure and PANSS scores in patients with schizophrenia. AB - BACKGROUND: The aim of this study was to characterize the relationship between accumulated exposure of clozapine and changes in Positive and Negative Syndrome Scale (PANSS) score in Chinese patients with schizophrenia by pharmacokinetic/pharmacodynamic (PK/PD) modeling. METHODS: Sparse clozapine PK data and PANSS scores were collected from 2 clinical studies of Chinese inpatients with schizophrenia. Two other rich PK data sets were included for more accurate assessment of clozapine PK characteristics. The relationship between clozapine-accumulated exposure and PANSS score was investigated using linear, log linear, E(max), and sigmoid models, and each model was evaluated using visual predictive condition and normalized prediction distribution error methods. Simulations based on the final PK/PD model were preformed to investigate the effect of clozapine on PANSS scores under different dose regimens. RESULTS: A total of 1391 blood clozapine concentrations from 198 subjects (180 patients and 18 healthy volunteers) and 576 PANSS scores from 137 patients were included for PK and PK/PD analysis. A first-order 2-compartment PK model with covariates gender and smoking status influencing systemic clearance adequately described the PK profile of clozapine. The decrease in total PANSS score during treatment was best characterized using cumulated clozapine area under the curve (AUC) data in the E(max) model. The maximum decrease in PANSS during clozapine treatment (Emax) was 55.4%, and the cumulated AUC(50) (cAUC(50)) required to attain half of E(max) was 296 mg.L(-1).h(-1).d(-1). The simulations demonstrated that the accelerated dose titration and constant dose regimens achieved a similar maximum drug response but with a slower relief of symptoms in dose titration regimen. CONCLUSIONS: The PK/PD model can describe the clinical response as measured by decreasing PANSS score during treatment and may be useful for optimizing the dose regimen for individual patients. PMID- 24342897 TI - Immediate cooling does not prevent the ex vivo hydrolysis of L-asparagine by asparaginase. AB - BACKGROUND: Monitoring of asparagine (ASN) during asparaginase (ASE) treatment directly links to the antileukemic effect of ASE but is challenging because of ASE-induced ex vivo hydrolysis of ASN. Assuming that ASE is not active at 4 degrees C, immediate cooling of blood samples became the accepted method for ASN determination during ASE therapy. METHODS: To evaluate the effect of immediate sample cooling on the ex vivo hydrolysis of ASN by ASE the degradation of C4-ASN in whole blood, spiked with different ASE concentrations were analyzed HPLC-MS. C4-ASN and ASE were added either to blood at 4 degrees C or to blood at 37 degrees C, which was instantly cooled down to 4 degrees C. RESULTS: Immediate cooling did not prevent the ex vivo hydrolysis of ASN by ASE. The rate of ASN degradation to aspartic acid depended on the amount of ASE, ASE preparation, and time. Spiked into blood at 4 degrees C 100 U/L native E. coli ASE already immediately degraded 100% of C4-ASN, whereas 10 U/L reduced the amount of C4-ASN by 30%. Spiked into blood at 37 degrees C, which was immediately cooled thereafter, 10 U/L native E. coli ASE hydrolyzed 60% of C4-ASN and 1 U/L between 5% and 10% of C4-ASN. Concentrations of aspartic acid increased in parallel with ASN degradation. In addition, the ex vivo hydrolysis also affected concentrations of glutamine and glutamic acid. CONCLUSIONS: Cooling of blood samples did not inactivate ASE. Thus, to evaluate the precise pharmacodynamics of ASE, alternative methods for effective ASE inactivation at the time of blood withdrawal are needed. PMID- 24342898 TI - Right ventricular dysfunction in children supported with pulsatile ventricular assist devices. AB - OBJECTIVES: To describe the incidence and severity of right ventricular dysfunction (RVD) in pediatric ventricular assist device (VAD) recipients and to identify the preoperative characteristics associated with RVD and their effect on outcomes. METHODS: Children bridged to transplantation from 2004 to 2011 were included. RVD was defined as the use of a left VAD (LVAD) with an elevated central venous pressure of >16 mm Hg with inotropic therapy and/or inhaled nitric oxide for >96 hours or biventricular assist (BiVAD). RESULTS: A total of 57 children (median age, 2.97 years; range 35 days to 15.8 years) were supported. Of the 57, 43 (75%) had an LVAD, and of those, 10 developed RVD. The remaining 14 (25%) required BiVAD. Thus, RVD occurred in 24 of 57 patients (42%). Preoperative variables such as younger age (P = .01), use of extracorporeal mechanical support (P = .006), and elevated urea (P = .03), creatinine (P = .02), and bilirubin (P = .001) were associated with RVD. Multiple logistic regression analysis indicated that elevated urea and extracorporeal mechanical support (odds ratio, 26.4; 95% confidence interval, 2.3-307.3; and odds ratio, 27.8; 95% confidence interval, 2.5-312.3, respectively) were risk factors for BiVAD. The patients who developed RVD on LVAD had a complicated postoperative course but excellent survival (100%), comparable to those with preserved right ventricular function (91%). The survival for those requiring BiVAD was reduced (71%). CONCLUSIONS: RVD occurred in approximately 40% of pediatric VAD recipients and affects their peri-implantation morbidity and bridging outcomes. Preoperative extracorporeal membrane oxygenation and elevated urea were risk factors for BiVAD. Additional studies of the management of RVD in children after VAD implantation are warranted. PMID- 24342899 TI - Cardiac allograft failure: retransplant or long-term ventricular assist device? PMID- 24342900 TI - Relative amplitude index: a new tool for hemodynamic evaluation of periprosthetic regurgitation after transcatheter valve implantation. AB - OBJECTIVE: The impact of paravalvular aortic regurgitation (PAR) on hemodynamic performance after transcatheter aortic valve implantation (TAVI) remains disputable. Common parameters such as the diastolic blood pressure or the blood pressure amplitude do not provide reproducible results. The aim of our study was to evaluate the impact of PAR on hemodynamics and outcome using the relative amplitude index (RAI). METHODS: PAR was prospectively evaluated by echocardiography before discharge in 110 patients. The RAI was calculated according to the formula: RAI = [(Post-TAVI BP amplitude)/(Post-TAVI SBP) - (Pre TAVI BP amplitude)/(Pre-TAVI SBP)] * 100%, where BP is blood pressure and SBP is systolic blood pressure. Correlations of increased RAI with perioperative outcome were investigated and factors influencing mortality were isolated. RESULTS: The incidence of moderate and severe PAR after TAVI was 9% and 1%, respectively. Diastolic pressure or post-TAVI amplitude did not correlate to perioperative outcome. RAI increased from 2 when PAR was <2+ to 7 when PAR was >=2+ (P = .006). A cut-off value of RAI >=14 was associated with increased perioperative mortality (29 vs 5%; P = .013) and acute renal injury requiring dialysis (71 vs 18%; P = .001). RAI >=14 was also associated with higher follow-up mortality at 1 year (57 vs 16%; P = .007). RAI >=14 (odds ratio [OR], 3.390; 95% confidence interval [CI], 1.6-7.194; P = .00146), PAR >=2+ (OR, 4.717; 95% CI, 1.828-12.195; P = .00135), and perioperative renal replacement therapy (OR, 12.820; 95% CI, 5.181 31.250; P = .00031) were found to be independent predictors of mortality at 1 year. CONCLUSIONS: The RAI is a useful tool to predict perioperative and 1-year outcome in patients with PAR after TAVI. PMID- 24342901 TI - Pediatric ventricular assist device use as a bridge to transplantation does not affect long-term quality of life. AB - OBJECTIVE: The present study sought to determine the long-term quality of life (QOL) of children who required long-term ventricular assist device (VAD) support as a bridge to transplantation (BTT) compared with children who underwent heart transplantation without VAD support. Currently, 20% of children undergoing heart transplantation have required a VAD as a BTT. Few data have been published assessing how children requiring a VAD as a BTT will fair in terms of their long term QOL. METHODS: The present study used a cross-sectional design, using the Core and Cardiac modules of the Pediatric Quality of Life Inventory survey. In a secondary analysis, the factors associated with worse QOL outcomes among the VAD patients were also investigated. RESULTS: At follow-up (median, 4.2 years), between the 21 children who required a VAD as a BTT and 42 who went straight to transplantation, no significant differences were found in the QOL as measured using the Psychosocial Health Summary Score, Physical Health Summary Score, or Total Score in the survey's Core Module, nor were any differences found in the outcomes assessed using the survey's Cardiac Module. Of the patients who required a VAD, only the presence of a neurologic complication was associated with worse QOL, which was demonstrated by decreased Physical Health Summary and Cardiac Communication scores. CONCLUSIONS: Over the long term, surviving children who required a long-term VAD as a BTT experience a similar QOL as those who went straight to transplantation. PMID- 24342902 TI - Discussion. PMID- 24342903 TI - Hyperbaric oxygen therapy for the treatment of anastomotic complications after tracheal resection and reconstruction. AB - OBJECTIVE: Failure of anastomotic healing is a rare but serious complication of laryngotracheal resection. Treatment options include reoperation, tracheostomy, or T-tube placement. Hyperbaric oxygen therapy (HBOT) is the delivery of 100% O2 at pressures greater than 1 atm, and has been shown to enhance wound healing after tracheal resection in animal models. To date, there have been no reports describing its usefulness in humans after tracheal resection. METHODS: Five consecutive patients with varying degrees of failed anastomotic healing, from necrotic cartilage to partial separation identified by bronchoscopy were treated with HBOT. HBOT was administered for 90 minutes via a hyperbaric chamber pressurized to 2 atm with 100% oxygen. Patients were treated with daily or twice daily HBOT. Four of 5 patients had buttressing of the anastomosis by strap muscle at the initial surgery. RESULTS: All patients had evidence of anastomotic healing on bronchoscopy. None of the patients in this series required tracheostomy, T tube, or reoperation after initiation of HBOT. On average it took 9.6 days for healing to occur (5-14 days). The size of the anastomotic defect ranged between 3 and 13 mm. One patient required bilateral tympanostomy tubes for inner ear discomfort and experienced blurry vision as complications of HBOT. One patient developed tracheal stenosis from granulation tissue that required bronchoscopic debridement. CONCLUSIONS: In select patients with anastomotic complications after tracheal resection, HBOT may aid in healing and avoid tracheostomy. Future investigations are necessary to further define the benefits of HBOT in the management of airway anastomotic complications. PMID- 24342904 TI - Reconstruction of right ventricular outflow tract in neonates and infants using valved cryopreserved femoral vein homografts. AB - OBJECTIVES: Aortic or pulmonary homografts (A/PHs) are common biomaterials used for restoration of right ventricle to pulmonary artery continuity for repair of various congenital heart defects. The smaller sized homografts required for early primary repair in neonates and infants are prone to early failure and are in short supply. Due to these limitations, since 2008 it has been our preference to use valved segments of cryopreserved femoral vein homograft (cFVH) for right ventricle to pulmonary artery reconstruction. This study was undertaken to assess the performance of cFVH compared with A/PH in neonates and infants. METHODS: A retrospective review of all infants and neonates who underwent biventricular early primary repair with right ventricle to pulmonary artery reconstruction using homograft conduits at a single center was conducted. Patients who received cFVH constituted the study group, whereas all other patients received A/PH and formed the control group. Patients with pulmonary atresia, ventricular septal defect, and major aortopulmonary collaterals who had conduits placed to promote pulmonary artery growth or to unifocalized pulmonary vasculature were excluded from the study because they have different clinical indications for reoperation and reintervention. Demographic, anatomical, perioperative, and follow-up variables were compared between the groups using univariate and multivariable Cox regression analyses. Kaplan-Meier analysis and log-rank tests were used to identify intergroup differences in freedom from catheter intervention, reoperation, or overall freedom from reintervention (catheter and/or surgical). RESULTS: A total of 36 patients (20 cFVH and 16 A/PH) were included in the study. There were no intergroup differences in the demographic, anatomic, and perioperative variables, except for significantly shorter aortic crossclamp time in the cFVH group. Univariate analysis revealed a higher catheter reintervention rate as well as higher reoperation rate in the A/PH group. Multivariate Cox regression correcting for the intergroup differences in the length of follow-up revealed comparable freedom from catheter intervention, freedom from reoperation, or freedom from either intervention in the cFVH and the A/PH groups. CONCLUSIONS: Valved femoral vein homografts have comparable short- and intermediate-term performance to A/PHs for right ventricular outflow tract reconstruction and are an attractive alternative to other small conduits for use in neonates and infants. PMID- 24342905 TI - Inferring land use and land cover impact on stream water quality using a Bayesian hierarchical modeling approach in the Xitiaoxi River Watershed, China. AB - Lake eutrophication has become a very serious environmental problem in China. If water pollution is to be controlled and ultimately eliminated, it is essential to understand how human activities affect surface water quality. A recently developed technique using the Bayesian hierarchical linear regression model revealed the effects of land use and land cover (LULC) on stream water quality at a watershed scale. Six LULC categories combined with watershed characteristics, including size, slope, and permeability were the variables that were studied. The pollutants of concern were nutrient concentrations of total nitrogen (TN) and total phosphorus (TP), common pollutants found in eutrophication. The monthly monitoring data at 41 sites in the Xitiaoxi Watershed, China during 2009-2010 were used for model demonstration. The results showed that the relationships between LULC and stream water quality are so complicated that the effects are varied over large areas. The models suggested that urban and agricultural land are important sources of TN and TP concentrations, while rural residential land is one of the major sources of TN. Certain agricultural practices (excessive fertilizer application) result in greater concentrations of nutrients in paddy fields, artificial grasslands, and artificial woodlands. This study suggests that Bayesian hierarchical modeling is a powerful tool for examining the complicated relationships between land use and water quality on different scales, and for developing land use and water management policies. PMID- 24342906 TI - The FDA agrees to ban powdered medical and surgical gloves. PMID- 24342907 TI - Are plain radiographs sufficient to exclude cervical spine injuries in low-risk adults? AB - BACKGROUND: The routine use of clinical decision rules and three-view plain radiography to clear the cervical spine in blunt trauma patients has been recently called into question. CLINICAL QUESTION: In low-risk adult blunt trauma patients, can plain radiographs adequately exclude cervical spine injury when clinical prediction rules cannot? EVIDENCE REVIEW: Four observational studies investigating the performance of plain radiographs in detecting cervical spine injury in low-risk adult blunt trauma patients were reviewed. CONCLUSION: The consistently poor performance of plain radiographs to rule out cervical spine injury in adult blunt trauma victims is concerning. Large, rigorously performed prospective trials focusing on low- or low/moderate-risk patients will be needed to truly define the utility of plain radiographs of the cervical spine in blunt trauma. PMID- 24342908 TI - Pre- and postnatal transplantation of fetal mesenchymal stem cells in osteogenesis imperfecta: a two-center experience. AB - Osteogenesis imperfecta (OI) can be recognized prenatally with ultrasound. Transplantation of mesenchymal stem cells (MSCs) has the potential to ameliorate skeletal damage. We report the clinical course of two patients with OI who received prenatal human fetal MSC (hfMSC) transplantation and postnatal boosting with same-donor MSCs. We have previously reported on prenatal transplantation for OI type III. This patient was retransplanted with 2.8 * 10(6) same-donor MSCs per kilogram at 8 years of age, resulting in low-level engraftment in bone and improved linear growth, mobility, and fracture incidence. An infant with an identical mutation who did not receive MSC therapy succumbed at 5 months despite postnatal bisphosphonate therapy. A second fetus with OI type IV was also transplanted with 30 * 10(6) hfMSCs per kilogram at 31 weeks of gestation and did not suffer any new fractures for the remainder of the pregnancy or during infancy. The patient followed her normal growth velocity until 13 months of age, at which time longitudinal length plateaued. A postnatal infusion of 10 * 10(6) MSCs per kilogram from the same donor was performed at 19 months of age, resulting in resumption of her growth trajectory. Neither patient demonstrated alloreactivity toward the donor hfMSCs or manifested any evidence of toxicities after transplantation. Our findings suggest that prenatal transplantation of allogeneic hfMSCs in OI appears safe and is of likely clinical benefit and that retransplantation with same-donor cells is feasible. However, the limited experience to date means that it is not possible to be conclusive and that further studies are required. PMID- 24342909 TI - Utilization of glycerin byproduct derived from soybean oil biodiesel as a carbon source for heterologous protein production in Pichia pastoris. AB - Crude glycerol, also known as glycerin, is the main byproduct of the biodiesel industry. It has been estimated that up to 40,000 tons of glycerin will be produced each year by 2020. This study evaluated the value-added use of crude glycerol derived from soybean biodiesel preparation as a carbon source for heterologous protein production using the yeast Pichia pastoris. Eleven glycerin samples were obtained by methanolysis of soybean oil using different acids or bases as catalysts. Cell growth experiments showed that crude glycerol containing either potassium or sodium hydroxide resulted in 1.5-2 times higher final cell densities when compared to glycerol P.A. Finally, crude glycerol containing sodium hydroxide was successfully utilized for constitutive heterologous alpha amylase production in P. pastoris. This study demonstrated that crude glycerol without any purification steps may be directly used as carbon source for protein production in P. pastoris. PMID- 24342910 TI - The language connectome: new pathways, new concepts. AB - The field of the neurobiology of language is experiencing a paradigm shift in which the predominant Broca-Wernicke-Geschwind language model is being revised in favor of models that acknowledge that language is processed within a distributed cortical and subcortical system. While it is important to identify the brain regions that are part of this system, it is equally important to establish the anatomical connectivity supporting their functional interactions. The most promising framework moving forward is one in which language is processed via two interacting "streams"--a dorsal and ventral stream--anchored by long association fiber pathways, namely the superior longitudinal fasciculus/arcuate fasciculus, uncinate fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and two less well-established pathways, the middle longitudinal fasciculus and extreme capsule. In this article, we review the most up-to-date literature on the anatomical connectivity and function of these pathways. We also review and emphasize the importance of the often overlooked cortico-subcortical connectivity for speech via the "motor stream" and associated fiber systems, including a recently identified cortical association tract, the frontal aslant tract. These pathways anchor the distributed cortical and subcortical systems that implement speech and language in the human brain. PMID- 24342912 TI - Application of acoustic bessel beams for handling of hollow porous spheres. AB - Acoustic manipulation of porous spherical shells, widely used as drug delivery carriers and magnetic resonance imaging contrast agents, is investigated analytically. The technique used for this purpose is based on the application of high-order Bessel beams as a single-beam acoustic manipulation device, by which particles lying on the axis of the beam can be pulled toward the beam source. The exerted acoustic radiation force is calculated using the standard partial-wave series method, and the wave propagation within the porous media is modeled using Biot's theory of poro-elasticity. Numerical simulations are performed for porous aluminum and silica shells of different thickness and porosity. Results indicate that manipulation of low-porosity shells is possible using Bessel beams with large conical angles, over a number of broadband frequency ranges, whereas manipulation of highly porous shells can occur over both narrowband and broadband frequency domains. PMID- 24342911 TI - Evaluation of utero-placental and fetal hemodynamic parameters throughout gestation in pregnant mice using high-frequency ultrasound. AB - Throughout gestation, changes in maternal and fetal Doppler parameters in pregnant mice, similar to those obtained in human fetuses, were detected using high-frequency ultrasound with a 55-MHz linear probe. In the uterine arteries (UtA), fetal umbilical artery (UA) and fetal ductus venosus (DV) peak systolic velocity increased (UtA, p = 0.04; UA, p = 0.0004; DV, p = 0.02), end-diastolic velocity increased (UtA, p < 0.001; UA, p < 0.0001; DV, p = 0.01) and resistance index decreased (UtA, p = 0.0004; UA, p = 0.0001; DV, p = 0.04) toward the end of pregnancy. In the middle cerebral and carotid arteries, end diastolic velocity increased (p = 0.02 and p < 0.0001) and resistance index decreased (both vessels, p < 0.0001). There was a reduction in the pulsatile pattern in the umbilical vein (p < 0.05). The increased velocities and reduced resistance index suggest a progressive increment in blood flow to the fetal mouse toward the end of pregnancy. Fetal and utero-placental vascular parameters in CD-1 mice can be reliably evaluated using high-frequency ultrasound. PMID- 24342913 TI - VEGFR2-targeted molecular imaging in the mouse embryo: an alternative to the tumor model. AB - As a tumor surrogate, the mouse embryo presents as an excellent alternative for examining the binding of angiogenesis-targeting microbubbles and assessing the quantitative nature of molecular ultrasound. We establish the validity of this model by developing a robust method to study microbubble kinetic behavior and investigate the reproducibility of targeted binding in the murine embryo. Vascular endothelial growth factor receptor 2 (VEGFR2)-targeted (MBV), rat immunoglobulin G2 (IgG2) control antibody-targeted (MBC) and untargeted (MBU) microbubbles were introduced into vasculature of living mouse embryos. Non-linear contrast-specific and B-mode ultrasound imaging, performed at 21 MHz with a Vevo 2100 scanner, was used to collect basic perfusion parameters and contrast mean power ratios for all bubble types. We observed a twofold increase (p < 0.001) in contrast mean power ratios for MBV (4.14 +/- 1.78) compared with those for MBC (1.95 +/- 0.78) and MBU (1.79 +/- 0.45). Targeted imaging of endogenous endothelial cell surface markers in mouse embryos is possible with labeled microbubbles. The mouse embryo thus presents as a versatile model for testing the performance of ultrasound molecular targeting, where further development of quantitative imaging techniques may enable rapid evaluations of biomarker expression in studies of vascular development, disease and angiogenesis. PMID- 24342914 TI - Synthesis and characterization of transiently stable albumin-coated microbubbles via a flow-focusing microfluidic device. AB - We describe a method for synthesizing albumin-shelled, large-diameter (>10 MUm), transiently stable microbubbles using a flow-focusing microfluidic device (FFMD). The microfluidic device enables microbubbles to be produced immediately before insonation, thus relaxing the requirements for stability. Both reconstituted fractionated bovine serum albumin (BSA) and fresh bovine blood plasma were investigated as shell stabilizers. Microbubble coalescence was inhibited by the addition of either dextrose or glycerol and propylene glycol. Microbubbles were observed to have an acoustic half-life of approximately 6 s. Microbubbles generated directly within a vessel phantom containing flowing blood produced a 6.5-dB increase in acoustic signal within the lumen. Microbubbles generated in real time upstream of in vitro rat aortic smooth muscle cells under physiologic flow conditions successfully permeabilized 58% of the cells on insonation at a peak negative pressure of 200 kPa. These results indicate that transiently stable microbubbles produced via flow-focusing microfluidic devices are capable of image enhancement and drug delivery. In addition, successful microbubble production with blood plasma suggests the potential to use blood as a stabilizing shell. PMID- 24342915 TI - In vivo estimation of flexor digitorum superficialis tendon displacement with speckle tracking on 2-D ultrasound images using Laplacian, Gaussian and Rayleigh techniques. AB - This study applies 2-D speckle tracking using B-scan ultrasound imaging to estimate the instantaneous and total displacement of the middle flexor digitorum superficialis (FDS) tendon proximal to the wrist. This is achieved by performing the study with human patients, during regular carpal tunnel surgeries. B-Scan images were collected with a 12-MHz transducer placed proximal to the wrist, while a video microscope simultaneously imaged the exposed flexor tendons in the palm as a reference for validation. The accuracy of the proposed speckle-based tracking method is compared using log-compressed Rayleigh (Fisher-Tippet)-, Gaussian (sum of squared differences)- and Laplacian (sum of absolute differences)-based statistics as similarity measures. Overall, tracking was successful and the Rayleigh technique performed better than the Laplacian or Gaussian technique. One goal of this research was to non-invasively monitor FDS tendon displacement in the wrist for the purposes of controlling a prosthetic device. An additional goal was to obtain pre- and post-operative clinical information. PMID- 24342916 TI - Narcolepsy and A(H1N1)pdm09 vaccination: shaping the research on the observed signal. AB - Epidemiological data from several European countries suggested an increased risk of the chronic sleep disorder narcolepsy following vaccination with Pandemrix(TM), an AS03-adjuvanted, pandemic A(H1N1)pdm09 influenza vaccine. Further research to investigate potential associations between PandemrixTM vaccination, A(H1N1)pdm09 influenza infection and narcolepsy is required. Narcolepsy is most commonly caused by a reduction or absence of hypocretin produced by hypocretin-secreting neurons in the hypothalamus, and is tightly associated with HLA-II DQB1*06:02. Consequently, research focusing on CD4(+) T cell responses, building on the hypothesis that for disease development, T cells specific for antigen(s) from hypocretin neurons must be activated or reactivated, is considered essential. Therefore, the following key areas of research can be identified, (1) characterization of hypothetical narcolepsy-specific auto-immune CD4(+) T cells, (2) mapping epitopes of such T cells, and (3) evaluating potential mechanisms that would enable such cells to gain access to the hypothalamus. Addressing these questions could further our understanding of the potential links between narcolepsy and A(H1N1)pdm09 vaccination and/or infection. Of particular interest is that any evidence of a mimicry-based mechanism could also explain the association between narcolepsy and A(H1N1)pdm09 influenza infection. PMID- 24342917 TI - Doctors need clear guidance, support, and advice from the GMC on relationships with patients. PMID- 24342919 TI - Wip1 and ATM in tumor evolution: role for BRCA1. PMID- 24342921 TI - Epigenetics: Reprogramming with TET. PMID- 24342922 TI - Genetic therapies: Correcting genetic defects with CRISPR-Cas9. PMID- 24342920 TI - Dynamic regulation of transcriptional states by chromatin and transcription factors. AB - The interaction of regulatory proteins with the complex nucleoprotein structures that are found in mammalian cells involves chromatin reorganization at multiple levels. Mechanisms that support these transitions are complex on many timescales, which range from milliseconds to minutes or hours. In this Review, we discuss emerging concepts regarding the function of regulatory elements in living cells. We also explore the involvement of these dynamic and stochastic processes in the evolution of fluctuating transcriptional activity states that are now commonly reported in eukaryotic systems. PMID- 24342923 TI - Dissociated effects of anticipating smoking versus monetary reward in the caudate as a function of smoking abstinence. AB - BACKGROUND: Theories of addiction suggest that chronic smoking may be associated with both hypersensitivity to smoking and related cues and hyposensitivity to alternative reinforcers. However, neural responses to smoking and nonsmoking rewards are rarely evaluated within the same paradigm, leaving the extent to which both processes operate simultaneously uncertain. Behavioral evidence and theoretical models suggest that dysregulated reward processing may be more pronounced during deprivation from nicotine, but neuroimaging evidence on the effects of deprivation on reward processing is limited. The current study examined the impact of deprivation from smoking on neural processing of both smoking and monetary rewards. METHODS: Two separate functional magnetic resonance imaging scans were performed in 38 daily smokers, one after smoking without restriction and one following 24 hours of abstinence. A rewarded guessing task was conducted during each scan to evaluate striatal blood oxygen level-dependent response during anticipation of both smoking and monetary rewards. RESULTS: A significant reward type by abstinence interaction was observed in the bilateral caudate and medial prefrontal cortex during reward anticipation. The blood oxygen level-dependent response to anticipation of smoking reward was significantly higher and anticipation of monetary rewards was significantly lower during abstinence compared with nonabstinence. Attenuation of monetary reward-related activation during abstinence was significantly correlated with abstinence-induced increases in craving and withdrawal. CONCLUSIONS: These results provide the first direct evidence of dissociated effects of smoking versus monetary rewards as a function of abstinence. The findings suggest an important neural pathway that may underlie the choice to smoke in lieu of alternative reinforcement during a quit attempt. PMID- 24342925 TI - Transcranial direct current stimulation for autistic disorder. PMID- 24342926 TI - Test providers should anticipate incidental and secondary findings, says US bioethics commission. PMID- 24342924 TI - Neuropeptide Y receptor gene expression in the primate amygdala predicts anxious temperament and brain metabolism. AB - BACKGROUND: Anxious temperament (AT) is identifiable early in life and predicts the later development of anxiety disorders and depression. Neuropeptide Y (NPY) is a putative endogenous anxiolytic neurotransmitter that adaptively regulates responses to stress and might confer resilience to stress-related psychopathology. With a well-validated nonhuman primate model of AT, we examined expression of the NPY system in the central nucleus (Ce) of the amygdala, a critical neural substrate for extreme anxiety. METHODS: In 24 young rhesus monkeys, we measured Ce messenger RNA (mRNA) levels of all members of the NPY system that are detectable in the Ce with quantitative real time polymerase chain reaction. We then examined the relationship between these mRNA levels and both AT expression and brain metabolism. RESULTS: Lower mRNA levels of neuropeptide Y receptor 1 (NPY1R) and NPY5R but not NPY or NPY2R in the Ce predicted elevated AT; mRNA levels for NPY1R and NPY5R in the motor cortex were not related to AT. In situ hybridization analysis provided for the first time a detailed description of NPY1R and NPY5R mRNA distribution in the rhesus amygdala and associated regions. Lastly, mRNA levels for these two receptors in the Ce predicted metabolic activity in several regions that have the capacity to regulate the Ce. CONCLUSIONS: Decreased NPY signaling in the Ce might contribute to the altered metabolic activity that is a component of the neural substrate underlying AT. This suggests that enhancement of NPY signaling might reduce the risk to develop psychopathology. PMID- 24342927 TI - Comparative study of the upper and lower limb skin blood flow control mechanisms in patients with essential hypertension. AB - OBJECTIVE: To investigate limb specific differences in cutaneous vascular function in patients (n=33) with essential hypertension (EHT). METHODS: In this observational cross-sectional study, baseline skin blood flow and the response to local heating were measured with a laser Doppler flowmeter (LDF) from the volar region of the forearm and the gaiter area of the foot at supine rest. The fractal analysis, detrended fluctuation analysis (DFA), was used to calculate the correlation properties of skin blood flow, LDF signal. The paired t-test and repeated measures ANOVA were used to determine the response to local heating and compare the scaling exponents of different anatomical locations respectively. RESULTS: We found three linear scaling regions that describe the fractal behavior of LDF signal with their slopes, scaling exponents. For cardiac (alpha(C)) and cardio-respiratory (alpha(CR)) scaling exponents, thermal hyperemia (T) induced greater change in the leg (alpha(C)=1.49 +/- 0.26; alpha(CT)=1.62 +/- 0.20 p<0.01 and alpha(CR)=0.84 +/- 0.29 alpha(CRT)=0.42 +/- 0.28 p<0.001) than in forearm (alpha(C)=1.28 +/- 0.13; alpha(CT)=1.33 +/- 0.13 p>0.05 and alpha(CR)=0.73 +/- 0.15; alpha(CRT)=0.65 +/- 0.018 p<0.05). Local scaling exponents (alpha(L) ~ alpha(LT) ~ 1) were not significantly different (p>0.05) and, local lines did not shift in parallel with local heating in both extremities. CONCLUSION: The results of the present study suggest that skin microvascular function is impaired in both extremities in EHT patients. However, myogenic response is not uniform in both extremities and pronounced response to local thermal hyperemia has been observed in the gaiter area compared with the volar region. Further studies are needed to determine if these limb specific microvascular differences is the result of posture-induced structural and functional adaptation. PMID- 24342928 TI - Rapid ultrasound score as an indicator of atherosclerosis' clinical manifestations in a population of hypertensives: the interrelationship between flow-mediated dilatation of brachial artery, carotid intima thickness, renal resistive index and retina resistive index of central artery. AB - OBJECTIVE: Flow-mediated dilatation (FMD) of brachial artery, renal resistive index (RRI), retina resistive index of central artery (RRICA) and carotid intima media thickness (IMT) have been used for ultrasound assessment of cardiovascular risk as good surrogate markers of pre-clinical atherosclerosis. We investigated the interrelationship of these four parameters and examined whether an integrated score is a good indicator of atherosclerotic disease in hypertensives. METHODS: One-hundred fifty-two consecutive subjects were enrolled in this study between April 2004 and April 2005. Each patient underwent cerebral computed tomography, coronarography, carotid, renal, central retinal and femoral arteries Doppler ultrasonographic evaluation. Statistical analysis was performed using ANOVA, Fisher test, Pearson correlation and stepwise regression analyses. RESULTS: FMD, RRICA, IMT and RRI were significantly correlated with each other. In multiple regression analysis age, pulse pressure, hypertension duration were independently related with the four parameters. Eighty-one findings of total atherosclerotic disease (ADAD were recorded overall (15 cerebrovascular disease, 20 coronary heart disease or myocardial infarction, 22 carotid plaques and 24 low limb plaques). Using an integrated score we were able to divide the population into three scoring bands. In the lowest band we classified 87 patients with 16% of total AD; in the intermediate 40 patients with 30% of total AD, in the highest 25 patients with 54% of total AD. Differences between groups were significant (p<0.05). CONCLUSION: A potential benefit of these integrated, low-cost and easy to-detect parameters, is the stratification of patients with atherosclerotic risk. This method may prove useful in discovering those with atherosclerosis in a pre-clinical stage for whom therapy initiated before complications could reduce the risk for a cerebro-cardio-vascular event. PMID- 24342929 TI - Apparently "low" serum asymmetric dimethylarginine is associated with fasting glucose and tends toward association with type-2 diabetes. AB - OBJECTIVE: We investigated the association of serum asymmetric dimethylarginine (ADMA) with metabolic syndrome (MetS), type-2 diabetes and coronary heart disease (CHD) in the general population. METHODS: Cross-sectional and, at 2000 person years' follow-up, prospective analysis. Adults with measured serum ADMA level (n=848) were analyzed using tertiles or dichotomized values. ADMA concentrations were measured by a validated commercial ELISA kit. RESULTS: Dichotomized subjects of combined sexes with low (<=0.68 umol/L) ADMA values had significantly higher fasting glucose, total cholesterol, apolipoprotein B and lower diastolic blood pressure. In linear regression analyses comprising age, smoking, triglyceride, HDL-cholesterol, C-reactive protein and waist circumference as well, creatinine was significantly and independently associated with ADMA, further in women glucose (inversely). In logistic regression analyses uniformly adjusted for age, smoking status and waist girth, prevalent MetS tended to positive independent association with ADMA tertiles only in men. Combined prevalent and incident diabetes weakly tended to be associated with the lowest (vs mid- and highest) ADMA tertiles in combined gender; and prevalent and incident CHD was not associated with ADMA tertiles in either sex. CONCLUSION: Apparently "low" circulating ADMA is independently associated with fasting glucose and tends to be so with type-2 diabetes. The lack of anticipated positive associations of ADMA with cardiometabolic disorders is likely due to autoimmune responses operating against serum ADMA under oxidative stress, rendering partial failure in immunoassay. PMID- 24342930 TI - Angiographically evident atherosclerotic stenosis associated with myocardial bridging and risk factors for the artery stenosis located proximally to myocardial bridging. AB - OBJECTIVE: The purpose of this study was to determine the prevalence of coronary angiographically evident atherosclerotic stenosis associated with myocardial bridging (MB) and to explore related risk factors of coronary artery stenosis located proximally to MB. METHODS: Overall, 603 patients with MB-mural coronary arteries (MB-MCAs) diagnosed by angiography initially were enrolled in this observational study during May 2004 to May 2009. One-way ANOVA, t-test, Pearson correlation test and stepwise multiple regression analysis were performed to explore related risk factors. RESULTS: Totally 644 MB-MCAs were examined. Prevalence of lesions located distally to MBs was significantly lower than those proximally to MBs [36 (5.9%) vs. 382 (62.4%), p<0.001]. Diastolic vessel diameters in MB segments were significantly smaller than reference segments p<0.001. Ulcer-like lesion was found in MB-MCA in 1 patient. Multivariate analysis suggested that vascular bifurcation lesions, the degree of narrowing and the number of diseased coronary vessels of non-MB-MCA arteries, age, low-density lipoprotein cholesterol (LDL-C)/high density lipoprotein cholesterol (HDL-C), male, course of diabetes, and systolic narrow rate (SNR) of MB-MCAs were positively related with the narrow degree of the first coronary artery stenosis (FCAS) located proximally to MBs (all p<0.05). Vascular bifurcation lesions, the degree of narrowing and the number of diseased coronary vessels of non-MB-MCA arteries, age, LDL-C/HDL-C, male, diabetes and dyslipidemia were positively related with the narrow degree of the most severe coronary artery stenosis(MSCAS) located proximally to MB (all p<0.05). CONCLUSION: The intramural and distal portions of a bridged artery are not the forbidden zone of artery atherosclerosis formation. SNR of MB-MCA may be one of the important decision factors to coronary artery stenosis located proximally to MB. PMID- 24342931 TI - Relation of ABO blood groups to coronary lesion complexity in patients with stable coronary artery disease. AB - OBJECTIVE: We aimed to investigate the relationship between ABO blood groups and complexity of coronary lesions assessed by SYNTAX score (SS) in stable coronary artery disease (CAD) patients. METHODS: Our cross-sectional and observational study population consisted of 559 stable CAD patients. From all patients, ABO blood group was determined and the SS was calculated as low SYNTAX score (0-22), intermediate SYNTAX (23-32) score and high SYNTAX score (>32). Statistical analysis was performed using Student's t-test or Mann-Whitney U test, ANOVA, or Kruskal-Wallis test and chi-square test. Multiple logistic regression analysis was used to identify the independent predictors of high SS. RESULTS: The analysis between the SS tertiles revealed that the frequency of non-O blood group was significantly higher in the upper SS tertiles (56.2% vs. 75.9 vs. 80.2%, p<0.05). However, the frequencies of Rh types were similar in all tertiles. Multiple logistic regression analysis was applied for determining the predictors of high SS. Accordingly, non-O blood group (OR: 2.68, 95% CI 1.65-4.35, p<0.001), LV-EF (OR: 0.93, 95% CI 0.91-0.95, p<0.001), LDL(OR: 0.98, 95% CI 0.97-0.99, p<0.001), and e-GFR (OR: 0.99, 95% CI 0.98-0.98, p<0.001) were found to be the independent predictors of high SS. CONCLUSION: We showed that there were significant associations between ABO blood groups and complexity of angiographic CAD. PMID- 24342932 TI - An ACE in the hole for patients with advanced chronic kidney disease? PMID- 24342934 TI - Genotoxic evaluation of chloroacetonitrile in murine marrow cells and effects on DNA damage repair gene expressions. AB - Although chloroacetonitrile (CAN), a disinfection by-product of chlorination of drinking water, is considered a rodent carcinogen that induces lung adenomas in mice, previous studies on its genotoxicity have yielded inconclusive results. Thus, its cancer mode of action has not been clearly defined. We evaluated CAN induced genotoxicity in mice using mouse bone marrow micronucleus test, comet assays and expression of genes associated with DNA damage repair. Mice exposed to CAN at 8.75, 17.5, 35 and 52.5mg/kg for 7 days did not exhibit any significant increases in the incidence of micronuclei formation at 24 and 48h after last exposure. However, CAN caused significant suppressions of erythroblast proliferation at the highest dose. In the alkaline comet assay, there was a significant increase in the incidence of DNA strand breaks in mice killed after 3h of last treatment with 35 and 52.5mg/kg/day CAN, while no significant difference in the DNA strand breaks was found in mice killed after 24h of the last treatment. However, slight (but significant) CAN-induced oxidative DNA damage was detected following Fpg digestion at 3-h sampling time, digestion with EndoIII resulted in considerable increases in oxidative DNA damage at 3 and 24h after the last exposure to 35 and 52.5mg/kg/day CAN as detected by oxidative comet assays. The expression of DNA repair genes OGG1 , Apex1, PARP1 and p53 were up-regulated in mice given 35mg/kg/day CAN at 3h but not in 24h after the last treatment except OGG1 . However, the significant up-regulation of OGG1 at 24h after the last treatment further indicates the occurrence of oxidative DNA damage. Overall, CAN exposure is associated with up-regulation of DNA repair gene expression and the induction of oxidative DNA damage, which may be at least partially responsible for CAN-induced genotoxicity and eventually cause carcinogenicity. PMID- 24342935 TI - Characteristics of nucleoplasmic bridges induced by 60Co gamma-rays in human peripheral blood lymphocytes. AB - Few studies have shown that the yields of ionising-radiation-induced nucleoplasmic bridges (NPBs) in human cells are dose dependent. However, a dose response curve between the NPB frequency and the absorbed dose of ionising radiation has not yet been established. This study aimed to investigate NPB frequencies in human peripheral blood lymphocytes induced by cobalt-60 (60Co) gamma-rays and to establish a dose-response curve. Human peripheral blood samples were collected from three healthy males, and some of these samples were irradiated with 0-6 Gy 60Co gamma-rays. A cytokinesis-block micronucleus cytome assay was then carried out to analyse NPBs and micronuclei (MN) in binucleated cells. The remaining blood samples were irradiated with 0, 2 and 5 Gy of gamma rays, and unstable chromosome aberrations (dicentric chromosome, ring chromosome and acentric chromosome fragment) were analysed. The correlation between NPBs and dicentric plus ring chromosome (dic+r) induced by the same gamma-ray dose was also analysed. Results showed that the NPB yields among the three subjects at each dose level were not significantly different. NPBs in binucleated cells at all gamma-ray doses conformed to Poisson distribution. The dose-response curve of the gamma-ray-induced NPB frequencies followed the linear-quadratic model y = (1.39*10-3)x 2 + (4.94*10-3)x. A positive correlation was observed between the frequencies of NPB and dic+r, as well as between the frequencies of MN and acentric fragments. Therefore, NPB is an important biomarker of early chromosome damage event induced by ionising radiation. PMID- 24342936 TI - An automated new technique for scoring the in vivo micronucleus assay with image analysis. AB - The mammalian erythrocyte micronucleus assay is frequently used to assess chemical-induced damage to the chromosomes or the mitotic apparatus of erythroblasts. Because quantitative analysis of micronuclei by microscopy is time consuming and laborious, several automatic scoring methodologies with image analysis have been reported. However, there have been cases in which it was difficult to examine the proportion of polychromatic erythrocytes (PCEs) among total erythrocytes as an index for bone marrow (BM) toxicity, and sample slide preparation has proven to be laborious with existing automatic methods. We developed an automatic scoring system with image analysis for the rodent erythrocyte micronucleus assay using 12-well plates employing high-content screening analyser. In our method, micronucleated PCEs (MNPCEs), PCEs and erythrocytes were identified from three kinds of images: bright field image, fluorescence image with Hoechst 33342, and fluorescence image with propidium iodide. The frequencies of MNPCEs and PCEs were subsequently calculated. A comparison of automatic and manual scoring was carried out using BM and peripheral blood (PB) obtained from mice treated with stepwise doses of mitomycin C. The scores obtained by automatic analysis corresponded to those obtained by manual scoring; the frequencies of MNPCEs in BM and PB obtained by automatic scoring were 132 and 113%, respectively, of those obtained by manual scoring, and the corresponding frequencies of PCEs were 95 and 120%, respectively. Furthermore, we performed five repeats of the examinations of mouse BM and PB treated with mitomycin C or vinblastine sulphate and showed that automatic scoring was equivalent to manual scoring in reproducibility. Meanwhile, the scoring data obtained by manual scoring tended to vary among observers. These results suggest that our automatic scoring system with image analysis is superior to manual microscopy scoring in terms of speed and objectivity, comparable in reproducibility and useful for the in vivo micronucleus assay. PMID- 24342941 TI - Clinical consideration for mesenchymal stem cells in hematopoietic stem cell transplantation. PMID- 24342942 TI - Isolation of mouse islet by collagenase perfusion through the splenic vein. PMID- 24342943 TI - Pitfall of right lateral sector graft procurement: supraportal right posterior hepatic artery. PMID- 24342944 TI - Human islet isolation processing times shortened by one hour: minimized incubation time between tissue harvest and islet purification. PMID- 24342945 TI - Towards uniformity in communication and a tailor-made treatment for displaced intra-articular calcaneal fractures. PMID- 24342946 TI - Ammonium removal from anaerobically treated effluent by Chlamydomonas acidophila. AB - Several batch culture studies were carried out to evaluate an anaerobically treated effluent as a low-cost growth medium for the microalga Chlamydomonas acidophila and to study the effectiveness of the microalga in removing NH4-N from the effluent. An initial decrease in the effluent pH to 3 was required for adequate growth of C. acidophila and removal of NH4-N. Growth of the microalgae was inhibited at high light intensity (224MUmolphotonsm(-2)s(-1) at the surface of the vessels). However, the growth was not greatly affected by the high solid content and turbidity of the effluent. The microalga was able to grow in media containing NH4-N at concentrations of up to 1000mgL(-1) (50% of effluent) and to remove 88mg of NH4-NL(-1) in 10days. C. acidophila therefore appears a promising agent for the removal of NH4-N from anaerobically treated effluents. PMID- 24342947 TI - High yield production of sugars from deproteinated palm kernel cake under microwave irradiation via dilute sulfuric acid hydrolysis. AB - Recent years, great interest has been devoted to the conversion of biomass derived carbohydrate into sugars, such as glucose, mannose and fructose. These are important versatile intermediate products that are easily processed into high value-added biofuels. In this work, microwave-assisted dilute sulfuric acid hydrolysis of deproteinated palm kernel cake (DPKC) was systematically studied using Response Surface Methodology. The highest mannose yield (92.11%) was achieved at the optimized condition of 148 degrees C, 0.75N H2SO4, 10min 31s and substrate to solvent (SS) ratio (w/v) of 1:49.69. Besides that, total fermentable sugars yield (77.11%), was obtained at 170 degrees C, 0.181N H2SO4, 6min 6s and SS ratio (w/v) of 1:40. Ridge analysis was employed to further verify the optimum conditions. Thus, this work provides fundamental data of the practical use of DPKC as low cost, high yield and environmental-friendly material for the production of mannose and other sugars. PMID- 24342948 TI - BCL2-specific inhibitor ABT-199 synergizes strongly with cytarabine against the early immature LOUCY cell line but not more-differentiated T-ALL cell lines. PMID- 24342949 TI - Pontin is a critical regulator for AML1-ETO-induced leukemia. AB - The oncogenic fusion protein AML1-ETO, also known as RUNX1-RUNX1T1 is generated by the t(8;21)(q22;q22) translocation, one of the most frequent chromosomal rearrangements in acute myeloid leukemia (AML). Identifying the genes that cooperate with or are required for the oncogenic activity of this chimeric transcription factor remains a major challenge. Our previous studies showed that Drosophila provides a genuine model to study how AML1-ETO promotes leukemia. Here, using an in vivo RNA interference screen for suppressors of AML1-ETO activity, we identified pontin/RUVBL1 as a gene required for AML1-ETO-induced lethality and blood cell proliferation in Drosophila. We further show that PONTIN inhibition strongly impaired the growth of human t(8;21)(+) or AML1-ETO expressing leukemic blood cells. Interestingly, AML1-ETO promoted the transcription of PONTIN. Moreover, transcriptome analysis in Kasumi-1 cells revealed a strong correlation between PONTIN and AML1-ETO gene signatures and demonstrated that PONTIN chiefly regulated the expression of genes implicated in cell cycle progression. Concordantly, PONTIN depletion inhibited leukemic self renewal and caused cell cycle arrest. All together our data suggest that the upregulation of PONTIN by AML1-ETO participate in the oncogenic growth of t(8;21) cells. PMID- 24342951 TI - [Survival advantage for colectomy in fulminant Clostridium difficile colitis: Results of a systematic review of the literature]. PMID- 24342950 TI - Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders. AB - In this study, we compared immunoglobulin heavy-chain-gene-based minimal residual disease (MRD) detection by real-time quantitative PCR (RQ-PCR) and next generation sequencing (NGS) to assess whether NGS could overcome some limitations of RQ-PCR and further increase sensitivity, specificity, accuracy and reproducibility. In total, 378 samples from 55 patients with acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL) or multiple myeloma (MM) were investigated for clonotype identification, clonotype identity and comparability of MRD results. Forty-five clonotypes were identified by RQ-PCR and 49 by NGS. Clonotypes identified by both tools were identical or >97% homologous in 96% of cases. Both tools were able to routinely reach a sensitivity level of 1 * E-05. A good correlation of MRD results was observed (R=0.791, P<0.001), with excellent concordance in 79.6% of cases. Few discordant cases were observed across all disease subtypes. NGS showed at least the same level of sensitivity as allele specific oligonucleotides-PCR, without the need for patient-specific reagents. We conclude that NGS is an effective tool for MRD monitoring in ALL, MCL and MM. Prospective comparative analysis of unselected cases is required to validate the clinical impact of NGS-based MRD assessment. PMID- 24342952 TI - [Mesohepatectomy for centrally located liver tumors]. PMID- 24342953 TI - Strategies for assignment of HIV-HCV genotype-1-coinfected patients to either dual-therapy or direct-acting antiviral agent-based triple-therapy. AB - BACKGROUND: The aim of this study was to evaluate strategies for assignment of HIV-HCV genotype-1-coinfected patients (HIV-HCV-GT1) to either dual-therapy or direct-acting antiviral agent (DAA)-based triple-therapy. METHODS: A total of 148 treatment-naive HIV-HCV-GT1 who received antiviral therapy with pegylated interferon/ribavirin were included in this multinational, retrospective analysis. Patients with rapid virological response (RVR) were treated for 48 weeks, while patients without RVR received either 48 or 72 weeks of treatment. IL28B rs12979860 (IL28B) non-C/C, advanced liver fibrosis and high HCV RNA were considered as established risk factors for treatment failure. RESULTS: A trend toward higher sustained virological response (SVR) rates in patients with IL28B C/C (65% [37/57] versus 51% [40/79]; P=0.097) was observed. Higher SVR rates were observed in patients without advanced liver fibrosis (61% [47/77] versus 42% [22/52]); P=0.036) and without high HCV RNA (73% [35/48] versus 49% [49/100]; P=0.006), as well as in patients with RVR (90% [35/39] versus 45% [49/109]; P<0.001). SVR rates varied statistically significantly between the risk factors for treatment failure subgroups (86% [6/7] versus 69% [34/49] versus 48% [21/44] versus 20% [4/20] for zero, one, two and three risk factors, respectively; P<0.001). In patients without RVR, higher rates of SVR were observed in those treated for 72 weeks (62% [23/37]), when compared to patients treated for 48 weeks (36% [26/72]; P=0.01). CONCLUSIONS: RVR had an excellent positive predictive value for the response to dual-therapy in HIV-HCV-GT1, emphasizing the utility of a lead-in phase for assigning these patients to dual-therapy or DAA based triple-therapy. The use of an IL28B-guided approach was suboptimal, while a combination of established baseline predictors may provide guidance for individual treatment decisions prior to the initiation of antiviral therapy. However, the extension of treatment duration to 72 weeks in HIV-HCV-GT1 without RVR should be strongly considered if triple-therapy is not available. PMID- 24342954 TI - Purification of a thermostable chitinase from Bacillus cereus by chitin affinity and its application in microbial community changes in soil. AB - A thermostable chitinase was purified by chitin affinity from the culture supernatant of Bacillus cereus TKU028 with shrimp head powder (SHP) as the sole carbon/nitrogen source. TKU028 chitinase was purified using a one-step affinity adsorbent system, and the molecular mass of TKU028 chitinase (approximately 40 kDa) was then determined using SDS-PAGE. The enzyme was stable for 60 min at temperatures below 60 degrees C and stable over a broad pH range of 4-9 for 60 min. In addition, the temporal changes of a bacterial community in mangrove river sediment of the Tamsui River with added SHP were also analysed by PCR-denaturing gradient gel electrophoresis to investigate the effects of B. cereus TKU028 on the degradation of SHP. The 6-week incubation sample of SHP and B. cereus TKU028 amended mangrove river sediment displayed the highest amount of biomass, reducing sugar and total sugar, and some variance of bacterial community composition existed in the soils. PMID- 24342955 TI - Mechanism and kinetics modeling of the enzymatic hydrolysis of alpha1-32 antibacterial peptide. AB - Several antibacterial peptides can be obtained by enzymatic hydrolysis of the alpha chain of bovine hemoglobin. The kinetics of alpha1-32 peptide hydrolysis by pepsin was studied at several temperatures (15, 23 and 37 degrees C). Intermediate and final peptides were identified, and their antibacterial activity was assessed against four bacterial species. Evolution of generated peptides concentration enabled to propose a reaction pathway describing the parallel and consecutive reactions taking place during the hydrolysis. A mathematical model, based on the proposed mechanism, was developed to describe the kinetics of generated peptides during alpha1-32 hydrolysis. The constants of the main reactions were identified based on the experimental data, and their dependence on temperature was established using Arrhenius-type equations. Validation of the proposed model was performed by predicting kinetics of alpha1-32 peptide hydrolysis at 30 degrees C (all other experimental conditions being unchanged) with a good accuracy. This mathematical model could allow defining the optimal conditions for the production of various intermediate peptides with antibacterial activity from peptic hydrolysis of alpha1-32 peptide. PMID- 24342956 TI - Peritoneal dialysis: Cognitive behavioural therapy might improve patient adherence to fluid restrictions. PMID- 24342957 TI - Transplantation immunology in 2013: New approaches to diagnosis of rejection. AB - In 2013, a key theme of research in renal transplantation was the diagnosis of rejection. Data from key studies published in the past year highlight aspects of rejection that warrant further investigation and should prompt the consideration of adjunctive tests to complement traditional histological assessment of allograft biopsy samples. PMID- 24342958 TI - Polycystic kidney disease: Periostin is involved in cell proliferation and interstitial fibrosis in polycystic kidney disease. PMID- 24342959 TI - Nephrotic syndrome: Negative feedback loop reveals novel potential therapy. PMID- 24342960 TI - Stem cells: Decorin has role in differentiation. PMID- 24342961 TI - SCN1A variations and response to multiple antiepileptic drugs. AB - In the current study, we have used the haplotype-tagging single-nucleotide polymorphisms (SNPs) to determine associations between genetic variants in SCN1A and treatment response in 519 Caucasian patients with known response status for epilepsy treated with antiepileptic drugs (AEDs) with sodium channel blocking effects. Nine SNPs within SCN1A were genotyped in this cohort. The only association observed was for rs10188577. A greater proportion of drug-resistant patients were heterozygous compared with drug responsive patients (48.3% vs 35.4%, P=0.014). After correction for potential confounding factors, the association for rs10188577 was only marginally significant (P=0.049). In light of our findings, it seems unlikely that rs10188577 could be a major determinant of response to AEDs. However, looking at the influence of rs10188577 on the expressed quantitative trait association patterns within the immediate vicinity of SCN1A, we found significant associations with neighbouring sodium channel genes, SCN7A and SCN9A (P<0.025), which warrants further studies. PMID- 24342963 TI - Authors' reply to Kolstad and colleagues. PMID- 24342964 TI - Characterization of the ATG8-conjugation system in 2 Plasmodium species with special focus on the liver stage: possible linkage between the apicoplastic and autophagic systems? AB - Plasmodium parasites successfully colonize different habitats within mammals and mosquitoes, and adaptation to various environments is accompanied by changes in their organelle composition and size. Previously, we observed that during hepatocyte infection, Plasmodium discards organelles involved in invasion and expands those implicated in biosynthetic pathways. We hypothesized that this process is regulated by autophagy. Plasmodium spp. possess a rudimentary set of known autophagy-related proteins that includes the ortholog of yeast Atg8. In this study, we analyzed the activity of the ATG8-conjugation pathway over the course of the lifecycle of Plasmodium falciparum and during the liver stage of Plasmodium berghei. We engineered a transgenic P. falciparum strain expressing mCherry-PfATG8. These transgenic parasites expressed mCherry-PfATG8 in human hepatocytes and erythrocytes, and in the midgut and salivary glands of Anopheles mosquitoes. In all observed stages, mCherry-PfATG8 was localized to tubular structures. Our EM and colocalization studies done in P. berghei showed the association of PbATG8 on the limiting membranes of the endosymbiont-derived plastid-like organelle known as the apicoplast. Interestingly, during parasite replication in hepatocytes, the association of PbATG8 with the apicoplast increases as this organelle expands in size. PbATG3, PbATG7 and PbATG8 are cotranscribed in all parasitic stages. Molecular analysis of PbATG8 and PbATG3 revealed a novel mechanism of interaction compared with that observed for other orthologs. This is further supported by the inability of Plasmodium ATG8 to functionally complement atg8Delta yeast or localize to autophagosomes in starved mammalian cells. Altogether, these data suggests a unique role for the ATG8 conjugation system in Plasmodium parasites. PMID- 24342965 TI - Recent advances in genome mining of secondary metabolite biosynthetic gene clusters and the development of heterologous expression systems in Aspergillus nidulans. AB - Fungi are prolific producers of secondary metabolites (SMs) that show a variety of biological activities. Recent advances in genome sequencing have shown that fungal genomes harbor far more SM gene clusters than are expressed under conventional laboratory conditions. Activation of these "silent" gene clusters is a major challenge, and many approaches have been taken to attempt to activate them and, thus, unlock the vast treasure chest of fungal SMs. This review will cover recent advances in genome mining of SMs in Aspergillus nidulans. We will also discuss current updates in gene annotation of A. nidulans and recent developments in A. nidulans as a molecular genetic system, both of which are essential for rapid and efficient experimental verification of SM gene clusters on a genome-wide scale. Finally, we will describe advances in the use of A. nidulans as a heterologous expression system to aid in the analysis of SM gene clusters from other fungal species that do not have an established molecular genetic system. PMID- 24342966 TI - Nisin production in a chitin-including continuous fermentation system with Lactococcus lactis displaying a cell wall chitin-binding domain. AB - The limiting factors in the continuous production of nisin are high amount of biomass loss and low dilution rate application. In this study, a chitin-including continuous nisin fermentation system (CICON-FER) was constructed for high volumetric nisin production using nisin producer L. lactis displaying cell wall chitin-binding domain (ChBD) together with chitin in the reactor. In this respect, the highest binding conditions of relevant L. lactis cells to chitin were determined. Then the chitin flakes carrying nisin-producing L. lactis cells were used within the CICON-FER system at different dilution rates (0.1-0.9 h-1) and initial glucose concentrations (20-60 g l-1). The results revealed that the pH 7 conditions and the use of 100 mM sodium phosphate buffer with 0.1 % Tween 20 and Triton X-100 significantly increased the binding capacity of ChBD displaying L. lactis cells to chitin. The constructed CICON-FER system maintained the presence of the ChBD surface displaying L. lactis cells in the reactor system until 0.9 h-1 dilution rate that resulted in a considerably high level of volumetric nisin production and productivity (10,500 IU ml-1 and 9,450 IU ml-1 h 1, respectively) with the combination of a 0.9-h-1 dilution rate and a 40-g l-1 initial glucose concentration. In conclusion, an innovative nisin fermentation system that yielded the highest nisin production thus far and that was feasible for industrial application was created. PMID- 24342968 TI - High-resolution magic angle spinning (1)H magnetic resonance spectroscopy detects choline as a biomarker in a swine obstructive chronic pancreatitis model at an early stage. AB - Chronic pancreatitis (CP) is a progressive inflammatory and fibrotic disease of the pancreas which encompasses a variety of clinical syndromes ranging from mild to life-threatening complications. Metabolomics has increasingly been applied to identify biomarkers for disease diagnosis with particular interest in diseases at an early stage. In this study, we tested a swine obstructive CP model by subtotal ligation of the main pancreatic duct, and the metabolic profiles of the Bama miniature swine pancreas were investigated using high-resolution magic angle spinning proton magnetic resonance spectroscopy (HR MAS (1)H MRS) combined with principal components analysis (PCA). Increases in lactate and choline for mild CP and decreases in glycerophosphocholine, phosphocholine, betaine and glycine were observed from normal pancreas to mild, moderate and severe CP. PCA results showed visual separations among the groups. The increase of choline at an early stage of CP and the decrease of glycerophosphocholine, phosphocholine, betaine and glycine reveal the pathogenesis of CP at a molecular level. The MRS results presented here demonstrate the potential of metabolic profiles in discriminating a normal pancreas from different stages of CP, which may be used to achieve CP early diagnosis and timely intervention to prevent irreversible destruction of the pancreas. PMID- 24342967 TI - Microbial genome mining for accelerated natural products discovery: is a renaissance in the making? AB - Microbial genome mining is a rapidly developing approach to discover new and novel secondary metabolites for drug discovery. Many advances have been made in the past decade to facilitate genome mining, and these are reviewed in this Special Issue of the Journal of Industrial Microbiology and Biotechnology. In this Introductory Review, we discuss the concept of genome mining and why it is important for the revitalization of natural product discovery; what microbes show the most promise for focused genome mining; how microbial genomes can be mined; how genome mining can be leveraged with other technologies; how progress on genome mining can be accelerated; and who should fund future progress in this promising field. We direct interested readers to more focused reviews on the individual topics in this Special Issue for more detailed summaries on the current state-of-the-art. PMID- 24342970 TI - New Zealand prostate cancer awareness programme is likely to increase unnecessary PSA testing, critics say. PMID- 24342971 TI - Physicians' preferences for hospice if they were terminally ill and the timing of hospice discussions with their patients. PMID- 24342972 TI - Comprehensive comparison of self-administered questionnaires for measuring quantitative autistic traits in adults. AB - We comprehensively compared all available questionnaires for measuring quantitative autistic traits (QATs) in terms of reliability and construct validity in 3,147 non-clinical and 60 clinical subjects with normal intelligence. We examined four full-length forms, the Subthreshold Autism Trait Questionnaire (SATQ), the Broader Autism Phenotype Questionnaire, the Social Responsiveness Scale2-Adult Self report (SRS2-AS), and the Autism-Spectrum Quotient (AQ). The SRS2-AS and the AQ each had several short forms that we also examined, bringing the total to 11 forms. Though all QAT questionnaires showed acceptable levels of test-retest reliability, the AQ and SRS2-AS, including their short forms, exhibited poor internal consistency and discriminant validity, respectively. The SATQ excelled in terms of classical test theory and due to its short length. PMID- 24342973 TI - Transplantation of co-aggregates of Sertoli cells and islet cells into liver without immunosuppression. AB - BACKGROUND: Transplantation of islets of Langerhans (islets) was used to treat insulin-dependent diabetes mellitus. However, islet grafts must be maintained by administration of immunosuppressive drugs, which can lead to complications in the long term. An approach that avoids immunosuppressive drug use is desirable. METHODS: Co-aggregates of Sertoli cells and islet cells from BALB/c mice that were prepared by the hanging drop method were transplanted into C57BL/6 mouse liver through the portal vein as in human clinical islet transplantation. RESULTS: The core part of the aggregates contained mainly Sertoli cells, and these cells were surrounded by islet cells. The co-aggregates retained the functions of both Sertoli and islet cells. When 800 co-aggregates were transplanted into seven C57BL/6 mice via the portal vein, six of seven recipient mice demonstrated quasi-normoglycemia for more than 100 days. CONCLUSIONS: The hanging drop method is suitable for preparing aggregates of Sertoli and islet cells for transplantation. Notably, transplantation of these allogeneic co aggregates into mice with chemically induced diabetes via the portal vein resulted in long-term graft survival without systemic immunosuppression. PMID- 24342975 TI - Prediabetic living kidney donors have preserved kidney function at 10 years after donation. AB - BACKGROUND: Potential living kidney donors with prediabetes are often excluded from donation because of concerns about the development of type 2 diabetes mellitus (DM) and progression to end-stage renal disease (ESRD). This strategy may be unnecessarily restrictive. Previous studies of living kidney donors have not specifically examined subsets with prediabetes. METHODS: We ascertained the vital status and development of ESRD in 143 living kidney donors from 1994 to 2007 with predonation impaired fasting glucose (IFG). We then compared the development of DM, the estimated glomerular filtration rate, and the level of albumin excretion in 45 of these IFG donors to 45 matched controls with normal predonation fasting glucose. RESULTS: The majority (57.8%) of IFG donors had reverted to normal fasting glucose at a mean follow-up of 10.4 years. Compared with donors with normal fasting glucose, a higher proportion of IFG donors had developed DM (15.56% vs. 2.2%, P=0.06). Predonation characteristics including age, sex, and body mass index did not correlate with the risk of developing DM. At follow- up, estimated glomerular filtration rate by the Modification of Diet in Renal Disease equation (70.7+/-16.1 mL/min/1.73 m vs. 67.3+/-16.6 mL/min/1.73 m, P=0.21) and albumin excretion (urine albumin/ creatinine 9.76+/-23.6 mg/g vs. 5.91+/-11 mg/g, P=0.29) were similar in IFG and normal glucose donors. CONCLUSION: Carefully screened prediabetic living kidney donors often revert to normal fasting glucose and do not seem to have a significantly increased risk of impaired kidney function in the short term. PMID- 24342976 TI - A single-center cohort study to define the role of pretransplant biopsy score in the long-term outcome of kidney transplantation. AB - BACKGROUND: The role of pretransplant biopsy in defining the quality of kidney grafts is still debated. The aim of this study was to investigate the influence of pretransplant biopsy score on long-term graft outcome. METHODS: In a retrospective cohort study, we analyzed 372 recipients of single kidney transplantation (SKT) from deceased donors between 1997 and 2007, with an available pretransplant biopsy. We evaluated 5- and 10-year graft survival, incidence of delayed graft function, and estimated glomerular filtration rate at 1 and 5 years. RESULTS: Graft survival at 5 and 10 years was significantly better for recipients with a score of 0 compared to transplants with a score of 1 to 5, whereas we did not observe any significant difference among transplants with a score of 1 through 4. Survival of kidneys with a score of 5 was significantly worse compared to grafts with a score of 1 to 4. In a multivariate Cox model, only pretransplant histological score was significantly associated with graft survival. Transplants with a score of 0 and 5 had the best and the worst graft function, respectively, both at 1 and 5 years, whereas we did not observe any difference among patients with a score of 1 through 4. In a multivariate logistic regression, pretransplant histological score was independently associated with the prevalence of an estimated glomerular filtration rate less than 30 mL/min at 5 years. Finally, delayed graft function rate was significantly higher in recipients with a score of 5 compared to patients with a score of 1 to 4 and score of 0. CONCLUSIONS: Our data suggest that 1) pretransplant histological score may predict long-term graft outcome and 2) allocation of kidneys with a score of 4 to SKT provides an acceptable long-term graft function and survival. PMID- 24342977 TI - Depression and kidney transplantation. AB - While kidney transplantation offers several advantages in terms of improved clinical outcomes and quality of life compared to dialysis modalities, depressive symptoms are still present in approximately 25% of patients, rates comparable to that of the hemodialysis population. Correlates of depressive symptoms include marital status, income, kidney function, history of affective illness, malnutrition, and inflammation. Depressive symptoms are also associated with poor outcomes following kidney transplantation including nonadherence to immunosuppressant medication, graft failure, and all-cause mortality. Efforts to detect and treat depression should be a priority if one is to improve treatment adherence, quality of life, and outcomes in transplant recipients. PMID- 24342978 TI - Recipient age and risk for mortality after kidney transplantation in England. AB - BACKGROUND: The aim of this study was to explore age-related mortality post kidney transplantation in England over the last decade. METHODS: This study used data from Hospital Episode Statistics to select all kidney transplant procedures performed in England between April 2001 and March 2012. Demographics and medical comorbidities (based upon ICD-10 codes) were extracted at baseline. Data linkage analysis was performed with the Office for National Statistics to identify all deaths occurring among this study cohort. RESULTS: Data for 19,103 kidney transplant procedures was analyzed, with a median follow-up of 4.4 years (interquartile range 2.2-7.3 years). Categorization of age cohorts at time of transplantation were age below 50 (n=11,421, 59.8%), 50 to 59 (n=4,195, 22.0%), 60 to 69 (n=2,887, 15.1%), 70 to 79 (n=589, 3.1%), and 80 and above (n=11, 0.1%). There were 2,085 deaths that occurred among the study cohort during follow-up and mortality risk increased with age: below 50 (5.8%), 50 to 59 (14.2%), 60 to 69 (22.0%), 70 to 79 (31.9%), and 80 and above (45.5%). The three most common causes of deaths for recipients 70 and over were cardiac (21.2%), infection (21.2%), and malignancy (20.2%), respectively. Lower mortality was observed with the receipt of a living-donor kidney for recipients aged 70 and above. On Cox regression analysis, risk for death increased with each additional decade of recipient age over 50. CONCLUSION: Increasing age is a strong, independent risk factor for death after kidney transplantation. Although lower mortality was observed with living kidney transplantation among elderly recipients, living-donor rates decrease with increasing recipient age. Pretransplant counseling and posttransplant tailored immunosuppression should be explored, the latter requiring targeted clinical trials. PMID- 24342979 TI - Regulation of anti-HLA antibody-dependent natural killer cell activation by immunosuppressive agents. AB - BACKGROUND: It was demonstrated that human natural killer (NK) cells, via antibody-dependent cellular cytotoxicity (ADCC)-like mechanism, increase IFNgamma production after exposure to alloantigens. This finding was associated with an increased risk for antibody-mediated rejection (ABMR). Although the effects of various immunosuppressive drugs on T cells and B cells have been extensively studied, their effects on NK cells are less clear. This study reports the effect of immunosuppressive agents on antibody-mediated NK cell activation in vitro. METHODS: Whole blood from normal individuals was incubated with irradiated peripheral blood mononuclear cells (PBMCs) pretreated with anti-HLA antibody+ sera (in vitro ADCC), with or without immunosuppressive agents. The %IFNgamma+ and CD107a+ (degranulation marker) in CD56+ NK cells were enumerated by flow cytometry. RESULTS: Cyclosporine A and tacrolimus significantly reduced IFNgamma production in a dose-dependent manner (53%-83%), but showed minimal effect on degranulation (20%). Prednisone significantly reduced both IFNgamma production and degranulation (50%-66% reduction at maximum therapeutic levels). Calcineurin inhibitors (CNIs) in combination with prednisone additively suppressed IFNgamma production and degranulation. The effect of sirolimus or mycophenolate mofetil on NK cells was minimal. CONCLUSIONS: These results suggest that potent suppressive effects of CNIs and prednisone on antibody-mediated NK cell activation may contribute to the reduction of ADCC in sensitized patients and possibly reduce the risk for ADCC-mediated ABMR. These further underscore the importance of medication compliance in prevention of ABMR and possibly chronic rejection, and suggest that ADCC-mediated injury may increase in strategies aimed at CNI or steroid minimization or avoidance. PMID- 24342980 TI - Safety of belatacept bridging immunosuppression in hepatitis C-positive liver transplant recipients with renal dysfunction. AB - BACKGROUND: Perioperative renal dysfunction in liver transplant recipients complicates maintenance immunosuppressive therapy, particularly in patients with hepatitis C. Calcineurin inhibitors exacerbate renal dysfunction and mammalian target-of-rapamycin inhibitors are generally avoided because of perceived perioperative risks. The authors' experience with seven liver transplant patients who received belatacept and mycophenolic acid maintenance immunosuppression is reported. METHODS: A retrospective review of adult liver transplant recipients with hepatitis C receiving belatacept was conducted under Institutional Review Board approval. All patients were Epstein-Barr virus IgG seropositive. The primary endpoint was patient and graft survival, with secondary endpoints including the incidence of acute rejection, degree of renal function recovery, and occurrence of major side effects. RESULTS: Between December 19, 2011 and January 25, 2013, seven liver transplant recipients with hepatitis C received belatacept immunosuppression in the perioperative period. The primary indication for belatacept was perioperative renal dysfunction. Belatacept was initiated between 2 and 90 days posttransplant and the duration of belatacept therapy ranged from 19 to 89 days. Patients were transitioned onto calcineurin inhibitor therapy when they reached chronic kidney disease stage 2 or better. Six-month patient and graft survival was 86%. There was one episode of graft rejection on belatacept therapy in a patient who had also had early rejection before initiation of belatacept. CONCLUSIONS: The results in this initial group of patients suggest that belatacept with mycophenolic acid may be a safe maintenance immunosuppression regimen in hepatitis C-positive liver transplant recipients with renal dysfunction, and that this regimen can serve as an effective bridge to calcineurin inhibitor therapy. PMID- 24342981 TI - Trajectories of perceived benefits in living kidney donors: association with donor characteristics and recipient outcomes. AB - BACKGROUND: While improved health of the recipient may serve as a primary motivating factor, living kidney donors (LDs) also may expect to accrue some personal benefit following donation. This study sought to identify trajectories of perceived benefit over the first 2 years after donation. METHODS: Prospective questionnaire data were collected from 133 LDs from three kidney transplant programs in the United States. Before surgery, LDs completed the Living Donation Expectancies Questionnaire to assess their expectations of personal growth, interpersonal benefits, and spiritual benefits from the donation experience. This report then assessed the degree to which these expectations were met at 1, 6, 12, and 24 months post-donation. RESULTS: Analyses revealed four (Interpersonal Benefit) and five (Personal Growth, Spiritual Benefit) distinct trajectories over time. For some LDs, pre-donation expectancies about benefit were met or exceeded over the 2 years, while for others the anticipated benefits were either short lived or not met at all. Trajectory group assignment was associated with some donor characteristics (e.g., age, gender, and relationship to recipient). Also, LDs whose recipients had functioning grafts and who reported improved health status following transplantation were more likely to have their pre-donation personal growth and interpersonal benefit expectations consistently met or exceeded. CONCLUSIONS: Longitudinal trajectory analysis can help to identify different outcomes patterns for LDs and factors associated with them. The relevance of these findings is discussed in the context of LD education, follow up care, and future research on donation benefits. PMID- 24342982 TI - Functional nanoprobes for ultrasensitive detection of biomolecules: an update. AB - With the rapidly increasing demands for ultrasensitive biodetection, the design and applications of functional nanoprobes have attracted substantial interest for biosensing with optical, electrochemical, and various other means. In particular, given the comparable sizes of nanomaterials and biomolecules, there exists plenty of opportunities to develop functional nanoprobes with biomolecules for highly sensitive and selective biosensing. Over the past decade, numerous nanoprobes have been developed for ultrasensitive bioaffinity sensing of proteins and nucleic acids in both laboratory and clinical applications. In this review, we provide an update on the recent advances in this direction, particularly in the past two years, which reflects new progress since the publication of our last review on the same topic in Chem. Soc. Rev. The types of probes under discussion include: (i) nanoamplifier probes: one nanomaterial loaded with multiple biomolecules; (ii) quantum dots probes: fluorescent nanomaterials with high brightness; (iii) superquenching nanoprobes: fluorescent background suppression; (iv) nanoscale Raman probes: nanoscale surface-enhanced Raman resonance scattering; (v) nanoFETs: nanomaterial-based electrical detection; and (vi) nanoscale enhancers: nanomaterial-induced metal deposition. PMID- 24342983 TI - Inflammatory myopathies. Understanding the link between chronic inflammation and muscle degeneration in myositis. PMID- 24342985 TI - Osteoarthritis. Does metal-on-metal hip resurfacing confer a survival advantage over total hip replacement? PMID- 24342984 TI - Systemic lupus erythematosus in 2013. Taking a closer look at biologic therapy for SLE. AB - Clinical, basic and translational research in systemic lupus erythematosus are fast-moving fields. 2013 has seen the publication of some potentially landmark papers, which not only explore the potential of novel agents but also glean new insights from past trials. PMID- 24342986 TI - Inflammation. Synovitis: are fats in the fire? PMID- 24342987 TI - Reply to Fedson. PMID- 24342988 TI - Influenza vaccination effectiveness, unmeasured confounding, and immunomodulatory treatment. PMID- 24342989 TI - Decreased peripheral brain-derived neurotrophic factor levels are a biomarker of disease activity in major psychiatric disorders: a comparative meta-analysis. PMID- 24342990 TI - Brain somatic mutations: the dark matter of psychiatric genetics? AB - Although inherited DNA sequences have a well-demonstrated role in psychiatric disease risk, for even the most heritable mental disorders, monozygotic twins are discordant at a significant rate. The genetic variation associated with mental disorders has heretofore been based on the search for rare or common variation in blood cells. This search is based on the premise that every somatic cell shares an identical DNA sequence, so that variation found in lymphocytes should reflect variation present in brain cells. Evidence from the study of cancer cells, stem cells and now neurons demonstrate that this premise is false. Somatic mutation is common in human cells and has been implicated in a range of diseases beyond cancer. The exuberant proliferation of cortical precursors during fetal development provides a likely environment for somatic mutation in neuronal and glial lineages. Studies of rare neurodevelopmental disorders, such as hemimegencephaly, demonstrate somatic mutations in affected cortical cells that cannot be detected in unaffected parts of the brain or in peripheral cells. This perspective argues for the need to investigate somatic variation in the brain as an explanation of the discordance in monozygotic twins, a proximate cause of mental disorders in individuals with inherited risk, and a potential guide to novel treatment targets. PMID- 24342991 TI - Hippocampal gene expression changes underlying stress sensitization and recovery. AB - Chronic and acute stressors have been linked to changes in hippocampal function and anxiety-like behaviors. Both produce changes in gene expression, but the extent to which these changes endure beyond the end of stress remains poorly understood. As an essential first step to characterize abnormal patterns of gene expression after stress, this study demonstrates how chronic restraint stress (CRS) modulates gene expression in response to a novel stressor in the hippocampus of wild-type mice and the extent to which these changes last beyond the end of CRS. Male C57/bl6 mice were subjected to (1) a forced swim test (FST), (2) corticosterone (Cort) or vehicle injections, (3) CRS for 21 days and then a FST, or (4) allowed to recover 21 days after CRS and subjected to FST. Hippocampal mRNA was extracted and used to generate cDNA libraries for microarray hybridization. Naive acute stressors (FST and vehicle injection) altered similar sets of genes, but Cort treatment produced a profile that was distinct from both FST and vehicle. Exposure to a novel stress after CRS activated substantially more and different genes than naive exposure. Most genes increased by CRS were decreased after recovery but many remained altered and did not return to baseline. Pathway analysis identified significant clusters of differentially expressed genes across conditions, most notably the nuclear factor kappa-light chain-enhancer of B cells (NF-kappaB) pathway. Quantitative reverse transcription PCR (qRT-PCR) validated changes from the microarrays in known stress-induced genes and confirmed alterations in the NF-kappaB pathway genes, Nfkbia, RelA and Nfkb1. FST increased anxiety-like behavior in both the naive and recovery from CRS conditions, but not in mice 24h subsequent to their CRS exposure. These findings suggest that the effects of naive stress are distinct from Cort elevation, and that a history of stress exposure can permanently alter gene expression patterns in the hippocampus and the behavioral response to a novel stressor. These findings establish a baseline profile of normal recovery and adaptation to stress. Importantly, they will serve as a conceptual basis to facilitate the future study of the cellular and regional basis of gene expression changes that lead to impaired recovery from stress, such as those that occur in mood and anxiety disorders. PMID- 24342993 TI - DISCovery in psychiatric genetics. PMID- 24342992 TI - Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis. AB - The limited success in understanding the pathophysiology of major depression may result from excessive focus on the dysfunctioning of neurons, as compared with other types of brain cells. Therefore, we examined the role of dynamic alterations in microglia activation status in the development of chronic unpredictable stress (CUS)-induced depressive-like condition in rodents. We report that following an initial period (2-3 days) of stress-induced microglial proliferation and activation, some microglia underwent apoptosis, leading to reductions in their numbers within the hippocampus, but not in other brain regions, following 5 weeks of CUS exposure. At that time, microglia displayed reduced expression of activation markers as well as dystrophic morphology. Blockade of the initial stress-induced microglial activation by minocycline or by transgenic interleukin-1 receptor antagonist overexpression rescued the subsequent microglial apoptosis and decline, as well as the CUS-induced depressive-like behavior and suppressed neurogenesis. Similarly, the antidepressant drug imipramine blocked the initial stress-induced microglial activation as well as the CUS-induced microglial decline and depressive-like behavior. Treatment of CUS-exposed mice with either endotoxin, macrophage colony stimulating factor or granulocyte-macrophage colony-stimulating factor, all of which stimulated hippocampal microglial proliferation, partially or completely reversed the depressive-like behavior and dramatically increased hippocampal neurogenesis, whereas treatment with imipramine or minocycline had minimal or no anti-depressive effects, respectively, in these mice. These findings provide direct causal evidence that disturbances in microglial functioning has an etiological role in chronic stress-induced depression, suggesting that microglia stimulators could serve as fast-acting anti-depressants in some forms of depressive and stress-related conditions. PMID- 24342994 TI - Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT). AB - It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder. PMID- 24342995 TI - Mechanisms with clinical implications for atrial fibrillation-associated remodeling: cathepsin K expression, regulation, and therapeutic target and biomarker. AB - BACKGROUND: The cysteine protease cathepsin K (CatK) has been implicated in the pathogenesis of cardiovascular disease. We sought to determine the link between atrial fibrillation (AF) and plasma CatK levels and to investigate the expression of and therapeutic target for CatK in vivo and in vitro. METHODS AND RESULTS: Plasma CatK and extracellular matrix protein peptides (intact procollagen type I of N-terminal propeptide; carboxyl-terminal telopeptide of type I collagen [ICTP]) were measured in 209 consecutive patients with AF (paroxysmal AF, 146; persistent AF, 63) and 112 control subjects. In addition, the regulation of CatK expression was investigated in vivo and vitro. Patients with AF had higher plasma CatK and ICTP levels than did control subjects. Patients with persistent AF had higher levels of plasma CatK and ICTP than did patients with paroxysmal AF. CatK was correlated with ICTP concentration and left atrial diameter in all subjects. In rabbits, superoxide production, CatK activity, fibrosis, and the levels of atrial tissue angiotensin II, angiotensin type 1 receptor, gp91phox, phospho-p38 mitogen-activated protein kinase, and CatK were greater in those with tachypacing induced AF than in controls, and these changes were reversed with angiotensin type 1 receptor antagonist. Olmesartan and mitogen-activated protein kinase inhibitor decreased the CatK expression induced by angiotensin II in rat neonatal myocytes. CONCLUSIONS: These data indicated that increased plasma CatK levels are linked with the presence of AF. Angiotensin type 1 receptor antagonist appears to be effective in alleviating atrial fibrosis in a rabbit AF model, partly reducing angiotensin type 1 receptor-p38mitogen-activated protein kinase-dependent and independent CatK activation, thus preventing AF. PMID- 24342997 TI - A predictable propensity: secondary revascularization is associated with further revascularization. PMID- 24342996 TI - Sorbin and SH3 domain-containing protein 2 is released from infarcted heart in the very early phase: proteomic analysis of cardiac tissues from patients. AB - BACKGROUND: Few proteomic studies have examined human cardiac tissue following acute lethal infarction. Here, we applied a novel proteomic approach to formalin fixed, paraffin-embedded human tissue and aimed to reveal the molecular changes in the very early phase of acute myocardial infarction. METHODS AND RESULTS: Heart tissue samples were collected from 5 patients who died within 7 hours of myocardial infarction and from 5 age- and sex-matched control cases. Infarcted and control myocardia were histopathologically diagnosed and captured using laser microdissection. Proteins were extracted using an originally established method and analyzed using liquid chromatography-tandem mass spectrometry. The label-free quantification demonstrated that the levels of 21 proteins differed significantly between patients and controls. In addition to known biomarkers, the sarcoplasmic protein sorbin and SH3 domain-containing protein 2 (SORBS2) was greatly reduced in infarcted myocardia. Immunohistochemical analysis of cardiac tissues confirmed the decrease, and Western blot analysis showed a significant increase in serum sorbin and SH3 domain-containing protein 2 in acute myocardial infarction patients (n=10) compared with control cases (n=11). CONCLUSIONS: Our advanced comprehensive analysis using patient tissues and serums indicated that sarcoplasmic sorbin and SH3 domain-containing protein 2 is released from damaged cardiac tissue into the bloodstream upon lethal acute myocardial infarction. The proteomic strategy presented here is based on precise microscopic findings and is quite useful for candidate biomarker discovery using human tissue samples stored in depositories. PMID- 24342998 TI - Unraveling the link between periodontitis and cardiovascular disease. PMID- 24342999 TI - HIF-2: the missing link between obesity and cardiomyopathy. PMID- 24343000 TI - MITK-US: real-time ultrasound support within MITK. AB - PURPOSE: Intra-procedural acquisition of the patient anatomy is a key technique in the context of computer-assisted interventions (CAI). Ultrasound (US) offers major advantages as an interventional imaging modality because it is real time and low cost and does not expose the patient or physician to harmful radiation. To advance US-related research, the purpose of this paper was to develop and evaluate an open-source framework for US-based CAI applications. MATERIALS AND METHODS: We developed the open-source software module MITK-US for acquiring and processing US data as part of the well-known medical imaging interaction toolkit (MITK). To demonstrate its utility, we applied the module to implement a new concept for US-guided needle insertion. Performance of the US module was assessed by determining frame rate and latency for both a simple sample application and a more complex needle guidance system. RESULTS: MITK-US has successfully been used to implement both sample applications. Modern laptops achieve frame rates above 24 frames per second. Latency is measured to be approximately 250 ms or less. CONCLUSION: MITK-US can be considered a viable rapid prototyping environment for US-based CAI applications. PMID- 24343001 TI - Effect of the coadministration of daclatasvir on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate. AB - BACKGROUND: Daclatasvir is a highly selective NS5A replication complex inhibitor currently in development for the treatment of chronic hepatitis C infection. Daclatasvir is active at picomolar concentrations and demonstrates in vitro activity against a broad range of HCV genotypes. The primary objective of this study was to assess the effect of daclatasvir on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate (Ortho Tri-Cyclen((r))). METHODS: In this open-label single-sequence study, 20 healthy female subjects received ethinyl estradiol and norgestimate for three cycles, with coadministration of daclatasvir in cycle 3. Pharmacokinetics of ethinyl estradiol and the active metabolites of norgestimate (norelgestromin and norgestrel) were assessed in cycles 2 and 3. RESULTS: Adjusted ratios of geometric means and 90% CIs were estimated for the maximum observed plasma concentration (ethinyl estradiol 1.11 [1.02, 1.20], norelgestromin 1.06 [0.99, 1.14] and norgestrel 1.07 [0.99, 1.16]) and area under the plasma concentration time curve in one dosing interval (ethinyl estradiol 1.01 [0.95, 1.07], norelgestromin 1.12 [1.06, 1.17] and norgestrel 1.12 [1.02, 1.23]). CONCLUSIONS: Coadministration of daclatasvir resulted in no clinically relevant effects on exposure to ethinyl estradiol, norelgestromin or norgestrel. PMID- 24343002 TI - Suspended ultra-small disk resonator on silicon for optical sensing. AB - An ultra-small disk resonator consisting of a suspended silicon disk with a submicron bending radius sitting on an SiO(2) pedestal is demonstrated experimentally. An asymmetrical suspended rib waveguide is integrated as the access waveguide for the suspended submicron disk resonator, which is used to realize an ultra-small optical sensor with an improved sensitivity due to the enhanced evanescent field interaction with the analyte. The present optical sensor also has a large measurement range because of the ultra-large free spectral range of the submicron-disk resonator. As an example, a suspended submicron disk sensor with a bending radius of 0.8 MUm is designed, fabricated, and characterized. The concentration of NaCl aqueous solution and organic liquids is measured with the suspended submicron-disk sensor, and the measured sensitivity is about 130 nm/RIU, which agrees well with the simulation value. PMID- 24343004 TI - Enhancing infrared extinction and absorption in a monolayer graphene sheet by harvesting the electric dipolar mode of split ring resonators. AB - Optical extinction and absorption enhancement in the infrared range of a monolayer graphene sheet by patterning split ring resonators (SRRs) is studied. It is found that the electric mode is stronger in enhancing infrared extinction and absorption compared to the magnetic mode and other higher-order modes. We improve the infrared extinction of the SRR graphene sheet by increasing the graphene area ratio in the SRR unit cell design. With the increase of the graphene area ratio, the radiation ability of the electric dipolar mode and dissipation of graphene compete for a maximum infrared absorption of about 50%. The findings on enhancing infrared extinction and absorption of the graphene sheet by harvesting the electric dipolar mode may have potential applications in terahertz and infrared detection and modulation for graphene photonics and optoelectronics. PMID- 24343005 TI - Beam shaping of edge-emitting diode lasers using a single double-axial hyperboloidal micro-lens. AB - We report an innovative approach for beam shaping of edge-emitting semiconductor diode lasers using a single double-axial hyperboloidal micro-lens fabricated with femtosecond laser direct writing technology. The two hyperboloids of different axial lengths focus the light from fast and slow axes to an identical focal spot. The divergence angles were shaped from 60 degrees and 9 degrees to 6.9 and 32.3 mrad, respectively, and the single-end fiber coupling efficiency is measured higher than 80%. The device is simple in fabrication, robust in structure, and easy for operation, by which multiple reflections and absorptions at interfaces are reduced, and assembly errors are minimized. PMID- 24343006 TI - Generation and propagation of an anomalous vortex beam. AB - A theoretical model is proposed to describe a novel vortex beam named anomalous vortex (AV) beam. Analytical propagation formula for the proposed beam passing through a paraxial ABCD optical system is derived, and the propagation properties of such beam in free space are studied numerically. It is interesting to find that an AV beam will eventually become an elegant Laguerre-Gaussian beam in the far field (or in the focal plane) in free space. Furthermore, we report experimental generation of an AV beam and measure its propagation properties. Our experimental results are consistent with the theoretical predictions. PMID- 24343007 TI - All-digital signal-processing open-loop fiber-optic gyroscope with enlarged dynamic range. AB - We propose and realize a new open-loop fiber-optic gyroscope (FOG) with an all digital signal-processing (DSP) system where an all-digital phase-locked loop is employed for digital demodulation to eliminate the variation of the source intensity and suppress the bias drift. A Sagnac phase-shift tracking method is proposed to enlarge the dynamic range, and, with its aid, a new open-loop FOG, which can achieve a large dynamic range and high sensitivity at the same time, is realized. The experimental results show that compared with the conventional open loop FOG with the same fiber coil and optical devices, the proposed FOG reduces the bias instability from 0.259 to 0.018 deg/h, and the angle random walk from 0.031 to 0.006 deg/h(1/2), moreover, enlarges the dynamic range to +/-360 deg/s, exceeding the maximum dynamic range +/-63 deg/s of the conventional open-loop FOG. PMID- 24343008 TI - Load-insensitive temperature sensor based on azobenzene-chloroform-solution filled microstructured optical fiber. AB - A solid-core microstructured optical fiber is infiltrated with the Dispersed Yellow 7 and chloroform mixture solution, resulting in the appearance of several transmission dips with different temperature and axial load responses. The temperature- and load-dependent spectral characteristics of these dips have been investigated and the experimental results indicate that they are pretty temperature-sensitive, but insensitive to the variation of applied axial load. Such a compact fiber-optic device with electric perturbation immunity could be employed for load-insensitive temperature sensing with high sensitivity. PMID- 24343009 TI - Two-channel pulse synthesis to overcome gain narrowing in femtosecond fiber amplifiers. AB - We demonstrate spectral coherent beam combining of two femtosecond fiber chirped pulse amplifiers seeded by a common oscillator. Using active phase stabilization based on an electro-optic phase modulator, an average power of 10 W before compression and a high gain factor of 30 dB are obtained. At this gain value, 130 fs pulses with a spectral width of 19 nm can be generated, highlighting the strong potential of pulse synthesis for the reduction of the minimum duration of ultrashort pulses in fiber chirped-pulse amplifiers. PMID- 24343010 TI - Heterogeneously integrated III-V/silicon distributed feedback lasers. AB - Heterogeneously integrated III-V-on-silicon second-order distributed feedback lasers utilizing an ultra-thin DVS-BCB die-to-wafer bonding process are reported. A novel DFB laser design exploiting high confinement in the active waveguide is demonstrated. A 14 mW single-facet output power coupled to a silicon waveguide, 50 dB side-mode suppression ratio and continuous wave operation up to 60 degrees C around 1550 nm is obtained. PMID- 24343011 TI - Accurate determination of terahertz optical constants by vector network analyzer of Fabry-Perot response. AB - We present a method based on a Fabry-Perot model to efficiently and accurately estimate optical constants of wafer samples in transmission-only measurements performed by a vector network analyzer (VNA). The method is demonstrated on two separate wafer samples: one of silicon and the other of polymethylmethacrylate. Results show that the method can not only acquire optical constants accurately and simply over a broad frequency domain but also overcome the limitations of calculation for dispersive and lossy materials to which existing methods are susceptible, such as those based on VNA-driven quasi-optical transmissometers and terahertz time-domain spectrometry. PMID- 24343012 TI - 1.1 kW average output power from a thin-disk multipass amplifier for ultrashort laser pulses. AB - We report on a thin-disk multipass amplifier for ultrashort laser pulses delivering an average output power of 1105 W. The amplifier was seeded by a Trumpf TruMicro5050 laser with a power of 80 W at a wavelength of 1030 nm, pulse duration of 6.5 ps, and repetition rate of 800 kHz. The energy of the amplified pulses is 1.38 mJ with a duration of 7.3 ps. The amplifier exhibits an optical efficiency of 44% and a slope efficiency of 46%. The beam quality was measured to be better than M2=1.25. PMID- 24343013 TI - Multiwavelength shearing interferometry for measuring the slopes, curvatures, and shapes of thin films/substrate systems. AB - Multiwavelength shearing interferometry, a full-field, real-time, and vibration insensitive method with enhanced accuracy, is proposed. Theoretically, the more wavelengths that are used for shearing interferometers, the higher the precision that can be achieved in the measurement of slopes, curvatures, and the shapes of reflective surfaces. A spherical mirror with specified curvature radius is used to calibrate this method, and then the nonuniform deformation and shape of the TiNi film/Si substrate system are obtained experimentally. PMID- 24343014 TI - Post-fabrication trimming of athermal silicon waveguides. AB - We experimentally demonstrate the post-fabrication trimming of polymer-coated athermal silicon waveguides by exploiting the photosensitivity of As(2)S(3) chalcogenide glass to near-bandgap visible light. Our technique enables compensation of fabrication tolerances and modification of specific circuit functionalities after fabrication. Moreover, our athermal and trimmable waveguide technology is highly resilient to high optical power, and thus extremely appealing for nonlinear applications. Finally, it enables to fix the absolute wavelength and spectral response of silicon devices with extremely low dependence from temperature and power. PMID- 24343015 TI - Holding spatial solitons in a pumped cavity with the help of nonlinear potentials. AB - We introduce a one-dimensional model of a cavity with the Kerr nonlinearity and saturated gain designed so as to hold solitons in the state of shuttle motion. The solitons are always unstable in the cavity bounded by the usual potential barriers, due to accumulation of noise generated by the linear gain. Complete stabilization of the shuttling soliton is achieved if the linear barrier potentials are replaced by nonlinear ones, which trap the soliton, being transparent to the radiation. The removal of the noise from the cavity is additionally facilitated by an external ramp potential. The stable dynamical regimes are found numerically, and their basic properties are explained analytically. PMID- 24343016 TI - Demonstration of a diode-pumped metastable Ar laser. AB - Pulsed lasing from optically pumped rare gas metastable atoms (Ne, Ar, Kr, and Xe) has been demonstrated previously. The laser relies on a three-level scheme, which involves the (n+1)p[5/2](3) and (n+1)p[1/2](1) states from the np(5)(n+1)p electronic configuration and the metastable (n+1)s[3/2](2) level of the np(5)(n+1)s configuration (Racah notation). Population inversions were achieved using relaxation from ((n+1)p[5/2](3) to (n+1)p[1/2](1) induced by collisions with helium or argon at pressures near 1 atm. Pulsed lasing was easily achieved using the high instantaneous pump intensities provided by a pulsed optical parametric oscillator excitation laser. In the present study we examine the potential for the development of a continuous wave (CW) optically pumped Ar laser. We report lasing of the 4p[1/2](1)->4s[3/2](2) (912.547 nm) transition following CW diode laser excitation of the 4p[5/2](3)<-4s[3/2](2) line (811.754 nm). A pulsed discharge was used to generate Ar 4s[3/2](2), and the time-resolved lasing kinetics provide insights concerning the radiative and collisional relaxation processes. PMID- 24343017 TI - Analytical solutions to the simplified spherical harmonics equations using eigen decompositions. AB - We develop a modified method to simplify the analytical solutions to the simplified spherical harmonics equations (SP(N)). The scheme decouples the SP(N) partial differential equations into independent equations using eigen decompositions and calculates the Green's function of the photon migrations based on the eigenvectors and eigenvalues. In contrast to the established solutions that are based on the original coupled equations, the proposed derivation is theoretically concise and universally extendable to other regular geometries. We validate the proposed method in comparison with Monte-Carlo simulations for an infinite scattering medium and a circular geometry as an example of the boundary value problems. PMID- 24343018 TI - Low-temperature-grown InGaAs terahertz photomixer embedded in InP thermal spreading layer regrown by metalorganic chemical vapor deposition. AB - A novel buried photomixer for integrated photonic terahertz devices is proposed. The active region of the mesa-structure InGaAs photomixer is buried in an InP layer grown by metalorganic chemical vapor deposition (MOCVD) to improve heat dissipation, which is an important problem for terahertz photomixers. The proposed photomixer shows good thermal properties compared to a conventional planar-type photomixer. The MOCVD regrowth process indicates the possibility for THz photomixers to be integrated monolithically with conventional photonic devices. PMID- 24343019 TI - Azimuthal and radial shaping of vortex beams generated in twisted nonlinear photonic crystals. AB - We experimentally demonstrate that the orbital angular momentum (OAM) of a second harmonic (SH) beam, generated within twisted nonlinear photonic crystals, depends both on the OAM of the input pump beam and on the quasi-angular momentum of the crystal. In addition, when the pump's radial index is zero, the radial index of the SH beam is equal to that of the nonlinear crystal. Furthermore, by mixing two noncollinear pump beams in this crystal, we generate, in addition to the SH beams, a new "virtual beam" having multiple values of OAM that are determined by the nonlinear process. PMID- 24343020 TI - High-power passively Q-switched thulium fiber laser with distributed stimulated Brillouin scattering. AB - We report a novel passively Q-switched 2 MUm Tm(3+) fiber laser simply by distributed stimulated Brillouin scattering with an all-fiber configuration. The maximum output power is 2.49 W with an optical-to-optical slope efficiency of 12%, and the laser wavelength is centered at ~1991 nm with a spectral width of >10 nm. The single pulse energy can be over 50 MUJ with a pulse width of about 20 ns, and the pulse repetition rate can be tuned from several kilohertz to tens of kilohertz by changing the pump power. To the best of our knowledge, this is the highest-average-power passively Q-switched 2 MUm Tm(3+) fiber laser in the nanosecond regime. PMID- 24343022 TI - Validity of European position paper on rhinosinusitis disease control assessment and modifications in chronic rhinosinusitis. AB - OBJECTIVES: To develop a chronic rhinosinusitis (CRS) disease control staging system that predicts patient and physician opinion. This involved exploring the predictive capacity of the proposed European Position Paper on Rhinosinusitis (EPOS) 2012 staging system and other potential scoring systems based on patient symptoms and objective criteria. STUDY DESIGN: Prospective study. SETTING: Tertiary hospitals. SUBJECTS AND METHODS: Adults CRS patients undergoing sinus surgery were prospectively enrolled from a tertiary clinic. The Sino-Nasal Outcome Test 22, endoscopy score, and systemic medication were recorded at 6 and 12 months. A physician and patient report of their condition as either "controlled,""partly controlled," or "uncontrolled" was also recorded. Ordinal regression was used for modeling a staging system. The EPOS criteria and various combinations were assessed. Kappa agreements between the staging systems and patient/physician reports were analyzed. RESULTS: One hundred six patients were assessed. Nasal obstruction (P = .02), endoscopic mucosal inflammation (P < .001), and thick and/or purulent discharge (P = .01) associated with progress reports. A modified staging system of Nasal Obstruction, Systemic medication used, and Endoscopic inflammation (NOSE) was selected on predictive strengths. The EPOS and NOSE had significant agreement with physician's (k = 0.29, P < .01, and k = 0.45, P < .01) and patient's report (k = 0.18, P = .01, and k = 0.32, P < .01). CONCLUSIONS: The disease control assessment by EPOS has slight agreement with patients and a physician. A simpler NOSE system using nasal obstruction, mucosa, and discharge is proposed. PMID- 24343023 TI - The implications of physical injury on otovestibular and cognitive symptomatology following blast exposure. AB - OBJECTIVE: Identify a potential difference in the spectrum of otovestibular and cognitive symptoms in blast-exposed patients comparing individuals with or without significant extremity injuries. STUDY DESIGN: Case series with chart review. SETTING: A military tertiary care medical center. SUBJECTS AND METHODS: All new patient referrals for otovestibular evaluation after a blast injury or exposure were identified in the electronic medical record. One hundred consecutive patients meeting these criteria were studied. Data including presence of severe extremity injuries, diagnosis of mild traumatic brain injury, symptoms of imbalance, vertigo, headache, tympanic membrane perforation, hearing loss, and tinnitus were collected and analyzed. RESULTS: Of 100 patients included, 38 suffered severe extremity injuries. Those patients with severe extremity injuries were more likely to suffer from tympanic membrane perforations (58% vs. 23%, P < .001, odds ratio [OR], 4.71, 95% confidence interval [CI], 1.96-11.33) and hearing loss (53% vs. 23%, P = .002, OR, 3.81, 95% CI, 1.59-9.11). However, those without severe extremity injuries were more likely to suffer from imbalance (79% vs. 32%, P < .001, OR, 8.17, 95% CI, 3.26-20.44) and vertigo (47% vs. 2%, P < .001, OR, 32.52, 95% CI, 4.19-252.07) and more likely to have been diagnosed with a mild traumatic brain injury following blast exposure (66% vs. 26%, P < .001, OR, 5.47, 95% CI, 2.24-13.36). CONCLUSION: Blast-exposed individuals who sustained severe extremity injuries reported significantly fewer cognitive and vestibular symptoms. In the aftermath of a blast, those who can walk away may have still sustained a significant injury. Specifically, they may suffer more long-term cognitive and vestibular symptoms than those with severe physical injuries. PMID- 24343024 TI - The changing landscape of total laryngectomy surgery. AB - OBJECTIVE: To determine if the number of total laryngectomies (TL) performed in California has changed over a 15-year period from 1996 to 2010. We also sought to investigate if the location of surgery, length of stay, use of rotational/free flaps, cost, and complications changed over this period. STUDY DESIGN: Cross sectional. SETTING: California Hospital Inpatient Discharge Data sets. SUBJECTS AND METHODS: All patient records enlisting International Classification of Diseases, Ninth Revision, Clinical Modification procedural codes for total/radical laryngectomy were extracted from 1996 to 2010 data sets. Patients' demographics were evaluated. Hospitals were coded as university medical centers (UMCs) vs others. Population-adjusted surgery rates, percentage of surgeries with rotational/free flap and/or percutaneous endoscopic gastrostomy (PEG), length of stay, total charges, and disposition status were then analyzed and compared between UMCs and non-UMCs. RESULTS: A total of 4145 TLs were performed in California during 1996 to 2010. The overall number of surgeries declined from 1.3 to 0.6 per 100,000 California residents (P < .001). The number of surgeries performed in non-UMCs dropped by 70% during this period (P < .001). The median length of stay increased from 10 to 12 days, and the median total charges increased from $45,000 to $192,000 over the 15-year period. The use of rotational/free flaps more than doubled, and the use of PEG tubes increased 7 fold. CONCLUSION: The total number of TLs in California has declined and surgeries are currently being performed equally at UMCs and non-UMCs. The use of rotational/free flaps, costs, hospital stay length, and complications have increased over the past 15 years. PMID- 24343026 TI - Identifying RNA-binding residues based on evolutionary conserved structural and energetic features. AB - Increasing numbers of protein structures are solved each year, but many of these structures belong to proteins whose sequences are homologous to sequences in the Protein Data Bank. Nevertheless, the structures of homologous proteins belonging to the same family contain useful information because functionally important residues are expected to preserve physico-chemical, structural and energetic features. This information forms the basis of our method, which detects RNA binding residues of a given RNA-binding protein as those residues that preserve physico-chemical, structural and energetic features in its homologs. Tests on 81 RNA-bound and 35 RNA-free protein structures showed that our method yields a higher fraction of true RNA-binding residues (higher precision) than two structure-based and two sequence-based machine-learning methods. Because the method requires no training data set and has no parameters, its precision does not degrade when applied to 'novel' protein sequences unlike methods that are parameterized for a given training data set. It was used to predict the 'unknown' RNA-binding residues in the C-terminal RNA-binding domain of human CPEB3. The two predicted residues, F430 and F474, were experimentally verified to bind RNA, in particular F430, whose mutation to alanine or asparagine nearly abolished RNA binding. The method has been implemented in a webserver called DR_bind1, which is freely available with no login requirement at http://drbind.limlab.ibms.sinica.edu.tw. PMID- 24343027 TI - Characterizing the strand-specific distribution of non-CpG methylation in human pluripotent cells. AB - DNA methylation is an important defense and regulatory mechanism. In mammals, most DNA methylation occurs at CpG sites, and asymmetric non-CpG methylation has only been detected at appreciable levels in a few cell types. We are the first to systematically study the strand-specific distribution of non-CpG methylation. With the divide-and-compare strategy, we show that CHG and CHH methylation are not intrinsically different in human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). We also find that non-CpG methylation is skewed between the two strands in introns, especially at intron boundaries and in highly expressed genes. Controlling for the proximal sequences of non-CpG sites, we show that the skew of non-CpG methylation in introns is mainly guided by sequence skew. By studying subgroups of transposable elements, we also found that non-CpG methylation is distributed in a strand-specific manner in both short interspersed nuclear elements (SINE) and long interspersed nuclear elements (LINE), but not in long terminal repeats (LTR). Finally, we show that on the antisense strand of Alus, a non-CpG site just downstream of the A-box is highly methylated. Together, the divide-and-compare strategy leads us to identify regions with strand-specific distributions of non-CpG methylation in humans. PMID- 24343028 TI - A life domains perspective on acculturation and psychological adjustment: a study of refugees from the former Soviet Union. AB - The study articulates a contextual approach to research on acculturation of immigrants, suggesting that the relationship between acculturation and adjustment is dependent on the cultural demands of the life domains considered. Specifically, the study investigated the mediating effects of adjustment in occupational and social life domains on the relationship between acculturation and psychological adjustment for 391 refugees from the former Soviet Union. The study used bilinear measures of acculturation to the host (American) and heritage (Russian) cultures. Using Structural Equation Modeling, the study confirmed the hypothesized relationships, such that the positive effects of American acculturation on psychological adjustment were mediated by occupational adjustment, and the effects of Russian acculturation on psychological adjustment were mediated by satisfaction with co-ethnic social support. Psychological adjustment was measured in two ways, as psychological well-being, using a measure of life satisfaction, and as symptoms of depression and anxiety, using the Hopkins symptom checklist (HSCL). Life satisfaction served as a mediator between adjustment in occupational and social domains and HSCL, suggesting that it may be an intervening variable through which environmental stress associated with immigration contributes to the development of symptoms of mental disorder. PMID- 24343029 TI - NHS medical director sets out detail of seven day working. PMID- 24343030 TI - Effect of a structured skin care regimen on patients with fecal incontinence: a comparison cohort study. AB - PURPOSE: The purpose of this study was to measure the effect of a structured skin care regimen for critically ill patients with fecal incontinence. DESIGN: A nonrandomized, quasi-experimental research design (comparison cohort) was used for data collection. SUBJECTS AND SETTING: Seventy-six patients with fecal incontinence, Bristol stool form 5, 6, and 7, and Braden Scale score of 16 or less in the intensive care units (ICUs) at Samsung Medical Center in Seoul, South Korea, participated in the study. METHODS: Of the 76 subjects enrolled, 38 were assigned to the experimental group and 38 to the control group. Participants in the active intervention group were being cared for in an ICU; participants in the comparison group were cared for on cardiac, thoracic surgery, general surgery, and neurosurgical ICUs. A structured skin care regimen was developed and implemented, which included the regular use of a no-rinse skin cleanser, application of a skin protectant, and an indwelling fecal drainage system when indicated. Stool consistency was evaluated via the Bristol stool chart. Nurses trained in data collection determined Incontinence-Associated Dermatitis and its Severity (IADS) scores and assessed the perianal and sacral skin for occurrence of pressure ulcers daily over a 7-day period. RESULTS: Patients in the intervention group had significantly lower IADS scores (t = 4.836, P < .001) than subjects in the control group and were less likely to develop a pressure ulcer than were patients in the control group (5 vs. 19, chi2 = 11.936, P = .001). Patients with higher IADS scores were significantly more likely to develop a pressure ulcer (OR = 1.168, 95% CI = 1.074-1.271). CONCLUSION: A structured skin care regimen decreased IADS scores and occurrence of pressure ulcers. Higher IADS scores were associated with an increased risk for development of pressure ulcers. PMID- 24343031 TI - Changes in copper concentrations affect the protein levels but not the mRNA levels of copper chaperones in human umbilical vein endothelial cells. AB - Copper chaperones are critical regulators of intracellular copper metabolism and distribution. The present study was undertaken to investigate the effects of changes in copper concentrations on the abundance of copper chaperones. Human umbilical vein endothelial cells (HUVECs) were treated with siRNA targeting copper transporter 1 (CTR1) or tetraethylenepentamine (TEPA) to decrease, or with copper sulfide to increase, intracellular copper concentrations, assayed using an atomic absorption spectrophotometer. Western blot analyses showed that CTR1 silencing or TEPA treatment increased the protein levels of copper chaperone ATOX1 and copper chaperone for superoxide dismutase 1 (CCS-1), but decreased copper chaperone for cytochrome c oxidase (COX17). In contrast, copper supplementation decreased the protein levels of ATOX1 and CCS-1 and increased COX17. Real-time RT-PCR analyses found no difference in the mRNA levels of the copper chaperones examined under the conditions defined above. This study thus demonstrated that changes in copper concentrations alter the protein levels, but not the mRNA levels, of copper chaperones, suggesting a role of copper in the post-translational modification of these proteins. PMID- 24343032 TI - [Chronic wounds and bacteria. Clinical relevance, detection and therapy]. AB - The importance of bacteria in the treatment of patients with chronic wounds has been a focus of attention in recent years. A bacteriological swab taken from the wound in a Essen rotary technique is usually adequate for the diagnosis. The current detection rate of bacteria in patients with chronic leg ulcers in Germany is about 50 % for Staphylococcus aureus, 30 % for Pseudomonas aeruginosa and Enterobacteriaceae and approximately 10 % for MRSA. Most of these patients have a clinically unimportant bacterial colonization, so that systemic administration of antibiotics usually is not required. For wound cleansing only sterile solutions such as Ringer's or physiological saline solution should be used. If tap water is used, then the use of sterile filters is strongly recommended. In patients with increased risk of infection, a critical colonization or local signs of infection, modern wound antiseptics using polyhexanide or octenidine are available. The use of systemic antibiotics should be strictly limited to patients with systemic signs of infections. PMID- 24343034 TI - Validity of ICD-9-CM codes for the identification of complications related to central venous catheterization. AB - Two complications of central venous catheterization (CVC), iatrogenic pneumothorax and central line-associated bloodstream infection (CLABSI), have dedicated International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Despite increasing use of ICD-9-CM codes for research and pay-for-performance purposes, their validity for detecting complications of CVC has not been established. Complications of CVCs placed between July 2010 and December 2011 were identified by ICD-9-CM codes in discharge records from a single hospital and compared with those revealed by medical record abstraction. The ICD-9-CM code for iatrogenic pneumothorax had a sensitivity of 66.7%, specificity of 100%, positive predictive value (PPV) of 100%, and negative predictive value (NPV) of 99.5%. The ICD-9-CM codes for CLABSI had a sensitivity of 33.3%, specificity of 99.0%, PPV of 28.6%, and NPV of 99.2%. The low sensitivity and variable PPV of ICD-9-CM codes for detection of complications of CVC raise concerns about their use for research or pay-for performance purposes. PMID- 24343037 TI - Teaching residents to provide cost-conscious care: a national survey of residency program directors. PMID- 24343036 TI - Diagnosis of Polycystic Ovary Syndrome: AMH in combination with clinical symptoms. AB - PURPOSE: We assessed the utility of using anti-Mullerian hormone (AMH) and clinical features of polycystic ovary syndrome (PCOS), polycystic ovarian morphology (PCOM), oligo/amenorrhea (OA), and hyperandrogenism (HA) for diagnosing PCOS, and compared their diagnostic accuracy with those of classical diagnostic systems. METHODS: A total of 606 females were admitted to a university hospital with menstrual irregularities or symptoms of hyperandrogenism were enrolled in this cross-sectional study. Fasting blood samples were collected. Pelvic and/or abdominal ultrasonography and clinical examination were performed. Patients were evaluated for the presence of PCOS according to conventional diagnostic criteria. The diagnostic performance of using serum AMH levels alone and in various combinations with the clinical features of PCOM, OA, and HA were investigated. RESULTS: For the diagnosis of PCOS, the combination of OA and/or HA with AMH showed 83% sensitivity and 100% specificity according to the Rotterdam criteria; 83% sensitivity and 89% specificity according to the National Institutes of Health (NIH) criteria; and 82% sensitivity and 93.5% specificity according to the Androgen Excess Society (AES) criteria. CONCLUSIONS: The serum AMH level is a useful diagnostic marker for PCOS and is correlated with conventional diagnostic criteria. The combination of AMH level with OA and/or HA markedly increased the clinical scope for PCOS diagnosis and can be introduced as a possible objective criterion for the diagnosis of this disease. PMID- 24343038 TI - Aspect-ratio- and size-dependent emergence of the surface-plasmon resonance in gold nanorods--an ab initio TDDFT study. AB - It is known that the surface-plasmon resonance (SPR) in small spherical Au nanoparticles of about 2 nm is strongly damped. We demonstrate that small Au nanorods with a high aspect ratio develop a strong longitudinal SPR, with intensity comparable to that in Ag rods, as soon as the resonance energy drops below the onset of the interband transitions due to the geometry. We present ab initio calculations of time-dependent density-functional theory of rods with lengths of up to 7 nm. By changing the length and width, not only the energy but also the character of the resonance in Au rods can be tuned. Moreover, the aspect ratio alone is not sufficient to predict the character of the spectrum; the absolute size matters. PMID- 24343039 TI - Serum creatinine elevation caused by bupropion. PMID- 24343040 TI - Effects of migration background on weight status and motor performance of preschool children. AB - BACKGROUND: The motor performance of children and adolescents declines. We questioned whether there are differences of motor performance and weight status between preschool children with and without migration background. METHODS: A total of 1,063 4- to 5-year-old children were recruited from 41 kindergartens in Tyrol, Austria. The language spoken at home served as the indicator for a migration background. The body mass index (BMI) was calculated using a German BMI reference system. To assess motor performance, the Karlsruhe Motor Screening (KMS) was used. RESULTS: Out of 1,063 preschool children, 265 were with migration background. KMS total scores were lower with migrant children (97.5 +/- 5.9 points) than with children without migration background (100.8 +/- 6.6 points; p < 0.001). Compared with 10.4 % of children without migration background, 21.1 % of the migrant children were overweight or obese (p < 0.001). CONCLUSIONS: Motor performance and weight status of preschool children differ significantly depending on the migration status. It seems advisable to offer additional measures to promote physical activity in preschool. Especially children with a migration background should be in the focus. PMID- 24343041 TI - A 56-year-old man with co-prevalence of Leriche syndrome and dilated cardiomyopathy: case report and review. AB - We report about a 56-year-old man with dyspnoea and leg pain diagnosed with Leriche syndrome and chronic heart failure caused by dilated cardiomyopathy (DCM) with acute cardiac decompensation. Optimising of chronic heart failure therapy with diuretic and antihypertensive drugs leaded to recompensation. A defibrillator was implanted, and afterwards surgical therapy of Leriche syndrome was planned.Leriche syndrome is an uncommon variant of atherosclerotic occlusive disease characterised by total occlusion in abdominal aorta and/or both iliac arteries. If aortic stenosis develops slowly, collateral vascular circulation can be found frequently. Typical symptoms are claudication, symptoms related to an arterial insufficiency of the lower extremities, erectile dysfunction and weight loss. Risk factors of Leriche syndrome are diabetes mellitus, hypertension, hyperlipaemia and smoking. Further it is often associated with chronic renal failure and coronary artery disease. Diagnosis is normally made by computed tomography (CT) or magnetic resonance imaging (MRI). Standard therapy is surgical revascularisation.DCM is a common cause of a congestive heart failure, which could be induced by coronary artery disease, hypertension, toxic, metabolic, inflammatory and infectious agents, and inherited gene defects. PMID- 24343042 TI - Insulin resistance may contribute to vascular dysfunction in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are at an increased cardiovascular risk; however, the underlying mechanisms for this relationship are ill defined. Altered glucose metabolism may increase cardiovascular risk via impaired endothelial function. METHODS: We conducted a longitudinal pilot study to assess the interrelationship between systemic vascular function, glucose metabolism, and lung function in patients with COPD. Eighteen non-smoking patients with stable moderate-to-severe COPD [67 % male; median (first to third quartiles) Forced Expiratory Volume in 1 second (FEV1) % predicted: 38 % (28-55 %); body mass index: 26 kg/m(2) (24-28 kg/m(2))] free from cardiovascular risk factors were evaluated. Systemic vascular function was assessed by means of flow-mediated dilation technique of the brachial artery. Laboratory measurements included fasting blood glucose levels, circulating concentrations of insulin, C-reactive protein, and fibrinogen. Homeostatic model assessment of insulin resistance (HOMA-IR) was determined. Measurements were performed at baseline and were repeated after 12 months. RESULTS: Flow-mediated dilation significantly decreased from 13.5 % (11-15 %) at baseline to 9.8 % (6-12 %; p = 0.002) at the follow-up visit, whereas both fasting blood glucose concentrations and HOMA-IR increased from 94 mg/dl (86-103 mg/dl) to 102 mg/dl (94-111 mg/dl; p = 0.027) and from 1.2 (0.8-2.1) to 1.7 (1.2-3.0; p = 0.023), respectively. There was a significant relationship between changes in endothelial function and changes in fasting serum glucose (r = - 0.483, p = 0.009), HOMA-IR (r = - 0.441, p = 0.019), and FEV1 (r = 0.336, p = 0.05). CONCLUSION: Altered glucose metabolism may be associated with progression of endothelial dysfunction in patients with COPD. PMID- 24343043 TI - [Recommendations on the structure of the care of adults with congenital heart disease (GUCH patients) in Austria -- update 2011th]. PMID- 24343044 TI - Nutrition and health: different forms of diet and their relationship with various health parameters among Austrian adults. AB - Population-based studies report a beneficial health effect and a lower mortality rate for diets rich in fruits and vegetables. Therefore, the aim of our study was to analyze differences between various forms of diet and health-related variables. The sample for this study was taken from the Austrian Health Interview Survey 2006/07 (N = 15,474). Multivariate analyses of variance adjusted by sex, age, and socioeconomic status (SES) were conducted to examine health-related behavior, health, and quality of life depending on different forms of diet. Additionally, differences in the SES and body mass index (BMI) were analyzed. Our results show that a vegetarian diet is associated with a better health-related behavior, a lower BMI, and a higher SES. Subjects eating a carnivorous diet less rich in meat self-report poorer health, a higher number of chronic conditions, an enhanced vascular risk, as well as lower quality of life. In conclusion, our results have shown that consuming a diet rich in fruits and vegetables is associated with better health and health-related behavior. Therefore, public health programs are needed for reducing the health risks associated with a carnivorous diet. PMID- 24343045 TI - Evaporation of free water causes concentrational alkalosis in vitro. AB - BACKGROUND: The development of metabolic alkalosis was described recently in patients with hypernatremia. However, the causes for this remain unknown. The current study serves to clarify whether metabolic alkalosis develops in vitro after removal of free water from plasma and whether this can be predicted by a mathematical model. MATERIALS AND METHODS: Ten serum samples of healthy humans were dehydrated by 29 % by vacuum centrifugation corresponding to an increase of the contained concentrations by 41 %. Constant partial pressure of carbon dioxide at 40 mmHg was simulated by mathematical correction of pH [pH(40)]. Metabolic acid-base state was assessed by Gilfix' base excess subsets. Changes of acid-base state were predicted by the physical-chemical model according to Watson. RESULTS: Evaporation increased serum sodium from 141 (140-142) to 200 (197-203) mmol/L, i.e., severe hypernatremia developed. Acid-base analyses before and after serum concentration showed metabolic alkalosis with alkalemia: pH(40): 7.43 (7.41 to 7.45) vs 7.53 (7.51 to 7.55), p = 0.0051; base excess: 1.9 (0.7 to 3.6) vs 10.0 (8.2 to 11.8), p = 0.0051; base excess of free water: 0.0 (- 0.2 to 0.3) vs 17.7 (16.8 to 18.6), p = 0.0051. The acidifying effects of evaporation, including hyperalbuminemic acidosis, were beneath the alkalinizing ones. Measured and predicted acid-base changes due to serum evaporation agreed well. CONCLUSIONS: Evaporation of water from serum causes concentrational alkalosis in vitro, with good agreement between measured and predicted acid-base values. At least part of the metabolic alkalosis accompanying hypernatremia is independent of renal function. PMID- 24343046 TI - Concomitant use of beta-1 adrenoreceptor blocker and norepinephrine in patients with septic shock. Reply to a letter to the authors. PMID- 24343047 TI - Rhabdomyolysis in influenza A/H1N1. PMID- 24343048 TI - Using social media to discover public values, interests, and perceptions about cattle grazing on park lands. AB - In the western United States, livestock grazing often co-exists with recreation, cultural resource management and biodiversity protection on federal and state protected rangelands as well as on many local government open space areas. While the value of livestock grazing for managing rangeland vegetation to reduce fire fuel loads and improve wildlife habitat is increasingly recognized by resource management professionals, public concerns, and conflict between recreationist and livestock have led to reductions in public land grazing. Traditional public input methods yield a constrained picture of people's attitudes toward cows and public land grazing. Public meetings, hearings, and surveys, the most commonly used mechanisms for public land managers to solicit public opinion, tend to foster participation of organized special interests or, in the case of surveys, focus on a specific topic. General public input is limited. This study explored the use of personal photography in social media to gain insight into public perceptions of livestock grazing in public spaces. Key findings of this study include that many recreationist in grazed San Francisco Bay Area parks shared views, interests, and concerns about cows and grazing on the photo-sharing website, Flickr(TM) that seldom show up at a public meeting or in surveys. Results suggest that social media analysis can help develop a more nuanced understanding of public viewpoints useful in making decisions and creating outreach and education programs for public grazing lands. This study demonstrates that using such media can be useful in gaining an understanding of public concerns about natural resource management. PMID- 24343049 TI - Effectiveness of 2012-2013 influenza vaccine against influenza-like illness in general population: estimation in a French web-based cohort. AB - Most of the methods used for estimating the influenza vaccine effectiveness (IVE) target the individuals who have an influenza-like illness (ILI) rather than virologically-proven influenza and access the healthcare system. The objective of this study was to estimate the 2012-2013 IVE in general French population, using a cohort of volunteers registered on GrippeNet.fr, an online surveillance system for ILI. The IVE estimations were obtained through a logistic regression, and analyses were also performed by focusing on at-risk population of severe influenza, and by varying inclusion period and ILI definition. Overall, 1996 individuals were included in the analyses. The corrected IVE was estimated to 49% (20 to 67) for the overall population, and 32% (0 to 58) for the at-risk population. Three covariables appeared with a significant effect on the occurrence of at least one ILI during the epidemic: the age (P = 0.045), the presence of a child in the household (P<10(-3)), and the frequency of cold/flu (P<10(-3)). Comparable results were found at epidemic peak time in the hypothesis of real-time feed of data. In this study, we proposed a novel, follow-up, web based method to reveal seasonal vaccine effectiveness, which enables analysis in a portion of the population that is not tracked by the health care system in most VE studies. PMID- 24343050 TI - Identification of early transcriptome-based biomarkers related to lipid metabolism in peripheral blood mononuclear cells of rats nutritionally programmed for improved metabolic health. AB - Moderate maternal calorie restriction during lactation protects rat offspring against obesity development in adulthood, due to an improved ability to handle and store excess dietary fuel. We used this model to identify early transcriptome based biomarkers of metabolic health using peripheral blood mononuclear cells (PBMCs), an easily accessible surrogate tissue, by focusing on molecular markers of lipid handling. Male and female offspring of control and 20 % calorie restricted lactating dams (CR) were studied. At weaning, a set of pups was killed, and PBMCs were isolated for whole-genome microarray analysis. The remaining pups were killed at 6 months of age. CR gave lower body weight, food intake and fat accumulation, and improved levels of insulin and leptin throughout life, particularly in females. Microarray analysis of weaned rat PBMCs identified 278 genes significantly differentially expressed between control and CR. Among lipid metabolism-related genes, expression of Cpt1a, Lipe and Star was increased and Fasn, Lrp1 and Rxrb decreased in CR versus control, with changes fully confirmed by qPCR. Among them, Cpt1a, Fasn and Star emerged as particularly interesting. Transcript levels of Cpt1a in PBMCs correlated with their levels in WAT and liver at both ages examined; Fasn expression levels in PBMCs at an early age correlated with their expression levels in WAT; and early changes in Star expression levels in PBMCs correlated with their expression levels in liver and were sustained in adulthood. These findings reveal the possibility of using transcript levels of lipid metabolism-related genes in PBMCs as early biomarkers of metabolic health status. PMID- 24343051 TI - Chronic hepatitis B monitoring and treatment patterns in five European countries with different access and reimbursement policies. AB - BACKGROUND: In Europe, health-care policies are determined at a national level and differ between countries. This analysis from a prospective, longitudinal, non interventional study aimed to describe patterns in the clinical monitoring and treatment of chronic hepatitis B (CHB) in five European countries. METHODS: Country-specific cohorts of adult patients with compensated CHB managed in clinics in Germany, France, Poland, Romania and Turkey were followed for up to 2 years between March 2008 and December 2010. RESULTS: A total of 1,267 patients were included. Baseline age and gender distribution were similar across countries for patients who were treated (n=567) and untreated (n=700) at baseline. Most treated patients were receiving monotherapy at baseline, most frequently with entecavir or tenofovir in Germany, France and Turkey, and with lamivudine in Poland and Romania. Use of pegylated interferon was more frequent in Poland and Romania than in other countries. In Romania monotherapy with entecavir increased after it became reimbursed in 2008. Hospitalizations during follow-up were more frequent in Romania (1.45 hospital days/patient-year) and Poland (1.81 days/patient-year) than in Turkey, France and Germany (0.00, 0.05 and 0.10 days/patient-year, respectively); clinic visits were more frequent in Poland (3.20 versus 0.30-1.78 visits/patient-year across other countries). CONCLUSIONS: These results illustrate country-specific patterns in the management of CHB patients across Europe. Observed monitoring patterns, hospitalization rates and other health-care utilization may be related to cost and reimbursement issues; however, further study in individual countries would be required to confirm these (post hoc) observations. PMID- 24343052 TI - Letter to the editor. PMID- 24343054 TI - Intermittent self-catheterization in tetraplegic patients: a 6-year experience gained in the spinal cord unit in Prague. AB - OBJECTIVES: To present a system of urological care for patients with cervical spinal cord injury (SCI) in the Spinal Cord Unit in Prague. METHODS: Forty-one out of 412 patients hospitalized with acute SCI between 2007 and 2012 with motor complete SCI (AIS A,B) at the C4-C7 motor level and with sufficient follow-up duration were selected. Patients were trained using a male bladder catheterization model (37 with a transurethral catheter and 4 with a suprapubic catheter) to perform intermittent catheterization (IC) using an ergohand device, and were later encouraged to perform self-catheterization. RESULTS: On the basis of the motor level of the SCI, 8 out of the 41 study patients were assigned to group 1 (C4), 11 to group 2 (C5), 15 to group 3 (C6) and 7 to group 4 (C7). All patients in group 1 had an indwelling urinary catheter. In group 2, 6 patients (54.6%) learned to perform IC, with 2 of them needing another person's assistance. In 5 patients (45.5%), suprapubic cystostomy was maintained (insufficient functional grip, severe autonomic dysreflexia, prompt reflex erection). Group 3 included 12 patients (80%) performing intermittent catheterization and 3 patients (20%) with suprapubic cystostomy (insufficient functional grip, post-bladder-surgery condition, cognitive impairment). In group 4, only 1 patient (14.3%) had an indwelling catheter due to severe abductor spasticity, whereas the remaining 6 (85.7%) learned to perform IC. CONCLUSIONS: These findings suggest that patients with cervical SCI below the C5 motor level are able to learn self-catheterization, which increases independence and decreases the risk of urinary infection and stone formation. PMID- 24343053 TI - Immunogenic HSV-mediated oncolysis shapes the antitumor immune response and contributes to therapeutic efficacy. AB - Within the oncolytic virus field, the extent of virus replication that is essential for immune stimulation to control tumor growth remains unresolved. Using infected cell protein 0 (ICP0)-defective oncolytic Herpes simplex virus type 1 (HSV-1) and HSV-2 viruses (dICP0 and dNLS) that show differences in their in vitro replication and cytotoxicity, we investigated the inherent features of oncolytic HSV viruses that are required for potent antitumor activity. In vitro, the HSV-2 vectors showed rapid cytotoxicity despite lower viral burst sizes compared to HSV-1 vectors. In vivo, although both of the dICP0 vectors initially replicated to a similar level, HSV-1 dICP0 was rapidly cleared from the tumors. In spite of this rapid clearance, HSV-1 dICP0 treatment conferred significant survival benefit. HSV-1 dICP0-treated tumors showed significantly higher levels of danger-associated molecular patterns that correlated with higher numbers of antigen-presenting cells within the tumor and increased antigen-specific CD8+ T cell levels in the peripheral blood. This study suggests that, at least in the context of oncolytic HSV, the initial stages of immunogenic virus replication leading to activation of antitumor immunity are more important than persistence of a replicating virus within the tumor. This knowledge provides important insight for the design of therapeutically successful oncolytic viruses. PMID- 24343055 TI - Individualised and health-related quality of life of persons with spinal cord injury. AB - STUDY DESIGN: Cross sectional. OBJECTIVES: To examine associations among functional status, health-related and individualised quality of life (QoL) and coping style in subjects with spinal cord injury (SCI). SETTING: Italy. METHODS: Forty subjects attending our hospital-based rehabilitation centre for SCI were administered the Spinal Cord Independence Measure-version III (SCIM-III), the Short Form-36 (SF-36), the Schedule for the Evaluation of Individual QoL-Direct Weighting (SEIQoL-DW) and the Coping Inventory for Stressful Situation (CISS) to assess functional status, health-related QoL, individualised QoL and coping strategies, respectively. RESULTS: The SCIM-III scores were positively correlated (P<0.01) with the physical functioning subscale of the SF-36. The only scale that correlated (P<0.01) with the SEIQoL-DW scores was the SF-36 mental health subscale. Positive correlations among task-oriented or avoidance-oriented coping and specific measures of health-related QoL emerged. CONCLUSIONS: Data from the present study showed only a few associations among different measures of QoL and suggest that patient-centered evaluations of QoL are not necessarily or strictly related to functional status or health-related QoL. Coping strategies seem to be significantly related to the subjects perceptions of QoL, but mostly in the health-related domains. PMID- 24343056 TI - [Lymphatic malformations in the head and neck region. Clinical aspects and therapeutic options]. AB - Lymphatic malformations are congenital abnormalities of the lymphatic system which occur predominantly in the head and neck region. According to their dominant clinical and morphological characteristics, these are classified into micro- and macrocystic forms. Established therapies for lymphatic malformations include conventional surgery, sclerotherapy and laser treatment. Despite the significant improvements in therapeutic options seen in recent years, treatment of extensive lymphatic malformations remains an interdisciplinary challenge. Close-knit interdisciplinary cooperation is necessary to provide optimized care for affected individuals. PMID- 24343057 TI - [Venous and arteriovenous malformations in the head and neck region. Therapeutic options and challenges]. AB - Venous malformations are the prototype low-flow malformations in the head and neck region. Arteriovenous malformations (AVM) represent the main high-flow malformations. In recent years it has been possible to significantly optimize the therapeutic options for venous malformations. In addition to conventional surgery, laser treatment and sclerotherapy have become established techniques and the importance of embolization with new alcohol-based materials is increasing. AVM are progressive and destructive diseases. Therapy of choice is usually a combined treatment comprising embolization and surgical removal of the arteriovenous nidus. This curative approach is usually possible if diagnosis is made at an early stage. Incomplete embolization or sole ligation of the arterial supply causes progression. There is a clear need for improved therapeutic methods and pharmacotherapeutic approaches. PMID- 24343058 TI - Betel quid chewing is responsible for half of oral cancer cases in India, finds study. PMID- 24343059 TI - [Genome-wide copy number scan in Chinese patients with premature ovarian failure]. AB - OBJECTIVE: To investigate genetic causes in Chinese women with primary ovarian insufficiency (POI) for Genome-wide copy number variations (CNVs), focusing on novel autosomal microdeletions and microduplications. METHODS: Genome-wide CNVs analysis using Affymetrix SNP 6.0 array was carried out in 30 Chinese POI subjects. And quantitative PCR (qPCR) was further performed for selected coding regions with microdeletions and microduplications in 30 POI subjects and another 40 POI cases. RESULTS: A total of 101 CNVs were identified by SNP arrays, ranging in size from 0.1 MB to 5.6 MB. These CNVs included 8 novel microduplications and 12 novel microdeletions. Then 4 microdeletions identified in chromosomal regions (10q26.12, 10q26.3, 2p16.3, and 6p26) and 2 microduplications which contained the coding regions (20p12.3 and 7p22.2) were verified by qPCR. CONCLUSION: We report the high-resolution rare CNV analysis, revealing novel microdeletions/microduplications in Chinese POI patients. In the selected verified coding regions, we find that the five genes including SYCE1, CYP2E1, NRXN1, PARK2 and CARD11 may be involved in reproduction, thus representing potential candidate genes in POI. PMID- 24343060 TI - [Application of human oocyte morphometric parameters in assessment of fertilization and embryo development]. AB - OBJECTIVE: To investigate the correlation of human oocyte morphometric parameters with fertilization and embryo development in the intracytoplasmic sperm injection (ICSI) cycles. METHODS: The morphometric parameters of oocytes collected and submitted to evaluation using OCTAX Eye-ware software just before ICSI. Oocyte diameter (OD), perivitelline space width (PSW), zonapellucida thickness (ZPT) and the shape of first polar body (FPB) (intact or fragmented) were analyzed. A stepwise multivariate Logistic regression was used to test the association between the morphometric parameters and fertilization and embryo development. RESULTS: In the study, 436 oocytes were measured and 370 were fertilized (84.9%), 225 fertilized oocytes were developed to high-quality embryos (60.8%). ZPT and PSW were associated with fertilization. The oocytes fertilized had thicker ZPT [(18.0+/-2.3) MUm vs. (16.9+/-2.7) MUm] and wider PSW [(14.4+/-3.3) MUm vs. (13.2+/-3.9) MUm]. The OD and shape of FPB were associated with embryos development. The oocytes developed to high-quality embryos had larger OD [(116.6+/-3.7) MUm vs. (114.7+/-3.6) MUm] and more intact FPB (86.2% vs. 66.7%). CONCLUSION: The morphometric parameters of oocytes can indicate fertilization and embryo development. PMID- 24343061 TI - [Combination of multiple displacement amplification with short tandem repeat polymorphismin preimplantation genetic diagnosis]. AB - OBJECTIVE: To explore the application of multiple displacement amplification (MDA) combined with short tandem repeats (STRs) in preimplantation genetic diagnosis (PGD). METHODS: MDA was applied to amplify the whole genome of a single cell and to retrieve and assemble the highly heterogeneous STR loci among human population. Haplotype analytic system was established with aiming at diagnosis of the single gene diseases by selecting the STR loci located within the pathogenic genes or on both bounding sides of the pathogenic genes. At the same time, allele specific amplification, PCR-reverse dot-blotting hybridization methods and gene sequencing methods were employed for direct detection of the pathogenic genes. The STR loci located at related chromosomes were selected to carry out allele number analysis on the basis of chromosome number and structural abnormality. RESULTS: In the study, 12 PGD systems were set up including 6 different monogenic diseases (spinal muscular atrophy, Duchenne muscular dystrophy, X-linked chronic granulomatous disease, osteopetrosis, achondroplasia, X-linked severe combined immunodeficiency), Robertsonian translocations, alpha-thalassemia combined with Robertsonian translocation, alpha- and beta-double thalassemia, beta-thalassemia with HLA typing and DMD with HLA typing. Then 44 PGD cycles were performed for 35 couples with different kinds of inherited diseases, which resulted in 20 healthy liveborns (12 singletons and 4 twins) and 5 ongoing pregnancies. The clinical pregnancy rate was 47.7% (21/44) per PGD cycle. The overall diagnostic rate was 94.6% (367/388). The MDA failed in 3.6% (14/388) single blastomeres. The amplification rate of the subsequent PCR was 97.1% and the average allele drop out (ADO) rate was 12.6% (range: 0-47.5%). CONCLUSION: The application of MDA combined with STRs provided a generic PGD approach for different genetic disorders, especially for simultaneous diagnosis of two or more hereditary statuses. The method could greatly shorten the time of developing PGD system of new diseases, which broadens the indications of PGD. PMID- 24343062 TI - [Expression of PPARgamma mRNA in granulosa cells and its correlation with clinical characteristics of polycystic ovary syndrome]. AB - OBJECTIVE: To study the expression of PPARgamma mRNA in granulosa cells of patients with polycystic ovary syndrome (PCOS) and the impact of testosterone, insulin and PPARgamma agonist rosiglitazone on granulosa cells (GCs). METHODS: The expression of PPARgamma mRNA in GCs of patients with PCOS and normal controls were analyzed by Real-time PCR. We assessed the level of PPARgamma mRNA in GCs from normal controls after treatment with testosterone, insulin, and rosiglitazone. RESULTS: The expression of PPARgamma mRNA was lower in the GCs of PCOS than that of the controls (P<0.05). When testosterone concentration was 1 nmol/L, the expression of PPARgamma mRNA was lower in the GCs as compared with the blank control (P<0.05). When testosterone concentration was 10 nmol/L, PPARgamma mRNA increased in the GCs as compared with the blank control, which was of no significance (P>0.05). When insulin concentration was 10 nmol/L, the expression of PPARgamma mRNA was higher in the GCs as compared with the blank control (P<0.05). When insulin concentration was 100 nmol/L, the expression of PPARgamma mRNA increased, but the difference was not statistically significant (P>0.05). When rosiglitazone concentration was 1 nmol/L, the expression of PPARgamma mRNA in ovarian GCs significantly increased, as compared with the blank control (P<0.05). When rosiglitazone concentration was at 10 nmol/L, the PPARgamma mRNA expression significantly increased, as compared with the concentration at 1 nmol/L (P<0.05). CONCLUSION: PPARgamma mRNA expression is down regulated by testosterone, and up-regulated by insulin and rosiglitazone with different dosages. Decreased PPARgamma mRNA in the GCs of PCOS is related to the clinical characteristics of PCOS. PMID- 24343063 TI - [Suppression of mitochondrial oxidative phosphorylation on in vitro maturation, fertilization and developmental competence of oocytes]. AB - OBJECTIVE: To investigate the roles of mitochondrial oxidative phosphorylation (OXPHOS) capacity in oocyte maturation, fertilization and embryo development. METHODS: Carbonyl cyanide p- (tri-fluromethoxy) phenyl-hydrazone (FCCP), a metabolic inhibitor of mitochondria, was introduced into culture medium. The integrity of spindle and chromosome alignment, reactive oxygen species (ROS) levels, and rates of maturation, germinal vesicle breakdown, fertilization and blastulation were assessed in vitro. RESULTS: Significant decreases were detected in the percentages of oocytes with nuclear maturation, normal spindle formation and chromosome alignment, ROS levels and capable for blastocyst formation between oocytes treated with FCCP and non-treated (control group), 55.8%, 37.9%, 0.67 and 57.9% (FCCP 10 nmol/L group), 47.3%,34.7%, 0.59 and 41.8% (FCCP 100 nmol/L group) versus 62.9%, 61.9%,0.94 and 68.3% (control group) respectively, P<0.05. However, No significant differences were found in the rates of GVBD and fertilization in oocytes from the FCCP treated and the control. CONCLUSION: Inhibition of mitochondrial metabolic capacity resulted in decreased the percentages of oocytes with nuclear maturation, normal spindle formation and chromosome alignment, ROS levels and capable for blastocyst formation. But the treatment of FCCP did not affect the rate of fertilization. PMID- 24343064 TI - [Luteal letrozole administration decreases serum estrogen level but not the risk of ovarian hyperstimulation syndrome]. AB - OBJECTIVE: To explore the efficiency of using aromatase inhibitors during luteal phase in in vitro fertilization IVF stimulated cycles for patients at high risk for ovarian hyperstimulation syndrome (OHSS). METHODS: A total of 139 infertile women undergoing assisted reproductive technique with high risk for OHSS were enrolled in this clinical trial. In the treatment group 43 patients received five consecutive doses of aromatase inhibitors (letrozole) and support therapy combined with embryo cryopreservation. In the control group 96 patients received support therapy alone. All the patients were evaluated clinically, echographically, hematologically and tested for their steroid hormone. RESULTS: There was significantly lower estrogen level in the treatment group 2, 5 and 8 days after oocyte retrieval compared with the control group (P<0.001), There was no significant difference in luteinizing hormone and progesterone levels 2, 5 and 8 days after oocyte retrieval in the treatment group and control group (P>0.05). There were 7 cases of severe OHSS in the treatment group and 18 cases of severe OHSS in the control group. The rate of severe OHSS was not significantly different in the treatment group and control group (P=0.12). No side effect was reported in either group. CONCLUSION: Treatment with letrzolein luteal phase decreases serum estrogen levels of patients after oocyte retrieval,but it couldn't reduce the risk of severe OHSS. PMID- 24343065 TI - [Influence of duration of gonadotropin administration on the clinical outcome of in vitro fertilization embryo transfer]. AB - OBJECTIVE: To investigate the influence of duration of gonadotropin (Gn) administration on the clinical outcome of in vitro fertilization embryo transfer (IVF-ET). METHODS: A total of 3 221 cycles of short protocol or antagonist protocol in our center from January 2012 to December 2012 were included in the retrospective study. According to the different duration of Gn administration, all patients were divided into group A (<=7 days, n=58) and group B (>7 days, n=3 163). The different clinical parameters, such as age, duration of infertility, body mass index (BMI), basis estradiol (E2), follicle-stimulating hormone (FSH), the number of antral follicle, the number of oocytes, endometrium thickness, fertility rate, good quality embryo rate, impatation rate and clinical pregnancy rate were compared between the two groups. RESULTS: There was no significant difference in age, duration of infertility, BMI, basis E2, FSH, the number of antral follicle between the two groups. The number of oocytes in group A was fewer than that in group B [(8.2+/-5.6)vs.(12.1+/-8.3), P=0.009]; endometrium thickness on the day of HCG in group A was thinner than that in group B [(9.9+/ 2.1) mm vs.(10.4+/-1.6) mm,P=0.002]. There was no significant difference in fertility rate, good quality embryo rate, impatation rate and clinical pregnancy rate (36.2% vs. 33.6%, P>0.05). There was no significant difference in clinical pregnancy rate between the two groups in short protocol (33.3% vs. 27.2%, P>0.05). In the same way, there was no significant difference in clinical pregnancy rate between the two groups in antagonist protocol (37.5% vs. 36.6%, P> 0.05). CONCLUSION: Although short duration of gonadotropin administration in short protocol and antagonist protocol has association with fewer number of oocytes, it may not affect the outcome of IVF-ET. PMID- 24343067 TI - [Evaluation for the clinical application of all embryos cryopreservation: a multi centre study in northern area of China]. AB - OBJECTIVE: To investigate the clinical outcome of patients who underwent cryopreservation of all embryos. METHODS: A retrospective analysis was made in the clinical data of patients with cryopreservation of all embryos between April 2011 and September 2011 in four hospitals of North China. The patients were divided into five groups according to the reasons of cryopreservation of all embryos: ovarian hyperstimulation syndrome (OHSS) group, serum progesterone elevation group, endometrial group, hydrosalpinx group and others. The clinical pregnancy rate per transfer, implantation rate and cumulative clinical pregnancy rate were analyzed. RESULTS: The clinical pregnancy rate, implantation rate and cumulative clinical pregnancy rate of the OHSS group were 55.4%, 34.8% and 73.7%, respectively. The rates of the serum progesterone elevation group were 25.5%, 11.2% and 43.1%, respectively. The rates of the endometrial group were 54.8%, 34.4% and 61.5%, respectively. The rates of the hydrosalpinx group were 60%, 30% and 60%, respectively. The rates of the other factors group were 36.0%, 24.5% and 44.0%, respectively. CONCLUSION: The strategy of cryopreservation of all embryos could improve the clinical outcomes of patients with severe OHSS. It still needs a large multi-centre, randomized trial to evaluate its effectiveness and side effects, although it has the positive clinical application for other reasons of cryopreservation of all embryos. PMID- 24343066 TI - [Comparison of gonadotropin releasing hormone agonist long protocol and gonadotropin releasing hormone antagonist protocol in infertile women]. AB - OBJECTIVE: To compare the clinical outcomes of GnRH agonist (GnRH-a) long protocol and GnRH antagonist (GnRH-ant)protocol in vitro fertilization (IVF) embryo transfer (ET) cycles, and to explore the optimized protocol for infertile women. METHODS: From June 2010 to June 2012, 2 444 infertile women underwent their IVF cycles in Peking University Third Hospital, which were divided into 1 706 GnRH agonist long protocol and 738 GnRH antagnist protocol groups. The data of the general demographic, treatment and clinical outcome were compared between the two groups. RESULTS: The age, body mass index(BMI), infertile duration, antral follicle count (AFC) did not reach statistical difference, the level of estradiol on the day of HCG: injection was higher in GnRH agonist group [(10 595+/-7 368)pmol/L vs. (9 087+/-7 035) pmol/L], and the mean length of stimulation was longer in GnRH agonist group[(12.5+/-1.8) d vs.(9.4+/-1.7) d], The dose of Gn [(3 107+/-1 377) IU vs. (2 084+/-903)IU]was higher in GnRH agonist group. The number of ovum was 13.4+/-6.6 in GnRH agonist group and 11.8+/-6.4 in GnRH antagonist group. Those clinical parameters all reached statistical difference (P<0.05). The number of the transfer embryos, fertilization rate, and cleavage rate did not reach statistical difference, but the number of the embryos was 5.6+/-4.5 in GnRH agonist group and 5.1+/-4.3 in GnRH antagonist group,reached statistical difference (P<0.05). The abortion rate, embryonic death rate, ectopic pregnancy rate, preterm labor rate, postterm pregnancy rate, fatal malformations rate showed no statistical difference, but the GnRH agonist long protocol had higher pregnancy rate (44.0% vs. 38.3%), and higher term pregnancy rate (64.2% vs. 56.9%) compared with GnRH antagonist protocol, thus those parameter reached significant difference (P<0.05). CONCLUSION: Compared with GnRH antagnist protocol, GnRH agonist long protocol had higher pregnancy rate and better pregnancy outcome. PMID- 24343068 TI - [Analysis of clinical factors affecting pregnancy rate of intrauterine insemination]. AB - OBJECTIVE: To analyze the factors affecting clinical pregnancy rate of intrauterine insemination in Center of Reproductive Medicine, Peking University Third Hospital, to guide clinical treatment. METHODS: In the study, 5 167 intrauterine insemination cycles were retrospectively analyzed from May 2011 to October 2012 in our reproductive center. The data were collected, the single factor was analyzed with chi2 test, and the multi-factor was analyzed with Logistic regression with a significant level of 0.05. RESULTS: The cycle clinical pregnancy rate was 12.8%, which decreased with the increase of the female age and infertile duration. The clinical pregnancy rate was low when the sperm density was less than 1*10(6)/mL. In the ovulation group, the clinical pregnancy rate was higher than the natural group. The group with more than 2 dominant follicles had higher clinical pregnancy rate as compared with the single dominant follicle group. The clinical pregnancy rate was the highest in the third cycle but decreased after the fourth cycle. The clinical pregnancy rate was higher in cervical factors, sexual dysfunction, and polycystic ovary than in the group with other reasons. CONCLUSION: The female age, infertile duration, ovarian stimulation and follicle number, cause of infertility were the main factors affecting clinical pregnancy outcome; the sperm density, and cycle numbers have influence too; the insemination timing, and frequency have little effect. PMID- 24343069 TI - [Comparison of clinical outcome of mild-stimulation and conventional ovarian stimulation in in vitro fertilization-embryo transfer (IVF-ET)]. AB - OBJECTIVE: To investigate the practical application value of the mild-stimulation method used in in vitro fertilization and embryo transfer (IVF-ET) treatment for IVF patients with normal ovarian function. METHODS: The patients (ages from 26 to 38 years) with normal ovarian function, who were treated with IVF-ET in Affiliated Reproductive Center of China Medical University from January 2004 to July 2012 were selected as our samples. We compared the clinical results of treatment between the mild-stimulation (104 cycles in experimental group) and the conventional stimulation (198 cycles in control group). RESULTS: The number of retrieved oocytes (3.1+/-1.6 vs. 10.2+/-5.7, P<0.05) and clinical pregnancy rate [34% (33/97) vs. 49.7% (93/187), P<0.05] of the mild-stimulation group (104 cycles) were lower than those of the control group (198 cycles), however, the duration of stimulation (4.7+/-2.1 vs. 9.16+/-1.87) and total doses of 75 U gonadotropins used (5.7+/-3.7 vs. 30.9+/-10.3) were also lower in the mild stimulation group than in the control group obviously (P<0.05). CONCLUSION: For the normal ovarian function patients, the mild-stimulation method has clear clinical effects, but not as good as the conventional-stimulation one. PMID- 24343070 TI - [Reliability of antral follicle counts using transvaginal two- and three dimensional sonography]. AB - OBJECTIVE: To assess the interobserver reliability of antral follicle counts (AFC) using Real-time two-dimensional (2D) ultrasound and three-dimensional (3D) ultrasound. METHODS: Two observers conducted transvaginal ultrasound examinations in 51 subfertile women in the early follicular phase of the menstrual cycle. Antral follicles were counted using Real-time 2D ultrasound and the time taken was recorded. A 3D volume was then acquired from each ovary and stored for subsequent offline analysis using the multiplanar view. The time taken for each step was recorded and the total time was calculated. Intraclass correlation coefficients (ICC) and limits of agreement were used to assess the reliability. RESULTS: There was no difference in the mean antral follicle counts using Real time 2D (18.63+/-11.39) and 3D (18.73+/-11.74) ultrasound. According to the ICC, there was a significantly higher interobserver reliability for counts made using 3D (mean, 0.994; 95% CI, 0.990-0.997) as compared with Real-time 2D ultrasound (mean, 0.979; 95% CI, 0.963-0.988), P<0.01. 3D ultrasound was also associated with narrower limits of agreement (-3.46, 3.35) than was 2D ultrasound (-6.78, 6.31). While the total time taken was significantly longer for the 3D technique [(204.0+/-53.0) s vs. (112.4+/-34.8) s, P<0.001], the time required for the actual ultrasound examination was significantly less [(48.0+/-7.5) s vs. (112.4+/ 34.8) s, P<0.001]. CONCLUSION: 3D ultrasound significantly improves the interobserver reliability of antral follicle counts. While this is at the expense of time overall, the duration of the actual ultrasound examination and the patient exposure is significantly reduced using 3D compared with Real-time 2D ultrasound. PMID- 24343071 TI - [Combined efficacy of parecoxib and incisional ropivacaine infiltration on pain management after diagnostic hysteroscopy and laparoscopy]. AB - OBJECTIVE: To evaluate the combined effect of premedication of parecoxib sodium and local infiltration of ropivocaine on postoperative shoulder pain and incisional pain in patients undergoing diagnostic hysteroscopy and laparoscopy. METHODS: In the study, 60 patients undergoing elective diagnostic hysteroscopy and laparoscopy were randomly allocated to two groups (each with 30 patients). The patients in group 1 were premedicated with 40 mg parecoxib sodium (diluted with 2 mL normal saline), and 0.5% ropivacaine (20 mL) were infiltrated around the incision site before establishment of CO2 pneumoperitoneum. The patients in group 2 received 2 mL normal saline intraveniously before anesthesia induction, and infiltration of 0.5% ropivacaine 20 mL were also applied as group 1. After anesthetic withdrawal, the patients' postoperative anesthesia recovery time and the time point of opening eyes on verbal command were noted. The intensities of postoperative shoulder pain and incisional pain were evaluated at 0, 2, 4, 8, 12, 24, and 48 h after surgery. The postoperative analgesic requirement was met by administration of tramadol. RESULTS: Compared with group 2, the incidence of postoperative shoulder pain was less in group 1 (37% vs. 67%, P=0.020), and the occurence of severe pain was lower (4 vs. 11, P=0.037). The numerical rating scales (NRS) of right shoulder pain of group 1 were significantly reduced than those of group 2 at 12 h postoperatively [0 (0, 2) vs. 0 (0, 8), P=0.012]. Left shoulder pain did not appear at 0 h and 2 h in both groups, while at 12 h and 24 h postoperatively, the NRS scores of group 1 were lower than those of group 2 [0 (0, 1) vs. 0 (0, 8), P=0.026; 0 (0, 4) vs. 2 (0, 9), P=0.014]. The dynamic and static abdominal pain scores of group 1 were significantly decreased than those of group 2 in post-anesthesia care unit (PACU) after surgery (P=0.001, P=0.005). The NRS scores of static abdominal pain of group 1 were significantly reduced than those of group 2 at 12 h and 24 h postoperatively (P=0.042, P=0.029). More patients in group 2 needed tramadol within 24 h postoperatively (8 vs. 0, P=0.002). CONCLUSION: Premedication of parecoxib sodium combined with local infiltration of ropinvocaine before incision could significantly reduce the postoperative shoulder pain and incisional pain as well as reduce opioid consumption in patients undergoing diagnostic hysteroscopy and laparoscopy. PMID- 24343072 TI - [Molecular diagnosis and prenatal diagnosis in a hereditary multiple osteochondromas family]. AB - OBJECTIVE: To identify the mutation in the disease gene and provide prenatal diagnosis for a hereditary multiple osteochondromas (HMO) family. METHODS: The exons of EXT1 gene in the proband with HMO and his family members were amplified by PCR. The products were analyzed by direct sequencing. Prenatal genetic diagnosis was performed by amniocentesis sampling after genotyping the proband. RESULTS: In the family, the affected proband was heterozygous of the mutation of 1476_1477delTC in the EXT1 gene, and the proband's father carried the same mutation in part of his somatic cells. No mutation was found in the EXT1 gene of the proband's mother and other 11 siblings of his father. CONCLUSION: METHODS for molecular diagnosis and prenatal diagnosis of HMO were established and applied to a family of HMO. PMID- 24343073 TI - [Efficacy of postoperative simple chemotherapy and concurrent chemoradiotherapy in FIGO stage IB2-IIB cervical cancer]. AB - OBJECTIVE: To evaluate the effectiveness of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy plus postoperative chemotherapy but no radiotherapy for stage IB2-IIB cervical cancer. METHODS: Seventy-nine patients with stage IB2-IIB cervical cancer were treated with NAC followed by radical hysterectomy. According to different adjuvant therapies, patients were divided into postoperative chemotherapy group (47 cases) and postoperative radiotherapy/concurrent chemoradiotherapy group (32 cases). Regimens for NAC and postoperative chemotherapy were BIP (bleomycin+ ifosfamide+ cisplatin/carboplatin) or TP (paclitaxel+ cisplatin/carboplatin). An average of 1.1+/-0.3 cycles of NAC and 3.4+/-1.2 cycles of postoperative chemotherapy were prescribed. RESULTS: Toxicities due to chemotherapy were generally tolerable. Overall response rate of NAC was 88.6%. With a median follow-up period of 42 months, the three-year progression-free survival rates of the two groups were 88.5% and 84.3%, the total survival rates were 90.3% and 86.4%, respectively. There was no statistically significant difference. The recurrent rates were 10.6% and 21.8% in the two groups. In the absence of radiotherapy, pelvic recurrence was observed in two patients; the other three had distant metastases. CONCLUSION: The results indicate that NAC followed by surgery plus postoperative chemotherapy but no radiotherapy offers a viable option in the treatment of stage IB2-IIB cervical cancer. The patients can tolerate the side effects of chemotherapy with better efficacy. PMID- 24343074 TI - [Relationship between radial augmentation index and other indices for evaluating arteriosclerosis]. AB - OBJECTIVE: To investigate the relationship between radial augmentation index (AI) and other noninvasive indices for evaluating arteriosclerosis. METHODS: From April to June 2010, a cross-sectional survey was performed in two communities of Shijingshan District, Beijing, China. This study involved 1 752 subjects (aged 23 to 90 years). AI was measured using Colin pulse wave detection device HEM9000AI. Brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI) were measured using Colin noninvasive arteriosclerosis tester VP-1000. Color Doppler flow imaging was used to measure intima-media thickness (IMT) of the bilateral carotid arteries. RESULTS: Compared with the control group, baPWV>=14 m/s, ABI<=0.9 and IMT>=0.9 mm groups showed no significant difference in AI75 (P>0.05). Hypertensive individuals had significantly higher baPWV than the healthy group. Elderly hypertensive individuals with diabetes mellitus or (and) dyslipidemia had lower ABI than the control group. There was no significant difference of AI75 between the disease groups and the healthy group (P>0.05). Pearson correlation analysis showed that AI75 was associated with women, central aortic systolic pressure, total cholesterol, low-density lipoprotein, high density lipoprotein, and inversely associated with body mass index, waist hip ratio, triglycerides, fasting serum glucose, and not associated with age (r=0.045, P=0.064). There was negative correlation between AI75 and ABI, IMT. AI75 was positively correlated with baPWV in the male group (r=0.101, P=0.005), but not correlated in the female group. Partial correlation analysis found that AI75 was inversely associated with ABI, baPWV and IMT. There was negative correlation between AI75 and baPWV, IMT in the female and male groups, and no correlation between AI75 and ABI (P>0.05). Multivariate gradual regression analysis demonstrated that the independent positive correlation factors of AI75 included female, age, waist hip ratio, central aortic systolic pressure, and the negative correlation factors were body mass index, height, fasting serum glucose (R(2)=0.372). CONCLUSION: The lack of correlation of radial augmentation index with indices for evaluating arteriosclerosis suggests that AI is not a sensitive and reliable index for evaluating the degree of arterial stiffness. PMID- 24343075 TI - [Significance of serum iron in the differential diagnosis between vasovagal syncope and postural orthostatic tachycardia syndrome in children]. AB - OBJECTIVE: To explore the predictive value of serum iron in differentiating between vasovagal syncope (VVS) and postural orthostatic tachycardia syndrome (POTS) in children. METHODS: Totally 57 children (aged 4-17 years, POTS 40 cases, and VVS 17 cases) who were at the syncope clinic or admitted to the Department of Pediatrics, Peking University First Hospital from August 2009 to September 2012 were included in the study. The diagnoses were analyzed by the value of serum iron and receiver operating characteristic (ROC) curves used to explore the predictive value of different serum iron in differential diagnosis between VVS and POTS. RESULTS: There were significant differences in the median value of POTS [17.4 (interquartile range 13.5 -21.8) MUmol/L] and VVS [8.9 (interquartile range 7.5-17.6) MUmol/L] (P<0.01). When the value of serum iron was 11.8 MUmol/L, the sensitivity and specificity of the differential diagnosis between VVS and POTS were 92.5% and 64.7%, respectively. CONCLUSION: The serum iron might be used as an initial diagnostic method in differential diagnosis between VVS and POTS, based on the history of the patients. PMID- 24343076 TI - [Impact of passing items above the ceiling on the assessment results of Peabody developmental motor scales]. AB - OBJECTIVE: To analyze the impact of passing items above the roof level in the gross motor subtest of Peabody development motor scales (PDMS-2) on its assessment results. METHODS: In the subtests of PDMS-2, 124 children from 1.2 to 71 months were administered. Except for the original scoring method, a new scoring method which includes passing items above the ceiling were developed. The standard scores and quotients of the two scoring methods were compared using the independent-samples t test. RESULTS: Only one child could pass the items above the ceiling in the stationary subtest, 19 children in the locomotion subtest, and 17 children in the visual-motor integration subtest. When the scores of these passing items were included in the raw scores, the total raw scores got the added points of 1-12, the standard scores added 0-1 points and the motor quotients added 0-3 points. The diagnostic classification was changed only in two children. There was no significant difference between those two methods about motor quotients or standard scores in the specific subtest (P>0.05). CONCLUSION: The passing items above a ceiling of PDMS-2 isn't a rare situation. It usually takes place in the locomotion subtest and visual-motor integration subtest. Including these passing items into the scoring system will not make significant difference in the standard scores of the subtests or the developmental motor quotients (DMQ), which supports the original setting of a ceiling established by upassing 3 items in a row. However, putting the passing items above the ceiling into the raw score will improve tracking of children's developmental trajectory and intervention effects. PMID- 24343077 TI - [Impact of sleep duration on cognitive functions among preschoolers]. AB - OBJECTIVE: To explore the effect of sleep duration including napping, night sleep and total sleep duration on cognitive functions among preschoolers. METHODS: The samples consisted of 94 preschoolers, aged from 2.58 to 6.75 years, from Hangzhou and Beijing. Peabody Picture Vocabulary Test-Revised (PPVT-R), Picture Deletion Task for Preschoolers (PDTP) and Spatial Working Memory Test were applied to assess the cognitive functions of these preschoolers. Basic demographic information and sleep information were collected with self-made questionnaires. RESULTS: The results of the present study indicated that among all the participants, there were significant grade differences in napping duration and total sleep duration (F0.05(3, 90)=6.346, P=0.001; F0.05(3, 90)=2.925, P=0.038). The total sleep duration was decreased with age. However, the night sleep duration was not changed significantly with age. The correlations between the night sleep and total sleep duration and the scores of attention and working memory were significantly positive (r=0.202-0.282). No significant correlations were noted between the napping and all the scores of cognitive tests. The regression analysis showed that the total sleep duration especially the night sleep duration could well explain the variance of attention and working memory. CONCLUSION: Total sleep duration, especially night sleep duration may have great impact on preschoolers' cognitive functions, such as attention and working memory. Enough sound night sleep may help to promote the cognitive functions of the target population. PMID- 24343078 TI - [Clinical characteristics and efficacy analysis for patients over 55 years of age with acute lymphoblastic leukemia]. AB - OBJECTIVE: We investigated the clinical characteristics and therapeutic of elderly patients (>=55) with acute lymphoblastic leukemia (ALL). METHODS: From Jenuary 2000 to July 2012, 45 elderly patients (>=55) were enrolled in the study. Patients assighed into CVDP VDP/VP induction chemotherapy based on organ function. Patients in complete remission (CR) undertake consolidation therapy, maintenance therapy or follow up. The patient who had appropriate donor received allogeneic hematopoietic stem cell transplantation (allo-HSCT). CR, Overall survival (OS), disease free survival (DFS), relapse rate and prognosis factors were analyzed. RESULTS: 45 elderly patients (>=55) about 9.6% in all 470 cases ALL simultaneity, and B-ALL about 88.9%. 27 patients (60%) obtained CR after 1 cycle of induction chemotherapy. 33 patients (73.3%) obtained overall CR. The CR rate significantly decreased in the elderly patients more than 60 years old vs. 55-60 years old patients (86.2% vs. 50%;P=0.009). All 45 patients 2 years OS rate was 33.7%, The median OS was 12 months (95%CI,6.68-17.32). 55-60 years (P=0.014), CR (P=0.002) and consolidation therapy (P=0.001) were independent favorite prognostic factors for OS. CVDP induction chemotherapy (P=0.013) and consolidation (P=0.049) were independent favorite prognostic factors for DFS. CONCLUSION: The outcomes of elderly patients with ALL were poor, 55-60 years, CVDP induction chemotherapy, CR and consolidation therapy were independent favorite prognostic factors. PMID- 24343079 TI - [Influence of inhaled anesthesia on bispectral index of elderly patients with cognitive decline]. AB - OBJECTIVE: To investigate the influence of inhaled anesthesia on bispectral index (BIS) of elderly patients with cognitive decline at loss of consciousness and regain of consciousness, and on deepening of sedation. METHODS: The patients aged more than 65 years undergoing elective operations from January 2012 to September 2012 were recruited, then 60 cognitive intact patients and 60 cognitive decline patients were screened by mini-mental state examinations. Inhaled anesthesia was administered using sevoflurane. BIS's of the two groups at loss of consciousness and regain of consciousness, and during end-tidal concentration of sevoflurane (CETSev) changing from 0.7% to 2.8% were recorded. The data were compared with independent-samples t test and repeated-measures general linear model of ANOVA. RESULTS: In the study, 117 patients finshed the investigation, The BIS's of the cognitive decline group at loss of consciousness were significantly higher than those of the cognitive intact group (P<0.01). There were no significant differences at regain of consciousness between the two groups (P>0.05). The BIS's of the cognitive decline group during CETSev changing from 0.7% to 2.8% were significantly lower than those of the cognitive intact group (P<0.05). The BIS's of the cognitive decline group at CETSev 0.7%, 1.05%, 1.4% and 1.75% were significantly lower than those of the cognitive intact group (P<0.05), but there were no significant differences at CETSev 2.1%, 2.45% and 2.8% between the two groups (P>0.05). CONCLUSION: During inhaled anesthesia, the BIS of the elderly patients with cognitive decline at loss of consciousness is higher than that of the patients with cognitive intact, The BIS of elderly patients with cognitive decline on deepening of anesthesia is lower than that of the patients with cognitive intact, especially during light anesthesia, and its mechanisms may attribute to cognitive decline related neurodegeneration and neurotransmitter system dysfunction. PMID- 24343080 TI - [Medical therapy of polyostotic fibrous dysplasia of the spinal column]. AB - OBJECTIVE: To discuss treatments of spinal polyostotic fibrous dysplasia (PFD) and their clinical outcomes. METHODS: A group of spinal PFD patients treated in orthopaedic department of Peking University Third Hospital from January 2005 to December 2010 was retrospectively reviewed. There were 3 males and 1 female. The age was 53, 17, 32, 38 years, respectively. Two cases underwent preoperative CT guided biopsy and the other two had previous pathologic results. All the patients complained localized pain and VAS (visual analogue scale) ranged from 3 to 5. All the cases had pathologic fractures and 3 cases had neurological impairment. The surgical procedures for each patient were as follows: lesion resection combined with cervicothoracic fixation and fusion; reduction combined with occipitocervical fixation and fusion; vertebroplasty (VP); VP combined with posterior decompression and fixation. RESULTS: Fibrous dysplasia in each patient was confirmed by postoperative pathological examination. The operation time was 420, 150, 120, 300 minutes and blood loss was 3 400, 500, 200, 2 000 mL. The follow-up period was 84, 24, 34, 12 months. The primary symptoms were fully relieved without any surgery related complication. There was no symptom recurrence or lesion progress during the follow-up. No signs of radiological improvements (filling of lytic lesion, cortical thickening, or both) were detected. CONCLUSION: Spinal PFD is a rare disease and mostly affects adults. Conventional excision therapy is an effective and reliable treatment for spinal PFD, but vertebroplasty is less invasive. VP alone might be more appropriate for patients complaining only pain symptoms and/or with pathologic fractures. VP combined with limited decompression and stabilization may be more suitable for patients with neurological deficits. PMID- 24343081 TI - [Ultrasound guided ablation therapy of hepatic colorectal metastases: initial experience of real time virtual sonography navigation system]. AB - OBJECTIVE: To evaluate the feasibility, accuracy and efficacy of the real time virtual sonography navigation and planning system in radio frequency ablation (RFA) of hepatic colorectal metastases. METHODS: Seventeen hepatic colorectal metastases lesions in 12 patients diagnosed pathologically or clinically in Peking University Third Hospital from Oct. 2011 to Apr. 2013 were enrolled, and all the lesions were diagnosed by CT/MRI but invisible in B-mode ultrasound. The patients included 9 males and 3 females, who were 45-82 years old, with an average age of (64.6+/-19.2) years. Before RFA, the puncture ablation plan of each lesion was made in the planning system, and during RFA the lesion and the 5 mm ablative margin around were ablated according to the puncture ablation plan. After the image fusion between the ultrasound and CT/MRI, the navigation system could decide the location and boundary of the hepatic colorectal metastases in the ultrasound image. Navigation assisted contrast-enhanced ultrasound (CEUS) was employed right after ablation to decide whether the area of the ablative zone had covered the whole tumor. Additional puncture was applied if the ablative zone had not completely covered the tumor. All the patients received CT/MRI one month after ablation to decide whether the carcinoma had been completely ablated. RESULTS: The image fusion was successfully applied in all the 17 hepatic colorectal metastases, and on average, 12 min (8-21 min) was spent in the image fusion. One tumor (1/17, 14.3%) received extra one puncture after navigation assisted CEUS. No severe complications and death occurred in all the 12 patients. Complete ablation of the 17 lesions were observed through CT or MRI scan one month after RFA, showing that all the 17 lesions had been completely ablated. CONCLUSION: The real time virtual sonography navigation system had high detection rate for invisible focal liver lesions in B-mode ultrasound. Navigation assisted CEUS could decide whether the area of the ablative zone had covered the whole tumor. Ultrasound CT or MRI navigation and planning system is safe, feasible and accurate in assisting ablation of hepatic colorectal metastases lesions with satisfactory clinical efficacy. PMID- 24343082 TI - [Diagnosis and surgical treatment of solitary fibrous tumor of the pelvis]. AB - OBJECTIVE: To explore the clinical diagnosis and surgical treatment of pelvic solitary fibrous tumor (SFT). METHODS: The data of nine cases of pelvic solitary fibrous tumor from April 2008 to February 2012 were reviewed retrospectively. RESULTS: There were 7 male and 2 female patients in this group with a median age of 56 years, of whom 6 were asymptomatic. Their CT showed the tissue density was inhomogencous. Multivisceral resections were performed in 5 patients. Microscopically, the tumor cells were shuttle-shaped, short spindle-shaped or round, and mitoses was rare, immunohistochemistry: CD34, CD99, Bcl-2, Vimentin positive rates were 100%. One patient died 34 months after the surgery, and there was no recurrence in other patients. CONCLUSION: Pelvic SFT is rare. It is difficult to make an accurate diagnosis. Surgery is the most effective therapy. Multivisceral resections are needed sometimes. The prognosis is good for most patients. PMID- 24343083 TI - [Prevalence and risk factors for hepatitis B in Hua County, Henan Province]. AB - OBJECTIVE: To determine the epidemiological characteristics and associated risk factors of hepatitis B surface antigens (HBsAg) prevalence in rural areas of Hua County, Henan Province, and to provide scientific evidence for Hepatitis B prevention and control in local areas. METHODS: On the basis of an ongoing esophageal cancer cohort study in rural Anyang, a total of 5 104 subjects aged 25 65 years were clustered and selected from 5 targeted villages for this study in rural areas of Hua County, Henan Province. HBsAg was detected in their blood samples and a questionnaire was completed by all the subjects in a manner of one on-one interview. All statistical analyses were conducted using SPSS for Windows version 13.0. RESULTS: Of the 5 104 studied subjects (overall participation rate: 92.05%), 5.17% were positive for HBsAg. The detection rate was significantly higher in males than in females (6.54% vs. 3.87%, P<0.001) and the highest detection rates were observed in the 25-29 and 55-59 years groups in both males and females. Multiple Logistic analyses showed unmarried status (OR=1.80, 95% CI: 1.00-3.25) and high frequency of sexual intercourse (Ptrend=0.049) were associated with higher the risk for hepatitis B virus (HBV) infection. CONCLUSION: The prevalence of HBsAg in rural Hua County, Henan Province, was slightly lower than the national average of the same time period. More attention should be attached to high risk groups of HBV infection in this population, i.e. males aged 25-29 years and 55-59 years and sexually active population. Immunization and health education projects against hepatitis B should be carried out in this population to further reduce the overall prevalence of hepatitis B. PMID- 24343084 TI - [Risk factors for the kidney stones: a hospital-based case-control study in a distric hospital in Beijing]. AB - OBJECTIVE: To explore the risk and protective factors of kidney calculi in order to put forward theoretical basis for preventive and control measures. METHODS: A 1:1 matched case-control study was performed using data from a hospital in Beijing. The case group included 100 inpatients who were diagnosed kidney calculi using B ultrasonic, X-ray and intravenous pyelography during the survey while other 100 urolithiasis and endocrine disease excluded inpatients who shared the same sex, within five years gap to the case group inpatients were for the control group. A face-to-face survey was conducted with self-made questionnaires which covered demographic characteristics, water issues, dietary habits, genetic and medical history. Epidata 3.0 was used to build the database and SPSS 19.0 for the statistical analysis. RESULTS: In the univariate Logistic regression analysis, ten variables were found showing statistical significance. For the multivariate Logistic regression analysis, variables left in the model were labor intensity (OR=0.622, 95%CI: 0.435-0.889), preferring to drink after dinner (OR=0.316, 95%CI: 0.122-0.815), loving drinking (OR=0.232, 95%CI: 0.084-0.642), drinking tea regularly (OR=1.463, 95%CI: 1.033-2.071), eating more vegetables (OR=0.571, 95%CI: 0.328-0.993), the history of the urolithiasis (OR=2.127, 95%CI: 1.065 90.145). CONCLUSION: Drinking tea regularly, urolithiasis history and brain work are the risk factors of kidney calculi while loving drinking and eating more vegetables for the protection. PMID- 24343085 TI - [Effect of icariin on osteoblastic differentiation gene expression of human periodontal ligament cells]. AB - OBJECTIVE: To observe the effect of icariin on human periodontal ligament cells (hPDLCs) differentiation to osteoblast gene expression. METHODS: The fifth generation of the cultured hPDLCs was added with the concentration of 0.01 mg/L icariin, and the added osteogenic medium used as blank control group, alizarin red staining of icariin on human periodontal ligament cells was observed for 21 days; the 2, 4, and 6 days of Q-PCR quantitative analysis of icariin on human periodontal ligament cells were made for osteogenesis gene alkaline phosphatase (ALP), type I collagen and osteocalcin (OC) gene expression. RESULTS: For the 21 days, alizarin red staining icariin group formed more mineralized nodules; on the 2nd, 4th, and 6th days, the group of icariin promoted the expression of ALP and OC mRNA, reached the peak value on day 6, compared with the control group with significant difference (20.15+/-6.67 vs. 7.90+/-0.71, 4.13+/-0.56 vs. 3.55+/ 0.08, P<0.01). The second day, the highest expression of type I collagen appeared, then decreased gradually after, statistically compared with the control group (P<0.05). CONCLUSION: Icariin can promote the human periodontal ligament cells differentiation to osteoblast, and promote the osteogenesis gene expression. PMID- 24343086 TI - [Effects of dental health awareness and behaviours on the glycemic metabolic characteristics and periodontal disease of patients with type 2 diabetic]. AB - OBJECTIVE: To analyze the effects of dental health awareness and behaviours on the relationship between glycemic metabolic characteristics and periodontal disease of type 2 diabetic patients. METHODS: In the study, 83 subjects with type 2 diabetes mellitus were recruited. The clinical periodontal indexes, such as pocket probing depth (PPD), attachment loss (AL), modified bleeding index (mBI), plaque index (PLI) were obtained with a Williams type periodontal probe; Laboratory examinations including glycosylated haemoglobin A1(HbA1C) were made, glucose assay tested, and the structured questionnaire interview conducted evaluationg the knowledge, attitude and practice (KAP) about periodontal health. RESULTS: The prevalence of moderate and severe periodontitis was 67.5%, compared with mild periodontitis, whose severities were affected by the higher level of HbA1C (>=8.0%) (OR 54.1-143.1), followed by using glycemic drug (OR=12.9-44.6), stress (OR=16.9-29.6), and the dissatisfaction with diabetic therapy (OR=16.9 18.0) et al. Meanwhile the attachment loss conditions were also correlated with the poor periodontal knowledge level(OR=3.4),older age(OR=1.1),and misjudgement of gingival inflammation (OR=13.3) et al. On the other hand, individuals with moderate and severe periodontitis, having bad teeth brushing effects and knowing about dental plaque inadequately, had a significantly higher risk for the poorly controlled glycemic results (HbA1C>=8.0%), and the OR was 8.61, 8.07, and 7.49 respectively. CONCLUSION: In patients with type 2 diabetes the severity of periodontal disease and the glycemic metabolic level (HbA1C) have a definite bidirectional adverse interrelationship, which is affected by the dental health awareness and behaviours. PMID- 24343088 TI - [Quantitative assessment on artifacts of dental restorative materials in cone beam computed tomography]. AB - OBJECTIVE: To quantitatively evaluate the artifacts appearance of eight kinds of common dental restorative materials, such as zirconia. METHODS: For the full crown tooth preparation of mandibular first molar, eight kinds of full-crowns, such as zirconia all-ceramic crown, glass ceramic crown, ceramage crown, Au-Pt based porcelain-fused-metal (PFM) crown, Pure Titanium PFM crown, Co-Cr PFM crown, Ni-Cr PFM crown, and Au-Pd metal crown were fabricated. And natural teeth in vitro were used as controls. These full-crown and natural teeth in vitro were mounted an ultraviolet-curable resin fixed plate. High resolution cone beam computed tomography (CBCT) was used to scan all of the crowns and natural teeth in vitro, and their DICOM data were imported into software MIMICS 10.0. Then, the number of stripes and the maximum diameters of artifacts around the full-crowns were evaluated quantitatively in two-dimensional tomography images. RESULTS: In the two-dimensional tomography images,the artifacts did not appear around the natural teeth in vitro, glass ceramic crown, and ceramage crown. But thr artifacts appeared around the zirconia all-ceramic and metal crown. The number of stripes of artifacts was five to nine per one crown. The maximum diameters of the artifacts were 2.4 to 2.6 cm and 2.2 to 2.7 cm. CONCLUSION: In the two dimensional tomography images of CBCT, stripe-like and radical artifacts were caused around the zirconia all-ceramic crown and metal based porcelain-fused metal crowns. These artifacts could lower the imaging quality of the full crown shape greatly. The artifact was not caused around the natural teeth in vitro, glass ceramic crown, and ceramage crown. PMID- 24343087 TI - [A retrospective study of 693 children's dental treatment under general anesthesia]. AB - OBJECTIVE: To retrospectively analyze the clinical features of children who received dental treatment under general anesthesia (GA) and the characteristics of dental treatment. METHODS: The records of 693 patients treated under GA in the Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology, between Jan. 2001 and Dec. 2012 were collected and analyzed. RESULTS: The numbers of patients treated under GA increased year-to-year. Most of them were under 4-year-old. The main reasons of dental treatment under GA were uncooperative and disabled. The average number of teeth treated was 12+/-4 for each child, and the average time for treating one tooth was 12 min. The 3 months follow-up rate was 60.31%, and the older, the fewer treated tooth number and out of-town associated with the less follow-up rate. CONCLUSION: The main reasons of dental treatment under GA are uncooperative and disabled. GA is an effective and safe method for dental rehabilitation in children. PMID- 24343089 TI - [8p11 myeloproliferative syndrome cured by allogeneic hematopoietic stem cell transplantation: two case reports and literature review]. AB - OBJECTIVE: To report 2 rare cases of 8p11 meyloproliferative syndrome cured by allogeneic hematopoietic stem cell transplantation. METHODS: The clinical and laboratory features of 2 cases of 8p11 meyloproliferative syndrome were summarized, including the diagnosis and treatment process of allogeneic hematopoietic stem cell transplantation. RESULTS: Patient 1 was presented with bilateral cervical lymphadenopathy and leukocytosis. The pathology of bone marrow showed extremely hyperplasia. The cytogenetic analysis showed a 46, XY, (8;13)(p11;q12) karyotype. The biopsy of the lymph node was peripheral T-cell lymphoma, unspecified. Patient 2 was presented with extensive lymphadenopathy with abnormal hemogram, which was leuekcytosis and thrombpenia. The bone marrow was hypercellular. The cytogenetic analysis on the bone marrow cells showed a translocation of t(8;9) (p11;q32). The CEP110-FGFR1 fusion transcript was detected by RT-PCR. The biopsy of the lymph node was T lymphoblastic lymphoma. These two patients received human leukocyte antigen (HLA)-identical allogeneic hematopoietic stem cell transplantation, remained disease-free and survived 16 years and 6 years after transplantation, respectively. CONCLUSION: Allogeneic hematopoietic stem cell transplantation is the curative therapy for 8p11 meyloproliferative syndrome. PMID- 24343090 TI - [Strategies for the treatment and prevention of priapism in children]. AB - Priapism is defined as abnormal persisting penile erection beyond or unrelated to sexual stimulation. It is rare in children and the appropriate management consensus is lacking. We have reviewed the literature on the treatment and prevention of priapism in children in the last 5 years. The following advances were reported: (1) compression or thrombin injection guided by ultrasound in nonischemic priapism prior to selective angioembolization; (2) anti-androgen therapy is the key for the prevention of nonischemic priapism occurring and reoccurring after angioembolization; (3) etiological interventions are enough to resolve some priapism in children; (4) T tunnel may be applied to the distal shunt failed cases in children. Combined with the new progress in treatment of priapism in children, we have designed the algorithm of priapism management and the algorithm of stuttering priapism prevention. The two algorithms will be helpful for clinicians dealing with the clinical challenges in children's priapism management. PMID- 24343091 TI - Where is the apex of the sacral hiatus for caudal epidural block in the pediatric population? A radio-anatomic study. AB - PURPOSE: Caudal epidural block (CEB), administered through the sacral hiatus, is a regional anesthetic technique commonly used in children. To facilitate and optimize pediatric CEB, morphometric data that may be important for the sacral hiatus have been obtained using multidetector computed tomography (MDCT). METHODS: This study is the first radio-anatomic study designed to address this topic in children. Images of 79 children (39 girls and 40 boys between 1 and 9 years old) were divided into three groups according to age [group I (ages 1-3), group II (ages 4-6), and group III (ages 7-9)] and were retrospectively examined. Data were gathered via 3D volume-rendered images. Measurements included the height and width of the sacral hiatus, S2-S4 (sacral vertebra) distance, the distances between the poles of the unfused spinous process of each sacral vertebra, and the dimensions of an imaginary triangle formed between the right and left posterior superior iliac spines (PSIS) and the apex of the sacral hiatus. RESULTS: The most frequently fused spinous process was at S2 level. The mean S2-S4 distance was 1.36 cm for group I, 1.78 cm for group II, and 2.17 cm for group III. There was not the imaginary equilateral triangle used in the method of finding the sacral hiatus for CEB, and the apex of this triangle did not occur at the standard level (S4) in most of the children. It was observed that the apex deriving from the most distal fused spinous process was at the level of S2 in one of two children. CONCLUSION: Dural puncture is inevitable for CEB applied at the S2 level. Consequently, CEB should be applied below this level (range, 1.36-2.17 cm) from the midpoint of the interspinous distance between the PSIS (at the same level with S2) in children aged 1-9 years. PMID- 24343092 TI - Metabolic complications and selected cytokines in HIV-infected individuals. AB - INTRODUCTION: Human immunodeficiency virus (HIV)-infected individuals are at a higher risk of developing metabolic disturbances. The pathogenesis of these complications is complex and not fully explored. OBJECTIVES: The aim of the study was to investigate the effect of HIV infection and antiretroviral (ARV) therapy on the development of metabolic changes and adipocytokine concentrations. The analysis of the differences in the investigated parameters among lipodystrophic and nonlipodystrophic patients was also performed. PATIENTS AND METHODS: A total of 42 HIV-infected patients on ARV therapy (HIV[+]ARV[+]), 13 HIV-infected ARV naive patients (HIV[+]ARV[-]), and 20 healthy controls were included in the study. A lipid profile, fasting free fatty acids (FFAs), glucose, insulin, and insulin resistance (homeostasis model assessment of insulin resistance--HOMA-IR) were tested. Serum concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), adiponectin, leptin, and fatty acid-binding protein 4 (FABP4) were determined. RESULTS: Increased FFA levels were observed in HIV(+)ARV(-) patients. HIV(+)ARV(+) patients had significantly higher triglycerides and insulin level compared with controls. HOMA-IR showed a tendency to be higher in HIV(+)ARV(+) patients compared with the other study groups. The ARV therapy longer than 2 years resulted in more pronounced metabolic abnormalities. HIV infection itself had a significant effect on inflammation expressed by elevated TNF-alpha and IL-6 levels. We did not observe differences in adiponectin and FABP4 concentrations among the study groups, while the leptin concentration was significantly lower in HIV-infected lipodystrophic than in nonlipodystrophic patients. CONCLUSIONS: HIV infection induces lipid disorders, especially associated with fatty acid turnover augmented by ARV therapy. Compared with FABP4, leptin is a better biological marker of metabolic complications in HIV-infected patients. PMID- 24343093 TI - Renoprotective effect of renin-angiotensin-aldosterone system blockade in patients with predialysis advanced chronic kidney disease, hypertension, and anemia. AB - IMPORTANCE: The benefit of using a renin-angiotensin-aldosterone system blocker such as an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) for patients with advanced chronic kidney disease (CKD) remains undetermined. OBJECTIVE: To assess the effectiveness and safety of ACEI/ARB use for advanced predialysis CKD in patients with hypertension and anemia. DESIGN Prospective cohort study. SETTING: Taiwan. PARTICIPANTS: From January 1, 2000, through June 30, 2009, we selected 28 497 hypertensive adult patients with CKD. Serum creatinine levels were greater than 6 mg/dL, hematocrit levels were less than 28%, and patients were treated with erythropoiesis stimulating agents. INTERVENTIONS: Users (n = 14,117) and nonusers (n = 14,380) of ACEIs/ARBs. MAIN OUTCOMES AND MEASURES: We used Cox proportional hazards regression models to estimate hazard ratios (HRs) for commencement of long-term dialysis and all-cause mortality for ACRI/ARB users vs nonusers. RESULTS: In a median follow-up of 7 months, 20,152 patients (70.7%) required long-term dialysis and 5696 (20.0%) died before progression to end-stage renal disease requiring dialysis. Use of ACEIs/ARBs was associated with a lower risk for long-term dialysis (HR, 0.94 [95% CI, 0.91-0.97]) and the composite outcome of long-term dialysis or death (0.94 [0.92-0.97]). The renal benefit of ACEI/ARB use was consistent across most patient subgroups, as was that of ACEI or ARB monotherapy. Compared with nonusers, the ACEI/ARB users had a higher hyperkalemia-associated hospitalization rate, but the risk of predialysis mortality caused by hyperkalemia was not significantly increased (HR, 1.03 [95% CI, 0.92-1.16]; P = .30). CONCLUSIONS AND RELEVANCE: Patients with stable hypertension and advanced CKD who receive therapy with ACEIs/ARBs exhibit an association with lower risk for long-term dialysis or death by 6%. This benefit does not increase the risk of all-cause mortality. PMID- 24343094 TI - The paradox of uric acid in cardiovascular diseases. PMID- 24343096 TI - Characterization of metal profiles in serum during the progression of Alzheimer's disease. AB - Metal dyshomeostasis is closely related to Alzheimer's disease, so the characterization of the metal profiles in these patients is of special interest for studying associated neurodegenerative processes and to discover potential markers of disease. An analytical approach, based on non-denaturing precipitation of proteins, has been optimized for the fractionation of high molecular mass (HMM) and low molecular mass (LMM) metal-species from serum, which were subjected to multielemental analysis by inductively coupled plasma mass spectrometry (ICP MS). This methodology was applied to healthy controls, Alzheimer's disease (AD) and mild cognitive impairment (MCI) patients in order to study the progression of dementia. Thus, it was found that some metals, such as iron, copper, zinc and aluminium, suffer progressive changes along the advance of neurodegeneration, suggesting that these imbalances could be related to the decline of cognitive functions. On the other hand, elements such as manganese, lithium or vanadium allow discriminating between controls and diseased subjects, both AD and MCI, but no differences were found between these two clinical stages, so they could be considered as precursors in the early development of neurodegenerative failures. In addition, it should be noted the important role that low molecular mass fractions of iron, copper, aluminium and cobalt appear to play in pathogenesis of Alzheimer. Finally, correlation analysis indicated that these metal abnormalities can be interrelated, participating in common processes such as oxidative stress, altered homeostasis and uptake into brain, as well as impaired glucose metabolism. PMID- 24343097 TI - Early outcomes and hemodynamics after implantation of the Trifecta aortic bioprosthesis. AB - OBJECTIVE: The Trifecta valve is a recent, newly designed high performance valve, with few studies on the clinical and hemodynamic data. The purpose of this study was to evaluate the early clinical and echocardiographic results of the Trifecta valve. METHODS: Between April 2012 and December 2012, 23 consecutive patients underwent aortic valve replacement with the Trifecta valve in our institution. Clinical and hemodynamic data were prospectively recorded and hemodynamic performance was assessed by transthoracic echocardiography. RESULTS: Nine patients were male and the overall mean age was 75 +/- 9 years. Twenty patients suffered aortic stenosis, and 3 suffered aortic insufficiency. Prosthesis sizes implanted were: 19 mm (n = 4), 21 mm (n = 12), and 23 mm (n = 7). There were no 30-day deaths and no valve-related events during follow-up, except for 1 postoperative stroke. The mean postoperative transprosthetic pressure gradient was 10.0 +/- 1.4, 9.6 +/- 3.6, and 7.1 +/- 3.6 mmHg, and the effective orifice area was 1.45 +/- 0.13, 1.68 +/- 0.16, and 1.90 +/- 0.28 cm(2), for valve sizes 19, 21, and 23 mm, respectively. One patient had moderate prosthesis-patient mismatch. No moderate to severe aortic regurgitation was observed. The mean pressure gradient in aortic stenosis patients decreased significantly from 49.9 +/- 20.7 to 8.9 +/- 3.6 mmHg (p < 0.001). Left ventricular mass index in all patients decreased significantly from 142.0 +/- 33.6 to 115.4 +/- 26.4 g/m(2) (p < 0.001). CONCLUSIONS: The Trifecta aortic bioprosthesis provided satisfactory early outcomes and hemodynamic function. PMID- 24343098 TI - Bone metastasis in primary endometrial carcinoma: features, outcomes, and predictors. AB - OBJECTIVES: This study aimed to describe the clinicopathologic characteristics and outcomes and to assess the predictors associated with prognosis in endometrial carcinoma that developed bone metastasis. METHODS: A retrospective review of medical records was performed to identify the patients with endometrial carcinoma who developed bone metastasis between October 1994 and May 2012. RESULTS: Of the 1185 patients with endometrial carcinoma, 22 (1.8%) were identified with bone metastasis, and 21 patients were analyzed in the study. Seventeen (80.9%) patients had advanced-stage disease (2009 International Federation of Gynecologists and Obstetricians stages III-IV). Four (19.0%) patients had a bone lesion at the diagnosis of endometrial cancer. The median time of recurrence to the bone in 17 patients was 9 months (range, 2-43 months). The median overall survival (OS) and survival after bone metastasis of the entire cohort were 33 months (range, 9-57 months) and 15 months (range, 12-17 months), respectively. The patients with bone metastasis at recurrence had significantly longer OS than those patients with bone metastasis at diagnosis of endometrial cancer (36 vs 13 months; P = 0.042). Metastasis to extrapelvic bone was significantly associated with longer OS (46 vs 19 months; P = 0.001) and longer survival after bone metastasis (25 vs 12 months; P = 0.002). Isolated bone recurrence without extraosseous metastases and extrapelvic bone metastasis revealed independent predictors for survival after bone metastasis (hazard ratio, 0.09; 95% confidence interval, 0.01-0.67; P = 0.019 and hazard ratio, 0.07; 95% confidence interval, 0.01-0.53; P = 0.01). CONCLUSIONS: In endometrial carcinoma that develops bone metastasis, isolated bone recurrence and extrapelvic bone metastasis are significant predictors of prolonged survival after the diagnosis of bone metastasis. Further researches on the optimal treatment modality and factors that have the clinical implications are warranted. PMID- 24343099 TI - Racial progress as threat to the status hierarchy: implications for perceptions of anti-White bias. AB - In three studies, we examined how racial progress affects Whites' perceptions of anti-White bias. When racial progress was chronically (Study 1) and experimentally (Study 2) salient, Whites who believed the current U.S. status hierarchy was legitimate were more likely to report that Whites were victims of racial discrimination. In contrast, Whites who perceived the current status system as illegitimate were unaffected by the salience of racial progress. The results of Study 3 point to the role of threat in explaining these divergent reactions to racial progress. When self-affirmed, Whites who perceived the status hierarchy as legitimate no longer showed increased perceptions of anti-White bias when confronted with evidence of racial progress. Implications for policies designed to remedy social inequality are discussed. PMID- 24343100 TI - Two copies of blaNDM-1 gene are present in NDM-1 producing Pseudomonas aeruginosa isolates from Serbia. AB - New Delhi metallo-beta-lactamase producing Pseudomonas aeruginosa isolates are of special interest since P. aeruginosa is a major cause of nosocomial infections, the treatment of which could now be jeopardized, especially in developing countries. Six additional NDM-1 positive P. aeruginosa clinical isolates belonging to two different genotypes were shown to be plasmid-free. PFGE hybridization experiments revealed the chromosomal location of the blaNDM-1 gene. Restriction analysis and hybridization revealed that two copies of the blaNDM-1 gene are present in the genomes of all tested isolates, as in previously characterized P. aeruginosa MMA83. Moreover, it was shown that increasing imipenem concentration did not have the effect on copy number of the blaNDM-1 gene in the genome of P. aeruginosa MMA83. PMID- 24343101 TI - Fictibacillus enclensis sp. nov., isolated from marine sediment. AB - A novel Gram-positive strain, designated NIO-1003(T), was isolated from a marine sediment sample collected from the Chorao Island, Goa Provence, India. Strain NIO 1003(T) was found to be strictly aerobic, motile, endospore-forming rods. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain NIO 1003(T) belongs to the genus Fictibacillus and to be most closely related to Fictibacillus rigui KCTC 13278(T), Fictibacillus solisalsi KCTC 13181(T) and Fictibacillus barbaricus DSM 14730(T) with 98.2, 98.0 and 97.2 % similarity and 25, 28, 39 nucleotide differences respectively. Strain NIO-1003(T) was characterized by having cell-wall peptidoglycan based on meso-diaminopimelic acid and MK-7 as the predominant menaquinone. The polar lipid profile exhibited the major compounds diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. In addition, minor amounts of an aminophospholipid were detected. The major fatty acids were identified as ai-C15:0, iso-C15:0, ai-C17:0 and C16:0, supporting the grouping of strain NIO-1003(T) into the family Bacillaceae. The DNA G+C content of strain NIO-1003(T) was determined to be 42.6 mol%. On the basis of phenotypic properties, phylogeny and DNA-DNA hybridisation analysis, strain NIO-1003(T) is considered to represent a novel species of the genus Fictibacillus for which the name Fictibacillus enclensis sp. nov. is proposed. The type strain is NIO-1003(T) (= NCIM 5458(T) = DSM 25142(T)). PMID- 24343102 TI - Multi-modal locomotion: from animal to application. AB - The majority of robotic vehicles that can be found today are bound to operations within a single media (i.e. land, air or water). This is very rarely the case when considering locomotive capabilities in natural systems. Utility for small robots often reflects the exact same problem domain as small animals, hence providing numerous avenues for biological inspiration. This paper begins to investigate the various modes of locomotion adopted by different genus groups in multiple media as an initial attempt to determine the compromise in ability adopted by the animals when achieving multi-modal locomotion. A review of current biologically inspired multi-modal robots is also presented. The primary aim of this research is to lay the foundation for a generation of vehicles capable of multi-modal locomotion, allowing ambulatory abilities in more than one media, surpassing current capabilities. By identifying and understanding when natural systems use specific locomotion mechanisms, when they opt for disparate mechanisms for each mode of locomotion rather than using a synergized singular mechanism, and how this affects their capability in each medium, similar combinations can be used as inspiration for future multi-modal biologically inspired robotic platforms. PMID- 24343103 TI - Corrective GUSB transfer to the canine mucopolysaccharidosis VII brain. AB - Severe deficiency in lysosomal beta-glucuronidase (beta-glu) enzymatic activity results in mucopolysaccharidosis (MPS) VII, an orphan disease with symptoms often appearing in early childhood. Symptoms are variable, but many patients have multiple organ disorders including neurological defects. At the cellular level, deficiency in beta-glu activity leads to abnormal accumulation of glycosaminoglycans (GAGs), and secondary accumulation of GM2 and GM3 gangliosides, which have been linked to neuroinflammation. There have been encouraging gene transfer studies in the MPS VII mouse brain, but this is the first study attempting the correction of the >200-fold larger and challenging canine MPS VII brain. Here, the efficacy of a helper-dependent (HD) canine adenovirus (CAV-2) vector harboring a human GUSB expression cassette (HD-RIGIE) in the MPS VII dog brain was tested. Vector genomes, beta-glu activity, GAG content, lysosome morphology and neuropathology were analyzed and quantified. Our data demonstrated that CAV-2 vectors preferentially transduced neurons and axonal retrograde transport from the injection site to efferent regions was efficient. HD-RIGIE injections, associated with mild and transient immunosuppression, corrected neuropathology in injected and noninjected structures throughout the cerebrum. These data support the clinical evaluation of HD CAV-2 vectors to treat the neurological defects associated with MPS VII and possibly other neuropathic lysosomal storage diseases. PMID- 24343104 TI - Retrograde ductal administration of the adenovirus-mediated NDRG2 gene leads to improved sialaden hypofunction in estrogen-deficient rats. AB - One of the most common oral manifestations of menopause is xerostomia. Oral dryness can profoundly affect quality of life and interfere with basic daily functions, such as chewing, deglutition, and speaking. Although the feeling of oral dryness can be ameliorated after estrogen supplementation, the side effects of estrogen greatly restrict its application. We previously found that N-myc downstream-regulated gene 2 (NDRG2) is involved in estrogen-mediated ion and fluid transport in a cell-based model. In the present study, we used an ovariectomized rat model to mimic xerostomia in menopausal women and constructed two adenovirus vectors bearing NDRG2 to validate their therapeutic potential. Ovariectomized rats exhibited severe sialaden hypofunction, including decreased saliva secretion and ion reabsorption as well as increased water intake. Immunohistochemistry revealed that the expression of NDRG2 and Na(+) reabsorption related Na(+)/K(+)-ATPase and epithelial sodium channels (EnaC) decreased in ovariectomized rat salivary glands. We further showed that the localized delivery of NDRG2 improved the dysfunction of Na(+) and Cl(-) reabsorption. In addition, the saliva flow rate and water drinking recovered to normal. This study elucidates the mechanism of estrogen deficiency-mediated xerostomia or sialaden hypofunction and provides a promising strategy for therapeutic intervention. PMID- 24343105 TI - Release of Cu2+ from a copper-filled TiO2 coating in a rabbit model for total knee arthroplasty. AB - The aim of this study was the investigation of a copper-filled TiO2 coating, that in vitro showed good antibacterial properties combined with good tissue tolerance in an animal model. To better understand the antibacterial mechanism of the bioactive coating the release of copper (Cu) ions over time was monitored to be able to detect possible threats as well as possible fields of application. 30 New Zealand White rabbits were divided into two groups with 15 animals per group. In group 1 (control group) Ti6Al4 V bolts were implanted into the distal femur, in group 2 the Ti6Al4 V bolts were coated with four TiO2-coatings with integrated Cu(2+)-ions (4 * Cu-TiO2). Blood tests were performed weekly until the animals were sacrificed 4 weeks postoperative. The maximum peak of Cu and ceruloplasmin concentration could be seen in both groups one week postoperative, whereas the Cu values in group II were significantly higher. The Cu concentration in both groups approximated the initial basic values 4 weeks postoperative. The 4 * Cu-TiO2 coating tested in our rabbit model for total knee arthroplasty is an active coating that releases potentially antibacterial Cu(2+) for 4 weeks with a peak 1 week postoperative. The bioactive coating could be a promising approach for a use in the field of implant related infection, orthopaedic revision and tumor surgery in the future. PMID- 24343106 TI - Guidelines in review: 2013 ACCF/AHA Guideline for the Management of Heart Failure. PMID- 24343108 TI - Assessment of Basal Metabolic Rate and Nutritional Status in Patients with Gaucher Disease Type III. AB - Gaucher disease type III (GD III) is a rare form of GD characterized by neurological involvement and severe systemic disease. The objective of this study was to assess the nutritional status and energy metabolism of patients with GD III. METHODS: The basal metabolic rate (BMR, measured by indirect calorimetry) and anthropometric parameters (height, weight, body mass index (BMI), and arm circumference) of three patients with GD III (p.L444P/L444P genotype) were assessed at different time points. The clinical severity of GD was assessed by means of physical examination, laboratory tests, imaging findings, and the severity scores proposed by Zimran (SSI) and Davies (SSNI). RESULTS: The measured BMR of patients 1 (age 14 years, not on enzyme replacement therapy (ERT), SSI score 33, SSNI score 14.5), 2 (age 17 years, on ERT, SSI score 33, SSNI score 16), and 3 (age 20 years, on ERT, SSI score 33, SSNI score 7.5) was, respectively, 47%, 72%, and 15% higher than that estimated by the Harris-Benedict equation. Patients with a more severe phenotype had more marked hypermetabolism. Patients 1 and 2 had BMI-for-age z scores of -1.09 and -1.39, respectively, and height-for-age z scores of -4.27 and -3.02, respectively; patient 3 had a BMI of 24.7 kg/m(2). CONCLUSION: All three patients showed hypermetabolism; however, the two patients with the highest BMR had more severe GD and were malnourished. Additional studies are warranted to assess whether hypermetabolism may be a biomarker of disease severity in GD. PMID- 24343109 TI - [Clinical prognosis of schizophrenic patients with cannabis addiction. Between nihilism and hope]. AB - Comorbid substance use disorders in schizophrenia are mostly associated with an unfavorable course of the disease and with difficulties in clinical management. Therefore, some therapists tend to react to these patients in a resigned manner. However, there is growing evidence for higher cognitive functioning and less severe deficits in brain morphology of these patients compared to patients without cannabis use. A common interpretation refers to relatively low vulnerability for psychosis in some of these patients, who mainly became schizophrenic because of the pro-psychotic properties of cannabis. Low vulnerability is reflected by a higher cognitive functioning; therefore, the pessimistic view of therapists seems unjustified for at least a subgroup of young patients. Provided that patients are treated in adequate therapeutic settings and that they stop using cannabis, a lower vulnerability may be associated with overall better socio-rehabilitative outcome parameters. PMID- 24343110 TI - [Differential diagnostics of diseases of the brachial plexus]. AB - Progressive, atrophic, asymmetrically distributed flaccid paresis of arm and hand muscles represents a frequent symptom of neuromuscular diseases that can be attributed to injury of the arm nerves, the plexus or the cervical roots. A timely and exact diagnosis is mandatory; however, the broad spectrum of differential diagnoses often represents a diagnostic challenge. A large variety of neuromuscular disorders need to be considered, encompassing autoimmune mediated inflammatory neuropathic conditions, such as multifocal motor neuropathy, as well as chronic degenerative and nerve compression disorders. This review provides an overview of the most frequent disorders of the upper plexus and cervical roots and summarizes the characteristic clinical features as well as electrodiagnostic and laboratory test results. In addition the diagnostic value of magnetic resonance imaging and sonography is discussed. PMID- 24343112 TI - The semiology of tilt-induced reflex syncope in relation to electroencephalographic changes. AB - Syncope is defined as transient loss of consciousness as a result of cerebral hypoperfusion. Electroencephalography during syncope shows either a 'slow-flat slow' or a 'slow' pattern. The first is believed to denote more severe hypoperfusion. Although the diagnosis of vasovagal syncope relies primarily on history taking, there is limited evidence regarding the relative importance of various clinical features, and none that relate them to the severity of electroencephalographic changes. The aim of this investigation was to study symptoms, signs and electroencephalographic changes with a 1 s resolution using electroencephalography and video data in 69 cases of tilt-induced vasovagal syncope. The main finding was that flattening of the electroencephalograph indicated more profound circulatory changes: the 'slow-flat-slow' group had a lower minimum blood pressure, longer maximum RR-interval, contained more cases with asystole and had a longer duration of loss of consciousness than the 'slow' group. Second, we describe a range of signs, including some that have rarely been reported in syncope, e.g. oral automatisms. Third, signs occurred at different rates depending on electroencephalographic flattening, suggesting a classification of syncopal signs. Type A signs (e.g. loss of consciousness, eye opening and general stiffening) develop during the first slow phase, stay present during flattening and stop in the second slow phase. Type B (particularly myoclonic jerks) occur when the electroencephalograph is slow but not flat: their abolition with electroencephalographic flattening suggests dependence on cortical activity. Type C signs (making sounds, roving eye movements and stertorous breathing) occur only in the flat phase, whereas type D (dropping the jaw and snoring) may occur either in slow or flat phases. In conclusion, our findings provide a detailed assessment of clinical symptoms in relation to electroencephalographic (EEG) changes during tilt-induced syncope. PMID- 24343113 TI - Lack of evidence for clinical and health policy decisions. PMID- 24343114 TI - The elephant in the room-your patient is dying: a teachable moment. PMID- 24343115 TI - Evidence that arbuscular mycorrhizal and phosphate-solubilizing fungi alleviate NaCl stress in the halophyte Kosteletzkya virginica: nutrient uptake and ion distribution within root tissues. AB - The effects of an arbuscular mycorrhizal (AM) fungus, Glomus mosseae, and a phosphate-solubilizing microorganism (PSM), Mortierella sp., and their interactions, on nutrient (N, P and K) uptake and the ionic composition of different root tissues of the halophyte Kosteletzkya virginica (L.), cultured with or without NaCl, were evaluated. Plant biomass, AM colonization and PSM populations were also assessed. Salt stress adversely affected plant nutrient acquisition, especially root P and K, resulting in an important reduction in shoot dry biomass. Inoculation of the AM fungus or/and PSM strongly promoted AM colonization, PSM populations, plant dry biomass, root/shoot dry weight ratio and nutrient uptake by K. virginica, regardless of salinity level. Ion accumulation in root tissues was inhibited by salt stress. However, dual inoculation of the AM fungus and PSM significantly enhanced ion (e.g., Na(+), Cl(-), K(+), Ca(2+), Mg(2+)) accumulation in different root tissues, and maintained lower Na(+)/K(+) and Ca(2+)/Mg(2+) ratios and a higher Na(+)/Ca(2+) ratio, compared to non inoculated plants under 100 mM NaCl conditions. Correlation coefficient analysis demonstrated that plant (shoot or root) dry biomass correlated positively with plant nutrient uptake and ion (e.g., Na(+), K(+), Mg(2+) and Cl(-)) concentrations of different root tissues, and correlated negatively with Na(+)/K(+) ratios in the epidermis and cortex. Simultaneously, root/shoot dry weight ratio correlated positively with Na(+)/Ca(2+) ratios in most root tissues. These findings suggest that combined AM fungus and PSM inoculation alleviates the deleterious effects of salt on plant growth by enabling greater nutrient (e.g., P, N and K) absorption, higher accumulation of Na(+), K(+), Mg(2+) and Cl(-) in different root tissues, and maintenance of lower root Na(+)/K(+) and higher Na(+)/Ca(2+) ratios when salinity is within acceptable limits. PMID- 24343117 TI - Emerging regulators of endosomal dynamics during mitosis. PMID- 24343118 TI - Cathepsin K activity controls injury-related vascular repair in mice. AB - Cathepsin K (CatK) is one of the most potent mammalian collagenases. We showed previously the increased expression of CatK in human and animal atherosclerotic lesions. Here, we hypothesized that ablation of CatK mitigates injury-induced neointimal hyperplasia. Male wild-type (CatK(+/+)) and CatK-deficient (CatK(-/-)) mice underwent ligation or a combination of ligation and polyethylene cuff replacement injuries to the right common carotid artery just proximal to its bifurcation, and they were then processed for morphological and biochemical studies at specific time points. On operative day 28, CatK(-/-) significantly reduced neointimal formation and neovessel formation in both single- and combination-injured arteries compared with the Cat K(+/+) mice. At early time points, CatK(-/-) reduced the lesion macrophage contents and medial smooth muscle cell proliferation, the mRNA levels of monocyte chemoattractant protein-1, toll like receptor-2, toll-like receptor-4, chemokine ligand-12, and the gelatinolytic activity related to matrix metalloproteinase-2/-9. An aorta-explant assay revealed that smooth muscle cell movement was impaired in the CatK(-/-) mice compared with the CatK(+/+) mice. In addition, the smooth muscle cells and macrophages from CatK(-/-) mice had less invasive ability through a reconstituted basement membrane barrier. This vasculoprotective effect was mimicked by Cat inhibition with trans-epoxysuccinyl-L-leucylamido-{4-guanidino} butane (E64d). These results demonstrate an essential role of CatK in neointimal lesion formation in response to injury, possibly via the reduction of toll-like receptor 2/-4-mediated inflammation and smooth muscle cell proliferation, suggesting a novel therapeutic strategy for the control of endovascular treatment-related restenosis by regulating CatK activity. PMID- 24343119 TI - Tight versus standard blood pressure control in patients with hypertension with and without cardiovascular disease. AB - An excessive blood pressure (BP) reduction might be dangerous in high-risk patients with cardiovascular disease. In the Studio Italiano Sugli Effetti CARDIOvascolari del Controllo della Pressione Arteriosa SIStolica (Cardio-Sis), 1111 nondiabetic patients with systolic BP >=150 mm Hg were randomly assigned to a systolic BP target <140 mm Hg (standard control) or <130 mm Hg (tight control). We stratified patients by absence (n=895) or presence (n=216) of established cardiovascular disease at entry. Antihypertensive treatment was open-label and tailored to each patient's needs. After 2-year follow-up, the primary end point of the study, electrocardiographic left ventricular hypertrophy, occurred less frequently in the tight than in the standard control group in the patients without (10.8% versus 15.2%) and with (14.1% versus 23.5%) established cardiovascular disease (P for interaction=0.82). The main secondary end point, a composite of cardiovascular events and all-cause death, occurred less frequently in the tight than in the standard control group both in patients without (1.47 versus 3.68 patient-years; P=0.016) and with (7.87 versus 11.22 patient-years; P=0.049) previous cardiovascular disease. In a multivariable Cox model, allocation to tight BP control reduced the risk of cardiovascular events to a similar extent in patients with or without overt cardiovascular disease at randomization (P for interaction=0.43). In conclusion, an intensive treatment aimed to lower systolic BP<130 mm Hg reduced left ventricular hypertrophy and improved clinical outcomes to a similar extent in patients with hypertension and without established cardiovascular disease. PMID- 24343120 TI - Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood-brain barrier. AB - Angiotensin II-mediated vascular brain inflammation emerged as a novel pathophysiological mechanism in neurogenic hypertension. However, the precise underlying mechanisms and functional consequences in relation to blood-brain barrier (BBB) integrity and central angiotensin II actions mediating neurohumoral activation in hypertension are poorly understood. Here, we aimed to determine whether BBB permeability within critical hypothalamic and brain stem regions involved in neurohumoral regulation was altered during hypertension. Using digital imaging quantification after intravascularly injected fluorescent dyes and immunohistochemistry, we found increased BBB permeability, along with altered key BBB protein constituents, in spontaneously hypertensive rats within the hypothalamic paraventricular nucleus, the nucleus of the solitary tract, and the rostral ventrolateral medulla, all critical brain regions known to contribute to neurohumoral activation during hypertension. BBB disruption, including increased permeability and downregulation of constituent proteins, was prevented in spontaneously hypertensive rats treated with the AT1 receptor antagonist losartan, but not with hydralazine, a direct vasodilator. Importantly, we found circulating angiotensin II to extravasate into these brain regions, colocalizing with neurons and microglial cells. Taken together, our studies reveal a novel angiotensin II-mediated feed-forward mechanism during hypertension, by which circulating angiotensin II evokes increased BBB permeability, facilitating in turn its access to critical brain regions known to participate in blood pressure regulation. PMID- 24343121 TI - CD247 modulates blood pressure by altering T-lymphocyte infiltration in the kidney. AB - The CD3 zeta chain (CD247), a gene involved in T-cell signaling, has been shown to associate with blood pressure in human genetic studies. To test the functional role of CD247 in hypertension and renal disease, zinc-finger nucleases targeting CD247 were injected into Dahl salt-sensitive (SS/JrHsdMcwi) embryos. The resulting 11-bp frameshift deletion in exon 1 of CD247 led to a predicted premature stop codon. Western blotting confirmed the absence of CD247 protein in the thymus, and flow cytometry (n=5-9 per group) demonstrated that the mutant rats (CD247(-/-)) have a >99% reduction in circulating CD3(+) T cells compared with littermate controls (CD247(+/+)). Studies were performed on age-matched, littermate male, CD247(+/+) and CD247(-/-) rats fed a 4.0% NaCl diet for 3 weeks. The infiltration of CD3(+) T cells into the kidney after high salt was significantly blunted in CD247(-/-) (1.4+/-0.4*10(5) cells per kidney) when compared with that in the CD247(+/+) (8.7+/-2.0*10(5) cells per kidney). Accompanying the reduced infiltration of T cells, mean arterial blood pressure was significantly lower in CD247(-/-) than in CD247(+/+) (134+/-1 versus 151+/-2 mm Hg). As an index of kidney disease, urinary albumin and protein excretion rates were significantly reduced in CD247(-/-) (17+/-1 and 62+/-2 mg/d, respectively) when compared with that in CD247(+/+) (49+/-3 and 121+/-5 mg/d, respectively). Glomerular and renal tubular damage were also attenuated in the CD247(-/-). These studies demonstrate that functional T cells are required for the full development of Dahl salt-sensitive hypertension and indicate that the association between CD247 and hypertension in humans may be related to altered immune cell function. PMID- 24343122 TI - Irritant-induced asthma in the workplace. AB - Irritant-induced asthma in the workplace has been the focus of several articles in the past few years, and reviewed here. A clinical case definition is most readily associated with a single acute/accidental exposure to a presumed high concentration of an agent or agents expected to be irritant to the airways, as was initially reported with the subgroup Reactive Airways Dysfunction Syndrome (RADS). When most but not all criteria for RADS are met, then a diagnosis of irritant-induced asthma may also be considered to be "more probable than not". However, in addition, there is evolving understanding from epidemiological studies that chronic exposures may be associated with an increased risk of developing asthma. Despite this recognition, the mechanisms and clinical case definitions of work-related asthma that might be caused by chronic exposures to irritants (vs. new-onset asthma that begins coincidentally to work exposures), remain unclear at present. PMID- 24343123 TI - New insights into the molecular diagnosis and management of heritable thoracic aortic aneurysms and dissections. AB - Since the identification of the fibrillin-1 gene as the causal gene for Marfan syndrome, our knowledge of molecular genetics and the applicability of genetic testing for heritable thoracic aneurysms and dissections (H-TAD) in clinical practice have increased substantially. Several new syndromes related to H-TAD have been described and the list of mutated genes in syndromal and nonsyndromal H TAD is rapidly expanding. This knowledge has led to a significant improvement of our insight into the underlying pathophysiology of H-TAD resulting in new opportunities for targeted treatment, as well as in improved risk stratification. Clinicians involved in the care for H-TAD patients require a basic knowledge of the disease entities and need to be correctly informed on the applicability of genetic testing in their patients and families. Gene-tailored treatment and management should now be considered as part of good clinical practice. We provide a systematic overview of genetic H-TAD entities and practical recommendations for genetic testing and patient management. PMID- 24343126 TI - Exploring non-covalent interactions in guanine- and xanthine-based model DNA quadruplex structures: a comprehensive quantum chemical approach. AB - The study aimed to cast light on the structure and internal energetics of guanine and xanthine-based model DNA quadruplexes and the physico-chemical nature of the non-covalent interactions involved. Several independent approaches were used for this purpose: DFT-D3 calculations, Quantum Theory of Atoms in Molecules, Natural Bond Orbital Analysis, Energy Decomposition Analysis, Compliance Constant Theory, and Non-Covalent Interaction Analysis. The results point to an excellent degree of structural and energetic compatibility between the two types of model quadruplexes. This fact stems from both the structural features (close values of van der Waals volumes, pore radii, geometrical parameters of the H-bonds) and the energetic characteristics (comparable values of the energies of formation). It was established that hydrogen bonding makes the greatest (~50%) contribution to the internal stability of the DNA quadruplexes, whereas the aromatic base stacking and ion coordination terms are commensurable and account for the rest. Energy decomposition analysis performed for guanine (Gua) and xanthine (Xan) quartets B4 and higher-order structures consisting of two or three stacked quartets indicates that whereas Gua structures benefit from a high degree of H bond cooperativity, Xan models are characterized by a more favorable and cooperative pi-pi stacking. The results of electron density topological analysis show that Na(+)/K(+) ion coordination deeply affects the network of non-covalent interactions in Gua models due to the change in the twist angle between the stacked tetrads. For Xan models, ion coordination makes tetrads in stacks more planar without changing the twist angle. Therefore, the presence of the ion seems to be essential for the formation of planar stacks in Xan-based DNA quadruplexes. Detailed study of the nature of ion-base coordination suggests that this interaction has a partially covalent character and cannot be considered as purely electrostatic. Investigation of the H-bond and ion-base coordination strengths by various independent approaches agrees well with the results of QTAIM analysis. PMID- 24343124 TI - Altered transition metal homeostasis in Niemann-Pick disease, type C1. AB - The loss of NPC1 protein function is the predominant cause of Niemann-Pick type C1 disease (NP-C1), a systemic and neurodegenerative disorder characterized by late-endosomal/lysosomal accumulation of cholesterol and other lipids. Limited evidence from post-mortem human tissues, an Npc1(-/-) mouse model, and cell culture studies also suggest failure of metal homeostasis in NP-C1. To investigate these findings, we performed a comprehensive transition metal analysis of cerebrospinal fluid (CSF), plasma and tissue samples from human NP-C1 patients and an Npc1(-/-) mouse model. NPC1 deficiency in the Npc1(-/-) mouse model resulted in a perturbation of transition metal homeostasis in the plasma and key organs (brain, liver, spleen, heart, lungs, and kidneys). Analysis of human patient CSF, plasma and post-mortem brain tissues also indicated disrupted metal homeostasis. There was a disparity in the direction of metal changes between the human and the Npc1(-/-) mouse samples, which may reflect species specific metal metabolism. Nevertheless, common to both species is brain zinc accumulation. Furthermore, treatment with the glucosylceramide synthase inhibitor miglustat, the only drug shown in a controlled clinical trial to have some efficacy for NP-C1, did not correct the alterations in CSF and plasma transition metal and ceruloplasmin (CP) metabolism in NP-C1 patients. These findings highlight the importance of NPC1 function in metal homeostasis, and indicate that metal-targeting therapy may be of value as a treatment for NP-C. PMID- 24343128 TI - Prescribing thiamine to inpatients with alcohol use disorders: how well are we doing? AB - OBJECTIVES: Thiamine deficiency is a potentially dangerous sequela of alcohol use disorders (AUDs). European and British guidelines recommend administering high dose parenteral thiamine 3 times daily to avoid consequences of thiamine deficiency such as Wernicke-Korsakoff syndrome (WKS), and suggest that traditional thiamine dosages are likely inadequate. Research into thiamine and WKS has lagged in the United States, and to date, no study has examined how thiamine is prescribed to inpatients with AUD in an American hospital. METHODS: Thiamine prescribing data (amount, route, and frequency schedule) were collected for inpatients at a large, American, teaching hospital, who were referred to the addiction psychiatry service for AUD. Data were analyzed using Statistical Product and Service Solutions. RESULTS: A total of 217 inpatients with AUD were included. A substantial percentage of them were not prescribed thiamine. Of those who were prescribed thiamine, nearly all were prescribed oral thiamine at traditional dosages, including high-risk patients. CONCLUSIONS: This is the first study to report on the prescribing of thiamine to inpatients with AUD at an American teaching hospital. It serves to confirm what many already suspected: that more education is needed to improve the diagnostic challenges of WKS, the detection of risk factors for WKS, and the adequate dosing of thiamine for prevention and treatment of WKS. PMID- 24343129 TI - NF-kappaB p65 recruited SHP regulates PDCD5-mediated apoptosis in cancer cells. AB - Transcription factor NF-kappaB promotes cell proliferation in response to cell injury. Increasing evidence, however, suggests that NF-kappaB can also play an apoptotic role depending on the stimulus and cell type. We have previously demonstrated that novel retinoid 4-[3-Cl-(1-adamantyl)-4-hydroxyphenyl]-3 chlorocinnamic acid (3-Cl-AHPC)-mediated apoptosis in breast carcinoma cells requires activation of canonical and non-canonical NF-kappaB pathways. The mechanism NF-kappaB uses to induce apoptosis remains largely unknown. NF-kappaB subunit p65 (RelA) was identified as one potent transcriptional activator in 3-Cl AHPC-mediated apoptosis in cells. Here we used ChIP-on-chip to identify NF-kappaB p65 genes activated in 3-Cl-AHPC mediated apoptosis. This paper focuses on one hit: pro-apoptotic protein programmed cell death 5 (PDCD5). 3-Cl-AHPC mediated apoptosis in MDA-MB-468 had three related effects on PDCD5: NF-kappaB p65 binding to the PDCD5 gene, enhanced PDCD5 promoter activity, and increased PDCD5 protein expression. Furthermore, 3-Cl-AHPC increased orphan nuclear receptor small heterodimer partner (SHP) mRNA expression, increased SHP protein bound to NF kappaB p65, and found the SHP/NF-kappaB p65 complex attached to the PDCD5 gene. PDCD5 triggered apoptosis through increased Bax protein and release of cytochrome C from mitochondria to cytosol. Lastly, knockdown of PDCD5 protein expression blocked 3-Cl-AHPC mediated apoptosis, while over-expression of PDCD5 enhanced apoptosis, suggesting PDCD5 is necessary and sufficient for NF-kappaB p65 mediated apoptosis. Our results demonstrate a novel pathway for NF-kappaB p65 in regulating apoptosis through SHP and PDCD5. PMID- 24343127 TI - Characteristics and impact of methamphetamine use in patients with chronic hepatitis C. AB - OBJECTIVES: Methamphetamine (MA) use has increased in the United States in the last 20 years and is a risk factor for hepatitis C virus(HCV) infection. The purpose of this study was to determine the characteristics and HCV infection outcomes of patients with a history of MA use. METHODS: Subjects consisted of newly entered patients in the Veterans Affairs (VA) HCV registry at a single VA medical center from January 1, 2004, to June 30, 2004, and from January 1, 2007, to June 30, 2007. Univariate and multivariate analyses related to HCV infection antiviral treatment outcomes through 2010 was performed. RESULTS: A total of 198 consecutive eligible HCV registry patients were analyzed, and 40% had a history of MA use. Of patients with MA use history, 46% (36/79) had active use (within 6 months) at initial contact. Active MA users were significantly younger (mean age, 45.5 years), with more concomitant drug use (86%), compared with patients without MA use (mean age, 53.5 years; 42% minority; 29% other drug use). Overall, 71% of the 198 patients reported a history of problematic alcohol use, and 47% of those reported active abuse. Logistic regression analyses indicated that MA use did not significantly adversely affect antiviral treatment initiation, completion, or sustained virological response rates compared with that in patients without MA use. Active alcohol users had lower treatment initiation than patients without alcohol use. CONCLUSIONS: MA use is common in recent US veterans with HCV infection and occurs in younger patients with polysubstance use. Prior history or active MA use does not seem to adversely affect HCV infection clinic treatment compared with that in HCV-infected patients without MA use. PMID- 24343130 TI - Optimal propulsive flapping in Stokes flows. AB - Swimming fish and flying insects use the flapping of fins and wings to generate thrust. In contrast, microscopic organisms typically deform their appendages in a wavelike fashion. Since a flapping motion with two degrees of freedom is able, in theory, to produce net forces from a time-periodic actuation at all Reynolds numbers, we compute in this paper the optimal flapping kinematics of a rigid spheroid in a Stokes flow. The hydrodynamics for the force generation and energetics of the flapping motion is solved exactly. We then compute analytically the gradient of a flapping efficiency in the space of all flapping gaits and employ it to derive numerically the optimal flapping kinematics as a function of the shape of the flapper and the amplitude of the motion. The kinematics of optimal flapping are observed to depend weakly on the flapper shape and are very similar to the figure-eight motion observed in the motion of insect wings. Our results suggest that flapping could be a exploited experimentally as a propulsion mechanism valid across the whole range of Reynolds numbers. PMID- 24343131 TI - [GeSRU residents training curriculum 2014]. PMID- 24343132 TI - Heart disease in the Netherlands: a quantitative update. AB - In this review we discuss cardiovascular mortality, incidence and prevalence of heart disease, and cardiac interventions and surgery in the Netherlands. We combined most recently available data from various Dutch cardiovascular registries, Dutch Hospital Data (LMR), Statistics Netherlands (CBS), and population-based cohort studies, to provide a broad quantitative update. The absolute number of people dying from cardiovascular diseases is declining and cardiovascular conditions are no longer the leading cause of death in the Netherlands. However, a substantial burden of morbidity persists with 400,000 hospitalisations for cardiovascular disease involving over 80,000 cardiac interventions annually. In the Netherlands alone, an estimated 730,000 persons are currently diagnosed with coronary heart disease, 120,000 with heart failure, and 260,000 with atrial fibrillation. These numbers emphasise the continuous need for dedicated research on prevention, diagnosis, and treatment of heart disease in our country. PMID- 24343133 TI - Expression of extracellular matrix-remodeling proteins is altered in vaginal tissue of premenopausal women with severe pelvic organ prolapse. AB - AIM: The molecular etiology of pelvic organ prolapse (POP) is complex and not well understood. We compared the expression/activity of extracellular matrix (ECM)-processing (procollagen I N-proteinase/ a disintegrin and metalloproteinase with thrombospondin motifs [ADAMTS]-2,-3,-14) and ECM-degrading (matrix metalloproteinase [MMP]-1, -2, -7, -8, -9, -12) enzymes and their natural tissue inhibitors (tissue inhibitors of metalloproteinase [TIMP]-1,-2,-3,-4) in vaginal tissues from premenopausal women with advanced POP (POP-Q stage >= 3) and asymptomatic controls (POP-Q = 0). STUDY DESIGN: We sampled the anterior vaginal wall of 36 premenopausal women (17 patients with POP and 19 controls) undergoing total hysterectomy. Exclusion criteria include steroid therapy, malignancy, previous pelvic surgery, and connective tissue diseases. Total RNAs and proteins were quantified by real-time polymerase chain reaction, immunoblotting, and Luminex assay; MMPs activity was analyzed by zymography and tissue localization by immunohistochemistry. RESULTS: The MMP-2 gelatinase activity as well as expression of 58-kDa isoform of ADAMTS-2 was upregulated in patients with POP, irrespective of menstrual phase status, secretory or proliferative, when compared to controls (P < .05). The TIMP-1-4 gene and TIMP-1 protein expression were significantly (P < .05) reduced, whereas protein expression of MMP-12 (pro and active forms) was significantly increased in vaginal biopsies of patients with POP in the proliferative phase of the menstrual cycle compared to corresponding controls. Analyses of MMP-12, TIMP-1, and ADAMTS-2 tissue immunostaining indicate similar localization in the vaginal specimens from control and patients with POP. CONCLUSION: Expression of ECM-remodeling proteins is altered in the vagina of premenopausal patients with severe POP. We speculate that dysregulation of MMP/TIMP complexes and ADAMTS-2 proteins may cause connective tissue defects, which result in weakened vaginal wall support and POP development. PMID- 24343135 TI - In vivo virtual intraoperative surgical photoacoustic microscopy. AB - We developed a virtual intraoperative surgical photoacoustic microscopy system by combining with a commercial surgical microscope and photoacoustic microscope (PAM). By sharing the common optical path in the microscope and PAM system, we could acquire the PAM and microscope images simultaneously. Moreover, by employing a beam projector to back-project 2D PAM images onto the microscope view plane as augmented reality, the conventional microscopic and 2D cross-sectional PAM images are concurrently mapped on the plane via an ocular lens of the microscope in real-time. Further, we guided needle insertion into phantom ex vivo and mice skins in vivo. PMID- 24343136 TI - [AINS -- a magazine in constant change]. PMID- 24343137 TI - [Is the laryngeal mask in the prone position an alternative?]. PMID- 24343138 TI - [Anaesthesia for extrathoracal vascular surgical procedures - part 1: optimization on the preoperative therapy]. AB - Vascular surgical patients have an increased perioperative risk for cardiovascular complications because of high incidence of cardiovascular risk factors. An optimization of the preoperative therapy is able to reduce the preventable cardiac complications. Cardiovascular risk factors such as high blood pressure, diabetes mellitus, heart failure have to be identified and treated. PMID- 24343139 TI - [Case report: extracorporeal life support for treatment of fulminant pulmonary embolism in a young woman during pregnancy]. AB - During pregnancy, prothrombotic changes of the coagulation system are associated with an increased risk for thrombotic events such as deep vein thrombosis and/or pulmonary embolism. We report the case of a thirty-one year old woman, who suffered severe pulmonary embolism with cardiogenic shock during pregnancy. Systemic fibrinolysis failed to improve hemodynamic deterioration. Finally, insertion of an extracorporeal life support system with subsequent pulmonary thromboendarterectomysaved the life of the patient. PMID- 24343140 TI - [Explosion injuries - prehospital care and management]. AB - Explosion injuries are not restricted to war-like military conflicts or terrorist attacks. The emergency physician may also encounter such injuries in the private or industrial fields, injuries caused by fireworks or gas explosions. In such cases the injury patterns are especially complex and may consist of blunt and penetrating injuries as well as thermal damage. Emergency medical personnel must be prepared to cope with explosion trauma not only in individual cases but also in major casualty incidents (MCI). This necessitates a sound knowledge about the mechanisms and processes of an explosion as well as the particular pathophysiological relationships of explosion injuries in order to be able to initiate the best possible, guideline-conform trauma therapy. PMID- 24343141 TI - [Pssst ... AINS-secrets! -- today in neurosurgery]. PMID- 24343142 TI - [Helsinki declaration on patient safety in anaesthesiology -part 10: infection control/hygiene]. AB - There is a plethora of laws, regulations, guidelines and recommendations relating to infection control and hygiene. Major issues are the prevention of nosocomial infections, staff protection and environmental protection. Of the highest relevance are the infection control law [Infektionsschutzgesetz (IfSG)], the hygiene regulations of the German federal states [Hygieneverordnungen der Bundeslander], the German technical rules for biological materials [Technische Regel Biologische Arbeitsstoffe 250 (TRBA 250)] - biological materials in health care and welfare work [Biologische Arbeitsstoffe im Gesundheitswesen und in der Wohlfahrtspflege], the guidelines for hospital hygiene and prevention of infection of the commission for hospital hygiene and prevention of infection of the Robert-Koch Institute [Richtlinie fur Krankenhaushygiene und Infektionspravention von der Kommission fur Krankenhaushygiene und Infektionspravention (KRINKO) beim Robert Koch-Institut], the recommendations of the commission on anti-infectives, resistance and therapy of the Robert-Koch Institute [Empfehlungen der Kommission Antiinfektiva, Resistenz und Therapie (ART) beim Robert Koch-Institut]. Of subordinate importance are, e.g., the recommendations of the German Society for Anesthesiology and Intensive Medicine (DGAI). It is practically impossible for an anesthesiologist working in a hospital to have knowledge of all laws, regulations, guidelines and recommendations. And this is also not reasonable. Thus it is necessary to distinguish the relevant from the irrelevant. Checklists can be useful here. The most important and effective individual action in hospital hygiene is and remains hand hygiene as is propagated in the action "clean hands", irrespective of all laws, regulations, guidelines and recommendations. PMID- 24343143 TI - [Training -- it urgently needs to change somewhat]. PMID- 24343144 TI - [Training -- competency-based education -- learning theory and practice]. AB - A lifelong learning process is necessarily the basis for the specialization and expertise in the field of anesthesiology. Thus competency as a physician is a complex, multidimensional construction of knowledge, skills and attitudes to be able to solve and persist the complex daily work challenges in a flexible and responsible way. Experts therefore showflexible and intuitive capabilities in pursuing their profession. Accordingly modern competency based learning objectives are very helpful. The DGAI Commission for "Further Education" already thought ahead in defining a competencybased curriculum for the specialization in the field of anesthesiology and could be integrated into the frameworks of the German Medical Association. In addition to the curricular framework elements of assessment are necessary. A single oral exam is consequently not representative for different levels of competencies. However, there is beside the responsibility of the learners for their learning processalso a high obligation of the clinical teachers to attend the learning process and to ensure a positive learning atmosphere with scope for feedback. Some competencies potentially could be better learned in a "sheltered" room based on simulation outside the OR, for example to train rare incidents or emergency procedures. In general there should be ongoing effort to enhance the process of expertise development, also in context of patient safety and quality management. PMID- 24343145 TI - [Knowledge transfer in the light of changing values]. AB - Besides its formal and legal relevance, postgraduate medical education plays an important role in recruiting and retaining employees. Success of graduate education is affected by a changing environment: the former employer market is turning into an employee market. Demographic changes are taking place and a new generation of employees 'Generation Y' is entering the job market. In addition, working conditions are changing: part-time work is increasing and the learning behavior of young professionals demands more flexibility and the use of digital media. These changes and conditions will shape graduate medical education. On the one hand, medical interventions are becoming increasingly complex, on the other hand patients are getting older and sicker. Therefore, simulation-based learning will play an important role in medical training. PMID- 24343146 TI - [A new postgraduate education program of the German Society of Anaesthesiology and Intensive Care Medicine]. AB - The postgraduate education program of the "Landesarztekammer" describes the aims to qualify for the "Facharzt" for anesthesiology and plays a key role in ensuring a high quality of medical care. The "Bundesarztekammer" was assigned by the "Deutsche Arztetag" to develop and improve postgraduate training. The German Society of Anaesthesiology and Intensive Care Medicine launched in 2011 a committee to develop this new training program. In 2013 the results of the committee were presented and submitted to the "Bundesarztekammer". The principle purpose of this paper was to describe all the new aspects related to this program and to describe all the qualifications needed to finish this program. PMID- 24343147 TI - [Development of the physician based prehospital emergency medicine system in the former GDR]. AB - The development of the physician based prehospital emergency medicine system of the former GDR started in the early 1960th. Initially the use of ambulances was trauma-orientated. Because of the increasing number for non-traumatic emergencies the so called SMH-system (emergency medical services) was stepwise established. The SMH-system consisted of two branches: the DMH for potentially life threatening emergencies and the DHD for urgent house visits. Parts of the system were also regional dispatch centers, a specific nationwide phone number (115), standardized equipment, and supervision by a physician. In addition regulations about documentation and staff-qualification were centrally installed. PMID- 24343148 TI - [Development of emergency medical services in Germany - Western part of Germany]. AB - Initially the premise of the rescue services was to deliver patients to medical care as quickly as possible. Due to the demands of the Heidelberger surgeon Kirchner a rethinking was initiated prior to World War 2. It was not until the 1960s that this concept was taken up again and physicians were incorporated into the rescue services. A prerequisite for this in the technical field was the development of physician escorted rescue vehicles for the prehospital management of road accident victims. After the economic and medical benefits of the deployment of emergency physicians had been demonstrated, the mandatory participation of emergency physicians was laid down in the laws on rescue services by the West German federal states. With increasing acceptance, there was a shift of the patient collective from accident victims to acute internal medical and neurological emergency cases. In order to realize the necessary efficacy of the cost-intensive organization the German Medical Council formulated guidelines for the qualification of emergency physicians. PMID- 24343149 TI - [Law on patient rights ("patientenrechtegesetz") - implications in the anesthesiological practice]. AB - Since the beginning of the year the Law on Patient Rights ("Patientenrechtegesetz")has been in force and has to be obeyed in anesthesiological practice.It has especially specific consequences for the patient information about all possible risks. The present article takes a look at specific problems, such as the content of the information about the risks, the delegation of the conversation with the patient, the information about the risks in the case of an inability to consent or in the case of foreign-speaking patients and -last but not least - the documentation. PMID- 24343152 TI - Paradoxical low flow aortic valve stenosis: incidence, evaluation, and clinical significance. AB - Paradoxical low-flow (PLF) aortic stenosis is defined by a stroke volume index <35 ml/m(2) despite the presence of preserved LV ejection fraction (>= 50 %). This entity is typically characterized by pronounced LV concentric remodeling with small LV cavity, impaired LV filling, increased arterial load, and reduced LV longitudinal shortening. Patients with PLF also have a worse prognosis compared to patients with normal flow. Because of the low flow state, these patients often have a low gradient despite the presence of severe stenosis, thus leading to discordant AS grading (i.e., aortic valve area < 1.0 cm(2) but mean gradient < 40 mmHg) and thus uncertainty about the indication of aortic valve replacement. Stress echocardiography and aortic valve calcium score by computed tomography may be helpful to differentiate true from pseudo severe stenosis and thereby guide therapeutic management in these patients. Aortic valve replacement improves outcomes in patients with PLF low gradient AS having evidence of severe stenosis. Transcatheter aortic valve replacement may provide an interesting alternative to surgery in these patients. PMID- 24343154 TI - Founder of PIP breast implant company gets four year prison sentence. PMID- 24343153 TI - Reviewer's comment concerning "Sleep apnea and cervical spine pathology" (10.1007/s00586-013-3046-4 by Adam Khan, Khoi D. Than, Kevin S. Chen, Anthony C. Wang, Frank La Marca, Paul Park). PMID- 24343155 TI - Prognostic value of EEG indexes for the Glasgow outcome scale of comatose patients in the acute phase. AB - The purpose of this work is the estimation of the Glasgow outcome scale (GOS) from a single continuous electroencephalogram (c-EEG) routinely recorded to monitor comatose patients in the neurosurgical intensive care unit. c-EEG was recorded from 13 patients in the acute phase: five with GOS = 5, four with GOS = 3 and four with GOS = 1. Different indexes were extracted from epochs of c-EEG (classical: amplitude and spectral estimators; non classical: from recurrence quantification analysis-RQA-and approximate entropy). Descriptors of different indexes (temporal variation and mean, standard deviation, skewness of the distribution across epochs) were used to train support vector machines to identify the correct GOS. We found classifiers allowing correct classification of the patients. Spectral indexes allowed to get optimal performances in classifying GOS 1 and 3. Nonlinear indexes (especially determinism from RQA) were optimal for identifying GOS = 5. Thus, the integration of information from classical/linear and nonlinear c-EEG descriptors in a multi-index classifier is important for GOS estimation. PMID- 24343156 TI - Theory and experiment on resonant frequencies of liquid-air interfaces trapped in microfluidic devices. AB - Bubble-based microfluidic devices have been proven to be useful for many biological and chemical studies. These bubble-based microdevices are particularly useful when operated at the trapped bubbles' resonance frequencies. In this work, we present an analytical expression that can be used to predict the resonant frequency of a bubble trapped over an arbitrary shape. Also, the effect of viscosity on the dispersion characteristics of trapped bubbles is determined. A good agreement between experimental data and theoretical results is observed for resonant frequency of bubbles trapped over different-sized rectangular-shaped structures, indicating that our expression can be valuable in determining optimized operational parameters for many bubble-based microfluidic devices. Furthermore, we provide a close estimate for the harmonics and a method to determine the dispersion characteristics of a bubble trapped over circular shapes. Finally, we present a new method to predict fluid properties in microfluidic devices and complement the explanation of acoustic microstreaming. PMID- 24343157 TI - Multiple sclerosis disease progression and paradichlorobenzene: a tale of mothballs and toilet cleaner. AB - IMPORTANCE: Environmental factors are thought to be critical in the initiation and perpetuation of multiple sclerosis disease activity. OBSERVATIONS: We describe the case of a woman in her late 30s with a diagnosis of relapsing remitting multiple sclerosis, who continued to accumulate neurological disability despite long-term natalizumab treatment. The patient continued to have visual symptoms, left leg weakness, and gait instability. In addition, she subacutely developed an encephalopathy. Our investigations revealed that the patient had a long-standing history of chewing on toilet bowl deodorizing cakes. The main ingredient in this product is 99.9% paradichlorobenzene, which is also used in mothballs. CONCLUSIONS AND RELEVANCE: This case illustrates that environmental causes for neurological deterioration should be investigated in patients with multiple sclerosis who display a rapidly progressive disease course and in whom potent pharmacotherapies fail. One possible cause is the ingestion of paradichlorobenzene-containing mothballs and toilet cleaners. PMID- 24343158 TI - II. beta-Blockers and cardiac protection: 5 yr on from POISE. PMID- 24343159 TI - The self-complexation of mono-urea-functionalized pillar[5]arenes with abnormal urea behaviors. AB - Mono-urea-functionalized pillar[5]arenes were prepared which exhibited abnormal urea behaviors. They were shown to form pseudo[1]rotaxanes with poor anion binding abilities in solution and [c2]daisy chains with an abnormal urea motif in the solid state. PMID- 24343160 TI - Near-infrared room temperature luminescence of few-atom Au aggregates in silica: a path for the energy-transfer to Er3+ ions. AB - Ultra-small molecule-like AuN nanoclusters made by a number of atoms N less than 30 were produced by ion implantation in silica substrates. Their room temperature photoluminescence properties in the visible and near-infrared range have been investigated and correlated with the Er sensitization effects observed in Er-Au co-implanted samples. The intense photoluminescence emission under 488 nm laser excitation occurs in three different spectral regions around 750 nm (band A), 980 nm (band B) and 1150 nm (band C) as a consequence of the formation of discrete energy levels in the electronic structure of the molecule-like AuN nanoclusters. Indeed, energy maxima of bands A and C scale with N(-1/3) as expected for quantum confined systems. Conversely, the energy maximum of band B appears to be almost independent of size, suggesting a contribution of electronic surface states. A clear correlation between the formation of band B in the samples and Er-related photoemission is demonstrated: the band at 980 nm related to AuN nanoclusters resonant with the corresponding Er(3+) absorption level, is suggested as an effective de-excitation channel through which the Au-related photon energy may be transferred from Au nanoclusters to Er ions (either directly or mediated by photon absorption), eventually producing the Er-related infrared emission at 1540 nm. PMID- 24343161 TI - RNA sequencing reveals the complex regulatory network in the maize kernel. AB - RNA sequencing can simultaneously identify exonic polymorphisms and quantitate gene expression. Here we report RNA sequencing of developing maize kernels from 368 inbred lines producing 25.8 billion reads and 3.6 million single-nucleotide polymorphisms. Both the MaizeSNP50 BeadChip and the Sequenom MassArray iPLEX platforms confirm a subset of high-quality SNPs. Of these SNPs, we have mapped 931,484 to gene regions with a mean density of 40.3 SNPs per gene. The genome wide association study identifies 16,408 expression quantitative trait loci. A two-step approach defines 95.1% of the eQTLs to a 10-kb region, and 67.7% of them include a single gene. The establishment of relationships between eQTLs and their targets reveals a large-scale gene regulatory network, which include the regulation of 31 zein and 16 key kernel genes. These results contribute to our understanding of kernel development and to the improvement of maize yield and nutritional quality. PMID- 24343162 TI - "Children are sexually innocent": Iranian parents' understanding of children's sexuality. AB - Sexuality education (SE) is hotly contested in the West and there is much abstinence-only education; however, it remains controversial in a variety of contexts, including in Iran. The lack of consensus about children's SE in Muslim societies obliges us to explore different aspects of this topic systematically. The qualitative research presented here was about how Iranian parents perceived children's sexuality. Data from parents of 26 children were collected during four focus group sessions. Informants were selected from Area 5 in West Tehran. This area included 72 primary schools for girls and 82 for boys. The sessions were facilitated by using a semi-structured focus group guide. Content analysis was adopted using combined free and analytical coding to reduce data, to extract meanings, and to categorize domains. One of the three main domains identified, family management of child sexuality, is comprised of the following: (1) understanding of child sexuality, (2) family rules, (3) parent-child interactions, and (4) opposite sex interactions. Parental misinformation, accumulated myths, and ignorance about children's sexual development were evident. Strict family rules and a lack of consistent policy and instruction for SE were also identified. Parents said they were neither well-prepared nor competent to educate their children about sexuality. In fact, a majority of mothers raised "incompetence" as an important determinant in their own parent child interactions. Societal changes as well as children's socialization patterns have forced parents to accept their children's opposite sex friendships as a reality. Results suggest a community need for developing comprehensive and culturally sensitive SE for schools and parental use. PMID- 24343164 TI - Probiotics reduce gut microbial translocation and improve adult atopic dermatitis. PMID- 24343165 TI - Kinematic feedback control laws for generating natural arm movements. AB - We propose a stochastic optimal feedback control law for generating natural robot arm motions. Our approach, inspired by the minimum variance principle of Harris and Wolpert (1998 Nature 394 780-4) and the optimal feedback control principles put forth by Todorov and Jordan (2002 Nature Neurosci. 5 1226-35) for explaining human movements, differs in two crucial respects: (i) the endpoint variance is minimized in joint space rather than Cartesian hand space, and (ii) we ignore the dynamics and instead consider only the second-order differential kinematics. The feedback control law generating the motions can be straightforwardly obtained by backward integration of a set of ordinary differential equations; these equations are obtained exactly, without any linear-quadratic approximations. The only parameters to be determined a priori are the variance scale factors, and for both the two-DOF planar arm and the seven-DOF spatial arm, a table of values is constructed based on the given initial and final arm configurations; these values are determined via an optimal fitting procedure, and consistent with existing findings about neuromuscular motor noise levels of human arm muscles. Experiments conducted with a two-link planar arm and a seven-DOF spatial arm verify that the trajectories generated by our feedback control law closely resemble human arm motions, in the sense of producing nearly straight-line hand trajectories, having bell-shaped velocity profiles, and satisfying Fitts Law. PMID- 24343166 TI - A novel wavelength-adjusting method in InGaN-based light-emitting diodes. AB - The pursuit of high internal quantum efficiency (IQE) for green emission spectral regime is referred as "green gap" challenge. Now researchers place their hope on the InGaN-based materials to develop high-brightness green light-emitting diodes. However, IQE drops fast when emission wavelength of InGaN LED increases by changing growth temperature or well thickness. In this paper, a new wavelength adjusting method is proposed and the optical properties of LED are investigated. By additional process of indium pre-deposition before InGaN well layer growth, the indium distribution along growth direction becomes more uniform, which leads to the increase of average indium content in InGaN well layer and results in a redshift of peak-wavelength. We also find that the IQE of LED with indium pre deposition increases with the wavelength redshift. Such dependence is opposite to the IQE-wavelength behavior in conventional InGaN LEDs. The relations among the IQE, wavelength and the indium pre-deposition process are discussed. PMID- 24343167 TI - Membrane estrogen receptors: their role in blood pressure regulation and cardiovascular disease. AB - Hypertension (HTN) is a leading risk factor for cardiovascular disease (CVD) and continues to affect millions of people in industrialized nations. The increasing prevalence of HTN is closely related to the growing prevalence of obesity. Despite heightened awareness of the disease, a significant percentage of patients are uncontrolled and are at higher risk of heart failure, stroke, and chronic kidney disease. Evidence of the cardiovascular protective role of estrogen in pre menopausal females has brought attention to estrogen receptor activation as a treatment strategy for HTN. Estrogen promotes vasodilation and decreases inflammation and atherosclerosis. It also controls blood pressure via modulation of the activity of the renin-angiotensin-aldosterone system. The effects of estrogen on the vasculature are partly mediated via membrane receptors. Membrane estrogen receptor alpha and G-protein-coupled GPER-1 have been studied extensively in the vasculature. This review will describe the available evidence supporting the role of estrogen membrane receptors in blood pressure control and CVD. PMID- 24343168 TI - Reactivity to dietary gluten: new insights into differential diagnosis among gluten-related gastrointestinal disorders. AB - The ingestion of dietary gluten sometimes may trigger allergic, autoimmune or nonallergic and nonautoimmune response. The typical gluten-related allergic disorder is the wheat allergy (WA). Celiac disease (CD) is a well-known gluten related autoimmune condition. The clinical expression of a gluten-related nonallergic and nonautoimmune response is nonceliac gluten sensitivity (NCGS), an emerging condition whose framework is yet unclear and whose diagnosis is suggested only by demonstration of gluten-dependency in patient' symptoms after exclusion of WA and CD. This review discusses the current tools to identify patients suffering from WA, CD, and NCGS, as well as the most recent insights in the differential diagnosis among these gluten-related gastrointestinal disorders . PMID- 24343169 TI - Arterial system of the atrium in the human heart. AB - We dissected the atrial arterial system of 22 adult human hearts from donated cadavers. Atrial branches (ABs) of coronary arteries, more than 0.5 mm in diameter at their origin, were selected to trace systematically their origin and course. A total of 135 ABs were observed, of which 68 were from the circumflex branch, and 67 from the right coronary artery. The origins of ABs were classified into the following five regions where they arose from coronary arteries: (A) from the left aortic bulb to the one-third of the left auricle, (B) from the end of region A to the point of anastomosis of the coronary sinus (CS) with an oblique vein of the left atrium (OVLA), (C) from the end of region B to the opening of the CS, (D) from the end of region C to two-thirds of the right auricle, (E) from the end of region D to the right aortic bulb. With regard to the course of the ABs, they were classified according to the following 8 areas where they passed: (I) underneath Bachmann's bundle (BB); (II) the area connecting the right and left superior pulmonary veins; (III) the dorsal part of the interatrial septum; (IV) beside the OVLA; (V) the atrial side beside the CS; (VI) the ventral part of the interatrial septum; (VII) the dorsal wall of the left atrium; (VIII) on the dorsal surface of the right atrium. Thus, ABs showed various combinations of regions and courses. PMID- 24343170 TI - The anatomy of the sacrococcygeal cornual region and its clinical relevance. AB - There has been no systematic study of the anatomy of the region between the sacral and coccygeal cornua. Reference texts describe an intercornual ligament connecting these structures. The aim of this study was to investigate the anatomy of this region, which may be relevant to unexplained cases of coccygeal pain (coccydynia) and local nerve blocks. The bony anatomy of the sacrococcygeal (SC) cornual region was analyzed in 33 CT scans obtained from supine adults of mostly European origin with no known SC pathology, 7 MUCT scans of cadaver SC specimens, and 105 Asian Indian adult skeletons. A further five cadaver SC specimens were examined histologically. SC cornual fusion was seen in 45% of CT/MUCT scans (mean age 67 years, 20 males) and in 20% of adult skeletons (78 males); there was no association with age or sex. In the absence of SC fusion, the mean intersacrococcygeal cornual gap was 7.1 +/- 2.4 mm; this was bridged by an intercornual ligament composed of parallel vertical collagen fibers reinforced by elastin fibers on its anterior surface. Small nerve branches were observed adjacent to the ventral aspect of the intercornual ligament and, in one case, traversing the ligament. Ipsilateral sacral and coccygeal cornua are therefore normally bridged by an intercornual ligament that is probably innervated. The cornua are fused on one or both sides in 20-45% of adults. These findings may have implications for some cases of coccydynia and for anesthetists performing local nerve blocks. PMID- 24343172 TI - Simultaneous resection of colorectal cancer and liver metastases in the right lobe using pure laparoscopic surgery. AB - It is now common to resect colorectal cancer by laparoscopic surgery. Hepatectomy has become a standard treatment for patients with colorectal cancer with resectable liver metastases. The resection of liver tumors can now be done partly by laparoscopic surgery. However, metastatic tumors in the right lobe are often difficult to resect laparoscopically. Furthermore, simultaneous resection of the colorectum and liver may also be difficult. In this study, we evaluated a new method to resect both colorectal cancer and liver metastases in the right lobe by laparoscopic surgery. Two cases are presented that underwent total laparoscopic resection of a right lobe tumor, associated with laparoscopic colorectal resection. The metastatic tumor in the right lobe was first resected in the left hemi-prone position. Then, the colorectal cancer was resected in the lithotomy position. The method for resecting the right lobe liver tumor and colorectal cancer was safe and feasible. The mean duration of surgery was 443.5 min, and the mean blood loss was 158 mL. The postoperative course was uneventful. In selected patients, laparoscopic hepatectomy for right lobe synchronous metastatic tumors can be safely performed simultaneously with colorectal surgery. PMID- 24343171 TI - Annual Report to the Nation on the status of cancer, 1975-2010, featuring prevalence of comorbidity and impact on survival among persons with lung, colorectal, breast, or prostate cancer. AB - BACKGROUND: The American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to provide updates on cancer incidence and death rates and trends in these outcomes for the United States. This year's report includes the prevalence of comorbidity at the time of first cancer diagnosis among patients with lung, colorectal, breast, or prostate cancer and survival among cancer patients based on comorbidity level. METHODS: Data on cancer incidence were obtained from the NCI, the CDC, and the NAACCR; and data on mortality were obtained from the CDC. Long-term (1975/1992 2010) and short-term (2001-2010) trends in age-adjusted incidence and death rates for all cancers combined and for the leading cancers among men and women were examined by joinpoint analysis. Through linkage with Medicare claims, the prevalence of comorbidity among cancer patients who were diagnosed between 1992 through 2005 residing in 11 Surveillance, Epidemiology, and End Results (SEER) areas were estimated and compared with the prevalence in a 5% random sample of cancer-free Medicare beneficiaries. Among cancer patients, survival and the probabilities of dying of their cancer and of other causes by comorbidity level, age, and stage were calculated. RESULTS: Death rates continued to decline for all cancers combined for men and women of all major racial and ethnic groups and for most major cancer sites; rates for both sexes combined decreased by 1.5% per year from 2001 through 2010. Overall incidence rates decreased in men and stabilized in women. The prevalence of comorbidity was similar among cancer-free Medicare beneficiaries (31.8%), breast cancer patients (32.2%), and prostate cancer patients (30.5%); highest among lung cancer patients (52.9%); and intermediate among colorectal cancer patients (40.7%). Among all cancer patients and especially for patients diagnosed with local and regional disease, age and comorbidity level were important influences on the probability of dying of other causes and, consequently, on overall survival. For patients diagnosed with distant disease, the probability of dying of cancer was much higher than the probability of dying of other causes, and age and comorbidity had a smaller effect on overall survival. CONCLUSIONS: Cancer death rates in the United States continue to decline. Estimates of survival that include the probability of dying of cancer and other causes stratified by comorbidity level, age, and stage can provide important information to facilitate treatment decisions. PMID- 24343173 TI - Unmasked renal impairment and prolonged hyperkalemia after unilateral adrenalectomy for primary aldosteronism coexisting with primary hyperparathyroidism: report of a case. AB - We herein report the case of a patient with critical hyperkalemia after unilateral adrenalectomy (ADX) for aldosterone-producing adenomas, which were coexisting with primary hyperparathyroidism. A right adrenal tumor oversecreting mineral corticoid was identified in a 62-year-old female whose kidney function had been impaired due to primary hyperaldosteronism and hyperparathyroidism. The ADX improved her hypertension with normalization of the plasma aldosterone concentration, but without adequately increasing her plasma renin activity. Her eGFR further decreased postoperatively, hyperkalemia appeared and the serum potassium level rose to 6.3 mEq/L at 3 months after ADX. Then, treatment with calcium polystyrene sulfonate jelly was started. Eight months after ADX, a left lower parathyroidectomy was performed, and the serum calcium and intact parathyroid hormone levels decreased to the normal range. The hyperkalemia was difficult to control within 20 months postoperatively without treatment with calcium polystyrene sulfonate jelly or hydrocortisone. This suggests that unmasking the renal impairment and relative hypoaldosteronism after ADX might induce critical hyperkalemia. PMID- 24343174 TI - Hydrogenophaga carboriunda sp. nov., a tertiary butyl alcohol-oxidizing, psychrotolerant aerobe derived from granular-activated carbon (GAC). AB - A Gram-negative, rod-shaped bacterium was isolated from a mixed culture that degraded tert-butyl alcohol (TBA) in a granular-activated carbon (GAC) sample from a Biological-GAC reactor. Strain YZ2(T) was assigned to the Betaproteobacteria within the family Comamonadaceae based on 16S rRNA gene similarities. The nearest phylogenetic relative (95.0 % similarity) with a valid name was Hydrogenophaga taeniospiralis. The DNA G+C content was 66.4 mol%. DNA:DNA hybridization indicated that the level of relatedness to members of the genus Hydrogenophaga ranged from 1.1 to 10.8 %. The dominant cellular fatty acids were: 18:1 w7c (75 %), 16:0 (4.9 %), 17:0 (3.85 %), 18:0 (2.93 %), 11 methyl 18:1 w7c (2.69 %), Summed Feature 2 (2.27 %), and 18:0 3OH (1.35 %). The primary substrate used was TBA, which is a fuel oxygenate and groundwater contaminant. YZ2(T) was non-motile, without apparent flagella. It is a psychrotolerant, facultative aerobe that grew between pH 6.5 and 9.5, and 4 and 30 degrees C. The culture grew on and mineralized TBA at 4 degrees C, which is the first report of psychrotolerant TBA degradation. Hydrogen was used as an alternative electron donor. The culture also grew well in defined freshwater medium with ethanol, butanol, hydroxy isobutyric acid, acetate, pyruvate, citrate, lactate, isopropanol, and benzoic acid as electron donors. Nitrate was reduced with hydrogen as the sole electron donor. On the basis of morphological, physiological, and chemotaxonomic data, a new species, Hydrogenophaga carboriunda is proposed, with YZ2(T) as the type strain. PMID- 24343175 TI - RNase III controls mltD mRNA degradation in Escherichia coli. AB - RNase III is a double-stranded RNA-specific endoribonuclease that processes and degrades numerous mRNA molecules in Escherichia coli. A previous genome-wide analysis of E. coli transcripts showed that steady-state levels of mltD mRNA, which encodes membrane-bound lytic murein transglycosylase D, was most affected by changes in cellular concentration of RNase III. Consistent with this observation, in vitro and in vivo analyses of mltD mRNA revealed RNase III cleavage sites in the coding region of mltD mRNA. Introduction of a nucleotide substitution at the identified RNase III cleavage sites inhibited RNase III cleavage activity on mltD mRNA, resulting in, consequently, approximately two fold increase in the steady-state level of the mRNA. These findings reveal an RNase III-mediated regulatory pathway that modulates mltD expression in E. coli. PMID- 24343177 TI - Modeling DNA condensation on freestanding cationic lipid membranes. AB - Motivated by recent experimental observations of a rapid spontaneous DNA coil globule transition on freestanding cationic lipid bilayers, we propose simple theoretical models for DNA condensation on cationic lipid membranes. First, for a single DNA rod, we examine the conditions of full wrapping of a cylindrical DNA like semi-flexible polyelectrolyte by an oppositely charged membrane. Then, for two parallel DNA rods, we self-consistently analyze the shape and the extent of the membrane enveloping them, focusing on membrane elastic deformations and the membrane-DNA embracing angle, which enables us to compute the membrane-mediated DNA-DNA interactions. We examine the effects of the membrane composition and its charge density, which are the experimentally tunable parameters. We show that membrane-driven rod-rod attraction is more pronounced for higher charge densities and for smaller surface tensions of the membrane. Thus, we demonstrate that for a long DNA chain adhered to a cationic lipid membrane, such membrane-induced DNA DNA attraction can trigger compaction of DNA. PMID- 24343176 TI - Mannosylated LigANI produced in Pichia pastoris protects hamsters against leptospirosis. AB - The C-terminal region of the Leptospiral immunoglobulin-like A protein (LigA) contains six carboxy-terminal Ig-like repeat domains (LigANI). Subunit vaccine preparations based on recombinant LigANI produced in Escherichia coli, are promising vaccine candidates, albeit with variable efficacy. In the present study, LigANI was expressed in the methylotrophic yeast Pichia pastoris using a 12 L bioreactor to produce mannosylated LigANI (mLigANI) for use in a vaccine preparation against leptospirosis. Hamsters immunized with a mLigANI vaccine preparation produced a significant IgG antibody response (P < 0.001) and were protected (83.3 %; P < 0.001) against lethal challenge with 36* LD50 of a virulent strain of L. interrogans serovar Copenhageni. A vaccine preparation based on demannosylated mLigANI (nmLigANI) elicited an immune response in hamsters, but did not afford protection. The production of mLigANI in bioreactor by P. pastoris yielded ~50 mg L(-1) of recombinant protein. P. pastoris is a potential platform for the production of leptospiral antigens on an industrial scale. The results demonstrate that LigANI secreted by P. pastoris on mannosylated form (mLigANI) protect hamsters as subunit vaccine of L. interrogans lethal infection. PMID- 24343178 TI - [Beethoven's ringlets--from a medical point of view]. AB - Ludwig van Beethoven suffered from various constitutional disorders, most publicly known his deafness. He died in 1827 from a decompensated liver cirrhosis. On his deathbed, admirers cut some ringlets from his head that can nowadays be used for scientific analyses. Hair analyses demonstrated that Beethoven was increasedly exposed to lead in his last 110 living days that may have contributed to the hepatic decompensation. The reason for the lead exposition was probably consumption of wines mixed with lead sugar, but also iatrogenic by lead-containing preparations administered for pneumonia in winter 1826/1827 as well as wound closure after puncturing for ascites four times. PMID- 24343179 TI - [Operative medicine in Wagner and Verdi operas]. PMID- 24343180 TI - [Honey in medicine]. PMID- 24343181 TI - [Moderate wine consumption and prevention of coronary heart disease]. AB - Moderate alcohol consumption and in particular wine consumption, is associated with a significant reduction in cardiovascular morbidity and mortality in epidemiological studies. Although no randomized placebo-controlled studies with wine intervention exist - and will probably never exist - the observed association can be interpreted as causal due to the existing high biological plausibility. There is more and more evidence that ethanol per se contributes to the most relevant preventive effects. When consumed in moderation the health benefits outweigh the health risks. Whether and to what extend the numerous plant compounds of wine (polyphenolic substances) can provide additional health benefits is still under investigation. PMID- 24343182 TI - ["Spirits" and "Movements of the Soul" in the medical work of Moses Maimonides]. AB - Maimonides describes his psychic concept of health as movements of soul. It has two poles, a positive and a negative one. Soul of man is in a direct connection with environment and vice versa. Already in his time air and water were polluted resp. contaminated. The great physician was convinced that this increasing strain of nature not only damaged the body, but also the soul of man. He shows that nature and body form and influence human thinking via the four spirits: Body-, natural, vital, and especially psychic spirit. The latter is settled in brain chambers, it is what we today regard as soul. Bad environment and negative emotions have negative effects on body and soul. If not minded, these effects confuse physical and psychic balance. It's a consequence of such a disequilibrium that diseases can't be avoided. This balance of body and soul is not static, but dynamic. In most persons it is subject to fluctuations. These are moving permanently between the two extremes of the Nicomachic ethics of Aristotle. Since Maimonides experienced this strong mutuality between body, soul and environment, he is regarded by several researchers as the founder of psychosomatics. Maimonides was a religious man and in many cases he also built in perceptions and findings from Jewish Talmud and even from Old Testament. But as an early illuminated philosopher he often dared to deviate from the rules of Talmud. For him human ratio was a reflection of divine ratio resp. Hebrew ruach. Thus from the sight of Maimonides religious Jewish tradition and human ratio don't exclude one another. PMID- 24343183 TI - [Evolutionary medicine]. AB - Evolutionary medicine allows new insights into long standing medical problems. Are we "really stoneagers on the fast lane"? This insight might have enormous consequences and will allow new answers that could never been provided by traditional anthropology. Only now this is made possible using data from molecular medicine and systems biology. Thereby evolutionary medicine takes a leap from a merely theoretical discipline to practical fields - reproductive, nutritional and preventive medicine, as well as microbiology, immunology and psychiatry. Evolutionary medicine is not another "just so story" but a serious candidate for the medical curriculum providing a universal understanding of health and disease based on our biological origin. PMID- 24343184 TI - [Do physicians live longer?--A medico-historical view]. PMID- 24343185 TI - [What is death?--Definitions and diagnoses from 2500 years of natural philosophy and medicine]. AB - For very long medicine has been dealing with the question what death means and when it has occurred. The promotion of this debate is mainly owed to the new medical findings and the concrete requirements of the clinical practice; but other factors like social-historical influences (in particular the dispute over the secure determination of death) as well as the (de-)medicalization of the concept of death have also to be taken into account. In a concise historical overlook this study aims to demonstrate the development of the definition of death: In ancient Greece Aristotle, disregarding the transcendent teleology, describes the natural or non-natural death that occurs when the production of the vegetative warmth in the central organ - the heart - has ceased. In the Enlightenment Johann August Unzer (emulated later by Bichat and Hufeland) worked out the concept of the step-by-step process of death: In the attempt to explain sudden death, apparent death and reanimation the enlightened physiologist differentiated between the cessation of the senses (caused by heart death and brain death) and the vegetative functions. In the second half of the 20th century progress made in transplanting and intensive care generated a broadened medical definition of death that met strong opposition in the discussions on the autonomy of the patient and the worth of human life. Generally considered, the increasing differences in interpreting death between physicians and medical laymen, but also in medical practice and basic research are mainly due to the divergent demands regarding the definition and diagnosis of death. PMID- 24343187 TI - [Reminiscences to Erwin Balz (1849-1913)--A German doctor takes western medicine to Japan]. PMID- 24343186 TI - [Niels Stensen--physician, naturalist and priest]. AB - Niels Stensen born 1638 not only characterized the ductus paroticus he also made fundamental discoveries in paleontology and crystallography. After converting to catholicism he spend all his creativeness to strengthen the catholic church living in Franciscan humility. PMID- 24343188 TI - [The boycott against German scientists and the German language after World War I]. AB - After the First World War, the Allied academies of sciences staged a boycott against German scientists and the German language. The objective of the boycott was to prevent the re-establishment of the prewar dominance of German scientists, the German language and German publications in the area of international scientific cooperation. Therefore the Allies excluded German scientists and the German language from international associations, congresses and publications, while they created new international scientific organizations under their leadership. Medical associations and congresses were also affected, e. g. congresses on surgery, ophthalmology and tuberculosis. Allied physicians replaced the "International Anti-Tuberculosis Association" founded in Berlin in 1902 with the "Union Internationale contre la Tuberculose"/"International Union against Tuberculosis", founded in Paris in 1920. Only French and English were used as the official languages of the new scientific organizations, just as in the League of Nations. The boycott was based on the fact that the German scientists had denied German war guilt and war crimes and glorified German militarism in a manifesto "To The Civilized World!" in 1914. The boycott first started in 1919 and had to be abolished in 1926, when Germany became a member of the League of Nations. Many German and foreign physicians as well as other scientists protested against the boycott. Some German scientists and institutions even staged a counter-boycott impeding the resumption of international collaboration. The boycott entailed an enduring decline of German as an international scientific language. After the Second World War scientists of the victorious Western Powers implemented a complete reorganization of the international scientific arena, based on the same organizational structures and language restrictions they had built up in 1919/1920. At the same time scientists from the U.S.A. staged an active language and publication policy, in order to establish the dominance of English in the international scientific arena. PMID- 24343189 TI - Malignant peripheral nerve sheath tumor in neurofibromatosis type 1. PMID- 24343190 TI - Child and adolescent psychopathology predicts increased adult body mass index: results from a prospective community sample. AB - OBJECTIVE: To examine the relationship between childhood and adolescent symptoms of (1) depression, (2) attention-deficit hyperactivity disorder (ADHD), and (3) conduct disorder (CD) with adult body mass index (BMI) in a prospective longitudinal study of 3294 community participants in the Ontario Child Health Survey. METHODS: One thousand nine hundred ninety-two children aged 4 to 11 years and 1302 adolescents aged 12 to 16 years at study entry in 1983 underwent follow up in 2000. Body mass index data were available for 1886 adult participants in the year 2000, which comprised the final study sample. Data were collected from youth, parents, and teachers using a combination of parental, youth, and teacher self-report and semistructured interview. Body mass index is a derived variable determined from the self-reported height and weight in 2000. RESULTS: Adults with depression, ADHD, or CD identified in childhood had increased body weight (BMI = 27.2 kg/m, 27.7 kg/m, and 27.9 kg/m, respectively) compared with their nonaffected peers (BMI = 24.8 kg/m; p < .001). Greater depressive symptoms in childhood were associated with increased adult BMI among boys (p = .02). Among adolescents, depression and sex interact in the association with adult BMI (p = .01). The association of childhood ADHD with adult overweight was completely accounted for by the effect of comorbid child conduct disturbance (p < .001) for both girls and boys. Greater conduct symptoms were associated with increased adult BMI (p = .04) among adolescent girls. CONCLUSION: This epidemiologic study suggests that psychopathology in childhood is associated with increased adult BMI. Early identification of psychiatric illness may present key opportunities for targeted prevention of obesity. PMID- 24343191 TI - An evaluation of the efficacy of a triple P-positive parenting program podcast series. AB - OBJECTIVE: Parenting programs based on cognitive-behavioral and social learning principles are effective in changing child behavior problems and parenting styles. However, such programs typically have limited population reach. The current study aimed to evaluate the efficacy of a brief radio series that provided parenting advice based on the Triple P-Positive Parenting Program. METHOD: One hundred thirty-nine parents of children aged 2 to 10 years who had concerns about their child's behavioral and/or emotional adjustment were recruited, randomly assigned to either an intervention or waitlist control group, and completed online self-report measures. Parents in the intervention group were given access to seven Triple P podcasts online over a period of 2 weeks. RESULTS: Parents in the intervention group improved significantly more than parents in the control group, from pre- to postintervention, on measures of child behavioral problems and parenting style, self-efficacy, and confidence. These short-term intervention effects were maintained at the 6-month follow-up. CONCLUSION: These results suggest that brief radio and online parenting programs can be effective and have the potential to reach a large proportion of parents experiencing child behavior problems. Limitations, clinical significance, and future research suggestions are discussed. PMID- 24343192 TI - Gender and psychiatric manifestations in Marfan syndrome - is there a link? PMID- 24343194 TI - The need for specialist services for serious and recurrent mood disorders. PMID- 24343193 TI - Childhood trauma in bipolar disorder. AB - OBJECTIVE: There has been little investigation of early trauma in bipolar disorder despite evidence that stress impacts on the course of this illness. We aimed to compare the rates of childhood trauma in adults with bipolar disorder to a healthy control group, and to investigate the impact of childhood trauma on the clinical course of bipolar disorder. METHODS: Retrospective assessment of childhood trauma was conducted using the Childhood Trauma Questionnaire (CTQ) in 60 outpatients with bipolar disorder being treated for a depressive episode and 55 control participants across two centres in north-east England and New Zealand. RESULTS: Significantly higher rates of childhood trauma were observed in patients with bipolar I and bipolar II disorder compared to controls. Logistic regression, controlling for age and sex, identified emotional neglect to be the only significant CTQ subscale associated with a diagnosis of bipolar disorder. Childhood history of sexual abuse was not a significant predictor. Associations with clinical severity or course were less clear. CONCLUSIONS: Childhood emotional neglect appears to be significantly associated with bipolar disorder. Limitations include the relatively small sample size, which potentially increases the risk of type II errors. Replication of this study is required, with further investigation into the neurobiological consequences of childhood trauma, particularly emotional neglect. PMID- 24343195 TI - Co-delivery of small interfering RNA using a camptothecin prodrug as the carrier. AB - We have reported the first effort towards directly using an anticancer prodrug (CPTssR5H5) as a carrier to co-deliver camptothecin (CPT) and small interfering RNA for multidrug resistant cancer chemotherapy. The results indicated that CPTssR5H5 is a promising co-delivery system for MDR cancer therapy. PMID- 24343196 TI - Community healthcare delivery post-Hurricane Sandy: lessons from a mobile health unit. AB - In the aftermath of Hurricane Sandy the North Shore LIJ Health System (NS-LIJ HS) organized and launched its first mobile health unit (MHU) operation to some of New York's hardest hit communities including Queens County and Long Island, NY. This document describes the initiation, operational strategies, outcomes and challenges of the NS-LIJ HS community relief effort using a MHU. The operation was divided into four phases: (1) community needs assessment, (2) MHU preparation, (3) staff recruitment and (4) program evaluation and feedback. From November 16th through March 21st, 2013 the Health System launched the MHU over 64 days serving 1,160 individuals with an age range of 3 months to 91 years. Vaccination requests were the most commonly encountered issue, and the most common complaint was upper respiratory illness. The MHU is an effective resource for delivering healthcare to displaced individuals in the aftermath of natural disaster. Future directions include the provision of psychosocial services, evaluating strategies for timely retreat of the unit and methods for effective transitions of care. PMID- 24343198 TI - Fine genetic characterization of elite maize germplasm using high-throughput SNP genotyping. AB - To investigate the genetic structure of Chinese maize germplasm, the MaizeSNP50 BeadChip with 56,110 single nucleotide polymorphisms (SNPs) was used to genotype a collection of 367 inbred lines widely used in maize breeding of China. A total of 41,819 informative SNPs with minor allele number of more than 0.05 were used to estimate the genetic diversity, relatedness, and linkage disequilibrium (LD) decay. Totally 1,015 SNPs evenly distributed in the genome were selected randomly to evaluate the population structure of these accessions. Results showed that two main groups could be determined i.e., the introduced germplasm and the local germplasm. Further, five subgroups corresponding to different heterotic groups, that is, Reid Yellow Dent (Reid), Lancaster Sure Crop (Lancaster), P group (P), Tang Sipingtou (TSPT), and Tem-tropic I group (Tem-tropic I), were determined. The genetic diversity of within subgroups was highest in the Tem-Tropic I and lowest in the P. Most lines in this panel showed limited relatedness with each other. Comparisons of gene diversity showed that there existed some conservative genetic regions in specific subgroups across the ten chromosomes, i.e., seven in the Lancaster, seven in the Reid, six in the TSPT, five in the P, and two in the Tem-Tropical I. In addition, the results also revealed that there existed fifteen conservative regions transmitted from Huangzaosi, an important foundation parent, to its descendants. These are important for further studies since the outcomes may provide clues to understand why Huangzaosi could become a foundation parent in Chinese maize breeding. For the panel of 367 elite lines, average LD distance was 391 kb and varied among different chromosomes as well as in different genomic regions of one chromosome. This analysis uncovered a high natural genetic diversity in the elite maize inbred set, suggesting that the panel can be used in association study, esp. for temperate regions. PMID- 24343199 TI - Using near-isogenic barley lines to validate deoxynivalenol (DON) QTL previously identified through association analysis. AB - Fusarium head blight (FHB) and its associated mycotoxin, deoxynivalenol (DON), are the major biotic factors limiting cereal production in many parts of the world. A recent association mapping (AM) study of US six-row spring barley identified several modest effect quantitative trait loci (QTL) for DON and FHB. To date, few studies have attempted to verify the results of association analyses, particularly for complex traits such as DON and FHB resistance in barley. While AM methods use measures to control for the effects of population structure and multiple testing, false positive associations may still occur. A previous AM study used elite breeding germplasm to identify QTL for FHB and DON. To verify the results of that study, we evaluated the effects of the nine DON QTL using near-isogenic lines (NILs). We created families of contrasting homozygous haplotypes from lines in the original AM populations that were heterozygous for the DON QTL. Seventeen NIL families were evaluated for FHB and DON in three field experiments. Significant differences between contrasting NIL haplotypes were detected for three QTL across environments and/or genetic backgrounds, thereby confirming QTL from the original AM study. Several explanations for those QTL that were not confirmed are discussed, including the effect of genetic background and incomplete sampling of relevant haplotypes. PMID- 24343200 TI - A locus conferring effective late blight resistance in potato cultivar Sarpo Mira maps to chromosome XI. AB - Late blight of potato, caused by Phytophthora infestans, is one of the most economically important diseases worldwide, resulting in substantial yield losses when not adequately controlled by fungicides. Late blight was a contributory factor in The Great Irish Famine, and breeding for resistance to the disease began soon after. Several disease-resistant cultivars have subsequently been obtained, and amongst them Sarpo Mira is currently one of the most effective. The aim of this work was to extend the knowledge about the genetic basis of the late blight resistance in Sarpo Mira and to identify molecular markers linked to the resistance locus which would be useful for marker-assisted selection. A tetraploid mapping population from a Sarpo Mira * Maris Piper cross was phenotyped for foliar late blight resistance using detached leaflet tests. A locus with strong effect on late blight resistance was mapped at the end of chromosome XI in the vicinity of the R3 locus. Sarpo Mira's genetic map of chromosome XI contained 11 markers. Marker 45/XI exhibited the strongest linkage to the resistance locus and accounted for between 55.8 and 67.9% of variance in the mean resistance scores noted in the detached leaflet assays. This marker was used in molecular marker-facilitated gene pyramiding. Ten breeding lines containing a late blight resistance locus from cultivar Sarpo Mira and the Rpi phu1 gene originating from the late blight resistant accession of Solanum phureja were obtained. These lines have extended the spectrum of late blight resistance compared with Sarpo Mira and it is expected that resistance in plants containing this gene pyramid will have enhanced durability. PMID- 24343201 TI - Smooth transition for CPG-based body shape control of a snake-like robot. AB - This paper presents a locomotion control based on central pattern generator (CPG) of a snake-like robot. The main point addressed in this paper is a method that produces a smooth transition of the body shape of a snake-like robot. Body shape transition is important for snake-like robot locomotion to adapt to different space widths and also for obstacle avoidance. By manipulating the phase difference of the CPG outputs instantly, it will results in a sharp point or discontinuity which lead to an unstable movement of the snake-like robot. To tackle the problem, we propose a way of controlling the body shape: by incorporating activation function in the phase oscillator CPG model. The simplicity of the method promises an easy implementation and simple control. Simulation results and torque analysis confirm the effectiveness of the proposed control method and thus, can be used as a locomotion control in various potential applications of a snake-like robot. PMID- 24343202 TI - Terahertz conductivity of topological surface states in Bi1.5Sb0.5Te1.8Se1.2. AB - Topological insulators are electronic materials with an insulating bulk and conducting surface. However, due to free carriers in the bulk, the properties of the metallic surface are difficult to detect and characterize in most topological insulator materials. Recently, a new topological insulator Bi1.5Sb0.5Te1.7Se1.3 (BSTS) was found, showing high bulk resistivities of 1-10 Omega.cm and greater contrast between the bulk and surface resistivities compared to other Bi-based topological insulators. Using Terahertz Time-Domain Spectroscopy (THz-TDS), we present complex conductivity of BSTS single crystals, disentangling the surface and bulk contributions. We find that the Drude spectral weight is 1-2 orders of magnitude smaller than in other Bi-based topological insulators, and similar to that of Bi2Se3 thin films, suggesting a significant contribution of the topological surface states to the conductivity of the BSTS sample. Moreover, an impurity band is present about 30 meV below the Fermi level, and the surface and bulk carrier densities agree with those obtained from transport data. Furthermore, from the surface Drude contribution, we obtain a ~98% transmission through one surface layer--this is consistent with the transmission through single-layer or bilayer graphene, which shares a common Dirac-cone feature in the band structure. PMID- 24343203 TI - Behavioral analysis of cloned puppies derived from an elite drug-detection dog. AB - Since the first cloned dog "Snuppy" was born, many cloned dogs have been produced by somatic cell nuclear transfer (SCNT) technology. We reported the production of seven cloned drug detection dogs (named "Toppies") in 2009. Although their genetic identity was confirmed, similarities in behavior and the drug-detecting ability were not examined. Therefore, this study is the first attempt to examine their behavior. We conducted the Campbell test which is commonly used to evaluate the tendency of dominance. Data were analyzed by the general linear mixed model. The scores among seven cloned puppies and four naturally-bred controls were significantly different (P < 0.0001). After the test, cloned and control puppies were trained according to the Korea Customs Detector Dog Training Center's manual. The selection rate for detector dog in the cloned puppies was higher (86 %) than that of naturally-bred dogs (30 %). Therefore, it can be concluded that drug detection dogs with high performance can be propagated more efficiently using SCNT. PMID- 24343205 TI - Melanoma in childhood: changing our mind-set. PMID- 24343204 TI - The role of constraint in the development of nicotine, marijuana, and alcohol dependence in young adulthood. AB - The personality-related construct of behavioral disinhibition is hypothesized to confer a generalized risk for alcohol and drug dependence. On average, rates of substance use and scores on measures of disinhibition peak in adolescence and decline as people mature into adulthood. The present study investigated this developmental change by evaluating the relationship between disinhibition and substance use disorders using a longitudinal study of 2,608 twins assessed at ages 17, 24, and 29. These ages include the period of highest risk for substance use disorders (ages 17-24) as well as when substance dependence symptoms typically decline (ages 24-29). Disinhibition was measured with the Multidimensional Personality Questionnaire higher-order scale of Constraint, as well as its constituent facet scales of Harm Avoidance, Control, and Traditionalism. Constraint's relationship with substance dependence was statistically significant but small and largely genetic, with the genetic relationship declining from adolescence into adulthood. However, this result appeared to be almost entirely driven by Traditionalism, a propensity to hold traditional moral and social values, and not an obvious component of behavioral disinhibition. The results suggest that personality measures of Control and Harm Avoidance play only a small role in the development of substance dependence during late adolescence, and previous findings linking personality measures of disinhibition and substance use may be driven significantly by social and moral values than deficits in impulse control. PMID- 24343206 TI - The nondiscrimination provision levels the playing field for nonphysicians. PMID- 24343207 TI - Melanoma arising in a tattoo: case report and review of the literature. AB - Various benign and malignant lesions have been described in relation to tattoos including melanoma. Few cases of malignant melanoma (MM) arising in tattoos have been reported in the literature. We report a 79-year-old man with an MM that arose in a tattoo he had for 60 years on the inferior aspect of the left arm. This case underscores the need for careful examination of tattoos to insure that dysplastic or malignant pigmented lesions are not overlooked. We also discuss the possibility of a pathogenic relationship between MM and tattoos. PMID- 24343208 TI - Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 1: a status report on the disease state, general measures, and adjunctive skin care. AB - Rosacea is a common clinical diagnosis that encompasses a variety of presentations, predominantly involving the centrofacial skin. Reported to present most commonly in adults of Northern European heritage with fair skin, rosacea can affect males and females of all ethnicities and skin types. Pathophysiologic mechanisms that appear to correlate with the manifestation of rosacea have been the focus of multiple research studies, with outcomes providing a better understanding of why some individuals are affected and how their visible signs and symptoms develop. A better appreciation of the pathophysiologic mechanisms and inflammatory pathways of rosacea has allowed therapeutic strategies to be optimally incorporated. Part 1 of this 5-part series discusses the rosacea disease state with an emphasis on clinical correlation, reviews adjunctive skin care for cutaneous rosacea, and provides management caveats. PMID- 24343209 TI - Gigapixel photography for skin cancer surveillance: a novel alternative to total body photography. AB - There is substantial evidence supporting the use of cutaneous imaging in combination with standard total-body skin examinations for early detection and treatment of melanoma. In the last 2 decades, total-body photography (TBP) has been widely used in combination with standard total-body skin examinations for active skin cancer surveillance with proven clinical utility; however, the groundbreaking image detail provided by gigapixel photography (GP) could improve dermatologists' ability to monitor suspicious lesions and therefore could serve a critical role in supplementing traditional total-body skin examinations for skin cancer surveillance. Although it has been successfully implemented in other fields, future studies are required to determine the effectiveness of GP in dermatology. PMID- 24343210 TI - Metastasizing basal cell carcinoma. AB - Basal cell carcinoma (BCC) is the most common malignancy worldwide and is characterized by invasive growth and local tissue destruction. Cure rates for BCC exceed 90% with most treatment modalities. Metastasizing BCC (MBCC) is a rare complication of BCC with high morbidity and mortality rates. We report the case of a 66-year-old man with a large ulcerative lesion on the left side of the flank that was histopathologically diagnosed as a BCC. Clinical and imaging evaluations revealed substantial local invasion with regional lymph node, lung, liver, bone marrow, and bone metastasis. The patient died 7 months after the diagnosis was made. Potentially metastasizing BCCs cannot be definitely identified; thus early intervention with adequate treatment of all BCCs is advised. PMID- 24343211 TI - Carcinosarcoma: a primary cutaneous tumor with biphasic differentiation. AB - We present a case of a primary cutaneous carcinosarcoma (PCS). Histopathologically, PCS is defined as a biphasic tumor composed of malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements. The diagnosis of PCS can be challenging, not only because of its rarity but also because superficial biopsies can result in sampling errors. Accurate diagnosis is essential, as PCS carries a higher recurrence and metastatic rate than epithelial carcinomas, thus requiring wider excision or Mohs micrographic surgery as well as closer clinical follow-up. PMID- 24343212 TI - An amelanotic malignant melanoma of the lip: unusual shape and atypical location. AB - Amelanotic malignant melanoma (AMM) is characterized by little or no visible pigment. The diagnosis of AMM is a challenge for clinicians because it is a rare entity that presents with various clinical features. We describe a case of AMM on the lower lip in a 63-year-woman, which manifested as an erythematous mass that resembled grouped papules. PMID- 24343213 TI - Pigmented basal cell carcinoma of the nipple: a case report and review of the literature. AB - Although basal cell carcinoma (BCC) of the nipple-areola complex (NAC) is rare, it is important for dermatologists to be aware of this potential malignancy, as it is thought to behave more aggressively than BCC arising in other anatomic locations and also can mimic a number of more serious conditions. A review of the literature failed to generate a consensus regarding staging or treatment of BCC of the NAC; current therapies range from simple excision of the lesion to mastectomy with sentinel lymph node biopsy. We report the case of a 23-year-old man who presented with a pigmented BCC of the nipple to highlight several important aspects of the diagnosis; we also review 49 cases of BCC of the NAC from the literature and give our recommendations for treatment approach. PMID- 24343214 TI - Disease burden and treatment adherence in psoriasis patients. AB - Psoriasis can have a large impact on a patient's quality of life, yet adherence to psoriasis treatment often is poor. A large international study was conducted in adults with psoriasis and/or psoriatic arthritis to characterize the disease burden of psoriasis and its relationship to treatment adherence using a detailed, self-administered questionnaire. The results presented in this article represent the subset of US respondents who were currently taking prescription medication (N=193). The impact of psoriasis was graded as moderate to extremely high by 71% of US survey respondents. Among the respondents who did not adhere to prescribed treatments, approximately 50% attributed their nonadherence to forgetfulness and reported using the medication when they deemed it necessary. Respondents expressed a strong willingness to adhere to medications that were effective and to try multiple new treatments to find an optimal therapy. Of the respondents who were currently taking prescription medication, 88% were using topical therapies. The greatest unmet needs associated with topical psoriasis treatment were identified as fewer side effects, more rapid onset of action, and increased efficacy. The majority of respondents described positive relationships with their physician and a positive outlook with regard to physician communication, indicating an opportunity for the physician to directly influence patients' perceptions of disease burden and quality of life. When treating psoriasis with topical therapies, physicians should focus on improving and maintaining patients' quality of life, as this practice can be expected to improve treatment adherence and efficacy. PMID- 24343215 TI - What is your diagnosis? primary cutaneous aspergillosis. PMID- 24343216 TI - Superficial plantar fibromatosis. PMID- 24343217 TI - Necrolytic migratory erythema: a common cutaneous clue of uncommon syndromes. PMID- 24343218 TI - An illustrative case report of secondary syphilis with alopecia syphilitica, perianal condyloma latum, and granuloma annulare-like lesions. PMID- 24343219 TI - Electronic brachytherapy and superficial radiation therapy: will you be adding it to your practice? PMID- 24343220 TI - Atypical presentation of secondary syphilis. PMID- 24343221 TI - Lung cancer-associated scalp hair loss: a rare cause of secondary alopecia neoplastica. PMID- 24343222 TI - Febrile ulceronecrotic Mucha-Habermann disease. PMID- 24343223 TI - Determining the optimum morphology in high-performance polymer-fullerene organic photovoltaic cells. AB - The morphology of bulk heterojunction organic photovoltaic cells controls many of the performance characteristics of devices. However, measuring this morphology is challenging because of the small length-scales and low contrast between organic materials. Here we use nanoscale photocurrent mapping, ultrafast fluorescence and exciton diffusion to observe the detailed morphology of a high-performance blend of PTB7:PC71BM. We show that optimized blends consist of elongated fullerene-rich and polymer-rich fibre-like domains, which are 10-50 nm wide and 200-400 nm long. These elongated domains provide a concentration gradient for directional charge diffusion that helps in the extraction of charge pairs with 80% efficiency. In contrast, blends with agglomerated fullerene domains show a much lower efficiency of charge extraction of ~45%, which is attributed to poor electron and hole transport. Our results show that the formation of narrow and elongated domains is desirable for efficient bulk heterojunction solar cells. PMID- 24343225 TI - "Dirty nanostructures": aerosol-assisted synthesis of temperature stable mesoporous metal oxide semiconductor spheres comprising hierarchically assembled zinc oxide nanocrystals controlled via impurities. AB - Structural disintegration or the loss of accessible surfaces of functional nanostructures due to processes involving mass transport (e.g. sintering) is a serious problem for any application of these materials at elevated temperatures, like in heterogeneous catalysis or chemical sensing. Phases with low sintering temperatures, e.g. some metals or metal oxides like zinc oxide (ZnO), are very sensitive in this respect. Therefore, it is not only relevant to prepare important materials with refined morphologies, but the desired features need to be stable under real conditions. In this study, we describe the preparation of mesoporous ZnO nano-/microspheres by means of a template-assisted aerosol technique. Furthermore, by intentional introduction of impurity elements as dopants, specific surface areas and porosities of the prepared materials can be increased significantly. The impurities also strongly improve the thermal stability of the described ZnO nanostructures against thermal sintering. Although the pure ZnO material suffers from a complete loss of porosity, the structures of the impure ("dirty") materials change only negligibly. Even at 500 degrees C morphology and porosity are preserved. The latter advantageous property was used for testing the novel nanocatalysts in heterogeneous catalysis. PMID- 24343224 TI - Mechanisms of spontaneous resolution of acute gouty inflammation. AB - Acute gout is an auto-inflammatory disease characterized by self-limiting inflammation in response to the deposition of monosodium urate (MSU) crystals in the joints or tissues. Recognition of MSU triggers activation of the NLRP3 inflammasome, release of active interleukin (IL)-1beta, and amplification of the inflammatory response by the surrounding tissue followed by recruitment and activation of inflammatory leukocytes. The shutdown of this inflammatory response is linked to a number of regulatory events ranging from crystal coating and apoptotic cell clearance through to pro-inflammatory cytokine regulation and transforming growth factor beta1 (TGFbeta1) production. This review will highlight mechanisms that limit acute inflammation triggered by MSU crystals and suggests areas for further research. PMID- 24343226 TI - Mesoporous silica-assisted carbon free Li2MnSiO4 cathode nanoparticles for high capacity Li rechargeable batteries. AB - Porous and spherical Li2MnSiO4 nanoparticles have been synthesized through a facile sol-gel route via a mesoporous silica template. Galvanostatic charge discharge of the resultant Li2MnSiO4 cathode exhibits enhanced charge-discharge capacity relative to that of particles prepared by the conventional sol-gel process, up to 25% in discharge capacity, even without any particulate process such as milling with conductive agents. The standout electrochemical performance could be attributed to the unique high surface-to-volume ratio, porous geometry and improved accommodation of transformation strains during the electrochemical lithiation-delithiation process. PMID- 24343227 TI - Surgical complications after transsphenoidal microscopic and endoscopic surgery for pituitary adenoma: a consecutive series of 506 procedures. AB - BACKGROUND: This single-institution, consecutive series of transsphenoidal procedures included all patients in a defined population of 2.6 million inhabitants who underwent surgery during a specific time period. OBJECTIVE: We sought to determine the surgical complication rate and overall survival rate after transsphenoidal surgery for pituitary adenoma. METHODS: All transsphenoidal procedures for histologically verified pituitary adenomas performed between September 2002 and February 2011 at our institution were included in this study. The data were obtained from a prospectively collected database and from reviewing medical records. No patients were lost to follow-up, and the median follow-up time was 28 months. RESULTS: A total of 506 transsphenoidal procedures were performed on 446 patients. There were 268 microscopic and 238 endoscopic procedures involving 352 non-functioning and 154 hormone-secreting adenomas. A total of 73% of the procedures were primary surgeries, and 27% were repeat surgeries for tumor recurrence. The overall complication rate was 9.1%. The three most frequent complications were cerebrospinal fluid (CSF) leakage (4.7%), meningitis (2%), and visual deterioration (2%). Multivariate analyses showed that the overall risk for complications increased with older age, surgery for recurrent tumors, and surgery performed by a low-volume surgeon. There was no significant difference in the overall complication rate between the microsurgical and endoscopic techniques. The rate of surgical mortality was 0.6%, and the overall survival rates at 1 and 5 years were 95% and 90%, respectively. The only negative predictor of survival was older age. CONCLUSIONS: Transsphenoidal surgery for pituitary adenomas has a low complication rate and a low rate of mortality. We did not find a significant difference in the complication rate between endoscopic and microscopic techniques. PMID- 24343229 TI - Superiority of the EF-120-00-3F biopsy forceps in the histopathological evaluation of upper urinary tract specimens. AB - PURPOSE: The purpose of this study was to analyze the efficacy of two different biopsy forceps with respect to their functionality and quality for histological assessment of upper urinary tract biopsies. METHODS: We compared flow rates, active deflection angle and histological quality of specimens taken from upper urinary tract biopsies of 40 consecutively treated patients between October 2011 and October 2012. Two different biopsy forceps [group A = 20 patients: "Piranha ((r)) " (Boston Scientific, Natick, USA) versus group B = 20 patients: "EF-120-00 3F" (Euromedical GmbH, Siegsdorf, GER)] were assessed. RESULTS: The specimens obtained with the "EF-120-00-3F" were superior in terms of tissue preservation such as intact urothelium/tissue fragmentation and the prevention of artifacts due to tissue compression (existence of artifacts/nucleus evaluation). Furthermore, due to superiority of tissue preservation, tissues obtained with the "EF-120-00-3F" showed better tissue orientation in the sense of anatomic evaluation of invasion and deep layer involvement. Irrigation flow rates did not differ significantly while deflection angle was more impaired with the "Piranha" biopsy forceps. No difference was observed with the handling of both biopsy forceps. CONCLUSIONS: We conclude that the "EF-120-00-3F" biopsy forceps represent a valuable modification of antegradely insertable instruments that qualifies for improved and correct staging as well as diagnosis of upper urinary specimens in comparison with standard biopsy forcipes. PMID- 24343228 TI - PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8+ T cells induced by melanoma vaccines. AB - Although melanoma vaccines stimulate tumor antigen-specific CD8(+) T cells, objective clinical responses are rarely observed. To investigate this discrepancy, we evaluated the character of vaccine-induced CD8(+) T cells with regard to the inhibitory T-cell coreceptors PD-1 and Tim-3 in patients with metastatic melanoma who were administered tumor vaccines. The vaccines included incomplete Freund's adjuvant, CpG oligodeoxynucleotide (CpG), and the HLA-A2 restricted analog peptide NY-ESO-1 157-165V, either by itself or in combination with the pan-DR epitope NY-ESO-1 119-143. Both vaccines stimulated rapid tumor antigen-specific CD8(+) T-cell responses detected ex vivo, however, tumor antigen specific CD8(+) T cells produced more IFN-gamma and exhibited higher lytic function upon immunization with MHC class I and class II epitopes. Notably, the vast majority of vaccine-induced CD8(+) T cells upregulated PD-1 and a minority also upregulated Tim-3. Levels of PD-1 and Tim-3 expression by vaccine-induced CD8(+) T cells at the time of vaccine administration correlated inversely with their expansion in vivo. Dual blockade of PD-1 and Tim-3 enhanced the expansion and cytokine production of vaccine-induced CD8(+) T cells in vitro. Collectively, our findings support the use of PD-1 and Tim-3 blockades with cancer vaccines to stimulate potent antitumor T-cell responses and increase the likelihood of clinical responses in patients with advanced melanoma. PMID- 24343230 TI - Optic nerve sheath fenestration for the treatment of papilledema secondary to cerebral venous thrombosis. AB - A 16-year-old adolescent girl with multiple risk factors for thrombosis presented with acute onset of headache, decreased vision, and papilledema. Evaluation demonstrated cerebral venous thrombosis (CVT) involving the left transverse and sigmoid sinuses and left internal jugular vein. Following bilateral optic nerve sheath fenestration (ONSF), she experienced improvement in vision and resolution of papilledema. In selected cases, ONSF is an effective surgical option for the treatment of papilledema due to CVT after medical treatment has failed. PMID- 24343231 TI - Isolated rotational vertigo due to internal capsular infarction. AB - Isolated rotational vertigo is most often associated with disorders of the semicircular canals, vestibular nerve, brainstem, or cerebellum but rarely observed following a supratentorial stroke. A 64-year-old man developed sudden onset of vertigo and horizontal right-beating nystagmus with a torsional component in primary and eccentric gazes, unsteady gait, and axial lateropulsion to the right side. Magnetic resonance imaging demonstrated an infarction in the posterior limb of left internal capsule, an unusual cause of the patient's signs and symptoms. PMID- 24343232 TI - Local proliferation of macrophages in adipose tissue during obesity-induced inflammation. AB - AIMS/HYPOTHESIS: Obesity is frequently associated with low-grade inflammation of adipose tissue (AT), and the increase in adipose tissue macrophages (ATMs) is linked to an increased risk of type 2 diabetes. Macrophages have been regarded as post-mitotic, but recent observations have challenged this view. In this study, we tested the hypothesis that macrophages proliferate within AT in diet-induced obesity in mice and humans. METHODS: We studied the expression of proliferation markers by immunofluorescence, PCR and flow cytometry in three different models of mouse obesity as well as in humans (n = 239). The cell fate of dividing macrophages was assessed by live imaging of AT explants. RESULTS: We show that ATMs undergo mitosis within AT, predominantly within crown-like structures (CLS). We found a time-dependent increase in ATM proliferation when mice were fed a high fat diet. Upregulation of CD206 and CD301 in proliferating ATMs indicated preferential M2 polarisation. Live imaging within AT explants from mice revealed that macrophages emigrate out of the CLS to become resident in the interstitium. In humans, we confirmed the increased expression of proliferation markers of CD68(+) macrophages in CLS and demonstrated a higher mRNA expression of the proliferation marker Ki67 in AT from obese patients. CONCLUSIONS/INTERPRETATION: Local proliferation contributes to the increase in M2 macrophages in AT. Our data confirm CLS as the primary site of proliferation and a new source of ATMs and support a model of different recruitment mechanisms for classically activated (M1) and alternatively activated (M2) macrophages in obesity. PMID- 24343233 TI - Effect of TMEM106B polymorphism on functional network connectivity in asymptomatic GRN mutation carriers. AB - IMPORTANCE: Granulin (GRN) mutations represent one of the most frequent genetic causes of inherited frontotemporal dementia. The study of asymptomatic carriers of GRN Thr272fs mutation (aGRN+) provides a unique opportunity to study the natural history of the disease and the role of modulating factors on disease onset. It has been demonstrated that the TMEM106B polymorphism is associated with GRN-related frontotemporal dementia and affects age at onset in GRN mutation carriers. OBJECTIVE: To ascertain whether TMEM106B genetic status modulates GRN disease by evaluating resting-state functional connectivity in aGRN+ individuals according to TMEM106 genetic variation. DESIGN, SETTING, AND PARTICIPANTS: Academic tertiary referral center for neurodegenerative disorders in 17 asymptomatic carriers of aGRN+ and 14 healthy controls. MAIN OUTCOMES AND MEASURES: Changes in resting-state functional connectivity, focusing on the default mode network, ventral and dorsal salience networks, executive network, frontoparietal networks, and attentive network and the effect of TMEM106B genotypes in aGRN+ participants and healthy controls (statistical nonparametric mapping). RESULTS: aGRN+ participants showed decreased brain connectivity within the left frontoparietal network and increased connectivity in the executive network compared with healthy controls. The TMEM106B at-risk polymorphism (T/T) was associated with decreased connectivity within the ventral salience network (ie, middle frontal gyrus) and the left frontoparietal network (ie, left precuneus). CONCLUSIONS AND RELEVANCE: This study suggests that the TMEM106B polymorphism modulates brain connectivity in aGRN+ individuals, with additional damage of the ventral salience network and left frontoparietal network observed. Genotyping TMEM106B is of importance in aGRN+ individuals for prognostic purposes and to assess early brain damage. PMID- 24343236 TI - Helium Ion Microscopy (HIM) for the imaging of biological samples at sub nanometer resolution. AB - Scanning Electron Microscopy (SEM) has long been the standard in imaging the sub micrometer surface ultrastructure of both hard and soft materials. In the case of biological samples, it has provided great insights into their physical architecture. However, three of the fundamental challenges in the SEM imaging of soft materials are that of limited imaging resolution at high magnification, charging caused by the insulating properties of most biological samples and the loss of subtle surface features by heavy metal coating. These challenges have recently been overcome with the development of the Helium Ion Microscope (HIM), which boasts advances in charge reduction, minimized sample damage, high surface contrast without the need for metal coating, increased depth of field, and 5 angstrom imaging resolution. We demonstrate the advantages of HIM for imaging biological surfaces as well as compare and contrast the effects of sample preparation techniques and their consequences on sub-nanometer ultrastructure. PMID- 24343237 TI - Multirater reliability of the historical, clinical, and risk management-20. AB - The assessment and management of risk for future violence is a core requirement of mental health professionals in many settings. Despite an increasing need for violence risk assessments across diverse contexts, little is known regarding the ecological validity of many widely used risk assessment schemes or the level of reliability with which actual practicing clinicians score these instruments. The current study investigated the interrater reliability of the Historical, Clinical, and Risk Management-20 (HCR-20), a widely used structured professional tool to assess violence risk, among 21 practicing clinicians in a forensic psychiatric program in Ontario, Canada. Results suggest that clinicians with varying professional training backgrounds and experience were able to rate the HCR-20 with good to excellent levels of reliability across three patients who varied in risk level. Consistent with studies investigating rater reliability for research purposes, we found that the risk management scale of the HCR-20 was the most challenging for clinicians to rate reliably. Importantly, results from generalizability theory analyses revealed that less than 3% of the variance in HCR-20 total scores and summary risk ratings is attributable to rater effects, whereas the majority of variance is attributable to differences among patients. PMID- 24343238 TI - "Deeply woven roots": health initiatives and community social services of faith based organizations of the Hidalgo County, Texas. AB - Faith-based organizations (FBO) continue to play a significant role in the lives of individuals and communities in the United States. This study focused on the contributions of FBO to the health and well-being of residents of Rio Grande Valley, South Texas. Specifically, this study examined two main areas of involvement of FBO in Hidalgo County, Texas: health initiatives and community social services. Despite their influential and historical involvement, FBO partnership in the delivery of health and social services is not well accounted for. This study explores the characteristics of the clergy, parishioners, and FBO that are associated with community health initiatives and social services. Analyses revealed that FBO deliver a remarkably wide range of services. On a weekly basis, one in six or 17% of Hidalgo County residents were reported as receiving some form of health assistance or social services from county FBO. Variations exist depending on the characteristics of the clergy and the FBO. Policy and practice recommendations include engaging in additional networking, organizing resources, and strengthening FBO health initiatives. PMID- 24343239 TI - Tuberculin skin test and interferon-gamma release assay in the detection of latent tuberculosis infection among Polish health care workers. AB - INTRODUCTION: For many years, Poland has had a mandatory vaccination program against tuberculosis, which recommended repeated vaccinations from birth to adulthood. Therefore, the clinical value of the tuberculin skin test (TST) in diagnosing latent tuberculosis infection (LTBI) in Poland remains unclear. OBJECTIVES: We conducted a study on the usefulness of the TST and QuantiFERON(r) TB test (QFT) for the evaluation of the prevalence and risk factors of L TBI among Polish health care workers. PATIENTS AND METHODS: The study group consisted of the Polish health care workers. TST and QFT were performed in each participant. The usefulness of TST and QFT was tested in relation to occupational risk factors. RESULTS: A total of 305 participants were included. A positive TST result was observed in 149 cases (48.9%) and a positive QFT result was observed only in 27 cases (8.9%). In the subgroup that declared contact with tuberculosis (n = 44), positive QFT and TST results were found in 20.5% and 63.3% cases, respectively. Past contact with tuberculosis was the only significant variable associated with a positive TST result. Independent variables associated with positive QFT results were older age, lower education level, longer period of work in health care, and previous contact with tuberculosis. CONCLUSIONS: The QFT has a higher diagnostic value than the TST in the assessment of LTBI in Polish health care workers. PMID- 24343241 TI - [Cerebral microhaemorrhage as imaging correlate of high-altitude cerebral edema in a patient under long-term ventilation]. AB - Within the scope of a cerebral magnetic resonance imaging to diagnose a dysphagia in a patient on long-term artificial respiration, the morphological criteria for a HACE (high-altitude cerebral edema) have been met. We found microangiopathic white matter lesions in the area of the corpus callosum and splenium, characteristic features of a HACE. HACE is a severe form of altitude sickness with truncal ataxia, disturbance of consciousness through to unconsciousness and coma. The exact pathophysiology is still not known but hypoxia seems to be the triggering stimulus. Thus the question arises: long-term ventilated patients suffering from severe gas exchange disorders develop constellations which are equivalent to HACE? PMID- 24343240 TI - A rare functional cardioprotective APOC3 variant has risen in frequency in distinct population isolates. AB - Isolated populations can empower the identification of rare variation associated with complex traits through next generation association studies, but the generalizability of such findings remains unknown. Here we genotype 1,267 individuals from a Greek population isolate on the Illumina HumanExome Beadchip, in search of functional coding variants associated with lipids traits. We find genome-wide significant evidence for association between R19X, a functional variant in APOC3, with increased high-density lipoprotein and decreased triglycerides levels. Approximately 3.8% of individuals are heterozygous for this cardioprotective variant, which was previously thought to be private to the Amish founder population. R19X is rare (<0.05% frequency) in outbred European populations. The increased frequency of R19X enables discovery of this lipid traits signal at genome-wide significance in a small sample size. This work exemplifies the value of isolated populations in successfully detecting transferable rare variant associations of high medical relevance. PMID- 24343242 TI - [Unilateral reduction of lung volume by application of intrabronchial valves on patients selected after endoscopic collateral ventilation assessment]. AB - BACKGROUND: Endoscopic collateral ventilation assessment (ECVA) can be used to select patients suffering from emphysema for application of valves to achieve a reduction of lung volume. The objective is to obtain a post-operatively minimal clinically important improvement of the selected patient's physical capacity. METHODS: Patients with severe chronic obstructive pulmonary disease (COPD) underwent examination for a possible reduction of lung volume. Those selected got ECVA. Patients whose collateral resistance (Rcoll) increased to Rcoll > 10 cm H2O/(mL/s) within a measurement duration of up to 300 s, were submitted to unilateral lobar application of intrabronchial valves (IBV). Differences in residual volume (RV) as well as distances in 6 minute walk tests (6MWT) between the time after application of valves (TX) and that before (T1) were calculated (TX minus T1). RESULTS: Of a tested 310 emphysema patients, 17 met criteria allowing ECVA; 10 of 17 proved eligible for valve application. After 312 +/- 170 days (TX - T1) the increase in walking distance was 44 +/- 89.7 m; 7 of 10 patients achieved clinically relevant improvements (> 25 m). Differences in RV proved to correlate with differences in walking distances, but not yet with differences in measurement duration in ECVA. CONCLUSIONS: Only a small portion of patients with progressive emphysema of the lung seem suitable for endoscopic reduction of lung volume by application of valves. Unilateral lobar application of IBV can result in durable, clinically relevant improvements of the patient's physical capacity. ECVA measurements should take a minimum of 300 s. PMID- 24343243 TI - Symbiophagy and biomineralization in the "living fossil" Astrosclera willeyana. AB - Representatives of all major metazoan lineages form biominerals. The molecular mechanisms that underlie this widespread and evolutionarily ancient ability are gradually being revealed for some lineages. However, until a wider range of metazoan biomineralization strategies are understood, the true diversity, and therefore the evolutionary origins of this process, will remain unknown. We have previously shown that the coralline demosponge, Astrosclera willeyana, in some way employs its endobiotic bacterial community to form its highly calcified skeleton. Here, using in situ hybridization and immunohistochemistry, we show that an ortholog of ATG8 (most likely a GABARAPL2/GATE-16 ortholog) is expressed in cells that construct the individual skeletal elements of the sponge. In TEM sections sponge cells can be observed to contain extensive populations of bacteria, and frequently possesses double-membrane structures which we interpret to be autophagosomes. In combination with our previous work, these findings support the hypothesis that the host sponge actively degrades a proportion of its bacterial community using an autophagy pathway, and uses the prokaryotic organic remains as a framework upon which calcification of the sponge skeleton is initiated. PMID- 24343244 TI - Perioperative complications of robot-assisted partial nephrectomy. AB - The incidence of renal cell carcinoma continues to increase with utilization of diagnostic abdominal imaging with migration towards a proportionally greater detection of small renal masses (SRM). Robot-assisted partial nephrectomy (RAPN) has become an attractive minimally invasive treatment modality for SRM's due to the technical advantages and shortened learning curve compared to laparoscopic partial nephrectomy (LPN) while preserving comparable perioperative outcomes. With advances in ablative approaches for stage I renal cell carcinoma (RCC) and controversy surrounding the role of extirpative surgery for SRM's, systematic understanding of the complications associated with RAPN has become even more imperative. This review aims to summarize and evaluate the contemporary literature, compile reported intraoperative complications, describe conventional and nephron-sparing surgery (NSS) specific postoperative complications, and assess factors associated with an increased likelihood for perioperative complications following RAPN. PMID- 24343245 TI - [Increase in examinations for cataracts, glaucoma, diabetic retinopathy and age related macular degeneration : Comparative cross-sectional study between 2010 and 1997 in ophthalmological practices]. AB - BACKGROUND: The importance of the four most commonly occurring vision-threatening diseases, age-related macular degeneration (AMD), glaucoma, diabetic retinopathy and cataract in ophthalmological practices has changed due to demographic developments, medical progress and transference of inpatient treatment to the outpatient area of private practice. METHODS: In the fourth quarter year of 2010 a survey of 15,125 patients (approximately 10%) from 96 private ophthalmology practices (mean 149 patients per ophthalmologist, range 45-376) was carried out. The results for the four most commonly occurring vision-threatening diseases were compared with the result from a previous survey carried out for the fourth quarter year of 1997. RESULTS: Compared to 1997 there was an increase in the age adjusted proportion of examinations in 2010 for cataracts by 29 %, for glaucoma by 21 %, for diabetic retinopathy by 39 % and for vitreoretinal diseases by 19 %. The number of AMD examinations in the age group over 70 years old showed a particularly high increase. CONCLUSIONS: The number of patients examined for the four most commonly occurring vision-threatening diseases increased from 1997 to 2010 not only in absolute numbers but also in relation to age. In the future financial and personnel resources must be made available for the early and guidelines-conform detection, diagnostics and therapy by ophthalmologists. PMID- 24343246 TI - Diatom-inspired templates for 3D replication: natural diatoms versus laser written artificial diatoms. AB - The diatoms are ubiquitous, exist in large numbers and show a great diversity of features on their porous silica structures. Therefore, they inspire the fabrication of nanostructured templates for nanoimprint processes (NIL), where large structured areas with nanometer precision are required. In this study, two approaches regarding the respective challenges and potential exploitations are followed and discussed: the first one takes advantage of a template that is directly made of natural occurring diatoms. Here, two replication steps via soft lithography are needed to obtain a template which is subsequently used for NIL. The second approach exploits the technical capabilities of the precise 3D laser lithography (3DLL) based on two-photon polymerization of organic materials. This method enables the fabrication of arbitrary artificial diatom-inspired micro- and nanostructures and the design of an inverse structure. Therefore, only one replication step is needed to obtain a template for NIL. In both approaches, a replication technique for true 3D structures is shown. PMID- 24343247 TI - An overview of stimulus-specific adaptation in the auditory thalamus. AB - In the auditory brain, some populations of neurons exhibit stimulus-specific adaptation (SSA), whereby they adapt to frequently occurring stimuli but retain sensitivity to stimuli that are rare. SA has been observed in auditory structures from the midbrain to the primary auditory cortex (A1) and has been proposed to be a precursor to the generation of deviance detection. SSA is strongly expressed in non-lemniscal regions of the medial geniculate body (MGB), the principal nucleus of the auditory thalamus. In this account we review the state of the art of SSA research in the MGB, highlighting the importance of this auditory centre in detecting sounds that may be relevant for survival. PMID- 24343248 TI - What controls gain in gain control? Mismatch negativity (MMN), priors and system biases. AB - Repetitious patterns enable the auditory system to form prediction models specifying the most likely characteristics of subsequent sounds. Pattern deviations elicit mismatch negativity (MMN), the amplitude of which is modulated by the size of the deviation and confidence in the model. Todd et al. (Neuropsychologia 49:3399-3405, 2011; J Neurophysiol 109:99-105, 2013) demonstrated that a multi-timescale sequence reveals a bias that profoundly distorts the impact of local sound statistics on the MMN amplitude. Two sounds alternate roles as repetitious "standard" and rare "deviant" rapidly (every 0.8 min) or slowly (every 2.4 min). The bias manifests as larger MMN to the sound first encountered as deviant in slow compared to fast changing sequences, but no difference for the sound first encountered as a standard. We propose that the bias is due to how Bayesian priors shape filters of sound relevance. By examining the time-course of change in MMN amplitude we show that the bias manifests immediately after roles change but rapidly disappears thereafter. The bias was reflected in the response to deviant sounds only (not in response to standards), consistent with precision estimates extracted from second order patterns modulating gain differentially for the two sounds. Evoked responses to deviants suggest that pattern extraction and reactivation of priors can operate over tens of minutes or longer. Both MMN and deviant responses establish that: (1) priors are defined by the most proximally encountered probability distribution when one exists but; (2) when no prior exists, one is instantiated by sequence onset characteristics; and (3) priors require context interruption to be updated. PMID- 24343249 TI - Can we trust intraoperative culture results in nonunions? AB - OBJECTIVES: To identify the presence of bacterial biofilms in nonunions comparing molecular techniques (multiplex polymerase chain reaction and mass spectrometry, fluorescent in situ hybridization) with routine intraoperative cultures. METHODS: Thirty-four patients with nonunions were scheduled for surgery and enrolled in this ongoing prospective study. Intraoperative specimens were collected from removed implants, surrounding tissue membrane, and local soft tissue followed by standard culture analysis, Ibis's second generation molecular diagnostics (Ibis Biosystems), and bacterial 16S rRNA-based fluorescence in situ hybridization (FISH). Confocal microscopy was used to visualize the tissue specimens reacted with the FISH probes, which were chosen based on the Ibis analysis. RESULTS: Thirty-four patient encounters were analyzed. Eight were diagnosed as infected nonunions by positive intraoperative culture results. Ibis confirmed the presence of bacteria in all 8 samples. Ibis identified bacteria in a total of 30 of 34 encounters, and these data were confirmed by FISH. Twenty-two of 30 Ibis-positive samples were culture-negative. Four samples were negative by all methods of analysis. No samples were positive by culture, but negative by molecular techniques. CONCLUSIONS: Our preliminary data indicate that molecular diagnostics are more sensitive for identifying bacteria than cultures in cases of bony nonunion. This is likely because of the inability of cultures to detect biofilms and bacteria previously exposed to antibiotic therapy. LEVEL OF EVIDENCE: Diagnostic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 24343250 TI - Open reduction and internal fixation of posterolateral tibial plateau fractures through fibula osteotomy-free posterolateral approach. AB - OBJECTIVE: To evaluate the outcome of patients with posterolateral tibial plateau fractures after open reduction and internal fixation with a fibula osteotomy-free posterolateral approach. DESIGN: Retrospective chart and operation note review. SETTING: A medical college-affiliated tertiary hospital. MATERIALS AND METHODS: A retrospective chart and radiographic review of posterolateral tibial plateau fractures treated with a posterolateral approach between January 2006 and July 2010 was performed. The primary (ie, the total Rasmussen function score) and secondary (ie, the postoperative infection, knee deformity, and complications) outcomes were analyzed. RESULTS: A total of 32 patients were identified for this study. Patients were followed for an average of 18.2 months (range, 12-36 months); the total Rasmussen function score was 24.8 +/- 2.9 points. The results were rated as excellent (>=27 points) in 19 patients, good (20-26 points) in 11, and fair (10-19 points) in 2 patients. No wound infections, screw loosening or implant fracture, and nonunion, deformity, or fracture redisplacement were seen. Stretch injury of the common peroneal nerve was found in 1 patient, who obtained recovery 2 months after additional conservative management. CONCLUSIONS: Adequate open reduction and internal fixation with a fibula osteotomy-free posterolateral approach can attain a satisfactory clinical outcome for patients with posterolateral tibial plateau fractures. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 24343251 TI - Femoral neck fractures in New York State. Is the rate of THA increasing, and do race or payer influence decision making? AB - OBJECTIVES: To evaluate the treatment trends for femoral neck fractures in New York State over the past 10 years. METHODS: The Statewide Planning and Research Cooperative System database from the New York State Department of Health was used to identify patients who sustained femoral neck fractures from 2000 to 2010. Multivariate logistic regression analysis was performed with the dependent variable being total hip arthroplasty (THA) versus hemiarthroplasty (HA) and independent variables being age, sex, race, insurance type, and comorbidity index. RESULTS: From 2000 to 2010, there were 44,425 patients admitted to New York State hospitals with femoral neck fractures, of which 86% occurred in patients older than 70. Of the total, 73.5% were treated with HA, 19.5% with internal fixation (IF), and 7% with THA. The overall rate of treatment with THA increased slightly, but this was not statistically significant (P = 0.11), and it only increased for patients younger than 70 years. The rate of HA increased significantly from 69.9% to 75.4% (P < 0.001), and the rate of IF showed a statistically significant reduction from 21.9% to 16.8% (P < 0.001). Results of the multivariate logistic regression analysis showed that for every 10-year increase in age, there was a 31% reduction in treatment with THA compared with HA. White patients were just as likely to receive THA as non-whites, and patients with private insurance were 41% more likely to receive THA than self-pay and federally insured patients. CONCLUSIONS: The rate that THA is being performed as treatment of femoral neck fractures is increasing for patients younger than 70 years but decreasing for patients older than 80 years. The rate of IF is decreasing. Patients with private insurance were more likely to receive THA than patients with federal insurance. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 24343252 TI - Plating of patella fractures: techniques and outcomes. AB - Operative treatment of displaced patella fractures with tension band fixation remains the gold standard, but is associated with a significant rate of complications and symptomatic implants. Despite the evolution of tension band fixation to include cannulated screws, surprisingly little other development has been made to improve overall patient outcomes. In this article, we present the techniques and outcomes of patella plating for displaced patella fractures and patella nonunions. PMID- 24343253 TI - Arthroscopic reduction and internal fixation of femoral head fractures. AB - Displaced femoral head fractures often require open reduction and internal fixation. This article describes 3 cases of displaced large-fragment femoral head fractures (OTA 31-C1.3) that were treated by arthroscopic reduction and internal fixation, which was accomplished using an anterolateral viewing portal, an anterior portal, and an accessory distal anterior working portal. By 3 months postoperatively, all 3 patients had returned to full function. Therefore, we conclude that an arthroscopic approach results in stable fixation and early joint motion, thereby effectively treating displaced femoral head fractures in a minimally invasive manner. PMID- 24343254 TI - Quality of Plaster Molding for Distal Radius Fractures Is Improved Through Focused Tuition of Junior Surgeons. AB - OBJECTIVES: Successful nonoperative management of distal radius fractures requires an adequately reduced fracture held in a well-molded cast. The purpose of this study was to determine whether a targeted teaching session to the same group of junior doctors led to objective improvement in fracture reduction and plaster molding and hence a decrease in the redisplacement of these fractures. DESIGN: Retrospective review. SETTING: Level I academic trauma center. METHODS: A retrospective review of all dorsally angulated distal radius fractures treated in plaster that presented to our plaster room over a 4-week period (group 1, n = 52). This was followed by the intervention and a subsequent 4-week prospective review (group 2, n = 36). Radiographs were reviewed before manipulation, after manipulation, and at follow-up by a single senior orthopaedic trainee using predetermined criteria. INTERVENTION: A targeted teaching session on fracture reduction and cast molding to the same group of junior doctors involved in managing all these cases. MAIN OUTCOME MEASURES: Adequate fracture reduction, plaster molding, redisplacement, and further intervention before and after the targeted intervention. RESULTS: In group 1, 85% had adequate fracture reduction but only 36% showed adequate molding. This was improved in group 2%-94% adequate reduction and 65% adequate molding (P = 0.022). The rate of redisplacement was improved from 65% to 44% in group 2. In both groups, the rate of redisplacement was around 20% for adequately reduced and molded fractures, compared with around 90% for adequately reduced but inadequately molded cases (P < 0.001). The rate of further intervention improved from 27% to 8% (P = 0.052). CONCLUSIONS: We recommend that specific teaching focusing on fracture reduction and molding techniques is included in orthopaedic juniors' induction teaching or as a separate session. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 24343255 TI - Effect of off-axis screw insertion, insertion torque, and plate contouring on locked screw strength. AB - OBJECTIVES: This study quantifies the effects of insertion torque, off-axis screw angulation, and plate contouring on the strength of locking plate constructs. METHODS: Groups of locking screws (n = 6-11 screws) were inserted at 50%, 100%, 150%, and 200% of the manufacturer-recommended torque (3.2 Nm) into locking compression plates at various angles: orthogonal (control), 5-degree angle off axis, and 10-degree angle off-axis. Screws were loaded to failure by a transverse force (parallel to the plate) either in the same ("+") or opposite direction (" ") of the initial screw angulation. Separately, locking plates were bent to 5 and 10-degree angles, with the bend apex at a screw hole. Locking screws inserted orthogonally into the apex hole at 100% torque were loaded to failure. RESULTS: Orthogonal insertion resulted in the highest average load to failure, 2577 +/- 141 N (range, 2413-2778 N), whereas any off-axis insertion significantly weakened constructs (165-1285 N, at 100% torque) (P < 0.05). For "+" loading, torque beyond 100% did not increase strength, but 50% torque reduced screw strength (P < 0.05). Loading in the "-" direction consistently resulted in higher strengths than "+" loading (P < 0.05). Plate contouring of 5-degree angle did not significantly change screw strength compared with straight plates but contouring of 10-degree angle significantly reduced load to failure (P < 0.05). CONCLUSIONS: To maximize the screw plate interface strength, locking screws should be inserted without cross-threading. The mechanical stability of locked screws is significantly compromised by loose insertion, off-axis insertion, or severe distortion of the locking mechanism. PMID- 24343256 TI - Entrapped posteromedial structures in pilon fractures. AB - OBJECTIVES: To analyze a patient cohort who sustained a tibial pilon fracture and report the incidence of interposed posteromedial soft tissue structures. DESIGN: Retrospective cohort review. SETTING: Regional Level 1 Trauma Center. PATIENTS/PARTICIPANTS: About 394 patients with 420 pilon fractures treated between January 2005 and November 2011. INTERVENTION: Each patient's preoperative radiographs and computed tomography (CT) images were reviewed. The axial and reconstructed images were used in bone and soft tissue windows to identify any posteromedial soft tissue structures incarcerated within the fracture. MAIN OUTCOME MEASUREMENTS: Medical charts reviewed for the presence of preoperative neurologic deficit, separate posteromedial incision, and whether attending radiology CT interpretation noted the interposed structure. RESULTS: 40 patients with 40 fractures (9.5%) had an entrapped posteromedial structure. The tibialis posterior tendon was interposed in 38/40 fractures (95%) and the posterior tibial neurovascular bundle in 4/40 fractures (10%). Preoperative neurologic deficit occurred in 5/40 patients (12%). A posteromedial incision was used in 11/40 fractures (27%). The attending radiology CT interpretation noted the interposed structure in 8/40 fractures (20%). CONCLUSIONS: In addition to the osseous injuries, CT imaging can demonstrate the posteromedial soft tissue structures. In our series, the tibialis posterior tendon was commonly incarcerated. In some cases, removal of the entrapped structure(s) may not be possible through the more commonly used anterolateral and anteromedial surgical approaches, and a separate posteromedial exposure may be required. Failure to recognize the presence of an interposed structure could lead to malreduction, impaired tendon function, neurovascular insult, and the need for further surgery. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 24343257 TI - Effects of Wnt5a Haploinsufficiency on Bone Repair. AB - OBJECTIVES: Wnt5a expression is upregulated during fracture repair and has previously been implicated as a potential regulator of skeletal development and bone mass accrual and maintenance. Our objective was to evaluate the function of Wnt5a in fracture healing. METHODS: Femoral fracture experiments on Wnt5a and Wnt5a mice were carried out. To better understand the effect of the Wnt5a on bone repair, we evaluated radiographs using a previously validated qualitative scoring system and performed microcomputed tomography analyses. Histomorphometric analyses determined the temporal distribution of stroma, cartilage matrix, and woven bone in the fracture callus. Finally, we performed tartrate-resistant acid phosphatase (TRAP) immunohistochemical staining to visualize and quantify bone resorbing cells. RESULTS: Radiographic evaluations at day 21 demonstrated significantly higher cortical remodeling and bridging parameters for the Wnt5a group compared with the Wnt5a group. The bone volume fraction by microcomputed tomography was also significantly increased in Wnt5a mice. Histological and histomorphometric analyses showed that although Wnt5a mice exhibit decreased cartilage matrix production at day 7 postfracture, they displayed increased residual cartilaginous callus at days 14 and 21 compared with the Wnt5a group. In addition, the total number of multinucleated tartrate-resistant acid phosphatase positive cells was significantly lower in the Wnt5a group than in the Wnt5a group. CONCLUSIONS: The data indicate that decreased Wnt5a signaling impaired proper fracture healing, possibly through decreased cartilaginous callus formation, and delayed cartilage matrix and mineralized tissue remodeling within the fracture callus. PMID- 24343258 TI - DCTN1 mutation analysis in families with progressive supranuclear palsy-like phenotypes. AB - IMPORTANCE: Progressive supranuclear palsy (PSP) is usually sporadic, but few pedigrees with familial clustering of PSP-like phenotypes have been described. Occasionally, MAPT, C9ORF72, and TARDBP mutations have been identified. OBJECTIVE: To analyze the DCTN1 gene in 19 families with a clinical phenotype of PSP (PSP-like phenotype). DESIGN, SETTING, AND PARTICIPANTS: Sequencing of the DCTN1 gene in familial forms of PSP at a referral center among 21 patients with familial PSP-like phenotypes. In addition, 8 patients and relatives from a family carrying a DCTN1 mutation were evaluated. MAIN OUTCOMES AND MEASURES: Identification of the DCTN1 mutation and clinical description of DCTN1 mutation carriers. RESULTS: We identified a DCTN1 mutation in a large family characterized by high intrafamilial clinical phenotype variability. Two patients had PSP-like phenotypes with dystonia, vertical gaze slowness, dysexecutive syndrome, predominant axial rigidity, and midbrain atrophy on brain magnetic resonance imaging. The other patients manifested Perry syndrome, isolated parkinsonism, or a predominant behavioral variant of frontotemporal dementia. CONCLUSIONS AND RELEVANCE: Mutations of the DCTN1 gene have been previously associated with amyotrophic lateral sclerosis and with Perry syndrome, a rare autosomal dominant disorder characterized by weight loss, parkinsonism, central hypoventilation, and psychiatric disturbances. Our study demonstrates that DCTN1 mutations should be searched for in patients with clinical PSP-like phenotypes and a behavioral variant of frontotemporal dementia, especially when a familial history of dementia, psychiatric disturbances, associated parkinsonism, or an autosomal dominant disorder is present. PMID- 24343259 TI - Two sides of a story: mothers' and adolescents' agreement on child disclosure in immigrant and native families. AB - Research on immigrant families often has suggested that the process of immigration can lead to a distancing of adolescents and their parents. This study examined the actual agreement of immigrant and native mother-adolescent dyads in their reports on children's disclosure as an indicator for a trusting mother child relationship. The research questions related to group-level differences (immigrant vs. native dyads) in mother-adolescent agreement, the prediction of interdyadic differences in mother-adolescent agreement, and the associations between mother-adolescent agreement and both family conflicts and adolescents' depressive symptoms. The sample was comprised of mother-adolescent dyads: 197 native German dyads (adolescents: mean age 14.7 years, 53% female) and 185 immigrant dyads from the former Soviet Union (adolescents: mean age 15.7 years, 60% female). Agreement was assessed using the intraclass correlation coefficient. The results revealed that mother-adolescent agreement was lower in immigrant dyads than in native dyads. In both samples, higher levels of adolescent autonomy predicted lower mother-adolescent agreement. Among immigrants, language brokering was an additional predictor of lower levels of mother-adolescent agreement. The interaction of language brokering and autonomy also turned out to be significant, indicating that if an adolescent was high in language brokering or autonomy, the effect of the other variable was negligible. In both groups, mother-adolescent agreement was negatively related to family conflicts. The study shows that processes in immigrant and native families are rather similar, but that in immigrant families some additional acculturation-related factors have to be considered for a full understanding of family dynamics. PMID- 24343260 TI - Relationships between racial-ethnic identity, self-esteem and in-group attitudes among First Nation children. AB - Positive in-group distinctiveness has been associated with self-esteem increases among adolescents and adults. To examine whether in-group biases are associated with self-esteem enhancement among minority group children, Native Canadian children (N = 414, 209 female) age 6-11 completed each year for 5 years, measures assessing their level of concrete operational thought, racial-ethnic identity, racial-ethnic centrality, implicit and explicit self-esteem, and implicit and explicit in-group attitudes. According to cognitive developmental theory, increases in the level of concrete operational thought will predict increases in racial-ethnic identity, and increases in identity should, in turn, predict more favorable in-group attitudes. Social identity theory predicts that more favorable in-group attitudes should predict increases in self-esteem. Multi-level structural equation modelling revealed support for these hypotheses. Cognitively mature children who identify closely with their group enhanced their level of self-esteem by positively differentiating between group members on dimensions that favor their group. Limitations of the present study and suggestions for future studies are also presented. PMID- 24343261 TI - The vacuole versus the lysosome: when size matters. AB - The morphometric examination of autophagic bodies provides useful information about the mechanism and magnitude of macroautophagy, and yeast researchers frequently utilize various measurements of these structures as part of their quantification of the process. The utility of this approach, however, has led to the common misconception that autophagic bodies can be found in the mammalian lysosome, which is generally not correct. PMID- 24343262 TI - Persistence and metabolism of fipronil in sugarcane leaves and juice. AB - Fipronil gives effective control of early shoot borer and termites in sugarcane. The persistence and metabolism of fipronil in sugarcane leaves and juice were studied following application of fipronil (Regent 0.3 G) at 75 and 300 g a.i. ha( 1). Samples of sugarcane leaves were collected at various time intervals. Samples of sugarcane juice were collected at harvest. Residues of fipronil and its metabolites were quantified by gas liquid chromatograph. The limit of quantification of fipronil and its metabolites was 0.01 mg kg(-1) for sugarcane leaves and juice. Total residues of fipronil and its metabolites in sugarcane leaves after 7 days of its application at 75 and 300 g a.i. ha(-1) were 0.26 and 0.66 mg kg(-1), respectively. Residues could not be detected after 60 and 90 following fipronil application at either concentration. In sugarcane leaves, fipronil was found to be the main constituent, followed by its metabolites amide, desulfinyl, sulfone and sulfide. Samples of sugarcane juice did not reveal the presence of fipronil or its metabolites following its application at both the dosages at harvest. PMID- 24343264 TI - A renewed focus on the interplay between viruses and mitochondrial metabolism. AB - Mitochondria fulfil several key functions within cellular metabolic and antiviral signalling pathways, including their central role in ATP generation. Viruses, as intracellular parasites, require from their cellular host the building blocks for generation of their viral progeny and the energy that drives viral replication and assembly. While some viruses have adopted ways to manipulate the infected cell such that cellular metabolism supports optimal virus production, other viruses simply exhaust cellular resources. The association of viruses with mitochondria is influenced by several important factors such as speed of the viral replication cycle and viral dependence on cellular enzymes and metabolites. This review will highlight the complex interconnectivity of viral life cycles with the three main mitochondrial metabolic pathways, namely beta-oxidation, the tricarboxylic (TCA) cycle, and oxidative phosphorylation. This interconnectivity has the potential to reveal interesting points for antiviral therapy with either prometabolites or antimetabolites and highlights the importance of the viral association with mitochondrial metabolism. PMID- 24343265 TI - A phylogeographical study of the cauliflower mosaic virus population in mid Eurasia Iran using complete genome analysis. AB - The full-length sequences of 34 Iranian cauliflower mosaic virus (CaMV) isolates were compared with others from public nucleotide sequence databases to provide a comprehensive overview of the genetic variability and patterns of genetic exchange in CaMV isolates from Iran. Based on the severity of symptoms and their ability to infect Brassica oleracea var. capitata, Iranian CaMV isolates were grouped into two distinct biotypes: latent/mild mottle (LI/MMo) and severe (S) infection. Recombination breakpoints were detected between the large intergenic region (LIR) and open reading frame (ORF) V (event 2); between ORF VII and ORF II (event 3), between ORF I and ORF III (event 4), and within ORF VI (event 1). Phylogenetic analysis indicated that Iranian CaMV isolates clustered into two subgroups belonging to group I (GI) that were distinct from North American and European isolates from group II (GII). Northeast Iranian isolates (subgroup B) and CaMV isolates from subgroup A closely corresponded to the S and LI/MMo biological groups, respectively. Genome-wide pairwise identity analysis of the CaMV isolates revealed three regions of pairwise identity representation: 92-94 % for GII and 94-96 % and 98-100 % for subgroups A and B. The within-population diversity was lower than the between-population diversity, suggesting the contribution of a founder effect on diversification of CaMV isolates. Amino acid sequences were conserved, with omega values ranging from 0.074 to 0.717 in different proteins. Thirteen amino acids in the deduced proteins of ORFs I, II, III, VI and VII were under positive selection (omega > 1), whereas purifying selection applied to the proteins encoded by ORFs IV and V. This study suggests that variation in the CaMV population can be explained by host-range differentiation and selection pressure. Moreover, recombination analysis revealed that a genomic exchange is responsible for the emergence of CaMV strains, providing valuable new information for understanding the diversity and evolution of caulimoviruses. PMID- 24343266 TI - Comparison and phylogenetic analysis based on the B2L gene of orf virus from goats and sheep in China during 2009-2011. AB - As a zoonotic infectious disease, orf outbreaks have been reported in China in recent years. However, molecular epidemiology analysis has not been performed for Chinese orf virus (ORFV) strains. Here, we have identified 13 ORFVs from goats and sheep in China between 2009 and 2011. Thirty-four complete B2L sequences were used to construct a phylogenetic tree to elucidate the molecular epidemiology of ORFV in China. Nucleotide sequences of B2L genes of clinical samples and attenuated vaccine strains were aligned and compared. Three genotypes were found by molecular epidemiology analysis. Amino acid substitutions were dispersed among B2 polypeptides from wild and attenuated ORFV strains. PMID- 24343267 TI - Development and evaluation of a survey to assess survivor knowledge change after survivorship care plans: WiSDOM-B (Wisconsin Survey of cancer DiagnOsis and Management in Breast cancer). AB - The oncology community has increased efforts to inform survivors about long-term risks and planned follow-up after cancer treatment. Survivorship care plans (SCPs) have been recommended since 2005, yet the benefits of implementation are only now being emphasized. SCPs are hypothesized to enhance patient knowledge. The Wisconsin Survey of Diagnosis and Management in Breast Cancer (WiSDOM-B) was developed to measure changes in breast cancer survivor knowledge pre- and postdelivery of an SCP. The WiSDOM-B was developed with input from oncologists (medical, radiation, and surgical), patient advocates, cancer survivors, and survey design experts. Initially, nine patients evaluated survey content, and modifications were made to enhance clarity. Subsequently, 38 patients were enrolled in a randomized pilot trial assessing SCP impact on knowledge of diagnosis, treatment, late effects, and follow-up (WiSDOM-B) and satisfaction with knowledge (existing survey). The WiSDOM-B was developed using feedback from multiple stakeholders. Baseline knowledge was poor and remained stable in the control arm. There was a suggestion of increased survivor knowledge following receipt of SCPs in the intervention arm (68.4 vs. 74.4%). Change was not statistically significant compared with the control arm. Despite knowledge deficits, baseline satisfaction with knowledge was high for both groups, with 100% of patients being satisfied/very satisfied with information provided. Satisfaction did not change significantly following SCP receipt. The WiSDOM-B assesses survivor knowledge of cancer diagnosis, treatment, follow-up, and side effects. It will be a useful tool for future studies assessing the impact of care plans on survivor knowledge. PMID- 24343268 TI - Human-induced nitrogen-phosphorus imbalances alter natural and managed ecosystems across the globe. AB - The availability of carbon from rising atmospheric carbon dioxide levels and of nitrogen from various human-induced inputs to ecosystems is continuously increasing; however, these increases are not paralleled by a similar increase in phosphorus inputs. The inexorable change in the stoichiometry of carbon and nitrogen relative to phosphorus has no equivalent in Earth's history. Here we report the profound and yet uncertain consequences of the human imprint on the phosphorus cycle and nitrogen:phosphorus stoichiometry for the structure, functioning and diversity of terrestrial and aquatic organisms and ecosystems. A mass balance approach is used to show that limited phosphorus and nitrogen availability are likely to jointly reduce future carbon storage by natural ecosystems during this century. Further, if phosphorus fertilizers cannot be made increasingly accessible, the crop yields projections of the Millennium Ecosystem Assessment imply an increase of the nutrient deficit in developing regions. PMID- 24343270 TI - What is the future of magnetic nanoparticles in the axillary management of breast cancer? AB - Magnetic nanoparticles (MNPs) possess unique properties, which make them highly attractive for medical applications. The use of MNPs in surgery has mainly been focused on their role in the identification of metastatic lymph node involvement. There have been developments within this field, including ongoing and newly conducted clinical trials. The current published evidence for the use of MNPs in assessing metastatic lymph node spread using sentinel lymph node biopsy and non invasive imaging modalities is reviewed and future applications considered. PMID- 24343269 TI - Selective inhibition of IFNG-induced autophagy by Mir155- and Mir31-responsive WNT5A and SHH signaling. AB - Autophagy is one of the major immune mechanisms engaged to clear intracellular infectious agents. However, several pathogens have evolved strategies to evade autophagy. Here, we demonstrated that Mycobacteria, Shigella, and Listeria but not Klebsiella, Staphylococcus, and Escherichia inhibit IFNG-induced autophagy in macrophages by evoking selective and robust activation of WNT and SHH pathways via MTOR. Utilization of gain- or loss-of-function analyses as well as mir155 null macrophages emphasized the role of MTOR-responsive epigenetic modifications in the induction of Mir155 and Mir31. Importantly, cellular levels of PP2A, a phosphatase, were regulated by Mir155 and Mir31 to fine-tune autophagy. Diminished expression of PP2A led to inhibition of GSK3B, thus facilitating the prolonged activation of WNT and SHH signaling pathways. Sustained WNT and SHH signaling effectuated the expression of anti-inflammatory lipoxygenases, which in tandem inhibited IFNG-induced JAK-STAT signaling and contributed to evasion of autophagy. Altogether, these results established a role for new host factors and inhibitory mechanisms employed by the pathogens to limit autophagy, which could be targeted for therapeutic interventions. PMID- 24343271 TI - Active and secreted IgA-coated bacterial fractions from the human gut reveal an under-represented microbiota core. AB - Host-associated microbiota varies in distribution depending on the body area inhabited. Gut microbes are known to interact with the human immune system, maintaining gut homoeostasis. Thus, we studied whether secreted-IgA (S-IgA) coat specific microbial taxa without inducing strong immune responses. To do so, we fractionated gut microbiota by flow cytometry. We found that active and S-IgA coated bacterial fractions were characterized by a higher diversity than those observed in raw faecal suspensions. A long-tail effect was observed in family distribution, revealing that rare bacteria represent up to 20% of total diversity. While Firmicutes was the most abundant phylum, the majority of its sequences were not assigned at the genus level. Finally, the single-cell-based approach enabled us to focus on active and S-IgA-coated bacteria. Thus, we revealed a microbiota core common to the healthy volunteers participating in the study. Interestingly, this core was composed mainly of low frequency taxa (e.g. Sphingomonadaceae). PMID- 24343272 TI - An analysis of complex, life-threatening infectious complications of hip and knee joint arthroplasty based on departmental data. AB - BACKGROUND: The growing popularity of arthroplasty results in an increase in the number of infectious complications. The clinical course of inflammation, silent initial symptoms of the disease and non-medical factors, such as poor public awareness and difficulty in finding specialist care, lead patients to postpone the decision about surgical intervention. This results in a state of imminent threat to health or life by endangering other organs of the body. The purpose of this study was to analyze extreme cases of vital organ damage due to infections following hip and knee replacement procedures. MATERIAL AND METHODS: Retrospective analysis of selected cases of life-threatening infectious complications resulting in vital organ damage (urinary tract, large vessels, cardiorespiratory system, etc.) treated at the Department of Orthopedics at the Center of Postgraduate Medical Education (CPME) over the past 12 years. RESULTS: Establishment of an early diagnosis, and above all, confirmation of periprosthetic infection are extremely important. This allows for a biologically reasonable, early and radical management with the best possible treatment options and prevents the risk of life-threatening complications. CONCLUSIONS: Universal access to antibiotics, suppression rather than treatment of infections, silent and unusual course of septic joint loosening and the lack of sufficient awareness of the problem among physicians, contribute to the reoccurrence of such cases and cause significant treatment challenge. They require management at multidisciplinary centers specializing in such cases and rarely end successfully. PMID- 24343273 TI - Interference of CuO nanoparticles with metal homeostasis in hepatocytes under sub toxic conditions. AB - Copper oxide nanoparticles (CuO-NP) were studied for their toxicity and mechanism of action on hepatocytes (HepG2), in relation to Cu homeostasis disruption. Indeed, hepatocytes, in the liver, are responsible for the whole body Cu balance and should be a major line of defence in the case of exposure to CuO-NP. We investigated the early responses to sub-toxic doses of CuO-NP and compared them to equivalent doses of Cu added as salt to see if there is a specific nano-effect related to Cu homeostasis in hepatocytes. The expression of the genes encoding the Cu-ATPase ATP7B, metallothionein 1X, heme oxygenase 1, heat shock protein 70, superoxide dismutase 1, glutamate cysteine ligase modifier subunit, metal responsive element-binding transcription factor 1 and zinc transporter 1 was analyzed by qRT-PCR. These genes are known to be involved in response to Cu, Zn and/or oxidative stresses. Except for MTF1, ATP7B and SOD1, we clearly observed an up regulation of these genes expression in CuO-NP treated cells, as compared to CuCl2. In addition, ATP7B trafficking from the Golgi network to the bile canaliculus membrane was observed in WIF-B9 cells, showing a need for Cu detoxification. This shows an increase in the intracellular Cu concentration, probably due to Cu release from endosomal CuO-NP solubilisation. Our data show that CuO-NP enter hepatic cells, most probably by endocytosis, bypassing the cellular defence mechanism against Cu, thus acting as a Trojan horse. Altogether, this study suggests that sub-toxic CuO-NP treatments induce successively a Cu overload, a Cu-Zn exchange on metallothioneins and MTF1 regulation on both Cu and Zn homeostasis. PMID- 24343274 TI - A novel inorganic solid state ion conductor for rechargeable Mg batteries. AB - The conduction of the bivalent magnesium cation, Mg(2+), in an inorganic solid state material, Mg(BH4)(NH2), has been demonstrated. This material exhibited a high ionic conductivity of 10(-6) S cm(-1) at 150 degrees C, and its electrochemical window was estimated to be approximately 3 V using cyclic voltammetry. PMID- 24343275 TI - Microencapsulated sodium butyrate administered to patients with diverticulosis decreases incidence of diverticulitis--a prospective randomized study. AB - BACKGROUND: Microencapsulated sodium butyrate (MSB) has been previously associated with anti-inflammatory and regenerative properties regarding large bowel mucosa. We aimed to examine a role of MSB in patients with diverticulosis, hypothesizing its potential for reduction of diverticulitis episodes and diverticulitis prevention. METHODS: Seventy-three patients with diverticulosis (diagnosed in colonoscopy or/and barium enema or/and CT colography) were recruited for the study and randomized. The investigated group was administered MSB 300 mg daily; the control group was administered placebo. After 12 months, a total of 52 patients completed the study and were subject to analysis (30 subjects and 22 controls). During the study, the number of episodes of diverticulitis (symptomatic diagnosis with acute pain, fever, and leukocytosis), hospitalizations, and surgery performed for diverticulitis were recorded. Additionally, a question regarding subjective improvement of symptoms reflected changes in quality of life during the analysis. RESULTS: After 12 months, the study group noted a significantly decreased number of diverticulitis episodes in comparison to the control group. The subjective quality of life in the study group was higher than in the control group. There were no side effects of the MSB during the therapy. CONCLUSIONS: MSB reduces the frequency of diverticulitis episodes, is safe, and improves the quality of life. It can play a role in the prevention of diverticulitis. PMID- 24343276 TI - Fecal calprotectin and lactoferrin as predictors of relapse in patients with quiescent ulcerative colitis during maintenance therapy. AB - PURPOSE: This prospective study was to evaluate the significance of fecal calprotectin and lactoferrin for the prediction of ulcerative colitis (UC) relapse. METHODS: Eighty UC patients in remission for >=3 months on mesalamine as maintenance therapy were included. At entry, stool samples were collected for the measurement of calprotectin and lactoferrin. All patients were followed up for the following 12 months. To identify predictive factors for relapse, time dependent analyses using the Kaplan-Meier graphs and Cox's proportional hazard model were applied. RESULTS: During the 12 months, 21 patients relapsed. Mean calprotectin and lactoferrin levels were significantly higher in patients with relapse than those in remission (calprotectin-173.7 vs 135.5 MUg/g, P = 0.02; lactoferrin-165.1 vs 130.7 MUg/g, P = 0.03). A cutoff value of 170 MUg/g for calprotectin had a sensitivity of 76 % and a specificity of 76 % to predict relapse, while a cutoff value of 140 MUg/g for lactoferrin had a sensitivity of 67 % and a specificity of 68 %. In a multivariate analysis, calprotectin (>=170 MUg/g) was a predictor of relapse (hazard ratio, 7.23; P = 0.002). None of the following parameters were significantly associated with relapse: age, gender, duration of UC, number of UC episode, severity of the previous episode, extent of UC, extraintestinal manifestation, and lactoferrin level. CONCLUSIONS: Fecal calprotectin showed a higher sensitivity and specificity than fecal lactoferrin for predicting UC relapse. Fecal calprotectin level appeared to be a significant predictor of relapse in patients with quiescent UC on mesalamine as maintenance therapy. PMID- 24343277 TI - A bio-inspired approach for in situ synthesis of tunable adhesive. AB - Inspired by the strong adhesive produced by English ivy, this paper proposes an in situ synthesis approach for fabricating tunable nanoparticle enhanced adhesives. Special attention was given to tunable features of the adhesive produced by the biological process. Parameters that may be used to tune properties of the adhesive will be proposed. To illustrate and validate the proposed approach, an experimental platform was presented for fabricating tunable chitosan adhesive enhanced by Au nanoparticles synthesized in situ. This study contributes to a bio-inspired approach for in situ synthesis of tunable nanocomposite adhesives by mimicking the natural biological processes of ivy adhesive synthesis. PMID- 24343278 TI - Insight into band positions and inter-particle electron transfer dynamics between CdS nanoclusters and spatially isolated TiO2 dispersed in cubic MCM-48 mesoporous materials: a highly efficient system for photocatalytic hydrogen evolution under visible light illumination. AB - CdS incorporated Si-MCM-48 and Ti-MCM-48 cubic phased mesoporous photocatalysts were prepared by a two-step modification synthetic approach under relatively mild conditions. A highly efficient (24.8%, apparent quantum yield (AQY)) photocatalyst for visible light (lambda > 400 nm) enabled solar hydrogen evolution can be realized by assembling CdS with Ti-MCM-48 cubic mesoporous materials in the absence of a noble metal co-catalyst. The photocatalytic mechanism was thoroughly investigated and demonstrated by conducting a wealth of characterization techniques such as powder X-ray diffraction (XRD), nitrogen adsorption isotherm, transmission electron microscopy (TEM), UV-visible diffuse reflectance spectroscopy (DRS), X-ray photoelectron spectroscopy (XPS), ultraviolet photoelectron spectroscopy (UVPS), atomic absorption spectroscopy (AAS), photoluminescence (PL) spectroscopy, time-resolved fluorescence emission decay, and electron paramagnetic resonance (EPR) spectroscopy studies. This work is the first to unambiguously identify the band positions of both CdS and TiO2 encapsulated in porous materials. The photocatalytic activity of the CdS incorporated Ti-MCM-48 mesoporous photocatalysts was found to be dependent on the content of both CdS and TiO2. A correlation between the electron injection efficiency and the photocatalytic activity was established as well in the CdS incorporated Ti-MCM-48 mesoporous photocatalysts. PMID- 24343279 TI - Anatomic single- versus double-bundle ACL reconstruction: a meta-analysis. AB - PURPOSE: To determine whether anatomic double-bundle anterior cruciate ligament (ACL) reconstruction compared to anatomic single-bundle ACL reconstruction more effectively restored antero-posterior (A-P) laxity, rotatory laxity and reduced frequency of graft rupture. Our hypothesis was that anatomic double-bundle ACL reconstruction results in superior rotational knee laxity and fewer graft ruptures due to its double-bundle tension pattern, compared with anatomic single bundle ACL reconstruction. METHODS: An electronic search was performed using the PubMed, EMBASE and Cochrane Library databases. All therapeutic trials written in English reporting knee kinematic outcomes and graft rupture rates of primary anatomic double- versus single-bundle ACL reconstruction were included. Only clinical studies of levels I-II evidence were included. Data regarding kinematic tests were extracted and included pivot-shift test, Lachman test, anterior drawer test, KT-1000 measurements, A-P laxity measures using navigation and total internal-external (IRER) laxity measured using navigation, as well as graft failure frequency. RESULTS: A total of 7,154 studies were identified of which 15 papers (8 randomized controlled trials and 7 prospective cohort studies, n = 970 patients) met the eligibility criteria. Anatomic ACL double-bundle reconstruction demonstrated less anterior laxity using KT-1000 arthrometer with a standard mean difference (SMD) = 0.36 (95% CI 0.214-0.513, p < 0.001) and less A-P laxity measured with navigation (SMD = 0.29 95% CI 0.01-0.565, p = 0.042). Anatomic double-bundle ACL reconstruction did not lead to significant improvements in pivot-shift test, Lachman test, anterior drawer test, total IRER or graft failure rates compared to anatomic single-bundle ACL reconstruction. CONCLUSION: Anatomic double-bundle ACL reconstruction is superior to anatomic single-bundle reconstruction in terms of restoration of knee kinematics, primarily A-P laxity. Whether these improvements of laxity result in long-term improvement of clinical meaningful outcomes remains uncertain. LEVEL OF EVIDENCE: II. PMID- 24343280 TI - Biological therapy in a pediatric Crohn disease population at a referral center. AB - OBJECTIVE: The antitumor necrosis factor alpha (TNFalpha) antibodies infliximab and adalimumab are effective in inducing and maintaining remission in pediatric patients with Crohn disease (CD). The aim of the study was to evaluate the long term efficacy and safety of biological therapy in pediatric patients with CD followed at a referral center. METHODS: This work is a retrospective observational study enrolling patients with CD treated with infliximab or adalimumab beyond the induction protocol. The patients' data were collected from the unit's IBD database (maximum follow-up evaluation after 36 months of treatment). The efficacy was evaluated by the Pediatric Crohn Disease Activity Index score and by analysis of the cumulative probability of continuing therapy; the safety was assessed in terms of adverse events. RESULTS: We enrolled 78 patients; the mean therapy duration was 27.2 +/- 16.7 months, and the mean age at enrollment was 15 +/- 3.1 years. The Kaplan-Meier analysis showed a cumulative probability of continuing therapy of 81%, 54%, and 33% at 1, 2, and 3 years, respectively, from the introduction of therapy. No association between the patients' baseline characteristics and the long-term outcome was found. The evaluation of the concomitant therapy with immunomodulators and anti-TNFalpha therapy versus anti-TNFalpha alone did not show a different outcome. No serious adverse events were recorded. CONCLUSIONS: The study indicates that biological therapy is effective and safe in pediatric patients with CD in a longer follow-up period. The response to treatment was not influenced by the patients' baseline characteristics or by the immunomodulator association. PMID- 24343281 TI - Predictors of depression in youth with Crohn disease. AB - OBJECTIVE: The aim of the study was to determine whether infliximab use and other potential predictors are associated with decreased prevalence and severity of depression in pediatric patients with Crohn disease (CD). METHODS: A total of 550 (n = 550) youth ages 9 to 17 years with biopsy-confirmed CD were consecutively recruited as part of a multicenter randomized controlled trial. Out of the 550, 499 patients met study criteria and were included in the analysis. At recruitment, each subject and a parent completed the Children's Depression Inventory (CDI). A child or parent CDI score >= 12 was used to denote clinically significant depressive symptoms (CSDS). Child and parent CDI scores were summed to form total CDI (CDIT). Infliximab use, demographic information, steroid use, laboratory values, and Pediatric Crohn's Disease Activity Index (PCDAI) were collected as the potential predictors of depression. Univariate regression models were constructed to determine the relations among predictors, CSDS, and CDIT. Stepwise multivariate regression models were constructed to predict the relation between infliximab use and depression while controlling for other predictors of depression. RESULTS: Infliximab use was not associated with a decreased proportion of CSDS and CDIT after adjusting for multiple comparisons. CSDS and CDIT were positively associated with PCDAI, erythrocyte sedimentation rate, and steroid dose (P < 0.01) and negatively associated with socioeconomic status (SES) (P < 0.001). In multivariate models, PCDAI and SES were the strongest predictors of depression. CONCLUSIONS: Disease activity and SES are significant predictors of depression in youth with Crohn disease. PMID- 24343282 TI - The scientific journey to predicting and preventing postoperative pain: recalling Dr. Wall's stories along the way. PMID- 24343283 TI - "I awaken to glory". PMID- 24343284 TI - "Seeing" how our drugs work brings translational added value. PMID- 24343286 TI - Pain in 1,000 women treated for breast cancer: a prospective study of pain sensitivity and postoperative pain. AB - BACKGROUND: This article describes the methods and results of the early part (experimental pain tests and postoperative analgesia) of a study that assesses genetic and other factors related to acute pain and persistent pain after treatment of breast cancer in a prospective cohort of 1,000 women. METHODS: One thousand consenting patients were recruited to the study. Before surgery (breast resection or mastectomy with axillary surgery), the patients filled in questionnaires about health, life style, depression (Beck Depression Inventory), and anxiety (State-Trait Anxiety Inventory). They were also exposed to experimental tests measuring heat (43 degrees and 48 degrees C, 5 s) and cold (2 4 degrees C) pain intensity and tolerance. Anesthesia was standardized with propofol and remifentanil, and postoperative analgesia was optimized with i.v. oxycodone. RESULTS: The patients showed significant interindividual variation in heat and cold pain sensitivity and cold pain tolerance. There was a strong correlation between the experimental pain measures across the tests. Presence of chronic pain, the number of previous operations, and particularly state anxiety were related to increased pain sensitivity. Previous smoking correlated with decreased heat pain sensitivity. These factors explained 4-5% of the total variance in pain sensitivity in these tests. Oxycodone consumption during 20 h was significantly higher in patients who had axillary clearance. Oxycodone consumption had only a weak correlation with the experimental pain measures. CONCLUSIONS: Contact heat and cold pressure tests identify variability in pain sensitivity which is modified by factors such as anxiety, chronic pain, previous surgery, and smoking. High levels of anxiety are connected to increased pain sensitivity in experimental and acute postoperative pain. PMID- 24343287 TI - Colon-morales' uterine displacement device. PMID- 24343288 TI - Effect of catechol-o-methyltransferase-gene (COMT) variants on experimental and acute postoperative pain in 1,000 women undergoing surgery for breast cancer. AB - BACKGROUND: Catechol-O-methyltransferase (COMT) metabolizes catecholamines in different tissues. Polymorphisms in COMT gene can attenuate COMT activity and increase sensitivity to pain. Human studies exploring the effect of COMT polymorphisms on pain sensitivity have mostly included small, heterogeneous samples and have ignored several important single nucleotide polymorphisms (SNPs). This study examines the effect of COMT polymorphisms on experimental and postoperative pain phenotypes in a large ethnically homogeneous female patient cohort. METHODS: Intensity of cold (+2-4 degrees C) and heat (+48 degrees C) pain and tolerance to cold pain were assessed in 1,000 patients scheduled for breast cancer surgery. Acute postoperative pain and oxycodone requirements were recorded. Twenty-two COMT SNPs were genotyped and their association with six pain phenotypes analyzed with linear regression. RESULTS: There was no association between any of the tested pain phenotypes and SNP rs4680. The strongest association signals were seen between rs165774 and heat pain intensity as well as rs887200 and cold pain intensity. In both cases, minor allele carriers reported less pain. Neither of these results remained significant after strict multiple testing corrections. When analyzed further, the effect of rs887200 was, however, shown to be significant and consistent throughout the cold pressure test. No evidence of association between the SNPs and postoperative oxycodone consumption was found. CONCLUSIONS: SNPs rs887200 and rs165774 located in the untranslated regions of the gene had the strongest effects on pain sensitivity. Their effect on pain is described here for the first time. These results should be confirmed in further studies and the potential functional mechanisms of the variants studied. PMID- 24343289 TI - Survey criteria for fibromyalgia independently predict increased postoperative opioid consumption after lower-extremity joint arthroplasty: a prospective, observational cohort study. AB - BACKGROUND: Variance in pain after total knee and hip arthroplasty may be due to a number of procedural and peripheral factors but also, in some individuals, to aberrant central pain processing as is described in conditions like fibromyalgia. To test this hypothesis, the authors conducted a prospective, observational cohort study of patients undergoing lower-extremity joint arthroplasty. METHODS: Five hundred nineteen patients were preoperatively phenotyped using validated self-reported pain questionnaires, psychological measures, and health information. In addition to being assessed for factors previously found to be associated with poor outcomes in arthroplasty, participants also completed the American College of Rheumatology survey criteria for fibromyalgia. Previous studies have suggested that rather than being "present" or "absent," features of fibromyalgia as measured by this instrument, occur over a wide continuum. Postoperative pain control was assessed by total postoperative opioid consumption. RESULTS: Preoperatively, patients with higher fibromyalgia survey scores were younger, more likely to be female, taking more opioids, reported higher pain severity, and had a more negative psychological profile. In the multivariate analysis, the fibromyalgia survey score, younger age, preoperative opioid use, knee (vs. hip), pain severity at baseline, and the anesthetic technique were all predictive of increased postoperative opioid consumption. CONCLUSIONS: The use of the survey criteria for fibromyalgia led to the finding of distinct phenotypic differences, and the measure was independently predictive of opioid consumption. This self-report measure may provide an additional simple means of predicting postoperative pain outcomes and analgesic requirements. Future studies are needed to determine whether tailored therapies can improve postoperative pain control in this population. PMID- 24343290 TI - Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients. AB - BACKGROUND: Chronic pain remains a significant challenge for modern health care as its pathologic mechanisms are largely unknown and preclinical animal models suffer from limitations in assessing this complex subjective experience. However, human brain neuroimaging techniques enable the assessment of functional and neurochemical alterations in patients experiencing chronic pain and how these factors may dynamically change with pharmacologic treatment. METHODS: To identify the clinical action of pregabalin, a proven analgesic, the authors performed three complementary brain neuroimaging procedures: (proton magnetic resonance spectroscopy, functional magnetic resonance imaging, and functional connectivity magnetic resonance imaging) in 17 chronic pain patients diagnosed with fibromyalgia. RESULTS: The authors found that pregabalin but not placebo reduces combined glutamate + glutamine levels within the posterior insula (pregabalin P = 0.016; placebo P = 0.71). Interestingly, reductions in clinical pain were associated with reductions in brain connectivity of this structure to brain regions within the default mode network during pregabalin (r = 0.82; P = 0.001) but not placebo (r = -0.13; P = 0.63). Response of default mode network regions to experimental pain was also reduced with pregabalin (P = 0.018) but not placebo (P = 0.182). Perhaps most importantly, baseline values for all three neuroimaging markers predicted subsequent analgesic response to pregabalin but not placebo. CONCLUSIONS: The results of this study suggest that pregabalin works in part by reducing insular glutamatergic activity, leading to a reduction of the increased functional connectivity seen between brain regions in chronic pain states. The study also supports a role for human brain imaging in the development, assessment, and personalized use of central-acting analgesics. PMID- 24343291 TI - Icteric vocal cords recorded during video laryngoscopy. PMID- 24343296 TI - Systematic review of the benefits and risks of metformin in treating obesity in children aged 18 years and younger. AB - IMPORTANCE: Childhood obesity is an important public health problem with increasing prevalence. Because treatment often has limited success, new approaches must be identified. OBJECTIVE: To evaluate the effectiveness and safety of metformin for treating obesity in children aged 18 years and younger without a diagnosis of diabetes mellitus. EVIDENCE REVIEW: We included randomized clinical trials identified through searches of MEDLINE, the Cochrane Library, and ClinicalTrials.gov. Our primary outcome measure was change in body mass index (BMI, calculated as weight in kilograms divided by height in meters squared). We assessed study quality, pooled data using a random-effects model, and performed subgroup and sensitivity analyses. FINDINGS: Fourteen randomized clinical trials were eligible. For BMI, moderate-strength evidence indicated a reduction of -1.38 (95% CI, -1.93 to -0.82) from baseline compared with control at 6 months. A similar, if less dramatic, effect was observed in studies less than 6 months, but the pooled estimate from studies of 1 year of treatment was not statistically significant. Subgroup analyses indicated smaller, but significant, effects for those with baseline BMI below 35, those of Hispanic ethnicity, those with acanthosis nigricans, those who had tried and failed diet and exercise programs, and in studies with more girls or higher mean age (adolescents). Moderate strength evidence indicated that with metformin, 26% reported a gastrointestinal event compared with 13% in control groups (relative risk, 2.05; 95% CI, 1.19 3.54), although there was no difference in discontinuations due to adverse events. No serious adverse events were reported. CONCLUSIONS AND RELEVANCE: Metformin provides a statistically significant, but very modest reduction in BMI when combined with lifestyle interventions over the short term. A large trial is needed to determine the benefits to subgroups or impacts of confounders. In the context of other options for treating childhood obesity, metformin has not been shown to be clinically superior. PMID- 24343297 TI - Synthesis and application of binuclear alpha-diimine nickel/palladium catalysts with a conjugated backbone. AB - A series of binuclear nickel/palladium catalysts C4-C7 with conjugated alpha diimine ligands were designed, prepared and fully characterized. The binuclear nickel complexes C6 and C7 were activated by modified methylalumoxanes (MMAO) to generate highly active ethylene polymerization catalysts with activities up to 1050 kg [mol (Ni) h](-1). The activity of C7 is twice that of the mononuclear analogue under the same conditions. The effects of the catalyst structure, cocatalyst ratio, polymerization time, solvent and feeding monomer on the catalytic activities, molecular weight and branching structures of the resulting polymers were evaluated. The binuclear palladium complexes C4-C5 produced polyethylene with two separate peaks in GPC curves in ethylene polymerization. In contrast, the mononuclear analogue C3 produces polyethylene with a unimodal GPC curve. Probably, two active species are generated in the binuclear palladium catalyst system and are responsible for the bimodal feature of the GPC curves. The performance of the binuclear palladium complexes in ethylene/methyl acrylate copolymerization was also investigated. PMID- 24343298 TI - Electrochemical analysis of the fibrillation of Parkinson's disease alpha synuclein. AB - Amyloid formation of proteins and peptides is an important biomedical and biotechnological problem, intensively studied and yet not fully understood. In this context, the development of fast and reliable methods for real-time monitoring of protein misfolding is of particular importance for unambiguous establishment of disease-, drug- and environmentally induced mechanisms of protein aggregation. Here we show that the extent of aggregation of alpha synuclein (alphaSN), involved in Parkinson's disease and other neurodegenerative disorders, can be electrochemically monitored by oxidizing tyrosine (Tyr) residues surface-exposed in monomeric alphaSN and buried in fibrillated alphaSN adsorbed onto graphite electrodes. Adsorption of alphaSN, analyzed through the Tyr electrochemistry, followed the Langmuir adsorption isotherm. The degree of electrooxidation of Tyr in alphaSN decreased upon protein fibrillation and correlated with the extent of alphaSN aggregation determined by the spectroscopic analysis of the fibrillation process. Minor changes in the adsorption state of alphaSN were followed through the shift of the Tyr oxidation potential, consistent with the compact and less-compact/unfolded conformation of alphaSN. Our results allow reliable electroanalysis of the extent of alphaSN fibrillation in vitro and offer an efficient tool for future in vivo monitoring of the protein conformational state. PMID- 24343299 TI - Diets high in total antioxidant capacity improve risk biomarkers of cardiovascular disease: a 9-month observational study among overweight/obese postmenopausal women. AB - BACKGROUND: Previous studies have shown that total antioxidant capacity (TAC) of typical diets is associated with higher plasma TAC and antioxidant enzyme activities. At present, however, little is known for the association between dietary TAC and inflammatory biomarkers. AIM: The present study was designed to examine the association between dietary TAC and inflammatory biomarkers in a group of overweight/obese postmenopausal women, a population with high cardiovascular disease (CVD) risk, during a 9-month period. METHODS: Thirty-five postmenopausal, overweight or obese, but apparently healthy women aged 40-70 years were recruited for a 9-month observational study. Seven-day food records and 12-h fasting blood samples were collected at baseline and at the end of the study for dietary and plasma biomarker assessments. Dietary TAC was calculated theoretically for taking account of both diet and dietary supplements, and energy adjusted values were obtained using residual method. RESULTS: At baseline, subjects consuming diets with high dietary TAC had lower levels of plasma C reactive protein (CRP) and monocyte chemoattractant protein-1 (p < 0.05) compared with those with low dietary TAC. Over the 9-month period, change in dietary TAC had a negative partial correlation with plasma CRP levels (p < 0.01) when age, ethnicity, and changes in BMI, blood total cholesterol and triglyceride were adjusted. CONCLUSIONS: Findings suggest that consumption of diets high in TAC are inversely associated with plasma CRP levels cross-sectionally and dynamically and may contribute to CVD protection. PMID- 24343300 TI - A validation study of the Iranian version of STarT Back Screening Tool (SBST) in lumbar central canal stenosis patients. AB - BACKGROUND: This study aimed to translate and validate the STarT Back Screening Tool (SBST) in Iran. METHODS: This was a prospective clinical validation study. The translation and cross-cultural adaptation of the original questionnaire was performed, and a total of 269 patients with lumbar central canal stenosis were asked to respond to the questionnaire at their first visits. Patients also were asked to complete the Oswestry Disability Index (ODI). Reliability was assessed by internal consistency using the Cronbach's alpha coefficient. Validity was evaluated by performing convergent validity and responsiveness to change. RESULTS: Mean patient age was 58.6 [standard deviation (SD) = 10.9] years; 56.5 % were women. According to patients' imaging, they were diagnosed as grade 1 (n = 86), grade 2 (n = 107), and grade 3 (n = 76). In general, the SBST showed good psychometric properties. Cronbach's alpha coefficient for overall scale (Q1-Q9) and psychosocial subscale (Q5-Q9) was 0.82 and 0.79, respectively. The ODI correlated strongly with overall SBST scores, lending support to its good convergent validity (r = 0.81; P < 0.001). Responsiveness to change also indicated desirable results. CONCLUSION: In general, the Iranian version of the SBST performed well, and findings suggest that it is a reliable and valid measure for screening low back pain in patients with lumbar central canal stenosis in primary care settings. PMID- 24343301 TI - Adjustable patella grapple versus cannulated screw and cable technique for treatment of transverse patellar fractures. AB - BACKGROUND: Although the cannulated screw and cable (CSC) tension band technique is an effective method for fixation of transverse patellar fractures, it has shortcomings, such as extensive soft tissue damage, osseous substance damage, and complex manipulation. We conducted a retrospective comparison of the adjustable patella grapple (APG) technique and the CSC tension band technique. PATIENTS AND METHODS: We retrospectively reviewed 78 patients with transverse patellar fractures (45 in the APG group and 33 in the CSC group). Follow-up was 18 months. Comparison criteria were operation time, fracture reduction, fracture healing time, the knee injury and osteoarthritis outcome score for knee function, and complications. RESULTS: The APG group showed shorter operation time and equal fracture reduction, fracture healing time, and knee function compared with the CSC group. Eleven patients in the APG group experienced skin irritation generated by implants. There was no complication in the CSC group. CONCLUSIONS: The APG technique should be considered as an alternative method for treatment of transverse patellar fractures. PMID- 24343303 TI - Iterative mass spectrometry and X-ray crystallography to study ion-trapping and rearrangements by a flexible cluster. AB - An important aspect of chemical reactions involves understanding the intermediate steps from reactants to products. The iterative use of mass spectrometry and X Ray crystallography is demonstrated to be a powerful combination in this respect. We have applied them in identifying molecular clusters in solution followed by their solid-state structural characterizations. We used a key ligand, 2-[(2 hydroxy-3-methoxy-benzylidene)-amino]-ethanesulfonate (L), which serves as chelating/bridging units to stabilize the precursor [Li4Ni6(OH)2(L)6(CH3CN)6](ClO4)2.4CH3CN. The results of subsequent reactions witness a cascade of processes involving fragmentation, inner bridging ligand substitution (OH- to OCH3-), changing modes of binding (chelate to monodentate) of the key ligand, ion-trapping and exchange (Li+, Na+ and Ca2+) and their site preferences, coordinating and non-coordinating solvents (CH3CN to CH3OH, H2O and EtOH) replacement. The flexibility of the Ni3OL3 species in solution permits the formation of six derivatives. The complimentary techniques open a broader prospect for cluster design and applications. PMID- 24343305 TI - Vibronic spectra of the p-benzoquinone radical anion and cation: a matrix isolation and computational study. AB - The electronic and vibrational absorption spectra of the radical anion and cation of p-benzoquinone (PBQ) in an Ar matrix between 500 and 40,000 cm(-1) are presented and discussed in detail. Of particular interest is the radical cation, which shows very unusual spectroscopic features that can be understood in terms of vibronic coupling between the ground and a very low-lying excited state. The infrared spectrum of PBQ(+) exhibits a very conspicuous and complicated pattern of features above 1900 cm(-1) that is due to this electronic transition, and offers an unusually vivid demonstration of the effects of vibronic coupling in what would usually be a relatively simple region of the electromagnetic spectrum associated only with vibrational transitions. As expected, the intensities of most of the IR transitions leading to levels that couple the ground to the very low-lying first excited state of PBQ(+) increase by large factors upon ionization, due to "intensity borrowing" from the D0 -> D1 electronic transition. A notable exception is the antisymmetric C=O stretching vibration, which contributes significantly to the vibronic coupling, but has nevertheless quite small intensity in the cation spectrum. This surprising feature is rationalized on the basis of a simple perturbation analysis. PMID- 24343302 TI - Tumour-associated mutant p53 drives the Warburg effect. AB - Tumour cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect. Its mechanism is not well understood. The tumour suppressor gene p53 is frequently mutated in tumours. Many tumour associated mutant p53 (mutp53) proteins not only lose tumour suppressive function but also gain new oncogenic functions that are independent of wild-type p53, defined as mutp53 gain of function (GOF). Here we show that tumour-associated mutp53 stimulates the Warburg effect in cultured cells and mutp53 knockin mice as a new mutp53 GOF. Mutp53 stimulates the Warburg effect through promoting GLUT1 translocation to the plasma membrane, which is mediated by activated RhoA and its downstream effector ROCK. Inhibition of RhoA/ROCK/GLUT1 signalling largely abolishes mutp53 GOF in stimulating the Warburg effect. Furthermore, inhibition of glycolysis in tumour cells greatly compromises mutp53 GOF in promoting tumorigenesis. Thus, our results reveal a new mutp53 GOF and a mechanism for controlling the Warburg effect. PMID- 24343306 TI - Constructing metallic nanoroads on a MoS2 monolayer via hydrogenation. AB - Monolayer transition metal dichalcogenides recently emerged as a new family of two-dimensional materials potentially suitable for numerous applications in electronic and optoelectronic devices due to the presence of a finite band gap. Many proposed applications require efficient transport of charge carriers within these semiconducting monolayers. However, constructing a stable conducting nanoroad on these atomically thin semiconductors is still a challenge. Here we demonstrate that hydrogenation on the surface of a MoS2 monolayer induces a semiconductor-metal transition, and strip-patterned hydrogenation is able to generate a conducting nanoroad. The band-gap closing arises from the formation of in-gap hybridized states mainly consisting of Mo 4d orbitals, as well as the electron donation from hydrogen to the lattice host. Ballistic conductance calculations reveal that such a nanoroad on the MoS2 surface exhibits an integer conductance, indicating small carrier scattering, and thus is ideal for serving as a conducting channel or an interconnect without compromising the mechanical and structural integrity of the monolayer. PMID- 24343304 TI - A collaborative study of the etiology of breast cancer subtypes in African American women: the AMBER consortium. AB - PURPOSE: Breast cancer is a heterogeneous disease, with at least five intrinsic subtypes defined by molecular characteristics. Tumors that express the estrogen receptor (ER+) have better outcomes than ER- tumors, due in part to the success of hormonal therapies that target ER+ tumors. The incidence of ER- breast cancer, and the subset of ER- cancers that are basal-like, is about twice as high among African American (AA) women as among US women of European descent (EA). This disparity appears to explain, in part, the disproportionately high mortality from breast cancer that occurs in AA women. Epidemiologic research on breast cancer in AA women lags behind research in EA women. Here, we review differences in the etiology of breast cancer subtypes among AA women and describe a new consortium of ongoing studies of breast cancer in AA women. METHODS: We combined samples and data from four large epidemiologic studies of breast cancer in AA women, two cohort and two case-control, creating the African American Breast Cancer Epidemiology and Risk consortium. Tumor tissue is obtained and stored in tissue microarrays, with assays of molecular markers carried out at a pathology core. Genotyping, carried out centrally, includes a whole exome SNP array and over 180,000 custom SNPs for fine-mapping of genome-wide association studies loci and candidate pathways. RESULTS: To date, questionnaire data from 5,739 breast cancer cases and 14,273 controls have been harmonized. Genotyping of the first 3,200 cases and 3,700 controls is underway, with a total of 6,000 each expected by the end of the study period. CONCLUSIONS: The new consortium will likely have sufficient statistical power to assess potential risk factors, both genetic and non-genetic, in relation to specific subtypes of breast cancer in AA women. PMID- 24343307 TI - Treatment of primary CNS lymphoma. AB - OPINION STATEMENT: Primary central nervous system lymphoma is a particular challenge in clinical neuro-oncology. In contrast to most other malignant brain tumors, it may be considered a curable disease at least in younger patients who can tolerate intensive treatment regimens. Yet, therapeutic progress has been limited with little measurable improvement in outcome over the last two decades, mainly due to the low incidence of this tumor, which impedes the execution of large randomized clinical trials, and the failure of most large cooperative groups to conduct such trials. Whenever possible, high-dose methotrexate (HD-MTX) is the backbone of the therapeutic regimen. Response rates can be increased by the addition of second agents like ifosfamide or cytarabine, however, their impact on overall survival is less clear. Similarly, the use of the anti-CD20 antibody rituximab, commonly used in the treatment of B cell lymphomas outside the CNS, remains controversial and has not been examined in adequate clinical trials. The prognosis of patients, who do not qualify for HD-MTX-based chemotherapy, is considerably poorer. Radiation therapy is an active treatment with high response rates but does typically not result in long-lasting remissions. It remains an important therapeutic option as a salvage therapy in patients progressing on or no longer responding to HD-MTX-based treatment. The combination of HD-MTX and radiation therapy does not prolong overall survival. It is associated with significant neurotoxicity, and it should be avoided. Another matter of debate is whether consolidation therapy by other means, such as high dose chemotherapy followed by stem cell support, is the most promising regimen. Given these numerous uncertainties, neuro-oncologists should strive for a treatment of PCNSL patients within clinical trials to allow for the development of improved therapeutic regimens. PMID- 24343308 TI - Improving care for women with a history of gestational diabetes: a provider perspective. AB - To identify perceived roles with regard to care for women with gestational diabetes mellitus (GDM) history and resources for improving care among women with a history of GDM from the perspective of obstetrician/gynecologists (OB/GYNs), certified nurse midwives (CNM), family practitioners, and internists. In 2010, a survey was sent to a random sample of OB/GYNs, CNM, family practitioners, and internists (n = 2,375) in Ohio to assess knowledge, attitudes, and postpartum practices regarding diabetes prevention for women with a history of GDM. A total of 904 practitioners completed the survey (46 %). Over 70 % of CNMs strongly agreed it is part of their job to help women with GDM history improve diet and increase exercise, compared with 60 % of family practitioners/internists and 55 % of OB/GYNs (p < 0.001). More OB/GYNs and CNMs identified a need for more local nutrition specialists and patient education materials, compared with family practitioners/ internists. Between 60 and 70 % of OB/GYNs and CNMs reported lifestyle modification programs and corresponding reimbursement would better support them to provide improved care. Health care providers giving care to women with GDM history have varying perceptions of their roles, however, there was agreement on resources needed to improve care. PMID- 24343309 TI - Comparative effectiveness of group and individual prenatal care on gestational weight gain. AB - This study examined differences in gestational weight gain for women in CenteringPregnancy (CP) group prenatal care versus individually delivered prenatal care. We conducted a retrospective chart review and used propensity scores to form a matched sample of 393 women (76 % African-American, 13 % Latina, 11 % White; average age 22 years) receiving prenatal care at a community health center in the South. Women were matched on a wide range of demographic and medical background characteristics. Compared to the matched group of women receiving standard individual prenatal care, CP participants were less likely to have excessive gestational weight gain, regardless of their pre-pregnancy weight (b = -.99, 95 % CI [-1.92, -.06], RRR = .37). CP reduced the risk of excessive weight gain during pregnancy to 54 % of what it would have been in the standard model of prenatal care (NNT = 5). The beneficial effect of CP was largest for women who were overweight or obese prior to their pregnancy. Effects did not vary by gestational age at delivery. Post-hoc analyses provided no evidence of adverse effects on newborn birth weight outcomes. Group prenatal care had statistically and clinically significant beneficial effects on reducing excessive gestational weight gain relative to traditional individual prenatal care. PMID- 24343310 TI - [Adaptation of the Composite International Diagnostic Interview (CIDI) for the assessment of comorbid mental disorders in oncology patients: the CIDI-O]. AB - This article describes the development of an oncology-specific adaptation of the Composite Diagnostic International Interview (CIDI) for the assessment of comorbid mental disorders in cancer patients. The specific problems related to the assessment of mental disorders in cancer patients are described, in particular the overlap of somatic and mental symptoms as well as the insufficiently elaborated assessment of adjustment disorders and cancer related posttraumatic stress using structured and standardized procedures. The modification strategies that fostered the development of the CIDI-Oncology (CIDI O) are described. Primary purpose of this adaptation is to enhance the diagnostic spectrum of the CIDI adding the diagnostic group of stress-related mental disorders. PMID- 24343311 TI - [The short form of the NMR scale (NMR-SF) as an instrument for measuring the self rated ability for negative mood regulation: review and construct validity]. AB - The NMR-SF is the short form of the NMR Scale. The NMR-SF is a self-rating instrument to measure negative mood regulation expectancies. This construct is an important variable in the etiology and psychotherapy of mental disorders. The present study investigates the construct validity of the NMR-SF in 2 non-clinical samples and a sample of depressed patients. The NMR-SF was positively correlated with adaptive strategies of mood regulation and negatively with maladaptive strategies. High scores on the NMR-SF were associated with less psychopathology. There was a small positive correlation with social desirability. The results of the current study support the construct validity of the NMR-SF and indicate that its psychometric properties are good. Due to its efficiency, the NMR-SF is well applicable in clinical samples, especially when using repeated measurements designs. PMID- 24343312 TI - [Do actual body experiences affect physical self-concept? A longitudinal study with patients with cardiac disease during sport therapy]. AB - The present study investigates variations of physical well-being and physical self-concept during sport therapy in rehabilitation of patients with heart diseases. Additionally, interrelationships between physical self-concept and physical well-being were assumed. In a sample of 43 heart disease patients (aged 44-86), physical self-concept (PSK-scale) was assessed before and after a 3-week physical exercise treatment. Actual physical well-being was assessed with the Perceived Physical State adjective list (WKV) at 3 measuring points (beginning, mid, and end of sport therapy). Enhancements of physical self-concept and actual physical well-being could be found. Furthermore, relationships between both constructs could be revealed: The progression of one construct depends on the initial state of the respective other. Low initial states facilitate positive progression. These results are discussed both as a ceiling effect and as the consequence of a physical stimulation below threshold. PMID- 24343313 TI - [An art therapy project day to promote health for clients from burnout self-help groups--an exploratory study]. AB - AIM: The present exploratory study dealt with the question whether a specialized concept of art therapy interventions could increase the current and habitual well being for participants of burnout self-help groups. METHOD: Quantitative: pre post: Current well-being: list of discomforts (Beschwerdenliste: B-L); current mood scale (Aktuelle Stimmungsskala: ASTS); Habitual well-being: quality of life (SF-36); qualitative: post: semi-structured interviews with open key questions; evaluation: structured content analysis of Mayring. RESULTS: Quantitative: significant increase of current and habitual well-being; qualitative: generation of 3 general and 8 specific art therapy work factors. CONCLUSION: Specialized resource-activating concepts of art therapy interventions can effectively complement existing programs for burnout prevention and health promotion. PMID- 24343314 TI - The V(H) repertoire and clonal diversification of B cells in inflammatory myopathies. AB - The contribution of antigen-driven B-cell adaptive immune responses within the inflamed muscle of inflammatory myopathies (IMs) is largely unknown. In this study, we investigated the immunoglobulin V(H) gene repertoire, somatic hypermutation, clonal diversification, and selection of infiltrating B cells in muscle biopsies from IM patients (dermatomyositis and polymyositis), to determine whether B cells and/or plasma cells contribute to the associated pathologies of these diseases. The data reveal that Ig V(H) gene repertoires of muscle infiltrating B cells deviate from the normal V(H) gene repertoire in individual patients, and differ between different types of IMs. Analysis of somatic mutations revealed clonal diversification of muscle-infiltrating B cells and evidence for a chronic B-cell response within the inflamed muscle. We conclude that muscle-infiltrating B cells undergo selection, somatic hypermutation and clonal diversification in situ during antigen-driven immune responses in patients with IMs, providing insight into the contribution of B cells to the pathological mechanisms of these disorders. PMID- 24343315 TI - Use of bearings with integrated ceramic insert in cementless total hip arthroplasty - a preliminary report. AB - BACKGROUND: Ceramic-on-ceramic articulation presents advancement in the development modern of hip prostheses. It is particularly important for young patients, in whom complications related with polyethylene damages and metalosis pose a serious clinical problem due to the long period of implant functioning. The aim of this study was to assess the effect of total cementless hip replacement using an implant with a ceramic insert embedded in a metal cup and large prosthetic head constituting a ceramic-on-ceramic system in patients with hip osteoarthritis. MATERIAL AND METHODS: During years 2012-2013 there were 26 total hip replacements in 24 patients with use of integrated ceramic cup at Department of Orthopedic and Traumatology of the Central Clinical Hospital of Ministry of Interior, Warsaw. We assessed clinical and radiological outcomes of this procedure using HHS (Harris Hip Score), WOMAC (The Western Ontario and McMaster Universities Arthritis Index) and NRS (Numeric Rating Scale) scores. RESULTS: In our study group patients presented with a significant degree of improvement in passive range of motion in the hip joint and no postoperative complications were noted. Significant statistical improvement was noted after surgery in each of the following scales HHS (50.84 vs. 87.16), WOMAC (51.01 vs. 91.88) and NRS (6.8 vs. 0.45). There were no signs of early or radiological evidence of loosening and implant migration among our patients. CONCLUSIONS: Cementless total hip arthroplasty using an acetabular component with a ceramic insert embedded in metal and a large prosthetic head (a ceramic-on-ceramic system) is an effective and a noteworthy method of treatment of hip osteoarthritis in young people. PMID- 24343316 TI - beta-TCP granules mixed with reticulated hyaluronic acid induce an increase in bone apposition. AB - beta beta-tricalcium phosphate (beta-TCP) granules are suitable for repair of bone defects. They have an osteoconductive effect shortly after implantation. However, dry granules are difficult to handle in the surgical room because of low weight and lack of cohesion. Incorporation of granules in a hydrogel could be a satisfactory solution. We have investigated the use of hyaluronic acid (HyA) as an aqueous binder of the granules. beta-TCP granules were prepared by the polyurethane foam technology. Commercially available linear (LHya) and reticulated hyaluronic acid (RHyA) in aqueous solution were used to prepare a pasty mixture that can be handled more easily than granules alone. Thirteen New Zealand White rabbits (3.5-3.75 kg) were used; a 4 mm hole was drilled in each femoral condyle. After flushing, holes were filled with either LHyA, RHyA, dry beta-TCP granules alone, beta-TCP granules + LHyA and beta-TCP granules + RHyA. Rabbits were allowed to heal for one month, sacrificed and femurs were harvested and analysed by microCT and histomorphometry. The net amount of newly formed bone was derived from measurements done after thresholding the microCT images for the material and for the material+bone. LHyA and RHyA did not result in healing of the grafted area. LHyA was rapidly eluted from the grafted zone but allowed deposition of more granules, although the amount of formed bone was not significantly higher than with beta-TCP granules alone. RHyA permitted the deposition of more granules which induced significantly more bone trabeculae without inducing an inflammatory reaction. RHyA appears to be a good vehicle to implant granules of beta-TCP, since HyA does not interfere with bone remodeling. PMID- 24343317 TI - Transplantation and surgery of the hand. PMID- 24343319 TI - Statistical analysis using the OMENS classification in Oriental patients with hemifacial microsomia: a comparative analysis with Western centers. AB - The purpose of this study was to analyze the statistical association between variable clinical phenotypes of the orbit, mandible, ear, nerve, soft tissue (OMENS) classification system in Oriental patients with hemifacial microsomia (HFM) and compare the data of Oriental children with data from other Western centers. One hundred consecutive patients with HFM referred to the Seoul National University Children Hospital were chosen between March 2009 and April 2010. They were classified according to the OMENS classification system, and statistical analyses were performed. The total OMENS scores were correlated significantly with all 5 component scores. In comparison with the previous data of Western centers, the orbit and ear components had statistically higher severity. Our retrospective study in Oriental children demonstrated that the pathophysiology of HFM is a complex process and that the components of HFM have a close relationship. For the ethnic difference, further etiologic studies on the molecular basis are required. PMID- 24343320 TI - Efficacy and safety profile of antibiotic prophylaxis usage in clean and clean contaminated plastic and reconstructive surgery: a meta-analysis of randomized controlled trials. AB - BACKGROUND: There is no consensus with regard to antibiotic prophylaxis usage in clean and clean-contaminated plastic and reconstructive surgery. This meta analysis sought to assess the efficacy and safety of antibiotic prophylaxis and to determine appropriate duration of prophylaxis. METHODS: An English language literature search was conducted using PubMed and the Cochrane Collaboration for randomized controlled trials (RCTs) that evaluate the use of antibiotic prophylaxis to prevent postoperative surgical site infection (SSI) in patients undergoing clean and clean-contaminated plastic and reconstructive surgery. Data from intention-to-treat analyses were used where available. For the dichotomous data, results for each study were odds ratio (OR) with 95% confidence interval (CI) and combined for meta-analysis using the Mantel-Haenszel method or the DerSimonian and Laird method. Study quality was critically appraised by 2 reviewers using established criteria. STATA version 12 was used for meta analyses. RESULTS: Twelve RCTs involving 2395 patients were included, of which 8 trials were considered to be of high methodological quality. Effect of antibiotic prophylaxis in plastic and reconstructive surgery was found favorable over placebo in SSI prevention (13 studies; 2449 participants; OR, 0.53; 95% CI, 0.4 0.7; P < 0.01) and the other wound complication (OWC) prevention (9 studies; 1843 participants; OR, 0.36; 95% CI, 0.15-0.84; P < 0.02). Subgroup analysis performed according to surgical wound type or the duration of prophylaxis did not modify the results except for the OWC with short-term antibiotic treatment. Compared with short-term antibiotic prophylaxis, long-term administration showed no evidence of a difference in risk of SSI (7 studies; 1012 participants; OR, 0.99; 95% CI, 0.63-1.55; P < 0.95), OWC (5 studies; 824 participants; OR, 0.92; 95% CI, 0.46-1.86; P < 0.82), and adverse event relative to antibiotic administration (3 studies; 653 participants; OR, 0.23; 95% CI, 0.01-4.92; P < 0.35). CONCLUSIONS: This meta-analysis of RCTs provides evidence supporting that antibiotic prophylaxis reduced postoperative SSI in clean plastic surgeries with high-risk factors and clean-contaminated plastic surgeries. Besides, a short-course administration regimen seemed to be of adequate efficacy and safety. High-quality prospective trials on larger scale are needed to further confirm these findings. PMID- 24343321 TI - Urogynecology digest : presented by J. Oliver Daly. PMID- 24343322 TI - Responsiveness of the double limb lowering test and lower abdominal muscle progression to core stabilization exercise programs in healthy adults: a pilot study. AB - Low back pain (LBP) is one of the most prevalent and expensive health care problems in the United States. Studies suggest that stabilization exercise may be effective in the management of people with LBP. To accurately assess the effect of stabilization programs on muscle performance, clinicians need an objective measure that is both valid and reliable. The purpose of this study was to determine whether the double limb lowering test (DLLT) and lower abdominal muscle progression (LAMP) can detect a change in abdominal muscle performance after stabilization exercises. Eleven healthy participants (4 men and 7 women) were randomly assigned to either a specific stabilization exercise (SSE) or general stabilization exercise (GSE) group and were evaluated by the DLLT and LAMP before, during, and at the end of 8 weeks of training. Subjects attended exercise sessions twice per week over 8 weeks. No significant difference in pretest performance existed between the 2 groups. No significant difference was detected with the DLLT for either the SSE or GSE over time or when groups were combined. The LAMP detected a significant difference for the combined groups and GSE but not SSE over time. These data indicate that the LAMP is sensitive to change after a spinal stabilization program, whereas the DLLT does not detect a change after these programs. Furthermore, the GSE was more effective in producing these changes. Additional testing of these assessments is necessary to further validate these tests and to identify specific populations for which these tests may be most appropriate. PMID- 24343323 TI - Chronic psychological stress impairs recovery of muscular function and somatic sensations over a 96-hour period. AB - The primary aim of this study was to determine whether chronic mental stress moderates recovery of muscular function and somatic sensations: perceived energy, fatigue, and soreness, in a 4-day period after a bout of strenuous resistance exercise. Undergraduate resistance training students (n = 31; age, 20.26 +/- 1.34 years) completed the Perceived Stress Scale and the Undergraduate Stress Questionnaire, a measure of life event stress. At a later visit, they performed an acute heavy-resistance exercise protocol (10 repetition maximum [RM] leg press test plus 6 sets: 80-100% of 10RM). Maximal isometric force (MIF), perceived energy, fatigue, and soreness were assessed in approximately 24-hour intervals after exercise. Recovery data were analyzed with hierarchical linear modeling growth curve analysis. Life event stress significantly moderated linear (p = 0.027) and squared (p = 0.031) recovery of MIF. This relationship held even when the model was adjusted for fitness, workload, and training experience. Perceived energy (p = 0.038), fatigue (p = 0.040), and soreness (p = 0.027) all were moderated by life stress. Mean perceived stress modulated linear and squared recovery of MIF (p < 0.001) and energy (p = 0.004) but not fatigue or soreness. In all analyses, higher stress was associated with worse recovery. Stress, whether assessed as life event stress or perceived stress, moderated the recovery trajectories of muscular function and somatic sensations in a 96-hour period after strenuous resistance exercise. Therefore, under conditions of inordinate stress, individuals may need to be more mindful about observing an appropriate length of recovery. PMID- 24343324 TI - The ACTN3 R577X polymorphism is associated with muscle power in male Japanese athletes. AB - In this study, we investigated whether the ACTN3 R577X polymorphism is associated with muscular power in Japanese collegiate athletes by analyzing the mean and peak power results of a 30-second Wingate anaerobic test (WAnT) with respect to the ACTN3 R577X genotype in 253 Japanese athletes (144 men and 109 women). Each athlete performed a 30-second WAnT with a resistance equal to 7.5% of his or her body weight. Genotyping for the ACTN3 R577X (rs1815739) polymorphism was performed using the TaqMan approach. The ACTN3 R577X genotypes exhibited a Hardy Weinberg equilibrium distribution in our population. The relative and absolute mean power results of the 30-second WAnT did not differ significantly among the genotypes. However, the relative peak power result of the WAnT was significantly higher in the R-allele-dominant model groups than in the XX group in male but not female athletes. These results suggest that the ACTN3 R allele is associated with the relative peak power during the WAnT in male Japanese collegiate athletes. PMID- 24343325 TI - Optimal recovery time for postactivation potentiation in professional soccer players. AB - Resistance exercise may acutely enhance muscle contractile activity, which is known as postactivation potentiation (PAP). Postactivation potentiation augments important skills that require power production that are necessary during soccer performance. The aim of this study was to determine the optimal recovery time to elicit PAP after a bout of high-intensity resistance exercise in professional soccer players. Twenty-two senior professional soccer players (mean [SD]; age, 23 [4.5] years; stature, 1.83 [6.6] m; body mass, 80.9 [7.8] kg) were randomized to either an experimental (n = 11) or a control group (n = 11). Both groups performed a standardized warm-up and baseline countermovement jump (CMJ) followed by a 10-minute recovery. The control group then performed a CMJ at 15 seconds and at 4, 8, 12, 16, and 20 minutes, whereas the experimental group performed a 3 repetition maximum (RM) squat and then an identical CMJ protocol. No significant differences were found between the groups for CMJ peak power (p > 0.05) or jump height (p > 0.05). No time effect for peak power (F(6,60) = 2.448; p = 0.063) or jump height (F(6,60) = 2.399; p = 0.089) was observed throughout the experimental group trials. Responders (n = 6) displayed individualized PAP profiles at 4 (n = 3), 12 (n = 1), and 16 (n = 2) minutes after conditioning contraction, whereas nonresponders (n = 5) did not. A set of 3RM squats failed to acutely potentiate all participants CMJ performance. Both PAP responders and nonresponders were identified and have individualized PAP time constants. This is not consistent with the previous literature, which used identical protocols. Strength and conditioning practitioners need to individualize recovery "windows" and identify athletes who respond to PAP before undertaking a complex training intervention. PMID- 24343326 TI - A microcycle of inflammation following a team handball game. AB - This study investigated the time-course of performance and inflammatory responses during a simulated 6-day in-season microcycle following a team handball (TH) game. Twenty-four handball players participated in a 1-week control trial and in an experimental trial (TH game participation followed by a 6-day training microcycle). Concentrations of lactate, glucose, glycerol, triglycerides, nonesterified fatty acids (NEFAs), and ammonia were measured pregame and postgame. Heart rate (HR) was monitored during the game. Performance (jumping, speed, agility, line-drill testing, and strength), muscle damage (knee range of motion [ROM], knee extensors/flexors delayed onset muscle soreness [DOMS], and creatine kinase activity [CK]), inflammatory (leukocyte count, C-reactive protein, interleukins 1beta and 6 [IL-1beta and IL-6], soluble vascular adhesion molecule 1 [sVCAM-1], p-selectin, uric acid, cortisol, and testosterone), and oxidative stress (malondialdehyde [MDA], protein carbonyls [PC], reduced [GSH] and oxidized glutathione [GSSG], total antioxidant capacity (TAC), catalase, glutathione peroxidase activity [GPX]) markers were determined pregame, postgame, and daily for 6 consecutive days postgame. The game induced a marked rise of HR (~170 b.min-1), lactate (~8-fold), glycerol (60%), NEFA (105%), and ammonia (~62%). Performance deteriorated until 24 hours postgame. Knee ROM decreased (3 5%), whereas DOMS and CK increased (3- to 5-fold and 80-100%, respectively) 24 hours postgame. Leukocyte count, IL-1beta, IL-6, cortisol, MDA, PC, and catalase increased only immediately postgame. C-reactive protein and uric acid increased at 24 hours; sVCAM-1, GSSG, and GPX peaked postgame and remained elevated for 24 hours. The GSH declined until 24 hours postgame. Results suggest that a TH game represents a strong metabolic challenge and induces a short-lived and modest inflammatory response that may affect performance for as long as 24 hours postgame. PMID- 24343327 TI - Neutral spine control exercises in rehabilitation after lumbar spine fusion. AB - Lumbar spine fusion (LSF) has been reported to change the biomechanics of the spine and therefore the rehabilitation after LSF is important. In this study, the effect of selected neutral spine control exercises on activation of trunk muscles after LSF was evaluated. Muscle activity was measured by surface electromyography of the rectus abdominis, external oblique, longissimus, and multifidus muscles during 6 exercises in 22 LSF patients (mean age = 59 years; age range = 25-84 years; 50% women). Muscle activity concurrent with trunk flexion and extension during maximal voluntary isometric contraction (MVIC) was used as a reference value. Pain during the effort was assessed with a visual analog scale (VAS). The highest activity in the rectus abdominis muscles was measured during bilateral shoulder extension (51% of MVIC), and in the external oblique, it occurred during unilateral shoulder horizontal adduction (48% of MVIC) and unilateral hip extension (46% of MVIC) exercises. The highest activation of the multifidus and longissimus muscles (60-104%) was measured during bilateral shoulder flexion and modified Roman chair exercises. The mean (SD) self-reported back pain VAS scores during exercises varied from 3 (7) to 16 (26). Neutral spine control exercises activate trunk muscles and cause minimal pain and are therefore feasible exercises for home-based training to improve muscle endurance and postural control after LSF. In addition, the level of muscle activity during bilateral shoulder flexion and modified Roman chair exercises was over 60% of MVIC, justifying their use in training for strength of the trunk extensor muscles. PMID- 24343328 TI - The effect of acute fluid consumption following exercise-induced fluid loss on hydration status, percent body fat, and minimum wrestling weight in wrestlers. AB - Acute fluid consumption (approximately 1 L) has been shown to reduce urine specific gravity (Usg) among subjects after an overnight fast, yet it is unknown if Usg may be reduced among subjects who have experienced exercise-induced fluid loss. The purpose of this study was to examine the effect of acute fluid consumption on Usg, body mass, percent body fat (%BF), and minimum wrestling weight (MWW) following an exercise-induced fluid loss protocol. National Collegiate Athletic Association coaches' perceptions of the weight certification program (WCP) were also evaluated. Twelve men wrestlers (19.8 +/- 1.14 years) were tested prepractice (PRE), postpractice (POST), and 1 hour after consuming 1 L of water (PFC). Percent body fat was measured by skinfolds (SF), air displacement plethysmography (ADP), and multifrequency and leg-to-leg bioelectrical impedance analysis to calculate MWW. Urine specific gravity measurements significantly increased above PRE (1.013 +/- 0.006) at the POST (1.019 +/- 0.007; p = 0.017) and PFC (1.022 +/- 0.008; p = 0.025) assessments; however, POST and PFC were not significantly different (p = 0.978) from one another. The %BF values were similar (p > 0.05) at each assessment point when using SF and ADP. When compared with PRE, MWW significantly reduced at the POST assessment when using SF (67.2 +/- 8.4 vs. 65.7 +/- 8.2 kg; p < 0.001) and ADP (66.6 +/- 9.1 vs. 64.8 +/- 9.0 kg; p = 0.001), reflecting the reduction in body mass observed after exercise. Forty-seven National Collegiate Athletic Association coaches completed the questionnaire and 2 central themes emerged: (a) concerns with the 1.5% weight loss plan and (b) wrestlers using strategies in an attempt to circumvent the WCP. Exercise-induced fluid loss followed by acute fluid consumption equal to 1 L was ineffective in reducing Usg. PMID- 24343329 TI - Pacing strategy determinants during a 10-km running time trial: contributions of perceived effort, physiological, and muscular parameters. AB - The purpose of this study was to identify the main determinants of the self selected pacing strategy during a 10-km running time trial. Twenty eight male long-distance runners performed the following tests: (a) maximal incremental treadmill test, (b) economy running test, (c) maximum dynamic strength test, and (d) 10-km running time trial on an outdoor track. A stepwise multiple regression model was used to identify the contribution of rating of perceived exertion (RPE), physiological, and muscular parameters on the pacing strategy adopted by athletes. In the start phase (first 400 m), RPE accounted for 72% (p = 0.001) of the pacing variance. Peak treadmill speed (PTS) measured during a maximal incremental test explained 52% (p = 0.001) of the pacing variance during the middle phase (400-9,600 m), whereas maximal oxygen uptake and maximum dynamic strength accounted for additional 23% (p = 0.002) and 5% (p = 0.003), respectively. In the end phase (last 400 m), PTS accounted alone for 66% (p = 0.003) of the pacing variance. These data suggest that predictors of the pacing strategy during a 10-km running time trial have a transitional behavior from perceptive (start phase) to muscular and physiological factors (middle and end phases). PMID- 24343330 TI - A profile of a National Football League team. AB - The purpose of this study was to document the physical profiles of players on the 2011 New York Giants (NYG) team and to make comparisons with the historical literature on previous National Football League (NFL) player profiles. In this study, height, body mass (BM), body fat percentage (BF%) using skinfold measurements, and several predicted 1 repetition maximal strength and power measures in 30 returning players from the 2011 NYG team, who recently won the Super Bowl, were collected. Players were grouped by position: running back, quarterback (QB), wide receiver (WR), tight end, offensive lineman (OL), defensive lineman (DL), linebacker (LB), and defensive back (DB). Pooled and weighted mean differences (NYG - NFL) and effect sizes were used to evaluate height, BM, and BF% comparisons of NYG to previous NFL studies from 1998 to 2009. The characteristics of the players as a group were: age, height, BM, BF%: 26 +/- 2 years, 183.8 +/- 9.0 cm, 144.9 +/- 20.8 kg, 14.3 +/- 5.5%, respectively. Comparisons highlight distinct position-specific dissimilarity in strength measures, BM, and BF%, which reflect current strength training, conditioning, and team play strategy. As expected, NYG positional differences were found for height (p <= 0.05), BM (p <= 0.037), BF% (p <= 0.048), bench press (p <= 0.048), inclined bench press (p <= 0.013), and squat (p <= 0.026). Anthropometrics profiles did not significantly differ from previously published trends in NFL players indicating equity in physical characteristics over the past 13 years. However, NYG LBs, DLs, OLs, QBs, and WRs trended toward less BF% but generally similar BM compared with NFL players, suggesting greater lean BM in these positions. This study adds new players' data to prototypical position-specific databases that may be used as templates for comparison of players for draft selection or physical training. PMID- 24343331 TI - The relationship between muscle action and repetition maximum on the squat and bench press in men and women. AB - The relationship between muscle action and fatigue is not well understood, especially in terms of potential sex-specific differences. The purpose of this investigation was to determine whether a different number of repetitions could be performed on the individual muscle actions of the bench press and squat in men and women. Ten resistance-trained men (n = 10; age, 25.2 +/- 1.2 years; height, 178.6 +/- 8.8 cm; weight, 91.4 +/- 18.1 kg; body fat, 12.7 +/- 3.6%) and women (n = 10; age, 25.4 +/- 2.4 years; height, 164 +/- 4.0 cm; weight, 58.45 +/- 3.3 kg; body fat, 20.8 +/- 1.5%) participated in this balanced and randomized within group study. Using 85% of a 1 repetition maximum, over the course of 3 visits, subjects performed 1 eccentric (ECC), concentric (CON), or combined (COMB) set to failure on the squat and bench press. Differences in muscle action and sex specific number of repetitions to failure were compared on the squat and bench press, where significance was p <= 0.05. Across both exercises and sex, we observed significant differences between each of the 3 muscle actions, where the number of repetitions decreased from ECC to COMB to CON. While no sex-specific differences were observed in the squat, women performed significantly more repetitions on the ECC and CON muscle actions of the bench press. Men performed more combined repetitions, however, indicating a greater reliance on the stretch shortening cycle. Different muscle actions contribute uniquely to the successful performance of a lift and fatigue. These contributions appear to differ in men and women. PMID- 24343332 TI - Itinerant magnetism in doped semiconducting beta-FeSi2 and CrSi2. AB - Novel or unusual magnetism is a subject of considerable interest, particularly in metals and degenerate semiconductors. In such materials the interplay of magnetism, transport and other Fermi liquid properties can lead to fascinating physical behavior. One example is in magnetic semiconductors, where spin polarized currents may be controlled and used. We report density functional calculations predicting magnetism in doped semiconducting beta-FeSi2 and CrSi2 at relatively low doping levels particularly for n-type. In this case, there is a rapid cross-over to a half-metallic state as a function of doping level. The results are discussed in relation to the electronic structure and other properties of these compounds. PMID- 24343333 TI - The reasons for ligand-dependent quantum yields and spectroscopic properties of platinum(II) complexes based on tetradentate O^N^C^N ligands: a DFT and TD-DFT study. AB - DFT and TD-DFT methods have been employed to theoretically investigate the properties of three recently synthesized green-emitting platinum(II) complexes (1 3) bearing tetradentate O^N^C^N ligands (O^C^N^C = 2-(4-(3,5-di-tert-butylphenyl) 6-(3-(pyridin-2-yl)phenyl)-pyridin-2-yl)phenolate and its derivatives) that have been testified to be good emitters in organic light-emitting diodes (OLEDs), especially for complex 3. The effect of the variation of the substituents on the electronic and optical properties is emphatically explored. Our calculation results reveal that the introduction of an electron-releasing group on one phenyl ring of the O^C^N^C ligand (complex 2) does not result in a distinct alteration of the spectra. However, the incorporation of the norbornane group to the O^C^N^C ligand (complex 3) leads to a blue-shift in the absorption and emission spectra as compared with 1. In addition, how the absorption and emission spectra are affected by the solvent polarity is studied. Both the absorption and the emission spectra display red-shifts of various degrees with the decrease of the solvent polarity. The different phosphorescent quantum yields of the three complexes are compared. It is reasonable to believe that the high (3)MLCT (metal-to-ligand charge transfer) contribution and high percentage of the metallic character (M(c), %) in the emission process, as well as the largest vertical transition energy for 3, result in the highest quantum efficiency. PMID- 24343334 TI - Improving emotional face perception in autism with diuretic bumetanide: a proof of-concept behavioral and functional brain imaging pilot study. AB - Clinical observations have shown that GABA-acting benzodiazepines exert paradoxical excitatory effects in autism, suggesting elevated intracellular chloride (Cl-)i and excitatory action of GABA. In a previous double-blind randomized study, we have shown that the diuretic NKCC1 chloride importer antagonist bumetanide, that decreases (Cl-)i and reinforces GABAergic inhibition, reduces the severity of autism symptoms. Here, we report results from an open label trial pilot study in which we used functional magnetic resonance imaging and neuropsychological testing to determine the effects of 10 months bumetanide treatment in adolescents and young adults with autism. We show that bumetanide treatment improves emotion recognition and enhances the activation of brain regions involved in social and emotional perception during the perception of emotional faces. The improvement of emotion processing by bumetanide reinforces the usefulness of bumetanide as a promising treatment to improve social interactions in autism. PMID- 24343335 TI - The construction and evaluation of three measures of affectionate behaviour for children with Asperger's syndrome. AB - Children with Asperger's syndrome are often reported by their parents as having difficulties communicating affection. This study aimed to develop a valid measure of affectionate behaviour that could be used to investigate and quantify these anecdotal reports and then be used in further intervention research. Using parent and expert focus groups, three measures (Affection for Others Questionnaire, Affection for You Questionnaire and General Affection Questionnaire) were developed with reference to the existing affection literature. The measures were completed by 131 parents of children with a clinician-confirmed diagnosis of Asperger's syndrome. Psychometric assessment of the measures revealed clear factor structures with high internal consistencies and significant concurrent validities. The findings suggest many children with Asperger's syndrome have difficulties with affectionate behaviour that significantly impact their daily functioning and relationships with others, signalling future research needs to develop interventions in this area. Limitations of the research are also discussed. PMID- 24343336 TI - Spin-to-charge conversion using Rashba coupling at the interface between non magnetic materials. AB - The Rashba effect is an interaction between the spin and the momentum of electrons induced by the spin-orbit coupling (SOC) in surface or interface states. Its potential for conversion between charge and spin currents has been theoretically predicted but never clearly demonstrated for surfaces or interfaces of metals. Here we present experiments evidencing a large spin-charge conversion by the Bi/Ag Rashba interface. We use spin pumping to inject a spin current from a NiFe layer into a Bi/Ag bilayer and we detect the resulting charge current. As the charge signal is much smaller (negligible) with only Bi (only Ag), the spin to-charge conversion can be unambiguously ascribed to the Rashba coupling at the Bi/Ag interface. This result demonstrates that the Rashba effect at interfaces can be used for efficient charge-spin conversion in spintronics. PMID- 24343337 TI - Prognostic significance of USP10 as a tumor-associated marker in gastric carcinoma. AB - Ubiquitin-specific protease 10 (USP10), a novel deubiquitinating enzyme, had been associated with growth of tumor cell. However, the role of USP10 in gastric cancer carcinogenesis had not been elucidated yet. The aim of this study was to investigate the expression level of USP10 in gastric carcinoma (GC) tissues and cell lines, then to evaluate the clinical significance of USP10 in GC patients. USP10, E-cadherin, Ki67 and p53 expressions were detected in 365 GC and 40 non cancerous mucosa tissues by immunohistochemistry. Western blot for USP10 was performed on additional fresh GC tissues and GC cell lines. The expression level of USP10 in GC tissues was proved lower than that in non-cancerous mucosa tissues (p < 0.05). It was also lower in GC cell lines (AGS, BGC-823 and MKN45 cells) than that in gastric epithelial immortalized cell line (GES-1). Clinicopathological analysis showed that USP10 expression was negatively correlated with gastric wall invasion (p = 0.009), nodal metastasis (p = 0.002), and TNM stage (p = 0.000). In contrast, a positively correlation between the expression of USP10 and E-cadherin was found (p < 0.05), but there was no relationship proved between Ki67, p53 and USP10 (p > 0.05). On the Kaplan-Meier survival curves, we found poor prognosis in GC patients was associated with negative USP10 expression (p < 0.05). Moreover, USP10 expression was an independent prognostic factor for the overall survival in multivariate analysis. Our findings suggested that USP10 was an independent predictor of prognosis of GC patients. PMID- 24343338 TI - Quantitative assessment of the influence of CYP1B1 polymorphisms and head and neck squamous cell carcinoma risk. AB - The associations between CYP1B1 polymorphisms and head and neck squamous cell carcinoma (HNSCC) risk have been conflicting. We therefore performed a meta analysis to derive a more precise relationship. Six published case-control studies were collected; odds ratios (ORs) with 95% confidence interval (CI) were used to assess the association between CYP1B1 Leu432Val, Asn453Ser polymorphisms, and HNSCC risk. The Sensitivity analysis and publication bias also were performed to guarantee the statistical power. Overall, the pooled OR with 95% CIs indicated that CYP1B1 Leu432Val polymorphism was significantly related with HNSCC risk (for Val vs. Leu: OR = 1.13, 95% CI = 1.03-1.25, P = 0.014, P(heterogeneity) = 0.141; for Val/Val vs. Leu/Leu: OR = 1.30, 95% CI = 1.06-1.60, P = 0.013, P heterogeneity = 0.253; for Val/Val vs. Leu/Leu + Leu/Val: OR = 1.23, 95% CI = 1.05-1.46, P = 0.013, P(heterogeneity) = 0.456). The similar results were also been found in succeeding analysis of HWE and stratified analysis of Caucasian population. Furthermore, no significant association between CYP1B1 Asn453Ser polymorphism and HNSCC risk was found in this meta-analysis. In conclusion, our meta-analysis demonstrates that CYP1B1 Leu432Val polymorphism may be a risk factor for developing HNSCC. PMID- 24343339 TI - Behavioral management for children and adolescents: assessing the evidence. AB - OBJECTIVE: Behavioral management services for children and adolescents are important components of the mental health service system. Behavioral management is a direct service designed to help develop or maintain prosocial behaviors in the home, school, or community. This review examined evidence for the effectiveness of family-centered, school-based, and integrated interventions. METHODS: Literature reviews and individual studies published from 1995 through 2012 were identified by searching PubMed, PsycINFO, Applied Social Sciences Index and Abstracts, Sociological Abstracts, Social Services Abstracts, Published International Literature on Traumatic Stress, the Educational Resources Information Center, and the Cumulative Index to Nursing and Allied Health Literature. Authors chose from three levels of evidence (high, moderate, and low) based on benchmarks for the number of studies and quality of their methodology. They also described the evidence of service effectiveness. RESULTS: The level of evidence for behavioral management was rated as high because of the number of well-designed randomized controlled trials across settings, particularly for family-centered and integrated family- and school-based interventions. Results for the effectiveness of behavioral management interventions were strong, depending on the type of intervention and mode of implementation. Evidence for school-based interventions as an isolated service was mixed, partly because complexities of evaluating group interventions in schools resulted in somewhat less rigor. CONCLUSIONS: Behavioral management services should be considered for inclusion in covered plans. Further research addressing the mechanisms of effect and specific populations, particularly at the school level, will assist in bolstering the evidence base for this important category of clinical intervention. PMID- 24343340 TI - MicroRNA-135b regulates metastasis suppressor 1 expression and promotes migration and invasion in colorectal cancer. AB - MicroRNAs (miRNAs, miRs) play important roles in pathogenesis and development of human diseases, including malignancy. Some may affect tumor progression through targeting tumor suppressor genes. MiR-135b has been shown to be upregulated in CRC. In this study, we evaluated the role of miR-135b in colorectal cancer (CRC) and its regulatory role for metastasis suppressor-1 (MTSS1) and its mechanisms. The levels of miR-135b and MTSS1 gene expression in 35 CRC and corresponding cancer-adjacent tissues, 27 colorectal adenoma, and 16 normal tissue samples were quantified using qRT-PCR and western blot analysis. The effect of miR-135b on MTSS1 expression was assessed by miR-135b mimics or inhibitor transfection to deregulate miR-135b expression. The direct interaction between them was verified by 3'-UTR dual-luciferase reporter assay. Furthermore, the roles of miR-135b in regulating CRC cells migration and invasion properties were analyzed with miR 135b mimics or inhibitor-transfected cells and silenced expression of MTSS1 in miR-135b inhibitor transfected cells. CRC tissues showed significantly upregulated miR-135b expression and reduced MTSS1 expression. High miR-135b levels were significantly associated with lymph node and distant metastasis. The miR-135b inhibitor decreased miR-135b expression and caused MTSS1 upregulation at the post-transcriptional level. However, overexpression of miR-135b caused MTSS1 protein downregulation. The 3'-UTR of MTSS1 harbored a binding site for miR-135b. Finally, miR-135b inhibitor-transfected cells exhibited markedly reduced cell migration and invasive abilities, and this effect could be reversed by MTSS1 siRNA. Our results demonstrated that miR-135b downregulated MTSS1 expression and contributed to CRC cell invasion, indicating its involvement in CRC progression. PMID- 24343341 TI - The mitochondrial cyclophilin D/p53 complexation mediates doxorubicin-induced non apoptotic death of A549 lung cancer cells. AB - Doxorubicin has displayed significant cytotoxic effects against the lung cancer cells; however, the underlying mechanisms remain inconclusive. In the current study, we provided evidence to show that mitochondrial p53 and cyclophilin D (Cyp D) complexation is required for doxorubicin-induced death of lung cancer A549 cells. Doxorubicin induced both apoptotic and non-apoptotic death of A549 cells. Cyclosporine A (CsA), the Cyp-D inhibitor, and Cyp-D silencing were prevented doxorubicin-induced non-apoptotic death of A549 cells, while cells overexpressing Cyp-D were hyper-sensitive to doxorubicin. In A549 cells, doxorubicin-activated p53, the latter translocated to mitochondria and physically interacted with Cyp D. The p53/Cyp-D mitochondrial complexation was prevented by CsA or Cyp-D silencing, or by p53 inhibitor pifithrin-alpha. Significantly, doxorubicin induced anti-tumor ability in vivo was also compromised by CsA, or when Cyp-D was silenced. Together, these data suggested that Dox-induced non-apoptotic death of A549 cells requires mitochondrial Cyp-D-p53 complexation. PMID- 24343342 TI - Molecular interactions of nanomaterials and organisms: defining biomarkers for toxicity and high-throughput screening using traditional and next-generation sequencing approaches. AB - The toxicity of nanomaterials depends on the basic interaction of the chemistry of the material with the molecular pathways in an organism. To design safe and sustainable nanomaterials, more detailed information on the molecular interaction and biochemical machinery that is altered in an organism upon contact with a nanomaterial is needed. There are a multitude of papers now on the toxicity of nanomaterials to various model organisms from human to ecological models, but many focus on acute high dose exposures and research on the toxicity of other chemicals has shown that the dose of a chemical can have a tremendous impact on the pathways that are affected within the organism. The most common pathways investigated in nanotoxicity experiments are related to oxidative stress, yet oxidative stress can be a temporary and natural response to an insult without a negative outcome. There are a multitude of other potential mechanisms that may be triggered in response to a toxin at sublethal exposures. Here we present a review documenting the evidence to date on the indicators of the molecular response to nanomaterials from in vitro and in vivo studies. Alternative pathways as indicated by single biomarker, global gene expression studies and next generation sequencing approaches are discussed as well as the impacts of nanomaterial type, dose, and the types of system studied. Specific mechanisms that are impacted by a nanomaterial can be used as the basis of better high-throughput methods for evaluating how nanomaterial chemistry impacts toxicity and support models to predict the toxicity of future nanomaterials. PMID- 24343343 TI - Cellular impact of combinations of endosulfan, atrazine, and chlorpyrifos on human primary hepatocytes and HepaRG cells after short and chronic exposures. AB - Chronic exposure to low doses of pesticides present in the environment is increasingly suspected to cause major health issues to humans. Toxicological evaluations become more complex when the exposure concerns chemical combinations. Atrazine, chlorpyrifos, and endosulfan are pesticides used worldwide in agriculture and are therefore currently found at residual levels in food and the environment, even in countries in which they are now banned. Our study aimed to use Real-Time Cell Impedance Analyzer to investigate changes in phenotypical status of primary human hepatocytes and differentiated HepaRG cells induced by short and chronic exposures to these three chemicals. In contrast to the traditionally used endpoint cytotoxicity test, this technology allows kinetic measurements in real-time throughout the entire experiment. Our data show significantly higher cytotoxic effects of mixtures as compared to individual pesticides and a greater susceptibility of human hepatocytes as compared to HepaRG to short-term exposure (24 h). Repeated exposure over 2 weeks to endosulfan and endosulfan-containing mixture induced HepaRG cell death in a time- and dose-dependent manner. Of the typical genes involved in metabolism and cell response to xenobiotics, we found an exposure time- and condition-dependent deregulation of the expression of CYP3A4 and UGT1A in HepaRG cells exposed to low doses of pesticides and mixtures. Our data demonstrate the usefulness of real time cell monitoring in long-term toxicological evaluations of co-exposure to xenobiotics. In addition, they support but at the same time highlight certain limitations in the use of HepaRG cells as the gold standard liver cell model in toxicity studies. PMID- 24343344 TI - Halogen bonds in crystal TTF derivatives: an ab initio quantum mechanical study. AB - The stabilisation energies of five ionic and neutral organic crystal structures containing various halogen bonds (I...I, Br...Br, I...Br, I...S and Br...S) were calculated using the DFT-D3 method (B97D/def2-QZVP). Besides them, the ionic I3( )...I2 and neutral I2...I2, complexes (in the crystal geometries) were also studied. The nature of the bonds was deduced from the electrostatic potential evaluated for all subsystems. In almost all the cases, the sigma-hole was positive; it was negative only for the ionic I3(-) system (although more positive than the respective belt value). The strongest halogen bonds were those that involved iodine as a halogen-bond donor and acceptor. Among ionic X...I3(-) and neutral X...I2 and X...Y dimers, the neutral X...I2 complexes were, surprisingly enough, the most stable; the highest stabilisation energy of 13.8 kcal mol(-1) was found for the I2...1,3-dithiole-2-thione-4-carboxylic acid complex. The stabilisation energies of the ionic I3(-)...I2 and neutral I2...1,3-dithiole-2 thione-4-carboxylic acid (20.2 and 20.42 kcal mol(-1), respectively) complexes are very high, which is explained by the favourable geometrical arrangement, allowing the formation of a strong halogen bond. An I...I halogen bond also exists in the neutral I2...I2 complex, having only moderate stabilisation energy (3.9 kcal mol(-1)). This stabilisation energy was, however, shown to be close to that in the optimal gas-phase L-shaped I2...I2 complex. In all the cases, the dispersion energy is important and comparable to electrostatic energy. Only in strong halogen bonds (e.g. I3(-)...I2), the electrostatic energy becomes dominant. PMID- 24343345 TI - Light extraction enhancement with radiation pattern shaping of LEDs by waveguiding nanorods with impedance-matching tips. AB - Syringe-like ZnO nanorods (NRs) were fabricated on InGaN/GaN light emitting diodes (LEDs) by a hydrothermal method. Without sacrificing the electrical performances of LEDs, syringe-like NRs can enhance light extraction capability by 10.5% at 20 mA and shape the radiation profile with a view angle collimated from 136 degrees to 121 degrees . By performing optical experiments and simulation, it is found that the superior light extraction efficiency with a more collimated radiation pattern is attributed to the waveguiding effect of NRs and the mitigation of abrupt index change by the tapered ends of syringe-like ZnO NRs. This work demonstrates the importance of the nanostructure morphology in LED performances and provides the architecture design guidelines of nanostructures to a variety of optical devices. PMID- 24343346 TI - Autophagy facilitates ventilator-induced lung injury partly through activation of NF-kappaB pathway. AB - Mechanical ventilation is an important supportive therapy in the intensive care unit (ICU) to assist the critically ill patients with respiratory failure. But longer ventilation time has been proven to contribute to the lung injury which has been recognized as ventilator-induced lung injury (VILI). Recently studies have suggested that NF-kappaB signaling pathways may play a critical role in the process of inflammation and autophagy, and autophagy can reduce the damage of VILI partly by activating the NF-kappaB pathways. Thus, we propose that autophagy may facilitate ventilator-induced lung injury partly through activation of NF kappaB pathway, which might be a new potential therapeutic target for ventilator induced lung injury. Although the exact mechanism of autophagy and its exact role in the VILI need to be further explored, at least it provides us a potential target in the future prevention of VILI. PMID- 24343348 TI - E-cigarettes and cardiovascular risk: beyond science and mysticism. AB - Cigarette smoking is the most important cause of premature death, and it is currently listed as a major independent risk factor for cardiovascular disease. Because of restrictive measures and widespread control policies, tobacco companies are now using aggressive marketing strategies in favor of smokeless tobacco, including electronic nicotine delivery systems, which are also known as electronic cigarettes or e-cigarettes. Although the regular use of these devices appears less hazardous than traditional cigarettes or other forms of smokeless tobacco, recent studies have shown that various potentially harmful substances, especially nicotine, ultraparticles, and volatile organic compounds, may be effectively inhaled or liberated in exhaled air during repeated e-cigarette puffing. This would enhance the risk of cardiac arrhythmias and hypertension, which may predispose some users to increased risk of cardiovascular events, which may be further magnified by other potential adverse effects such as arrhythmias, increased respiratory, and flow respiratory resistance. Some cases of intoxication have also been described, wherein large amounts of nicotine and other harmful compounds may be effectively absorbed. As the use of e-cigarettes is continuously rising, and it is also considered a potentially effective method for smoking cessation, more focused research is urgently needed to definitely establish the cardiovascular safeness of these devices. PMID- 24343349 TI - Behavior of acid etching on titanium: topography, hydrophility and hydrogen concentration. AB - Since acid etching is easily controlled and effective, it has become one of the most common methods of surface modification. However, the behavior of etching is seldom discussed. In this study, different surfaces of titanium were prepared by changing the etching temperature and time. Surface topography, roughness, contact angles, surface crystalline structure, hydrogen concentration and mechanical properties were observed. As a result, surface topography and roughness were more proportional to etching temperature; however, diffusion of hydrogen and tensile strength are more time-related to titanium hydride formation on the surface. Titanium becomes more hydrophilic after etching even though the micropits were not formed after etching. More and deeper cracks were found on the specimens with more hydrogen diffusion. Therefore, higher temperature and shorter time are an effective way to get a uniform surface and decrease the diffusion of hydrogen to prevent hydrogen embrittlement. PMID- 24343350 TI - Permanent supportive housing: assessing the evidence. AB - OBJECTIVES: Permanent supportive housing provides safe, stable housing for people with mental and substance use disorders who are homeless or disabled. This article describes permanent supportive housing and reviews research. METHODS: Authors reviewed individual studies and literature reviews from 1995 through 2012. Databases surveyed were PubMed, PsycINFO, Applied Social Sciences Index and Abstracts, Sociological Abstracts, Social Services Abstracts, Published International Literature on Traumatic Stress, the Educational Resources Information Center, and the Cumulative Index to Nursing and Allied Health Literature. The authors chose from three levels of evidence (high, moderate, and low) on the basis of benchmarks for the number of studies and quality of their methodology. They also described the evidence of service effectiveness. RESULTS: The level of evidence for permanent supportive housing was graded as moderate. Substantial literature, including seven randomized controlled trials, demonstrated that components of the model reduced homelessness, increased housing tenure, and decreased emergency room visits and hospitalization. Consumers consistently rated this model more positively than other housing models. Methodological flaws limited the ability to draw firm conclusions. Results were stronger for studies that compared permanent supportive housing with treatment as usual or no housing rather than with other models. CONCLUSIONS: The moderate level of evidence indicates that permanent supportive housing is promising, but research is needed to clarify the model and determine the most effective elements for various subpopulations. Policy makers should consider including permanent supportive housing as a covered service for individuals with mental and substance use disorders. An evaluation component is needed to continue building its evidence base. PMID- 24343352 TI - Novel perspectives on laboratory techniques and sport performance. PMID- 24343353 TI - Foam rolling as a recovery tool after an intense bout of physical activity. AB - PURPOSE: The objective of this study is to understand the effectiveness of foam rolling (FR) as a recovery tool after exercise-induced muscle damage, analyzing thigh girth, muscle soreness, range of motion (ROM), evoked and voluntary contractile properties, vertical jump, perceived pain while FR, and force placed on the foam roller. METHODS: Twenty male subjects (>=3 yr of strength training experience) were randomly assigned into the control (n = 10) or FR (n = 10) group. All the subjects followed the same testing protocol. The subjects participated in five testing sessions: 1) orientation and one-repetition maximum back squat, 2) pretest measurements, 10 * 10 squat protocol, and POST-0 (posttest 0) measurements, along with measurements at 3) POST-24, 4) POST-48, and 5) POST 72. The only between-group difference was that the FR group performed a 20-min FR exercise protocol at the end of each testing session (POST-0, POST-24, and POST 48). RESULTS: FR substantially reduced muscle soreness at all time points while substantially improving ROM. FR negatively affected evoked contractile properties with the exception of half relaxation time and electromechanical delay (EMD), with FR substantially improving EMD. Voluntary contractile properties showed no substantial between-group differences for all measurements besides voluntary muscle activation and vertical jump, with FR substantially improving muscle activation at all time points and vertical jump at POST-48. When performing the five FR exercises, measurements of the subjects' force placed on the foam roller and perceived pain while FR ranged between 26 and 46 kg (32%-55% body weight) and 2.5 and 7.5 points, respectively. CONCLUSION: The most important findings of the present study were that FR was beneficial in attenuating muscle soreness while improving vertical jump height, muscle activation, and passive and dynamic ROM in comparison with control. FR negatively affected several evoked contractile properties of the muscle, except for half relaxation time and EMD, indicating that FR benefits are primarily accrued through neural responses and connective tissue. PMID- 24343354 TI - Does mild hypohydration really reduce cycling endurance performance in the heat? PMID- 24343355 TI - Response. PMID- 24343356 TI - Increased physical education and muscle strength of primary school students. PMID- 24343358 TI - Id2, Id3 and Id4 overcome a Smad7-mediated block in tumorigenesis, generating TGF beta-independent melanoma. AB - The role for the inhibitors of differentiation (Ids) proteins in melanomagenesis has been poorly explored. In other cell types, Ids have been shown to contribute to cell proliferation, migration and angiogenesis and, along with a number of other genes, are direct downstream targets of the transforming growth factor (TGF)-beta pathway. Expression of Smad7, which suppress TGF-beta signaling, or synthetic TGF-beta inhibitors, was shown to potently suppress melanomagenesis. We found that endogenous Id2, Id3 and Id4 expression was elevated in 1205Lu versus 1205Lu cells constitutively expressing Smad7, indicating Ids may play a role in melanomagenesis. Therefore, the effects of Tet-inducible expression of Id2, Id3 or Id4 along with Smad7 in TGF-beta-dependent 1205Lu human melanoma cells were explored in vitro and in vivo. 1205Lu cells formed subcutaneous tumors in athymic mice, whereas cells expressing Smad7 failed to form tumors. However, 1205Lu cells expressing Smad7 along with doxycycline-induced Id2, Id3 or Id4 were able to overcome the potent tumorigenic block mediated by S7, to varying degrees. Conversely, Id small interfering RNA knockdown suppressed anchorage-independent growth of melanoma. Histology of tumors from 1205Lu cells expressing Smad7 + Id4 revealed an average of 31% necrosis, compared with 5.2% in tumors from 1205Lu with vector only. Downstream, Ids suppressed cyclin-dependent kinase inhibitors, and re-upregulated invasion and metastasis-related genes matrix metalloproteinase 2 (MMP2), MMP9, CXCR4 and osteopontin, shown previously to be downregulated in response to Smad7. This study shows that Id2, Id3 and Id4 are each able to overcome TGF-beta dependence, and establish a role for Ids as key mediators of TGF-beta melanomagenesis. PMID- 24343359 TI - Polyphenon E(R), a standardized green tea extract, induces endoplasmic reticulum stress, leading to death of immortalized PNT1a cells by anoikis and tumorigenic PC3 by necroptosis. AB - Increasing doses of Polyphenon E(r), a standardized green tea extract, were given to PNT1a and PC3 prostate epithelial cells mimicking initial and advanced stages of prostate cancer (PCa), respectively. Cell death occurred in both cell lines, with PNT1a being more sensitive [half-maximal inhibitory concentration (IC50) = 35 MUg/ml] than PC3 (IC50 = 145 MUg/ml) to Polyphenon E(r). Cell cycle arrest occurred at G0/G1 checkpoint for PNT1a, and G2/M for PC3 cells. Endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) occurred in both cell lines, with each exhibiting different timing in response to Polyphenon E(r). Autophagy was transiently activated in PNT1a cells within 12 h after treatment as a survival response to overcome ERS; then activation of caspases and cleavage of poly (ADP ribose) polymerase 1 occurred, committing cells to anoikis death. Polyphenon E(r) induced severe ERS in PC3 cells, causing a dramatic enlargement of the ER; persistent activation of UPR produced strong upregulation of GADD153/CHOP, a key protein of ERS-mediated cell death. Thereafter, GADD153/CHOP activated Puma, a BH3-only protein, committing cells to necroptosis, a programmed caspase-independent mechanism of cell death. Our results provide a foundation for the identification of novel targets and strategies aimed at sensitizing apoptosis resistant cells to alternative death pathways. PMID- 24343360 TI - Coffee consumption and risk of prostate cancer: a meta-analysis of prospective cohort studies. AB - Observational studies and animal evidence suggest an association between coffee consumption and the risk of prostate cancer. However, the results are inconsistent. We evaluated the association by conducting a meta-analysis of prospective cohort studies. PubMed and Embase were searched through June 2013 to identify studies that met predetermined inclusion criterion. A random-effects model was used to calculate the pooled risk estimates. Ten prospective cohort studies involving 8973 patients with prostate cancer and 206 096 participants were included in this systematic review. Compared with individuals who seldom or never drink coffee, the pooled relative risk of prostate cancer was 0.88 (95% confidence interval: 0.82-0.95) for regular coffee drinkers. Exclusion of any single study did not materially alter the combined risk estimate. Visual inspection of a funnel plot and Begg's and Egger's tests did not indicate evidence of publication bias. In summary, integrated evidence from prospective cohort studies supports the hypothesis that coffee consumption may decrease the risk of prostate cancer. PMID- 24343362 TI - DNA barcode authentication of saw palmetto herbal dietary supplements. AB - Herbal dietary supplements made from saw palmetto (Serenoa repens; Arecaceae) fruit are commonly consumed to ameliorate benign prostate hyperplasia. A novel DNA mini-barcode assay to accurately identify [specificity = 1.00 (95% confidence interval = 0.74-1.00); sensitivity = 1.00 (95% confidence interval = 0.66-1.00); n = 31] saw palmetto dietary supplements was designed from a DNA barcode reference library created for this purpose. The mini-barcodes were used to estimate the frequency of mislabeled saw palmetto herbal dietary supplements on the market in the United States of America. Of the 37 supplements examined, amplifiable DNA could be extracted from 34 (92%). Mini-barcode analysis of these supplements demonstrated that 29 (85%) contain saw palmetto and that 2 (6%) supplements contain related species that cannot be legally sold as herbal dietary supplements in the United States of America. The identity of 3 (9%) supplements could not be conclusively determined. PMID- 24343363 TI - Transdifferentiation of parathyroid cells into cervical thymi promotes atypical T cell development. AB - The thoracic thymus is the primary vertebrate organ for T-cell generation. Accessory cervical thymi have also been identified in humans and mice, and shown in mice to be independent functional organs that support T-cell development. However, their origin and functional significance remain unclear. Here we show that cervical thymi in mice have following two origins: delayed differentiation of endodermal precursors and transdifferentiation of parathyroid-fated cells. Compared with thoracic thymus, parathyroid-origin cervical thymi (pCT) express low levels of the thymic epithelial cell-specific transcription factor FOXN1. Consequently, pCT form a distinct microenvironment that supports an atypical thymocyte development pathway, generating T cells with unconventional phenotypic characteristics. Our data demonstrate a transdifferentiation origin for a subset of cervical thymi, with specific functional consequences for T-cell development. PMID- 24343365 TI - Synthesis, structure and spectroscopic properties of Re(I) complexes incorporating 5-arylazo-8-hydroxyquinoline: a density functional theory/time dependent density functional theory investigation. AB - Dinuclear rhenium(I) complexes having a fac-[Re(CO)3](+) moiety of general formula fac-[Re2(CO)6(hq)2] have been synthesized in excellent yield by reacting [Re(CO)5Cl] with Hhq in a ratio of 1 : 1 in toluene in an argon atmosphere. Here hq(-) is the deprotonated form of 5-phenylazo-8-hydroxyquinoline (Hhq(1)), 5-(2 naphthylazo)-8-hydroxyquinoline (Hhq(2)) and 5-(2-fluorineazo)-8-hydroxyquinoline (Hhq(3)). The reaction of synthesized dinuclear complexes with imidazole (Im) and N-methylimidazole (N-MeIm) in dry dichloromethane under argon atmosphere afforded the mononuclear complexes of general formula fac-[Re(CO)3(hq)(Im)] and fac [Re(CO)3(hq)(N-MeIm)] respectively in high yield. The elemental analysis and ESI mass spectroscopic measurements confirm the formation of the desired complexes. Molecular structures of fac-[Re(CO)3(hq(1))(Im)] and fac-[Re(CO)3(hq(1))(N-MeIm)] were confirmed by single-crystal X-ray diffraction. The complexes were also characterized by different spectroscopic techniques. The complexes displayed bathochromically shifted intramolecular charge transfer (CT) bands as compared to complexes with unsubstituted 8-hydroxyquinoline complexes. The ground and excited state geometries, NMR, absorption, and phosphorescence properties of nine Re(i) complexes were examined by DFT and TDDFT methods. The natural transition orbital (NTO) and spin density difference map analysis reveals the nature of excitations. The lowest lying triplet excited is associated with the (3)IL excited state (ligand-localized) having a cis conformation of the pendant arylazo moiety. The emission-like transition is consistent with the strong (3)ILCT character. PMID- 24343361 TI - Cancer as a metabolic disease: implications for novel therapeutics. AB - Emerging evidence indicates that cancer is primarily a metabolic disease involving disturbances in energy production through respiration and fermentation. The genomic instability observed in tumor cells and all other recognized hallmarks of cancer are considered downstream epiphenomena of the initial disturbance of cellular energy metabolism. The disturbances in tumor cell energy metabolism can be linked to abnormalities in the structure and function of the mitochondria. When viewed as a mitochondrial metabolic disease, the evolutionary theory of Lamarck can better explain cancer progression than can the evolutionary theory of Darwin. Cancer growth and progression can be managed following a whole body transition from fermentable metabolites, primarily glucose and glutamine, to respiratory metabolites, primarily ketone bodies. As each individual is a unique metabolic entity, personalization of metabolic therapy as a broad-based cancer treatment strategy will require fine-tuning to match the therapy to an individual's unique physiology. PMID- 24343364 TI - Risk of osteonecrosis in patients taking bisphosphonates for prevention of osteoporosis: a systematic review and meta-analysis. AB - SUMMARY: We aimed to systematically review observational studies evaluating use of bisphosphonates (BPs) and risk of osteonecrosis of jaw (ONJ) or other sites among non-cancer patients. INTRODUCTION: PubMed, EMBASE, and Cochrane Library were screened from database inception to Dec 2012. METHODS: Two reviewers independently identified cohort and case-control studies evaluating the use of oral or intravenous (IV) BPs and the risk of ONJ and extracted the characteristics of the studies and risk estimates. Pooled estimates of odds ratios and 95 % confidence intervals (CI) were derived by random effects meta analysis. Subgroup analyses were carried according to patients' characteristics and route of BP use. RESULTS: We identified 12 studies, including 2,652 cases and 1,571,997 controls. Use of BPs was associated with a significantly increased risk of ONJ or ON of other sites [odds ratio (OR) 2.32; 95 % CI 1.38-3.91; I (2) = 91 %]. The summary OR was 2.91 (95 % CI 1.62-5.22; I (2) = 85.9 %) for adjusted studies. Use of BPs were associated with higher risk on ONJ (OR 2.57; 95 % CI 1.37-4.84; I (2) = 92.2 %) than ON of other sites (OR 1.79; 95 % CI 0.71-4.47; I (2) = 83.3 %). Meta-regression analysis did not find design characteristics or outcome definitions to be significant sources of heterogeneity. CONCLUSION: The available evidence suggests that use of BPs in cancer patients is associated with a substantial risk for ONJ. Patients receiving IV BP are at highest risk. PMID- 24343366 TI - Response to "Letter to the editor" by Balta et al. entitled "The neutrophil lymphocyte ratio is not enough to describe inflammatory condition". PMID- 24343367 TI - From idealized clinical empathy to empathic communication in medical care. PMID- 24343368 TI - Bioconversion of corncob acid hydrolysate into microbial oil by the oleaginous yeast Lipomyces starkeyi. AB - For the first time, corncob acid hydrolysate was used for microbial oil production by the oleaginous yeast Lipomyces starkeyi. After hydrolysis by dilute sulfuric acid, corncob could turn into an acid hydrolysate with a sugar concentration of about 42.3 g/L. Detoxified by overliming and absorption with activated carbon, the corncob hydrolysate could be used by L. starkeyi efficiently that a total biomass of 17.2 g/L with a lipid content of 47.0 % (corresponding to a lipid yield of 8.1 g/L) and a lipid coefficient of 20.9 could be obtained after cultivation on the corncob hydrolysate for 8 days. Therefore, L. starkeyi is a promising strain for microbial oil production from lignocellulosic biomass. Glucose and xylose were used by L. starkeyi simultaneously during lipid fermentation while arabinose could not be utilized by it. Besides, the lipid composition of L. starkeyi was similar to that of vegetable oils; thus, it is a promising feedstock for biodiesel production. PMID- 24343369 TI - Solid-state fermentation for humic acids production by a Trichoderma reesei strain using an oil palm empty fruit bunch as the substrate. AB - Empty fruit bunch (EFB), an underutilized waste product of oil palm processing, was studied as a substrate for the production of humic acids (HA) by a Trichoderma reesei strain by solid-state fermentation (SSF) in Raimbault columns. HA have attracted the attention of many investigators due to their applications in agriculture, industry, the environment, and biomedicine. Commercial HA are currently chemically extracted from peat and coal, which are nonrenewable carbon sources. Biotechnological processes are important for their sustainable and controlled production, with SSF being especially promising for mimicking the natural habitat of fungi. Trichoderma sporulation and HA production are related, and the results of this study showed that SSF stimulated fast sporulation. The productivity related to HA was much higher than that of the biomass, indicating an efficient utilization of EFB. These findings, added to the low cost of EFB, make SSF an attractive process for HA production. PMID- 24343370 TI - Ventilation during cardiopulmonary bypass: impact on heat shock protein release. AB - AIM: Cardiopulmonary bypass (CPB), utilized in on-pump coronary artery bypass graft procedures (CABG) induces generalized immune suppression, release of heat shock proteins (HSP), inflammatory markers and apoptosis-specific proteins. We hypothesized that continued mechanical ventilation during cardiopulmonary bypass attenuates immune response and HSP liberation. METHODS: Thirty patients undergoing conventional coronary artery bypass graft (CABG) operation were randomized into a ventilated on CPB (VG; N.=15) and a non-ventilated CPB group (NVG; N.=15). Blood samples were drawn at the beginning and end of surgery, as well as on the five consecutive postoperative days (POD). Molecular markers were measured by ELISA. Data are given as mean +/- (SD). Mann-Whitney-U-test was used for statistical analysis. RESULTS: Serum concentrations of HSP70 were significantly lower in VG compared to NVG on POD-1 (VG: 1629+/-608 vs. NVG: 5203+/-2128.6 pg/mL, P<0.001). HSP27 and HSP60 depicted a minor increase in both study groups at the end of surgery without any intergroup differences (HSP27: VG 6207.9+/-1252.5 vs. NVG 7424.1+/-2632.5; HSP60: VG 1046.2+/-478.8 vs. NVG 1223.5+/-510.1). IL-8 and CK-18 M30 evidenced the highest serum concentrations at the end of surgery (IL-8: VG 119.5+/-77.9 vs. NVG 148.0+/-184.55; CK-18 M30: VG 62.1+/-39.2 vs. NVG 67.5+/-33.9) with no differences between groups. Decreased ICAM-1 serum concentrations were detected postoperatively, however ICAM-1 concentrations on POD-1 to POD-5 showed slightly elevated concentrations in both study groups with no intergroup differences. CONCLUSION: Significantly less HSP70 was detectable in patients receiving uninterrupted mechanical lung ventilation on CPB, indicating either different inflammatory response, cellular stress or cell damage between the ventilated and non-ventilated group. These data suggest that continued mechanical ventilation has a modulatory effect on the immune response in patients after CABG surgery. PMID- 24343371 TI - Coronary artery bypass graft type and outcomes in maintenance dialysis. AB - AIM: Patients with end-stage renal disease (ESRD) on maintenance dialysis have a high burden of coronary disease. Prior studies in non-dialysis patients show better outcomes in coronary artery bypass surgery using the internal mammary artery (IMA) compared with the saphenous vein graft (SVG), but less is known about outcomes in ESRD. We sought to compare the effectiveness of multivessel bypass grafting using IMA versus SVG in patients on maintenance dialysis in the United States. METHODS: Cohort study using data from the United States Renal Data System to examine IMA versus SVG in patients on maintenance dialysis undergoing multivessel coronary revascularization. We used Cox proportional hazards regression with multivariable adjustment in the full cohort and in a propensity score matched cohort. The primary outcome was death from any cause; the secondary outcome was a composite of non-fatal myocardial infarction or death. RESULTS: Overall survival rates were low in this patient population (5-year survival in the matched cohort 25.3%). Use of the IMA compared to SVG was associated with lower risk of death (adjusted hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.84-0.92) and lower risk of the composite outcome (adjusted HR 0.89; CI 0.85-0.93). Results did not materially change in analyses using the propensity score matched cohort. We found similar results irrespective of patient sex, age, race, or the presence of diabetes, peripheral vascular disease or heart failure. CONCLUSION: Although overall survival rates were low, IMA was associated with lower risk of mortality and cardiovascular morbidity compared to SVG in patients on dialysis. PMID- 24343372 TI - David operation: single center 10-year experience. AB - AIM: Aortic valve-sparing operation has been progressively widely performed for the treatment of aortic root aneurysm. Nowadays, this procedure has been proposed even in presence of a bicuspid aortic valve, severe aortic regurgitation or in primary aortic dissection repair. We present our ten-year experience focusing on mid-term echocardiographic follow-up. METHODS: Between June 2002 and February 2012, 139 patients (mean age of 61+/-12 years) underwent aortic valve-sparing operation with valve reimplantation. Twenty-seven patients (19%) had bicuspid aortic valve; in eighteen cases (13%) cusp motion or anatomical abnormalities concurred in determining aortic regurgitation and needed an adjunct cusp repair. A Gelweave ValsalvaTM graft was implanted in all the patients. RESULTS: The mortality pre-discharge was 0.7% (1 patient). The cumulative 1-year, 5-years and 8-years survival rates were 99%, 93% and 87% respectively. Postoperative aortic regurgitation more than mild degree (>2+/4+) was the only significant risk factors for redo aortic valve surgery Freedom from reoperation due to aortic valve regurgitation was 96% at 1 year, 90% at 5 years and 86% at 8 years. When comparing freedom from reoperation in patients with bicuspid vs tricuspid aortic valve, no differences were found (P=0.31) and the rate of aortic valve reoperation was significantly higher (P<0.001) in patients who received leaflet's repair. CONCLUSION: The durability of valve reimplantation was found to be excellent in patients with tricuspid aortic valve and normal or nearly normal cusps. Cusp prolapse and complication after cusp repair turned out to be the main causes for early failure. PMID- 24343373 TI - Integrated approach to evaluating the toxicity of novel cysteine-capped silver nanoparticles to Escherichia coli and Pseudomonas aeruginosa. AB - Because of microbial resistance to conventional antibiotics, there is increasing interest in silver, including silver nanoparticles (nano-Ag), in antimicrobial applications. However, questions remain regarding the relative roles of nano-Ag particles, versus Ag(+) ions released from nano-Ag dissolution, in imparting bacterial toxicity. Here, we developed a novel nano-Ag that, based on its cysteine cap, was expected to dissolve slowly and thus potentially allow for differentiating nanoparticle, versus ionic, effects of Ag. The nano-Ag was systematically tested for its differential toxicity to Escherichia coli and Pseudomonas aeruginosa. Bacterial growth, reactive oxygen species (ROS) generation, particle dissolution, cellular electron transfer activity, and cell membrane damage and potential were evaluated. In minimal growth medium, E. coli and P. aeruginosa growth were slowed at 100 mg L(-1) (0.93 mM) and 5 mg L(-1) (0.046 mM), respectively; P. aeruginosa was completely inhibited at and above 10 mg L(-1) (0.093 mM). For both strains, toxicity was associated with ROS and cell membrane damage. Based on comparisons to AgNO3 exposures, toxicity from nano-Ag was due to Ag(+) ions and not intact nano-Ag, even though nanoparticle dissolution was less than 2% in minimal growth medium. Because of their stability and slow Ag(+) ion release, the cysteine-capped nano-Ag particles here are useful to antimicrobial applications. Additionally, our systematic approach to evaluating toxicity, membrane damage, and ROS generation can be applied with other nanomaterials and bacteria. PMID- 24343374 TI - Synthesis of Mn2O3 nanomaterials with controllable porosity and thickness for enhanced lithium-ion batteries performance. AB - Mn2O3 has been demonstrated to be a promising electrode material for lithium-ion batteries. Thus, the fabrication of Mn2O3 nanomaterials with high specific capacity and cycling stability is greatly desired. Here we report a simple but effective method to synthesis Mn2O3 nanomaterials from a Mn(OH)2 precursor, which was prepared from manganese acetate in ethylene glycol and water at 180 degrees C for 12 h. The morphology and sheet thickness of Mn(OH)2 precursor could be tuned by controlling the ethylene glycol/H2O volume ratio, resulting in a further tunable morphology and sheet thickness of the porous Mn2O3 nanomaterials. In the electrochemical tests the prepared Mn2O3 nanomaterials, with the porous architecture and thin thickness exhibited a high and stable reversible capacity, indicating that both small thickness and porous sheets structure are crucial for improving the electrochemical performance of Mn2O3 in terms of specific capacity and stability. PMID- 24343375 TI - Methane oxidation activity and diversity of aerobic methanotrophs in pH-neutral and semi-neutral thermal springs of the Kunashir Island, Russian Far East. AB - Aerobic methane oxidation has been mostly studied in environments with moderate to low temperatures. However, the process also occurs in terrestrial thermal springs, where little research on the subject has been done to date. The potential activity of methane oxidation and diversity of aerobic methanotrophic bacteria were studied in sediments of thermal springs with various chemical and physical properties, sampled across the Kunashir Island, the Kuriles archipelago. Activity was measured by means of the radioisotope tracer technique utilizing (14)C-labeled methane. Biodiversity assessments were based on the particulate methane monooxygenase (pmoA) gene, which is found in all known thermophilic and thermotolerant methanotrophs. We demonstrated the possibility of methane oxidation in springs with temperature exceeding 74 degrees C, and the most intensive methane uptake was shown in springs with temperatures about 46 degrees C. PmoA was detected in 19 out of 30 springs investigated and the number of pmoA gene copies varied between 10(4) and 10(6) copies per ml of sediment. Phylogenetic analysis of PmoA sequences revealed the presence of methanotrophs from both the Alpha- and Gammaproteobacteria. Our results suggest that methanotrophs inhabiting thermal springs with temperature exceeding 50 degrees C may represent novel thermophilic and thermotolerant species of the genera Methylocystis and Methylothermus, as well as previously undescribed Gammaproteobacteria. PMID- 24343376 TI - Structural and biochemical properties of an extreme 'salt-loving' proteasome activating nucleotidase from the archaeon Haloferax volcanii. AB - In eukaryotes, the 26S proteasome degrades ubiquitinylated proteins in an ATP dependent manner. Archaea mediate a form of post-translational modification of proteins termed sampylation that resembles ubiquitinylation. Sampylation was identified in Haloferax volcanii, a moderate halophilic archaeon that synthesizes homologs of 26S proteasome subunits including 20S core particles and regulatory particle triple-A ATPases (Rpt)-like proteasome-associated nucleotidases (PAN-A/1 and PAN-B/2). To determine whether sampylated proteins associate with the Rpt subunit homologs, PAN-A/1 was purified to homogeneity from Hfx. volcanii and analyzed for its subunit stoichiometry, nucleotide-hydrolyzing activity and binding to sampylated protein targets. PAN-A/1 was found to be associated as a dodecamer (630 kDa) with a configuration in TEM suggesting a complex of two stacked hexameric rings. PAN-A/1 had high affinity for ATP (K m of ~0.44 mM) and hydrolyzed this nucleotide with a specific activity of 0.33 +/- 0.1 MUmol Pi/h per mg protein and maximum at 42 degrees C. PAN-A1 was stabilized by 2 M salt with a decrease in activity at lower concentrations of salt that correlated with dissociation of the dodecamer into trimers to monomers. Binding of PAN-A/1 to a sampylated protein was demonstrated by modification of a far Western blotting technique (derived from the standard Western blot method to detect protein protein interaction in vitro) for halophilic proteins. Overall, our results support a model in which sampylated proteins associate with the PAN-A/1 AAA+ ATPase in proteasome-mediated proteolysis and/or protein remodeling and provide a method for assay of halophilic protein-protein interactions. PMID- 24343377 TI - Morphological diversity of GABAergic and cholinergic interneurons in the striatal dorsolateral and ventromedial regions of rats. AB - The striatum plays a fundamental role in sensorimotor and cognitive functions of the body, and different sub-regions control different physiological functions. The striatal interneurons play important roles in the striatal function, yet their specific functions are not clearly elucidated so far. The present study aimed to investigate the morphological properties of the GABAergic interneurons expressing neuropeptide Y (NPY), calretinin (Cr), and parvalbumin (Parv) as well as the cholinergic interneurons expressing choline acetyltransferase (ChAT) in the striatal dorsolateral (DL) and ventromedial (VM) regions of rats using immunohistochemistry and Western blot. The present results showed that the somatic size of Cr+ was the smallest, while ChAT+ was the largest among the four types of interneurons. There was no regional difference in neuronal somatic size of all types of interneurons. Cr+ and Parv+ neurons were differentially distributed in the striatum. Moreover, Parv+ had the longest primary dendrites in the DL region, while NPY+ had the longest ones in the VM region of striatum. But there was regional difference in the length of primary dendrites of Parv. The numbers of primary dendrites of Parv+ were the largest in both DL and VM regions of striatum. Both Cr+ and Parv+ primary dendrites displayed regional difference in the striatum. Western blot further confirmed the regional differences in the protein expression level of Cr and Parv. Hence, the present study indicates that GABAergic and cholinergic interneurons might be involved in different physiological functions based on their morphological and distributional diversity in different regions of the rat striatum. PMID- 24343378 TI - Pitfalls in interpreting the patient-prosthesis mismatch outcome. PMID- 24343379 TI - Effect of glyceryl trinitrate on staphylococcus aureus growth and leukocyte activation during simulated extracorporeal circulation. AB - BACKGROUND: Previously, nitric oxide has been shown to possess antimicrobial effects. In this study, we aim to test the effect of glyceryl trinitrate (GTN) on Staphylococcus aureus growth during simulated extracorporeal circulation (SECC) and also to examine the effect of S. aureus, alone and in combination with GTN, on activation markers of the innate immune system during SECC. METHODS: In an in vitro system of SECC, we measured GTN-induced changes in markers of leukocyte activation in whole blood caused by S. aureus infestation, as well as the effect of GTN on S. aureus growth. RESULTS: GTN had no effect on S. aureus growth after 240 minutes SECC. Staphylococcus aureus reduced the expression of granulocyte Fcgamma-receptor CD32 but stimulated the expression of monocyte CD32. Staphylococcus aureus stimulated expression of some leukocyte adhesion key proteins, activation marker CD66b, lipopolysaccharide-receptor CD14, and C3b receptor CD35. Staphylococcus aureus and GTN addition induced significant increases in monocyte CD63 (lysosomal granule protein) levels. CONCLUSION: GTN does not affect S. aureus growth during SECC and has no effect on SECC-induced leukocyte activation. PMID- 24343381 TI - {CoIII2DyIII2} single molecule magnet with two resolved thermal activated magnetization relaxation pathways at zero field. AB - The new complex [Co(III)2Dy(III)2(OMe)2(teaH)2(Piv)6] in the {Co(III)2Dy(III)2} family, shows two well resolved thermal activated magnetization relaxation pathways under AC experiments in zero DC field. Fitted crystal field parameters suggest that the origin of these two pathways relies on two different excited mJ sub-levels. PMID- 24343380 TI - Phylogenetic and molecular characterization of chicken anemia virus in southern China from 2011 to 2012. AB - Chicken anemia virus (CAV) is an important pathogen that causes severe immunosuppression in young chickens. We have characterized 13 CAVs isolated from different commercial farms in southern China between 2011 and 2012. We discovered 92 variable residues compared to 37 other CAV complete genome sequences from other parts of the world listed in GenBank; these residues have not been previously observed. All of the Chinese CAV genomes that were characterized in this study had a glutamine at position 394, a hallmark of highly pathogenic CAVs. We also discovered that intra-group genetic recombination plays a role in generating genetic diversity in natural populations of CAV. The GD-J-12 isolate was a possible recombinant between GD-C-12 and GD-M-12 in the genomic region that encompassed both the coding and non-coding regions. PMID- 24343382 TI - Robust antiferromagnetic coupling in hard-soft bi-magnetic core/shell nanoparticles. AB - The growing miniaturization demand of magnetic devices is fuelling the recent interest in bi-magnetic nanoparticles as ultimate small components. One of the main goals has been to reproduce practical magnetic properties observed so far in layered systems. In this context, although useful effects such as exchange bias or spring magnets have been demonstrated in core/shell nanoparticles, other interesting key properties for devices remain elusive. Here we show a robust antiferromagnetic (AFM) coupling in core/shell nanoparticles which, in turn, leads to the foremost elucidation of positive exchange bias in bi-magnetic hard soft systems and the remarkable regulation of the resonance field and amplitude. The AFM coupling in iron oxide-manganese oxide based, soft/hard and hard/soft, core/shell nanoparticles is demonstrated by magnetometry, ferromagnetic resonance and X-ray magnetic circular dichroism. Monte Carlo simulations prove the consistency of the AFM coupling. This unique coupling could give rise to more advanced applications of bi-magnetic core/shell nanoparticles. PMID- 24343383 TI - The gap between clinical evidence and practice: venous ulcer disease. PMID- 24343384 TI - Addressing the educational needs of wound care professionals. PMID- 24343387 TI - 2014 procedure code changes. PMID- 24343388 TI - Activated chlorine dioxide solution can be used as a biocompatible antiseptic wound irrigant. AB - OBJECTIVE: The purpose of this study was to compare cosmesis at 3 to 4 months and infection in simple lacerations irrigated with normal saline (NS) versus activated chlorine dioxide (CD). DESIGN: This was a prospective, randomized trial of a convenience sample of patients. This study was approved by the institutional review board and Food and Drug Administration as a physician-sponsored trial (FDA investigational new drug no. 68762). SETTING: The study was conducted in a large urban, academic emergency department. PATIENTS: Patients aged 18 to 100 with simple, uncomplicated lacerations requiring repair that were less than 8 hours old were enrolled. INTERVENTIONS: Patients were randomized to receive either NS or CD wound irrigation. MAIN OUTCOME MEASURES: Demographics, infection, and cosmesis were analyzed and assessed. Cosmetic outcome was assessed at 3 to 4 months using a visual analog scale (VAS), wound evaluation score (WES), patient VAS (VASPt), and digital imaging VAS by 2 plastic surgeons (VASPlast). MAIN RESULTS: One hundred ninety-three patients were enrolled. Data analysis was available for 175 cases (86 NS and 89 CD). Wound infection follow-up was obtained in 74.9% of the patients. The 3- to 4-month cosmesis follow-up was 37.7% for VAS/WES, 40.0% for VASPt, and 37.7% for VASPlast. There were no significant differences in demographics, key wound characteristics, infection, adverse reactions, and cosmesis. CONCLUSION: The authors report the use of a novel antimicrobial irrigation solution. Chlorine dioxide appears to be a safe biologically acceptable antiseptic wound irrigant that does not appear to interfere with cosmetic outcomes. PMID- 24343389 TI - Dressing the split-thickness skin graft donor site: a randomized clinical trial. AB - OBJECTIVE: The primary objective of this study was to compare Aquacel (ConvaTec, Skillman, New Jersey), Allevyn (Smith & Nephew, St Petersburg, Florida), and Mediskin I (Molnlycke, Health Care AB, Gothenburg, Sweden) in the treatment of split-thickness skin graft donor sites. DESIGN: This study was performed as a prospective randomized, 3-arm, clinical study. SETTING: A clinical study performed at a hand and plastic surgery department with burn unit. PARTICIPANTS: The study included 67 adults with a total of 73 donor sites, which were on the thigh, not reharvested, and ranged between 30- and 400-cm area. INTERVENTIONS: Subjects were randomly assigned to treatment with Aquacel, Allevyn, or Mediskin I. MAIN OUTCOME MEASURES: The donor site was assessed on postoperative days 3, 14, and 21 for healing, infection, pain, impact on everyday life, ease of use, and cost. MAIN RESULTS: The obtained results demonstrate significantly faster re epithelialization for patients treated with Aquacel or Mediskin I compared with Allevyn. Regarding infections, there were no significant differences between the groups. Patients wearing Aquacel experienced significantly less pain changing the dressing and less impact on everyday life than the patients wearing Allevyn. Aquacel was shown to be significantly easier for the caregiver to use than Allevyn and Mediskin I. There is a significant difference in cost of treatment between the dressings, whereas Mediskin I is the most expensive. CONCLUSION: The authors' results support the use of Aquacel in the treatment of split-thickness skin graft donor sites. Aquacel has a low cost per unit, is user friendly, gives short healing time, and minimizes patient discomfort. PMID- 24343390 TI - The relationship between pressure ulcer prevalence, body mass index, and Braden scales and subscales: a further analysis. AB - The purpose of this study was to evaluate whether any of the Braden subscales were more strongly related to pressure ulcer occurrence than the Braden total score in obese and nonobese hospitalized patients. The authors investigated whether defining high risk for the total Braden score of 16 or less was associated with pressure ulcer occurrence. PMID- 24343391 TI - Disney resort plays host to the 28th annual Clinical Symposium. PMID- 24343392 TI - Chronic venous leg ulcers: is topical zinc the answer? A review of the literature. AB - PURPOSE: To enhance the learner's competence with knowledge of research data on topical zinc for treatment of chronic leg ulcers. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant should be better able to: ABSTRACT: Venous leg ulcers (VLUs) are chronic leg wounds that can have a debilitating effect on the physical and psychological health of patients. Older patients, who are a vulnerable group, suffer from VLUs more frequently, and the prevalence of these ulcers increases as the population ages. Venous leg ulcers also pose a serious cost to the healthcare industry. Zinc, in the form of topical creams and lotions, has been used in wound care for more than 3,000 years and is now contained in a variety of wound care products that are used in the treatment of chronic VLUs. OBJECTIVE: The aim of this review was to examine the current empirical evidence to assess if topical zinc-based wound products are effective in promoting the healing of VLUs. METHODS: Following a systematic search and review of the literature, based on selected keywords, 11 studies were identified as being relevant, and data were extracted using content analysis. RESULTS: The results show that there is currently very poor-quality evidence to suggest that topical zinc-based wound products are effective in healing VLUs, either in conjunction with compression therapy, as compression bandages themselves, or as a topical skin protectant. Some of the studies were sponsored by industry, which challenges the validity and reliability of their results. CONCLUSIONS: It is apparent that not only was much of the literature conducted on a small scale, it is also outdated and methodologically inconsistent. There is scant high-quality evidence to suggest that topical zinc-based wound products are effective in promoting the healing of VLUs. New studies are urgently needed that are larger, scientifically rigorous, and without bias from industry. This will enable clinicians to implement evidenced-based practice and choose the most appropriate wound management product to improve patient care and reduce the costs of healthcare. PMID- 24343394 TI - Meaningful reports drive process improvement: part 3. PMID- 24343396 TI - Vitamin D and calcium supplementation to prevent fractures in adults. PMID- 24343397 TI - Vitamin D and calcium supplementation to prevent fractures in adults. PMID- 24343398 TI - Lack of transparency in emergency care. PMID- 24343399 TI - Methylprednisolone injections for the carpal tunnel syndrome. PMID- 24343400 TI - Obesity and serious infections. PMID- 24343401 TI - Obesity and serious infections. PMID- 24343402 TI - Web Exclusives. The consult guys: hyperglycemia: am I a control freak? PMID- 24343403 TI - ACP Journal Club. At 10 years, 55% of patients with Parkinson disease died; 23% had a good outcome. PMID- 24343404 TI - ACP Journal Club. Review: Contemporary oral contraceptives are associated with venous thromboembolism and stroke. PMID- 24343405 TI - ACP Journal Club. Review: Combined oral contraceptives are associated with venous thrombosis. PMID- 24343406 TI - ACP Journal Club. A 13-item score predicted survival to discharge with good neurologic status after CPR for in-hospital cardiac arrest. PMID- 24343407 TI - ACP Journal Club. Review: In noncardiac surgery, beta-blockers started before surgery increase 30-day mortality. PMID- 24343408 TI - ACP Journal Club. PCI in noninfarction arteries reduced cardiac events in acute STEMI with multivessel coronary disease. PMID- 24343409 TI - ACP Journal Club. HPV vaccination reduced cytologic abnormalities compared with control vaccination in young women. PMID- 24343410 TI - ACP Journal Club. Risk-stratified vs routine antithrombotics for TKA: fewer wound complications without increasing DVT. PMID- 24343411 TI - ACP Journal Club. Dabigatran increased bleeding and stroke compared with warfarin after mechanical heart valve implantation. PMID- 24343412 TI - ACP Journal Club. Review: Strength training, with or without flexibility and aerobic training, reduces pain in lower limb osteoarthritis. PMID- 24343413 TI - ACP Journal Club. Review: Glucosamine (sulfate or hydrochloride) does not reduce pain in knee or hip osteoarthritis. PMID- 24343414 TI - ACP Journal Club. Fixed-dose combination pills reduced SBP and LDL-C in patients with, or at high risk for, cardiovascular disease. PMID- 24343415 TI - Effects of histidine and N-acetylcysteine on doxorubicin-induced cardiomyopathy in rats. AB - The amino acids histidine and n-acetylcysteine have many biological activities such as antioxidant effect. The present study investigated the effects of histidine and n-acetylcysteine on the heart lesions induced by doxorubicin (DOX) in rats. Forty-eight male Wistar rats were divided into two major groups treated intraperitoneally (i.p.) with normal saline and 4 mg/kg of DOX, respectively. Each group was further divided into four subgroups that were treated with separate and combined i.p. injections of histidine and n-acetylcysteine (NAC) at a same dose of 40 mg/kg. Electrocardiography (ECG) was recorded using lead II. The heart lesions were evaluated by light microscopy. Serum levels of creatine phosphokinase and lactate dehydrogenase and heart tissue malondialdehyde levels were measured. Histidine and especially NAC at a same dose of 40 mg/kg recovered ECG changes, improved heart lesions and prevented biochemical changes induced by DOX. Co-administration of histidine and NAC showed better responses when compared with them used alone. The results of the present study showed protective effects for histidine and NAC on the heart. Reduction in free radical-induced toxic effects may be involved in cardioprotective properties of histidine and NAC. PMID- 24343416 TI - Stabilisation of MU-peroxido-bridged Fe(III) intermediates with non-symmetric bidentate N-donor ligands. AB - The spectroscopic characterisation of the (MU-1,2-peroxido)diiron(iii) species formed transiently upon reaction of [Fe(ii)(NN)3](2+) complexes with H2O2 by UV/vis absorption and resonance Raman spectroscopy is reported. The intermediacy of such species in the disproportionation of H2O2 is demonstrated. PMID- 24343417 TI - Alternate dipping preparation of biomimetic apatite layers in the presence of carbonate ions. AB - The classical simulated body fluids method cannot be employed to prepare biomimetic apatites encompassing metallic ions that lead to very stable phosphates. This is the case for heavy metals such as uranium, whose presence in bone mineral after contamination deserves toxicological study. We have demonstrated that existing methods, based on alternate dipping into calcium and phosphate ions solutions, can be adapted to achieve this aim. We have also especially studied the impact of the presence of carbonate ions in the medium as these are necessary to avoid hydrolysis of the contaminating metallic cations. Both the apatite-collagen complex method and a standard chemical (STD) method employing only mineral solutions lead to biomimetic apatites when calcium and carbonate ions are introduced simultaneously. The obtained materials were fully characterized and we established that the STD method tolerates the presence of carbonate ions much better, and this leads to homogeneous samples. Emphasis was set on the repeatability of the method to ensure the relevancy of further work performed on series of samples. Finally, osteoblasts cultured on these samples also proved a similar yield and standard-deviation in their adenosine triphosphate content when compared to commercially available substrates designed to study of such cell cultures. PMID- 24343419 TI - Physical exercise prevents suppression of hippocampal neurogenesis and reduces cognitive impairment in chemotherapy-treated rats. AB - RATIONALE: Chemotherapy, used for the treatment of cancer, often produces cognitive impairment that has been related to suppression of neurogenesis. Physical exercise, which promotes neurogenesis, is known to improve cognitive function in neurologically challenged animals and humans. It is unknown whether exercise similarly protects against chemotherapy-induced cognitive impairment and whether recovery of neurogenesis is a critical factor. OBJECTIVE: The present study investigated the relationship between hippocampal neurogenesis and cognitive performance in chemotherapy-treated rats that engaged in different amounts of physical activity. METHODS: Groups of rats, housed individually in standard cages or in specially designed cages that allowed unlimited access to a running wheel, received three injections of the chemotherapeutic drugs methotrexate and 5-fluorouracil, or equal volumes of saline. They were then administered the following cognitive tests in a water maze: (1) spatial memory (SM), (2) cued memory, (3) non-matching to sample (NMTS) rule learning; (4) delayed NMTS (DNMTS). Hippocampal neurogenesis was quantified by counting doublecortin-expressing cells in the dentate gyrus. RESULTS: Chemotherapy administered to rats in standard cages resulted in a significant reduction in hippocampal neurogenesis and impaired performance on the SM, NMTS, and DNMTS tasks. In rats receiving chemotherapy and housed in exercise cages, neurogenesis was not suppressed and cognitive performance was similar to controls. CONCLUSIONS: Physical exercise can reduce cognitive deficits that result from chemotherapy and this effect is mediated, at least in part, by preventing suppression of drug-induced hippocampal neurogenesis. The results suggest benefits of exercise in preventing or treating cognitive impairment associated with chemotherapy. PMID- 24343420 TI - Defining indications to ALPPS procedure: technical aspects and open issues. AB - The limit to surgical treatment of patients with hepatic tumors is represented by the proportion of residual hepatic parenchyma at the end of surgery (FLR, future liver remnant) that provides an estimation of the risk of postoperative liver failure. Recently, a new two-stage technique has been developed with the acronym (ALPPS) associating liver partitioning and portal vein ligation for staged hepatectomy with the aim of obtaining a more rapid and effective increase in FLR, even though indications are not clear yet. Between January and December 2012, eight patients were candidates to ALPPS at the Hepatobiliary Surgery Unit of San Raffaele Hospital, Milan. The first three patients (Series 1) underwent right trisectionectomy and were affected by tumors infiltrating biliary confluence, while the others (Series 2) were candidates to right hepatectomy for colorectal liver metastases. Two patients were then excluded from Series 2 because intraoperative finding of irresectable disease. Intra- and postoperative outcome was evaluated with the aim of defining indications to ALPPS. All patients reached an adequate FLR after a median of 7.5 days from the first procedure (rate of program completion 100 %). In Series 1 two patients developed complications related to bile leakage from the raw surface of the liver to be resected and septic events secondary to ischemic necrosis of the liver segment IV. One patient died following multi-organ failure secondary to sepsis. In Series 2 postoperative course was uneventful in all the patients, and in particular no patient showed disease progression between the two procedures or signs of postoperative liver failure. ALPPS approach was initially considered suitable for patients affected by Klatskin tumors who require, despite a small tumor volume, extended hepatectomies associated with surgery of the biliary tract: the analysis of this first series of patients has led to a re-evaluation of the indication to this strategy, as a consequence of encountered criticisms. Actually only a subset of patients affected by colorectal liver metastases are candidates to ALPPS. PMID- 24343421 TI - Karyotype evolution in monitor lizards: cross-species chromosome mapping of cDNA reveals highly conserved synteny and gene order in the Toxicofera clade. AB - The water monitor lizard (Varanus salvator macromaculatus (VSA), Platynota) has a chromosome number of 2n = 40: its karyotype consists of 16 macrochromosomes and 24 microchromosomes. To delineate the process of karyotype evolution in V. salvator macromaculatus, we constructed a cytogenetic map with 86 functional genes and compared it with those of the butterfly lizard (Leiolepis reevesii rubritaeniata (LRE); 2n = 36) and Japanese four-striped rat snake (Elaphe quadrivirgata (EQU); 2n = 36), members of the Toxicofera clade. The syntenies and gene orders of macrochromosomes were highly conserved between these species except for several chromosomal rearrangements: eight pairs of VSA macrochromosomes and/or chromosome arms exhibited homology with six pairs of LRE macrochromosomes and eight pairs of EQU macrochromosomes. Furthermore, the genes mapped to microchromosomes of three species were all located on chicken microchromosomes or chromosome 4p. No reciprocal translocations were found in the species, and their karyotypic differences were caused by: low frequencies of interchromosomal rearrangements, such as tandem fusions, or centric fissions/fusions between macrochromosomes and between macro- and microchromosomes; and intrachromosomal rearrangements, such as paracentric inversions or centromere repositioning. The chromosomal rearrangements that occurred in macrochromosomes of the Varanus lineage were also identified through comparative cytogenetic mapping of V. salvator macromaculatus and V. exanthematicus. Morphologic differences in chromosomes 6-8 between the two species could have resulted from pericentric inversion or centromere repositioning. PMID- 24343422 TI - A DFT study on the NHC catalysed Michael addition of enols to alpha,beta unsaturated acyl-azoliums. A base catalysed C-C bond-formation step. AB - The NHC catalysed nucleophilic additions of enols to alpha,beta-unsaturated acyl azolium intermediates have been investigated using DFT methods at the MPWB1K/6 31G** computational level. In the direct and the conjugate additions, formation of a hydrogen bond (HB) with the carboxyl oxygen is not sufficient to favour the C-C bond formation as a consequence of the low nucleophilic character of enols. Interestingly, when enols form a HB with the chloride counterion, the activation energies associated with the conjugate addition decrease as a consequence of the increased nucleophilic character of enols and the increased electrophilic character of the 'acyl-azolium + Cl' ion pair. Analysis of the DFT reactivity indices allows establishing a base catalysed C-C bond-formation step promoted by the chloride counterion. PMID- 24343423 TI - Pathogenesis related-10 proteins are small, structurally similar but with diverse role in stress signaling. AB - Pathogenesis related-10 proteins are small proteins with cytosolic localization, conserved three dimensional structures and single intron at 185 bp position. These proteins have a broad spectrum of roles significantly in biotic and abiotic stresses. The RNase activity, ligand binding activity, posttranslational modification (phosphorylation) and phytohormone signaling provide some information into the mechanism of the regulation of PR-10 proteins, however the presence of isoforms makes it difficult to decipher its exact mode of function. The involvement of phosphorylation/dephosphorylation events in its activation is interesting and provides unique and unbiased insights into the complexity of its regulation. Studies on upstream region of different PR-10 genes indicate the presence of cis-acting elements for WRKY, RAVI, bZ1P, ERF, SEBF and Pti4 transcription factors indicating their role in regulating PR-10 promoter. In this review, we discuss in detail the structure and mechanism of regulation of PR-10 proteins. PMID- 24343424 TI - Identification and expression profiles of prdm1 in medaka Oryzias latipes. AB - Mouse Prdm1, also known as Blimp1, plays important roles in maturation and survival of lymphoid cells, as well as in organogenesis of muscle, limb, sensor organs and primordial germ cells. The homologues of mouse prdm1 have been identified in a diverse of animals including zebrafish and fugu. Here, we report the identification and expression profiles of two homologues of prdm1, namely prdm1a and prdm1b in medaka, Oryzias latipes. The transcripts of prdm1a and prdm1b were detectable in all the tissues including immune organs such as gill, spleen, kidney, liver and intestine that we have checked on. The transcripts of prdm1a could be detected in the embryonic shield at mid-gastrula stage and later in the somite, eye, otic vesicle, branchial arches, fin, intestine and cloaca during embryogenesis using in situ hybridization. Moreover, the expression of prdm1a in the liver of both medaka and zebrafish could be up-regulated by the immune stimuli including lipopolysaccharide, polyI:C and the grass carp reovirus, similarly to the up-regulation of IL1B. These results indicate that Prdm1a may play important roles in embryogenesis and also in immune response in fish. PMID- 24343425 TI - Highly efficient plastic crystal ionic conductors for solid-state dye-sensitized solar cells. AB - We have developed highly efficient, ambient temperature, solid-state ionic conductors (SSICs) for dye-sensitized solar cells (DSSCs) by doping a molecular plastic crystal, succinonitrile (SN), with trialkyl-substituted imidazolium iodide salts. High performance SSICs with enhanced ionic conductivity (2-4 mScm 1) were obtained. High performance solid-state DSSCs with power conversion efficiency of 7.8% were fabricated using our SSICs combined with unique hierarchically nanostructured TiO2 sphere (TiO2-SP) photoelectrodes; these electrodes have significant macroporosity, which assists penetration of the solid electrolyte into the electrode. The performance of our solid-state DSSCs is, to the best of our knowledge, the highest reported thus far for cells using plastic crystal-based SSICs, and is comparable to that of the state-of-the-art DSSCs which use ionic liquid type electrolytes. This report provides a logical strategy for the development of efficient plastic crystal-based SSICs for DSSCs and other electrochemical devices. PMID- 24343426 TI - Expression, regulation and roles of miR-26a and MEG3 in tongue squamous cell carcinoma. AB - MicroRNA miR-26a and long noncoding RNA (lncRNA) MEG3 gene have been independently reported to be tumor suppressor genes in various cancers, but neither has been previously associated with tongue squamous cell carcinoma (TSCC). We report here that miR-26a and lncRNA MEG3 gene expression were both strongly reduced in TSCC compared with levels in matched nonmalignant tissues, and combined low expression levels of both miR-26a and MEG3 emerged as an independent prognostic factor for poor clinical outcome in TSCC patients. Assays in the human TSCC cell lines SCC-15 and CAL27 showed that miR-26a targets the DNA methyltransferase 3B transcript and that its inhibition may result in the upregulation of MEG3, providing a plausible link between the observed reduction of miR-26a and MEG3 in TSCC tissue. Furthermore, the overexpression of miR-26a or MEG3 in SCC-15 and CAL27 cells inhibited cell proliferation and cell cycle progression, and promoted cell apoptosis. Considering the poor prognostic outcomes associated with reduced miR-26a and MEG3, our findings imply that these factors likely play important antitumor effects in TSCC pathogenesis. Furthermore, they represent potential prognostic biomarkers for stratification of TSCC patients. PMID- 24343427 TI - Bicondylar tibial plateau fractures: assessing and treating the medial fragment. AB - Successful treatment of bicondylar tibial plateau requires focused and specific assessment and treatment of the medial fragment. Many fragment variations exist that help guide treatment. This may include posteromedial or medial plating using a variety of reduction and fixation techniques, or indirect reduction and lateral locked plating. With appropriate assessment, good results can be achieved. PMID- 24343428 TI - Postoperative complications after repair of tibial plateau fractures. AB - Tibial plateau fractures are common orthopedic injuries and represent a spectrum of injury severity defined by the fracture morphology and the associated soft tissue injury. The management of tibial plateau fractures is challenging, and patients are at risk for adverse outcomes including infection, malunion, nonunion, and stiffness. Accurate diagnosis and early management can mitigate the impact of these complications. When complications do occur, a principle-based approach outlined in this review can minimize the burden to patients in their return to function. PMID- 24343429 TI - HipA-mediated antibiotic persistence via phosphorylation of the glutamyl-tRNA synthetase. AB - Bacterial persistence has been shown to be an underlying factor in the failure of antibiotic treatments. Although many pathways, among them the stringent response and toxin-antitoxin modules, have been linked to antibiotic persistence, a clear molecular mechanism for the growth arrest that characterizes persistent bacteria remained elusive. Here, we screened an expression library for putative targets of HipA, the first toxin linked to persistence, and a serine/threonine kinase. We found that the expression of GltX, the glutamyl-tRNA-synthetase, reverses the toxicity of HipA and prevents persister formation. We show that upon HipA expression, GltX undergoes phosphorylation at Ser239, its ATP-binding site. This phosphorylation leads to accumulation of uncharged tRNA(Glu) in the cell, which results in the activation of the stringent response. Our findings demonstrate a mechanism for persister formation by the hipBA toxin-antitoxin module and provide an explanation for the long-observed connection between persistence and the stringent response. PMID- 24343430 TI - Construction of a bFGF-tethered multi-functional extracellular matrix protein through coiled-coil structures for neurite outgrowth induction. AB - In this study, an artificial multi-functional extracellular matrix (ECM) protein, tethered with a growth factor, was developed for neurite outgrowth induction. The designed ECM protein was comprised of an elastin-like peptide, as a structural unit, as well as the AG73 peptide sequence derived from the laminin and the C3 peptide sequence, which binds to neural cell adhesion molecules (derived from a synthetic peptide library) as functional units. Both AG73 and C3 have been demonstrated to promote cell adhesion and enhance neurite outgrowth. For the tethering of basic fibroblast growth factor (bFGF) to the ECM protein, helical peptides were fused to the ECM protein to form a coiled-coil helical structure with helical peptide-fused bFGF. Neurite outgrowth was induced in the PC12 cells that were cultured on this ECM protein as a result of the tethered-bFGF. Moreover, neurite outgrowth was enhanced by the AG73 and C3 peptides of the ECM protein. PMID- 24343431 TI - Al3+ selective colorimetric and fluorescent red shifting chemosensor: application in living cell imaging. AB - We report the development of a fluorescent probe based on the benzothiazole unit to monitor intracellular Al(3+) levels in living cells. The fluorescent probe exhibits a fluorescence response towards Al(3+) under physiological conditions with high sensitivity and selectivity and even facilitates naked-eye detection of Al(3+). The fluorescence intensity was significantly quenched with red shifting upon addition of 0.5 equiv. of Al(3+). The simple and cost effective receptor avails rapid detection of Al(3+) ions at concentrations as low as 0.42 MUM and is expected to be effective for the design of efficient biological sensor. PMID- 24343432 TI - Electron impact induced anion production in acetylene. AB - A detailed experimental investigation of electron induced anion production in acetylene, C2H2, in the energy range between 1 and 90 eV is presented. The anions are formed by two processes in this energy range: dissociative electron attachment (DEA) and dipolar dissociation (DD). DEA in C2H2 is found to lead to the formation of H(-) and C2(-)/C2H(-) through excitation of resonances in the electron energy range 1-15 eV. These anionic fragments are formed with super thermal kinetic energy and reveal no anisotropy in the angular distributions. DD in C2H2 leads to the formation of H(-), C(-)/CH(-) and C2(-)/C2H(-) with threshold energies of 15.7, 20.0 and 16.5 eV respectively. The measured anion yields have been used to calculate anion production rates for H(-), C(-)/CH(-) and C2(-)/C2H(-) in Titan's ionosphere. PMID- 24343433 TI - Using a portable terahertz spectrometer to measure the optical properties of in vivo human skin. AB - Terahertz (THz) time-domain spectroscopy systems permit the measurement of a tissue's hydration level. This feature makes THz spectrometers excellent tools for the noninvasive assessment of skin; however, current systems are large, heavy and not ideal for clinical settings. We previously demonstrated that a portable, compact THz spectrometer permitted measurement of porcine skin optical properties that were comparable to those collected with conventional systems. In order to move toward human use of this system, the goal for this study was to measure the absorption coefficient (MUa) and index of refraction (n) of human subjects in vivo. Spectra were collected from 0.1 to 2 THz, and measurements were made from skin at three sites: the palm, ventral and dorsal forearm. Additionally, we used a multiprobe adapter system to measure each subject's skin hydration levels, transepidermal water loss, and melanin concentration. Our results suggest that the measured optical properties varied considerably for skin tissues that exhibited dissimilar hydration levels. These data provide a framework for using compact THz spectrometers for clinical applications. PMID- 24343434 TI - Feasibility of skin surface elastography by tracking skin surface topography. AB - Recent advances have led to a multitude of image modalities being used for visualization of tissue stiffness. High-resolution images of tissue stiffness are desirable, as they have the potential to provide useful diagnostic information. A noncontact optical imaging method has the attractions of low cost, simplicity, and utility when skin contact is undesirable. However, previous optical techniques have required the application of paint or ink to the surface of the skin and so have required contact. Therefore, the present study assessed the feasibility of tracking skin surface topography to produce elastograms. The study showed, by analyzing a variety of silicone skin surface replicas from various body sites of subjects of different ages, that skin surface elastography by tracking surface topography would be feasible. The study further showed that the quality of the strain images can be optimized by measuring skin line pattern frequency. Skin samples with high skin line frequency will achieve best spatial resolution, in the order of 1 mm, comparable to contact techniques reported previously. A mechanically inhomogeneous silicone replica was then imaged, illustrating the technique's ability to detect strain contrast. Finally, the feasibility of implementing the technique in vivo was illustrated using a single pigmented skin lesion. PMID- 24343435 TI - Infrared skin damage thresholds from 1319-nm continuous-wave laser exposures. AB - A series of experiments were conducted in vivo using Yucatan miniature pigs (Sus scrofa domestica) to determine thermal damage thresholds to the skin from 1319-nm continuous-wave Nd:YAG laser irradiation. Experiments employed exposure durations of 0.25, 1.0, 2.5, and 10 s and beam diameters of ~0.6 and 1 cm. Thermal imagery data provided a time-dependent surface temperature response from the laser. A damage endpoint of fifty percent probability of a minimally visible effect was used to determine threshold for damage at 1 and 24 h postexposure. Predicted thermal response and damage thresholds are compared with a numerical model of optical-thermal interaction. Resultant trends with respect to exposure duration and beam diameter are compared with current standardized exposure limits for laser safety. Mathematical modeling agreed well with experimental data, predicting that though laser safety standards are sufficient for exposures <10 s, they may become less safe for very long exposures. PMID- 24343436 TI - Separating spectral mixtures in hyperspectral image data using independent component analysis: validation with oral cancer tissue sections. AB - Recently, hyperspectral imaging (HSI) systems, which can provide 100 or more wavelengths of emission autofluorescence measures, have been used to delineate more complete spectral patterns associated with certain molecules relevant to cancerization. Such a spectral fingerprint may reliably correspond to a certain type of molecule and thus can be treated as a biomarker for the presence of that molecule. However, the outcomes of HSI systems can be a complex mixture of characteristic spectra of a variety of molecules as well as optical interferences due to reflection, scattering, and refraction. As a result, the mixed nature of raw HSI data might obscure the extraction of consistent spectral fingerprints. Here we present the extraction of the characteristic spectra associated with keratinized tissues from the HSI data of tissue sections from 30 oral cancer patients (31 tissue samples in total), excited at two different wavelength ranges (330 to 385 and 470 to 490 nm), using independent and principal component analysis (ICA and PCA) methods. The results showed that for both excitation wavelength ranges, ICA was able to resolve much more reliable spectral fingerprints associated with the keratinized tissues for all the oral cancer tissue sections with significantly higher mean correlation coefficients as compared to PCA (p<0.001). PMID- 24343438 TI - Nanosecond ratio imaging of redox states in tumor cell spheroids using light sheet-based fluorescence microscopy. AB - A new concept of three-dimensional imaging of tumor cell spheroids by light sheet based fluorescence microscopy and nanosecond ratio imaging is described. Due to its low light dose and alternative excitation by two laser wavelengths (391 and 470 nm), this method maintains cell viability and permits recording of real-time kinetics. A genetically encoded sensor permits measurement of the redox state of glutathione and visualization of the impact of oxygen radicals. The pharmaceutically relevant system is tested upon addition of an oxidizing agent (H2O2), as well as upon addition of the apoptosis-inducing agent staurosporine. PMID- 24343437 TI - Indocyanine green enhanced co-registered diffuse optical tomography and photoacoustic tomography. AB - To overcome the intensive light scattering in biological tissue, diffuse optical tomography (DOT) in the near-infrared range for breast lesion detection is usually combined with other imaging modalities, such as ultrasound, x-ray, and magnetic resonance imaging, to provide guidance. However, these guiding imaging modalities may depend on different contrast mechanisms compared to the optical contrast in the DOT. As a result, they cannot provide reliable guidance for DOT because some lesions may not be detectable by a nonoptical modality but may have a high optical contrast. An imaging modality that relies on optical contrast to provide guidance is desirable for DOT. We present a system that combines a frequency-domain DOT and real-time photoacoustic tomography (PAT) systems to detect and characterize deeply seated targets embedded in a turbid medium. To further improve the contrast, the exogenous contrast agent, indocyanine green (ICG), is used. Our experimental results show that the combined system can detect a tumor-mimicking phantom, which is immersed in intralipid solution with the concentrations ranging from 100 to 10 MUM and with the dimensions of 0.8 cm * 0.8 cm * 0.6 cm, up to 2.5 cm in depth. Mice experiments also confirmed that the combined system can detect tumors and monitor the ICG uptake and washout in the tumor region. This method can potentially improve the accuracy to detect small breast lesions as well as lesions that are sensitive to background tissue changes, such as the lesions located just above the chest wall. PMID- 24343439 TI - In vivo full-field en face correlation mapping optical coherence tomography. AB - A full-field optical coherence tomography (OCT) system has been developed for the purpose of performing nonscanning en face flow imaging. The light source is centered at 840 nm with a bandwidth of 50 nm resulting in an axial resolution of 8 MUm in air. Microscope objectives with a numerical aperture of 0.1 were incorporated giving a transverse resolution of 5 MUm. A magnification of 5.65 was measured, resulting in a field of view of 1260*945 MUm. Pairs of interference fringe images are captured with opposing phase and a two-step phase image reconstruction method is applied to reconstruct each en face image. The OCT frame rate is 10 Hz. A two-dimensional cross-correlation technique is applied to pairs of consecutive en face images in order to distinguish dynamic from static light scatterers. The feasibility of the method was examined by simulating blood flow by creating a phantom with 5% intralipid solution. In vivo imaging of a Xenopus laevis tadpole was also performed in order to investigate the feasibility of imaging the vascular system. We present for what we believe to be the first time, the application of correlation mapping optical coherence tomography to full-field OCT to provide in vivo functional imaging of blood vessels. PMID- 24343440 TI - Appearance of breast cysts in planar geometry photoacoustic mammography using 1064-nm excitation. AB - In the search for improved imaging modalities for detection and diagnosis of breast cancer, a high negative prediction value is also important. Photoacoustic (optoacoustic) imaging is a relatively new technique that has high potential for visualizing breast malignancies, but little is known about the photoacoustic appearance of benign lesions. In this work, we investigate the visibility of benign breast cysts in forward-mode photoacoustic mammography using 1064-nm light, as currently applied in the Twente photoacoustic mammoscope. Results from (Monte Carlo and k-wave) simulations and phantom measurements were used to interpret results from patient measurements. There was a strong agreement among the results from simulations, phantom, and patient measurements. Depending on the absorption contrast between cyst and breast tissue, cysts were visible as either one or two confined high-contrast areas representing the front and the back of the cyst, respectively. This edge enhancement is most likely the consequence of the local sudden change in the absorbed energy density and Gruneisen coefficients. Although the current forward-mode single-wavelength photoacoustic mammoscope cannot always unambiguously discriminate cysts from malignancies, this study reveals specific features of cysts compared to malignancies, which can be exploited for discrimination of the two abnormalities in future modifications of the imager. PMID- 24343441 TI - Real-time monitoring of changes in plasma membrane potential via imaging of fluorescence resonance energy transfer at individual cell resolution in suspension. AB - A method for monitoring heterogeneity in changes of plasma membrane potential (PMP) at an individual cell resolution while in suspension, utilizing a simple and low-cost wide-field illumination arrangement, is presented. The method is modeled via HEK-293 cell line in suspension, double stained with coumarin and oxonol (donor and acceptor), which were loaded into an array of nanoliter wells, each designed to preserve the individuality of the nontethered cell it holds during vigorous biomanipulation. Depolarization of PMP was induced by high K(+) solution, reducing the proximity between the membrane fluorophores and subsequently reducing the efficiency (E%) of resonance energy transfer between them. Spatial plots of E% were produced from both images of fluorescence intensity and polarization. The spatial resolution of E% plots seem to be higher, and their contrast greater, when calculated from the polarization, rather than from the intensity of the fluorescence. PMID- 24343442 TI - Two-dimensional segmentation of the retinal vascular network from optical coherence tomography. AB - The automatic segmentation of the retinal vascular network from ocular fundus images has been performed by several research groups. Although different approaches have been proposed for traditional imaging modalities, only a few have addressed this problem for optical coherence tomography (OCT). Furthermore, these approaches were focused on the optic nerve head region. Compared to color fundus photography and fluorescein angiography, two-dimensional ocular fundus reference images computed from three-dimensional OCT data present additional problems related to system lateral resolution, image contrast, and noise. Specifically, the combination of system lateral resolution and vessel diameter in the macular region renders the process particularly complex, which might partly explain the focus on the optic disc region. In this report, we describe a set of features computed from standard OCT data of the human macula that are used by a supervised learning process (support vector machines) to automatically segment the vascular network. For a set of macular OCT scans of healthy subjects and diabetic patients, the proposed method achieves 98% accuracy, 99% specificity, and 83% sensitivity. This method was also tested on OCT data of the optic nerve head region achieving similar results. PMID- 24343444 TI - mPlum-IFP 1.4 fluorescent fusion protein may display Forster resonance energy transfer associated properties that can be used for near-infrared based reporter gene imaging. AB - Bacteriophytochrome infrared fluorescent protein (IFP) has a long emission wavelength that is appropriate for detecting pathophysiological effects via near infrared (NIR) based imaging. However, the brightness and photostability of IFP are suboptimal, although an exogenous supply of biliverdin (BV) IXalpha is able to enhance these properties. In this study, we fused a far red mPlum fluorescent protein to IFP 1.4 via a linker deoxyribonucleic acid (DNA) sequence encoding eight amino acids. The brightness of mPlum-IFP 1.4 fusion protein at the IFP emission channel was comparable to that of native IFP 1.4 protein when fusion protein and IFP 1.4 were excited by 543 and 633 nm using confocal microscopy, respectively. Visualization of IFP 1.4 fluorescence by excitation of mPlum in mPlum-IFP 1.4 fusion protein is likely to be associated with Forster resonance energy transfer (FRET). The FRET phenomenon was also predicted by acceptor photobleaching using confocal microscopy. Furthermore, the expression of mPlum IFP 1.4 fusion protein could be detected in cell culture and in xenograft tumors in the absence of BV using in vivo imaging system, although the BV was still essential for detecting native IFP 1.4. Therefore, this innovative-fluorescent fusion protein would be useful for NIR-based imaging in vitro and in vivo. PMID- 24343443 TI - Vasodilation by in vivo activation of astrocyte endfeet via two-photon calcium uncaging as a strategy to prevent brain ischemia. AB - Decreased cerebral blood flow causes brain ischemia and plays an important role in the pathophysiology of many neurodegenerative diseases, including Alzheimer's disease and vascular dementia. In this study, we photomodulated astrocytes in the live animal by a combination of two-photon calcium uncaging in the astrocyte endfoot and in vivo imaging of neurovasculature and astrocytes by intravital two photon microscopy after labeling with cell type specific fluorescent dyes. Our study demonstrates that photomodulation at the endfoot of a single astrocyte led to a 25% increase in the diameter of a neighboring arteriole, which is a crucial factor regulating cerebral microcirculation in downstream capillaries. Two-photon uncaging in the astrocyte soma or endfoot near veins does not show the same effect on microcirculation. These experimental results suggest that infrared photomodulation on astrocyte endfeet may be a strategy to increase cerebral local microcirculation and thus prevent brain ischemia. PMID- 24343445 TI - Rapid and nondestructive method for evaluation of embryo culture media using drop coating deposition Raman spectroscopy. AB - In this study, a rapid and simple method which combines drop coating deposition and Raman spectroscopy (DCDR) was developed to characterize the dry embryo culture media (ECM) droplet. We demonstrated that Raman spectra obtained from the droplet edge presented useful and characteristic signatures for protein and amino acids assessment. Using a different analytical method, scanning electron microscopy coupled with energy dispersive X-ray analysis, we further confirmed that Na, K, and Cl were mainly detected in the central area of the dry ECM droplet while sulphur, an indicative of the presence of macromolecules such as proteins, was mainly found at the periphery of the droplet. In addition, to reduce sample preparation time, different temperatures for drying the droplets were tested. The results showed that drying temperature at 50 degrees C can effectively reduce the sample preparation time to 6 min (as compared to 50 min for drying at room temperature, ~25 degrees C) without inducing thermal damage to the proteins. This work demonstrated that DCDR has potential for rapid and reliable metabolomic profiling of ECM in clinical applications. PMID- 24343446 TI - Effect of low-level laser treatment on cochlea hair-cell recovery after ototoxic hearing loss. AB - The primary cause of hearing loss includes damage to cochlear hair cells. Low level laser therapy (LLLT) has become a popular treatment for damaged nervous systems. Based on the idea that cochlea hair cells and neural cells are from same developmental origin, the effect of LLLT on hearing loss in animal models is evaluated. Hearing loss animal models were established, and the animals were irradiated by 830-nm diode laser once a day for 10 days. Power density of the laser treatment was 900 mW/cm(2), and the fluence was 162 to 194 J. The tympanic membrane was evaluated after LLLT. Thresholds of auditory brainstem responses were evaluated before treatment, after gentamicin, and after 10 days of LLLT. Quantitative scanning electron microscopic (SEM) observations were done by counting remaining hair cells. Tympanic membranes were intact at the end of the experiment. No adverse tissue reaction was found. On SEM images, LLLT significantly increased the number of hair cells in middle and basal turns. Hearing was significantly improved by laser irradiation. After LLLT treatment, both the hearing threshold and hair-cell count significantly improved. PMID- 24343447 TI - Effects of phototherapy on cartilage structure and inflammatory markers in an experimental model of osteoarthritis. AB - The aim of this study was to evaluate the effects of laser phototherapy on the degenerative modifications on the articular cartilage after the anterior cruciate ligament transection (ACLT) in the knee of rats. Eighty male rats (Wistar) were distributed into four groups: intact control group (IG), injured control group (CG), injured laser treated group at 10 J/cm(2) (L10), and injured laser treated group at 50 J/cm(2) (L50). Animals were distributed into two subgroups, sacrificed in 5 and 8 weeks postsurgery. The ACLT was used to induce knee osteoarthritis in rats. After 2 weeks postsurgery, laser phototherapy initiated and it was performed for 15 and 30 sessions. The histological findings revealed that laser irradiation, especially at 10 J/cm(2), modulated the progression of the degenerative process, showing a better cartilage structure and lower number of condrocytes compared to the other groups. Laser phototherapy was not able to decrease the degenerative process measured by Mankin score and prevent the increase of cartilage thickness related to the degenerative process. Moreover, it did not have any effect in the biomodulation of the expression of markers IL1beta, tumor necrosis factor-alpha, and metalloprotein-13. Furthermore, laser irradiated animals, at 50 J/cm(2) showed a lower amount of collagen type 1. PMID- 24343448 TI - Near-infrared stimulation on globus pallidus and subthalamus. AB - Near-infrared stimulation (NIS) is an emerging technique used to evoke action potentials in nervous systems. Its efficacy of evoking action potentials has been demonstrated in different nerve tissues. However, few studies have been performed using NIS to stimulate the deep brain structures, such as globus pallidus (GP) and subthalamic nucleus (STN). Male Sprague-Dawley rats were randomly divided into GP stimulation group (n=11) and STN stimulation group (n=6). After introducing optrodes stereotaxically into the GP or STN, we stimulated neural tissue for 2 min with continuous near-infrared light of 808 nm while varying the radiant exposure from 40 to 10 mW. The effects were investigated with extracellular recordings and the temperature rises at the stimulation site were also measured. NIS was found to elicit excitatory responses in eight out of 11 cases (73%) and inhibitory responses in three cases in the GP stimulation group, whereas it predominantly evoked inhibitory responses in seven out of eight cases (87.5%) and an excitatory response in one case in STN stimulation group. Only radiation above 20 mW, accompanying temperature increases of more than 2 degrees C, elicited a statistically significant neural response (p<0.05). The responsiveness to NIS was linearly dependent on the power of radiation exposure. PMID- 24343449 TI - Quantification of conjunctival TNF-alpha in aqueous-deficient dry eye. AB - PURPOSE: This study aimed to quantify and compare conjunctival epithelial tumor necrosis factor (NF) alpha mRNA expression in Sjogren syndrome (SS), non-Sjogren syndrome aqueous-deficient dry eye (non-SS DE), and non-dry eye (NDE) control subjects. METHODS: A total of 76 subjects were recruited for this study: 25 SS (confirmed via American-European Consensus Criteria 2002), 25 non-SS DE (confirmed by symptoms and Schirmer scores <= 10 mm), and 26 NDE. Superior and temporal bulbar conjunctival epithelial cells were collected via impression cytology. Epithelial RNA was extracted, and TNF-alpha mRNA expression was quantified by real-time quantitative polymerase chain reaction. RESULTS: The expression of TNF-alpha mRNA was found to be significantly higher in the SS group (2.48 +/- 1.79) compared to both non-SS DE (0.95 +/- 1.18; p < 0.05) and NDE (0.84 +/- 0.51; p < 0.05) groups. No difference in TNF-alpha mRNA expression was found between the non-SS DE and NDE groups (p = 0.67). CONCLUSIONS: These results demonstrate that SS-associated aqueous-deficient dry eye is associated with a significant upregulation of conjunctival epithelial TNF-alpha mRNA relative to both non-SS DE and control groups. The degree to which TNF-alpha mRNA is upregulated in SS may contribute to the severe ocular surface damage observed in these patients. PMID- 24343450 TI - A proteomic analysis of placental trophoblastic cells in preeclampsia-eclampsia. AB - To explore the proteomic changes of placental trophoblastic cells in preeclampsia eclampsia (PE), placental trophoblastic cells from normally pregnant women and women with hypertension during gestational period were prepared by laser capture microdissection (LCM), and proteins isolated from these cells were subjected to labeling and proteolysis with isotope-coded affinity tag reagent. A qualitative and quantitative analysis of the proteome expression of placental trophoblastic cells was made using two-dimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS). A total of 831 proteins in placental trophoblastic cells were identified by combined use of LCM technique and 2D LC-MS/MS. The result was superior to that of conventional two-dimensional electrophoresis method. There were marked differences in 169 proteins of placental trophoblastic cells between normally pregnant women and women with PE. Of 70 (41.4 %) proteins with more than twofold differences, 31 proteins were down-regulated, and 39 were up-regulated in placental trophoblastic cells of the woman with PE. Laminin expression in placenta trophoblastic cells of women with PE was significantly down-regulated as confirmed by Western blot analysis. These findings provide insights into the proteomic changes in placental trophoblastic cells in response to PE and may identify novel protein targets associated with the pathogenesis of PE. PMID- 24343451 TI - Using electrospray laser desorption ionization mass spectrometry to rapidly examine the integrity of proteins stored in various solutions. AB - Electrospray laser desorption ionization mass spectrometry (ELDI/MS) allows the rapid desorption and ionization of proteins from solutions under ambient conditions. In this study, we have demonstrated the use of ELDI/MS to efficiently examine the integrity of the proteins stored in various solutions before they were further used for other biochemical tests. The protein standards were prepared in the solutions containing buffers, organic salts, inorganic salts, strong acid, strong base, and organic solvents, respectively, to simulate those collected from solvent extraction, filtration, dialysis, or chromatographic separation. Other than the deposit of a drop of the sample solution on the metallic sample plate in an ELDI source, no additional sample pretreatment is needed. The sample drop was then irradiated with a pulsed laser; this led to desorption of the analyte molecules, which subsequently entered the ESI plume to undergo post-ionization. Because adjustment of the composition of the sample solution is unnecessary, this technique appears to be useful for rapidly evaluating the integrity of proteins after storage or prior to further biochemical treatment. In addition, when using acid-free and low-organic-solvent ESI solutions for ELDI/MS analysis, the native conformations of the proteins in solution could be detected. PMID- 24343453 TI - Molecularly imprinted solid-phase extraction monolithic capillary column for selective extraction and sensitive determination of safranine T in wolfberry. AB - A method was developed to sensitively determine safranine T in wolfberry by molecularly imprinted solid-phase extraction (MISPE) coupled with high performance liquid chromatography and laser-induced fluorescence detection (HPLC LIF). The MISPE capillary monolithic column was prepared by water-bath in situ polymerization, using safranine T, methacrylic acid (MAA), and ethylene dimethacrylate (EDMA) as template, functional monomer, and cross-linker, respectively. The properties of the homemade MISPE capillary monolithic column, including capacity and specificity, were investigated under optimized conditions and the morphologies of inner polymers were characterized by scanning electron microscopy (SEM). The mean recoveries of safranine T in wolfberry ranged from 91.2 % to 92.9 % and the intraday and interday relative standard deviation (RSD) values all ranged from 3.4 % to 4.2 %. Good linearity was obtained over 0.001-1.0 MUg mL(-1) (r = 0.9999) with a detection limit (S/N = 3) of 0.4 ng g(-1). Under the selected conditions, enrichment factors of over 90-fold were obtained and the extraction on the monolithic column effectively cleaned up the wolfberry matrix. The results demonstrated that the proposed MISPE-HPLC-LIF method could be applied to sensitively determine safranine T in wolfberry. PMID- 24343452 TI - Rapid method for the measurement of circulating thyroid hormones in low volumes of teleost fish plasma by LC-ESI/MS/MS. AB - Thyroid hormones are critical regulators of normal development and physiological functioning in all vertebrates. Radioimmunoassay (RIA) approaches have been the method of choice for measuring circulating levels of thyroid hormones in vertebrates. While sensitive, RIA-based approaches only allow for a single analyte measurement per assay, can lack concordance across platforms and laboratories, and can be prone to analytical interferences especially when used with fish plasma. Ongoing advances in liquid chromatography tandem mass spectrometry (LC/MS/MS) have led to substantial decreases in detection limits for thyroid hormones and other biomolecules in complex matrices, including human plasma. Despite these advances, current analytical approaches do not allow for the measurement of native thyroid hormone in teleost fish plasma by mass spectrometry and continue to rely on immunoassay. In this study, we developed a new method that allows for the rapid extraction and simultaneous measurement of total T4 (TT4) and total T3 (TT3) in low volumes (50 MUL) of fish plasma by LC/MS/MS. Methods were optimized initially in plasma from rainbow trout (Oncorhynchus mykiss) and applied to plasma from other teleost fishes, including fathead minnows (Pimephales promelas), mummichogs (Fundulus heteroclitus), sockeye salmon (Oncorhynchus nerka), and coho salmon (Oncorhynchus kisutch). Validation of method performance with T4- and T3-spiked rainbow trout plasma at 2 and 4 ng/mL produced mean recoveries ranging from 82 to 95 % and 97 to 105 %, respectively. Recovery of (13)C12-T4 internal standard in plasma extractions was: 99 +/- 1.8 % in rainbow trout, 85 +/- 11 % in fathead minnow, 73 +/- 5.0 % in mummichog, 73 +/- 1.7 % in sockeye salmon, and 80 +/- 8.4 % in coho salmon. While absolute levels of thyroid hormones measured in identical plasma samples by LC/MS/MS and RIA varied depending on the assay used, T4/T3 ratios were generally consistent across both techniques. Less variability was measured among samples subjected to LC/MS/MS suggesting a more precise estimate of thyroid hormone homeostasis in the species targeted. Overall, a sensitive and reproducible method was established that takes advantage of LC/MS/MS techniques to rapidly measure TT4 and TT3 with negligible interferences in low volumes of plasma across a variety of teleost fishes. PMID- 24343454 TI - A multiple hollow fibre liquid-phase microextraction method for the determination of halogenated solvent residues in olive oil. AB - The present paper describes a method based on the extraction of analytes by multiple hollow fibre liquid-phase microextraction and detection by ion-trap mass spectrometry and electron capture detectors after gas chromatographic separation. The limits of detection are in the range of 0.13-0.67 MUg kg(-1), five orders of magnitude lower than those reached with the European Commission Official method of analysis, with three orders of magnitude of linear range (from the quantification limits to 400 MUg kg(-1) for all the analytes) and recoveries in fortified olive oils in the range of 78-104 %. The main advantages of the analytical method are the absence of sample carryover (due to the disposable nature of the membranes), high enrichment factors in the range of 79-488, high throughput and low cost. The repeatability of the analytical method ranged from 8 to 15 % for all the analytes, showing a good performance. PMID- 24343455 TI - Hepatitis reactivation in patients with rheumatic diseases after immunosuppressive therapy--a report of long-term follow-up of serial cases and literature review. AB - The aims of this paper are to report hepatitis B virus reactivation in 12 patients with rheumatic disease undergoing immunosuppressive therapy and to evaluate whether pre-emptive antiviral therapy is necessary in patients receiving disease-modifying anti-rheumatic drugs. From January 2008 to March 2012, a total of 12 HBV-infected patients with rheumatic diseases were consecutively enrolled in the long-term follow-up. Liver function, HBV DNA, and serum aminotransferase level were tested during the follow-up. We also reviewed the published reports and summarized the clinical characteristics of HBV reactivation during immunosuppressive therapy in patients with rheumatic diseases. The medium duration of follow-up was 41 months (range 16-48). Patients were treated with prednisone, disease-modifying anti-rheumatic drugs (DMARDs) or tumor necrosis factor-alpha-blocking agents (TNFBA). HBV reactivation was only documented in two patients treated with prednisone without pre-emptive antiviral therapy. One hundred patients from literature review were identified as having HBV reactivation; 20.8 % of the patients receiving prednisone experienced HBV reactivation compared to only 4.46 and 9.52 % of patients treated with DMARDs or TNFBA, respectively. This long-term follow-up of serial cases suggests that pre emptive antiviral therapy should be administered in patients receiving prednisone therapy for rheumatic disease. In contrast, DMARDs and TNFBA are relatively safe to HBV-infected patients with rheumatic diseases. Close monitoring of HBV DNA and ALT levels is necessary in the management of HBV reactivation. PMID- 24343456 TI - Refractory hemophagocytic syndrome in systemic lupus erythematosus successfully treated with intermittent intravenous cyclophosphamide: three case reports and literature review. AB - We experienced three patients with refractory or severe hemophagocytic syndrome associated with the activity of systemic lupus erythematosus, so-called acute lupus hemophagocytic syndrome (ALHS). All patients were successfully treated with intermittent intravenous injections of cyclophosphamide (IVCY). In each patient, hemophagocytosis was found during bone marrow examination, and infectious causes of hemophagocytic syndrome were carefully excluded. Patients 1 and 2 were refractory to combination therapy with a high-dose corticosteroid and rituximab or cyclosporine and were successfully treated with additive IVCY. Patient 3 had very severe ALHS that developed after cardiac surgery but was successfully treated with a high-dose corticosteroid and IVCY. We conducted a literature review of adult ALHS and analyzed 54 cases reported from 2006 to 2013. Although the clinical and laboratory features were diverse, fever, bicytopenia or pancytopenia, and hyperferritinemia were almost universal. Including our 3 patients, a total of 16 have reportedly been treated with IVCY-containing regimens, and ALHS was successfully controlled in most of them without switching or adding other therapies. We suggest that combination therapy with IVCY and corticosteroids may be useful to treat severe or refractory ALHS. PMID- 24343457 TI - The effect of balneotherapy on chronic shoulder pain. A randomized, controlled, single-blind follow-up trial. A pilot study. AB - The effects of balneotherapy on chronic shoulder pain were studied. In this single-blind, randomized, follow-up study involving 46 patients with chronic shoulder pain, one group of patients received physiotherapy--exercise and transcutaneous electrical nerve stimulation--and the other group received balneotherapy in addition to physiotherapy for 4 weeks on 15 occasions. The following parameters were recorded before treatment (at week 0) and after treatment (at weeks 4, 7, and 13): Shoulder Pain and Disability Index (SPADI), the Short Form (36) Health Survey (SF-36) and EuroQuol-5D (EQ-5D) quality of life questionnaires, pain at rest and on movement on the visual analog scale (VAS), and active and passive range of motion. The SPADI pain, function, and total scores and the VAS scores at rest and on movement significantly improved in both groups after treatments. A greater improvement was observed in the balneotherapy group compared to the control group; regarding some parameters (VAS score on movement and SPADI function score at visit 2; VAS score at rest at visits 3 and 4), the difference between the groups was significant. The improvement of SF-36 and EQ-5D quality of life scores and the active range of motion was more pronounced in the balneotherapy group, the difference between the groups was not significant, except for EQ-5D at visit 2. Improvement of passive range of motion was not significant. Balneotherapy may have a beneficial effect on the clinical parameters and quality of life of patients with chronic shoulder pain. The number of patients should be increased. PMID- 24343458 TI - Therapy for Parkinson's disease: what is in the pipeline? AB - Despite advances in the treatment of Parkinson's disease there are still many unmet needs, including neuroprotection, treatment of motor complications, treatment of dyskinesia, treatment of psychosis, and treatment of nondopaminergic symptoms. In this review, I highlight the obstacles to develop a neuroprotective drug and some of the treatment strategies recently approved or still in clinical trials designed to meet these unmet needs. PMID- 24343459 TI - State of art imaging of the pituitary tumors. PMID- 24343460 TI - Making advanced trauma life support more effective. PMID- 24343461 TI - Proximal gastrectomy versus total gastrectomy for proximal gastric carcinoma. A meta-analysis on postoperative complications, 5-year survival, and recurrence rate. AB - OBJECTIVE: To compare proximal gastrectomy (PG) with total gastrectomy (TG) for proximal gastric carcinoma, through the 5-year survival rate, recurrence rate, postoperative complications, and long-term life quality. METHODS: The meta analysis was carried out in the General Surgery Department of the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China. We searched Medline, EMBASE, and the Cochrane Library from June to November 2012. The literature searches were carried out using medical subject headings and free text word: 'proximal gastrectomy' 'total gastrectomy' 'partial gastrectomy' 'stomach neoplasms' and 'gastric cancer'. Two different reviewers carried out the search and evaluated studies independently. RESULTS: Two randomized controlled trials and 9 retrospective studies were included. A total of 1364 patients were included in our study. Our analysis showed that there is no statistically significant difference in 5-year survival rate between PG and TG (60.9% versus 64.4%). But, the recurrence is higher in the PG group than the TG (38.7% versus 24.4%). The anastomotic stenosis rate is also higher in the PG than the TG (27.4% versus 7.4%). CONCLUSION: Proximal gastrectomy is an option for upper third gastric cancer in terms of safety. However, it is associated with high risk of reflux symptoms and anastomotic stenosis. Therefore, TG should be the first choice for proximal gastric cancer to prevent reflux symptoms. PMID- 24343462 TI - A meta-analysis of robotic-assisted pancreatectomy versus laparoscopic and open pancreatectomy. AB - OBJECTIVE: To perform a meta-analysis of eligible studies from multiple medical centers to assess the safety, feasibility, and efficacy of robotic-assisted pancreatectomy (RP). METHODS: We searched the electronic databases PubMed and EMBASE for studies comparing RP with laparoscopic pancreatectomy (LP) and open pancreatectomy (OP) for patients with pancreatic disease from June 2009 to June 2012. Continuous variables were pooled using the standardized mean difference (SMD) and odds ratio (OR), and dichotomous variables were pooled using the risk difference (RD) method. For all analyses, the 95% confidence interval (CI) was calculated. Three studies comparing RP and LP, and 4 studies comparing RP and OP were suitable for meta-analysis. RESULTS: Six published studies met the inclusion criteria. Our results showed that RP can reduce estimated blood loss and duration of hospitalization more than OP. For pancreatic fistula, there were no statistical differences between RP, OP, and LP, and no significant differences in intraoperative conversion rates between RP and LP. Robotic-assisted pancreatectomy may be able to increase microscopic negative margins of resection (R0) and spleen preserving rates. CONCLUSION: Robotic-assisted pancreatectomy was associated with increased R0 resection rates and spleen preserving rates than LP and OP. Moreover, RP can reduce estimated blood loss and duration of hospitalization more than OP. A robotic approach to pancreatectomy may be suited to patients with pancreatic disease. PMID- 24343463 TI - Morphological, biochemical, histological, and ultrastructural protective effects of misoprostol on cisplatin induced-hepatotoxicity in adult male rats. AB - OBJECTIVE: To investigate the possible protective effect of misoprostol on cisplatin-induced hepatotoxicity. METHODS: Four-equal sized groups (control, cisplatin-treated, misoprostol-treated, combined misoprostol, and cisplatin treated) adult male Wistar rats (6 each) were used in this study. Body weight, liver weight, and liver weight/body weight ratio was calculated. Blood samples were obtained from the hearts of rats to determine the levels of total serum bilirubin (TSB), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and albumin. Liver specimens were prepared for both light and electron microscopes. The study was carried out between June 2012 and April 2013 at the Anatomy Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt, and the Department of Anatomy, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia. RESULTS: A single cisplatin dose (7.5 mg/kg intraperitoneally) resulted in significant elevation of AST, ALT, and TSB serum levels, and a significant reduction of serum albumin level, body weight, liver weight, and liver weight/body weight ratio. A combination of misoprostol (200 ug/kg/day) with cisplatin improved most of the previous parameters. Examination of specimens by both light and electron microscopes revealed pericentral hepatic necrosis, periportal fibrosis, dilatation, and congestion of central vein and blood sinusoids, diminished glycogen content, degenerated mitochondria, vesicular dilated rough endoplasmic reticulum, and nuclear changes in cisplatin-treated rats. Oral intake of misoprostol with cisplatin improved many of these changes. CONCLUSION: The results indicate that misoprostol may have a protective effect on cisplatin-induced hepatotoxicity. PMID- 24343464 TI - Effects of Roselle on arterial pulse pressure and left ventricular hypertrophy in hypertensive patients. AB - OBJECTIVE: To characterize the effects of regular Roselle ingestion on blood pressure and left ventricular hypertrophy (LVH) in patients with established moderate essential hypertension. METHODS: This non-randomized quasi-experimental study was conducted in Kafr El-Shaikh, Egypt, for 8 weeks, from September 2012 to November 2012. The effects of a 4-week period of regular Roselle ingestion followed by a 4-week recovery period on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and heart rates (HR) was studied in 2 equal, gender- and age-matched groups (n=50 each; average age - 50+/-5 years) of normotensive subjects, and patients with moderate essential hypertension. Electrocardiographic assessments of LVH were also made prior to, and at the end of both treatment and recovery periods. RESULTS: Pulse pressure (PP) significantly fell from baseline values by 10.9% (normotensive group [NG]), 21.2% (hypertensive group [HG]); SBP by 10% (NG), 19.6% (HG); DBP by 9.5% (NG), 18.7% (HG), and HR by 14.6% (NG), 17.1% (HG) by the end of week 4 of treatment. Following treatment cessation, SBP, DBP, PP, and HR returned to pretreatment levels over 4 weeks. Before intervention, none of the normotensive subjects, but 14 hypertensive patients showed LVH. However, Roselle treatment was associated with regression of LVH in 10 patients with only 4 patients showing LVH after 4 weeks of treatment. This became 10 patients 4 weeks after ceasing treatment. CONCLUSION: These findings empirically suggest favorable cardiovascular effects of Roselle in patients with established moderate essential hypertension. PMID- 24343465 TI - Impact of backpack load on ventilatory function among 9-12 year old Saudi girls. AB - OBJECTIVE: To explore the backpack load as a percentile of body weight (BW) and its impact on ventilatory function including tidal volume (Vt), vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in one second (FEV1), FEV1/FVC, peak expiratory flow (PEF), and maximum voluntary ventilation (MVV) among 9-12 year old Saudi girls. METHODS: This is a prospective, experimental study of 91 Saudi girls aged between 9-12 years from primary schools in Riyadh, Saudi Arabia. The study took place in King Saud University, Riyadh, Saudi Arabia between April 2012 and May 2012. Ventilatory function was measured under 2 conditions: a free standing position without carrying a backpack, and while carrying a backpack. RESULTS: The backpack load observed was 13.8% of the BW, which is greater than the recommended limit (10% BW). All values of ventilatory function were significantly reduced after carrying the backpack (p<0.001) with the exception of FEV1/FVC (p>0.178). The reduction was observed even with the lowest backpack load (7.4% BW). CONCLUSION: A significant reduction was reported for most of the ventilatory function parameters while carrying the backpack. This reduction was apparent even with the least backpack load (7.4% BW) carried by the participants. This study recommends that the upper safe limit of backpack load carried by Saudi girls aged 9-12 years should be less than 7.4% of BW. PMID- 24343466 TI - Appraisal of antimicrobial prescribing practices of governmental and non governmental dentists for hospitals in the western region of Saudi Arabia. AB - OBJECTIVE: To scrutinize the knowledge, attitude, and antimicrobial practices in Saudi Arabian Dentistry. METHODS: In this cross-sectional survey of dentists, a self-administered questionnaire comprising of 61 questions was dispersed to the participants randomly, which included their professional profile, awareness of the current scope of antimicrobial resistance, prescribing practice, frequency of antimicrobial prescription, and sources of continuing education of antimicrobials. The study took place in the Faculty of Dentistry, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia between February and April 2013. RESULTS: Knowledge and awareness concerning specific antimicrobials, with specific oral cavity lesion was 78% for the students and interns, 80% for residents, and 95.3% for specialists. Approximately 89% of the students, interns and residents, and 98.4% of the specialists endorsed indiscriminate use of antibiotics. In addition, 93.4% of students, 90% of interns and residents, and 90.6% of specialists agreed that lack of health education is one of the contributors to overuse of antimicrobials. Moreover, 91.9% of the interns, 80% of residents, and 75.5% of specialists preferred amoxicillin + clavulanate as their first choice; however, a wide variation in the dosage frequency, and duration was observed. CONCLUSION: Participants are well aware of the significance of antimicrobial resistance, and considered that judicious use of antimicrobials is highly imperative to restrain this fiery predicament. Divergence was demonstrated between specialists and residents in prescribing practices. Institutional antimicrobial guideline was not interesting to all the respondents. This highlights the need for incessant instructive intervention in order to accomplish the prime objective of retreating antimicrobial resistance. PMID- 24343467 TI - Bone metastasis from ovarian cancer. Clinical analysis of 26 cases. AB - OBJECTIVE: To study the clinical characteristics of bone metastasis from ovarian cancer, and facilitate physicians to develop treatment strategies. METHODS: This retrospective study was carried out in the Provincial Hospital Affiliated to Shandong University, Shandong, China. Twenty-six cases of bone metastasis from ovarian cancer treated between January 2002 and May 2008 were reviewed, and the clinical data were collected. RESULTS: In the current study, the incidence of bone metastasis is 0.82%. Twelve cases of bone metastasis occurred in the cervical vertebra, 10 in the lumbar vertebra, 8 in the pelvis, 7 in the thoracic vertebra, 5 in the limbs, one in the ribs, and 2 in the sternum. Lung metastasis occurred concomitantly in 9 cases, liver metastasis in 5 cases, brain metastasis in 4 cases, splenic metastasis in 3 cases, adrenal metastasis in 2 cases, and lymphatic metastasis in 12 cases. Twenty-three cases (88.5%) of bone metastasis were detected in stage III-IV, and 3 (11.5%) in stage II (p=0.000). The survival time in cases treated using comprehensive therapy was longer than those using radiotherapy or chemotherapy alone (p=0.047). CONCLUSION: Bone metastasis from ovarian cancer is rare, however, the increasing pathological stage of ovarian cancer may add to the risk of bone metastasis, especially in the cases with lung or lymphatic metastasis. The pelvis and vertebral bone are the most common location of bone metastasis, and comprehensive treatment may improve the survival time of patients. PMID- 24343468 TI - Neonatal hemochromatosis. Case series from Bahrain. AB - OBJECTIVE: To review clinical presentations, diagnosis, response to treatment, and outcome of infants with neonatal hemochromatosis (NH). METHODS: This is a retrospective review of all cases admitted to the Pediatric Department at Salmaniya Medical Center, Manama, Bahrain between March 2008 and May 2011. The diagnosis was based on serum iron and ferritin, alpha-fetoprotein levels (AFP), liver and buccal biopsies, and abdominal MRI scan. RESULTS: Ten patients (8 males and 2 females) were diagnosed with NH. Two patients were intrauterine growth restriction (IUGR) and 6 were preterm. The median birth weight was 1.700 grams. The median age at presentation was 16 days, and at diagnosis was 23 days. Two patients had positive consanguinity. Clinical presentations of the infants were hepatosplenomegaly (n=5), ascites (n=3), and hypoglycemia (n=6). All patients had raised ferritin levels, prolonged prothrombin time, and 9 patients had high serum iron and serum AFP. Abdominal MRI showed iron overload in the liver (n=8). Liver biopsies showed evidence of hemochromatosis (n=3). Buccal biopsies stained positive for iron (n=1). Eight patients received antioxidant therapy and survived. Two patients passed away. CONCLUSION: Neonatal hemochromatosis is a rare liver disease of newborns with a spectrum of clinical severity. Elevated serum ferritin and AFP support the diagnosis after excluding other causes of neonatal liver failure. The use of antioxidant therapy helps to improve the outcome. PMID- 24343469 TI - Quality of life among children with beta-thalassemia major treated in Western Saudi Arabia. AB - OBJECTIVE: To assess the quality of life among children and adolescents with thalassemia major. METHODS: This cross-sectional study used the Pediatric Quality of Life Inventory (PedsQL). Children and adolescents with beta-thalassemia major who attended the Day Care Unit at King Abdulaziz University Hospital, Jeddah, Saudi Arabia from October 2012 to February 2013 were surveyed. The questions highlighted 4 health status scales, namely physical functioning (PF), emotional functioning (EF), school performance (SC), and social functioning (SF). Scores were calculated for each patient and data were analyzed using the Statistical Package for Social Sciences. RESULTS: We recruited 46 children (60.9% males). The median age of the sample was 12 years (range, 2-18 years). Most patients (84.8%) had 3 weekly blood transfusions. The mean+/-SD physical functioning (PF) score was 57.2+/-25.9; the EF score was 74.1+/-20.3, SF score was 78.5+/-24, and SC score was 54.3+/-24.2. The PF score was significantly lower in patients with a family history of thalassemia (p=0.003), and in those whose families had low incomes (p=0.049). Conversely, the SF score was significantly higher in school educated patients (p=0.01). CONCLUSION: The quality of life of thalassemic children is affected by multiple factors, such as family income and a family history of thalassemia. Education appeared to increase patient functionality. Supportive measures could improve the quality of life in thalassemic patients. PMID- 24343470 TI - Perceptions and effects of antenatal education. AB - OBJECTIVE: To assess the quality and effect of antenatal health education on health-related issues during pregnancy, and the benefits to women during the peri partum period. METHODS: This is a descriptive study of 300 women attending the Postnatal Clinics and Women Health Clinics in 2 Family Medicine centers at King AbdulAziz Medical City, National Guard Health Affairs, Riyadh, Saudi Arabia. The study was carried out between November 2009 and February 2010. A predesigned questionnaire was used. RESULTS: Three hundred women completed the questionnaire. Most women made their first antenatal visit during the fourth month of pregnancy, and most had 3-6 antenatal care (ANC) visits. Highly educated mothers had significantly more ANC visits and attended the first visit earlier. Nearly 80% of subjects were satisfied with the health education provided during ANC visits. Multiparous women were found to receive less health education than primiparous women. Most reported receiving education on breast feeding (83%), signs of labor (75.3%), and baby care (74.7%). However, most of the subjects did not receive all of the important information that should be given during ANC. There was a negative linear relationship between health education score of women and their age. CONCLUSION: This study quantified the inadequate level of health education received by pregnant women during ANC. PMID- 24343471 TI - Idiopathic scrotal calcinosis. AB - Idiopathic scrotal calcinosis is a rare scrotal benign disease. Its distinct features are painless, non-pruritic, semi-soft palpable calcific transdermal nodules. We report a 42-year-old-man with asymptomatic multiple calcified scrotal skin nodules for 10 years. Under spinal anesthesia, the affected scrotal skin was excised and the nodules removed. We aim to explain the etiology, pathophysiology, diagnosis, and treatment modalities of this rare disease. PMID- 24343472 TI - Paraspinal tuberculosis mimicking malignancy. AB - Tuberculosis (TB) of the paraspinal muscles is a rare clinical entity. We present a case of an 18-year-old, Saudi male patient presenting with the clinical picture of a paraspinal mass that turned out to be paraspinal TB. It originated from the paraspinal tissues and muscles, and invaded the C6 and C7 vertebrae. Initially, it was highly suspicious for malignancy. A biopsy confirmed the diagnosis of TB, and the patient was treated successfully with anti-TB therapy. It is important to be aware that paraspinal TB can mimic malignancy. PMID- 24343473 TI - Diffusion tensor imaging findings associated with cognitive performance in hydrocephalus patients. PMID- 24343474 TI - Propylene glycol allergic contact dermatitis. A quick reference guide for propylene glycol-free topical corticosteroids in Saudi Arabia. PMID- 24343475 TI - Multiple myeloma presenting as dysphagia. PMID- 24343476 TI - Aripiprazole versus risperidone for treating children and adolescents with tic disorder: a randomized double blind clinical trial. AB - There are some uncontrolled studies about the efficacy and safety of both aripiprazole and risperidone for treating tic disorder. Moreover, the efficacy of these medications has never been compared. This is the first double blind randomized clinical trial comparing the safety and efficacy of aripiprazole and risperidone for treating patients with tic disorder. Sixty children and adolescents with tic disorder were randomly allocated into one of the two groups to receive either aripiprazole or risperidone for 2 months. The primary outcome measure was the score of Yale Global Tic Severity Scale. In addition, health related quality of life and adverse events were assessed. Both aripiprazole and risperidone decreased the Yale Global Tic Severity Scale score during this trial. Moreover, both medications increased the health related quality of life score. Both aripiprazole and risperidone were tolerated well. Aripiprazole [3.22 (1.9) mg/day] decreased tic score as much as risperidone [0.6 (0.2) mg/day]. Their adverse effects and their effects on health related quality of life were comparable. However, risperidone increased the patients' social functioning more than aripiprazole in short term. PMID- 24343477 TI - Using cognitive theory and methodology to inform the study of sexual victimization. AB - Sexual victimization is a prevalent problem among college-aged women. In order to investigate the mechanisms underlying sexual victimization, researchers have focused on the role of cognitive processes such as perception of sexual victimization risk, positing that difficulties with risk perception heighten women's risk for victimization. However, researchers generally have not conceptualized risk perception in the context of a comprehensive cognitive model or utilized tasks and stimuli that allow them to examine specific cognitive processes linked to increased risk for sexual victimization. This review examines the research on sexual victimization risk perception, citing benefits and limitations to the extant literature, and discusses how a promising hybrid approach using cognitive theory and methodology can be applied to this area to better understand women's risk for sexual victimization. PMID- 24343478 TI - A comparison of the types of screening tool administration methods used for the detection of intimate partner violence: a systematic review and meta-analysis. AB - Intimate partner violence (IPV) is associated with significant health consequences for victims, including acute/chronic pain, depression, trauma, suicide, death, as well as physical, emotional, and mental harms for families and children. The objective of this systematic review and meta-analysis was to assess the rate of IPV disclosure in adult women (>18 years of age) with the use of three different screening tool administration methods: computer-assisted self administered screen, self-administered written screen, and face-to-face interview screen. A comprehensive literature search was conducted in the MEDLINE, EMBASE, PsycINFO, CINAHL, Database of Abstracts of Reviews of Effectiveness, and the Cochrane library databases. We identified 746 potentially relevant articles; however, only 6 were randomized controlled trials (RCTs) and included for analysis. No significant differences were observed when women were screened in face-to-face interviews or with a self-administered written screen (Odds of disclosing: 1.02, 95% confidence interval [CI]: [0.77, 1.35]); however, a computer-assisted self-administered screen was found to increase the odds of IPV disclosure by 37% in comparison to a face-to-face interview screen (odds ratio: 0.63, 95% CI: [0.31, 1.30]). Disclosure of IPV was also 23% higher for computer assisted self-administered screen in comparison to self-administered written screen (Odds of disclosure: 1.23, 95% CI: [0.0.92, 1.64]). The results of this review suggest that computer-assisted self-administered screens leads to higher rates of IPV disclosure in comparison to both face-to-face interview and self administered written screens. PMID- 24343479 TI - Understanding strong magnetostriction in Fe(100-x)Ga(x) alloys. AB - Magnetostriction of ferromagnetic materials describes the change of their shape or dimension in response to the reorientation of magnetization under the influence of external magnetic field. Fe(100-x)Ga(x) binary alloys (Galfenol) have large magnetostriction and excellent ductility; and they are very promising rare-earth free materials for applications in sensors, actuators, energy harvesters and spintronic devices. Here we report results of large-scale ab initio molecular dynamics (AIMD) simulations for Galfenol, especially regarding the mechanism that leads to the sudden drop of tetragonal magnetostriction at x ~ 19, a long-standing puzzle for the community. Based on rigid band analysis, we propose possible ways to further optimize the performance of Galfenol for device applications. For example, we found that the substitution of a small amount of Cu for Ga (1.6%) in certain configuration may double the magnetostriction of Galfenol. PMID- 24343484 TI - [Skin sensitization to aeroallergens in the child: cross-sectional study of 200 cases]. AB - BACKGROUND: The prevalence of the allergic diseases increased considerably during the last decades. The clinical expression of allergy depends on the interaction of genetic and environmental factors. AIM: The aim of our study was to evaluate the prevalence of sensitizing to aeroallergens in the child and to determine the risk factors of sensitizing. METHODS: We carried out a cross-sectional study relating to 200 pediatric patients of the Mahmoud El Matri hospital, aged from 3 to14 years. We performed skin prick test to 12 current aeroallergens. RESULTS: The prevalence of sensitizing to aeroallergens was 14%. Acarina (DP and/or DF) represented the allergens accused in the majority of the cases (96,4% of the cases). The statistical analysis of the various risk factors of sensitizing showed that these factors were: the presence of a family atopy (p= 0,0034) particularly a maternal asthma (p< 0,001), the personal atopy specially an asthma, an allergic rhinitis or eczema atopic (p< 10-5), the short breast-feeding (p= 0,033) and the home humidity (p=0,0072). Several risk factors reported in the literature did not seem to intervene in our study (the passive smoking, the urban dweling, the age of food diversification, infections at the low age). CONCLUSION: The prevalence of sensitizing to aeroallergens is relatively high in our series. Many factors could explain the increase of the allergic diseases. Our study stresses the importance of the genetic, nutritional and environmental factors in the appearance of aeroallergens sensitization. PMID- 24343480 TI - Retromer promotes immune quiescence by suppressing Spatzle-Toll pathway in Drosophila. AB - The Toll and Toll-like receptor signaling pathways are evolutionarily conserved pathways that regulate innate immunity in insects and mammals. While efforts have been made to clarify the signal transduction events that occur during infection, much less is known about the components that maintain immune quiescence. Here we show that retromer, an intracellular protein complex known for regulating vesicle trafficking, functions in modulating the Toll pathway in Drosophila melanogaster. In mutant animals lacking retromer function, the Toll pathway but not JAK-STAT or IMD pathway is activated, triggering both cellular and humoral responses. Genetic epistasis and clonal analysis suggest that retromer regulates a component that acts upstream of Toll. Our data further show that in the mutant the Toll ligand Spatzle has a processing pattern similar to that of after infection. Together, the results suggest a novel function of retromer in regulating Toll pathway and innate immunity at a step that modulates ligand processing or activity. PMID- 24343485 TI - [Study of bone mineral density in adolescent handball players: a study of 20 cases]. AB - BACKGROUND: The physical activity during adolescence seems to correlate with bone mass at the end of the growth period. aim : To determine the effect of handball regularly practiced by teenage girls on the anthropometric parameters and bone mineral density. METHODS: Cross-sectional case-control, made in the rheumatology department of the Rabta hospital, has enrolled adolescent handball players of high level, which were compared to a control group matched by age and sex, but sedentary. We evaluated our two groups for anthropometric parameters and BMD. RESULTS: The lean mass (LM), fat mass (FM), the mean values of BMD at the lumbar spine and femur of our sports were significantly higher than that of sedentary controls. On bone mineral content (BMC), a statistically significant difference was observed between groups of sedentary and athletic teenagers. Positive and significant correlations were found between anthropometric parameters and measurements of BMD, BMC and of bone area. CONCLUSION: The regular practice of handball seems to be an osteogenic factor. It may be advisable in adolescents during the growth period to optimize the bone. PMID- 24343486 TI - [Determinants factors of hospital morbidity and mortality after reintervention of valve replacement]. AB - BACKGROUND: Valve surgery involves valvular substitutes that expose to different types of complications that can lead to re subsequent interventions. AIM: was to identify the predictors factors of in-hospital morbidity and mortality of re interventions after valve replacement. METHODS: Retrospective study of 73 consecutive patients who underwent a re valve replacement between 1985 and 2010 in the Cardiovascular Surgical department of La Rabta hospital. RESULTS: The average age at further surgery was 44 years ( 15-80 years) and sex ratio of 0.87 . The average time between interventions was 10 years (3 days -33 years). Different etiologies were found prosthesis thrombosis (36.9% ). The overall hospital mortality was 36.9 % , 11 intraoperative deaths and 16 immediate postoperative deaths. CONCLUSION: The iterative intervention of valve replacement surgery is increasingly mastered by the surgical team. According to this study , the prognosis depends mainly on the patient preoperatively state, the cause of further surgery and its mode of occurrence. PMID- 24343487 TI - [Early hearning screening by otoacoustic emissions and auditory brain stem response in Nabeul]. AB - BACKGROUND: Hearing loss is the most common congenital abnormality with a reported prevalence of 1 to 3 0/00 live births. Early detection and intervention is critical to prevent the adverse consequences of a delayed diagnosis on speech language and cognitive development. AIM: study the frequency of deafness in the newborns and the infants under 6 months followed in Tlatli Hospital in Nabeul and to search for correlations with risk factors identified by the Joint Committee on Infant Screening. METHODS: 397 children aged between 04 days and 5 months with deafness risks are tested on two-stage strategy of evoked otoacoustic emissions (EOAE) and auditory brain stem response (ABR). RESULTS: EOAE test is positif in 9,32 % of cases (37 children) and the ABR test is positif at 7 of these ; that is 1,76 % of cases. Significant statistic correlations were found with the antecedent of bacterial meningitis (p=0,001) and trisomy 21 (p=0,018). Unfortunately 40 % of the children were lost to follow-up. CONCLUSION: EOAE with ABR provide an excellent procosis screening technique of hearing loss. Such screening implies however the creation of networks to assure patient follow up. PMID- 24343488 TI - [Validity and reliability of the Tunisian version of section G of the Composite International Diagnostic Interview, relative to schizophrenia]. AB - BACKGROUND: Early diagnosis of schizophrenia can improve its outcome. Hence, screening policies should be held and suitable tools must be available for general practitioners. AIM: To translate the section G (about schizophrenia) of the Composite International Diagnostic Interview to the Tunisian dialect and to check its validity and reliability. METHODS: The Arabic version of section G of the Composite International Diagnostic Interview has been translated to the Tunisian dialect by psychiatrists speaking fluently both languages. Metric features of the instrument (sensitivity, specificity and predictive values) were assessed by checking its results against those of the gold standard i.e. the expert's opinion owing to the criteria of the Diagnostical and Statistical Manual of mental disorders 3rd revised edition. Reliability has been measured by the index of observer agreement. RESULTS: The instrument showed a low sensitivity of 45% [32% - 58%] and a high specificity of 96% [93% - 99%]. It looked as a diagnostical test that can avoid wrong diagnoses of such a serious and stigmatizing illness. These values are similar or even better than those of literature. The observer agreement index was 0.83 showing a very good reliability. The interviews mean duration was 20 minutes. The instrument showed no variability towards the sex, the age or the educational level of interviewees. CONCLUSION: Even though section G of the Composite International Diagnostic Interview failed to detect most cases with schizophrenia and showed a poor sensitivity, this instrument can be useful for screening strategies carried out by lay interviewers in the general population. PMID- 24343489 TI - Endoscopic diagnosis in a Tunisian pediatric population with upper gastrointestinal bleeding. AB - BACKGROUND: Esophagogastroduodenoscopy (EGD) is currently considered the first line diagnostic procedure chosen for Upper Gastrointestinal Bleeding (UGIB) since 1970. However, studies are still limited in our country. AIM: Finding out the most common causes of UGIB in children and whether the causes differed according to age in developing and developed countries. METHODS: A retrospective review of the medical records of children referred to the Paediatric Gastroenterology Department of The Tunis Hospital of Children between January 1998 and December 2006 for upper gastrointestinal bleeding. The children were divided into three groups; G1: neonates; G2: infants; G 3: children and adolescents. RESULTS: The study involved 614 endoscopies. The aetiology was not ascertained in 20.68%of cases. G1 included 125 newborns: 24 with no identified causes, 97 mucosal lesions (isolated or associated); two ulcers and two tumours. G2 and G3 included respectively 205 infants and 289 children. Toxic drug intake was recorded in 140 out of 489 patients. Endoscopy was normal in 101 cases. Peptic oesophagitis was recorded in 57/205 (27.8%) of G2 infants versus 52/284 (10%) of G3 children (p=0.015). Gastritis was recorded in 164/284 (55.6%) of G2 infants versus 86/205 (41.9%) of G3 children (p<=0.001). Peptic ulcers were reported in ten boys. Mallory Weiss tears and Variceal lesions were found in respectively eleven and ten cases. CONCLUSION: Aetiologies of UGIB in children in Tunisia varied according to age and geographic areas. PMID- 24343490 TI - [Stromal gastrointestinal tumors: retrospective study of 24 cases]. AB - BACKGROUND: Gastrointestinal stromal tumors (GIST) are the most common digestive sarcomas. They develop in most cases in the stomach and small intestine, more rarely rectum, colon, esophagus or mesentery. These tumors typically express the phenotype CD117/KIT + and CD34 +. AIM: To evaluate epidemiologic, clinical, pathologic, therapeutic, characteristics and evaluative pattern of gastrointestinal tumor treated in our surgical department. PATIENTS AND METHODS: We collected 24 cases of GIST (confirmed by the positivity of CD 117 and/or CD 33) treated between 1997 and 2010 in the department of surgery B of Charles Nicolle's Hospital. We analyzed demographic characteristics, clinic pattern, investigations treatment and therapeutic variables of our patients. We calculated the survival rate and identified prognostic predictive factors of survival. RESULTS: Our retrospective study interested, during 13 years, 24 patients presenting GIST with a median age of 66 years and a sex ratio of 0.8. The median time for diagnosis was two months (3 days to 24 months). Abdominal pain, gastrointestinal bleeding and vomiting were the most common symptoms. The endoscopic appearance was tumor arising from muscular layer found in the stomach (13/24 cases; 54%), small bowel in four cases (16.5%) and duodenal or rectum three patients (12,5 %). Twenty three within 24 patients underwent surgical resection with R0 in 20/23 cases. Three patients were treated with neoadjuvant imatinib for an average of 12 months, one patient had adjuvant treatment and four patients in locoregional evolutive tumor and / or metastatic. The overall survival was 70% at one year and 65% at two years with a pejorative impact, in univariate analysis of abdominal pain, asthenia, anorexia, weight loss, cytonuclear atypia, tumor size >= 10 cm and a mitotic index >= 5/50. Multivariate analysis showed that tumor size (Hazard Ratio = 6 if size >= 10 cm 95% CI [1,539 24,017]) and weight loss (Hazard Ratio = 7 95% CI [1,664-29,100]) were influential factors on overall survival and recurrence-free survival. CONCLUSION: The prognostic predictive factors identified were the size of tumor >= 10cm and the mitotic index. PMID- 24343491 TI - [Cervical trophoblastic tumor: a rare etiology of massive genital hemorrhage]. PMID- 24343492 TI - [Duplication of the gallbladder]. PMID- 24343493 TI - Renal abscess in a healthy child. PMID- 24343494 TI - [Nephrogenic ascites: a poorly understood syndrome: a case report]. PMID- 24343495 TI - Skin flaps and grafts for reconstruction of complex genitalia sequelae of thermal burn. PMID- 24343496 TI - [Peripheral neuropathy associated with cerebrovascular disease revealing systemic scleroderma]. PMID- 24343497 TI - Systemic scleroderma associated with ulnar nerve entrapment at the elbow. PMID- 24343498 TI - [Cholesteatoma of the external auditory canal: seven cases]. PMID- 24343499 TI - [Familial multiple angiolipomatosis]. PMID- 24343500 TI - [How can an ossifying fibroma mimic a fibrous dysplasia? Case report]. PMID- 24343501 TI - Left hepato-pleural fistula complicating primary hepatic hydatidosis. PMID- 24343503 TI - Germany's new old way. PMID- 24343502 TI - [Primary hypertriglyceridemia type IV : early presentation of a severe case]. PMID- 24343509 TI - Water splitting: An adaptive junction. PMID- 24343510 TI - Organic photovoltaics: Efficient relaxation. PMID- 24343511 TI - Shape-memory materials: Nanoscale oxides shape up. PMID- 24343512 TI - Material witness: Joint enterprise. PMID- 24343513 TI - Directed colloidal assembly: Printing with magnets. PMID- 24343514 TI - Spin-torque building blocks. AB - The discovery of the spin-torque effect has made magnetic nanodevices realistic candidates for active elements of memory devices and applications. Magnetoresistive effects allow the read-out of increasingly small magnetic bits, and the spin torque provides an efficient tool to manipulate - precisely, rapidly and at low energy cost - the magnetic state, which is in turn the central information medium of spintronic devices. By keeping the same magnetic stack, but by tuning a device's shape and bias conditions, the spin torque can be engineered to build a variety of advanced magnetic nanodevices. Here we show that by assembling these nanodevices as building blocks with different functionalities, novel types of computing architecture can be envisaged. We focus in particular on recent concepts such as magnonics and spintronic neural networks. PMID- 24343516 TI - Bioactive glass/ZrO2 composites for orthopaedic applications. AB - Binary biocomposites were realized by combining yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) with a bioactive glass matrix. Few works are available regarding composites containing zirconia and a relatively high content of glass because the resulting samples are usually biocompatible but not bioactive after thermal treatment. In the present research, the promising properties of the new BG_Ca-K glass, with its low tendency to crystallize and high apatite-forming ability, allowed us to sinter the composites at a relatively low temperature with excellent effects in terms of bioactivity. In addition, it was possible to benefit from the good mechanical behaviour of Y-TZP, thus obtaining samples with microhardness values that were among the highest reported in the literature. After a detailed analysis regarding the thermal behaviour of the composite powders, the sintered bodies were fully characterized by means of x ray diffraction, SEM equipped with EDS, density measurements, volumetric shrinkage determination, mechanical testing and in vitro evaluation in a simulated body fluid (SBF) solution. According to the experimental results, the presence of Y-TZP improved the mechanical performance. Meanwhile, the BG_Ca-K glass, which mainly preserved its amorphous structure after sintering, provided the composites with a good apatite-forming ability in SBF. PMID- 24343517 TI - Fabrication of graphene wrapped ZnIn2S4 microspheres heterojunction with enhanced interfacial contact and its improved photocatalytic performance. AB - Due to their build-in electric fields locating at interfaces of different materials, heterojunctions have shown excellent carrier separation ability and received wide attention in photocatalysis and photovoltaics. In general, larger interface area and smoother carrier transfer pathway are favorable for heterojunctions to achieve larger active area of build-in electric fields and longer photogenerated charge lifetime, respectively, and sequentially the heterojunctions may show optimized separation ability. However, there is hardly any report about this topic. In this paper, we design a new heterojunction material where a graphene (Gr) layer is close-fitting as the surface of the ZnIn2S4 microspheres (ZnIn2S4@Gr) in virtue of the electrostatic interaction between the functional groups of GO and the amino groups of ZnIn2S4 microspheres. Benefiting from the effective contact of Gr and ZnIn2S4 at their interface as well as the superior charge transfer ability of Gr, this structure displays good photocatalytic capability. The kinetic constant of phenol degradation on ZnIn2S4@Gr was 3.03 h(-1), which was 8.4-fold and 1.5-fold higher than those on ZnIn2S4 and ZnIn2S4-Gr composites, respectively. Furthermore, the excellent performance was stable according to the result of the consecutive cycling experiment. These experimental results demonstrated that the large interface area and smooth carrier transfer pathway were significant for heterojunction materials to provide better photogenerated charge separation properties. PMID- 24343518 TI - How DNA is damaged by external electric fields: selective mutation vs. random degradation. AB - DNA is constantly exposed to exogenous agents that randomly damage the genetic code. However, external perturbations might also be used to induce malignant cell death if the mutation processes are controlled. The present communication reports a set of parameters allowing DNA mutation through the use of intense external electric fields. This is a step towards the design of pulsed electric field therapy for genetic diseases. PMID- 24343519 TI - Hybrid search in the temporal domain: Evidence for rapid, serial logarithmic search through memory. AB - In hybrid search, observers memorize a number of possible targets and then search for any of these in visual arrays of items. Wolfe (2012) has previously shown that the response times in hybrid search increase with the log of the memory set size. What enables this logarithmic search of memory? One possibility is a series of steps in which subsets of the memory set are compared to all items in the visual set simultaneously. In the present experiments, we presented single visual items sequentially in a rapid serial visual presentation (RSVP) display, eliminating the possibility of simultaneous testing of all items. We used a staircasing procedure to estimate the time necessary to effectively detect the target in the RSVP stream. Processing time increased in a log-linear fashion with the number of potential targets. This finding eliminates the class of models that require simultaneous comparison of some memory items to all (or many) items in the visual display. Experiment 3 showed that, similar to visual search, memory search efficiency in this paradigm is influenced by the similarity between the target set and the distractors. These results indicate that observers perform separate memory searches on each eligible item in the visual display. Moreover, it appears that memory search for one item can proceed while other items are being categorized as "eligible" or "not eligible." PMID- 24343521 TI - Inflammatory mechanisms in atherosclerosis. AB - Throughout the last two decades inflammation has been recognized as the central mechanism underlying atherogenesis. A multitude of basic science work demonstrates the pivotal role of inflammatory processes during every step of atherosclerotic plaque formation: From initiation via propagation to complication. This review describes some of the key mechanisms involved with a particular focus on the diverse group of inflammatory cells and their subsets that distinctly contribute to atherogenic and anti-atherogenic phenomena. Furthermore, we summarize the controlling action of a tight network of co stimulatory molecules and cytokines orchestrating the inflammatory and anti inflammatory effector functions. Finally, the current status of clinical trials evaluating anti-inflammatory/immune-modulatory treatment strategies is summarized and an outlook for future therapeutic implications is provided. PMID- 24343520 TI - Choroid plexus implants rescue Alzheimer's disease-like pathologies by modulating amyloid-beta degradation. AB - The choroid plexuses (CP) release numerous biologically active enzymes and neurotrophic factors, and contain a subpopulation of neural progenitor cells providing the capacity to proliferate and differentiate into other types of cells. These characteristics make CP epithelial cells (CPECs) excellent candidates for cell therapy aiming at restoring brain tissue in neurodegenerative illnesses, including Alzheimer's disease (AD). In the present study, using in vitro approaches, we demonstrated that CP were able to diminish amyloid-beta (Abeta) levels in cell cultures, reducing Abeta-induced neurotoxicity. For in vivo studies, CPECs were transplanted into the brain of the APP/PS1 murine model of AD that exhibits advanced Abeta accumulation and memory impairment. Brain examination after cell implantation revealed a significant reduction in brain Abeta deposits, hyperphosphorylation of tau, and astrocytic reactivity. Remarkably, the transplantation of CPECs was accompanied by a total behavioral recovery in APP/PS1 mice, improving spatial and non-spatial memory. These findings reinforce the neuroprotective potential of CPECs and the use of cell therapies as useful tools in AD. PMID- 24343522 TI - High-throughput micro-plate HCI-vanillin assay for screening tannin content in sorghum grain. AB - BACKGROUND: The HCI-vanillin assay is a well-accepted method for determining tannin content in sorghum but is limited to small sample sets due to the time consuming nature of the method. The objective was to develop an accurate and repeatable high-throughput 96-well plate assay for breeders to screen large sample sets of sorghum for tannin content. Validation of the high-throughput assay was tested on 25 sorghums suspected to contain tannin. RESULTS: Approximately 30 measurements per day were completed using the conventional assay compared to 224 measurements using the 96-well platform. The correlation between the two tannin assays was 0.98. The coefficient of variation (CV) was 3.54% and 3.21% for the 96-well and conventional method, respectively. The 96-well assay exhibited good repeatability, with the inter-plate CV between 2.77% and 4.85%. CONCLUSION: The high-throughput 96-well HCI-vanillin assay exhibited an eightfold increase in the number of measurements completed and was as accurate as the conventional HCI-vanillin assay. PMID- 24343523 TI - Medullary thyroid carcinoma: a 25-year perspective. AB - This article summarizes the major clinical, pathological, and molecular features of medullary thyroid carcinoma (MTC), based on a review of the most significant advances in our understanding of this tumor type over the last 25 years. MTC is a neuroendocrine carcinoma that shows evidence of C-cell differentiation. The tumor has a distinctive morphologic appearance, including the presence of amyloid deposits. Immunostaining for calcitonin, carcinoembryonic antigen, calcitonin gene-related peptide, and thyroid transcription factor 1 is helpful in differential diagnosis. Identification of RET mutations in familial and sporadic MTC has brought important changes in early diagnosis and treatment. Surgery remains the cornerstone of effective therapy. Understanding the molecular basis of MTC will allow identification of novel approaches for individualized treatment. PMID- 24343524 TI - Nocturnal homing in the tropical amblypygid Phrynus pseudoparvulus (Class Arachnida, Order Amblypygi). AB - Arthropods are renowned for their navigational capabilities, with numerous examples known from insects and crustaceans. Early studies of amblypygids (Class Arachnida, Order Amblypygi) also suggest complex nocturnal navigation, despite their apparent lack of visual adaptations to the low-light conditions of a tropical understory. In a series of two studies, we use the tropical amblypygid, Phrynus pseudoparvulus, to assess their nocturnal homing ability. Our first experiment displaced and tracked resident and nonresident individuals. Resident individuals, displaced up to 4.5 m from their home refuges and released onto their home tree, were more likely to return to their previously occupied refuge than were nonresident individuals that were collected from trees outside the study area and released at the same locations. In a follow-up study, we displaced amblypygids longer distances (6-8.7 m) from their home trees and tracked them by telemetry. These individuals returned to home trees, typically within 1-3 nights, often via indirect paths. Taken together, our results provide evidence that P. pseudoparvulus are able to navigate home, often taking indirect routes, and can do so through a mechanism other than path integration. PMID- 24343525 TI - Exploring the effect of organizational culture on consumer perceptions of agency support for mental health recovery. AB - This research explores the impact of mental health agency culture on consumers' perceptions of agency support for their recovery. This study hypothesized that a constructive organizational culture must be present for consumers to perceive agency support for recovery. A sample of 12 mental health agencies in rural Pennsylvania participated in the research. Agency administrators completed an instrument called the recovery oriented service environment, which measured the number of recovery model program components offered by the agency. Consumers completed the recovery oriented services indicators, which taps into their perception of agency support for recovery. Direct service staff completed the organizational social context, which measured their agency's culture. Results showed that in this sample stronger consumer perceptions of agency support for recovery were correlated with higher ratings of agency constructive culture. The results suggest that agency culture is an important variable to target when implementing recovery model programming. PMID- 24343527 TI - Fructus ligustri lucidi ethanol extract improves bone mineral density and properties through modulating calcium absorption-related gene expression in kidney and duodenum of growing rats. AB - Optimizing peak bone mass in early life is one of key preventive strategies against osteoporosis. Fructus ligustri lucidi (FLL), the fruit of Ligustrum lucidum Ait., is a commonly prescribed herb in many kidney-tonifying traditional Chinese medicinal formulas to alleviate osteoporosis. Previously, FLL extracts have been shown to have osteoprotective effect in aged or ovariectomized rats. In the present study, we investigated the effects of FLL ethanol extract on bone mineral density (BMD) and mechanical properties in growing male rats and explored the underlying mechanisms. Male weaning Sprague-Dawley rats were randomized into four groups and orally administrated for 4 months an AIN-93G formula-based diet supplementing with different doses of FLL ethanol extract (0.40, 0.65, and 0.90 %) or vehicle control, respectively. Then calcium balance, serum level of Ca, P, 25(OH)2D3, 1,25(OH)2D3, osteocalcin (OCN), C-terminal telopeptide of type I collagen (CTX-I), and parathyroid hormone, bone microarchitecture, and calcium absorption-related genes expression in duodenum and kidney were analyzed. The results demonstrated that FLL ethanol extract increased BMD of growing rats and improved their bone microarchitecture and mechanical properties. FLL ethanol extract altered bone turnover, as evidenced by increasing a bone formation maker, OCN, and decreasing a bone resorption maker, CTX-I. Intriguingly, both Ca absorption and Ca retention rate were elevated by FLL ethanol extract treatment, possibly through the mechanisms of up-regulating the transcriptions of calcitropic genes in kidney (1alpha-hydroxylase) and duodenum (vitamin D receptor, calcium transporter calbindin-D9k, and transient receptor potential vanilloid 6). In conclusion, FLL ethanol extract increased bone mass gain and improved bone properties via modulating bone turnover and up-regulating calcium absorption-related gene expression in kidney and duodenum, which could then activate 1,25(OH)2D3-dependent calcium transport in male growing rats. PMID- 24343526 TI - Timelines in the insect brain: fates of identified neural stem cells generating the central complex in the grasshopper Schistocerca gregaria. AB - This study employs labels for cell proliferation and cell death, as well as classical histology to examine the fates of all eight neural stem cells (neuroblasts) whose progeny generate the central complex of the grasshopper brain during embryogenesis. These neuroblasts delaminate from the neuroectoderm between 25 and 30 % of embryogenesis and form a linear array running from ventral (neuroblasts Z, Y, X, and W) to dorsal (neuroblasts 1-2, 1-3, 1-4, and 1-5) along the medial border of each protocerebral hemisphere. Their stereotypic location within the array, characteristic size, and nuclear morphologies, identify these neuroblasts up to about 70 % of embryogenesis after which cell shrinkage and shape changes render progressively more cells histologically unrecognizable. Molecular labels show all neuroblasts in the array are proliferative up to 70 % of embryogenesis, but subsequently first the more ventral cells (72-75 %), and then the dorsal ones (77-80 %), cease proliferation. By contrast, neuroblasts elsewhere in the brain and optic lobe remain proliferative. Apoptosis markers label the more ventral neuroblasts first (70-72 %), then the dorsal cells (77 %), and the absence of any labeling thereafter confirms that central complex neuroblasts have exited the cell cycle via programmed cell death. Our data reveal appearance, proliferation, and cell death proceeding as successive waves from ventral to dorsal along the array of neuroblasts. The resulting timelines offer a temporal blueprint for building the neuroarchitecture of the various modules of the central complex. PMID- 24343528 TI - Dopamine D1 receptor activation rescues extinction impairments in low-estrogen female rats and induces cortical layer-specific activation changes in prefrontal amygdala circuits. AB - Post-traumatic stress disorder (PTSD) is twice as common in women as in men; it is a major public health problem whose neurobiological basis is unknown. In preclinical studies using fear conditioning and extinction paradigms, women and female animals with low estrogen levels exhibit impaired extinction retrieval, but the mechanisms that underlie these hormone-based discrepancies have not been identified. There is much evidence that estrogen can modulate dopaminergic transmission, and here we tested the hypothesis that dopamine-estrogen interactions drive extinction processes in females. Intact male and female rats were trained on cued fear conditioning, and received an intraperitoneal injection of a D1 agonist or vehicle before extinction learning. As reported previously, females that underwent extinction during low estrogen estrous phases (estrus/metaestrus/diestrus (EMD)) froze more during extinction retrieval than those that had been in the high-estrogen phase (proestrus; PRO). However, D1 stimulation reversed this relationship, impairing extinction retrieval in PRO and enhancing it in EMD. We also combined retrograde tracing and fluorescent immunohistochemistry to measure c-fos expression in infralimbic (IL) projections to the basolateral area of the amygdala (BLA), a neural pathway known to be critical to extinction retrieval. Again we observed diverging, estrous-dependent effects; SKF treatment induced a positive correlation between freezing and IL-BLA circuit activation in EMD animals, and a negative correlation in PRO animals. These results show for the first time that hormone-dependent extinction deficits can be overcome with non-hormone-based interventions, and suggest a circuit specific mechanism by which these behavioral effects occur. PMID- 24343529 TI - Increased voluntary ethanol consumption and changes in hippocampal synaptic plasticity in isolated C57BL/6J mice. AB - Social isolation (SI) is a notable model of prolonged mild stress, characterized by multiple neurochemical and behavioral alterations, that appears particularly suitable for studying different aspects of the interplay between stress and ethanol (EtOH) consumption in order to characterize potential molecular mechanisms, including changes in the function of inhibitory GABAergic synapses, underlying such interaction. In C57BL/6J mice, SI is associated with an altered hippocampal concentration of the neuroactive steroids 3alpha-hydroxy-5alpha pregnan-20-one (3alpha-5alpha-THP), an increased expression of the alpha4 and delta subunit of gamma-aminobutyric acid type A receptors (GABAARs) in the dentate gyrus (DG), and a parallel enhancement of the stimulatory action of 4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridin-3-ol (THIP) on GABAergic tonic currents recorded in voltage-clamped DG granule cells (DGGCs). In addition, SI in C57BL/6J mice determines an increase in voluntary EtOH consumption and EtOH preference when compared to group-housed (GH) control animals. Furthermore, in hippocampal slices of SI mice we also observed a marked reduction of both cellular excitability and long term potentiation (LTP) in pyramidal neurons of the CA1 hippocampal sub-region, effects that were prevented by the long term treatment of SI mice with the neuroactive steroid precursor progesterone. In this article, we summarize some of our recent findings on the effects of SI in C57BL/6J mice on voluntary EtOH intake, regulation of GABAARs gene expression and function and hippocampal long term synaptic plasticity. PMID- 24343530 TI - Early transplantation of bone marrow mononuclear cells promotes neuroprotection and modulation of inflammation after status epilepticus in mice by paracrine mechanisms. AB - Status epilepticus (SE) is a severe clinical manifestation of epilepsy associated with intense neuronal loss and inflammation, two key factors involved in the pathophysiology of temporal lobe epilepsy. Bone marrow mononuclear cells (BMMC) attenuated the consequences of pilocarpine-induced SE, including neuronal loss, in addition to frequency and duration of seizures. Here we investigated the effects of BMMC transplanted early after the onset of SE in mice, as well as the involvement of soluble factors produced by BMMC in the effects of the cell therapy. Mice were injected with pilocarpine for SE induction and randomized into three groups: transplanted intravenously with 1 * 10(7) BMMC isolated from GFP transgenic mice, injected with BMMC lysate, and saline-treated controls. Cell tracking, neuronal counting in hippocampal subfields and cytokine analysis in the serum and brain were performed. BMMC were found in the brain 4 h following transplantation and their numbers progressively decreased until 24 h following transplantation. A reduction in hippocampal neuronal loss after SE was found in mice treated with live BMMC and BMMC lysate when compared to saline-treated, SE induced mice. Moreover, the expression of inflammatory cytokines IL-1beta, TNF alpha, IL-6 was decreased after injection of live BMMC and to a lesser extent, of BMMC lysate, when compared to SE-induced controls. In contrast, IL-10 expression was increased. Analysis of markers for microglia activation demonstrated a reduction of the expression of genes related to type 1-activation. BMMC transplantation promotes neuroprotection and mediates anti-inflammatory effects following SE in mice, possibly through the secretion of soluble factors. PMID- 24343531 TI - Daphnetin, a natural coumarin derivative, provides the neuroprotection against glutamate-induced toxicity in HT22 cells and ischemic brain injury. AB - Daphnetin (DAP), a coumarin derivative, has been reported to have multiple pharmacological actions including analgesia, antimalarial, anti-arthritic, and anti-pyretic properties. It is unclear whether DAP has neuroprotective effects on ischemic brain injury. In this study, we found that DAP treatment (i.c.v.) reduced the infarct volume at 24 h after ischemia/reperfusion injury and improved neurological behaviors in a middle cerebral artery occlusion mouse model. Moreover, we provided evidences that DAP had protective effects on infarct volume in neonate rats even it was administrated at 4 h after cerebral hypoxia/ischemia injury. To explore its neuroprotective mechanisms of DAP, we examined the protection of DAP on glutamate toxicity-induced cell death in hippocampal HT-22 cells. Our results demonstrated that DAP protected against glutamate toxicity in HT-22 cells in a concentration-dependent manner. Further, we found that DAP maintained the cellular levels of glutathione and superoxide dismutase activity, suggesting the anti-oxidatant activity of DAP. Since DAP has been used for the treatment of coagulation disorder and rheumatoid arthritis for long time with a safety profile, DAP will be a promising agent for the treatment of stroke. PMID- 24343533 TI - Robustness of chimera states in complex dynamical systems. AB - The remarkable phenomenon of chimera state in systems of non-locally coupled, identical oscillators has attracted a great deal of recent theoretical and experimental interests. In such a state, different groups of oscillators can exhibit characteristically distinct types of dynamical behaviors, in spite of identity of the oscillators. But how robust are chimera states against random perturbations to the structure of the underlying network? We address this fundamental issue by studying the effects of random removal of links on the probability for chimera states. Using direct numerical calculations and two independent theoretical approaches, we find that the likelihood of chimera state decreases with the probability of random-link removal. A striking finding is that, even when a large number of links are removed so that chimera states are deemed not possible, in the state space there are generally both coherent and incoherent regions. The regime of chimera state is a particular case in which the oscillators in the coherent region happen to be synchronized or phase-locked. PMID- 24343532 TI - Evaluation of potential antidepressant-like activity of chalcone-1203 in various murine experimental depressant models. AB - Two classic animal behavior despair tests-the forced swimming test (FST) and the tail suspension test (TST) were used to evaluate antidepressant-like activity of a new chalcone compound, chalcone-1203 in mice. It was observed that chalcone 1203 at dose of 1, 5, and 10 mg/kg significantly reduced the immobility time in the FST and TST in mice 30 min after treatment. In addition, chalcone-1203 was found to exhibit significant oral activity in the FST in mice. It also produced a reduction in the ambulation in the open-field test in mice not previously habituated to the arena, but no effect in the locomotor activity in mice previously habituated to the open-field. The main monoamine neurotransmitters and their metabolites in mouse brain regions were also simultaneously determined by HPLC-ECD. It was found that chalcone-1203 significantly increased the concentrations of the main neurotransmitters 5-HT and NE in the hippocampus, hypothalamus and cortex. Chalcone-1203 also significantly reduced the ratio of 5 HIAA/5-HT in the hippocampus and cortex, shown down 5-HT metabolism compared with mice treated with stress vehicle. In conclusion, chalcone-1203 produced significant antidepressant-like activity, and the mechanism of action may be due to increased 5-HT and NE in the mouse hippocampus and cortex. PMID- 24343534 TI - [Something's moving in chronic migraine]. PMID- 24343535 TI - [Mortality associated with a diagnosis of Guillain-Barre syndrome in adults of Mexican health institutions]. AB - INTRODUCTION: Guillain-Barre syndrome (GBS) is a neurological emergency representing the main cause of flaccid paralysis around the world, affecting all age groups. Little is known about the essential epidemiology of GBS in most Latin American countries. AIM: To determine the mortality associated with the diagnosis of GBS in hospital discharges during 2010 in hospitals of the Ministry of Health, Mexico. PATIENTS AND METHODS: We analyzed the database of hospital discharges of institutions pertaining to the Ministry of Health. Study cases were identified by the code G61.0 of the International Classification of Diseases, 10th revision (ICD-10). We excluded records of patients younger than 18 years and patients without complete demographic information. RESULTS: During the year 2010 there were 2,634,339 discharges from hospitals of the Ministry of Health. We identified a total of 467 hospitalizations due to GBS in adults (median age: 41 years; 62.1% male) from 121 health institutions of the 32 Republic States. The highest frequency of GBS hospitalizations occurred during summer and fall. The median hospital stay was 8 days. The hospital mortality rate was 10.5%. The probability of death was directly associated with age, without a particular trend regarding gender, hospital care or state. CONCLUSIONS: In 2010 GBS hospital mortality in this part of the Mexican health system was higher than that reported in contemporary studies. A seasonal association was observed regarding the frequency of hospitalizations for GBS. PMID- 24343536 TI - [Clinico-radiological profile of acute disseminated encephalomyelitis in the childhood population. A retrospective analysis of a series of 20 patients in a tertiary hospital]. AB - INTRODUCTION: Acute disseminated encephalomyelitis (ADE) is an inflammatory disorder of the central nervous system that is mediated immunologically and of unknown pathogenesis. It can present at any age, but is much more frequent in children. ADE has no specific biological marker and diagnosis is based on findings from clinical and neuroimaging studies. AIM: To enhance our knowledge of the clinico-radiological profile of this disease. PATIENTS AND METHODS: This retrospective study involved patients under 14 years of age who were admitted to a tertiary hospital over the last 15 years with a diagnosis of ADE. History, clinical presenting symptoms, lab findings from blood/cerebrospinal fluid analyses and radiological semiology were reviewed. In 16 cases an average follow up of 25 months was performed. RESULTS: The study examined 20 patients, 70% children, with a mean age of 4.4 years. Forty per cent had a previous febrile episode. Eighty-five per cent presented fever or vomiting, and 70% had altered states of mind. Motor deficits (45%), convulsions (35%) and involvement of the cranial nerves (30%) were predominant. Three children progressed with relapses and three others were left with motor sequelae. Magnetic resonance imaging showed hyperintense lesions in T2, with a pattern of scarce/no enhancement, which were predominantly located in the thalamus (70%), the spinal cord (67%) and the white matter of the sub-cortex (50%). Haemorrhagic ADE was diagnosed in two patients. CONCLUSIONS: ADE is a condition with an important degree of general involvement and neurological repercussions, as well as considerable potential to leave the patient with sequelae. Clinico-analytical data and magnetic resonance scans of the head and spinal cord are relevant for the initial diagnosis and follow-up of patients with ADE. PMID- 24343537 TI - [Encephalopathy and neuromyelitis optica: the importance of recognising atypical symptoms]. AB - INTRODUCTION: Neuromyelitis optica (NMO), or Devic's disease, is an autoimmune, inflammatory and demyelinating disease of the central nervous system which mainly and characteristically involves the optic nerve and the spinal cord. Anti aquaporin-4 (AQ-4) antibodies are a specific biomarker of the entity and, since their discovery, both the number of symptoms and the radiological data about the disease have progressively increased, and the concept of clinical spectrum of NMO has been defined. CASE REPORT: A 66-year-old female diagnosed with NMO after suffering attacks of optic neuritis and recurrent myelitis, and showing positive for AQ-4 antibodies. The patient presented a diminished level of consciousness, and magnetic resonance imaging of the head revealed a number of lesions in the white matter, without contrast enhancement, which resolved without treatment. One month later, her general state had declined and was accompanied by symptoms of confusion and blindness. A magnetic resonance imaging scan showed new lesions in the white matter and an increase in the size of those already present. The patient was diagnosed as suffering from encephalopathy within the context of NMO and she was treated with intravenous immunoglobulins and corticoids, which resulted in a clinical and radiological improvement. CONCLUSIONS: Since the discovery of AQ-4 antibodies, there has been an increase in the number of clinical and radiological manifestations of NMO beyond involvement of the optic nerve and the spinal cord, including manifestations in the brain. It is important to recognise them in order to make an early diagnosis, to avoid unnecessary complementary tests and to establish the most suitable treatment. PMID- 24343538 TI - [Dopaminergic treatment in Parkinson's disease: what has each therapeutic family got to offer?]. AB - Different families of dopaminergic agents have allowed to increase the availability of dopamine within the central nervous system by different mechanisms of action. Each drug family has specific efficacious properties, as well as a different profile of adverse events. The knowledge in detail of these specificities is mandatory to avoid severe systemic or neuropsychiatric complications. Despite these limitations, the development of new drugs within the past 20 years has prolonged survival in Parkinson's disease, increasing the time with preserved daily day functionality compared with the levodopa era, when this drug was the only dopaminergic drug available. The correct combination of dopaminergic drugs with different mechanisms of action allows the management of Parkinson's disease motor symptoms within safety dose ranges, and up to day, this appears as the best algorithm to maintain functionality for longer periods of time. PMID- 24343539 TI - Pediatric insomnia: clinical, diagnosis, and treatment. AB - Pediatric insomnia is an extrinsic sleep disorder subdivided into two categories: behavioral insomnia and insomnia related to medical, neurological, and psychiatric diseases. This review will cover several types of insomnia, comorbidities and specific pediatric therapies according to clinical characteristics and age. Behavioral insomnia should be differentiated from pediatric insomnia due to medical conditions, mostly occurring during the first year of life. Multiple night awakenings and diurnal hypersomnolence are strong indicators of insomnia due to medical conditions. Insomnia during adolescence and pediatric insomnia associated with psychiatric comorbidity, cognitive disabilities and epilepsy, will be discussed in terms of diagnosis, clinical features and implications for treatment. PMID- 24343540 TI - [White cerebellum sign (reversal sign)]. PMID- 24343541 TI - [Acute herpes simplex virus type 1 retinal necrosis three years after herpes simplex encephalitis]. PMID- 24343542 TI - [Amplitude-integrated electroencephalography in non-ketotic hyperglycinaemia]. PMID- 24343543 TI - [Neurons and values]. PMID- 24343544 TI - The in vitro and in vivo evaluation of the biocompatibility of Mg alloys. AB - Magnesium (Mg) and its alloys are being widely investigated for their potential use as resorbable biomaterials for orthopaedic applications. However, the natural corrosion of the metals results in potentially harmful perturbations to the physiological environment, which requires a comprehensive understanding of their biocompatibility. Currently, most investigations proceed directly from in vitro biocompatibility studies to intraosseous implantation. However, this can result in the unnecessary elimination of appropriate materials due to over sensitive in vitro methods or the implantation of potentially harmful materials. This study involved the development of a relevant in vitro cell culture method, and an in vivo soft tissue implantation technique to provide an intermediate step between basic cell culture methods and large animal intraosseous investigations. A Live/Dead fluorescent assay was used to investigate the viability of both L929 and SaOS-2 cells exposed to Mg alloys, with the results compared to those seen with the intramuscular implantation of the same materials in Lewis rats. These methods were able to successfully provide data on the corrosion of Mg alloys, allowing the identification of slowly and safely corroding materials that may be used in future intraosseous investigations. PMID- 24343545 TI - Effect of Helicobacter pylori eradication on metachronous recurrence after endoscopic resection of gastric neoplasm. AB - OBJECTIVES: Although many epidemiologic studies have shown that Helicobacter pylori (H. pylori) eradication has prophylactic effects on gastric cancer, their results are less clear in high-risk populations. We conducted this study to examine whether H. pylori eradication would affect the occurrence of metachronous gastric cancer after endoscopic resection in patients with early gastric cancer. METHODS: We retrospectively analyzed 2,089 adults who underwent endoscopic resection of gastric low-grade neoplasia, high-grade neoplasia, or differentiated invasive neoplasia from 2004 to 2008 at Asan Medical Center. Of these, a total of 1,007 patients with early gastric cancer were enrolled in this study. We evaluated the demographic data, the pathology, and the incidence of metachronous recurrence by dividing them into three groups: those without active H. pylori infection (Hp negative group, n=340), those who successfully underwent H. pylori eradication (eradicated group, n=485), and those who failed or did not undergo H. pylori eradication (noneradicated group, n=182). RESULTS: Metachronous recurrence was diagnosed in 75 patients, including 17 in the Hp, 34 in the eradicated, and 24 in the noneradicated groups. Median time to metachronous recurrence was 18 months (range, 7-75 months). The incidence of metachronous gastric cancer was 10.9 cases per 1,000 person-years in the Hp negative group, 14.7 cases per 1,000 person-years in the eradicated group, and 29.7 cases per 1,000 person-years in the noneradicated group. The hazard ratios in the noneradicated group compared with the Hp negative and eradicated groups were 2.5 (P<0.01) and 1.9 (P=0.02), respectively. H. pylori eradication reduced metachronous recurrence of gastric neoplasm, which was also shown in the secondary analysis of 1,487 patients with low-grade neoplasia and early gastric cancer. CONCLUSIONS: Successful H. pylori eradication may reduce the occurrence of metachronous gastric cancer after endoscopic resection in patients with early gastric cancer. PMID- 24343546 TI - Comparing trends in esophageal adenocarcinoma incidence and lifestyle factors between the United States, Spain, and the Netherlands. AB - OBJECTIVES: The incidence of esophageal adenocarcinoma (EAC) in the western world has been rapidly increasing. The trends in obesity and other lifestyle-associated factors have been hypothesized to be important drivers of this increase. We tested this hypothesis by comparing changes in these factors with changes in EAC incidence over time between three western countries. METHODS: Data on EAC incidence trends were abstracted from the SEER-9 registry (1975-2009) for the United States, from multiple cancer registries (1980-2004) in Spain, and from Eindhoven Cancer Registry in the Netherlands (1974-2010). In addition, we collected trend data on obesity, smoking, and alcohol consumption. The trend data were analyzed using log-linear regression. RESULTS: In 1980, the EAC incidence was similar among the three countries ((0.46-0.63) per 100,000). EAC incidence increased in all, with the largest increase observed in the Netherlands, followed by the United States and Spain (estimated annual percentage of change=9.7%, 7.4%, 4.3%, respectively). However, this pattern was not observed in lifestyle factors associated with EAC. With regards to obesity, the United States clearly has had the highest prevalence rates both in the past and in the present. For alcohol, the highest consumption rates are seen in Spain. Smoking showed a reverse trend compared with EAC among all three countries in the last 20 years. CONCLUSIONS: International trends in EAC incidence do not match corresponding trends in lifestyle-associated factors including obesity. Our findings suggest that factors other than obesity must be the important drivers for the increase in EAC incidence. PMID- 24343548 TI - Diagnostic performance of guaiac-based fecal occult blood test in routine screening: state-wide analysis from Bavaria, Germany. AB - OBJECTIVES: Randomized trials have shown that annual or biannual screening by guaiac-based fecal occult blood tests (gFOBTs) reduces colorectal cancer (CRC) mortality. Few clinical studies have evaluated diagnostic performance of gFOBT through validation by colonoscopy in all participants. We aimed for a comprehensive evaluation of diagnostic performance of gFOBT by age and sex under routine screening conditions. METHODS: Our analysis is based on 20,884 colonoscopies following up a positive gFOBT and 182,956 primary screening colonoscopies documented in a state-wide quality assurance program in Bavaria, Germany, in 2007-2009. Positive likelihood ratios (LR+), which represent an integrative measure of diagnostic performance, were derived, by age groups (55 59, 60-64, 65-69, 70-74 years) and sex, from a joint and comparative analysis of prevalences of colorectal neoplasms in both groups. RESULTS: Overall LR+ (95% confidence intervals) were 1.11 (1.06-1.15), 1.80 (1.72-1.88), and 5.04 (4.64 5.47) for non-advanced adenoma, advanced adenoma, and cancer, respectively. Assuming a specificity of gFOBT of 95.2%, as recently observed in a German study among 2,235 participants of screening colonoscopy, these LR+ would translate to sensitivities of 5.3%, 8.6%, and 24.2% for the three outcomes, respectively. Diagnostic performance was similarly poor among women and men and across age groups. CONCLUSIONS: The performance of gFOBT under routine screening conditions is even worse than previously estimated from clinical studies. In routine screening application, gFOBTs are expected to miss more than 9 out of 10 advanced adenomas and 3 out of 4 cancers. These results underline the need and the potential for better noninvasive CRC screening tests. PMID- 24343549 TI - Standardized long-term follow-up after endoscopic resection of large, nonpedunculated colorectal lesions: a prospective two-center study. AB - OBJECTIVES: Endoscopic removal of large, nonpedunculated colorectal lesions is challenging. Long-term outcome data based on standardized protocols, including detailed inspection of the resection site, are scarce. The aims of the present study were to evaluate the safety and efficacy of endoscopic resection (ER) of large, nonpedunculated lesions (LNLs; >20 mm) and to assess the long-term recurrence rate afterward. METHODS: A total of 243 consecutive patients (141 men, 102 women) with 252 adenomas (>20 mm) was followed up using a standardized protocol after complete ER. After endoscopic treatment, the patients received standardized follow-up examinations after 3-6 months and 12 months. The postpolypectomy scar was re-examined, assessed for residual neoplasia, and biopsied at each follow-up colonoscopy. RESULTS: Evident residual neoplasia was noted after 3-6 months in 58 of 183 lesions (31.69%). After 12 months, 126 LNLs were examined, with 19 late recurrences (16.37%). Twenty-one (6.5%) postpolypectomy scars were not detected during 321 surveillance examinations. Biopsy evidence of residual/recurrent lesions was found in 16 of 228 macroscopically inconspicuous polypectomy scars (7%). All residual adenomas were treated using ER and/or argon plasma coagulation. There were 43 complications with the 252 lesions (17%), including 20 major complications (7.9%), all managed conservatively. CONCLUSIONS: A detailed study design with systematic biopsies of inconspicuous scars reveals a significant number of residual adenomas after completed resection. However, these residual neoplasias can be effectively treated at follow-up colonoscopies. PMID- 24343547 TI - Development of an online library of patient-reported outcome measures in gastroenterology: the GI-PRO database. AB - OBJECTIVES: Because gastrointestinal (GI) illnesses can cause physical, emotional, and social distress, patient-reported outcomes (PROs) are used to guide clinical decision making, conduct research, and seek drug approval. It is important to develop a mechanism for identifying, categorizing, and evaluating the over 100 GI PROs that exist. Here we describe a new, National Institutes of Health (NIH)-supported, online PRO clearinghouse-the GI-PRO database. METHODS: Using a protocol developed by the NIH Patient-Reported Outcome Measurement Information System (PROMIS((r))), we performed a systematic review to identify English-language GI PROs. We abstracted PRO items and developed an online searchable item database. We categorized symptoms into content "bins" to evaluate a framework for GI symptom reporting. Finally, we assigned a score for the methodological quality of each PRO represented in the published literature (0-20 range; higher indicates better). RESULTS: We reviewed 15,697 titles (kappa>0.6 for title and abstract selection), from which we identified 126 PROs. Review of the PROs revealed eight GI symptom "bins": (i) abdominal pain, (ii) bloat/gas, (iii) diarrhea, (iv) constipation, (v) bowel incontinence/soilage, (vi) heartburn/reflux, (vii) swallowing, and (viii) nausea/vomiting. In addition to these symptoms, the PROs covered four psychosocial domains: (i) behaviors, (ii) cognitions, (iii) emotions, and (iv) psychosocial impact. The quality scores were generally low (mean 8.88 +/- 4.19; 0 (min)-20 (max). In addition, 51% did not include patient input in developing the PRO, and 41% provided no information on score interpretation. CONCLUSIONS: GI PROs cover a wide range of biopsychosocial symptoms. Although plentiful, GI PROs are limited by low methodological quality. Our online PRO library (www.researchcore.org/gipro/) can help in selecting PROs for clinical and research purposes. PMID- 24343550 TI - Barrett's esophagus suspected at endoscopy but no specialized intestinal metaplasia on biopsy, what's next? AB - OBJECTIVES: There are no guidelines regarding the best practice for when Barrett's esophagus (BE) is suspected but not confirmed by histology. The aim of this study was to examine the value of endoscopic follow-up for individuals with endoscopic only BE at index endoscopy. METHODS: We performed a longitudinal study of patients diagnosed with suspected columnar lined esophagus (CLE) (suspected BE in the absence of histological confirmation of specialized intestinal metaplasia (IM)). We examined three possible outcomes (definite BE defined as CLE plus IM in targeted biopsies, suspected CLE, or no suspected CLE) on repeat endoscopy within 2 years after the index endoscopy and their predictors (clinical, demographic as well as endoscopists' identity). RESULTS: A total of 107 of 1,844 patients had suspected CLE (101 were <3 cm), and 80 underwent a repeat endoscopy within 2 years. Approximately, 71% (95% confidence interval (CI) 61.1-80.9%) had suspected CLE confirmed at repeat endoscopy and only 29% (95% CI 19.1-38.9%) had IM. The length of CLE on the index esophagogastroduodenoscopies was slightly longer among patients with definite BE on repeat endoscopy than those with suspected CLE and no IM or no CLE (1.6 cm (s.d. 1.3) vs. 1.5 cm (s.d. 1.4), and 1.4 cm (s.d. 1.2), respectively P>0.1). Patient demographics, body mass index, gastro-esophageal reflux disease symptoms, hiatal hernia, and endoscopists' identity were not significantly associated with the outcome on the repeat endoscopy. CONCLUSIONS: Most (71%) patients with suspected CLE remain negative for IM in the 2 years following the index endoscopy. The findings support withholding BE diagnosis for individuals with suspected CLE. PMID- 24343551 TI - Visual similarity effects on masked priming. AB - We investigated the role of the visual similarity of masked primes to targets in a lexical decision experiment. In the primes, some letters in the target (e.g., A in ABANDON) had either visually similar letters (e.g., H), dissimilar letters (D), visually similar digits (4), or dissimilar digits (6) substituted for them. The similarities of the digits and letters to the base letter were equated and verified in a two-alternative forced choice (2AFC) perceptual identification task. Using targets presented in lowercase (e.g., abandon) and primes presented in uppercase, visually similar digit primes (e.g., 484NDON) produced more priming than did visually dissimilar digit primes (676NDON), but little difference was found between the visually similar and dissimilar letter primes (HRHNDON vs. DWDNDON). These results were explained in terms of task-driven competition between the target letter and the visually similar letter. PMID- 24343552 TI - Myocardial delayed enhancement by cardiac magnetic resonance imaging in Pulmonary Arterial Hypertension: a marker of disease severity. PMID- 24343553 TI - Acute coronary syndromes in 2011 and 2012. PMID- 24343554 TI - Sports events and Acute Coronary Syndrome: possible confounding factors and bias. PMID- 24343555 TI - Case 5: a 73 year-old man with heart failure, preserved systolic function and associated renal failure. PMID- 24343556 TI - Steal of blood flow from the vertebral artery to the internal thoracic artery anastomosed to the coronary artery. PMID- 24343557 TI - Korotkoff sounds -- the improbable also occurs. AB - Very few discoveries have had such a large impact on and relevance to clinical medicine as the noninvasive measurement of the diastolic blood pressure. A number of gifted physiologists and clinicians were ineffectively in search of a noninvasive method to determine the diastolic pressure. Nonetheless, the quantification of the diastolic BP was not achieved by any of these clinical or physiological researchers, but by an unlikely and unexpected figure: Nikolai Sergeevich Korotkoff (1874-1920), a young Russian army surgeon, working under precarious conditions in the hardship of diverse wars. It is easy to dismiss the achievement of Korotkoff as a serendipitous discovery, similar to that of Alexander Fleming in the discovery of penicillin. However, Nassim N. Taleb's recent black swan theory may serve to illustrate his discovery in a new and, perhaps, surprising way. PMID- 24343558 TI - Pooling of cultured samples and comparison of multistate laboratory workflows with the MagMAX sample preparation system and VetMAX quantitative polymerase chain reaction reagents for detection of Tritrichomonas foetus-colonized bulls. AB - The objectives of the current study were 1) to compare sample preparation workflows and quantitative real-time polymerase chain reaction assays (qPCR) as currently used in veterinary diagnostic laboratories with a study protocol utilizing commercially available reagents for individual Tritrichomonas foetus testing, 2) to assess the accuracy of pooling cultured smegma samples followed by extraction and qPCR testing as used in the study laboratory, and 3) to assess the specificity of the currently used primers and probes by sequencing all positive and presumptive positive samples identified in the study laboratory in an attempt to capture any nucleotide variability between T. foetus isolates and to rule out false-positive results possibly due to Simplicimonas moskowitzi. Eight hundred three cultured smegma samples were collected from different regions of the United States with the collaboration of 5 veterinary testing laboratories. The samples were processed individually by the respective laboratories, and then sent to the study laboratory and retested using the study protocol. Comparison testing showed an overall agreement of 95.89% between the veterinary testing laboratories and the study laboratory. One hundred seventy-six positive or presumptive positive samples plus 625 negative qPCR samples were combined and retested using a pooling protocol. Pools consisted of 1 positive sample and 4 negative samples (1/5). These pools were processed using the same study laboratory protocols, and 96% of the positive samples were detected in these pools. Nested PCR followed by sequencing confirmed 175 of the 178 samples classified as positive or presumptive positive in the study laboratory as containing T. foetus-specific DNA. PMID- 24343559 TI - Water balance model for polymer electrolyte fuel cells with ultrathin catalyst layers. AB - We present a water balance model of membrane electrode assemblies (MEAs) with ultrathin catalyst layers (UTCLs). The model treats the catalyst layers in an interface approximation and the gas diffusion layers as linear transmission lines of water fluxes. It relates current density, pressure distribution, and water fluxes in the different functional layers of the assembly. The optimal mode of operation of UTCLs is in a fully flooded state. The main challenge for MEAs with UTCLs is efficient liquid water removal, to avoid flooding of the gas diffusion layers. The model provides strategies for increasing the critical current density for the onset of flooding, via liquid permeabilities, vaporization areas, and gas pressure differentials. Finally, we discuss methods to identify regimes of transport via water flux measurements. PMID- 24343560 TI - Synthesis of zeolites using highly amphiphilic cations as organic structure directing agents by hydrothermal treatment of a dense silicate gel. AB - Silicalite-1 and siliceous *MRE zeolite were synthesized with a series of highly amphiphilic ammonium cations as organic SDAs. The relationship between the framework type and the chain length of the amphiphilic cation is explained in terms of the intermolecular N-N distance of the elongated SDA. PMID- 24343561 TI - [What is thinking inside the individual? Figurations of Collectivity in Ludwik Fleck, Tadeusz Bilikiewicz, and Ludwig Gumplowicz]. AB - "What thinks in man, is not he himself, but his social community." These words by the early sociologist Ludwig Gumplowicz (1838-1909) were quoted several times by Ludwik Fleck (1896-1961) and seem to be in complete agreement with his own theory of thought collectives. The assumption that even scientific ideas were not so much generated by the scientist as an autonomous individual but rather by and within the social environment was still considered provocative by Fleck in the 1930s. This article will explore the implications of this assumption by comparing Fleck with Gumplowicz as well as with Tadeusz Bilikiewicz (1901-1980), a psychiatrist, philosopher and historian of medicine working like Fleck in the cultural milieu of Lwow/Lemberg. PMID- 24343562 TI - Three coordination polymers constructed from various polynuclear clusters spaced by 2,2'-azodibenzoic acid: syntheses and fluorescent properties. AB - Solvothermal reactions of M(OAc)2.2H2O (M = Zn, Cd, Pb) with 2,2'-azodibenzoic acid (H2L) in MeOH-H2O (MeOH = methanol) at 120 degrees C gave rise to three coordination polymers, [Zn12(MU4-O)3L9]n (1), [CdL(H2O)]n (2) and [Pb3(MU4-O)L2]n (3). Compounds 1-3 are characterized by elemental analysis, IR, powder X-ray diffraction and single-crystal X-ray diffraction. Compound 1 has two similar tetranuclear [Zn4(MU4-O)(MU2-CO2)6] units as nodes and displays an intriguing three-dimensional (3D) 6-connected network with a 4(12)6(3) topology. Compound 2 exhibits a 3D framework constructed by linking infinite helical Cd-carboxylate chains through L ligands. Compound 3 holds a 3D structure in which each hexanuclear [Pb6(MU4-O)2(CO2)4] unit works as a six-connecting node to connect its equivalent ones via sharing L ligands. In addition, the fluorescent properties and thermal stabilities of 1-3 were also investigated. PMID- 24343563 TI - Ventriculostomy-associated infection: a new, standardized reporting definition and institutional experience. AB - OBJECTIVE: Shortcomings created by the lack of both a uniform definition of ventriculostomy-associated infection (VAI) and reporting standards have led to widely ranging infections rates (2-24%) whose significance is uncertain. We propose a standardized definition of VAI and a consistent reporting format compliant with Centers for Disease Control and Prevention (CDC) for device related infections. Using those parameters to establish an infection-control surveillance program, we report our 4-year institutional VAI rates. METHODS: In this prospective study covering ventriculostomy utilization (October 2006 December 2010), 498 patients had a total of 4,673 ventriculostomy days. By review of the literature and our institutional analysis, we defined VAI as a positive CSF culture in a patient with ventriculostomy catheter, plus one or more of the following (1) fever recorded >101.5 degrees F or (2) cerebrospinal fluid (CSF) glucose level, either <50 mg/dL or <50% of a serum glucose level drawn within 24 h of the CSF glucose. In a report format that is CDC compliant, rates of VAI are reported. RESULTS: Among our patients, the CDC-compliant infection rate was 2.14 per 1,000 ventriculostomy days. Of the 10 VAIs occurring in 498 patients during 4,673 ventriculostomy days, this 2.0% infection rate was lower than the previously reported 8.8% composite rates of VAI. Average duration of ventriculostomy was 9.4 days. Neither antibiotic-impregnated catheters nor periprocedural or prophylactic antibiotics were used. CONCLUSIONS: Our standardized VAI definition and CDC format seems promising toward facilitating future study and guideline development. Given our strict protocol of sterile catheter placement and care, and our institution's low 2.0% infection rates, we propose an infection-rate target of <=5 per 1,000 device days. Our results suggest that the use of antibiotics or antibiotic-impregnated catheters is unwarranted--a positive given concerns of evolving anti-microbial resistance. PMID- 24343565 TI - Resilience as a universal criterion of health. AB - To promote and maintain health in agricultural and food systems, appropriate criteria are needed for the description and assessment of the health of soils, plants, animals, humans and ecosystems. Here we identify the concept of resilience as a universally applicable and fundamentally important criterion of health in all relevant areas of agriculture. We discuss definitions of resilience for soils, plants, animals, humans and ecosystems, and explore ways in which resilience can be applied as a criterion of health in different agricultural contexts. We show how and why resilience can be seen as a key criterion of health. Based on this, we discuss how resilience can be used as a link between soil, plant, animal, human and ecosystem health. Finally, we highlight four key areas for future research on resilience in agriculture, namely spatial and temporal scaling of resilience; effects of diversity; the role of networks for resilience; and stakeholder involvement. PMID- 24343566 TI - Highly conductive poly(3,4-ethylenedioxypyrrole) and poly(3,4 ethylenedioxythiophene) enwrapped Sb2S3 nanorods for flexible supercapacitors. AB - Composites of poly(3,4-ethylenedioxypyrrole) or PEDOP and poly(3,4 ethylenedioxythiophene) or PEDOT enwrapped Sb2S3 nanorods have been synthesized for the first time for use as supercapacitor electrodes. Hydrothermally synthesized Sb2S3 nanorods, several microns in length and 50-150 nm wide, offer high surface area and serve as a scaffold for coating conducting polymers, and are a viable alternative to carbon nanostructures. Fibrillar morphologies are achieved for the PEDOP-Sb2S3 and PEDOT-Sb2S3 films in contrast to the regular granular topologies attained for the neat polymers. The remarkably high nanoscale (~5 S cm(-1)) conductivity of the Sb2S3 nanorods enables facile electron transport in the composites. We constructed asymmetric supercapacitors using the neat polymer or composite and graphite as electrodes. High specific capacitances of 1008 F g(-1) and 830 F g(-1) (at 1 A g(-1)), enhanced power densities (504 and 415 W kg(-1)) and excellent cycling stability (88 and 85% capacitance retention at the end of 1000 cycles) are delivered by the PEDOP-Sb2S3 and PEDOT-Sb2S3 cells relative to the neat polymer cells. A demonstration of a light emitting diode illumination using a light-weight, flexible, supercapacitor fabricated with PEDOP Sb2S3 and carbon-fiber cloth shows the applicability of Sb2S3 enwrapped conducting polymers as sustainable electrodes for ultra-thin supercapacitors. PMID- 24343564 TI - Detection of spreading depolarization with intraparenchymal electrodes in the injured human brain. AB - BACKGROUND: Spreading depolarization events following ischemic and traumatic brain injury are associated with poor patient outcome. Currently, monitoring these events is limited to patients in whom subdural electrodes can be placed at open craniotomy. This study examined whether these events can be detected using intra-cortical electrodes, opening the way for electrode insertion via burr hole. METHODS: Animal work was carried out on adult Sprague-Dawley rats in a laboratory setting to investigate the feasibility of recording depolarization events. Subsequently, 8 human patients requiring craniotomy for traumatic brain injury or aneurysmal subarachnoid hemorrhage were monitored for depolarization events in an intensive care setting with concurrent strip (subdural) and depth (intra parenchymal) electrode recordings. RESULTS: (1) Depolarization events can be reliably detected from intra-cortically placed electrodes. (2) A reproducible slow potential change (SPC) waveform morphology was identified from intra cortical electrodes on the depth array. (3) The depression of cortical activity known to follow depolarization events was identified consistently from both intra cortical and sub-cortical electrodes on the depth array. CONCLUSIONS: Intra parenchymally sited electrodes can be used to consistently identify depolarization events in humans. This technique greatly extends the capability of monitoring for spreading depolarization events in injured patients, as electrodes can be sited without the need for craniotomy. The method provides a new investigative tool for the evaluation of the contribution of these events to secondary brain injury in human patients. PMID- 24343567 TI - 'Take as directed'--strategies to improve adherence to cardiac medication. AB - In patients with cardiovascular diseases, adherence to medication is a fundamental prerequisite for pharmacological therapy to be effective. Nonadherence to medication is a major public health problem that compromises the effectiveness of therapies and results in suboptimal clinical outcomes. The behaviour of nonadherence is complex and is strongly influenced by an interaction between various factors, such as patient education, communication between patients and physicians, drug dosing schedules, and access to health care. Interventions have been implemented to target these barriers to adherence; however, individual interventions have generally been associated with fairly modest improvements in adherence. Financial incentive schemes and modern technology, such as mobile telephone applications, are being harnessed as novel strategies to improve adherence. Ultimately, multifaceted strategies tailored to individual patients are likely to be required to improve long-term adherence to medication and consequently enhance patient health. PMID- 24343569 TI - A TACTful reappraisal of chelation therapy in cardiovascular disease. AB - Atherosclerotic cardiovascular disease (CVD) is highly prevalent and, despite therapeutic advances, remains a leading cause of morbidity and mortality. Many patients with CVD seek additional alternative therapies when symptoms are not controlled with evidence-based therapies. Although its therapeutic efficacy is unproven, chelation therapy with ethylenediamine tetra acetic acid (EDTA) is increasingly being used in patients with CVD. Early studies of chelation in atherosclerotic CVD provided the basis for the randomized Trial to Assess Chelation Therapy (TACT), in which chelation with disodium EDTA was compared with placebo in patients who had experienced a myocardial infarction. Here, we discuss the results, limitations, and implications of TACT in the context of other studies in the field. We believe that the findings from TACT are not robust and do not marshal evidence in support of the potential clinical use of chelation therapy for CVD, with the potential exception of certain high-risk cohorts such as patients with diabetes mellitus. Therefore, chelation is unlikely to become a widely-accepted approach until additional data are available. PMID- 24343568 TI - Endovascular treatment of abdominal aortic aneurysms. AB - Patients with abdominal aortic aneurysms (AAAs) are usually treated with endovascular aneurysm repair (EVAR), which has become the standard of care in many hospitals for patients with suitable anatomy. Clinical evidence indicates that EVAR is associated with superior perioperative outcomes and similar long term survival compared with open repair. Since the randomized, controlled trials that provided this evidence were conducted, however, the stent graft technology for infrarenal AAA has been further developed. Improvements include profile downsizing, optimization of sealing and fixation, and the use of low porosity fabrics. In addition, imaging techniques have improved, enabling better preoperative planning, stent graft placement, and postoperative surveillance. Also in the past few years, fenestrated and branched stent grafts have increasingly been used to manage anatomically challenging aneurysms, and experiments with off-label use of stent grafts have been performed to treat patients deemed unfit or unsuitable for other treatment strategies. Overall, the indications for endovascular management of AAA are expanding to include increasingly complex and anatomically challenging aneurysms. Ongoing studies and optimization of imaging, in addition to technological refinement of stent grafts, will hopefully continue to broaden the utilization of EVAR. PMID- 24343570 TI - Early life stress and sex-specific sensitivity of the catecholaminergic systems in prefrontal and limbic regions of Octodon degus. AB - Previous work in the precocious rodent Octodon degus has shown that exposure to early life stress (ELS) (induced by repeated parental separation) results in changes of excitatory, inhibitory and modulatory transmitter systems in prefrontal and limbic regions of the male brain. The aim of this study was to test the hypothesis that catecholaminergic fibers and dopamine transporters (DAT) are differentially vulnerable towards ELS-induced neuronal changes in male and female brains. The brains of adult male and female animals exposed to repeated early life stress (1 h/day separation from the family from P1 to P21) and control animals were compared and the densities of tyrosine hydroxylase (TH) immunoreactive structures were quantified in prefrontal cortical regions. In the nucleus accumbens (NAc) and striatum, DAT-immunoreactivity as well as TH immunoreactivity was measured. Layer II of the prelimbic cortex displayed reduced TH-fiber densities in ELS males compared to control males; this effect was not seen in females. In contrast, layer V/VI of the lateral orbitofrontal cortex displayed elevated fiber densities in ELS males compared to controls; again this difference was not observed in females. The same trend was observed for layer III/IV of the ventral orbitofrontal cortex. No sex-specific effects in response to ELS were observed for DAT, whose density was elevated in the NAc of ELS males and females. These results are in line with our working hypothesis that ELS affects the development of catecholaminergic systems and we show here that ELS induced differences of TH-immunoreactive fibers were more pronounced in male brains than in female brains. PMID- 24343571 TI - The C-terminal transmembrane domain of human phospholipid scramblase 1 is essential for the protein flip-flop activity and Ca2+-binding. AB - Human phospholipid scramblase 1 (SCR) is a 318 amino acid protein that was originally described as catalyzing phospholipid transbilayer (flip-flop) motion in plasma membranes in a Ca2+-dependent, ATP-independent way. Further studies have suggested an intranuclear role for this protein in addition. A putative transmembrane domain located at the C terminus (aa 291-309) has been related to the flip-flop catalysis. In order to clarify the role of the C-terminal region of SCR, a mutant was produced (SCRDelta) in which the last 28 amino acid residues were lacking, including the alpha-helix. SCRDelta had lost the scramblase activity and its affinity for Ca2+ was decreased by one order of magnitude. Fluorescence and IR spectroscopic studies revealed that the C-terminal region of SCR was essential for the proper folding of the protein. Moreover, it was found that Ca2+ exerted an overall destabilizing effect on SCR, which might facilitate its binding to membranes. PMID- 24343572 TI - Effects of novel dinuclear cisplatinum(II) complexes on the electric properties of human breast cancer cells. AB - The aim of this study was to determine the influence of cisplatin and novel dinuclear platinum(II) complexes on the electrical properties of the membrane and the level of lipid peroxidation in the human breast cancer cell lines MDA-MB-231 and MCF-7. The basal electrical surface properties of cells are known. Changes in cell function may affect these surface properties, and those changes can be detected by electrokinetic measurements. The surface charge density of the breast cancer cell lines MDA-MB-231 and MCF-7 were measured as a function of pH. A four component equilibrium model was used to describe the interaction between the solution ions and the breast cancer cell surface. The experimental and the theoretical charge variation curves of the breast cancer cells at pH 2.5-9 were in agreement. Measurements of the cellular malondialdehyde levels with high performance liquid chromatography were used to determine the extent of lipid peroxidation. The acid and base functional group concentrations and average association constants with hydroxyl ions were smaller in breast cancer cell membranes treated with cisplatin or novel dinuclear platinum(II) complexes compared with untreated cancer cells, and the average association constants with hydrogen ions were higher. The levels of lipid peroxidation products in breast cancer cells treated with cisplatin or novel dinuclear platinum(II) complexes were also higher than in untreated cancer cells. PMID- 24343573 TI - Standardizing economic analysis in prevention will require substantial effort. AB - It is exceedingly difficult to compare results of economic analyses across studies due to variations in assumptions, methodology, and outcome measures, a fact which surely decreases the impact and usefulness of prevention-related economic research. Therefore, Crowley et al. (Prevention Science, 2013) are precisely correct in their call for increased standardization and have usefully highlighted the issues that must be addressed. However, having made the need clear, the questions become what form the solution should take, and how should it be implemented. The present discussion outlines the rudiments of a comprehensive framework for promoting standardized methodology in the estimation of economic outcomes, as encouraged by Crowley et al. In short, a single, standard, reference case approach should be clearly articulated, and all economic research should be encouraged to apply that standard approach, with results from compliant analyses being reported in a central archive. Properly done, the process would increase the ability of those without specialized training to contribute to the body of economic research pertaining to prevention, and the most difficult tasks of predicting and monetizing distal outcomes would be readily completed through predetermined models. These recommendations might be viewed as somewhat forcible, insomuch as they advocate for prescribing the details of a standard methodology and establishing a means of verifying compliance. However, it is unclear that the best practices proposed by Crowley et al. will be widely adopted in the absence of a strong and determined approach. PMID- 24343574 TI - Structural and functional comparison of the persistent and resolved amblyopia. AB - PURPOSE: To assess structural or functional differences of the retina among subjects with persistent and resolved amblyopia. METHODS: Fourteen eyes with persistent amblyopia that did not reach normal visual acuity (VA) levels (<=0.1 LogMAR) despite amblyopia treatment, 18 eyes with resolved amblyopia, and 16 eyes of 16 normal subjects were included. All subjects underwent optical coherence tomography (OCT), pattern visual evoked potential (PVEP), and pattern electroretinography (PERG) evaluation. RESULTS: There was no significant difference in foveal thickness, foveal volume, macular volume, ganglion cell layer thickness, and total and sectorial retinal nerve fiber layer measurements among three groups (p > 0.05). Foveolar thickness was significantly increased in both resolved and persistent amblyopia groups compared with the control group (p = 0.031). However, there was no difference between amblyopic groups (p = 0.98). Although, in the PVEP study, N75 implicit time was found significantly prolonged in both amblyopia groups (p = 0.046), there were no significant differences in P100 implicit time and amplitude among the groups (p > 0.05). PERG amplitude of the persistent group was significantly lower than that of the control group (p = 0.003). There were no significant differences in P50, N95 implicit times among groups (p > 0.05). CONCLUSIONS: In our study, the only significant difference between persistent and resolved amblyopia groups was the initial VA. Neither OCT nor electrophysiological examinations were found to be useful in order to explain why some cases were resistant to the treatment for amblyopia. PMID- 24343575 TI - Cholecystokinin from the entorhinal cortex enables neural plasticity in the auditory cortex. AB - Patients with damage to the medial temporal lobe show deficits in forming new declarative memories but can still recall older memories, suggesting that the medial temporal lobe is necessary for encoding memories in the neocortex. Here, we found that cortical projection neurons in the perirhinal and entorhinal cortices were mostly immunopositive for cholecystokinin (CCK). Local infusion of CCK in the auditory cortex of anesthetized rats induced plastic changes that enabled cortical neurons to potentiate their responses or to start responding to an auditory stimulus that was paired with a tone that robustly triggered action potentials. CCK infusion also enabled auditory neurons to start responding to a light stimulus that was paired with a noise burst. In vivo intracellular recordings in the auditory cortex showed that synaptic strength was potentiated after two pairings of presynaptic and postsynaptic activity in the presence of CCK. Infusion of a CCKB antagonist in the auditory cortex prevented the formation of a visuo-auditory association in awake rats. Finally, activation of the entorhinal cortex potentiated neuronal responses in the auditory cortex, which was suppressed by infusion of a CCKB antagonist. Together, these findings suggest that the medial temporal lobe influences neocortical plasticity via CCK-positive cortical projection neurons in the entorhinal cortex. PMID- 24343576 TI - A DELLA protein complex controls the arbuscular mycorrhizal symbiosis in plants. PMID- 24343577 TI - Innate IFNgamma-producing B cells. AB - In a recent paper published in Cell Research, Yan Bao and colleagues characterize a new population of IFNgamma-producing innate-like B cells that promotes innate immune responses and contributes to early pathogen control following intracellular bacterial infection. PMID- 24343579 TI - Regenerative medicine: transdifferentiation in vivo. AB - A major challenge in regenerative medicine is the generation of functionally effective target cells to replace or repair damaged tissues. Transdifferentiation in vivo is a novel strategy to achieve cell fate conversion within the native physiological niche; this technology may provide a time- and cost-effective alternative for applications in regenerative medicine and may also minimize the concerns associated with in vitro culture and cell transplantation. PMID- 24343580 TI - Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV Medicine Association of the Infectious Diseases Society of America. AB - Evidence-based guidelines for the management of persons infected with human immunodeficiency virus (HIV) were prepared by an expert panel of the HIV Medicine Association of the Infectious Diseases Society of America. These updated guidelines replace those published in 2009. The guidelines are intended for use by healthcare providers who care for HIV-infected patients. Since 2009, new antiretroviral drugs and classes have become available, and the prognosis of persons with HIV infection continues to improve. However, with fewer complications and increased survival, HIV-infected persons are increasingly developing common health problems that also affect the general population. Some of these conditions may be related to HIV infection itself or its treatment. HIV infected persons should be managed and monitored for all relevant age- and sex specific health problems. New information based on publications from the period 2009-2013 has been incorporated into this document. PMID- 24343581 TI - Photoquiz. Holoinspiratory wheezing in a 46-year-old HIV-seropositive man. PMID- 24343578 TI - Autophagy regulation by nutrient signaling. AB - The ability of cells to respond to changes in nutrient availability is essential for the maintenance of metabolic homeostasis and viability. One of the key cellular responses to nutrient withdrawal is the upregulation of autophagy. Recently, there has been a rapid expansion in our knowledge of the molecular mechanisms involved in the regulation of mammalian autophagy induction in response to depletion of key nutrients. Intracellular amino acids, ATP, and oxygen levels are intimately tied to the cellular balance of anabolic and catabolic processes. Signaling from key nutrient-sensitive kinases mTORC1 and AMP activated protein kinase (AMPK) is essential for the nutrient sensing of the autophagy pathway. Recent advances have shown that the nutrient status of the cell is largely passed on to the autophagic machinery through the coordinated regulation of the ULK and VPS34 kinase complexes. Identification of extensive crosstalk and feedback loops converging on the regulation of ULK and VPS34 can be attributed to the importance of these kinases in autophagy induction and maintaining cellular homeostasis. PMID- 24343583 TI - Crossing borders: one world, global health. PMID- 24343584 TI - Synthesis and characterisation of new MO(OH)2 (M = Zr, Hf) oxyhydroxides and related Li2MO3 salts. AB - Two new solid MO(OH)2 (M = Zr, Hf) oxyhydroxides have been synthesised by an ion exchange reaction from Li2MO3 (M = Zr, Hf) precursors obtained by a citrate combustion technique. The crystal structure of the oxyhydroxides has been solved by direct methods and refined using Rietveld full profile fitting based on X-ray powder diffraction data. Both oxyhydroxides crystallize in a P2(1)/c monoclinic unit cell and have a structure resembling that of the related salts. Detailed characterisation of the fine-structure features and chemical bonding in precursors and oxyhydroxide powders has been performed using vibrational spectroscopy, nuclear magnetic resonance spectroscopy, scanning electron microscopy, pair distribution function analysis and quantum-chemical modelling. PMID- 24343585 TI - Hyperbaric oxygen therapy for treating acute surgical and traumatic wounds. AB - BACKGROUND: Hyperbaric oxygen therapy (HBOT) is used as a treatment for acute wounds (such as those arising from surgery and trauma). However, the effects of HBOT on wound healing are unclear. OBJECTIVES: To determine the effects of HBOT on the healing of acute surgical and traumatic wounds. SEARCH METHODS: We searched the Cochrane Wounds Group Specialised Register (searched 9 August 2013); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 12); Ovid MEDLINE (2010 to July Week 5 2013); Ovid MEDLINE (In-Process & Other Non-Indexed Citations, August 08, 2013); Ovid EMBASE (2010 to 2013 Week 31); EBSCO CINAHL (2010 to 8 August 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing HBOT with other interventions such as dressings, steroids, or sham HOBT or comparisons between alternative HBOT regimens. DATA COLLECTION AND ANALYSIS: Two review authors conducted selection of trials, risk of bias assessment, data extraction and data synthesis independently. Any disagreements were referred to a third review author. MAIN RESULTS: Four trials involving 229 participants were included. The studies were clinically heterogeneous, which precluded a meta-analysis.One trial (48 participants with burn wounds undergoing split skin grafts) compared HBOT with usual care and reported a significantly higher complete graft survival associated with HBOT (95% healthy graft area risk ratio (RR) 3.50; 95% confidence interval (CI) 1.35 to 9.11). A second trial (10 participants in free flap surgery) reported no significant difference between graft survival (no data available). A third trial (36 participants with crush injuries) reported significantly more wounds healed (RR 1.70; 95% CI 1.11 to 2.61), and significantly less tissue necrosis (RR 0.13; 95% CI 0.02 to 0.90) with HBOT compared to sham HBOT. The fourth trial (135 people undergoing flap grafting) reported no significant differences in complete graft survival with HBOT compared with dexamethasone (RR 1.14; 95% CI 0.95 to 1.38) or heparin (RR 1.21; 95% CI 0.99 to 1.49).Many of the predefined secondary outcomes of the review were not reported. All four trials were at unclear or high risk of bias. AUTHORS' CONCLUSIONS: There is a lack of high quality, valid research evidence regarding the effects of HBOT on wound healing. Whilst two small trials suggested that HBOT may improve the outcomes of skin grafting and trauma, these trials were at risk of bias. Further evaluation by means of high quality RCTs is needed. PMID- 24343587 TI - Polymorphism in 9,9-diarylfluorene-based organic semiconductors: influence on optoelectronic functions. AB - Polymorphism is observed in 9,9-diarylfluorene-based organic semiconductors. The effects of rich phase behavior on the charge transport and photoluminescence properties of these semiconductors are investigated. Polymorphism control is a rational way to tailor the optoelectronic functions of their films. PMID- 24343586 TI - Labeling thiols on proteins, living cells, and tissues with enhanced emission induced by FRET. AB - Using N-(2-Aminoethyl)maleimide-cysteine(StBu) (Mal-Cys) as a medium, protein thiols were converted into N-terminal cysteines. After a biocompatible condensation reaction between the N-terminal cysteine and fluorescent probe 2 cyanobenzothiazole-Gly-Gly-Gly-fluorescein isothiocyanate (CBT-GGG-FITC), a new fluorogenic structure Luciferin-GGG-FITC was obtained. The latter exhibits near one order of magnitude (7 folds) enhanced fluorescence emission compared to the precursor moiety due to fluorescence resonance energy transfer (FRET) effect between the newly formed luciferin structure and the FITC motif. Theoretical investigations revealed the underlying mechanism that satisfactorily explained the experimental results. With this method, enhanced fluorescence imaging of thiols on proteins, outer membranes of living cells, translocation of membrane proteins, and endothelial cell layers of small arteries was successfully achieved. PMID- 24343589 TI - Harvesting UV photons for solar energy conversion applications. AB - We report the synthesis and characterization of five new donor-pi-spacer-acceptor dye molecules with a diphenylamine donor, fluorene-1,2,5-oxadiazole spacers and a range of acceptor/anchor groups (carboxylic acid 1, cyanoacrylic acid 2 and 3, alcohol 4 and cyano 5) to facilitate electron injection from the excited dye into the TiO2 photoanode in dye-sensitized solar cells (DSSCs). Detailed photophysical studies have probed the dyes' excited state properties and revealed structure property relationships within the series. Density functional theory (DFT) and time dependent DFT (TDDFT) calculations provide further insights into how the molecular geometry and electronic properties impact on the photovoltaic performance. A special feature of these dyes is that their absorption features are located predominantly in the UV region, which means the dye-sensitized TiO2 is essentially colorless. Nevertheless, DSSCs assembled from 1 and 2 exhibit photovoltaic power conversion efficiencies of eta = 1.3 and 2.2%, respectively, which makes the dyes viable candidates for low-power solar cells that need to be transparent and colorless and for applications that require enhanced harvesting of UV photons. PMID- 24343588 TI - Recent treatment advances and novel therapies in pancreas cancer: a review. AB - PURPOSE: Over the last couple of years, we have witnessed the availability of a wide variety of different therapeutic agents and the identification of effective combinations of existing ones that have transformed the way we approach and treat pancreatic cancer. Proof of this are the recent validations that combinations of conventional chemotherapy drugs, the FOLFIRINOX regimen and gemcitabine plus nab paclitaxel, significantly improves clinical outcomes in patients with metastatic disease. However, deeper and more sophisticated understanding of the biology of this cancer as well as the ability to develop better and perhaps more precise drugs predict that the landscape may be changing even more. METHODOLOGY AND RESULTS: In this review, we will summarize the most recent treatment advances including FOLFIRINOX, gemcitabine plus nab-paclitaxel and discuss novel approaches such as immune-mediated therapies, drugs that disrupt the tumor stromal compartment, PARP inhibitors for BRCA pathway-deficient pancreatic cancer and new generations of conventional chemotherapeutics, which are in early phases of clinical development and have shown promising early results. We will also discuss some examples of drugs that failed, despite very good preliminary data, in order to appraise the lessons learned from these negative clinical trials. Lastly, we will comment on ongoing adjuvant and neoadjuvant trials. CONCLUSION: We hope that at least some of these will result in positive trials and add to our armamentarium for treating this challenging malignancy. PMID- 24343590 TI - HPLC study of migration of terephthalic acid and isophthalic acid from PET bottles into edible oils. AB - BACKGROUND: Polyethylene terephthalate (PET) containers for food oil packaging were evaluated with a newly established determination method for terephthalic acid (TPA) and isophthalic acid (IPA). The analysis of monomers, TPA and IPA that migrate from PET bottles into oils was performed using high-pressure liquid chromatography with a diode array detector. Three types of commercial oils (sunflower oil, canola oil and blended oil which included sunflower oil, soy bean oil and cottonseed oil) were bottled in PET containers. These samples were incubated for 10 days at 49 degrees C as accelerated test condition. RESULTS: The means of recovery for this method varied from 70% to 72% and from 101% to 111% for TPA and IPA, respectively. The results showed that the amounts of specific migration of TPA and IPA into the samples conform to European Union legislation that identifies specific migration limits. More important, the results highlighted a different behavior of migration as a function of the fatty acid profile. CONCLUSION: Previous investigations have been performed with food simulants such as HB307 or 20% ethanol but our study used real food samples and determined trace amounts of the migrated compounds. Further investigation will be needed to better explain the influence of fatty acid conformation on migration of PET monomers. PMID- 24343591 TI - Minimally invasive vitreo retinal surgery: how small do we go? PMID- 24343592 TI - Evaluation of anterior segment parameters using pentacam in silicone oil-injected patients after pars plana vitrectomy. AB - BACKGROUND: The aim of this study is to evaluate anterior segment changes with Pentacam Scheimpflug camera after pars plana vitrectomy (PPV) and silicone oil injection. MATERIALS AND METHODS: In all, 44 eyes of 44 patients who underwent PPV by one surgeon were evaluated with Pentacam preoperatively, first week, and first month after surgery. The patients were divided into two groups, eyes with silicone injection after PPV and eyes with PPV and no endotamponade. Main outcome measures were preoperative and postoperative anterior chamber volume (ACV), anterior chamber depth (ACD), anterior chamber angle (ACA), and central corneal thickness (CCT) obtained with pentacam. RESULTS: Each group consisted of 22 patients. In both groups no significant difference was detected among preop and postop changes in ACV and ACA values (p > 0.05). The increase in ACD in silicone oil-injected group and the decrease in ACD in PPV group at postop 1 week were statistically significant (p < 0.05). The increase in CCT in silicone oil injected group at postop 1 week and then decrease in postop 1 month were also significant (p < 0.05). Surgically induced astigmatism (SIA) was 3.7 Dioptry (D) in silicone oil-injected group and 2.4 D in PPV group at postop 1 week. SIA decreased to 1.7 D and 1.5 D, respectively, at postop 1 month. Changes in SIA were significant (p < 0.05). CONCLUSION: PPV effects cornea and anterior segment. Changes in cornea and anterior segment after PPV seem to return to preoperative values among 1 month after surgery. PMID- 24343593 TI - Visual outcome and rotational stability of open loop toric intraocular lens implantation in Indian eyes. AB - PURPOSE: To assess the visual outcome and rotational stability of single-piece open loop toric Intra Ocular Lens (IOL) in a clinical setting. MATERIALS AND METHODS: In a prospective study, 122 eyes of 77 patients were followed up for a period of 12 months after cataract surgery with toric open loop IOL implantation. The pre-operative markings for the position of incision and IOL placement were done under slit lamp by anterior stromal puncture. The visual acuity, refraction, and IOL position were assessed at day 1, 1 week, 1 month, 3 months, 6 months, and 12 months after surgery. RESULTS: The mean age of the cohort was 56 yrs (S.D. 13.88; range 16 to 87 years). The mean pre-operative cylinder of corneal astigmatism was 1.37 D. (SD 0.79, range 1.0 to 5.87 D). Mean post-operative refractive cylinder was 0.36 D (SD 0.57, range 0 to 1.50 D) at 12 months. Ninety seven percent of the eyes were within 1 D of residual astigmatism. Ninety-four percent of patients had uncorrected visual acuity of 20/30 or better. Four eyes required IOL repositioning due to rotation. At 12 months, 96.7% of the IOLs were within 10 degrees of the target axis. There was no rotation seen after 6 months. CONCLUSION: Toric IOLs are very effective and consistent in correcting astigmatism during the cataract surgery. IOL rotation happens mostly within a month of surgery, and if significant, requires early repositioning. PMID- 24343594 TI - Factors predicting recurrence in successfully treated cases of anisometropic amblyopia. AB - CONTEXT: Recurrence after successful treatment of amblyopia is known and understanding the risk factors could help effective management. AIM: To measure incidence of recurrence in successfully treated cases of anisometropic amblyopia and evaluate factors predicting it. SETTINGS AND DESIGN: Cohort Study at a tertiary level institution. MATERIALS AND METHODS: Successfully treated anisometropic amblyopes aged 4-12 years were followed up for 1 year after stopping therapy. Best corrected visual acuity (BCVA), refractive error, stereoacuity and contrast sensitivity were evaluated at baseline and follow-up. STATISTICAL ANALYSIS: Intergroup analysis with appropriate tests: Chi-square test, Fisher's exact test, Wilcoxon rank sum test and paired t-test. RESULTS: One hundred and two patients with mean age at diagnosis 7.06 MU 1.81 years were followed-up for a mean duration of 1.0 MU 0.2 years. The mean pre-treatment BCVA (LogMAR score) at diagnosis was 0.73 MU 0.36 units which improved to 0.20 MU 0.00 with treatment and after 1 year of stopping treatment was 0.22 MU 0.07. Thirteen (12.74%) patients showed amblyopia recurrence during follow-up. Risk of recurrence was higher with older age of onset of treatment (6.64 MU 1.77 years without recurrence v/s 8.53 MU 1.39 years with recurrence, P = 0.0014). Greater extent of improvement of VA (P = 0.048) and final VA at stopping occlusion (P = 0.03) were associated with higher recurrence. Binocularity status or stereoacuity changes were not associated with risk of recurrence. CONCLUSIONS: Significant numbers of children suffer recurrence of amblyopia after stopping therapy. Older age, better BCVA after stopping therapy and greater magnitude of improvement in BCVA are important risk factors for recurrence. Careful follow-up is essential for early detection and management of recurrence. PMID- 24343595 TI - Flash visual evoked potentials in patients with periventricular leucomalacia in children less than 1 year of age. AB - BACKGROUND AND AIM: Children with periventricular leucomalacia (PVL) are known to have visual impairment of various forms starting from reduced vision, field defects, congnitive problems, and problems with hand eye coordination. There is very scant data/literature on the visual evoked potentials (VEPs) at an early age in children with PVL. We did a study to evaluate the flash visual evoked potentials (fVEPs) in children with PVL less than 1 year of age. MATERIALS AND METHODS: A total of nine children diagnosed as having PVL on magnetic resonance imaging were included in the study. The mean age was 9.7MU 3.5 months. All children underwent handheld fVEPs under sedation at two different flash frequencies 1.4 and 8 Hz. RESULTS: The mean latency of N1 and P1 on stimulation with 1.4 Hz was 47.9MU 15.2 and 77.7MU 26.0 ms, respectively. However, on stimulation with 8 Hz the mean latency of N1 and P1 was 189.8MU 25.6 and 238.4MU 33.6 ms, respectively. The mean amplitude with 1.4 Hz and 8 stimulation frequency was 5.6MU 4.5 and 5.59MU 3 mV, respectively. CONCLUSION: We have found for the first time that there is a change in the latency and the delay occurs at 8 Hz frequency but not at 1.4 Hz. We also conclude that amplitudes by fVEPs may be normal even in presence of periventricular changes. The amplitudes of fVEPs are not reliable in children with PVL. PMID- 24343596 TI - Morphological features of choroidal metastases: an OCT analysis. AB - The morphological characteristics and retinal changes of chroidal metastases using Spectral Domain OCT are described in a case with primary lung adenocarcinoma and secondary choroidal involvement. PMID- 24343597 TI - Macular hemorrhage as a cause of acute angle closure. PMID- 24343598 TI - Treatment of polypoidal choroidal vasculopathy with intravitreal bevacizumab monotherapy. PMID- 24343599 TI - The neutrophil lymphocyte ratio may be useful inflammatory indicator before applying other expensive and invasive procedures. PMID- 24343600 TI - Comment on "Submacular hemorrhage: a study among Indian eyes. PMID- 24343601 TI - Low-fluence PDT better than anti-vascular endothelial growth factor. PMID- 24343602 TI - Platelet indices in retinal vein occlusion in hypertensive patients. PMID- 24343603 TI - Isolated interrupted aortic arch in adulthood: A case report. PMID- 24343604 TI - Comparative pharmacokinetics studies of benzoylhypaconine, benzoylmesaconine, benzoylaconine and hypaconitine in rats by LC-MS method after administration of Radix Aconiti Lateralis Praeparata extract and Dahuang Fuzi Decoction. AB - A rapid and sensitive high-performance liquid chromatography-mass spectrometric (HPLC-MS) method was developed and validated for simultaneous determination of benzoylhypaconine (BHA), benzoylmesaconine (BMA), benzoylaconine (BAC) and hypaconitine (HA) in rat plasma for the first time. The analytes were separated on a Kromasil C18 column with a total running time of 11 min. The validation data demonstrated a sound feasibility for the newly developed method and it was then applied to the pharmacokinetic study of these analytes in rats. Pharmacokinetic behaviors of BHA, BMA, BAC and HA in rats were studied after oral administration of Radix Aconiti Lateralis Praeparata extract (FZ) and Dahuang Fuzi Decoction (DFD). The main parameters for the two groups of subjects were compared, and significant differences between Radix Aconiti Lateralis Praeparata extract group and Dahuang Fuzi Decoction group in calculated parameters, such as the area under the plasma concentration-time from zero to the last quantifiable time-point (AUC(0-t)), the area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)), peak plasma concentration (C(max)), half-life of elimination (T1/2), mean retention time (MRT(0-t)), plasma clearance (CL), volume of distribution (V(d)) and time to reach Cmax (T(max)), were found. After oral administration of DFD, the AUC(0-t), AUC(0-infinity) and C(max) of BHA, BMA, BAC and HA decreased remarkably (p < 0.05) compared with those of the FZ extract group. Vd and CL values of BHA, BMA, BAC and HA increased, two of which showed significant difference (p < 0.05). T1/2 and MRT(0-t) values of BHA, BMA and BAC in the DFD group were significantly delayed compared with those of FZ extract group. Only the T(max) of HA, the toxic ingredient in FZ, delayed significantly in DFD group compared with the value of FZ group. All these pharmacokinetic parameters were statistically compared, and the rationality of the combination for DFD was clearly demonstrated. PMID- 24343605 TI - Preparing for the scale-up of rotavirus vaccine introduction in Africa: establishing surveillance platforms to monitor disease burden and vaccine impact. AB - Countries in Africa have begun introducing rotavirus vaccines in their national immunization programs, and wide-scale rollout across the continent is expected during the next few years. In preparation for vaccine introduction, many countries initiated surveillance for rotavirus and other studies to document disease burden, to describe the epidemiology and to monitor circulating rotavirus strains in Africa. In addition, 2 countries sought to systematically investigate cases of intussusception, a rare adverse event that has been associated with rotavirus vaccines in some settings. The ongoing surveillance provided data that will serve as a baseline against which the impact of rotavirus vaccines in Africa can be assessed. PMID- 24343606 TI - High index of suspicion of intussusception in an 8-month South African child: a case report. AB - This case report describes diagnosis and management of intussusception in an 8 month-old baby girl seen at the Ventersdorp District Hospital, South Africa. According to the vaccination card, the child had been immunized with rotavirus vaccine with the last dose given 6 months and 2 weeks before presentation to Ventersdorp Hospital. This case of intussusception was unlikely associated with rotavirus vaccination. PMID- 24343607 TI - Surveillance for rotavirus gastroenteritis in children less than 5 years of age in Togo. AB - BACKGROUND: Rotavirus is the most common cause of severe gastroenteritis and dehydration in young children in both industrialized and developing countries. The anticipated introduction of rotavirus vaccine into Togo's national immunization program highlights the need for baseline data on the burden of this disease. METHODS: We conducted sentinel surveillance for rotavirus gastroenteritis among children <5 years of age in Sylvanus Olympio Teaching Hospital of Lome (Togo) from February 2008 through January 2012, based on the World Health Organization's generic protocol. Rotavirus was detected in stool specimens by enzyme linked immunosorbent assay. The strain characterization by genotyping was performed at Noguchi Memorial Institute for Medical Research in Accra (Ghana) and at Medunsa campus in Pretoria (South Africa). RESULTS: 803 children with acute gastroenteritis were enrolled and of which 390 (48%) were positive for rotavirus. The difference of age among children with rotavirus and nonrotavirus gastroenteritis was significant (P < 0.010) with rotavirus cases younger than nonrotavirus cases. From December to February, significantly (P < 0.002) more cases of rotavirus gastroenteritis were enrolled compared with other months of the year. Vomiting (P = 0.04) was more common in children with rotavirus than nonrotavirus gastroenteritis. The most common G-P combinations were G3P[6] (23%), G1P[8] (12%), G1P[6/8] (8%), G2P[6] (7%), G12P[6] (7%) and G3/12P[6] (6%). CONCLUSIONS: The prevalence of rotavirus is high among children with acute gastroenteritis in Togo. Continued and extended rotavirus surveillance will be important to monitor changes in the epidemiology of rotavirus disease and the impact of vaccination after introduction. PMID- 24343608 TI - Epidemiology of rotavirus diarrhea among children younger than 5 years in Enugu, South East, Nigeria. AB - BACKGROUND: Severe rotavirus diarrhea in children is a major cause of morbidity globally and mortality in developing countries. It is estimated to be responsible for >453,000 deaths in children <5 years of age globally and 232,000 in the African region. The aim of the current study was to determine the prevalence of rotavirus gastroenteritis among hospitalized children <5 years of age in Enugu and to support awareness and advocacy efforts for the introduction of rotavirus vaccines in Nigeria. METHODS: World Health Organization-standardized case forms were used to collect data from eligible children with non-bloody diarrhea from October 2010 to September 2012. Data collected included socio-demographic and clinical information. Stool samples were obtained from recruited children and tested for rotavirus antigen using the Oxoid Prospect ELISA Kit (Basingstoke, United Kingdom). RESULTS: Of the 615 diarrhea stool samples collected, 344 (56%) were positive for human rotavirus. Of the 344 positive samples, 329 (96%) were children <2 years of age, while 247 (77%) were <1 year of age. Peak rotavirus season occurred during the cold dry months of December to April during which 95% of all cases occurred. CONCLUSIONS: This study found a relatively high incidence of severe rotavirus-associated diarrhea disease in Nigeria and infants were the most affected. It highlights the urgent need for introduction of rotavirus vaccine into the national immunization program and the need to adequately equip health facilities to enable them administer intravenous fluids to severe diarrhea patients to reduce morbidity and mortality. PMID- 24343609 TI - Baseline burden of rotavirus disease in Sudan to monitor the impact of vaccination. AB - BACKGROUND: In 2011, Sudan became the first low-income country in Africa to introduce a rotavirus vaccine. Prevaccine baseline data on rotavirus disease burden are crucial for monitoring the impact of this new vaccine program. METHODS: We conducted active, hospital-based surveillance for rotavirus disease at 8 regional public hospitals in Sudan using a standard protocol recommended by the World Health Organization for 2 full years immediately preceding vaccine introduction. Cases were children <5 years hospitalized with gastroenteritis, defined as acute onset of 3 or more loose stools or 2 or more episodes of vomiting in a 24-hour period. Stool specimens from cases were tested for rotavirus using a commercially available assay. RESULTS: From June 2009 to May 2011, rotavirus was detected in 3985 (36%) of 10,953 children hospitalized for gastroenteritis, with detection rates ranging from 25% to 48% at the 8 hospitals. Approximately 61% of the rotavirus hospitalizations occurred before 1 year of age and most (91%) occurred before 2 years of age. Rotavirus was detected year-round in Sudan with peaks during March to May and November to December. Applying rotavirus prevalence to national estimates of diarrhea events, we calculated 9800 deaths, 22,800 hospitalizations and 55,400 outpatient visits related to rotavirus per year among children <5 years of age in Sudan. CONCLUSIONS: The high burden of rotavirus disease in Sudan indicates that the recently implemented vaccination program should substantially improve child health in Sudan. This nationwide rotavirus surveillance system will be an important platform for assessing the benefits and value of rotavirus vaccine in a developing country setting. PMID- 24343610 TI - Hospital-based surveillance for rotavirus gastroenteritis in children younger than 5 years of age in Ethiopia: 2007-2012. AB - BACKGROUND: Rotavirus surveillance was initiated in Ethiopia to estimate the burden of rotavirus gastroenteritis in children <5 years of age, to generate data to assist the policy-making process for new vaccine introduction and to monitor impact of vaccination on disease burden after introduction. METHODS: Sentinel surveillance was conducted at 3 hospitals in Addis Ababa, Ethiopia using a standardized WHO surveillance protocol from August 2007 to March 2012. Children <5 years of age, hospitalized for the primary reason of treatment for acute gastroenteritis, were enrolled, stool samples were collected and tested for group A rotavirus using an enzyme immunoassay. Confirmed positive specimens were further characterized by rotavirus genotyping. RESULTS: A total of 1841 children were enrolled and 21% were rotavirus positive. Children 6-12 months of age had the highest proportion of rotavirus (36%) followed by children <6 months of age (23%). There was no significant difference between sexes. Significant differences in clinical characteristics, such as vomiting, vomiting episodes, cases with vomiting and diarrhea among rotavirus positive cases, were observed. Rotavirus circulated year round with peak prevalence from October through January. The most prevalent detected genotypes were G1P[8] (20%), G12P[8] (17%) and G3P[6] (15%), respectively. CONCLUSIONS: Rotavirus infection is common in Ethiopian children. A safe and effective intervention against the infection is needed to prevent severity of the disease. Rotavirus vaccine introduction is planned before the end of 2013. The established surveillance system and the data generated can be used to monitor the impact of rotavirus vaccination program on severe disease. PMID- 24343611 TI - High burden of rotavirus gastroenteritis in young children in rural western Kenya, 2010-2011. AB - BACKGROUND: Diarrhea is a leading cause of hospitalization and death in children <5 years of age. OBJECTIVES: To facilitate evaluation of the impact of rotavirus vaccine introduction in western Kenya, we estimated baseline rates of rotavirus associated hospitalization and mortality among children <5 years of age. METHODS: From January 2010 to December 2011, we collected demographic, clinical and laboratory data for children <5 years of age seeking care at the district hospital and 2 outpatient facilities within a Health and Demographic Surveillance System (HDSS). Children with acute gastroenteritis (AGE), defined as >=3 loose stools and/or >=1 episode of unexplained vomiting followed by loose stool within a 24-hour period, were asked to provide a stool sample for rotavirus ELISA testing. Rates of rotavirus-associated hospitalization and mortality were estimated using time of residence in the HDSS to calculate person-years of observation. To estimate the rotavirus-associated mortality rate, we applied the percentage positive for rotavirus among AGE hospitalizations to verbal autopsy estimates of diarrhea deaths in the HDSS. RESULTS: There were 4991 hospitalizations of children <5 years of age; 1134 (23%) were for AGE and stool specimens were obtained from 790 (70%). Rotavirus was detected in 211 (27%) specimens. Among 4951 <5 outpatient sick visits, 608 (12%) were for AGE; 320 (51%) provided specimens and 62 (20%) were positive for rotavirus. Rotavirus AGE accounted for 501 <5 hospitalizations per 100,000 person-years of observation. Rotavirus-associated <5 mortality was 136 deaths per 100,000 person-years of observation. CONCLUSIONS: Continued surveillance of rotavirus AGE will provide timely data on the population-level impact of rotavirus vaccine following its likely introduction in 2014. PMID- 24343612 TI - Rotavirus prevalence and genotypes among children younger than 5 years with acute diarrhea at Mulago National Referral Hospital, Kampala, Uganda. AB - BACKGROUND: Rotavirus is the most common cause of severe diarrhea among children <5 years of age worldwide. To determine the prevalence of severe rotavirus infection in children admitted with acute diarrhea attending Mulago National Referral Hospital in Uganda, active sentinel surveillance was conducted from July 2006 to December 2012. METHODS: A total of 6387 children with acute diarrhea were enrolled into the public health surveillance system and of these, 5627 had stool samples collected and tested for rotavirus antigens by enzyme immunoassay ProSpecT Rotavirus kit. RESULTS: Rotavirus was detected in 1844 (32.8%) of 5627 children with acute diarrhea that had stool specimens collected, and 93% of positive cases of rotavirus gastroenteritis were between 3 and 23 months of age, with highest prevalence in children 6-11 months of age. Rotavirus infections occurred throughout the year. During the surveillance period (2006-2012), a total of 354 positive stool samples were subjected to reverse transcription polymerase chain reaction and genotyping assays. The most common genotypes detected were G1P[8] (16.1%) and G9P[8] (15.3%), followed by G2P[4] (7.6%), G9P[6] (7.1%), G8P[4] (6.5%) and G12P[6](5.6%). Mixed G or P types (17.9%) and partially typed either G or P types (10.7%) were common. CONCLUSION: Uganda would benefit by introducing rotavirus vaccine and hence reduce the hospitalization burden of managing acute diarrhea cases. PMID- 24343613 TI - Epidemiologic and genotypic characteristics of rotavirus strains detected in children less than 5 years of age with gastroenteritis treated at 3 pediatric hospitals in Zimbabwe during 2008-2011. AB - BACKGROUND: In anticipation of rotavirus vaccine introduction, the Zimbabwe Ministry of Health initiated rotavirus surveillance in 2008 to describe the rotavirus epidemiological trends and circulating genotypes among children <5 years of age. METHODS: Active hospital-based surveillance for diarrhea was conducted at 3 sentinel sites from January 2008 to December 2011. Children aged <5 years, who presented with acute gastroenteritis as a primary illness and who were admitted to a hospital ward or treated at the emergency unit, were enrolled in the surveillance program and had a stool specimen collected and tested for rotavirus by enzyme immunoassay. Genotyping of a sample of positive specimens was performed using reverse-transcription polymerase chain reaction. RESULTS: A total of 3728 faecal samples were collected and tested during the 4 year surveillance period and 1804 (48.5%) tested rotavirus positive. The highest prevalence of rotavirus diarrhea was found during the dry, cool season. Rotavirus positivity peaked in children 3-17 months of age with almost 80% of cases. Compared with rotavirus-negative cases, rotavirus-positive cases were more likely to be dehydrated (26% vs. 14%, P <= 0.001) and have vomiting (77% vs. 57%, P <= 0.001) and less likely to have fever (17% vs. 24%, P = 0.03). G9P[8] (43.3%), G1P[8] (11.8%), G2P[4] (8.7%), G2P[6] (8.7%) and G12P[6] (8.7%) were the most common genotypes detected. DISCUSSION: Rotavirus causes a significant disease burden among children <5 years of age in Zimbabwe. This active surveillance system can serve as a platform to monitor the impact of rotavirus vaccine on disease burden following vaccine introduction. PMID- 24343614 TI - Epidemiology of rotavirus diarrhea and diversity of rotavirus strains among children less than 5 years of age with acute gastroenteritis in Mauritius: June 2008 to December 2010. AB - BACKGROUND: Rotavirus is an important etiologic agent of diarrhea worldwide and ongoing surveillance is essential to monitor strain diversity. To describe the epidemiology of rotavirus disease and circulating rotavirus strains in Mauritius, surveillance for rotavirus diarrhea was conducted at 2 regional hospitals from June 2008 through December 2010. METHODS: A total of 787 fecal samples from children <5 years of age admitted to the pediatric ward with acute gastroenteritis was collected within 48 hours of hospitalization and analyzed for group A rotavirus. A subset of rotavirus-positive samples was subjected to polyacrylamide gel electrophoresis and VP4 and VP7 genotyping. RESULTS: Rotavirus was detected in 327 (41.6%) stools. Highest prevalence of rotavirus infection occurred in children <2 years of age, predominately between 12 and 23 months. Three seasonal peaks were observed during the study period: July to October 2008, October to December 2009 and July to October 2010. Polyacrylamide gel electrophoresis analysis of 116 positive samples yielded only long electropherotypes. The predominant circulating strain was G3P[8] (89%) from June through December 2008, G4P[8] (76%) from January through December 2009 and G1P[8] (90%) from January through December 2010. CONCLUSIONS: The diversity of rotavirus strains detected in this study highlights the need for continuous surveillance and data generated can be used to advocate for rotavirus vaccine introduction. PMID- 24343615 TI - Use of population-based surveillance to determine the incidence of rotavirus gastroenteritis in an urban slum and a rural setting in Kenya. AB - BACKGROUND: Rotavirus gastroenteritis is a major cause of mortality among children <2 years of age. Disease burden data are important for introducing and sustaining new rotavirus vaccines in immunization programs. METHODS: We analyzed population-based infectious disease surveillance data from 2007 to 2010 from Kenyan sites in rural and urban slum areas. Stool specimens were collected from patients of all ages presenting to study clinics with diarrheal disease and tested for rotavirus by enzyme immunoassay. Incidence rates were adjusted using data on healthcare utilization (from biweekly home visits) and proportion of stools collected at study clinics from patients meeting case definitions. RESULTS: Rotavirus was detected in 285 (9.0%) of 3174 stools tested, including 122 (11.9%) from children <5 years of age and 162 (7.6%) from participants >=5 years of age. Adjusted incidence rates for infants were 13,419 and 12,135 per 100,000 person-years of observation in rural and urban areas, respectively. Adjusted incidence rates were high in adults across age ranges. The rates suggest that annually, among children <5 years of age, there are >54,500 cases of rotavirus-associated gastroenteritis in rural Nyanza Province and >16,750 cases in Nairobi urban slums. CONCLUSIONS: Community-based surveillance in urban and rural Kenya suggests that rotavirus plays an important role as a cause of acute gastroenteritis in adults, as well as in children. In addition to substantially preventing illness and complications from diarrheal disease in children, rotavirus infant immunization has the potential of indirectly preventing diarrheal disease in older children and adults, assuming children are the predominant sources of transmission. PMID- 24343616 TI - African rotavirus surveillance network: a brief overview. AB - With the imminent availability of new and prospective rotavirus vaccines, reliable information on burden of rotavirus diseases in the different African countries was required to enable evidence-based decision making regarding introduction of rotavirus vaccines. World Health Organization has been supporting Member States since 2006 to establish sentinel surveillance for rotavirus diarrhea in children <5 years of age using standardized guidelines. African countries are using this platform to generate high quality country specific data to document and demonstrate the burden of rotavirus gastroenteritis. The data gathered are being used by policy makers to guide decisions on appropriate intervention strategies for diarrhea control including the value and timing of the introduction of new rotavirus vaccines in the national immunization programs. PMID- 24343617 TI - Rotavirus genotypes associated with acute diarrhea in Egyptian infants. AB - BACKGROUND: Before the introduction of rotavirus vaccine in Egypt, information on the burden of disease and the circulating rotavirus genotypes is critical to monitor vaccine effectiveness. METHODS: A cohort of 348 Egyptian children was followed from birth to 2 years of age with twice-weekly home visits to detect diarrheal illness. VP7 and VP4 genes were genotyped by reverse-transcription polymerase chain reaction and DNA sequencing. RESULTS: Forty percentage of children had rotavirus-associated diarrhea at least once by their second birthday. One hundred and twelve children experienced a single rotavirus diarrheal episodes (RDE) at a median age of 9 months; while 27 infants had their second RDE at a median age of 15 months and 1 infant had 3 RDE at the age of 2, 16 and 22 months. Of the 169 RDE, 82% could be assigned a G-type, while 58% had been identified a P-type. The most prevalent genotype was G2 (32%), followed by G1 (24%) and G9 (19%). G2P[4] rotavirus episodes were significantly associated with fever (P = 0.03) and vomiting (P = 0.06) when compared with other genotypes. G2 strains were the predominant genotype causing 50% of the second RDE while G9 represented 25% of the second RDE. CONCLUSIONS: Genotypes identified are similar to those detected globally except for absence of G4. Our finding that 75% of the second RDE were due to G2 and G9 indicates a possible reduction in natural protection afforded by these types compared with G1, where 90% of G1 cases did not experience a second xposure, indicating greater protection against recurrent symptomatic infection. PMID- 24343618 TI - High genotypic diversity among rotavirus strains infecting Gambian children. AB - BACKGROUND: Rotavirus is the leading cause of diarrhea in children <5 years of age. In light of the implementation of rotavirus vaccines of limited valency, it is important to characterize the genotypic diversity of circulating rotavirus in sub-Saharan Africa. METHODS: We collected stool samples from children 0-59 months of age who presented at the health centres as cases with moderate-to-severe diarrhea in the Upper River Region of The Gambia. Stool samples were also collected from age, sex and area-matched healthy controls. All stool samples were assayed for rotavirus antigens by enzyme-linked immunosorbent assay and genotyping was done using reverse transcriptase polymerase chain reaction. RESULTS: We enrolled 1029 cases and 1569 controls during the 3-year study period (2008-2010). The detection rate of rotavirus among the cases was 20% (204/1029) and 3% (42/1569) among controls. At least 18 genotypes were found and the predominant genotypes were G2P[6] (28%), G1P[8] (26%) and G1P[10] (10%). The rare identified genotypes (<1%) were G2P[14], G8P[6], G9P[6] and G4P[10]. There was also a strong positive association between rotavirus infection and the dry season (odds ratio: 9.83, 95% confidence interval: 6.18-15.63, P < 0.001). A significant increase in the odds of rotavirus and G1P[8] detection with the use of untreated water and the presence of cats, rodents and cows in the child's residence was also found. CONCLUSION: This study provides important baseline data for the genotypes circulating before vaccine implementation. The wide diversity of genotypes circulating in The Gambia implies the need for vigilant effectiveness surveillance following the implementation of RotaTeq in August 2013. PMID- 24343619 TI - Update of rotavirus strains circulating in Africa from 2007 through 2011. AB - BACKGROUND: The African Rotavirus Surveillance Network has been detecting and documenting rotavirus genotypes in the subcontinent since 1998, largely based on intercountry workshops conducted at Rotavirus Regional Reference Laboratories. This article reports on rotavirus genotypes generated at Regional Reference Laboratories, South Africa between 2007 and 2011 from 16 African countries. METHODS: Stool samples were collected from <5-year-old children with diarrhea following World Health Organization criteria of hospital-based rotavirus surveillance. Enzyme immunoassay (EIA) was performed by National Laboratories. Regional Reference Laboratories retested 10% of randomly selected EIA positives and 10% of EIA negatives from each country as part of quality control. At least 50 rotavirus EIA positives from each country per year were subjected to reverse transcriptase polymerase chain reaction based on G-/P-types. Sequencing was conducted in 5-10% of each representative G or P genotype to confirm the genotype, as well as to type some of the samples that could not be genotyped with reverse transcriptase polymerase chain reaction-based methods. RESULTS: A total of 2555 of rotavirus EIA positives were genotyped. G1 was the most predominant (28.8%), followed by G9 (17.3%), G2 (16.8%), G8 (8.2%), G12 (6.2%) and G3 (5.9%). Similarly, the P[8] strain was the most prevalent (40.6%), followed by P[6] (30.9%) and P[4] (13.9%). The top G/P combinations detected were G1P[8] (18.4%), G9P[8] (11.7%), G2P[4] (8.6%), G2P[6] (6.2%), G1P[6] (4.9%), G3P[6] (4.3%), G8P[6] (3.8%) and G12P[8] (3.1%). CONCLUSIONS: There is high genetic diversity of rotavirus strains circulating in the subcontinent. Understanding the strain diversity pre- and postvaccine introduction are important in Africa to understand the broader impact of the rotavirus vaccines on regionally circulating strains. PMID- 24343621 TI - Can routinely collected national data on childhood morbidity and mortality from diarrhea be used to monitor health impact of rotavirus vaccination in Africa? Examination of pre-vaccine baseline data from Rwanda. AB - BACKGROUND: As rotavirus vaccine is introduced into routine childhood immunization programs in Africa, understanding its impact on diarrheal disease burden is important. The objective of this analysis was to determine whether routinely collected health information on national diarrhea hospitalizations, in hospital deaths and outpatient visits would be useful to monitor rotavirus vaccine impact. METHODS: We analyzed data for all-cause, nonbloody diarrheal disease among children <5 years of age from the routine health management information system (HMIS) in Rwanda from January 2008 through December 2011. We described trends in absolute numbers of inpatient admissions, in-hospital deaths and outpatient visits by year, age and setting. RESULTS: All-cause, nonbloody diarrheal hospitalizations and outpatient visits among children <5 years of age in Rwanda from 2008 to 2011 peaked during the June to August dry season, coinciding with the rotavirus season. The bulk of the diarrheal disease burden occurred in children <1 year of age. Health centers provided many care to children with diarrhea including 60-72% of hospitalizations and 97-99% of outpatient visits. Many in-hospital diarrheal deaths (84%) occurred in district hospitals. DISCUSSION: Given the stable and consistent trends and the prominent seasonality consistent with that of rotavirus, HMIS data should provide a useful baseline to monitor rotavirus vaccine impact on the overall diarrheal disease burden in Rwanda. Active, sentinel surveillance for rotavirus diarrhea will help interpret changes in diarrheal disease trends following vaccine introduction. Other countries planning rotavirus vaccine introduction should explore the availability and quality of their HMIS data. PMID- 24343620 TI - Rotavirus G and P types circulating in the eastern region of Kenya: predominance of G9 and emergence of G12 genotypes. AB - BACKGROUND: The World Health Organization has recommended that rotavirus (RV) vaccines be included in all national immunization programs as part of a strategy to control RV-associated diarrheal diseases. Hospital-based surveillance of RV infection is therefore crucial in monitoring the impact pre- and post-vaccine introduction and also to document changes in genotype distribution. This study sought to determine the RV genotypes circulating in the eastern region of Kenya before introduction of the RV vaccine. METHODS: During September 2009 to August 2011, 500 stool samples were collected from children <5 years of age admitted for acute diarrhea in hospitals in the eastern region of Kenya and analyzed for the presence of group A RV using an enzyme immunoassay. G and P genotypes were determined using hemi-nested reverse transcriptase polymerase chain reaction. RESULTS: One hundred and eighty nine out of 500 (38%) samples analyzed were positive for rotavirus. The following G types were detected: G9 (50.9%), G1 (26.8%), G8 (12.1%), G12 (3.1%), G2 (0.6%), mixed G (1.3%) and 5.1% were G nontypeable. P types detected included: P[8] (63.7%), P[4] (12.1%), P[6] (4.5%), mixed P (7.6%) and 12.1% were P nontypeable. The most dominant strain was G9P[8] (35%), followed by G1P[8] (26.8%), G8P[4] (9.6%), G12P[6] (2.5%), G9P[6] (1.9%), G9P[4] (1.3%), G8P[8] (1.3%), and G2P[4] (0.6%). CONCLUSIONS: The present study demonstrates the recurring changing genotypes of RV circulating in Kenya, with genotypes G9, G1 and G8 being the dominant strains circulating in the eastern region of Kenya between 2009 and 2011. Additionally, G12 genotype was detected for the first time in Kenya. PMID- 24343622 TI - Severe acute rotavirus gastroenteritis in children less than 5 years in southern Ghana: 2006-2011. AB - BACKGROUND: Rotavirus is a major cause of acute gastroenteritis (AGE) globally. Local data on disease burden will guide recommendations for rotavirus vaccination and monitoring impact of the intervention. METHODS: Prospective surveillance for rotavirus gastroenteritis was conducted in 3 hospitals in southern Ghana during the period August 2006 to December 2011, as part of the African Rotavirus Surveillance Network. Clinical data and stool specimens were collected from children <5 years of age and hospitalized with AGE (defined as 3 or more watery stools for up to 7 days). Stool was tested for rotavirus by enzyme immunoassay and rotavirus genotype identified by reverse-transcriptase polymerase chain reaction. RESULTS: We tested 3044 stool samples from 3939 children. Rotavirus was detected in 45.6%, 51.3% and 48.5% of cases at the primary, secondary and tertiary care hospital, respectively. Both genders were equally affected; 75% (2954/3939) of the cohort were aged 3-18 months. Overall, rotavirus was detected in 49.4% (1504/3044) of cases, caused over 30% of AGE hospitalizations all year round and up to 70% of cases during peak seasons. Peak season occurred during cool dry months in 2008, 2010 and 2011 and the rainy season in 2009. Mortality from AGE occurred in 1.5% (45/3044) of cases and 48.9% (22/45) of these were rotavirus positive. CONCLUSIONS: Rotavirus causes significant morbidity and mortality in young Ghanaian children. As Ghana introduced rotavirus vaccination in the national immunization program in 2012, continued surveillance is required to monitor the impact of this intervention. PMID- 24343623 TI - Intussusception incidence rates in 9 Zambian hospitals, 2007-2011: prerotavirus vaccine introduction. AB - BACKGROUND: Intussusception, a rare adverse event associated with rotavirus vaccines in some settings, is a common cause of intestinal obstruction in infants and toddlers globally with a peak age of 4-6 months. This age group may overlap with the extended age of administering rotavirus vaccine. METHODS: A retrospective (January 2007 to June 2009) and prospective (July 2009 to June 2012) survey was conducted in 9 Zambian hospitals. Children between 0 and 24 months who were operated on for intestinal obstruction/intussusception were identified in theatre log books. In the latter part of the survey, patients were recruited prospectively. Demographic, clinical and surgical data from hospital files were collected for each patient. RESULTS: One-hundred and five children were identified to have undergone surgery for intussusceptions. Many were boys 57.6% (57/99). Of those with complete data, intussusception was common in infants 86.9% (86/99) and many children (68.0%) were between 3 and 8 months of age with a peak age of 5-6 months. Lusaka had the highest number of children with intussusception with an estimated annual incidence rate of 12/100,000 in children <2 years of age. The overall case fatality rate was very high 33.7% (31/92). CONCLUSION: Intussusception was common in infants with a peak age of 5-6 months, and of particular concern is the group of 2-4 months the age of rotavirus vaccination. The estimated incidence rate of 12/100,000 is an underestimate as many cases may not present for care. The high case fatality rate of 33.7% is due to both delayed presentation and diagnosis in hospital. PMID- 24343624 TI - Preparing for safety monitoring after rotavirus vaccine implementation: a retrospective review of intussusception cases among children at a large teaching hospital in Rwanda, 2009-2012. AB - BACKGROUND: In some settings, rotavirus vaccines have been associated with a small risk of intussusception. This study describes the demographics, clinical characteristics and outcomes of children with intussusception in Rwanda before vaccine introduction in May 2012. METHODS: We retrospectively reviewed data on pediatric patients treated for intussusception at University Teaching Hospital of Kigali from January 2009 to June 2012. Hospital registries were reviewed to identify intussusception cases. Archived patient files were abstracted to collect data on demographics, clinical presentation, surgery and outcome. RESULTS: During the study period, 70 children <=19 years of age were treated for intussusception and patient files were retrieved for 60 (86%) cases. Over half of patients (58%) were <1 year of age and 90% were transferred from a district hospital. Only 30% of patients presented within 3 days of symptom onset and 35% experienced a delay of >=6 hours between surgical review and surgery. Surgical complications were experienced by 35% of children. Over 1 quarter (28%) of children died. Compared with children who survived, children who died were significantly more likely to have experienced complications (21% vs. 71%; P < 0.001) and to be female (28% vs. 65%; P = 0.009). DISCUSSION: Mortality due to intussusception was high among Rwanda children. Delays in presentation and treatment were common. Assessing trends in the number of cases to monitor for vaccine-associated intussusception will be difficult. Additional work is needed to further understand risk factors for mortality, to calculate incidence rates and to monitor the safety of the rotavirus vaccination program. PMID- 24343625 TI - Diagnosis and treatment of Paget's disease of bone: a mini-review. AB - Paget's disease of bone (PDB) is a chronic progressive disorder of bone metabolism that may go undetected for many years, and endocrinologists should be alert to its clinical signs and promptly diagnose and treat PDB before it results in irreversible complications, such as deformity, fracture or neurological sequelae. Most commonly, PDB is suspected upon the incidental finding of elevated serum alkaline phosphatase levels or a radiographic abnormality in an otherwise healthy individual above 55 years of age. Some of these individuals may have symptoms such as bone pain or enlargement with increased warmth. In general, a basic laboratory evaluation of bone metabolism, plain radiographies of affected bones and bone scintigraphy are sufficient to corroborate the diagnosis. Antiresorptive therapy with bisphosphonates is the mainstay of treatment of symptomatic PDB, and intravenous zoledronic acid has emerged as an effective and safe treatment option, leading to sustained remission and improved quality of life. It is extremely important, though, to ensure calcium and vitamin D sufficiency before and during treatment in order to prevent hypocalcemia. The benefit of treating all asymptomatic patients is not clear, but treatment is warranted if the pagetic lesion is located in a site where progression to fracture, deformity, or compression would significantly impair the patient quality of life. This mini-review focuses on important aspects of the diagnosis and treatment of PDB. PMID- 24343626 TI - [Biochemical, hormonal and genetic evaluation of the families of two Brazilian patients with type 2 familial partial lipodystrophy]. AB - OBJECTIVE: To evaluate clinical, biochemical, hormonal and genetic characteristics of relatives of two patients with familial partial lipodystrophy (FPLD) type 2. MATERIALS AND METHODS: Fifty subjects, members of two non-related Brazilian families from two different probands with FPLD phenotype, were evaluated. A mutation in exon 8 of LMNA gene was confirmed in 18 of them, and a heterozygous substitution at codon 482 was identified, predicting a p.R482W mutation. Based on the presence or absence of the mutation, subjects were classified in affected and unaffected, and compared in terms of clinical, biochemical and hormonal parameters. RESULTS: Affected subjects were 2.8 times more likely to manifest diabetes and PCOS, higher HOMA-IR, insulin and triglyceride levels, and lower levels of leptin. These changes preceded the onset of diabetes, because they were observed in diabetic and non-diabetic affected patients. A phenotypic heterogeneity was found among mutation carriers. CONCLUSION: A mutation in the LMNA gene is a determinant of clinical, biochemical and hormonal changes that imply in metabolic deterioration in mutation carriers. PMID- 24343627 TI - Interval training attenuates the metabolic disturbances in type 1 diabetes rat model. AB - OBJECTIVE: This study investigated the effect of interval training on blood biochemistry and immune parameters in type 1 diabetic rats. MATERIALS AND METHODS: Male Wistar rats were divided into four groups: sedentary (SE, n = 15), interval training (IT, n = 17), diabetic sedentary (DSE, n = 17), diabetic interval training (DIT, n = 17). Diabetes was induced by i.v. injection of streptozotocin (60 mg/kg). Swimming Interval Training consisted of 30-s exercise with 30-s rest, for 30 minutes, during 6 weeks, four times a week, with an overload of 15% of body mass. Plasma glucose, lactate, triacylglycerol and total cholesterol concentrations, phagocytic capacity, cationic vesicle content, and superoxide anion and hydrogen peroxide production by blood neutrophils and peritoneal macrophages were evaluated. Proliferation of mesenteric lymphocytes was also estimated. RESULTS: Interval training resulted in attenuation of the resting hyperglycemic state and decreased blood lipids in the DIT group. Diabetes increased the functionality of blood neutrophils and peritoneal macrophages in the DSE group. Interval training increased all functionality parameters of peritoneal macrophages in the IT group. Interval training also led to a twofold increase in the proliferation of mesenteric lymphocytes after 6 weeks of exercise in the DIT group. CONCLUSION: Low-volume high-intensity physical exercise attenuates hyperglycemia and dislipidemia induced by type 1 diabetes, and induces changes in the functionality of innate and acquired immunity. PMID- 24343628 TI - Polymorphisms in LEPR, PPARG and APM1 genes: associations with energy intake and metabolic traits in young children. AB - OBJECTIVE: To assess the association of single nucleotide polymorphisms (SNPs) in five genes - leptin, leptin receptor (LEPR), adiponectin (APM1), peroxisome proliferator-activated receptor gamma (PPARG) and uncoupling protein 1 - with anthropometric, metabolic, and dietary parameters in a Southern Brazilian cohort of 325 children followed up from birth to 4 years old. MATERIALS AND METHODS: SNPs were analyzed using polymerase chain reaction-based procedures, and their association with phenotypes was evaluated by t-test, analysis of variance, and general linear models. RESULTS: LEPR223Arg allele (rs1137101) was associated with higher daily energy intake at 4 years of age (P = 0.002; Pcorrected = 0.024). PPARG 12Ala-carriers (rs1801282) presented higher glucose levels than Pro/Pro homozygotes (P = 0.007; Pcorrected = 0.042). CONCLUSIONS: Two of the six studied SNPs presented consistent associations, showing that it is already possible to detect the influences of genetic variants on susceptibility to overweight in 4 year-old children. PMID- 24343629 TI - Frequency of various types of neoplasia in a group of acromegalic patients. AB - OBJECTIVE: To determine the frequency of colon cancer, primary hyperparathyroidism, thyroid tumor, and skin cancer in all acromegalic patients in follow-up at the Clinics Hospital - Botucatu Medical School, from 2005 to 2011. SUBJECTS AND METHODS: These patients were evaluated retrospectively for colon cancer, primary hyperparathyroidism, dermatological, and thyroid tumors. RESULTS: Of 29 patients included at the beginning of the study, two were excluded. Among 19 patients submitted to colonoscopy, one presented colon adenocarcinoma (5%). Thyroid nodules were present in 63% of patients, and papilliferous carcinoma was confirmed in two patients (7,7%). Four patients were confirmed as having primary hyperparathyroidism (15%). The most common dermatologic lesions were thickened skin (100%), acrochordons (64%), epidermal cysts (50%), and pseudo-acanthosis nigricans (50%). Only one patient presented basal cell carcinoma. CONCLUSION: Although a small number of acromegalic patients was studied, our findings confirm the high frequency of thyroid neoplasias and primary hyperparathyroidism in this group of patients. PMID- 24343630 TI - Serum uric acid levels and non-alcoholic fatty liver disease in Uyghur and Han ethnic groups in northwestern China. AB - OBJECTIVE: The aim of this study was to compare serum uric acid values in two ethnically distinct Chinese populations: Uyghur, with a high prevalence of nonalcoholic fatty liver disease, and Han, with a lower prevalence. SUBJECTS AND METHODS: Serum uric acid and several clinical features and laboratory tests relevant to the metabolic syndrome were measured in 4,157 Uyghur and 6,448 Han subjects in a health examination program. The diagnosis of hepatic steatosis was established by abdominal ultrasound examination. RESULTS: The prevalence of nonalcoholic fatty liver disease was 42.3% and 33.3% among Uyghur and Han subjects, respectively. The corresponding prevalence of hyperuricemia was 8.8% and 14.7%. The mean concentration of serum uric acid in Uyghurs also was lower than in Hans (282.75 vs. 310.79 umol/L; p < 0.01). However, in both populations, the prevalence of nonalcoholic fatty liver disease was increased in association with increasing serum uric acid concentrations, a trend that was more pronounced in Uyghur than in Han subjects (OR 3.279 and 3.230, respectively). Several components of the metabolic syndrome were more pronounced in Uyghurs than in Hans. CONCLUSIONS: Serum uric acid is an independent risk factor in nonalcoholic fatty liver disease in both Uyghurs and Hans, but other risk factors may be more important in the differences in prevalence of the disease between the two ethnic groups. PMID- 24343631 TI - [Growth and body composition of a cohort of children and adolescents with type 1 diabetes]. AB - OBJECTIVE: To evaluate the growth and body composition of children and adolescents with type 1 diabetes mellitus (T1DM). SUBJECTS AND METHODS: A cohort of 44 patients with T1DM were followed up for approximately four years and compared with a control group. Weight, height, body mass index (BMI), body fat percentage (BF%), fat mass index, waist circumference (WC) and waist-height ratio were determined. RESULTS: In females, in the first evaluation, BF% was lower in patients than in controls, while in the second evaluation, mean WC was higher in patients than in controls. In males, height of the patients was lower in the first evaluation, while body mass index (BMI) was higher in the second one. We did not find any differences among the changes in height, weight and BMI z-scores and BF% or in the distribution of those z-scores between the two evaluations, in both groups. Multiple regression analysis found differences in BMI and waist height ratio in both sexes and also in WC in females. CONCLUSION: The patients had adequate growth but showed discrepancy in their body composition during the study. PMID- 24343632 TI - Association of insulin resistance and GLP-2 secretion in obesity: a pilot study. AB - OBJECTIVE: The objective of this pilot study was to determine whether glugagon like peptide 2 (GLP-2) secretion relates to insulin sensitivity (IS) in obese subjects. SUBJECTS AND METHODS: Twenty four obese subjects [body mass index (BMI) 40.0 +/- 3.0 kg/m2 (mean +/- standard deviation)] were included, nine of which were male, age 43 +/- 8 years. Twelve subjects had type 2 diabetes, all treated with oral anti-diabetic agents only. The subjects were submitted to standard meal tolerance test (MTT) for dosage of the curves: glucose, insulin, and GLP-2. Insulin sensitivity was measured by HOMA-IR, and OGIS was derived from the MTT. Spearman linear correlations and partial correlations were obtained. RESULTS: There was an inverse relationship between the GLP-2 secretion and IS: HOMA-IR correlated with GLP-2 AUC (R = 0.504; p = 0.012), and OGIS correlated with GLP-2 incremental AUC (R = -0.54; p = 0.054). The correlation persisted after controlling for BMI. CONCLUSION: We found an association of GLP-2 secretion and insulin resistance (IR). The understanding of the underlying mechanisms may provide future directions in the pharmacological manipulation of incretins, and in the treatment of obesity and related metabolic disorders. PMID- 24343633 TI - Aldosterone secretion in patients with septic shock: a prospective study. AB - OBJECTIVE: To assess serum levels of the main factors that regulate the activation of the zona glomerulosa and aldosterone production in patients with septic shock, as well as their response to a high-dose (250 ug) adrenocorticotropic hormone (ACTH) stimulation test. SUBJECTS AND METHODS: In 27 patients with septic shock, baseline levels of aldosterone, cortisol, ACTH, renin, sodium, potassium, and lactate were measured, followed by a cortrosyn test. RESULTS: Renin correlated with baseline aldosterone and its variation after cortrosyn stimulation. Baseline cortisol and its variation did not correlate with ACTH. Only three patients had concomitant dysfunction of aldosterone and cortisol secretion. CONCLUSIONS: Activation of the zona glomerulosa and zona fasciculata are independent. Aldosterone secretion is dependent on the integrity of the renin angiotensin-aldosterone system, whereas cortisol secretion does not appear to depend predominantly on the hypothalamic-pituitary-adrenal axis. These results suggest that activation of the adrenal gland in critically ill patients occurs by multiple mechanisms. PMID- 24343634 TI - Effects of chronic stress and high-fat diet on metabolic and nutritional parameters in Wistar rats. AB - OBJECTIVE: The aim of this study was assess the role of chronic stress on the metabolic and nutritional profile of rats exposed to a high-fat diet. MATERIALS AND METHODS: Thirty-day-old male Wistar rats (70-100 g) were distributed into four groups: normal-diet (NC), chronic stress (St), high-fat diet (HD), and chronic stress/high-fat diet (HD/St). Stress consisted at immobilization during 15 weeks, 5 times per week, 1h per day; and exposure to the high-fat diet lasted 15 weeks. Nutritional and metabolic parameters were assessed. The level of significance was 5%. RESULTS: The HD group had final body weight, total fat, as well as insulin and leptin increased, and they were insulin resistant. The St and HD/St had arterial hypertension and increased levels of corticosterone. Stress blocked the effects of the high-fat diet. CONCLUSION: Chronic stress prevented the appearance of obesity. Our results help to clarify the mechanisms involved in metabolic and nutritional dysfunction, and contribute to clinical cases linked to stress and high-fat diet. PMID- 24343635 TI - Celiac crisis in an adult type 1 diabetes mellitus patient: a rare manifestation of celiac disease. AB - Celiac crisis, an acute severe onset of celiac disease, is a rare and life threatening manifestation. We report a 30-year-old woman with type 1 diabetes mellitus who arrived at our service with one-month history of severe acute watery diarrhea associated with nausea, vomiting, abdominal pain, and weight loss of 9 kg. The diagnostic hypothesis of celiac crisis was reached based on profuse diarrhea leading to dehydration, severe metabolic and electrolyte abnormalities, and subsequent improvement after introduction of a gluten-free diet. PMID- 24343636 TI - [Bezafibrate in an infant with congenital generalized lipodystrophy and severe hypertriglyceridemia]. AB - Congenital generalized lipodystrophy (CGL) with severe hypertriglyceridemia in a children less than 1 year of age is associated with worse metabolic risk. We used data from patient records, as well as extensive literature research to write the manuscript. We report the case of an infant with typical phenotype of CGL and hypertriglyceridemia of 1,360 mg/dL who was treated with bezafibrate at a dose of 30 to 60 mg/day from age 11 months to 5.5 years old, with a measurement of nadir of triglycerides of 55 mg/dL. Clinical evolution and clinical laboratory tests before and after bezafibrate were carried out over 5 years and 6 months. Phenotype was classified as CGL type 2. Despite the efficient control of hypertriglyceridemia and absence of development of diabetes mellitus, the use of bezafibrate did not prevent the onset of hepatic steatosis during evolution. Hypolipidemic therapy with bezafibrate proved effective in maintaining the levels of triglycerides, cholesterol and its fractions at normal levels, and its use was not correlated with severe side effects during the described period. PMID- 24343637 TI - Follow-up of a case of subacute thyroiditis with uncommon thyroid (99m)Tc uptake. AB - Thyroidal 99mTc uptake in the acute thyrotoxic phase of subacute thyroiditis (SAT) is always inhibited. However, a patient with SAT had signs in the right side thyroid gland with transient thyrotoxicosis and slightly high 99mTc uptake levels in the right lobe, low 99mTc uptake in the left lobe, and normal overall uptake. Histological examination showed cellular destruction and granulomatous inflammatory changes in the right lobe, with marked interstitial fibrosis in the left lobe. The patient was thyrotrophin-receptor antibody (TRAb) positive. After a short course of prednisolone, SAT-like symptoms and signs improved. TRAb positivity resolved spontaneously after 22 months, and TSH levels were slightly low for 22 months. Levels then kept normal in the following four years. In conclusion, high 99mTc uptake by the right lobe was due to the combined effects of TRAb and left thyroid gland fibrosis. PMID- 24343638 TI - What is the contribution of physical activity on outcome in patients with type 2 diabetes mellitus? PMID- 24343639 TI - Improving patient's independence and treating depressive symptoms can promote physical activity in diabetic patients. PMID- 24343642 TI - Water-dispersible nanospheres of hydrogen-bonded supramolecular polymers and their application for mimicking light-harvesting systems. AB - Water-dispersible nanospheres of hydrogen-bonded supramolecular polymers have been prepared for the first time by using the miniemulsion method. Nanospheres containing chromophores with high fluorescence quantum yields were fabricated to mimic the natural light-harvesting system. PMID- 24343640 TI - Multiple ITS haplotypes in the genome of the lichenized basidiomycete Cora inversa (Hygrophoraceae): fact or artifact? AB - The internal transcribed spacer region (ITS) of the nuclear rDNA cistron represents the barcoding locus for Fungi. Intragenomic variation of this multicopy gene can interfere with accurate phylogenetic reconstruction of biological entities. We investigated the amount and nature of this variation for the lichenized fungus Cora inversa in the Hygrophoraceae (Basidiomycota: Agaricales), analyzing base call and length variation in ITS1 454 pyrosequencing data of three samples of the target mycobiont, for a total of 16,665 reads obtained from three separate repeats of the same samples under different conditions. Using multiple fixed alignment methods (PaPaRa) and maximum likelihood phylogenetic analysis (RAxML), we assessed phylogenetic relationships of the obtained reads, together with Sanger ITS sequences from the same samples. Phylogenetic analysis showed that all ITS1 reads belonged to a single species, C. inversa. Pyrosequencing data showed 266 insertion sites in addition to the 325 sites expected from Sanger sequences, for a total of 15,654 insertions (0.94 insertions per read). An additional 3,279 substitutions relative to the Sanger sequences were detected in the dataset, out of 5,461,125 bases to be called. Up to 99.3% of the observed indels in the dataset could be interpreted as 454 pyrosequencing errors, approximately 65% corresponding to incorrectly recovered homopolymer segments, and 35% to carry-forward-incomplete-extension errors. Comparison of automated clustering and alignment-based phylogenetic analysis demonstrated that clustering of these reads produced a 35-fold overestimation of biological diversity in the dataset at the 95% similarity threshold level, whereas phylogenetic analysis using a maximum likelihood approach accurately recovered a single biological entity. We conclude that variation detected in 454 pyrosequencing data must be interpreted with great care and that a combination of a sufficiently large number of reads per taxon, a set of Sanger references for the same taxon, and at least two runs under different emulsion PCR and sequencing conditions, are necessary to reliably separate biological variation from 454 sequencing errors. Our study shows that clustering methods are highly sensitive to artifactual sequence variation and inadequate to properly recover biological diversity in a dataset, if sequencing errors are substantial and not removed prior to clustering analysis. PMID- 24343641 TI - Predicting the emergence of H3N2 influenza viruses reveals contrasted modes of evolution of HA and NA antigens. AB - Vaccine design for rapidly changing viruses is based on empirical surveillance of strains circulating in a given season to assess those that will most likely spread during the next season. The choice of which strains to include in the vaccine is critical, as an erroneous decision can lead to a nonimmunized human population that will then be at risk in the face of an epidemic or, worse, a pandemic. Here, we present the first steps toward a very general phylogenetic approach to predict the emergence of novel viruses. Our genomic model builds upon natural features of viral evolution such as selection and recombination / reassortment, and incorporates episodic bursts of evolution and or of recombination. As a proof-of-concept, we assess the performance of this model in a retrospective study, focusing: (i) on the emergence of an unexpected H3N2 influenza strain in 2007, and (ii) on a longitudinal design. Based on the analysis of hemagglutinin (HA) and neuraminidase (NA) genes, our results show a lack of predictive power in both experimental designs, but shed light on the mode of evolution of these two antigens: (i) supporting the lack of significance of recombination in the evolution of this influenza virus, and (ii) showing that HA evolves episodically while NA changes gradually. PMID- 24343643 TI - Perspectives: a journal on the cutting edge of educational research and development. Introduction from the new Editor in Chief. PMID- 24343644 TI - Reduced live organism recovery and lack of hydrosalpinx in mice infected with plasmid-free Chlamydia muridarum. AB - Plasmid-free Chlamydia trachomatis and Chlamydia muridarum fail to induce severe pathology. To evaluate whether the attenuated pathogenicity is due to insufficient infection or inability of the plasmidless chlamydial organisms to trigger pathological responses, we compared plasmid-competent and plasmid-free C. muridarum infections in 5 different strains of mice. All 5 strains developed hydrosalpinx following intravaginal inoculation with plasmid-competent, but not inoculation with plasmid-free, C. muridarum. The lack of hydrosalpinx induction by plasmid-free C. muridarum correlated with significantly reduced live organism recovery from the lower genital tract and shortened infection in the upper genital tract. The plasmid-free C. muridarum organisms failed to induce hydrosalpinx even when the organisms were directly inoculated into the oviduct via an intrabursal injection, which was accompanied by significantly reduced survival of the plasmidless organisms in the genital tracts. Furthermore, plasmid competent C. muridarum organisms after UV inactivation were no longer able to induce hydrosalpinx even when directly delivered into the oviduct at a high dose. Together, these observations suggest that decreased survival of and shortened infection with plasmid-free C. muridarum may contribute significantly to its attenuated pathogenicity. We conclude that adequate live chlamydial infection in the oviduct may be necessary to induce hydrosalpinx. PMID- 24343646 TI - Statistics in Infection and immunity revisited. AB - In 2003, a review of the use of statistics in Infection and Immunity (IAI) found that more than half of articles had errors of statistical analysis or reporting of statistical results. This updated review of recent articles identifies and discusses the most common statistical methods reported in IAI and provides examples of both good reporting and common mistakes. Furthermore, it expands on the criteria for statistical analysis and reporting presented in the IAI "Instructions to Authors," with the goal of helping both readers and authors better understand and apply the criteria. PMID- 24343645 TI - Janus kinase 3 activity is necessary for phosphorylation of cytosolic phospholipase A2 and prostaglandin E2 synthesis by macrophages infected with Francisella tularensis live vaccine strain. AB - Francisella tularensis, the causative agent of tularemia, modulates the host immune response to gain a survival advantage within the host. One mechanism of immune evasion is the ability of F. tularensis to induce the synthesis of the small lipid mediator prostaglandin E2 (PGE2), which alters the host T cell response making the host more susceptible to Francisella growth. PGE2 is synthesized by a tightly regulated biosynthetic pathway following stimulation. The synthesis of PGE2 begins with the liberation of arachidonic acid (AA) from membrane phospholipids by cytosolic phospholipase A2 (cPLA2). AA is subsequently converted to the unstable intermediate PGH2 by cyclooxygenase-2 (COX-2), and PGH2 undergoes an isomerization reaction to generate PGE2. Our objective was to identify F. tularensis-activated host signaling pathways that regulate the activity of the enzymes in the PGE2-biosynthetic pathway. In this study, we show that cPLA2, p38 mitogen-activated protein kinase (MAPK), and Janus kinase 3 (JAK3) signaling are necessary for F. tularensis-induced PGE2 production. Inhibition of JAK3 activity reduced the phosphorylation of cPLA2 and COX-2 protein levels. In addition, JAK3 regulates cPLA2 phosphorylation independent of transcription. Moreover, p38 MAPK activity is required for F. tularensis-induced COX-2 protein synthesis, but not for the phosphorylation of cPLA2. This research highlights a unique signaling axis in which JAK3 and p38 MAPK regulate the activity of multiple enzymes of the PGE2-biosynthetic pathway in macrophages infected with F. tularensis. PMID- 24343647 TI - Interleukin-17-induced protein lipocalin 2 is dispensable for immunity to oral candidiasis. AB - Oropharyngeal candidiasis (OPC; thrush) is an opportunistic fungal infection caused by the commensal microbe Candida albicans. Immunity to OPC is strongly dependent on CD4+ T cells, particularly those of the Th17 subset. Interleukin-17 (IL-17) deficiency in mice or humans leads to chronic mucocutaneous candidiasis, but the specific downstream mechanisms of IL-17-mediated host defense remain unclear. Lipocalin 2 (Lcn2; 24p3; neutrophil gelatinase-associated lipocalin [NGAL]) is an antimicrobial host defense factor produced in response to inflammatory cytokines, particularly IL-17. Lcn2 plays a key role in preventing iron acquisition by bacteria that use catecholate-type siderophores, and lipocalin 2(-/-) mice are highly susceptible to infection by Escherichia coli and Klebsiella pneumoniae. The role of Lcn2 in mediating immunity to fungi is poorly defined. Accordingly, in this study, we evaluated the role of Lcn2 in immunity to oral infection with C. albicans. Lcn2 is strongly upregulated following oral infection with C. albicans, and its expression is almost entirely abrogated in mice with defective IL-17 signaling (IL-17RA(-/-) or Act1(-/-) mice). However, Lcn2(-/-) mice were completely resistant to OPC, comparably to wild-type (WT) mice. Moreover, Lcn2 deficiency mediated protection from OPC induced by steroid immunosuppression. Therefore, despite its potent regulation during C. albicans infection, Lcn2 is not required for immunity to mucosal candidiasis. PMID- 24343648 TI - Biofilm matrix exoproteins induce a protective immune response against Staphylococcus aureus biofilm infection. AB - The Staphylococcus aureus biofilm mode of growth is associated with several chronic infections that are very difficult to treat due to the recalcitrant nature of biofilms to clearance by antimicrobials. Accordingly, there is an increasing interest in preventing the formation of S. aureus biofilms and developing efficient antibiofilm vaccines. Given the fact that during a biofilm associated infection, the first primary interface between the host and the bacteria is the self-produced extracellular matrix, in this study we analyzed the potential of extracellular proteins found in the biofilm matrix to induce a protective immune response against S. aureus infections. By using proteomic approaches, we characterized the exoproteomes of exopolysaccharide-based and protein-based biofilm matrices produced by two clinical S. aureus strains. Remarkably, results showed that independently of the nature of the biofilm matrix, a common core of secreted proteins is contained in both types of exoproteomes. Intradermal administration of an exoproteome extract of an exopolysaccharide-dependent biofilm induced a humoral immune response and elicited the production of interleukin 10 (IL-10) and IL-17 in mice. Antibodies against such an extract promoted opsonophagocytosis and killing of S. aureus. Immunization with the biofilm matrix exoproteome significantly reduced the number of bacterial cells inside a biofilm and on the surrounding tissue, using an in vivo model of mesh-associated biofilm infection. Furthermore, immunized mice also showed limited organ colonization by bacteria released from the matrix at the dispersive stage of the biofilm cycle. Altogether, these data illustrate the potential of biofilm matrix exoproteins as a promising candidate multivalent vaccine against S. aureus biofilm-associated infections. PMID- 24343649 TI - BsaB, a novel adherence factor of group B Streptococcus. AB - Streptococcus agalactiae (group B Streptococcus [GBS]) is a leading cause of neonatal sepsis and meningitis, peripartum infections in women, and invasive infections in chronically ill or elderly individuals. GBS can be isolated from the gastrointestinal or genital tracts of up to 30% of healthy adults, and infection is thought to arise from invasion from a colonized mucosal site. Accordingly, bacterial surface components that mediate attachment of GBS to host cells or the extracellular matrix represent key factors in the colonization and infection of the human host. We identified a conserved GBS gene of unknown function that was predicted to encode a cell wall-anchored surface protein. Deletion of the gene and a cotranscribed upstream open reading frame (ORF) in GBS strain 515 reduced bacterial adherence to VK2 vaginal epithelial cells in vitro and reduced GBS binding to fibronectin-coated microtiter wells. Expression of the gene product in Lactococcus lactis conferred the ability to adhere to VK2 cells, to fibronectin and laminin, and to fibronectin-coated ME-180 cervical epithelial cells. Expression of the recombinant protein in L. lactis also markedly increased biofilm formation. The adherence function of the protein, named bacterial surface adhesin of GBS (BsaB), depended both on a central BID1 domain found in bacterial intimin-like proteins and on the C-terminal portion of the BsaB protein. Expression of BsaB in GBS, like that of several other adhesins, was regulated by the CsrRS two-component system. We conclude that BsaB represents a newly identified adhesin that participates in GBS attachment to epithelial cells and the extracellular matrix. PMID- 24343650 TI - Cooperation, quorum sensing, and evolution of virulence in Staphylococcus aureus. AB - The virulence and fitness in vivo of the major human pathogen Staphylococcus aureus are associated with a cell-to-cell signaling mechanism known as quorum sensing (QS). QS coordinates the production of virulence factors via the production and sensing of autoinducing peptide (AIP) signal molecules by the agr locus. Here we show, in a wax moth larva virulence model, that (i) QS in S. aureus is a cooperative social trait that provides a benefit to the local population of cells, (ii) agr mutants, which do not produce or respond to QS signal, are able to exploit the benefits provided by the QS of others ("cheat"), allowing them to increase in frequency when in mixed populations with cooperators, (iii) these social interactions between cells determine virulence, with the host mortality rate being negatively correlated to the percentage of agr mutants ("cheats") in a population, and (iv) a higher within-host relatedness (lower strain diversity) selects for QS and hence higher virulence. Our results provide an explanation for why agr mutants show reduced virulence in animal models but can be isolated from infections of humans. More generally, by providing the first evidence that QS is a cooperative social behavior in a Gram positive bacterium, our results suggest convergent, and potentially widespread, evolution for signaling to coordinate cooperation in bacteria. PMID- 24343651 TI - Chlamydia trachomatis-infected epithelial cells and fibroblasts retain the ability to express surface-presented major histocompatibility complex class I molecules. AB - The obligate intracellular bacterial pathogen Chlamydia trachomatis is the causative agent of a variety of infectious diseases such as trachoma and sexually transmitted diseases. In infected target cells, C. trachomatis replicates within parasitophorous vacuoles and expresses the protease-like activity factor CPAF. Previous studies have suggested that CPAF degrades the host transcription factors RFX5 and NF-kappaB p65, which are involved in the regulation of constitutive and inducible expression of major histocompatibility complex class I (MHC I). It was speculated that Chlamydia suppresses the surface presentation of MHC I in order to evade an effective immune response. Nevertheless, a recent study suggested that RFX5 and NF-kappaB p65 may not serve as target substrates for CPAF-mediated degradation, raising concerns about the proposed MHC I subversion by Chlamydia. Hence, we investigated the direct influence of Chlamydia on MHC I expression and surface presentation in infected host cells. By using nine different human cells and cell lines infected with C. trachomatis (serovar D or LGV2), we demonstrate that chlamydial infection does not interfere with expression, maturation, transport, and surface presentation of MHC I, suggesting functional antigen processing in bacterium-infected cells. Our findings provide novel insights into the interaction of chlamydiae with their host cells and should be taken into consideration for the design of future therapies and vaccines. PMID- 24343652 TI - Salmonella enterica serovar Typhimurium infection-induced CD11b+ Gr1+ cells ameliorate allergic airway inflammation. AB - Allergies are mainly characterized as an unrestrained Th2-biased immune response. Epidemiological data associate protection from allergic diseases with the exposure to certain infectious agents during early stages of life. Modulation of the immune response by pathogens has been considered to be a major factor influencing this protection. Recent evidence indicates that immunoregulatory mechanisms induced upon infection ameliorate allergic disorders. A longitudinal study has demonstrated reduced frequency and incidence of asthma in children who reported a prior infection with Salmonella. Experimental studies involving Salmonella enterica serovar Typhimurium-infected murine models have confirmed protection from induced allergic airway inflammation; however, the underlying cause leading to this amelioration remains incompletely defined. In this study, we aimed to delineate the regulatory function of Salmonella Typhimurium infection in the amelioration of allergic airway inflammation in mice. We observed a significant increase in CD11b+ Gr1+ myeloid cell populations in mice after infection with S. Typhimurium. Using in vitro and in vivo studies, we confirmed that these myeloid cells reduce airway inflammation by influencing Th2 cells. Further characterization showed that the CD11b+ Gr1+ myeloid cells exhibited their inhibitory effect by altering GATA-3 expression and interleukin-4 (IL-4) production by Th2 cells. These results indicate that the expansion of myeloid cells upon S. Typhimurium infection could potentially play a significant role in curtailing allergic airway inflammation. These findings signify the contribution of myeloid cells in preventing Th2-mediated diseases and suggest their possible application as therapeutics. PMID- 24343653 TI - Role of Dectin-2 for host defense against systemic infection with Candida glabrata. AB - Although Candida glabrata is an important pathogenic Candida species, relatively little is known about its innate immune recognition. Here, we explore the potential role of Dectin-2 for host defense against C. glabrata. Dectin-2 deficient (Dectin-2(-/-)) mice were found to be more susceptible to C. glabrata infections, showing a defective fungal clearance in kidneys but not in the liver. The increased susceptibility to infection was accompanied by lower production of T helper 1 (Th1) and Th17-derived cytokines by splenocytes of Dectin-2(-/-) mice, while macrophage-derived cytokines were less affected. These defects were associated with a moderate yet significant decrease in phagocytosis of the fungus by the Dectin-2(-/-) macrophages and neutrophils. Neutrophils of Dectin-2(-/-) mice also displayed lower production of reactive oxygen species (ROS) upon challenge with opsonized C. glabrata or C. albicans. This study suggests that Dectin-2 is important in host defense against C. glabrata and provides new insights into the host defense mechanisms against this important fungal pathogen. PMID- 24343655 TI - Inside scoop on outside proteins. AB - Invasion into red blood cells is an essential step in the life cycle of parasites that cause human malaria. Antibodies targeting the key parasite proteins in this process are important for developing a protective immune response. In the current issue, Boyle and colleagues provide a detailed examination of Plasmodium falciparum invasion and specifically illuminate the fate of surface-exposed parasite proteins during and immediately after invasion. PMID- 24343654 TI - Assembly of NADPH oxidase in human neutrophils is modulated by the opacity associated protein expression State of Neisseria gonorrhoeae. AB - Neisseria gonorrhoeae (the gonococcus, Gc) triggers a potent inflammatory response and recruitment of neutrophils to the site of infection. Gc survives exposure to neutrophils despite these cells' antimicrobial products, such as reactive oxygen species (ROS). ROS production in neutrophils is initiated by NADPH oxidase, which converts oxygen into superoxide. The subunits of NADPH oxidase are spatially separated between granules (gp91(phox)/p22(phox)) and the cytoplasm (p47(phox), p67(phox), and p40(phox)). Activation of neutrophils promotes the coassembly of NADPH oxidase subunits at phagosome and/or plasma membranes. While Gc-expressing opacity-associated (Opa) proteins can induce neutrophils to produce ROS, Opa-negative (Opa-) Gc does not stimulate neutrophil ROS production. Using constitutively Opa- and OpaD-positive (OpaD+) Gc bacteria in strain FA1090, we now show that the difference in ROS production levels in primary human neutrophils between these backgrounds can be attributed to differential assembly of NADPH oxidase. Neutrophils infected with Opa- Gc showed limited translocation of NADPH oxidase cytoplasmic subunits to cellular membranes, including the bacterial phagosome. In contrast, these subunits rapidly translocated to neutrophil membranes following infection with OpaD+ Gc. gp91(phox) and p22(phox) were recruited to Gc phagosomes regardless of bacterial Opa expression. These results suggest that Opa- Gc interferes with the recruitment of neutrophil NADPH oxidase cytoplasmic subunits to membranes, in particular, the p47(phox) "organizing" subunit, to prevent assembly of the holoenzyme, resulting in an absence of the oxidative burst. PMID- 24343656 TI - Essential role of invasin for colonization and persistence of Yersinia enterocolitica in its natural reservoir host, the pig. AB - In this study, an oral minipig infection model was established to investigate the pathogenicity of Yersinia enterocolitica bioserotype 4/O:3. O:3 strains are highly prevalent in pigs, which are usually symptomless carriers, and they represent the most common cause of human yersiniosis. To assess the pathogenic potential of the O:3 serotype, we compared the colonization properties of Y. enterocolitica O:3 with O:8, a highly mouse-virulent Y. enterocolitica serotype, in minipigs and mice. We found that O:3 is a significantly better colonizer of swine than is O:8. Coinfection studies with O:3 mutant strains demonstrated that small variations within the O:3 genome leading to higher amounts of the primary adhesion factor invasin (InvA) improved colonization and/or survival of this serotype in swine but had only a minor effect on the colonization of mice. We further demonstrated that a deletion of the invA gene abolished long-term colonization in the pigs. Our results indicate a primary role for invasin in naturally occurring Y. enterocolitica O:3 infections in pigs and reveal a higher adaptation of O:3 than O:8 strains to their natural pig reservoir host. PMID- 24343657 TI - Low-dose intradermal infection with trypanosoma congolense leads to expansion of regulatory T cells and enhanced susceptibility to reinfection. AB - BALB/c mice are highly susceptible to experimental intraperitoneal Trypanosoma congolense infection. However, a recent report showed that these mice are relatively resistant to primary intradermal low-dose infection. Paradoxically, repeated low-dose intradermal infections predispose mice to enhanced susceptibility to an otherwise noninfectious dose challenge. Here, we explored the mechanisms responsible for this low-dose-induced susceptibility to subsequent low-dose challenge infection. We found that akin to intraperitoneal infection, low-dose intradermal infection led to production of interleukin-10 (IL-10), IL-6, IL-12, tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), and gamma interferon (IFN-gamma) by spleen and draining lymph node cells. Interestingly, despite the absence of parasitemia, low-dose intradermal infection led to expansion of CD4+ CD25+ Foxp3+ cells (T regulatory cells [Tregs]) in both the spleens and lymph nodes draining the infection site. Depletion of Tregs by anti-CD25 monoclonal antibody (MAb) treatment during primary infection or before challenge infection following repeated low-dose infection completely abolished the low-dose-induced enhanced susceptibility. In addition, Treg depletion was associated with dramatic reduction in serum levels of TGF-beta and IL-10. Collectively, these findings show that low-dose intradermal infection leads to rapid expansion of Tregs, and these cells mediate enhanced susceptibility to subsequent infection. PMID- 24343659 TI - High individual consistency in fear of humans throughout the adult lifespan of rural and urban burrowing owls. AB - Human-induced rapid environmental changes challenge individuals by creating evolutionarily novel scenarios, where species encounter novel enemies, the new species sometimes being humans themselves. However, little is known about how individuals react to human presence, specifically whether they are able to habituate to human presence, as frequently assumed, or are selected based on their fear of humans. We tested whether fear of humans (measured as flight initiation distance in a diurnal owl) is reduced through habituation to human presence (plasticity) or whether it remains unchanged throughout the individuals' life. Results show an unusually high level of individual consistency in fear of humans throughout the adult lifespan of both rural (r = 0.96) and urban (r = 0.90) birds, lending no support to habituation. Further research should assess the role of inter-individual variability in fear of humans in shaping the distribution of individuals and species in an increasingly humanized world. PMID- 24343658 TI - Rosetting Plasmodium falciparum-infected erythrocytes bind to human brain microvascular endothelial cells in vitro, demonstrating a dual adhesion phenotype mediated by distinct P. falciparum erythrocyte membrane protein 1 domains. AB - Adhesion interactions between Plasmodium falciparum-infected erythrocytes (IE) and human cells underlie the pathology of severe malaria. IE cytoadhere to microvascular endothelium or form rosettes with uninfected erythrocytes to survive in vivo by sequestering IE in the microvasculature and avoiding splenic clearance mechanisms. Both rosetting and cytoadherence are mediated by the parasite-derived IE surface protein family Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). Rosetting and cytoadherence have been widely studied as separate entities; however, the ability of rosetting P. falciparum strains to cytoadhere has received little attention. Here, we show that IE of the IT/R29 strain expressing a rosette-mediating PfEMP1 variant (IT4var09) cytoadhere in vitro to a human brain microvascular endothelial cell line (HBEC-5i). Cytoadherence was inhibited by heparin and by treatment of HBEC-5i with heparinase III, suggesting that the endothelial receptors for IE binding are heparan sulfate proteoglycans. Antibodies to the N-terminal regions of the IT4var09 PfEMP1 variant (NTS-DBL1alpha and DBL2gamma domains) specifically inhibited and reversed cytoadherence down to low concentrations (<10 MUg/ml of total IgG). Surface plasmon resonance experiments showed that the NTS-DBLalpha and DBL2gamma domains bind strongly to heparin, with half-maximal binding at a concentration of ~0.5 MUM in both cases. Therefore, cytoadherence of IT/R29 IE is distinct from rosetting, which is primarily mediated by NTS-DBL1alpha interactions with complement receptor 1. These data show that IT4var09-expressing parasites are capable of dual interactions with both endothelial cells and uninfected erythrocytes via distinct receptor-ligand interactions. PMID- 24343660 TI - Ln[DO3A-N-alpha-(pyrenebutanamido)propionate] complexes: optimized relaxivity and NIR optical properties. AB - We have proposed recently that the DO3A-N-alpha-(amino)propionate chelator and its amide conjugates are leads to targeted, high relaxivity, safe contrast agents for magnetic resonance imaging. In this work we illustrate further the expeditious nature and robustness of the synthetic methodologies developed by preparing the DO3A-N-(alpha-pyrenebutanamido)propionate chelator. Its Gd(3+) chelate retains the optimized water exchange, high stability and inertness of the parent complex. The pyrene moiety imparts concentration-dependent self-assembly properties and aggregation-sensitive fluorescence emission to the Gd(3+) complex. The Gd(3+) complex displays pyrene-centred fluorescence whilst the Yb(3+) and Nd(3+) complexes exhibit sensitized lanthanide-centred near-infrared luminescence. The aggregated form of the complex displays high relaxivity (32 mM( 1) s(-1), 20 MHz, 25 degrees C) thanks to simultaneous optimization of the rotational correlation time and of the water exchange rate. The relaxivity is however still limited by chelate flexibility. This report demonstrates that the DO3A-N-(alpha-amino)propionate chelator is a valuable platform for constructing high relaxivity CA using simple design principles and robust chemistries accessible to most chemistry labs. PMID- 24343661 TI - Self-eating to remove cilia roadblock. AB - Autophagy delivers many proteins and cellular components to the lysosome for degradation via selective or nonselective mechanisms. By controlling the stability of defined protein factors, autophagy might regulate cellular processes in a precise and finely-tuned manner. In this study, we demonstrated that autophagy positively regulates the biogenesis of the primary cilium, an antenna like organelle that senses the environment and transduces signals. Defects in the function or structure of cilia cause a number of human diseases called "ciliopathies." We found that the autophagosome membrane anchored protein LC3 interacts with OFD1 (oral-facial-digital syndrome 1) and removes it from the centriolar satellite upon serum starvation to initiate primary cilium biogenesis. OFD1 regulation and primary cilium formation are defective in autophagy-deficient cells, and reducing OFD1 protein levels through RNA interference rescues primary cilium formation. More strikingly, knockdown of OFD1 induces primary cilium formation in unstressed cells as well as in a human breast cancer cell that was previously reported to have lost the ability to form primary cilia. These findings therefore suggest an unexpected link among autophagy, ciliogenesis, ciliopathy, and cancers. PMID- 24343662 TI - Shifting responses in quality of life: people living with dialysis. AB - PURPOSE: People assess their quality of life (QoL) using internal standards, values, and priorities. With health changes, QoL responses shift to reflect current realities. This qualitative study investigated the life experience and QoL assessments of people living with dialysis (PWDs). METHODS: Thirty-one interviews with 20 PWDs over the age of 70 (mean time on dialysis 34 months) and 11 family members investigated experience with disease and dialysis, related life challenges, medical decision-making, and future planning. Interviews were recorded, transcribed, and analyzed for themes and hypotheses using qualitative methods and description. RESULTS: When beginning dialysis, PWDs' reported that life on dialysis was worth living and recalibrated their QoL assessments incorporating this standard into their daily lives. Three themes emerged as the disease progressed and dialysis became more difficult: PWDs first reported thriving on dialysis and then surviving with the support of dialysis, and when QoL was reported as poor, PWDs were reconsidering whether dialysis was still worth the life it was providing. Each of these steps involved changes in health circumstances, and PWDs explained their QoL assessments at each step using differing values and priorities. These steps in reconceptualization and reprioritization demonstrated PWDs' Response Shift and eventually led to another (recalibrated) standard: Life with dialysis was no longer worth living. CONCLUSIONS: Quality-of-life assessment is an on-going process for older dialysis patients. Clinicians should be alert for changes in subjective QoL statements as dialysis and underlying diseases progress. Response Shift explains these changes in assessment. PMID- 24343663 TI - DNAM-1 control of natural killer cells functions through nectin and nectin-like proteins. AB - Natural killer (NK) cells represent key innate immune cells that restrain viral infection and malignant transformation and help mount an adaptive immune response. To perform such complicated tasks, NK cells express a wide set of inhibitory and activating receptors that alert them against cellular stress without damaging healthy cells. A new family of receptors that recognize nectin and nectin-like molecules has recently emerged as a critical regulator of NK cell functions. The most famous member of this family, DNAX accessory molecule (DNAM 1, CD226), is an adhesion molecule that control NK cell cytotoxicity and interferon-gamma production against a wide range of cancer and infected cells. Its ligands CD112 and CD155 have been described in different pathological conditions, and recent evidence indicates that their expression is regulated by cellular stress. Additional receptors have been shown to bind DNAM-1 ligands and modulate NK cell functions bringing another level of complexity. These include CD96 (TACTILE) and TIGIT (WUCAM, VSTM3). Here, we review the role of DNAM-1, TIGIT and CD96 in NK cell biology summarizing the recent advances made on the role of these receptors in various pathologies, such as cancer, viral infections and autoimmunity. PMID- 24343664 TI - The Rho GTPase Rac1 is required for recycling endosome-mediated secretion of TNF in macrophages. AB - Rho GTPases are required for many cellular events such as adhesion, motility, and membrane trafficking. Here we show that in macrophages, the Rho GTPases Rac1 and Cdc42 are involved in lamellipodia and filopodia formation, respectively, and that both of these Rho GTPases are essential for the efficient surface delivery of tumor necrosis factor (TNF) to the plasma membrane following TLR4 stimulation. We have previously demonstrated intracellular trafficking of TNF via recycling endosomes in lipopolysaccharide (LPS)-activated macrophages. Here, we further define a specific role for Rac1 in intracellular TNF trafficking, demonstrating impairment in TNF release following TLR4 stimulation in the presence of a Rac inhibitor, in cells expressing a dominant negative (DN) form of Rac1, and following small interfering RNA (siRNA) knockdown of Rac1. Rac1 activity was required for TNF trafficking but not for TLR4 signaling following LPS stimulation. Reduced TNF secretion was due to a defect in Rac1 activity, but not of the closely related Rho GTPase Rac2, demonstrated by the additional use of macrophages derived from Rac2-deficient mice. Labeling recycling endosomes by the uptake of fluorescent transferrin enabled us to show that Rac1 was required for the final stages of TNF trafficking and delivery from recycling endosomes to the plasma membrane. Thus, actin remodeling by the Rho GTPase Rac1 is required for TNF cell surface delivery and release from macrophages. PMID- 24343665 TI - Haematological cancer: Deep molecular response predicts survival in CML. PMID- 24343666 TI - Celebrating treatment completion in sub-Saharan Africa. PMID- 24343667 TI - Haematological cancer: Ikaros--not a myth for myeloma. PMID- 24343668 TI - Haematological cancer: Radioimmunotherapy--time to be upfront and fractionated? PMID- 24343669 TI - Targeted therapies: Juggling combinations--not the way forward. PMID- 24343670 TI - The effect of alginate and chitosan concentrations on some properties of chitosan coated alginate beads and survivability of encapsulated Lactobacillus rhamnosus in simulated gastrointestinal conditions and during heat processing. AB - BACKGROUND: In this study, chitosan-coated alginate beads were produced with different concentrations of chitosan and alginate to evaluate the survival of encapsulated Lactobacillus rhamnosus GG during exposure to adverse conditions in gastrointestinal simulated juice and heat processing. RESULTS: The encapsulation yield of different encapsulation treatments was between 25 and 53.2%. Although there was a drastic decrease in pH within 48 h of incubation in MRS medium inoculated with free and encapsulated bacteria, no significant changes (P > 0.05) in bacterial count were observed among different encapsulation treatments. Moreover, the survival rate after gastrointestinal juice exposure of all prepared beads was 10-87 times greater than that of free cells and was significantly enhanced by increasing chitosan and alginate concentrations. The encapsulated bacteria survived significantly (P < 0.05) better than the free cells during heat exposure at 55, 60 and 65 degrees C: free cells experienced about 5 log cycles reduction after heat treatment at 65 degrees C for 30 min, whereas 40 g L(-1) alginate/10 g L(-1) chitosan-encapsulated L. rhamnosus was reduced by only 2.55 log cycles. CONCLUSION: Encapsulation effectively protected L. rhamnosus against heat treatment and gastrointestinal conditions, and this effect is important in delivering sufficient numbers of viable probiotic bacteria to the gastrointestinal tract. PMID- 24343671 TI - Combination formoterol and budesonide as maintenance and reliever therapy versus combination inhaler maintenance for chronic asthma in adults and children. AB - BACKGROUND: Asthma is characterised by chronic inflammation of the airways and recurrent exacerbations with wheezing, chest tightness and cough. Treatment with inhaled steroids and bronchodilators often results in good control of symptoms, prevention of further morbidity and mortality and improved quality of life. Several steroids and beta2-agonists (long- and short-acting) as well as combinations of these treatments are available in a single inhaler to be used once or twice a day, with a separate inhaler for relief of symptoms when needed (for patients in Step three or higher, according to Global Initiative for Asthma (GINA) guidelines). Budesonide/formoterol is also licenced for use as maintenance and reliever therapy from a single inhaler (SiT; sometimes referred to as SMART therapy). SiT can be prescribed at a lower dose than other combination therapy because of the additional steroid doses being received as reliever therapy. It has been suggested that using SiT improves compliance and hence reduces symptoms and exacerbations, but it is unclear whether it increases side effects associated with the use of inhaled steroids. OBJECTIVES: To assess the efficacy and safety of budesonide/formoterol in a single inhaler (SiT) to be used for both maintenance and reliever therapy in asthma in comparison with maintenance treatment provided through combination inhalers with a higher maintenance steroid dose (either fluticasone/salmeterol or budesonide/formoterol), along with additional fast-acting beta2-agonists for relief of symptoms. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials, online trial registries and drug company websites. The most recent search was conducted in November 2013. SELECTION CRITERIA: We included parallel-group, randomised controlled trials of at least 12 weeks' duration. Studies were included if they compared single-inhaler therapy with budesonide/formoterol (SiT) versus combination inhalers at a higher maintenance dose of steroids than was given in the SiT arm (either salmeterol/fluticasone or budesonide/formoterol). DATA COLLECTION AND ANALYSIS: We used standard methods expected by The Cochrane Collaboration. Primary outcomes were exacerbations requiring hospitalisation, exacerbations requiring oral corticosteroids and serious adverse events (including mortality). MAIN RESULTS: Four studies randomly assigning 9130 people with asthma were included; two were six-month double-blind studies, and two were 12-month open-label studies. No trials included children younger than age 12. Trials included more women than men, with mean age ranging from 38 to 45, and mean baseline steroid dose (inhaled beclomethasone (BDP) equivalent) from 636 to 888 MUg. Mean baseline forced expiratory volume in one second (FEV1) percentage predicted was between 70% and 73% in three of the trials, and 96% in another. All studies were funded by AstraZeneca and were generally free from methodological biases, although the two open-label studies were rated as having high risk for blinding, and some evidence of selective outcome reporting was found. These possible sources of bias did not lead us to downgrade the quality of the evidence. The quantity of inhaled steroids, including puffs taken for relief from symptoms, was consistently lower for SiT than for the comparison groups.Separate data for exacerbations leading to hospitalisations, to emergency room (ER) visits or to a course of oral steroids could not be obtained. Compared with higher fixed dose combination inhalers, fewer people using SiT had exacerbations requiring hospitalisation or a visit to the ER (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.57 to 0.90; I(2) = 0%, P = 0.66), and fewer had exacerbations requiring a course of oral corticosteroids (OR 0.75, 95% CI 0.65 to 0.87; I(2) = 0%, P = 0.82). This translates to one less person admitted to hospital or visiting the ER (95% CI 0 to 2 fewer) and two fewer people needing oral steroids (95% CI 1 to 3 fewer) compared with fixed-dose combination treatment with a short acting beta-agonist (SABA) reliever (per 100 treated over eight months). No statistical heterogeneity was observed in either outcome, and the evidence was rated of high quality. Although issues with blinding were evident in two of the studies, and one study recruited a less severe population, sensitivity analyses did not change the main results, so quality was not downgraded.We could not rule out the possibility that SiT increased rates of serious adverse events (OR 0.92, 95% CI 0.74 to 1.13; I(2) = 0%, P = 0.98; moderate-quality evidence, downgraded owing to imprecision).We were unable to say whether SiT improved results for several secondary outcomes (morning and evening peak expiratory flow (PEF), rescue medication use, symptoms scales), and in cases where results were significant, the effect sizes were not considered clinically meaningful (predose FEV1, nocturnal awakenings and quality of life). AUTHORS' CONCLUSIONS: SiT reduces the number of people having asthma exacerbations requiring oral steroids and the number requiring hospitalisation or an ER visit compared with fixed-dose combination inhalers. Evidence for serious adverse events was unclear. The mean daily dose of inhaled corticosteroids (ICS) in SiT, including the total dose administered with reliever use, was always lower than that of the other combination groups. This suggests that the flexibility in steroid administration that is possible with SiT might be more effective than a standard fixed-dose combination by increasing the dose only when needed and keeping it low during stable stages of the disease. Data for hospitalisations alone could not be obtained, and no studies have yet addressed this question in children younger than age 12. PMID- 24343673 TI - Low skeletal muscle is associated with toxicity in patients included in phase I trials. AB - BACKGROUND: Low muscle mass has been associated with chemotherapy toxicity. We conducted this prospective study to evaluate the effects of body composition on the occurrence of toxicity in phase I trials. PATIENTS AND METHODS: Patients were consecutively enrolled irrespective of the type of tumor or the type of drug. The Skeletal Muscle Index (SMIndex) and visceral and subcutaneous adipose tissue were assessed with computed tomography imaging by measuring cross-sectional areas of the tissues (cm(2)/m(2)). Dose-limiting toxicity (DLT) corresponded to toxicities occurring during the 1(st) cycle that necessitated dose reduction, postponement or interruption of drug administration and severe toxicity events (STE) corresponded to DLT or permanent treatment withdrawal due to toxicity. RESULTS: 93 patients were evaluated. Ten percent of patients experienced DLT and had a lower SMIndex: 40.8 +/- 4.6 vs. 48.1 +/- 9.6 cm(2)/m(2) (p = 0.01). STE occurred in 14 % of the patients. The only factor associated with STE was a low SMIndex: 42.4 +/- 5.8 vs. 48.4 +/- 9.7 cm(2)/m(2) (p = 0.02). STE were observed in 25.5 % of the patients when the SMIndex was below the median value compared to 6.5 % of patients with a high SMIndex (p = 0.02). CONCLUSION: Muscle mass is a critical predictor of severe toxicity events in phase I patients, suggesting that sarcopenia may be considered in assessing patients for eligibility of phase-1 studies. PMID- 24343672 TI - Dysphonia induced by anti-angiogenic compounds. AB - The number of studies reporting the benefit of angiogenesis inhibition is steadily increasing. Anti-angiogenic drugs, used as monotherapy or in association with chemotherapy, have been shown to benefit patients with several different malignancies. Despite the benefits of these therapies, however, each drug has different side effects. This review is specifically focused on analyzing the frequency of one of the complications the most frequently overlooked by physicians, dysphonia. Perhaps this side effect is overlooked because it is not life-threatening, but dysphonia may nevertheless affect quality of life considerably. We reviewed 88 studies concerning treatment with anti-angiogenics (bevacizumab, aflibercept, sunitinib, sorafenib, pazopanib, axitinib and regorafenib) presently approved for clinical use, to review the incidence of dysphonia or voice changes in phase I, II and III closed clinical studies reported in ClinicalTrials.gov until March 2013. We found that almost all studies reported certain degree of dysphonia in the trial arms associated with anti angiogenic treatment. We discuss these findings in light of the fact that it is not an uncommon side effect in patients exposed to these kinds of drugs. Particularly for treatments with axitinib, aflibercept and regorafenib, the angiogenesis inhibition possibly plays a role by altering the larynx in some way and modifying vocal fold vibrations, leading to dysphonia. PMID- 24343674 TI - Infant deaths in slings. AB - Although the incidence of sudden unexpected death in infancy (SUDI) decreased markedly after campaigns to promote supine positioning during sleeping, it has remained unchanged over the last decade. Epidemiological data suggest a role for new causes such as suffocation, asphyxia, and entrapment. Health authorities in several countries have issued warnings about slings used to carry infants. However, few reports of infant deaths in slings have been published in medical journals. Our paediatric intensive care unit has admitted two infants who experienced cardiorespiratory arrest while carried in a sling. Diagnostic investigations including a post-mortem examination established asphyxia as the mechanism of death. In conclusion, baby slings may carry a risk of SUDI, either by compression of the baby into a forward-flexed position or by direct suffocation. European recommendations for the cautious use of baby slings should be disseminated to families and professionals involved in caring for infants, as done recently in Australia, Canada, and the USA. PMID- 24343676 TI - The effects of low- and high-dose-rate brachytherapy on depressive symptoms in prostate cancer patients. AB - OBJECTIVE: To compare the prevalence of depressive symptoms between prostate cancer (PCa) patients who have received low-dose-rate brachytherapy (LDRB) and those receiving high-dose-rate brachytherapy (HDRB). METHOD: Direct comparisons were made between the prevalence of the DSM-IV-TR symptoms of major depressive disorder (MDD) based upon Zung Self-Rating Depression Scale responses and patients' records on 164 PCa patients from Queensland, Australia. RESULTS: HDRB patients had significantly greater frequency of self-reported symptoms of crying (or feeling like it) (MDD criterion 1), and restlessness and inability to sit still (MDD criterion 5), and a nonsignificant trend towards more frequent fatigue (MDD criterion 7). There was no significant association between fatigue and having received hormone therapy. CONCLUSION: These three MDD symptoms, which include one of the two alternative key required symptoms (criterion 1), suggest that HDRB PCa patients may present with clinically significantly different depression profiles from their peers who receive LDRB. Treatment choices need to be focused upon possible serotonergic dysfunction as well as somatic complaints of depression. The presence of subsyndromal depression in HDRB patients also warrants consideration. PMID- 24343677 TI - Cardiac hybrid SPECT/CTA imaging to detect "functionally relevant coronary artery lesion": a potential gatekeeper for coronary revascularization? AB - OBJECTIVE: Combination of both morphological and functional information has gained more and more appreciation with the concept of "functionally relevant coronary artery lesion (FRCAL)" and "functional revascularization". This has paved the way for non-invasive single-photon emission computed tomography (SPECT)/computed tomography angiography (CTA) hybrid imaging. We aimed at assessing the value of cardiac hybrid imaging on the detection of FRCAL and its potential as a gatekeeper for invasive examination and treatment. METHODS: In Two hundred and thirty-eight patients with known or suspected coronary artery disease (CAD) underwent CTA and myocardial perfusion imaging (MPI) using SPECT on a dual system scanner in one session before treatment. 78 patients underwent invasive coronary angiography (CAG) within 1 month. Detection of FRCAL by the combination of SPECT/CTA was compared with SPECT/CAG, which served as a standard of reference. According to the both combination results, treatment decision (revascularization or medical treatment) was chosen in the catheterization laboratory. RESULTS: Sensitivity, specificity, accuracy, positive and negative prediction rate by SPECT/CTA vs. SPECT/CAG for the detection of flow-limiting coronary stenosis on patient- and vessel-based analysis were 94.33, 72.00, 87.18, 87.71, 85.71 % and 88.71, 92.44, 91.45, 80.89, 95.78 %, respectively. No revascularization procedures were performed in patients without flow-limiting stenosis. However, more than one-third (25/67, 37 %) of revascularized vessels were not associated with ischemia on MPI. CONCLUSIONS: The cardiac SPECT/CTA hybrid imaging can accurately detect FRCAL and thereby it may be used as a gatekeeper for CAG and revascularization procedures. PMID- 24343678 TI - Assessment of template-free modeling in CASP10 and ROLL. AB - We present the assessment of predictions for Template-Free Modeling in CASP10 and a report on the first ROLL experiment wherein predictions are collected year round for review at the regular CASP season. Models were first clustered so that duplicated or very similar ones were grouped together and represented by one model in the cluster. The representatives were then compared with targets using GDT_TS, QCS, and three additional superposition-independent score functions newly developed for CASP10. For each target, the top 15 representatives by each score were pooled to form the Top15Union set. All models in this set were visually inspected by four of us independently using the new plugin, EvalScore, which we developed with the UCSF Chimera group. The best models were selected for each target after extensive debate among the four examiners. Groups were ranked by the number of targets (hits) for which a group's model was selected as one of the best models. The Keasar group had most hits in both categories, with four of 19 FM and eight of 36 ROLL targets. The most successful prediction servers were QUARK from Zhang's group for FM category with three hits and Zhang-server for the ROLL category with seven hits. As observed in CASP9, many successful groups were not true "template-free" modelers but used remote templates and/or server models to obtain their winning models. The results of the first ROLL experiment were broadly similar to those of the CASP10 FM exercise. PMID- 24343679 TI - New information technology in cardiac surgery: development of an applicative about ascending aortic aneurysm ("aortic surgery"). AB - An app in the area of Aortic Diseases (ascending aortic aneurysm) was developed. This article offers a brief introduction about the information received and transmitted in the app and the process through which it was developed as well as its contents. PMID- 24343680 TI - The descending branch of the lateral femoral circumflex artery is a good option in CABG with arterial grafts. AB - INTRODUCTION: The descending branch of the lateral femoral circumflex artery is an option for coronary artery bypass grafting. OBJECTIVE: To evaluate the early patency and adaptation of lumen diameter using multidetector computed angiotomography. METHODS: Thirty-two patients were selected to undergo coronary artery bypass grafting using the descending branch of the lateral circumflex artery, the internal thoracic artery, and other grafts. Evaluations were carried out through high resolution computed tomography performed on the 7th and 90th postoperative day. Diameters of the descending branch of the lateral circumflex artery and the left internal thoracic artery were measured 3 cm before the distal anastomosis, in the middle portion, and 3 cm after the proximal anastomosis. Diameters were compared using paired t-test (P<0.05). RESULTS: Descending branch of the lateral femoral circumflex artery wDescending branch of the lateral femoral circumflex artery was used in 26 patients, as its use was not viable in six patients (18%). It was used as composite graft in all cases. The anterior descending branch was revascularized by the left internal thoracic artery in all cases. Patency rates of the descending branch of the lateral femoral circumflex artery were 96% and 92%, respectively. No occlusions were observed in the left internal thoracic artery (LITA) and no ischemic events were observed in the descending branch of the lateral circumflex. Descending branch of the lateral femoral circumflex artery increased the lumen diameter in the middle (P=0.001) and distal portions (P=0.006); the left internal thoracic artery (LITA) increased in the middle portion (P=0.001). CONCLUSION: Similar to the left internal thoracic artery, the descending branch of the lateral femoral circumflex artery showed high patency rate and positive luminal adaptation. This early evaluation confirms the descending branch of the lateral femoral circumflex artery as a potential alternative for grafting. Due to anatomical variations, preoperative femoral angiographic evaluation appears to be mandatory. PMID- 24343681 TI - Minimally invasive redo mitral valve surgery without aortic crossclamp. AB - INTRODUCTION: Reoperations of the mitral valve have a higher rate of complications when compared with the first surgery. With the field of video assisted techniques for the first surgery of mitral valve became routine, reoperation cases began to arouse interest for this less invasive procedures. OBJECTIVE: To assess the results and the technical difficulties in 10 patients undergoing minimally invasive redo mitral valve surgery. METHOD: Cardiopulmonary bypass was installed through a cannula placed in the femoral vessels and right internal jugular vein, conducted in 28 degrees of temperature in ventricular fibrillation. A right lateral thoracotomy with 5 to 6 cm in the third or fourth intercostal space was done, pericardium was displaced only at the point of atriotomy. The aorta was not clamped. RESULTS: Ten patients with mean age of 56.9 +/- 10.5 years, four were in atrial fibrilation rhythm and six in sinusal. Average time between first operation and reoperations was 11 +/- 3.43 years. The mean EuroSCORE group was 8.3 +/- 1.82. The mean ventricular fibrillation and cardiopulmonary bypass was respectively 70.9 +/- 17.66 min and 109.4 +/- 25.37 min. The average length of stay was 7.6 +/- 1.5 days. There were no deaths in this series. CONCLUSION: Mitral valve reoperation can be performed through less invasive techniques with good immediate results, low morbidity and mortality. However, this type of surgery requires a longer duration of cardiopulmonary bypass, especially in cases where the patient already has prosthesis. The presence of a minimal aortic insufficiency also makes this procedure technically more challenging. PMID- 24343682 TI - Effects of reprocessing on chemical and morphological properties of guide wires used in angioplasty. AB - OBJECTIVE: To investigate the influence of the reprocessing technique of enzymatic bath with ultrasonic cleaning and ethylene oxide sterilization on the chemical properties and morphological structure of polymeric coatings of guide wire for regular guiding catheter. METHODS: These techniques simulated the routine of guide wire reprocessing in many hemodynamic services in Brazil and other countries. Samples from three different manufacturers were verified by scanning electron microscopy and X-ray photoelectron spectroscopy. RESULTS: A single or double sterilization of the catheters with ethylene oxide was not associated with morphological or chemical changes. However, scanning electron microscopy images showed that the washing method was associated with rough morphological changes, including superficial holes and bubbles, in addition to chemical changes of external atomic layers of polymeric coating surfaces, as detected by the X-ray photoelectron spectroscopy method, which is compatible with extended chemical changes on catheter surfaces. CONCLUSION: The reprocessing of the catheters with ethylene oxide was not associated with morphological or chemical changes, and it seemed appropriate to maintain guide wire coating integrity. However, the method combining chemical cleaning with mechanical vibration resulted in rough anatomical and chemical surface deterioration, suggesting that this reprocessing method should be discouraged. PMID- 24343683 TI - Randomized and comparative study between two intra-hospital exercise programs for heart transplant patients. AB - OBJECTIVE: To compare the effects of two physical therapy exercise in-hospital programs in pulmonary function and functional capacity of patients in the postoperative period of heart transplantation. METHODS: Twenty-two heart transplanted patients were randomized to the control group (CG, n=11) and training group (TG, n=11). The control group conducted the exercise program adopted as routine in the institution and the training group has had a protocol consisting of 10 stages, with incremental exercises: breathing exercises, resistance training, stretching and walking. The programs began on the first day after extubation and stretched until hospital discharge. Assessed pulmonary function, distance walked in six minutes walk test (6MWT) and peripheral muscle strength by one repetition maximum test (1RM). RESULTS: Similar behavior was observed between the two groups treated, with statistically significant increases between the first and second test of the following variables: FVC (59% in CG and 35.2% in TG); MIP (8.6% in CG and 53.5% in TG), MEP (28.8% in CG and 40.7% in TG) and 6MWT (44.5% in CG and 31.4% in TG). There was an increase of peripheral strength by 1RM test, over time, to the muscle groups of the elbow flexors, shoulder flexors, hip abductors and knee flexors. CONCLUSION: Heart transplant patients benefit from exercise programs in hospital, regardless of the program type applied. A new training proposal did not result in superiority compared to routine programme applied. Exercise protocols provided improves in ventilatory variables and functional capacity of this population. PMID- 24343684 TI - Impact of aspirin use in the incidence of thromboembolic events after bioprosthesis replacement in patients with rheumatic disease. AB - INTRODUCTION: There is still much debate regarding the kind of antithrombotic therapy in the immediate postoperative period of bioprosthesis replacement (first three months). Thus, the authors consider relevant to determine the contemporary incidence of thromboembolic events in rheumatic patients early after implantation of aortic and mitral bioprosthesis replacement (first 90 days in the post operative period) and perform a comparison between isolated Aspirin uses versus no-antiplatelet therapy, in this same context. METHODS: Between the period of January 2010 to July 2012, all consecutive rheumatic patients, with basal sinus rhythm, who performed mitral and aortic valve replacement with bioprosthesis (pericardial bovine), were included in this prospective cohort study, 184 patients in total. The primary endpoint evaluated were the rate of embolic events. RESULTS: In the first 30 days, there were three cerebral ischemic events among patients treated in Aspirin group (5.2%) compared with two events in patients without Aspirin therapy (1.7%), HR = 3.18; 95% CI 0.5 to 19.6; P=0.33. Between 31 and 90 days postoperatively, no patient had a primary outcome. The embolism-free survival, bleeding events and the overall survival were not statistically significant between the aspirin and no-antiplatelet groups. CONCLUSION: In conclusion, in this prospective cohort of rheumatic patients, we found a low and very rare incidence rate of embolic events during the first 90 days postoperative period in mitral and isolated aortic position, respectively. The use of aspirin did not significantly reduce the rate of thromboembolism. PMID- 24343685 TI - Risk factors for prolonged hospital stay after isolated coronary artery bypass grafting. AB - INTRODUCTION: Characteristics of the patient and the coronary artery bypass grafting may predispose individuals to prolonged hospitalization, increasing costs and morbidity and mortality. OBJECTIVE: The objective of this study was to evaluate individual and perioperative risk factors of prolonged hospitalization in intensive care units and wards. METHODS: We conducted a case-control study of 104 patients undergoing isolated coronary artery bypass grafting with cardiopulmonary bypass. Patients hospitalized >3 days in the intensive care unit or >7 days in the ward were considered for the study. The association between variables was estimated by the chi-square test, odds ratio and logistic regression; P <0.05 was considered statistically significant. RESULTS: Hospital stay >3 days in the intensive care unit occurred for 22.1% of patients and >7 days in the ward for 27.9%. Among preoperative factors, diabetes (OR=3.17) and smoking (OR=4.07) were predictors of prolonged intensive care unit stay. Combining the pre-, intra-and postoperative variables, only mechanical ventilation for more than 24 hours (OR=6.10) was predictive of intensive care unit outcome. For the ward outcome, the preoperative predictor was left ventricular ejection fraction <50% (OR=3.04). Combining pre- and intraoperative factors, diabetes (OR=2.81), and including postoperative factors, presence of infection (OR=4.54) were predictors of prolonged hospitalization in the ward. CONCLUSION: Diabetes and smoking were predictors of intensive care unit outcome, and ejection fraction <50% of ward outcome. For the set of perioperative factors, prolonged hospitalization after isolated coronary artery bypass grafting was associated with mechanical ventilation >24 hours for the intensive care unit and presence of infection for the ward. PMID- 24343686 TI - Factors associated to hypoxemia in patients undergoing coronary artery bypass grafting. AB - INTRODUCTION: Hypoxemia is a frequent pulmonary complication in the postoperative coronary artery bypass graft. Detection of factors associated with their occurrence may indicate patients at risk for this complication, which allows tracing specific therapeutic and consequently reduce morbidity and mortality. OBJECTIVE: To identify related factors to hypoxemia occurrence in immediate coronary artery bypass graft postoperative. METHODS: In this retrospective cohort study, we studied 100 patients submitted to elective om-pump artery bypass graft , between April 2010 and December 2011, at a reference university hospital for cardiac surgery in the state of Maranhao. It was considered hypoxemia gas exchange ratio less than or equal to 300 mmHg. Associated variables with perioperative hypoxemia were defined by the Student T test, G or Mann-Whitney tests, Chi-square, or Fisher's exact test and multiple linear regression. RESULTS: Among studied variables, high body mass index (P=0.036) and smoking (P=0.024) were significantly associated with hypoxemia in the immediate coronary artery bypass graft postoperative. Hypoxemia incidence in this period was 55% and did not affects mechanical ventilation duration and Intensive Care Unit lengh of stay. CONCLUSION: In this sample, body mass index and smoking were associated to hypoxemia. These data reinforce the importance of clinical assessment to identify patients at risk for this complication, considering its high incidence in immediate postoperative period. PMID- 24343687 TI - Adult congenital heart disease: experience with the surgical approach. AB - OBJECTIVE: To report the institution experience with the surgical treatment of adults with congenital heart disease due to the increasing number of these patients and the need for a better discussion of the subject. METHODS: Retrospective analysis describing demographic data, risk factors and results. RESULTS: 191 patients between 16 and 74 years old were operated on. Primary correction was done in 171 cases, 93 (55%) for atrial septal defect repair. Among 20 (12%) reoperations, pulmonary valve replacement was done in six cases. The mean intensive care and hospital stay were 2.7 and 8.5 days respectively, significantly greater for the reoperated cases (P=0.001). The mean bypass and clamping times were 68.6 and 44.7 minutes respectively, greater for the reoperated cases (P<0.0001 and P=0.0003 respectively). Hospital mortality was 4.2% and male sex, functional class III-IV and older age at operation were predictive risk factors. Significant complications were more frequent in the reoperated cases (P<0.003), mainly atrial flutter and fibrillation. Among 183 patients discharged, 149 (82%) are being followed and atrial flutter and fibrillation are common. The mean functional class value improved significantly after operation (1.66 to 1.11; P<0.0001). The estimated survival was 96.2% in six years. CONCLUSION: Heart surgery in adults with congenital heart disease can be accomplished with low mortality and functional class improvement. Immediate and late complications are frequent. Multicenter studies are important to better characterize this patient population in the country. PMID- 24343688 TI - Effects of different PEEP levels on respiratory mechanics and oxygenation after coronary artery bypass grafting. AB - OBJECTIVE: To compare the effects of different levels of positive end-expiratory pressure on respiratory mechanics and oxygenation indexes in the immediate postoperative period of coronary artery bypass grafting. METHODS: Randomized clinical trial in which 136 patients underwent coronary artery bypass grafting between January 2011 and March 2012 were divided into three groups and admitted to mechanical ventilation with different positive end-expiratory pressure levels: Group A, 5 cmH2O (n=44), Group B, 8 cmH2O (n=47) and Group C, 10 cmH2O (n=45). Data about respiratory mechanics were obtained from mechanical ventilator monitor and oxygenation indexes from arterial blood gas samples, collected twenty minutes after intensive care unit admission. Patients with chronic obstructive pulmonary disease and patients submitted to off-pump, emergency or combined operations were not included. For statistical analysis, we used Kruskal-Wallis, G and Chi-square tests, considering results significant when P<0.05. RESULTS: Groups were homogeneous in terms of demographic, clinical and surgical variables. Patients ventilated with positive end-expiratory pressure of 10 cmH2O (Group C) had best compliance (P=0.04) and airway resistance values, this, however, without statistical significance. They also had best oxygenation indexes, with statistical difference in all analyzed variables, and lower frequency of hypoxemia (P=0.03). CONCLUSION: Higher levels of positive end-expiratory pressure in immediate postoperative period of coronary artery bypass grafting improved pulmonary compliance values and increased oxygenation indexes, resulting in lower frequency of hypoxemia. PMID- 24343689 TI - Assessment of sternal closure using titanium plate. AB - INTRODUCTION: The use of plates and screws for more rigid fixation of the sternum, without maintaining contact between the upper portion of the sternum and mediastinum. The present study seeks new choice of plate with a significant difference, the same does not need to be removed in order to proceed to open when necessary sternal emerging opening of the bone. OBJECTIVE: The current study aims to evaluate the efficacy and safety of this procedure. METHODS: To this end, we selected ten patients with coronary artery disease have shown no significant risk factors for mediastinitis. The surgery was thus performed in the usual way that all patients with coronary artery disease surgeries are done at the institution. Only at the time of sternal closure is that there was a change, with the combination of steel wires and plates. RESULTS: All cases had sternal closure properly with good outcome in the medium term. CONCLUSION: The use of plates ENGIMPLAN proved safe and effective for sternal closure. PMID- 24343690 TI - Unstable angina does not increase mortality in coronary artery bypass graft surgery. AB - INTRODUCTION: Coronary artery bypass graft is often the treatment of choice for patients who suffer from unstable angina. We do not know whether this condition adds morbidity in this scenario. OBJECTIVE: To compare the outcomes of patients undergoing coronary artery bypass graft with unstable angina framework with patients who underwent coronary artery bypass graft showed no unstable angina. METHODS: Retrospective cohort study. Unstable angina was defined as acute coronary syndrome without ST elevation and without enzymatic alteration and/or class IV angina. RESULTS: Between February 1996 and July 2010, to 2,818 isolated coronary artery bypass graft performed, 1,016 (36.1%) patients had unstable angina. Multivariate analysis showed that patients with preoperative unstable angina used more medications such as acetylsalicylic acid, beta-blocker, heparin (anticoagulation), nitrate and less need for diuretics than patients without unstable angina. Patients with unstable angina used increased monitoring with Swan-Ganz and support with intra-aortic balloon than stable patients. On outcomes, required longer hospitalization (P=0.030) and had a lower death rate (P=0.018) in the post-coronary artery bypass graft alone. CONCLUSION: Submit patients to coronary artery bypass graft in the presence of acute coronary syndrome such as unstable angina did not increase the mortality rate. PMID- 24343691 TI - Ventricular assist device implantation with CentriMag VAS(r) for biventricular mechanical support. AB - Despite recent advances in acute heart failure treatment, actual results remain limited in refractory cardiogenic shock. Temporary ventricular assist devices have emerged as an alternative in this serious and challenging medical. The purpose of this communication is to present a case of refractory cardiogenic shock, underwent temporary left ventricular assistance device implantation, progressing to right ventricular failure and conversion to biventricular support. PMID- 24343692 TI - Presentation of a needle for direct or percutaneous myocardium stem cells injection. AB - The instrument has a locking mechanism and is composed of an external needle with blunt tip, with multiple 0.5 mm diameter holes. Internally it is fitted with a mandrill needle, which can be mobilized inside occluding or releasing the lateral holes. The procedure for producing micro lesions is done by exchanging the blunt mandrill for a brush-mandrill, provided with micro bristles that are structurally designed to fill the holes with small exteriorization of bristles. As an option to brush mandrill there is a second self-expandable feather shaped mandrill. PMID- 24343693 TI - Giant thymic cyst with atypical location: case report. AB - A 47-year-old woman was admitted with a history of dyspnea on mild exertion as her only symptom. Clinical exam, laboratory tests, and electrocardiography were normal. Chest X-ray demonstrated right hemithorax base mass, and CT scan revealed a well-defined cystic mass measuring approximately 11.3 x 10.6 x 10.9 cm, suggesting the diagnosis of pericardial cyst. The patient underwent right thoracotomy for resection of the cyst. The patient's progress- was uneventful. The result of histopathological examination, contrary to expectations, revealed thymic cyst. PMID- 24343695 TI - Changing scientific communication. PMID- 24343696 TI - Cardiology in Brazilian scientific journals: an overview. Retraction. PMID- 24343697 TI - Enhancing the quality of scientific research. PMID- 24343698 TI - Deleterious effects of reprocessing guide wires: an alert. PMID- 24343699 TI - Screening of fetal congenital heart disease: the challenge continues. PMID- 24343700 TI - SIRT1 is upregulated in cutaneous T-cell lymphoma, and its inhibition induces growth arrest and apoptosis. AB - Silent information regulator type-1 (SIRT1) is the best-studied member of the Sirtuin (Sir2) family of nicotinamide dinucleotide (NAD)-dependent class III histone deacetylases (HDACs), but has not yet been explored in cutaneous T-cell lymphoma (CTCL). We analyzed five CTCL cell lines and lesional tissues using flow cytometry, immunostaining, immunoblotting, cell death, viability, and apoptosis assays, small-molecule inhibitors, and shRNA knockdown. We found strong SIRT1 expression among CTCL lines relative to normal lymphocytes. CTCL cells in lesional tissues also expressed SIRT1 strongly. SIRT1 knockdown resulted in reduced cellular metabolism and proliferation, increased apoptosis, and PARP cleavage products. Tenovin-1, which reversibly inhibits class III HDACs (SIRT1 and SIRT2), reduced SIRT enzymatic activity and SIRT1 expression and led to increased apoptosis. These alterations were accompanied by increased forkhead box O3 (FoxO3) in several cell lines and increased nuclear p53, as well as acetylated p53 in wtp53 MyLa CTCL line. A combination of class I/II and class III HDACIs (vorinostat and tenovin-1) produced significantly greater growth inhibition, cell death via apoptosis, as well as superior p53 promoter upregulation in wtp53 MyLa cells as compared with either agent alone. This occurred in a partially p53 dependent manner, as these effects were blunted by p53 knockdown. Our results indicate that SIRT1 is strongly expressed in CTCL. Its inhibition results in reduced growth and increased apoptosis of CTCL cells. Furthermore, our findings suggest that some CTCL patients, such as those with wtp53, might benefit more from treatment with a combination of different classes of HDACIs than with a single agent. PMID- 24343701 TI - Grading of carotid artery stenosis in the presence of extensive calcifications: dual-energy CT angiography in comparison with contrast-enhanced MR angiography. AB - PURPOSE: We investigated the agreement of dual-energy computed tomography angiography (DE-CTA) and contrast-enhanced magnetic resonance angiography (CE MRA)in the quantitative measurement of stenoses of the internal carotid artery in comparison with digital subtraction angiography (DSA). METHODS: A total of 21 patients with stenoses of the external carotid artery were investigated with a DE CTA and CE-MRA before undergoing carotid angioplasty. The grade of the stenoses was assessed in axial multiplanar reformations (MPR) before and multi-intensity projections (MIP) after plaque subtraction (PS) and compared with results from CE MRA and DSA according to the North American Symptomatic Carotid Endarterectomy Trial. RESULTS: Average grades of stenoses were 80.7 +/- 16.1 % (DSA), 81.4 +/- 15.3 % (MRA), 80.0 +/- 16.7 % (DE-CTA-MPR), and 85.2 +/- 14.7 % (DE-CTA-PS-MIP). Of 21 stenoses, 6 were filiform (stenosis grade, 99 %) in the DSA examination. Five of these cases were identified as pseudo-occlusions in MRA, while four were considered as occlusions in DE-CTA-PS-MIP. Another four cases were identified as pseudo-occlusion in DE-CTA-PS-MIP, which were identified as 90 % stenosis in the DSA examination. CONCLUSIONS: In comparison with the gold standard DSA, DE-CTA MPR had a slightly better agreement in measuring the degree of stenosis of the internal carotid arteries than CE-MRA. In DE-CTA-PS-MIP images, a systematic overestimation has to be taken into account due to partial extinction of the lumen by the PS algorithm. Nevertheless, DE-CTA should be preferred in imaging patients with carotid artery stenosis in the presence of extensive calcifications. PMID- 24343703 TI - Seroprevalence of Chlamydophila abortus infection in yaks (Bos grunniens) in Qinghai, China. AB - Chlamydophila abortus is an important amphixenosis which in a wide range of animals, associated with reproductive disorders in yaks. In order to assess the prevalence of this infection in yaks in Qinghai, China, a cross-sectional study was carried out, and a total of 674 serum samples were collected from June to October 2012 in six counties, and antibodies to C. abortus were examined by indirect hemagglutination (IHA) test. The overall seroprevalence of C. abortus in yaks was 17.66 % (119/674), and the seroprevalence of antibodies to C. abortus in yaks ranged from 11.82 to 28.43 % among the six different areas, and the difference was statistically significant (P < 0.05). The seropositivity of C. abortus infection in different age groups varied from 16.33 to 18.49 %, and prevalence in yaks of >=3 year (18.49 %) was slightly higher than that in yaks of <3 year, but the differences among the age groups were not statistically significant (P > 0.05). The seroprevalence of C. abortus infection in male yak (16.8 %) was slightly lower than that in females (17.85 %), and the difference was not statistically significant (P > 0.05). So far, this is the first systematic and comprehensive investigation of C. abortus infectionin in yaks in this area. PMID- 24343704 TI - A novel LC-MS/MS method for determination of tissue distribution and excretion of timosaponin B-II in rat biological matrices. AB - Timosaponin B-II (TB-II) is a natural bioactive steroid glycoside extracted from the Chinese medicinal herb Anemarrhena asphodeloides Bge. (Fam. Liliaceae). It has been demonstrated to have a good anti-inflammatory effect and a low bioavailability (1.1%). Clinical research has focused on developing it into a completely new medicine. In this study, a rapid and sensitive analytical method based on LC-MS/MS has been developed for the determination of TB-II in rat biological matrices (tissues, bile, urine and feces samples). The analytes and internal standard were isolated from 100 MUL samples by solid-phase extraction and then separated using a DIKMA Inertsil ODS-3 column (5 um, 2.1 * 150 mm) with an isocratic mobile phase consisting of acetonitrile-0.05% formic acid (35:65) at a flow rate of 0.25 mL/min. Calibration curves (1/chi(2) -weighted) offered satisfactory linearity (r(2) >= 0.990) within the test range. The accuracy, precision, recoveries and matrix effects were satisfactory in all the biological matrices examined. The assay was successfully applied to a tissue distribution and excretion study in rats. The preclinical data are useful for the design of clinical trials of TB-II. PMID- 24343705 TI - Group 3 metal stilbene complexes: synthesis, reactivity, and electronic structure studies. AB - Group 3 metal (E)-stilbene complexes supported by a ferrocene diamide ligand were synthesized and characterized. Reactivity studies showed that they behave similar to analogous naphthalene complexes. Experimental and computational results indicated that the double bond was reduced and not a phenyl ring, in contrast to a previously reported uranium (E)-stilbene complex. PMID- 24343707 TI - Noise tolerance of algorithms for estimating chlorophyll a concentration in turbid waters. AB - The accuracy and noise tolerance of 13 global models and 5 Case II chlorophyll a (chl a) retrieval models were evaluated using three dataset. It was found that if 5% input noise related to atmospheric correction is considered, then the uncertainty associated with noise tolerance varied from 5.5% to 55.6%, and these uncertainties generally accounts for 15.63% to 24.75% of the total uncertainty. This observation suggests that an optimal algorithm not only should have a strong chl a concentration prediction ability but also should possess high insensitivity to the noise of remote-sensing imagery. The accuracy evaluations of chl a models were based on comparisons of chl a predicted models with chl a concentration measured analytically for field measurements. The results indicate that none of the selected chl a estimation algorithms provide accurate retrievals of chl a in turbid waters. This may be attributed to the strong optical influence of organic and inorganic matter at the blue green range, and the non-negligible of non organic matter absorption at the red and near-infrared ranges. In order to solve this problem, the chl a concentration retrieval models must be further optimized. After being optimized using the empirical optimized method constructed in this paper, a single parameterized NDCI (normalized difference chl a index) model produces accurate retrievals in the Yellow River Estuary, Taihu Lake and Chesapeake Bay. If 5% input noise associated with residual uncertainty 0of atmospheric correction is taken into account, the model produces only 29.96% uncertainty for the remote sensing of chl a concentration in these three turbid waters. PMID- 24343708 TI - Heavy metal concentration in deepwater rose shrimp species (Parapenaeus longirostris, Lucas, 1846) collected from the Marmara Sea coast in Tekirdag. AB - Zn, Cd, Cr, Hg, As (total), Cu, Pb, and Ni levels of the deepwater rose shrimp (Parapenaeus longirostris, Lucas 1846), which were collected from the Tekirdag coast of the Marmara Sea, were evaluated. The Marmara Sea is the recipient of discharges from both land-based sources and the Black Sea Bosphorus stream. There are large numbers of anthropogenic activities in the coastal region of the northern Marmara Sea that include urban effluent, discharges from touristic resorts, agricultural runoff, fishing, and transportation. Heavy metal contamination of water resources may cause critical health problems for the people living around these water bodies. In deepwater rose shrimp (P. longirostris), the highest concentration level detected for Zn was 22.4 +/- 24.4 mg/kg in winter 2012, Cd 0.106 +/- 0.01 mg/kg in summer 2012, Cr 0.77 +/- 0.05 mg/kg in winter 2012, Hg 0.18 +/- 0.04 mg/kg in summer 2011, As 9.93 +/- 1.4 mg/kg in spring 2012, Cu 25.48 +/- 0.3 mg/kg in winter 2012, Pb 2.12 +/- 0.8 mg/kg in spring, and Ni 19.25 +/- 7.1 mg/kg in spring. The values of heavy metal analysis were compared to both the Turkish Food Codex (TFC) limits and international standards for human consumption. The Pb, As, and Cu levels were found to be higher than the maximum allowable limits. PMID- 24343706 TI - Engineering of three-dimensional microenvironments to promote contractile behavior in primary intestinal organoids. AB - Multiple culture techniques now exist for the long-term maintenance of neonatal primary murine intestinal organoids in vitro; however, the achievement of contractile behavior within cultured organoids has thus far been infrequent and unpredictable. Here we combine finite element simulation of oxygen transport and quantitative comparative analysis of cellular microenvironments to elucidate the critical variables that promote reproducible intestinal organoid contraction. Experimentally, oxygen distribution was manipulated by adjusting the ambient oxygen concentration along with the use of semi-permeable membranes to enhance transport. The culture microenvironment was further tailored through variation of collagen type-I matrix density, addition of exogenous R-spondin1, and specification of culture geometry. "Air-liquid interface" cultures resulted in significantly higher numbers of contractile cultures relative to traditional submerged cultures. These interface cultures were confirmed to have enhanced and more symmetric oxygen transport relative to traditional submerged cultures. While oxygen availability was found to impact in vitro contraction rate and the orientation of contractile movement, it was not a key factor in enabling contractility. For all conditions tested, reproducible contractile behavior only occurred within a consistent and narrow range of collagen type-I matrix densities with porosities of approximately 20% and storage moduli near 30 Pa. This suggests that matrix density acts as a "permissive switch" that enables contractions to occur. Similarly, contractions were only observed in cultures with diameters less than 15.5 mm that had relatively large interfacial surface area between the compliant matrix and the rigid culture dish. Taken together, these data suggest that spatial geometry and mechanics of the microenvironment, which includes both the encapsulating matrix as well as the surrounding culture device, may be key determinants of intestinal organoid functionality. As peristaltic contractility is a crucial requirement for normal digestive tract function, this achievement of reproducible organoid contraction marks a pivotal advancement towards engineering physiologically functional replacement tissue constructs. PMID- 24343709 TI - Study on phosphorus loadings in ten natural and agricultural watersheds in subtropical region of China. AB - Water eutrophication in subtropical regions of southern China threatens watershed health and is of major concern. However, annual phosphorus (P) loading and its dominant causes are still unclear, especially at the watershed scale. In this study, we investigated dynamic P loadings and associated factors (e.g., land use, livestock production, and runoff depth) in ten watersheds that varied in area from 9 to 5,212 ha in a hilly area of Hunan Province, China. A flowmeter was installed at the outlet of each watershed, and total P (TP) and soluble P (SP) concentrations were monitored periodically from June 2010 to October 2012. The results showed that annual P loadings (APLs) in the ten watersheds ranged from 22.8 to 247.8 kg P/km(2) and that P loss primarily occurred from April to June of each year during the main rainfall season in the study area. In addition, the average eutrophication (>0.05 mg P/L) ratio for stream waters was 86.7 % during the study period, which was indicative of a potentially serious condition for the local water environments. Annual P loadings were linearly related to livestock density (LD; R = 0.92, p < 0.01), whereas the eutrophication ratio of stream water was significantly (p < 0.05) correlated with LD (R = 0.61), percentage cropland (R = 0.71), and percentage forest cover (R = -0.68). Thus, it is concluded that the control of livestock production has the greatest potential for reducing P loadings in watersheds in this subtropical area. This will be beneficial to the amelioration and protection of local environment. PMID- 24343712 TI - Diagnostic criteria for atypical hemolytic uremic syndrome proposed by the Joint Committee of the Japanese Society of Nephrology and the Japan Pediatric Society. AB - Atypical hemolytic uremic syndrome (aHUS) is rare and comprises the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Recently, abnormalities in the mechanisms underlying complement regulation have been focused upon as causes of aHUS. The prognosis for patients who present with aHUS is very poor, with the first aHUS attack being associated with a mortality rate of ~25 %, and with ~50 % of cases resulting in end-stage renal disease requiring dialysis. If treatment is delayed, there is a high risk of this syndrome progressing to renal failure. Therefore, we have developed diagnostic criteria for aHUS to enable its early diagnosis and to facilitate the timely initiation of appropriate treatment. We hope these diagnostic criteria will be disseminated to as many clinicians as possible and that they will be used widely. PMID- 24343710 TI - Expression of six drug transporters in vaginal, cervical, and colorectal tissues: Implications for drug disposition in HIV prevention. AB - Effective antiretroviral (ARV)-based HIV prevention strategies require optimizing drug exposure in mucosal tissues; yet factors influencing mucosal tissue disposition remain unknown. We hypothesized drug transporter expression in vaginal, cervical, and colorectal tissues is a contributing factor and selected 3 efflux (ABCB1/MDR1, ABCC2/MRP2, ABCC4/MRP4) and 3 uptake (SLC22A6/OAT1, SLC22A8/OAT3, SLCO1B1/OATP1B1) transporters to further investigate based on their affinity for 2 ARVs central to prevention (tenofovir, maraviroc). Tissue was collected from 98 donors. mRNA and protein expression were quantified using qPCR and immunohistochemistry (IHC). Hundred percent of tissues expressed efflux transporter mRNA. IHC localized them to the epithelium and/or submucosa. Multivariable analysis adjusted for age, smoking, and co-medications revealed significant (P < 0.05) differences in efflux transporter mRNA between tissue types (vaginal ABCB1 3.9-fold > colorectal; vaginal ABCC2 2.9-fold > colorectal; colorectal ABCC4 2.0-fold > cervical). In contrast, uptake transporter mRNA was expressed in <25% of tissues. OAT1 protein was detected in 0% of female genital tissues and in 100% of colorectal tissues, but only in rare epithelial cells. These data support clinical findings of higher maraviroc and tenofovir concentrations in rectal tissue compared to vaginal or cervical tissue after oral dosing. Quantifying mucosal transporter expression and localization can facilitate ARV selection to target these tissues. PMID- 24343713 TI - Effect of aquaporin-4 deficiency on intravenous anaesthetic induced hypnotic effects in mice. AB - The deficiency of aquaporin-4 (AQP4) has been reported to alter release of neurotransmitters in the mouse brain. However, the functional relevance of AQP4 in mediating essential components of the general anaesthetic state is unknown. The aim of the present study was to investigate the role of AQP4 in general anaesthesia in mice lacking AQP4. The hypnotic effects of propofol, ketamine, and pentobarbital in AQP4 knockout (KO) and CD1 control mice were evaluated using the behavioural endpoint of loss of righting reflex (LORR). The effects of propofol on extracellular levels of amino acids in prefrontal cortex of freely moving mice were investigated using microdialysis coupled to high performance liquid chromatography with fluorescent detection. The result showed that, after receiving ketamine or pentobarbital, LORR occurred at earlier time in KO mice than that in control animals. Intraperitoneal injection of ketamine or pentobarbital increased the duration of LORR. After the administration of propofol, the duration of LORR was significantly reduced in KO mice compared with that in controls. Propofol increased the extracellular levels of aspartate, glutamate, and GABA, but not taurine, in prefrontal cortex. There were significant differences of increase patterns of the three kinds of neurotransmitters between KO and WT mice. Notably, the duration of GABA level increase correlated with the duration of LORR in two genotypes of mice. These results provide in vivo evidence of different responses in time-dependent release of excitatory and inhibitory neurotransmitters in prefrontal cortex of the two genotypes of mice. It is suggested that changes in anaesthetic reactions in mice with AQP4 loss may be related to neurotransmitter regulation, and that normal functioning of AQP4 plays an important role in the maintenance of anaesthetic hypnosis. PMID- 24343714 TI - [Hippocampus quinolinic acid modulates glutamate and NMDAR/mGluR1 in chronic unpredictable mild stress-induced depression]. AB - The present study was to investigate the role of the quinolinic acid (QUIN) and its relationship with N-methyl-D-aspartic acid (NMDA) receptor and metabotropic glutamate receptor 1 (mGluR1) in depression induced by chronic unpredictable mild stress (CUMS) in hippocampus. CUMS-induced depression model was established in Sprague-Dawley rats. Intrahippocampal injections of QUIN, QUIN antagonist Ro61 8048, non-competitive NMDA receptor antagonist MK-801 and mGluR1 antagonist AIDA were respectively adopted by rat brain stereotaxic coordinates. The behavioral observations were conducted by measurement of weight changes, sucrose preference test, open-field test and tail suspension test. The concentration of glutamic acid (Glu) and the expression of its receptor subunits in hippocampus were detected by HPLC and Western blot, respectively. The QUIN content in hippocampus was determined by enzyme linked immunosorbent assay (ELISA). The result showed that CUMS significantly induced the depressive-like behaviors in rats, increased the contents of QUIN and Glu, and upregulated the expression of NMDA receptor subunits NR2B and mGluR1 in hippocampus. Microinjection of QUIN into hippocampus resulted in animal depressive-like behaviors, and increased the content of Glu and the expression of NR2B and mGluR1 significantly. QUIN antagonist Ro61-8048 effectively restrained the depression-like behaviors induced by CUMS, and decreased the content of Glu and the expression of NR2B and mGluR1 significantly. Intrahippocampal injections of MK-801 and AIDA effectively improved the depression-like behaviors induced by CUMS and decreased the Glu content. The results suggest that CUMS may contribute to the production and release of QUIN in hippocampal microglia. QUIN results in elevation of Glu level via NMDA receptor and mGluR1, and the increase of expression of NR2B and mGluR1 in hippocampus, which leads to depression-like behaviors in the end. PMID- 24343715 TI - [Long-term plasticity of HVC-RA synapses in adult male zebra finches]. AB - Long-term synaptic plasticity is considered as a key part of the neural mechanism of learning and memory. The production of learned vocalization of male zebra finches is closely related to high vocal center (HVC)-robust nucleus of the arcopallium (RA) pathway. However, the long-term plasticity of HVC-RA synapses is unclear. This study investigated the long-term plasticity of HVC-RA synapses in adult male zebra finches through in vivo field potential recording. The results showed that physiologic stimulation, i.e., delta rhythmic stimulation and low frequency stimulation could not effectively induce long-term synaptic plasticity. The former leaded to no change of the amplitudes of evoked population spikes, and the latter induced short-term depression (STD) of the amplitudes of the second evoked population spikes caused by paired pulses. But high frequency stimulation induced long-term depression (LTD) of the amplitudes of evoked population spikes to show out long-term synaptic plasticity. These results suggest that LTD represents the long-term plasticity of HVC-RA synapses in adult male zebra finches, which may be a key part of the neural mechanism of vocal learning and memory and can explain the plasticity of adult song to some degree. PMID- 24343716 TI - [Inhibitory effect of octreotide on the cross excitation of adjacent segment of spinal nerve in rat]. AB - This study was to observe the effect and possible mechanism of somatostatin analogue octreotide (OCT) on cross excitation of adjacent segment of spinal nerve in rat. Cutaneous branches of T9-T13 spinal dorsal rami were chosen and dissected free for the following recording and stimulation. Only single unit fiber was used for recording, and the adjacent segment of nerve stem was used for antidromic electrical stimulation. To investigate the change of discharge rate and mechanical threshold, OCT and (or) somatostatin receptor antagonist cyclo somatostatin (c-SOM) were applied to the receptive field following the antidromic electrical stimulation. The result showed that injection of OCT inhibited the increase of discharge rate and the decrease of mechanical threshold induced by the electrical stimulation (cross excitation); c-SOM reversed the effects of OCT. Application of c-SOM alone enhanced the cross excitation effects. The results suggest local application of somatostatin analogue OCT can inhibit the cross excitation between the two segments of spinal nerve by somatostatin receptor. PMID- 24343717 TI - [Palmitate induces apoptosis and endoplasmic reticulum stress in human umbilical cord-derived mesenchymal stem cells]. AB - The saturated free fatty acid (FFA), palmitate, could induce apoptosis in various cell types, but little is known about its effects on human umbilical cord-derived mesenchymal stem cells (hUC-MSCs). Here, we investigated whether palmitate induced apoptosis and endoplasmic reticulum (ER) stress in hUC-MSCs. hUC-MSCs were stained by labeled antibodies and identified by flow cytometry. After administration with palmitate, apoptotic cell was assessed by flow cytometry using the Annexin V-FITC/7-AAD apoptosis detection kit. Relative spliced XBP1 levels were analyzed using semi-quantitative RT-PCR. The mRNA of BiP, GRP94, ATF4 and CHOP were analyzed by real-time PCR. Relative BiP and CHOP protein were analyzed using Western blot analysis. The results showed that hUC-MSCs were homogeneously positive for MSC markers; palmitate increased apoptosis of hUC-MSCs and activated XBP1 splicing, BiP, GRP94, ATF4 and CHOP transcription. These findings suggest that palmitate induces apoptosis and ER stress in hUC-MSCs. PMID- 24343718 TI - [Involvement of cross interaction between central cholinergic and histaminergic systems in the nucleus tractus solitarius in regulating carotid sinus baroreceptor reflex]. AB - The carotid sinus baroreceptor reflex (CSR) is an important approach for regulating arterial blood pressure homeostasis instantaneously and physiologically. Activation of the central histaminergic or cholinergic systems results in CSR functional inhibitory resetting. However, it is unclear whether two systems at the nucleus tractus solitarius (NTS) level display cross interaction to regulate the CSR or not. In the present study, the left or right carotid sinus region was isolated from the systemic circulation in Sprague-Dawley rats (sinus nerve was reserved) anesthetized with pentobarbital sodium. Respective intubation was conducted into one side isolated carotid sinus and into the femoral artery for recording the intracarotid sinus pressure (ISP) and mean arterial pressure (MAP) simultaneously with pressure transducers connection in vivo. ISP was set at the level of 0 mmHg to eliminate the effect of initial internal pressure of the carotid sinus on the CSR function. To trigger CSR, the ISP was quickly elevated from 0 mmHg to 280 mmHg in a stepwise manner (40 mmHg) which was added at every step for over 4 s, and then ISP returned to 0 mmHg in similar steps. The original data of ISP and corresponding MAP were fitted to a modified logistic equation with five parameters to obtain the ISP-MAP, ISP-Gain relationship curves and the CSR characteristic parameters, which were statistically compared and analyzed separately. Under the precondition of no influence on the basic levels of the artery blood pressure, the effects and potential regulatory mechanism of preceding microinjection with different cholinoceptor antagonists, the selective cholinergic M1 receptor antagonist, i.e., pirenzepine (PRZ), the M2 receptor antagonist, i.e., methoctramine (MTR) or the N1 receptor antagonist, i.e., hexamethonium (HEX) into the NTS on the changes in function of CSR induced by intracerebroventricular injection (i.c.v.) of histamine (HA) in rats were observed. Meanwhile, the actions and possible modulatory mechanism of preceding microinjection with different histaminergic receptor antagonists, the selective histaminergic H1 receptor antagonist, i.e., chlorpheniramine (CHL) or the H2 receptor antagonist, i.e., cimetidine (CIM) into the NTS on the changes in function of CSR resulted from the i.c.v. cholinesterase inhibitor, physostigmine (PHY) were also examined in order to confirm and to analyze effects of cross interaction between central histaminergic and cholinergic systems on CSR. The main results obtained are as follows. (1) Standalone microinjection of different selective cholinergic receptor antagonists (PRZ, MTR or HEX) or different selective histaminergic receptor antagonists (CHL or CIM) into the NTS with each given dose had no effects on the CSR function and on the basic levels of the artery blood pressure, respectively (P > 0.05). (2) The pretreatment of PRZ or MTR into the NTS with each corresponding dose could attenuate CSR resetting resulted from i.c.v. HA in some degrees, which remarkably moved the posterior half range of ISP-MAP relationship curve downwards (P < 0.05), shifted the middle part of ISP-Gain relationship curve upwards (P < 0.05), and increased reflex parameters such as the MAP range and maximum gain (P < 0.05), but decreased parameters such as saturation pressure and intracarotid sinus pressure at maximum gain (P < 0.05). The catabatic effects of pretreatment with MTR into the NTS on CSR resetting induced by i.c.v. HA were more obvious than those with PRZ (P < 0.05), but pretreatment of HEX with given dose into the NTS had no effects on CSR resetting induced by i.c.v. HA (P > 0.05). (3) The effects of pretreatment of CHL or CIM into the NTS with each corresponding dose on CSR resetting made by i.c.v. PHY were similar to those of pretreatment of PRZ or MTR into the NTS on CSR resetting resulted from i.c.v. HA, and the decreasing effects of pretreatment with CHL into the NTS on CSR resetting induced by i.c.v. PHY were more remarkable than those with CIM (P < 0.05). These findings suggest that CSR resetting resulted from either HA or PHY into the lateral ventricle may partly involve the descending histaminergic or cholinergic pathway from the hypothalamus to NTS, which might evoke a cross activation of the cholinergic system in the NTS, via cholinergic M1 and M2 receptors mediation, especially the M2 receptors showing actions, or trigger another cross activation of the histaminergic system in the NTS, by histaminergic H1 and H2 receptors mediation, especially the H1 receptors displaying effects. PMID- 24343719 TI - [MCPIP1 mediates MCP-1-induced vascular smooth muscle cell proliferation]. AB - The aim of the present study is to investigate whether monocyte chemotactic protein-1 (MCP-1)-induced vascular smooth muscle cell (VSMC) proliferation is mediated via monocyte chemotactic protein-1 induced protein-1 (MCPIP1). MCPIP1 expressions in cultured VSMC were detected by real-time PCR and Western blot following MCP-1 incubation. After MCPIP1 was silenced by siRNA, cell number was counted by hemocytometer, VSMC activity was analyzed by CCK-8 kit, percentage of DNA synthesis was detected by EdU kit, percentage of S phase cell numbers were measured by flow cytometry, and c-fos mRNA expression induced by MCP-1 or platelet-derived growth factor (PDGF) was detected by real-time PCR. The results showed MCP-1 increased MCPIP1 mRNA and up-regulated MCPIP1 protein expression in dose- and time-dependent manners. Cell counts, cellular activity, the percentage of DNA synthesis, and the percentage of S phase cell numbers were remarkably decreased in MCPIP1 siRNA group, compared with those in MCP-1 group. The enhancing effect of MCP-1 or PDGF on c-fos mRNA expression was inhibited by MCPIP1 siRNA. These results suggest that MCP-1-induced VSMC proliferation is mediated via MCPIP1, and the underlying mechanism may involve c-fos expression up regulation. PMID- 24343720 TI - Candesartan inhibits LPS-induced expression increase of toll-like receptor 4 and downstream inflammatory factors likely via angiotensin II type 1 receptor independent pathway in human renal tubular epithelial cells. AB - The present study was to determine whether candesartan, an angiotensin II type 1 receptor blocker (ARB), exerts anti-inflammatory effects through inhibiting the toll-like receptor 4 (TLR4) pathway in human renal tubular epithelial cells (HKCs). The experiments were carried on cultured HKCs. By means of flow cytometry, Western blot, RT-PCR and ELISA techniques, the TLR4 protein, angiotensin II type 1 receptor (AT1R) and phosphorylated nuclear factor-kappa B (NF-kappaB) p65 protein level, mRNA levels of macrophage chemoattractant protein 1 (MCP-1) and regulated upon expression normal T cell expressed and secreted (RANTES), as well as MCP-1 and RANTES protein concentrations in conditioned media were measured. The results showed that lipopolysaccharide (LPS) upregulated the TLR4 protein level in cultured HKCs. Application of LPS increased NF-kappaB activation and induced release of its downstream inflammatory factors including MCP-1 and RANTES. Candesartan reversed LPS-induced upregulation of TLR4 expression, inhibited NF-kappaB activation, and reduced MCP-1 and RANTES release. However, knockdown on AT1R by siRNA did not change those previous effects of candesartan. These results suggest that candesartan-induced anti-inflammatory effect may be through a novel pathway, independent of AT1R. PMID- 24343721 TI - [Effects of carnitine on respiratory chain and metabolism of oxygen radical in mitochondria of skeletal muscle after exhaustive running in training rat]. AB - The aim of the present study was to investigate the effect of carnitine on function of respiratory chain and metabolism of oxygen radical in mitochondria of skeletal muscle after exhaustive running in training rats. Forty male Wistar rats were randomly divided into 4 groups (n = 10): control, carnitine, training and training + carnitine groups. The training and training + carnitine groups received 6-week treadmill training, whereas carnitine and training + carnitine groups were administered intragastrically with carnitine (300 mg/kg per day, 6 d/week) for 6 weeks. After exhaustive running, all the rats from 4 groups were sacrificed to obtain quadriceps muscles samples, and muscle mitochondria were extracted by differential centrifugation. Spectrophotometric analysis was used to evaluate activities of respiratory chain complexes (RCC) I-IV, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and the content of malondialdehyde (MDA) in the skeletal muscle mitochondria. The results showed that, compared with the control group, the carnitine group exhibited increased RCCI and RCCIII activities (P < 0.05), the training + carnitine group exhibited increased RCCI, RCCIII and RCCIV activities (P < 0.05 or 0.01). Moreover, RCCIII activity in the training + carnitine group was higher than that in training group (P < 0.05). Compared with the control group, the carnitine, training and training + carnitine groups showed increased SOD activities ( P < 0.01), the carnitine and training + carnitine groups showed increased GSH-Px activities ( P < 0.01), the carnitine, training and training + carnitine groups showed increased MDA contents (P < 0.05 or 0.01). The SOD and GSH-Px activities in training + carnitine group were higher than those in training group (P < 0.01), and the MDA level in the training + carnitine group was higher than that in the carnitine and training groups (P < 0.01). These results suggest that training and carnitine can increase function of respiratory chain, antioxidation and lipid peroxidation tolerance capacity in skeletal muscle mitochondria, and the improving effects of training and carnitine are synergistic. PMID- 24343722 TI - [Multi-channel in vivo recording technique: microdrive array fabrication and electrode implantation in mice]. AB - Here we describe and illustrate our methods for multi-channel in vivo recording in mice, including the fabrication of the microdrive array and the surgical procedure for implanting electrodes. The multi-channel microdrive is fabricated from printed circuit board base, screws, nuts and clamping screws. Rotation of the screw drives both the nut and the attached electrodes to move forward simultaneously. Each full turn of the screw corresponds to 280 um in depth penetration. The recording electrodes are self-made tetrodes consisting 4 wires (13 um in diameter). The major steps of headstage fabrication include: tetrode making, microdrive construction, headstage assembling and tetrode plating. The finished headstage is suitable for multi-channel recording in freely moving rodents with the modest weight and the adjustable number of recording electrodes. Additionally, the recording site is allowed to be manipulated after implantation at any time. In the latter part of this paper, we introduce the procedure of the implant surgery to record in bilateral hippocampus in mice. Using these headstages, we simultaneously recorded population activity in bilateral CA1 in freely behaving mice. PMID- 24343723 TI - [In vitro heart models simulating in vivo cardiac ischemia-reperfusion injury]. AB - The aim of this study was to compare in vivo and several in vitro cardiac ischemia-reperfusion (I-R) myocardial injury models, and choose a superior in vitro cardiac I-R model. Sprague-Dawley (SD) rats were randomly grouped into in vivo, Langendorff, Langendorff + pacing, and working heart groups. Left anterior descending (LAD) coronary artery was ligated for 60 min and then reperfused for 120 min in in vivo and in vitro rat hearts. Cardiac function and myocardial infarct size were measured by using pressure transducer and TTC/Evans blue double staining, respectively. The results showed that heart rate was greater in in vivo model than those in the three in vitro models. Coronary flows were dropped after LAD ligation and could recover at early phase of releasing LAD ligation in I-R models of the isolated working heart, Langendorff and Langendorff with 300 beats/min of electrical stimulation. Left ventricular end-systolic pressure (LVESP) decreased during ischemia, and partially restored during reperfusion in the three in vitro models. Left ventricular end-diastolic pressure (LVEDP) increased during ischemia in the three in vitro models. LVEDP was significantly higher in the isolated working heart than those in Langendorff models during ischemia, whereafter decreased slowly during reperfusion. LVEDP elevated further in the initiation of reperfusion period and then decreased, but did not recover to normal levels during reperfusion in Langendorff and Langendorff + pacing groups. Left ventricular myocardial infarct size was (60.4 +/- 5.4)% in in vivo I R model, which was significantly higher than that in Langendorff model and the isolated working heart. Notably, there was no significant difference in myocardial infarct size between in vivo model and Langendorff model with electrical stimulation. These results suggest that Langendorff I-R model with 300 beats/min of electrical stimulation can simulate the in vivo I-R myocardial injury. PMID- 24343724 TI - [Roles of retinal Muller cells in health and glaucoma]. AB - In the vertebrate retina, Muller cells are principal glial cells which stretch across the whole thickness of the retina and contact with the somata and processes of all retinal neurons, thus forming an anatomical and functional link between glial cells and retinal neurons. Numerous studies have shown that Muller cells express various neurotransmitter receptors, transporters, ion channels and enzymes that are relative to cellular activities. In addition, the cells also release factors, such as D-serine and glutamate etc., to regulate the neuron excitability. Therefore, retinal Muller cells may play more curious roles in addition to supporting the retinal neurons. The information exchange and interaction between Muller cells and neurons may regulate and maintain retinal neuronal functions. In the glaucomatous retina, Muller cells are reactivated (gliosis). Reactivated Muller cells undergo a variety of changes in cellular physiology, biochemistry and morphological features. Meanwhile, the reactivated Muller cells may produce and release cytotoxic factors, such as nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), reactive oxygen species (ROS) and prostaglandin E2 (PGE2), thus involving in the induction of retinal ganglion cell apoptosis and death. Here, we reviewed the physiological properties of retinal Muller cells, and the functional changes of Muller cells in the glaucomatous retina. PMID- 24343725 TI - [Progress in the role of oxidative stress in the pathogenesis of type 2 diabetes]. AB - Diabetes mellitus (DM) is characterized by hyperglycemia and disturbances of carbohydrate and fat metabolism resulted from an absolute or relative deficiency of insulin and insulin resistance. Recent studies indicate that oxidative stress may have a central role in the pathogenesis of type 2 diabetes. Currently, the diagnosis of body oxidative stress level mainly depends on the detection of oxidative stress markers including reactive oxygen species (ROS), reactive nitrogen species (RNS) and lipid peroxide in clinical and experimental studies with methods combining physical and chemical means. The mechanism underlying oxidative stress-induced diabetes mainly may be through two ways. Firstly oxidative stress damages the normal function of islet beta cells, through the destruction of mitochondrial structure and inducing apoptosis, activation of nuclear transcription factor kappa B (NF-kappaB) signaling pathway, causing cell inflammatory response, and reducing insulin synthesis and secretion by inhibiting pancreatic and duodenal homeobox 1 (PDX-1) nuclear cytoplasm translocation as well as inhibiting energy metabolism; Secondly, oxidative stress induces insulin resistance by interfering physiological activities related to insulin signaling including phosphorylation of insulin receptor (InsR) and insulin receptor substrate (IRS), the activation of phosphatidylinositol 3-kinase (PI3K) and the translocation of glucose transporter 4 (GLUT4), as well as injuring the cytoskeleton. Studying the role of oxidative stress in the pathogenesis of diabetes not only helps to reveal the pathogenesis of diabetes, but also provides a theoretical basis for the prevention and treatment of diabetes. PMID- 24343726 TI - A review of safety-related pregnancy data surrounding the oral disease-modifying drugs for multiple sclerosis. AB - The recent approval of several oral disease-modifying drugs (DMDs) for multiple sclerosis (MS) brings promise of improved clinical effectiveness as well as greater drug compliance compared to the existing non-oral DMDs, and substantially increases patient choice and therapeutic options in the effective management of MS. However, for men and women with MS of childbearing age, concerns about the effect of oral DMDs on pregnancy and the fetus may arise. Some limited data from animal reproductive studies of oral DMDs suggest a potential increased risk of early pregnancy loss, impaired growth and birth defects. Although active surveillance mechanisms exist, there is limited data to inform clinical practice. Using existing information from published clinical trials and drug monographs, as well as recent conference proceedings, this review summarizes the mechanism of action (in relation to embryogenesis and pregnancy) and existing animal or human pregnancy-related data for approved (fingolimod, teriflunomide and dimethyl fumarate) and investigational (laquinimod and firategrast) oral DMDs for MS. PMID- 24343727 TI - Expression and immune characterization of a novel enzyme, protein arginine methyltransferase 1, from Schistosoma japonicum. AB - Protein arginine methyltransferase 1 (PRMT1) is an arginine-specific protein methyltransferase that methylates a number of proteins involved in transcription and RNA metabolism in all parasitic helminths, including the human blood fluke, Schistosoma japonicum. To characterize the role of PRMT1 in the development of S. japonicum and to investigate its influence on parasite-host interactions, we cloned and expressed the protein from an existing cDNA library. We report that the clone encoded a polypeptide comprising 360 amino acids with a predictive Mr of 42 kDa. Bioinformatic analyses predicted that there were many potential B cell epitopes and T cell epitopes associated with SjcPRMT1, suggesting it is a potential candidate molecule for vaccine development. The purified recombinant protein of S. japonicum (Chinese strain) (rSjcPRMT1) was found to be immunogenic, eliciting a high antibody titer in mice. Moreover, Western blot analysis revealed that the protein could be recognized by the sera of infected mice. Using flow cytometry, we showed that rSjcPRMT1 slightly upregulated the expression of CD40, CD80, CD86, and MHC-II molecules of mouse bone marrow-derived dendritic cell (BMDC), indicating that rSjcPRMT1 could induce mouse BMDC to mature and, therefore, activate their immune response. Overall, our findings provide evidence that rSjcPRMT1 could serve as an effective candidate molecule for the development of a vaccine against infection with S. japonicum. PMID- 24343728 TI - Primary prophylaxis for venous thromboembolism in people undergoing major amputation of the lower extremity. AB - BACKGROUND: Patients undergoing major amputation of the lower limb are at increased risk of venous thromboembolism (VTE). Risk factors for VTE in amputees include advanced age, sedentary lifestyle, longstanding arterial disease and an identifiable hypercoagulable condition. Evidence suggests that pharmacological prophylaxis (for example heparin, factor Xa inhibitors, vitamin K antagonists, direct thrombin inhibitors, antiplatelets) is effective in preventing deep vein thrombosis (DVT) but it is associated with an increased risk of bleeding. Mechanical prophylaxis (for example antiembolism stockings, intermittent pneumatic compression and foot impulse devices), on the other hand, is non invasive and has no side effects. However, it is not always appropriate in patients with contraindications such as peripheral arterial disease (PAD), arteriosclerosis or bilateral lower limb amputations. It is important to determine the most effective thromboprophylaxis and whether this is one treatment alone or in combination with another. To date, no systematic review has been conducted examining the effectiveness of thromboprophylaxis in preventing VTE in people undergoing amputation. OBJECTIVES: To determine the effectiveness of thromboprophylaxis in preventing VTE in people undergoing major amputation of the lower extremity. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2013) and CENTRAL (2013, Issue 4). Clinical trials databases were searched (May 2013). No date or language restrictions were applied. Non-English trials were translated where required and reference lists of identified studies were handsearched. SELECTION CRITERIA: Randomised controlled trials and quasi randomised controlled trials in which people undergoing a major unilateral or bilateral amputation (for example hip disarticulation, transfemoral, knee disarticulation and transtibial) of the lower extremity were allocated to different types or regimens of thromboprophylaxis (including pharmacological or mechanical prophylaxis) or placebo. DATA COLLECTION AND ANALYSIS: Selection of studies, data extraction and risk of bias were completed independently by two review authors. Any disagreements were resolved by discussion. Meta-analysis could not be completed as the two included studies compared different treatments and therefore the data could not be pooled. MAIN RESULTS: Two studies with a combined total of 288 participants met the inclusion criteria for this review. One study compared low molecular weight heparin with unfractionated heparin and found no difference between the treatments in the prevention of DVT (odds ratio (OR) 1.23, 95% confidence interval (CI) 0.28 to 5.35). No bleeding events or deaths occurred. This study was open label and therefore at a high risk of performance bias. Additionally, the method of randomisation was not reported and therefore the risk of selection bias was unclear. In the second study heparin did not significantly improve prevention of pulmonary embolism (OR 1.02, 95% CI 0.44 to 2.37) when compared to placebo. Furthermore, when the level of amputation was considered, the incidence of pulmonary embolism was similar between the two treatment groups: above knee amputation (OR 0.79, 95% CI 0.31 to 1.97) and below knee amputation (OR 1.53, 95% CI 0.09 to 26.43). Ten participants died during the study; five underwent a post-mortem and three were found to have had a recent pulmonary embolism, all of whom had been on placebo. Bleeding events were reported in less than 10% of participants in both treatment groups but specific data were not presented. This study did not report the methods used to conceal allocation of treatment and therefore it was unclear if selection bias occurred. However, this study appeared to be free from all other sources of bias. No study looked at mechanical prophylaxis. AUTHORS' CONCLUSIONS: As only two studies were included in this review, each comparing different interventions, there is insufficient evidence to make any conclusions regarding the most effective thromboprophylaxis regimen in patients undergoing lower limb amputation. Further large-scale studies that are of good quality are required. PMID- 24343729 TI - Practice variation and resource use in the evaluation of pediatric vasovagal syncope: are pediatric cardiologists over-testing? AB - Syncope is a common problem in children and adolescents. Usually vasovagal in etiology, this benign problem often results in considerable testing and expense. We sought to define the current practice, practice variation, and resource utilization as well as evaluate a screening strategy for syncope at an academic tertiary care center. We reviewed the medical records of all patients age 8 to 19 years who presented with syncope between January 1994 and January 2012 and collected data regarding demographics, history, physical examination, and diagnostic tests. Practice variation was evaluated based on provider experience and subspecialty. The sensitivity and specificity of history, physical examination, and electrocardiogram (ECG) to identify a cardiac cause for syncope were calculated. Of the 617 patients studied, a cardiac cause for syncope was found in 15 (2 %). A screening strategy consisting of history, physical examination, and ECG was 100 % sensitive and 55 % specific for diagnosing a cardiac cause for syncope. Despite having a negative screen, 314 (54 %) patients had a total of 334 additional tests at an average charge of $983/patient. Although practice variation existed, it was not explained by provider experience or electrophysiology training. Factors associated with increased testing included greater number of clinic visits and increased frequency of events, whereas those associated with decreased testing included increased number of syncopal episodes and history of psychiatric medication use. A more standardized approach to syncope is needed to decrease resource use and cost while maintaining quality of care. PMID- 24343730 TI - Quantification of congenital aortic valve stenosis in pediatric patients: comparison between cardiac magnetic resonance imaging and transthoracic echocardiography. AB - Previous studies showed the reliability of cardiac magnetic resonance imaging (cMRI) in the quantification of aortic valve stenosis in adults. The aim of this retrospective study was to assess the ability of cMRI in the quantification of congenital aortic valve stenosis (CAS) in children. Nineteen patients (mean age 14.0 +/- 3.2 years, 15 boys and 4 girls) with CAS were imaged by cMRI and transthoracic echocardiography (TTE). cMRI was performed on a 1.5-Tesla MR scanner (Magnetom Avanto; Siemens Healthcare, Erlangen, Germany) using cine steady-state free precession sequences for the assessment of the aortic valve area (AVA) by MR planimetry and left-ventricular function. Phase-contrast measurement was used in cMRI to assess peak flow velocity above the aortic valve. A positive correlation was found between maximum systolic pressure gradient (MPG) as assessed by cMRI and TTE (28.9 +/- 21.2 vs. 41.3 +/- 22.7 mmHg, r = 0.84, p = 0.001) with a mean underestimation of 12.4 mmHg by cMRI. Only a weak correlation could be observed between AVA by cMRI and MPG at the aortic valve by TTE (r = 0.50, p = 0.029) and cMRI (r = -0.27, p = 0.40). Furthermore, a positive correlation between myocardial mass (cMRI) and MPG (TTE, r = 0.57, p = 0.01), but not between myocardial mass (cMRI) and AVA (cMRI, r = 0.07, p = 0.77), was found. The assessment of MPG by cMRI in patients with CAS is feasible with a trend toward underestimatation compared with TTE. Moreover, MPG seems to be a more accurate parameter than AVA regarding the prediction of myocardial hypertrophy. PMID- 24343731 TI - Evaluation of cardiac functions and atrial electromechanical delay in children with adenotonsillar hypertrophy. AB - Deterioration of the right ventricular (RV) functions and the increase in the pulmonary arterial pressure (PAP) of children with moderate to severe adenotonsillar hypertrophy (ATH) have been well described. In addition to these complications, this study aimed to investigate the influence of ATH on the conduction system. The study investigated 46 patients with a diagnosis of ATH and 46 healthy control subjects. Conventional echocardiography, P-wave dispersion (Pd), tissue Doppler imaging (TDI) findings, and atrial electromechanical delay (AED) were compared between the patients and the control subjects before and after adenotonsillectomy. The maximum P-wave duration and Pd were significantly higher in the patients than in the control subjects (p < 0.001). The patient group showed significantly greater RV end-diastolic dimension (p = 0.01), right atrial area (p < 0.001), and mean PAP (p = 0.03) but lower E/A ratios for the mitral (p = 0.04) and tricuspid (p = 0.01) valves and a shorter pulmonary flow trace acceleration time (p = 0.03). The tricuspid annular-plane systolic excursion was similar between these groups (p = 0.21). In the patient group, TDI studies showed significantly lower E'/A' ratios for the tricuspid lateral (p = 0.006) and mitral septal (p = 0.003) segments than in the control group. The myocardial performance index was lower for the mitral lateral, mitral septal, and tricuspid lateral segments in patient group (p < 0.001). Similarly, AED was prolonged in the patient group at all three segments (p < 0.001). Also, the patient group showed a significantly longer interatrial (p = 0.03) and intraatrial (p = 0.04) electromechanical delay. However, all the electro- and echocardiographic parameters were similar between the patients and the control subjects after adenotonsillectomy (p > 0.05). The prolongations in P-wave duration, Pd, and inter- and intraatrial electromechanical delays were first shown in this population. The cardiac changes induced by ATH-associated hypoxia may facilitate arrhythmias during the long term. PMID- 24343732 TI - Pathology consultation on HbA(1c) methods and interferences. AB - OBJECTIVES: To review the various hemoglobin (Hb) A1c methods, with a focus on interferences resulting from Hb variants. METHODS: HbA1c is a marker used for the diagnosis and management of diabetes. Each available HbA1c method has advantages and challenges, such as its susceptibility to interferences. RESULTS: The presence of Hb variants and/or abnormalities in RBC turnover cannot only interfere analytically with HbA1c measurements but also may affect the clinical interpretation of HbA1c values. CONCLUSIONS: Familiarity with the advantages and challenges of the various methods used for HbA1c testing is essential when establishing therapeutic management and goals based on HbA1c results, especially in populations with a high prevalence of Hb variants. PMID- 24343733 TI - Democratizing molecular diagnostics for the developing world. AB - OBJECTIVES: Infectious diseases that are largely treatable continue to pose a tremendous burden on the developing world despite the availability of highly potent drugs. The high mortality and morbidity rates of these diseases are largely due to a lack of affordable diagnostics that are accessible to resource limited areas and that can deliver high-quality results. In fact, modified molecular diagnostics for infectious diseases were rated as the top biotechnology to improve health in developing countries. METHODS: In this review, we describe the characteristics of accessible molecular diagnostic tools and discuss the challenges associated with implementing such tools at low infrastructure sites. RESULTS: We highlight our experience as part of the "Grand Challenge" project supported by the Gates Foundation for addressing global health inequities and describe issues and solutions associated with developing adequate technologies or molecular assays needed for broad access in the developing world. CONCLUSIONS: We believe that sharing this knowledge will facilitate the development of new molecular technologies that are extremely valuable for improving global health. PMID- 24343734 TI - Comparison of MALDI-TOF MS with HPLC and nucleic acid sequencing for the identification of Mycobacterium species in cultures using solid medium and broth. AB - OBJECTIVES: The genus Mycobacterium contains over 150 species including pathogenic and nonpathogenic strains. Accurate species level identification can aid in differentiating environmental contamination from true infection, and also can aid in selection of antimicrobial therapy. METHODS: We evaluated the performance of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for the routine identification of clinical isolates of mycobacteria using 2 commercially available spectral reference libraries, and also assessed the impact of mycobacterial culture using solid medium and broth on MALDI-TOF MS-based identification. RESULTS: All results were compared with those obtained on high-pressure liquid chromatography and nucleic acid sequencing. Optimal results were obtained with a mycobacterium-specific reference library (Mycobacterium Library v1.0). The identification rate was 89.8% (79/88) for isolates cultured on solid medium and 98.8% (85/86) for isolates analyzed directly from broth. Among these, the proportion identified with a high confidence level was 50.0% (44/88) for isolates cultured on solid medium and 80.2% (69/86) for isolates cultured in broth. CONCLUSIONS: Agreement with nucleic acid sequencing for species present in Mycobacterium Library v1.0 was 97.6% (81/83) for isolates cultured on solid medium and 97.5% (79/81) for those cultured in broth. PMID- 24343735 TI - Histopathologic findings of small renal tumor biopsies performed immediately after cryoablation therapy: a retrospective study of 50 cases. AB - OBJECTIVES: To evaluate the histopathology of small renal tumor biopsies following cryoablation. METHODS: We retrospectively evaluated small renal tumor biopsy specimens after cryoablation treatment for renal cell carcinoma and determined the ability to differentiate tumor types, effect on nuclear grading, immunohistochemical staining, and if the number of freeze cycles affected interpretation. RESULTS: Of the biopsy specimens, 66% were diagnostic of tumor and 34% showed normal renal parenchyma. Tumor subtype was determined in 91% of diagnostic cases. Nuclear grading was affected due to freeze effect, complicating the assessment of chromatin pattern and nucleolar details at low magnification. In particular, the distinction between Fuhrman nuclear grades I and II was compromised; these were designated as low nuclear grade. Immunohistochemical staining was retained similar to untreated tumors. Tumor subtyping was not affected after one or two freeze cycles. CONCLUSIONS: Biopsies performed immediately after cryoablation can be used to render an optimal histologic diagnosis. PMID- 24343736 TI - Clinical value of procalcitonin for patients with suspected bloodstream infection. AB - OBJECTIVES: Procalcitonin (PCT) might be a useful marker to exclude bacteremia or to predict the severity of bacteremia and its outcome. However, most previous studies of PCT were limited to particular patient populations. In addition, reports about PCT levels in patients with renal dysfunction have been conflicting. We investigated the predictive value of PCT in an unselected population with suspected bloodstream infections and also assessed the relationship between PCT and renal function. METHODS: We retrospectively analyzed medical records of 1,331 patients (age >=1 8 years) with suspected bloodstream infections who had concurrent biochemical data and blood culture results. RESULTS: The PCT level was significantly elevated in patients with positive blood cultures, and it showed a significant relation with survival in patients with bacteremia. The optimal cutoff value of PCT for predicting a positive blood culture showed an increase as the estimated glomerular filtration rate declined. CONCLUSION: PCT can be a useful marker to exclude bacteremia and also to predict severe bacteremia, but renal function should be taken into account. PMID- 24343737 TI - Increased concentrations of apo A-I and apo A-II fragments in the serum of patients with hepatocellular carcinoma by magnetic beads-assisted MALDI-TOF mass spectrometry. AB - OBJECTIVES: Recent advances in sophisticated technologies in proteomics should provide promising ways to discover novel markers for hepatocellular carcinoma (HCC) in the early diagnosis. METHODS: Serum peptide and protein profiling was conducted by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Profiling was carried out in a training set of 16 patients with HCC and a testing set of 15 patients with cirrhosis without HCC. All the patients were hepatitis C virus positive. Candidate peaks were processed to partial purification, followed by protein identification by amino acid sequence analysis. Immunoprecipitation was conducted to confirm the protein identity. RESULTS: Partial purification and protein identification revealed that one peak that was up-regulated in HCC sera both in the training and the testing sets was a fragment of apolipoprotein A-I (apo A-I). Immunoprecipitation confirmed this result. CONCLUSIONS: MALDI-TOF MS analysis revealed that apo A-I is a potential novel serum marker of HCC. Combination of these pretreatments and the current magnet bead-assisted MALDI-TOF MS will further enhance the efficiency of biomarker discovery for HCC. PMID- 24343738 TI - Marrow assessment for hemophagocytic lymphohistiocytosis demonstrates poor correlation with disease probability. AB - OBJECTIVES: To evaluate the amount of hemophagocytosis in 64 marrow core biopsy specimens and aspirates from 58 patients with clinical suspicion for secondary hemophagocytic lymphohistiocytosis (HLH) or reported findings of hemophagocytosis. METHODS: A review of medical records assigned patients to a low risk (45 patients) or high-risk (13 patients) HLH group, and association with histologic findings was examined using the Fisher exact test. RESULTS: The amount of hemophagocytosis in aspirate or the core biopsy specimen did not correlate with disease probability (P = .17 and P = .63, respectively). Of the clinical/laboratory criteria assessed, the most significant correlations with HLH were highly elevated ferritin (P = .01), cytopenias (P = .02), and fever (P = .009). CONCLUSIONS: Our findings indicated that marrow histologic findings alone do not reliably predict the probability of HLH, and an isolated finding of hemophagocytosis, even when present in a high amount, lacks specificity for HLH. PMID- 24343739 TI - Study on hyperuricemia in HBV-associated glomerulonephritis. AB - OBJECTIVES: To determine the prevalence and risk factors for hyperuricemia in hepatitis B virus-associated glomerulonephritis (HBV-GN). METHODS: Univariate and multivariate logistic regression analysis was applied to decide the risk factors of hyperuricemia in HBV-GN, and clinical and pathologic data were compared between HBV-GN patients with hyperuricemia and those with normal serum uric acid. RESULTS: Among our 227 HBV-GN cases, 31.3% of the patients had hyperuricemia at the time of renal biopsy. Univariate analysis showed that the level of serum creatinine and the severity of glomerular and tubular interstitial injury were significantly related to hyperuricemia. Multivariate logistic regression analysis identified the levels of serum creatinine and tubular interstitial injury as independent factors for hyperuricemia. The incidence of hypertension and lower estimated glomerular filtration rate was significantly higher in hyperuricemic patients with HBV-GN than in normouricemic patients. There were also fewer membranous nephropathy, more proliferative sclerosing glomerulonephritis, and more tubular interstitial injury in hyperuricemic patients with HBV-GN. CONCLUSIONS: Our study results suggest that hyperuricemia is common in HBV-GN, which may facilitate the progression of HBV-GN and renal tubular interstitial injury as well as the development of hypertension. PMID- 24343740 TI - Evaluation of real-time clinical decision support systems for platelet and cryoprecipitate orders. AB - OBJECTIVES: To evaluate cryoprecipitate and platelet ordering practices after the implementation of real-time clinical decision support systems (CDSSs) in a computerized physician order entry (CPOE) system. METHODS: Uniform platelet and cryoprecipitate transfusion thresholds were implemented at 11 hospitals in a regional health care system with a common CPOE system. Over 6 months, a variety of information was collected on the ordering physicians and the number of alerts generated by the CDSSs when these products were ordered outside of the institutional guidelines. RESULTS: There were 1,889 orders for platelets and 152 orders for cryoprecipitate placed in 6 months. Of these, 1,102 (58.3%) platelet and 74 (48.7%) cryoprecipitate orders triggered an alert. The proportion of orders canceled after an alert was generated ranged from 13.5% to 17.9% for platelets and 0% to 50.0% for cryoprecipitate orders. CONCLUSIONS: CDSS alerts reduce, but do not eliminate, platelet and cryoprecipitate transfusions that do not meet institutional guidelines. PMID- 24343741 TI - Comparative immunohistochemical analysis of IMP3, GLUT1, EMA, CD146, and desmin for distinguishing malignant mesothelioma from reactive mesothelial cells. AB - OBJECTIVES: To identify useful biomarkers for differentiating between malignant mesothelioma (MM) and reactive mesothelial cells (RMCs). METHODS: Formalin-fixed, paraffin-embedded (FFPE) tissues from 34 MM and 40 RMC samples were analyzed using immunohistochemistry, and the findings were compared. RESULTS: Positive markers for MM included insulin-like growth factor 2 messenger RNA binding protein 3 (IMP3), glucose transporter 1 (GLUT1), epithelial membrane antigen (EMA), and CD146, which showed sensitivities of 94%, 85%, 79%, and 71% and specificities of 78%, 100%, 88%, and 98%, respectively. In sarcomatoid MM, EMA had significantly lower expression than did IMP3, GLUT1, and CD146 (P < .001). The areas under receiver operating characteristic curves were the highest for IMP3 (0.95), followed by GLUT1 (0.93). When the optimal cutoff points for IMP3 (30%) and GLUT1 (10%) were used, the sensitivity of IMP3 and GLUT1 for MM was 100%, and the specificity of both for MM was 95%. CONCLUSIONS: The combination of IMP3 and GLUT1 is most appropriate for distinguishing MM from RMC using FFPE sections. PMID- 24343742 TI - Limited flow cytometry panels on bone marrow specimens reduce costs and predict negative cytogenetics. AB - OBJECTIVES: To determine the clinical and financial impact and predictive value of a limited flow cytometry strategy in the evaluation of bone marrow specimens. METHODS: Consecutive bone marrow cases (n = 1,242) were reviewed following the independent, prospective application of two flow cytometry protocols: a limited marker strategy and a multimarker strategy. Combined morphologic and flow cytometry findings were also compared with cytogenetic results. RESULTS: A limited flow cytometry strategy did not have a negative impact on disease detection and resulted in reduced utilization and cost. In addition, negative combined morphology and flow cytometry had a 98.4% predictive value for negative cytogenetics (P < .001). CONCLUSIONS: Careful initial evaluation of bone marrow specimens can markedly reduce the costs of bone marrow examination and significantly reduce the need for flow cytometric and cytogenetic studies on these samples. PMID- 24343743 TI - Bright-field HER2 dual in situ hybridization (DISH) assay vs fluorescence in situ hybridization (FISH): focused study of immunohistochemical 2+ cases. AB - OBJECTIVES: To compare the INFORM HER2 bright-field dual in situ hybridization (DISH) DNA probe cocktail assay with the PathVysion fluorescence in situ hybridization (FISH) assay on 103 invasive breast carcinomas with a 2+ score on immunohistochemistry (IHC). METHODS: The cases were categorized as positive, equivocal, or negative for HER2 gene amplification using the 2007 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) HER2:CEP17 ratio criteria and also based on mean HER2 gene copies/cell. The third criterion used a HER2:CEP17 ratio of 2 to categorize cases as positive or negative. RESULTS: The agreement between FISH and DISH was 85% using the 2007 ASCO/CAP ratio criterion, 79% using the mean HER2 gene copies/cell criterion, and 92% using the 2.0 cutoff HER2:CEP17 ratio criterion. In addition, 20 known IHC 3+ breast carcinomas analyzed by DISH showed clusters of the HER2 gene consistent with unequivocal amplification. CONCLUSIONS: Despite some technical and interpretational issues associated with DISH, it compares favorably with FISH in this group of challenging breast cancer cases. PMID- 24343744 TI - Comparison of clinical and histologic diagnoses in 16,587 total joint arthroplasties: implications for orthopedic and pathologic practices. AB - OBJECTIVES: To confirm how often histologic diagnoses correspond to reported clinical diagnoses in patients undergoing total joint arthroplasties. METHODS: We compared the submitting operative diagnosis with the pathologic diagnosis in 16,587 total joint arthroplasties for the seven most common diagnoses. RESULTS: The discrepancy rates between the submitted operative and histologic diagnosis were 18.8% for 7,968 total hip replacements and 9.4% for 8,619 total knee replacements. In addition, 5.4% of hip joints and 1.4% of knee joints demonstrated discordant histologic findings that had not been suspected clinically and should have affected clinical management and patient outcomes. CONCLUSIONS: Our findings demonstrated significantly more diagnostic discrepancies and discordance than has been suggested by the previously published literature. A large part of the difference may be due to more careful diagnostic analyses of orthopedic specimens than in other institutions. These analyses include some diagnoses that are not often made elsewhere but may have important future implications for patients. PMID- 24343745 TI - Primary and secondary hepatic lymphomas diagnosed by image-guided fine-needle aspiration: a retrospective study of clinical and cytomorphologic findings. AB - OBJECTIVES: To explore the diagnosis of hematolymphoid malignancies of the liver (hepatic lymphoma [HeL]) by image-guided fine-needle aspiration (FNA), which can often be difficult due to a low index of suspicion and nonspecific patient presentations, especially in the rare cases where the liver is the only site of disease (primary HeL [PHeL]). Understanding the clinical setting in which such lesions arise, as well as the cytomorphologic findings, may assist cytopathologists in making an accurate diagnosis and triaging samples for ancillary studies. METHODS: In this retrospective study of 32 patients with HeL, the largest such study to our knowledge, we review the clinical and diagnostic features of HeL. RESULTS: HeL and especially PHeL most commonly show a diffuse large B-cell lymphoma phenotype and have a poor prognosis (median survival of seven months). PHeL is strongly associated with human immunodeficiency virus infection (12/16 patients). CONCLUSIONS: Image-guided FNA with immediate evaluation is a reliable means to obtain diagnostic material and triage for ancillary tests. PMID- 24343746 TI - Revisiting overdiagnosis and fatality in thyroid cancer. AB - OBJECTIVES: To examine the rates of incidence and fatality in cohorts of patients diagnosed with thyroid cancer from 1975 to 1999. METHODS: This study uses National Cancer Institute's Surveillance, Epidemiology and End Results data and derives hazard functions in order to examine the fatality in thyroid cancer. RESULTS: The study documents forms of rapidly evolving and fatal tumors as well as forms of tumor that evolve more slowly to cause death. It demonstrates that the incidences of nonfatal forms of thyroid cancer have risen dramatically in the years from 1975 to 1999-mostly due to papillary carcinomas-but that the incidences of fatal forms of thyroid cancer have remained nearly constant. CONCLUSIONS: The results of this study support the notion that many thyroid cancers are part of a reservoir of nonfatal tumors that are increasingly being overdetected and overdiagnosed. PMID- 24343747 TI - Diagnosis of endometrial stromal tumors: a clinicopathologic study of 25 biopsy specimens with identification of problematic areas. AB - OBJECTIVES: To assess the difficulties associated with diagnosing endometrial stromal tumors (ESTs) on endometrial biopsy. METHODS: We examined 25 endometrial biopsy specimens from 19 consecutive women diagnosed with either endometrial stromal nodule (n = 3) or endometrial stromal sarcoma (n = 16). RESULTS: Rereview of the biopsy specimens revealed a stromal fragment suspicious for an EST in 16, of which eight had received a benign diagnosis on initial review. Most ESTs had an aglandular stromal fragment that was 5 mm or larger. Stromal fragments of this size were not encountered in the control material. Problematic areas included highly cellular leiomyoma and a lack of attention to the stromal compartment. CONCLUSIONS: Most endometrial stromal tumors present with large aglandular stromal fragments (>=5 mm). These fragments are large enough that difficulties in diagnosis appear to be due to a lack of attention to the stromal compartment. PMID- 24343749 TI - Leg ischaemia before circulatory arrest alters brain leucocyte count and respiratory chain redox state. AB - OBJECTIVES: Remote ischaemic preconditioning and its neuroprotective abilities are currently under investigation and the method has shown significant effects in several small and large animal studies. In our previous studies, leucocyte filtration during cardiopulmonary bypass reduced cerebrocortical adherent leucocyte count and mitigated cerebral damage after hypothermic circulatory arrest (HCA) in piglets. This study aimed to obtain and assess direct visual data of leucocyte behaviour in cerebral vessels after hypothermic circulatory arrest following remote ischaemic preconditioning. METHODS: Twelve native stock piglets were randomized into a remote ischaemic preconditioning group (n = 6) and a control group (n = 6). The intervention group underwent hind-leg ischaemia, whereas the control group received a sham-treatment before a 60-min period of hypothermic circulatory arrest. An intravital microscope was used to obtain measurements from the cerebrocortical vessel in vivo. It included three sets of filters: a violet filter to visualize microvascular perfusion and vessel diameter, a green filter for visualization of rhodamine-labelled leucocytes and an ultraviolet filter for reduced nicotinamide adenine dinucleotide (NADH) analysis. The final magnification on the microscope was 400. After the experiment, cerebral and cerebellar biopsies were collected and analysed with transmission electron microscope by a blinded analyst. RESULTS: In the transmission electron microscope analysis, the entire intervention group had normal, unaffected rough endoplasmic reticulum's in their cerebellar tissue, whereas the control group had a mean score of 1.06 (standard deviation 0.41) (P = 0.026). The measured amount of adherent leucocytes was lower in the remote ischaemic preconditioning group. The difference was statistically significant at 5, 15 and 45 min after circulatory arrest. Statistically significant differences were seen also in the recovery phase at 90 and 120 min after reperfusion. Nicotinamide adenine dinucleotide autofluorescence had statistically significant differences at 10 min after cooling and at 120 and 180 min after hypothermic circulatory arrest. CONCLUSIONS: Remote ischaemic preconditioning seems to provide better mitochondrial respiratory chain function as indicated by the higher NADH content. It simultaneously provides a reduction of adherent leucocytes in cerebral vessels after hypothermic circulatory arrest. Additionally, it might provide some degree of cellular organ preservation as implied by the electron microscopy results. PMID- 24343750 TI - Student-generated reading questions: diagnosing student thinking with diverse formative assessments. AB - Formative assessment has long been identified as a critical element to teaching for conceptual development in science. It is therefore important for university instructors to have an arsenal of formative assessment tools at their disposal which enable them to effectively uncover and diagnose all students' thinking, not just the most vocal or assertive. We illustrate the utility of one type of formative assessment prompt (reading question assignment) in producing high quality evidence of student thinking (student-generated reading questions). Specifically, we characterized student assessment data using three distinct analytic frames to exemplify their effectiveness in diagnosing student learning in relationship to three sample learning outcomes. Our data will be useful for university faculty, particularly those engaged in teaching upper-level biochemistry courses and their prerequisites, as they provide an alternative mechanism for uncovering and diagnosing student understanding. PMID- 24343751 TI - Differential effects of exposure to social violence and natural disaster on children's mental health. AB - Disaster mental health, particularly postdisaster child mental health, is neglected in India. This study compares the impact of a natural disaster versus a spate of communal riots that occurred in Gujarat, India on January 26, 2001, and February 2002 to June 2002, respectively. Children aged 8-15 years from highly exposed earthquake sites (n = 128) and riot sites (n = 171) were approached for participation. A matching control sample of 351 nontrauma-exposed children was sought to compare with the trauma groups. Trauma and postdisaster adversities were studied using the UCLA disaster trauma tool; Goodman's Strengths and Difficulties Questionnaire was used to assess adjustment difficulties. Spearman's correlations were calculated to find associations between trauma items on UCLA's brief trauma scale and Strengths and Difficulties Questionnaire items. Results suggest that 7.6% of the earthquake sample and 38.7% from the riots sample manifested clinically significant mental health problems. The earthquake sample had 24.8% of those above clinical cutoff for probable posttraumatic stress disorder and the riots sample had 27.3% children who displayed posttraumatic stress symptoms. Children exposed to violence were psychologically more affected and in the presence of postdisaster adversities, posttraumatic stress symptoms persisted long term. This finding should enable development of differential psychotherapeutic interventions for children exposed to extreme events. PMID- 24343752 TI - Immediate and longer-term stressors and the mental health of Hurricane Ike survivors. AB - Previous research has documented that individuals exposed to more stressors during disasters and their immediate aftermath (immediate stressors) are at risk of experiencing longer-term postdisaster stressors. Longer-term stressors, in turn, have been found to play a key role in shaping postdisaster psychological functioning. Few studies have simultaneously explored the links from immediate to longer-term stressors, and from longer-term stressors to psychological functioning, however. Additionally, studies have inadequately explored whether postdisaster psychological symptoms influence longer-term stressors. In the current study, we aimed to fill these gaps. Participants (N = 448) were from population-based study of Hurricane Ike survivors and completed assessments 2-5 months (Wave 1), 5-9 months (Wave 2) and 14-18 months (Wave 3) postdisaster. Through path analysis, we found that immediate stressors, assessed at Wave 1, were positively associated with Wave 2 and Wave 3 stressors, which in turn were positively associated with Wave 2 and Wave 3 posttraumatic stress and depressive symptoms. Wave 2 posttraumatic stress symptoms were positively associated with Wave 3 stressors, and Wave 1 depressive symptoms were positively associated with Wave 2 stressors. The findings suggest that policies and interventions can reduce the impact of disasters on mental health by preventing and alleviating both immediate and longer-term postdisaster stressors. PMID- 24343753 TI - Psychological effects of the marathon bombing on Boston-area veterans with posttraumatic stress disorder. AB - This study examined the psychological impact of the Boston Marathon bombing using data from an ongoing longitudinal study of Boston-area veterans with posttraumatic stress disorder (PTSD; N = 71). Participants were assessed by telephone within 1 week of the end of the event; 42.3% of participants reported being personally affected by the bombings and/or the manhunt that followed. The majority of them reported that the bombing reminded them of their own traumas and/or caused other emotional distress. Examination of change in posttraumatic stress disorder (PTSD) symptoms from a prebombing assessment an average of 2 months earlier to 1 week after the event revealed no significant change in symptoms across the sample as a whole. However, examination of patterns of change at the individual level revealed significant correlations (r = .33; p = .005) between distress at the time of the event and change in total PTSD symptom severity, with this effect accounted for primarily by increases in intrusion and avoidance symptoms (rs = .35 and .31, ps = .002 and .008, respectively). Findings of this study should raise awareness of the potential impact of terror attacks, mass shootings, and other events of this type on the well-being of individuals with histories of trauma and/or pre-existing PTSD. PMID- 24343754 TI - Relationship of trauma symptoms to amygdala-based functional brain changes in adolescents. AB - In this pilot study, amygdala connectivity related to trauma symptoms was explored using resting-state functional magnetic resonance imaging (R-fMRI) in 23 healthy adolescents ages 13-17 years with no psychiatric diagnoses. Adolescents completed a self-report trauma symptom checklist and a R-fMRI scan. We examined the relationship of trauma symptoms to resting-state functional connectivity of the amygdala. Increasing self-report of trauma symptoms by adolescents was associated with increasing functional connectivity with the right amygdala and a local limbic cluster and decreasing functional connectivity with the amygdala and a long-range frontoparietal cluster to the left amygdala, which can be a hallmark of immaturity. These pilot findings in adolescents provide preliminary evidence that even mild trauma symptoms can be linked to the configuration of brain networks associated with the amygdala. PMID- 24343756 TI - A modified dinucleotide for site-specific RNA-labelling by transcription priming and click chemistry. AB - An improved strategy for RNA labelling using an alkyne-carrying dinucleotide is reported. This involves near-quantitative priming by phage RNA-polymerases followed by conjugation of different labels using click chemistry. Moreover, these transcripts bear a ligation compatible 5'-end, and thus through ligation the terminal label can be transformed to an internal one. PMID- 24343755 TI - Association between PM2.5 and primary care visits due to asthma attack in Japan: relation to Beijing's air pollution episode in January 2013. AB - AIM: In January 2013, extremely high concentrations of fine particles (PM2.5) were observed around Beijing, China. In Japan, the health effects of transboundary air pollution have been a matter of concern. We examined the association between the levels of outdoor PM2.5 and other air pollutants with primary care visits (PCVs) at night due to asthma attack in Himeji City, western Japan. METHODS: A case-crossover study was conducted in a primary care clinic in Himeji City, Japan, involving 112 subjects aged 0-80 years who visited the clinic due to an asthma attack between 9 p.m. and 6 a.m. during the period January March, 2013. Daily concentrations of particulate matter, ozone, nitrogen dioxide, and some meteorological elements were measured, and a conditional logistic regression model was used to estimate the odds ratios (OR) of PCVs per unit increment in air pollutants or meteorological elements. RESULTS: Of the 112 subjects, 76 (68 %) were aged <15 years. We did not note any association between daily PM2.5 levels and PCVs due to asthma attack at night. A positive relation between ozone and PCVs due to asthma attack was detected. The OR per 10 ppb increment in daily mean ozone the day before the visit was 2.31 (95 % confidence interval 1.16-4.61). CONCLUSION: These findings do not support an association between daily mean concentration of PM2.5 and PCVs at night. However, we did find evidence suggesting that ozone is associated with PCVs. PMID- 24343758 TI - Meso- and microscopic motions in photoresponsive liquid crystalline polymer films. AB - Photoresponsive azobenzene-containing systems ranging from molecular to macroscopic material levels have greatly been increasing their significance in materials chemistry. This review focuses on the studies on light induced or triggered motions in azobenzene liquid crystalline (LC) polymer films at mesoscopic and microscopic levels. Due to the cooperative nature of liquid crystalline materials, highly efficient photoalignment and photo-triggered migrating motions are realized in mostly repeated manners. Here, recent advances in surface-grafted LC polymer brushes, LC block copolymer films, and LC polymer films that exhibit mass migrations are overviewed. Such newly emerged photoresponsive systems are expected to provide new possibilities and applications in polymer thin film technologies. PMID- 24343757 TI - Interfractional variability in intensity-modulated radiotherapy of prostate cancer with or without thermoplastic pelvic immobilization. AB - PURPOSE: To determine the variability of patient positioning errors associated with intensity-modulated radiotherapy (IMRT) for prostate cancer and to assess the impact of thermoplastic pelvic immobilization on these errors using kilovoltage (kV) cone-beam computed tomography (CBCT). MATERIALS AND METHODS: From February 2012 to June 2012, the records of 314 IMRT sessions in 19 patients with prostate cancer, performed with or without immobilization at two different facilities in the Korea University Hospital were analyzed. The kV CBCT images were matched to simulation computed tomography (CT) images to determine the simulation-to-treatment variability. The shifts along the x (lateral)-, y (longitudinal)- and z (vertical)-axes were measured, as was the shift in the three dimensional (3D) vector. RESULTS: The measured systematic errors in the immobilized group during treatment were 0.46 +/- 1.75 mm along the x-axis, - 0.35 +/- 3.83 mm along the y-axis, 0.20 +/- 2.75 mm along the z-axis and 4.05 +/- 3.02 mm in the 3D vector. Those of nonimmobilized group were - 1.45 +/- 7.50 mm along the x-axis, 1.89 +/- 5.07 mm along the y-axis, 0.28 +/- 3.81 mm along the z-axis and 8.90 +/- 4.79 mm in the 3D vector. The group immobilized with pelvic thermoplastics showed reduced interfractional variability along the x- and y-axes and in the 3D vector compared to the nonimmobilized group (p < 0.05). CONCLUSION: IMRT with thermoplastic pelvic immobilization in patients with prostate cancer appears to be useful in stabilizing interfractional variability during the planned treatment course. PMID- 24343759 TI - Diel changes in plasma cortisol and effects of size and stress duration on the cortisol response in European sea bass (Dicentrarchus labrax). AB - European sea bass (Dicentrarchus labrax), one of the most economically important fish in Mediterranean mariculture, shows high basal cortisol concentrations compared with other teleosts. The present study aims (a) to identify cortisol diel variation in fish held under a 12L:12D cycle and minimum handling stress, and (b) to establish the effect of fish size and stressor duration on the cortisol response. The results indicate high intrapopulation variability in plasma cortisol and a significant diel fluctuation with a peak value at dusk (18 h). Stressors of different intensity and/or duration affected the cortisol stress response in a differential manner according to fish size (and/or age). Maximum cortisol values in small-size fish were found at 1 and 2 h post-stress, depending on the duration of the stressor, while at 0.5 h post-stress in large fish regardless stress duration. PMID- 24343760 TI - Rib deformities in congenital scoliosis. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: To identify the incidence and characteristics of rib anomalies in patients with congenital scoliosis (CS) in a Chinese population. SUMMARY OF BACKGROUND DATA: Rib deformities and intraspinal anomalies often coexist in individuals with CS. Rib deformities may assist in diagnosing occult anomalies in these patients. The incidence of rib anomalies and the relationship between rib and vertebral abnormalities in Chinese patients with CS have not been reported. METHODS: A total of 382 patients operated on at Peking Union Medical College Hospital during January 2010 to October 2012 were identified from a single institutional database. The demographic distribution, clinical and radiographical data were collected to investigate the incidence of rib anomalies, and the vertebral and intraspinal abnormalities associated with it. RESULTS: A total of 192 patients (50.3%) were documented with rib anomalies including numerical variation (46.4%) and structural changes (72.4%). Missing ribs was the most commonly seen anomaly in these patients, accounting for 43.8% of the rib anomalies. Of the patients with rib anomalies, a slightly higher proportion of patients had simple anomalies, 106 (55.2%) versus 86 (44.8%). Rib changes were most common in patients with thoracic or thoracolumbar vertebral anomalies, and occurred most frequently on the concave side (65.5%) or in the lower thoracic spine (36.5%). The overall incidence rate of intraspinal anomalies was 40.1% (153/382), and these were most commonly seen in patients with thoracic vertebral anomalies or with upper and middle thoracic rib anomalies. CONCLUSION: The incidence of rib anomalies was 50.3% in surgical patients with CS. The rib anomalies vary with the location and type of vertebral anomalies. The incidence of intraspinal anomalies was significantly higher in patients with rib anomalies than in those without rib anomalies. LEVEL OF EVIDENCE: 4. PMID- 24343761 TI - Safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel gamma secretase modulator, E2212, in healthy human subjects. AB - E2212, a novel gamma-secretase modulator, is under development for the treatment of Alzheimer's disease. The safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending oral doses (10-250 mg, double-blind, placebo controlled, randomized) of E2212 were evaluated. In this phase I clinical trial, E2212 was found to be well tolerated in single doses. Maximum tolerated dose was not achieved up to 250 mg. Most AEs were mild to moderate in severity with no identifiable dose related pattern. There were no clinically significant findings on physical and ophthalmologic examinations as well as vital signs, laboratory, ECG and C-SSRS assessments. E2212 was rapidly absorbed, with median tmax values ranging from 0.5 to 1.0 h. E2212 exhibited biphasic disposition with the terminal t1/2 of 12.5-19.0 h. Renal excretion was the minor pathway for E2212 elimination. Increased PD response (reduction in plasma concentrations of Abeta(x-42)) was observed with increasing doses. The maximum PD response was observed in the highest dose 250 mg cohort, with DeltaAUAC(0-24 h) of 44.1% and Amax of 53.6%. These results support further clinical development of E2212. PMID- 24343762 TI - Ripple formation in unilamellar-supported lipid bilayer revealed by FRAPP. AB - The mechanisms of formation and conditions of the existence of the ripple phase are fundamental thermodynamic questions with practical implications for medicine and pharmaceuticals. We reveal a new case of ripple formation occurring in unilamellar-supported bilayers in water, which results solely from the bilayer/support interaction, without using lipid mixtures or specific ions. This ripple phase is detected by FRAPP using diffusion coefficient measurements as a function of temperature: a diffusivity plateau is observed. It occurs in the same temperature range where ripple phase existence has been observed using other methods. When AFM experiments are performed in the appropriate temperature range the ripple phase is confirmed. PMID- 24343765 TI - vigiGrade: a tool to identify well-documented individual case reports and highlight systematic data quality issues. AB - BACKGROUND: Individual case safety reports of suspected harm from medicines are fundamental to post-marketing surveillance. Their value is directly proportional to the amount of clinically relevant information they include. To improve the quality of the data, communication between stakeholders is essential and can be facilitated by a simple score and visualisation of the results. OBJECTIVE: The objective of this study was to propose a measure of completeness and identify predictors of well-documented reports, globally. METHODS: The Uppsala Monitoring Centre has developed the vigiGrade completeness score to measure the amount of clinically relevant information in structured format, without reflecting whether the information establishes causality between the drug and adverse event. The vigiGrade completeness score (C) starts at 1 for reports with information on time to-onset, age, sex, indication, outcome, report type, dose, country, primary reporter and comments. For each missing dimension, a penalty is detracted which varies with clinical relevance. We classified reports with C > 0.8 as well documented and identified all such reports in the WHO global individual case safety report database, VigiBase, from 2007 to January 2012. We utilised odds ratios with statistical shrinkage to identify subgroups with unexpectedly high proportions of well-documented reports. RESULTS: Altogether, 430,000 (13 %) of the studied reports achieved C > 0.8 in VigiBase. For VigiBase as a whole, the median completeness was 0.41 with an interquartile range of 0.26-0.63. Two out of three well-documented reports come from Europe, and two out of three from physicians. Among the countries with more than 1,000 reports in total, the highest rate of well-documented reports is 65 % in Italy. Tunisia, Spain, Portugal, Croatia and Denmark each have rates above 50 %, and another 20 countries have rates above 30 %. On the whole, 24 % of the reports from physicians are well-documented compared with only 4 % for consumers/non-health professionals. Notably, Denmark and Norway have more than 50 % well-documented reports from consumers/non-health professionals and higher rates than for physicians. The rate of well-documented reports for the E2B format is 11 % compared with 22 % for the older INTDIS (International Drug Information System) format. However, for E2B reports entered via the WHO programme's e-reporting system VigiFlow, the rate is 29 %. CONCLUSION: Overall, only one report in eight provides the desired level of information, but much higher proportions are observed for individual countries. Physicians and e-reporting tools also generate greater proportions of well-documented reports overall. Reports from consumers/non-health professionals in specific regions have excellent quality, which illustrates their potential for the future. vigiGrade has already provided valuable information by highlighting data quality issues both in Italy and the USA. PMID- 24343764 TI - Identification and profiling of novel and conserved microRNAs during the flower opening process in Prunus mume via deep sequencing. AB - MicroRNAs (miRNAs) are small (20-24 nucleotide) RNAs that are critical regulators of genes involved in diverse plant processes, including development, metabolism, abiotic stress and flowering. Prunus mume is a widely cultivated ornamental plant in East Asia that blooms in early spring, even at temperatures below 0 degrees C. While miRNAs involved in pistil development have been identified in P. mume, few studies have profiled miRNA expression patterns during flower opening. Here, we used high-throughput sequencing and bioinformatic analysis to identify and profile miRNAs that function during flower opening in P. mume. We identified 47 conserved miRNA sequences belonging to 25 miRNA families from 92 loci in P. mume, along with 33 novel miRNA sequences from 43 loci, including their complementary miRNA* strands. The expression levels of most differentially expressed miRNAs decreased during flower opening, while miR156e-f and miR477b were upregulated at the flowering stage. We predicted 88 target genes for conserved and novel miRNAs using computational analysis and annotated their functions. Seven target genes, encoding squamosa promoter binding protein-like (SPL) and auxin response factor (ARF), scarecrow-like transcription factor (SCL) and APETALA2-like transcription factors (AP2), were verified by 5'-RACE to be the targets of miR156, miR167, miR171 and miR172, respectively. Quantitative real-time PCR validated the expression of the miRNAs and seven target genes. The results help lay the foundation for investigating the roles of miRNAs in the blooming of P. mume. PMID- 24343766 TI - Lipid and fatty acid metabolism in Ralstonia eutropha: relevance for the biotechnological production of value-added products. AB - Lipid and fatty acid metabolism has been well studied in model microbial organisms like Escherichia coli and Bacillus subtilis. The major precursor of fatty acid biosynthesis is also the major product of fatty acid degradation (beta oxidation), acetyl-CoA, which is a key metabolite for all organisms. Controlling carbon flux to fatty acid biosynthesis and from beta-oxidation allows for the biosynthesis of natural products of biotechnological importance. Ralstonia eutropha can utilize acetyl-CoA from fatty acid metabolism to produce intracellular polyhydroxyalkanoate (PHA). R. eutropha can also be engineered to utilize fatty acid metabolism intermediates to produce different PHA precursors. Metabolism of lipids and fatty acids can be rerouted to convert carbon into other value-added compounds like biofuels. This review discusses the lipid and fatty acid metabolic pathways in R. eutropha and how they can be used to construct reagents for the biosynthesis of products of industrial importance. Specifically, how the use of lipids or fatty acids as the sole carbon source in R. eutropha cultures adds value to these biotechnological products will be discussed here. PMID- 24343767 TI - Characterization of modular bifunctional processive endoglucanase Cel5 from Hahella chejuensis KCTC 2396. AB - Cel5 from marine Hahella chejuensis is composed of glycoside hydrolase family-5 (GH5) catalytic domain (CD) and two carbohydrate binding modules (CBM6-2). The enzyme was expressed in Escherichia coli and purified to homogeneity. The optimum endoglucanase and xylanase activities of recombinant Cel5 were observed at 65 degrees C, pH 6.5 and 55 degrees C, pH 5.5, respectively. It exhibited K m of 1.8 and 7.1 mg/ml for carboxymethyl cellulose and birchwood xylan, respectively. The addition of Ca(2+) greatly improved thermostability and endoglucanase activity of Cel5. The Cel5 retained 90 % of its endoglucanase activity after 24 h incubation in presence of 5 M concentration of NaCl. Recombinant Cel5 showed production of cellobiose after hydrolysis of cellulosic substrates (soluble/insoluble) and methylglucuronic acid substituted xylooligosaccharides after hydrolysis of glucuronoxylans by endo-wise cleavage. These results indicated that Cel5 as bifunctional enzyme having both processive endoglucanase and xylanase activities. The multidomain structure of Cel5 is clearly distinguished from the GH5 bifunctional glycoside hydrolases characterized to date, which are single domain enzymes. Sequence analysis and homology modeling suggested presence of two conserved binding sites with different substrate specificities in CBM6-2 and a single catalytic site in CD. Residues Glu132 and Glu219 were identified as key catalytic amino acids by sequence alignment and further verified by using site directed mutagenesis. CBM6-2 plays vital role in catalytic activity and thermostability of Cel5. The bifunctional activities and multiple substrate specificities of Cel5 can be utilized for efficient hydrolysis of cellulose and hemicellulose into soluble sugars. PMID- 24343768 TI - Nerve blocks for initial pain management of femoral fractures in children. AB - BACKGROUND: Children and adolescents with femoral fractures are almost always admitted to hospital. They invariably start their hospital experience in the Emergency Department, often requiring transfer to a specialist children's hospital. They require analgesia or anaesthesia so that radiographs can be obtained and for management of their fractures. The initial care process involves from two to six transfers from stretcher to stretcher/imaging/operating-suite table or hospital bed within the first few hours, so prompt pain relief is essential. Systemic analgesia can be provided orally or parenterally. Alternatively, a nerve block may be used where local anaesthetic is injected around a nerve to block sensation or freeze the involved area. OBJECTIVES: To assess the effects (benefits and harms) of femoral nerve block (FNB) or fascia iliaca compartment block (FICB) for initial pain management of children with fractures of the femur (thigh bone) in the pre-hospital or in-hospital emergency setting, with or without systemic analgesia. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (11 January 2013), the Cochrane Central Register of Controlled Trials (2012 Issue 12), MEDLINE (1946 to January Week 1 2013), EMBASE (1980 to 2013 Week 01), Google Scholar (31 January 2013) and trial registries (31 January 2013). We handsearched recent issues of specialist journals and references of relevant articles. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials assessing the effects of FNB or FICB for initial pain management compared with systemic opiates in children (aged under 18 years) with fractures of the femur receiving pre-hospital or in hospital emergency care. Primary outcomes included failure of analgesia at 30 minutes, pain levels during procedures and transfers (e.g. to a stretcher or hospital ward) for up to eight hours, and adverse effects. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data using a pre-piloted form. Two authors independently assessed the risk of bias for the included study and assessed quality of the evidence for each outcome using the GRADE approach; i.e. as very low, low, moderate or high. Meta-analysis of results was not possible as we found only one trial that could be included in the review. MAIN RESULTS: We included one randomised trial of 55 children aged between 16 months to 15 years. It compared anatomically-guided FICB versus systemic analgesia with intravenous morphine sulphate. The small sample size and the high risk of bias relating to lack of blinding resulted in a low quality rating for all outcomes.Overall, the trial provided low quality evidence for better pain management in the FICB group. Fewer children in the FICB group had analgesia failure at 30 minutes than in the morphine group (2/26 (8%) versus 8/28 (29%); risk ratio (RR) 0.33, 95% confidence interval (CI) 0.09 to 1.20; P value 0.09). The trial did not report on pain during procedures or transfers, or application of analgesia. The trial provided low quality evidence that FICB has a better safety profile than morphine, with only four (15%) reports of redness and pain at the injection site, and no reports of the type of adverse effects of systematic analgesia that occurred in the morphine group, such as respiratory depression (six cases (21%)) and vomiting (four cases (14%)). No long-term adverse events were reported for either intervention. Clinically significant pain relief was achieved in both groups at five minutes; with limited evidence of greater initial pain relief in the FICB group. Based on an inspection of graphically-presented data, at least 46% (12/26) of children in the FICB group had no supplementary medication (mainly analgesia) for the six hours of the study, while only 5% (1 or 2/28) of children in the intravenous morphine group went without additional analgesia. There was insufficient evidence to determine whether child or parental satisfaction with the method of analgesia favoured either method. Resource use was not measured. AUTHORS' CONCLUSIONS: Low quality evidence from one small trial suggests that FICB provides better and longer lasting pain relief with fewer adverse events than intravenous opioids for femur fractures in children. Well conducted and reported randomised trials that compare nerve blocks (both FNB and FICB) with systemic analgesia and that use validated pain scores are needed. PMID- 24343769 TI - Extending simulation learning experiences to patients with chronic health conditions. PMID- 24343771 TI - Assay formats: Recommendation for best practices and harmonization from the global bioanalysis consortium harmonization team. AB - As part of the GBC (Global Bioanalysis Consortium), the L3 assay format team has focused on reviewing common platforms used to support ligand binding assays in the detection of biotherapeutics. The following review is an overview of discussions and presentations from around the globe with a group of experts from different companies to allow an international harmonization of common practices and suggestions for different platforms. Some of the major platforms include Gyrolab, Erenna, RIA, AlphaLISA, Delfia, Immuno-PCR, Luminex, BIAcore, and ELISAs. The review is meant to support bioanalysts in taking decisions between different platforms depending on the needs of the analyte with a number of recommendations to help integration of platforms into a GLP environment. PMID- 24343770 TI - Hyaluronidase-sensitive nanoparticle templates for triggered release of HIV/AIDS microbicide in vitro. AB - This study was designed to test the hypothesis that a triggered release of a topical microbicide (tenofovir) from hyaluronic acid nanoparticles (HA-NPs) can be achieved under the influence of hyaluronidase (HAase) enzyme. A fractional factorial experimental design was used to examine the factors [molar concentrations of adipic acid dihydrazide (X1) and 1-ethyl-3-[3 dimethylaminopropyl] carbodiimide hydrochloride (X2), volume of acetone (X3) and reaction time (X4)] influencing the responses, Y1; particle mean diameter: PMD (nanometers: nm), Y2; polydispersity index: PDI and Y3; zeta (zeta) potential: (millivolts). The amide bond formation between HA and ADH after cross-linking was confirmed by FT-IR and (13)C-NMR analyses. These NPs were also characterized for cytotoxicity on a human vaginal epithelial cell line and L. crispatus. When formulated with factors X1; 2.49 mM, X2; 9.96 mM, X3; 60 mL, X4; 6 h, HA-NPs exhibited a spherical shape with PMD, PDI, zeta potential, encapsulation efficiency, and drug loading of 70.6 +/- 4.1 nm, 0.07 +/- 0.02, -38.2 +/- 2.8 mV, 51.8 +/- 2.4% w/w and 26.1 +/- 1.2% w/w, respectively, (n = 3). Unlike for HA based gel, HAase significantly triggered the drug release and HA degradation from the NPs after 24 h (~90% w/w and 65% w/w, respectively); whereas, in its absence, these values were ~39% w/w and 26% w/w, respectively. The NPs were non-cytotoxic to human vaginal VK2/E6E7, End1/E6E7 cells and Lactobacillus crispatus. These data highlight the potential of HAase-sensitive HA-NPs templates for the controlled and vaginal delivery of anti-HIV/AIDS microbicides. PMID- 24343772 TI - Substituent steering of dihedral angles around single bonds: the case of succinonitrile. AB - Succinonitrile is a material of plastic crystal nature arising from the low energy barrier between synclinal and antiperiplanar isomerization around the central C-C bond, while its high polarity makes it an efficient solvent for a wide variety of salts including ionic liquids. A prediction of the equilibrium dihedral angle - in the absence of experimental data - suffers from the shallow potential energy curve and electron diffraction results contain large standard errors. Here, to provide accurate structural data, the Fourier transform microwave spectrum and the mm-wave spectrum of the major isotopologues of synclinal succinonitrile have been measured, assigned and fitted to produce rotational, centrifugal distortion and quadrupole coupling constants. The mm-wave spectrum of the (13)C and (15)N singly substituted isotopologues in natural abundance has been assigned together with that of the chemically singly substituted (2)H isotopologues. The resultant rotational constants have been used to calculate the substitution geometry for succinonitrile. All parameters and constants are compared with theoretical values computed at the B3LYP, MP2 and CCSD/cc-pVTZ levels of theory. The dihedral angle of succinonitrile, which is a strong driver of the plastic crystal nature of succinonitrile, is found to be 66(2) degrees best comparable to CCSD/cc-pVTZ predictions and noticeably different from the 60 degrees expected without substituent effects. PMID- 24343773 TI - "...the human frame made in God's own likeness, filled with that nice machinery...". PMID- 24343774 TI - Clinical anatomy of the cranial nerves. PMID- 24343775 TI - Arterial supply of the lower cranial nerves: a comprehensive review. AB - The lower cranial nerves receive their arterial supply from an intricate network of tributaries derived from the external carotid, internal carotid, and vertebrobasilar territories. A contemporary, comprehensive literature review of the vascular supply of the lower cranial nerves was performed. The vascular supply to the trigeminal, facial, vestibulocochlear, glossopharyngeal, vagus, spinal accessory, and hypoglossal nerves are illustrated with a special emphasis on clinical issues. Frequently the external carotid, internal carotid, and vertebrobasilar territories all contribute to the vascular supply of an individual cranial nerve along its course. Understanding of the vasculature of the lower cranial nerves is of great relevance for skull base surgery. PMID- 24343776 TI - Self-reported skin symptoms and skin-related quality of life among Latino immigrant poultry processing and other manual workers. AB - BACKGROUND: Manual labor employment occurs in environments with exposures likely to impact skin-related quality of life (SRQOL). OBJECTIVES: The objectives of this paper are to (1) document the dimensions of SRQOL, (2) examine its association with skin symptoms, and (3) identify the predictors of SRQOL in Latino manual workers. METHODS: A population-based survey of 733 Latino manual workers obtained Dermatology Life Quality Index (DLQI) and skin symptoms in the prior year. RESULTS: Two-thirds of workers were employed in production. Skin symptoms in prior year were reported by 23%. Impaired SRQOL was reported by 23%. In multivariate analyses, reduced SRQOL was associated with age, occupation, childhood indigenous language use, and experience of skin symptoms in the prior year. CONCLUSIONS: Despite overall high SRQOL exposures in some immigrant occupational groups produce reduce SRQOL. This rural, immigrant population faces significant obstacles to obtaining dermatological care; efforts are needed to improve their SRQOL. PMID- 24343780 TI - Production of microsclerotia by Brazilian strains of Metarhizium spp. using submerged liquid culture fermentation. AB - We investigated the potential production and desiccation tolerance of microsclerotia (MS) by Brazilian strains of Metarhizium anisopliae (Ma), M. acridum (Mc) and M. robertsii (Mr). These fungi were grown in a liquid medium containing 16 g carbon l-1 with a carbon:nitrogen ratio of 50:1. One hundred milliliters cultures were grown in 250 ml Erlenmeyer flasks in a rotary incubator shaker at 28 degrees C and 200 rpm for 5 days. Five-day-old MS were harvested, mixed with diatomaceous earth (DE) and air-dried for 2 days at 30 degrees C. The air-dried MS-DE granular preparations were milled by mortar + pestle and stored in centrifuged tubes at either 26 or -20 degrees C. Desiccation tolerance and conidia production were assessed for dried MS granules by measuring hyphal germination after incubation for 2 days on water agar plates at 26 degrees C and for conidia production following 7 days incubation. Yields of MS by all strains of Metarhizium were 6.1-7.3 * 106 l-1 after 3 days growth with maximum MS yields (0.7-1.1 * 107 l-1) after 5 days growth. No differences in biomass accumulation were observed after 3 days growth, whereas Ma-CG168 showed the highest biomass accumulation after 5 days growth. Dried MS-DE preparations of all fungal strains were equally tolerant to desiccation (>=93 % germination) and the highest conidia production was obtained by MS granules of Mc-CG423 (4 * 109 conidia g-1). All MS granules showed similar stability after storage at either 26 or -20 degrees C for 3.5 months. PMID- 24343777 TI - Angiotensin-II induces phosphorylation of ERK1/2 and promotes aortic adventitial fibroblasts differentiating into myofibroblasts during aortic dissection formation. AB - The development of acute aortic dissection (AD) is attributed to unbearable wall tension superimposed on disordered of cells and extracellular matrix (ECM) in the aortic wall. Adventitial fibroblasts (AFs) phenotypic differentiation response to stress exhibits essential function to regulate the remolding of vascular. Little is known about the AFs phenotypic differentiation and its possible mechanism in patients with AD. In this study, we examined their roles in AD. Surgical specimens of the aorta from AD patients (n = 10) and controls (n = 10) were tested for alpha-smooth muscle actin (alpha-SMA), extracellular signal-regulated kinase 1,2 (ERK1/2) and phospho-ERK1/2 expression, respectively by western blot. When compared with controls, protein levels of alpha-SMA was significantly decreased and levels of phospho-ERK1/2 was increased significantly in the aortic wall from patients with AD. Immunohistochemistry results showed elevated staining of both alpha-SMA and phospho-ERK1/2 in the adventitia of the aortic wall from patients with AD, on the contrary, staining of alpha-SMA in the media was decreased compared with controls. In vitro, the Raf/MEK/ERK pathway was involved in Ang-II-induced phenotypic differentiation and matrix metalloproteinase-2 (MMP 2) mRNA expression in AFs. This study provides a new insight into the biological action of AFs and phospho-ERK1/2 promoting phenotypic differentiation and MMP-2 expression, suggesting an important role of AFs in leading to disorder the delicate balance of ECM metabolism in the aortic wall, so that AFs may be an essential participant during AD formation. PMID- 24343779 TI - Additive interaction of oral health disorders on risk of hypertension in a Japanese urban population: the Suita Study. AB - BACKGROUND: This study assessed the relationship between different oral health markers-periodontitis, gingival bleeding, tooth number, and occlusal status-and hypertension in a Japanese urban population. METHODS: A total of 1,643 participants with no prior cardiovascular disease (mean age = 66.6 years; 43.4% women) underwent comprehensive health checkups, including a lifestyle questionnaire and dental examination in the Suita Study. RESULTS: In the multivariable-adjusted logistic model, none of the individual oral health markers, namely severe periodontitis, gingival bleeding, lowest quartile of tooth number, and malocclusion, were significantly associated with increased odds of hypertension. The additive effects of oral health markers on hypertension were examined and showed that, compared with subjects with no component of the oral health markers, the multivariale-adjusted odds ratio of hypertension in those with >=3 components was 1.82 (95% confidence interval (CI) = 1.23-2.72; P = 0.003). In the subpopulation without antihypertensive medication (n = 1,148; 59.8% women), a significant graded relationship between multivariable-adjusted systolic blood pressure and the number of components was found (P trend = 0.03), and, compared with subjects with no component of the oral health markers, having >=3 components was related to a higher systolic blood pressure (beta = 5.41; 95% CI = 1.16-9.66; P = 0.01). CONCLUSIONS: There is an additive relationship between oral health disorders and risk of hypertension. Our results suggest that the existence of moderate or severe oral health disorders-that is, several concomitant oral health disorders-is associated with risk of hypertension. PMID- 24343781 TI - Heat treatment induced bacterial changes in irrigation water and their implications for plant disease management. AB - A new heat treatment for recycled irrigation water using 48 degrees C for 24 h to inactivate Phytophthora and bacterial plant pathogens is estimated to reduce fuel cost and environmental footprint by more than 50 % compared to current protocol (95 degrees C for 30 s). The objective of this study was to determine the impact of this new heat treatment temperature regime on bacterial community structure in water and its practical implications. Bacterial communities in irrigation water were analyzed before and after heat treatment using both culture dependent and -independent strategies based on the 16S ribosomal DNA. A significant shift was observed in the bacterial community after heat treatment. Most importantly, bacteria with biological control potential--Bacillus and Paenibacillus, and Pseudomonas species became more abundant at both 48 and 42 degrees C. These findings imply that the new heat treatment procedure not only controls existing plant pathogens but also may make the heat-treated irrigation water a more antagonistic environment against plant pathogens, promoting sustainable disease management. PMID- 24343782 TI - Cobicistat: a review of its use as a pharmacokinetic enhancer of atazanavir and darunavir in patients with HIV-1 infection. AB - Cobicistat (TybostTM) is a mechanism-based inhibitor of cytochrome P450 (CYP) 3A enzymes that is indicated in the EU as a pharmacokinetic enhancer (i.e. booster) of the HIV-1 protease inhibitors (PIs) atazanavir and darunavir in adults. Cobicistat has a lower potential for off-target drug interactions than the standard boosting agent ritonavir, due to its more selective inhibition of CYP3A and lower likelihood for enzymatic induction, and is devoid of anti-HIV activity. When used to boost darunavir or atazanavir in healthy volunteers, oral cobicistat 150 mg once daily provided bioequivalent PI exposure to that seen with oral ritonavir 100 mg once daily (i.e. low-dose ritonavir). Moreover, in treatment naive adults infected with HIV-1 participating in a large, double-blind, phase III trial, an atazanavir-based antiretroviral regimen boosted with cobicistat 150 mg once daily provided a high rate of virological suppression after 48 weeks of therapy that was noninferior to that seen with low-dose ritonavir boosting. Cobicistat was generally well tolerated in this study, with a tolerability profile similar to that of ritonavir. Cobicistat may increase serum creatinine levels (possibly via inhibition of proximal renal tubular cell transporters) and thus reduce estimated glomerular filtration rate (GFR), although it does not appear to affect actual GFR. The drug is more soluble than ritonavir, making coformulation easier, and fixed-dose formulations combining cobicistat with darunavir and atazanavir are in development. Thus, cobicistat is an emerging alternative to ritonavir for the pharmacokinetic enhancement of PIs in adults with HIV-1 infection. PMID- 24343783 TI - Indwelling pleural catheters for non-malignant effusions: a multicentre review of practice. AB - Indwelling pleural catheters (IPCs) are commonly used in the management of malignant pleural effusion (MPE). There is little data on their use in non malignant conditions. All IPC insertions for non-malignant cases from five large UK centres were found using prospectively maintained databases. Data were collected on 57 IPC insertions. The commonest indications were hepatic hydrothorax (33%) and inflammatory pleuritis (26%). The mean weekly fluid output was 2.8 L (SD 2.52). 48/57 (84%) patients had no complications. Suspected pleural infection was documented in 2 (3.5%) cases. 33% (19/57) of patients underwent 'spontaneous' pleurodesis at a median time of 71 days. Patients with hepatic disease achieved pleurodesis significantly less often than those with non-hepatic disease (p=0.03). These data support the use of IPCs in select cases of non malignant disease when maximal medical therapy has failed. PMID- 24343785 TI - Interpretation of genetic variants. AB - Sequencing of the human genome and introduction of clinical next-generation sequencing enable discovery of all DNA variants carried by an individual. Variants may be solely responsible for disease, may contribute to disease, or may have no influence on the development of disease. Interpreting the effect of these variants upon disease is a major challenge for medicine. Although the process is still evolving, certain methods are useful in discriminating the effect of variants upon phenotype. These methods have been employed to the greatest extent in Mendelian disorders where deleterious changes in one gene can cause disease. Here, we briefly review the relative merits of these methods, with emphasis on using a comprehensive approach modelled after the analysis of variants that causes cystic fibrosis. PMID- 24343787 TI - Determining collateral ventilation during bronchoscopy: unanswered questions. PMID- 24343784 TI - Management dilemmas in acute pulmonary embolism. AB - BACKGROUND: Physicians treating acute pulmonary embolism (PE) are faced with difficult management decisions while specific guidance from recent guidelines may be absent. METHODS: Fourteen clinical dilemmas were identified by physicians and haematologists with specific interests in acute and chronic PE. Current evidence was reviewed and a practical approach suggested. RESULTS: Management dilemmas discussed include: sub-massive PE, PE following recent stroke or surgery, thrombolysis dosing and use in cardiac arrest, surgical or catheter-based therapy, failure to respond to initial thrombolysis, PE in pregnancy, right atrial thrombus, role of caval filter insertion, incidental and sub-segmental PE, differentiating acute from chronic PE, early discharge and novel oral anticoagulants. CONCLUSION: The suggested approaches are based on a review of the available evidence and guidelines and on our clinical experience. Management in an individual patient requires clinical assessment of risks and benefits and also depends on local availability of therapeutic interventions. PMID- 24343788 TI - T2 relaxometry of the infrapatellar fat pad after arthroscopic surgery. AB - OBJECTIVE: To investigate the T2 relaxation values of the infrapatellar fat pad (IFP) after arthroscopic surgery. MATERIALS AND METHODS: This study was approved by the institutional review board; all individuals signed informed consent. We performed MRI in 16 knees from 8 subjects. Prior to imaging, each subject had unilateral arthroscopic knee surgery and an asymptomatic non-operated contralateral knee. We used a 10-echo multiple-TE fast-spin echo pulse sequence for creation of T2 relaxation time maps. Two musculoskeletal radiologists independently placed regions of interest in the IFP, suprapatellar subcutaneous and deep intermuscular adipose tissue. Qualitative assessments were performed to assess fibrotic changes affecting patellar retinaculum and IFP. Statistical analyses of T2 values determined differences between groups, correlation with time after surgery, and cut-off values to differentiate groups. RESULTS: The average time between arthroscopy and imaging was 3.5 +/- 0.4 years. IFP of knees with prior surgery had significantly shorter mean T2 values (133 +/- 14 ms) compared with control knees (147 +/- 8 ms, P = 0.03). There was no significant difference between operated and control knees regarding T2 values of suprapatellar subcutaneous (P = 0.3) or deep intermuscular adipose tissue (P = 0.2). There was no correlation between IFP T2 values and time after surgery (P > 0.2). IFP T2 values <= 139 ms had 75 % sensitivity and 88 % specificity in identifying prior arthroscopy. CONCLUSION: Shortening of T2 relaxation values is present in IFP chronically after arthroscopic surgery and may be an indicator of adipose tissue fibrosis. PMID- 24343789 TI - Chitosan nanoparticle encapsulated hemagglutinin-split influenza virus mucosal vaccine. AB - Subunit/split influenza vaccines are less reactogenic compared with the whole virus vaccines. However, their immunogenicity is relatively low and thus required proper adjuvant and/or delivery vehicle for immunogenicity enhancement. Influenza vaccines administered intramuscularly induce minimum, if any, mucosal immunity at the respiratory mucosa which is the prime site of the infection. In this study, chitosan (CS) nanoparticles were prepared by ionic cross-linking of the CS with sodium tripolyphosphate (TPP) at the CS/TPP ratio of 1:0.6 using 2 h mixing time. The CS/TPP nanoparticles were used as delivery vehicle of an intranasal influenza vaccine made of hemagglutinin (HA)-split influenza virus product. Innocuousness, immunogenicity, and protective efficacy of the CS/TPP-HA vaccine were tested in influenza mouse model in comparison with the antigen alone vaccine. The CS/TPP-HA nanoparticles had required characteristics including nano-sizes, positive charges, and high antigen encapsulation efficiency. Mice that received two doses of the CS/TPP-HA vaccine intranasally showed no adverse symptoms indicating the vaccine innocuousness. The animals developed higher systemic and mucosal antibody responses than vaccine made of the HA-split influenza virus alone. The CS/TPP-HA vaccine could induce also a cell-mediated immune response shown as high numbers of IFN-gamma-secreting cells in spleens while the HA vaccine alone could not. Besides, the CS nanoparticle encapsulated HA-split vaccine reduced markedly the influenza morbidity and also conferred 100% protective rate to the vaccinated mice against lethal influenza virus challenge. Overall results indicated that the CS nanoparticles invented in this study is an effective and safe delivery vehicle/adjuvant for the influenza vaccine. PMID- 24343790 TI - External versus internal abutment connection implants: a survey of opinions and decision making among experienced implant dentists in Japan. AB - Internal connection implants have been attracting attention in recent years leading to their being adopted for many implant systems and an increase in market share over other connections. However, internal connection implants have only been used clinically for a short period of time resulting in few clinical studies investigating outcomes and a lack of comparative clinical evidence to support their use over external hex systems at this time. Given the fact that clinical evidence is lacking regarding implant connection performance comparisons, it is important to understand what information clinicians use to choose between systems. The purpose of this study regarding implant decision-making was to ask clinicians to provide subjective evaluations of internal connection implants, in comparison with external connection implants. The survey was constructed to cover four aspects of interest; general responder information, surgical procedures and experience, prosthodontic treatments and outcomes, and implant complications. The dentists' responses indicated that internal connection implants are as user friendly as external hex implants with respect to implant surgery, but they are favored for prosthodontic handling because impression coping and abutment placement are felt to be easier. In addition, it was revealed that dentists strongly feel that there is a lack of biological and prosthodontic evidence to support the use of internal connection implants. The findings reveal the responding clinicians recognize that they often make decisions without compelling evidence to favor one system over another. Decisions are often based on perceived ease of use or third party (colleague or manufacturer) input. For future investigations, we will seek to better understand the relative influence and validity of all forms of information used (especially third party input), as well as what barriers exist to clinicians' use of more evidence based data. PMID- 24343792 TI - Pharmacological treatment for memory disorder in multiple sclerosis. AB - BACKGROUND: This is an update of the Cochrane review "Pharmacologic treatment for memory disorder in multiple sclerosis" (first published in The Cochrane Library 2011, Issue 10).Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) and can cause both neurological and neuropsychological disability. Both demyelination and axonal and neuronal loss are believed to contribute to MS related cognitive impairment. Memory disorder is one of the most frequent cognitive dysfunctions and presents a considerable burden to people with MS and to society due to the negative impact on function. A number of pharmacological agents have been evaluated in many existing randomised controlled trials for their efficacy on memory disorder in people with MS but the results were not consistent. OBJECTIVES: To assess the absolute and comparative efficacy, tolerability and safety of pharmacological treatments for memory disorder in adults with MS. SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Register (24 July 2013), PsycINFO (January 1980 to 26 June 2013) and CBMdisc (1978 to 24 June 2013), and checked reference lists of identified articles, searched some relevant journals manually, registers of clinical trials and published abstracts of conference proceedings. SELECTION CRITERIA: All double-blind, randomised controlled parallel trials on pharmacological treatment versus placebo or one or more pharmacological treatments in adults with MS who had at least mild memory impairment (at 0.5 standard deviations below age- and sex-based normative data on a validated memory scale). We placed no restrictions regarding dose, route of administration and frequency; however, we only included trials with an administration duration of 12 weeks or greater. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We discussed disagreements and resolved them by consensus among review authors. We contacted principal investigators of included studies for additional data or confirmation. MAIN RESULTS: We included seven randomised controlled trials (RCTs) involving 625 people mostly with relapsing-remitting, secondary-progressive and primary progressive MS, evaluating the absolute efficacy of donepezil, ginkgo biloba, memantine and rivastigmine versus placebo in improving memory performance with diverse assessment scales. Overall, clinical and methodological heterogeneities existed across these studies. Moreover, most of them had methodological limitations on non-specific selections of targeted sample, non-matched variables at baseline or incomplete outcome data (high attrition bias). Only the two studies on donepezil had clinical and methodological homogeneity and relatively low risks for bias. One RCT evaluating estriol versus placebo is currently ongoing.We could not carry out a meta-analysis due to the heterogeneities across studies and the high attrition bias. A subgroup analysis for donepezil versus placebo showed no treatment effects on total recall on the Selective Reminding Test (mean difference (MD) 1.68; 95% confidence interval (CI) -2.21 to 5.58), total correct scores on the 10/36 Spatial Recall Test (MD -0.93; 95% CI -3.18 to 1.32), the Symbol Digit Modalities Test (MD -1.27; 95% CI -3.15 to 0.61) and the Paced Auditory Serial Addition Test (2+3 sec) (MD 2.23; 95% CI -1.87 to 6.33). Concerning safety, the main adverse events were: diarrhoea (risk ratio (RR) 3.88; 95% CI 1.66 to 9.05), nausea (RR 1.71; 95% CI 0.93 to 3.18) and abnormal dreams (RR 2.91; 95% CI 1.38 to 6.14). However, the results in both studies were subjected to a serious imprecision resulting from the small sample sizes and the low power of test (lower than 80%), which contributed to a moderate quality of the evidence. No serious adverse events were attributed to the treatments in all experimental groups. AUTHORS' CONCLUSIONS: We found no convincing evidence to support the efficacy of pharmacological symptomatic treatment for MS-associated memory disorder because most of available RCTs had a limited quality. Whether pharmacological treatment is effective for memory disorder in patients with MS remains inconclusive. However, there is moderate-quality evidence that donepezil 10 mg daily was not effective in improving memory in MS patients with mild memory impairment, but had a good tolerability. Adverse events such as nausea, diarrhoea and abnormal dreams were not frequent but were associated with treatment. Ginkgo biloba, memantine and rivastigmine were safe and well tolerated and no serious adverse effects were reported. Future large-scale RCTs with higher methodological quality are needed. PMID- 24343791 TI - Fibroblast growth factor signaling in mammalian tooth development. AB - In this review, we discuss the central role of fibroblast growth factor (FGF) signaling in mammalian tooth development. The FGF family consists of 22 members, most of which bind to four different receptor tyrosine kinases, which in turn signal through a cascade of intracellular proteins. This signaling regulates a number of cellular processes, including proliferation, differentiation, cell adhesion and cell mobility. FGF signaling first becomes important in the presumptive dental epithelium at the initiation stage of tooth development, and subsequently, it controls the invagination of the dental epithelium into the underlying mesenchyme. Later, FGFs are critical in tooth shape formation and differentiation of ameloblasts and odontoblasts, as well as in the development and homeostasis of the stem cell niche that fuels the continuously growing mouse incisor. In addition, FGF signaling is critical in human teeth, as mutations in genes encoding FGF ligands or receptors result in several congenital syndromes characterized by alterations in tooth number, morphology or enamel structure. The parallel roles of FGF signaling in mouse and human tooth development demonstrate the conserved importance of FGF signaling in mammalian odontogenesis. PMID- 24343793 TI - Reciprocal associations between depressive symptoms and disordered eating among adolescent girls and boys: a multiwave, prospective study. AB - Symptoms of depression and eating disorders increase during adolescence, particularly among girls, and they tend to co-occur. Despite this evidence, there is meager research on whether depression increases the risk of future eating pathology, or vice versa, and we do not know whether these processes are different for adolescent girls and boys. Accordingly, this study explored the prospective reciprocal associations between depressive symptoms and disordered eating at different time points from preadolescence to mid-adolescence and tested the moderator effect of gender on these associations. A community-based sample of Spanish youth (N = 942, 49 % female) was assessed at ages of approximately 10-11 (T1), 12-13 (T2), 14-15 (T3), and 16-17 (T4) years. The bidirectional relationships between depressive symptoms and disordered eating were estimated in an autoregressive cross-lagged model with latent variables. A unidirectional, age specific association between depressive symptoms at T1 and disordered eating at T2 was found. No other significant cross-lagged effect emerged, but the stability of the constructs was considerable. Gender did not moderate any of the links examined. Regardless of gender, the transition from childhood to adolescence appears to be a key period when depressive symptoms foster the development of disordered eating. These findings suggest that early prevention and treatment of depression targeting both girls and boys may result in lower levels of depressive symptoms and disordered eating in adolescence. PMID- 24343794 TI - Changes in ADHD symptom endorsement: preschool to school age. AB - To investigate endorsement patterns among the 18 DSM-IV symptoms of ADHD in a longitudinal sample of children with and without ADHD (n = 144), as assessed at ages 4-5, 5-6, and 6-7 years. Symptom endorsements and diagnoses were determined at all time-points via K-SADS-PL interview administered to parents and supplemented by teacher questionnaires and clinician observations. Changes in endorsement patterns over time for each of the 18 DSM-IV symptoms were ascertained. Several symptoms, particularly those of inattention, were infrequently endorsed and of apparently limited diagnostic utility at ages 4-5; hyperactive/impulsive symptoms were more frequently endorsed among young children with ADHD than were inattentive symptoms. However, by ages 6-7, inattention items were somewhat superior at discriminating ADHD from Non-ADHD children. Several DSM IV and now DSM-V symptoms provide limited diagnostic differentiation prior to school-age, particularly those most commonly observed in the context of formal schooling. Consideration should be made in future iterations of the DSM that account for such developmental and contextual differences. PMID- 24343795 TI - Longitudinal analysis of adolescent NSSI: the role of intrapersonal and interpersonal factors. AB - Non-suicidal self-injury (NSSI) occurs in approximately 10 % of adolescents. To establish effective prevention and intervention initiatives, it is important to understand onset, maintenance and cessation of NSSI. We explored whether the relationships between interpersonal factors (i.e. attachment, social support) and NSSI were mediated by intrapersonal factors (i.e. emotion regulation, self esteem, self-efficacy). Participants were 1973 students (1414 female and 559 male) aged between 12 and 18 years (M = 13.89, SD = 0.97) recruited from 40 Australian high schools. Participants completed a questionnaire at two time points with a 12-month interval. At baseline, 8.3 % of adolescents engaged in NSSI, increasing to 11.9 % at follow-up. Family support was most salient in onset, maintenance and cessation of NSSI. Attachment anxiety was related to NSSI onset. Of the intrapersonal variables, self-esteem and self-efficacy were significant in predicting onset of NSSI. Self-esteem, self-efficacy and cognitive reappraisal mediated the relationship between attachment anxiety and NSSI onset. A combination of interpersonal and intrapersonal variables contributes to the onset, maintenance and cessation of NSSI in adolescence. Perceived family support appears to be an important safeguard against NSSI. Strategies targeting family functioning and teaching cognitive reappraisal techniques to adolescents may reduce the number engaging in NSSI. PMID- 24343796 TI - Leptin receptor deficient diabetic (db/db) mice are compromised in postnatal bone regeneration. AB - Increased fragility fracture risk with improper healing is a frequent and severe complication of insulin resistance (IR). The mechanisms impairing bone health in IR are still not fully appreciated, which gives importance to studies on bone pathologies in animal models of diabetes. Mice deficient in leptin signaling are widely used models of IR and its comorbidities. Leptin was first recognized as a hormone, regulating appetite and energy balance; however, recent studies have expanded its role showing that leptin is a link between insulin-dependent metabolism and bone homeostasis. In the light of these findings, it is intriguing to consider the role of leptin resistance in bone regeneration. In this study, we show that obese diabetic mice lacking leptin receptor (db/db) are deficient in postnatal regenerative osteogenesis. We apply an ectopic osteogenesis and a fracture healing model, both showing that db/db mice display compromised bone acquisition and regeneration capacity. The underlying mechanisms include delayed periosteal mesenchymatic osteogenesis, premature apoptosis of the cartilage callus and impaired microvascular invasion of the healing tissue. Our study supports the use of the db/db mouse as a model of IR associated bone-healing deficits and can aid further studies of mesenchymatic cell homing and differentiation, microvascular invasion, cartilage to bone transition and callus remodeling in diabetic fracture healing. PMID- 24343797 TI - Anatomical topography of the mandibular symphysis in the Korean population: a computed tomography analysis. AB - The objective of this study was to reveal the topography of the mandibular symphysis according to gender and age in the Korean population using computed tomography (CT) to provide a mean anatomical database for the safety zone during block bone harvesting. The following parameters were measured in CT images taken from Korean subjects: interforaminal distance (ID), vertical distance between the inferior mandibular border and the apices of the anterior teeth (VD), and horizontal distance between the labial cortical bone and the apices of the anterior teeth (HD). Differences between genders and among age groups, and the correlations among measurements were analyzed. A total of 973 images (411 males and 562 females; mean age = 41.2 years) were selected. The overall mean ID, VD, and HD were 55.38 +/- 5.13, 22.16 +/- 3.84 and 5.21 +/- 1.70 mm, respectively. The ID and VD were significantly larger in males than in females (P < 0.001), and ID was significantly smaller in the youngest age group than in other age groups (P < 0.001), while HD differed significantly only between the youngest and oldest groups (P < 0.05). There was a weak positive correlation between ID and HD (gamma > 0.10). This study provides information on the topography of the mandibular symphysis in the Korean population based on a large number of CT images. In general, gender seemed to influence the symphyseal dimensions strongly, whereas the influence of age was limited. PMID- 24343798 TI - The biennial International Bioluminescence and Chemiluminescence Symposium series: a 35-year heritage. PMID- 24343799 TI - Probable hepatic tuberculosis masquerading as Klatskin tumour in an immunocompetent patient. AB - A 55-year-old immunocompetent woman was presented with features of obstructive jaundice and a clinicoradiological picture suggestive of a hilar cholangiocarcinoma (Klatskin tumour). However, caseating granulomatous lesion associated with miliary nodules were revealed intraoperatively. The lesion responded to standard antituberculous therapy. This unusual presentation highlights the considerable diagnostic challenge in such case. PMID- 24343800 TI - The development of peripheral T-cell lymphoma after successful treatment for diffuse large B-cell lymphoma in a patient with suspected adult onset immunodeficiency: more questions than answers? AB - We present the case of a 60-year-old woman who developed peripheral T-cell lymphoma following successful treatment for high-grade B-cell non-Hodgkin's lymphoma. We consider the possible aetiology of this unusual occurrence. We hypothesise that this case represents one of the undiagnosed adult-onset immunodeficiency, in which the pathogenesis of the patient's T-cell lymphoma may have been in part iatrogenic, namely related to previous immunotherapy with rituximab. We feel this case highlights the importance of rebiopsy in patients with recurrent lymphadenopathy and a history of haematological malignancy and hence acts as an important aide memoir in the investigation of such cases. PMID- 24343801 TI - Pemphigus vulgaris: a multidisciplinary approach to management. AB - Pemphigus vulgaris (PV) is a rare but potentially life-threatening autoimmune disease affecting the mucosa and the skin. The disease is caused by circulating antibodies to desmosomes (important adhesion proteins linking cells together). Disruption of these intercellular connections results in a loss of cohesion between cells (acantholysis). The clinical result of this process is the development of multiple blisters that easily rupture, leaving behind painful sloughing eroded areas of mucosa and/or skin. We report a case of severe PV in a 56-year-old man presenting with widespread, painful, eroded mucocutaneous lesions. The severity of the disease demanded a range of medical and surgical specialties to successfully manage the problem. This paper highlights the importance of an early multidisciplinary team approach to improve the outcome of patients suffering with this disease. PMID- 24343802 TI - A gastrointestinal stromal tumour with pulmonary metastases mimicking unilateral gynaecomastia. AB - Gastrointestinal stromal tumours (GISTs) represent 1% of primary gastrointestinal cancers. These neoplasms most frequently metastasise to the liver and peritoneum and rarely to the lungs and bones. Treatment of unresectable GISTs involves systemic chemotherapy with tyrosine kinase inhibitors, imatinib and sunitinib being first-line and second-line drugs. We report the case of a 52-year-old man with GIST who developed a right-sided subareolar breast swelling and subsequently discovered to be an invasive metastatic pulmonary GIST. Given that gynaecomastia is a known adverse effect of imatinib and sunitinib, this case report illustrates the importance of including metastatic disease in the differential diagnosis of patients with GIST and with the new onset of soft tissue masses. PMID- 24343803 TI - Fibrolipomas masquerading as abdominal hernias. AB - A 15-year-old Caucasian girl presented to her general practitioner with a tender, irreducible mass in the paraumbilical region. On examination, two small masses could be felt. She was referred to general surgery. Ultrasound imaging and MRI were unremarkable. However, clinical suspicion suggested multiple areas of abdominal wall herniation. The patient was admitted for elective surgery to exclude herniation. At operation, three subcutaneous masses were found but with no evidence of abdominal wall herniation. Histopathology results from the specimens showed mature adipose tissue mixed with fibrous deposits. There was no evidence of malignancy. A diagnosis of fibrolipoma was given. PMID- 24343804 TI - Pure motor monoparesis: solitary cysticercus granuloma. AB - Solitary cysticercus granuloma (SCG) is the most common form of neurocysticercosis in India and usually presents with seizures. Pure motor monoparesis (PMM) due to cerebral cysticercus lesions has been rarely reported and it has not been seen with SCG. We describe a young girl with SCG who presented with PMM without any other neurological manifestations. The lesion was located in the Penfield homunculus area of the opposite leg. The patient was treated with steroids and antihelminthic drugs. She responded well to the treatment. PMID- 24343805 TI - Pancreatic herniation: a rare cause of acute pancreatitis? AB - Acute pancreatitis is a common and potentially fatal condition, with several well known causes including gallstones, excessive alcohol consumption and specific medications. We report a case of an 89-year-old man presenting with acute pancreatitis, which we believe to be secondary to a diaphragmatic herniation of the pancreas. This extremely rare anatomical abnormality can be found incidentally in the asymptomatic patient or may present with a variety of acute symptoms. However, there have been only isolated reports of these cases presenting as acute pancreatitis. While the majority of acute pancreatitis cases can be explained by common causes, it is important that clinicians be aware of and should consider investigating for other more unusual possibilities, such as pancreatic herniation, before labelling an episode as 'idiopathic'. PMID- 24343806 TI - Epstein-Barr virus-associated cholestatic hepatitis. AB - Epstein-Barr virus infection is common in children, usually presenting as infectious mononucleosis, including fever, tonsillitis and lymphadenopathy associated with self-resolving increase in transaminases. Cholestasis is rare in children with only a few cases reported but it was described in up to 55% of the adult population affected. We present a case of a 6-year-old boy with fever, vomiting and choluria. The physical examination showed hepatomegaly and jaundice and was otherwise unremarkable. The laboratory studies revealed increased transaminases (aspartate aminotransferase 97 U/L, alanine aminotransferase 166 U/L), hyperbilirubinaemia (total bilirubin 3.2 mg/dL, direct bilirubin 2.89 mg/dL) and increased gamma-glutamyl transpeptidase (114 mg/dL). Urine urobilinogen was increased. The abdominal ultrasound showed hepatomegaly. Epstein Barr viral capsid antibody IgM was positive and IgG was negative. Serological studies for other viruses were negative. We underline the need to consider Epstein-Barr virus in the cholestatic hepatitis differential diagnosis, in order to avoid unnecessary investigations. PMID- 24343807 TI - Exploring avoidant/restrictive food intake disorder in eating disordered patients: a descriptive study. AB - OBJECTIVE: To assess and compare clinical characteristics of patients with avoidant/restrictive food intake disorder (ARFID) to those with anorexia nervosa (AN). METHOD: A retrospective review of adolescent eating disorder (ED) patients assessed between 2000 and 2011 that qualified for a diagnosis of ARFID was completed. A matched AN sample was used to compare characteristics between groups. RESULTS: Two hundred and five patients met inclusion criteria and were reviewed in detail. Of these, 34 (5%) patients met criteria for ARFID. A matched sample of 36 patients with AN was used to draw comparisons. Patients with ARFID were younger than those with AN, more likely to present before age 12, and more likely to be male. Patients in both groups presented at low weights. Common eating-specific behaviors and symptoms in the ARFID group included food avoidance, loss of appetite, abdominal pain, and fear of vomiting. Rates of comorbid psychiatric diagnoses and medical morbidity were high in both groups. Almost 80% of AN patients and one-third of ARFID patients required hospital admission as a result of medical instability. Symptom profiles in 4/34 ARFID patients resulted in eventual reclassification to AN. DISCUSSION: This study supports the notion that a small percentage of adolescent patients presenting with restrictive eating disorders meet criteria for ARFID. Patients are younger than average, more likely to be male compared to adolescent AN samples, and have high rates of psychiatric and medical morbidity. The study also suggests that a proportion of patients evolve into AN as treatment progresses. PMID- 24343809 TI - Multimodality imaging of thyroid-like follicular renal cell carcinoma with lung metastases, a new emerging tumor entity. AB - The International Society of Urological Pathology recently proposed classifying thyroid-like follicular renal cell carcinoma (TLF-RCC) as an emerging entity in renal epithelial tumors. Their entire proposal will be the framework for the next World Health Organization classification of renal tumors. Fewer than 15 cases of TLF-RCC have been reported in the literature up to date. We describe the multimodality imaging features of a patient with TLF-RCC. To our knowledge, this is the first case report in the literature commenting on the multimodality imaging appearance of this tumor. PMID- 24343814 TI - Aligning research and practice: implications of patient-centered care for placebo effects. PMID- 24343815 TI - Revisiting Darwin's hypothesis: Does greater intraspecific variability increase species' ecological breadth? AB - PREMISE OF THE STUDY: Darwin first proposed that species with larger ecological breadth have greater phenotypic variation. We tested this hypothesis by comparing intraspecific variation in specific leaf area (SLA) to species' local elevational range and by assessing how external (abiotic) filters may influence observed differences in ecological breadth among species. Understanding the patterns of individual variation within and between populations will help evaluate differing hypotheses for structuring of communities and distribution of species. METHODS: We selected 21 species with varying elevational ranges and compared the coefficient of variation of SLA for each species against its local elevational range. We examined the influence of external filters on local trait composition by determining if intraspecific changes in SLA with elevation have the same direction and similar rates of change as the change in community mean SLA value. KEY RESULTS: In support of Darwin's hypothesis, we found a positive relationship between species' coefficient of variation for SLA with species' local elevational range. Intraspecific changes in SLA had the same sign, but generally lower magnitude than the community mean SLA. CONCLUSIONS: The results indicate that wide-ranging species are indeed characterized by greater intraspecific variation and that species' phenotypes shift along environmental gradients in the same direction as the community phenotypes. However, across species, the rate of intraspecific trait change, reflecting plastic and/or adaptive changes across populations, is limited and prevents species from adjusting to environmental gradients as quickly as interspecific changes resulting from community assembly. PMID- 24343816 TI - Activity, activity restriction, and sedentarism in nursing research. PMID- 24343817 TI - Salivary proteomic analysis of diabetic patients for possible oral squamous cell carcinoma biomarkers. AB - Since oral squamous cell carcinoma (OSCC) is one of the most important causes of death worldwide, the prevention and early detection plays a crucial role. Recent epidemiological studies have incriminated diabetes as a risk factor for the development of OSCC, as well as oral premalignant lesions. As for the last 20 years diabetes and oral squamous cell carcinoma rates have been increasing rapidly, therefore a reliable detection method of major saliva proteins as possible biomarkers for OSCC is of key priority. In this study we collected whole saliva samples from patients with diabetes and from healthy subjects. To reduce the risk of failure and to keep the investigation good reproducible, we proposed an examination and saliva collecting technique. The proteins were analyzed using SDS-PAGE and MALDI TOF/TOF mass spectrometry. Our findings show that the expression of Annexin A8, Peroxiredoxin-2 and Tyrosine kinase is elevated by patients having diabetes. All these proteins have been previously described in cancer saliva samples also in OSCC. Our current findings showed that testing saliva may be an effective and reliable method for detecting oral cancer in early stages. PMID- 24343818 TI - Aryl hydrocarbon receptor protects against bacterial infection by promoting macrophage survival and reactive oxygen species production. AB - Aryl hydrocarbon receptor (AhR) is crucial for various immune responses. The relationship between AhR and infection with the intracellular bacteria Listeria monocytogenes (LM) is poorly understood. Here, we show that in response to LM infection, AhR is required for bacterial clearance by promoting macrophage survival and reactive oxygen species (ROS) production. AhR-deficient mice were more susceptible to listeriosis, and AhR deficiency enhances bacterial growth in vivo and in vitro. On the other hand, pro-inflammatory cytokines were increased in AhR-deficient macrophages infected with LM despite enhanced susceptibility to LM infection in AhR-deficient mice. Subsequent studies demonstrate that AhR protects against macrophage cell death induced by LM infection through the induction of the antiapoptotic factor, the apoptosis inhibitor of macrophages, which promotes macrophage survival in the setting of LM infection. Furthermore, AhR promotes ROS production for bacterial clearance. Our results demonstrate that AhR is essential to the resistance against LM infection as it promotes macrophage survival and ROS production. This suggests that the activation of AhR by its ligands may be an effective strategy against listeriosis. PMID- 24343819 TI - Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis. AB - Perturbations in immune processes are a hallmark of a number of autoimmune and inflammatory disorders. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is an inflammatory disorder with possible autoimmune correlates, characterized by reduced NK cell activity, elevations in regulatory T cells (Tregs) and dysregulation in cytokine levels. The purpose of this article is to examine innate and adaptive immune cell phenotypes and functional characteristics that have not been previously examined in CFS/ME patients. Thirty patients with CFS/ME and 25 non-fatigued controls were recruited for this study. Whole blood samples were collected from all participants for the assessment of cell phenotypes, functional properties, receptors, adhesion molecules, antigens and intracellular proteins using flow cytometric protocols. The cells investigated included NK cells, dendritic cells, neutrophils, B cells, T cells, gammadeltaT cells and Tregs. Significant changes were observed in B-cell subsets, Tregs, CD4(+)CD73(+)CD39(+) T cells, cytotoxic activity, granzyme B, neutrophil antigens, TNF-alpha and IFN-gamma in the CFS/ME patients in comparison with the non-fatigued controls. Alterations in B cells, Tregs, NK cells and neutrophils suggest significant impairments in immune regulation in CFS/ME and these may have similarities to a number of autoimmune disorders. PMID- 24343820 TI - S1P lyase in thymic perivascular spaces promotes egress of mature thymocytes via up-regulation of S1P receptor 1. AB - Sphingosine 1-phosphate (S1P) and S1P receptor 1 (S1P1) play an important role in the egress of mature CD4 or CD8 single-positive (SP) thymocytes from the thymus. Fingolimod hydrochloride (FTY720), an S1P1 functional antagonist, induced significant accumulation of CD62L(high)CD69(low) mature SP thymocytes in the thymic medulla. Immunohistochemical staining using anti-S1P1 antibody revealed that S1P1 is predominantly expressed on thymocytes in the thymic medulla and is strongly down-regulated even at 3h after FTY720 administration. 2-Acetyl-4 tetrahydroxybutylimidazole (THI), an S1P lyase inhibitor, also induced accumulation of mature SP thymocytes in the thymic medulla with an enlargement of the perivascular spaces (PVS). At 6h after THI administration, S1P1-expressing thymocytes reduced partially as if to form clusters and hardly existed in the proximity of CD31-expressing blood vessels in the thymic medulla, suggesting S1P lyase expression in the cells constructing thymic medullary PVS. To determine the cells expressing S1P lyase in the thymus, we newly established a mAb (YK19-2) specific for mouse S1P lyase. Immunohistochemical staining with YK19-2 revealed that S1P lyase is predominantly expressed in non-lymphoid thymic stromal cells in the thymic medulla. In the thymic medullary PVS, S1P lyase was expressed in ER TR7-positive cells (reticular fibroblasts and pericytes) and CD31-positive vascular endothelial cells. Our findings suggest that S1P lyase expressed in the thymic medullary PVS keeps the tissue S1P concentration low around the vessels and promotes thymic egress via up-regulation of S1P1. PMID- 24343821 TI - Pathogenic Th2-type follicular helper T cells contribute to the development of lupus in Fas-deficient mice. AB - Fas mutant mice are well recognized as autoimmune mouse models, which develop symptoms similar to human systemic lupus erythematosus. Although disease severity in Fas mutant mice is greatly affected by the genetic background, the mechanisms affecting pathological heterogeneity among different strains of Fas mutant mice are poorly understood. In this study, we examined the phenotypic differences between Fas-deficient (Fas (-/-)) mice on the BALB/c and C57BL/6 backgrounds to gain insight into the etiological and pathological heterogeneity of monogenic autoimmune diseases. Fas (-/-) mice on the BALB/c background (BALB/c-Fas (-/-)) developed more severe autoimmune disease with high serum auto-antibodies and renal disease compared with those on the C57BL/6 background (C57BL/6-Fas (-/-)). Splenic B cells were highly activated, and germinal center formation was enhanced in BALB/c-Fas (-/-) but not in C57BL/6-Fas (-/-) mice. Follicular helper T (Tfh) cells were equally abundant in the spleens from both strains of Fas (-/-) mice. However, Tfh cells from BALB/c-Fas (-/-) mice produced much higher amounts of B cell-activating cytokines, including IL-4 and IL-10, a phenotype reminiscent of Th2-type Tfh cells described in human studies. Our results revealed a qualitative difference in Tfh cells between the two strains of Fas (-/-) mice. We propose that the pathogenic Th2-type Tfh cells in BALB/c-Fas (-/-) mice contribute to the excessive activation of B cells, resulting in high serum immunoglobulin levels and the severe lupus phenotype, which may account for the differential outcomes of human monogenic autoimmune diseases. PMID- 24343822 TI - Persistence of lymphatic filarial infection in the paediatric population of rural community, after six rounds of annual mass drug administrations. AB - Under the Global Programme to Eliminate Lymphatic Filariasis (LF), mass drug administration (MDA) is being implemented in Tamil Nadu, south India, by the State health machinery. The impact of six annual rounds of MDA using diethylcarbamazine (DEC) with and without albendazole (ALB) on filarial infection (microfilaraemia prevalence-MFP; antigenaemia prevalence-AGP) in paediatric population of 2-9 years was determined in two revenue blocks, with a population of 321 000. After each MDA, 300-400 children were screened for filarial infection. After six MDAs, an overall MFP reduction of 84.67% and 57.95% was observed in DEC+ALB and DEC alone arms, respectively. Corresponding AGP reductions were 72.88% (p < 0.001) and 41.51% (p = 0.023). Observation of microfilaraemic children after six MDAs (0.32% in DEC+ALB; 0.75% in DEC alone), necessitates the need for supplementary control strategies (viz., vector control), in order to achieve the goal of LF elimination. PMID- 24343823 TI - Effect of therapeutic hypothermia on DNA damage and neurodevelopmental outcome among term neonates with perinatal asphyxia: a randomized controlled trial. AB - OBJECTIVE: To study the effect of therapeutic hypothermia (TH) on deoxyribonucleic acid (DNA) damage and the neurodevelopmental outcome in term babies with perinatal asphyxia. METHODS: Babies in the hypothermia group were cooled for the first 72 h, using gel packs. Rectal temperature of 33-34 degrees C was maintained. Blood sample was collected before, at 36 h and after completion of TH for assessment of comet assay and 8-hydroxy2-deoxyguanosine (8-OHdG). Infants were followed up till 12 months. RESULTS: Baseline parameters were similar. After 72 h, the hypothermia group showed lower olive tail moment (12.88 +/- 2.14) than the control group (22.16 +/- 5.26) (p < 0.001). 8-HDG levels increased significantly in the control group (1252.87 +/- 357.07) as compared to the hypothermia group (757.03 +/- 198.49) (p < 0.001). Neurodevelopmental assessment at 12 months showed significantly low motor and mental developmental quotient in the control than hypothermia group. CONCLUSIONS: TH reduces oxidative stress-induced DNA damage and improves neurodevelopmental outcome. PMID- 24343824 TI - Effect of inhaled MgSO4 on FEV1 and PEF in children with asthma induced by acetylcholine: a randomized controlled clinical trail of 330 cases. AB - OBJECTIVES: To determine the response of nebulized magnesium sulfate on the lung function of acetylcholine-induced asthma children. METHODS: Three hundred and thirty children of asthma with positive bronchial provocation test were randomly divided into three groups: magnesium sulfate, albuterol, and a combination of magnesium sulfate and albuterol. Lung function was compared between the three groups. RESULTS: Forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF) as percentage over predicted at 10 min and 20 min in albuterol and combination group were significantly improved when compared to magnesium group. The changes in FEV1 and PEF expressed as absolute and percentage over predicted was not statistically significant from baseline to 20 min in magnesium, albuterol, and combination of magnesium sulfate and albuterol. There was no significant adverse effect observed during the present study. CONCLUSION: Nebulized magnesium sulfate alone has a bronchodilatory effect in Ach-induced asthmatic children. The combination of MgSO4 and albuterol did not has a synergistic effect. PMID- 24343825 TI - Diffusion tensor imaging and tractography of the human language pathways: moving into the clinical realm. AB - The functional correlates of anatomical derangements are of interest to the neurological clinician. Diffusion tensor tractography (DTT) is a relatively new tool in the arsenal of functional neuroimaging, by which to assess white matter tracts in the brain. While much import has been given to tracking corticospinal tracts in neurological disease, studying language pathway interconnections using DTT has largely remained in the research realm. Hardware and software advances have allowed this tool to ease into clinical practice, with several radiologists, neurologists, and neurosurgeons now familiar with its applications. DTT images, although visually appealing, are founded in mathematical equations and assumptions, and require a more than basic understanding of principles and limitations before they can be integrated into routine clinical practice. Cognitive pathways like that of language, that are normally hard to assess and especially more so when pathologically affected, have been at the receiving end of several opposing and often controversial hypotheses, and the past decade has seen the clarification, validation or rejection of several of these by the in vivo charting of functional connectivity using DTT. The focus of this review is to illustrate DTT of the language pathways with emphasis on practical considerations, clinical applications, and limitations. PMID- 24343826 TI - Tedizolid: a novel oxazolidinone for Gram-positive infections. PMID- 24343827 TI - Methicillin-resistant Staphylococcus aureus: an evolving pathogen. AB - The horizontal transmission of methicillin resistance to Staphylococcus aureus (MRSA) in hospital and community settings, and growing prevalence of these strains, presents a significant clinical challenge to the management of serious infections worldwide. While infection control initiatives have stemmed the rising prevalence, MRSA remains a significant pathogen. More recently, evidence that MRSA is becoming resistant to glycopeptides and newer therapies raises concern about the use of these therapies in clinical practice. Vancomycin resistance has become evident in select clinical settings through rising MICs, growing awareness of heteroresistance, and emergence of intermediate-resistant and fully resistant strains. While resistance to linezolid and daptomycin remains low overall, point mutations leading to resistance have been described for linezolid, and horizontal transmission of cfr-mediated resistance to linezolid has been reported in clinical isolates. These resistance trends for newer therapies highlight the ongoing need for new and more potent antimicrobial therapies. PMID- 24343828 TI - Methicillin-resistant Staphylococcus aureus therapy: past, present, and future. AB - Methicillin-resistant Staphylococcus aureus (MRSA) continues to be associated with significant morbidity and mortality. Vancomycin was the "gold standard" of treatment for serious MRSA infections; however, the emergence of less-susceptible strains, poor clinical outcomes, and increased nephrotoxicity with high-dose therapy are challenging its current role as first-line therapy. Linezolid is recommended for PO or IV treatment of skin and skin structure infections (SSSIs) and pneumonia caused by MRSA. Daptomycin (IV) should be considered in patients with MRSA bacteremia and right-sided endocarditis as well as in complicated SSSIs, but should not be used to treat MRSA pneumonia. Tigecycline and telavancin are alternative (IV) treatments for SSSIs caused by MRSA; however, safety concerns have limited use of these agents. Ceftaroline is the newest of the approved parenteral agents for SSSIs caused by MRSA. Several investigational agents with activity against drug-resistant gram-positive pathogens are being developed primarily for treatment of MRSA infections, including tedizolid, dalbavancin, and oritavancin. PMID- 24343829 TI - Use of pharmacokinetic/pharmacodynamic systems analyses to inform dose selection of tedizolid phosphate. AB - In the Staphylococcus aureus neutropenic murine thigh-infection model, the ratio of the free area under the 24-hour concentration-time curve to the minimum inhibitory concentration (fAUC/MIC) was found to be the pharmacodynamic index most closely linked to bacterial effect, with a ratio of approximately 50 producing a static effect. Further work was undertaken in neutropenic versus non neutropenic animals. The presence of granulocytes increased the activity of tedizolid considerably, 25-fold on average, and maximal effect was achieved at an exposure equivalent to approximately 200 mg tedizolid phosphate per day in humans (dosing regimen used in phase 2 and 3 clinical trials). The fAUC/MIC was also found to be the pharmacodynamically linked variable in the S. aureus neutropenic murine pneumonia model; the fAUC/MIC ratio required for a static effect was approximately 20. Pharmacokinetic (PK) data demonstrate that tedizolid penetrates well into the epithelial lining fluid (ELF) of the lung. Data from the pneumonia infection model and ELF penetration PK study support exploring its use in pneumonia. PMID- 24343830 TI - Tedizolid for the management of human infections: in vitro characteristics. AB - The emerging antibiotic resistance of Gram-positive pathogens represents a significant challenge to the management of human infections. The novel oxazolidinone tedizolid demonstrates antimicrobial activity across a broad range of Gram-positive pathogens and greater potency than linezolid against wild-type and drug-resistant pathogens, including linezolid-resistant Staphylococcus aureus strains possessing mutations in chromosomal genes encoding 23S rRNA or ribosomal proteins L3 or L4. Strains harboring such mutations are also selected for much less frequently with tedizolid than with linezolid. In addition, tedizolid has a significant potency advantage over linezolid-resistant strains carrying the horizontally transferable cfr gene. Methylation of A2503 of 23S rRNA by the Cfr methyltransferase confers resistance to linezolid (and a variety of other 50S ribosomal subunit-targeted antibiotics) but not to tedizolid because of structural differences in A-ring C5 substituents between the 2 drugs. The greater potency and improved resistance profile of tedizolid provides the microbiologic basis for considering this molecule as an alternative to linezolid for the treatment of serious infections caused by Gram-positive pathogens. PMID- 24343831 TI - FDA guidance for ABSSSI trials: implications for conducting and interpreting clinical trials. AB - Recent guidance from the US Food and Drug Administration (FDA) on the conduct of clinical trials for acute bacterial skin and skin structure infection (ABSSSI) has changed the framework for clinical trial design and conduct. Notable changes included new disease state definitions, new primary endpoint definitions and the timing of assessments at these endpoints, and updated guidance on patient inclusion/exclusion criteria. Supportive evidence and statistical justification for the proposed noninferiority margins were described in detail. Although the updated guidelines are still considered drafts and have been adopted in some trials, they serve as the basis for study protocol discussions between pharmaceutical companies and the FDA in advancing the development of promising new agents. Not only will the new trial designs impact researchers and sponsors responsible for drug development programs, but they will also affect healthcare providers participating in clinical trials and the ways in which clinicians develop patient treatment plans based on the results of those trials. This review provides a summary of key changes that will impact future clinical trial design and outcomes. PMID- 24343832 TI - Tedizolid phosphate for the management of acute bacterial skin and skin structure infections: efficacy summary. AB - The novel oxazolidinone tedizolid phosphate is in late-stage development for acute bacterial skin and skin structure infections (ABSSSIs). Preclinical and phase 1 trials have shown that 200-mg once-daily tedizolid phosphate dosing achieves the appropriate pharmacokinetic goals for optimal antimicrobial effect, and a randomized phase 2 dose-ranging trial confirmed that tedizolid phosphate may be an option for the treatment of ABSSSIs at the 200-mg dose, the lowest effective dose, over a mean of 6.4 days of therapy. In the first of two phase 3 trials, 6 days of 200-mg once-daily oral tedizolid phosphate (plus 4 days of placebo) was noninferior to 10 days of 600-mg twice-daily oral linezolid when evaluated at both the early (48- to 72-hour assessment) and test-of-cure (7-14 days after the last dose of active or placebo agent was given) time points. Initial results from the second phase 3 trial (intravenous to oral therapy design) confirm the study met all primary and secondary endpoints and continues to add insight into the clinical utility of tedizolid phosphate. PMID- 24343833 TI - Tedizolid phosphate for the management of acute bacterial skin and skin structure infections: safety summary. AB - The novel oxazolidinone tedizolid phosphate is in late-stage clinical development. In an effort to improve efficacy and safety, the adverse event profile and safety aspects of tedizolid phosphate have been evaluated in several preclinical animal models and through ongoing clinical trials. Early dose-ranging studies demonstrated a favorable overall adverse event profile and low thrombocytopenia rates, which have been consistently confirmed in phase 2 and 3 clinical trials. Pharmacokinetic modeling suggests a lower potential for monoamine oxidase interaction, and animal and human subject testing has confirmed these predictions. Studies in special patient populations showed a consistent and predictable pharmacokinetic profile across age groups and comorbid conditions, without evidence of increased incidence of adverse effects over matched controls. The favorable safety profile makes tedizolid phosphate an important new option for the management of serious Gram-positive infections, including those caused by methicillin-resistant Staphylococcus aureus. PMID- 24343834 TI - Heart rate variability associates with asymptomatic coronary atherosclerosis. AB - PURPOSE: Heart rate variability (HRV) becomes impaired in symptomatic coronary artery disease (CAD), particularly, after myocardial infarction. The mechanism how CAD results in impairment of cardiac autonomic regulation is not known. Whether it results rather from coronary atherosclerosis itself than myocardial ischemia and myocardial injury has remained elusive. METHODS: Quantitative coronary angiography was performed in 30 subjects without history of myocardial ischemia, but with high familial risk for CAD. HRV was measured from 24-h ambulatory ECG recordings in time and frequency domain and also non-linear HRV variables SD1 and SD2 in Poincare plot were calculated. Myocardial ischemia was excluded by Tc-99m sestamibi scintigraphy at rest and during exercise. RESULTS: Coronary angiography revealed mean diameter stenosis of 32 +/- 19 % in left anterior descending coronary artery, 26 +/- 16 % in left circumflex coronary artery and 25 +/- 20 % in right coronary artery. An inverse correlation was found between pNN50 and global severity of coronary artery diameter stenosis (r = 0.415, p < 0.05). Correspondingly, power of HF spectral component correlated negatively with global extent of coronary atherosclerosis (r = -0.366, p < 0.05). In Poincare plot, SD1/SD2 ratio correlated with global extent (r = -0.394, p < 0.05) and global burden (r = -0.388, p < 0.05) of coronary arteries. CONCLUSIONS: The severity and extent of coronary atherosclerosis were related to a shift of cardiac autonomic regulation towards sympathetic predominance in asymptomatic subjects without evidence of myocardial ischemia. PMID- 24343835 TI - Effects of protein in combination with carbohydrate supplements on acute or repeat endurance exercise performance: a systematic review. AB - BACKGROUND: Protein supplements are consumed frequently by athletes and recreationally active adults for various reasons, including improved exercise performance and recovery after exercise. Yet, far too often, the decision to purchase and consume protein supplements is based on marketing claims rather than available evidence-based research. OBJECTIVE: The purpose of this review was to provide a systematic and comprehensive analysis of the literature that tested the hypothesis that protein supplements, when combined with carbohydrate, directly enhance endurance performance by sparing muscle glycogen during exercise and increasing the rate of glycogen restoration during recovery. The analysis was used to create evidence statements based on an accepted strength of recommendation taxonomy. DATA SOURCES: English language articles were searched with PubMed and Google Scholar using protein and supplements together with performance, exercise, competition, and muscle, alone or in combination as keywords. Additional articles were retrieved from reference lists found in these papers. STUDY SELECTION: Inclusion criteria specified recruiting healthy active adults less than 50 years of age and evaluating the effects of protein supplements in combination with carbohydrate on endurance performance metrics such as time-to-exhaustion, time-trial, or total power output during sprint intervals. The literature search identified 28 articles, of which 26 incorporated test metrics that permitted exclusive categorization into one of the following sections: ingestion during an acute bout of exercise (n = 11) and ingestion during and after exercise to affect subsequent endurance performance (n = 15). The remaining two articles contained performance metrics that spanned both categories. STUDY APPRAISAL AND SYNTHESIS METHODS: All papers were read in detail and searched for experimental design confounders such as energy content of the supplements, dietary control, use of trained or untrained participants, number of subjects recruited, direct measures of muscle glycogen utilization and restoration, and the sensitivity of the test metrics to explain the discrepant findings. RESULTS: Our evidence statements assert that when carbohydrate supplementation was delivered at optimal rates during or after exercise, protein supplements provided no further ergogenic effect, regardless of the performance metric used. In addition, the limited data available suggested recovery of muscle glycogen stores together with subsequent rate of utilization during exercise is not related to the potential ergogenic effect of protein supplements. LIMITATIONS: Many studies lacked ability to measure direct effects of protein supplementation on muscle metabolism through determination of muscle glycogen, kinetic assessments of protein turnover, or changes in key signaling proteins, and therefore could not substantiate changes in rates of synthesis or degradation of protein. As a result, the interpretation of their data was often biased and inconclusive since they lacked ability to test the proposed underlying mechanism of action. CONCLUSIONS: When carbohydrate is delivered at optimal rates during or after endurance exercise, protein supplements appear to have no direct endurance performance enhancing effect. PMID- 24343836 TI - Agomelatine versus other antidepressive agents for major depression. AB - BACKGROUND: Major depressive disorder (MDD), or depression, is a syndrome characterised by a number of behavioural, cognitive and emotional features. It is most commonly associated with a sad or depressed mood, a reduced capacity to feel pleasure, feelings of hopelessness, loss of energy, altered sleep patterns, weight fluctuations, difficulty in concentrating and suicidal ideation. There is a need for more effective and better tolerated antidepressants to combat this condition. Agomelatine was recently added to the list of available antidepressant drugs; it is a novel antidepressant that works on melatonergic (MT1 and MT2), 5 HT 2B and 5-HT2C receptors. Because the mechanism of action is claimed to be novel, it may provide a useful, alternative pharmacological strategy to existing antidepressant drugs. OBJECTIVES: The objective of this review was 1) to determine the efficacy of agomelatine in alleviating acute symptoms of major depressive disorder in comparison with other antidepressants, 2) to review the acceptability of agomelatine in comparison with other antidepressant drugs, and, 3) to investigate the adverse effects of agomelatine, including the general prevalence of side effects in adults. SEARCH METHODS: We searched the Cochrane Collaboration's Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR) to 31 July 2013. The CCDANCTR includes relevant randomised controlled trials from the following bibliographic databases: CENTRAL (the Cochrane Central Register of Controlled Trials) (all years), EMBASE (1974 onwards), MEDLINE (1950 onwards) and PsycINFO (1967 onwards). We checked reference lists of relevant studies together with reviews and regulatory agency reports. No restrictions on date, language or publication status were applied to the search. Servier Laboratories (developers of agomelatine) and other experts in the field were contacted for supplemental data. SELECTION CRITERIA: Randomised controlled trials allocating adult participants with major depression to agomelatine versus any other antidepressive agent. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and a double-entry procedure was employed. Information extracted included study characteristics, participant characteristics, intervention details and outcome measures in terms of efficacy, acceptability and tolerability. MAIN RESULTS: A total of 13 studies (4495 participants) were included in this review. Agomelatine was compared to selective serotonin reuptake inhibitors (SSRIs), namely paroxetine, fluoxetine, sertraline, escitalopram, and to the serotonin-norepinephrine reuptake inhibitor (SNRI), venlafaxine. Participants were followed up for six to 12 weeks. Agomelatine did not show any advantage or disadvantage over the other antidepressants for our primary outcome, response to treatment (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.95 to 1.08, P value 0.75 compared to SSRIs, and RR 1.06; 95% CI 0.98 to 1.16, P value 0.16 compared to venlafaxine). Also, agomelatine showed no advantage or disadvantage over other antidepressants for remission (RR 0.83; 95% CI 0.68 to 1.01, P value 0.07 compared to SSRIs, and RR 1.08; 95% CI 0.94 to 1.24, P value 0.73 compared to venlafaxine). Overall, agomelatine appeared to be better tolerated than venlafaxine in terms of lower rates of drop outs (RR 0.40; 95% CI 0.24 to 0.67, P value 0.0005), and showed the same level of tolerability as SSRIs (RR 0.95; 95% CI 0.83 to 1.09, P value 0.44). Agomelatine induced a lower rate of dizziness than venlafaxine (RR 0.19, 95% CI 0.06 to 0.64, P value 0.007).With regard to the quality of the body of evidence, there was a moderate risk of bias for all outcomes, due to the number of included unpublished studies. There was some heterogeneity, particularly between published and unpublished studies. The included studies were conducted in inpatient and outpatient settings, thus limiting the generalisability of the results to primary care settings. With regard to precision, the efficacy outcomes were precise, but the tolerability outcomes were mostly imprecise. Publication bias was variable and depended on the outcome of the trial. Our review included unpublished studies, and we think that this reduced the impact of publication bias. The overall methodological quality of the studies was not very good. Almost all of the studies were sponsored by the pharmaceutical company that manufactures agomelatine (Servier), and some of these were unpublished. Attempts to contact the pharmaceutical company Servier for additional information on all unpublished studies were unsuccessful. AUTHORS' CONCLUSIONS: Agomelatine did not seem to provide a significant advantage in efficacy over other antidepressive agents for the acute-phase treatment of major depression. Agomelatine was better tolerated than paroxetine and venlafaxine in terms of overall side effects, and fewer participants treated with agomelatine dropped out of the trials due to side effects compared to sertraline and venlafaxine, but data were limited because the number of included studies was small. We found evidence that compared agomelatine with only a small number of other active antidepressive agents, and there were only a few trials for each comparison, which limits the generalisability of the results. Moreover, the overall methodological quality of the studies was low, and, therefore, no firm conclusions can be drawn concerning the efficacy and tolerability of agomelatine. PMID- 24343838 TI - Electron transfer reactions of ruthenium(II)-bipyridine complexes carrying tyrosine moiety with quinones. AB - Three ruthenium(II)-bipyridine complexes carrying a tyrosine moiety were synthesized and photophysical and electron transfer studies with quinones were carried out using absorption and emission spectral techniques. The binding efficiency of quinones with ruthenium(II)-bipyridine complexes was also studied using these techniques. The binding efficiency was moderate and similar for all complexes with all quinones. The quenching modes were also similar and efficient for all complexes with all quinones. The quenching processes were diffusion controlled. The rate of electron transfer was calculated using semiclassical theory. PMID- 24343837 TI - Surgical anatomy imaging associated with cervical cancer treatment: A cadaveric study. AB - The objectives of this study were to visualize the surgical anatomical structures in the female pelvis by computed tomography and to investigate the components of the parametrium for anatomical education, radiological diagnosis, and surgical simulation. We surgically dissected fresh female cadavers maintained in precise surgical anatomic positions and examined the anatomical structures using experimental fine cell detector multislice computed tomography (FDCT) with a slice thickness of 0.3125 mm. In addition, we established a three-dimensional (3D) reconstruction model for precise observation of the surgical anatomy using Materialise's Interactive Medical Image Control System (Mimics). We evaluated two dimensional (2D) images of the surgical anatomical structures in combination with the 3D reconstruction model. The 3D model was reconstructed from 430 serial axial pelvic CT images of a cadaver. The cardinal ligament, uterosacral ligament, paravesical space, and pararectal space were visualized on the CT images obtained from the surgically dissected part. The parametrium components were clearly distinguished on the surgically dissected side. Based on the information from the dissected side, these components on the undissected side could be distinguished as well. We recognized the parametrium components in the area extirpated during radical hysterectomy. The approach using cadavers, experimental FDCT, and 3D software provided excellent visualization of pelvic structures. High-quality images of surgical anatomical structures provide new insight regarding precise surgical anatomy in the female pelvis. The radiological information has practical usefulness for radiotherapeutic planning and surgical simulation. PMID- 24343839 TI - Antidyslipidemic effect and antioxidant activity of anthraquinone derivatives from Rheum emodi rhizomes in dyslipidemic rats. AB - The aim of the present study was to evaluate the antidyslipidemic effect of ethanolic extract of Rheum emodi rhizomes and its constituents in Triton-WR-1339 and high-fat diet (HFD)-induced dyslipidemic rats. In preliminary screening, the ethanolic extract showed significant activity in Triton-treated rats. Bioassay guided fractionation of the ethanolic extract resulted in the identification of four anthraquinone derivatives, viz. chrysophanol, emodin, chrysophanol 8-O-beta D-glucopyranoside and emodin 8-O-beta-D-glucopyranoside as active constituents. All these compounds significantly reduced plasma lipid levels. The most active compound emodin showed significant lipid-lowering activity in the HFD-fed model. In addition, these compounds showed significant antioxidant activity. The effect of emodin on enzymes modulating lipid metabolism confirms and supports the efficiency of emodin as a potent antidyslipidemic agent. PMID- 24343840 TI - Comparison between T1 relaxation time of Gd-EOB-DTPA-enhanced MRI and liver stiffness measurement of ultrasound elastography in the evaluation of cirrhotic liver. AB - PURPOSE: To compare four imaging approaches in cirrhotic estimation; pre enhancement T1 relaxation time (T1RT), reduction rate (RR) of T1RT, signal-based liver-to-muscle ratio (L/M ratio) on gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI), and liver stiffness measurement (LSM) of US elastography. MATERIALS AND METHODS: Consecutive 58 patients with chronic liver diseases who underwent both Gd-EOB-DTPA-enhanced MRI and FibroScan were analyzed. Four imaging approaches were evaluated by fibrosis score from liver biopsy and receiver operating characteristic (ROC) analysis. RESULTS: RR was found to be inversely correlated with LSM (r = -0.65). RR decreased with degree of fibrosis (F0-F1, 58.5 +/- 6.2%, versus F2-F3-F4, 48.8 +/- 11.7%, P = 0.010, F0-F1-F2, 58.2 +/- 6.2% versus F3-F4, 45.5 +/- 12.3%, P = 0.010 and F0-F1, 58.5 +/- 6.2%, versus F2 F3, 52.1 +/- 12.0%, P = 0.0038). LSM increased with degree of fibrosis (F0-F1, 5.4 +/- 2.2 kPa versus F2-F3-F3, 19.3 +/- 15.5 kPa, P = 0.0011 and F0-F1-F2, 6.8 +/- 3.6 kPa versus F3-F4, 23.8 +/- 17.1 kPa, P = 0.0029 and F0-F1, 5.4 +/- 2.2 kPa, versus F2-F3, 11.4 +/- 7.2 kPa, P = 0.0098). Area under ROC curves were 0.83 (F3-F4), 0.72 (F2-F3-F4), 0.68 (F2-F3) for RR and 0.83 (F3-F4), 0.88 (F2-F3-F4), 0.81 (F2-F3) for LSM in discriminating between patients with fibrosis. CONCLUSION: The capability by LSM was better than those by RR of T1RT, pre enhancement T1RT, and L/M ratio to differentiate F >= 2, but LSM and RR of T1RT showed the same value to differentiate F >= 3. PMID- 24343841 TI - Lamotrigine use in patients with binge eating and purging, significant affect dysregulation, and poor impulse control. AB - OBJECTIVE: Some patients with symptoms of binge eating and purging are successfully treated with specific serotonin reuptake inhibitors (SSRIs), but others experience only partial or no benefit. Significant affect dysregulation and poor impulse control may be characteristics that limit responsiveness. METHOD: We report on the treatment of five patients with bulimia nervosa (BN), anorexia nervosa-binge/purge type (AN-B/P) or eating disorder not otherwise specified (EDNOS), using the anticonvulsant lamotrigine after inadequate response to SSRIs. RESULTS: Following addition of lamotrigine to an antidepressant in four cases, and switch from an antidepressant to lamotrigine in one case, patients experienced substantial improvement in mood reactivity and instability, impulsive drives and behaviors, and eating-disordered symptoms. DISCUSSION: These findings raise the possibility that lamotrigine, either as monotherapy or as an augmenting agent to antidepressants, may be useful in patients who binge eat and purge, and have significant affect dysregulation with poor impulse control. PMID- 24343842 TI - From cooperation to combat: adverse effect of thermal stress in a symbiotic coral crustacean community. AB - Although mutualisms are ubiquitous in nature, our understanding of the potential impacts of climate change on these important ecological interactions is deficient. Here, we report on a thermal stress-related shift from cooperation to antagonism between members of a mutualistic coral-dwelling community. Increased mortality of coral-defending crustacean symbionts Trapezia cymodoce (coral crab) and Alpheus lottini (snapping shrimp) was observed in response to experimentally elevated temperatures and reduced coral-host (Pocillopora damicornis) condition. However, strong differential numerical effects occurred among crustaceans as a function of species and sex, with shrimp (75%), and female crabs (55%), exhibiting the fastest and greatest declines in numbers. These declines were due to forceful eviction from the coral-host by male crabs. Furthermore, surviving female crabs were impacted by a dramatic decline (85%) in egg production, which could have deleterious consequences for population sustainability. Our results suggest that elevated temperature switches the fundamental nature of this interaction from cooperation to competition, leading to asymmetrical effects on species and/or sexes. Our study illustrates the importance of evaluating not only individual responses to climate change, but also potentially fragile interactions within and among susceptible species. PMID- 24343843 TI - Associations between cigarette smoking, hormone therapy, and folate intake with incident colorectal cancer by TP53 protein expression level in a population-based cohort of older women. AB - Cigarette smoking (CS), hormone therapy (HT), and folate intake (FI) are each thought to influence colorectal cancer risk, but the underlying molecular mechanisms remain incompletely defined. The TP53 (p53) protein, encoded by the TP53 tumor-suppressor gene that is commonly mutated in colorectal cancer, can be readily assessed to differentiate biologically distinct colorectal cancer subtypes. In this prospective cohort study, we examined CS-, HT-, and FI associated colorectal cancer risks by TP53 protein expression level among Iowa Women's Health Study (IWHS) participants. The IWHS recruited 41,836 randomly selected Iowa women, ages 55 to 69 years, with a valid driver's license at study entry in 1986. Self-reported exposure variables were assessed at baseline. Incident colorectal cancer cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected and evaluated for TP53 protein expression by immunohistochemistry. Multivariate Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI) for associations between CS, HT, or FI and TP53-defined colorectal cancer subtypes. Informative environmental exposure and protein expression data were available for 492 incident colorectal cancer cases: 222 (45.1%) TP53 negative, 72 (14.6%) TP53 low, and 198 (40.2%) TP53 high. Longer duration (>5 years) of HT was inversely associated with TP53 high colorectal cancers (RR, 0.50; 95% CI, 0.27-0.94). No other statistically significant associations were observed. These data support possible heterogeneous effects from HT on TP53 related pathways of colorectal carcinogenesis in older women. PMID- 24343844 TI - The association between dietary omega-3 fatty acids and cardiovascular death: the Singapore Chinese Health Study. AB - BACKGROUND: Although studies suggest that omega-3 fatty acids intake may reduce cardiovascular disease (CVD) mortality risk, few studies have differentiated dietary eicosapentaenoic/docosahexaenoic acid (EPA/DHA) from alpha-linolenic acid (ALA), and epidemiological research in Asian populations is limited. METHODS: The Singapore Chinese Health Study is a population-based cohort that recruited 63,257 Chinese adults aged 45-74 years from 1993 to 1998. Usual diet was measured at recruitment using a validated semiquantitative food-frequency questionnaire, and mortality information was identified via registry linkage up to 31 December 2011. Cox proportional hazard models were used to calculate hazard ratios (HRs) with adjustment for potential confounders. RESULTS: We documented 4780 cardiovascular deaths (including 2697 coronary heart disease (CHD) deaths and 1298 stroke deaths) during 890,473 person-years of follow up. Omega-3 fatty acids intake was monotonically associated with reduced risk of cardiovascular mortality. Compared to the lowest quartile, the HR was 0.88 (95% confidence interval, CI, 0.81-0.96), 0.88 (95% CI 0.80-0.97), and 0.83 (95% CI 0.74-0.92) for the second, third, and highest quartile, respectively (p-trend = 0.003). Both EPA/DHA and ALA were independently associated with reduced risk of cardiovascular mortality: HR comparing extreme quartiles was 0.86 (95% CI 0.77-0.96, p-trend = 0.002) and 0.81 (95% CI 0.73-0.90, p-trend < 0.001), respectively. The associations were similar for deaths from CHD and stroke and persisted in participants who were free of CVD at baseline. CONCLUSIONS: Higher intakes of marine (EPA/DHA) and plant (ALA) omega-3 fatty acids are both associated with reduced risk of cardiovascular mortality in a Chinese population. PMID- 24343850 TI - Pigmentary traits, family history of melanoma and the risk of endometriosis: a cohort study of US women. AB - BACKGROUND: Endometriosis has been associated with a higher risk of cutaneous melanoma, but the mechanisms underlying this association are unknown.Some constitutional factors known to influence melanoma risk have been associated with endometriosis in some retrospective studies. However, prospective data are scarce, and more research is needed to confirm this potentially novel endometriosis risk profile. METHODS: To investigate the relationships between pigmentary traits, family history of melanoma and endometriosis risk, we analysed data from the Nurses' Health Study II, a cohort of 116 430 female US nurses aged 25-42 years at inclusion in 1989. Data were collected every 2 years with 20 years of follow-up for these analyses. We used Cox proportional hazards regression models to compute relative risks(RRs) and 95% confidence intervals (CIs). RESULTS: During 1 212 499 woman-years of follow-up, 4763 cases of laparoscopically-confirmed endometriosis were reported among premenopausal Caucasian women. Endometriosis risk was increased with presence of naevi on the lower legs (RR=1.08, 95% CI=1.021.14) and higher level of skin's burning reaction to sun exposure in childhood/adolescence ('burn with blisters': RR=1.20,95% CI=1.061.36) compared with 'practically none';P(trend)=0.0006) and family history of melanoma (RR=1.13, 95%CI=1.011.26). CONCLUSION: This assessment reports modest associations between several pigmentary traits, family history of melanoma and endometriosis risk,corroborating the results from previous retrospective studies. Our findings call for further research to better understand the mechanisms under lying these associations. PMID- 24343851 TI - Impaired hyperemic myocardial blood flow is associated with inducibility of ventricular arrhythmia in ischemic cardiomyopathy. AB - BACKGROUND: Risk stratification for ventricular arrhythmias (VAs) is important to refine selection criteria for primary prevention implantable cardioverter defibrillator therapy. Impaired hyperemic myocardial blood flow (MBF) is associated with increased mortality rate in ischemic and nonischemic cardiomyopathy, which may be attributed to electric instability inducing VAs. The aim of this pilot study was to assess whether hyperemic MBF impairment may be related with VA inducibility in patients with ischemic cardiomyopathy. METHODS AND RESULTS: Thirty patients with ischemic cardiomyopathy referred for primary prevention implantable cardioverter defibrillator implantation were prospectively included (26 men; 65+/-8 years old; left ventricular ejection fraction, 29+/-6%). [15O]H2O positron-emission tomography was performed to quantify resting MBF, hyperemic MBF, and coronary flow reserve. Left ventricular dimensions, function, and scar burden were assessed with cardiovascular magnetic resonance imaging. An electrophysiological study was performed to test VA inducibility. Positive electrophysiological study patients (n=12) showed reduced hyperemic MBF (1.25+/ 0.30 versus 1.66+/-0.38 mL.min(-1).g(-1); P<0.01) and coronary flow reserve (1.59+/-0.49 versus 2.12+/-0.48; P<0.01) compared with electrophysiological study negative patients (n=18). In electrophysiological study positive patients, the number of scar segments>75% transmurality was higher (P<0.05), although scar size and border zone did not differ. Receiver-operating characteristic curve analysis indicated that impaired hyperemic MBF (area under the curve, 0.84; 95% confidence intervals [0.69-0.99]) and coronary flow reserve (area under the curve, 0.77; 95% confidence intervals [0.57-0.96]) were associated with VA inducibility. CONCLUSIONS: In this pilot study, impaired hyperemic MBF and coronary flow reserve were associated with VA inducibility in patients with ischemic cardiomyopathy. These results are hypothesis generating for a potential role of quantitative positron-emission tomography perfusion imaging in risk stratification for VAs. PMID- 24343852 TI - The effect of age and educational level on the cognitive processes used to comprehend the meaning of pictograms. AB - BACKGROUND AND AIMS: Pictograms, designed to be a universal communication system, are often created from several concrete and easily recognizable drawings. Does understanding depend on a logical approach? Or is it the ability to inhibit the concrete sense of each picture that allows access to a higher level of comprehension? (ability to abstract). These executive functions are sensitive to the effects of aging and educational level. The aim of our study was to evaluate the nature of the cognitive processes underlying the meaning of pictograms and to test the effect of aging and educational level. METHODS: We enrolled 19 older adults (60-69 years old) and 63 young adults (20-29 years old). Of these 63 young adults, 43 had a high educational level (Young-High participants), and 20 had a lower educational level (Young-Low participants). Each participant was asked the meaning of 20 pictograms and underwent an assessment of abstraction and logical abilities with WAIS-III test. RESULTS: Older adults had lower pictogram assessment scores and abstraction and logical abilities when compared with young adults. In both groups, abstraction and logical abilities were correlated with the interpretation of pictograms but only abstraction ability remains strongly correlated with pictogram comprehension in the older group after adjustment of sex, age and educational level. Consequently, the poorer performances of older adults to determine the meaning of pictograms could be explained by the decline of abstraction ability in elderly. CONCLUSIONS: Pictograms are not the universal communication system as we formerly thought. Age and educational level may influence the performance in determining the meaning of pictograms. PMID- 24343853 TI - E-learning to improve the drug prescribing in the hospitalized elderly patients: the ELICADHE feasibility pilot study. AB - BACKGROUND: E-learning is an efficient and cost-effective educational method. AIMS: This study aimed at evaluating the feasibility of an educational e-learning intervention, focused on teaching geriatric pharmacology and notions of comprehensive geriatric assessment, to improve drug prescribing to hospitalized elderly patients. METHODS: Eight geriatric and internal medicine wards were randomized to intervention (e-learning educational program) or control. Clinicians of the two groups had to complete a specific per group e-learning program in 30 days. Then, ten patients (aged >=75 years) had to be consecutively enrolled collecting clinical data at hospital admission, discharge, and 3 months later. The quality of prescription was evaluated comparing the prevalence of potentially inappropriate medications through Beer's criteria and of potential drug-drug interactions through a specific computerized database. RESULTS: The study feasibility was confirmed by the high percentage (90 %) of clinicians who completed the e-learning program, the recruitment, and follow-up of all planned patients. The intervention was well accepted by all participating clinicians who judged positively (a mean score of >3 points on a scale of 5 points: 0 = useless; 5 = most useful) the specific contents, the methodology applied, the clinical relevance and utility of e-learning contents and tools for the evaluation of the appropriateness of drug prescribing. CONCLUSIONS: The pilot study met all the requested goals. The main study is currently ongoing and is planned to finish on July 2015. PMID- 24343854 TI - Age-associated aberrations in mouse cellular and humoral immune responses. AB - BACKGROUND AND AIMS: Several contradictions and inconsistent reports regarding nature of dysfunction of immune system with age are known. The lack of multipoint age comparisons in immune functions contributes to the observed ambiguity in understanding immunosenescence. Thus, the present study aimed at a concurrent analysis of different immune cells in an attempt to delineate the nature of dysregulation with progressive aging in mice. METHODS: 4, 8, 12 and 16 months old mice were analyzed for various immune parameters involving neutrophils, peripheral blood lymphocytes, peritoneal macrophages, splenocytes, inflamm-aging markers in plasma and humoral immune response in intestine. RESULTS: Neutrophils registered a remarkable decrease in activities of respiratory burst enzymes and phagocytosis, while macrophages recorded a decrease in TLR-2 and TLR-4 expression. MCP-1 and CRP levels increased in plasma, whereas stimulation index and CD28 expression decreased in lymphocytes. Interleukins analysis (IFN-gamma, IL-4, IL-10) showed a remarkable shift towards Th2 response which further resulted in increased IgG1/IgG2a ratio and IgE levels in intestine. CONCLUSION: A decline in cell-mediated immune response, chronic inflammation and aggravation of humoral immunity was evident which conclusively suggests a skewed Th2 pathway during aging. PMID- 24343855 TI - Antibacterial agents in composite restorations for the prevention of dental caries. AB - BACKGROUND: Dental caries is a multifactorial disease in which the fermentation of food sugars by bacteria from the biofilm (dental plaque) leads to localised demineralisation of tooth surfaces, which may ultimately result in cavity formation. Resin composites are widely used in dentistry to restore teeth. These restorations can fail for a number of reasons, such as secondary caries, and restorative material fracture and other minor reasons. From these, secondary caries, which are caries lesions developed adjacent to restorations, is the main cause for restorations replacement. The presence of antibacterials in both the filling material and the bonding systems would theoretically be able to affect the initiation and progression of caries adjacent to restorations. This is an update of the Cochrane review published in 2009. OBJECTIVES: To assess the effects of antibacterial agents incorporated into composite restorations for the prevention of dental caries. SEARCH METHODS: We searched the following electronic databases: the Cochrane Oral Health Group's Trials Register (to 23 July 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 6), MEDLINE via OVID (1946 to 23 July 2013) and EMBASE via OVID (1980 to 23 July 2013). We searched the US National Institutes of Health Trials Register (http://clinicaltrials.gov), the metaRegister of Controlled Trials (www.controlled-trials.com) and the World Health Organization International Clinical Trials Registry platform (www.who.int/trialsearch) for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: Randomised controlled trials comparing resin composite restorations containing antibacterial agents with composite restorations not containing antibacterial agents. DATA COLLECTION AND ANALYSIS: Two review authors conducted screening of studies in duplicate and independently, and although no eligible trials were identified, the two authors had planned to extract data independently and assess trial quality using standard Cochrane Collaboration methodologies. MAIN RESULTS: We retrieved 308 references to studies, none of which matched the inclusion criteria for this review and all of which were excluded. AUTHORS' CONCLUSIONS: We were unable to identify any randomised controlled trials on the effects of antibacterial agents incorporated into composite restorations for the prevention of dental caries. The absence of high level evidence for the effectiveness of this intervention emphasises the need for well designed, adequately powered, randomised controlled clinical trials. Thus, conclusions remain the same as the previously published review, with no included clinical trials. PMID- 24343856 TI - Condylar process contributes to mandibular asymmetry: In vivo 3D MRI study. AB - The purpose of this study was to investigate the differences in mandibular morphology between the deviated and nondeviated sides in patients with noncongenital skeletal mandibular asymmetry. Divergences from control values were assessed to determine which region of the mandible contributes most to mandibular asymmetry. We measured various dimensions of the mandible in 20 young patients and 20 controls using noninvasive high-quality three-dimensional (3D) volumetric magnetic resonance imaging. Mandibular dimensions including the length of the condylar process were significantly greater on the nondeviated side of patients than the deviated side. Measurements of the deviated side were similar to control values, but measurements of the nondeviated side including condylar process length differed significantly from control values. These findings strongly suggest that overgrowth of the condylar process on the nondeviated side in these patients results in mandibular asymmetry, and therefore needs attention in orthodontic treatment, orthognathic surgery, and follow-up. PMID- 24343857 TI - Asymmetric consequences of host plant occupation on the competition between the whiteflies Bemisia tabaci cryptic species MEAM1 and Trialeurodes vaporariorum (Hemiptera: Aleyrodidae). AB - BACKGROUND: The two common whitefly species, Bemisia tabaci (Gennadius) MEAM1 and Trialeurodes vaporariorum (Westwood), often co-occur on their host plants. The effect of host plant occupation by one species on later-arriving conspecific individuals or on the other competing species was examined. RESULTS: Resource preoccupied by T. vaporariorum had mostly negative effects on the life history parameters of later-arriving conspecifics. Red-eyed nymph and immature survival of T. vaporariorum decreased when resource was preoccupied by conspecifics, irrespective of the previous occupation scenario. However, resource preoccupied by T. vaporariorum had only minor detrimental effects on the performance of later arriving B. tabaci MEAM1. In the opposite colonisation sequence, previous occupation by B. tabaci MEAM1 had no significant effects on the life history parameters of later-arriving conspecifics, but severe detrimental effects were observed on the performance of later-arriving T. vaporariorum. Total immature survival of T. vaporariorum decreased in both weak and strong previous occupation situations by B. tabaci MEAM1. CONCLUSION: The interspecific interactions between B. tabaci MEAM1 and T. vaporariorum were asymmetric, with B. tabaci MEAM1 being the superior competitor. This superiority could partially explain the rapid spread of B. tabaci MEAM1 in China. PMID- 24343858 TI - Respiratory-gated noncontrast SPACE MR angiography sequence at 3T for evaluation of the central veins of the chest: a feasibility study. AB - PURPOSE: To evaluate the feasibility of a respiratory-gated noncontrast magnetic resonance angiography (MRA) sequence for imaging the central veins of the chest. MATERIALS AND METHODS: Eleven healthy subjects underwent MRA of the central veins of the chest with a respiratory-gated noncontrast (SPACE) sequence. Qualitative visualization and signal homogeneity of each central venous segment were scored by two radiologists on a scale of 1-4. Signal-to-noise and contrast-to-noise ratios (SNR and CNR) were also calculated. Retrospective review of our imaging database revealed 13 patients with suspected pathology of the central veins who underwent a clinical MRA examination using the SPACE sequence as well as reference standard central venous imaging with contrast-enhanced MRA or conventional venography. RESULTS: In healthy subjects, all central venous segments demonstrated good to excellent venous visualization and homogeneity scores with the noncontrast SPACE sequence. The mean SNR and CNR of the central venous system were 192.7 and 175.0, respectively. In the 13 clinical examinations, the sensitivity and specificity for detection of stenosis or occlusions was 100% and 100% for reader 1 and 95% and 91% for reader 2, respectively. CONCLUSION: The respiratory-gated noncontrast SPACE sequence provided excellent imaging characteristics of the central veins in healthy subjects with promising diagnostic accuracy in patients with central venous pathology. PMID- 24343859 TI - Bayesian sequential meta-analysis design in evaluating cardiovascular risk in a new antidiabetic drug development program. AB - Recently, the Center for Drug Evaluation and Research at the Food and Drug Administration released a guidance that makes recommendations about how to demonstrate that a new antidiabetic therapy to treat type 2 diabetes is not associated with an unacceptable increase in cardiovascular risk. One of the recommendations from the guidance is that phases II and III trials should be appropriately designed and conducted so that a meta-analysis can be performed. In addition, the guidance implies that a sequential meta-analysis strategy could be adopted. That is, the initial meta-analysis could aim at demonstrating the upper bound of a 95% confidence interval (CI) for the estimated hazard ratio to be < 1.8 for the purpose of enabling a new drug application or a biologics license application. Subsequently after the marketing authorization, a final meta analysis would need to show the upper bound to be < 1.3. In this context, we develop a new Bayesian sequential meta-analysis approach using survival regression models to assess whether the size of a clinical development program is adequate to evaluate a particular safety endpoint. We propose a Bayesian sample size determination methodology for sequential meta-analysis clinical trial design with a focus on controlling the familywise type I error rate and power. We use the partial borrowing power prior to incorporate the historical survival meta data into the Bayesian design. We examine various properties of the proposed methodology, and simulation-based computational algorithms are developed to generate predictive data at various interim analyses, sample from the posterior distributions, and compute various quantities such as the power and the type I error in the Bayesian sequential meta-analysis trial design. We apply the proposed methodology to the design of a hypothetical antidiabetic drug development program for evaluating cardiovascular risk. PMID- 24343860 TI - Prospects for analyzing ancient RNA in preserved materials. AB - An ever increasing wealth of ancient biological material is providing opportunities to study biomolecules. Animal, plant, and microbial samples dating back hundreds, thousands, and even millions of years have been preserved in a dry state under climatic conditions ranging from the arctic to hot deserts. Various small molecules, often crystalized or polymerized, have improved preservation. Modern methods such as polymerase chain reaction (PCR), mass spectrometry, and shotgun sequencing have detected and characterized ancient biomolecules. Modern sequencing has the capacity not only to assemble the whole genome of the target host but also those of the host's parasites, mutualists, and commensals. The study of ancient RNA has barely begun. Several studies show that RNA has been preserved for decades to hundreds of years and the germination of ancient seeds implies that messenger RNA can be preserved for thousands of years. This review briefly examines the types of ancient materials available and assesses their suitability for the study of ancient RNA. Sequencing RNA from this material has the potential not only to illuminate the target host's transcriptome and small RNAs but also to characterize the host's RNA parasites: viruses and viroids. PMID- 24343861 TI - IRES mediated translational regulation of p53 isoforms. AB - p53 is a well known tumor suppressor protein that plays a critical role in cell cycle arrest and apoptosis. It has several isoforms which are produced by transcriptional and posttranscriptional regulatory mechanisms. p53 mRNA has been demonstrated to be translated into two isoforms, full-length p53 (FL-p53) and a truncated isoform DeltaN-p53 by the use of alternative translation initiation sites. The mechanism of translation regulation of these two isoforms was further elucidated by the discovery of IRES elements in the p53 mRNA. These two IRESs were shown to regulate the translation of p53 and DeltaN-p53 in a distinct cell cycle phase-dependent manner. This review focuses on the current understanding of the regulation of p53 IRES mediated translation and the role of cis and trans acting factors that influence expression of p53 isoforms. PMID- 24343864 TI - Fast hemicellulose quantification via a simple one-step acid hydrolysis. AB - As the second most common polysaccharides in nature, hemicellulose has received much attention in recent years for its importance in biomass conversion in terms of producing high yields of fermentable sugars and value-added products, as well as its role in reducing biomass recalcitrance. Therefore, a time and labor efficient method that specifically analyzes hemicellulose content would be valuable to facilitate the screening of biomass feedstocks. In this study, a one step acid hydrolysis method was developed, which applied 4 wt% sulfuric acid at 121 degrees C for 1 h to rapidly quantify XGM (xylan + galactan + mannan) contents in various types of lignocellulosic biomass and model hemicelluloses. This method gave statistically identical results in XGM contents compared to results from conventional two-step acid hydrolysis while significantly shortening analysis time. PMID- 24343863 TI - Simple diagnosis of STAT1 gain-of-function alleles in patients with chronic mucocutaneous candidiasis. AB - CMCD is a rare congenital disorder characterized by persistent or recurrent skin, nail, and mucosal membrane infections caused by Candida albicans. Heterozygous GOF STAT1 mutations have been shown to confer AD CMCD as a result of impaired dephosphorylation of STAT1. We aimed to identify and characterize STAT1 mutations in CMCD patients and to develop a simple diagnostic assay of CMCD. Genetic analysis of STAT1 was performed in patients and their relatives. The mutations identified were characterized by immunoblot and reporter assay using transient gene expression experiments. Patients' leukocytes are investigated by flow cytometry and immunoblot. Six GOF mutations were identified, three of which are reported for the first time, that affect the CCD and DBD of STAT1 in two sporadic and four multiplex cases in 10 CMCD patients from Japan. Two of the 10 patients presented with clinical symptoms atypical to CMCD, including other fungal and viral infections, and three patients developed bronchiectasis. Immunoblot analyses of patients' leukocytes showed abnormally high levels of pSTAT1 following IFN-gamma stimulation. Based on this finding, we performed a flow cytometry-based functional analysis of STAT1 GOF alleles using IFN-gamma stimulation and the tyrosine kinase inhibitor, staurosporine. The higher levels of pSTAT1 observed in primary CD14(+) cells from patients compared with control cells persisted and were amplified by the presence of staurosporine. We developed a flow cytometry-based STAT1 functional screening method that would greatly facilitate the diagnosis of CMCD patients with GOF STAT1 mutations. PMID- 24343865 TI - Gross anatomical observations of attachments of the middle pharyngeal constrictor. AB - The pharyngeal muscles overlap each other and some of their parts have different areas of origin. Such arrangements make the interrelationships among pharyngeal muscles complicated. This study investigated the attachments of the middle constrictor to clarify its configuration and re-examine its functions. The gross anatomies of the pharyngeal and neighboring muscles were examined in 41 cadavers. The middle constrictor arose from the stylohyoid ligament and the hyoid bone, and its fibers were divided into three overlapping groups. The anterosuperior group ascended posterosuperiorly from the ligament and the lesser horn and fanned out. The middle group ascended posterosuperiorly from the greater horn and fanned out. The posteroinferior group fanned out from the posterior part of the greater horn, while the middle constrictor arose internally to the hyoglossus; some fibers often passed externally, and their fibers sometimes intersected around the lingual artery, which ran between them. Some fibers attached to the hyoglossus, occasionally to the stylohyoid and the posterior belly of the digastric, but seldom to the lingual artery and the triticeal cartilage in the thyrohyoid ligament. The three groups were inserted into the pharyngeal raphe, and the descending fibers joined the longitudinal pharyngeal muscles. The ascending and descending fibers rarely reached the top of the pharynx and the thyroid cartilage, respectively. The fiber arrangement suggested that, besides constriction of the pharynx, the ascending and descending fibers of the middle constrictor can act as an elevator muscle, and the irregular attachments could affect the functions of the muscles and vessels. PMID- 24343866 TI - Synthesis, double-helix formation, and higher-assembly formation of chiral polycyclic aromatic compounds: conceptual development of polyketide aldol synthesis. AB - Polycyclic aromatic compounds are an important group of substances in chemistry, and the study of their properties is a subject of interest in the development of drugs and materials. We have been conducting studies to develop chiral polycyclic aromatic compounds, i.e., helicenes and equatorenes. These helical molecules showed notable aggregate-forming properties and the capability for chiral recognition exerted by noncovalent bond interactions, which were not observed in compounds with central chirality. Homo- and hetero-double-helix-forming helicene oligomers were developed, and the latter self-assembled to form gels and vesicles. In this article, we describe such hierarchical studies of polycyclic aromatic compounds, which were started from polyketide aldol synthesis. PMID- 24343867 TI - Positively charged nanogold label allows the observation of fine cell filopodia and flagella in solution by atmospheric scanning electron microscopy. AB - Optical microscopy is generally the first choice to observe microbes and cells. However, its resolution is not always sufficient to reveal specific target structures, such as flagella and pili, which are only nanometers wide. ASEM is an attractive higher resolution alternative, as the sample is observed in aqueous solution at atmospheric pressure. Sample pretreatment for ASEM only comprises simple tasks including fixation, gold labeling, and reagent exchange, taking less than 1 h in total. The lengthy sample pretreatments often required for more classical electron microscopies, such as embedding and dehydration, are unnecessary, and native morphology is preserved. In this study, positively charged nanogold particles were used to label the surfaces of bacteria and cultured animal cells, exploiting their net negative surface charge. After gold enhancement to increase the size of the nanogold particles, ASEM imaging of the bacteria in aqueous solution revealed pili and delicate spiral flagella. This natural shape contrasts starkly with images of dried flagella recorded by standard SEM. Positively charged nanogold labeled the plasma membrane of cultured COS7 cells, and after enhancement allowed filopodia as thin as 100 nm in diameter to be clearly visualized. Based on these studies, ASEM combined with positively charged nanogold labeling promises to become an important tool for the study of cell morphology and dynamics in the near future. PMID- 24343868 TI - Bayesian models for cost-effectiveness analysis in the presence of structural zero costs. AB - Bayesian modelling for cost-effectiveness data has received much attention in both the health economics and the statistical literature, in recent years. Cost effectiveness data are characterised by a relatively complex structure of relationships linking a suitable measure of clinical benefit (e.g. quality adjusted life years) and the associated costs. Simplifying assumptions, such as (bivariate) normality of the underlying distributions, are usually not granted, particularly for the cost variable, which is characterised by markedly skewed distributions. In addition, individual-level data sets are often characterised by the presence of structural zeros in the cost variable. Hurdle models can be used to account for the presence of excess zeros in a distribution and have been applied in the context of cost data. We extend their application to cost effectiveness data, defining a full Bayesian specification, which consists of a model for the individual probability of null costs, a marginal model for the costs and a conditional model for the measure of effectiveness (given the observed costs). We presented the model using a working example to describe its main features. PMID- 24343869 TI - CARS based label-free assay for assessment of drugs by monitoring lipid droplets in tumour cells. AB - Coherent anti-Stokes Raman scattering (CARS) is becoming an established tool for label-free multi-photon imaging based on molecule specific vibrations in the sample. The technique has proven to be particularly useful for imaging lipids, which are abundant in cells and tissues, including cytoplasmic lipid droplets (LD), which are recognized as dynamic organelles involved in many cellular functions. The increase in the number of lipid droplets in cells undergoing cell proliferation is a common feature in many neoplastic processes [1] and an increase in LD number also appears to be an early marker of drug-induced cell stress and subsequent apoptosis [3]. In this paper, a CARS-based label-free method is presented to monitor the increase in LD content in HCT116 colon tumour cells treated with the chemotherapeutic drugs Etoposide, Camptothecin and the protein kinase inhibitor Staurosporine. Using CARS, LDs can easily be distinguished from other cell components without the application of fluorescent dyes and provides a label-free non-invasive drug screening assay that could be used not only with cells and tissues ex vivo but potentially also in vivo. PMID- 24343870 TI - An extension of the placebo-based pattern-mixture model. AB - Pattern-mixture models provide a general and flexible framework for sensitivity analyses of nonignorable missing data in longitudinal studies. The placebo-based pattern-mixture model handles missing data in a transparent and clinically interpretable manner. We extend this model to include a sensitivity parameter that characterizes the gradual departure of the missing data mechanism from being missing at random toward being missing not at random under the standard placebo based pattern-mixture model. We derive the treatment effect implied by the extended model. We propose to utilize the primary analysis based on a mixed effects model for repeated measures to draw inference about the treatment effect under the extended placebo-based pattern-mixture model. We use simulation studies to confirm the validity of the proposed method. We apply the proposed method to a clinical study of major depressive disorders. PMID- 24343871 TI - Cutaneous innervation of the ankle: an anatomical study showing danger zones for ankle surgery. AB - Three nerves innervate the skin in the foot and ankle region: the saphenous, sural, and superficial peroneal nerves. Because they are close to the medial and lateral malleoli, these nerves are at significant risk during orthopedic interventions. The aims of this study were to investigate the distal courses of the three cutaneous nerves of the ankle and to determine their exact relationships with easily identifiable bony landmarks. Ten freshly frozen and 40 embalmed lower extremities of adults were dissected. The positions of the superficial peroneal, sural, and saphenous nerves were determined using reference lines based on easily palpable osseous landmarks. The frequencies and distributions of all three nerves and their branches were converted into absolute numbers. A danger zone for each nerve was established on the basis of the distribution of crossings between the nerves and the different reference lines. Determination of the exact orientation of the nerves around the ankle should help minimize the nerve injury rate during surgical approaches in this area. Using this easily translatable new grid system, the course and danger zones of each cutaneous nerve around the ankle can be estimated clinically. PMID- 24343872 TI - Effects of multitasking-training on gray matter structure and resting state neural mechanisms. AB - Multitasking (MT) constitutes engaging in two or more cognitive activities at the same time. MT-training improves performance on untrained MT tasks and alters the functional activity of the brain during MT. However, the effects of MT-training on neural mechanisms beyond MT-related functions are not known. We investigated the effects of 4 weeks of MT-training on regional gray matter volume (rGMV) and functional connectivity during rest (resting-FC) in young human adults. MT training was associated with increased rGMV in three prefrontal cortical regions (left lateral rostral prefrontal cortex (PFC), dorsolateral PFC (DLPFC), and left inferior frontal junction), the left posterior parietal cortex, and the left temporal and lateral occipital areas as well as decreased resting-FC between the right DLPFC and an anatomical cluster around the ventral anterior cingulate cortex (ACC). Our findings suggest that participation in MT-training is as a whole associated with task-irrelevant plasticity (i.e., neural changes are not limited to certain specific task conditions) in regions and the network that are assumed to play roles in MT as well as diverse higher-order cognitive functions. We could not dissociate the effects of each task component and the diverse cognitive processes involved in MT because of the nature of the study, and these remain to be investigated. PMID- 24343873 TI - Novel tacrine analogs as potential cholinesterase inhibitors in Alzheimer's disease. AB - Acetylcholinesterase inhibitors (AChEIs) are used for the treatment of Alzheimer's disease (AD). The increase in ACh levels ameliorates the symptoms of the disease. Tacrine is the first clinically approved drug as AChEI used in the treatment of AD. In this paper, we synthesized new tacrine analogs to act on catalytic and peripheral sites of AChE. Their inhibitory activity was evaluated. All novel compounds except 7a showed promising results toward AChE. Two compounds, 10b and 11b, are more potent than tacrine. Furthermore, molecular modeling studies were performed for these two compounds to rationalize the obtained pharmacological activity. Moreover, various drug-likeness properties of the new compounds were predicted. PMID- 24343874 TI - Shall we crosstalk? - The relationship between DNA methylation and histone H3 lysine 27 trimethylation. PMID- 24343875 TI - Hyperspectral darkfield microscopy of PEGylated gold nanoparticles targeting CD44 expressing cancer cells. AB - We present a new hyperspectral darkfield imaging system with a scanned broadband supercontinuum light source. We observed the specific attachment of the functionalized gold plasmonic nanoparticles (AuNPs) targeting CD44(+) human breast cancer cells by conventional and by proposed hyperspectral darkfield microscopy. This wide-field and low phototoxic hyperspectral imaging system has been successful for performing spectral three-dimensional (3D) localization and spectroscopic identification of CD44-targeted PEGylated AuNPs in fixed cell preparations. Such spatial and spectral information is essential for the improvement of nanoplasmonic-based imaging, disease detection and treatment in complex biological environment. Presented system capability for 3D NP tracking will also enable investigation of specific sub-cellular activity with the use of NPs as spectral sensors. PMID- 24343876 TI - Determination of chromatographic dissociation constants of some carbapenem group antibiotics and quantification of these compounds in human urine. AB - The dissociation constant values (s (s) pKa ) of some carbapenem group drugs (ertapenem, meropenem, doripenem) in different percentages of methanol-water binary mixtures (18, 20 and 22%, v/v) were determined from the mobile phase pH dependence of their retention factor. Evaluation of these data was performed using the NLREG program. From calculated pKa values, the aqueous pKa values of these subtances were calculated by different approaches. Moreover, the correlation established between retention factor and the pH of the water-methanol mobile phase was used to determine the optimum separation conditions. In order to validate the optimized conditions, these drugs were studied in human urine. The chromatographic separation was realized using a Gemini NX C18 column (250 * 4.6 mm i.d., 5 um particles) and UV detector set at 220 and 295 nm. PMID- 24343877 TI - Analysis of cardiac anomalies in VACTERL association. AB - BACKGROUND: Congenital heart disease (CHD) is estimated to affect between 3 and 5% of all newborns. Extra-cardiac malformations are observed in 7 to 50% of patients with CHD. One relatively well-known association that can occur in the context of CHD is VACTERL. Controversy still remains regarding the definition of VATER association and its expansion to VACTERL, the appropriate diagnostic criteria and the overall incidence. METHODS: We conducted a description of a case series to characterize the cardiac findings present in a cohort of patients meeting the criteria for VACTERL association. RESULTS: Forty-six of 220 were eligible for inclusion into the study, 67% (31 of 46) had CHD. The most common CHD was ventricular septal defect, present in 18 of 31 patients (58%). There was no statistically significant association between CHD severity and the presence or absence of other VACTERL component features, specifically anorectal malformation (p = 0.18) or tracheo-esophageal fistula (p = 0.72). CHD presence also did not correlate with the presence of tracheo-esophageal fistula or anorectal malformation. CONCLUSION: Although this study does not, by design, provide further evidence toward the questions of whether CHD is a defining feature of VACTERL association, the frequency of CHD in our cohort does lend support to it being an important medical consideration in patients with VACTERL association. Based on our experience, we strongly recommend a screening echocardiogram to evaluate for CHD in individuals with a potential diagnosis of VACTERL association. PMID- 24343878 TI - Genetic basis of congenital upper limb anomalies: analysis of 487 cases of a specialized clinic. AB - BACKGROUND: Specific data regarding the frequencies of the congenital upper limb anomalies (CULA) according to their etiology are hardly available due to the heterogeneity across classification systems. In this study, we aim at defining the CULA etiology of patients that have been evaluated at the Modena University Hospital's Congenital Hand Malformations multidisciplinary clinic in the years 2004 to 2012. METHODS: Medical records of 487 patients were retrospectively reviewed. On the basis of clinical, anamnestic, and genetic data, the CULA were distributed into two main groups: (1) non-Mendelian etiology, including prenatal exposure, somatic mutations and amniotic bands; and (2) Mendelian etiology, including single gene and genomic/chromosomal diseases. CULA were further grouped according to the embryological damage (formation, separation and growth defects) and to the involved axis (radial, ulnar, central). RESULTS: A Mendelian etiology was diagnosed in 199 patients (40.9%), whereas the remaining 288 cases (59.1%) were described as non-Mendelian. The involvement of the lower limbs, the presence of malformations in other organs and facial dysmorphisms were significantly more represented in the Mendelian cases. The formation defects were significantly more frequent in the non-Mendelian group (p < 0.001), whereas the frequency of separation defects was higher in the Mendelian cases (p = 0.0025). Patients with non-Mendelian etiologies showed a significantly higher frequency of central defects (p = 0.0031). CONCLUSION: The two etiologies differ in terms of patient's clinical features, morphology defect and axis involvement. This data may be helpful to the clinician during the patient's diagnostic workup by indicating the necessity for genetic testing and for determining the anomaly's recurrence risk. PMID- 24343879 TI - Prenatal ultrasound findings observed in the Wolf-Hirschhorn syndrome: data from the registry of congenital malformations in Auvergne. AB - BACKGROUND: Wolf-Hirschhorn syndrome (WHS) is associated with facial dysmorphism including high forehead, high nasal bridge, hypertelorism and severe mental retardation. WHS results from a 4p16.3 deletion. Only a small number of reports have been made on the prenatal ultrasound findings observed in WHS. CASES: Here we report our experience on 10 cases of WHS ascertained prenatally between 1983 and 2009 through the CEMC-Auvergne registry of congenital malformations. CONCLUSION: The assumption that a "Greek warrior helmet" facies is pathognomonic of WHS could lead to misdiagnosis. Other clinical findings such as severe and early onset intrauterine growth retardation, facial dysmorphism (high forehead, high nasal bridge, low-set ears, micrognathia, hypertelorism), atrial or ventricular septal defect, and renal dysplasia should help obstetricians to suspect the diagnosis of WHS prenatally. PMID- 24343880 TI - Complex regional pain syndrome type I of the knee: a systematic literature review. AB - In our Center for Pain Medicine, a group of patients reported to have symptoms possibly attributable to complex regional pain syndrome (CRPS) of only the knee(s). Therefore, this study aimed to investigate whether the literature reports on patients with CRPS type I in the knee(s) alone and, if so, to summarize the reported diagnostics, aetiology and treatment strategies of CRPS of the knee(s). Medline, Embase, Cochrane Library, PubMed and Web of Science were searched for articles focusing on a painful disorder of the knee, most likely CRPS type I. Screening on title and abstract was followed by full-text reading and searching of reference lists to determine the final set of relevant articles. Of the 513 articles identified, 31 met the inclusion criteria. These articles reported on a total of 368 patients diagnosed with CRPS of the knee(s) based on the diagnostic criteria used at the time of publication. Knee surgery, especially arthroscopic surgery, was the most common inciting event in developing CRPS of the knee(s). Various treatment strategies were applied with variable outcomes. In conclusion, the scientific literature does report cases of CRPS type I of only the knee(s). This applies when using the diagnostic criteria prevailing at the time of publication and, obviously for a smaller number of cases, also when using the current Budapest criteria set. Arthroscopic knee surgery is described multiple times as the inciting event. We recommend to include CRPS of the knee in future research on the aetiological mechanisms of and optimal treatment for CRPS. PMID- 24343881 TI - Synthesis and antiproliferative activity of some androstene oximes and their O alkylated derivatives. AB - In order to study the structure-activity relationship with respect to the cytotoxicity of steroidal oximes, several 6E-hydroximino-4-ene steroids and their O-alkylated derivatives were synthesized. The oxime ethers were solidified and purified by preparing their corresponding oxalate salts. The new derivatives as well as some previously synthesized ones were evaluated for in vitro antineoplastic activity against a panel of 60 cancer cell lines at 10 uM. The oximes and oxime ethers were found to have moderate to good antiproliferative activity against various leukemia, colon, melanoma, and renal cancer cell lines. PMID- 24343882 TI - Assessing the survival of Mycobacterium tuberculosis in unembalmed and embalmed human remains. AB - Anatomy and mortuary technical staff faces an ever existing risk of contracting an infectious disease, such as Mycobacterium tuberculosis (MTB), when exposed to human remains. The transfer and handling of a corpse expels air from the lungs of the diseased and this aerosolizes the bacilli. It is for this reason that personal protective equipment and work space precautions such as ultraviolet germicidal irradiation is a necessity. In this study, the authors explore the viability of MTB before and after embalming. Briefly, lung tissue samples, both apical and hilar, were obtained from 20 cadavers whose death certificate indicated MTB as cause of death. The first sample was taken before embalming and second set 3 weeks after embalming. Tissue was deposited into sterile specimen containers and transported for analysis which included Mycobacterium growth indicator tube cultures and polymerase chain reaction. Results demonstrated that both the apical and the perihilar sample tested positive prior to embalming, 36 days after death. After three weeks post-embalming none tested positive. The results demonstrated that MTB can remain viable after death for up to 36 days. This viability extends beyond the documented cases and highlights the need for precautionary measures and standard operating procedures in accordance with occupational health and safety guidelines. PMID- 24343883 TI - Seroprevalence and risk factors for severe fever with thrombocytopenia syndrome virus infection in Jiangsu Province, China, 2011. AB - Severe fever with thrombocytopenia syndrome (SFTS), which is caused by a novel bunyavirus, is an emerging infectious disease in China. In 2011, this new virus was designated as severe fever with thrombocytopenia syndrome virus (SFTSV). The aim of the present study was to determine the seroprevalence and risk factors of SFTSV infection. The investigation was conducted among the general population in Jiangsu Province, China in 2011. A total of 2,510 serum samples were collected. Testing by enzyme-linked immunosorbent assay was conducted to determine the seroprevalence of SFTSV infection. Result showed that the overall seroprevalence of SFTSV infection was 0.44% (11 of 2,510) in seven counties in Jiangsu Province. Multiple variable logistic regression analysis showed that raising goats, farming, and grazing were risk factors for SFTSV infection. Raising goats, farming, and grazing might be important risk factors for virus exposure, and appropriate health education could be useful in preventing infections. PMID- 24343884 TI - Soil-transmitted helminth infection and nutritional status among urban slum children in Kenya. AB - To evaluate the nutritional impact of soil-transmitted helminth (STH) infection, we conducted a cross-sectional survey of 205 pre-school (PSC) and 487 school-aged children (SAC) randomly selected from the surveillance registry of the Centers for Disease Control and Prevention of the Kibera slum in Kenya. Hemoglobin, iron deficiency (ID), vitamin A deficiency (VAD), inflammation, malaria, anthropometry, and STH ova were measured. Poisson regression models evaluated associations between STH and malnutrition outcomes and controlled for confounders. Approximately 40% of PSC and SAC had STH infection, primarily Ascaris and Trichuris; 2.9% of PSC and 1.1% of SAC had high-intensity infection. Malnutrition prevalence among PSC and SAC was anemia (38.3% and 14.0%, respectively), ID (23.0% and 5.0%, respectively), VAD (16.9% and 4.5%, respectively), and stunting (29.7% and 16.9%, respectively). In multivariate analysis, STH in PSC was associated with VAD (prevalence ratio [PR] = 2.2, 95% confidence interval = 1.1-4.6) and ID (PR = 3.3, 95% confidence interval = 1.6 6.6) but not anemia or stunting. No associations were significant in SAC. Integrated deworming and micronutrient supplementation strategies should be evaluated in this population. PMID- 24343885 TI - Serosurveillance to monitor onchocerciasis elimination: the Ugandan experience. AB - Uganda is the only African country whose onchocerciasis elimination program uses a two-pronged approach of vector control and mass drug distribution. The Ugandan program relies heavily upon the use of serosurveys of children to monitor progress toward elimination. The program has tested over 39,000 individuals from 11 foci for Onchocerca volvulus exposure, using the Ov16 ELISA test. The data show that the Ov16 ELISA is a useful operational tool to monitor onchocerciasis transmission interruption in Africa at the World Health Organization (WHO) recommended threshold of < 0.1% in children. The Ugandan experience has also resulted in a re-examination of the statistical methods used to estimate the boundary of the upper 95% confidence interval for the WHO prevalence threshold when all samples tested are negative. This has resulted in the development of Bayesian and hypergeometric statistical methods that reduce the number of individuals who must be tested to meet the WHO criterion. PMID- 24343886 TI - Determinants and coverage of vaccination in children in western Kenya from a 2003 cross-sectional survey. AB - This study assesses full and timely vaccination coverage and factors associated with full vaccination in children ages 12-23 months in Gem, Nyanza Province, Kenya in 2003. A simple random sample of 1,769 households was selected, and guardians were invited to bring children under 5 years of age to participate in a survey. Full vaccination coverage was 31.1% among 244 children. Only 2.2% received all vaccinations in the target month for each vaccination. In multivariate logistic regression, children of mothers of higher parity (odds ratio [OR] = 0.27, 95% confidence interval [95% CI] = 0.13-0.65, P <= 0.01), children of mothers with lower maternal education (OR = 0.35, 95% CI = 0.13-0.97, P <= 0.05), or children in households with the spouse absent versus present (OR = 0.40, 95% CI = 0.17-0.91, P <= 0.05) were less likely to be fully vaccinated. These data serve as a baseline from which changes in vaccination coverage will be measured as interventions to improve vaccination timeliness are introduced. PMID- 24343887 TI - Hospitalizations and deaths caused by diarrhea in children five years old and younger at four hospitals in Haiti, 2010-2012. AB - Worldwide, diarrhea is a major contributor to morbidity and mortality in children; however, there are few data on the burden of diarrheal disease in Haiti. We conducted a retrospective review of hospital discharge registries from 2010 to 2012 in the pediatric wards of four Haitian hospitals and recorded the number of all-cause hospitalizations and deaths as well as diarrheal hospitalizations and deaths by age (<= 2 and 3-5 years) and epidemiological week. Diarrhea was associated with 3,582 (33.7%) of 10,621 hospitalizations and 62 (11.5%) of 540 in-hospital deaths in children <= 5 years old. Of these children, 88.5% and 96.8%, respectively, were among children <= 2 years old. The highest proportions of diarrhea-associated hospitalizations occurred from January to April. At four Haitian hospitals over a 3-year period, during which time a major epidemic of cholera occurred, diarrheal disease in children <= 5 years was a major contributor to pediatric hospitalizations and mortality. PMID- 24343888 TI - Glycoprotein 60 diversity in Cryptosporidium parvum causing human and cattle cryptosporidiosis in the rural region of Northern Tunisia. AB - The zoonotic potential of Cryptosporidium parvum was studied in an extensive cattle farming region of northern Tunisia. Seventy fecal samples from pre-weaning calves and 403 fecal samples from children were examined by microscopy after modified Ziehl-Neelsen (MZN) staining. Positive Cryptosporidium specimens were identified at a species level using an 18S rRNA nested polymerase chain reaction (PCR) followed by an Restriction Fragment Length Polymorphism (RFLP) analysis. C. parvum isolates were subgenotyped by sequence analysis of the glycoprotein 60 (gp60) gene. Among calf samples, 14 samples were positive by MZN method. C. parvum was identified in all cases. Twelve parvum isolates (85.7%) belonged to family subtype IIa. Subtype IIaA15G2R1 was more prevalent (50%). Two C. parvum isolates corresponded to the IIdA16G1 subtype. Seven human samples were positive by MZN method. C. parvum and C. meleagridis were identified in four and three cases, respectively. Intraspecific characterization of C. parvum identified two subtypes, the IIaA15G2R1 and the IIdA16G1, also found in calves. PMID- 24343889 TI - Primary visual cortex represents the difference between past and present. AB - The visual system is confronted with rapidly changing stimuli in everyday life. It is not well understood how information in such a stream of input is updated within the brain. We performed voltage-sensitive dye imaging across the primary visual cortex (V1) to capture responses to sequences of natural scene contours. We presented vertically and horizontally filtered natural images, and their superpositions, at 10 or 33 Hz. At low frequency, the encoding was found to represent not the currently presented images, but differences in orientation between consecutive images. This was in sharp contrast to more rapid sequences for which we found an ongoing representation of current input, consistent with earlier studies. Our finding that for slower image sequences, V1 does no longer report actual features but represents their relative difference in time counteracts the view that the first cortical processing stage must always transfer complete information. Instead, we show its capacities for change detection with a new emphasis on the role of automatic computation evolving in the 100-ms range, inevitably affecting information transmission further downstream. PMID- 24343890 TI - Neonatal hypoxia, hippocampal atrophy, and memory impairment: evidence of a causal sequence. AB - Neonates treated for acute respiratory failure experience episodes of hypoxia. The hippocampus, a structure essential for memory, is particularly vulnerable to such insults. Hence, some neonates undergoing treatment for acute respiratory failure might sustain bilateral hippocampal pathology early in life and memory problems later in childhood. We investigated this possibility in a cohort of 40 children who had been treated neonatally for acute respiratory failure but were free of overt neurological impairment. The cohort had mean hippocampal volumes (HVs) significantly below normal control values, memory scores significantly below the standard population means, and memory quotients significantly below those predicted by their full scale IQs. Brain white matter volume also fell below the volume of the controls, but brain gray matter volumes and scores on nonmnemonic neuropsychological tests were within the normal range. Stepwise linear regression models revealed that the cohort's HVs were predictive of degree of memory impairment, and gestational age at treatment was predictive of HVs: the younger the age, the greater the atrophy. We conclude that many neonates treated for acute respiratory failure sustain significant hippocampal atrophy as a result of the associated hypoxia and, consequently, show deficient memory later in life. PMID- 24343891 TI - Selective attentional enhancement and inhibition of fronto-posterior connectivity by the basal ganglia during attention switching. AB - The prefrontal cortex and the basal ganglia interact to selectively gate a desired action. Recent studies have shown that this selective gating mechanism of the basal ganglia extends to the domain of attention. Here, we investigate the nature of this action-like gating mechanism for attention using a spatial attention-switching paradigm in combination with functional neuroimaging and dynamic causal modeling. We show that the basal ganglia guide attention by focally releasing inhibition of task-relevant representations, while simultaneously inhibiting task-irrelevant representations by selectively modulating prefrontal top-down connections. These results strengthen and specify the role of the basal ganglia in attention. Moreover, our findings have implications for psychological theorizing by suggesting that inhibition of unattended sensory regions is not only a consequence of mutual suppression, but is an active process, subserved by the basal ganglia. PMID- 24343892 TI - Preferential detachment during human brain development: age- and sex-specific structural connectivity in diffusion tensor imaging (DTI) data. AB - Human brain maturation is characterized by the prolonged development of structural and functional properties of large-scale networks that extends into adulthood. However, it is not clearly understood which features change and which remain stable over time. Here, we examined structural connectivity based on diffusion tensor imaging (DTI) in 121 participants between 4 and 40 years of age. DTI data were analyzed for small-world parameters, modularity, and the number of fiber tracts at the level of streamlines. First, our findings showed that the number of fiber tracts, small-world topology, and modular organization remained largely stable despite a substantial overall decrease in the number of streamlines with age. Second, this decrease mainly affected fiber tracts that had a large number of streamlines, were short, within modules and within hemispheres; such connections were affected significantly more often than would be expected given their number of occurrences in the network. Third, streamline loss occurred earlier in females than in males. In summary, our findings suggest that core properties of structural brain connectivity, such as the small-world and modular organization, remain stable during brain maturation by focusing streamline loss to specific types of fiber tracts. PMID- 24343894 TI - Comment on: Selective decontamination of the oropharynx and the digestive tract, and antimicrobial resistance: a 4 year ecological study in 38 intensive care units in the Netherlands. PMID- 24343893 TI - Pharmacokinetic interaction of rifapentine and raltegravir in healthy volunteers. AB - OBJECTIVES: Latent tuberculosis infection and tuberculosis disease are prevalent worldwide. However, antimycobacterial rifamycins have drug interactions with many antiretroviral drugs. We evaluated the effect of rifapentine on the pharmacokinetic properties of raltegravir. METHODS: In this open-label, fixed sequence, three-period study, 21 healthy volunteers were given: raltegravir alone (400 mg every 12 h for 4 days) on days 1-4 of Period 1; rifapentine (900 mg once weekly for 3 weeks) on days 1, 8 and 15 of Period 2 and raltegravir (400 mg every 12 h for 4 days) on days 12-15 of Period 2; and rifapentine (600 mg once daily for 10 scheduled doses) on days 1, 4-8 and 11-14 of Period 3 and raltegravir (400 mg every 12 h for 4 days) on days 11-14 of Period 3. Plasma raltegravir concentrations were measured. ClinicalTrials.gov database: NCT00809718. RESULTS: In 16 subjects who completed the study, coadministration of raltegravir with rifapentine (900 mg once weekly; Period 2) compared with raltegravir alone resulted in the geometric mean of the raltegravir AUC from 0 to 12 h (AUC0-12) being increased by 71%; the peak concentration increased by 89% and the trough concentration decreased by 12%. Coadministration of raltegravir with rifapentine in Period 3 did not change the geometric mean of the raltegravir AUC0-12 or the peak concentration, but it decreased the trough concentration by 41%. Raltegravir coadministered with rifapentine was generally well tolerated. CONCLUSIONS: The increased raltegravir exposure observed with once-weekly rifapentine was safe and tolerable. Once-weekly rifapentine can be used with raltegravir to treat latent tuberculosis infection in patients who are infected with HIV. PMID- 24343895 TI - Co-transfer of resistance to high concentrations of copper and first-line antibiotics among Enterococcus from different origins (humans, animals, the environment and foods) and clonal lineages. AB - OBJECTIVES: We studied the occurrence of diverse copper (Cu) tolerance genes from Gram-positive bacteria and their co-transfer with antibiotic resistance genes among Enterococcus from diverse sources. METHODS: Enterococcus (n = 922) of several species and from human, animal, environment and food samples were included. Antimicrobial and CuSO4 susceptibility and conjugation assays were performed by standard procedures, bacterial screening of Cu and antibiotic resistance genes by PCR, and clonality by PFGE/multilocus sequence typing. RESULTS: tcrB and cueO genes occurred in 15% (n = 137/922) and 14% (n = 128/922) of isolates, respectively, with the highest occurrence in piggeries (P < 0.05). They were more frequent among Enterococcus faecium (tcrB: 23% versus 8% in Enterococcus faecalis and 12% in other species; cueO: 25% versus 5% and 9%, respectively; P < 0.05). A correlation between phenotypic and genotypic assays was observed for most E. faecium (CuSO4 MIC50 = 24 mM in tcrB/cueO(+) versus CuSO4 MIC50 = 12 mM in tcrB/cueO(-)), but not for other species. Co-transfer of Cu tolerance (associated with tcrB, cueO or an unknown mechanism) with erythromycin, tetracycline, vancomycin, aminoglycosides or ampicillin resistance was demonstrated. A variety of PFGE types was detected among isolates carrying Cu tolerance mechanisms, some identified in sequence types (STs) often linked to human infections (E. faecium from ST18 and ST78 clonal lineages and E. faecalis clonal complex 2). CONCLUSIONS: Cu tolerance might contribute to the selection/maintenance of multidrug-resistant Enterococcus (including resistance to first-line antibiotics used to treat enterococcal infections) due to the use of Cu compounds (e.g. antiseptics/animal feed supplements). The distribution of the multicopper oxidase cueO and the co-transfer of ampicillin resistance along with Cu tolerance genes are described for the first time. PMID- 24343896 TI - Genetic determinants and elements associated with antibiotic resistance in viridans group streptococci. AB - OBJECTIVES: To investigate the distribution of erythromycin, tetracycline and chloramphenicol resistance mechanisms and determinants and the relevant genetic environments and elements in viridans group streptococci (VGS). METHODS: A total of 263 VGS collected from routine throat swabs in 2010-12 and identified to the species level were studied. Antibiotic resistance determinants and the relevant genetic contexts and elements were determined using amplification and sequencing assays and restriction analysis. RESULTS: The investigation provided original information on the distribution of resistance mechanisms, determinants and genetic elements in VGS. Erythromycin-resistant isolates totalled 148 (56.3%; 37 belonging to the cMLS phenotype and 111 belonging to the M phenotype); there were 72 (27.4%) and 7 (2.7%) tetracycline- and chloramphenicol-resistant isolates, respectively. A number of variants of known genetic contexts and elements carrying determinants of resistance to these antibiotics were detected, including the mega element, Phi10394.4, Tn2009, Tn2010, the IQ element, Tn917, Tn3872, Tn6002, Tn916, Tn5801, a tet(O) fragment from ICE2096-RD.2 and ICESp23FST81. CONCLUSIONS: These findings shed new light on the distribution of antibiotic resistance mechanisms and determinants and their genetic environments in VGS, for which very few such data are currently available. The high frequency and broad variety of such elements supports the notion that VGS may be important reservoirs of resistance genes for the more pathogenic streptococci. The high rates of macrolide resistance confirm the persistence of a marked prevalence of resistant VGS in Europe, where macrolide resistance is, conversely, declining among the major streptococcal pathogens. PMID- 24343897 TI - Brown adipose tissue dynamics in wild-type and UCP1-knockout mice: in vivo insights with magnetic resonance. AB - We used noninvasive magnetic resonance imaging (MRI) and magnetic resonance spectroscopy to compare interscapular brown adipose tissue (iBAT) of wild-type (WT) and uncoupling protein 1 (UCP1)-knockout mice lacking UCP1-mediated nonshivering thermogenesis (NST). Mice were sequentially acclimated to an ambient temperature of 30 degrees C, 18 degrees C, and 5 degrees C. We detected a remodeling of iBAT and a decrease in its lipid content in all mice during cold exposure. Ratios of energy-rich phosphates (ATP/ADP, phosphocreatine/ATP) in iBAT were maintained stable during noradrenergic stimulation of thermogenesis in cold- and warm-adapted mice and no difference between the genotypes was observed. As free fatty acids (FFAs) serve as fuel for thermogenesis and activate UCP1 for uncoupling of oxidative phosphorylation, brown adipose tissue is considered to be a main acceptor and consumer of FFAs. We measured a major loss of FFAs from iBAT during noradrenergic stimulation of thermogenesis. This mobilization of FFAs was observed in iBAT of WT mice as well as in mice lacking UCP1. The high turnover and the release of FFAs from iBAT suggests an enhancement of lipid metabolism, which in itself contributes to the sympathetically activated NST and which is independent from uncoupled respiration mediated by UCP1. Our study demonstrates that MRI, besides its potential for visualizing and quantification of fat tissue, is a valuable tool for monitoring functional in vivo processes like lipid and phosphate metabolism during NST. PMID- 24343898 TI - Bioactive lipid mediators in polycystic kidney disease. AB - Inflammatory activity is evident in patients with chronic kidney disease with limited data available in autosomal dominant polycystic kidney disease (ADPKD). We hypothesized that inflammation is an upstream event in the pathogenesis of ADPKD and may be a contributing factor in the disease severity and progression. Serum samples from 61 HALT study A group patients were compared with samples from 49 patients from HALT study B group with moderately advanced disease. Targeted MS analysis of bioactive lipid mediators as markers of inflammation was performed and correlated with eGFR and total kidney volume (TKV) normalized to the body surface area (BSAR) to assess if these markers are predictive of ADPKD severity. ADPKD patients with eGFR >60 ml/min/1.73 m(2) showed higher levels of 5- and 12/15-lipoxygenase (LOX) and cyclooxygenase, and generated higher levels of hydroxy-octadecadienoic acids 9-HODE and 13-HODE and HETEs 8-HETE, 11-HETE, 12 HETE, and 15-HETE as compared with healthy subjects. Linear regression of 9-HODE and 13-HODE revealed a significant relationship with eGFR and TKV, while 15-HETE significantly correlated with TKV/BSAR. Production of 20-HETE, a P450-produced metabolite of arachidonic acid, was higher in ADPKD patients as compared with healthy subjects and significantly correlated with eGFR and TKV/BSAR. Perturbation in fatty acid metabolism is evident early in ADPKD patients, even in those with preserved kidney function. The identified LOX pathways may be potential therapeutic targets for slowing down ADPKD progression. PMID- 24343900 TI - Development and validation of an LC-MS/MS method for simultaneous quantitative analysis of free and conjugated bisphenol A in human urine. AB - Bisphenol A (BPA) is an environmental endocrine-disrupting chemicals that is widely used in common consumer products. There is an increasing concern regarding human exposure to BPA owing to the potential adverse effects associated with its estrogenic activity. For assessing environmental exposure to BPA, it is essential to have a sensitive, accurate and selective analytical method, especially one that can detect low BPA levels in complex sample matrices. In this study, we developed and validated an accurate, sensitive, and robust liquid chromatography tandem mass spectrometry method for simultaneous quantification of free BPA and BPA beta-d-glucuronide (BPA-gluc) concentrations in human urine with only a single injection. Calibration curves were linear over a concentration range of 1 100 ng/mL for BPA and 10-1000 ng/mL for BPA-gluc. The levels of the analytes were determined quantitatively with HPLC/ESI-MS/MS by using negative electrospray ionization in the select ion monitoring mode and a pentaflouraphenyl propyl column. The validated method was applied to the analysis of spot urine specimens collected from randomly selected healthy human subjects. PMID- 24343899 TI - Intestinal CYP3A4 protects against lithocholic acid-induced hepatotoxicity in intestine-specific VDR-deficient mice. AB - Vitamin D receptor (VDR) mediates vitamin D signaling involved in bone metabolism, cellular growth and differentiation, cardiovascular function, and bile acid regulation. Mice with an intestine-specific disruption of VDR (Vdr(DeltaIEpC)) have abnormal body size, colon structure, and imbalance of bile acid metabolism. Lithocholic acid (LCA), a secondary bile acid that activates VDR, is among the most toxic of the bile acids that when overaccumulated in the liver causes hepatotoxicity. Because cytochrome P450 3A4 (CYP3A4) is a target gene of VDR-involved bile acid metabolism, the role of CYP3A4 in VDR biology and bile acid metabolism was investigated. The CYP3A4 gene was inserted into Vdr(DeltaIEpC) mice to produce the Vdr(DeltaIEpC)/3A4 line. LCA was administered to control, transgenic-CYP3A4, Vdr(DeltaIEpC), and Vdr(DeltaIEpC)/3A4 mice, and hepatic toxicity and bile acid levels in the liver, intestine, bile, and urine were measured. VDR deficiency in the intestine of the Vdr(DeltaIEpC) mice exacerbates LCA-induced hepatotoxicity manifested by increased necrosis and inflammation, due in part to over-accumulation of hepatic bile acids including taurocholic acid and taurodeoxycholic acid. Intestinal expression of CYP3A4 in the Vdr(DeltaIEpC)/3A4 mouse line reduces LCA-induced hepatotoxicity through elevation of LCA metabolism and detoxification, and suppression of bile acid transporter expression in the small intestine. This study reveals that intestinal CYP3A4 protects against LCA hepatotoxicity. PMID- 24343901 TI - Improving the selection of true incident cases of low back pain by screening retrospective administrative data. AB - BACKGROUND: The difficulty in identifying the onset of low back pain (LBP) limits the capacity to determine the incidence of LBP at the population level and, further, to identify risk factors. In the literature, incidence cohorts have been built with patients initially considered LBP-free for 6-12 months prior to their selection. This 'clearance period' might not be sufficient to exclude recurrent patients having experienced previous LBP episodes and might result in a misclassification bias. METHODS: Using the Canadian province of Quebec's medical administrative physicians' claims database, a cohort of prevalent claims-based recurrent LBP patients was built for 2007. The medical history of 81,329 patients was screened for a period of 11 years. Positive predictive values (PPVs), kappa statistics and a survival function were calculated to determine the optimal clearance period for capturing first-time events. RESULTS: The 2007 annual incidence of adult claims-based recurrent LBP was estimated at 242 per 100,000 persons. Men between 18 and 34 years of age were found to be 1.18 times more at risk than their counterparts. Altogether, the elderly (over 80 years) had 52% more new cases than the 18-34 age group. A very good convergence for PPV and kappa was found for a 7-year clearance period. This allowed determining the annual incidence from 2000 to 2007, showing a decrease of 26%. CONCLUSION: Screening the medical history of LBP patients can provide more accurate incidence estimates by limiting the over-ascertainment of first-time LBP patients. A 4- to 7-year clearance period should be considered. PMID- 24343902 TI - Transcriptomic analysis by RNA-seq reveals AP-1 pathway as key regulator that green tea may rely on to inhibit lung tumorigenesis. AB - Green tea is a promising chemopreventive agent for lung cancer. Multiple signaling events have been reported, however, the relative importance of these mechanisms in mediating the chemopreventive function of green tea is unclear. In the present study, to examine the involvement of AP-1 in green tea polyphenols induced tumor inhibition, human NSCLC cell line H1299 and mouse SPON 10 cells were identified as AP-1 dependent, as these two lines exhibit high constitutive AP-1 activity, and when TAM67 expression was induced with doxycycline, cell growth was inhibited and correlated with suppressed AP-1 activity. RNA-seq was used to determine the global transcriptional effects of AP-1 inhibition and also uncover the possible involvement of AP-1 in tea polyphenols induced chemoprevention. TAM67 mediated changes in gene expression were identified, and within down-regulated genes, AP-1 was identified as a key transcription regulator. RNA-seq analysis revealed that Polyphenon E-treated cells shared 293 commonly down-regulated genes within TAM67 expressing H1299 cells, and by analysis of limited Chip-seq data, over 10% of the down-regulated genes contain a direct AP-1 binding site, indicating that Polyphenon E elicits chemopreventive activity by regulating AP-1 target genes. Conditional TAM67 expressing transgenic mice and NSCLC cell lines were used to further confirm that the chemopreventive activity of green tea is AP-1 dependent. Polyphenon E lost its chempreventive function both in vitro and in vivo when AP-1 was inhibited, indicating that AP-1 inhibition is a major pathway through which green tea exhibits chemopreventive effects. PMID- 24343903 TI - Synthesis, antioxidant, and xanthine oxidase inhibitory activities of 5-[4-[2-(5 ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione derivatives. AB - Xanthine oxidase (XO) is a complex metalloflavoprotein, the overproduction of which usually leads to a pathological condition called gout. The XO inhibitors may prove to be promising antigout agents. The XO generates superoxide anions and H2O2 for the self-defense system of the organism. Abnormal production of this superoxide (reactive oxygen species) is responsible for a number of complications including inflammation, metabolic disorder, cellular aging, reperfusion damage, atherosclerosis, and carcinogenesis. In this paper, we report the synthesis of N substituted analogs of thiazolidinedione derivatives as effective and new class of XO inhibitors and also as antioxidant agents. Among all the compounds in the series, compound 2i produced relatively better activity against human milk XO (72% inhibition), which was also supported by docking studies. PMID- 24343904 TI - Introduction: Shankopathies and related autism spectrum disorders. PMID- 24343905 TI - Poor owner knowledge of feline reproduction contributes to the high proportion of accidental litters born to UK pet cats. AB - 'Accidental' litters contribute to population growth and the number of unwanted animals entering animal welfare organisations. Assessing the problem's extent and determining risk factors enables identification of education targets. Data were obtained from 715 cat-owning households in a cross-sectional telephone survey. Demographic and lifestyle factors were assessed for their association with accidental litters and with owner knowledge of cat reproduction. A total of 128 litters were reported from 552 female cats, and the proportion of accidental litters reported by owners was 80 per cent. Multivariable analysis identified that respondents were more likely to report an accidental litter of kittens if they believed a female cat should have a litter prior to being neutered, if they had more than one cat and if they rented rather than owned their home. Misconceptions relating to cat reproduction were common. The opinion that the youngest age a cat could get pregnant was five months of age (or older) was held by 83.5 per cent of cat-owning respondents, with over a quarter (26.4 per cent; 174/659) believing a queen is unable to conceive until at least a year of age. Almost half the respondents (49.0 per cent; 334/682) believed a female cat should have a litter before being neutered or were not sure; 38.8 per cent (264/681) thought that un-neutered, related cats would not mate or were not sure. This study suggests that improving cat-owner knowledge of the reproductive capacity of cats is likely to have a significant impact on the numbers of accidental litters born. PMID- 24343906 TI - Climate warming feedback from mountain birch forest expansion: reduced albedo dominates carbon uptake. AB - Expanding high-elevation and high-latitude forest has contrasting climate feedbacks through carbon sequestration (cooling) and reduced surface reflectance (warming), which are yet poorly quantified. Here, we present an empirically based projection of mountain birch forest expansion in south-central Norway under climate change and absence of land use. Climate effects of carbon sequestration and albedo change are compared using four emission metrics. Forest expansion was modeled for a projected 2.6 degrees C increase in summer temperature in 2100, with associated reduced snow cover. We find that the current (year 2000) forest line of the region is circa 100 m lower than its climatic potential due to land use history. In the future scenarios, forest cover increased from 12% to 27% between 2000 and 2100, resulting in a 59% increase in biomass carbon storage and an albedo change from 0.46 to 0.30. Forest expansion in 2100 was behind its climatic potential, forest migration rates being the primary limiting factor. In 2100, the warming caused by lower albedo from expanding forest was 10 to 17 times stronger than the cooling effect from carbon sequestration for all emission metrics considered. Reduced snow cover further exacerbated the net warming feedback. The warming effect is considerably stronger than previously reported for boreal forest cover, because of the typically low biomass density in mountain forests and the large changes in albedo of snow-covered tundra areas. The positive climate feedback of high-latitude and high-elevation expanding forests with seasonal snow cover exceeds those of afforestation at lower elevation, and calls for further attention of both modelers and empiricists. The inclusion and upscaling of these climate feedbacks from mountain forests into global models is warranted to assess the potential global impacts. PMID- 24343907 TI - Single-layer transition metal dichalcogenide nanosheet-assisted assembly of aggregation-induced emission molecules to form organic nanosheets with enhanced fluorescence. AB - Single-layer transition metal dichalcogenide nanosheets including MoS2, TiS2 and TaS2 can be used as novel platforms for the fluorescence enhancement of aggregation-induced emission fluorophores. The small organic AIE unit can be assembled into a two-dimensional sheet structure via a simple precipitation technique assisted by these monolayers. The resultant organic sheets possess a size of 0.2-2 MUm and a thickness of 9-20 nm. PMID- 24343908 TI - Global and local superconductivity in boron-doped granular diamond. AB - Strong granularity-correlated and intragrain modulations of the superconducting order parameter are demonstrated in heavily boron-doped diamond situated not yet in the vicinity of the metal-insulator transition. These modulations at the superconducting state (SC) and at the global normal state (NS) above the resistive superconducting transition, reveal that local Cooper pairing sets in prior to the global phase coherence. PMID- 24343909 TI - Can variable pH and low oxygen moderate ocean acidification outcomes for mussel larvae? AB - Natural variation and changing climate in coastal oceans subject meroplanktonic organisms to broad ranges of pH and oxygen ([O2 ]) levels. In controlled laboratory experiments we explored the interactive effects of pH, [O2 ], and semidiurnal pH fluctuations on the survivorship, development, and size of early life stages of two mytilid mussels, Mytilus californianus and M. galloprovincialis. Survivorship of larvae was unaffected by low pH, low [O2 ], or semidiurnal fluctuations for both mytilid species. Low pH (<7.6) resulted in delayed transition from the trochophore to veliger stage, but this effect of low pH was absent when incorporating semidiurnal fluctuations in both species. Also at low pH, larval shells were smaller and had greater variance; this effect was absent when semidiurnal fluctuations of 0.3 units were incorporated at low pH for M. galloprovincialis but not for M. californianus. Low [O2 ] in combination with low pH had no effect on larval development and size, indicating that early life stages of mytilid mussels are largely tolerant to a broad range of [O2 ] reflective of their environment (80-260 MUmol kg(-1) ). The role of pH variability should be recognized as an important feature in coastal oceans that has the capacity to modulate the effects of ocean acidification on biological responses. PMID- 24343910 TI - Tissue engineering in periodontal tissue. AB - Periodontitis, a recognized disease worldwide, is bacterial infection-induced inflammation of the periodontal tissues that results in loss of alveolar bone. Once it occurs, damaged tissue cannot be restored to its original form, even if decontaminating treatments are performed. For more than half a century, studies have been conducted to investigate true periodontal regeneration. Periodontal regeneration is the complete reconstruction of the damaged attachment apparatus, which contains both hard tissue (alveolar bone and cementum) and soft tissue (periodontal ligament). Several treatments, including bone grafts, guided tissue regeneration with physical barriers for epithelial cells, and growth factors have been approved for clinical use; however, their indications and outcomes are limited. To overcome these limitations, the concept of "tissue engineering" was introduced. Combination treatment using cells, growth factors, and scaffolds, has been studied in experimental animal models, and some studies have been translated into clinical trials. In this review, we focus on recent progressive tissue engineering studies and discuss future perspectives on periodontal regeneration. PMID- 24343911 TI - Cell sheet-based cardiac tissue engineering. AB - Tissue engineering is indispensable for the advancement of regenerative medicine and the development of tissue models. Cell sheet-based method is one the promising strategies for cardiac tissue engineering. To date, cell sheet transplantation using wide variety of cells has been performed for the treatment of various heart diseases. These cell sheet transplantations have shown to ameliorate cardiac dysfunction and improve symptoms of heart failure. Recent progress of the technologies on the layering of cardiac cell sheets accompanied with vascularization and the large scale cultivation system of embryonic stem cell and induced pluripotent stem cell is about to turn the fabrication of thickened human cardiac tissue for transplant and tissue models into reality. PMID- 24343912 TI - Functional tissue engineering of the liver and islets. AB - Cell-based therapies by using hepatocytes and islets have recently been evaluated as a new therapeutic modality for patients with many forms of liver diseases and insulin-deficient diabetes mellitus. In most of the recently conducted clinical trials, cells have been delivered into liver vasculatures by infusing them through the portal circulation. More recently, tissue engineering-based approaches have spurred significant interests, using hepatocytes and islets in which small but functional new tissues would be created in vivo. Under circumstances in which a higher level of cell engraftment could be obtained, these approaches could provide therapeutic effects. Considerable efforts have been given to sustaining engineered tissues and maintaining their therapeutic effects. This review highlights several strategies that can achieve a higher level of cell survival for creating new functional liver and islet tissues. PMID- 24343914 TI - Understanding the Wolbachia-mediated inhibition of arboviruses in mosquitoes: progress and challenges. AB - Arthropod-borne viruses (arboviruses) pose a considerable threat to human and animal health, yet effective control measures have proven difficult to implement, and novel means of controlling their replication in arthropod vectors, such as mosquitoes, are urgently required. One of the most exciting approaches to emerge from research on arthropods is the use of the endosymbiotic intracellular bacterium Wolbachia to control arbovirus transmission from mosquito to vertebrate. These alpha-proteobacteria propagate through insects, in part through modulation of host reproduction, thus ensuring spread through species and maintenance in nature. Since it was discovered that Wolbachia endosymbiosis inhibits insect virus replication in Drosophila species, these bacteria have also been shown to inhibit arbovirus replication and spread in mosquitoes. Importantly, it is not clear how these antiviral effects are mediated. This review will summarize recent work and discuss determinants of antiviral effectiveness that may differ between individual Wolbachia/vector/arbovirus interactions. We will also discuss the application of this approach to field settings and the associated risks. PMID- 24343916 TI - Direct-to-consumer pharmacogenomic testing is associated with increased physician utilisation. AB - BACKGROUND: Direct-to-consumer (DTC) genomic testing has generated controversy, however the actual impact of testing on consumer behaviour has been understudied, particularly for pharmacogenomic (PGx) testing. METHODS: We recruited a sample of adults who purchased a DTC genomic test and had previously received their genomic test results for complex disease risk. All participants additionally underwent PGx testing. At follow-up, to assess the impact of PGx testing on consumer behaviour, healthcare utilisation and psychological status were compared between approximately a third of participants who had received their PGx results and the remaining two-thirds of participants who were still awaiting results. The PGx test included genetic testing for drug effectiveness or risk of side effects for 12 medications. RESULTS: At follow-up, there were 481 PGx test recipients and 844 non-recipients still awaiting results. PGx test recipients had more physician visits (p=0.04) and were more likely to share their results with their physician (p=0.001). Both groups showed a decrease in anxiety symptoms from baseline to follow-up, with a trend for PGx recipients to show less of a decrease compared with non-recipients (p=0.10). PGx recipients were more likely to report that their physician ordered additional tests (p=0.01) based on their genomic test. There were no group differences in follow-up test-related distress (p=0.67). CONCLUSIONS: DTC PGx risk profiling among a selected sample of individuals was associated with increased physician utilisation and did not result in any adverse changes in psychological health or follow-up test-related distress. PMID- 24343915 TI - A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus. AB - BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. AIM: To identify CNVs associated with osteoporotic bone fracture risk. METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p = 8.69 * 10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p = 0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis. PMID- 24343917 TI - A new scoring system in cancer genetics: application to criteria for BRCA1 and BRCA2 mutation screening. AB - BACKGROUND: In hereditary forms of cancer due to mutations of genes such as BRCA1 and BRCA2, methods have been proposed to predict the presence of a mutation in a family. METHODS: Relying on carriage probability computation is the most predictive, but scores are a good proxy and avoid using computer software. An empirical method, the Manchester scoring system, has been elaborated for BRCA1 and BRCA2 mutation identification. We propose a general scoring system based on a transformation of the carriage probability. Up to an approximation, the transformed carriage probability becomes an additive score. We applied this new scoring system to the diagnosis of BRCA1-associated and BRCA2-associated breast ovarian cancer predisposition. Using simulations, its performance was evaluated and compared with that of the Manchester scoring system and of the exact probability. Finally, the score system was used on a sample of 4563 families screened for BRCA1 and BRCA2 mutations. RESULTS: The performance of the new scoring system was superior to the Manchester scoring system, but the probability computation remained the most predictive. The better performance of the new scoring system was attributed to accounting for unaffected family members and for the degree of kinship of relatives with the proband. CONCLUSIONS: The new scoring system has a theoretical basis and may be applied to any cancer family syndrome and, more generally, to any disease with monogenic subentities, in which the causal gene mutations have been identified. It will be easily modified when additional predictive factors are found. PMID- 24343918 TI - Invasion trajectory of alien trees: the role of introduction pathway and planting history. AB - Global change is driving a massive rearrangement of the world's biota. Trajectories of distributional shifts are shaped by species traits, the recipient environment and driving forces with many of the driving forces directly due to human activities. The relative importance of each in determining the distributions of introduced species is poorly understood. We consider 11 Australian Acacia species introduced to South Africa for different reasons (commercial forestry, dune stabilization and ornamentation) to determine how features of the introduction pathway have shaped their invasion history. Projections from species distribution models (SDMs) were developed to assess how the reason for introduction influences the similarity between climatic envelopes in native and alien ranges. A lattice model for an idealized invasion was developed to assess the relative contribution of intrinsic traits and introduction dynamics on the abundance and extent over the course of simulated invasions. SDMs show that alien populations of ornamental species in South Africa occupy substantially different climate space from their native ranges, whereas species introduced for forestry occupy a similar climate space in native and introduced ranges. This may partly explain the slow spread rates observed for some alien ornamental plants. Such mismatches are likely to become less pronounced with the current drive towards 'eco gardens' resulting in more introductions of ornamental species with a close climate match between native and newly introduced regions. The results from the lattice model showed that the conditions associated with the introduction pathway (especially introduction pressure) dominate early invasion dynamics. The placement of introduction foci in urban areas limited the extent and abundance of invasive populations. Features of introduction events appear to initially mask the influence of intrinsic species traits on invasions and help to explain the relative success of species introduced for different purposes. Introduction dynamics therefore can have long lasting influences on the outcomes of species redistributions, and must be explicitly considered in management plans. PMID- 24343919 TI - An approach to assess the regulatory relevance of microevolutionary effects in ecological risk assessment of chemicals: a case study with cadmium. AB - The authors suggest an approach to assess the regulatory relevance of microevolutionary effects of chemicals based on a comparison of concentrations at which microevolutionary effects have been reported in the literature and conventionally derived ecotoxicological threshold concentrations. The authors found reports of microevolutionary effects of cadmium in freshwater organisms at hardness-normalized concentrations between 0.5 ug Cd L(-1) and 6290 ug Cd L(-1) (normalized to a hardness of 50 mg CaCO3 L(-1)). These concentrations were at least 1.5 times higher than the hardness-normalized hazardous concentration for 5% of the organisms of 0.34 ug Cd L(-1). This suggests that there is no immediate need to consider microevolutionary effects of Cd in environmental risk assessments of freshwater environments. However, some other aspects should be kept in mind as well. First, microevolutionary effects have so far only been investigated at few, relatively high concentrations of Cd and not encompassing the 5% hazardous concentration. Second, different types of microevolutionary effects or investigated ecotoxicological end points may influence the conclusions of the suggested comparative approach. Finally, factors influencing the bioavailability of Cd were not commonly reported in the literature, which made normalization of concentrations at which evolutionary effects occurred impossible and affected the number of studies that could be evaluated in the suggested approach. PMID- 24343920 TI - The influence of admission characteristics on outcome: evidence from a medium secure forensic cohort. AB - OBJECTIVE: Outcomes for any mental health service will vary with the characteristics of those admitted as well as with the clinical provision of the service itself. This study aims to explore, for a medium secure forensic service in England, temporal changes in (1) characteristics of those admitted and (2) outcome after discharge and (3) to examine whether such changes are related. METHOD: Baseline characteristics and reconviction outcomes were derived from multiple data sources for 550 first admissions to a medium secure forensic unit for a 20-year period. Time to reconviction was examined using Kaplan-Meier analysis and Cox regression. RESULTS: Over time, severity of admissions increased, as did discharges to prison; discharges to non-secure hospitals reduced. Risk of reconviction increased by 3.9%-4.2% for each year of admission from 1983, which was explained by the increased admission of higher-risk patients. CONCLUSION: This medium secure service admitted patients with increasing levels of risk; reoffending rates reflect admission characteristics. Service funding decisions should take account of the characteristics of those admitted. SIGNIFICANT OUTCOMES: This study indicates that the profile of patients admitted over a 20-year period increased in severity. Over time, reconviction after discharge occurred earlier after release. This increase in reconviction was explained by the type of patient admitted. LIMITATIONS: Examination of a cohort from a single medium secure unit limits the generalizability of the findings. The study focuses on a criminological outcome measure (i.e. reconviction); other domains may be equally relevant (e.g. the relief of psychological distress). Examining an entire series of admissions introduces heterogeneity by, for example, considering the outcome of men and women together. PMID- 24343921 TI - Adult antisocial syndrome co-morbid with borderline personality disorder is associated with severe conduct disorder, substance dependence and violent antisociality. AB - This study tested the hypothesis that syndromal adult antisocial behaviour (AABS) co-morbid with borderline personality disorder (BPD) is a syndrome that emerges from severe conduct disorder (CD) in childhood and adolescence and is strongly associated, in adulthood, with both violence and substance dependence. In a sample of 8 580 community-resident adults screened for the presence of personality disorders, the following predictions arising from this hypothesis were tested: first, that those with AABS co-morbid with BPD would, in comparison with those showing AABS or BPD only, show a high level of antisocial outcomes, including violence; second, that adjusting for co-morbid alcohol dependence would attenuate group differences in many of the antisocial outcomes, and violence in particular; and third, that the AABS/BPD group would show both a high prevalence and a high severity of CD, and that adjusting for co-morbid CD would attenuate any association found between AABS/BPD co-morbidity and violence. Results confirmed these predictions, suggesting that AABS/BPD co-morbidity mediates the relationship between childhood CD and a predisposition to adult violence. The triad of AABS/BPD co-morbidity, alcohol dependence and severe CD is likely associated with the risk of criminal recidivism in offenders with personality disorder following release into the community. PMID- 24343922 TI - Pharmacotherapy for personality disorder-prescribing practice at a high secure hospital: a preliminary report. AB - The aim of this study was to examine the prescription of psychotropic medication for patients with a primary diagnosis of personality disorder (PD) detained at Rampton High Secure Hospital, compared with that for patients with a primary diagnosis of mental illness. The name and the dose of psychotropic medication prescribed for each patient in the sample, on 2 July 2010, were examined. Although nearly all patients with a primary diagnosis of mental illness were prescribed psychotropic medication (98%), the percentage within the Personality Disorder (73%) and the Dangerous and Severe Personality Disorder services (62%) was also high, with the most commonly prescribed drug being an antipsychotic in all groups. The dose of antipsychotic and mood-stabilizing medication was lower for patients with a primary diagnosis of PD, and clozapine was the antipsychotic of choice for a significant proportion of these patients. Medication may have a key role to play in the management of some groups of patients with PD. PMID- 24343923 TI - The role of psychopathic traits and substance abuse in predicting violent victimization in patients with schizophrenia spectrum disorders. AB - We examined the relationship between psychopathic traits and substance abuse and violent victimization in 94 community patients meeting DSM-IV criteria for schizophrenia spectrum disorders in contact with public mental health services in Victoria, Australia. Data on violence and victimization were collated from multiple sources and combined to categorize patients into victims of serious violence (VV; n = 74) and those who were not victims of serious violence (NVV; n = 20) groups. The VV group had higher rates of unemployment and previous violence but did not differ from the NVV on current symptom ratings. The VV group has significantly higher substance abuse and psychopathy scores, but only psychopathy score significantly contributed to the prediction of victimization. All psychopathy facets were reasonably good predictors of victimization status, but the antisocial facet contributed most to the prediction of victimization. A better understanding of the role and contribution of antisocial (particularly psychopathic) traits in violent victimization in mentally ill populations is needed to better inform community management plans. PMID- 24343925 TI - Non-suicidal self-injury: the contribution of general personality functioning. AB - Non-suicidal self-injury (NSSI) is a public health problem of increasing significance. The purpose of the present study was to determine if individuals with and without a history of NSSI would differ significantly on the domains and facets of the Five Factor Model (FFM) as well as the facets from the UPPS-P Impulsive Behaviour Scale. Self-report measures of personality, borderline personality disorder and NSSI were administered to an undergraduate sample (n = 211). Individuals who had engaged in NSSI had significantly elevated levels of FFM facets of neuroticism (i.e. anxiousness, angry hostility, depressiveness, self-consciousness, impulsiveness and vulnerability) and openness (i.e. aesthetics, feelings and values) and significantly lower levels of conscientiousness (i.e. order, achievement, self-discipline and deliberation). Additionally, those with an NSSI history scored higher on UPPS-P negative urgency, lack of premeditation and lack of perseverance. The knowledge gained from this study provides further support for personality's role in NSSI. This information may aid in the identification of risk factors for NSSI and assist in efforts examining interventions for NSSI that are targeted toward personality relevant strategies. PMID- 24343924 TI - The roles of behavioural activation and inhibition among young adults engaging in self-injury. AB - Non-suicidal self-injury (NSSI) is a prevalent behaviour, particularly among young adults. Little is known, however, about the mechanisms underlying NSSI or the personality correlates of these behaviours. The goal of this study was to examine the roles of the behavioural activation and inhibition systems (BAS and BIS) in NSSI. A total of 604 undergraduates completed two self-report measures of BAS and BIS, as well as NSSI history. Logistic and negative binomial linear regressions were used to examine the relationships between measures of BAS and BIS and the presence and course characteristics of NSSI. Approximately 30% of participants reported a history of NSSI. High scores on BAS (drive, reward and fun seeking), combined with low scores on BIS total, predicted NSSI history. However, the opposite was also true, with high levels of BIS total, combined with low levels of BAS (drive, reward and fun seeking), also predicting NSSI history. In addition, several BAS by BIS interactions predicted an NSSI course characterized by more acts and methods used. This study supports the roles of both BAS and BIS in NSSI and takes the first step in identifying how these personality correlates may help identify individuals at risk for NSSI. PMID- 24343926 TI - Post-therapy functional impairment as a treatment outcome measure in non-suicidal self-injury disorder using archival data. AB - There have been calls for the creation of a non-suicidal self-injury (NSSI) disorder, and a recent DSM-5 work group has delineated potential diagnostic criteria for the proposed disorder. Preliminary research comparing NSSI disorder to Axis I disorders and its closest diagnostic 'neighbor', borderline personality disorder (BPD), suggests that impairment at intake, patient history of associated features and diagnostic co-occurrence rates set NSSI disorder apart from existing DSM-IV-TR disorders. However, few studies have examined the treatment course of NSSI disorder relative to other disorders. The purpose of this study was to distinguish potential treatment outcome differences between a potential NSSI disorder, BPD and Axis I. Archival data (N = 571), which included ratings of functioning at therapy intake and termination, were analysed to determine between group differences. Although no significant differences in the number of months in therapy or number of sessions attended were found, findings suggest that the NSSI group made strong gains in therapy, as evidenced by improvements in clinician ratings of functional impairment from intake to termination. These findings suggest that NSSI disorder may have a positive prognosis with treatment. PMID- 24343927 TI - Recovery from chronic factitious disorder (Munchausen's syndrome): a personal account. AB - This case report provides an account by a patient (with permission) of chronic factitious disorder and the factors that led to recovery. Such accounts are extremely rare in the literature. This account also throws into sharp focus current controversies in the classification of factitious disorders. PMID- 24343928 TI - The means and ends of Munchausen's disease. PMID- 24343929 TI - Commentary on 'recovery from chronic factitious disorders (Munchausne's syndrome): a personal account' by Bass and Taylor, 2012. PMID- 24343930 TI - Highly stretchable piezoresistive graphene-nanocellulose nanopaper for strain sensors. AB - Highly stretchable graphene-nanocellulose composite nanopaper is fabricated for strain-sensor applications. Three-dimensional macroporous nanopaper from crumpled graphene and nanocellulose is embedded in elastomer matrix to achieve stretchability up to 100%. The stretchable graphene nanopaper is demonstrated for efficient human-motion detection applications. PMID- 24343932 TI - Predictors of Clostridium difficile infections in hospitalized children. AB - BACKGROUND: Recent studies report an increasing incidence of Clostridium difficile infections (CDIs) in children and suggest that CDIs may occur outside known populations at risk. OBJECTIVE: To identify clinical factors associated with CDI in a hospitalized pediatric population. METHODS: A retrospective case control study was conducted with C difficile cases (CD) and controls (CTLs) in hospitalized children over a 2-year period. CDs (N = 134) and 2:1 age-matched CTLs (N = 274) with diarrheal illness were evaluated. RESULTS: CDs and CTLs were similar in gender and race. Watery diarrhea was the most common type of diarrhea in CDs and CTLs. Immunodeficiency (46% vs 6%; P < 0.001), gastrointestinal (GI) disease (31% vs 18%; P = 0.005), and proton pump inhibitor (PPI) use (22% vs 7%; P < 0.001) were more frequent in CDs. Of CDs, 30% were defined as community acquired. Bloody diarrhea was more frequent in community-acquired CD (28% vs 4% P < 0.001); however, other clinical variables were not statistically different. No antibiotic exposure, recent hospitalization, prolonged hospitalization, or past history of CDI existed in 8% of CDs. Multivariate logistic regression demonstrated that antibiotic use (odds ratio [OR]: 2.80, P = 0.001), recent hospitalization (OR: 2.33, P = 0.007), and immunodeficiency (OR: 6.02, P < 0.001) were significantly associated with cases when controlling for PPI use, having GI disease, and history of abdominal surgery. CONCLUSIONS: Clinical history is of greater value than symptoms in distinguishing CD, with immunodeficiency having the strongest association. An important percentage of CDs did not have any risk factors, confirming concerns that CDIs do occur in otherwise low-risk pediatric populations. PMID- 24343931 TI - Passive sampling methods for contaminated sediments: risk assessment and management. AB - This paper details how activity-based passive sampling methods (PSMs), which provide information on bioavailability in terms of freely dissolved contaminant concentrations (Cfree ), can be used to better inform risk management decision making at multiple points in the process of assessing and managing contaminated sediment sites. PSMs can increase certainty in site investigation and management, because Cfree is a better predictor of bioavailability than total bulk sediment concentration (Ctotal ) for 4 key endpoints included in conceptual site models (benthic organism toxicity, bioaccumulation, sediment flux, and water column exposures). The use of passive sampling devices (PSDs) presents challenges with respect to representative sampling for estimating average concentrations and other metrics relevant for exposure and risk assessment. These challenges can be addressed by designing studies that account for sources of variation associated with PSMs and considering appropriate spatial scales to meet study objectives. Possible applications of PSMs include: quantifying spatial and temporal trends in bioavailable contaminants, identifying and evaluating contaminant source contributions, calibrating site-specific models, and, improving weight-of evidence based decision frameworks. PSM data can be used to assist in delineating sediment management zones based on likelihood of exposure effects, monitor remedy effectiveness, and, evaluate risk reduction after sediment treatment, disposal, or beneficial reuse after management actions. Examples are provided illustrating why PSMs and freely dissolved contaminant concentrations (Cfree ) should be incorporated into contaminated sediment investigations and study designs to better focus on and understand contaminant bioavailability, more accurately estimate exposure to sediment-associated contaminants, and better inform risk management decisions. Research and communication needs for encouraging broader use are discussed. PMID- 24343933 TI - Ethylene rather than dissolved organic carbon controls methane uptake in upland soils. PMID- 24343934 TI - In situ and non-volatile bandgap tuning of multilayer graphene oxide in an all solid-state electric double-layer transistor. AB - The sp(2) /sp(3) domain fraction of multilayer graphene oxide (GO) is tuned in situ and in a non-volatile manner by using a proton-induced redox reaction at the interface of GO and the yttria-stabilized zirconia proton-conductor. This method opens the door for transparent, ultrathin, flexible, and low cost carbon nanoionics devices that can control not only electronic transport, but also other properties such as photoluminescence and optics. PMID- 24343937 TI - Personality dysfunction and social functioning in schizophrenia. AB - AIM: To determine if personality dysfunction is associated with poorer clinical and social indicators in patients with schizophrenia. METHODOLOGY: An observational study of patients with schizophrenia in psychiatric care assessed patient satisfaction with care, social functioning and psychopathology. Analysis of the relationship between personality and these three domains quantitatively assessed differences between patients with and without comorbid personality dysfunction. Diagnostic confounding was assessed using partial correlation coefficients. RESULTS: Forty-five patients with schizophrenia were studied. In the schizophrenia group, personality dysfunction correlated with poorer social functioning but not poorer satisfaction with care. Linear regression found that the relationship between poorer social functioning and personality disorder in schizophrenia remained, taking other diagnoses and age into account. Partial correlation coefficients confirmed that this was no related to an overlap between personality and schizophrenia symptoms in this sample. CONCLUSION: Personality dysfunction may negatively influence social functioning in patients with schizophrenia but does not appear to impact on patients' views of the care they receive. This is not due to the potential for diagnostic confounding between schizophrenia and personality disorder. Further research using larger samples is needed to confirm this association. PMID- 24343936 TI - Person-environment transactions: personality traits moderate and mediate the effects of child sexual victimization on psychopathology. AB - Personality, environmental adversity and psychopathology are related, and different models have been proposed to explain their interaction. The theory of person-environment transactions may elucidate the role of personality in these interactions beyond traditional conceptualizations. To our knowledge, hardly any studies have explored the relationships between the Five Factor Model, child sexual victimization and general psychopathology. We hypothesized (1) that neuroticism and conscientiousness will moderate the effect of sexual victimization on psychopathology and (2) that neuroticism will mediate the relationship between sexual victimization and psychopathology. Our findings partially support these hypotheses. Neuroticism, conscientiousness and sexual victimization have a direct effect on psychopathology, whereas extraversion, openness to experience and agreeableness do not. With regard to interactive effects, conscientiousness, but not neuroticism, moderates the effect of sexual victimization on psychopathology, and neuroticism does mediate the aforementioned effect. No other interactions were found with regard to extraversion, agreeableness or openness to experience. To our knowledge, the present study represents the first global test of person-environment transactions with regard to psychopathology and sexual victimization within the framework of the Five Factor Model. PMID- 24343935 TI - Borderline personality disorder in suicidal adolescents. AB - The diagnosis of borderline personality disorder (BPD) in adolescents has been controversial. Thus, few studies have examined BPD in suicidal adolescents, even though it is strongly associated with suicidal behaviours in adults. This study examines differences between suicidal adolescents with (n = 47) and without (n = 72) BPD on history and characteristics of suicidal behaviour, Axis I co morbidity, affect regulation and aggression. Assessments were completed with both adolescents and parents, and consensus ratings based on best available data were analysed. BPD participants were more likely to have a history of suicide attempts and to have been admitted because of a suicide attempt (vs. suicidal ideation). There were no significant differences in self-injurious behaviours or degree of suicidal ideation. BPD participants also had more psychiatric co-morbidity and higher aggression scores but no significant differences in affective dysregulation compared with suicidal adolescents without BPD. Diagnostic stability over 6 months was modest. Our results demonstrate that, compared with other acutely suicidal adolescents, the clinical profile of BPD participants is unique and suggests an increased risk for suicidal behaviours. This extends upon other studies that support the construct validity of BPD during adolescence and suggests that BPD should be considered in suicide risk assessment for adolescents. PMID- 24343938 TI - The Standardized Assessment of Personality-Abbreviated Scale as a screening instrument for personality disorders in substance-dependent criminal offenders. AB - Personality disorders (PDs) are considered to be potential predictors of treatment outcome in substance-dependent patients and potential treatment matching variables. There is a need for a brief and simple screening instrument for PDs that can be used in routine psychological assessment, especially in a treatment setting for previously substance-dependent criminal offenders, where a high prevalence of PDs is expected. This study investigated the psychometric properties of the Standardized Assessment of Personality-Abbreviated Scale (SAPAS), a commonly used screening interview for PDs, in a population of inpatient criminal offenders with a history of substance dependence. Various statistical procedures were used to establish reliability and validity measures, such as Kuder-Richardson 20, confirmative factor analysis, receiver operating characteristic analysis and multitrait multimethod matrix. The SAPAS was administered to 101 inpatient criminal offenders with a history of substance dependence at baseline. Within three weeks, participants were administered the Structured Interview for DSM-IV Personality in order to assess the presence of PDs. Results show limited evidence to make firm conclusions on the psychometric qualities of the SAPAS as a screening instrument for comorbid PDs in a substance dependence treatment setting for criminal offenders. Suggestions for improvement concerning the psychometric qualities of the SAPAS as a screening instrument for this population are noted. PMID- 24343939 TI - Differentiating normal and disordered personality using the General Assessment of Personality Disorder (GAPD). AB - Criteria to differentiate personality disorder from extremes of normal personality variations are important given growing interest in dimensional classification because an extreme level of a personality dimension does not necessarily indicate disorder. The DSM-5 proposed classification of personality disorder offers a definition of general personality disorder based on chronic interpersonal and self/identity pathology. The ability of this approach to differentiate personality disorder from other mental disorders was evaluated using a self-report questionnaire, the General Assessment of Personality Disorder (GAPD). This measure was administered to a sample of psychiatric patients (N = 149) from different clinical sub-sites. Patients were divided into personality disordered and non-personality disordered groups on the basis of the Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II). The results showed a hit rate of 82% correct identified patients and a good accuracy of the predicted model. There was a substantial agreement between SCID-II interview and GAPD personality disorder diagnoses. The GAPD appears to predict personality disorder in general, which provides support of the DSM-5 general diagnostic criteria of personality disorder. PMID- 24343940 TI - Bold, smart, dangerous and evil: perceived correlates of core psychopathic traits among jury panel members. AB - Relatively few studies have investigated how laypersons perceive psychopathy, what factors they believe to be commonly associated with this disorder, or what rater personality characteristics might predict perceived psychopathic traits of the target person. An ethnically diverse sample of 285 US community members attending jury duty reviewed a case vignette regarding a capital murder trial and then rated (1) their perceptions of the defendant's psychopathic characteristics loosely based on trait indicators from the Psychopathy Checklist-Revised; (2) other characteristics of the defendant that might be associated with psychopathy (e.g. intelligence, violence potential); and (3) their own personality, using a very brief measure of Five Factor traits. Multivariate regression analyses indicated that participant ratings of psychopathy pertaining to the defendant were strongly associated with ratings on measures of his perceived boldness (i.e. social dominance and fearlessness), intelligence, violence potential, and perceptions that he was 'evil'. Big Five personality characteristics of the layperson raters, however, were only modestly associated with their ratings of psychopathy for the defendant. We review these results in terms of the potential stigmatization of individuals labelled as 'psychopaths' in forensic settings. PMID- 24343941 TI - Psychopathy and deception detection. AB - Researchers have found that most people have difficulty detecting deception; however, certain individuals are able to consistently detect deception above the level of chance. This study examined whether psychopathic traits are related to deception detection. Undergraduate participants (n = 117) indicated whether individuals in video clips were lying or telling the truth and completed a measure of psychopathy. Overall, participants' performance was significantly greater than chance. Scores on the psychopathy measure were unrelated to participants' performance and their confidence on the lie detection task. Possible explanations for the findings are briefly discussed. PMID- 24343942 TI - The narcissistic mask: an exploration of 'the defensive grandiosity hypothesis'. AB - Narcissism has been conceptualized as involving attempts to defend against negative self-schemata (implicit negative beliefs about one's own self-worth). This idea has been termed the 'mask model of narcissism'. This study explores the mask model, examining the association between extreme narcissistic personality traits and performance on a task purported to assess the influence of negative self-schemata. Participants (n = 232) from the UK and the UAE completed the Narcissistic Personality Inventory and also performed an incidental learning task involving the surprise recall of self-referential adjectives (traits). A greater recall of negative adjectives was viewed as indicative of negative self-schemata. Looking at the sample as a whole, there were no associations between narcissistic traits and negative adjective recall. However, amongst those scoring in the upper quartile of the Narcissistic Personality Inventory, narcissism scores were positively correlated with the recall of negative adjectives even after controlling for age and memory. Narcissism may reflect self-enhancement strategies rooted in negative self-beliefs. PMID- 24343943 TI - A biofeedback intervention to control impulsiveness in a severely personality disordered forensic patient. AB - Impulsiveness in personality disordered forensic patients is associated with poor treatment completion and high risk of re-offending. A biofeedback training protocol, previously found to reduce impulsiveness and improve attention in children with Attention Deficit Hyperactivity Disorder, was used in an initial attempt to reduce impulsiveness in a severely personality disordered man with borderline, antisocial and histrionic features. Electrocortical, behavioural and self-report measures of impulsiveness were taken before and immediately following 6 weeks of biofeedback training and at 3 months follow-up. The patient successfully engaged with the intervention. His self-reports of reduced impulsiveness and improved attention were corroborated by behavioural and electrocortical measures that indicated reduced impulsiveness and better focused attention. Results suggest this intervention might prove useful in improving behavioural and emotional self-regulation in severely personality disordered patients. PMID- 24343944 TI - Complex case: a biofeedback intervention to control impulsiveness in a severely personality disordered forensic patient by Rick Howard, Klaus Schellhorn and John Lumsden. PMID- 24343945 TI - Complex case: a biofeedback intervention to control impulsiveness in a severely personality disordered forensic patient. PMID- 24343946 TI - Reconceiving the therapeutic obligation. AB - The "therapeutic obligation" (TO) is a physician's duty to provide his patients with what he believes is the best available treatment. We begin by discussing some prominent formulations of the obligation before raising two related considerations against those formulations. First, they do not make sense of cases where doctors are permitted to provide suboptimal care. Second, they give incorrect results in cases where doctors are choosing treatments in challenging epistemic environments. We then propose and defend an account of the therapeutic obligation that solves the problems that undermined previous efforts at formulating the TO. We conclude by considering how apparent problems with our proposal actually rest on difficulties with informed consent. PMID- 24343947 TI - Responding to clinicians who fail to follow patient safety practices: perceptions of physicians, nurses, trainees, and patients. AB - BACKGROUND: The field of patient safety grapples with the tension between a "no blame" systems approach and the need to hold providers accountable for substandard performance. Attitudes of clinicians and patients regarding methods of promoting adherence to safety practices have not been described. METHODS: We surveyed attending and resident physicians in the University of California, San Francisco (UCSF) Department of Medicine, nurses and inpatients at the UCSF Medical Center, and UCSF medical students regarding attitudes toward violations of 3 safety protocols: hand hygiene, fall risk assessment, and preoperative time out. RESULTS: Responses to protocol lapses were grouped into 3 categories: feedback (universally endorsed and thus excluded from the analysis), public reporting, and penalty (fines, suspension, firing). We examined group differences regarding whether public reporting and penalties were ever appropriate and the number of transgressions at which public reporting and penalties were favored. Respondents favored both public reporting and penalties more frequently for not conducting a preoperative time-out or fall risk assessment than for hand-hygiene lapses (public reporting: time-out, odds ratio [OR]: 2.82 [95% confidence interval {CI}: 2.03-3.91]; fall, OR: 1.47 [95% CI: 1.09-1.98]. Penalty: time-out, OR: 4.29 [95% CI: 2.97-6.20]; fall, OR: 1.74 [95% CI: 1.27-2.37]). Penalties were endorsed more frequently than public reporting for all groups and scenarios. Attending physicians and patients expressed similar attitudes regarding public reporting and penalties, but patients favored penalties after significantly fewer transgressions (P < 0.05). CONCLUSION: After a decade emphasizing no-blame responses to patient safety hazards, both healthcare providers and patients now believe clinicians should be held accountable for following basic safety protocols. PMID- 24343948 TI - Nanoscale electrical investigation of layer-by-layer grown molecular wires. AB - Nanoscopic metal-molecule-metal junctions consisting of Fe-bis(terpyridine)-based ordered nanostructures are grown in layer-by-layer fashion on a solid support. Hopping is demonstrated as the main charge-transport mechanism both experimentally and theoretically. PMID- 24343949 TI - Controls of dissolved organic matter quality: evidence from a large-scale boreal lake survey. AB - Inland waters transport large amounts of dissolved organic matter (DOM) from terrestrial environments to the oceans, but DOM also reacts en route, with substantial water column losses by mineralization and sedimentation. For DOM transformations along the aquatic continuum, lakes play an important role as they retain waters in the landscape allowing for more time to alter DOM. We know DOM losses are significant at the global scale, yet little is known about how the reactivity of DOM varies across landscapes and climates. DOM reactivity is inherently linked to its chemical composition. We used fluorescence spectroscopy to explore DOM quality from 560 lakes distributed across Sweden and encompassed a wide climatic gradient typical of the boreal ecozone. Six fluorescence components were identified using parallel factor analysis (PARAFAC). The intensity and relative abundance of these components were analyzed in relation to lake chemistry, catchment, and climate characteristics. Land cover, particularly the percentage of water in the catchment, was a primary factor explaining variability in PARAFAC components. Likewise, lake water retention time influenced DOM quality. These results suggest that processes occurring in upstream water bodies, in addition to the lake itself, have a dominant influence on DOM quality. PARAFAC components with longer emission wavelengths, or red-shifted components, were most reactive. In contrast, protein-like components were most persistent within lakes. Generalized characteristics of PARAFAC components based on emission wavelength could ease future interpretation of fluorescence spectra. An important secondary influence on DOM quality was mean annual temperature, which ranged between -6.2 and +7.5 degrees C. These results suggest that DOM reactivity depends more heavily on the duration of time taken to pass through the landscape, rather than temperature. Projected increases in runoff in the boreal region may force lake DOM toward a higher overall amount and proportion of humic-like substances. PMID- 24343954 TI - Nicotine and tobacco research special supplement: economic aspects of tobacco use in low- and middle-income countries. PMID- 24343955 TI - Exploring the relationship between cigarette prices and smoking among adults: a cross-country study of low- and middle-income nations. AB - INTRODUCTION: Evidence on the relationship between cigarette prices and adult smoking in low- and middle-income countries (LMICs) is relatively limited. This study offers new descriptive evidence on this relationship using data from a set of 13 LMICs. METHODS: We use Global Adult Tobacco Survey (GATS) cross-country data from approximately 200,000 participants aged 15 and older. Estimates on the relationship between prices and adult smoking were obtained from logit models of smoking participation and ordinary least squares models of conditional cigarette demand. RESULTS: Higher prices were associated with lower demand across countries, in terms of both smoking prevalence and daily number of cigarettes smoked among smokers. Our estimates suggest that the total price elasticity of cigarette demand in LMICs is approximately -0.53. We find that higher socioeconomic status (SES), represented through wealth and education effects is associated with lower chance of smoking overall, but among existing smokers, it may be associated with a larger number of cigarettes smoked. CONCLUSIONS: After controlling for a set of individual demographic and country characteristics, cigarette prices retain a significant role in shaping cigarette demand across LMICs. Because higher SES is associated with a reduced chance of smoking overall but also with increased daily consumption among current smokers, optimal tobacco tax policies in LMICs may face an added need to accommodate to shifting SES structures within the populations of these countries. PMID- 24343956 TI - The impact of cigarette excise taxes on smoking cessation rates from 1994 to 2010 in Poland, Russia, and Ukraine. AB - INTRODUCTION: We studied the impact of cigarette excise taxes on the rates of smoking cessation with data from 3 neighboring Eastern European countries (Russia, Poland, and Ukraine) during the post-transitional period of the 1990s and 2000s. METHODS: Using Global Adult Tobacco Survey data from 11,106 former and current smokers, we estimated the impact of cigarette taxes on the smokers' likelihood of quitting over time. We first transformed the survey's cross sectional data into a pseudo-longitudinal format in which the average observation period for individual subjects was 12 years and then employed duration analysis. RESULTS: We estimated that a 10% increase in cigarette taxes during the observation period increased the probability of smoking cessation among smokers in these countries by 1.6% to 2.3%. CONCLUSIONS: Cigarette tax increases have played a significant role in driving smoking cessation in Poland, Russia, and Ukraine. Further increases in cigarette excise taxes are likely to encourage further cessation and thus impact the prevalence of smoking in the region. PMID- 24343957 TI - Who quits? An overview of quitters in low- and middle-income countries. AB - INTRODUCTION: Using the Global Adult Tobacco Surveys from 14 primarily low- and middle-income countries, we describe the association between the probability of being a recent quitter and a number of demographic and policy-relevant factors such as exposure to warning labels, work-site smoking bans, antismoking media messaging, tobacco marketing, and current cigarette and bidi prices. METHODS: Logistic regressions were used to examine the potential correlates of recent quitting and recent quit attempts. RESULTS: After accounting for country-specific attributes in pooled analyses, we found that higher rates of exposure to work site smoking bans are associated with higher odds of being a quitter (odds ratio [OR] with 95% confidence interval [CI] = 1.13 [1.04, 1.22]). Exposure to antismoking media messaging (OR with 95% CI = 1.08 [1.00, 1.17]), work-site smoking bans (OR with 95% CI = 1.11 [0.99, 1.26]), and warning labels (OR with 95% CI = 1.03 [1.01, 1.05]); cigarette prices (OR with 95% CI = 1.01 [1.00, 1.02]), and bidi prices (OR with 95% CI =1.17 [1.11, 1.22]) are factors associated with higher odds of recent quit attempts in the pooled analysis. These effects vary by country. Exposure to warning labels is found to be associated with greater likelihood of recent quitting in Egypt (OR with 95% CI = 3.20 [1.53, 6.68]), and the positive association between exposure to work-site smoking bans and quitting is particularly strong for Southeast Asia (OR with 95% CI = 1.20 [1.06, 1.35]) and Asia Pacific countries (OR with 95% CI = 1.85 [0.93, 3.68]). Additionally, exposure to tobacco industry marketing is significantly associated with smaller odds of quitting in Asia Pacific (OR with 95% CI = 0.83 [0.79, 0.87]) and Latin American countries (OR with 95% CI = 0.78 [0.74, 0.82]). CONCLUSIONS: Although our results vary by country, they generally suggest that greater exposure to tobacco control polices is significantly associated with quitting. PMID- 24343958 TI - Conference report on tobacco taxes in Central America: current situation and opportunities to reduce prevalence and increase fiscal revenues. AB - INTRODUCTION: As stated in Article 6 of Framework Convention on Tobacco Control (FCTC), increasing tobacco prices through higher taxes is one of the most effective interventions to reduce tobacco use and to encourage smokers to quit. The potential for tax increases on tobacco products in Central America is ample. We aim to synthesize the current tobacco taxes situation and highlight research needs to strengthen taxation. BACKGROUND: In May 2012, a workshop was carried out with representatives from each Central American country to analyze the tobacco tax situation in each country and to identify key research gaps with experts in the field. DISCUSSION: Tobacco taxes in Central America fall far short of the levels recommended by FCTC. Moreover, the legal framework is complex and creates barriers for higher taxes that require further research and political will. Top research priorities are an in-depth analysis of tobacco tax legislation, impact of tax and price policies, analysis of costs associated to health care of tobacco related diseases and lost productivity, and the feasibility of approaches to increasing tobacco taxes in certain contexts. An additional area of research is the interrelationship between human rights and tobacco control. CONCLUSION: Central American countries would benefit from increasing excise taxes on tobacco products. The lack of available data and research to counteract tobacco industry arguments are significant obstacles. Active leadership of civil society in support of the partnership of chronic disease interventions is vital in order to obtain tax increases on tobacco products. PMID- 24343959 TI - Monolayer hexagonal boron nitride films with large domain size and clean interface for enhancing the mobility of graphene-based field-effect transistors. AB - Viable and general techniques that allow effective size control of triangular shaped, single-crystal, monolayer h-BN domains grown by the CVD method, direct optical visualization of h-BN domains, and the cleaning of the h-BN surface to achieve reliable graphene device quality are reported for the first time. This study points to a critical role of the interfacial properties between the graphene and the monolayer h-BN in determining reliable, enhanced graphene-device performance. PMID- 24343960 TI - Quercetin differently regulates insulin-mediated glucose transporter 4 translocation under basal and inflammatory conditions in adipocytes. AB - SCOPE: Quercetin is the most abundant dietary flavonol with beneficial regulation of glucose homeostasis, but its regulation of insulin action remains uncertain. This study aims to investigate the effects of quercetin on insulin-mediated glucose transporter 4 (GLUT4) translocation under basal and inflammatory conditions as well as the molecular mechanisms in adipocytes. METHODS AND RESULTS: The effects of quercetin on insulin-mediated GLUT4 translocation in 3T3 L1 cells under basal and insulin resistant conditions were investigated. Meanwhile, we investigated the effect of quercetin on AMP-activated protein kinase (AMPK) activation implicated in regulation of insulin action. Quercetin inhibited insulin-mediated GLUT4 translocation by inhibiting AS160 phosphorylation. Differently, when inflammatory challenge impaired insulin action in 3T3-L1 cells, quercetin inhibited IkappaB kinase beta (IKKbeta) phosphorylation and facilitated insulin signaling, leading to the restoration of insulin-mediated AS160 phosphorylation and downstream GLUT4 translocation. AMPK inhibitor Compound C or knockdown of AMPKalpha by small interfering RNA (siRNA) abolished both actions of quercetin. Results from mice adipose tissue (AT) further confirmed its positive regulation of AMPK phosphorylation and opposite effects on AS160 phosphorylation in vivo. CONCLUSION: Quercetin demonstrated divergent effects on insulin-mediated GLUT4 translocation in adipocytes under basal and insulin resistant conditions, which were related to its regulation of AMPK activity. PMID- 24343961 TI - Post-traumatic stress disorder and the outcome of dialectical behaviour therapy for borderline personality disorder. AB - BACKGROUND: Individuals with borderline personality disorder (BPD) and comorbid post-traumatic stress disorder (PTSD) have a worse prognosis than individuals with BPD alone. A common view is that the emotional instability and impulsivity of BPD should be treated before attempting to address trauma. However, PTSD symptoms may interfere with patients' ability to benefit from such 'stabilizing' treatments. METHODS: The effect of BPD-PTSD comorbidity on self-harm and BPD symptom outcomes was evaluated in 89 patients receiving dialectical behaviour therapy, using multilevel modelling. RESULTS: Patients with comorbid BPD-PTSD showed a trend towards elevated BPD symptoms throughout the treatment year (beta = 2.12, 95% CI = -0.21-4.44, p = 0.07). There was a three-way interaction between PTSD comorbidity, treatment completion and time, whereby PTSD comorbidity was associated with less reduction in self-harm frequency over time, but only in those completing the full 12 months of treatment (incident risk ratio = 1.16, 95% CI = 1.04-1.30, p < 0.01). CONCLUSION: Patients with comorbid PTSD had a poorer outcome from dialectical behaviour therapy than those with BPD alone, possibly because of the negative impact of unaddressed trauma. The results provide further grounds for recently developed treatments targeting BPD traits and PTSD symptoms simultaneously. PMID- 24343962 TI - Difficulties with emotion regulation mediate the relationship between borderline personality disorder symptom severity and interpersonal problems. AB - Problems with interpersonal functioning and difficulties with emotion regulation are core characteristics of borderline personality disorder (BPD). Little is known, however, about the interrelationship between these areas of dysfunction in accounting for BPD symptom severity. The present study examines a model of the relationship between difficulties with emotion regulation and interpersonal dysfunction in a community sample of adults (n = 124) with the full range of BPD symptoms. Results showed that difficulties with emotion regulation fully mediated the relationship between BPD symptom severity and interpersonal dysfunction. An alternative model indicated that interpersonal problems partially mediated the relationship between difficulties with emotion regulation and BPD symptom severity. These findings support existing theories of BPD, which propose that difficulties with emotion regulation may account for the types of interpersonal problems experienced by individuals with BPD and suggest further examination of the possibility that interpersonal dysfunction may worsen these individuals' difficulties with emotion regulation. PMID- 24343963 TI - Personality pathology and mental health treatment seeking in a community sample of older adults. AB - Sampling issues are extremely important in studies of psychopathology, especially with regard to the investigation of personality disorders (PDs). Many studies rely on clinical samples whereas others have focused on representative samples of community residents. Do people who qualify for a PD diagnosis seek and receive mental health services with greater (or possibly reduced) frequency compared with others in the community? Do community-based studies of PDs include people who have been treated? Analyses presented here examine connections between personality pathology and various aspects of treatment seeking in a representative sample of 1 630 middle-aged adults who completed a semi-structured diagnostic interview (Structured Interview for DSM-IV Personality). Results demonstrate a disorder-specific effect. Antisocial, borderline, avoidant and dependent PDs are associated with increased levels of seeking treatment. Four PDs are associated with greater length of treatment. After accounting for lifetime presence of major depression and alcohol dependence, borderline, avoidant and dependent pathology remained associated with increased treatment seeking. These findings point to several conclusions, including (1) community samples do include a substantial proportion of people who have received various kinds of mental health services; (2) the association between personality pathology and mental health treatment seeking is not fully explained by comorbid depression and alcohol dependence. PMID- 24343964 TI - New directions for an old construct: Depressive personality research in the DSM-5 era. AB - The DSM-5 Personality and Personality Disorders Work Group has suggested that the DSM-IV depressive personality disorder (DPD) construct be assessed within a proposed set of trait domains, which include anxiousness, depressivity, and anhedonia, and that the diagnostic category itself be removed from the DSM-5. A review of studies on DPD has demonstrated many challenges and limitations to DPD research, despite strong evidence of its validity and clinical utility. Nevertheless, there remains much interest in how a depressive personality construct fits into a dimensionalized framework of assessing psychopathology. In this paper, I offer three major research directions that can help advance our understanding of the depressive personality construct. These directions can inform researchers and clinicians how depressive personality fits within broad trait dimensions of classification, as well as the internal psychological processes, dynamics and content that characterize this type of psychopathology. PMID- 24343965 TI - Manifestations of interpersonal dependency and depressive subtypes in outpatient psychotherapy patients. AB - The present study investigated the relationship between normative and pathological dependency and anaclitic and introjective depressive experiences among 71 patients participating in outpatient psychotherapy at a university-based psychology clinic. We examined the interrelationships among the Relationship Profile Test subscales, the Depressive Experiences Questionnaire subscales and the Outcome Questionnaire-45.2. Results indicated that destructive overdependence was positively correlated with anaclitic and introjective depression and negatively correlated with overall perceptions of mental health. Dysfunctional detachment was positively correlated with introjective depression and negatively correlated with generalized perceptions of one's own mental health. Healthy dependency was negatively correlated with introjective depression and positively correlated with mental health. These results not only support the construct validity of the Relationship Profile Test but also shed light on a link between depression, dependence and self-criticism. PMID- 24343966 TI - Comorbidity between personality disorders and depressive symptomatology in women: A cross-sectional study of three different transitional life stages. AB - This study assessed the prevalence of personality disorders (PDs), according to DSM-IV criteria, in relation to depressive symptomatology at three different periods of life in female subjects. Depressive symptoms and personality disorders were assessed in a sample of 568 women from three different transitional stages: 134 students, 314 primiparous women after childbirth and 120 women diagnosed with breast cancer. Depressive symptoms were assessed by the Hospital Depression and Anxiety Scale in the first and third groups and by the Edinburgh Post-natal Depression Scale in the second group, whereas PDs were assessed by the French version of the Vragenlijst voor Kenmerken van de Persoonlijkheid. Depressive symptomatology and rates of PD (20.4% and 6.3%) were equivalent in the three groups. The prevalence of PD was higher in the depressed group compared with the non-depressed group, with more paranoid, borderline, avoidant, obsessive compulsive, schizotypal, antisocial, dependent and histrionic PD. Our findings support the hypothesis that PDs are more frequently associated with depressive symptoms. Borderline and avoidant PDs were more prevalent among young women. All cluster C PD (dependent, avoidant and obsessive-compulsive) co-occurred significantly with depressive symptoms. PMID- 24343967 TI - Working with borderline personality disorder: A small-scale qualitative investigation into community psychiatric nurses' constructs of borderline personality disorder. AB - Borderline personality disorder (BPD) is a complex presentation that can have a significant impact upon the individual and on his or her quality of life. BPD has often been associated with negative connotations (e.g. 'manipulative', 'attention seeking'). The aim of the current study was to gain a fuller understanding of how community psychiatric nurses (CPNs) make sense of the diagnosis of BPD and how their constructs of BPD impact their approach to this client group. Four CPNs, three women and one man, were interviewed using a semi-structured interview schedule. The data were analysed using interpretative phenomenological analysis, to reveal over-arching and sub-themes. The results indicated that participants attempted to ascribe meaning to the client's presentation 'in the moment'. When they had a framework to explain behaviour, participants were more likely to express positive attitudes. When they did not have such a framework, participants could view clients in more pejorative terms. As participants were deriving meaning 'in the moment', there could be fluidity with regards to participants' attitudes, ranging from 'dread' to a 'desire to help'. This could lead to participants shifting between 'connected' and 'disconnected' interactions with clients. The limitations and implications for clinical practise will also be considered. PMID- 24343968 TI - Paranoid personality disorder and the schizophrenia spectrum-Where to draw the line? AB - By means of a case vignette, this study explores the clinical intersection between paranoid personality disorder and other schizophrenia-spectrum illness. Even though the patient described had paramount signs of a paranoid personality disorder and was diagnosed as such, psychopathological symptoms extended considerably beyond the common concept and diagnostic criteria of the disorder. Management strategies included psychopharmacological and non-pharmacological interventions, yet psychosocial functioning permanently appeared defective. While there is a persistent need for an opportunity to distinguish the characteristic syndromal pattern of paranoid personality attributes, the case exemplifies the challenges associated with classifying some largely suspicious and distrustful eccentrics within the schizophrenia spectrum. PMID- 24343969 TI - Unifying or splitting-how to find a diagnosis that unifies the psychopathology. PMID- 24343970 TI - Paranoid case vignette. PMID- 24343971 TI - Mechanistic insights into the effects of climate change on larval cod. AB - Understanding the biophysical mechanisms that shape variability in fisheries recruitment is critical for estimating the effects of climate change on fisheries. In this study, we used an Earth System Model (ESM) and a mechanistic individual-based model (IBM) for larval fish to analyze how climate change may impact the growth and survival of larval cod in the North Atlantic. We focused our analysis on five regions that span the current geographical range of cod and are known to contain important spawning populations. Under the SRES A2 (high emissions) scenario, the ESM-projected surface ocean temperatures are expected to increase by >1 degrees C for 3 of the 5 regions, and stratification is expected to increase at all sites between 1950-1999 and 2050-2099. This enhanced stratification is projected to decrease large (>5 MUm ESD) phytoplankton productivity and mesozooplankton biomass at all 5 sites. Higher temperatures are projected to increase larval metabolic costs, which combined with decreased food resources will reduce larval weight, increase the probability of larvae dying from starvation and increase larval exposure to visual and invertebrate predators at most sites. If current concentrations of piscivore and invertebrate predators are maintained, larval survival is projected to decrease at all five sites by 2050-2099. In contrast to past observed responses to climate variability in which warm anomalies led to better recruitment in cold-water stocks, our simulations indicated that reduced prey availability under climate change may cause a reduction in larval survival despite higher temperatures in these regions. In the lower prey environment projected under climate change, higher metabolic costs due to higher temperatures outweigh the advantages of higher growth potential, leading to negative effects on northern cod stocks. Our results provide an important first large-scale assessment of the impacts of climate change on larval cod in the North Atlantic. PMID- 24343972 TI - CIITA: a master regulator of adaptive immunity shows its innate side in the bone. PMID- 24343973 TI - Biomonitoring in wearers of permethrin impregnated battle dress uniforms in Afghanistan and Germany. AB - OBJECTIVES: To analyse differences in uptake of the insecticide permethrin in wearers of non-impregnated and permethrin impregnated battle dress uniforms (BDU) in Afghanistan and Germany. METHODS: In two separate studies, in April 2003 January 2004 (study I, n=549) and in February-April 2005 (study II, n=195), healthy female and male members of the German Federal Armed Forces were equipped with permethrin impregnated BDU (two sub-cohorts in Germany and one in Afghanistan) while members equipped with non-impregnated uniforms served as a control group. Human biomonitoring was conducted before, during and after wearing the uniforms by measuring permethrin metabolites in urine samples via GC-MS. RESULTS: Subjects of the Afghan and German control groups had permethrin levels in the range of the German general population. In contrast, subjects wearing impregnated BDU had about 200-fold higher exposure levels. Within this group, subjects located in Afghanistan and smokers had significantly higher exposure levels. Internal exposure decreased with increasing duration of use of impregnated BDU. CONCLUSIONS: There is no evidence for a higher background permethrin contamination in military bases located in Afghanistan compared to Germany. Daily use of permethrin impregnated BDU is associated with significantly higher permethrin uptake compared to the general population. Hand-mouth contact by smoking can increase uptake which also seems to be influenced by the duration of use of impregnated BDU. PMID- 24343974 TI - FOLFOX 4 combined with herbal medicine for advanced colorectal cancer: a systematic review. AB - This systematic review evaluates the clinical evidence for the addition of herbal medicines (HMs) to FOLFOX 4 for advanced colorectal cancer (ACRC) in terms of tumor response rate (tRR), survival, quality of life and reduction in adverse events (AEs). Seven electronic databases were searched for randomized controlled trials (RCTs) of FOLFOX4 combined with HMs compared to FOLFOX4 alone. Outcome data for 13 randomized controlled trials were analysed using Review Manager 5.1. Risk of bias for objective outcomes including tumor response and survival was judged as low. Publication bias was not evident. Meta-analyses found the addition of HMs improved tRR (RR 1.25, 95%CI 1.06-1.47, I(2) = 0%), one year survival (RR 1.51, 95%CI 1.19-1.90, I(2) = 0%) and quality of life in terms of Karnofsky Performance Status (KPS) gained (RR 1.84, 95%CI 1.54-2.19, I(2) = 0%); alleviated grade 3 and 4 chemotherapy-related AEs for neutropenia (RR 0.33, 95%CI 0.18-0.60, I(2) = 0%), nausea and vomiting (RR 0.34, 95%CI 0.17-0.67, I(2) = 0%) and neurotoxicity (RR 0.39, 95%CI 0.15-1.00, I(2) = 0%), compared to FOLFOX4 alone. The most frequently used herbs were Astragalus membranaceus, Panax ginseng, Atractylodes macrocephala, Poria cocos, Coix lachryma-jobi and Sophora flavescens. In experimental studies, each of these herbs has shown actions that could have contributed to improved tumor response. PMID- 24343975 TI - Daidzein regulates proinflammatory adipokines thereby improving obesity-related inflammation through PPARgamma. AB - SCOPE: Daidzein was recently reported to act like an activator of peroxisome proliferator-activated receptor gamma (PPARgamma) thereby enhancing differentiation of adipocytes. Although PPARgamma plays a role in adipokine expression, it has not been well researched whether daidzein affects expression of adipokines. This study aimed to clarify the effects of daidzein on proinflammatory adipokines and adipose inflammation causing insulin resistance in obesity. METHODS AND RESULTS: 3T3-L1 adipocytes were treated with daidzein or genistein. Diet-induced obese C57BL/6J mice were fed high-fat high-sucrose diets with daidzein (1.0 g/kg chow) for 12 wk. The results showed that both isoflavones, especially daidzein, stimulated adipogenic differentiation in 3T3-L1 adipocytes with the activation of PPARgamma. Daidzein also increased adiponectin expression and decreased MCP-1 expression with the consistent regulation of their secretion. In obese mice, daidzein inhibited hypertrophy in fat cell size and improved insulin sensitivity, concomitant with upregulation of PPARgamma in fat tissue. Decreased expression of MCP-1 and TNF-alpha, and increased expression of adiponectin were also observed in adipose tissue of daidzein-fed mice. Additionally, daidzein administration significantly inhibited macrophage accumulation in adipose tissue. CONCLUSION: Daidzein regulates adipokine expression through the PPARgamma, thereby improving the adverse effects of adipose inflammation, such as insulin resistance, in obesity. PMID- 24343976 TI - Large variation of severity and longitudinal change of symptom distress among patients with personality disorders. AB - Main objectives were to investigate (1) the longitudinal course of symptom distress among patients with personality disorders (PD) and (2) how different Axis-I and Axis-II pathology and treatment factors predict or moderate long-term outcome. All patients (n = 751) were admitted to short-term day hospital treatment, and 47% continued in group psychotherapy (mean duration 2.3 years). Symptom distress was assessed repeatedly over 5 years (Symptom Check List 90-R). Mixed models were chosen for statistical analyses. A main finding was the large variation in severity and longitudinal course of symptom distress. Five-year trends ranged from full symptom remission (31%) to pervasive, severe distress (36%). Co-occurring Axis-I disorders did not explain longitudinal variability of symptom distress. However, the presence and increasing severity of Axis-II pathology was strongly associated with more severe baseline symptom distress. Poor long-term outcomes were associated with the combination of avoidant PD and long treatment durations (>2.5 years), and borderline PD and short treatment durations (<0.4 years). Contrastingly, considerable symptom relief was associated with borderline PD and long treatment duration. In conclusion, the severity and longitudinal course of symptom distress among PD patients is closely associated with their personality structures and not sufficiently explained by Axis-I comorbidity. PMID- 24343977 TI - The impact of extended longitudinal observation on the assessment of personality disorders. AB - Multiple sources of information are necessary for a valid assessment of personality disorders (PDs). This study investigates the impact of longitudinal observation. The sample comprised 1217 patients from 15 different treatment units. PDs were assessed at admission to treatment using the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II) and additional clinical information (best estimate diagnosis). After approximately 18 weeks of treatment, the SCID-II protocols were re-examined at clinical conferences and the diagnostic status reassessed on the basis of longitudinal observations in multiple group situations (longitudinal, expert, all data principle). Using this procedure, 78% of the patients' diagnostic criteria sets were changed, and 32% of patients' diagnostic statuses were changed. Many (32%) patients who were evaluated initially as not having a PD received a PD diagnosis after re examination. The information provided by customary clinical assessment has important limitations, and longitudinal observation provides additional information that may change the diagnostic status in approximately one-third of PD cases. PMID- 24343978 TI - Normal personality versus pathological personality: dimensional and predictive study. AB - The present study aimed to replicate the previous relationship between the Zuckerman personality model and the Dimensional Assessment of Personality Pathology-Basic Questionnaire (DAPP-BQ) and to evaluate the contribution of the facets and factors from Zuckerman's new instrument Zuckerman-Kuhlman-Aluja Personality Questionnaire (ZKA-PQ) versus the old Zuckerman-Kuhlman Personality Questionnaire to the four clusters of the DAPP-BQ. The sample consisted of 443 subjects from the general population of both sexes. The ZKA-PQ dimensions predicted between 35 % and 61% of the DAPP-BQ cluster variance and facets between 54% and 63%. Local regression graphical analysis (LOESS) showed that neuroticism and aggressiveness are the dimensions most related with emotional dysregulation. Sensation seeking and aggressiveness were associated with dissocial behaviour. Neuroticism and extraversion (negative) were associated with social avoidance and activity and sensation seeking (negative) with compulsiveness. The new ZKA-PQ improves the psychometric properties of the old Zuckerman-Kuhlman Personality Questionnaire. Both dimensional personality measures can play a role in the prediction of the future DSM-V personality disorder dimensional system. PMID- 24343979 TI - A treatment goal checklist for people with personality disorder. AB - BACKGROUND: Agreement between client and therapist on treatment goals has been consistently linked with improved treatment outcomes. Having clear and collaborative goals may be particularly important when working with clients diagnosed with personality disorders who are often difficult to engage and test the boundaries of therapy. This paper outlines the development of a personality disorder treatment goal checklist aimed at helping clients and therapists to identify and prioritize their goals for therapy. METHOD: The checklist was developed using self-reported problems of the first 90 participants randomized into the psychoeducation and problem solving (PEPS) trial. Problems were coded and categorized into problem areas. The checklist was viewed by two service users who gave suggestions for improvements. RESULTS: The final checklist consists of 161 items in 16 problem areas. CONCLUSIONS: The checklist may provide a clinically useful tool for working with this client group. PMID- 24343980 TI - Self-esteem and other-esteem in college students with borderline and avoidant personality disorder features: An experimental vignette study. AB - An experimental study investigated self-esteem and other-esteem responses to either fully supportive or less supportive interpersonal feedback in college students with avoidant and borderline personality disorder features (APD and BPD respectively). Disturbances in self-esteem and in evaluations of others are central to definitions of both APD and BPD, but the extent to which such interpersonal appraisals are responsive to contextual features, such as evaluative feedback from others, is not yet clear. In theory, we would expect that individuals with pronounced PD features would show more inflexible and more negative self-evaluations and others- evaluations than those without PD features. In this study with 169 undergraduates, APD but not BPD features were associated with other-contingent state self-esteem and other-esteem. A significant interaction indicated that highly avoidant respondents felt particularly negatively about themselves and their close others in situations that conveyed subtle criticism but not in situations signalling unequivocal support. This suggests that their self-esteem and other-esteem, rather than being rigidly negative, are instead highly contingent upon interpersonal feedback. Such context contingency has implications for the trait-like description of diagnostic characteristics within current taxonomies and is in line with contemporary dynamic models of personality structure and process. PMID- 24343981 TI - Emotion dysregulation and impulsivity additively predict borderline personality disorder features in Italian nonclinical adolescents. AB - The present study aimed to test if measures of emotion dysregulation and impulsivity additively predicted dimensional scores of borderline personality disorder assessed using the Borderline Personality Disorder Scale of the Personality Diagnostic Questionnaire-4+ in two independent samples of Italian nonclinical adolescents. Hierarchical regression analyses showed that three dimensions of emotion dysregulation (difficulties controlling impulsive behaviours when distressed, limited access to effective emotional regulation strategies and lack of emotional clarity) were significantly associated with BPD features in both samples. Further, impulsivity scores accounted for a significant amount of additional variance in BPD features above and beyond emotion dysregulation. PMID- 24343982 TI - Commentary: Google glass: a head-up display to facilitate teaching and learning. PMID- 24343983 TI - Late onset ataxia: MSA-C or SCA 17? A gene penetrance dilemma. PMID- 24343984 TI - Functional and morphological effects of grape seed proanthocyanidins on peripheral neuropathy in rats with type 2 diabetes mellitus. AB - Grape seed proanthocyanidins (GSPs) possess a broad spectrum of pharmacological and therapeutic properties. The aim of this study was to examine the effect of GSPs on functional and morphological abnormalities in the peripheral nerves of rats with type 2 diabetes mellitus. Diabetic rats were induced by two injections of 25 mg streptozotocin/kg body weight and 8 weeks of a high-carbohydrate/high fat diet. GSPs were then administrated to the rats for 16 weeks. Thermal and mechanical sensitivity thresholds and nerve conductive velocity were measured to evaluate peripheral nerve function. Light microscopy was used with special stains to observe the morphological changes in the central and peripheral nervous systems. Calcium (Ca(2+)) homeostasis and ATPase activities in the sciatic nerves were also determined. In diabetic rats receiving GSP treatment (especially at the 500 mg/kg dose), the abnormal peripheral nerve function and impaired nervous tissues (L4 to L5 spinal cord segments, L5 dorsal root ganglion, and sciatic nerves) were improved to a significant extent. Moreover, 500 mg/kg GSP treatment significantly reduced the concentration of free Ca(2+) and elevated Ca(2+)-ATPase activity in sciatic nerves. These results suggest that GSPs may prevent early functional and morphological abnormalities in the peripheral nerves of rats with type 2 diabetes mellitus. PMID- 24343985 TI - Problem-solving test: E2F: a family of S phase regulating transcription factors. AB - Terms to be familiar with before you start to solve the test: transcription factors, gene induction, DNA synthesis, S phase, retinoblastoma, immunoprecipitation, radioactive labeling, oligonucleotide, enhancer element, polyacrylamide gel electrophoresis, autoradiography, gel retardation assay PMID- 24343986 TI - 18F-fluorodihydroxyphenylalanine PET/CT in patients with neuroendocrine tumors of unknown origin: relation to tumor origin and differentiation. AB - This work was performed to evaluate the performance of (18)F fluorodihydroxyphenylalanine ((18)F-FDOPA) PET/CT in detecting primary neuroendocrine tumors (NETs) occult on morphologic and functional imaging, in relation to tumor origin and differentiation. METHODS: A retrospective study of NET patients who were investigated with (18)F-FDOPA PET/CT imaging in 2 academic endocrine tumor centers was conducted. Only patients with negative conventional and somatostatin receptor scintigraphy (SRS) results were studied. RESULTS: Twenty-seven patients were evaluated with (18)F-FDOPA PET/CT, 23 at their initial staging and 4 during their follow-up. The primary occult NET was localized by (18)F-FDOPA PET/CT in 12 patients (overall sensitivity, 44%; 52% in patients evaluated at initial diagnosis), leading to tumor resection in all cases. The primary tumors were distributed and graded as follows: 1 duodenum G2 lesion, 7 ileum G2 lesions, 2 terminal ileum G1 lesions, 1 pancreas G2 lesion, and 1 gallbladder G3 lesion. Patients with positive (18)F-FDOPA PET/CT results had higher values of serum chromogranin A (100% vs. 20%, P = 0.0003), serotonin, or urinary 5-hydroxyindolacetic acid (83% vs. 20%, P = 0.003). Two false-negative results were related to poorly differentiated duodenal and prostatic NETs (G3). (18)F-FDOPA PET/CT showed more metastatic anatomic regions than SRS in 17 patients. CONCLUSION: (18)F-FDOPA PET appears to be a sensitive functional imaging tool for the detection of primary NETs occult on SRS, especially tumors with a well-differentiated pattern and serotonin secretion. PMID- 24343988 TI - Probing lipid coating dynamics of quantum dot core micelles via Forster resonance energy transfer. AB - Lipid coated nanocrystal assemblies are among the most extensively investigated nanoparticle platforms for biomedical imaging and therapeutic purposes. However, very few efforts have been addressed to the lipid coating exchange dynamics in such systems, which is key to our understanding of the nanoparticles' coating stability and their interactions with the environment. Here, we apply the Forster resonance energy transfer (FRET) from quantum dot (QD) core to Cy5.5 dye labeled lipids at the surface to monitor the lipid exchange dynamics in situ and to study its dependence on concentration, temperature and solvent. A kinetic model is developed to describe the experimental data, allowing the rate constants and the activation energy for lipid exchange to be determined. The activation energy for lipid exchange on QD micelles is 155 kJ/mol in saline environment and 130 kJ/mol in pure water. The findings presented here provide basic knowledge on these self assembled structures and contribute to understanding their performance and to further design of nanomedicine. PMID- 24343987 TI - Bone-seeking radiopharmaceuticals for treatment of osseous metastases, Part 1: alpha therapy with 223Ra-dichloride. AB - Metastatic disease to bone is commonly seen in the advanced stages of many cancers. The cardinal symptom, pain, is often the cause of significant morbidity and reduced quality of life. Treatment of bone pain includes nonsteroidal analgesics and opiates; however, long-term use of these drugs is commonly associated with significant side effects, and tolerance is common. External-beam radiation therapy is effective mainly in localized disease sites. Bone-targeting radiopharmaceuticals are beneficial in the management of patients with multiple metastatic lesions. This article focuses on the 3 most commonly used agents: the Food and Drug Administration-approved (89)Sr-chloride, (153)Sm ethylenediaminetetramethylene phosphonic acid (EDTMP), and (223)Ra-dichloride. We will discuss the physical characteristics, clinical data, dosage, and administration of these agents, including optimal patient selection and toxicity associated with their use. These radioactive agents have proven efficacy in the treatment of painful osseous metastases from prostate cancer and breast cancer. Significant recent advances include use of these agents in combination with chemotherapy and the use of the alpha emitter (223)Ra-dichloride in prostate cancer, primarily to improve survival and skeletal related events. The review is presented in 2 parts. The first will discuss the characteristics and clinical use of (223)Ra-dichloride, and the second will discuss the beta emitters (89)Sr and (153)Sm-EDTMP. PMID- 24343989 TI - The overall relationship between CT imaging and symptom scores in chronic rhinosinusitis (CRS). PMID- 24343990 TI - Distant pseudomeningoceles of the ventral skull base: a report of 2 cases. AB - BACKGROUND: The objective of this case series was to report what is to the best of our knowledge the first reports of nasopharyngeal and soft palate pseudomeningoceles tracking submucosally from the sphenoid sinus. METHODS: Analysis of cases through medical records. RESULTS: Two cases of middle-aged male patients presented to our tertiary care university teaching hospital for recurrent meningitis and a history of cerebrospinal fluid (CSF) rhinorrhea. Both were found to have pseudomeningoceles distant from the sphenoid sinus. One was tracking to the mucosa of the Eustachian tube, and the other to the dorsum of the soft palate. Both were found to be tracking submucosally from the sphenoid sinus, to the vidian canal, to the lateral nasopharyngeal wall, to their respective locations at the Eustachian tube and dorsum of the soft palate. CSF closure was performed with a transnasal endoscopic repair using the pedicled nasoseptal flap for 1 patient and Alloderm for the other, both with successful cessation of CSF rhinorrhea. CONCLUSION: We present these cases of distant spontaneous CSF leaks. We review the literature and discuss case management. PMID- 24343996 TI - Characterization of metabolic states of Arabidopsis thaliana under diverse carbon and nitrogen nutrient conditions via targeted metabolomic analysis. AB - Plant growth and metabolism are regulated in response to various environmental factors. To investigate modulations in plant metabolism by the combined action of elevated atmospheric CO2 concentration and other nutritional factors, we performed targeted metabolomic analysis using Arabidopsis thaliana plants grown under 24 different conditions where the CO2 concentration, amounts and species of nitrogen source, and light intensity were modified. Our results indicate that both the biosynthesis of diverse metabolites and growth are promoted in proportion to the CO2 concentration at a wide range of CO2 levels, from ambient concentrations to an extremely high concentration (3,600 p.p.m.) of CO2. This suggests that A. thaliana has the potential to utilize effectively very high concentrations of CO2. On the other hand, ammonium (but not nitrate) supplied as an additional nitrogen source induced drastic alterations in metabolite composition, including increases in the contents of glucose, starch and several amino acids, and reductions in the tricarboxylic acid (TCA) cycle-related organic acid content under any CO2 conditions. Hierarchical clustering analysis using the metabolite profiles revealed that ammonium is a prominent factor determining metabolic status, while the CO2 concentration is not. However, ammonium-induced metabolic alterations were differently modified by high concentrations of CO2. Hence, our results imply that increases in CO2 concentration may differently influence plant metabolism depending on the nitrogen nutrient conditions. PMID- 24343997 TI - Identification and characterization of an Arabidopsis mutant with altered localization of NIP5;1, a plasma membrane boric acid channel, reveals the requirement for D-galactose in endomembrane organization. AB - Endomembrane organization is important for various aspects of cell physiology, including membrane protein trafficking. To explore the molecular mechanisms regulating the trafficking of plasma membrane-localized proteins in plants, we screened for Arabidopsis mutants with defective localization of green fluorescent protein (GFP)-nodulin 26-like intrinsic protein (NIP)5;1. Fluorescence imaging based screening led to the isolation of a mutant which accumulated abnormal intracellular aggregates labeled by GFP-NIP5;1. The aggregates appeared in epidermal cells in the root elongation zone and included the trans-Golgi network/early endosomes. Rough mapping and whole-genome sequencing identified the mutant as an allele of UDP-glucose 4-epimerase 4 (uge4)/root hair defective 1 (rhd1) /root epidermal bulgar 1 (reb 1), which was originally defined as a cell wall mutant. The responsible gene encodes UDP-glucose 4-epimerase 4 (UGE4), which functions in the biosynthesis of d-galactose, especially for the synthesis of the cell wall polysaccharide xyloglucan and arabinogalactan proteins (AGPs). The endomembrane aggregates in the mutants were absent in the presence of d galactose, indicative of a requirement for a d-galactose-containing component in endomembrane organization. Genetic and pharmacological analyses suggested that the aggregates were not caused by the disruption of cell wall polysaccharides or the cytoskeleton. Overall, our results suggest that UGE4 activity in d-galactose synthesis is required for the structure of cell wall polysaccharides and endomembrane organization. PMID- 24343998 TI - Hoarding severity predicts functional disability in late-life hoarding disorder patients. AB - OBJECTIVE: Late-life hoarding is a serious psychiatric condition with significant implications in health and functioning. Geriatric hoarding patients show greater impairment in activities of daily living and have a greater number of medical conditions compared with same-aged nonhoarders. This study examined the relationship between geriatric hoarding severity and functional disability severity. METHODS: Sixty-five subjects age 60 or older with hoarding disorder (HD) participated in the current study. Participants were assessed with measures of hoarding severity, psychiatric symptoms, and general disability. Hierarchical regression was used to test the unique association of hoarding symptoms with functional disability beyond the effects of demographic factors, anxiety, and depression. RESULTS: When controlling for demographics (age and gender) and psychiatric symptoms (anxiety and depression), hoarding severity predicts functional disability severity. Analyses also show that clinician-administered measures of hoarding are stronger predictors of disability than patient self report measures. CONCLUSIONS: When treating older adults with HD, clinicians must consider symptom impact on daily life. A multidisciplinary team must be utilized to address the wide-ranging consequences of hoarding symptoms. Future work should examine how psychiatric treatment of HD affects functional disability. PMID- 24343999 TI - Graveoline isolated from ethanolic extract of Ruta graveolens triggers apoptosis and autophagy in skin melanoma cells: a novel apoptosis-independent autophagic signaling pathway. AB - Anti-cancer drugs generally kill cancer cells by apoptosis but fail to do so when they become resistant and escape apoptosis signals. But these resistant cells can still be killed by autophagy. Therefore, drugs having both apoptotic and autophagic abilities are solicited in effective cancer management. In search of such a drug, we examined the efficacy of graveoline, a bioactive compound isolated from Ruta graveolens on skin melanoma A375 cells through the use of specific signaling cascades and their inhibitors. Cytotoxicity of graveoline was tested by conducting MTT assay. Induction of autophagy and apoptosis was checked. Expression of related proteins and their localization were studied by conducting immunoblot assay and through confocal microscopy, respectively. We found graveoline-induced Beclin-1 associated autophagy in A375 cells and 3 methyladenine, an inhibitor of autophagy did not affect apoptosis. Conversely, caspase inhibitor that blocked apoptosis did not affect autophagic cell death, suggesting thereby that these two were independent events. Use of reactive oxygen species (ROS) scavengers inhibited cell death, but blocking autophagy did not affect graveoline-induced ROS generation, suggesting that ROS generation ensued autophagy. Thus, graveoline-induced both apoptotic and autophagic cell death in skin melanoma cells, a desirable quality in effective anti-cancer drug design. PMID- 24344000 TI - Mechanisms of antibacterial activity of MgO: non-ROS mediated toxicity of MgO nanoparticles towards Escherichia coli. AB - The toxicity of metal oxide nanomaterials and their antimicrobial activity is attracting increasing attention. Among these materials, MgO is particularly interesting as a low cost, environmentally-friendly material. The toxicity of MgO, similar to other metal oxide nanomaterials, is commonly attributed to the production of reactive oxygen species (ROS). We investigated the toxicity of three different MgO nanoparticle samples, and clearly demonstrated robust toxicity towards Escherichia coli bacterial cells in the absence of ROS production for two MgO nanoparticle samples. Proteomics data also clearly demonstrate the absence of oxidative stress and indicate that the primary mechanism of cell death is related to the cell membrane damage, which does not appear to be due to lipid peroxidation. PMID- 24344001 TI - A call to action answered: highlights from the ASBMB student-centered education in the molecular life sciences symposium. PMID- 24344002 TI - Current role of immunotherapy for the treatment of prostate cancer. AB - Chemotherapy is the conventional treatment for castration-resistant prostate cancer (CRPC) which provides only modest benefits. In the last few years, immunotherapy has emerged as an exciting therapeutic modality for advanced prostate cancer. Several characteristics of prostate cancer make it an ideal target for immunotherapy, and FDA approved recently sipuleucel-T based on improvement in overall survival (OS) in patients with CRPC. Current trials investigate the role of various immunological approaches in the treatment of prostate cancer, as far as the clinical benefit they provide is concerned and also deal with the issue of the measurability of this benefit. Future studies will focus on the combination of immunotherapeutic agents with conventional treatments in an effort to optimize patient outcomes. PMID- 24344003 TI - Sexual dysfunction in cancer patients: a review. AB - Cancer is a life-threatening disease despite the advanced therapeutic strategies now available. A common problem is that physicians and patients tend to concentrate on intensive medical treatment options and underestimate the treatment-related adverse effects. In this review, we summarize one of these adverse effects in cancer patients; sexual dysfunction (SD). In addition, current therapeutic choices with optimal doses and patient selection strategies are defined. All patients should be informed about problems associated with therapy related SD and must be guided toward the most appropriate therapeutic options before starting treatment. PMID- 24344004 TI - Impact of the obesity on lymph node status in operable breast cancer patients. AB - PURPOSE: Although many studies have shown association of obesity and tumor size, the association with the lymph node status is not clear. We examined the relationship of the lymph node status and obesity and other possible factors in early breast cancer patients. METHODS: In this retrospective cohort study, 1295 breast cancer patients who had axillary dissection were included. Patients were grouped according to their body mass index (BMI) values at the time of diagnosis. We analyzed the relationship between BMI and patient and tumor characteristics, especially lymph node status. RESULTS: The median patient age was 48 years (range 20- 84). Of the patients 69.6% had modified radical mastectomy and the remaining 30.4% had breast-conserving surgery and axillary dissection. Median BMI of the patients was 27.2 kg/m(2) and 33.1% (N-429) of them had normal BMI, 36% (N-471) were overweight and 30.5% (N=395) were obese at the time of the diagnosis. Of the patients, 44.2% had N0 disease, and 55.8% had lymph node metastasis. N1 disease had 28.3% (N=367), 13.8% (N=179) had N2 and 13.7% (N=177) had N3 disease. When patients were classified as normal (<=24.9 kg/m(2)) and obese (>24.9 kg/m(2)) group, the total number of lymph nodes removed was higher in the obese group and this difference was statistically significant (18.12+/-10.48 and 20.36+/-11.37, respectively, p= 0.001). There was strong correlation between the number of the dissected lymph nodes and BMI (r=0.11; p<0.001). However, there was no statistically significant correlation between the number of metastatic lymph nodes and BMI. The mean number of the dissected and involved lymph nodes was higher in the HER2 positive group compared to the negative ones (21 vs 19, p=0.008; 6 vs 3, p<0.001; respectively) CONCLUSION: The number of the dissected lymph nodes was slightly higher in obese patients but there was no correlation between metastatic lymph node number and BMI. The number of the dissected and involved lymph nodes was higher in the HER2 positive group. PMID- 24344005 TI - Capecitabine/cisplatin doublet in anthracycline and taxane pretreated and HER-2 negative metastatic breast carcinoma patients. AB - PURPOSE: To evaluate the activity and toxicity of the combination of capecitabine and cisplatin (CapCisp) in anthracycline- and taxane-pretreated HER-2 negative metastatic breast carcinoma (MBC) female patients. METHODS: Patients with HER-2 negative MBC pretreated with anthracycline and taxane and who were then treated with CapCisp combination were retrospectively evaluated. All patients received Cap 1000 mg/m(2) on days 1-14, and Cisp 60 mg/m(2) on day 1, repeated every 3 weeks. In case of disease control without severe toxicity, single agent Cap was continued until progression or unacceptable toxicities after Cisp cessation. RESULTS: Sixty-four MBC patients with median age 43 years (range 20-66) were included the study. Infiltrative ductal carcinoma prevailed (85.9%). Ten percent of the patients had grade I, 42% grade II, and 48.0% grade III tumors. Estrogen receptor (ER) and progesterone receptor (PR) were positive in 48.4 and 51.6% of the patients, respectively. Twenty-eight percent of the patients had triple negative tumors. Almost the entire patient group had this regimen as a third-line treatment. The median combination chemotherapy cycles were 6 (range 2-8). Twenty seven non-progressive patients continued treatment with single-agent Cap. Median single-agent Cap cycles after the combination chemotherapy were 4 (range 1-38). Disease control rate was 81.3% (complete response 6.3%; partial response 48.4%, stable disease 26.6%, progressive disease 18.8%). Median follow-up time was 10.6 months. Median time to disease progression was 7 months, median overall survival (OS) was 17 months (95% CI, 6.9-16.1) measured from the start of CapCisp chemotherapy. There were no treatment-related deaths. The most frequent grade 3-4 toxicities were neutropenia (8.1%), nausea - vomiting (7.8%) and thrombocytopenia (6.3%). CONCLUSION: CapCisp doublet has an encouraging antitumor activity with acceptable and manageable toxicity in anthracycline- and taxane-pretreated HER-2 negative metastatic breast carcinoma patients. PMID- 24344006 TI - Comparative efficacy study of 5-year letrozole or anastrozole in postmenopausal hormone receptor-positive early breast cancer. AB - PURPOSE: To compare the efficacy of adjuvant anastrozole and letrozole in hormone receptor-positive postmenopausal patients with early breast cancer. METHODS: A total of 569 hormone receptor-positive postmenopausal early breast cancer patients were included and analyzed in this study. Of them 238 were taking adjuvant anastrozole and 331 adjuvant letrozole. Demographic and medical data including age, menopausal status, weight, height, treatment history and comorbid diseases were collected from their medical charts. RESULTS: In both anastrozole and letrozole users, the baseline clinicopathologic characteristics and the treatment history with radiotherapy and chemotherapy were similar. The median patient follow-up was 26.4 months. In the anastrozole arm disease free survival (DFS) was 94.9, 81.3 and 66.0%, whereas in the letrozole arm DFS was 90.6, 78.7 and 68.5% in the first, third and fifth years, respectively (p=0.25). Median overall survival (OS) could not be reached due to the low number of events in both arms. Three-year survival rate in the anastrozole arm was 98.8%, whereas in the letrozole arm it was 96.7% (p = 0.20). CONCLUSION: This study showed that both letrozole and anastrozole have similar effects on DFS and OS in the adjuvant hormonal treatment of postmenopausal hormone receptor-positive breast cancer. We believe that this retrospective study is the first to directly compare the efficacy of letrozole and anastrozole. PMID- 24344007 TI - The relationship of insulin resistance and metabolic syndrome with known breast cancer prognostic factors in postmenopausal breast cancer patients. AB - PURPOSE: The aim of this study was to investigate the effect of metabolic syndrome and insulin resistance at the time of diagnosis on the known prognostic factors of breast cancer in postmenopausal breast cancer patients. METHODS: The study included 71 patients with a recent diagnosis of postmenopausal breast cancer, admitted at the Medical Oncology outpatient clinic of the Izmir Ataturk Training and Research Hospital between June 2010 and June 2011. We determined whether the patients had metabolic syndrome and insulin resistance at diagnosis, and recorded known prognostic factors, such as tumor size, axillary lymph node involvement, presence of distant metastasis, tumor grade, estrogen receptor (ER), progesterone receptor (PR), and CerbB-2 status. RESULTS: Among 71 patients, 25 (35%) had metabolic syndrome at the time of diagnosis, and 33 (46%) had insulin resistance with Homeostasis Model of Assessment-Insulin Resistance (HOMA-IR)>2.7. No statistically significant difference was found in the prognostic values of breast cancer, i.e. tumor size, axillary lymph node involvement, distant metastasis, tumor grade, ER, PR, and CerbB-2 status between the patients with and without metabolic syndrome. There was no statistically significant difference in the prognostic factors of breast cancer at the time of diagnosis between 33 patients with insulin resistance and 38 patients without insulin resistance. CONCLUSION: Several previous studies showed a negative relationship between metabolic syndrome and insulin resistance and prognostic factors of breast cancer in postmenopausal breast cancer patients. However, our study failed to show such a relationship. The relationship between metabolic syndrome and insulin resistance and postmenopausal breast cancer was not well demonstrated due to the small number of patients, unknown duration of the metabolic syndrome and insulin resistance, and shorter follow-up period. Further studies are required to demonstrate the effect of metabolic syndrome and insulin resistance on the prognosis of breast cancer, including larger number of patients and longer follow up periods. PMID- 24344008 TI - Age related influence of triple receptor status on metastatic breast cancer post relapse survival. AB - PURPOSE: Prognostic factors in metastatic breast cancer (MBC) differ from those of primary breast cancer. The aim of this study was to identify the clinical significance of combined estrogen and progesterone receptors (ER,PR) and human epidermal growth factor receptor-2 (HER2) status on MBC post relapse survival. METHODS: The survival of 109 MBC patients was analyzed according to clinical characteristics and ER/PR status (tested by ligand binding assay) and HER2 status (tested by chromogenic in situ hybridization/CISH). RESULTS: Proper parameters for follow up of MBC patients were patient age, duration of disease free interval (DFI), dominant site of metastasis, number of metastatic sites and ER, PR status. Follow up of MBC patients showed the statistically significant difference in post relapse survival between patients with extreme phenotypes ER+PR+ and ER-PR-. Addition of HER2 status confirmed negative effect of HER2 amplification on MBC post relapse survival resulting in worse prognosis of ER-PR-HER2+ patients. The corresponding triple receptor (ER,PR,HER2) combination repeated the same pattern. In combination with patient age it was shown that difference in post relapse survival between extreme phenotypes (ER+PR+HER2- and ER-PRHER2+) was age related i.e. patients older than 50 years, with ER-PR-HER2+ phenotype, had mortality rate 100% and median survival time 14 months. CONCLUSION: There is a strong indication for use of combined triple receptor status for follow-up of MBC patients. Based on our results, the worst phenotype was neither triple positive nor triple negative, but the one that most likely reflects the biological background of these biomarkers (ERPR- HER2+). Double and triple receptor status showed repeated pattern of influence on prognosis, but the finding that ER-PR-HER2+ phenotype in an age-restricted subgroup of patients means extremely poor prognosis and a highest mortality rate deserves further consideration regarding therapy efficiency. PMID- 24344009 TI - Prognostic factors for longer disease free survival and overall survival after surgical resection of isolated liver metastasis from breast cancer. AB - PURPOSE: Isolated liver metastases (LMs) from breast cancer (BC) occur in only 1 3% of the cases. Resection of isolated LMs improves survival. We examined the prognostic factors for time to LM development, disease free survival (DFS) and overall survival (OS) after BCLM resection. METHODS: From 2006 to 2009, 32 patients underwent LM resection. All of them had breast cancer surgery for their primary tumor and developed resectable LMs as the first and only site of disease progression. RESULTS: LMs developed after a median of 25 months. With a median follow up of 37 months (range 7-66) after metastases resection, median DFS and OS (with 95% CI) were 22.5 (12-40) and 37 (>=23) months, respectively. Tumor size >=3 vs <3 cm and adjuvant chemotherapy vs no adjuvant chemotherapy correlated with shorter time to LM development (p<0.01 for both parameters). These parameters and BC negative estrogen (ER)/ progesterone receptors (PR) (ER?/PR? vs other) were related with shorter DFS. Positive (vs negative) axillary lymph nodes and BC negative ER/ PR (ER?/PR? vs other) status correlated with shorter OS (p<0.01 for both parameters). A period to metastases development >= 24 months (vs <=24) and single (vs multiple) metastases were related with longer DFS and OS (p<0.01 for both conditions). CONCLUSION: Despite the relatively small number of patients in this study, we believe that positive ER/PR status for both BC and LMs, negative axillary lymph nodes, time to liver metastases development >24 months and single liver metastases predict longer DFS and OS after LM resection. PMID- 24344010 TI - The prognostic role of interleukin-8 (IL-8) and matrix metalloproteinases -2 and 9 in lymph node-negative untreated breast cancer patients. AB - PURPOSE: To investigate the relationships, if any, between interleukin (IL) 8/matrix metalloproteinase (MMP)-2/ MMP-9 and other prognostic variables in lymph node-negative untreated breast cancer patients, and to determine the prognostic value of these potential biomarkers. METHODS: The study included 135 patients with known clinicopathological parameters. IL-8, MMP-2 and MMP-9 levels were determined by ELISA in primary tumor tissue lysates. RESULTS: There were no significant relationships between IL-8/MMP-2/MMP-9 expression and available clinicopathological parameters (patient age, menopausal status, tumor size and tumor grade). Estrogen receptor (ER)- patients had higher levels of both IL-8 and MMP-9 (p=0.006 and p=0.04, respectively) compared to ER+ patients; there was a significant negative correlation between ER and IL-8 (p=0.02). MMP-9 expression was significantly higher in patients with higher levels of IL-8 (p<0.001) and there was a significant positive correlation between IL-8 and MMP-9, as well as between progesterone receptor (PR) and MMP-2 (p<0.001 and p=0.05, respectively). PR+ patients had higher levels of MMP-2 than PR- patients (p=0.03). Among the investigated biomarkers, only IL-8 had a statistically significant prognostic value in terms of relapse free survival (RFS) (p<0.001). Patients with higher levels of IL-8 had worse prognosis. CONCLUSIONS: Expression of IL-8 and consequently expression of MMP-9 could be hormonally regulated in breast cancer. IL-8 could be a marker of more aggressive, ER- breast cancer phenotype. Different expression of MMP-2 and MMP-9 regarding differential hormonal receptor expression could indicate distinct mechanisms of their regulation. It seems that IL-8 is a strong and independent unfavorable prognostic parameter in node-negative breast cancer. Node-negative patients with higher levels of IL-8 should be treated with adjuvant, especially IL-8 targeted therapy. PMID- 24344011 TI - The effects of anastrozole on the proliferation of FM3A cells. AB - PURPOSE: In this study, the antiproliferative effects of the aromatase inhibitor anastrozole (arimidex(r)) was evaluated on estrogen receptor (ER) positive FM3A cell line originated from C3H mouse mammary carcinoma. METHODS: For this purpose cell kinetic parameters including viability analysis, mitotic index and labelling index were used. Three different doses of anostrozole (D1= 0.01 MUM, D2= 0.1MUM, D3= 1MUM) were applied to cells for 24 h to determine the most effective dose. A dose of 1MUM dose was determined as the most effective and this was used in all subsequent applications for 0-72 h. RESULTS: The results showed that there was a significant decrease in viability, mitotic index and labelling index for all experimental groups. The differences between control and all experimental groups were statistically significant (p<0.01) for all applications. CONCLUSIONS: Anastrozole offers a promising treatment modality in estrogen sensitive breast cancer. PMID- 24344012 TI - Prognostic value of EZH2, paxillin expression and DNA ploidy of breast adenocarcinoma: correlation to pathologic predictors. AB - PURPOSE: The objective of this study was to examine the association of EZH2 and paxillin expression and DNA ploidy status with pathological parameters of breast cancer, aiming to correlate tumor phenotype with its malignant behavior. METHODS: EZH2 and paxillin expression and DNA ploidy were evaluated in imprint smear samples obtained from 105 breast tumors after surgical removal. RESULTS: Increased expression of paxillin was associated with p53 expression (p=0.005), Ki 67 expression (p=0.018) and EZH2 expression (p<0.0001). EZH2 expression correlated with estrogen receptor (ER) and progesterone receptor (PR) status (p=0.01 and p=0.035, respectively), and expression of p53 and Ki-67 (p=0.007 and p<0.0001, respectively). Aneuploid tumors were significantly correlated with poor differentiation (p=0.000), stage of disease (p=0.000), size of the primary tumor (p=0.015), presence of nodal metastasis (p=0.001), ER status (p=0.008), cerbB2 status (p=0.012), and expression of Ki-67 (p=0.001) and EGFR (p=0.018). Multivariate analysis of ploidy results using paxillin and EZH2 expression as dependent variables revealed that aneuploid tumors were associated with disease stage and grade of differentiation, cerbB2 expression and EZH2 expression. CONCLUSION: Our results show that aneuploid tumors, EZH2 expression and paxillin expression correlate with more aggressive phenotype of breast cancer. PMID- 24344013 TI - Characterization of immunohistochemical markers in triple negative breast carcinomas. AB - PURPOSE: Triple negative (TN) breast carcinomas (estrogen receptor/ER, progesterone receptor/PR and HER-2/neu negative) constitute 15-25% of all breast carcinomas and have been correlated with aggressive behavior and poor prognosis. Our aim was to describe and characterize the immunophenotype of these tumors in a group of patients from Turkey. METHODS: We used the immunohistochemical markers CK5/6, CK14, EGFR, E-cadherin, p53 and androgen receptor. Formalin-fixed, paraffin-embedded tissues from 51 breast carcinoma patients (36 TN and 15 non TN) were included into this study. RESULTS: The mean values of the distribution of immunohistochemical markers in TN vs non-TN groups were as follows: CK5/6 78.4 vs 5.3%, CK14 84.8 vs 8%, EGFR 87.2 vs 8%, E-cadherin 96.9 vs 53.2%, p53 87.3 vs 7.3% and androgen receptor 89.5 vs 33.3% (all p-values<0.001). CK5/6 stained significantly different in the grade 2 and 3 cases (p=0.035) in the TN group.The other markers demonstrated no significant differences between grades. CONCLUSION: TN breast carcinomas in Turkish patients express basal cytokeratins, and have high levels of p53 compared to non-TN breast carcinomas. PMID- 24344014 TI - Promoter methylation assay of SASH1 gene in breast cancer. AB - PURPOSE: To analyze the relationship between the expression of SASH1 and its methylation level of SASH1 gene promoter in human breast cancer. METHODS: Expression levels of SASH1 were examined in breast cancer tissues and adjacent normal tissues with immunohistochemistry and with real time PCR (RT-PCR) methylation analysis was performed with MassArray. RESULTS: Immunohistochemistry showed that SASH1 expression was strongly reduced in breast cancer compared with adjacent normal tissues. Quantitative methylation analysis by MassArray revealed that CpG sites in SASH1 promoter shared similar methylation pattern in tumor tissue and adjacent normal tissue. The CpG sites with significant difference in methylation level were CpG_26.27 and CpG_54.55. Moreover, 5-aza-2'-deoxycytidine (5-Aza-dc) treatment of tumor cell line MDA-MB-231 caused significant elevation of SASH1 mRNA. CONCLUSION: Based on these data, we propose that increase of DNA methylation level in the promoter region of gene SASH1, particularly CpG_26.27 or CpG_54.55 sites, possibly repressed SASH1 expression in breast cancer. PMID- 24344015 TI - Third-line therapy in advanced non-small cell lung cancer. AB - PURPOSE: With the improvements in first- and second-line treatments in non-small cell lung cancer (NSCLC), there is an increasing number of patients who receive third-line therapy. No other standard choice for third-line therapy aside from erlotinib is possible. This study investigated the efficacy and safety of single agent chemotherapy, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), doublet chemotherapy and chemo-targeted therapy as third-line treatment in advanced NSCLC. METHODS: This study included 233 stage IIIb or IV NSCLC patients who were retrospectively reviewed to explore the differences in survival between different treatments. RESULTS: The median progression free survival (PFS) in the EGFR-TKIs, single-agent, doublet and chemo-targeted groups was 3.83, 2.72, 2.86 and 3.29 months, respectively (p = 0.073). The median OS from the initiation of the third-line treatment was 11.16, 8.24, 8.49 and 9.33 months in the 4 groups (p=0.02). The rates of grade IIIIV toxicities were 16.4, 27.6, 57.3 and 44.0% ( p <0.001), respectively with the third-line treatment, and overall survival (OS) was prolonged in patients who never smoked (p=0.040), had adenocarcinoma (p=0.034), had good ECOG performance status (PS) (p=0.012) and achieved disease control after both first-and second-line treatments (p =0.031). CONCLUSION: Patients with advanced NSCLC who never smoked, had adenocarcinoma, have good PS, and good disease control from the first- and second-line therapies could benefit more with third-line treatment. EGFR-TKIs and chemo-targeted therapy showed increased OS compared with single-agent and doublet chemotherapy. PMID- 24344016 TI - Lentivirus-mediated shRNA interference targeting cyclooxygenase-2 inhibits growth of human non-small cell lung cancer. AB - PURPOSE: Cyclooxygenase-2 (COX-2), one isoform of cyclooxygenase proinflammatory enzymes, plays an important role in tumor development and progression. Researches of human cancers have revealed high expression levels of COX-2 in a variety of cancers including lung cancer. The mechanism of COX-2 in the pathogenesis of non small cell lung cancer (NSCLC) cells is not well understood. METHODS: We constructed a lentivirus vector mediated RNA interference (RNAi) targeting COX-2 for the treatment of human NSCLC cells. RNAi technology was used to knockdown the expression of COX-2 in NSCLC cell lines. The efficiency and specificity was validated by quantitative real-time PCR and western blotting. The cell growth and cell cycle were determined by MTT and flow cytometry assay, respectively. Cell cycle-regulated gene expression, including cyclin D1, p21 and survivin, whose expression was modulated by COX-2, was also examined. RESULTS: LV-COX-2-silencing (si)RNA lentivirus vector was effective and its inhibitory effects on COX-2 mRNA and protein expression was efficient and specific. Gene knockdown of COX-2 by LV COX-2-siRNA significantly inhibited the growth and induced cell cycle arrest of NSCLC cell lines. In addition, silence of COX-2 mediated by LV-COX-2-siRNA modulated the expression of cell cycle-regulated gene, upregulating p21 and downregulating cyclin D1 and survivin. CONCLUSIONS: Our findings imply that COX-2 and its signaling pathway may provide a novel therapeutic target for the treatment of NSCLC. PMID- 24344017 TI - Stress protein Hsp27 expression predicts the outcome in operated small cell lung carcinoma and large cell neuroendocrine carcinoma patients. AB - PURPOSE: Heat shock protein (Hsp)27 is overexpressed in a range of human cancers and is implicated in tumor cell proliferation, differentiation, invasion, metastasis, and survival. The aim of the present study was to determine the prognostic significance of Hsp27 expression in small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC). METHODS: Surgically resected SCLCs (N=51) and LCNECs (N=15) were studied. The Hsp27 expression was detected immunohistochemically. RESULTS: Hsp27 positive immunoreaction in the cytoplasm was observed in 45 (88%) SCLCs and 14 (93%) LCNECs. A combination of cytoplasmic with nuclear Hsp27 expression was observed in 28 (62%) SCLCs and 14 (100%) LCNECs. There was a correlation between Hsp27 cytoplasmic overexpression and Hsp27 nuclear expression with patient survival confirmed by Cox multivariate analysis. CONCLUSION: We conclude that the higher Hsp27 cytoplasmic expression and nuclear expression may represent favorable prognostic factors in SCLC and LCNEC. PMID- 24344018 TI - Clinical and prognostic importance of XIAP and USP8 in advanced stages of non small cell lung cancer. AB - PURPOSE: To investigate the relationship of the apoptosis regulators X-linked inhibitor of apoptosis (XIAP) and ubiquitin specific protease 8 (USP8) with clinical parameters, survival and response to chemotherapy in patients with advanced stages of non-small cell lung cancer (NSCLC). METHODS: The study included 34 NSCLC patients (28 females, 6 males) and 44 healthy individuals (17 males, 27 females) as a control group. XIAP and USP8 levels were determined by ELISA. RESULTS: The median serum XIAP level of the patients and the control group showed no significant difference. USP8 level was higher in patients than in controls (p<0.0001). In univariate analysis, there was no significant relationship between XIAP and USP8 serum levels and age, sex, performance status, weight loss, stage of disease, histopatological type and response to chemotherapy. Response to chemotherapy did not differ between the high and low XIAP and USP8 groups . There was no significant difference in progression- free survival (PFS) (p=0.432 and p=0.50, respectively) and overall survival (OS) (p=0.989 and p=0.90, respectively) between the low and high XIAP and USP8 groups. CONCLUSION: No relationship was found in serum XIAP and USP8 levels with clinical parameters, response to chemotherapy, PFS and OS in patients with advanced stages of NSCLC. PMID- 24344019 TI - Differential diagnosis of pulmonary lesions by parametric imaging in (18)F-FDG PET/CT dynamic multi-bed scanning. AB - PURPOSE: Benign and malignant pulmonary lesions are not easy to distinguish in a clinical setting. We investigated the feasibility of using parametric imaging of the rate constant Ki to diagnose the nature of pulmonary lesions. METHODS: Dynamic multi-bed scanning followed by a routine examination was performed on 21 patients with pulmonary lesions who were divided into two groups with malignant or benign lesions based on biopsy and follow-up. The number of patients in the malignant and benign groups were 10 with 15 lesions and 11 with 14 lesions, respectively. The left ventricular blood pool was used for an image-derived input function. The influx rate constant Ki of the pulmonary lesions and parametric images was generated with the Patlak plot method, and the inter-group differences for Ki, maximum standardized uptake value (SUVmax), and the time-activity curves (TAC) of fluorine-18-fludeoxyglucose ((18)F-FDG) were analyzed. At the same time, we investigated the correlation of Ki to SUVmax. RESULTS: The maximum diameters of the pulmonary lesions were not significantly different between the malignant and benign groups (p>0.05). Ki and SUVmax were significantly higher in malignant lesions compared to benign lesions (p<0.05). Ki was highly correlated with SUVmax in pulmonary lesions (r=0.815, p<0.01). The malignant lesions showed gradually increasing TAC, and benign lesions exhibited gradually decreasing curves. The parametric images of Ki were useful to distinguish malignant lesions from normal tissue. CONCLUSION: Our results indicate that Ki parametric imaging in (18)F-FDG PET/computed tomography (CT) dynamic multi-bed scanning may be useful in the differential diagnosis of pulmonary lesions. PMID- 24344020 TI - Diagnostic value of PET/CT in differentiating benign from malignant solitary pulmonary nodules. AB - PURPOSE: Solitary pulmonary nodules (SPNs) are round or oval lesions with a clear border with the surrounding parenchymal tissue and a radiologic diameter smaller than 3 cm which are not associated with atelectasis, pneumonia, lymphadenopathy, or chest wall pathologies. The purpose of the present study was to evaluate the efficacy of positron emission tomography (PET) / computerized tomography (CT) in differentiating benign from malignant SPNs. METHODS: In this retrospective study, 209 patients, who were diagnosed with SPN by thoracic CT and demonstrated positive or negative results for malignancy in the PET/ CT examination between January 2007 and June 2010, were enrolled. Among the 91 patients who gave consent for interventional procedures, performed were bronchoscopic endobronchial biopsy in 10, transbronchial biopsy in 15, bronchoscopic brushing in 4, transthoracic needle biopsy in 11, video-assisted thoracoscopy (VATS) in 4, lobectomy in 22, pneumonectomy in 2, and wedge resection in 23. The materials were histopathologically examined. RESULTS: 129 (61.72%) of the SPN cases were benign and 80 (38.27%) malignant. The mean SUVmax value for the benign SPNs was 2.06 +/- 3.29 and 7.39+/-5.69 for the malignant SPNs (p=0.000). Positive correlation was found between the nodule diameter and risk for malignancy. A SUVmax value of 4 was found to have the best sensitivity and specificity. CONCLUSION: PET/CT was shown to be an accurate method in the differential diagnosis of benign from malignant solitary pulmonary nodules. PMID- 24344021 TI - Evaluation of efficacy and toxicity in two different hypofractionated 3D conformal external beam radiotherapy schedules in localised muscle invasive bladder cancer. AB - PURPOSE: To evaluate the efficacy as well as acute and late toxicity of two different accelerated hypofractionated 3D-conformal radiotherapy (Hypo-3DCRT) schedules in patients with bladder cancer. METHODS: Between February 2006 and June 2011, 50 elderly patients with cT1-2N0 bladder carcinoma were treated with Hypo-3DCRT. Mean age was 75 years. All patients were medically inoperable, with poor performance status, who couldn't tolerate either cystectomy or radical external beam irradiation on a daily basis. A dose of 36 Gy in 6 weekly fractions (arm A, N=39) or 39.96 Gy of 3.33 Gy twice daily, once a week, for 6 weeks (arm B, N=11) were prescribed. The primary study endpoints were the evaluation of acute/late gastrointestinal (GI) toxicity according to the EORTC/RTOG scale together with the visual analogue bladder-related pain score (VAS). RESULTS: The GI acute toxicities were: grade 1: arm A 24/39 (61.5%), arm B 9/11 (81.8%); grade 2: arm A 14/39 (35.9%), arm B 1/11 (9.1%); grade 3: arm A 1/39 (9.1%) (x(2), p=0.29). Only grade 1 late GI toxicity was seen and was significantly higher in arm A: arm A 17/39 (43.6%) and arm B 1/11 (9.1%) (x(2), p=0.037). The reduction of VAS score was similar in both arms (p=0.065). The median relapse free survival (RFS) was 15 and 16 months for arm A and B, respectively (log rank, p=0.71). CONCLUSIONS: Beyond the non-randomized design of the trial, the Hypo-3DCRT schedules used appear to be an acceptable alternative to the traditional longer radiotherapy (RT) schedules for elderly patients unfit for daily irradiation. PMID- 24344022 TI - Neoadjuvant hormonal therapy in prostate cancer - impact of PSA level before radiotherapy. AB - PURPOSE: To retrospectively investigate the impact of prostate specific antigen (PSA) level after neoadjuvant androgen- deprivation therapy (ADT) on biochemical relapse-free survival in patients with prostate cancer who received radical radiotherapy (RT). METHODS: Between March 2003 and March 2008, 128 men with localized prostate cancer underwent neoadjuvant ADT for 4-6 months followed by radical RT. Biochemical relapse-free survival was compared between patients with pre-RT PSA <= 0.1 vs > 0.1 ng/mL. RESULTS: At a median follow up of 47.3 months, biochemical relapse-free survival was significantly higher in patients with a pre RT PSA <= 0.1 ng/mL compared with pre-RT PSA > 0.1 ng/mL (85.6 vs 63.2%, p = 0.0025). CONCLUSION: The current analysis demonstrating better treatment outcome in patients with excellent biochemical response to neoadjuvant ADT, supports an individualized treatment strategy. PMID- 24344023 TI - Preoperative Gleason score, percent of positive prostate biopsies and PSA in predicting biochemical recurrence after radical prostatectomy. AB - PURPOSE: To determine the factors that can improve the prediction of biochemical recurrence after radical prostatectomy for the patients with prostate adenocarcinoma. METHODS: Our study included 182 patients with prostate adenocarcinoma who were biopsied and underwent radical surgical treatment at the Clinic of Urology, Clinical Center of Serbia, Medical Faculty in Belgrade from 1994 to 2004. Patients were prospectively followed-up and monitored for a minimum of 8 years and data were statistically processed by multivariate regression analysis. We arranged the predictors into 3 regressive models. In the first model the predictors were clinical stage of the disease, preoperative Gleason score, F/T PSA ratio and PSA. In the second model these predictors were accompanied with the number of positive biopsies and percent of positive prostate biopsies. In the third model, patient follow-up was added to the predictors. In all 3 models biochemical recurrence was considered as a dependent variable. RESULTS: On multivariate analysis, patient follow-up (p<0.0001), percent of positive prostate biopsies (p<0.0001), bioptic Gleason score (p<0.0001) and preoperative PSA (p<0.003) were significant independent predictors of biochemical recurrence. The most successful prediction of recurrence that provided accurate prognosis for 80% of the patients was obtained by the third model using the percent of positive prostate biopsies, PSA and patient follow-up. CONCLUSION: As stated in multivariate analysis, the independent predictors according to the significance are the follows: patient follow-up, percent of positive prostate biopsies, bioptic Gleason score and preoperative PSA, whereas preoperative F/T PSA ratio is dependent predictor. The number of positive biopsies and clinical stage of the disease are of no significance. PMID- 24344024 TI - Genetic polymorphisms of vitamin D receptor and the risk of prostate cancer: a meta-analysis. AB - PURPOSE: Vitamin D receptor (VDR) polymorphisms are considered to be risk factors for prostate cancer. However, previous case-control studies on the association between the variants of VDR and prostate cancer have shown contradictory results. Therefore, the role of VDR in prostate cancer remains unresolved. To investigate a potential correlation between VDR polymorphisms and prostate cancer risk, a meta-analysis of case-control and cohort studies was conducted. METHODS: Eligible studies were retrieved via both computerized searches and review of references. The association of VDR polymorphisms to prostate cancer was evaluated for 4 well known VDR polymorphisms (FokI, BsmI, ApaI and TaqI) separately. Stratified analyses on ethnic characteristics (Caucasians or Asians), cancer stage (localized or advanced) and Gleason score (<7 or >>7) were performed. Fixed- or random-effect models were used to summarize the estimates of odds ratio (OR) with 95%CI according to the heterogeneity. Sensitivity analyses were conducted. RESULTS: A total of 40 studies met the inclusion criteria of the meta-analysis. The FF genotype illustrated a protective effect on prostate cancer in the Caucasian subgroup (OR=0.905, 95%CI 0.823, 0.995). Conversely, the bb and the TT genotypes were associated with increased risk of prostate cancer (OR=0.838, 95%CI 0.709,0.990; OR=1.127, 95%CI 1.023,1.242, respectively). CONCLUSION: Our analysis supported the hypothesis that several different VDR polymorphisms may increase the risk of prostate cancer. However, others illustrated a protective effect on carcinogenesis. Further efforts should be made to establish the mechanisms between VDR polymorphisms and prostate cancer. PMID- 24344026 TI - Determination of matrix metalloproteinase 9 (MMP-9) protein expression in laryngeal squamous cell carcinomas based on digital image analysis. AB - PURPOSE: Matrix metalloproteinases (MMPs) is a superfamily of proteins involved in angiogenesis and metastatic tissue invasion in many cancers. Overexpression of MMP- 9 has been detected in significant proportions of laryngeal squamous cell carcinomas (LSCCs), but its prognostic impact remains unclear. In this study we performed a digital image analysis for analyzing MMP-9 protein expression in a series of LSCCs correlating them with clinicopathological factors. METHODS: MMP-9 protein expression level was determined immunohistochemically in 30 tissue sections surgically derived from patients (21 male and 9 female) with LSCC. Using digital image analysis, we measured their corresponding protein expression levels (staining intensity/S.I. range values 0-255). RESULTS: Moderate and high MMP-9 protein expression levels (grouping as 2+/3+ overexpression) were detected in 19/30 (63.3%) cases. Statistical significance was observed correlating stage with SI (p=0.02), whereas a borderline association with differentiation grade of the examined tumors was also registered (p=0.05). Interestingly, high levels of MMP-9 expression were observed in cases that demonstrated a significant level of inflammatory (predominantly lymphocytic) infiltration. CONCLUSION: MMP-9 protein overactivation is a frequent and significant genetic event in LSCC, correlating with its biological behavior (increased TNM stage). MMP-9 seems to mediate an epithelial-stromal intra-reaction correlating also with induction of specific inflammation pathways. PMID- 24344025 TI - Experience with intensity-modulated radiotherapy in the treatment of head and neck cancer. AB - PURPOSE: Studies using intensity-modulated radiation therapy (IMRT) in the treatment of head and neck tumors have shown to decrease acute and late radiation toxicity. However, the high conformity of this technique can increase the risk of recurrence due to geographic miss. The aim of this study was to analyze whether the results of IMRT met the theoretical expectations concerning treatment efficacy. METHODS: From a total of 185 patients (152 males and 33 females, mean age 58+/-10.36 years) 176 were evaluable and were studied. Eighty-nine (48.1%) patients had surgical treatment and 50 of them were scheduled for concomitant cisplatin chemotherapy. Irradiation was performed using IMRT, a sliding window with 9 fields in a Varian 2100 C/D linear accelerator, X-ray beam, 6 MeV. The prescribed dose in the planning treatment volume (PTV1), i.e., the area of the primary tumor and nodal area, was 66 Gy/2.2 Gy-70 Gy/2.12 Gy. In the PTV2 (the area at high risk) the dose was 60Gy/2 Gy-59.4 Gy/ 1.8 Gy, and in the PTV 3 (the area treated with prophylactic irradiation) the prescribed dose was 54 Gy/1.8 Gy/50.4 Gy/1.53 Gy. RESULTS: The 3-year overall survival (OS) and relapse-free survival (RFS) of IMRT-treated patients, most of whom were in stages III and IV (158 out of 177), were 50 and 57%, respectively. Using postoperative radiotherapy/chemoradiotherapy 3-year locoregioncal control was achieved in 75% of the cases as compared with 35% in non-operated patients. CONCLUSIONS: The worst outcomes were found in oral cavity and hypopharyngeal tumors, and the best in laryngeal and oropharyngeal tumors. Better results were found in surgically treated patients, and in lower disease stages. Despite the high conformity of dose distribution and efforts to spare healthy tissues, most cases of locoregional relapse occurred in areas receiving the full radiation dose. If dividing relapses into cases of persistence and local recurrence, the former predominated. PMID- 24344028 TI - What is the significance of a microscopically positive resection margin in the curative-intent treatment of rectal adenocarcinoma? A retrospective study. AB - PURPOSE: The aim of this study was to analyze the characteristics of patients with rectal cancer operated with a microscopic positive margin (R1) and thus avoid these situations or adapt treatment in these particular cases. METHODS: We reviewed all the pathology data of resected specimens from patients with rectal or recto-sigmoid cancer operated with curative intent at the Institute of Oncology "Prof. Dr. Ion Chiricuta" between 2000-2011 (763 patients in 12 years) and the pathology files of patients from other institutions referred for adjuvant treatment to our hospital (318 patients). We included patients with anterior resection, Hartmann's procedure and abdomino-perineal resection, but we excluded patients with local excision and patients with R2/R1 at first, but R0 after re resection (56 patients). We have identified 31 patients with R1, but had to exclude one case from analysis because this patient was lost to follow-up. RESULTS: With surgery alone the local relapse (LR) was unavoidable. In the neoadjuvant chemoradiation (CRT) group 85.7% of the patients did not develop LR despite of R1. In the adjuvant CRT cohort 50% of the patients were LR-free at 2 years after conventional radiotherapy (p<0.01). CONCLUSION: Based on these results it is concluded that a clear resection margin is extremely important for the local control of rectal cancer, because it cannot be always compensated by adjuvant CRT. In R1 cases neoadjuvant CRT seems to offer better prognosis than adjuvant CRT. To avoid R1 and its consequences a good quality control of total mesorectal excision (TME) is needed and CRT should be done before and not after surgery. R1 after primary surgery needs to be compensated by re-resection if possible, otherwise probably high dose radiotherapy with chemotherapy is needed. PMID- 24344027 TI - Combination of p16 levels and pre-radiotherapy factors predicts outcome in patients treated for oropharyngeal carcinoma. AB - PURPOSE: To explore whether tumor biomarkers and pre-treatment factors correlate with treatment outcome in patients with oropharyngeal squamous cell carcinoma (SCC). METHODS: Fifty-seven consecutive patients diagnosed with oropharyngeal SCC were treated using intensity modulated radiotherapy (IMRT). Thirty-four (60%) patients were treated with definitive chemoradiotherapy to a median total dose of 70 Gy and 23 (40%) were treated with postoperative RT to a median total dose of 66 Gy. Concurrent platinum- based chemotherapy was used in 51 patients (90%) and cetuximab in 3 (5%) patients. RESULTS: Forty-four (77%) cases were positive and 13 (23%) were negative for p16 expression. Eighty-eight percent of non-smokers, 87% of smokers in their remote past and 56% of active smokers were diagnosed with p16-positive cancer. After 22 months median follow up, 51 (89%) patients were alive. Forty-five (77%) patients were without evidence of disease at their last follow up, 82% of the patients with p16-positive tumors vs 58% of those with p16 negative cancer, respectively (p= 0.04). Locoregional disease-free survival was 82% for the entire cohort, 91% for patients treated postoperatively and 76% for patients treated with definitive chemoradiotherapy. Five (9%) patients developed distant metastases, and 3 (5%) developed new malignancies. One third of the patients with pre-RT hemoglobin level of <= 11 g/dL experienced persistent/recurrent disease; 80% of patients with hemoglobin <= 11 g/dL were smokers and 42% had p16-negative tumors. CONCLUSIONS: Smoking, p16 expression and pre-RT anemia are interrelated and influence outcome in oropharyngeal cancer patients and should be evaluated as stratifying variables in further clinical trials. PMID- 24344029 TI - Proteomic studies of multiple myeloma in RPMI8226 cell line treated with bendamustine. AB - PURPOSE: Multiple myeloma (MM) is a malignant and incurable neoplasm of plasma cells that accumulate in the bone marrow. Bendamustine, an antitumor agent including double property of alkylating agent and purine analogues, displayed clinical antitumor activity in patients with MM. However, the precise mechanism of action of bendamustine has not been completely elucidated. METHODS: In this study, we established the cell model of bendamustine-induced MM RPMI8226 cell apoptosis, and used two dimensional differential in-gel electrophoresis (2D-DIGE) proteomics to analyze the bendamustine-induced protein alterations. RESULTS: Our results revealed that compared with control group, bendamustine significantly inhibited the proliferation of RPMI8226 cells in a concentration-dependent and time-dependent manner. Proteomic approach was performed to identify 30 differentially expressed proteins in RPMI8226 cells upon bendamustine treatment, which included 15 up-regulated and 15 down-regulated proteins. Of these, protein disulfide isomerase A3 (PDIA3) and cytokine- induced apoptosis inhibitor 1 (CPIN1), were selected for further studies. CONCLUSION: These results implicate PDIA3 and CPIN1 as potential molecular targets for drug intervention in MM and thus provide novel insights into the mechanisms of antitumor activity of bendamustine. PMID- 24344030 TI - CDC25B, Ki-67, and p53 expressions in reactive gliosis and astrocytomas. AB - PURPOSE: To investigate the expression of CDC25B, which is a member of the cyclin dependent kinase activating phosphatase family, in diffuse astrocytoma (DA), anaplastic astrocytoma (AA), glioblastoma multiforme (GBM), pilocytic astrocytoma (PA) and reactive gliosis (RG). Also, to study the relationship of the expression level of CDC25B with clinical parameters and with p53 and Ki-67 proliferation index (PI). METHODS: Tissues were collected from 36 cases diagnosed with astrocytoma (10 DA, 6 AA, 20 GBM), 10 PA, 10 RG and 10 normal brain tissues for controlling purposes. The sections were immunohistochemically stained with CDC25B, Ki-67 and p53. For each marker, 1000 tumor cells were counted and the ratio of positive tumor cells was calculated. RESULTS: The average CDC2B staining index (CSI) was 0.6% in PA, 0.4% in DA , 7.7% in AA and 25.5% in GBM. The increase of CSI in parallel with the increase of WHO grade was significant (p=0.001). No expressions were identified in RG and normal brain. There was also significant relationship between the tumor size and CSI (p=0.027) and also between Ki-67 PI and CSI (p=0.001). Among the groups with low and high CSI in astrocytoma cases, the disease free survival (DFS) was significantly higher in the low CSI group (p=0.0001). CONCLUSIONS: Positive expression of CDC25B in astrocytoma affects the prognosis in an adverse manner. CSI can be used as a diagnostic method and CDC25B may be a possible target molecule for treatment. PMID- 24344031 TI - Preclinical evidence for the antihyperalgesic activity of CDP-choline in oxaliplatin-induced neuropathic pain. AB - PURPOSE: This study was designed to evaluate the antihyperalgesic effect of CDP choline (cytidine-5'-diphosphate- choline; citicoline) in a rat model of neuropathic pain produced by oxaliplatin (OXA). METHODS: A single administration of OXA (6 mg/kg intraperitoneally/ ip) was used for induction of neuropathy. We assessed the antihyperalgesic effect of intracerebroventricularly (icv) administered CDP-choline (0.5, 1.0 and 2.0 MUmol) using the rat paw pressure test (Randall-Selitto). RESULTS: CDP-choline significantly reduced OXA-induced mechanical hyperalgesia, in a dose- and time-dependent manner. The antihyperalgesic effect of CDP-choline was blocked by the neuronal high affinity choline uptake inhibitor hemicholinium-3 (1 MUg; icv), the nonselective nicotinic receptor antagonist mecamylamine (50 MUg; icv), the alpha7 selective nicotinic acetylcholine receptor antagonist alpha-bungarotoxin (2 MUg; icv), and the gamma amino butyric acid (GABA)-B receptor antagonist CGP-35348 (20 MUg; icv), but not by the nonselective opioid receptor antagonist naloxone (10 MUg; icv) and the nonselective muscarinic receptor antagonist atropine (10 MUg; icv). CONCLUSION: These findings indicate that CDP-choline exerts an antihyperalgesic effect in OXA induced neuropatic pain and it can be tested in clinical trials. PMID- 24344032 TI - The importance of the blood levels of homocysteine, folic acid and vitamin B12 in children with malignant diseases. AB - PURPOSE: Hyperhomocysteinemia is associated with carcinogenesis. Since only little research exists on hyperhomocysteinemia and malignancy in children, the possible relationship between homocysteine and childhood malignancies remains unknown. The aim of the present study was to determine the serum levels of homocysteine, folic acid and vitamin B12 in children with malignant and benign tumors prior to therapy (surgical treatment and/or chemotherapy), and after treatment of malignant diseases as well. METHODS: Forty-six children with newly diagnosed malignant diseases (solid tumors and lymphoproliferative/myeloproliferative (LP/MP) malignancies) and 6 children with benign tumors were included in the present study. The patient age ranged between 2 months and 18 years. RESULTS: Significantly increased homocysteine concentrations were identified in children with malignant diseases compared with those with benign tumors (p<0.01). The plasma concentration of homocysteine in children with malignant diseases decreased significantly following treatment (p<0.05). Before treatment, the concentration of folic acid in children with malignant solid tumors was significantly higher than in children with malignant LP/MP diseases (p<0.01). Following treatment, the concentration of folic acid was significantly decreased (p<0.05) in children with malignant solid tumors, while it was not significantly increased in children with malignant LP/MP diseases (p<0.05). The concentration of vitamin B12 in children with malignant diseases (solid tumors and LP/MP diseases) increased significantly following treatment (p<0.01), while it increased substantially (p<0.01) in patients with solid malignancies following treatment. CONCLUSION: Homocysteine could be a marker of malignancy in children. Further research is needed to establish the importance of homocysteine, folic acid and vitamin B12 in pediatric malignant diseases. PMID- 24344033 TI - Clinicopathological features and management of hepatic vascular tumors. A 20-year experience in a Greek University Hospital. AB - PURPOSE: The aim of this study was to review the clinical features, diagnostic modalities, treatment options and pathological characteristics of various types of hepatic vascular tumors treated in our Institution over the last 20 years. METHODS: From 1991 to 2011, 761 cases of various hepatic lesions, benign and malignant, were surgically treated in our hospital. Among these, 56 (7.35%) hepatectomy specimens referred to vascular tumors. The records of these patients were retrieved and demographics , tumor characteristics, treatment, and actuarial survival were analyzed. The various therapeutic procedures, postoperative complications, follow-up data and the pre-and postoperative diagnostic difficulties were registered and analyzed. RESULTS: Pathological examination showed: hepatic hemangiomas in 35 (62.5%) patients (80% females), hepatic angiosarcomas in 7 patients (12.5%; males 71.4%), hepatic epithelioid hemangioendotheliomas in 9 (16%; females 50%) and hepatic angiomyolipomas in 5 patients (9%; females 60%). CONCLUSIONS: Vascular tumors of the liver comprise a heterogeneous group of neoplasms, benign, malignant and of intermediate degree of malignant behavior. These lesions can create great diagnostic difficulties, pre- and postoperative considerations, but the correct pathological diagnosis and classification of vascular hepatic tumors are most of the times mandatory in order to choose the proper therapeutic actions. PMID- 24344034 TI - Histone deacetylase inhibitors suppress the growth of human osteosarcomas in vitro and in vivo. AB - PURPOSE: Although the antitumor efficacy of histone deacetylase inhibitors (HDACIs) has been referred to as a promising new treatment strategy in malignancies, how they exert their effects on human osteosarcoma in vitro and in vivo is yet not well understood. In this study, we employed HDACIs suberoylanilide hydroxamic acid (SAHA) and sodium butyrate (SB) to investigate their effects on human osteosarcoma in vitro and in vivo. METHODS: The in vitro effects of HDACIs SAHA and SB were evaluated in SaOS2 and U2OS human osteosarcoma cell lines. Cell growth, cell cycle progression and histone acetylation were investigated by MTS, flow cytometry and western blotting, respectively. In addition, SAHA or SB was administered for 4 weeks in mice xenograph models for assessing the in vivo effects. RESULTS: MTS assays revealed that SAHA and SB significantly suppressed the growth of SaOS2 and U2OS cells in a concentration dependent manner. Western blotting analysis indicated that the levels of acetylated H3 were increased after HDACIs treatment. Flow cytometry showed that SAHA arrested the cell cycle in G1 and G2/M phase, while SB arrested the cell cycle in G2/M phase. The tumor growth of mice xenograph models with SaOS2 was inhibited by SAHA and SB compared with vehicle control. CONCLUSION: HDACIs SAHA and SB significantly inhibit the growth of human osteosarcoma cells and induce cell cycle arrest. The tumor inhibitory effects were also validated in mice xenograft models. PMID- 24344035 TI - Cancer burden of breast and gynecological cancers in Bulgaria: epidemiology and clinical aspects. AB - PURPOSE: In Bulgaria, there are over 3700 cases diagnosed with breast cancer annually and over 3300 with gynecological cancers. The purpose of this study was to estimate the burden of breast and gynecological cancers in Bulgaria, analyzing trends of incidence, mortality and survival for the past two decades. METHODS: Data from the Bulgarian National Cancer Registry for women diagnosed with cancer of breast (C50, ICD10), cervix uteri (C53), corpus uteri (C54) and ovary (C56) during 1993 - 2009 were analyzed. Age-standardized incidence and mortality rates (ASR) per 100,000 persons were calculated using the world standard population. Average annual percent changes (AAPC) for 1993-2009 were estimated by Joinpoint regression. The observed survival was analyzed with the Life Table method for two periods: 1993-1997 and 2005-2009. RESULTS: Incidence rates of the most frequent cancers among Bulgarian women are increasing - from 1.7% to 2.6% annually. Mortality rates are decreasing significantly for breast (-0.8% annually) and increasing for corpus uteri cancers (4.9% annually). Survival for all sites increased from 3 to 8% over the study period. We observed greater proportion of cases diagnosed in stage I in 2009 than in 1993, for the 4 sites. CONCLUSION: These results indicate some differences in trends in incidence and mortality of the reviewed sites compared with other European countries, highlighting the need for more strict adherence to integrated treatment standards and the necessity of introduction of population screening programs. PMID- 24344036 TI - Significance of using DICOM communication standard in quality assurance in radiation oncology - an institutional experience. AB - PURPOSE: The purpose of this article was to highlight the importance of data management systems in radiotherapy. METHODS: We performed a database search to review the errors or potential errors in radiotherapy planning and delivery which could be prevented in case of using the DICOM communication system. RESULTS: We registered the following rates of errors: 1) Errors caused by manual rewriting of treatment plan 30%; 2) Errors caused by wrong assignment of the verification system 15%; 3) Errors during the manual rewriting of treatment data to the verification system 15%; 4) Patient identification 5%; 5) Field verification 15% 6) Wedge orientation 10%. CONCLUSION: DICOM communication system may significantly improve the quality assurance in radiotherapy. PMID- 24344037 TI - The prevalence of usage of herbal medicines among cancer patients. AB - PURPOSE: To study the prevalence of the usage of herbal medicines among cancer patients. METHODS: This study was carried out between October 1, 2009 and May 31, 2011, by using face-to-face interviews with cancer patients attending oncology departments (clinics and outpatient clinics, chemotherapy units). A special questionnaire was filled in during the interviews. RESULTS: Of the patients 68.2% reported usage of herbal medicines, 66% stated that their usage of herbal medicines was based on the media and the Internet as a source and 64% stated that they received information about herbal medicines from relatives and friends. Only 24% of herbal medicines users had consulted or discussed their use with a physician. CONCLUSION: In Turkey, especially among cancer patients, there is a high prevalence of complementary and alternative medicine (CAM) usage and the most commonly used form of CAM is herbal medicines. This prevalence has also been found to be high in our research as well. Due to the probable side effects and potential drug interactions of herbal agents, all cancer patients should be asked about their use of herbal medicines. PMID- 24344038 TI - Can the epirubicin cardiotoxicity in cancer patients be prevented by angiotensin converting enzyme inhibitors? AB - PURPOSE: The aim of this study was to assess whether treatment with angiotensin converting enzyme inhibitors (ACEI) can prevent the alteration of left ventricular systolic and diastolic performance in cancer patients treated with different chemotherapy regimens containing epirubicin. METHODS: In this prospective study , 68 patients with different malignant tumors treated with epirubicin and perindopril in different chemotherapy protocols (study group), and a gender- and age-matched group of 68 patients with different malignant tumors treated with epirubicin without perindopril in different chemotherapy protocols (control group), were assessed by Doppler echocardiography. Left ventricular systolic function was assessed by measuring left ventricular ejection fraction (EF). Left ventricular diastolic function was assessed by Doppler ultrasound by evaluating the transmitral flow. We also assessed the QTc on the 12 lead electrocardiograms. RESULTS: At the end of chemotherapy the left ventricular systolic function was less altered in the study group compared to the control group and was superior in the study group (epirubicin+ACEI) compared to the control group (epirubicin alone). We documented a significantly deteriorated left ventricular diastolic function in both groups at the completion of chemotherapy. QTc time in both arms was also significantly prolonged. CONCLUSION: In the present echo-Doppler study we documented a preserved left ventricular systolic performance in patients with various malignancies treated with epirubicin plus perindopril. Although co-treatment with ACEI prevented the alteration of systolic performance, it failed to prevent the deterioration of the left ventricular diastolic performance impairment due to poor left ventricular compliance. PMID- 24344039 TI - Administration of gemcitabine and cisplatin in cancer patients with renal failure under hemodialysis. AB - PURPOSE: There is no optimal dosing schedule of gemcitabine (GEM) and cisplatin (CDDP) combination for cancer patients with renal failure (RF) on hemodialysis (HD). The purpose of this study was to share our experience of using GEM and CDDP in such patients. METHODS: The starting dose of GEM was defined based on single agent treatment of two cancer patients with RF. Between November 2006 and June 2009, 4 RF cancer patients on HD received a GEM and CDDP combination chemotherapy (CDDP 30mg/m(2) on days 1, 8, 15 and GEM 600mg/m(2) on day 15; repeated every 28 days). The HD was conducted within 24 hours after the completion of GEM and/or CDDP administration. RESULTS: Reduced-dose GEM and CDDP combination showed efficacy and good tolerability for cancer patients with RF under HD. PMID- 24344040 TI - In vitro study on the effect of doxorubicin on the proliferation markers MCM3 and Ki-67. AB - PURPOSE: Aberrant proliferation is an essential feature of cancer cells, which can be caused by alterations in components of the cell cycle, such as minichromosome maintenance protein-3 (MCM3) and Ki-67. Doxorubicin is a cytotoxic/cytostatic anticancer agent commonly used in chemotherapy. We investigated the effect of this drug on MCM3 and Ki-67 in the KB cell line, which is considered a subline of HeLa cell line. METHODS: KB cells were treated with doxorubicin and its effect on apoptosis, mRNA levels and protein expression of MCM3 and Ki-67 was determined by flow cytometry (annexin V-FITC/PI assay), quantitative real-time RT-PCR (qRT-PCR) and immunocytochemistry, respectively. Cytotoxicity was assessed using the MTT assay. One-way analysis of variance (ANOVA) was used for comparing groups and differences were assessed by a Tukey's post hoc test. RESULTS: Protein expression of both biomarkers and MCM3 mRNA were not affected by doxorubicin, but Ki-67 mRNA significantly increased after treatment (p=0.049). CONCLUSIONS: Considering that doxorubicin can influence certain biochemical events that lead to modifications in Ki- 67, this factor might be useful in evaluating the impact of anthracycline-based chemotherapeutic agents. Changes in MCM3 following doxorubicin treatment require further investigation. PMID- 24344041 TI - Construction and identification of the recombinant lentiviral expression vector targeting human BAX inhibitor-1 gene. AB - PURPOSE: The aim of this study was to construct a recombinant lentiviral expression vector targeting human BAX inhibitor- 1(BI-1) gene and observe its expression in NIH3T3 cells. METHODS: Human BI-1 gene was amplified by polymerase chain reaction (PCR), and then cloned into the vector pLCMV- IG using DNA recombinant technique. After the inserted sequences in the recombinant plasmids were identified by PCR, and double digesting and DNA sequencing analysis, the recombinant lentivirus was packaged and administered into NIH3T3 cells. The BI-1 mRNA and protein expression were examined by real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. RESULTS: PCR double digesting analysis and DNA sequencing confirmed that the BI-1 DNA sequences were successfully inserted into the lentiviral vectors. After transfection with the recombinant lentivirus, BI-1 expression in NIH3T3 cells was significantly increased at both mRNA and protein levels. CONCLUSION: The lentiviral vector expressing BI-1 has been successfully constructed, which allowed for the subsequent analysis of the role of BI-1 in cell growth and transduction. PMID- 24344042 TI - Technetium-99m- Arg-Arg-Leu(g2), a modified peptide probe targeted to neovascularization in molecular tumor imaging. AB - PURPOSE: The (131)I-tRRL small peptide probe has been identified in our previous study as a robust tumor molecular radiopharmaceutical that specifically binds to tumor-derived endothelial cells. In this study we developed a smaller structure cyclic tRRL (g2) radiolabeled with (99m)Tc as a novel and optimized peptide probe on tumor angiogenesis molecular imaging. METHODS: Both tRRL (g2) and control peptide GGG (g2), as well as FITC-RRL (g2) and FITC-GGG (g2) peptide chains were synthesized and characterized by high performance liquid chromatography (HPLC) and electrospray ionization mass spectrometry (EMI-MS) analysis. After synthesis and purification, the peptides were radiolabeled with (99m)Tc by a one-step method for quantitative cell-binding assay and biodistribution experiments. A cell adhesion assay was performed to image tumor-derived endothelial cells binding specificity with the novel RRL (g2) peptide probe in vitro. The biodistribution experiment was performed to show the tumor uptake of (99m)Tc-RRL (g2) compared with other tissues in human glioblastoma-bearing nude mice in vivo. RESULTS: FITC-RRL (g2) had significantly higher tumor-derived endothelial cell binding affinity and specificity than the control FITC-GGG (g2). (99m)Tc-RRL (g2) had higher tumor uptake (2,578 +/- 0.293 at 30 min postinjection) and longer tumor retention than (99m)Tc-GGG (g2) in the tumor models tested. The tumor specificity of (99m)Tc-RRL (g2) was also confirmed by successful quantitative cell binding experiments. CONCLUSION: (99m)Tc-RRL (g2) has more good characteristics such as higher tumor uptake ratio and short half life time compared with (131I)-tRRL. The information obtained here may guide the future development of RRL peptide-based tumor angiogenesis molecular imaging and internal radiotherapeutic agents targeting tumor neovascularity. PMID- 24344043 TI - An international survey of practice patterns and difficulties in cancer pain management in Southeastern Europe: a Turkish & Balkan Oncology Group common initiative. AB - PURPOSE: While pain is highly prevalent in cancer patients and its management is universally challenging, it is more commonly undertreated in the developing world. Southeastern European countries have limited resources and manpower to allocate for delivery of effective care for cancer-related pain. The purpose of this study was to explore the practice methods and the barriers to effective pain management in Southeastern Europe. METHODS: We conducted a Web-based survey using a specially designed questionnaire among physicians practicing in member countries of the Balkan Union of Oncology (BUON). RESULTS: A representative from each of the member countries of BUON (including Armenia and Georgia) and close to 100 physicians from 8 countries responded. The majority (89%) of respondents were medical oncologists and had been practising for 10 years on average. For pain assessment, only 35.4% of the physicians used a formal pain scale. Of the respondents 34.1% were not able to reach the optimal doses of narcotic medications while managing cancer pain, mostly due to concerns about toxicity, such as constipation and nausea. Most physicians listed their inability to consult sub-specialists to seek assistance for improving pain management cases as one of the major difficulties in day-to- day clinical practice, along with lack of time. CONCLUSIONS: The limitations faced by our respondents seem to be related mostly to the shortcomings of the respective health care systems, along with the need for more experience and knowledge about the titration of pain medications and dealing with toxicities. PMID- 24344044 TI - Increasing performance of a hospital-based cancer registry: Hacettepe University hospitals experience. AB - PURPOSE: High-quality hospital-based cancer registry systems are the key elements of a healthy population-based cancer data. The purpose of this study was to present a recent history of establishing a valuable and reliable hospital- based cancer registry in a university hospital in Turkey, and the data gathered by this system in the last 9 years. METHODS: This study included the cancer registry records of Hacettepe University Hospitals between 1-Jan-2003, and 31-Dec-2011. The study cohort included data of 39351 cancer patients and the cancer registry system was based on active data acquisition method. RESULTS: Most frequent departments of reference were Medical Oncology, Radiation Oncology, General Surgery, Urology, and Pediatrics. The annual number of records gradually increased from 2675 in 2003 to 5152 in 2011. The 5 cancer types most frequency seen in adults were lung (15.5%), prostate (13.5%), stomach (6.6%), bladder (6.2%), and colon (5.8%) in men; and breast (32.7%), ovary (6.4%), uterine corpus (6.2%), uterine cervix (5.6%), and thyroid (5.0%) in women. Childhood cancers were classified according to the International Classification of Childhood Cancers, 3rd Edition (ICCC-3), and the most frequent 5 cancer types in children were tumors of the central nervous system (20.1%), lymphomas (14.6%), leukemia (14.1%), retinoblastoma (9.4%), and tumors of the sympathetic nervous system (7.7%). CONCLUSION: Active data acquisition from departments that deal with oncologic patients in a hospital is the precise method for establishing a high quality cancer registry system that is able to resemble the general population. Hospital- based cancer registry systems also provide highly critical information for planning, monitoring, and measuring the cancer-related services, research, and education. PMID- 24344045 TI - Possible role for furazolidone in the treatment of glioblastoma multiforme. PMID- 24344046 TI - Dissociated evolution of a multifocal primary CNS lymphoma. PMID- 24344047 TI - Correlation of serum proteomics patterns of sCD200 (OX-2), sApo-2L (sTRAIL), vitamin-D and homocysteine to quantitative FDG-PET/CT findings in newly diagnosed non-small cell lung cancer. PMID- 24344048 TI - The eminent dermatologist Moriz Kaposi (1837-1902) and the first description of idiopathic multiple pigmented sarcoma of the skin. AB - In 1872, the Hungarian born dermatologist Moriz Kaposi that was practicing in Vienna first described a rare endemic disease that bears his name, among elderly persons of Central European or Mediterranean origin named "idiopathic multiple pigmented sarcoma of the skin". Ten years later the Italian dermatologist Tommaso de Amicis confirms Kaposi's findings. For more than a century the disease was known as a rare low grade malignancy till the 1980s AIDS epidemic. PMID- 24344049 TI - Combination of Mangifera indica L. extract supplementation plus methotrexate in rheumatoid arthritis patients: a pilot study. AB - The purpose of the present study was to evaluate the possible therapeutic effects and the safety of Mangifera indica extract (Vimang tablets, 300 mg) combined with methotrexate (MTX) on reducing disease activity in rheumatoid arthritis (RA). Twenty patients with active RA underwent a year of treatment with MTX (12.5 mg/week) associated to non-steroidal anti-inflammatory drugs (NSAIDs) and/or prednisone (5-10 mg/day) were randomly allocated to the experimental group (n=10), that received the extract supplementation (900 mg/day) or preceding usual treatment (n=10) during 180 days. RA activity was evaluated using the tender and swollen joint counts, erythrocyte sedimentation rate, disease activity score-28 (DAS 28), visual analogue scale (VAS) and health assessment questionnaire (HAQ). Treatment's efficacy was demonstrated with ACR criteria. Only the patients of MTX Vimang group revealed statistically significant improvement in DAS 28 parameters with respect baseline data but no differences were observed between groups. ACR improvements amounted 80% only in MTX-Vimang group at the 90 days (p<0.001). In MTX-Vimang group, 100% of patients decreased NSAIDs administration (p<0.01) and 70% of those eradicated gastrointestinal side effects (p<0.01) ensuing of the preceding treatment. Other adverse effects were not reported. PMID- 24344050 TI - Simultaneous quantification of paracetamol, acetylsalicylic acid and papaverine with a validated HPLC method. AB - Combined drug products have the advantages of better patient compliance and possible synergic effects. The simultaneous application of several active ingredients at a time is therefore frequently chosen. However, the quantitative analysis of such medicines can be challenging. The aim of this study is to provide a validated method for the investigation of a multidose packed oral powder that contained acetylsalicylic acid, paracetamol and papaverine-HCl. Reversed-phase high-pressure liquid chromatography was used. The Agilent Zorbax SB-C18 column was found to be the most suitable of the three different stationary phases tested for the separation of the components of this sample. The key parameters in the method development (apart from the nature of the column) were the pH of the aqueous phase (set to 3.4) and the ratio of the organic (acetonitrile) and the aqueous (25 mM phosphate buffer) phases, which was varied from 7:93 (v/v) to 25:75 (v/v) in a linear gradient, preceded by an initial hold. The method was validated: linearity, precision (repeatability and intermediate precision), accuracy, specificity and robustness were all tested, and the results met the ICH guidelines. PMID- 24344051 TI - Transition metal-depleted graphenes for electrochemical applications via reduction of CO2 by lithium. AB - Graphene has immense potential for future applications in the electrochemical field, such as in supercapacitors, fuel cells, batteries, or sensors. Graphene materials for such applications are typically fabricated through a top-down approach towards oxidation of graphite to graphite oxide, with consequent exfoliation/reduction to yield reduced graphenes. Such a method allows the manufacture of graphenes in gram/kilogram quantities. However, graphenes prepared by this method can contain residual metallic impurities from graphite which dominate the electrochemical properties of the graphene formed. This dominance hampers their electrochemical application. The fabrication of transition metal depleted graphene is described, using ultrapure CO2 (with benefits of low cost and easy availability) and elemental lithium by means of reduction of CO2 to graphene. This preparation method produces graphene of high purity with electrochemical behavior that is not dominated by any residual transition metal impurities which would dramatically alter its electrochemical properties. Wide application of such methodology in industry and research laboratories is foreseen, especially where graphene is used for electrochemical devices. PMID- 24344052 TI - The genesis of microarrays. AB - This review provides a perspective on the initial development of microarray technologies by two independent groups in the late 1980s. PMID- 24344053 TI - Critical assessment of methods of protein structure prediction (CASP)--round x. AB - This article is an introduction to the special issue of the journal PROTEINS, dedicated to the tenth Critical Assessment of Structure Prediction (CASP) experiment to assess the state of the art in protein structure modeling. The article describes the conduct of the experiment, the categories of prediction included, and outlines the evaluation and assessment procedures. The 10 CASP experiments span almost 20 years of progress in the field of protein structure modeling, and there have been enormous advances in methods and model accuracy in that period. Notable in this round is the first sustained improvement of models with refinement methods, using molecular dynamics. For the first time, we tested the ability of modeling methods to make use of sparse experimental three dimensional contact information, such as may be obtained from new experimental techniques, with encouraging results. On the other hand, new contact prediction methods, though holding considerable promise, have yet to make an impact in CASP testing. The nature of CASP targets has been changing in recent CASPs, reflecting shifts in experimental structural biology, with more irregular structures, more multi-domain and multi-subunit structures, and less standard versions of known folds. When allowance is made for these factors, we continue to see steady progress in the overall accuracy of models, particularly resulting from improvement of non-template regions. PMID- 24344054 TI - Humans make efficient use of natural image statistics when performing spatial interpolation. AB - Visual systems learn through evolution and experience over the lifespan to exploit the statistical structure of natural images when performing visual tasks. Understanding which aspects of this statistical structure are incorporated into the human nervous system is a fundamental goal in vision science. To address this goal, we measured human ability to estimate the intensity of missing image pixels in natural images. Human estimation accuracy is compared with various simple heuristics (e.g., local mean) and with optimal observers that have nearly complete knowledge of the local statistical structure of natural images. Human estimates are more accurate than those of simple heuristics, and they match the performance of an optimal observer that knows the local statistical structure of relative intensities (contrasts). This optimal observer predicts the detailed pattern of human estimation errors and hence the results place strong constraints on the underlying neural mechanisms. However, humans do not reach the performance of an optimal observer that knows the local statistical structure of the absolute intensities, which reflect both local relative intensities and local mean intensity. As predicted from a statistical analysis of natural images, human estimation accuracy is negligibly improved by expanding the context from a local patch to the whole image. Our results demonstrate that the human visual system exploits efficiently the statistical structure of natural images. PMID- 24344055 TI - Detecting shape change: characterizing the interaction between texture-defined and contour-defined borders. AB - The human visual system's extreme sensitivity to subtle changes in shape can often be attributed to global pooling of local information. This has been shown for shapes described by paths of contiguous elements, but it was unknown whether this global pooling translated to shapes defined by texture-segmentation borders. Also, previous research suggests that texture and luminance cues-to-shape are integrated by the visual system for shape detection but it has not been established whether they combined for shape discrimination. Controlled shapes defined either by an explicit path of Gabors, texture-segmentation borders, or both of these cues were used. Results show that all stimuli used were globally processed. Thresholds for shapes defined by both cues matched predictions based on an independent-cue vector sum of individual thresholds. Thus, while local elements are integrated around the contour and are processed by global shape detection mechanisms, integration did not occur across different shape-cues. PMID- 24344056 TI - Contrast negation differentiates visual pathways underlying dynamic and invariant facial processing. AB - Bruce and Young (1986) proposed a model for face processing that begins with structural encoding, followed by a split into two processing streams: one for the dynamic aspects of the face (e.g., facial expressions of emotion) and the other for the invariant aspects of the face (e.g., gender, identity). Yet how this is accomplished remains unclear. Here, we took a psychophysical approach using contrast negation to test the Bruce and Young model. Previous research suggests that contrast negation impairs processing of invariant features (e.g., gender) but not dynamic features (e.g., expression). In our first experiment, participants discriminated differences in gender and facial expressions of emotion in upright, inverted, and contrast-negated faces. Results revealed a profound impairment for contrast-negated gender discrimination, whereas expression discrimination remained relatively robust to contrast negation. To test whether this differential effect occurs during perceptual encoding, we conducted three additional experiments in which we measured aftereffects following upright, inverted, or contrast-negated face adaptation for the same discrimination task as in the first experiment. Results showed a mild impairment with contrast negation during perceptual encoding for both gender and expression, followed by a marked gender-specific deficit during contrast-negated face discrimination. Taken together, our results suggest that there are shared neural mechanisms during perceptual encoding, and at least partially separate neural mechanisms during recognition and decision making for dynamic and invariant facial-feature processing. PMID- 24344057 TI - Pitfalls of efficiency determination in cycling ergometry. PMID- 24344058 TI - Reply to Boning and Pries. PMID- 24344059 TI - Dendritic cells in cardiovascular diseases: epiphenomenon, contributor, or therapeutic opportunity. PMID- 24344060 TI - Venous thromboembolism and cancer. PMID- 24344062 TI - Hyperkalemia: a clue to the diagnosis of adrenal insufficiency. PMID- 24344066 TI - Congenital left ventricular diverticulum: diagnostic usefulness of color Doppler echocardiography and computed tomography. PMID- 24344068 TI - Letter by Kern regarding article, "comparison of clinical interpretation with visual assessment and quantitative coronary angiography in patients undergoing percutaneous coronary intervention in contemporary practice: the assessing angiography (A2) project". PMID- 24344069 TI - Letter by Khandelwal regarding article, "comparison of clinical interpretation with visual assessment and quantitative coronary angiography in patients undergoing percutaneous coronary intervention in contemporary practice: the assessing angiography (A2) project". PMID- 24344070 TI - Response to letters regarding article, "comparison of clinical interpretation with visual assessment and quantitative coronary angiography in patients undergoing percutaneous coronary intervention in contemporary practice: the assessing angiography (A2) project". PMID- 24344072 TI - The role of overweight perception and depressive symptoms in child and adolescent unhealthy weight control behaviors: a mediation model. AB - OBJECTIVE: Children who are overweight or obese are at risk for depression and development of unhealthy weight control behaviors (UWCBs), including using diet pills, purging, or fasting. Explications of pathways leading to UWCBs are needed to prevent the associated negative health outcomes. METHODS: Participants were 106 children/adolescents 8-17 years of age at a pediatric clinic. Measures included child body mass index, the Child Depression Inventory-Short Form, and questionnaires assessing perception of overweight and UWCBs used in the past year. Depression was hypothesized to mediate the relationship between perception of overweight and UWCBs. RESULTS: A bootstrapped mediation model revealed that depressive symptoms mediated the relationship between youth perception of overweight and UWCBs accounting for youth body mass index z-score. The total model explained 24% of the variance in UWCBs. Discussion This study presents a potential mechanism by which youth perception of overweight may influence UWCBs. Longitudinal research is needed to further elucidate the directionality of these relationships. PMID- 24344073 TI - LC-MS-MS analysis of dietary supplements for N-ethyl-alpha-ethyl-phenethylamine (ETH), N, N-diethylphenethylamine and phenethylamine. AB - There has been a recent rise in the number of cases of athletes being banned from competition because of positive tests for prohibited substances in their biological specimens. Most of these substances are on the World Anti-Doping Agency (WADA) prohibited list, while others are not specifically named on the list. N-Ethyl-alpha-ethyl-phenethylamine (ETH), a derivative of phenethylamine (PEA), is one of these unlisted substances and shares chemical and biological effects to the amphetamines, which are listed on the WADA prohibited substances list. It is classified as Category 6B stimulant on the list. This study was directed toward the development of an liquid chromatography tandem mass spectrometry (LC-MS-MS) method for the analysis of ETH in performance-enhancing dietary supplement. A standard was prepared and confirmed by spectroscopic analysis, which was then used to develop the analytical procedure. The procedure was validated and found to have an limit of detection of 2.5 ng/mL, limit of quantification of 5 ng/mL and upper limit of linearity of 500 ng/mL, with within day variability at the 10-ng/mL level range of 3.88-7.89% (n = 6) and 1.39-3.36% (n = 6) for the 100-ng/mL level. The day-to-day variability was 9.8% for the low control and 3.1% for the high control. The method was used to analyze a variety of dietary supplements for ETH as well as PEA and its N, N-diethyl derivative (NDP). PMID- 24344085 TI - Direct oral anticoagulants for acute venous thromboembolism: closing the circle? PMID- 24344084 TI - Airflow obstruction, lung function, and incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study. AB - BACKGROUND: Reduced low forced expiratory volume in 1 second (FEV1) is reportedly associated with an increased risk of atrial fibrillation (AF). Extant reports do not provide separate estimates for never smokers or for blacks, who incongruously have lower AF incidence than whites. METHODS AND RESULTS: We examined 15 004 middle-aged blacks and whites enrolled in the Atherosclerosis Risk in Communities (ARIC) cohort study. Standardized spirometry data were collected at the baseline examination. Incident AF was identified from the first among the following: International Classification of Diseases codes for AF on hospital discharge records or death certificates or 12-lead ECGs performed during 3 triennial follow up visits. Over an average follow-up of 17.5 years, a total of 1691 participants (11%) developed new-onset AF. The rate of incident AF was inversely associated with FEV1 in each of the 4 race and sex groups. After multivariable adjustment for traditional cardiovascular disease risk factors and height, hazard ratios of AF comparing the lowest with the highest quartile of FEV1 were 1.37 (95% confidence interval, 1.02-1.83) for white women, 1.49 (95% confidence interval, 1.16-1.91) for white men, 1.63 (95% confidence interval, 1.00-2.66) for black women, and 2.36 (95% confidence interval, 1.30-4.29) for black men. The above associations were observed across all smoking status categories. Moderate/severe airflow obstruction (FEV1/forced vital capacity <0.70 and FEV1 < 80% of predicted value) was also associated with higher AF incidence. CONCLUSIONS: In this large population-based study with a long-term follow-up, reduced FEV1 and obstructive respiratory disease were associated with a higher AF incidence after adjustment for measured confounders. PMID- 24344095 TI - Changes in health promotion practice in hospitals across England: the National Health Promotion in Hospital Audit 2009 and 2011. AB - BACKGROUND: There is increasing focus on hospitals to provide health promotion (HP) to patients who smoke, misuse alcohol, are obese or physically inactive, yet there is little published literature on assessment and HP in English hospitals. METHODS: Thirty hospitals participated in national audits, both in 2009 and 2011, to assess HP in hospitalized patients. Random samples of 100 patients were selected per hospital per year. RESULTS: Between the 2009 and 2011 audit, assessment rates increased for smoking (82 versus 86%; P < 0.001) and obesity (38 versus 53%; P < 0.001), alcohol assessments remained similar (71 versus 73%; P = 0.123) and physical activity assessments decreased (34 versus 28%; P < 0.001). Provision of HP was similar in both audits for smoking (22 versus 26%; P = 0.17), alcohol misuse (47 versus 44%; P = 0.12) and physical inactivity (43 versus 44%; P = 0.865), but fell for obesity (26 versus 14%; P < 0.001). Few hospitals met the standards for assessment and HP for each risk factor. CONCLUSIONS: Whilst patients are being assessed for most lifestyle risk factors, and despite an increased policy focus, there remains little evidence of HP practice in English hospitals. There is potential for health gain across England that could be exploited through wider provision of HP for hospitalized patients. PMID- 24344096 TI - Sickle cell disease and pregnancy outcomes: population-based study on 8.8 million births. AB - OBJECTIVE: To estimate the prevalence of sickle cell disease (SCD) in pregnancy, and to measure risk factors, morbidity, and mortality among women with SCD with and without crisis at the time of birth. METHODS: We conducted a population based, retrospective cohort study on all births in the Healthcare Cost and Utilization Project Nationwide Inpatient Sample (HCUP-NIS) from 1999 to 2008. Births to SCD with and without crisis were identified using ICD-9 codes. Adjusted effects of risk factors and outcomes were estimated using logistic regression analyses. Effect of hemoglobin variants among women with SCD was analyzed as a predictor of crisis. RESULTS: There were 4262 births to women with SCD for an overall prevalence of 4.83 per 10,000 deliveries. 28.5% of women with SCD developed crisis at the time of delivery. The maternal mortality rate was 1.6 per 1000 deliveries in women with SCD, compared to 0.1 per 1000 in women without SCD. Pregnant women with SCD had a higher risk of developing preeclampsia, eclampsia, venous thromboembolism, cardiomyopathy, intrauterine fetal demise, and intrauterine growth restriction. Cesarean delivery rates were higher in women with SCD. Among the 1898 SCD women with identified hemoglobin variants, homozygous SS was the greatest risk factor for sickle cell crisis, accounting for 89.8% of all women who developed crisis. CONCLUSION: Pregnant women with SCD have a high risk of morbidity and mortality. Developing acute sickle cell crisis worsened perinatal outcomes. PMID- 24344097 TI - Human species and mating systems: Neandertal-Homo sapiens reproductive isolation and the archaeological and fossil records. AB - The present paper examined the assumption of strong reproductive isolation (RI) between Homo neanderthalensis and Homo sapiens, as well as the question of what form it might have taken, using insights from the parallel case of chimpanzee bonobo hybridization. RI from hybrid sterility or inviability was thought unlikely based on the short separation-to-introgression timeline. The forms of RI that typically develop in primates have relatively short timelines (especially for partial implementation); they generally preclude mating or influence hybrid survival and reproduction in certain contexts, and they have the potential to skew introgression directionality. These RI barriers are also consistent with some interpretations of the archaeological and fossil records, especially when behavioral, cognitive, morphological, and genetic differences between the two human species are taken into consideration. Differences potentially influencing patterns of survival and reproduction include interspecies violence, Neandertal xenophobia, provisioning behavior, and ontogenetic, morphological, and behavioral differences affecting matters such as kin and mate recognition, infanticide, and sexual selection. These factors may have skewed the occurrence of interbreeding or the survival and reproduction of hybrids in a way that might at least partially explain the pattern of introgression. PMID- 24344098 TI - Opening Science to Society, a new initiative of the Istituto Italiano di Antropologia. PMID- 24344099 TI - Anthropology and the Statistical Sciences, a one-day meeting in memory of Fosca Veronesi Martuzzi. PMID- 24344086 TI - Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. AB - BACKGROUND: Dabigatran and warfarin have been compared for the treatment of acute venous thromboembolism (VTE) in a previous trial. We undertook this study to extend those findings. METHODS AND RESULTS: In a randomized, double-blind, double dummy trial of 2589 patients with acute VTE treated with low-molecular-weight or unfractionated heparin for 5 to 11 days, we compared dabigatran 150 mg twice daily with warfarin. The primary outcome, recurrent symptomatic, objectively confirmed VTE and related deaths during 6 months of treatment occurred in 30 of the 1279 dabigatran patients (2.3%) compared with 28 of the 1289 warfarin patients (2.2%; hazard ratio, 1.08; 95% confidence interval [CI], 0.64-1.80; absolute risk difference, 0.2%; 95% CI, -1.0 to 1.3; P<0.001 for the prespecified noninferiority margin for both criteria). The safety end point, major bleeding, occurred in 15 patients receiving dabigatran (1.2%) and in 22 receiving warfarin (1.7%; hazard ratio, 0.69; 95% CI, 0.36-1.32). Any bleeding occurred in 200 dabigatran (15.6%) and 285 warfarin (22.1%; hazard ratio, 0.67; 95% CI, 0.56 0.81) patients. Deaths, adverse events, and acute coronary syndromes were similar in both groups. Pooled analysis of this study RE-COVER II and the RE-COVER trial gave hazard ratios for recurrent VTE of 1.09 (95% CI, 0.76-1.57), for major bleeding of 0.73 (95% CI, 0.48-1.11), and for any bleeding of 0.70 (95% CI, 0.61 0.79). CONCLUSION: Dabigatran has similar effects on VTE recurrence and a lower risk of bleeding compared with warfarin for the treatment of acute VTE. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov. Unique identifiers: NCT00680186 and NCT00291330. PMID- 24344100 TI - Secretome from senescent melanoma engages the STAT3 pathway to favor reprogramming of naive melanoma towards a tumor-initiating cell phenotype. AB - Here, we showed that the secretome of senescent melanoma cells drives basal melanoma cells towards a mesenchymal phenotype, with characteristic of stems illustrated by increased level of the prototype genes FN1, SNAIL, OCT4 and NANOG. This molecular reprogramming leads to an increase in the low-MITF and slow growing cell population endowed with melanoma-initiating cell features. The secretome of senescent melanoma cells induces a panel of 52 genes, involved in cell movement and cell/cell interaction, among which AXL and ALDH1A3 have been implicated in melanoma development. We found that the secretome of senescent melanoma cells activates the STAT3 pathway and STAT3 inhibition prevents secretome effects, including the acquisition of tumorigenic properties. Collectively, the findings provide insights into how the secretome of melanoma cells entering senescence upon chemotherapy treatments increases the tumorigenicity of naive melanoma cells by inducing, through STAT3 activation, a melanoma-initiating cell phenotype that could favor chemotherapy resistance and relapse. PMID- 24344101 TI - Health care worker exposures to pertussis: missed opportunities for prevention. AB - OBJECTIVE: Pediatric health care workers (HCWs) are at particular risk for pertussis exposure, infection, and subsequent disease transmission to susceptible patients. This cross-sectional study describes the epidemiology of occupational exposures to pertussis and identifies factors that may inform interventions to promote effective implementation of infection prevention and control (IPC) guidelines. METHODS: We abstracted data from occupational health (OH) and IPC records for pertussis cases that resulted in an exposure investigation in a large quaternary pediatric care network, January 1, 2002 to July 18, 2011. We calculated the frequency of occupational exposures and measured associated characteristics. To assess the frequency of potential missed exposures, we reviewed electronic health record (EHR) data identifying laboratory-confirmed pertussis cases not documented in OH or IPC records. RESULTS: A total of 1193 confirmed HCW pertussis exposures were associated with 219 index cases during the study period. Of these, 38.8% were infants <6 months old and 7 were HCWs. Most (77.5%) of exposures occurred in the emergency department or an ambulatory site; 27.0% of exposures occurred after documented initiation of IPC precautions. We identified 450 laboratory-confirmed pertussis cases through EHR review, of which 49.8% (N = 224) had no OH or IPC investigation. The majority of uninvestigated cases (77.2%) were from ambulatory sites. CONCLUSIONS: Occupational exposures to pertussis occur frequently in pediatric health care settings despite appropriate IPC guidelines. Interventions are needed to ensure consistent implementation of IPC practices and timely identification and reporting of pertussis index cases to prevent HCW exposures and potential transmission to patients. PMID- 24344103 TI - Antenatal and postnatal growth and 5-year cognitive outcome in very preterm infants. AB - OBJECTIVES: To study how antenatal growth affects cognitive outcome in very preterm infants and to determine whether there is an association between growth in any particular time period between birth and 5 years of age and cognitive outcome. Small for gestational age (SGA) and non-SGA infants were analyzed separately, because antenatal growth may affect postnatal growth. METHODS: Very low birth weight (<1501 g) infants born between 2001 and 2006 and infants born at <32 gestational weeks between 2004 and 2006 who were treated at Turku University Hospital (n = 181) were followed. Weight, length, and head circumference (HC) of the infants were measured at 9 time points between birth and 5 years. The growth was determined as a z score change between measurement points. Cognitive development was assessed at 5 years of age with the Wechsler Preschool and Primary Scales of Intelligence-Revised. The association between growth and full scale IQ (FSIQ) was studied. RESULTS: Growth in length and height was not associated with 5-year cognitive outcome. However, weight (r = 0.18, P = .04) and HC growth (r = 0.25, P = .01) between birth and 2 years of corrected age correlated to FSIQ in non-SGA children. In SGA children, HC growth (r = 0.33, P = .03) around term age correlated to FSIQ. CONCLUSIONS: Cognitive outcome was similar in SGA and non-SGA very preterm infants. Growth affected cognition positively in both subgroups, but the critical time period was different. PMID- 24344102 TI - Accuracy of brief screening tools for identifying postpartum depression among adolescent mothers. AB - OBJECTIVE: To evaluate the accuracy of the Edinburgh Postnatal Depression Scale (EPDS) and 3 subscales for identifying postpartum depression among primiparous adolescent mothers. METHODS: Mothers enrolled in a randomized controlled trial to prevent postpartum depression completed a psychiatric diagnostic interview and the 10-item EPDS at 6 weeks, 3 months, and 6 months postpartum. Three subscales of the EPDS were assessed as brief screening tools: 3-item anxiety subscale (EPDS 3), 7-item depressive symptoms subscale (EPDS-7), and 2-item subscale (EPDS-2) that resemble the Patient Health Questionnaire-2. Receiver operating characteristic curves and the areas under the curves for each tool were compared to assess accuracy. The sensitivities and specificities of each screening tool were calculated in comparison with diagnostic criteria for a major depressive disorder. Repeated-measures longitudinal analytical techniques were used. RESULTS: A total of 106 women contributed 289 postpartum visits; 18% of the women met criteria for incident postpartum depression by psychiatric diagnostic interview. When used as continuous measures, the full EPDS, EPDS-7, and EPDS-2 performed equally well (area under the curve >0.9). Optimal cutoff scores for a positive depression screen for the EPDS and EPDS-7 were lower (>= 9 and >= 7, respectively) than currently recommended cutoff scores (>= 10). At optimal cutoff scores, the EPDS and EPDS-7 both had sensitivities of 90% and specificities of >85%. CONCLUSIONS: The EPDS, EPDS-7, and EPDS-2 are highly accurate at identifying postpartum depression among adolescent mothers. In primary care pediatric settings, the EPDS and its shorter subscales have potential for use as effective depression screening tools. PMID- 24344104 TI - Vitamin D during pregnancy and infancy and infant serum 25-hydroxyvitamin D concentration. AB - OBJECTIVE: To determine the vitamin D dose necessary to achieve serum 25 hydroxyvitamin D (25(OH)D) concentration >= 20 ng/mL during infancy. METHODS: A randomized, double-blind, placebo-controlled trial in New Zealand. Pregnant mothers, from 27 weeks' gestation to birth, and then their infants, from birth to age 6 months, were randomly assigned to 1 of 3 mother/infant groups: placebo/placebo, vitamin D3 1000/400 IU, or vitamin D3 2000/800 IU. Serum 25(OH)D and calcium concentrations were measured at enrollment, 36 weeks' gestation, in cord blood, and in infants at 2, 4, and 6 months of age. RESULTS: Two-hundred-and sixty pregnant women were randomized. At enrollment, the proportions with serum 25(OH)D >= 20 ng/mL for placebo, lower-dose, and higher-dose groups were 54%, 64%, and 55%, respectively. The proportion with 25(OH)D >= 20 ng/mL was larger in both intervention groups at 36 weeks' gestation (50%, 91%, 89%, P < .001). In comparison with placebo, the proportion of infants with 25(OH)D >= 20 ng/mL was larger in both intervention groups to age 4 months: cord blood (22%, 72%, 71%, P < .001), 2 months (50%, 82%, 92%, P < .001), and 4 months (66%, 87%, 87%, P = .004), but only in the higher-dose group at age 6 months (74%, 82%, 89%, P = .07; higher dose versus placebo P = .03, lower dose versus placebo P = .21). CONCLUSIONS: Daily vitamin D supplementation during pregnancy and then infancy with 1000/400 IU or 2000/800 IU increases the proportion of infants with 25(OH)D >= 20 ng/mL, with the higher dose sustaining this increase for longer. PMID- 24344105 TI - Consumption of raw or unpasteurized milk and milk products by pregnant women and children. AB - Sales of raw or unpasteurized milk and milk products are still legal in at least 30 states in the United States. Raw milk and milk products from cows, goats, and sheep continue to be a source of bacterial infections attributable to a number of virulent pathogens, including Listeria monocytogenes, Campylobacter jejuni, Salmonella species, Brucella species, and Escherichia coli O157. These infections can occur in both healthy and immunocompromised individuals, including older adults, infants, young children, and pregnant women and their unborn fetuses, in whom life-threatening infections and fetal miscarriage can occur. Efforts to limit the sale of raw milk products have met with opposition from those who are proponents of the purported health benefits of consuming raw milk products, which contain natural or unprocessed factors not inactivated by pasteurization. However, the benefits of these natural factors have not been clearly demonstrated in evidence-based studies and, therefore, do not outweigh the risks of raw milk consumption. Substantial data suggest that pasteurized milk confers equivalent health benefits compared with raw milk, without the additional risk of bacterial infections. The purpose of this policy statement was to review the risks of raw milk consumption in the United States and to provide evidence of the risks of infectious complications associated with consumption of unpasteurized milk and milk products, especially among pregnant women, infants, and children. PMID- 24344106 TI - Bedside ultrasound in pediatric practice. PMID- 24344107 TI - A new leukocyte hyperadhesion syndrome of delayed cord separation, skin infection, and nephrosis. AB - Leukocyte adhesion deficiency (LAD) I is a well-described genetic disorder in which leukocytes are unable to migrate to sites of inflammation due to mutations in the ITGB2 gene coding for the beta subunit of beta2 (CD18) leukocyte integrins. The classic symptoms of the disease present in the newborn period as failure of separation of the umbilical cord and recurrent bacterial infections, which continue throughout life. We report on a patient with these clinical manifestations but with normal ITGB2 gene sequencing excluding LAD-I, normal carbohydrate-deficient transferrin testing excluding LAD-II, and normal platelet function excluding LAD-III. With testing for CD18 integrin function by flow cytometry, adhesion assay analysis, and time-lapse microscopy, we found the patient's T lymphocytes to express normal levels of beta1 and beta2 integrins but to be highly adhesive to integrin ligands and to display decreased migration compared with control T lymphocytes. The hyperadhesiveness of the cells suggests that they might be prevented from reaching infected tissues. Interestingly, administration of glucocorticoids, for the patient's nephrotic syndrome, alleviated the patient's chronic diarrhea and decreased the incidence of skin infections. The hyperadhesiveness rather than adhesion deficiency of the patient's leukocytes suggests that a novel lesion in a pathway regulating integrin adhesion is responsible for the patient's unique LAD-I-like symptoms. PMID- 24344108 TI - Accuracy of pulse oximetry in children. AB - OBJECTIVE: For children with cyanotic congenital heart disease or acute hypoxemic respiratory failure, providers frequently make decisions based on pulse oximetry, in the absence of an arterial blood gas. The study objective was to measure the accuracy of pulse oximetry in the saturations from pulse oximetry (SpO2) range of 65% to 97%. METHODS: This institutional review board-approved prospective, multicenter observational study in 5 PICUs included 225 mechanically ventilated children with an arterial catheter. With each arterial blood gas sample, SpO2 from pulse oximetry and arterial oxygen saturations from CO-oximetry (SaO2) were simultaneously obtained if the SpO2 was <= 97%. RESULTS: The lowest SpO2 obtained in the study was 65%. In the range of SpO2 65% to 97%, 1980 simultaneous values for SpO2 and SaO2 were obtained. The bias (SpO2 - SaO2) varied through the range of SpO2 values. The bias was greatest in the SpO2 range 81% to 85% (336 samples, median 6%, mean 6.6%, accuracy root mean squared 9.1%). SpO2 measurements were close to SaO2 in the SpO2 range 91% to 97% (901 samples, median 1%, mean 1.5%, accuracy root mean squared 4.2%). CONCLUSIONS: Previous studies on pulse oximeter accuracy in children present a single number for bias. This study identified that the accuracy of pulse oximetry varies significantly as a function of the SpO2 range. Saturations measured by pulse oximetry on average overestimate SaO2 from CO-oximetry in the SpO2 range of 76% to 90%. Better pulse oximetry algorithms are needed for accurate assessment of children with saturations in the hypoxemic range. PMID- 24344109 TI - Acute and chronic effects of sleep duration on blood pressure. AB - OBJECTIVE: To evaluate the association between ambulatory blood pressure (ABP) and sleep duration as measured by 7-day sleep diary and nocturnal polysomnography in normal-weight adolescents without significant obstructive sleep apnea. METHODS: Subjects aged 10 to 17.9 years with an obstructive apnea hypopnea index <5 underwent polysomnography for 9.5 hours and 24-hour ABP monitoring commencing at noon on the same day. ABP was divided into prepolysomnography, in bed during polysomnography, and postpolysomnography periods for separate analyses. Sleep duration (SpD7) was obtained from a 7-day sleep diary, reflecting the sleep pattern in the week before admission. Total sleep time (TST) and sleep efficiency (SpE) were obtained from polysomnography. RESULTS: A total of 143 adolescents participated. SpD7 was inversely associated with systolic blood pressure (SBP) in prepolysomnography, in-bed, and postpolysomnography periods (all beta = -2 mm Hg) and with diastolic blood pressure (DBP) in prepolysomnography and in-bed periods (all beta = -1 mm Hg). TST was inversely associated with SBP in the postpolysomnography period (beta = -1.5 mm Hg). SpE was inversely associated with SBP in in-bed period (beta = -0.1 mm Hg) and with DBP in in-bed (beta = -0.1 mm Hg) and postpolysomnography (beta = -0.2 mm Hg) periods. Neither TST nor SpE was associated with SBP and DBP in prepolysomnography period. CONCLUSIONS: Short sleep duration as reflected by 7-day sleep diary was associated with higher blood pressure in normal-weight adolescents. Occasional adequate sleep may partially ameliorate the risk of high blood pressure but may not completely reverse the effect of long-term sleep insufficiency. PMID- 24344110 TI - Decreasing hypothermia during delivery room stabilization of preterm neonates. AB - BACKGROUND AND OBJECTIVE: Hypothermia during delivery room stabilization of very low birth weight (VLBW) newborns is independently associated with mortality, yet it occurred frequently both in collaborative networks and at our institution. We aimed to attain admission temperatures in the target range of 36 degrees C to 38 degrees C in >= 90% of inborn VLBW neonates through implementation of a thermoregulation bundle. METHODS: This quality improvement project extended over 60 consecutive months, using sequential plan-do-check-act cycles. During the 14 baseline months, we standardized temperature measurements and developed the Operation Toasty Tot thermoregulation bundle (including consistent head and torso wrapping with plastic, warmed blankets, and a closed stabilization room). We introduced this bundle in month 15 and added servo-controlled, battery-powered radiant warmers for stabilization and transfer in month 21. We provided results and feedback to staff throughout, using simple graphics and control charts. RESULTS: There were 164 inborn VLBW babies before and 477 after bundle implementation. Introduction and optimization of the bundle decreased the incidence of hypothermia, with rates remaining in the target range for the last 13 study months. The incidence of temperatures >38 degrees C was ~ 2% both before and after bundle implementation. CONCLUSIONS: This thermoregulation bundle resulted in sustained improvement in normothermia rates during delivery room stabilization of VLBW newborns. Our benchmark goal of >= 90% admission temperatures above 36 degrees C was met without increasing hyperthermia rates. Because these results compare favorably with those of recently published research or improvement collaboratives, we aim to maintain our performance through routine surveillance of admission temperatures. PMID- 24344111 TI - 7% Hypertonic saline in acute bronchiolitis: a randomized controlled trial. AB - BACKGROUND: Research suggests that hypertonic saline (HS) may improve mucous flow in infants with acute bronchiolitis. Data suggest a trend favoring reduced length of hospital stay and improved pulmonary scores with increasing concentration of nebulized solution to 3% and 5% saline as compared with 0.9% saline mixed with epinephrine. To our knowledge, 7% HS has not been previously investigated. METHODS: We conducted a prospective, double-blind, randomized controlled trial in 101 infants presenting with moderate to severe acute bronchiolitis. Subjects received either 7% saline or 0.9% saline, both with epinephrine. Our primary outcome was a change in bronchiolitis severity score (BSS), obtained before and after treatment, and at the time of disposition from the emergency department (ED). Secondary outcomes measured were hospitalization rate, proportion of admitted patients discharged at 23 hours, and ED and inpatient length of stay. RESULTS: At baseline, study groups were similar in demographic and clinical characteristics. The decrease in mean BSS was not statistically significant between groups (2.6 vs 2.4 for HS and control groups, respectively). The difference between the groups in proportion of admitted patients (42% in HS versus 49% in normal saline), ED or inpatient length of stay, and proportion of admitted patients discharged at 23 hours was not statistically significant. CONCLUSIONS: In moderate to severe acute bronchiolitis, inhalation of 7% HS with epinephrine does not appear to confer any clinically significant decrease in BSS when compared with 0.9% saline with epinephrine. PMID- 24344112 TI - Association between pediatric clinical trials and global burden of disease. AB - BACKGROUND: The allocation of research resources should favor conditions responsible for the greatest disease burden. This is particularly important in pediatric populations, which have been underrepresented in clinical research. Our aim was to measure the association between the focus of pediatric clinical trials and burden of disease and to identify neglected clinical domains. METHODS: We performed a cross-sectional study of clinical trials by using trial records in ClinicalTrials.gov. All trials started in 2006 or after and studying patient level interventions in pediatric populations were included. Age-specific measures of disease burden were obtained for 21 separate conditions for high-, middle-, and low-income countries. We measured the correlation between number of pediatric clinical trials and disease burden for each condition. RESULTS: Neuropsychiatric conditions and infectious diseases were the most studied conditions globally in terms of number of trials (874 and 847 trials, respectively), while intentional injuries (5 trials) and maternal conditions (4 trials) were the least studied. Clinical trials were only moderately correlated with global disease burden (r = 0.58, P = .006). Correlations were also moderate within each of the country income levels, but lowest in low-income countries (r = .47, P = .03). Globally, the conditions most understudied relative to disease burden were injuries (-260 trials for unintentional injuries and -160 trials for intentional injuries), nutritional deficiencies (-175 trials), and respiratory infections (-171 trials). CONCLUSIONS: Pediatric clinical trial activity is only moderately associated with pediatric burden of disease, and least associated in low-income countries. The mismatch between clinical trials and disease burden identifies key clinical areas for focus and investment. PMID- 24344113 TI - Bronchiolitis: doing less and still getting better. PMID- 24344114 TI - Extracellular p53 fragment re-enters K-Ras mutated cells through the caveolin-1 dependent early endosomal system. AB - K-Ras mutation is detected in over 30% of human malignancies. In particular, 90% of human pancreatic cancers are initiated by K-Ras mutation. Thus, selective elimination of K-Ras mutated cells would be a plausible strategy to prevent or cure the malignancies. In our previous reports, it has been revealed that oncogenic K-Ras promotes the exocytosis of p53 with Snail. In this study, we have followed the final destination of extracellular p53, which is secreted by the Snail complex. Here we provide evidences that p53, exported from K-Ras-mutated cells, is specifically re-endocytosed by oncogenic K-Ras-containing cancer cells. The p53 DNA-binding domain directly associates with caveolin-1 and enters K-Ras mutated cells through early endosome-mediated endocytosis. Using a serial deletion approach, we revealed that a fragment of human p53 extending from 93-143 amino acids (AA) is responsible for binding with caveolin-1 and for endocytosis. In contrast, p53-Snail binding occurs at the 143-193 aa region. Finally, through in vivo study, we confirmed that injected recombinant p53 could be up-taken by tumor tissues, constructed by oncogenic K-Ras transformed MEF cells. In contrast, the tumors formed by H-Ras mutated MEF cells did not accumulate the injected p53 protein. These results indicate that the p53 fragment might be useful as a specific delivery tool into K- Ras mutated cells as well as a diagnostic method. PMID- 24344116 TI - Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-kB target genes in human breast cancer. AB - NF-kB has been linked to doxorubicin resistance in breast cancer patients. NF-kB nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined; however its functional relevance at transcriptional level on NF-kB-dependent genes and the biological consequences are unclear. We studied NF-kB-dependent gene expression induced by doxorubicin in breast cancer cells and fresh human cancer specimens with different genetic backgrounds focusing on their p53 status. NF-kB-dependent signature of doxorubicin was identified by gene expression microarrays in breast cancer cells treated with doxorubicin and the IKKbeta-inhibitor MLN120B, and confirmed ex vivo in human cancer samples. The association with p53 was functionally validated. Finally, NF-kB activation and p53 status was determined in a cohort of breast cancer patients treated with adjuvant doxorubicin-based chemotherapy. Doxorubicin treatment in the p53-mutated MDA-MB-231 cells resulted in NF-kB driven-gene transcription signature. Modulation of genes related with invasion, metastasis and chemoresistance (ICAM-1, CXCL1, TNFAIP3, IL8) were confirmed in additional doxorubicin-treated cell lines and fresh primary human breast tumors. In both systems, p53-deficient background correlated with the activation of the NF-kB dependent signature. Furthermore, restoration of p53WT in the mutant p53 MDA-MB 231 cells impaired NF-kB driven transcription induced by doxorubicin. Moreover, a p53 deficient background and nuclear NF-kB/p65 in breast cancer patients correlated with reduced disease free-survival. This study supports that p53 deficiency is necessary for a doxorubicin driven NF-kB-response that limits doxorubicin cytotoxicity in breast cancer and is linked to an aggressive clinical behavior. PMID- 24344117 TI - FAM83D promotes cell proliferation and motility by downregulating tumor suppressor gene FBXW7. AB - Amplification of chromosome 20q is frequently found in various types of human cancers, including breast cancer. The list of candidate oncogenes in 20q has expanded over the past decade. Here, we investigate whether FAM83D (family with sequence similarity 83, member D) on chromosome 20q plays any role in breast cancer development. The expression level of FAM83D is significantly elevated in breast cancer cell lines and primary human breast cancers. High expression levels of FAM83D are significantly associated with poor clinical outcome and distant metastasis in breast cancer patients. We show that ectopic expression of FAM83D in human mammary epithelial cells promotes cell proliferation, migration and invasion along with epithelial-mesenchymal transition (EMT). Ablation of FAM83D in breast cancer cells induces apoptosis and consequently inhibits cell proliferation and colony formation. Mechanistic studies reveal that overexpression of FAM83D downregulates FBXW7 expression levels through a physical interaction, which results in elevated protein levels of oncogenic substrates downstream to FBXW7, such as mTOR, whose inhibition by rapamycin can suppress FAM83D-induced cell migration and invasion. The results demonstrate that FAM83D has prognostic value for breast cancer patients and is a novel oncogene in breast cancer development that at least in part acts through mTOR hyper-activation by inhibiting FBXW7. PMID- 24344118 TI - Guidelines and their use in clinical practice. PMID- 24344115 TI - Psychostimulants and cognition: a continuum of behavioral and cognitive activation. AB - Psychostimulants such as cocaine have been used as performance enhancers throughout recorded history. Although psychostimulants are commonly prescribed to improve attention and cognition, a great deal of literature has described their ability to induce cognitive deficits, as well as addiction. How can a single drug class be known to produce both cognitive enhancement and impairment? Properties of the particular stimulant drug itself and individual differences between users have both been suggested to dictate the outcome of stimulant use. A more parsimonious alternative, which we endorse, is that dose is the critical determining factor in cognitive effects of stimulant drugs. Herein, we review several popular stimulants (cocaine, amphetamine, methylphenidate, modafinil, and caffeine), outlining their history of use, mechanism of action, and use and abuse today. One common graphic depiction of the cognitive effects of psychostimulants is an inverted U-shaped dose-effect curve. Moderate arousal is beneficial to cognition, whereas too much activation leads to cognitive impairment. In parallel to this schematic, we propose a continuum of psychostimulant activation that covers the transition from one drug effect to another as stimulant intake is increased. Low doses of stimulants effect increased arousal, attention, and cognitive enhancement; moderate doses can lead to feelings of euphoria and power, as well as addiction and cognitive impairment; and very high doses lead to psychosis and circulatory collapse. This continuum helps account for the seemingly disparate effects of stimulant drugs, with the same drug being associated with cognitive enhancement and impairment. PMID- 24344120 TI - Translating research into practice: criteria for applying literature search results to your work. AB - Evidence-based practices in the fields of health education and health promotion require evaluating the validity and reliability of relevant and timely research. Skills associated with effectively assessing and applying research findings are essential when researchers and practitioners are developing a new program, writing a grant, or completing a research project. This Tool outlines steps and resources with which health educators and health promotion specialists can critically appraise the literature before deciding to apply a concept or practice. It also includes descriptions of "levels of evidence" for determining level of academic rigor, and questions to guide critical appraisals of published literature and other resources for determining their relevance to the work at hand. Assessing the evidence involves two steps: synthesizing selected articles and then applying their content to a certain situation, population, or need. This Tool is intended to advance the profession by offering tips for assessing and applying the results of literature searches, which involves evaluating the quality of the articles and determining how to best put the research into practice. PMID- 24344119 TI - Association of prediabetes by fasting glucose and/or haemoglobin A1c levels with subclinical atherosclerosis and impaired renal function: observations from the Dallas Heart Study. AB - BACKGROUND: Prediabetes defined by fasting plasma glucose (FPG) and glycosylated haemoglobin (HbA1c) predicts incident diabetes, but their individual and joint associations with micro- and macro-vascular risk remain poorly defined. METHODS: FPG, HbA1c, coronary artery calcium (CAC), carotid wall thickness, estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) were measured in adults free from prior diabetes or cardiovascular disease (CVD) in the Dallas Heart Study 2 (DHS-2), a population-based cohort study. Prediabetes was defined by FPG 100-125 mg/dL and/or HbA1c 5.7%-6.4%. Multivariable logistic regression was used to analyse associations of HbA1c and/or FPG in the prediabetes range with subclinical atherosclerosis and renal measures. RESULTS: The study comprised 2340 participants, median age = 49 years; 60% women and 50% black. Those with prediabetes were older (52 vs 48 years), more often men (63% vs 53%), black (53% vs 47%) and obese (58% vs 40%; p < 0.001 for each). Prediabetes was captured by FPG alone (43%), HbA1c alone (30%) or both (27%). Those with prediabetes by HbA1c or FPG versus normal HbA1c/FPG had more CAC [odds ratio (OR) = 1.8; 95% confidence interval (CI) = 1.5-2.2], higher carotid wall thickness (1.32 vs 1.29 mm, p < 0.001), eGFR < 60 mL/min [OR = 1.6 (95% CI = 1.1-2.4)], UACR > 30 mg/dL [OR = 1.8 (95% CI = 1.2-2.7)] and a higher odds for the composite eGFR + UACR [chronic kidney disease (CKD) >= 2] [OR = 1.9 (95% CI = 1.5-2.6)]. After multivariable adjustment, none of these associations remained significant. CONCLUSION: Prediabetes defined by HbA1c and/or FPG criteria is crudely associated with markers of diabetic macro- and micro-vascular disease, but not after statistical adjustment, suggesting the relationships are attributable to other characteristics of the prediabetes population. PMID- 24344125 TI - Evidence for transceptor function of cellodextrin transporters in Neurospora crassa. AB - Neurospora crassa colonizes burnt grasslands and metabolizes both cellulose and hemicellulose from plant cell walls. When switched from a favored carbon source to cellulose, N. crassa dramatically up-regulates expression and secretion of genes encoding lignocellulolytic enzymes. However, the means by which N. crassa and other filamentous fungi sense the presence of cellulose in the environment remains unclear. Previously, we have shown that a N. crassa mutant carrying deletions of three beta-glucosidase enzymes (Delta3betaG) lacks beta-glucosidase activity, but efficiently induces cellulase gene expression and cellulolytic activity in the presence of cellobiose as the sole carbon source. These observations indicate that cellobiose, or a modified version of cellobiose, functions as an inducer of lignocellulolytic gene expression and activity in N. crassa. Here, we show that in N. crassa, two cellodextrin transporters, CDT-1 and CDT-2, contribute to cellulose sensing. A N. crassa mutant carrying deletions for both transporters is unable to induce cellulase gene expression in response to crystalline cellulose. Furthermore, a mutant lacking genes encoding both the beta glucosidase enzymes and cellodextrin transporters (Delta3betaGDelta2T) does not induce cellulase gene expression in response to cellobiose. Point mutations that severely reduce cellobiose transport by either CDT-1 or CDT-2 when expressed individually do not greatly impact cellobiose induction of cellulase gene expression. These data suggest that the N. crassa cellodextrin transporters act as "transceptors" with dual functions - cellodextrin transport and receptor signaling that results in downstream activation of cellulolytic gene expression. Similar mechanisms of transceptor activity likely occur in related ascomycetes used for industrial cellulase production. PMID- 24344126 TI - An essential role of small ubiquitin-like modifier (SUMO)-specific Protease 2 in myostatin expression and myogenesis. AB - Sentrin/small ubiquitin-like modifier (SUMO)-specific protease 2 (SENP2) has broad de-SUMOylation activities in vitro, which is essential for embryonic heart development. Here, we show that myostatin, a key factor in skeletal muscle development, is markedly reduced in Senp2(-/-) mouse embryonic fibroblast cells and embryos. SENP2 regulates the transcription of myostatin mainly through de SUMOylation of MEF2A. Silencing SENP2 can reduce myostatin expression and, therefore, promote myogenesis of skeletal muscle. These results reveal the important role of SENP2 in the regulation of myostatin expression and myogenesis. PMID- 24344128 TI - N-acetylglucosaminylation of serine-aspartate repeat proteins promotes Staphylococcus aureus bloodstream infection. AB - Staphylococcus aureus secretes products that convert host fibrinogen to fibrin and promote its agglutination with fibrin fibrils, thereby shielding bacteria from immune defenses. The agglutination reaction involves ClfA (clumping factor A), a surface protein with serine-aspartate (SD) repeats that captures fibrin fibrils and fibrinogen. Pathogenic staphylococci express several different SD proteins that are modified by two glycosyltransferases, SdgA and SdgB. Here, we characterized three genes of S. aureus, aggA, aggB (sdgA), and aggC (sdgB), and show that aggA and aggC contribute to staphylococcal agglutination with fibrin fibrils in human plasma. We demonstrate that aggB (sdgA) and aggC (sdgB) are involved in GlcNAc modification of the ClfA SD repeats. However, only sdgB is essential for GlcNAc modification, and an sdgB mutant is defective in the pathogenesis of sepsis in mice. Thus, GlcNAc modification of proteins promotes S. aureus replication in the bloodstream of mammalian hosts. PMID- 24344127 TI - Novel structural features in Candida albicans hyphal glucan provide a basis for differential innate immune recognition of hyphae versus yeast. AB - The innate immune system differentially recognizes Candida albicans yeast and hyphae. It is not clear how the innate immune system effectively discriminates between yeast and hyphal forms of C. albicans. Glucans are major components of the fungal cell wall and key fungal pathogen-associated molecular patterns. C. albicans yeast glucan has been characterized; however, little is known about glucan structure in C. albicans hyphae. Using an extraction procedure that minimizes degradation of the native structure, we extracted glucans from C. albicans hyphal cell walls. (1)H NMR data analysis revealed that, when compared with reference (1->3,1->6) beta-linked glucans and C. albicans yeast glucan, hyphal glucan has a unique cyclical or "closed chain" structure that is not found in yeast glucan. GC/MS analyses showed a high abundance of 3- and 6-linked glucose units when compared with yeast beta-glucan. In addition to the expected (1->3), (1->6), and 3,6 linkages, we also identified a 2,3 linkage that has not been reported previously in C. albicans. Hyphal glucan induced robust immune responses in human peripheral blood mononuclear cells and macrophages via a Dectin-1-dependent mechanism. In contrast, C. albicans yeast glucan was a much less potent stimulus. We also demonstrated the capacity of C. albicans hyphal glucan, but not yeast glucan, to induce IL-1beta processing and secretion. This finding provides important evidence for understanding the immune discrimination between colonization and invasion at the mucosal level. When taken together, these data provide a structural basis for differential innate immune recognition of C. albicans yeast versus hyphae. PMID- 24344130 TI - Mitsugumin 53 (MG53) ligase ubiquitinates focal adhesion kinase during skeletal myogenesis. AB - The striated muscle-specific mitsugumin 53 (MG53) is a novel E3 ligase that induces the ubiquitination of insulin receptor substrate 1 (IRS-1) during skeletal myogenesis, negatively regulating insulin-like growth factor and insulin signaling. Here we show that focal adhesion kinase (FAK) is the second target of MG53 during skeletal myogenesis. The FAK protein level gradually decreased, whereas its mRNA level was constant during myogenesis in C2C12 cells and MyoD overexpressing mouse embryonic fibroblasts. The FAK protein was associated with the E2 enzyme UBE2H and the E3 enzyme MG53 in endogenous and exogenous immunoprecipitation experiments. FAK ubiquitination and degradation was induced by MG53 overexpression in myoblasts but abolished by MG53 or UBE2H knockdown in myotubes. Because RING-disrupted MG53 mutants (C14A and DeltaR) did not induce FAK ubiquitination and degradation, the RING domain was determined to be required for MG53-induced FAK ubiquitination. Taken together, these data indicate that MG53 induces FAK ubiquitination with the aid of UBE2H during skeletal myogenesis. PMID- 24344129 TI - UBE4B protein couples ubiquitination and sorting machineries to enable epidermal growth factor receptor (EGFR) degradation. AB - The signaling of plasma membrane proteins is tuned by internalization and sorting in the endocytic pathway prior to recycling or degradation in lysosomes. Ubiquitin modification allows recognition and association of cargo with endosomally associated protein complexes, enabling sorting of proteins to be degraded from those to be recycled. The mechanism that provides coordination between the cellular machineries that mediate ubiquitination and endosomal sorting is unknown. We report that the ubiquitin ligase UBE4B is recruited to endosomes in response to epidermal growth factor receptor (EGFR) activation by binding to Hrs, a key component of endosomal sorting complex required for transport (ESCRT) 0. We identify the EGFR as a substrate for UBE4B, establish UBE4B as a regulator of EGFR degradation, and describe a mechanism by which UBE4B regulates endosomal sorting, affecting cellular levels of the EGFR and its downstream signaling. We propose a model in which the coordinated action of UBE4B, ESCRT-0, and the deubiquitinating enzyme USP8 enable the endosomal sorting and lysosomal degradation of the EGFR. PMID- 24344131 TI - CCAAT/enhancer-binding protein beta regulates the repression of type II collagen expression during the differentiation from proliferative to hypertrophic chondrocytes. AB - CCAAT/enhancer-binding protein beta (C/EBPbeta) is a transcription factor that promotes hypertrophic differentiation by stimulating type X collagen and matrix metalloproteinase 13 during chondrocyte differentiation. However, the effect of C/EBPbeta on proliferative chondrocytes is unclear. Here, we investigated whether C/EBPbeta represses type II collagen (COL2A1) expression and is involved in the regulation of sex-determining region Y-type high mobility group box 9 (SOX9), a crucial factor for transactivation of Col2a1. Endogenous expression of C/EBPbeta in the embryonic growth plate and differentiated ATDC5 cells were opposite to those of COL2A1 and SOX9. Overexpression of C/EBPbeta by adenovirus vector in ATDC5 cells caused marked repression of Col2a1. The expression of Sox9 mRNA and nuclear protein was also repressed, resulting in decreased binding of SOX9 to the Col2a1 enhancer as shown by a ChIP assay. Knockdown of C/EBPbeta by lentivirus expressing shRNA caused significant stimulation of these genes in ATDC5 cells. Reporter assays demonstrated that C/EBPbeta repressed transcriptional activity of Col2a1. Deletion and mutation analysis showed that the C/EBPbeta core responsive element was located between +2144 and +2152 bp within the Col2a1 enhancer. EMSA and ChIP assays also revealed that C/EBPbeta directly bound to this region. Ex vivo organ cultures of mouse limbs transfected with C/EBPbeta showed that the expression of COL2A1 and SOX9 was reduced upon ectopic C/EBPbeta expression. Together, these results indicated that C/EBPbeta represses the transcriptional activity of Col2a1 both directly and indirectly through modulation of Sox9 expression. This consequently promotes the phenotypic conversion from proliferative to hypertrophic chondrocytes during chondrocyte differentiation. PMID- 24344132 TI - Aortic carboxypeptidase-like protein (ACLP) enhances lung myofibroblast differentiation through transforming growth factor beta receptor-dependent and independent pathways. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal lung disease characterized by the overgrowth, hardening, and scarring of lung tissue. The exact mechanisms of how IPF develops and progresses are unknown. IPF is characterized by extracellular matrix remodeling and accumulation of active TGFbeta, which promotes collagen expression and the differentiation of smooth muscle alpha-actin (SMA)-positive myofibroblasts. Aortic carboxypeptidase-like protein (ACLP) is an extracellular matrix protein secreted by fibroblasts and myofibroblasts and is expressed in fibrotic human lung tissue and in mice with bleomycin-induced fibrosis. Importantly, ACLP knockout mice are significantly protected from bleomycin-induced fibrosis. The goal of this study was to identify the mechanisms of ACLP action on fibroblast differentiation. As primary lung fibroblasts differentiated into myofibroblasts, ACLP expression preceded SMA and collagen expression. Recombinant ACLP induced SMA and collagen expression in mouse and human lung fibroblasts. Knockdown of ACLP slowed the fibroblast-to myofibroblast transition and partially reverted differentiated myofibroblasts by reducing SMA expression. We hypothesized that ACLP stimulates myofibroblast formation partly through activating TGFbeta signaling. Treatment of fibroblasts with recombinant ACLP induced phosphorylation and nuclear translocation of Smad3. This phosphorylation and induction of SMA was dependent on TGFbeta receptor binding and kinase activity. ACLP-induced collagen expression was independent of interaction with the TGFbeta receptor. These findings indicate that ACLP stimulates the fibroblast-to-myofibroblast transition by promoting SMA expression via TGFbeta signaling and promoting collagen expression through a TGFbeta receptor-independent pathway. PMID- 24344133 TI - Recognition of malondialdehyde-modified proteins by the C terminus of complement factor H is mediated via the polyanion binding site and impaired by mutations found in atypical hemolytic uremic syndrome. AB - Atypical hemolytic uremic syndrome (aHUS) is a severe thrombotic microangiopathy characterized by uncontrolled complement activation against endothelial and blood cells. Mutations in the C-terminal target recognition domains 19-20 of complement regulator factor H (FH) are strongly associated with aHUS, but the mechanisms triggering disease onset have remained unresolved. Here we report that several aHUS-related mutations alter the binding of FH19-20 to proteins where lysines have reacted with malondialdehyde (MDA). Although FH19-20 did not interact with MDA-modified hexylamine, lysine-containing peptides, or a proteolytically degraded protein, it bound to MDA-modified polylysine. This suggests that FH19-20 recognizes only clustered MDA adducts. Binding of MDA-modified BSA to FH19-20 was ionic by nature, depended on positive residues of FH19-20, and competed with the polyanions heparin and DNA. This could not be explained with the mainly neutral adducts known to form in MDA modification. When positive charges of lysines were eliminated by acetic anhydride instead of MDA, the acetylated BSA started to bind FH19-20. Together, these results indicate that negative charges on the modified proteins dominate the interaction with FH19-20. This is beneficial for the physiological function of FH because by binding to the negative charges of the modified target, FH could prevent excess complement activation initiated by naturally occurring antibodies recognizing MDA epitopes with multiple different structures. We propose that oxidative stress leading to formation of MDA adducts is a common feature for triggers of aHUS and that failure of FH in protecting MDA modified surfaces from complement activation is involved in the pathogenesis of the disease. PMID- 24344134 TI - PIASxalpha ligase enhances SUMO1 modification of PTEN protein as a SUMO E3 ligase. AB - The tumor suppressor PTEN plays a critical role in the regulation of multiple cellular processes that include survival, cell cycle, proliferation, and apoptosis. PTEN is frequently mutated or deleted in various human cancer cells to promote tumorigenesis. PTEN is regulated by SUMOylation, but the SUMO E3 ligase involved in the SUMOylation of PTEN remains unclear. Here, we demonstrated that PIASxalpha is a SUMO E3 ligase for PTEN. PIASxalpha physically interacted with PTEN both in vitro and in vivo. Their interaction depended on the integrity of phosphatase and C2 domains of PTEN and the region of PIASxalpha comprising residues 134-347. PIASxalpha enhanced PTEN protein stability by reducing PTEN ubiquitination, whereas the mutation of PTEN SUMO1 conjugation sites neutralized the effect of PIASxalpha on PTEN protein half-life. Functionally, PIASxalpha, as a potential tumor suppressor, negatively regulated the PI3K-Akt pathway through stabilizing PTEN protein. Overexpression of PIASxalpha led to G0/G1 cell cycle arrest, thus triggering cell proliferation inhibition and tumor suppression, whereas PIASxalpha knockdown or deficiency in catalytic activity abolished the inhibition. Together our studies suggest that PIASxalpha is a novel SUMO E3 ligase for PTEN, and it positively regulates PTEN protein level in tumor suppression. PMID- 24344135 TI - The transcription factor TEAD1 represses smooth muscle-specific gene expression by abolishing myocardin function. AB - The TEAD (transcriptional enhancer activator domain) proteins share an evolutionarily conserved DNA-binding TEA domain, which binds to the MCAT cis acting regulatory element. Previous studies have shown that TEAD proteins are involved in regulating the expression of smooth muscle alpha-actin. However, it remains undetermined whether TEAD proteins play a broader role in regulating expression of other genes in vascular smooth muscle cells. In this study, we show that the expression of TEAD1 is significantly induced during smooth muscle cell phenotypic modulation and negatively correlates with smooth muscle-specific gene expression. We further demonstrate that TEAD1 plays a novel role in suppressing expression of smooth muscle-specific genes, including smooth muscle alpha-actin, by abolishing the promyogenic function of myocardin, a key mediator of smooth muscle differentiation. Mechanistically, we found that TEAD1 competes with myocardin for binding to serum response factor (SRF), resulting in disruption of myocardin and SRF interactions and thereby attenuating expression of smooth muscle-specific genes. This study provides the first evidence demonstrating that TEAD1 is a novel general repressor of smooth muscle-specific gene expression through interfering with myocardin binding to SRF. PMID- 24344136 TI - Quantitative aspects of cGMP phosphodiesterase activation in carp rods and cones. AB - Cones are less light-sensitive than rods. We showed previously in carp that more light (>100-fold) is required in cones than in rods to activate 50% of cGMP phosphodiesterase (PDE). The lower effectiveness of PDE activation in carp cones is due partly to the fact that the activation rate of transducin (Tr) by light activated visual pigment (R*) is 5-fold lower in carp cones than in rods. In this study, we tried to explain the remaining difference. First, we examined the efficiency of activation of PDE by activated Tr (Tr*). By activating PDE with known concentrations of the active (guanosine 5'-Omicron-(gamma-thio)triphosphate (GTPgammaS)-bound) form of Tr*, we found that Tr* activated PDE at a similar efficiency in rods and cones. Next, we examined the contribution of R* and Tr* lifetimes. In a comparison of PDE activation in the presence (with GTP) and absence (with GTPgammaS) of Tr* inactivation, PDE activation required more light (and was therefore less effective) when Tr* was inactivated in both rod and cone membranes. This is probably because inactivation of Tr* shortened its lifetime, thereby reducing the number of activated PDE molecules. The effect of Tr* inactivation was larger in cones, probably because the lifetime of Tr* is shorter in cones than in rods. The shorter lifetimes of Tr* and R* in cones seem to explain the remaining difference in the effectiveness of PDE activation between rods and cones. PMID- 24344137 TI - The hypertrophic cardiomyopathy myosin mutation R453C alters ATP binding and hydrolysis of human cardiac beta-myosin. AB - The human hypertrophic cardiomyopathy mutation R453C results in one of the more severe forms of the myopathy. Arg-453 is found in a conserved surface loop of the upper 50-kDa domain of the myosin motor domain and lies between the nucleotide binding pocket and the actin binding site. It connects to the cardiomyopathy loop via a long alpha-helix, helix O, and to Switch-2 via the fifth strand of the central beta-sheet. The mutation is, therefore, in a position to perturb a wide range of myosin molecular activities. We report here the first detailed biochemical kinetic analysis of the motor domain of the human beta-cardiac myosin carrying the R453C mutation. A recent report of the same mutation (Sommese, R. F., Sung, J., Nag, S., Sutton, S., Deacon, J. C., Choe, E., Leinwand, L. A., Ruppel, K., and Spudich, J. A. (2013) Proc. Natl. Acad. Sci. U.S.A. 110, 12607 12612) found reduced ATPase and in vitro motility but increased force production using an optical trap. Surprisingly, our results show that the mutation alters few biochemical kinetic parameters significantly. The exceptions are the rate constants for ATP binding to the motor domain (reduced by 35%) and the ATP hydrolysis step/recovery stroke (slowed 3-fold), which could be the rate-limiting step for the ATPase cycle. Effects of the mutation on the recovery stroke are consistent with a perturbation of Switch-2 closure, which is required for the recovery stroke and the subsequent ATP hydrolysis. PMID- 24344138 TI - Biogeographic variation in genetic variability, apomixis expression and ploidy of St. John's wort (Hypericum perforatum) across its native and introduced range. AB - BACKGROUND AND AIMS: St. John's wort (Hypericum perforatum) is becoming an important model plant system for investigations into ecology, reproductive biology and pharmacology. This study investigates biogeographic variation for population genetic structure and reproduction in its ancestral (European) and introduced (North America) ranges. METHODS: Over 2000 individuals from 43 localities were analysed for ploidy, microsatellite variation (19 loci) and reproduction (flow cytometric seed screen). Most individuals were tetraploid (93%), while lower frequencies of hexaploid (6%), diploid (<1%) and triploid (<1%) individuals were also identified. KEY RESULTS: A flow cytometric analysis of 24 single seeds per individual, and five individuals per population demonstrated opposite patterns between ploidy types, with tetraploids producing more apomictic (73%) than sexual (24%) seed, while hexaploids produced more sexual (73%) than apomictic (23%) seed. As hexaploids are derived from tetraploids, these data imply that gene dosage, in addition to the effects of hybridization, influences the switch from apomictic to sexual reproduction. No significant differences in seed production were found between Europe and North America. An analysis of population structure based upon microsatellite profiling demonstrated three major genetic clusters in Europe, whose distribution was reflective of Pleistocene glaciation (e.g. refugia) and post-glacial recolonization of Europe. CONCLUSIONS: The presence of pure and mixed populations representing all three genetic clusters in North America demonstrates that H. perforatum was introduced multiple times onto the continent, followed by gene flow between the different gene pools. Taken together, the data presented here suggest that plasticity in reproduction has no influence on the invasive potential of H. perforatum. PMID- 24344139 TI - Differences in proleptic and epicormic shoot structures in relation to water deficit and growth rate in almond trees (Prunus dulcis). AB - BACKGROUND AND AIMS: Shoot characteristics differ depending on the meristem tissue that they originate from and environmental conditions during their development. This study focused on the effects of plant water status on axillary meristem fate and flowering patterns along proleptic and epicormic shoots, as well as on shoot growth rates on 'Nonpareil' almond trees (Prunus dulcis). The aims were (1) to characterize the structural differences between proleptic and epicormic shoots, (2) to determine whether water deficits modify shoot structures differently depending on shoot type, and (3) to determine whether shoot structures are related to shoot growth rates. METHODS: A hidden semi-Markov model of the axillary meristem fate and number of flower buds per node was built for two shoot types growing on trees exposed to three plant water status treatments. The models segmented observed shoots into successive homogeneous zones, which were compared between treatments. Shoot growth rates were calculated from shoot extension measurements made during the growing season. KEY RESULTS: Proleptic shoots had seven successive homogeneous zones while epicormic shoots had five zones. Shoot structures were associated with changes in growth rate over the season. Water deficit (1) affected the occurrence and lengths of the first zones of proleptic shoots, but only the occurrence of the third zone was reduced in epicormic shoots; (2) had a minor effect on zone flowering patterns and did not modify shoot or zone composition of axillary meristem fates; and (3) reduced growth rates, although patterns over the season were similar among treatments. CONCLUSIONS: Two meristem types, with different latency durations, produced shoots with different growth rates and distinct structures. Differences between shoot type structure responses to water deficit appeared to reflect their ontogenetic characteristics and/or resource availability for their development. Tree water deficit appeared to stimulate a more rapid progression through ontogenetic states. PMID- 24344140 TI - Effects of nitrogen nutrition on the synthesis and deposition of the omega gliadins of wheat. AB - BACKGROUND AND AIMS: The omega-gliadin storage proteins of wheat are of interest in relation to their impact on grain processing properties and their role in food allergy, particularly the omega-5 sub-group and wheat-dependent exercise-induced anaphylaxis. The omega-gliadins are also known to be responsive to nitrogen application. This study therefore compares the effects of cultivar and nitrogen availability on the synthesis and deposition of omega-gliadins in wheat grown under field conditions in the UK, including temporal and spatial analyses at the protein and transcript levels. METHODS: SDS-PAGE, western blotting and N-terminal amino acid sequencing were used to compare the patterns of omega-gliadin components in mature grain of six British wheat (Triticum aestivum) cultivars and their accumulation during the development of grain grown in field plots with varying nitrogen supply. Changes in gene expression during development were determined using real-time reverse transcription-PCR (RT-PCR). Spatial patterns of gene expression and protein accumulation were determined by in situ hybridization and immunofluorescence microscopy, respectively. KEY RESULTS: Two patterns of omega-gliadins were identified in the six cultivars, including both monomeric 'gliadin' proteins and subunits present in polymeric 'glutenin' fractions. Increasing the level of nitrogen fertilizer in field plots resulted in increased expression of omega-gliadin transcripts and increased proportions of omega-5 gliadins. Nitrogen supply also affected the spatial patterns of omega gliadin synthesis and deposition, which were differentially increased in the outer layers of the starchy endosperm with high levels of nitrogen. CONCLUSIONS: Wheat omega-gliadins vary in amount and composition between cultivars, and in their response to nitrogen supply. Their spatial distribution is also affected by nitrogen supply, being most highly concentrated in the sub-aleurone cells of the starchy endosperm under higher nitrogen availability. PMID- 24344141 TI - Pneumococcal serotype diversity among adults in various countries, influenced by pediatric pneumococcal vaccination uptake. AB - Streptococcus pneumoniae serotypes differ in clinical manifestations among adults. Indirect effects of pediatric use of pneumococcal conjugate vaccines (PCVs) affect rates of adult serotype-specific invasive pneumococcal disease (IPD). To characterize PCV effect on adult serotype patterns, we reviewed the literature for differences in proportions and incidence matching the 23-valent pneumococcal polysaccharide vaccine (PPSV23) and 13-valent PCV within specified geographic and time conditions. For adult IPD serotype distribution before widespread pediatric PCV7 use, the median differential between the 23 and 13 serotypes was 16.3% in the core analysis. After pediatric PCV7 adoption, the median differential was 24.4% (P < .003).The median differential in IPD incidence among adults was 5.6 cases per 100 000 population before pediatric PCV7 use and 6.4 afterward (P = .52). The differential for the serotypes in alternate vaccines helps explain recent national recommendations for one or both vaccines in various populations. These differences may widen further, with more extensive pediatric uptake of higher-valence PCVs. PMID- 24344142 TI - 10 health stories that mattered: Dec. 9-13. PMID- 24344143 TI - Cardiac effects of panhypopituitarism in a 71-year-old woman. PMID- 24344145 TI - The illness experience. PMID- 24344144 TI - Guidelines 2.0: systematic development of a comprehensive checklist for a successful guideline enterprise. AB - BACKGROUND: Although several tools to evaluate the credibility of health care guidelines exist, guidance on practical steps for developing guidelines is lacking. We systematically compiled a comprehensive checklist of items linked to relevant resources and tools that guideline developers could consider, without the expectation that every guideline would address each item. METHODS: We searched data sources, including manuals of international guideline developers, literature on guidelines for guidelines (with a focus on methodology reports from international and national agencies, and professional societies) and recent articles providing systematic guidance. We reviewed these sources in duplicate, extracted items for the checklist using a sensitive approach and developed overarching topics relevant to guidelines. In an iterative process, we reviewed items for duplication and omissions and involved experts in guideline development for revisions and suggestions for items to be added. RESULTS: We developed a checklist with 18 topics and 146 items and a webpage to facilitate its use by guideline developers. The topics and included items cover all stages of the guideline enterprise, from the planning and formulation of guidelines, to their implementation and evaluation. The final checklist includes links to training materials as well as resources with suggested methodology for applying the items. INTERPRETATION: The checklist will serve as a resource for guideline developers. Consideration of items on the checklist will support the development, implementation and evaluation of guidelines. We will use crowdsourcing to revise the checklist and keep it up to date. PMID- 24344146 TI - Management of hyponatremia. PMID- 24344147 TI - Improving the process of deceased organ and tissue donation: a role for donation physicians as specialists. PMID- 24344148 TI - Obamacare accelerating into prime time. PMID- 24344149 TI - Privacy commissioner wants new criteria for entering health information in police database. PMID- 24344150 TI - Gym exclusively for overweight people comes to Canada. PMID- 24344152 TI - Health course helps Inuit interpreters tackle tough jobs. PMID- 24344151 TI - Treating Clostridium difficile infection. PMID- 24344153 TI - Canadians balk at longer brand-name drug patents. PMID- 24344154 TI - Response to the editorial "do epistatic modules exist in the genetic control of blood pressure in Dahl rats? A critical perspective". PMID- 24344155 TI - Solitary lesions with fibrosis and increased IgG4+ plasma cells: part of the expanding spectrum of IgG4-related disease or a nonspecific inflammatory response? AB - We assessed 6 cases acquired during routine surgical sign-out for IgG4-related disease (IRD) according to criteria from a recent consensus meeting. These cases fulfilled the morphologic criteria-that is, dense lymphoplasmacytic infiltrates, IgG4:IgG ratio greater than or equal to 0.4, and fibrosis (storiform in 4 cases but were associated with malignancy or did not fulfill the criteria for a new site. These criteria include increased serum IgG4 (normal in the majority of IRD) and a response to glucocorticoids, which is not appropriate treatment for resectable lesions as in our cases. Until more is known about the natural history of the disease, we propose that the possibility of an early, localized, or forme fruste of IRD should be considered and that cases associated with malignancy should at least be documented. Although we acknowledge the value of the consensus criteria, their strict application may result in missed opportunities to study the disease. PMID- 24344156 TI - Concordance Between Prostate Needle Biopsy and Surgical Histopathology in a Primarily African-American Population. AB - INTRODUCTION: Prior studies have revealed that the concordance between biopsy and surgical specimens has been improving over time. However, to date, this has not been analyzed in an African American population, for whom data have often shown more aggressive prostate cancer than for other races. METHODS: We analyzed 250 patients who were operated on at the NY Harbor Department of Veterans Affairs for localized prostate cancer between 2003 and 2010. The clinical biopsy scores were compared with the pathological biopsy scores. We compared the concordance using the kappa coefficient. Univariate and multivariate logistic regressions were used to identify predictors for poor concordance. RESULTS: This population consisted of 59.6% African Americans, 32% Caucasians, and 8.4% Hispanics. Overall, there was a 50% exact concordance between the biopsy and surgical specimens. The kappa was 0.33, indicating fair agreement. Patients with a Gleason score of 6 were found to have an exact concordance 66% of the time, and those with a score of Gleason 7 (3 + 4) had an exact concordance 50% of the time. On univariate and multivariate analyses, only an increasing prostate-specific antigen was associated with reduced concordance. Race was not a significant predictor. CONCLUSIONS: These data are in line with prior studies of concordance. Despite being a population with more aggressive prostate cancer, there does not appear to be an increase in the risk of discordance in African American men. PMID- 24344157 TI - Squamous cell carcinomas of the anterior oral cavity are commonly associated with simplex (or differentiated) oral intraepithelial neoplasia: clinical and pathologic significance. AB - INTRODUCTION: We investigated the occurrence of differentiated oral intraepithelial neoplasia (DOIN) that met the criteria for differentiated intravulvar neoplasia, associated with invasive squamous cell carcinoma (SCC) of the anterior oral cavity, and its clinicopathologic significance. MATERIALS AND METHODS: Sixty-nine consecutive cases of SCC of the anterior oral cavity were categorized into 2 groups: group A comprised SCC associated with DOIN; Group B consisted of cases associated with classical SCC in situ. RESULTS: Fifty-five cases (80%) were classified as group A, or DOIN lesions, with only 14 (20%) as group B. All cases were associated with invasive SCC, except 2 cases in group B. Squamous epithelium continuous or adjacent to invasive SCC displayed consistent changes in the parabasal and basal layers with (1) cytologic atypia with proliferation of parabasal cells in downward expansion causing reactive proliferation of the basal cell layer in early stage and invading the basal layer in late stage, (2) disordered nuclear/cytoplasmic arrangement, and (3) a "cobblestone" appearance characterized by prominent intercellular spaces and cytoplasmic density involving the entire cell (dyskeratosis) of the parabasal layer. p53 and Ki67 immunostaining revealed linear reactivity mainly in the parabasal layer. CONCLUSIONS: DOIN lesions are frequently associated with invasive SCC of anterior oral cavity. Due to the subtle histopathologic changes, DOIN lesions pose potential diagnostic difficulty with differentiation from mild dysplasia or reactive atypia. PMID- 24344158 TI - Confocal technology in fluorescence in situ hybridization evaluation for cancer: a diagnostic improvement. PMID- 24344159 TI - Fibrosis biomarkers in isolated Raynaud's phenomenon: too little, too soon? PMID- 24344161 TI - The effect of enhanced storybook interaction on signing deaf children's vocabulary. AB - The link between vocabulary and later literacy is well documented in the research base. One way children gain vocabulary is through incidental learning. Deaf or hard-of-hearing children (D/HH) often struggle with incidental learning and require vocabulary intervention to increase their lexicon. An effective vocabulary intervention is storybook reading. When dialogic methods are added to storybook reading, the gains are greater than with traditional storybook reading. The purpose of this study was to investigate the effect of an enhanced storybook reading intervention, which included scripted questions and picture prompts, on the vocabulary of young signing D/HH children. We utilized a multiple baseline across content probe design. We discovered a functional relation between the storybook intervention and picture vocabulary identification for several participants. This outcome offers insight into appropriate interventions to increase vocabulary for signing D/HH children. PMID- 24344160 TI - Golimumab 3-year safety update: an analysis of pooled data from the long-term extensions of randomised, double-blind, placebo-controlled trials conducted in patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis. AB - OBJECTIVE: To assess pooled golimumab safety up to year 3 of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) trials. METHODS: Golimumab 50 and 100 mg, administered subcutaneously (SC) every 4 weeks (q4wk), were assessed in patients with active RA (methotrexate-naive, methotrexate experienced and anti-TNF (tumour necrosis factor)-experienced), PsA or AS, despite conventional therapy. Placebo control continued up to week (wk) 24 (wk 52, methotrexate-naive), with early escape at wk 16 (wk 28, methotrexate-naive); subsequently, all patients received golimumab 50 or 100 mg q4wk. After the blinded controlled period, golimumab doses could be adjusted per investigator discretion. Pooled safety analyses reported herein include data from placebo controlled and uncontrolled study periods up to wk 160. Determinations of incidences/100 patient-years (pt-yrs) for rare events also included RA patients from a phase IIb trial. RESULTS: Across five phase III trials of SC golimumab, 639 patients received placebo and 2226 received golimumab 50 mg (n=1249) and/or 100 mg (n=1501) up to wk 160 (patients may be included in more than one group because non-responders were allowed early escape); 1179 patients were treated for >=156 weeks. For placebo, golimumab 50 mg and golimumab 100 mg, respective adverse event incidences/100 pt-yrs (95% CIs) up to wk 160 were: 0.28 (0.01 to 1.56), 0.30 (0.12 to 0.62), 0.41 (0.23 to 0.69) for death; 5.31 (3.20 to 8.30), 3.03 (2.36 to 3.82), 5.09 (4.36 to 5.90) for serious infection; 0.00 (0.00 to 0.84), 0.17 (0.05 to 0.44), 0.35 (0.18 to 0.62) for tuberculosis; 0.00 (0.00 to 0.84), 0.13 (0.03 to 0.38), 0.24 (0.10 to 0.46) for opportunistic infection; 0.00 (0.00 to 0.84), 0.00 (0.00 to 0.13), 0.12 (0.03 to 0.30) for demyelination; and 0.00 (0.00 to 0.84), 0.04 (0.00 to 0.24), 0.18 (0.06 to 0.38) for lymphoma. CONCLUSIONS: SC golimumab safety up to 3 years remained consistent with that of other TNF antagonists. Golimumab 100 mg showed numerically higher incidences of serious infections, demyelinating events and lymphoma than 50 mg; safety follow up up to year 5 continues. PMID- 24344162 TI - Effective connectivity of the subthalamic nucleus-globus pallidus network during Parkinsonian oscillations. AB - In Parkinsonism, subthalamic nucleus (STN) neurons and two types of external globus pallidus (GP) neuron inappropriately synchronise their firing in time with slow (~1 Hz) or beta (13-30 Hz) oscillations in cortex. We recorded the activities of STN, Type-I GP (GP-TI) and Type-A GP (GP-TA) neurons in anaesthetised Parkinsonian rats during such oscillations to constrain a series of computational models that systematically explored the effective connections and physiological parameters underlying neuronal rhythmic firing and phase preferences in vivo. The best candidate model, identified with a genetic algorithm optimising accuracy/complexity measures, faithfully reproduced experimental data and predicted that the effective connections of GP-TI and GP-TA neurons are quantitatively different. Estimated inhibitory connections from striatum were much stronger to GP-TI neurons than to GP-TA neurons, whereas excitatory connections from thalamus were much stronger to GP-TA and STN neurons than to GP-TI neurons. Reciprocal connections between GP-TI and STN neurons were matched in weight, but those between GP-TA and STN neurons were not; only GP-TI neurons sent substantial connections back to STN. Different connection weights between and within the two types of GP neuron were also evident. Adding to connection differences, GP-TA and GP-TI neurons were predicted to have disparate intrinsic physiological properties, reflected in distinct autonomous firing rates. Our results elucidate potential substrates of GP functional dichotomy, and emphasise that rhythmic inputs from striatum, thalamus and cortex are important for setting activity in the STN-GP network during Parkinsonian beta oscillations, suggesting they arise from interactions between most nodes of basal ganglia thalamocortical circuits. PMID- 24344163 TI - Carbachol excites sublaterodorsal nucleus neurons projecting to the spinal cord. AB - Considerable electrophysiological and pharmacological evidence has long suggested an important role for acetylcholine in the regulation of rapid-eye-movement (REM) sleep. For example, injection of the cholinergic agonist carbachol into the dorsomedial pons produces an REM sleep-like state with muscle atonia and cortical activation, both of which are cardinal features of REM sleep. Located within this region of the pons is the sublaterodorsal nucleus (SLD), a structure thought to be both necessary and sufficient for generating REM sleep muscle atonia. Subsets of glutamatergic SLD neurons potently contribute to motor inhibition during REM sleep through descending projections to motor-related glycinergic/GABAergic neurons in the spinal cord and ventromedial medulla. Prior electrophysiological and pharmacological studies examining the effects of acetylcholine on SLD neurons have, however, produced conflicting results. In the present study, we sought to clarify how acetylcholine influences the activity of spinally projecting SLD (SLDsp) neurons. We used retrograde tracing in combination with patch-clamp recordings and recorded pre- and postsynaptic effects of carbachol on SLDsp neurons. Carbachol acted presynaptically by increasing the frequency of glutamatergic miniature excitatory postsynaptic currents. We also found that carbachol directly excited SLDsp neurons by activating an Na(+)-Ca(2+) exchanger. Both pre- and postsynaptic effects were mediated by co-activation of M1 and M3 muscarinic receptors. These observations suggest that acetylcholine produces synergistic, excitatory pre- and postsynaptic responses on SLDsp neurons that, in turn, probably serve to promote muscle atonia during REM sleep. PMID- 24344164 TI - Effects of natriuretic peptides on electrical conduction in the sinoatrial node and atrial myocardium of the heart. AB - Natriuretic peptides, including B-type and C-type natriuretic peptide (BNP and CNP), are powerful regulators of the cardiovascular system; however, their electrophysiological effects in the heart, particularly in the sinoatrial node (SAN), are incompletely understood. We have used high-resolution optical mapping to measure the effects of BNP and CNP, and the roles of natriuretic peptide receptors (NPR-A, NPR-B and NPR-C), on electrical conduction within the SAN and atrial myocardium. In basal conditions BNP and CNP (50-500 nm) increased conduction velocity (CV) within the SAN by ~30% at the high dose and shifted the initial exit site superiorly. These effects sped conduction from the SAN to the surrounding atrial myocardium and were mediated by the NPR-A and NPR-B receptors. In the presence of isoproterenol (1 MUm) the NPR-C receptor made a major contribution to the effects of BNP and CNP in the heart. In these conditions BNP, CNP and the NPR-C agonist cANF each decreased SAN CV and shifted the initial exit site inferiorly. The effects of cANF (30% reduction) were larger than BNP or CNP (~15% reduction), indicating that BNP and CNP activate multiple natriuretic peptide receptors. In support of this, the inhibitory effects of BNP were absent in NPR-C knockout mice, where BNP instead elicited a further increase (~25%) in CV. Measurements in externally paced atrial preparations demonstrate that the effects of natriuretic peptides on CV are partially independent of changes in cycle length. These data provide detailed novel insight into the complex effects of natriuretic peptides and their receptors on electrical conduction in the heart. PMID- 24344165 TI - Properties of cholinergic and non-cholinergic submucosal neurons along the mouse colon. AB - Submucosal neurons are vital regulators of water and electrolyte secretion and local blood flow in the gut. Due to the availability of transgenic models for enteric neuropathies, the mouse has emerged as the research model of choice, but much is still unknown about the murine submucosal plexus. The progeny of choline acetyltransferase (ChAT)-Cre * ROSA26(YFP) reporter mice, ChAT-Cre;R26R-yellow fluorescent protein (YFP) mice, express YFP in every neuron that has ever expressed ChAT. With the aid of the robust YFP staining in these mice, we correlated the neurochemistry, morphology and electrophysiology of submucosal neurons in distal colon. We also examined whether there are differences in neurochemistry along the colon and in neurally mediated vectorial ion transport between the proximal and distal colon. All YFP(+) submucosal neurons also contained ChAT. Two main neurochemical but not electrophysiological groups of neurons were identified: cholinergic (containing ChAT) or non-cholinergic. The vast majority of neurons in the middle and distal colon were non-cholinergic but contained vasoactive intestinal peptide. In the distal colon, non-cholinergic neurons had one or two axons, whereas the cholinergic neurons examined had only one axon. All submucosal neurons exhibited S-type electrophysiology, shown by the lack of long after-hyperpolarizing potentials following their action potentials and fast excitatory postsynaptic potentials (EPSPs). Fast EPSPs were predominantly nicotinic, and somatic action potentials were mediated by tetrodotoxin-resistant voltage-gated channels. The size of submucosal ganglia decreased but the proportion of cholinergic neurons increased distally along the colon. The distal colon had a significantly larger nicotinic ion transport response than the proximal colon. This work shows that the properties of murine submucosal neurons and their control of epithelial ion transport differ between colonic regions. There are several key differences between the murine submucous plexus and that of other animals, including a lack of conventional intrinsic sensory neurons, which suggests there is an incomplete neuronal circuitry within the murine submucous plexus. PMID- 24344166 TI - The non-linear elasticity of the muscle sarcomere and the compliance of myosin motors. AB - Force in striated muscle is due to attachment of the heads of the myosin, the molecular motors extending from the myosin filament, to the actin filament in each half-sarcomere, the functional unit where myosin motors act in parallel. Mechanical and X-ray structural evidence indicates that at the plateau of isometric contraction (force T0), less than half of the elastic strain of the half-sarcomere is due to the strain in the array of myosin motors (s), with the remainder being accounted for by the compliance of filaments acting as linear elastic elements in series with the motor array. Early during the development of isometric force, however, the half-sarcomere compliance has been found to be less than that expected from the linear elastic model assumed above, and this non linearity may affect the estimate of s. This question is investigated here by applying nanometre-microsecond-resolution mechanics to single intact fibres from frog skeletal muscle at 4 degrees C, to record the mechanical properties of the half-sarcomere throughout the development of force in isometric contraction. The results are interpreted with mechanical models to estimate the compliance of the myosin motors. Our conclusions are as follows: (i) early during the development of an isometric tetanus, an elastic element is present in parallel with the myosin motors, with a compliance of ~200 nm MPa(-1) (~20 times larger than the compliance of the motor array at T0); and (ii) during isometric contraction, s is 1.66 +/- 0.05 nm, which is not significantly different from the value estimated with the linear elastic model. PMID- 24344167 TI - Ouabain-digoxin antagonism in rat arteries and neurones. AB - 'Classic' cardiotonic steroids (CTSs) such as digoxin and ouabain selectively inhibit Na+, K+ -ATPase (the Na+ pump) and, via Na+ / Ca2+ exchange (NCX), exert cardiotonic and vasotonic effects. CTS action is more complex than previously thought: prolonged subcutaneous administration of ouabain, but not digoxin, induces hypertension, and digoxin antagonizes ouabain's hypertensinogenic effect. We studied the acute interactions between CTSs in two indirect assays of Na+ pump function: myogenic tone (MT) in isolated, pressurized rat mesenteric small arteries, and Ca2+ signalling in primary cultured rat hippocampal neurones. The 'classic' CTSs (0.3-10 nm) behaved as 'agonists': all increased MT70 (MT at 70 mmHg) and augmented glutamate-evoked Ca2+ (Fura-2) signals. We then tested one CTS in the presence of another. Most CTSs could be divided into ouabain-like (ouabagenin, dihydroouabain (DHO), strophanthidin) or digoxin-like CTS (digoxigenin, digitoxin, bufalin). Within each group, the CTSs were synergistic, but ouabain-like and digoxin-like CTSs antagonized one another in both assays: For example, the ouabain-evoked (3 nm) increases in MT70 and neuronal Ca2+ signals were both greatly attenuated by the addition of 10 nm digoxin or 10 nm bufalin, and vice versa. Rostafuroxin (PST2238), a digoxigenin derivative that displaces 3H-ouabain from Na+, K+ -ATPase, and attenuates some forms of hypertension, antagonized the effects of ouabain, but not digoxin. SEA0400, a Na+ / Ca2+ exchanger (NCX) blocker, antagonized the effects of both ouabain and digoxin. CTSs bind to the alpha subunit of pump alphabeta protomers. Analysis of potential models suggests that, in vivo, Na+ pumps function as tetraprotomers ((alphabeta)4) in which the binding of a single CTS to one protomer blocks all pumping activity. The paradoxical ability of digoxin-like CTSs to reactivate the ouabain-inhibited complex can be explained by de-oligomerization of the tetrameric state. The interactions between these common CTSs may be of considerable therapeutic relevance. PMID- 24344168 TI - Activity-dependent regulation of NMDA receptors in substantia nigra dopaminergic neurones. AB - N-Methyl-d-aspartate receptors (NMDARs) are Ca(2+)-permeable glutamate receptors that play a critical role in synaptic plasticity and promoting cell survival. However, overactive NMDARs can trigger cell death signalling pathways and have been implicated in substantia nigra pars compacta (SNc) pathology in Parkinson's disease. Calcium ion influx through NMDARs recruits Ca(2+)-dependent proteins that can regulate NMDAR activity. The surface density of NMDARs can also be regulated dynamically in response to receptor activity via Ca(2+)-independent mechanisms. We have investigated the activity-dependent regulation of NMDARs in SNc dopaminergic neurones. Repeated whole-cell agonist applications resulted in a decline in the amplitude of NMDAR currents (current run-down) that was use dependent and not readily reversible. Run-down was reduced by increasing intracellular Ca(2+) buffering or by reducing Ca(2+) influx but did not appear to be mediated by the same regulatory proteins that cause Ca(2+)-dependent run-down in hippocampal neurones. The NMDAR current run-down may be mediated in part by a Ca(2+)-independent mechanism, because intracellular dialysis with a dynamin inhibitory peptide reduced run-down, suggesting a role for clathrin-mediated endocytosis in the regulation of the surface density of receptors. Synaptic NMDARs were also subject to current run-down during repeated low-frequency synaptic stimulation in a Ca(2+)-dependent but dynamin-independent manner. Thus, we report, for the first time, regulation of NMDARs in SNc dopaminergic neurones by changes in intracellular Ca(2+) at both synaptic and extrasynaptic sites and provide evidence for activity-dependent changes in receptor trafficking. These mechanisms may contribute to intracellular Ca(2+) homeostasis in dopaminergic neurones by limiting Ca(2+) influx through the NMDAR. PMID- 24344169 TI - Sarcomere-length dependence of myosin filament structure in skeletal muscle fibres of the frog. AB - X-ray diffraction patterns were recorded at beamline ID02 of the European Synchrotron Radiation Facility from small bundles of skeletal muscle fibres from Rana esculenta at sarcomere lengths between 2.1 and 3.5 MUm at 4 degrees C. The intensities of the X-ray reflections from resting fibres associated with the quasi-helical order of the myosin heads and myosin binding protein C (MyBP-C) decreased in the sarcomere length range 2.6-3.0 MUm but were constant outside it, suggesting that an OFF conformation of the thick filament is maintained by an interaction between MyBP-C and the thin filaments. During active isometric contraction the intensity of the M3 reflection from the regular repeat of the myosin heads along the filaments decreased in proportion to the overlap between thick and thin filaments, with no change in its interference fine structure. Thus, myosin heads in the regions of the thick filaments that do not overlap with thin filaments are highly disordered during isometric contraction, in contrast to their quasi-helical order at rest. Heads in the overlap region that belong to two headed myosin molecules that are fully detached from actin are also highly disordered, in contrast to the detached partners of actin-attached heads. These results provide strong support for the concept of a regulatory structural transition in the thick filament involving changes in both the organisation of the myosin heads on its surface and the axial periodicity of the myosin tails in its backbone, mediated by an interaction between MyBP-C and the thin filaments. PMID- 24344170 TI - Freeze-thaw stress: effects of temperature on hydraulic conductivity and ultrasonic activity in ten woody angiosperms. AB - Freeze-thaw events can affect plant hydraulics by inducing embolism. This study analyzed the effect of temperature during the freezing process on hydraulic conductivity and ultrasonic emissions (UE). Stems of 10 angiosperms were dehydrated to a water potential at 12% percentage loss of hydraulic conductivity (PLC) and exposed to freeze-thaw cycles. The minimal temperature of the frost cycle correlated positively with induced PLC, whereby species with wider conduits (hydraulic diameter) showed higher freeze-thaw-induced PLC. Ultrasonic activity started with the onset of freezing and increased with decreasing subzero temperatures, whereas no UE were recorded during thawing. The temperature at which 50% of UE were reached varied between -9.1 degrees C and -31.0 degrees C across species. These findings indicate that temperatures during freezing are of relevance for bubble formation and air seeding. We suggest that species-specific cavitation thresholds are reached during freezing due to the temperature dependent decrease of water potential in the ice, while bubble expansion and the resulting PLC occur during thawing. UE analysis can be used to monitor the cavitation process and estimate freeze-thaw-induced PLC. PMID- 24344171 TI - Gibberellic acid-induced aleurone layers responding to heat shock or tunicamycin provide insight into the N-glycoproteome, protein secretion, and endoplasmic reticulum stress. AB - The growing relevance of plants for the production of recombinant proteins makes understanding the secretory machinery, including the identification of glycosylation sites in secreted proteins, an important goal of plant proteomics. Barley (Hordeum vulgare) aleurone layers maintained in vitro respond to gibberellic acid by secreting an array of proteins and provide a unique system for the analysis of plant protein secretion. Perturbation of protein secretion in gibberellic acid-induced aleurone layers by two independent mechanisms, heat shock and tunicamycin treatment, demonstrated overlapping effects on both the intracellular and secreted proteomes. Proteins in a total of 22 and 178 two dimensional gel spots changing in intensity in extracellular and intracellular fractions, respectively, were identified by mass spectrometry. Among these are proteins with key roles in protein processing and secretion, such as calreticulin, protein disulfide isomerase, proteasome subunits, and isopentenyl diphosphate isomerase. Sixteen heat shock proteins in 29 spots showed diverse responses to the treatments, with only a minority increasing in response to heat shock. The majority, all of which were small heat shock proteins, decreased in heat-shocked aleurone layers. Additionally, glycopeptide enrichment and N glycosylation analysis identified 73 glycosylation sites in 65 aleurone layer proteins, with 53 of the glycoproteins found in extracellular fractions and 36 found in intracellular fractions. This represents major progress in characterization of the barley N-glycoproteome, since only four of these sites were previously described. Overall, these findings considerably advance knowledge of the plant protein secretion system in general and emphasize the versatility of the aleurone layer as a model system for studying plant protein secretion. PMID- 24344173 TI - Review: 15 antipsychotic drugs are more effective than placebo for the treatment of schizophrenia, but vary in their tolerability. PMID- 24344174 TI - Genetics and the investigation of developmental delay/intellectual disability. AB - Global developmental delay and intellectual disabilities are common reasons for diagnostic assessment by paediatricians. There are a multiplicity of possible causes many of which have genetic, management and treatment implications for the child and family. Genetic causes are estimated to be responsible for approximately a quarter to one-half of identified cases. The multiplicity of individually rare genetic causes challenges the practitioner with respect to the selection of diagnostic tests and accurate diagnosis. To assist the practitioner practice guidelines have been formulated and these are reviewed and summarised in this particular article. PMID- 24344175 TI - Child death review five years on. PMID- 24344176 TI - Gender bias in child care and child health: global patterns. AB - Gender-based discrimination is reported across the spectrum of paediatric healthcare including emergency, inpatient, outpatient and preventive care and is mostly reported from South Asia and China with sporadic reports from Africa and South America. Biases against young girls have been documented even in immunisation percentage, home food allocation, seeking medical care for childhood ailments and percentage of household healthcare expenditures allocated to them. Such gender discrimination in access to medical care is likely to have an influence on the overall health of female children. Over the last five decades, the under-5 sex ratios are worsening in India with declining number of girls. Deliberate parental neglect of girls' essential and life-saving medical care is also an important contributing factor apart from sex-selective abortions to the declining gender ratios. Corrective measures and focused action are needed. PMID- 24344177 TI - The 5-HT3A receptor is essential for fear extinction. AB - The 5-HT3 receptor, the only ionotropic 5-HT receptor, is expressed in limbic regions, including the hippocampus, amygdala, and cortex. However, it is not known whether it has a role in fear memory processes. Analysis of 5-HT3A receptor knockout mice in fear conditioning paradigms revealed that the 5-HT3A receptor is not required for the acquisition or retention of fear memory but is essential for the extinction of contextual and tone-cued fear. Our data suggest that the 5-HT3A receptor could be a key molecule regulating fear memory processes and a potential therapeutic target for fear disorders. PMID- 24344178 TI - Stress reduces the incorporation of misinformation into an established memory. AB - Memory can be distorted by misleading post-event information. These memory distortions may have serious consequences, for example in eyewitness testimony. Many situations in which memory reports are solicited, and suggestive or misleading information is presented, are highly stressful for the respondent, yet little is known about how stress affects people's susceptibility to misinformation. Here, we exposed participants to a stressor or a control manipulation before they were presented misinformation about a previous event. We report that stressed participants endorsed misinformation in a subsequent memory test less often than control participants, suggesting that stress reduces distortions of memory by misleading information. PMID- 24344172 TI - Sequence analysis of the genome of carnation (Dianthus caryophyllus L.). AB - The whole-genome sequence of carnation (Dianthus caryophyllus L.) cv. 'Francesco' was determined using a combination of different new-generation multiplex sequencing platforms. The total length of the non-redundant sequences was 568,887,315 bp, consisting of 45,088 scaffolds, which covered 91% of the 622 Mb carnation genome estimated by k-mer analysis. The N50 values of contigs and scaffolds were 16,644 bp and 60,737 bp, respectively, and the longest scaffold was 1,287,144 bp. The average GC content of the contig sequences was 36%. A total of 1050, 13, 92 and 143 genes for tRNAs, rRNAs, snoRNA and miRNA, respectively, were identified in the assembled genomic sequences. For protein-encoding genes, 43 266 complete and partial gene structures excluding those in transposable elements were deduced. Gene coverage was ~ 98%, as deduced from the coverage of the core eukaryotic genes. Intensive characterization of the assigned carnation genes and comparison with those of other plant species revealed characteristic features of the carnation genome. The results of this study will serve as a valuable resource for fundamental and applied research of carnation, especially for breeding new carnation varieties. Further information on the genomic sequences is available at http://carnation.kazusa.or.jp. PMID- 24344179 TI - The ubiquitin-specific protease 14 (USP14) is a critical regulator of long-term memory formation. AB - Numerous studies have suggested a role for ubiquitin-proteasome-mediated protein degradation in learning-dependent synaptic plasticity; however, very little is known about how protein degradation is regulated at the level of the proteasome during memory formation. The ubiquitin-specific protease 14 (USP14) is a proteasomal deubiquitinating enzyme that is thought to regulate protein degradation in neurons; however, it is unknown if USP14 is involved in learning dependent synaptic plasticity. We found that infusion of a USP14 inhibitor into the amygdala impaired long-term memory for a fear conditioning task, suggesting that USP14 is a critical regulator of long-term memory formation in the amygdala. PMID- 24344180 TI - Activity in prelimbic cortex subserves fear memory reconsolidation over time. AB - The prelimbic cortex has been implicated in the consolidation of previously learned fear. Herein, we report that temporarily inactivating this medial prefrontal cortex subregion with the GABAA agonist muscimol (4.0 nmol in 0.2 MUL per hemisphere) was able to equally disrupt 1-, 7-, and 21-d-old contextual fear memories after their brief retrieval in rats. In all cases, this effect was prevented when memory reactivation was omitted. These results indicate that recent and remote fear memories are susceptible to reconsolidation blockade induced by prelimbic cortex inactivation. It was also demonstrated that the disrupting effect of prelimbic cortex inactivation on fear memory persisted over 11 d, and did not show extinction-related features, such as reinstatement. Infusing the same dose and volume of muscimol bilaterally into the infralimbic cortex after brief retrieval/reactivation of the fear memory did not disrupt it, as seen in prelimbic cortex-inactivated animals. The expression of Zif268/Egr1, the product of an immediate early gene related to memory reconsolidation, was also less pronounced in the infralimbic cortex than in prelimbic cortex following memory retrieval/reactivation. Altogether, the present findings highlight that activity in the prelimbic cortex may reestablish reactivated aversive memories and, therefore, contribute to their maintenance over time. PMID- 24344181 TI - Spindle assembly checkpoint robustness requires Tpr-mediated regulation of Mad1/Mad2 proteostasis. AB - Tpr is a conserved nuclear pore complex (NPC) protein implicated in the spindle assembly checkpoint (SAC) by an unknown mechanism. Here, we show that Tpr is required for normal SAC response by stabilizing Mad1 and Mad2 before mitosis. Tpr coimmunoprecipitated with Mad1 and Mad2 (hereafter designated as Tpr/Mad1/Mad2 or TM2 complex) during interphase and mitosis, and is required for Mad1-c-Mad2 recruitment to NPCs. Interestingly, Tpr was normally undetectable at kinetochores and dispensable for Mad1, but not for Mad2, kinetochore localization, which suggests that SAC robustness depends on Mad2 levels at kinetochores. Protein half life measurements demonstrate that Tpr stabilizes Mad1 and Mad2, ensuring normal Mad1-c-Mad2 production in an mRNA- and kinetochore-independent manner. Overexpression of GFP-Mad2 restored normal SAC response and Mad2 kinetochore levels in Tpr-depleted cells. Mechanistically, we provide evidence that Tpr might spatially regulate SAC proteostasis through the SUMO-isopeptidases SENP1 and SENP2 at NPCs. Thus, Tpr is a kinetochore-independent, rate-limiting factor required to mount and sustain a robust SAC response. PMID- 24344182 TI - Novel septin 9 repeat motifs altered in neuralgic amyotrophy bind and bundle microtubules. AB - Septin 9 (SEPT9) interacts with microtubules (MTs) and is mutated in hereditary neuralgic amyotrophy (HNA), an autosomal-dominant neuropathy. The mechanism of SEPT9 interaction with MTs and the molecular basis of HNA are unknown. Here, we show that the N-terminal domain of SEPT9 contains the novel repeat motifs K/R-x-x E/D and R/K-R-x-E, which bind and bundle MTs by interacting with the acidic C terminal tails of beta-tubulin. Alanine scanning mutagenesis revealed that the K/R-R/x-x-E/D motifs pair electrostatically with one another and the tails of beta-tubulin, enabling septin-septin interactions that link MTs together. SEPT9 isoforms lacking repeat motifs or containing the HNA-linked mutation R88W, which maps to the R/K-R-x-E motif, diminished intracellular MT bundling and impaired asymmetric neurite growth in PC-12 cells. Thus, the SEPT9 repeat motifs bind and bundle MTs, and thereby promote asymmetric neurite growth. These results provide the first insight into the mechanism of septin interaction with MTs and the molecular and cellular basis of HNA. PMID- 24344183 TI - Arrayed BUB recruitment modules in the kinetochore scaffold KNL1 promote accurate chromosome segregation. AB - Fidelity of chromosome segregation relies on coordination of chromosome biorientation and the spindle checkpoint. Central to this is the kinetochore scaffold KNL1 that integrates the functions of various mitotic regulators including BUB1 and BUBR1. We show that KNL1 contains an extensive array of short linear sequence modules that encompass TxxOmega and MELT motifs and that can independently localize BUB1. Engineered KNL1 variants with few modules recruit low levels of BUB1 to kinetochores but support a robust checkpoint. Increasing numbers of modules concomitantly increase kinetochore BUB1 levels and progressively enhance efficiency of chromosome biorientation. Remarkably, normal KNL1 function is maintained by replacing all modules with a short array of naturally occurring or identical, artificially designed ones. A minimal array of generic BUB recruitment modules in KNL1 thus suffices for accurate chromosome segregation. Widespread divergence in the amount and sequence of these modules in KNL1 homologues may represent flexibility in adapting regulation of mitotic processes to altered requirements for chromosome segregation during evolution. PMID- 24344184 TI - Loss of Arp2/3 induces an NF-kappaB-dependent, nonautonomous effect on chemotactic signaling. AB - Arp2/3-branched actin is critical for cytoskeletal dynamics and cell migration. However, perturbations and diseases affecting this network have phenotypes that cannot be fully explained by cell-autonomous effects. In this paper, we report nonautonomous effects of Arp2/3 depletion. We show that, upon Arp2/3 depletion, the expression of numerous genes encoding secreted factors, including chemokines, growth factors, and matrix metalloproteases, was increased, a signature resembling the senescence-associated secretory phenotype. These factors affected epidermal growth factor chemotaxis in a nonautonomous way, resolving the recent contradictions about the role of Arp2/3 in chemotaxis. We demonstrate that these genes were activated by nuclear factor kappaB via a CCM2-MEKK3 pathway that has been implicated in hyperosmotic stress signaling. Consistent with this, Arp2/3 depleted cells showed misregulation of volume control and reduced actin in the submembranous cortex. The defects in osmotic signaling in the Arp2/3-depleted cells can be rescued by hypoosmotic treatment. Thus, perturbations of Arp2/3 have nonautonomous effects that should be considered when evaluating experimental manipulations and diseases affecting the Arp2/3-actin cytoskeleton. PMID- 24344185 TI - Endosomal WASH and exocyst complexes control exocytosis of MT1-MMP at invadopodia. AB - Remodeling of the extracellular matrix by carcinoma cells during metastatic dissemination requires formation of actin-based protrusions of the plasma membrane called invadopodia, where the trans-membrane type 1 matrix metalloproteinase (MT1-MMP) accumulates. Here, we describe an interaction between the exocyst complex and the endosomal Arp2/3 activator Wiskott-Aldrich syndrome protein and Scar homolog (WASH) on MT1-MMP-containing late endosomes in invasive breast carcinoma cells. We found that WASH and exocyst are required for matrix degradation by an exocytic mechanism that involves tubular connections between MT1-MMP-positive late endosomes and the plasma membrane in contact with the matrix. This ensures focal delivery of MT1-MMP and supports pericellular matrix degradation and tumor cell invasion into different pathologically relevant matrix environments. Our data suggest a general mechanism used by tumor cells to breach the basement membrane and for invasive migration through fibrous collagen enriched tissues surrounding the tumor. PMID- 24344186 TI - Higher-order unfolding of satellite heterochromatin is a consistent and early event in cell senescence. AB - Epigenetic changes to chromatin are thought to be essential to cell senescence, which is key to tumorigenesis and aging. Although many studies focus on heterochromatin gain, this work demonstrates large-scale unraveling of peri/centromeric satellites, which occurs in all models of human and mouse senescence examined. This was not seen in cancer cells, except in a benign senescent tumor in vivo. Senescence-associated distension of satellites (SADS) occurs earlier and more consistently than heterochromatin foci formation, and SADS is not exclusive to either the p16 or p21 pathways. Because Hutchinson Guilford progeria syndrome patient cells do not form excess heterochromatin, the question remained whether or not proliferative arrest in this aging syndrome involved distinct epigenetic mechanisms. Here, we show that SADS provides a unifying event in both progeria and normal senescence. Additionally, SADS represents a novel, cytological-scale unfolding of chromatin, which is not concomitant with change to several canonical histone marks nor a result of DNA hypomethylation. Rather, SADS is likely mediated by changes to higher-order nuclear structural proteins, such as LaminB1. PMID- 24344187 TI - Autophagy and metacaspase determine the mode of cell death in plants. AB - Although animals eliminate apoptotic cells using macrophages, plants use cell corpses throughout development and disassemble cells in a cell-autonomous manner by vacuolar cell death. During vacuolar cell death, lytic vacuoles gradually engulf and digest the cytoplasmic content. On the other hand, acute stress triggers an alternative cell death, necrosis, which is characterized by mitochondrial dysfunction, early rupture of the plasma membrane, and disordered cell disassembly. How both types of cell death are regulated remains obscure. In this paper, we show that vacuolar death in the embryo suspensor of Norway spruce requires autophagy. In turn, activation of autophagy lies downstream of metacaspase mcII-Pa, a key protease essential for suspensor cell death. Genetic suppression of the metacaspase-autophagy pathway induced a switch from vacuolar to necrotic death, resulting in failure of suspensor differentiation and embryonic arrest. Our results establish metacaspase-dependent autophagy as a bona fide mechanism that is responsible for cell disassembly during vacuolar cell death and for inhibition of necrosis. PMID- 24344189 TI - Adverse left ventricular remodelling after acute myocardial infarction: is there a simple treatment that really works? PMID- 24344188 TI - KNL1 facilitates phosphorylation of outer kinetochore proteins by promoting Aurora B kinase activity. AB - Aurora B kinase phosphorylates kinetochore proteins during early mitosis, increasing kinetochore-microtubule (MT) turnover and preventing premature stabilization of kinetochore-MT attachments. Phosphorylation of kinetochore proteins during late mitosis is low, promoting attachment stabilization, which is required for anaphase onset. The kinetochore protein KNL1 recruits Aurora B counteracting phosphatases and the Aurora B-targeting factor Bub1, yet the consequences of KNL1 depletion on Aurora B phospho-regulation remain unknown. Here, we demonstrate that the KNL1 N terminus is essential for Aurora B activity at kinetochores. This region of KNL1 is also required for Bub1 kinase activity at kinetochores, suggesting that KNL1 promotes Aurora B activity through Bub1 mediated Aurora B targeting. However, ectopic targeting of Aurora B to kinetochores does not fully rescue Aurora B activity in KNL1-depleted cells, suggesting KNL1 influences Aurora B activity through an additional pathway. Our findings establish KNL1 as a requirement for Aurora B activity at kinetochores and for wild-type kinetochore-MT attachment dynamics. PMID- 24344190 TI - Sudden cardiac death in children (1-18 years): symptoms and causes of death in a nationwide setting. AB - AIMS: Hitherto, sudden cardiac death in children (SCDc)-defined as sudden cardiac death (SCD) in the 1-18 years old-has been incompletely described in the general population. Knowledge on incidence rates, causes of death and symptoms prior to death is sparse and has been affected by reporting and referral bias. METHODS AND RESULTS: In a nationwide setting all deaths in children aged 1-18 years in Denmark in 2000-06 were included. To chart causes of death and incidence rates, death certificates and autopsy reports were collected and read. By additional use of the extensive healthcare registries in Denmark, we were also able to investigate prior disease and symptoms. During the 7-year study period there was an average of 1.11 million persons aged 1-18 years. There were a total of 1504 deaths (214 deaths per year) from 7.78 million person-years. A total of 114 (7.5%) were sudden and unexpected. A cardiac disease was known prior to death in 18% of all sudden unexpected death cases. In two-thirds of all sudden unexpected death cases no previous medical history was registered. Causes of death in autopsied cases were cardiac or unknown in 70%. Unexplained deaths, presumed to be a primary cardiac arrhythmia, accounted for 28% of autopsied sudden unexpected death cases. Autopsy rate was 77%. There were a total of 87 cases of SCDc (5.8% of all deaths). Prodromal symptoms were noted in 26% and antecedent symptoms in 45% of SCDc cases. The most frequent antecedent symptoms were seizures, dyspnoea, and syncope. In total, 61% of SCDc were not known with any prior disease; 23% were known with congenital or other heart disease prior to death. In total, 43 (49%) of all sudden unexpected deaths died of a potential inherited cardiac disease. The incidence rate of sudden unexpected death was 1.5 per 100 000 person years. The highest possible incidence rate of SCDc was 1.1 per 100 000 person years. CONCLUSION: From a nationwide study of all deaths in a 7-year period more than half of all victims of SCDc experienced antecedent and/or prodromal symptoms prior to death. The incidence rate of sudden death and SCDc was 1.5 and 1.1 per 100 000 person-years, respectively. Cardiac symptoms in young persons should warrant clinical work-up and an autopsy should be performed in all cases of sudden unexpected death in which the deceased was not known with congenital heart disease prior to death. This is pivotal, in the subsequent familial cascade screening, to diagnose and treat potential inherited cardiac diseases in family members. PMID- 24344191 TI - Family history of premature cardiovascular disease: blood pressure control and long-term mortality outcomes in hypertensive patients. AB - AIMS: Current guidelines recommend early referral and initiation of intensive cardiovascular (CV) risk reduction in individuals with a positive family history of coronary heart disease (CHD). We hypothesized that a family history of premature CHD and stroke [CV disease (CVD)] would lead to earlier referral of hypertensive patients to secondary care clinic, leading to better control of risk factors, mitigating the excess risk seen in these individuals. METHODS AND RESULTS: We studied the association of a positive family history of CVD in 10 787 individuals with longitudinal changes in risk factors and long-term cause specific mortality in the Glasgow Blood Pressure Clinic using generalized estimating equations and the Cox proportional hazard models, respectively. The total time at risk was 193 756 person-years with a median survival time of 29.2 years. A positive family history of CVD was associated with an earlier presentation to the clinic, a lower burden of traditional CV risk factors, and similar longitudinal blood pressure reduction and drug adherence compared with those without. But despite these positive features, all-cause [hazard ratio (HR) = 1.12, 95% confidence interval 1.01-1.25] and CV (HR = 1.20, 1.04-1.38) mortality independent of baseline risk factors were worse. Consistent results were observed in propensity score-matched analysis. Inclusion of family history of CVD did not improve mortality risk discrimination over and above traditional risk factors. CONCLUSION: Our study suggests that despite earlier referral and treatment of individuals with a positive family history of premature CVD, excess risk persists, indicating the need for continued and sustained efforts to reduce risk factors and drug adherence in these individuals. PMID- 24344193 TI - A hierarchical statistical modeling approach to analyze proteomic isobaric tag for relative and absolute quantitation data. AB - MOTIVATION: Isobaric tag for relative and absolute quantitation (iTRAQ) is a widely used method in quantitative proteomics. A robust data analysis strategy is required to determine protein quantification reliability, i.e. changes due to biological regulation rather than technical variation, so that proteins that are differentially expressed can be identified. METHODS: Samples were created by mixing 5, 10, 15 and 20 MUg Escherichia coli cell lysate with 100 MUg of cell lysate from mouse, corresponding to expected relative fold changes of one for mouse proteins and from 0.25 to 4 for E.coli proteins. Relative quantification was carried out using eight channel isobaric tagging with iTRAQ reagent, and proteins were identified using a TripleTOF 5600 mass spectrometer. Technical variation inherent in this iTRAQ dataset was systematically investigated. RESULTS: A hierarchical statistical model was developed to use quantitative information at peptide level and protein level simultaneously to estimate variation present in each individual peptide and protein. A novel data analysis strategy for iTRAQ, denoted in short as WHATraq, was subsequently proposed with its performance evaluated by the proportion of E.coli proteins that are successfully identified as differentially expressed. Compared with two benchmark data analysis strategies WHATraq was able to identify at least 62.8% more true positive proteins that are differentially expressed. Further validated using a biological iTRAQ dataset including multiple biological replicates from varied murine cell lines, WHATraq performed consistently and identified 375% more proteins as being differentially expressed among different cell lines than the other data analysis strategies. PMID- 24344194 TI - SILVER: an efficient tool for stable isotope labeling LC-MS data quantitative analysis with quality control methods. AB - SUMMARY: With the advance of experimental technologies, different stable isotope labeling methods have been widely applied to quantitative proteomics. Here, we present an efficient tool named SILVER for processing the stable isotope labeling mass spectrometry data. SILVER implements novel methods for quality control of quantification at spectrum, peptide and protein levels, respectively. Several new quantification confidence filters and indices are used to improve the accuracy of quantification results. The performance of SILVER was verified and compared with MaxQuant and Proteome Discoverer using a large-scale dataset and two standard datasets. The results suggest that SILVER shows high accuracy and robustness while consuming much less processing time. Additionally, SILVER provides user friendly interfaces for parameter setting, result visualization, manual validation and some useful statistics analyses. AVAILABILITY AND IMPLEMENTATION: SILVER and its source codes are freely available under the GNU General Public License v3.0 at http://bioinfo.hupo.org.cn/silver. PMID- 24344195 TI - Quantification of aortic regurgitation using high-pulse repetition frequency three-dimensional colour Doppler. AB - AIMS: The aim of this study was to validate and assess the feasibility of a previously described method using multibeam high-pulse repetition frequency (HPRF) colour Doppler to quantify the vena contracta area (VCA) in aortic regurgitation (AR). METHODS: Twenty-nine patients with mild to severe AR were studied. Regurgitant volume and fraction measured by magnetic resonance imaging (MRI) were used as the standard of reference. The VCA was measured automatically by combining the Doppler power from multiple beams with a priori knowledge of the individual beam profiles, to give an absolute measurement of the VCA. The regurgitant volume was calculated as the product of the VCA and the velocity time integral, measured separately by continuous wave Doppler. RESULTS: The Spearman's rank correlation between regurgitant volume by MRI and multibeam HPRF colour Doppler was rs = 0.73 (P < 0.01), with 95% limits of agreement of -14.4 +/- 29.1 mL. The mean difference between the methods in those with MRI regurgitant volume of >=30 mL (n = 14) was -7.6 (95% confidence interval -13.9 to -1.2) mL. CONCLUSION: There was good agreement between MRI and multibeam HPRF colour Doppler in patients with moderate to severe AR, while agreement for those with mild AR was modest. PMID- 24344196 TI - Dual sensory impairment and hearing aid use among clients attending low-vision services in Australia: the vision-hearing project. AB - OBJECTIVE: To report the frequency of hearing impairment among vision rehabilitation clients, and to identify patterns of hearing service and aid use. METHOD: In the Vision-Hearing Project, 300 participants (65+ years) completed interviews and a hearing test at low-vision clinics. Visual impairment was defined as visual acuity <20/40 (better eye) wearing glasses if owned, and hearing impairment as average pure-tone air conduction threshold >25 dB hearing level (HL) over four frequencies (500, 1000, 2000, 4000 Hz, better ear). Dual sensory impairment (DSI) was defined as presence of both impairments. RESULTS: Bilateral hearing impairment was identified in 79.7% of participants and DSI in 62.1%. Only 59.8% of hearing impaired participants owned hearing aids and 33.8% reported low use (<1 hr/day). DISCUSSION: Four in five low-vision clients experience hearing impairment, and many have unmet needs. New models of sensory assessment that take account of hearing and vision are needed to support early detection and timely rehabilitation for DSI. PMID- 24344197 TI - The apoptosis repressor with a CARD domain (ARC) gene is a direct hypoxia inducible factor 1 target gene and promotes survival and proliferation of VHL deficient renal cancer cells. AB - The induction of hypoxia-inducible factors (HIFs) is essential for the adaptation of tumor cells to a low-oxygen environment. We found that the expression of the apoptosis inhibitor ARC (apoptosis repressor with a CARD domain) was induced by hypoxia in a variety of cancer cell types, and its induction is primarily HIF1 dependent. Chromatin immunoprecipitation (ChIP) and reporter assays also indicate that the ARC gene is regulated by direct binding of HIF1 to a hypoxia response element (HRE) located at bp -190 upstream of the transcription start site. HIFs play an essential role in the pathogenesis of renal cell carcinoma (RCC) under normoxic conditions, through the loss of the Von Hippel-Lindau gene (VHL). Accordingly, our results show that ARC is not expressed in normal renal tissue but is highly expressed in 65% of RCC tumors, which also express high levels of carbonic anhydrase IX (CAIX), a HIF1-dependent protein. Compared to controls, ARC deficient RCCs exhibited decreased colony formation and increased apoptosis in vitro. In addition, loss of ARC resulted in a dramatic reduction of RCC tumor growth in SCID mice in vivo. Thus, HIF-mediated increased expression of ARC in RCC can explain how loss of VHL can promote survival early in tumor formation. PMID- 24344198 TI - ELL inhibits E2F1 transcriptional activity by enhancing E2F1 deacetylation via recruitment of histone deacetylase 1. AB - ELL (eleven-nineteen lysine-rich leukemia protein) was first identified as a translocation partner of MLL in acute myeloid leukemia; however, the exact mechanism of its action has remained elusive. In this study, we identified ELL as a direct downstream target gene of E2F1. Coimmunoprecipitation assays showed that ELL interacted with E2F1 in vitro and in vivo, leading to inhibition of E2F1 transcriptional activity. In addition, ELL enhanced E2F1 deacetylation via recruitment of histone deacetylase 1 (HDAC1). Notably, the MLL-ELL fusion protein lost the inhibitory role of ELL in E2F1 transcriptional activity. Furthermore, DNA damage induced ELL in an E2F1-dependent manner and ELL protected cells against E2F1-dependent apoptosis. Our findings not only connect ELL to E2F1 function and uncover a novel role of ELL in response to DNA damage but also provide an insight into the mechanism for MLL-ELL-associated leukemogenesis. PMID- 24344199 TI - Regulation of the follistatin gene by RSPO-LGR4 signaling via activation of the WNT/beta-catenin pathway in skeletal myogenesis. AB - WNT signaling plays multiple roles in skeletal myogenesis during gestation and postnatal stages. The R-spondin (RSPO) family of secreted proteins and their cognate receptors, members of leucine-rich repeat-containing G protein-coupled receptor (LGR) family, have emerged as new regulatory components of the WNT signaling pathway. We previously showed that RSPO2 promoted myogenic differentiation via activation of WNT/beta-catenin signaling in mouse myoblast C2C12 cells in vitro. However, the molecular mechanism by which RSPO2 regulates myogenic differentiation is unknown. Herein, we show that depletion of the LGR4 receptor severely disrupts myogenic differentiation and significantly diminishes the response to RSPO2 in C2C12 cells, showing a requirement of LGR4 in RSPO signaling during myogenic differentiation. We identify the transforming growth factor beta (TGF-beta) antagonist follistatin (Fst) as a key mediator of RSPO LGR4 signaling in myogenic differentiation. We further demonstrate that Fst is a direct target of the WNT/beta-catenin pathway. Activation and inactivation of beta-catenin induced and inhibited Fst expression, respectively, in both C2C12 cells and mouse embryos. Specific TCF/LEF1 binding sites within the promoter and intron 1 region of the Fst gene were required for RSPO2 and WNT/beta-catenin induced Fst expression. This study uncovers a molecular cross talk between WNT/beta-catenin and TGF-beta signaling pivotal in myogenic differentiation. PMID- 24344200 TI - Immunosuppression by N-methyl-D-aspartate receptor antagonists is mediated through inhibition of Kv1.3 and KCa3.1 channels in T cells. AB - N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels that play an important role in neuronal development, plasticity, and excitotoxicity. NMDAR antagonists are neuroprotective in animal models of neuronal diseases, and the NMDAR open-channel blocker memantine is used to treat Alzheimer's disease. In view of the clinical application of these pharmaceuticals and the reported expression of NMDARs in immune cells, we analyzed the drug's effects on T-cell function. NMDAR antagonists inhibited antigen-specific T-cell proliferation and cytotoxicity of T cells and the migration of the cells toward chemokines. These activities correlated with a reduction in T-cell receptor (TCR)-induced Ca(2+) mobilization and nuclear localization of NFATc1, and they attenuated the activation of Erk1/2 and Akt. In the presence of antagonists, Th1 effector cells produced less interleukin-2 (IL-2) and gamma interferon (IFN-gamma), whereas Th2 cells produced more IL-10 and IL-13. However, in NMDAR knockout mice, the presumptive expression of functional NMDARs in wild-type T cells was inconclusive. Instead, inhibition of NMDAR antagonists on the conductivity of Kv1.3 and KCa3.1 potassium channels was found. Hence, NMDAR antagonists are potent immunosuppressants with therapeutic potential in the treatment of immune diseases, but their effects on T cells have to be considered in that Kv1.3 and KCa3.1 channels are their major effectors. PMID- 24344201 TI - Phosphorylation-regulated transitions in an oligomeric state control the activity of the Sae2 DNA repair enzyme. AB - In the DNA damage response, many repair and signaling molecules mobilize rapidly at the sites of DNA double-strand breaks. This network of immediate responses is regulated at the level of posttranslational modifications that control the activation of DNA processing enzymes, protein kinases, and scaffold proteins to coordinate DNA repair and checkpoint signaling. Here we investigated the DNA damage-induced oligomeric transitions of the Sae2 protein, an important enzyme in the initiation of DNA double-strand break repair. Sae2 is a target of multiple phosphorylation events, which we identified and characterized in vivo in the budding yeast Saccharomyces cerevisiae. Both cell cycle-dependent and DNA damage dependent phosphorylation sites in Sae2 are important for the survival of DNA damage, and the cell cycle-regulated modifications are required to prime the damage-dependent events. We found that Sae2 exists in the form of inactive oligomers that are transiently released into smaller active units by this series of phosphorylations. DNA damage also triggers removal of Sae2 through autophagy and proteasomal degradation, ensuring that active Sae2 is present only transiently in cells. Overall, this analysis provides evidence for a novel type of protein regulation where the activity of an enzyme is controlled dynamically by posttranslational modifications that regulate its solubility and oligomeric state. PMID- 24344203 TI - Isp7 is a novel regulator of amino acid uptake in the TOR signaling pathway. AB - TOR proteins reside in two distinct complexes, TOR complexes 1 and 2 (TORC1 and TORC2), that are central for the regulation of cellular growth, proliferation, and survival. TOR is also the target for the immunosuppressive and anticancer drug rapamycin. In Schizosaccharomyces pombe, disruption of the TSC complex, mutations in which can lead to the tuberous sclerosis syndrome in humans, results in a rapamycin-sensitive phenotype under poor nitrogen conditions. We show here that the sensitivity to rapamycin is mediated via inhibition of TORC1 and suppressed by overexpression of isp7(+), a member of the family of 2-oxoglutarate Fe(II)-dependent oxygenase genes. The transcript level of isp7(+) is negatively regulated by TORC1 but positively regulated by TORC2. Yet we find extensive similarity between the transcriptome of cells disrupted for isp7(+) and cells mutated in the catalytic subunit of TORC1. Moreover, Isp7 regulates amino acid permease expression in a fashion similar to that of TORC1 and opposite that of TORC2. Overexpression of isp7(+) induces TORC1-dependent phosphorylation of ribosomal protein Rps6 while inhibiting TORC2-dependent phosphorylation and activation of the AGC-like kinase Gad8. Taken together, our findings suggest a central role for Isp7 in amino acid homeostasis and the presence of isp7(+) dependent regulatory loops that affect both TORC1 and TORC2. PMID- 24344202 TI - SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. AB - Mitochondrial morphology is regulated by the balance between two counteracting mitochondrial processes of fusion and fission. There is significant evidence suggesting a stringent association between morphology and bioenergetics of mitochondria. Morphological alterations in mitochondria are linked to several pathological disorders, including cardiovascular diseases. The consequences of stress-induced acetylation of mitochondrial proteins on the organelle morphology remain largely unexplored. Here we report that OPA1, a mitochondrial fusion protein, was hyperacetylated in hearts under pathological stress and this posttranslational modification reduced the GTPase activity of the protein. The mitochondrial deacetylase SIRT3 was capable of deacetylating OPA1 and elevating its GTPase activity. Mass spectrometry and mutagenesis analyses indicated that in SIRT3-deficient cells OPA1 was acetylated at lysine 926 and 931 residues. Overexpression of a deacetylation-mimetic version of OPA1 recovered the mitochondrial functions of OPA1-null cells, thus demonstrating the functional significance of K926/931 acetylation in regulating OPA1 activity. Moreover, SIRT3 dependent activation of OPA1 contributed to the preservation of mitochondrial networking and protection of cardiomyocytes from doxorubicin-mediated cell death. In summary, these data indicated that SIRT3 promotes mitochondrial function not only by regulating activity of metabolic enzymes, as previously reported, but also by regulating mitochondrial dynamics by targeting OPA1. PMID- 24344204 TI - TIMMDC1/C3orf1 functions as a membrane-embedded mitochondrial complex I assembly factor through association with the MCIA complex. AB - Complex I (CI) of the electron transport chain, a large membrane-embedded NADH dehydrogenase, couples electron transfer to the release of protons into the mitochondrial inner membrane space to promote ATP production through ATP synthase. In addition to being a central conduit for ATP production, CI activity has been linked to neurodegenerative disorders, including Parkinson's disease. CI is built in a stepwise fashion through the actions of several assembly factors. We employed interaction proteomics to interrogate the molecular associations of 15 core subunits and assembly factors previously linked to human CI deficiency, resulting in a network of 101 proteins and 335 interactions (edges). TIMMDC1, a predicted 4-pass membrane protein, reciprocally associated with multiple members of the MCIA CI assembly factor complex and core CI subunits and was localized in the mitochondrial inner membrane, and its depletion resulted in reduced CI activity and cellular respiration. Quantitative proteomics demonstrated a role for TIMMDC1 in assembly of membrane-embedded and soluble arms of the complex. This study defines a new membrane-embedded CI assembly factor and provides a resource for further analysis of CI biology. PMID- 24344205 TI - Change of point mutations in Helicobacter pylori rRNA associated with clarithromycin resistance in Italy. AB - Primary clarithromycin resistance is the main factor affecting the efficacy of Helicobacter pylori therapy. This study aimed: (i) to assess the concordance between phenotypic (culture) and genotypic (real-time PCR) tests in resistant strains; (ii) to search, in the case of disagreement between the methods, for point mutations other than those reported as the most frequent in Europe; and (iii) to compare the MICs associated with the single point mutations. In order to perform real-time PCR, we retrieved biopsies from patients in whom H. pylori infection was successful diagnosed by bacterial culture and clarithromycin resistance was assessed using the Etest. Only patients who had never been previously treated, and with H. pylori strains that were either resistant exclusively to clarithromycin or without any resistance, were included. Biopsies from 82 infected patients were analysed, including 42 strains that were clarithromycin resistant and 40 that were clarithromycin susceptible on culture. On genotypic analysis, at least one of the three most frequently reported point mutations (A2142C, A2142G and A2143G) was detected in only 23 cases (54.8%), with a concordance between the two methods of 0.67. Novel point mutations (A2115G, G2141A and A2144T) were detected in a further 14 out of 19 discordant cases, increasing the resistance detection rate of PCR to 88% (P<0.001; odds ratio 6.1, 95% confidence interval 2-18.6) and the concordance to 0.81. No significant differences in MIC values among different point mutations were observed. This study suggests that: (i) the prevalence of the usually reported point mutations may be decreasing, with a concomitant emergence of new mutations; (ii) PCR-based methods should search for at least six point mutations to achieve good accuracy in detecting clarithromycin resistance; and (iii) none of the tested point mutations is associated with significantly higher MIC values than the others. PMID- 24344206 TI - Molecular epidemiology of Clostridium difficile in a tertiary hospital of China. AB - Clostridium difficile infection (CDI) is caused by toxin-producing strains. It accounts for 20-30 % of antibiotic-associated diarrhoea and particularly accounts for 90 % of pseudomembranous colitis. The epidemiological study of C. difficile is thus important. In this study, we report the molecular epidemiology and ward distribution of C. difficile in a tertiary hospital of China. A total of 161 toxigenic strains were isolated from 1845 patients originating from different wards and the strains were characterized based on toxin profile and multilocus sequence typing. Variable isolation rates were observed in different wards and the occurrence was higher in intensive care unit and geriatric wards. Toxin gene profiling revealed that, out of the 161 isolates, 134 (83.2)% were positive for both toxin A (tcdA) and toxin B (tcdB) (A+B+) followed by toxin A-negative and B positive (A-B+) (16.8 %) isolates. However, only three of the toxigenic strains (1.9 %) were positive for both the cdtA and cdtB genes. Based on the molecular epidemiology study, a total of 30 different sequence types (STs), including one new ST (ST-220), were distinguishable. ST-54 was the most prevalent (23.0 %), followed by ST-35 (19.3 %) and ST-37 (10.0 %). None of the isolates belonged to ST-1 (ribotype 027) or ST-11 (ribotype 078). Taken together, the toxin profile and the molecular epidemiological data showed that all the ST-37 clades were of toxin type A-B+, which accounted for 59.3 % of all type A-B+ isolates. Meanwhile the clade 1 genotype, ST-54, was widely distributed among the geriatric, infection and haematology wards. There was no outbreak of C. difficile infection during our study; however the possibility of prolonged outbreaks cannot be completely ignored. PMID- 24344207 TI - The value of signs and symptoms in differentiating between bacterial, viral and mixed aetiology in patients with community-acquired pneumonia. AB - Current diagnostics for community-acquired pneumonia (CAP) include testing for a wide range of pathogens, which is costly and not always informative. We compared clinical and laboratory parameters of patients with CAP caused by different groups of pathogens to evaluate the potential for targeted diagnostics and directed treatment. In a prospective study, conducted between April 2008 and April 2009, adult patients with CAP were tested for the presence of a broad range of possible respiratory pathogens using bacterial cultures, PCR, urinary antigen testing and serology. Of 408 patients with CAP, pathogens were detected in 263 patients (64.5%). Streptococcus pneumoniae and influenza A virus were the most frequently identified bacterial and viral pathogens, respectively. Age had a significant effect on the prediction of aetiology (P = 0.054), with an increase in the relative contribution of viruses with advancing age. Multivariate analyses further showed that the presence of cough increased the likelihood of detecting a viral pathogen [odds ratio (OR) 5.536, 95% confidence interval (CI) 2.130 14.390], the presence of immunodeficiency decreased the likelihood of detecting a bacterial pathogen (OR 0.595, 95 % CI 0.246-1.437) and an increase in pneumonia severity index score increased the likelihood of detecting a pathogen in general. Although several variables were independently associated with the detection of a pathogen group, substantial overlap meant there were no reliable clinical predictors to distinguish aetiologies. Therefore, testing for common respiratory pathogens is still necessary to optimize treatment. PMID- 24344208 TI - Invasion of endothelial cells and arthritogenic potential of endocarditis associated Corynebacterium diphtheriae. AB - Although infection by Corynebacterium diphtheriae is a model of extracellular mucosal pathogenesis, different clones have been also associated with invasive infections such as sepsis, endocarditis, septic arthritis and osteomyelitis. The mechanisms that promote C. diphtheriae infection and haematogenic dissemination need further investigation. In this study we evaluated the association and invasion mechanisms with human umbilical vein endothelial cells (HUVECs) and experimental arthritis in mice of endocarditis-associated strains and control non invasive strains. C. diphtheriae strains were able to adhere to and invade HUVECs at different levels. The endocarditis-associated strains displayed an aggregative adherence pattern and a higher number of internalized viable cells in HUVECs. Transmission electron microscopy (TEM) analysis revealed intracellular bacteria free in the cytoplasm and/or contained in a host-membrane-confined compartment as single micro-organisms. Data showed bacterial internalization dependent on microfilament and microtubule stability and involvement of protein phosphorylation in the HUVEC signalling pathway. A high number of affected joints and high arthritis index in addition to the histopathological features indicated a strain-dependent ability of C. diphtheriae to cause severe polyarthritis. A correlation between the arthritis index and increased systemic levels of IL-6 and TNF-alpha was observed for endocarditis-associated strains. In conclusion, higher incidence of potential mechanisms by which C. diphtheriae may access the bloodstream through the endothelial barrier and stimulate the production of pro inflammatory cytokines such as IL-6 and TNF-alpha, in addition to the ability to affect the joints and induce arthritis through haematogenic spread are thought to be related to the pathogenesis of endocarditis-associated strains. PMID- 24344209 TI - Disproportional plastome-wide increase of substitution rates and relaxed purifying selection in genes of carnivorous Lentibulariaceae. AB - Carnivorous Lentibulariaceae exhibit the most sophisticated implementation of the carnivorous syndrome in plants. Their unusual lifestyle coincides with distinct genomic peculiarities such as the smallest angiosperm nuclear genomes and extremely high nucleotide substitution rates across all genomic compartments. Here, we report the complete plastid genomes from each of the three genera Pinguicula, Utricularia, and Genlisea, and investigate plastome-wide changes in their molecular evolution as the carnivorous syndrome unfolds. We observe a size reduction by up to 9% mostly due to the independent loss of genes for the plastid NAD(P)H dehydrogenase and altered proportions of plastid repeat DNA, as well as a significant plastome-wide increase of substitution rates and microstructural changes. Protein-coding genes across all gene classes show a disproportional elevation of nonsynonymous substitutions, particularly in Utricularia and Genlisea. Significant relaxation of purifying selection relative to noncarnivores occurs in the plastid-encoded fraction of the photosynthesis ATP synthase complex, the photosystem I, and in several other photosynthesis and metabolic genes. Shifts in selective regimes also affect housekeeping genes including the plastid-encoded polymerase, for which evidence for relaxed purifying selection was found once during the transition to carnivory, and a second time during the diversification of the family. Lentibulariaceae significantly exhibit enhanced rates of nucleotide substitution in most of the 130 noncoding regions. Various factors may underlie the observed patterns of relaxation of purifying selection and substitution rate increases, such as reduced net photosynthesis rates, alternative paths of nutrient uptake (including organic carbon), and impaired DNA repair mechanisms. PMID- 24344210 TI - Autologous or reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chemotherapy-sensitive mantle-cell lymphoma: analysis of transplantation timing and modality. AB - PURPOSE: To examine the outcomes of patients with chemotherapy-sensitive mantle cell lymphoma (MCL) following a first hematopoietic stem-cell transplantation (HCT), comparing outcomes with autologous (auto) versus reduced-intensity conditioning allogeneic (RIC allo) HCT and with transplantation applied at different times in the disease course. PATIENTS AND METHODS: In all, 519 patients who received transplantations between 1996 and 2007 and were reported to the Center for International Blood and Marrow Transplant Research were analyzed. The early transplantation cohort was defined as those patients in first partial or complete remission with no more than two lines of chemotherapy. The late transplantation cohort was defined as all the remaining patients. RESULTS: Auto HCT and RIC allo-HCT resulted in similar overall survival from transplantation for both the early (at 5 years: 61% auto-HCT v 62% RIC allo-HCT; P = .951) and late cohorts (at 5 years: 44% auto-HCT v 31% RIC allo-HCT; P = .202). In both early and late transplantation cohorts, progression/relapse was lower and nonrelapse mortality was higher in the allo-HCT group. Overall survival and progression-free survival were highest in patients who underwent auto-HCT in first complete response. Multivariate analysis of survival from diagnosis identified a survival benefit favoring early HCT for both auto-HCT and RIC allo HCT. CONCLUSION: For patients with chemotherapy-sensitive MCL, the optimal timing for HCT is early in the disease course. Outcomes are particularly favorable for patients undergoing auto-HCT in first complete remission. For those unable to achieve complete remission after two lines of chemotherapy or those with relapsed disease, either auto-HCT or RIC allo-HCT may be effective, although the chance for long-term remission and survival is lower. PMID- 24344211 TI - Phase II pilot study of intravenous high-dose interferon with or without maintenance treatment in melanoma at high risk of recurrence. AB - PURPOSE: High-dose interferon alfa-2b (HDI) has emerged as a potentially effective adjuvant therapy in patients with resected melanoma at high risk of recurrence. Evidence suggests it may be the early, very-high-dose part of the regimen that is critical. This pilot study sought to provide an early indication of whether the same effects can be achieved with the intravenous component of HDI alone and inform the feasibility and design of a phase III trial. PATIENTS AND METHODS: Patients with stage 2B, 2C, 3B, and 3C melanoma were randomly assigned to receive interferon alfa-2b (IFN-alpha-2b) 20 MIU/m(2) intravenously (IV) daily 5 days per week for 4 weeks (arm A) versus the same regimen followed by IFN-alpha 2b 10 MIU/m(2) administered subcutaneously three times per week for 48 weeks (arm B) and observed for relapse-free survival (RFS) and overall survival. RESULTS: Between 2003 and 2009, 194 patients were enrolled (arm A, 96; arm B, 98). After median follow-up of 39.5 months, RFS was 22.7 months (95% CI, 14.1 to 38.1 months) in arm A versus 33.3 months (95% CI, 18.2 to not reached) in arm B (P = .28). The proportions of patients free of relapse at 2 years were 50% and 54.1% (P = .569; hazard ratio, 0.89), respectively. Overall survival favored arm B (median, 41.5 months v not reached; P = .05). CONCLUSION: Clinical outcomes were better in patients who had the longer regimen. Our results do not support either the use of a month of IV HDI alone in place of the year-long regimen or the initiation of a larger trial on this question. PMID- 24344212 TI - Predicting and communicating the risk of recurrence and death in women with early stage breast cancer: a systematic review of risk prediction models. AB - BACKGROUND: It is a challenge for oncologists to distinguish patients with breast cancer who can forego adjuvant systemic treatment without negatively affecting survival from those who cannot. Risk prediction models (RPMs) have been developed for this purpose. Oncologists seem to have embraced RPMs (particularly Adjuvant!) in clinical practice and often use them to communicate prognosis to patients. We performed a systematic review of published RPMs and provide an overview of the prognosticators incorporated and reported clinical validity. Subsequently, we selected the RPMs that are currently used in the clinic for a more in-depth assessment of clinical validity. Finally, we assessed lay comprehensibility of the reports generated by RPMs. METHODS: Pubmed, EMBASE, and Web of Science were searched. Two reviewers independently selected relevant articles and extracted data. Agreement on article selection and data extraction was achieved in consensus meetings. RESULTS: We identified RPMs based on clinical prognosticators (N = 6) and biomolecular features (N = 14). Generally predictions from RPMs seem to be accurate, except for patients <= 50 years or >= 75 years at diagnosis, in addition to Asian populations. RPM reports contain much medical jargon or technical details, which are seldom explained in lay terms. CONCLUSION: The accuracy of RPMs' prognostic estimates is suboptimal in some patient subgroups. This urgently needs to be addressed. In their current format, RPM reports are not conducive to patient comprehension. Communicating survival probabilities using RPM might seem straightforward, but it is fraught with difficulties. If not done properly, it can backfire and confuse patients. Evidence to guide best communication practice is needed. PMID- 24344213 TI - Expanding clinical trial networks in pediatric acute lymphoblastic leukemia. PMID- 24344214 TI - Serum 2-hydroxyglutarate production in IDH1- and IDH2-mutated de novo acute myeloid leukemia: a study by the Acute Leukemia French Association group. AB - PURPOSE: Mutated isocitrate dehydrogenases (IDHs) 1 and 2 produce high levels of 2-hydroxyglutarate (2-HG). We investigated whether, in acute myeloid leukemia (AML), serum 2-HG would predict the presence of IDH1/2 mutations at diagnosis and provide a marker of minimal residual disease (MRD). PATIENTS AND METHODS: Serum samples from 82 patients at diagnosis of de novo AML (IDH1/2 mutated, n = 53) and 68 patients without AML were analyzed for total 2-HG and its ratio of D to L stereoisomers by mass spectrometry. We measured 2-HG levels and molecular markers of MRD (WT1 and NPM1) in serial samples of 36 patients with IDH1/2 mutations after induction therapy. RESULTS: In patients with AML with IDH1/2 mutations, 2 HG serum levels were significantly higher than in patients with IDH1/2 wild type (P < .001). Area under the receiver operating characteristic curve was 99%. The optimum diagnostic cutoff between IDH1/2 mutated and normal was 2 MUmol/L (sensitivity, 100%; specificity, 79%). Quantification of the D/L stereoisomers increased specificity (100%; 95% CI, 83% to 100%) compared with total 2-HG (P = .031). In patients with IDH2 R172 mutations, 2-HG levels were higher relative to those with other IDH1/2 mutations (P < .05). During follow-up, serum 2-HG levels showed strong positive correlation with WT1 and NPM1 (P < .001). After induction therapy, total 2-HG serum levels < 2 MUmol/L were associated with better overall (P = .008) and disease-free survival (P = .005). CONCLUSION: Serum 2-HG is a predictor of the presence of IDH1/2 mutations and outcome in these patients. Discrimination between D/L stereoisomers improved specificity. PMID- 24344216 TI - Adjuvant interferon in melanoma: is duration of therapy important? PMID- 24344215 TI - Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. AB - PURPOSE: From 2002 to 2007, the International Berlin-Frankfurt-Munster Study Group conducted a prospective randomized clinical trial (ALL IC-BFM 2002) for the management of childhood acute lymphoblastic leukemia (ALL) in 15 countries on three continents. The aim of this trial was to explore the impact of differential delayed intensification (DI) on outcome in all risk groups. PATIENTS AND METHODS: For this trial, 5,060 eligible patients were divided into three risk groups according to age, WBC, early treatment response, and unfavorable genetic aberrations. DI was randomized as follows: standard risk (SR), two 4-week intensive elements (protocol III) versus one 7-week protocol II; intermediate risk (IR), protocol III * 3 versus protocol II * 1; high risk (HR), protocol III * 3 versus either protocol II * 2 (Associazione Italiana Ematologia Oncologia Pediatrica [AIEOP] option), or 3 HR blocks plus single protocol II (Berlin Frankfurt-Munster [BFM] option). RESULTS: At 5 years, the probabilities of event free survival and survival were 74% (+/- 1%) and 82% (+/- 1%) for all 5,060 eligible patients, 81% and 90% for the SR (n = 1,564), 75% and 83% for the IR (n = 2,650), and 55% and 62% for the HR (n = 846) groups, respectively. No improvement was accomplished by more intense and/or prolonged DI. CONCLUSION: The ALL IC-BFM 2002 trial is a good example of international collaboration in pediatric oncology. A wide platform of countries able to run randomized studies in ALL has been established. Although the alternative DI did not improve outcome compared with standard treatment and the overall results are worse than those achieved by longer established leukemia groups, the national results have generally improved. PMID- 24344217 TI - Is early hematopoietic stem-cell transplantation necessary in mantle-cell lymphoma? PMID- 24344218 TI - Effects of exercise on treatment-related adverse effects for patients with prostate cancer receiving androgen-deprivation therapy: a systematic review. AB - PURPOSE: Androgen-deprivation therapy is a commonly used treatment for men with prostate cancer; however, the adverse effects can be detrimental to patient health and quality of life. Exercise has been proposed as a strategy for ameliorating a range of these treatment-related adverse effects. We conducted a systematic review of the literature regarding the effects of exercise on treatment-related adverse effects in men receiving androgen-deprivation therapy for prostate cancer. METHODS: An online electronic search of the Cochrane Library, EMBASE, MEDLINE, CINAHL, SPORTDiscus, and Health Source databases was performed to identify relevant peer-reviewed articles published between January 1980 and June 2013. Eligible study designs included randomized controlled trials as well as uncontrolled trials with pre- and postintervention data. Information was extracted regarding participant and exercise intervention characteristics as well as the effects of exercise on bone health, body composition, physical performance, cardiometabolic risk, fatigue, and quality of life. RESULTS: Ten studies were included, with exercise interventions involving aerobic and/or resistance training. Exercise training demonstrated benefits in muscular strength, cardiorespiratory fitness, functional task performance, lean body mass, and fatigue, with inconsistent effects observed for adiposity. The impact of exercise on bone health, cardiometabolic risk markers, and quality of life are currently unclear. CONCLUSION: Among patients with prostate cancer treated with androgen-deprivation therapy, appropriately prescribed exercise is safe and may ameliorate a range of treatment-induced adverse effects. Ongoing research of high methodologic quality is required to consolidate and expand on current knowledge and to allow the development of specific evidence-based exercise prescription recommendations. PMID- 24344219 TI - Prostate cancer and the therapeutic benefits of structured exercise. PMID- 24344221 TI - US Food and Drug Administration approval of drugs for the treatment of prostate cancer: a new era has begun. PMID- 24344220 TI - Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. AB - PURPOSE: Tumor cells from approximately 40% of patients with Hodgkin or non Hodgkin lymphoma express the type II latency Epstein-Barr virus (EBV) antigens latent membrane protein 1 (LMP1) and LMP2, which represent attractive targets for immunotherapy. Because T cells specific for these antigens are present with low frequency and may be rendered anergic by the tumors that express them, we expanded LMP-cytotoxic T lymphocytes (CTLs) from patients with lymphoma using autologous dendritic cells and EBV-transformed B-lymphoblastoid cell lines transduced with an adenoviral vector expressing either LMP2 alone (n = 17) or both LMP2 and DeltaLMP1 (n = 33). PATIENTS AND METHODS: These genetically modified antigen-presenting cells expanded CTLs that were enriched for specificity against type II latency LMP antigens. When infused into 50 patients with EBV-associated lymphoma, the expanded CTLs did not produce infusional toxicities. RESULTS: Twenty-eight of 29 high-risk or multiple-relapse patients receiving LMP-CTLs as adjuvant therapy remained in remission at a median of 3.1 years after CTL infusion. None subsequently died as a result of lymphoma, but nine succumbed to complications associated with extensive prior chemoradiotherapy, including myocardial infarction and secondary malignancies. Of 21 patients with relapsed or resistant disease at the time of CTL infusion, 13 had clinical responses, including 11 complete responses. T cells specific for LMP as well as nonviral tumor-associated antigens (epitope spreading) could be detected in the peripheral blood within 2 months after CTL infusion, but this evidence for epitope spreading was seen only in patients achieving clinical responses. CONCLUSION: Autologous T cells directed to the LMP2 or LMP1 and LMP2 antigens can induce durable complete responses without significant toxicity. Their earlier use in the disease course may reduce delayed treatment-related mortality. PMID- 24344222 TI - Electronic self-report assessment for cancer and self-care support: results of a multicenter randomized trial. AB - PURPOSE: The purpose of this trial was to evaluate the effect of a Web-based, self-report assessment and educational intervention on symptom distress during cancer therapy. PATIENTS AND METHODS: A total of 752 ambulatory adult participants were randomly assigned to symptom/quality-of-life (SxQOL) screening at four time points (control) versus screening, targeted education, communication coaching, and the opportunity to track/graph SxQOL over time (intervention). A summary of the participant-reported data was delivered to clinicians at each time point in both groups. All participants used the assessment before a new therapeutic regimen, at 3 to 6 weeks and 6 to 8 weeks later, completing the final assessment at the end of therapy. Change in Symptom Distress Scale-15 (SDS-15) score from pretreatment to end of study was compared using analysis of covariance and regression analysis adjusting for selected variables. RESULTS: We detected a significant difference between study groups in mean SDS-15 score change from baseline to end of study: 1.27 (standard deviation [SD], 6.7) in the control group (higher distress) versus -0.04 (SD, 5.8) in the intervention group (lower distress). SDS-15 score was reduced by an estimated 1.21 (95% CI, 0.23 to 2.20; P = .02) in the intervention group. Baseline SDS-15 score (P < .001) and clinical service (P = .01) were predictive. Multivariable analyses suggested an interaction between age and study group (P = .06); in subset analysis, the benefit of intervention was strongest in those age > 50 years (P = .002). CONCLUSION: Web-based self-care support and communication coaching added to SxQOL screening reduced symptom distress in a multicenter sample of participants with various diagnoses during and after active cancer treatment. Participants age > 50 years, in particular, may have benefited from the intervention. PMID- 24344223 TI - Internal jugular vein removal and intraocular pressure. PMID- 24344224 TI - How urgent is the treatment of transient vision loss? PMID- 24344225 TI - Quality of internet-derived information on common ophthalmic conditions. PMID- 24344226 TI - Author's response: Outcomes of polypoidal choroidal vasculopathy treated with ranibizumab monotherapy. PMID- 24344227 TI - Microbiologic spectrum and susceptibility of isolates in acute postcataract surgery endophthalmitis: are they same as they were more than a decade ago? PMID- 24344228 TI - Mapping trachoma in 25 local government areas of Sokoto and Kebbi states, northwestern Nigeria. AB - INTRODUCTION: The WHO global initiative on elimination of trachoma by 2020 (GET 2020) recommends mapping of trachoma at district (Local Government Area (LGA)) levels to enable planning and control activities in affected communities worldwide. The aim of the present study was to provide baseline data on trachoma for the LGAs of Sokoto and Kebbi states, Nigeria. METHODS: A population-based cross-sectional survey was conducted in 25 LGAs between November 2011 and May 2012. The WHO guidelines for trachoma control and risk factor assessment were used in the planning and conduct of the survey. RESULTS: The prevalence of trachomatous inflammation-follicular in children aged 1-9 years ranged from 0.3% in Sokoto South to 15.6% in Kalgo LGA. The prevalence of trachomatous trichiasis (TT) in adults (>14 years) ranged from 0.03% in three LGAs to 0.6% in Gudu LGA. Logistic regression analysis for the trachoma risk factors after chi(2) analysis showed only distance from water source as a significant risk factor (OR>1, p<0.5). Clean face, access to latrines and knowledge of trachoma prevention were significantly protective (OR<1, p<0.5) against active disease. The average number of persons in need of TT lid surgery ranged from 0 in 3 LGAs to 397 in Danko Wasagu LGA. Mass antibiotic distribution is needed in 4 LGAs. The estimated number of households in need of latrines and improved water sources are high, with 1 LGA requiring 34 500 latrines and 20 000 improved water sources. CONCLUSIONS: There is a burden of active trachoma of different endemicity levels in all the surveyed LGAs. The burden of trachoma risk factors remains a challenge despite the global effort to decrease the risk factors through the Millennium Development Goals. PMID- 24344229 TI - Transdermal androgen patches in evaporative dry eye syndrome with androgen deficiency: a pilot study. PMID- 24344230 TI - A mobile phone-based retinal camera for portable wide field imaging. AB - Digital fundus imaging is used extensively in the diagnosis, monitoring and management of many retinal diseases. Access to fundus photography is often limited by patient morbidity, high equipment cost and shortage of trained personnel. Advancements in telemedicine methods and the development of portable fundus cameras have increased the accessibility of retinal imaging, but most of these approaches rely on separate computers for viewing and transmission of fundus images. We describe a novel portable handheld smartphone-based retinal camera capable of capturing high-quality, wide field fundus images. The use of the mobile phone platform creates a fully embedded system capable of acquisition, storage and analysis of fundus images that can be directly transmitted from the phone via the wireless telecommunication system for remote evaluation. PMID- 24344231 TI - Decreased tear volume in patients with metabolic syndrome: the Osaka study. PMID- 24344232 TI - Systematic review of randomised clinical trials on topical ciclosporin A for the treatment of dry eye disease. AB - AIMS: Topical ciclosporin A (CsA) is a therapeutic option for dry eye disease (DED) to control ocular surface inflammation and improve tear function. The aim of this study is to systematically review data from randomised clinical trials (RCTs) evaluating efficacy and safety of topical CsA treatment for DED. METHODS: Articles published up to December 2012 were identified from Medline, Embase and the Cochrane Controlled Trials Register. A total of 18 RCTs that evaluated the efficacy and safety of different topical CsA formulations for the treatment of DED were selected according to the set criteria. The Jadad score was calculated to assess RCT quality. RESULTS: The mean Jadad score of the included RCTs was 2.8+/-0.6. All CsA formulations proved safe for the treatment of DED. Symptoms improved in 100% (9/9) RCTs, tear function improved in 72% (13/18) RCTs and ocular surface damage was ameliorated in 53% (9/17) RCTs in patients with DED. No improvements with CsA treatment versus control were observed in DED resulting from surgical procedures, contact lens use and thyroid orbitopathy. Statistical comparison of CsA efficacy through a meta-analysis of data was not possible due to a lack of standardised criteria and comparable outcomes among studies. CONCLUSIONS: Although topical CsA appears to be a safe treatment for DED, evidence emerging from RCTs is limited, and this affects the strength of recommendations to healthcare providers and policymakers for optimal management. Standardised diagnostic criteria to assess the efficacy of topical CsA are recommended to improve the design of future RCTs in DED. PMID- 24344233 TI - Retinopathy of prematurity: an evaluation of existing screening criteria in Pakistan. AB - AIM: To evaluate if broadening the criteria for retinopathy of prematurity (ROP) screening to include babies with gestational age >=32 weeks and/or birth weight >=1500 g, would have an impact on the number of babies diagnosed as having ROP. METHODS: A prospective cohort study was carried out at the Aga Khan University Hospital, Karachi, Pakistan. Infants with gestational age <=35 weeks or birth weight <=2000 g born in this hospital from May 2010 to December 2012 were screened for the presence of ROP 4-6 weeks after birth. Subsequent examinations were performed at intervals based on the findings of initial eye examinations. Infants diagnosed as having ROP were treated with argon laser therapy. Neonatal risk factors were also assessed. Cumulative incidence of ROP was calculated for babies falling within and outside current screening criteria. Multivariate logistic regression analysis was performed to examine the predictors of ROP. RESULTS: A total of 301 infants were screened: 27 (9%) babies developed ROP, of which 19 had stage 3 ROP or worse. None of the babies falling outside the current screening criteria developed ROP. The incidence of ROP in the infants meeting the current screening criteria was 11.5%. Multivariate logistic regression analysis showed that only gestational age (adjusted relative risk 0.774, 95% CI 0.603 to 0.994) was independently associated with the development of ROP. CONCLUSIONS: In our population ROP was not seen to occur in infants older than 32 weeks gestational age and/or weighing more than 1500 g. PMID- 24344234 TI - Outcomes of ptosis surgery assessed using a patient-reported outcome measure: an exploration of time effects. AB - AIMS: To explore effects of time following ptosis surgery on patient-reported quality-of-life outcomes. METHODS: The Glasgow Benefit Inventory (GBI), a validated, postinterventional questionnaire was administered to consecutive adults undergoing ptosis surgery on the operating list of one surgeon over a 30 month period. Patients who were not contactable or unable to provide answers were excluded. Mean scores of patients grouped by time since surgery were compared (unpaired t test and Westlake intervals to test equivalence). RESULTS: Of 63 consecutive patients, 50 (79%) were included. Mean age was 63 years. Mean time since surgery was 561 days (range 21-973). There was no significant difference in mean total scores of patients assessed less than 18 months since surgery compared with those assessed later (p=0.544). Distributions of total scores were similar. No significant differences were found for subscores or when patients were divided into three groups according to time after surgery. Multivariate logistic regression revealed no significant effect of time since surgery. Trends were seen with regard to age and type of operation, but did not reach significance. CONCLUSIONS: Patient-perceived benefit following ptosis surgery shows stability with time, as assessed using the GBI. Future studies could explore correlations with age and type of surgery. PMID- 24344235 TI - Novel neutralizing hedgehog antibody MEDI-5304 exhibits antitumor activity by inhibiting paracrine hedgehog signaling. AB - The hedgehog pathway has been implicated in the tumorigenesis, tumor progression, and metastasis of numerous human cancers. We generated the first fully human hedgehog antibody MEDI-5304 and characterized its antitumor activity and preclinical toxicology. MEDI-5304 bound sonic hedgehog (SHH) and Indian hedgehog (IHH) with low picomolar affinity and neutralized SHH and IHH activity in cellular mGLI1 reporter assays. The antibody inhibited transcription of hedgehog target genes and osteoblast differentiation of C3H10T1/2 cells. We evaluated the activity of MEDI-5304 in vivo in model systems that allowed us to evaluate two primary hypotheses of hedgehog function in human cancer, paracrine signaling between tumor and stromal cells and cancer stem cell (CSC) self-renewal. MEDI 5304 displayed robust pharmacodynamic effects in stromal cells that translated to antitumor efficacy as a single agent in an HT-29/MEF coimplantation model of paracrine hedgehog signaling. MEDI-5304 also improved responses to carboplatin in the HT-29/MEF model. The antibody, however, had no effect as a single agent or in combination with gemcitabine on the CSC frequency or growth of several primary pancreatic cancer explant models. These findings support the conclusion that hedgehog contributes to tumor biology via paracrine tumor-stromal signaling but not via CSC maintenance or propagation. Finally, the only safety study finding associated with MEDI-5304 was ondontodysplasia in rats. Thus, MEDI-5304 represents a potent dual hedgehog inhibitor suitable for continued development to evaluate efficacy and safety in human patients with tumors harboring elevated levels of SHH or IHH. PMID- 24344236 TI - GP commissioners fund urgent care in bid to prevent winter crises. PMID- 24344237 TI - EndoU is a novel regulator of AICD during peripheral B cell selection. AB - Balanced transmembrane signals maintain a competent peripheral B cell pool limited in self-reactive B cells that may produce pathogenic autoantibodies. To identify molecules regulating peripheral B cell survival and tolerance to self antigens (Ags), a gene modifier screen was performed with B cells from CD22 deficient C57BL/6 (CD22(-/-[B6])) mice that undergo activation-induced cell death (AICD) and fail to up-regulate c-Myc expression after B cell Ag receptor ligation. Likewise, lysozyme auto-Ag-specific B cells in Ig(Tg) hen egg lysozyme (HEL) transgenic mice inhabit the spleen but undergo AICD after auto-Ag encounter. This gene modifier screen identified EndoU, a single-stranded RNA binding protein of ancient origin, as a major regulator of B cell survival in both models. EndoU gene disruption prevents AICD and normalizes c-Myc expression. These findings reveal that EndoU is a critical regulator of an unexpected and novel RNA-dependent pathway controlling peripheral B cell survival and Ag responsiveness that may contribute to peripheral B cell tolerance. PMID- 24344239 TI - Breast infection. PMID- 24344238 TI - Jab1 regulates Schwann cell proliferation and axonal sorting through p27. AB - Axonal sorting is a crucial event in nerve formation and requires proper Schwann cell proliferation, differentiation, and contact with axons. Any defect in axonal sorting results in dysmyelinating peripheral neuropathies. Evidence from mouse models shows that axonal sorting is regulated by laminin211- and, possibly, neuregulin 1 (Nrg1)-derived signals. However, how these signals are integrated in Schwann cells is largely unknown. We now report that the nuclear Jun activation domain-binding protein 1 (Jab1) may transduce laminin211 signals to regulate Schwann cell number and differentiation during axonal sorting. Mice with inactivation of Jab1 in Schwann cells develop a dysmyelinating neuropathy with axonal sorting defects. Loss of Jab1 increases p27 levels in Schwann cells, which causes defective cell cycle progression and aberrant differentiation. Genetic down-regulation of p27 levels in Jab1-null mice restores Schwann cell number, differentiation, and axonal sorting and rescues the dysmyelinating neuropathy. Thus, Jab1 constitutes a regulatory molecule that integrates laminin211 signals in Schwann cells to govern cell cycle, cell number, and differentiation. Finally, Jab1 may constitute a key molecule in the pathogenesis of dysmyelinating neuropathies. PMID- 24344240 TI - IL-33 enhances proliferation and invasiveness of decidual stromal cells by up regulation of CCL2/CCR2 via NF-kappaB and ERK1/2 signaling. AB - Interleukin (IL)-33, a newly described member of the IL-1 family, has been reported to facilitate primary tumor progression and metastatic dissemination. However, its biological function on decidual stromal cells (DSCs) remains unclear. In this study, we tested the hypothesis whether IL-33 promotes proliferation and invasion of DSCs, and the possible mechanism. IL-33 and its orphan receptor ST2 was found to be co-expressed by DSCs in human first-trimester pregnancy. Addition of IL-33, enhanced the proliferation and invasion of DSCs in a dosage-dependent manner, concomitantly with increasing expression of proliferation relative gene (PCNA, survivin) and invasion relative gene (titin, MMP2). Blocking IL-33/ST2 signaling by soluble sST2 apparently abolished the stimulatory effect on the proliferation, invasiveness and related gene expression in DSCs. We also demonstrated that chemokines CCL2/CCR2 was significantly increased with IL-33 administration. Moreover, inhibition of CCL2/CCR2 activation using CCL2 neutralizing antibody or CCR2 blocker prevented IL-33-stimulated proliferation and invasiveness capacity of DSCs. Increasing phosphorylation of nuclear factor NF-kappaB p65 and extracellular signal-regulated kinases ERK1/2 after treatment with IL-33 was confirmed by western blotting. And the IL-33 induced CCL2/CCR2 expression was abrogated by treatment with the NF-kappaB inhibitor BAY 11-7082 or ERK1/2 inhibitor U0126. Finally, we showed that decreased IL-33/ST2 expression was observed in DSCs from spontaneous abortion compared with normal pregnancy at both gene and protein levels. This study provides evidence for the molecular mechanism of IL-33 in promoting proliferation and invasiveness of DSCs by up-regulation of CCL2/CCR2 via NF-kappaB and ERK1/2 signal pathways and thus contributes insight to the potential of IL-33 involved in successful pregnancy via inducing DSCs mitosis and invasion. PMID- 24344242 TI - The Erasmus programme for postgraduate education in orthodontics in Europe: an update of the guidelines. AB - In 1989, the ERASMUS Bureau of the European Cultural Foundation of the Commission of the European Communities funded the development of a new 3-year curriculum for postgraduate education in orthodontics. The new curriculum was created by directors for orthodontic education representing 15 European countries. The curriculum entitled 'Three years Postgraduate Programme in Orthodontics: the Final Report of the Erasmus Project' was published 1992. In 2012, the 'Network of Erasmus Based European Orthodontic Programmes' developed and approved an updated version of the guidelines. The core programme consists of eight sections: general biological and medical subjects; basic orthodontic subjects; general orthodontic subjects; orthodontic techniques; interdisciplinary subjects; management of health and safety; practice management, administration, and ethics; extramural educational activities. The programme goals and objectives are described and the competencies to be reached are outlined. These guidelines may serve as a baseline for programme development and quality assessment for postgraduate programme directors, national associations, and governmental bodies and could assist future residents when selecting a postgraduate programme. PMID- 24344244 TI - Protonation controls ASIC1a activity via coordinated movements in multiple domains. AB - Acid-sensing ion channels (ASICs) are neuronal Na(+)-conducting channels activated by extracellular acidification. ASICs are involved in pain sensation, expression of fear, and neurodegeneration after ischemic stroke. Functional ASICs are composed of three identical or homologous subunits, whose extracellular part has a handlike structure. Currently, it is unclear how protonation of residues in extracellular domains controls ASIC activity. Knowledge of these mechanisms would allow a rational development of drugs acting on ASICs. Protonation may induce conformational changes that control the position of the channel gate. We used voltage-clamp fluorometry with fluorophores attached to residues in different domains of ASIC1a to detect conformational changes. Comparison of the timing of fluorescence and current signals identified residues involved in movements that preceded desensitization and may therefore be associated with channel opening or early steps leading to desensitization. Other residues participated in movements intimately linked to desensitization and recovery from desensitization. Fluorescence signals of all mutants were detected at more alkaline pH than ionic currents. Their midpoint of pH dependence was close to that of steady-state desensitization, whereas the steepness of the pH fluorescence relationship was closer to that of current activation. A sequence of movements was observed upon acidification, and its backward movements during recovery from desensitization occurred in the reverse order, indicating that the individual steps are interdependent. Furthermore, the fluorescence signal of some labeled residues in the finger domain was strongly quenched by a Trp residue in the neighboring beta ball domain. Upon channel activation, their fluorescence intensity increased, indicating that the finger moved away from the beta ball. This extensive analysis of activity-dependent conformational changes in ASICs sheds new light on the mechanisms by which protonation controls ASIC activity. PMID- 24344243 TI - Synergy against PML-RARa: targeting transcription, proteolysis, differentiation, and self-renewal in acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL) is a hematological malignancy driven by a chimeric oncoprotein containing the C terminus of the retinoic acid receptor-a (RARa) fused to an N-terminal partner, most commonly promyelocytic leukemia protein (PML). Mechanistically, PML-RARa acts as a transcriptional repressor of RARa and non-RARa target genes and antagonizes the formation and function of PML nuclear bodies that regulate numerous signaling pathways. The empirical discoveries that PML-RARa-associated APL is sensitive to both all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO), and the subsequent understanding of the mechanisms of action of these drugs, have led to efforts to understand the contribution of molecular events to APL cell differentiation, leukemia-initiating cell (LIC) clearance, and disease eradication in vitro and in vivo. Critically, the mechanistic insights gleaned from these studies have resulted not only in a better understanding of APL itself, but also carry valuable lessons for other malignancies. PMID- 24344245 TI - Divalent cations activate TRPV1 through promoting conformational change of the extracellular region. AB - Divalent cations Mg(2+) and Ba(2+) selectively and directly potentiate transient receptor potential vanilloid type 1 heat activation by lowering the activation threshold into the room temperature range. We found that Mg(2+) potentiates channel activation only from the extracellular side; on the intracellular side, Mg(2+) inhibits channel current. By dividing the extracellularly accessible region of the channel protein into small segments and perturbing the structure of each segment with sequence replacement mutations, we observed that the S1-S2 linker, the S3-S4 linker, and the pore turret are all required for Mg(2+) potentiation. Sequence replacements at these regions substantially reduced or eliminated Mg(2+)-induced activation at room temperature while sparing capsaicin activation. Heat activation was affected by many, but not all, of these structural alternations. These observations indicate that extracellular linkers and the turret may interact with each other. Site-directed fluorescence resonance energy transfer measurements further revealed that, like heat, Mg(2+) also induces structural changes in the pore turret. Interestingly, turret movement induced by Mg(2+) precedes channel activation, suggesting that Mg(2+)-induced conformational change in the extracellular region most likely serves as the cause of channel activation instead of a coincidental or accommodating structural adjustment. PMID- 24344246 TI - Functional reconstitution of the mitochondrial Ca2+/H+ antiporter Letm1. AB - The leucine zipper, EF hand-containing transmembrane protein 1 (Letm1) gene encodes a mitochondrial inner membrane protein, whose depletion severely perturbs mitochondrial Ca(2+) and K(+) homeostasis. Here we expressed, purified, and reconstituted human Letm1 protein in liposomes. Using Ca(2+) fluorophore and (45)Ca(2+)-based assays, we demonstrate directly that Letm1 is a Ca(2+) transporter, with apparent affinities of cations in the sequence of Ca(2+) ~ Mn(2+) > Gd(3+) ~ La(3+) > Sr(2+) >> Ba(2+), Mg(2+), K(+), Na(+). Kinetic analysis yields a Letm1 turnover rate of 2 Ca(2+)/s and a Km of ~25 uM. Further experiments show that Letm1 mediates electroneutral 1 Ca(2+)/2 H(+) antiport. Letm1 is insensitive to ruthenium red, an inhibitor of the mitochondrial calcium uniporter, and CGP-37157, an inhibitor of the mitochondrial Na(+)/Ca(2+) exchanger. Functional properties of Letm1 described here are remarkably similar to those of the H(+)-dependent Ca(2+) transport mechanism identified in intact mitochondria. PMID- 24344247 TI - Divalent cations potentiate TRPV1 channel by lowering the heat activation threshold. AB - Transient receptor potential vanilloid type 1 (TRPV1) channel responds to a wide spectrum of physical and chemical stimuli. In doing so, it serves as a polymodal cellular sensor for temperature change and pain. Many chemicals are known to strongly potentiate TRPV1 activation, though how this is achieved remains unclear. In this study we investigated the molecular mechanism underlying the gating effects of divalent cations Mg(2+) and Ba(2+). Using a combination of fluorescence imaging and patch-clamp analysis, we found that these cations potentiate TRPV1 gating by most likely promoting the heat activation process. Mg(2+) substantially lowers the activation threshold temperature; as a result, a significant fraction of channels are heat-activated at room temperature. Although Mg(2+) also potentiates capsaicin- and voltage-dependent activation, these processes were found either to be not required (in the case of capsaicin) or insufficient (in the case of voltage) to mediate the activating effect. In support of a selective effect on heat activation, Mg(2+) and Ba(2+) cause a Ca(2+)-independent desensitization that specifically prevents heat-induced channel activation but does not prevent capsaicin-induced activation. These results can be satisfactorily explained within an allosteric gating framework in which divalent cations strongly promote the heat-dependent conformational change or its coupling to channel activation, which is further coupled to the voltage- and capsaicin-dependent processes. PMID- 24344248 TI - Sarcolemmal ATP-sensitive potassium channels modulate skeletal muscle function under low-intensity workloads. AB - ATP-sensitive potassium (KATP) channels have the unique ability to adjust membrane excitability and functions in accordance with the metabolic status of the cell. Skeletal muscles are primary sites of activity-related energy consumption and have KATP channels expressed in very high density. Previously, we demonstrated that transgenic mice with skeletal muscle-specific disruption of KATP channel function consume more energy than wild-type littermates. However, how KATP channel activation modulates skeletal muscle resting and action potentials under physiological conditions, particularly low-intensity workloads, and how this can be translated to muscle energy expenditure are yet to be determined. Here, we developed a technique that allows evaluation of skeletal muscle excitability in situ, with minimal disruption of the physiological environment. Isometric twitching of the tibialis anterior muscle at 1 Hz was used as a model of low-intensity physical activity in mice with normal and genetically disrupted KATP channel function. This workload was sufficient to induce KATP channel opening, resulting in membrane hyperpolarization as well as reduction in action potential overshoot and duration. Loss of KATP channel function resulted in increased calcium release and aggravated activity-induced heat production. Thus, this study identifies low-intensity workload as a trigger for opening skeletal muscle KATP channels and establishes that this coupling is important for regulation of myocyte function and thermogenesis. These mechanisms may provide a foundation for novel strategies to combat metabolic derangements when energy conservation or dissipation is required. PMID- 24344250 TI - Diet-induced macrophage inhibitory cytokine 1 promotes prostate cancer progression. AB - Recent studies have indicated that a high-fat diet (HFD) plays an important role in prostate cancer (PCa) progression. Palmitic acid (PA) is one of the most abundant saturated free fatty acids (FAs) and is associated with carcinogenesis. In this study, we investigated the mechanism underlying the association of dietary fat, including PA, with PCa progression. In four PCa cell lines, in vitro PA administration stimulated the expression of macrophage inhibitory cytokine 1 (MIC1), which is a divergent member of the transforming growth factor-beta family. In vivo, LNCaP xenograft tumor growth, serum MIC1 levels, and FA levels in xenograft tumors were significantly higher in mice receiving an HFD containing high amounts of PA than in those receiving a low-fat diet (LFD). In addition, tumor cells with high MIC1 expression invaded to venules and lymph vessels in the LNCaP xenograft. In vitro studies showed that proliferation and invasive capacity were significantly higher in PCa cells cultured with serum from HFD-fed mice than in those cultured with the serum from LFD-fed mice. This effect was attenuated by the addition of neutralizing antibodies against MIC1, but not by isotype control antibodies. Clinically, serum MIC1 levels were significantly higher in PCa patients than in healthy controls, and higher levels were associated with higher pathological grade and obesity. In conclusion, our results indicate that an HFD containing PA may promote growth and invasiveness of PCa cells through the upregulation of MIC1 expression. PMID- 24344249 TI - Grading the neuroendocrine tumors of the lung: an evidence-based proposal. AB - Lung neuroendocrine tumors are catalogued in four categories by the World Health Organization (WHO 2004) classification. Its reproducibility and prognostic efficacy was disputed. The WHO 2010 classification of digestive neuroendocrine neoplasms is based on Ki67 proliferation assessment and proved prognostically effective. This study aims at comparing these two classifications and at defining a prognostic grading system for lung neuroendocrine tumors. The study included 399 patients who underwent surgery and with at least 1 year follow-up between 1989 and 2011. Data on 21 variables were collected, and performance of grading systems and their components was compared by Cox regression and multivariable analyses. All statistical tests were two-sided. At Cox analysis, WHO 2004 stratified patients into three major groups with statistically significant survival difference (typical carcinoid vs atypical carcinoid (AC), P=0.021; AC vs large-cell/small-cell lung neuroendocrine carcinomas, P<0.001). Optimal discrimination in three groups was observed by Ki67% (Ki67% cutoffs: G1 <4, G2 4 <25, G3 >=25; G1 vs G2, P=0.021; and G2 vs G3, P<=0.001), mitotic count (G1 <=2, G2 >2-47, G3 >47; G1 vs G2, P<=0.001; and G2 vs G3, P<=0.001), and presence of necrosis (G1 absent, G2 <10% of sample, G3 >10% of sample; G1 vs G2, P<=0.001; and G2 vs G3, P<=0.001) at uni and multivariable analyses. The combination of these three variables resulted in a simple and effective grading system. A three tiers grading system based on Ki67 index, mitotic count, and necrosis with cutoffs specifically generated for lung neuroendocrine tumors is prognostically effective and accurate. PMID- 24344252 TI - Adaptive functional divergence of the warm temperature acclimation-related protein (WAP65) in fishes and the ortholog hemopexin (HPX) in mammals. AB - Gene duplication is an important mechanism that leads to genetic novelty. Different, nonexclusive processes are likely involved, and many adaptive and nonadaptive events may contribute to the maintenance of duplicated genes. In some teleosts, a duplicate copy of the mammalian ortholog Hemopexin (HPX) is present, known as the warm temperature acclimation-related protein (WAP65). Both WAP65 and HPX have been associated with iron homeostasis due to the affinity to bind the toxic-free heme circulating in the blood stream. We have assessed the evolutionary dynamics of WAP65 and HPX genes to understand the adaptive role of positive selection at both nucleotide and amino acid level. Our results showed an asymmetrical evolution between the paralogs WAP65-1 and WAP65-2 after duplication with a slight acceleration of the evolutionary rate in WAP65-1, but not in WAP65 2, and few sites contributing to the functional distinction between the paralogs, whereas the majority of the protein remained under negative selection or relaxed negative selection. WAP65-1 is functionally more distinct from the ancestral protein function than WAP65-2. HPX is phylogenetically closer to WAP65-2 but even so functional divergence was detected between both proteins. In addition, HPX showed a fast rate of evolution when compared with both WAP65-1 and WAP65-2 genes. The assessed 3-dimensional (3-D) structure of WAP65-1 and WAP65-2 suggests that the functional differences detected are not causing noticeable structural changes in these proteins. However, such subtle changes between WAP65 paralogs may be important to understand the differential gene retention of both copies in 20 out of 30 teleosts species studied. PMID- 24344253 TI - Determinants of Survival in Adult HIV Clients on Antiretroviral Therapy in Lawra and Jirapa Districts of Upper West Region, Ghana. AB - We describe the rate of death and identify the determinants of survival in a cohort of adults starting antiretroviral therapy (ART) in 2 hospitals in Upper West Region, Ghana. Kaplan-Meier model was used to estimate the survival probability after ART initiation and Cox proportional hazard model used to assess the relationship between baseline variables and mortality. A total of 91 clients who were initiated on ART in both hospitals participated in the study. Clients staged in the World Health Organization (WHO) clinical stage III/IV had a higher risk of mortality than those staging I/II (hazard ratio [HR] of 3.93). Hemoglobin value at baseline with a cutoff >=12 g/dL for women (and >=13 for men) was strongly associated with mortality in participants with an HR of 3.87 (95% confidence interval [CI]: 0.71-21.19) for severe anemia, 2.11 (95% CI: 0.45-9.93) for moderate anemia, and 0.88 (95% CI: 0.16-4.82) for mild anemia. Anemia and WHO staging were independent predictors of mortality. PMID- 24344254 TI - Special nutrition challenges: current approach to acute kidney injury. AB - Acute kidney injury (AKI), previously known as acute renal failure, is defined as a sudden decline in glomerular filtration rate with accumulation of metabolic waste products, toxins, and drugs, as well as alteration in the intrinsic functions of the kidney. Reports of mortality are as high as 80%, with numerous contributing causes including infection, cardiorespiratory complications, and cardiovascular disease. Concurrent with the high prevalence of critical illness in this population is the protein energy wasting (PEW), seen in up to 42% of patients upon intensive care unit admission. The pathophysiologic derangements of critical illness, the low energy and protein stores, and uremic complications require early nutrition intervention to attenuate the inflammatory response and oxidative stress, improve endothelial function, stabilize blood sugar, and preserve lean body mass. This article addresses the unique challenges of nutrition support for the patient with AKI in the setting of critical illness and renal replacement therapy. Evidence-based recommendations are provided to meet the macronutrient and micronutrient requirements of this heterogeneous and complex patient population. PMID- 24344255 TI - Improving the provision of enteral nutrition in the intensive care unit: a description of a multifaceted intervention tailored to overcome local barriers. AB - BACKGROUND: Tailoring interventions to address identified barriers to change may be an effective strategy to implement guidelines and improve practice. The purpose of this article is to describe the development and implementation of a tailored intervention to overcome barriers to enterally feeding critically ill patients. METHODS: A before-after study was conducted in 5 hospitals in North America. We adopted a pragmatic stepwise approach to developing and implementing a tailored intervention-namely, (1) formation of a guideline implementation team, (2) identification of barriers to the provision of enteral nutrition (ie, guideline-practice gap analysis, staff survey, focus group with key stakeholders), (3) focus group to prioritize these barriers, (4) brainstorming to select interventions to overcome the prioritized barriers, (5) a 12-month implementation phase including bimonthly progress meetings, and (6) evaluation of the tailored intervention. RESULTS: All sites identified and prioritized barriers to target for change and developed a tailored action plan. Three of the 22 potential barriers were prioritized by all sites, resulting in common components to the action plans. However, barriers and interventions that were unique to specific sites were also identified. All sites were successful in implementing most of the selected strategies during the implementation phase, although the degree of implementation varied depending on the type of strategy and the site. CONCLUSION: This stepwise process to developing and implementing an intervention tailored to barriers is promising and could be considered by dietitians and other providers seeking to improve nutrition practice. PMID- 24344256 TI - Confirmation of gastric tube bedside placement with the sky blue method. AB - BACKGROUND: The purpose was to review our experiences and determine if applying the sky blue method is reliable in confirming gastric tube (GT) placement in neonates. METHODS: The study population consisted of 44 infants (55 placements) who were admitted to the Takeda General Hospital between April 2012 and March 2013 and who required GT exchange. The sky blue method using indigo carmine (IC) was indicated for planned tube exchange only. Diluted IC was injected into the gastric space via the old GT just before the tube exchange. The tube was exchanged using a standard method. Then, we checked whether the diluted IC could be collected through the new GT or not. RESULTS: The reasons for GT placement were a gestational age of < 35 weeks in 31 (56.4%), poor sucking or swallowing disorders in 17 (30.4%), and respiratory disorders in 7 (12.7%) of the 55 placements. GT placement using the sky blue method was considered successful in 52 placements (94.4%), with the remaining 3 placements (5.6%) considered to be failures due to the inability to obtain IC from the gastric space. No adverse events were observed during the tube exchange period. CONCLUSION: Based on the results, the sky blue method can be considered to be reliable method for the confirmation of GT placement. These results also suggest that the number of radiologic evaluations performed to confirm correct replacement of the GT in infants can be reduced in the future. PMID- 24344257 TI - Rare event of histone demethylation can initiate singular gene expression of olfactory receptors. AB - Mammals sense odors through the gene family of olfactory receptors (ORs). Despite the enormous number of OR genes (~1,400 in mouse), each olfactory sensory neuron expresses one, and only one, of them. In neurobiology, it remains a long-standing mystery how this singularity can be achieved despite intrinsic stochasticity of gene expression. Recent experiments showed an epigenetic mechanism for maintaining singular OR expression: Once any ORs are activated, their expression inhibits further OR activation by down-regulating a histone demethylase Lsd1 (also known as Aof2 or Kdm1a), an enzyme required for the removal of the repressive histone marker H3K9me3 on OR genes. However, it remains unclear at a quantitative level how singularity can be initiated in the first place. In particular, does a simple activation/feedback scheme suffice to generate singularity? Here we show theoretically that rare events of histone demethylation can indeed produce robust singularity by separating two timescales: slow OR activation by stepwise H3K9me3 demethylation, and fast feedback to turn off Lsd1. Given a typical 1-h response of transcriptional feedback, to achieve the observed extent of singularity (only 2% of neurons express more than one ORs), we predict that OR activation must be as slow as 5-10 d-a timescale compatible with experiments. Our model further suggests H3K9me3-to-H3K9me2 demethylation as an additional rate-limiting step responsible for OR singularity. Our conclusions may be generally applicable to other systems where monoallelic expression is desired, and provide guidelines for the design of a synthetic system of singular expression. PMID- 24344258 TI - Epstein-Barr virus nuclear antigen 3C binds to BATF/IRF4 or SPI1/IRF4 composite sites and recruits Sin3A to repress CDKN2A. AB - Epstein-Barr virus nuclear antigen 3C (EBNA3C) repression of CDKN2A p14(ARF) and p16(INK4A) is essential for immortal human B-lymphoblastoid cell line (LCL) growth. EBNA3C ChIP-sequencing identified >13,000 EBNA3C sites in LCL DNA. Most EBNA3C sites were associated with active transcription; 64% were strong H3K4me1- and H3K27ac-marked enhancers and 16% were active promoters marked by H3K4me3 and H3K9ac. Using ENCODE LCL transcription factor ChIP-sequencing data, EBNA3C sites coincided (+/-250 bp) with RUNX3 (64%), BATF (55%), ATF2 (51%), IRF4 (41%), MEF2A (35%), PAX5 (34%), SPI1 (29%), BCL11a (28%), SP1 (26%), TCF12 (23%), NF-kappaB (23%), POU2F2 (23%), and RBPJ (16%). EBNA3C sites separated into five distinct clusters: (i) Sin3A, (ii) EBNA2/RBPJ, (iii) SPI1, and (iv) strong or (v) weak BATF/IRF4. EBNA3C signals were positively affected by RUNX3, BATF/IRF4 (AICE) and SPI1/IRF4 (EICE) cooccupancy. Gene set enrichment analyses correlated EBNA3C/Sin3A promoter sites with transcription down-regulation (P < 1.6 * 10( 4)). EBNA3C signals were strongest at BATF/IRF4 and SPI1/IRF4 composite sites. EBNA3C bound strongly to the p14(ARF) promoter through SPI1/IRF4/BATF/RUNX3, establishing RBPJ-, Sin3A-, and REST-mediated repression. EBNA3C immune precipitated with Sin3A and conditional EBNA3C inactivation significantly decreased Sin3A binding at the p14(ARF) promoter (P < 0.05). These data support a model in which EBNA3C binds strongly to BATF/IRF4/SPI1/RUNX3 sites to enhance transcription and recruits RBPJ/Sin3A- and REST/NRSF-repressive complexes to repress p14(ARF) and p16(INK4A) expression. PMID- 24344259 TI - Production and stabilization of the trimeric influenza hemagglutinin stem domain for potentially broadly protective influenza vaccines. AB - The rapid dissemination of the 2009 pandemic H1N1 influenza virus emphasizes the need for universal influenza vaccines that would broadly protect against multiple mutated strains. Recent efforts have focused on the highly conserved hemagglutinin (HA) stem domain, which must undergo a significant conformational change for effective viral infection. Although the production of isolated domains of multimeric ectodomain proteins has proven difficult, we report a method to rapidly produce the properly folded HA stem domain protein from influenza virus A/California/05/2009 (H1N1) by using Escherichia coli-based cell-free protein synthesis and a simple refolding protocol. The T4 bacteriophage fibritin foldon placed at the C terminus of the HA stem domain induces trimer formation. Placing emphasis on newly exposed protein surfaces, several hydrophobic residues were mutated, two polypeptide segments were deleted, and the number of disulfide bonds in each monomer was reduced from four to two. High pH and Brij 35 detergent emerged as the most beneficial factors for improving the refolding yield. To stabilize the trimer of the HA stem-foldon fusion, new intermolecular disulfide bonds were finally introduced between foldon monomers and between stem domain monomers. The correct immunogenic conformation of the stabilized HA stem domain trimer was confirmed by using antibodies CR6261, C179, and FI6 that block influenza infection by binding to the HA stem domain trimer. These results suggest great promise for a broadly protective vaccine and also demonstrate a unique approach for producing individual domains of complex multimeric proteins. PMID- 24344260 TI - Automatic Classification of Cellular Expression by Nonlinear Stochastic Embedding (ACCENSE). AB - Mass cytometry enables an unprecedented number of parameters to be measured in individual cells at a high throughput, but the large dimensionality of the resulting data severely limits approaches relying on manual "gating." Clustering cells based on phenotypic similarity comes at a loss of single-cell resolution and often the number of subpopulations is unknown a priori. Here we describe ACCENSE, a tool that combines nonlinear dimensionality reduction with density based partitioning, and displays multivariate cellular phenotypes on a 2D plot. We apply ACCENSE to 35-parameter mass cytometry data from CD8(+) T cells derived from specific pathogen-free and germ-free mice, and stratify cells into phenotypic subpopulations. Our results show significant heterogeneity within the known CD8(+) T-cell subpopulations, and of particular note is that we find a large novel subpopulation in both specific pathogen-free and germ-free mice that has not been described previously. This subpopulation possesses a phenotypic signature that is distinct from conventional naive and memory subpopulations when analyzed by ACCENSE, but is not distinguishable on a biaxial plot of standard markers. We are able to automatically identify cellular subpopulations based on all proteins analyzed, thus aiding the full utilization of powerful new single cell technologies such as mass cytometry. PMID- 24344261 TI - Diatom traits regulate Southern Ocean silica leakage. PMID- 24344262 TI - Dynamic control of beta1 integrin adhesion by the plexinD1-sema3E axis. AB - Plexins and semaphorins comprise a large family of receptor-ligand pairs controlling cell guidance in nervous, immune, and vascular systems. How plexin regulation of neurite outgrowth, lymphoid trafficking, and vascular endothelial cell branching is linked to integrin function, central to most directed movement, remains unclear. Here we show that on developing thymocytes, plexinD1 controls surface topology of nanometer-scaled beta1 integrin adhesion domains in cis, whereas its ligation by sema3E in trans regulates individual beta1 integrin catch bonds. Loss of plexinD1 expression reduces beta1 integrin clustering, thereby diminishing avidity, whereas sema3E ligation shortens individual integrin bond lifetimes under force to reduce stability. Consequently, both decreased expression of plexinD1 during developmental progression and a thymic medulla emanating sema3E gradient enhance thymocyte movement toward the medulla, thus enforcing the orchestrated lymphoid trafficking required for effective immune repertoire selection. Our results demonstrate plexin-tunable molecular features of integrin adhesion with broad implications for many cellular processes. PMID- 24344263 TI - Initial stages of calcium uptake and mineral deposition in sea urchin embryos. AB - Sea urchin larvae have an endoskeleton consisting of two calcitic spicules. We reconstructed various stages of the formation pathway of calcium carbonate from calcium ions in sea water to mineral deposition and integration into the forming spicules. Monitoring calcium uptake with the fluorescent dye calcein shows that calcium ions first penetrate the embryo and later are deposited intracellularly. Surprisingly, calcium carbonate deposits are distributed widely all over the embryo, including in the primary mesenchyme cells and in the surface epithelial cells. Using cryo-SEM, we show that the intracellular calcium carbonate deposits are contained in vesicles of diameter 0.5-1.5 MUm. Using the newly developed airSEM, which allows direct correlation between fluorescence and energy dispersive spectroscopy, we confirmed the presence of solid calcium carbonate in the vesicles. This mineral phase appears as aggregates of 20-30-nm nanospheres, consistent with amorphous calcium carbonate. The aggregates finally are introduced into the spicule compartment, where they integrate into the growing spicule. PMID- 24344264 TI - De novo selection of oncogenes. AB - All cellular proteins are derived from preexisting ones by natural selection. Because of the random nature of this process, many potentially useful protein structures never arose or were discarded during evolution. Here, we used a single round of genetic selection in mouse cells to isolate chemically simple, biologically active transmembrane proteins that do not contain any amino acid sequences from preexisting proteins. We screened a retroviral library expressing hundreds of thousands of proteins consisting of hydrophobic amino acids in random order to isolate four 29-aa proteins that induced focus formation in mouse and human fibroblasts and tumors in mice. These proteins share no amino acid sequences with known cellular or viral proteins, and the simplest of them contains only seven different amino acids. They transformed cells by forming a stable complex with the platelet-derived growth factor beta receptor transmembrane domain and causing ligand-independent receptor activation. We term this approach de novo selection and suggest that it can be used to generate structures and activities not observed in nature, create prototypes for novel research reagents and therapeutics, and provide insight into cell biology, transmembrane protein-protein interactions, and possibly virus evolution and the origin of life. PMID- 24344265 TI - Carbon residence time dominates uncertainty in terrestrial vegetation responses to future climate and atmospheric CO2. AB - Future climate change and increasing atmospheric CO2 are expected to cause major changes in vegetation structure and function over large fractions of the global land surface. Seven global vegetation models are used to analyze possible responses to future climate simulated by a range of general circulation models run under all four representative concentration pathway scenarios of changing concentrations of greenhouse gases. All 110 simulations predict an increase in global vegetation carbon to 2100, but with substantial variation between vegetation models. For example, at 4 degrees C of global land surface warming (510-758 ppm of CO2), vegetation carbon increases by 52-477 Pg C (224 Pg C mean), mainly due to CO2 fertilization of photosynthesis. Simulations agree on large regional increases across much of the boreal forest, western Amazonia, central Africa, western China, and southeast Asia, with reductions across southwestern North America, central South America, southern Mediterranean areas, southwestern Africa, and southwestern Australia. Four vegetation models display discontinuities across 4 degrees C of warming, indicating global thresholds in the balance of positive and negative influences on productivity and biomass. In contrast to previous global vegetation model studies, we emphasize the importance of uncertainties in projected changes in carbon residence times. We find, when all seven models are considered for one representative concentration pathway * general circulation model combination, such uncertainties explain 30% more variation in modeled vegetation carbon change than responses of net primary productivity alone, increasing to 151% for non-HYBRID4 models. A change in research priorities away from production and toward structural dynamics and demographic processes is recommended. PMID- 24344266 TI - Hydrological droughts in the 21st century, hotspots and uncertainties from a global multimodel ensemble experiment. AB - Increasing concentrations of greenhouse gases in the atmosphere are expected to modify the global water cycle with significant consequences for terrestrial hydrology. We assess the impact of climate change on hydrological droughts in a multimodel experiment including seven global impact models (GIMs) driven by bias corrected climate from five global climate models under four representative concentration pathways (RCPs). Drought severity is defined as the fraction of land under drought conditions. Results show a likely increase in the global severity of hydrological drought at the end of the 21st century, with systematically greater increases for RCPs describing stronger radiative forcings. Under RCP8.5, droughts exceeding 40% of analyzed land area are projected by nearly half of the simulations. This increase in drought severity has a strong signal-to-noise ratio at the global scale, and Southern Europe, the Middle East, the Southeast United States, Chile, and South West Australia are identified as possible hotspots for future water security issues. The uncertainty due to GIMs is greater than that from global climate models, particularly if including a GIM that accounts for the dynamic response of plants to CO2 and climate, as this model simulates little or no increase in drought frequency. Our study demonstrates that different representations of terrestrial water-cycle processes in GIMs are responsible for a much larger uncertainty in the response of hydrological drought to climate change than previously thought. When assessing the impact of climate change on hydrology, it is therefore critical to consider a diverse range of GIMs to better capture the uncertainty. PMID- 24344267 TI - Effective functional maturation of invariant natural killer T cells is constrained by negative selection and T-cell antigen receptor affinity. AB - The self-reactivity of their T-cell antigen receptor (TCR) is thought to contribute to the development of immune regulatory cells, such as invariant NK T cells (iNKT). In the mouse, iNKT cells express TCRs composed of a unique Valpha14 Jalpha18 rearrangement and recognize lipid antigens presented by CD1d molecules. We created mice expressing a transgenic TCR-beta chain that confers high affinity for self-lipid/CD1d complexes when randomly paired with the mouse iNKT Valpha14 Jalpha18 rearrangement to study their development. We show that although iNKT cells undergo agonist selection, their development is also shaped by negative selection in vivo. In addition, iNKT cells that avoid negative selection in these mice express natural sequence variants of the canonical TCR-alpha and decreased affinity for self/CD1d. However, limiting the affinity of the iNKT TCRs for "self" leads to inefficient Egr2 induction, poor expression of the iNKT lineage specific zinc-finger transcription factor PLZF, inadequate proliferation of iNKT cell precursors, defects in trafficking, and impaired effector functions. Thus, proper development of fully functional iNKT cells is constrained by a limited range of TCR affinity that plays a key role in triggering the iNKT cell differentiation pathway. These results provide a direct link between the affinity of the TCR expressed by T-cell precursors for self-antigens and the proper development of a unique population of lymphocytes essential to immune responses. PMID- 24344268 TI - Rewiring yeast sugar transporter preference through modifying a conserved protein motif. AB - Utilization of exogenous sugars found in lignocellulosic biomass hydrolysates, such as xylose, must be improved before yeast can serve as an efficient biofuel and biochemical production platform. In particular, the first step in this process, the molecular transport of xylose into the cell, can serve as a significant flux bottleneck and is highly inhibited by other sugars. Here we demonstrate that sugar transport preference and kinetics can be rewired through the programming of a sequence motif of the general form G-G/F-XXX-G found in the first transmembrane span. By evaluating 46 different heterologously expressed transporters, we find that this motif is conserved among functional transporters and highly enriched in transporters that confer growth on xylose. Through saturation mutagenesis and subsequent rational mutagenesis, four transporter mutants unable to confer growth on glucose but able to sustain growth on xylose were engineered. Specifically, Candida intermedia gxs1 Phe(38)Ile(39)Met(40), Scheffersomyces stipitis rgt2 Phe(38) and Met(40), and Saccharomyces cerevisiae hxt7 Ile(39)Met(40)Met(340) all exhibit this phenotype. In these cases, primary hexose transporters were rewired into xylose transporters. These xylose transporters nevertheless remained inhibited by glucose. Furthermore, in the course of identifying this motif, novel wild-type transporters with superior monosaccharide growth profiles were discovered, namely S. stipitis RGT2 and Debaryomyces hansenii 2D01474. These findings build toward the engineering of efficient pentose utilization in yeast and provide a blueprint for reprogramming transporter properties. PMID- 24344269 TI - Evaluation of intramitochondrial ATP levels identifies G0/G1 switch gene 2 as a positive regulator of oxidative phosphorylation. AB - The oxidative phosphorylation (OXPHOS) system generates most of the ATP in respiring cells. ATP-depleting conditions, such as hypoxia, trigger responses that promote ATP production. However, how OXPHOS is regulated during hypoxia has yet to be elucidated. In this study, selective measurement of intramitochondrial ATP levels identified the hypoxia-inducible protein G0/G1 switch gene 2 (G0s2) as a positive regulator of OXPHOS. A mitochondria-targeted, FRET-based ATP biosensor enabled us to assess OXPHOS activity in living cells. Mitochondria-targeted, FRET based ATP biosensor and ATP production assay in a semiintact cell system revealed that G0s2 increases mitochondrial ATP production. The expression of G0s2 was rapidly and transiently induced by hypoxic stimuli, and G0s2 interacts with OXPHOS complex V (FoF1-ATP synthase). Furthermore, physiological enhancement of G0s2 expression prevented cells from ATP depletion and induced a cellular tolerance for hypoxic stress. These results show that G0s2 positively regulates OXPHOS activity by interacting with FoF1-ATP synthase, which causes an increase in ATP production in response to hypoxic stress and protects cells from a critical energy crisis. These findings contribute to the understanding of a unique stress response to energy depletion. Additionally, this study shows the importance of assessing intramitochondrial ATP levels to evaluate OXPHOS activity in living cells. PMID- 24344270 TI - Multisectoral climate impact hotspots in a warming world. AB - The impacts of global climate change on different aspects of humanity's diverse life-support systems are complex and often difficult to predict. To facilitate policy decisions on mitigation and adaptation strategies, it is necessary to understand, quantify, and synthesize these climate-change impacts, taking into account their uncertainties. Crucial to these decisions is an understanding of how impacts in different sectors overlap, as overlapping impacts increase exposure, lead to interactions of impacts, and are likely to raise adaptation pressure. As a first step we develop herein a framework to study coinciding impacts and identify regional exposure hotspots. This framework can then be used as a starting point for regional case studies on vulnerability and multifaceted adaptation strategies. We consider impacts related to water, agriculture, ecosystems, and malaria at different levels of global warming. Multisectoral overlap starts to be seen robustly at a mean global warming of 3 degrees C above the 1980-2010 mean, with 11% of the world population subject to severe impacts in at least two of the four impact sectors at 4 degrees C. Despite these general conclusions, we find that uncertainty arising from the impact models is considerable, and larger than that from the climate models. In a low probability high impact worst-case assessment, almost the whole inhabited world is at risk for multisectoral pressures. Hence, there is a pressing need for an increased research effort to develop a more comprehensive understanding of impacts, as well as for the development of policy measures under existing uncertainty. PMID- 24344271 TI - IL-25 and type 2 innate lymphoid cells induce pulmonary fibrosis. AB - Disease conditions associated with pulmonary fibrosis are progressive and have a poor long-term prognosis with irreversible changes in airway architecture leading to marked morbidity and mortalities. Using murine models we demonstrate a role for interleukin (IL)-25 in the generation of pulmonary fibrosis. Mechanistically, we identify IL-13 release from type 2 innate lymphoid cells (ILC2) as sufficient to drive collagen deposition in the lungs of challenged mice and suggest this as a potential mechanism through which IL-25 is acting. Additionally, we demonstrate that in human idiopathic pulmonary fibrosis there is increased pulmonary expression of IL-25 and also observe a population ILC2 in the lungs of idiopathic pulmonary fibrosis patients. Collectively, we present an innate mechanism for the generation of pulmonary fibrosis, via IL-25 and ILC2, that occurs independently of T-cell-mediated antigen-specific immune responses. These results suggest the potential of therapeutically targeting IL-25 and ILC2 for the treatment of human fibrotic diseases. PMID- 24344272 TI - Tonic GABAA conductance bidirectionally controls interneuron firing pattern and synchronization in the CA3 hippocampal network. AB - The spiking output of interneurons is key for rhythm generation in the brain. However, what controls interneuronal firing remains incompletely understood. Here we combine dynamic clamp experiments with neural network simulations to understand how tonic GABAA conductance regulates the firing pattern of CA3 interneurons. In baseline conditions, tonic GABAA depolarizes these cells, thus exerting an excitatory action while also reducing the excitatory postsynaptic potential (EPSP) amplitude through shunting. As a result, the emergence of weak tonic GABAA conductance transforms the interneuron firing pattern driven by individual EPSPs into a more regular spiking mode determined by the cell intrinsic properties. The increased regularity of spiking parallels stronger synchronization of the local network. With further increases in tonic GABAA conductance the shunting inhibition starts to dominate over excitatory actions and thus moderates interneuronal firing. The remaining spikes tend to follow the timing of suprathreshold EPSPs and thus become less regular again. The latter parallels a weakening in network synchronization. Thus, our observations suggest that tonic GABAA conductance can bidirectionally control brain rhythms through changes in the excitability of interneurons and in the temporal structure of their firing patterns. PMID- 24344273 TI - Biomass use, production, feed efficiencies, and greenhouse gas emissions from global livestock systems. AB - We present a unique, biologically consistent, spatially disaggregated global livestock dataset containing information on biomass use, production, feed efficiency, excretion, and greenhouse gas emissions for 28 regions, 8 livestock production systems, 4 animal species (cattle, small ruminants, pigs, and poultry), and 3 livestock products (milk, meat, and eggs). The dataset contains over 50 new global maps containing high-resolution information for understanding the multiple roles (biophysical, economic, social) that livestock can play in different parts of the world. The dataset highlights: (i) feed efficiency as a key driver of productivity, resource use, and greenhouse gas emission intensities, with vast differences between production systems and animal products; (ii) the importance of grasslands as a global resource, supplying almost 50% of biomass for animals while continuing to be at the epicentre of land conversion processes; and (iii) the importance of mixed crop-livestock systems, producing the greater part of animal production (over 60%) in both the developed and the developing world. These data provide critical information for developing targeted, sustainable solutions for the livestock sector and its widely ranging contribution to the global food system. PMID- 24344274 TI - Re-Os geochronology and coupled Os-Sr isotope constraints on the Sturtian snowball Earth. AB - After nearly a billion years with no evidence for glaciation, ice advanced to equatorial latitudes at least twice between 717 and 635 Mya. Although the initiation mechanism of these Neoproterozoic Snowball Earth events has remained a mystery, the broad synchronicity of rifting of the supercontinent Rodinia, the emplacement of large igneous provinces at low latitude, and the onset of the Sturtian glaciation has suggested a tectonic forcing. We present unique Re-Os geochronology and high-resolution Os and Sr isotope profiles bracketing Sturtian age glacial deposits of the Rapitan Group in northwest Canada. Coupled with existing U-Pb dates, the postglacial Re-Os date of 662.4 +/- 3.9 Mya represents direct geochronological constraints for both the onset and demise of a Cryogenian glaciation from the same continental margin and suggests a 55-My duration of the Sturtian glacial epoch. The Os and Sr isotope data allow us to assess the relative weathering input of old radiogenic crust and more juvenile, mantle derived substrate. The preglacial isotopic signals are consistent with an enhanced contribution of juvenile material to the oceans and glacial initiation through enhanced global weatherability. In contrast, postglacial strata feature radiogenic Os and Sr isotope compositions indicative of extensive glacial scouring of the continents and intense silicate weathering in a post-Snowball Earth hothouse. PMID- 24344275 TI - Global water resources affected by human interventions and climate change. AB - Humans directly change the dynamics of the water cycle through dams constructed for water storage, and through water withdrawals for industrial, agricultural, or domestic purposes. Climate change is expected to additionally affect water supply and demand. Here, analyses of climate change and direct human impacts on the terrestrial water cycle are presented and compared using a multimodel approach. Seven global hydrological models have been forced with multiple climate projections, and with and without taking into account impacts of human interventions such as dams and water withdrawals on the hydrological cycle. Model results are analyzed for different levels of global warming, allowing for analyses in line with temperature targets for climate change mitigation. The results indicate that direct human impacts on the water cycle in some regions, e.g., parts of Asia and in the western United States, are of the same order of magnitude, or even exceed impacts to be expected for moderate levels of global warming (+2 K). Despite some spread in model projections, irrigation water consumption is generally projected to increase with higher global mean temperatures. Irrigation water scarcity is particularly large in parts of southern and eastern Asia, and is expected to become even larger in the future. PMID- 24344276 TI - Early Pleistocene third metacarpal from Kenya and the evolution of modern human like hand morphology. AB - Despite discoveries of relatively complete hands from two early hominin species (Ardipithecus ramidus and Australopithecus sediba) and partial hands from another (Australopithecus afarensis), fundamental questions remain about the evolution of human-like hand anatomy and function. These questions are driven by the paucity of hand fossils in the hominin fossil record between 800,000 and 1.8 My old, a time interval well documented for the emergence and subsequent proliferation of Acheulian technology (shaped bifacial stone tools). Modern and Middle to Late Pleistocene humans share a suite of derived features in the thumb, wrist, and radial carpometacarpal joints that is noticeably absent in early hominins. Here we show that one of the most distinctive features of this suite in the Middle Pleistocene to recent human hand, the third metacarpal styloid process, was present ~1.42 Mya in an East African hominin from Kaitio, West Turkana, Kenya. This fossil thus provides the earliest unambiguous evidence for the evolution of a key shared derived characteristic of modern human and Neandertal hand morphology and suggests that the distinctive complex of radial carpometacarpal joint features in the human hand arose early in the evolution of the genus Homo and probably in Homo erectus sensu lato. PMID- 24344277 TI - Growth feedback as a basis for persister bistability. AB - A small fraction of cells in many bacterial populations, called persisters, are much less sensitive to antibiotic treatment than the majority. Persisters are in a dormant metabolic state, even while remaining genetically identical to the actively growing cells. Toxin and antitoxin modules in bacteria are believed to be one possible cause of persistence. A two-gene operon, HipBA, is one of many chromosomally encoded toxin and antitoxin modules in Escherichia coli and the HipA7 allelic variant was the first validated high-persistence mutant. Here, we present a stochastic model that can generate bistability of the HipBA system, via the reciprocal coupling of free HipA to the cellular growth rate. The actively growing state and the dormant state each correspond to a stable state of this model. Fluctuations enable transitions from one to the other. This model is fully in agreement with experimental data obtained with synthetic promoter constructs. PMID- 24344278 TI - Mangarevan invention of binary steps for easier calculation. AB - When Leibniz demonstrated the advantages of the binary system for computations as early as 1703, he laid the foundation for computing machines. However, is a binary system also suitable for human cognition? One of two number systems traditionally used on Mangareva, a small island in French Polynesia, had three binary steps superposed onto a decimal structure. Here, we show how this system functions, how it facilitated arithmetic, and why it is unique. The Mangarevan invention of binary steps, centuries before their formal description by Leibniz, attests to the advancements possible in numeracy even in the absence of notation and thereby highlights the role of culture for the evolution of and diversity in numerical cognition. PMID- 24344279 TI - Earliest evidence for commensal processes of cat domestication. AB - Domestic cats are one of the most popular pets globally, but the process of their domestication is not well understood. Near Eastern wildcats are thought to have been attracted to food sources in early agricultural settlements, following a commensal pathway to domestication. Early evidence for close human-cat relationships comes from a wildcat interred near a human on Cyprus ca. 9,500 y ago, but the earliest domestic cats are known only from Egyptian art dating to 4,000 y ago. Evidence is lacking from the key period of cat domestication 9,500 4,000 y ago. We report on the presence of cats directly dated between 5560-5280 cal B.P. in the early agricultural village of Quanhucun in Shaanxi, China. These cats were outside the wild range of Near Eastern wildcats and biometrically smaller, but within the size-range of domestic cats. The delta(13)C and delta(15)N values of human and animal bone collagen revealed substantial consumption of millet-based foods by humans, rodents, and cats. Ceramic storage containers designed to exclude rodents indicated a threat to stored grain in Yangshao villages. Taken together, isotopic and archaeological data demonstrate that cats were advantageous for ancient farmers. Isotopic data also show that one cat ate less meat and consumed more millet-based foods than expected, indicating that it scavenged among or was fed by people. This study offers fresh perspectives on cat domestication, providing the earliest known evidence for commensal relationships between people and cats. PMID- 24344281 TI - QnAs with Davis Masten and Peter Zandan. PMID- 24344280 TI - Scan statistic-based analysis of exome sequencing data identifies FAN1 at 15q13.3 as a susceptibility gene for schizophrenia and autism. AB - We used a family-based cluster detection approach designed to localize significant rare disease-risk variants clusters within a region of interest to systematically search for schizophrenia (SCZ) susceptibility genes within 49 genomic loci previously implicated by de novo copy number variants. Using two independent whole-exome sequencing family datasets and a follow-up autism spectrum disorder (ASD) case/control whole-exome sequencing dataset, we identified variants in one gene, Fanconi-associated nuclease 1 (FAN1), as being associated with both SCZ and ASD. FAN1 is located in a region on chromosome 15q13.3 implicated by a recurrent copy number variant, which predisposes to an array of psychiatric and neurodevelopmental phenotypes. In both SCZ and ASD datasets, rare nonsynonymous risk variants cluster significantly in affected individuals within a 20-kb window that spans several key functional domains of the gene. Our finding suggests that FAN1 is a key driver in the 15q13.3 locus for the associated psychiatric and neurodevelopmental phenotypes. FAN1 encodes a DNA repair enzyme, thus implicating abnormalities in DNA repair in the susceptibility to SCZ or ASD. PMID- 24344282 TI - A mechanism for retromer endosomal coat complex assembly with cargo. AB - Retromer is an evolutionarily conserved protein complex composed of the VPS26, VPS29, and VPS35 proteins that selects and packages cargo proteins into transport carriers that export cargo from the endosome. The mechanisms by which retromer is recruited to the endosome and captures cargo are unknown. We show that membrane recruitment of retromer is mediated by bivalent recognition of an effector of PI3K, SNX3, and the RAB7A GTPase, by the VPS35 retromer subunit. These bivalent interactions prime retromer to capture integral membrane cargo, which enhances membrane association of retromer and initiates cargo sorting. The role of RAB7A is severely impaired by a mutation, K157N, that causes Charcot-Marie-Tooth neuropathy 2B. The results elucidate minimal requirements for retromer assembly on the endosome membrane and reveal how PI3K and RAB signaling are coupled to initiate retromer-mediated cargo export. PMID- 24344284 TI - SuperBiHelix method for predicting the pleiotropic ensemble of G-protein-coupled receptor conformations. AB - There is overwhelming evidence that G-protein-coupled receptors (GPCRs) exhibit several distinct low-energy conformations, each of which might favor binding to different ligands and/or lead to different downstream functions. Understanding the function of such proteins requires knowledge of the ensemble of low-energy configurations that might play a role in this pleiotropic functionality. We earlier reported the BiHelix method for efficiently sampling the (12)(7) = 35 million conformations resulting from 30 degrees rotations about the axis (eta) of all seven transmembrane helices (TMHs), showing that the experimental structure is reliably selected as the best conformation from this ensemble. However, various GPCRs differ sufficiently in the tilts of the TMHs that this method need not predict the optimum conformation starting from any other template. In this paper, we introduce the SuperBiHelix method in which the tilt angles (theta, phi) are optimized simultaneously with rotations (eta) efficiently enough that it is practical and sufficient to sample (5 * 3 * 5)(7) = 13 trillion configurations. This method can correctly identify the optimum structure of a GPCR starting with the template from a different GPCR. We have validated this method by predicting known crystal structure conformations starting from the template of a different protein structure. We find that the SuperBiHelix conformational ensemble includes the higher energy conformations associated with the active protein in addition to those associated with the more stable inactive protein. This methodology was then applied to design and experimentally confirm structures of three mutants of the CB1 cannabinoid receptor associated with different functions. PMID- 24344283 TI - Constraints and potentials of future irrigation water availability on agricultural production under climate change. AB - We compare ensembles of water supply and demand projections from 10 global hydrological models and six global gridded crop models. These are produced as part of the Inter-Sectoral Impacts Model Intercomparison Project, with coordination from the Agricultural Model Intercomparison and Improvement Project, and driven by outputs of general circulation models run under representative concentration pathway 8.5 as part of the Fifth Coupled Model Intercomparison Project. Models project that direct climate impacts to maize, soybean, wheat, and rice involve losses of 400-1,400 Pcal (8-24% of present-day total) when CO2 fertilization effects are accounted for or 1,400-2,600 Pcal (24-43%) otherwise. Freshwater limitations in some irrigated regions (western United States; China; and West, South, and Central Asia) could necessitate the reversion of 20-60 Mha of cropland from irrigated to rainfed management by end-of-century, and a further loss of 600-2,900 Pcal of food production. In other regions (northern/eastern United States, parts of South America, much of Europe, and South East Asia) surplus water supply could in principle support a net increase in irrigation, although substantial investments in irrigation infrastructure would be required. PMID- 24344285 TI - Climate change effects on agriculture: economic responses to biophysical shocks. AB - Agricultural production is sensitive to weather and thus directly affected by climate change. Plausible estimates of these climate change impacts require combined use of climate, crop, and economic models. Results from previous studies vary substantially due to differences in models, scenarios, and data. This paper is part of a collective effort to systematically integrate these three types of models. We focus on the economic component of the assessment, investigating how nine global economic models of agriculture represent endogenous responses to seven standardized climate change scenarios produced by two climate and five crop models. These responses include adjustments in yields, area, consumption, and international trade. We apply biophysical shocks derived from the Intergovernmental Panel on Climate Change's representative concentration pathway with end-of-century radiative forcing of 8.5 W/m(2). The mean biophysical yield effect with no incremental CO2 fertilization is a 17% reduction globally by 2050 relative to a scenario with unchanging climate. Endogenous economic responses reduce yield loss to 11%, increase area of major crops by 11%, and reduce consumption by 3%. Agricultural production, cropland area, trade, and prices show the greatest degree of variability in response to climate change, and consumption the lowest. The sources of these differences include model structure and specification; in particular, model assumptions about ease of land use conversion, intensification, and trade. This study identifies where models disagree on the relative responses to climate shocks and highlights research activities needed to improve the representation of agricultural adaptation responses to climate change. PMID- 24344286 TI - Evidence supporting an intentional Neandertal burial at La Chapelle-aux-Saints. AB - The bouffia Bonneval at La Chapelle-aux-Saints is well known for the discovery of the first secure Neandertal burial in the early 20th century. However, the intentionality of the burial remains an issue of some debate. Here, we present the results of a 12-y fieldwork project, along with a taphonomic analysis of the human remains, designed to assess the funerary context of the La Chapelle-aux Saints Neandertal. We have established the anthropogenic nature of the burial pit and underlined the taphonomic evidence of a rapid burial of the body. These multiple lines of evidence support the hypothesis of an intentional burial. Finally, the discovery of skeletal elements belonging to the original La Chapelle aux Saints 1 individual, two additional young individuals, and a second adult in the bouffia Bonneval highlights a more complex site-formation history than previously proposed. PMID- 24344287 TI - Local domains of motor cortical activity revealed by fiber-optic calcium recordings in behaving nonhuman primates. AB - Brain mapping experiments involving electrical microstimulation indicate that the primary motor cortex (M1) directly regulates muscle contraction and thereby controls specific movements. Possibly, M1 contains a small circuit "map" of the body that is formed by discrete local networks that code for specific movements. Alternatively, movements may be controlled by distributed, larger-scale overlapping circuits. Because of technical limitations, it remained unclear how movement-determining circuits are organized in M1. Here we introduce a method that allows the functional mapping of small local neuronal circuits in awake behaving nonhuman primates. For this purpose, we combined optic-fiber-based calcium recordings of neuronal activity and cortical microstimulation. The method requires targeted bulk loading of synthetic calcium indicators (e.g., OGB-1 AM) for the staining of neuronal microdomains. The tip of a thin (200 um) optical fiber can detect the coherent activity of a small cluster of neurons, but is insensitive to the asynchronous activity of individual cells. By combining such optical recordings with microstimulation at two well-separated sites of M1, we demonstrate that local cortical activity was tightly associated with distinct and stereotypical simple movements. Increasing stimulation intensity increased both the amplitude of the movements and the level of neuronal activity. Importantly, the activity remained local, without invading the recording domain of the second optical fiber. Furthermore, there was clear response specificity at the two recording sites in a trained behavioral task. Thus, the results provide support for movement control in M1 by local neuronal clusters that are organized in discrete cortical domains. PMID- 24344288 TI - Direct observation of single stationary-phase bacteria reveals a surprisingly long period of constant protein production activity. AB - Exponentially growing bacteria are rarely found in the wild, as microorganisms tend to spend most of their lifetime at stationary phase. Despite this general prevalence of stationary-phase bacteria, they are as yet poorly characterized. Our goal was to quantitatively study this phase by direct observation of single bacteria as they enter into stationary phase and by monitoring their activity over several days during growth arrest. For this purpose, we devised an experimental procedure for starving single Escherichia coli bacteria in microfluidic devices and measured their activity by monitoring the production rate of fluorescent proteins. When amino acids were the sole carbon source, the production rate decreased by an order of magnitude upon entry into stationary phase. We found that, even while growth-arrested, bacteria continued to produce proteins at a surprisingly constant rate over several days. Our identification of this newly observed period of constant activity in nongrowing cells, designated as constant activity stationary phase, makes possible the conduction of assays that require constant protein expression over time, and are therefore difficult to perform under exponential growth conditions. Moreover, we show that exogenous protein expression bears no fitness cost on the regrowth of the population when starvation ends. Further characterization of constant activity stationary phase-a phase where nongrowing bacteria can be quantitatively studied over several days in a reproducible manner-should contribute to a better understanding of this ubiquitous but overlooked physiological state of bacteria in nature. PMID- 24344289 TI - Multimodel assessment of water scarcity under climate change. AB - Water scarcity severely impairs food security and economic prosperity in many countries today. Expected future population changes will, in many countries as well as globally, increase the pressure on available water resources. On the supply side, renewable water resources will be affected by projected changes in precipitation patterns, temperature, and other climate variables. Here we use a large ensemble of global hydrological models (GHMs) forced by five global climate models and the latest greenhouse-gas concentration scenarios (Representative Concentration Pathways) to synthesize the current knowledge about climate change impacts on water resources. We show that climate change is likely to exacerbate regional and global water scarcity considerably. In particular, the ensemble average projects that a global warming of 2 degrees C above present (approximately 2.7 degrees C above preindustrial) will confront an additional approximate 15% of the global population with a severe decrease in water resources and will increase the number of people living under absolute water scarcity (<500 m(3) per capita per year) by another 40% (according to some models, more than 100%) compared with the effect of population growth alone. For some indicators of moderate impacts, the steepest increase is seen between the present day and 2 degrees C, whereas indicators of very severe impacts increase unabated beyond 2 degrees C. At the same time, the study highlights large uncertainties associated with these estimates, with both global climate models and GHMs contributing to the spread. GHM uncertainty is particularly dominant in many regions affected by declining water resources, suggesting a high potential for improved water resource projections through hydrological model development. PMID- 24344290 TI - First look at changes in flood hazard in the Inter-Sectoral Impact Model Intercomparison Project ensemble. AB - Climate change due to anthropogenic greenhouse gas emissions is expected to increase the frequency and intensity of precipitation events, which is likely to affect the probability of flooding into the future. In this paper we use river flow simulations from nine global hydrology and land surface models to explore uncertainties in the potential impacts of climate change on flood hazard at global scale. As an indicator of flood hazard we looked at changes in the 30-y return level of 5-d average peak flows under representative concentration pathway RCP8.5 at the end of this century. Not everywhere does climate change result in an increase in flood hazard: decreases in the magnitude and frequency of the 30-y return level of river flow occur at roughly one-third (20-45%) of the global land grid points, particularly in areas where the hydrograph is dominated by the snowmelt flood peak in spring. In most model experiments, however, an increase in flooding frequency was found in more than half of the grid points. The current 30 y flood peak is projected to occur in more than 1 in 5 y across 5-30% of land grid points. The large-scale patterns of change are remarkably consistent among impact models and even the driving climate models, but at local scale and in individual river basins there can be disagreement even on the sign of change, indicating large modeling uncertainty which needs to be taken into account in local adaptation studies. PMID- 24344291 TI - Imaging the wave functions of adsorbed molecules. AB - The basis for a quantum-mechanical description of matter is electron wave functions. For atoms and molecules, their spatial distributions and phases are known as orbitals. Although orbitals are very powerful concepts, experimentally only the electron densities and -energy levels are directly observable. Regardless whether orbitals are observed in real space with scanning probe experiments, or in reciprocal space by photoemission, the phase information of the orbital is lost. Here, we show that the experimental momentum maps of angle resolved photoemission from molecular orbitals can be transformed to real-space orbitals via an iterative procedure which also retrieves the lost phase information. This is demonstrated with images obtained of a number of orbitals of the molecules pentacene (C22H14) and perylene-3,4,9,10-tetracarboxylic dianhydride (C24H8O6), adsorbed on silver, which are in excellent agreement with ab initio calculations. The procedure requires no a priori knowledge of the orbitals and is shown to be simple and robust. PMID- 24344292 TI - How risk management can prevent future wildfire disasters in the wildland-urban interface. AB - Recent fire seasons in the western United States are some of the most damaging and costly on record. Wildfires in the wildland-urban interface on the Colorado Front Range, resulting in thousands of homes burned and civilian fatalities, although devastating, are not without historical reference. These fires are consistent with the characteristics of large, damaging, interface fires that threaten communities across much of the western United States. Wildfires are inevitable, but the destruction of homes, ecosystems, and lives is not. We propose the principles of risk analysis to provide land management agencies, first responders, and affected communities who face the inevitability of wildfires the ability to reduce the potential for loss. Overcoming perceptions of wildland-urban interface fire disasters as a wildfire control problem rather than a home ignition problem, determined by home ignition conditions, will reduce home loss. PMID- 24344293 TI - Amphitheater-headed canyons formed by megaflooding at Malad Gorge, Idaho. AB - Many bedrock canyons on Earth and Mars were eroded by upstream propagating headwalls, and a prominent goal in geomorphology and planetary science is to determine formation processes from canyon morphology. A diagnostic link between process and form remains highly controversial, however, and field investigations that isolate controls on canyon morphology are needed. Here we investigate the origin of Malad Gorge, Idaho, a canyon system cut into basalt with three remarkably distinct heads: two with amphitheater headwalls and the third housing the active Wood River and ending in a 7% grade knickzone. Scoured rims of the headwalls, relict plunge pools, sediment-transport constraints, and cosmogenic ((3)He) exposure ages indicate formation of the amphitheater-headed canyons by large-scale flooding ~46 ka, coeval with formation of Box Canyon 18 km to the south as well as the eruption of McKinney Butte Basalt, suggesting widespread canyon formation following lava-flow diversion of the paleo-Wood River. Exposure ages within the knickzone-headed canyon indicate progressive upstream younging of strath terraces and a knickzone propagation rate of 2.5 cm/y over at least the past 33 ka. Results point to a potential diagnostic link between vertical amphitheater headwalls in basalt and rapid erosion during megaflooding due to the onset of block toppling, rather than previous interpretations of seepage erosion, with implications for quantifying the early hydrosphere of Mars. PMID- 24344294 TI - FMRP and Ataxin-2 function together in long-term olfactory habituation and neuronal translational control. AB - Fragile X mental retardation protein (FMRP) and Ataxin-2 (Atx2) are triplet expansion disease- and stress granule-associated proteins implicated in neuronal translational control and microRNA function. We show that Drosophila FMRP (dFMR1) is required for long-term olfactory habituation (LTH), a phenomenon dependent on Atx2-dependent potentiation of inhibitory transmission from local interneurons (LNs) to projection neurons (PNs) in the antennal lobe. dFMR1 is also required for LTH-associated depression of odor-evoked calcium transients in PNs. Strong transdominant genetic interactions among dFMR1, atx2, the deadbox helicase me31B, and argonaute1 (ago1) mutants, as well as coimmunoprecitation of dFMR1 with Atx2, indicate that dFMR1 and Atx2 function together in a microRNA-dependent process necessary for LTH. Consistently, PN or LN knockdown of dFMR1, Atx2, Me31B, or the miRNA-pathway protein GW182 increases expression of a Ca2+/calmodulin-dependent protein kinase II (CaMKII) translational reporter. Moreover, brain immunoprecipitates of dFMR1 and Atx2 proteins include CaMKII mRNA, indicating respective physical interactions with this mRNA. Because CaMKII is necessary for LTH, these data indicate that fragile X mental retardation protein and Atx2 act via at least one common target RNA for memory-associated long-term synaptic plasticity. The observed requirement in LNs and PNs supports an emerging view that both presynaptic and postsynaptic translation are necessary for long-term synaptic plasticity. However, whereas Atx2 is necessary for the integrity of dendritic and somatic Me31B-containing particles, dFmr1 is not. Together, these data indicate that dFmr1 and Atx2 function in long-term but not short-term memory, regulating translation of at least some common presynaptic and postsynaptic target mRNAs in the same cells. PMID- 24344296 TI - Profile of Paul Schulze-Lefert. PMID- 24344295 TI - Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated self-epitopes. AB - HLA molecules presenting peptides derived from tumor-associated self-antigens (self-TAA) are attractive targets for T-cell-based immunotherapy of cancer. However, detection of such epitopes is hampered by self-tolerance and limitations in the sensitivity of mass spectrometry. Here, we used T cells from HLA-A2 negative donors as tools to detect HLA-A2-bound peptides from two leukemia associated differentiation antigens; CD20 and the previously undescribed cancer target myeloperoxidase. A high-throughput platform for epitope discovery was designed using dendritic cells cotransfected with full-length transcripts of self TAA and HLA-A2 to allow presentation of all naturally processed peptides from a predefined self-protein on foreign HLA. Antigen-reactive T cells were directly detected using panels of color-coded peptide-HLA multimers containing epitopes predicted by a computer algorithm. Strikingly, cytotoxic T cells were generated against 37 out of 50 peptides predicted to bind HLA-A2. Among these, 36 epitopes were previously undescribed. The allorestricted T cells were exquisitely peptide- and HLA-specific and responded strongly to HLA-A2-positive leukemic cells with endogenous expression of CD20 or myeloperoxidase. These results indicate that the repertoire of self-peptides presented on HLA class I has been underestimated and that a wealth of self-TAA can be targeted by T cells when using nontolerized T cell repertoires. PMID- 24344297 TI - Large effect of membrane tension on the fluid-solid phase transitions of two component phosphatidylcholine vesicles. AB - Model phospholipid membranes and vesicles have long provided insight into the nature of confined materials and membranes while also providing a platform for drug delivery. The rich thermodynamic behavior and interesting domain shapes in these membranes have previously been mapped in extensive studies that vary temperature and composition; however, the thermodynamic impact of tension on bilayers has been restricted to recent reports of subtly reduced fluid-fluid transition temperatures. In two-component phosphatidylcholine unilamellar vesicles [1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)/1,2-dipalmitoyl-sn glycero-3-phosphocholine (DPPC)], we report a dramatic influence of tension on the fluid-solid transition and resulting phases: At fixed composition, systematic variations in tension produce differently shaped solid domains (striped or irregular hexagons), shift fluid-solid transition temperatures, and produce a triple-point-like intersection of coexistence curves at elevated tensions, about 3 mN/m for 30% DOPC/70% DPPC. Tension therefore represents a potential switch of microstructure in responsive engineered materials; it is an important morphology determining variable in confined systems, and, in biological membranes, it may provide a means to regulate dynamic structure. PMID- 24344298 TI - Founding father of FACS: Professor Leonard A. Herzenberg (1931-2013). PMID- 24344299 TI - Data-poor management of African lion hunting using a relative index of abundance. AB - Sustainable management of terrestrial hunting requires managers to set quotas restricting offtake. This often takes place in the absence of reliable information on the population size, and as a consequence, quotas are set in an arbitrary fashion, leading to population decline and revenue loss. In this investigation, we show how an indirect measure of abundance can be used to set quotas in a sustainable manner, even in the absence of information on population size. Focusing on lion hunting in Africa, we developed a simple algorithm to convert changes in the number of safari days required to kill a lion into a quota for the following year. This was tested against a simulation model of population dynamics, accounting for uncertainties in demography, observation, and implementation. Results showed it to reliably set sustainable quotas despite these uncertainties, providing a robust foundation for the conservation of hunted species. PMID- 24344300 TI - Aggregation-triggering segments of SOD1 fibril formation support a common pathway for familial and sporadic ALS. AB - ALS is a terminal disease of motor neurons that is characterized by accumulation of proteinaceous deposits in affected cells. Pathological deposition of mutated Cu/Zn superoxide dismutase (SOD1) accounts for ~20% of the familial ALS (fALS) cases. However, understanding the molecular link between mutation and disease has been difficult, given that more than 140 different SOD1 mutants have been observed in fALS patients. In addition, the molecular origin of sporadic ALS (sALS) is unclear. By dissecting the amino acid sequence of SOD1, we identified four short segments with a high propensity for amyloid fibril formation. We find that fALS mutations in these segments do not reduce their propensity to form fibrils. The atomic structures of two fibril-forming segments from the C terminus, (101)DSVISLS(107) and (147)GVIGIAQ(153), reveal tightly packed beta sheets with steric zipper interfaces characteristic of the amyloid state. Based on these structures, we conclude that both C-terminal segments are likely to form aggregates if available for interaction. Proline substitutions in (101)DSVISLS(107) and (147)GVIGIAQ(153) impaired nucleation and fibril growth of full-length protein, confirming that these segments participate in aggregate formation. Our hypothesis is that improper protein maturation and incompletely folded states that render these aggregation-prone segments available for interaction offer a common molecular pathway for sALS and fALS. PMID- 24344301 TI - TALEN-mediated single-base-pair editing identification of an intergenic mutation upstream of BUB1B as causative of PCS (MVA) syndrome. AB - Cancer-prone syndrome of premature chromatid separation with mosaic variegated aneuploidy [PCS (MVA) syndrome] is a rare autosomal recessive disorder characterized by constitutional aneuploidy and a high risk of childhood cancer. We previously reported monoallelic mutations in the BUB1B gene (encoding BUBR1) in seven Japanese families with the syndrome. No second mutation was found in the opposite allele of any of the families studied, although a conserved BUB1B haplotype and a decreased transcript were identified. To clarify the molecular pathology of the second allele, we extended our mutational search to a candidate region surrounding BUB1B. A unique single nucleotide substitution, G > A at ss802470619, was identified in an intergenic region 44 kb upstream of a BUB1B transcription start site, which cosegregated with the disorder. To examine whether this is the causal mutation, we designed a transcription activator-like effector nuclease-mediated two-step single-base pair editing strategy and biallelically introduced this substitution into cultured human cells. The cell clones showed reduced BUB1B transcripts, increased PCS frequency, and MVA, which are the hallmarks of the syndrome. We also encountered a case of a Japanese infant with PCS (MVA) syndrome carrying a homozygous single nucleotide substitution at ss802470619. These results suggested that the nucleotide substitution identified was the causal mutation of PCS (MVA) syndrome. PMID- 24344302 TI - Autocatalytically generated Thr-Gln ester bond cross-links stabilize the repetitive Ig-domain shaft of a bacterial cell surface adhesin. AB - Gram-positive bacteria are decorated by a variety of proteins that are anchored to the cell wall and project from it to mediate colonization, attachment to host cells, and pathogenesis. These proteins, and protein assemblies, such as pili, are typically long and thin yet must withstand high levels of mechanical stress and proteolytic attack. The recent discovery of intramolecular isopeptide bond cross-links, formed autocatalytically, in the pili from Streptococcus pyogenes has highlighted the role that such cross-links can play in stabilizing such structures. We have investigated a putative cell-surface adhesin from Clostridium perfringens comprising an N-terminal adhesin domain followed by 11 repeat domains. The crystal structure of a two-domain fragment shows that each domain has an IgG-like fold and contains an unprecedented ester bond joining Thr and Gln side chains. MS confirms the presence of these bonds. We show that the bonds form through an autocatalytic intramolecular reaction catalyzed by an adjacent His residue in a serine protease-like mechanism. Two buried acidic residues assist in the reaction. By mutagenesis, we show that loss of the ester bond reduces the thermal stability drastically and increases susceptibility to proteolysis. As in pilin domains, the bonds are placed at a strategic position joining the first and last strands, even though the Ig fold type differs. Bioinformatic analysis suggests that similar domains and ester bond cross-links are widespread in Gram positive bacterial adhesins. PMID- 24344303 TI - Bidirectional homeostatic plasticity induced by interneuron cell death and transplantation in vivo. AB - Chronic changes in excitability and activity can induce homeostatic plasticity. These perturbations may be associated with neurological disorders, particularly those involving loss or dysfunction of GABA interneurons. In distal-less homeobox 1 (Dlx1(-/-)) mice with late-onset interneuron loss and reduced inhibition, we observed both excitatory synaptic silencing and decreased intrinsic neuronal excitability. These homeostatic changes do not fully restore normal circuit function, because synaptic silencing results in enhanced potential for long-term potentiation and abnormal gamma oscillations. Transplanting medial ganglionic eminence interneuron progenitors to introduce new GABAergic interneurons, we demonstrate restoration of hippocampal function. Specifically, miniature excitatory postsynaptic currents, input resistance, hippocampal long-term potentiation, and gamma oscillations are all normalized. Thus, in vivo homeostatic plasticity is a highly dynamic and bidirectional process that responds to changes in inhibition. PMID- 24344304 TI - Circadian clock-dependent and -independent rhythmic proteomes implement distinct diurnal functions in mouse liver. AB - Diurnal oscillations of gene expression controlled by the circadian clock underlie rhythmic physiology across most living organisms. Although such rhythms have been extensively studied at the level of transcription and mRNA accumulation, little is known about the accumulation patterns of proteins. Here, we quantified temporal profiles in the murine hepatic proteome under physiological light-dark conditions using stable isotope labeling by amino acids quantitative MS. Our analysis identified over 5,000 proteins, of which several hundred showed robust diurnal oscillations with peak phases enriched in the morning and during the night and related to core hepatic physiological functions. Combined mathematical modeling of temporal protein and mRNA profiles indicated that proteins accumulate with reduced amplitudes and significant delays, consistent with protein half-life data. Moreover, a group comprising about one half of the rhythmic proteins showed no corresponding rhythmic mRNAs, indicating significant translational or posttranslational diurnal control. Such rhythms were highly enriched in secreted proteins accumulating tightly during the night. Also, these rhythms persisted in clock-deficient animals subjected to rhythmic feeding, suggesting that food-related entrainment signals influence rhythms in circulating plasma factors. PMID- 24344305 TI - JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1alpha-mediated glucose metabolism. AB - JMJD5, a Jumonji C domain-containing dioxygenase, is important for embryonic development and cancer growth. Here, we show that JMJD5 is up-regulated by hypoxia and is crucial for hypoxia-induced cell proliferation. JMJD5 interacts directly with pyruvate kinase muscle isozyme (PKM)2 to modulate metabolic flux in cancer cells. The JMJD5-PKM2 interaction resides at the intersubunit interface region of PKM2, which hinders PKM2 tetramerization and blocks pyruvate kinase activity. This interaction also influences translocation of PKM2 into the nucleus and promotes hypoxia-inducible factor (HIF)-1alpha-mediated transactivation. JMJD5 knockdown inhibits the transcription of the PKM2-HIF-1alpha target genes involved in glucose metabolism, resulting in a reduction of glucose uptake and lactate secretion in cancer cells. JMJD5, along with PKM2 and HIF-1alpha, is recruited to the hypoxia response element site in the lactate dehydrogenase A and PKM2 loci and mediates the recruitment of the latter two proteins. Our data uncover a mechanism whereby PKM2 can be regulated by factor-binding-induced homo/heterooligomeric restructuring, paving the way to cell metabolic reprogram. PMID- 24344306 TI - Transmembrane allosteric coupling of the gates in a potassium channel. AB - It has been hypothesized that transmembrane allostery is the basis for inactivation of the potassium channel KcsA: opening the intracellular gate is spontaneously followed by ion expulsion at the extracellular selectivity filter. This suggests a corollary: following ion expulsion at neutral pH, a spontaneous global conformation change of the transmembrane helices, similar to the motion involved in opening, is expected. Consequently, both the low potassium state and the low pH state of the system could provide useful models for the inactivated state. Unique NMR studies of full-length KcsA in hydrated bilayers provide strong evidence for such a mutual coupling across the bilayer: namely, upon removing ambient potassium ions, changes are seen in the NMR shifts of carboxylates E118 and E120 in the pH gate in the hinges of the inner transmembrane helix (98-103), and in the selectivity filter, all of which resemble changes seen upon acid induced opening and inhibition and suggest that ion release can trigger channel helix opening. PMID- 24344307 TI - Quantitation of the DNA tethering effect in long-range DNA looping in vivo and in vitro using the Lac and lambda repressors. AB - Efficient and specific interactions between proteins bound to the same DNA molecule can be dependent on the length of the DNA tether that connects them. Measurement of the strength of this DNA tethering effect has been largely confined to short separations between sites, and it is not clear how it contributes to long-range DNA looping interactions, such as occur over separations of tens to hundreds of kilobase pairs in vivo. Here, gene regulation experiments using the LacI and lambda CI repressors, combined with mathematical modeling, were used to quantitate DNA tethering inside Escherichia coli cells over the 250- to 10,000-bp range. Although LacI and CI loop DNA in distinct ways, measurements of the tethering effect were very similar for both proteins. Tethering strength decreased with increasing separation, but even at 5- to 10-kb distances, was able to increase contact probability 10- to 20-fold and drive efficient looping. Tethering in vitro with the Lac repressor was measured for the same 600-to 3,200-bp DNAs using tethered particle motion, a single molecule technique, and was 5- to 45-fold weaker than in vivo over this range. Thus, the enhancement of looping seen previously in vivo at separations below 500 bp extends to large separations, underlining the need to understand how in vivo factors aid DNA looping. Our analysis also suggests how efficient and specific looping could be achieved over very long DNA separations, such as what occurs between enhancers and promoters in eukaryotic cells. PMID- 24344308 TI - Altered inactivation of commensal LPS due to acyloxyacyl hydrolase deficiency in colonic dendritic cells impairs mucosal Th17 immunity. AB - Interleukin (IL) 17-secreting CD4(+) helper T cells (Th17 cells) are essential for host defense at mucosal surfaces, and Th17 cell dysregulation can result in autoimmunity. Exposure to microbial products, such as bacterial LPS, can affect the ability of dendritic cells (DCs) to polarize Th17 cells. Acyloxyacyl hydrolase (AOAH) is a mammalian enzyme expressed by antigen (Ag)-presenting cells that deacylates and thereby inactivates LPS in host tissues. We hypothesized that inactivation of intestinal microbiota-derived LPS by AOAH influences the ability of DCs to polarize and generate Th17 effector cells. We found that LPS-containing Gram-negative microbiota augmented the differentiation of Ag-specific Th17 cells, and identified a colonic DC subset (CD103(+)CD11b(+)ALDH(-)) displaying a unique capacity to both express AOAH and polarize Th17 cells. Compared with WT, these Aoah(-/-) colonic DCs produce less IL-6, resulting in diminished Ag-specific Th17 polarization and increased regulatory T-cell induction in vitro. Oral administration of LPS led to reduced IL-6 production from CD103(+)CD11b(+)ALDH(-) colonic DCs in Aoah(-/-) mice compared with Aoah(+/+) mice, resulting in an abrogated Ag-specific Th17 response in the colon after mucosal immunization that could be rescued by systemic delivery of recombinant IL-6. These data identify the ability of AOAH to modulate microbiota signals that drive Th17 polarization and influence mucosal T-cell immunity, and suggest that host pathways to handle microbiota-derived products may be targeted to modulate Th17 responses in the context of inflammatory disorders or infection at mucosal surfaces. PMID- 24344309 TI - Nucleolin is important for Epstein-Barr virus nuclear antigen 1-mediated episome binding, maintenance, and transcription. AB - Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is essential for EBV episome maintenance, replication, and transcription. These effects are mediated by EBNA1 binding to cognate oriP DNA, which comprise 20 imperfect copies of a 30-bp dyad symmetry enhancer and an origin for DNA replication. To identify cell proteins essential for these EBNA1 functions, EBNA1 associated cell proteins were immune precipitated and analyzed by liquid chromatography-tandem mass spectrometry. Nucleolin (NCL) was identified to be EBNA1 associated. EBNA1's N-terminal 100 aa and NCL's RNA-binding domains were critical for EBNA1/NCL interaction. Lentivirus shRNA-mediated NCL depletion substantially reduced EBNA1 recruitment to oriP DNA, EBNA1-dependent transcription of an EBV oriP luciferase reporter, and EBV genome maintenance in lymphoblastoid cell lines. NCL RNA-binding domain K429 was critical for ATP and EBNA1 binding. NCL overexpression increased EBNA1 binding to oriP and transcription, whereas NCL K429A was deficient. Moreover, NCL silencing impaired lymphoblastoid cell line growth. These experiments reveal a surprisingly critical role for NCL K429 in EBNA1 episome maintenance and transcription, which may be a target for therapeutic intervention. PMID- 24344310 TI - O-mannosylation of cadherins. PMID- 24344311 TI - A unique covalent bond in basement membrane is a primordial innovation for tissue evolution. AB - Basement membrane, a specialized ECM that underlies polarized epithelium of eumetazoans, provides signaling cues that regulate cell behavior and function in tissue genesis and homeostasis. A collagen IV scaffold, a major component, is essential for tissues and dysfunctional in several diseases. Studies of bovine and Drosophila tissues reveal that the scaffold is stabilized by sulfilimine chemical bonds (S = N) that covalently cross-link methionine and hydroxylysine residues at the interface of adjoining triple helical protomers. Peroxidasin, a heme peroxidase embedded in the basement membrane, produces hypohalous acid intermediates that oxidize methionine, forming the sulfilimine cross-link. We explored whether the sulfilimine cross-link is a fundamental requirement in the genesis and evolution of epithelial tissues by determining its occurrence and evolutionary origin in Eumetazoa and its essentiality in zebrafish development; 31 species, spanning 11 major phyla, were investigated for the occurrence of the sulfilimine cross-link by electrophoresis, MS, and multiple sequence alignment of de novo transcriptome and available genomic data for collagen IV and peroxidasin. The results show that the cross-link is conserved throughout Eumetazoa and arose at the divergence of Porifera and Cnidaria over 500 Mya. Also, peroxidasin, the enzyme that forms the bond, is evolutionarily conserved throughout Metazoa. Morpholino knockdown of peroxidasin in zebrafish revealed that the cross-link is essential for organogenesis. Collectively, our findings establish that the triad a collagen IV scaffold with sulfilimine cross-links, peroxidasin, and hypohalous acids-is a primordial innovation of the ECM essential for organogenesis and tissue evolution. PMID- 24344312 TI - Quantum mechanical calculations suggest that lytic polysaccharide monooxygenases use a copper-oxyl, oxygen-rebound mechanism. AB - Lytic polysaccharide monooxygenases (LPMOs) exhibit a mononuclear copper containing active site and use dioxygen and a reducing agent to oxidatively cleave glycosidic linkages in polysaccharides. LPMOs represent a unique paradigm in carbohydrate turnover and exhibit synergy with hydrolytic enzymes in biomass depolymerization. To date, several features of copper binding to LPMOs have been elucidated, but the identity of the reactive oxygen species and the key steps in the oxidative mechanism have not been elucidated. Here, density functional theory calculations are used with an enzyme active site model to identify the reactive oxygen species and compare two hypothesized reaction pathways in LPMOs for hydrogen abstraction and polysaccharide hydroxylation; namely, a mechanism that employs a eta(1)-superoxo intermediate, which abstracts a substrate hydrogen and a hydroperoxo species is responsible for substrate hydroxylation, and a mechanism wherein a copper-oxyl radical abstracts a hydrogen and subsequently hydroxylates the substrate via an oxygen-rebound mechanism. The results predict that oxygen binds end-on (eta(1)) to copper, and that a copper-oxyl-mediated, oxygen-rebound mechanism is energetically preferred. The N-terminal histidine methylation is also examined, which is thought to modify the structure and reactivity of the enzyme. Density functional theory calculations suggest that this posttranslational modification has only a minor effect on the LPMO active site structure or reactivity for the examined steps. Overall, this study suggests the steps in the LPMO mechanism for oxidative cleavage of glycosidic bonds. PMID- 24344313 TI - Livestock and global change: emerging issues for sustainable food systems. PMID- 24344314 TI - Assessing agricultural risks of climate change in the 21st century in a global gridded crop model intercomparison. AB - Here we present the results from an intercomparison of multiple global gridded crop models (GGCMs) within the framework of the Agricultural Model Intercomparison and Improvement Project and the Inter-Sectoral Impacts Model Intercomparison Project. Results indicate strong negative effects of climate change, especially at higher levels of warming and at low latitudes; models that include explicit nitrogen stress project more severe impacts. Across seven GGCMs, five global climate models, and four representative concentration pathways, model agreement on direction of yield changes is found in many major agricultural regions at both low and high latitudes; however, reducing uncertainty in sign of response in mid-latitude regions remains a challenge. Uncertainties related to the representation of carbon dioxide, nitrogen, and high temperature effects demonstrated here show that further research is urgently needed to better understand effects of climate change on agricultural production and to devise targeted adaptation strategies. PMID- 24344315 TI - Structure of Est3 reveals a bimodal surface with differential roles in telomere replication. AB - Telomerase is essential for continuous cellular proliferation. Substantial insights have come from studies of budding yeast telomerase, which consists of a catalytic core in association with two regulatory proteins, ever shorter telomeres 1 and 3 (Est1 and Est3). We report here a high-resolution structure of the Est3 telomerase subunit determined using a recently developed strategy that combines minimal NMR experimental data with Rosetta de novo structure prediction algorithms. Est3 adopts an overall protein fold which is structurally similar to that adopted by the shelterin component TPP1. However, the characteristics of the surface of the experimentally determined Est3 structure are substantially different from those predicted by prior homology-based models of Est3. Structure guided mutagenesis of the complete surface of the Est3 protein reveals two adjacent patches on a noncanonical face of the protein that differentially mediate telomere function. Mapping these two patches on the Est3 structure defines a set of shared features between Est3 and HsTPP1, suggesting an analogous multifunctional surface on TPP1. PMID- 24344316 TI - The Inter-Sectoral Impact Model Intercomparison Project (ISI-MIP): project framework. AB - The Inter-Sectoral Impact Model Intercomparison Project offers a framework to compare climate impact projections in different sectors and at different scales. Consistent climate and socio-economic input data provide the basis for a cross sectoral integration of impact projections. The project is designed to enable quantitative synthesis of climate change impacts at different levels of global warming. This report briefly outlines the objectives and framework of the first, fast-tracked phase of Inter-Sectoral Impact Model Intercomparison Project, based on global impact models, and provides an overview of the participating models, input data, and scenario set-up. PMID- 24344317 TI - Algorithmic framework for X-ray nanocrystallographic reconstruction in the presence of the indexing ambiguity. AB - X-ray nanocrystallography allows the structure of a macromolecule to be determined from a large ensemble of nanocrystals. However, several parameters, including crystal sizes, orientations, and incident photon flux densities, are initially unknown and images are highly corrupted with noise. Autoindexing techniques, commonly used in conventional crystallography, can determine orientations using Bragg peak patterns, but only up to crystal lattice symmetry. This limitation results in an ambiguity in the orientations, known as the indexing ambiguity, when the diffraction pattern displays less symmetry than the lattice and leads to data that appear twinned if left unresolved. Furthermore, missing phase information must be recovered to determine the imaged object's structure. We present an algorithmic framework to determine crystal size, incident photon flux density, and orientation in the presence of the indexing ambiguity. We show that phase information can be computed from nanocrystallographic diffraction using an iterative phasing algorithm, without extra experimental requirements, atomicity assumptions, or knowledge of similar structures required by current phasing methods. The feasibility of this approach is tested on simulated data with parameters and noise levels common in current experiments. PMID- 24344318 TI - House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defense against allergens and virus infection. AB - Exposure to dogs in early infancy has been shown to reduce the risk of childhood allergic disease development, and dog ownership is associated with a distinct house dust microbial exposure. Here, we demonstrate, using murine models, that exposure of mice to dog-associated house dust protects against ovalbumin or cockroach allergen-mediated airway pathology. Protected animals exhibited significant reduction in the total number of airway T cells, down-regulation of Th2-related airway responses, as well as mucin secretion. Following dog associated dust exposure, the cecal microbiome of protected animals was extensively restructured with significant enrichment of, amongst others, Lactobacillus johnsonii. Supplementation of wild-type animals with L. johnsonii protected them against both airway allergen challenge or infection with respiratory syncytial virus. L. johnsonii-mediated protection was associated with significant reductions in the total number and proportion of activated CD11c(+)/CD11b(+) and CD11c(+)/CD8(+) cells, as well as significantly reduced airway Th2 cytokine expression. Our results reveal that exposure to dog associated household dust results in protection against airway allergen challenge and a distinct gastrointestinal microbiome composition. Moreover, the study identifies L. johnsonii as a pivotal species within the gastrointestinal tract capable of influencing adaptive immunity at remote mucosal surfaces in a manner that is protective against a variety of respiratory insults. PMID- 24344319 TI - Type I interferon blockade in systemic lupus erythematosus: where do we stand? AB - SLE is an autoimmune condition characterized by loss of tolerance to chromatin constituents and the production of ANAs. The majority of SLE patients display spontaneous expression of type I IFN-induced genes in circulating mononuclear cells and peripheral tissues, and type I IFNs play a role in the pathogenesis of the disease via the sustained activation of autoreactive T and B cells necessary for the production of pathogenic autoantibodies. Several IFN-blocking strategies are currently being evaluated in clinical trials: monoclonal antibodies directed against IFN-alpha and type I IFN-alpha receptor (IFNAR), as well as active immunization against IFN-alpha. This review describes the rationale behind these trials and the results obtained, and discusses the perspectives for further development of these drugs. PMID- 24344320 TI - Identification of expressed and conserved human noncoding RNAs. AB - The past decade has shown mammalian genomes to be pervasively transcribed and identified thousands of noncoding (nc) transcripts. It is currently unclear to what extent these transcripts are of functional importance, as experimental functional evidence exists for only a small fraction. Here, we characterize the expression and evolutionary conservation properties of 12,115 known and novel nc transcripts, including structural RNAs, long nc RNAs (lncRNAs), antisense RNAs, EvoFold predictions, ultraconserved elements, and expressed nc regions. Expression levels are evaluated across 12 human tissues using a custom-designed microarray, supplemented with RNAseq. Conservation levels are evaluated at both the base level and at the syntenic level. We combine these measures with epigenetic mark annotations to identify subsets of novel nc transcripts that show characteristics similar to known functional ncRNAs. Few novel nc transcripts show both high expression and conservation levels. However, overall, we observe a positive correlation between expression and both conservation and epigenetic annotations, suggesting that a subset of the expressed transcripts are under purifying selection and likely functional. The identified subsets of expressed and conserved novel nc transcripts may form the basis for further functional characterization. PMID- 24344321 TI - Trans-splicing with the group I intron ribozyme from Azoarcus. AB - Group I introns are ribozymes (catalytic RNAs) that excise themselves from RNA primary transcripts by catalyzing two successive transesterification reactions. These cis-splicing ribozymes can be converted into trans-splicing ribozymes, which can modify the sequence of a separate substrate RNA, both in vitro and in vivo. Previous work on trans-splicing ribozymes has mostly focused on the 16S rRNA group I intron ribozyme from Tetrahymena thermophila. Here, we test the trans-splicing potential of the tRNA(Ile) group I intron ribozyme from the bacterium Azoarcus. This ribozyme is only half the size of the Tetrahymena ribozyme and folds faster into its active conformation in vitro. Our results showed that in vitro, the Azoarcus and Tetrahymena ribozymes favored the same set of splice sites on a substrate RNA. Both ribozymes showed the same trans-splicing efficiency when containing their individually optimized 5' terminus. In contrast to the previously optimized 5'-terminal design of the Tetrahymena ribozyme, the Azoarcus ribozyme was most efficient with a trans-splicing design that resembled the secondary structure context of the natural cis-splicing Azoarcus ribozyme, which includes base-pairing between the substrate 5' portion and the ribozyme 3' exon. These results suggested preferred trans-splicing interactions for the Azoarcus ribozyme under near-physiological in vitro conditions. Despite the high activity in vitro, however, the splicing efficiency of the Azoarcus ribozyme in Escherichia coli cells was significantly below that of the Tetrahymena ribozyme. PMID- 24344323 TI - Atrial flutter with 1 : 1 atrioventricular conduction after administration of vernakalant for atrial fibrillation. PMID- 24344322 TI - Identification and codon reading properties of 5-cyanomethyl uridine, a new modified nucleoside found in the anticodon wobble position of mutant haloarchaeal isoleucine tRNAs. AB - Most archaea and bacteria use a modified C in the anticodon wobble position of isoleucine tRNA to base pair with A but not with G of the mRNA. This allows the tRNA to read the isoleucine codon AUA without also reading the methionine codon AUG. To understand why a modified C, and not U or modified U, is used to base pair with A, we mutated the C34 in the anticodon of Haloarcula marismortui isoleucine tRNA (tRNA2(Ile)) to U, expressed the mutant tRNA in Haloferax volcanii, and purified and analyzed the tRNA. Ribosome binding experiments show that although the wild-type tRNA2(Ile) binds exclusively to the isoleucine codon AUA, the mutant tRNA binds not only to AUA but also to AUU, another isoleucine codon, and to AUG, a methionine codon. The G34 to U mutant in the anticodon of another H. marismortui isoleucine tRNA species showed similar codon binding properties. Binding of the mutant tRNA to AUG could lead to misreading of the AUG codon and insertion of isoleucine in place of methionine. This result would explain why most archaea and bacteria do not normally use U or a modified U in the anticodon wobble position of isoleucine tRNA for reading the codon AUA. Biochemical and mass spectrometric analyses of the mutant tRNAs have led to the discovery of a new modified nucleoside, 5-cyanomethyl U in the anticodon wobble position of the mutant tRNAs. 5-Cyanomethyl U is present in total tRNAs from euryarchaea but not in crenarchaea, eubacteria, or eukaryotes. PMID- 24344324 TI - Giant coronary arteriovenous fistula between left superior pulmonary vein and left atrial appendage. PMID- 24344325 TI - Remote monitoring of cardiac implantable electronic devices in Europe: results of the European Heart Rhythm Association survey. AB - The aim of this European Heart Rhythm Association survey was to provide an insight into the current use of remote monitoring for cardiac implantable electronic devices in Europe. The following topics were explored: use of remote monitoring, infrastructure and organization, patient selection and benefits. Centres using remote monitoring reported performing face-to-face visits less frequently. In many centres (56.9%), a nurse reviews all the data and forwards them to the responsible physician. The majority of the centres (91.4%) stated that remote monitoring is best used in patients with implantable cardioverter defibrillators and those live far from the hospital (76.6% top benefit). Supraventricular and ventricular arrhythmias were reported to be the major events detected earlier by remote monitoring. Remote monitoring will have a significant impact on device management. PMID- 24344326 TI - Should catheter atrial fibrillation ablation be considered as a 'high bleeding risk' intervention? PMID- 24344327 TI - Author reply: To PMID 23625942. PMID- 24344328 TI - Implementation of smoking ban: a survey in a public hospital setting. AB - Smoking in hospitals is banned in most of European countries; nevertheless, implementing a total smoking ban is particularly difficult and policy breaches are frequent. Aim of our study was to monitor the compliance with the smoke-free policy within a hospital district by measuring particulate matters (PM2.5). We designed an observational study and identified six sensitive locations within the hospitals: surgical units, administrative offices, hall, outdoor main entrances and as controls an outdoor and an indoor area. To rule out potential confounders we included in the evaluation the roadways surrounding the hospital district. PM2.5 median concentrations observed in outdoor main entrances and in hall were significantly higher (16.4 and 13.4 ug m(-3)), as compared with the other settings (P < 0.0001). This data warrant an implementation of current policies to protect patients, visitors and employees from passive second-hand smoke leading to a smoking prohibition in any hospital surroundings. PMID- 24344329 TI - Sublytic C5b-9 induces IL-6 and TGF-beta1 production by glomerular mesangial cells in rat Thy-1 nephritis through p300-mediated C/EBPbeta acetylation. AB - CCAAT/enhancer-binding protein (C/EBPbeta)-enhanced IL-6 and TGF-beta1 promoter activity and p300-mediated C/EBPbeta acetylation were involved in up-regulation of IL-6 and TGF-beta1 expression in GMCs attacked by sublytic C5b-9. In detail, the elements of C/EBPbeta binding to rat IL-6 and TGF-beta1 promoter and 3 acetylated sites of rat C/EBPbeta protein were first revealed. Furthermore, silencing the p300 or C/EBPbeta gene in rat kidney significantly reduced the production of IL-6 and TGF-beta1 and renal lesions in Thy-1N rats. Together, these data indicate that the mechanism of IL-6 and TGF-beta1 production in renal tissue of Thy-1N rats is associated with sublytic C5b-9 up-regulated p300 and p300-mediated C/EBPbeta acetylation as well as C/EBPbeta-activated IL-6 and TGF beta1 genes. PMID- 24344330 TI - Altered regulation of energy homeostasis in older rats in response to thyroid hormone administration. AB - Hyperthyroidism causes increased energy intake and expenditure, although anorexia and higher weight loss have been reported in elderly individuals with hyperthyroidism. To determine the effect of age on energy homeostasis in response to experimental hyperthyroidism, we administered 200 MUg tri-iodothyronine (T3) in 7- and 27-mo-old rats for 14 d. T3 increased energy expenditure (EE) in both the young and the old rats, although the old rats lost more weight (147 g) than the young rats (58 g) because of the discordant effect of T3 on food intake, with a 40% increase in the young rats, but a 40% decrease in the old ones. The increased food intake in the young rats corresponded with a T3-mediated increase in the appetite-regulating proteins agouti-related peptide, neuropeptide Y, and uncoupling protein 2 in the hypothalamus, but no increase occurred in the old rats. Evidence of mitochondrial biogenesis in response to T3 was similar in the soleus muscle and heart of the young and old animals, but less consistent in old plantaris muscle and liver. Despite the comparable increase in EE, T3's effect on mitochondrial function was modulated by age in a tissue-specific manner. We conclude that older rats lack compensatory mechanisms to increase caloric intake in response to a T3-induced increase in EE, demonstrating a detrimental effect of age on energy homeostasis. PMID- 24344331 TI - Protective role of RAD50 on chromatin bridges during abnormal cytokinesis. AB - Faithful chromosome segregation is required for preserving genomic integrity. Failure of this process may entail chromatin bridges preventing normal cytokinesis. To test whether RAD50, a protein normally involved in DNA double strand break repair, is involved in abnormal cytokinesis and formation of chromatin bridges, we used immunocytochemical and protein interaction assays. RAD50 localizes to chromatin bridges during aberrant cytokinesis and subsequent stages of the cell cycle, either decorating the entire bridge or focally accumulating at the midbody zone. Ionizing radiation led to an ~4-fold increase in the rate of chromatin bridges in an ataxia telangiectatica mutated (ATM) dependent manner in human RAD50-proficient fibroblasts but not in RAD50-deficient cells. Cells with a RAD50-positive chromatin bridge were able to continue cell cycling and to progress through S phase (44%), whereas RAD50 knockdown caused a deficiency in chromatin bridges as well as an ~4-fold prolonged duration of mitosis. RAD50 colocalized and directly interacted with Aurora B kinase and phospho-histone H3, and Aurora B kinase inhibition led to a deficiency in RAD50 positive bridges. Based on these observations, we propose that RAD50 is a crucial factor for the stabilization and shielding of chromatin bridges. Our study provides evidence for a hitherto unknown role of RAD50 in abnormal cytokinesis. PMID- 24344332 TI - Teneurin-4 promotes cellular protrusion formation and neurite outgrowth through focal adhesion kinase signaling. AB - Teneurin-4 (Ten-4), a transmembrane protein, is highly expressed in the central nervous system; however, its cellular and molecular function in neuronal differentiation remains unknown. In this study, we aimed to elucidate the function of Ten-4 in neurite outgrowth. Ten-4 expression was induced during neurite outgrowth of the neuroblastoma cell line Neuro-2a. Ten-4 protein was localized at the neurite growth cones. Knockdown of Ten-4 expression in Neuro-2a cells decreased the formation of the filopodia-like protrusions and the length of individual neurites. Conversely, overexpression of Ten-4 promoted filopodia-like protrusion formation. In addition, knockdown and overexpression of Ten-4 reduced and elevated the activation of focal adhesion kinase (FAK) and Rho-family small GTPases, Cdc42 and Rac1, key molecules for the membranous protrusion formation downstream of FAK, respectively. Inhibition of the activation of FAK and neural Wiskott-Aldrich syndrome protein (N-WASP), which is a downstream regulator of FAK and Cdc42, blocked protrusion formation by Ten-4 overexpression. Further, Ten-4 colocalized with phosphorylated FAK in the filopodia-like protrusion regions. Together, our findings show that Ten-4 is a novel positive regulator of cellular protrusion formation and neurite outgrowth through the FAK signaling pathway. PMID- 24344334 TI - Identification and characterization of Eci3, a murine kidney-specific Delta3,Delta2-enoyl-CoA isomerase. AB - Oxidation of unsaturated fatty acids requires the action of auxiliary enzymes, such as Delta(3),Delta(2)-enoyl-CoA isomerases. Here we describe a detailed biochemical, molecular, histological, and evolutionary characterization of Eci3, the fourth member of the mammalian enoyl-CoA isomerase family. Eci3 specifically evolved in rodents after gene duplication of Eci2. Eci3 is with 79% identity homologous to Eci2 and contains a peroxisomal targeting signal type 1. Subcellular fractionation of mouse kidney and immunofluorescence studies revealed a specific peroxisomal localization for Eci3. Expression studies showed that mouse Eci3 is almost exclusively expressed in kidney. By using immunohistochemistry, we found that Eci3 is not only expressed in cells of the proximal tubule, but also in a subset of cells in the tubulointerstitium and the glomerulus. In vitro, Eci3 catalyzed the isomerization of trans-3-nonenoyl-CoA to trans-2-nonenoyl-CoA equally efficient as Eci2, suggesting a role in oxidation of unsaturated fatty acids. However, in contrast to Eci2, in silico gene coexpression and enrichment analysis for Eci3 in kidney did not yield carboxylic acid metabolism, but diverse biological functions, such as ion transport (P=7.1E 3) and tissue morphogenesis (P=1.0E-3). Thus, Eci3 picked up a novel and unexpected role in kidney function during rodent evolution. PMID- 24344335 TI - Remarks on the boundary set of spectral equipartitions. AB - Given a bounded open set in R2 (or in a Riemannian manifold), and a partition of Omega by k open sets omegaj, we consider the quantity maxj lambda(omegaj), where lambda(omegaj) is the ground state energy of the Dirichlet realization of the Laplacian in omegaj. We denote by Lk(Omega) the infimum of maxj lambda(omega) over all k-partitions. A minimal k-partition is a partition that realizes the infimum. Although the analysis of minimal k-partitions is rather standard when k=2 (we find the nodal domains of a second eigenfunction), the analysis for higher values of k becomes non-trivial and quite interesting. Minimal partitions are in particular spectral equipartitions, i.e. the ground state energies lambda(omegaj) are all equal. The purpose of this paper is to revisit various properties of nodal sets, and to explore if they are also true for minimal partitions, or more generally for spectral equipartitions. We prove a lower bound for the length of the boundary set of a partition in the two-dimensional situation. We consider estimates involving the cardinality of the partition. PMID- 24344333 TI - ApoER2 processing by presenilin-1 modulates reelin expression. AB - The reelin signaling protein and its downstream components have been associated with synaptic plasticity and neurotransmission. The reelin signaling pathway begins with the binding of reelin to the transmembrane lipoprotein receptor apolipoprotein E receptor 2 (ApoER2), which in turns induces the sequential cleavage of ApoER2 by the sequential action of alpha- and gamma-secretases. Using conditional-knockout mice of the catalytic component of the gamma-secretase complex, presenilin 1 (PS1), we demonstrated increased brain ApoER2 and reelin protein and transcript levels, with no changes in the number of reelin-positive cells. Using the human SH-SY5Y neuroblastoma cell line, we showed that ApoER2 processing occurs in the presence of PS1, producing an intracellular ApoER2 C terminal fragment. In addition, the pharmacologic inhibition of gamma-secretase in SH-SY5Y cells led to increased reelin levels. Overexpression of ApoER2 decreased reelin mRNA levels in these cells. A luciferase reporter gene assay and nuclear fractionation confirmed that increased amounts of intracellular fragment of ApoER2 suppressed reelin expression at a transcriptional level. Chromatin immunoprecipitation experiments corroborated that the intracellular fragment of ApoER2 bound to the RELN promoter region. Our study suggests that PS1/gamma secretase-dependent processing of the reelin receptor ApoER2 inhibits reelin expression and may regulate its signaling. PMID- 24344336 TI - Freezing transitions and extreme values: random matrix theory, zeta (1/2 + it) and disordered landscapes. AB - We argue that the freezing transition scenario, previously conjectured to occur in the statistical mechanics of 1/f-noise random energy models, governs, after reinterpretation, the value distribution of the maximum of the modulus of the characteristic polynomials pN(theta) of large N*N random unitary (circular unitary ensemble) matrices UN; i.e. the extreme value statistics of pN(theta) when N -> infinity. In addition, we argue that it leads to multi-fractal-like behaviour in the total length MUN(x) of the intervals in which |pN(theta)|>N(x), x>0, in the same limit. We speculate that our results extend to the large values taken by the Riemann zeta function zeta(s) over stretches of the critical line s = 1/2 + it of given constant length and present the results of numerical computations of the large values of zeta(1/2 + it). Our main purpose is to draw attention to the unexpected connections between these different extreme value problems. PMID- 24344337 TI - The nodal count {0,1,2,3,...} implies the graph is a tree. AB - Sturm's oscillation theorem states that the nth eigenfunction of a Sturm Liouville operator on the interval has n-1 zeros (nodes) (Sturm 1836 J. Math. Pures Appl. 1, 106-186; 373-444). This result was generalized for all metric tree graphs (Pokorny et al. 1996 Mat. Zametki 60, 468-470 (doi:10.1007/BF02320380); Schapotschnikow 2006 Waves Random Complex Media 16, 167-178 (doi:10.1080/1745530600702535)) and an analogous theorem was proved for discrete tree graphs (Berkolaiko 2007 Commun. Math. Phys. 278, 803-819 (doi:10.1007/S00220 007-0391-3); Dhar & Ramaswamy 1985 Phys. Rev. Lett. 54, 1346-1349 (doi:10.1103/PhysRevLett.54.1346); Fiedler 1975 Czechoslovak Math. J. 25, 607 618). We prove the converse theorems for both discrete and metric graphs. Namely if for all n, the nth eigenfunction of the graph has n-1 zeros, then the graph is a tree. Our proofs use a recently obtained connection between the graph's nodal count and the magnetic stability of its eigenvalues (Berkolaiko 2013 Anal. PDE 6, 1213-1233 (doi:10.2140/apde.2013.6.1213); Berkolaiko & Weyand 2014 Phil. Trans. R. Soc. A 372, 20120522 (doi:10.1098/rsta.2012.0522); Colin de Verdiere 2013 Anal. PDE 6, 1235-1242 (doi:10.2140/apde.2013.6.1235)). In the course of the proof, we show that it is not possible for all (or even almost all, in the metric case) the eigenvalues to exhibit a diamagnetic behaviour. In addition, we develop a notion of 'discretized' versions of a metric graph and prove that their nodal counts are related to those of the metric graph. PMID- 24344338 TI - Neumann nodal domains. AB - As an alternative to nodal domains in the usual sense, we propose a partition of the domain of a real-valued eigenfunction in R2 by trajectories of the gradient, linking saddle points to extrema. Its most elementary properties are listed and exemplified. The main point is that the problem of avoided crossings is largely eliminated. PMID- 24344339 TI - Spectral statistics of permutation matrices. AB - We compute the mean two-point spectral form factor and the spectral number variance for permutation matrices of large order. The two-point correlation function is expressed in terms of generalized divisor functions, which are frequently discussed in number theory. Using classical results from number theory and casting them in a convenient form, we derive expressions which include the leading and next to leading terms in the asymptotic expansion, thus providing a new point of view on the subject, and improving some known results. PMID- 24344340 TI - Quantum chaos for point scatterers on flat tori. AB - This survey article deals with a delta potential--also known as a point scatterer -on flat two- and three-dimensional tori. We introduce the main conjectures regarding the spectral and wave function statistics of this model in the so called weak and strong coupling regimes. We report on recent progress as well as a number of open problems in this field. PMID- 24344341 TI - Quantum ergodicity of random orthonormal bases of spaces of high dimension. AB - We consider a sequence HN of finite-dimensional Hilbert spaces of dimensions dN > infinity. Motivating examples are eigenspaces, or spaces of quasi-modes, for a Laplace or Schrodinger operator on a compact Riemannian manifold. The set of Hermitian orthonormal bases of HN may be identified with U(dN), and a random orthonormal basis of is a choice of a random sequence UN?U(dN) from the product of normalized Haar measures. We prove that if dN -> infinity and if(1/dN)TrA|HN tends to a unique limit state omega(A), then almost surely an orthonormal basis is quantum ergodic with limit state omega(A). This generalizes an earlier result of the author in the case where HN is the space of spherical harmonics on S(2). In particular, it holds on the flat torus Rd/Zd if d>=5 and shows that a highly localized orthonormal basis can be synthesized from quantum ergodic ones and vice versa in relatively small dimensions. PMID- 24344342 TI - Calculation of multi-fractal dimensions in spin chains. AB - It was demonstrated in Atas & Bogomolny (2012 Phys. Rev. E 86, 021104) that the ground-state wave functions for a large variety of one-dimensional spin- models are multi-fractals in the natural spin-z basis. We present here the details of analytical derivations and numerical confirmations of this statement. PMID- 24344343 TI - Remarks on nodal volume statistics for regular and chaotic wave functions in various dimensions. AB - We discuss the statistical properties of the volume of the nodal set of wave functions for two paradigmatic model systems which we consider in arbitrary dimension s>=2: the cuboid as a paradigm for a regular shape with separable wave functions and planar random waves as an established model for chaotic wave functions in irregular shapes. We give explicit results for the mean and variance of the nodal volume in the arbitrary dimension, and for their limiting distribution. For the mean nodal volume, we calculate the effect of the boundary of the cuboid where Dirichlet boundary conditions reduce the nodal volume compared with the bulk. Boundary effects for chaotic wave functions are calculated using random waves which satisfy a Dirichlet boundary condition on a hyperplane. We put forward several conjectures on what properties of cuboids generalize to general regular shapes with separable wave functions and what properties of random waves can be expected for general irregular shapes. These universal features clearly distinguish between the two cases. PMID- 24344344 TI - Stability of eigenvalues of quantum graphs with respect to magnetic perturbation and the nodal count of the eigenfunctions. AB - We prove an analogue of the magnetic nodal theorem on quantum graphs: the number of zeros of the nth eigenfunction of the Schrodinger operator on a quantum graph is related to the stability of the nth eigenvalue of the perturbation of the operator by magnetic potential. More precisely, we consider the nth eigenvalue as a function of the magnetic perturbation and show that its Morse index at zero magnetic field is equal to phi - (n-1). PMID- 24344345 TI - Nonlinear Schrodinger equation on graphs: recent results and open problems. AB - In this paper, an introduction to the new subject of nonlinear dispersive Hamiltonian equations on graphs is given. The focus is on recently established properties of solutions in the case of the nonlinear Schrodinger (NLS) equation. Special consideration is given to the existence and behaviour of solitary solutions. Two subjects are discussed in some detail concerning the NLS equation on a star graph: the standing waves of the NLS equation on a graph with a delta interaction at the vertex, and the scattering of fast solitons through a Y junction in the cubic case. The emphasis is on a description of concepts and results and on physical context, without reporting detailed proofs; some perspectives and more ambitious open problems are discussed. PMID- 24344346 TI - Statistics of Gaussian packets on metric and decorated graphs. AB - We study a semiclassical asymptotics of the Cauchy problem for a time-dependent Schrodinger equation on metric and decorated graphs with a localized initial function. A decorated graph is a topological space obtained from a graph via replacing vertices with smooth Riemannian manifolds. The main term of an asymptotic solution at an arbitrary finite time is a sum of Gaussian packets and generalized Gaussian packets (localized near a certain set of codimension one). We study the number of packets as time tends to infinity. We prove that under certain assumptions this number grows in time as a polynomial and packets fill the graph uniformly. We discuss a simple example of the opposite situation: in this case, a numerical experiment shows a subexponential growth. PMID- 24344347 TI - Complex patterns in wave functions: drums, graphs and disorder. PMID- 24344349 TI - Review of neutron calibration facilities and monitoring techniques: new needs for emerging fields. AB - Neutron calibration facilities and monitoring techniques have been developed since the middle of the 20th century to support research and nuclear power energy development. The technical areas needing reference neutron fields and related instruments were mainly cross section measurements, radiation protection, dosimetry and fission reactors, with energy ranging from a few millielectronvolts to about 20 MeV. The reference neutron fields and calibration techniques developed for these purposes will be presented in this paper. However, in recent years, emerging fields have brought new needs for calibration facilities and monitoring techniques. These new challenges for neutron metrology will be exposed with their technical difficulties. PMID- 24344348 TI - Measurement of dose equivalent distribution on-board commercial jet aircraft. AB - The annual effective doses of aircrew members often exceed the limit of 1 mSv for the public due to the increased level of cosmic radiation at the flight altitudes, and thus, it is recommended to monitor them [International Commission on Radiation Protection. 1990 Recommendations of the International Commission on Radiological Protection. ICRP Publication 60. Ann. ICRP 21: (1-3), (1991)]. According to the Monte Carlo simulations [Battistoni, G., Ferrari, A., Pelliccioni, M. and Villari, R. Evaluation of the doses to aircrew members taking into consideration the aircraft structures. Adv. Space Res. 36: , 1645-1652 (2005) and Ferrari, A., Pelliccioni, M. and Villari, R. Evaluation of the influence of aircraft shielding on the aircrew exposure through an aircraft mathematical model. Radiat. Prot. Dosim. 108: (2), 91-105 (2004)], the ambient dose equivalent rate H*(10) depends on the location in the aircraft. The aim of this article is to experimentally evaluate H*(10) on-board selected types of aircraft. The authors found that H*(10) values are higher in the front and the back of the cabin and lesser in the middle of the cabin. Moreover, total dosimetry characteristics obtained in this way are in a reasonable agreement with other data, in particular with the above-mentioned simulations. PMID- 24344350 TI - Measurement of the 250Cf component in a 252Cf neutron source at KRISS. AB - Neutron emission rate measurements have been carried out at the Korea Research Institute of Standards and Science using a manganese sulphate bath system for (252)Cf and (241)Am-Be sources since 2004. The relative measurement method was chosen in 2012, and the neutron emission rates agreed with those by the absolute measurement method within uncertainties. The neutron emission rate of an old (252)Cf source has been measured three times: in 2004, 2009 and 2012. The (250)Cf component was fitted to a double-exponential function of (252)Cf+(250)Cf, and the ratio of the (250)Cf component to the (252)Cf component was estimated to be 7.8 % in 2004 and 46.8 % in 2012. Underestimation of the neutron emission rates of old (252)Cf sources can be corrected if the neutron emission rate of the (250)Cf component is taken into account. PMID- 24344351 TI - Air shower simulation for WASAVIES: warning system for aviation exposure to solar energetic particles. AB - WASAVIES, a warning system for aviation exposure to solar energetic particles (SEPs), is under development by collaboration between several institutes in Japan and the USA. It is designed to deterministically forecast the SEP fluxes incident on the atmosphere within 6 h after flare onset using the latest space weather research. To immediately estimate the aircrew doses from the obtained SEP fluxes, the response functions of the particle fluxes generated by the incidence of monoenergetic protons into the atmosphere were developed by performing air shower simulations using the Particle and Heavy Ion Transport code system. The accuracy of the simulation was well verified by calculating the increase count rates of a neutron monitor during a ground-level enhancement, combining the response function with the SEP fluxes measured by the PAMELA spectrometer. The response function will be implemented in WASAVIES and used to protect aircrews from additional SEP exposure. PMID- 24344353 TI - [Search for synapses-forming mechanism for the discovery of therapeutic targets]. PMID- 24344352 TI - Structural and spectral characterization of novel non-centrosymmetric 2,4 dintrobenzene derivative. AB - A novel organic compound 9-(2,4-dinitrophenyloxy)-3,3,8-trimethyl-1,5-dihydro [1,3]dioxepino[5,6-c]pyridine (DNPAP) has been synthesized and a nonlinear optical (NLO) crystal has been grown by slow evaporation method. Compound was subjected to different characterization analyses in order to find out its suitability for optoelectronic applications. Single crystal and powder X-ray diffraction analyses show that DNPAP crystallizes in the orthorhombic space group Pca21. The range of optical absorption was ascertained by recording UV-Vis spectrum. The second harmonic generation (SHG) test has shown that DNPAP possesses 6.4-times higher NLO efficiency compared to KDP. PMID- 24344354 TI - Retraction notice to "UHRF2, another E3 ubiquitin ligase for p53" [Biochem. Biophys. Res. Commun. 425 (2012) 908-911]. PMID- 24344355 TI - Retracted: Sphingosine kinase-1/sphingosine-1-phosphate receptor type 1 signalling axis is induced by transforming growth factor-beta1 and stimulates cell migration in RAW264.7 [Biochem. Biophys. Res. Commun. 426 (2012) 415-420]. PMID- 24344356 TI - Genetic engineering of cell lines using lentiviral vectors to achieve antibody secretion following encapsulated implantation. AB - The controlled delivery of antibodies by immunoisolated bioimplants containing genetically engineered cells is an attractive and safe approach for chronic treatments. To reach therapeutic antibody levels there is a need to generate renewable cell lines, which can long-term survive in macroencapsulation devices while maintaining high antibody specific productivity. Here we have developed a dual lentiviral vector strategy for the genetic engineering of cell lines compatible with macroencapsulation, using separate vectors encoding IgG light and heavy chains. We show that IgG expression level can be maximized as a function of vector dose and transgene ratio. This approach allows for the generation of stable populations of IgG-expressing C2C12 mouse myoblasts, and for the subsequent isolation of clones stably secreting high IgG levels. Moreover, we demonstrate that cell transduction using this lentiviral system leads to the production of a functional glycosylated antibody by myogenic cells. Subsequent implantation of antibody-secreting cells in a high-capacity macroencapsulation device enables continuous delivery of recombinant antibodies in the mouse subcutaneous tissue, leading to substantial levels of therapeutic IgG detectable in the plasma. PMID- 24344358 TI - Dr. Henderson, et al reply. PMID- 24344359 TI - In vitro reconstruction of inflammatory reaction in human semen: effect on sperm DNA fragmentation. AB - The study was aimed at evaluating an in vitro induction of DNA damage in three sperm subpopulations exposed to selected inflammatory mediators, such as leukocytes, two combinations of pro-inflammatory cytokines (interleukin [IL]-6 + IL-8 and IL-12 + IL-18) and two bacterial strains (Escherichia coli and Bacteroides ureolyticus). Semen samples from normozoospermic volunteers were differentiated by swim-up (swim-up fraction) and Percoll gradient procedures (90% and 47% Percoll fractions). Leukocytes were isolated from the whole heparinized blood using the density gradient centrifugation technique. DNA fragmentation in sperm fractions was evaluated using flow cytometry with TUNEL labeling and Comet assay. Out of the inflammatory factors tested, bacteria were found to have a greatest toxic effect on sperm DNA, especially in fractions isolated by Percoll gradient, compared with untreated cells (P < 0.05). The results indicate that inflammatory mediators can be a direct cause of DNA fragmentation in ejaculated spermatozoa, which can ultimately lead to limited fertilizing abilities of the germ cells. In contrast to the swim-up technique, the selection of spermatozoa by gradient procedures increases the vulnerability of mature spermatozoa to the harmful effects of infectious agents on DNA integrity. This observation may have some meaning for recommendations concerning laboratory techniques used in assisted reproductive therapy. PMID- 24344357 TI - The genotype-dependent influence of functionalized multiwalled carbon nanotubes on fetal development. AB - In many cases cancer is caused by gene deficiency that is being passed along from generation to generation. Soluble carbon nanotubes (CNTs) have shown promising applications in the diagnosis and therapy of cancer, however, the potential relationship between cancer-prone individuals and response to CNT exposure as a prerequisite for development of personalized nanomedicine, is still poorly understood. Here we report that intravenous injections of multi-walled carbon nanotubes into p53 (a well-known cancer-susceptible gene) heterozygous pregnant mice can induce p53- dependent responses in fetal development. Larger sized multi walled carbon nanotubes moved across the blood-placenta barrier (BPB), restricted the development of fetuses, and induced brain deformity, whereas single-walled and smaller sized multi-walled carbon nanotubes showed no or less fetotoxicity. A molecular mechanism study found that multi-walled carbon nanotubes directly triggered p53-dependent apoptosis and cell cycle arrest in response to DNA damage. Based on the molecular mechanism, we also incorporated N-acetylcysteine (NAC), an FDA approved antioxidant, to prevent CNTs induced nuclear DNA damage and reduce brain development abnormalities. Our findings suggest that CNTs might have genetic background-dependent toxic effect on the normal development of the embryo, and provide new insights into protection against nanoparticle-induced toxicity in potential clinical applications. PMID- 24344360 TI - Tocopherol from seeds of Cucurbita pepo against diabetes: validation by in vivo experiments supported by computational docking. AB - BACKGROUND/PURPOSE: Tocopherol from raw pumpkin seeds has been reported to be effective in the alleviation of diabetes through its antioxidant activities. This study evaluates the antidiabetic activities of the tocopherol fraction of raw seeds of Cucurbita pepo L. (CPSE) in a diabetic rat model. In addition, the putative action mechanisms of its botanicals were computationally investigated. METHODS: Seed water activity (Aw) was assessed. Tocopherol was extracted and quantified from raw seed oil. The effect of CPSE was studied in poloxamer-407 (PX 407)-induced type 2 diabetic Wistar rats. Glycemic, insulinemic, and lipid profiles, as well as lipid peroxidation status, were evaluated. Glucagon like peptide-1 (GLP-1) content in the cecum was evaluated and histopathological analysis of the pancreas was performed. Further, HYBRID and FRED docking were performed for 10 documented CPSE botanicals, for putative action mechanisms concerning three proteins [protein-tyrosine phosphatase 1B (PTP-1B), peroxisome proliferator-activated receptor gamma (PPAR-gamma), and dipeptidyl peptidase IV (DPP-IV)] known to have diabetic therapeutic potential. RESULTS: The Aw of raw seeds was found to be 0.544 +/- 0.002. Using tocopherol standards, HPLC determination of CPSE revealed the presence of tocopherol isomers (alpha, beta, gamma, and delta). The tocopherol content was found to be 107.4 +/- 2.9 mg/100 g of CPSE. When compared to diabetic control (DC) rats, the CPSE-treated diabetic rats presented a significant amelioration of glycemia, insulinemia, and lipid dysmetabolism. A remarkable reduction in oxidative markers and improved cecal and pancreatic characteristics were also observed. Tocopherol isomers have shown a considerable interaction potential with the aforesaid proteins in docking. CONCLUSION: The results provide pharmacological evidence of CPSE as an antihyperglycemic mediated by the interaction of various botanicals with multiple targets operating in diabetes mellitus (DM). PMID- 24344361 TI - Chest X-ray quiz. PMID- 24344362 TI - Is there a relationship with coil use after coronary perforation and ventricular tachycardia? PMID- 24344363 TI - Author reply: To PMID 24088420. PMID- 24344365 TI - Author response. PMID- 24344364 TI - Speech training alters tone frequency tuning in rat primary auditory cortex. AB - Previous studies in both humans and animals have documented improved performance following discrimination training. This enhanced performance is often associated with cortical response changes. In this study, we tested the hypothesis that long term speech training on multiple tasks can improve primary auditory cortex (A1) responses compared to rats trained on a single speech discrimination task or experimentally naive rats. Specifically, we compared the percent of A1 responding to trained sounds, the responses to both trained and untrained sounds, receptive field properties of A1 neurons, and the neural discrimination of pairs of speech sounds in speech trained and naive rats. Speech training led to accurate discrimination of consonant and vowel sounds, but did not enhance A1 response strength or the neural discrimination of these sounds. Speech training altered tone responses in rats trained on six speech discrimination tasks but not in rats trained on a single speech discrimination task. Extensive speech training resulted in broader frequency tuning, shorter onset latencies, a decreased driven response to tones, and caused a shift in the frequency map to favor tones in the range where speech sounds are the loudest. Both the number of trained tasks and the number of days of training strongly predict the percent of A1 responding to a low frequency tone. Rats trained on a single speech discrimination task performed less accurately than rats trained on multiple tasks and did not exhibit A1 response changes. Our results indicate that extensive speech training can reorganize the A1 frequency map, which may have downstream consequences on speech sound processing. PMID- 24344366 TI - The latest research advances in invasive cardiology. PMID- 24344367 TI - Summaries for patients. A home score for streptococcal pharyngitis. PMID- 24344368 TI - [Response letter]. PMID- 24344369 TI - In response. PMID- 24344370 TI - Sleep-induced hypoxaemia:remember medroxyprogesterone and acetazolamide. PMID- 24344371 TI - Sleep-induced hypoxaemia: remember medroxyprogesterone and acetazolamide. PMID- 24344372 TI - CDC resources, tools, and programs for health promotion in the worksite. PMID- 24344373 TI - The Centers for Disease Control and prevention worksite health ScoreCard. PMID- 24344374 TI - CDC-funded worksite health promotion and protection programs. PMID- 24344375 TI - Why CDC ideas pass the tests of time. PMID- 24344376 TI - Should scientists tell stories? PMID- 24344377 TI - Significance, P values and t-tests. PMID- 24344378 TI - Roadblocks to reprogramming, cleared. PMID- 24344379 TI - Finding function in the folds. PMID- 24344380 TI - Modifying chromatin to shut off enhancers. PMID- 24344381 TI - A well-preserved program. PMID- 24344382 TI - Designer binders. PMID- 24344383 TI - When rodents run the research. PMID- 24344384 TI - Single-cell epigenetics. PMID- 24344385 TI - Heart rate variability at rest and after the 6-minute walk test (6MWT) in children with cystic fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) is a multisystem disease that affects the cardiorespiratory system and the cardiac autonomic control may be altered at rest and after a submaximal exercise. OBJECTIVE: To assess the cardiac autonomic control by heart rate variability (HRV) analysis before and after a 6-minute walk test (6MWT). METHOD: Thirteen children diagnosed with Cystic Fibrosis (CFG) aged 12+/-2.7 years (FEV1/FVC: 0.83+/-0.11, FEV1: 71.4+/-21 %pred) and 12 healthy children (control group-CG) aged 11.4+/-2.4 years (FEV1/FVC: 0.91+/-0.12, FEV1: 91.6+/-17.4 %pred) were included in the study. HRV was evaluated prior to and immediately after the 6MWT and the heart rate recovery assessed on the first and second minute after test. RESULTS: Prior to exercise, CF patients presented higher values for the variables LF(nu) (53.2+/-15.0 vs. 32.8+/-7.9, p=0.0003) and LF/HF (1.25+/-0.72 vs. 0.49+/-0.18, p<0.006) as well as lower values of HF(%) (25.4+/-18.4 vs. 53+/-9.6, p=0.002) and HF(nu) (47.3+/-14.7 vs. 68.3+/-8.7, p0.001) when compared to CG. After the 6MWT, both groups demonstrated HRV recovery to baseline levels; however, the differences between CFG and CG were maintained for the variables LF(ms 2) (846.7+/-754.8 vs. 345.6+/-197.2, p=0.02); LF(%) (35.4+/-8.1 vs. 25.9+/-6.2, p=0.002); LF(nu) (60.0+/-16.3 vs. 34.9+/-8.7, p<0.0001); HF(%) (27.4+/-13.7 vs. 48.1+/-6.3, p=0.0003); HF(nu) (40.4+/-15.8 vs. 65.6+/-8.2, p=0.0003) and LF/HF (1.9+/-1.7 vs. 0.5+/-0.2, p=0.0001). CONCLUSIONS: Children with cystic fibrosis exhibited predominance of sympathetic activity at rest that persisted after the 6-minute walking test when compared to the control group. PMID- 24344386 TI - [To the Editors: Comment on Harsanyi et al., "Why is the scientometric gap widening? Deterioration of the scientific parameters of surgical specialties in Hungary"]. PMID- 24344387 TI - Alternatives to animal experimentation. PMID- 24344388 TI - Correlation between magnetic resonance imaging and clinical outcomes after knee cartilage repair: author's response. PMID- 24344389 TI - The tibial tubercle-trochlear groove distance: author's response. PMID- 24344391 TI - Shift to coordinated care. Qualifying for ACOs a tough challenge for rurals. PMID- 24344390 TI - Consolidation pace quickens. Providers ink 93 transactions in third quarter. PMID- 24344392 TI - Molecular docking: a potential tool to aid ecotoxicity testing in environmental risk assessment of pharmaceuticals. AB - A cocktail of human pharmaceuticals pollute aquatic environments and there is considerable scientific uncertainty about the effects that this may have on aquatic organisms. Human drug target proteins can be highly conserved in non target species suggesting that similar modes of action (MoA) may occur. The aim of this work was to explore whether molecular docking offers a potential tool to predict the effects of pharmaceutical compounds on non target organisms. Three highly prescribed drugs, diclofenac, ibuprofen and levonorgestrel which regularly pollute freshwater environments were used as examples. Their primary drug targets are cyclooxygenase 2 (COX2) and progesterone receptor (PR). Molecular docking experiments were performed using these drugs and their primary drug target homologues for Danio rerio, Salmo salar, Oncorhynchus mykiss, Xenopus tropicalis, Xenopus laevis and Daphnia pulex. The results show that fish and frog COX2 enzymes are likely to bind diclofenac and ibuprofen in the same way as humans but that D. pulex would not. Binding will probably lead to inhibition of COX function and reduced prostaglandin production. Levonorgestrel was found to bind in the same binding pocket of the progesterone receptor in frogs and fish as the human form. This suggests implications for the fecundity of fish and frogs which are exposed to levonorgestrel. Chronic ecotoxicological effects of these drugs reported in the literature support these findings. Molecular docking may provide a valuable tool for ecotoxicity tests by guiding selection of test species and incorporating the MoA of drugs for relevant chronic test end points in environmental risk assessments. PMID- 24344393 TI - Differential physiological, ultramorphological and metabolic responses of cotton cultivars under cadmium stress. AB - Cadmium (Cd) stress may cause serious physiological, ultramorphological and biochemical anomalies in plants. Cd-induced physiological, subcellular and metabolic alterations in two transgenic cotton cultivars (BR001, GK30) and their parent line (Coker 312) were evaluated using 10, 100 and 1000 uM Cd. Germination, fresh biomass of roots, stems and leaves were significantly inhibited at 1000 uM Cd. Root volume tolerance index significantly increased (124.16%) in Coker 312 at 1000 uM Cd. In non-Cd stressed conditions, electron micrographs showed well configured root meristem and leaf mesophyll cells. At 1000 uM Cd, greater ultramorphological alterations were observed in BR001 followed by GK30 and Coker 312. These changes were observed in nucleus, vacuoles, mitochondria and chloroplast. Dense precipitates, probably Cd, were seen in vacuoles, which were also attached to the cell walls. A considerable increase in number of nuclei, vacuoles, starch granules and plastoglobuli was observed in the electron micrographs of both roots and leaves at 1000 uM Cd. MDA contents were higher in roots of BR001 at 1000 uM Cd. Mean values of SOD activity in leaves of both BR001 and GK30 at 1000 uM Cd significantly increased as compared to the controls. POD activity in roots of BR001 and Coker 312 was greater at all Cd (10, 100, 1000 uM) levels over the control. Regarding APX, highest percent increase (71.64%) in roots of GK30 at 1000 uM Cd was found. Non-significant differences in CAT activity were observed at all levels of Cd stress in leaves of BR001 and GK30. Both transgenic cotton cultivars and their parental line invariably responded towards Cd stress. However, Coker 312 showed Cd-resistant behavior as compared to its progeny lines (BR001 and GK30). PMID- 24344394 TI - Development and application of LC-APCI-MS method for biomonitoring of animal and human exposure to imidacloprid. AB - Imidacloprid (IMI) is a relatively new neuro-active neonicotinoid insecticide and nowadays one of the largest selling insecticides worldwide. In the present study a LC-APCI-MS based method was developed and validated for the quantification of imidacloprid and its main metabolite 6-chloronicotinic acid (6- CINA) in urine and hair specimens. The method was tested in biomonitoring of intentionally exposed animals and subsequently applied for biomonitoring of Cretan urban and rural population. The developed analytical method comprises two main steps of analytes isolation from specimen (solid- liquid extraction with methanol for hair, liquid-liquid extraction with methanol for urine) and subsequent instrumental analysis by LC-APCI-MS. The developed method was applied for the monitoring of IMI and 6-ClNA in hair and urine of laboratory animals (rabbits) intentionally fed with insecticide at low or high doses (40 and 80 mg kg(-1) weight d(-1) respectively) for 24 weeks. The analytes were detected in the regularly acquired hair and urine specimens and their found levels were proportional to the feeding dose and time of exposure with the exception of slight decline of IMI levels in high dose fed rabbits after 24 weeks of feeding. This decline can be explained by the induction of IMI metabolizing enzymes by the substrate. After testing on animal models the method was applied for pilot biomonitoring of Crete urban (n = 26) and rural (n = 32) population. Rural but not urban population is exposed to IMI with 21 positive samples (65.6%) and found median concentration 0.03 ng mg(-1). Maximum concentration detected was 27 ng mg( 1) PMID- 24344395 TI - In memoriam: Joseph P. Whalen, M.D. PMID- 24344396 TI - National Society Cardiovascular Journals and the New European Society of Cardiology search engine. PMID- 24344397 TI - Clinical trials: how to get closer to the right answer with less effort. PMID- 24344398 TI - [Strategy for research development of therapeutic agents for autoimmune diseases]. PMID- 24344400 TI - Combination of strong MMP-2 and weak TIMP-2 immunostainings is a significant prognostic factor in endometrial carcinoma. AB - OBJECTIVE: The aim of this study was to evaluate the combined effects of MMP-2 and TIMP-2 protein immunoreactivities on the prognosis in endometrial carcinoma. METHODS: Paraffin-embedded tissue samples from 225 primary endometrioid adenocarcinomas and 13 histologies other than endometrioid adenocarcinoma were immunohistochemically stained for MMP-2 and TIMP-2. RESULTS: In Kaplan-Meier analysis, the 5-year cancer-specific survival rate of the endometrioid adenocarcinoma patients with negative MMP-2 and positive TIMP-2 staining was 100%, whereas only 78% of patients presenting with positive MMP-2 and negative TIMP-2 staining results were alive at that time. In Cox regression analysis, patients with positive MMP-2 and negative TIMP-2 immunostaining had a 4.7-fold relative risk of death from endometrial carcinoma compared to the group of patients with negative MMP-2 and positive or negative TIMP-2 immunoreaction. CONCLUSIONS: MMP-2 seems to be the main metalloproteinase determining the prognosis in endometrial carcinoma. Combination of strong MMP-2 and weak TIMP-2 immunostainings was the most potent prognostic marker for poor survival. PMID- 24344401 TI - Pituitary tumor-transforming gene 1 is expressed in primary ductal breast carcinoma, lymph node infiltration, and distant metastases. AB - Despite the advances that have been made in the fields of molecular and cell biology, there is still considerable debate explaining how the breast cancer cells progress through carcinogenesis and acquire their metastatic ability. The lack of preventive methods and effective therapies underlines the pressing need to identify new biomarkers that can aid early diagnosis and may be targets for effective therapeutic strategies. In this study we explore the pituitary tumor transforming gene 1 (PTTG1) expression in primary ductal breast carcinoma, lymph node infiltration, and distant metastases. Three human cell lines, 184B5 derived from normal mammary epithelium, HCC70 from a primary ductal carcinoma, and MDA-MB 361 from a breast metastasis, were used for quantifying PTTG1 mRNA expression. The PTTG1 immunohistochemical expression was carried out on specimens taken from eight patients with invasive ductal breast cancer who underwent surgical treatment and followup for five years retrospectively selected. The study demonstrated that PTTG1 is expressed gradually in primary ductal breast carcinoma, lymph node infiltration, and distant metastases. Our findings suggest that the immunohistochemical evaluation of PTTG1 expression might be a powerful biomarker of recognition and quantification of the breast cancer cells in routine pathological specimens and a potential target for developing an effective immunotherapeutic strategy for primary and metastatic breast cancer. PMID- 24344402 TI - [Meeting of the French Development Agency on healthcare financing in developing countries, Paris, May 27 and 28, 2013]. PMID- 24344399 TI - Association of obesity-mediated insulin resistance and hypothalamic volumes: possible sex differences. AB - The hypothalamus is important in hunger and metabolism. Although a lot is known about the basic role of the human hypothalamus, less is known about how the in vivo volume is affected in obesity, particularly among adolescents. Based on pediatric body mass index percentiles, 95 participants were assigned to lean or obese groups. All subjects had medical evaluations, including fasting blood tests, to assess insulin sensitivity and circulating CRP and neurotrophins (NGF and BDNF) and an MRI of the brain. Hypothalamic volumes were measured by a segmentation method combining manual and automated steps. Overall, obese participants had descriptively smaller hypothalamic volumes, although this difference did not reach statistical significance; however, among obese participants, females had significantly smaller hypothalamic volumes than their male counterparts. There was a significant interaction between insulin resistance and sex on hypothalamus volume; obese females with significant insulin resistance have smaller hypothalamic volumes than obese males. Obese adolescents had higher circulating CRP and neurotrophin levels. Furthermore, among obese females, BDNF concentrations were inversely associated with hypothalamus volumes (r = -0.48). Given this negative association between BDNF and hypothalamus volumes among obese insulin-resistant females, elevated neurotrophin levels may suggest an attempt at protective compensation. PMID- 24344403 TI - [Breast cancer screening]. PMID- 24344404 TI - [Brucellosis is endemic]. PMID- 24344405 TI - [Histoplasmosis in the forest]. PMID- 24344406 TI - [Congenital toxoplasmosis is common]. PMID- 24344407 TI - [Oral cysticercosis]. PMID- 24344408 TI - [Sharp improvement in vaccination coverage]. PMID- 24344409 TI - Reply to Jones and Crowe: Correcting mistaken views of sedimentary geology, Mn oxidation rates, and molecular clocks. PMID- 24344410 TI - Reply to Perkin et al.: Experimental observations demonstrate that ionic liquids form both bound (Stern) and diffuse electric double layers. PMID- 24344411 TI - Reply to Chawla and Seneff: Near-death electrical brain activity in humans and animals requires additional studies. PMID- 24344412 TI - [Prevention of nosocomial ventilator-associated pneumonia. The Commission for Hospital Hygiene and Infection Prevention (KRINKO) at the Robert Koch Institute]. PMID- 24344413 TI - How high can "accuracy" be for iFR (or IVUS, or SPECT, or OCT...) if using fractional flow reserve as the gold standard? PMID- 24344414 TI - Painful renal denervation=effective procedure? PMID- 24344415 TI - Starch safety in resuscitation. PMID- 24344416 TI - Starch safety in resuscitation. PMID- 24344417 TI - Starch safety in resuscitation. Parrish and Blockman respond. PMID- 24344418 TI - Poisoning and the pesticides. PMID- 24344419 TI - Prediction equations for spirometry in South Africa. PMID- 24344420 TI - Temperature regulation in emergency, surgical and critical care. PMID- 24344421 TI - HIV-prevention studies: educate smarter, boost women's earning power. PMID- 24344422 TI - Drug stock-outs: inept supply-chain management and corruption. PMID- 24344423 TI - Doctor shortages: unpacking the 'Cuban solution'. PMID- 24344424 TI - An insider view: a Cuban trainee's journey. PMID- 24344425 TI - [Reply]. PMID- 24344426 TI - [Risk factors of conversion to laparotomy during the laparoscopic cholecystectomy]. PMID- 24344427 TI - [Solid-pseudopapillary tumor of the pancreas: actual clinic-morphological and molecular aspects]. PMID- 24344428 TI - [Bleeding from the esophageal and gastric varices in patients with liver cirrhosis]. PMID- 24344429 TI - [The modern possibilities of the hepato-renal syndrome treatment]. PMID- 24344430 TI - [The risk factors of extrahepatic abdominal operations in patients with liver cirrhosis]. PMID- 24344432 TI - [Backgrounds of dentistry]. PMID- 24344431 TI - [To the 130th anniversary of birth of Yu. Yu. Dzhanelidze- the chief surgeon of the Russian Navy]. PMID- 24344433 TI - [Efficiency of cryotherapy in complex oral treatment]. PMID- 24344434 TI - [Application of cellular technology in maxillofacial surgery. Part 1]. PMID- 24344435 TI - Retraction. Factors affecting hospital readmission rates for breast cancer patients in Western Australia. Journal of Surgical Oncology, Published online January 17, 2007, DOI: 10.1002/jso.20742. PMID- 24344436 TI - [Endoscopic hemostasis in the treatment of the gastroduodenal ulcer bleeding]. PMID- 24344437 TI - [Functional disorders of the gastrointestinal motility in critically ill patients]. PMID- 24344438 TI - [Acute gastric ulcers on the background of the intestinal obstruction]. PMID- 24344439 TI - Nurse practitioner leads groundbreaking research. PMID- 24344440 TI - Menstruation celebrated by pre-colonial Maori. PMID- 24344441 TI - Leading nurses--it's a balancing act. PMID- 24344442 TI - [What helps better: intratympanic gentamicin or methylprednisolone?]. PMID- 24344443 TI - [Long term results of vocal fold medicalization]. PMID- 24344444 TI - [Hamburg Hemophilia Symposium 2012]. PMID- 24344446 TI - [Experience with rivaroxaban and dabigatran]. PMID- 24344445 TI - Recruitment update of AHEAD. AB - The multicenter prospective non-interventional AHEAD study was initiated to obtain long-term outcome data on joint health, HR-QoL, haemophilia-related co morbidities, and the effectiveness and safety of ADVATE (recombinant anti hemophilic factor VIII, plasma-free method [octocog alfa]) in routine clinical practice. The German AHEAD study arm aims to enroll up to 500 patients in up to 35 haemophilia treatment centers (HTCs); patient recruitment started in June 2010. The study arm conducted in other European countries is expected to enroll 350 patients from more than 50 HTCs; recruitment started in June 2011. In both study arms, recruitment will continue through the end of 2015, and each enrolled patient will be followed for a total of four years. PMID- 24344447 TI - Rare bleeding disorders are associated with depression and anxiety. AB - Thrombotic thrombocytopenic purpura (TTP), immune thrombocytopenia (ITP) and acquired haemophilia are very rare haemorrhagic disorders (1) associated with surgery, hospitalization (2) and death being reported (3). Despite the rapid development of interventional techniques, therapeutic options for patients with these illnesses remain limited. We suppose that depression and anxiety disorders appear more frequently than in the normal population in patients with rare haemorrhagic disorders. PMID- 24344448 TI - National data of class A, B, and C communicable diseases in August 2013 in China. PMID- 24344449 TI - Abstracts of the 42nd Annual Meeting of the Child Neurology Society. October 30 November 2, 2013. Austin, Texas, USA. PMID- 24344451 TI - Pancytopenia following vivax malaria in a CLL patient. PMID- 24344450 TI - Corrigendum to: "Publication bias and time-trend bias in meta-analysis of bicycle helmet efficacy: a re-analysis of Attewell, Glase and McFadden, 2001" [Accid. Anal. Prev. 43 (2011) 1245-1251]. AB - This paper is a corrigendum to the previously published paper: "Publication bias and time-trend bias in meta-analysis of bicycle helmet efficacy: A re-analysis of Attewell, Glase and McFadden, 2001" [Accid. Anal. Prev. (2011) 1245-1251]. This corrigendum was prepared to correct errors in data and analysis in the previously published paper. Like the previously published paper, this paper confirms that the meta-analysis of bicycle helmet efficacy reported by Attewell, Glase and McFadden (Accident Analysis and Prevention, 2001, 345-352) was influenced by publication bias and time-trend bias that was not controlled for. As a result, the analysis reported inflated estimates of the effects of bicycle helmets. This paper presents a re-analysis of the study. The re-analysis included: (1) Ensuring the inclusion of all published studies by means of continuity corrections of estimates of effect relying on zero counts; (2) detecting and adjusting for publication bias by means of the trim-and-fill method; (3) detecting and trying to account for a time-trend bias in estimates of the effects of bicycle helmets; (4) updating the study by including recently published studies evaluating the effects of bicycle helmets. The re-analysis shows smaller safety benefits associated with the use of bicycle helmets than the original study. PMID- 24344452 TI - Multiple "doughnut" granulomas in Coxiella burnetii infection (Q fever). PMID- 24344453 TI - Abstracts of the XIX National Congress of the Italian Society of Neonatology. Firenze, Italy. October 28-30, 2013. PMID- 24344454 TI - Response. PMID- 24344455 TI - Response. PMID- 24344456 TI - Response. PMID- 24344457 TI - Response. PMID- 24344458 TI - Response. PMID- 24344459 TI - [Report of the session "Mathematics and the Biology of cancer", Curie Institute, Paris, June 12, 2013]. PMID- 24344460 TI - Clinical profile and management of craniocerebral Madurella mycetoma. Author reply. PMID- 24344461 TI - Neonatal intraventricular hemorrhage. Author reply. PMID- 24344462 TI - Occipitocervical fusion. Author reply. PMID- 24344463 TI - Pediatric neurosurgery. Author reply. PMID- 24344464 TI - Response. PMID- 24344465 TI - Response. PMID- 24344467 TI - New points of entry. Stand-alone ERs offer systems path to higher volume. PMID- 24344466 TI - Providers threaten lawsuits. Advantage plans pass along 2% sequester rate cuts. PMID- 24344468 TI - How states stand to gain or lose federal funds by opting in or out of the Medicaid expansion. AB - Following the Supreme Court's decision in 2012, state officials are now deciding whether to expand their Medicaid programs under the Affordable Care Act. While the states' costs of participating in the Medicaid expansion have been at the forefront of this discussion, the expansion has much larger implications for the flow of federal funds going to the states. This issue brief examines how participating in the Medicaid expansion will affect the movement of federal funds to each state. States that choose to participate in the expansion will experience a more positive net flow of federal funds than will states that choose not to participate. In addition to providing valuable health insurance benefits to low income state residents, and steady sources of financing to state health care providers, the Medicaid expansion will be an important source of new federal funds for states. PMID- 24344469 TI - Proceedings of the 7th International Work, Global Crisis and Health Seminar, 19 23 Oct 2009, Bogota, Columbia. PMID- 24344470 TI - [Abstracts of the 76ste National Congress SIMLII, October 9-11, 2013, Messina, Italy]. PMID- 24344472 TI - [About the legal awareness surgeons]. PMID- 24344471 TI - [Abstracts of the 27th National Congress AINR. September 18-21, 2013, Coppito, Italy]. PMID- 24344473 TI - [Not Available]. PMID- 24344474 TI - [Chronic venous oedema (C3 according to CEAP): new international guidelines and consensuses]. AB - The review based on analysing the results of epidemiological studies, as well as international guidelines and consensuses published in 2011-2012 reflects the present-day data concerning prevalence, principles of diagnosis and treatment of chronic venous oedema. This is followed by determining the role of compression and drug therapy in treatment thereof from the positions of evidence-based medicine. PMID- 24344475 TI - [Review of the materials presented at the Annual Congress <>: (January 17-19, 2013, Paris, France)]. AB - The author herein gives a comprehensive review of the materials of the Annual Congress "Controversies and Updates in Vascular Surgery" held on January 17-19, 2013 in Paris, thoroughly analysing the most important reports concerning achievements and results of scientific studies in the area of modern technologies pertaining to management of aortic aneurysms, endovascular surgery of carotid and peripheral arteries, also covering various aspects of progress in diagnosis and treatment of venous pathology. PMID- 24344476 TI - [Not Available]. PMID- 24344477 TI - [Not Available]. PMID- 24344479 TI - Plane and practice parallels: our journey to AVA 2013. PMID- 24344478 TI - [Cardiovascular function in acute respiratory tract disorders. 1938]. PMID- 24344480 TI - Periphally inserted central catheters- a 'serious' complication. AB - Peripherally inserted central catheter (PICC) placement in the upper arm appears to have led to an increased incidence of the inadvertent puncture of lymph vessels, which transport lymph fluid around the body. The fluid flows from the lymph vessel in the arm, through the subcutaneous tract created by the PICC, accumulating in discharge of serous fluid at the exit site. The symptoms may be minimal or excessive and currently there are no published data or guidance as to how to manage this complication. Possible management strategies are proposed in this article. They involve the assessment of the amount and persistence of the discharge, with removal indicated when symptoms persist or when the volume is excessive. PMID- 24344481 TI - Patients initiating peritoneal dialysis started on two icodextrin exchanges daily. AB - Patients with end-stage renal disease treated with peritoneal dialysis (PD) are often put on standard one size fits all" regimens, despite having varying degrees of residual renal function (RRF). The present study reports our experience with initiation of PD using 2 icodextrin exchanges daily in patients with RRF corresponding to a weekly Kt/Vurea of at least 1.0. Peritoneal and RRF Kt/Vurea were tracked closely, and total Kt/Vurea was maintained between 1.7 and 2.0. One patient developed a rash and was changed to 3 dextrose exchanges daily. All patients were satisfied with their treatment regimen, and no other adverse events or symptoms were reported. PMID- 24344482 TI - When should icodextrin be started to improve atherosclerosis in peritoneal dialysis patients? AB - Icodextrin-based peritoneal dialysis (PD) has many advantages over glucose-based PD. The present study aimed to investigate when icodextrin should be started for better management of cardiovascular status (as defined by echocardiography findings) and residual renal function (RRF). We retrospectively analyzed 40 patients treated with continuous ambulatory PD or automated PD. The patients were divided into these groups: Group A: started icodextrin within 2 weeks after PD onset. Group B: started icodextrin 1 year after PD onset. Group C: started icodextrin 2 years after PD onset. Group D: never used icodextrin during the study period. At the start of PD, we observed no significant difference in left ventricular mass index (LVMI) or urine volume (UV) between the groups. At 4 years, LVMI and UV were both significantly improved in group A compared with group D. The amelioration in LVMI was negatively associated with phosphate elimination. Our study showed that icodextrin preserved RRF and ameliorated left ventricular hypertrophy. Moreover, the timing of icodextrin introduction in PD patients influenced the clinical effects, including progression of cardiac hypertrophy and RRF. PMID- 24344483 TI - Icodextrin eliminates phosphate and ameliorates cardiac hypertrophy and valvular calcification in patients with end-stage renal disease and diabetes mellitus undergoing peritoneal dialysis. AB - Among end-stage renal disease (ESRD) patients, cardiovascular disease is a common comorbidity and one of most important factors affecting clinical prognosis. Calcium deposition has been reported to correlate with plasma phosphate. Icodextrin (Ico)-based peritoneal dialysis (PD) has many advantages over glucose (Glu)-based PD. We aimed to identify factors that suppress arteriosclerosis and valvular disease in patients with ESRD and diabetes mellitus (DM) undergoing Ico based PD. In this retrospective study, we evaluated the effects of Ico-based PD (n = 20) on phosphate elimination and cardiovascular disease progression in patients with ESRD andDM, and we compared the results with those for Glu-based PD (n = 20). Left ventricular mass index (LVMI) and aortic valve calcification (AVC) score were significantly decreased and daily phosphate elimination was significantly increased in the Ico group compared with the Glu group. Furthermore, mean daily phosphate elimination was significantly and negatively correlated with the amelioration in LVMI and AVC score. Our study suggests that, compared with glucose, icodextrin has the ability to eliminate more phosphate from the body, indicating that phosphate elimination might potentially be a means of controlling cardiovascular disease in PD patients with DM. PMID- 24344484 TI - Icodextrin-based continuous ambulatory peritoneal dialysis therapy effectively reduces left ventricular mass index and protects cardiac function in patients with end-stage renal disease. AB - Increased left ventricular mass index (LVMI) is commonly observed in patients undergoing peritoneal dialysis (PD). The present study aimed to determine the effect of icodextrin (Ico) on LVMI in PD patients with maintained residual renal function (RRF). This retrospective study included 18 patients (12 men, 6 women; average age: 62 +/- 10 years) diagnosed with indications for PD therapy and divided into two groups: those treated with Ico (Ico group) and without Ico (non Ico group). Echocardiography was performed at the beginning of continuous ambulatory PD and after 6 and 12 months. A significant reduction in LVMI (p < 0.01) and an increase in ultrafiltration (p < 0.01) were observed after 6 months of lco treatment and were maintained for 12 months. Ejection fraction was significantly lower in the non-Ico group after 12 months (p < 0.01), but was not altered in the Ico group. Blood pressure, cardiothoracic ratio, urine volume, and N-terminal prohormone of brain natriuretic peptide were unaffected by PD treatment up to 12 months. The year-averaged ultrafiltration and the reduction in LVMI were significantly correlated (p < 0.05). Ico effectively improved LVMI and maintained ejection fraction in end-stage renal disease patients within 1 year from PD initiation. Notably, treatment with Ico resulted in a reduction of LVMI (associated with increased ultrafiltration), with no significant reduction in RRF. PMID- 24344485 TI - The importance of residual renal function in peritoneal dialysis patients. AB - Increased peritoneal clearance can compensate for reductions in renal solute removal in patients receiving peritoneal dialysis (PD); however there is abundant evidence to suggest that renal rather than peritoneal clearance contributes to clinical outcomes. We review the evidence investigating the impact of residual renal function (RRF) and peritoneal solute clearances on survival and quality of life in PD patients. We also provide a comparison of the relative contribution of RRF and peritoneal clearance to patient survival. In addition, mechanisms of survival benefit in patients with preserved renal function, factors contributing to RRF decline, and interventions that may limit the progressive loss of RRF are discussed. PMID- 24344486 TI - The outcome of nephrectomy in peritoneal dialysis patients. AB - Data regarding the outcomes of peritoneal dialysis (PD) patients undergoing nephrectomy are limited. In the 20-year retrospective study reported here, we included patients who underwent nephrectomy and then subsequently started PD within 1 year (group A) and those who underwent nephrectomy while already on PD (group B). We examined mechanical complications including incisional hernia, peritoneal leak, and wound infection or dehiscence. Among biochemical outcomes (group B only), we analyzed serum creatinine, albumin, potassium, and phosphate for 1 year pre- and post-nephrectomy. Among the 8 patients identified (4 in group A, 4 in group B), 7 underwent unilateral nephrectomy, and 1, bilateral nephrectomy. Surgery was laparoscopic in 1 patient and open in 7 patients. The approach was transperitoneal in 5 patients, and retroperitoneal in 3 patients. Incisional hernia occurred in 4 patients (2 in each group), and retroperitoneal leak was seen in 1 patient in group B after 2 months. No wound dehiscence or other complications occurred. In group B, 2 patients required hybrid therapy in the form of once-weekly hemodialysis with continuous ambulatory PD. Among the biochemical complications, we noted that serum creatinine increased (as expected), and serum albumin significantly declined and remained lower post nephrectomy. Our data show that, post-nephrectomy, PD patients have a high incidence of incisional hernia. They also experience a significant decline in serum albumin and a substantial loss in residual kidney function potentially requiring intensified dialysis. The retroperitoneal approach may on occasion predispose to retroperitoneal leak of dialysate. PMID- 24344487 TI - Excellent ultrafiltration and clearance after more than 12 years of peritoneal dialysis: two case reports. AB - Because of a higher (but improving) incidence of technique failure, peritoneal dialysis (PD) is not thought to equal hemodialysis (HD) for long-term use. Other than death and transplantation, the reasons that patients leave PD include peritonitis, catheter problems, patient burnout, and (in long-duration patients) the development of encapsulating peritoneal sclerosis or ultrafiltration failure. Here, we report 2 patients who have been on continuous ambulatory PD continuously for more than 12 years, maintaining good ultrafiltration and clearances. In the case reports, we suggest potential reasons for the long duration of therapy in these women. We conclude that, in some patients on continuous ambulatory PD who sparingly use very hyperosmolar dextrose solutions and who are able to avoid frequent episodes of peritonitis, long-term PD is possible and may not require transition to HD. PMID- 24344488 TI - Beneficial role of tolvaptan in the control of body fluids without reductions in residual renal function in patients undergoing peritoneal dialysis. AB - The V2 receptor antagonist tolvaptan has been approved for volume control in heart-failure patients in Japan. Tolvaptan increases renal blood flow, and so the present study was designed to ascertain whether tolvaptan could be a useful diuretic for volume control without reducing residual renal function (RRF) in peritoneal dialysis (PD) patients. Tolvaptan was administered in 15 PD patients (15 mg daily). Urine volume, body weight, and blood pressure were monitored Urinary excretion of urea nitrogen Na+, the osmolality of plasma and urine, and peritoneal and renal Kt/V were analyzed before and after tolvaptan treatment. In 11 of 15 patients, urine volume increased to more than 400 mL daily. A significant increase in diluted urine was observed, as indicated by a reduction in the specific gravity or osmolality of urine (or both). Urinary excretion of urea nitrogen, and Na+ was significantly increased Increases in renal Kt/V were observed, but peritoneal Kt/V was unchanged. Singnificant increase in creatinine clearance was also observed These data suggest that tolvaptan not only stimulates water diuresis, but also natriuresis, without reducing RRF in PD patients. Hence, tolvaptan could be a beneficial tool for the control of body fluid and maintenance of RRF in PD patients. PMID- 24344489 TI - Hepatorenal syndrome treated for eight months with continuous-flow peritoneal dialysis. AB - The case documented here represents the longest course of continuous-flow peritoneal dialysis (PD) reported in the literature. A 61-year-old man with hepatorenal syndrome type 1 and ascites presented with hypotension and bright red blood per rectum and was found to be in acute renal failure with severe anemia. Continuous-flow PD was initiated, and the patient improved clinically. The patient died of a jejunal bleed 8 months later, before discharge. Acute PD or continuous-flow PD is a viable alternative in the setting of hemodynamic instability and ascites, can be used as a chronic modality, and addresses many of the weaknesses of continuous ambulatory and automated PD. PMID- 24344490 TI - Clinical outcomes in elderly (more than 80 years of age) peritoneal dialysis patients: five years' experience at two centers. AB - The proportion of elderly people requiring renal replacement therapy has been increasing in Japan. Although several studies have shown the benefits of peritoneal dialysis (PD) in the elderly, few have reported on outcomes, including prognosis, in elderly PD patients, especially those more than 80 years of age. The purpose of the present study was to evaluate clinical outcomes in elderly (more than 80 years of age) PD patients. We retrospectively evaluated the medical records of elderly PD patients who commenced PD between 2007 and 2011. The frequency of perioperative complications, rate of PD-associated peritonitis, technique survival, overall survival, and utilization of nursing-care insurance systems were investigated as clinical outcomes. The 12 patients eligible for this study (7 men, 5 women; mean age: 85 +/- 3 years) had a median duration of follow up of 1.2 years (interquartile range: 0.65-1.74 years). Perioperative complications were not observed in any of the patients. The frequency of PD associated peritonitis was 1 episode in 56 months. During follow-up, 6 patients died, and 3 patients switched to hemodialysis because of tunnel infection or lack of family support. The overall survival rate at 12 months was 83%. Nursing-care insurance was used by 63% of patients. In elderly patients, it is important to predict the potential short-term issues at the initiation of PD to facilitate implementation of social services, such as home-visit nursing-care services, at the time of worsening general condition. PMID- 24344491 TI - The experience of dialysis therapy among younger adults. AB - The present study was undertaken to examine the experience of younger dialysis patients with end-stage renal disease (ESRD) care. Structured tape-recorded interviews focusing on perceptions of ESRD care and how that care could be improved were initially conducted with 25 dialysis patients [16 on conventional hemodialysis (HD), 6 on nocturnal in-center HD, 2 on home peritoneal dialysis (PD), and 1 on home HD]. The mean age of the patients was 43.8 +/- 12.2 years, and their mean dialysis duration was 4.6 +/- 3. Oyears. Five important domains were identified from the interviews. Based on those findings, a questionnaire was developed and distributed to 62 ESRD patients (49 on HD, 13 on PD). Several domains were identified that provide insight into how the patients thought their care could be improved. Our results suggest that certain changes in ESRD care might improve the experience of younger dialysis patients. PMID- 24344492 TI - Changing the paradigm from contraction of peritoneal dialysis programs to increasing prevalent peritoneal dialysis numbers. AB - Compared with other European and North American countries, the United Kingdom traditionally had proportionally more dialysis patients treated by peritoneal dialysis. However as in many economically developed countries, peritoneal dialysis numbers have fallen in the United Kingdom, particularly since the early 2000s. In an effort to increase home-based dialysis therapies, the U.K. Department of Health introduced a new system of reimbursement tariffs favoring peritoneal dialysis and home hemodialysis compared with standard hospital-based hemodialysis. Here, we report how our own center responded to the impending change in reimbursement rates and turned what had been a declining peritoneal dialysis program into one that almost doubled in size within 3 years. PMID- 24344493 TI - Hypoalbuminemia in peritoneal dialysis patients. AB - Clinicians caring for patients on peritoneal dialysis (PD) have relied on a variety of laboratory measures to assess the health of patients and their response to treatment. Traditionally, serum albumin has been an indicator of nutrition status and has therefore been included in monthly blood testing in most centers. The development of hypoalbuminemia in dialysis patients has been associated with increased mortality and often leads to interventions such as trials of nutritional supplements. In PD, hypoalbuminemia combined with ongoing losses of protein into effluent raise particular concerns with clinicians. Serum albumin may be affected by a variety of non-nutrition factors such as inflammation, volume status, and comorbidities. Albumin synthesis in the liver exceeds, in most cases, albumin losses in urine or effluent. Interpreting the medical implications of declining serum albumin in PD patients can therefore be a challenge. This paper reviews protein balance in PD. The nutritional and non nutritional factors affecting serum albumin are discussed, with specific emphasis on how membrane physiology contributes to dialysate protein losses. A general clinical approach to the PD patient developing hypoalbuminemia is discussed. PMID- 24344494 TI - Relationship between alkaline phosphatase and all-cause mortality in peritoneal dialysis patients. AB - Elevated levels of serum alkaline phosphatase (AlkPhos) have been reported to be associated with increased mortality risk in hemodialysis (HD) patients. We examined the association of serum AlkPhos with all-cause mortality in our PD patients. The study enrolled 90 PD patients beginning in 1995. On enrollment, demographics and clinical and biochemical data were recorded. Patients were followed to September 2011. Mean age of the enrollees was 52 years, with 61% being women, and most (81%) being of African descent. Mean and median AlkPhos were 135 U/L and 113 U/L respectively. Mean and maximum follow-up were 2.61 and 16 years respectively. As expected, AlkPhos correlated directly with serum intact parathyroid hormone (r = 0.36, p = 0.003). In a Cox multivariate regression analysis with adjustment for confounding variables, AlkPhos as a continuous (relative risk: 1.016; p = 0.004) anda categorical variable [> 120 U/L and < or = 120 U/L (relative risk: 6.0; p = 0.03)] remained a significant independent predictor of mortality. For each unit increase in enrollment AlkPhos, there was a 1.6% increase in the relative risk of death. Elevated serum AlkPhos is significantly and independently associated with increased mortality risk in our PD patients followed for up to 16 years. AlkPhos should be evaluated prospectively as a potential therapeutic target in clinical practice. PMID- 24344495 TI - Does bioimpedance analysis or measurement of natriuretic peptides aid volume assessment in peritoneal dialysis patients? AB - Cardiovascular mortality remains the commonest cause of death for peritoneal dialysis patients. As such, preventing persistent hypervolemia is important. On the other hand, hypovolemia may potentially risk episodes of acute kidney injury and loss of residual renal function, a major determinant of peritoneal dialysis technique survival. Bioimpedance has developed from a single-frequency research tool to a multi-frequency bioelectrical impedance analysis readily available in the clinic and capable of measuring extracellular, intracellular, and total body water. Similarly, natriuretic peptides released from the heart because of myocardial stretch and increased intracardiac volume have also been variously reported to be helpful in assessing volume status in peritoneal dialysis patients. The question then arises whether these newer technologies and biomarkers have supplanted the time-honored clinical assessment of hydration status or whether they are merely adjuncts that aid the experienced clinician. PMID- 24344496 TI - Hemoperitoneum in a peritoneal dialysis patient from a retroperitoneal source. AB - Hemoperitoneum in peritoneal dialysis patients is a known but infrequent complication. Hemoperitoneum is more frequent in women because of its association with a variety of gynecologic presentations such as reflux menstruation, ovulation, endometrial tissue implants within the peritoneal cavity (endometriosis), and bleeding follicular cysts. Other intraperitoneal causes of hemoperitoneum include minor catheter or abdominal trauma, vascular anomalies, or hepatic or splenic cysts. Less frequently encountered is a presentation of hemoperitoneum from a retroperitoneal source. These presentations result either from peritoneal inflammation and subsequent peritoneal bleeding or retroperitoneal cavity pathology rupturing into the peritoneal cavity. Here, we present the case of a peritoneal dialysis patient presenting with hemoperitoneum several days after undergoing cardiac catheterization. The catheterization was complicated by a large retroperitoneal hematoma. Details of the case are reported, and other retroperitoneal causes of hemoperitoneum are reviewed. PMID- 24344497 TI - Nondialytic therapy for end-stage renal disease is an underutilized care paradigm in the United States: time for a more robust reappraisal of this treatment option. AB - Nondialytic therapy (NDT)--also calledconservative kidney management--is a growing modality of treatment for select chronic kidney disease and end-stage renal disease (ESRD) patients globally. Nevertheless, NDT is rarely practiced in the United States. We set out to investigate NDT activity before initiation of renal replacement therapy in a Northwestern Wisconsin Mayo Clinic ESRD population. Records of all prevalent ESRD patients on chronic hemodialysis in our practice were retrospectively reviewed in May 2012. Dialysis nurses and social workers were informally interviewed to augment the review process. Of the 166 ESRD patients reviewed, 82 (49%) were 70 years of age or older, 46 (28%) were 70 79 years, and 36 (22%) were 80-89 years. Most of these older patients had multiple significant comorbidities ("multimorbidity"). Evidence for NDT activity before initiation of renal replacement therapy was virtually nonexistent. The older ESRD patients with multimorbidity experienced frequent hospitalizations. Our preliminary review suggests that their quality of life may have been better with NDT. Almost one half of our ESRD population was made up of people more than 70 years of age, most with multimorbidity. In our practice, NDT is a neglected paradigm, as it is in most U.S. nephrology practices. The place of NDT, actively provided by a specialized multidisciplinary team, for U.S. ESRD patients demands urgent attention and robust reappraisal by U.S. nephrologists. PMID- 24344498 TI - Urothelial dysplasia of the bladder: diagnostic features and clinical significance. AB - The 2004 World Health Organization classification system for urothelial neoplasia identifies urothelial dysplasia (low-grade intraurothelial neoplasia) as a premalignant lesion of the urothelium. Although diagnostic criteria of urothelial dysplasia have been improved in recent years, there is a frequent lack of interobserver reproducibility. Follow-up studies suggest that dysplasia is a marker for urothelial instability and disease progression in up to 19% of patients, thus supporting an active clinical follow-up in these patients. The main differential diagnosis of urothelial dysplasia includes flat urothelial lesions with atypia, mainly flat (simple) urothelial hyperplasia, reactive urothelial atypia, urothelial atypia of unknown significance, and urothelial carcinoma in situ (high-grade intraurothelial neoplasia). In most cases, morphologic features alone suffice for diagnosis. Some cases may require a panel of immunohistochemical antibodies consisting of cytokeratin 20, p53 and CD44 for diagnosis. We present pathologic features and clinical significance of urothelial dysplasia with emphasis on differential diagnosis from common flat urothelial lesions with atypia. PMID- 24344499 TI - Prostate needle biopsy: what we do and what should be improved. AB - Prostate cancer (PCa) is the cancer most frequently diagnosed in older men and the second most frequent for incidence of all tumors. With the widespread use of serum prostate-specific antigen (PSA), the detection rate as well as the incidence of localized tumors has been increasing, thus leading to a drop in PCa related mortality. However, a corresponding estimated rate of overdiagnosis as high as 50% has been reported, and the adverse side effects related to unnecessary treatments make the overall benefit of PSA mass screening unclear. The lower PSA threshold and extended prostate biopsy protocols have led to a marked increase of small, low-grade tumors that will never threaten a patient's survival. Sextant biopsy technique, extended biopsy protocols (12-18 cores) and saturation prostate schemes are already familiar terms, together with quantitative histology in the pathology departments. This brief review will try to focus on what usually is done and what should be improved in prostate needle biopsy in order to answer many critical points such as the clinical implication of different modalities of prostate biopsy (transrectal, transperineal or even targeted), the use of quantitative histology and the importance of the new molecular findings in addition to conventional histological parameters in the era of the active surveillance protocols. PMID- 24344500 TI - Association of human papillomavirus L1 capsid protein with koilocytosis, expression of p16, and Ki-67, and its potential as a prognostic marker for cervical intraepithelial neoplasia. AB - OBJECTIVE: To study the relationship between human papillomavirus (HPV) L1 capsid protein (L1) and koilocytosis on ThinPrep cytology tests (TCTs) and the association of HPV L1 with p16 and Ki-67 expression in their corresponding biopsies. STUDY DESIGN: TCTs of 75 patients with high-risk HPV infection were studied for cytologic features of koilocytosis and for HPV L1 expression using combined detection of in situ hybridization and immunocytochemistry. All TCTs had follow-up biopsies on which p16 and Ki-67 were confirmed by immunostaining. RESULTS: Of 75 TCTs, 45 expressed HPV L1, while 23 displayed koilocytosis. All TCTs with koilocytosis expressed HPV L1. HPV L1 was lost in 23.3% of cervical intraepithelial neplasia (CIN) I, 16.7% of CIN II, and 60% of CIN III or higher (carcinoma in situ including suspected minor infiltration), categorized by biopsy, and the difference among CIN grades was statistically significant (chi2, p = 0.015). Expression scores of p16 and Ki-67 were higher in L1 negative cases than in positive cases (1.63 vs. 1.54 for p16; 1.53 vs. 1.32 for Ki-67); however, the difference was not significant (Mann-Whitney test: p = 0.57 for p16, p = 0.27 for Ki-67). CONCLUSION: HPV L1 expression was significantly associated with koilocytosis on TCT, and loss of L1 was associated with increase in CIN grade but not with p16 or Ki-67 expression. Our study suggests that HPV L1 is a more sensitive method than koilocytosis for detecting active HPV infection. Detection of HPV L1 on TCTs of high-risk HPV-infected patients can be helpful in risk assessment and prognostic prediction of CIN. PMID- 24344501 TI - A comparative study of telomerase activity and cytologic diagnosis in malignant ascites. AB - OBJECTIVE: To evaluate telomerase activity as an adjunct in the cytologic diagnosis of malignant ascites. STUDY DESIGN: Malignant ascites collected from 19 gastrointestinal or liver cancer patients with clinical or pathologic evidence of peritoneal metastasis were tested for routine cytology with a liquid-based preparation, and telomerase activity was measured by telomere-repeat amplification protocol (TRAP) and real-time quantitative TRAP (RTQ-TRAP) assays. For comparison, controls from peritoneal washings from 8 early gastric cancer patients were used. RESULTS: Cytological examination detected cancer cells in 8 patients (42%), and 3 cases (16%) were diagnosed as "atypia." With TRAP and RTQ TRAP assays 16 (84%) and 15 (78%) cases, respectively, were positive for telomerase activity. The sensitivity of telomerase activity by TRAP, RTQ-TRAP assays, and cytology was 84%, 78%, and 58%, respectively. All cases with "atypia" by cytological examination were positive for both TRAP and RTQ-PCR assays. In all negative controls, cytology, TRAP and RTQ-TRAP assays were negative. CONCLUSION: Based on our findings telomerase activity is a more sensitive method than ascitic fluid cytology and therefore can be considered as a useful diagnostic adjunct to current standard diagnostic methods. However, further large cohort studies with clinical correlation are needed to confirm our findings. PMID- 24344502 TI - Hybrid capture 2 high-risk human papillomavirus test: should "grey zone" results justify repeating the test? AB - OBJECTIVE: To determine the clinical importance of repeating the Hybrid Capture 2 (HC2) high-risk human papillomavirus (HPV) test when the result obtained falls between 2.7 and 0.8 pg/mL, the so-called "grey zone." STUDY DESIGN: Repeat testing was performed on 139 thin-layer liquid-based cytology cervicovaginal samples that were found to fall in the grey zone. The samples represented a variety of cytological diagnoses. The results of both HPV HC2 tests were analyzed related to the cytological diagnosis of both the previous and the follow-up cytological samples. RESULTS: The change of the HPV HC2 result from positive (2.7 1 pg/mL) to negative (< 1 pg/mL) when repeating the test is not related with the diagnosis obtained in the cytological follow-up of the patient. CONCLUSION: The HC2 test should not be repeated when the result falls between 2.7 and 0.8 pg/mL. In these cases the result of the cytology is more relevant and should be used in the clinical assessment of the patient. PMID- 24344503 TI - Pancreatic metastases of renal clear cell carcinoma: a clinicopathological study of 11 cases with special emphasis on the usefulness of PAX2 and mesothelin for the distinction from primary ductal adenocarcinoma of the pancreas. AB - OBJECTIVE: To determine whether PAX2 and mesothelin immunohistochemistry add additional diagnostic value in discriminating between pancreatic metastasis of renal clear cell carcinoma (PMRCC) and primary ductal adenocarcinoma of the pancreas (PDAC). STUDY DESIGN: We retrospectively collected tissue from PMRCC and PDAC. Eleven cases of PMRCC registered at Lille University Hospitals from 2001 to 2010 were included. Eleven cases of PDAC were randomly selected from our files. A comparative immunohistochemical study with anti-PAX2, anti-mesothelin, and the classical renal antibodies anti-CD10 and anti-vimentin was performed on PMRCC and PDAC. RESULTS: We found that PMRCC displays a clinical presentation that might mimic primary pancreatic tumor, as PMRCC presented as a solitary mass in 8 cases and appeared a long time after diagnosis of a renal tumor (12.8 years, mean for metachronous metastasis). By immunohistochemistry we observed that PAX2, mesothelin, CD10 and vimentin stainings were noted in 10/11 (91%), 0/11 (0%), 11/11 (100%) and 7/11 cases (64%), respectively, among 11 PMRCC cases. All PDACs displayed diffuse mesothelin (100%) expression without PAX2 and vimentin (0%) staining, whereas CD10 was noted in 4/11 cases (36%). CONCLUSION: These data suggest that in difficult diagnostic cases both PAX2 and mesothelin immunohistochemical study may be useful in discriminating between PMRCC and primary pancreatic carcinoma. PMID- 24344504 TI - Propanil-induced histopathological changes in the liver and kidney of mice. AB - OBJECTIVE: To examine sublethal toxic effects of propanil on liver and kidney of albino Swiss mice, Mus musculus. STUDY DESIGN: Different doses of propanil (75, 150, and 300 mg/kg) were administered to determine histologic defects on liver and kidney tissues of mice for 30 consecutive days. Biometric analyses (area measurements of hepatocyte/nucleus and glomerulus/renal corpuscle) were also conducted to determine whether there were statistical differences in these end points. RESULTS: Cloudy swelling, cytoplasmic vacuolization, nuclear degeneration, nucleus loss, mononuclear cell infiltration, congestion, enlargement of the sinusoids, and increases in the number of Kupffer cells were prominent in the liver of exposed mice. In kidney tissue mononuclear cell infiltration, glomerular degeneration, glomerular loss, and congestion were determined in propanil-treated groups. CONCLUSION: Propanil induced dose dependent histopathological changes in the liver and kidney tissues of exposed mice. This study showed that propanil exposure might cause harmful effects to nontarget organisms, including humans. PMID- 24344505 TI - BMP-9 induces rabbit adipose-derived stem cells to differentiation into osteoblasts via BMP signaling pathway. AB - OBJECTIVE: To explore the role of BMP-9 in osteoblast differentiation from adipose-derived stem cells (ADSCs). STUDY DESIGN: Rabbit ADSCs were isolated from subcutaneous tissues of the abdomen and inguinal fat pads and then purified and expanded in vitro. AdBMP9, SB203580 (P38 MAPK inhibitors), and PD98059 (ERK1/2 inhibitor) were used for osteoblastic differentiation. RESULTS: The results show that bone morphogenetic proteins (BMPs) could affect the differential direction of ADSCs. Polymerase chain reaction assays reveal the important role of BMP signaling pathway in osteoblastic differentiation of ADSCs, and the members included Smad 1, Smad 4, Smad 5, Smad 8, P38, ERK1/2, Runx 2, collagen type I and osteopontin. CONCLUSION: This study provides some theoretical basis and experimental evidence for the application of ADSCs into treatment of bone injury. PMID- 24344506 TI - Schistosomiasis of the prostate: a case report. AB - BACKGROUND: Schistosomiasis with involvement of the prostate is relatively uncommon and is rarely diagnosed in needle core biopsies. CASE: A 45-year-old, African American man who had recently returned from the Middle East presented with hematospermia of unknown etiology. He also had an elevated PSA level and a positive family history of prostate cancer. Prostate needle core biopsies were obtained. On microscopy he had multiple foci of acute and chronic inflammation. In other foci, Schistosoma haematobium ova were identified in the absence of a host inflammatory response. All his biopsies were negative for carcinoma. A diagnosis of schistosomiasis of the prostate was made. CONCLUSION: Schistosomiasis should be considered in the differential diagnosis of parasitic diseases involving the prostate, especially in patients who live in or have recently visited endemic regions. PMID- 24344507 TI - Plasma exogenous creatinine excretion for the assessment of renal function in avian medicine--pharmacokinetic modeling in racing pigeons (Columba livia). AB - The diagnostic evaluation of the glomerular filtration rate by urinary clearance has significant practical limitations in birds because urine is excreted together with feces. Thus, pharmacokinetic modeling of an exogenous plasma creatinine clearance could be useful for assessing renal creatinine excretion in birds. For this study, creatinine (50 mg/kg) was administered to 2 groups of 15 pigeons (Columba livia) each; in one group by the intravenous (IV) route and in the second by the intramuscular (IM) route. The time series of the plasma creatinine concentrations were analyzed by pharmacokinetic models. Body mass-specific creatinine excretion was determined for IV and IM administration to be between 6.30 and 6.44 mL/min per kg, respectively. Body surface area-specific creatinine clearance, which is related to the metabolic rate, was calculated between 0.506 and 0.523 mL/min per dm2, respectively. The results showed that IV as well as IM administration can be used for assessing renal creatinine excretion in pigeons. For practical reasons, IM administration is recommended, with the use of the Bateman function to calculate creatinine elimination. PMID- 24344508 TI - Pharmacokinetic and pharmacodynamic properties of enrofloxacin in southern crested caracaras (Caracara plancus). AB - To determine the dosage of enrofloxacin in southern crested caracaras (Caracara plancus), plasma concentrations of enrofloxacin were measured by high-performance liquid chromatography after intravenous (IV) (5 mg/kg) and intramuscular (IM) (10 mg/kg) administration. This compound presented a relatively high volume of distribution (2.09 L/kg), a total body clearance of 0.24 L/kg x h, and a long permanence as shown by an elimination half-life of 7.81 hours after IV administration and a terminal half-life of 6.58 hours after IM administration. The areas under the concentration-time curves (AUC) were 21.92 and 34.38 microg x h/mL for IM and IV administration, respectively. Enrofloxacin was rapidly absorbed after IM administration with a time to reach maximum concentration of 0.72 hours and bioavailability of 78.76%. After IM administration, the peak drug concentration (C(max)) was 3.92 microg/mL. Values of minimum inhibitory concentration (MIC), C(max), and AUC have been used to predict the clinical efficacy of a drug in treating bacterial infections, with a C(max)/MIC value of 10 and an AUC/MIC ratio of 125-250 associated with optimal bactericidal effects. By using the study data and a MIC breakpoint of 0.25 microg/mL, values of C(max)/MIC were 13.74 and 15.94 and for AUC/MIC were 90.73 and 139.63, for the IV and IM routes respectively. For the treatment of infectious diseases caused by microorganisms with MIC < or = 0.25 microg/mL, the calculated optimal dosages were 7.5 and 9.5 mg/kg q24h by the IV and IM routes, respectively. For less susceptible bacteria, a dose increase should be evaluated. To treat caracara by the IV route against microorganisms with MIC < or = 0.25 microg/mL, the dose should be higher than the 5 mg/kg used in our study, but possible side effects derived from an increase in the IV dose and efficacy in sick birds should be assessed. PMID- 24344509 TI - Assessment of plasma concentrations and potential adverse effects of doxycycline in cockatiels (Nymphicus hollandicus) fed a medicated pelleted diet. AB - Doxycycline hyclate was mixed with soybean oil and then added to a low-fat pelleted diet that contained approximately 2.4% fat, which produced a final diet that contained a calculated 6.4% fat and 300 mg doxycycline per kilogram of diet. The medicated diet was fed to 9 healthy adult cockatiels (Nymphicus hollandicus) for 47 days; a control group of 6 birds received the identical diet without doxycycline. Trough doxycycline plasma concentrations were measured 7 times during treatment and ranged from 0.98 to 3.83 microg/mL with an overall median of 2.09 microg/ mL. The birds were observed daily, weighed, and examined at least weekly, and selected plasma biochemical parameters were measured before treatment and at days 21 and 42. No adverse effects were noted, except one treatment bird became obese. This medicated diet may be suitable for treating spiral bacteria and Chlamydophila psittaci infections in cockatiels that will consume a pelleted diet. PMID- 24344510 TI - Use of an indirect sampling method to produce reference intervals for hematologic and biochemical analyses in psittaciform species. AB - As with other animal species, comprehensive reference intervals (RI) for psittaciform species are rare and plagued by common issues, including sparse information regarding methods used to analyze specimens, low sample sizes, and improper statistical analyses. The purpose of this study was to examine the use of an indirect sampling method of RI generation from several years of data collected from specimens of multiple psittaciform species submitted to a veterinary diagnostic laboratory. These data were unselected for health status. A previously published method for indirect RI generation was applied to data collected for routine hematologic and biochemical analyses. Seven species groups were examined, and sample size ranged from 346 to 2358. Results showed that RI varied by species and appeared to represent a broader range than expected compared with other RI and traditional clinical expectations for core health assessments, such as total white blood cell count and white blood cell differential results. Some biochemical results reflected more narrow ranges, and a few were consistent with other published ranges. The intervals were likely influenced by changes related to stress and underlying disease. The results of the current study reflect the imprecision of this method related to data obtained from the population served by this laboratory. Overall, this method is not suitable for the production of comprehensive RI, although it may provide rough estimates for some limited analyses until traditional RI can be generated. PMID- 24344512 TI - Complete blood cell count in psittaciformes by using high-throughput image cytometry: a pilot study. AB - The avian hemogram is usually performed in veterinary diagnostic laboratories by using manual cell counting techniques and differential counts determined by light microscopy. There is no standard automated technique for avian blood cell count and differentiation to date. These shortcomings in birds are primarily because erythrocytes and thrombocytes are nucleated, which precludes the use of automated analyzers programmed to perform mammal complete blood cell counts. In addition, there is no standard avian antibody panel, which would allow cell differentiation by immunophenotyping across all commonly seen bird species. We report an alternative hematologic approach for quantification and differentiation of avian blood cells by using high-throughput image cytometry on blood smears in psittacine bird species. A pilot study was designed with 70 blood smears of different psittacine bird species stained with a Wright-Giemsa stain. The slides were scanned at 0.23 microm/pixel. The open-source softwares CellProfiler and CellProfiler Analyst were used for analyzing and sorting each cell by image cytometry. A "pipeline" was constructed in the CellProfiler by using different modules to identify and export hundreds of measures per cell for shape, intensity, and texture. Rules for classifying the different blood cell phenotypes were then determined based on these measurements by iterative feedback and machine learning by using CellProfiler Analyst. Although this approach shows promises, avian Leukopet results could not be duplicated when using this technique as is. Further studies and more standardized prospective investigations may be needed to refine the "pipeline" strategy and the machine learning algorithm. PMID- 24344511 TI - Pharmacokinetics of a single dose of intravenous and oral meloxicam in red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus). AB - Pharmacokinetic data were determined after a single dose of meloxicam in red tailed hawks (RTH; Buteo jamaicensis) and great horned owls (GHO; Bubo virginianus). In a nonrandomized crossover design, individual birds of each species received 1 dose of intravenous meloxicam (0.5 mg/kg i.v.; n = 7 for each species) followed by a 2-week washout period, and then each received 1 dose of oral meloxicam (0.5 mg/kg PO; n = 5 for each species). Blood samples were collected intermittently after administration, and meloxicam was detected in plasma by high-performance liquid chromatography. Time versus plasma concentration data were subjected to noncompartmental analysis. Red-tailed hawks were determined to have the shortest elimination half-life for meloxicam (0.49 +/ 0.5 hours) of any species documented. Great horned owls also eliminated meloxicam very rapidly (0.78 +/- 0.52 hours). Great horned owls achieved higher plasma concentrations (368 +/- 87 ng/mL) of meloxicam than RTH (182 +/- 167 ng/mL) after oral administration, although RTH had a markedly higher volume of distribution (832 +/- 711 mL/kg) than GHO (137.6 +/- 62.7 mL/kg). The differences in meloxicam pharmacokinetics between these 2 raptor species supports the need for species-dependent studies and underlines the challenges of extrapolating drug dosages between species. Results of this study suggest that the current recommended once-daily dosing interval of oral meloxicam is unlikely to maintain plasma concentrations anticipated to be therapeutic in either RTH or GHO, and practical dosing options are questionable for this nonsteriodal anti-inflammatory drug in these raptor species. PMID- 24344513 TI - Osteoma in a blue-fronted Amazon parrot (Amazona aestiva). AB - Osteoma is an uncommon bone formation documented in avian species and other animals. A blue-fronted Amazon parrot (Amazona aestiva) with clinical respiratory symptoms was examined because of a hard mass present on the left nostril. Radiographs suggested a bone tumor, and the mass was surgically excised. Histopathologic examination revealed features of an osteoma. To our knowledge, this is the first description of an osteoma in a blue-fronted Amazon parrot. Osteoma should be considered as a differential diagnosis in birds with respiratory distress and swelling of the nostril. PMID- 24344514 TI - Mucus accumulation and necrosis of the ventral air pouch in a marabou stork (Leptoptilos crumeniferus) with productive rhinitis. AB - A captive-born marabou stork (Leptoptilos crumeniferus) was presented for swelling of the ventral air pouch of 1 month's duration. The pouch appeared fluid filled, and its distal third wall was markedly inspissated. The thickened distal portion of the pouch wall was removed surgically. During anesthesia, mucous discharge from the nares was evident and the nasal mucosa was hyperemic. Aeromonas and Proteus species were isolated from a nasal culture. Postoperative therapy that consisted of nasal flushing, antimicrobial agents, and nonsteroidal anti-inflammatory drugs was effective in managing the disease. On histologic examination, diffuse hemorrhage, necrosis, and multifocal vasculitis with moderate-to-severe heterophilic inflammation were present within sections of the ventral pouch. To our knowledge this is the first report of a mucus-filled ventral air pouch with associated pathologic changes secondary to a productive infection of the upper respiratory tract in a marabou stork. The unique communication between nasal cavities and the ventral air pouch should be considered in future cases of respiratory infection in marabou storks. PMID- 24344515 TI - New graduates: facts, feelings, and future. PMID- 24344516 TI - What is your diagnosis? Ovarian adenocarcinoma. PMID- 24344517 TI - A call for best practice guidelines in nephrology nursing. PMID- 24344518 TI - A renal nursing professional practice model: the next generation. AB - Professional practice models provide a structure for excellence in nursing practice. Our centre has had a long tradition of working with a professional practice model with proven nursing outcomes such as job satisfaction, empowerment and perceptions of improved patient care. Our model, in place since 1999, has provided an opportunity to discuss and articulate a vision for nursing practice based on the values of accountability, evidence-informed care and empowerment. In order for the model to effectively guide nursing practice, a revision was necessary to keep pace with the changes in the renal program and the health care environment. The revised model needed to address the enhancements in nursing roles, practice environment, corporate requirements and patient care needs. This paper describes a revised professional practice model unique to nephrology nursing. PMID- 24344519 TI - The connection between neurosciences and dialysis: a quick neurological assessment for hemodialysis nurses. AB - Stroke is a significant medical emergency and occurs frequently in patients receiving renal replacement therapy. In 2005, the Registered Nurses Association of Ontario (RNAO) published Nursing Best Practice Guidelines for Stroke, highlighting the necessity and expectation that all nurses, regardless of specialty, are able to perform an abbreviated neurological assessment, identify the symptoms of stroke, and respond to these as a medical emergency. This article highlights the significance of neurovascular disease in persons who receive renal replacement therapy, and serves as an educational review for dialysis nurses to increase their neurological functional assessment skills. The outlined abbreviated neurological assessment parallels the Canadian Neurological Scale, and is based on the practice recommendations published in the RNAO Nursing Best Practice Guidelines in 2005. PMID- 24344520 TI - Pain assessment and management in hemodialysis patients. PMID- 24344521 TI - This is who I am. PMID- 24344522 TI - Understanding the hemodialysis patient with dementia. PMID- 24344523 TI - Pharmacists make inroads as members of medical homes. PMID- 24344524 TI - No easy passage to integrated care because vested interests are at stake. PMID- 24344525 TI - Mobile health: real game-changer. PMID- 24344526 TI - A conversation with Delos M.'Toby' Cosgrove, MD. Provider-side economics. Interview by John Marcille. PMID- 24344527 TI - AHRQ's free research can help plans anticipate coverage issues. PMID- 24344528 TI - Registries retooled for better data mining. PMID- 24344529 TI - What's fair in bundled payment contracting? PMID- 24344530 TI - Patient-centered medical home pays off for Philly Blues plan. PMID- 24344531 TI - Laser desorption ionization time-of-flight mass spectrometry for identification of bacteria. PMID- 24344533 TI - WHO releases guidance on mental health care after trauma. PMID- 24344532 TI - Patients' satisfaction with sexual and reproductive health services delivered in HIV clinics across European regions. AB - BACKGROUND: Throughout Europe, differences in satisfaction with HIV-care of people living with HIV (PLHIV) persist, despite a tendency towards harmonisation of policy and management. METHODS: A European sample of 1,549 PLHIV responded to an anonymous questionnaire assessing demographic background, general health, mental health, sexual health, and HIV-service provision. We compared the results across 3 regions: Western, Southern and Central/Eastern Europe. RESULTS: PLHIV differed in several socio-demographic variables (gender, migrant status, sexual orientation, and financial situation) as well as specific psychosocial aspects (HIV-related discrimination, satisfaction with sexual and reproductive health (SRH) services in HIV-care settings, and complaints about service provision). Using multivariate analysis, a predictive model for satisfaction with SRH services in HIV clinics was developed, resulting into region of residence, and participants' satisfaction with their own health status as significant predictors. CONCLUSIONS: Better integration of SRH services in HIV-care should be encouraged. Service providers should be trained and encouraged to discuss SRH issues with their patients to create a supportive environment, free of discrimination. More time should be allocated to discuss SRH issues with individual patients. PMID- 24344534 TI - What can public endorsement for a smoking ban policy mean? Preliminary findings from a qualitative study. AB - OBJECTIVES: The aim of the study is to describe attitudes which underlie Pole's declarations of support for a smoking ban in public places. METHODS: The qualitative study using semi-structured individual in-depth interviews was conducted. The 30 IDI-s (in depth interviews) being a part of a larger research project entitled 'Lay meanings of health and life orientation of Polish society versus prevention and health promotion attitudes' were realized between 2007 2009. People belonging to all key socio-demographic categories identified by variables such as sex, age, education, and place of domicile were interviewed. The resulting material was subjected to content analysis. In the study the structural concept of 'attitude' was adopted. In order to identify the attitudes towards smoking bans in public places statements related to all three components of attitudes were analysed, but the typology of attitudes was constructed mainly on the basis of the emotional-evaluative component. RESULTS: The study identified as many as four attitudes behind the declared support for a smoking ban in public places. Those attitudes were labelled 'supportive', 'accepting', 'conditionally accepting', and 'ambivalent'. They differ as regards degree of acceptance for the ban, conviction about harmfulness of passive smoking, setting great store by other regulators of smoking like cultural norms or healthy consciousness, and propensity to observe and execute the smoking ban. The 'supportive' attitude can be characterized not only by total support for the smoking ban in public places but also by insistence on the need for its extension. The 'accepting' attitude means approval for the smoking ban, and the 'conditionally accepting' attitude is distinguished from the others by the stress put on the right of smokers to have an access to places where smoking is permitted. The 'ambivalent' attitude can be typified by underlining other than legal ways of influencing smoking in public places. CONCLUSIONS: The study suggests that the attitudes underlying the Pole's declarations of support for a smoking ban in public places can be differentiated. However, because of the low number of participants in the study the results should be verified thus the further research is needed. Therefore, there is a need not only to study people's declaration of support or objection for the smoking ban in public places but also to examine their attitudes including cognitive and behavioural components using both qualitative and quantitative methods of social research. PMID- 24344535 TI - Breastfeeding: only 1 in 5 countries fully implement WHO's infant formula code. PMID- 24344536 TI - Global Health Professions Student Survey--Turkey: second-hand smoke exposure and opinions of medical students on anti-tobacco law. AB - AIM: This study, as a part of "the Global Health Professions Student Survey" (GHPSS), aimed to assess medical students' tobacco use, exposure to second-hand tobacco smoke (SHS), and opinions as well as smoking policies at medical faculties in Turkey. METHODS: The study was conducted in 2010 as a school-based survey of third-year students in 12 medical schools. GHPSS uses a standardised methodology for selecting schools (probability proportional to student enrolment size) and data processing. In total, data from 1,217 of third year medical students were analysed. RESULTS: Prevalence of current tobacco use among participating students was 28.5%. Exposure to SHS in the last seven days was 46.9% at home, and 42.2% in other places. Among smokers, over 7 in 10 students reported smoking on medical school premises during the past 30 days and the past year. CONCLUSION: Medical students' exposure to SHS is common and smoking on medical school premises/buildings constitutes a problem. Turkey passed an anti tobacco law in 2008, yet enforcement of the law must be stronger. In addition, medical schools must evaluate, and likely revise their education curricula to better prepare medical students to advocate tobacco control. PMID- 24344538 TI - New UN food safety and nutrition standards will benefit consumers. PMID- 24344537 TI - The impact of the July 2007 heat wave on daily mortality in Belgrade, Serbia. AB - OBJECTIVE: Mortality has been shown to increase with heat waves. Serbia experienced the hottest heat wave in July 2007. In this study, we examined patterns of non-traumatic excess mortality in Belgrade during this event. METHODS: The numbers of deaths observed during the 9-day heat wave were compared to those expected on the basis of mortality rates reported for the previous eight years and two following years. Excess mortality was analyzed by age, gender and cause of death. RESULTS: There was a total of 167 excess deaths (38%) between 16 and 24 July. People aged 75 years and older accounted for 151 (90%) of all excess deaths. An increase of mortality among elderly was 76% in comparison to the baseline mortality. Excess female mortality was over two times higher than excess male mortality (54% : 23%). The biggest increase in mortality was from diabetes mellitus (286%), chronic kidney disease (200%), respiratory system diseases (73%), and nervous system diseases (67%). Cardiovascular and malignant neoplasms mortality accounted for the highest absolute numbers of excess deaths (77 and 49, respectively). There was no decrease in mortality in the 60-day period after the heat wave. CONCLUSIONS: There are several causes of an increase in heat-related mortality. The most vulnerable population group is the elderly females. PMID- 24344539 TI - Hygiene training of food handlers in hospital settings: important factor in the prevention of nosocomial infections. AB - The aim of this study was to evaluate the effects of food hygiene training of food handlers on sanitary-hygienic conditions in hospital kitchens, based on microbiological analysis of smears taken in hospital kitchens. The study was conducted in the 1995-2009 period at the Clinical Centre Nis, Serbia. The food hygiene training was conducted in February 2005, by an infection control officer. 1,076 smears in the central kitchen and 4,025 smears in distributive kitchens were taken from hands and work clothes, work surfaces, equipment, and kitchen utensils. Microbiological analysis of smears was carried out in an accredited laboratory of the Public Health Institute Nis (Serbia). A significantly lower percentage of smears with isolates of bacteria (p < 0.001) taken from hands and work clothes, work surfaces, equipment and kitchen utensils in the central and distributive kitchens was observed in the period following the food safety education programme (2005-2009). The most commonly isolated bacteria was: Enterobacter spp., Acinetobacter spp., Citrobacter spp., and E. coli. Our results confirmed that food hygiene training improved hygiene and is also an important component for the prevention of nosocomial infection. PMID- 24344540 TI - HPV vaccine could also prevent oropharyngeal cancer, says IARC. PMID- 24344541 TI - Occupational exposures in healthcare workers in University Hospital Dubrava--10 year follow-up study. AB - Occupational hazardous exposure in healthcare workers is any contact with a material that carries the risk of acquiring an infection during their working activities. Among the most frequent viral occupational infections are those transmitted by blood such as hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Therefore, they represent a significant public health problem related to the majority of documented cases of professionally acquired infections. Reporting of occupational exposures in University Hospital Dubrava has been implemented in connection with the activity of the Committee for Hospital Infections since January 2002. During the period of occupational exposures' monitoring (from January 2002 to December 2011) 451 cases were reported. The majority of occupational exposures were reported by nurses and medical technicians (55.4%). The most common type of exposure was the needlestick injury (77.6%). 27.9% of the accidents occurred during the blood sampling and 23.5% during the surgical procedure. In 59.4% of the exposed workers aHBs-titer status was assessed as satisfactory. Positive serology with respect to HBV was confirmed in 1.6% of patients, HCV in 2.2% of patients and none for HIV. Cases of professionally acquired infections were not recorded in the registry. Consequences of the occupational exposure could include the development of professional infection, ban or inability to work further in health care services and last but not least a threat to healthcare workers life. It is therefore deemed necessary to prevent occupational exposure to blood-borne infections. The most important preventive action in respect to HBV, HCV and HIV infections is nonspecific pre-exposure prophylaxis. PMID- 24344542 TI - Associations between overweight/obesity and physical fitness variables in Korean women. AB - AIM: The purpose of this study was to investigate whether physical fitness variables are related to overweight or obesity in Korean women. METHODS: From 2007 to 2011, 10,790 women aged 20-82 years visited a public health centre for evaluation of cardiovascular function, health-related physical fitness, and motor related physical fitness. We used the definitions of overweight and obesity provided in the World Health Organization's Asia-Pacific Standard Report. Cardiovascular function was evaluated using the Resting Heart Rate (RHR) and vital capacity. Health-related physical fitness was evaluated using the VO2max measure, sit-up number, grip strength, and sit-and-reach distance. Motor-related physical fitness was evaluated using the vertical-jump distance, side-step number, and balance (standing on 1 foot with eyes open) measure. RESULTS: The prevalence rates of overweight and obesity were 26.9% and 28.8%, respectively. Results are presented as odds ratios (with 95% confidence intervals) after adjusting for age and number of alcoholic drinks consumed per week, cigarettes smoked per day, and exercise sessions per week. When RHR increased by 1 beat per minute, overweight prevalence was 1.012 times higher (1.007-1.017, p < 0.001) and obesity prevalence was 1.006 times higher (1.000-1.011, p = 0.037). When VO2max increased by 1 mL x kg(-1) x min(-1), overweight was 0.949 times less prevalent (0.939-0.959, p < 0.001), and obesity was 0.916 times less prevalent (0.906 0.926, p < 0.001). As grip strength increased, overweight prevalence and obesity prevalence increased. An increase in vertical-jump distance by 1 cm was accompanied by a decrease in overweight prevalence by a factor of 0.975 (0.967 0.982, p < 0.001) and a decrease in obesity prevalence by a factor of 0.940 (0.932-0.948, p < 0.001). CONCLUSION: Overweight and obesity were associated with poor physical fitness as assessed by variables related to cardiovascular function and health-related and motor-related physical fitness. PMID- 24344543 TI - Age- and gender-specific prevalence of self-reported symptoms in adults. AB - OBJECTIVE: The aim of the study was to determine the age- and gender-specific prevalence of predefined symptoms in adults. METHODS: Cross-sectional study using a method of computer assisted telephone interview. RESULTS: At least one of the symptoms was experienced by 71.4% of men and 84.6% of women in the past month. Most common symptoms in men were back pain, joint pain, irritability, nervousness, and muscle pain; in women back pain, joint pain, fatigue, headache, and nervousness. The trend of symptoms' prevalence through the age groups was increasing, stable or biphasic. CONCLUSIONS: The results from this study are important for recognizing and understanding of symptoms' self-perception in both genders. PMID- 24344545 TI - Systemic lupus erythematosus--disease impact on patients. AB - AIM: Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease that can affect almost all organs of the body. Lupus is a non-curable disease and the treatment is based on symptom control by immunosuppressive and anti inflammatory treatment. The disease itself as well as treatment-related adverse events have a significant negative impact on life expectancy and quality of life of patients. The aim of this study was to identify the impact of the disease on life of SLE patients. METHODS: Data were collected anonymously using a special questionnaire. The survey involved 76 patients with SLE, results were processed by conventional methods and descriptive statistic methods. RESULTS: The survey has confirmed the impact of SLE on professional activities i.e. up to 63% of patients are registered disabled, of which 46% are granted full disability pension. SLE negatively affects patients' career--up to 39% of SLE patients stated that they had to change a job due to their disease. SLE has a strong impact on everyday life of patients. SLE symptoms are significant even during the period of quiescence--predominantly fatigue, reduced physical activity, pain. The most influenced activities of daily living included sunbathing and more strenuous activities or sport. The fact that limitations in all monitored activities are present in more than 50% of patients is a serious finding. Treatment-related adverse events have negative impact on the quality of life in almost 70% of patients. The most frequent events include gastrointestinal symptoms, visual disturbance and osteoporosis. CONCLUSION: SLE has a significant impact on the quality of life of patients and hinders them from leading everyday life at the level comparable to healthy population. PMID- 24344544 TI - Effect of TiO2 nanofibres on selected bronchoalveolar parameters in acute and subacute phase--experimental study. AB - Titanium dioxide nanofibres (TiO2) were intratracheally instilled in dose of 4 mg/0.2 mL saline solution per animal (Wistar rats). After 48 hours and 14 days the animals were exsanguinated (under i.p. thiopental narcosis), bronchoalveolar lavage (BAL) was perfomed and cells from BAL fluid were isolated. Following inflammatory, cytotoxic and oxidative stress BAL parameters were examined: differential cell count (% of alveolar macrophages (AM), polymorphonuclears and lymphocytes); the viability and phagocytic activity of AM; the proportion of immature cells; the proportion of multinucleated cells; count of AM/mL lavage; count of BAL cells/mL lavage; the level of ascorbic acid and activity of superoxide dismutase, both in tissue homogenate and in bronchoalveolar lavage fluid. The majority of examined BAL parameters in the acute and subacute phase in our study suggest serious inflammatory and cytotoxic processes in lung after exposure to TiO2. PMID- 24344546 TI - Healthy working lives in healthy businesses: new OSH strategy for small enterprises? PMID- 24344548 TI - Holistic face processing is induced by shape and texture. AB - There is increasing evidence that shape and texture are integral parts of face identity. However, it is less clear whether face-specific processing mechanisms are triggered by face shape alone, or if texture might play an important role. We address this question by studying mechanisms involved in holistic face processing. Face stimuli were either full-color pictures of real faces (shape and texture) or line drawings of the same faces (shape without texture). In a change detection task subjects judged whether eyes and eyebrows in two otherwise identical, sequentially presented faces were different in size or not. Afterwards, subjects had to identify the just presented face among two distractor faces (forced-choice identification task). The results obtained from the two tasks give rise to the conclusion that face identification and change detection tasks engage different processing strategies, which capture different aspects of holistic processing. Real faces were processed holistically, irrespective of task requirements, whereas line drawings were processed holistically only if face identification was required. On the basis of the data we conclude that face shape is relevant for the initial processing stage and feature binding, whereas face texture seems to be involved in processing of face configuration more specifically. Moreover, results demonstrate considerable flexibility of the face processing systems allowing for goal-directed and task-specific recall of face information. PMID- 24344547 TI - Developmental changes in the balance of disparity, blur, and looming/proximity cues to drive ocular alignment and focus. AB - Accurate coordination of accommodation and convergence is necessary to view near objects and develop fine motor coordination. We used a remote haploscopic videorefraction paradigm to measure longitudinal changes in simultaneous ocular accommodation and vergence to targets at different depths, and to all combinations of blur, binocular disparity, and change-in-size ('proximity') cues. Infants were followed longitudinally and compared with older children and young adults, with the prediction that sensitivity to different cues would change during development. Mean infant responses to the most naturalistic condition were similar to those of adults from 6-7 weeks (accommodation) and 8-9 weeks (vergence). Proximity cues influenced responses most in infants of less than 14 weeks of age, but sensitivity declined thereafter. Between 12 and 28 weeks of age infants were equally responsive to all three cues, while in older children and adults manipulation of disparity resulted in the greatest changes in response. Despite rapid development of visual acuity (thus increasing availability of blur cues), responses to blur were stable throughout development. Our results suggest that, during much of infancy, vergence and accommodation responses are not dependent on the development of specific depth cues, but make use of any cues available to drive appropriate changes in response. PMID- 24344549 TI - Colour detection thresholds in faces and colour patches. AB - Human facial skin colour reflects individuals' underlying health (Stephen et al 2011 Evolution & Human Behavior 32 216-227); and enhanced facial skin CIELab b* (yellowness), a* (redness), and L* (lightness) are perceived as healthy (also Stephen et al 2009a International Journal of Primatology 30 845-857). Here, we examine Malaysian Chinese participants' detection thresholds for CIELab L* (lightness), a* (redness), and b* (yellowness) colour changes in Asian, African, and Caucasian faces and skin coloured patches. Twelve face photos and three skin coloured patches were transformed to produce four pairs of images of each individual face and colour patch with different amounts of red, yellow, or lightness, from very subtle (deltaE = 1.2) to quite large differences (deltaE = 9.6). Participants were asked to decide which of sequentially displayed, paired same-face images or colour patches were lighter, redder, or yellower. Changes in facial redness, followed by changes in yellowness, were more easily discriminated than changes in luminance. However, visual sensitivity was not greater for redness and yellowness in nonface stimuli, suggesting red facial skin colour special salience. Participants were also significantly better at recognizing colour differences in own-race (Asian) and Caucasian faces than in African faces, suggesting the existence of cross-race effect in discriminating facial colours. Humans' colour vision may have been selected for skin colour signalling (Changizi et al 2006 Biology Letters 2 217-221), enabling individuals to perceive subtle changes in skin colour, reflecting health and emotional status. PMID- 24344550 TI - Motion illusions in optical art presented for long durations are temporally distorted. AB - Static figurative images implying human body movements observed for shorter and longer durations affect the perception of time. This study examined whether images of static geometric shapes would affect the perception of time. Undergraduate participants observed two Optical Art paintings by Bridget Riley for 9 or 36 s (group G9 and G36, respectively). Paintings implying different intensities of movement (2.0 and 6.0 point stimuli) were randomly presented. The prospective paradigm in the reproduction method was used to record time estimations. Data analysis did not show time distortions in the G9 group. In the G36 group the paintings were differently perceived: that for the 2.0 point one are estimated to be shorter than that for the 6.0 point one. Also for G36, the 2.0 point painting was underestimated in comparison with the actual time of exposure. Motion illusions in static images affected time estimation according to the attention given to the complexity of movement by the observer, probably leading to changes in the storage velocity of internal clock pulses. PMID- 24344551 TI - Visual jitter inhibits roll vection for an upright observer. AB - It is widely known that visual jitter convoluted with an expanding optical flow can robustly enhance an observer's illusory perception of forward self-motion (eg Palmisano et al 2000 Perception 29 57-67). In the present investigation I examine the effects of visual jitter on visually induced self-rotation (roll vection). The results showed that the strength of roll vection was decreased under conditions where the visual jitter was convoluted into the rotating visual stimulus. Although the extent of the decrement differed according to the amplitude and direction of the jitter, visual jitters in any direction with any amplitude can significantly reduce vection strength, at least under the conditions examined in the present experiment. The perceptual process underlying jitter effects on vection is discussed in the context of visuo-vestibular conflict in perception of self-motion. PMID- 24344552 TI - Effects of using multiple hands and fingers on haptic performance. AB - It remains controversial whether using two hands and multiple fingers provides any perceptual advantage over a single index finger. The present study examines this long-running question in the haptic-exploration literature by applying rigorous, psychophysical, and mathematical modeling techniques. We compared the performance of fourteen blindfolded sighted participants on seven tactile-map tasks using seven finger conditions. All tasks were benefited by multiple fingers, but it varied whether multiple fingers were beneficial on one hand, two hands, or both. Line-tracing tasks were performed faster when two hands were used, but not more than one finger per hand. Local and global search tasks were faster with multiple fingers, but not two hands. Distance comparison tasks were also performed faster with multiple fingers, and sometimes with two hands. Lastly, moving in a straight line was faster with multiple fingers, but was especially difficult with just two index fingers. These results provide empirical evidence that multiple hands and fingers benefit haptic perception, but the benefits are more complex than simply extending the tactile field of 'view'. This analogy between touch and vision fails to account for the autonomous movements and sensations of the fingers, which we show benefit the haptic perceptual system. PMID- 24344553 TI - Postural responses accompanying Achilles tendon vibration stimulation during various phases of sit-to-stand movement. AB - The aim of this study was to determine the postural response accompanying Achilles tendon vibration stimulation during various phases of the sit-to-stand movement. Twelve healthy young adults performed the sit-to-stand movement in response to an auditory signal 2 s after a first one. Vibration stimulation with a 100 Hz frequency was applied to both Achilles tendons during the following phases: (1) 10 s of sitting before standing up; (2) 10 s plus a period until the standing position was achieved; and (3) 5 s after standing. The postural response after standing was analyzed with the center of foot pressure in the anteroposterior direction. Forward-leaning responses were identified in 78.3% and 63.3% of trials under conditions 1 and 2, respectively. Backward-leaning responses were identified in 93.3% of the trials under condition 3. Response latency (+/- standard deviation) was significantly longer under conditions 1 and 2 than under condition 3 (1: 872 +/- 576, 2: 1026 +/- 542, and 3:555 +/- 322 ms; ps < 0.05). Sensory information at the standing point might be anticipated based on sensory information received while sitting. Consequently, postural response as a compensatory movement would occur via the sensory reference system within the supraspinal nervous system. PMID- 24344554 TI - On the Muller-Lyer illusion in the Carpentered World. AB - Implications of the little noticed fact that projective geometry restricts the range of interfin angles of the Muller-Lyer illusion, which are congruent with retinal projections cast by carpentered objects, are presented and tested. Experimental results support the theoretical restrictions. This implies that only Muller-Lyer figures with interfin angles within the 90 degrees to 180 degrees range are appropriate for investigation of the Carpentered World hypothesis. PMID- 24344555 TI - An archival exploration of 19th-century American adult female offender parricides. AB - Social and behavioral scientists have increasingly attended to the contexts and motivational dynamics underlying parricidal events. These efforts notwithstanding, most research has focused on adolescent or adult male offender populations. One largely neglected area of study is that of adult female offender parricide. The present study utilizes archival records to examine the contexts and sources of conflict that gave rise to adult female offender parricides in the late 19th century. Three general themes emerged, representing the primary contexts behind adult female offender parricide: (1) abuse and neglect; (2) instrumental, financially-motivated killings; and (3) expressive killings, often during the course of arguments. Each of these contexts is explored. PMID- 24344556 TI - Attachment and severity of grief: the mediating role of negative appraisal and inflexible coping. AB - According to the Dual Process Model of coping with bereavement (DPM; Stroebe & Schut, 1999), adjustment to bereavement involves a flexible oscillation between two types of coping strategies: loss-oriented (LO) and restoration-oriented (RO). This model postulates that extremely anxious or avoidant attachment disturbs the oscillation process by focusing more on one type of strategy, either LO or RO. The present study examined this assumption. We recruited 321 bereaved individuals who had lost a romantic partner. Our results showed that less negative appraisal of bereavement-related stressors, as well as higher use of RO strategies, mediated the link between attachment avoidance and low severity of grief reactions. However, the DPM variables were not found to mediate the link between attachment anxiety and elevated grief reactions. We discuss how these results provide an empirical basis of the DPM. PMID- 24344557 TI - Complicated grief in children--the perspectives of experienced professionals. AB - A total of 39 very experienced clinicians and researchers worldwide responded to a survey consisting of both structured and open-ended questions on complicated grief in children. The questions assessed their opinion on: a) what constitutes complicated grief in children; b) whether to develop a diagnosis for children as suggested for adults and, if so, would adult criteria be sufficient for children; and c) other aspects of normal and complicated grief in children. The analyses showed that the professionals struggled with defining complicated grief in children, although they agreed that the major defining aspects were intensity, duration, and longevity of reactions. They identified traumatic and delayed or inhibited grief as major types, and also agreed that adult criteria were inappropriate for children. PMID- 24344558 TI - A focus on solutions: the appropriate coping response to suffering and pain. AB - The study explored ways that therapeutic work can be done with bereaved families in the Zimbabwean, African cultural context. The study used stories that families provided about their losses. These narratives were explored as ways to inform therapeutic practice. Findings were that a focus on solutions is valuable as an adaptive intervention and might prove to be one of the most effective means by which a number of people in Zimbabwe learn to cope with grief and adapt after the death of loved ones. PMID- 24344559 TI - A scale to measure the desire to be dead. AB - Andrej Marusic suggested that it might be useful for therapists to assess the wish to be dead in clients, a preliminary step in the pathway to suicide. The aim of the present research was to develop a brief scale to measure the wish to be dead. Two samples of undergraduate students were administered a brief 10-item scale to measure the wish to be dead. The scale had moderately good test-retest reliability and internal consistency (as measured with Cronbach alpha). Scores on the wish to be dead scale had modest correlations with a history of suicidal ideation and attempts and with scores on a scale to measure obsession with death. The wish to be dead scale, therefore, appears to measure a state of mind different from suicidal ideation and obsession with death, has adequate psychometric properties (reliability and validity), and may prove useful for clinical practice and research. PMID- 24344560 TI - [In vitro investigation of three NiTi rotary instruments]. AB - The purpose of our study was to compare the shaping ability of three nickel titanium rotary instruments (RaCe/FKG Dentaire/, ProTaper /Dentsply-Maillefer/ and M(two)/VDW/) by measuring the asymmetry that occurs in curved canals during instrumentation. Eight simulated canals in resin blocks (Morita Europe) were prepared in each group by the same operator according to the instructions of the manufacturers. We used M(two) direct (VDW-Sirona) contra-angle with torque control function. Copious irrigation of the canals was performed with the use of Chloramine B solution and File-Eze (Ultradent) was used for lubrication. We accomplished our measurements on the pre- and postoperatively scanned images of the resin blocks with the aid of Image Tool for Windows 3.0 (UTHSCSA). Measuring points were assigned along the curvature of the canal axis line to represent 1 millimeter distance from the apex and from each other. The centre of the curvature was edited and radius lines were drawn from the centre through the measuring points. We determined the value of the preparation asymmetry at the levels of these measuring points along the radius lines. RaCe prepared with the greatest asymmetry at the first, second, fourth and fifth measuring points, at the third level ProTaper produced the highest value of asymmetry. In general M(two) prepared with the lowest asymmetry while it proved as a safe instrument system. The main disadvantage about ProTaper was the high risk of fracture. The RaCe sequence used in this study showed great asymmetry values at the apical area. PMID- 24344561 TI - [Investigation of the venodilatory effect of vascular endothelial growth factor (VEGF) in rat gingiva]. AB - VEGF induces proliferation of endothelial cells, stimulates angiogenesis, and increases vascular permeability in many organs. Nevertheless, we have only limited information about its role on gingival hemodynamics, especially in venules. Therefor the aim of this study was to assess the acute circulatory effects of VEGF on rat gingival venules by means of the following protocol. Wister rats (n=63) were devided into five study groups after anesthesia; each animal received 10 microl of experimental solution dripped onto the lower interincisal gingiva. The groups included: 1) saline control (after the experiment, gingiva was excised for VEGF receptor 2 [VEGFR2] immunohistochemistry); 2) VEGF (0.1, 1, 10, or 50 microg/ml); 3) VEGF2 receptor antagonist 5-((7-benzyloxyquinazolin-4-yl)amino)-4-fluoro-2-methyl-phenol hydrochloride (ZM323881; 20 microg/ml); 4) ZM323881 (20 microg/ml) followed by VEGF application (50 microg/ml after 15 minutes); and 5) VEGF (10 microg/ml), these rats were premedicated with nitric oxide (NO) synthase blocker (NG-nitro-L arginine-methyl-ester [L-NAME]; 1 mg/ml in drinking water) for 1 week before the experiment. Changes in gingival superficial venule diameter were measured by vital microscopy prior to and 1, 5, 15, 30, and 60 minutes after the administration of the experimental solutions. According to our findings, VEGF dose-dependently increased the venular diameter compared to saline. ZM323881 alone did not cause any alteration. Premedication with ZM323881 or L-NAME decreased the dilatory effects of VEGF. Occassionally moderate VEGFR2 immunohistochemical labeling was observed in the wall components of the venules. Concluding our results we can say, that there is no remarkable VEGF production under physiologic circumstances in rat gingiva, but VEGF is able to increase gingival blood flow through the activation of VEGF2 receptors and consequent NO release. PMID- 24344562 TI - [Surgical correction of excessive gingival enlargements. Case studies]. AB - INTRODUCTION: Gingival enlargement is a common form of periodontal tissue reaction to several irritating factors. The most common form is the drug related gingival hyperplasia--nevertheless the heredity gingival fibromatosis and hematological cases can also occur and might impose a challenge to periodontists. After a short literature summary three Case reports are presented. The first case is a drug related gingival overgrowth in a young kidney transplant women who took Cyclosporin-A. The excessive mass of fibrotic tissue was removed by a series of internal beveled incision and the oral and buccal gingival flaps were united with sutures. The healing was uneventful and during the follow up patient's compliance and oral hygiene was superb. The second case is a very severe antihypertensive drug related gingival overgrowth in a 62 years old man interfering with the closure of his lip and corrected with a combination of conventional gingivectomy and internal reverse beveled incision both and Ca-channel blockers. The third case is a 42 years old woman with chronic idiopathic hemolytic anemia who presented a sudden onset acute excessive generalized gingival enlargement accompanied with severe pain and fever. At admission she was suspect for leukemia. After obtaining biopsy samples and having negative histology the soft tissue mass was removed under general anesthesia with conventional gingivectomy technique, but after a couple of days the severe pain and gingival swelling recurred. With administering systemic corticosteroid therapy (32 mg Medrol), the gingiva healed in five days and the one year follow-up showed a stable hematological and periodontal status. Today the more conservative internal beveled incision is preferred over the conventional gingivectomy in the most cases because it provides a more predictable healing and better esthetics. The recurrence of the drug related gingival hyperplasia can be anticipated by meticulous postoperative individual oral hygiene and regular supportive therapy. CONCLUSION: The combined conservative and surgical therapy leads to predictable postoperative result even in very severe systematically motivated gingival enlargements, nevertheless the successful patients management needs good cooperation with medical doctors and with the patients themselves. PMID- 24344563 TI - [Salvage of a tooth with necrotised periodontium, caused by endodontic use of radiosurgery. Long-term results. Case report]. AB - Electrosurgery and radiosurgery bear certain popularity in contemporary dentistry. Nevertheless, the inadequate treatment allocation may lead to tissue necrosis. A young female patient was referred to our department following root canal treatment (RCT) by radiosurgical device. Necrotised alveolar bone, lack of keratinized gingiva and increased tooth mobility were noticed. After considering all the treatment options, we attempted to keep the tooth. Therefore, the necrotised part of the alveolar process was removed and the gingival fringe was rejuvenated alongside root surface debridement. The tooth was then splinted with glass fibre reinforced composite and appropriate RCT was completed. After ten months of improvement periodontal reconstructive surgery with deproteinized bovine bone mineral and connective tissue graft was carried out. Substantial improvement was observed at the six month reassessment, including complete healing of the gingiva. The composite splint was then removed due to discontinued mobility. The tooth and the adjacent periodontium remained stable for seven years. Nevertheless, external root resorption was recently developed that was treated with glass ionomer cement filling and regenerative periodontal surgery using enamel matrix derivative (EMD). Ultimately, the tooth is still in place providing satisfactory function and aesthetics. PMID- 24344564 TI - [Removable dentures with implants for edentulous lower jaw]. AB - Fabrication of a complete mandibular denture that offers patient comfort, function, and aesthetics along with stability and acceptable retention remains one of the most challenging procedures in dental practice. Based on a thorough treatment planning and a successful surgical procedure implants have been shown to be reliable abutment for both retention and support of overdentures. During planning important relevant factors must be considered such as old age, systemic diseases, increased financial capability, etc. Implants retained overdentures can be divided into three groups according to the type of support: mucosal, muco implantal and implantal. Key factors concerning the planning of prosthetic rehabilitation are the number and length of the implants, together with the quality and quantity of the anchoring bone tissue. PMID- 24344565 TI - [The combination therapy of an upper permanent impacted canine. Case report]. AB - The impaction of the upper canine is the second most common type of developmental anomaly following the impaction of the third molars. The authors have diagnosed the impaction of the left upper canine in the case of a 17 year-old female patient. The failure of the eruption resulting in tooth spacing of the 23 teeth mainly caused esthetical problems for the young patient and her firm request was the treatment of the spacing caused by the residual canine. The authors on the basis of the clinical and radiological examinations prepared the plans of combination therapy of oral surgery and orthodontic therapy, which were welcomed both by the patient, and her parents. The authors by describing the individual steps of the combination therapy and with the presentation of the achieved results' illustrations will review the good esthetical and functional achievements. PMID- 24344566 TI - [Prosthodontic rehabilitation of immediately placed dental implants following soft tissue augmentation. Case report]. AB - A 68-year-old nonsmoking male patient with thin gingival biotype presented for treatment of mobile mandibular left premolars. Extraction of teeth and immediate dental implant placement has been suggested. To prevent vestibular gingival recession and insure tissue stability by increasing thickness of marginal gingiva, acellular dermal matrix allograft was applied using the coronally advanced modified tunnelling technique. Six months later premolars were extracted, immediately replaced with implants and temporary crowns. After another four months, definitive gold ceramic crowns were cemented on prefabricated titanium abutments. Due to the altered gingival biotype and application of the platform switching phenomenon no vertical bone resorption and gingival recession was recorded at 6, 12 and 24 month follow-up with a well acceptable esthetic appearance. PMID- 24344567 TI - [Study of salivary biomarkers for oral squamous cell carcinoma in patients with type-2 diabetes]. AB - According to the latest epidemiological data the occurrence of oral squamous cell carcinoma has increased recently in the last 4 decades. In spite of the great emphasis and effort in the field of prevention, novel medication therapy, our knowledge has to be enlarged in the development of this serious disease. Recent epidemiological studies and animal experiments have shown that there is a relationship between type-2 diabetes and oral squamous cell carcinoma. Our goal was to screen human saliva samples for possible biomarkers for oral malignancies in diabetic patients. PMID- 24344568 TI - Stratospheric ozone, global warming, and the principle of unintended consequences -an ongoing science and policy story. PMID- 24344569 TI - Aerosol species concentrations and source apportionment of ammonia at Rocky Mountain National Park. AB - Changes in ecosystem function at Rocky Mountain National Park (RMNP) are occurring because of emissions of nitrogen and sulfate species along the Front Range of the Colorado Rocky Mountains, as well as sources farther east and west. The nitrogen compounds include both oxidized and reduced nitrogen. A year-long monitoring program of various oxidized and reduced nitrogen species was initiated to better understand their origins as well as the complex chemistry occurring during transport from source to receptor. Specifically the goals of the study were to characterize the atmospheric concentrations of nitrogen species in gaseous, particulate, and aqueous phases (precipitation and clouds) along the east and west sides of the Continental Divide; identify the relative contributions to atmospheric nitrogen species in RMNP from within and outside of the state of Colorado; identify the relative contributions to atmospheric nitrogen species in RMNP from emission sources along the Colorado Front Range versus other areas within Colorado; and identify the relative contributions to atmospheric nitrogen species from mobile sources, agricultural activities, and large and small point sources within the state of Colorado. Measured ammonia concentrations are combined with modeled releases of conservative tracers from ammonia source regions around the United States to apportion ammonia to its respective sources, using receptor modeling tools. PMID- 24344570 TI - Characterization of Halyomorpha halys (brown marmorated stink bug) biogenic volatile organic compound emissions and their role in secondary organic aerosol formation. AB - The formation of aerosols is a key component in understanding cloud formation in the context of radiative forcings and global climate modeling. Biogenic volatile organic compounds (BVOCs) are a significant source of aerosols, yet there is still much to be learned about their structures, sources, and interactions. The aims of this project were to identify the BVOCs found in the defense chemicals of the brown marmorated stink bug Halymorpha halys and quantify them using gas chromatography-mass spectrometry (GC/MS) and test whether oxidation of these compounds by ozone-promoted aerosol and cloud seed formation. The bugs were tested under two conditions: agitation by asphyxiation and direct glandular exposure. Tridecane, 2(5H)-furanone 5-ethyl, and (E)-2-decenal were identified as the three most abundant compounds. H. halys were also tested in the agitated condition in a smog chamber. It was found that in the presence of 100-180 ppm ozone, secondary aerosols do form. A scanning mobility particle sizer (SMPS) and a cloud condensation nuclei counter (CCNC) were used to characterize the secondary aerosols that formed. This reaction resulted in 0.23 microg/ bug of particulate mass. It was also found that these secondary organic aerosol particles could act as cloud condensation nuclei. At a supersaturation of 1%, we found a kappa value of 0.09. Once regional populations of these stink bugs stablilize and the populations estimates can be made, the additional impacts of their contribution to regional air quality can be calculated. PMID- 24344571 TI - Radical precursors and related species from traffic as observed and modeled at an urban highway junction. AB - Nitrous acid (HONO) and formaldehyde (HCHO) are important precursors for radicals and are believed to favor ozone formation significantly. Traffic emission data for both compounds are scarce and mostly outdated. A better knowledge of today's HCHO and HONO emissions related to traffic is needed to refine air quality models. Here the authors report results from continuous ambient air measurements taken at a highway junction in Houston, Texas, from July 15 to October 15, 2009. The observational data were compared with emission estimates from currently available mobile emission models (MOBILE6; MOVES [MOtor Vehicle Emission Simulator]). Observations indicated a molar carbon monoxide (CO) versus nitrogen oxides (NO(x)) ratio of 6.01 +/- 0.15 (r2 = 0.91), which is in agreement with other field studies. Both MOBILE6 and MOVES overestimate this emission ratio by 92% and 24%, respectively. For HCHO/CO, an overall slope of 3.14 +/- 0.14 g HCHO/kg CO was observed. Whereas MOBILE6 largely underestimates this ratio by 77%, MOVES calculates somewhat higher HCHO/CO ratios (1.87) than MOBILE6, but is still significantly lower than the observed ratio. MOVES shows high HCHO/CO ratios during the early morning hours due to heavy-duty diesel off-network emissions. The differences of the modeled CO/NO(x) and HCHO/CO ratios are largely due to higher NO(x) and HCHO emissions in MOVES (30% and 57%, respectively, increased from MOBILE6 for 2009), as CO emissions were about the same in both models. The observed HONO/NO(x) emission ratio is around 0.017 +/- 0.0009 kg HONO/kg NO(x) which is twice as high as in MOVES. The observed NO2/NO(x) emission ratio is around 0.16 +/- 0.01 kg NO2/kg NO(x), which is a bit more than 50% higher than in MOVES. MOVES overestimates the CO/CO2 emission ratio by a factor of 3 compared with the observations, which is 0.0033 +/- 0.0002 kg CO/kg CO2. This as well as CO/NO(x) overestimation is coming from light-duty gasoline vehicles. PMID- 24344572 TI - Gaseous pollutants emitted from a mechanical biological treatment plant for municipal solid waste: odor assessment and photochemical reactivity. AB - The concentrations and chromatographic profiles of gaseous pollutants emitted from a municipal solid waste (MSW) biological treatment plant were investigated to identify the major odor substances and atmospheric photochemical reactive species (PRS). Four methods were used to measure different gaseous pollutants in this study, including colorimetric tubes, gas chromatography with mass spectrometry/flame ionization detection/pulsed flame photometric detection (GC MS/FID/PFPD) preceded by cold trap concentration, GC-FID preceded by solid-phase microextraction (SPME), and high-performance liquid chromatography (HPLC) after derivation by 2,4-dinitrophenylhydrazine (DNPH). Seventy-five gaseous compounds belonging to nine groups (nitrogen compounds, sulfur compounds, alkanes, alkenes, aromatics, terpenes, alcohols, carbonyls, and volatile fatty acids [VFAs]) were identified. In the pre-biotreatment facility, the total concentration of the gaseous pollutants reached the maximum value on day 7 (317 ppm). During the post biotreatment process, the total concentration of gaseous pollutants decreased from 331 ppm at the beginning to 162 ppm in the end. The group with the greatest decrease was carbonyls, from 64 to 7.4 ppm, followed by alcohols, from 40 to 4.5 ppm, which were both oxygenated compounds. The proportion of aromatics was notably high in the pre-mechanical treatment facility, accounting for 50.6% of the total, revealing the xenobiotic compounds disseminated by stirring and agitating the waste in the initial stage. The proportions of nitrogen compounds were lower in the pre- and post-mechanical treatment facilities (1.5% and 6.9%) than in the pre- and post-biotreatment facilities (11.9% and 13:8%), suggesting that their generation was closely associated with waste degradation. The major odor compounds in the facilities were acetic acid, butyric acid, valeric acid, isovaleric acid, and dimethyl sulfide. The major PRS in the facilities were aromatics, acetaldehyde, butyraldehyde, hexanal, isopentyl aldehyde, alcohol, alpha-pinene, limonene, and terpinene. Outside the facilities, VFAs and aromatics were the most important compounds causing an environmental impact. PMID- 24344573 TI - Greenhouse gas emissions in the state of Morelos, Mexico: a first approximation for establishing mitigation strategies. AB - In this study, the authors report the first greenhouse gas emission inventory of Morelos, a state in central Mexico, in which the emissions of carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O) have been identified using the Intergovernmental Panel on Climate Change (IPCC) methodology. Greenhouse gas (GHG) emissions were estimated as CO2 equivalents (CO2 eq) for the years 2005, 2007, and 2009, with 2005 being treated as the base year. The percentage contributions from each category to the CO2 eq emissions in the base year were as follows: 38% from energy, 30% from industrial processes, 23% from waste, 5% from agriculture, and 4% from land use/land use change and forestry (LULUCF). As observed in other state inventories in Mexico, road transportation is the main source of CO2 emissions, wastewater handling and solid waste disposal are the main sources of CH4 emissions, and agricultural soils are the source of the most significant N2O emissions. The information reported in this inventory identifies the main emission sources. Based on these results, the government can propose public policies specifically designed for the state of Morelos to establish GHG mitigation strategies in the near future. PMID- 24344574 TI - Improved atmospheric sampling of hexavalent chromium. AB - Hexavalent chromium (Cr(VI)) and trivalent chromium (Cr(III)) are the primary chromium oxidation states found in ambient atmospheric particulate matter. While Cr(III) is relatively nontoxic, Cr(VI) is toxic and exposure to Cr(VI) may lead to cancer, nasal damage, asthma, bronchitis, and pneumonitis. Accurate measurement of the ambient Cr(VI) concentrations is an environmental challenge since Cr(VI) can be reduced to Cr(III) and vice versa during sampling. In the present study, a new Cr(VI) sampler (Clarkson sampler) was designed, constructed, and field tested to improve the sampling of Cr(VI) in ambient air. The new Clarkson Cr(VI) sampler was based on the concept that deliquescence during sampling leads to aqueous phase reactions. Thus, the relative humidity of the sampled air was reduced below the deliquescence relative humidity (DRH) of the ambient particles. The new sampler was operated to collect total suspended particles (TSP), and compared side-by-side with the current National Air Toxics Trends Stations (NATTS) Cr(VI) sampler that is utilized in the US. Environmental Protection Agency (EPA) air toxics monitoring program. Side-by-side field testing of the samplers occurred in Elizabeth, NJ during the winter and summer of 2012. The average recovery values of Cr(VI) spikes after 24-hr sampling intervals during summer and winter sampling were 57 and 72%, respectively, for the Clarkson sampler while the corresponding average values for NATTS samplers were 46% for both summer and winter sampling, respectively. Preventing the ambient aerosol collected on the filters from deliquescing is a key to improving the sampling of Cr(VI). PMID- 24344575 TI - Calibration of a fugitive emission rate measurement of an area source. AB - A major challenge to measuring fugitive emission rates from large area sources, such as landfills or tailings ponds, has been the establishment of the accuracy of such methods, or of a particular measurement. When such measurements are carried out, they are invariably associated with a relatively high degree of uncertainty. The Airborne Matter Mapping (AMM) method is a new method of measuring fugitive emission rates that can be applied to large area sources. The method was applied to the measurement of methane emissions from a landfill to assess the potential accuracy of the method, and the measurement process was calibrated to increase confidence in the measured value. First, a measured rate of methane from a gas cylinder was released from near the center of the landfill and the AMM method was applied to measure the methane flow rate across a measurement surface. Then, the AMM method was performed a second time along the same measurement surface without the intentional release of methane. The difference of the flow rates across the measurement surface were then compared with the measured rate of methane released from the gas cylinder. The relatively small difference of -5.7% between the flow rates, relative to the methane release rate from the gas cylinder provides confidence in the accuracy of this AMM method measurement. An adjustment to the AMM method analysis was made such that the difference between the flow rates was negligible, which resulted in a calibrated measurement of the methane emission rate from the landfill of 0.87 g/sec. PMID- 24344576 TI - Effects of the NO(x) SIP Call program on ozone levels in New York. AB - This study looks at the effects of the major U.S. Environmental Protection Agency (EPA)-mandated ozone (O3) control program implemented by New York State Department of Environmental Conservation since 2003. The study is based on ozone concentrations from eight sites representative of a range of geographic and land use conditions in the period 1995-2012. All sites show lower sample maximums of daily maximum 8-hr ozone concentrations. For example, in the period 2003-2012 compared to the period 1995-2002, the New York Botanical Gardens site experienced an 81%, 56%, and 25% drop in the number of days with daily maximum 8-hr ozone exceeding 85 ppb, 75 ppb, and 65 ppb respectively. For the same site, the frequency of hot days (with temperatures above 32 degrees C) was about the same in both periods. However, a hot day from the period 1995-2002 was 2.1 times more likely to have daily maximum 8-hr ozone exceeding 75 ppb than a hot day in the period 2003-2012. Other sites showed similar results. A comparison of the underlying distributions of ozone and temperature indicates a broad-based reduction of expected ozone values and variability, confirmed as significant by bootstrap tests. Most of the sites exhibit significant albeit small (30%) increases in expected values of maximum afternoon temperatures, favoring increased ozone production. The contrary actually happened. Consequently, trends in observed concentrations are caused by reduced ozone production rather than by favorable meteorological conditions. The study findings are consistent with previous studies that relied on different data sets and analysis methods. Taken together they demonstrate the effectiveness of the NO(x) emission reduction programs in the New York state. PMID- 24344578 TI - Municipal solid waste shear strength parameters defined through laboratorial and in situ tests. AB - This paper presents the parameters of municipal solid waste shear strength determined in the laboratory (triaxial tests) and by in situ tests: standard penetration tests (SPT) and cone penetration tests (CPT). The results analyzed here are part of a study carried out on the Santo Tirso landfill (north of Portugal) between 2001 and 2007. The influence of the strain levels, waste composition, and waste age on the shear strength parameters is presented, as well as an attempt to establish some correlations between the SPT and CPT tests and to estimate municipal solid waste (MSW) friction angles from the SPT tests. The results indicate that the aging of the waste, which is characterized by a decrease in fibrous and organic materials and an increase in inert materials and fine fraction, leads to an increase in frictional resistance and to a decrease in cohesion. The results of the SPT and CPT tests indicate higher penetration resistance in older and deeper waste. Estimating the frictional resistance from the SPT test seems to obey an empirical relationship expressed by a power function, which depends on the strain level. PMID- 24344577 TI - Biofiltration of odorous fume emitted from recycled nylon melting operations. AB - This study aimed to develop a biofilter packed only with fern chips for the removal of odorous compounds from recycled nylon melting operations. The fern chip biofilters could avoid the shortcomings of traditional media, such as compaction, drying, and breakdown, which lead to the performance failure of the biofilters. A pilot-scale biofilter consisting of an acrylic column (14 cm2 x 120 cm height) packed with fern chips to a volume of around 19.6 L was used for the test. Experimental results indicate that oxygen- and nitrogen-containing hydrocarbons as well as paraffins were major volatile organic compounds (VOCs) emitted from thermal smelting of recycled nylon at 250 degrees C. With operation conditions of medium pH of 5.5-7.0, empty bed retention time (EBRT) of 6-12 sec, influent total hydrocarbon (THC) concentrations of 0.65-2.61 mg m(-3), and volumetric organic loading of 0.05-0.85 g m(-3) hr(-1), the fern-chip-packed biofilter with nutrients of milk, potassium dihydrogen phosphate, and glucose could achieve an overall THC removal efficiency of around 80%. Burnt odor emitted from the smelting of the recycled nylon could be eliminated by the biofilter. PMID- 24344579 TI - Patient safety in the healthcare education research triad. PMID- 24344580 TI - [The implication of social support in the lives of people with hypertension]. AB - This study aimed to know the types of support offered by the network of social support and implications on hypertensive life. Qualitative study whose methodology was based on Grounded Theory. 35 people were interviewed between October 2008 and August 2010, 22 hypertensive compulsorily enrolled in HIPERDIA at a Health Unit in Belem / PA, 5 family members, 5 health professionals and 3 representatives of community institutions, referenced by hypertensive patients, as members of the network support Data were subjected to coding procedures: analysis, comparison and categorization. The category "Identifying the types of social support offered to people in their living with hypertension" was the Intervening Condition of the Theory The types of emotional informational and instrumental support originated mainly from family relationships and may mean alternative treatments,featuring a care focused on people with hypertension and their network of relationships which requires attention from healthcare professionals, including nurses. PMID- 24344582 TI - [School blogs about sexuality: an exploratory documentary study]. AB - The objective was to analyze the structure of school blogs on sexuality and their utilization by adolescents. This quantitative, exploratory and documentary study was performed with 11 blogs designed by students and available online in March of 2012. The information was submitted to hypertext analysis and descriptive statistics, taking research ethics norms into consideration. Group and education blogs developed in Portuguese and Brazilian schools were most often signed by their authors and suffered few updates. The written posts mixed scientific and informal languages, besides presenting videos and images. Every blog included information regarding the number of followers, visits, comments and a contact to answer questions. The highlighted discussed topics were birth control methods and sexually transmitted diseases (STDs). Blogs are a resource for health education that should promote active discussions and rely on the participation of health care professionals. PMID- 24344581 TI - [Adequacy of prenatal care in a family health strategy program from Porto Alegre RS]. AB - The study aimed to evaluate the adequacy of low-risk prenatal care, as recommended by the Ministry of Health, concerning the minimum number of consultations, and identify possible associated factors. Prenatal care was evaluated in a historical cohort study of 95 pregnant women. Over 50% of the women underwent six or more prenatal consultations. The beginning of the prenatal care began in the first trimester of the gestation for 52% of the women, 84.2% of the women did all their prenatal medical tests, and only 16.8% had postpartum consultations. Prenatal assistance was considered adequate for 2.1% of the sample. A higher number of prenatal consultation was observed among women who had a partner and who had other children. The records reveal a low adequacy level with all minimum criteria established and few factors seem to explain this scenario. PMID- 24344583 TI - [Bariatric surgery: its effects for obese in the workplace]. AB - This descriptive exploratory research aims to analyze the effects of bariatric surgery in the lifestyle of people with class III obesity in the workplace, through individual interviews with patients undergoing gastric bypass in gamma Rouz. Data collection was conducted in June and July, 2011, by means of individual interviews, yielding three Collective Subject Discourse: "More willingness to work" "Life without comorbidities" and "Other effects of bariatric surgery." 30 patients with mean age 44 +/- 12 years old, 24 (80%) female, 19 (63%) performed paid professional activities, 10 (34%) did not work and one (3.3%) students, 23 (96%) hypertension and eight (33%) with a diagnosis of diabetes mellitus were included in the study. Difficulty handling with physical appearance: 13 (43%) and the emotional aspect: 21 (70%). Bariatric surgery positively affected the lifestyle of obese at work with reduction in comorbidities and physical and emotional problems, favoring social and professional reintegration of the individuals. PMID- 24344584 TI - [Complications during the hospitalization of kidney transplant recipients]. AB - The objective of the study was to identify the complications in patients that have received a renal transplant. A Historical cohort performed in a university hospital from January/2007 through January/2009 with a sample of 179 patients; data collected retrospectively from the medical history of patients and submitted to statistical analyses. Mean age of patients was 43 (SD=13.7) years, 114 (63.7%) men, 95 (65.1%) non smokers and 118(66.93%) received the graft from a deceased donor. The main complications were rejection 68 (32.1%) and infection 62 (29.2%). There was statistical significance between rejection and median days of hospital stay (p < 0.001); days of use of central venous catheter (p = 0.010) and smoking status (p = 0.008); infection and central venous catheter (p = 0.029); median days of hospital stay (p < 0.001) and time of use of urinary catheter (p = 0.009). It was concluded that it is important to reduce the days of hospital stay and permanence of catheters, which may be considered in the planning of nursing care. PMID- 24344585 TI - [Nursing team knowledge on behavioral assessment of pain in critical care patients]. AB - This investigation consisted on a prospective cross-sectional study that aimed to describe the nursing team knowledge on behavioral assessment of pain. The study was conducted in a private hospital in the city of Sao Paulo, Brazil in November 2011, with nursing professionals from a general adult intensive care unit. They answered a questionnaire that contained sociodemographic data and questions related to knowledge about a behavioral assessment of pain. Descriptive data analysis was carried out and the average positive score was compared among categories using the Mann-Whitney test. Out of the 113 participants, over 70% have demonstrated knowledge of the main aspects of this assessment and there was no statistical significant difference among the professional categories. It was concluded that the knowledge of the professionals was satisfactory, but it can be improved. PMID- 24344586 TI - [Demands of home care of children born exposed to HIV in the perspective of the environmental theory]. AB - The purpose of this study was to identify the demands of home care of children born exposed to HIV in the perspective of the environmental theory. It consists of an exploratory descriptive qualitative study, developed between January and April of 2011. Study participants were ten HIV-infected mothers with infants exposed to the virus, living in Fortaleza, Ceara. The data collection instruments included a disposable digital camera and forms to obtain information on health associated with the home environment. Results were contextualized according to the theory and organized into the following categories: vulnerabilities associated with the physical structure of the house; contaminated intra and peridomestic air; unclean water used for drinking; sanitation and sewerage system; lighting and ventilation of the house. In conclusion, the home environment offers unfavorable environmental conditions for the child. Targeted interventions in the home environment are necessary so as to promote the health of children born exposed to HIV. PMID- 24344587 TI - [Children's chronic disease:family needs and their relationship with the family health strategy]. AB - The purpose of this study was to learn the perception that families of children with a chronic disease make of their relationships with the Family Health Unit (FHU). This qualitative study was performed using symbolic interactionism as the theoretical ground and narrative inquiry as the method. Data were collected through semi-structured interviews with seven families of children with chronic disease, enrolled in the FHU of a region with high social vulnerability, in Sdo Paulo state, Brazil. Results showed that the family's relationship with the FHU is influenced by elements from their experience and trajectory, and that their experience as a family of a child with a chronic disease is strongly marked by their relationship with the health care services. This has great influence on the responses of the family, thus requiring a systematic and committed engagement of the health system in relieving their suffering, beyond merely treating the disease. PMID- 24344588 TI - [Health education in radiology service: orientations for breast and thyroid aspiration puncture]. AB - This is a convergent care research developed in a school hospital's radiology service whose purpose is to learn about the concerns and expectations of clients submitted to breast and thyroid Fine Needle Aspiration Puncture. Data collection was conducted from September 2010 to April 2011, through 10 educational meetings in the waiting room interviewing 88 clients. The results show: clients' perception of the test, cancer as a stigma and healthcare education as a confrontation strategy. In addition, they revealed fear of both the procedure and the diagnosis of cancer. Educational practice in the waiting room is a space to decrease anxiety and allows the exchange of experiences and knowledge between professional and client, it also fosters a support network among clients. It is characterized as important space of action to the nurse within radiology service. PMID- 24344589 TI - [Perceived health status and pharmacological adherence of patients who underwent percutaneous coronary intervention]. AB - The objectives of this study were to evaluate the perceived health status and pharmacological adherence, and to verify the correlation between these measures in patients who underwent percutaneous coronary intervention, after hospital discharge. It was a cross-sectional study carried out from May 2011 to July 2012. The instruments used were: SF-86 and Measurement of Adherence to Treatment, with 101 patients, 54 (53.5%) of which were men; average age of 59.5 +/- 10.3; and 32 (32.7%) with previous cardiac treatment. All study participants were using antihypertensive drugs; the majority 99 (98%) used antiplatelet drugs; 98 (97%) used cholesterol reducers, and 59 (58.4%) used coronary vasodilators. The average number of drugs used was 6.8 +/- 2.1. Pharmacological adherence was observed in 98 (97%) patients. The participants presented best perceived health status in Social Functioning and Physical Functioning. Positive correlations of moderate magnitude were found between measurements of pharmacological adherence and Physical Functioning, General Health and Social Functioning. There was correlation between pharmacological adherence and perceived health status. PMID- 24344590 TI - [The daily life of men who lives with chronic venous ulcer: phenomenological study]. AB - The chronic venous leg ulcer is the major therapeutic problem of lower limb injuries, which can trigger changes in the daily life of the person affected by it. This study aimed to understand the daily life of men who lives with chronic venous ulcers. A phenomenological study was conducted with eight men, who were interviewed during June and July of 2001. The study asked questions related to: "Restrictions in social life" and "Recovering the skin integrity and restart the activities affected by the wound". The answers revealed that men with these ulcers have social implications in the areas of productivity and sexuality. This leads to restrictions in everyday life with loss in performance of socially established roles for men, leading to anxiety for his return at full performance of his social role. The findings suggest significant experiential aspects that may guide professionals in the planning and implementation of health actions aimed to treat these patients. PMID- 24344591 TI - [Implications of the visibility in professional nursing practices]. AB - Nursing construction image is permeated by historical socioeconomic and cultural aspects. This theme aims to understand the perception of nurses regarding the visibility of nursing staff's daily work. This qualitative research is exploratory, with 30 nurses at a university hospital in southern Brazil. The data was collected from July to October 2012, through semi-structured interviews and submitted for a discursive textual analysis. The results show that nursing visibility is related to a professional historical trajectory, to an absence of recognition of the scientific aspect of Nursing, to erroneous placement in the media, to improper behavior towards the staff and also to work overload. Thus, the demystification of nursing's image includes greater media visibility, conducting personnel marketing, appropriate behavior in front of health staff and professional demonstrations of autonomy, challenges that must be overcome by nursing. PMID- 24344592 TI - [Nausea, vomiting and quality of life in women with breast cancer receiving chemotherapy]. AB - The aim of this study was to assess the quality of life (QoL) of women with breast cancer during chemotherapy and to identify the incidence of nausea and vomiting during the treatment Data were assessed with the application of the instrument of the European Organization for Research and Treatment of Cancer, EORTC-QLQ-C30 Portuguese version and breast cancer module BR-23, which was applied before, in the middle and in the end of the treatment. The participants were 79 women, of which 93% had nausea and 87% had vomited at least once during the treatment. QoL showed a slight decrease during treatment. Cronbach's alpha for each application of the questionnaires was 0.890492, 0.936392 and 0.937639. The availability of treatment information and guidelines on the management of nausea and vomiting is crucial for the proper management of the toxicities of chemotherapy. PMID- 24344593 TI - [Nursing teaching on HIV/AIDS in the perspective of citizenship]. AB - The aim was to investigate the perception of nursing faculty about their responsibility in teaching practice on HIV/AIDS and if they value the construction of knowledge on the subject of HIV/AIDS focused on parameters aimed to citizenship. This qualitative study had its theoretical framework on Morin Complex Thought. Seven professors from jive institutions of higher education in Sao Paulo participated of the study in the period from January to July 2010. Data were collected through focus group and analysed through content analysis. The semantic categories were: The importance of reflection and criticality of the professor in teaching HIV/AIDS; the exercise of citizenship through education of HIV/AIDS and; the understanding of the human in learning from the experience of a person with HIV/AIDS. The study shows that the role of the professor when teaching HIV/AIDS is essential to an ethical and a citizen development for the future nurse. PMID- 24344594 TI - [A profile of admittances to hospital due to non-contagious chronic diseases sensitive to primary health care among chronologically advantaged patients in the southern half of Rio Grande do Sul]. AB - The purpose here established was that of establishing, within the municipalities in the southern part of the Brazilian State of Rio Grande do Sul, the profile of admittances to hospital resulting from Non-Contagious Chronic Diseases Sensitive to Primary Health Care (NCCDSPHC) among chronologically advantaged patients. This is a transversal study with secondary data obtained from the Information Technology Department of the Brazilian Public Health System--SUS (DATASUS), including variables related to admittance to hospital and also the mortality rates in hospitals (according to causes, gender, age, and time spent in hospital). The NCCDSPHC are responsible for 43.99% of hospital admittances for all causes (AAC), with Pulmonary Diseases standing out as the most prevalent single group (18%), followed by Heart Failure (12.28%). The female sex, with the exception of the Pulmonary Disease category, is the one that causes most admittances to hospital through other causes. We also found a linear trend towards an increase in the mortality rate of the NCCDSPHC when grouped together Our conclusion is that, due to the magnitude of the admittances to hospital, as also the increase in the mortality caused by the NCCDSPHC, it is urgent to embark on more in-depth considerations about care to be taken as part of primary care for the chronologically advantaged in this region. PMID- 24344595 TI - [Nursing practice of care to patients undergoing elective surgery in the immediate preoperative period]. AB - Research that aimed to analyze the care of nurses to patients, in the daily professional practice, provided in the preoperative period for patients undergoing elective surgery. It is a descriptive research with a qualitative approach that involved 15 nurses from Surgical Units and two nurses from the Surgical Centre of a hospital in the southern region of Brazil. Data was collected in semi-structured interviews conducted from April to July 2011. Data was analyzed using the Collective Subject Discourse (CSD) technique. The information obtained generated three CDS focused on the following ideas: administrative care, instruction in the preoperative period and surgical care in the immediate preoperative period. The results showed that caring consists mostly of giving instructions to the patient in the preoperative period. It is concluded that the care was directed to the physical aspects to the detriment of the psychological, in disagreement with the assistance methodology adopted in the hospital, supported by the Theory of Basic Human Needs. PMID- 24344596 TI - [Quality of life in patients with diabetes using the Diabetes 39 (D-39) instrument]. AB - The purpose of this study is to investigate the specific quality of life of patients with diabetes mellitus. It is a cross-sectional study, which was conducted from August 2-28, 2012 in two basic health units, in the interior of Sao Paulo. A convenience sample, made up of 75 patients, 18 years old or older, both sexes, in a group of self-monitoring of blood glucose, was used. The Diabetes 39 (D-39) Instrument Evaluation, containing five dimensions: energy and mobility (15 items), diabetes control (12), anxiety and worry (4) social overload (5) and sexual behavior (3), was used. Quality of life proved to be highly affected in the items related to the social overload dimension, embarrassment for having diabetes, being called diabetic and diabetes interfering with family life. The elucidation of the assessed factors contributes to the planning of educational programs, insofar as they may hinder the achievement of metabolic control in patients with diabetes. PMID- 24344597 TI - [Enterprising tendencies of nurses in a university hospital]. AB - Quantitative study aimed to identify the enterprising tendency of nurses at a university hospital and to relate them with age, length of work in the hospital and conclusion of the nursing course. This cross-sectional quantitative study was developed in 2010. All 60 nurses from the hospital answered the questionnaire General measure of Enterprising Tendency, which contains five categories. In the creativity category one nurse obtained two points; in need for achievement one nurse totaled 12 points; one nurse obtained two points; in motivation four nurses achieved higher scores; in taking calculated risks, the highest score was 10 points, in autonomy, nine nurses obtained one point each. Individuals aged between 27 and 33 years showed higher enterprising tendencies. Reduced enterprising tendencies were found for nurses aged between 43 and 56 years, graduated more than 17 years ago and with a greater length of work. Actions are necessary to encourage nurses in the age range of enterprising tendency decline and those who graduated longer ago and who have worked for a longer period of time in the hospital. PMID- 24344598 TI - [Community integrative therapy: situations of emotional suffering and patients' coping strategies]. AB - Community Integrative Therapy (CIT) has emerged as a strategy to support the mental health of users of the public Unified Health System (SUS). This study had the objective to identify the principal problems presented by patients of group therapy, and to identify strategies that they use to cope with situations that cause emotional suffering. Secondary research carried out at the Municipal Secretary of Health, with information sources being organization forms with data from CIT The results demonstrate that the most frequent problem fcause of suffering] is stress, the coping strategy most used is spirituality, and through the discourses of the participants it is possible to perceive the positive perception that they have of the meetings. CIT is a space where the relationships that are forged transmit emotional support, strengthen ties and diminish cases of social exclusion. PMID- 24344599 TI - [Sexual-affective trajectories of people with chronic leg ulcers: aspects of therapeutic listening]. AB - This is a qualitative study that aims to discuss the trajectories of people with chronic sores on the lower limbs,focusing on their affective and sexual experiences. Fifty-one adult outpatients participated and they received care at the infirmary of a public hospital in Salvador-Bahia, between 2008 and 2009. Data was collected through techniques that included themed-story drawings and in-depth interviews, during therapeutic listening sessions,followed by an analysis of the content and an analysis of the drawing contents. Three categories emerged solitary sexual-affective trajectory, fragmented sexual-affective trajectory, and continuous or linear sexual-affective trajectory. It was concluded that the limitations imposed by sores influence the subjectivity of these people, leading them to processes of loss of self-confidence, self-deprecation and fear of sexual affective demands. It becomes clear, therefore, for the need to promote, not only curative interventions for the body, but also to include therapeutic listening and psychological support in the assistance offered to these people. PMID- 24344600 TI - [Family experiences post-acute myocardial infarction]. AB - This study aimed to describe the family experiences post-infarction. Qualitative, descriptive and exploratory research, carried out with six families of post infarction patients. Data collection was conducted in families' homes, in the period of February to May of 2012, through observation and interviews with the family. The software Atlas Ti 6.2 was used to code the interviews and the data were explored with thematic analysis. Two categories emerged "Difficult times": immediate consequence of acute myocardial infarction for the families; and "We reeducate ourselves--we can adapt ourselves": current experience of families. The immediate post-infarction experience is permeated by several feelings, with the need for families to adapt to fit into the needs. The current experience shows changes in families due to the disease. The family is the main responsible for the care giving, although Nursing should exchange and share knowledge. PMID- 24344601 TI - [Vulnerability of adolescent students to STD / HIV in Imperatriz - Maranhao]. AB - The aim of this study was to investigate the vulnerability of adolescent students related to sexually transmitted diseases (STD) and the human immunodeficiency virus (HIV), identifying the main risk behaviors and prevention. This quantitative, cross-sectional study was performed in three public schools in Imperatriz--Maranhao, with 295 adolescents, using a structured questionnaire. The results show that: most young people (86.3%) who used a condom the last time they had intercourse, usually keep this practice, 82.8% of adolescents who understand the concept of HIV protect themselves against these infections and believe the main form of contamination is through sex, infected blood or through the placental barrier. We conclude that most teenager participants showed coherent knowledge about sexual practices and risk behaviors that make them vulnerable to STD/HIK presenting a positive aspect for the prevention of these diseases. PMID- 24344602 TI - [Playful strategies for data collection with child cancer patients: an integrative review]. AB - Children are the best sources of information on their experiences and opinions, and qualitative studies have favored the development and application of techniques that facilitate their self-expression and approaching the researcher. Through an integrative literature review, the objective of this research was to identify playful resources used in qualitative research data collection with child cancer patients, and their forms of application. Systemized searches of electronic databases and a virtual library were undertaken, which, combined with a non-systemized sample, totaled 15 studies spanning the period from 2000 and 2010. Drawing, toys, puppets, photography and creativity and sensitivity dynamics were identified which, in association with interviews or not, were shown to directly or indirectly facilitate data collection, thereby broadening the interaction with the children, and permitting further expression of their feelings. The advantages and limitations of using these resources are presented thus contributing to planning research with children. PMID- 24344603 TI - [Patient identification in healthcare organizations: an emerging debate]. AB - The patient identification process is essential to ensure safety and quality of assistance in healthcare institutions. The use of a wristband for identification is common practice, although cultural organization, material and human factors cause non-conformity resulting in errors or adverse events. The aim of this article is to highlight constituent elements of the patient identification process by means of wristbands and discuss topics related to the implementation of this process in hospitals. This study was based on theoretic references and standardizations of accrediting organizations and bodies that debate security in the hospital environment and incentives for safe patient identification. It was concluded that patient identification by means of wristbands is recommended internationally although there are loopholes in relation to protocol, effective execution and evaluation of the process to support management and healthcare actions. PMID- 24344604 TI - [A careful look to postmodern tribes: caring for adolescent health in the context of their everyday lives]. AB - This is a theoretical reflection, based on Michel Maffesoli's Comprehensive Sociology, which is concerned with the health care of adolescents in contemporary everyday life, and particularly with the phenomenon of urban tribes. These are understood as groups of people who have emotional ties, building a bond of sociality towards a common goal. This study focuses on the importance to take into account the lifestyle of adolescents and aims to raise awareness among health professionals about such issues, seeking for strategies tuned with reality and care needs in order to promote health, devising ways to improve caring, rethinking health policies for adolescents in contemporary society. PMID- 24344606 TI - The informal and hidden curricula of mobile device use in medical education. PMID- 24344607 TI - And finally.... PMID- 24344605 TI - Constituents of an extract of Cryptocarya rubra housed in a repository with cytotoxic and glucose transport inhibitory effects. AB - A new alkylated chalcone (1), a new 1,16-hexadecanediol diester (2), and eight known compounds were isolated from a dichloromethane-soluble repository extract of the leaves and twigs of Cryptocarya rubra collected in Hawaii. The structures of the new compounds were determined by interpretation of their spectroscopic data, and the absolute configurations of the two known cryptocaryanone-type flavonoid dimers, (+)-bicaryanone A (3) and (+)-chalcocaryanone C (4), were ascertained by analysis of their electronic circular dichroism and NOESY NMR spectra. All compounds isolated were evaluated against HT-29 human colon cancer cells, and, of these, (+)-cryptocaryone (5) was found to be potently cytotoxic toward this cancer cell line, with an IC50 value of 0.32 MUM. This compound also exhibited glucose transport inhibitory activity when tested in a glucose uptake assay. PMID- 24344608 TI - Biomolecular analysis and biological tissue diagnostics by electrospray ionization with a metal wire inserted gel-loading tip. AB - A metal wire-inserted disposable gel-loading tip was examined as an electrospray emitter. Its performance was similar to that of conventional electrospray ionization (ESI) with a relatively low flow rate (~100 nL/min) and without the need for solvent pumps. It was also used as an emitter for solid probe-assisted ESI (SPA-ESI) (e.g., biofluid was sampled from the biological tissue by a needle and was inserted into the solvent-preloaded gel-loading tip). Selective detection of lipids and proteins, such alpha and beta chains of hemoglobin could be accomplished by choosing appropriate solvents. A suitable protocol for cancer diagnosis was established by this method. A good figure of merit of this method is its applicability to biological tissue diagnostics with high cost efficiency and on a disposable basis. PMID- 24344609 TI - Vertical Ridge Augmentation of Atrophic Posterior Mandible Using Platelet-Derived Growth Factor: Two Case Reports. PMID- 24344610 TI - TUBB1 mutation disrupting microtubule assembly impairs proplatelet formation and results in congenital macrothrombocytopenia. AB - This report describes a family with TUBB1-associated macrothrombocytopenia diagnosed based on abnormal platelet beta1-tubulin distribution. A circumferential marginal microtubule band was undetectable, whereas microtubules were frayed and disorganized in every platelet from the affected individuals. Patients were heterozygous for novel TUBB1 p.F260S that locates at the alpha- and beta-tubulin intradimer interface. Mutant beta1-tubulin was not incorporated into microtubules with endogenous alpha-tubulin, and alpha-tubulin expression was decreased in transfected Chinese hamster ovary cells. Transduction of mutant beta1-tubulin into mouse fetal liver-derived megakaryocytes demonstrated no incorporation of mutant beta1-tubulin into microtubules with endogenous alpha tubulin and diminished proplatelet formation, leading to the production of fewer, but larger, proplatelet tips. Furthermore, mutant beta1-tubulin was not associated with endogenous alpha-tubulin in the proplatelets. Deficient functional microtubules might lead to defective proplatelet formation and abnormal protrusion-like platelet release, resulting in congenital macrothrombocytopenia. PMID- 24344612 TI - Serum levels of nitric oxide and endothelin-1 in patients treated with continuous ambulatory peritoneal dialysis. AB - End-stage renal disease (ESRD) and its treatment modules affect almost all organs and organ systems including vascular endothelium. It is well known that disturbance of vasoactive substances (nitric oxide - NO and endothelin-1 - ET-1) production appears in these patients. There is a small number of studies which investigated serum levels of NO and ET-1 in ESRD patients treated with continuous ambulatory peritoneal dialysis (CAPD). Therefore our study aimed to measure serum levels of NO and ET-1 in this population. This study included 23 ESRD patients (10 males and 13 females) treated with CAPD, mean age 55.8 +/- 15.8 years. Mean duration of CAPD treatment in this group of patients was 3.4 +/- 14.7 years. Besides this group of patients (CAPD), we included a second group which consisted of 30 healthy controls [14 males, 16 females, mean age 51.8 (+/-15.6) years]. Our results show significantly higher serum levels of NO in CAPD patients x +/- SD = 19.09 +/- 6.9) in comparison to the control group (x +/- SD = 9.5 +/- 1.9) (p < 0.05). There was no significant difference in serum levels of ET-1 between CAPD patients x +/- SD = 7.3 +/- 5.6) and the control group (x +/- SD = 6.6 +/- 4.2), (p > 0.05). From our results, we concluded that imbalance in production of vasoactive substances is present in CAPD patients. This imbalance can lead to disturbance in local blood flow control. These pathophysiological mechanisms can cause significant hemodynamic disturbance (hypertension) and atherosclerosis. PMID- 24344611 TI - Adverse childhood experiences and the cardiovascular health of children: a cross sectional study. AB - BACKGROUND: Adverse childhood experiences (ACEs), such as abuse, household dysfunction, and neglect, have been shown to increase adults' risk of developing chronic conditions and risk factors for chronic conditions, including cardiovascular disease (CVD). Much less work has investigated the effect of ACEs on children's physical health status that may lead to adult chronic health conditions. Therefore, the present study examined the relationship between ACEs and early childhood risk factors for adult cardiovascular disease. METHODS: 1 234 grade six to eight students participated in school-based data collection, which included resting measures of blood pressure (BP), heart rate (HR), body mass index (BMI) and waist circumference (WC). Parents of these children completed an inventory of ACEs taken from the Childhood Trust Events Survey. Linear regression models were used to assess the relationship between experiencing more than 4 ACEs experienced, systolic BP, HR, BMI and WC. In additional analysis, ACEs were assessed ordinally in their relationship with systolic BP, HR, and BMI as well as clinical obesity and hypertension status. RESULTS: After adjustment for family education, income, age, sex, physical activity, and parental history of hypertension, and WC for HR models, four or more ACEs had a significant effect on HR (b = 1.8 bpm, 95% CI (0.1-3.6)) BMI (b =1.1 kg/m2, 95% CI (0.5-1.8)), and WC (b = 3.6 cm, 95% CI (1.8-5.3)). A dose-response relationship between ACE accumulation and both BMI and WC was also found to be significant. Furthermore, accumulation of 4 or more ACEs was significantly associated with clinical obesity (95th percentile), after controlling for the aforementioned covariates. CONCLUSIONS: In a community sample of grade six to eight children, accumulation of 4 or more ACEs significantly increased BMI, WC and resting HR. Therefore, risk factors related to reported associations between ACEs and cardiovascular outcomes among adults are identifiable in childhood suggesting earlier interventions to reduce CVD risk are required. PMID- 24344613 TI - Closing data gaps for LCA of food products: estimating the energy demand of food processing. AB - Food is one of the most energy and CO2-intensive consumer goods. While environmental data on primary agricultural products are increasingly becoming available, there are large data gaps concerning food processing. Bridging these gaps is important; for example, the food industry can use such data to optimize processes from an environmental perspective, and retailers may use this information for purchasing decisions. Producers and retailers can then market sustainable products and deliver the information demanded by governments and consumers. Finally, consumers are increasingly interested in the environmental information of foods in order to lower their consumption impacts. This study provides estimation tools for the energy demand of a representative set of food process unit operations such as dehydration, evaporation, or pasteurization. These operations are used to manufacture a variety of foods and can be combined, according to the product recipe, to quantify the heat and electricity demand during processing. In combination with inventory data on the production of the primary ingredients, this toolbox will be a basis to perform life cycle assessment studies of a large number of processed food products and to provide decision support to the stakeholders. Furthermore, a case study is performed to illustrate the application of the tools. PMID- 24344615 TI - The most-cited sources on the orthopaedic in-training examination: question yield, reading efficiency, and time lag from publication. AB - BACKGROUND: Each Orthopaedic In-Training Examination (OITE) question references one or more journal articles or textbook sections as the evidence-based origin of its "preferred response." Previous studies identified the number of references to the top sources but not the number of questions covered by these top sources. The current study analyzes the question yield, time lag from publication, and sequential benefit-in terms of OITE questions covered-of the most referenced sources in order to provide residents and educators strategies for developing an efficient reading program. METHODS: We analyzed all OITE references from 2002 to 2009 and identified 1. The most referenced journals, text- books, authors, and journal articles; 2. The question yield of the top journals; 3. The time lag from article publication to OITE reference; and 4. The additional question benefit of the top sources when added sequentially. We repeated the analysis considering only journal articles published within 5 years of each respective OITE. RESULTS: The most referenced journals were the The Journal of Bone and Joint Surgery, American Edition (JBJS-Am), Clinical Orthopaedics and Related Research (CORR), and the The Journal of the American Academy of Orthopaedic Surgeons (JAAOS). JBJS Am accounted for 14% of all references and was referenced on 24% of questions; CORR and JAAOS each contributed 6% of references and were referenced on 11% of questions. The average time from article publication to OITE reference was 8.1 years (median: 6 years, mode: 2 years). The top 29 authors were referenced on 15% of OITE questions. The two most-referenced articles were each referenced 7 times in 8 years. Regarding question yield, 18% of published JAAOS articles were referenced on an OITE, as opposed to 7% of JBJS-Am articles and 2% of CORR articles. Considering articles published within 5 years of an OITE, the number of questions referencing JBJS-Am decreased from 24% to 10%. The sequential benefit of adding JAAOS and CORR during the 5 years was an additional 8% of total questions. CONCLUSIONS: When developing a reading curriculum, educators and residents should be aware of the question yield, reading efficiency, and time lag to publication of the most common OITE reference sources. PMID- 24344616 TI - Rink-side management of ice hockey related injuries to the face, neck, and chest. AB - Ice hockey is a fast paced sport with unique injury potential. A covering physician must be prepared to acutely manage injuries to the face, neck, and chest that are not common in orthopedic practice. Injuries about the face seen in ice hockey include facial fractures, lacerations, and eye and dental injuries. Neck trauma can result in lacerations and neurologic injury. Commotio cordis and sudden cardiac death are potentially fatal conditions seen in ice hockey. This review details the appropriate acute management of these conditions for the physician covering an ice hockey game. Knowledge of these conditions and appropriate rink-side management can be potentially life-saving. PMID- 24344617 TI - Predictors of postoperative infection in spinal deformity surgery - which curves are at greatest risk? AB - BACKGROUND: Numerous studies have reported on post- operative infection following spinal arthrodesis for spinal deformity. The incidence of infection associated with spinal surgery overall ranges from less than 1% to 15%. Certain factors may increase the risk of surgical site infection (SSI) in patients who undergo surgical treatment for spinal deformities. These include a diagnosis of neuromuscular disease, use of surgical drain or lack thereof, patient comorbidities, increased blood transfusions, and an allergic inflammatory response to the use of instrumentation. Many of these studies, however, have been limited by small numbers and confounded by multiple surgeons and hospitals. PURPOSE: The purpose of this study was to determine the rate of spinal wound infection following spinal deformity surgery in a single surgeon's practice and to identify risk factors for infection, particularly those related to type of deformity and surgical procedures performed. STUDY DESIGN: This is a retrospective review of prospectively collected data from a single surgeon. Only spinal deformity patients' records were reviewed. METHODS: We reviewed 941 spinal deformity operative procedures (806 patients, 584 females, 222 males) done by a single surgeon from 1999 to 2009. Outcome measures were superficial wound infection, deep wound infection, possible infection, and no infection. The following variables were assessed: gender, age, height, weight, body mass index (BMI), primary diagnosis, associated comorbidities, prior spinal surgeries, surgical approach, type and number of procedures performed, radiographic measurements, operative data (including operative time), and complications. A one way ANOVA and Turkey post-hoc analysis was used. RESULTS: The average age was 22.3 years (range 1.8 to 82 years). There were 13 deep wound infections (1.4%) and 17 incidences of superficial wound infection (1.8%), for an overall infection rate of 3.2%. The following variables were found to be independent predictors of deep infection: neuromuscular scoliosis (odd ratio (O.R. 9.2) and Lenke 3 or 4 curve types in adolescent idiopathic scoliosis patients (O.R. 7.4). Kyphosis (O.R. 4.38), combined approach (O.R. 0.81), total number of levels fused (O.R. 1.16), and Lenke 3 or 4 curve types in AIS (O.R. 4.54) were independent predictors of superficial infection. Lastly, logistic regression identified the following as predictors of any infection: BMI (O.R. 1.11), total number of comorbidities (O.R. 1.24), osteotomy procedure (O.R. 3.14), number of levels fused (O.R. 1.13), and Lenke 3 or 4 curve types (O.R. 1.67). CONCLUSION: Age, BMI, number of levels, Lenke 3-4 curves, osteotomy, and number of comorbidities were found to be predictors of any infection. Of these, only Lenke 3-4 and neuromuscular comorbidity was correlated with deep infection. PMID- 24344618 TI - Shoulder arthroplasty expected outcomes: surgeons' opinion survey. AB - BACKGROUND: Shoulder arthroplasty provides predictable pain relief and functional improvement of the shoulder for glenohumeral disease. With recent emphasis on health economic planning and rising patient expectation, physicians are encouraged to adopt more evidence-based strategies for decision-making. In the context of shoulder arthroplasty, surgeon preference and bias may play a large role in the choice of the procedure performed. The purpose of this study is to objectively examine the perceived differences and similarities, from the surgeon's perspective, between total shoulder arthroplasty (TSA) and hemiarthroplasty anticipated outcomes. METHODS: We conducted a web-based survey that asked surgeons to weigh the relative values of these procedures in relation to one another. Within the survey, there were numerous variables in which the surgeon was asked to choose the preferred surgical outcome. Ninety-eight surgeons responded to the survey. The average age was 51.7 years. RESULTS: Surgeons in our study chose pain relief and improved ROM as a more likely outcome in TSA than any level of complication and as a more likely out-come than improved strength compared to hemiarthroplasty. These results emphasized the perception amongst the polled surgeons that TSA is a preferred treatment option for patients who expect a high level of pain relief and ROM even at the expense of a decreased strength. CONCLUSION: This study is a first step in the construction of a patient oriented model for treatment decisions. With this information, we may be better able to tailor our patients' needs and wishes to the procedures that most predictably result in the outcomes they desire. PMID- 24344619 TI - Hospital cost analysis of neuromuscular scoliosis surgery. AB - STUDY DESIGN: A retrospective review of 74 consecutive, surgical patients with neuromuscular scoliosis (NMS). OBJECTIVE: This study evaluates the distribution of hospital and operating room costs incurred during surgical correction of NMS. BACKGROUND DATA: Recent studies have demonstrated that surgical treatment improves both medical outcomes and the quality of life in patients with progressive NMS. Characterization of the costs incurred at the time of surgery and hospitalization will facilitate the identification of opportunities for cost reduction. METHODS: Demographic data collected included gender, age, preoperative height, weight, and BMI. Major coronal curvatures and T5-T12 kyphosis were assessed from radiographs. Construct type and number of screws, hooks, and wires implanted were recorded. Surgical costs were calculated based on cost of surgical correction, hospital stay, and postoperative care. RESULTS: Mean age was 15.8 +/- 7.3 years; 57% were male. Comorbidities included cerebral palsy (28%) and familial dysautonomia (14%). The mean preoperative major curve magnitude was 60 degrees ; minor curve magnitude was 33 degrees . Posterior approach (76%) and pedicle screws (75%) were predominantly utilized. The average length of hospitalization was 8 days (range: 3 to 47). There were six major complications (8%). The total surgical cost was $50,096 +/- $23,998. The highest individual cost was for implants ($13,916; 24% of total costs). The second highest was inpatient room and ICU costs ($12,483; 22%); bone grafts were the third ($6,398; 11%). Increased major and minor structural curve, increased total (A/P) levels fused, and increased length of hospital stay predicted an increase in total cost. CONCLUSIONS: Major contributors to cost in NMS surgery are implants, inpatient room and ICU costs, and bone grafts. Independent predictors of higher cost are the degree of major and minor structural curve, total number of A/P levels fused, and length of hospital stay. These conclusions provide insight into costs associated with care for a medically fragile and challenging patient population. PMID- 24344620 TI - Scapular notching in reverse shoulder arthroplasty: validation of a computer impingement model. AB - PURPOSE: The purpose of this study is to validate a reverse shoulder computer impingement model and quantify the impact of implant position on scapular impingement by comparing it to that of a radiographic analysis of 256 patients who received the same prosthesis and were followed postoperatively for an average of 22.2 months. METHODS: A geometric computer analysis quantified anterior and posterior scapular impingement as the humerus was internally and externally rotated at varying levels of abduction and adduction relative to a fixed scapula at defined glenoid implant positions. These impingement results were compared to radiographic study of 256 patients who were analyzed for notching, glenoid baseplate position, and glenosphere overhang. RESULTS: The computer model predicted no impingement at 0 degrees humeral abduction in the scapular plane for the 38 mm, 42 mm, and 46 mm devices when the glenoid baseplate cage peg is positioned 18.6 mm, 20.4 mm, and 22.7 mm from the inferior glenoid rim (of the reamed glenoid) or when glenosphere overhang of 4.6 mm, 4.7 mm, and 4.5 mm was obtained with each size glenosphere, respectively. When compared to the radiographic analysis, the computer model correctly predicted impingement based upon glenoid base- plate position in 18 of 26 patients with scapular notching and based upon glenosphere overhang in 15 of 26 patients with scapular notching. CONCLUSIONS: Reverse shoulder implant positioning plays an important role in scapular notching. The results of this study demonstrate that the computer impingement model can effectively predict impingement based upon implant positioning in a majority of patients who developed scapular notching clinically. This computer analysis provides guidance to surgeons on implant positions that reduce scapular notching, a well-documented complication of reverse shoulder arthroplasty. PMID- 24344621 TI - Impact of inferior glenoid tilt, humeral retroversion, bone grafting, and design parameters on muscle length and deltoid wrapping in reverse shoulder arthroplasty. AB - PURPOSE: This study quantifies the ability of humeral retroversion, glenoid tilt, bone graft, and varying prosthesis design parameters to restore anatomic muscle length and deltoid wrapping with reverse shoulder arthroplasty. METHODS: A computer model simulated abduction and internal and external rotation for a normal shoulder, the RSP reverse shoulder, the Equinoxe reverse shoulder, and the Grammont reverse shoulder when implanted using various implantation methods. The length of eight different muscles and the deltoid wrapping angle were quantified to evaluate the ability of each implantation method and design to restore anatomic muscle tensioning. RESULTS: Each reverse shoulder shifted the center of rotation medially and inferiorly relative to the normal shoulder and caused a corresponding shift in the position of the humerus. Each reverse shoulder elongated each head of the deltoid and shortened the internal and external rotators relative to the normal shoulder. The surgical techniques and prosthesis designs, which resulted in a more lateral humeral position, were associated with more deltoid wrapping and better tensioning of the anterior and posterior shoulder muscles. CONCLUSIONS: Muscle tensioning and deltoid wrapping can be substantially altered by surgical implantation meth- ods using the Grammont reverse shoulder. However, the results of this study demonstrate that more anatomic muscle tensioning and improved deltoid wrapping are achieved using alternative prosthesis designs that better restore the lateral position of the humerus. PMID- 24344622 TI - Primary total elbow replacement in a patient with old unreduced complex posterior elbow dislocation. AB - A 65-year-old female presented with history of a fall on an outstretched hand 2 months back and with complaints of pain, limitation of movement of right elbow, and inability to carry out her daily routine activities. On examination, there was swelling and tenderness at the elbow, three point relation was altered, had fixed flexion deformity of 50 degrees with range of motion from 50 degrees to 60 degrees . Radiographs showed neglected old unreduced posterior elbow dislocation, fractures of radial head, and coronoid process. Patient was treated with total elbow replacement using 3rd generation sloppy hinged elbow prosthesis. At 3 weeks, range of motion was from 30 degrees to 120 degrees . At 6 weeks follow-up, patient was able to do her routine activities independently with ROM of 20 degrees to 140 degrees and minimum pain. PMID- 24344623 TI - Injury to the superior gluteal artery during intramedullary fixation of an atypical subtrochanteric stress fracture - a case report. AB - Iatrogenic vascular injury during hip fracture surgery is a rare complication, with infrequent reports of injury during the procedure of cepahalomedullary nailing. We describe a case report of injury to the superior gluteal artery which occurred during insertion of a nail for prophylactic fixation of an incomplete femur fracture secondary to alendronate use. We describe the anatomy of the arterial branches, the postoperative course, and the management strategy and hope this will increase awareness of these rare injuries. PMID- 24344624 TI - Iliac wing insufficiency fractures as unusual postoperative complication following total hip arthroplasty - a case report. AB - Insufficiency fractures present a significant problem in patients with osteoporosis. We report a case of bilateral iliac wing insufficiency fracture following low energy injury in an 87-year-old osteoporotic woman occurring 2 weeks after primary total hip arthroplasty. There are only a few reports of insufficiency fractures involving the ilium in the literature, and diagnosis has proven challenging, as radiographs are often negative at symptom onset. Magnetic resonance or radionuclide imaging is generally necessary for definitive diagnosis. This case highlights the importance of careful perioperative management of patients with osteoporosis. PMID- 24344626 TI - Melanoma in mankind's best friend. PMID- 24344625 TI - Microfluidics-assisted fabrication of gelatin-silica core-shell microgels for injectable tissue constructs. AB - Microfabrication technology provides a highly versatile platform for engineering hydrogels used in biomedical applications with high-resolution control and injectability. Herein, we present a strategy of microfluidics-assisted fabrication photo-cross-linkable gelatin microgels, coupled with providing protective silica hydrogel layer on the microgel surface to ultimately generate gelatin-silica core-shell microgels for applications as in vitro cell culture platform and injectable tissue constructs. A microfluidic device having flow focusing channel geometry was utilized to generate droplets containing methacrylated gelatin (GelMA), followed by a photo-cross-linking step to synthesize GelMA microgels. The size of the microgels could easily be controlled by varying the ratio of flow rates of aqueous and oil phases. Then, the GelMA microgels were used as in vitro cell culture platform to grow cardiac side population cells on the microgel surface. The cells readily adhered on the microgel surface and proliferated over time while maintaining high viability (~90%). The cells on the microgels were also able to migrate to their surrounding area. In addition, the microgels eventually degraded over time. These results demonstrate that cell-seeded GelMA microgels have a great potential as injectable tissue constructs. Furthermore, we demonstrated that coating the cells on GelMA microgels with biocompatible and biodegradable silica hydrogels via sol-gel method provided significant protection against oxidative stress which is often encountered during and after injection into host tissues, and detrimental to the cells. Overall, the microfluidic approach to generate cell-adhesive microgel core, coupled with silica hydrogels as a protective shell, will be highly useful as a cell culture platform to generate a wide range of injectable tissue constructs. PMID- 24344627 TI - Systematic review: questionnaires for assessment of gastroesophageal reflux disease. AB - Numerous questionnaires with a wide variety of characteristics have been developed for the assessment of gastroesophageal reflux disease (GERD). Four well defined dimensions are noticeable in these GERD questionnaires, which are symptoms, response to treatment, diagnosis, and burden on the quality of life of GERD patients. The aim of this review is to develop a complete overview of all available questionnaires, categorized per dimension of the assessment of GERD. A systematic search of the literature up to January 2013 using the Pubmed database and the Embase database, and search of references and conference abstract books were conducted. A total number of 65 questionnaires were extracted and evaluated. Thirty-nine questionnaires were found applicable for the assessment of GERD symptoms, three of which are generic gastrointestinal questionnaires. For the assessment of response to treatment, 14 questionnaires were considered applicable. Seven questionnaires with diagnostic purposes were found. In the assessment of quality of life in GERD patients, 18 questionnaires were found and evaluated. Twenty questionnaires were found to be used for more than one assessment dimension, and eight questionnaires were found for GERD assessment in infants and/or children. A wide variety of GERD questionnaires is available, of which the majority is used for assessment of GERD symptoms. Questionnaires differ in aspects such as design, validation and translations. Also, numerous multidimensional questionnaires are available, of which the Reflux Disease Questionnaire is widely applicable. We provided an overview of GERD questionnaires to aid investigators and clinicians in their search for the most appropriate questionnaire for their specific purposes. PMID- 24344628 TI - Singlet oxygen generation by cyclometalated complexes and applications. AB - While cyclometalated complexes have been extensively studied for optoelectronic applications, these compounds also represent a relatively new class of photosensitizers for the production of singlet oxygen. Thus far, singlet oxygen generation from cyclometalated Ir and Pt complexes has been studied in detail. In this review, photophysical data for singlet oxygen generation from these complexes are presented, and the mechanism of (1) O2 generation is discussed, including evidence for singlet oxygen generation via an electron-transfer mechanism for some of cyclometalated Ir complexes. The period from the first report of singlet oxygen generation by a cyclometalated Ir complex in 2002 through August 2013 is covered in this review. This new class of singlet oxygen photosensitizers may prove to be rather versatile due to the ease of substitution of ancillary ligands without loss of activity. Several cyclometalated complexes have been tethered to zeolites, polystyrene, or quantum dots. Applications for photooxygenation of organic molecules, including "traditional" singlet oxygen reactions (ene reaction, [4 + 2] and [2 + 2] cycloadditions) as well as oxidative coupling of amines are presented. Potential biomedical applications are also reviewed. PMID- 24344629 TI - Immigrant sexual minority Latino men in rural North Carolina: an exploration of social context, social behaviors, and sexual outcomes. AB - Immigrant sexual minority Latino men-who may or may not self-identify as gay constitute a minority within a minority. Often labeled "hidden" and "hard-to reach," and marginalized along multiple dimensions, it is a subgroup about whom little is known. Informed by a social ecological framework, we sought to describe key social variables for 190 such men in rural North Carolina and to test associations with three sexual outcomes: consistent condom use, number of sex partners, and sexual compulsivity. Participants reported limited English-language use, predominantly Latino close friends, middle levels of social support despite numerous social ties, and frequent experiences of discrimination. There were unique sets of correlates for each sexual outcome. Findings may inform health promotion interventions and guide future research. PMID- 24344630 TI - Synthesis, microstructure, and magnetic properties of monosized MnxZnyFe3 - x - yO4 ferrite nanocrystals. AB - We report the synthesis and characterization of ferrite nanocrystals which exhibit high crystallinity and narrow size distributions. The three types of samples including Zn ferrite, Mn ferrite, and Mn-Zn ferrite were prepared via a non-aqueous nanoemulsion method. The structural, chemical, and magnetic properties of the nanocrystals are analyzed by transmission electron microscopy, X-ray diffraction, X-ray fluorescence, and physical property measurement system. The characterization indicates that the three types of ferrite nanocrystals were successfully produced, which show well-behaved magnetic properties, ferrimagnetism at 5 K and superparamagnetism at 300 K, respectively. In addition, the magnetization value of the ferrites increases with the increasing concentration of Mn. PMID- 24344632 TI - Broad ranges and fast responses of single-component blue-phase liquid crystals containing banana-shaped 1,3,4-oxadiazole cores. AB - In this study, we synthesized two novel 1,3,4-oxadiazole-based bent-core liquid crystals (OXD7*, OXD5B7F*) containing a chiral tail that display broad ranges of the blue phase III (34 and 7 K, respectively); we characterized them using polarized optical microscopy, differential scanning calorimetry, and circular dichroism. The electro-optical responses of both of these liquid crystals are much faster than those of previously reported single-component blue-phase liquid crystals. To optimize its electro-optical performance, we mixed OXD7* (the blue phase range of which is broader than that of OXD5B7F*) with its analogue OXD6 (at weight ratios of 6:4 and 4:6). We also performed molecular modeling of single component BPLCs (OXD7* and OXD5B7F*) to analyze the possible parameters affecting their blue phase ranges. PMID- 24344631 TI - Effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG) in transgenic mouse models of frontotemporal lobar degeneration and Alzheimer's disease. AB - Alzheimer's disease (AD), the most common dementia, is characterized by potentially neurotoxic aggregation of Abeta peptide and tau protein, and their deposition as amyloid plaques and neurofibrillary tangles (NFTs). Tau aggregation also occurs in other common neurodegenerative diseases. Frontotemporal dementia (FTD) can be caused by tau mutations that increase the susceptibility of tau to hyperphosphorylation and aggregation, which may cause neuronal dysfunction and deposition of NFTs. 17-allylamino-17-demethoxygeldanamycin (17-AAG) is a potent inhibitor of heat shock protein 90 (Hsp90), a cytosolic chaperone implicated in the proper folding and functions of a repertoire of client proteins. 17-AAG binds to Hsp90 and enhances degradation of Hsp90 client protein. We sought to determine whether 17-AAG can reduce Abeta and tau pathology in the brains of AD and FTD model mice expressing Abeta or P301L mutant tau, respectively. Mice were randomized to receive 25, 5, or 0 mg/kg 17-AAG thrice weekly from age eight to 11 months. Analysis was performed by rotarod test on motor function, on the area occupied by plaques in hippocampus or NFTs in medulla tissue sections, and on mortality. A high dose of 17-AAG tended to decrease NFTs in male mice (p = 0.08). Further studies are required to confirm the effect of 17-AAG in diseases of tau aggregation. PMID- 24344633 TI - A new rechargeable sodium battery utilizing reversible topotactic oxygen extraction/insertion of CaFeO(z) (2.5 <= z <= 3) in an organic electrolyte. AB - At present, significant research efforts are being devoted both to identifying means of upgrading existing batteries, including lithium ion types, and also to developing alternate technologies, such as sodium ion, metal-air, and lithium sulfur batteries. In addition, new battery systems incorporating novel electrode reactions are being identified. One such system utilizes the reaction of electrolyte ions with oxygen atoms reversibly extracted and reinserted topotactically from cathode materials. Batteries based on this system allow the use of various anode materials, such as lithium and sodium, without the requirement to develop new cathode intercalation materials. In the present study, this concept is employed and a new battery based on a CaFeO3 cathode with a sodium anode is demonstrated. PMID- 24344634 TI - Direct visualization of in vitro drug mobilization from Lescol XL tablets using two-dimensional (19)F and (1)H magnetic resonance imaging. AB - This article reports the application of in vitro multinuclear ((19)F and (1)H) two-dimensional magnetic resonance imaging (MRI) to study both dissolution media ingress and drug egress from a commercial Lescol XL extended release tablet in a United States Pharmacopeia Type IV (USP-IV) dissolution cell under pharmacopoeial conditions. Noninvasive spatial maps of tablet swelling and dissolution, as well as the mobilization and distribution of the drug are quantified and visualized. Two-dimensional active pharmaceutical ingredient (API) mobilization and distribution maps were obtained via (19)F MRI. (19)F API maps were coregistered with (1)H T2-relaxation time maps enabling the simultaneous visualization of drug distribution and gel layer dynamics within the swollen tablet. The behavior of the MRI data is also discussed in terms of its relationship to the UV drug release behavior. PMID- 24344636 TI - Both Zundel and Eigen isomers contribute to the IR spectrum of the gas-phase H9O4+ cluster. AB - The "Eigen cation", H3O+(H2O)3, is the most prevalent protonated water structure in the liquid phase and the most stable gas-phase isomer of the H+(H2O)4 cluster. Nevertheless, its 50 K argon predissociation vibrational spectrum contains unexplainable low frequency peak(s). We have simulated the IR spectra of 10 gas phase H+(H2O)4 isomers, that include zero to three argon ligands, using dipole autocorrelation functions from ab initio molecular dynamics with the CP2K software. We have also tested the effect of elevated temperature and dispersion correction. The Eigen isomers describe well the high frequency portion of the spectrum but do not agree with experiment below 2000 cm(-1). Most notably, they completely lack the "proton transfer bands" observed at 1050 and 1750 cm(-1), which characterize Zundel-type (H5O2+) isomers. In contrast, linear isomers with a Zundel core, although not the lowest in energy, show very good agreement with experiment, particularly at low frequencies. Peak assignments made with partial velocity autocorrelation functions verify that the 1750 cm(-1) band does not originate with the Eigen isomer but is rather due to coupled proton transfer/water bend in the Zundel isomer. PMID- 24344637 TI - Dural ectasia in Loeys-Dietz syndrome: comprehensive study of 30 patients with a TGFBR1 or TGFBR2 mutation. AB - The purpose of this study was to assess the frequency, severity, and clinical associations of dural ectasia (DE) in Loeys-Dietz syndrome (LDS). Database analysis of three German metropolitan regions identified 30 patients with LDS and TGFBR1 mutation in 6 and a TGFBR2 mutation in 24 individuals (17 men; mean age: 31 +/- 19 years), as well as 60 age and sex-matched control patients with Marfan syndrome carrying a FBN1 mutation. DE was present in 22 patients with LDS (73%), and it related to skeletal score points (p = 0.008), non-skeletal score points (p < 0.001), and to the presence of >=7 systemic score points (p = 0.010). Similarly, the severity of DE was related to body height (p = 0.010) and non skeletal score points (p = 0.004). Frequency (p = 0.131) and severity of DE (p = 0.567) was similar in LDS and Marfan syndrome. DE is a manifestation of LDS that occurs with similar frequency and severity as in Marfan syndrome. Severity of DE may serve as a marker of the overall connective tissue disease severity. LDS may be considered in patients with DE. PMID- 24344638 TI - Clinical outcomes of colo-anal pull-through procedure for complex rectal conditions. AB - AIM: Pull-through with colo-anal sleeve anastomosis may be used as a last resort to avoid permanent diversion in patients with complex rectal conditions. This procedure allows the preservation of intestinal continuity by minimizing the hazards of deep dissection in an inflamed and fibrosed pelvis. METHOD: A retrospective study was performed of colo-anal pull-through procedures carried out between January 1998 and December 2012 at St Mark's Hospital by one surgeon. Patients were identified from operative logbooks and their case notes were reviewed. Thirty-four patients (21 women) with a median age of 54 (21-75) years underwent the pull-through operation for complex rectal conditions involving fistulae and/or a hostile pelvis as a final attempt to restore intestinal continuity. RESULTS: The median length of hospital stay was 7.5 (5-45) days. Median follow-up was 23 (3-71) months. There was no peri-operative mortality. There were two (6%) outright failures. Early complications occurred in 14 (41%) patients and late complications in 10 (29%). Fistulae recurred in seven (25%) of 28 patients but with further treatment four healed, giving an overall healing rate of 89%. Normal continence was achieved in 19 (79%) of 24 patients who were evaluated. CONCLUSION: In clinically difficult rectal situations the colo-anal pull-through procedure is a suitable salvage procedure to restore intestinal continuity before considering a permanent stoma. PMID- 24344639 TI - Correlates of men's sexual interest: a cross-cultural study. AB - INTRODUCTION: Low sexual desire has been studied more extensively in women than in men. AIM: The study aims to analyze the correlates of distressing lack of sexual interest and the self-assessed reasons for the lack of sexual interest among heterosexual men from three countries. METHODS: A web-based survey was completed by 5,255 men aged 18-75 years from Portugal, Croatia, and Norway. MAIN OUTCOME MEASURES: We used an item that assesses lack of sexual interest from the British NATSAL 2000. Anxiety and depression were measured with the SCL-ANX4 and SCL-DEP6. Relationship intimacy was measured using a five-item version of the Emotional Intimacy Scale. A shortened version of the Sexual Boredom Scale was used to assess proneness to sexual boredom in relation to the duration of relationship, and personal distress was evaluated using an item created for this study. RESULTS: Distressing lack of sexual interest lasting at least 2 months in the previous year was reported by 14.4% of the participants. The most prevalent comorbidity among these men was erectile difficulty (48.7%). Men with low confidence levels in erectile function, not feeling attracted to the partner, and those in long-term relationships were more likely to have experienced lack of sexual interest than were men with high confidence levels and those who felt attracted to their partner and those in shorter-term relationships. Professional stress was the most frequently reported reason for lack of sexual interest. Sexual boredom as a result of a long-term relationship was significantly and negatively correlated with the level of intimacy (r = -0.351, P < 0.001) and sexual satisfaction (r = -0.497, P < 0.001). CONCLUSIONS: Distressing lack of sexual interest in heterosexual men was associated with a number of intrapersonal (self-confidence in erectile function, stress), interpersonal (relationship duration, partner attractiveness), and sociocultural variables. PMID- 24344640 TI - A systems-based partnership learning model for strengthening primary healthcare. AB - BACKGROUND: Strengthening primary healthcare systems is vital to improving health outcomes and reducing inequity. However, there are few tools and models available in published literature showing how primary care system strengthening can be achieved on a large scale. Challenges to strengthening primary healthcare (PHC) systems include the dispersion, diversity and relative independence of primary care providers; the scope and complexity of PHC; limited infrastructure available to support population health approaches; and the generally poor and fragmented state of PHC information systems.Drawing on concepts of comprehensive PHC, integrated quality improvement (IQI) methods, system-based research networks, and system-based participatory action research, we describe a learning model for strengthening PHC that addresses these challenges. We describe the evolution of this model within the Australian Aboriginal and Torres Strait Islander primary healthcare context, successes and challenges in its application, and key issues for further research. DISCUSSION: IQI approaches combined with system-based participatory action research and system-based research networks offer potential to support program implementation and ongoing learning across a wide scope of primary healthcare practice and on a large scale. The Partnership Learning Model (PLM) can be seen as an integrated model for large-scale knowledge translation across the scope of priority aspects of PHC. With appropriate engagement of relevant stakeholders, the model may be applicable to a wide range of settings. In IQI, and in the PLM specifically, there is a clear role for research in contributing to refining and evaluating existing tools and processes, and in developing and trialling innovations. Achieving an appropriate balance between funding IQI activity as part of routine service delivery and funding IQI related research will be vital to developing and sustaining this type of PLM. SUMMARY: This paper draws together several different previously described concepts and extends the understanding of how PHC systems can be strengthened through systematic and partnership-based approaches. We describe a model developed from these concepts and its application in the Australian Indigenous primary healthcare context, and raise questions about sustainability and wider relevance of the model. PMID- 24344641 TI - Simultaneous atelectasis in human bocavirus infected monozygotic twins: was it plastic bronchitis? AB - BACKGROUND: Plastic bronchitis is an extremely rare disease characterized by the formation of tracheobronchial airway casts, which are composed of a fibrinous exudate with rubber-like consistency and cause respiratory distress as a result of severe airflow obstruction. Bronchial casts may be associated with congenital and acquired cardiopathies, bronchopulmonary diseases leading to mucus hypersecretion, and pulmonary lymphatic abnormalities. In recent years, however, there is growing evidence that plastic bronchitis can also be triggered by common respiratory tract infections and thereby cause atelectasis even in otherwise healthy children. CASE PRESENTATION: We report on 22-month-old monozygotic twins presenting with atelectasis triggered by a simple respiratory tract infection. The clinical, laboratory, and radiographic findings given, bronchial cast formation was suspected in both infants but could only be confirmed after bronchoscopy in the first case. Real-time polymerase chain reaction of the removed cast as well as nasal lavage fluid of both infants demonstrated strong positivity for human bocavirus. CONCLUSION: Our case report is the first to describe two simultaneously affected monozygotic twins and substantiates the hypothesis of a contributing genetic factor in the pathophysiology of this disease. In this second report related to human bocavirus, we show additional evidence that this condition can be triggered by a simple respiratory tract infection in previously healthy infants. PMID- 24344642 TI - Heparanase-mediated cleavage of macromolecular heparin accelerates release of granular components of mast cells from extracellular matrices. AB - Heparanase cleaves macromolecular heparin in the secretory granules of connective tissue-type mast cells. We investigated roles of the cleavage under a microenvironment mimicking where the mast cells physiologically reside. A connective tissue-type mast cell line MST and mouse peritoneal cell-derived mast cells stored macromolecular heparin in the secretory granules. The cells expressing heparanase stored fragmented heparin (~10 kDa) due to heparanase dependent cleavage of the heparin. We produced an artificial collagen-based extracellular matrix and placed the live cells or glycosaminoglycans purified from the cells in the matrix to measure the release of sulfated macromolecules into the medium. The sulfate-radiolabelled molecules from the degranulating heparanase-expressing cells and the purified glycosaminoglycans showed significantly greater release into the medium than those derived from mock cells, which was not the case in suspension culture. The mast cell granular enzyme chymase, but not beta-hexosaminidase, showed significantly greater release from the degranulating heparanase-expressing cells than from mock cells. Purified chymase mixed with fragmented heparin derived from heparanase-expressing cells showed greater release from collagen gels than the enzyme alone or mixed with macromolecular heparin derived from mock cells. We propose that the cleavage of macromolecular heparin by heparanase accelerates the release of heparin and chymase from extracellular matrices. PMID- 24344643 TI - Effects of Chinese herbal medicine on plasma glucose, protein and energy metabolism in sheep. AB - BACKGROUND: The use of antibiotics in animal diets is facing negative feedback due to the hidden danger of drug residues to human health. Traditional Chinese herbal medicine has been used to replace antibiotics in the past two decades and played an increasingly important role in livestock production. The present study was carried out to assess the feeding effects of a traditional nourishing Chinese herbal medicine mixture on kinetics of plasma glucose, protein and energy metabolism in sheep. Ruminal fermentation characteristics were also determined. METHODS: Four sheep were fed on either mixed hay (MH-diet) or MH-diet supplemented with 2% of Chinese herbal medicine (mixture of Astragalus root, Angelica root and Atractylodes rhizome; CHM-diet) over two 35-day periods using a crossover design. The turnover rate of plasma glucose was measured with an isotope dilution method using [U-13C]glucose. The rates of plasma leucine turnover and leucine oxidation, whole body protein synthesis (WBPS) and metabolic heat production were measured using the [1-13C]leucine dilution and open circuit calorimetry. RESULTS: Body weight gain of sheep was higher (P = 0.03) for CHM diet than for MH-diet. Rumen pH was lower (P = 0.02), concentration of rumen total volatile fatty acid tended to be higher (P = 0.05) and acetate was higher (P = 0.04) for CHM-diet than for MH-diet. Turnover rates of plasma glucose and leucine did not differ between diets. Oxidation rate of leucine tended to be higher (P = 0.06) for CHM-diet than for MH-diet, but the WBPS did not differ between diets. Metabolic heat production tended to be greater (P = 0.05) for CHM diet than for MH-diet. CONCLUSIONS: The sheep fed on CHM-diet had a higher body weight gain and showed positive impacts on rumen fermentation and energy metabolism without resulting in any adverse response. Therefore, these results suggested that the Chinese herbal medicine mixture should be considered as a potential feed additive for sheep. PMID- 24344644 TI - Effect of physisorption and chemisorption of water on resonant modes of rolled-up tubular microcavities. AB - Both blue- and redshifts of resonant modes are observed in the rolled-up Y2O3/ZrO2 tubular microcavity during a conformal oxide coating process. Our investigation based on spectral analyses suggests that there are two competitive processes during coating: desorption of both chemically and physically absorbed water molecules and increase of the tube wall thickness. The redshift is due to the increase of the wall thickness and corresponding light confinement enhancement. On the other hand, desorption of water molecules by heating leads to a blueshift. The balance of these two factors produces the observed bi directional shift of the modes while they both contribute to promoted quality factor after coating. PMID- 24344645 TI - Comparison of proton therapy techniques for treatment of the whole brain as a component of craniospinal radiation. AB - BACKGROUND: For treatment of the entire cranium using passive scattering proton therapy (PSPT) compensators are often employed in order to reduce lens and cochlear exposure. We sought to assess the advantages and consequences of utilizing compensators for the treatment of the whole brain as a component of craniospinal radiation (CSI) with PSPT. Moreover, we evaluated the potential benefits of spot scanning beam delivery in comparison to PSPT. METHODS: Planning computed tomography scans for 50 consecutive CSI patients were utilized to generate passive scattering proton therapy treatment plans with and without Lucite compensators (PSW and PSWO respectively). A subset of 10 patients was randomly chosen to generate scanning beam treatment plans for comparison. All plans were generated using an Eclipse treatment planning system and were prescribed to a dose of 36 Gy(RBE), delivered in 20 fractions, to the whole brain PTV. Plans were normalized to ensure equal whole brain target coverage. Dosimetric data was compiled and statistical analyses performed using a two tailed Student's t-test with Bonferroni corrections to account for multiple comparisons. RESULTS: Whole brain target coverage was comparable between all methods. However, cribriform plate coverage was superior in PSWO plans in comparison to PSW (V95%; 92.9 +/- 14 vs. 97.4 +/- 5, p < 0.05). As predicted, PSWO plans had significantly higher lens exposure in comparison to PSW plans (max lens dose Gy(RBE): left; 24.8 +/- 0.8 vs. 22.2 +/- 0.7, p < 0.05, right; 25.2 +/- 0.8 vs. 22.8 +/- 0.7, p < 0.05). However, PSW plans demonstrated no significant cochlear sparing vs. PSWO (mean cochlea dose Gy(RBE): 36.4 +/- 0.2 vs. 36.7 +/- 0.1, p = NS). Moreover, dose homogeneity was inferior in PSW plans in comparison to PSWO plans as reflected by significant alterations in both whole brain and brainstem homogeneity index (HI) and inhomogeneity coefficient (IC). In comparison to both PSPT techniques, multi-field optimized intensity modulated (MFO-IMPT) spot scanning treatment plans displayed superior sparing of both lens and cochlea (max lens: 12.5 +/- 0.6 and 12.9 +/- 0.7 right and left respectively; mean cochlea 28.6 +/- 0.5 and 27.4 +/- 0.2), although heterogeneity within target volumes was comparable to PSW plans. CONCLUSIONS: For PSPT treatments, the addition of a compensator imparts little clinical advantage. In contrast, the incorporation of spot scanning technology as a component of CSI treatments, offers additional normal tissue sparing which is likely of clinical significance. PMID- 24344646 TI - Uptake of liquid-based cytology as an adjunct to conventional cytology for cervical screening in NSW, Australia: a cross-sectional and population-based cohort analysis. AB - BACKGROUND: Cervical screening is currently recommended every two years in sexually active women aged 18-20 to 69 years in Australia. Direct replacement of conventional cytology with liquid-based cytology (LBC) for cervical screening was rejected for public funding on grounds of cost-effectiveness, first in 2002 and again in 2009, but LBC is performed as an adjunct to conventional cytology in women who elect to pay. The objective of this study was to describe prevalence and predictors of use of LBC in Australia's most populous state, New South Wales (NSW). METHODS: We performed cross-sectional and population-based cohort analyses using data from the state Pap Test Register in NSW. We calculated the age adjusted proportion of women aged 20-69 years electing to have adjunctive LBC over the period from 2006-2010. We also calculated the fully-adjusted odds ratios for the association between subsequent LBC use and age, socioeconomic status, place of residence, previous cytological history and provider type in a cohort of 360,247 women who had an index cervical cytology test in 2006-8. RESULTS: Uptake of LBC varied between 29.7% (95% Confidence Interval (CI): 29.5-30.0%) in 2006/7 and 26.6% (95% CI: 26.4-26.9%) in 2009/10. LBC was more likely to be used in women aged 30-44 years, if it had been used previously (OR13.58, 95% CI: 13.33 13.84), if the previous test result was abnormal (OR2.62, 95% CI:2.53-2.72) or unsatisfactory (OR2.37, 95% CI:2.27-3.47), or if a gynaecologist requested the test (OR1.50, 95% CI:1.46-1.54). Uptake was least for women in remote/very remote areas (OR0.68; 95% CI:0.57-0.80 referenced to those in major cities) and in lower socioeconomic groups (OR 0.41, 95% CI:0.40-0.42 for lowest versus highest SES quintile). CONCLUSION: In the current environment in NSW, Australia, in which public funding for LBC has not been available, adjunctive uptake of LBC depends strongly on a woman's age, her screening history and socioeconomic factors. These findings provide important context for a current review of technologies used in the National Cervical Screening Program in Australia. PMID- 24344647 TI - Impaired plasticity of cortical dendritic spines in P301S tau transgenic mice. AB - BACKGROUND: Illuminating the role of the microtubule-associated protein tau in neurodegenerative diseases is of increasing importance, supported by recent studies establishing novel functions of tau in synaptic signalling and cytoskeletal organization. In severe dementias like Alzheimer's disease (AD), synaptic failure and cognitive decline correlate best with the grade of tau pathology. To address synaptic alterations in tauopathies, we analyzed the effects of mutant tau expression on excitatory postsynapses in vivo. RESULTS: Here we followed the fate of single dendritic spines in the neocortex of a tauopathy mouse model, expressing human P301S mutated tau, for a period of two weeks. We observed a continuous decrease in spine density during disease progression, which we could ascribe to a diminished fraction of gained spines. Remaining spines were enlarged and elongated, thus providing evidence for morphological reorganization in compensation for synaptic dysfunction. Remarkably, loss of dendritic spines in cortical pyramidal neurons occurred in the absence of neurofibrillary tangles (NFTs). Therefore, we consider prefibrillar tau species as causative for the observed impairment in spine plasticity. CONCLUSIONS: Dendritic spine plasticity and morphology are altered in layer V cortical neurons of P301S tau transgenic mice in vivo. This does not coincide with the detection of hyperphosphorylated tau in dendritic spines. PMID- 24344648 TI - Children's and adolescent's self - assessment of metabolic control versus professional judgment: a cross-sectional retrospective and prospective cohort study. AB - BACKGROUND: Morbidity and mortality in T1DM depend on metabolic control, which is assessed by HbA1c measurements every 3-4 months. Patients' self-perception of glycemic control depends on daily blood glucose monitoring. Little is known about the congruence of patients' and professionals' perception of metabolic control in T1DM. OBJECTIVE: To assess the actual patients' self-perception and objective assessment (HbA1c) of metabolic control in T1DM children and adolescents and to investigate the possible factors involved in any difference. METHODS: Patients with T1DM aged 8 - 18 years were recruited in a cross-sectional, retrospective and prospective cohort study. Data collection consisted of clinical details, measured HbA1c, self-monitored blood glucose values and questionnaires assessing self and professionals' judgment of metabolic control. RESULTS: 91 patients participated. Mean HbA1c was 8.03%. HbA1c was higher in patients with a diabetes duration > 2 years (p = 0.025) and in patients of lower socioeconomic level (p = 0.032). No significant correlation was found for self-perception of metabolic control in well and poorly controlled patients. We found a trend towards false positive memory of the last HbA1c in patients with a HbA1c > 8.5% (p = 0.069) but no difference in patients' knowledge on target HbA1c between well and poorly controlled patients. CONCLUSIONS: T1DM patients are aware of a target HbA1c representing good metabolic control. Ill controlled patients appear to have a poorer recollection of their HbA1c. Self-perception of actual metabolic control is similar in well and poorly controlled T1DM children and adolescents. Therefore, professionals should pay special attention that ill controlled T1DM patients perceive their HbA1c correctly. PMID- 24344649 TI - Resolvin E1 promotes resolution of inflammation in a mouse model of an acute exacerbation of allergic asthma. AB - Endogenous mediators, such as RvE1 (resolvin E1), promote resolution of an inflammatory response and have potential as novel therapeutic agents. In the present study, we investigated the activity of RvE1 in a model of an acute exacerbation of chronic allergic asthma in mice. Animals sensitized to OVA (ovalbumin) received controlled low-level challenge with aerosolized antigen for 4 weeks, followed by a single moderate-level challenge to simulate an allergen induced exacerbation of asthmatic inflammation. Induction of an exacerbation was associated with rapid recruitment of neutrophils, lymphocytes and eosinophils, together with increased levels of Th2 and pro-inflammatory cytokines. When administered before the final moderate-level challenge, RvE1 had only a modest effect on airway inflammation. To assess its effects when administered after induction of an exacerbation, we first characterized the cellular and molecular events associated with spontaneous resolution of airway inflammation over the following 96 h. Subsequently, we showed that administration of RvE1 at 2 and 8 h after the final challenge accelerated this process significantly. Specifically, RvE1 promoted a decline in the number of inflammatory cells, concentration of cytokines in lavage fluid and expression of mRNA for cytokines by macrophages, confirming its pro-resolution activity. In vitro, RvE1 had no apparent effect on lymphocytes, but suppressed significantly cytokine production by pulmonary macrophages, with evidence of down-regulation of the nuclear translocation of NF kappaB (nuclear factor kappaB) p65 in these cells. The present study provides novel evidence that RvE1 can facilitate resolution of airway inflammation in a clinically relevant model of an acute exacerbation of asthma, possibly via its effects on activated pulmonary macrophages. PMID- 24344650 TI - Phellinus linteus polysaccharide extracts increase the mitochondrial membrane potential and cause apoptotic death of THP-1 monocytes. AB - BACKGROUND: The differentiation resp. death of human monocytic THP-1 cells induced by polysaccharide extracts of the medicinal mushrooms Phellinus linteus, Agaricus bisporus and Agaricus brasiliensis have been studied. This study aims to identify leads for the causal effects of these mushroom components on cell differentiation and death. METHODS: THP-1 cells were treated with different polysaccharide extracts of mushrooms and controls. Morphological effects were observed by light microscopy. Flow cytometry was applied to follow the cell differentiation by cell cycle shifts after staining with propidium iodide, changes of mitochondrial membrane potential after incubation with JC-1, and occurrence of intracellular reactive oxygen species after incubation with hydroethidine. Principal component analysis of the data was performed to evaluate the cellular effects of the different treatments. RESULTS: P. linteus polysaccharide extracts induced dose-dependent apoptosis of THP-1 cells within 24 h, while A. bisporus and A. brasiliensis polysaccharide extracts caused differentiation into macrophages. A pure P. linteus polysaccharide had no effect. Apoptosis was inhibited by preincubating THP-1 cells with human serum. The principal component analysis revealed that P. linteus, A. bisporus and A. brasiliensis polysaccharide extracts increased reactive oxygen species production. Both A. bisporus and A. brasiliensis polysaccharide extracts decreased the mitochondrial membrane potential, while this was increased by P. linteus polysaccharide extracts. CONCLUSIONS: P. linteus polysaccharide extracts caused apoptosis of THP-1 monocytes while A. bisporus and A. brasiliensis polysaccharide extracts caused these cells to differentiate into macrophages. The protective effects of human serum suggested that P. linteus polysaccharide extract induced apoptosis by extrinsic pathway, i.e. by binding to the TRAIL receptor. The mitochondrial membrane potential together with reactive oxygen species seems to play an important role in cell differentiation and cell death. PMID- 24344651 TI - Antioxidant effects of maslinic acid in livers, hearts and kidneys of streptozotocin-induced diabetic rats: effects on kidney function. AB - Studies indicate that hyperglycemia-induced oxidative stress triggers the development of microvascular and macrovascular complications in diabetes. Accordingly, we hypothesized that maslinic acid (MA) prevents these complications due to its antioxidant properties. We, therefore, investigated the effects of 5 week MA treatment of streptozotocin (STZ)-induced diabetic rats on anti-oxidative status of cardiac, hepatic and renal tissues as well as on kidney function. Proximal tubular effects of MA were studied in anesthetized rats challenged with hypotonic saline after a 3.5 h equilibration for 4 h of 1 h control, 1.5 h treatment and 1.5 h recovery periods using lithium clearance. MA was added to the infusate during the treatment period. Oral glucose tolerance responses to MA were monitored in rats given a glucose load after an 18 h fast. Compared with untreated diabetic rats, MA-treated diabetic animals exhibited significantly low malondialdehyde (MDA, a marker of lipid peroxidation) and increased the activity of antioxidant enzymes; superoxide dismutase and glutathione peroxidase in hepatic, cardiac and renal tissues. The expressions of gastrocnemius muscle GLUT4 and kidney GLUT1 and GLUT2 were assessed to elucidate the mechanism of the hypoglycemic effects of MA. MA-treatment diminished the expression of GLUT1 and GLUT2 in diabetic kidney and reduced glycemia values of diabetic rats. MA administration increased urinary Na+ outputs and additionally the FENa indicating that at least part of the overall reduction in Na+ reabsorption occurred in the proximal tubules. These results suggest antioxidant effects of MA can ameliorate oxidative stress and improve kidney function in diabetes mellitus. PMID- 24344652 TI - Optogenetics' promise: pacing and cardioversion by light? PMID- 24344653 TI - Virtual 3D heart models to aid pacemaker implantation in children. PMID- 24344654 TI - Platelet RNA as a novel biomarker for the response to antiplatelet therapy. PMID- 24344656 TI - Dabigatran use in mechanical heart valve patients. AB - Current guidelines have no recommendations on the utilization of novel oral anticoagulants, such as dabigatran, for the prevention of thromboembolic events in patients with mechanical heart valves. However, recent studies on the use of dabigatran in patients with atrial fibrillation and animal studies have suggested a new potential role for dabigatran in patients with mechanical heart valves. The study by Eikelboom et al. investigates this important clinical question in a prospective, randomized controlled Phase II clinical trial. The authors randomly assigned 252 patients from 39 centers in ten countries to receive dabigatran or warfarin in a 2:1 ratio. The objective of the study was to validate a dosing regimen for use of dabigatran in patients with mechanical heart valves. The trial was prematurely terminated after a recommendation by the data and safety monitoring board. The composite of stroke, systemic embolism, myocardial infarction and death was 8% in the dabigatran group and 2% in the warfarin group (hazard ratio: 3.37; 95% CI: 0.76-14.95; p = 0.11). There were significantly higher bleeding rates of any type in the dabigatran group (27%) compared with the warfarin group (12%; hazard ratio: 2.45; 95% CI: 1.23-4.86; p = 0.01). These results demonstrated a higher risk and no additional benefits in using dabigatran compared with warfarin in patients with mechanical heart valves. PMID- 24344657 TI - European Society of Cardiology Congress 2013 highlights. AB - The European Society of Cardiology (ESC) Congress in 2013 met in Amsterdam (The Netherlands) as an innovative and interactive congress involving more than 30,000 participants. There were 10,490 abstract submissions and a total of 227 hotline, basic science hotline and trial update submissions. Participants were involved from more than 150 countries. To make the congress manageable for participants, related topics were grouped together in 'villages' and a smart electronic application allowed the participants to guide their way through the congress and choose the sessions of interest. The innovative new program was initiated by the ESC Congress Programme Committee and the Congress Chair (Keith AA Fox, Chair 2012 2014) has responsibility for the design and delivery of the scientific program. The spotlight of the congress was 'the heart interacting with systemic organs', chosen because of the importance of cardiovascular disease conditions crossing conventional boundaries. In all 572 abstracts, the work involved an interaction between the heart and another organ, such as the brain, lungs, kidney, vasculature or inflammation system. In addition, innovative new approaches linked basic science and clinical science and the new 'hubs of the congress' allowed excellent interaction and exchange of ideas. PMID- 24344658 TI - A profile of Keith AA Fox, cardiologist and researcher. AB - Professor Keith AA Fox speaks to Caroline Telfer, Commissioning Editor. Professor Keith AA Fox is the British Heart Foundation and the Duke of Edinburgh Professor of Cardiology at the University of Edinburgh (UK). He is a founding fellow of the European Society of Cardiology and is currently Chair of the Programme of the European Society of Cardiology. In addition, he was President of the British Cardiovascular Society from 2009 to 2012. Professor Fox gave the State-of-the-Art lecture on acute coronary syndromes at the American Heart Association, as well as the 2009 Plenary lecture at the European Society of Cardiology-American College of Cardiology Symposium, the Lord Rayner lecture of the Royal College of Physicians (London, UK) and the Sir Stanley Davidson Lecture of the Royal College (Edinburgh, UK). He was awarded the Silver Medal of the European Society of Cardiology in 2010. Professor Fox's major research interest lies in the mechanisms and manifestations of acute coronary arterial disease; his work extends from underlying biological mechanisms to in vitro and in vivo studies and clinical trials. He is the author of more than 587 scientific papers (H-index Web of Science 73, Citations: 30,261 to March 2013). Professor Fox is chairman of the RITA program, co-chairman of ROCKET-AF and OASIS program, and chair of the GRACE program (the largest multinational study in acute coronary syndromes), and a lead investigator for studies on novel antithrombins, anticoagulants and antiplatelets. He is an International Associate Editor of the European Heart Journal and a member of the editorial boards of a number of journals. His current areas of research include the inhibition of coronary thrombosis and the role of platelets and inflammation in acute coronary syndromes. PMID- 24344659 TI - Diagnosis of myocardial infarction in women: are we doing our best? Interviewed by Caroline Telfer. AB - Dr Anoop Shah speaks to Caroline Telfer, Commissioning Editor. Dr Anoop Shah is a British Heart Foundation Clinical Research Fellow at the University of Edinburgh (UK). He completed his undergraduate training at the University of Edinburgh and is now in the process of completing his specialist training in cardiology. He has a keen interest in cardiovascular epidemiology. His areas of interest include acute coronary syndrome and cardiac biomarkers. PMID- 24344660 TI - Influenza virus vaccine reduces risk of ischemic events: time for a large-scale randomized trial? PMID- 24344661 TI - Insights from major themes at EuroPRevent 2013, Rome, Italy. PMID- 24344662 TI - Betrixaban (PRT054021): pharmacology, dose selection and clinical studies. AB - The recently introduced oral anticoagulants, dabigatran, rivaroxaban and apixaban, were shown, in randomized controlled trials, to be at least as effective and safe as monitored warfarin therapy for the treatment of venous thromboembolism and stroke prevention in atrial fibrillation. These new oral anticoagulants have predictable pharmacology, less variability in anticoagulant effect and fewer drug and food interactions than warfarin, allowing unmonitored and fixed dosing, which renders their use appealing. The remaining limitations of currently available new oral anticoagulants include their dependence on renal and hepatic clearance, and the lack of an antidote, which is problematic in bleeding patients and those requiring urgent surgery. Betrixaban is a new direct factor Xa inhibitor with distinct pharmacological characteristics, including a long half life, minimal renal clearance and minimal hepatic metabolism. Betrixaban was tested in Phase II studies in orthopedic thromboprophylaxis (EXPERT) and atrial fibrillation (EXPLORE-Xa), and is being evaluated in a Phase III trial of extended thromboprophylaxis in medical patients (APEX). This article details the pharmacology, preclinical and clinical development of betrixaban. PMID- 24344663 TI - Myocardial cardiotrophin-1 is differentially induced in congenital cardiac defects depending on hypoxemia. AB - AIM: Cardiotrophin-1 (CT-1) is upregulated by hypoxemia and hemodynamic overload and is characterized by potent hypertrophic and protective properties on cardiac cells. This study aimed to investigate whether CT-1 is differentially induced in the myocardium of infants with congenital cardiac defects depending on hypoxemia. METHODS & RESULTS: Infants with Tetralogy of Fallot (n = 8) or with large nonrestrictive ventricular septal defect (n = 8) undergoing corrective surgery were investigated. Expression of CT-1 was assessed at mRNA and protein levels in the right atrial and ventricular myocardium. The activation of the STAT-3 and VEGF were measured. Degradation of cardiac troponin-I served as a marker of myocardial damage. CT-1 was detected in all patients with levels negatively correlating to the arterial oxygen saturation. Higher CT-1 expression in Tetralogy of Fallot patients was associated with activation of the JAK/STAT pathway and higher cardiac troponin-I degradation. CONCLUSION: CT-1 may mediate myocardial hypertrophy and dysfunction in infants with congenital cardiac defects, particularly in those with hypoxemia. PMID- 24344665 TI - Obesity paradox in different populations: evidence and controversies. AB - An inverse association between BMI and mortality has been reported in patients with coronary heart disease and heart failure. This 'obesity paradox' has recently been reported in other disease states, including stroke, hypertension, incident diabetes, atrial fibrillation, hemodialysis and transcatheter aortic valve replacement. Cardiorespiratory fitness influences the obesity paradox and this inverse association may be present only in individuals with low fitness levels. Intentional weight loss, exercise training and improving lean mass are important and should be advised to all patients. Recent studies have also explored the association between measures of central obesity and direct measures of body fat with mortality. This review will summarize the evidence, controversies and mechanisms associated with the puzzling obesity paradox. PMID- 24344664 TI - FREEDOM, SYNTAX, FAME and FUNCTIONALITY: the future of surgical revascularization in stable ischemic heart disease. AB - At the age of nearly 50 years, the procedure of coronary artery bypass grafting (CABG) now has the most solid evidence supporting its role in revascularization for stable ischemic heart disease in its history. In what is a relatively infrequent occurrence in medicine, the results from large-scale observational database analyses are now aligned with and supported by data from recent randomized trials, providing important contemporary evidence in support of CABG. However, even with strong evidence, the changing landscape of revascularization for stable ischemic heart disease threatens to make this evidence irrelevant in deciding which patients should be referred for CABG in the future. How the procedure of CABG could be modified and optimized for incorporation into this new landscape is discussed in this article. PMID- 24344666 TI - Tissue engineering of autologous heart valves: a focused update. AB - The prevalence of valvular heart disease is expected to increase in the coming decades, with an associated rise in valve-related surgeries. Current options for valve prostheses remain limited, essentially confined to mechanical or biological valves. Neither selection provides an optimal balance between structural integrity and associated morbidity. Mechanical valves offer exceptional durability coupled with a considerable risk of thrombogenesis. Conversely, a biological prosthesis affords freedom from anticoagulation, but with a truncated valve lifespan. Tissue-engineered heart valves have been touted as a solution to this dilemma, by offering an immunopriviledged prosthesis combined with resistance from degeneration and the potential to grow. Although the reality of commercially available tissue-engineered heart valves remains distant, this article will highlight the cellular and clinical advancements in recent years. PMID- 24344667 TI - Aortic valve repair and replacement in children. AB - Several aortic valve (AV) pathologies might necessitate intervention. Percutaneous or surgical AV repair is generally recommended as the initial management strategy in children with AV disease, offering the advantage of stabilization of the heart dimensions and improvement of patients' symptoms. When AV repair is not possible or fails, AV replacement is necessary and is associated with several challenges in children. This review will focus on treatment strategy, AV repair techniques, AV replacement choices and outcomes of AV disease management in children. PMID- 24344668 TI - Cardiac MRI as a diagnostic tool in pulmonary hypertension. AB - Pulmonary hypertension is characterized by alterations in the viscoelastic properties of the pulmonary arteries, leading to increased pulmonary arterial stiffness and elevated pressures. Early detection and accurate quantification of pulmonary hypertension are limitations to conventional noninvasive imaging and may have therapeutic implications. Cardiac MRI provides important information that can aid the clinician, particularly relating to morphologic right ventricular alterations and quantification of stiffness, as well as providing a novel prognostic framework. PMID- 24344669 TI - Recent advances in the diagnosis and management of cardiac amyloidosis. AB - The heart is commonly involved in various forms of amyloidosis and cardiomyopathy is a major cause of morbidity and mortality in these patients. Diagnosis of cardiac amyloidosis is often delayed due to nonspecific presenting symptoms and failure to recognize early signs of amyloid heart disease on routine cardiac imaging. Treatment of cardiac amyloidosis depends upon the type of amyloid protein. Systemic chemotherapy with or without stem cell transplantation is used to treat immunoglobulin-related amyloidosis and liver transplantation is used for familial transthyretin amyloidosis in select patients. Clinical trials with siRNA for the treatment of transthyretin amyloid cardiomyopathies and amyloid protein stabilizers are ongoing. Prognosis depends on the type of amyloid protein with poorer outcomes noted in immunoglobulin light-chain amyloidosis. Supportive care forms the cornerstone of management and advancements in cardiac imaging and proteomics are expected to positively impact our ability to diagnose, prognosticate and treat cardiac amyloidosis. PMID- 24344670 TI - Metabolic parameters of postmenopausal women after quinoa or corn flakes intake- a prospective and double-blind study. AB - A prospective and double-blind study was conducted on 35 women with weight excess who consumed 25 grams of quinoa flakes (QF) or corn flakes (CF) daily during a period of four consecutive weeks. At the beginning (T1) and at the end (T2) of the intervention, total calorie intake was evaluated, anthropometric assessment was performed, blood was collected for the determination of glucose, total cholesterol and fractions, oxidative stress markers, vitamin E and enterolignans. Significant reductions were detected in serum triglyceride (CF group = 133.9 +/- 89.4 to 113.7 +/- 57 mg/dl and QF group = 112.3 +/- 35 to 107.9 +/- 33.1 mg/dl), TBARS (CF group = 3.2 +/- 0.8 to 2.9 +/- 0.5 umol/l and QF group = 3.06 +/- 0.6 to 2.89 +/- 0.5 umol/l) and vitamin E concentrations (CF group = 19.5 +/- 5 to 17.9 +/- 4 uM and QF group = 17.9 +/- 4 to 16.9 +/- 3 uM) and an increase in urinary excretion of enterolignans (CF group = 2.05 +/- 1.3 to 2.24 +/- 1.4 nm/ml and QF group = 2.9 +/- 1.6 to 3.2 +/- 2.7 nm/l), in both study groups. The reduction of total cholesterol (191 +/- 35 to 181 +/- 28 mg/dl) and LDL cholesterol (LDL-c) (129 +/- 35 to 121 +/- 26 mg/dl), and the increase in GSH (1.78 +/- 0.4 to 1.91 +/- 0.4 umol/l) occurred only in the QF group, showing a possible beneficial effect of QF intake. PMID- 24344672 TI - The effect of high dose antibiotic impregnated cement on rate of surgical site infection after hip hemiarthroplasty for fractured neck of femur: a protocol for a double-blind quasi randomised controlled trial. AB - BACKGROUND: Mortality following hip hemiarthroplasty is in the range of 10-40% in the first year, with much attributed to post-operative complications. One such complication is surgical site infection (SSI), which at the start of this trial affected 4.68% of patients in the UK having this operation. Compared to SSI rates of elective hip surgery, at less than 1%, this figure is elevated. The aim of this quasi randomised controlled trial (RCT) is to determine if high dose antibiotic impregnated cement can reduce the SSI in patients at 12-months after hemiarthroplasty for intracapsular fractured neck of femur. METHODS: 848 patients with an intracapsular fractured neck of femur requiring a hip hemiarthroplasty are been recruited into this two-centre double-blind quasi RCT. Participants were recruited before surgery and quasi randomised to standard care or intervention group. Participants, statistician and outcome assessors were blind to treatment allocation throughout the study. The intervention consisted of high dose antibiotic impregnated cement consisting of 1 gram Clindamycin and 1 gram of Gentamicin. The primary outcome is Health Protection Agency (HPA) defined deep surgical site infection at 12 months. Secondary outcomes include HPA defined superficial surgical site infection at 30 days, 30 and 90-day mortality, length of hospital stay, critical care stay, and complications. DISCUSSION: Large randomised controlled trials assessing the effectiveness of a surgical intervention are uncommon, particularly in the speciality of orthopaedics. The results from this trial will inform evidence-based recommendations for antibiotic impregnated cement in the management of patients with a fractured neck of femur undergoing a hip hemiarthroplasty. If high dose antibiotic impregnated cement is found to be an effective intervention, implementation into clinical practice could improve long-term outcomes for patients undergoing hip hemiarthroplasty. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN25633145. PMID- 24344673 TI - Czech version of Rey Auditory Verbal Learning test: normative data. AB - The present study provides normative data stratified by age for the Rey Auditory Verbal Learning test Czech version (RAVLT) derived from a sample of 306 cognitively normal subjects (20-85 years). Participants met strict inclusion criteria (absence of any active or past neurological or psychiatric disorder) and performed within normal limits on other neuropsychological measures. Our analyses revealed significant relationships between most RAVLT indices and age and education. Normative data are provided not only for basic RAVLT scores, but for the first time also for a variety of derived (gained/lost access, primacy/recency effect) and error scores. The study confirmed a logarithmic character of the learning slope and is consistent with other studies. It enables the clinician to evaluate more precisely subject's RAVLT memory performance on a vast number of indices and can be viewed as a concrete example of Quantified Process Approach to neuropsychological assessment. PMID- 24344674 TI - Nerve Retraction During Inferior Alveolar Nerve Repositioning Procedure: A New Simple Method and Review of the Literature. AB - Nerve repositioning surgery is one of the treatments chosen for the patients with edentulous posterior atrophic mandible. Like any other treatments, this therapy has its advantages and disadvantages, indications and contraindications. The most important complication of this procedure is neurosensory disturbance. This problem may occur at different stages of the treatment. One common time when nerve damage happens is when the nerve is located outside the canal and drilling and insertion of the implant are performed. Accordingly, this report describes a simple and feasible method to retract and protect nerves outside the canal during the treatment of nerve transposition. This will reduce the risk of nerve damage. PMID- 24344675 TI - Inter-domain interactions in charged lipid monolayers. AB - Phase coexistence is common in model biomembranes with the presence of domains formed by lipids in a dense phase state modulating lateral diffusion of species through hydrodynamic and electrostatic interactions. In this study, interdomain interactions in monolayers of charged surfactants were analyzed and compared with neutral systems. Interactions were investigated at different interdomain distances and by varying the ionic strength (I) of the subphase. At low percentages of condensed area (%Ac), i.e., high interdomain distances, domains were approximated as point charges or dipoles, and a comparison between the simulated and experimental results was made. At high %Ac, domains were arranged in a distorted hexagonal lattice, and the energy of a domain around its equilibrium position in the lattice was modeled using a harmonic potential and the spring constant determined. On subphases of high I, charged domains interacted in a manner similar to neutral domains with domain motion being precluded at high percentages of condensed area. At low I, a higher interdomain repulsion was observed along with a lower domain motion and, therefore, a higher apparent viscosity at comparable %Ac. Interestingly, this effect was observed at conditions where the Debye-Huckel length was still 2 orders lower than the interdomain distances. PMID- 24344677 TI - Closing the circuit on cloning complex constructs. PMID- 24344678 TI - Decomposition of waste DNA with extended autoclaving under unsaturated steam. AB - Carryover and false-positive amplification of undesired DNA sequences are serious problems in research and diagnostic testing using PCR. One possible source of DNA cross-contamination can be the autoclave if DNA contained in waste is not effectively decomposed and contaminates the autoclave. To assess this possibility, we used a 2682 bp PCR product as a model waste DNA and quantified the amplifiability of an 84 bp short fragment derived from the model waste DNA in the steam and the residual bottom water after autoclaving. Autoclaving under the standard conditions of 121 degrees C for 20 min did not sufficiently remove amplifiability from the model DNA and was found to be a possible source of laboratory contamination. However, the amplifiable template was removed after autoclaving at 121 degrees C for 80 min. Fragmentation and hydrolysis may occur during autoclaving, and the presence of atmospheric oxygen facilitated the decomposition. These findings will help researchers develop better strategies for disposing of DNA waste. PMID- 24344679 TI - Quantitative PCR as a predictor of aligned ancient DNA read counts following targeted enrichment. AB - Targeted DNA enrichment through hybridization capture (EHC) is rapidly replacing PCR as the method of choice for enrichment prior to genomic resequencing. This is especially true in the case of ancient DNA (aDNA) from long-dead organisms, where targets tend to be highly fragmented and outnumbered by contaminant DNA. However, the behavior of EHC using aDNA has been quite variable, making success difficult to predict and preventing efficient sample equilibration during multiplexed sequencing runs. Here, we evaluate whether quantitative PCR (qPCR) measurements of aDNA samples correlate with on-target read counts before and after EHC. Our data indicate that not only do simple target qPCRs correlate strongly with high throughput sequencing (HTS) data but that certain sample characteristics, such as overall target abundance as well as experimental parameters (e.g., bait concentration and secondary structure propensity), consistently influenced enrichment of our diverse set of aDNA samples. Taken together, our results should help guide experimental design, screening strategies, and multiplexed sample equilibration, increasing yield and reducing the expected and actual cost of aDNA EHC high-throughput sequencing projects in the future. PMID- 24344680 TI - An assay for small scale screening of candidate beta cell proliferative factors using intact islets. AB - Current protocols for screening proliferative factors for beta cells ex vivo are time-consuming, require cell lines or dissociated islets, and often entail expensive specialized screening equipment. Here we present an efficient and lower cost alternative that utilizes intact mouse islets for the initial screening of proliferative compounds and allows confirmation of beta cell proliferation from the same islets. This protocol simplifies the process, saves money, and provides a way to identify beta cell proliferative factors using equipment that is ubiquitous in most laboratories. PMID- 24344681 TI - A method for high-throughput PCR-based genotyping of larval zebrafish tail biopsies. AB - Here we describe a method for high-throughput genotyping of live larval zebrafish as early as 72 h post-fertilization (hpf). Importantly, this technique allows rapid and cost-effective PCR-based genotyping from very small fin biopsies, which regenerate as the embryo develops, thereby allowing researchers to select embryos with desired genotypes to be raised to adulthood. PMID- 24344682 TI - Production of lactic acid/lactates from biomass and their catalytic transformations to commodities. PMID- 24344683 TI - A quarter of a century as a trendsetter in implant dentistry. PMID- 24344684 TI - Sediment-porewater partitioning, total sulfur, and methylmercury production in estuaries. AB - Mercury (Hg) speciation and the activity of Hg(II)-methylating bacteria are responsible for the rate of methylmercury production and thus bioaccumulation in marine foodwebs. Factors affecting porewater partitioning (Kd) and methylation of Hg(II) were examined at 11 sites in sediment of 4 biogeochemically diverse estuaries in the Northeast U.S. In Long Island Sound, 88% of total mercury (HgT) log Kd variability was described by porewater dissolved organic carbon concentration and sediment total sulfur (S) content. Whereas across all estuaries, regression analyses showed that S alone drives about 70% of Kd variability and 50% of changes in methylation rates; and the inclusion of DOC and sulfides did not improve the prediction. Thus, we demonstrated that S is a better predictor of HgT log Kd than the sediment organic matter across multiple estuaries, and while organic matter and S are interchangeable in small-scale studies, on a larger scale, sediment S content is the simplest and most effective variable to measure. PMID- 24344685 TI - Human pathogens in marine mammal meat - a northern perspective. AB - Only a few countries worldwide hunt seals and whales commercially. In Norway, hooded and harp seals and minke whales are commercially harvested, and coastal seals (harbour and grey seals) are hunted as game. Marine mammal meat is sold to the public and thus included in general microbiological meat control regulations. Slaughtering and dressing of marine mammals are performed in the open air on deck, and many factors on board sealing or whaling vessels may affect meat quality, such as the ice used for cooling whale meat and the seawater used for cleaning, storage of whale meat in the open air until ambient temperature is reached, and the hygienic conditions of equipment, decks, and other surfaces. Based on existing reports, it appears that meat of seal and whale does not usually represent a microbiological hazard to consumers in Norway, because human disease has not been associated with consumption of such foods. However, as hygienic control on marine mammal meat is ad hoc, mainly based on spot-testing, and addresses very few human pathogens, this conclusion may be premature. Additionally, few data from surveys or systematic quality control screenings have been published. This review examines the occurrence of potential human pathogens in marine mammals, as well as critical points for contamination of meat during the slaughter, dressing, cooling, storage and processing of meat. Some zoonotic agents are of particular relevance as foodborne pathogens, such as Trichinella spp., Toxoplasma gondii, Salmonella and Leptospira spp. In addition, Mycoplasma spp. parapoxvirus and Mycobacterium spp. constitute occupational risks during handling of marine mammals and marine mammal products. Adequate training in hygienic procedures is necessary to minimize the risk of contamination on board, and acquiring further data is essential for obtaining a realistic assessment of the microbiological risk to humans from consuming marine mammal meat. PMID- 24344686 TI - Quantitative T2 mapping to characterize the process of intervertebral disc degeneration in a rabbit model. AB - BACKGROUND: To investigate the potential of T2 mapping for characterizing the process of intervertebral disc degeneration (IDD) in a rabbit model. METHODS: Thirty-five rabbits underwent an annular stab to the L4/5 discs (L5/6 discs served as internal normal controls). Degenerative changes were graded according to the modified Thompson classification and quantified in T2 respectively at pre operation, 1, 3, 6, 12 and 24 weeks postoperatively. After MRI analysis, expression analysis of aggrecan and type II collagen gene in nucleus pulposus (NP) was performed using real time polymerase chain reaction (real-time PCR). The longitudinal changes in NP T2 and gene expressions were studied by repeated measures and ANOVA, linear regression was performed for their correlations through the process of IDD. The reliability analysis of method of measurement of NP T2 was also performed. RESULTS: There was a strong inverse correlation between NP T2 and Thompson grades (r = -0.85). The decline of L4/5 NP T2 through 24 weeks was nonlinear, the most significant decrease was observed in 3 weeks postoperatively (P<0.05). The tendency was confirmed at gene expression levels. NP T2 correlated strongly with aggrecan (R2 = 0.85, P<0.01) and type II collagen (R2 = 0.78, P<0.01) gene expressions. The intraclass correlation coefficients for interobserver and intraobserver reliability were 0.963 and 0.977 respectively. CONCLUSIONS: NP T2 correlates well with aggrecan and type II collagen gene expressions. T2 mapping could act as a sensitive, noninvasive tool for quantitatively characterizing the process of IDD in longitudinal study, help better understanding of the pathophysiology of IDD, assist us to detect the degenerative cascade, and develop a T2-based quantification scale for evaluation of IDD and efficacy of therapeutic interventions. PMID- 24344688 TI - Predictors of decreased binge eating following laparoscopic adjustable gastric banding using the Health Action Process Approach model. AB - The current study aimed to examine predictors of reduced binge eating in patients undergoing laparoscopic adjustable gastric banding (LAGB) for severe obesity. Participants were 49 patients (13 males and 36 females) who completed measures of binge eating, behavioural intentions, planning and self-efficacy two weeks prior and three months after their operation. Reduced binge eating following surgery was predicted by behavioural intentions. Planning and volitional self-efficacy were unable to predict a significant amount of variance over and above intentions. The results highlight how the role of intentions must not be overlooked when investigating the prediction of health behaviour change and challenge the notion that post-intentional constructs that translate intentions into action are more important. Interventions aiming to increase preoperative levels of intention to follow the post-operative eating guidelines in patients presenting with binge eating might be a useful way of decreasing this behaviour in patients opting for LAGB surgery in order to achieve weight loss and physical well-being. PMID- 24344687 TI - Phenotypic variability and identification of novel YARS2 mutations in YARS2 mitochondrial myopathy, lactic acidosis and sideroblastic anaemia. AB - BACKGROUND: Mutations in the mitochondrial tyrosyl-tRNA synthetase (YARS2) gene have previously been identified as a cause of the tissue specific mitochondrial respiratory chain (RC) disorder, Myopathy, Lactic Acidosis, Sideroblastic Anaemia (MLASA). In this study, a cohort of patients with a mitochondrial RC disorder for who anaemia was a feature, were screened for mutations in YARS2. METHODS: Twelve patients were screened for YARS2 mutations by Sanger sequencing. Clinical data were compared. Functional assays were performed to confirm the pathogenicity of the novel mutations and to investigate tissue specific effects. RESULTS: PathogenicYARS2 mutations were identified in three of twelve patients screened. Two patients were found to be homozygous for the previously reported p.Phe52Leu mutation, one severely and one mildly affected. These patients had different mtDNA haplogroups which may contribute to the observed phenotypic variability. A mildly affected patient was a compound heterozygote for two novel YARS2 mutations, p.Gly191Asp and p.Arg360X. The p.Gly191Asp mutation resulted in a 38 fold loss in YARS2 catalytic efficiency and the p.Arg360X mutation did not produce a stable protein. The p.Phe52Leu and p.Gly191Asp/p.Arg360X mutations resulted in more severe RC deficiency of complexes I, III and IV in muscle cells compared to fibroblasts, but had relatively normal YARS2 protein levels. The muscle-specific RC deficiency can be related to the increased requirement for RC complexes in muscle. There was also a failure of mtDNA proliferation upon myogenesis in patient cells which may compound the RC defect. Patient muscle had increased levels of PGC1-alpha and TFAM suggesting mitochondrial biogenesis was activated as a potential compensatory mechanism. CONCLUSION: In this study we have identified novel YARS2 mutations and noted marked phenotypic variability among YARS2 MLASA patients, with phenotypes ranging from mild to lethal, and we suggest that the background mtDNA haplotype may be contributing to the phenotypic variability. These findings have implications for diagnosis and prognostication of the MLASA and related phenotypes. PMID- 24344689 TI - Inter-observer reliability of computed tomographic classifications of diverticulitis. AB - AIM: The wide use of computed tomography (CT) for diverticulitis has initiated new classifications, but their reliability has not been studied. The aim of the study was to assess the inter-observer agreement of radiologists on the classifications of diverticulitis. METHOD: A set of 100 CT examinations of patients with an episode of diverticulitis was used to assess inter-observer agreement. Cases were derived from two prospective trials and a retrospective cohort to comprise an evenly distributed case mix of patients. The reference standard was the modified Hinchey classification based on all available information. Three blinded radiologists independently read all CT examinations. We calculated the proportion of agreement and kappa values for the Hinchey and Ambrosetti classifications. For the Dharmarajan classification only inter observer agreement was calculated. RESULTS: The agreement with the reference standard was substantial for both the modified Hinchey and the Ambrosetti classifications (P = 0.68 and P = 0.76). Overall inter-observer agreement for the modified Hinchey classification was substantial (median kappa 0.72), for the Ambrosetti classification almost perfect (median kappa 0.83) and for the Dharmarajan classification substantial (median kappa 0.76). CONCLUSION: The Ambrosetti classification is more reproducible than the modified Hinchey and Dharmarajan classifications. The Ambrosetti and modified Hinchey classifications have a substantial agreement with the reference standard and therefore produce a reliable classification. The Dhamarajan is applicable only in complicated diverticulitis and is an important complementary classification to the other more general classifications of diverticulitis. PMID- 24344690 TI - Rational design of allosteric regulation of homoserine dehydrogenase by a nonnatural inhibitor L-lysine. AB - Allosteric proteins, which can sense different signals, are interesting biological parts for synthetic biology. In particular, the design of an artificial allosteric enzyme to sense an unnatural signal is both challenging and highly desired, for example, for a precise and dynamical control of fluxes of growth-essential but byproduct pathways in metabolic engineering of industrial microorganisms. In this work, we used homoserine dehydrogenase (HSDH) of Corynebacterium glutamicum, which is naturally allosterically regulated by threonine and isoleucine, as an example to demonstrate the feasibility of reengineering an allosteric enzyme to respond to an unnatural inhibitor L-lysine. For this purpose, the natural threonine binding sites of HSD were first predicted and verified by mutagenesis experiments. The threonine binding sites were then engineered to a lysine binding pocket. The reengineered HSD only responds to lysine inhibition but not to threonine. This is a significant step toward the construction of artificial molecular circuits for dynamic control of growth essential byproduct formation pathway for lysine biosynthesis. PMID- 24344691 TI - Aggregation of sparse linear discriminant analyses for event-related potential classification in brain-computer interface. AB - Two main issues for event-related potential (ERP) classification in brain computer interface (BCI) application are curse-of-dimensionality and bias variance tradeoff, which may deteriorate classification performance, especially with insufficient training samples resulted from limited calibration time. This study introduces an aggregation of sparse linear discriminant analyses (ASLDA) to overcome these problems. In the ASLDA, multiple sparse discriminant vectors are learned from differently l1-regularized least-squares regressions by exploiting the equivalence between LDA and least-squares regression, and are subsequently aggregated to form an ensemble classifier, which could not only implement automatic feature selection for dimensionality reduction to alleviate curse-of dimensionality, but also decrease the variance to improve generalization capacity for new test samples. Extensive investigation and comparison are carried out among the ASLDA, the ordinary LDA and other competing ERP classification algorithms, based on different three ERP datasets. Experimental results indicate that the ASLDA yields better overall performance for single-trial ERP classification when insufficient training samples are available. This suggests the proposed ASLDA is promising for ERP classification in small sample size scenario to improve the practicability of BCI. PMID- 24344692 TI - Self-supervised MRI tissue segmentation by discriminative clustering. AB - The study of brain lesions can benefit from a clear identification of transitions between healthy and pathological tissues, through the analysis of brain imaging data. Current signal processing methods, able to address these issues, often rely on strong prior information. In this article, a new method for tissue segmentation is proposed. It is based on a discriminative strategy, in a self supervised machine learning approach. This method avoids the use of prior information, which makes it very versatile, and able to cope with different tissue types. It also returns tissue probabilities for each voxel, crucial for a good characterization of the evolution of brain lesions. Simulated as well as real benchmark data were used to validate the accuracy of the method and compare it against other segmentation algorithms. PMID- 24344693 TI - Drug polyconsumption is associated with increased synchronization of brain electrical-activity at rest and in a counting task. AB - Drug abusers typically consume not just one but several types of drugs, starting from alcohol and marijuana consumption, and then dramatically lapsing into addiction to harder drugs, such as cocaine, heroin, or amphetamine. The brain of drug abusers presents various structural and neurophysiological abnormalities, some of which may predate drug consumption onset. However, how these changes translate into modifications in functional brain connectivity is still poorly understood. To characterize functional connectivity patterns, we recorded Electroencephalogram (EEG) activity from 21 detoxified drug abusers and 20 age matched control subjects performing a simple counting task and at rest activity. To evaluate the cortical brain connectivity network we applied the Synchronization Likelihood algorithm. The results showed that drug abusers had higher synchronization levels at low frequencies, mainly in the theta band (4-8 Hz) between frontal and posterior cortical regions. During the counting task, patients showed increased synchronization in the beta (14-35 Hz), and gamma (35 45 Hz) frequency bands, in fronto-posterior and interhemispheric temporal regions. Taken together 'slow-down' at rest and task-related 'over-exertion' could indicate that the brain of drug abusers is suffering from a premature form of ageing. Future studies will clarify whether this condition can be reversed following prolonged periods of abstinence. PMID- 24344694 TI - Effects of extremely low-frequency magnetic fields on the response of a conductance-based neuron model. AB - To provide insights into the modulation of neuronal activity by extremely low frequency (ELF) magnetic field (MF), we present a conductance-based neuron model and introduce ELF sinusoidal MF as an additive voltage input. By analyzing spike times and spiking frequency, it is observed that neuron with distinct spiking patterns exhibits different response properties in the presence of MF exposure. For tonic spiking neuron, the perturbations of MF exposure on spike times is maximized at the harmonics of neuronal intrinsic spiking frequency, while it is maximized at the harmonics of bursting frequency for burst spiking neuron. As MF intensity increases, the perturbations also increase. Compared with tonic spiking, bursting dynamics are less sensitive to the perturbations of ELF MF exposure. Further, ELF MF exposure is more prone to perturb neuronal spike times relative to spiking frequency. Our finding suggests that the resonance may be one of the neural mechanisms underlying the modulatory effects of the low-intensity ELF MFs on neuronal activities. The results highlight the impacts of ELF MFs exposure on neuronal activity from the single cell level, and demonstrate various factors including ELF MF properties and neuronal spiking characteristics could determine the outcome of exposure. These insights into the mechanism of MF exposure may be relevant for the design of multi-intensity magnetic stimulus protocols, and may even contribute to the interpretation of MF effects on the central nervous systems. PMID- 24344695 TI - Multi-strategy coevolving aging particle optimization. AB - We propose Multi-Strategy Coevolving Aging Particles (MS-CAP), a novel population based algorithm for black-box optimization. In a memetic fashion, MS-CAP combines two components with complementary algorithm logics. In the first stage, each particle is perturbed independently along each dimension with a progressively shrinking (decaying) radius, and attracted towards the current best solution with an increasing force. In the second phase, the particles are mutated and recombined according to a multi-strategy approach in the fashion of the ensemble of mutation strategies in Differential Evolution. The proposed algorithm is tested, at different dimensionalities, on two complete black-box optimization benchmarks proposed at the Congress on Evolutionary Computation 2010 and 2013. To demonstrate the applicability of the approach, we also test MS-CAP to train a Feedforward Neural Network modeling the kinematics of an 8-link robot manipulator. The numerical results show that MS-CAP, for the setting considered in this study, tends to outperform the state-of-the-art optimization algorithms on a large set of problems, thus resulting in a robust and versatile optimizer. PMID- 24344696 TI - A neural observer with time-varying learning rate: analysis and applications. AB - In this paper, a reduced order neural observer (RONO) with a time-varying learning rate is proposed. The proposed scheme is based on a discrete-time recurrent high order neural network (RHONN) trained with an extended Kalman filter (EKF)-based algorithm. A time-varying learning rate is designed in order to improve the learning of the neuronal network in presence of disturbances and parameter variations. This work includes the stability proof of the time-varying learning. The applicability of the developed observer is illustrated via simulations for a nonlinear anaerobic digestion process. PMID- 24344697 TI - Do hormones influence women's sex? Sexual activity over the menstrual cycle. AB - INTRODUCTION: In mammals, the effects of ovarian steroids influence sexual behavior. In humans, there are a few studies that take into account if ovulation occurs. AIM: The study aims to investigate if a woman's sexuality changes during the week and over the menstrual cycle, and if so, in what way. METHODS: This is a prospective cohort study; 1,957 heterosexual women were involved over the period January 2004-December 2011. Two subgroups were taken into consideration, women having a partner and singles. MAIN OUTCOME MEASURE: Sexual interview and the Female Sexual Function Index and Female Sexual Distress Scale questionnaires were used to exclude women with sexual dysfunction. Women with ovulation confirmed by sonography were enrolled. Women were given diary cards on which to report their daily sexual activity. Serum concentrations of estradiol, progesterone, total testosterone, sex hormone binding globulin, and free androgen index were measured during the follicular, periovular, and luteal phase of the menstrual cycle. RESULTS: One thousand one hundred eighty women (age range 18-40 years) were included in the analyses. Of them, 925 had a heterosexual relationship and 255 were single. Women with a partner had more sexual activity during the weekend, while the singles had a constant sexual activity over the week. The sexual activity of singles was higher during the ovulatory phase and lower during menses than that of the women with a partner. A linear correlation between sexual activity and androgenic hormonal profile during the menstrual cycle in women with and without a partner was observed. CONCLUSIONS: Ovarian steroids modulate a woman's sexual activity. This aspect was more evident in singles than in women having a partner, in which a variety of nonhormonal factors can have a role. PMID- 24344699 TI - Greetings from the new editor in chief. PMID- 24344698 TI - Laggeric acid, a novel seco-eudesmane sesquiterpenoid from Laggera crispata. AB - Laggeric acid (1), a novel 4,5-seco-eudesmane sesquiterpene acid, along with 19 known compounds, was isolated from the MeOH extract of the whole plant of Laggera crispata. The structure of 1 was elucidated to be (4S,5S*,7R*,10R*)-4,5-seco-4,5 dihydroxy-11(13)-eudesmen-12-oic acid on the basis of spectroscopic analysis and a convenient Mosher's method. PMID- 24344700 TI - Cultural issues in perinatal care. PMID- 24344702 TI - Baby-friendly hospital practices and birth costs. AB - BACKGROUND: Hospital practices supportive of breastfeeding can improve breastfeeding rates. There are limited data available on how improved hospital practices are associated with hospital costs. We describe the association between the number of breastfeeding supportive practices a hospital has in place and the cost of an uncomplicated birth. METHODS: Data from hospitals in 20 states that participated in the 2007 Maternity Practices in Infant Nutrition and Care (mPINC) survey and Healthcare Cost and Utilization Project's (HCUP) State Inpatient Databases (SID) were merged to calculate the average median hospital cost of uncomplicated vaginal and cesarean section births by number of ideal practices from the Ten Steps to Successful Breastfeeding. Linear regression analyses were conducted to estimate change in birth cost for each additional ideal practice in place. RESULTS: Sixty-one percent of hospitals had ideal practice on 3-5 of the 10 steps, whereas 29 percent of hospitals had ideal practice on 6-8. Adjusted analyses of uncomplicated births revealed a higher but nonsignificant increase in any of the birth categories (all births, $19; vaginal, $15; cesarean section, $39) with each additional breastfeeding supportive maternity care practice in place. CONCLUSIONS: Our results revealed that the number of breastfeeding supportive practices a hospital has in place is not significantly associated with higher birth costs. Concern for higher birth costs should not be a barrier for improving maternity care practices that support women who choose to breastfeed. PMID- 24344703 TI - Use of nonmedical methods of labor induction and pain management among U.S. women. AB - BACKGROUND: There exists limited documentation of nonmedical methods of labor induction and pain management during childbirth in the United States. We estimated the prevalence of nonmedical interventions for induction and pain management and examined the association between medical and nonmedical care during labor. METHODS: We used a nationally representative survey of U.S. women who gave birth in 2005 (N = 1,382) to examine use of nonmedical methods of labor induction and pain management. Using logistic regression, we calculated odds of nonmedical and medical interventions to induce labor or mitigate pain, and the odds of medical induction and obstetric analgesia by whether nonmedical methods were reported. RESULTS: Nearly 30 percent of women used nonmedical methods to start labor, and over 70 percent of women used nonmedical pain management. Doula support was the strongest predictor of nonmedical methods of labor induction (Adjusted Odds Ratio [AOR] = 3.0) and labor pain management (AOR = 5.7). Use of nonmedical pain management was significantly associated with decreased odds of medical pain management (OR = 0.65); this relationship was attenuated with covariate adjustment. CONCLUSIONS: Nonmedical methods to induce labor and manage pain during childbirth are commonly used by U.S. women. Future research should examine effectiveness of these strategies and their influence on medical services use. PMID- 24344704 TI - Institute of medicine 2009 gestational weight gain guideline knowledge: survey of obstetrics/gynecology and family medicine residents of the United States. AB - BACKGROUND: In 2009, the Institute of Medicine revised gestational weight gain recommendations; revisions included body mass index (BMI) category cut-point changes and provision of range of gain for obese women. Our objective was to examine resident prenatal caregivers' knowledge of revised guidelines. METHODS: Anonymous electronic survey of obstetrics/gynecology and family medicine residents across the United States from January to April 2010. RESULTS: Overall, 660 completed the survey; 79 percent female and 69 percent aged between 21 and 30. When permitted to select >= 1 response, 87.0 percent reported using BMI to assess weight status at initial visits, 44.4 percent reported using "clinical impression based on patient appearance," and 1.4 percent reported not using any parameters. When asked the most important baseline parameter for providing recommendations, 35.8 percent correctly identified prepregnancy BMI, 2.1 percent reported "I don't provide guidelines," and 4.5 percent reported "I do not discuss gestational weight gain." Among respondents, 57.6 percent reported not being aware of new guidelines. Only 7.6 percent selected correct BMI ranges for each category, and only 5.8 percent selected correct gestational weight gain ranges. Only 2.3 percent correctly identified both BMI cutoffs and recommended gestational weight gain ranges per 2009 guidelines. CONCLUSIONS: Guideline knowledge is the foundation of accurate counseling, yet resident prenatal caregivers were minimally aware of the 2009 Institute of Medicine gestational weight gain guidelines almost a year after their publication. PMID- 24344705 TI - The use of episiotomy in a low-risk population in the Netherlands: a secondary analysis. AB - BACKGROUND: To examine the episiotomy incidence and determinants and outcomes associated with its use in primary care midwifery practices. METHODS: Secondary analysis of two prospective cohort studies (n = 3,404). RESULTS: The episiotomy incidence was 10.8 percent (20.9% for nulliparous and 6.3% for parous women). Episiotomy was associated with prolonged second stage of labor (adj. OR 12.09 [95% CI 6.0-24.2] for nulliparous and adj. OR 2.79 [1.7-4.6] for parous women) and hospital birth (adj. OR 1.75 [1.2-2.5] for parous women). Compared with episiotomy, perineal tears were associated with a lower rate of postpartum hemorrhage in parous women (adj. OR 0.58 [0.4-0.9]). Fewer women with perineal tears reported perineal discomfort (adj. OR 0.35 [0.2-0.6] for nulliparous and adj. OR 0.22 [0.1-0.3] for parous women). Among nulliparous women episiotomy was performed most frequently for prolonged second stage of labor (38.8%) and among parous women for history of episiotomy or prevention of major perineal trauma (21.1%). CONCLUSIONS: The incidence of episiotomy is high compared with some low risk settings in other Western countries. Episiotomy was associated with higher rates of adverse maternal outcomes. Restricted use of episiotomy is likely to be beneficial for women. PMID- 24344706 TI - Women's experiences, emotional responses, and perceptions of care after emergency peripartum hysterectomy: a qualitative survey of women from 6 months to 3 years postpartum. AB - BACKGROUND: Little is known of the experience and perceptions of care for survivors of emergency peripartum hysterectomy (EPH), an obstetric event that is increasing in incidence. We sought to explore women's experiences of EPH to make recommendations for care. METHODS: This qualitative study utilized purposive sampling through an online support group of women who experienced EPH. Eligible participants were at least 18 years old, had their hysterectomy at least 6 months but no more than 3 years before the interview, had a surviving infant associated with the delivery, and did not report suicidal ideation. In-depth, semi structured telephone interviews were conducted and analyzed using Constant Comparative Analysis. Kappa statistics assessed interrater reliability for two independent coders. RESULTS: Fifteen women participated with a mean age of 32.5 years. Most had a cesarean section, with uterine atony as the most common indication for EPH. Kappa statistics indicated near-perfect interrater agreement between two coders, ranging from .82 to .89. Seven major themes were identified: fear; pain; death and dying; numbness or delay in emotional reaction; bonding with baby; communication; and the need for information. Psychological upset occurred postpartum and was often delayed. A major finding is the need for additional follow-up visits to address the emotional after-effects and to fill in gaps in women's understanding and memory of what had occurred. CONCLUSION: Understanding women's experiences with EPH can help practitioners address not only women's initial complications but provide needed long-term support. PMID- 24344707 TI - "Too posh to push": the rise and rise of a catchphrase. AB - BACKGROUND: The phrase "too posh to push" was coined over 14 years ago to describe maternal request for cesarean section in the absence of clinical indications. The phrase was readily taken up and used by the United Kingdom media despite limited evidence that many women request cesarean sections or have an aversion to vaginal birth. The objectives of this study were to explore the way in which the phrase was used; the context and themes associated with it. METHODS: To better understand the part the news media might play in public and health care professionals' perceptions, all articles using the phrase in eight UK national weekday newspapers from 1999 to 2011 (n = 335) were subjected to content analysis. RESULTS: Key themes have changed over the years but some themes, such as celebrity cesareans, the risks of cesarean section, and the rising cesarean rate, have remained. Four different definitions of the term "too posh to push" were identified. Levels of usage of these terms changed over time. Misinterpretation of the National Sentinel Cesarean Section Audit results and a tendency to confuse elective cesarean section with maternal request for a cesarean have suggested that more "too posh to push" cesareans occurred than is probably the case. CONCLUSION: The phrase seems to have become well established. It is likely that press handling of the topic has continued to contribute to the impression that cesarean purely for maternal request is common. The association with celebrity continues to fuel press interest in the topic. PMID- 24344708 TI - Antenatal hypnosis training and childbirth experience: a randomized controlled trial. AB - BACKGROUND: Childbirth is a demanding event in a woman's life. The aim of this study was to explore whether a brief intervention in the form of an antenatal course in self-hypnosis to ease childbirth could improve the childbirth experience. METHOD: In a randomized, controlled, single-blinded trial, 1,222 healthy nulliparous women were allocated to one of three groups during pregnancy: A hypnosis group participating in three 1-hour sessions teaching self-hypnosis to ease childbirth, a relaxation group receiving three 1-hour lessons in various relaxation methods and Mindfulness, and a usual care group receiving ordinary antenatal care only. Wijmas Delivery Expectancy/Experience Questionnaire (W-DEQ) was used to measure the childbirth experience 6 weeks postpartum. RESULTS: The intention-to-treat analysis indicated that women in the hypnosis group experienced their childbirth as better compared with the other two groups (mean W DEQ score of 42.9 in the Hypnosis group, 47.2 in the Relaxation group, and 47.5 in the Care as usual group (p = 0.01)). The tendency toward a better childbirth experience in the hypnosis group was also seen in subgroup analyses for mode of delivery and for levels of fear. CONCLUSION: In this large randomized controlled trial, a brief course in self-hypnosis improved the women's childbirth experience. PMID- 24344709 TI - Sexual violence and antenatal hospitalization. AB - BACKGROUND: Studies have shown the negative impact sexual violence has on pregnancy outcome, yet the impact on antenatal hospitalization has been poorly examined. The aim of this study was to investigate if a history of sexual violence was associated with hospitalization during pregnancy. METHODS: A population-based national cohort study conducted by the Institute of Public Health, The Norwegian Mother and Child Cohort study. Women filled out questionnaires at 17 and 30 weeks' gestation. History of sexual violence was reported at three levels: pressured to sexual acts (mild), forced with violence (moderate), and raped (severe). The comparison group did not report sexual violence. Differences were assessed using Pearson's X(2) tests and logistic regression analyses. RESULTS: Of 78,660 women, 12.0% were pressured to sexual acts, 2.8% forced with violence, and 3.6% reported rape. A history of sexual violence was associated with significantly more hospitalizations during pregnancy, 6.6 percent for mild, 8.7 percent for moderate and 12.5 percent for severe, compared to 5.8 percent for no sexual violence. Women were significantly more often admitted for hyperemesis, bleeding, threatening preterm birth, other reasons and admitted without giving any reason. Reporting severe sexual violence had an AOR for being hospitalized with hyperemesis or threatening preterm birth of 1.9 (95% CI 1.4-2.5), and 1.9 (1.3-2.7) respectively. Similarly, severe sexual violence was associated with being admitted more than once during pregnancy AOR 1.9 (1.3-2.7). CONCLUSION: Women with a history of sexual violence reported significantly more antenatal hospitalizations during pregnancy than women without such a history. PMID- 24344710 TI - Birth experience in women with low, intermediate or high levels of fear: findings from the first baby study. AB - BACKGROUND: Fear of childbirth and mode of delivery are two known factors that affect birth experience. The interactions between these two factors are unknown. The aim of this study was to estimate the effects of different levels of fear of birth and mode of delivery on birth experience 1 month after birth. METHODS: As part of an ongoing prospective study, we interviewed 3,006 women in their third trimester and 1 month after first childbirth to assess fear of birth and birth experience. Logistic regression was performed to examine the interactions and associations between fear of birth, mode of delivery and birth experience. RESULTS: Compared with women with low levels of fear of birth, women with intermediate levels of fear, and women with high levels of fear had a more negative birth experience and were more affected by an unplanned cesarean section or instrumental vaginal delivery. Compared with women with low levels of fears with a noninstrumental vaginal delivery, women with high levels of fear who were delivered by unplanned cesarean section had a 12-fold increased risk of reporting a negative birth experience (OR 12.25; 95% CI 7.19-20.86). A noninstrumental vaginal delivery was associated with the most positive birth experience among the women in this study. CONCLUSIONS: This study shows that both levels of prenatal fear of childbirth and mode of delivery are important for birth experience. Women with low fear of childbirth who had a noninstrumental vaginal delivery reported the most positive birth experience. PMID- 24344711 TI - Referral for management of emotional health issues during the perinatal period: does mental health assessment make a difference? AB - BACKGROUND: There exists little evidence that routine assessment of current or past mental health in the perinatal period positively impacts on rates of referral for emotional health issues. This study aimed to evaluate the impact of this early intervention approach on reported referrals for emotional health issues during pregnancy and the first postpartum year. METHOD: A subsample of women (N = 1,804) drawn from the Australian Longitudinal Study on Women's Health participated in the study. RESULTS: Multivariate analyses showed that predictors of being given a referral for emotional health issues during pregnancy and the postnatal period, respectively, included assessment of past mental health (Adjusted Odds Ratio [AOR] = 4.40, p < 0.001, and AOR = 5.69, p < 0.001), assessment of current mental health (AOR = 2.47, p < 0.001, and AOR = 2.72, p < 0.001), and reported experience of significant emotional distress (AOR = 2.58, p < 0.001, and AOR = 2.83, p < 0.001). The odds of receiving a referral were up to 16 times greater for women who were asked about both their past and current mental health than for women who did not receive any form of mental health assessment. CONCLUSIONS: This study highlights that enquiry into risk factors such as past history (in addition to current mental health) enhances initiation of referrals. Importantly, results suggest that enquiry about current mental health is associated with appropriate rates of referral rather than a nonspecific inflation of referrals. In line with Australia's Clinical Practice Guidelines for Perinatal Mental Health, the value of a comprehensive approach to mental health assessment to aid decision making around referral for further assessment or care is particularly evident. PMID- 24344712 TI - Risk of episiotomy and perineal lacerations recurring after first delivery. AB - BACKGROUND: To assess whether the presence of an episiotomy or spontaneous perineal trauma at the first delivery increases the risk of perineal trauma at the following one. METHODS: We studied 2,695 women who gave birth twice at Virgen de las Nieves University Hospital of Granada, Spain. All second deliveries were from 2004 to 2011 and prenatal database records were used to obtain information about the first deliveries. All births, first and second, were single, vaginal, unassisted, and in a cephalic presentation. Two groups were made as follows: Intact perineum (no perineal trauma or first-degree spontaneous tear at the first delivery) and perineal trauma (episiotomy or second-degree or higher spontaneous tear at the first delivery). Both groups were compared according to the degree of perineal trauma at the second delivery. RESULTS: Women included in the perineal trauma group were significantly older and a higher proportion was attended by a midwife with an obstetrician present in the delivery room. No differences were observed according to gestational age, epidural analgesia or fetal birth weight. Adjusting for these possible compounding factors and the year of birth, the risk of undergoing a second-degree or higher spontaneous tear at their next delivery was fivefold (adjusted OR 5.15, 95% CI 3.11-8.54), and the risk of undergoing an episiotomy in the second delivery was threefold (adjusted OR 3.20, 95% CI 2.19 4.69) for the perineal trauma group. CONCLUSION: The risk of undergoing a spontaneous perineal tear or an episiotomy in the second delivery is increased by the practice of episiotomy in the first one. PMID- 24344714 TI - What is the purpose of the baby-friendly hospital initiative for neonatal wards? Commentary to a letter by Adik Levin in Birth, 40:2, June 2013. PMID- 24344716 TI - Interaction of differently functionalized fluorescent silica nanoparticles with neural stem- and tissue-type cells. AB - Engineered amorphous silica nanoparticles (SiO2 NPs), due to simple and low cost production, are increasingly used in commercial products and produced on an industrial scale. Despite the potential benefits, there is a concern that exposure to certain types of SiO2 NPs may lead to adverse health effects. As some NPs can cross the blood--brain barrier and may, in addition, reach the central nervous system through the nasal epithelium, this study addresses the responses of different neural tissue-type cells including neural stem cells, neurons, astrocytes and microglia cells to increasing doses of 50 nm fluorescent core/shell SiO2 NPs with different [-NH2, -SH and polyvinylpyrrolidone (PVP)] surface chemistry. The SiO2 NPs are characterized using a variety of physicochemical methods. Assays of cytotoxicity and cellular metabolism indicates that SiO2 NPs cause cell death only at high particle doses, except PVP-coated SiO2 NPs which do not harm cells even at very high concentrations. All SiO2 NPs, except those coated with PVP, form large agglomerates in physiological solutions and adsorb a variety of proteins. Except PVP-NPs, all SiO2 NPs adhere strongly to cell surfaces, but internalization differs depending on neural cell type. Neural stem cells and astrocytes internalize plain SiO2, SiO2-NH2 and SiO2-SH NPs, while neurons do not take up any NPs. The data indicates that the PVP coat, by lowering the particle-biomolecular component interactions, reduces the biological effects of SiO2 NPs on the investigated neural cells. PMID- 24344717 TI - Successful three-way kidney paired donation with compatible pairs to increase donor pool. AB - Despite heightened international interest in performing living donor kidney paired donation (KPD) transplantation after the publication of a research protocol by Ross and colleagues in 1997, only a few hundred have been performed worldwide. The major obstacle is that many individuals in end-stage renal disease are of blood type O and can only receive an organ from a donor of blood type O, whereas blood type O donors are "universal donors" and will be able to donate directly with an intended recipient of any blood type unless there is a positive crossmatch. To overcome this, patients with compatible but non-HLA identical donors over 45 years of age should be approached for inclusion in KPD program especially O blood group donors. Inclusion of all these additional pairs into the algorithm greatly increases chances of possible matches for O blood group recipients. We report successful three-way KPD transplantation resulting in transplantation of O blood group patient using compatible O blood group donor from India. None of the patients had delayed graft function or rejection and all had stable graft function on discharge without any medical and surgical complications. We need to allocate O blood group kidneys from compatible donors to overcome the barrier of HLA, non-HLA antibodies and other donor related factors to improve transplant quality and long term outcomes. This will increase transplantation of O blood group patients. PMID- 24344718 TI - Sexual behaviors, sexual health practices, and community engagement among gay and bisexually identified men living in rural areas of the United States. AB - Limited research has focused on the sexual behaviors of men who have sex with men (MSM) from rural communities. We examined the sexual and health-related behaviors of MSM living in rural areas of the United States in order to understand the sexual health repertoire of this population. A total of 5,357 participants living in rural settings were recruited online and completed an anonymous Internet-based survey that assessed sexual behaviors, condom use, and men's engagement with various community activities and events. These data provide a greater understanding of sexual health profiles that exist among rural MSM and will help inform the design of effective programs for men in these often underserved communities. PMID- 24344719 TI - P16INK4A as a surrogate biomarker for human papillomavirus-associated oropharyngeal carcinoma: consideration of some aspects. AB - Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinomas (OPSCCs) frequently show different clinical and pathological features, which tend to be younger age, better performance status, less tobacco and alcohol consumption, more poorly differentiated histopathology, but usually with better treatment response and prognosis compared with HPV-negative OPSCCs. In tumor tissue, HPV infection is closely correlated with p16(INK4A) expression, which has been suggested to be a surrogate biomarker of HPV infection. However, there is diversity of sensitivity and specificity about p16(INK4A) in surrogate detection of HPV status. Herein, we summarize the current knowledge and note some aspects for consideration concerning p16(INK4A) as a surrogate biomarker for HPV associated OPSCC. PMID- 24344720 TI - IPH-926 lobular breast cancer cells are triple-negative but their microarray profile uncovers a luminal subtype. AB - Human primary breast cancers and breast cancer cell lines are classified by microarray-defined molecular subtypes, which reflect differentiation characteristics. Estrogen receptor (ER) expression is indicative of the luminal molecular subtype. We have previously established IPH-926, the first well characterized cell line from infiltrating lobular breast cancer. IPH-926 displays an ER/PR/ErbB2 triple-negative immunophenotype, which is due to a loss of ER expression in its in vivo clonal ancestry. Loss of ER might indicate a fundamental change of cellular differentiation and it is unclear whether a luminal subtype is preserved beyond ER conversion. Using Affymetrix microarray analysis, seven different classifier gene lists (PAM305, DISC256, TN1288, PAM50, UNC1300, LAB704, INT500) and a background population of 50 common mammary carcinoma cell lines, we have now determined the molecular subtype of IPH-926. Strikingly, the IPH-926 expression profile is highly consistent with a luminal subtype. It is nearest to luminal/ER-positive breast cancer cell lines and far apart from basal breast cancer cell lines. Quantitative real-time RT-PCR confirmed enhanced expression of luminal marker genes (AGR2, CLU, CA12, EMP2, CLDN3) and low or absent expression of basal marker genes (KRT5, CD44, CAV1, VIM). Moreover, IPH-926 lacked androgen receptor (AR) expression, a transcription factor previously associated with luminal-like gene expression in a subset of triple-negative or molecular apocrine breast cancers. In conclusion, IPH-926 is triple-negative but belongs to the luminal subtype. Luminal differentiation characteristics can be preserved beyond ER conversion and might not require a compensatory expression of AR. PMID- 24344724 TI - Recent progress in rare earth micro/nanocrystals: soft chemical synthesis, luminescent properties, and biomedical applications. PMID- 24344725 TI - Is there a link between the extracranial venous system and central nervous system pathology? AB - The extracranial venous system is complex and variable between individuals. Until recently, these variations were acknowledged as developmental variants and were not considered pathological findings. However, in the last decade, the presence and severity of uni- or bi-lateral jugular venous reflux (JVR) was linked to several central nervous system (CNS) disorders such as transient global amnesia, transient monocular blindness, cough headache, primary exertional headache and, most recently, to Alzheimer's disease. The most recent introduction of a composite criteria-based vascular condition named chronic cerebrospinal venous insufficiency (CCSVI), which was originally linked to multiple sclerosis, increased the interest in better understanding the role of the extracranial venous system in the pathophysiology of CNS disorders. The ultimate cause consequence relationship between these conditions and CNS disorders has not been firmly established and further research is needed. The purpose of this article collection in BMC Medicine and BMC Neurology is to synthesize current concepts and most recent findings concerning the evaluation, etiology, pathophysiology and clinical relevance of the potential involvement of the extracranial venous system in the pathology of multiple CNS disorders and in aging. PMID- 24344726 TI - High-performance lithium-ion battery anode by direct growth of hierarchical ZnCo2O4 nanostructures on current collectors. AB - Hierarchical nanostructures that can be directly grown on a conducting substrate are a new trend in the design of active materials for high-performance lithium ion batteries (LIBs). This article reports our design and fabrication of a 3D hierarchical ZnCo2O4 nanostructure (3D-ZCO-NS) directly grown on Ni foams. The goose-feather-like ZnCo2O4 bundled into a loose array structure with a large electrolyte contact area and good electrical and mechanical connection to the current collector. Electrochemical measurements confirmed the good performance of the electrode for reversible Li(+) storage (specific capacity of 932 mAh g(-1) in the 50th cycle at 1 A g(-1)) relative to a pasted electrode of 3D-ZCO-NSs (599 mAh g(-1) in the 50th cycle at 0.1 A g(-1)). PMID- 24344727 TI - Effects of thalidomide on Fgf8, Bmp4 and Hoxa11 expression in the limb bud in Kbl:JW rabbit embryos. AB - Thalidomide (TM) induces limb defects in humans and some animal species including rabbits. Although the mechanism of TM-induced limb defects has been investigated for a long period, the limb development-related genes expressions have not been vigorously characterized in rabbits. In this study, we investigated the Fgf8, Bmp4 and Hoxa11 expressions in TM-treated JW rabbit embryos on gestation days (GDs) 10, 11 and 12 by whole mount in situ hybridization. On GDs 10 and 11, growth retardation of the embryo was induced by TM treatment. The Fgf8 expression lengths on GDs 10 and 11 in the forelimb bud were significantly or tended to be decreased in the TM-treated embryos, which was correlated to the growth retardation and was not considered to be directly relevant to the teratogenic effect of TM in the forelimb. The TM-induced characteristic changes in the expression pattern of Hoxa11 and Bmp4 on GDs 10 and/or 11 were not noted. On GD 12, TM-induced growth retardation was not noted and the Fgf8 and Bmp4 expressions were not changed. On the contrary, Hoxa11 expression was narrowed at the anterior region, which was located on the radial side, and was not changed at the middle and posterior regions in the forelimb bud and in all regions in the hindlimb bud. Because the radius malformations were induced by TM treatment, we concluded the decrease in the Hoxa11 expression was related to the TM-induced limb defects and can be a good marker for early prediction of the teratogenic effect of TM. PMID- 24344728 TI - The role of acupoint stimulation as an adjunct therapy for lung cancer: a systematic review and meta-analysis. AB - BACKGROUND: Lung cancer is the leading cause of death in cancer patients. Clinical studies showed that a variety of acupoint stimulations have been extensively used for lung cancer patients, including needle insertion, injection with herbal extraction, plaster application, and moxibustion. However, the role of acupoint stimulation in lung cancer treatment was not fully reviewed. METHODS: In the present study, we conducted a systematic review and meta-analysis on the role of acupoint stimulation in lung cancer treatment by electronic and manual searching in seven databases, including Ovid (Ovid MEDLINE, AMED, CAB Abstracts, EMBASE), EBSCOhost research databases (Academic Search premier, MEDLINE, CIHAHL Plus), PreQuest (British Nursing Index, ProQuest Medical Library, ProQuest Dissertations & Theses A&I, PsycINFO), and ISI web of knowledge (Web of Science, BIOSIS Citation Index, Biological Abstracts, Chinese Science Citation Database), CNKI, Wanfang Data, and CQVIP. RESULTS: Our study showed that acupoint stimulation has strong immunomodulatory effect for lung cancer patients as demonstrated by the significant increase of IL-2, T cell subtypes (CD3+ and CD4+, but not CD8+ cells), and natural killer cells. Further analysis revealed that acupoint stimulation remarkably alleviates the conventional therapy-induced bone marrow suppression (hemoglobin, platelet, and WBC reduction) in lung cancer patients, as well as decreases nausea and vomiting. The pooled studies also showed that acupoint stimulation can improve Karnofsky performance status, immediate tumor response, quality of life (EORCT-QLQ-C30), and pain control of cancer patients. CONCLUSIONS: Acupoint stimulation is found to be effective in lung cancer treatment, further confirmatory evaluation via large scale randomized trials is warranted. PMID- 24344729 TI - Camelus dromedarius brucellosis and its public health associated risks in the Afar National Regional State in northeastern Ethiopia. AB - BACKGROUND: A cross-sectional study was carried out in four districts of the Afar region in Ethiopia to determine the prevalence of brucellosis in camels, and to identify risky practices that would facilitate the transmission of zoonoses to humans. This study involved testing 461 camels and interviewing 120 livestock owners. The modified Rose Bengal plate test (mRBPT) and complement fixation test (CFT) were used as screening and confirmatory tests, respectively. SPSS 16 was used to analyze the overall prevalence and potential risk factors for seropositivity, using a multivariable logistic regression analysis. RESULTS: In the camel herds tested, 5.4% had antibodies against Brucella species, and the district level seroprevalence ranged from 11.7% to 15.5% in camels. The logistic regression model for camels in a herd size > 20 animals (OR = 2.8; 95% CI: 1.16 6.62) and greater than four years of age (OR = 4.9; 95% CI: 1.45-16.82) showed a higher risk of infection when compared to small herds and those <= 4 years old. The questionnaire survey revealed that most respondents did not know about the transmission of zoonotic diseases, and that their practices could potentially facilitate the transmission of zoonotic pathogens. CONCLUSIONS: The results of this study revealed that camel brucellosis is prevalent in the study areas. Therefore, there is a need for implementing control measures and increasing public awareness in the prevention methods of brucellosis. PMID- 24344730 TI - The role of Kupffer cells in the hepatic response to silver nanoparticles. AB - Engineered nanoparticles are increasingly used in medical applications and day-to day consumer products, leading to concerns about the potential environmental and human health impacts. Silver nanoparticles are particularly prevalent because of their use as anti-bacterial agents in many commonly available products. Nanoparticles (NPs) are believed to accumulate, often preferentially, in the liver. This study therefore investigates the effect of a silver NP (20 nm) on the liver, and in particular, the role of Kupffer cells (KCs; resident liver macrophages) in the overall inflammatory response in the organ. Cytokine expression in the normal liver was measured in terms of IL2, IL4, TNF-alpha, IFN gamma and IL10 released from the organ with significant up-regulation of TNF alpha and IL10 being observed. For livers in which the KC population was specifically targeted and destroyed this cytokine increase was significantly decreased in comparison to the normal tissue. IL10 was secreted at approximately three times the concentration of TNF-alpha in all the test cases. The high levels of IL10 released from the normal tissue in comparison to the KC depleted livers suggest that the cytokine may help to protect against a pro-inflammatory response to these Ag NPs. This may indicate a potentially important role for KCs in the anti-inflammatory response and suggests that tolerance to the Ag NPs is favoured over a fully activated immune response. In addition, albumin production was measured as an indicator of hepatic function. It was noted that the liver function was unaffected by the Ag NPs. PMID- 24344731 TI - LGBT health in the midlands: a rural/urban comparison of basic health indicators. AB - Research into the health and wellbeing of rural lesbian, gay, bisexual, and transgender (LGBT) populations is limited. A community-based participatory research (CBPR) approach was used to develop an online survey for LGBT Nebraskans. The 770 participants replied to an array of questions on social determinants of health and basic health outcomes. Only significant differences in having health insurance were found between urban and rural participants. Social determinants of health were explored. Results of this study suggest that regional culture may be more salient to health for lesbian, gay, bisexual, and transgender persons living in the Midwest than rural or urban residence. PMID- 24344733 TI - Helping a 10-year-old Haitian girl with vaginitis. AB - PURPOSE: The purpose of this case study is to demonstrate how nurses who work with Haitian children and families can use NANDA-I (diagnosis), the Nursing Outcomes Classification, and the Nursing Interventions Classification to assist a 10-year-old child with symptoms of vaginitis. DATA SOURCES: The case study derives from the author's experience and literature sources. DATA SYNTHESIS: This case study demonstrates a nurse's clinical decision making while providing care to a 10-year-old girl with symptoms of vaginitis. CONCLUSIONS: Increased knowledge and awareness about appropriate health behaviors can increase patients' power and enable them to freely act and adopt health behaviors to improve health outcomes. IMPLICATIONS FOR NURSING: Placing patients at the center of the nursing process and partnering with patients to plan and develop interventions enable them to take actions and improve health outcomes. PMID- 24344732 TI - Mesenchymal-transitioned cancer cells instigate the invasion of epithelial cancer cells through secretion of WNT3 and WNT5B. AB - Although the heterogeneities of epithelial and mesenchymal-transitioned cancer cells are often observed within the tumor microenvironment, the biological significance of the interaction between epithelial cancer cells and mesenchymal transitioned cancer cells is not yet understood. In this study, we show that the mesenchymal-transitioned cancer cells instigate the invasive ability and metastatic potential of the neighboring epithelial cancer cells in vitro and in vivo. We identify WNT3 and WNT5B as critical factors secreted from Transforming growth factor-induced mesenchymal cancer cells for instigating the epithelial cancer cell invasion along with the induction of secondary EMT phenotype. These results shed light on the significance of cancer heterogeneity and the interaction between epithelial and mesenchymal-transitioned cancer cells within the tumor microenvironment in promoting metastatic disease through the WNT dependent mechanism. PMID- 24344734 TI - Pre-transplant co-infusion of donor-adipose tissue derived mesenchymal stem cells and hematopoietic stem cells may help in achieving tolerance in living donor renal transplantation. AB - Transplantation tolerance is still a Utopian dream for many transplanters. Mesenchymal stem cells (MSC) have shown immuno-modulatory and tolerogenic effects in experimental models. We present a 29-year-old male with end stage renal disease (ESRD) who was transplanted with HLA 4/6 matched kidney from 51-year-old father in June 2010 preceded by co-infusion of donor-adipose tissue derived mesenchymal stem cells (AD-MSC) and bone marrow derived hematopoietic stem cells (BM-HSC) under non-myeloablative conditioning for deleting rejecting T and B cells. He has maintained fairly stable graft function with serum creatinine (SCr) between 1.5 and 1.8 mg/dL at 3 years post-transplant with absence of donor specific antibodies (DSA), normal protocol graft biopsy, and peripheral T regulatory cell levels (pTregs) (CD127(low/-)CD25(high)CD4+) of 4.57% on zero immunosuppression since 6 months. PMID- 24344736 TI - Two new compounds from the fungus Penicilliumcrustosum YN-HT-15. AB - Our current natural product program researches the second metabolites of a fungus Penicilliumcrustosum YN-HT-15 isolated from the red soil (Yunnan Province, China), to discover potential antitumor chemical entities. Two new compounds were isolated from the ethyl acetate extract of the fermentation broth of the fungus, and their structures were characterized as 1-(2',4'-dihydroxy-5'-methyl-3' methylsulfanylmethyl-phenyl)-ethanone and R-3-(3'-acetyl-2',6'-dihydroxy-5' methylphenyl)-2-methyl-propionic acid methyl ester on the basis of spectroscopic data. PMID- 24344735 TI - Depressive symptoms linked to 1-h plasma glucose concentrations during the oral glucose tolerance test in men and women with the metabolic syndrome. AB - AIMS: The addition of the 1-h plasma glucose concentration measure from an oral glucose tolerance test to prediction models of future Type 2 diabetes has shown to significantly strengthen their predictive power. The present study examined the relationship between severity of depressive symptoms and hyperglycaemia, focusing on the 1-h glucose concentration vs. fasting and 2-h glucose measures from the oral glucose tolerance test. METHODS: Participants included 140 adults with the metabolic syndrome and without diabetes who completed a baseline psychobiological assessment and a 2-h oral glucose tolerance test, with measurements taken every 30 min. Depressive symptoms were assessed using the Beck Depression Inventory. RESULTS: Multivariate linear regression revealed that higher levels of depressive symptoms were associated with higher levels of 1-h plasma glucose concentrations after adjusting for age, gender, ethnicity, BMI, antidepressant use and high-sensitivity C-reactive protein. Results were maintained after controlling for fasting glucose as well as for indices of insulin resistance and secretion. Neither fasting nor 2-h plasma glucose concentrations were significantly associated with depressive symptoms. CONCLUSIONS: Elevated depressive symptoms in persons with the metabolic syndrome were associated with greater glycaemic excursion 1-h following a glucose load that was not accounted for by differences in insulin secretory function or insulin sensitivity. Consistent with previous findings, this study highlights the value of the 1-h plasma glucose measurement from the oral glucose tolerance test in the relation between depressive symptoms and glucose metabolism as an indicator of metabolic abnormalities not visible when focusing on fasting and 2-h post-oral glucose tolerance test measurements alone. PMID- 24344737 TI - Effects of sub-acute exposure to TiO2, ZnO and Al2O3 nanoparticles on oxidative stress and histological changes in mouse liver and brain. AB - Nanomaterials are at the leading edge of the rapidly developing field of nanotechnology. However the information regarding toxicity of these nanoparticles on humans and environment is still deficient. The present study investigated the toxic effects of three metal oxide nanoparticles, TiO2, ZnO and Al2O3 on mouse erythrocytes, brain and liver. Male mice were administered a single oral dose of 500 mg/kg of each nanoparticles for 21 consecutive days. The results suggest that exposure to these nano metallic particles produced a significant oxidative stress in erythrocyte, liver and brain as evident from enhanced levels of Reactive Oxygen Species (ROS) and altered antioxidant enzymes activities. A significant increase in dopamine and norepinephrine levels in brain cerebral cortex and increased brain oxidative stress suggest neurotoxic potential of these nanoparticles. Transmission electron microscopic (TEM) analysis indicated the presence of these nanoparticles inside the cytoplasm and nucleus. These changes were also supported by the inhibition of CuZnSOD and MnSOD, considered as important biomarkers of oxidative stress. The toxic effects produced by these nanoparticles were more pronounced in the case of zinc oxide, followed by aluminum oxide and titanium dioxide, respectively. The present results further suggest the involvement of oxidative stress as one of the main mechanisms involved in nanoparticles induced toxic manifestations. PMID- 24344739 TI - Surfactant-assisted porphyrin based hierarchical nano/micro assemblies and their efficient photocatalytic behavior. AB - In this report, we have demonstrated the synthesis of surfactant-assisted different morphologies of meso-tetra(4-carboxyphenyl)porphyrin assemblies (spherical to flower shaped). These nano/micro assemblies are well characterized by scanning electron microscopy and X-ray diffraction. The formation of assemblies is driven by noncovalent interactions such as hydrophobic-hydrophobic and aromatic pi-pi stacking between the molecules. The steady state and time resolved spectroscopic investigation reveal that different assemblies are formed by virtue of special supramolecular organizations. The photocatalytic activities of different assemblies have been demonstrated with an organic pollutant Rhodamine B dye under the visible light irradiation. Such porphyrin based assemblies could pave the way for designing new optical based materials for the applications in photocatalytic, photovoltaic, and light harvesting system. PMID- 24344738 TI - The prevalence of sexual dysfunction among male patients on methadone and buprenorphine treatments: a meta-analysis study. AB - INTRODUCTION: For many years, methadone has been recognized as an effective maintenance treatment for opioid dependence. However, of the many adverse events reported, sexual dysfunction is one of the most common side effects. AIM: We conducted a meta-analysis to evaluate the prevalence of sexual dysfunction among male patients on methadone and buprenorphine treatments. METHODS: Relevant studies published from inception until December 2012 were identified by searching PubMed, OVID, and Embase. Studies were selected using prior defined criteria. Heterogeneity, publication bias, and odds ratio were assessed thoroughly. MAIN OUTCOME MEASURES: To examine the prevalence and odds ratio of sexual dysfunctions among the methadone and buprenorphine groups. RESULTS: A total of 1,570 participants from 16 eligible studies were identified in this meta-analysis. The studies provided prevalence estimates for sexual dysfunction among methadone users with a meta-analytical pooled prevalence of 52% (95% confidence interval [CI], 0.39-0.65). Only four studies compared sexual dysfunction between the two groups, with a significantly higher combined odds ratio in the methadone group (OR = 4.01, 95% CI, 1.52-10.55, P = 0.0049). CONCLUSIONS: Evidence showed that the prevalence of sexual dysfunction was higher among the users of methadone compared with buprenorphine. Patients with sexual difficulty while on methadone treatment were advised to switch to buprenorphine. PMID- 24344740 TI - Aphadilactones A-D, four diterpenoid dimers with DGAT inhibitory and antimalarial activities from a Meliaceae plant. AB - Aphadilactones A-D (1-4), four diastereoisomers possessing an unprecedented carbon skeleton, were isolated from the Meliaceae plant Aphanamixis grandifolia. Their challenging structures and absolute configurations were determined by a combination of spectroscopic data, chemical degradation, fragment synthesis, experimental CD spectra, and ECD calculations. Aphadilactone C (3) with the 5S,11S,5'S,11'S configuration showed potent and selective inhibition against the diacylglycerol O-acyltransferase-1 (DGAT-1) enzyme (IC50 = 0.46 +/- 0.09 MUM, selectivity index > 217) and is the strongest natural DGAT-1 inhibitor discovered to date. In addition, compounds 1-4 showed significant antimalarial activities with IC50 values of 190 +/- 60, 1350 +/- 150, 170 +/- 10, and 120 +/- 50 nM, respectively. PMID- 24344741 TI - Coupled exposure to ingredients of cosmetic products: II. Preservatives. AB - BACKGROUND: The use of cosmetics exposes consumers to mixtures of ingredients, many of which are potential allergens. Many cosmetics contain one or several preservatives, some being important contact allergens. OBJECTIVE: To examine the pattern of co-exposure to preservatives in different categories of cosmetics. METHODS: A survey of products marketed in Germany, conducted in 2006-2009 by the Chemical and Veterinary Investigation Office in Karlsruhe, identified 4680 products categorizable according to Annex I to the Cosmetics Directive with information on the presence of preservatives. The occurrence and co-occurrence of preservatives were analysed and presented in tabular and graphical format. RESULTS: Thirty per cent of all products were not declared to contain any preservatives; for 8%, no INCI labelling was present. For the remainder, the number of preservatives used tended to be higher in leave-on than in rinse-off products. Most often, combinations of (up to all five) parabens were used (39% of all products). Combinations with phenoxyethanol were also frequent. Formaldehyde releasers were found in 8% of products overall. CONCLUSIONS: The pattern of co exposure to preservatives in important categories of cosmetic products illustrates the 'cocktail' of allergens that may facilitate sensitization, although, conversely, the combination of preservatives allows individual use levels to be kept lower, thereby possibly reducing sensitization risk. PMID- 24344743 TI - Histopathological effects of anthrax lethal factor on rat liver. AB - Bacillus anthracis, the causative agent of anthrax, has become an increasingly important scientific topic due to its potential role in bioterrorism. The lethal toxin (LT) of B. anthracis consists of lethal factor (LF) and a protective antigen (PA). This study investigated whether only lethal factor was efficient as a hepatotoxin in the absence of the PA. To achieve this aim, LF (100 ug/kg body weight, dissolved in sterile distilled water) or distilled water vehicle were intraperitoneally injected once into adult rats. At 24 h post-injection, the hosts were euthanized and their livers removed and tissue samples examined under light and electron microscopes. As a result of LF application, hepatic injury - including cytoplasmic and nuclear damage in hepatocytes, sinusoidal dilatation, and hepatocellular lysis - became apparent. Further, light microscopic analyses of liver sections from the LF-injected rats revealed ballooning degeneration and cytoplasmic loss within hepatocytes, as well as peri-sinusoidal inflammation. Additionally, an increase in the numbers of Kupffer cells was evident. Common vascular injuries were also found in the liver samples; these injuries caused hypoxia and pathological changes. In addition, some cytoplasmic and nuclear changes were detected within the liver ultrastructure. The results of these studies allow one to suggest that LF could be an effective toxicant alone and that PA might act in situ to modify the effect of this agent (or the reverse situation wherein LF modifies effects of PA) such that lethality results. PMID- 24344744 TI - The role of memory in awareness of memory deficits in Alzheimer's disease, schizophrenia, and brain injury. AB - Patients with neuropsychiatric disorders such as Alzheimer's disease (AD), schizophrenia (Sz), and brain injury (BI) often show memory deficits and lack of awareness of those deficits. This study aimed to investigate the role of memory in awareness of memory deficits and illness in multiple patient groups. Comparison of awareness profiles between groups can reveal common or distinct patterns of awareness and predictors, which may inform theories about the structure of awareness. Using the same standardized measures, AD (N = 27) Sz (N = 31), and BI (N = 26) patients were compared on memory functioning, awareness of illness, and awareness of memory deficits-measured by discrepancy of pretest estimate and actual test scores. All groups were poor at pretest estimation of memory functioning, particularly the AD and BI groups. In AD, patients with the lowest memory functioning rated their performance highest. The BI group and to a lesser extent the AD group showed improved estimations of performance following the memory test. Those with the poorest memory showed the greatest improvement in ratings accuracy post test. The relationship between memory and awareness of memory was stronger than the association between memory and awareness of illness. There was a double dissociation between awareness of memory and awareness of illness across patient groups. The study shows that awareness of memory is linked to memory functioning, while memory is only modestly related to awareness of illness. Dissociations in the role of memory in different domains of awareness and "online" awareness of performance provide information to refine cognitive models of awareness. However, the results should be interpreted with caution given the heterogeneous nature of the sample. PMID- 24344745 TI - Accuracy of skinfold and bioelectrical impedance assessments of body fat percentage in ambulatory individuals with cerebral palsy. AB - AIM: This study assessed the accuracy of measurements of body fat percentage in ambulatory individuals with cerebral palsy (CP) from bioelectrical impedance analysis (BIA) and skinfold equations. METHOD: One hundred and twenty-eight individuals (65 males, 63 females; mean age 12y, SD 3, range 6-18y) with CP (Gross Motor Function Classification System [GMFCS] levels I (n=6), II (n=46), and III (n=19) participated. Body fat percentage was estimated from (1) BIA using standing height and estimated heights (knee height and tibial length) and (2) triceps and subscapular skinfolds using standard and CP-specific equations. All estimates of body fat percentage were compared with body fat percentage from dual energy X-ray absorptiometry (DXA) scans. Differences between DXA, BIA, and skinfold body fat percentage were analyzed by comparing mean differences. Agreement was assessed by Bland-Altman plots and concordance correlation coefficients (CCC). RESULTS: BMI was moderately correlated with DXA (Pearson's r=0.53). BIA body fat percentage was significantly different from DXA when using estimated heights (95% confidence intervals [CIs] do not contain 0) but not standing height (95% CI -1.9 to 0.4). CCCs for all BIA comparisons indicated good to excellent agreement (0.75-0.82) with DXA. Body fat percentage from skinfold measurements and CP-specific equations was not significantly different from DXA (mean 0.8%; SD 5.3%; 95% CI -0.2 to 1.7) and demonstrated strong agreement with DXA (CCC 0.86). INTERPRETATION: Accurate measures of body fat percentage can be obtained using BIA and two skinfold measurements (CP-specific equations) in ambulatory individuals with CP. These findings should encourage assessments of body fat in clinical and research practices. PMID- 24344742 TI - Potential involvement of the extracranial venous system in central nervous system disorders and aging. AB - BACKGROUND: The role of the extracranial venous system in the pathology of central nervous system (CNS) disorders and aging is largely unknown. It is acknowledged that the development of the venous system is subject to many variations and that these variations do not necessarily represent pathological findings. The idea has been changing with regards to the extracranial venous system. DISCUSSION: A range of extracranial venous abnormalities have recently been reported, which could be classified as structural/morphological, hemodynamic/functional and those determined only by the composite criteria and use of multimodal imaging. The presence of these abnormalities usually disrupts normal blood flow and is associated with the development of prominent collateral circulation. The etiology of these abnormalities may be related to embryologic developmental arrest, aging or other comorbidities. Several CNS disorders have been linked to the presence and severity of jugular venous reflux. Another composite criteria-based vascular condition named chronic cerebrospinal venous insufficiency (CCSVI) was recently introduced. CCSVI is characterized by abnormalities of the main extracranial cerebrospinal venous outflow routes that may interfere with normal venous outflow. SUMMARY: Additional research is needed to better define the role of the extracranial venous system in relation to CNS disorders and aging. The use of endovascular treatment for the correction of these extracranial venous abnormalities should be discouraged, until potential benefit is demonstrated in properly-designed, blinded, randomized and controlled clinical trials. PMID- 24344746 TI - Neoadjuvant chemotherapy and primary-first approach for rectal cancer with synchronous liver metastases. AB - AIM: Up to a quarter of patients with rectal cancer have synchronous liver metastases at the time of diagnosis. This is a predictor of poor outcome. There are no standardized guidelines for treatment. We reviewed the outcomes of our patients with synchronous rectal liver metastases treated with a curative intent by neoadjuvant chemotherapy with or without chemoradiotherapy followed by resection of the primary tumour and then liver metastases. METHOD: Between 2004 and 2012, patients who presented with rectal cancer and synchronous liver metastasis were treated with curative intent with peri-operative systemic chemotherapy as the first line of treatment. Responders to chemotherapy underwent resection of the primary tumour with or without preoperative chemoradiotherapy followed by hepatic resection. RESULTS: Fifty-three rectal cancer patients with 152 synchronous liver lesions were identified. After a median follow-up of 29.6 months, the median survival was 41.4 months. Overall survival was 59.0% at 3 years and 39.0% at 5 years. CONCLUSION: Rectal resection before hepatic resection combined with neoadjuvant chemotherapy is associated with promising clinical outcome. It allows downstaging of liver lesions and removal of the primary tumour before the progression of further micrometastases. Furthermore, patients who do not respond to chemotherapy can be identified and may avoid major surgical intervention. PMID- 24344747 TI - Iodine-induced thyrotoxic hypokalemic paralysis after ingestion of Salicornia herbace. AB - A 56-year-old Korean man visited to emergency room due to paroxysmal flaccid paralysis in his lower extremities. There was no family or personal history of periodic paralysis. His initial potassium levels were 1.8 mmol/L. The patient had been taking Salicornia herbacea for the treatment of diabetes and hypertension. Results of a thyroid function test were as follows: T3 = 130.40 ng/dL, TSH = 0.06 mIU/L, and free T4 = 1.73 ng/dL. A thyroid scan exhibited a decreased uptake (0.6%). His symptoms clearly improved and serum potassium levels increased to 4.4 mmol/L by intravenous infusion of only 40 mmol of potassium chloride. Eight months after the discontinuation of only Salicornia herbacea, the patient's thyroid function tests were normalized. Large amounts of iodine can induce hypokalemic thyrotoxic paralysis and it may be necessary to inquire about the ingestion of iatrogenic iodine compounds, such as Salicornia herbacea. PMID- 24344748 TI - On the dynamics of implicit emotion regulation: counter-regulation after remembering events of high but not of low emotional intensity. AB - Valence biases in attention allocation were assessed after remembering positive or negative personal events that were either still emotionally hot or to which the person had already adapted psychologically. Differences regarding the current state of psychological adjustment were manipulated experimentally by instructing participants to recall distant vs. recent events (Experiment 1) or affectively hot events vs. events to which the person had accommodated already (Experiment 2). Valence biases in affective processing were measured with a valence search task. Processes of emotional counter-regulation (i.e., attention allocation to stimuli of opposite valence to the emotional event) were elicited by remembering affectively hot events, whereas congruency effects (i.e., attention allocation to stimuli of the same valence as the emotional event) were obtained for events for which a final appraisal had already been established. The results of our study help to resolve conflicting findings from the literature regarding congruent vs. incongruent effects of remembering emotional events on affective processing. We discuss implications of our findings for the conception of emotions and for the dynamics of emotion regulation processes. PMID- 24344749 TI - 1'-(Diphenylphosphino)-1-cyanoferrocene: a simple ligand with complicated coordination behavior toward copper(I). AB - 1'-(Diphenylphosphino)-1-cyanoferrocene (3), a new donor-asymmetric ferrocene ligand obtained in two steps from 1'-(diphenylphosphino)ferrocene-1 carboxaldehyde, reacts with CuCl at a Cu/3 molar ratio of 1:1 to give the heterocubane complex [Cu(MU3-Cl)(3-kappaP)]4 (4). When the Cu/3 ratio is changed to 1:2 or 1:3, the reaction takes a different course, producing the P,N-bridged dimer [CuCl(3-kappaP)(MU(P,N)-3)]2 (5) after crystallization. Notably, CuBr and CuI behave differently, affording the corresponding 2D coordination polymers [CuX(MU(P,N)-3)]n [X = I (7), and Br (8)], regardless of the Cu/3 ratio. Reaction of 3 with sources of naked Cu(+), such as [Cu(MeCN)4](+) salts or their synthetic equivalents, provides the 1D coordination polymer [Cu(MeCN-kappaN)(MU(P,N) 3)][BF4] (9) or salts of a quadruply bridged dicopper(I) cation, [Cu2(MU(P,N) 3)4]X2 ([10]X2), depending on the Cu/3 molar ratio (1:1 vs 1:2 and 1:3). Except for 4, in which 3 binds as a simple P-monodentate ligand, the complexes reported here represent the first structurally characterized compounds in which a phosphinonitrile ligand coordinates through both of its soft donor moieties, thereby extending the coordination chemistry of these ligands. PMID- 24344750 TI - Pre- and post-training session evaluation for interobserver agreement and diagnostic accuracy of probe-based confocal laser endomicroscopy for biliary strictures. AB - BACKGROUND AND AIM: Current diagnostic modalities for indeterminate biliary strictures offer low accuracy. Probe-based confocal laser endomicroscopy (pCLE) permits microscopic assessment of mucosal structures by obtaining real-time high resolution images of the mucosal layers of the gastrointestinal tract. Previously, an interobserver study demonstrated poor to fair agreement even among experienced confocal endomicroscopy operators. Our objective was to assess interobserver agreement and diagnostic accuracy upon completion of a pCLE training session. METHODS: Forty de-identified pCLE video clips of indeterminate biliary strictures were sent to five endoscopists at four tertiary care centers for scoring. Observers subsequently attended a teaching session by an expert pCLE user that included 20 training clips and rescored the same pCLE video clips, which were randomized and renumbered. RESULTS: Pre-training interobserver agreement for all observers was 'fair' (Kappa: 0.31, P-value: <0.0001) and diagnostic accuracy was 72% (55-80%). Post-training interobserver agreement for all observers was 'substantial' (Kappa: 0.74, P-value: <0.0001) and diagnostic accuracy was 89% (80-95%). Using a paired t-test, we observed an increase of 17% (95% CI 7.6-26.4) in post-training diagnostic accuracy (t = 5.01, df = 4, P-value 0.007). CONCLUSIONS: Interobserver agreement and diagnostic accuracy improved after observers underwent training by an expert pCLE user with a specific sequence set. Users should participate in such training programs to maximize diagnostic accuracy of pCLE evaluation. PMID- 24344751 TI - Rural LGBT health: Introduction to a dedicated issue of the Journal of Homosexuality. PMID- 24344753 TI - Karyotypic analysis and FISH mapping of microsatellite motifs reveal highly differentiated XX/XY sex chromosomes in the pink-tailed worm-lizard (Aprasia parapulchella, Pygopodidae, Squamata). AB - BACKGROUND: The infraorder Gekkota is intriguing because it contains multiple chromosomal and environmental sex determination systems that vary even among closely related taxa. Here, we compare male and females karyotypes of the pink tailed worm-lizard (Aprasia parapulchella), a small legless lizard belonging to the endemic Australian family Pygopodidae. RESULTS: We applied comparative genomic hybridization to reveal an XX/XY sex chromosome system in which the Y chromosome is highly differentiated from the X in both gross morphology and DNA sequence. In addition, FISH mapping has revealed that two microsatellite repeat motifs, (AGAT)n and (AC)n, have been amplified multiple times on the Y chromosome. CONCLUSION: XY karyotypes are found in other pygopodids (Delma inornata and Lialis burtonis), suggesting that the common ancestor of Pygopodidae also had XY sex chromosomes. However, the morphology and size of the Y chromosomes are different among the three species, suggesting that the processes underlying the evolution of sex chromosomes in the Pygopodidae involved chromosome rearrangements and accumulation and amplification of repeats. PMID- 24344752 TI - Systematic review of clinical decision support interventions with potential for inpatient cost reduction. AB - BACKGROUND: Healthcare costs are increasing rapidly and at an unsustainable rate in many countries, and inpatient hospitalizations are a significant driver of these costs. Clinical decision support (CDS) represents a promising approach to not only improve care but to reduce costs in the inpatient setting. The purpose of this study was to systematically review trials of CDS interventions with the potential to reduce inpatient costs, so as to identify promising interventions for more widespread implementation and to inform future research in this area. METHODS: To identify relevant studies, MEDLINE was searched up to July 2013. CDS intervention studies with the potential to reduce inpatient healthcare costs were identified through titles and abstracts, and full text articles were reviewed to make a final determination on inclusion. Relevant characteristics of the studies were extracted and summarized. RESULTS: Following a screening of 7,663 articles, 78 manuscripts were included. 78.2% of studies were controlled before-after studies, and 15.4% were randomized controlled trials. 53.8% of the studies were focused on pharmacotherapy. The majority of manuscripts were published during or after 2008. 70.5% of the studies resulted in statistically and clinically significant improvements in an explicit financial measure or a proxy financial measure. Only 12.8% of the studies directly measured the financial impact of an intervention, whereas the financial impact was inferred in the remainder of studies. Data on cost effectiveness was available for only one study. CONCLUSIONS: Significantly more research is required on the impact of clinical decision support on inpatient costs. In particular, there is a remarkable gap in the availability of cost effectiveness studies required by policy makers and decision makers in healthcare systems. PMID- 24344754 TI - IDH2 and TP53 mutations are correlated with gliomagenesis in a patient with Maffucci syndrome. AB - We report on a 24-year-old woman who was diagnosed as having Maffucci syndrome with anaplastic astrocytoma. We analyzed the IDH1 and IDH2 mutations of enchondroma, hemangioma and anaplastic astrocytoma tissues and the same somatic mosaic mutation in IDH2 gene was identified in all these tissues. In addition, we identified additional mutation of the TP53 gene in anaplastic astrocytoma tissue but not in other benign tumors. This is the first report of the detection of an identical IDH2 mutation in multiple tissues and TP53 mutation in anaplastic astrocytoma in a patient with Maffucci syndrome. This case is unique and supports the IDH2-dependent genetic pathway and second-hit model for gliomagenesis. PMID- 24344755 TI - Simple steps to equity in child survival. AB - Although the number of child deaths has declined globally over the past 20 years, many countries still lag behind their millennium development goal targets, and inequity in child health remains a pernicious problem both between and within countries. Breastfeeding is a key intervention to reduce child mortality, and in an article published in BMC Medicine, Roberts and colleagues have shown that breastfeeding interventions can have a significant role in reducing inequity in child health. With the proper attention paid to overcoming the barriers to scaling up breastfeeding interventions, deployment of effective interventions in health facilities and the community, and improvements in support for breastfeeding interventions across society, many countries that are struggling to meet their millennium development goals could make significant gains in child survival and inequity. PMID- 24344756 TI - Spontaneous intracerebral hemorrhage in CADASIL. AB - BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary small vascular disease and its mainly clinical manifestations are ischemic events. Spontaneous intracerebral hemorrhage (ICH) involvement in patients with CADASIL is extremely uncommon. CASE REPORT: A 46-year-old normotensive Chinese man developed a large hematoma in the left basal ganglia after he was diagnosed with CADASIL 2 months ago, the patient did not take any antithrombotics. Susceptibility weighted imaging at pre-ICH showed multiple cerebral microbleeds (CMBs) in the bilateral basal ganglia. He experienced migraine at about 10 months post-ICH. To our knowledge, this is the first report of ICH in CADASIL patients with Arg90Cys mutation in exon 3. DISCUSSION AND CONCLUSIONS: ICH should be considered when evaluating new attacks in CADASIL patients. Thus, MRI screening for CMBs might be helpful in predicting the risk of ICH and guiding antithrombotic therapy. In addition, strict control of hypertension and cautious use of antithrombotics may be important in this context. PMID- 24344758 TI - Semitransparent polymer solar cells with 5% power conversion efficiency using photonic crystal reflector. AB - Efficient semitransparent polymer solar cells (ST-PSCs) have been fabricated with one-dimensional photonic crystals (1DPCs) as a high reflector. The 1DPCs are composed of several pairs of WO3 (65.8 nm)/LiF (95.5 nm). By optimizing the pairs of WO3/LiF, 1DPCs can reflect the light back into the ST-PSCs due to the photonic band gap, when the high reflectance range of 1DPCs is matched with absorption spectrum of the active layer. ST-PSCs with 8 pairs of 1DPC exhibit an attractive performance. The short-circuit current density (Jsc) and power conversion efficiency (PCE), respectively, reach to 9.76 mA/cm(2) and 5.16% compared to 8.12 mA/cm(2) and 4.24% of the reference ST-PSCs without 1DPCs. A maximum enhancement of 20.2% in Jsc is obtained and the PCE increases by ~21.7%. This approach provides a simple, fascinating and promising method to realize the highly efficient ST-PSCs toward applications. PMID- 24344757 TI - Association of fasting glucose with subclinical cerebrovascular disease in older adults without Type 2 diabetes. AB - AIMS: To examine how fasting glucose and glucose tolerance are related to magnetic resonance imaging-assessed indicators of subclinical cerebrovascular disease and brain atrophy and their variation according to age, sex and education. METHODS: Participants in the present study were 172 healthy, community dwelling older adults. An oral glucose tolerance test was administered and magnetic resonance imaging performed. Fasting, 2-h, and 2-h area-under-the-curve glucose levels, their associations with subclinical cerebrovascular disease and brain atrophy, and their respective interactions with age, sex and education were examined. RESULTS: A positive association between fasting glucose and subclinical cerebrovascular disease (but not brain atrophy) emerged; this association was more pronounced for participants with < 12 years of education; however, glucose tolerance was not related to subclinical cerebrovascular disease or brain atrophy. CONCLUSIONS: Findings revealed a potential link between fasting glucose levels and the presence of subclinical cerebrovascular disease indicators - white matter hyperintensities and silent brain infarction - in older adults without diabetes and with an education level below high school. Additional research is needed to confirm these associations and to determine the need for interventions aimed at closely monitoring and preventing elevated glucose levels in this population to reduce the prevalence of subclinical cerebrovascular disease. PMID- 24344759 TI - Current attitudes regarding the use of perioperative analgesics in dogs and cats by Brazilian veterinarians. AB - OBJECTIVE: To correlate the demographic data of Brazilian veterinarians with their use of, attitudes towards, knowledge of and preference for continuing education regarding use of analgesics in small animal practice. STUDY DESIGN: Prospective survey. METHODS: The questionnaire was composed of sections pertaining to demographics, personal data, use of analgesics in general and specific procedures, analgesia used, and attitudes towards the assessment and relief of pain. The descriptive statistics with frequency analysis was performed using sas for Windows 9.1.3. Chi-square for simple comparisons test was used. RESULTS: Questionnaires were obtained from 1298 small animal veterinarians. Women and younger graduates attributed higher pain scores than men and older graduates but the frequency and duration of analgesic treatment did not differ between genders. The most commonly used opioids were tramadol (79%) and morphine (51%). NSAIDs of choice were meloxicam (81%) and ketoprofen (70%). Cats received lower pain scores for laparotomy, orchiectomy and dental procedures than dogs. Practical experience (64%) and national (47%) and regional meetings (43%) were the main sources of information for identifying and treating pain in small animals. CONCLUSIONS: Although the number of Brazilian veterinarians believed that their knowledge in the area was lower than in other countries, the focus in pain management was similar or higher than in other countries, showing a good attitude in pain relief in animals. PMID- 24344761 TI - Prevalence, incidence, and risk factors of intestinal parasites in Danish primary care patients with irritable bowel syndrome. AB - The gut microbiota may be involved in the aetiopathogenesis of irritable bowel syndrome (IBS). We studied the role of intestinal parasites by describing the epidemiology and risk factors for infection in primary care patients aged 18-50 y with IBS. One hundred and thirty-eight patients at baseline and 78/116 patients returning 1 y later, submitted faecal samples that were examined by microscopy, culture for Blastocystis, and real-time PCR for Dientamoeba fragilis, Entamoeba (dispar and histolytica), Cryptosporidium spp., and Giardia intestinalis. Overall, 42-45% of patients harboured intestinal parasites (baseline and follow up, respectively): D. fragilis carriage was 35-41%; Blastocystis 14-20%. Incidence rates for D. fragilis and Blastocystis were 10 and 4 per 100 person-y, respectively. Blastocystis carriage increased the odds for carrying D. fragilis. Clinical comparisons showed D. fragilis to be associated with a low frequency of defecation. Further, D. fragilis was associated with having children aged 5-18 y and Blastocystis with increasing age. PMID- 24344762 TI - Changes in colonization of residents and staff of a long-term care facility and an adjacent acute-care hospital geriatric unit by multidrug-resistant bacteria over a four-year period. AB - BACKGROUND: In 2012 we undertook a screening study for Enterobacteriaceae with extended-spectrum beta-lactamases (ESBLs), derepressed or acquired high-level AmpC cephalosporinases, and metallo-beta-lactamases (MBLs), and also methicillin resistant Staphylococcus aureus (MRSA), in a long-term care facility (LTCF1) and the associated acute care hospital geriatric ward in Bolzano, northern Italy. The study followed up an initial survey carried out in LTCF1 in 2008. For comparison, screening in 2012 was extended to a second LTCF. METHODS: Urine samples and rectal, inguinal, oropharyngeal, and nasal swabs were plated on selective agars. Isolates were typed by pulsed-field gel electrophoresis. Resistance genes and Escherichia coli belonging to ST131 were sought by PCR. Demographic data were collected. RESULTS: Fewer residents of LTCF1 were colonized with multidrug resistant (MDR) bacteria in 2012: all MDR organisms, 53.8% vs 74.8% in 2008; ESBL producers, 49.0% vs 64.0% in 2008; MRSA, 13.2% vs 38.7% in 2008; only 2 MBL producers were isolated in 2012 vs 8 in 2008. Colonization of staff in LTCF1 by MDR bacteria had also decreased (overall 10.5% in 2012 vs 27.5% in 2008). Changed case mixes and risk factors, together with strengthened hygiene measures probably underlie the changes. Colonization proportions in 2012 in LTCF2 were similar to those in LTCF1. By contrast there was no significant change in the proportion of patients colonized by MDR bacteria in the geriatric ward (22.2% in 2008 vs 22.7% in 2012). CONCLUSIONS: A significant decrease in the proportions of staff and residents of an LTCF colonized by MDR bacteria was observed over a 4-y interval. PMID- 24344764 TI - Cu-catalyzed conversion of propargyl acetates to E-alpha,beta-unsaturated amides via ketenimine formation with sulfonyl azides. AB - The reaction between readily accessible propargyl acetates and sulfonyl azides in the presence of CuI catalyst yields trans-alpha,beta-unsaturated N-tosylamides via N-sulfonyl ketenimine formation followed by a probable 1,3-OAc migration ([3,3]-sigmatropic rearrangement). The reaction is very general, allowing all kinds of substitution, including alkyl, aryl (electron-donating, -withdrawing, and -neutral), heteroaryl, and vinyl groups, on the C-terminal of acrylamide. Also, the method affords the products at ambient temperature with excellent diastereoselectivity in moderate to good yields. PMID- 24344763 TI - Factors associated with sex hormones and erectile dysfunction in male Taiwanese participants with obesity. AB - INTRODUCTION: Obesity has been receiving an increasing amount of attention recently, but investigations regarding the potential impact of obesity, sexual behaviors, and sex hormones on erectile dysfunction (ED) in men have not completely clarified the association. AIM: To identify the relationship between ED, sexual behavior, sexual satisfaction, sex hormones, and obesity in older adult males in Taiwan. METHODS: Data were obtained from a baseline survey of 476 older adult males (?40 years old). Their demographic data, body mass index (BMI), sex hormones, sexual desire, sexual satisfaction, and ED status were assessed. MAIN OUTCOME MEASURES: The International Index of Erectile Function-5 (IIEF-5), Sexual Desire Inventory (SDI), and Sexual Satisfaction Scale (SSS) were used to assess ED, sexual desire, and sexual satisfaction. RESULTS: In all, 476 men were available for analysis. The mean age of the sample was 51.34 +/- 7.84 years (range 40 to 70 years). The IIEF total score had a mean of 19.44 +/- 4.98; 264 (55.5%) subjects had ED, 250 (52.9%) were currently obese (BMI ?27), and 297 (62.4%) had metabolic syndrome. The results showed an increased risk of ED among obese men and subjects with lower levels of sex hormones and lower sexual desire. Testosterone levels were lower in subjects with obesity (P < 0.001). Among the predictors of ED, obesity (odds ratio [OR] = 1.62, 95% CI = 1.07-2.44, P = 0.021), abnormal high sensitivity C-reactive protein (hs-CRP) (OR = 10.59, 95% CI = 4.70-23.87, P < 0.001), and lower serum full testosterone (OR = 3.27, 95% CI = 2.16-4.93, P < 0.001) were significantly independent factors. CONCLUSIONS: This study supports the idea of a close relationship between low levels of sex hormones, sexual desire, sexual satisfaction, obesity, and ED, and also shows that low free testosterone and hs-CRP may predict ED, even in obese populations. PMID- 24344765 TI - First isolation and characterization of Edwardsiella tarda from diseased striped catfish, Pangasianodon hypophthalmus (Sauvage). PMID- 24344766 TI - Attentional bias towards emotional facial expressions in survivors of dating violence. AB - This study identified components of attentional bias (e.g. attentional vigilance, attentional avoidance and difficulty with disengagement) that are critical characteristics of survivors of dating violence (DV). Eye movements were recorded to obtain accurate and continuous information regarding attention. DV survivors with high post-traumatic stress symptoms (DV-High PTSS group; n = 20) and low post-traumatic stress symptoms (DV-Low PTSS group; n = 22) and participants who had never experienced DV (NDV group; n = 21) were shown screens displaying emotional (angry, fearful and happy) faces paired with neutral faces and negative (angry and fearful) faces paired with happy faces for 10 s. The results indicate that the DV-High PTSS group spent longer dwelling on angry faces over time compared with the DV-Low PTSS and NDV groups. This result implies that the DV High PTSS group focused on specific trauma-related stimuli but does not provide evidence of an attentional bias towards threatening stimuli in general. PMID- 24344767 TI - Development and reliability of a system to classify the eating and drinking ability of people with cerebral palsy. AB - AIM: The aim of this study was to develop a valid classification system to describe eating and drinking ability in people with cerebral palsy (CP), and to test its reliability. METHOD: The Eating and Drinking Ability Classification System (EDACS) was developed in four stages in consultation with individuals with CP, parents, and health professionals: Stage 1, drafting informed by literature and clinical experience; Stage 2, modification by nominal groups; Stage 3, refinement in an international Delphi survey; and Stage 4, testing of agreement and reliability between classifications made by speech and language therapists (SaLTs), and between SaLTs and parents. RESULTS: Seven nominal groups involved 56 participants; 95 people participated in two rounds of the Delphi survey. Using the version of EDACS produced from this process, SaLTs in pairs classified 100 children. The rate of absolute agreement was 78% (kappa=0.72; intraclass correlation coefficient [ICC]=0.93; 95% confidence interval [CI] 0.90-0.95). Any disagreement was only by one level, with one exception. SaLTs and parents classified 48 children. The rate of absolute agreement was 58% (kappa=0.45, ICC=0.86; 95% CI 0.76-0.92). Parents either agreed with SaLTs or rated their children as more able by one level. INTERPRETATION: The EDACS provides a valid and reliable system for classifying eating and drinking performance of people with CP, for use in both clinical and research contexts. PMID- 24344768 TI - Emotion-recognition abilities and behavior problem dimensions in preschoolers: evidence for a specific role for childhood hyperactivity. AB - Facial emotion-recognition difficulties have been reported in school-aged children with behavior problems; little is known, however, about either this association in preschool children or with regard to vocal emotion recognition. The current study explored the association between facial and vocal emotion recognition and behavior problems in a sample of 3 to 6-year-old children. A sample of 57 children enriched for risk of behavior problems (41 were recruited from the general population while 16 had been referred for behavior problems to local clinics) were each presented with a series of vocal and facial stimuli expressing different emotions (i.e., angry, happy, and sad) of low and high intensity. Parents rated children's externalizing and internalizing behavior problems. Vocal and facial emotion recognition accuracy was negatively correlated with externalizing but not internalizing behavior problems independent of emotion type. The effects with the externalizing domain were independently associated with hyperactivity rather than conduct problems. The results highlight the importance of using vocal as well as facial stimuli when studying the relationship between emotion-recognition and behavior problems. Future studies should test the hypothesis that difficulties in responding to adult instructions and commands seen in children with attention deficit/hyperactivity disorder (ADHD) may be due to deficits in the processing of vocal emotions. PMID- 24344769 TI - Pharmacokinetics and in vivo biodistribution of optimized PLGA nanoparticulate drug delivery system for controlled release of emtricitabine. AB - The objective of this study was to develop systematically optimized (OPT) nanoparticles (NPs) providing a controlled release using PLGA of emtricitabine (FTC) employing Formulation by Design (FbD), and evaluate their in vitro and in vivo performance. FTC generates severe adverse effects with risks of toxicity. Thus, NPs were prepared to reduce these drawbacks in this study. The NPs were prepared by water-in-oil-in-water (w/o/w) emulsion method, followed by high pressure homogenization. The FTC NPs were systematically OPT using 3(2) central composite design and the OPT formulation located using overlay plot. The pharmacokinetics and in vivo biodistribution of OPT-FTC NPs were investigated in male Wistar rats via the oral administration. Transmission electron microscopy studies on OPT-FTC NPs demonstrated uniform shape and size of particles. In vitro release was sustained up to 15 days in PBS pH 7.4. Augmentation in the values of Cmax (1.63 fold) and AUC0-infinity (5.39 fold) indicated significant enhancement in the rate and extent of bioavailability by the OPT-FTC NPs compared to pure drug. OPT-FTC NPs showed 2.325 fold increase in the values of FTC concentrations in liver. The OPT-FTC NPs was found to be quite stable during 6 months of study period. Hence, the developed OPT-FTC NPs can be used as drug carrier for sustained/prolonged drug release and/or to reduce toxic effects. PMID- 24344770 TI - Room temperature rapid functionalization of E-H bonds (E = O, N, S) via the metal ligand cooperation mechanism. AB - An arylpalladium PNF-type pincer complex reacts with water and anilines under very mild conditions, providing access to new PNO- and PNN-pincer complexes with concomitant hydrogen transfer to the ligand core. Such a metal-ligand cooperation mode allows for the irreversible double activation of even highly sterically hindered aniline molecules. With thiols, the activation mode depends on the nature of the substituent at the sulfur atom, with thiophenols giving products of C-S elimination. PMID- 24344771 TI - Mean platelet volume measurement in chronic renal failure: confounding factors must have been taken into account. PMID- 24344772 TI - Incorporation of a triglutamyl spacer improves the biodistribution of synthetic affibody molecules radiofluorinated at the N-terminus via oxime formation with (18)F-4-fluorobenzaldehyde. AB - Affibody molecules are a class of affinity agents for molecular imaging based on a non-immunoglobulin protein scaffold. Previous studies have demonstrated high contrast for in vivo imaging of cancer-associated molecular abnormalities using Affibody molecules. Using the radionuclide (18)F for labeling and PET as the imaging modality, the sensitivity of molecular imaging using Affibody molecules can be further increased. The use of oxime formation between an aminooxy functionalized peptide and (18)F-fluorobenzaldehyde ((18)F-FBA) is a promising way of radiolabeling of targeting peptides. However, previous studies demonstrated that application of this method to Affibody molecules is associated with high liver uptake. We hypothesized that incorporation of a triglutamyl spacer between the aminooxy moiety and the N-terminus of a synthetic Affibody molecule would decrease the hepatic uptake of the (18)F-N-(4 fluorobenzylidine)oxime) ((18)F-FBO)-labeled tracer. To verify this, we have produced two variants of the HER2-targeting ZHER2:342 Affibody molecule by peptide synthesis: OA-PEP4313, where aminooxyacetic acid was conjugated directly to the N-terminal alanine, and OA-E3-PEP4313, where a triglutamyl spacer was introduced between the aminooxy moiety and the N-terminus. We have found that the use of the spacer is associated with a minor decrease of affinity, from KD = 49 pM to KD = 180 pM. Radiolabeled (18)F-FBO-E3-PEP4313 demonstrated specific binding to HER2-expressing ovarian carcinoma SKOV-3 cells and slow internalization. Biodistribution studies in mice demonstrated that the use of a triglutamyl linker decreased uptake of radioactivity in liver 2.7-fold at 2 h after injection. Interestingly, radioactivity uptake in kidneys was also reduced (2.4-fold). Experiments in BALB/C nu/nu mice bearing SKOV-3 xenografts demonstrated HER2-specific uptake of (18)F-FBO-E3-PEP4313 in tumors. At 2 h pi, the tumor uptake (20 +/- 2% ID/g) exceeded uptake in liver 5-fold and uptake in kidneys 3.6-fold. The tumor-to-blood ratio was 21 +/- 3. The microPET/CT imaging experiment confirmed the biodistribution data. In conclusion, the use of a triglutamyl spacer is a convenient way to improve the biodistribution profile of Affibody molecules labeled at the N-terminus using (18)F-FBA. It provides a tracer capable of producing high-contrast images of HER2-expressing tumors. PMID- 24344773 TI - Combinations of eight key mutations in the X/preC region and genomic activity of hepatitis B virus are associated with hepatocellular carcinoma. AB - Accumulation of eight key mutations located in the X/preC regions of the hepatitis B virus (HBV) genome (G1613A, C1653T, T1753V, A1762T, G1764A, A1846T, G1896A and G1899A) is a risk marker for the development of hepatocellular carcinoma (HCC). In this study, we analysed the 8 key mutations in 442 serum samples collected from 310 non-HCC and 132 HCC patients to identify the combinations linked to HCC. After the patients were stratified according to the age groups and mutation combinations, clinical parameters were compared between the HCC and the non-HCC groups. Analyses were focused on patient >=40 years of age infected by HBV genotype C with A1762T and G1764A mutations in the basal core promoter region (BCP double mutation). In patients with >=6 mutations, the combination of [G1613A + C1653T + A1846T + G1896A] mutations was closely linked to HCC, whereas no specific single or double mutation combination was associated with HCC. In patients with <=5 mutations, HBeAg and HBV DNA serum titres were lower in the HCC group than those in the non-HCC group. Unlike the number of mutations, no specific combination correlated with advanced clinical stage in HCC. Of the BCP double mutation-based HBV mutant types, combinations of >=6 mutations that include G1613A + C1653T + A1846T + G1896A, and combinations of <=5 mutations with reduced HBeAg production, may be more specific indicators of HCC risk than only the number of mutations or any specific combination(s). PMID- 24344774 TI - Cardiovascular disease risk factors in the South Asian population living in Kuwait: a cross-sectional study. AB - BACKGROUND: High rates of diabetes and cardiovascular disease have been reported in South Asian immigrants in many countries. However, the prevalence and characteristics of cardiovascular disease risk factors among a South Asian population living in Kuwait have not yet been investigated. This study was therefore designed to estimate the prevalence of cardiovascular disease risk factors and determine whether they are independently associated with diabetes in such a population. METHODS: A population-based cross-sectional study was conducted on 1094 South Asians (781 men and 313 women), mainly Indian and Pakistani (>= 18 years of age), of whom 75.1% were Indians. Interviews were carried out, during which socio-demographic and anthropometric data were collected, followed by a physical examination and collection of fasting blood samples for laboratory investigations. Diabetes was defined by fasting plasma glucose >= 7 mmol/l, or being on treatment, and/or self-reported previously diagnosed Type 2 diabetes. RESULTS: The prevalence of diabetes was 21.1%, with 3.4% of that percentage of people being newly diagnosed. Using BMI measurements, 24.0% of those who participated in the study were obese and 46.1% were overweight. Dyslipidaemia was found in 77.6% and hypertension in 44.8%. Advancing age (>= 40 years), male gender, high LDL, high total cholesterol, hypertension and positive family history of diabetes were significantly associated with increased risk of diabetes. CONCLUSION: Our study shows that the prevalence of cardiovascular disease risk factors in South Asian expatriates in Kuwait exceeds prevalence rates reported in their homeland and other countries. This may suggest the added stress of environmental factors on the development of cardiovascular disease risk factors in such populations. Specialized prevention programmes targeting such high-risk ethnic populations are paramount and need to be implemented. PMID- 24344775 TI - Correlates of suicide ideation among LGBT Nebraskans. AB - The aim of this investigation is to outline correlates of suicide ideation among LGBT individuals living in Nebraska. A community-based participatory research approach was utilized to develop a 30-minute, online anonymous survey. Almost half of the sample had seriously considered suicide at some point in their lives. Significant correlates of increased likelihood of suicide ideation are age, gender, transgender identity, income, depression, and discrimination. Suicide ideation is a serious concern for the health of LGBT Nebraskans. Steps should be taken to incorporate individuals who fall into these high-risk categories in suicide outreach programs. PMID- 24344776 TI - Intrinsic predisposition of naive cystic fibrosis T cells to differentiate towards a Th17 phenotype. AB - BACKGROUND: Cystic fibrosis (CF) is a complex, multi-system, life-shortening, autosomal recessive disease most common among Caucasians. Pulmonary pathology, the major cause of morbidity and mortality in CF, is characterized by dysregulation of cytokines and a vicious cycle of infection and inflammation. This cycle causes a progressive decline in lung function, eventually resulting in respiratory failure and death. The Th17 immune response plays an active role in the pathogenesis of CF pulmonary pathology, but it is not known whether the pathophysiology of CF disease contributes to a heightened Th17 response or whether CF naive CD4+ T lymphocytes (Th0 cells) intrinsically have a heightened predisposition to Th17 differentiation. METHODS: To address this question, Th0 cells were isolated from the peripheral blood of CF mice, human CF subjects and corresponding controls. Murine Th0 cells were isolated from single spleen cell suspensions using fluorescence-activated cell sorting. Lymphocytes from human buffy coats were isolated by gradient centrifugation and Th0 cells were further isolated using a human naive T cell isolation kit. Th0 cells were then assessed for their capacity to differentiate along Th17, Th1 or Treg lineages in response to corresponding cytokine stimulation. The T cell responses of human peripheral blood cells were also assessed ex vivo using flow cytometry. RESULTS: Here we identify in both mouse and human CF an intrinsically enhanced predisposition of Th0 cells to differentiate towards a Th17 phenotype, while having a normal propensity for differentiation into Th1 and Treg lineages. Furthermore, we identify an active Th17 response in the peripheral blood of human CF subjects. CONCLUSIONS: We propose that these novel observations offer an explanation, at least in part, for the known increased Th17-associated inflammation of CF and the early signs of inflammation in CF lungs before any evidence of infection. Moreover, these findings point towards direct modulation of T cell responses as a novel potential therapeutic strategy for combating excessive inflammation in CF. PMID- 24344777 TI - Skeletal recombination reaction of N-fused pentaphyrin(1.1.1.1.1) via bromination. AB - N-Fused [22]pentaphyrin(1.1.1.1.1) transformed into recombined N-fused pentaphyrin bromide after treatment with N-bromosuccinimide. This bromide was highly reactive to nucleophiles to give the corresponding substituted products including aminated, oxidized, and unsubstituted derivatives. PMID- 24344778 TI - Distinctive features of degenerating Purkinje cells in spinocerebellar ataxia type 31. AB - Spinocerebellar ataxia type 31 (SCA31) is an autosomal dominant form of pure cerebellar ataxia that is caused by a disease-specific insertion containing penta nucleotide repeats (TGGAA)n . Neuropathologically, cerebellar Purkinje cells are preferentially affected and reduced in number in SCA31, and they are often surrounded by halo-like amorphous materials. In the present study, we performed neuropathological analyses on two SCA31 brains, and discussed the serial morphological changes of Purkinje cells in SCA31.We found that bent, elongated, often folded nuclei were observed frequently in degenerating Purkinje cells with the halo-like structure. Conversely, Purkinje cells without this structure developed marked atrophy with severely slender and condensed nuclei. On the basis of these pathological findings, we propose two different processes for Purkinje cell degeneration in SCA31, namely, shrinkage of Purkinje cells with or without the halo-like amorphous materials. The former, but not the latter, was considered to be specific to SCA31. Correspondingly, fragmentation of the Golgi apparatus was observed more frequently in Purkinje cells with the halo-like structure than in those without this structure. We consider that the profound nuclear deformity and fragmentation of the Golgi apparatus are closely linked with the formation of the halo-like structure in SCA31. PMID- 24344779 TI - Prevention praised, cure preferred: results of between-subjects experimental studies comparing (monetary) appreciation for preventive and curative interventions. AB - BACKGROUND: 'An ounce of prevention is worth a pound of cure' is a common saying, and indeed, most health economic studies conclude that people are more willing to pay for preventive measures than for treatment activities. This may be because most health economic studies ask respondents to compare preventive measures with treatment, and thus prompt respondents to consider other uses of resources. However, psychological theorizing suggests that, when methods do not challenge subjects to consider other uses of resources, curative treatment is favored over prevention. Could it be that while prevention is praised, cure is preferred? METHODS: In two experimental studies, we investigated, from a psychological perspective and using a between-subjects design, whether prevention or treatment is preferred and why. In both studies, participants first read a lung cancer prevention or treatment intervention scenario that varied on the prevention treatment dimension, but that were the same on factors like 'costs per saved life' and kind of disease. Then participants completed a survey measuring appreciation (general and monetary) as well as a number of potential mediating variables. RESULTS: Both studies clearly demonstrated that, when the design was between-subjects, participants had greater (general and monetary) appreciation for treatment interventions than for preventive interventions with perceived urgency of the intervention quite consistently mediating this effect. Differences in appreciation of treatment over preventive treatment were shown to be .59 (Study 1) and .45 (Study 2) on a 5-point scale. Furthermore, participants thought that health insurance should compensate more for the treatment than for preventive measures, differences of 16% (Study 1), and 22% (Study 2). When participants were asked to directly compare both interventions on the basis of a short description, they preferred the preventive intervention. CONCLUSION: It appears that people claim to prefer prevention when they are asked to consider other use of resources, but otherwise they prefer treatment. This preference is related to perceived urgency. The preference for treatment may be related to the prevention-treatment dimension itself, but also to variations on other dimensions that are inherently linked to prevention and treatment (like different efficacy rates and costs per treatment). PMID- 24344780 TI - LPS and TNF alpha modulate AMPA/NMDA receptor subunit expression and induce PGE2 and glutamate release in preterm fetal ovine mixed glial cultures. AB - BACKGROUND: White matter injury (WMI) is the major antecedent of cerebral palsy in premature infants, and is often associated with maternal infection and the fetal inflammatory response. The current study explores the therapeutic potential of glutamate receptor blockade or cyclooxygenase-2 (COX-2) inhibition for inflammatory WMI. METHODS: Using fetal ovine derived mixed glia cultures exposed to tumour necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS), the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and N methyl D-aspartate (NMDA) glutamate receptors and their contribution to inflammation mediated pre-oligodendrocyte (OL) death was evaluated. The functional significance of TNF-alpha and COX-2 signalling in glutamate release in association with TNF-alpha and LPS exposure was also assessed. RESULTS: AMPA and NMDA receptors were expressed in primary mixed glial cultures on developing OLs, the main cell-type present in fetal white matter at a period of high risk for WMI. We show that glutamate receptor expression and configuration are regulated by TNF-alpha and LPS exposure, but AMPA and NMDA blockade, either alone or in combination, did not reduce pre-OL death. Furthermore, we demonstrate that glutamate and prostaglandin E2 (PGE2) release following TNF-alpha or LPS are mediated by a TNF-alpha-COX-2 dependent mechanism. CONCLUSIONS: Overall, these findings suggest that glial-localised glutamate receptors likely play a limited role in OL demise associated with chronic inflammation, but supports the COX-2 pathway as a potential therapeutic target for infection/inflammatory-mediated WMI. PMID- 24344782 TI - Gender differences in adolescent coping behaviors and suicidal ideation: findings from a sample of 73,238 adolescents. AB - Suicide among adolescents is an emerging global public health problem as well as a socioeconomic problem. Stress-coping strategies have been shown to be associated with suicidal ideation. We examined coping behaviors related to suicidal ideation and gender differences in adolescents using the data from the 2010 Korea Youth Risk Behavior Survey (ages 12-19 years; N = 73,238). Logistic regression analysis was used to evaluate associations between suicidal ideation and specific coping behaviors while controlling for potentially confounding variables. In both male and female groups, the coping behavior "drinking alcoholic beverages" and "smoking cigarettes" were positively associated with suicidal ideation. "Watching TV," "playing online/mobile games," and "sleeping" were negatively associated with suicidal ideation in both groups. In males, "engaging in sports" was negatively related to suicidal ideation. In females, "venting by talking to others" and "eating" were negatively related to suicidal ideation. The results indicate that there are gender differences in the effects of coping behaviors on adolescent suicidal ideation, and that developing adaptive coping strategies may function to reduce suicidality. Future studies are needed to examine whether improving coping skills can reduce suicidal ideation in a gender-specific manner. PMID- 24344783 TI - Cardiovascular effects of a continuous rate infusion of lidocaine in calves anesthetized with xylazine, midazolam, ketamine and isoflurane. AB - OBJECTIVE: To assess the cardiovascular changes of a continuous rate infusion of lidocaine in calves anesthetized with xylazine, midazolam, ketamine and isoflurane during mechanical ventilation. STUDY DESIGN: Prospective, randomized, cross-over, experimental trial. ANIMALS: A total of eight, healthy, male Holstein calves, aged 10 +/- 1 months and weighing 114 +/- 11 kg were included in the study. METHODS: Calves were administered xylazine followed by ketamine and midazolam, orotracheal intubation and maintenance on isoflurane (1.3%) using mechanical ventilation. Forty minutes after induction, lidocaine (2 mg kg-1 bolus) or an equivalent volume of saline (0.9%) was administered IV followed by a continuous rate infusion (100 MUg kg-1 minute-1) of lidocaine (treatment L) or saline (treatment C). Heart rate (HR), systolic, diastolic and mean arterial pressures (SAP, DAP and MAP), central venous pressure (CVP), mean pulmonary arterial pressure (mPAP), pulmonary arterial occlusion pressure (PAOP), cardiac output, end-tidal carbon dioxide (Pe'CO2 ) and core temperature (CT) were recorded before lidocaine or saline administration (Baseline) and at 20-minute intervals (T20-T80). Plasma concentrations of lidocaine were measured in treatment L. RESULTS: The HR was significantly lower in treatment L compared with treatment C. There was no difference between the treatments with regards to SAP, DAP, MAP and SVRI. CI was significantly lower at T60 in treatment L when compared with treatment C. PAOP and CVP increased significantly at all times compared with Baseline in treatment L. There was no significant difference between times within each treatment and between treatments with regards to other measured variables. Plasma concentrations of lidocaine ranged from 1.85 to 2.06 MUg mL-1 during the CRI. CONCLUSION AND CLINICAL RELEVANCE: At the studied rate, lidocaine causes a decrease in heart rate which is unlikely to be of clinical significance in healthy animals, but could be a concern in compromised animals. PMID- 24344784 TI - Motivational and cognitive determinants of control during conflict processing. AB - Previous studies suggest that both reward anticipation and expected or experienced conflicts activate cognitive control. The present study investigated how these factors interact during conflict processing. In two experiments, participants performed a variant of the Stroop task, receiving performance dependent monetary rewards in some blocks. In addition, we manipulated the level of conflict-triggered reactive and expectancy-driven proactive control: In Experiment 1, we compared the Stroop effect after previously congruent and incongruent trials to examine the conflict adaptation effect (reactive control). We found that the level of motivation did not interact with conflict adaptation. In Experiment 2, we varied the proportion of congruent and incongruent trials to manipulate conflict expectancy (proactive control). The data suggest the effects of motivation to be less pronounced under conditions of high conflict expectancy. We conclude that the interaction of motivation with cognitive determinants of control depends on whether these activate proactive or reactive control processes. PMID- 24344781 TI - Integrating human omics data to prioritize candidate genes. AB - BACKGROUND: The identification of genes involved in human complex diseases remains a great challenge in computational systems biology. Although methods have been developed to use disease phenotypic similarities with a protein-protein interaction network for the prioritization of candidate genes, other valuable omics data sources have been largely overlooked in these methods. METHODS: With this understanding, we proposed a method called BRIDGE to prioritize candidate genes by integrating disease phenotypic similarities with such omics data as protein-protein interactions, gene sequence similarities, gene expression patterns, gene ontology annotations, and gene pathway memberships. BRIDGE utilizes a multiple regression model with lasso penalty to automatically weight different data sources and is capable of discovering genes associated with diseases whose genetic bases are completely unknown. RESULTS: We conducted large scale cross-validation experiments and demonstrated that more than 60% known disease genes can be ranked top one by BRIDGE in simulated linkage intervals, suggesting the superior performance of this method. We further performed two comprehensive case studies by applying BRIDGE to predict novel genes and transcriptional networks involved in obesity and type II diabetes. CONCLUSION: The proposed method provides an effective and scalable way for integrating multi omics data to infer disease genes. Further applications of BRIDGE will be benefit to providing novel disease genes and underlying mechanisms of human diseases. PMID- 24344785 TI - Association of angiotensinogen gene M235T polymorphism with the risk of IgA nephropathy: a meta-analysis. AB - The association between angiotensinogen (AGT) M235T gene polymorphism and IgA nephropathy (IgAN) risk remains elusive. Our aim was to evaluate the association between AGT M235T gene polymorphism and IgAN susceptibility by performing a meta analysis. Eligible studies were searched according to predefined criteria using electronic databases. Eight studies were identified for the analysis of the association between AGT M235T gene polymorphism and IgAN risk. M allele/MM genotype were not associated with IgAN risk in overall populations, Caucasians and Asians (overall populations: p = 0.448 and 0.861, Caucasians: p = 0.618 and 0.886, Asians: p = 0.566 and 0.652). TT/MT genotype were not associated with IgAN risk in overall populations, Caucasians and Asians (overall populations: p = 0.703 and 0.454, Caucasians: p = 0.975 and 0.946, Asians: p = 0.697 and 0.353). No evidence of publication bias was observed. In conclusion, AGT M235T gene polymorphism may not be correlated with IgAN susceptibility in overall populations, Caucasians and Asians. However, more studies should be performed in the future. PMID- 24344786 TI - Optimization of PEGylated nanoemulsions for improved pharmacokinetics of BCS class II compounds. AB - The objective of the study was the optimization of nanoemulsion formulations to prevent their rapid systemic clearance after intravenous administration. An amphiphilic PEG derivative DSPE-PEG (1,2-distearoyl-sn-glycero-3 phosphoethanolamine-N-methoxy-poly(polyethylene glycol) with different chain lengths and concentration was used as a nanoemulsion droplet surface modifier. The danazol loading in all nanoemulsions was kept on the same level of ~2 mg/mL. In the present investigation, PEGylated and non-PEGylated nanoemulsions were compared in vitro phagocytosis by incubating with lung macrophages and in vivo after intravenous administration in rats. Danazol-containing nanoemulsions (NE) modified with various PEG chain lengths (2000-10 000) and concentrations (3-12 mg/mL) were prepared and characterized. Nanoemulsion droplets were reproducibly obtained in the size range of 213-340 nm. The non-PEGylated NE had the surface charge of -25.4 mV. This absolute charge value decreased with increasing chain length and concentration. With increase in chain length and density the macrophage uptake decreased which could be due to decrease in surface charge and hydrophilicity of droplets. The greatest shielding of the NE droplets was reached with DSPE-PEG5000 at the concentration of 6 mg/mL where the surface charge changed to -1.27 mV. Following intravenous administration a maximum danazol exposure (401 +/- 68.2 h ng/mL) was observed with the lowest clearance rate (5.06 +/- 0.95 L/h/kg) from 6 mg/mL DSPE-PEG5000 nanoemulsion. PEG5000 and PEG10000 altered the pharmacokinetic of danazol by decreasing clearance and volume of distribution which is likely explained by the presence of hydrophilic shields around the droplets that prevent their rapid systemic clearance and tissue partitioning. PMID- 24344787 TI - The safety and effectiveness of a long-acting transdermal fentanyl solution compared with oxymorphone for the control of postoperative pain in dogs: a randomized, multicentered clinical study. AB - A prospective, double-blinded, positive-controlled, multicenter, noninferiority study was conducted to evaluate the safety and effectiveness of transdermal fentanyl solution (TFS) compared with oxymorphone for the control of postoperative pain in dogs. Five hundred and two (502) client-owned dogs were assigned to a single dose of TFS (2.7 mg/kg) applied 2-4 h prior to surgery or oxymorphone hydrochloride (0.22 mg/kg) administered subcutaneously 2-4 h prior to surgery and q6h through 90 h. Pain was evaluated over 4 days by blinded observers using a modified Glasgow composite pain scale, and the a priori criteria for treatment failure was a pain score >= 8 or adverse event necessitating withdrawal. Four TFS- and eight oxymorphone-treated dogs were withdrawn due to lack of pain control. Eighteen oxymorphone-treated, but no TFS-treated dogs were withdrawn due to severe adverse events. The one-sided upper 95% confidence interval of the difference between TFS and oxymorphone treatment failure rates was -5.3%. Adverse events associated with oxymorphone were greater in number and severity compared with TFS. It was concluded that a single administration of TFS was safe and noninferior to repeated injections of oxymorphone for the control of postoperative pain over 4 days at the dose rates of both formulations used in this study. PMID- 24344788 TI - Effects of different steps in gender reassignment therapy on psychopathology: a prospective study of persons with a gender identity disorder. AB - INTRODUCTION: At the start of gender reassignment therapy, persons with a gender identity disorder (GID) may deal with various forms of psychopathology. Until now, a limited number of publications focus on the effect of the different phases of treatment on this comorbidity and other psychosocial factors. AIMS: The aim of this study was to investigate how gender reassignment therapy affects psychopathology and other psychosocial factors. METHODS: This is a prospective study that assessed 57 individuals with GID by using the Symptom Checklist-90 (SCL-90) at three different points of time: at presentation, after the start of hormonal treatment, and after sex reassignment surgery (SRS). Questionnaires on psychosocial variables were used to evaluate the evolution between the presentation and the postoperative period. The data were statistically analyzed by using SPSS 19.0, with significance levels set at P < 0.05. MAIN OUTCOME MEASURES: The psychopathological parameters include overall psychoneurotic distress, anxiety, agoraphobia, depression, somatization, paranoid ideation/psychoticism, interpersonal sensitivity, hostility, and sleeping problems. The psychosocial parameters consist of relationship, living situation, employment, sexual contacts, social contacts, substance abuse, and suicide attempt. RESULTS: A difference in SCL-90 overall psychoneurotic distress was observed at the different points of assessments (P = 0.003), with the most prominent decrease occurring after the initiation of hormone therapy (P < 0.001). Significant decreases were found in the subscales such as anxiety, depression, interpersonal sensitivity, and hostility. Furthermore, the SCL-90 scores resembled those of a general population after hormone therapy was initiated. Analysis of the psychosocial variables showed no significant differences between pre- and postoperative assessments. CONCLUSIONS: A marked reduction in psychopathology occurs during the process of sex reassignment therapy, especially after the initiation of hormone therapy. PMID- 24344789 TI - Fast and accurate database searches with MS-GF+Percolator. AB - One can interpret fragmentation spectra stemming from peptides in mass spectrometry-based proteomics experiments using so-called database search engines. Frequently, one also runs post-processors such as Percolator to assess the confidence, infer unique peptides, and increase the number of identifications. A recent search engine, MS-GF+, has shown promising results, due to a new and efficient scoring algorithm. However, MS-GF+ provides few statistical estimates about the peptide-spectrum matches, hence limiting the biological interpretation. Here, we enabled Percolator processing for MS-GF+ output and observed an increased number of identified peptides for a wide variety of data sets. In addition, Percolator directly reports p values and false discovery rate estimates, such as q values and posterior error probabilities, for peptide-spectrum matches, peptides, and proteins, functions that are useful for the whole proteomics community. PMID- 24344790 TI - Assessment of effort in children: a systematic review. AB - The assessment of response validity is now considered an important and necessary component of neuropsychological evaluations. One way for assessing response validity is with performance validity tests (PVTs), which measure the degree of effort applied to testing to achieve optimal performance. Numerous studies have shown that normal and neurologically impaired children are capable of passing certain free-standing PVTs using adult cutoffs. Despite this, PVT use appears to be more common in adults compared to children. The overall purpose of this systematic review is to provide the reader with a general overview of the existing literature on PVTs in children. As part of this review, goals are to inform the reader why PVT use is not as prevalent in children compared to adults, to discuss why PVTs and related methods are important in pediatric cognitive evaluations, and to discuss practical limitations and future directions. PMID- 24344791 TI - Detecting small groundwater discharge springs using handheld thermal infrared imagery. AB - Ground-based handheld thermal infrared imagery was used for the detection of small-scale groundwater springs at the northwestern beach of Spiekeroog Island (northwest Germany). The surveys and in situ measurements of electric conductivity were carried out from shortly before to shortly after low tide along the low water line. Several brackish groundwater discharge springs with a diameter of 1-2 cm were observed along the beach at a distance of 2-3 m above the low water line. The high fresh water portion in the discharging water derives from the fresh water lens in the center of the island. During cold weather, the springs were identified by a significantly increased temperature (3-5 degrees C higher) and a lower electric conductivity (<10 mS/cm) in contrast to the surrounding sea water (1-2 degrees C, >30 mS/cm). During warmer weather conditions, an inverse temperature contrast was observed. The measurements confirm the applicability of thermal imagery for the detection of small-scale groundwater discharge locations as an extension to the established method of aerial thermal scans and prove the existence of submarine groundwater seeps in porous systems. A ground-based handheld thermal infrared imagery survey enables a precise installation of sampling devices as, for example, seepage meters. PMID- 24344792 TI - Progress in understanding oral health and HIV/AIDS. AB - Over the last 30 years, there have been significant advances in our scientific knowledge of HIV disease, including prevention, detection, medical management, and attempts at cure. Investigations and observations of the oral cavity in individuals with HIV disease have contributed substantially to scientific discovery and innovation. Challenges remain for managing existing and emerging oral diseases associated with HIV and understanding the contribution of latent oral mucosal reservoirs to HIV eradication. PMID- 24344793 TI - Rhodium amidinate dimers as structural and functional hubs for multimetallic assemblies. AB - The synthesis and characterization of multichromophore assemblies based on a dirhodium tetra-N,N'-diphenylisonicotinamidinate dimer are reported. The pyridyl moieties were used to coordinate up to four positively charged rhenium(I) chromophores of the form fac-[Re(bpy)(CO)3L]PF6 (bpy = 2,2'-bipyridine, L = a pyridyl group on the Rh2 dimer). The mono-, bis-, tris-, and tetrarhenium assemblies were isolated by size-exclusion chromatography, and their spectroscopic and electrochemical properties were studied and compared with DFT and time-dependent (TD) DFT models of the original rhodium dimer and the mono- and tetrarhenium assembly. The rhenium chromophores modify the properties of the rhodium dimer: for example, the first oxidation of the Rh2 dimer (Rh-Rh delta* orbital) increased from the original 210 mV versus SCE in acetonitrile, by 45 mV per rhenium complex added, finishing at 390 mV for the tetrarhenium complex. The rhodium dimers display solvatochromism with acetonitrile (MeCN) due to the formation of an axial adduct and has an association constant that increased by a factor of 3.8 when the dimer has four rhenium chromophores. The absorption data clearly exhibited the cumulative effect of the addition of rhenium chromophores in the 230 to 400 nm range. The main visible band, a metal-dimer-to-ligand charge transfer ((1)M2LCT) transition determined by TD-DFT, red-shifts from 541 nm to 603 nm, while the main near-IR band, a (1)Rh2(pi*->sigma*) transition, has a small blue-shift (~26 cm(-1)/Re), varying from 837 to 831 nm upon addition of the four Re(I) chromophores. This was observed in TD-DFT also with a total shift of 105 cm(-1) for the tetrarhenium assembly. In terms of emission, the rhenium excited state was completely quenched upon coordination to the dimer, suggesting fast electron transfer of the rhodium dimer. All other aspects of the rhenium chromophore are similar to the parent complex where L = pyridine, showing similar redox couples and additive spectral characteristics. PMID- 24344795 TI - Novel Pb2+ ion imprinted polymers based on ionic interaction via synergy of dual functional monomers for selective solid-phase extraction of Pb2+ in water samples. AB - A novel kind of Pb(2+) ion imprinted polymers (IIPs) was prepared based on ionic interactions via the synergy of dual functional monomers of methacrylic acid and vinyl pyridine for selective solid-phase extraction (SPE) of Pb(2+) in water samples. Suspension polymerization was employed for the formation of template Pb(2+)/monomer complex by self-assembly in the presence of ethylene glycol dimethacrylate cross-linker. The resulted Pb(2+) IIPs showed fast kinetics, high binding capacity, and the adsorption processes obeyed intraparticle diffusion kinetics and Langmuir isotherm models. The IIPs displayed excellent selectivity toward Pb(2+) over other metal ions such as Cu(2+), Cd(2+), Zn(2+), and Mn(2+) with selective coefficients above 30, as well as high anti-interference ability for Pb(2+) confronting with common coexisting various ions. Through 10 adsorption desorption cycles, the reusable IIPs exhibited a good recoverability with the standard error within 5%. These features suggested the IIPs were ideal candidates for extraction and removal of Pb(2+) ions. Consequently, the IIPs were utilized as SPE sorbents and related parameters were optimized. An excellent linearity was presented in the range of 0.2-50 MUg L(-1) (R(2) = 0.9998), as well as the limits of detection and quantification were achieved of 0.06 and 0.19 MUg L(-1), respectively. A good repeatability was obtained with the relative standard deviation of 2.8%. Furthermore, real water samples were successfully analyzed and satisfactory recoveries varying from 95.5 to 104.6% were attained. The IIPs-SPE demonstrated potential application perspectives for rapid and high-effective cleanup and enrichment of trace Pb(2+) ions in complicated matrices. PMID- 24344794 TI - Changes in procoagulants track longitudinally with insulin resistance: findings from the coronary artery risk development in young adults (CARDIA) study. AB - AIMS: To examine the association between changes in procoagulants (fibrinogen factors VII and VIII and von Willebrand factor) and the risk of insulin resistance. METHODS: Using data from the Coronary Artery Risk Development in Young Adults study, we followed 2398 black and white adults without diabetes, aged 25-37 years at year 7, to year 20. Levels of fibrinogen factors VII and VIII and von Willebrand factor were divided in tertiles (low/middle/high) at years 7 and 20 and four groups reflecting changes were defined: 'low' (low at years 7 and 20), 'stable' (low/middle at years 7 and 20, but not both low at years 7 and 20), 'high' (high at year 7 and low/middle at year 20; or low/middle at year 7 and high at year 20) and 'highest' (high at years 7 and 20). Linear regression models were used to evaluate 13-year changes (year 20-year 7) in fibrinogen level and factors VII, VIII and von Willebrand change groups in relation to insulin resistance measures. RESULTS: Homeostasis model assessment of insulin resistance (year 20) and changes in log homeostasis model assessment of insulin resistance (year 20-year 7) were significantly associated with the 13-year increase in fibrinogen (P < 0.001). Compared with participants in the low group, those in the high group had significantly higher levels of homeostasis model assessment of insulin resistance (year 20) and changes in homeostasis model assessment of insulin resistance (year 20-year 7) for fibrinogen factor VII and von Willebrand factor (P < 0.017). No significant associations were observed between fibrinogen VIII and insulin resistance measures. CONCLUSIONS: An increase in fibrinogen level and persistently high levels of factor VII and von Willebrand factor are significantly associated with increased risk of insulin resistance. These findings provide new insight into the mechanisms to explain the heightened risk for thrombosis in adults with insulin resistance/diabetes. PMID- 24344796 TI - Synthesis of chiral building blocks for oxygenated terpenoids through a simultaneous and stereocontrolled construction of contiguous quaternary stereocenters by an Ireland-Claisen rearrangement. AB - Methods for highly stereocontrolled syntheses of chiral building blocks with a triad of contiguous stereocenters, including two quaternary ones, have been developed. Ireland-Claisen rearrangement of the (Z)-silyl ketene acetal generated stereoselectively from the (R)-3-methylcyclohex-2-enyl ester derived from an acyclic carboxylic acid proceeded through a chairlike transition state to give the rearranged product with an S configuration at the position alpha to the carboxyl group. Introduction of a cyclic conformational constraint in the acid component completely switched the transition state of the rearrangement to a boatlike one, leading to the predominant formation of a product with an R configuration, from which pseudodiastereomeric alpha-hydroxy esters were obtained in a four-step sequence. The enyne obtained through a base-mediated double eliminative ring-opening reaction was successfully converted into advanced intermediates for the synthesis of 9-oxygenated labdane diterpenoids through a Heck reaction and a regioselective transformation of the resultant diene. PMID- 24344803 TI - Biarsenical ligands bind to endogenous G-protein alpha-subunits and enable allosteric sensing of nucleotide binding. AB - BACKGROUND: Heterotrimeric G-proteins relay extracellular signals to intracellular effector proteins. Multiple methods have been developed to monitor their activity; including labeled nucleotides and biosensors based on genetically engineered G-proteins. Here we describe a method for monitoring unlabeled nucleotide binding to endogenous G-proteins alpha-subunits in a homogeneous assay based on the interaction of 4',5'-bis(1,2,3-dithioarsolan-2-yl)-2',7' difluorofluorescein (F2FlAsH) with G-protein alpha-subunits. RESULTS: The biarsenic fluorescent ligand F2FlAsH binds to various wild-type G-protein alpha subunits (alphai1, alphai2, alphai3, alphaslong, alphasshort, alphaolf, alphaq, alpha13) via high affinity As-cysteine interactions. This allosteric label enables real time monitoring of the nucleotide bound states of alpha-subunits via changes in fluorescence anisotropy and intensity of their F2FlAsH-complexes. We have found that different alpha-subunits displayed different signal amplitudes when interacting with F2FlAsH, being more sensitive to nucleotide binding to alphai, alphas, alphaolf and alphaq than to alpha13. Addition of nucleotides to F2FlAsH-labeled alpha-subunits caused concentration-dependent effects on their fluorescence anisotropy. pEC50 values of studied nucleotides depended on the subtype of the alpha-subunit and were from 5.7 to 8.2 for GTPgammaS, from 5.4 to 8.1 for GppNHp and from 4.8 to 8.2 for GDP and lastly up to 5.9 for GMP. While GDP and GMP increased the fluorescence anisotropy of F2FlAsH complexes with alphai-subunits, they had the opposite effect on the other alphabetagammaM complexes studied. CONCLUSIONS: Biarsenical ligands interact allosterically with endogenous G-protein alpha-subunits in a nucleotide-sensitive manner, so the presence or absence of guanine nucleotides has an effect on the fluorescence anisotropy, intensity and lifetime of F2FlAsH-G-protein complexes. PMID- 24344804 TI - Community-based measles mortality surveillance in two districts of Katanga Province, Democratic Republic of Congo. AB - BACKGROUND: Mortality due to measles is often under-reported. Traditional methods of measuring mortality can be time and resource-intensive. We describe the implementation of a community-based method to monitor measles mortality. FINDINGS: Using standardized questionnaires in the midst of a measles outbreak, a community-based network of volunteers recorded a much larger number of deaths (376) than deaths recorded in health centres (27). Deaths were predominantly (93.5%) among children aged less than 5 years; 54.5% of measles deaths reported antecedent measles vaccination. CONCLUSIONS: In this setting, the number of deaths due to measles reported in community-based surveillance was much higher than deaths reported in health centres. Lack of reliable population data and incomplete coverage of the surveillance system make it impossible to calculate overall attack rates and cause-specific mortality rates. Similar systems could be rapidly implemented in other difficult outbreak settings. PMID- 24344806 TI - The neurotrophic hepatocyte growth factor attenuates CD8+ cytotoxic T-lymphocyte activity. AB - BACKGROUND: Accumulating evidence suggests a deleterious role for CD8+ T cells in multiple sclerosis (MS) pathogenesis. We have recently reported that hepatocyte growth factor (HGF), a potent neuroprotective factor, limits CD4+ T cell-mediated autoimmune neuroinflammation by promoting tolerogenic dendritic cells (DCs) and subsequently regulatory T cells. Whether HGF modulates cell-mediated immunity driven by MHC class I-restricted CD8+ T cells remains to be determined. METHODS: Here we examined whether HGF regulates antigen-specific CD8+ T cell responses using an established model of murine cytotoxic T lymphocyte (CTL)-mediated killing. RESULTS: We found that HGF treatment of gp100-pulsed DCs reduced the activation of gp100-specific T cell receptor (Pmel-1) CD8+ T cells and subsequent MHC class I-restricted CTL-mediated cytolysis of gp100-pulsed target cells. The levels of perforin, granzyme B, IFN-gamma, and the degranulation marker CD107a as well as Fas ligand were decreased among CD8+ T cells, suggestive of a dual inhibitory effect of HGF on the perforin/granzyme B- and Fas-based lytic pathways in cell-mediated cytotoxicity. Treatment of CD8+ T cells with concanamycin A, a potent inhibitor of the perforin-mediated cytotoxic pathway, abrogated CTL cytotoxicity indicating that blockade of the perforin-dependent killing is a major mechanism by which HGF diminished cytolysis of gp100-pulsed target cells. Moreover, HGF suppressed the generation of effector memory CTLs. CONCLUSIONS: Our findings indicate that HGF treatment limits both the generation and activity of effector CTL from naive CD8+ T cells. Complementary to its impact on CD4+ T-cell CNS autoimmunity and myelin repair, our findings further suggest that HGF treatment could be exploited to control CD8+ T-cell-mediated, MHC I-restricted autoimmune dysfunctions such as MS. PMID- 24344807 TI - Use of color Doppler ultrasonography for evaluating vascularity of small intestinal lesions in Crohn's disease: correlation with endoscopic and surgical macroscopic findings. AB - OBJECTIVE. Ultrasonography (US) is a simple, inexpensive and minimally invasive method. We evaluated the vascularity of small intestinal lesions in Crohn's disease using color Doppler US (CD-US) and retrospectively compared them with endoscopic and surgical macroscopic findings. MATERIAL AND METHODS. In order to compare CD-US and endoscopic findings, 108 Crohn's disease patients who underwent examination of the terminal ileum by both colonoscopy and CD-US were included in the study. Vascularity was evaluated in CD-US using a semiquantitative method, the Limberg score. We analyzed correlations between Limberg score and simple endoscopic score for Crohn's disease (SES-CD), an index reflecting endoscopic activity. Scores of SES-CD 3 and higher were defined as endoscopically active. For comparison with surgical macroscopic findings, 22 Crohn's disease patients who received CD-US and subsequent iliectomies were included. Lesions with apparent open ulcers were defined as active, and those without as non-active. These findings were compared with the Limberg score. RESULTS. A substantial positive correlation was observed between Limberg scores and SES-CD (rho = 0.709 [p < 0.001]). Notably, all 27 cases with a Limberg score of 3 or 4 were classified as endoscopically active. Compared to surgical macroscopic activity, Limberg scores of active lesions were significantly higher than those of non active lesions (p = 0.005). In particular, all 11 cases with a Limberg score of 3 or 4 were classified as active lesions. CONCLUSION. Vascularity of small intestinal lesions of Crohn's disease evaluated by CD-US with Limberg score is well correlated with endoscopic and surgical macroscopic findings. PMID- 24344805 TI - Baseline assessment of adult and adolescent primary care delivery in Rwanda: an opportunity for quality improvement. AB - BACKGROUND: As resource-limited health systems evolve to address complex diseases, attention must be returned to basic primary care delivery. Limited data exists detailing the quality of general adult and adolescent primary care delivered at front-line facilities in these regions. Here we describe the baseline quality of care for adults and adolescents in rural Rwanda. METHODS: Patients aged 13 and older presenting to eight rural health center outpatient departments in one district in southeastern Rwanda between February and March 2011 were included. Routine nurse-delivered care was observed by clinical mentors trained in the WHO Integrated Management of Adolescent & Adult Illness (IMAI) protocol using standardized checklists, and compared to decisions made by the clinical mentor as the gold standard. RESULTS: Four hundred and seventy consultations were observed. Of these, only 1.5% were screened and triaged for emergency conditions. Fewer than 10% of patients were routinely screened for chronic conditions including HIV, tuberculosis, anemia or malnutrition. Nurses correctly diagnosed 50.1% of patient complaints (95% CI: 45.7%-54.5%) and determined the correct treatment 44.9% of the time (95% CI: 40.6%-49.3%). Correct diagnosis and treatment varied significantly across health centers (p = 0.03 and p = 0.04, respectively). CONCLUSION: Fundamental gaps exist in adult and adolescent primary care delivery in Rwanda, including triage, screening, diagnosis, and treatment, with significant variability across conditions and facilities. Research and innovation toward improving and standardizing primary care delivery in sub-Saharan Africa is required. IMAI, supported by routine mentorship, is one potentially important approach to establishing the standards necessary for high-quality care. PMID- 24344808 TI - Adiponectin gene polymorphisms and susceptibility to diabetic nephropathy: a meta analysis. AB - Adiponectin (ADIPOQ) plays an important role in the pathogenesis of diabetic nephropathy (DN) and previous studies regarding the association between ADIPOQ polymorphisms and DN risk reported conflicting results. To derive a more precise estimation of this association, we performed a meta-analysis to assess the association between four ADIPOQ polymorphisms [-11391G > A (rs17300539), -11377C > G (rs266729), +45T > G (rs2241766), and +276G > T (rs1501299)] and risk for DN. Odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) were pooled to assess the association between four aforementioned polymorphisms and susceptibility to DN. Based on the included criteria, we selected 13 articles, among which 7 studies (cases/controls: 2749/7585) for -11391G > A, 8 studies for 11377C > G (3074/3842), 9 studies for +45T > G (2654/7710), and 10 studies for +276G > T (2812/7821), respectively. Our meta-analysis indicated no evidence heterogeneity among the included studies; thus, the fixed-effects model was used. Overall, there was an association between ADIPOQ -11391A allele with increased DN risk (OR = 1.186, 95% CI: 1.051-1.338, p = 0.006). Subgroup by ethnicity suggested significant association between +45T > G polymorphism and DN risk among Caucasians (OR = 1.122, 95% CI: 1.007-1.250, p = 0.038). Sensitivity analysis suggested exclusion of any single study did not materially alter the overall pooled ORs above. Future studies are needed to validate these findings. PMID- 24344809 TI - Phosphate transporters OsPHT1;9 and OsPHT1;10 are involved in phosphate uptake in rice. AB - We characterized the function of two rice phosphate (Pi) transporters: OsPHT1;9 (OsPT9) and OsPHT1;10 (OsPT10). OsPT9 and OsPT10 were expressed in the root epidermis, root hairs and lateral roots, with their expression being specifically induced by Pi starvation. In leaves, expression of the two genes was observed in both mesophyll and vasculature. High-affinity Km values for Pi transport of OsPT9 and OsPT10 were determined by yeast experiments and two-electrode voltage clamp analysis of anion transport in Xenopus oocytes expressing OsPT9 and OsPT10. Pi uptake and Pi concentrations in transgenic plants harbouring overexpressed OsPT9 and OsPT10 were determined by Pi concentration analysis and (33) P-labelled Pi uptake rate analysis. Significantly higher Pi uptake rates in transgenic plants compared with wild-type plants were observed under both high-Pi and low-Pi solution culture conditions. Conversely, although no alterations in Pi concentration were found in OsPT9 or OsPT10 knockdown plants, a significant reduction in Pi concentration in both shoots and roots was observed in double knockdown plants grown under both high- and low-Pi conditions. Taken together, our results suggest that OsPT9 and OsPT10 redundantly function in Pi uptake. PMID- 24344810 TI - Short- and long-term clinical skin effects of testosterone treatment in trans men. AB - INTRODUCTION: Our knowledge concerning the effects of testosterone (T) therapy on the skin of trans men (female-to-male transsexuals) is scarce. AIM: The aim of this study was to evaluate the short- and long-term clinical effects of T treatment on the skin of trans men. METHODS: We conducted a prospective intervention study in 20 hormone naive trans men and a cross-sectional study in 50 trans men with an average of 10 years on T therapy. MAIN OUTCOME MEASURES: Acne lesions were assessed using the Gradual Acne Grading Scale, hair patterns using the Ferriman and Gallwey classification (F&G), and androgenetic alopecia using the Norwood Hamilton Scale. RESULTS: T treatment increased facial and body hair growth. The F&G score increased progressively from a median value of 0.5 at baseline to a value of 12 after 12 months of T administration. After long-term T treatment, all but one trans man achieved an F&G score indicative of hirsutism in women, with a median value of 24. Only one trans man acquired mild frontotemporal hair loss during the first year of T treatment, whereas 32.7% of trans men had mild frontotemporal hair loss and 31% had moderate to severe androgenetic alopecia after long-term T therapy. The presence and severity of acne increased during the first year of T therapy, and peaked at 6 months. After long-term T treatment, most participants had no or mild acne lesions (93.9%). Dermatological outcome was not demonstrably related to individual serum T or dihydrotestosterone levels. CONCLUSIONS: T treatment increased facial and body hair in a time dependent manner. The prevalence and severity of acne in the majority of trans men peaked 6 months after beginning T therapy. Severe skin problems were absent after short- and long-term T treatment. PMID- 24344811 TI - Therapeutic effects of hybrid liposomes without drugs for rheumatoid arthritis. AB - Hybrid liposomes (HLs) can be prepared by simply sonicating a mixture of vesicular and micellar molecules in buffer solutions. This study aims to demonstrate inhibitory effects of HLs on the growth of fibroblast-like synoviocytes along with apoptosis and therapeutic effects of HLs in a mouse model with rheumatoid arthritis (RA). HLs composed of 95 mol% L-alpha dimyristoylphosphatidylcholine (DMPC) and 5 mol% polyoxyethylene(23)dodecyl ether (C12(EO)23) were prepared by the sonication method. The inhibitory effects of HLs on the growth of human fibroblast-like synoviocytes-RA (HFLS-RA) cells in vitro and their inhibitory mechanism were examined. High inhibitory effects of HLs on the growth of HFLS-RA cells were observed. The induction of apoptosis by HLs was revealed on the basis of flow cytometric analysis. Furthermore, therapeutic effects of HLs in the mouse model with RA were examined in vivo. Our results demonstrate that HLs showed inhibitory effects on the growth of HFLS-RA cells in vitro along with apoptosis and therapeutic effects in mouse models of RA in vivo. PMID- 24344812 TI - Determinants of asthma control among children in Saudi Arabia. AB - OBJECTIVE: Asthma is the most common chronic disease among children. Uncontrolled asthma may considerably decrease the quality of life for patients and their families. Our objective was to identify possible risk factors for poor asthma control in children. METHODS: A cross-sectional study was conducted among children with asthma aged 4-11 years who attended a pediatric clinic for follow up visits at one of the major teaching hospitals in Riyadh, Saudi Arabia. Asthma control status was measured by the childhood asthma control test. Multiple logistic regression analysis was performed to explore the relationships between the outcome and exposure variables. RESULTS: Uncontrolled asthma was present in 89 out of 158 children (59.3%). Asthma control improved with the number of siblings. Control improved by 69% with two or three siblings (OR = 0.31, 95% CI = 0.10-0.96) and by 87% with four or more siblings (OR = 0.13, 95% CI = 0.04-0.48). Similarly, asthma control improved with an increased asthma knowledge of the caregiver (OR = 0.87, 95% CI = 0.81-0.93). Household incomes less than SAR 15 000 and sharing a bedroom increased the odds of having uncontrolled asthma by 2.30 (95% CI = 1.02-5.21) and 3.33 (95% CI = 1.33-8.35), respectively. CONCLUSIONS: In addition to knowledge, socioeconomic factors, such as family income, household crowding, and the number of siblings are associated with asthma control among children in Saudi Arabia. Further research is needed to investigate the role of these factors. PMID- 24344813 TI - Pre-hospital delay in patients with diabetic foot problems: influencing factors and subsequent quality of care. AB - AIMS: To assess pre-hospital patient delay and its associated variables in patients with diabetic foot problems. METHODS: We classified 270 patients with diabetic foot problems retrospectively based on the distribution of pre-hospital delay. Clinical, demographic and socio-economic data were collected. Logistic regression analysis was performed to examine independent associations with patient delay. RESULTS: The median pre-hospital delay time was 46.49 days. Patients reported short (<= 1 week; 77 patients, 28.5%), moderate (> 1 week and <= 1 month; 106 patients, 39.3%) and long delays (> 1 month; 87 patients, 32.2%). In a univariate analysis, nine variables were associated with a longer delay (P < 0.05): (1) no previous ulcer; (2) no health insurance; (3) poor housing conditions; (4) low income level; (5) low educational level; (6) infrequent foot inspection; (7) few follow-up medical visits; (8) absence of diabetic foot education; (9) lack of knowledge of foot lesion warning signals. A multivariate analysis showed that absence of diabetic foot education (odds ratio 2.70, 95% CI 1.03-7.06, P = 0.043) and lack of knowledge of foot lesion warning signals (odds ratio 2.14, 95% CI 1.16-3.94, P = 0.015) were independent predictors of long patient delay. Long delay increased the risk of amputation (odds ratio 2.22, 95% CI 1.36-3.64, P = 0.002) and mortality (odds ratio 2.69, 95% CI 1.35-5.33, P = 0.005). CONCLUSIONS: A number of factors were involved in pre-hospital delay among patients with diabetic foot problems and contributed to poor outcomes. We recommend developing a community intervention programme that targets at-risk communities to encourage earlier multidisciplinary team assessment to reduce disparities and improve foot outcomes in patients with diabetes. PMID- 24344814 TI - An evidence-based medicine approach to small animal anaesthetic mortality in a referral practice: the influence of initiating three recommendations on subsequent anaesthetic deaths. AB - OBJECTIVE: To evaluate anaesthetic death after implementation of recommendations and its risk factors in a small animal practice. STUDY DESIGN: Observational cohort study. ANIMALS: All cats and dogs anaesthetized at the Centre Hospitalier Veterinaire des Cordeliers during two periods, from April 15th, 2008 to April 15th, 2010 (period 1) and from June 15th, 2010 to August 24th, 2011 (period 2). METHODS: Death occurring during or before full recovery from anaesthesia was recorded. At the end of period 1, a logistic regression model was generated to describe anaesthetic death and identify risk factors. Potential risk factors in our practice setting were identified, and three recommendations, relating to improving physical status and anaesthetic/analgesic regimen implemented for period 2. The relationship between anaesthetic death and recorded variables were analyzed, and where relevant, compared between periods. RESULTS: Six thousand two hundred and thirty-one animals underwent general anaesthesia. The overall death rate during period 1 was 1.35% (48 in 3546, 95% CI [1.0-1.7%]) and during period 2 was 0.8% (21 in 2685, 95% CI [0.6-1.2%]). For sick animals (ASA status 3 and over), the overall death rate was 4.8% (45 of 944 95% [CI 3.5-6.4%]) during period 1 and 2.2% (18 of 834 95% CI [1.3-3.5%]) during period 2; this represented a significant decrease in death rate in period 2 (p = 0.002). In period 2, the main factors associated with an increased odds ratio of anaesthetic death were poor health status (ASA physical status classification) and old age. Species, gender, anaesthetic regimen, the nature and urgency of the procedure were not associated with risk. CONCLUSION AND CLINICAL RELEVANCE: Following evidence based recommendations, the death rate related to anaesthesia was significantly decreased during period 2 compared to period 1. Application of evidence-based medicine may contribute to an effective approach to decrease death rates. Other factors, not monitored in this study, may also have had an impact. PMID- 24344815 TI - Phonological generalizations in dyslexia: the phonological grammar may not be impaired. AB - Dyslexia is commonly attributed to a phonological deficit, but whether it effectively compromises the phonological grammar or lower level systems is rarely explored. To address this question, we gauge the sensitivity of dyslexics to grammatical phonological restrictions on spoken onset clusters (e.g., bl in block). Across languages, certain onsets are preferred to others (e.g., blif ? bnif ? bdif, where ? indicates a preference). Here, we show that dyslexic participants (adult native speakers of Hebrew) are fully sensitive to these phonological restrictions, and they extend them irrespective of whether the onsets are attested in their language (e.g., bnif vs. bdif) or unattested (e.g., mlif vs. mdif). Dyslexics, however, showed reduced sensitivity to phonetic contrasts (e.g., blif vs. belif; ba vs. pa). Together, these results suggest that the known difficulties of dyslexics in speech processing could emanate not from the phonological grammar, but rather from lower level impairments to acoustic/phonetic encoding, lexical storage, and retrieval. PMID- 24344816 TI - Amusic does not mean unmusical: beat perception and synchronization ability despite pitch deafness. AB - Pitch deafness, the most commonly known form of congenital amusia, refers to a severe deficit in musical pitch processing (i.e., melody discrimination and recognition) that can leave time processing--including rhythm, metre, and "feeling the beat"--preserved. In Experiment 1, we show that by presenting musical excerpts in nonpitched drum timbres, rather than pitched piano tones, amusics show normal metre recognition. Experiment 2 reveals that body movement influences amusics' interpretation of the beat of an ambiguous drum rhythm. Experiment 3 and a subsequent exploratory study show an ability to synchronize movement to the beat of popular dance music and potential for improvement when given a modest amount of practice. Together the present results are consistent with the idea that rhythm and beat processing are spared in pitch deafness--that is, being pitch-deaf does not mean one is beat-deaf. In the context of drum music especially, amusics can be musical. PMID- 24344817 TI - Atypical signed language development: a case study of challenges with visual spatial processing. AB - In signed languages, the articulatory space in front of the signer is used grammatically, topographically, and to depict a real or imagined space around a signer and thus is an important consideration in signed language acquisition. It has been suggested that children who acquire signed languages rely on concomitant visual-spatial development to support their linguistic development. We consider the case of a native-signing deaf adolescent female with average intelligence who had been reported to struggle with spatial aspects of American Sign Language (ASL) as a child. Results of a battery of linguistic and nonlinguistic tests suggest that she has relatively good ASL skills with the exception of some specific difficulties on spatial tasks that require attention to ASL and nonlinguistic topographic space or changes in visual perspective (e.g., classifiers and referential shift). This child has some difficulties with visual spatial abilities, and we suggest that this has affected her acquisition of those aspects of ASL that are heavily dependent on visual-spatial processing. PMID- 24344818 TI - Expanding federal funding to community health centers slows decline in access for low-income adults. AB - OBJECTIVE: To identify the impact of the Health Center Growth Initiative on access to care for low-income adults. DATA SOURCES: Data on federal funding for health centers are from the Bureau of Primary Health Care's Uniform Data System (2000-2007), and individual-level measures of access and use are derived from the National Health Interview Survey (2001-2008). STUDY DESIGN: We estimate person level models of access and use as a function of individual- and market-level characteristics. By using market-level fixed effects, we identify the effects of health center funding on access using changes within markets over time. We explore effects on low-income adults and further examine how those effects vary by insurance coverage. DATA COLLECTION: We calculate health center funding per poor person in a health care market and attach this information to individual observations on the National Health Interview Survey. Health care markets are defined as hospital referral regions. PRINCIPAL FINDINGS: Low-income adults in markets with larger funding increases were more likely to have an office visit and to have a general doctor visit. These results were stronger for uninsured and publicly insured adults. CONCLUSIONS: Expansions in federal health center funding had some mitigating effects on the access declines that were generally experienced by low-income adults over this time period. PMID- 24344819 TI - Yersinia Ysc-Yop type III secretion feedback inhibition is relieved through YscV dependent recognition and secretion of LcrQ. AB - Human pathogenic Yersinia species share a virulence plasmid encoding the Ysc-Yop type III secretion system (T3SS). A plasmid-encoded anti-activator, LcrQ, negatively regulates the expression of this secretion system. Under inducible conditions, LcrQ is secreted outside of bacterial cells and this activates the T3SS, but the mechanism of targeting LcrQ for type III secretion remains largely unknown. In this study, we characterized the regulatory role of the export apparatus component YscV. Depletion or overexpression of YscV compromised Yop synthesis and this primarily prevented secretion of LcrQ. It followed that a lcrQ deletion reversed the repressive effects of excessive YscV. Further characterization demonstrated that the YscV residues 493-511 located within the C terminal soluble cytoplasmic domain directly bound with LcrQ. Critically, YscV LcrQ complex formation was a requirement for LcrQ secretion, since YscVDelta493 511 failed to secrete LcrQ. This forced a cytoplasmic accumulation of LcrQ, which predictably caused the feedback inhibition of Yops synthesis. Based on these observations, we proposed a model for the YscV-dependent secretion of LcrQ and its role in regulating Yop synthesis in Yersinia. PMID- 24344820 TI - Identification of trans-golgi network proteins in Arabidopsis thaliana root tissue. AB - Knowledge of protein subcellular localization assists in the elucidation of protein function and understanding of different biological mechanisms that occur at discrete subcellular niches. Organelle-centric proteomics enables localization of thousands of proteins simultaneously. Although such techniques have successfully allowed organelle protein catalogues to be achieved, they rely on the purification or significant enrichment of the organelle of interest, which is not achievable for many organelles. Incomplete separation of organelles leads to false discoveries, with erroneous assignments. Proteomics methods that measure the distribution patterns of specific organelle markers along density gradients are able to assign proteins of unknown localization based on comigration with known organelle markers, without the need for organelle purification. These methods are greatly enhanced when coupled to sophisticated computational tools. Here we apply and compare multiple approaches to establish a high-confidence data set of Arabidopsis root tissue trans-Golgi network (TGN) proteins. The method employed involves immunoisolations of the TGN, coupled to probability-based organelle proteomics techniques. Specifically, the technique known as LOPIT (localization of organelle protein by isotope tagging), couples density centrifugation with quantitative mass-spectometry-based proteomics using isobaric labeling and targeted methods with semisupervised machine learning methods. We demonstrate that while the immunoisolation method gives rise to a significant data set, the approach is unable to distinguish cargo proteins and persistent contaminants from full-time residents of the TGN. The LOPIT approach, however, returns information about many subcellular niches simultaneously and the steady state location of proteins. Importantly, therefore, it is able to dissect proteins present in more than one organelle and cargo proteins en route to other cellular destinations from proteins whose steady-state location favors the TGN. Using this approach, we present a robust list of Arabidopsis TGN proteins. PMID- 24344821 TI - Executive functions, social information processing, and social adjustment in young children born with very low birth weight. AB - Children born with very low birth weight (VLBW) are at risk for neurocognitive and behavioral sequelae. Although VLBW infants are at higher risk for deficits in executive functions (EFs) and social functioning during school-age years, few studies have investigated those sequelae or their association in young children born VLBW. We examined the associations between EFs and social functioning in preterm, VLBW children age 4-6 years (n = 20) and matched, term-born, normal birth weight controls admitted to the neonatal intensive care unit (NICU) after birth (n = 18). The groups did not differ significantly on measures of EFs, social information processing, or parent-reported social adjustment. The VLBW group had lower IQs than controls, though both group means were in the average range. Within the VLBW group, medical predictors of better EFs included older gestational age at birth and no history of bronchopulmonary dysplasia. Across groups, EFs and social information processing were positively correlated. Deficits in EFs and social functioning may emerge after the preschool years in VLBW children, or improved care of children born VLBW may be reducing the cognitive and psychosocial sequelae observed in earlier cohorts. Among children born VLBW, early EFs may be directly related to social information processing. PMID- 24344822 TI - Helping mothers survive bleeding after birth: an evaluation of simulation-based training in a low-resource setting. AB - OBJECTIVE: To evaluate "Helping Mothers Survive Bleeding After Birth" (HMS BAB) simulation-based training in a low-resource setting. DESIGN: Educational intervention study. SETTING: Rural referral hospital in Northern Tanzania. POPULATION: Clinicians, nurse-midwives, medical attendants, and ambulance drivers involved in maternity care. METHODS: In March 2012, health care workers were trained in HMS BAB, a half-day simulation-based training, using a train-the trainer model. The training focused on basic delivery care, active management of third stage of labor, and treatment of postpartum hemorrhage, including bimanual uterine compression. MAIN OUTCOME MEASURES: Evaluation questionnaires provided information on course perception. Knowledge, skills, and confidence of facilitators and learners were tested before and after training. RESULTS: Four master trainers trained eight local facilitators, who subsequently trained 89 learners. After training, all facilitators passed the knowledge test, but pass rates for the skills test were low (29% pass rate for basic delivery and 0% pass rate for management of postpartum hemorrhage). Evaluation revealed that HMS BAB training was considered acceptable and feasible, although more time should be allocated for training, and teaching materials should be translated into the local language. Knowledge, skills, and confidence of learners increased significantly immediately after training. However, overall pass rates for skills tests of learners after training were low (3% pass rate for basic delivery and management of postpartum hemorrhage). CONCLUSIONS: The HMS BAB simulation-based training has potential to contribute to education of health care providers. We recommend a full day of training and validation of the facilitators to improve the training. PMID- 24344827 TI - Reactions of lanthanide atoms with oxygen difluoride and the role of the Ln oxidation state. AB - Laser-ablated lanthanide metal atoms were condensed with OF2 in excess argon or neon at 4 K. New infrared absorption bands were observed and assigned to the oxidative addition products OLnF2 and OLnF on the basis of (18)O isotopic substitution and electronic structure calculations of the vibrational frequencies. The dominant absorptions in the 500 cm(-1) region are identified as Ln-F stretching modes, which follow the lanthanide contraction. The Ln-O stretching frequency is an important measure of the oxidation states of the Ln and oxygen and the spin state of the complex. The OCeF2, OPrF2, and OTbF2 molecules have higher frequency Ln-O stretching modes. The Ce is assigned to the IV oxidation state and the Pr and Tb are assigned to a mixed III/IV oxidation state. The remaining OLnF2 compounds have lower Ln-O stretches, and the Ln is in the III oxidation state and the O is in the -1 oxidation state. For all of the OLnF compounds, the metal is in the III oxidation state, and the Ln-F bonds are ionic. In OCeF2, OLaF, and OLuF, the bonding between the Ln and O is best described as a highly polarized sigma bond and two pseudo pi bonds formed by donation from the two 2p lone pairs on the O to the Ln. Bonding for the OLnF2 compounds in the III oxidation state is predicted to be fully ionic. The bonding in OLnF2 and OLnF is dominated by the oxidation state on the lanthanide and the spin state of the molecule. The observation of larger neon to argon matrix shifts for Ln-O modes in several OLnF molecules as compared to their OLnF2 analogues is indicative of more ionic character in the OLnF species, consistent with the more formal negative charge on the oxygen in OLnF. PMID- 24344828 TI - Synthesis of near-infrared quantum dots in cultured cancer cells. AB - Intracellular synthesis of near-infrared fluorescent silver sulfide quantum dots in HepG2 cancer cells is demonstrated. By delivering quantum dot precursors into cultured hepatoma carcinoma cells (HepG2 cells), silver sulfide quantum dots with emission efficiency qualified for in vivo imaging were successfully synthesized with the aid of endogenous glutathione in the cells. PMID- 24344829 TI - Eosinophilic myocarditis: two case reports and review of the literature. AB - BACKGROUND: Eosinophilic myocarditis is a rare and often under-diagnosed subtype of myocarditis with only around 30 cases published in the medical literature. In this article we present two patients with eosinophilic myocarditis with the aim to demonstrate the often elusive nature of the disease and present the current scientific literature on this topic. CASE PRESENTATION: A 76 years old Caucasian gentleman and a 36 years old Aboriginal gentleman both presenting with heart failure symptoms were eventually diagnosed with eosinophilic myocarditis after extensive evaluation. Their presentation, assessment, and medical management is explored in this article. CONCLUSIONS: Eosinophilic myocarditis remains a rare and likely under-diagnosed subtype of myocarditis. The key features of this disease include myocardial injury in the setting of non-contributory coronary artery disease. Endomyocardial biopsy remains the definitive gold standard for diagnosis of noninfectious eosinophilic myocarditis. Non-invasive cardiac imaging in the setting of peripheral eosinophilia can be strongly suggestive of eosinophilic myocarditis with potential for earlier diagnosis. Failure to diagnose eosinophilic myocarditis and the delay of therapy may lead to irreversible myocardial injury. Therapies for this disease have yet to be validated in large prospective studies. PMID- 24344830 TI - A genome wide study of genetic adaptation to high altitude in feral Andean Horses of the paramo. AB - BACKGROUND: Life at high altitude results in physiological and metabolic challenges that put strong evolutionary pressure on performance due to oxidative stress, UV radiation and other factors dependent on the natural history of the species. To look for genes involved in altitude adaptation in a large herbivore, this study explored genome differentiation between a feral population of Andean horses introduced by the Spanish in the 1500s to the high Andes and their Iberian breed relatives. RESULTS: Using allelic genetic models and Fst analyses of ~50 K single nucleotide polymorphisms (SNPs) across the horse genome, 131 candidate genes for altitude adaptation were revealed (Bonferoni of p <= 2 * 10(-7)). Significant signals included the EPAS1 in the hypoxia-induction-pathway (HIF) that was previously discovered in human studies (p = 9.27 * 10(-8)); validating the approach and emphasizing the importance of this gene to hypoxia adaptation. Strong signals in the cytochrome P450 3A gene family (p = 1.5 *10(-8)) indicate that other factors, such as highly endemic vegetation in altitude environments are also important in adaptation. Signals in tenuerin 2 (TENM2, p = 7.9 * 10( 14)) along with several other genes in the nervous system (gene categories representation p = 5.1 * 10(-5)) indicate the nervous system is important in altitude adaptation. CONCLUSIONS: In this study of a large introduced herbivore, it becomes apparent that some gene pathways, such as the HIF pathway are universally important for high altitude adaptation in mammals, but several others may be selected upon based on the natural history of a species and the unique ecology of the altitude environment. PMID- 24344831 TI - A preliminary analysis of the effect of the new rural cooperative medical scheme on inpatient care at a county hospital. AB - BACKGROUND: China in 2009 committed to reach universal health coverage by promoting three forms of health insurance; NCMS for the rural population, UEBMI for formally employed urban residents and URBMI for other urban residents. NCMS has expanded to near universal coverage in rural China since launching in 2003. The objective of this study aimed to assess the effect of NCMS on inpatient care utilization from 2003 to 2012 at Longyou county hospital, Zhejiang province. METHODS: The research was conducted at Longyou county, Zhejiang province. All registered inpatient admissions from January 1, 2003, to June 30, 2012, were included in the study. The PLSQL Developer software was used to select the interesting variables in the hospital information database and saved in an Excel 2003 file. The interesting variables included the patients' general information (name, gender, age, payment method), discharge diagnosis, length of hospital stay, and expenditure (total expenditure and out-of-pocket payment). Two common diseases (coronary arteriosclerotic disease and pneumonia) were selected as tracer conditions. RESULTS: 292,400 rural residents were enrolled in the Longyou county NCMS by 2011, 95.4% of the eligible population. A total of 145,744 inpatient admissions were registered from 1 January 2003 to 30 June 2012. The proportion of inpatients covered by NCMS increased from 30.3% in 2004 to 54.2% in 2012 while the proportion of inpatients covered by UEBMI increased from 7.7% in 2003 to 14.7% in 2012. The average expenditure for UEBMI insured inpatients was higher than the average for NCMS insured inpatients, although the gap was narrowing. The average length of hospital stay increased every year for all inpatients, but was higher for UEBMI inpatients than for NCMS insured inpatients. For both tracer conditions the results were similar to the above findings. CONCLUSIONS: NCMS has improved coverage height for its enrollees and resulted in increased cost of care per inpatient admission at the county hospital. However, wide differences persist between the two insurance systems in coverage height. Both systems are associated with increasing lengths of stay and rising cost per inpatient admission. We found that around 30% of inpatients were not covered by any of the two public health insurance systems, which calls for further studies. PMID- 24344832 TI - Gastrointestinal involvement in patients affected with 22q11.2 deletion syndrome. AB - OBJECTIVE. Enteropathy is a very common feature in patients with primary immunodeficiencies. In patients with Del22 gastrointestinal (GI) alterations, including feeding disorders and congenital abnormalities have been often reported, mostly in the first year of life. MATERIAL AND METHODS. Aim of this monocentric study is to better define the GI involvement in a cohort of 26 patients affected with Del22 syndrome. Anamnestic information was retrospectively collected for each patient. Weight and height parameters at the time of the screening were recorded. Plasma levels of hemoglobin, iron, ferritin, albumin, total protein, calcium, phosphorus, transaminase levels, antigliadin (AGA) IgA and IgG, and antitissue transglutaminase (anti-TGase) titers were measured. RESULTS. A GI involvement was identified in the 58% of patients. The prominent problems were abdominal pain, vomiting, gastroesophageal reflux and chronic constipation. Weight deficiency, short stature and failure to thrive were reported in 54, 42, and 30% of the patients, respectively. The evidence of sideropenic anemia, in keeping with hypoproteinemia, impaired acid steatocrit or cellobiose/mannitol test suggested an abnormal intestinal permeability. In this cohort, a high prevalence of AGA IgA and IgG positivity was observed. Celiac disease (CD) was suspected in three patients, and in one of them confirmed by histology. In this patient, a long-lasting gluten-free diet failed to restore the intestinal architecture. CONCLUSIONS. In conclusion, GI involvement is a very common feature in Del22 patients. A better characterization of GI involvement would be very useful to improve the management of these patients. PMID- 24344833 TI - Acute kidney injury induced by aristolochic acid in patients with primary glomerular nephritis. AB - BACKGROUND: Acute kidney injury induced by aristolochic acid (AA) might occur in patients with chronic glomerular nephritis (CGN). In this study, the clinical and pathological features of patients with acute aristolochic acid nephropathy (AAN) superimposing CGN (AAN-CGN) were investigated. METHODS: Eighteen patients diagnosed as acute AAN were included in this retrospective study, from January 2001 to December 2009. According to the pre-existing CGN, 13 patients were identified as the AAN-CGN group, and 5 isolated AAN patients as the control group. Clinical and pathological features were compared between the two groups. RESULTS: In the AAN-CGN group, six patients complained with gastrointestinal symptoms, such as nausea, vomiting, or loss of appetite. The rest of seven cases were asymptomatic or minimally uncomfortable, who were found with elevated serum creatinine (Scr) in the follow up of CGN. Compared with the control group, the patients in AAN-CGN group had higher levels of serum uric acid, urine n-acetyl beta-d-glucosaminidase, and urine protein excretion (366.2 +/- 122.8 vs. 218.0 +/ 125.8 MUmol/L, p = 0.037; 9.74 +/- 4.4 vs. 1.38 +/- 1.01 g/d, p = 0.001; 61.2 +/ 21.9 vs. 27.4 +/- 15.8 MU/g c cr, p = 0.007, respectively). In addition to, the AAN-CGN patients had an absolutely prominent percentage of macromolecule substance in the urine protein electrophoresis (25.0 +/- 6.32 vs. 15.8 +/- 7.8%, p = 0.029). The occurrence of hypokalemia and excretion of aminoaciduria were lower than that in the control group. Pathologically, 84.6% of patients were found with tubular brush border dropping, 30.8% with naked tubular basement membrane, and 15.4% with different stages of vascular lesion. There were no statistical differences in the above-mentioned pathological parameters between the two groups. In the follow-up, 10 patients with AAN-CGN recovered with normal Scr, accounting for 76.9%, which was better than the recovery in the control group. CONCLUSION: Patients with acute AAN-CGN manifested with a great mass of urine protein excretion, low incidence of hypokalemia and aminoaciduria, however, the tubular-interstitial lesions were similar to the isolated AAN. PMID- 24344834 TI - General motor function assessment scale--reliability of a Norwegian version. AB - PURPOSE: The General Motor Function assessment scale (GMF) measures activity related dependence, pain and insecurity among older people in frail health. The aim of the present study was to translate the GMF into a Norwegian version (N GMF) and establish its reliability and clinical feasibility. METHODS: The procedure used in translating the GMF was a forward and backward process, testing a convenience sample of 30 frail elderly people with it. The intra-rater reliability tests were performed by three physiotherapists, and the inter reliability test was done by the same three plus nine independent colleagues. The statistical analyses were performed with a pairwise analysis for intra- and inter rater reliability, using Cronbach's alpha, Percentage Agreement (PA), Svensson's rank transformable method and Cohen's kappa. RESULTS: The Cronbach's alpha coefficients for the different subscales of N-GMF were 0.68 for Dependency, 0.73 for Pain and 0.75 for Insecurity. Intra-rater reliability: The variation in the PA for the total score was 40-70% in Dependence, 30-40% in Pain and 30-60% in Insecurity. The Relative Rank Variant (RV) indicated a modest individual bias and an augmented rank-order agreement coefficient ra of 0.96, 0.96 and 0.99, respectively. The variation in the kappa statistics was 0.27-0.62 for Dependence, 0.17-0.35 for Pain and 0.13-0.47 for Insecurity. Inter-rater reliability: The PA between different testers in Dependence, Pain and Insecurity was 74%, 89% and 74%, respectively. The augmented rank-order agreement coefficients were: for Dependence r(a) = 0.97; for Pain, r(a) = 0.99; and for Insecurity, r(a) = 0.99. CONCLUSION: The N-GMF is a fairly reliable instrument for use with frail elderly people, with intra-rater and inter-rater reliability moderate in Dependence and slight to fair in Pain and Insecurity. The clinical usefulness was stressed in regard to its main focus, the frail elderly, and for communication within a multidisciplinary team. Implications for Rehabilitation The Norwegian-General Motor Function Assessment Scale (N-GMF) is a reliable instrument. The N-GMF is an instrument for screening and assessment of activity-related dependence, pain and insecurity in frail older people. The N-GMF may be used as a tool of communication in a multidisciplinary team. PMID- 24344835 TI - Morphometry of the pelvic floor muscles in women with and without provoked vestibulodynia using 4D ultrasound. AB - INTRODUCTION: It has been suggested that pelvic floor muscles (PFMs) play an important role in provoked vestibulodynia (PVD) pathophysiology. Controversy in determining their exact contribution may be explained by methodological limitations related to the PFM assessment tools, specifically the pain elicited by the measurement itself, which may trigger a PFM reaction and introduce a strong bias. AIM: The aim of this study was to compare PFM morphometry in women suffering from PVD to asymptomatic healthy control women using a pain-free methodology, transperineal four-dimensional (4D) ultrasound. METHODS: Fifty-one asymptomatic women and 49 women suffering from PVD were recruited. Diagnosis of PVD was confirmed by a gynecologist following a standardized examination. All the participants were nulliparous and had no other urogynecological conditions. The women were evaluated in a supine position at rest and during PFM maximal contraction. MAIN OUTCOME MEASURES: Transperineal 4D ultrasound, which consists of a probe applied on the surface of the perineum without any vaginal insertion, was used to assess PFM morphometry. Different parameters were assessed in sagittal and axial planes: anorectal angle, levator plate angle, displacement of the bladder neck, and levator hiatus area. The investigator analyzing the data was blinded to the clinical data. RESULTS: Women with PVD showed a significantly smaller levator hiatus area, a smaller anorectal angle, and a larger levator plate angle at rest compared with asymptomatic women, suggesting an increase in PFM tone. During PFM maximal contraction, smaller changes in levator hiatus area narrowing, displacement of the bladder neck, and changes of the anorectal and of the levator plate angles were found in women with PVD compared with controls, which may indicate poorer PFM strength and control. CONCLUSION: Using a reliable and pain-free methodology, this research provides sound evidence that women with PVD display differences in PFM morphometry suggesting increased tone and reduced strength. PMID- 24344837 TI - Neonatal Molluscum contagiosum: five new cases and a literature review. AB - Congenital or neonatal Molluscum contagiosum (MC) is an unusual infection, barely reported in the literature. In these patients a mechanism of transmission that is neither via contact or sexual transmission should be considered. We describe five cases of neonatal MC and review the cases already published to discuss the possible aetiopathogenic mechanism. PMID- 24344836 TI - Cellular and temporal expression of NADPH oxidase (NOX) isotypes after brain injury. AB - BACKGROUND: Brain injury results in an increase in the activity of the reactive oxygen species generating NADPH oxidase (NOX) enzymes. Preliminary studies have shown that NOX2, NOX3, and NOX4 are the most prominently expressed NOX isotypes in the brain. However, the cellular and temporal expression profile of these isotypes in the injured and non-injured brain is currently unclear. METHODS: Double immunofluorescence for NOX isotypes and brain cell types was performed at acute (24 hours), sub-acute (7 days), and chronic (28 days) time points after controlled cortical impact-induced brain injury or sham-injury in rats. RESULTS: NOX2, NOX3, and NOX4 isotypes were found to be expressed in neurons, astrocytes, and microglia, and this expression was dependent on both cellular source and post injury time. NOX4 was found in all cell types assessed, while NOX3 was positively identified in neurons only, and NOX2 was identified in microglia and neurons. NOX2 was the most responsive to injury, increasing primarily in microglia in response to injury. Quantitation of this isotype showed a significant increase in NOX2 expression at 24 hours, with reduced expression at 7 days and 28 days post injury, although expression remained above sham levels at later time points. Cellular confirmation using purified primary or cell line culture demonstrated similar patterns in microglia, astrocytes, and neurons. Further, inhibition of NOX, and more specifically NOX2, reduced pro-inflammatory activity in microglia, demonstrating that NOX is not only up-regulated after stimulation, but may also play a significant role in post-injury neuroinflammation. CONCLUSIONS: This study illustrates the expression profiles of NOX isotypes in the brain after injury, and demonstrates that NOX2, and to a lesser extent, NOX4, may be responsible for the majority of oxidative stress observed acutely after traumatic brain injury. These data may provide insight into the design of future therapeutic approaches. PMID- 24344838 TI - Water footprint: pitfalls on common ground. PMID- 24344839 TI - Callous-Unemotional traits in youth from a DSM-5 trait perspective. AB - The current study investigated how the Callous-Unemotional (CU) trait specifier is empirically associated with the proposed trait system for personality pathology in DSM-5, and addressed the use of multiple raters in the assessment of CU traits and additional maladaptive traits in an adolescent community sample. Both mothers and adolescents (N = 197) participated in the present study. Results showed that CU traits are located in different parts of the personality space, and are significantly associated with four broad maladaptive trait dimensions, Negative Affect, Detachment, Antagonism, and Disinhibition. Despite moderate agreement between raters, self- and maternal-rated CU traits were related in a congruent manner with PID-5 traits, and adolescents provided incremental information in CU trait assessment above maternal ratings. The present results have clear implications for the conceptualization of CU traits within the overarching model of personality pathology, proposed in DSM-5, and partially supported the application of a multi-informant approach in CU trait assessment. PMID- 24344840 TI - Association between genetic polymorphisms in the serotonergic system and comorbid personality disorders among patients with first-episode depression. AB - Studies on the association between genetic polymorphisms and personality disorders have provided inconsistent results. Using the "enriched sample method," the authors of the present study aimed to assess the association between polymorphisms in the serotonergic transmitter system and comorbid personality disorders in patients recently diagnosed with first-episode depression. A total of 290 participants were systematically recruited via the Danish Psychiatric Central Research Register. Diagnoses of personality disorders were assessed by a SCID-II interview, and polymorphisms in the genes encoding the serotonin transporter, serotonin receptors 1A, 2A, 2C, and tryptophan hydroxylase 1 were genotyped. The authors found a significant effect of the length polymorphism in the serotonin transporter gene (5-HTTLPR) on cluster B personality disorder (mainly borderline disorder), but no influence on cluster C personality disorder, and no associations between other polymorphisms and personality disorders. The study adds evidence to the effect of the serotonin transporter gene specifically on cluster B personality disorders. PMID- 24344841 TI - Agreeableness accounts for the factor structure of the youth psychopathic traits inventory. AB - The present study investigated the relationship between the Five-Factor Model (FFM) and the Youth Psychopathic Traits Inventory (YPI; Andershed, Ker, Stattin, & Levander, 2002) in an undergraduate sample. It was hypothesized that Agreeableness would saturate the lower- and higher-order scales of the YPI, and that taking Agreeableness into account would reduce the intercorrelations among the three factors of the YPI. These hypotheses were explored in a sample of 466 undergraduates who completed the YPI and the Revised NEO Personality Inventory (NEO-PI-R; Costa & McCrae, 1992). Results demonstrated that Agreeableness was the strongest, most consistent correlate of the lower-order scales and three higher order factors of the YPI. Additionally, analyses showed that Agreeableness accounted for large portions of the three YPI factors, as well as the overlap among factors, helping explain their intercorrelations. Current results underscore the centrality of Agreeableness to the assessment and understanding of psychopathy, particularly as measured by the YPI. PMID- 24344842 TI - An examination of the correlates of fearless dominance and self-centered impulsivity among high-frequency gamblers. AB - The Psychopathic Personality Inventory (PPI) is a commonly used assessment of psychopathy. Questions have been raised, however, regarding the validity of its Fearless Dominance (FD) factor. In the current study, the correlations manifested by FD and Self-centered Impulsivity (ScI) in relation to external criteria were examined in a sample of gamblers. Two key hypotheses were also tested: (a) does FD perform differently when paired with high scores on ScI, and (b) does FD serve as an index of narcissism. As expected, FD and ScI manifested a divergent pattern of correlations such that only ScI was associated with psychopathology or impairment. FD's relations with the external criteria were not generally moderated by scores on ScI. FD was significantly correlated with narcissism, but the two differed such that only narcissism was associated with any degree of maladaptivity. It remains unclear whether FD should be considered a core component of psychopathy. PMID- 24344843 TI - Discrete subgroups of adolescents diagnosed with borderline personality disorder: a latent class analysis of personality features. AB - Research suggests that borderline personality disorder (BPD) can be diagnosed in adolescents and is marked by considerable heterogeneity. This study aimed to identify personality features characterizing adolescents with BPD and possible meaningful patterns of heterogeneity that could lead to personality subgroups. The authors analyzed data on 60 adolescents, ages 15 to 18 years, who met DSM criteria for a BPD diagnosis. The authors used latent class analysis (LCA) to identify subgroups based on the personality pattern scales from the Millon Adolescent Clinical Inventory (MACI). LCA indicated that the best-fitting solution was a two-class model, identifying two discrete subgroups of BPD adolescents that were described as internalizing and externalizing. The subgroups were then compared on clinical and sociodemographic variables, measures of personality dimensions, DSM BPD criteria, and perception of attachment styles. Adolescents with a BPD diagnosis constitute a heterogeneous group and vary meaningfully on personality features that can have clinical implications for treatment. PMID- 24344845 TI - AVMA seeks to promote intraprofessional dialogue about animal welfare issues. PMID- 24344846 TI - 6-month vs 12-month heartworm prevention. PMID- 24344847 TI - What is your diagnosis? Perineal hernia. PMID- 24344848 TI - What is your diagnosis? Unilateral inflammatory polyp. PMID- 24344849 TI - Diagnostic imaging in veterinary dental practice. Odontogenic cysts. PMID- 24344850 TI - ECG of the Month. Hypoadrenocorticism. PMID- 24344851 TI - Animal behavior case of the month. Petting intolerance. PMID- 24344852 TI - Pathology in practice. Bovine cryptosporidiosis. PMID- 24344853 TI - Use of lidocaine-bupivacaine-infused absorbable gelatin hemostatic sponges versus lidocaine-bupivacaine retrobulbar injections for postoperative analgesia following eye enucleation in dogs. AB - OBJECTIVE: To compare use of lidocaine-bupivacaine-infused absorbable gelatin hemostatic sponges versus lidocaine-bupivacaine retrobulbar injections for postoperative analgesia in dogs following eye enucleation. DESIGN: Randomized case-control study. ANIMALS: 19 dogs that underwent eye enucleation. PROCEDURES: 19 client-owned dogs admitted to a referral hospital for routine eye enucleation were enrolled with owner consent and randomly assigned to receive an orbital absorbable gelatin hemostatic sponge infused with lidocaine and bupivacaine after globe removal (n = 8) or retrobulbar injection of lidocaine and bupivacaine before globe removal (11). Baseline pain scores were recorded on the basis of an ordinal pain scale. Anesthetic premedication consisted of hydromorphone, midazolam, and glycopyrrolate. Propofol was used for anesthetic induction and isoflurane for maintenance. A transpalpebral eye enucleation was performed by a board-certified ophthalmologist. Pain scores and heart rate were again recorded 15 and 30 minutes and 1, 2, 4, 6, 8, and 24 hours after extubation by trained observers masked to treatment groups. Dogs were given hydromorphone as rescue analgesia if the total pain score was >= 9 of 18 or any categorical pain score was >= 3 (on a scale from 0 to 3 or 0 to 4). RESULTS: There were significant differences over time for comfort level, response to touch, behavior, heart rate, and total pain score; however, there was no difference between treatment groups. One dog in the absorbable gelatin hemostatic sponge group required rescue hydromorphone 4 hours after surgery. CONCLUSIONS AND CLINICAL RELEVANCE: The absorbable gelatin hemostatic sponge proved to be as effective in providing local analgesia for eye enucleation in dogs as the retrobulbar injections. PMID- 24344854 TI - Refractometric total protein concentrations in icteric serum from dogs. AB - OBJECTIVE: To determine whether high serum bilirubin concentrations interfere with the measurement of serum total protein concentration by refractometry and to assess potential biases among refractometer measurements. DESIGN: Evaluation study. SAMPLE: Sera from 2 healthy Greyhounds. PROCEDURES: Bilirubin was dissolved in 0.1M NaOH, and the resulting solution was mixed with sera from 2 dogs from which food had been withheld to achieve various bilirubin concentrations up to 40 mg/dL. Refractometric total protein concentrations were estimated with 3 clinical refractometers. A biochemical analyzer was used to measure biuret assay-based total protein and bilirubin concentrations with spectrophotometric assays. RESULTS: No interference with refractometric measurement of total protein concentrations was detected with bilirubin concentrations up to 41.5 mg/dL. Biases in refractometric total protein concentrations were detected and were related to the conversion of refractive index values to total protein concentrations. CONCLUSIONS AND CLINICAL RELEVANCE: Hyperbilirubinemia did not interfere with the refractometric estimation of serum total protein concentration. The agreement among total protein concentrations estimated by 3 refractometers was dependent on the method of conversion of refractive index to total protein concentration and was independent of hyperbilirubinemia. PMID- 24344855 TI - Presumed primary and secondary hepatic copper accumulation in cats. AB - OBJECTIVE: To determine signalments, clinical features, clinicopathologic variables, imaging findings, treatments, and survival time of cats with presumed primary copper-associated hepatopathy (PCH) and to determine quantitative measures and histologic characteristics of the accumulation and distribution of copper in liver samples of cats with presumed PCH, extrahepatic bile duct obstruction, chronic nonsuppurative cholangitis-cholangiohepatitis, and miscellaneous other hepatobiliary disorders and liver samples of cats without hepatobiliary disease. DESIGN: Retrospective cross-sectional study. ANIMALS: 100 cats with hepatobiliary disease (PCH [n = 11], extrahepatic bile duct obstruction [14], cholangitis-cholangiohepatitis [37], and miscellaneous hepatobiliary disorders [38]) and 14 cats without hepatobiliary disease. PROCEDURES: From 1980 to 2013, cats with and without hepatobiliary disease confirmed by liver biopsy and measurement of hepatic copper concentrations were identified. Clinical, clinicopathologic, and imaging data were compared between cats with and without PCH. RESULTS: Cats with PCH were typically young (median age, 2.0 years); clinicopathologic and imaging characteristics were similar to those of cats with other liver disorders. Copper-specific staining patterns and quantification of copper in liver samples confirmed PCH (on the basis of detection of > 700 MUg/g of liver sample dry weight). Six cats with PCH underwent successful treatment with chelation (penicillamine; n = 5), antioxidants (5), low doses of elemental zinc (2), and feeding of hepatic support or high-protein, low-carbohydrate diets, and other hepatic support treatments. One cat that received penicillamine developed hemolytic anemia, which resolved after discontinuation of administration. Three cats with high hepatic copper concentrations developed hepatocellular neoplasia. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that copper accumulates in livers of cats as primary and secondary processes. Long-term management of cats with PCH was possible. PMID- 24344856 TI - Endovascular evaluation and treatment of intrahepatic portosystemic shunts in dogs: 100 cases (2001-2011). AB - OBJECTIVE: To evaluate short- and long-term outcome following endovascular treatment of intrahepatic portosystemic shunts in dogs. DESIGN: Retrospective case series. ANIMALS: 100 dogs. PROCEDURES: All patients had angiographic evaluation with or without endovascular shunt attenuation. The medical records were reviewed for pertinent data, complications, outcome, and survival time. RESULTS: 95 dogs with congenital intrahepatic portosystemic shunts received 111 procedures (83% [79/95] had 1 treatment, and 17% [16/95] had > 1 treatment; 5 dogs had no treatment because of excessive portal venous pressure-central venous pressure gradients). Angiography identified 38 right, 33 left, and 19 central divisional single shunts (n = 90) and 10 complex or multiple shunts. Partial shunt attenuation was performed in 92 dogs by means of caval stent placement and insertion of thrombogenic coils within the shunt, and 3 had complete acute shunt occlusion. Major intraoperative complications (3/111 [3%]) included temporary severe portal hypertension in 2 dogs and gastrointestinal hemorrhage in 1 dog. Major postoperative (< 1 week after surgery) complications (14/111 [13%]) included seizures or hepatoencephalopathy (7/111 [6%]), cardiac arrest (2/111 [2%]), jugular site bleeding (2/111 [2%]), pneumonia (1/111 [1%]), suspected portal hypertension (1/111 [1%]), and acute death (1/111 [1%]). Median follow-up time was 958 days (range, 0 to 3,411 days). Median survival time for treated dogs was 2,204 days (range, 0 to 3,411 days). Outcome was considered excellent (57/86 [66%]) or fair (13/86 [15%]) in 70 of 86 (81%) treated dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that endovascular treatment of intrahepatic shunts in dogs may result in lower morbidity and mortality rates, with similar success rates, compared with previously reported outcomes for open surgical procedures. Gastrointestinal ulceration was a common finding among this population of dogs, and lifelong gastroprotectant medications are now recommended. PMID- 24344857 TI - Concentrated tea tree oil toxicosis in dogs and cats: 443 cases (2002-2012). AB - OBJECTIVE: To determine the frequency, types, and severity of clinical signs; geographic distribution; and treatment information associated with toxicosis caused by 100% tea tree oil (TTO) in dogs and cats in the United States and Canada. DESIGN: Retrospective case series. ANIMALS: 337 dogs and 106 cats with evidence of exposure to 100% TTO. PROCEDURES: 10-year incident data were retrieved from the ASPCA Animal Poison Control Center database from January 2002 to December 2012. Only evidenced or witnessed incidents assessed as toxicosis or suspected toxicosis were included. Signalment, amount of TTO used, intention of use, and outcome information were evaluated. Severity of illness and correlations with breed, sex, age, and weight were determined. RESULTS: TTO was intentionally used in 395 of 443 (89%) animals. The amount used ranged from 0.1 to 85 mL. Incidents were reported from 41 states, the District of Columbia, and 4 Canadian provinces. Exposure route was cutaneous in 221 (50%) animals, cutaneous and oral in 133 (30%), and oral in 67 (15%). Clinical signs developed within 2 to 12 hours and lasted up to 72 hours. The most common signs were increased salivation or drooling, signs of CNS depression or lethargy, paresis, ataxia, and tremors. A significant association with severity of illness was found for age and weight, with higher prevalence of major illness in younger and smaller cats. CONCLUSIONS AND CLINICAL RELEVANCE: Intentional or accidental use of 100% TTO in dogs or cats caused serious signs of CNS depression, paresis, ataxia, or tremors within hours after exposure and lasting up to 3 days. Younger cats and those with lighter body weight were at greater risk of developing major illness. PMID- 24344858 TI - Associations between infectious bovine keratoconjunctivitis at weaning and ultrasongraphically measured body composition traits in yearling cattle. AB - OBJECTIVE: To assess associations between infectious bovine keratoconjunctivitis (IBK) diagnosed at weaning and production traits in yearling beef calves. DESIGN: Retrospective population-based cohort study. ANIMALS: 1,882 Angus calves. PROCEDURES: Angus calves from 1 farm were evaluated over 7 years. The association between yearling body production traits and detection of IBK lesions at weaning was evaluated. RESULTS: Yearlings that had evidence of IBK at weaning had less 12th rib fat depth, ribeye area, and body weight than did cohorts without evidence of IBK. Average daily gain was greater in cattle that had IBK lesions at weaning, but this did not offset lower body weight at weaning. CONCLUSIONS AND CLINICAL RELEVANCE: The associations between IBK at weaning and production variables persisted well into the postweaning period, and there appeared to be a relationship between decreased body composition traits at yearling evaluation and IBK infection before weaning. PMID- 24344859 TI - Comparison of anesthesia with fully reversible dexmedetomidine-butorphanol midazolam versus ketamine-midazolam in captive Asian small-clawed otters (Aonyx cinereus). AB - OBJECTIVE: To evaluate the efficacy and safety of a combination of dexmedetomidine, butorphanol, and midazolam administered IM for anesthesia in captive Asian small-clawed otters (Aonyx cinereus) and to compare this combination with a combination of ketamine and midazolam. DESIGN: Prospective crossover study. ANIMALS: 10 captive Asian small-clawed otters. PROCEDURES: A combination of either dexmedetomidine (0.03 mg/kg [0.014 mg/lb]), butorphanol (0.2 mg/kg [0.091 mg/lb]), and midazolam (0.15 mg/kg [0.068 mg/lb]) or ketamine (10.1 mg/kg [4.59 mg/lb]) and midazolam (0.3 mg/kg [0.14 mg/lb]) was administered IM to otters for immobilization to allow scheduled wellness examinations. Otters were intubated and administered 100% oxygen during the examination. Anesthesia was supplemented with isoflurane in oxygen if necessary. Routine medical procedures, including blood collection, radiography, echocardiography, dental scaling, vaccinations, and contraception administration, were performed as indicated during the immobilization. Physiologic, clinicopathologic, and anesthetic variables were recorded and compared. Otters given dexmedetomidine butorphanol-midazolam were administered atipamezole (0.2 mg/kg [0.091 mg/lb]), naltrexone (0.6 mg/kg [0.27 mg/lb]), and flumazenil (0.05 mg/kg [0.023 mg/lb]) IM at the completion of the examination. RESULTS: The need for and duration of isoflurane administration were greater for ketamine-midazolam anesthesia, compared with dexmedetomidine-butorphanol-midazolam anesthesia. Recoveries were shorter and subjectively smoother with dexmedetomidine-butorphanol-midazolam. Heart rates were significantly higher during ketamine-midazolam anesthesia. Regardless of protocol, all otters developed hypothermia and hypercapnia during anesthesia. CONCLUSIONS AND CLINICAL RELEVANCE: Both protocols were safe and effective for this species, but the reversible nature of dexmedetomidine butorphanol-midazolam resulted in more rapid recoveries than did ketamine midazolam. Otters anesthetized with ketamine-midazolam may require additional anesthetic medications for routine examinations, and assisted ventilation and thermal support may be of benefit with either protocol. PMID- 24344860 TI - Factors associated with prolonged observation services stays and the impact of long stays on patient cost. AB - BACKGROUND: Patients are treated using observation services (OS) when their care needs exceed standard outpatient care (i.e., clinic or emergency department) but do not qualify for admission. Medicare and other private payers seek to limit this care setting to 48 hours. DATA SOURCE/STUDY SETTING: Healthcare Cost and Utilization Project data from 10 states and data collected from two additional states for 2009. STUDY DESIGN: Bivariate analyses and hierarchical linear modeling were used to examine patient- and hospital-level predictors of OS stays exceeding 48 (and 72) hours (prolonged OS). Hierarchical models were used to examine the additional cost associated with longer OS stays. PRINCIPAL FINDINGS: Of the 696,732 patient OS stays, 8.8 percent were for visits exceeding 48 hours. Having Medicaid or no insurance, a condition associated with no OS treatment protocol, and being discharged to skilled nursing were associated with having a prolonged OS stay. Among Medicare patients, the mean charge for OS stays was $10,373. OS visits of 48-72 hours were associated with a 42 percent increase in costs; visits exceeding 72 hours were associated with a 61 percent increase in costs. CONCLUSION: Patient cost sharing for most OS stays of less than 24 hours is lower than the Medicare inpatient deductible. However, prolonged OS stays potentially increase this cost sharing. PMID- 24344861 TI - Effect of thermal interface on heat flow in carbon nanofiber composites. AB - The thermal transport process in carbon nanofiber (CNF)/epoxy composites is addressed through combined micromechanics and finite element modeling, guided by experiments. The heat exchange between CNF constituents and matrix is studied by explicitly accounting for interface thermal resistance between the CNFs and the epoxy matrix. The effects of nanofiber orientation and discontinuity on heat flow and thermal conductivity of nanocomposites are investigated through simulation of the laser flash experiment technique and Fourier's model of heat conduction. Our results indicate that when continuous CNFs are misoriented with respect to the average temperature gradient, the presence of interfacial resistance does not affect the thermal conductivity of the nanocomposites, as most of the heat flow will be through CNFs; however, interface thermal resistance can significantly alter the patterns of heat flow within the nanocomposite. It was found that very high interface resistance leads to heat entrapment at the interface near to the heat source, which can promote interface thermal degradation. The magnitude of heat entrapment, quantified via the peak transient temperature rise at the interface, in the case of high thermal resistance interfaces becomes an order of magnitude more intense as compared to the case of low thermal resistance interfaces. Moreover, high interface thermal resistance in the case of discontinuous fibers leads to a nearly complete thermal isolation of the fibers from the matrix, which will marginalize the contribution of the CNF thermal conductivity to the heat transfer in the composite. PMID- 24344862 TI - Predicting cognitive ability in ageing cohorts using Type 2 diabetes genetic risk. AB - AIMS: To investigate whether there is overlap in the genetic determinants of Type 2 diabetes and cognitive ageing by testing whether a genetic risk score for Type 2 diabetes can predict variation in cognitive function in older people without dementia. METHODS: Type 2 diabetes genetic risk scores were estimated using various single nucleotide polymorphism significance inclusion criteria from an initial genome-wide association study, the largest in Type 2 diabetes to date. Scores were available for 2775-3057 individuals, depending on the cognitive trait. RESULTS: Type 2 diabetes genetic risk was associated with self-reported diabetes mellitus. Across varying single nucleotide polymorphism-inclusion levels, a significant association between Type 2 diabetes genetic risk and change in general cognitive function was found (median r = 0.04); however, this was such that higher Type 2 diabetes genetic risk related to higher cognitive scores. CONCLUSIONS: To investigate more fully the source of the often observed comorbidity between Type 2 diabetes and cognitive impairment, one direction for future research will be to use cognitive ability polygenic risk scores to predict Type 2 diabetes in line with the reverse causation hypothesis that people with lower pre-morbid cognitive ability are more likely to develop Type 2 diabetes. PMID- 24344868 TI - Deciphering the genetic basis of Moraxella catarrhalis complement resistance: a critical role for the disulphide bond formation system. AB - The complement system is an important innate defence mechanism, and the ability to resist complement-mediated killing is considered a key virulence trait of the respiratory tract pathogen M. catarrhalis. We studied the molecular basis of complement resistance by transcriptional profiling and Tn-seq, a genome-wide negative-selection screenings technology. Exposure of M. catarrhalis to human serum resulted in increased expression of 84 genes and reduced expression of 134 genes, among which genes encoding ABC transporter systems and surface proteins UspA1 and McaP. By subjecting a ~ 15 800 transposon mutant library to serum, mutants of 53 genes were negatively selected, including the key complement resistance factor uspA2H. Validation with directed mutants confirmed Tn-seq phenotypes of uspA2H and 11 newly identified genes, with mutants of MCR_0424, olpA, MCR_1483, and dsbB most severely attenuated. Detailed analysis showed that both components of the disulphide bond formation (DSB) system, DsbB and DsbA, were required for complement-resistance in multiple isolates, and fulfil a critical role in evasion of IgG-dependent classical pathway-mediated killing. Lipooligosaccharide (LOS) structure and membrane stability were severely affected in DeltadsbA strains, suggesting a pivotal role for the DSB system in LOS structure safeguarding and membrane stability maintenance. PMID- 24344869 TI - Health psychology interventions. PMID- 24344870 TI - Evaluation of the effects of selected phytochemicals on quorum sensing inhibition and in vitro cytotoxicity. AB - Quorum sensing (QS) is an important regulatory mechanism in biofilm formation and differentiation. Interference with QS can affect biofilm development and antimicrobial susceptibility. This study evaluates the potential of selected phytochemical products to inhibit QS. Three isothiocyanates (allylisothiocyanate AITC, benzylisothiocyanate - BITC and 2-phenylethylisothiocyanate - PEITC) and six phenolic products (gallic acid - GA, ferulic acid - FA, caffeic acid - CA, phloridzin - PHL, (-) epicatechin - EPI and oleuropein glucoside - OG) were tested. A disc diffusion assay based on pigment inhibition in Chromobacterium violaceum CV12472 was performed. In addition, the mechanisms of QS inhibition (QSI) based on the modulation of N-acyl homoserine lactone (AHLs) activity and synthesis by the phytochemicals were investigated. The cytotoxicity of each product was tested on a cell line of mouse lung fibroblasts. AITC, BITC and PEITC demonstrated a capacity for QSI by modulation of AHL activity and synthesis, interfering the with QS systems of C. violaceum CviI/CviR homologs of LuxI/LuxR systems. The cytotoxic assays demonstrated low effects on the metabolic viability of the fibroblast cell line only for FA, PHL and EPI. PMID- 24344871 TI - Effects of working memory and reading acceleration training on improving working memory abilities and reading skills among third graders. AB - Working memory (WM) plays a crucial role in supporting learning, including reading. This study investigated the influence of reading acceleration and WM training programs on improving reading skills and WM abilities. Ninety-seven children in third grade were divided into three study groups and one control group. The three study groups each received a different combination of two training programs: only reading acceleration, WM followed by reading acceleration, and reading acceleration followed by WM. All training programs significantly improved reading skills and WM abilities. Compared with the control group, the group trained with only the reading acceleration program improved word accuracy, whereas the groups trained with a combination of reading and WM programs improved word and pseudo-word fluency. The reading-acceleration-alone group and the WM-program-followed-by-reading-acceleration group improved phonological complex memory. We conclude that a training program that combines a long reading acceleration program and a short WM program is the most effective for improving the abilities most related to scholastic achievement. PMID- 24344872 TI - Testosterone with dutasteride, but not anastrazole, improves insulin sensitivity in young obese men: a randomized controlled trial. AB - INTRODUCTION: Testosterone (T) administration to men increases T, estradiol (E2), dihydrotestosterone (DHT), and fat-free mass (FFM), and decreases fat mass (FM) but does not consistently improve insulin sensitivity (IS). AIM: The aim of this study was to examine the effects of T administration in obese, nondiabetic men on body composition and IS, and to determine if inhibition (i) of metabolism of T to E2 with anastrazole or to DHT with dutasteride alters these effects. METHODS: This was a 98-day randomized, double-blind, parallel group, placebo-controlled trial of 57 men, 24-51 year, free T in the lower 25% of normal range (<0.33 nmol/L), body mass index >= 30.0 kg/m(2). Subjects were randomized to one of four groups: (i) placebo: gel, pills, and injection; (ii) T/DHT/iE2: T gel, anastrazole, and acyline (gonadotropin releasing-hormone antagonist to suppress endogenous T); (iii) T/iDHT/E2: T gel, dutasteride, and acyline; (iv) T/DHT/E2: T gel, placebo pills, and acyline. MAIN OUTCOME MEASURES: Main outcome measures are insulin sensitivity as percent change (%Delta) in glucose disposal rates (GDR) from a two-step euglycemic clamp (GDR1 and 2), and %FM and %FFM by dual X-ray absorptiometry scan. RESULTS: Insulin Sensitivity: %Delta GDR1 differed across groups (P = 0.02, anova) and was significantly higher in the dutasteride (T/iDHT/E2) compared with the placebo and T gel (T/DHT/E2) groups. %DeltaGDR2 was higher in the dutasteride (T/iDHT/E2) compared with the anastrazole (T/DHT/iE2) group. Body Composition: T gel alone (T/DHT/E2) or with dutasteride (T/iDHT/E2) significantly increased %FFM (P < 0.05) and decreased %FM (P < 0.05). There was no change in %FFM or %FM after placebo or anastrazole (T/DHT/iE2). CONCLUSIONS: The combination of T plus dutasteride improved body composition and IS while T alone improved body composition but not IS, suggesting that when T is administered to men, reduction to DHT attenuates the beneficial effects of aromatization to E2 on IS but not body composition. PMID- 24344873 TI - A case study of binary outcome data extraction across three systematic reviews of hip arthroplasty: errors and differences of selection. AB - BACKGROUND: Data extraction is a key stage in systematic review, yet it is the subject of little research. The aim of the present research was to use a small case study to highlight some important issues affecting this fundamental process. METHODS: The authors undertook an analysis of differences in the binary event data extracted and analysed by three systematic reviews on the same topic: a comparison of total hip arthroplasty and hemiarthroplasty. The following binary event data were extracted for three key outcomes, common to all three reviews, from those trials common to all three reviews: Dislocation rates, 1-year mortality, and revision rates. Differences between the data extracted by the three reviews were categorised as either errors or an issue of data selection. Meta-analysis was performed to assess whether these differences led to differences in summary estimates of effect. RESULTS: Across the three outcomes, differences in selection accounted for between 8% and 42% of the data differences between reviews, and errors accounted for between 8% and 17%. No rationale was given in any of these former cases for the choice of event data being reported. These differences did lead to small differences in meta-analysed relative risks between the two treatments in the three reviews, but none was significant. CONCLUSIONS: Systematic reviewers should use double-data extraction to minimise error and also make every effort to clarify or explain their choice of data, within the scope of their publication. Reviewers frequently exercise selection when faced with a choice of alternative but potentially equally appropriate data for an outcome. However, this selection is rarely made clear by review authors. Systematic review was developed as a method specifically to be both reproducible and transparent. This case study suggests that neither objective is always being achieved. PMID- 24344875 TI - Usage of inhalation devices in asthma and chronic obstructive pulmonary disease: a Delphi consensus statement. AB - OBJECTIVES: The study aimed to assess usage of inhalation devices in asthma and chronic obstructive pulmonary disease (COPD). METHODS: In this two-round Delphi survey, 50 experts in asthma and COPD completed a 13-item, Internet-based, self administered questionnaire about choice of inhalation device, training and monitoring of inhalation techniques, the interchangeability and the role of costs in the selection of inhalation devices. For each item, the median (central tendency) and interquartile ranges (degree of consensus) were calculated. RESULTS: Experts considered that the choice of inhalation device was as important as that of active substance (very good consensus) and should be driven by ease of use (good to very good consensus) and teaching (very good consensus). Experts recommended giving oral and visual instructions (good consensus) and systematic monitoring inhalation techniques. Pulmonologists and paramedics have predominantly educational roles (very good consensus). Experts discouraged inhalation device interchangeability (good consensus) and switching for cost reasons (good to very good consensus) without medical consultation (good consensus). CONCLUSIONS: The results of this survey thus suggested that inhalation devices are as important as active substances and training and monitoring are essential in ensuring effective treatment of asthma and COPD. Inhalation device switching without medical consultation should be avoided. PMID- 24344876 TI - Hierarchically porous carbon encapsulating sulfur as a superior cathode material for high performance lithium-sulfur batteries. AB - Lithium-sulfur (Li-S) batteries are deemed to be a promising energy storage device for next-generation high energy power system. However, insulation of S and dissolution of lithium polysulfides in the electrolyte lead to low utilization of sulfur and poor cycling performance, which seriously hamper the rapid development of Li-S batteries. Herein, we reported that encapsulating sulfur into hierarchically porous carbon (HPC) derived from the soluble starch with a template of needle-like nanosized Mg(OH)2. HPC has a relatively high specific surface area of 902.5 m(2) g(-1) and large total pore volume of 2.60 cm(3) g(-1), resulting that a weight percent of sulfur in S/HPC is up to 84 wt %. When evaluated as cathodes for Li-S batteries, the S/HPC composite has a high discharge capacity of 1249 mAh g(-1) in the first cycle and a Coulombic efficiency as high as 94% with stable cycling over prolonged 100 charge/discharge cycles at a high current density of 1675 mA g(-1). The superior electrochemical performance of S/HPC is closely related to its unique structure, exhibiting the graphitic structure with a high developed porosity framework of macropores in combination with mesopores and micropores. Such nanostructure could shorten the transport pathway for both ions and electrons during prolonged cycling. PMID- 24344874 TI - Erythropoietin improves motor and cognitive deficit, axonal pathology, and neuroinflammation in a combined model of diffuse traumatic brain injury and hypoxia, in association with upregulation of the erythropoietin receptor. AB - BACKGROUND: Diffuse axonal injury is a common consequence of traumatic brain injury (TBI) and often co-occurs with hypoxia, resulting in poor neurological outcome for which there is no current therapy. Here, we investigate the ability of the multifunctional compound erythropoietin (EPO) to provide neuroprotection when administered to rats after diffuse TBI alone or with post-traumatic hypoxia. METHODS: Sprague-Dawley rats were subjected to diffuse traumatic axonal injury (TAI) followed by 30 minutes of hypoxic (Hx, 12% O2) or normoxic ventilation, and were administered recombinant human EPO-alpha (5000 IU/kg) or saline at 1 and 24 hours post-injury. The parameters examined included: 1) behavioural and cognitive deficit using the Rotarod, open field and novel object recognition tests; 2) axonal pathology (NF-200); 3) callosal degradation (hematoxylin and eosin stain); 3) dendritic loss (MAP2); 4) expression and localisation of the EPO receptor (EpoR); 5) activation/infiltration of microglia/macrophages (CD68) and production of IL-1beta. RESULTS: EPO significantly improved sensorimotor and cognitive recovery when administered to TAI rats with hypoxia (TAI + Hx). A single dose of EPO at 1 hour reduced axonal damage in the white matter of TAI + Hx rats at 1 day by 60% compared to vehicle. MAP2 was decreased in the lateral septal nucleus of TAI + Hx rats; however, EPO prevented this loss, and maintained MAP2 density over time. EPO administration elicited an early enhanced expression of EpoR 1 day after TAI + Hx compared with a 7-day peak in vehicle controls. Furthermore, EPO reduced IL-1beta to sham levels 2 hours after TAI + Hx, concomitant to a decrease in CD68 positive cells at 7 and 14 days. CONCLUSIONS: When administered EPO, TAI + Hx rats had improved behavioural and cognitive performance, attenuated white matter damage, resolution of neuronal damage spanning from the axon to the dendrite, and suppressed neuroinflammation, alongside enhanced expression of EpoR. These data provide compelling evidence of EPO's neuroprotective capability. Few benefits were observed when EPO was administered to TAI rats without hypoxia, indicating that EPO's neuroprotective capacity is bolstered under hypoxic conditions, which may be an important consideration when EPO is employed for neuroprotection in the clinic. PMID- 24344877 TI - Expression of glutathione S-transferase variants in human airway wall after long term response to sulfur mustard. AB - CONTEXT: Sulfur mustard (SM) is an alkylating agent identified as a potent chemical warfare agent. More recently, SM was used in the Iraq conflict against Iranian troops and civilians. At present, there are many people suffering from chronic obstructive pulmonary disease (COPD) due to mustard gas in Iran. SM increases the endogenous production of reactive oxygen species (ROS). The oxidant/antioxidant imbalance present in the lungs of these patients also results from the impaired capacity of the antioxidant/detoxification enzymes to detoxify the harmful reactive oxygen metabolites. OBJECTIVE: One of the major antioxidants in human airways is glutathione S-transferase. They facilitate the detoxification of various environmental of oxidative stress. In this study, we attempted to understand the significance different in expression of GSTs in airway wall of chemical patients and control. MATERIALS AND METHODS: Seven normal and 20 SM induced COPD individuals were studied. Bronchoscopy was performed in all subjects and two specimens were taken from the main bronchus for mRNA extraction, PCR analysis and immunohistochemistry. RESULTS: SM-induced COPD individuals showed expression of GSTA1 2.51 +/- 0.83-, GSTM1 2.84 +/- 1.71- and GSTP1 5.61 +/- 2.59 folds higher than those of controls that revealed. GSTP1-immunoreactivity was strongly expressed in luminal border of normal samples. SM patient samples immunoreactivity for GSTP1 in the same area were negative. DISCUSSION AND CONCLUSION: According to these findings, we speculated that overexpression of GSTs mRNA in patients revealed that GSTs plays an important role in cellular protection against oxidative stress of MS in airway wall of patients. PMID- 24344878 TI - Labour saver or building a cohesive interprofessional team? The role of the nurse practitioner within hospitals. AB - Nurse practitioners (NP) are employed within hospital interprofessional (IP) teams in several countries worldwide. There have been some efforts to describe the nature of the NP role within IP teams largely focussing on how the role may augment care processes. Here, using a constructivist grounded theory approach, the perceptions of NPs about their role were compared and integrated into a previously published team perspective as the second phase of a larger study. Seventeen hospital-based (HB) NPs across Ontario, Canada, participated in group and individual interviews. The NP perspective substantiated and expanded the previously reported team perspective, resulting in an IP perspective. The three practice foci illustrating role value meaning of this perspective became: evolve NP role and advance the specialty, focus on team working, and hold patient care together. The IP perspective, juxtaposed with an existing contingency approach, revealed that NPs were promoting IP work, predominantly at the collaboration and teamwork levels, and aiding IP team transitions to appropriate forms of IP work. The practice, "focus on team working"' was strongly related to promoting IP work. The findings were consistent with HB NPs enacting a role in building IP team cohesiveness rather than merely acting as a labour saver. This is the first study to align NP and team understanding of HB NP role value using an IP framework. PMID- 24344879 TI - Temperature-mediated survival, development and hatching variation of Pacific cod Gadus macrocephalus eggs. AB - Laboratory-validated data on the survival, development and hatching responses of fertilized Pacific cod Gadus macrocephalus eggs from the northern Japan stock were determined through an incubation experiment. The optimum temperature for survival until hatching ranged from 4 to 8 degrees C. No significant difference in development rates was found between the populations from Mutsu Bay, Japan, and western Canadian coastal waters even though the samples may belong to different G. macrocephalus stocks. Gadus macrocephalus larvae hatched asynchronously from egg batches despite incubation under the same environment during their development. Both incubation temperature and temperature-mediated hatch rank affect size and yolk reserve. These data suggest that variations in water temperatures within an ecological range markedly influence the development rates, survival and hatching of the eggs, as well as the stage at hatch larvae of G. macrocephalus. Asynchronous hatching and the production of offspring with variable sizes and yolk reserves are considered evolutionary bet-hedging strategies that enable the species to maximize their likelihood of survival in an environment with variable temperatures. PMID- 24344880 TI - The oestrogen receptor 2 (ESR2) gene in female-pattern hair loss: replication of association with rs10137185 in German patients. PMID- 24344881 TI - The role of the one-carbon cycle in the developmental origins of Type 2 diabetes and obesity. AB - Vitamin B12 deficiency is common in certain populations, such as in India, where there is also a rising prevalence of Type 2 diabetes, obesity and their complications. Human cohorts and animal models provide compelling data suggesting the role of the one-carbon cycle in modulating the risk of diabetes and adiposity via developmental programming. Early mechanistic studies in animals suggest that alterations to the cellular provision of methyl groups (via the one-carbon cycle) in early developmental life may disrupt DNA methylation and induce future adverse phenotypic changes. Furthermore, replacement of micronutrient deficits at suitable developmental stages may modulate this risk. Current human studies are limited by a range of factors, including the accuracy and availability of methods to measure nutritional components in the one-carbon cycle, and whether its disruptions exert tissue-specific effects. A greater understanding of the causal and mechanistic role of the one-carbon cycle is hoped to generate substantial insights into its role in the developmental origins of complex metabolic diseases and the potential of targeted and population-wide prevention strategies. PMID- 24344882 TI - A developmental psychopathology perspective on personality disorder: introduction to the special issue. PMID- 24344883 TI - Reward: empirical contribution. Temporal discounting and conduct disorder in adolescents. AB - The current study examined temporal discounting (the decrease in subjective reward value as a function of increasing delay) in youths with conduct disorder (CD) and the extent to which this was modulated by level of psychopathic traits. In the temporal discounting task, participants were asked to choose between immediate rewards of varying values and a larger reward, held at a constant value ($10), whose receipt was delayed by different time intervals across trials (e.g., 7 days, 360 days). The level of immediate reward necessary for selection over the larger, delayed reward is the measure of temporal discounting. Forty-six youths (21 with CD and 25 healthy youths) participated in this study. Compared with healthy youths, youths with CD chose significantly smaller amounts of immediate reward rather than the larger future rewards. This was the case even in youths with CD without comorbid attention-deficit/hyperactivity disorder. However, level of psychopathic traits did not modulate temporal discounting in this sample. These results are discussed in terms of neurobiological models of CD and psychopathic traits. PMID- 24344884 TI - Reward: commentary. Temporal discounting in conduct disorder: toward an experience-adaptation hypothesis of the role of psychosocial insecurity. AB - Young people with conduct disorder often experience histories of psychosocial adversity and socioeconomic insecurity. For these individuals, real-world future outcomes are not only delayed in their delivery but also highly uncertain. Under such circumstances, accentuated time preference (extreme favoring of the present over the future) is a rational response to the everyday reality of social and economic transactions. Building on this observation, the author sets out the hypothesis that the exaggerated temporal discounting displayed by individuals with conduct disorder reported by White et al. (2014) is an adaptation to chronic exposure to psychosocial insecurity during development. The author postulates that this adaptation leads to (a) a decision-making bias whereby delay and uncertainty are coded as inseparable characteristics of choice outcomes and/or (b) reprogramming of the brain networks regulating intertemporal decision making. Future research could explore the putative role of environmental exposures to adversity in the development of exaggerated temporal discounting in conduct disorder as well as the mediating role of putative cognitive and neurobiological adaptations. PMID- 24344885 TI - Hormones: empirical contribution. Cortisol reactivity and recovery in the context of adolescent personality disorder. AB - The present study examined whether the associations between stress responses and psychopathology were moderated by adolescent personality disorder (PD) traits. Participants were a community sample of 106 adolescents (47 male, Mage = 16.01) and their parents. Parents reported on adolescents' PD traits and behavioral problems. Changes in salivary cortisol were assessed in response to a laboratory based stress induction. Moderated regression analyses revealed significant linear and quadratic interactions between cortisol recovery and PD traits in the prediction of behavioral problems. Although typically conceptualized as "adaptive," steeper poststressor recovery was associated with more behavioral problems when PD traits were high. These findings suggest that, in the presence of maladaptive personality traits, premature recovery from environmental stressors may indicate an inability to respond appropriately to negative environmental stimuli, thus reflecting a core disturbance in PD trait functioning. The results underscore the informative role that personality plays in illuminating the nature of hormone functioning in adolescents and are interpreted in a developmental psychopathology framework. PMID- 24344886 TI - Hormones: commentary. Riding the physiological roller coaster: adaptive significance of cortisol stress reactivity to social contexts. AB - The authors conjecture that to understand normal stress regulation, including cortisol stress reactivity, it is important to understand why these biomarkers are released and what they function to accomplish within the individual. This perspective holds that high (or rising) cortisol has advantages and disadvantages that must be understood within a context to understand how individual differences unfold. This perspective is juxtaposed with a popular vantage point of this stress hormone or of stress exposure that emphasizes the deleterious consequences or problems of this hormone. While the costs and benefits of cortisol are emphasized for normal stress regulation, this dynamic context-dependent purpose of stress hormones should extend to the development of psychopathology as well. This functional and dynamic view of cortisol is helpful for interpreting why Tackett and colleagues (2014) appear to observe advantageous cortisol recovery from stress in individuals with elevated personality disorder symptoms. PMID- 24344887 TI - Emotion: empirical contribution. Maternal borderline personality pathology and infant emotion regulation: examining the influence of maternal emotion-related difficulties and infant attachment. AB - Evidence suggests that maternal borderline personality (BP) pathology increases offspring risk. This study examined the relations between maternal BP pathology and related emotional dysfunction (including emotion regulation [ER] difficulties and emotional intensity/reactivity) and infant ER difficulties. Specifically, we examined both self-focused and caregiver-focused ER behaviors and the modulation of emotional expressions (one indicator of ER in young children) in response to fear- and anger-eliciting stimuli among 101 infants (12 to 23 months old) of mothers with and without clinically relevant BP pathology. The authors also examined the moderating role of mother-infant attachment. Findings of a series of multiple regression mediation analyses revealed an indirect effect of maternal BP pathology on infant ER difficulties through maternal emotional dysfunction, with maternal ER difficulties facilitating an indirect effect of maternal BP pathology on expressivity-related indicators of infant ER difficulties and maternal emotional intensity/reactivity linking maternal BP pathology to lower self focused ER for infants in insecure-resistant attachment relationships. PMID- 24344888 TI - Emotion: commentary. A biopsychosocial perspective on maternal psychopathology and the development of child emotion regulation. AB - In this commentary, the authors note that Gratz and colleagues (2014) have made an important step in understanding the effect of maternal borderline personality (BP) pathology on children's developing emotion regulation. The emphasis on mechanisms of transmission in their article has implications for our understanding of the relationships between parental mental health and child functioning more generally. The authors of the commentary argue that using a biopsychosocial framework to understand the multiple levels that characterize the developmental system will push this kind of focus on behavioral mechanisms a step further. A biopsychosocial framework implies that a set of hierarchically organized, but reciprocally interacting, processes, from the genetic to the environmental, provide the essential elements of development (Gottlieb, 2007). Thus, in studying the effects of maternal BP pathology on child outcomes, consideration may also be given to the role of underlying biological processes that are influenced by maternal functioning and may alter child outcomes. Challenges to using this general approach in studying the effects of parental psychopathology are discussed. PMID- 24344889 TI - Social cognition: empirical contribution. The developmental building blocks of psychopathic traits: revisiting the role of theory of mind. AB - In the context of personality disorder development, theories of typical and atypical development both emphasize social cognition as an important building block for personality development. Prior claims of intact theory of mind (ToM) abilities in psychopathic individuals have relied upon a narrow conception of ToM as equivalent to "cognitive empathy." In this article, the authors make use of a broader conception of ToM comprising top-down and bottom-up processing, as well as the fractionation of ToM in terms of reduced or excessive ToM function, to examine relationships between ToM and psychopathic traits. A total of 342 adolescents (ages 12-17; Mage 15.39; SD = 1.45; 61.5% females) completed the Movie Assessment for Social Cognition (Dziobek, Fleck, Kalbe, et al., 2006) and the Child Eyes Test (Baron-Cohen, Wheelwright, Hill, Raste, & Plumb, 2001) in addition to three measures of psychopathic traits. Results demonstrated unique relations between the affective components of psychopathy (callous-unemotional traits [CU traits]) and impairment in both top-down and bottom-up ToM. In addition, excessive ToM related to affective components of psychopathy, while reduced or no ToM related to behavioral components of psychopathy. In mediational analyses, bottom-up ToM was shown to be necessary for top-town ToM in its relation with CU traits. Taken together, these results from the study lend support to revisiting the link between ToM and psychopathy. PMID- 24344890 TI - Social cognition: commentary: Do theory of mind deficits lead to psychopathology or is it the other way around? PMID- 24344891 TI - Identity: empirical contribution. Changes in the identity integration of adolescents in treatment for personality disorders. AB - A renewed interest in identity as one of the core markers of personality disorders has been introduced by the DSM-5 Level of Personality Functioning Scale. However, little is known about the utility of the construct of identity in children and adolescents. This study aimed to broaden the knowledge of identity integration as a core component of personality functioning in adolescents. The authors investigated levels of identity integration, as measured by the Severity Indices of Personality Problems (SIPP-118; Verheul et al., 2008), in adolescents in both normal (n = 406) and clinical populations (n = 285). Furthermore, changes in levels of identity integration during treatment were investigated in a clinical subsample (n = 76). Levels of identity integration were not associated with age. They were, however, associated with the absence or presence of personality pathology. Most adolescents receiving inpatient psychotherapy gradually changed toward more healthy levels of identity integration; a significant number, however, remained at maladaptive levels of identity functioning after intensive psychotherapy. PMID- 24344892 TI - Identity: commentary. Identity development: dialogue between normative and pathological developmental approaches. AB - This commentary places the article by Feenstra and colleagues (in press) within the frameworks and findings of normative identity development research. Points of overlap between the way identity is conceptualized by Feenstra and colleagues and the way identity is conceptualized in normative work are outlined. In addition, areas where juxtaposing psychopathology and normative developmental findings could yield new insights for researchers working in both areas are briefly highlighted. PMID- 24344893 TI - Relationships: empirical contribution. Understanding personality pathology in adolescents: the five factor model of personality and social information processing. AB - This study seeks to integrate two research traditions that lie at the base of the understanding of personality pathology in adolescents. The first research tradition refers to normal personality according to the Five Factor Model (FFM). The second tradition specifies the key feature of personality disorder as the capacity to mentalize, which can be reflected in Social Information Processing (SIP). In a clinical sample of 96 adolescents, the authors investigated response generation, coping strategy, and memories of past frustrating experiences as part of SIP, as mediator in the relationship between personality and personality pathology, and a possible moderating role of personality on the relationship between SIP and personality pathology. The hypothesized mediation, by which the effects of personality dimensions on personality pathology was expected to be mediated by SIP variables, was found only for the effect of Neuroticism, most specifically on BPD, which appeared to be mediated by memories the patients had about past frustrating conflict situations with peers. Some moderating effects of personality on the relationship between SIP variables and personality pathology were found, suggesting that high Agreeableness and sometimes low Neuroticism can buffer this relationship. These results suggest that personality dimensions and social cognitions both independently and together play a role in adolescents' personality pathology. PMID- 24344894 TI - Relationships: commentary. Personality, relationships, and behavior problems: it's hard to be disagreeable. AB - Low agreeableness is defined and discussed. Disagreeable youth are antagonistic, disputatious, and uncooperative. The low agreeable share two common problems: behavior troubles and interpersonal troubles. A cascade model is suggested whereby initial modest difficulties follow a progressively accelerating trajectory. The cascade begins with temperamental difficultness, manifest in uncooperativeness and poor self-control. These traits elicit negativity, giving rise to relationship troubles that interfere with socialization and isolate these children from good-tempered peers. Behavior problems and coercive interaction strategies combine to exacerbate disagreeable inclinations that tend to worsen adjustment and interpersonal difficulties. PMID- 24344895 TI - Aging: empirical contribution. A longitudinal analysis of personality disorder dimensions and personality traits in a community sample of older adults: perspectives from selves and informants. AB - Research has indicated that personality disorders (PDs) and normal-range personality traits generally "get better" with time, as evidenced by mean-level decreases in PD traits and mean-level increases in broad factors such as emotional stability, agreeableness, and conscientiousness. One limitation of many of these studies is their reliance on self reported data. In the current study, the authors analyzed the 2.5-year course of PD dimensions and normal personality traits in a representative sample of adults approaching later life (originally ages 55-65) by using a semistructured diagnostic interview as well as self- and informant-reported data from two personality inventories. Consistent with previous literature, many self-reported PD traits showed mean-level decreases over time, and self-reported normal-range personality traits generally showed positive aging effects (e.g., mean-level increases in emotional stability, agreeableness, and conscientiousness). Surprisingly, however, informant-reported PD traits often demonstrated small but significant increases over time, and informant-reported normal-range personality generally "worsened" with age (e.g., mean-level decreases in extraversion, agreeableness, and conscientiousness). Informant reports may challenge the finding that personality and PDs tend to "improve" over time. PMID- 24344896 TI - Aging: commentary. Change in perceptions of personality disorder in late life: the view from socioemotional aging. AB - Cooper, Balsis, and Oltmanns (2014) present evidence that older adults view changes in their own levels of personality disorders, but that their informants do not report such positive changes. In this commentary, the author considers these provocative findings in light of current theory and research from socioemotional aging on emotion-cognition links and how they might vary as a function of age. PMID- 24344897 TI - Illustrative developmental psychopathology perspectives on precursors and pathways to personality disorder: commentary on the special issue. PMID- 24344898 TI - Driving a musculoskeletal model with inertial and magnetic measurement units. AB - We developed and evaluated a new kinematic driver for musculoskeletal models using ambulatory inertial and magnetic measurement units (IMMUs). The new driver uses the orientation estimates based on sensor fusion of each individual IMMU and benefits from two important properties of musculoskeletal models. First, these models contain more complex, anatomical, kinematic models than those currently used for sensor fusion of multiple IMMUs and are continuously improved. Second, they allow movement between segment and measured sensor. For three different tasks, the new IMMU driver, (optical) marker drivers and a combination of both were used to reconstruct the motion. Maximal root mean square (RMS) joint angle differences with respect to the silver standard (combined IMMU/marker drivers) were found for the hip joint; 4 degrees , 2 degrees and 5 degrees during squat, gait and slideboard tasks for IMMU-driven reconstructions, compared with 6 degrees , 5 degrees and 5 degrees for marker-driven reconstructions, respectively. The measured angular velocities corresponded best to the IMMU driven reconstructions, with a maximal RMS difference of 66 degrees /s, compared with 108 degrees /s and 91 degrees /s for marker-driven reconstructions and silver standard. However, large oscillations in global accelerations occurred during IMMU-driven reconstructions resulting in a maximal RMS difference with respect to measured acceleration of 23 m/s2, compared with 9 m/s2 for reconstructions that included marker drivers. The new driver facilitates direct implementation of IMMU-based orientation estimates in currently available biomechanical models. As such, it can help in the rapid expansion of biomechanical analysis based on outdoor measurements. PMID- 24344899 TI - Patients with unexplained physical symptoms have poorer quality of life and higher costs than other patient groups: a cross-sectional study on burden. AB - BACKGROUND: To determine whether healthcare resources are allocated fairly, it is helpful to have information on the quality of life (QoL) of patients with Unexplained Physical Symptoms (UPS) and on the costs associated with them, and on how these relate to corresponding data in other patient groups. As studies to date have been limited to specific patient populations with UPS, the objective of this study was to assess QoL and costs in a general sample of patients with UPS using generic measures. METHODS: In a cross-sectional study, 162 patients with UPS reported on their QoL, use of healthcare resources and lost productivity in paid and unpaid work. To assess QoL, the generic SF-36 questionnaire was used, from which multidimensional quality-of-life scores and a one-dimensional score (utility) using the SF-6D scorings algorithm were derived. To assess costs, the TiC-P questionnaire was used. RESULTS: Patients with UPS reported a poor QoL. Their QoL was mostly decreased by limitations in functioning due to physical health, and the least by limitations in functioning due to emotional problems. The median of utilities was 0.57, and the mean was 0.58 (SD = .09).The cost for the use of healthcare services was estimated to be ?3,123 (SD = ?2,952) per patient per year. This cost was enlarged by work-related costs: absence from work (absenteeism), lower on-the-job productivity (presenteeism), and paid substitution of domestic tasks. The resulting mean total cost was estimated to be ?6,815 per patient per year. CONCLUSIONS: These findings suggest that patients with UPS have a high burden of disease and use a considerable amount of healthcare resources. In comparison with other patient groups, the QoL values of patients with UPS were among the poorest and their costs were among the highest of all patient groups. The burden for both patients and society helps to justify the allocation of sufficient resources to effective treatment for patients with UPS. PMID- 24344900 TI - Peptidomic profile of milk of Holstein cows at peak lactation. AB - Bovine milk is known to contain naturally occurring peptides, but relatively few of their sequences have been determined. Human milk contains hundreds of endogenous peptides, and the ensemble has been documented for antimicrobial actions. Naturally occurring peptides from bovine milk were sequenced and compared with human milk peptides. Bovine milk samples from six cows in second stage peak lactation at 78-121 days postpartum revealed 159 peptides. Most peptides (73%) were found in all six cows sampled, demonstrating the similarity of the intramammary peptide degradation across these cows. One peptide sequence, ALPIIQKLEPQIA from bovine perilipin 2, was identical to another found in human milk. Most peptides derived from beta-casein, alphas1-casein, and alphas2-casein. No peptides derived from abundant bovine milk proteins such as lactoferrin, beta lactoglobulin, and secretory immunoglobulin A. The enzymatic cleavage analysis revealed that milk proteins were degraded by plasmin, cathepsins B and D, and elastase in all samples. PMID- 24344901 TI - Expression of CaV 2.2 and splice variants of CaV 2.1 in oxytocin- and vasopressin releasing supraoptic neurones. AB - The magnocellular neurosecretory cells (MNCs) release vasopressin (VP) and oxytocin (OT) from their axon terminals into the circulation and from their somata and dendrites to exert paracrine effects on other MNCs. MNCs express several types of voltage-gated Ca(2+) channels, including Ca(V)2.1 and Ca(V)2.2. These two channels types are similar in structure and function in other cells, but although influx of Ca(2+) through Ca(V)2.2 triggers the release of both OT and VP into the circulation, Ca(V)2.1 is involved in stimulating the release of VP but not OT. Release of OT from MNC somata is also triggered by Ca(V)2.2 but not Ca(V)2.1. These observations could be explained by differences in the level of expression of Ca(V)2.1 in VP and OT MNCs or by differences in the way that the two channels interact with the exocytotic apparatus. We used immunohistochemistry to confirm earlier work suggesting that MNCs express variants of Ca(V)2.1 lacking portions of an internal loop that enables the channels to interact with synaptic proteins. We used an antibody that would recognise both the full-length Ca(V)2.1 and the deletion variants to show that OT MNCs express fewer Ca(V)2.1 channels than do VP MNCs in both somata and axon terminals. We used the reverse transcriptase-polymerase chain reaction and immunocytochemistry to test whether MNCs express similar deletion variants of Ca(V)2.2 and were unable to find any evidence to support this. Our data suggest that the different roles that Ca(V)2.1 and Ca(V)2.2 play in MNC secretion may be a result of the different levels of expression of Ca(V)2.1 in VP and OT MNCs, as well as the expression in MNCs of deletion variants of Ca(V)2.1 that do not interact with exocytotic proteins and therefore may be less likely to mediate exocytotic release. PMID- 24344902 TI - Patient satisfaction with testosterone replacement therapies: the reasons behind the choices. AB - INTRODUCTION: Testosterone replacement therapy (TRT) for male hypogonadism is rapidly gaining popularity and acceptance. Options include gels, injections, and implantable subcutaneous pellets. AIMS: The aim of this study was to determine rates of patient satisfaction and reasons for patient preferences in hypogonadal men on TRT. METHODS: An anonymous, prospective survey was distributed to men presenting for TRT at an academic urology clinic. The survey was organized into multiple domains including patient satisfaction and treatment motivation. MAIN OUTCOME MEASURES: Patient satisfaction responses obtained via anonymous survey. RESULTS: Average patient age was 49 +/- 0.7 years (n = 382). Injectable testosterone was chosen by 53%, gel-based regimens by 31%, and pellets by 17%. Overall, 70% of patients were satisfied with their TRT and 14% reported dissatisfaction. Satisfaction rates were similar between gels (68%), injections (73%), and implantable pellets (70%). Doctor recommendation was the sole significant reason for patients preferring gel-based TRT (66% vs. 37% injection users vs. 31% pellet users). Injectable TRT was favored because of lower cost (35% vs. 21% gel users vs. 19% pellet users). Pellets were favored for ease of use (64% vs. 44% injection users vs. 43% gel users) and convenience (58% vs. 26% injection users vs. 19% gel users). Pellets had increased rates of satisfaction within the first 12 months. Improvements in concentration and mood occurred at higher percentages in satisfied patients. CONCLUSIONS: Patients are satisfied with TRT. Lower costs are important to patients on injections. Convenience and ease of use are central in choosing pellet therapy. Men on TRT should be questioned about mood and concentration because these factors exhibited the greatest improvements in satisfied patients. PMID- 24344903 TI - Haemoglobin A1c: comparing performance of two point of care devices with laboratory analyser. AB - BACKGROUND: Measurement of HbA1c has been widely used for long-term monitoring and management of diabetes control. There is increasing use of point-of-care (POC) devices for measuring HbA1c where quicker results would allow immediate clinical management decisions to be made. Therefore, it is important to evaluate and compare the performance of such devices to the reference laboratory method. FINDINGS: A total of 274 venous blood was collected from normal healthy adults during the community screening programmes. The performance of POC devices, Afinion and Quo-test were compared to central laboratory HPLC method; Adams A1c HA 8160. Both POC devices showed good correlation to HA 8160 with r = 0.94 (p < 0.001) and r = 0.95 (p < 0.001) for Afinion and Quo-test respectively. The means difference were statistically higher between POC and HA 8160 with 0.23% (95% CI 0.19-0.26, p < 0.001) and 0.29% (95% CI 0.24-0.34, p < 0.001) for Afinion and Quo test respectively. CONCLUSIONS: Both POC devices could be considered in health clinics for diabetes management but not to be used for the diagnostic purposes. PMID- 24344904 TI - Plasma elevation of vascular endothelial growth factor leads to the reduction of mouse hematopoietic and mesenchymal stem/progenitor cells in the bone marrow. AB - Vascular endothelial growth factor (VEGF) is reported to exhibit potent hematopoietic stem/progenitor cell (HSPC) mobilization activity. However, the detailed mechanisms of HSPC mobilization by VEGF have not been examined. In this study, we investigated the effect of VEGF on bone marrow (BM) cell and the BM environment by intravenous injection of VEGF-expressing adenovirus vector (Ad VEGF) into mice. A colony assay using peripheral blood cells revealed that plasma elevation of VEGF leads to the mobilization of HSPCs into the circulation. Granulocyte colony-stimulating factor (G-CSF) is known to mobilize HSPCs by decreasing CXC chemokine ligand 12 (CXCL12) levels in the BM. However, we found almost no changes in the CXCL12 levels in the BM after Ad-VEGF injection, suggesting that VEGF can alter the BM microenvironment by different mechanisms from G-CSF. Furthermore, flow cytometric analysis and colony forming unit fibroblast assay showed a reduction in the number of mesenchymal progenitor cells (MPCs), which have been reported to serve as niche cells to support HSPCs, in the BM of Ad-VEGF-injected mice. Adhesion of donor cells to the recipient BM after transplantation was also impaired in mice injected with Ad-VEGF, suggesting a decrease in the niche cell number. We also observed a dose-dependent chemoattractive effect of VEGF on primary BM stromal cells in vitro. These data suggest that VEGF alters the distribution of MPCs in the BM and can also mobilize MPCs to peripheral tissues. Taken together, our results imply that VEGF-elicited egress of HSPCs would be mediated, in part, by changing the number of MPCs in the BM. PMID- 24344910 TI - Sexual dimorphism in ALS: exploring gender-specific neuroimaging signatures. AB - Our objective was to explore neuroanatomical differences between female and male ALS patients in the context of sexual dimorphism in healthy controls. Fourteen female ALS patients, 13 male ALS patients, 22 healthy male controls and 20 healthy female controls were recruited into a comprehensive neuroimaging study. Cortical thickness measurements and diffusion tensor imaging (DTI) were utilized to explore gender-specific anatomical vulnerability. DTI analysis across all study groups revealed higher fractional anisotropy in association with male gender in the brainstem, cerebellum, fornix, thalamus, anterior forceps and corticospinal tracts accounting for diagnosis and age. While females showed a trend of higher age-adjusted cortical thickness in the right parieto-occipital and left mid-frontal regions, males demonstrated higher cortical thickness in the left lingual and left superior temporal regions, accounting for diagnosis. Significant multifocal white matter differences have also been identified between healthy male and female controls. In conclusion, sexual dimorphism is an overlooked and potentially confounding factor in admixed ALS neuroimaging studies. Our results suggest that gender is an additional dimension of disease heterogeneity in ALS. Given the significant pre- and post-morbid gender differences, we feel that ALS imaging studies should be controlled for gender or, alternatively, single gender studies should be considered. PMID- 24344911 TI - Reducing regioisomers of fullerene-bisadducts by tether-directed remote functionalization: investigation of electronically and sterically isomeric effects on bulk-heterojunction solar cells. AB - C60 bis-adduct containing a mixture of regio-isomers with different LUMO energy levels and steric geometries could greatly affect the morphological and bulk properties. To investigate the regio-isomer effect on solar cell performance, we have successfully designed and synthesized a regio-selective 4-acetatephenyl-4' methylphenylmethano C60 bis-adduct (S-APM-CBA) by "tether-directed remote functionalization" strategy and a random 4-acetatephenyl-4'-methylphenylmethano C60 bis-adduct denoted as R-APM-CBA by traditional cyclopropanation. The dramatic reduction in the number of regio-isomers in S-APM-CBA is confirmed by the (1)H NMR and HPLC measurements and theoretical calculation. Compared to the R-APM-CBA based device with a Jsc of 6.63 mA/cm(2), an FF of 44.3% and a PCE of 2.46%, the device using S-APM-CBA yielded a much lower Jsc of 1.48 mA/cm(2), an FF of 32.2%, and a PCE of 0.38%. Consistently, the electron-only device using S-AMP-CBA exhibited lower electron mobility than the R-AMP-CBA-based device. These results imply that the electronic shallow-trap effect ascribed to the LUMO energy variations turned out to be insignificant in the AMP-CBA system. The lower efficiency and mobility of S-AMP-CBA might due to the assumption that the most probable trans-4-III isomer in S-AMP-CBA prevents the intermolecular facial contact of fullerenes, thereby hindering the electron transporting. Furthermore, the nanomorphology of S-AMP-CBA and R-AMP-CBA active layers could be different because of their different three-dimensional structures. This research demonstrated that steric effect of regio-isomers in a given C60 bis-adduct is more crucial than electronic shallow-trap effect. PMID- 24344912 TI - Three-year clinical evaluation of a silorane composite resin. AB - STATEMENT OF PROBLEM: Composite resins are still outperformed by amalgams in the clinical practice with secondary caries and fractures being their most common failures. A material that suffers less polymerization shrinkage might improve the clinical performance of composite resins. PURPOSE: To evaluate the clinical performance of a low-shrink silorane-based composite resin (Filtek LS Low Shrink Posterior Restorative, 3M ESPE, St. Paul, MN, USA) in comparison with a methacrylate-based composite resin (Tetric EvoCeram, Ivoclar Vivadent, Schaan, Principality of Liechtenstein) over time. MATERIALS AND METHODS: Candidates in need of Class II composite resin restorations participated in this randomized controlled clinical trial. Those were 25 female and six male subjects with average age of 44.3 +/- 12.7 years. Participants received 82 restorations, being 54 in premolars and 28 in molars. Procedures, which included the restoration of primary caries lesions or replacement of failing restorations, were done using modified preparations with no bevels or additional retention. Restorations were placed using Filtek LS (and dedicated self-etch adhesive) or Tetric EvoCeram (with AdheSE, Ivoclar Vivadent), following manufacturers' instructions. Incremental placement technique was applied and the restorations were immediately finished. Follow-up evaluations occurred at six, 12, 24, and 36 months and were done using the Federation Dentaire Internationale criteria. Statistical analysis was performed using generalized estimating equations. RESULTS: The recall rate at 36 months was 89%. All interaction terms were not significant. CONCLUSIONS: Filtek LS performs as well as Tetric EvoCeram performs in the clinical setting at 36 months. CLINICAL SIGNIFICANCE: The silorane-based composite resin Filtek LS and the conventional methacrylate-based composite resin Tetric EvoCeram performed similarly well in posterior restorations over at least 36 months of clinical service. PMID- 24344913 TI - RD Lawrence lecture 2013. Stratified approaches to the management of diabetes. AB - A stratified approach to medicine aims to identify subgroups of patients who should be managed differently from others. Diabetes is a condition that offers considerable potential for stratification, in areas of drug response, complication risk and rate of progression amongst others. Approaches to stratification can be simple, using clinical phenotyping, or more complex involving genomic and other '-omic' technologies. In this review, I will highlight the utility of measuring endogenous insulin production to aid in diagnosis and appropriate treatment; outline key advances in monogenic diabetes where determining genetic aetiology can result in dramatic changes in treatment, and describe the developments in the field of pharmacogenetics in Type 2 diabetes. PMID- 24344914 TI - Theme and variations: amphibious air-breathing intertidal fishes. AB - Over 70 species of intertidal fishes from 12 families breathe air while emerging from water. Amphibious intertidal fishes generally have no specialized air breathing organ but rely on vascularized mucosae and cutaneous surfaces in air to exchange both oxygen and carbon dioxide. They differ from air-breathing freshwater fishes in morphology, physiology, ecology and behaviour. Air breathing and terrestrial activity are present to varying degrees in intertidal fish species, correlated with the tidal height of their habitat. The gradient of amphibious lifestyle includes passive remainers that stay in the intertidal zone as tides ebb, active emergers that deliberately leave water in response to poor aquatic conditions and highly mobile amphibious skipper fishes that may spend more time out of water than in it. Normal terrestrial activity is usually aerobic and metabolic rates in air and water are similar. Anaerobic metabolism may be employed during forced exercise or when exposed to aquatic hypoxia. Adaptations for amphibious life include reductions in gill surface area, increased reliance on the skin for respiration and ion exchange, high affinity of haemoglobin for oxygen and adjustments to ventilation and metabolism while in air. Intertidal fishes remain close to water and do not travel far terrestrially, and are unlikely to migrate or colonize new habitats at present, although in the past this may have happened. Many fish species spawn in the intertidal zone, including some that do not breathe air, as eggs and embryos that develop in the intertidal zone benefit from tidal air emergence. With air breathing, amphibious intertidal fishes survive in a variable habitat with minimal adjustments to existing structures. Closely related species in different microhabitats provide unique opportunities for comparative studies. PMID- 24344915 TI - The lack of synchronization between iron uptake and cell growth leads to iron overload in Saccharomyces cerevisiae during post-exponential growth modes. AB - Fermenting cells growing exponentially on rich (YPAD) medium underwent a transition to a slow-growing state as glucose levels declined and their metabolism shifted to respiration. During exponential growth, Fe import and cell growth rates were matched, affording an approximately invariant cellular Fe concentration. During the transition period, the high-affinity Fe import rate declined slower than the cell-growth rate declined, causing Fe to accumulate, initially as Fe(III) oxyhydroxide nanoparticles but eventually as mitochondrial and vacuolar Fe. Once the cells had reached slow-growth mode, Fe import and cell growth rates were again matched, and the cellular Fe concentration was again approximately invariant. Fermenting cells grown on minimal medium (MM) grew more slowly during the exponential phase and underwent a transition to a true stationary state as glucose levels declined. The Fe concentration of MM cells that just entered the stationary state was similar to that of YPAD cells, but MM cells continued to accumulate Fe in the stationary state. Fe initially accumulated as nanoparticles and high-spin Fe(II) species, but vacuolar Fe(III) also eventually accumulated. Surprisingly, Fe-packed 5-day-old MM cells suffered no more reactive oxygen species (ROS) damage than younger cells, suggesting that the Fe concentration alone does not accurately predict the extent of ROS damage. The mode and rate of growth at the time of harvesting dramatically affected cellular Fe content. A mathematical model of Fe metabolism in a growing cell was developed. The model included the import of Fe via a regulated high-affinity pathway and an unregulated low-affinity pathway. The import of Fe from the cytosol to vacuoles and mitochondria and nanoparticle formation were also included. The model captured essential trafficking behavior, demonstrating that cells regulate Fe import in accordance with their overall growth rate and that they misregulate Fe import when nanoparticles accumulate. The lack of regulation of Fe in yeast is perhaps unique compared to the tight regulation of other cellular metabolites. This phenomenon likely derives from the unique chemistry associated with Fe nanoparticle formation. PMID- 24344917 TI - New renal anemia drugs: is there really anything new on the horizon? AB - Anemia has remained one of the most characteristic and visible manifestations of chronic renal failure for over 150 years. The pathogenesis of anemia of chronic kidney disease (CKD) is multifactorial with inadequate production of erythropoietin being the leading factor. The development of recombinant human erythropoietin (epoetin) in the late 1980s was a milestone in treatment of renal anemia. Despite new drugs, our 'good old friend' erythropoietin-stimulating agents are our everyday life in nephrology practice. It seems that peginesatide would not become a new approach for treating anemia of CKD patients, but rather a falling star. Several new strategies for treating the anemia of CKD are currently being investigated in clinical trials, including prolyl hydroxylase inhibitors and modulators of hepcidin activity, but their role in the management of this condition remains to be established. As shown by the expert in this review, we have to take into account not only the safety and convenience of administration but also cost-effectiveness, while biosimilars are consequently knocking at the doors of dialysis units more and more, particularly in Europe. PMID- 24344916 TI - Differential inhibition of LINE1 and LINE2 retrotransposition by vertebrate AID/APOBEC proteins. AB - BACKGROUND: The role of AID/APOBEC proteins in the mammalian immune response against retroviruses and retrotransposons is well established. G to A hypermutations, the hallmark of their cytidine deaminase activity, are present in several mammalian retrotransposons. However, the role of AID/APOBEC proteins in non-mammalian retroelement restriction is not completely understood. RESULTS: Here we provide the first evidence of anti-retroelement activity of a reptilian APOBEC protein. The green anole lizard A1 protein displayed potent DNA mutator activity and inhibited ex vivo retrotransposition of LINE1 and LINE2 ORF1 protein encoding elements, displaying a mechanism of action similar to that of the human A1 protein. In contrast, the human A3 proteins did not require ORF1 protein to inhibit LINE retrotransposition, suggesting a differential mechanism of anti-LINE action of A1 proteins, which emerged in amniotes, and A3 proteins, exclusive to placental mammals. In accordance, genomic analyses demonstrate differential G to A DNA editing of LINE retrotransposons in the lizard genome, which is also the first evidence for G to A DNA editing in non-mammalian genomes. CONCLUSION: Our data suggest that vertebrate APOBEC proteins differentially inhibit the retrotransposition of LINE elements and that the anti-retroelement activity of APOBEC proteins predates mammals. PMID- 24344918 TI - Exploring the aldol reaction using catalytic antibodies and "on water" organocatalysts from QM/MM calculations. AB - The aldol reaction between benzaldehyde and acetone has been investigated using QM/MM Monte Carlo calculations and free-energy perturbation theory to determine the origin of the enhanced rates and enantioselectivities (% ee) derived from an enamine-based catalytic antibody 33F12 and a chiral organocatalyst. Electrostatic stabilization of the general acid/base TyrL36 by TrpH103, SerH100, and AsnL34 enabled the 33F12 active site to exclusively adopt an si-face benzaldehyde orientation for C-C bond formation with the LysH93-enamine. Whereas preorganization was responsible for the exclusive (S)-aldol product in the antibody, the organocatalyst featuring a chiral diphenyl amino alcohol moiety instead derived its preferred (R)-aldol product from an interplay between sterics and electronic stabilization. The si-face benzaldehyde conformation had unfavorable interactions with the organocatalyst in contrast to the re-face. Gas phase calculations predicted a 73% ee; however, solution boosted the % ee values despite similar reaction geometries. An "on water" environment, defined as a reaction that proceeds in an aqueous organic emulsion, yielded a computed 94% ee (exptl 93% ee) compared to a calculated 87% ee in "neat" acetone (exptl 85% ee). Specific hydrogen bonding between the interfacial waters and an amide oxygen on the catalyst was found to control the % ee. A more compact si-face transition structure reduced solvent accessibility to the amide oxygen with a "closed state" steric barrier compared to an "open state" for the re-face. New insight into the synthetically important aldol reaction and state-of-the-art methodology is presented herein. PMID- 24344919 TI - Epigenetic regulation of MDR1 gene through post-translational histone modifications in prostate cancer. AB - BACKGROUND: Multidrug resistance 1 (MDR1) gene encodes for an ATP binding cassette transporter--P-glycoprotein (P-gp)-- involved in chemoresistance to taxanes. MDR1 promoter methylation is frequent in prostate carcinoma (PCa), suggesting an epigenetic regulation but no functional correlation has been established. We aimed to elucidate the epigenetic mechanisms involved in MDR1 deregulation in PCa. RESULTS: MDR1 promoter methylation and P-gp expression were assessed in 121 PCa, 39 high-grade prostatic intraepithelial neoplasia (HGPIN), 28 benign prostatic hyperplasia (BPH) and 10 morphologically normal prostate tissue (NPT) samples, using quantitative methylation specific PCR and immunohistochemistry, respectively. PCa cell lines were exposed to a DNA methyltransferases inhibitor 5-aza-2'deoxycytidine (DAC) and histone deacetylases inhibitor trichostatin A (TSA). Methylation and histone posttranscriptional modifications status were characterized and correlated with mRNA and protein expression. MDR1 promoter methylation levels and frequency significantly increased from NPTs, to HGPIN and to PCa. Conversely, decreased or absent P-gp immunoexpression was observed in HGPIN and PCa, inversely correlating with methylation levels. Exposure to DAC alone did not alter significantly methylation levels, although increased expression was apparent. However, P-gp mRNA and protein re-expression were higher in cell lines exposed to TSA alone or combined with DAC. Accordingly, histone active marks H3Ac, H3K4me2, H3K4me3, H3K9Ac, and H4Ac were increased at the MDR1 promoter after exposure to TSA alone or combined with DAC. CONCLUSION: Our data suggests that, in prostate carcinogenesis, MDR1 downregulation is mainly due to histone post-translational modifications. This occurs concomitantly with aberrant promoter methylation, substantiating the association with P-gp decreased expression. PMID- 24344920 TI - Mechanism of killing of spores of Bacillus anthracis in a high-temperature gas environment, and analysis of DNA damage generated by various decontamination treatments of spores of Bacillus anthracis, Bacillus subtilis and Bacillus thuringiensis. AB - AIMS: To determine how hydrated Bacillus anthracis spores are killed in a high temperature gas environment (HTGE), and how spores of several Bacillus species including B. anthracis are killed by UV radiation, dry heat, wet heat and desiccation. METHODS AND RESULTS: Hydrated B. anthracis spores were HTGE treated at c. 220 degrees C for 50 ms, and the treated spores were tested for germination, mutagenesis, rupture and loss of dipicolinic acid. Spores of this and other Bacillus species were also examined for mutagenesis by UV, wet and dry heat and desiccation. There was no rupture of HTGE-treated B. anthracis spores killed 90-99.9%, no mutagenesis, and release of DPA and loss of germination were much slower than spore killing. However, killing of spores of B. anthracis, Bacillus thuringiensis and Bacillus subtilis by UV radiation or dry heat, but not wet heat in water or ethanol, was accompanied by mutagenesis. CONCLUSIONS: It appears likely that HTGE treatment kills B. anthracis spores by damage to spore core proteins. In addition, various killing regimens inactivate spores of a number of Bacillus species by the same mechanisms. SIGNIFICANCE AND IMPACT OF THE STUDY: This work indicates how hydrated spores treated in a HTGE such as might be used to destroy biological warfare agent stocks are killed. The work also indicates that mechanisms whereby different agents kill spores are similar with spores of different Bacillus species. PMID- 24344921 TI - Identification of a novel PNPLA1 mutation in a Spanish family with autosomal recessive congenital ichthyosis. PMID- 24344922 TI - Temporal course of changes in gene expression suggests a cytokine-related mechanism for long-term hippocampal alteration after controlled cortical impact. AB - Mild traumatic brain injury (mTBI) often has long-term effects on cognitive function and social behavior. Altered gene expression may be predictive of long term psychological effects of mTBI, even when acute clinical effects are minimal or transient. Controlled cortical impact (CCI), which causes concussive, but nonpenetrant, trauma to underlying (non-cortical) brain, resulting in persistent changes in hippocampal synaptic function, was used as a model of mTBI. The hippocampal transcriptomes of sham-operated or injured male rats at 1, 7, and 30 days postinjury were examined using microarrays comprising a comprehensive set of expressed genes, subsequently confirmed by quantitative reverse-transcriptase polymerase chain reaction. Transcripts encoding the chemokines, chemokine (C-C motif) ligand (Ccl)2 and Ccl7, inflammatory mediators lipocalin-2 (Lcn2) and tissue inhibitor of metalloproteinase 1 (Timp1), immunocyte activators C-C chemokine receptor type 5 (Ccr5) and Fc fragment of IgG, low affinity IIb, receptor (CD32) (Fcgr2b), the major histocompatibility complex II immune response related genes, Cd74 and RT1 class II, locus Da (RT1-Da), the complement component, C3, and the transcription factor, Kruppel-like factor 4 (Klf4), were identified as early (Ccl2, Ccl7, Lcn2, and Timp1), intermediate (Ccr5, Fcgr2b, Cd74, RT1-Da, and C3), and late (Klf4) markers for bilateral hippocampal response to CCI. Ccl2 and Ccl7 transcripts were up-regulated within 24 h after CCI, and their elevation subsided within 1 week of injury. Other transcriptional changes occurred later and were more stable, some persisting for at least 1 month, suggesting that short-term inflammatory responses trigger longer-term alteration in the expression of genes previously associated with injury, aging, and neuronal function in the brain. These transcriptional responses to mTBI may underlie long term changes in excitatory and inhibitory neuronal imbalance in hippocampus, leading to long-term behavioral consequences of mTBI. PMID- 24344924 TI - Functional fiber mats with tunable diffuse reflectance composed of electrospun VO2/PVP composite fibers. AB - Thermochromic VO2 nanoparticles have been dispersed into polyvinyl pyrrolidone (PVP) fibers by electrospinning of a VO2-PVP blend solution. The structure and optical properties of the obtained composite fiber mat were studied by X-ray diffraction (XRD), scanning electron microscopy (SEM), ultraviolet-visible (UV Vis) spectrophotometry, and Fourier transform infrared (FT-IR) spectroscopy. The fiber mat revealed two diffuse reflectance states in infrared spectral region at temperatures under and above the phase transition temperature of VO2 and its IR reflectance is smaller in high temperature. The difference of diffuse reflectance between the two states (DeltaRdif) was obvious to be more than 25% in the wavelengths from 1.5 MUm to 6 MUm. The diffuse reflectance of the fiber mat could be controlled by adjusting the diameter of the fiber or the content of VO2 in the fibers and this particular optical property was explained by a multiple scattering-absorbing process. PMID- 24344923 TI - GTP-dependent run-up of Piezo2-type mechanically activated currents in rat dorsal root ganglion neurons. AB - Rapidly adapting mechanically activated channels (RA) are expressed in primary afferent neurons and identified as Piezo2 ion channels. We made whole-cell voltage-clamp recordings from cultured dorsal root ganglion (DRG) neurons to study RA channel regulation. RA currents showed gradual increases in current amplitude (current "run-up") after establishing whole-cell mode when 0.33 mM GTP or 0.33 mM GTPgammaS was included in the patch pipette internal solution. RA current run-up was also observed in HEK293 cells that heterologously expressed Piezo2 ion channels. No significant RA current run-up was observed in DRG neurons when GTP was omitted from the patch pipette internal solution, when GTP was replaced with 0.33 mM GDP, or when recordings were made under the perforated patch-clamp recording configuration. Our findings revealed a GTP-dependent up regulation of the function of piezo2 ion channels in DRG neurons. PMID- 24344925 TI - Achieving universal health coverage through voluntary insurance: what can we learn from the experience of Lao PDR? AB - BACKGROUND: The Government of Lao Peoples' Democratic Republic (Lao PDR) has embarked on a path to achieve universal health coverage (UHC) through implementation of four risk-protection schemes. One of these schemes is community based health insurance (CBHI) - a voluntary scheme that targets roughly half the population. However, after 12 years of implementation, coverage through CBHI remains very low. Increasing coverage of the scheme would require expansion to households in both villages where CBHI is currently operating, and new geographic areas. In this study we explore the prospects of both types of expansion by examining household and district level data. METHODS: Using a household survey based on a case-comparison design of 3000 households, we examine the determinants of enrolment at the household level in areas where the scheme is currently operating. We model the determinants of enrolment using a probit model and predicted probabilities. Findings from focus group discussions are used to explain the quantitative findings. To examine the prospects for geographic scale up, we use secondary data to compare characteristics of districts with and without insurance, using a combination of univariate and multivariate analyses. The multivariate analysis is a probit model, which models the factors associated with roll-out of CBHI to the districts. RESULTS: The household findings show that enrolment is concentrated among the better off and that adverse selection is present in the scheme. The district level findings show that to date, the scheme has been implemented in the most affluent areas, in closest proximity to the district hospitals, and in areas where quality of care is relatively good. CONCLUSIONS: The household-level findings indicate that the scheme suffers from poor risk-pooling, which threatens financial sustainability. The district-level findings call into question whether or not the Government of Laos can successfully expand to more remote, less affluent districts, with lower population density. We discuss the policy implications of the findings and specifically address whether CBHI can serve as a foundation for a national scheme, while exploring alternative approaches to reaching the informal sector in Laos and other countries attempting to achieve UHC. PMID- 24344926 TI - Volunteer stratification is more relevant than technological treatment in orange juice flavanone bioavailability. AB - The effect of two technological treatments on orange juice flavanone bioavailability in humans was assessed. Processing affected flavanone solubility and particle size of the cloud. Volunteers were stratified in high, medium, and low urinary excretion capabilities. Flavanones from high-pressure homogenized juice showed better absorption than those of conventional pasteurized juice in high excretors. These differences were not observed in medium and low excretors. High flavanone excretors took advantage of the high-pressure homogenization juice attributes (smaller cloud particle size) and showed an improved absorption/excretion. Stratification of the individuals by their excretion capability is more relevant than technological treatments in terms of flavanone bioavailability. This stratification should be considered in clinical studies with citrus juices and extracts as it could explain the large interindividual variability that is often observed. PMID- 24344927 TI - Sequence and gene content of a large fragment of a lizard sex chromosome and evaluation of candidate sex differentiating gene R-spondin 1. AB - BACKGROUND: Scant genomic information from non-avian reptile sex chromosomes is available, and for only a few lizards, several snakes and one turtle species, and it represents only a small fraction of the total sex chromosome sequences in these species. RESULTS: We report a 352 kb of contiguous sequence from the sex chromosome of a squamate reptile, Pogona vitticeps, with a ZZ/ZW sex microchromosome system. This contig contains five protein coding genes (oprd1, rcc1, znf91, znf131, znf180), and major families of repetitive sequences with a high number of copies of LTR and non-LTR retrotransposons, including the CR1 and Bov-B LINEs. The two genes, oprd1 and rcc1 are part of a homologous syntenic block, which is conserved among amniotes. While oprd1 and rcc1 have no known function in sex determination or differentiation in amniotes, this homologous syntenic block in mammals and chicken also contains R-spondin 1 (rspo1), the ovarian differentiating gene in mammals. In order to explore the probability that rspo1 is sex determining in dragon lizards, genomic BAC and cDNA clones were mapped using fluorescence in situ hybridisation. Their location on an autosomal microchromosome pair, not on the ZW sex microchromosomes, eliminates rspo1 as a candidate sex determining gene in P. vitticeps. CONCLUSION: Our study has characterized the largest contiguous stretch of physically mapped sex chromosome sequence (352 kb) from a ZZ/ZW lizard species. Although this region represents only a small fraction of the sex chromosomes of P. vitticeps, it has revealed several features typically associated with sex chromosomes including the accumulation of large blocks of repetitive sequences. PMID- 24344929 TI - Fish assemblages associated with oil industry structures on the continental shelf of north-western Australia. AB - This study provides the first assessment of fish associations with oil and gas structures located in deep water (85-175 m) on Australia's north-west continental shelf, using rare oil industry video footage obtained from remotely operated vehicles. A diverse range of taxa were observed associating with the structures, including reef-dependent species and transient pelagic species. Ten commercially fished species were observed, the most abundant of which was Lutjanus argentimaculatus, with an estimated biomass for the two deepest structures (Goodwyn and Echo) of 109 kg. PMID- 24344930 TI - Combination of debulking single-tract percutaneous nephrolithotomy followed by retrograde intrarenal surgery for staghorn stones in solitary kidneys. AB - OBJECTIVE: The aim of this study was to report a therapeutic approach comprising a combination of debulking single-tract percutaneous nephrolithotomy (PCNL) and subsequent retrograde intrarenal surgery (RIRS) for treatment of staghorn stones in patients with solitary kidney. MATERIALS AND METHODS: A retrospective review was undertaken of 56 patients with staghorn stones in a solitary kidney who underwent the above-mentioned combination therapy. PCNL was first performed for stone debulking and RIRS was then used to remove residual stones after an interval of 2-4 days. Data were collected on operative parameters, stone-free rate (SFR), complications and renal functions. RESULTS: The staghorn stones had a mean stone burden of 2548 +/- 1028 mm(2) (range 1438-3956 mm(2)). The SFR after 3 months was 89.3%. The overall blood transfusion rate was 7.1%. Complications were observed in nine patients (16.1%), including selective renal artery embolization, fever, gross haematuria and steinstrasse in one, two, three and three cases, respectively. At a mean follow-up of 31 months, available in 38 patients, kidney function was stable in 71%, improved in 26.3% and worsened in 2.7%, according to serum creatinine levels that remained within +/-20%, or that increased or decreased outside this range. No patient required haemodialysis. CONCLUSIONS: Combining single-tract PCNL with subsequent RIRS was an effective strategic option for treating staghorn stones in solitary kidneys. The method gave an excellent SFR, satisfactory preservation of renal function, reduced bleeding risk and potentially less morbidity than that associated with multiple-tract PCNL. PMID- 24344931 TI - HIV-1-associated PKA acts as a cofactor for genome reverse transcription. AB - BACKGROUND: Host cell proteins, including cellular kinases, are embarked into intact HIV-1 particles. We have previously shown that the Calpha catalytic subunit of cAMP-dependent protein kinase is packaged within HIV-1 virions as an enzymatically active form able to phosphorylate a synthetic substrate in vitro (Cartier et al. J. Biol. Chem. 278:35211 (2003)). The present study was conceived to investigate the contribution of HIV-1-associated PKA to the retroviral life cycle. RESULTS: NL4.3 viruses were produced from cells cultured in the presence of PKA inhibitors H89 (H89-NL4.3) or Myr-PKI (PKI-NL4.3) and analyzed for viral replication. Despite being mature and normally assembled, and containing expected levels of genomic RNA and RT enzymatic activity, such viruses showed poor infectivity. Indeed, infection generated reduced amounts of strong-strop minus strand DNA, while incoming RNA levels in target cells were unaffected. Decreased cDNA synthesis was also evidenced in intact H89-NL4.3 and PKI-NL4.3 cell free particles using endogenous reverse transcription (ERT) experiments. Moreover, similar defects were reproduced when wild type NL4.3 particles preincubated with PKA inhibitors were subjected to ERT reactions. CONCLUSIONS: Altogether, our results indicate that HIV-1-associated PKA is required for early reverse transcription of the retroviral genome both in cell free intact viruses and in target cells. Accordingly, virus-associated PKA behaves as a cofactor of an intraviral process required for optimal reverse transcription and for early post entry events. PMID- 24344932 TI - A fully synthetic and biochemically validated phosphatidyl inositol-3-phosphate hapten via asymmetric synthesis and native chemical ligation. AB - We report the synthesis and biochemical validation of a phosphatidyl inositol-3 phosphate (PI3P) immunogen. The inositol stereochemistry was secured through peptide-catalyzed asymmetric phosphorylation catalysis, and the subsequent incorporation of a cysteine residue was achieved by native chemical ligation (NCL). Conjugation of the PI3P hapten to maleimide-activated keyhole limpet hemocyanin (KLH) provided a PI3P immunogen, which was successfully used to generate selective PI3P antibodies. The incorporation of a sulfhydryl nucleophile into a phosphoinositide hapten demonstrates a general strategy to reliably access phosphoinositide immunogens. PMID- 24344928 TI - Associations of blood glucose and prevalent diabetes with risk of cardiovascular disease in 500 000 adult Chinese: the China Kadoorie Biobank. AB - AIMS: To examine the relationship of self-reported diabetes, and of random blood glucose levels among individuals without known diabetes, with the prevalence of cardiovascular disease in Chinese adults. METHODS: We examined cross-sectional data from the China Kadoorie Biobank of 0.5 million people aged 30-79 years recruited from 10 diverse regions of China in the period 2004-2008. Logistic regression was used to estimate the odds ratios of prevalent cardiovascular disease associated with self-reported diabetes, and with measured random blood glucose levels among participants with no history of diabetes, adjusting simultaneously for age, sex, area, education, smoking, alcohol, blood pressure and physical activity. RESULTS: A total of 3.2% of participants had self-reported diabetes (men 2.9%; women 3.3%) and 2.8% had screen-detected diabetes (men 2.6%; women 2.8%), i.e. they had no self-reported history of diabetes but a blood glucose level suggestive of a diagnosis of diabetes. Compared with individuals without a history of diabetes, the odds ratios associated with self-reported diabetes were 2.18 (95% CI 2.06-2.30) and 1.88 (95% CI 1.75-2.01) for prevalent ischaemic heart disease and stroke/transient ischaemic attack, respectively. Among participants without self-reported diabetes there was a positive association between random blood glucose and ischaemic heart disease and stroke/transient ischaemic attack prevalence (P for trend <0.0001). Below the diabetic threshold (<11.1 mmol/l) each additional 1 mmol/l of random blood glucose was associated with 4% (95% CI 2-5%) and 5% (95% CI 3-7%) higher odds of prevalent ischaemic heart disease and stroke/transient ischaemic attack, respectively. CONCLUSIONS: In this adult Chinese population, self-reported diabetes was associated with a doubling of the odds of prevalent cardiovascular disease. Below the threshold for diabetes there was still a modest, positive association between random blood glucose and prevalent cardiovascular disease. PMID- 24344933 TI - Management patterns of medicare patients undergoing treatment for upper urinary tract calculi. AB - PURPOSE: We conducted this study to identify differences in the re-treatment rates and ancillary procedures for the two most commonly utilized stone treatment procedures in the Medicare population: ureteroscopy (URS) and shock wave lithotripsy (SWL). MATERIALS AND METHODS: A retrospective claims analysis of the Medicare standard analytical file 5% sample was conducted to identify patients with a new diagnosis of urolithiasis undergoing treatment with URS or SWL from 2009-2010. Outcomes evaluated: (1) repeat stone removal procedures within 120 days post index procedure, (2) stent placement procedures on the index date, 30 days prior to and 120 days post index date, and (3) use of general anesthesia. RESULTS: We identified 3885 eligible patients, of which 2165 (56%) underwent SWL and 1720 (44%) underwent URS. Overall, SWL patients were 1.73 times more likely to undergo at least one repeat procedure than URS patients, and twice as likely to require multiple re-treatments compared to URS. Among those with ureteral stones, SWL patients were 2.27 times more likely to undergo repeat procedures. The difference was not statistically significant in renal stone patients. Overall, SWL patients were 1.41 times more likely than URS patients to have a stent placed prior to index procedure, and 1.33 times more likely to have a stent placed subsequent to the index procedure. The majority of URS patients (77.8%) had a stent placed at the time of index procedure. There was no significant difference in anesthetic approaches between SWL and URS. CONCLUSIONS: Patients undergoing SWL are significantly more likely to require re-treatments than URS patients. SWL patients are also significantly more likely to require ureteral stent placement as a separate event. SWL and URS patients have similar rates of general anesthesia. PMID- 24344934 TI - Targeted reengineering of protein geranylgeranyltransferase type I selectivity functionally implicates active-site residues in protein-substrate recognition. AB - Posttranslational modifications are vital for the function of many proteins. Prenylation is one such modification, wherein protein geranylgeranyltransferase type I (GGTase-I) or protein farnesyltransferase (FTase) modify proteins by attaching a 20- or 15-carbon isoprenoid group, respectively, to a cysteine residue near the C-terminus of a target protein. These enzymes require a C terminal Ca1a2X sequence on their substrates, with the a1, a2, and X residues serving as substrate-recognition elements for FTase and/or GGTase-I. While crystallographic structures of rat GGTase-I show a tightly packed and hydrophobic a2 residue binding pocket, consistent with a preference for moderately sized a2 residues in GGTase-I substrates, the functional impact of enzyme-substrate contacts within this active site remains to be determined. Using site-directed mutagenesis and peptide substrate structure-activity studies, we have identified specific active-site residues within rat GGTase-I involved in substrate recognition and developed novel GGTase-I variants with expanded/altered substrate selectivity. The ability to drastically alter GGTase-I selectivity mirrors similar behavior observed in FTase but employs mutation of a distinct set of structurally homologous active-site residues. Our work demonstrates that tunable selectivity may be a general phenomenon among multispecific enzymes involved in posttranslational modification and raises the possibility of variable substrate selectivity among GGTase-I orthologues from different organisms. Furthermore, the GGTase-I variants developed herein can serve as tools for studying GGTase-I substrate selectivity and the effects of prenylation pathway modifications on specific proteins. PMID- 24344935 TI - Vitamin B12-loaded solid lipid nanoparticles as a drug carrier in cancer therapy. AB - Nanostructure-mediated drug delivery, a key technology for the realization of nanomedicine, has the potential to improve drug bioavailability, ameliorate release deviation of drug molecules and enable precision drug targeting. Due to their multifunctional properties, solid lipid nanoparticles (SLNs) have received great attention of scientists to find a solution to cancer. Vitamin supplements may contribute to a reduction in the risk of cancer. Vitamin B12 has several characteristics that make it an attractive entity for cancer treatment and possible therapeutic applications. The aim of this study was to produce B12 loaded SLNs (B12-SLNs) and determine the cytotoxic effects of B12-SLNs on H-Ras 5RP7 and NIH/3T3 control cell line. Results obtained by MTT assay, transmission electron and confocal microscopy showed that B12-loaded SLNs are more effective than free vitamin B12 on cancer cells. In addition, characterization studies indicate that while the average diameter of the B12 was about 650 nm, B12-SLNs were about 200 nm and the drug release efficiency of vit. B12 by means of SLNs increased up to 3 h. These observations point to the fact that B12-SLNs could be used as carrier systems due to the therapeutic effects on cancer. PMID- 24344936 TI - AL amyloidosis or multiple myeloma? An important distinction--response to Falk. PMID- 24344937 TI - How severe is diabetes after total pancreatectomy? A case-matched analysis. AB - OBJECTIVES: Total pancreatectomy (TP) is associated with significant morbidity and mortality. The severity of postoperative diabetes and existence of 'brittle diabetes' are unclear. This study sought to identify quality of life (QoL) and diabetes-specific outcomes after TP. METHODS: Patients who underwent TP were matched for age, sex and duration of diabetes with patients with type 1 diabetes. General QoL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire QLQ-C30 and the PAN26 tool. Diabetes-specific outcomes were assessed using the Problem Areas in Diabetes (PAID) tool and an assessment of diabetes-specific complications and outcomes. RESULTS: A total of 123 patients underwent TP; 88 died (none of diabetic complications) and two were lost to follow-up. Of the remaining 33 patients, 28 returned questionnaires. Fourteen general and pancreas-specific QoL measurements were all significantly worse amongst the TP cohort (QLQ-C30 + PAN26). However, when diabetes-specific outcomes were compared using the PAID tool, only one of 20 was significantly worse. HbA1c values were comparable (P = 0.299), as were diabetes-related complications such as hypoglycaemic attacks and organ dysfunction. CONCLUSIONS: Total pancreatectomy is associated with impaired QoL on general measures compared with that in type 1 diabetes patients. Importantly, however, there was almost no significant difference in diabetes specific outcomes as assessed by a diabetes-specific questionnaire, or in diabetes control. This study does not support the existence of 'brittle diabetes' after TP. PMID- 24344938 TI - Recent advances in pancreatic transplantation. AB - Pancreatic transplantation has progressed in the past 25 years since its initial stages, proving to be highly promising for those with diabetes and its resultant multiorgan disorders. Several studies have shown that patients who receive transplants have better glycemic control, blood pressure control, lipid control, and show reversal of microscopic diabetic changes including neuropathy and improved cardiovascular risks. Advances in many fields have made it possible for more than 32,000 procedures to be done worldwide, and 1- and 5-year posttransplant survival to be 95% and 83%. We sought to explore what advances have taken place in surgical techniques, patient selection, and immuno suppressant therapy to allow this improvement and reduction in complications. New techniques (ie, islet cell implantation) promise early results. However, pancreatic transplant is currently the single existing therapy to establish normal glucose without exogenous insulin. PMID- 24344939 TI - Assessing medication adherence in solid-organ transplant recipients. AB - OBJECTIVES: We sought to determine and compare the prevalence of nonadherence in lung, kidney, and liver transplant recipients, and identify potential risk factors for nonadherence. MATERIALS AND METHODS: This cross-sectional, single center, retrospective cohort study, evaluated 225 outpatient lung, kidney, and liver transplant recipients' adherence to immunosuppressant medication. Based on immunosuppressant dosages and dispensing records, medication possession ratio (days of medication supplied/actual days) and gaps in prescription refills (> 30 day lapse between expected depletion of supply and next refill) were used as surrogate markers in assessing adherence for 2 years. Patients were adherent to their immunosuppressant medication regimens if their medication possession ratio was >= 80%. RESULTS: The mean age of the subjects was slightly greater than 50 years of age, and they were a median of 2.0, 1.3, and 1.1 years posttransplant at the start of data collection for lung, kidney, and liver recipients. Overall medication possession ratios were 95.4% +/- 7.5%, 95.9% +/- 7.6%, and 92.7% +/- 12.3% in our lung, kidney, and liver recipients. Only 7.1% of patients had a medication possession ratio lower than 80%, which was the cutoff for nonadherence. No statistical analyses were performed to identify potential factors for nonadherence because of the small number of nonadherent patients. CONCLUSIONS: Immunosuppressant medication adherence at our center was high for all 3 organ cohorts, as measured by a medication possession ratio of 80% or better. Further study is needed to evaluate immunosuppressant adherence over time after transplant, and confirm the clinical factors that optimize adherence in high-risk patients. PMID- 24344940 TI - Hyperuricemia in pediatric renal transplant recipients. AB - OBJECTIVES: We sought to evaluate the prevalence and confounding clinical variables of hyperuricemia in pediatric kidney transplant patients. MATERIALS AND METHODS: We retrospectively evaluated the medical records of 151 pediatric renal transplant recipients who received their grafts at Akdeniz University Medical Faculty in Antalya, Turkey, with a follow-up longer than 6 months. This retrospective, single-center study included 117 pediatric renal transplant recipients, after we had excluded the patients with changes in immunosuppressive treatment and graft loss, who were receiving therapy with allopurinol and furosemide. Patient information and laboratory data were obtained from patient charts and an electronic hospital database. RESULTS: Mean uric acid levels of patients were 311 +/- 74 MUmol/L, and 24 of all of the patients (20%) had high uric acid levels. Fifteen patients taking tacrolimus (16%), and 9 of patients taking cyclosporine (39%) had hyperuricemia. The hyperuricemia rate of patients taking cyclosporine was significantly higher than it was for those patients taking tacrolimus (P = .014). Mean levels of uric acid in patients taking cyclosporine were higher than those of patients taking tacrolimus (344 +/- 62 MUmol/L and 303 +/- 75 MUmol/L; P = .006). There was a significant positive correlation between mean uric acid concentrations, and both serum creatinine (P = .000; r=0.487) and cystatin C (P = .000; r=0.433). There was negative correlation between mean uric acid concentration and estimated glomerular filtration rate (P = .000; r=-0.417). Mean uric acid levels of patients with intact graft function (estimated glomerular filtration rate >= 60 mL/min/1.73 m2) was lower than the patients with a low estimated glomerular filtration rate (291 +/- 67 MUmol/L and 353 +/- 71 MUmol/L; P = .000). Mean uric acid level of patients with normal body mass index was significantly lower than that of patients who were obese overweight (301 +/- 64 MUmol/L vs 343 +/- 94 MUmol/L; P = .045). CONCLUSIONS: We found 20% of our patient group had high uric acid levels. We also found that lower glomerular filtration rate, higher serum creatinine, cystatin c, obesity, and being overweight were risk factors for hyperuricemia in pediatric renal transplant recipients. PMID- 24344941 TI - Sitagliptin might be a favorable antiobesity drug for new onset diabetes after a renal transplant. AB - OBJECTIVES: The aim of this study was to evaluate the effectiveness of sitagliptin, alone or in combination with metformin, in kidney transplant patients with newly diagnosed new-onset diabetes mellitus after transplant who had inadequate glycemic control, compared with a group of patients receiving insulin glargine with special emphasis on weight gain. MATERIALS AND METHODS: Newly diagnosed renal transplant patients with new-onset diabetes mellitus after a transplant was defined by a blood glucose >= 11.1 mmol/L after an oral glucose tolerance test were examined. They were treated with standard immunosuppression composed of triple therapy with tacrolimus or cyclosporine, mycophenolate mofetil or azathioprine, and prednisone. They had stable graft function for more than 6 months after the transplant. RESULTS: Patients with new-onset diabetes mellitus after transplant (n=28) whose glycemia was not controlled adequately with oral hypoglycemic agents (either alone or in combination) received oral sitagliptin 100 mg once daily in addition to existing therapy for 12 weeks. Patients who received insulin glargine as add-on therapy (n=17) served as the control group. Data analyses included glycated hemoglobin, fasting plasma glucose, lipid profile, body weight, and the occurrence of hypoglycemia. We found significant reductions in glycated hemoglobin and fasting plasma glucose values after 12 weeks of additional sitagliptin therapy that were comparable to those with insulin glargine. While the addition of stagliptin resulted in a small weight loss (0.4 kg), the addition of insulin glargine resulted in a weight gain (0.8 kg). The overall incidence of adverse experiences was low and generally mild in both groups. CONCLUSIONS: In a group of renal transplant recipients with new onset diabetes mellitus after a transplant in whom glycemia was not controlled adequately by oral hypoglycemic agents, the addition of sitagliptin helped to achieve glycemic control similar to insulin glargine but with a marginal weight advantage. PMID- 24344942 TI - HLA-DR overexpression in tubules of renal allografts during early and late renal allograft injuries. AB - OBJECTIVES: We sought to discover which types of injuries were related to human leukocyte antigen DR expression in acute rejection and late chronic injury in renal allografts. MATERIALS AND METHODS: Ninety-two recipients were separated into the early acute rejection group, the late monocyte infiltration group, and the late chronic injury group. Ten subjects with acute cellular rejection received a repeat biopsy. All samples were stained with CD4, CD8, CD20, CD68, and human leukocyte antigen DR by immunochemical staining. Levels of these markers were compared among the subgroups of each group. RESULTS: Human leukocyte antigen DR expression was greater in the early C4d-negative acute rejection group than it was in the early C4d-positive acute rejection group. Human leukocyte antigen DR expression was greater during acute rejection than that was on a repeat biopsy. Human leukocyte antigen DR expression was accord with the infiltration of monocyte infiltration in the acute cellular rejection group. Human leukocyte antigen DR expression was greater during late acute rejection than it was in BK virus nephropathy, which was not in accord with monocyte infiltration. Human leukocyte antigen DR expression was greater during chronic rejection than it was in IgAN, BK virus nephropathy, and TA/IF groups, and even in tubular atrophy. CONCLUSIONS: Human leukocyte antigen DR expression in renal tubular cells was associated with early acute cellular rejection and was in accord with monocyte infiltration. Human leukocyte antigen DR expression in renal tubular cells during the late phase (especially in tubular atrophy) was a marker of chronic rejection, but was not in accord with monocyte infiltration in renal allografts. PMID- 24344943 TI - Kidney transplant grafts with complete ureteral duplication. AB - OBJECTIVES: To evaluate the outcome of renal transplants using donor grafts with complete ureteral duplication. MATERIALS AND METHODS: Between 1999 and 2011, we performed 1368 kidney transplant procedures, including 87 dual kidney transplants. There were 12 transplants with donor kidneys that had complete ureteral duplication, including 2 patients who had grafts with ureteral duplication that were used to perform a dual kidney transplant. In 11 patients with ureteral duplication, the 2 ureters were anastomosed separately to the bladder with a double Lich-Gregoir technique; in 1 patient, a ureteroureteral terminolateral anastomosis and single ureteroneocystostomy were performed. RESULTS: Urinary tract infections were noted during the first year after transplant in 7 patients (58%) that had kidney grafts with duplicated ureters (4 patients with 1 infection each; 3 patients with 2 infections each), but none developed pyelonephritis, functional impairment, or graft loss. There were no other urologic or renal complications observed in recipients of grafts with ureteral duplication. CONCLUSIONS: Donor kidneys with ureteral duplication may be used in renal transplant. The double Lich-Gregoir technique may provide excellent results. PMID- 24344944 TI - Survival without biliary complications after liver transplant for primary sclerosing cholangitis. AB - OBJECTIVES: Patients who have a liver transplant for primary sclerosing cholangitis may develop recurrent disease and biliary complications, organ loss necessitating revision liver transplant, or death. We evaluated long-term outcomes in patients who had liver transplant for primary sclerosing cholangitis. MATERIALS AND METHODS: In 71 patients who had a liver transplant for end-stage liver disease because of primary sclerosing cholangitis, a retrospective review was done to evaluate biliary complication-free survival, transplanted organ survival, and death. Human leukocyte antigen typing and matching were reviewed. RESULTS: There were 39 patients (55%) who had biliary complications, loss of the liver transplant, or death at a mean 12.1 years after transplant. The 5- and 10 year event-free survival reached 74.6% and 45% (53 patients after 5 years, and 32 patients after 10 years). Male sex of transplant recipients was a significant risk factor for biliary complications, revision liver transplant, or death. Most patients had inflammatory bowel disease, primarily ulcerative colitis. The human leukocyte antigen profile or number of mismatches had no effect on complication free survival. CONCLUSIONS: Biliary complications, revision liver transplant, and death are a useful combined primary endpoint for recurrent primary sclerosing cholangitis after liver transplant. PMID- 24344945 TI - Chronotropic incompetence on dobutamine stress echocardiography in candidates for a liver transplant. AB - OBJECTIVES: We evaluated dobutamine stress echocardiography as an initial screening test for a cardiac evaluation before a liver transplant. MATERIALS AND METHODS: We retrospectively examined 111 liver transplant candidates who had undergone previous cardiac evaluation; 30 of whom had undergone a liver transplant. RESULTS: Eighty patients (72.1%) completed a dobutamine stress echocardiography (41 chronotropically competent, 39 incompetent), while 31 patients (27.9%) required us to terminate early. Overall, 68 patients (61%) were on beta-blockers (21 required early dobutamine stress echocardiography termination, 30 chronotropically incompetent, and 17 competent). Patient results were normal. Thirty patients underwent a liver transplant. Among candidates requiring termination of early dobutamine stress echocardiography, posttransplant cardiac events included 1 fatal acute myocardial infarction, 1 nonfatal acute myocardial infarction, and 1 idiopathic cardiomyopathy. Among chronotropically incompetent patients, 2 patients had transient bradycardia, and among those who were chronotropically competent, 1 had refractory atrial fibrillation, and 1 had transient bradycardia. CONCLUSIONS: Nearly 50% of patients with end-stage liver disease may not reach the target heart rate. Early termination of dobutamine stress echocardiography because of cardiac symptoms or significant echocardiographic changes have more effect in predicting postoperative cardiac events, but further evaluation is required even if their target heart rate is close to that desired. Lower target heart rate may be acceptable in chronotropically incompetent individuals provided they are asymptomatic, have no echocardiographic changes, or cardiovascular risk factors, especially if they are on beta-blockers. PMID- 24344946 TI - Mucormycosis of the transplanted kidney with renal papillary necrosis. AB - The occurrence of renal allograft mucormycosis is uncommon, but its association with renal papillary necrosis has not been reported. We describe such an association in a patient who survived on peritoneal dialysis after nephrectomy and antifungal therapy. PMID- 24344947 TI - Candida arteritis in a pair of renal transplant recipients. AB - Graft site candidiasis is a rare but life-threatening complication of renal transplant. We report the course and management of 2 renal transplant recipients, using kidneys from a single donor, both of whom developed vascular complications secondary to Candida infection. PMID- 24344948 TI - Sudden hearing loss associated with tacrolimus after pediatric renal transplant. AB - OBJECTIVES: Hearing impairment is a frequent problem that can easily influence the quality of life for the individual. It may affect one's social and academic life. Knowledge regarding hearing impairment after renal transplant is sparse. It has been suggested that renal transplant improves hearing function. Potential ototoxic side effects may be related to immunosuppression with calcineurin inhibitors. In pediatric renal transplanted patients, we do not have enough information about this subject. We report 2 cases that developed sudden hearing loss after a renal transplant that was associated with high serum levels of tacrolimus. CASE REPORTS: Two renal transplanted children (a 15-year-old boy and a 17-year-old girl), in the fourth year of their follow-up after transplant, developed symptomatic bilateral sudden hearing loss. There was a marked hearing impairment for the higher frequencies between 4000 and 8000 Hz in pure-tone audiometry evaluation. Also, a decrease of speech understanding was found, but the patients were not conscious of this problem. Hearing loss in these patients was not associated with any known risk factors such as chronic renal disease, ototoxic drugs, or acoustic trauma. Sudden hearing loss occurred under high serum levels of tacrolimus, and after dosage correction of tacrolimus pure-tone audiometry ruled out hearing loss progression for each patient. CONCLUSIONS: Awareness of this potential complication of tacrolimus may be helpful for early recognition and treatment. PMID- 24344949 TI - A malignant hyperthermialike episode in a liver transplant recipient. AB - We report a case of malignant hyperthermialike syndrome in a living-donor liver transplant recipient with no familial history of malignant hyperthermia or exposure to known triggering drugs. The patient showed many features of a typical malignant hyperthermia episode, and The Clinical Grading Scale defined this case as almost certain to be an episode of malignant hyperthermia (rank 5). However, the diagnosis was questionable. The intraoperative and perioperative periods during liver transplant can involve drastic alterations of physiological parameters, which can make malignant hyperthermia difficult to diagnosis. The data we obtained using a pulmonary artery catheter suggest an intraoperative increase in systemic oxygen consumption. PMID- 24344950 TI - Is warm ischemia not a risk factor for delayed graft function in a living-donor kidney transplant? AB - The association between prolonged donor warm ischemia time and poor early graft function has been challenged, but with little evidence. We intend to remove ambiguities and present evidence from the current literature. All donor surgeons must strive to limit warm ischemia to reduce poor early graft function and improve long-term outcomes. PMID- 24344951 TI - Warm ischemia is not a risk factor for delayed graft function in a living-donor kidney transplant. PMID- 24344952 TI - Patterns of early emotional and neuropsychological sequelae after mild traumatic brain injury. AB - Although mild traumatic brain injury (mTBI) is now recognized as a major health issue, there have been relatively few studies of its acute effects. Previous studies of mTBI assessed at 1 week or less post-injury have produced inconsistent results, spanning reports of no ill effects to findings of robust dysfunction. These gross disparities reflect study differences such as the criteria for mTBI diagnosis and selection of comparison groups. In consideration of these issues, this study investigated outcome in the first 96 hours after injury in adolescents and adults ages 12-30 years with mTBI (n=73) compared with orthopedically injured (OI, n=65) and typically developing controls (TDC, n=40). The mTBI group reported significantly greater general psychological distress, post-concussion symptom severity, and post-traumatic stress severity than OI (all p<0.0001) and TDC (all p<0.0001); the OI and TDC groups responded similarly on these variables. There was a significant Group * Age interaction on the Total score (p<0.009), and the Cognitive (p=0.01) and Somatic (p<0.032) subscales of the Rivermead Post Concussion Symptoms Questionnaire where increasing symptom severity was associated with increasing age in the mTBI group. On neuropsychological assessment, the mTBI group performed significantly more poorly compared with OI for Verbal Selective Reminding Test (delayed recall, p=0.0003) and Symbol-Digit Modalities Test (SDMT written p=0.03; oral, p=0.001). The TDC group more robustly outperformed the mTBI group on these measures and also on the Brief Visuospatial Memory Test (delayed recall, p<0.04), Letter Fluency (p<0.02), and Category Switching (p<0.04). The TDC group outperformed the OI group on SDMT and Letter Fluency. These findings are consistent with previous reports of acute deficits in episodic memory and processing speed acutely after mTBI. Notably, however, these data also demonstrate the challenges of comparison group selection because differences were also found between the TDC and OI groups. PMID- 24344954 TI - Improved accuracy in 3D analysis using DLT after lens distortion correction. AB - This study aimed at assessing the applicability of a robust method to determine and correct lens distortion before using the direct linear transformation (DLT) algorithm in three-dimensional motion analysis. The known length of a rigid bar was reconstructed under different conditions of working volume (interpolation or extrapolation), number of cameras (2 or 4), position of the cameras (wide or narrow angle between optical axes), camera focal distance (4 or 8 mm) and number of control points (CPs; 8, 12, 18 or 162), through four different camera set-ups. The accuracy (percent root mean square error) of Set-up 2 (non-extrapolated working volume; two cameras; 4 mm focal distance; narrow optical axes angle) decreased with less CPs (162: 0.73%; 8: 2.78%). Set-up 1 (non-extrapolated working volume; two cameras; 8 mm focal distance; wide optical axes angle), Set up 3 (Set-ups 1 and 2 used simultaneously) and Set-up 4 (extrapolated working volume; two cameras; 4 mm focal distance; wide optical axes angle) showed minor differences in accuracy across groups of CPs, with maximum values of 0.84%, 1.20% and 1.71%, respectively. Random errors were the main source of decreased accuracy of Set-ups 2 and 4.The proposed procedure enables accurate results with no modification in the DLT-based analysis system, even with smaller calibration frames, less CPs and wide field-of-view cameras. PMID- 24344953 TI - Short communication: CD4 T cell declines occurring during suppressive antiretroviral therapy reflect continued production of Casp8p41. AB - Most patients on suppressive antiretroviral therapy (ART) experience improvements in CD4 T cell count. However, some patients with undetectable viral load continue to lose CD4 T cells for unknown reasons. Casp8p41 is a host-derived protein fragment that is present only in productively infected cells and that causes the death of HIV-infected cells. We questioned whether ongoing CD4(+) T cell losses while on suppressive ART were associated with subclinical HIV replication causing production of Casp8p41. We analyzed the association of Casp8p41 content with subsequent CD4 losses in patients on continuous suppressive ART and in patients who discontinued ART after Casp8p41 content was determined, adjusting for age, baseline CD4(+) T cell count, and baseline HIV RNA level. Casp8p41 expression in memory CD4(+) T cells was measured by intracellular flow cytometry and was correlated with viral load and CD4(+) T cell change over time. In patients who stopped therapy after Casp8p41 content was determined, baseline Casp8p41 content did not predict CD4(+) T cell change. However, in patients on continuous ART, higher baseline Casp8p41 content was associated with a greater odds of a CD4(+) T cell decline at 6 months (p=0.01). Therefore, patients on suppressive ART, who have ongoing production of Casp8p41, have an increased risk of CD4 T cell losses, suggesting that subclinical HIV replication is driving both Casp8p41, which in turn causes a CD4(+) T cell decline. PMID- 24344955 TI - Analysis of the esthetic outcome after root coverage procedures using a comprehensive approach. AB - STATEMENT OF THE PROBLEM: There is a reported gap between the relative satisfaction of the clinician and patient after a root coverage procedure. In addition, there may also be a disparity between objective esthetic evaluation tools and subjective satisfaction. METHODS: This study included 58 sites in 31 patients who had undergone root coverage procedures. The percentage of root coverage and the root coverage esthetic score system were used as objective measurements. A questionnaire with a five-point ordinal scale was used for subjective evaluation. Initial recession depth and width, Miller classification, tissue biotype, treatment procedures, and follow-up periods were considered as associated factors. RESULTS: After a period of at least 6 months from the procedure, the patient-perceived outcome showed a better match with the root coverage esthetic scoring system than the percentage of root coverage alone. A lower value for objective outcome was obtained for a deeper gingival recession and higher Miller class, but the subjective outcome displayed a steady trend. All four esthetic results were at their lowest after an epithelialized free soft tissue graft. CONCLUSION: An esthetic outcome according to patient satisfaction was not always consistent with that determined by professional scoring. In addition, partial root coverage may be viewed as a positive outcome by patients and clinicians in cases of deep gingival recession and high Miller class. CLINICAL SIGNIFICANCE: This study evaluates the esthetic outcome of root coverage procedures using an objective method, including the percentage of root coverage, root coverage esthetic scoring system, and subjective assessment by patient and clinician-based questionnaires. The results will be helpful for the understanding of the differences that exist in esthetic satisfaction. PMID- 24344956 TI - Distribution of sleeping sites of the Yunnan snub-nosed monkey (Rhinopithecus bieti) in the Samage Forest, China. AB - Sleeping site locations are important to free-ranging primate groups. Sites are strategically selected by primates so as to optimize security, comfort and foraging efficiency. Data were collected on the distribution of sleeping sites of the Yunnan snub-nosed monkey (Rhinopithecus bieti) between Sep 2005 and Sep 2006 at Gehuaqing in Baimaxueshan Nature Reserve, China. We identified 54 sleeping sites, which were used 137 times during the study period. These sleeping sites were distributed throughout the monkey group's total home range. R. bieti preferred certain sleeping sites over others: 63% of the sleeping sites were used 2 or more times in 13 months. Groups reused locations in an unpredictable long term pattern, but avoided using the same sleeping site on consecutive nights. To reduce the time and energetic costs of travel, monkeys preferred sleeping near commonly used feeding sites. We recorded 124 feeding sites in the home range, which were used 174 times. A total of 27 sleeping sites were also feeding sites, and all remaining sleeping sites were close to feeding sites. There was a positive correlation between the intensity of use of sleeping sites and feeding sites. The present study suggests that the availability and the location of immediate sources of food is a key factor in the choice of sleeping sites. PMID- 24344957 TI - Substrate use and postural behavior in free-ranging snub-nosed monkeys (Rhinopithecus bieti) in Yunnan. AB - Extant colobines represent a predominantly arboreal primate radiation, but there are outliers such as some species of snub-nosed monkeys (Rhinopithecus spp.) that utilize both arboreal and terrestrial substrates. We quantified the degree of terrestriality and the distribution of individuals across canopy levels, the extrinsic and intrinsic determinants and constraints of strata association as well as use of postures in relation to behavior and food sources in a wild population of Yunnan snub-nosed monkeys (Rhinopithecus bieti) in the Samage Forest, China. The subjects spent 80.5% of the observation time in the trees and 19.5% on the ground. Ground use occurred most frequently in the context of travelling (61%) and less often in the context of feeding and resting (30% combined). Adult males frequented the ground significantly more often than other age-sex classes. Age-sex differences were also apparent in substrate preferences, which likely reflect body weight constraints. Adult males were significantly more associated with solid substrates and less with terminal branches than adult females and juveniles. Juveniles were seen more often on unstable ground (i.e. on thin and oblique branches) and in the upper canopy. Substrate use also varied with behavior: feeding was much more common in the upper stratum, outer canopy, on highly inclined and thin branches, as compared to resting. Severe weather also influenced canopy use in that tree crowns were used less often during periods of snowfall. The most frequently exhibited resting and feeding postures was sitting. Standing and suspensory postures were most often used in the context of feeding on lichens. PMID- 24344958 TI - Habitat use and locomotion of the Francois' langur (Trachypithecus francoisi) in limestone habitats of Nonggang, China. AB - We collected data on habitat use and locomotion of the Francois' langur (Trachypithecus francoisi) between August 2003 and July 2004 at Nonggang Nature Reserve, China. A total of 739 h of behavioral data were collected during this study. We tested 2 predictions: (1) that the langurs may have special patterns of habitat use and locomotion adaptive to the limestone habitat, and (2) the langurs may exhibit different patterns of habitat use and locomotion among different zones of limestone hill. Our results indicated that Francois- langurs spent more time in the low-risk, relatively food-poor cliff-hilltop areas. When young leaves and fruit were scarce in the dry season, the langurs increased their time in the high-risk, food-rich valley basin. Francois- langurs were semi-terrestrial, and leaping and climbing were their main locomotor modes. These behavioral patterns are considered to be related to characteristics of topography and vegetation in limestone habitat, such as large areas of cliff and discontinuous canopy. Our results also supported Prediction 2. The langurs confined locomotion to the main canopy and frequently adopted leaping while traveling in the hillside and valley basin. While traveling in cliff-hilltop areas, they tended to stay in the lower stratus (<=5 m) or move on the ground, and walking and climbing were their dominant traveling modes. PMID- 24344959 TI - Locomotion behavior of cao vit gibbon (Nomascus nasutus) living in karst forest in Bangliang Nature Reserve, Guangxi, China. AB - The cao vit gibbon is a critically endangered species. Only approximately 110 individuals remain in degraded karst forest along the China-Vietnam border. Karst forest is unusual gibbon habitat. Currently, the canopy height of cao vit gibbon habitat is approximately 10 m. Research on the locomotor behavior of gibbons living in this particular forest type might provide important insight into locomotor stability and variability of gibbons. We used 5 min scan samples to record the locomotion mode, support use and canopy strata of gibbons in 3 groups for 2096 h between January 2008 and December 2009. Although cao vit gibbon habitat has a lower canopy in comparison to that of other forests inhabited by gibbons, cao vit gibbons displayed a similar overall locomotor pattern to other gibbon species (Symphalangus syndactylus, Hylobates lar and Hylobates agilis) in which brachiation dominate their locomotor behavior. Cao vit gibbons spent most of their time travelling on inclined branches (2-10 cm) in the middle stratum through the forest canopy. Adult females appear to more often employ safer modes of locomotion (bridging more often and brachiation less), while adult males choose riskier modes (leaping more and climbing less). As gibbons increased in body weight, as they grew from infant to adult, they tended to use larger supports. This research documented that locomotor behavior in Hylobatidae is strongly determined by anatomical characters, but cao vit gibbons also show the ability to use various supports, enabling them to survive in karst forest. PMID- 24344960 TI - Male attacks on infants and infant death during male takeovers in wild white headed langurs (Trachypithecus leucocephalus). AB - Infanticide was first observed in langurs nearly 50 years ago, and this rare phenomenon has been inferred to have either an evolutionarily adaptive function or to be a pathological and non-functional behavior. In this study, we report 5 male takeover events in one-male groups of white-headed langurs in the Nongguan Karst Hills, Guangxi, China from 1998 to 2006. We recorded 13 attacks on 9 infants by extra-group males or new resident males. During the male takeovers, all of the infants younger than 6 months (with an average age of 3.6 months [N = 11]) in the groups disappeared. The infant death rate during the 4.2 months after takeover by a new male was significantly higher than the infant death rate calculated for most of the year. Older infants that were still nursing (with an average age of 14.1 months [N = 7]) were often attacked and seriously wounded by the extra-group males or new resident males, but all of them survived. The interbirth intervals of females whose infants were assumed to be killed by males were significantly reduced relative to those of females in groups with stable male tenure (mean = 10 months vs 25 months). Our data suggest that males kill unrelated and unweaned infants during the takeover period to decrease the time until the infants' mothers resume fertility. Thus, infanticide would support sexual selection theory in white-headed langurs. The data also show that infanticidal behavior was directed toward the infants, especially those who were still nursing. Female dispersal may function as a counter-strategy to avoid infanticide. PMID- 24344961 TI - Foot use and hand preference during feeding in captive black-and-white snub-nosed monkeys (Rhinopithecus bieti). AB - Postural origin theory predicts that body postures are related to hand preference in nonhuman primates due to hemispheric specialization. Foot preference, especially in manipulating objects, is also a good predictor of hemispheric specialization in humans. We studied limb (hand and foot) preferences in 11 captive adult black-and-white snub-nosed monkeys (Rhinopithecus bieti) to see how limb preference is influenced by postures and foot manipulation. Hand preference was significantly different for this group between quadrupedal standing and clinging postures, and sitting and clinging postures, but not between bipedal standing and clinging postures. Individuals were significantly more likely to use the right hand in the clinging posture than in quadrupedal standing or sitting postures. In the sitting posture, individuals maintained their respective hand preference even when the food was on the other side of the body. There was a gender difference in the sitting posture, where females preferred their right hand but males preferred their left. Individuals who did not routinely use their feet to manipulate objects, compared to those who did, shifted to greater right hand use from the clinging posture to the bipedal posture. One male individual and his offspring were more likely to use their feet to manipulate objects than the rest of the monkeys. In the present study, we reveal the first evidence of a postural effect on hand preference in R. bieti as well as a foot preference in this species. Our results mostly agree with the postural origin theory and hemispheric specialization. PMID- 24344962 TI - A short note on extractive foraging behavior in gray snub-nosed monkeys. AB - Extractive foraging (EF) involves the exploitation of hidden or embedded foods, generally any food that is not visible to the naked eye. Therefore, EF is particularly important for survival in marginal habitats as it provides seasonal fallback foods in low food availability seasons. Although many studies consider primates' EF behavior and category, colobine species are usually categorized as non-extractive foragers and few studies quantitatively examine their EF behavior. In this study, we examined the EF behavior of one colobine species, the gray snub nosed monkey (Rhinopithecus brelichi), at Yangaoping in Fanjingshan National Nature Reserve, Guizhou. We recorded 6 categories of EF behaviors. The most frequently sought-out foods were seeds, young bamboo and invertebrates. Extracted foods accounted for an average of 26.02% of feeding records. As the monkey engages in little EF behavior in the winter when the food availability is low, these results seem to do not support the hypothesis that EF serves to secure additional resources during lean times in marginal or seasonal habitats. According to these findings, we suggest R. brelich should be considered as an extractive forager. Our study also highlights the need for increased representation of colobines in the EF literature to better inform the discussion concerning its link to primate brain evolution. PMID- 24344963 TI - A short note on seed dispersal by colobines: the case of the proboscis monkey. AB - Although the role of primates in seed dispersal is generally well recognized, this is not the case for colobines, which are widely distributed in Asian and African tropical forests. Colobines consume leaves, seeds and fruits, usually unripe. A group of proboscis monkeys (Colobinae, Nasalis larvatus) consisting of 1 alpha-male, 6 adult females and several immatures, was observed from May 2005 to May 2006. A total of 400 fecal samples from focal group members covering 13 months were examined, with over 3500 h of focal observation data on the group members in a forest along the Menanggul River, Sabah, Malaysia. Intact small seeds were only found in 23 of 71 samples in Nov 2005, 15 of 38 in Dec 2005 and 5 of 21 in Mar 2006. Seeds of Ficus (all <1.5 mm in length) were found in all 3 months and seeds from Antidesma thwaitesianum (all <3 mm) and Nauclea subdita (all <2 mm) only in Nov and Dec, which was consistent with members of the study group consuming fruits of these species mostly at these times. To our knowledge, these are the first records of seeds in the fecal samples of colobines. Even if colobines pass relatively few seeds intact, their high abundance and biomass could make them quantitatively significant in seed dispersal. The potential role of colobines as seed dispersers should be considered by colobine researchers. PMID- 24344964 TI - A newly-found pattern of social relationships among adults within one-male units of golden snub-nosed monkeys (Rhinopithecus roxenalla) in the Qinling Mountains, China. AB - Group living provides various advantages to individuals in regards to protection avoidance, intergroup competition, productive success and social information. Stable one-male units (OMUs) consist of relationships between the adult females and the resident male as well as the relationships among adult females. Based on continuous observation of a reproductive group of golden snub-nosed monkeys (Rhinopithecus roxellana) in the Qinling Mountains, we analyzed the relationships among adult individual dyads within 4 OMUs. The results indicated that in golden snub-nosed monkey societies, females not only had no strong tendency to build a relationship with the resident male in the OMU but also had no strong tendency to build relationships with other females in the OMU. In comparison with hamadryas (Papio hamadryas) and gelada baboons (Theropithecus gelada), the relationships within golden snub-nosed monkeys OMUs showed neither the star-shaped pattern observed in hamadryas baboons nor the net-shaped pattern observed in gelada baboons. We concluded that the relationships within golden snub-nosed monkey OMUs indicated a third pattern in nonhuman primate societies. Future research is required to determine the potential mechanisms for such a pattern. PMID- 24344965 TI - Genetic analysis of group composition and relatedness in white-headed langurs. AB - We collected fecal samples of white-headed langurs from 3 of the 4 remaining habitat fragments (Fa, Fb and CZ) located in southwestern Guangxi, China in Nov 2005, and used 5 microsatellite loci and the SRY gene to assess the relatedness between 46 langurs within and between groups. We observed 2 forms of group structure: one-male/multi-female groups (OMGs) and all-male groups (AMGs). One AMG in Fa was composed of 2 generations, included a father, 2 sons and 1 unrelated male, and all OMGs in all 3 habitats included 1 resident male, several adult females and offspring. Of the 21 identified father-offspring cases, the resident male fathered 20 (95%) and the non-resident male sired 1 (5%), suggesting that adult males had overwhelming priority of access to females as the resident male in an OMG, while the non-resident male may also have the opportunity to adopt surreptitious mating strategies. PMID- 24344966 TI - Southeast Asian primate communities: the effects of ecology and Pleistocene refuges on species richness. AB - We examined historical and ecological factors affecting current primate biodiversity in Southeast Asia. In Africa, Madagascar and South America, but not Southeast Asia, primate species richness is positively associated with average rainfall and distance from the equator (latitude). We predicted that Southeast Asia's non-conformance may be due to the effect of dispersed Pleistocene refuges (locations of constricted tropical forests during glacial maxima which today are at least 305 m in altitude). Based on 45 forested sites (13 on large islands; 32 on the mainland) of at least 100 km(2) to minimize recent human impact, we determined correlations between extant primate species richness and rainfall, latitude and supplementary ecological variables, while controlling for refuges and islands. We found that refuge sites had significantly higher primate species richness than non-refuges (t = -2.76, P < 0.05), and distance from the nearest Pleistocene refuge was negatively correlated with species richness for non-refuge sites (r = -0.51, P < 0.05). There was no difference in species richness between sites on large islands and the mainland (t = -1.4, P = 0.16). The expected positive relationship between rainfall and species richness was not found (r = 0.17, P = 0.28). As predicted, primate species richness was negatively correlated with latitude (r = -0.39, P < 0.05) and positively correlated with mean temperature (r = 0.45, P < 0.05). General linear models indicated that a site's latitude (F1,38 = 6.18, P < 0.05) and Pleistocene refuge classification (F1,42 = 5.96, P < 0.05) were the best predictors of species richness. Both ecological and historical factors contribute to present day primate species richness in Southeast Asia, making its biodiversity less of an outlier than previously believed. PMID- 24344967 TI - Observation of intra-group and extra-group copulation and reproductive characters in free ranging groups of western black crested gibbon (Nomascus concolor jingdongensis). AB - Black crested gibbons (Nomascus concolor) are 1 of only 3 gibbon species that have been observed in long-term polygynous groups, but their mating behavior and reproductive characters have never been reported. Based on population monitoring over 7 years and direct observation for 26 months of the study groups in Wuliang Mountain, central Yunnan, we describe for the first time the copulation behavior and breeding pattern of free-ranging western black crested gibbons. The gestation period of black crested gibbons is estimated to be between 6 and 7 months. The average breeding interval is 3.5 years, with infant independence at approximately 2.5 years. We observed 2 intra-group copulations and 5 extra-group copulations. Copulations were initiated when a female gave a 'solicitation' gesture. When a male made any mating attempt, the female might refuse it. These results demonstrate direct female mate choice. Both male and female gibbons dispersed from their natal groups and sometimes replaced paired adults in other groups. We observed no evidence of infanticide during inter-group conflicts or after replacement of adults. Together with extra-group copulations, these phenomena indicate a flexible social organization and complex mating system. We also observed a male-biased sex ratio among offspring. More genetic work is necessary to describe the effects of inter-group copulation and the genetic diversity of this population. PMID- 24344968 TI - Sex-specific participation in inter-group conflicts within a multilevel society: the first evidence at the individual level. AB - Inter-group conflicts are common among many group-living animals and involve potentially complex motivations and interactions. Mammals living in multilevel societies offer a good opportunity to study inter-group conflicts. This study is the first to explore the function of sex-specific participation during inter group conflicts within a multilevel society at the individual level. The Sichuan snub-nosed monkey (Rhinopithecus roxellana) is an endangered seasonal breeding species living in a multilevel society. From Sep 2007 to May 2008 we recorded 290 inter-group conflicts of a free-ranging provisioned band of R. roxellana in the Qinling Mountains of China to investigate the function of individual aggression during inter-group encounters. Our findings show that adult males were the main participants in inter-group conflicts, while females took part in them only occasionally. The male participation rate during the mating season, when adult females were estrous, was significantly higher than that during the non-mating season. Furthermore, males directed their aggression to other males, and directed more intense aggression towards bachelor males than towards other resident males. For both sexes, the participation rate as initiators was higher in the winter than that in the spring; and there was a significant positive correlation between group size and the participation rate as initiators. Our results suggest that inter-group aggression in Sichuan snub-nosed monkeys is linked to both mate defense and resource defense. PMID- 24344969 TI - The importance of validating proposed genetic profiles in IBD. PMID- 24344970 TI - CVDHD: a cardiovascular disease herbal database for drug discovery and network pharmacology. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death and associates with multiple risk factors. Herb medicines have been used to treat CVD long ago in china and several natural products or derivatives (e.g., aspirin and reserpine) are most common drugs all over the world. The objective of this work was to construct a systematic database for drug discovery based on natural products separated from CVD-related medicinal herbs and to research on action mechanism of herb medicines. DESCRIPTION: The cardiovascular disease herbal database (CVDHD) was designed to be a comprehensive resource for virtual screening and drug discovery from natural products isolated from medicinal herbs for cardiovascular-related diseases. CVDHD comprises 35230 distinct molecules and their identification information (chemical name, CAS registry number, molecular formula, molecular weight, international chemical identifier (InChI) and SMILES), calculated molecular properties (AlogP, number of hydrogen bond acceptor and donors, etc.), docking results between all molecules and 2395 target proteins, cardiovascular-related diseases, pathways and clinical biomarkers. All 3D structures were optimized in the MMFF94 force field and can be freely accessed. CONCLUSIONS: CVDHD integrated medicinal herbs, natural products, CVD-related target proteins, docking results, diseases and clinical biomarkers. By using the methods of virtual screening and network pharmacology, CVDHD will provide a platform to streamline drug/lead discovery from natural products and explore the action mechanism of medicinal herbs. CVDHD is freely available at http://pkuxxj.pku.edu.cn/CVDHD. PMID- 24344971 TI - Role of copper oxides in contact killing of bacteria. AB - The potential of metallic copper as an intrinsically antibacterial material is gaining increasing attention in the face of growing antibiotics resistance of bacteria. However, the mechanism of the so-called "contact killing" of bacteria by copper surfaces is poorly understood and requires further investigation. In particular, the influences of bacteria-metal interaction, media composition, and copper surface chemistry on contact killing are not fully understood. In this study, copper oxide formation on copper during standard antimicrobial testing was measured in situ by spectroscopic ellipsometry. In parallel, contact killing under these conditions was assessed with bacteria in phosphate buffered saline (PBS) or Tris-Cl. For comparison, defined Cu2O and CuO layers were thermally generated and characterized by grazing incidence X-ray diffraction. The antibacterial properties of these copper oxides were tested under the conditions used above. Finally, copper ion release was recorded for both buffer systems by inductively coupled plasma atomic absorption spectroscopy, and exposed copper samples were analyzed for topographical surface alterations. It was found that there was a fairly even growth of CuO under wet plating conditions, reaching 4-10 nm in 300 min, but no measurable Cu2O was formed during this time. CuO was found to significantly inhibit contact killing, compared to pure copper. In contrast, thermally generated Cu2O was essentially as effective in contact killing as pure copper. Copper ion release from the different surfaces roughly correlated with their antibacterial efficacy and was highest for pure copper, followed by Cu2O and CuO. Tris-Cl induced a 10-50-fold faster copper ion release compared to PBS. Since the Cu2O that primarily forms on copper under ambient conditions is as active in contact killing as pure copper, antimicrobial objects will retain their antimicrobial properties even after oxide formation. PMID- 24344972 TI - Large surface area ordered porous carbons via nanocasting zeolite 10X and high performance for hydrogen storage application. AB - We report the preparation of ordered porous carbons for the first time via nanocasting zeolite 10X with an aim to evaluate their potential application for hydrogen storage. The synthesized carbons exhibit large Brunauer-Emmett-Teller surface areas in the 1300-3331 m(2)/g range and pore volumes up to 1.94 cm(3)/g with a pore size centered at 1.2 nm. The effects of different synthesis processes with pyrolysis temperature varied in the 600-800 degrees C range on the surface areas, and pore structures of carbons were explored. During the carbonization process, carbons derived from the liquid-gas two-step routes at around 700 degrees C are nongraphitic and retain the particle morphology of 10X zeolite, whereas the higher pyrolysis temperature results in some graphitic domains and hollow-shell morphologies. In contrast, carbons derived from the direct acetylene infiltration process have some incident nanoribbon or nanofiber morphologies. A considerable hydrogen storage capacity of 6.1 wt % at 77 K and 20 bar was attained for the carbon with the surface area up to 3331 m(2)/g, one of the top ranked capacities ever observed for large surface area adsorbents, demonstrating their potential uses for compacting gaseous fuels of hydrogen. The hydrogen capacity is comparable to those of previously reported values on other kinds of carbon-based materials and highly dependent on the surface area and micropore volume of carbons related to the optimum pore size, therefore providing guidance for the further search of nanoporous materials for hydrogen storage. PMID- 24344973 TI - Chemotherapy prescribing errors: an observational study on the role of information technology and computerized physician order entry systems. AB - BACKGROUND: Chemotherapy administration is a high-risk process. Aim of this study was to evaluate the frequency, type, preventability, as well as potential and actual severity of outpatient chemotherapy prescribing errors in an Oncology Department where electronic prescribing is used. METHODS: Up to three electronic prescriptions per patient record were selected from the clinical records of consecutive patients who received cytotoxic chemotherapy between January 2007 and December 2008. Wrong prescriptions were classified as incomplete, incorrect or inappropriate. Error preventability was classified using a four-point scale. Severity was defined according to the Healthcare Failure Mode and Effect Analysis Severity Scale. RESULTS: Eight hundred and thirty-five prescriptions were eligible. The overall error rate was 20%. Excluding systematic errors (i.e. errors due to an initially faulty implementation of chemotherapy protocols into computerized dictionaries) from the analysis, the error rate decreased to 8%. Incomplete prescriptions were the majority. Most errors were deemed definitely preventable. According to error presumptive potential for damage, 72% were classified as minor; only 3% had the potential to produce major or catastrophic injury. Sixty-eight percent were classified as near misses; adverse drug events had no or little effect on clinical outcome. CONCLUSIONS: Chemotherapy prescribing errors may arise even using electronic prescribing. Although periodic audits may be useful to detect common errors and guide corrective actions, it is crucial to get the computerized physician order entry system and set-ups correct before implementation. PMID- 24344974 TI - Healthcare-associated infections in a department of urology: incidence and patterns of antibiotic resistance. AB - OBJECTIVE: Healthcare-associated infections (HAIs) constitute a potentially severe complication which implies higher costs. A full knowledge of their microbiological characteristics and risk factors is of paramount importance for adequate management. The purpose of this study was to carry out an analysis of HAIs in patients admitted to a department of urology. MATERIAL AND METHODS: Between November 2011 and October 2012, a prospective observational study was carried out analysing HAIs in patients admitted to the urology department of a tertiary care university hospital in Spain, reviewing the incidence and types of HAIs, the microorganisms isolated and patterns of resistance to antibiotics. Risk factors for HAIs were also evaluated. RESULTS: HAIs were seen in 110 (6.5%) out of 1701 patients. Hypertension, a higher American Society of Anesthesiologists (ASA) score and surgery showed a statistical association with a higher risk of HAIs, and patients who underwent radical cystectomy had a high incidence of HAIs (10 out of 14). The most common HAIs were urinary tract infections (66.1%), followed by surgical site infections (16.5%), intra-abdominal abscesses (10.4%) and venous catheter-associated bacteraemia (6.1%). The most frequently isolated microorganisms were Escherichia coli (31.8%), then Enterococcus (17.6%) and Pseudomonas (12.9%). Escherichia coli showed resistance rates of 48.1% for ampicillin/amoxicillin plus beta-lactamase inhibitor, 51.9% for fluoroquinolones, and 33.3% were extended-spectrum beta-lactamase-producing E. coli. Pseudomonas aeruginosa showed a resistance rate of 36.4% for fluoroquinolones and carbapenems. CONCLUSIONS: HAIs usually occur in patients with risk factors. Radical cystectomy is associated with a high incidence of HAIs. Microorganisms associated with HAIs show high rates of resistance, which must be taken into account when selecting appropriate antibiotic therapy. PMID- 24344975 TI - Radioligand binding to nanodisc-reconstituted membrane transporters assessed by the scintillation proximity assay. AB - The scintillation proximity assay is a powerful technique for measuring radioligand binding to membrane transporters and has become an integral part of high-throughput drug discovery screening efforts. Here we adapt the method for use with purified LeuT, a prokaryotic secondary transporter, reconstituted into phospholipid bilayer nanodiscs. This application surmounts potential challenges with background interference from endogenously expressed proteins, aggregation and loss of binding activity often accompanying detergent solubilization from native cell membranes, and heterogeneity in size and transporter orientation, where at least some ligand binding sites are inaccessible, associated with reconstitution into lipid vesicles. PMID- 24344976 TI - Ab initio investigation of the thermal decomposition of n-butylcyclohexane. AB - Environmental and energy security concerns have motivated an increased focus on developing clean, efficient combustors, which increasingly relies on insight into the combustion chemistry of fuels. In particular, naphthenes (cycloalkanes and alkylcycloalkanes) are important chemical components of distillate fuels, such as diesel and jet fuels. As such, there is a growing interest in describing napthene reactivity with kinetic mechanisms. Use of these mechanisms in predictive combustion models aids in the development of combustors. This study focuses on the pyrolysis of n-butylcyclohexane (n-BCH), an important representative of naphthenes in jet fuels. Seven different unimolecular decomposition pathways of C C bond fission were explored utilizing ab initio/DFT methods. Accurate reaction energies were computed using the high-level quantum composite G3B3 method. Variational transition state theory, Rice-Ramsperger-Kassel-Marcus/master equation simulations provided temperature- and pressure-dependent rate constants. Implementation of these pathways into an existing chemical kinetic mechanism improved the prediction of experimental OH radical and H2O speciation in shock tube oxidation. Simulations of this combustion showed a change in the expected decomposition chemistry of n-BCH, predicting increased production of cyclic alkyl radicals instead of straight-chain alkenes. The most prominent reaction pathway for the decomposition of n-BCH is n-BCH = C3H7 + C7H13. The results of this study provide insight into the combustion of n-BCH and will aid in the future development of naphthene kinetic mechanisms. PMID- 24344977 TI - The influence of deep frying using various vegetable oils on acrylamide formation in sweet potato (Ipomoea batatas L. Lam) chips. AB - The objective of this study was to evaluate the precursors of acrylamide formation in sweet potato (SP) (Ipomoea batatas L. Lam) chips and to determine the effect of different types of vegetable oils (VOs), that is, palm olein, coconut oil, canola oil, and soya bean oil, on acrylamide formation. The reducing sugars and amino acids in the SP slices were analyzed, and the acrylamide concentrations of SP chips were measured. SP chips that were fried in a lower degree of unsaturation oils contained a lower acrylamide concentration (1443 MUg/kg), whereas those fried with higher degree of unsaturated oils contained a higher acrylamide concentration (2019 MUg/kg). SP roots were found to contain acrylamide precursors, that is, 4.17 mg/g glucose and 5.05 mg/g fructose, and 1.63 mg/g free asparagine. The type of VO and condition used for frying, significantly influenced acrylamide formation. This study clearly indicates that the contribution of lipids in the formation of acrylamide should not be neglected. PMID- 24344978 TI - Offspring pay sooner, parents pay later: experimental manipulation of body mass reveals trade-offs between immune function, reproduction and survival. AB - INTRODUCTION: Life-history theory predicts that organisms trade off survival against reproduction. However, the time scales on which various consequences become evident and the physiology mediating the cost of reproduction remain poorly understood. Yet, explaining not only which mechanisms mediate this trade off, but also how fast or slow the mechanisms act, is crucial for an improved understanding of life-history evolution. We investigated three time scales on which an experimental increase in body mass could affect this trade-off: within broods, within season and between years. We handicapped adult skylarks (Alauda arvensis) by attaching extra weight during first broods to both adults of a pair. We measured body mass, immune function and return rates in these birds. We also measured nest success, feeding rates, diet composition, nestling size, nestling immune function and recruitment rates. RESULTS: When nestlings of first broods fledged, parent body condition had not changed, but experimental birds experienced higher nest failure. Depending on the year, immune parameters of nestlings from experimental parents were either higher or lower than of control nestlings. Later, when parents were feeding their second brood, the balance between self-maintenance and nest success had shifted. Control and experimental adults differed in immune function, while mass and immune function of their nestlings did not differ. Although weights were removed after breeding, immune measurements during the second brood had the capacity to predict return rates to the next breeding season. Among birds that returned the next year, body condition and reproductive performance a year after the experiment did not differ between treatment groups. CONCLUSIONS: We conclude that the balance between current reproduction and survival shifts from affecting nestlings to affecting parents as the reproductive season progresses. Furthermore, immune function is apparently one physiological mechanism involved in this trade-off. By unravelling a physiological mechanism underlying the trade-offs between current and future reproduction and by demonstrating the different time scales on which it acts, our study represents an important step in understanding a central theory of life history evolution. PMID- 24344979 TI - Potato and mushroom polyphenol oxidase activities are differently modulated by natural plant extracts. AB - Enzymatic browning is a major quality issue in fruit and vegetable processing and can be counteracted by different natural inhibitors. Often, model systems containing a single polyphenol oxidase (PPO) are used to screen for new inhibitors. To investigate the impact of the source of PPO on the outcome of such screening, this study compared the effect of 60 plant extracts on the activity of PPO from mushroom ( Agaricus bisporus , AbPPO) and PPO from potato ( Solanum tuberosum , StPPO). Some plant extracts had different effects on the two PPOs: an extract that inhibited one PPO could be an activator for the other. As an example of this, the mate ( Ilex paraguariensis ) extract was investigated in more detail. In the presence of mate extract, oxygen consumption by AbPPO was found to be reduced >5-fold compared to a control reaction, whereas that of StPPO was increased >9-fold. RP-UHPLC-MS analysis showed that the mate extract contained a mixture of phenolic compounds and saponins. Upon incubation of mate extract with StPPO, phenolic compounds disappeared completely and saponins remained. Flash chromatography was used to separate saponins and phenolic compounds. It was found that the phenolic fraction was mainly responsible for inhibition of AbPPO and activation of StPPO. Activation of StPPO was probably caused by activation of latent StPPO by chlorogenic acid quinones. PMID- 24344980 TI - Variability in kidney stone incidence between black and white South Africans: AGT Pro11Leu polymorphism is not a factor. AB - BACKGROUND AND PURPOSE: Kidney stone disease is rare in the South African black (B) population and more prevalent in the white (W) population. Genetic studies have not previously examined this anomaly. The AGT Pro11Leu polymorphism in the alanine:glyoxylate aminotransferase (AGT) enzyme has been suggested as possibly playing a role in the pathogenesis of idiopathic calcium oxalate kidney stones. The present study was undertaken to investigate whether differences occur in the frequency of this polymorphism in subjects of both race groups. MATERIALS AND METHODS: Healthy B (n=60) and W (n=60) male subjects each provided early morning spot urine, blood, and buccal cell samples. The AGT Pro11Leu locus was amplified using the polymerase chain reaction and polymorphism was genotyped using a restriction fragment length polymorphism. RESULTS: There was no difference in the frequency of the AGT Pro11Leu polymorphism, and the major allele (C) was present at a frequency of 0.82 in B and 0.83 in W. Thus, the most common genotype homozygous normal CC genotype was observed at similar frequencies in both groups (0.68 and 0.65 in B and W, respectively), as were the heterozygous CT genotype (CT) and the homozygous variant TT genotype (TT) genotypes (0.33 & 0.02 and 0.28 & 0.03 in B and W, respectively). Neither urinary oxalate nor any other component in the two groups was correlated with the frequency of the AGT Pro11Leu polymorphism. CONCLUSIONS: Our data imply that the AGT Pro11Leu polymorphism is not directly responsible for the low incidence of stone formation in B. We conclude that other factors must be instrumental in protecting the B population from urolithiasis. PMID- 24344981 TI - Safety and efficacy of (90) yttrium-ibritumomab-tiuxetan for untreated follicular lymphoma patients. An Italian cooperative study. AB - (90) Yttrium ((90) Y)-Ibritumomab-Tiuxetan combines the targeting advantage of a monoclonal antibody with the radiosensitivity of Follicular Lymphoma (FL). Previous studies showed that 90Y-IT is safe and effective in relapsed/refractory indolent FL, irrespective of prior treatment with rituximab. This multicentre trial aimed to evaluate the safety and the efficacy of "upfront" single-agent ((90) Y)-Ibritumomab-Tiuxetan in advanced-stage FL. The primary objective was the incidence of responses in terms of complete (CR) and partial remission (PR). Fifty patients with stage II "bulky", III or IV FL received a single treatment course with ((90) Y)-Ibritumomab-Tiuxetan as initial therapy. The median age was 60 years. Bone marrow involvement (<25%) was observed in 24 patients (48%) and 7 (14%) had an elevated lactate dehydrogenase level. The overall response (ORR) and CR rates were 94% and 86%, respectively with a median follow-up of 38.8 months. The median progression-free survival (PFS) was not reached, whereas the 3-year estimated PFS and overall survival (OS) rate was 63.4% and 90%, respectively. Grade 3/4 neutropenia and thrombocytopenia occurred in 30% and 26% of patients respectively; none experienced grade 3/4 non-haematological toxicity. No cases of secondary haematological malignancies were observed. ((90) Y)-Ibritumomab Tiuxetan was demonstrated to be highly effective and safe as first-line treatment for advanced-stage FL. PMID- 24344982 TI - Quantification of small-scale variation in the size and composition of phenanthrene-degrader populations and PAH contaminants in traffic-impacted topsoil. AB - Small-scale colocalisation of microbial polycyclic aromatic hydrocarbon (PAH) degraders and PAHs in contaminated soil is a prerequisite for efficient biodegradation of the PAHs. We therefore tested the hypothesis that phenanthrene degrading bacteria are colocalised with PAHs at the millimetre-to-centimetre scale. Microbial populations and PAH concentrations were determined for 40-mg samples from a 112-mm transect of a traffic-impacted topsoil. The spatial distribution of cultivable phenanthrene degraders (0.3 * 10(5) -7.2 * 10(5) cells g(-1) ) mirrored neither the distribution of PAHs, nor the distribution of the total cultivable heterotrophic populations. Quantitative real-time PCR (qPCR) analysis of PAH dioxygenase genes (2 * 10(6) -4 * 10(6) cells g(-1) ) from a second transect showed distributions similar to the cultivable phenanthrene degraders, but at a 20-fold higher level. The omnipresence of high densities of PAH degraders at the millimetre scale indicate that PAH persistence may not be caused by local lack of degrader cells. To the best of our knowledge, this is the first time that either MPN of pollutant degraders, qPCR of functional genes, CFU of heterotrophic micro-organisms, or the content of PAHs have been determined with such high spatial resolution. PMID- 24344983 TI - Comparison of upstream regulators in human ex vivo cultured cornea limbal epithelial stem cells and differentiated corneal epithelial cells. AB - BACKGROUND: The surface of the human eye is covered by corneal epithelial cells (CECs) which regenerate from a small population of limbal epithelial stem cells (LESCs). Cell therapy with LESCs is a non-penetrating treatment for preventing blindness due to LESC deficiency or dysfunction. Our aim was to identify new putative molecular markers and upstream regulators in the LESCs and associated molecular pathways. RESULTS: Genome-wide microarray transcriptional profiling was used to compare LESCs to differentiated human CECs. Ingenuity-based pathway analysis was applied to identify upstream regulators and pathways specific to LESCs. ELISA and flow cytometry were used to measure secreted and surface expressed proteins, respectively. More than 2 fold increase and decrease in expression could be found in 1830 genes between the two cell types. A number of molecules functioning in cellular movement (381), proliferation (567), development (552), death and survival (520), and cell-to-cell signaling (290) were detected having top biological functions in LESCs and several of these were confirmed by flow cytometric surface protein analysis. Custom-selected gene groups related to stemness, differentiation, cell adhesion, cytokines and growth factors as well as angiogenesis could be analyzed. The results show that LESCs play a key role not only in epithelial differentiation and tissue repair, but also in controlling angiogenesis and extracellular matrix integrity. Some pro inflammatory cytokines were found to be important in stemness-, differentiation- and angiogenesis-related biological functions: IL-6 and IL-8 participated in most of these biological pathways as validated by their secretion from LESC cultures. CONCLUSIONS: The gene and molecular pathways may provide a more specific understanding of the signaling molecules associated with LESCs, therefore, help better identify and use these cells in the treatment of ocular surface diseases. PMID- 24344985 TI - Years of life lost among Iranian people killed in the Iraq-Iran war: the 25-year perspective. AB - To estimate the years of life lost (YLL), registered deaths due to Iraq-Iran war (1980-2005) were identified considering ICD10 codes of Y36.0 to Y36.9. Estimated YLL was calculated by taking age-weighting options and discount rates. Population life expectancy in each corresponding year was retrieved from the national health database. During 1980-2005, 178,298 Iranian men and 5325 Iranian women died in war. The mean death age was 22.8 +/- 9 years, 96.6% occurred during the years of war (September 1980-August 1988). In the years after the war (1988-2005) 6243 (3.4%) of deaths occurred as the result of complication of the war-related injuries or implanted landmines/unexploded ordnances (ICD10 code: Y36.8). YLL in Iraq-Iran war among Iranian victims were calculated as 10,479,405.0 years considering the age weighting and discount rate equal to 0. Age-adjusted YLL were estimated as 10,169,546.2 years in males. Female cases that comprised 2.9% of total victims lost 309,858.8 years. The mean YLL was calculated as 57.1 years for each Iranian victim killed in Iraq-Iran war. The war-related YLL was estimated more than 10 million years that comprised a majority of young men. This study is the first step in estimation of disability adjusted life year (DALY) of Iraq-Iran war on Iranian side. PMID- 24344984 TI - Mutation spectrum in South American Lynch syndrome families. AB - BACKGROUND: Genetic counselling and testing for Lynch syndrome have recently been introduced in several South American countries, though yet not available in the public health care system. METHODS: We compiled data from publications and hereditary cancer registries to characterize the Lynch syndrome mutation spectrum in South America. In total, data from 267 families that fulfilled the Amsterdam criteria and/or the Bethesda guidelines from Argentina, Brazil, Chile, Colombia and Uruguay were included. RESULTS: Disease-predisposing mutations were identified in 37% of the families and affected MLH1 in 60% and MSH2 in 40%. Half of the mutations have not previously been reported and potential founder effects were identified in Brazil and in Colombia. CONCLUSION: The South American Lynch syndrome mutation spectrum includes multiple new mutations, identifies potential founder effects and is useful for future development of genetic testing in this continent. PMID- 24344987 TI - Minimally invasive preparation and design of a cantilevered, all-ceramic, resin bonded, fixed partial denture in the esthetic zone: a case report and descriptive review. AB - Resin-bonded, fixed partial dentures have the potential to offer a minimally invasive, fixed-prosthetic approach to tooth replacement in patients who may not be candidates for implant therapy. However, traditional preparation protocols often recommend extensive preparation designs on two abutment teeth, thereby potentially compromising the long-term health of the adjacent abutments and often resulting in unilateral debonding of one of the retainers in the long term. In light of advances in high-strength ceramic systems capable of being reliably bonded to tooth structure and offering improved esthetic outcomes, as well as clinical and case-series research demonstrating improved survivability of cantilevered resin-bonded fixed partial dentures, new preparation designs and methodologies can be advocated. The following case report demonstrates the clinical application of sonoabrasion, coupled with a dental operating microscope, to minimally prepare a single abutment for a cantilevered, all-ceramic resin bonded fixed partial denture. Relevant historic and contemporary literature regarding double versus single-retainer resin-bonded fixed partial dentures are reviewed, as well as clinical conditions that are most favorable for such restorations to have an optimal long-term prognosis. CLINICAL SIGNIFICANCE: If appropriate clinical conditions exist, a cantilevered, all-ceramic, resin-bonded, fixed partial denture may be the most conservative means of tooth replacement in a patient who is not a candidate for an endosseous implant. PMID- 24344986 TI - Anticoagulation policy after venous resection with a pancreatectomy: a systematic review. AB - BACKGROUND: Portal vein (PV) resection is used increasingly in pancreatic resections. There is no agreed policy regarding anticoagulation. METHODS: A systematic review was performed to compare studies with an anticoagulation policy (AC+) to no anticoagulation policy (AC-) after venous resection. RESULTS: There were eight AC+ studies (n = 266) and five AC- studies (n = 95). The AC+ studies included aspirin, clopidogrel, heparin or warfarin. Only 50% of patients in the AC+ group received anticoagulation. There were more prosthetic grafts in the AC+ group (30 versus 2, Fisher's exact P < 0.001). The overall morbidity and mortality was similar in both groups. Early PV thrombosis (EPVT) was similar in the AC+ group and the AC- group (7%, versus 3%, Fisher's exact P = 0.270) and was associated with a high mortality (8/20, 40%). When prosthetic grafts were excluded there was no difference in the incidence of EPVT between both groups (1% vs 2%, Fisher's exact test P = 0.621). CONCLUSION: There is significant heterogeneity in the use of anticoagulation after PV resection. Overall morbidity, mortality and EPVT in both groups were similar. EPVT has a high associated mortality. While we have been unable to demonstrate a benefit for anticoagulation, the incidence of EPVT is low in the absence of prosthetic grafts. PMID- 24344989 TI - Is it time to challenge the established theories surrounding type 1 diabetes? AB - Type one diabetes (T1D) seems a well-defined disease, but its classification may be difficult. Evidence is weak that an autoimmune process with insulitis causes loss of the beta cells in all patients. Some scientists propose that it may be caused by a virus, increased hygiene or the early introduction of cow's milk or gluten, while views about the nerve supply, vascular function and the beta cells own role tend to be disregarded. Immune interventions have had limited success. There are differences, but also similarities, between T1D and type 2 diabetes (T2D). CONCLUSION: Several views on T1D have become so widely accepted that they may actually hamper progress into the true cause of this disease. Research on T1D needs to be carried out with an open mind, and clinicians might be wise to recommend a lifestyle that aims to decrease both the risk of T1D and T2D. PMID- 24344990 TI - Exposure to vehicle emissions results in altered blood brain barrier permeability and expression of matrix metalloproteinases and tight junction proteins in mice. AB - BACKGROUND: Traffic-generated air pollution-exposure is associated with adverse effects in the central nervous system (CNS) in both human exposures and animal models, including neuroinflammation and neurodegeneration. While alterations in the blood brain barrier (BBB) have been implicated as a potential mechanism of air pollution-induced CNS pathologies, pathways involved have not been elucidated. OBJECTIVES: To determine whether inhalation exposure to mixed vehicle exhaust (MVE) mediates alterations in BBB permeability, activation of matrix metalloproteinases (MMP) -2 and -9, and altered tight junction (TJ) protein expression. METHODS: Apolipoprotein (Apo) E(-/-) and C57Bl6 mice were exposed to either MVE (100 MUg/m(3) PM) or filtered air (FA) for 6 hr/day for 30 days and resulting BBB permeability, expression of ROS, TJ proteins, markers of neuroinflammation, and MMP activity were assessed. Serum from study mice was applied to an in vitro BBB co-culture model and resulting alterations in transport and permeability were quantified. RESULTS: MVE-exposed Apo E(-/-) mice showed increased BBB permeability, elevated ROS and increased MMP-2 and -9 activity, compared to FA controls. Additionally, cerebral vessels from MVE exposed mice expressed decreased levels of TJ proteins, occludin and claudin-5, and increased levels of inducible nitric oxide synthase (iNOS) and interleukin (IL)-1beta in the parenchyma. Serum from MVE-exposed animals also resulted in increased in vitro BBB permeability and altered P-glycoprotein transport activity. CONCLUSIONS: These data indicate that inhalation exposure to traffic generated air pollutants promotes increased MMP activity and degradation of TJ proteins in the cerebral vasculature, resulting in altered BBB permeability and expression of neuroinflammatory markers. PMID- 24344991 TI - The critical role of NIR spectroscopy and statistical process control (SPC) strategy towards captopril tablets (25 mg) manufacturing process understanding: a case study. AB - In this work, near-infrared spectroscopy (NIRS) method was used to evaluate the uniformity of dosage units of three captopril 25 mg tablets commercial batches. The performance of the calibration method was assessed by determination of Q value (0.9986), standard error of estimation (C-set SEE = 1.956), standard error of prediction (V-set SEP = 2.076) as well as the consistency (106.1%). These results indicated the adequacy of the selected model. The method validation revealed the agreement of the reference high pressure liquid chromatography (HPLC) and NIRS methods. The process evaluation using the NIRS method showed that the variability was due to common causes and delivered predictable results consistently. Cp and Cpk values were, respectively, 2.05 and 1.80. These results revealed a non-centered process in relation to the average target (100% w/w), in the specified range (85-115%). The probability of failure was 21:100 million tablets of captopril. The NIRS in combination with the method of multivariate calibration, partial least squares (PLS) regression, allowed the development of methodology for the uniformity of dosage units evaluation of captopril tablets 25 mg. The statistical process control strategy associated with NIRS method as PAT played a critical role in understanding of the sources and degree of variation and its impact on the process. This approach led towards a better process understanding and provided the sound scientific basis for its continuous improvement. PMID- 24344992 TI - One-pot multi-component route to propargylamines using zinc oxide under solvent free conditions. AB - In this paper, commercially available ZnO was found to be a highly effective catalyst for three-component coupling reactions of alkynes, aldehydes/or ketone and amines (A(3)-coupling) via C-H activation. The reactions could be applied to both aromatic and aliphatic aldehydes. Nearly quantitative yields of the desired products were obtained in most cases. No co-catalyst or activator is required, and water is the only by-product in the reactions. Heterogeneous nature of the catalyst made it reusable for further chemical reactions. PMID- 24344993 TI - Computational evidence for the reactivation process of human acetylcholinesterase inhibited by carbamates. AB - Acetylcholinesterase (AChE) is responsible for hydrolysis of acetylcholine (ACh), a function, which if disrupted, leads to cholinergic syndrome. Carbamates (CB) and organophosphorus compounds (OP) are AChE inhibitors, toxic and capable of causing severe poisoning or death to exposed individuals. The AChE reactivation is considered the main function of the oximes. In case of poisoning by CB, there is no consistent data in the literature for an oxime reactivation mechanism. In this work, we evaluated the affinity and reactivity of oximes with activity already reported against AChE inhibited by the OP chemical warfare agent ciclosarin, with MmAChE and HsAChE active sites inhibited by the CB pesticide carbofuran. Thus, our theoretical data indicate that HLO-7, BI-6 and K005 compounds may be promising reactivators of AChE inhibited by carbofuran. PMID- 24344994 TI - Angiolipoma of the colon: A case report and literature review. PMID- 24344995 TI - Weight, socio-demographics, and health behaviour related correlates of academic performance in first year university students. AB - BACKGROUND: This study aimed to examine differences in socio-demographics and health behaviour between Belgian first year university students who attended all final course exams and those who did not. Secondly, this study aimed to identify weight and health behaviour related correlates of academic performance in those students who attended all course exams. METHODS: Anthropometrics of 101 first year university students were measured at both the beginning of the first (T1) and second (T2) semester of the academic year. An on-line health behaviour questionnaire was filled out at T2. As a measure of academic performance student end-of-year Grade Point Averages (GPA) were obtained from the university's registration office. Independent samples t-tests and chi2-tests were executed to compare students who attended all course exams during the first year of university and students who did not carry through. Uni- and multivariate linear regression analyses were conducted to identify correlates of academic performance in students who attended all course exams during the first year of university. RESULTS: Students who did not attend all course exams were predominantly male, showed higher increases in waist circumference during the first semester and consumed more French fries than those who attended all final course exams. Being male, lower secondary school grades, increases in weight, Body Mass Index and waist circumference over the first semester, more gaming on weekdays, being on a diet, eating at the student restaurant more frequently, higher soda and French fries consumption, and higher frequency of alcohol use predicted lower GPA's in first year university students. When controlled for each other, being on a diet and higher frequency of alcohol use remained significant in the multivariate regression model, with frequency of alcohol use being the strongest correlate of GPA. CONCLUSIONS: This study, conducted in Belgian first year university students, showed that academic performance is associated with a wide range of weight and health related behaviours. Future studies should investigate whether interventions aiming at promoting healthy behaviours among students could also have a positive impact on academic performance. PMID- 24344997 TI - Toward a better understanding of Fe(III)-EDDS photochemistry: theoretical stability calculation and experimental investigation of 4-tert-butylphenol degradation. AB - The present work describes in detail the chemical structure of the complex Fe(III)-EDDS and the predominance of different species with respect to pH. These results were obtained with ab initio calculations. From the photoredox process, the formation of hydroxyl radical was confirmed, and HO(*) is the main species responsible for the degradation of the organic compound present in aqueous solution. The degradation of 4-tert-butylphenol (4-t-BP), used as a model pollutant, was investigated in different conditions. For the first time, the second-order rate constant of the reaction between HO(*) and 4-t-BP and the formation rate of HO(*) (R(HO(*))(f)) from the photochemical process were evaluated. Through the degradation of 4-t-BP, the effect of Fe(III)-EDDS concentration, oxygen, and pH was also investigated. The pH, which plays a role in the iron cycle and in the Fe(III)-EDDS speciation, was noticed as an important parameter for the efficiency of 4-t-BP degradation. Such a result could be explained by taking into account the complex speciation and presence of a predominant form (FeL-) up to pH 8. These results are very useful for the use and optimization of such iron complexes in water treatment processes. PMID- 24344996 TI - Precisely tunable engineering of sub-30 nm monodisperse oligonucleotide nanoparticles. AB - Advancement of RNAi therapies is mainly hindered by the development of efficient delivery vehicles. The ability to create small size (<30 nm) oligonucleotide nanoparticles is essential for many aspects of the delivery process but is often overlooked. In this report, we describe diblock star polymers that can reproducibly complex double-stranded oligonucleotides into monodisperse nanoparticles with 15, 23, or 30 nm in diameter. The polymer-nucleic acid nanoparticles have a core-shell architecture with dense PEG brush coating. We characterized these nanoparticles using ITC, DLS, FRET, FCS, TIRF, and TEM. In addition to small size, these nanoparticles have neutral zeta-potentials, making the presented polymer architecture a very attractive platform for investigation of yet poorly studied polyplex size range for siRNA and antisense oligonucleotide delivery applications. PMID- 24344998 TI - Purification, identification, and in vivo activity of angiotensin I-converting enzyme inhibitory peptide, from ribbonfish (Trichiurus haumela) backbone. AB - Ribbonfish (Trichiurus haumela) backbone is normally discarded as an industrial waste from fish processing. A method of developing angiotensin I-converting enzyme inhibitory (ACEI) peptides from ribbonfish backbone was previously optimized. The purposes of the study were to characterize the active peptides in the hydrolysate and to evaluate its in vivo activity. Ribbonfish backbone protein hydrolysate prepared by acid protease was fractionated into 4 fractions (I, MW < 1 kDa; II, MW = 1 to 5 kDa; III, MW = 5 to 10 kDa; and IV, MW > 10 kDa) through ultrafiltration membranes. Fraction I, showing the highest ACEI activity, was further purified using consecutive chromatographic techniques including gel filtration and reversed phase high-performance liquid chromatography. The purified ACE inhibitory peptide was determined to have a molecular weight of 317.25 Da, with a sequence of Leu-Trp and an IC50 value of 5.6 MUM. Systolic blood pressure of spontaneously hypertensive rats was significantly decreased from 181 +/- 2.0 to 161.3 +/- 2.3 mm Hg after 4 h of oral administration of Leu Trp at a dose of 10 mg/kg of body weight. These results indicated that ribbonfish backbone protein could be used for development of antihypertensive agent. PMID- 24344999 TI - Response to Letter to the Editor 'Red cell distribution width in patients with atrial fibrillation'. PMID- 24345000 TI - Infants and toddlers with autism: the promise and the challenges. AB - There has been a marked increase in interest in early identification of young children with and at risk for autism. This interest has reflected advances in research as well as an awareness of the potential for major changes in long-term outcome as a result of intervention. Several issues have complicated these efforts. There continue to be challenges to implementation of effective screening and diagnostic approaches in young children. Although the body of evidence-based research on treatment has increased, it remains limited. Despite these issues, important findings have emerged that may assist in fostering better approaches to screening, diagnosis, and documenting treatment impact. PMID- 24345001 TI - Cost of speech-language interventions for children and youth with foetal alcohol spectrum disorder in Canada. AB - This study, which is part of a large economic project on the overall burden and cost associated with Foetal Alcohol Spectrum Disorder (FASD) in Canada, estimated the cost of 1:1 speech-language interventions among children and youth with FASD for Canada in 2011. The number of children and youth with FASD and speech language disorder(s) (SLD), the distribution of the level of severity, and the number of hours needed to treat were estimated using data from the available literature. 1:1 speech-language interventions were computed using the average cost per hour for speech-language pathologists. It was estimated that ~ 37,928 children and youth with FASD had SLD in Canada in 2011. Using the most conservative approach, the annual cost of 1:1 speech-language interventions among children and youth with FASD is substantial, ranging from $72.5 million to $144.1 million Canadian dollars. Speech-language pathologists should be aware of the disproportionate number of children and youth with FASD who have SLD and the need for early identification to improve access to early intervention. Early identification and access to high quality services may have a role in decreasing the risk of developing the secondary disabilities and in reducing the economic burden of FASD on society. PMID- 24345002 TI - The lived experience of dysphagia following non-surgical treatment for head and neck cancer. AB - The prevalence and severity of dysphagia in people treated non-surgically for primary head and neck cancer (HNC) is well documented. However, few studies have looked beyond the physiological impairment to explore the lived experience of dysphagia in the post-treatment period of HNC. The current study adopted a person centred, qualitative approach to describe the experiences of people living with dysphagia in the months and years following non-surgical treatment for HNC. Using maximum variation sampling, 24 participants who had undergone radiotherapy treatment for HNC were recruited. Individual interviews were conducted to explore the impact of dysphagia on participants' everyday lives. The themes identified included: (1) physical changes related to swallowing; (2) emotions evoked by living with dysphagia; (3) altered perceptions and changes in appreciation of food; and (4) personal and lifestyle impacts. The data revealed the breadth and significance of the impact of dysphagia on the lives of people treated curatively for HNC. Assessment and management in the post-treatment period must be sufficiently holistic to address both the changing physical states and the psychosocial needs of people with dysphagia following HNC. Rehabilitation services which focus only on impairment-based management will fail to fully meet the support needs of this clinical population. PMID- 24345003 TI - Problematic but predictive: individual differences in children with autism spectrum disorders. AB - Camarata highlights the impact that symptom hetereogeneity, overlap, and individual differences can have on the accurate early diagnosis of children with autism spectrum disorders (ASD) and measurement of treatment outcomes. Nevertheless, these individual differences may provide avenues for predicting individual responses to treatment with the view to prospectively matching children with ASD to treatments best-suited to meeting their individual needs. This commentary suggests that the behavioural characterstics that are critical to accurate early diferential diagnosis of ASD may be poor predictors of outcomes. However, factors that are not unique to ASD may in fact be good predictors of treatment outcomes. This commentary illustrates these points with reference to the results of recent studies demonstrating the problems, and possibilities, that individual differences currently present when it comes to understanding and promoting learning in children with ASD. PMID- 24345004 TI - Tongue-palate contact during selected vowels in children with speech sound disorders. AB - There is evidence that complete tongue-palate contact across the palate during production of vowels can be observed in some children with speech disorders associated with cleft palate in the English-speaking and Japanese-speaking populations. Although it has been shown that this is not a feature of typical vowel articulation in English-speaking adults, tongue-palate contact during vowel production in typical children and English-speaking children with speech sound disorders (SSD) have not been reported in detail. Therefore, this study sought to determine whether complete tongue-palate contact occurs during production of five selected vowels in 10 children with SSD and eight typically-developing children. The results showed that none of the typical children had complete contact across the palate during any of the vowels. However, of the 119 vowels produced by the children with SSD, 24% showed complete contact across the palate during at least a portion of the vowel segment. The results from the typically-developing children suggest that complete tongue-palate contact is an atypical articulatory feature. However, the evidence suggests that this pattern occurs relatively frequently in children with SSD. Further research is needed to determine the prevalence, cause, and perceptual consequence of complete tongue-palate contact. PMID- 24345005 TI - Bortezomib induces clinical remission and reduction of ADAMTS13 inhibitory antibodies in relapsed refractory idiopathic thrombotic thrombocytopenic purpura. PMID- 24345006 TI - The drug:H+ antiporters of family 2 (DHA2), siderophore transporters (ARN) and glutathione:H+ antiporters (GEX) have a common evolutionary origin in hemiascomycete yeasts. AB - BACKGROUND: The Saccharomyces cerevisiae 14-spanner Drug:H+ Antiporter family 2 (DHA2) are transporters of the Major Facilitator Superfamily (MFS) involved in multidrug resistance (MDR). Although poorly characterized, DHA2 family members were found to participate in the export of structurally and functionally unrelated compounds or in the uptake of amino acids into the vacuole or the cell. In S. cerevisiae, the four ARN/SIT family members encode siderophore transporters and the two GEX family members encode glutathione extrusion pumps. The evolutionary history of DHA2, ARN and GEX genes, encoding 14-spanner MFS transporters, is reconstructed in this study. RESULTS: The translated ORFs of 31 strains from 25 hemiascomycetous species, including 10 pathogenic Candida species, were compared using a local sequence similarity algorithm. The constraining and traversing of a network representing the pairwise similarity data gathered 355 full size proteins and retrieved ARN and GEX family members together with DHA2 transporters, suggesting the existence of a close phylogenetic relationship among these 14-spanner major facilitators. Gene neighbourhood analysis was combined with tree construction methodologies to reconstruct their evolutionary history and 7 DHA2 gene lineages, 5 ARN gene lineages, and 1 GEX gene lineage, were identified. The S. cerevisiae DHA2 proteins Sge1, Azr1, Vba3 and Vba5 co-clustered in a large phylogenetic branch, the ATR1 and YMR279C genes were proposed to be paralogs formed during the Whole Genome Duplication (WGD) whereas the closely related ORF YOR378W resides in its own lineage. Homologs of S. cerevisiae DHA2 vacuolar proteins Vba1, Vba2 and Vba4 occur widespread in the Hemiascomycetes. Arn1/Arn2 homologs were only found in species belonging to the Saccharomyces complex and are more abundant in the pre-WGD species. Arn4 homologs were only found in sub-telomeric regions of species belonging to the Sacharomyces sensu strictu group (SSSG). Arn3 type siderophore transporters are abundant in the Hemiascomycetes and form an ancient gene lineage extending to the filamentous fungi. CONCLUSIONS: The evolutionary history of DHA2, ARN and GEX genes was reconstructed and a common evolutionary root shared by the encoded proteins is hypothesized. A new protein family, denominated DAG, is proposed to span these three phylogenetic subfamilies of 14-spanner MFS transporters. PMID- 24345008 TI - Editorial comment for Salami et al. PMID- 24345007 TI - Angiographic identification of extrahepatic perfusion after hepatic arterial pump placement: implications for surgical prevention. AB - BACKGROUND: Hepatic arterial infusion (HAI) chemotherapy is an effective treatment for patients with liver malignancy. Extrahepatic perfusion (EHP) after HAI pump placement requires correction prior to starting chemotherapy. The aim of this study was to define the origin of arterial branches causing EHP in order to determine if alterations in surgical technique during pump placement might prevent EHP. METHODS: A prospectively maintained, single-centre HAI database was reviewed for all patients (2008-2011) with EHP. The origin of arterial branches causing EHP was classified anatomically and patient outcomes were analysed. RESULTS: Of the 327 patients with pumps implanted, 24 evidenced EHP. The arterial branch responsible for EHP perfused the duodenum, pancreas and/or stomach. The branch responsible for EHP arose from the proper hepatic artery (PHA), 1(st) , 2(nd) , or 3(rd) order hepatic artery branches in 7, 10, 5 and 2 patients, respectively. The majority of branches beyond the PHA causing EHP (13/17) originated from the right hepatic artery. In 18 patients, aberrant branches were successfully treated with embolization. CONCLUSION: These findings provide the anatomic basis for prevention of up to one-third of the cases of EHP intra operatively, decreasing the number of patients who will require additional procedures for correction of EHP post-operatively. PMID- 24345010 TI - An unusual challenge in performing sphenopalatine ganglion block with enlarged coronoid process: Jacob's disease. AB - OBJECTIVES: Sphenopalatine ganglion block for the treatment of cluster headache has been well-described for medically refractory cases. Technical challenges in performing this procedure via the mandibular notch can be found in patients with elongation of the coronoid process. Objectives include correlation of physical exam findings and computed tomography (CT) imaging, followed by recommendations for future treatment. METHODS: Case report. RESULTS: Patient had a history of cluster headache and a 35 mm interincisal opening. Initially, sphenopalatine ganglion block could not be performed via standard mandibular notch approach due to the inability to advance past superficial tissues. Subsequent CT scan revealed a congenitally enlarged coronoid process with a shortened ramus. Usage of a bite block facilitated completion of the sphenopalatine block on subsequent visit. CONCLUSIONS: Patients with diminished oral interincisal opening and deviation of the jaw to one side are consistent with Jacob's disease. Using a bite block in these patients may be critical to completion of the procedure. PMID- 24345009 TI - Characterization of black raspberry functional food products for cancer prevention human clinical trials. AB - Our team is designing and fully characterizing black raspberry (BRB) food products suitable for long-term cancer prevention studies. The processing, scale up, and storage effects on the consistency, quality, bioactive stability, and sensory acceptability of two BRB delivery systems of various matrices are presented. BRB dosage, pH, water activity, and texture were consistent in the scale-up production. Confections retained >90% of anthocyanins and ellagitannin after processing. Nectars had >69% of anthocyanins and >66% of ellagitannin retention, which varied with BRB dosage due to the processing difference. Texture remained unchanged during storage. BRB products consumed in a prostate cancer clinical trial were well accepted in sensory tests. Thus, this study demonstrates that two different BRB foods can be formulated to meet quality standards with a consistent bioactive pattern and successfully scaled up for a large human clinical trial focusing on cancer risk and other health outcomes. PMID- 24345011 TI - Comparing drug detection in oral fluid and blood: data from a national sample of nighttime drivers. AB - OBJECTIVE: The National Roadside Survey is a study undertaken in the United States to determine the prevalence of alcohol and drugs in randomly selected drivers. Following the success of a 2006 pilot study, the 2007 survey incorporated, for the first time, the collection of biological specimens for drug analysis. This article compares the results obtained from blinded analyses of pairs of oral fluid and blood samples obtained from the same subject. METHODS: During the 2007 survey, more than 7000 nighttime drivers were randomly stopped and surveyed for their self-reported drug use and were requested to donate an oral fluid specimen using the Quantisal (Immunalysis Corporation, Pomona, CA) device and a blood sample. Overall, 5869 oral fluid specimens were collected from nighttime drivers with 3236 corresponding blood samples. RESULTS: Biological specimens were analyzed for a wide range of drugs. At nighttime, 14.4 percent of the drivers were positive for drugs in oral fluid, with just over half of those having marijuana present (7.6%). Of the 3236 pairs of specimens, 2676 were negative for all drugs, and 326 matched pairs of samples were both positive, out of which 247 (75.8%) were an exact match for all drug classes and 70 (21.5%) were positive for at least one common drug class. CONCLUSIONS: Oral fluid and blood samples provided very similar information regarding recent drug intake by randomly tested drivers and oral fluid yielded a higher detection rate for one drug (cocaine) than blood. Oral fluid can be considered a reliable alternative to blood as a matrix for drug testing. PMID- 24345012 TI - Correlates of drug use and driving among undergraduate college students. AB - OBJECTIVE: Drug use by drivers is a significant and growing highway safety problem. College students are an important population to understand drugged driving. The objective of this study was to examine correlates of drugged driving among undergraduate college students. METHODS: We conducted an anonymous, confidential, 24-question survey at a large New England public university during the 2010-2011 academic year among undergraduates in courses that met a graduation requirement. Data include demographics; academics; housing status; lifestyle; personal values; high school/college drug use; and driving following alcohol use, drug use, or both; and as a passenger with a driver who used alcohol, drugs, or both. Descriptive statistics were calculated. Chi-square tests compared driver alcohol use, drug use, or both with demographic, academic, and lifestyle variables. Logistic regression analyses were performed with drugged driving as the dependent variable. Odds ratios and corresponding 95 percent confidence intervals were calculated for each of the potential explanatory variables in relation to the outcome. RESULTS: Four hundred forty-four of 675 students completed surveys (66% participation rate). Participants were representative of the student body with a mean age of 19.4 (+/-1.3 years), 51 percent male, 75 percent white, and 10 percent Hispanic. Seventy-eight percent lived on campus, 93 percent had a driver's license, and 37 percent had access to a car. Students disagreed that cannabinoids impair driving (18%) compared to other drugs (17%), stimulants (13%), depressants (11%), hallucinogens (8%), and alcohol (7%). Twenty three percent drove after alcohol use and 22 percent drove after drug use. Forty one percent reported having been a passenger with a driver who had been drinking and 37 percent with a driver using drugs. Drugged driving was more likely among males vs. females (30% vs. 14%, P < .01), those living off campus (34% vs. 19%, P < .01), those reporting that parties are important (33% vs. 14%, P < .01), those reporting that community service is not important (28% vs. 18%, P < .05), those reporting that religion is not important (28% vs. 14%, P < .01), and those reporting personal drug use in high school (75% vs. 14%, P < .01) and well as that their best friends used drugs in high school (42% vs. 12%, P < .01) and college (50% vs. 8%, P < .01). Those factors most associated with drugged driving included using drugs in high school (odds ratio [OR] = 9.5, 95% confidence interval [CI]: 4.6-19.6) and best friends in college used drugs regularly (OR = 6.2, 95% CI: 3.4-11.6). CONCLUSION: Self-reported drugged driving and riding as a passenger with a drugged driver is common among subgroups of college students. The identification of undergraduate subgroups at risk for drugged driving will guide the design and implementation of traffic safety activities. PMID- 24345013 TI - An examination of the validity of the standardized field sobriety test in detecting drug impairment using data from the Drug Evaluation and Classification program. AB - OBJECTIVE: The purpose of this study is to assess the validity of the 3 components of the Standardized Field Sobriety Test (SFST), including the Horizontal Gaze Nystagmus (HGN), One Leg Stand (OLS), and Walk and Turn (WAT) tests, in identifying impairment among suspected drug-impaired drivers using data recorded during drug evaluation and classification (DEC) evaluations. METHODS: Data from 2142 completed DEC evaluations of central nervous system (CNS) stimulants, CNS depressants, narcotic analgesics, cannabis, or no drugs were analyzed using multinomial logistic regression. RESULTS: All drug categories were significantly associated with impaired performance. On the HGN, users of CNS depressants were significantly more likely to experience lack of smooth pursuit and distinct nystagmus at maximum deviation compared to non-drug users. On the OLS, users of all drug classes were significantly more likely to sway while balancing and use their arms to maintain balance but significantly less likely to hop compared to drug-free cases. Users of CNS depressants, CNS stimulants, and narcotic analgesics were significantly more likely to put their raised foot down during the test. On the WAT, users of CNS depressants, CNS stimulants, and narcotic analgesics were significantly less likely to keep their balance while listening to test instructions compared to those who had not used drugs. Users of CNS depressants were less likely to touch heel-to-toe while walking, whereas individuals who had used narcotic analgesics were less likely to take the correct number of steps. CONCLUSIONS: These findings provide support for the use of the SFST as a screening tool for law enforcement to identify impairment in persons who have used CNS stimulants, CNS depressants, cannabis, or narcotic analgesics. PMID- 24345014 TI - Deterioration in driving performance during sleep deprivation is similar in professional and nonprofessional drivers. AB - OBJECTIVE: There is some suggestion in the literature that professional drivers might self-select to be more resistant to the effects of sleep deprivation; however, this question has not been directly examined. The current laboratory study aimed to compare performance changes during acute sleep deprivation between professional and nonprofessional drivers. METHODS: Twenty volunteer male professional drivers and 20 nonprofessional drivers performed a simulated driving task (AusEd) and the Psychomotor Vigilance Task (PVT) during 24 hours of continuous wakefulness. Ratings of subjective sleepiness were also examined. RESULTS: There was a progressive and significant increase in lateral lane position and speed variability on the simulated driving task and an increase in PVT reaction times and lapses after participants had been awake for 17 to 24 hours (Ps < .01). There was no difference in performance changes between the professional and nonprofessional drivers. CONCLUSIONS: Professional drivers in this study had the same susceptibility to sleep deprivation as nonprofessional drivers. This finding does not support the concept that professional drivers are resistant to sleep loss. PMID- 24345015 TI - Prognosis of outcome in adult survivors of road accidents in France: one-year follow-Up in the ESPARR cohort. AB - OBJECTIVE: The consequences of road crashes are various, and few studies have dealt with the multidimensionality of outcomes. The aim of the present study was to assess the multidimensional nature of outcomes one year after a crash and to determine predictive factors that could help in adapting medical and social care to prevent such consequences to improve road crash victims' prognosis. METHODS: The study population was the 886 respondents to the one-year follow-up from the ESPARR (Etude et Suivi d'une Population d'Accidentes de la Route du Rhone) cohort, aged >= 16 years; the analysis was carried out only on the 616 subjects who fully completed a self-report questionnaire on health, social, emotional, and financial status one year after a crash. Multiple correspondence analysis and hierarchical clustering was implemented to produce homogeneous groups according to differences in outcome. Groups were compared using the World Health Organization Quality of Life Assessment (WHOQOL-BREF, a standard instrument of quality of life, assessing physical health, psychological health, social relationships, and environment) and the Injury Impairment Scale (IIS), a tool to predict road crash sequelae. Baseline predictive factors for group attribution were analyzed by weighted multinomial logistic regression models. RESULTS: Three hundred seventeen of the 616 subjects (60.1%) were men. Mean age was 36.9 years (SD = 16.5). Five victim groups were identified in terms of consequences at one year: one group (206 subjects, 33.4%) with few problems, one with essentially physical sequelae, one with problems that were essentially both physical and social, and 2 groups with a wider range of problems (one including psychological problems but fewer environmental problems; the last one reported negative physical, psychological, social, and environmental impact; notably, all had post concussion syndrome [PCS]). There were significant differences between groups in terms of family status, injury severity, and certain types of injury (thorax, spine, lower limbs). Comparison on the WHOQOL-BREF confirmed that groups reporting more adverse outcomes had a lower quality of life. Description of the 5 groups by IIS indicators showed that IIS underestimated physical consequences one year after the crash. In addition to the known prognostic factors such as age, initial injury severity, and injury type, socioeconomic fragility and having a relative involved in the accident emerged as predictive of poor outcome at one year. CONCLUSIONS: One year after the crash, victims may still be experiencing multiple problems in terms of not only physical health but also of mental health, social life, and environment. Poor outcome may be predicted from both accident related factors and socioeconomic fragility. Our results are useful in catching the attention of both clinicians and the public administration regarding victims at risk of suffering from important consequences after an accident. If those suffering head injuries are recognized, it would be very important to better consider and treat posttraumatic stress disorder (PTSD) or PCS. Furthermore, subjects from lower socioeconomic backgrounds, with or without lower limb injuries, have numerous difficulties after an accident, notably for returning to work. An objective would be to provide them with more specific support. Supplemental materials are available for this article. Go to the publisher's online edition of Traffic Injury Prevention to view the supplemental file. PMID- 24345016 TI - The prevalence of mobile phone use among motorcyclists in three Mexican cities. AB - OBJECTIVE: To quantify the prevalence of mobile phone use among motorcyclists in 3 Mexican cities and to identify associated factors. METHODS: Two rounds of roadside observations were conducted in Guadalajara-Zapopan, Leon, and Cuernavaca from December 2011 to May 2012. Observation sites were selected randomly and all motorcyclists circulating at those sites were recorded. Motorcyclists observed talking into a phone (either handheld or hands-free) or texting were recorded as using a mobile phone while driving. RESULTS: A total of 4244 motorcyclists were observed. The overall prevalence of mobile phone use was 0.64 percent (95% confidence interval [CI]: 0.42-0.92); it was highest in Guadalajara-Zapopan (1.03%; 95% CI: 0.61-1.63) and among motorcyclists not using a helmet (1.45% versus 0.4%; P = .000) and those riding on 1-lane roads (1.6% versus 0.8% on 2 lane roads and 0.5% in 3- to 5-lane roads; P = .046). CONCLUSIONS: To our knowledge this is the first study that reports the prevalence of mobile phone use while driving among motorcyclists. The observed prevalence is higher than the prevalence stated in a previous report from China on electric bicycle riders. This risk factor should be monitored in the future given the growing popularity of motorcycles and the availability of mobile devices. Current legislation should be enforced to avoid potential injuries and deaths attributable to this risk factor. PMID- 24345017 TI - Predictors of nonstandard helmet use among San Francisco Bay-area motorcyclists. AB - OBJECTIVE: The use of helmets that do not comply with safety standards is common in California. The objective of this study was to describe the use of these nonstandard helmets among San Francisco Bay-area (SFBA) motorcyclists and to identify personal and motorcycle characteristics that are associated with the use of nonstandard helmets. METHODS: A survey of 860 SFBA motorcyclists was conducted. Log-binomial regression was used to estimate risk ratios to compare probabilities of nonstandard helmet use. RESULTS: Fifteen percent of motorcyclists reported wearing a nonstandard helmet sometimes or often. BMW riders had the lowest use of nonstandard helmet (5%) and Harley-Davidson riders had the highest use (51%). Among non-Harley-Davidsons, riders of cruiser-style motorcycles were 3.1 times as likely to wear a nonstandard helmet as riders of motorcycles of other styles. African American riders were more than twice as likely to use nonstandard helmets compared to riders with other self-reported race. DISCUSSION: Behavioral countermeasures are needed to improve motorcycle helmet choice in California. This study identified riders of Harley-Davidsons and riders of cruiser-style motorcycles of other brands as potential targets of interventions. PMID- 24345018 TI - Relationship between motorcyclists' attitudes, behavior, and other attributes with declared accident involvement in Europe. AB - OBJECTIVE: The objective of this study is to investigate patterns of road safety attitudes and behaviors of motorcyclists in Europe on the basis of the results of the pan-European questionnaire-based survey SARTRE-4, carried out in late 2010 in 18 European countries and Israel. In addition, we attempt to explore the link between attitudes, behaviors, and other motorcyclist attributes with motorcyclist involvement in accidents in the past 3 years, in which someone, including the rider, was injured and received medical attention as stated in the motorcyclists' responses. METHODS: The various components of motorcyclist attitudes and behaviors such as reasons for driving a motorcycle, driving while impaired, perceived risk factors, and risk-taking behavior were determined by means of a principal component analysis (PCA) on 38 variables contained in the survey. A binary logistic regression model was then applied in order to link the attitudes and the stated behavior with the declared involvement in past accidents. RESULTS: The results revealed 8 components. Component 1 (driving while impaired and speeding accident factors), component 2 (motorcycle benefits), component 3 (perceived risk of maneuvers), component 4 (sensation seeking), component 5 (road, vehicle, and environmental risk factors), component 7 (no modal options), and component 8 (attitudes toward drinking and friends' drinking) are associated with stated preferences and attitudes, whereas component 6 (dangerous and angry behaviors) is associated with stated behavior. Moreover, it was found that motorcyclists who tend to have dangerous attitudes and behaviors as well as younger motorcyclists are more likely to have been involved in an accident. It was also showed that driving exposure is positively associated with increased probability of a past accident. CONCLUSIONS: The findings of the study provide some insight into the association between attitudes, behaviors, and declared past accident involvement. Furthermore, the analysis of such large databases with the inclusion of many different countries constitutes a step for further research in the field of motorcyclists' behaviors and safety. Supplemental materials are available for this article. Go to the publisher's online edition of Traffic Injury Prevention to view the supplemental file. PMID- 24345019 TI - Hospitalizations and fatalities in crashes with light trucks. AB - OBJECTIVE: This study examined 2-car crashes including one passenger car and one light truck (van, minivan, pickup truck, or sport utility vehicle) and investigated the likelihood of hospitalization, hospitalization charges, and the likelihood of fatality of an occupant by vehicle type differentiating between passengers and drivers. METHODS: We used unique data from Minnesota's Crash Outcome Data Evaluation System (CODES) linked with hospital discharge data from 2004 to 2005. We focused on police-reported crashes that involved 2 vehicles, one car and one light truck. First, we estimated models to predict the likelihood of hospitalization. Next, we estimated models to predict hospitalization charges among the hospitalized. Finally, we modeled the likelihood of fatality. In all models, we distinguished between the 2 vehicle types and controlled for a broad range of occupant, crash, and vehicle characteristics. We estimated separate models for passengers and drivers. RESULTS: We found that in a crash between a car and a light truck, drivers of light trucks were less likely to be hospitalized (odds ratio [OR] = 64%; 95% confidence interval [CI], 59-70%) and killed (OR = 35%; 95% CI, 18-68%) relative to the drivers of cars. Similarly, passengers of light trucks had a lower likelihood of hospitalization (OR = 66%; 95% CI, 57-77%) and fatality (OR = 14%; 95% CI, 3-54%) relative to the passengers of cars. Among hospitalized occupants, we did not find statistically significant differences in hospital charges between light truck drivers and car drivers, but hospital charges for hospitalized light truck passengers were 59% (95% CI, 40 87%) of the hospital charges of hospitalized car passengers. CONCLUSIONS: Though previous studies have shown high fatality costs associated with light trucks, this study is the first to explore the hospitalization costs associated with these vehicles. The existing traffic liability systems (tort or no-fault systems) likely fail to fully make light trucks accountable for costs they impose on other cars, pedestrians, and other road occupants. Our findings suggest the importance of a close examination of a broad range of cost implications even beyond hospitalization and fatality costs to evaluate the optimal amount of corrective taxes or other corrective policies in future research. Supplemental materials are available for this article. Go to the publisher's online edition of Traffic Injury Prevention to view the supplemental file. PMID- 24345020 TI - Formation and Evaluation of Act and Anticipate Hazard Perception Training (AAHPT) intervention for young novice drivers. AB - OBJECTIVE: Young novice drivers' poor hazard perception (HP) skills are a prominent cause for their overinvolvement in traffic crashes. HP, the ability to read the road and anticipate forthcoming events, is receptive to training. This study explored the formation and evaluation of a new HP training intervention-the Act and Anticipate Hazard Perception Training (AAHPT), which is based upon exposing young novice drivers to a vast array of actual traffic hazards, aiming to enhance their ability to anticipate potential hazards during testing. METHOD: Forty young novices underwent one of 3 AAHPT intervention modes (active, instructional, or hybrid) or a control group. Active members observed video-based traffic scenes and were asked to press a response button each time they detected a hazard. Instructional members underwent a tutorial that included both written material and video-based examples regarding HP. Hybrid members received a condensed theoretical component followed by a succinct active component. Control was presented with a road safety tutorial. Approximately one week later, participants performed a hazard perception test (HPT), during which they observed other movies and pressed a response button each time they detected a hazard. Twenty-one experienced drivers also performed the HPT and served as a gold standard for comparison. RESULTS: Overall, the active and hybrid modes were more aware of potential hazards relative to the control. CONCLUSIONS: Inclusion of an active-practical component generates an effective intervention. Using several evaluation measurements aids performance assessment process. Advantages of each of the training methodologies are discussed. Supplemental materials are available for this article. Go to the publisher's online edition of Traffic Injury Prevention to view the supplemental file. PMID- 24345021 TI - Validation of simulated chestband data in frontal and lateral loading using a human body finite element model. AB - OBJECTIVE: Finite element (FE) computer models are an emerging tool to examine the thoracic response of the human body in the simulated environment. In this study, a recently developed human body model, the Global Human Body Models Consortium (GHBMC) mid-sized male, was used to examine chestband contour deformations in a frontal and lateral impact. The objective of this study was 2 fold. First, a methodology for extracting and analyzing virtual chestband data from a full-body FE model is presented. Then, this method is applied to virtual chestband data from 2 simulations to evaluate the model's performance against experimental data. METHODS: One frontal and one lateral impact case were simulated using the FE model, which was preprogrammed with upper, middle, and lower chestbands. Maximum compression was determined using established techniques. Furthermore, a quadrant-based analysis technique for the results was introduced that enabled regional comparisons between the model and the experimental data in the anterior, posterior, right, and left sections of the chestband. RESULTS: For the frontal case at 13.3 m/s, the model predicted a peak compression of 13.6 and 12.9 percent for the upper and middle chestbands. For the lateral case at 6.7 m/s, the model predicted peak compression of the upper, middle, and lower chestbands of 27.9, 26.0, and 20.4 percent. Regional analysis showed average differences at maximum deformation between the model and experiments ranging from 0.9 percent (posterior) to 6.3 percent (anterior) in the frontal case and 2.3 percent (posterior) to 10.8 percent (anterior) in the lateral case. The greatest difference between model and experimental findings was found in the anterior quadrant. CONCLUSIONS: Though this work was focused on techniques to extract and analyze chestband data from FE models, the comparative results provide further validation of the model used in this study. The results suggest the importance of evaluating comparisons between virtual and experimental chestband data on a regional basis. These data also provide the potential to correlate chestband deformations to the loading of underlying thoraco-abdominal structures. Supplemental materials are available for this article. Go to the publisher's online edition of Traffic Injury Prevention to view the supplemental file. PMID- 24345022 TI - Volvo drivers' experiences with advanced crash avoidance and related technologies. AB - OBJECTIVE: Crash avoidance technologies can potentially prevent or mitigate many crashes, but their success depends in part on driver acceptance. Owners of 2010 2012 model Volvo vehicles with several technologies were interviewed about their experiences. METHODS: Interviews were conducted in summer 2012 with 155 owners of vehicles with City Safety as a standard feature; 145 owners with an optional technology package that included adaptive cruise control, distance alert, collision warning with full auto brake (and pedestrian detection on certain models), driver alert control, and lane departure warning; and 172 owners with both City Safety and the technology package. The survey response rates were 21 percent for owners with City Safety, 30 percent for owners with the technology package, and 27 percent for owners with both. Ten percent of owners opted out before the telephone survey began, and 18 percent declined to participate when called. RESULTS: Despite some annoyance, most respondents always leave the systems on, although fewer do so for lane departure warning (59%). For each of the systems, at least 80 percent of respondents with the system would want it on their next vehicle. Many respondents reported safer driving habits with the systems (e.g., following less closely with adaptive cruise control, using turn signals more often with lane departure warning). Fewer respondents reported potentially unsafe behavior, such as allowing the vehicle to brake for them at least some of the time. About one third of respondents experienced autonomous braking when they believed they were at risk of crashing, and about one fifth of respondents thought it had prevented a crash. About one fifth of respondents with the technology package reported that they were confused or misunderstood which safety system had activated in their vehicle. CONCLUSIONS: Consistent with the results for early adopters in the previous survey of Volvo and Infiniti owners, the present survey found that driver acceptance of the technologies remains high, although less so for lane departure warning. This study is the first to report drivers' experiences with City Safety, a collision avoidance system provided as standard equipment on certain Volvo 2010-2012 models, and driver acceptance of this system was high, although not to the same extent as the optional forward collision avoidance system. Future research should continue to monitor drivers' experiences with these technologies as they become available in more vehicles. PMID- 24345023 TI - Improving Hybrid III injury assessment in steering wheel rim to chest impacts using responses from finite element Hybrid III and human body model. AB - OBJECTIVE: The main aim of this study was to improve the quality of injury risk assessments in steering wheel rim to chest impacts when using the Hybrid III crash test dummy in frontal heavy goods vehicle (HGV) collision tests. Correction factors for chest injury criteria were calculated as the model chest injury parameter ratios between finite element (FE) Hybrid III, evaluated in relevant load cases, and the Total Human Model for Safety (THUMS). This is proposed to be used to compensate Hybrid III measurements in crash tests where steering wheel rim to chest impacts occur. METHODS: The study was conducted in an FE environment using an FE-Hybrid III model and the THUMS. Two impactor shapes were used, a circular hub and a long, thin horizontal bar. Chest impacts at velocities ranging from 3.0 to 6.0 m/s were simulated at 3 impact height levels. A ratio between FE Hybrid III and THUMS chest injury parameters, maximum chest compression C max, and maximum viscous criterion VC max, were calculated for the different chest impact conditions to form a set of correction factors. The definition of the correction factor is based on the assumption that the response from a circular hub impact to the middle of the chest is well characterized and that injury risk measures are independent of impact height. The current limits for these chest injury criteria were used as a basis to develop correction factors that compensate for the limitations in biofidelity of the Hybrid III in steering wheel rim to chest impacts. RESULTS: The hub and bar impactors produced considerably higher C max and VC max responses in the THUMS compared to the FE-Hybrid III. The correction factor for the responses of the FE-Hybrid III showed that the criteria responses for the bar impactor were consistently overestimated. Ratios based on Hybrid III and THUMS responses provided correction factors for the Hybrid III responses ranging from 0.84 to 0.93. These factors can be used to estimate C max and VC max values when the Hybrid III is used in crash tests for which steering wheel rim to chest interaction occurs. CONCLUSIONS: For the FE-Hybrid III, bar impacts caused higher chest deflection compared to hub impacts, although the contrary results were obtained with the more humanlike THUMS. Correction factors were developed that can be used to correct the Hybrid III chest responses. Higher injury criteria capping limits for steering wheel impacts are acceptable. Supplemental materials are available for this article. Go to the publisher's online edition of Traffic Injury Prevention to view the supplemental file. PMID- 24345024 TI - Analysis of effects of manhole covers on motorcycle driver maneuvers: a nonparametric classification tree approach. AB - OBJECTIVE: A manhole cover is a removable plate forming the lid over the opening of a manhole to allow traffic to pass over the manhole and to prevent people from falling in. Because most manhole covers are placed in roadway traffic lanes, if these manhole covers are not appropriately installed or maintained, they can represent unexpected hazards on the road, especially for motorcycle drivers. The objective of this study is to identify the effects of manhole cover characteristics as well as driver factors and traffic and roadway conditions on motorcycle driver maneuvers. METHOD: A video camera was used to record motorcycle drivers' maneuvers when they encountered an inappropriately installed or maintained manhole cover. Information on 3059 drivers' maneuver decisions was recorded. Classification and regression tree (CART) models were applied to explore factors that can significantly affect motorcycle driver maneuvers when passing a manhole cover. RESULTS: Nearly 50 percent of the motorcycle drivers decelerated or changed their driving path to reduce the effects of the manhole cover. The manhole cover characteristics including the level difference between manhole cover and pavement, the pavement condition over the manhole cover, and the size of the manhole cover can significantly affect motorcycle driver maneuvers. Other factors, including traffic conditions, lane width, motorcycle speed, and loading conditions, also have significant effects on motorcycle driver maneuvers. CONCLUSIONS: To reduce the effects and potential risks from the manhole covers, highway authorities not only need to make sure that any newly installed manhole covers are as level as possible but also need to regularly maintain all the manhole covers to ensure that they are in good condition. In the long run, the size of manhole covers should be kept as small as possible so that the impact of manhole covers on motorcycle drivers can be effectively reduced. Supplemental materials are available for this article. Go to the publisher's online edition of Traffic Injury Prevention to view the supplemental file. PMID- 24345026 TI - Building a drug ontology based on RxNorm and other sources. AB - BACKGROUND: We built the Drug Ontology (DrOn) because we required correct and consistent drug information in a format for use in semantic web applications, and no existing resource met this requirement or could be altered to meet it. One of the obstacles we faced when creating DrOn was the difficulty in reusing drug information from existing sources. The primary external source we have used at this stage in DrOn's development is RxNorm, a standard drug terminology curated by the National Library of Medicine (NLM). To build DrOn, we (1) mined data from historical releases of RxNorm and (2) mapped many RxNorm entities to Chemical Entities of Biological Interest (ChEBI) classes, pulling relevant information from ChEBI while doing so. RESULTS: We built DrOn in a modular fashion to facilitate simpler extension and development of the ontology and to allow reasoning and construction to scale. Classes derived from each source are serialized in separate modules. For example, the classes in DrOn that are programmatically derived from RxNorm are stored in a separate module and subsumed by classes in a manually-curated, realist, upper-level module of DrOn with terms such as 'clinical drug role', 'tablet', 'capsule', etc. CONCLUSIONS: DrOn is a modular, extensible ontology of drug products, their ingredients, and their biological activity that avoids many of the fundamental flaws found in other, similar artifacts and meets the requirements of our comparative-effectiveness research use-case. PMID- 24345025 TI - Injuries from falling objects in the United Arab Emirates. AB - Our aim was to study the demography, anatomical regions injured, severity, and outcome of hospitalised trauma patients who were injured by falling objects in order to give recommendations regarding their prevention in the UAE. All trauma patients who were injured by falling objects and were admitted to Al Ain Hospital for more than 24 hours, or died after arrival to the hospital were studied for over 3 years. One hundred forty nine patients having a mean age (SD) > 34 (12.1) years were studied. The annual incidence of hospitalisation was 10.7/100,000 persons per year. Majority (97.3%) were males and 73.2% from the Indian subcontinent. The most common location for injury was work (88.6%), followed by home (9.4%). Patients injured at home were younger (p < 0.0001), and were more females (p < 0.0001). Extremities and head/neck were the most common injured regions; 1.3% of patients died. Males from the Indian subcontinent are at a higher risk of being injured by falling objects especially at work. Safety education and programs, environmental changes, use of protective devices including helmets or special shoes, and proper enforcement of the safety guidelines could reduce hospitalisations, disability, and death from these injuries. PMID- 24345028 TI - Measuring visual acuity is not as simple as it seems. PMID- 24345027 TI - Challenges in sodium intake reduction and meal consumption patterns among participants with metabolic syndrome in a dietary trial. AB - BACKGROUND: Dietary guidelines suggest limiting daily sodium intake to <2,300 mg for the general population, and <1,500 mg/d for those with certain cardiovascular risk factors. Despite these recommendations, few Americans are able to achieve this goal. Identifying challenges in meeting these guidelines is integral for successful compliance. This analysis examined patterns and amount of daily sodium intake among participants with metabolic syndrome enrolled in a one-year dietary intervention study. METHODS: Two hundred forty participants with metabolic syndrome enrolled in a dietary intervention trial to lose weight and improve dietary quality. Three 24-hour dietary recalls were collected at each visit which provided meal patterns and nutrient data, including sodium intake. A secondary data analysis was conducted to examine sodium consumption patterns at baseline and at one-year study visits. Sodium consumption patterns over time were examined using linear mixed models. RESULTS: The percentage of meals reported eaten in the home at both baseline and one-year follow-up was approximately 69%. Follow-up for the one-year dietary intervention revealed that the participants who consumed sodium greater than 2,300 mg/d declined from 75% (at baseline) to 59%, and those that consumed higher than 1,500 mg/d declined from 96% (at baseline) to 85%. Average sodium intake decreased from 2,994 mg at baseline to 2,558 mg at one-year (P < 0.001), and the sodium potassium ratio also decreased from 1.211 to 1.047 (P < 0.001). Sodium intake per meal varied significantly by meal type, location, and weekday, with higher intake at dinner, in restaurants, and on weekends. At-home lunch and dinner sodium intake decreased (P < 0.05), while dinner sodium intake at restaurant/fast food chains increased from baseline to one-year (P < 0.05). CONCLUSION: Sodium intake for the majority of participants exceeded the recommended dietary guidelines. Findings support actions that encourage low sodium food preparation at home and encourage public health policies that decrease sodium in restaurants and prepared foods. PMID- 24345031 TI - The use of intravenous and inhaled magnesium sulphate in management of children with bronchial asthma. AB - BACKGROUND: Asthma is the most common chronic disease of childhood and the leading cause of childhood morbidity. When uncontrolled, asthma can place significant limits on daily life, and is sometimes fatal. The use of magnesium sulphate (MgSO4) is one of numerous treatment options available during acute severe asthma in children. The efficacy of intravenous, or inhaled MgSO4 has been demonstrated, while little is known about the actual clinical use of either intravenous (IV) or inhaled MgSO4. OBJECTIVE: To assess the effectiveness of intravenous (IV) and/or inhaled MgSO4 on hospital admissions and pulmonary function in children with asthma. This systematic review assessed the best available evidence for the use of either intravenous or inhaled MgSO4 in children with acute asthma. Magnesium deficiency is a common electrolyte disorder in children with acute severe asthma. Several authors reported that IV magnesium was effective in the treatment of moderate to acute asthma in children but evidence for nebulised magnesium was insufficient. In addition, it is used in severe, progressed cases to prevent respiratory failure and/or admission to the intensive care unit. It has bronchodilating and anti-inflammatory effects and modulates ion transport and influences intracellular calcium concentration. Intravenous MgSO4 therapy helps in achieving earlier improvement in clinical signs and symptoms of asthma, e.g. respiratory function and significantly reduced hospital admission, in children with acute severe asthma. The role of nebulised MgSO4 in asthmatic children requires further investigation. CONCLUSION: According to the previous studies, the author recommends the use of intravenous MgSO4 as a safe and effective adjunct to conventional bronchodilator therapy in acute severe asthma in children. PMID- 24345033 TI - Red cell distribution width in patients with atrial fibrillation. PMID- 24345034 TI - Ab initio theoretical study on the 4f(2) and 4f5d electronic manifolds of cubic defects in CaF2:Pr3+. AB - Wave function-based embedded cluster ab initio calculations have been carried out in order to study the 4f(2) and 4f5d energy levels of the cubic substitutional defect of Pr-doped CaF2. The 4f(2) -> 4f5d absorption spectrum and 4f5d -> 4f(2) emission spectrum have been calculated. The 4f(2 1)S0 level is found to be immersed in the 4f5d(eg) manifold, so that no quantum cutting from (1)S0 can occur and only strong 4f5d(eg) -> 4f(2) emission is predicted, which supports previous assumptions made in order to explain results in CaF2:Pr(3+). The details of the 4f(2) -> 4f5d(eg) and 4f(2) -> 4f5d(t2g) bands of the absorption spectrum are interpreted and assignments are made. The lowest level of the 4f5d(eg) configuration is found to have 80% of singlet character, in opposition to Hund's Rules, and the issue is discussed in detail. The comparison between the experimental 4f5d(eg) -> 4f(2) high resolution emission spectrum of the cubic site of CaF2:Pr(3+) and the calculated emission spectra from the two lowest 4f5d(eg) states 1T2u((1)T2u) and 1Eu(1(3)T2u) suggests the possibility that the experimental emission of the cubic Pr defect of CaF2:Pr(3+) is in fact a multiple emission. PMID- 24345032 TI - Experimental gastritis leads to anxiety- and depression-like behaviors in female but not male rats. AB - Human and animals studies support the idea that there is a gender-related co morbidity of pain-related and inflammatory gastrointestinal (GI) diseases with psychological disorders. This co-morbidity is the evidence for the existence of GI-brain axis which consists of immune (cytokines), neural (vagus nerve) and neuroendocrine (HPA axis) pathways. Psychological stress causes disturbances in GI physiology, such as altered GI barrier function, changes in motility and secretion, development of visceral hypersensitivity, and dysfunction of inflammatory responses. Whether GI inflammation would exert impact on psychological behavior is not well established. We examined the effect of experimental gastritis on anxiety- and depression-like behaviors in male and female Sprague-Dawley rats, and evaluated potential mechanisms of action. Gastritis was induced by adding 0.1% (w/v) iodoacetamide (IAA) to the sterile drinking water for 7 days. Sucrose preference test assessed the depression-like behavior, open field test and elevated plus maze evaluated the anxiety-like behavior. IAA treatment induced gastric inflammation in rats of either gender. No behavioral abnormality or dysfunction of GI-brain axis was observed in male rats with IAA-induced gastritis. Anxiety- and depression-like behaviors were apparent and the HPA axis was hyperactive in female rats with IAA-induced gastritis. Our results show that gastric inflammation leads to anxiety- and depression-like behaviors in female but not male rats via the neuroendocrine (HPA axis) pathway, suggesting that the GI inflammation can impair normal brain function and induce changes in psychological behavior in a gender-related manner through the GI-to brain signaling. PMID- 24345036 TI - Financial crisis, virtual carbon in global value chains, and the importance of linkage effects. The Spain-china case. AB - Trade has a disproportionate environmental impact, while the international fragmentation of production promotes different patterns of intermediate inputs and final goods. Therefore, we split up the balance of domestic embodied emissions in trade (BDEET) to assess it. We find that Spain has a significant emissions deficit with China between 2005 and 2011. The Global Financial Crisis of 2008 reduced Spanish imports of pollution-intensive inputs from China and slightly improved the BDEET. China primarily exports indirect virtual carbon, representing 86% of the total, especially from Production of electricity, gas, and water sector. These linkages effects in China indicate that post-Kyoto agreements must focus not only on traded goods but also on the environmental efficiency of all domestic production chains. The methodology proposed allows us to identify the agents responsible for this trade in both Spain and China, namely the sectors importing intermediate inputs (Construction and Transport equipment) and industries and consumers importing final goods (Textiles, Other manufactures, Computers, and Machinery). The relevant sectors uncertainties found when we compare the results for BDEET and emissions embodied in bilateral trade (BEET) lead us to recommend the former methodology to evaluate the implications of environmental and energy policy for different industries and agents. PMID- 24345035 TI - Non-essential genes form the hubs of genome scale protein function and environmental gene expression networks in Salmonella enterica serovar Typhimurium. AB - BACKGROUND: Salmonella Typhimurium is an important pathogen of human and animals. It shows a broad growth range and survives in harsh conditions. The aim of this study was to analyze transcriptional responses to a number of growth and stress conditions as well as the relationship of metabolic pathways and/or cell functions at the genome-scale-level by network analysis, and further to explore whether highly connected genes (hubs) in these networks were essential for growth, stress adaptation and virulence. RESULTS: De novo generated as well as published transcriptional data for 425 selected genes under a number of growth and stress conditions were used to construct a bipartite network connecting culture conditions and significantly regulated genes (transcriptional network). Also, a genome scale network was constructed for strain LT2. The latter connected genes with metabolic pathways and cellular functions. Both networks were shown to belong to the family of scale-free networks characterized by the presence of highly connected nodes or hubs which are genes whose transcription is regulated when responding to many of the assayed culture conditions or genes encoding products involved in a high number of metabolic pathways and cell functions.The five genes with most connections in the transcriptional network (wraB, ygaU, uspA, cbpA and osmC) and in the genome scale network (ychN, siiF (STM4262), yajD, ybeB and dcoC) were selected for mutations, however mutagenesis of ygaU and ybeB proved unsuccessful. No difference between mutants and the wild type strain was observed during growth at unfavorable temperatures, pH values, NaCl concentrations and in the presence of H2O2. Eight mutants were evaluated for virulence in C57/BL6 mice and none differed from the wild type strain. Notably, however, deviations of phenotypes with respect to the wild type were observed when combinations of these genes were deleted. CONCLUSION: Network analysis revealed the presence of hubs in both transcriptional and functional networks of S. Typhimurium. Hubs theoretically confer higher resistance to random mutation but a greater susceptibility to directed attacks, however, we found that genes that formed hubs were dispensable for growth, stress adaptation and virulence, suggesting that evolution favors non-essential genes as main connectors in cellular networks. PMID- 24345037 TI - Transition from paediatric to adult care for patients with sickle cell disease. AB - Advances achieved over the last three decades have transformed sickle cell disease (SCD) from a fatal childhood disease to a long-term chronic condition. Consequently, patients must transition from paediatric to adult care. The transition is a high-risk period associated with increases in hospital admissions and death. The factors underlying this increased risk include not only characteristics of the disease itself, with the accumulation of disabilities and progression of organ damage, but also psychological factors and a frequent paucity of adult-care resources for SCD. Leaving the familiar paediatric team causes marked anxiety in many patients. The transition of care coincides with the many other transitions that characterize the emotional, social and academic development of adolescents. The shift from protection by parents and physicians to independent self-management may be difficult. Finally, young adults may have limited access to health insurance. In recent years, many medical groups have suggested the development of transitioning programmes combining transition schedules, printed and web-based materials, and, in some cases, transition dedicated physicians, nurses and psychologists. Transition must begin early, involve both the paediatric and the adult team, direct appropriate attention to the parents and occur over a period of several years. Evaluations of these programmes are urgently needed. PMID- 24345038 TI - Steering acoustically propelled nanowire motors toward cells in a biologically compatible environment using magnetic fields. AB - The recent discovery of fuel-free propulsion of nanomotors using acoustic energy has provided a new avenue for using nanomotors in biocompatible media. Crucial to the application of nanomotors in biosensing and biomedical applications is the ability to remotely control and steer them toward targets of interest, such as specific cells and tissues. We demonstrate in vitro magnetic steering of acoustically powered nanorod motors in a biologically compatible environment. Steering was accomplished by incorporating (40 +/- 5) nm thick nickel stripes into the electrochemically grown nanowires. An external magnetic field of 40-45 mT was used to orient the motors, which were acoustically propelled along their long axes. In the absence of a magnetic field, (300 +/- 30) nm diameter, (4.3 +/- 0.2) MUm long nanowires with (40 +/- 5) nm thick magnetic stripes exhibit the same self-acoustophoretic behavior, including pattern formation into concentric nanowire circles, aligned spinning chains, and autonomous axial motion, as their non-magnetic counterparts. In a magnetic field, these wires and their paths are oriented as evidenced by their relatively linear trajectories. Coordinated motion of multiple motors and targeting of individual motors toward HeLa cells with micrometer-level precision was demonstrated. PMID- 24345039 TI - A ventilation intervention study in classrooms to improve indoor air quality: the FRESH study. AB - BACKGROUND: Classroom ventilation rates often do not meet building standards, although it is considered to be important to improve indoor air quality. Poor indoor air quality is thought to influence both children's health and performance. Poor ventilation in The Netherlands most often occurs in the heating season. To improve classroom ventilation a tailor made mechanical ventilation device was developed to improve outdoor air supply. This paper studies the effect of this intervention. METHODS: The FRESH study (Forced-ventilation Related Environmental School Health) was designed to investigate the effect of a CO2 controlled mechanical ventilation intervention on classroom CO2 levels using a longitudinal cross-over design. Target CO2 concentrations were 800 and 1200 parts per million (ppm), respectively. The study included 18 classrooms from 17 schools from the north-eastern part of The Netherlands, 12 experimental classrooms and 6 control classrooms. Data on indoor levels of CO2, temperature and relative humidity were collected during three consecutive weeks per school during the heating seasons of 2010-2012. Associations between the intervention and weekly average indoor CO2 levels, classroom temperature and relative humidity were assessed by means of mixed models with random school-effects. RESULTS: At baseline, mean CO2 concentration for all schools was 1335 ppm (range: 763-2000 ppm). The intervention was able to significantly decrease CO2 levels in the intervention classrooms (F (2,10) = 17.59, p < 0.001), with a mean decrease of 491 ppm. With the target set at 800 ppm, mean CO2 was 841 ppm (range: 743-925 ppm); with the target set at 1200 ppm, mean CO2 was 975 ppm (range: 887-1077 ppm). CONCLUSIONS: Although the device was not capable of precisely achieving the two predefined levels of CO2, our study showed that classroom CO2 levels can be reduced by intervening on classroom ventilation using a CO2 controlled mechanical ventilation system. PMID- 24345040 TI - Multidisciplinary diabetes team care: the experiences of young adults with Type 1 diabetes. AB - BACKGROUND: This research examined whether young adults with Type 1 diabetes engage with the multidisciplinary consultation process and if not, then why. METHODS: We designed a web-based self-reported survey, available online from February to May 2011, for Australian adults 18-35 years with Type 1 diabetes. Respondents were asked about which clinicians they consulted to assist with self management. To expand on the results of the survey, we interviewed 33 respondents. RESULTS: SURVEY: Respondents (n = 150) consulted with the following clinicians: endocrinologist and diabetes educators: 23.3%; endocrinologist only: 18.0%; endocrinologist, diabetes educators and dieticians: 14.6%; endocrinologist, diabetes educators, dietician and general practitioners (GP): 11.3%; endocrinologist and GP: 10.6%; GP only: 4.6%; all clinicians recommended to assist with self-management: 1.3%; 2.7% did not consult any clinician. Interview: Participants (n = 33) reported eight key disincentives to consultation with multidisciplinary clinicians. These were time constraints; provision of conflicting advice; inaccessibility of health services; variation in service standards; cost constraints; failure of clinicians to refer to other clinicians; lack of opportunity to build a therapeutic relationship; and failure of clinicians to engage in shared decision making. CONCLUSION: Our results indicate that high attrition rates of young adults with Type 1 diabetes from recommended diabetes health services is linked to the failure of those services to meet the needs and preferences of their patients. The identified needs and preferences included joint consultation with multi-disciplinary team clinicians; flexible access to advice by email or telephone consultation; and shared decision making. Patient engagement in health-service re-design has implications for improved health-service delivery and enhanced treatment outcomes. PMID- 24345041 TI - Quantification of individual phenolic compounds' contribution to antioxidant capacity in apple: a novel analytical tool based on liquid chromatography with diode array, electrochemical, and charged aerosol detection. AB - Phenolics, particularly from apples, hold great interest because of their antioxidant properties. In the present study, the total antioxidant capacity of different apple extracts obtained by pressurized hot water extraction (PHWE) was determined by cyclic voltammetry (CV), which was compared with the conventional antioxidant assays. To measure the antioxidant capacity of individual antioxidants present in apple extracts, a novel method was developed based on high-performance liquid chromatography (HPLC) with photodiode array (DAD), electrochemical (ECD), and charged aerosol (CAD) detection. HPLC-DAD-ECD-CAD enabled rapid, qualitative, and quantitative determination of antioxidants in the apple extracts. The main advantage of using CAD was that this detector enabled quantification of a large number of phenolics using only a few standards. The results showed that phenolic acids and flavonols were mainly responsible for the total antioxidant capacity of apple extracts. In addition, protocatechuic acid, chlorogenic acid, hyperoside, an unidentified phenolic acid, and a quercetin derivative presented the highest antioxidant capacities. PMID- 24345042 TI - What is a segment? AB - Animals have been described as segmented for more than 2,000 years, yet a precise definition of segmentation remains elusive. Here we give the history of the definition of segmentation, followed by a discussion on current controversies in defining a segment. While there is a general consensus that segmentation involves the repetition of units along the anterior-posterior (a-p) axis, long-running debates exist over whether a segment can be composed of only one tissue layer, whether the most anterior region of the arthropod head is considered segmented, and whether and how the vertebrate head is segmented. Additionally, we discuss whether a segment can be composed of a single cell in a column of cells, or a single row of cells within a grid of cells. We suggest that 'segmentation' be used in its more general sense, the repetition of units with a-p polarity along the a-p axis, to prevent artificial classification of animals. We further suggest that this general definition be combined with an exact description of what is being studied, as well as a clearly stated hypothesis concerning the specific nature of the potential homology of structures. These suggestions should facilitate dialogue among scientists who study vastly differing segmental structures. PMID- 24345043 TI - Isolated thoracic aortitis. AB - Isolated thoracic aortitis is a new pathological entity. We review the histopathological features of this disease, the role of imaging, and diagnostic modalities necessary to make the diagnosis of aortitis and discuss the management of patients with an established diagnosis of isolated thoracic aortitis. PMID- 24345044 TI - Microbial source tracking: a tool for identifying sources of microbial contamination in the food chain. AB - The ability to trace fecal indicators and food-borne pathogens to the point of origin has major ramifications for food industry, food regulatory agencies, and public health. Such information would enable food producers and processors to better understand sources of contamination and thereby take corrective actions to prevent transmission. Microbial source tracking (MST), which currently is largely focused on determining sources of fecal contamination in waterways, is also providing the scientific community tools for tracking both fecal bacteria and food-borne pathogens contamination in the food chain. Approaches to MST are commonly classified as library-dependent methods (LDMs) or library-independent methods (LIMs). These tools will have widespread applications, including the use for regulatory compliance, pollution remediation, and risk assessment. These tools will reduce the incidence of illness associated with food and water. Our aim in this review is to highlight the use of molecular MST methods in application to understanding the source and transmission of food-borne pathogens. Moreover, the future directions of MST research are also discussed. PMID- 24345045 TI - Acrylamide: formation, occurrence in food products, detection methods, and legislation. AB - This review aims at summarizing the most recent updates in the field of acrylamide (AA) formation (mechanism, conditions) and the determination of AA in a number of foods (fried or baked potatoes, chips, coffee, bread, etc). The methods applied for AA detection [Capillary Electrophoresis-Mass Spectrometry (CE MS), Liquid Chromatography-Mass Spectrometry (LC-MS), Non-Aqueous Capillary Electrophoresis (NACE), High Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS), Pressurized Fluid Extraction (PFE), Matrix Solid-Phase Dispersion (MSPD), Gas Chromatography-Mass Spectrometry (GC-MS), Solid-Phase MicroExtraction Gas Chromatography (SPME-GC), Enzyme Linked Immunosorbent Assay (ELISA), and MicroEmulsion ElectroKinetic Chromatography (MEEKC) are presented and commented. Several informative figures and tables are included to show the effect of conditions (temperature, time) on the AA formation. A section is also included related to AA legislation in EU and US. PMID- 24345046 TI - Resveratrol in peanuts. AB - Peanuts are important dietary food source of resveratrol with potent antioxidant properties implicated in reducing risk of cancer, cardiovascular and Alzheimer's disease, and delaying aging. Resveratrol is a naturally occurring stilbene phytoalexin phenolic compound produced in response to a variety of biotic and abiotic stresses. This paper is a review of trans-resveratrol and related stilbenes from peanuts--their chemical structures, mechanisms for their biosynthesis, and concentrations in comparison with other major food sources. It will also discuss trans-resveratrol's absorption, bioavailability, and major health benefits; processes to enhance their biosynthesis in peanuts by biotic and abiotic stresses; process optimization for enhanced levels in peanuts and their potential food applications; and methods used for its extraction and analysis. PMID- 24345047 TI - Molecular basis of taste sense: involvement of GPCR receptors. AB - Taste perception is one of the senses crucial for many organisms. There are five basic tastes, i.e., sweet, bitter, salty, sour, and umami, and it is suggested that the taste of fat should be included in this list. This paper reviews the current state of knowledge about the involvement of G protein coupled receptors (GPCRs) in taste sensing and intracellular signaling. GPCR receptors are focal point of interest for pharmaceutical industry. However, their ability to interact with a variety of taste substances makes these receptors interesting target for food and nutrient companies. PMID- 24345048 TI - Evidence for contributions of interactions of constituents to the anti inflammatory activity of Hypericum perforatum. AB - Hypericum perforatum (Hp) extracts contain many different classes of constituents including flavonoids and biflavonoids, phloroglucinols, naphthodianthrones, caffeic acid derivatives, and unknown and/or unidentified compounds. Many constituents may be responsible for the anti-inflammatory activity of Hp including quercetin and derivatives, hyperforin, pseudohypericin, and amentoflavone. In line with antidepressant data, it appears that the interactions of constituents may be important for the anti-inflammatory activity of Hp. Interactions of constituents, tested in bioavailability models, may explain why synergistic mechanisms have been found to be important for antidepressant and antiproliferative bioactivities. This review highlights the relationship among individual constituents and the anti-inflammatory activity of Hp extracts and proposes that interactions of constituents may be important for the anti inflammatory activity of botanical extracts, although the exact mechanisms of the interactions are still unclear. PMID- 24345049 TI - Strawberry as a functional food: an evidence-based review. AB - Emerging research provides substantial evidence to classify strawberries as a functional food with several preventive and therapeutic health benefits. Strawberries, a rich source of phytochemicals (ellagic acid, anthocyanins, quercetin, and catechin) and vitamins (ascorbic acid and folic acid), have been highly ranked among dietary sources of polyphenols and antioxidant capacity. It should however be noted that these bioactive factors can be significantly affected by differences in strawberry cultivars, agricultural practices, storage, and processing methods: freezing versus dry heat has been associated with maximum retention of strawberry bioactives in several studies. Nutritional epidemiology shows inverse association between strawberry consumption and incidence of hypertension or serum C-reactive protein; controlled feeding studies have identified the ability of strawberries to attenuate high-fat diet induced postprandial oxidative stress and inflammation, or postprandial hyperglycemia, or hyperlipidemia in subjects with cardiovascular risk factors. Mechanistic studies have elucidated specific biochemical pathways that might confer these protective effects of strawberries: upregulation of endothelial nitric oxide synthase (eNOS) activity, downregulation of NF-kB activity and subsequent inflammation, or inhibitions of carbohydrate digestive enzymes. These health effects may be attributed to the synergistic effects of nutrients and phytochemicals in strawberries. Further studies are needed to define the optimal dose and duration of strawberry intake in affecting levels of biomarkers or pathways related to chronic diseases. PMID- 24345050 TI - Rice bran: a novel functional ingredient. AB - Rice (Oryza sativa) is the most important staple food for a large part of the world's human population, especially in East and South Asia, the Middle East, Latin America, and the West Indies. It provides more than one fifth of the calories consumed worldwide by the human. It is the second leading cereal crop and staple food of half of the world's population. It is grown in at least 114 countries with global production of 645 million tons; share of Asian farmers is about 90% of the total produce. Rice bran, brown outer layer of rice kernel, is mainly composed of pericarp, aleurone, subaleurone layer, and germ. It contains appreciable quantities of nutrients like protein, fat, and dietary fiber. Furthermore, it contains substantial amount of minerals like K, Ca, Mg, and Fe. Presence of antioxidants like tocopherols, tocotrienols, and gamma-oryzanol also brighten prospects of rice bran utilization for humans as functional ingredient to mitigate the life-threatening disorders. Moreover, in the developing countries, budding dilemma of food crisis, arising due to lower crop yields and escalating population, needs to utilize each pent of available resources. To provide enough food to all people, there is the holistic approach of using the by products generated during food processing and preparations. Rice is being processed in well-established industry, but the major apprehension is the utilization of its by-products; rice bran (5-8%) and polishing (2-3%) that are going as waste. Rice processing or milling produces several streams of materials including milled rice, bran, and husk. In developing countries, rice bran is considered as a by-product of the milling process and commonly used in animal feed or discarded as a waste. The potential of producing rice bran at the global level is 29.3 million tons annually, whereas the share of Pakistan is worked out to be 0.5 million tons. In present paper, attempt has been made to highlight the significance of these valuable but neglected ingredients under various headings. PMID- 24345051 TI - Advances in wine aging technologies for enhancing wine quality and accelerating wine aging process. AB - Wine aging is an important process to produce high-quality wines. Traditionally, wines are aged in oak barrel aging systems. However, due to the disadvantages of the traditional aging technology, such as lengthy time needed, high cost, etc., innovative aging technologies have been developed. These technologies involve aging wines using wood fragments, application of micro-oxygenation, aging on lees, or application of some physical methods. Moreover, wine bottling can be regarded as the second phase of wine aging and is essential for most wines. Each technology can benefit the aging process from different aspects. Traditional oak barrel aging technology is the oldest and widely accepted technology. The application of wood fragments and physical methods are promising in accelerating aging process artificially, while application of micro-oxygenation and lees is reliable to improve wine quality. This paper reviews recent developments of the wine aging technologies. The impacts of operational parameters of each technology on wine quality during aging are analyzed, and comparisons among these aging technologies are made. In addition, several strategies to produce high-quality wines in a short aging period are also proposed. PMID- 24345052 TI - Multidimensional LC-MS/MS enables simultaneous quantification of intact human insulin and five recombinant analogs in human plasma. AB - This work provides a multidimensional method for the simultaneous, direct quantification of intact human insulin and five insulin analogs in human plasma. This investigation solves both the selectivity and sensitivity problems encountered for accurate quantification of insulins in plasma since the former is not possible with conventional assays and the latter with conventional LC-MS/MS. The method uses a mixed-mode SPE and a multidimensional LC method including a solid-core particle column containing an anion exchange stationary phase. Matrix factors for all analogs were calculated in 6 sources of human plasma and CVs of the matrix factors were <15% in all cases supporting the selectivity of the method, while achieving LLOQs of 50-200 pg/mL (1.4-5.6 MUIU/mL) for each insulin from 250 MUL of human plasma. The average accuracy for the standard curve points in extracted human plasma was 99-100%. Average inter- and intraday accuracies for QC samples were 98% and 94%, respectively. Average inter- and intraday precisions for QC samples were 7.5 and 5.3%, respectively. Patient samples were analyzed in a blind study and results concurred with their diabetes multidosing regimes. The study also demonstrated that the presence of high levels of human insulin and bovine insulin does not interfere with quantification of any of the analyzed analogs. We propose this method for the accurate pharmacokinetic monitoring of diabetic patients, for sport antidoping and forensic toxicology analysis. PMID- 24345053 TI - Serum ischemia-modified albumin levels at diagnosis and during treatment of late onset neonatal sepsis. AB - Sepsis is one of the most common infectious conditions in the neonatal period, and continues as a major source of morbidity and mortality. The aim of this study is to determine serum ischemia-modified albumin (IMA) levels in late-onset neonatal sepsis at the time of diagnosis and after therapy, and to show the meaningful on the follow-up. Also, it is aimed to compare serum IMA levels with serum C-reactive protein (CRP), procalcitonin (PCT) levels and white blood cell count. The study was performed on 33 premature babies with sepsis and 21 healthy premature controls at 7-28 days of age. In the sepsis group, biochemical parameters and blood culture samples were obtained from the blood at the onset and on the fifth day of treatment for each patient. Serum IMA, CRP, PCT and white blood cell count were significantly higher in the sepsis group before treatment when compared with the control group. In addition, the levels of IMA were positively correlated with white blood cell count, CRP and PCT in the sepsis group before treatment. In conclusion, serum IMA levels may be useful in late onset neonatal sepsis at the time of diagnosis and after therapy. As far as we know this is the first report about the assesment of illness diagnosis and after therapy using serum IMA levels, and further studies are needed to confirm our results in larger groups of patients. PMID- 24345054 TI - Motor neuropathy-associated mutation impairs Seipin functions in neurotransmission. AB - Gain-of-toxic-function mutations in Seipin (Asparagine 88 to Serine (N88S) and Serine 90 to Leucine (S90L) mutations, both of which disrupt the N-glycosylation) cause autosomal dominant motor neuron diseases. However, the mechanism of how these missense mutations lead to motor neuropathy is unclear. Here, we analyze the impact of disruption of N-glycosylation of Seipin on synaptic transmission by over-expressing mutant Seipin in cultured cortical neurons via lentiviral infection. Immunostaining shows that over-expressed Seipin is partly colocalized with synaptic vesicle marker synaptophysin. Electrophysiological recordings reveal that the Seipin mutation significantly decreases the frequency, but not the amplitudes of miniature excitatory post-synaptic currents and miniature inhibitory post-synaptic currents. The amplitude of both evoked excitatory post synaptic currents and inhibitory post-synaptic current is also compromised by mutant Seipin over-expression. The readily releasable pool and vesicular release probability of synaptic vesicles are both altered in neurons over-expressing Seipin-N88S, whereas neither gamma-amino butyric acid (GABA) nor alpha-Amino-3 hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) induced whole cell currents are affected. Moreover, electron microscopy analysis reveals decreased number of morphologically docked synaptic vesicles in Seipin-N88S-expressing neurons. These data demonstrate that Seipin-N88S mutation impairs synaptic neurotransmission, possibly by regulating the priming and docking of synaptic vesicles at the synapse. PMID- 24345055 TI - Effect of physical therapy on muscle strength, respiratory muscles and functional parameters in patients with intensive care unit-acquired weakness. AB - OBJECTIVES: The aim of this study was to evaluate the effect of an intensive physical therapy protocol in patients who contract 'intensive care unit-acquired weakness' (ICUAW), in terms of muscle strength, breathing and functional indices. METHODS: This was a prospective, single-blinded study in a general hospital intensive care unit (ICU). Patients who required mechanical ventilation longer than 48 h and who were expected to remain mechanically ventilated for at least another 48 h were randomly divided into two intervention groups: group I (n = 9) the routine care group, received physical therapy according to our daily custom protocol; and group II (n = 9) - the intensive treatment group, were treated by the same protocol twice a day. The main outcome measures included the Medical Research Council (MRC) physical strength examination, maximal inspiratory pressure (MIP), hand grip dynamometer and sitting balance test. RESULTS: Significant strength improvement from first (T1) to second (T2) measurements was demonstrated for variables MIP and MRC physical strength examination in favor of the intensive treatment group (P < 0.05). The intensive treatment group also required shorter intensive care length of stay than the routine care group (P = 0.043). CONCLUSIONS: It is possible that an intensive therapy protocol may facilitate the initial recovery process in patients who suffer from ICUAW. PMID- 24345056 TI - Non-hepatosplenic extramedullary haematopoiesis in primary myelofibrosis. PMID- 24345057 TI - Counseling parents who are considering newborn male circumcision. AB - The American Academy of Pediatrics recently issued a statement that the health benefits of newborn male circumcision exceed the risks and therefore justify access to the procedure for families who choose it. Further, clinicians are charged with providing factually correct information that communicates the risks and benefits of elective newborn male circumcision in a nonbiased manner. However, many clinicians lack adequate information to discuss the risks and benefits of male circumcision. The purpose of this review is to highlight evidence on the risks and benefits of newborn male circumcision and provide clinicians with counseling points that can be used to guide discussion with parents considering newborn male circumcision. PMID- 24345058 TI - Environmental exposure to pyrethroids and sperm sex chromosome disomy: a cross sectional study. AB - BACKGROUND: The role of environmental pesticide exposures, such as pyrethroids, and their relationship to sperm abnormalities are not well understood. This study investigated whether environmental exposure to pyrethroids was associated with altered frequency of sperm sex chromosome disomy in adult men. METHODS: A sample of 75 subjects recruited through a Massachusetts infertility clinic provided urine and semen samples. Individual exposures were measured as urinary concentrations of three pyrethroid metabolites ((3-phenoxybenzoic acid (3PBA), cis- and trans- 3-(2,2-Dichlorovinyl)-1-methylcyclopropane-1,2-dicarboxylic acid (CDCCA and TDCCA)). Multiprobe fluorescence in situ hybridization for chromosomes X, Y, and 18 was used to determine XX, YY, XY, 1818, and total sex chromosome disomy in sperm nuclei. Poisson regression analysis was used to examine the association between aneuploidy rates and pyrethroid metabolites while adjusting for covariates. RESULTS: Between 25-56% of the sample were above the limit of detection (LOD) for the pyrethroid metabolites. All sex chromosome disomies were increased by 7-30% when comparing men with CDCCA and TDCCA levels above the LOD to those below the LOD. For 3PBA, compared to those below the LOD, those above the LOD had YY18 disomy rates 1.28 times higher (95% CI: 1.15, 1.42) whereas a reduced rate was seen for XY18 and total disomy (IRR = 0.82; 95% CI: 0.77, 0.87; IRR = 0.93; 95% CI: 0.87-0.97), and no association was seen for XX18 and 1818. CONCLUSIONS: Our findings suggest that urinary concentrations of CDCCA and TDCCA above the LOD were associated with increased rates of aneuploidy. However the findings for 3BPA were not consistent. This is the first study to examine these relationships, and replication of our findings is needed before the association between pyrethroid metabolites and aneuploidy can be fully defined. PMID- 24345059 TI - Road safety: laws and implementation. PMID- 24345060 TI - To P or not to P. PMID- 24345064 TI - Continuous professional competence (CPC) for emergency medical technicians in Ireland: educational needs assessment. AB - BACKGROUND: As in other countries, the Irish Regulator for Pre-Hospital practitioners, the Pre-Hospital Emergency Care Council (PHECC), will introduce a Continuous Professional Competence (CPC) framework for all Emergency Medical Technicians (EMTs), Paramedics and Advanced Paramedics (APs). This framework involves EMTs participating in regular and structured training to maintain professional competence and enable continuous professional developments. To inform the development of this framework, this study aimed to identify what EMTs consider the optimum educational outcomes and activity and their attitude towards CPC. METHODS: All EMTs registered in Ireland (n = 925) were invited via email to complete an anonymous online survey. Survey questions were designed based on Continuous Professional Development (CPD) questionnaires used by other healthcare professions. Quantitative and qualitative analyses were performed. RESULTS: Response rate was 43% (n = 399). 84% of participants had been registered in Ireland for less than 24 months, while 59% had been registered EMTs for more than one year. Outcomes were: evidence of CPC should be a condition for EMT registration in Ireland (95%), 78% believed that EMTs who do not maintain CPC should be denied the option to re-register. Although not required to do so at the time of survey, 69% maintained a professional portfolio and 24% had completed up to 20 hours of CPC activities in the prior 12 months. From a list of 22 proposed CPC activities, 97% stated that practical scenario-based exercises were most relevant to their role. E-learning curricula without practical components were considered irrelevant (32%), but the majority of participants (91%) welcomed access to e-learning when supplemented by related practical modules. CONCLUSION: EMTs are supportive of CPC as a key part of their professional development and registration. Blended learning, which involves clinical and practical skills and e-learning, is the optimum approach. PMID- 24345063 TI - Diagnostic and prognostic value of circulating microRNAs in patients with acute chest pain. AB - OBJECTIVES: To address the diagnostic value of circulating microRNAs (miRNAs) in patients presenting with acute chest pain. DESIGN: In a prospective, international, multicentre study, six miRNAs (miR-133a, miR-208b, miR-223, miR 320a, miR-451 and miR-499) were simultaneously measured in a blinded fashion in 1155 unselected patients presenting with acute chest pain to the emergency department. The final diagnosis was adjudicated by two independent cardiologists. The clinical follow-up period was 2 years. RESULTS: Acute myocardial infarction (AMI) was the adjudicated final diagnosis in 224 patients (19%). Levels of miR 208b, miR-499 and miR-320a were significantly higher in patients with AMI compared to those with other final diagnoses. MiR-208b provided the highest diagnostic accuracy for AMI (area under the receiver operating characteristic curve 0.76, 95% confidence interval 0.72-0.80). This diagnostic value was lower than that of the fourth-generation cardiac troponin T (cTnT; 0.84) or the high sensitivity cTnT (hs-cTnT; 0.94; both P < 0.001 for comparison). None of the six miRNAs provided added diagnostic value when combined with cTnT or hs-cTnT (ns for the comparison of combinations vs. cTnT or hs-cTnT alone). During follow-up, 102 (9%) patients died. Levels of MiR-208b were higher in patients who died within 30 days, but the prognostic accuracy was low to moderate. None of the miRNAs predicted long-term mortality. CONCLUSION: The miRNAs investigated in this study do not seem to provide incremental diagnostic or prognostic value in patients presenting with suspected AMI. PMID- 24345065 TI - Effect of phacoemulsification on trabeculectomy function. AB - BACKGROUND: To evaluate the effect of phacoemulsification on trabeculectomy function. DESIGN: Retrospective case-control study. PARTICIPANTS: Forty-eight patients who underwent trabeculectomy surgery and had at least 2 years of follow up. METHODS: Patients were classified into two groups: patients who had phacoemulsification subsequent to trabeculectomy (Trab_phaco, n = 18) and patients who were pseudophakic for greater than 6 months preceding their trabeculectomy (Phaco_trab, n = 30). Groups were matched for length of follow up of 2 years from time of trabeculectomy. MAIN OUTCOME MEASURES: The primary outcome measures were target intraocular pressure of criteria A, <=12 mmHg; B, <=15 mmHg; C, <=18 mmHg with or without additional topical treatment. A separate measure for bleb function failure was also used; with failure defined as the need for additional topical antiglaucoma therapy or surgical intervention to achieve control of intraocular pressure. RESULTS: There was no significant difference in achieving each intraocular pressure criterion between groups (12 months, P = 1.0; 24 months, P = 0.330). In the first 12 months, significantly more trabeculectomies in the Trab_phaco group failed, requiring additional intervention to control the IOP (39%) compared with the Phaco_trab (10%) group (P = 0.028). Although this trend continued at 24 months, there were no significant differences in failure rates (P = 0.522). CONCLUSIONS: Phacoemulsification performed after trabeculectomy significantly increased rates of bleb failure in the following 12 months but not at 24 months. PMID- 24345066 TI - Anthracycline-based chemotherapy in extraskeletal myxoid chondrosarcoma: a retrospective study. AB - BACKGROUND: Extraskeletal myxoid chondrosarcoma (EMC) is a rare subgroup within soft tissue sarcomas. Its sensitivity to chemotherapy is reported to be low. METHODS: We retrospectively reviewed a series of 11 EMC patients treated as from 2001 within the Italian Rare Cancer Network (RCN) with anthracycline-based chemotherapy. Pathologic diagnosis was centrally reviewed in all cases and confirmed by the presence of the specific chromosomal rearrangements, involving the NR4A3 gene locus on chromosome 9. RESULTS: Eleven patients treated with anthracycline-based chemotherapy were included (M/F: 9/2 - mean age: 52 years - site of primary: lower limb/other = 9/2 - metastatic = 11 - front line/ further line = 10/1 - anthracycline as single agent/ combined with ifosfamide = 1/10). Ten patients are evaluable for response. Overall, best response according to RECIST was: partial response (PR) = 4 (40 %), stable disease (SD) = 3, progressive disease (PD) = 3 cases. Median PFS was 8 (range 2-10) months. CONCLUSIONS: By contrast to what reported so far, anthracycline-based chemotherapy is active in a distinct proportion of EMC patients. PMID- 24345067 TI - Ovulation induction in young girls with menometrorragia: a safe and effective treatment. AB - The prevalence of menometrorrhagia in fertile women is 11.4-13.2% and increases with aging. The presence of metrorrhagia is a relatively common cause of concern among adolescents and their parents, as well as a frequent cause of visits to emergency departments, gynaecologists, and pediatricians. Clomiphene is a selective estrogen receptor modulator (SERM) that increases the production of gonadotropins by inhibiting negative feedback on the hypothalamus. Clomiphene is primarily used in the treatment of female infertility for ovulation induction to reverse oligoovulation or anovulation, as occurs in polycystic ovary syndrome. OBJECTIVE: The aim of our study was to evaluate the use of clomiphene citrate in ovulation induction, and therefore, in the cessation of bleeding in adolescents with menometrorrhagia in the absence of uterine, ovarian, or systemic pathologies. DESIGN: Cohort study. MATERIALS AND METHODS: The study group was comprised of 50 subjects (age range, 13-16 years) with menometrorrhagia (bleeding >7 days in length with an average blood loss >80 ml). The treatment with clomiphene citrate at a dose of 50 mg/day for 5 days during the attack cycle, and from days 3 to 7 of three subsequent cycles, was offered to the patients. RESULTS: After three cycles of therapy, all patients had resolution of the menometrorrhagia and resumption of ovulatory cycles. No patient reported unwanted side effects. CONCLUSION: We propose that low-dose clomiphene should be the first step in the treatment of adolescent dysfunctional bleeding (DUB). PMID- 24345068 TI - Hygrothermal aging effects on buried molecular structures at epoxy interfaces. AB - Interfacial properties such as adhesion are determined by interfacial molecular structures. Adhesive interfaces in microelectronic packages that include organic polymers such as epoxy are susceptible to delamination during accelerated stress testing. Infrared-visible sum frequency generation vibrational spectroscopy (SFG) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR FTIR) were used to study molecular structures at buried epoxy interfaces during hygrothermal aging to relate molecular structural changes at buried interfaces to decreases in macroscopic adhesion strength. SFG peaks associated with strongly hydrogen bonded water were detected at hydrophilic epoxy interfaces. Ordered interfacial water was also correlated to large decreases in interfacial adhesion strength that occurred as a result of hygrothermal aging, which suggests that water diffused to the interface and replaced original hydrogen bond networks. No water peaks were observed at hydrophobic epoxy interfaces, which was correlated with a much smaller decrease in adhesion strength from the same aging process. ATR-FTIR water signals observed in the epoxy bulk were mainly contributed by relatively weakly hydrogen bonded water molecules, which suggests that the bulk and interfacial water structure was different. Changes in interfacial methyl structures were observed regardless of the interfacial hydrophobicity which could be due to water acting as a plasticizer that restructured both the bulk and interfacial molecular structure. This research demonstrates that SFG studies of molecular structural changes at buried epoxy interfaces during hygrothermal aging can contribute to the understanding of moisture-induced failure mechanisms in electronic packages that contain organic adhesives. PMID- 24345069 TI - Ipomoea batatas (L.) Lam.: a rich source of lipophilic phytochemicals. AB - The lipophilic extracts from the storage root of 13 cultivars of sweet potato (Ipomoea batatas (L.) Lam.) were evaluated by gas chromatography-mass spectrometry with the aim to valorize them and offer information on their nutritional properties and potential health benefits. The amount of lipophilic extractives ranged from 0.87 to 1.32% dry weight. Fatty acids and sterols were the major families of compounds identified. The most abundant saturated and unsaturated fatty acids were hexadecanoic acid (182-428 mg/kg) and octadeca-9,12 dienoic acid (133-554 mg/kg), respectively. beta-Sitosterol was the principal phytosterol, representing 55.2-77.6% of this family, followed by campesterol. Long-chain aliphatic alcohols and alpha-tocopherol were also detected but in smaller amounts. The results suggest that sweet potato should be considered as an important dietary source of lipophilic phytochemicals. PMID- 24345070 TI - The use of fecal calprotectin as a biomarker in gastrointestinal disease. AB - Abdominal discomfort including pain, bloating and diarrhea is common. It often arises from functional gastrointestinal disorders but may indicate inflammatory bowel disease (IBD). Calprotectin is an abundant neutrophil protein that is released during inflammation. When measured in feces, it can be used to differentiate between non-organic and inflammatory intestinal disorders, especially to identify IBD. Fecal calprotectin might also be useful to monitor patients with IBD under treatment and to predict the risk of recurrence of active disease prior to clinical relapse. The use of fecal calprotectin has been investigated in a number of gastrointestinal disorders other than IBD, for example, as screening test for colorectal cancer but the available data are limited. This article summarizes the current literature on the use of fecal calprotectin in clinical practice. PMID- 24345072 TI - Management for breast implants in patients undergoing mitral valve surgery through a right minithoracotomy. AB - We present the surgical technique and rationale for the management of breast implants in two patients who underwent mitral valve repair through a right minithoracotomy. PMID- 24345073 TI - Physiotherapy to improve physical activity in community-dwelling older adults with mobility problems (Coach2Move): study protocol for a randomized controlled trial. AB - BACKGROUND: Older adults can benefit from physical activity in numerous ways. Physical activity is considered to be one of the few ways to influence the level of frailty. Standardized exercise programs do not necessarily lead to more physical activity in daily life, however, and a more personalized approach seems appropriate. The main objective of this study is to investigate whether a focused, problem-oriented coaching intervention ('Coach2Move') delivered by a physiotherapist specializing in geriatrics is more effective for improving physical activity, mobility and health status in community-dwelling older adults than usual physiotherapy care. In addition, cost-effectiveness will be determined. METHODS/DESIGN: The design of this study is a single-blind randomized controlled trial in thirteen physiotherapy practices. Randomization will take place at the individual patient level. The study population consists of older adults, >=70 years of age, with decreased physical functioning and mobility and/or a physically inactive lifestyle. The intervention group will receive geriatric physiotherapy according to the Coach2Move strategy. The control group will receive the usual physiotherapy care. Measurements will be performed by research assistants not aware of group assignment. The results will be evaluated on the amount of physical activity (LASA Physical Activity Questionnaire), mobility (modified 'get up and go' test, walking speed and six-minute walking test), quality of life (SF-36), degree of frailty (Evaluative Frailty Index for Physical Activity), fatigue (NRS-fatigue), perceived effect (Global Perceived Effect and Patient Specific Complaints questionnaire) and health care costs. DISCUSSION: Most studies on the effect of exercise or physical activity consist of standardized programs. In this study, a personalized approach is evaluated within a group of frail older adults, many of whom suffer from multiple and complex diseases and problems. A complicating factor in evaluating a new approach is that it may not be automatically adopted by clinicians. Specific actions are undertaken to optimize implementation of the Coach2Move strategy during the trial. Whether or not these will be sufficient is a matter we will consider subsequently, using quality indicators and process analysis. TRIAL REGISTRATION: The Netherlands National Trial Register: NTR3527. PMID- 24345074 TI - Epidemiology of active tuberculosis in lung cancer patients: a systematic review. AB - OBJECTIVES: The aim of this review article is to evaluate the available literature concerning the prevalence of active tuberculosis in lung cancer patients. DATA SOURCE: MEDLINE, PubMed, EMBASE and Medscape databases were searched for studies with quantitative data on the interaction between tuberculosis (TB) and lung cancer, published since 1952. We used the Medical Subject Headings' term 'tuberculosis' and the text-word terms 'TB' and 'Mycobacterium infection', and also, the Medical Subject Headings' terms 'neoplasm' and 'lung neoplasm', or the text-word term 'lung cancer'. DATA SELECTION: We selected studies with cases verified by bacteriological examinations and biopsies that contained enough data to estimate tuberculosis prevalence. We did not exclude any study on the basis of language. RESULTS: The prevalence of active tuberculosis among lung cancer patients varies depending on spatial and regional factors. Lung cancer patients who are more prone to developing tuberculosis are Asian and Caucasian males, with an average age of 60 years old. The prevalence of tuberculosis is higher in patients with chest X-ray evidence of old tuberculosis and/or history of tuberculosis, chronic obstructive pulmonary disease, heavy cigarette smoking, increased alcohol consumption, and/or diabetes mellitus. A high mortality rate because of tuberculosis in lung cancer patients was also estimated. CONCLUSION: Active tuberculosis complicating lung cancer is a significant clinical issue in countries with high prevalence of tuberculosis. However, as the there is a lack of reports from developed countries over the last 20 years, the significance of this interaction in countries with low tuberculosis burden remains controversial. PMID- 24345075 TI - Direct quantification of molar masses of copolymers by online liquid chromatography under critical conditions-nuclear magnetic resonance and size exclusion chromatography-nuclear magnetic resonance. AB - Online LCCC-NMR and SEC-NMR are compared regarding the determination of molar masses of block copolymers. Two different direct referencing methods are particularly demonstrated in LCCC-NMR for a detailed characterization of diblock copolymers and their co-monomers. First, an intramolecular reference group was used for the direct determination of block lengths and molar masses. For the first time, it was shown that LCCC-NMR can be used for an accurate determination of Mw and Mn of copolymers. These data were in perfect agreement with SEC-NMR measurements using the same intramolecular referencing method. In contrast, the determination of molar masses with common relative methods based on calibrations with homopolymers delivered inaccurate results for all investigated diblock copolymers due to different hydrodynamic volumes of the diblock copolymer compared to their homopolymers. The intramolecular referencing method provided detailed insights in the co-monomer behavior during the chromatographic separation of LCCC. Especially, accurate chain lengths and chemical compositions of the "invisible" and "visible" blocks were quantified during the elution under critical conditions and provided new aspects to the concept of critical conditions. Second, an external reference NMR signal was used to directly determine concentrations and molar masses of the block copolymers from the chromatographic elution profile. Consequently, the intensity axes of the resulting chromatograms were converted to molar amounts and masses, allowing for determination of the amount of polymer chains with respect to elution volume, the evaluation of the limiting magnitude of concentration for LCCC-NMR, and determination of the molar masses of copolymers. PMID- 24345071 TI - Visual activity and its association with myopia stabilisation. AB - PURPOSE: To evaluate the association between outdoor and nearwork activities at baseline and myopia stabilisation by age 15 in the Correction of Myopia Evaluation Trial (COMET). METHODS: Correction of Myopia Evaluation Trial enrolled 469 children (ages: 6-11 years) with spherical equivalent myopia between -1.25 and -4.50 D, who were randomised to progressive addition or single vision lenses and followed for 5 years in their original lenses. At baseline, families recorded the child's outdoor and nearwork activities for 3 days within a week. Weekly hours spent in nearwork and outdoor activities were calculated for each participant. Refractions collected over 11 years were fit using the Gompertz function to determine each participant's myopia stabilisation age. Myopia for each child was then categorized as stable/not stable by age 15. RESULTS: Half (233/469) of participants had usable baseline activity diaries and refraction data that could be fit with the Gompertz function, 59.7% (139/233) had stable myopia by age 15 and 40.3% had myopia that was not yet stable. The frequency of stable myopia was similar for the two categories (median split) of outdoor activities: 60% (71/118) for <=9.0 hours/week(-1) and 59% (68/115) for >9.0 hours/week(-1) . 56% (64/114) of children reporting >21.0 h of baseline weekly nearwork activity had stable myopia by age 15 compared to 63% (75/119) with <=21.0 h of near work (adjusted OR = 0.74; 95% CI: 0.43-1.29). Using baseline nearwork as a continuous variable, the multivariable odds ratio for the association between baseline nearwork hours and stabilisation by age 15 is 0.98: 95% CI: 0.96-1.00, a result trending towards significance. CONCLUSION: While time spent in outdoor activities in childhood does not appear to be related to myopia stabilisation by age 15, less near work activity might potentially be associated with myopia stabilisation by that age. PMID- 24345076 TI - Malignant transformation of intracranial epidermoid cyst. AB - Intracranial epidermoid cysts (ECs) are rare, histologically benign, slow growing, congenital neoplasms of central nervous system that may arise from retained ectodermal implants. Malignant transformation of an EC to squamous-cell carcinoma is rare; only 13 cases have been reported. We present the case of a 42 year-old woman presenting with left hemiparesis 18 months after performing partial resection of an epidermoid cyst of right middle and posterior fossa, whose pathological report revealed to be a malignant transformation of previous epidermoid tumor. Additionally, we performed pertinent literature review. PMID- 24345077 TI - LPS or ethanol triggers clathrin- and rafts/caveolae-dependent endocytosis of TLR4 in cortical astrocytes. AB - Toll-like receptor 4 (TLR4) activation and signalling in glial cells play critical roles in neurological disorders and in alcohol-induced brain damage. TLR4 endocytosis upon lipopolysaccharide (LPS) stimulation regulates which signalling pathway is activated, the MyD88-dependent or the TIR-domain-containing adapter-inducing interferon-beta (TRIF)-dependent pathway. However, it remains elusive whether ethanol-induced TLR4 signalling is associated with receptor internalization and trafficking, and which endocytic pathway(s) are used in cortical astrocytes. Using the adenoviral over-expression of TLR4(GFP) , confocal microscopy and the imagestream technique, we show that upon ethanol or LPS stimulation, TLR4 co-localizes with markers of the clathrin and caveolin endocytic pathways, and that this endocytosis is dependent on dynamin. Using chlorpromazin and filipin as inhibitors of the clathrin and rafts/caveolae endocytic pathways, respectively, we demostrate that TRIF-dependent signalling relies on an intact clathrin pathway, whereas disruption of rafts/caveolae inhibits the MyD88- and TRIF-dependent signalling pathways. Immunofluorescence studies also suggest that lipid rafts and clathrin cooperate for appropriate TLR4 internalization. We also show that ethanol can trigger similar endocytic pathways as LPS does, although ethanol delays clathrin internalization and alters TLR4 vesicular trafficking. Our results provide new insights into the effects of ethanol or LPS on TLR4 signalling in cortical astrocytes, events that may underlie neuroinflammation and brain damage. The results demonstrate that ethanol or lipopolysaccharide (LPS) triggers toll-like receptor 4 (TLR4) endocytosis by caveolae and clathrin-dependent pathways in astrocytes. We proposed that while clathrin is the protein responsible for TLR4 internalization, caveolin-1/lipid rafts membrane microdomains are required for TLR4 signaling. The results provide new insights into the effects of ethanol on TLR4 signalling in astrocytes, events that may underlie neuroinflammation. PMID- 24345079 TI - Thrombin generation and fibrin formation under flow on biomimetic tissue factor rich surfaces. AB - BACKGROUND: Blood flow regulates coagulation and fibrin assembly by controlling the rate of transport of zymogens, enzymes and plasma proteins to and from the site of an injury. OBJECTIVE: The objective of this work was to define the hemodynamic conditions under which fibrin can form under flow on tissue factor (TF)-rich substrates. METHODS: TF-coated silica beads (~ 800 nm) were patterned into 18-85-MUm spots. Normal pooled plasma and factors VIII, IX and XI deficient plasmas were perfused over the beads coated with 0.08, 0.8 and 8 molecules-TF MUm(-2) at shear rates of 50-1000 s(-1) . Fibrin deposition and thrombin generation were measured by fluorescence microscopy in a hydrodynamic focusing microfluidic device. RESULTS AND CONCLUSIONS: Fibrin deposition was supported on patterned bead spots, but not planar TF substrates at the same surface TF concentration. There was a threshold spot size and a shear rate dependent TF concentration that was necessary to support fibrin polymerization. FVIII and FIX had minor effects on fibrin dynamics at 8 molecules-TF MUm(-2) , but were essential at 0.8 molecules-TF MUm(-2) . The absence of FXI influenced thrombin generation and fibrin deposition at both 0.8 and 8 molecules-TF MUm(-2) . These results show that fibrin deposition requires perturbations in the flow field that protect reactions from dilution by flow under venous and arterial conditions. FVIII and FIX have a modest effect on fibrin deposition at high TF concentrations, but are necessary for fibrin deposition at low TF concentrations. FXI amplifies thrombin generation under flow at both low and high TF concentrations. PMID- 24345078 TI - New insights into pharmacological tools to TR(i)P cancer up. AB - The aim of this review is to address the recent advances regarding the use of pharmacological agents to target transient receptor potential (TRP) channels in cancer and their potential application in therapeutics. Physiologically, TRP channels are responsible for cation entry (Ca(2+) , Na(+) , Mg(2+) ) in many mammalian cells and regulate a large number of cellular functions. However, dysfunction in channel expression and/or activity can be linked to human diseases like cancer. Indeed, there is growing evidence that TRP channel expression is altered in cancer tissues in comparison with normal ones. Moreover, these proteins are involved in many cancerous processes, including cell proliferation, apoptosis, migration and invasion, as well as resistance to chemotherapy. Among the TRP superfamily, TRPC, TRPV, TRPM and TRPA1 have been shown to play a role in many cancer types, including breast, digestive, gliomal, head and neck, lung and prostate cancers. Pharmacological modulators are used to characterize the functional implications of TRP channels in whole-cell membrane currents, resting membrane potential regulation and intracellular Ca(2+) signalling. Moreover, pharmacological modulation of TRP activity in cancer cells is systematically linked to the effect on cancerous processes (proliferation, survival, migration, invasion, sensitivity to chemotherapeutic drugs). Here we describe the effects of such TRP modulators on TRP activity and cancer cell phenotype. Furthermore, the potency and specificity of these agents will be discussed, as well as the development of new strategies for targeting TRP channels in cancer. PMID- 24345081 TI - Understanding social support burden among family caregivers. AB - Despite the abundance of research on social support, both as a variable in larger studies and as a central focus of examination, there is little consensus about the relationship between social support and health outcomes. Current social support measures typically account only for frequency and size of network, and a paucity of research exists that has explained social support burden, defined as the burden associated with accessing and receiving support from others. We analyzed audio-recorded discussions by hospice family caregivers about their caregiving problems and potential solutions to examine social relationships within networks and identify the processes that influence social support seeking and receiving. Using qualitative thematic analysis, we found that caregivers providing hospice care experience social support burden resulting from perceived relational barriers between friends and family, the inclination to remain in control, recognition of the loss of the patient as a source of social support and guidance in decision making, family dynamics, and decreased availability of emotional support. Social support researchers should consider how the quality of communication and relationships within social networks impacts the provision and subsequent outcomes of social support in varying contexts. Findings from this study suggest that hospice social support resources should be tailored to the caregiver's support needs and include assessment on the type of support to be offered. PMID- 24345083 TI - N-annulated perylene as an efficient electron donor for porphyrin-based dyes: enhanced light-harvesting ability and high-efficiency Co(II/III)-based dye sensitized solar cells. AB - Porphyrin-based dyes recently have become good candidates for dye-sensitized solar cells (DSCs). However, the bottleneck is how to further improve their light harvesting ability. In this work, N-annulated perylene (NP) was used to functionalize the Zn-porphyrin, and four "push-pull"-type NP-substituted and fused porphyrin dyes with intense absorption in the visible and even in the near infrared (NIR) region were synthesized. Co(II/III)-based DSC device characterizations revealed that dyes WW-5 and WW-6, in which an ethynylene spacer is incorporated between the NP and porphyrin core, showed pantochromatic photon to-current conversion efficiency action spectra in the visible and NIR region, with a further red-shift of about 90 and 60 nm, respectively, compared to the benchmark molecule YD2-o-C8. As a result, the short-circuit current density was largely increased, and the devices displayed power conversion efficiencies as high as 10.3% and 10.5%, respectively, which is comparable to that of the YD2-o C8 cell (eta = 10.5%) under the same conditions. On the other hand, the dye WW-3 in which the NP unit is directly attached to the porphyrin core showed a moderate power conversion efficiency (eta = 5.6%) due to the inefficient pi-conjugation, and the NP-fused dye WW-4 exhibited even poorer performance due to its low-lying LUMO energy level and nondisjointed HOMO/LUMO profile. Our detailed physical measurements (optical and electrochemical), density functional theory calculations, and photovoltaic characterizations disclosed that the energy level alignment, the molecular orbital profile, and dye aggregation all played very important roles on the interface electron transfer and charge recombination kinetics. PMID- 24345082 TI - A survey of Australian chiropractors' attitudes and beliefs about evidence-based practice and their use of research literature and clinical practice guidelines. AB - BACKGROUND: Research into chiropractors' use of evidence in clinical practice appears limited to a single small qualitative study. The paucity of research in this area suggests that it is timely to undertake a more extensive study to build a more detailed understanding of the factors that influence chiropractors' adoption of evidence-based practice (EBP) principles. This study aimed to identify Australian chiropractors' attitudes and beliefs towards EBP in clinical practice, and also examine their use of research literature and clinical practice guidelines. METHODS: We used an online questionnaire about attitudes, beliefs and behaviours towards the use of EBP in clinical practice that had been developed to survey physiotherapists and modified it to ensure that it was relevant to chiropractic practice. We endeavoured to survey all registered Australian chiropractors (n = 4378) via email invitation distributed by Australian chiropractic professional organisations and the Chiropractic Board of Australia. Logistic regression analyses were conducted to examine univariate associations between responses to items measuring attitudes and beliefs with items measuring: age; years since registration; attention to literature; and use of clinical practice guidelines. RESULTS: Questionnaires were returned by 584 respondents (response rate approximately 13%). The respondents' perceptions of EBP were generally positive: most agreed that the application of EBP is necessary (77.9%), literature and research findings are useful (80.2%), EBP helps them make decisions about patient care (66.5%), and expressed an interest in learning or improving EBP skills (74.9%). Almost half of the respondents (45.1%) read between two to five articles a month. Close to half of the respondents (44.7%) used literature in the process of clinical decision making two to five times each month. About half of the respondents (52.4%) agreed that they used clinical practice guidelines, and around half (54.4%) agreed that they were able to incorporate patient preferences with clinical practice guidelines. The most common factor associated with increased research uptake was the perception that EBP helps make decisions about patient care. CONCLUSIONS: Most Australian chiropractors hold positive attitudes towards EBP, thought EBP was useful, and were interested in improving EBP skills. However, despite the favourable inclination towards EBP, many Australian chiropractors did not use clinical practice guidelines. Our findings should be interpreted cautiously due to the low response rate. PMID- 24345084 TI - Nitrogen-doped carbon nanoparticles by flame synthesis as anode material for rechargeable lithium-ion batteries. AB - Nitrogen-doped turbostratic carbon nanoparticles (NPs) are prepared using fast single-step flame synthesis by directly burning acetonitrile in air atmosphere and investigated as an anode material for lithium-ion batteries. The as-prepared N-doped carbon NPs show excellent Li-ion stoarage properties with initial discharge capacity of 596 mA h g(-1), which is 17% more than that shown by the corresponding undoped carbon NPs synthesized by identical process with acetone as carbon precursor and also much higher than that of commercial graphite anode. Further analysis shows that the charge-discharge process of N-doped carbon is highly stable and reversible not only at high current density but also over 100 cycles, retaining 71% of initial discharge capacity. Electrochemical impedance spectroscopy also shows that N-doped carbon has better conductivity for charge and ions than that of undoped carbon. The high specific capacity and very stable cyclic performance are attributed to large number of turbostratic defects and N and associated increased O content in the flame-synthesized N-doped carbon. To the best of our knowledge, this is the first report which demonstrates single step, direct flame synthesis of N-doped turbostratic carbon NPs and their application as a potential anode material with high capacity and superior battery performance. The method is extremely simple, low cost, energy efficient, very effective, and can be easily scaled up for large scale production. PMID- 24345080 TI - Haptoglobin phenotype and abnormal uterine artery Doppler in a racially diverse cohort. AB - OBJECTIVE: The anti-oxidant and proangiogenic protein haptoglobin (Hp) is believed to be important for implantation and pregnancy, although its specific role is not known. The three phenotypes (1-1, 2-1 and 2-2) differ in structure and function. Hp 2-2 is associated with increased vascular stiffness in other populations. We examined whether Hp phenotype is associated with abnormal uterine artery Doppler (UAD) in pregnancy. METHODS: We conducted a secondary analysis of a preeclampsia prediction cohort nested within a larger placebo-controlled randomized clinical trial of antioxidants for prevention of preeclampsia. We determined Hp phenotype in 2184 women who completed UAD assessments at 17 weeks gestation. Women with notching were re-evaluated for persistent notching at 24 weeks' gestation. Logistic regression was used to assess differences in UAD indices between phenotype groups. RESULTS: Hp phenotype did not significantly influence the odds of having any notch (p = 0.32), bilateral notches (p = 0.72), or a resistance index (p = 0.28) or pulsatility index (p = 0.67) above the 90th percentile at 17 weeks' gestation. Hp phenotype also did not influence the odds of persistent notching at 24 weeks (p = 0.25). CONCLUSIONS: Hp phenotype is not associated with abnormal UAD at 17 weeks' gestation or with persistent notching at 24 weeks. PMID- 24345085 TI - Development of an antimicrobial material based on a nanocomposite cellulose acetate film for active food packaging. AB - Nanocomposites based on biopolymers have been recognised as potential materials for the development of new ecofriendly food packaging. In addition, if these materials incorporate active substances in their structure, the potential applications are much higher. Therefore, this work was oriented to develop nanocomposites with antimicrobial activity based on cellulose acetate (CA), a commercial organoclay Cloisite30B (C30B), thymol (T) as natural antimicrobial component and tri-ethyl citrate (TEC) as plasticiser. Nanocomposites were prepared by a solvent casting method and consisted of 5% (w/w) of C30B, 5% (w/w) of TEC and variable content of T (0%, 0.5% and 2% w/w). To evaluate the effect of C30B into the CA matrix, CA films without this organoclay but with T were also prepared. All nanocomposites showed the intercalation of CA into the organoclay structure; furthermore this intercalation was favoured when 2% (w/w) of T was added to the nanocomposite. In spite of the observed intercalation, the presence of C30B inside the CA matrices increased the opacity of the films significantly. On the other hand, T showed a plasticiser effect on the thermal properties of CA nanocomposites decreasing glass transition, melting temperature and melting enthalpy. The presence of T in CA nanocomposites also allowed the control de Listeria innocua growth when these materials were placed in contact with this Gram-positive bacterium. Interestingly, antimicrobial activity was increased with the presence of C30B. Finally, studies on T release showed that the clay structure inside the CA matrix did not affect its release rate; however, this nanofiller affected the partition coefficient KP/FS which was higher to CA nanocomposites films than in CA films without organoclay. The results obtained in the present study are really promising to be applied in the manufacture of food packaging materials. PMID- 24345086 TI - Social engagement in older residents of assisted living facilities. AB - OBJECTIVES: As a core component of successful aging, social engagement is widely known to play an important role in promoting the health and well-being of older populations. Given the unique nature of assisted living facility (ALF) settings, the present study made a distinction between social engagement within and outside the facility and explored how these two types of social engagement would interact with functional disability in predicting depressive symptoms of older residents in ALFs. We hypothesized that the positive impact of social engagement within the facility would be greater among residents with higher levels of functional disability. METHOD: Using data from 150 ALF residents in Florida (Mage = 82.8, SD = 9.41), the direct and moderating effects of functional disability and the two types of social engagement on depressive symptoms were assessed. RESULTS: Supporting the hypothesis, the interaction between functional disability and social engagement within the facility was found to be significant. The finding demonstrates the particular importance of social engagement within the facility for those with reduced physical function. For them, the limited but available opportunities for social activities and interpersonal contacts within the facility seem to bring substantial psychological benefits. CONCLUSION: The findings call attention to efforts to promote social activities and interpersonal contacts within ALFs. PMID- 24345087 TI - Novel S1P(1) receptor agonists--part 2: from bicyclo[3.1.0]hexane-fused thiophenes to isobutyl substituted thiophenes. AB - Previously, we reported on the discovery of a novel series of bicyclo[3.1.0]hexane fused thiophene derivatives that serve as potent and selective S1P1 receptor agonists. Here, we discuss our efforts to simplify the bicyclohexane fused thiophene head. In a first step the bicyclohexane moiety could be replaced by a simpler, less rigid cyclohexane ring without compromising the S1P receptor affinity profile of these novel compounds. In a second step, the thiophene head was simplified even further by replacing the cyclohexane ring with an isobutyl group attached either to position 4 or position 5 of the thiophene. These structurally much simpler headgroups again furnished potent and selective S1P1 agonists (e.g., 87), which efficiently and dose dependently reduced the number of circulating lymphocytes upon oral administration to male Wistar rats. For several compounds discussed in this report lymphatic transport is an important route of absorption that may offer opportunities for a tissue targeted approach with minimal plasma exposure. PMID- 24345088 TI - The fraction of exhaled nitric oxide improves prediction of clinical allergic reaction to peanut challenge in children. AB - BACKGROUND: Retrospective studies of childhood peanut allergy demonstrate serum specific IgE (IgE) levels against the peanut allergen Ara h2 may help predict a clinical reaction at food challenge. Fraction of exhaled nitric oxide (FeNO) is a non-invasive tool correlating to allergic airways inflammation and has been independently associated with increased food-specific IgE. OBJECTIVE: To assess the validity of serum-specific Ara h2 IgE measured prospectively to diagnose peanut allergy and explore the utility of FeNO as a non-invasive screening tool for childhood food challenge. METHODS: We recruited 53 participants from a cohort of consecutive children scheduled for an open-labelled peanut food challenge (OFC) by their paediatric allergist. Participants underwent skin prick test (SPT) measurement for sensitization to whole peanut extract, and serum was collected for Ara h2-specific IgE. FeNO was also measured in all cooperative children before the challenge. OFC and assessment of reaction were undertaken by clinicians blinded to test results. RESULTS: Ara h2-specific IgE and FeNO each showed improved diagnostic accuracy when compared to SPT. Receiver operator characteristic curve analysis gave an area under the curve (AUC) for Ara h2 sIgE of 0.84 (95% CI, 0.72-0.96). The AUC for FeNO, 0.83 (95% CI, 0.71-0.95), was equivalent to that of Ara h2. Combined AUC for SPT, sIgE to Ara h2 and FeNO was 0.96 (95% CI 0.90-1.00). There was no correlation between FeNO and serum nitrite levels (rs = -0.13, P = 0.6, n = 18). CONCLUSION AND CLINICAL RELEVANCE: Prospectively measured Ara h2-specific IgE improves diagnostic accuracy and reduces unsuccessful challenge to peanut. FeNO levels may provide improved diagnostic accuracy in a paediatric population undergoing OFC. The proposed FeNO based diagnostic algorithm requires further validation studies. PMID- 24345089 TI - A retrospective study of acute pancreatitis in patients with hemorrhagic fever with renal syndrome. AB - BACKGROUND: Etiological diagnosis is an important part of the diagnosis and treatment of acute pancreatitis. Hantavirus infection is a rare cause of acute pancreatitis, which is easy to ignore. There is a need to analyze clinical features of acute pancreatitis caused by Hantavirus. METHODS: This is a retrospective study conducted from May 1, 2006 to May 31, 2012 on patients diagnosed with hemorrhagic fever with renal syndrome at our hospital. We reviewed these patients medical records, laboratory results and radiologic examinations to determine the prevalence and summarize clinical features of acute pancreatitis in patients with hemorrhagic fever with renal syndrome. RESULTS: A total of 218 patients were diagnosed with hemorrhagic fever with renal syndrome during the 6 year study period. Only 2.8% (6/218) of the total hemorrhagic fever with renal syndrome patients were diagnosed with acute pancreatitis. The first symptom for all six of the patients with acute pancreatitis was fever. All six patients experienced hemorrhage and thrombocytopenia during the disease course, which was different from general acute pancreatitis. In addition, we presented two misdiagnosed clinical cases. CONCLUSIONS: Acute pancreatitis is not a frequent complication in patients with hemorrhagic fever with renal syndrome. Clinicians should be alerted to the possibility of hemorrhagic fever with renal syndrome when acute pancreatitis patients with epidemiological data have high fever before abdominal pain. PMID- 24345090 TI - An investigation into the validity of self-reported classification of refractive error. AB - PURPOSE: To assess the validity of questionnaire use in the self-identification of refractive status. METHODS: Two hundred and forty adults (21-60 years of age) presenting for a routine eye examination at various optometric practices in Northern Ireland were asked to complete one of two questionnaires. Both questionnaires used identical questions to ascertain age, gender, current spectacle use, age of first spectacle use and level of education. For the identification of refractive status, Questionnaire 1 used layman's terminology whilst Questionnaire 2 combined optometric terminology with descriptive explanations. Current refractive status was identified by the examining optometrist who did not see the completed questionnaire. The spherical equivalent refractive error of the non-cycloplegic subjective refraction was used to categorise myopia as <0D and hyperopia as >=+1.00D. Astigmatism was defined according to two different criteria: >=0.50DC and >=1.00DC. RESULTS: Questionnaire 1 had a sensitivity of 0.63 and a specificity of 0.90 for identifying myopia; a sensitivity of 0.58 and a specificity of 0.71 for identifying hyperopia; a sensitivity of 0.12 and a specificity of 0.98 for identifying astigmatism >=0.50DC and a sensitivity of 0.19 and a specificity of 0.95 for identifying astigmatism >=1.00DC. Questionnaire 2 had a sensitivity of 0.83 and a specificity of 0.93 for identifying myopia; a sensitivity of 0.45 and a specificity of 0.86 for identifying hyperopia; a sensitivity of 0.32 and a specificity of 0.88 for identifying astigmatism >=0.50DC and a sensitivity of 0.50 and a specificity of 0.84 for identifying astigmatism >=1.00DC. For both questionnaires, altering a positive self-identification of myopia to include only those who had worn spectacles prior to age 30 reduced the sensitivity and increased the specificity slightly. CONCLUSIONS: Questionnaires are a valid tool in self-identification of myopic refractive status. However, they are not an effective way of identifying hyperopia and astigmatism and objective or subjective refraction remains the most appropriate method of identifying such individuals. PMID- 24345091 TI - Exposure to environmental tobacco smoke (ETS) and risk of lung cancer in Montreal: a case-control study. AB - BACKGROUND: The objective of the present study was to examine the association between environmental tobacco smoke (ETS) and risk of lung cancer among never smokers, defined as subjects who smoked less than 100 cigarettes in their lifetime. METHODS: We conducted a population-based case-control study on lung cancer in Montreal, Canada (1996-2000) including 1,203 cases and 1513 controls. The present analysis is restricted to the 44 cases and 436 population controls who reported never smoking and completed the questionnaire on lifetime ETS exposure. Collected information included duration and intensity of exposure from multiple sources: inside home (parents, spouses, roommates and any other co resident) and outside homes (in vehicles, social settings, and workplace). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated between ETS and lung cancer, adjusting for age, sex, socioeconomic status (SES), and proxy respondent. RESULTS: Overall there was no association between ETS cumulative exposure from all sources (measured in pack-years) and lung cancer: OR = 0.98 (95%CI: 0.40-2.38), comparing upper with lower tertiles of exposure. While there were no elevated ORs associated with ever having lived with parents who smoked (OR = 0.62; 95%CI: 0.32-1.21) or with spouses who smoked (OR = 0.39; 95%CI: 0.18 0.85), ETS exposure from sources outside homes was associated with a slight, although non-significant increased risk: OR = 2.30 (95%CI: 0.85-6.19) for the upper 50% exposed. There were no clear differences in ORs by age at exposure to ETS or by histologic type of tumour, though numbers of subjects in subgroup analyses were too small to provide reliable estimates. CONCLUSION: No clear association between lifetime ETS exposure from all sources and increased risk of lung cancer was found in the current study. PMID- 24345092 TI - Role of coronary artery calcium in cardiovascular risk assessment. AB - Coronary artery disease (CAD) is associated with substantial morbidity and mortality worldwide. Despite many advances in prevention and therapy for CAD, a third to one-half of cardiovascular events occur in those with no prior symptoms. Assessing subclinical disease using coronary artery calcium (CAC) has been shown to provide additional risk stratification and to improve prediction of cardiovascular events over traditional strategies such as the Framingham Risk Score. In this review, we aim to cover the current data available on utilization of CAC as a tool in the general population as well as in targeted subgroups such as those with diabetes and metabolic syndrome. For this review, the authors performed thorough Pubmed and Medline searches using keywords coronary artery calcification, X-ray computed tomography, multidetector computed tomography, CAD, diabetes mellitus and metabolic syndrome. Based on the authors' review of literature, they believe that CAC is an excellent risk stratification imaging modality, especially in patients with diabetes and metabolic syndrome; behavioral changes in patients and therapeutic interventions based on CAC scoring are cost effective. PMID- 24345093 TI - Established and emerging cardiovascular magnetic resonance techniques for prognostication and guiding therapy in heart failure. AB - The syndrome of heart failure is prevalent and a cause of significant morbidity and mortality. Cardiovascular magnetic resonance (CMR) offers a unique method to quantify the extent of left ventricular dysfunction and also characterize the myocardium, particularly according to the presence and distribution of late gadolinium enhancement. The prognostic value of late gadolinium enhancement in various etiologies of heart failure has been demonstrated. Newer techniques that non-invasively assess the extracellular volume may also add to the prognostic value of CMR in heart failure. Management decisions in patients with heart failure can often be complex. CMR can provide useful information when planning cardiac device therapy and the CMR assessment of viability is key when planning revascularization. PMID- 24345094 TI - The role of computed tomography in cardiovascular imaging: from X-ray department to emergency room. AB - Computed tomography coronary angiography (CTCA) is widely accepted in the evaluation of patients with stable chest pain. Its use in patients with unstable chest pain is more controversial. CTCA can be performed alone or with a computed tomography pulmonary angiogram and aortogram as a 'triple rule-out' scan. Published trial data show that discharging a patient with low-risk acute chest pain after a normal CTCA is a very safe thing to do. Length of stay is generally reduced, but radiation exposure is higher and there is more downstream testing, so it is broadly cost-neutral. Future studies should evaluate this approach in intermediate- to high-risk patients. PMID- 24345095 TI - Drug-eluting stent outcomes in diabetes. AB - Diabetic population still remains a challenging subgroup of patients for percutaneous coronary intervention (PCI). However, with rapid advancements of PCI techniques, devices and adjunctive drug therapy, clinical outcomes for diabetic patients after PCI have markedly improved. The plethora of recent encouraging data with newer generation drug-eluting stent (DES), with a lower frequency of major cardiac adverse events, lead to an increasing use of DES in this particular high-risk population. However, diabetes remains an important risk factor for coronary events, even in the DES era. This review summarizes the outcomes in diabetic patients undergoing PCI with DES implantation. PMID- 24345096 TI - Cardiac tumors: the role of cardiovascular imaging. AB - Evaluation of cardiac tumors with cardiovascular imaging aims to establish aetiology, identify complications of tumor and help define management strategy. 2D echocardiography remains the primary diagnostic modality. Additional use of newer echocardiographic techniques such as 3D, strain and contrast echocardiography better characterise tumor morphology, tissue characteristics and vascularity respectively. Cardiac MRI and computed tomography provide complementary information and are able to identify extra-cardiac infiltration and also provide further tissue characterisation. This review explores the non invasive diagnostic approach to evaluation of cardiac tumors. PMID- 24345097 TI - Alternative approach for repair of total anomalous pulmonary venous connection to the coronary sinus at the time of extracardiac total cavopulmonary connection. AB - Total anomalous pulmonary venous connection can be encountered in patients with a univentricular heart and must be addressed to at the time of univentricular palliation. We present an alternative technique of re-channeling of the pulmonary venous return toward the left heart in these patients. PMID- 24345098 TI - Utilizing exhaled carbon monoxide measurement with self-declared smoking cessation: enhancing abstinence effectiveness in Taiwanese outpatients. AB - BACKGROUND: Presently, the Department of Health Taiwan has begun to fund a smoking cessation program, and the annual cessation rate was 8.9% in 2010. This study aims to see whether to enhance abstinence effectiveness by utilizing exhaled carbon monoxide (COExh) measurement with self-declared smoking cessation. METHODS: The longitudinal prospective study gathered 33 subjects on quitting smoking with the motivation to join the grant program in chest outpatient from August 2009 to July 2010. Overall, subjects were given nicotine replacement therapy (NRT) in the first stage, and explored abstinence rate results in evaluation stage. The cutoff point of COExh 6 ppm or less than (<=) and patients' self-declared abstinence reports confirmed a smoking cessation success status. Point abstinences were defined as the smokers refrained from smoking at least 7 days, while continuous abstinences were defined as nonsmoking at least 3, 6 and 12 months. RESULTS: The validities were 198 tracking results for two stages (P < 0.001 vs P < 0.001), and sensitivity (56.5% vs 60.0%), specificity (90.1% vs 82.6%), positive predictive value (63.4% vs 60.0%) and negative predictive value (87.2% vs 82.6%) were detected. Moreover, the validities were 33 results for point and continuous abstinences at 3 month (P < 0.001 vs P < 0.001), and higher successful rates. Point abstinence rates at 3, 6 and 12 months follow-up for overall subjects were 27.2%, 15.2% and 18.1%, respectively. Continuous abstinence rates at 3, 6 and 12 months were 24.2%, 12.1% and 12.1%, respectively. CONCLUSIONS: Utilizing COExh measurement with self-declared smoking cessation enhanced abstinence effectiveness in Taiwanese outpatients. PMID- 24345100 TI - The partial thromboplastin time. PMID- 24345099 TI - Design and rationale of the AngioSeal versus the Radial approach In acute coronary SyndromE (ARISE) trial: a randomized comparison of a vascular closure device versus the radial approach to prevent vascular access site complications in non-ST-segment elevation acute coronary syndrome patients. AB - BACKGROUND: Arterial access is a major site of bleeding complications after invasive coronary procedures. Among strategies to decrease vascular complications, the radial approach is an established one. Vascular closure devices provide more comfort to patients and decrease hemostasis and need for bed rest. However, the inconsistency of data proving their safety limits their routine adoption as a strategy to prevent vascular complications, requiring evidence through adequately designed randomized trials. The aim of this study is to compare the radial versus femoral approach using a vascular closure device for the incidence of arterial puncture site vascular complications among non-ST segment elevation acute coronary syndrome patients submitted to an early invasive strategy. METHODS: ARISE is a national, multicenter, non-inferiority randomized clinical trial. Two hundred patients with non-ST-segment elevation acute coronary syndrome will be randomized to either radial or femoral access using a vascular closure device. The primary outcome is the occurrence of vascular complications at an arterial puncture site 30 days after the procedure, including major bleeding, retroperitoneal hematoma, compartment syndrome, hematoma >= 5 cm, pseudoaneurysm, arterio-venous fistula, infection, limb ischemia, arterial occlusion, adjacent nerve injury or the need for vascular surgical repair. RESULTS: Enrollment was initiated in September 2012, and until October 2013 91 patients were included. The inclusion phase is expected to last until the second half of 2014. CONCLUSIONS: The ARISE trial will help define the role of a vascular closure device as a bleeding avoidance strategy in patients with NSTEACS. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01653587. PMID- 24345101 TI - Lateralized hybrid faces: evidence of a valence-specific bias in the processing of implicit emotions. AB - It is well known that hemispheric asymmetries exist for both the analyses of low level visual information (such as spatial frequency) and high-level visual information (such as emotional expressions). In this study, we assessed which of the above factors underlies perceptual laterality effects with "hybrid faces": a type of stimulus that allows testing for unaware processing of emotional expressions, when the emotion is displayed in the low-frequency information while an image of the same face with a neutral expression is superimposed to it. Despite hybrid faces being perceived as neutral, the emotional information modulates observers' social judgements. In the present study, participants were asked to assess friendliness of hybrid faces displayed tachistoscopically, either centrally or laterally to fixation. We found a clear influence of the hidden emotions also with lateral presentations. Happy faces were rated as more friendly and angry faces as less friendly with respect to neutral faces. In general, hybrid faces were evaluated as less friendly when they were presented in the left visual field/right hemisphere than in the right visual field/left hemisphere. The results extend the validity of the valence hypothesis in the specific domain of unaware (subcortical) emotion processing. PMID- 24345102 TI - Bioaccessibility of As, Cd, Cu, Ni, Pb, and Sb in toys and low-cost jewelry. AB - Children can be exposed to toxic elements in toys and jewelry following ingestion. As, Cd, Cu, Ni, Pb, and Sb bioavailability was assessed (n = 24) via the in vitro gastrointestinal protocol (IVG), the physiologically based extraction test (PBET), and the European Toy Safety Standard protocol (EN 71-3), and health risks were characterized. Cd, Cu, Ni, and Pb were mobilized from 19 metallic toys and jewelry (MJ) and one crayon set. Bioaccessible Cd, Ni, or Pb exceeded EU migratable concentration limits in four to six MJ, depending on the protocol. Using two-phase (gastric + intestinal) IVG or PBET might be preferable over EN 71-3 since they better represent gastrointestinal physiology. Bioaccessible and total metal concentrations were different and not always correlated, indicating that bioaccessibility measurement may provide more accurate risk characterization. More information on impacts of multiple factors affecting metals mobilization from toys and jewelry is needed before recommending specific tests. Hazard index (HI) for Cd, Ni, or Pb were >1 for all six MJ exceeding the EU limits. For infants (6-12 mo old), 10 MJ had HI > 1 for Cd, Cu, Ni, or Pb (up to 75 for Cd and 43 for Pb). Research on prolonged exposure to MJ and comprehensive risk characterization for toys and jewelry exposure is recommended. PMID- 24345103 TI - The ideal gift? A fairer deal for all in 2014. PMID- 24345110 TI - Training for all more effective than champions, say dementia experts. PMID- 24345114 TI - Healthcare guidance calls for more nurse involvement in coma care. PMID- 24345116 TI - Experience and resilience to the fore in drama about profession. PMID- 24345121 TI - 2013: a year of nursing odes, ratios, close scrutiny and Robert Francis. PMID- 24345122 TI - A case of deep ignorance and gender injustice. PMID- 24345128 TI - Surgical site infection. PMID- 24345129 TI - Leaner and smarter. AB - The NHS faces an estimated annual funding gap of 30 billion pounds by 2021. Improved productivity is the only sustainable solution , according to a report by the health regulator Monitor, and nurses can do a great deal to help. PMID- 24345130 TI - Fast and effective? AB - The 5.2 diet involves two days of fasting each week. It is being promoted as the key to sustained weight loss, as well as wider health benefits, despite the lack of evidence on the long-term effects. Nurses need to support patients who wish to try intermittent fasting. PMID- 24345143 TI - Flexible education programmes will secure profession's future. PMID- 24345144 TI - As a former addict, I am treated like a pariah by my colleagues. PMID- 24345145 TI - We must put an end to the human and financial costs of PFI projects. PMID- 24345146 TI - Clarification on neuromuscular conditions in careers article. PMID- 24345149 TI - Bursaries to help with learning and development opportunities. PMID- 24345151 TI - Patients need advice about the kinds of support available. PMID- 24345150 TI - A positive counselling style can make a difference to patients. PMID- 24345152 TI - Providing nursing care and support to individuals and families with genetic/genomic healthcare needs. AB - This is the final article in a series looking at how nurses can develop confidence and competence in genetics and genomics health care. This article focuses on the role of the nurse in providing ongoing care and support for families affected by genetics and/or genomics issues. PMID- 24345153 TI - Advanced clinical practitioner role in the emergency department. AB - The advanced clinical practitioner role in emergency departments in the UK has developed in an ad hoc manner, without a national framework of registration requirements. This article describes the structure adopted by one NHS trust in England to certify the clinical competence of advanced clinical practitioners in emergency departments through the completion of two portfolios, with a third portfolio to record professional development. The portfolios cover history taking, clinical examination, and interpretation of information and basic investigations to enable the practitioner to undertake medical clerking of a patient attending the emergency department. The portfolios contain evidence of learning and observation of practitioners by middle-grade doctors and consultants. PMID- 24345154 TI - Ankylosing spondylitis: diagnosis and management. AB - This article provides an overview of ankylosing spondylitis, including signs and symptoms, diagnosis and management. The article focuses on the difficulties and delays associated with diagnosing this chronic inflammatory disease and developments in diagnostic criteria. Changes in the management of patients with the disease are also discussed, particularly in light of anti-tumour necrosis factor therapy. PMID- 24345155 TI - Respiratory infection. PMID- 24345156 TI - Laying the foundations. PMID- 24345157 TI - Learning in a virtual world. PMID- 24345159 TI - Time to share good practice. PMID- 24345160 TI - Hats off to further study. PMID- 24345161 TI - H2 S modulates duodenal motility in male rats via activating TRPV1 and K(ATP) channels. AB - BACKGROUND AND PURPOSE: H2 S induces vasodilatation by opening KATP channels but it may also affect other ion channels. The aim of this study was to investigate the effect of H2 S on intestinal motility in rats and its underlying mechanism. EXPERIMENTAL APPROACH: The tension of intestinal muscle strips, afferent firing of intestinal mesenteric nerves, length of duodenal smooth muscle cells and whole cell membrane potential of dorsal root ganglion (DRG) neurons were monitored. H2 S-producing enzymes were located by immunofluorescence staining. KEY RESULTS: NaHS exerted early transient excitation and late long-lasting inhibition on the intestinal contraction. The excitation was attenuated by TRPV1 antagonists capsazepine, A784168, SB-366791 and NK1 receptor antagonist L703606, while the inhibition was attenuated by glibenclamide. NaHS increased duodenal afferent nerve firing and depolarized DRG neurons. These effects were reduced by capsazepine and A784168. NaHS relaxed isolated duodenal smooth muscle cells. The KATP channels were expressed in smooth muscle cells. Cystathionine beta-synthase and cystathionine gamma-lyase were expressed in rat duodenal myenteric neurons. L cysteine and S-adenosyl-L-methionine increased the contraction of duodenal muscle strips, an effect attenuated by capsazepine and L703606. CONCLUSIONS AND IMPLICATIONS: NaHS induces biphasic effects on intestinal motility in rats while endogenous H2 S only exerts an excitatory effect. This transient excitatory effect might be mediated by activation of TRPV1 channels in sensory nerve terminals with the consequent release of substance P. The long-lasting inhibitory effect might be mediated by activation of KATP channels in the smooth muscle cells. These findings reveal a novel mechanism for the excitatory effect of H2 S on gastrointestinal motility. PMID- 24345163 TI - Aggregation and separation in ternary particle/oil/water systems with fully wettable particles. AB - We report that a variety of ternary particle/liquid/liquid mixtures heavily aggregate or separate completely if (1) the particles are fully or almost fully wetted by one fluid, and (2) if the wetting fluid volume fraction is comparable to the particle volume fraction. Aggregation and separation do not happen if the particles are partially wetted by both fluids, in which case Pickering emulsions appear at all compositions. Rheological and geometric criteria for aggregation are proposed and compared with a state diagram of a ternary system composed of oil, water, and hydrophilic glass particles. Analogies are drawn to wet granulation and spherical agglomeration, two particle processing operations in which wetting phenomena are important. PMID- 24345162 TI - Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2. AB - Benefits on cognition from docosahexaenoic acid (DHA, 22 : 6 n-3) intake are absent in humans carrying apolipoprotein E epsilon4 allele (APOE4), the most important genetic risk factor for Alzheimer's disease (AD). To test the hypothesis that carrying APOE4 impairs DHA distribution, we evaluated plasma and brain fatty acid profiles and uptake of [(14) C]-DHA using in situ cerebral perfusion through the blood-brain barrier in 4- and 13-month-old male and female APOE-targeted replacement mice (APOE2, APOE3, and APOE4), fed with a DHA-depleted diet. Cortical and plasma DHA were 9% lower and 34% higher in APOE4 compared to APOE2 mice, respectively. Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice. A significant relationship was established between DHA and apoE concentrations in the cortex of mice (r(2) = 0.21) and AD patients (r(2) = 0.32). Altogether, our results suggest that lower brain uptake of DHA in APOE4 than in APOE2 mice may limit the accumulation of DHA in cerebral tissues. These data provide a mechanistic explanation for the lack of benefit of DHA in APOE4 carriers on cognitive function and the risk of AD. Using human APOE2, 3, and 4 isoform-specific transgenic mice, we found a lower brain uptake of docosahexaenoic acid (DHA) in APOE4 than in APOE2 mice that may limit the biodistribution of DHA in cerebral tissues. These data provide a mechanistic explanation for the lack of benefit of DHA in APOE4 carriers on cognitive function and the risk of Alzheimer's disease (AD). PMID- 24345164 TI - Rule activity related to spatial and numerical magnitudes: comparison of prefrontal, premotor, and cingulate motor cortices. AB - In everyday situations, quantitative rules, such as "greater than/less than," need to be applied to a multitude of magnitude comparisons, be they sensory, spatial, temporal, or numerical. We have previously shown that rules applied to different magnitudes are encoded in the lateral PFC. To investigate if and how other frontal lobe areas also contribute to the encoding of quantitative rules applied to multiple magnitudes, we trained monkeys to switch between "greater than/less than" rules applied to either line lengths (spatial magnitudes) or dot numerosities (discrete numerical magnitudes). We recorded single-cell activity from the dorsal premotor cortex (dPMC) and cingulate motor cortex (CMA) and compared it with PFC activity. We found the largest proportion of quantitative rule-selective cells in PFC (24% of randomly selected cells), whereas neurons in dPMC and CMA rarely encoded the rule (6% of the cells). In addition, rule selectivity of individual cells was highest in PFC neurons compared with dPMC and CMA neurons. Rule-selective neurons that simultaneously represented the "greater than/less than" rules applied to line lengths and numerosities ("rule generalists") were exclusively present in PFC. In dPMC and CMA, however, neurons primarily encoded rules applied to only one of the two magnitude types ("rule specialists"). Our data suggest a special involvement of PFC in representing quantitative rules at an abstract level, both in terms of the proportion of neurons engaged and the coding capacities. PMID- 24345166 TI - Competitive interactions of attentional resources in early visual cortex during sustained visuospatial attention within or between visual hemifields: evidence for the different-hemifield advantage. AB - Performing a task across the left and right visual hemifields results in better performance than in a within-hemifield version of the task, termed the different hemifield advantage. Although recent studies used transient stimuli that were presented with long ISIs, here we used a continuous objective electrophysiological (EEG) measure of competitive interactions for attentional processing resources in early visual cortex, the steady-state visual evoked potential (SSVEP). We frequency-tagged locations in each visual quadrant and at central fixation by flickering light-emitting diodes (LEDs) at different frequencies to elicit distinguishable SSVEPs. Stimuli were presented for several seconds, and participants were cued to attend to two LEDs either in one (Within) or distributed across left and right visual hemifields (Across). In addition, we introduced two reference measures: one for suppressive interactions between the peripheral LEDs by using a task at fixation where attention was withdrawn from the periphery and another estimating the upper bound of SSVEP amplitude by cueing participants to attend to only one of the peripheral LEDs. We found significantly greater SSVEP amplitude modulations in Across compared with Within hemifield conditions. No differences were found between SSVEP amplitudes elicited by the peripheral LEDs when participants attended to the centrally located LEDs compared with when peripheral LEDs had to be ignored in Across and Within trials. Attending to only one LED elicited the same SSVEP amplitude as Across conditions. Although behavioral data displayed a more complex pattern, SSVEP amplitudes were well in line with the predictions of the different-hemifield advantage account during sustained visuospatial attention. PMID- 24345167 TI - Commonalities for numerical and continuous quantity skills at temporo-parietal junction. AB - How do our abilities to process number and other continuous quantities such as time and space relate to each other? Recent evidence suggests that these abilities share common magnitude processing and neural resources, although other findings also highlight the role of dimension-specific processes. To further characterize the relation between number, time, and space, we first examined them in a population with a developmental numerical dysfunction (developmental dyscalculia) and then assessed the extent to which these abilities correlated both behaviorally and anatomically in numerically normal participants. We found that (1) participants with dyscalculia showed preserved continuous quantity processing and (2) in numerically normal adults, numerical and continuous quantity abilities were at least partially dissociated both behaviorally and anatomically. Specifically, gray matter volume correlated with both measures of numerical and continuous quantity processing in the right TPJ; in contrast, individual differences in number proficiency were associated with gray matter volume in number-specific cortical regions in the right parietal lobe. Together, our new converging evidence of selective numerical impairment and of number specific brain areas at least partially distinct from common magnitude areas suggests that the human brain is equipped with different ways of quantifying the outside world. PMID- 24345165 TI - Love to win or hate to Lose? Asymmetry of dopamine D2 receptor binding predicts sensitivity to reward versus punishment. AB - Humans show consistent differences in the extent to which their behavior reflects a bias toward appetitive approach-related behavior or avoidance of aversive stimuli [Elliot, A. J. Approach and avoidance motivation. In A. J. Elliot (Ed.), Handbook of approach and avoidance motivation (pp. 3-14). New York: Psychology Press, 2008]. We examined the hypothesis that in healthy participants this motivational bias (assessed by self-report and by a probabilistic learning task that allows direct comparison of the relative sensitivity to reward and punishment) reflects lateralization of dopamine signaling. Using [F-18]fallypride to measure D2/D3 binding, we found that self-reported motivational bias was predicted by the asymmetry of frontal D2 binding. Similarly, striatal and frontal asymmetries in D2 dopamine receptor binding, rather than absolute binding levels, predicted individual differences in learning from reward versus punishment. These results suggest that normal variation in asymmetry of dopamine signaling may, in part, underlie human personality and cognition. PMID- 24345168 TI - The neural mechanism underlying ordinal numerosity processing. AB - Changes in the sensory properties of numerosity stimuli have a direct effect on the outcomes of nonsymbolic number tasks. This suggests a prominent role of sensory properties in numerosity processing. However, the current consensus holds that numerosity is processed independent of its sensory properties. To investigate the role of sensory cues in ordinal number processes, we manipulated both dimensions orthogonally. Participants passively viewed the stimuli while their brain activity was measured using EEG. The results revealed an interaction between numerosity and its sensory properties in the absence of main effects. Different neural responses were present for trials where numerosity and sensory cues changed in the same direction compared with trials where they changed in opposite directions. These results show that the sensory cues are expected to change in concert with numerosity and support the notion that the visual cues are taken into account when judging numerosity. PMID- 24345169 TI - Efficiency of conscious access improves with coupling of slow and fast neural oscillations. AB - Global workspace access is considered as a critical factor for the ability to report a visual target. A plausible candidate mechanism for global workspace access is coupling of slow and fast brain activity. We studied coupling in EEG data using cross-frequency phase-amplitude modulation measurement between delta/theta phases and beta/gamma amplitudes from two experimental sessions, held on different days, of a typical attentional blink (AB) task, implying conscious access to targets. As the AB effect improved with practice between sessions, theta-gamma and theta-beta coupling increased generically. Most importantly, practice effects observed in delta-gamma and delta-beta couplings were specific to performance on the AB task. In particular, delta-gamma coupling showed the largest increase in cases of correct target detection in the most challenging AB conditions. All these practice effects were observed in the right temporal region. Given that the delta band is the main frequency of the P3 ERP, which is a marker of global workspace activity for conscious access, and because the gamma band is involved in visual object processing, the current results substantiate the role of phase-amplitude modulation in conscious access to visual target representations. PMID- 24345170 TI - Processing graded feedback: electrophysiological correlates of learning from small and large errors. AB - Feedback processing is important for learning and therefore may affect the consolidation of skills. Considerable research demonstrates electrophysiological differences between correct and incorrect feedback, but how we learn from small versus large errors is usually overlooked. This study investigated electrophysiological differences when processing small or large error feedback during a time estimation task. Data from high-learners and low-learners were analyzed separately. In both high- and low-learners, large error feedback was associated with higher feedback-related negativity (FRN) and small error feedback was associated with a larger P300 and increased amplitude over the motor related areas of the left hemisphere. In addition, small error feedback induced larger desynchronization in the alpha and beta bands with distinctly different topographies between the two learning groups: The high-learners showed a more localized decrease in beta power over the left frontocentral areas, and the low learners showed a widespread reduction in the alpha power following small error feedback. Furthermore, only the high-learners showed an increase in phase synchronization between the midfrontal and left central areas. Importantly, this synchronization was correlated to how well the participants consolidated the estimation of the time interval. Thus, although large errors were associated with higher FRN, small errors were associated with larger oscillatory responses, which was more evident in the high-learners. Altogether, our results suggest an important role of the motor areas in the processing of error feedback for skill consolidation. PMID- 24345171 TI - The dynamics of proactive and reactive cognitive control processes in the human brain. AB - In this study, we leveraged the high temporal resolution of EEG to examine the neural mechanisms underlying the flexible regulation of cognitive control that unfolds over different timescales. We measured behavioral and neural effects of color-word incongruency, as different groups of participants performed three different versions of color-word Stroop tasks in which the relative timing of the color and word features varied from trial to trial. For this purpose, we used a standard Stroop color identification task with equal congruent-to-incongruent proportions (50%/50%), along with two versions of the "Reverse Stroop" word identification tasks, for which we manipulated the incongruency proportion (50%/50% and 80%/20%). Two canonical ERP markers of neural processing of stimulus incongruency, the frontocentral negative polarity incongruency wave (NINC) and the late positive component (LPC), were evoked across the various conditions. Results indicated that color-word incongruency interacted with the relative feature timing, producing greater neural and behavioral effects when the task irrelevant stimulus preceded the target, but still significant effects when it followed. Additionally, both behavioral and neural incongruency effects were reduced by nearly half in the word identification task (Reverse Stroop 50/50) relative to the color identification task (Stroop 50/50), with these effects essentially fully recovering when incongruent trials appeared only infrequently (Reverse Stroop 80/20). Across the conditions, NINC amplitudes closely paralleled RTs, indicating this component is sensitive to the overall level of stimulus conflict. In contrast, LPC amplitudes were largest with infrequent incongruent trials, suggesting a possible readjustment role when proactive control is reduced. These findings thus unveil distinct control mechanisms that unfold over time in response to conflicting stimulus input under different contexts. PMID- 24345172 TI - What role does the anterior temporal lobe play in sentence-level processing? Neural correlates of syntactic processing in semantic variant primary progressive aphasia. AB - Neuroimaging and neuropsychological studies have implicated the anterior temporal lobe (ATL) in sentence-level processing, with syntactic structure-building and/or combinatorial semantic processing suggested as possible roles. A potential challenge to the view that the ATL is involved in syntactic aspects of sentence processing comes from the clinical syndrome of semantic variant primary progressive aphasia (semantic PPA; also known as semantic dementia). In semantic PPA, bilateral neurodegeneration of the ATLs is associated with profound lexical semantic deficits, yet syntax is strikingly spared. The goal of this study was to investigate the neural correlates of syntactic processing in semantic PPA to determine which regions normally involved in syntactic processing are damaged in semantic PPA and whether spared syntactic processing depends on preserved functionality of intact regions, preserved functionality of atrophic regions, or compensatory functional reorganization. We scanned 20 individuals with semantic PPA and 24 age-matched controls using structural MRI and fMRI. Participants performed a sentence comprehension task that emphasized syntactic processing and minimized lexical semantic demands. We found that, in controls, left inferior frontal and left posterior temporal regions were modulated by syntactic processing, whereas anterior temporal regions were not significantly modulated. In the semantic PPA group, atrophy was most severe in the ATLs but extended to the posterior temporal regions involved in syntactic processing. Functional activity for syntactic processing was broadly similar in patients and controls; in particular, whole-brain analyses revealed no significant differences between patients and controls in the regions modulated by syntactic processing. The atrophic left ATL did show abnormal functionality in semantic PPA patients; however, this took the unexpected form of a failure to deactivate. Taken together, our findings indicate that spared syntactic processing in semantic PPA depends on preserved functionality of structurally intact left frontal regions and moderately atrophic left posterior temporal regions, but no functional reorganization was apparent as a consequence of anterior temporal atrophy and dysfunction. These results suggest that the role of the ATL in sentence processing is less likely to relate to syntactic structure-building and more likely to relate to higher-level processes such as combinatorial semantic processing. PMID- 24345173 TI - Dissociating motivation from reward in human striatal activity. AB - Neural activity in the striatum has consistently been shown to scale with the value of anticipated rewards. As a result, it is common across a number of neuroscientific subdiscliplines to associate activation in the striatum with anticipation of a rewarding outcome or a positive emotional state. However, most studies have failed to dissociate expected value from the motivation associated with seeking a reward. Although motivation generally scales positively with increases in potential reward, there are circumstances in which this linkage does not apply. The current study dissociates value-related activation from that induced by motivation alone by employing a task in which motivation increased as anticipated reward decreased. This design reverses the typical relationship between motivation and reward, allowing us to differentially investigate fMRI BOLD responses that scale with each. We report that activity scaled differently with value and motivation across the striatum. Specifically, responses in the caudate and putamen increased with motivation, whereas nucleus accumbens activity increased with expected reward. Consistent with this, self-report ratings indicated a positive association between caudate and putamen activity and arousal, whereas activity in the nucleus accumbens was more associated with liking. We conclude that there exist regional limits on inferring reward expectation from striatal activation. PMID- 24345174 TI - A conceptual lemon: theta burst stimulation to the left anterior temporal lobe untangles object representation and its canonical color. AB - Object recognition benefits greatly from our knowledge of typical color (e.g., a lemon is usually yellow). Most research on object color knowledge focuses on whether both knowledge and perception of object color recruit the well established neural substrates of color vision (the V4 complex). Compared with the intensive investigation of the V4 complex, we know little about where and how neural mechanisms beyond V4 contribute to color knowledge. The anterior temporal lobe (ATL) is thought to act as a "hub" that supports semantic memory by integrating different modality-specific contents into a meaningful entity at a supramodal conceptual level, making it a good candidate zone for mediating the mappings between object attributes. Here, we explore whether the ATL is critical for integrating typical color with other object attributes (object shape and name), akin to its role in combining nonperceptual semantic representations. In separate experimental sessions, we applied TMS to disrupt neural processing in the left ATL and a control site (the occipital pole). Participants performed an object naming task that probes color knowledge and elicits a reliable color congruency effect as well as a control quantity naming task that also elicits a cognitive congruency effect but involves no conceptual integration. Critically, ATL stimulation eliminated the otherwise robust color congruency effect but had no impact on the numerical congruency effect, indicating a selective disruption of object color knowledge. Neither color nor numerical congruency effects were affected by stimulation at the control occipital site, ruling out nonspecific effects of cortical stimulation. Our findings suggest that the ATL is involved in the representation of object concepts that include their canonical colors. PMID- 24345176 TI - Reward- and attention-related biasing of sensory selection in visual cortex. AB - Attention to task-relevant features leads to a biasing of sensory selection in extrastriate cortex. Features signaling reward seem to produce a similar bias, but how modulatory effects due to reward and attention relate to each other is largely unexplored. To address this issue, it is critical to separate top-down settings defining reward relevance from those defining attention. To this end, we used a visual search paradigm in which the target's definition (attention to color) was dissociated from reward relevance by delivering monetary reward on search frames where a certain task-irrelevant color was combined with the target defining color to form the target object. We assessed the state of neural biasing for the attended and reward-relevant color by analyzing the neuromagnetic brain response to asynchronously presented irrelevant distractor probes drawn in the target-defining color, the reward-relevant color, and a completely irrelevant color as a reference. We observed that for the prospect of moderate rewards, the target-defining color but not the reward-relevant color produced a selective enhancement of the neuromagnetic response between 180 and 280 msec in ventral extrastriate visual cortex. Increasing reward prospect caused a delayed attenuation (220-250 msec) of the response to reward probes, which followed a prior (160-180 msec) response enhancement in dorsal ACC. Notably, shorter latency responses in dorsal ACC were associated with stronger attenuation in extrastriate visual cortex. Finally, an analysis of the brain response to the search frames revealed that the presence of the reward-relevant color in search distractors elicited an enhanced response that was abolished after increasing reward size. The present data together indicate that when top-down definitions of reward relevance and attention are separated, the behavioral significance of reward associated features is still rapidly coded in higher-level cortex areas, thereby commanding effective top-down inhibitory control to counter a selection bias for those features in extrastriate visual cortex. PMID- 24345175 TI - Interpersonal competence in young adulthood and right laterality in white matter. AB - The right hemisphere of the human brain is known to be involved in processes underlying emotion and social cognition. Clinical neuropsychology investigations and brain lesion studies have linked a number of personality and social disorders to abnormal white matter (WM) integrity in the right hemisphere. Here, we tested the hypothesis that interpersonal competencies are associated with integrity of WM tracts in the right hemisphere of healthy young adults. Thirty-one participants underwent diffusion tensor imaging scanning. Fractional anisotropy was used to quantify water diffusion. After the scanning session, participants completed the Adolescent Interpersonal Competence Questionnaire. Fractional anisotropy was subsequently correlated with Adolescent Interpersonal Competence Questionnaire scores using tract-based spatial statistics. Higher interpersonal competencies are related to higher WM integrity in several major tracts of the right hemisphere, in specific the uncinate fasciculus, the cingulum, the forceps minor, the infero-fronto occipital fasciculus, the inferior longitudinal fasciculus, and the superior longitudinal fasciculus. These results provide the first direct analysis of the neuroanatomical basis of interpersonal competencies and young adult self-reported skills in social contexts. PMID- 24345177 TI - Reorganization of retinotopic maps after occipital lobe infarction. AB - We studied patient JS, who had a right occipital infarct that encroached on visual areas V1, V2v, and VP. When tested psychophysically, he was very impaired at detecting the direction of motion in random dot displays where a variable proportion of dots moving in one direction (signal) were embedded in masking motion noise (noise dots). The impairment on this motion coherence task was especially marked when the display was presented to the upper left (affected) visual quadrant, contralateral to his lesion. However, with extensive training, by 11 months his threshold fell to the level of healthy participants. Training on the motion coherence task generalized to another motion task, the motion discontinuity task, on which he had to detect the presence of an edge that was defined by the difference in the direction of the coherently moving dots (signal) within the display. He was much better at this task at 8 than 3 months, and this improvement was associated with an increase in the activation of the human MT complex (hMT(+)) and in the kinetic occipital region as shown by repeated fMRI scans. We also used fMRI to perform retinotopic mapping at 3, 8, and 11 months after the infarct. We quantified the retinotopy and areal shifts by measuring the distances between the center of mass of functionally defined areas, computed in spherical surface-based coordinates. The functionally defined retinotopic areas V1, V2v, V2d, and VP were initially smaller in the lesioned right hemisphere, but they increased in size between 3 and 11 months. This change was not found in the normal, left hemisphere of the patient or in either hemispheres of the healthy control participants. We were interested in whether practice on the motion coherence task promoted the changes in the retinotopic maps. We compared the results for patient JS with those from another patient (PF) who had a comparable lesion but had not been given such practice. We found similar changes in the maps in the lesioned hemisphere of PF. However, PF was only scanned at 3 and 7 months, and the biggest shifts in patient JS were found between 8 and 11 months. Thus, it is important to carry out a prospective study with a trained and untrained group so as to determine whether the patterns of reorganization that we have observed can be further promoted by training. PMID- 24345178 TI - White noise improves learning by modulating activity in dopaminergic midbrain regions and right superior temporal sulcus. AB - In neural systems, information processing can be facilitated by adding an optimal level of white noise. Although this phenomenon, the so-called stochastic resonance, has traditionally been linked with perception, recent evidence indicates that white noise may also exert positive effects on cognitive functions, such as learning and memory. The underlying neural mechanisms, however, remain unclear. Here, on the basis of recent theories, we tested the hypothesis that auditory white noise, when presented during the encoding of scene images, enhances subsequent recognition memory performance and modulates activity within the dopaminergic midbrain (i.e., substantia nigra/ventral tegmental area, SN/VTA). Indeed, in a behavioral experiment, we can show in healthy humans that auditory white noise-but not control sounds, such as a sinus tone-slightly improves recognition memory. In an fMRI experiment, white noise selectively enhances stimulus-driven phasic activity in the SN/VTA and auditory cortex. Moreover, it induces stronger connectivity between SN/VTA and right STS, which, in addition, exhibited a positive correlation with subsequent memory improvement by white noise. Our results suggest that the beneficial effects of auditory white noise on learning depend on dopaminergic neuromodulation and enhanced connectivity between midbrain regions and the STS-a key player in attention modulation. Moreover, they indicate that white noise could be particularly useful to facilitate learning in conditions where changes of the mesolimbic system are causally related to memory deficits including healthy and pathological aging. PMID- 24345179 TI - Haptic shape processing in visual cortex. AB - Humans typically rely upon vision to identify object shape, but we can also recognize shape via touch (haptics). Our haptic shape recognition ability raises an intriguing question: To what extent do visual cortical shape recognition mechanisms support haptic object recognition? We addressed this question using a haptic fMRI repetition design, which allowed us to identify neuronal populations sensitive to the shape of objects that were touched but not seen. In addition to the expected shape-selective fMRI responses in dorsal frontoparietal areas, we observed widespread shape-selective responses in the ventral visual cortical pathway, including primary visual cortex. Our results indicate that shape processing via touch engages many of the same neural mechanisms as visual object recognition. The shape-specific repetition effects we observed in primary visual cortex show that visual sensory areas are engaged during the haptic exploration of object shape, even in the absence of concurrent shape-related visual input. Our results complement related findings in visually deprived individuals and highlight the fundamental role of the visual system in the processing of object shape. PMID- 24345180 TI - Prefrontal structural correlates of cognitive control during adolescent development: a 4-year longitudinal study. AB - Maturation of cognitive control abilities has been attributed to the protracted structural maturation of underlying neural correlates during adolescence. This study examined the relationship between development of two forms of cognitive control (proactive and reactive control) and structural maturation of the ACC, dorsolateral pFC, and ventrolateral pFC (vlPFC) between early and mid adolescence using a longitudinal design. Adolescents (n = 92) underwent baseline assessments when they were 12 years old and follow-up assessments approximately 4 years later. At each assessment, structural MRI scans were acquired, and a modified Stroop task was performed. Results showed longitudinal improvements in reactive control between early and mid adolescence. Furthermore, magnitude of the improvement in proactive control was associated with reduced thinning of the right vlPFC across the sample, whereas the magnitude of the improvements in reactive control was associated with reduced thinning of the left ACC in men alone. These findings suggest that individual differences in the maturation of ACC and vlPFC underlie the development of two distinct forms of cognitive control between early and mid adolescence as well as highlight sex differences in this relationship. PMID- 24345181 TI - Relational dialectics theory: Disentangling physician-perceived tensions of end of-life communication. AB - Existing literature evidences the centrality of interpersonal communication during end-of-life care, but several barriers currently compromise its effectiveness. One of them is a common lack of communication skills among physicians in this challenging context. Several strategies have been suggested to enhance end-of-life interactions; however, a solid theoretical framework is needed for the development of effective systematic guidelines and interventions that can facilitate this goal. The present research study addresses this gap, choosing to focus particularly on the physician's perspective. It relies on Baxter and Montgomery's (1996) Relational Dialectics Theory to illuminate the complexity of reality doctors commonly face in interactions with their patients during end-of-life care. Semistructured interviews were conducted with 11 physicians in a southern canton of Switzerland who had experienced at least one end-of-life encounter with a patient. The interviews probed whether and under what conditions Baxter and Montgomery's theoretical contradictions translate to physicians' end-of-life communication with their patients and the patients' family members. The results replicated and extended the original theoretical contradictions, evidencing that Relational Dialectics Theory is very applicable to end-of-life conversations. Thus, this study adds a theoretically framed, empirically grounded contribution to the current literature on the communicative challenges physicians commonly face during end-of-life interactions with their patients and their patients' family members. PMID- 24345182 TI - Failure of further learning: activities, structure, and meaning. AB - Previous research has shown that little benefit is achieved through spaced study and recall of text passages after the first recall attempt, an effect that we term the failure-of-further-learning. We hypothesized that the effect occurs because a situation model of the text's gist is formed when the text is first comprehended and is consolidated when recalled; it dominates later recall after verbatim memories of more recent study episodes have been lost. Experiments 1 and 2 attempted to circumvent the effect by varying the activities of participants and requiring interactive exploration. In both experiments, recall after four, weekly sessions showed little benefit beyond performance on the first recall. Experiment 3 interfered with the formation of an immediate situation model by introducing passages that were hard to comprehend without a title. Performance improved substantially across four sessions when titles were not supplied, but the standard effect was replicated when titles were given. Experiment 4 made verbatim memories available by incorporating all re-presentations and tests into one session; as predicted, recall improved over successive tests. PMID- 24345183 TI - Emotional impact feedback affects how people remember an analogue trauma event. AB - Do external motivational processes-in the form of social influences-shape people's memories for trauma? In this experiment, we examined the effects of social influence on memory and post-traumatic stress disorder (PTSD) symptomology for an analogue traumatic event. Seventy-two participants watched a distressing film; some received feedback about others' reactions to the film that either emphasised or downplayed the distressing nature of the film; control participants received no feedback. A week later, participants reported their symptoms, rated their memory on a number of characteristics and we tested their memory for the film's content. Participants who received feedback downplaying the film reported fewer PTSD-related analogue symptoms and weaker memory characteristics than their counterparts. The results suggest that people's memory phenomenology and analogue symptoms are influenced by others' feedback, but only when others' reactions downplayed the distressing nature of the film. PMID- 24345184 TI - Nicotine content of electronic cigarettes, its release in vapour and its consistency across batches: regulatory implications. AB - BACKGROUND AND AIMS: Electronic cigarettes (EC) may have a potential for public health benefit as a safer alternative to smoking, but questions have been raised about whether EC should be licensed as a medicine, with accurate labelling of nicotine content. This study determined the nicotine content of the cartridges of the most popular EC brands in the United Kingdom and the nicotine levels they deliver in the vapour, and estimated the safety and consistency of nicotine delivery across batches of the same product as a proxy for quality control for individual brands and within the industry. METHODS: We studied five UK brands (six products) with high internet popularity. MEASUREMENTS: Two samples of each brand were purchased 4 weeks apart, and analysed for nicotine content in the cartridges and nicotine delivery in vapour. RESULTS: The nicotine content of cartridges within the same batch varied by up to 12% relative standard deviation (RSD) and the mean difference between different batches of the same brand ranged from 1% [95% confidence interval (CI) = -5 to 7%] to 20% (95% CI=14-25%) for five brands and 31% (95% CI=21-39%) for the sixth. The puffing schedule used in this study vaporized 10-81% of the nicotine present in the cartridges. The nicotine delivery from 300 puffs ranged from ~2 mg to ~15 mg and was not related significantly to the variation of nicotine content in e-liquid (r=0.06, P=0.92). None of the tested products allowed access to e-liquid or produced vapour nicotine concentrations as high as conventional cigarettes. CONCLUSIONS: There is very little risk of nicotine toxicity from major electronic cigarette (EC) brands in the United Kingdom. Variation in nicotine concentration in the vapour from a given brand is low. Nicotine concentration in e-liquid is not well related to nicotine in vapour. Other EC brands may be of lower quality and consumer protection regulation needs to be implemented, but in terms of accuracy of labelling of nicotine content and risks of nicotine overdose, regulation over and above such safeguards seems unnecessary. PMID- 24345185 TI - ENV7 and YCK3, which encode vacuolar membrane protein kinases, genetically interact to impact cell fitness and vacuole morphology. AB - Saccharomyces cerevisiae vacuoles serve as a model for membrane fusion and fission. Yck3, a vacuolar membrane kinase, has been implicated in regulation of vacuole fusion. Recently, we established Env7 as another vacuolar membrane protein kinase with similar but nonredundant function to Yck3. Here, we report that native Env7 localizes to the vacuole independent of Yck3, where as its phosphorylation is YCK3 dependent. We also show that env7Deltayck3Delta double mutant exhibits severely compromised fitness, altered cell size and bud vacuoles, and F-class vacuolar morphology. Our results establish negative genetic interactions between ENV7 and YCK3 and suggest cooperative roles for the two conserved genes in regulation of membrane dynamics. Such genetic buffering supports a critical role for membrane flux in global cell fitness. PMID- 24345187 TI - Hypovitaminosis D in patients with cystic fibrosis: a cross-section study in South Brazil. AB - INTRODUCTION: Cystic fibrosis (CF) patients have a susceptibility to vitamin D deficiency because of nutrient malabsorption. OBJECTIVES: To evaluate the prevalence of hypovitaminosis D in CF patients and the factors associated with serum 25-hydroxyvitamin D levels. METHODS: We evaluated the prevalence of vitamin D deficiency defined as 25-hydroxyvitamin D <30 ng/mL, as suggested recently by the Cystic Fibrosis Foundation, and factors associated with its serum levels. Patients with confirmed CF were included. Nutritional status and hospital admissions were evaluated. Serum C-reactive protein, calcium, phosphate, magnesium, albumin, 25-hydroxyvitamin D and parathyroid hormone levels were measured. Lung function was evaluated by spirometry, and clinical and chest radiographic scores were assessed. Statistical significance level was set at P < 0.05. RESULTS: Fifty-nine patients were included. Prevalence of hypovitaminosis D was 61%. Patients with pancreatic insufficiency had a trend to have higher vitamin D levels. Sixteen patients had severe lung disease with percentage of forced expiratory volume in 1 s predicted below 40%. After multivariate analysis, body mass index and hospitalization in the last month remained significantly associated with serum vitamin D levels. CONCLUSIONS: Vitamin D insufficiency is still a problem in CF patients, even in those receiving supplementation. PMID- 24345188 TI - Glomuvenous malformations with smooth muscle and eccrine glands: unusual histopathologic features in a familial setting. AB - Glomuvenous malformations (OMIM 138000) are hamartomas presenting in childhood as multiple, bluish papules and nodules in the skin, which are characterized histopathologically by irregular vascular spaces surrounded by typical glomus cells. Glomuvenous malformations are caused by autosomal dominant mutations of the GLMN gene. A 34-year-old woman and her 16-year-old son presented with bluish papules and nodules since childhood. Biopsy specimens from both patients showed histopathologic features of glomuvenous malformations, unusually in consistent and close association with smooth muscle, hair follicles and eccrine glands. Sequencing of the GLMN gene revealed the p.C36X (c.108C>A) mutation in germline DNA from both patients. This is probably the first report describing the hamartomatous features of familial glomuvenous malformations consistently associated with a prominent smooth muscle component and eccrine glands. PMID- 24345189 TI - Allopurinol use in pregnancy in three women with inflammatory bowel disease: safety and outcomes: a case series. AB - BACKGROUND: Allopurinol is a frequently prescribed drug. In inflammatory bowel disease patients who shunt thiopurine metabolism towards more toxic and less desirable pathways, allopurinol is proving to be an effective add on therapy with good resultant disease control and less treatment side effects. As many such patients are young, the potential for pregnant women to be exposed to allopurinol is increasing. The safety of allopurinol in pregnancy is not known however. CASE PRESENTATION: We report three cases of safe use of allopurinol in pregnancy for women with inflammatory bowel disease. This included 2 patients with ulcerative colitis and 1 patient with fistulising Crohn's disease. Allopurinol was used throughout pregnancy in all patients. All 3 pregnancies resulted in normal healthy babies born at term by Caesarean section. CONCLUSION: It is important to evaluate and document the safety of allopurinol during pregnancy, as it is finding new roles in young patients. These three cases add significantly to the very limited data on allopurinol use in pregnancy. We encourage reporting of all cases of allopurinol use in pregnant patients and suggest an allopurinol pregnancy registry to document drug exposures and outcomes. PMID- 24345191 TI - Working upstream: how far can you go with sewage-based drug epidemiology? AB - The field of drug epidemiology based upon sewer sampling has only emerged in the last 10 years and has great potential to aid in drug epidemiological studies. This rapidly expanding field can provide an unbiased look into the illicit drug habits of large populations as well as specific, smaller groups. How far the field has evolved is discussed as well as where the future for these types of monitoring studies could go. PMID- 24345190 TI - The Vibrio parahaemolyticus effector VopC mediates Cdc42-dependent invasion of cultured cells but is not required for pathogenicity in an animal model of infection. AB - Vibrio parahaemolyticus is a Gram-negative marine bacterium that causes acute gastroenteritis in humans. The virulence of V. parahaemolyticus is dependent upon a type III secretion system (T3SS2). One effector for T3SS2, VopC, is a homologue of the catalytic domain of cytotoxic necrotizing factor (CNF), and was recently reported to be a Rho family GTPase activator and to be linked to internalization of V. parahaemolyticus by non-phagocytic cultured cells. Here, we provide direct evidence that VopC deamidates Rac1 and CDC42, but not RhoA, in vivo. Our results alsosuggest that VopC, through its activation of Rac1, contributes to formation of actin stress fibres in infected cells. Invasion of host cells, which occurs at a low frequency, does not seem linked to Rac1 activation, but instead appears to require CDC42. Finally, using an infant rabbit model of V. parahaemolyticus infection, we show that the virulence of V. parahaemolyticus is not dependent upon VopC-mediated invasion. Genetic inactivation of VopC did not impair intestinal colonization nor reduce signs of disease, including fluid accumulation, diarrhoea and tissue destruction. Thus, although VopC can promote host cell invasion, such internalization is not a critical step of the disease process, consistent with the traditional view of V. parahaemolyticus as an extracellular pathogen. PMID- 24345192 TI - Breastfeeding practices of ethnic Indian immigrant women in Melbourne, Australia. AB - BACKGROUND: The health benefits of breastfeeding are well documented in public health and medical literature worldwide. Despite this, global rates of breastfeeding steadily decline during the first couple of months postpartum. Although immigrant women have higher initiation rates and a longer duration of breastfeeding overall, breastfeeding practices are compromised because of a myriad of socioeconomic and cultural factors, including the acculturation process. The objective of this study was to show how acculturation and cultural identity influenced breastfeeding practices among Indian immigrants in Melbourne, Australia. METHODS: Twelve case studies were employed to gather narratives of women's lived experiences. Ethnographic field research methods were used to collect data, including participant observation, semi-structured interviews, case studies, and life histories. This provided in-depth information from women on various aspects of the immigrant experience of motherhood, including infant care and feeding. Participants were opportunistically recruited from Indian obstetricians and gynaecologists. Women identifying as ethnic Indian and in their third trimester of pregnancy were recruited. Interviews were conducted in women's homes in metropolitan Melbourne over a 12 month period between 2004 and 2005. Data were coded and analysed thematically. RESULTS: All women identified as ethnic Indian and initiated breastfeeding in accordance with their cultural identity. Social support and cultural connectivity impacted positively on duration of breastfeeding. However, acculturation (adopting Australian cultural values and gender norms, including returning to paid employment) negatively influenced breastfeeding duration. In addition, the high reliance of recent immigrants on the advice of healthcare professionals who gave inconsistent advice negatively affected exclusive breastfeeding. CONCLUSIONS: For ethnic Indian immigrant women breastfeeding practice is closely linked to acculturation and identity construction, both personal and communal. The lack of social and cultural networks for recent immigrants prevents their involvement in the cultural systems that traditionally support breastfeeding. With this in mind, healthcare professionals should deliver services in a culturally appropriate and sensitive manner where women feel supported as well as empowered. PMID- 24345193 TI - On-chip electrophoresis in supported lipid bilayer membranes achieved using low potentials. AB - A micro supported lipid bilayer (SLB) electrophoresis method was developed, which functions at low potentials and appreciable operating times. To this end, (hydroxymethyl)-ferrocene (FcCH2OH) was employed to provide an electrochemical reaction at the anode and cathode at low applied potential to avoid electrolysis of water. The addition of FcCH2OH did not alter the SLB characteristics or affect biomolecule function, and pH and temperature variations and bubble formation were eliminated. Applying potentials of 0.25-1.2 V during flow gave homogeneous electrical fields and a fast, reversible, and strong build-up of a charged dye modified lipid in the direction of the oppositely charged electrode. Moreover, streptavidin mobility could be modulated. This method paves the way for further development of analytical devices. PMID- 24345194 TI - 1 year test-retest reliability of ImPACT in professional ice hockey players. AB - The Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) battery is widely used to assess neurocognitive outcomes following sports-related concussion. The purpose of this study was to examine the 1 year test-retest reliability of ImPACT in a multilingual sample of professional hockey players. A total of 305 professional hockey players were tested 1 year apart using ImPACT. Reliable change confidence intervals were calculated and test-retest reliability was measured using Pearson and Intraclass correlation coefficients. Results indicated that the 1-year test-retest reliabilities for the Visual Motor and Reaction Time Composites ranged from low to high (.52 to .81). In contrast, 1 year test-retest reliabilities for the Verbal and Visual Memory Composites were low (.22 to .58). The 1-year test-retest results provided mixed support for the use of Visual Motor and Reaction Time Composites in select samples; in contrast, the Verbal and Visual Memory Composites may not be sensitive to clinical change. PMID- 24345195 TI - Persistence of related bla-IMP-4 metallo-beta-lactamase producing Enterobacteriaceae from clinical and environmental specimens within a burns unit in Australia - a six-year retrospective study. AB - BACKGROUND: To describe the clinical epidemiology, environmental surveillance and infection control interventions undertaken in a six-year persistence of bla-IMP-4 metallo-beta-lactamase (MBL) producing Enterobacteriaceae within a separately confined hospital burns unit in a tertiary hospital in Sydney, Australia. METHODS: MBL positive clinical and environmental isolates were collected from the Burns Unit, from the first detection of isolates in September 2006 to August 2012. Unit-acquired clinical isolates were included, and patient outcomes analyzed amongst those who acquired clinically significant infections. Environmental isolates were analyzed with regard to relationship to clinical isolates, bacterial species, and persistence despite cleaning efforts. RESULTS: Thirty clinical isolates detected from 23 patients were identified. Clinically significant infection developed in 7 (30%) patients - 2 bacteremias, 2 central venous catheter tip infections without bacteremia, and 3 wound infections. All patients survived at 30 days. Seventy-one environmental isolates were confirmed to be MBL-positive, with 85% sourced from shower facilities or equipment. MBL organisms persisted at these sites despite both usual hospital cleaning, and following targeted environmental disinfection interventions. CONCLUSIONS: Clear association exists between environmental Burns Unit contamination by MBLs and subsequent patient colonization. Clinical infection occurred in a small proportion of patients colonized by MBLs, and with generally favorable outcomes. Its persistence in the Burns Unit environment, despite concerted infection control measures, pose concern for ongoing clinical transmission. PMID- 24345196 TI - Video-assisted thoracic placement of epicardial leads. AB - Cardiac resynchronization therapy is one of the cornerstones of heart failure treatment. Inability to access the coronary sinus or one of its sidebranches is one of the most common causes of therapeutic failure. We describe a technique using video-assisted thoracic surgery for epicardial placement of the left ventricular lead and use an intrathoracic route to connect the lead to the device. PMID- 24345197 TI - Injectable MMP-sensitive alginate hydrogels as hMSC delivery systems. AB - Hydrogels with the potential to provide minimally invasive cell delivery represent a powerful tool for tissue-regeneration therapies. In this context, entrapped cells should be able to escape the matrix becoming more available to actively participate in the healing process. Here, we analyzed the performance of proteolytically degradable alginate hydrogels as vehicles for human mesenchymal stem cells (hMSC) transplantation. Alginate was modified with the matrix metalloproteinase (MMP)-sensitive peptide Pro-Val-Gly-Leu-Iso-Gly (PVGLIG), which did not promote dendritic cell maturation in vitro, neither free nor conjugated to alginate chains, indicating low immunogenicity. hMSC were entrapped within MMP sensitive and MMP-insensitive alginate hydrogels, both containing cell-adhesion RGD peptides. Softer (2 wt % alginate) and stiffer (4 wt % alginate) matrices were tested. When embedded in a Matrigel layer, hMSC-laden MMP-sensitive alginate hydrogels promoted more extensive outward cell migration and invasion into the tissue mimic. In vivo, after 4 weeks of subcutaneous implantation in a xenograft mouse model, hMSC-laden MMP-sensitive alginate hydrogels showed higher degradation and host tissue invasion than their MMP-insensitive equivalents. In both cases, softer matrices degraded faster than stiffer ones. The transplanted hMSC were able to produce their own collagenous extracellular matrix, and were located not only inside the hydrogels, but also outside, integrated in the host tissue. In summary, injectable MMP-sensitive alginate hydrogels can act as localized depots of cells and confer protection to transplanted cells while facilitating tissue regeneration. PMID- 24345198 TI - The cultural life script as cognitive schema: how the life script shapes memory for fictional life stories. AB - We tested, across three studies, the effect of the cultural life script on memory and its phenomenological properties. We focused in particular on the mnemonic effects of both schema-consistency and frequency in the life script. In addition to testing recognition (in Study 1) and recall (in Studies 2 and 3), we also collected remember/know judgements for remembered events (in Studies 1 and 2) and memory for their emotional valence (in Study 2). Our primary finding was that, across all three studies, higher-frequency events were more memorable than lower frequency events, as measured through either recognition or recall. We also attained three additional, complementary effects: First, schema-inconsistent events received remember ratings more often than schema-consistent events (in Study 2, with a trend to this effect in Study 1); second, where an event's emotional valence was inconsistent with the life script, memory for its valence was reconstructed to fit the script (in Study 2); and, third, intrusions in recall were disproportionately for life script events (in Study 3), although that was not the case in recognition (in Study 1). We conclude that the life script serves as a cognitive schema in how it shapes memory and its phenomenological properties. PMID- 24345199 TI - Exponential strand-displacement amplification for detection of microRNAs. AB - MicroRNAs (miRNAs) are promising targets for disease diagnosis. However, miRNA detection requires rapid, sensitive, and selective detection to be effective as a diagnostic tool. Herein, a miRNA-initiated exponential strand-displacement amplification (SDA) assay was reported. With the Klenow fragment, nicking enzyme Nt.AlwI, and two primers, the miRNA target can trigger two cycles of nicking, polymerization, and displacement reactions. These reaction cycles amplified the target miRNA exponentially and generated dsDNAs detectable with SYBR Green I in real-time PCR. As low as 16 zmol of the target miRNA was detected by this one-pot assay within 90 min, and the dynamic range spanned over 9 orders of magnitude. Negligible impact from the complex biological matrix was observed on the amplification reaction, indicating the assay's capability to directly detect miRNAs in biofluids. PMID- 24345200 TI - A rare case of simple syndactyly in a puppy. AB - A case of non-syndromic, complete syndactyly involving all four limbs is described in a three-month-old male crossbreed dog for the first time. Syndactyly is a rare condition in most animal species, in dogs it has been infrequently reported. Findings of clinical, radiographic and cytogenetic analyses are described and demonstrate probably for the first time that numerical and structural chromosome aberrations are not involved in the pathogenesis of this case of syndactyly. PMID- 24345201 TI - Nucleotide prodrugs of 2'-deoxy-2'-spirooxetane ribonucleosides as novel inhibitors of the HCV NS5B polymerase. AB - The limited efficacy, in particular against the genotype 1 virus, as well as the variety of side effects associated with the current therapy for hepatitis C virus (HCV) infection necessitates more efficacious drugs. We found that phosphoramidate prodrugs of 2'-deoxy-2'-spirooxetane ribonucleosides form a novel class of HCV NS5B RNA-dependent RNA polymerase inhibitors, displaying EC50 values ranging from 0.2 to >98 MUM, measured in the Huh7-replicon cell line, with no apparent cytotoxicity (CC50 > 98.4 MUM). Confirming recent findings, the 2' spirooxetane moiety was identified as a novel structural motif in the field of anti-HCV nucleosides. A convenient synthesis was developed that enabled the synthesis of a broad set of nucleotide prodrugs with varying substitution patterns. Extensive formation of the triphosphate metabolite was observed in both rat and human hepatocyte cultures. In addition, after oral dosing of several phosphoramidate derivatives of compound 21 to rats, substantial hepatic levels of the active triphosphate metabolite were found. PMID- 24345203 TI - Cholesterol-induced condensing and disordering effects on a rigid catanionic bilayer: a molecular dynamics study. AB - Molecular dynamics simulation is applied to investigate the bilayer properties of a novel catanionic vesicle composed of an ion pair amphiphile, hexadecyltrimethylammonium-dodecylsulfate (HTMA-DS), with cholesterol. Structural properties, such as molecular organization, orientation, and conformation, were analyzed from the resulting trajectory. Simulation results showed that cholesterol could induce both condensing and disordering effects on the rigid HTMA-DS bilayer. The condensing effect of cholesterol was ascribed to the maximizing contact between cholesterol ring and the neighboring hydrocarbon chains. Thus, the inserted cholesterol ring restrained the neighboring hydrocarbon chain segments from motion and increased the order of the neighboring hydrocarbon chains. However, the presence of cholesterol would increase the distance between head groups of HTMA-DS and induce a shift of DS(-) head groups toward the inside of the bilayer. This led to the protrusion of the HTMA(+) head groups and conformational disorder in the front segments of HTMA(+) hydrocarbon chains. In addition, the cholesterol-induced void in the hydrophobic core of the HTMA-DS bilayer increased the motion freedom of the terminal segments of the hydrocarbon chains. The cholesterol-induced space in the polar region and void in the nonpolar region of the bilayer led to a conformational disorder. With high cholesterol contents, the conformational disorder effect would overwhelm the condensing effect, resulting in the apparent disordering effect on the rigid HTMA DS bilayer. PMID- 24345202 TI - Increased 8-hydroxy-2'-deoxyguanosine in plasma and decreased mRNA expression of human 8-oxoguanine DNA glycosylase 1, anti-oxidant enzymes, mitochondrial biogenesis-related proteins and glycolytic enzymes in leucocytes in patients with systemic lupus erythematosus. AB - We measured plasma levels of the oxidative DNA damage marker 8-hydroxy-2' deoxyguanosine (8-OHdG) and leucocyte mRNA expression levels of the genes encoding the 8-OHdG repair enzyme human 8-oxoguanine DNA glycosylase 1 (hOGG1), the anti-oxidant enzymes copper/zinc superoxide dismutase (Cu/ZnSOD), manganese superoxide dismutase (MnSOD), catalase, glutathione peroxidase-1 (GPx-1), GPx-4, glutathione reductase (GR) and glutathione synthetase (GS), the mitochondrial biogenesis-related proteins mtDNA-encoded ND 1 polypeptide (ND1), ND6, ATPase 6, mitochondrial transcription factor A (Tfam), nuclear respiratory factor 1(NRF-1), pyruvate dehydrogenase E1 component alpha subunit (PDHA1), pyruvate dehydrogenase kinase isoenzyme 1 (PDK-1) and hypoxia inducible factor-1alpha (HIF-1alpha) and the glycolytic enzymes hexokinase-II (HK-II), glucose 6-phosphate isomerase (GPI), phosphofructokinase (PFK), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and lactate dehydrogenase A (LDHa). We analysed their relevance to oxidative damage in 85 systemic lupus erythematosus (SLE) patients, four complicated SLE patients undergoing rituximab treatment and 45 healthy individuals. SLE patients had higher plasma 8-OHdG levels (P < 0.01) but lower leucocyte expression of the genes encoding hOGG1(P < 0.01), anti-oxidant enzymes (P < 0.05), mitochondrial biogenesis-related proteins (P < 0.05) and glycolytic enzymes (P < 0.05) than healthy individuals. The increase in plasma 8-OHdG was correlated positively with the elevation of leucocyte expression of the genes encoding hOGG1 (P < 0.05), anti-oxidant enzymes (P < 0.05), several mitochondrial biogenesis-related proteins (P < 0.05) and glycolytic enzymes (P < 0.05) in lupus patients. The patients, whose leucocyte mtDNA harboured D310 heteroplasmy, exhibited a positive correlation between the mtDNA copy number and expression of ND1, ND6 and ATPase 6 (P < 0.05) and a negative correlation between mtDNA copy number and systemic lupus erythematosus disease activity index (SLEDAI) (P < 0.05), as well as plasma 8-OHdG (P < 0.05). In particular, four complicated SLE patients with increased expression of the genes encoding the anti-oxidant enzymes, GAPDH, Tfam and PDHA1, experienced better therapeutic outcomes after rituximab therapy. In conclusion, higher oxidative damage with suboptimal increases in DNA repair, anti-oxidant capacity, mitochondrial biogenesis and glucose metabolism may be implicated in SLE deterioration, and this impairment might be improved by targeted biological therapy. PMID- 24345204 TI - The effects of different orthodontic appliances upon microbial communities. AB - OBJECTIVES: Orthodontic appliances can promote accumulation of dental plaque, with associated enamel decalcification or gingival inflammation. The aim of this study was to examine longer-term microbiological changes during orthodontic treatment with fixed appliances. MATERIALS AND METHODS: Twenty-four orthodontic patients aged 11-14 years undergoing fixed appliance therapy were recruited into the study. Each was randomized for cross-mouth assignment of molar bands and bonded molar tubes to contralateral quadrants of the mouth. All patients received self-ligating brackets, but again using randomization, one upper lateral incisor bracket (left or right) also received an elastomeric ligature. Plaque samples from the molars and upper lateral incisors were obtained at intervals during treatment and up to 1 year after appliance removal. Denaturing gradient gel electrophoresis and 16S rDNA microarray were used to compare plaque microbial fingerprints. RESULTS: Plaque populations changed within 3 months of commencing treatment at all sites. The greatest differences in plaque composition were seen with self-ligating brackets with an elastomeric ligature. Post-treatment plaque associated with both types of molar attachment contained increased levels of periodontal pathogens Porphyromonas gingivalis, Tannerella forsythia, and Eubacterium nodatum, while Campylobacter rectus, Parvimonas micra, and Actinomyces odontolyticus were also elevated with bonds. CONCLUSIONS: The results suggest that orthodontic treatment may cause sustained changes in plaque microbiotas and that molar bond-associated plaque may have raised disease potential. PMID- 24345205 TI - Cryotherapy in inflammatory rheumatic diseases: a systematic review. AB - The aim of this article was to review current evidence about cryotherapy in inflammatory rheumatic diseases (therapeutic and biological effects). For therapeutic effects, we performed a systematic review (PubMed, EMBASE, Cochrane Library, LILACS databases, unpublished data) and selected studies including non operated and non-infected arthritic patients treated with local cryotherapy or whole-body cryotherapy. By pooling 6 studies including 257 rheumatoid arthritis (RA) patients, we showed a significant decrease in pain visual analogic scale (mm) and 28-joint disease activity score after chronic cryotherapy in RA patients. For molecular pathways, local cryotherapy induces an intrajoint temperature decrease, which might downregulate several mediators involved in joint inflammation and destruction (cytokines, cartilage-degrading enzymes, proangiogenic factors), but studies in RA are rare. Cryotherapy should be included in RA therapeutic strategies as an adjunct therapy, with potential corticosteroid and nonsteroidal anti-inflammatory drug dose-sparing effects. However, techniques and protocols should be more precisely defined in randomized controlled trials with stronger methodology. PMID- 24345206 TI - Lurking as an active participation process: a longitudinal investigation of engagement with an online cancer support group. AB - To better understand participation in computer-mediated social support (CMSS) groups for breast cancer patients, this study examines two overarching questions of (1) who are posters, lurkers, or nonusers and (2) what role do these different types of engagement play in explaining psychosocial health outcomes? This study incorporates the comprehensive model of information seeking and two competing models of social enhancement and social compensation, as well as the literature on lurking and posting behaviors in online groups to answer research questions. Our findings suggest that patterns of engagement in a CMSS group differed according to patients' sociodemographic characteristics and psychosocial factors. In addition, we found that lurkers had a higher level of perceived functional well-being than posters at 3 months post baseline. Theoretical and practical implications for effective online cancer support group campaigns are discussed. PMID- 24345208 TI - ZIP4 is a novel diagnostic and prognostic marker in human pancreatic cancer: a systemic comparison between EUS-FNA and surgical specimens. AB - Aberrant expression of a zinc transporter ZIP4 in pancreatic ductal adenocarcinoma (PDAC) has been shown to contribute to tumor progression and is a potential target for individualized therapy. The overall objective of this study was to determine whether ZIP4 could serve as a novel diagnostic and prognostic marker in human PDAC, and if it can be assessed by minimally invasive sampling using endoscopic ultrasound guided fine needle aspiration (EUS-FNA). Immunohistochemistry was performed to compare ZIP4 expression in the PDAC samples obtained from EUS-FNA and matched surgical tumors (parallel control). Samples were reported by sensitivity, specificity, and predictive values, all with 95% confidence intervals (CI). A total of 23 cases with both FNA and surgical specimens were evaluated. We found that ZIP4 was significantly overexpressed in tumor cells from both sets of samples. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ZIP4 for the diagnosis of PDAC were 72.9%, 72.5%, 76.1%, and 69.0% in EUS-FNA samples, and were 97.9%, 65.4%, 83.9%, and 94.4% in surgical specimens, respectively. The association between the positive rate of ZIP4 expression in FNA and surgical samples is statistically significant (P=0.0216). Both the intensity and percentage of ZIP4 positive cells from the surgical samples correlated significantly with tumor stage (P=0.0025 and P=0.0002). ZIP4 intensity level in FNA samples was significantly associated with tumor differentiation and patient survival. These results indicate that EUS-FNA is capable of non-operative detection of ZIP4, thus offering the potential to direct pre-operative detection and targeted therapy of PDAC. PMID- 24345207 TI - Profiles of cytokines secreted by isolated human endometrial cells under the influence of chorionic gonadotropin during the window of embryo implantation. AB - BACKGROUND: Several studies have indicated that human pre-implantation embryo derived chorionic gonadotropin (hCG) may influence the implantation process by its action on human endometrial epithelial and stromal cells. Despite reports indicating that hCG acts on these cells to affect the production of several cytokines and growth factors (e.g., MIF, IGF-I, VEGF, LIF, IL-11, GMCSF, CXL10 and FGF2), our understanding of the integral influence of hCG on paracrine interactions between endometrial stromal and epithelial cells during implantation is very limited. METHODS: In the present study, we examined the profile of 48 cytokines in the conditioned media of primary cell cultures of human implantation stage endometrium. Endometrial epithelial cells (group 1; n = 20), stromal cells (group 2; n = 20), and epithelial plus stromal cells (group 3; n = 20) obtained from mid-secretory stage endometrial samples (n = 60) were grown on collagen and exposed to different doses (0, 1, 10 and 100 IU/ml) of rhCG for 24 h in vitro. Immunochemical and qRT-PCR methods were used to determine cytokine profiles. Enrichment and process networks analyses were implemented using a list of cytokines showing differential secretion in response to hCG. RESULTS: Under basal conditions, endometrial epithelial and stromal cells exhibited cell type-specific profiles of secreted cytokines. Administration of hCG (100 IU) resulted in significantly (P < 0.05) different cytokine secretion profiles indicative of macropinocytic transport (HGF, MCSF) in epithelial cells, signal transduction (CCL4, FGF2, IL-1b, IL-6, IL-17, VEGF) in stromal cells, and epithelial mesenchymal transition (FGF2, HGF, IL-1b, TNF) in mixed cells. Overall, the administration of hCG affected cytokines involved in the immune response, chemotaxis, inflammatory changes, proliferation, cell adhesion and apoptosis. CONCLUSIONS: CG can influence the function of the endometrium during blastocyst implantation via its differential action on endometrial epithelial and stromal cells. CG may also affect complex paracrine processes in the different endometrial cell types. PMID- 24345209 TI - FROGG high-risk prostate cancer workshop: patterns of practice and literature review. Part II post-radical prostatectomy. AB - Australian and New Zealand radiation oncologists with an interest in uro-oncology were invited to undertake a pattern of practice survey dealing with issues encountered in the management of high-risk prostate cancer in the post prostatectomy setting. Responses from practitioners revealed a lack of consensus regarding the optimal timing of radiation therapy, the use of whole pelvic radiation therapy and the use of androgen deprivation therapy. A review of the literature outlining the current body of knowledge and the clinical studies that will inform future practice is presented. PMID- 24345210 TI - Association between perioperative blood transfusion and early postoperative cognitive dysfunction in aged patients following total hip replacement surgery. AB - INTRODUCTION: Accumulating evidence suggests that enhanced inflammatory responses contribute to the pathogenesis of postoperative cognitive dysfunction (POCD). Blood transfusion can trigger an enhancement of acute inflammatory responses. Therefore, we hypothesized that perioperative blood transfusion is associated with a higher risk of POCD in aged patients following total hip replacement surgery. MATERIAL AND METHODS: Patients older than 65 years undergoing elective total hip replacement surgery were enrolled from October 2011 to December 2012. Neurocognitive tests were evaluated at baseline and at 7 d after surgery by a Mini-Mental State Test. Multivariate logistic regression analysis was used to determine risk factors associated with POCD. RESULTS: Fifty-six patients (27.3%) developed POCD 7 d postoperatively. Patients who developed POCD were older, had a lower education level and preoperative hemoglobin concentration, had more blood loss, and had a lower body weight (p < 0.05). Patients with POCD were more likely to receive red blood cells (RBCs) transfusion (51.8% versus 31.5%; p < 0.05). A multivariable logistic regression model identified older age, lower education level, and perioperative blood transfusion of more than 3 units as independent risk factors for POCD 7 d postoperatively. CONCLUSION: Our data suggested that perioperative blood transfusion of more than 3 units of RBCs is an independent risk factor for POCD in aged patients following total hip replacement surgery. PMID- 24345211 TI - Contribution of particle-size-fractionated airborne lead to blood lead during the National Health and Nutrition Examination Survey, 1999-2008. AB - The objective of this work is to examine associations between blood lead (PbB) and air lead (PbA) in particulate matter measured at different size cuts by use of PbB concentrations from the National Health and Nutrition Examination Survey and PbA concentrations from the U.S. Environmental Protection Agency for 1999 2008. Three size fractions of particle-bound PbA (TSP, PM10, and PM2.5) data with different averaging times (current and past 90-day average) were utilized. A multilevel linear mixed effect model was used to characterize the PbB-PbA relationship. At 0.15 MUg/m(3), a unit decrease in PbA in PM10 was significantly associated with a decrease in PbB of 0.3-2.2 MUg/dL across age groups and averaging times. For PbA in PM2.5 and TSP, slopes were generally positive but not significant. PbB levels were more sensitive to the change in PbA concentrations for children (1-5 and 6-11 years) and older adults (>= 60 years) than teenagers (12-19 years) and adults (20-59 years). For the years following the phase-out of Pb in gasoline and a resulting upward shift in the PbA particle size distribution, PbA in PM10 was a statistically significant predictor of PbB. The results also suggest that age could affect the PbB-PbA association, with children having higher sensitivity than adults. PMID- 24345212 TI - Effects of respiration on the velocity of tricuspid regurgitation and estimation of systolic pulmonary artery pressure in patients with right ventricle systolic dysfunction. AB - OBJECTIVE: We investigated the effects of quiet respiration on the peak velocity of tricuspid regurgitation (TR) and estimation of systolic pulmonary artery pressure (SPAP) in patients with right ventricle (RV) systolic dysfunction using Doppler echocardiography. METHODS: Continuous-wave Doppler spectra of TR were recorded in 32 patients with and 28 controls without RV systolic dysfunction. Electrocardiography and respiratory tracing were recorded simultaneously. Expiratory and inspiratory peak velocities of TR were acquired and averaged for five consecutive respiratory cycles. The SPAP during expiration and inspiration was calculated. RESULTS: The velocity of TR and SPAP was not significantly different between expiration and inspiration in controls (2.77 +/- 0.23 and 2.82 +/- 0.26 m/s, P = 0.776; 35.94 +/- 4.96 and 36.18 +/- 5.12 mmHg, P = 0.747), whereas the velocity of TR and SPAP decreased significantly from expiration to inspiration in patients with RV systolic dysfunction (3.27 +/- 0.35 and 2.59 +/- 0.22 m/s, P < 0.001; 53.72 +/- 7.39, 38.45 +/- 5.63 mmHg, P < 0.001). CONCLUSIONS: Quiet respiration has significant effects on the velocity of TR in patients with RV systolic dysfunction. This factor should be taken into account when using Doppler echocardiography to estimate these patients' SPAP, and the measurements should be performed in patients at the end of expiration. PMID- 24345213 TI - The Salmonella enterica giant adhesin SiiE binds to polarized epithelial cells in a lectin-like manner. AB - The invasion of polarized epithelial cells by Salmonella enterica requires the cooperative activity of the Salmonella pathogenicity island (SPI) 1-encoded type III secretion system (T3SS) and the SPI4-encoded giant non-fimbrial adhesin SiiE. SiiE is a highly repetitive protein composed of 53 bacterial Ig (BIg) domains and mediates binding to the apical side of polarized epithelial cells. We analysed the binding properties of SiiE and observed lectin-like activity. SiiE-dependent cell invasion can be ablated by chemical or enzymatic deglycosylation. Lectin blockade experiments revealed that SiiE binding is specific for glycostructures with terminal N-acetyl-glucosamine (GlcNAc) and/or alpha 2,3-linked sialic acid. In line with these data, we found that SiiE-expressing Salmonella bind to the GlcNAc polymer chitin. Various recombinant SiiE fragments were analysed for host cell binding. We observed that C-terminal portions of SiiE bind to the apical side of polarized cells and the intensity of binding increases with the number of BIg domains present in the recombinant proteins. Based on these results, we propose that SiiE mediates multiple interactions per molecule with glycoproteins and/or glycosylated phospholipids present in the apical membrane of polarized epithelial cells. Thisintimate binding enables the subsequent function of the SPI1-T3SS, resulting in host cell invasion. PMID- 24345214 TI - Reproducibility of small animal cine and scar cardiac magnetic resonance imaging using a clinical 3.0 tesla system. AB - BACKGROUND: To evaluate the inter-study, inter-reader and intra-reader reproducibility of cardiac cine and scar imaging in rats using a clinical 3.0 Tesla magnetic resonance (MR) system. METHODS: Thirty-three adult rats (Sprague Dawley) were imaged 24 hours after surgical occlusion of the left anterior descending coronary artery using a 3.0 Tesla clinical MR scanner (Philips Healthcare, Best, The Netherlands) equipped with a dedicated 70 mm solenoid receive-only coil. Left-ventricular (LV) volumes, mass, ejection fraction and amount of myocardial scar tissue were measured. Intra-and inter-observer reproducibility was assessed in all animals. In addition, repeat MR exams were performed in 6 randomly chosen rats within 24 hours to assess inter-study reproducibility. RESULTS: The MR imaging protocol was successfully completed in 32 (97%) animals. Bland-Altman analysis demonstrated high intra-reader reproducibility (mean bias%: LV end-diastolic volume (LVEDV), -1.7%; LV end systolic volume (LVESV), -2.2%; LV ejection fraction (LVEF), 1.0%; LV mass, 2.7%; and scar mass, -1.2%) and high inter-reader reproducibility (mean bias%: LVEDV, 3.3%; LVESV, 6.2%; LVEF, -4.8%; LV mass, -1.9%; and scar mass, -1.8%). In addition, a high inter-study reproducibility was found (mean bias%: LVEDV, 0.1%; LVESV, -1.8%; LVEF, 1.0%; LV mass, -4.6%; and scar mass, -6.2%). CONCLUSIONS: Cardiac MR imaging of rats yielded highly reproducible measurements of cardiac volumes/function and myocardial infarct size on a clinical 3.0 Tesla MR scanner system. Consequently, more widely available high field clinical MR scanners can be employed for small animal imaging of the heart e.g. when aiming at serial assessments during therapeutic intervention studies. PMID- 24345215 TI - LPS-induced inflammation in the chicken is associated with CCAAT/enhancer binding protein beta-mediated fat mass and obesity associated gene down-regulation in the liver but not hypothalamus. AB - BACKGROUND: The fat mass and obesity associated gene (FTO) is widely investigated in humans regarding its important roles in obesity and type 2 diabetes. Studies in mammals demonstrate that FTO is also associated with inflammation markers. However, the association of FTO with inflammation in chickens remains unclear. In this study, male chickens on day 28 posthatching were injected intraperitoneally with lipopolysaccharide (LPS) or saline to investigate whether the FTO gene is involved in LPS-induced inflammation. RESULTS: We detected significant down regulation of FTO mRNA in the liver (P < 0.01), but not in the hypothalamus, 2 and 24 h after LPS challenge. Toll-like receptor (TLR) 2 (P < 0.01) and TLR4 (P < 0.01) followed the same pattern as FTO, being suppressed significantly in liver but not in hypothalamus. IL-1beta was dramatically up-regulated (P < 0.01) in both liver and hypothalamus 2 h after LPS challenge, while activation of IL-6 was observed in the liver (P < 0.01), but not in hypothalamus. The 5'-flanking sequence of the chicken FTO gene contains nine predicted binding sites for CCAAT/enhancer binding protein beta (C/EBP beta) and one for signal transducer and activator of transcription 3 (STAT3). Significant elevation of C/EBP beta was detected in the liver (P < 0.01), but not in the hypothalamus, 2 h after LPS challenge. Lipopolysaccharide challenge increased the C/EBP beta binding to FTO promoter in the liver (P < 0.01 for fragment 1, P < 0.05 for fragment 2), although the protein content of C/EBP beta was not altered. Moreover, injection of LPS resulted in enhanced phosphorylation of liver STAT3, a downstream transcription factor in IL-6 signaling. Although phosphorylated STAT3 was not detected to directly bind to FTO promoter, it was found to interact with C/EBP beta. CONCLUSION: Our results reveal that FTO expression in liver, but not in hypothalamus, is affected by the i.p. injection of LPS, which may be mediated through tissue-specific FTO transcriptional regulation by C/EBP beta and STAT3 interaction. PMID- 24345216 TI - Advances on regulatory T cells from the 15th International Congress of Immunology. AB - The International Congress of Immunology is the largest congregation of immunologists and meets every three years. This year, the congress was held in Milan and included talks on both basic and translational aspects of immunology. Talks on the field of regulatory T cell biology and function are highlighted in this report. PMID- 24345217 TI - A "ship in a bottle" strategy to load a hydrophilic anticancer drug in porous metal organic framework nanoparticles: efficient encapsulation, matrix stabilization, and photodelivery. AB - An essential challenge in the development of nanosized metal organic framework (nanoMOF) materials in biomedicine is to develop a strategy to stabilize their supramolecular structure in biological media while being able to control drug encapsulation and release. We have developed a method to efficiently encapsulate topotecan (TPT, 1), an important cytotoxic drug, in biodegradable nanoMOFs. Once inside the pores, 1 monomers aggregate in a "ship in a bottle" fashion, thus filling practically all of the nanoMOFs' available free volume and stabilizing their crystalline supramolecular structures. Highly efficient results have been found with the human pancreatic cell line PANC1, in contrast with free 1. We also demonstrate that one- and two-photon light irradiation emerges as a highly promising strategy to promote stimuli-dependent 1 release from the nanoMOFs, hence opening new standpoints for further developments in triggered drug delivery. PMID- 24345218 TI - Deposition and release of graphene oxide nanomaterials using a quartz crystal microbalance. AB - Interactions of graphene oxide (GO) with silica surfaces were investigated using a quartz crystal microbalance with dissipation monitoring (QCM-D). Both GO deposition and release were monitored on silica- and poly-l-lysine (PLL) coated surfaces as a function of GO concentration and in NaCl, CaCl2, and MgCl2 as a function of ionic strength (IS). Under favorable conditions (PLL-coated positive surface), GO deposition rates increased with GO concentration, as expected from colloidal theory. Increased NaCl concentration resulted in a greater deposition attachment efficiency of GO on the silica surface, indicating that deposition of GO follows Derjaguin-Landau-Verwey-Overbeek (DLVO) theory; GO deposition rates decreased at high IS, however, due to large aggregate formation. GO critical deposition concentration (CDC) on the silica surface is determined to be 40 mM NaCl which is higher than the reported CDC values of fullerenes and lower than carbon nanotubes. A similar trend is observed for MgCl2 which has a CDC value of 1.2 mM MgCl2. Only a minimal amount of GO (frequency shift <2 Hz) was deposited on the silica surface in CaCl2 due to the bridging ability of Ca(2+) ions with GO functional groups. Significant GO release from silica surface was observed after adding deionized water, indicating that GO deposition is reversible. The release rates of GO were at least 10-fold higher than the deposition rates under similar conditions indicating potential high release and mobility of GO in the environment. Under favorable conditions, a significant amount of GO was released which indicates potential multilayer GO deposition. However, a negligible amount of deposited GO was released in CaCl2 under favorable conditions due to the binding of GO layers with Ca(2+) ions. Release of GO was significantly dependent on salt type with an overall trend of NaCl > MgCl2 > CaCl2. PMID- 24345219 TI - Facile preparation of glycoprotein-imprinted 96-well microplates for enzyme linked immunosorbent assay by boronate affinity-based oriented surface imprinting. AB - Molecularly imprinted polymers (MIPs), as inexpensive and stable substitutes of antibodies, have shown great promise in immunoassays. Glycoproteins are of significant diagnostic value. To facilitate the application of MIPs in clinical diagnostics, a general and facile imprinting method toward glycoproteins oriented for an enzyme-linked immunosorbent assay (ELISA) in the form of a 96-well microplate is essential but has not been fully explored yet. In this study, a new method called boronate affinity-based oriented surface imprinting was proposed for facile preparation of glycoprotein-imprinted microplates. A template glycoprotein was first immobilized by a boronic acid-modified microplate through boronate affinity binding, and then, a thin layer of polyaniline was formed to cover the microplate surface via in-water self-copolymerization. After the template was removed by an acidic solution, 3D cavities that can rebind the template were fabricated on the microplate surface. Using horseradish peroxidase (HRP) as a model target, the effects of imprinting conditions as well as the properties and performance of the prepared MIPs were investigated. alpha Fetoprotein (AFP)-imprinted microplate was then prepared, and thereby, a MIP based ELISA method was established. The prepared MIPs exhibited several highly favorable features, including excellent specificity, widely applicable binding pH, superb tolerance for interference, high binding strength, fast equilibrium kinetics, and reusability. The MIP-based ELISA method was finally applied to the analysis of AFP in human serum. The result was in good agreement with that by radioimmunoassay, showing a promising prospect of the proposed method in clinical diagnostics. PMID- 24345220 TI - Cytokines and chemokines in neuromyelitis optica: pathogenetic and therapeutic implications. AB - Neuromyelitis optica (NMO) is characterized by severe optic neuritis and longitudinally extensive transverse myelitis. The discovery of an NMO-specific autoantibody to the aquaporin-4 (AQP4) water channel has improved knowledge of NMO pathogenesis. Many studies have focused on inflammatory and pathological biomarkers of NMO, including cytokines and chemokines. Increased concentrations of T helper (Th)17- and Th2-related cytokines and chemokines may be essential factors for developing NMO inflammatory lesions. For example, interleukin-6 could play important roles in NMO pathogenesis, as it is involved in the survival of plasmablasts that produce anti-AQP4 antibody in peripheral circulation and in the enhancement of inflammation in the central nervous system. Therefore, assessment of these useful biomarkers may become a supportive criterion for diagnosing NMO. Significant advances in the understanding of NMO pathogenesis will lead to the development of novel treatment strategies. This review focuses on the current advances in NMO immunological research, particularly that of cytokines and chemokines. PMID- 24345221 TI - Experimental models of neuromyelitis optica. AB - For a long time, the most important inflammatory demyelinating diseases of the central nervous system (CNS), for example, multiple sclerosis (MS) and neuromyelitis optica (NMO), were extremely hard to differentiate, often with severe consequences for affected patients. This changed with the discovery of NMO immunoglobulin G (IgG), a specific autoantibody which was detected in the vast majority of NMO patients, and with the demonstration that this autoantibody targets aquaporin 4 (AQP4), a water channel found on astrocytes in the CNS. These findings paved the way for the generation of experimental models of NMO. This chapter will discuss the contribution of experimental models to NMO research and what key questions remain to be addressed. PMID- 24345223 TI - A 42-year-old male with a new onset generalized seizure. PMID- 24345224 TI - 79-year old man with Parkinsonism and acute spinal cord compression. PMID- 24345225 TI - A 29-year-old man with progressive short term memory loss. PMID- 24345222 TI - The pathology of an autoimmune astrocytopathy: lessons learned from neuromyelitis optica. AB - Neuromyelitis optica (NMO) is a disabling autoimmune astrocytopathy characterized by typically severe and recurrent attacks of optic neuritis and longitudinally extensive myelitis. Until recently, NMO was considered an acute aggressive variant of multiple sclerosis (MS), despite the fact that early studies postulated that NMO and MS may be two distinct diseases with a common clinical picture. With the discovery of a highly specific serum autoantibody (NMO-IgG), Lennon and colleagues provided the first unequivocal evidence distinguishing NMO from MS and other central nervous system (CNS) inflammatory demyelinating disorders. The target antigen of NMO-IgG was confirmed to be aquaporin-4 (AQP4), the most abundant water channel protein in the CNS, mainly expressed on astrocytic foot processes at the blood-brain barrier, subpial and subependymal regions. Pathological studies demonstrated that astrocytes were selectively targeted in NMO as evidenced by the extensive loss of immunoreactivities for the astrocytic proteins, AQP4 and glial fibrillary acidic protein (GFAP), as well as perivascular deposition of immunoglobulins and activation of complement even within lesions with a relative preservation of myelin. In support of these pathological findings, GFAP levels in the cerebrospinal fluid (CSF) during acute NMO exacerbations were found to be remarkably elevated in contrast to MS where CSF-GFAP levels did not substantially differ from controls. Additionally, recent experimental studies showed that AQP4 antibody is pathogenic, resulting in selective astrocyte destruction and dysfunction in vitro, ex vivo and in vivo. These findings strongly suggest that NMO is an autoimmune astrocytopathy where damage to astrocytes exceeds both myelin and neuronal damage. This chapter will review recent neuropathological studies that have provided novel insights into the pathogenic mechanisms, cellular targets, as well as the spectrum of tissue damage in NMO. PMID- 24345226 TI - A 34-year-old man with bitemporal hemianopsia. PMID- 24345231 TI - Characterization of the house sparrow (Passer domesticus) transcriptome: a resource for molecular ecology and immunogenetics. AB - The house sparrow (Passer domesticus) is an important model species in ecology and evolution. However, until recently, genomic resources for molecular ecological projects have been lacking in this species. Here, we present transcriptome sequencing data (RNA-Seq) from three different house sparrow tissues (spleen, blood and bursa). These tissues were specifically chosen to obtain a diverse representation of expressed genes and to maximize the yield of immune-related gene functions. After de novo assembly, 15,250 contigs were identified, representing sequence data from a total of 8756 known avian genes (as inferred from the closely related zebra finch). The transcriptome assembly contain sequence data from nine manually annotated MHC genes, including an almost complete MHC class I coding sequence. There were 407, 303 and 68 genes overexpressed in spleen, blood and bursa, respectively. Gene ontology terms related to ribosomal function were associated with overexpression in spleen and oxygen transport functions with overexpression in blood. In addition to the transcript sequences, we provide 327 gene-linked microsatellites (SSRs) with sufficient flanking sequences for primer design, and 3177 single-nucleotide polymorphisms (SNPs) within genes, that can be used in follow-up molecular ecology studies of this ecological well-studied species. PMID- 24345232 TI - Yes indeed, most Americans do eat GMOs every day! PMID- 24345233 TI - Association between inflammatory markers, hemostatic markers, and traditional risk factors on coronary artery spasm in patients with normal coronary angiography. AB - BACKGROUND: Coronary artery spasm is an important pathophysiological mechanism in some forms of myocardial ischemic disease. The relationship between inflammatory markers, mean platelet volume (MPV), and coronary artery spasm is unclear. METHODS AND RESULTS: During coronary angiography, methylergometrin was injected intravenously to 345 patients with chest pain but without significant coronary disease on angiogram to provoke coronary artery spasm. Based on provocation test results, patients were divided into 2 groups: spasm group (60 patients) and nonspasm group (285 patients). Inflammatory markers (C-reactive protein, CRP; white blood cells; polymorphonuclear neutrophils, PMN; monocytes, MO; lymphocytes, LY), hemostasis markers (MPV; platelet count; fibrinogen [FIB]; D dimers), and traditional risk factors (body mass index; hyperlipidemia; triglycerides [TGs]; total, low-density, and high-density lipoprotein cholesterol [TC, LDL-C, and HDL-C]) were measured and compared between groups. More male patients experienced spasm (23.56% vs. 11.11%, P = 0.002). CRP, PMN, and MO were significantly higher in the spasm group (P < 0.05). There was no significant difference in serum levels of LDL-C, HDL-C, TG, TC, LY, MPV, and FIB between groups. Smoking and hyperlipidemia were more common among patients with spasm; males more frequently were smokers (58.04% vs. 46.78%, P = 0.041). By multivariate analysis, smoking, PMN, and MO were significantly associated with coronary artery spasm with odds ratios of 3.52 (95% CI 1.79-6.90, P = 0.0001), 1.21 (95% CI 1.07-1.46, P = 0.04), and 5.35 (95% CI 1.37-21.07, P = 0.01), respectively. CONCLUSIONS: Inflammation may partake in the pathogenesis of coronary artery spasm. Smoking, PMN count, and MO count appear to be clinical risk factors for coronary artery spasm. Conversely, coronary artery spasm does not seem to be associated with abnormalities in thrombogenesis. PMID- 24345234 TI - Comparison of the oxidation products produced by tetrahalobisphenol A flame retardants as a result of potassium monopersulfate oxidation with an iron(III) tetrakis(p-sulfonatophenyl)porphyrin in the presence of humic acid. AB - Tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA), commercially used halogenated flame retardants, can be found in leachates from landfills, because hydrophobic interactions with humic acids (HAs), major organic components in landfills, result in an increase in their solubility. The oxidation characteristics of TBBPA and TCBPA in the presence of HA were compared using a catalytic system comprised of a combination of iron(III)-tetrakis(p sulfophenyl)porphyrin (FeTPPS) and KHSO5 that can mimic the enzymatic reactions that occur in landfills. The levels of degradation and dehalogenation of TBBPA and TCBPA at pH 4 were significantly lower than at pH 8, which is a typical pH value for landfill leachates. In the presence of HA at pH 8, 2-hydroxyisopropyl 2,6 -dihalophenols (2HIP-26DXPs) were detected as major by-products. These compounds are likely produced via the beta-carbon scission of the substrates, and their levels decreased with increasing reaction time. The levels of coupling compounds between 2,6-dihalopnenols and TBBPA or TCBPA increased with reaction time. The 27% of Br in the degraded TBBPA and 50% of Cl in the degraded TCBPA were incorporated into the HA as a result of catalytic oxidation via the FeTPPS/KHSO5 system. These results suggest that TCBPA is incorporated into HA more readily than TBBPA. The coupling compounds between HA and halogenated intermediates from TBBPA or TCBPA were assigned by pyrolysis-gas chromatography/mass spectrometry. PMID- 24345235 TI - The effect of chitosan on the concentration of 17beta-estradiol and free triiodothyronine in mice exposed to polychlorinated biphenyls (PCBs). AB - The aim of this work was to examine (i) how the applied PCB mixture influences the level of 17beta-estradiol (E2) and free triiodothyronine (FT3) in the blood plasma of mice (C57/BL/6J) and (ii) whether supplementation with chitosan would protect against the observed changes in the examined plasma hormone concentrations. In the study we used a mixture of indicator PCBs (CB no. 28, 52, 101, 118, 138, 153, 180) and our results showed their anti-estrogenic effects. Exposure to the mixture resulted in a significant decrease (P < 0.05) in plasma concentration of E2 relative to the control, and chitosan administration did not prevent the decrease. To the contrary, E2 concentration in the blood plasma of the mice which received both the PCB mixture and chitosan was lower compared to those which did not receive chitosan. Exposure to the PCBs also resulted in a decrease in FT3 concentration in the treatedgroup, although it was not as pronounced as for E2 and was prevented with dietary supplementation with chitosan, with the observed FT3 level in the chitosan-treated group similar to the control. In summary, supplementation with chitosan can only to a certain extent minimize the negative effects of exposure to PCBs. PMID- 24345236 TI - The occurrence of polycyclic aromatic hydrocarbons and their derivatives and the proinflammatory potential of fractionated extracts of diesel exhaust and wood smoke particles. AB - Exposure to combustion emissions, including diesel engine exhaust and wood smoke particles (DEPs and WSPs), has been associated with inflammatory responses. To investigate the possible role of polycyclic aromatic hydrocarbons (PAHs) and PAH derivatives, the DEPs and WSPs methanol extracts were fractionated by solid phase extraction (SPE), and the fractions were analyzed for more than ~120 compounds. The pro-inflammatory effects of the fractionated extracts were characterized by exposure of bronchial epithelial lung cells (BEAS-2B). Both native DEPs and WSPs caused a concentration-dependent increase in IL-6 and IL-8 release and cytotoxicity. This is consistent with the finding of a rather similar total content of PAHs and PAH-derivatives. Yet, the samples differed in specific components, suggesting that different species contribute to the toxicological response in these two types of particles. The majority of the IL-6 release and cytotoxicity was induced upon exposure to the most polar (methanol) SPE fraction of extracts from both samples. In these fractions hydroxy-PAHs, carboxy-PAHs were observed along with nitro-amino-PAHs in DEP. However, the biological effects induced by the polar fractions could not be attributed only to the occurrence of PAH-derivatives. The present findings indicate a need for further characterization of organic extracts, beyond an extensive analysis of commonly suspected PAH and PAH-derivatives. Supplemental materials are available for this article. Go to the publisher's online edition of Journal of Environmental Science and Health, Part A, to view the supplemental file. PMID- 24345237 TI - Inactivation of MS2 coliphage by UV and hydrogen peroxide: comparison by cultural and molecular methodologies. AB - The use of advanced oxidation processes (AOP) are expected to increase for removal of emerging contaminants and pathogens from drinking water. In this study, the performance of a small community ultraviolet light reactor in combination with hydrogen peroxide (H2O2) for MS2 coliphage inactivation with two different flow rate conditions of 1 gal/min (gpm) and 2 gpm was evaluated. Following UV radiation, MS2 showed a reduction of 5.3-5.8 log10 when quantified with cultural plaque counts, whereas corresponding quantitative polymerase chain reaction (qPCR) data showed only a 1.7-2.8 log10 reduction in viral RNA copy number. When H2O2 was added at either 2.5 or 5 ppm with UV at both flow rate conditions, enhanced MS2 inactivation occurred with a more than 7 log10 reduction observed via plaque counts, indicating that all added MS2 had been inactivated, since no plaques were formed after incubation at 37 degrees C for 24 h. In contrast, qPCR only showed a corresponding 3-4 log10 reduction in viral RNA copy number. This research also sheds light on the inactivation of MS2 with ultraviolet light and in the presence of hydroxyl radicals and provides a practical use of qPCR to detect MS2 concentration following advanced oxidation relative to traditional plaque methodology; however qPCR detection overestimates the true number of infective virus. PMID- 24345238 TI - T-2 toxin and its metabolite HT-2 toxin combined with insulin-like growth factor I modify progesterone secretion by porcine ovarian granulosa cells. AB - The aim of this study was to examine the effect of A-trichothecenes T-2 and HT-2 toxins combined with insulin-like growth factor I (IGF-I) on the release of steroid hormone progesterone (P4) by porcine ovarian granulosa cells (GCs). The cells were incubated without (control) or with treatments of A-trichothecenes T-2 (100 and 1000 ng/mL)/ HT-2 (100 and 1000 ng/mL) combined with IGF-I (1, 10 and 100 ng/mL) for 24 h. Progesterone secretion was determined by RIA. The release of P4 by GCs after addition of T-2 toxin (at 100 ng/mL) combined with IGF-I (at 10 but not at 1 and 100 ng/mL) and HT-2 toxin (at 100 ng/mL) combined with IGF-I (at all doses) was significantly (P < 0.05) inhibited. On the other hand the release of P4 after addition of T-2/ HT-2 toxin (at 1000 ng/mL) combined with IGF-I (at all doses) was significantly (P < 0.05) stimulated. Alone IGF-I addition (at 10, 100 but not at 1 ng/mL) significantly (P < 0.05) stimulated P4 release by GCs. The results of our in vitro study indicate the T-2 and HT-2 toxins combined with IGF-I could modify progesterone secretion by porcine ovarian granulosa cells and potentially regulate process of steroidogenesis in the ovaries. Currently, occurrence of mycotoxins in food and feed is a worldwide problem and therefore study of these toxins as well as their interaction with different substances such as growth factors could be beneficial for better understanding of mechanism of their toxic effects in organism. PMID- 24345239 TI - Some ozone advanced oxidation processes to improve the biological removal of selected pharmaceutical contaminants from urban wastewater. AB - Removal of nine pharmaceutical compounds--acetaminophen (AAF), antipyrine (ANT), caffeine (CAF), carbamazepine (CRB), diclofenac (DCF), hydrochlorothiazide (HCT), ketorolac (KET), metoprolol (MET) and sulfamethoxazole (SMX)-spiked in a primary sedimentation effluent of a municipal wastewater has been studied with sequential aerobic biological and ozone advanced oxidation systems. Combinations of ozone, UVA black light and Fe(III) or Fe3O4 constituted the chemical systems. During the biological treatment (hydraulic residence time, HRT = 24 h), only AAF and CAF were completely eliminated, MET, SMX and HCT reached partial removal rates and the rest of compounds were completely refractory. With any ozone advanced oxidation process applied, the remaining pharmaceuticals disappear in less than 10 min. Fe3O4 or Fe(III) photocatalytic ozonation leads to 35% mineralization compared to 13% reached during ozonation alone after about 30-min reaction. Also, biodegradability of the treated wastewater increased 50% in the biological process plus another 150% after the ozonation processes. Both untreated and treated wastewater was non-toxic for Daphnia magna (D. magna) except when Fe(III) was used in photocatalytic ozonation. In this case, toxicity was likely due to the ferryoxalate formed in the process. Kinetic information on ozone processes reveals that pharmaceuticals at concentrations they have in urban wastewater are mainly removed through free radical oxidation. PMID- 24345240 TI - Optimization of naproxen and ibuprofen removal in photolysis using a Box-Behnken design: effect of Fe(III), NO3-, and humic acid. AB - This study investigated the roles and optimum conditions of four independent variables [ultraviolet (UV) intensity, Fe(III), NO3 (-), and humic acid (HA) concentration] in the photolytic removal of naproxen (NPX) and ibuprofen (IBP) in water using a response surface method based on the Box-Behnken design. Lab-scale experiments used analysis of variance and t-test statistics to test the significance of independent variables and their interactions. Predicted levels of NPX and IBP removals were found to be in good agreement with experimental levels (R(2) = 0.9891 for NPX and 0.9936 for IBP). UV intensity and HA were the most positively and negatively significant variables (P < 0.001), respectively. However, Fe(III) and NO3 (-) ions had a less significant impact (P > 0.05). This result implies that NPX was removed by both direct photolysis (photons) and indirect reaction (OH radical), while IBP was removed mainly by the OH radical. NPX was more susceptible to the OH radical than IBP (kOH/NPX = 8.24 * 10(9) M( 1)s(-1) and kOH/IBP = 7.51 * 10(9) M(-1)s(-1)). According to a quadratic regression model, the predicted maximum removal efficiencies for NPX and IBP were 71.66% and 63.58% when the predicted optimum ratio of UV (mW cm(-2)):Fe(III) (mg/L):NO3(-) (mg/L):HA (mg/L) was 6.3:0.94:0:0 and 6.3:0.94:20:0, respectively, which was similar to the respective experimental NPX and IBP removal values of 70.21% and 62.16%. Supplemental materials are available for this article. Go to the publisher's online edition of the Journal of Environmental Science and Health, Part A, to view the supplemental file. PMID- 24345241 TI - The impact of hygiene and localised treatment on the quality of drinking water in Masaka, Rwanda. AB - The worldwide prevalence of waterborne diseases has been attributed to the lack of safe water, inadequate sanitation and hygiene. This study evaluated socio demographic factors, microbiological quality of water at source and point of use (POU) at households, water handling and sanitation practices in a rural Rwandan community. Thirty five water samples from the source, Nyabarongo River, and water at point of use (POU) treated with the Slow Sand Filter (SSF) and Sur'Eau methods, were analysed for total coliform and faecal coliform counts. Turbidity was measured in household samples. A structured questionnaire regarding water collection, storage, usage and waterborne disease awareness was administered to 324 women. Despite the significant reduction in coliforms and faecal coliforms from the Nyabarongo River following treatment using either SSF or Sur'Eau, the water at point of use was found to be unsafe for human consumption. The frequency of diarrheal diseases were significantly higher among people who did not wash hands before food preparation (P = 0.002) and after using a toilet (P = 0.007) than among those who did. There was a statistically significant association between education levels and water treatment practices at the households (P < 0.05). Participants had limited knowledge regarding water storage practices for prevention of household water contamination. A combination of treatment methods with appropriate water handling should be considered. In addition, education is a fundamental precursor to advocating water treatment at POU. PMID- 24345242 TI - Seasonal and spatial variation in dithiothreitol (DTT) activity of quasi ultrafine particles in the Los Angeles Basin and its association with chemical species. AB - A year-long sampling campaign of quasi-ultrafine particles (dp < 0.25 MUm) was conducted at 10 distinct sites representing source, urban and/or near-freeway, rural receptor and desert locations across the Los Angeles air basin. Redox activity of the PM samples was measured by means of the Dithiothreitol (DTT) assay and detailed chemical analysis was performed to measure the concentrations of chemical species. DTT activity per unit air volume and unit PM mass (expressed in nmol min(-1) m(-3) and nmol/min/MUg PM, respectively) showed similar trends across sites and seasons. DTT activity was generally higher during cold seasons (winter and fall) compared to warm seasons (summer and spring). Noticeable peaks were observed at urban near-freeway locations representing "source" sites impacted by fresh traffic emissions. Regression analysis indicated strong association (R > 0.7) between the DTT activity and the concentrations of carbonaceous species (OC, EC, WSOC and WIOC) across all seasons and strong winter time correlations with organic tracers of primary vehicular emissions including polycyclic aromatic hydrocarbons (PAHs), alkanes, hopanes and steranes. Strong correlations were also observed, particularly during winter, between DTT activity and transition metals (e.g., Cr, Mn, V, Fe, Cu, Cd and Zn), which share similar vehicular sources with primary organics. A multivariate linear regression analysis indicated that the variability in DTT activity is best explained by the variability in concentrations of WSOC, WIOC, EC and hopanes. Combined contributions from these species explained 88% of the DTT activity. The appearance of WSOC as a typical tracer of secondary organic aerosol, along with EC, WIOC and hopanes, all markers of emissions from primary combustion sources, emphasizes the contributions of both primary and secondary sources to the overall oxidative potential of quasi-ultrafine particles. Supplemental materials are available for this article. Go to the publisher's online edition of the Journal of Environmental Science and Health, Part A, to view the supplemental file. PMID- 24345243 TI - Optimized photocatalytic degradation of Reactive Blue 2 by TiO2/UV process. AB - The photocatalytic degradation of synthetic dye solution of Reactive Blue 2 was investigated using UV irradiation in aqueous suspension of nanotitania as photocatalyst and H2O2 as electron acceptor in a slurry photoreactor. To determine the optimum condition of decolorization, the influential parameters including initial dye concentration, catalyst quantity, hydrogen peroxide concentration, pH value and UV light intensity were evaluated using the Taguchi statistical method. The results indicated that compared to the other parameters, UV light intensity was the most effective. The theoretically predicted value of decolorization efficiency (95.48%) was confirmed by the experimental value (95.22%). The mineralization was considered significant with regard to the obtained values of total organic carbon (TOC) analysis (92.52%) and chemical oxygen demand (COD) analysis (94.05%) in the optimum condition. Investigations were also carried out to determine the appropriate adsorption isotherm and kinetic model in the optimum condition. The obtained optimum condition for dye removal was finally examined applying a real sample of textile wastewater containing the dye. PMID- 24345244 TI - Source apportionment using reconstructed mass calculations. AB - A long-term study was undertaken to investigate the air quality of the Islamabad/Rawalpindi area. In this regard fine and coarse particulate matter were collected from 4 sites in the Islamabad/Rawalpindi region from 1998 to 2010 using Gent samplers and polycarbonate filters and analyzed for their elemental composition using the techniques of Neutron Activation Analysis (NAA), Proton Induced X-ray Emission/Proton Induced Gamma-ray Emission (PIXE/PIGE) and X-ray Fluorescence (XRF) Spectroscopy. The elemental data along with the gravimetric measurements and black carbon (BC) results obtained by reflectance measurement were used to approximate or reconstruct the particulate mass (RCM) by estimation of pseudo sources such as soil, smoke, sea salt, sulfate and black carbon or soot. This simple analysis shows that if the analytical technique used does not measure important major elements then the data will not be representative of the sample composition and cannot be further utilized for source apportionment studies or to perform transboundary analysis. In this regard PIXE/PIGE and XRF techniques that can provide elemental compositional data for most of the major environmentally important elements appear to be more useful as compared to NAA. Therefore %RCM calculations for such datasets can be used as a quality assurance (QA) measure to treat data prior to application of chemometrical tools such as factor analysis (FA) or cluster analysis (CA). PMID- 24345245 TI - Multivariate analysis of the heterogeneous geochemical processes controlling arsenic enrichment in a shallow groundwater system. AB - The effects of various geochemical processes on arsenic enrichment in a high arsenic aquifer at Jianghan Plain in Central China were investigated using multivariate models developed from combined adaptive neuro-fuzzy inference system (ANFIS) and multiple linear regression (MLR). The results indicated that the optimum variable group for the AFNIS model consisted of bicarbonate, ammonium, phosphorus, iron, manganese, fluorescence index, pH, and siderite saturation. These data suggest that reductive dissolution of iron/manganese oxides, phosphate competitive adsorption, pH-dependent desorption, and siderite precipitation could integrally affect arsenic concentration. Analysis of the MLR models indicated that reductive dissolution of iron(III) was primarily responsible for arsenic mobilization in groundwaters with low arsenic concentration. By contrast, for groundwaters with high arsenic concentration (i.e., > 170 MUg/L), reductive dissolution of iron oxides approached a dynamic equilibrium. The desorption effects from phosphate-competitive adsorption and the increase in pH exhibited arsenic enrichment superior to that caused by iron(III) reductive dissolution as the groundwater chemistry evolved. The inhibition effect of siderite precipitation on arsenic mobilization was expected to exist in groundwater that was highly saturated with siderite. The results suggest an evolutionary dominance of specific geochemical process over other factors controlling arsenic concentration, which presented a heterogeneous distribution in aquifers. Supplemental materials are available for this article. Go to the publisher's online edition of the Journal of Environmental Science and Health, Part A, to view the supplemental file. PMID- 24345246 TI - Emerging issues and future directions of the field of health communication. AB - The interdisciplinary intersections between communication science and health related fields are pervasive, with numerous differences in regard to epistemology, career planning, funding perspectives, educational goals, and cultural orientations. This article identifies and elaborates on these challenges with illustrative examples. Furthermore, concrete suggestions for future scholarship are recommended to facilitate compatible, coherent, and interdisciplinary health communication inquiry. The authors hope that this article helps current and future generations of health communication scholars to make more informed decisions when facing some of the challenges discussed in this article so that they will be able to seize the interdisciplinary and international potential of this unique and important field of study. PMID- 24345247 TI - Single-dot spectroscopy of zinc-blende CdSe/CdS core/shell nanocrystals: nonblinking and correlation with ensemble measurements. AB - Here we report the first series of phase-pure zinc-blende CdSe/CdS core/shell quantum dots (QDs) with reproducibly controlled shell thickness (4-16 monolayers), which are nonblinking (>=95% 'on' time) in single-exciton regime for the entire series. These unique QDs possess well-controlled yet simple excited state decay dynamics at both single-dot and ensemble levels, extremely small nonblinking volume threshold, if any, and unique 'on' and 'off' probability statistics. The outstanding optical properties of the QDs at the single-dot level were found to be correlated well with their ensemble properties. These small and bright nonblinking QDs offer promising technical application prospect in both single-dot and ensemble levels. The consistent and reproducible experimental results shed new light on the mechanisms of blinking of QDs. PMID- 24345248 TI - Actin dynamics in Phytophthora infestans; rapidly reorganizing cables and immobile, long-lived plaques. AB - The actin cytoskeleton is a dynamic but well-organized intracellular framework that is essential for proper functioning of eukaryotic cells. Here, we use the actin binding peptide Lifeact to investigate the in vivo actin cytoskeleton dynamics in the oomycete plant pathogen Phytophthora infestans. Lifeact-eGFP labelled thick and thin actin bundles and actin filament plaques allowing visualization of actin dynamics. All actin structures in the hyphae were cortically localized. In growing hyphae actin filament cables were axially oriented in the sub-apical region whereas in the extreme apex in growing hyphae, waves of fine F-actin polymerization were observed. Upon growth termination, actin filament plaques appeared in the hyphal tip. The distance between a hyphal tip and the first actin filament plaque correlated strongly with hyphal growth velocity. The actin filament plaques were nearly immobile with average lifetimes exceeding 1 h, relatively long when compared to the lifetime of actin patches known in other eukaryotes. Plaque assembly required ~30 s while disassembly was accomplished in ~10 s. Remarkably, plaque disassembly was not accompanied with internalization and the formation of endocytic vesicles. These findings suggest that the functions of actin plaques in oomycetes differ from those of actin patches present in other organisms. PMID- 24345249 TI - The use of comparative effectiveness research in mental healthcare policy and practice. PMID- 24345251 TI - From methods to policy: key questions remain unanswered. PMID- 24345252 TI - Interview: a 20-year 'search for evidence' leads to the Center for Medical Technology Policy. PMID- 24345253 TI - Risks and benefits of comparative effectiveness research in preterm infants: SUPPORT. PMID- 24345254 TI - Oral clefts and wellbeing: a lifelong perspective and an agenda for comparative effectiveness research. PMID- 24345255 TI - Comparative effectiveness of oral diabetes drug combinations in reducing glycosylated hemoglobin. AB - AIMS: To provide evidence on the comparative effectiveness of oral diabetes drug combinations. METHODS: We performed a retrospective, observational cohort study of glycosylated hemoglobin change in outpatients newly exposed to dual- or triple drug oral diabetes treatment. RESULTS: Adjusted response to a second drug added to metformin ranged from 0.85 to 1.21% glycosylated hemoglobin decline. Response to a third drug was smaller (0.53-0.91%). Higher baseline glycosylated hemoglobin was associated with larger response; sulfonylurea effectiveness declined over time; and thiazolidinediones were more effective in obese patients and women. CONCLUSION: Observational data provide results qualitatively consistent with the limited available randomized data on diabetes drug effectiveness, and extend these findings into common clinical scenarios where randomized data are unavailable. Sex and BMI influence the comparative effectiveness of diabetes drug combinations. PMID- 24345256 TI - Measures to improve angiotensin receptor blocker prescribing efficiency in the UK: findings and implications. AB - BACKGROUND: Generic losartan provides an opportunity to enhance angiotensin receptor blocker (ARB) prescribing efficiency, with all ARBs essentially being similar. Initially, there was limited activity in NHS Bury (UK). This changed in March 2011 with therapeutic switching and other measures encouraging the prescribing of losartan following generics to enhance its utilization versus patented ARBs. AIM: This study aims to assess the impact of multiple measures on losartan utilization, its price and total ARB expenditure. METHODS: An interrupted time series analysis was performed. Utilization was measured as prescription items dispensed, typically 28 days. RESULTS: No immediate change in losartan utilization was observed following generics. This changed after the multiple initiatives with losartan accounting for 65% of all single ARB items dispensed by the study end. ARB expenditure was 59% below prestudy levels by the study end, which was helped by a 92% reduction in expenditure per item for losartan. Annual net savings from the program were estimated at just under GBL290,000, which is over eight-times the cost of implementation. CONCLUSION: Multiple measures can enhance prescribing efficiency. Health authorities cannot rely on a 'spillover' effect from other classes in order to affect changes in physician prescribing habits. PMID- 24345257 TI - Through the looking glass: making the design and output of economic models useful for setting medical policy. AB - Economic modeling has rarely been considered to be an essential component of healthcare policy-making in the USA, due to a lack of transparency in model design and assumptions, as well as political interests that equate examination of cost with unfair rationing. The Institute for Clinical and Economic Review has been involved in several efforts to bring economic modeling into public discussion of the comparative value of healthcare interventions, efforts that have evolved over time to suit the needs of multiple public forums. In this article, we review these initiatives and present a template that attempts to 'unpack' model output and present the major drivers of outcomes and cost. We conclude with a series of recommendations for effective presentation of economic models to US policy-makers. PMID- 24345258 TI - Evaluating methodological assumptions in comparative effectiveness research: overcoming pitfalls. AB - The scope of comparative effectiveness research (CER) is wide and therefore requires the application of complex statistical tools and nonstandard procedures. The commonly used methods presuppose the realization of important, and often untestable, assumptions pertaining to the underlying distribution, study heterogeneity and targeted population. Accordingly, the value of the results obtained based on such tools is in large part dependent on the validity of the underlying assumptions relating to the operating characteristics of the procedures. In this article, we elucidate some of the pitfalls that may arise with use of the most commonly used techniques, including those that are applied in network meta-analysis, observational data analysis and patient-reported outcome evaluation. In addition, reference is made to the impact of data quality and database heterogeneity on the performance of commonly used CER tools and the need for standards in order to inform researchers engaged in CER. PMID- 24345259 TI - Comparative effectiveness research in follicular lymphoma: current and future perspectives and challenges. AB - Follicular lymphoma (FL) is the most common indolent non-Hodgkin's lymphoma in northern America. FL is an incurable disease with relapsing-remitting courses requiring serial intermittent treatments. Duration of remission will often become progressively shorter and most patients will die from refractory disease or transformation to aggressive lymphoma. Given the incurable nature of FL, current goals of treatment are focused on improving symptoms and survival by a variety of available treatment options, while considering potential adverse events. Although randomized controlled trials are universally perceived as the gold standard of clinical research, randomized controlled trials are not always practical and have several limitations. Therapeutic and diagnostic options of FLs are expanding faster than randomized controlled trials can test them, so employing comparative effectiveness research on other research designs are needed to efficiently improve global FL care. Implementing comparative effectiveness research with judicious use of appropriate research designs will hopefully fill current knowledge gaps and provide insights for FL managements. PMID- 24345261 TI - Fine-scale diversity and distribution of ectomycorrhizal fungal mycelium in a Scots pine forest. AB - Ectomycorrhizal (ECM) mycelium is a key component of the ectomycorrhizal symbiosis, yet we know little regarding the fine-scale diversity and distribution of mycelium in ECM fungal communities. We collected four 20 * 20 * 2-cm(3) (800 cm(3)) slices of Scots pine (Pinus sylvestris) forest soil and divided each into 100 2 * 2 * 2-cm(3) (8-cm(3)) cubes. The presence of mycelium of ECM fungi was determined using an internal transcribed spacer (ITS) database terminal restriction fragment length polymorphism (T-RFLP) approach. As expected, many more ECM fungi were detected as mycelium than as ectomycorrhizas in a cube or slice. More surprisingly, up to one-quarter of the 43 species previously detected as ectomycorrhizas over an area of 400 m(2) could be detected in a single 8-cm(3) cube, and up to three-quarters in a single 800-cm(3) slice. ECM mycelium frequency decreased markedly with depth and there were distinct 'hotspots' of mycelium in the moss/F1 layer. Our data demonstrate a high diversity of ECM mycelium in a small (8-cm(3) ) volume of substrate, and indicate that the spatial scale at which ECM species are distributed as mycelium may be very different from the spatial scale at which they are distributed as tips. PMID- 24345260 TI - Triptolide ameliorates lipopolysaccharide-induced acute lung injury in rats. AB - BACKGROUND: Acute lung injury (ALI) is a serious clinical syndrome with a high rate of mortality. In this study, the effects of triptolide on lipopolysaccharide (LPS)-induced ALI in rats were investigated. METHODS: Sixty-five male Sprague Dawley rats(approved by ethics committee of the First Affiliated Hospital of Soochow University) were randomly divided into five groups. The control group was injected with 2.5 mL saline/kg body weight via the tail vein and intraperitoneally with 1% dimethyl sulfoxide (DMSO) (n = 5). The L group was administered with 0.2% LPS dissolved in saline (5 mg/kg) to induce ALI via the tail vein (n = 15). The TP1, TP2, and TP3 groups were treated as rats in the L group and then intraperitoneally injected with 25, 50, and 100 MUg triptolide/kg body weight, respectively (15 rats per group). Blood samples from the left heart artery were taken for blood gas analysis at 1 hour before injection and at 1, 3, 6, and 12 hours after saline and DMSO administration in the control group, LPS injection in the L group, and triptolide injection in the TP1, TP2, and TP3 groups. Lung wet-to-dry weight (W/D) ratio, diffuse alveolar damage (DAD) score, TNF-alpha levels, and mRNA and protein expression of toll-like receptor 4 (TLR4) were analyzed. RESULTS: Compared with the control group, the arterial partial pressure of oxygen (PaO2) declined (P <0.05), the W/D ratio and DAD score increased (P <0.05), and TNF-alpha levels in serum and bronchoalveolar lavage fluid (BALF) and mRNA and protein expression of TLR4 were significantly increased in the L group (P <0.05). Compared with the L group, PaO2 significantly increased in the TP2 and TP3 groups (P <0.05), while the W/D ratio and DAD score were significantly decreased in the TP2 and TP3 groups (P <0.05). TNF-alpha levels and mRNA and protein expression of TLR4 were significantly decreased in the TP2 and TP3 groups compared with the L group (P <0.05). CONCLUSIONS: Triptolide can ameliorate LPS-induced ALI by reducing the release of the inflammatory mediator TNF-alpha and inhibiting TLR4 expression. PMID- 24345263 TI - Attentional set-shifting in rodents: a review of behavioural methods and pharmacological results. AB - Attentional set-shifting tasks have been used as a measure of human fronto executive function for over 60 years. The major contribution these tasks have made has been the quantification of cognitive deficits associated with human pathologies such as schizophrenia, attention deficit/hyperactivity disorder and dementias related to Parkinson's, Huntington's and Alzheimer's diseases. Thirteen years ago an intradimensional/extradimensional attentional set-shifting task was developed for rats. Since then, there have been over 70 publications detailing the effects of various manipulations on task performance in rats, and 17 publications describing adaptations of the task for mice. Much of this literature has focused on animal models of neuropathology and cognitive deficits associated with schizophrenia and other human conditions. Altogether, these results have elucidated the roles of multiple neurotransmitters in the manifestation of cognitive deficits, and their subsequent amelioration, including dopamine, serotonin, acetylcholine and noradrenaline. However, the fundamental promise of the attentional set-shifting task, to measure cognitive flexibility in humans and rodents in a formally analogous way, has often been under investigated and over simplified. This review explores the research that led to the development of the rat attentional set-shifting task, and how subsequent use of the task has expanded our understanding of the psychological and neurological underpinnings of discrimination and reversal learning, as well as the formation, maintenance and shifting of attentional set. PMID- 24345262 TI - Incremental validity of neuropsychological assessment in the identification and treatment of youth with ADHD. AB - Comprehensive neuropsychological assessments for youth with ADHD allow for thorough consideration of co-occurring disorders and provide targeted recommendations for treating ADHD and comorbid conditions. This study offers a preliminary evaluation of the added value (compared to routine care) associated with neuropsychological assessment in the identification and treatment of ADHD in youth ages 3-17 years. First we describe a novel measure developed to evaluate broad-based outcomes for youth with ADHD following neuropsychological assessment. Next we compare parent ratings of child symptoms and quality of life between two groups of youth with ADHD: those who have recently received neuropsychological assessments (NP+), and those who have not (NP-). Participants were surveyed again 5 months after baseline to assess changes in symptoms, quality of life, and service utilization. While both groups experienced significant improvements in behavioral/emotional symptoms, the NP+ group had greater initiation of parent behavior management training and special education services and greater initiation of medication management over the follow-up period, compared with the NP- group. Satisfaction with neuropsychological assessment was high overall but slightly decreased over the course of the follow-up period. The findings offer preliminary support for the incremental efficacy of neuropsychological evaluation in the diagnosis and management of ADHD. PMID- 24345264 TI - Editorial: Current pro-cognitive therapeutic strategies for improved pharmacological treatment in schizophrenia. PMID- 24345266 TI - Intracellular signaling and approaches to the treatment of schizophrenia and associated cognitive impairment. AB - Schizophrenia is a pervasive neuropsychiatric disorder affecting over 1% of the world's population. Dopamine system dysfunction is strongly implicated in the etiology of schizophrenia. Data support the long-standing concept of schizophrenia as a disease characterized by hyperactivity within midbrain (striatal D2) dopamine systems. In addition, there is now considerable evidence that glutamate neurotransmission, mediated through NMDA-type receptors, is deficient in schizophrenic patients and that hypoactivity in cortical dopamine and glutamate pathways is a key feature of the schizophrenic brain. While current antipsychotic medications-typically dopamine D2 antagonists-adequately address positive symptoms of the disease, such as the acute hallucinations and delusions, they fail to substantially improve negative features, such as social isolation, and can further compromise poor cognitive function in schizophrenic patients. In fact, cognitive impairment is a core feature of schizophrenia. The treatment of cognitive impairment and other residual symptoms associated with schizophrenia, therefore, remains a significant unmet medical need. With current cell-surface receptor-based pharmacology falling short of addressing these core symptoms associated with schizophrenia, more recent approaches to treatment development have focused on processes within the cell. In this review, we discuss the importance of a number of intracellular targets, including cyclic nucleotide phosphodiestereases, and non-phosphodiesterase approaches such as ITI-007, which have been proposed to regulate hyperdopaminergic function, hypoglutamatergic function and/or the delicate balance of the two associated with cognitive deficits in schizophrenia. We also discuss the challenge facing those developing drugs to target specific pathways involved in psychopathology without involving other systems that produce concomitant side effects. PMID- 24345267 TI - The attentional set-shifting test paradigm in rats for the screening of novel pro cognitive compounds with relevance for cognitive deficits in schizophrenia. AB - Cognition deficits in schizophrenia remain an untreated area, and one in which R&D investment by pharmaceutical companies is high. However, whilst many preclinical assays demonstrate pro-cognitive activity with new drugs, in the main, they have not yet been translated successfully to the clinic. In an attempt to address this and reduce the high attrition rate for drugs in the clinic, selected preclinical researchers are re-focusing their efforts on the development and validation of more translational assays. The attentional setshifting task is an example of such an assay, which has been back-translated from the clinic to a preclinical setting. Here we review its application in schizophrenia research across humans and animals, specifically with regards to the neural basis underlying cognitive performance, the various disease-like or symptom models employed in rodents to mimic cognitive dysfunction in schizophrenia, and the resulting impact of drug treatment on executive function. Using the attentional set-shifting task, we highlight the potential promise a more translational approach can bring, whilst demonstrating the need for closer alignment in the validation and integration of this task to fully realize this promise. PMID- 24345269 TI - The novel object recognition test in rodents in relation to cognitive impairment in schizophrenia. AB - Novel object recognition (NOR) in rodents is analogous in some ways to human declarative (episodic) memory, one of the seven cognitive domains which are abnormal in schizophrenia. Cognitive impairment in schizophrenia (CIS) accounts for the largest proportion of the poor functional outcomes in this complex syndrome, with psychosis and negative symptoms accounting for much of the rest. Current atypical antipsychotic drugs (APDs) e.g. amisulpride, aripiprazole, clozapine, lurasidone, olanzapine and risperidone, and typical APDs as well, significantly improve some, but not all aspects of CIS, including declarative memory, but not in all patients, and rarely restore normal function. Thus, finding new ways to prevent or treat CIS is a major goal of current schizophrenia research, with animal models as an essential tool. NOR in rodents is valuable in this regard because of its relationship to declarative memory, the extensive knowledge of its underlying circuitry, and the ease and reliability of assessment. Sub-chronic administration of an N-methyl-Daspartate receptor (NMDAR) non-competitive antagonist, e.g. phencyclidine (PCP), dizocilpine (MK-801) or ketamine, is a favored means to study NOR as a model of CIS, because it produces deficient glutamatergic and GABAergic function, both of which have been implicated in the development of CIS. Transgenic mice and anti-cholinergic induced deficits in NOR have received less attention. We review here NOR studies in rodents that bear upon CIS, including the evidence that atypical, but not typical APDs, as well as specific ligands, e.g. 5-HT1A partial agonists, 5-HT7 antagonists, D1 agonists, among others, can restore NOR following sub-chronic NMDAR antagonist treatment, and can also prevent the impairment in NOR produced by sub-chronic NMDAR antagonists. We discuss how well these findings translate to the bedside. PMID- 24345268 TI - The role of alpha5 GABAA receptor agonists in the treatment of cognitive deficits in schizophrenia. AB - Currently available pharmacotherapies for the treatment of schizophrenia are ineffective in restoring the disrupted cognitive function associated with this disorder. As such, there is a continued search for more viable novel drug targets. Engaging in cognitive behaviors is associated with distinct coordinated oscillatory activity across brain regions, in particular the hippocampus and prefrontal cortex. In schizophrenia patients, pathological alterations in the functionality of GABAergic interneurons in the PFC and HPC responsible for generating network oscillations are thought to contribute to impaired cognition. Destabilized GABAergic interneuron activity in the HPC is further associated with aberrant increases in HPC output and enhanced dopamine neuron activity. Consequently, drugs directed at restoring HPC function could impact both oscillatory activity along with dopamine tone. There is compelling evidence from animal models of schizophrenia that allosteric modulation of the alpha5 subunit of the GABAA receptor is a viable means of resolving aberrant dopamine system activity through indirect alteration of HPC output. Consequently, these compounds are promising for their potential in also ameliorating cognitive deficits attributed to dysfunction in HPC network activity. PMID- 24345270 TI - Salt sensitivity of blood pressure in non-dialysis patients with chronic kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) is a world-wide public health problem. Hypertension is both a cause and a complication of CKD, and a risk factor for progression of kidney disease. The effect of salt intake on blood pressure (BP) and the salt sensitivity in non-dialysis patients with CKD were studied. METHODS: One hundred and thirty non-dialysis patients with CKD were enrolled in the present study. Daily urinary excretion of sodium (representative of daily sodium intake) and BP was monitored in conditions of original eating habits. Estimated glomerular filtration rate (eGFR) was measured by the creatinine clearance (Ccr). RESULTS: There was a linear positive relationship between the salt intake and systolic blood pressure (SBP) (beta = 0.250, p = 0.004). It had been found that the log of BP/24-h urinary sodium (salt sensitivity index) had linear relationship with the log of eGFR (betasyst = -0.364, p = 0.000, betadiast = 0.345, p = 0.000, respectively). Multi-stepwise regression analysis showed SBP was mainly influenced by salt intake and eGFR. There was a negative correlation between diastolic blood pressure (DBP) and age. CONCLUSION: These results demonstrated a linear relationship between the salt intake and SBP in non dialysis patients with CKD. The salt sensitivity of BP rose with the decline of renal function. PMID- 24345265 TI - Going up in smoke? A review of nAChRs-based treatment strategies for improving cognition in schizophrenia. AB - Cognitive impairment is known to be a core deficit in schizophrenia. Existing treatments for schizophrenia have limited efficacy against cognitive impairment. The ubiquitous use of nicotine in this population is thought to reflect an attempt by patients to selfmedicate certain symptoms associated with the illness. Concurrently there is evidence that nicotinic receptors that have lower affinity for nicotine are more important in cognition. Therefore, a number of medications that target nicotinic acetylcholine receptors (nAChRs) have been tested or are in development. In this article we summarize the clinical evidence of nAChRs dysfunction in schizophrenia and review clinical studies testing either nicotine or nicotinic medications for the treatment of cognitive impairment in schizophrenia. Some evidence suggests beneficial effects of nAChRs based treatments for the attentional deficits associated with schizophrenia. Standardized cognitive test batteries have failed to capture consistent improvements from drugs acting at nAChRs. However, more proximal measures of brain function, such as ERPs relevant to information processing impairments in schizophrenia, have shown some benefit. Further work is necessary to conclude that nAChRs based treatments are of clinical utility in the treatment of cognitive deficits of schizophrenia. PMID- 24345271 TI - Physical performance and 25-hydroxyvitamin D: a cross-sectional study of pregnant Swedish and Somali immigrant women and new mothers. AB - BACKGROUND: Severe vitamin D deficiency can impair muscle strength. The study aims were to examine physical performance in the hands and upper legs, and analyze plasma 25-hydroxyvitamin D (25(OH)D) concentrations in women with presumably low (veiled, Somali-born) and high levels (unveiled, Swedish-born). METHODS: Women (n=123, 58% Swedish) enrolled at a Swedish antenatal clinic, latitude 60 degrees N, were recruited. Plasma 25(OH) D was analyzed, measured as nmol/L, then categorized as <10 = undetectable, 10-24, 25-49, 50-74 or >75. Muscle strength was tested: maximal hand grip strength (in Newtons, N), and upper leg performance (categorized as able/unable to perform squatting, standing on one leg, standing from a chair, and lifting their hips). Social and anthropometric data were collected. Non-parametric statistics tested the data for differences in their ability to perform the tests across 25(OH)D categories. Undetectable values (<10 nmol/L) were replaced with '9' in the linear correlation statistics. A final main effect model for grip strength (in N) was calculated using stepwise linear regression for independent variables: country of birth, 25(OH)D levels, age, height, weight, physical activity, lactation status, parity, and gestational age. RESULTS: Somali participants (35%) had 25(OH)D levels of <10 nmol/L, and 90% had <25 nmol/L; 10% of Swedish participants had <25 nmol/L of 25(OH)D, and 54% had <50 nmol/L. Somali women had a relatively weak grip strength compared with Swedish women: median 202 N (inter-quartile range 167-246) vs. median 316 N (inter-quartile range 278-359), respectively. Somali women were also weak in upper leg performance: 73% were unable to squat, 29% unable to stand on one leg, and 21% could not lift their hips (not significant across 25(OH)D categories); most Swedish women could perform these tests. In the final model, grip strength (N) was significantly associated with 25(OH)D levels (B 0.94, p=0.013) together with Somali birth (B -63.9, p<0.001), age (B 2.5, p=0.02) and height (B 2.6, p=0.01). CONCLUSIONS: Many Somali women had undetectable/severely low 25(OH)D concentrations and pronounced hand and upper leg weakness; grip strength was strongly associated with 25(OH)D. Maternity health care personnel should be aware of this increased frequency and manage care accordingly. PMID- 24345272 TI - Acute exposure to low lead levels and its implications on the activity and expression of cytosolic thioredoxin reductase in the kidney. AB - Renal thioredoxin reductase-1 (TrxR-1) activity is stimulated at lead doses lower than that necessary to inhibit delta-aminolevulinate dehydratase activity (delta ALA-D), which is a classical early biomarker of lead effects. Thus, we hypothesized that the activity of TrxR-1 could be a more sensitive early indicator of lead effects than is delta-ALA-D. To evaluate this hypothesis, we assessed the blood and renal TrxR-1 activity and its gene expression along with biomarkers of oxidative damage, antioxidant enzyme activities and biomarkers of lead exposure in rats acutely exposed to lead. A histopathological analysis was performed to verify renal damage. The increase in renal TrxR-1 activity paralleled the increase in the blood and renal lead levels at 6, 24 and 48 hr after the exposure to 25 mg/kg lead acetate (p < 0.05), whereas its expression was increased 24 and 48 hr after exposure. These effects were not accompanied by oxidative or tissue damage in the kidneys. Blood TrxR-1 activity was not affected by lead exposure (up to 25 mg/kg). Erythrocyte delta-ALA-D activity was inhibited 6 hr after the exposure to 25 mg/kg lead acetate (p < 0.05) but recovered thereafter. Renal delta-ALA-D activity decreased 24 and 48 hr after the exposure to 25 mg/kg lead acetate. There were no changes in any parameters at lead acetate doses <25 mg/kg. Our results indicate that blood TrxR-1 activity is not a suitable indicator of lead effects. In contrast, the increase in renal TrxR-1 expression and activity is implicated in the early events of lead exposure, most likely as a protective cellular mechanism against lead toxicity. PMID- 24345273 TI - Design, synthesis, and biological activity of pyridopyrimidine scaffolds as novel PI3K/mTOR dual inhibitors. AB - The design, synthesis, and screening of dual PI3K/mTOR inhibitors that gave nanomolar enzymatic and cellular activities on both targets with an acceptable kinase selectivity profile are described. A docking study was performed to understand the binding mode of the compounds and to explain the differences in biological activity. In addition, cellular effects of the best dual inhibitors were determined on six cancer cell lines and compared to those on a healthy diploid cell line for cellular cytotoxicity. Two compounds are highly potent on cancer cells in the submicromolar range without any toxicity on healthy cells. A more detailed analysis of the cellular effect of these PI3K/mTOR dual inhibitors demonstrated that they induce G1-phase cell cycle arrest in breast cancer cells and trigger apoptosis. These compounds show an interesting kinase profile as dual PI3K/mTOR tool compounds or as a chemical series for further optimization to progress into in vivo experiments. PMID- 24345275 TI - Isomer-specific biodegradation of nonylphenol in river sediments and structure biodegradability relationship. AB - Nonylphenol (NP), a well-known environmental estrogen with numerous isomers, is frequently found in surface water and sediments. Recent studies showed that NP isomers exhibited different estrogenicity. However, at present little information is available on its isomer-specific degradation in the bed sediment, which is the primary sink of NP in surface aquatic systems. In this study, we investigated the biodegradability of 19 NP isomers in two river sediments under oxic and anoxic conditions. Under oxic conditions, the half-lives of NP isomers in an upper river sediment ranged from 0.9 to 13.2 d. Under reduced conditions, the persistence of NP isomers generally increased, with negligible dissipation under strongly reduced conditions. In the well-aerated sediment, NP isomers with short side chain and/or bulky alpha-substituents were found to be more recalcitrant to degradation. Moreover, when a total of 57 molecular descriptors were examined, the degree of branching as quantified by IDWbar was found to result in the best linear correlation with half-lives of NP isomers (R(2) = 0.88). These results indicated that the isomer-specificity of NP in environmental processes should be considered, and that simple molecular descriptors may be used to identify the more recalcitrant isomers, thus allowing prioritization in the evaluation of environmental fate and risks of NP isomers. PMID- 24345274 TI - BRAF-mutated pleomorphic xanthoastrocytoma is associated with temporal location, reticulin fiber deposition and CD34 expression. AB - BRAF V600E mutation and homozygous deletion of CDKN2A (p16) are frequent molecular alterations in pleomorphic xanthoastrocytomas (PXAs). We investigated 49 PXAs for clinical, histological and immunohistochemical characteristics related to BRAF mutation status. BRAF mutation was detected by immunohistochemical assay and DNA sequencing in 38/49 (78%) tumors. All but one PXA located in the temporal lobe harbored a BRAF V600E mutation (23/24; 96%) compared with 10/19 nontemporal PXAs (53%; P = 0.0009). Histological and immunohistochemical analysis demonstrated increased reticulin deposition (76% vs. 27%; P = 0.003) and a more frequent expression of CD34 in BRAF-mutant PXAs (76% vs. 27%; P = 0.003). We further investigated the utility of combined BRAF V600E (VE1) and p16 analysis by immunohistochemistry to distinguish PXAs from relevant histological mimics like giant-cell glioblastoma. Among PXAs, 38/49 (78%) were VE1-positive, and 30/49 (61%) had a loss of p16 expression. The combined features (VE1 positivity/p16 loss) were observed in 25/49 PXAs (51%) but were not observed in giant-cell glioblastoma (VE1 0/28, p16 loss 14/28). We demonstrate that temporal location, reticulin deposition and CD34 expression are associated with BRAF mutation in PXA. Combined VE1 positivity and p16 loss represents a frequent immunoprofile of PXA and may therefore constitute an additional diagnostic tool for its differential diagnosis. PMID- 24345276 TI - Design and static calibration of a six-dimensional force/torque sensor for minimally invasive surgery. AB - INTRODUCTION: The use of surgery robotics is getting more and more important worldwide. In the present study, we propose a novel small-size six-dimensional force/torque sensor with the structure of double cross beams. This technology can be applied in robotic tele-operation systems used in minimally invasive surgery (MIS) robotic systems. MATERIAL AND METHODS: The proposed sensor is made of duralumin which totally meets the stiffness requirement. The output voltage of the sensor will alter with the deformation of the elastic body and strain gauges. The feasibility was discussed by finite element analysis (FEA) and the coupling coefficient matrix was established with dimension reduced according to FEA. In addition, we designed a calibration platform and completed static calibration for the sensor. The methods and principles of measurements and data analysis were provided. RESULTS: The calibration curves and coupling coefficient matrix were acquired by using the least squares method (LSM). CONCLUSION: Experimental tests and calibration error analysis showed that the proposed sensor has high accuracy, appropriate range, and played a role in promoting the application of force feedback technology in MIS. PMID- 24345277 TI - A controlled cohort study of sickness absence and disability pension in colorectal cancer survivors. AB - PURPOSE: To investigate long-term development of sickness absence and disability pension among colorectal cancer (CRC) survivors compared to matched cancer-free controls, and to assess to what degree socio-demographic and disease characteristics influence these outcomes. PATIENTS AND METHODS: In a register based cohort study with data from the Cancer Registry of Norway and longitudinal data from other national registries, 740 patients with CRC diagnosed 1992-1996 at the age 45-54 years were observed up to 14 years post-diagnosis. Also 740 matched controls were observed over the same time period. RESULTS: During the first year after diagnosis, 85% of the CRC survivors were on sick-leave at some point, compared to 19% of the controls. Among survivors with localized cancer, 21% were on sick-leave 12 months after diagnosis, versus 33% with regional, and 52% with distant cancer. Survivors with rectum cancer were more likely than colon cancer survivors to be on sick-leave the first year after diagnosis (OR 2.53, 95% CI 1.61-3.98). CRC survivors were at higher risk for disability pension (DP) than controls, depending on extent of disease. Hazard ratios for DP were 1.67 (95% CI 1.13-2.46) for survivors with localized cancer, 3.12 (95% CI 2.06-4.72) for regional, and 10.13 (95% CI 4.17-24.62) for distant cancer, respectively. In survivors, distant cancer, low level of education, not having children<18 years in the household, pre-diagnostic sick-leave and not being employed at diagnosis were associated with increased likelihood for DP. CONCLUSION: A considerable proportion of CRC survivors, for years after diagnosis, will experience reduced work ability compared to controls. Rehabilitation and workplace adjustment to reduce sickness absence and improve work ability should be a long-term concern. PMID- 24345278 TI - Angiosarcoma after breast-conserving therapy: long-term disease control and late effects with hyperfractionated accelerated re-irradiation (HART). AB - BACKGROUND: Secondary angiosarcoma is a malignant cancer that develops in approximately 1% of patients treated with breast-conserving therapy (BCT) for primary breast cancer. Most treatments for secondary angiosarcoma have been unsuccessful and no consensus has been reached on what is the best therapeutic strategy. We report long-term outcomes of patients with secondary angiosarcoma treated with hyperfractionated and accelerated re-irradiation (HART). MATERIAL AND METHODS: We retrospectively reviewed the medical records of, and established direct contact with, 14 consecutive patients with secondary angiosarcoma after BCT with axillary lymph node dissection who were treated at our institution with HART with or without surgery from November 1997 to March 2006. With HART, patients received three radiation therapy treatments each day, with a minimum interfraction interval of four hours, five days a week, at 1 Gy per fraction, to total doses of 45 Gy, 60 Gy, and 75 Gy for areas with a moderate risk for subclinical disease, a high risk for subclinical disease, and gross disease, respectively. The minimum follow-up for these patients was six years. RESULTS: Median survival was 7.0 years (range 0.4-14.7 years), with five- and 10-year overall survival rates of 79% [95% confidence interval (CI), 51-93%] and 63% (95% CI 37-84%), respectively, and five- and 10-year cause-specific survival rates of 79% (95% CI 51-93%) and 71% (95% CI 44-89%), respectively. Toxicity was minimal. CONCLUSION: Our long-term study provides evidence that patients with secondary angiosarcoma after BCT can frequently be cured. Patients treated with HART have higher overall survival, progression-free survival, and cause-specific survival rates than patients who receive only surgery, conventional radiation therapy, or chemotherapy. HART is well tolerated. PMID- 24345279 TI - Correlations between colonic crypt mucin chemotype, inflammatory grade and Desulfovibrio species in ulcerative colitis. AB - AIM: The colonic mucus gel layer is composed of mucins that may be sulphated or sialyated. Sulphated mucins predominate in health while in ulcerative colitis (UC) sulphation is reduced. These differences result directly from inflammatory events. It may also be hypothesized that they arise in part from alterations in the colonic microbiota, particularly changes in the burden of sulphated mucin metabolizing species, such as Desulfovibrio (DSV) bacteria. The aim of this study was to correlate colonic mucin chemotypes and inflammatory scores in health and UC and relate these changes to changes in the colonization of colonic crypts by DSV. METHOD: Paired colonic biopsies from 34 healthy controls (HC) and 19 patients with active UC were collected for the purpose of parallel histological and microbiological assessment. High-iron diamine and Alcian blue staining and haematoxylin and eosin of mucosal biopsy specimens were used to assess histological changes within the clinical spectrum of UC. Quantitative real-time polymerase chain reaction analysis was employed to determine the total and DSV copy number within the colonic crypts. RESULTS: Compared with HC, the mucin chemotype in UC was less sulphated and inversely correlated with the degree of mucosal inflammation. A weak but significant negative correlation was found between the abundance of sulphated mucins and DSV burden. CONCLUSION: Mucin composition strongly correlates with the degree of mucosal inflammation, and to a lesser extent with DSV burden. These data suggest that mucin chemotype and DSV burden are linked phenomena and highlight the need to consider changes in mucin chemotype in the setting of microbial dysbiosis occurring within the colitic colon. What does this paper add to the literature? Decreased sulphation of mucins has been associated with inflammation in ulcerative colitis. Currently there are few data describing the relationship between microbial species and changes in mucin chemotype. This study validates previous findings and presents evidence of changes in mucin chemotype occurring in tandem with coherent changes in the microbiota within crypt niches. PMID- 24345280 TI - Medical tourism in India: perceptions of physicians in tertiary care hospitals. AB - Senior physicians of modern medicine in India play a key role in shaping policies and public opinion and institutional management. This paper explores their perceptions of medical tourism (MT) within India which is a complex process involving international demands and policy shifts from service to commercialisation of health care for trade, gross domestic profit, and foreign exchange. Through interviews of 91 physicians in tertiary care hospitals in three cities of India, this paper explores four areas of concern: their understanding of MT, their views of the hospitals they work in, perceptions of the value and place of MT in their hospital and their views on the implications of MT for medical care in the country. An overwhelming majority (90%) of physicians in the private tertiary sector and 74.3 percent in the public tertiary sector see huge scope for MT in the private tertiary sector in India. The private tertiary sector physicians were concerned about their patients alone and felt that health of the poor was the responsibility of the state. The public tertiary sector physicians' however, were sensitive to the problems of the common man and felt responsible. Even though the glamour of hi-tech associated with MT dazzled them, only 35.8 percent wanted MT in their hospitals and a total of 56 percent of them said MT cannot be a public sector priority. 10 percent in the private sector expressed reservations towards MT while the rest demanded state subsidies for MT. The disconnect between their concern for the common man and professionals views on MT was due to the lack of appreciation of the continuum between commercialisation, the denial of resources to public hospitals and shift of subsidies to the private sector. The paper highlights the differences and similarities in the perceptions and context of the two sets of physicians, presents evidence, that questions the support for MT and finally analyzes some key implications of MT on Indian health services, ethical issues emerging out of that and the need for understanding the linkages between public and private sectors for a more effective intervention for an equitable medical care policy. PMID- 24345282 TI - Single-step delamination of a MWW borosilicate layered zeolite precursor under mild conditions without surfactant and sonication. AB - Layered borosilicate zeolite precursor ERB-1P (Si/B = 11) is delaminated via isomorphous substitution of Al for B using a simple aqueous Al(NO3)3 treatment. Characterization by PXRD shows loss of long-range order, and TEM demonstrates transformation of rectilinear layers in the precursor to single and curved layers in the delaminated material. N2 physisorption and base titration confirm the expected decrease of micropore volume and increase in external surface area for delaminated materials relative to their calcined 3D zeolite counterpart, whereas FTIR and multinuclear NMR spectroscopies demonstrate synthesis of Bronsted acid sites upon delamination. Comparative synthetic studies demonstrate that this new delamination method requires (i) a borosilicate layered zeolite precursor, in which boron atoms can be isomorphously substituted by aluminum, (ii) neutral amine pore fillers instead of rigid and large quaternary amine SDAs, and (iii) careful temperature control, with the preferred temperature window being around 135 degrees C for ERB-1P delamination. Acylation of 2-methoxynaphthalene was used as a model reaction to investigate the catalytic benefits of delamination. A partially dealuminated delaminated material displays a 2.3-fold enhancement in its initial rate of catalysis relative to the 3D calcined material, which is nearly equal to its 2.5-fold measured increase in external surface area. This simple, surfactant- and sonication-free, mild delamination method is expected to find broad implementation for the synthesis of delaminated zeolite catalysts. PMID- 24345281 TI - Clinical outcomes among renal transplant recipients with pre-transplant weakly reactive donor-specific antibodies. AB - BACKGROUND: Alloantibody can lead to antibody-mediated rejection and graft loss in renal transplantation, necessitating an assessment of cross-match compatibility. Within the past decade, more specific solid phase assays of alloantibody have been widely adopted, allowing virtual cross-matching based on unacceptable antigens, the threshold of which is determined by individual centers. METHODS: We examined the clinical outcomes of 482 patients transplanted 2007-2009 in a single center, focusing on 30 patients with weakly reactive donor specific antibody (DSA) determined prospectively prior to renal transplant. RESULTS: Compared with patients without DSA, patients with weakly reactive DSA do not have increased rates of antibody-mediated rejection, cellular rejection, or graft loss despite conventional immunosuppression utilization. CONCLUSIONS: Using the screening methodology and immunosuppression regimen, we have applied to the patients with weak DSA allows them to be transplanted with equivalent outcomes as those without DSA, despite the overall higher risk characteristics of the patients in the weak DSA group. PMID- 24345283 TI - Dehydroascorbate: a possible surveillance molecule of oxidative stress and programmed cell death in the green alga Chlamydomonas reinhardtii. AB - Chlamydomonas reinhardtii tolerates relatively high H2 O2 levels that induce an array of antioxidant activities. However, rather than rendering the cells more resistant to oxidative stress, the cells become far more sensitive to an additional H2 O2 dose. If H2 O2 is provided 1.5-9 h after an initial dose, it induces programmed cell death (PCD) in the wild-type, but not in the dum1 mutant impaired in the mitochondrial respiratory complex III. This mutant does not exhibit a secondary oxidative burst 4-5 h after the inducing H2 O2 , nor does it activate metacaspase-1 after the second H2 O2 treatment. The intracellular dehydroascorbate level, a product of ascorbate peroxidase, increases under conditions leading to PCD. The addition of dehydroascorbate induces PCD in the wild-type and dum1 cultures, but higher levels are required in dum1 cells, where it is metabolized faster. The application of dehydroascorbate induces the expression of metacaspase-2, which is much stronger than the expression of metacaspase-1. The presence or absence of oxidative stress, in addition to the rise in internal dehydroascorbate, may determine which metacaspase is activated during Chlamydomonas PCD. Cell death is strongly affected by the timing of H2 O2 or dehydroascorbate admission to synchronously grown cultures, suggesting that the cell cycle phase may distinguish cells that perish from those that do not. PMID- 24345284 TI - Historical and non-invasive samples: a study case of genotyping errors in newly isolated microsatellites for the lesser anteater (Tamandua tetradactyla L., Pilosa). AB - Tamandua tetradactyla (Pilosa), the lesser anteater, is a medium-size mammal from South America. Its wide distribution through different landscapes, solitary and nocturnal habits, and the difficulty to capture and contain specimens limit the amount of individuals and populations sampled during fieldworks. These features along with the lack of specific molecular markers for the lesser anteater might be the causes for paucity in population genetic studies for the species. Historical samples from museum specimens, such as skins, and non-invasive samples, such as plucked hair, can be supplementary sources of DNA samples. However, the DNA quantity and quality of these samples may be limiting factors in molecular studies. In this study, we describe nine microsatellite loci for T. tetradactyla and test the amplification success, data reliability and estimate errors on both historical and non-invasive sample sets. We tested nine polymorphic microsatellites and applied the quality index approach to evaluate the relative performance in genotype analysis of 138 historical samples (study skin) and 19 non-invasive samples (plucked hair). The observed results show a much superior DNA quality of non-invasive over historical samples and support the quality index analysis as a practical tool to exclude samples with doubtful performance in genetic studies. We also found a relationship between the age of non-invasive samples and DNA quality, but lack of evidence of this pattern for historical samples. PMID- 24345285 TI - Gait algorithm of personal mobility vehicle for negotiating obstacles. AB - PURPOSE: Personal mobility vehicles (PMVs) are under active development. Most PMVs are wheel-driven, a mode of transport notable for its efficiency. However, wheeled PMVs tend to have poor mobility against negotiating obstacles. The four wheeled vehicle RT-Mover PType 3 has been developed featuring wheeled legs capable of leg motion. This allows the PMV to overcome uneven terrains, including a step approached at an angle, which ordinary wheelchairs cannot negotiate. METHOD: This article discusses a gait algorithm in which a leg executes the necessary leg motion when optionally presented with obstacles on a road. In order to lift a wheel off the ground and perform a leg motion, the support wheels must be moved to support points to ensure that the vehicle remains stable on three wheels. When moving towards the target support point, a wheel may encounter another obstacle, and a response method for this case is also described. RESULTS: To assess the gait algorithm, several configurations of obstacles were used for performance tests with a passenger. The capabilities of the PMV were demonstrated through experiments. CONCLUSION: We proposed a novel gait algorithm for our PMV and realised the proposed motion pattern for PMV-based negotiating obstacles. IMPLICATIONS FOR REHABILITATION: Our single-seat personal mobility vehicle, RT Mover PType 3 features wheels attached on legs capable of performing leg motion, which allows the vehicle to traverse rough terrains in urban areas. We proposed a gait algorithm for RT-Mover PType 3 consisting of a series of leg motions in response to rough terrain. With this algorithm, the vehicle can traverse not only randomly placed obstacles, but also a step approached at an oblique angle, which conventional powered wheelchairs cannot navigate. Experiments with a passenger demonstrated the effectiveness of the proposed gait algorithm, suggesting that RT Mover PType 3 can expand the mobility and range of activities of wheelchair users. PMID- 24345288 TI - Measuring the perception of symptom, drug use and allergen immunotherapy efficacy using the Visual Analogue Scale. AB - The availability of a simple and reliable tool for quantitatively measuring symptom perception is surely very important in the daily practice. Especially, this concept appears to be fundamental in doctor's office and at home, where there are no adequate resources. The Visual Analogue Scale is a very simple and popular tool that could be used by anyone anywhere. The advantage given by the Visual Analogue Scale consists in the translation of a subjective sensation in an objective measure provided by numbers. PMID- 24345287 TI - Intramyocardial injection of a synthetic hydrogel with delivery of bFGF and IGF1 in a rat model of ischemic cardiomyopathy. AB - It is increasingly appreciated that the properties of a biomaterial used in intramyocardial injection therapy influence the outcomes of infarcted hearts that are treated. In this report the extended in vivo efficacy of a thermally responsive material that can deliver dual growth factors while providing a slow degradation time and high mechanical stiffness is examined. Copolymers consisting of N-isopropylacrylamide, 2-hydroxyethyl methacrylate, and degradable methacrylate polylactide were synthesized. The release of bioactive basic fibroblast growth factor (bFGF) and insulin-like growth factor 1 (IGF1) from the gel and loaded poly(lactide-co-glycolide) microparticles was assessed. Hydrogel with or without loaded growth factors was injected into 2 week-old infarcts in Lewis rats and animals were followed for 16 weeks. The hydrogel released bioactive bFGF and IGF1 as shown by mitogenic effects on rat smooth muscle cells in vitro. Cardiac function and geometry were improved for 16 weeks after hydrogel injection compared to saline injection. Despite demonstrating that left ventricular levels of bFGF and IGF1 were elevated for two weeks after injection of growth factor loaded gels, both functional and histological assessment showed no added benefit to inclusion of these proteins. This result points to the complexity of designing appropriate materials for this application and suggests that the nature of the material alone, without exogenous growth factors, has a direct ability to influence cardiac remodeling. PMID- 24345289 TI - Amniotic membrane transplantation ineffective as additional therapy in patients with aggressive Mooren's ulcer. AB - BACKGROUND: Mooren's ulcer is a severe ulcerative inflammation of the cornea. The exact pathogenesis remains unclear. Therefore many therapies of Mooren's ulcer are recommended in literature. To shed more light on the ongoing question of optimal treatment of severe progressive Mooren's ulcer, we here report on a retrospective case series of patients treated with systemic immunosuppressive therapy and additional amniotic membrane transplantation. METHODS: Medical records from seven patients (eleven eyes), 4 male and 3 female, with severe progressive Mooren's ulcer were analysed retrospectively. The mean follow up was 88.4 +/- 80.8 months (range 12-232 month). A HLA-typing was performed in all patients. A systemic immunosuppressive therapy was administered in all patients. The amniotic membrane was transplanted after the base of the ulcer was resected. RESULTS: Multiple amniotic membrane transplantations were necessary in six patients. The visual outcome of all patients was poor. No patient achieved a visual acuity better than 20/630 Snellen chart. Five patients were positive for HLA-DQ2 and four patients were positive for HLA-DR17(3). CONCLUSIONS: The aggressive and highly inflammatory form of Mooren's ulcer is difficult to treat and the progression of the disease is hard to influence positively even under systemic immunosuppressive therapy. Therefore, the main intention of therapy is to achieve a stable epithelialized corneal surface without the risk of perforation. Amniotic membrane transplantation is not able to cure severe forms of Mooren's ulcer. However it supports the immunosuppressive therapy in acute situations as in critical corneal thinning. PMID- 24345290 TI - 4 G/4 G polymorphism of plasminogen activator inhibitor-1 gene increases the risk of diabetic nephropathy. AB - Diabetic nephropathy (DN) has become the most common pathogenesis of end-stage renal disease. Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the pathogenesis of DN. A meta-analysis was conducted to investigate the association between 4 G/5 G variants in the PAI-1 gene and DN susceptibility. Databases including Pubmed, EMBASE, ISI, etc., were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of associations. Ten studies involving 1366 cases and 1888 controls were included. Significant association between 4 G/4 G variant and DN risk was observed (OR 1.26, 95% CI 1.08-1.48, p = 0.004) in overall populations by the recessive model. 4 G allele was also associated with the risk of DN than the 5 G allele (OR 1.15, 95% CI 1.04-1.27, p = 0.008). In the subgroup analysis performed by the ethnicity, 4 G/4 G polymorphism was significantly associated with DN risk than 4 G/5 G + 5 G/5 G in East Asians (OR 1.42, 95% CI 1.03-1.96; p = 0.03), but not in Caucasians. In the stratified analysis by types of DM, the results showed significant association between 4 G/4 G variant and DN in Type-2 DM (OR 1.42, 95% CI 1.03-1.96, p = 0.03). In conclusion, 4 G/4 G phenotype of PAI 1 gene may be associated with DN risk. Additional larger studies should be conducted in future analyses. PMID- 24345291 TI - Are available electrocardiographic methods accurate enough to diagnose ventricular tachycardia in the emergency department? PMID- 24345292 TI - The expression of relaxin-3 in adipose tissue and its effects on adipogenesis. AB - Energy homeostasis is regulated by endocrine factors. The concentration of relaxin-3 in serum is related to body mass index. However, relaxin-3 is found only in the brain and testis. In this study, we examined the expression of relaxin- 3 in adipose tissue and its effects on adipogenesis. The expression of relaxin-3 was determined using RT-PCR, a relaxin- 3 C-peptide-specific radioimmunoassay, specifically in the stromal-vascular fraction (SVF) cells rather than adipocytes. The release of C-peptide was regulated by glucose concentration in the SVF cells. However, the differentiated adipocytes did not express relaxin-3. In glucose perfusion experiments, C-peptide was released in response to high glucose concentrations in the mesenteric perfusate, opposite to insulin release. Additionally, GPCR135 mRNA was expressed in adipocytes. Relaxin 3 increased triglycerides in adipocytes and decreased lipase activity. The present study showed that relaxin-3 is secreted from SVF cells and that it regulates lipid accumulation in adipocytes. PMID- 24345294 TI - Lipid bilayer phase transformations detected using microcantilevers. AB - We report the use of microcantilevers to measure the phase transition temperature (T(m)) of supported lipid bilayers or lipid monolayers. During the solid-liquid phase transition, a supported lipid bilayer or monolayer undergoes a conformational change in which the lipid acyl chains transition from an ordered state to a disordered state. This process is accompanied by a free energy change, which is coupled to changes in the surface stress in the underlying solid support layer. These surface stress changes can be readily detected using microcantilevers. The surface stress of the solid-like phase of 1-myristoyl-2 palmitoyl-sn-glycero-3-phosphocholine (MPPC) decreases linearly as the temperature increases and abruptly jumps at the main phase transition temperature. This phase transition temperature corresponds well with that found for free membranes. For an MPPC monolayer, this phase transition temperature is shifted, indicating that the existence of the solid support affects the monolayer structure. The addition of cholesterol into the bilayer decreases the phase transition temperature by ~0.38 degrees C per mol % of cholesterol. Differences in MPPC stability when it is either a bilayer or a monolayer can be detected through these sensitive surface stress measurements. PMID- 24345293 TI - Low prolactin is associated with sexual dysfunction and psychological or metabolic disturbances in middle-aged and elderly men: the European Male Aging Study (EMAS). AB - INTRODUCTION: We previously reported that in male patients consulting for sexual dysfunction, low prolactin (PRL) levels were associated with metabolic syndrome (MetS), arteriogenic erectile dysfunction, and incident major cardiovascular events. AIM: The aim of this study is to assess the clinical associations of PRL levels in the European Male Ageing Study (EMAS). METHODS: EMAS is a prospective, observational cohort of community-dwelling men aged 40-79 years old (mean age 60 +/- 11 years old). PRL was available for 2,948 men. MAIN OUTCOME MEASURES: Different parameters were evaluated including the Short Form-36 questionnaire, Becks Depression Inventory, the Adverse Life Events Scale, the Physical Activity Scale for the Elderly, and the EMAS sexual function questionnaire (EMAS-SFQ). RESULTS: After the adjustment for confounders, PRL levels were inversely related with worsening of sexual function as compared with the previous year, as derived from change in sexual functioning domain of the EMAS-SFQ (adj. r = -0.043; P = 0.029). The strongest correlation (Wald = 6.840; P = 0.009) was observed between lower PRL levels and reduced enjoyment of orgasmic experiences. Furthermore, an inverse relationship between PRL levels and stressful life events or depressive symptoms was observed. Low PRL was also negatively associated with an unhealthy metabolic phenotype as well as with the MetS (Wald = 5.229; P = 0.022). In line with these data, low PRL was associated with a lower level of physical activity and feeling unhealthier. CONCLUSIONS: Low PRL is related to several metabolic, psychological, and sexual unhealthy characteristics in European men. Checking PRL might be useful to stratify men for cardiovascular risk and to encourage appropriate lifestyle changes. PMID- 24345295 TI - Predictors of early postoperative pain after stapled haemorrhoidopexy. AB - AIM: Moderate to severe pain after stapled haemorrhoidopexy (SH) is not uncommon. This study was designed to identify the predictors of postoperative pain after SH in a single centre. METHOD: Seventy-six patients with Grade II to IV haemorrhoids who underwent SH were selected from a prospectively compiled database. Preoperative data, including patient characteristics, manometry results and surgical data, were documented. Pain was evaluated during the first 24 h after the operation. Its intensity was classified into three grades according to the visual analogue scale (VAS) score: mild (VAS <= 3), moderate (VAS >3 to <5) and severe (VAS >= 5). Analgesics were not routinely given but were administered if the patient had moderate or severe pain. Both univariate and multivariate analyses were used to determine the predictors of postoperative pain. RESULTS: Moderate and severe pain was noted in 43 (58.9%) patients. No patient was readmitted due to persistent anal pain during the month following discharge. Postoperative pain was significantly associated with gender (P = 0.017), age (P = 0.014), first initial sensory volume (P = 0.023) and constipation (P = 0.005) in univariate analysis. Multivariate analysis identified male gender as an independent predictor of postoperative moderate to severe pain (P = 0.037, OR = 3.1, 95% CI 1.07-9.09). The initial sensory volume and preoperative coexisting constipation were negative predictors of postoperative moderate to severe pain after SH (P = 0.037, OR = 0.320, 95% CI 0.110-0.934, and P = 0.036, OR = 0.255, 95% CI 0.071-0.913, respectively). CONCLUSION: Male gender and the initial sensory volume are predictors of postoperative pain after SH. Anal manometry is recommended before the SH procedure. An active analgesia protocol should be considered for male patients with a low initial sensory volume after SH. PMID- 24345296 TI - Correlations between mass activity and physicochemical properties of Fe/N/C catalysts for the ORR in PEM fuel cell via 57Fe Mossbauer spectroscopy and other techniques. AB - The aim of this work is to clarify the origin of the enhanced PEM-FC performance of catalysts prepared by the procedures described in Science 2009, 324, 71 and Nat. Commun. 2011, 2, 416. Catalysts were characterized after a first heat treatment in argon at 1050 degrees C (Ar) and a second heat treatment in ammonia at 950 degrees C (Ar + NH3). For the NC catalysts a variation of the nitrogen precursor was also implemented. (57)Fe Mossbauer spectroscopy, X-ray photoelectron spectroscopy, neutron activation analysis, and N2 sorption measurements were used to characterize all catalysts. The results were correlated to the mass activity of these catalysts measured at 0.8 V in H2/O2 PEM-FC. It was found that all catalysts contain the same FeN4-like species already found in INRS Standard (Phys. Chem. Chem. Phys. 2012, 14, 11673). Among all FeN4-like species, only D1 sites, assigned to FeN4/C, and D3, assigned to N-FeN2+2 /C sites, were active for the oxygen reduction reaction (ORR). The difference between INRS Standard and the new catalysts is simply that there are many more D1 and D3 sites available in the new catalysts. All (Ar + NH3)-type catalysts have a much larger porosity than Ar-type catalysts, while the maximum number of their active sites is only slightly larger after a second heat treatment in NH3. The large difference in activity between the Ar-type catalysts and the Ar + NH3 ones stems from the availability of the sites to perform ORR, as many sites of the Ar-type catalysts are secluded in the material, while they are available at the surface of the Ar + NH3-type catalysts. PMID- 24345297 TI - The 50-year anniversary of Acta Oncologica. PMID- 24345298 TI - Stronger transferability but lower variability in transcriptomic- than in anonymous microsatellites: evidence from Hylid frogs. AB - A simple way to quickly optimize microsatellites in nonmodel organisms is to reuse loci available in closely related taxa; however, this approach can be limited by the stochastic and low cross-amplification success experienced in some groups (e.g. amphibians). An efficient alternative is to develop loci from transcriptome sequences. Transcriptomic microsatellites have been found to vary in their levels of cross-species amplification and variability, but this has to date never been tested in amphibians. Here, we compare the patterns of cross amplification and levels of polymorphism of 18 published anonymous microsatellites isolated from genomic DNA vs. 17 loci derived from a transcriptome, across nine species of tree frogs (Hyla arborea and Hyla cinerea group). We established a clear negative relationship between divergence time and amplification success, which was much steeper for anonymous than transcriptomic markers, with half-lives (time at which 50% of the markers still amplify) of 1.1 and 37 My, respectively. Transcriptomic markers are significantly less polymorphic than anonymous loci, but remain variable across diverged taxa. We conclude that the exploitation of amphibian transcriptomes for developing microsatellites seems an optimal approach for multispecies surveys (e.g. analyses of hybrid zones, comparative linkage mapping), whereas anonymous microsatellites may be more informative for fine-scale analyses of intraspecific variation. Moreover, our results confirm the pattern that microsatellite cross-amplification is greatly variable among amphibians and should be assessed independently within target lineages. Finally, we provide a bank of microsatellites for Palaearctic tree frogs (so far only available for H. arborea), which will be useful for conservation and evolutionary studies in this radiation. PMID- 24345299 TI - The South Carolina LGBT needs assessment: a descriptive overview. AB - Limited quantitative information exists about the demographics and needs of lesbian, gay, bisexual, and transgender (LGBT) persons in South Carolina, a predominately rural Southern state. Responses to a needs assessment survey (n = 715) were analyzed to understand the diversity and needs of members of the LGBT community in SC. The purpose was to inform future programming and guide the development of a more comprehensive portfolio of services to be offered by a local LGBT community center. Findings suggest that a diverse LGBT community exists in SC and needs include increased programming for community members as well as efforts to provide policy-level support and increased acceptability and understanding of LGBT persons in South Carolina. PMID- 24345300 TI - Pathological changes, TGF-beta1 expression, and the effects of hepatocyte growth factor in 5/6 nephrectomized rats. AB - Several studies have shown that hepatocyte growth factor (HGF) ameliorates chronic renal failure, but its mechanism of action is unclear. This study was designed to test the delivery of HGF in the PCI-neo vector, using the 5/6 nephrectomized rat as a model for chronic renal failure, and to confirm that this protective function is associated with decreased protein expression of transforming growth factor-beta1 (TGF-beta1). Rats were randomly divided into the following groups: Control (untreated), PCI-neo (vector control), 5/6 nephrectomy, and PCI-neo-HGF. Rats were sacrificed at both the fifth and ninth week after 5/6 nephrectomy. Kidney specimens were used for pathological examination (hematoxylin eosin staining), and detection of TGF-beta1 protein (Western blot and immunohistochemistry) expression. Blood urea nitrogen, serum creatinine, and 24-h urinary protein excretion (UPE) were increased, renal interstitium was seriously injured, and TGF-beta1 protein expression was elevated in 5/6 nephrectomized rats compared to control rats at either time point. Red blood cell and hemoglobin levels decreased in the ninth week after 5/6 nephrectomy. PCI-neo-HGF expression ameliorated the aforementioned changes and decreased TGF-beta1 expression, not only in the fifth week, but also in the ninth week after surgery. The process of renal injury in the 5/6 nephrectomized rat was consistent with that of chronic renal failure. The increase in TGF-beta1 expression was maintained after 5/6 nephrectomy. HGF relieved chronic renal failure, this protection was associated with down-regulation of TGF-beta1 protein expression, and the protective effects were long-term and stable after 5/6 nephrectomy. PMID- 24345301 TI - The world's tallest trees grow in thermally similar climates. PMID- 24345302 TI - Pulmonary atresia and intact ventricular septum with transposed arterial trunks. AB - We report a case of pulmonary atresia with intact ventricular septum, but in the setting of transposed great arteries, and thus the left rather than the right ventricle was hypoplastic. PMID- 24345304 TI - QT interval prolongation in users of selective serotonin reuptake inhibitors in an elderly surgical population: a cross-sectional study. AB - OBJECTIVE: To investigate the association between the use of a selective serotonin reuptake inhibitor (SSRI) and the occurrence of QT interval prolongation in an elderly surgical population. METHOD: A cross-sectional study was conducted among patients (> 60 years) scheduled for outpatient preanesthesia evaluation in the period 2007 until 2012. The index group included elderly users of an SSRI. The reference group of nonusers of antidepressants was matched to the index group on sex and year of scheduled surgery (ratio, 1:1). The primary outcome was the occurrence of QT interval prolongation shown on electrocardiogram. The QT interval was corrected for heart rate (QTc interval). The secondary outcome was the duration of the QTc interval. The outcomes were adjusted for confounding by using regression techniques. RESULTS: The index and reference groups included 397 users of an SSRI and 397 nonusers, respectively. QTc interval prolongation occurred in 25 (6%) and 19 (5%) index and reference patients, respectively. After adjustment for confounding, users of an SSRI did not have a higher risk for QTc interval prolongation compared to nonusers: OR = 1.1 (95% CI, 0.5 to 2.0). The adjusted mean QTc interval length in users of an SSRI and nonusers was comparable (difference of 1.5 milliseconds [95% CI, -1.8 to 4.8]). Use of the most frequently used SSRIs citalopram and paroxetine was not associated with a higher risk of QTc interval prolongation nor with lengthening of the QTc interval duration. CONCLUSIONS: The use of an SSRI by elderly surgical patients was not associated with the occurrence of QT interval prolongation. PMID- 24345306 TI - Collisions of sodium atoms with liquid glycerol: insights into solvation and ionization. AB - The reactive uptake and ionization of sodium atoms in glycerol were investigated by gas-liquid scattering experiments and ab initio molecular dynamics (AIMD) simulations. A nearly effusive beam of Na atoms at 670 K was directed at liquid glycerol in vacuum, and the scattered Na atoms were detected by a rotatable mass spectrometer. The Na velocity and angular distributions imply that all impinging Na atoms that thermally equilibrate on the surface remain behind, likely ionizing to e(-) and Na(+). The reactive uptake of Na atoms into glycerol was determined to be greater than 75%. Complementary AIMD simulations of Na striking a 17 molecule glycerol cluster indicate that the glycerol hydroxyl groups reorient around the Na atom as it makes contact with the cluster and begins to ionize. Although complete ionization did not occur during the 10 ps simulation, distinct correlations among the extent of ionization, separation between Na(+) and e(-), solvent coordination, and binding energies of the Na atom and electron were observed. The combination of experiments and simulations indicates that Na-atom deposition provides a low-energy pathway for generating solvated electrons in the near-interfacial region of protic liquids. PMID- 24345303 TI - Surgical neuroanatomy and programming in deep brain stimulation for obsessive compulsive disorder. AB - OBJECTIVES: Deep brain stimulation (DBS) has been established as a safe, effective therapy for movement disorders (Parkinson's disease, essential tremor, etc.), and its application is expanding to the treatment of other intractable neuropsychiatric disorders including depression and obsessive-compulsive disorder (OCD). Several published studies have supported the efficacy of DBS for severely debilitating OCD. However, questions remain regarding the optimal anatomic target and the lack of a bedside programming paradigm for OCD DBS. Management of OCD DBS can be highly variable and is typically guided by each center's individual expertise. In this paper, we review the various approaches to targeting and programming for OCD DBS. We also review the clinical experience for each proposed target and discuss the relevant neuroanatomy. MATERIALS AND METHODS: A PubMed review was performed searching for literature on OCD DBS and included all articles published before March 2012. We included all available studies with a clear description of the anatomic targets, programming details, and the outcomes. RESULTS: Six different DBS approaches were identified. High-frequency stimulation with high voltage was applied in most cases, and predictive factors for favorable outcomes were discussed in the literature. CONCLUSION: DBS remains an experimental treatment for medication refractory OCD. Target selection and programming paradigms are not yet standardized, though an improved understanding of the relationship between the DBS lead and the surrounding neuroanatomic structures will aid in the selection of targets and the approach to programming. We propose to form a registry to track OCD DBS cases for future clinical study design. PMID- 24345307 TI - Observer-rated depression in long-term care: frequency and risk factors. AB - The objectives of this study were: (1) to describe the prevalence and 6-month incidence of observer-rated depression in residents age 65 and over of long-term care (LTC) facilities; (2) to describe risk factors for depression, at baseline and over time. A multisite, prospective observational study was conducted in residents aged 65 and over of 7 LTC facilities. The Cornell Scale for Depression in Dementia (CSDD) was completed by nurses monthly for 6 months. We measured demographic, medical, and functional factors at baseline and monthly intervals, using data from research assessments, nurse interviews, and chart reviews. 274 residents were recruited and completed baseline depression assessments. The prevalence of depression (CSDD score of 6+) was 19.0%. The incidence of depression among those without prevalent depression was 73.3 per 100 person years. A delirium diagnosis, pain, and diabetes were independently associated with prevalent depression. CSDD score at baseline and development of severe cognitive impairment at follow-up were independent risk factors for incident depression. A diagnosis of delirium and uncorrected visual impairment at follow up occurred concurrently with incident depression. The results of this study have implications for the detection and prevention of depression in LTC. Delirium diagnosis, pain and diabetes at baseline were associated with prevalent depression; depression symptoms at baseline and development of severe cognitive impairment at follow-up were risk factors for incident depression. PMID- 24345305 TI - Clinical prediction models for bronchopulmonary dysplasia: a systematic review and external validation study. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Very different models using clinical parameters at an early postnatal age to predict BPD have been developed with little extensive quantitative validation. The objective of this study is to review and validate clinical prediction models for BPD. METHODS: We searched the main electronic databases and abstracts from annual meetings. The STROBE instrument was used to assess the methodological quality. External validation of the retrieved models was performed using an individual patient dataset of 3229 patients at risk for BPD. Receiver operating characteristic curves were used to assess discrimination for each model by calculating the area under the curve (AUC). Calibration was assessed for the best discriminating models by visually comparing predicted and observed BPD probabilities. RESULTS: We identified 26 clinical prediction models for BPD. Although the STROBE instrument judged the quality from moderate to excellent, only four models utilised external validation and none presented calibration of the predictive value. For 19 prediction models with variables matched to our dataset, the AUCs ranged from 0.50 to 0.76 for the outcome BPD. Only two of the five best discriminating models showed good calibration. CONCLUSIONS: External validation demonstrates that, except for two promising models, most existing clinical prediction models are poor to moderate predictors for BPD. To improve the predictive accuracy and identify preterm infants for future intervention studies aiming to reduce the risk of BPD, additional variables are required. Subsequently, that model should be externally validated using a proper impact analysis before its clinical implementation. PMID- 24345308 TI - Health-related services use and the onset of functional disability: 10 year follow-up study. AB - This study aimed to examine the effect of health-related service use on the development of functional disability in an older adult Taiwanese cohort. The sample population consisted of 871 participants without Instrumental Activities of Daily Living (IADL) disabilities, 1061 participants without Activities of Daily Living (ADL) disabilities and 817 participants without IADL and ADL disabilities at baseline. The onset of IADL and ADL disabilities were estimated as the follow-up survey year that these functional disabilities were first noted, or the follow-up survey year that the participant was noted as having died. A Cox proportional hazards model, with time-dependent covariates, was used to analyze the association between the time of onset of the functional disabilities and the health-related service use, after controlling for age, gender, education, marital status and time varying chronic disease status. This study found that an increase in the number of services used by the participants resulted in fewer IADL and ADL disabilities. Furthermore, participants who attended recreational programs, regular health examinations, and who received the information assistance and meal preparation were significantly less likely to develop disabilities. Participants who used one or more services were 55-77% less likely to be IADL disabled, and were 54-81% less likely to be ADL disabled, and were also 59-89% less likely to develop IADL and ADL disabilities as compared to those who used none. In the present study therefore, as the number of health services used increased the likelihood of developing a functional disability decreased. PMID- 24345309 TI - Prescription opioid use among university students: assessment of post-cue exposure craving. AB - Despite the increasing number of prescriptions written to adolescents and young adults for opioid analgesics, the rise in non-medical use of such drugs among university students, and the potential role of craving in the misuse of opioids, there have been no published studies assessing craving for prescription opioids in this population. Therefore, the current study was designed to assess the impact of prescription opioid-related cue exposure on craving in university students. Students (n=277) recruited from a large university in the Midwestern United States were randomly assigned to two conditions to test the impact of cue exposure to either prescription opioid-related stimuli or control stimuli. Relative to the control condition, prescription opioid-related cue exposure significantly increased overall craving, desire and intention to use prescription opioids, relief from negative states by using prescription opioids, and perceived control over prescription opioid use. In addition, when assessing correlates of post-cue exposure craving, negative mood and procurement of prescription opioids from non-medical sources were the only measured variables that were significantly associated with overall craving and/or any of the craving measure's subscales. Craving may be important aspect of prescription opioid use among university students. Future research assessing craving as a function of non-medical user subtype is warranted. PMID- 24345310 TI - Do adolescent drug use consequences predict externalizing and internalizing problems in emerging adulthood as well as traditional drug use measures in a Hispanic sample? AB - The present study compares statistical models for three conceptualizations of drug use in 11th grade (past 30 day ever/never use, past 30 day frequency of drug use and past 30 day drug use consequences) with externalizing and internalizing problems in emerging adulthood when controlling for age, academic achievement and socioeconomic status in a Hispanic sample. Multivariate logistic regression models for the different drug use variables were compared when modeling weapon carrying, arrest, multiple lifetime sex partners, drug/alcohol use before sex and condom use in emerging adulthood. A multivariate linear regression model was used to model depression in emerging adulthood as a function of drug use measurement controlling for other covariates and depression in adolescence. Our findings suggest that any conceptualization of drug use will produce equitable results and model fit statistics when examining externalizing problems. However, when investigating internalizing problems, such as depression, lower frequency drug use-and not high frequency-was more strongly associated with depression whereas experiencing high levels of drug use consequences-and not low levels of consequences-was associated with depression in emerging adulthood despite similar model fit values. Variation between drug use and the experience of drug use consequences may lead to misspecification of "at-risk" subgroups of drug users. Implications and future directions are discussed. PMID- 24345312 TI - Picosecond pulse radiolysis study of dynamics of solvation of electron and fluorenone anion in primary alcohols. AB - We have studied the dynamics of solvation of electron injected directly into primary alcohols as well as that of fluorenone anion using pulse radiolysis technique with the time resolution of about 15 ps. Unlike in the previous reports, we observe nonexponential dynamics of both electron and anion solvation. While the ultrafast component, tau1 (<15 ps) representing the inertial time scale of the dynamics is faster than the time resolution of the spectrometer, the slower component, tau2, has been assigned to the translational motion leading to structural changes of the hydrogen bonding network of the solvent in the inner solvation cell or alcohol cluster. tau2 agrees well with the electron solvation times reported by the earlier authors. tau3 is associated with the restructuring of the hydrogen bond network structure of the solvent in the region outside the solvation cell. Nonexponential solvation dynamics of the fluorenone anion has been described well by a two-component process. The most important observation in this work is that the lifetime of the shorter component, tau1, determined in four alcoholic solvents, is much longer than the electron solvation time in the corresponding solvents determined in this work or anion solvation time reported earlier. The lifetime of this component is nearly comparable with the average dipolar solvation time but shorter than the longitudinal relaxation time of the solvent. In the case of anion, tau1 has been assigned to the restructuring of the first solvation shell by breakage of solvent hydrogen bonds of the fluorenone molecule and formation of hydrogen bonds with the anion. In this case, too, the longer component, tau2, with the lifetime of a few nanoseconds, has been assigned to reorganization of hydrogen bonds in the solvent hydrogen bond network structure. PMID- 24345311 TI - Irreversible airway obstruction in adulthood after bronchiolitis in infancy: evidence from a 30-year follow-up study. AB - AIM: Lower respiratory infections in infancy may be associated with lung function deficits in adulthood. Our aim was to evaluate lung function, with a special focus on irreversible airway obstruction, thirty years after bronchiolitis or pneumonia in infancy. METHODS: In 1981-1982, 83 children under two years of age were hospitalized for bronchiolitis and 44 for pneumonia at Kuopio University Hospital, Finland. In 2010, 47 bronchiolitis patients, 22 pneumonia patients and 138 controls attended the study, including spirometry before (pre-BD) and after bronchodilatation (post-BD). The measured indices were forced vital capacity (FVC) and forced expiratory volume in one second (FEV1), that were presented as % of predicted value (FVC% and FEV1%). FEV1/FVC was presented as both absolute FVC/FEV1-ratio and % of predicted (FEV1/FVC%). Irreversible airway obstruction was defined as post-BD FEV1/FVC% below 88% of predicted (FEV1/FVC% <88%) according to Finnish reference values or FEV1/FVC-ratio below fifth percentile (FEV1/FVC <5th percentile), according to Global Lung Function Initiative reference values. RESULTS: All lung function indices were lower in former bronchiolitis patients and pre- and post-BD FEV1% in pneumonia patients, compared to controls. 21% of bronchiolitis (OR, 95%CI; 5.59, 1.72-18.21) and 9% of pneumonia patients (2.24, 0.34-13.56) had FEV1/FVC% <88% compared to controls (4%). Likewise 7 (15%) of bronchiolitis (7.07, 1.33-37.22) and 1 (5%) of pneumonia patients (1.73, 0.12-24.77) had FEV1/FVC <5th percentile compared to controls 2 (1%). CONCLUSION: Evidence of reduced lung function was present 30 years after hospitalization for bronchiolitis or pneumonia in infancy. Irreversible airway obstruction after severe bronchiolitis in infancy suggests permanent, structural alterations in airways. PMID- 24345313 TI - Detection of Candidatus Neoehrlichia mikurensis, Borrelia burgdorferi sensu lato genospecies and Anaplasma phagocytophilum in a tick population from Austria. AB - Candidatus Neoehrlichia mikurensis DNA was discovered in Ixodes ricinus ticks in 1999 and is referred to as an emerging human pathogen since its first detection in patients with febrile illness reported in 2010. In recent years, Ca. Neoehrlichia mikurensis has been detected in ticks from several European, Asian, and African countries. However, no epidemiological data exist for Austria, which is a highly endemic region for tick-transmitted diseases. To assess the geographic spread and prevalence of Ca. Neoehrlichia mikurensis sympatric with other tick-transmitted pathogens, we analysed 518 I. ricinus ticks collected in 2002 and 2003 in Graz, Austria. The prevalence of Ca. Neoehrlichia mikurensis was 4.2%, that of Borrelia burgdorferi sensu lato 25.7%, and that of Anaplasma phagocytophilum 1%. Coinfections with Ca. Neoehrlichia mikurensis and B. burgdorferi sensu lato were found in 2.3% of all ticks. Thus, the results show a relatively high prevalence of Ca. Neoehrlichia mikurensis in Austrian ticks suggesting a high probability for the occurrence of undiagnosed human infections in Austria. PMID- 24345314 TI - Complex fasciculation potentials and survival in amyotrophic lateral sclerosis. AB - OBJECTIVE: We investigated the relationship between fasciculation potentials (FPs) and survival in patients with ALS. METHODS: In 85 ALS patients, we prospectively performed needle EMG in five to seven muscles of each patient. The shape of the detected FPs was analyzed by inspection, and FPs with >4 phases were judged as complex FPs. We analyzed the correlation between complex FPs and survival period using the Cox proportional hazard model. RESULTS: Complex FPs were observed in 47 patients, more frequently in the muscles with normal strength or mild weakness. The presence of complex FPs was associated with shorter survival (hazard ratio 3.055; p=0.004). The greater the number of muscles with complex FPs, the shorter the survival and the faster the progression speed. CONCLUSION: Wide distribution of complex FPs is associated with shorter survival in ALS. SIGNIFICANCE: Complex FPs are useful to predict prognosis of ALS patients and should be evaluated in the EMG examination. PMID- 24345315 TI - Fasciculations, axonal hyperecitability, and motoneuronal death in Amyotrophic Lateral Sclerosis. PMID- 24345316 TI - Modulation of short- and long-interval intracortical inhibition with increasing motor evoked potential amplitude in a human hand muscle. AB - OBJECTIVE: The aim of the current study was to investigate the effect of increasing test motor evoked potential (MEP) amplitude on short- (SICI) and long interval intracortical inhibition (LICI) at rest and during activation of the first dorsal interosseous (FDI) muscle. METHODS: In 22 young subjects, a conditioning-test transcranial magnetic stimulation (TMS) paradigm was used to assess SICI and LICI at 5 different test TMS intensities (110-150% motor threshold) in resting and active FDI. In 9 additional subjects, SICI and LICI data were quantified when the test MEP amplitude represented specific proportions of the maximal compound muscle action potential (Mmax) in each subject. RESULTS: Test TMS intensity influenced SICI and LICI in rest and active FDI muscle. The normalised test MEP amplitude (%Mmax) did not influence SICI at rest, whereas there was a decrease in LICI at rest and an increase in SICI in active FDI with an increased normalised test MEP amplitude (%Mmax). CONCLUSIONS: Our results demonstrate differential effects of normalised test MEP amplitude (%Mmax) on SICI and LICI in resting and active FDI muscle. SIGNIFICANCE: Estimation of SICI and LICI under some circumstances may be influenced by the normalised test MEP amplitude in subject populations with different Mmax characteristics. PMID- 24345317 TI - Effect of nepafenac eye drops on intraocular pressure: a randomized prospective study. AB - PURPOSE: To report the effect of nepafenac (0.1%) eye drops on intraocular pressure in eyes with cataract. DESIGN: Prospective randomized clinical trial. METHODS: Three hundred and twenty-seven patients with bilateral cataracts in an institutional setting were included. All patients had a baseline intraocular pressure (IOP) <= 21 mm Hg without a history of intraocular surgery in the past 3 months. One eye of each individual was randomized to the treatment group, with the other eye acting as a control. Nepafenac (0.1%) eye drops were instilled 3 times a day in the eye that received treatment. Intraocular pressure (IOP) with Goldmann applanation tonometer (GAT) was measured at baseline and at 4 and 8 weeks. Proportion of eyes with an IOP elevation of >4 mm Hg was the main outcome measure. RESULTS: The mean age of the participants was 45.7 +/- 4.4 years. Participants included 192 female and 135 male patients. The mean IOP at baseline in the treated and control eyes was, respectively, 13.8 +/- 2.5 mm Hg and 13.4 +/ 3.0 mm Hg, which reduced to 12.0 +/- 2.0 mm Hg and 12.1 +/- 1.5 mm Hg, respectively, at the end of 8 weeks. This reduction in IOP in both groups was significant (P < .01). The difference between the IOP in the treated and control eyes at 8 weeks was not statistically significant (P = .34). One eye in the treated group and 2 eyes in the control group had an IOP elevation of >4 mm Hg. CONCLUSION: Nepafenac eye drops do not increase the IOP. They can possibly be used as an alternative to steroid medications where steroid responsiveness is a concern. PMID- 24345318 TI - Comparison of Hoffer Q and Haigis formulae for intraocular lens power calculation according to the anterior chamber depth in short eyes. AB - PURPOSE: To compare the accuracy of the Hoffer Q and Haigis formulae according to the anterior chamber depth (ACD) in cases of short axial length (AL). DESIGN: Retrospective cross-sectional study. METHODS: A total of 75 eyes from 75 patients with an AL of less than 22.0 mm implanted with an Acrysof IQ intraocular lens (IOL) were enrolled. The median absolute errors (MedAEs) predicted by the Hoffer Q and Haigis formulae were compared. The correlations between ACD and the predicted refractive error calculated using the 2 formulae were analyzed. RESULTS: There were no significant differences in the MedAEs predicted by the Hoffer Q and Haigis formulae (0.40 and 0.40 diopter [D], respectively). The difference between the refractive errors predicted by the Hoffer Q and Haigis formulae increased significantly as the ACD decreased (R(2) = 0.644, P < .001). The MedAE predicted by the Haigis formula (0.40 D) was significantly smaller than that predicted by the Hoffer Q formula (0.66 D) in eyes with an ACD of less than 2.40 mm (P = .027). There were no significant differences found between the MedAEs predicted by the Hoffer Q and Haigis formulae in eyes with an ACD of 2.40 mm or more. CONCLUSIONS: The differences between the predicted refractive errors of the Hoffer Q and Haigis formula increased as ACD decreased in short eyes. Therefore, ACD should be taken into consideration when evaluating the accuracy of the IOL power calculation formulae in short eyes. PMID- 24345319 TI - Relationship between preferred sleeping position and asymmetric visual field loss in open-angle glaucoma patients. AB - PURPOSE: To investigate the relationship between preferred sleeping position and asymmetric visual field (VF) loss in open-angle glaucoma (OAG) patients. DESIGN: Retrospective, cross-sectional study. METHODS: Six hundred and ninety-two (692) patients with bilateral normal-tension glaucoma (NTG) or high-tension glaucoma were consecutively enrolled. A questionnaire to determine the preferred sleeping position was administered to each patient. Asymmetric VF loss was defined as a difference in mean deviation between the 2 eyes of at least 2 dB. According to these values, the better eye and worse eye were defined. Among the patients with asymmetric VF loss, the numbers preferring the worse eye-dependent lateral decubitus position and the better eye-dependent lateral decubitus position were compared. RESULTS: Among the enrolled patients, 309 (60.6%) with NTG and 121 (66.5%) with high-tension glaucoma had asymmetric VF between the 2 eyes. Among the 309 NTG patients, 100 (32.4%) preferred the lateral decubitus position. Of these, 66 (66.0%) preferred the worse eye-dependent lateral decubitus position (P = .001). Among the 121 high-tension glaucoma patients, 32 (26.4%) preferred the lateral decubitus position, and of these, 23 (71.9%) preferred the worse eye dependent lateral decubitus position (P = .013). CONCLUSION: Our results suggest that the sleep position habitually preferred by glaucoma patients may be associated with greater VF loss. PMID- 24345320 TI - Distinct microRNA-155 expression in the vitreous of patients with primary vitreoretinal lymphoma and uveitis. AB - PURPOSE: To use micro-ribonucleic acid (microRNA) profiles in the vitreous for differential diagnosis of primary vitreoretinal lymphoma and uveitis. DESIGN: Prospective cross-sectional study. METHODS: This prospective cross-sectional study included 17 diffuse large B-cell primary vitreoretinal lymphoma and 12 uveitis patients. The supernatant of ocular fluid was subjected to total RNA extraction, followed by complementary deoxyribonucleic acid (cDNA) synthesis. Selected samples (primary vitreoretinal lymphoma, n = 3; uveitis, n = 3) were arrayed by a real-time polymerase chain reaction (RT-PCR)-based microRNA panel that detects 168 human mature microRNAs. The markers promising in distinct levels between uveitis and lymphoma were further tested for in all the other 23 samples by individual RT-PCR analysis. RESULTS: Of 168 microRNAs in the array, 66.5% were detectable with consistent higher microRNA-484, microRNA-197, and microRNA-132 in the primary vitreoretinal lymphoma vitreous and higher microRNA-155, microRNA 200c, and microRNA-22* in the uveitic ocular fluids. The results were normalized by different combinations of 7 control microRNAs (microRNA-103, microRNA-191, microRNA-42-5p, microRNA-16, microRNA-425, microRNA-93, and microRNA-451). After optimization, normalization against microRNA-16 was equally as reliable as the average of the 7 control microRNAs. Individual assays of all samples supported the pattern yielded from the array analysis. But only microRNA-155 was significantly higher in the uveitic vitreous compared to that with lymphoma. CONCLUSIONS: Mature microRNAs are detectable in ocular fluid samples. Primary vitreoretinal B-cell lymphoma and uveitis might be characterized by distinct microRNA signatures. Quantification of ocular microRNA-155 might be helpful in the differential diagnosis of these 2 diseases. PMID- 24345321 TI - Effect of scan quality on diagnostic accuracy of spectral-domain optical coherence tomography in glaucoma. AB - PURPOSE: To evaluate the effect of scan quality on the diagnostic accuracies of optic nerve head (ONH), retinal nerve fiber layer (RNFL), and ganglion cell complex (GCC) parameters of spectral-domain optical coherence tomography (SD OCT) in glaucoma. DESIGN: Cross-sectional study. METHODS: Two hundred fifty-two eyes of 183 control subjects (mean deviation [MD]: -1.84 dB) and 207 eyes of 159 glaucoma patients (MD: -7.31 dB) underwent ONH, RNFL, and GCC scanning with SD OCT. Scan quality of SD OCT images was based on signal strength index (SSI) values. Influence of SSI on diagnostic accuracy of SD OCT was evaluated by receiver operating characteristic (ROC) regression. RESULTS: Diagnostic accuracies of all SD OCT parameters were better when the SSI values were higher. This effect was statistically significant (P < .05) for ONH and RNFL but not for GCC parameters. In mild glaucoma (MD of -5 dB), area under ROC curve (AUC) for rim area, average RNFL thickness, and average GCC thickness parameters improved from 0.651, 0.678, and 0.726, respectively, at an SSI value of 30 to 0.873, 0.962, and 0.886, respectively, at an SSI of 70. AUCs of the same parameters in advanced glaucoma (MD of -15 dB) improved from 0.747, 0.890, and 0.873, respectively, at an SSI value of 30 to 0.922, 0.994, and 0.959, respectively, at an SSI of 70. CONCLUSION: Diagnostic accuracies of SD OCT parameters in glaucoma were significantly influenced by the scan quality even when the SSI values were within the manufacturer-recommended limits. These results should be considered while interpreting the SD OCT scans for glaucoma. PMID- 24345322 TI - Choroidal neovascularization associated with focal choroidal excavation. AB - PURPOSE: To describe the clinical and imaging characteristics of choroidal neovascularization (CNV) accompanied by focal choroidal excavation. DESIGN: Retrospective, interventional case series. METHODS: The medical records of 16 patients (16 eyes) were reviewed. Imaging findings including fluorescein angiography (FA), indocyanine green angiography, and spectral-domain optical coherence tomography (SD OCT) were analyzed. RESULTS: CNV complexes were primarily located beneath the retinal pigment epithelium (type 1 CNV) in 9 eyes and in the subneurosensory retinal space (type 2 CNV) in 7 eyes, as assessed by SD OCT. Seven of 8 patients over 50 years old had type 1 CNV, and 6 of 8 patients under 50 had type 2 lesions. All 7 eyes with type 2 CNV exhibited classic CNV on FA. Additionally, 7 of 9 eyes with type 1 CNV had the classic pattern, and in these eyes, the CNV complexes were confined to the concavity of choroidal excavation. In 15 patients treated by anti-vascular endothelial growth factor (anti-VEGF) injections, the mean best-corrected visual acuity improved from 20/44 to 20/26 with a mean of 3.7 injections during a mean follow-up period of 14.5 months. CONCLUSIONS: The CNV growth pattern and extent seem to be determined by the degree of damage to the retinal pigment epithelium/Bruch membrane complex resulting from choroidal excavation, as well as age. Neovascular complexes tend to be located within the boundary of choroidal excavation and are revealed as classic patterns on FA, even in type 1 CNV. Anti-VEGF was notably effective for treating these lesions, with a low rate of recurrence. PMID- 24345323 TI - Ocular phenotype analysis of a family with biallelic mutations in the BEST1 gene. AB - PURPOSE: To investigate the genetic cause and perform a comprehensive clinical analysis of a Danish family with autosomal recessive bestrophinopathy; to investigate whether Bestrophin may be expressed in normal human retina. DESIGN: Retrospective clinical and molecular genetic analysis and immunohistochemical observational study. METHODS: setting: National referral center. participants: A family with 5 individuals and biallelic BEST1 mutations, and enucleated eyes from 2 individuals with nonaffected retinas. observation procedures: Molecular genetic analysis included sequencing of BEST1 and co-segregation analysis. Clinical investigations included electro-oculography, full-field electroretinography, multifocal electroretinography, spectral-domain optical coherence tomography, and fundus autofluorescence imaging. Immunohistochemical analysis was performed. main outcome measures: BEST1 mutations, imaging findings, electroretinography amplitudes, and implicit times. RESULTS: The index case was compound heterozygous for p.A195V and a novel 15 base pair deletion leading to p.Q238L. The index case at age 10 demonstrated multifocal vitelliform changes that were hyperautofluorescent, cystoid macular edema in the inner nuclear layer, no light rise in the electro-oculography, and a reduced central but preserved peripheral retinal function by multifocal electroretinography. Full-field electroretinography demonstrated a reduced rod response and inner retina dysfunction. Retinal structure was normal in all 3 family members who carried a sequence change in BEST1. Electro-oculography light peak was reduced in both the mother and sister (heterozygous for p.Q238L). Immunohistochemistry could not confirm the presence of Bestrophin in normal human retina. CONCLUSIONS: Because of a relatively well preserved retinal function, autosomal recessive bestrophinopathy may be a suitable first candidate, among the BEST1-related ocular conditions, for gene replacement therapy. PMID- 24345324 TI - Complex regulation of acute and chronic neuroinflammatory responses in mouse models deficient for nuclear factor kappa B p50 subunit. AB - Inflammation is a major mechanism of acute brain injury and chronic neurodegeneration. This neuroinflammation is known to be substantially regulated by the transcription factor NF-kappaB, which is predominantly found in the form of heterodimer of p65 (RelA) and p50 subunit, with p50/p50 homodimers being also common. The p65 subunit has a transactivation domain, whereas p50 is chiefly involved in DNA binding. Binding of the p65/p50 heterodimers is thought to induce expression of numerous proinflammatory genes in microglia. Here we show that cultured microglia deficient for the gene (Nfkb1) encoding p50 subunit show reduced induction of proinflammatory mediators, increased expression of anti inflammatory genes, and increased expression of CD45, an immunoregulatory molecule, in response to lipopolysaccharide (LPS) exposure, but increased capacity to take up beta-amyloid (Abeta) which is associated with enhanced release of tumor necrosis factor alpha (TNFalpha). However, Nfkb1 deficiency strongly increases leukocyte infiltration and the expression of proinflammatory genes in response to intrahippocampal administration of LPS. Also, when crossing Nfkb1 deficient mice with APdE9 transgenic mice the expression of proinflammatory genes was strongly enhanced, whereas Abeta burden was slightly but significantly reduced. These alterations in expression of inflammatory mediators in Nfkb1 deficient mice were associated with reduced expression of CD45. Our data demonstrates a crucial and complex role p50 subunit of NF-kappaB in brain inflammation, especially in regulating the phenotype of microglia after acute and chronic inflammatory insults relevant to clinical conditions, contributing to both pro-inflammatory and anti-inflammatory responses of microglia, infiltration of leukocytes, and clearance of Abeta in Alzheimer's disease. PMID- 24345325 TI - Child temperament and maternal predictors of preschool children's eating and body mass index. A prospective study. AB - Research has previously identified relationships between child temperament and BMI during childhood. However, few studies have addressed the broader implications of child temperament on the development of obesogenic risk factors, such as maternal feeding, child eating and body mass index (BMI) of pre schoolers. Hence, the current study evaluated cross-sectional and prospective associations between child temperament, maternal feeding, maternal parenting styles, mother-child interaction, preschoolers' eating behaviours and BMI. Child irritability, cooperation-manageability and easy-difficult temperaments, mother child dysfunctional interaction, maternal pressure to eat and restriction were significantly cross-sectionally associated with child eating behaviours. Child enjoyment of food was significantly associated with child BMI. Child easy difficult temperament and mother-child dysfunctional interaction predicted child eating behaviours longitudinally and baseline child BMI measures predicted child BMI longitudinally. Average maternal ratings of child temperament were relatively neutral, potentially explaining why most associations were not robust longitudinally. Future research should include a sample of greater socio-economic and BMI diversity as well as objective measures of child temperament, diet composition, maternal feeding practices, and mother-child interaction. PMID- 24345326 TI - Anomalous left coronary artery from the right coronary cusp with gene positive apical hypertrophic cardiomyopathy: a case report and literature review. AB - In the United States, hypertrophic cardiomyopathy and coronary artery anomalies account for the leading two causes of sudden death in athletes. We present a case of a patient with an anomalous origin of the left main from the right coronary sinus with associated gene-confirmed hypertrophic cardiomyopathy. The patient underwent surgical repair with unroofing of the intramural portion of the left main coronary artery with a good result. We also review the reported cases in the medical literature describing this uncommon association between anomalous coronary artery origin and hypertrophic cardiomyopathy. PMID- 24345327 TI - Cognitive responses to positively and negatively framed health messages: a thought-listing study. AB - This study compared spontaneous cognitive responses to a positively vs. negatively framed health message. Deakin University students (n = 51) read one of two versions of a message concerning a type of heart disease. In the negative condition, the message focused on the prospect of experiencing heart disease; in the positive condition, it focused on the prospect of avoiding heart disease. Participants completed a thought-listing task, reporting any thought that occurred to them while they were reading the message. Consistent with hypotheses derived from Prospect Theory, the negative condition prompted more extensive processing and more defensive processing. Participants in the negative condition were also more likely to consider taking protective action. Findings are discussed in the context of the health-framing literature. PMID- 24345328 TI - Evaluating the effectiveness of fish consumption advisories: modeling prenatal, postnatal, and childhood exposures to persistent organic pollutants. AB - BACKGROUND: Because human exposure to persistent organic pollutants (POPs) occurs mainly through ingestion of contaminated food, regulatory bodies issue dietary consumption advisories to describe safe intake levels for food items of concern, particularly fish. OBJECTIVES: Our study goal was to estimate the effectiveness of fish consumption advisories in reducing exposure of infants and children to POPs. METHODS: We used the time-variant mechanistic model CoZMoMAN to estimate and compare prenatal, postnatal, and childhood exposure to polychlorinated biphenyl congener PCB-153 under different scenarios of maternal guideline adherence for both hypothetical constant and realistic time-variant chemical emissions. The scenarios differed in terms of length of compliance (1 vs. 5 years), extent of fish substitution (all vs. half), and replacement diet (uncontaminated produce vs. beef). We also estimated potential exposure reductions for a range of theoretical chemicals to explore how guideline effectiveness varies with a chemical's partitioning and degradation properties. RESULTS: When assuming realistic time periods of advisory compliance, our findings suggest that temporarily eliminating or reducing maternal fish consumption is largely ineffective in reducing pre- and postnatal exposure to substances with long elimination half-lives in humans, especially during periods of decreasing environmental emissions. Substituting fish with beef may actually result in higher exposure to certain groups of environmental contaminants. On the other hand, advisories may be highly effective in reducing exposure to substances with elimination half-lives in humans shorter than the length of compliance. CONCLUSIONS: Our model estimates suggest that fish consumption advisories are unlikely to be effective in reducing prenatal, postnatal, and childhood exposures to compounds with long elimination half-lives in humans. PMID- 24345329 TI - A randomized, placebo-controlled trial of N-acetylcysteine plus imaginal desensitization for nicotine-dependent pathological gamblers. AB - OBJECTIVE: Pathological gambling is associated with elevated proportions of nicotine dependence, and tobacco smoking in pathological gamblers has been associated with increased problem-gambling severity. This study examined the addition of N-acetylcysteine to imaginal desensitization in adults with co occurring nicotine dependence and pathological gambling. METHOD: Twenty-eight individuals with co-occurring DSM-IV nicotine dependence and pathological gambling who were receiving behavioral therapy were recruited from December 2009 to February 2012 and randomized to augmentation with N-acetylcysteine or placebo in an 12-week, double-blind trial. Subjects were assessed with measures of nicotine and gambling severity and followed for 3 months after treatment. The primary outcomes were the Fagerstrom Test for Nicotine Dependence and the pathological gambling adaptation of the Yale-Brown Obsessive-Compulsive Scale. RESULTS: During the first 6 weeks, there was a significant benefit of N acetylcysteine treatment versus placebo on Fagerstrom Test for Nicotine Dependence total scores (t = -2.224; P = .031). After the initial 6 weeks, all subjects significantly (P < .001) benefited from imaginal desensitization. During the 3-month follow-up, there was a significant additional benefit for N acetylcysteine versus placebo on measures of problem-gambling severity (t = 2.069; P = .043). CONCLUSIONS: N-acetylcysteine treatment during therapy facilitates long-term application of behavioral therapy techniques once patients are in the community after therapy has been completed. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00967005. PMID- 24345330 TI - Aspirin attenuates vinorelbine-induced endothelial inflammation via modulating SIRT1/AMPK axis. AB - Vinorelbine (VNR), a semisynthetic vinca alkaloid acquired from vinblastine, is frequently used as the candidate for intervention of solid tumors. Nevertheless, VNR-caused endothelial injuries may lead a mitigative effect of clinical treatment efficiency. A growing body of evidence reveals that aspirin is a potent antioxidant and anti-inflammation drug. We investigated whether aspirin attenuate VNR-induced endothelial dysfunction. Human endothelial cells (EA.hy 926) were treated with VNR to cause endothelial inflammation. Western blotting, ROS assay, ELISA were used to confirm the anti-inflammatory effect of aspirin. We confirmed that VNR suppresses SIRT1 expression, reduced LKB1 and AMPK phosphorylation as well as enriched PKC activation in treated endothelial cells. Furthermore, the membrane translocation assay displayed that the levels of NADPH oxidase subunits p47phox and Rac-1 in membrane fractions of endothelial cells were higher in cells that had been treated with VNR for than in untreated cells. We corroborated that treatment of Aspirin significantly diminishes VNR-repressed SIRT1, LKB1 and AMPK phosphorylation and VNR-promoted NADPH oxidase activation, however, those findings were vanished by SIRT1 and AMPK siRNAs. Our data also shown that Aspirin represses VNR-activated TGF-beta-activated kinase-1 (TAK1) activation, inhibited the interaction of TAK1/TAK-binding protein1 (TAB1), suppressed NF-kappa B activation and pro-inflammatory cytokine secretion. We demonstrated a novel connection between VNR-caused oxidative damages and endothelial dysfunction, and provide further insight into the protective effects of aspirin in VNR-caused endothelial dysfunction. PMID- 24345331 TI - Cap-dependent translation initiation factor, eIF4E, is the target for Ouabain mediated inhibition of HIF-1alpha. AB - Hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that mediates the adaptation of tumor cells and tissues to the hypoxic microenvironment, has attracted considerable interest as a potential therapeutic target. Recently, HIF-1alpha has been recognized as the critical target of cardiac glycosides for cancer therapy, but the molecular mechanism of cardiac glycosides' inhibition of HIF-1alpha is still poorly understood. In the present study, we observed that neither HIF-1alpha mRNA levels nor HIF-1alpha protein degradation are affected by Ouabain. However, Ouabain was found to be associated with the regulation of HIF-1alpha translation. Basing on in silico, in vitro and ex vivo models of translation processing, further studies revealed that eIF4E plays a critical role in the inhibitory effect of Ouabain on HIF-1alpha protein synthesis, rather than mTORC1, eIF2alpha signaling or Na(+)/K(+)-ATPase inhibition. Mechanistically, Ouabain directly binds eIF4E, disrupts eIF4E/eIF4G association (200 MUM, Inhibit rate =61 +/- 3%) but not the eIF4E/mRNA complex formation (200 MUM, Inhibit rate =18 +/- 5%) both in vitro and in cells, thereby inhibiting the intracellular cap-dependent translation. The association between Ouabain and eIF4E not only raises the hope of using cardiac glycosides for cancer therapeutics more rational, but also offers a pharmacologic means for developing novel anti-cancer HIF-1alpha antagonists. PMID- 24345332 TI - Regulation of autophagy by miR-30d impacts sensitivity of anaplastic thyroid carcinoma to cisplatin. AB - miR-30d has been observed to be significantly down-regulated in human anaplastic thyroid carcinoma (ATC), and is believed to be an important event in thyroid cell transformation. In this study, we found that miR-30d has a critical role in modulating sensitivity of ATC cells to cisplatin, a commonly used chemotherapeutic drug for treatment of this neoplasm. Using a mimic of miR-30d, we demonstrated that miR-30d could negatively regulate the expression of beclin 1, a key autophagy gene, leading to suppression of the cisplatin-activated autophagic response that protects ATC cells from apoptosis. A reporter gene assay demonstrated that the binding sequences of miR-30d in the beclin 1-3' UTR was the region required for the inhibition of beclin 1 expression by this miRNA. We further showed that inhibition of the beclin 1-mediated autophagy by the miR-30d mimic sensitized ATC cells to cisplatin both in vitro (cell culture) and in vivo (animal xenograft model). These results suggest that dysregulation of miR-30d in ATC cells is responsible for the insensitivity to cisplatin by promoting autophagic survival. Thus, miR-30d may be exploited as a potential target for therapeutic intervention in the treatment of ATC. PMID- 24345333 TI - CYP2E1 hydroxylation of aniline involves negative cooperativity. AB - CYP2E1 plays a role in the metabolic activation and elimination of aniline, yet there are conflicting reports on its mechanism of action, and hence relevance, in aniline metabolism. Based on our work with similar compounds, we hypothesized that aniline binds two CYP2E1 sites during metabolism resulting in cooperative reaction kinetics and tested this hypothesis through rigorous in vitro studies. The kinetic profile for recombinant CYP2E1 demonstrated significant negative cooperativity based on a fit of data to the Hill equation (n=0.56). Mechanistically, the data were best explained through a two-binding site cooperative model in which aniline binds with high affinity (K(s)=30 MUM) followed by a second weaker binding event (K(ss)=1100 uM) resulting in a threefold increase in the oxidation rate. Binding sites for aniline were confirmed by inhibition studies with 4-methylpyrazole. Inhibitor phenotyping experiments with human liver microsomes validated the central role for CYP2E1 in aniline hydroxylation and indicated minor roles for CYP2A6 and CYP2C9. Importantly, inhibition of minor metabolic pathways resulted in a kinetic profile for microsomal CYP2E1 that replicated the preferred mechanism and parameters observed with the recombinant enzyme. Scaled modeling of in vitro CYP2E1 metabolism of aniline to in vivo clearance, especially at low aniline levels, led to significant deviations from the traditional model based on non-cooperative, Michaelis-Menten kinetics. These findings provide a critical mechanistic perspective on the potential importance of CYP2E1 in the metabolic activation and elimination of aniline as well as the first experimental evidence of a negatively cooperative metabolic reaction catalyzed by CYP2E1. PMID- 24345334 TI - The molecular structure of the liquid-ordered phase of lipid bilayers. AB - Molecular dynamics simulations reveal substructures within the liquid-ordered phase of lipid bilayers. These substructures, identified in a 10 MUs all-atom trajectory of liquid-ordered/liquid-disordered coexistence (L(o)/L(d)) are composed of saturated hydrocarbon chains packed with local hexagonal order and separated by interstitial regions enriched in cholesterol and unsaturated chains. Lipid hydrocarbon chain order parameters calculated from the L(o) phase are in excellent agreement with (2)H NMR measurements; the local hexagonal packing is also consistent with (1)H-MAS NMR spectra of the L(o) phase, NMR diffusion experiments, and small-angle X-ray and neutron scattering. The balance of cholesterol-rich to local hexagonal order is proposed to control the partitioning of membrane components into the L(o) regions. The latter have been frequently associated with formation of so-called rafts, platforms in the plasma membranes of cells that facilitate interaction between components of signaling pathways. PMID- 24345335 TI - Cardiac, skeletal muscle and serum irisin responses to with or without water exercise in young and old male rats: cardiac muscle produces more irisin than skeletal muscle. AB - Irisin converts white adipose tissue (WAT) into brown adipose tissue (BAT), as regulated by energy expenditure. The relationship between irisin concentrations after exercise in rats compared humans after exercise remains controversial. We therefore: (1) measured irisin expression in cardiac and skeletal muscle, liver, kidney, peripheral nerve sheath and skin tissues, as also serum irisin level in 10 week-old rats without exercise, and (2) measured tissue supernatant irisin levels in cardiac and skeletal muscle, and in response to exercise in young and old rats to establishing which tissues produced most irisin. Young (12 months) and old rats (24 months) with or without 10min exercise (water floating) and healthy 10 week-old Sprague-Dawley rats without exercise were used. Irisin was absent from sections of skeletal muscle of unexercised rats, the only part being stained being the perimysium. In contrast, cardiac muscle tissue, peripheral myelin sheath, liver, kidneys, and skin dermis and hypodermis were strongly immunoreactivity. No irisin was seen in skeletal muscle of unexercised young and old rats, but a slight amount was detected after exercise. Strong immunoreactivity occurred in cardiac muscle of young and old rats with or without exercise, notably in pericardial connective tissue. Serum irisin increased after exercise, being higher in younger than older rats. Irisin in tissue supernatants (cardiac and skeletal muscle) was high with or without exercise. High supernatant irisin could come from connective tissues around skeletal muscle, especially nerve sheaths located within it. Skeletal muscle is probably not a main irisin source. PMID- 24345336 TI - Molecular identification and expression analysis of a diapause hormone receptor in the corn earworm, Helicoverpa zea. AB - Diapause hormone (DH) is an insect neuropeptide that is highly effective in terminating the overwintering pupal diapause in members of the Helicoverpa/Heliothis complex of agricultural pests, thus DH and related compounds have promise as tools for pest management. To augment our development of effective DH analogs and antagonists that could be used as diapause disruptors this study focuses on the cloning and identification of the DH receptor (DHR) in the corn earworm, Helicoverpa zea. The full-length dhr cDNA contains 2153 nucleotides encoding 511 amino acids. Our results suggest there are at least two splicing variants of Hezea-DHR. Hydrophobicity analysis and sequence alignment indicate that Hezea-DHR has 7 transmembrane regions and a highly conserved C terminal region that is also present in related receptors. Hezea-DHR has 95%, 82% and 79% identity to a partial DHR sequence from Heliothis virescens, a full length DHR in Orgyia thyellina, and DHR-1 in Bombyx mori, but only 45-49% identity to pheromone biosynthesis activating neuropeptide receptor (PBANR). Expression of dhr mRNA remained low in whole body extracts throughout diapause and in young nondiapausing pupae, but was distinctly elevated as development ensued in pharate adults 7 days after pupation. The highest expression of dhr mRNA we noted was in the ovary. A DHR fusion protein with enhanced-green fluorescent protein was successfully expressed heterologously in X. laevis oocytes, as verified by fluorescent imaging and Western blots, but an electrophysiological assay failed to detect receptor-ligand binding activity, which suggests that an essential cofactor and/or accessory protein is required for functional activity of the DHR. PMID- 24345338 TI - Clinical next generation sequencing in cancer. PMID- 24345337 TI - Anaphylactic shock after amiodarone infusion resulting in haemodynamic collapse requiring a temporary ventricular assist device. AB - Acute heart failure related to anaphylactic shock is often reversible and necessitates aggressive support to ensure full recovery. We report the case of a 15-year-old boy who developed severe ventricular dysfunction and haemodynamic instability after administration of amiodarone and required temporary mechanical circulatory support with a left ventricular assist device. He had full recovery of cardiac function and returned to baseline neurologic status. This is the first report of successful left ventricular assist device use for recovery from cardiovascular collapse due to anaphylaxis. PMID- 24345339 TI - Doppler flow signals in small amount pericardial effusion after radiofrequency ablation. PMID- 24345340 TI - Low circulating level of IGF-1 is a distinct indicator for the development of cardiovascular disease caused by combined hyperglycemia and dyslipidemia. PMID- 24345341 TI - Relationship between female sex workers and gatekeeper: the impact on female sex worker's mental health in China. AB - Global literature suggests that gatekeepers exert enormous influences on lives of female sex workers (FSWs). However, virtually no available studies have examined the FSW-gatekeeper relationship (F-G relationship) and its impact on FSW's mental health. The current study was conducted in 2008-2009 in two cities of southwest China. A total of 1022 FSW were recruited through community outreach from nine different types of commercial sex establishments. Both bivariate and multivariate analyses were employed to depict the association between F-G relationship and measures of FSW's mental health. Findings of the current study revealed that FSW with a close relationship with their gatekeepers reported a better mental health status. After adjusting for demographics and potential confounders of mental health, F-G relationship was positively associated with hopefulness ( beta = .09, 95% CI = .01, .16), but negatively associated with perceived stigma ( beta = .25, 95% CI = -.44, -.07), suicidal intention or attempt (aOR = .90, 95% CI = .83, .99), and loneliness ( beta = -.29, 95% CI = -.47, -.12). F-G relationship is an independent predictor of mental health of FSW over and above potential confounders including partner violence and substance use. Future health promotion programs targeting FSW need to recognize the role of gatekeepers in the life of FSW and engage them in a socially and legally acceptable way in safeguarding or improving mental health status of FSW in China. PMID- 24345342 TI - Dante's syncopes. PMID- 24345344 TI - Neuroinflammation in ischemic brain injury as an adaptive process. AB - Cerebral ischaemia triggers various physiological processes, some of which have been considered deleterious and others beneficial. These processes have been characterized in one influential model as being part of a transition from injury to repair processes. We argue that another important distinction is between dysregulated and regulated processes. Although intervening in the course of dysregulated processes may be neuroprotective, this is unlikely to be true for regulated processes. This is because from an evolutionary perspective, regulated complex processes that are conserved across many species are likely to be adaptive and provide a survival advantage. We argue that the neuroinflammatory cascade is an adaptive process in this sense, and contrast this with a currently popular theory which we term the maladaptive immune response theory. We review the evidence from clinical and preclinical pharmacology with respect to this theory, and deduced that the evidence is inconclusive at best, and probably falsifies the theory. We argue that this is why there are no anti-inflammatory treatments for cerebral ischaemia, despite 30 years of seemingly promising preclinical results. We therefore propose an opposing theory, which we call the adaptive immune response hypothesis. PMID- 24345343 TI - What lies behind gender inequalities in HIV/AIDS in sub-Saharan African countries: evidence from Kenya, Lesotho and Tanzania. AB - Within sub-Saharan Africa, women are disproportionately at risk for acquiring and having human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). It is important to clarify whether gender inequalities in HIV prevalence in this region are explained by differences in the distributions of HIV risk factors, differences in the effects of these risk factors or some combination of both. We used an extension of the Blinder-Oaxaca decomposition approach to explain gender inequalities in HIV/AIDS in Kenya, Lesotho and Tanzania using data from the demographic and health and AIDS indicator surveys. After adjusting for covariates using Poisson regression models, female gender was associated with a higher prevalence of HIV/AIDS in Kenya [prevalence ratio (PR) = 1.73, 95% confidence interval (CI) = 1.33, 2.23 in 2003] and Lesotho (PR = 1.39, 95% CI = 1.20, 1.62 in 2004/05), but not in Tanzania. Decomposition analyses demonstrated two distinct patterns over time. In Tanzania, the gender inequality in HIV/AIDS was explained by differences in the distributions of HIV risk factors between men and women. In contrast, in Kenya and Lesotho, this inequality was partly explained by differences in the effects across men and women of measured HIV/AIDS risk factors, including socio-demographic characteristics (age and marital status) and sexual behaviours (age at first sex); these results imply that gender inequalities in HIV/AIDS would persist in Kenya and Lesotho even if men and women had similar distributions of HIV risk factors. The production of gender inequalities may vary across countries, with inequalities attributable to the unequal distribution of risk factors among men and women in some countries and the differential effect of these factors between groups in others. These different patterns have important implications for policies to reduce gender inequalities in HIV/AIDS. PMID- 24345345 TI - Exploiting radiation damage to map proteins in nucleoprotein complexes: the internal structure of bacteriophage T7. AB - In the final stage of radiation damage in cryo-electron microscopy of proteins, bubbles of hydrogen gas are generated. Proteins embedded in DNA bubble sooner than free-standing proteins and DNA does not bubble under the same conditions. These properties make it possible to distinguish protein from DNA. Here we explored the scope of this technique ("bubblegram imaging") by applying it to bacteriophage T7, viewed as a partially defined model system. T7 has a thin walled icosahedral capsid, 60 nm in diameter, with a barrel-shaped protein core under one of its twelve vertices (the portal vertex). The core is densely wrapped with DNA but details of their interaction and how their injection into a host bacterium is coordinated are lacking. With short (10 s) intervals between exposures of 17 electrons/A(2) each, bubbling starts in the third exposure, with 1-4 bubbles nucleating in the core: in subsequent exposures, these bubbles grow and merge. A 3D reconstruction from fifth-exposure images depicts a bipartite cylindrical gas cloud in the core. In its portal-proximal half, the axial region is gaseous whereas in the portal-distal half, it is occupied by a 3 nm-wide dense rod. We propose that they respectively represent core protein and an end of the packaged genome, poised for injection into a host cell. Single bubbles at other sites may represent residual scaffolding protein. Thus, bubbling depends on dose rate, protein amount, and tightness of the DNA seal. PMID- 24345346 TI - Evidence of alpha-helical coiled coils and beta-sheets in hornet silk. AB - alpha-Helical coiled coil and beta-sheet complexes are essential structural building elements of silk proteins produced by different species of the Hymenoptera. Beside X-ray scattering at wide and small angles we applied cryo electron diffraction and microscopy to demonstrate the presence and the details of such structures in silk of the giant hornet Vespa mandarinia japonica. Our studies on the assembly of the fibrous silk proteins and their internal organization in relation to the primary chain structure suggest a 172 A pitch supercoil consisting of four intertwined alanine-rich alpha-helical strands. The axial periodicity may adopt even multiples of the pitch value. Coiled coil motifs form the largest portion of the hornet silk structure and are aligned nearly parallel to the cocoon fiber axis in the same way as the membrane-like parts of the cocoon are molecularly orientated in the spinning direction. Supercoils were found to be associated with beta-crystals, predominantly localized in the l serine-rich chain sequences terminating each of the four predominant silk proteins. Such beta-sheet blocks are considered resulting from transformation of random coil molecular sequences due to the action of elongational forces during the spinning process. PMID- 24345347 TI - Biobanks containing clinical specimens: defining characteristics, policies, and practices. AB - OBJECTIVES: Biobanks - collections of human biological specimens stored for future research use - are crucial for biomedical advancement. One of the most common ways that biobanks acquire specimens is to obtain residual or "leftover" samples originally collected for clinical care from hospitals, clinical laboratories and pathology departments. Little is known about the characteristics of biobanks that store specimens from clinical sources, or their policies and practices. DESIGN AND METHODS: In this paper, we present data from the subset of 261 biobanks in our 2012 national survey that stores specimens from clinical sources, focusing on a number of ethical issues that have been raised in the literature. RESULTS: Most biobanks are part of larger organizations, mainly academic medical centers, and most report standardized systems for managing acquisition, storage, and release to researchers. Yet, there is considerable diversity in policies and practices regarding informed consent, return of research results, ownership of specimens and technology developed, utilization, and disposition of remaining specimens after researchers have acquired, them. We document tremendous heterogeneity in the composition of these collections, the number and type of specimens stored, and number of requests for specimens per year. CONCLUSION: Responding to this variation presents significant challenges for those who manage the collections, demanding careful consideration and planning to maintain high quality practices in acquisition, storage, and release of specimens all the while striving to protect the rights of subjects. PMID- 24345348 TI - The A640G polymorphism in the NAD(P)H oxidase p22phox gene (CYBA) is associated with risk reduction of coronary heart disease: a meta-analysis. AB - BACKGROUND: Recently, studies have focused on the association between the p22phox gene A640G polymorphism and coronary heart disease (CHD). However, the results are inconsistent. In this study, we aimed to further evaluate this association by using meta-analysis. METHODS: The PubMed, Embase, CBM, CNKI, WanFang and Chongqing VIP databases were searched for relevant articles. Hardy-Weinberg equilibrium (HWE) of the distribution of genotypes was tested using Pearson's chi squared test. Odds ratios (ORs) with the corresponding 95% confidence intervals (CIs) were used to assess the strength of the association; Cochran's Q test and the I(2) statistic were used to evaluate heterogeneity. The random effects model and the fixed effects model were used according to heterogeneity; Begg's test and Egger's test were used to analyze publication bias. Sensitivity analysis was carried out to guarantee the stability of the results. Cumulative analysis was used to evaluate tendencies in the pooled OR. RESULTS: A total of eight articles including 3904 CHD cases and 3498 controls were included. A significant association between the A640G polymorphism and CHD was observed in codominant model 2 (AG versus AA: OR=0.86, 95% CI: 0.77-0.96). In the subgroup analysis, a significant association was observed between the A640G polymorphism and CHD in Caucasians, and in PB (population-based), non-PB, HWE (studies followed HWE) and non-HWE studies. CONCLUSIONS: Our results reveal that the A640G polymorphism may play a protective role in CHD. PMID- 24345349 TI - National trends in long-term use of antidepressant medications: results from the U.S. National Health and Nutrition Examination Survey. AB - OBJECTIVE: To assess the trend in long-term use of antidepressants by persons aged >= 18 years, and the correlates of such use, in the United States from 1999 to 2010. METHOD: We examined trends in duration of antidepressant use and correlates of long-term use in data from 6 waves of the cross-sectional National Health and Nutrition Examination Survey (N = 35,379), a representative survey of the general population. RESULTS: The overall prevalence of antidepressant use increased from 6.5% in 1999-2000 to 10.4% in 2009-2010 (odds ratio [OR] = 1.54; 95% CI, 1.31-1.81; P < .001). This included an increase from 3.0% to 6.9% in long term use (>= 24 months; OR = 2.12; 95% CI, 1.75-2.57; P < .001). Medium-term (6 to < 24 months; from 1.3% to 1.6%) and short-term use (< 6 months; from 2.2% to 1.8%) of antidepressants did not change appreciably in this period. The increasing trend in long-term antidepressant use was limited to adults who received their care from general medical providers (adjusted OR = 3.86; 95% CI, 2.57-5.80; P < .001). CONCLUSIONS: From 1999 to 2010, there was a marked increase in long-term use of antidepressant medications in the United States, explaining the overall increasing trend in antidepressant use. This trend calls for greater vigilance in prescribing antidepressants for long periods of time. PMID- 24345351 TI - Cor triatriatum dexter and coarctation of the aorta--a rare association in a 7 year-old child with type 1 neurofibromatosis. AB - Cor triatriatum dexter is an extremely rare congenital anomaly of the right atrium. It occurs because of the persistence of the right sinus venosus valve, resulting in partitioning of the right atrium. Most of the described cases of cor triatriatum dexter in the literature were incidental findings on echocardiogram or at necropsy. We present a case report of a 7-year-old girl who was referred to us for further assessment, with a possible diagnosis of coarctation of the aorta. Initial investigations confirmed not only the presence of a long segment coarctation of the aorta, but also a large obstructive membrane in the right atrium. A catheter intervention was performed to stent the coarctation segment, and the fibro-muscular shelf in the right atrium was surgically resected. PMID- 24345350 TI - Associations between extreme precipitation and gastrointestinal-related hospital admissions in Chennai, India. AB - BACKGROUND: Understanding the potential links between extreme weather events and human health in India is important in the context of vulnerability and adaptation to climate change. Research exploring such linkages in India is sparse. OBJECTIVES: We evaluated the association between extreme precipitation and gastrointestinal (GI) illness-related hospital admissions in Chennai, India, from 2004 to 2007. METHODS: Daily hospital admissions were extracted from two government hospitals in Chennai, India, and meteorological data were retrieved from the Chennai International Airport. We evaluated the association between extreme precipitation (>= 90th percentile) and hospital admissions using generalized additive models. Both single-day and distributed lag models were explored over a 15-day period, controlling for apparent temperature, day of week, and long-term time trends. We used a stratified analysis to explore the association across age and season. RESULTS: Extreme precipitation was consistently associated with GI-related hospital admissions. The cumulative summary of risk ratios estimated for a 15-day period corresponding to an extreme event (relative to no precipitation) was 1.60 (95% CI: 1.29, 1.98) among all ages, 2.72 (95% CI: 1.25, 5.92) among the young (<= 5 years of age), and 1.62 (95% CI: 0.97, 2.70) among the old (>= 65 years of age). The association was stronger during the pre-monsoon season (March-May), with a cumulative risk ratio of 6.50 (95% CI: 2.22, 19.04) for all ages combined compared with other seasons. CONCLUSIONS: Hospital admissions related to GI illness were positively associated with extreme precipitation in Chennai, India, with positive cumulative risk ratios for a 15-day period following an extreme event in all age groups. Projected changes in precipitation and extreme weather events suggest that climate change will have important implications for human health in India, where health disparities already exist. CITATION: Bush KF, O'Neill MS, Li S, Mukherjee B, Hu H, Ghosh S, Balakrishnan K. 2014. Associations between extreme precipitation and gastrointestinal-related hospital admissions in Chennai, India. Environ Health Perspect 122:249-254; http://dx.doi.org/10.1289/ehp.1306807. PMID- 24345352 TI - Interactions between xylene-linked carbamoyl bis-pyridinium mono-oximes and organophosphates inhibited-AChE: a kinetic study. AB - Reactivation of organophosphate (OP) inhibited acetylcholinesterase (AChE) by oximes is inadequate against various OP nerve agents known till date owing to their diverse structural features. As a consequence, in the past decades widespread research programs have been undertaken independently throughout the world to develop and identify more effective oxime reactivators. The efficacy of oxime reactivators is estimated through different in vitro and in vivo models using AChE from various sources against structurally different OPs. In the present study, reactivation kinetics of OP (paraoxon, DFP, sarin and VX) inhibited AChE by xylene linked carbamoyl bis-pyridinum mono-oximes have been described. It was found that the reactivation potency of tested oximes varied with the inhibitors used as 5l (4-carbamoyl-2' hydroxyiminomethyl-1-1'-(1,3 phenylenedimethyl)-bis-pyridinium dibromide) was found to be the most effective reactivator against paraoxon. In case of DFP, 5k (3-carbamoyl-2' hydroxyiminomethyl-1-1'-(1,3-phenylenedimethyl)-bis-pyridinium dibromide) showed best reactivation while in case of sarin 5e (3-carbamoyl-2' hydroxyiminomethyl-1 1'-(1,4-phenylenedimethyl)-bis-pyridinium dibromide) exhibited outstanding reactivation ability in comparison to standard oximes (2-PAM, obidoxime and TMB 4) as indicated by its highest value of second order reactivation rate constant (k(r2)) 3.26 mM-1 min-1. The enhanced reactivation efficacy of oximes may be attributed to the optimal length of xylene linker which facilitates appropriate positioning of carbamoyl function to the peripheral anionic site (PAS) and extending the oxime moiety to the active site of AChE. PMID- 24345353 TI - Are selective estrogen receptor modulators (SERMs) a therapeutic option for HPV associated cervical lesions and cancers? AB - This Commentary highlights the article by Spurgeon et al which evaluates oral SERM raloxifene as a potential therapeutic agent for HPV-associated cancer. PMID- 24345354 TI - Self-efficacy toward physical activity and the physical activity behavior of children with and without Developmental Coordination Disorder. AB - PURPOSE: Affecting 5-6% of children, Developmental Coordination Disorder (DCD) is a prevalent chronic condition. The nature of the disorder - impaired motor coordination - makes avoidance of physical activity (PA) common. The purpose of this study was to examine the effect of barrier and task self-efficacy on PA behavior in children with DCD and a group of typically developing (TD) children. METHODS: Children were compared on their perceived ability to complete different intensities and duration of PA (task efficacy) and their confidence in completing PA when faced with everyday barriers (barrier efficacy). An accelerometer was used to record their activity over the subsequent week. RESULTS: Children with DCD were found to have significantly lower task efficacy and barrier efficacy. They also spent significantly less time in moderate to vigorous physical activity (MVPA). Multivariate analyses revealed that gender modified the relationship for both groups. Separate multivariate regressions, were therefore conducted by gender. A direct effect of DCD on PA was observed for boys, but not for girls. Further analyses showed that neither task efficacy nor barrier efficacy influenced the relationship between DCD and PA. CONCLUSION: Results from this study confirm that children with DCD have lower task and barrier self-efficacy than TD children and that males have lower PA levels than their TD peers; however neither task or barrier self-efficacy mediated the relationship between DCD and PA. PMID- 24345355 TI - Impact of fresh versus cryopreserved testicular sperm upon intracytoplasmic sperm injection pregnancy outcomes in men with azoospermia due to spermatogenic dysfunction: a meta-analysis. AB - OBJECTIVE: To determine if clinical pregnancy rates and fertilization rates with the use of cryopreserved sperm for intracytoplasmic sperm injection (ICSI) in patients with azoospermia due to spermatogenic dysfunction (i.e., nonobstructive azoospermia) are similar to those with fresh sperm. DESIGN: Systematic review and meta-analysis. SETTING: Academic medical center. PATIENT(S): Azoospermic men secondary to spermatogenic dysfunction. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate, fertilization rate. RESULT(S): Eleven studies met criteria for the outcome of clinical pregnancy rate. Seventy nine (28.7%) of 275 intracytoplasmic sperm injection cycles using fresh testicular sperm resulted in a clinical pregnancy, compared with 84 (28.1%) of 299 intracytoplasmic sperm injection cycles using cryopreserved sperm (relative risk [RR] 1.00, 95% confidence interval [CI] 0.75-1.33). Ten studies met criteria for the outcome of fertilization rate. A total of 1,422 (52.9%) of 2,687 oocytes injected with fresh testicular sperm were fertilized, compared with 1,490 (54.0%) of 2,757 oocytes injected with cryopreserved sperm (RR 0.97, 95% CI 0.92-1.02). CONCLUSION(S): In men with azoospermia due to spermatogenic dysfunction, there is no statistical difference between the use of fresh versus cryopreserved-thawed testicular sperm when assessing clinical pregnancy or fertilization rates in couples undergoing ICSI. PMID- 24345357 TI - Coronary artery treatment with paclitaxel-coated balloon using a BTHC excipient: clinical results of the international real-world DELUX registry. AB - AIMS: Safety and efficacy of percutaneous coronary interventions using the Pantera Lux paclitaxel-coated balloon have been demonstrated in the PEPPER first in-man trial. This prospective, multicentre, clinical registry aims to evaluate its safety and efficacy in an international real-world setting in a larger cohort of patients. METHODS AND RESULTS: Between April 2010 and April 2011, 1,064 patients were treated for predominantly diffuse and proliferative in-stent restenosis of bare metal stents (BMS-ISR) and drug-eluting stents (DES-ISR), or for de novo lesions. Clinical device success was obtained in 98.2% of the patients. The study endpoint was major adverse cardiac events (MACE), defined as a composite of all-cause mortality, non-fatal myocardial infarction and clinically driven target vessel revascularisation, and was 8.5% in the overall, 6.0% in the BMS-ISR, 11.5% in the DES-ISR and 7.0% in the de novo population at six months, and 15.1%, 11.6%, 20.6% and 9.4% at 12 months, respectively. Definitive stent thrombosis occurred in 0.4% of the patients within 12 months. CONCLUSIONS: Safety and efficacy of the Pantera Lux paclitaxel-coated balloon was confirmed in a real-world setting with low major adverse cardiac event rates in patients with in-stent restenosis or de novo lesions. (ClinicalTrials.gov: NCT01081366). PMID- 24345356 TI - A randomized trial of concurrent smoking-cessation and substance use disorder treatment in stimulant-dependent smokers. AB - OBJECTIVE: To evaluate the impact of concurrent treatments for substance use disorder and nicotine-dependence for stimulant-dependent patients. METHOD: A randomized, 10-week trial with follow-up at 3 and 6 months after smoking quit date conducted at 12 substance use disorder treatment programs between February 2010 and July 2012. Adults meeting DSM-IV-TR criteria for cocaine and/or methamphetamine dependence and interested in quitting smoking were randomized to treatment as usual (n = 271) or treatment as usual with smoking-cessation treatment (n = 267). All participants received treatment as usual for substance use disorder treatment. Participants assigned to treatment as usual with concurrent smoking-cessation treatment received weekly individual smoking cessation counseling and extended-release bupropion (300 mg/d) during weeks 1-10. During post-quit treatment (weeks 4-10), participants assigned to treatment as usual with smoking-cessation treatment received a nicotine inhaler and contingency management for smoking abstinence. Weekly proportion of stimulant abstinent participants during the treatment phase, as assessed by urine drug screens and self-report, was the primary outcome. Secondary measures included other substance/nicotine use outcomes and treatment attendance. RESULTS: There were no significant treatment effects on stimulant-use outcomes, as measured by the primary outcome and stimulant-free days, on drug-abstinence, or on attendance. Participants assigned to treatment as usual with smoking-cessation treatment, relative to those assigned to treatment as usual, had significantly better outcomes for drug-free days at 6-month follow-up (chi(2)(1) = 4.09, P <.05), with a decrease in drug-free days from baseline of -1.3% in treatment as usual with smoking-cessation treatment and of -7.6% in treatment as usual. Participants receiving treatment as usual with smoking-cessation treatment, relative to those receiving treatment as usual, had significantly better outcomes on smoking point-prevalence abstinence (25.5% vs 2.2%; chi(2)(1) = 44.69, P < .001; OR =18.2). CONCLUSIONS: These results suggest that providing smoking cessation treatment to illicit stimulant-dependent patients in outpatient substance use disorder treatment will not worsen, and may enhance, abstinence from nonnicotine substance use. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01077024. PMID- 24345358 TI - [Life-threatening psychosis caused by using sibutramine-contaminated weight-loss coffee]. AB - BACKGROUND: Weight-loss products, which are freely available in some other countries and on the Internet, may be contaminated with ingredients not mentioned on the label. CASE DESCRIPTION: We describe a 43-year-old woman who presented to the emergency ward of our hospital after stabbing herself in the stomach with a knife, because of severe psychosis. A few days after admission her symptoms were completely gone and there were no longer signs of psychosis. The most likely explanation for the psychosis was the use of sibutramine-contaminated weight-loss coffee (Brazil Potent Slimming Coffee). CONCLUSION: Brazil Potent Slimming Coffee and possibly also other weight-loss products may be contaminated with sibutramine and as a result cause severe adverse reactions. It is always important to consider intoxication due to the use of herbal supplements and other OTC products in the differential diagnosis. PMID- 24345359 TI - [E-research: problems with anonymity and consent]. AB - The Medical Research Involving Human Subjects Act (WMO) requires that participants in medical-scientific studies provide written consent. This requirement makes e-research (online research) unnecessarily difficult and sometimes impossible. Much of e-research involves online interventions that focus on sensitive issues such as sexual dysfunction, addiction and child abuse, for which anonymity is an important condition. WMO procedures, however, strictly interpret the word "written" as "on paper", and participants are not permitted to give consent by email, for example. A second requirement, which mainly makes studies among minors between the ages of 12 and 18 more difficult, is that both parents or the guardian must provide written consent. This undermines anonymity to such an extent that virtually no subjects remain. Participants in medical scientific studies must always be identifiable to the investigator. But, apart from this, he/she should be possible to guarantee anonymity within the regulatory framework. There is good reason to adapt legal regulations to today's needs. PMID- 24345360 TI - [Autism as an example for an android]. AB - Since its introduction in 1921 in the play R.U.R. by Karel Capek we have used the word 'robot'. Robot stories have a number of themes in common: mortality and immortality, human emotions (and the lack of them), slavery and the possibility of rising up against its (or his?) creator, who wants to sit on Gods throne. The android Data from the Star Trek series The Next Generation shows that there are also medical features which may explain his behaviour. PMID- 24345361 TI - [A cyborg is only human]. AB - New biomedical technologies make it possible to replace parts of the human body or to substitute its functions. Examples include artificial joints, eye lenses and arterial stents. Newer technologies use electronics and software, for example in brain-computer interfaces such as retinal implants and the exoskeleton MindWalker. Gradually we are creating cyborgs: hybrids of man and machine. This raises the question: are cyborgs still humans? It is argued that they are. First, because employing technology is a typically human characteristic. Second, because in western thought the human mind, and not the body, is considered to be the seat of personhood. However, it has been argued by phenomenological philosophers that the body is more than just an object but is also a subject, important for human identity. From this perspective, we can appreciate that a bionic body does not make one less human, but it does influence the experience of being human. PMID- 24345362 TI - [Hearing implants]. AB - In the Netherlands, more than 1.5 million people suffer from sensorineural hearing loss or deafness. However, fitting conventional hearing aids does not provide a solution for everyone. In recent decades, developments in medical technology have produced implantable and other devices that restore both sensorineural and conductive hearing losses. These hearing devices can be categorized into bone conductive devices, implantable middle ear prostheses, cochlear implants and auditory brainstem implants. Furthermore, new implants aimed at treating tinnitus and loss of vestibular function have recently been developed. PMID- 24345363 TI - [A woman with thick nails and a white tongue]. AB - A 22-year-old women visited the dermatologist with hypertrophic finger- and toenails, palmoplantar keratoderma and oral leukokeratosis since her childhood. The diagnosis 'pachyonychia congenita type 1' was made. This is a rare dermatosis with an autosomal dominant inheritance pattern. The treatment is symptomatic. PMID- 24345364 TI - [Give more attention to work participation]. AB - As a result of an ageing work force and the continuing economic crisis, the coming decades will demand a long-term active role on the part of the Dutch in participating in paid and voluntary work as well as volunteer aid. This will provide a significant stimulus for so-called work-related healthcare: care that incorporates prevention and treatment of work-related symptoms and diseases, thereby enabling timely and sustainable work participation. Both patients and an increasing number of doctors are willing to contribute to this system of integrated care. The division of financial resources in the Dutch healthcare sector impedes the existing opportunities in providing work-related care, resulting in less care being given and reduced efficiency of the care. The extra costs for introducing structural attention to work in healthcare are estimated at 2-3 Euros per employee. PMID- 24345365 TI - [Quantified Self: insight in yourself through self-monitoring]. AB - Quantified Self is a movement concerned with the question of how people can gain insight into their bodily functions to become and remain healthy. Latching on to trends such as 'do it yourself' and 'peer-to-peer', new technology is increasingly offering the means for this. The applications are not just for patients but for everyone. Technological innovations also allow care givers to base consultations with their patients on objective data collected by the patients themselves. PMID- 24345366 TI - [The bionic heart patient: care about aftercare]. AB - During the last few decades, care for heart patients has significantly improved. The enormous increase in the number of diagnostic and therapeutic options has resulted in a much better prognosis for many patients with cardiovascular disorders. Implantable cardioverter defibrillators (ICDs) and resynchronization therapy combined with ICDs decrease the risk of sudden death due to ventricular arrhythmias and improve symptoms related to cardiovascular failure. Percutaneous valve implants and percutaneous techniques to repair valve leakages have improved the prognosis of patients deemed inoperable. As well as positive effects, all these interventions are associated with a risk of sometimes severe complications. Infections, perforations and even death can occur related to the procedure. Long term complications caused by infections in or failure of technically complicated devices and electrodes are still a threat for many patients. Careful multi disciplinary patient selection prior to the procedure and extensive follow-up are therefore mandatory to achieve the best results for these procedures. PMID- 24345367 TI - [Ill after drinking untreated milk; 'die Amelander Krankheit']. AB - In 2012 three patients consulted their general practitioner with symptoms of gastro-enteritis with bloody stools. This was caused by drinking untreated milk infected with Campylobacter jejuni. Another patient developed reactive arthritis. He too had drunk untreated milk that had probably been infected with Yersinia enterocolitica. Between 1958 and 1995 many German children living in the region of Cologne developed gastro-enteritis after holidaying on Ameland, one of the Dutch islands. This condition was known as 'die Amelander Krankheit', and was caused by drinking untreated milk that had been infected with Campylobacter jejuni. After instructions to boil the milk before drinking were followed, the illness disappeared. These cases show that consumption of untreated milk can have negative consequences for health. Hence, if patients develop gastroenteritis symptoms after visiting a farm we recommend that the possibility that they may have drunk untreated milk is taken into account. PMID- 24345368 TI - [An artificial heart: bridge to transplantation or permanent?]. AB - An artificial heart is a continuous-flow pump device with a constant output, which usually supports the left ventricle. Over the past five years, survival rates with an artificial heart have increased dramatically, but with an annual mortality of 10% per year compared with 6% for heart transplantation the artificial heart is mainly a 'bridge to transplantation' or an alternative for those patients who are not suitable for heart transplant, 'destination therapy'. It is anticipated that the number and severity of complications will decrease as a result of technological progress. The artificial heart could then become a long term treatment option providing a good quality of life and thus become equivalent to a heart transplant. PMID- 24345369 TI - [The white coat as a cape: doctors, superheroes and bionics]. AB - OBJECTIVE: To study the relationship between doctors and comic books, cartoons, superheroes and bionic prosthetic organs. DESIGN: Descriptive survey. METHOD: For this study, 341 doctors and medical students filled in a digital survey in the autumn of 2013. The questionnaire contained questions about comic books and cartoons, their superheroes, prosthetic organs and about bionic and non-bionic super powers. RESULTS: As a child more than half of the participants read comic books regularly or often, and most watched cartoons regularly or often. Now their childhood interest in this subject has mostly been lost. In their youth, Suske & Wiske were the favourite, and now it is Donald Duck. The number of doctors with a favourite superhero decreased as aged increased from 52% to 37%. The care givers entertain lively fantasies about having bionic superpowers. According to the participants, the idea doctor would have ultrasonic eyes and all sorts of other super senses. Ninety-one per cent thought that 'the development of prosthetic organs is not a waste of money'. CONCLUSION: If Batman and Superman come to blows, Catwoman wins. PMID- 24345371 TI - High glucose-induced barrier impairment of human retinal pigment epithelium is ameliorated by treatment with Goji berry extracts through modulation of cAMP levels. AB - Human retinal pigment epithelium cells were used to investigate the mechanisms underlying blood-retinal barrier disruption under conditions of chronic hyperglycemia. The treatment with 25 mM glucose caused a rapid drop in the transepithelial electrical resistance (TEER), which was reversed by the addition of either a methanolic extract from Goji (Lycium barbarum L.) berries or its main component, taurine. Intracellular cAMP levels increased concurrently with the high glucose-induced TEER decrease, and were correlated to an increased activity of the cytosolic isoform of the enzyme adenylyl cyclase. The treatment with plant extract or taurine restored control levels. Data are discussed in view of a possible prevention approach for diabetic retinopathy. PMID- 24345370 TI - A low-density lipoprotein receptor-related protein (LRP)-like molecule identified from Chlamys farreri participated in immune response against bacterial infection. AB - Low-density lipoprotein receptor-related protein (LRP) is a group of important endocytic receptors contributing to binding ligands and maintaining internal environment. In the present study, an LRP-like molecule was identified from Zhikong scallop Chlamys farreri (CfLPR), and its mRNA expression profiles, tissue location, and immunology activities were analyzed to explore its possible function in the innate immune system. The ORF of CfLRP was of 1971 bp encoding a polypeptide of 656 amino acids with ten low-density lipoprotein-receptor YWTD (LY) domains and one scavenger receptor cysteine-rich (SRCR) domain. It shared similar structure with out-membrane domains of LRP family members in mammalian. The mRNA transcripts of CfLRP were dominantly expressed in hepatopancreas and mantle (P < 0.01), and its mRNA level in hemocytes was up-regulated (P < 0.01) significantly after the stimulations of lipopolysaccharides (LPS), peptidoglycan (PGN) and beta-glucan. Western blotting assay using polyclonal antibody specific for CfLRP revealed that CfLRP was localized in the plasma. The recombinant protein of CfLRP (rCfLRP) could bind acetylated low density lipoprotein (Ac-LDL), metalloprotease SPF1 of Vibrio splendidus and mannan, but could not bind other typical PAMPs such as LPS, PGN, beta-glucan and zymosan. Meanwhile, rCfLRP also exhibited strong bacteriostatic activity to Gram-negative bacteria Vibrio anguillarum and V. splendidus. These results indicated that CfLRP could serve as a receptor to recognize and eliminate the invading pathogens, which provided a new implication in the function of LRP-like molecules in invertebrate immunity. PMID- 24345372 TI - Effects of heat-treatment on plasma rich in growth factors-derived autologous eye drop. AB - We have developed and characterized a new type of plasma rich in growth factors (PRGF) derived eye-drop therapy for patients suffering from autoimmune diseases. To determine the concentration of several growth factors, proteins, immunoglobulins and complement activity of the heat-inactivated eye-drop and to study its biological effects on cell proliferation and migration of different ocular surface cells, blood from healthy donors was collected, centrifuged and PRGF was prepared avoiding the buffy coat. The half volume of the obtained plasma supernatant from each donor was heat-inactivated at 56 degrees C for 1 h (heat inactivated PRGF). The concentration of several proteins involved on corneal wound healing, immunoglubolins G, M and E and functional integrity of the complement system assayed by CH50 test were determined. The proliferative and migratory potential of inactivated and non-inactivated PRGF eye drops were assayed on corneal epithelial cells (HCE), keratocytes (HK) and conjunctival fibroblasts (HConF). Heat-inactivated PRGF preserves the content of most of the proteins and morphogens involved in its wound healing effects while reduces drastically the content of IgE and complement activity. Heat-inactivated PRGF eye drops increased proliferation and migration potential of ocular surface cells with regard to PRGF showing significant differences on proliferation and migration rate of HCE and HConF respectively. In summary, heat-inactivation of PRGF eye drops completely reduced complement activity and deceased significantly the presence of IgE, maintaining the biological activity of PRGF on ocular surface cells. PMID- 24345374 TI - The LC3 interactome at a glance. AB - Continuous synthesis of all cellular components requires their constant turnover in order for a cell to achieve homeostasis. To this end, eukaryotic cells are endowed with two degradation pathways - the ubiquitin-proteasome system and the lysosomal pathway. The latter pathway is partly fed by autophagy, which targets intracellular material in distinct vesicles, termed autophagosomes, to the lysosome. Central to this pathway is a set of key autophagy proteins, including the ubiquitin-like modifier Atg8, that orchestrate autophagosome initiation and biogenesis. In higher eukaryotes, the Atg8 family comprises six members known as the light chain 3 (LC3) or gamma-aminobutyric acid (GABA)-receptor-associated protein (GABARAP) proteins. Considerable effort during the last 15 years to decipher the molecular mechanisms that govern autophagy has significantly advanced our understanding of the functioning of this protein family. In this Cell Science at a Glance article and the accompanying poster, we present the current LC3 protein interaction network, which has been and continues to be vital for gaining insight into the regulation of autophagy. PMID- 24345373 TI - How do bacteria localize proteins to the cell pole? AB - It is now well appreciated that bacterial cells are highly organized, which is far from the initial concept that they are merely bags of randomly distributed macromolecules and chemicals. Central to their spatial organization is the precise positioning of certain proteins in subcellular domains of the cell. In particular, the cell poles - the ends of rod-shaped cells - constitute important platforms for cellular regulation that underlie processes as essential as cell cycle progression, cellular differentiation, virulence, chemotaxis and growth of appendages. Thus, understanding how the polar localization of specific proteins is achieved and regulated is a crucial question in bacterial cell biology. Often, polarly localized proteins are recruited to the poles through their interaction with other proteins or protein complexes that were already located there, in a so called diffusion-and-capture mechanism. Bacteria are also starting to reveal their secrets on how the initial pole 'recognition' can occur and how this event can be regulated to generate dynamic, reproducible patterns in time (for example, during the cell cycle) and space (for example, at a specific cell pole). Here, we review the major mechanisms that have been described in the literature, with an emphasis on the self-organizing principles. We also present regulation strategies adopted by bacterial cells to obtain complex spatiotemporal patterns of protein localization. PMID- 24345375 TI - The peroxisomal receptor dislocation pathway: to the exportomer and beyond. AB - The biogenesis of peroxisomes is an ubiquitin-dependent process. In particular, the import of matrix proteins into the peroxisomal lumen requires the modification of import receptors with ubiquitin. The matrix proteins are synthesized on free polyribosomes in the cytosol and are recognized by import receptors via a peroxisomal targeting sequence (PTS). Subsequent to the transport of the receptor/cargo-complex to the peroxisomal membrane and the release of the cargo into the peroxisomal lumen, the PTS-receptors are exported back to the cytosol for further rounds of matrix protein import. The exportomer represents the molecular machinery required for the retrotranslocation of the PTS-receptors. It comprises enzymes for the ubiquitination as well as for the ATP-dependent extraction of the PTS-receptors from the peroxisomal membrane. Furthermore, recent evidence indicates a mechanistic interconnection of the ATP-dependent removal of the PTS-receptors with the translocation of the matrix protein into the organellar lumen. Interestingly, the components of the peroxisomal exportomer seem also to be involved in cellular tasks that are distinct from the ubiquitination and dislocation of the peroxisomal PTS-receptors. This includes work that indicates a central function of this machinery in the export of peroxisomal matrix proteins in plants, while a subset of exportomer components is involved in the meiocyte formation in some fungi, the peroxisome-chloroplast contact during photorespiration in plants and possibly even the selective degradation of peroxisomes via pexophagy. In this review, we want to discuss the central role of the exportomer during matrix protein import, but also highlight distinct roles of exportomer constituents in additional cellular processes. This article is part of a Special Issue entitled: Peroxisomes: biogenesis, functions and diseases. PMID- 24345376 TI - A "thickness series": weak signal extraction of ELNES in EELS spectra from surfaces. AB - We report a new simple but effective method to extract the weak surface signals from a "thickness series" of recorded electron energy-loss spectra. Using precise thickness measurements and energy-loss near-edge structures measured at increasing thicknesses, we are able to extract the surface and bulk components in the series. The electronic structure and bonding information from SrTiO3 (001) reconstructed surfaces have been successfully obtained by applying this approach. This approach can be applied to study many other cases including absorbed monolayers and beam-sensitive interfaces. PMID- 24345377 TI - Pulmonary arterial hypertension in HIV infection: a concise review. AB - Pulmonary arterial hypertension (PAH) is an infrequent but nevertheless serious life threatening severe complication of human immunodeficiency virus (HIV) infection. In today's era of antiretroviral therapy (ART), the mortality of HIV patients has greatly reduced due to improved immune function and fewer opportunistic infections. However, these patients have an increased incidence of PAH. In this review, we will mainly discuss HIV-related pulmonary arterial hypertension (HRPH) in terms of the epidemiology, pathogenesis, clinical characteristics and treatment. PMID- 24345378 TI - Right ventricular outflow tract enlargement prior to pulmonary valve replacement is associated with poorer structural and functional outcomes, in adults with repaired Tetralogy of Fallot. AB - BACKGROUND: Pulmonary valve replacement (PVR) is commonly performed late after Tetralogy of Fallot (TOF) repair. We examined the effects of PVR on cardiac structure, function and exercise capacity in adults with repaired TOF. METHODS: Eighteen adult patients with repaired TOF and severe pulmonary regurgitation (PR) with right ventricular (RV) dilatation requiring PVR for clinical reasons (age; 25+/-8 years) were recruited to undergo cardiac MRI (1.5T) and cardiopulmonary exercise testing before and 14+/-3 months after PVR. RESULTS: Reduced indexed RV end-diastolic volume (RVEDVi; 186+/-32mL/m(2) pre-op vs 114+/-20mL/m(2) post-op, p<0.001) was observed after PVR. "Normalisation" of RVEDVi (<=108mL/m(2)) was achieved in only seven of 18 patients. Pre-PVR RVEDVi correlated with post operative change in RVEDVi (change=-72.1+/-20.4mL/m(2), r=-0.815, p<0.001). Exercise capacity remained high-normal post-PVR (% predicted maximal workload: 93+/-16% vs 91+/-12%, p=0.5). Regional RV volumes were assessed; RV outflow tract (RVOT) volumes were compared to the RV muscular corpus. Large pre-PVR RVOT volumes correlated negatively with post-surgical RV ejection fraction, peak VO2 and delta VO2 at anaerobic threshold (p<0.05 for all). CONCLUSIONS: Normalisation of RV volume is unlikely to be achieved above a pre-PVR RVEDVi of 165mL/m(2) or more. In particular, an enlarged RVOT prior to PVR predicts suboptimal structural and functional outcomes. PMID- 24345379 TI - Single-centre experience with perioperative use of intraaortic balloon pump in cardiac surgery. AB - BACKGROUND: Intraaortic balloon pump (IABP) is frequently used in cardiac surgery in order to prevent or treat low cardiac output syndrome. Although being widely used and forming the first line therapy in these haemodynamically unstable patients despite maximal medication, optimal timing for IABP insertion is still discussed. This retrospective study evaluates hospital outcomes of patients receiving IABP at preoperative, intraoperative and postoperative periods during cardiac surgery. MATERIALS AND METHODS: Between 2006 and 2012, 2196 patients underwent open cardiac surgery in our centre. IABP was used in 121 (5.4%) patients. Nine patients had preoperative IABP insertion, 76 patients (62.8%) had intraoperative insertion to ease weaning from cardiopulmonary bypass, and 36 patients (29.8%) had postoperative insertion in the intensive care unit mainly due to refractory haemodynamic instability. Hospital outcomes of these 121 patients were analysed retrospectively. RESULTS: The majority of the patients were male (men 89, 73.6% and women 32, 26.4%; mean age was 65.9+/-11.5 years). Among the cohort 87 (71.9%) underwent isolated coronary artery bypass surgery (CABG) and the rest (34 patients, 28.1%) were operated for valve disease with/without CABG or for CABG with carotid endarterectomy, left ventricular aneurysm repair, post myocardial infarction ventricular septal defect or pathologies involving ascending aorta. The overall hospital mortality of the whole cohort was 27.3%. Mortality rates according to IABP timing were 33.3%, 19.7% and 41.7% for pre, intra and postoperative insertion, respectively. Logistic regression analysis identified female gender, low ejection fraction (<30%), complex surgery and postoperative insertion as risk factors for mortality. CONCLUSION: IABP insertion timing in cardiac surgery is crucial and many reports advocate early insertion since patient outcomes are poor for late insertions. This single centre study also confirms that the least favourable results are among patients with postoperative IABP insertion. PMID- 24345380 TI - Higher critical plaque wall stress in patients who died of coronary artery disease compared with those who died of other causes: a 3D FSI study based on ex vivo MRI of coronary plaques. AB - Mechanical forces play an important role in the rupture of vulnerable plaques. This process is often associated with cardiovascular syndromes, such as heart attack and stroke. In this study, magnetic resonance imaging (MRI)-based models were used to investigate the association between plaque wall stress (PWS) and coronary artery disease (CAD). Ex vivo MRI data of coronary plaques from 12 patients were used to construct 12 three-dimensional (3D) fluid-structure interaction (FSI) computational models. Six of the patients had died from CAD and six had died from non-CAD causes. PWS was assessed using all nodal points on the lumen surface of each plaque. The maximum PWS from all possible vulnerable sites of each plaque was defined as the 3D critical plaque wall stress (CPWS). Mean 3D CPWS in the CAD group was 94.3% higher than that in the non-CAD group (265.6 vs. 136.7 kPa, P=0.0029). There was no statistically significant difference in global maximum plaque wall stress (GMPWS) between the two groups (P=0.347). There was also no statistically significant difference in plaque burden between the CAD group (84.4+/-5%) and the non-CAD group (82.0+/-8%, P=0.552). The results indicate that plaques from patients who died from CAD were associated with higher CPWS compared with those from patients who died from non-CAD causes. With further validation, analysis of CPWS may prove to be an important component in assessment of plaque vulnerability. PMID- 24345381 TI - Depletion of chondrocyte primary cilia reduces the compressive modulus of articular cartilage. AB - Primary cilia are slender, microtubule based structures found in the majority of cell types with one cilium per cell. In articular cartilage, primary cilia are required for chondrocyte mechanotransduction and the development of healthy tissue. Loss of primary cilia in Col2aCre;ift88(fl/fl) transgenic mice results in up-regulation of osteoarthritic (OA) markers and development of OA like cartilage with greater thickness and reduced mechanical stiffness. However no previous studies have examined whether loss of primary cilia influences the intrinsic mechanical properties of articular cartilage matrix in the form of the modulus or just the structural properties of the tissue. The present study describes a modified analytical model to derive the viscoelastic moduli based on previous experimental indentation data. Results show that the increased thickness of the articular cartilage in the Col2aCre;ift88(fl/fl) transgenic mice is associated with a reduction in both the instantaneous and equilibrium moduli at indentation strains of greater than 20%. This reveals that the loss of primary cilia causes a significant reduction in the mechanical properties of cartilage particularly in the deeper zones and possibly the underlying bone. This is consistent with histological analysis and confirms the importance of primary cilia in the development of a mechanically functional articular cartilage. PMID- 24345382 TI - Rapid treatment response of suicidal symptoms to lithium, sleep deprivation, and light therapy (chronotherapeutics) in drug-resistant bipolar depression. AB - BACKGROUND: One third of patients with bipolar disorder attempt suicide. Depression in bipolar disorder is associated with drug resistance. The efficacy of antidepressants on suicidality has been questioned. Total sleep deprivation and light therapy prompt a rapid and stable antidepressant response in bipolar disorder. METHOD: We studied 143 consecutively admitted inpatients (December 2006 August 2012) with a major depressive episode in the course of bipolar disorder (DSM-IV criteria). Among the 141 study completers, 23% had a positive history of attempted suicide and 83% had a positive history of drug resistance. During 1 week, patients were administered 3 consecutive total sleep deprivation cycles (each composed of a period of 36 hours awake followed by recovery sleep) combined with bright light therapy in the morning for 2 weeks. At admission, patients who had been taking lithium continued it, and those who had not been taking lithium started it. Severity of depression was rated according to the Hamilton Depression Rating Scale (HDRS) (primary outcome measure) and Beck Depression Inventory (BDI). RESULTS: Two patients switched polarity. Among the 141 who completed the treatment, 70% achieved a 50% reduction in HDRS score in 1 week, which persisted 1 month after in 55%. The amelioration involved an immediate and persistent decrease in suicide scores soon after the first total sleep deprivation cycle (F3,411 = 42.78, P < .00001). A positive history of suicide attempts was associated with worse early life stress and with worse suicide scores at baseline, but it did not influence response. Patients with current suicidal thinking or planning responded equally well (F3,42 = 20.70, P < .000001). Remarkably, however, nonresponders achieved a benefit, with significantly decreased final scores also including suicidality ratings (F3,120 = 6.55, P = .0004). Self-ratings showed the same pattern of change. Previous history of drug resistance did not hamper response. During the following month, 78 of 99 responders continued to stay well and were discharged from the hospital on lithium therapy alone. CONCLUSIONS: The combination of total sleep deprivation, light therapy, and lithium is able to rapidly decrease depressive suicidality and prompt antidepressant response in drug-resistant major depression in the course of bipolar disorder. PMID- 24345383 TI - Seasonal changes in the prostatic complex of Artibeus planirostris (Chiroptera: Phyllostomidae). AB - The male reproductive accessory glands are important organs that secrete products that ensure the survival, viability and motility of spermatozoa, not only in the male reproductive tract, but also in the female. Most studies relating to the reproduction of bats do not include these glands, and detailed studies of these glands describing annual variations in the morphology and physiology are scarce. The aim of this study was to evaluate the impact of these variations on morphophysiology of the prostatic complex (PC) of Artibeus planirostris (Chiroptera: Phyllostomidae). Adult males were collected from June 2009 to July 2010, and the PC was subjected to various analyses. We observed that the PC showed marked variations throughout the year. Both PC and testicular weight increased synchronously with an increasing rate of circulating testosterone, from the autumn until summer, demonstrating that both organs are regulated by this hormone. Each region of the PC (ventral and dorsal) was unique and distinct. The ventral region showed the glandular lumen as a predominant component, in contrast to the dorsal introduced epithelium; acid phosphatase activity was observed in the epithelium of all acini in the dorsal region, but only in the stroma of the ventral region, in addition each region responded differently to variations in the environment and circulating testosterone. We concluded that the PC of A. planirostris produces two secretory peaks, which were related to a gradual increase in the rate of circulating testosterone, which stimulates both of the prostate regions to prepare for the two reproductive periods. PMID- 24345384 TI - Neuropeptides and polypeptide hormones in echinoderms: new insights from analysis of the transcriptome of the sea cucumber Apostichopus japonicus. AB - Echinoderms are of special interest for studies in comparative endocrinology because of their phylogenetic position in the animal kingdom as deuterostomian invertebrates. Furthermore, their pentaradial symmetry as adult animals provides a unique context for analysis of the physiological and behavioral roles of peptide signaling systems. Here we report the first extensive survey of neuropeptide and peptide hormone precursors in a species belonging to the class Holothuroidea. Transcriptome sequence data obtained from the sea cucumber Apostichopus japonicus were analyzed to identify homologs of precursor proteins that have recently been identified in the sea urchin Strongylocentrotus purpuratus (class Echinoidea). A total of 17 precursor proteins have been identified in A. japonicus, including precursors of peptides related to thyrotropin-releasing hormone, pedal peptide/orcokinin-type peptides, AN peptides/tachykinins, luqins, corticotropin-releasing hormone (CRH), GPA2-type glycoprotein hormone subunits and bursicon. In addition, an unusual finding was an A. japonicus calcitonin-type precursor protein (AjCTLPP), the first to be discovered that comprises two calcitonin-like peptides; this contrasts with the products of the alternatively-spliced calcitonin/CGRP gene in vertebrates, which comprise either calcitonin or CGRP. Collectively, the data obtained provide new insights on the evolution and diversity of neuropeptides and polypeptide hormones. Furthermore, because A. japonicus is one of several sea cucumber species that are used for human consumption, our findings may have practical and economic impact by providing a basis for neuroendocrine-based strategies to improve methods of aquaculture. PMID- 24345385 TI - Everolimus-eluting versus sirolimus-eluting coronary stents in patients with and without diabetes mellitus. AB - AIMS: Patients with diabetes mellitus have a higher risk of adverse events after percutaneous coronary intervention (PCI). This study aimed to elucidate the relative efficacy of everolimus-eluting stents (EES) versus sirolimus-eluting stents (SES) according to diabetic status. METHODS AND RESULTS: Data from the EXCELLENT randomised trial and registry were pooled in a per protocol analysis manner. The primary endpoint was target lesion failure (TLF), a composite of cardiac death, target vessel-related myocardial infarction, or target vessel revascularisation. Among a total of 6,524 patients, 2,404 (36.8%) had diabetes mellitus. Patients with diabetes were shown to have a higher rate of TLF after PCI, which was mainly driven by differences in cardiac death and myocardial infarction, while the rate of repeat revascularisation and stent thrombosis did not differ significantly. TLF occurred at a similar rate between patients treated with EES versus SES in each subgroup stratified by diabetic status (interaction p=0.384). In addition, no significant interactions were present with regard to any pre-specified clinical endpoints. The results were corroborated by analysis with inverse probability of treatment weighting (interaction p=0.329). We also found that insulin-dependent diabetes imposed an even greater risk of TLF on patients treated with PCI. CONCLUSIONS: Despite the recent advances in drug eluting stent technology, diabetic patients are still at higher risk of adverse clinical events after PCI than those without diabetes mellitus. Whether a patient was treated with EES or SES had no significant interaction with diabetic status in terms of clinical outcome after PCI. PMID- 24345386 TI - The effect of irradiation and mass rearing on the anti-predator behaviour of the Mexican fruit fly, Anastrepha ludens (Diptera: Tephritidae). AB - Fruit flies (Diptera: Tephritidae) are major pests worldwide. The sterile insect technique, where millions of flies are reared, sterilized by irradiation and then released, is one of the most successful and ecologically friendly methods of controlling populations of these pests. The mating behaviour of irradiated and non-irradiated flies has been compared in earlier studies, but there has been little attention paid to the anti-predator behaviour of mass-reared flies, especially with respect to wild flies. Tephritid flies perform a supination display to their jumping spider predators in order to deter attacks. In this study, we evaluated the possibility of using this display to determine the anti predator capabilities of mass-reared irradiated, non-irradiated flies, and wild flies. We used an arena setup and observed bouts between jumping spiders (Phidippus audax Hentz) and male Mexican fruit flies (Anastrepha ludens Loew). We show that although all flies performed a supination display to their predator, wild flies were more likely to perform a display and were significantly more successful in avoiding attack than mass-reared flies. We suggest that this interaction can be used to develop a rapid realistic method of quality control in evaluating anti-predator abilities of mass-reared fruit flies. PMID- 24345387 TI - A DCM for resting state fMRI. AB - This technical note introduces a dynamic causal model (DCM) for resting state fMRI time series based upon observed functional connectivity--as measured by the cross spectra among different brain regions. This DCM is based upon a deterministic model that generates predicted crossed spectra from a biophysically plausible model of coupled neuronal fluctuations in a distributed neuronal network or graph. Effectively, the resulting scheme finds the best effective connectivity among hidden neuronal states that explains the observed functional connectivity among haemodynamic responses. This is because the cross spectra contain all the information about (second order) statistical dependencies among regional dynamics. In this note, we focus on describing the model, its relationship to existing measures of directed and undirected functional connectivity and establishing its face validity using simulations. In subsequent papers, we will evaluate its construct validity in relation to stochastic DCM and its predictive validity in Parkinson's and Huntington's disease. PMID- 24345388 TI - Quantitative comparison of cortical surface reconstructions from MP2RAGE and multi-echo MPRAGE data at 3 and 7 T. AB - The Magnetization-Prepared 2 Rapid Acquisition Gradient Echo (MP2RAGE) method achieves spatially uniform contrast across the entire brain between gray matter and surrounding white matter tissue and cerebrospinal fluid by rapidly acquiring data at two points during an inversion recovery, and then combining the two volumes so as to cancel out sources of intensity and contrast bias, making it useful for neuroimaging studies at ultrahigh field strengths (>=7T). To quantify the effectiveness of the MP2RAGE method for quantitative morphometric neuroimaging, we performed tissue segmentation and cerebral cortical surface reconstruction of the MP2RAGE data and compared the results with those generated from conventional multi-echo MPRAGE (MEMPRAGE) data across a group of healthy subjects. To do so, we developed a preprocessing scheme for the MP2RAGE image data to allow for automatic cortical segmentation and surface reconstruction using FreeSurfer and analysis methods to compare the positioning of the surface meshes. Using image volumes with 1mm isotropic voxels we found a scan-rescan reproducibility of cortical thickness estimates to be 0.15 mm (or 6%) for the MEMPRAGE data and a slightly lower reproducibility of 0.19 mm (or 8%) for the MP2RAGE data. We also found that the thickness estimates were systematically smaller in the MP2RAGE data, and that both the interior and exterior cortical boundaries estimated from the MP2RAGE data were consistently positioned within the corresponding boundaries estimated from the MEMPRAGE data. Therefore several measureable differences exist in the appearance of cortical gray matter and its effect on automatic segmentation methods that must be considered when choosing an acquisition or segmentation method for studies requiring cortical surface reconstructions. We propose potential extensions to the MP2RAGE method that may help to reduce or eliminate these discrepancies. PMID- 24345389 TI - Optimization of multifocal transcranial current stimulation for weighted cortical pattern targeting from realistic modeling of electric fields. AB - Recently, multifocal transcranial current stimulation (tCS) devices using several relatively small electrodes have been used to achieve more focal stimulation of specific cortical targets. However, it is becoming increasingly recognized that many behavioral manifestations of neurological and psychiatric disease are not solely the result of abnormality in one isolated brain region but represent alterations in brain networks. In this paper we describe a method for optimizing the configuration of multifocal tCS for stimulation of brain networks, represented by spatially extended cortical targets. We show how, based on fMRI, PET, EEG or other data specifying a target map on the cortical surface for excitatory, inhibitory or neutral stimulation and a constraint on the maximal number of electrodes, a solution can be produced with the optimal currents and locations of the electrodes. The method described here relies on a fast calculation of multifocal tCS electric fields (including components normal and tangential to the cortical boundaries) using a five layer finite element model of a realistic head. Based on the hypothesis that the effects of current stimulation are to first order due to the interaction of electric fields with populations of elongated cortical neurons, it is argued that the optimization problem for tCS stimulation can be defined in terms of the component of the electric field normal to the cortical surface. Solutions are found using constrained least squares to optimize current intensities, while electrode number and their locations are selected using a genetic algorithm. For direct current tCS (tDCS) applications, we provide some examples of this technique using an available tCS system providing 8 small Ag/AgCl stimulation electrodes. We demonstrate the approach both for localized and spatially extended targets defined using rs-fcMRI and PET data, with clinical applications in stroke and depression. Finally, we extend these ideas to more general stimulation protocols, such as alternating current tCS (tACS). PMID- 24345390 TI - Whole brain mapping of water pools and molecular dynamics with rotating frame MR relaxation using gradient modulated low-power adiabatic pulses. AB - Nuclear magnetic resonance (NMR) relaxation in the rotating frame is sensitive to molecular dynamics on the time scale of water molecules interacting with macromolecules or supramolecular complexes, such as proteins, myelin and cell membranes. Hence, longitudinal (T1rho) and transverse (T2rho) relaxation in the rotating frame may have a great potential to probe the macromolecular fraction of tissues. This stimulated a large interest in using this MR contrast to image brain under healthy and disease conditions. However, experimental challenges related to the use of intense radiofrequency irradiation have limited the widespread use of T1rho and T2rho imaging. Here, we present methodological development to acquire 3D high-resolution or 2D (multi-)slice selective T1rho and T2rho maps of the entire human brain within short acquisition times. These improvements are based on a class of gradient modulated adiabatic pulses that reduce the power deposition, provide slice selection, and mitigate artifacts resulting from inhomogeneities of B1 and B0 magnetic fields. Based on an analytical model of the T1rho and T2rho relaxation we compute the maps of macromolecular bound water fraction, correlation and exchange time constants as quantitative biomarkers informative of tissue macromolecular content. Results obtained from simulations, phantoms and five healthy subjects are included. PMID- 24345391 TI - Mitral valve prosthesis choice for patients aged 65 years and over in the UK. Are the guidelines being followed and does it matter? AB - OBJECTIVE: Current guidelines recommend that most patients aged >=65 years should undergo mitral valve replacement (MVR) using a biological prosthesis. The objectives of this study were to assess whether these guidelines are being followed in UK practice, and to investigate whether the guidelines are appropriate based on in-hospital mortality and mid-term survival. METHODS: Data from the National Institute for Cardiovascular Outcomes Research Adult Cardiac Surgery Audit database from all National Health Service (NHS) hospitals and some private hospitals performing adult cardiac surgery in the UK between April 2001 and March 2011 were analysed. The overall cohort included 3862 patients aged >=65 years who underwent first-time MVR. Propensity score matching and regression adjustment were used to compare outcomes between prosthesis groups. RESULTS: The mean age was 73.0 years (SD 4.9) with 50% of patients having surgery with a mechanical prosthesis. This proportion decreased over the study period and with increasing patient age with marked variation between hospitals. In the propensity matched cohort, in-hospital mortality in the biological group was 6.9%, and in the mechanical group it was 5.9% giving an unadjusted OR of 1.17 (95% CI 0.84 to 1.63). There was no significant difference in mid-term survival between the matched groups with an unadjusted HR for biological prosthesis of 1.08 (95% CI 0.93 to 1.24). Similar results were found when using regression adjustment on unmatched data. CONCLUSIONS: Current guidelines concerning age and mitral valve prosthesis choice are not being followed for patients aged >=65 years. With regards to in-hospital and mid-term mortality, this study demonstrates that there is no difference between prosthesis types. PMID- 24345392 TI - How to monitor cardiac toxicity of chemotherapy: time is muscle! PMID- 24345393 TI - Thermodynamic balance of photosynthesis and transpiration at increasing CO2 concentrations and rapid light fluctuations. AB - Experimental and theoretical flux models have been developed to reveal the influence of sun flecks and increasing CO2 concentrations on the energy and entropy balances of the leaf. The rapid and wide range of fluctuations in light intensity under field conditions were simulated in a climatic gas exchange chamber and we determined the energy and entropy balance of the leaf based on radiation and gas exchange measurements. It was estimated that the energy of photosynthetic active radiation (PAR) accounts for half of transpiration, which is the main factor responsible for the exportation of the entropy generated in photosynthesis (Sg) out of the leaf in order to maintain functional the photosynthetic machinery. Although the response of net photosynthetic production to increasing concentrations of CO2 under fluctuating light is similar to that under continuous light, rates of transpiration respond slowly to changes of light intensity and are barely affected by the concentration of CO2 in the range of 260 495 ppm, in which net photosynthesis increases by more than 100%. The analysis of the results confirms that future increases of CO2 will improve the efficiency of the conversion of radiant energy into biomass, but will not reduce the contribution of plant transpiration to the leaf thermal balance. PMID- 24345394 TI - A convenient system for highly specific and sensitive detection of miRNA expression. AB - Since the first miRNA was discovered in 1993, miRNAs have become a hotspot for biological research. In order to feed this demand, a robust method is required to detect miRNA gene expression. Development of a detection method is more difficult for miRNAs than for long RNAs, such as mRNA, owing to their small size. Existing methods have limitations; thus, new methods are required. We describe a new system for detecting miRNA expression, which can distinguish miRNA from its precursor and has single-nucleotide resolution. It has single molecule and multiplex detection potential. It may be performed as a polymerase chain reaction (PCR) method, a blotting method, or a macroarray method according to the analyst's preference. This personalized system provides a convenient tool for the detection of miRNA gene expression. PMID- 24345395 TI - RNA detection in situ with FISH-STICs. AB - The ability to detect RNA molecules in situ has long had important applications for molecular biological studies. Enzyme or dye-labeled antisense in vitro runoff transcripts and synthetic oligodeoxynucleotides (ODN) both have a proven track record of success, but each of these also has scientific and practical drawbacks and limitations to its use. We devised a means to use commercially synthesized oligonucleotides as RNA-FISH probes without further modification and show that such probes work well for detection of RNA in cultured cells. This approach can bind a high concentration of fluorescent ODN to a short stretch of an RNA using commercial DNA synthesis outlets available to any laboratory. We call this approach for creating in situ hybridization probes Fluorescence In Situ Hybridization with Sequential Tethered and Intertwined ODN Complexes (FISH STICs). We demonstrate that one FISH-STIC probe can detect mRNA molecules in culture, and that probe detection can be improved by the addition of multiple probes that can be easily adapted for robust mRNA quantification. Using FISH STICs, we demonstrate a nonoverlapping distribution for beta-actin and gamma actin mRNA in cultured fibroblasts, and the detection of neuron-specific transcripts within cultured primary hippocampal neurons. PMID- 24345397 TI - Challenges in the delivery of quality breast cancer care: initiation of adjuvant hormone therapy at an urban safety net hospital. AB - PURPOSE: Breast cancer treatment disparities in racial/ethnic minority and low income populations are well documented; however, underlying reasons remain poorly understood. This study sought to identify barriers to the delivery of quality breast cancer treatment, addressing compliance with the National Quality Forum (NQF) quality metric for adjuvant hormone therapy (HT; administration of HT within 365 days of diagnosis in eligible patients) at an urban safety net hospital. METHODS: This retrospective, observational study included women diagnosed with nonmetastatic, T1c or greater, estrogen and/or progesterone receptor-positive breast cancer from 2006 to 2008. Data sources included the hospital cancer registry and electronic medical record. Compliance with the NQF quality metric was defined as HT prescription within 365 days of diagnosis. Bivariate analysis compared compliant with noncompliant patients. Qualitative analysis assessed reasons for delayed compliance (HT at > 365 days) and never compliance (no HT at 4 years). RESULTS: Of 113 eligible patients, the majority were racial/ethnic minority (56%), stage II (54%), unmarried (60%), and had public or no insurance (72%). Sixty-four percent were compliant, and 36% were noncompliant. Of the noncompliant, 78% had delayed compliance, and 22% were never compliant. Noncompliant patients were significantly more likely to be Black, Hispanic, foreign-born, and stage III at diagnosis. Ten reasons for delayed compliance were identified, including patient- and system-level barriers. Most patients (56%) had more than one reason contributing to delay. CONCLUSION: Urgently needed interventions to reduce disparities in breast cancer treatment should take into account obstacles inherent among immigrant and indigent populations and complexities of multidisciplinary cancer care. PMID- 24345396 TI - An unusual mechanism for EF-Tu activation during tmRNA-mediated ribosome rescue. AB - In bacteria, ribosomes stalled on truncated mRNAs are rescued by transfer messenger RNA (tmRNA) and its protein partner SmpB. Acting like tRNA, the aminoacyl-tmRNA/SmpB complex is delivered to the ribosomal A site by EF-Tu and accepts the transfer of the nascent polypeptide. Although SmpB binding within the decoding center is clearly critical for licensing tmRNA entry into the ribosome, it is not known how activation of EF-Tu occurs in the absence of a codon anticodon interaction. A recent crystal structure revealed that SmpB residue His136 stacks on 16S rRNA nucleotide G530, a critical player in the canonical decoding mechanism. Here we use pre-steady-state kinetic methods to probe the role of this interaction in ribosome rescue. We find that although mutation of His136 does not reduce SmpB's affinity for the ribosomal A-site, it dramatically reduces the rate of GTP hydrolysis by EF-Tu. Surprisingly, the same mutation has little effect on the apparent rate of peptide-bond formation, suggesting that release of EF-Tu from the tmRNA/SmpB complex on the ribosome may occur prior to GTP hydrolysis. Consistent with this idea, we find that peptidyl transfer to tmRNA is relatively insensitive to the antibiotic kirromycin. Taken together, our studies provide a model for the initial stages of ribosomal rescue by tmRNA. PMID- 24345398 TI - The effect of acutely administered MDMA on subjective and BOLD-fMRI responses to favourite and worst autobiographical memories. AB - 3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine-releaser that is widely used as a recreational drug. Preliminary work has supported the potential of MDMA in psychotherapy for post-traumatic stress disorder (PTSD). The neurobiological mechanisms underlying its putative efficacy are, however, poorly understood. Psychotherapy for PTSD usually requires that patients revisit traumatic memories, and it has been argued that this is easier to do under MDMA. Functional magnetic resonance imaging (fMRI) was used to investigate the effect of MDMA on recollection of favourite and worst autobiographical memories (AMs). Nineteen participants (five females) with previous experience with MDMA performed a blocked AM recollection (AMR) paradigm after ingestion of 100 mg of MDMA-HCl or ascorbic acid (placebo) in a double-blind, repeated-measures design. Memory cues describing participants' AMs were read by them in the scanner. Favourite memories were rated as significantly more vivid, emotionally intense and positive after MDMA than placebo and worst memories were rated as less negative. Functional MRI data from 17 participants showed robust activations to AMs in regions known to be involved in AMR. There was also a significant effect of memory valence: hippocampal regions showed preferential activations to favourite memories and executive regions to worst memories. MDMA augmented activations to favourite memories in the bilateral fusiform gyrus and somatosensory cortex and attenuated activations to worst memories in the left anterior temporal cortex. These findings are consistent with a positive emotional-bias likely mediated by MDMA's pro-monoaminergic pharmacology. PMID- 24345399 TI - Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. AB - BACKGROUND: The global burden of atrial fibrillation (AF) is unknown. METHODS AND RESULTS: We systematically reviewed population-based studies of AF published from 1980 to 2010 from the 21 Global Burden of Disease regions to estimate global/regional prevalence, incidence, and morbidity and mortality related to AF (DisModMR software). Of 377 potential studies identified, 184 met prespecified eligibility criteria. The estimated number of individuals with AF globally in 2010 was 33.5 million (20.9 million men [95% uncertainty interval (UI), 19.5-22.2 million] and 12.6 million women [95% UI, 12.0-13.7 million]). Burden associated with AF, measured as disability-adjusted life-years, increased by 18.8% (95% UI, 15.8-19.3) in men and 18.9% (95% UI, 15.8-23.5) in women from 1990 to 2010. In 1990, the estimated age-adjusted prevalence rates of AF (per 100 000 population) were 569.5 in men (95% UI, 532.8-612.7) and 359.9 in women (95% UI, 334.7-392.6); the estimated age-adjusted incidence rates were 60.7 per 100 000 person-years in men (95% UI, 49.2-78.5) and 43.8 in women (95% UI, 35.9-55.0). In 2010, the prevalence rates increased to 596.2 (95% UI, 558.4-636.7) in men and 373.1 (95% UI, 347.9-402.2) in women; the incidence rates increased to 77.5 (95% UI, 65.2 95.4) in men and 59.5 (95% UI, 49.9-74.9) in women. Mortality associated with AF was higher in women and increased by 2-fold (95% UI, 2.0-2.2) and 1.9-fold (95% UI, 1.8-2.0) in men and women, respectively, from 1990 to 2010. There was evidence of significant regional heterogeneity in AF estimations and availability of population-based data. CONCLUSIONS: These findings provide evidence of progressive increases in overall burden, incidence, prevalence, and AF-associated mortality between 1990 and 2010, with significant public health implications. Systematic, regional surveillance of AF is required to better direct prevention and treatment strategies. PMID- 24345400 TI - A rising tide: the global epidemic of atrial fibrillation. PMID- 24345401 TI - Are we moving towards concordance on the principle that lipid discordance matters? PMID- 24345402 TI - Discordance of low-density lipoprotein (LDL) cholesterol with alternative LDL related measures and future coronary events. AB - BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is the traditional measure of risk attributable to LDL. Non-high-density lipoprotein cholesterol (NHDL-C), apolipoprotein B (apoB), and LDL particle number (LDL-P) are alternative measures of LDL-related risk. However, the clinical utility of these measures may only become apparent among individuals for whom levels are inconsistent (discordant) with LDL-C. METHODS AND RESULTS: LDL-C was measured directly, NHDL-C was calculated, apoB was measured with immunoassay, and LDL-P was measured with nuclear magnetic resonance spectroscopy among 27 533 healthy women (median follow-up 17.2 years; 1070 incident coronary events). Participants were grouped by median LDL-C (121 mg/dL) and each of NHDL-C, apoB, and LDL-P. Discordance was defined as LDL-C greater than or equal to the median and the alternative measure less than the median, or vice versa. Despite high LDL-C correlations with NHDL-C, apoB, and LDL-P (r=0.910, 0.785, and 0.692; all P<0.0001), prevalence of LDL-C discordance as defined by median cut points was 11.6%, 18.9%, and 24.3% for NHDL-C, apoB, and LDL-P, respectively. Among women with LDL-C less than the median, coronary risk was underestimated for women with discordant (greater than or equal to the median) NHDL-C (age-adjusted hazard ratio, 2.92; 95% confidence interval, 2.33-3.67), apoB (2.48, 2.01-3.07), or LDL P (2.32, 1.88-2.85) compared with women with concordant levels. Conversely, among women with LDL-C greater than or equal to the median, risk was overestimated for women with discordant (less than the median) NHDL-C (0.40, 0.29-0.57), apoB (0.34, 0.26-0.46), or LDL-P (0.42, 0.33-0.53). After multivariable adjustment for potentially mediating factors, including HDL cholesterol and triglycerides, coronary risk remained underestimated or overestimated by ~20% to 50% for women with discordant levels. CONCLUSIONS: For women with discordant LDL-related measures, coronary risk may be underestimated or overestimated when LDL-C alone is used. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000479. PMID- 24345404 TI - Nature versus nurture in bicuspid aortic valve aortopathy: more evidence that altered hemodynamics may play a role. PMID- 24345405 TI - Strength of the pathogenicity caused by feminizing Wolbachia after transfer in a new host: strain or dose effect? AB - The alphaproteobacteria Wolbachia pipientis are among the most common and widespread symbionts in the animal world. Their vertical transmission mode is predicted to favour genotypes with low virulence. On the contrary, horizontal transfers of Wolbachia from one host to another have been shown to possibly increase the symbiont virulence. This situation has been previously described when two feminizing Wolbachia strains, wVulC and wVulM, from the ovaries of the woodlouse Armadillidium vulgare were introduced into another woodlouse named Porcellio dilatatus. These two Wolbachia strains induced severe symptoms and eventually caused the death of the recipient host. However, symptoms and death appeared sooner with wVulC than with wVulM. To know whether this difference was due to variation in the dose of infection or a difference in virulence between the two Wolbachia strains, we performed controlled and gradual doses of injection with wVulC and wVulM in P. dilatatus. We showed that the two strains differed intrinsically in their virulence against P. dilatatus and that their virulence is related to the injection dose. Moreover, we showed that wVulC reached higher concentrations in the recipient host than wVulM suggesting a potential link between the bacterial titers and the levels of virulence. We also addressed the impact of the tissue source of the Wolbachia used for the transinfection and demonstrated that Wolbachia transinfected via hemolymph colonized the body of the recipient more quickly and caused accelerated symptoms compared to Wolbachia introduced via a crushed ovaries suspension. PMID- 24345406 TI - Speaking a more consistent language when discussing severe depression: a calibration study of 3 self-report measures of depressive symptoms. AB - OBJECTIVE: We recently found marked disparities between 3 self-report scales that assess the DSM-IV criteria for major depressive disorder in the percentage of depressed outpatients considered to have severe depression. The goal of the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project was to calibrate the measures against a clinician-rated criterion standard and to establish a cutoff point on each scale that identifies a similar prevalence of severe depression and increases the level of agreement between the scales in identifying severe depression. METHOD: 353 depressed outpatients (DSM-IV) completed the Clinically Useful Depression Outcome Scale, Quick Inventory of Depressive Symptomatology, and Patient Health Questionnaire from June 2010 to January 2013. The patients were also rated on the 17-item Hamilton Depression Rating Scale (HDRS). The goal of the analyses was to identify the cutoff point on each of the self-report scales that would identify a prevalence of severe depression similar to that identified by the HDRS (defined as a score of 25 and above). RESULTS: On the basis of the scale developers' recommended cutoffs, the prevalence of severe depression varied greatly (range, 15.3%-67.4%), and the level of agreement between the pairs of scales was low. After calibration, the self-report scales identified a similar percentage of patients as severely depressed (range, 22.2%-26.5%), and the level of agreement between the scales in identifying severe depression increased. DISCUSSION: If clinicians are to follow treatment guidelines' recommendations to base initial treatment selection, in part, on depression severity, then it is important to have a consistent method of determining depression severity. The present calibration study of 3 self-report depression questionnaires identified cutoff scores that resulted in similar prevalence rates of severe depression and increased the level of agreement between the scales. PMID- 24345403 TI - Bicuspid aortic cusp fusion morphology alters aortic three-dimensional outflow patterns, wall shear stress, and expression of aortopathy. AB - BACKGROUND: Aortic 3-dimensional blood flow was analyzed to investigate altered ascending aorta (AAo) hemodynamics in bicuspid aortic valve (BAV) patients and its association with differences in cusp fusion patterns (right-left, RL versus right-noncoronary, RN) and expression of aortopathy. METHODS AND RESULTS: Four dimensional flow MRI measured in vivo 3-dimensional blood flow in the aorta of 75 subjects: BAV patients with aortic dilatation stratified by leaflet fusion pattern (n=15 RL-BAV, mid AAo diameter=39.9+/-4.4 mm; n=15 RN-BAV, 39.6+/-7.2 mm); aorta size controls with tricuspid aortic valves (n=30, 41.0+/-4.4 mm); healthy volunteers (n=15, 24.9+/-3.0 mm). Aortopathy type (0-3), systolic flow angle, flow displacement, and regional wall shear stress were determined for all subjects. Eccentric outflow jet patterns in BAV patients resulted in elevated regional wall shear stress (P<0.0125) at the right-anterior walls for RL-BAV and right-posterior walls for RN-BAV in comparison with aorta size controls. Dilatation of the aortic root only (type 1) or involving the entire AAo and arch (type 3) was found in the majority of RN-BAV patients (87%) but was mostly absent for RL-BAV patients (87% type 2). Differences in aortopathy type between RL-BAV and RN-BAV patients were associated with altered flow displacement in the proximal and mid AAo for type 1 (42%-81% decrease versus type 2) and distal AAo for type 3 (33%-39% increase versus type 2). CONCLUSIONS: The presence and type of BAV fusion was associated with changes in regional wall shear stress distribution, systolic flow eccentricity, and expression of BAV aortopathy. Hemodynamic markers suggest a physiological mechanism by which the valve morphology phenotype can influence phenotypes of BAV aortopathy. PMID- 24345407 TI - First-in-man assessment of the InSeal VCD, a novel closure device for large puncture accesses. AB - AIMS: To demonstrate the feasibility and efficacy of the novel InSeal VCD for the closure of large puncture holes following percutaneous structural interventions. METHODS AND RESULTS: Prospective, non-randomised, single-arm, single-centre study with a series of patients submitted to endovascular treatment of abdominal and thoracic aortic aneurysm as well as transcatheter aortic valve implantation in whom the InSeal VCD was used to close the access site. These patients were followed up for one year with clinical examination, ankle-brachial index and Doppler ultrasound. The primary endpoint was the occurrence of major vascular complications at the puncture site. From a total of nine patients screened, seven were selected to receive the InSeal VCD. Technical and therapeutic successes were achieved in all cases. The sheath profiles used in these procedures ranged from 18 Fr to 25 Fr. No major vascular complications were observed during the follow up period. Average ankle-brachial index pre-intervention and at one-month follow up were 0.85 and 0.82, respectively. CONCLUSIONS: The InSeal VCD was shown to be effective in achieving acute and chronic haemostasis after usage of higher profile endovascular devices in this study. These results translated into no clinical complications up to one-year clinical follow-up. PMID- 24345408 TI - Characterization of microsatellite DNA libraries from three mealybug species and development of microsatellite markers for Pseudococcus viburni (Hemiptera: Pseudococcidae). AB - Mealybugs (Hemiptera: Pseudococcidae) are important pests for crops worldwide. Different species, cryptic taxa under the same species name or even populations within a species can differ in biological characteristics, such as phenology, resistance to insecticides, virus transmission and susceptibility to natural enemies. Therefore, their management efficacy depends on their accurate identification. Microsatellite genetic markers are efficient in revealing the fine-scale taxonomic status of insects, both at inter- and intra-specific level. Despite their potential uses, microsatellites have been developed only for one mealybug species so far. Hence, it is unclear whether microsatellites may be useful to assess mealybug population differentiation and structuring. In this work, we tested the feasibility of developing microsatellite markers in mealybugs by: (i) producing and characterizing microsatellite DNA libraries for three species: Pseudococcus viburni, Pseudococcus comstocki and Heliococcus bohemicus, and (ii) by developing and testing markers for Ps. viburni. The obtained libraries contained balanced percentages of dinucleotide (ranging from 15 to 25%) and trinucleotide (from 5 to 17%) motifs. The marker setup for Ps. viburni was successful, although 70% of the primers initially tested were discarded for a lack of polymorphism. Finally, 25 markers were combined in two multiplex polymerase chain reactions with 21 displaying no evidence of deviation from Hardy Weinberg equilibrium. Ps. viburni markers were tested on one population from France and one from Chile. The markers revealed a significant genetic differentiation between the two populations with an Fst estimate of 0.266. PMID- 24345409 TI - Identification of Arcanobacterium pluranimalium by matrix-assisted laser desorption ionization-time of flight mass spectrometry and, as novel target, by sequencing pluranimaliumlysin encoding gene pla. AB - In the present study 13 Arcanobacterium pluranimalium strains isolated from various animal origin could successfully be identified phenotypically by matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and genotypically by sequencing 16S rDNA and the pluranimaliumlysin encoding gene pla. The detection of mass spectra by MALDI-TOF MS and the novel genotypic approach using gene pla might help to identify A. pluranimalium in future and might elucidate the role this species plays in infections of animals. PMID- 24345410 TI - Genetic diversity of Mycoplasma hyopneumoniae isolates of abattoir pigs. AB - Mycoplasma hyopneumoniae, the causative agent of porcine enzootic pneumonia, is present in swine herds worldwide. However, there is little information on strains infecting herds in Canada. A total of 160 swine lungs with lesions suggestive of enzootic pneumonia originating from 48 different farms were recovered from two slaughterhouses and submitted for gross pathology. The pneumonic lesion scores ranged from 2% to 84%. Eighty nine percent of the lungs (143/160) were positive for M. hyopneumoniae by real-time PCR whereas 10% (16/160) and 8.8% (14/160) were positive by PCR for M. hyorhinis and M. flocculare, respectively. By culture, only 6% of the samples were positive for M. hyopneumoniae (10/160). Among the selected M. hyopneumoniae-positive lungs (n=25), 9 lungs were co-infected with M. hyorhinis, 9 lungs with PCV2, 2 lungs with PRRSV, 12 lungs with S. suis and 10 lungs with P. multocida. MLVA and PCR-RFLP clustering of M. hyopneumoniae revealed that analyzed strains were distributed among three and five clusters respectively, regardless of severity of lesions, indicating that no cluster is associated with virulence. However, strains missing a specific MLVA locus showed significantly less severe lesions and lower numbers of bacteria. MLVA and PCR RFLP analyses also showed a high diversity among field isolates of M. hyopneumoniae with a greater homogeneity within the same herd. Almost half of the field isolates presented less than 55% homology with selected vaccine and reference strains. PMID- 24345411 TI - Evaluation of cross-protection against three topotypes of serotype O foot-and mouth disease virus in pigs vaccinated with multi-epitope protein vaccine incorporated with poly(I:C). AB - Epitope-based vaccines are always questioned for their cross-protection against the antigenically variable foot-and-mouth disease virus (FMDV). In this study, we proved the cross-protection effect of a multi-epitope vaccine incorporated with poly(I:C) against three topotypes of O type FMDV. A total of 45 naive pigs were vaccinated with different doses of multi-epitope protein vaccine incorporated with poly(I:C). At 28 days post-vaccination, 45 vaccinated and 6 unvaccinated control pigs (two pigs for each group) were challenged with three topotypes of virulent O type FMDV, namely, O/Mya/98 (Southeast Asia topotype), O/HN/CHA/93 (Cathay topotype) and O/Tibet/CHA/99 (PanAsia topotype) strains. All unvaccinated pigs developed generalised FMD clinical signs. Results showed that all pigs (n=15) conferred complete protection against the O/Mya/98 and O/HN/CHA/93 FMDV strains, 11 of which were protected against the O/Tibet/CHA/99 FMDV strain. The 50% protective dose values of the vaccine against the O/Mya/98, O/HN/CHA/93 and O/Tibet/CHA/99 FMDV strains were 15.59, 15.59 and 7.05, respectively. Contact challenge experiment showed that transmission occurred from the donors to the unvaccinated but not to vaccinated pigs. These results showed that vaccination with multi-epitope protein vaccine incorporated with poly(I:C) can efficiently prevent FMD in pigs. PMID- 24345412 TI - The siderophore-interacting protein is involved in iron acquisition and virulence of Riemerella anatipestifer strain CH3. AB - Riemerella anatipestifer causes epizootic infectious disease in poultry and serious economic losses especially to the duck industry. However, little is known regarding the molecular basis of its pathogenesis. The ability to acquire iron under low-iron conditions is related to the virulence of a variety of bacterial pathogens. In this study, a sip (Riean_1281) deletion mutant CH3Deltasip was constructed and characterized for iron-limited growth, biofilm formation, and pathogenicity to ducklings. Results showed that siderophore-interacting protein (SIP) was involved in iron utilization and the sip deletion significantly reduced biofilm formation and adherence to and invasion of Vero cells. In addition, the sip gene was absent in 1 of 24 (4.17%) virulent strains and 2 of 3 (66.7%) avirulent strains of R. anatipestifer, and the sip gene from six R. anatipestifer strains, which belong to serotypes 1, 2, and 10, respectively, shared 100% amino acid identities to those of R. anatipestifer strains DSM15868 and RA-GD. These results suggested that siderophore-mediated iron acquisition may be an important iron-uptake pathway in R. anatipestifer. Animal experiments indicated that the median lethal dose of the CH3Deltasip mutant in ducklings was about 35-fold higher than that of the wild-type CH3 strain. Thus, our results demonstrated that R. anatipestifer SIP was involved in iron acquisition and necessary for its optimal virulence. PMID- 24345413 TI - Accurate reconstruction of 3D cardiac geometry from coarsely-sliced MRI. AB - We present a comprehensive validation analysis to assess the geometric impact of using coarsely-sliced short-axis images to reconstruct patient-specific cardiac geometry. The methods utilize high-resolution diffusion tensor MRI (DTMRI) datasets as reference geometries from which synthesized coarsely-sliced datasets simulating in vivo MRI were produced. 3D models are reconstructed from the coarse data using variational implicit surfaces through a commonly used modeling tool, CardioViz3D. The resulting geometries were then compared to the reference DTMRI models from which they were derived to analyze how well the synthesized geometries approximate the reference anatomy. Averaged over seven hearts, 95% spatial overlap, less than 3% volume variability, and normal-to-surface distance of 0.32 mm was observed between the synthesized myocardial geometries reconstructed from 8 mm sliced images and the reference data. The results provide strong supportive evidence to validate the hypothesis that coarsely-sliced MRI may be used to accurately reconstruct geometric ventricular models. Furthermore, the use of DTMRI for validation of in vivo MRI presents a novel benchmark procedure for studies which aim to substantiate their modeling and simulation methods using coarsely-sliced cardiac data. In addition, the paper outlines a suggested original procedure for deriving image-based ventricular models using the CardioViz3D software. PMID- 24345415 TI - Selective action of an atypical neuroleptic on the mechanisms related to the development of cocaine addiction: a pre-clinical behavioural study. AB - An increased function in the mesolimbic dopaminergic system has been extensively associated with the rewarding effects of both natural stimuli and drugs of abuse. Thus, dopamine receptor blockers, such as neuroleptic drugs, can be proposed as candidates for potential therapeutic approaches to treat drug dependence. Notwithstanding, this therapeutic potential of neuroleptics critically depends on a selective action on the specific mechanisms related to the development of addiction. We compared the effects of different doses of haloperidol, ziprasidone and aripiprazole (first-, second- and third-generation neuroleptics, respectively) on spontaneous locomotor activity of mice in a novel environment, hyperlocomotion induced by acute cocaine administration and cocaine-induced locomotor sensitization by a two-injection protocol. Whereas high doses of haloperidol abolished the three behavioural paradigms without selectivity, low doses of ziprasidone selectively abolished the development of the behavioural sensitization phenomenon. Finally, low doses of aripiprazole inhibited acute cocaine-induced hyperlocomotion and behavioural sensitization without modifying spontaneous locomotor activity. Thus, aripiprazole at lower doses was the most selective antipsychotic drug concerning the inhibition of the development of behavioural sensitization to cocaine. Because locomotor sensitization in rodents has been proposed to share plastic mechanisms with drug addiction in humans, our data provide relevant suggestions to the clinical practice. PMID- 24345416 TI - Prevalence of methotrexate intolerance in rheumatoid arthritis and psoriatic arthritis. AB - INTRODUCTION: The aim of this study was to determine the prevalence of gastrointestinal and behavioural symptoms occurring before (anticipatory/associative) and after methotrexate (MTX) administration, termed MTX intolerance, in rheumatoid (RA) and psoriatic arthritis (PsA). METHODS: Methotrexate Intolerance Severity Score (MISS), previously validated in juvenile idiopathic arthritis patients, was used to determine MTX intolerance prevalence in 291 RA/PsA patients. The MISS consisted of four domains: abdominal pain, nausea, vomiting and behavioural symptoms, occurring upon, prior to (anticipatory) and when thinking of MTX (associative). MTX intolerance was defined as >=6 on the MISS with >=1 point on anticipatory and/or associative and/or behavioural items. RESULTS: A total of 123 patients (42.3%) experienced at least one gastrointestinal adverse effect. The prevalence of MTX intolerance was 11%. MTX intolerance prevalence was higher in patients on parenteral (20.6%) than on oral MTX (6.2%) (p < 0.001). CONCLUSION: Besides well-known gastrointestinal symptoms after MTX, RA and PsA patients experienced these symptoms also before MTX intake. RA and PsA patients on MTX should be closely monitored with the MISS for early detection of MTX intolerance, in order to intervene timely and avoid discontinuation of an effective treatment. PMID- 24345417 TI - Toluene decreases Purkinje cell output by enhancing inhibitory synaptic transmission in the cerebellar cortex. AB - Toluene belongs to a class of psychoactive drugs known as inhalants. Found in common household products such as adhesives, paint products, and aerosols, toluene is inhaled for its intoxicating and euphoric properties. Additionally, exposure to toluene disrupts motor behaviors in a manner consistent with impairments to cerebellar function. Previous work has suggested a role of GABA in mediating toluene's neurobehavioral effects, but how this manifests in the cerebellar cortex is not yet understood. In the present study, we examined the effects of toluene on cerebellar Purkinje cell action potential output and inhibitory synaptic transmission onto Purkinje cells using patch clamp electrophysiology in acute rat cerebellar slices. Toluene (1mM) reduced the frequency of Purkinje cell action potential output without affecting input resistance. Furthermore, toluene dose-dependently enhanced inhibitory synaptic transmission onto Purkinje cells, increasing the amplitude and frequency of inhibitory postsynaptic currents; no change in the frequency of action potentials from molecular layer interneurons was noted. The observed decreases in Purkinje cell action potential output could contribute to toluene-evoked impairments in cerebellar and motor functions. PMID- 24345418 TI - Involvement of spinal microglia and interleukin-18 in the anti-nociceptive effect of dexmedetomidine in rats subjected to CCI. AB - Dexmedetomidine, a selective alpha 2-adrenoceptor (alpha2AR) agonist, has provided significant analgesia in neuropathic pain. However, its underlying molecular mechanism has not been fully elucidated. In the present study, we found that intrathecal administration of dexmedetomidine alleviated mechanical allodynia induced by chronic constriction injury (CCI), and pretreatment with BRL44408 significantly reversed the dexmedetomidine-induced anti-nociceptive effect. Western blotting revealed that dexmedetomidine reduced the activation of microglia and the upregulation of interleukin-18 (IL-18) protein expression in the ipsilateral lumbar spinal dorsal horn, while BRL44408 pretreatment significantly blocked these effects of dexmedetomidine. Immunocytochemistry/immunohistochemistry indicated that the alpha2A-adrenoceptor was localised to microglia in primary culture, and IL-18 predominantly colocalised with the microglial marker Iba-1 in the dorsal horn of the spinal cord. These results suggest that the IL-18 signalling pathway in microglia may be involved in the anti-nociceptive effect of dexmedetomidine in rats subjected to CCI. PMID- 24345419 TI - A novel alternative for renal replacement therapy: 2-year successful colonic dialysis via a Malone antegrade continent enema stoma. AB - This study is a case report of home-based colonic dialysis (CD) for treating end stage renal disease in a 20-year-old woman. She had a history of Malone antegrade continence enema (MACE) for treating neuropathic bowel at the age of 11 years. The patient refused any type of renal replacement therapy. However, she agreed to CD through the MACE stoma by changing the colonic irrigation solution to the peritoneal dialysis solution. The patient was discharged with a plasma creatinine (Cr) level of 1.7 mg/dL and blood urea nitrogen (BUN) level of 8 mg/dL. She has continued CD on a regular basis at home. The patient's serum Cr and BUN has remained in the steady low state during 24 months of follow-up (mean Cr level = 2.8 mg/dL and mean BUN level = 10.7 mg/dL). PMID- 24345414 TI - Substance abuse, memory, and post-traumatic stress disorder. AB - A large body of literature demonstrates the effects of abused substances on memory. These effects differ depending on the drug, the pattern of delivery (acute or chronic), and the drug state at the time of learning or assessment. Substance use disorders involving these drugs are often comorbid with anxiety disorders, such as post-traumatic stress disorder (PTSD). When the cognitive effects of these drugs are considered in the context of the treatment of these disorders, it becomes clear that these drugs may play a deleterious role in the development, maintenance, and treatment of PTSD. In this review, we examine the literature evaluating the cognitive effects of three commonly abused drugs: nicotine, cocaine, and alcohol. These three drugs operate through both common and distinct neurobiological mechanisms and alter learning and memory in multiple ways. We consider how the cognitive and affective effects of these drugs interact with the acquisition, consolidation, and extinction of learned fear, and we discuss the potential impediments that substance abuse creates for the treatment of PTSD. PMID- 24345420 TI - Work/non-workday differences in mother, child, and mother-child morning cortisol in a sample of working mothers and their children. AB - BACKGROUND: Mothers have been shown to have higher morning cortisol on days they go to work compared to non-workdays; however, it is unknown how maternal workday associates with child morning cortisol or the attunement of mother-child morning cortisol. AIMS: This study examined the presence and stability of morning cortisol levels and slopes (i.e., cortisol awakening response or CAR) in a sample of 2-4year old children in out-of-home child care with working mothers. In addition, we examined the differential contributions of maternal workday on mother-child attunement in morning cortisol. METHOD: Mother and child morning cortisol was sampled twice a day (awakening and 30min later) across four consecutive days (2 non-workdays; 2 workdays) among 47 working mothers and their young children. Mothers also reported on compliance with sampling procedures and provided demographic information. RESULTS: While children exhibited stability in cortisol levels, children's CARs were variable, with children's non-work CARs not predictive of work CARs. Similarly, a significant morning rise in cortisol was only found on workdays, not non-workdays. Overall, mothers had higher cortisol levels and steeper CARs than their children. Further, maternal workday moderated the attunement of mother-child morning cortisol, such that mothers and children had concordant cortisol levels on non-workdays, but discordant cortisol levels on workdays. CONCLUSIONS: Morning cortisol may be more variable in pre-school aged children than adults but may be similarly responsive to the social environment. Further, workday mornings may be a time of reduced mother-child cortisol attunement. PMID- 24345422 TI - Benefit of allogeneic transplantation in patients age >= 60 years with acute myeloid leukemia is limited to those in first complete remission at time of transplant. AB - We evaluated the impact of age and remission status on 242 consecutive patients who underwent allogeneic hematopoietic cell transplantation for acute myeloid leukemia (AML) in our program between 1999 and 2011. Median age of all patients was 48 years (range, 18 to 71). Based on age and remission status, patients were divided into 4 groups: first complete remission (CR1) age <60 years (n = 116), second complete remission (CR2) age <60 years (n = 78), CR1 age >=60 years (n = 32), and CR2 age >=60 years (n = 16). Donors were matched related (n = 155, 64%) or matched unrelated (n = 87, 36%). Median follow-up of survivors was 65 months (range, 12 to 145). In a univariate analysis, 3-year overall survival rates of the 4 groups were 57%, 43%, 39%, and 16% (P = .003), respectively. In a multivariable analysis, hazard ratios of nonrelapse mortality and survival were 2.08 (P = .06) and 1.52 (P = .23), respectively, in patients >=60 years in CR2 compared with >= 60 years in CR1. Although a plateau in survival was observed for patients >=60 years in CR1 similar to those <60 years in CR1 and CR2, no long term survivors were seen in patients >=60 years in CR2. Our data suggest disappointing outcomes in AML patients >=60 years of age transplanted in CR2. Therefore, if a transplant is indicated, early referral is recommended in patients >=60 years with AML. PMID- 24345421 TI - Caveolin-3 regulates compartmentation of cardiomyocyte beta2-adrenergic receptor mediated cAMP signaling. AB - The purpose of this study was to investigate whether caveolin-3 (Cav3) regulates localization of beta2-adrenergic receptor (beta2AR) and its cAMP signaling in healthy or failing cardiomyocytes. We co-expressed wildtype Cav3 or its dominant negative mutant (Cav3DN) together with the Forster resonance energy transfer (FRET)-based cAMP sensor Epac2-camps in adult rat ventricular myocytes (ARVMs). FRET and scanning ion conductance microscopy were used to locally stimulate beta2AR and to measure cytosolic cAMP. Cav3 overexpression increased the number of caveolae and decreased the magnitude of beta2AR-cAMP signal. Conversely, Cav3DN expression resulted in an increased beta2AR-cAMP response without altering the whole-cell L-type calcium current. Following local stimulation of Cav3DN expressing ARVMs, beta2AR response could only be generated in T-tubules. However, the normally compartmentalized beta2AR-cAMP signal became diffuse, similar to the situation observed in heart failure. Finally, overexpression of Cav3 in failing myocytes led to partial beta2AR redistribution back into the T-tubules. In conclusion, Cav3 plays a crucial role for the localization of beta2AR and compartmentation of beta2AR-cAMP signaling to the T-tubules of healthy ARVMs, and overexpression of Cav3 in failing myocytes can partially restore the disrupted localization of these receptors. PMID- 24345423 TI - NOD2/CARD15 single nucleotide polymorphism 13 (3020insC) is associated with risk of sepsis and single nucleotide polymorphism 8 (2104C>T) with herpes viruses reactivation in patients after allogeneic hematopoietic stem cell transplantation. AB - Three NOD2 polymorphisms (single nucleotide polymorphism [SNP]8 [2104C>T, Arg702Trp], SNP12 [2722G>C, Gly908Arg], and SNP13 [3020insC, Leu1007 fsins C]), identified as disease-associated variants in Crohn's disease, have recently been suggested as gene markers of the outcome of hematopoietic stem cell transplantation (HSCT). In the present multicenter study of 464 donor-recipient pairs, we focused on the effect of NOD2 mutation(s) on the risk of infections and acute graft-versus-host disease (aGVHD). The presence of SNP13 in recipients, donors, or both was more frequently seen in patients having sepsis than in those lacking sepsis (9 of 48 versus 33 of 386, P = .046). The presence of SNP8 (recipient and/or donor positive) was associated with a higher rate of Herpes viruses reactivation (17 of 21 versus 86 of 173, P = .007). In the SNP8-positive group, a trend for a higher rate of bacteremia well controlled by antibiotics was found (9 of 10 versus 47 of 81, P = .106). In contrast, the presence of SNP13 in recipient and/or donor resulted in a poor response to antibiotics (5 of 11 versus 9 of 10, P = .042). A statistically significant association between the presence of NOD2 SNPs and acute grade > II GVHD was found in a subgroup of HSCT patients who received transplants from unrelated donors with a myeloablative conditioning regimen that included antithymocyte globulin (ATG). In this subgroup of patients, donor positivity for any SNPs investigated (7 of 18 versus 17 of 113, P = .036) and, independently, only the presence of SNP8 (4 of 8 versus 20 of 123, P = .055) were associated with severe grade >= II aGVHD. In conclusion, SNP8 positivity in donors or recipients makes patients more prone to Herpes viruses reactivation and bacteremia but not to sepsis. Septic complications were associated with SNP13 polymorphism. SNP8 in donors constitutes a risk factor of severe aGVHD, but only if patients received transplants from unrelated donors and received ATG as part of a conditioning regimen. PMID- 24345424 TI - The effect of patient narratives on information search in a web-based breast cancer decision aid: an eye-tracking study. AB - BACKGROUND: Previous research has examined the impact of patient narratives on treatment choices, but to our knowledge, no study has examined the effect of narratives on information search. Further, no research has considered the relative impact of their format (text vs video) on health care decisions in a single study. OBJECTIVE: Our goal was to examine the impact of video and text based narratives on information search in a Web-based patient decision aid for early stage breast cancer. METHODS: Fifty-six women were asked to imagine that they had been diagnosed with early stage breast cancer and needed to choose between two surgical treatments (lumpectomy with radiation or mastectomy). Participants were randomly assigned to view one of four versions of a Web decision aid. Two versions of the decision aid included videos of interviews with patients and physicians or videos of interviews with physicians only. To distinguish between the effect of narratives and the effect of videos, we created two text versions of the Web decision aid by replacing the patient and physician interviews with text transcripts of the videos. Participants could freely browse the Web decision aid until they developed a treatment preference. We recorded participants' eye movements using the Tobii 1750 eye-tracking system equipped with Tobii Studio software. A priori, we defined 24 areas of interest (AOIs) in the Web decision aid. These AOIs were either separate pages of the Web decision aid or sections within a single page covering different content. RESULTS: We used multilevel modeling to examine the effect of narrative presence, narrative format, and their interaction on information search. There was a significant main effect of condition, P=.02; participants viewing decision aids with patient narratives spent more time searching for information than participants viewing the decision aids without narratives. The main effect of format was not significant, P=.10. However, there was a significant condition by format interaction on fixation duration, P<.001. When comparing the two video decision aids, participants viewing the narrative version spent more time searching for information than participants viewing the control version of the decision aid. In contrast, participants viewing the narrative version of the text decision aid spent less time searching for information than participants viewing the control version of the text decision aid. Further, narratives appear to have a global effect on information search; these effects were not limited to specific sections of the decision aid that contained topics discussed in the patient stories. CONCLUSIONS: The observed increase in fixation duration with video patient testimonials is consistent with the idea that the vividness of the video content could cause greater elaboration of the message, thereby encouraging greater information search. Conversely, because reading requires more effortful processing than watching, reading patient narratives may have decreased participant motivation to engage in more reading in the remaining sections of the Web decision aid. These findings suggest that the format of patient stories may be equally as important as their content in determining their effect on decision making. More research is needed to understand why differences in format result in fundamental differences in information search. PMID- 24345425 TI - Prolonged abstinence from developmental cocaine exposure dysregulates BDNF and its signaling network in the medial prefrontal cortex of adult rats. AB - Although evidence exists that chronic cocaine exposure during adulthood is associated with changes in BDNF expression, whether and how cocaine exposure during adolescence modulates BDNF is still unknown. To address this issue, we exposed rats to repeated cocaine injections from post-natal day (PD) 28 to PD 42, a period that roughly approximates adolescence in humans, and we carried out a detailed analysis of the BDNF system in the medial prefrontal cortex (mPFC) of rats sacrificed 3 d (PD 45) and 48 d (PD 90) after the last cocaine treatment. We found that developmental exposure to cocaine altered transcriptional and translational mechanisms governing neurotrophin expression. Total BDNF mRNA levels, in fact, were enhanced in the mPFC of PD 90 rats exposed to cocaine in adolescence, an effect sustained by changes in BDNF exon IV through the transcription factors CaRF and NF-kB. While a profound reduction of specific BDNF related miRNAs (let7d, miR124 and miR132) may contribute to explaining the increased proBDNF levels, the up-regulation of the extracellular proteases tPA is indicative of increased processing leading to higher levels of released mBDNF. These changes were associated with increased activation of the trkB-Akt pathway resulting in enhanced pmTOR and pS6 kinase, which ultimately produced an up regulation of Arc and a consequent reduction of GluA1 expression in the mPFC of PD 90 cocaine-treated rats. These findings demonstrate that developmental exposure to cocaine dynamically dysregulates BDNF and its signaling network in the mPFC of adult rats, providing novel mechanisms that may contribute to cocaine induced changes in synaptic plasticity. PMID- 24345426 TI - Consumption of transgenic milk containing the antimicrobials lactoferrin and lysozyme separately and in conjunction by 6-week-old pigs improves intestinal and systemic health. AB - Lactoferrin and lysozyme are antimicrobial and immunomodulatory proteins produced in high quantities in human milk that aid in gastrointestinal (GI) health and have beneficial effects when supplemented separately and in conjunction in human and animal diets. Ruminants produce low levels of lactoferrin and lysozyme; however, there are genetically engineered cattle and goats that respectively secrete recombinant human lactoferrin (rhLF-milk), and human lysozyme (hLZ-milk) in their milk. Effects of consumption of rhLF-milk, hLZ-milk and a combination of rhLF-and hLZ-milk were tested on young pigs as an animal model for the GI tract of children. Compared with control milk-fed pigs, pigs fed a combination of rhLF and hLZ (rhLF+hLZ) milk had a significantly deeper intestinal crypts and a thinner lamina propria layer. Pigs fed hLZ-milk, rhLF-milk and rhLF+hLZ had significantly reduced mean corpuscular volume (MCV) and red blood cells (RBCs) were significantly increased in pigs fed hLZ-milk and rhLF-milk and tended to be increased in rhLF+hLZ-fed pigs, indicating more mature RBCs. These results support previous research demonstrating that pigs fed milk containing rhLF or hLZ had decreased intestinal inflammation, and suggest that in some parameters the combination of lactoferrin and lysozyme have additive effects, in contrast to the synergistic effects reported when utilising in-vitro models. PMID- 24345427 TI - Latent class analysis of personality disorders in adults with posttraumatic stress disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions. AB - OBJECTIVE: To characterize predominant typologies of co-occurring personality disorders among adults with posttraumatic stress disorder (PTSD) and examine their relation to Axis I comorbidities, health-related quality of life, and course and treatment of PTSD. METHOD: Latent class analysis was conducted on the 10 DSM-IV personality disorders in a nationally representative sample of 2,463 adults with a lifetime diagnosis of PTSD from Wave 2 (2004-2005) of the National Epidemiologic Survey on Alcohol and Related Conditions. RESULTS: Three latent classes of personality disorders were identified: a borderline-dysregulated class (11.4%), an obsessive-paranoid class (13.1%), and a no/low personality disorders class (75.5%). The borderline-dysregulated and obsessive-paranoid classes were more likely than the no/low personality disorder class to have a broad range of comorbid Axis I diagnoses and to have ever attempted suicide (ORs = 1.50-8.01), and they reported lower mental health-related quality of life. The borderline dysregulated class was less likely than the no/low personality disorder class to have experienced remission of their most recent episode of PTSD (OR = 0.54; 95% CI, 0.38-0.75) and was more likely to have been prescribed medication for PTSD (OR = 1.65; 95% CI, 1.20-2.28) and to have used alcohol and drugs to mitigate their PTSD symptoms (OR = 2.77; 95% CI, 1.62-4.74). The obsessive-paranoid class was more likely than the no/low personality disorders class to report sexual assault as their worst trauma (OR = 2.22; 95% CI, 1.36-3.61) and had an earlier age at onset of PTSD symptoms compared to the other 2 classes. CONCLUSIONS: Among US adults with PTSD, the 10 DSM-IV personality disorders can be classified into 3 "person-based" typologies, which are differentially associated with comorbid Axis I disorders, mental health-related quality of life, and clinical and treatment characteristics of this disorder. These results suggest that comprehensive assessment of personality disorders may help inform etiologic models and treatment approaches for PTSD. PMID- 24345428 TI - A randomized, double-blind, double-dummy comparison of short- and long-acting dihydrocodeine in chronic non-malignant pain. AB - Guidelines for opioid treatment of chronic non-malignant pain recommend long acting over short-acting opioid formulations. The evidence for this recommendation is weak. This study is a randomized, double-blind, double-dummy, 8 week comparison of long-acting dihydrocodeine tablets (DHC-Continus) with short acting dihydrocodeine tablets in 60 patients with chronic non-malignant pain who were referred to a multidisciplinary pain clinic. All patients used codeine paracetamol tablets before the trial, and paracetamol was added in both groups during the trial. The primary outcome was stability in pain intensity, measured as the difference between the highest and least pain intensity reported on an 11 point numerical rating scale in a 7-day diary. The secondary outcomes were differences in quality of life, quality of sleep, depression, and episodes of breakthrough pain between the 2 formulations. Spontaneously reported adverse events were recorded. In all, 38 patients completed the trial, and 22 withdrew before the end. The reasons for withdrawal were adverse events, lack of efficacy, or both, and were similar between the groups. There were no significant differences in stability of pain intensity between groups. There were no significant differences between groups in quality of sleep, depression, health related quality of life, or adverse events. Breakthrough pain was experienced in both groups during the trial. Long-acting dihydrocodeine was not observed to be superior for any of the outcomes in this trial. The results of this study do not support current guidelines recommending long-acting opioids. PMID- 24345430 TI - Insight into the roles of microbial extracellular polymer substances in metal biosorption. AB - Biosorption presents a potent technology to remediate metal-contaminated aqueous environment or even to recover precious metals. Extracellular polymeric substances (EPS) are believed to play an important role in metal biosorption by microorganisms, but the reported results have been rather contradictory and the underlying mechanisms remain largely unclear so far. This review aims to clarify why large discrepancies existed for different EPS-metal systems through systematically exploring into the adsorption mechanisms and influential factors, and to offer some implications for advancing the implementation of metal biosorption technologies. The state-of-the-art methodologies for characterizing metal-EPS binding are summarized; several interaction mechanisms, including ion exchange, complexation and surface precipitation, are analyzed; the major influential factors such as EPS composition, metal species, solution chemistry and operating conditions are discussed; and lastly future research needs to advance the investigations and implementations of such biosorption processes are proposed. PMID- 24345429 TI - The role of cardiovascular activity in fibromyalgia and conditioned pain modulation. AB - Fibromyalgia (FM) is a chronic widespread pain condition of unknown origin. Reduced endogenous pain inhibition could be related to high pain sensitivity in FM. Associations between conditioned pain modulation (CPM) and cardiovascular responses to pain have been observed in healthy subjects (HS). Because reduced cardiovascular reactivity to various stressors has been reported in FM patients, we investigated relationships between CPM and cardiovascular response to the cold pressor test (CPT) in 22 FM patients and 25 HS. CPM was evaluated by comparing pain intensity produced by a 120-second heat test stimulus (HTS) before and after a CPT (2minutes, 12 degrees C). The CPT, used to activate CPM, produced greater pain intensity in FM patients. Patients with FM had higher heart rates than HS at baseline and during CPT. Higher heart rate was related with higher pain intensity during the CPT. Blood pressure increments during CPT were weaker in the FM group. CPM was less effective in FM patients than in HS. Importantly, systolic blood pressure responses during CPT were positively related to CPM effectiveness, suggesting that reduced blood pressure response during the conditioning stimulus could be involved in CPM dysfunction in the FM group. Higher heart rate could be implicated in the greater sensitivity to cold pain in FM. Patients with FM have reduced blood pressure response to a painful CPT. Reduced cardiovascular reactivity to pain could have important involvement in diminished endogenous pain inhibition efficacy and FM pathophysiology. PMID- 24345431 TI - Influence of micellar calcium and phosphorus on rennet coagulation properties of cows milk. AB - The main requirement for milk processed in most cheese typologies is its rennet coagulation ability. Despite the increasing number of studies, the causes for abnormal coagulation of milk are not fully understood. The aim of this study was to ascertain relationships between milk characteristics and its rennet coagulation ability, focusing on the influence of calcium (Ca) and phosphorus (P). Ca and P are essential constituents of the micelles. Micellar P can be present as part of colloidal calcium phosphate (inorganic-P) or covalently bound to caseins as phosphate groups (casein-P). Eighty one herd milk samples (SCC<400 000 cell/ml) were classified as Optimal (8), Suboptimal (39) Poor (29) and Non coagulating milk (5), according to their rennet coagulation parameters as assessed by lactodynamographic test. Samples were analysed for their chemical composition (basic composition, protein fractions, minerals and salt equilibria), physicochemical parameters (pH and titratable acidity) and rheological properties. Optimal milk was characterised by the highest contents of major constituents, protein fractions and minerals, lowest content of chloride and highest values of titratable acidity. Non-coagulating milk was characterised by the highest values of pH and the lowest of titratable acidity. At micellar level, Optimal milk showed the highest values of colloidal Ca, casein-P and colloidal Mg (g/100 g casein), while Non-coagulating milk showed the lowest values. Interestingly, there was no statistical difference regarding the content of colloidal inorganic-P (g/100 g casein) between Optimal and Non-coagulating milks. Overall, high mineralisation of the micelle (expressed as g inorganic-P/100 g casein) positively affect its rennetability. However, excessive mineralisation could lead to a reduction of the phosphate groups (g casein-P/100 g casein) available for curd formation. PMID- 24345434 TI - What are the Risk Factors Associated with the Increased Incidence of Pediatric Stone Disease in America? PMID- 24345435 TI - Percutaneous tibial nerve stimulation for refractory lower urinary tract symptoms in patients with neurogenic bladder conditions. PMID- 24345432 TI - Progesterone receptor assembly of a transcriptional complex along with activator protein 1, signal transducer and activator of transcription 3 and ErbB-2 governs breast cancer growth and predicts response to endocrine therapy. AB - INTRODUCTION: The role of the progesterone receptor (PR) in breast cancer remains a major clinical challenge. Although PR induces mammary tumor growth, its presence in breast tumors is a marker of good prognosis. We investigated coordinated PR rapid and nonclassical transcriptional effects governing breast cancer growth and endocrine therapy resistance. METHODS: We used breast cancer cell lines expressing wild-type and mutant PRs, cells sensitive and resistant to endocrine therapy, a variety of molecular and cellular biology approaches, in vitro proliferation studies and preclinical models to explore PR regulation of cyclin D1 expression, tumor growth, and response to endocrine therapy. We investigated the clinical significance of activator protein 1 (AP-1) and PR interaction in a cohort of 99 PR-positive breast tumors by an immunofluorescence protocol we developed. The prognostic value of AP-1/PR nuclear colocalization in overall survival (OS) was evaluated using Kaplan-Meier method, and Cox model was used to explore said colocalization as an independent prognostic factor for OS. RESULTS: We demonstrated that at the cyclin D1 promoter and through coordinated rapid and transcriptional effects, progestin induces the assembly of a transcriptional complex among AP-1, Stat3, PR, and ErbB-2 which functions as an enhanceosome to drive breast cancer growth. Our studies in a cohort of human breast tumors identified PR and AP-1 nuclear interaction as a marker of good prognosis and better OS in patients treated with tamoxifen (Tam), an anti estrogen receptor therapy. Rationale for this finding was provided by our demonstration that Tam inhibits rapid and genomic PR effects, rendering breast cancer cells sensitive to its antiproliferative effects. CONCLUSIONS: We here provided novel insight into the paradox of PR action as well as new tools to identify the subgroup of ER+/PR + patients unlikely to respond to ER-targeted therapies. PMID- 24345436 TI - When, for How Long and in Whom Should Medical Expulsive Therapy be Used? PMID- 24345437 TI - First time stones. PMID- 24345438 TI - Grading renal cell carcinoma: the International Society of Urological Pathology grading system. PMID- 24345440 TI - Adrenocortical carcinoma presenting with Cushing syndrome. PMID- 24345439 TI - Prostate cancer risk alleles are associated with prostate cancer volume and prostate size. AB - PURPOSE: Genome-wide association studies have identified an increasing number of single nucleotide polymorphisms associated with prostate cancer risk. Some of these genetic variants are also associated with serum prostate specific antigen levels and lower urinary tract symptoms, raising the question of whether they are truly prostate cancer biomarkers or simply lead to detection bias. Therefore, we determined whether single nucleotide polymorphisms associated with prostate cancer risk are more strongly associated with tumor or prostate volume. MATERIALS AND METHODS: The genotypes of 38 validated prostate cancer risk single nucleotide polymorphisms were determined in 1,321 white men who underwent radical prostatectomy. Univariate and multivariate analyses were performed to compare the relationship of single nucleotide polymorphism frequency with total prostate and tumor volumes. RESULTS: On multivariate analysis 2 single nucleotide polymorphisms on chromosome 8q24, rs16901979 (A) and rs6983267 (G), were significantly associated with increased tumor volume (p=0.01 and 0.02, respectively). In contrast, rs17632542 (T) near the PSA gene on 19q13 was associated with significantly lower tumor volume and rs10788160 (A) on 10q26 was associated with significantly larger prostate volume (p=0.02 and 0.01, respectively). CONCLUSIONS: Analysis of 38 single nucleotide polymorphisms associated with prostate cancer risk revealed a significant association between several on chromosome 8q24 and increased tumor volume but not prostate volume. This suggests that they are bona fide markers of prostate cancer susceptibility and possibly more aggressive disease. Other prostate cancer risk alleles are associated with prostate specific antigen and increased prostate or decreased tumor volume, suggesting detection bias due to their phenotypic influence. PMID- 24345442 TI - Infection related hospitalizations after prostate biopsy in a statewide quality improvement collaborative. AB - PURPOSE: While transrectal prostate biopsy is the cornerstone of prostate cancer diagnosis, serious post-biopsy infectious complications are reported to be increasing. A better understanding of the true prevalence and microbiology of these events is needed to guide quality improvement in this area and ultimately better early detection practices. MATERIALS AND METHODS: Using data from the MUSIC registry we identified all men who underwent transrectal prostate biopsy at 21 practices in Michigan from March 2012 to June 2013. Trained data abstractors recorded pertinent data including prophylactic antibiotics and all biopsy related hospitalizations. Claims data and followup telephone calls were used for validation. All men admitted to the hospital for an infectious complication were identified and their culture data were obtained. We then compared the frequency of infection related hospitalization rates across practices and according to antibiotic prophylaxis in concordance with AUA best practice recommendations. RESULTS: The overall 30-day hospital admission rate after prostate biopsy was 0.97%, ranging from 0% to 4.2% across 21 MUSIC practices. Of these hospital admissions 95% were for infectious complications and the majority of cultures identified fluoroquinolone resistant organisms. AUA concordant antibiotics were administered in 96.3% of biopsies. Patients on noncompliant antibiotic regimens were significantly more likely to be hospitalized for infectious complications (3.8% vs 0.89%, p=0.0026). CONCLUSIONS: Infection related hospitalizations occur in approximately 1% of men undergoing prostate biopsy in Michigan. Our findings suggest that many of these events could be avoided by implementing new protocols (eg culture specific or augmented antibiotic prophylaxis) that adhere to AUA best practice recommendations and address fluoroquinolone resistance. PMID- 24345443 TI - Recent trends in thyroid surgery in Wales. AB - INTRODUCTION: Our objective was to analyse trends in thyroid surgery in Wales over a recent 12-year period. METHODS: Details of patients who underwent thyroid surgery across Wales from 1999 to 2010 were analysed from the Patient Episodes Database for Wales [n = 6570, 83% (5429) female, 86% (5634) benign thyroid disease]. We determined age-adjusted thyroidectomy rates from the European standard population and a Poisson regression model was fitted to assess temporal trends. Joinpoint regression was used to calculate annual percentage change (APC) in thyroidectomy rates. RESULTS: An increase in thyroidectomy rates was observed for malignant disease [APC 4.5, 95% confidence interval (CI) 1.6-7.5] while surgery rates for benign disease declined over the period (APC -3.2, 95% CI -5.1 to -1.3). The use of total thyroidectomy rose from 17% (599/3501) in 1999-2004 to 30% (912/3069) in 2005-2010 (p < 0.001). Total thyroidectomies were performed in a higher proportion of males than females [26% (291/1141) vs. 22% (1220/5429), p = 0.03] and in a greater percentage of patients with malignant disease than benign [36% (337/936) vs. 21% (1174/5634), p < 0.001). General surgeons undertook 83% of thyroid surgery but with a growing involvement of ENT surgeons. Regional disparities were seen in the type of surgery offered to patients with benign thyroid disease. CONCLUSION: The use of total thyroidectomy for benign and malignant thyroid disease has risen in Wales. The increase in surgeries performed for malignancy would support a rising incidence of thyroid cancer in the region. Regional disparities in choice of surgery for benign disease require further exploration. PMID- 24345445 TI - Syntheses of novel beta-carboline derivatives and the activities against five tumor-cell lines. AB - A series of beta-carbolines possessing the aryl group at C-1 position has been synthesized from tryptophan. The newly synthesized compounds were screened for their in vitro anticancer activity against various human cancer cell lines by MTT assay. Some of them exhibited anticancer activity with IC50 values lower than 10MUM outdistanced the cisplatin level. Structure-activity relationship reveals that the alcohol substituents at C-3 position played an important role in inhibition activity. PMID- 24345444 TI - Memantine for fragile X-associated tremor/ataxia syndrome: a randomized, double blind, placebo-controlled trial. AB - OBJECTIVE: Memantine, an uncompetitive N-methyl-d-aspartate receptor antagonist, is currently approved by the US Food and Drug Administration for the treatment of moderate to severe Alzheimer's disease. Anecdotal reports have suggested that memantine may improve neurologic and cognitive symptoms of individuals with the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS); however, its efficacy and safety in this population have not been assessed in a controlled trial. METHOD: Individuals with FXTAS aged 34-80 years were enrolled in a randomized, double-blind, placebo-controlled, 1-year trial between September 2007 and August 2012. Inclusion required definite, probable, or possible FXTAS in clinical stages 1-5 according to previously published criteria. Primary outcome measures were the Behavioral Dyscontrol Scale (BDS) score and CATSYS intention tremor severity. RESULTS: Ninety-four participants were randomized from 205 screened; of those, 43 and 45 started treatment with memantine (titrated to 10 mg twice daily) and placebo, respectively. Thirty-four participants receiving memantine and 36 receiving placebo completed the 1-year endpoint assessment (n = 70). Intention-to-treat analysis showed no improvement with respect to intention tremor severity (mean [SD] values with memantine vs placebo: 1.05 [0.73] vs 1.89 [2.19], P = .047) or BDS score (16.12 [5.43] vs 15.72 [3.93], P = .727) at follow up. Post hoc analyses of participants with early FXTAS (stage <= 3), those with late FXTAS (stage > 3), and those in different age groups (<= 65 years and > 65 years) also indicated no significant improvement. More frequent mild adverse events were observed in the placebo group, while more frequent moderate adverse events occurred in the memantine group (P = .007). CONCLUSION: This randomized, double-blind, placebo-controlled trial of memantine for individuals with FXTAS showed no benefit compared to placebo with respect to the selected outcome measures. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00584948. PMID- 24345446 TI - Lactam based 7-amino suberoylamide hydroxamic acids as potent HDAC inhibitors. AB - A series of SAHA-like molecules were prepared introducing different lactam carboxyamides in position 7 of the suberoylanilide skeleton. The activity against different HDAC isoforms was tested and the data compared with the corresponding linear products, without substituent in position 7. In general, this modification provided an effective reinforcement of in vitro activity. While the lactam size or the CO/NH group orientation did not strongly influence the inhibition, the contemporary modification of the suberoylamide fragment gave vary active variants in the lactam series, with compound 28 (ST8078AA1) that showed IC50 values between 2 and 10nM against all Class I HDAC isoforms, demonstrating it to be a large spectrum pan-inhibitor. This strong affinity with HDAC was also confirmed by the value of IC50=0.5MUM against H460 cells, ranking 28 as one of the most potent HDAC inhibitors described so far. PMID- 24345447 TI - Discovery of hybrid Hsp90 inhibitors and their anti-neoplastic effects against gefitinib-resistant non-small cell lung cancer (NSCLC). AB - Heat shock protein 90 (Hsp90) represents an attractive cancer therapeutic target due to its role in the stabilization and maturation of many oncogenic proteins. We have designed a series of hybrid Hsp90 inhibitors by connecting the resorcinol ring of VER-49009 (2) and the trimethoxyphenyl ring of PU3 (3) using structure based approach. Subsequent testing established that compound 1f inhibited gefitinib-resistant H1975 cell proliferation, brought about the degradation of Hsp90 client proteins including EGFR, Met, Her2 and Akt and induced the expression of Hsp70. The design, synthesis, and evaluation of 1f are described herein. PMID- 24345448 TI - Azide-alkyne cycloaddition affording enzymatically tunable bisubstrate based inhibitors of histone acetyltransferase PCAF. AB - A novel strategy to prepare bisubstrate based inhibitors for histone acetyltransferases is presented. To obtain these, azido peptides derived from histone H3 incorporating either a serine or a phosphoserine residue were connected to a propargyl coenzyme A derivative through copper catalyzed click chemistry. The resulting inhibitors were tested with therapeutically relevant acetyltransferase PCAF. Increased potency of the phosphoserine containing inhibitor was observed. The synthetic strategy presented may be used for developing bisubstrate based inhibitors against any acetyltransferase. PMID- 24345449 TI - TMEDA-derived biscationic amphiphiles: An economical preparation of potent antibacterial agents. AB - Bis-alkylated derivatives of N,N,N',N'-tetramethylethylenediamine (TMEDA) represent a well-known class of versatile biscationic amphiphiles, owing to their low cost and ease of preparation. Asymmetric TMEDA derivatives, however, have been studied significantly less, particularly in regards to their antimicrobial properties. We have thus prepared a series of 36 mono- and bis-alkylated TMEDA derivatives to evaluate their inhibition of bacterial growth. This series of compounds showed low micromolar activity against a panel of four bacteria. Optimal inhibition was observed when the biscationic amphiphiles possessed modest asymmetry and were composed of between 20 and 24 total carbon atoms in the side chains. These amphiphiles were prepared in a simple two-step procedure, utilizing inexpensive materials and atom-economical reactions, making them practical for further development. PMID- 24345450 TI - Evaluation of the Compliance, Acceptance, and Usability of a Web-Based eHealth Intervention for Parents of Children With Infantile Hemangiomas: Usability Study. AB - BACKGROUND: Infantile hemangiomas (IH) are common benign vascular tumors in children. Recognition and timely referral of high risk IH to specialized centers is important. This might be achieved by involving parents in the care for IH by means of an eHealth intervention. OBJECTIVE: The objective of our study was to evaluate parent compliance, acceptance, and usability of an open access, Web based eHealth intervention (including e-learning and e-consult) designed to increase parents' knowledge and (risk) evaluation of IH. METHODS: A cross sectional study of parents who completed the eHealth intervention between October 2010 and November 2012 was carried out. All parents were sent a study questionnaire. Questions to evaluate compliance (to the advice given by a dermatologist during e-consultation) were asked. Acceptance and usability were evaluated by using the modified Technology Acceptance Model. RESULTS: A total of 224 parents completed the eHealth intervention and received the questionnaire, 135/224 parents responded (response rate was 60.3%). There were 128/135 questionnaires that were completed and included. A total of 110/128 (85.9%) parents were compliant to the advice of the dermatologist. There were 116.8/128 (91.3%) that perceived the eHealth intervention as useful and almost all parents (98.4%, 126/128) found the information in the e-learning clear. There were 29/128 (22.7%) that experienced technical problems. The majority of the parents (94.5%, 121/128) found the eHealth intervention reliable and most of them (98.4%, 126/128) would recommend the eHealth intervention to other parents. Noncompliant parents judged the eHealth intervention significantly less reliable compared to compliant parents (71%, 10/14 versus 97.3%, 107/110; P=.003). CONCLUSIONS: Parents of children with an IH showed a high compliance (85.9%, 110/128) to the advice of the dermatologist given via our Web-based eHealth intervention. This high compliance might be positively influenced by the good acceptance and usability of the eHealth intervention and might result in timely presentation and treatment of children with high risk IH in specialized centers. PMID- 24345451 TI - Enhanced fear expression in Spir-1 actin organizer mutant mice. AB - Spir proteins nucleate actin filaments at vesicle membranes and facilitate intracellular transport processes. The mammalian genome encodes two Spir proteins, namely Spir-1 and Spir-2. While the mouse spir-2 gene has a rather broad expression pattern, high levels of spir-1 expression are restricted to the nervous system, oocytes, and testis. Spir-1 mutant mice generated by a gene trap method have been employed to address Spir-1 function during mouse development and in adult mouse tissues, with a specific emphasis on viability, reproduction, and the nervous system. The gene trap cassette disrupts Spir-1 expression between the N-terminal KIND domain and the WH2 domain cluster. Spir-1 mutant mice are viable and were born in a Mendelian ratio. In accordance with the redundant function of Spir-1 and Spir-2 in oocyte maturation, spir-1 mutant mice are fertile. The overall brain anatomy of spir-1 mutant mice is not altered and visual and motor functions of the mice remain normal. Microscopic analysis shows a slight reduction in the number of dendritic spines on cortical neurons. Detailed behavioral studies of the spir-1 mutant mice, however, unveiled a very specific and highly significant phenotype in terms of fear learning in male mice. In contextual and cued fear conditioning experiments the male spir-1 mutant mice display increased fear memory when compared to their control littermates. Our data point toward a particular function of the vesicle associated Spir-1 actin organizer in neuronal circuits determining fear behavior. PMID- 24345452 TI - Cumulative adversity in childhood and emergent risk factors for long-term health. AB - OBJECTIVE: To examine whether and when effects of cumulative adversity in the first 7 years of life are evident in relation to 3 childhood markers of risk for poor adult physical health. STUDY DESIGN: The study data are from an English birth cohort. Parental reports of 8 social risk factors were obtained during the child's first 7 years, and scores were created to reflect cumulative adversity at 4 developmental periods. At age 7 and 11 years, weight, height, and blood pressure (BP) were measured by clinic staff, and caregivers reported behavior problems. Linear regression was used to estimate associations of cumulative adversity with each outcome (n = 4361) and changes in these outcomes between 7 and 11 years (n = 3348). RESULTS: At age 7 years, mean adversity and chronic exposure to high adversity were associated with elevated body mass index (BMI) and internalizing and externalizing symptoms (P < .05), but not elevated BP. Adversity in all developmental periods was associated with elevated numbers of internalizing and externalizing symptoms (P < .0001), but associations were less robust for BMI. Adversity did not predict change in BMI or BP between age 7 and 11 years, however, it predicted increases in internalizing and externalizing symptoms (P < .0001). CONCLUSION: Cumulative adversity was associated with BMI and behavior problems at age 7 years, and our data indicate that timing and chronicity of exposure to adversity differentially influence diverse indicators of long-term health risk commonly measured in childhood. This research suggests the hypothesis that interventions to address adversity could reduce the development of multiple chronic disease risk factors and limit their effects on health. PMID- 24345453 TI - The effects of nasal continuous positive airway pressure on cardiac function in premature infants with minimal lung disease: a crossover randomized trial. AB - OBJECTIVE: To assess the effects of different nasal continuous positive airway pressure (nCPAP) pressures on cardiac performance in preterm infants with minimal lung disease, we conducted a randomized, blinded crossover study. STUDY DESIGN: We studied infants between 28 and 34 weeks' corrected gestational age, treated with nCPAP of 5 cm H2O, in air. Infants with significant cardiac shunts were excluded. Infants were randomly assigned to nCPAP levels of 4, 6, and 8 cm H2O for 15 minutes each. Right and left ventricular outputs and left pulmonary artery and superior vena cava flows were measured 15 minutes after each change. RESULTS: Thirty-four infants born at a mean gestational age of 29 weeks with a birth weight of 1.3 kg were studied. There were no significant differences in right and left ventricular outputs and left pulmonary artery and superior vena cava flows at different levels of nCPAP. CONCLUSION: We investigated the effect of increasing nCPAP levels on cardiac output. We conclude that nCPAP levels between 4 and 8 cm H2O did not have an effect on cardiac output in stable preterm infants with minimal lung disease. PMID- 24345454 TI - Renal tubular acidosis. PMID- 24345455 TI - How are childhood thyroid nodules discovered: opportunities for improving early detection. AB - In a retrospective analysis of childhood thyroid nodules, 18% were radiographic incidentalomas and 41% were discovered by a clinician's palpation; 40% were discovered by patients' families. The latter group had the largest nodules and highest rates of thyroid cancer metastasis, suggesting opportunities for earlier detection through annual well-child visits. PMID- 24345456 TI - Mitochondrial function in metabolic health: a genetic and environmental tug of war. AB - BACKGROUND: The increased prevalence of obesity and its co-morbidities and their strong association with inactivity have produced an 'exercise-deficient phenotype' in which individuals with a particular combination of disease susceptible genes collide with environmental influences to cross a biological 'threshold' that ultimately manifests as overt clinical conditions (i.e., risk factors for disease states). These risk-factors have been linked to impairments in skeletal muscle mitochondrial function. SCOPE OF REVIEW: The question of whether 'inborn' mitochondrial deficiencies and/or defective mitochondrial metabolism contribute to metabolic disease, or if environmental factors are the major determinant, will be examined. MAJOR CONCLUSIONS: We contend that impaired whole-body insulin resistance along with impaired skeletal muscle handling of carbohydrate and lipid fuels (i.e., metabolic inflexibility) is associated with a reduced skeletal muscle mitochondrial content which, in large part, is a maladaptive response to an 'inactivity cycle' which predisposes to a reduced level of habitual physical activity. While genetic components play a role in the pathogenesis of metabolic disease, exercise is a powerful environmental stimulus capable of restoring the metabolic flexibility of fuel selection and reduces risk factors for metabolic disease in genetically-susceptible individuals. GENERAL SIGNIFICANCE: Given the apathy towards voluntary physical activity in most Western societies, it is clear that there is an urgent need for innovative, clinically-effective exercise strategies, coupled with changes in current attitudes and methods of delivering exercise prescription and dietary advice, in order to improve metabolic health and reduce metabolic disease risk at the population level. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research. PMID- 24345457 TI - Clozapine ameliorates epigenetic and behavioral abnormalities induced by phencyclidine through activation of dopamine D1 receptor. AB - Accumulating evidence suggests that dysregulation of histone modification is involved in the pathogenesis and/or pathophysiology of psychiatric disorders. However, the abnormalities in histone modification in the animal model of schizophrenia and the efficacy of antipsychotics for such abnormalities remain unclear. Here, we investigated the involvement of histone modification in phencyclidine-induced behavioral abnormalities and the effects of antipsychotics on these abnormalities. After repeated phencyclidine (10 mg/kg) treatment for 14 consecutive days, mice were treated with antipsychotics (clozapine or haloperidol) or the histone deacetylase inhibitor sodium butyrate for 7 d. Repeated phencyclidine treatments induced memory impairment and social deficit in the mice. The acetylation of histone H3 at lysine 9 residues decreased in the prefrontal cortex with phencyclidine treatment, whereas the expression level of histone deacetylase 5 increased. In addition, the phosphorylation of Ca2+/calmodulin-dependent protein kinase II in the nucleus decreased in the prefrontal cortex of phencyclidine-treated mice. These behavioral and epigenetic changes in phencyclidine-treated mice were attenuated by clozapine and sodium butyrate but not by haloperidol. The dopamine D1 receptor antagonist SCH-23390 blocked the ameliorating effects of clozapine but not of sodium butyrate. Furthermore, clozapine and sodium butyrate attenuated the decrease in expression level of GABAergic system-related genes in the prefrontal cortex of phencyclidine treated mice. These findings suggest that the antipsychotic effect of clozapine develops, at least in part, through epigenetic modification by activation of the dopamine D1 receptor in the prefrontal cortex. PMID- 24345459 TI - Absence of growth of Listeria monocytogenes in naturally contaminated Cheddar cheese. AB - Each cheese producer is responsible by the legislation for the number of Listeria monocytogenes in cheese and is required to prove that numbers will not exceed 100 cfu/g throughout the shelf-life of the cheese. Even in the case of hard-cheese such as Cheddar cheese, the absence of growth of List. monocytogenes during ripening has to be demonstrated to comply with EU legislation. Studies dedicated to assessing List. monocytogenes growth throughout cheese shelf-life are generally based on artificially contaminated cheeses. Contrary to the majority of works, the current study focused on the growth of List. monocytogenes in naturally contaminated raw milk farmhouse Cheddar cheeses during a five-month ripening period. List. monocytogenes growth was assessed by direct count and its presence was detected by enrichment in two naturally contaminated cheese batches. In order to track routes of contamination, 199 processing environment samples from inside and outside the processing facility were taken, and their analysis for the presence of List. monocytogenes was performed on four occasions over a 9 month period. List. monocytogenes isolates were differentiated using PFGE and serotyping. List. monocytogenes never exceeded 20 cfu/g in the cheeses and could not be detected after five months of ripening. Eleven pulsotypes were identified. One pulsotype was found in the yard outside the processing facility, in a vat, on the processing area floor and in a cheese. This indicated that the outside environment constitutes a potential source of contamination of the processing environment and of the cheese. These results demonstrate that this farmhouse Cheddar cheese does not support List. monocytogenes growth and suggests that the efforts to reduce processing environment contamination are worthwhile. PMID- 24345458 TI - Seasonal changes in humidity impact drought resistance in tropical Drosophila leontia: testing developmental effects of thermal versus humidity changes. AB - Drosophila leontia is native to highly humid equatorial tropical habitats but its desiccation sensitivity (~10h) is not consistent with its abundance during the drier autumn season in the subtropical regions. We have tested the effects of developmental acclimation on desiccation resistance and water balance related traits of D. leontia collected during rainy and autumn seasons. The isofemale lines of seasonal populations were reared under ecologically relevant growth temperatures (18 or 26 degrees C) or humidity conditions (35 or 85% RH) but tested at different times under identical experimental conditions. The larvae as well as flies reared under two thermal conditions (18 or 26 degrees C) showed no effect on desiccation related traits as well as storage and utilization of energy metabolites. In contrast, for D. leontia reared under low humidity (35% RH), significant changes at larval as well adult stages include increase in the desiccation resistance as well as cuticular lipid quantity, reduced levels of rate of body water loss, higher storage of carbohydrates but lower rate of utilization of carbohydrates as compared with flies reared at high humidity (85% RH). D. leontia has responded to rearing under low humidity conditions by increasing its desiccation resistance but not due to changes in the growth temperatures. These laboratory observations on seasonal populations highlight differences due to rearing conditions but not due to seasons. Further, direct analysis of wild-caught seasonal populations has shown trends similar to developmental acclimation effects. For wild caught flies, there are significant seasonal differences i.e. higher desiccation resistance as well as cuticular lipid quantity but reduced rate of water loss for autumn than rainy season flies. Thus, our laboratory observations are relevant for understanding seasonal adaptations of natural populations of tropical D. leontia to wet-dry conditions in the wild. PMID- 24345460 TI - Dual-energy CT in assessing therapeutic response to radiofrequency ablation of renal cell carcinomas. AB - PURPOSE: To investigate the utility of dual-energy (DE) CT using virtual noncontrast (VNC) and iodine overlay (IO) images to assess therapeutic response to radiofrequency ablation (RFA) for renal cell carcinomas (RCCs). MATERIALS AND METHODS: In this institutional review board-approved study (with waiver of informed consent), 47 patients with RCCs that underwent DECT after RFA were enrolled in this study. DECT protocols included true noncontrast (TNC), linearly blended DE corticomedullary and late nephrographic phase imaging. Two types of VNC and IO images were derived from corticomedullary and late nephrographic phases, respectively. To predict local tumor progression at RFA site, linearly blended and IO images were analyzed both qualitatively and quantitatively. Contrast-to-noise ratios (CNR) of renal cortex-to-RFA zones were calculated. The overall imaging quality of VNC images was compared with TNC images. RESULTS: The IO images from corticomedullary and late nephrographic phases showed excellent diagnostic performance (each sensitivity 100% and each specificity 91.5%) for predicting local tumor progression. The degree of enhancement of local tumor progression was not significantly different between linearly blended and IO images (P>0.05). The mean CT numbers were not significantly different between TNC and VNC images (P>0.05). In renal cortex-to-RFA site, CNR between linearly blended and IO images was not significantly different (P>0.05). The VNC imaging quality from the two phases was given a good rating. CONCLUSION: VNC and IO images from DECT may allow acceptable diagnostic performance with less radiation exposure as a follow-up imaging tool after RFA for RCC, compared to the linearly blended CT images. PMID- 24345461 TI - Cardiac expression and atrial fibrillation-associated remodeling of K2p2.1 (TREK 1) K+ channels in a porcine model. AB - AIMS: Effective management of atrial fibrillation (AF) often remains an unmet need. Cardiac two-pore-domain K(+) (K2P) channels are implicated in action potential regulation, and their inhibition has been proposed as a novel antiarrhythmic strategy. K2P2.1 (TREK-1) channels are expressed in the human heart. This study was designed to identify and functionally express porcine K2P2.1 channels. In addition, we sought to analyze cardiac expression and AF associated K2P2.1 remodeling in a clinically relevant porcine AF model. MAIN METHODS: Three pK2P2.1 isoforms were identified and amplified. Currents were recorded using voltage clamp electrophysiology in the Xenopus oocyte expression system. K2P2.1 remodeling was studied by quantitative real time PCR and Western blot in domestic pigs during AF induced by atrial burst pacing. KEY FINDINGS: Human and porcine K2P2.1 proteins share 99% identity. Residues involved in phosphorylation or glycosylation are conserved. Porcine K2P2.1 channels carried outwardly rectifying K(+) currents similar to their human counterparts. In pigs, K2P2.1 was expressed ubiquitously in the heart with predominance in the atrial tissue. AF was associated with time-dependent reduction of K2P2.1 protein in the RA by 70% (7 days of AF) and 80% (21 days of AF) compared to control animals in sinus rhythm. K2P2.1 expression in the left atrium, AV node, and ventricles was not affected by AF. SIGNIFICANCE: Similarities between porcine and human K2P2.1 channels indicate that the pig may represent a valid model for mechanistic and preclinical studies. AF-related atrial K2P2.1 remodeling has potential implications for arrhythmia maintenance and antiarrhythmic therapy. PMID- 24345462 TI - A new active thermal neutron detector. AB - This communication presents the main results about the design and in-house fabrication of a new solid-state neutron detector, which produces a DC output signal proportional to the thermal neutron fluence rate. The detector has been developed within the framework of the 3-y project NESCOFI@BTF of INFN (CSN V). Due to its sensitivity, photon rejection, low cost and minimum size, this device is suited to be used in moderator-based spectrometers. PMID- 24345463 TI - Dosimetry of secondary cosmic radiation up to an altitude of 30 km. AB - Dosimetric measurements in the field of secondary cosmic radiation were extensively made during the last years. Since the majority of these measurements were performed on-board passenger aircraft at altitudes between 10 and 12 km, measurements at higher altitudes are desirable for the verification of the legal dose assessment procedures for aircrew. A simple solution is to use a high altitude balloon that reaches altitudes as high as 30 km. In this work, it is shown that the dose rate profile up to 30 km can be measured with acceptable uncertainties using a Si-detector. PMID- 24345464 TI - Measurements and Monte Carlo simulations of the spectral variations of the cosmic ray-induced neutrons at the Pic du Midi over a 2-y period. AB - In this paper, a Bonner Sphere Spectrometer extended to high energies (HERMEIS) was employed to measure continuously the cosmic-ray-induced neutron spectra over a long-term period (2 y) at mountain altitude and medium geomagnetic latitude (Pic du Midi de Bigorre in the French Pyrenees, +2885 m, 5.6 GV). The results showed 1-y sinusoidal oscillations in the integrated fluence rates. The amplitude of these oscillations depends on the neutron energetic domain. The fluence rate of thermal neutrons was 53 % higher in August than that in February. Those of epithermal neutrons with energies between 0.4 eV and 0.1 MeV and evaporation neutrons (from 0.1 to 20 MeV) were ~25 % higher in the summer than those in the winter. Finally, the cascade neutron fluence rate (>20 MeV) remained quite the same (<10 % variation). To understand the effects of local and seasonal changes in the measurement environment, GEANT4 simulations were performed. The nature of rock and thickness of the snow cover during the winter period (given by meteorological data) were investigated. A reasonable agreement between experiments and calculations was found. PMID- 24345465 TI - Improved apoptotic cell death in drug-resistant non-small-cell lung cancer cells by tumor necrosis factor-related apoptosis-inducing ligand-based treatment. AB - Since response to platinum-based therapy in non-small-cell lung cancer (NSCLC) is poor, the present study was designed to rationally identify novel drug combinations in cell models including the A549 cell line and the cisplatin resistant subline A549/Pt, characterized by reduced sensitivity to cisplatin induced apoptosis and by upregulation of efflux transporters of the ATP binding cassette (ABC) superfamily. Given the molecular features of these cells, we focused on compounds triggering apoptosis through different mechanisms, such as the mitochondria-targeting drug arsenic trioxide and the phenanthridine analog sanguinarine, which induce apoptosis through the extrinsic pathway. Sanguinarine, not recognized by ABC transporters, could overcome cisplatin resistance and, when used in combination with arsenic trioxide, was synergistic in A549 and A549/Pt cells. The arsenic trioxide/sanguinarine cotreatment upregulated genes implicated in apoptosis activation through the extrinsic pathway. Drug combination experiments indicated that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment improved arsenic trioxide/sanguinarine efficacy, a feature associated with a striking apoptosis induction, particularly in the cisplatin-resistant variant. Thus, a synergistic interaction between sanguinarine and arsenic trioxide could be obtained independent of relative cell sensitivity to arsenic trioxide, and an enhanced apoptosis induction could be achieved in combination with TRAIL through modulation of the extrinsic apoptotic pathway. Antitumor activity studies supported the interest of drug combinations including TRAIL in NSCLC, indicating that drug-resistant NSCLC cells can efficiently be killed by the combination of proapoptotic agents. Our results suggest that the molecular changes occurring in treated cells may be exploited to rationally hit surviving cells. PMID- 24345466 TI - Anti-inflammatory and antinociceptive action of an orally available nociceptin receptor agonist SCH 221510 in a mouse model of inflammatory bowel diseases. AB - The nociceptin receptors (NOPs) are expressed in the gastrointestinal (GI) tract on muscle cell membranes and neurons, as well as the immune cells that infiltrate the mucosa. The involvement of NOPs in the pathophysiology of GI inflammation has been suggested, but due to the lack of selective NOP agonists, it never fully elucidated. Our aim was to characterize the anti-inflammatory and antinociceptive effect of the NOP agonist, SCH 221510 [3-endo-8-[bis(2-methylphenyl)methyl]-3 phenyl-8-azabicyclo [3.2.1]octan-3-ol], as a potential therapeutic strategy in the treatment of inflammatory bowel diseases (IBD). The anti-inflammatory action of SCH 221510 was determined after intraperitoneal, oral, and intracolonic administration of SCH 221510 (0.1-3.0 mg/kg once or twice daily) in mice treated with 2,4,6-trinitrobenzenesulfonic acid (TNBS). Antinociceptive action of SCH 221510 was evaluated in the mouse model of mustard oil (MO)-induced abdominal pain. Relative NOP mRNA expression was assessed in patients with IBD using real time reverse transcriptase-polymerase chain reaction. We found that the expression of NOP mRNA was significantly decreased in patients with IBD. The administration (0.1 and 1.0 mg/kg i.p. twice daily and 3 mg/kg p.o. twice daily) of SCH 221510 attenuated TNBS colitis in mice. This effect was blocked by a selective NOP antagonist [J-113397 [(+/-)-1-[(3R*,4R*)-1-(cyclooctylmethyl)-3 (hydroxymethyl)-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one]]. The intracolonic injections of SCH 221510 did not improve colitis in mice. The antinociceptive effect of SCH 221510 was observed after oral administration of SCH 221510 in MO-induced pain tests in mice with acute colitis. In conclusion, our results show a potent anti-inflammatory and antinociceptive effect upon selective activation of NOP receptors and suggest that the NOP agonist SCH 221510 is a promising drug candidate for future treatment of IBD. PMID- 24345467 TI - Orally active opioid MU/delta dual agonist MGM-16, a derivative of the indole alkaloid mitragynine, exhibits potent antiallodynic effect on neuropathic pain in mice. AB - (E)-Methyl 2-((2S,3S,7aS,12bS)-3-ethyl-7a-hydroxy-8-methoxy-1,2,3,4,6,7,7a,12b octahydroindolo[2,3-a]quinolizin-2-yl)-3-methoxyacrylate (7-hydroxymitragynine), a main active constituent of the traditional herbal medicine Mitragyna speciosa, is an indole alkaloid that is structurally different from morphine. 7 Hydroxymitragynine induces a potent antinociceptive effect on mouse acute pain through MU-opioid receptors. In this study, we developed dual-acting MU- and delta-opioid agonists MGM-15 and MGM-16 from 7-hydroxymitragynine for the treatment of acute and chronic pain. MGM-16 showed a higher potency than that of 7-hydroxymitragynine and MGM-15 in in vitro and in vivo assays. MGM-16 exhibited a high affinity for MU- and delta-opioid receptors, with K(i) values of 2.1 and 7.0 nM, respectively. MGM-16 showed MU- and delta-opioid full agonistic effects in a guanosine 5'-O-(3-[(35)S]thiotriphosphate) binding assay and in a functional test using electrically elicited guinea pig ileum and mouse vas deferens contractions. Systemic administration of MGM-16 produced antinociceptive effects in a mouse acute pain model and antiallodynic effects in a chronic pain model. The antinociceptive effect of MGM-16 was approximately 240 times more potent than that of morphine in a mouse tail-flick test, and its antiallodynic effect was approximately 100 times more potent than that of gabapentin in partial sciatic nerve-ligated mice, especially with oral administration. The antinociceptive effect of MGM-16 was completely and partially blocked by the MU-selective antagonist beta-funaltrexamine hydrochloride (beta-FNA) and by the delta selective antagonist naltrindole, respectively, in a tail-flick test. The antiallodynic effect of MGM-16 was completely blocked by beta-FNA and naltrindole in a neuropathic pain model. These findings suggest that MGM-16 could become a class of a compound with potential therapeutic utility for treating neuropathic pain. PMID- 24345468 TI - Predicting outcomes of neuroreflexotherapy in patients with subacute or chronic neck or low back pain. AB - BACKGROUND CONTEXT: In the context of shared decision-making, a valid estimation of the probability that a given patient will improve after a specific treatment is valuable. PURPOSE: To develop models that predict the improvement of spinal pain, referred pain, and disability in patients with subacute or chronic neck or low back pain undergoing a conservative treatment. STUDY DESIGN AND SETTING: Analysis of data from a prospective registry in routine practice. PATIENT SAMPLE: All patients who had been discharged after receiving a conservative treatment within the Spanish National Health Service (SNHS) (n=8,778). OUTCOME MEASURES: Spinal pain, referred pain, and disability were assessed before the conservative treatment and at discharge by the use of previously validated methods. METHODS: Improvement in spinal pain, referred pain, and disability was defined as a reduction in score greater than the minimal clinically important change. A predictive model that included demographic, clinical, and work-related variables was developed for each outcome using multivariate logistic regression. Missing data were addressed using multiple imputation. Discrimination and calibration were assessed for each model. The models were validated by bootstrap, and nomograms were developed. RESULTS: The following variables showed a predictive value in the three models: baseline scores for pain and disability, pain duration, having undergone X-ray, having undergone spine surgery, and receiving financial assistance for neck or low back pain. Discrimination of the three models ranged from slight to moderate, and calibration was good. CONCLUSIONS: A registry in routine practice can be used to develop models that estimate the probability of improvement for each individual patient undergoing a specific form of treatment. Generalizing this approach to other treatments can be valuable for shared decision making. PMID- 24345469 TI - In vitro lifespan and senescence mechanisms of human nucleus pulposus chondrocytes. AB - BACKGROUND CONTEXT: Our previous in vivo study demonstrated that human nucleus pulposus chondrocytes (NPCs) in aging discs exhibited characteristic senescent features such as an increased senescence-associated beta-galactosidase (SA-beta gal) expression, shortened telomere, and decreased telomerase activity. The replicative p53-p21-pRB pathway, rather than the stress-induced p16-pRB pathway, played a more important role in the senescence of NPCs in an in vivo condition, although there is a situation in which both the pathways can be activated simultaneously. However, the in vitro lifespan and senescence mechanisms of human NPCs remain unclear. PURPOSE: To evaluate the underlying mechanisms of in vitro lifespan and in vitro senescence of the human NPCs and to verify whether the in vitro senescence mechanisms of the human NPC can represent the in vivo aging mechanisms of the cell. STUDY DESIGN/SETTING: An in vitro study. METHODS: We serially cultivated human NPCs from patients of different ages (35, 42, 55, 66, and 76 years) until the cells reached the end of their in vitro lifespan. During each subcultivation, we calculated NPCs cumulative population doubling level (PDL) and examined senescence markers (SA-beta-gal, telomere length, telomerase activity, and p53, p21, pRB, and p16 expressions). RESULTS: The cumulative PDLs of the NPCs from patients aged 35, 42 55, 66, and 76 years were 32, 29, 11, 9, and 11, respectively. The younger patients (35 and 42 years) had a higher mean of cumulative PDLs than the elderly patients did (55, 66, and 76 years; 30.5 vs. 10.3; p=.001). In addition, there was a significant, negative correlation between the cumulative PDLs and patient's age (r=-0.89; p=.04). With advancing culture passages, the NPCs irrespective of patient's age exhibited characteristic senescent features, such as an increase in SA-beta-gal expression, shortening of telomeres, decrease in telomerase activity, and activation of both replicative p53-p21-pRB and stress-induced p16-pRB pathways. However, all the senescent features occurred at the earlier passages in elderly compared with younger patients. CONCLUSIONS: The present study demonstrated that the human NPCs had a finite in vitro lifespan, which declined with host aging. The in vitro lifespan was determined by both replicative and stress-induced senescence mechanisms. The similarity in the in vitro senescent features with those apparent in the previous in vivo study suggests a possibility of the in vitro senescence mechanisms of the human NPC as a model of the in vivo aging mechanisms of the cell for future studies. PMID- 24345470 TI - Desmoplastic fibroma of the spine: a series of 12 cases and outcomes. AB - BACKGROUND CONTEXT: Desmoplastic fibroma (DF) is a benign, yet locally aggressive, tumor of the connective tissue. Desmoplastic fibroma in the spine is extremely rare, and only a few cases have been reported. Although surgical resection of DF arising in the spine is commonly regarded as a recommended treatment, it is difficult to achieve satisfactory results. PURPOSE: This study reviews the clinical patterns and follow-up data of patients with DF in the spine who underwent surgical treatment. We attempted to correlate surgical treatment and outcomes over time. STUDY DESIGN: A retrospective clinical study of the surgical managements, including subtotal resection, total spondylectomy, and en bloc resection, for DF in the spine. Desmoplastic fibroma of the spine treatment occurred from 2004 to 2009 at the Department of Bone Tumor Surgery, AA Hospital. PATIENT SAMPLE: Twelve consecutive cases of DF of the spine underwent surgical treatment at our center between 2004 and 2009. OUTCOME MEASURES: Neurologic outcomes were evaluated using Frankel score system and recurrence and metastasis were evaluated by computed tomography or magnetic resonance imaging of the surgical segments involved. Imaging was performed 3, 6, and 12 months after surgery, every 6 months for the next 2 years, and then annually for life. METHODS: Overall, two different surgery protocols were applied. One protocol involved subtotal resection followed by radiotherapy (n=4), whereas the other involved total tumor resection (n=8). Postoperative radiotherapy was administered in six cases. Clinical data and surgery efficacy were analyzed via chart review. RESULTS: Eleven patients were disease-free during their follow-up period, whereas one patient experienced recurrence without metastasis. Radicular pain nearly disappeared, and patients suffering from spinal cord compression recovered well. Local recurrence was detected in one-fourth (25%) of the cases that underwent subtotal resection and was not detected in any of the cases involving total spondylectomy. CONCLUSIONS: Local recurrence of DF is not uncommon after insufficient removal. Therefore, total excision, while also preserving neural function, is recommended. In our study, patients who underwent a total spondylectomy had significantly lower local recurrence rates for DF in the spine. Radiotherapy may be an acceptable alternative therapy, whereas en bloc resection has the potential to result in significant functional impairment. PMID- 24345471 TI - Pediatric cervical spondylolysis and American football. AB - BACKGROUND CONTEXT: Cervical spondylolysis (CS) is a rare condition and is even more uncommon in pediatric patients. It is characterized by a disruption of the articular mass at the junction of the superior and inferior facet joints and often is diagnosed incidentally. The C6 level is most commonly involved, and the cause of CS remains unknown. There are no recommendations in the literature regarding activity modification in patients with CS and no discussion as to risks of participation in American football or other contact sports. PURPOSE: To report a case of C6 bilateral cervical spondylolysis with bicuspid spinous process and to discuss radiographic/clinical findings and issues related to participation in contact sports and minimizing the risk of spinal cord injury. STUDY DESIGN/SETTING: Case report with 6 months clinical/radiographic follow-up METHODS: Radiographic description, clinical findings, and current review of the literature. RESULTS: A pediatric patient presented with a bilateral C6 cervical spondylolysis and bicuspid spinous process after an American football-related minor cervical spine trauma. Findings on radiographs indicated that the spondylolysis appeared to be chronic in nature, without evidence of instability. The patient and his family were educated on ways to decrease the risk of spinal cord injury with contact sports, after which the patient was allowed to participate fully in sports without restrictions or adverse events. CONCLUSION: Pediatric cervical spondylolysis is a rare condition, the cause of which remains debated. Although there is theoretical risk, more than 1.5 million youth participate in American football annually, and there have been no reported cases of significant spinal cord injury in patients with CS from football or other contact sports. PMID- 24345472 TI - Survivorship analysis after primary fusion for adult scoliosis. Prognostic factors for reoperation. AB - BACKGROUND CONTEXT: Adult scoliosis surgery is a challenging procedure with high rate of complications and reoperations. Reoperation rates vary widely. Long-term survival for this surgery still remains unknown, and the prognostic factors for reoperation are not well defined. PURPOSE: To assess adult scoliosis surgery survival (without the need of reoperation) after primary fusion in adults with mainly frontal deformity and to define prognostic factors for reoperation. STUDY DESIGN: Survival analysis of a cohort of consecutive adult patients, primarily operated on scoliosis using segmental instrumentation (retrospective cohort study). PATIENT SAMPLE: Fifty-nine patients older than 21 years at primary surgery (median age, 42 years), who presented idiopathic or degenerative curves with frontal Cobb >40 degrees (median preoperative frontal Cobb 59 degrees ), more than four-level fusion, and a 2-year minimum postoperative follow-up (median, 8.5 years; 41% patients had a longer than 10-year follow-up). OUTCOME MEASURES: Clinical and preoperative radiographic parameters were analyzed preoperatively and evaluated as prognostic factors for reoperation. METHODS: Survival was estimated using Kaplan-Meier method. Prognostic factors (clinical and radiographic) for reoperation were evaluated. Logistic regression using backward elimination was used for multivariate analysis. RESULTS: Survival was 89.8% at 1 year, 79.4% at 2 years, 73.4% at 3 years, 64% at 5 years, and 60.9% at 10 years. Overall, 21 patients (35.6%) underwent revision surgery. The most common reasons for reoperation were painful/prominent implants, adjacent-segment degeneration, and infection. American Society of Anesthesiologists Type II patients and double surgical approach were associated with a higher revision rate. Preoperative thoracic kyphosis was significantly higher in reoperated patients. CONCLUSIONS: The 10-year survival rate of primary scoliosis surgery in adult patients is 61%. Risk factors identified for reoperation included patients with higher morbidity, double surgical approach, and preoperative thoracic hyperkyphosis. PMID- 24345473 TI - Cognitive symptoms in patients with major depressive disorder and their implications for clinical practice. AB - CONTEXT: The literature regarding cognitive symptoms in major depressive disorder (MDD) is vast and often contradictory. To provide clinicians with a concise understanding of these prevalent and disabling symptoms, this overview describes what is known regarding cognitive symptoms in patients with MDD, the limitations of the current literature, and the implications of these data for current and future clinical practice. EVIDENCE ACQUISITION: PubMed searches were conducted to identify studies, meta-analyses, and systematic reviews evaluating cognitive function (not cognitive bias) in patients with MDD. Search terms used in combination with MDD were cognition, cognitive dysfunction, memory, psychomotor processing, and executive function. Searches were limited to articles available in the English language and those published between April 2007 and March 2012. Additional studies and those describing screening tools were identified using reference lists and PubMed "related citations." Ongoing trials were identified by searching for cognitive dysfunction and MDD at www.ClinicalTrials.gov. Relevant articles were obtained and reviewed by the author. RESULTS: Small sample size and inconsistent assessment tools were identified as major limitations of studies assessing clinical characteristics and risk factors for cognitive symptoms. Meta analyses and systematic reviews were used to mitigate this limitation. CONCLUSIONS: Cognitive symptoms of depression are prevalent and associated with earlier illness onset and longer episode duration. They can have an adverse impact on the treatment course of MDD as well as on functional recovery in depression. Further studies are needed to help determine whether certain treatments can be more effective than others at targeting these symptoms. PMID- 24345475 TI - Herpes zoster and IBD: are we being brash about a rash? PMID- 24345474 TI - Integrative DNA methylation and gene expression analysis in high-grade soft tissue sarcomas. AB - BACKGROUND: High-grade soft tissue sarcomas are a heterogeneous, complex group of aggressive malignant tumors showing mesenchymal differentiation. Recently, soft tissue sarcomas have increasingly been classified on the basis of underlying genetic alterations; however, the role of aberrant DNA methylation in these tumors is not well understood and, consequently, the usefulness of methylation based classification is unclear. RESULTS: We used the Infinium HumanMethylation27 platform to profile DNA methylation in 80 primary, untreated high-grade soft tissue sarcomas, representing eight relevant subtypes, two non-neoplastic fat samples and 14 representative sarcoma cell lines. The primary samples were partitioned into seven stable clusters. A classification algorithm identified 216 CpG sites, mapping to 246 genes, showing different degrees of DNA methylation between these seven groups. The differences between the clusters were best represented by a set of eight CpG sites located in the genes SPEG, NNAT, FBLN2, PYROXD2, ZNF217, COL14A1, DMRT2 and CDKN2A. By integrating DNA methylation and mRNA expression data, we identified 27 genes showing negative and three genes showing positive correlation. Compared with non-neoplastic fat, NNAT showed DNA hypomethylation and inverse gene expression in myxoid liposarcomas, and DNA hypermethylation and inverse gene expression in dedifferentiated and pleomorphic liposarcomas. Recovery of NNAT in a hypermethylated myxoid liposarcoma cell line decreased cell migration and viability. CONCLUSIONS: Our analysis represents the first comprehensive integration of DNA methylation and transcriptional data in primary high-grade soft tissue sarcomas. We propose novel biomarkers and genes relevant for pathogenesis, including NNAT as a potential tumor suppressor in myxoid liposarcomas. PMID- 24345476 TI - Lack of BDNF expression through promoter IV disturbs expression of monoamine genes in the frontal cortex and hippocampus. AB - Brain-derived neurotrophic factor (BDNF) is implicated in the pathophysiology of psychiatric conditions including major depression and schizophrenia. Mice lacking activity-driven BDNF expression through promoter IV (knock-in promoter IV: KIV) exhibit depression-like behavior, inflexible learning, and impaired response inhibition. Monoamine systems (serotonin, dopamine, and noradrenaline) are suggested to be involved in depression and schizophrenia since many of the current antidepressants and antipsychotics increase the brain levels of monoamines and/or act on monoamine receptors. To elucidate the impact of activity driven BDNF on the monoamine systems, we examined mRNA levels for 30 monoamine related genes, including receptors, transporters, and synthesizing enzymes, in KIV and control wild-type mice by using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). mRNA levels were measured in the frontal cortex and hippocampus, which are regions related to depression and schizophrenia and where promoter IV is active. The frontal cortex of KIV mice showed reduced levels of mRNA expression for serotonin receptors 1b, 2a, and 5b (5HTR1b, 5HTR2a, 5HTR5b), dopamine D2 receptors (DRD2), and adrenergic receptors alpha 1a and 1d (AdRalpha1a and AdRalpha1b), but increased levels for serotonin synthesizing enzyme, tryptophan hydroxylase (TPH), and dopamine D4 receptor (DRD4) when compared to control wild-type mice. The hippocampus of KIV mice showed decreased levels of 5HTR5b. Our results provide causal evidence that lack of promoter IV driven BDNF disturbs expression of monoaminergic genes in the frontal cortex and hippocampus. These disturbed expression changes in the monoamine systems may mediate the depression- and schizophrenia-like behavior of KIV mice. Our results also suggest that antidepressant and antipsychotic treatments may actually interfere with and normalize the disturbed monoamine systems caused by reduced activity-dependent BDNF, while the treatment responses to these drugs may differ in the subject with reduced BDNF levels caused by stress and lack of neuronal activity. PMID- 24345478 TI - Effect of type of cognitive task and walking speed on cognitive-motor interference during dual-task walking. AB - OBJECTIVE: We aimed to determine the effect of distinctly different cognitive tasks and walking speed on cognitive-motor interference of dual-task walking. METHODS: Fifteen healthy adults performed four cognitive tasks: visuomotor reaction time (VMRT) task, word list generation (WLG) task, serial subtraction (SS) task, and the Stroop (STR) task while sitting and during walking at preferred-speed (dual-task normal walking) and slow-speed (dual-task slow-speed walking). Gait speed was recorded to determine effect on walking. Motor and cognitive costs were measured. RESULTS: Dual-task walking had a significant effect on motor and cognitive parameters. At preferred-speed, the motor cost was lowest for the VMRT task and highest for the STR task. In contrast, the cognitive cost was highest for the VMRT task and lowest for the STR task. Dual-task slow walking resulted in increased motor cost and decreased cognitive cost only for the STR task. CONCLUSIONS: Results show that the motor and cognitive cost of dual task walking depends heavily on the type and perceived complexity of the cognitive task being performed. Cognitive cost for the STR task was low irrespective of walking speed, suggesting that at preferred-speed individuals prioritize complex cognitive tasks requiring higher attentional and processing resources over walking. While performing VMRT task, individuals preferred to prioritize more complex walking task over VMRT task resulting in lesser motor cost and increased cognitive cost for VMRT task. Furthermore, slow walking can assist in diverting greater attention towards complex cognitive tasks, improving its performance while walking. PMID- 24345477 TI - Vasopressin indirectly excites dorsal raphe serotonin neurons through activation of the vasopressin1A receptor. AB - The neuropeptide vasopressin (AVP; arginine-vasopressin) is produced in a handful of brain nuclei located in the hypothalamus and extended amygdala and is released both peripherally as a hormone and within the central nervous system as a neurotransmitter. Central projections have been associated with a number of functions including regulation of physiological homeostasis, control of circadian rhythms, and modulation of social behavior. The AVP neurons located in the bed nucleus of the stria terminalis and medial amygdala (i.e., extended amygdala) in particular have been associated with affiliative social behavior in multiple species. It was recently demonstrated that in the mouse AVP projections emanating from extended amygdala neurons innervate a number of forebrain and midbrain brain regions including the dorsal raphe nucleus (DR), the site of origin of most forebrain-projecting serotonin neurons. Based on the presence of AVP fibers in the DR, we hypothesized that AVP would alter the physiology of serotonin neurons via AVP 1A receptor (V1AR) activation. Using whole-cell electrophysiology techniques, we found that AVP increased the frequency and amplitude of excitatory post-synaptic currents (EPSCs) in serotonin neurons of male mice. The indirect stimulation of serotonin neurons was AMPA/kainate receptor dependent and blocked by the sodium channel blocker tetrodotoxin, suggesting an effect of AVP on glutamate neurons. Further, the increase in EPSC frequency induced by AVP was blocked by selective V1AR antagonists. Our data suggest that AVP had an excitatory influence on serotonin neurons. This work highlights a new target (i.e., V1AR) for manipulating serotonin neuron excitability. In light of our data, we propose that some of the diverse effects of AVP on physiology and behavior, including social behavior, may be due to activation of the DR serotonin system. PMID- 24345479 TI - In vitro hepatic microsomal metabolism of meloxicam in koalas (Phascolarctos cinereus), brushtail possums (Trichosurus vulpecula), ringtail possums (Pseudocheirus peregrinus), rats (Rattus norvegicus) and dogs (Canis lupus familiaris). AB - Quantitative and qualitative aspects of in vitro metabolism of the non-steroidal anti-inflammatory drug meloxicam, mediated via hepatic microsomes of specialized foliage (Eucalyptus) eating marsupials (koalas and ringtail possums), a generalized foliage eating marsupial (brushtail possum), rats, and dogs, are described. Using a substrate depletion method, intrinsic hepatic clearance (in vitro Clint) was determined. Significantly, rates of oxidative transformation of meloxicam, likely mediated via cytochromes P450 (CYP), were higher in marsupials compared to rats or dogs. The rank order of apparent in vitro Clint was brushtail possums (n=3) (mean: 394MUL/min/mg protein), >koalas (n=6) (50), >ringtail possums (n=2) (36) (with no significant difference between koalas and ringtail possums), >pooled rats (3.2)>pooled dogs (in which the rate of depletion, as calculated by the ratio of the substrate remaining was <20% and too slow to determine). During the depletion of meloxicam, at a first-order rate constant, 5 hydroxymethyl metabolite (M1) was identified in the brushtail possums and the rat as the major metabolite. However, multiple hydroxyl metabolites were observed in the koala (M1, M2, and M3) and the ringtail possum (M1 and M3) indicating that these specialized foliage-eating marsupials have diverse oxidation capacity to metabolize meloxicam. Using a well-stirred model, the apparent in vitro Clint of meloxicam for koalas and the rat was further scaled to compare with published in vivo Cl. The closest in vivo Cl prediction from in vitro data of koalas was demonstrated with scaled hepatic Cl(total) (average fold error=1.9) excluding unbound fractions in the blood and microsome values; whereas for rats, the in vitro scaled hepatic Cl fu(blood, mic), corrected with unbound fractions in the blood and microsome values, provided the best prediction (fold error=1.86). This study indicates that eutherians such as rats or dogs serve as inadequate models for dosage extrapolation of this drug to marsupials due to differences in hepatic turnover rate. Furthermore, as in vivo Cl is one of the pharmacokinetic indexes for determining therapeutic drug dosages, this study demonstrates the utility of in vitro to in vivo scaling as an alternative prediction method of drug Cl in koalas. PMID- 24345480 TI - MiR-181c modulates the proliferation, migration, and invasion of neuroblastoma cells by targeting Smad7. AB - MicroRNAs (miRNAs) function as key regulators of gene expression in various cancers. In this study, the aim is to explore the roles and regulation mechanism of miR-181c in neuroblastoma (NB) cells. We found that miR-181c was downregulated in metastatic NB tissues, compared with primary NB tissues. Then functional studies indicated that miR-181c overexpression inhibited NB cell proliferation, migration, and invasion, while miR-181c inhibition increased cell proliferation, migration, and invasion. EGFP reporter assay, real-time polymerase chain reaction and western blot analysis validated that Smad7 was a direct target of miR-181c. MiR-181c reduced Smad7 expression at both mRNA and protein levels. Finally, functional assays showed that the effect of Smad7 knockdown on cells was similar to that of miR-181c overexpression. Importantly, Smad7 overexpression could restore the antitumor effects that were induced by miR-181c. In conclusion, our results demonstrated that miR-181c inhibits NB cell growth and metastasis-related traits through the suppression of Smad7, functioning as a tumor suppressor. Moreover, our results suggested that miR-181c may serve as an important therapeutic target for NB patients. PMID- 24345482 TI - Introduction of antioxidant-loaded liposomes into endothelial cell surfaces through DNA hybridization. AB - Ischemia-reperfusion damage is a problem in organ transplantation. Reactive oxygen species are produced in cells by blood-mediated reactions at the time of blood reperfusion. In this study, we developed a method to immobilize and internalize antioxidants in endothelial cells, using vitamin E-loaded liposomes. The liposomes loaded with vitamin E and human umbilical vein endothelial cells (HUVECs) were modified with poly(ethylene glycol)-phospholipid conjugates carrying 20-mer of deoxyadenylic acid (oligo(dA)20) and 20-mer of complementary deoxythymidylic acid (oligo(dT)20), respectively. The liposomes were effectively immobilized on HUVECs through DNA hybridization between oligo(dA)20 and oligo(dT)20. The liposomes loaded with vitamin E were gradually internalized into HUVECs. Then, the cells were treated with antimycin A to induce oxidative stress. We found the amount of reactive oxygen species was greatly reduced in HUVECs carrying vitamin E-loaded liposomes. PMID- 24345481 TI - Investigation of fluorinated and bifunctionalized 3-phenylchroman-4-one (isoflavanone) aromatase inhibitors. AB - Fluorinated isoflavanones and bifunctionalized isoflavanones were synthesized through a one-step gold(I)-catalyzed annulation reaction. These compounds were evaluated for their in vitro inhibitory activities against aromatase in a fluorescence-based enzymatic assay. Selected compounds were tested for their anti proliferative effects on human breast cancer cell line MCF-7. Compounds 6-methoxy 3-(pyridin-3-yl)chroman-4-one (3c) and 6-fluoro-3-(pyridin-3-yl)chroman-4-one (3e) were identified as the most potent aromatase inhibitors with IC50 values of 2.5 MUM and 0.8 MUM. Therefore, these compounds have great potential for the development of pharmaceutical agents against breast cancer. PMID- 24345483 TI - Treatment of depression with onabotulinumtoxinA: a randomized, double-blind, placebo controlled trial. AB - Converging lines of evidence suggest a role for facial expressions in the pathophysiology and treatment of mood disorders. To determine the antidepressant effect of onabotulinumtoxinA (OBA) treatment of corrugator and procerus muscles in people with major depressive disorder, we conducted a double blind, randomized, placebo-controlled trial. In an outpatient clinical research center, eighty-five subjects with DSM-IV major depression were randomized to receive either OBA (29 units for females and 40 units for males) or saline injections into corrugator and procerus frown muscles (74 subjects were entered into the analysis). Subjects were rated at screening, and 3 and 6 weeks after OBA treatment. The primary outcome measure was the response rate, as defined by >= 50% decrease in score on the Montgomery-Asberg Depression Rating Scale (MADRS). Response rates at 6 weeks from the date of injection were 52% and 15% in the OBA and placebo groups, respectively (Chi-Square (1) = 11.2, p < 0.001, Fisher p < 0.001). The secondary outcome measure of remission rate (MADRS score of 10 or less) was 27% with OBA and 7% with placebo (Chi-square (1) = 5.1, p < 0.02, Fisher p < 0.03). Six weeks after a single treatment, MADRS scores of subjects were reduced on average by 47% in those given OBA, and by 21% in those given placebo (Mann-Whitney U, p < 0.0005). In conclusion, a single treatment with OBA to the corrugator and procerus muscles appears to induce a significant and sustained antidepressant effect in patients with major depression. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01556971. PMID- 24345484 TI - Puerarin alleviates cognitive impairment and oxidative stress in APP/PS1 transgenic mice. AB - Increasing evidence demonstrates that beta-amyloid (Abeta) elicits oxidative stress, which contributes to the pathogenesis and disease progression of Alzheimer's disease (AD). Thus, there is interest in developing antioxidant therapies for the prevention/treatment of cognitive decline during AD. We reported previously that puerarin has antioxidative properties in vitro. Therefore, the aim of the present study was to determine whether puerarin improves cognitive function and reduces oxidative stress in amyloid precursor protein/presenilin-1 (APP/PS1) mice, a well established AD mouse model, and explore its potential mechanism. Our results show that oral administration of puerarin significantly ameliorates cognitive impairment in APP/PS1 mice assessed by the Morris water maze (MWM) test. This was accompanied by a significant decrease in the levels of lipid peroxidation (LPO) through, at least in part, induction of nuclear factor erythroid 2-related factor 2 (Nrf2) target gene heme oxygenase 1 (HO-1) in the hippocampus of APP/PS1 transgenic mice at 9 months of age, but without altering brain Abeta burden. Furthermore, puerarin significantly activated Akt, reduced activation of glycogen synthase kinase 3beta (GSK-3beta), and induced nuclear translocation of Nrf2 in the hippocampus of APP/PS1 mice but did not alter ERK1/2 phosphorylation. Thus, puerarin may improve cognitive performance in APP/PS1 mice through activation of the Akt/GSK-3beta signaling pathway. These findings suggest that puerarin might be an attractive agent for prevention and treatment of cognitive impairment and dementia. PMID- 24345485 TI - [Change of ERCC1 expression of residual VX2 squamous carcinoma cells in rabbit lung after radiofrequency ablation]. AB - BACKGROUND AND OBJECTIVE: Residual carcinoma cells play an important role in the result of radiofrequency ablation (RFA) of pulmonary malignancies, and Platinum based adjuvant chemotherapy is one of the important treatment regimen to reduce residual carcinoma cells after RFA. ERCC1 (excision repair cross-complementation group 1) is an important factor affecting Platinum-based chemotherapy effects. Residual carcinoma cells exhibit some changes of their features after RFA; however, there is no report about the change of their ERCC1 expression by now. This study focused on the change of ERCC1 expression in residual VX2 squamous carcinoma cells in rabbit lung after RFA. METHODS: The model of VX2 squamous carcinoma in rabbit lung was established by injection of tissue block suspension. Fifty-eight New Zealand White rabbits with VX2 squamous carcinoma were randomly divided into the control group (n=10) and the RFA group (n=48). During the RFA procedure in these models, residual carcinoma cells were achieved by controlling the range of electrode expanding, power output and treatment time. At different points of time, the positive rates of ERCC1 expression in residual carcinoma were detected by immunohistochemistry. RESULTS: Comparing with the control group, the positive rate of ERCC1 expression in residual carcinoma in RFA group increases transiently within 1 d to 5 d (53.7% +/- 1.6% & 32.9% +/- 2.5%), and 5 d later, it decline to the level of the control group. CONCLUSIONS: The ERCC1 expression of residual pulmonary carcinoma increase within 5 d after RFA. Thus platinum based adjuvant chemotherapy may be ineffective in this period. PMID- 24345486 TI - [Effects of cetuximab combined with celecoxib on apoptosis and KDR and AQP1 expression in lung cancer]. AB - BACKGROUND AND OBJECTIVE: Neoadjuvant chemotherapy is a new development in the treatment of lung cancer. In recent years, cetuximab and celecoxib have been commonly used in this procedure. This study aims to explore the effect of cetuximab combined with celecoxib on apoptosis and KDR and AQP1 expression in lung cancer A549 cells. METHODS: The cells were cultured in RPMI-1640 and then divided into four groups: control group, 1 nmol/L cetuximab group, 25 umol/L celecoxib group, and 1 nmol/L cetuximab+25 umol/L celecoxib group. The treatment time was 48 h. The mRNA and protein expression levels of KDR and AQP1 were detected by RT-PCR and Western blot, respectively. The apoptosis, proliferation, and invasive ability of A549 cells before and after transfection were examined using flow cytometry, MTT, and transwell methods. RESULTS: Cetuximab and celecoxib inhibited the growth of A549 cells in a dose-dependent manner. Their combination produced a greater growth inhibition than when either was used alone (P<0.01). Cetuximab and celecoxib both induced the apoptosis of A549 cells, and their combination produced a higher apoptosis rate (P<0.01). Cetuximab in combination with celecoxib also induced G1 phase arrest and downregulated the expression of KDR and AQP1 in A549 cells (P<0.05). As a result, the invasion ability of the A549 cells was significantly decreased. CONCLUSIONS: Cetuximab in combination with celecoxib can synergistically inhibit the growth of A549 cells and downregulate the expression of KDR and AQP1 in A549 cells. The combination of cetuximab and celecoxib is a potential strategy for lung cancer therapy. PMID- 24345487 TI - [Relationship between BIM gene polymorphism and therapeutic efficacy in the retreatment of advanced non-small cell lung cancer with tyrosine kinase inhibitor]. AB - BACKGROUND AND OBJECTIVE: BIM gene is a member of the BCL-2 family, is involved in cell death. The aim of this study is to explore the relationship between BIM gene polymorphism and therapeutic efficacy in the retreatment advanced non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor (EGFR-TKI). METHODS: In the study, there were 123 patients who were diagnosed with advanced NSCLC in Zhejiang Province Cancer Hospital between January 2009 to October 2012, all of who were received gefitinib and erlotinib therapy after failure to chemotherapy. We detected the genotype of peripheral blood leukocytes of patients with BIM gene polymorphism though polymerase chain reaction (PCR). Statistical analysis was performed by SPSS version 13.0. RESULTS: On the disease control rates, BIM gene with no polymorphism type was slightly better trend than polymorphism types in disease control rate DCR (75.5% vs 57.1%, chi2=2.931, P=0.087). Univariate analysis the median PFS, women were longer than men (6.9 months vs 4.5 months, chi2 =7.077, P=0.008). Non-smokers were longer than smokers (8.0 months vs 2.5 months, chi2 =15.277, P<0.001). Adenocarcinoma were longer than others pathological type (7.0 months vs 2.0 months, chi2 =14.978, P<0.001). The median PFS in BIM gene with no polymorphism type were longer than with polymorphism type (6.0 months vs 3.5 months, chi2=7.035, P=0.008). Multi-factor analysis showed that smoking, pathological type, the BIM gene polymorphism were the independent prognostic factors for PFS. CONCLUSIONS: The patients with the BIM gene no polymorphism have longer the median progression-free time than the polymorphism types in retreatment advanced non-small cell lung cancer patients with tyrosine kinase inhibitor. PMID- 24345488 TI - [Value of surgery for stage IIIa non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: Nowadays, comprehensive treatment, including surgery, chemotherapy and radiotherapy is advocated for stage III non-small cell lung cancer (NSCLC). However, many researchers have questioned the effectiveness of surgery. The aim of this study is to evaluate the effect of surgery for stage III NSCLC. METHODS: Between March 2002 and October 2012, 310 cases that have completed followed-up data with stage III NSCLC were received in the Peking Union Medical College Hospital. They were divided into surgical and non-surgical groups according to whether received surgery when diagnosed. In TNM staging, stage III NSCLC includes stage IIIa and IIIb, and stage IIIa NSCLC can be grouped into stage T4N0/T3-4N1M0 and T1-3N2M0 according to different N stages. Analyzed the enumeration data by Chi-Square test. Kaplan-Meier survival method was used to calculate the overall survival (OS) and progression-free survival (PFS), and to draw the survival curves. A P value less than 0.05 was evaluated as statistically significant. RESULTS: Three hundred and ten stage III NSCLC patients include surgical group 189 cases and non-surgical group 121 cases. One hundred and eighty eight stage IIIa NSCLC patients include surgical group 152 cases and non-surgical group 36 cases. In stage IIIa, stage T4N0/T3-4N1M0 had 57 patients with 44 surgical and 13 non-surgical patients, and stage T1-3N2M0 had 131 patients with 108 surgical and 23 non-surgical patients. Thirty-seven out of 121 stage IIIb NSCLC patients received surgery. They had 22 stage T4N2M0 cases and 15 stage T1 4N3M0 cases. The patient whose performance status was 0 and staging was stage IIIa was more inclined to undergo surgery. For stage IIIa NSCLC patients, the median OS of surgical and non-surgical groups were 38.9 and 21.8 months, and the median PFS of them were 19.2 and 11.9 months respectively. The difference of OS between the two groups was significant (P=0.041), but the PFS of them had no significant difference (P=0.209). For stage T4N0/T3-4N1M0 which belongs to stage IIIa, the median OS of surgical and non-surgical groups were 48.7 and 20.1 months, and the median PFS of them were 14.6 and 10.5 months respectively. There were no significant differences of OS and PFS between the two groups (P>0.05). For stage T1-3N2M0 which also belongs to stage IIIa, the median OS of surgical and non-surgical groups were 38.9 and 30.8 months, and the median PFS of them were 19.8 and 12.7 months respectively. There were also no significant differences of OS and PFS between the two groups (P>0.05). The maximum diameter of tumor and auxillary chemotherapy had significant influences on OS and PFS of stage IIIa-N2 NSCLC patients, while the histology of tumor only influenced the OS of them (P<0.05). CONCLUSIONS: The patient whose performance status is 0 and staging is stage IIIa is more inclined to undergo surgery. Surgery can prolong OS of patients with stage IIIa, especially for stage T4N0/T3-4N1M0. However, it has no benefit on PFS. The maximum diameter of tumor and auxillary chemotherapy have significant influences on OS and PFS of stage IIIa-N2 NSCLC patients, while the histology of tumor only influence the OS of them. PMID- 24345489 TI - [Surgical treatment for non-small cell lung cancer patients with synchronous solitary brain metastasis]. AB - BACKGROUND AND OBJECTIVE: Brain metastases are common in non-small cell lung cancer. Usual treatments include radiotherapy and chemotherapy. However, these methods result in poor patient prognosis. The aim of this study is to assess the effectiveness of surgical resection in the multimodality management of non-small cell lung cancer patients with synchronous solitary brain metastasis. METHODS: The clinical data of 46 non-small cell lung cancer patients with synchronous solitary brain metastasis were retrospectively reviewed. All patients underwent surgical resection of primary lung tumor, followed by whole brain radiotherapy and chemotherapy. In addition, 13 out of the 46 patients underwent resection of brain metastasis, whereas the remaining 33 patients received stereotactic radiosurgery. RESULTS: The median survival time of the enrolled patients was 16.8 months. The 1-, 2-, and 3-year survival rates were 76.1%, 20.9%, and 4.7%, respectively. The median survival times of the patients with brain metastasis resection or stereotactic radiosurgery were 18.3 and 15.8 months, respectively (P=0.091,2). CONCLUSIONS: Surgical resection of primary lung tumor and brain metastasis may improve prognosis of non-small cell lung cancer patients with synchronous solitary brain metastasis. However, the survival benefit of surgical resection over brain metastasis resection or stereotactic radiosurgery is uncertain. PMID- 24345490 TI - [Comparison of the changes of thyroid hormones after video-assisted thoracoscopic surgery and conventional thoracotomy in patients with non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: Video-assisted thoracoscopic surgery (VATS) is the representative thoracic minimally invasive surgery. Compared with traditional open surgery (TOS), VATS has an advantage of less invasiveness, quicker recovery and milder postoperative pain. The aim of this study is to compare the influences of VATS and conventional thoracotomic lobectomy on thyroid hormones in treatment for non-small cell lung cancer (NSCLC). METHODS: From Oct. 2010 to Aug. 2012, 44 consecutive patients with NSCLC were recruited and divided into two groups: VATS group (25 patients) and TOS group (19 patients). All the patients were drawn blood to measure the plasma levels of free T3, free T4, reverse T3 and TSH on the morning of the day before surgery, the postoperative day (POD)1, POD2, POD3 and POD7. We described the perioperative variation trend of the thyroid hormones and compared the differences between VATS group and TOS group. RESULTS: There were no differences of thyroid hormone levels between the two groups before surgery. After surgery, the levels of FT3 and TSH were first dropped, then elevated and reached the lowest level on POD3 and POD1 separately. On POD7, they regained the before-surgery levels in VATS group while FT3 level was still significantly lower in TOS group (P=0.032). The FT4 and rT3 levels were first elevated, and then dropped after surgery. They both reached the peak concentrations on POD2, and rT3 levels of TOS group were significantly higher than those of VATS group on POD1, POD2 and POD3 (P<0.05). The changes of FT3 and rT3 levels were beyond normal ranges while changes of FT4 and TSH levels were within normal ranges. When variation trend of all the thyroid hormones were compared between the two groups, only rT3 level was found to have significant statistical differences (F=7.557, P=0.009). CONCLUSIONS: All NSCLC patients after lobectomy have Euthyroid sick syndrome (ESS). Compared with traditional thoracotomy, VATS surgery has smaller influence on perioperative thyroid hormones and demonstrates a weaker acute stress reaction, which can benefit postoperative recovery of NSCLC patients. PMID- 24345491 TI - [Effect of chemotherapy on the quality of life of lung cancer patients]. AB - BACKGROUND AND OBJECTIVE: With development of modern medicine, eliminating patients' pain and mental disorder and improving the quality of life has become an important problem in patients with cancer. The aim of this study is to observe the impact of chemotherapy on quality of life and influencing factor of quality of life among lung cancer patients. METHODS: Sixty-one lung cancer patients were assessed with clinical outcomes and the EORTC QLQ-C30 questionnaires before chemotherapy, one week after 2 cycles of chemotherapy, one week after 4 cycles of chemotherapy. RESULTS: After 2 cycles of chemotherapy, effective rate was 40.0%. Social function decreased. Nause and vomiting, insomnia and appetite loss deteriorated (P<0.05). After 4 cycles of chemotherapy, effective rate was 23%. But after chemotherapy, physical, role, emotional, social function decreased; Appetite loss, nausea and vomiting, insomnia deteriorated, economics became difficult to some patients (P<0.05). In our study, we find female patients had more fatigue and appetite loss than male patients (P<0.05). Patients of low level of education had more fatigue and insomnia than patients of high level of education (P<0.05). Elder patients had more fatigue, appetite loss, nausea and vomiting than middle-aged patients (P<0.05). Grouped according to body mass index, the difference wasn't statistically significant (P>0.05). Grouped according to the plasma albumin level, the difference wasn't statistically significant (P>0.05). In hypoproteinemia group, symptoms and economic difficulties score was higher; High protein group, function and general health scores was higher. CONCLUSIONS: After the chemotherapy, patients' the lesion of cancer became smaller and clinical symptoms relieved, but some patients, fatigue, appetite loss, nausea and vomiting symptom deteriorated, emotion became bad. Quality of life of lung cancer patients decrease. We should pay more attention to the adverse reactions of chemotherapy and cope with them, give positive psychological intervention and improve patients, nutrition to improve the quality of life. PMID- 24345492 TI - [The Sixth South-North Forum of Lung Cancer in China was held in CPPCC auditorium]. PMID- 24345493 TI - [Clinical significance of ROS1 rearrangements in non-small cell lung cancer]. AB - Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase gene have recently been described in multiple malignancies, including non-small cell lung cancer (NSCLC). ROS1 rearrangement defines a new molecular subset of NSCLC with the prevalence of ROS1 rearrangements around 1%-2%. ROS1-positive NSCLCs arise in young never-smokers with adenocarcinoma that are similar to those observed in patients with ALK-rearranged NSCLC. Crizotinib demonstrates in vitro activity and early clinical trial shows marked antitumor activity in ROS1-rearranged patients. The overall response rate is around 56% and the disease control rate at 8 weeks is about 76%. Further understanding the ROS1 fusions in the pathogenesis of NSCLC, methods to detect ROS1 rearrangements, and targeting ROS1-rearranged NSCLC patients with specific kinase inhibitors would lead to an era of personalized medicine. PMID- 24345494 TI - [Advances of molecular targeted therapy in squamous cell lung cancer]. AB - Squamous cell lung cancer (SQCLC) is one of the most prevalent subtypes of lung cancer worldwide, about 400,000 persons die from squamous-cell lung cancer around the world, and its pathogenesis is closely linked with tobacco exposure. Unfortunately, squamous-cell lung cancer patients do not benefit from major advances in the development of targeted therapeutics such as epidermal growth factor receptor (EGFR) inhibitors or anaplastic lymphoma kinase (ALK) inhibitors that show exquisite activity in lung adenocarcinomas with EGFR mutations or echinoderm microtubule associated protein like-4 (EML4)-ALK fusions, respectively. Major efforts have been launched to characterize the genomes of squamous-cell lung cancers. Among the new results emanating from these efforts are amplifications of the fibroblast growth factor receptor 1 (FGFR1) gene, the discoidin domain receptor 2 (DDR2) gene mutation as potential novel targets for the treatment of SQCLCs. Researchers find that there are many specific molecular targeted genes in the genome of squamous-cell lung cancer patients. These changes play a vital role in cell cycle regulation, oxidative stress, cell apoptosis, squamous epithelium differentiation, may be the candidate targeted moleculars in SQCLCs. Here, we provide a review on these discoveries and their implications for clinical trials in squamous-cell lung cancer assessing the value of novel therapeutics addressing these targets. PMID- 24345495 TI - [Advances on mechanisms of coagulation with non-small cell lung cancer]. AB - Recently, researchers have been increasingly finding coagulation disorders are commonly the first sign of malignancy. It has now been established that cancer development leads to an increased risk of thrombosis, and conversely, excessive activation of blood coagulation profoundly influences cancer progression. In patients with lung cancer, a sustained stimulation of blood coagulation takes place. Cancer cells trigger coagulation through expression of tissue factor, and affect coagulation through expression of thrombin, release of microparticles that augment coagulation and so on. Coagulation also facilitates tumour progression through release of platelet granule contents, inhibition of natural killer cells and recruitment of macrophages. Non-small cell lung cancer (NSCLC) accounts for about 80%-85% of all lung malignancies. In the present review, we summarized the newly updated data about the physiopathological mechanisms of various components of the clotting system in different stages of carcinogenesis in NSCLC. PMID- 24345496 TI - A predator-prey model with generic birth and death rates for the predator. AB - We propose and study a predator-prey model in which the predator has a Holling type II functional response and generic per capita birth and death rates. Given that prey consumption provides the energy for predator activity, and that the predator functional response represents the prey consumption rate per predator, we assume that the per capita birth and death rates for the predator are, respectively, increasing and decreasing functions of the predator functional response. These functions are monotonic, but not necessarily strictly monotonic, for all values of the argument. In particular, we allow the possibility that the predator birth rate is zero for all sufficiently small values of the predator functional response, reflecting the idea that a certain level of energy intake is needed before a predator can reproduce. Our analysis reveals that the model exhibits the behaviours typically found in predator-prey models - extinction of the predator population, convergence to a periodic orbit, or convergence to a co existence fixed point. For a specific example, in which the predator birth and death rates are constant for all sufficiently small or large values of the predator functional response, we corroborate our analysis with numerical simulations. In the unlikely case where these birth and death rates equal the same constant for all sufficiently large values of the predator functional response, the model is capable of structurally unstable behaviour, with a small change in the initial conditions leading to a more pronounced change in the long term dynamics. PMID- 24345497 TI - A mathematical model of HiF-1alpha-mediated response to hypoxia on the G1/S transition. AB - Hypoxia is known to influence the cell cycle by increasing the G1 phase duration or by inducing a quiescent state (arrest of cell proliferation). This entry into quiescence is a mean for the cell to escape from hypoxia-induced apoptosis. It is suggested that some cancer cells have gain the advantage over normal cells to easily enter into quiescence when environmental conditions, such as oxygen pressure, are unfavorable [43,1]. This ability contributes in the appearance of highly resistant and aggressive tumor phenotypes [2]. The HiF-1alpha factor is the key actor of the intracellular hypoxia pathway. As tumor cells undergo chronic hypoxic conditions, HiF-1alpha is present in higher level in cancer than in normal cells. Besides, it was shown that genetic mutations promoting overstabilization of HiF-1alpha are a feature of various types of cancers [7]. Finally, it is suggested that the intracellular level of HiF-1alpha can be related to the aggressiveness of the tumors [53,24,4,10]. However, up to now, mathematical models describing the G1/S transition under hypoxia, did not take into account the HiF-1alpha factor in the hypoxia pathway. Therefore, we propose a mathematical model of the G1/S transition under hypoxia, which explicitly integrates the HiF-1alpha pathway. The model reproduces the slowing down of G1 phase under moderate hypoxia, and the entry into quiescence of proliferating cells under severe hypoxia. We show how the inhibition of cyclin D by HiF-1alpha can induce quiescence; this result provides a theoretical explanation to the experimental observations of Wen et al. (2010) [50]. Thus, our model confirms that hypoxia-induced chemoresistance can be linked, for a part, to the negative regulation of cyclin D by HiF-1alpha. PMID- 24345498 TI - Phytochemical and pharmacological studies on Radix Angelica sinensis. AB - The roots of Angelica sinensis (RAS), are a Chinese herbal medicine traditionally used in prescriptions for replenishing blood, treating abnormal menstruation, and other women's diseases. It has also been widely marketed as health food for women's care in Asia, and as a dietary supplement in Europe and America. RAS is well-known for its hematopoietic, antioxidant, and immunoregulatory activities. RAS also possesses anti-cancer, memory, radioprotective, and neuroprotective effects. Phytochemical investigations on this plant led to organic acids, phthalides, polysaccharides, and other metabolites. Based on recent animal studies and clinical trials, RAS has been used in the treatment of gynecologic diseases, cardio-cerebrovascular disease, nervous system diseases, and nephrotic syndrome. In this review, the recent phytochemical and pharmacological studies, drug-drug interactions, clinical applications, and toxicity of RAS are summarized. PMID- 24345499 TI - Progress on the protective effect of compounds from natural medicines on cerebral ischemia. AB - The treatment of cerebral ischemic disease by natural medicines has a long history, and has accumulated a rich theoretical knowledge and treatment experience. The objective of this review is to critically evaluate the experimental research situation of the protective effect of the individual compounds from natural medicine on cerebral ischemia in the past ten years, emphasizing the major mechanisms underlying cerebral ischemic pathophysiology. Sixteen representative compounds from natural medicines which are often used to treat stroke are discussed. The results indicate that these components possess a protective effect on cerebral ischemia, and that these components have different mechanisms, including inhibiting excitotoxicity by ginkgolide B, antiapoptosis of breviscapine, influencing astrocytic activation and proliferation of tanshinone IIA, influencing free radicals by ginsenoside Rd, impairing blood-brain barrier disruption by baicalin, and the anti-inflammatory activity of tetramethylpyrazine. Moreover, some components have multiple neuroprotective mechanisms. Therefore, the combination of individual compounds from natural medicines, considering the mechanisms of cerebral ischemia, may be beneficial to patients with cerebral ischemia in the future. This approach will provide a direction for the further application and exploitation of new drug development in the treatment of cerebral ischemia. PMID- 24345500 TI - Quality control of traditional Chinese medicines: a review. AB - Traditional Chinese medicines (TCMs) are in great demand all over the world, especially in the developing world, for primary health care due to their superior merits such as low cost, minimal side effects, better cultural acceptability, and compatibility with humans. However, Chinese medicines consist of several herbs which may contain tens, hundreds, or even thousands of constituents. How these constituents interact with each other, and what the special active ones are, may be the biggest bottleneck for the modernization and globalization of TCMs. Valid methods to evaluate the quality of TCMs are therefore essential and should be promoted and be developed further through advanced separation and chromatography techniques. This paper reviews the strategies used to control the quality of TCMs in a progressive perspective, from selecting single or several ingredients as the evaluation marker, to using different kinds of chromatography fingerprint methods. In summary, the analysis and quality control of TCMs are developing in a more effective and comprehensive manner to better address the inherent holistic nature of TCMs. PMID- 24345501 TI - Diosgenin inhibits tumor necrosis factor-induced tissue factor activity and expression in THP-1 cells via down-regulation of the NF-kappaB, Akt, and MAPK signaling pathways. AB - AIM: To investigate whether diosgenin could modulate tissue factor (TF) procoagulation activity, expression, and related signal transduction pathways. METHODS: Human THP-1 monocytic cells were exposed to tumor necrosis factor-alpha (TNF-alpha, 10 ng.mL(-1)) with or without diosgenin (0.01, 0.1, and 1 MUmol . L( 1)) for 2 h or 5 h to induce TF procoagulant activity and expression, which were determined by the simplified chromogenic assay, reverse transcription-polymerase chain reaction (RT-PCR), real-time quantitative PCR, and Western blotting assays. In addition, the activation of the NF-kappaB, Akt, and MAPK signaling pathways were also measured by Western blotting. RESULTS: Diosgenin significantly inhibited TNF-alpha-induced TF procoagulant activity at concentrations of 0.01 to 1 MUmol . L(-1) with IC50 of 0.25 MUmol . L(-1). It also reduced protein expression and mRNA accumulation of TF dose-dependently in activated THP-1 cells. TNF-alpha stimulated significantly phosphorylation on Ser536 of NF-kappaB/p65, Ser473 of Akt at 5-15 min, and activations of IKK-beta and ERK at 15-30 min. Diosgenin (1 MUmol . L(-1)) could inhibit the phosphorylation of NF-kappaB/p65, IKK-beta, Akt, ERK, and JNK, but had no remarkable effects on IkappaB and p38 phosphorylation in THP-1 cells. CONCLUSION: Diosgenin inhibits TNF-alpha-induced TF activity and expression in monocytes, partly due to its down-regulation of the phosphorylation of NF-kappaB/p65, IKK-beta, Akt, ERK, and JNK. PMID- 24345502 TI - Mushroom tyrosinase inhibition activity of Aloe vera L. gel from different germplasms. AB - In this study, lyophilized and methanolic extracts of aloe gel from different germplasms were evaluated for their potential to inhibit mushroom tyrosinase activity. The results showed potent inhibitory effect of Aloe vera gel extracts on L-dihydroxyphenylalanine (L-DOPA) oxidation catalyzed by tyrosinase in a dose dependent manner. Significant differences in % inhibition of tyrosinase among the extraction methods and the germplasms were observed. The relative performance of the germplasms was evaluated with the help of posthoc multicomparison test. The methanolic extract was more effective than the lyophilized crude gel in all the germplasms. The inhibitory effect of the lyophilized gel and methanolic extract tested from five germplasms followed the order: RM > TN > S24 > OR > RJN. The germplasm RM showed the highest tyrosinase inhibition, and the maximum % inhibition noted was 26.04% and 41.18%, respectively for the lyophilized and methanolic extracts at 6 mg . mL(-1) concentration. Lineweaver-Burk plots of the different concentrations of L-DOPA in the absence and presence of lyophilized gel extract showed competitive inhibition of mushroom tyrosinase in all the germplasms. This study suggests that the germplasm RM could potentially be used for the isolation and identification of the effective tyrosinase inhibitory component, and ascertains the critical role of selecting the best source of germplasm for natural product isolation and characterization. PMID- 24345503 TI - In vitro and in vivo antioxidant potentials of an ethanolic extract of Ganoderma lucidum in rat mammary carcinogenesis. AB - AIM: Considering the importance of diet in the prevention of cellular damage caused by reactive oxygen species which has been implicated for several diseases, this present study was undertaken to evaluate the in vitro and in vivo antioxidant potential of the ethanolic extract of the fruiting bodies of Ganoderma lucidum on 7, 12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis in Sprague Dawley rats. METHODS: Ganoderma lucidum extract was tested for in vitro antioxidant and radical scavenging assays, such as (ABTS(+)) radical cation decolorization assay, DPPH radical scavenging, hydroxyl radical, and superoxide radical scavenging assays. The in vivo antioxidant potentials were analyzed by SOD, CAT, and GPx in plasma, mammary, and liver tissues. RESULTS: In all the in vitro antioxidant and radical scavenging assays the extract exhibited good scavenging activity. In vivo enzymatic antioxidant levels, such as SOD, CAT, and GPx were decreased in DMBA-induced animals. Moreover, pretreatment with G. lucidum (500 mg . kg(-1) bw) to DMBA-induced animals significantly (P < 0.05) increased the levels of SOD, CAT, and GPx in plasma, mammary, and liver tissues compared to DMBA induced animals. CONCLUSIONS: From these findings, it is suggested that G. lucidum extract could be considered as a potential source of natural antioxidants and can be used as an effective chemopreventive agent against mammary cancer. PMID- 24345504 TI - Hypoglycemic and antioxidant activities of the hydroethanolic leaf extract of Byrsocarpus coccineus Schumach. & Thonn. (Connaraceae). AB - AIM: Diabetes Mellitus is associated with significant morbidity and mortality worldwide. The need for enhanced efficacy and safety, and cheaper and more readily available new drugs has increased the search for new antidiabetic drugs from plants. This study was conducted to investigate the antidiabetic activity of the hydroethanolic leaf extract of B. coccineus in rats. METHODS: The effect of B. coccineus extract (100-800 mg . kg(-1), p.o.) on blood glucose levels in normal and glucose loaded rats, and alloxan-induced diabetic rats was determined. After 10 days of treatment, blood samples were collected from rats for lipid and insulin profiling. Animals were thereafter sacrificed and the kidneys, heart, and liver were harvested for antioxidant indices assay. RESULTS: In normal rats, B. coccineus did not cause significant reduction in blood glucose. At the dose of 800 mg . kg(-1), significant increase in blood glucose level was not observed 30 min. after glucose load. B. coccineus administered acutely did not generally produce significant reduction in blood glucose level in diabetic rats. Administered subacutely, the extract significantly reduced blood glucose level in diabetic rats from the 3(rd) day with peak effect observed at the dose of 800 mg . kg(-1) on the 10(th) day. The extract generally preserved in vivo antioxidant levels in the kidneys, heart, and liver, increased the level of high density lipoprotein and insulin, and reduced the level of triglycerides and low density lipoprotein compared to diabetic control. CONCLUSION: The findings in this study suggest that the hydroethanolic leaf extract Byrsocarpus coccineus possesses antidiabetic activity possibly mediated through inhibition of intestinal glucose absorption, in vivo antioxidant activity, and enhancement of regeneration of beta cells of the pancreas and insulin secretion. PMID- 24345506 TI - Reversing effects of silybin on TAA-induced hepatic CYP3A dysfunction through PXR regulation. AB - AIM: Silybin (SB), a major constituent of the milk thistle, has been used to treat several liver disorders. However, liver diseases were always accompanied by CYP450 dysfunction. This study was designed to explore the relationship between the hepatoprotective effect and CYP3A regulation of SB during thioacetamide (TAA) induced rat liver injury. METHODS: Serum biochemical analysis and histopathological study were taken to evaluate the hepatoprotectinve effect of SB. alpha-SMA were detected by immunohistochemical analysis and cytokine release in rat liver was determined by ELISA assay. CYP3A and PXR expression were determined by RT-PCR and Western blot analysis, and CYP3A activity was based on the midazolam 4-hydroxylation reaction. Also, siRNA transfection was induced in HepG2 cells to evaluate the effect of PXR on cytotoxicity and CYP3A4 dysregulation caused by TAA. RESULTS: SB showed powerful hepatoprotective effects, and anti-inflammatory and anti-fibrosis effects, and reversed the loss of CYP3A and PXR in TAA-injured rat liver, and decreased PXR translocation into the cell nucleus. PXR silencing weakened the effect of SB on cytoprotection and CYP3A regulation. CONCLUSIONS: PXR was a very important factor of CYP3A regulation and might be the target of SB in TAA-induced liver disease. Also, because of the potential interactions of SB and co-administered medicines, it might be necessary to adjust the dosage in the clinical medication of liver disease. PMID- 24345505 TI - The effect of Qi'ao Decoction on ovalbumin induced and lipopolysaccharide enhanced severe asthma mice and its mechanism. AB - AIM: To evaluate the effect of Qi'ao Deocoction (QAD) on the inflammation and hyperresponsiveness of asthma mice. METHODS: 120 Balb/C mice were randomly divided into six groups: normal group, model group, dexamethasone group, high dose QAD group, medium dose QAD group and low dose QAD group. The asthma model was reproduced in Balb/C mice sensitized by ovalbumin, challenged by OVA and LPS. The mice of the normal group were sensitized, challenged and intranasally instilled by PBS. On day 28-34, 6.7, 13.4 and 26.8 g . kg(-1) Qi'ao Decoction were administrated; 0.002 4 g . kg(-1) dexamethasone solution was given to the dexamethasone group; normal and model groups were given the same amount of normal saline. Bronchoalveolar lavage fluid, airway hyperresponsiveness, lung histopathology and cytokines were then collected and analyzed. RESULTS: Compared with normal group, total cellular score, the number of macrophages, lymphocytes, eosinophils and neutrophils of model group significantly increased (P < 0.01). Compared with model group, the administration of dexamethasone induced a significant decrease in eosinophils and neutrophils (P < 0.05, P < 0.01). The number of eosinophils, which plays an important role in airway inflammatory reaction of asthma, of the three QAD groups all decreased (P < 0.01). RL before and after Ach (5 mg . mL(-1)) stimulation in the model group both overtook that in the normal group (P < 0.01). Compared with model group, dexamethasone group, high dose QAD group, medium dose QAD group and low dose QAD group groups all had significantly lower RL before and after Ach stimulation (P < 0.01). Normal pulmonary histopathology was found in the normal group. In the model group, mice exhibited marked increases in inflammatory cell infiltration, mostly including neutrophils and macrophages, perivascular inflammation and thickened alveolus wall (P < 0.01). Dexamethasone application mitigated inflammation around the bronchi (P < 0.05). These histopathological changes were ameliorated in the three decoction groups (P < 0.01, P < 0.05). In addition, alveolus and airway wall lesions of medium dose QAD group and high dose QAD group were reduced, the number of inflammatory cells infiltrated around the walls decreased, no clear degeneration of bronchial epithelial cells was found, and exudates in bronchi declined in different degrees. Compared with normal group, IFN-gamma and IL-12 of model group significantly decreased, while IL-4 increased, showing statistic difference (P < 0.05). Compared with model group, IFN-gamma and IL-12 level of dexamethasone group went up too, but IL-4 declined (P < 0.05). The level of IFN gamma of medium dose QAD group and high dose QAD group both increased; IL-4 and IL-12 of medium dose group were found significant differences (P < 0.05); but none of the cytokines of low dose QAD group showed statistical significance (P > 0.05). CONCLUSION: QAD can significantly inhibit airway inflammation and airway hyperresponsiveness of mice with severe asthma induced by ovalumin and lipopolysaccharide, adjust the balance of cytokines, and improve lung histopathological condition. So, it exhibits great effect on severe asthma. PMID- 24345507 TI - Metabolomics and proteomics approaches to characterize and assess proteins of bear bile powder for hepatitis C virus. AB - Metabolomics represents an emerging and powerful discipline that provides an accurate and dynamic picture of the phenotype of bio-systems through the study of potential metabolites that could be used as therapeutic targets and for the discovery of new drugs. Hepatitis C virus (HCV) is a leading cause of liver disease worldwide, and is a major burden on public health. It is hypothesized that an animal model of HCV infection would produce unique patterns of endogenous metabolites. Herein, a method for the construction of efficient networks is presented with regard to the proteins of bear bile powder (PBBP) that protect against HCV as a case study. Ultra-performance liquid chromatography, coupled with electrospray ionization/quadrupole-time-of-flight high definition mass spectrometry (UPLC-HDMS), coupled with pattern recognition methods and computational systems analysis were integrated to obtain comprehensive metabolomic profiling and pathways of the large biological data sets. Among the regulated pathways, 38 biomarkers were identified and two unique metabolic pathways were indicated to be differentially affected in HCV animals. The results provided a systematic view of the development and progression of HCV, and also could be used to analyze the therapeutic effects of PBBP, a widely used anti-HCV medicine. The results also showed that PBBP could provide satisfactory effects on HCV infection through partially regulating the perturbed pathway. The most promising use in the near future would be to clarify the pathways for the drugs and obtain biomarkers for these pathways to help guide testable predictions, provide insights into drug action mechanisms, and enable an increase in research productivity toward metabolomic drug discovery. PMID- 24345508 TI - Beneficial effects of the Chinese herbal medicine Sanjie Zhentong Capsule on experimental endometriosis in rats. AB - AIM: To analyze the composition of the Chinese herbal medicine Sanjie Zhentong Capsule (SJZTC) and test the therapeutic efficacy of each component in a rat model of endometriosis. METHODS: A rapid resolution liquid chromatography (RRLC) method coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (Q-TOF MS) has been developed for the analysis of SJZTC. Two main ingredients, Drac(h)onis sanguis and saponin, were tested in the endometriosis model. Sixty Lewis female rats were in the estrous cycle stage when endometriosis was experimentally initiated by peritoneal implantation of endometrial tissue. Four weeks later, a second laparotomy was performed and implant volumes were measured. After that, the implanted rats were randomized into five study groups: control group (treatment with saline), anastrozole group (treatment with anastrole, 18 MUg per day), loureirin A group (treated with loureirin A, 97.2 mg), ginsenoside Re group (treated with ginsenoside Re, 64.8 mg), and SJZTC groups (treated with SJZTC, 86.4 mg) administered once a day for 4 weeks via gastric gavage. After four weeks of treatment, a third laparotomy was performed, implant volumes were re-measured, and the levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-alpha) were tested. RESULTS: A total of 38 compounds including, both the target and unknown compounds, were rapidly predicted in the capsule extract by the developed method. Compared with the control group, the anastrozole group, loureirin A group, ginsenoside Re group, and SJZTC treated group showed smaller implant volumes, as well as lower levels of VEGF and TNF-alpha in the peritoneal focus (P < 0.01 for all comparisons). Furthermore, parameters in the groups treated with SJZTC, loureirin A and ginsenoside Re were significantly better than the control group and the anastrozole group. These results indicate that SJZTC and its two main components are effective in reducing the development of endometriosis. PMID- 24345509 TI - A new diphenyl ether from the endophytic fungus Verticillium sp. isolated from Rehmannia glutinosa. AB - AIM: To investigate the chemical constituents of the endophytic fungus Verticillium sp. isolated from Rehmannia glutinosa. METHODS: The compounds were isolated and purified by repeated column chromatography, and their structures were determined on the basis of physicochemical properties and spectral analysis. Their cytotoxic and antifungal activities were evaluated. RESULTS: Ten compounds were obtained and their structures were identified as 2, 4-dihydroxy-2', 6 diacetoxy-3'-methoxy-5'-methyl-diphenyl ether (1), paecilospirone (2), alpha acetylorcinol (3), 2-methoxy-1,8-dimethyl-xanthen-9-one (4), 4-hydroxy-alpha lapachone (5), enalin A (6), 2,3,4-trimethyl-5,7-dihydroxy-2,3-dihydrobenzofuran (7), 4-hydroxyethyl-phenol (8), 2,4-dihydroxy-3,5,6-trimethyl- methylbenzoate (9), and 3-isopropenyl-(Z)-monomethyl maleate (10). CONCLUSIONS: Compound 1 is a new diphenyl ether, and showed cytotoxic activity against HL-60 cells (IC50 2.24 MUg . mL(-1)), and antifungal activities against Candida albicans (MIC 8 MUg . mL(-1)) and Aspergillus fumigatus (MIC 16 MUg . mL(-1)). PMID- 24345510 TI - Total synthesis of neokotalanol, a potent alpha-glucosidase inhibitor isolated from Salacia reticulata. AB - Neokotalanol, a potent alpha-glucosidase inhibitor isolated from Salacia reticulata, was synthesized through a key coupling reaction between a perbenzylated thiosugar and an appropriately protected perseitol triflate derived from D-mannose. This key step was found to be quite temperature dependent, and a simultaneous cyclization of the triflate leading to a characteristic 2,4,7 trioxabicyclo[4.2.1]nonane system was detected. PMID- 24345511 TI - Selective hydrolysis of flavonoid glycosides by Curvularia lunata. AB - Twelve flavonoid glycosides were involved in the biotransformation of the glycosyl moieties by Curvularia lunata 3.4381, and the products were analyzed by UPLC/PDA-Q-TOF-MS(E). Curvularia lunata displayed hydrolyzing activities on the terminal Rha or Glc units of some flavonoid glycosides. Terminal Rha with a 1 -> 2 linkage of isorhamnetin-3-O-neohesperidoside and typhaneoside could be hydrolyzed by Curvularia lunata, but terminal Rha with a 1 -> 6 linkage of rutin, typhaneoside, and quercetin-3-O-apiosyl-(1 -> 2)-[rhamnosyl-(1 -> 6)]-glucoside could not be hydrolyzed. Curvularia lunata could also hydrolyze the Glc of icariin, floramanoside B, and naringin. This is the first report of the hydrolysis of glycosyl units of flavonoid glycosides by Curvularia lunata. A new way to convert naringin to naringenin was found in this research. PMID- 24345512 TI - Qualitative and quantitative analysis of flavonoids in Sophora tonkinensis by LC/MS and HPLC. AB - AIM: To develop analytical methods for the identification and determination of the flavonoids in Sophora tonkinensis for comprehensive quality evaluation. METHODS: An HPLC-DAD-ESI-MS method was used for the separation and characterization of the flavonoids in S. tonkinensis, and a liquid chromatographic method was employed to simultaneously determine five major active flavonoids in this crude drug. RESULTS: Seventeen flavonoids were identified, among which, seven were unambiguously identified as trifolirhizin, quercetin, formononetin, macckiain, kurarinone, sophoranone, and sophoranochromene by comparing their retention times, and UV and MS spectra with those of the authentic compounds, and the other ten flavonoids were tentatively identified by comparing their UV and MS/MS spectra with those of literature data. Furthermore, five major active flavonoids, including trifolirhizin, quercetin, maackiain, sophoranone, and sophoranochromene were determined in S. tonkinensis. All calibration curves expressed good linearity (r > 0.999 8) within the test ranges, and the recovery from this method was 96.40%-104.43%. The developed HPLC method was successfully applied to quantitatively determine the five flavonoids in seventeen samples of S. tonkinensis. CONCLUSION: The developed method rapidly characterized the bioactive flavonoids of S. tonkinensis, and could be readily utilized to enhance the quality assurance approaches for this traditional Chinese medicine. PMID- 24345513 TI - Contribution evaluation of the floral parts to orientin and vitexin concentrations in the flowers of Trollius chinensis. AB - AIM: To provide a comprehensive procedure to evaluate the contribution of the floral parts to the yield of the major components from the flowers of Trollius chinensis, to underlay the selective breeding, cultivation, development, and utilization of the flowers. METHODS: Five floral parts from eleven batches of the flowers of T. chinensis were examined by HPLC analysis for the content of orientin and vitexin, and by gravimetric analysis for their respective mass fraction. The contribution of each floral part was calculated using mathematical methods based on the results of the content and mass fraction. Variance analysis was carried out by Kruskal-Wallis H test and PCA method. RESULTS: The calculated mean contributions of calyx, corolla, stamens and pistils, stalk, and ovary to the yield of both orientin and vitexin were 76.99% and 71.93%, 9.60% and 8.33%, 9.21% and 8.10%, 2.17% and 6.62%, and 2.03% and 5.02%, respectively. CONCLUSION: The floral parts contribute unequally to the yield of orientin and vitexin, and the calyx contributes the highest and makes a significant difference compared with any other part. PMID- 24345514 TI - Marker genes for activation of the RNA interference (RNAi) pathway in the free living nematode Caenorhabditis elegans and RNAi development in the ovine nematode Teladorsagia circumcincta. AB - The nematode Teladorsagia circumcincta is a major cause of parasitic gastroenteritis in sheep in temperate regions. The development of resistance to the major anthelmintic classes used for its control is a threat to small ruminant farming sustainability. Vaccination is a potential alternative control method for this nematode. Gene datasets can be exploited to identify potential vaccine candidates and these validated further by methods such as RNA interference (RNAi) prior to vaccine trials. Previous reports indicate that RNAi in parasitic nematodes is inconsistent and, to date, there are no internal controls that indicate activation of the RNAi pathway in response to double-stranded RNA (dsRNA). The present aims were to determine whether or not the transcription levels of potential marker genes in the RNAi pathway could indicate activation of the pathway in Caenorhabditis elegans and to develop an RNAi platform in T. circumcincta. In C. elegans, transcript levels of three candidate marker genes, Ce-dcr-1 (Dicer), Ce-ego-1 (Enhancer of Glp-One family member) and Ce-rsd-3 (RNAi Spreading Defective), were analysed and results indicated that activation of the pathway had no effect on transcript levels of these genes. In T. circumcincta, two vaccine candidate genes from the Activation-associated Secreted Protein (ASP) family were targets for knockdown. RNAi experiments showed successful silencing of both targets, although inconsistencies in efficacy were observed. After testing a number of parameters that might affect variability, it was found that the length of the storage period of the larvae plays an important role in the consistency of the RNAi results. PMID- 24345516 TI - 'Lifting the ban on alcohol at Scottish football matches: an own goal for public health progress?'. PMID- 24345518 TI - Group display in the socially monogamous Northern Double-collared Sunbird (Cinnyris reichenowi). AB - Several sunbird species (Nectariniidae) exhibit group display, but the function of this behaviour still remains unclear. We test two hypotheses (reproductive tactic and joint territory defence) to explain the function of this behaviour using data gathered on Northern Double-collared Sunbirds (Cinnyris reichenowi) from the Cameroon Mountains. Sunbirds exhibited group display throughout the breeding cycle. Groups of birds were mainly comprised of neighbouring pairs aggregated at territory boundaries. The frequency of group displays varied significantly among individuals and over the breeding cycle, with the highest frequency during the pre-breeding period and the lowest during egg-laying (~female's fertile period). Time spent on group display was significantly longer at the end of breeding. Off-territory forays were recorded for both males and females, males significantly increased the time spent on these forays during incubation. Extra-pair copulations were recorded only in five cases for females (4%) suggesting that most off-territory forays were motivated by feeding on nectar in neighbouring territories. Therefore, we suggest that the behaviour is used for joint territory defence rather than as an information centre for choosing mates for extra-pair copulations. Its function for choosing primary mates is also unlikely, because group displays were mainly observed in complete pairs. PMID- 24345517 TI - Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users. AB - Cannabis use is associated with an earlier age of onset of psychosis (AOP). However, the reasons for this remain debated. METHODS: We applied a Cox proportional hazards model to 410 first-episode psychosis patients to investigate the association between gender, patterns of cannabis use, and AOP. RESULTS: Patients with a history of cannabis use presented with their first episode of psychosis at a younger age (mean years = 28.2, SD = 8.0; median years = 27.1) than those who never used cannabis (mean years = 31.4, SD = 9.9; median years = 30.0; hazard ratio [HR] = 1.42; 95% CI: 1.16-1.74; P < .001). This association remained significant after controlling for gender (HR = 1.39; 95% CI: 1.11-1.68; P < .001). Those who had started cannabis at age 15 or younger had an earlier onset of psychosis (mean years = 27.0, SD = 6.2; median years = 26.9) than those who had started after 15 years (mean years = 29.1, SD = 8.5; median years = 27.8; HR = 1.40; 95% CI: 1.06-1.84; P = .050). Importantly, subjects who had been using high-potency cannabis (skunk-type) every day had the earliest onset (mean years = 25.2, SD = 6.3; median years = 24.6) compared to never users among all the groups tested (HR = 1.99; 95% CI: 1.50- 2.65; P < .0001); these daily users of high potency cannabis had an onset an average of 6 years earlier than that of non cannabis users. CONCLUSIONS: Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users. PMID- 24345515 TI - Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations. AB - Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ~50 000 cosmopolitan tagged SNPs across ~2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 * 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (beta +/- SE, 0.048 +/- 0.008, P = 7.7 * 10(-9)) as was rs7302703-G in HOXC10 (beta = 0.044 +/- 0.008, P = 2.9 * 10(-7)) and rs936108 C in PEMT (beta = 0.035 +/- 0.007, P = 1.9 * 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (beta = 0.10 +/- 0.02, P = 1.9 * 10(-6)) and rs1037575-A in ATBDB4 (beta = 0.046 +/- 0.01, P = 2.2 * 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue. PMID- 24345519 TI - Genetic diversity and phylogeny of Mycobacterium avium. AB - Mycobacterium avium, one of the species of the M. avium complex (MAC), includes 4 subspecies, i.e., M. avium subsp. hominissuis (MAH), M. avium subsp. avium (MAA), M. avium subsp. silvaticum (MAS) and M. avium subsp. paratuberculosis (MAP), in turn classified into the S (sheep) and C (cattle) types. These subspecies, although closely related, represent distinct organisms, each endowed with specific pathogenetic and host range characteristics, ranging from environmental opportunistic bacteria that cause infections in swine and immunocompromised patients to pathogens of birds and ruminants. The present review summarizes the basic epidemiological and pathological features of the M. avium subspecies, describes the major genomic events responsible of M. avium subspecies diversity (insertion sequences, sequence variations in specific chromosome loci or genes, deletions, duplications and insertions of large genomic regions) and then reconstructs the phylogenetic relationships among the M. avium subspecies. PMID- 24345520 TI - Cost-effectiveness of omega-3 fatty acid supplements in parenteral nutrition therapy in hospitals: a discrete event simulation model. AB - BACKGROUND & AIMS: A recent meta-analysis showed that supplementation of omega-3 fatty acids in parenteral nutrition (PN) regimens is associated with a statistically and clinically significant reduction in infection rate, and length of hospital stay (LOS) in medical and surgical patients admitted to the ICU and in surgical patients not admitted to the ICU. The objective of this present study was to evaluate the cost-effectiveness of the addition of omega-3 fatty acids to standard PN regimens in four European countries (Italy, France, Germany and the UK) from the healthcare provider perspective. METHODS: Using a discrete event simulation scheme, a patient-level simulation model was developed, based on outcomes from the Italian ICU patient population and published literature. Comparative efficacy data for PN regimens containing omega-3 fatty acids versus standard PN regimens was taken from the meta-analysis of published randomised clinical trials (n = 23 studies with a total of 1502 patients), and hospital LOS reduction was further processed in order to split the reduction in ICU stay from that in-ward stays for patients admitted to the ICU. Country-specific cost data was obtained for Italian, French, German and UK healthcare systems. Clinical outcomes included in the model were death rates, nosocomial infection rates, and ICU/hospital LOS. Probabilistic and deterministic sensitivity analyses were undertaken to test the reliability of results. RESULTS: PN regimens containing omega-3 fatty acids were more effective on average than standard PN both in ICU and in non-ICU patients in the four countries considered, reducing infection rates and overall LOS, and resulting in a lower total cost per patient. Overall costs for patients receiving PN regimens containing omega-3 fatty acids were between ?14 144 to ?19 825 per ICU patient and ?5484 to ?14 232 per non-ICU patient, translating into savings of between ?3972 and ?4897 per ICU patient and savings of between ?561 and ?1762 per non-ICU patient. Treatment costs were completely offset by the reduction in hospital stay costs and antibiotic costs. Sensitivity analyses confirmed the robustness of these findings. CONCLUSIONS: These results suggest that the supplementation of PN regimens with omega-3 fatty acids would be cost effective in Italian, French, German and UK hospitals. PMID- 24345522 TI - Direct measurement of 60Co and 125I activity by the sum-peak method in PTKMR BATAN. AB - The sum-peak method was successfully applied to the determination of the activity of (60)Co and (125)I sources measured by HPGe and well-type NaI(Tl) detectors in PTKMR-BATAN. The result of the (60)Co activity agrees with the activity value measured by using a calibrated ionization chamber within a range of about 0.35 0.5% and the activity result of (125)I agrees with the activity value measured using the photon-photon coincidence method within a range of 0.05-0.26%. PMID- 24345521 TI - A full digital approach to the TDCR method. AB - Current state of the art solutions based on the Triple to Double Coincidence Ratio method are generally large size, heavy-weight and not transportable systems. This is due, on one side, to large detectors and scintillation chambers and, on the other, to bulky analog electronics for data acquisition. CAEN developed a new, full digital approach to TDCR technique based on a portable, stand-alone, high-speed multichannel digitizer, on-board Digital Pulse Processing and dedicated DAQ software that emulates the well-known MAC3 analog board. PMID- 24345523 TI - Methods for dose measurements in small phantoms irradiated at BNCT epithermal column. AB - Suitable dosimeter methods have been proposed and tested, to measure the different dose contributions in small phantoms exposed to epithermal/thermal neutron beams designed for BNCT. One method is based on Fricke-gel dosimeter in small tubes of 2.8mm of external diameter, that allow determining profiles of gamma dose and of boron dose. The other method is based on the use of TLD-700 chips, from whose answer the contribution of thermal neutrons is subtracted by means of appropriate parameters of the glow curve. PMID- 24345524 TI - Activity determination of 229Th by means of liquid scintillation counting. AB - Liquid scintillation measurements of (229)Th in radioactive equilibrium with its progenies were carried out. The counting efficiency was determined by means of a free parameter model. The measurements were made in a custom-built triple-to double coincidence ratio (TDCR) system. In addition, a new portable mini-TDCR system with three channel photomultipliers and two commercial counters were tested. The decay of the short-lived (213)Po requires great care, since it often occurs during the dead time of the counter systems. Also the rather short-lived (217)At may decay during the dead time caused by (221)Fr decay events. The overall counting efficiency of the TDCR system of PTB was found to be about 700% (depending on the degree of chemical quenching) and the relative standard uncertainty of the activity concentration was found to be about 0.23%. The determined activity concentration was compared with the outcome of alpha spectrometry under defined solid angle and excellent agreement was found. The TDCR efficiency calculations can be easily adapted to activity determinations of (225)Ra or (225)Ac in equilibrium with their progenies. PMID- 24345525 TI - Beam shaping assembly optimization for (7)Li(p,n)(7)Be accelerator based BNCT. AB - Within the framework of accelerator-based BNCT, a project to develop a folded Tandem-ElectroStatic-Quadrupole accelerator is under way at the Atomic Energy Commission of Argentina. The proposed accelerator is conceived to deliver a proton beam of 30mA at about 2.5MeV. In this work we explore a Beam Shaping Assembly (BSA) design based on the (7)Li(p,n)(7)Be neutron production reaction to obtain neutron beams to treat deep seated tumors. PMID- 24345526 TI - A novel model for orthotopic liver transplantation in rats using hepatic rearterialization and biliary extradrainage system. AB - BACKGROUND: Although the rat orthotopic liver transplantation (OLT) model has existed for many years, only a few models can be applied for dynamic bile collection. The aim of this study was to introduce a dependent rat OLT model with hepatic rearterialization and an expediently dynamic bile collection system. METHODS: Forty-five male Sprague-Dawley rats were divided into the following three groups (n = 15 each): group A, OLT without hepatic rearterialization; group B, OLT with hepatic rearterialization; group C, OLT with hepatic rearterialization and a biliary extradrainage system. In groups B and C, a modified sleeve anastomosis between the donor common hepatic artery and the recipient proper hepatic artery was performed to restore the hepatic artery blood flow. In group C, after hepatic rearterialization, biliary extradrainage and jejunum stoma were performed to reestablish the bile flow, and a waistcoat-like external fixator was introduced to protect this system. RESULTS: The surgical success rates in groups A, B, and C were 100% (15/15), 93% (14/15), and 93% (14/15), respectively. In groups B and C, the hepatic artery patency rates were 93% and 86% on postoperative day 3 and postoperative day 21, respectively. Also, the liver function and bile duct integrity were preserved better than that in group A. In group C, the biliary extradrainage system was well preserved and bile collection was easily performed. CONCLUSIONS: The rat OLT model with hepatic rearterialization and a convenient biliary extradrainage system was satisfactory in maintaining the survival rate, hepatic artery patency rate, and recovery of graft function, so it can be applied in various studies after transplantation. PMID- 24345527 TI - Does dose matter? Editorial comments to Morris et al. Whole prostate D90 and V100: a dose-response analysis of 2000 consecutive (125)I monotherapy cases. PMID- 24345528 TI - Protection against acetaminophen-induced liver injury by allopurinol is dependent on aldehyde oxidase-mediated liver preconditioning. AB - Acetaminophen (APAP) overdose causes severe and occasionally fatal liver injury. Numerous drugs that attenuate APAP toxicity have been described. However these compounds frequently protect by cytochrome P450 inhibition, thereby preventing the initiating step of toxicity. We have previously shown that pretreatment with allopurinol can effectively protect against APAP toxicity, but the mechanism remains unclear. In the current study, C3HeB/FeJ mice were administered allopurinol 18h or 1h prior to an APAP overdose. Administration of allopurinol 18h prior to APAP overdose resulted in an 88% reduction in liver injury (serum ALT) 6h after APAP; however, 1h pretreatment offered no protection. APAP-cysteine adducts and glutathione depletion kinetics were similar with or without allopurinol pretreatment. The phosphorylation and mitochondrial translocation of c-jun-N-terminal-kinase (JNK) have been implicated in the progression of APAP toxicity. In our study we showed equivalent early JNK activation (2h) however late JNK activation (6h) was attenuated in allopurinol treated mice, which suggests that later JNK activation is more critical for the toxicity. Additional mice were administered oxypurinol (primary metabolite of allopurinol) 18h or 1h pre-APAP, but neither treatment protected. This finding implicated an aldehyde oxidase (AO)-mediated metabolism of allopurinol, so mice were treated with hydralazine to inhibit AO prior to allopurinol/APAP administration, which eliminated the protective effects of allopurinol. We evaluated potential targets of AO-mediated preconditioning and found increased hepatic metallothionein 18h post-allopurinol. These data show metabolism of allopurinol occurring independent of P450 isoenzymes preconditions the liver and renders the animal less susceptible to an APAP overdose. PMID- 24345529 TI - Once-daily nepafenac ophthalmic suspension 0.3% to prevent and treat ocular inflammation and pain after cataract surgery: phase 3 study. AB - PURPOSE: To evaluate once-daily nepafenac 0.3% to prevent and treat ocular pain and inflammation after cataract surgery. SETTING: Sixty-five centers in the United States and Europe. DESIGN: Randomized double-masked vehicle- and active controlled phase 3 study. METHODS: Patients received nepafenac 0.3% once daily, nepafenac 0.1% 3 times daily, or their respective vehicles from day -1 to day 14 after cataract extraction. An additional drop of study drug was administered 30 to 120 minutes preoperatively. The primary endpoint was the percentage of patients with a cure for inflammation (score of 0 for both aqueous cells and flare) at day 14. RESULTS: Of randomized patients, 817 received nepafenac 0.3%, 819 received nepafenac 0.1%, and 200 and 206 received the respective vehicles. Significantly more nepafenac 0.3% patients had no inflammation (68.4% versus 34.0%) and were pain free (91.0% versus 49.7%) at day 14 than vehicle patients (both P<.0001). Nepafenac 0.3% was noninferior to nepafenac 0.1% for inflammation (95% confidence interval [CI], -5.73% to 3.17%) and pain-free rates (95% CI, 3.08% to 2.70%). At all postoperative visits, fewer treatment failures (P<=.0012) and more clinical successes (P <= .0264) were observed with nepafenac 0.3% versus vehicle. Nepafenac 0.3% was well tolerated and had a safety profile comparable to that of nepafenac 0.1%. CONCLUSIONS: Once-daily nepafenac 0.3% was noninferior to nepafenac 0.1% 3 times daily for prevention and treatment of ocular inflammation and pain following cataract surgery. The safety of nepafenac 0.3% was comparable to that of nepafenac 0.1%, with the added convenience of once-daily dosing. FINANCIAL DISCLOSURE: Drs. Modi, Lehmann, Walters, Fong, Christie, Roel, Nethery, and Reiser have been paid consultants to Alcon Research, Ltd. Ms. Sager is an employee of Alcon Research, Ltd. Drs. Tsorbatzoglou, Philipson, and Traverso have no financial or proprietary interest in any material or method mentioned. PMID- 24345530 TI - Safety, efficacy, and predictability of laser in situ keratomileusis to correct myopia or myopic astigmatism with a 750 Hz scanning-spot laser system. AB - PURPOSE: To evaluate the clinical outcomes of laser in situ keratomileusis (LASIK) to correct myopia or myopic astigmatism using the Amaris 750S 750 Hz excimer laser. SETTING: Private LASIK center, Tokyo, Japan. DESIGN: Case series. METHODS: Patients with myopia or myopic astigmatism (spherical equivalent -0.50 to -11.63 diopters [D]), a corrected distance visual acuity (CDVA) of 20/20 or better, and an estimated residual bed thickness of 300 MUm or more had LASIK using the aspheric aberration-free ablation profile of the 750 Hz scanning-spot laser and the Femto LDV Crystal Line femtosecond laser for flap creation. Study parameters included uncorrected distance visual acuity (UDVA), CDVA, manifest refraction, astigmatism, and higher-order aberrations (HOAs). RESULTS: The study included 1280 eyes (685 patients). At 3 months, 96.6% of eyes had a UDVA of 20/20 or better and 99.1% had 20/32 or better; 94.1% of eyes were within +/- 0.50 D of the intended correction and 98.9% were within +/- 1.00 D; 89.7% of eyes had no residual cylinder and 96.0% had a postoperative astigmatism of less than 0.50 D. All eyes had a postoperative CDVA of 20/20 or better. The HOAs increased postoperatively (P<.001), with mean total postoperative corneal and ocular HOAs of 0.66 MUm +/- 0.20 (SD) and 0.56 +/- 0.23 MUm, respectively. The efficacy index and safety index were 1.02 and 1.06, respectively. CONCLUSION: Laser in situ keratomileusis with the 750 Hz scanning-spot laser was safe, effective, and predictable. No specific clinical side effects that might be associated with a high repetition rate occurred. FINANCIAL DISCLOSURE: Mr. Magnago is an employee of Schwind eye-tech-solutions GmbH. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 24345531 TI - Diamond knife-assisted deep anterior lamellar keratoplasty to manage keratoconus. AB - PURPOSE: To evaluate the outcomes of a new surgical technique, diamond knife assisted deep anterior lamellar keratoplasty (DALK), and compare its visual and refractive results with big-bubble DALK in cases of keratoconus. SETTING: Tertiary eyecare hospital. DESIGN: Comparative case series. METHODS: The visual and surgical outcomes of diamond knife-assisted DALK were compared with those of successful big-bubble DALK. RESULTS: Diamond knife-assisted DALK was performed in 19 eyes and big-bubble DALK, in 11 eyes. All surgeries were completed successfully. No intraoperative or postoperative complications occurred with diamond knife-assisted DALK. Six months after diamond knife-assisted DALK, the mean corrected distance visual acuity (CDVA) improved significantly from 1.87 logMAR +/- 0.22 (SD) to 0.23 +/- 0.06 logMAR, the mean keratometry improved from 65.99 +/- 8.86 diopters (D) to 45.13 +/- 1.16 D, and the mean keratometric cylinder improved from 7.99 +/- 3.81 D to 2.87 +/- 0.59 D (all P=.005). Postoperatively, the mean refractive astigmatism was 2.55 +/- 0.49 D and the mean spherical equivalent was -1.97 +/- 0.56 D. The mean logMAR CDVA (P = .06), postoperative keratometry (P=.64), refractive cylinder (P=.63), and endothelial cell loss (P=.11) were comparable between diamond knife-assisted DALK and big bubble DALK. CONCLUSIONS: Diamond knife-assisted DALK was effective and predictable as a surgical technique for management of keratoconus cases. This technique has the potential to offer visual and refractive outcomes comparable to those of big-bubble DALK. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24345532 TI - Keeping up! Older workers' adaptation in the workplace after age 55. AB - How do older workers keep up and adapt to a changing workplace after age 55? In exploring that question, this study specifically examined how age-related changes affect workers, how older workers deal with a loss of resources, how they engage in life management, and why some are more successful than others. An in-depth analysis was undertaken using 32 semi-structured interviews conducted with workers aged 55 to 64. Findings revealed that older workers use various strategies to adapt to a change in resources, and that these strategies help them cope and maintain their functioning in the workplace. Because older workers require different types of employer support, this study offers an understanding of how employers can provide that support to encourage older workers to remain in the workforce longer. Several avenues for future research are suggested, including an exploration of the role played by internal sources of support. PMID- 24345534 TI - Growth hormone insensitivity and obesity: Insights from human and animal models. PMID- 24345535 TI - The obesity of patients with Laron Syndrome is not associated with excessive nutritional intake. AB - SUMMARY: OBJECTIVE: To study the metabolic parameters which may affect the excessive weight of treated and untreated patients with Laron Syndrome. DESIGN: Body composition, daily caloric intake and resting energy expenditure (REE), when possible, were measured for each patient. Caloric intake was calculated based on 7-day food records, REE was measured by indirect calorimetry and body composition was determined by dual energy X-ray absorptiometry (DEXA). SUBJECTS: Nine untreated adult subjects with Laron Syndrome (6 female subjects, 3 male subjects) aged 28-53 years and 4 girls with Laron Syndrome treated by insulin-like growth factor-I (IGF-I) 120-150 MUg/kg/d were included in the study. RESULTS: Patients with Laron Syndrome have an abnormally high body fat (BF) mass (54 +/- 10% of body weight) and a relatively low lean body mass (LBM) compared to a healthy normal population. Energy intake varied but in most of the patients was not significantly higher than the measured REE. The REE corrected for LBM was higher than expected, based on our norms for healthy adults. The mean distribution of energy sources in the food was 47% carbohydrates, 17% protein and 36% fat. CONCLUSION: The severe obesity of patients with Laron Syndrome is not due to hyperphagia or hypometabolism. PMID- 24345533 TI - Norepinephrine transporter occupancy by nortriptyline in patients with depression: a positron emission tomography study with (S,S)-[18F]FMeNER-D2. AB - Norepinephrine transporter (NET) plays important roles in the treatment of various neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder (ADHD). Nortriptyline is a NET-selective tricyclic antidepressant (TCAs) that has been widely used for the treatment of depression. Previous positron emission tomography (PET) studies have reported over 80% serotonin transporter occupancy with clinical doses of selective serotonin reuptake inhibitors (SSRIs), but there has been no report of NET occupancy in patients treated with relatively NET-selective antidepressants. In the present study, we used PET and (S,S)-[1818F]FMeNER-D2 to investigate NET occupancies in the thalamus in 10 patients with major depressive disorder taking various doses of nortriptyline, who were considered to be responders to the treatment. Reference data for the calculation of occupancy were derived from age-matched healthy controls. The result showed approximately 50-70% NET occupancies in the brain as a result of the administration of 75-200 mg/d of nortriptyline. The estimated effective dose (ED50) and concentration (EC50) required to induce 50% occupancy was 65.9 mg/d and 79.8 ng/ml, respectively. Furthermore, as the minimum therapeutic level of plasma nortriptyline for the treatment of depression has been reported to be 70 ng/ml, our data indicate that this plasma nortriptyline concentration corresponds to approximately 50% NET occupancy measured with PET, suggesting that more than 50% of central NET occupancy would be appropriate for the nortriptyline treatment of patients with depression. PMID- 24345536 TI - Obesity is associated with impaired human coronary endothelial function. AB - SUMMARY: BACKGROUND: Obesity is an independent risk factor for cardiovascular disease. Endothelial dysfunction assessed in the peripheral circulation is associated with obesity, however, little is known if this association also exists in the coronary circulation. METHODS: Stable patients with coronary artery disease were evaluated. Baseline characteristics were evaluated, including assessment of body mass index [(BMI), kg/m(2)]. Coronary diameter (quantitative coronary angiography) and blood flow (0.014 in. Doppler Flo-wire) were measured at baseline and in response to intracoronary acetylcholine (10(-7) and 10(-6) M) to evaluate endothelial dependent effects with endothelial independent effects evaluated in response to intracoronary nitroglycerin and adenosine. The cohort was divided into tertiles around BMI values, i.e. normal weight (BMI < 25), overweight (BMI 25-29.9) and obese (BMI >= 30) groups. RESULTS: 83 patients were evaluated, with 20 patients in the normal weight (BMI 22.6 +/- 0.3 kg/m(2)), 40 subjects in the overweight (BMI 27.3 +/- 0.2 kg/m(2)) and 23 in the obese (BMI 34.3 +/- 0.3 kg/m(2)) groups. A significant difference was seen in the primary endpoint of Ach mediated % change in coronary blood flow between the normal (101 +/- 28%) and the obese (37 +/- 15%) groups (p = 0.04). No significant difference was observed in epicardial constrictor response to acetylcholine across these three groups of patients. CONCLUSIONS: In a cohort of subjects with coronary artery disease, patients with a high BMI had associated impaired microvascular coronary endothelial dependent function. PMID- 24345537 TI - Obesity remains under diagnosed in English hospital in-patients. AB - SUMMARY: There is a high prevalence of obesity in hospital populations. BMI and waist circumference are both simple and inexpensive screening tools for detection of obesity and if used would allow clinical guidelines for weight management to be implemented. Health care professionals should routinely screen all in-patients for overweight and obesity in UK hospitals, but compliance with this performance measure is poor. We found that weight was recorded only in 50-70% hospital in patients. BMI was recorded in less than 50% of patients and waist circumference was never even mentioned in hospital notes.: PMID- 24345538 TI - Trends of body mass index distribution in schoolchildren in Sendai, Japan, 1989 2003. AB - SUMMARY: Accumulating evidence indicates a strong association between obesity and health problems. Childhood obesity increases the risk of adulthood obesity. Although it is reported that the number of obese children in Japan has increased, it is unclear whether the obesity index distribution pattern has changed. To clarify this distribution pattern, we analyzed the changes in the body mass index (BMI) of primary (6th grade, 12 years old) and junior high (3rd year, 15 years old) schoolchildren in the city of Sendai during the period from 1989 to 2003. Our department has accumulated information on the height and body weight of all the schoolchildren in the city of Sendai. BMI was calculated using both the height and body weight data. The change in median BMI for 15 years had a slightly upward trend every year with both gender and school year. Although the BMI distribution showed that there was little or no change over time in the lower (10th and 25th) percentiles, the increases in the 75th and 90th percentiles were more marked than that in the 50th percentile in primary school children. On the other hand, there was only a small increase in BMI in the 3rd year of junior high school. Our results indicated that the changes in BMI distribution were concentrated at the upper end of the distribution in primary school children. The shifts in the value of high percentiles might be due to effect modification of the corresponding exposure by another environmental exposure or genetic predisposition. It is suggested that the factors causing this change influenced only part of this population, and affected individuals might represent a susceptible subpopulation of the exposed children.: PMID- 24345539 TI - Heterozygosity for leptin receptor (fa) accelerates hepatic triglyceride accumulation without hyperphagia in Zucker rats. AB - SUMMARY: Leptin, ob gene product, and its receptors are involved in the regulation of peripheral lipid and glucose metabolism. The present study sought to clarify the functional role of peripheral leptin receptors in hepatic lipid metabolism through analysis of Zucker rats (fa/fa, +/fa), as complete or partial leptin receptor insufficiency models, respectively. In Zucker fa/fa rats, calorie intake, body weight, liver weight, hepatic triglyceride content and serum insulin, triglycerides, FFA, and leptin were elevated compared to lean littermates (+/+ rats). In contrast, Zucker +/fa rats showed no remarkable changes in calorie intake, body weight and serum FFA compared with +/+ rats. Nevertheless, hepatic triglyceride content, liver weight and other serum parameters such as insulin, triglyceride and leptin were higher than in +/+ rats. In the representation of fatty acids component in the liver, there were no changes in +/fa rats relative to +/+ rats. Thus, in Zucker +/fa rats, fatty liver may develop in the absence of hyperphagia, obesity or changes in hepatic fatty acid metabolism. These results indicate that partial insufficiency of leptin receptor rather than changes in serum insulin, triglyceride and leptin may contribute to the increase in hepatic triglyceride content observed in +/fa rats.: PMID- 24345540 TI - Weight loss behavior in obese patients before seeking professional treatment in Taiwan. AB - SUMMARY: OBJECTIVE: To assess weight loss strategies and behaviors in obese patients prior to seeking professional obesity treatment in Taiwan. DESIGN: A cross-sectional study was conducted between 1 July 2004 and 30 June 2005. SETTING AND SUBJECTS: Obese subjects (1060; 791 females; age, >=18 years; median BMI, 29.5 kg/m(2)) seeking treatment in 18 Taiwan clinics specializing in obesity treatment were enrolled and completed a self-administered questionnaire. RESULTS: Of the 1060 subjects, the prevalence of anti-obesity drug use was 50.8%; more females than males used anti-obesity drugs (53.6% vs. 42.4%). Approximately one third of normal weight or overweight subjects with no concomitant obesity-related risk factors took anti-obesity drugs. Merely 26.7% of female and 34.7% of male subjects regularly received panel-recommended levels of physical activity. Further, two-thirds (66.1%) of subjects expressed an intention to lose more than 20% of initial body weight. Multiple logistic regression analyses revealed a substantially higher odds ratio (OR) for anti-obesity drug use in females than in males (OR, 2.3, 95% CI: 1.7-3.2). Obesity was also associated with younger age and higher body mass index (BMI). Females were more likely than males to have unrealistic weight loss goals. Younger patients and those with high BMI were also more likely to have unrealistic weight goals than their reference groups. CONCLUSION: Obese patients in Taiwan tend to use anti-obesity drugs, receive inadequate physical activity and have unrealistic weight loss expectations before seeking professional treatment for obesity. PMID- 24345541 TI - Obesity and cardiovascular dysfunction: A role for resveratrol? AB - SUMMARY: Obesity, characterized by excess adipose tissue is now becoming a worldwide epidemic. Various studies have suggested that obesity per se is an independent cardiovascular risk factor, as well as predisposing to type 2 diabetes, hypertension and dyslipidaemia. Furthermore, obesity induces insulin resistance, which is associated with development of cardiovascular diseases that include hypertension, and reduced endothelial function. A variety of pharmacological and physiological as well as surgical interventions have been used to counteract deleterious effects of obesity with some degree of success. A number of new medicinal agents are being considered as a candidate for managing obesity and its associated cardiovascular abnormalities. Resveratrol, a naturally occurring phenolic trihydroxystilbene substance, which is present in a variety of plants have been shown to reverse detrimental effects of diet-induced obesity. This review examines role of resveratrol as a future anti-obesity agent.: PMID- 24345542 TI - [New evidence of SUN Si-miao's date of death]. AB - About the date of death of Sun Si-miao, there are hypotheses of "Yongchun" and "Yonghui". Some scholars even give a concrete date of "February 15th????? of the first year of Yongchun". Based on my own textual research of historical materials, the record in the Sun Si-miao's Biography of Biography in the Facts About the Popularization of the Garland Sutra (Avatamsaka Sutra) in China, written by Fazang is most believable, i.e., the "Pre-Yongchun hypothesis". Therefore, a more reasonable description of his death date should be "Sun Si-miao was died in about the second year of Tiaolu/the first year of Yonglong (680)", or "Sun Si-miao was died in 680 +/- 1" PMID- 24345543 TI - [Differentiation of species of Bupleurum and its changes]. AB - Bupleurum is originated from the genus of Bupleurum chinensis DC of Umbelliferae. In China, the species of bupleurum for medicinal used are very complicate. During the Han-Tang Dynasties the bupleurum used covered a variety of its genera from Umbelliferae. "Yinzhou bupleurum" is the most famous in the Song Dynasty. Due to the continuous deterioration of its growing environment, the resources of the wild species of Yinzhou Bupleurum was declined, hence, those grown in other locations gradually attracted people's interests. Bupleutum was differentiated as Northern and Southern ones in the Ming Dynasty based on its different properties. Similar in its morphology and growing location to the Yinzhou Bupleurum, the Stellaria dichotoma lanceolata of the Caryophyllaceae was used as a substitute for the former. However, due to its prominent medicinal effects different from the Yinzhou one, the latter was continuously applied as a new herb. There are 2 great varieties of bupleurum used in modern times, the Bupleurum chinensis DC, and the Bupleurm scorzonerifolium Willd. Since the species of bupleurum in the current market are very complicate, and its clinical applications are quite confused, standardization and strengthening of its research are badly needed so as to promote its marketing. PMID- 24345544 TI - [Xiamen Professional School of Traditional Chinese Medicine in modern Times]. AB - Established in 1932, the Xiamen Professional School of Traditional Chinese Medicine, was the leading educational institution of traditional Chinese medicine (TCM) in the Fujian region in modern times. Without the support of government, Wu Rui-fu and his partners self-funded for running the school hardly, insisted strictly the idea of converging TCM and western medicine, paid attention to the academic construction, launched the academic journals, including the Ten-day Periodical of Traditional Chinese Medicine and Xiamen Medicine, and set up a TCM library. Through the 6 years of painstaking works, the school trained many TCM talents, and accumulated practical experience for exploring the model of TCM education in modern times. PMID- 24345545 TI - [Incidents in reposition of smallpox virus laboratories and its retrospect and ponderation]. AB - Reposition of variola virus in some laboratories in the UK led to some serious incidents before the announcement by WHO of the Global Eradication of Smallpox in 1980. These three incidents resulted in 78 people recorded as infected with smallpox, among them 3 died, with very many others misdiagnosed at the time as suffering from chickenpox. Therefore WHO discussed the problems and decided to reduce gradually the number of repositories of variola virus in laboratories world-wide from previously unknown numbers to two. However, suppose in the event of a sudden outbreak of a new, mutated species of smallpox virus, what should we do? Maybe, the obsolete ancient prophylactic practice of variolation could be of considerable contingency value. PMID- 24345546 TI - [Comparison of Dongeuisoosebowon sasung caobenjuan (The Four Constitutional Medicine of A Draft Volume of Longevity and Life Preservation in Eastern Medicine) and Dongeuisoosebowon (Longevity and Life Preservation in Eastern Medicine)]. AB - In 1894, Lee Je-ma finished the book Dongeuisoosebowon sasung caobenjuan (The Four Constitutional Medicine of A Draft Volume of Longevity and Life Preservation in Eastern Medicine), and later, in 1900, he started revising the book. However, he passed away and didn't finish his work. In 1901, Lee's disciples edited the revised edition, and published it in the title Dongeuisoosebowon (Longevity and Life Preservation in Eastern Medicine). Some hand-copied versions of Dongeuisoosebowon sasung caobenjuan were still available. After comparing these two books, it was found that Lee's disciples made rather more changes: including addition of its contents, adjustment of its order, modification of the texts and prescriptions, etc. By comparison, the contents in the hand-copied edition more closely reflects Lee's recognition on the Sasung Euihak (Four-Constitution medicine), while those of the published ones were deleted a bulk of the original contents of the Four-Constitutional medicine, yet supplemented much contents of traditional Chinese medicine. PMID- 24345547 TI - [A historical retrospect of Pre-hospital emergency treatment]. AB - In 1240, the first organization of first aid medical service for rescuing and transferring the wounded in the world was established at Florence, Italy. The stations of Air Ambulances were set up in most of the developed countries at the end of the 1960s. In the middle of the 1970s, the International Red Cross put forward the principles of internationalization, international cooperation and its standardization, thus, promoting the development of pre-hospital emergency treatment. In 1972, the first Emergency Medical Service Center was established and in 1973, Congress of the United States passed the Emergency Medical Services Act (EMSS). In 1976, the legislative procedure was finished and the National Emergency Network was formed, afterwards, pre-hospital emergency treatment, on site rescue and transfer care, patient monitoring system of ICU-CCU were set up successively. Since the first rescue group of "three failure" (heart failure, lung failure and renal failure) was first formed at Tianjin First Center Hospital in August 1974, the pre-hospital emergency of China had been developing gradually. PMID- 24345548 TI - [The initiative of patient safety culture and its development]. AB - Safety culture is the culture of all the connotations to a safe direction for the purpose of advancing a unified organizational behavior. Safety culture was first introduced to the field of medicine by the American researchers in the 1990s. Subsequently, researchers from different countries initiated the relevant studies and put forward five subcultures of patient safety culture. At present, the patient safety culture research is mainly conducted in the United States, China and the UK of which cross-sectional studies are the most popular study designs including the evaluation of patient safety scale, reliability and validity analysis. Non-sectional studies are focused on the study of subcultures including leadership, communication, cooperation and reports. Compared with the studies abroad, the studies on patient safety culture in China are rather late, yet also mainly on reliability and validity analysis of scales. Most participants we investigated are nurses from teaching hospitals. But in the real healthcare situation, fostering a positive safety culture is still very lacking and many ideas and behaviors are in the state of traditional blaming culture. PMID- 24345549 TI - [A Study on the quotations in the Wu xing da yi (The Gist of Five Phases) cited from Nei jing (Inner Canon)]. AB - In the Wu xing da yi (The Gist of Five Phases), written by Xiao Ji of the Sui Dynasty, there were 9 quotations cited from Huang di nei jing (Inner Canon of Huangdi). By comparison with current version of Huang di nei jing, most of the descriptions are similar, yet still with some differences, such as yin-yang nature of the five zang visceras, the liver being the root of "pi ji", the spleen being the root of "cang lin" etc. Wu xing da yi epitomizes the books about yin yang and five phases before the Sui Dynasty, while Xiao Ji's quotations from Huang di nei jing interpreted from the views of yin-yang and five phases, are different from the annotations of later ages. PMID- 24345550 TI - [An investigation into the Jin xiao fang (Prescriptions of Instant Effect), a lost recipe book of the Tang Dynasty]. AB - Altogether 141 prescriptions in the Jin xiao fang (Prescriptions of Instant Effect), a lost recipe book of the Tang Dynasty are cited in the Wai tai mi yao (Medical Secrets of An Official). Based on the analysis of these citations, it can be sure that the Jin xiao fang was written by Li Jian-yi of the Tang Dynasty, and completed around 724 to 733. These cited prescriptions are related to the clinical subjects, with complicate origins, for example, physicians and scholars. It is characterized by its "xiao yan (efficacy)". PMID- 24345552 TI - Bone repair of critical size defects treated with mussel powder associated or not with bovine bone graft: histologic and histomorphometric study in rat calvaria. AB - The objective of this study was to evaluate the bone repair of critical size defects treated with mussel powder with or without additional bovine bone. Critical size defects of 5 mm were realized in the calvaria of 70 rats, which were randomly divided in 5 groups - Control (C), Autogenous Bone (AB), Mussel Powder (MP), Mussel Powder and Bovine Bone (MP-BB) and Bovine Bone (BB). Histological and histomorphometric analysis were performed 30 and 90 days after the surgical procedures (ANOVA e Tukey p < 0.05). After 30 days, the measures of remaining particles were: 28.36% (MP-BB), 26.63% (BB) and 8.64% (MP) with a statistically significant difference between BB and MP. The percentage of osseous matrix after 30 days was, AB (55.17%), 23.31% (BB), 11.66% (MP) and 10.71% (MP BB) with statistically significant differences among all groups. After 90 days the figures were 25.05% (BB), 21.53% (MP-BB) and 1.97% (MP) with statistically significant differences between MP-BB and MP. Percentages of new bone formation after 90 days were 89.47% (AB), 35.70% (BB), 26.48% (MP-BB) and 7.37% (MP) with statistically significant differences between AB and the other groups. Within the limits of this study, we conclude that mussel powder, with or without additional bovine bone, did not induce new bone formation and did not repair critical size defects in rat calvaria. PMID- 24345553 TI - Computational fluid dynamics in patients with continuous-flow left ventricular assist device support show hemodynamic alterations in the ascending aorta. AB - OBJECTIVE: Increased use of continuous-flow left ventricular assist devices for long-term mechanical support necessitates a better understanding of hemodynamic changes in the native heart and the ascending aorta. By using patient-specific computational models, correlations of potentially adverse hemodynamic conditions with the orientation of the left ventricular assist device outflow graft and their relationship with aortic insufficiency and ischemic events were investigated. METHODS: Computed hemodynamic parameters, including wall shear stress, pressure in the ascending aorta, and dissipation of turbulent energy, were correlated with the orientation of the left ventricular assist device graft outflow in 5 patients (4 with the HeartMate II device [Thoratec Corp, Pleasanton, Calif] and 1 with the HeartWare Ventricular Assist Device [HeartWare Inc, Framingham, Mass]; 3 patients experienced moderate aortic insufficiency, and 2 patients experienced ischemic events). Hemodynamic conditions for aortic insufficiency and ischemic events were differentiated by linear discriminant analysis. RESULTS: Positive correlations between left ventricular assist device outflow graft orientation and wall shear stress, pressure, and turbulent energy dissipation in the ascending aorta were found (R(2) > 0.68). Linear discriminant analysis indicated a relationship of the velocity magnitude of retrograde flow toward the aortic root with aortic insufficiency and of the turbulent energy and wall shear stress with ischemic events. CONCLUSIONS: Computational fluid dynamic simulations using clinical image data indicate altered hemodynamic conditions after left ventricular assist device implantation. Consequently, the left ventricular assist device outflow graft should be placed so the jet of blood is aimed toward the lumen of the aortic arch to avoid turbulences that will increase wall shear stress and retrograde pressure of the aortic root. Further investigations are warranted to confirm these findings in a larger patient cohort. PMID- 24345551 TI - Tillering and panicle branching genes in rice. AB - Rice (Oryza sativa L.) is one of the most important staple food crops in the world, and rice tillering and panicle branching are important traits determining grain yield. Since the gene MONOCULM 1 (MOC 1) was first characterized as a key regulator in controlling rice tillering and branching, great progress has been achieved in identifying important genes associated with grain yield, elucidating the genetic basis of yield-related traits. Some of these important genes were shown to be applicable for molecular breeding of high-yielding rice. This review focuses on recent advances, with emphasis on rice tillering and panicle branching genes, and their regulatory networks. PMID- 24345554 TI - Poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co glycolic acid) thermogel as a novel submucosal cushion for endoscopic submucosal dissection. AB - Endoscopic submucosal dissection (ESD) is a clinical therapy for early stage neoplastic lesions in the gastrointestinal tract. It is, however, faced with a crucial problem: the high occurrence of perforation. The formation of a submucosal fluid cushion (SFC) via a fluid injection is the best way to avoid perforation, and thus an appropriate biomaterial is vital for this minimally invasive endoscopic technique. In this study, we introduced an injectable thermogel as a novel submucosal injection substance in ESD. The hydrogel synthesized by us was composed of poly(lactic acid-co-glycolic acid) poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers. The polymer/water system was a low-viscosity fluid at room temperature and thus easily injected, and turned into a non-flowing gel at body temperature after injection. The submucosal injection of the thermogel to create SFCs was performed in both resected porcine stomachs and living minipigs. High mucosal elevation with a clear margin was maintained for a long duration. Accurate en bloc resection was achieved with the assistance of the thermogel. The mean procedure time was strikingly reduced. Meanwhile, no obvious bleeding, perforation and tissue damage were observed. The application of the thermogel not only facilitated the ESD procedure, but also increased the efficacy and safety of ESD. Therefore, the PLGA-PEG-PLGA thermogel provides an excellent submucosal injection system, and has great potential to improve the ESD technique significantly. PMID- 24345555 TI - Organic interlamellar layers, mesolayers and mineral nanobridges: contribution to strength in abalone (Haliotis rufescence) nacre. AB - The contributions of mesolayers, organic interlamellar layers and nanoasperities/mineral bridges to the strength of nacre from red abalone (Haliotis rufescens) shell nacre are investigated. Samples were demineralized and deproteinized to separate the organic and mineral components, respectively. Tensile tests were performed on both the isolated organic constituent and the isolated mineral. The strength of the isolated organic component suggests that growth bands play an important role in the mechanical behavior as they are thick regions of protein that are a significant fraction (~0.4) of the total organic content. The thickness variation of the nacre tablets was measured and found to be a small fraction of the mean tablet thickness (0.568MUm); the standard deviation is 26nm, indicating that the wedge mechanism of toughening does not operate in the nacre investigated. Results obtained from the isolated mineral validate the importance of the organic constituent as the mechanical properties decline greatly when the organic component is removed. The results presented herein add to the understanding of the mechanical response of the organic interlayers and growth bands and their effect on the toughness of the abalone nacre. PMID- 24345556 TI - Alcohol and drug use during unprotected anal intercourse among gay and bisexual men in Scotland: what are the implications for HIV prevention? AB - OBJECTIVES: To examine alcohol and drug use during unprotected anal intercourse (UAI), and whether use is associated with HIV-related risk behaviours among gay and bisexual men in Scotland. METHODS: Cross-sectional survey of 17 gay commercial venues in Glasgow and Edinburgh in May 2011 (n=1515, 65.2% response rate); 639 men reporting UAI are included. RESULTS: 14.4% were always and 63.4% were sometimes drunk during UAI in the previous 12 months; 36.3% always/sometimes used poppers; 22.2% always/sometimes used stimulant or other recreational/illicit drugs; and 14.1% always/sometimes used Viagra. All were significantly correlated and, in multivariate analysis, the adjusted odds of having UAI with 2+ partners in the previous 12 months were significantly higher for men who reported stimulant or recreational/illicit drug use during UAI (AOR=2.75, 95% CI 1.74 to 4.34) and the adjusted odds of UAI with casual partners were higher for men who reported poppers use (AOR=1.50, 95% CI 1.03 to 2.17). Men who reported always being drunk during UAI were more likely to report UAI with 2+ partners (AOR=1.68, 95% CI 1.01 to 2.81), casual partners (AOR=2.18, 95% CI 1.27 to 3.73), and partners of unknown/discordant HIV status (AOR=2.14, 95% CI 1.29 to 3.53), than men who were not. CONCLUSIONS: Our study suggests alcohol and drug use may be relatively common during UAI among gay and bisexual men in Scotland. Brief alcohol or drug interventions, particularly in clinical settings, are justified, but should be properly evaluated and take into account the potential influence of broader, situational and social factors on sexual risk. PMID- 24345557 TI - Enhancement of alcohol drinking in mice depends on alterations in RNA editing of serotonin 2C receptors. AB - Serotonin 2C receptors (5-HT(2C)R) are G-protein-coupled receptors with various actions, including involvement in drug addiction. 5-HT2CR undergoes mRNA editing, converting genomically encoded adenosine residues to inosines via adenosine deaminases acting on RNA (ADARs). Here we show that enhanced alcohol drinking behaviour in mice is associated with the degree of 5-HT(2C)R mRNA editing in the nucleus accumbens and dorsal raphe nuceus, brain regions important for reward and addiction. Following chronic alcohol vapour exposure, voluntary alcohol intake increased in C57BL/6J mice, but remained unchanged in C3H/HeJ and DBA/2J mice. 5 HT(2C)R mRNA editing frequency in both regions increased significantly in C57BL/6J mice, as did expressions of 5-HT(2C)R, ADAR1 and ADAR2, but not in other strains. Moreover, mice that exclusively express the unedited isoform (INI) of 5 HT(2C)R mRNA on a C57BL/6J background did not exhibit increased alcohol intake compared with wild-type mice. Our results indicate that alterations in 5-HT(2C)R mRNA editing underlie alcohol preference in mice. PMID- 24345558 TI - Static magnetic fields modulate X-ray-induced DNA damage in human glioblastoma primary cells. AB - Although static magnetic fields (SMFs) are used extensively in the occupational and medical fields, few comprehensive studies have investigated their possible genotoxic effect and the findings are controversial. With the advent of magnetic resonance imaging-guided radiation therapy, the potential effects of SMFs on ionizing radiation (IR) have become increasingly important. In this study we focused on the genotoxic effect of 80 mT SMFs, both alone and in combination with (i.e. preceding or following) X-ray (XR) irradiation, on primary glioblastoma cells in culture. The cells were exposed to: (i) SMFs alone; (ii) XRs alone; (iii) XR, with SMFs applied during recovery; (iv) SMFs both before and after XR irradiation. XR-induced DNA damage was analyzed by Single Cell Gel Electrophoresis assay (comet assay) using statistical tools designed to assess the tail DNA (TD) and tail length (TL) as indicators of DNA fragmentation. Mitochondrial membrane potential, known to be affected by IR, was assessed using the JC-1 mitochondrial probe. Our results showed that exposure of cells to 5 Gy of XR irradiation alone led to extensive DNA damage, which was significantly reduced by post-irradiation exposure to SMFs. The XR-induced loss of mitochondrial membrane potential was to a large extent averted by exposure to SMFs. These data suggest that SMFs modulate DNA damage and/or damage repair, possibly through a mechanism that affects mitochondria. PMID- 24345559 TI - Index of the systemic balance of end products of glucocorticoid metabolism in fresh urine from humans. AB - SUMMARY: OBJECTIVE: Dysregulation of tissue-specific intracellular glucocorticoid reactivation is implicated in obesity and related metabolic diseases in humans. The ratio of end products of glucocorticoid metabolism in fresh urine sample, tetrahydrocortisol (THF) + allo-tetrahydrocortisol (allo-THF) vs. tetrahydrocortisone (THE), i.e., the urinary ratio is regarded as an index of the systemic balance underlying intracellular glucocorticoid metabolism, where the enzymes, 11beta-hydroxysteroid dehydrogenase type 1 and type 2 as well as 5alpha- and 5beta-reductase are involved in a tissue-specific manner. METHODS: To explore the clinical implications of the urinary ratio in obesity and related metabolic diseases, the urinary ratio was determined by gas chromatography and mass spectrometry. RESULTS: The urinary ratio was shown to be constant and reproducible in the same individuals. The ratio was found to inversely correlate with BMI (P < 0.01), waist circumference (P < 0.01), and liver transaminase (P < 0.05) in a large cohort of ~200 Japanese subjects. This finding suggests that the systemic balance underlying intracellular glucocorticoid reactivation was suppressed in obesity and liver dysfunction. Consistent with this notion, the ratio was decreased in patients with non-alcoholic steatohepatitis (P < 0.01). The urinary ratio was not altered in patients with type 2 diabetes on a 2-month mild calorie restriction. In contrast, the ratio was significantly reduced in patients who responded to the anti-diabetic pioglitazone (P < 0.01). CONCLUSION: The present study provides novel evidence that the urinary ratio reflects the facet of adipose tissue and liver function in humans, thereby offering a unique opportunity to evaluate obesity-related diseases. PMID- 24345560 TI - Resistin gene variations are associated with the metabolic syndrome in Japanese men. AB - SUMMARY: OBJECTIVES: Metabolic syndrome is defined as a cluster of risk factors for cardiovascular disease and is intimately related to insulin resistance. Resistin, a hormone secreted by adipocytes, may play an important role in communication between adiposity and insulin resistance. We investigated whether variations in the resistin gene associated with metabolic syndrome in a Japanese population. METHOD: We analyzed five SNPs, two of which were located in the promoter region (-420C > G, -358G > A), two in intron 2 (+157C > T, +299G > A), and one in the 3'-untranslated region (3'UTR) (+1263G > C) across the resistin gene in 2968 residents from an urban Japanese cohort. The associations of SNPs and haplotypes with metabolic syndrome were analyzed. RESULTS: The GAC and CGC haplotypes (comprising -420C > G, -358G > A, and +157C > T) had opposite influences on metabolic syndrome susceptibility in men; the former was associated with an increased risk and the latter with a decreased risk. We also found that the -420G allele was significantly associated with an increased risk of metabolic syndrome and significantly correlated with high diastolic blood pressure, high HOMA-IR values, high serum triglyceride levels, low HDL-cholesterol levels and high serum levels of adiponectin. CONCLUSION: We identified a risk-conferring SNP and haplotype of the resistin gene for metabolic syndrome in a Japanese population. Our data suggested that resistin gene is a susceptibility gene for metabolic syndrome in Japanese men. PMID- 24345561 TI - Overweight and obesity: Prevalence and their association with some social characteristics in a random sample population-based study in Cordoba city, Argentina. AB - SUMMARY: BACKGROUND: Obesity has become a threat to public health, as the epidemic is not confined to developed countries but is affecting many developing countries. Because obesity is known to vary according to socio-cultural factors, including socio-economic position and social roles, a multi-stage random sample population-based study was conducted in Cordoba, Argentina, from January 2005 to December 2006, to explore the effect of selected social factors on the prevalence of obesity. METHODS: Information was obtained about demographic, anthropometric, lifestyle, dietary and physical activity characteristics. Logistic regression (LR) and proportional odds models (POM) were used in data analysis. RESULTS: The prevalence of overweight and obesity was 52 and 17%, respectively. LR models revealed that overweight was positively associated with gender (men), decreasing socio-economic status (SES), married and divorced status and negatively with increasing levels of physical activity whereas obesity was positively associated with decreasing SES levels, married status and negatively associated with physical activity levels. POM revealed strong associations between variables and the outcomes and an effect modification among women aged 30 years or older with a low SES. CONCLUSIONS: Our data indicate a high prevalence of overweight and obesity in this population; several social factors and lifestyle characteristics are associated with both overweight and obesity. However, a prospective cohort study would be needed to investigate causality. PMID- 24345562 TI - Changes in food intake patterns associated with body weight loss during a 12-week health promotion program and a 9-month follow-up period in a Japanese population. AB - SUMMARY: Recently, food intake pattern analysis associated with body weight has been conducted instead of traditional dietary analysis focusing on a single nutrient or food group, but there have been few studies examining the association between change in food intake patterns and body weight loss. In this study, short and long-term relationships between changes in food intake patterns and body weight loss were examined. Subjects were 506 overweight/obese men and women who participated in a 12-week health promotion program and a follow-up check 9 months later. Diet was assessed with a FFQ and food intake patterns named "Plant foods and seafood" and "Sweets, meats, dairy products and alcohol" were derived by cluster analysis using the intake of 17 food groups at the baseline. During the program, body weight loss of the subjects changed pattern from "Sweets, meats, dairy products and alcohol" to "Plant foods and seafood" (SP group) was significantly larger than that of the subjects who showed an opposite pattern change (PS group) or the subjects who maintained "Sweets, meats, dairy products and alcohol" pattern after adjusting for age, sex, body weight at the baseline, changes in energy intake and exercise habit. Body weight loss of the SP group was also significantly greater than that of the PS group during the follow-up period. Changes in food intake patterns were related to body weight loss and changing the pattern from "Sweets, meats, dairy products and alcohol" to "Plant foods and seafood" was most effective for short- and long-term body weight loss.: PMID- 24345563 TI - Lifestyle risk factors for obesity in 7-year-old children. AB - SUMMARY: OBJECTIVE: To evaluate the associates of obesity and overweight in 7 year-old children. DESIGN: Cross-sectional study. SUBJECTS: 855 children out of all 1278 school beginners in the city of Oulu, Northern Finland. METHODS: A questionnaire to be filled in by parents was delivered by the school nurses to 1278 children. The child's eating habits, dietary intake and physical activity patterns were enquired about. There were also questions about the household and parents' level of education and physical activity. Overweight and obesity were defined by BMI according to internationally accepted criteria. The chi(2) test was used to evaluate the significance of the differences between normal and overweight children. Multivariate logistic regression model was used to find the most predictive variables associated with overweight and obesity. The final models are reported using odds ratios (ORs) and their 95% confidence intervals (CI). RESULTS: The number of responders was 855 (66.9%). The prevalence of overweight was 16.7% and that of obesity 4.9%. Fifty-seven percent of the parents who had an overweight or obese child 7-year-old did not recognise their child's overweight. The factors associated with obesity were: mother's obesity (OR 13.04, CI 2.81-60.53), low physical activity (OR 10.95, CI 3.28-36.50), skipping breakfast (OR 10.12, CI 1.81-56.63), habitual overeating (OR 9.35, CI 2.58 33.82), father's overweight (OR 5.89, CI 1.23-28.10) and mother's age over 40 years (OR 2.91, CI 1.09-7.80). CONCLUSION: This cross-sectional study promotes the importance of child's eating behaviour and family's eating patterns. Parents should be helped to recognise their child's overweight, and educational strategies should be targeted at both children and their parents. Avoiding inactivity is essential in preventing obesity in children. PMID- 24345564 TI - Waist circumference is positively associated with insulin resistance but not with fasting blood glucose among moderately to highly obese young Japanese men. AB - SUMMARY: OBJECTIVE: To investigate the association of waist circumference with insulin resistance in obese young Japanese men. METHODS: In this cross-sectional study, we evaluated 92 obese young Japanese men (age: 18-29 years; mean BMI +/- SD: 33 +/- 3 kg/m(2)) for anthropometric and metabolic parameters and the homeostasis model assessment of insulin resistance (Homa-IR). RESULTS: Waist circumference ranged from 87.5 cm to 129 cm. Subjects with waist circumferences in the top quartile had higher insulin (Ln-transformed) and Homa-IR (Ln transformed) compared with those in the bottom quartile. Fasting blood glucose and HbA1c were lower among subjects in the second-lowest quartile but not the second-highest quartile or the top quartile compared with those in the bottom quartile. CONCLUSION: Insulin resistance is associated with waist circumference in moderately to highly obese young Japanese men. Suppression of blood glucose by enhanced insulin secretion triggered by the increase of insulin resistance may begin to lose its effect as waist circumference becomes larger. PMID- 24345565 TI - Uncontrolled eating and obesity in adult primary care patients. AB - SUMMARY: OBJECTIVE: The purpose of this study was to assess the independent effects of health confidence and uncontrolled eating on obesity risk in primary care patients. METHODS: A random sample of primary care patients served by a large medical clinic in the mid-western United States was surveyed January-March of 2008; and 944 cases met criteria for the study. The odds of being obese (BMI >= 30) were modeled using multiple logistic regression. Uncontrolled eating was measured with a single question addressing problems with food control. Weight control motivation, health confidence, demographic variables, and health behaviors were used as covariates. RESULTS: Nearly 47 percent of our respondents reported uncontrolled eating; 42.2 percent of uncontrolled eaters were obese, compared with only 9.4 percent of persons who never had problems with food control. About 27 percent of non-obese persons reported no trouble with food control, compared to 9.4 percent of obese patients having no trouble. Over 70 percent of obese respondents reported at least some trouble with food control, compared to only 37 percent of non-obese patients. Not being able to control food or having some trouble controlling food exhibited the strongest independent association with obesity (OR 6.67, CI 3.91-11.4). CONCLUSIONS: Adult primary care patients who reported inability to control their eating behavior were more likely to be obese. These effects persisted after adjusting for demographic and behavioral variables. The results of this study suggest that obesity is partly the result of uncontrolled eating. Health promotion programs may have to be patterned after those designed for substance abuse and dependency. PMID- 24345566 TI - Biodegradation of polyacrylamide by anaerobic digestion under mesophilic condition and its performance in actual dewatered sludge system. AB - Polyacrylamide (PAM) used in sludge dewatering widely exists in high-solid anaerobic digestion. Degradation of polyacrylamide accompanied with accumulation of its toxic monomer is important to disposition of biogas residues. The potential of anaerobic digestion activity in microbial utilization of PAM was investigated in this study. The results indicated that the utilization rate of PAM (as nitrogen source) was influenced by accumulation of ammonia, while cumulative removal of amide group was accorded with zeroth order reaction in actual dewatered system. The adjoining amide group can combined into ether group after biodegradation. PAM can be broken down in different position of its carbon chain backbone. In actual sludge system, the hydrolytic PAM was liable to combined tyrosine-rich protein to form colloid complex, and then consumed as carbon source to form monomer when easily degradable organics were exhausted. The accumulation of acrylamide was leveled off ultimately, accompanied with the yield of methane. PMID- 24345567 TI - Inoculation and alkali coeffect in volatile fatty acids production and microbial community shift in the anaerobic fermentation of waste activated sludge. AB - Batch fermentations of waste activated sludge (WAS) at alkaline pH with different inocula were performed. Paper mill anaerobic granular sludge (PAS) and dyeing mill anaerobic sludge (DAS) were used as inocula. At pH 10 the inoculation did not increase the volatile fatty acids (VFAs) production compared to the non inoculated samples fermented in the same conditions, and the maximal VFAs yield of non-inoculated WAS was higher than inoculated WAS. However, at pH 9 the inoculation with PAS increased the sludge hydrolysis and VFAs production was 1.7 fold higher than that in non-inoculated WAS (yield 52.40mg/g of volatile solid). Denaturing gradient gel electrophoresis analysis revealed that 3 bacterial species, identified as Proteocatella, Tepidibacter, and Clostridium, disappeared when inoculated with PAS at pH 9 or at pH?10. The results showed that the inoculation with PAS can be helpful to achieve a relatively high VFAs production from WAS in a moderate alkaline environment. PMID- 24345568 TI - Hydroxylation and hydrolysis: two main metabolic ways of spiramycin I in anaerobic digestion. AB - The anaerobic degradation behaviors of five macrolides including spiramycin I, II, III, midecamycin and josamycin by sludge were investigated. Within 32days, 95% of spiramycin I, II or III was degraded, while the remove rate of midecamycin or josamycin was 75%. SPM I degradation was much higher in nutrition supplementation than that just in sludge. The degradation products and processes of spiramycin I were further characterized. Three molecules, designated P-1, P-2 and P-3 according to their order of occurrence, were obtained and purified. Structural determination was then performed by nuclear magnetic resonance and MS/MS spectra, and data indicated that hydroxylation and hydrolysis were main reactions during the anaerobic digestion of spiramycin I. P-1 is the intermediate of hydroxylation, and P-2 is the intermediate of hydrolysis. P-3 is the final product of the both reaction. This study revealed a hydroxylation and hydrolysis mechanism of macrolide in anaerobic digestion. PMID- 24345569 TI - Ethanol production from glucose and xylose obtained from steam exploded water extracted olive tree pruning using phosphoric acid as catalyst. AB - In this work, the effect of phosphoric acid (1% w/w) in steam explosion pretreatment of water extracted olive tree pruning at 175 degrees C and 195 degrees C was evaluated. The objective is to produce ethanol from all sugars (mainly glucose and xylose) contained in the pretreated material. The water insoluble fraction obtained after pretreatment was used as substrate in a simultaneous saccharification and fermentation (SSF) process by a commercial strain of Saccharomyces cerevisiae. The liquid fraction, containing mainly xylose, was detoxified by alkali and ion-exchange resin and then fermented by the xylose fermenting yeast Scheffersomyces stipitis. Ethanol yields reached in a SSF process were close to 80% when using 15% (w/w) substrate consistency and about 70% of theoretical when using prehydrolysates detoxified by ion-exchange resins. Considering sugars recovery and ethanol yields about 160g of ethanol from kg of water extracted olive tree pruning could be obtained. PMID- 24345570 TI - Genomic selection using beef commercial carcass phenotypes. AB - In this study, an industry terminal breeding goal was used in a deterministic simulation, using selection index methodology, to predict genetic gain in a beef population modelled on the UK pedigree Limousin, when using genomic selection (GS) and incorporating phenotype information from novel commercial carcass traits. The effect of genotype-environment interaction was investigated by including the model variations of the genetic correlation between purebred and commercial cross-bred performance (rhoX). Three genomic scenarios were considered: (1) genomic breeding values (GBV)+estimated breeding values (EBV) for existing selection traits; (2) GBV for three novel commercial carcass traits+EBV in existing traits; and (3) GBV for novel and existing traits plus EBV for existing traits. Each of the three scenarios was simulated for a range of training population (TP) sizes and with three values of rhoX. Scenarios 2 and 3 predicted substantially higher percentage increases over current selection than Scenario 1. A TP of 2000 sires, each with 20 commercial progeny with carcass phenotypes, and assuming a rhoX of 0.7, is predicted to increase gain by 40% over current selection in Scenario 3. The percentage increase in gain over current selection increased with decreasing rhoX; however, the effect of varying rhoX was reduced at high TP sizes for Scenarios 2 and 3. A further non-genomic scenario (4) was considered simulating a conventional population-wide progeny test using EBV only. With 20 commercial cross-bred progenies per sire, similar gain was predicted to Scenario 3 with TP=5000 and rhoX=1.0. The range of increases in genetic gain predicted for terminal traits when using GS are of similar magnitude to those observed after the implementation of BLUP technology in the United Kingdom. It is concluded that implementation of GS in a terminal sire breeding goal, using purebred phenotypes alone, will be sub-optimal compared with the inclusion of novel commercial carcass phenotypes in genomic evaluations. PMID- 24345571 TI - Serotonin 1A receptors and sexual behavior in a genetic model of depression. AB - The Flinder Sensitive Line (FSL) is a rat strain that displays distinct behavioral and neurochemical features of major depression. Chronic selective serotonin reuptake inhibitors (SSRIs) are able to reverse these symptoms in FSL rats. It is well known that several abnormalities in the serotonergic system have been found in FSL rats, including increased 5-HT brain tissue levels and reduced 5-HT synthesis. SSRIs are known to exert (part of) their effects by desensitization of the 5-HT1A receptor and FSL rats appear to have lower 5-HT1A receptor densities compared with Flinder Resistant Line (FRL) rats. We therefore studied the sensitivity of this receptor on the sexual behavior performance in both FRL and FSL rats. First, basal sexual performance was studied after saline treatment followed by treatment of two different doses of the 5-HT1A receptor agonist +/-8-OH-DPAT. Finally we measured the effect of a 5-HT1A receptor antagonist to check for specificity of the 5-HT1A receptor activation. Our results show that FSL rats have higher ejaculation frequencies compared with FRL rats which do not fit with a more depressive-like phenotype. Moreover FRL rats are more sensitive to effects of +/-8-OH-DPAT upon EL and IF than FSL rats. The blunted response of FSL rats to the effects of +/-8-OH-DPAT may be due to lower densities of 5-HT1A receptors. PMID- 24345572 TI - A possible mechanism for the anxiolytic-like effect of gallic acid in the rat elevated plus maze. AB - This work was performed to characterize the possible mechanisms involved in the anxiolytic-like activity of gallic acid (GA) in the rat elevated plus maze (EPM) test. Male Wistar rats were acutely treated with a single dose of GA (10-500 mg/kg, i.p.) or diazepam and buspirone, 30 min prior to behavioral assessment in the EPM, open-field and rotarod tests. Treatment with GA markedly produced an increase in the time spent and entries in the open arms of EPM at doses of 30 and 300 mg/kg, respectively. These effects were comparable to those of the diazepam (1 mg/kg, i.p.) and buspirone (1 mg/kg, i.p.). Pretreatment with benzodiazepine antagonist flumazenil (3 mg/kg, i.p.) partially blocked the anxiolytic-like effect of GA. However, an increase in the time spent and entries in the open arms of EPM observed with GA treatment were significantly inhibited by the 5-HT1A receptor antagonist WAY-100635 (0.5 mg/kg, i.p.). In the open-field test, only GA at a dose of 500 mg/kg decreased locomotor activity in rats. Moreover, GA (10-300 mg/kg, i.p.) or diazepam and buspirone did not alter motor coordination in the rotarod test. These results indicate that GA is an effective anxiolytic agent at low doses, while at the highest dose it has sedative effect. Also this study suggests that the anxiolytic-like activity of GA is primarily mediated by the 5 HT1A but not benzodiazepine receptors. PMID- 24345573 TI - Silibinin pretreatment attenuates biochemical and behavioral changes induced by intrastriatal MPP+ injection in rats. AB - Silymarin commonly known for its hepatoprotective effect is reported to show protection against 6-hydroxydopamine-induced neurotoxicity. Silibinin forms the major active constituent of silymarin. Therefore, the neuroprotective effect of silibinin (50, 100 and 200 mg/kg) was evaluated in the unilaterally injected 1 methyl-4-phenylpyridinium (MPP(+))-induced dopaminergic neurotoxicity in male rats. A battery of tests such as elevated plus maze (EPM), narrow beam walk, open field, bar catalepsy, grip strength, and foot print analysis was performed to evaluate the behavioral symptoms of striatal dopaminergic toxicity. Furthermore, the mechanism of action of silibinin was investigated by evaluating the mitochondrial complex enzyme activities, mitochondrial integrity and oxidative status. Striatal caspase-3 and NFkappaB were expressed to evaluate the effect of silibinin on apoptosis and inflammation respectively. Silibinin (100 and 200 mg/kg) protected against MPP(+)-induced dopamine depletion in striatum. Silibinin reversed MPP(+)-induced decrease in transfer latency indicating memory consolidation in the EPM test. Silibinin (100 and 200 mg/kg) attenuated MPP(+) induced motor deficits, such as fine motor movements and gait. MPP(+)-induced mitochondrial dysfunction, loss of integrity and oxidative stress were attenuated by silibinin. Silibinin decreased striatal caspase-3 and NFkappaB expression indicating potential anti-apoptotic and anti-inflammatory effects respectively. Hence, silibinin exhibited neuroprotective effect in the MPP(+) induced striatal toxicity augmenting dopamine levels. The mechanism of action may be linked to maintenance of mitochondrial bioenergetics and integrity apart from anti apoptotic and anti-inflammatory activities. PMID- 24345574 TI - Development of protocol for screening the formulation components and the assessment of common quality problems of nano-structured lipid carriers. AB - The present study investigates the screening of the formulation components as well as evaluates the quality issues of the nanostructured lipid carriers (NLCs) for the anticancer agent, CPT-11. The stepwise screening of the components for the preparation of NLCs requires the selection of liquid lipid or oil, based on the relative solubility of CPT-11 in different oils. Maximum solubility of the CPT-11 was found in capmul MCM-C8 (81+/-0.5 mg/ml). Hence, it was selected as the liquid lipid for the development of NLCs. Solid lipids gelucire 39/1, glyceryl mono stearate (GSM) and compritol ATO 888 were observed to have good affinity for the drug on systematic screening of different solid lipids. However, gelucire 39/1 and GSM were found to have lower physical compatibility (miscibility) with capmul MCM C-8. Hence, compritol ATO 888 was selected as the solid lipid phase for the preparation of NLCs. Ratio of liquid lipid (oil) to solid lipid was optimized with the intention of maximizing the oil concentration (as oil was found to have higher solubility of drug) as well as producing a lipid mix with sufficient melting point to maintain solid state. The liquid-solid lipid mixture in the ratio up to 30:70 was observed to have sufficient melting point (52.48+/ 1.2 degrees C). Pluronic F-68 was selected as the main surfactant for the preparation of NLCs because of its good emulsification efficacy for the solid lipid liquid mix. The optimized formulation was also evaluated for the different quality issues. PXRD data revealed that the characteristic peaks of the compritol were present in the NLC samples and there was no appreciable polymorphic change when the formulation was stored for 6 months. Electron microscopic and DLS studies proved the absence of different colloidal species. Thermal analysis by DSC revealed that the lipid particles maintained sufficiently good melting point even after nanosizing. Absence of gelation on multiple syringing and resilience for the stress provided by autoclaving further established the quality of the developed NLCs. PMID- 24345575 TI - Ensuring the success of interprofessional teams: key lessons learned in memory clinics. AB - Primary care-based memory clinics are attracting increasing interest because they present an opportunity to improve dementia diagnosis and management. In Ontario, more than 30 primary care setting participated in a training program aimed at assisting participants to establish an independent memory clinic in their practice setting. This article outlines the key lessons learned in implementing these clinics, on the basis of a study that--used an interview methodology with memory clinic team members and--identified facilitating factors, challenges, and suggestions for sustainability. Of key importance was access to training that facilitates knowledge transfer and supports practice change, interprofessional collaboration, and ongoing infrastructure support. Suggestions for clinic implementation and ongoing capacity building were identified. Lessons learned are applicable to the implementation of other chronic-disease care models aimed at improving the primary care management of complex chronic conditions. PMID- 24345576 TI - The role of interchain disulfide bond in a recombinant human interleukin-17A variant. AB - Interleukin-17A (IL-17A) is the prototype of IL-17 family and has been implicated in the pathogenesis of a variety of autoimmune diseases. Therefore its structural and functional properties are of great medical interest. During our research on a recombinant human IL-17A (rhIL-17A) variant, four isoforms were obtained when it was refolded. While isoforms 1 and 2 represented non-covalent dimers, isoforms 3 and 4 were determined to be covalent dimers. All four isoforms were structurally similar by Circular Dichroism and fluorescence spectroscopy studies, but differential scanning calorimetry demonstrated thermal stability in the order of isoform 1=isoform 225%. The ROC curve analysis indicated that the BMI cut-off >=23 kg/m(2) was appropriate for detecting obesity relative to hypertension. It was observed that the prevalence of hypertension increased significantly with age (r = 0.226, p < 0.001). Adjusting for age, the subjects with BMI 23-24.99 kg/m(2) had about 3.2 times (95% CI: 1.61-6.27) greater risk of hypertension than those with BMI < 23 kg/m(2), and the risk for those with BMI >= 25 kg/m(2) was about 4.5 times (95% CI: 2.06-9.57). As for PBF, the risk of hypertension was about 2.6 times (95% CI: 1.38-4.80) for the subjects with PBF > 25% compared to those with PBF <= 25%. CONCLUSIONS: Our study validated the BMI cut-off point proposed by the WHO for Asia-Pacific populations for screening the individuals who are likely at risk of overweight. However, such data should be substantiated by independent risks of adverse health outcomes that need for public health intervention. PMID- 24345585 TI - Comparison of two self-directed weight loss interventions: Limited weekly support vs. no outside support. AB - SUMMARY: OBJECTIVE: The purpose of this study was to compare the efficacy of two home-based weight loss interventions that differ only in the amount of outside support provided. METHODS: This was a 12-week, randomized, controlled trial. One group received limited support (LWS, n = 35) via a single 10 min phone call each week while another group received no weekly support (NWS, n = 28). Both the LWS and NWS received pre-packaged meals (PM) and shakes. A third group served as control (CON, n = 30) and received no components of the intervention. Weight loss at 12 weeks was the primary outcome. Diet (PM, shake, and fruit/vegetable (F/V) intake) and physical activity (PA) were self-monitored, recorded daily and reported weekly. An exit survey was completed by participants in the intervention groups upon completion of the study. RESULTS: Weight loss and percent weight loss in the LWS, NWS, and CON groups were 7.7 +/- 4.4 kg (8.5 +/- 4.2%), 5.9 +/- 4.1 kg (6.0 +/- 4.2%), and 0.3 +/- 1.9 kg (0.4 +/- 1.2%), respectively. The decrease in body weight and percent weight loss was significantly greater in the LWS and NWS groups when compared to the CON group and the percent weight loss was significantly greater in the LWS when compared to both the NWS and CON groups. CONCLUSION: A home-based weight loss program utilizing PM and shakes results in clinically significant percent weight loss and the addition of a brief weekly call promotes additional percent weight loss. PMID- 24345586 TI - Population attributable risk (PAR) of overweight and obesity on chronic diseases: South Australian representative, cross-sectional data, 2004-2006. AB - SUMMARY: BACKGROUND: To determine the contribution of overweight and obesity to five chronic conditions using the population attributable risk (PAR) statistic. METHOD: Self-reported data were collected in Australia using a representative, ongoing monthly risk factor surveillance system using computer assisted telephone interviewing (CATI) for the period 2004-2006 (n = 15,261). The PAR, adjusted for various demographic and health-related risk factors, was used to determine the contribution of overweight and obesity to diabetes, asthma, cardiovascular disease (CVD), arthritis and osteoporosis for people aged 18 years and over. RESULTS: In total, 19.0% of South Australians aged 18 years and over were obese, and 36.0% were overweight. The PAR of overweight and obesity was highest among those with diabetes (17.3% and 28.4%). After adjusting for demographic and risk factors, overweight and obesity had a significantly high PAR for diabetes (11.3% and 23.1%), asthma (4.0% and 10.3%) and arthritis (6.7% and 8.1%). The unadjusted PAR of overweight and obesity for CVD was significant (10.8% and 11.7%) but was reduced when controlled for other factors. The PAR of overweight and obesity was significant for osteoporosis but the association was protective. CONCLUSIONS: The use of PAR contributes to the understanding of how overweight and obesity are related to various chronic conditions however the size of this association depends on the chronic disease and other socio-demographic and health-related risk factors that may or may not be modifiable. The information provides evidence of the association of overweight and obesity with chronic disease and the potential for reducing the burden of chronic disease by addressing the obesity epidemic. PMID- 24345587 TI - Licorice flavonoid oil reduces total body fat and visceral fat in overweight subjects: A randomized, double-blind, placebo-controlled study. AB - SUMMARY: OBJECTIVES: To evaluate effects of licorice flavonoid oil (LFO) on total body fat and visceral fat together with body weight, body mass index (BMI) and safety parameters in overweight subjects. METHODS: In this randomized, double blind, placebo-controlled study, moderately overweight participants (56 males, 28 females, BMI 24-30 kg/m(2)) were assigned to four groups receiving a daily dose of either 0 (placebo), 300, 600, or 900 mg of LFO. Total body fat mass was measured by dual-energy X-ray absorptiometry (DXA) and visceral fat area by abdominal computed tomography (CT) scan at baseline and after 8 weeks of LFO ingestion. Body weight, BMI, and blood samples were examined at baseline and after 4 and 8 weeks of LFO ingestion. RESULTS: Although caloric intake was similar in all four groups, total body fat mass decreased significantly in the three LFO groups after 8 weeks of ingestion. LFO (900 mg/day) resulted in significant decreases from baseline levels in visceral fat area, body weight, BMI, and LDL-cholesterol. No significant adverse effects were observed. PMID- 24345588 TI - The promise and pitfalls of community resilience. AB - An important shift in terminology has occurred in emergency preparedness, and the concept of community resilience has become ubiquitous. Although enhancing community resilience is broader than preparedness, and emphasizes a distinct set of activities and participants, the terms are often used interchangeably. The implications of this shift have not been fully explored. This commentary describes the potential promise and pitfalls of the concept of community resilience and recommends strategies to overcome its limitations. We believe that resilience has the power to dramatically change this field in immense, positive ways, but some important challenges such as confusion about definitions and lack of accountability must first be overcome. (Disaster Med Public Health Preparedness. 2013;7:603-606). PMID- 24345589 TI - Decreased global methylation in patients with bipolar disorder who respond to lithium. AB - Mitochondrial dysfunction, oxidative stress, and alterations in DNA methylation, are all associated with the pathophysiology of bipolar disorder (BD). We therefore studied the relationship between oxidative stress and DNA methylation in patients with BD with an excellent response to lithium treatment, their affected and unaffected relatives and healthy controls. Transformed lymphoblasts were cultured in the presence or absence of lithium chloride (0.75 mM). DNA and proteins were extracted from the cells to determine levels of 8-hydroxy-2 deoxyguanosine (8-OHdG), 5-methylcytosine (5-mc), mitochondrial complex I and glutathione peroxidase (GPx) activities. Methylation was decreased in BD subjects and their relatives compared to controls and remained so after lithium treatment in BD subjects but not in their relatives. 8-OHdG levels and complex I activity did not differ between groups before and after lithium treatment. Finally, relatives of patients showed increased GPx activity before and after lithium treatment, which negatively correlated with 5-mc levels. Changes in global methylation may be specific for BD and lithium may be involved in glutathione regulation. The present study supports the importance of DNA methylation to the pathophysiology of BD and the therapeutic potential of antioxidants in this illness. PMID- 24345590 TI - The effect of physical activity across the menstrual cycle on reproductive function. AB - PURPOSE: To evaluate the association between physical activity (PA) across the menstrual cycle and reproductive function. METHODS: The BioCycle Study (2005 2007) followed 259 healthy premenopausal women not using hormonal contraceptives for up to two menstrual cycles (N = 509 cycles). Serum leptin, estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, and testosterone were measured five to eight times per cycle. Linear mixed models were used to estimate the effect of past-week PA (measured four times during each cycle) on hormone levels. Past-week PA was categorized into tertiles based on metabolic equivalent of task hours per week (cut-points were 15.3 and 35.7). Risk ratios for sporadic anovulation were estimated using generalized linear models. Analyses adjusted for habitual PA (assessed at baseline), body mass index, race, age, and perceived stress. Linear mixed models used inverse probability weights to control for concurrent reproductive hormones and caloric intake. RESULTS: High past-week PA was inversely associated with leptin (-6.6%; 95% confidence interval, -10.6 to -2.5) and luteal phase progesterone (-22.1%; -36.2 to -4.7) as compared with low past-week PA. High past-week PA was not significantly associated with sporadic anovulation (adjusted risk ratio, 1.5; 0.6 to 3.4). CONCLUSIONS: High levels of PA were modestly associated with changes in select hormones but not sporadic anovulation among moderate to highly active premenopausal women. PMID- 24345591 TI - In vivo loads in the lumbar L3-4 disc during a weight lifting extension. AB - BACKGROUND: Knowledge of in vivo human lumbar loading is critical for understanding the lumbar function and for improving surgical treatments of lumbar pathology. Although numerous experimental measurements and computational simulations have been reported, non-invasive determination of in vivo spinal disc loads is still a challenge in biomedical engineering. The object of the study is to investigate the in vivo human lumbar disc loads using a subject-specific and kinematic driven finite element approach. METHODS: Three dimensional lumbar spine models of three living subjects were created using MR images. Finite element model of the L3-4 disc was built for each subject. The endplate kinematics of the L3-4 segment of each subject during a dynamic weight lifting extension was determined using a dual fluoroscopic imaging technique. The endplate kinematics was used as displacement boundary conditions to calculate the in-vivo disc forces and moments during the weight lifting activity. FINDINGS: During the weight lifting extension, the L3-4 disc experienced maximum shear load of about 230 N or 0.34 bodyweight at the flexion position and maximum compressive load of 1500 N or 2.28 bodyweight at the upright position. The disc experienced a primary flexion extension moment during the motion which reached a maximum of 4.2 Nm at upright position with stretched arms holding the weight. INTERPRETATION: This study provided quantitative data on in vivo disc loading that could help understand intrinsic biomechanics of the spine and improve surgical treatment of pathological discs using fusion or arthroplasty techniques. PMID- 24345592 TI - Risk of myocardial infarction and heart failure among metabolically healthy but obese individuals: HUNT (Nord-Trondelag Health Study), Norway. AB - OBJECTIVES: This study sought to investigate whether obesity in the absence of metabolic abnormalities might be a relatively benign condition in relation to acute myocardial infarction (AMI) and heart failure (HF). BACKGROUND: The results of previous studies are conflicting for AMI and largely unknown for HF, and the role of the duration of obesity has not been investigated. METHODS: In a population-based prospective cohort study, a total of 61,299 men and women free of cardiovascular disease were classified according to body mass index (BMI) and metabolic status at baseline. BMI also was measured 10 and 30 years before baseline for 27,196 participants. RESULTS: During 12 years of follow-up, 2,547 participants had a first AMI, and 1,201 participants had a first HF. Compared with being normal weight (BMI <25 kg/m(2)) and metabolically healthy, the multivariable-adjusted hazard ratio (HR) for AMI was 1.1 (95% confidence interval [CI]: 0.9 to 1.4) among obese (BMI >=30 kg/m(2)) and metabolically healthy participants and 2.0 (95% CI: 1.7 to 2.3) among obese and metabolically unhealthy participants. We found similar results for severe (BMI >=35 kg/m(2)), long lasting (>30 years), and abdominal obesity stratified for metabolic status. For HF, the HRs associated with obesity were 1.7 (95% CI: 1.3 to 2.3) and 1.7 (95% CI: 1.4 to 2.2) for metabolically healthy and unhealthy participants, respectively. Severe and long-lasting obesity were particularly harmful in relation to HF, regardless of metabolic status. CONCLUSIONS: In relation to AMI, obesity without metabolic abnormalities did not confer substantial excess risk, not even for severe or long-lasting obesity. For HF, even metabolically healthy obesity was associated with increased risk, particularly for long-lasting or severe obesity. PMID- 24345593 TI - Reply: catheter ablation to treat sustained ventricular tachycardia in patients with chagas cardiomyopathy and implantable cardioverter-defibrillator. PMID- 24345594 TI - Catheter ablation to treat sustained ventricular tachycardia in patients with chagas cardiomyopathy and implantable cardioverter-defibrillator. PMID- 24345595 TI - High-intensity signals in coronary plaques on noncontrast T1-weighted magnetic resonance imaging as a novel determinant of coronary events. AB - OBJECTIVES: The aim of this study was to determine whether coronary high intensity plaques (HIPs) visualized by noncontrast T1-weighted imaging can predict future coronary events. BACKGROUND: Coronary HIPs are associated with characteristics of vulnerable plaques, including positive remodeling, lower Hounsfield units, and ultrasound attenuation. However, it remains unclear whether the presence of HIPs is associated with increased risk for coronary events. METHODS: The signal intensity of coronary plaques was prospectively examined in 568 patients with suspected or known coronary artery disease (CAD) who underwent noncontrast T1-weighted imaging to determine the plaque-to-myocardium signal intensity ratio (PMR). RESULTS: During the follow-up period (median 55 months), coronary events were observed in 55 patients. Receiver-operating characteristic curve analysis identified a PMR of 1.4 as the optimal cutoff for predicting prognosis. Multivariate Cox regression analysis identified the presence of plaques with PMRs >=1.4 as the significant independent predictor of coronary events (hazard ratio: 3.96; 95% confidence interval: 1.92 to 8.17; p < 0.001) compared with the presence of CAD (hazard ratio: 3.56; 95% confidence interval: 1.76 to 7.20; p < 0.001) and other traditional risk factors. Among the 4 groups based on PMR cutoff and the presence of CAD, coronary event-free survival was lowest in the group with PMRs >=1.4 and CAD and highest in the group with PMRs <1.4 but no CAD. Importantly, the group with PMRs >=1.4 and no CAD had an intermediate rate of coronary events, similar to the group with PMRs <1.4 and CAD. CONCLUSIONS: HIPs identified in a noninvasive, quantitative manner are significantly associated with coronary events and may thus represent a novel predictive factor. PMID- 24345596 TI - Reply: a vision of future treatment in chagas heart disease. PMID- 24345597 TI - Disparate effects of metabolically healthy obesity in coronary heart disease and heart failure. PMID- 24345598 TI - Plaque trek: "to boldly go where no man has gone before". PMID- 24345599 TI - A vision of future treatment in chagas heart disease. PMID- 24345600 TI - Effects of habitat light conditions on the excitation quenching pathways in desiccating Haberlea rhodopensis leaves: an Intelligent FluoroSensor study. AB - Resurrection plants can survive dehydration to air-dry state, thus they are excellent models of understanding drought and dehydration tolerance mechanisms. Haberlea rhodopensis, a chlorophyll-retaining resurrection plant, can survive desiccation to relative water content below 10%. Leaves, detached from plants of sun and shade habitats, were moderately (~50%) dehydrated in darkness. During desiccation, chlorophyll a fluorescence was detected by the recently innovated wireless Intelligent FluoroSensor (IFS) chlorophyll fluorometer, working with three different detectors: a pulse-amplitude-modulated (PAM) broadband channel and two channels to measure non-modulated red and far-red fluorescence. No change in area-based chlorophyll content of leaves was observed. The maximal quantum efficiency of photosystem II decreased gradually in both shade and sun leaves. Shade leaves could not increase antennae-based quenching, thus inactivated photosystem II took part in quenching of excess irradiation. Sun leaves seemed to be pre-adapted to quench excess light as they established an intensive increase in antennae-based non-photochemical quenching parallel to desiccation. The higher far-red to red antennae-based quenching may sign light-harvesting complex reorganization. Thus, compared to PAM, IFS chlorophyll fluorometer has additional benefits including (i) parallel estimation of changes in the Chl content and (ii) prediction of underlying processes of excitation energy quenching. PMID- 24345601 TI - Effectiveness of a web-based physical activity intervention for adults with Type 2 diabetes-a randomised controlled trial. AB - OBJECTIVE: This study examined the effectiveness of a fully automated web-based programme to increase physical activity in adults with Type 2 diabetes. METHODS: Between May and July 2010, participants were randomly allocated into either a 12 week intervention (n=195) or a control (n=202) group. Participants were adults diagnosed with Type 2 diabetes, residing in Australia. Participants were assessed at baseline, 12 and 36weeks. The primary physical activity outcome was self reported minutes of total physical activity. Secondary physical activity outcomes included minutes spent walking, and engaged in moderate, and vigorous physical activity. Additional measures included website satisfaction and website usage. The intervention consisted of a 12-week web-based physical activity intervention developed based on the Theory of Planned Behavior and self-management framework. Data were analysed from 2011 to 2012. RESULTS: There was a significant group-by time interaction (X(2) (df=1)=6.37, p<.05) for total physical activity favouring the intervention group d=0.11, for those who completed the intervention, however this was not significant in the intention-to-treat analysis d=0.01. The intervention yielded high website satisfaction and usage. CONCLUSIONS: In general, there is some evidence for the effectiveness of web-based interventions for improving physical activity levels; however it is clear that maintaining improvements remains an issue. PMID- 24345603 TI - European transnational ecological deprivation index and participation in population-based breast cancer screening programmes in France. AB - BACKGROUND: We investigated factors explaining low breast cancer screening programme (BCSP) attendance taking into account a European transnational ecological Deprivation Index. PATIENTS AND METHODS: Data of 13,565 women aged 51 74years old invited to attend an organised mammography screening session between 2010 and 2011 in thirteen French departments were randomly selected. Information on the women's participation in BCSP, their individual characteristics and the characteristics of their area of residence were recorded and analysed in a multilevel model. RESULTS: Between 2010 and 2012, 7121 (52.5%) women of the studied population had their mammography examination after they received the invitation. Women living in the most deprived neighbourhood were less likely than those living in the most affluent neighbourhood to participate in BCSP (OR 95%CI=0.84[0.78-0.92]) as were those living in rural areas compared with those living in urban areas (OR 95%CI=0.87[0.80-0.95]). Being self-employed (p<0.0001) or living more than 15min away from an accredited screening centre (p=0.02) was also a barrier to participation in BCSP. CONCLUSION: Despite the classless delivery of BCSP, inequalities in uptake remain. To take advantage of prevention and to avoid exacerbating disparities in cancer mortality, BCSP should be adapted to women's personal and contextual characteristics. PMID- 24345604 TI - Application of pitch range evaluation subsequent to arytenoid adduction and thyroplasty. AB - OBJECTIVE: The purpose of this study was to figure out the application of pitch range (PR) evaluation subsequent to arytenoid adduction (AA) combined with type 1 thyroplasty (TP1) in unilateral vocal fold paralysis (UVFP). STUDY DESIGN: Retrospective review of clinical records. METHODS: Subjects were 50 patients with UVFP for whom PR and maximum phonation time (MPT) could be evaluated before and 1 year after AA + TP1. Subjects were divided into two groups based on preoperative PR (pre-PR) (group 1: <=1 semitone (ST); group 2: >=2 ST). Correlations among pre PR and post-PR, MPT, and age were assessed. We also evaluated PRs in subjects with PR deterioration and PRs by causative diseases. RESULTS: PR was significantly extended from a median of 17.0-22.0 ST in all subjects. Pre-PR was correlated with post-PR. Post-PR correlated with post-MPT in group 2 but not in group 1. There was no correlation between post-PR and age or causative diseases. The mean change in PR among subjects with PR deterioration (28.0%, 14/50) was 3.6 ST. Pre-PR and the improvement of post-PR were negatively correlated in group 2. CONCLUSION: PR evaluation can be useful for predicting post-PR. The effects of age and causative diseases were small compared with other factors, such as pre-PR width and surgical effects. The successful surgery may improve both PR and MPT. However, several cases showed obvious discrepancy of those postoperative improvements. It will be necessary to assess this discrepancy, particularly in subjects with postoperative voice insufficiency. PMID- 24345602 TI - Weight gain prevention in the school worksite setting: results of a multi-level cluster randomized trial. AB - OBJECTIVE: To describe the effectiveness, reach and implementation of a weight gain prevention intervention among public school employees. METHOD: A multi-level intervention was tested in a cluster randomized trial among 782 employees in 12 central Massachusetts public high schools from 2009 to 2012. The intervention targeted the nutrition and physical activity environment and policies, the social environment and individual knowledge, attitudes and skills. The intervention was compared to a materials only condition. The primary outcome measures were change in weight and body mass index (BMI) at 24-month follow-up. Implementation of physical environment, policy and social environment strategies at the school and interpersonal levels, and intervention participation at the individual level were assessed. RESULTS: At 24-month follow-up, there was a net change (difference of the difference) of -3.03 pounds (p=.04) and of -.48 BMI units (p=.05) between intervention and comparison conditions. The majority of intervention strategies were successfully implemented by all intervention schools, although establishing formal policies was challenging. Employee participation in programs targeting the physical and social environment was maintained over time. CONCLUSION: This study supports that a multi-level intervention integrated within the organizational culture can be successfully implemented and prevent weight gain in public high school employees. PMID- 24345605 TI - Falls risk and hospitalization among retired workers with occupational noise induced hearing loss. AB - This study sought to ascertain whether occupational noise-induced hearing loss (NIHL) increased the risk of falls requiring hospitalization among retired workers. The study population consisted of males (age >= 65) with an average occupational noise exposure of 30.6 years and whose mean bilateral hearing loss was 42.2 dB HL at 3, 4, and 6 kHz. Seventy-two retired workers admitted to hospitals after a fall were matched with 216 controls from the same industrial sectors. Conditional logistic regression models were used to estimate the risk (odds ratio; [OR]) of falls leading to hospitalization by NIHL categories. Results showed a relationship between severe NIHL (>= 52.5 dB HL) and the occurrence of a fall (OR: 1.97, CI95%: 1.001-3.876). Reducing falls among seniors fosters the maintenance of their autonomy. There is a definite need to acquire knowledge about harmful effects of occupational noise to support the prevention of NIHL and ensure healthier workplaces. PMID- 24345606 TI - Epidemiology in a changing world: implications for population-based research on mental disorders. AB - Introduction and objectives. Population-based research on mental disorders needs to keep pace with trends in general epidemiology. At present, this requirement is complicated by uncertainty within the parent discipline about its future development. The present study examines proposals for new directions in strategy and methods and considers their significance for psychiatric epidemiology. Method. Narrative review, cross-checked by search of English-language journals of epidemiology for new trends and developments reported in the years from 2000 onwards. Results. The proposals reviewed here are divided into three groups: 1. A new research paradigm of 'eco-epidemiology', which includes both individual risk factors and macro-environmental systems that mediate population levels of health and sickness. 2. Improved 'translation' of research findings - i.e. more rapid and effective implementation of epidemiological evidence into health policy and practice. 3. Adaptation of epidemiology to a globalised economy, with firmer regulation of funding and resources. Conclusions. Each of these proposals has implications for psychiatric epidemiology. Workers in this field, however, are still preoccupied by relatively specific problems of definition, measurement and classification, and so far the current debates in general epidemiology are scarcely reflected. The proposals outlined above call for: * a working model of eco-epidemiology as it relates to psychiatric disorders; * implementation strategies to encourage more active participation in epidemiological research by community health services and caregiver organisations; * international collaborative projects that offer practical benefits in training and service facilities for the countries taking part. PMID- 24345607 TI - PmPPAF is a pro-phenoloxidase activating factor involved in innate immunity response of the shrimp Penaeus monodon. AB - One of the major steps in the innate immune response of shrimp includes the activation of serine proteinases of the pro-phenoloxidase pathway by the prophenoloxidase activation enzyme (PPAF). In this study, the cDNA encoding a serine proteinase homologue (SPH) with prophenoloxidase activating activity of Penaeus monodon (PmPPAF) was cloned and characterized. PmPPAF cDNA consists of 1444 nucleotides encoding a protein with 394 amino acid residues. The estimated molecular weight of PmPPAF is 43.5 kDa with an isoelectric point of 5.19. PmPPAF consists of a signal peptide, a CLIP domain and a carboxyl-terminal trypsin-like serine protease domain. It is highly similar to the masquerade-like protein 2A (61% similarity) of the crayfish Pacifastacus leniusculus, other serine proteases (42.9-67% identity) of P. monodon, and the PPAF of the crab (61% similarity). Unlike other SPH of P. monodon, which express mainly in the hemocytes, PmPPAF transcripts were detected in the hemocytes, eyestalk, hypodermis, gill, swimming leg and brain. Similar to the crab PPAF, PmPPAF transcript level is high in shrimp at the premolt stages and PmPPAF expression is up-regulated in shrimp infected with white spot syndrome virus (WSSV). Gene silencing of PmPPAF decreased expression of a prophenoloxidase-like gene and injection of Anti-PmPPAF antibody causes a decrease in PO activity. Taken together, these results provided evidence that PmPPAF is a serine proteinase homologue, and is involved in the pro PO activation pathway of the shrimp innate immune system. PMID- 24345608 TI - A comparative study of selected disperse azo dye derivatives based on spectroscopic (FT-IR, NMR and UV-Vis) and nonlinear optical behaviors. AB - In the present work, a combined experimental and quantum chemical study on ground state equilibrium structure, spectroscopic and nonlinear optical properties of selected disperse azo dye molecules are reported. The vibrational transitions were identified based on the recorded FT-IR spectra in the range of 4000-400 cm( 1) for solid state, simulated IR spectra and total energy distribution (TED) of vibrational modes. The chemical shifts were determined from the results of observed (1)H and (13)C NMR spectra in chloroform and dimethylsulfoxide solution. The DFT/gauge-invariant atomic orbital (GIAO) methodology was applied to predict the magnetic properties. Electronic properties were carried out by UV-Vis spectroscopy and TD-DFT/CIS approach. The nonlinear optical (NLO) features were addressed theoretically. A detailed description of spectroscopic and NLO behaviors of studied disperse azo dyes was reported with the help of comparison of experimental measurements and theoretical calculations. PMID- 24345609 TI - Spectroscopic studies of the binding of Cu(II) complexes of oxicam NSAIDs to alternating G-C and homopolymeric G-C sequences. AB - Drugs belonging to the Non-steroidal anti-inflammatory (NSAID) group are not only used as anti-inflammatory, analgesic and anti-pyretic agents, but also show anti cancer effects. Complexing them with a bioactive metal like copper, show an enhancement in their anti-cancer effects compared to the bare drugs, whose exact mechanism of action is not yet fully understood. For the first time, it was shown by our group that Cu(II)-NSAIDs can directly bind to the DNA backbone. The ability of the copper complexes of NSAIDs namely meloxicam and piroxicam to bind to the DNA backbone could be a possible molecular mechanism behind their enhanced anticancer effects. Elucidating base sequence specific interaction of Cu(II) NSAIDs to the DNA will provide information on their possible binding sites in the genome sequence. In this work, we present how these complexes respond to differences in structure and hydration pattern of GC rich sequences. For this, binding studies of Cu(II) complexes of piroxicam [Cu(II)-(Px)2 (L)2] and meloxicam [Cu(II)-(Mx)2 (L)] with alternating GC (polydG-dC) and homopolymeric GC (polydG-polydC) sequences were carried out using a combination of spectroscopic techniques that include UV-Vis absorption, fluorescence and circular dichroism (CD) spectroscopy. The Cu(II)-NSAIDs show strong binding affinity to both polydG dC and polydG-polydC. The role reversal of Cu(II)-meloxicam from a strong binder of polydG-dC (Kb=11.5*10(3) M(-1)) to a weak binder of polydG-polydC (Kb=5.02*10(3) M(-1)), while Cu(II)-piroxicam changes from a strong binder of polydG-polydC (Kb=8.18*10(3) M(-1)) to a weak one of polydG-dC (Kb=2.18*10(3) M( 1)), point to the sensitivity of these complexes to changes in the backbone structures/hydration. Changes in the profiles of UV absorption band and CD difference spectra, upon complex binding to polynucleotides and the results of competitive binding assay using ethidium bromide (EtBr) fluorescence indicate different binding modes in each case. PMID- 24345610 TI - Racial and gender discrimination, early life factors, and chronic physical health conditions in midlife. AB - PURPOSE: Most studies of perceived discrimination have been cross-sectional and focused primarily on mental rather than physical health conditions. We examined the associations of perceived racial and gender discrimination reported in adulthood with early life factors and self-reported physician diagnosis of chronic physical health conditions. METHODS: We used data from a racially diverse birth cohort of U.S. women (n = 168; average age, 41 years) with prospectively collected early life data (e.g., parental socioeconomic factors) and adult reported data on perceived discrimination, physical health conditions, and relevant risk factors. We performed modified robust Poisson regression owing to the high prevalence of the outcomes. RESULTS: Fifty percent of participants reported racial and 39% reported gender discrimination. Early life factors did not have strong associations with perceived discrimination. In adjusted regression models, participants reporting at least three experiences of gender or racial discrimination had a 38% increased risk of having at least one physical health condition (relative risk, 1.38; 95% confidence interval, 1.01-1.87). Using standardized regression coefficients, the magnitude of the association of having physical health condition(s) was larger for perceived discrimination than for being overweight or obese. CONCLUSION: Our results suggest a substantial chronic disease burden associated with perceived discrimination, which may exceed the impact of established risk factors for poor physical health. PMID- 24345611 TI - Maternal serum AGEs levels in pregnancies associated with neural tube defects. AB - Advanced glycation end products (AGEs) plays an important role in diabetic embryopathy. AGE-mediated DNA damage could be a significant factor in the teratogenicity. The aim of the present study was to evaluate the association between the AGEs level and neural tube defects (NTDs) occurrence risk. Forty eight mothers with NTD-affected pregnancies and 50 normal mothers were selected in this study. Blood were collected from the mothers and were assayed for serum AGEs, malondiadehyde (MDA) and hemoglobin A1c (HbA1c). Data were analyzed by logistic regression method. The study indicated that there were significant but modest lower prevalence for cases mothers on age, BMI and glucose levels compared with controls. NTD-affected mothers were significantly more likely to have higher AGEs levels (5.6+/-0.48 AU vs. 4.6+/-0.68 AU rho<0.01) than controls. The AGEs levels were not correlated with MDA and HbA1c in NTDs mothers (r(2)=0.0006 p=0.8691 and r(2)=0.001 p=0.8172, respectively). The conclusion is that AGEs might be associated with NTDs occurrence. PMID- 24345613 TI - Assessing the relationships between nurse work hours/overtime and nurse and patient outcomes: systematic literature review. AB - BACKGROUND: The effects of work hours/overtime on nurse and patient outcomes and specific components of work hours (per shift and per week) and overtime on these effects have not been systematically examined. PURPOSE: The purpose of this review was to systematically evaluate the effect of nurse overtime and long work hours on nurse and patient outcomes. METHODS: An online search of six electronic bibliographic databases was conducted for research published from 2000 to 2013. DISCUSSION: Twenty-one nurse outcome measures and 19 patient outcome measures were found in relationships with work hours and overtime. A total of 67 relationships to nurse outcomes and 41 relationships to patient outcomes were examined. CONCLUSIONS: The findings of this review suggested that evidence supporting positive relationships between working long hours and adverse outcomes to the nurses is strong. However, to make a conclusion of the positive relationship between long work hours and adverse patient outcomes, more evidence is needed. PMID- 24345612 TI - Chromatin regulators of genomic imprinting. AB - Genomic imprinting is an epigenetic phenomenon in which genes are expressed monoallelically in a parent-of-origin-specific manner. Each chromosome is imprinted with its parental identity. Here we will discuss the nature of this imprinting mark. DNA methylation has a well-established central role in imprinting, and the details of DNA methylation dynamics and the mechanisms that target it to imprinted loci are areas of active investigation. However, there is increasing evidence that DNA methylation is not solely responsible for imprinted expression. At the same time, there is growing appreciation for the contributions of post-translational histone modifications to the regulation of imprinting. The integration of our understanding of these two mechanisms is an important goal for the future of the imprinting field. This article is part of a Special Issue entitled: Chromatin and epigenetic regulation of animal development. PMID- 24345614 TI - Immigration policy and internationally educated nurses in the United States: A brief history. AB - Since the 1980s, U.S. policy makers have used immigration policy to influence the supply of nurses by allowing or restricting the entry of internationally educated nurses (IENs) into the U.S. workforce. The methods pursued have shifted over time from temporary visa categories in the 1980s and 1990s to permanent immigrant visas in the 2000s. The impact of policy measures adopted during nursing shortages has often been blunted by political and economic events, but the number and representation of IENs in the U.S. nursing workforce has increased substantially since the 1980s. Even as the United States seeks to increase domestic production of nurses, it remains a desirable destination for IENs and a target market for nurse-producing source countries. Hiring organizations and nurse leaders play a critical role in ensuring that the hiring and integration of IENs into U.S. health care organizations is constructive for nurses, source countries, and the U.S. health care system. PMID- 24345616 TI - Waiting and watching: Nurse migration trends before a change to the National Council Licensure Examination as entry to practice for Canada's nurses. AB - BACKGROUND: A number of factors in the health care environment, including a change in regulatory policy, may affect a country's nursing workforce and nurse migration and mobility. PURPOSE: This study compared the characteristics of Canadian-educated nurses who had migrated to the United States to work with their colleagues in the United States and Canada in anticipation of a change in Canada's RN entry to practice requirements in 2015. METHODS: We conducted a retrospective comparative study of nurses in Canada and the U.S. using 2008 data from the US National Sample Survey of Registered Nurses and the Canadian Institute of Health Information. DISCUSSION: There was little change in the number of Canadian-educated nurses working in the United States in 2008 compared with 2004. We found differences between U.S. nurses and Canadian-educated nurses working in the United States in educational level, work status, work location, and age. No differences were found between Canadian-educated nurses working in the United States and those working in Canada. CONCLUSIONS: This research highlights the value of international comparisons of the nursing workforce, especially in the context of anticipated regulatory changes, which may affect a country's nursing health human resources. PMID- 24345615 TI - Managing large-volume literature searches in research synthesis studies. AB - BACKGROUND: Systematic reviews typically require searching for, retrieving, and screening a large volume of literature, yet little guidance is available on how to manage this volume. PURPOSE: We detail methods used to search for and manage the yield of relevant citations for a mixed-methods, mixed research synthesis study focused on the intersection between family life and childhood chronic physical conditions. METHODS: We designed inclusive search strings and searched nine bibliographic databases to identify relevant research regardless of methodological origin. We customized searches to individual databases, developed work-arounds for transferring large volumes of citations and eliminating duplicate citations using reference management software, and used this software as a portal to select citations for inclusion or exclusion. We identified 67,555 citations, retrieved and screened 3,617 reports, and selected 800 reports for inclusion. DISCUSSION/CONCLUSIONS: Systematic reviews require search procedures to allow consistent and comprehensive approaches and the ability to work around technical obstacles. PMID- 24345618 TI - Think globally, act locally. PMID- 24345617 TI - The association of Chinese hospital work environment with nurse burnout, job satisfaction, and intention to leave. AB - The purpose of this study was to describe nurse burnout, job satisfaction, and intention to leave and to explore the relationship of work environment to nursing outcomes in a sample of 9,698 nurses from 181 hospitals in China. Nurses reported moderate levels of emotional exhaustion and depersonalization and high levels of reduced personal accomplishment. Nearly one-fifth of the nurses reported high levels of burnout on all three dimensions. Forty-five percent of the nurses were dissatisfied with their current job; these nurses were most dissatisfied with their salary. Five percent of nurses reported an intention to leave. Nurses reporting mixed and good work environments were less likely to report high burnout, job dissatisfaction, and intention to leave compared with those in poor work environments. The results suggest that high burnout and low job satisfaction are prominent problems for Chinese nurses, and improving work environment might be an effective strategy for better nursing outcomes in Chinese hospitals. PMID- 24345619 TI - The role of internationally educated nurses in a quality, safe workforce. AB - Migration and globalization of the nursing workforce affect source countries and destination countries. Policies and regulations governing the movement of nurses from one country to another safeguard the public by ensuring educational comparability and competence. The global movement of nurses and other health care workers calls for quality and safety competencies that meet standards such as those defined by the Institute of Medicine. This article examines nurse migration and employment of internationally educated nurses (IENs) in the context of supporting and maintaining safe, quality patient care environments. Migration to the United States is featured as an exemplar to consider the following key factors: the impact of nurse migration on the nursing workforce; issues in determining educational comparability of nursing programs between countries; quality and safety concerns in transitioning IENs into the workforce; and strategies for helping IENs transition as safe, qualified members of the nursing workforce in the destination country. PMID- 24345620 TI - Estimation of whole-body skeletal muscle mass by bioelectrical impedance analysis in the standing position. PMID- 24345621 TI - Insulin resistance, as expressed by HOMA-R, is strongly determined by waist circumference or body mass index among Japanese working men. AB - SUMMARY: OBJECTIVE: This study was intended to identify significant determinant factors of insulin resistance. METHODS: Insulin resistance was assessed using the homeostasis model assessment for insulin resistance (HOMA-R) and was calculated as "Fasting plasma glucose * Fasting serum insulin)/405". The target subjects were 3008 working men. The serum lipid profiles, uric acid level, insulin level, plasma glucose level, hemoglobin A1C level, and blood pressure, in addition to the waist circumference or body mass index, were also measured. A stepwise multiple regression analysis was performed using log-transformed values of HOMA-R as the dependent variable. RESULTS: The standardized regression coefficient for waist circumference was about six times larger than that for hemoglobin A1c (0.45 and 0.08, respectively). The standardized regression coefficients for the other factors were 0.15 for diastolic blood pressure, 0.10 for the low-density lipoprotein cholesterol level, -0.06 for age, -0.04 for habitual exercise, 0.14 for no habitual drinking, and 0.07 for no smoking. When body mass index was substituted for waist circumference, almost the same results were obtained. The adverse effects of no smoking and no habitual drinking on the HOMA-R score might be explained, at least in part, by the relation of these factors with obesity. Regular exercise had a protective effect on lowering insulin resistance. CONCLUSIONS: A close relation exists between obesity-related indices (waist circumference and body mass index) and insulin resistance, independent of age and other vascular risk factors in Japanese working men. PMID- 24345622 TI - Gender and age differences in the impact of overweight on obesity-related quality of life among Korean adults. AB - SUMMARY: OBJECTIVE: To investigate gender and age difference in impact of overweight on health-related quality of life (HRQOL) among Korean adults. METHODS: Cross-sectional obesity-related quality of life (QOL) scores were measured by a Korean obesity-related QOL scale (KOQOL) from 448 Korean adults aged 20-80 years. A body mass index (BMI) was categorized with normal-weight as BMI < 23 kg/m(2), overweight as BMI >= 23 kg/m(2) based on the alternative cutoff points for Asians. Each gender was respectively stratified by median age, 45 years for men and 50 years for women, to examine the obesity-related QOL by age groups. RESULTS: Women had a poorer obesity-related QOL compared to men (p < 0.001). In the younger age group, overweight women had a poorer obesity-related QOL compared with normal-weight women (p < 0.001), however normal-weight and overweight men showed no difference in obesity-related QOL. In the older age group, overweight men showed better QOL on the domains of work-related and psychosocial health than those for normal-weight men, but overweight women still suffered from work-related and routine life QOL. CONCLUSIONS: This study showed the impact of overweight on obesity-related QOL was different for gender and age group. We should consider the results to manage weight in overweight persons. PMID- 24345623 TI - Comparison of body mass index with abdominal obesity indicators and waist-to stature ratio for prediction of type 2 diabetes: The Isfahan diabetes prevention study. AB - SUMMARY: OBJECTIVES: The aim of this study was to compare the ability of the body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-stature ratio (WSR) to predict progression to diabetes in non-diabetic first-degree relatives (FDRs) of patients with type 2 diabetes. METHODS: A total of 704 non-diabetics FDRs 20-70 years old in 2003-2005 were followed through 2008 for the occurrence of type 2 diabetes mellitus. At baseline and through follow ups, participants were underwent a standard 75 g 2-h oral glucose tolerance test. Prediction of progression to type 2 diabetes was assessed with area under the receiver operating characteristic (ROC) curves based upon measurement of BMI, WC, WHR and WSR. RESULTS: The incidence of type 2 diabetes was 3.3% per year in men and 4.8% in women. BMI, WC and WSR were related to diabetes. These three obesity indicators have similar associations with incident diabetes. Areas under the ROC curves were 0.625 for BMI, 0.620 for WC, 0.611 for WSR and 0.538 for WHR. CONCLUSIONS: These data indicate that BMI was as strong as WC or WSR in predicting progression to diabetes. PMID- 24345624 TI - Barriers to increasing physical activity and limiting small screen recreation among obese children. AB - SUMMARY: OBJECTIVE: To investigate the barriers to increasing physical activity and limiting small screen recreation time among obese children. DESIGN: Qualitative study using a case study design incorporating focus groups and interviews with parents and pair interviews with children. PARTICIPANTS: Nine obese children (age range 5-12 years) and their parents. METHODS: Parents participated in focus groups followed by individual interviews to explain their perceptions of the barriers their child faced in spending more time participating in physical activity and less time in small screen recreation. Children took part in pair interviews to identify their barriers. Parents and children also discussed strategies to promote physical activity and limit small screen recreation time. RESULTS: A wide range of barriers were identified. These included family dynamics, lack of social support, the physical environment and perceived competence. Parents were unable to identify strategies to overcome these barriers. CONCLUSION AND IMPLICATIONS: Among obese children and their parents, there are an array of barriers to increasing physical activity and limiting small screen recreation. Parents believe that they know what they have to do to overcome many of these barriers but they are unaware of the actions they need to take. PMID- 24345625 TI - Factors affecting carotid intima media thickness predicts early atherosclerosis in overweight and obese adolescents. AB - SUMMARY: OBJECTIVE: Aims of this study were to compare serum leptin levels, atherosclerotic markers and carotid intima media thickness (IMT) among the overweight, obese and normal weight healthy adolescents and to investigate the association of carotid IMT with leptin and atherosclerotic markers in adolescence. METHODS: Seventy obese-overweight adolescents (27 of them obese, 43 of them overweight) and 72 two normal weight adolescents aged 14-18 years were included in this study. Leptin and homocysteine levels and lipid profiles were determined and carotid IMT were measured in all adolescents. Subjects were evaluated as obese-overweight and normal weight and obese, overweight and normal weight. RESULTS: Carotid IMT was significantly different among the overweight adolescents, obese adolescents and the control group (p < 0.001). Leptin levels were significantly higher in obese-overweight adolescents compared to the control group (p < 0.001). Apolipoprotein (Apo) B levels were significantly higher in obese adolescents than the overweight ones and the control group (p < 0.016). There were significantly positive correlations of carotid IMT with leptin, homocysteine and Apo B levels (p < 0.05, r = 0.33, 0.28, 021, respectively). The factors associated with carotid IMT were leptin and ApoB levels (beta = 0.632, p < 0.04, beta = 0.264, p = 0.019, respectively). CONCLUSION: Subclinical atherosclerosis determined by carotid IMT begins in overweight adolescents. Elevated leptin and Apo B levels are independent predictors of subclinical atherosclerosis. Leptin resistance, which is related to subclinical atherosclerosis, also begins in overweight adolescents. High Apo B levels, which promote development of atherosclerosis are more prominent in obese adolescents than other groups. For these reasons, all necessary precautions should be taken in overweight adolescents to prevent atherosclerosis as well as in obese adolescents. PMID- 24345626 TI - Endothelial function in young women with polycystic ovary syndrome (PCOS): Implications of body mass index (BMI) and insulin resistance. AB - SUMMARY: BACKGROUND: Evidence regarding endothelial function in both obese and nonobese women with PCOS is contradictory. It is unknown whether obese women with PCOS carry an increased risk related to body mass index (BMI). AIM: To identify endothelial function and investigate its relationship to body mass index and insulin resistance in young women with PCOS. SUBJECTS AND METHODS: Twenty-two obese women with PCOS (BMI 35.2 +/- 3.2) as well as fourteen lean women (BMI 22.8 +/- 2.1)with PCOS were included in the study. Fasting serum insulin, blood glucose were estimated and HOMA and Quicki index were calculated. All patients were subjected to ultrasound recording of brachial artery diameter at rest and after reactive hyperemia (FMD) for assessment of endothelial function. Ten age matched healthy females with normal BMI were chosen as a control group. RESULTS: There were higher basal insulin levels with lower Quicki index and higher HOMA index in women with PCOS than normal group, but the differences were significant only between obese PCOS subgroup and control. On the other hand, FMD was significantly and equally decreased in both groups of women with PCOS, compared with control subjects (3.7 +/- 3.2% in the nonobese subgroup and 3.5 +/- 2.8% in the obese one vs. 10.6 +/- 4.1% in control subjects, P, 0.001). FMD was not correlated with BMI nor insulin resistance indices. CONCLUSIONS: Endothelial dysfunction is already present in young women with PCOS. In this patient group, it cannot be attributed to insulin resistance or obesity. PMID- 24345627 TI - Gene expression modulation of rat liver cholesterol metabolism by oleoyl-estrone. AB - SUMMARY: OBJECTIVE: Since oleoyl-estrone (OE) decreases circulating cholesterol in the rat, we analyzed the response to OE treatment of hepatic gene expressions related with cholesterol metabolism. METHODS: Male overweight rats treated with oral OE (10 nmol/g daily) were compared with a pair-fed (PF) group and controls fed ad libitum. Serum parameters and liver lipid and cholesterol contents were measured. Total tissue RNA was used for real-time PCR analysis of the gene expression of enzymes and regulatory factors of liver cholesterol metabolism. Cholesterol-7alpha-hydroxylase and ABC transporter A1 protein levels were estimated by Western blot. RESULTS: Pair-feeding and OE treatment reduced the expression of 3-hydroxy-3-methyl-glutaryl-CoA synthase. OE increased the expression of the LDL receptor. Cholesterol disposal, through bile acids synthesis, was increased in PF and more markedly in OE rats. Gene expressions of the ABC transporter A1 and apolipoproteins A1 and E were increased in OE rats. The expression of liver X receptor was lower in PF than in OE and controls. CONCLUSION: The rapid disappearance of circulating cholesterol elicited by OE is consequence of: (1) decreased mevalonate pathway activity, (2) a higher expression of the LDL-receptor, and (3) the activation of the oxidation of cholesterol to form bile acids as a consequence of the higher cholesterol concentrations found in liver, also affected by energy availability. PMID- 24345628 TI - A telephonic coaching program has more impact when body mass index is over 35. AB - SUMMARY: PURPOSE: The purpose of this study was to test the theory that two indicators of risk (body mass index (BMI) and overall medical risk at baseline) are correlated with weight change in a telephone employer-provided coaching program. DESIGN: A retrospective cohort study with assessments at baseline and six months after program completion. SETTING: A large manufacturing employer in the United States. SUBJECTS: Adult employees and dependents enrolled in a voluntary weight loss program. INTERVENTION: The weight program was based on the Self-Management of Care model. Coaching was based on collaborative goal-setting and included telephonic self-management health education. Clients were staged according to readiness to change. MEASURES: Weight change (in kilograms), percent weight change, BMI, health risk indices, readiness to change, and demographic variables. ANALYSIS: Age, gender, race, education, income, total health risk, readiness to change, and baseline body mass index (BMI) were included as model covariates in a multiple linear regression analysis. RESULTS: Individuals with a BMI >35 at baseline lost more weight than those with normal weight (p = 0.001). Total health risk at baseline was not significantly related to weight loss at p < 0.05. CONCLUSION: Our findings suggest that the greatest weight loss could be achieved in this telephone coaching program by targeting morbidly obese employees. PMID- 24345629 TI - Alanine aminotransferase and gamma-glutamyltransferase as markers for elevated insulin resistance-associated metabolic abnormalities in obese Japanese men younger than 30 years of age. AB - SUMMARY: OBJECTIVE: This study aimed to understand whether liver function tests predict insulin resistance and its associated metabolic abnormalities in obese young men who are younger than 30 years of age. METHODS: In this cross-sectional study, we determined anthropometric and metabolic parameters and the homeostasis model assessment of insulin resistance (Homa-IR) in 208 obese young Japanese men (age, 18-29 years; BMI +/- SD, 31.3 +/- 3.1 kg/m(2)). RESULTS: After adjusting for age and BMI, alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) were significantly associated with Homa-IR. Both ALT and GGT but not fasting glucose levels had significant positive associations with total cholesterol, LDL, TG, and UA. After adjusting for ALT, GGT remained a significant predictor of total cholesterol, LDL, TG, and UA, but ALT did not remain a significant predictor of these variables after adjusting for GGT. CONCLUSION: ALT and GGT have significant associations with insulin resistance and its associated metabolic abnormalities in obese young Japanese men. ALT and GGT may be used as markers of insulin resistance-associated metabolic abnormalities in this cohort. PMID- 24345630 TI - Rao et al.'s "Which doctor for primary health care? Quality of care and non physician clinicians in India 84 (2013) 30-34". PMID- 24345631 TI - Acceleration time of systolic coronary flow velocity to diagnose coronary stenosis in patients with microvascular dysfunction. AB - BACKGROUND: The aim of this study was to test whether acceleration time of systolic coronary flow velocity could contribute to the diagnosis of coronary stenosis in patients with microvascular dysfunction, on the basis of the hypothesis that systolic coronary flow is less influenced by microvascular function because of compressed myocardium. METHODS: Coronary flow velocity was assessed in the left anterior descending coronary artery during hyperemia with intravenous adenosine by echocardiography in 502 patients who were scheduled for coronary angiography because of coronary artery disease and significant valvular disease. Coronary flow velocity reserve (CFVR) and the percentage acceleration time (%AT), as the percentage of the time from the beginning to the peak of systolic coronary flow over systolic time during hyperemia, were calculated. The diagnostic ability of CFVR and %AT for angiographic coronary artery stenosis was then analyzed. As invasive substudies, fractional flow reserve and %AT by a dual sensor (pressure and Doppler velocity) guidewire were measured simultaneously with %AT on transthoracic echocardiography (n = 14). RESULTS: Patients with coronary stenosis had significantly lower CFVR (1.7 +/- 0.4) and greater %AT (65 +/- 9%) compared with those without stenosis (2.6 +/- 0.6 and 50 +/- 13%, respectively). Percentage acceleration time by Doppler echocardiography was in good agreement with %AT (r = 0.98) and fractional flow reserve (r = 0.74) invasively measured by dual-sensor guidewire. Cutoff values of CFVR and %AT were determined as 2.0 and 60% in receiver operating characteristic curve analysis. The sensitivity, specificity, and accuracy of CFVR to detect coronary stenosis were 71.1%, 77.3%, and 75.4%, while those of %AT were 83.4%, 71.8%, and 75.4%, respectively. In addition, %AT provided high accuracy to detect coronary stenosis, especially in patients with previous myocardial infarctions, valvular disease, and left ventricular hypertrophy (81.1%, 84.1%, and 73.4%, respectively). CONCLUSIONS: The %AT of systolic coronary flow velocity is a promising marker to diagnose coronary stenosis in patients with microvascular dysfunction. PMID- 24345632 TI - Etiology and relevance of the figure-of-eight artifact on echocardiography after percutaneous left atrial appendage closure with the Amplatzer Cardiac Plug. AB - BACKGROUND: The Amplatzer Cardiac Plug (ACP) device, used for percutaneous left atrial appendage closure, frequently presents as an unexplained figure-of-eight on echocardiography. The aim of this study was to clarify the figure-of-eight display of the ACP device during echocardiography and to relate this finding to device position and function. METHODS: A mathematical model was developed to resemble device geometry and predict the echocardiographic appearance of the ACP device. In addition, an in vitro setup was used to validate the model. Finally, echocardiographic images of consecutive patients referred for percutaneous left atrial appendage closure (n = 24) were analyzed for the presence of a figure-of eight display. RESULTS: Because the ACP device resembles an epitrochoid curve, those points with tangent vector perpendicular to the ultrasound waves are emphasized, resulting in a figure-of-eight display, which can be replicated in vitro in the coronal imaging position. We found the figure-of-eight display in 100% (11 of 11) of three-dimensional periprocedural transesophageal images and in 87% (34 of 39) of postprocedural transthoracic echocardiographic images. CONCLUSIONS: The figure-of-eight display of the ACP device during echocardiography is the result of the specific epitrochoid geometry of the device mesh and its interaction with ultrasound waves. It is important to recognize the figure-of-eight as being a normal imaging artifact of a correctly deployed device in the coronal imaging position on both transesophageal and transthoracic echocardiography. In the future, this could be used during follow-up to aid clinical practitioners in assessing device position and function. PMID- 24345633 TI - Definition and significance of polycystic ovarian morphology: a task force report from the Androgen Excess and Polycystic Ovary Syndrome Society. AB - BACKGROUND The diagnosis of polycystic ovary syndrome (PCOS) relies on clinical, biological and morphological criteria. With the advent of ultrasonography, follicle excess has become the main aspect of polycystic ovarian morphology (PCOM). Since 2003, most investigators have used a threshold of 12 follicles (measuring 2-9 mm in diameter) per whole ovary, but that now seems obsolete. An increase in ovarian volume (OV) and/or area may also be considered accurate markers of PCOM, yet their utility compared with follicle excess remains unclear. METHODS Published peer-reviewed medical literature about PCOM was searched using PubMed.gov online facilities and was submitted to critical assessment by a panel of experts. Studies reporting antral follicle counts (AFC) or follicle number per ovary (FNPO) using transvaginal ultrasonography in healthy women of reproductive age were also included. Only studies that reported the mean or median AFC or FNPO of follicles measuring 2-9 mm, 2-10 mm or <10 mm in diameter, or visualized all follicles, were included. RESULTS Studies addressing women recruited from the general population and studies comparing control and PCOS populations with appropriate statistics were convergent towards setting the threshold for increased FNPO at >=25 follicles, in women aged 18-35 years. These studies suggested maintaining the threshold for increased OV at >=10 ml. Critical analysis of the literature showed that OV had less diagnostic potential for PCOM compared with FNPO. The review did not identify any additional diagnostic advantage for other ultrasound metrics such as specific measurements of ovarian stroma or blood flow. Even though serum concentrations of anti-Mullerian hormone (AMH) showed a diagnostic performance for PCOM that was equal to or better than that of FNPO in some series, the accuracy and reproducibility issues of currently available AMH assays preclude the establishment of a threshold value for its use as a surrogate marker of PCOM. PCOM does not associate with significant consequences for health in the absence of other symptoms of PCOS but, because of the use of inconsistent definitions of PCOM among studies, this question cannot be answered with absolute certainty. CONCLUSIONS The Task Force recommends using FNPO for the definition of PCOM setting the threshold at >=25, but only when using newer technology that affords maximal resolution of ovarian follicles (i.e. transducer frequency >=8 MHz). If such technology is not available, we recommend using OV rather than FNPO for the diagnosis of PCOM for routine daily practice but not for research studies that require the precise full characterization of patients. The Task Force recognizes the still unmet need for standardization of the follicle counting technique and the need for regularly updating the thresholds used to define follicle excess, particularly in diverse populations. Serum AMH concentration generated great expectations as a surrogate marker for the follicle excess of PCOM, but full standardization of AMH assays is needed before they can be routinely used for clinical practice and research. Finally, the finding of PCOM in ovulatory women not showing clinical or biochemical androgen excess may be inconsequential, even though some studies suggest that isolated PCOM may represent the milder end of the PCOS spectrum. PMID- 24345634 TI - Abnormal dynamic changes in beta-tubulin in somatic nuclear transfer cloned mouse embryos. AB - The efficiency of somatic cell nuclear transfer (SCNT) cloning remains low, thus limiting the applications of this technique. In this study, we used immunochemistry and confocal microscopy to detect the microtubule component, beta tubulin, in SCNT, parthenogenetic (PA), and intracytoplasmic sperm injection (ICSI) embryos before the first mitotic division. beta-Tubulin is the component subunit of microtubule, which plays critical roles in regulating localization of cellular organelles, and the growth, maturation and fertilization of oocytes. Our results demonstrated similar changes of spindle patterns in PA and ICSI embryos. The second meiotic division resumed 1 h post-treatment, and the cytoplasmic asters (CAs) disappeared. After about 4-6 h of treatment, pronuclei formed with the midbodies connecting each other. Meanwhile, the CAs reappeared and a microtubule network developed in the cytoplasm. However, SCNT embryos showed abnormal multipolar spindles, and the pseudopronuclei that contained many nucleoli existed after 6 h of SrCl2 activation. Enucleated oocytes alone did not form spindle-like structures when they were artificially activated for 6 h, indicating that somatic cell chromosomes might be necessary for spindle formation in SCNT embryos. These results demonstrated abnormal changes of beta-tubulin in mouse SCNT embryos, compared with PA and ICSI embryos. PMID- 24345635 TI - Assessment of strategies for male involvement in the prevention of mother-to child transmission of HIV services in Blantyre, Malawi. AB - BACKGROUND: Despite the documented benefits of prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) services, the uptake remains low in sub-Saharan Africa. The lack of male involvement (MI) may be one of the reasons for this. However, there are limited data on strategies for MI in PMTCT. OBJECTIVE: The objective of this study was to identify strategies that may promote MI in PMTCT services in antenatal care (ANC) services in Blantyre, Malawi. STUDY DESIGN: An exploratory qualitative study was conducted from December 2012 to January 2013 at South Lunzu Health Centre (SLHC) in Blantyre, Malawi. It consisted of six face-to-face key informant interviews (KIIs) with healthcare workers and four focus group discussions (FGDs) with 18 men and 17 pregnant women attending ANC at SLHC. The FGDs were divided according to sex and age. All FGDs and KIIs were digitally recorded and simultaneously transcribed and translated verbatim into English. Data were analyzed using thematic content analysis. RESULTS: Three major themes with several subcategories emerged. Theme 1 was a gatekeeping strategy with two subcategories: (1) healthcare workers refusing service provision to women accessing antenatal clinic without their partners and (2) women refusing ANC attention in the absence of a partner. Theme 2 comprised extending invitations and had six subcategories: (1) word of mouth, (2) card invites, (3) woman's health passport book invites, (4) telephonic invites, (5) use of influential people, and (6) home visits. Theme 3 was information education and communication, such as health education forums and advertisements. Of all the strategies, an invitation card addressed to the male partner was most preferred by study participants. CONCLUSIONS: There are several strategies by which men may be involved in PMTCT. Healthcare workers should offer a pregnant woman all strategies available for MI for her to select the appropriate one. Further research and consultations with men should continue to achieve higher levels of MI. PMID- 24345637 TI - Spatial memory: behavioral determinants of persistence in the watermaze delayed matching-to-place task. AB - The watermaze delayed matching-to-place (DMP) task was modified to include probe trials, to quantify search preference for the correct place. Using a zone analysis of search preference, a gradual decay of one-trial memory in rats was observed over 24 h with weak memory consistently detected at a retention interval of 6 h, but unreliably at 24 h. This forgetting function in the watermaze was similar to that found using a search-preference measure in a food-reinforced dry land DMP task in a previous study. In a search for strong and weak encoding conditions, essential for a later behavioral tagging study, three encoding trials gave strong 6-h and 24-h memory when trials were separated by 10 min (spaced training) but not 15 sec (massed training). The use of six encoding trials gave good 6-h memory with both spaced and massed training. With respect to weak encoding, placement on the escape platform, instead of the rat swimming to it, resulted in detectable memory at 30 min but this had faded to chance within 24 h. In contrast to the search-preference measure, latencies to cross the correct place revealed neither the gradual forgetting of place memory nor the benefit of spaced training. PMID- 24345636 TI - Negative affect impairs associative memory but not item memory. AB - The formation of associations between items and their context has been proposed to rely on mechanisms distinct from those supporting memory for a single item. Although emotional experiences can profoundly affect memory, our understanding of how it interacts with different aspects of memory remains unclear. We performed three experiments to examine the effects of emotion on memory for items and their associations. By presenting neutral and negative items with background contexts, Experiment 1 demonstrated that item memory was facilitated by emotional affect, whereas memory for an associated context was reduced. In Experiment 2, arousal was manipulated independently of the memoranda, by a threat of shock, whereby encoding trials occurred under conditions of threat or safety. Memory for context was equally impaired by the presence of negative affect, whether induced by threat of shock or a negative item, relative to retrieval of the context of a neutral item in safety. In Experiment 3, participants were presented with neutral and negative items as paired associates, including all combinations of neutral and negative items. The results showed both above effects: compared to a neutral item, memory for the associate of a negative item (a second item here, context in Experiments 1 and 2) is impaired, whereas retrieval of the item itself is enhanced. Our findings suggest that negative affect impairs associative memory while recognition of a negative item is enhanced. They support dual-processing models in which negative affect or stress impairs hippocampal-dependent associative memory while the storage of negative sensory/perceptual representations is spared or even strengthened. PMID- 24345638 TI - The sports concussion picture: fewer 'pixels', more HD. PMID- 24345639 TI - Psychiatric epidemiology: interactions with mainstream epidemiology as it undergoes transition. PMID- 24345641 TI - Farinose alpine Primula species: phytochemical and morphological investigations. AB - This work investigated the epicuticular and tissue flavonoids, the volatiles and the glandular trichome structure of the leaves of four species of Primula L. that grow in the Italian Eastern Alps. Primula albenensis Banfi and Ferlinghetti, P. auricula L., P. farinosa L., P. halleri Gmelin produce farinose exudates that are deposited on the leaf surface as filamentous crystalloids. In addition to compounds already known, a new flavone, the 3,5-dihydroxyflavone, was isolated from the acetone extract of leaf farinas and three new flavonol glycosides, 3'-O (beta-galactopyranosyl)-2'-hydroxyflavone, isorhamnetin 3-O-alpha-rhamnopyranosyl (1->3)-O-[alpha-rhamnopyranosyl-(1->6)]-O-beta-galactopyranoside, quercetin 3-O alpha-rhamnopyranosyl-(1->3)-O-[alpha-rhamnopyranosyl-(1->6)]-O-beta galactopyranoside, were isolated from the MeOH extract of the leaves. All the structures were elucidated on the basis of their (1)H and (13)C NMR data and 2D NMR techniques, as well as on HPLC-MS. The leaf-volatiles emitted by these Primula species were mainly sesquiterpene hydrocarbons, with the exception of P. albenensis, which produced almost exclusively a non-terpene derivative; P. halleri flowers were also examined and the volatiles emitted by the flower parts (corolla and calyx) were compared with the corresponding leaves. PMID- 24345642 TI - Neuronatin gene: Imprinted and misfolded: Studies in Lafora disease, diabetes and cancer may implicate NNAT-aggregates as a common downstream participant in neuronal loss. AB - Neuronatin (NNAT) is a ubiquitous and highly conserved mammalian gene involved in brain development. Its mRNA isoforms, chromosomal location, genomic DNA structure and regulation have been characterized. More recently there has been rapid progress in the understanding of its function in physiology and human disease. In particular there is fairly direct evidence implicating neuronatin in the causation of Lafora disease and diabetes. Neuronatin protein has a strong predisposition to misfold and form cellular aggregates that cause cell death by apoptosis. Aggregation of Neuronatin within cortical neurons and resulting cell death is the hallmark of Lafora disease, a progressive and fatal neurodegenerative disease. Under high glucose conditions simulating diabetes, neuronatin protein also accumulates and destroys pancreatic beta cells. The neuronatin gene is imprinted and only the paternal allele is normally expressed in the adult. However, changes in DNA methylation may cause the maternal allele to lose imprinting and trigger cell proliferation and metastasis. Neuronatin has also been shown to be translated peripherally within the dendrites of neurons, a finding of relevance in synaptic plasticity. The current understanding of the function of neuronatin raises the possibility that this gene may participate in the common downstream mechanisms associated with aberrant neuronal growth and death. A better understanding of these mechanisms may open new therapeutic targets to help modify the progression of devastating neurodegenerative conditions such as Alzheimer's and anterior horn cell disease. PMID- 24345643 TI - Prostaglandin D(2) induces apoptosis of human osteoclasts through ERK1/2 and Akt signaling pathways. AB - In a recent study we have shown that prostaglandin D2 (PGD2) induces human osteoclast (OC) apoptosis through the activation of the chemoattractant receptor homologous molecule expressed on T-helper type 2 cell (CRTH2) receptor and the intrinsic apoptotic pathway. However, the molecular mechanisms underlying this response remain elusive. The objective of this study is to investigate the intracellular signaling pathways mediating PGD2-induced OC apoptosis. OCs were generated by in vitro differentiation of human peripheral blood mononuclear cells (PBMCs), and then treated with or without the selective inhibitors of mitogen activated protein kinase-extracellular signal-regulated kinase (ERK) kinase, (MEK)-1/2, phosphatidylinositol3-kinase (PI3K) and NF-kappaB/IkappaB kinase-2 (IKK2) prior to the treatments of PGD2 as well as its agonists and antagonists. Fluorogenic substrate assay and immunoblotting were performed to determine the caspase-3 activity and key proteins involved in Akt, ERK1/2 and NF-kappaB signaling pathways. Treatments with both PGD2 and a CRTH2 agonist decreased ERK1/2 (Thr202/Tyr204) and Akt (Ser473) phosphorylation, whereas both treatments increased beta-arrestin-1 phosphorylation (Ser412) in the presence of naproxen, which was used to eliminate endogenous prostaglandin production. In the absence of naproxen, treatment with a CRTH2 antagonist increased both ERK1/2 and Akt phosphorylations, and reduced the phosphorylation of beta-arrestin-1. Treatment of OCs with a selective MEK-1/2 inhibitor increased caspase-3 activity and OC apoptosis induced by both PGD2 and a CRTH2 agonist. Moreover, a CRTH2 antagonist diminished the selective MEK-1/2 inhibitor-induced increase in caspase-3 activity in the presence of endogenous prostaglandins. In addition, treatment of OCs with a selective PI3K inhibitor decreased ERK1/2 (Thr202/Tyr204) phosphorylation caused by PGD2, whereas increased ERK1/2 (Thr202/Tyr204) phosphorylation by a CRTH2 antagonist was attenuated with a PI3K inhibitor treatment. The DP receptor was not implicated in any of the parameters evaluated. Treatment of OCs with PGD2 as well as its receptor agonists and antagonists did not alter the phosphorylation of RelA/p65 (Ser536). Moreover, the caspase-3 activity was not altered in OCs treated with a selective IKK2/NF-kappaB inhibitor. In conclusion, endogenous or exogenous PGD2 induces CRTH2-dependent apoptosis in human differentiated OCs; beta-arrestin-1, ERK1/2, and Akt, but not IKK2/NF-kappaB are probably implicated in the signaling pathways of this receptor in the model studied. PMID- 24345640 TI - Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer. AB - Epoxygenated fatty acids (EpFAs), which are lipid mediators produced by cytochrome P450 epoxygenases from polyunsaturated fatty acids, are important signaling molecules known to regulate various biological processes including inflammation, pain and angiogenesis. The EpFAs are further metabolized by soluble epoxide hydrolase (sEH) to form fatty acid diols which are usually less-active. Pharmacological inhibitors of sEH that stabilize endogenous EpFAs are being considered for human clinical uses. Here we review the biology of omega-3 and omega-6 EpFAs on inflammation, pain, angiogenesis and tumorigenesis. PMID- 24345645 TI - Effect of eslicarbazepine acetate in the corneal kindling progression and the amygdala kindling model of temporal lobe epilepsy. AB - OBJECTIVE: The present study was aimed at determining the effect of eslicarbazepine acetate (ESL), eslicarbazepine and (R)-licarbazepine administration in the mouse corneal kindling and amygdala kindling models. METHODS: NMRI mice were kindled by bilateral corneal stimulation twice daily. In amygdala kindling, mice were stimulated once daily via an implanted depth electrode until 10 generalized seizures were elicited. Maximal electroshocks (MES) were administered via corneal electrodes. RESULTS: The average number of stimulations to reach a fully kindled generalized seizure was markedly increased by ESL. Administration of eslicarbazepine also inhibited the acquisition of kindling, whereas administration of R-licarbazepine did not affect the number of stimulations necessary to induce a specific seizure stage, and did not exert any relevant effect on mean seizure severity during kindling progression. ESL dose dependently increased the focal seizure threshold and reduced seizure severity in amygdala kindling. Whereas eslicarbazepine treatment increased the afterdischarge threshold in a significant manner, (R)-licarbazepine treatment failed to exert a significant effect on thresholds in fully kindled mice. Administration of ESL and of eslicarbazepine significantly protected mice against MES-induced seizures, whereas that of (R)-licarbazepine failed to provide protection. CONCLUSIONS: These data provide evidence of the anticonvulsant effect of ESL and its active metabolite eslicarbazepine on partial-onset seizures in corneal and amygdala kindling models. Based on an effect of the parent compound and the active metabolite eslicarbazepine, ESL treatment may not merely suppress seizure activity but may also provide a disease-modifying or antiepileptogenic effect. Future studies will be necessary to further evaluate a putative preventive effect, in particular when considering that re-stimulation following wash-out did not indicate a persistent effect. The findings reported here raise doubts on the contribution of (R)-licarbazepine as an active anticonvulsant. PMID- 24345644 TI - COX-2 inhibition prevents the appearance of cutaneous squamous cell carcinomas accelerated by BRAF inhibitors. AB - Keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cuSCCs) develop in 15-30% of patients with BRAF(V600E) metastatic melanoma treated with BRAF inhibitors (BRAFi). These lesions resemble mouse skin tumors induced by the two stage DMBA/TPA skin carcinogenesis protocol; in this protocol BRAFi accelerates tumor induction. Since prior studies demonstrated cyclooxygenase 2 (COX-2) is necessary for DMBA/TPA tumor induction, we hypothesized that COX-2 inhibition might prevent BRAFi-accelerated skin tumors. Celecoxib, a COX-2 inhibitor, significantly delayed tumor acceleration by the BRAFi inhibitor PLX7420 and decreased tumor number by 90%. Tumor gene expression profiling demonstrated that celecoxib partially reversed the PLX4720-induced gene signature. In PDV cuSCC cells, vemurafenib (a clinically approved BRAFi) increased ERK phosphorylation and soft agar colony formation; both responses were greatly decreased by celecoxib. In clinical trials trametinib, a MEK inhibitor (MEKi) increases BRAFi therapy efficacy in BRAF(V600E) melanomas and reduces BRAFi-induced KA and cuSCC frequency. Trametinib also reduced vemurafenib-induced PDV soft agar colonies, but less efficiently than celecoxib. The trametinb/celecoxib combination was more effective than either inhibitor alone. In conclusion, celecoxib suppressed both BRAFi-accelerated skin tumors and soft-agar colonies, warranting its testing as a chemopreventive agent for non-melanoma skin lesions in patients treated with BRAFi alone or in combination with MEKi. PMID- 24345646 TI - Association of increased reactive oxygen species production with abdominal obesity in type 2 diabetes. AB - SUMMARY: OBJECTIVE: The close relationship between oxidative stress and abdominal obesity is well known, but the association is unclear in diabetic patients. The aim of this study was to confirm that increased reactive oxygen species (ROS) production is associated with abdominal obesity in diabetic patients. METHODS: ROS production was assayed in Epstein-Barr virus-transformed immortalized lymphoblasts by means of a cypridina luciferin analogue chemiluminescence method. We divided 96 Japanese male diabetic patients into 2 groups: patients with abdominal obesity according to the accepted Japanese criteria (waist circumference is more than 85 cm) (group AO, n = 36); and patients without abdominal obesity (group N, n = 60). Subjects with body mass index (BMI) in the normal range (21 <= BMI < 25 kg/m(2)) were then selected and assigned to 2 subgroups (group AOnormal-BMI [n = 13]; and group Nnormal-BMI [n = 35]); ROS production was compared between these 2 subgroups. RESULTS: Stimulation with arachidonic acid (AA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) increased ROS production in lymphoblasts, which was more greatly elevated in lymphoblasts derived from group AO than those from group N. Even in the subjects with normal BMI, AA- and TPA-stimulated ROS production in group AO was significantly higher than that in group N. CONCLUSIONS: These data suggest that increased ROS production is more closely associated with abdominal obesity than high BMI or insulin resistance in diabetic patients. PMID- 24345647 TI - Differential effects of rapid and slow body mass reduction on body composition during an equivalent weight loss in rats. AB - SUMMARY: It is unclear whether the rate of body mass (BM) reduction affects the body composition with an equivalent BM reduction and whether this is influenced by the intensity of BM reduction. To elucidate this, two experiments (Exp.) were conducted. In Exp. 1, the rats fasted for 3 days to decrease BM rapidly (R3); energy was restricted at 85% of their estimated basal metabolic rate to decrease BM slowly, until it reached the same BM as R3 (S20). In Exp. 2, the rats fasted for 7 days (R7); received a restricted diet as in Exp. 1 (S50). The BM decreased 11% in R3 and S20 showed a BM equivalent to R3 on Day 20. In Exp. 2, the BM decreased 18% in R7 and S50 reached the BM of R7 on Day 50. The mass and water and protein in the skeletal muscle and adipose tissue mass did not differ between the groups in both experiments. In contrast, the stomach mass was 12.9% lower in R3 than S20 (P < 0.05) and the liver mass was 9.9% lower in R3 (P = 0.078). In Exp. 2, the stomach and liver masses were 13.2% and 18.2% lower in R7 than S50 (P < 0.05), respectively. The differences in the rate of BM reduction were seen in splanchnic tissues than in skeletal muscles and adipose tissues regardless of BM intensity. The larger BM reduction appeared to be related to a greater difference in the liver mass between the rapid and slow BM reduction.: PMID- 24345648 TI - Heat shock treatment with mild electrical stimulation safely reduced inflammatory markers in healthy male subjects. AB - SUMMARY: OBJECTIVE: Obesity induces chronic inflammation, which contributes to the development and progression of insulin resistance, diabetes and atherosclerosis. We have recently shown that induction of heat shock protein 72 by mild electric current and thermo (MET) treatment in mouse model of type 2 diabetes ameliorated glucose homeostasis and insulin resistance accompanied by reduced adiposity. For clinical application of MET, we confirmed its safety in healthy subjects. METHODS: MET was applied for 10 healthy Japanese male (12 V, 55 pulses/s, 30 min at 42 degrees C) twice a week for 8 weeks. Fat volume was measured by CT scan and several parameters were investigated. RESULTS: MET did not induce any adverse effects nor muscle contraction/pain. There were no significant alterations in glucose homeostasis or insulin resistance. Visceral and subcutaneous fat volume showed a trend of decrease without significant difference (-3.9% and -4.3%, respectively), which were restored 8 weeks after withdrawal of MET. Interestingly, serum tumor necrosis factor-alpha (TNF-alpha: 0.91 +/- 0.05 pg/mL vs. 0.67 +/- 0.06 pg/mL; p = 0.006) and high sensitivity C reactive protein (hs-CRP: 521.9 +/- 73.9 ng/mL vs. 270.8 +/- 43.7 ng/mL; p = 0.023) levels, both of which are associated with chronic inflammation, were significantly decreased. CONCLUSION: MET may be beneficial for the reduction of an inflammatory response observed in diabetes and metabolic syndrome. PMID- 24345649 TI - Evaluation of whole-abdominal fat volume by 700-slice CT scanning and comparison with the umbilical fat area anthropometric indices. AB - SUMMARY: BACKGROUND: The fat area at the umbilical region on CT scans is widely used to identify visceral obesity. However, whether it precisely represents the abdominal visceral fat volume is uncertain, because of technical difficulty in evaluating whole-abdominal visceral fat volume. In this study, we compared the whole-abdominal visceral fat and subcutaneous fat volumes with the visceral fat area at the umbilical region and anthropometric indices. METHODS: The study population consisted of 131 Japanese diabetic and non-diabetic subjects (72 males and 59 females) who underwent anthropometric measurements (height, weight, waist circumference, and hip circumference) and CT scanning from the top of the liver to the pelvic floor (about 700 slices) to analyze the whole-abdominal and umbilical contents of visceral and subcutaneous fat. RESULTS: The visceral fat volume of the male group was 1.3-fold higher than that of the female group, while the subcutaneous fat volume of the female group was 1.3-fold higher than that of the male group. The visceral fat area at the umbilical region was strongly correlated with visceral fat volume (r = 0.921 in males and 0.931 in females). Both visceral and subcutaneous fat volumes were strongly correlated with the waist circumference (r = 0.768 and 0.809 in males and 0.744 and 0.803 in females), but not with the BMI or waist/hip ratio. CONCLUSION: The visceral fat area at the umbilical region is an optimal indicator for whole-abdominal visceral fat volume, and the waist circumference is the anthropometric index that reflects visceral obesity more closely than BMI or the waist/hip ratio. PMID- 24345650 TI - Temporal trends in overweight and obesity among Nicobarese adults in Nicobar Islands, India, 1960s-1999. AB - SUMMARY: OBJECTIVE: The aim of the present study is to assess the change in the prevalence of overweight and obesity among Nicobarese adults from 1960s to 1999 using WHO recommendations for the classification of overweight and obesity. METHODS: The sample includes 774 individuals (424 men and 350 women) during 1960s and 484 individuals (259 men and 225 women) during 1999, aged 20-64 years from Nicobar Islands, India. Height (cm), weight (kg) and sitting height (cm) were measured and BMI (kg/m(2)) was calculated. Overweight and obesity were defined as BMI >= 25 kg/m(2) and BMI >= 30 kg/m(2), respectively. RESULTS: There was significant increase of height, weight and BMI among both the men and women of 20 39, and 40 and above years age groups. However, the higher magnitude of increment was observed in 20-39 years. The prevalence of overweight increased from 5.42% to 22.01% among men and from 4% to 21.78% among women, while obese individual was absent during 1960s and the prevalence of obesity increased to 2.70% in men and 8.89% in women. The magnitude of increment was higher among women compared to men. CONCLUSION: The results indicate remarkable increase in the prevalence of both overweight and obesity among Nicobarese adult in Nicobar Islands. PMID- 24345651 TI - Relational analysis among fibrinogenic Bbeta-chain gene polymorphisms and its functional expression and obesity. AB - SUMMARY: Recently, there have been a few studies showing the association between obesity and fibrinogen (Fg) gene polymorphisms, but the reasons still do not clear completely. In this research, we studied the relationship among overweight, obesity and -854G/A, -455G/A, -249C/T, -148C/T, 448G/A, Bcl-1G/A gene polymorphisms of Fg beta-chain and its functional expression such as plasma Fg concentration and molecule conglomerate function. 1391 subjects of retired aged employees from Kailuan Group were enrolled with medical examination and questionnaire survey, and which were divided into normal weight group (597 cases), overweight group (609 cases), obese group (185 cases) based on body mass index (BMI). Plasma Fg concentration, fibrin monomer polymerized velocity (FMPV), absorbance maximum (Amax) and FMPV/Amax were measured in all subjects. The gene polymorphisms at six sites of Fg beta-chain were detected by polymerase chain reaction-restriction fragment length polymorphism. We found that only the frequencies of Bcl-1A allele and its mutated genotypes in overweight group were significantly higher than ones in normal weight group (P < 0.01). The loose linkage disequilibrium was evident between FgbetaBcl-1G/A and -455G/A, -148C/T polymorphisms. Fg concentration, FMPV, FMPV/Amax of subjects only with beta-854 mutated genotype were significantly higher those with wild genotype in three groups (P < 0.01), and FMPV/Amax of subjects with beta-455 mutated genotypes and FMPV of ones with beta-249 mutated genotypes were yet higher than those with wild genotype in overweight group (P < 0.05). In conclusion, the Fg beta-854 site is an important locus regulating plasma Fg concentration and conglomerate functional expression. Only the people with FgbetaBcl-1 mutated genotype is the genetic susceptible population of overweight with obvious stable phase. This overweight people can enhance plasma fibrinogenic molecular activity expression by activating mutated genotypes of Fgbeta-455 and -249. There are different genetic basis and genetic susceptible population between the overweight patients with obvious stable phase and the patients of progressive development to obesity without obvious overweight stable phase.: PMID- 24345652 TI - High general self-efficacy is associated with less weight loss under a supervised dietary modification program. AB - SUMMARY: Self-efficacy is an important prospective predictor for behavior modification. As for weight loss intervention, many studies have shown significant associations between situation-specific self-efficacy and weight loss. In this study, we investigated the association between general self efficacy and body weight change during a 14-week supervised dietary modification program. In total, 154 obese, middle-aged, Japanese women were selected as the subjects. The intervention program mainly comprised diet counseling. The diet counseling consisted of weekly lectures on weight loss practices and individual counseling by skilled dieticians. All subjects were instructed to choose and consume a well-balanced, 1200 kcal diet per day while also keeping a daily food diary in which they recorded in detail every food they ate during the intervention period. Body weight, waist circumference, and coronary heart disease risk factors were measured before and after the intervention. Energy intake and activity energy expenditure were assessed before and during the intervention. General self-efficacy was assessed with the General Self-Efficacy Scale (GSES) before the intervention. Body weight decreased significantly (-7.8 +/- 2.7 kg; 11.4 +/- 3.7%) following the intervention. The weight reduction was significantly greater for the low GSES group than for the other GSES groups. Self-efficacy regarding "degree of confidence in one's ability relative to others" especially influenced the association between the weight loss and the GSES score. Subjects' fat intake influenced the weight loss differences among GSES groups. In conclusion, inconsistent with previous studies, high general self-efficacy was associated with less weight loss under a supervised dietary modification program among middle-aged, Japanese women.: PMID- 24345653 TI - Telmisartan reduced abdominal circumference and body weight with decreasing triglyceride level in patients with type 2 diabetes and metabolic syndrome. AB - SUMMARY: Telmisartan has the dual ability to inhibit angiotensin II type 1 receptors and activate peroxisome proliferator-activated receptor gamma (PPAR), especially as a selective PPAR modulator that does not strongly promote adipogenesis for weight gain. Accordingly, Telmisartan is expected to provide beneficial effects for glucose and lipid metabolism without causing obesity. In the present study, we examined the effects of Telmisartan in patients with type 2 diabetes and metabolic syndrome. Thirty-two patients enrolled in this study were administered 40 mg per day of Telmisartan for 6 months. Telmisartan treatment significantly reduced systolic and diastolic blood pressure accompanied by induction of plasma renin activity (PRA) and reduction of serum aldosterone concentration and significantly decreased waist circumference, body mass index (BMI), and triglycerides (TG). In the 16 patients who did not take sulfonylurea, fasting plasma glucose (FPG) decreased and HbA1c significantly decreased from 3 months to 6 months. The results provide evidence that Telmisartan may improve glucose and lipid metabolism with the reduction in visceral fat mass in patients with type 2 diabetes and metabolic syndrome.: PMID- 24345654 TI - Gas gangrene of the thigh in a morbidly obese patient with occult colon cancer. AB - SUMMARY: We report a case of atraumatic gas gangrene and myonecrosis of the leg secondary to infection with Clostridium septicum in a severely obese patient with an occult cancer. She was treated successfully for both conditions. A review of the current literature describes this constellation of findings and the appropriate treatment.: PMID- 24345655 TI - Autosomal recessive hypercholesterolemia and bilio-pancreatic diversion: A case report. AB - SUMMARY: Familial hypercholesterolemia (FH) is typically an autosomal dominant disorder but a rare variant, autosomal recessive FH (ARH) does also exist. The most serious symptom is sudden death, myocardial infarction, or angina due to atherosclerotic coronary artery disease. Therefore, treatment of ARH is aimed to alter the course of disease before the onset of CAD. Multiple treatment options available varying from life style modification to organ replacement with favourable outcome. We report a case of autosomal recessive hypercholesterolemia (ARH) who was treated with bilio-pancreatic diversion (BPD) with satisfying results.: PMID- 24345656 TI - Raised IL-2 and TNF-alpha concentrations are associated with postoperative delirium in patients undergoing coronary-artery bypass graft surgery. AB - BACKGROUND: The knowledge base regarding the pathogenesis of postoperative delirium is limited. The primary aim of this study is to investigate whether increased levels of IL-2 and TNF-alpha are associated with delirium in patients who underwent coronary-artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB). The secondary aim is to establish whether any association between raised cytokine levels and delirium is related to surgical and anesthetic procedures or mediated by pre-existing conditions associated with raised cytokine levels, such as major depressive disorder (MDD), cognitive impairment, or aging. METHODS: Patients were examined and screened for MDD and cognitive impairment one day preoperatively, using the Mini International Neuropsychiatric Interview and The Montreal Cognitive Assessment and Trail Making Test Part B. Blood samples were collected postoperatively for cytokine levels. RESULTS: Postoperative delirium screening was found positive in 36% (41 of 113) of patients. A multivariate logistic regression revealed that an increased concentration of pro inflammatory cytokines is associated with delirium, and related to advancing age, preoperative cognitive decline of participants, and duration of CPB. According to receiver operating characteristic analysis, the most optimal cut-off for IL-2 and TNF-alpha concentrations in predicting the development of delirium were 907.5 U/ml and 10.95 pg/ml, respectively. CONCLUSIONS: The present study suggests that raised postoperative cytokine concentrations are associated with delirium after CABG surgery. Postoperative monitoring of pro-inflammatory markers combined with regular surveillance may be helpful in the early detection of postoperative delirium in this patient group. PMID- 24345657 TI - Has psychiatric epidemiology reached a critical juncture? PMID- 24345658 TI - Effect of body mass on hibernation strategies of woodchucks (Marmota monax). AB - The benefits of mammalian hibernation have been well documented. However, the physiological and ecological costs of torpor have been emphasized only recently as part of a hibernation-optimization hypothesis. This hypothesis predicts that hibernators with greater availability of energy minimize costs of torpor by less frequent utilization of torpor and by maintaining higher body temperatures (T(b)) during torpor. In order to further examine the relationship between body mass and other parameters of hibernation, we present data, collected over a 12-year period, on the hibernation patterns of free-living woodchucks (Marmota monax) in southeastern Pennsylvania. Body mass was positively correlated with T(b) and negatively correlated with percentage of the heterothermic period spent in torpor. Thus, woodchucks with greater mass exhibited less time in torpor as a proportion of their heterothermic period and at higher T(b) than those with lesser mass. This strategy potentially enhances the physiological and physical ability of woodchucks to defend territories, avoid predation, find mates, and complete the reproductive cycle upon emergence from hibernation. Our results further support the hibernation-optimization hypothesis by demonstrating the relationship between body mass and characteristics of torpor and contributing toward a fuller understanding of this concept. PMID- 24345659 TI - Association of smoking status, insulin resistance, body mass index, and metabolic syndrome in workers: A 1-year follow-up study. AB - SUMMARY: OBJECTIVE: We performed a 1-year follow-up study to determine the effects of smoking status and insulin resistance on the prevalence of metabolic syndrome. METHODS: This study included 2136 workers without metabolic syndrome at baseline who were followed for 1 year. The subjects were divided into four categories of smoking and work history, respectively. Insulin resistance was evaluated using the homeostasis model assessment for insulin resistance (HOMA-R). RESULTS: The prevalence of metabolic syndrome after 1 year was 6.3%. A multiple logistic regression analysis showed that the current smokers category versus the non-smokers category, a 0.1-point increase in the HOMA-R score, a 1-point increase in the uric acid level, age, and body mass index were significantly correlated with increased odds for metabolic syndrome, yielding odds ratios (95% confidence intervals) of 1.61 (1.09-2.39), 1.14 (1.04-1.25), 1.31 (1.12-1.54), and 1.06 (1.03-1.09), and 1.23 (1.15-1.31), respectively. CONCLUSIONS: Current smoking, insulin resistance, uric acid level, and age contributed positively to the prevalence of metabolic syndrome. In contrast, smoking cessation within 1 year and work history did not contribute to metabolic syndrome. PMID- 24345660 TI - Body mass index, waist circumference, and risk of coronary heart disease: A prospective study among men and women. AB - SUMMARY: OBJECTIVE: The purpose of the study was to assess the risk of CHD associated with excess weight measured by BMI and waist circumference (WC) in two large cohorts of men and women. DESIGN, SETTING, SUBJECTS: Participants in two prospective cohort studies, the Health Professionals Follow-up Study (N = 27,859 men; age range 39-75 years) and the Nurses' Health Study (N = 41,534 women; 39-65 years) underwent 16-year follow-up through 2004. RESULTS: 1823 incident cases of CHD among men and 1173 cases among women were documented. Compared to men with BMI 18.5-22.9 kg/m(2), those with a BMI > 30.0 kg/m(2) had a multivariate adjusted RR of CHD of 1.81 (95% CI 1.48-2.22). Among women, those with a BMI > 30.0 kg/m(2) had a RR of CHD of 2.16 (95% CI 1.81-2.58). Compared to men with a WC < 84.0 cm, those with WC of greater than 102.0 cm had a RR of 2.25 (95% CI 1.77-2.84). Among women, the RR of CHD was 2.75 (95% CI 2.20-3.45) for those with WC of greater than 88.0 cm. CONCLUSIONS: In these analyses from two large ongoing prospective cohort studies, both BMI and WC strongly predicted future risk of CHD. Furthermore, WC thresholds as low as 84.0 cm in men and 71.0 cm in women may be useful in identifying those at increased risk of developing CHD. The findings have broad implications in terms of CHD risk assessment in both clinical practice and epidemiologic studies. PMID- 24345661 TI - Growth curve analysis of BMI in relation to primary care utilization in prostate cancer survivors. AB - SUMMARY: Cancer survivors are advised to maintain a healthy BMI to optimize quality of life. In the VA healthcare system, multidisciplinary primary care clinics are responsible for screening and management of overweight or obesity, but it is unclear if cancer survivors are accessing or benefiting from these services. This study aimed to determine if primary care utilization was associated with changes in BMI of prostate cancer survivors, a group with very high rates of long-term survival. Data on demographics, comorbidities, cancer treatment, body size, and number of primary care encounters (medical, behavioral health, nutrition, and weight management program) were collected from electronic medical records and the local tumor registry for 406 early stage prostate cancer survivors who were overweight or obese at diagnosis. Growth curve modeling assessed BMI trajectories in relation to primary care utilization. Results indicated that survivors averaged 18 primary care encounters over the observation period but rarely accessed behavioral health, nutrition, or weight management program services. The average BMI trajectory was non-linear, showing an increase in BMI until 3.2 years after diagnosis followed by deceleration. Primary care utilization was inversely associated with BMI growth, (beta = -0.05, p < 0.01). This association was not impacted by demographic, cancer treatment, or comorbidities. Although primary medical care encounters were associated with modest reductions in BMI, overweight or obese prostate cancer survivors appear to be underutilizing the full range of primary care services that could address the motivational, informational, dietary, and physical activity barriers associated with weight loss.: PMID- 24345662 TI - Effects of short-term refeeding after rapid or slow body mass reduction on body composition in adult rats. AB - SUMMARY: We previously observed that digestive tract mass decreased more in rats experiencing rapid body mass (BM) reduction than in those undergoing slow BM reduction. To determine if BM reduction speed influences body composition after refeeding, rats were assigned to three groups. The control group (C) ate ad libitum, the slow group (S) received restricted food for 21 days to slowly reduce BM, and the rapid group (R) ate ad libitum for 18 days and fasted for the last 3 days to rapidly reach a BM comparable to that of S. Water was restricted for R on day 21. After the BM reduction, both R and S were re-fed ad libitum for 12 h and then were sacrificed with C 4-h later. The BM and masses of the carcass, adipose tissue, and small intestine in both R and S did not return to that of C during the 16-h recovery, although no differences were observed between R and S. The liver and stomach mass in both R and S recovered to that of C. The mass and water, protein, total lipid and glycogen content in the skeletal muscle did not differ between R and S. We concluded that body composition after short-term refeeding is not influenced by the speed of BM reduction.: PMID- 24345663 TI - Decreased SIRT1 expression and LKB1 phosphorylation occur with long-term high-fat diet feeding, in addition to AMPK phosphorylation impairment in the early phase. AB - SUMMARY: AIMS: Energy sensing systems including AMPK and SIRT1 play important roles in the regulation of hepatic gluconeogenesis and fatty acid oxidation. In this study, we investigated how hepatic LKB1-AMPK signaling and SIRT1 expression are altered after 2 or 8 weeks of HFD feeding. METHODS: The livers of male mice fed a HFD or a standard diet for 2 or 8 weeks were removed. The expression and phosphorylation levels of LKB1, AMPK, ACC and TORC2, and SIRT1 expression levels were examined by immunoblotting. RESULTS: In mice fed a HFD for 2 weeks, the phosphorylations of AMPKalpha and ACC were decreased without significant alterations in LKB1 phosphorylation or SIRT1 protein levels, while TORC2 protein levels were increased. In mice fed a HFD for 8 weeks, marked reductions in LKB1 phosphorylation and SIRT1 protein amount were observed in addition to the decreased phosphorylations of AMPKalpha and ACC. CONCLUSIONS: The mechanisms underlying impaired energy sensing signaling differ with the duration of HFD feeding. In the early phase of HFD feeding, LKB1 and SIRT1 were not impaired, while in the later phase of HFD feeding, decreased SIRT1 expression and LKB1 phosphorylation may be involved in the development of severe glucose and lipid intolerance. PMID- 24345664 TI - Evaluation of oxidative stress and total antioxidant capacity in women with general and abdominal adiposity. AB - SUMMARY: BACKGROUND: Previous studies have shown that general and abdominal adiposity are closely associated with risk of diabetes and cardiovascular disease events. We sought to evaluate the oxidative stress and plasma total antioxidant capacity (TAC) levels in women with general and abdominal adiposity. METHODS: In this study, 160 women 20-45 years old were randomly selected. General information data were gathered from each sample using questionnaires and face-to-face interviews. Venous blood samples were drawn from subjects and plasma was separated. In this study, oxidative stress levels were assessed by measuring the concentrations of plasma malondialdehyde (MDA). We also evaluated total antioxidant capacity (TAC) of plasma in subjects. RESULTS: Mean plasma concentration of MDA was significantly higher in overweight and obese women groups compared to healthy women group (2.62 +/- 0.81 vs. 1.96 +/- 0.72, p < 0.01 and 3.25 +/- 0.74 vs. 1.96 +/- 0.72, p < 0.001, respectively). Furthermore, plasma TAC levels were significantly lower in obese women compared to healthy women group (2.57 +/- 0.58 vs. 3.45 +/- 0.73, p < 0.01). No significant difference was observed between overweight and normal weight women in plasma TAC levels. In addition, women with central body fat distribution had higher MDA (3.28 +/- 0.78 vs. 2.23 +/- 0.52, p < 0.001) and lower TAC levels (p < 0.01) compared to normal body fat distribution (2.41 +/- 0.59 vs. 3.16 +/- 0.84, p < 0.01). We also observed that aforementioned relationships remained significant even after adjusting for several confounders. CONCLUSIONS: Our results provides further evidence suggesting that obesity and, especially, abdominal adiposity associated with elevated oxidative stress and decreased levels of TAC in plasma which in turn, may contribute to obesity related diseases such as atherosclerosis, diabetes mellitus and arterial hypertension. PMID- 24345665 TI - Metabolic syndrome predicts the incidence of hepatic steatosis in Koreans. AB - SUMMARY: PROBLEM: It has not been well elucidated whether the development of metabolic syndrome and its components predicts the incidence of hepatic steatosis. METHODS: A cohort of 1705 apparently healthy Korean adults (954 men and 751 women, 43.6 +/- 8.5 years old) without ultrasonographically defined hepatic steatosis and with normal serum gamma-glutamyl-transpeptidase and alanine aminotransferase was followed from 2004 to 2007. Metabolic syndrome was defined as the presence of at least three of the following components: obesity (BMI >= 25.0 kg/m(2)), high blood pressure, elevated levels of triglycerides and fasting glucose, and low level of high-density lipoprotein cholesterol. The outcome was ultrasonographically diagnosed hepatic steatosis. The analyses were conducted using the Cox proportional hazards model and time-dependent Cox model. RESULTS: A total of 226 individuals developed hepatic steatosis during 3716 person-years of follow-up. The presence of one to two metabolic syndrome components at baseline significantly predicted the development of hepatic steatosis. Metabolic syndrome itself, having >=1 metabolic syndrome components, and maintenance of metabolic syndrome during follow-up significantly increased the risk (hazard ratio 2.0-4.1 for men, 3.4-10.8 for women) after adjustment for the follow-up period, age and BMI at baseline or updated during follow-up. Occurrence of obesity, high triglycerides or high fasting glucose during follow-up significantly predicted the development of hepatic steatosis, even after adjustment for metabolic syndrome components at baseline. CONCLUSIONS: The presence at baseline and the development of metabolic syndrome during follow-up were risk factors for ultrasonographically detected hepatic steatosis. PMID- 24345666 TI - Comparison of methods used to predict energy requirements in a whole room calorimeter. AB - SUMMARY: BACKGROUND AND AIMS: Studies examining diet-induced thermogenesis and substrate oxidation in a whole room calorimeter (WRC) benefit from a state of energy balance in the measurement period. We found reports on four approaches to assessing energy needs in this context, and they vary considerably. This study assessed the utility of three simple alternatives for predicting energy requirements for calorimeter studies. METHODS: Energy expenditure (EE) data on 37 males and 104 females was obtained from the baseline measurements of three weight loss trials. The EE data was from 3-d RT3 accelerometer measurements in a free living environment, and 24-h WRC measurements. A linear regression model was developed from Study 1 and Study 2 (N = 97), using mean 3-d EE as the independent variable. Twenty-four hours WRC EE (N = 29) was compared with three prediction methods: (a) Schofield equation, (b) regression model, and (c) free-living EE * 85%. RESULTS: Energy expenditure measured by accelerometers was 2454.1 +/- 491.9 kcal/d in the free-living condition and 2022.7 +/- 295.8 kcal/d during the 24-h calorimeter stay (83.8% +/- 10.6% of free-living). Energy requirements in the whole room calorimeter was estimated as 0.405 * mean [3-d RT3 energy expenditure] + 1009.6 kcal/d (N = 97, R(2) = 0.479, P < 0.001). Predicted energy requirements were not significantly different from the WRC EE but the Schofield method produced the lowest mean bias and standard deviation. CONCLUSION: Schofield equations are an inexpensive and convenient alternative for predicting energy requirements in WRC studies. PMID- 24345667 TI - Effect of modest changes in BMI on cardiovascular disease risk markers in severely obese, minority adolescents. AB - SUMMARY: BACKGROUND: African American and Hispanic adolescents have disproportionately higher rates of obesity compared to white adolescents. In adults, modest weight loss of five percent improves CVD risk marker levels. Less is known about the effects of modest changes in BMI on CVD risk markers in adolescents, particularly newer markers such as C reactive protein (CRP), lipoprotein (a) and homocysteine. OBJECTIVE: To examine the effect of modest BMI change on CVD risk marker levels in a group of severely obese, African American and Hispanic adolescents. STUDY DESIGN: A six-month longitudinal analysis. SUBJECTS: Eighty-three African American and Hispanic adolescents were recruited (mean age +/- sd: 15.1 +/- 2.0 years); 50 (60%) were reevaluated at 6 +/- 2 months. RESULTS: At baseline, mean BMI was 42.3 +/- 7.8 kg/m(2). BMI directly correlated with CRP (p = < 0.001); homocysteine (p = 0.02); insulin (p = 0.05); and systolic and diastolic blood pressures (both p = <0.001). BMI remained significantly associated with CRP and insulin after adjusting for age, sex and ethnicity (p = 0.001). At six-month follow up, there was a significant p for trend between the three groups of BMI change (those with a >=5% BMI decrease, those who maintained BMI within 5% and those with >=5% BMI increase) and CRP (p = 0.05) and insulin (p = 0.04). CONCLUSIONS: A modest decrease in BMI is associated with improvement in CRP and insulin levels. Obese adolescents should be encouraged to continue with modest weight loss goals as they result in improvement in cardiovascular disease risk markers. PMID- 24345668 TI - The challenges of accurate waist and hip measurement over clothing: Pilot data. AB - SUMMARY: BACKGROUND: Accurate waist and hip measurement are increasingly central to the goal of weight control and the battle against diabetes and cardiovascular disease. Protocols and methods vary widely, with little guidance on clothing. This pilot study investigated the effect of light clothing on measurement. AIMS: To determine whether light clothing and underwear make a potentially clinically significant difference of 0.5 cm to the measurement of waist and hip circumference in a group of volunteer subjects. METHODS: We measured waist circumference over light clothing and then over bare skin. We measured hip circumference over light clothing and then over underwear and with a small sub group, on bare skin. RESULTS: 50 volunteers were measured. Potentially clinically significant differences were found in the mean values as followed (mean; 95% CI): light clothing compared to bare skin at the waist (0.50 cm; -1.54 to 2.55 cm); light clothing compared to underwear at the hip (2.58 cm; -0.75 to 5.91 cm). CONCLUSION: This study demonstrates that the effect of clothing on waist and hip measurements is not always trivial, and deserves a larger study. Waist circumference measurements should be made on bare skin whenever possible and hip circumference measurements over underwear. PMID- 24345669 TI - Obesity and swine flu: An observation. PMID- 24345670 TI - First case of T-cell/histiocyte-rich-large B-cell lymphoma presenting with duodenal obstruction. PMID- 24345672 TI - Sustainable agricultural use of natural water sources containing elevated radium activity. AB - Relatively elevated concentrations of naturally occurring radium isotopes ((226)Ra, (228)Ra and (224)Ra) are found in two main aquifers in the arid southern part of Israel, in activity concentrations frequently exceeding the limits set in the drinking water quality regulations. We aimed to explore the environmental implications of using water containing Ra for irrigation. Several crops (cucumbers, melons, radish, lettuce, alfalfa and wheat), grown in weighing lysimeters were irrigated at 3 levels of (226)Ra activity concentration: Low Radium Water (LRW)<0.04 Bq L(-1); High Radium Water (HRW) at 1.8 Bq L(-1) and (3) Radium Enriched Water (REW) at 50 times the concentration in HRW. The HYDRUS 1-D software package was used to simulate the long-term (226)Ra distribution in a soil irrigated with HRW for 15 years. Radium uptake by plants was found to be controlled by its activity in the irrigation water and in the soil solution, the physical properties of the soil and the potential evapotranspiration. The (226)Ra apeared to accumulate mainly in the leaves of crops following the evapotranspiration current, while its accumulation in the edible parts (fruits and roots) was minimal. The simulation of 15 years of crop irrigation by HYDERUS 1-D, showed a low Ra activity concentration in the soil solution of the root zone and a limited downward mobility. It was therefore concluded that the crops investigated in this study can be irrigated with the natural occurring activity concentration of (226)Ra of 0.6-1.6 Bq L(-1). This should be accompanied by a continuous monitoring of radium in the edible parts of the crops. PMID- 24345671 TI - Evaluation of kynurenine pathway metabolism in Toxoplasma gondii-infected mice: implications for schizophrenia. AB - Toxoplasma gondii, an intracellular protozoan parasite, is a major cause of opportunistic infectious disease affecting the brain and has been linked to an increased incidence of schizophrenia. In murine hosts, infection with T. gondii stimulates tryptophan degradation along the kynurenine pathway (KP), which contains several neuroactive metabolites, including 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA). As these endogenous compounds may provide a mechanistic connection between T. gondii and the pathophysiology of schizophrenia, we measured KP metabolites in both the brain and periphery of T. gondii-treated C57BL/6 mice 8 and 28 days post-infection. Infected mice showed early decreases in the levels of tryptophan in the brain and serum, but not in the liver. These reductions were associated with elevated levels of kynurenine, KYNA, 3-HK and QUIN in the brain. In quantitative terms, the most significant increases in these KP metabolites were observed in the brain at 28 days post infection. Notably, the anti-parasitic drugs pyrimethamine and sulfadiazine, a standard treatment of toxoplasmosis, significantly reduced 3-HK and KYNA levels in the brain of infected mice when applied between 28 and 56 days post-infection. In summary, T. gondii infection, probably by activating microglia and astrocytes, enhances the production of KP metabolites in the brain. However, during the first two months after infection, the KP changes in these mice do not reliably duplicate abnormalities seen in the brain of individuals with schizophrenia. PMID- 24345673 TI - BOLDSync: a MATLAB-based toolbox for synchronized stimulus presentation in functional MRI. AB - BACKGROUND: Precise and synchronized presentation of paradigm stimuli in functional magnetic resonance imaging (fMRI) is central to obtaining accurate information about brain regions involved in a specific task. NEW METHOD: In this manuscript, we present a new MATLAB-based toolbox, BOLDSync, for synchronized stimulus presentation in fMRI. RESULTS: BOLDSync provides a user friendly platform for design and presentation of visual, audio, as well as multimodal audio-visual (AV) stimuli in functional imaging experiments. We present simulation experiments that demonstrate the millisecond synchronization accuracy of BOLDSync, and also illustrate the functionalities of BOLDSync through application to an AV fMRI study. COMPARISON WITH EXISTING METHODS: BOLDSync gains an advantage over other available proprietary and open-source toolboxes by offering a user friendly and accessible interface that affords both precision in stimulus presentation and versatility across various types of stimulus designs and system setups. CONCLUSIONS: BOLDSync is a reliable, efficient, and versatile solution for synchronized stimulus presentation in fMRI study. PMID- 24345674 TI - Effect of repetition proportion on language-driven anticipatory eye movements. AB - Previous masked priming research in word recognition has demonstrated that repetition priming is influenced by experiment-wise information structure, such as proportion of target repetition. Research using naturalistic tasks and eye tracking has shown that people use linguistic knowledge to anticipate upcoming words. We examined whether the proportion of target repetition within an experiment can have a similar effect on anticipatory eye movements. We used a word-to-picture matching task (i.e., the visual world paradigm) with target repetition proportion carefully controlled. Participants' eye movements were tracked starting when the pictures appeared, one second prior to the onset of the target word. Targets repeated from the previous trial were fixated more than other items during this preview period when target repetition proportion was high and less than other items when target repetition proportion was low. These results indicate that linguistic anticipation can be driven by short-term within experiment trial structure, with implications for the generalization of priming effects, the bases of anticipatory eye movements, and experiment design. PMID- 24345675 TI - Disowned recollections: denying true experiences undermines belief in occurrence but not judgments of remembering. AB - Recent research findings have illustrated that false memories induced in the laboratory can be dissociated from the beliefs that the events had in fact occurred. In this study we assessed whether this dissociability is a quality peculiar to false memory, or whether it represents a general characteristic of autobiographical memory. To this end we examined whether people can be induced to stop believing in memories for true experiences. Participants observed and performed simple actions, and were later falsely informed that they had not performed some of them--that false memories for these actions had been implanted through the use of fabricated evidence. Before and after receiving this misinformation, participants rated their belief in and memory of performing those actions, other actions that they had also performed, and actions that they had not performed. Whereas the misinformation substantially undermined participants' beliefs in the specific performed actions about which they had been misinformed, it had little effect on their endorsement of remembering those actions. The misinformation thus boosted the proportion of occasions in which participants rated their memories as stronger than their beliefs, and it weakened the correlation between belief and memory ratings. Thus, this study provides the first experimental demonstration of non-believed memories of true experiences. We discuss our findings with reference to the small literature concerning the use of socially-communicated misinformation to undermine event memories, and with reference to the structure of autobiographical memory. PMID- 24345676 TI - Delayed extracorporeal membrane oxygenation in children after cardiac surgery: two-institution experience. AB - OBJECTIVE: There are limited data on the outcomes of children receiving delayed (>=7 days) extracorporeal membrane oxygenation after cardiac surgery. The primary aim of this project is to identify the aetiology and outcomes of extracorporeal membrane oxygenation in children receiving delayed (>=7 days) extracorporeal membrane oxygenation after cardiac surgery. PATIENTS AND METHODS: We conducted a retrospective review of all children <=18 years supported with delayed extracorporeal membrane oxygenation after cardiac surgery between the period January, 2001 and March, 2012 at the Arkansas Children's Hospital, United States of America, and Royal Children's Hospital, Australia. The data collected in our study included patient demographic information, diagnoses, extracorporeal membrane oxygenation indication, extracorporeal membrane oxygenation support details, medical and surgical history, laboratory, microbiological, and radiographic data, information on organ dysfunction, complications, and patient outcomes. The outcome variables evaluated in this report included: survival to hospital discharge and current survival with emphasis on neurological, renal, pulmonary, and other end-organ function. RESULTS: During the study period, 423 patients undergoing cardiac surgery were supported with extracorporeal membrane oxygenation at two institutions, with a survival of 232 patients (55%). Of these, 371 patients received extracorporeal membrane oxygenation <7 days after cardiac surgery, with a survival of 205 (55%) patients, and 52 patients received extracorporeal membrane oxygenation >=7 days after cardiac surgery, with a survival of 27 (52%) patients. The median duration of extracorporeal membrane oxygenation run for the study cohort was 5 days (interquartile range: 3, 10). In all, 14 patients (25%) received extracorporeal membrane oxygenation during active cardiopulmonary resuscitation with chest compressions. There were 24 patients (44%) who received dialysis while being on extracorporeal membrane oxygenation. There were eight patients (15%) who had positive blood cultures and four patients (7%) who had positive urine cultures while being on extracorporeal membrane oxygenation. There were nine patients (16%) who had bleeding complications associated with extracorporeal membrane oxygenation runs. There were 10 patients (18%) who had cerebrovascular thromboembolic events associated with extracorporeal membrane oxygenation runs. Of these, 19 patients are still alive with significant comorbidities. CONCLUSIONS: This study demonstrates that mortality outcomes are comparable among children receiving extracorporeal membrane oxygenation >=7 days and <7 days after cardiac surgery. The proportion of patients receiving extracorporeal membrane oxygenation >=7 days is small and the aetiology diverse. PMID- 24345677 TI - The immune response to stress in orchestra musicians: setting the stage for naturalistic paradigms. PMID- 24345678 TI - Death of a Titan. AB - When Tony Pawson passed away this summer, the cell signaling community lost a great scientist. His outgoing nature and inquisitiveness and excitement about science influenced many members of the field. Researchers who knew Tony offer fond remembrances here to commemorate his impact on our understanding the molecular mechanisms governing signal transduction and on many individual careers. PMID- 24345680 TI - Integration of protein abundance and structure data reveals competition in the ErbB signaling network. AB - The mechanisms of context-specific differences in signal transduction, such as those that occur among different cell types, are not fully understood. One possibility is that differences in the abundance of proteins change signaling outputs because these proteins compete for binding to hub proteins at critical network branch points. Focusing on the ErbB signaling, we created a protein interaction network that included information about protein domains and analyzed the role of competing protein interactions. By leveraging three-dimensional protein structures to infer steric interactions among binding partners for a common binding domain or linear motif (node) and including information about protein abundance and interaction affinities, we identified a large number of competitive, mutually exclusive (XOR) protein interactions. Modeling changes in protein abundance with different patterns of partner proteins and XOR nodes (XOR motifs) revealed that each motif conferred a different response. We experimentally investigated the XOR motif containing the hub protein Ras and its binding partners RIN1 (Ras and Rab interactor 1) and CRAF (v-raf-leukemia viral oncogene 1). Consistent with the computational prediction, overexpression of RIN1 in cultured cells decreased the phosphorylation of CRAF and its downstream targets. Thus, our analyses provide evidence that variation in the abundance of proteins that compete for binding to XOR nodes could contribute to context specific signaling plasticity. PMID- 24345679 TI - PLCepsilon, PKD1, and SSH1L transduce RhoA signaling to protect mitochondria from oxidative stress in the heart. AB - Activation of the small guanosine triphosphatase RhoA can promote cell survival in cultured cardiomyocytes and in the heart. We showed that the circulating lysophospholipid sphingosine 1-phosphate (S1P), a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) agonist, signaled through RhoA and phospholipase Cepsilon (PLCepsilon) to increase the phosphorylation and activation of protein kinase D1 (PKD1). Genetic deletion of either PKD1 or its upstream regulator PLCepsilon inhibited S1P-mediated cardioprotection against ischemia/reperfusion injury. Cardioprotection involved PKD1-mediated phosphorylation and inhibition of the cofilin phosphatase Slingshot 1L (SSH1L). Cofilin 2 translocates to mitochondria in response to oxidative stress or ischemia/reperfusion injury, and both S1P pretreatment and SSH1L knockdown attenuated translocation of cofilin 2 to mitochondria. Cofilin 2 associates with the proapoptotic protein Bax, and the mitochondrial translocation of Bax in response to oxidative stress was also attenuated by S1P treatment in isolated hearts or by knockdown of SSH1L or cofilin 2 in cardiomyocytes. Furthermore, SSH1L knockdown, like S1P treatment, increased cardiomyocyte survival and preserved mitochondrial integrity after oxidative stress. These findings reveal a pathway initiated by GPCR agonist-induced RhoA activation, in which PLCepsilon signals to PKD1-mediated phosphorylation of cytoskeletal proteins to prevent the mitochondrial translocation and proapoptotic function of cofilin 2 and Bax and thereby promote cell survival. PMID- 24345681 TI - Activation of the transcription factor c-Maf in T cells is dependent on the CARMA1-IKKbeta signaling cascade. AB - The proto-oncogene c-Maf is a transcription factor that plays a critical role in the differentiation of various T helper (T(H)) cell subsets. The amount of c-Maf increases after stimulation of the T cell receptor (TCR), which results in the production of multiple cytokines. We showed that two essential regulators of the transcription factor nuclear factor kappaB (NF-kappaB), the scaffold protein CARMA1 and the kinase IKKbeta [inhibitor of NF-kappaB (IkappaB) kinase beta], are also critical for the activation of c-Maf. Although CARMA1 deficiency did not affect the TCR-dependent increase in c-Maf abundance in T cells, CARMA1-dependent activation of the IKK complex was required for the nuclear translocation of c-Maf and its binding to the promoters of its target genes. Consistent with a role for c-Maf in the development of T follicular helper (T(FH)) cells, which provide help to B cells in the germinal centers of the spleen, CARMA1- or IKKbeta-deficient mice immunized with peptide antigen had defects in the generation of T(FH) cells, formation of germinal centers, and production of antigen-specific antibodies. Together, these data suggest a mechanism by which c-Maf is regulated during T cell activation and differentiation. PMID- 24345683 TI - The associations between resilience, social capital and self-rated health among HIV-positive South Africans. AB - This study examined the relationship between resilience, social capital and self rated health among 263 HIV-positive South Africans living in poverty, using questionnaires. Self-rated good health was predicted by younger age, trust in community-based organizations and having contacts of different religions. The findings highlight the importance of community-based networks and resources for care and support for persons living with HIV/AIDS in poor, rural areas. Furthermore, resilience, which also related positively to education and income, contributed positively to self-rated health, drawing attention to the interplay between resources at individual and community levels. PMID- 24345682 TI - Deep sequencing and high-resolution imaging reveal compartment-specific localization of Bdnf mRNA in hippocampal neurons. AB - Brain-derived neurotrophic factor (BDNF) is a small protein of the neurotrophin family that regulates various brain functions. Although much is known about how its transcription is regulated, the abundance of endogenous BDNF mRNA and its subcellular localization pattern are matters of debate. We used next-generation sequencing and high-resolution in situ hybridization in the rat hippocampus to reexamine this question. We performed 3' end sequencing on rat hippocampal slices and detected two isoforms of Bdnf containing either a short or a long 3' untranslated region (3'UTR). Most of the Bdnf transcripts contained the short 3'UTR isoform and were present in low amounts relative to other neuronal transcripts. Bdnf mRNA was present in the somatic compartment of rat hippocampal slices or the somata of cultured rat hippocampal neurons but was rarely detected in the dendritic processes. Pharmacological stimulation of hippocampal neurons induced Bdnf expression but did not change the ratio of Bdnf isoform abundance. The findings indicate that endogenous Bdnf mRNA, although weakly abundant, is primarily localized to the somatic compartment of hippocampal neurons. Both Bdnf mRNA isoforms have shorter half-lives compared with other neuronal mRNAs. Furthermore, the findings show that using complementary high-resolution techniques can provide sensitive measures of endogenous transcript abundance. PMID- 24345684 TI - Lectin histochemistry of palatine glands in the developing rat. AB - This study examined the binding pattern of lectins, soybean agglutinin (SBA), Dolichos biflorus agglutinin (DBA), Vicia villosa agglutinin (VVA), Ulex europaeus agglutinin-I (UEA-I), peanut agglutinin (PNA), wheat germ agglutinin (WGA), and succinylated WGA (sucWGA) in the developing rat palatine glands. In adult rats, heterogeneous lectin binding patterns were revealed between the anterior and posterior portions of palatine glands, as DBA, VVA, and WGA were bound more intensely and broadly in the posterior portion. SBA, PNA, and sucWGA showed far less reactivity in the anterior than in the posterior portion. At embryonic day 18 (E18), weak labeling was observed with UEA-I and WGA at the basal membrane of terminal buds, UEA-I and PNA labeled the epithelial cord, and there was no apparent binding for SBA, DBA, VVA, and sucWGA. At E20, after acinar lumenization, all lectins were detected at the acinar cell basal membranes. After birth, all lectins detectably labeled at the mucous cell apical membranes and progressively, with maturation, extended from the apical to basal portions of the cytoplasm. Apparent serous cells were observed around postnatal day 10 (PN10) and bound UEA-I. Lectins reached peak reactivity at PN21 and the binding patterns became identical to those of adults around PN28. PMID- 24345685 TI - Immunohistochemical demonstration of connexins in the developing feather follicle of the chicken. AB - Based on immunohistochemistry, the study demonstrates the varying distribution and reaction intensity of connexins (Cx26 [chicken 31sim], 30 [chicken 31], 31, 32, 43, 45) in the developing feather follicle of the chicken (White Leghorn). The different embryonal stages were identified according to the normal table of Hamburger and Hamilton (1951). The development of the feather follicle complex is closely related to skin layer development, making use of the controlling function of connexins. This was evident during feather follicle differentiation, based on communication between ectomesodermal (fibroblasts) and ectodermal cells (developing epidermis), but also by the subsequent separation of the two cell line types related to their connexin-dependent differentiation degree. With the increase in mesenchymal cell numbers during feather placode development, the multiple connexins Cx26 [chicken 31sim] and 43, supported by Cx30 [chicken 31], 31 and 32, were increasingly activating the fibroblast concentrations as related to epidermal follicle buds, the specific follicle structure, the endothelial cells of capillaries and larger blood vessels, as well as the collagen fiber production and the growing feather musculature shortly before hatching; Cx45 could not be demonstrated. In conclusion, it seems that connexin expression is not only coupled to the origin of embryonic cells, but also connected with tissue formation before the follicle system can be formed. PMID- 24345686 TI - Dilated cardiomyopathy secondary to rickets-related hypocalcaemia: eight case reports and a review of the literature. AB - INTRODUCTION: Dilated cardiomyopathy is usually idiopathic and may arise secondary to infections or metabolic or genetic causes. Another rare cause is hypocalcaemia. Owing to the fact that calcium plays an essential role in excitation and contraction of myocardial muscle, myocardial contractility may decline in patients with hypocalcaemia. MATERIALS AND METHODS: Patients with symptoms of congestive heart failure and rickets-related hypocalcaemia were assessed clinically and by echocardiography in a paediatric cardiology clinic. Echocardiography was performed for all patients. Rickets was diagnosed according to the clinical, laboratory, and radiologic findings. Maternal lifestyle and living conditions were investigated, and the maternal 25-OH vitamin D3 blood level was measured. RESULTS: We evaluated eight patients who developed heart failure as a result of severe hypocalcaemia associated with rickets between August, 1999 and June, 2012. The age distribution of the patients was 3-12 months. Laboratory results were consistent with advanced-stage rickets. Severe hypocalcaemia was detected in all patients. The maternal 25-OH vitamin D3 levels were low. Echocardiography revealed increased pre-treatment left ventricle end systolic and end-diastolic diameters for age and reduced ejection fraction and fractional shortening. After clinical improvement, the patients were discharged. CONCLUSIONS: Severe hypocalcaemia associated with rickets must always be kept in mind among the causes of dilated cardiomyopathy and impaired cardiac function in infants. If diagnosed and treated in time, dilated cardiomyopathy and severe heart failure related to rickets respond well. PMID- 24345687 TI - Perceptions of transmission of body weight and telemonitoring in patients with heart failure? AB - Chronic heart failure (HF) is associated with a high burden of morbidity and mortality and with reduced quality of life. New techniques such as telemonitoring (TM) have recently been introduced in the care of patients with HF in order to improve outcomes. TM is defined as sending data from the patients' home to healthcare professionals. Most studies have focussed on endpoints such as morbidity and mortality, and relatively little attention has been paid to patients' perceptions of TM. Therefore, the aim of this study was to explore and describe patients' perceptions of transmission of body weight (BW) and TM, regularly accomplished from patients' homes to an HF clinic. An explorative design with a phenomenographic approach was used, and semi-structured interviews were conducted with a maximum variation sampling of 20 participants. The findings are described in five metaphoric categories that were assigned and used as a description: the habitual patient, the concerned patient, the technical patient, the secure patient, and the self-caring patient. The conclusions were that the transmission of BW made the patients active in their own care and increased self care activities. In clinical care, concerns for deterioration in HF as well as the reliability of the TM system should be considered. Future research may focus on healthcare professionals and their perceptions of transmission of BW and TM in the care of patients with HF. PMID- 24345689 TI - Direct effect of khat and garlic extracts on blood lipids contents: Preliminary in vitro study. AB - SUMMARY: Khat (Catha edulis) as well as garlic (Allium sativum) has a potential effect on reducing the lipid contents of blood. However, a mechanism by which garlic or khat reduces plasma lipids has not been fully investigated. This study aimed to investigate the direct action of khat and/or garlic (in vitro). The effects of extracted khat and/or garlic on human blood constituents (cholesterol and triglycerides) and on vegetable oil were investigated. The results showed that aqueous garlic extract was able to form an emulsion with oil but not khat extract. Even though, either khat or garlic extract has slight effect on reducing lipid contents of blood; a higher reduction was obtained when the extracts were added in combination. The mechanism of garlic on reducing lipids could be explained by its emulsifying property, while the mechanism of khat is by lipolysis. In conclusion, the synergistic effect of garlic and khat extracts opened an interesting area for further investigation on their roles in combating cardiovascular and obesity disorders.: PMID- 24345688 TI - Comparing coronary artery bypass grafting with drug-eluting stenting in patients with diabetes mellitus and multivessel coronary artery disease: a meta-analysis. AB - OBJECTIVES: Although drug-eluting stents (DESs) reduce the rate of target vessel revascularization compared with bare-metal stents, the results of DESs for patients with diabetes and multivessel coronary artery disease (CAD) in the DES era are inconsistent. This meta-analysis was undertaken to assess the efficacy and safety of coronary artery bypass grafting (CABG) compared with drug-eluting stent implantation in patients with diabetes mellitus and multivessel coronary artery disease. METHODS: We conducted a search of Medline, EMBASE from January 2003 to July 2013 by two reviewers independently, using the terms 'coronary artery bypass graft surgery', 'drug-eluting stent', 'sirolimus-eluting stent', 'paclitaxel-eluting stent', 'diabetes mellitus' and 'multivessel disease', according to established criteria. Studies comparing CABG with DES in patients with diabetes and multivessel CAD with a minimum follow-up of 1 year were included. RESULTS: Thirteen studies including 6653 patients with diabetes (3237 who underwent CABG and 3416 who underwent DES implantation) met the selection criteria. The mean follow-up period was 2.9 years (range 1-5). Compared with DES, CABG was associated with a lower risk for major adverse cardiac events (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.46-0.58), driven mainly by a lower risk for repeat revascularization (OR 0.29, 95% CI 0.23-0.35). There was no significant difference with regard to death (OR 0.89, 95% CI 0.75-1.05). Patients in the CABG group had a higher risk for stroke events (OR 2.09, 95% CI 1.45 3.02). CONCLUSIONS: Percutaneous coronary intervention with DES in patients with diabetes and multivessel CAD is safe, but has a high risk of long-term repeat revascularization. CABG should remain the standard procedure for diabetic patients with multivessel CAD. PMID- 24345690 TI - Relationships between visceral adipose tissue measurement site and the metabolic syndrome in the Korean population. AB - SUMMARY: OBJECTIVE: Visceral adipose tissue (VAT) is presumed to play an important role in the development of metabolic syndrome (MS). The purpose of this study was to evaluate the influence of measurement location of VAT on the cardiometabolic risk factors and the MS in the Korean population. METHODS: To assess abdominal fat distribution, 5 single-slice computed tomography (CT) images were obtained in 470 healthy subjects. The five CT images were obtained at the intervertebral space from L1 to S1 using known anatomical landmarks. Multiple logistic regression analysis was performed to assess the relationship between regional adipose tissue areas and MS. RESULTS: All risk factors were more closely correlated with VAT than subcutaneous adipose tissue (SAT), except waist circumference and blood pressure. Images located at L2-L3 or L3-L4 provided high correlations between VAT area and all cardiometabolic risk factors. The highest adjusted odds (per SD) between VAT and MS were the L2-L3 image in men (OR 4.53) and the L1-L2 in women (OR 4.87), which was higher than measures at L4-L5 (OR 3.22 in men, OR 4.71 in women). However, differences in OR between L1-L2 VAT (OR 4.87) and L4-L5 (OR 4.71) were not great in women. CONCLUSIONS: The results of this study suggest that VAT has a stronger association with MS than ASAT in Korean population regardless of measurement site, and an image located in the upper abdomen (L2-L3 or L3-L4) would be a better predictor of the relationship between VAT and MS in Korean men. PMID- 24345691 TI - Prevalence and risk factors for gastroesophageal reflux disease in an impoverished minority population. AB - SUMMARY: BACKGROUND AND AIMS: An epidemiological link between an increased body mass index and complaints of typical heartburn symptoms has been identified. It appears that increasing waist circumference, rather than overall weight is most important. Studies to date have not included minority, impoverished communities. Our aim was to determine the impact of obesity on the prevalence of reflux disease in an impoverished community while controlling for known confounders. METHODS: DESIGN: Cross-sectional survey delivered by in-home interviews, convenience sampling, and targeted mailing. Data queried include demographics, medical history, lifestyle habits, and symptoms of reflux disease. Height, weight, hip and waist circumference measured in participating subjects. PARTICIPANTS: 503 subjects living in the zip code immediately surrounding Temple University Hospital. Included only adults living in the hospital's zip code for at least 3 years. RESULTS: The highest quartile of waist circumference (>=42 in.) demonstrated a strong association with GERD (AOR = 2.15; 95% CI 1.18-3.90). Smoking increased the odds by 1.72 (95% CI 1.13-2.62). There was no relationship between body mass index, waist-hip ratio, or diet and reflux classification. CONCLUSIONS: Increasing waist circumference, but not overall body mass index or waist-hip ratio, and smoking are risk factors for prevalent GERD. No association between reflux disease and lifestyle choices such as coffee drinking and fast food dining were found. LIMITATIONS: Potential for recall bias and disease misclassification. Possible methodological errors in self-measurement of waist and hip circumference. PMID- 24345692 TI - Effect of obesity on TAFI in postmenopausal period. AB - SUMMARY: AIM: The aim of the study was to evaluate how obesity effects the coagulation and fibrinolytic system in the postmenopausal period. METHOD: Forty eight obese (body mass index (BMI) >=30 kg/m(2)) and 38 nonobese (BMI < 30 kg/m(2)) postmenopausal women were enrolled in the study. Fat mass and insulin resistance were calculated. Plasma levels of plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), d-dimer, thrombomodulin, and thrombin activatable fibrinolysis inhibitor (TAFI) antigen were determined by ELISA method. TAFI activity was measured using the chromogenic assay. RESULTS: Obese subjects had higher PAI-1 (73.5 +/- 35.7 ng/mL vs. 57.1 +/- 34.2 ng/mL, p < 0.05) levels but lower tPA/PAI-1 ratio (0.59 +/- 0.50 vs. 38 +/- 0.21, p < 0.05) than their nonobese counterparts. Obesity was not statistically significant for other haemostatic variables. BMI and fat mass were positively correlated with PAI 1 (r = 0.312, p = 0.003; r = 0.381, p = 0.005, respectively) and negatively correlated with tPA/PAI-1 ratio (r = -0.273, p = 0.01; r = -0.545, p = 0.01, respectively). HOMA scores were also positively correlated with PAI-1 levels (r = 0.236, p = 0.04). CONCLUSION: We found that tendency to hypercoagulability in the postmenopausal women was due to increased PAI-1 rather than TAFI levels, which may contribute to adverse cardiovascular outcomes in this cohort. Further studies should be undertaken to evaluate effects of weight loss on the coagulation and fibrinolytic system. PMID- 24345693 TI - Is air-displacement plethysmography a reliable method of detecting ongoing changes in percent body fat within obese children involved in a weight management program? AB - SUMMARY: BACKGROUND: The prevalence of childhood obesity in the US has increased considerably over the last few decades and continues to increase. To monitor the progress of patients enrolled in weight management programs, clinicians need accurate methods of detecting changes in body composition (percent body fat) over time. The gold standard method, hydrodensitometry, has severe limitations for the pediatric population. OBJECTIVE: This study examines the reliability of air displacement plethysmography (ADP) in detecting percent body fat changes within obese children over time. METHODS: Percent body fat by ADP, weight, and body mass index (BMI) were measured for eight obese children aged 5-12 years enrolled in a weight management program over a 12-month period. These measurements were taken at initial evaluation, 1.5 months, 3 months, 6 months, and 12 months to monitor the progress of the subjects and detect any changes in these measures over time. Statistical analysis was used to determine the reliability of the data collected. RESULTS: The reliability estimate for percent body fat by ADP was 0.78. This was much lower than the reliability of BMI, 0.98, and weight measurements, 0.99. The low reliability estimate of ADP indicates a large standard error of measurement by this method. CONCLUSION: The measurement error of ADP is large, and in our study, ADP measured changes in percent body fat that far exceeded levels of true change that would have been clinically useful and important to detect. Hence, this method yielded change measures that did not allow meaningful clinical interpretations and often did not reflect true differences in status across time. ADP is not a reliable method for detecting changes in percent body fat over the time intervals employed within this study of obese children. PMID- 24345694 TI - Is success in weight loss treatment contagious (do attendance and outcomes cluster within treatment groups)? AB - SUMMARY: Data from a trial of a 26-session structured group behavioral weight loss intervention were used to examine how group attendance, weight loss, and changes in depression clustered within therapy groups. Participants were recruited via a population-based survey of female health plan members aged 40-65. The sample included 143 women attending 13 therapy groups. Average number of sessions attended was 15.9 (S.D. 7.2) and average weight loss over 12 months was 4.24 kg (S.D. 7.79 kg). In hierarchical (random effects) linear models predicting attendance and weight loss, attendance did cluster significantly within therapy groups (F = 2.83, df = 12, p = .002; ICC = .14) but weight loss (F = 0.89, df = 12, p = .56; ICC = .00) and change in depressive symptoms (F = 0.25, df = 12, p = .99; ICC = .00) did not. Accounting for baseline characteristics of group participants had no significant effect on these findings. Relatively small average weight loss in this sample may have limited our ability to detect clustering of weight loss within groups. We conclude that clinicians should consider addressing the effects of drop-out on other group members and that researchers should consider the impact of clustering in analyses of data regarding group treatments.: PMID- 24345695 TI - Characteristics of metabolic syndrome and its clinical components among diabetic Vietnamese patients: A survry at two institutions in Ho Chi Minh City. AB - SUMMARY: OBJECTIVE: The purpose of this study was to estimate the prevalence of metabolic syndrome among Vietnamese diabetic patients and to investigate their characteristics. METHODS: This cross-sectional study was conducted among 652 outpatients who were recruited from one public general hospital (People Hospital 115) and one private clinic (Medic Center) in Ho Chi Minh City, Vietnam. We obtained informed consent from participants, collected clinical information from medical files, and conducted patient interviews. We evaluated the collected information descriptively and diagnosed metabolic syndrome according to the International Diabetes Federation (IDF) Worldwide Definition of the Metabolic Syndrome. RESULTS: A total of 517 eligible patients (175 men and 342 women) were analyzed. Mean age was 54.6 years for men and 60.7 years for women. Metabolic syndrome was observed in 39.4% of men and 70.5% of women. Central obesity was more prevalent among women (72.5%) compared to men (39.4%). Participants with metabolic syndrome were less likely to endorse a sense of general well-being, and women with metabolic syndrome were likely to have less diabetes-related distress. CONCLUSIONS: this study revealed a high prevalence of metabolic syndrome in diabetic Vietnamese patients, especially among women, and revealed central obesity as a key feature. A prospective study should be conducted in this population in order to assess impacts of metabolic syndrome on disease outcome. PMID- 24345696 TI - High prevalence of periodontitis in non-elderly obese Japanese adults. AB - SUMMARY: OBJECTIVES: Several recent reports have indicated a high prevalence of periodontitis in obese subjects, but the results have not been consistent. This study was performed to investigate the prevalence of periodontitis in non-elderly obese Japanese adults and to explore the relationship between obesity and periodontitis. METHODS: Ninety-five obese subjects (BMI >= 25; males: 44, females: 51) and 102 subjects with normal weight (BMI 18.5-25; males: 66, females: 36) were enrolled from April 1997 to March 1999 in the study. All subjects were aged 25-40 years old. The status of periodontitis was evaluated based on the intraoral community periodontal index (CPI) codes of the WHO, and the numbers of present teeth, untreated decayed teeth, missing teeth, and filled teeth were also examined. RESULTS: The prevalence of periodontitis was significantly higher in obese subjects, and particularly in females, compared to controls, whereas the numbers of present teeth, decayed teeth, missing teeth and filled teeth did not differ significantly between the obese subjects and the controls for both males and females. Multiple logistic regression analysis revealed that obesity was significantly related to periodontitis. CONCLUSION: A high prevalence of periodontitis was found in non-elderly Japanese obese subjects, and particularly in obese female adults. Correlation analysis also suggested that obesity carries a high risk for development of periodontitis. PMID- 24345697 TI - Waist circumference and body fat distribution indexes as screening tools for the overweight and obesity in Thai preschool children. AB - SUMMARY: BACKGROUND: Evidence shows that waist circumference (WC) is one reliable index to predict abdominal obesity in children. This study aims to examine the relationship of WC to other anthropometric indexes and to determine the ability of WC as obesity screening tool. SUBJECTS: 811, 5-6 years old children in Saraburi province, central region of Thailand. METHODS: Anthropometric measurements were performed in children; 406 boys and 405 girls. WC measurement was performed at the umbilicus level. Subcutaneous skinfold was measured on subscapular, suprailiac and abdominal regions. Total body fat was measured with bioelectrical impedance analyzer. Receiver operating characteristic (ROC) analysis was employed to determine WC cut-offs for predicting obesity in children. RESULTS: WC highly correlated with weight-for-height Z-score (WHZ) (r = 0.92-0.94, p = 0.01), body mass index (BMI) (r = 0.95-0.96, p = 0.01), trunk skinfold (r = 0.92-0.93, p = 0.01) and total body fat (r = 0.94-0.95, p = 0.01) for both genders. Based on Thai national reference, the optimal WC cut-offs for predicting obesity were 59.6 cm for boys and 60.5 cm for girls. When IOTF-BMI was employed as reference, WC thresholds were 64.4 cm for boys and 63.1 cm for girls. The latter WC cut-offs provided the slightly underestimated obesity prevalence compared with national reference. CONCLUSION: The strongly positive correlation between WC and weight-height based index and between WC and body fat in Thai preschool children suggests that WC should be the additional index for obesity screening in young children. Further study needs to explore the association between the increased WC and other adverse health outcomes. PMID- 24345698 TI - Triiodothyronine level predicts visceral obesity and atherosclerosis in euthyroid, overweight and obese subjects: T3 and visceral obesity. AB - SUMMARY: OBJECTIVE: We assessed how thyroid hormones affect the visceral obesity and atherosclerosis in euthyroid, overweight and obese Asian subjects. METHODS: Metabolic parameters and thyroid hormone levels were measured in 177 subjects who visited obesity clinic at Gangnam Severance Hospital. Total adipose tissue area (TAT), subcutaneous adipose tissue area (SAT), visceral adipose tissue area (VAT) were quantified by computerized tomography scan, and, pulse wave velocity (PWV) was measured as a marker of atherosclerosis. RESULTS: T3 was significantly related to all the measures of abdominal fat, TAT (P = 0.001), SAT (P = 0.015), VAT (P < 0.001), and waist circumference (P = 0.001) as well as BMI (P = 0.017) and total body fat percent (P = 0.001) after adjusting for age and sex. In multiple regression analysis, T3 was independently associated with VAT (beta = 0.486, P = 0.009). There was a positive correlation between T3 and PWV. CONCLUSIONS: T3 level is positively associated with the amount of visceral fat and PWV. Visceral obesity seems to cause an increase in circulating T3 level as an adaptational response to increase the energy expenditure, and thus a more close attention and an effort to assess cardiovascular risks should be made to people with high normal T3 level. PMID- 24345699 TI - No association between peroxisome proliferator-activated receptor and uncoupling protein gene polymorphisms and obesity in Malaysian university students. AB - SUMMARY: Peroxisome proliferator-activated receptors (PPARs) and uncoupling proteins (UCPs) are expressed in adipose tissue, where PPARs are nuclear receptors that function as transcription regulators of the expression of UCPs, mitochondria proteins which uncouple protons in exchange of heat released. The PPARalpha L162V; PPARgamma2 C161T; UCP1 -3826A/G; UCP2 45 bp Ins/Del and -866G/A; and UCP3 -55C/T gene polymorphisms have been previously associated with obesity in different populations, but with inconclusive findings. This study was to investigate the prevalence of these gene polymorphisms and their possible association with obesity in a cohort of Malaysian university students in Kuala Lumpur. Random convenience sampling was performed with informed consents and anthropometric measurements were taken. Mouthwash samples were obtained for genomic DNA extraction and genotyping was performed using Polymerase Chain Reaction - Restriction Fragment Length Polymorphism. Out of the 256 subjects (140 males and 116 females), 170 were lean and 86 were overweight/obese. The mutated PPARalpha L162V; PPARgamma2 C161T; UCP1 -3826A/G; UCP2 45 bp Ins/Del and -866G/A; and UCP3 -55C/T allele frequencies were 0.006, 0.36, 0.58, 0.12, 0.56 and 0.34, respectively. This study failed to find significant differences in the anthropometric indicators of obesity (Body Mass Index, Waist-Hip Ratio and Total Body Fat) between the genotypes of all the PPAR and UCP gene variants. Overall, the genotype and allele distributions were also not significantly different between genders and BMI status. In conclusion, overweight/obesity is not prevalent among the Malaysian university students and the PPAR and UCP gene polymorphisms are not associated with obesity.: PMID- 24345700 TI - High cardiovascular risk factors among obese children in an urban area of Japan. AB - SUMMARY: The association between degree of obesity and cardiovascular and related metabolic risk factors were examined in 355 Japanese obese school children from 11 to 12 years old. The parameters evaluated were blood pressure, serum lipids, fasting blood glucose, and serum ALT and AST. ALT, AST and triglycerides were more commonly evaluated in obese boys than in obese girls, while HDL-cholesterol was more commonly lowered in obese girls. Hypercholesterolemia was 2-fold, and abnormal liver functions were 3-fold more common in severely obese than in moderate obese children. Thus, cardiovascular and related metabolic risk factors are present in obesity in school-aged children, particularly in boys.: PMID- 24345701 TI - Activation of hypothalamo-pituitary-adrenal axis and ACTH-producing pituitary cell hyperplasia in massive obesity. PMID- 24345702 TI - Immunotherapeutic potential of recombinant ESAT-6 protein in mouse model of experimental tuberculosis. AB - Recent understanding of the pathogenesis of tuberculosis allows the possible application of immunotherapy for the treatment of tuberculosis. Therapies that would upregulate the host antimycobacterial immune response and/or attenuate T cell suppressive and macrophage-deactivating cytokines may prove to be useful in the treatment of tuberculosis. ESAT6, 6-kDa early secreted antigenic target, is a potent protective antigen and is considered as major target for long-lived memory cells. In the present study the immunotherapeutic potential of ESAT-6 has been evaluated in mouse model of experimental tuberculosis. In the present study the ESAT-6 protein was cloned in Escherichia coli using pET23a(+) plasmid and purified by Ni(2+)-NTA chromatography. Further, the immunotherapeutic potential of the recombinant ESAT-6 (in terms of CFU enumeration in the target organs and histopathological analysis of lungs) was evaluated against experimental tuberculosis. The recombinant ESAT-6 with C-terminal histidine-tag and free N terminus mimics the natural form of ESAT-6 has been successfully cloned and purified. The recombinant ESAT-6 protein adjuvanted with dimethyl dioctadecylammonium bromide (DDA) moderately reduced the bacterial load in the target organs of infected mice. Further, the formulation (ESAT-6-DDA) was able to act synergistically when given in combination with antituberculosis drugs. This recombinant ESAT-6 showed good immunotherapeutic potential against experimental tuberculosis and can be used as an adjunct to the conventional antituberculosis chemotherapy. PMID- 24345703 TI - Changes of CD4+CD25+FOXP3+ and CD8+CD28- regulatory T cells in non-small cell lung cancer patients undergoing surgery. AB - Little is known about the regulatory T cells (Tregs) in the peripheral blood after surgery of non-small cell lung cancer (NSCLC) patients. In this study, we investigated whether CD4+CD25+FOXP3+ and CD8+CD28- regulatory T cells are decreased in the peripheral blood of NSCLC patients undergoing surgery. The study group (n = 49) comprised NSCLC, and the control group (n = 24) consisted of age- and sex-matched nonmalignant diseases. The prevalence of CD4+CD25+FOXP3+ and CD8+CD28- Tregs was analyzed using flow cytometry. The study group showed significantly higher percentage of CD4+CD25+FOXP3+ and CD8+CD28- Tregs than control. The percentage of CD4+CD25+FOXP3+ and CD8+CD28- Tregs increased with tumor stage. One way ANOVA test shows the significant differences between all subgroups. LSD test shows that there was a statistical significance between each of the two subgroups except stage II in CD4+CD25+FOXP3+ Tregs and control vs. each stage, stage I vs. stage III, and stage IV in CD8+CD28- Tregs. There is no significant difference among stages II, III, and IV in CD8+CD28- Tregs. No differences were found between squamous carcinoma and adenocarcinoma. These levels were dropped significantly after operation. Furthermore postoperative Treg percentage in the early stages (stage I and stage II) was not statistically different from that of controls. Postoperative Treg percentage in advanced stage (III+IV) remained above the values shown by controls. Our findings indicate that the percentage of CD4+CD25+FOXP3+ and CD8+CD28- Tregs correlated with the pathological stage in NSCLC and tumor burden. PMID- 24345705 TI - Clarification of the anatomic definition of the bunion deformity. AB - Evolution of the terminology applied to the bunion deformity has progressed in parallel with our changing understanding of the deformity itself. Along this path of progression have been multiple terms, sometimes with multiple meanings. Hallux valgus and metatarsus primus varus are 2 of the most common terms for the deformity. Although commonly used, these descriptors can have multiple meanings, and inconsistencies in interpretation can lead to confusion. We propose a more detailed terminology to provide a more accurate description of the entire bunion deformity in 3 planes and for both the hallux and the metatarsal component of the deformity. The term we propose is hallux abducto valgus with metatarsus primus adducto valgus. An accurate understanding of the multiplanar position of the deformed foot is important for planning deformity correction. The descriptors in the terminology proposed will keep in the forefront the aspects of correction required for the first ray and hallux to be returned to an anatomically correct position. PMID- 24345704 TI - Supplemental oxygen reverses hypoxia-induced smooth muscle cell proliferation by modulating HIF-alpha and VEGF levels in a rabbit arteriovenous fistula model. AB - BACKGROUND: Numerous mechanisms for the formation of intimal hyperplasia have been proposed but none have been proven or accepted. Our research focuses on the potential role of hypoxia-inducible factors (HIFs), vascular endothelial growth factor (VEGF), and platelet-derived growth factors as well as the extracellular signal-regulated kinase (ERK), phosphatidylinositide 3-kinase /protein Kinase B (PI3-K/AKT) pathway in hypoxia-mediated intimal hyperplasia processes. We hypothesize that HIF and VEGF will be downregulated with supplemental oxygen in our arteriovenous fistula rabbit model. METHODS: Rabbits were randomized into different experimental groups with varying oxygen exposure (21% O2 or 30% O2) and receipt of surgery (surgery with fistula formation, no surgery, or sham operation with skin incision only). Plasma samples were collected at designated intervals in which cytokines and smooth muscle cell proliferation were measured. In addition, cell specimens were exposed to hyperoxic, normoxic, and hypoxic environments with cytokines measured at various time points. RESULTS: Placement of an arteriovenous fistula resulted in hypoxia-induced HIF stabilization with a concurrent increase in VEGF levels. There was a 4.2-fold induction in HIF-1alpha levels in animals that were placed in normal air after surgery when compared with animals that were exposed to hyperoxic air. Also, VEGF level significantly increased after surgery in the normoxic group, reaching a maximum of 959 pg/mL. Plasma VEGF levels in the surgery and supplemental oxygen group were significantly lower than the normoxic surgery group with almost a 45% reduction in plasma VEGF levels (524 pg/mL). Activation of VEGF receptors on smooth muscle cells through ERK1 and AKT pathways resulted in significant smooth muscle cell proliferation and migration. These effects are dramatically reduced in animals that are exposed to a hyperoxic environment of 30% oxygen. CONCLUSIONS: Our results suggest that short-term administration of supplemental oxygen inhibits HIFs and VEGF signaling to reduce smooth muscle proliferation in the local blood vessel. These results provide strong support for the therapeutic use of supplemental oxygen after arterial surgery to reduce intimal hyperplasia. These findings also provide a nidus for future clinical trials to determine whether this is clinically applicable in humans. PMID- 24345706 TI - Diagnosis of gas gangrene: does a discrepancy exist between the published data and practice. AB - The Infectious Disease Society of America has defined gas gangrene as an infection caused by Clostridium species. However, in many clinical settings, soft tissue infections that produce subcutaneous gas have been diagnosed as gas gangrene without identification of the presence of Clostridium species. Instead, the diagnosis was based on clinical and radiographic findings. A chart review was performed of 25 consecutive patients treated at the Atlantic Health System for infections of the lower extremity that were diagnosed as gas gangrene. Wound cultures from the 25 patients grew 31 different species of bacteria. The most prevalent organism was Staphylococcus aureus, which accounted for 17 of 31 (54.84%) different organisms identified and 19.77% of 86 separate aerobic or anaerobic cultures. The most prevalent genus was Streptococcus, which accounted for 20 (64.52%) of the organisms identified and 23.26% of the cultures. The most prevalent anaerobic genus was Peptostreptococcus, which accounted for 8 (25.81%) of the organisms identified and 9.3% of the cultures. None of the cultures grew Clostridium species. These findings showed that gas-forming soft tissue infections of the lower extremity, commonly diagnosed as gas gangrene, are rarely caused by Clostridium species. PMID- 24345707 TI - Arthroscopic synovectomy, irrigation, and debridement for treatment of septic ankle arthrosis: a systematic review and case series. AB - Septic arthrosis of the ankle is a rare, often devastating, infection, with a high potential for morbidity and mortality. Delay in treatment can lead to cartilage erosion, painful synovitis, and osteomyelitis. Septic ankle arthrosis deserves prompt recognition and intervention. However, quality, sound, protocol directed arthroscopic treatment of septic ankle arthrosis of the ankle has not yet been reported. We performed a systematic review of the electronic databases and other relevant peer-reviewed sources to determine the outcomes and treatment protocols associated with septic ankle arthrosis treated with arthroscopic synovectomy, irrigation, and debridement. Nine studies, involving a total of 15 ankles, met our inclusion criteria. In addition, we present the short-term outcomes of a protocol-driven arthroscopic synovial biopsy, deep culture procurement, synovectomy, irrigation, and debridement approach for 8 ankles (8 patients). To our knowledge, this would be the largest individual case series specific to arthroscopic treatment of septic ankle arthrosis. The most common infectious organism reported in the systematic review and in our case series was methicillin-sensitive Staphylococcus aureus. Arthroscopic synovectomy, irrigation, and debridement represents an acceptable treatment method for septic ankle arthrosis and demonstrated outcomes similar to the more traditional open approach, with fewer complications. Additional, appropriately weighted, randomized controlled studies with long-term follow-up are warranted. PMID- 24345708 TI - A comparative study of incorporation rates between non-xenograft and bovine-based structural bone graft in foot and ankle surgery. AB - Several types of structural bone grafts are available, each with different characteristics. Our previous study showed poor performance with the bovine-based xenograft in foot and ankle applications. In the present study, we compared the incorporation rates of non-xenografts, including allografts and autografts, with the bovine-based xenograft to determine whether the poor result was unique to the graft type and not institutional. The proportion of incorporated grafts at 12, 24, 36, and 48 weeks was compared between the nonxenograft and xenograft groups. Furthermore, Cox regression analysis was used to evaluate the factors associated with nonunion. A total of 61 patients (23 women and 38 men) with a median age of 24.0 years were enrolled. The factors associated with slower incorporation included side of operation (p = .033), tobacco use (p = .010), and graft type (p = .001). At 48 weeks, 5% of the nonxenografts and 58% of the xenografts were not incorporated. The median incorporation time for the non-xenograft and xenograft group was 16 and 57 weeks, respectively. We have concluded that it is not advisable to use a bovine-based bone xenograft in foot and ankle surgery. PMID- 24345709 TI - Twisting the night away: a review of the neurobiology, genetics, diagnosis, and treatment of shift work disorder. AB - Although not all individuals who work outside of standard daytime hours develop physical and psychiatric issues, there is a substantial portion of shift workers who develop shift work disorder. Shift work disorder is due to a misalignment between an individual's endogenous circadian rhythms and environmental stimuli, and can have potentially serious consequences to an individual's health and quality of life. This article reviews the neurobiological and genetic underpinnings of shift work disorder, and describes how desynchronization of the molecular clock may lead to both physical and psychiatric illnesses. Diagnostic tools and treatment guidelines to address the circadian misalignment, excessive sleepiness, and insomnia experienced by patients with shift work disorder are also discussed. PMID- 24345710 TI - Understanding depot antipsychotics: an illustrated guide to kinetics. AB - Long-acting injectable (LAI) antipsychotics can have considerable advantages over oral medications for the management of patients with schizophrenia. Despite the high prevalence of treatment nonadherence with oral pharmacotherapy, LAI antipsychotics are significantly underutilized in this patient population. The availability of newer LAI antipsychotic preparations combined with a resurgent interest in the use of typical antipsychotics has rekindled awareness of the value of LAI medications. This article is intended to provide a visual understanding of the various kinetic profiles of LAI antipsychotics to facilitate initiation and greater use of these agents. PMID- 24345711 TI - Stereotype threat and executive functions: which functions mediate different threat-related outcomes? AB - Stereotype threat research shows that women's math performance can be reduced by activating gender-based math stereotypes. Models of stereotype threat assert that threat reduces cognitive functioning, thereby accounting for its negative effects. This work provides a more detailed understanding of the cognitive processes through which stereotype threat leads women to underperform at math and to take risks, by examining which basic executive functions (inhibition, shifting, and updating) account for these outcomes. In Experiments 1 and 2, women under threat showed reduced inhibition, reduced updating, and reduced math performance compared with women in a control condition (or men); however, only updating accounted for women's poor math performance under threat. In Experiment 3, only updating accounted for stereotype threat's effect on women's math performance, whereas only inhibition accounted for the effect of threat on risk taking, suggesting that distinct executive functions can account for different stereotype threat-related outcomes. PMID- 24345712 TI - The brief self-control scale predicts jail inmates' recidivism, substance dependence, and post-release adjustment. AB - Previous research finds that self-control is positively associated with adaptive and negatively associated with maladaptive behavior. However, most previous studies use cross-sectional designs, low-risk samples, and limited assessments of self-control. This study of 553 jail inmates examined the relationship of a valid measure of self-control (Brief Self-Control Scale) completed on incarceration with behavior before, during, and 1 year after incarceration. After controlling for positive impression management (PIM), self-control was negatively related to substance misuse, suicidality, risky sex, and criminal history prior to incarceration and post-release illegal substance misuse, recidivism, and positive adjustment. Lower self-control predicted increases in substance dependence at post-release compared with pre-incarceration. Self-control was not related to misbehavior during incarceration, nor alcohol use or HIV-risk behavior 1 year post-release. Results were consistent as a function of age, race, and gender. This study supports self-control as an important risk and protective factor in a sample of criminal offenders. PMID- 24345713 TI - A flexible impact of affective feelings on priming effects: assimilation and contrast. AB - Four experiments found that positive and negative affect dictated whether primed social categories and trait concepts led to assimilation or contrast. This influence was further found to be flexibly responsive to the momentary activation of a global or local focus. When a global focus was dominant, positive affect resulted in assimilation to primed traits and social categories, and negative affect resulted in contrast. But, when a local focus was dominant, the opposite pattern of assimilation and contrast as a consequence of positive and negative affect was observed. These results are consistent with the more general view that positive and negative affect signal the value of currently accessible response tendencies and are, therefore, flexibly responsive in their influence cognition to changing situations and mental contexts. PMID- 24345714 TI - Down-regulating narcissistic tendencies: communal focus reduces state narcissism. AB - Narcissism has been conceptualized as a set of coherent, mutually reinforcing attributes that orients individuals toward self-enhancement and positive self feelings. In this view, reducing one element of narcissism--such as a greater concern for agency than communion--may situationally reduce narcissism in a state like manner. Across five studies, we found that increasing communal focus toward others decreases state narcissism. In Study 1, participants induced to feel empathy reported less state narcissism. In Studies 2 to 4, participants primed with interdependent self-construal reported less state narcissism than control participants and those primed with independent self-construal. Furthermore, in Study 4, changes in state narcissism mediated changes in desire for fame and perceptions that others deserve help. Thus, changes in one element of narcissism may situationally reduce narcissistic tendencies. These findings suggest that narcissism is more state-like and context-dependent than previously assumed. PMID- 24345715 TI - Intraductal membranous fat necrosis in a fibroadenoma of breast: a case report. AB - Membranous fat necrosis is an unusual type of fat necrosis occurring in the breast and normally involves the parenchyma. This report describes an apparently unique intraductal focus in a fibroadenoma following prior needling. Displacement of fatty tissue in the form of membranous fat necrosis within ducts could be added to the list of histological features following core biopsy. PMID- 24345716 TI - Saint Bernadette, the Saint of Lourdes. PMID- 24345718 TI - Joint angles of the ankle, knee, and hip and loading conditions during split squats. AB - The aim of this study was to quantify how step length and the front tibia angle influence joint angles and loading conditions during the split squat exercise. Eleven subjects performed split squats with an additional load of 25% body weight applied using a barbell. Each subject's movements were recorded using a motion capture system, and the ground reaction force was measured under each foot. The joint angles and loading conditions were calculated using a cluster-based kinematic approach and inverse dynamics modeling respectively. Increases in the tibia angle resulted in a smaller range of motion (ROM) of the front knee and a larger ROM of the rear knee and hip. The external flexion moment in the front knee/hip and the external extension moment in the rear hip decreased as the tibia angle increased. The flexion moment in the rear knee increased as the tibia angle increased. The load distribution between the legs changed < 25% when split squat execution was varied. Our results describing the changes in joint angles and the resulting differences in the moments of the knee and hip will allow coaches and therapists to adapt the split squat exercise to the individual motion and load demands of athletes. PMID- 24345717 TI - Influence of sex and menopausal status on response, remission, and recurrence in patients with recurrent major depressive disorder treated with venlafaxine extended release or fluoxetine: analysis of data from the PREVENT study. AB - OBJECTIVE: To evaluate the effects of sex and menopausal status on acute-, continuation-, and maintenance-phase treatment outcomes in patients with recurrent major depressive disorder (MDD). METHOD: This was a secondary analysis of data from the Prevention of Recurrent Episodes of Depression With Venlafaxine for Two Years (PREVENT) trial, a multiphase, multicenter, double-blind study in which adult outpatients with recurrent MDD (by DSM-IV criteria) were randomly assigned to 10 weeks of acute-phase venlafaxine extended release (ER) (75-300 mg/d) or fluoxetine (20-60 mg/d). Patients achieving response or remission had 6 months of continuation-phase treatment. Responding or remitting patients in the venlafaxine ER group were randomly assigned to venlafaxine ER or placebo for 2 consecutive 12-month maintenance phases; fluoxetine-treated patients continued receiving fluoxetine. The outcome measures for this analysis were acute- and continuation-phase response and remission rates (as measured by the 17-item Hamilton Depression Rating Scale) and time to depression recurrence in the maintenance phases according to sex and menopausal status at baseline. RESULTS: The intent-to-treat population comprised 781 patients in the venlafaxine ER group (65% women) and 266 patients in the fluoxetine group (61% women); 64% of all women were premenopausal, and 25% were postmenopausal (5% perimenopausal; not analyzed). At acute-phase end, remission rates in the venlafaxine ER vs fluoxetine groups were 44% vs 47% in men, 51% vs 52% in women, 50% vs 52% in premenopausal women, and 52% vs 55% in postmenopausal women. At continuation phase end, remission rates in the venlafaxine ER vs fluoxetine groups were 71% vs 74% in men, 72% vs 67% in women, 72% vs 69% in premenopausal women and 71% vs 63% in postmenopausal women. Response rates were consistent with these findings. Based on a Cox proportional hazards model, sex was not a significant predictor of recurrence during the first or second maintenance phase (hazard ratio [HR] = 1.233; P = .3712 and HR = 1.103; P = .8075, respectively), and neither was menopausal status at acute-phase baseline (HR = 0.941; P = .8234 and HR = 0.531; P = .2065, respectively). CONCLUSIONS: In this study of patients with recurrent MDD, treatment outcomes with venlafaxine ER and fluoxetine did not differ on the basis of sex or menopausal status. Our confidence in these findings is limited by the lack of a placebo arm during the acute and continuation phases and by the small sample sizes for subgroup analyses in the maintenance phases. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00046020. PMID- 24345719 TI - Characterization and mechanism of action of Microbacterium imperiale glucan 1,4 alpha-maltotriohydrolase. AB - In this study, glucan 1,4-alpha-maltotriohydrolase (AMTS) from Microbacterium imperiale was purified and characterized. Hydrolysis by AMTS was affected by starch structure (e.g., amylose versus amylopectin) and hydrolysis time. During the initial phase of hydrolysis of maltooligosaccharides (G4-G7), AMTS displayed a unique transfer specificity to the transfer of maltotriosyl units. After extensive hydrolysis, maltotriose became the major end product, followed by glucose and maltose. Maltotetraose (G4) was the smallest donor in transglycosylation reactions by AMTS. This is the first study that reports transglycosylation activity of AMTS on maltooligosaccharides. The results of this study suggest that high purity maltotriose can be produced by the hydrolytic action of AMTS on starch. PMID- 24345720 TI - Synthesis of two trisaccharides related to the hepatoprotective phenylethanoids leonoside E and F isolated from Leonurus japonicus Houtt. AB - The chemical synthesis of two trisaccharides related to leonoside E and F is reported. The target oligosaccharides were prepared in the form of their p methoxyphenyl glycosides using a common disaccharide acceptor. All reaction steps were high yielding (>80%) and the stereoselective glycosylations were achieved by activation of the thioglycoside donors using N-iodosuccinimide in the presence of La(OTf)3. PMID- 24345721 TI - Brain alterations in adult ADHD: effects of gender, treatment and comorbid depression. AB - Children with attention-deficit/hyperactivity disorder (ADHD) have smaller volumes of total brain matter and subcortical regions, but it is unclear whether these represent delayed maturation or persist into adulthood. We performed a structural MRI study in 119 adult ADHD patients and 107 controls and investigated total gray and white matter and volumes of accumbens, caudate, globus pallidus, putamen, thalamus, amygdala and hippocampus. Additionally, we investigated effects of gender, stimulant treatment and history of major depression (MDD). There was no main effect of ADHD on the volumetric measures, nor was any effect observed in a secondary voxel-based morphometry (VBM) analysis of the entire brain. However, in the volumetric analysis a significant gender by diagnosis interaction was found for caudate volume. Male patients showed reduced right caudate volume compared to male controls, and caudate volume correlated with hyperactive/impulsive symptoms. Furthermore, patients using stimulant treatment had a smaller right hippocampus volume compared to medication-naive patients and controls. ADHD patients with previous MDD showed smaller hippocampus volume compared to ADHD patients with no MDD. While these data were obtained in a cross sectional sample and need to be replicated in a longitudinal study, the findings suggest that developmental brain differences in ADHD largely normalize in adulthood. Reduced caudate volume in male patients may point to distinct neurobiological deficits underlying ADHD in the two genders. Smaller hippocampus volume in ADHD patients with previous MDD is consistent with neurobiological alterations observed in MDD. PMID- 24345722 TI - Leaving antegrade pulmonary blood flow results in reversal of flow in the azygous vein and decompression of the cavopulmonary circulation: mechanism of cyanosis defined with cardiac magnetic resonance imaging. AB - We report the case of a 2.5-year-old patient with single-ventricle physiology who underwent cardiac magnetic resonance study for cyanosis after Kawashima operation. Magnetic resonance imaging study showed a veno-venous collateral redirecting systemic venous flow, responsible for cyanosis. PMID- 24345723 TI - Counting injury deaths: a comparison of two definitions and two countries. AB - OBJECTIVES: This study sought to examine the discrepancy in counting injury deaths according to two definitions, that is, (a) external cause of injury as the underlying cause of death (UCOD), and (b) with mention of external cause of injury, and differences in certification practices between Taiwan and the USA. METHODS: We calculated the percentage (U/M%) in which external cause of injury was selected as the UCOD (U) among deaths with mention (M) of external cause of injury anywhere on the death certificate to assess the discrepancy between the two definitions in counting injury deaths. RESULTS: The discrepancy was small in Taiwan and in the USA for transport injuries (with U/M% 99% and 98%) and intentional self-harm (100% and 100%) and large for accidental suffocation (64% and 29%) as well as complications of medical and surgical care (61% and 10%). The magnitude of discrepancy was not consistent between countries in accidental falls (96% vs 81%) and accidental drowning (80% vs 97%). Certifiers in Taiwan were more likely to report an accidental fall in Part I of the death certificate and less likely to report medical conditions (such as stroke, Alzheimer's disease or Parkinson's disease, etc) with accidental suffocation than their counterpart US certifiers. CONCLUSIONS: The counting of injury deaths according to two definitions varied by external cause of injury as well as between countries. For some external causes of injury with high discrepancies, we suggest presenting the number of injury deaths according to two definitions. PMID- 24345724 TI - Goodbye to old friends. PMID- 24345726 TI - Low-frequency noise in individual carbon nanotube field-effect transistors with top, side and back gate configurations: effect of gamma irradiation. AB - We report on the influence of low gamma irradiation (10(4) Gy) on the noise properties of individual carbon nanotube (CNT) field-effect transistors (FETs) with different gate configurations and two different dielectric layers, SiO2 and Al2O3. Before treatment, strong generation-recombination (GR) noise components are observed. These data are used to identify several charge traps related to dielectric layers of the FETs by determining their activation energy. Investigation of samples with a single SiO2 dielectric layer as well as with two dielectric layers allows us to separate traps for each of the two dielectric layers. We reveal that each charge trap level observed in the side gate operation splits into two levels in top gate operation due to a different potential profile along the CNT channel. After gamma irradiation, only reduced flicker noise is registered in the noise spectra, which indicates a decrease of the number of charge traps. The mobility, which is estimated to be larger than 2 * 10(4) cm(2) V(-1) s(-1) at room temperature, decreases only slightly after radiation treatment, demonstrating high radiation hardness of the CNTs. Finally, we study the influence of Schottky barriers at the metal-nanotube interface on the transport properties of FETs, analyzing the behavior of the flicker noise component. PMID- 24345727 TI - A standard for Faecal Immunochemical TesTs for haemoglobin evaluation reporting (FITTER). PMID- 24345725 TI - Prediction of outcome following early salvage radiotherapy among patients with biochemical recurrence after radical prostatectomy. AB - BACKGROUND: Early salvage radiotherapy (eSRT) represents the only curative option for prostate cancer patients experiencing biochemical recurrence (BCR) for local recurrence after radical prostatectomy (RP). OBJECTIVE: To develop and internally validate a novel nomogram predicting BCR after eSRT in patients treated with RP. DESIGN, SETTING, AND PARTICIPANTS: Using a multi-institutional cohort, 472 node negative patients who experienced BCR after RP were identified. All patients received eSRT, defined as local radiation to the prostate and seminal vesicle bed, delivered at prostate-specific antigen (PSA) <= 0.5 ng/ml. OUTCOME MEASUREMENT AND STATISTICAL ANALYSIS: BCR after eSRT was defined as two consecutive PSA values >= 0.2 ng/ml. Uni- and multivariable Cox regression models predicting BCR after eSRT were fitted. Regression-based coefficients were used to develop a nomogram predicting the risk of 5-yr BCR after eSRT. The discrimination of the nomogram was quantified with the Harrell concordance index and the calibration plot method. Two hundred bootstrap resamples were used for internal validation. RESULTS AND LIMITATIONS: Mean follow-up was 58 mo (median: 48 mo). Overall, 5-yr BCR-free survival rate after eSRT was 73.4%. In univariable analyses, pathologic stage, Gleason score, and positive surgical margins were associated with the risk of BCR after eSRT (all p <= 0.04). These results were confirmed in multivariable analysis, where all the previously mentioned covariates as well as pre-RT PSA were significantly associated with BCR after eSRT (all p <= 0.04). A coefficient-based nomogram demonstrated a bootstrap corrected discrimination of 0.74. Our study is limited by its retrospective nature and use of BCR as an end point. CONCLUSIONS: eSRT leads to excellent cancer control in patients with BCR for presumed local failure after RP. We developed the first nomogram to predict outcome after eSRT. Our model facilitates risk stratification and patient counselling regarding the use of secondary therapy for individuals experiencing BCR after RP. PATIENT SUMMARY: Salvage radiotherapy leads to optimal cancer control in patients who experience recurrence after radical prostatectomy. We developed a novel tool to identify the best candidates for salvage treatment and to allow selection of patients to be considered for additional forms of therapy. PMID- 24345728 TI - Cigarette smoke affects posttranslational modifications and inhibits capacitation induced changes in human sperm proteins. AB - Sperm are highly dependent on posttranslational modifications of proteins. Massive phosphorylation on tyrosine residue is required for sperm capacitation. Sumoylation has also been recently implicated in spermatogenesis and sperm functions. Cigarette smoke is known to cause oxidative stress in different tissues, and several studies suggest that it causes oxidative stress in sperm. Whether tobacco affects posttranslational modifications in human sperm is currently unknown. In this study, we show that a short exposure of human sperm to physiological concentrations of cigarette smoke extract (CSE) causes the partial de-sumoylation of many sperm proteins. Furthermore, the presence of a low concentration of CSE in the human tubal fluid during an induction of in vitro capacitation inhibits the capacitation-associated increase in protein phosphorylation. Collectively, changes in posttranslational modifications may be one of the mechanisms through which exposure to tobacco can negatively affect sperm functions and cause fertility problems. PMID- 24345729 TI - Antiretroviral therapy and drug resistance in human immunodeficiency virus type 2 infection. AB - One to two million people worldwide are infected with the human immunodeficiency virus type 2 (HIV-2), with highest prevalences in West African countries, but also present in Western Europe, Asia and North America. Compared to HIV-1, HIV-2 infection undergoes a longer asymptomatic phase and progresses to AIDS more slowly. In addition, HIV-2 shows lower transmission rates, probably due to its lower viremia in infected individuals. There is limited experience in the treatment of HIV-2 infection and several antiretroviral drugs used to fight HIV-1 are not effective against HIV-2. Effective drugs against HIV-2 include nucleoside analogue reverse transcriptase (RT) inhibitors (e.g. zidovudine, tenofovir, lamivudine, emtricitabine, abacavir, stavudine and didanosine), protease inhibitors (saquinavir, lopinavir and darunavir), and integrase inhibitors (raltegravir, elvitegravir and dolutegravir). Maraviroc, a CCR5 antagonist blocking coreceptor binding during HIV entry, is active in vitro against CCR5 tropic HIV-2 but more studies are needed to validate its use in therapeutic treatments against HIV-2 infection. HIV-2 strains are naturally resistant to a few antiretroviral drugs developed to suppress HIV-1 propagation such as nonnucleoside RT inhibitors, several protease inhibitors and the fusion inhibitor enfuvirtide. Resistance selection in HIV-2 appears to be faster than in HIV-1. In this scenario, the development of novel drugs specific for HIV-2 is an important priority. In this review, we discuss current anti-HIV-2 therapies and mutational pathways leading to drug resistance. PMID- 24345730 TI - Self-assembly of fatty acids in the presence of amines and cationic components. AB - Fatty acids can self-assemble under various shapes in the presence of amines or cationic components. We assemble and compare these types of self-assembly leading toward a catanionic system either with a cationic surfactant or with an amine component playing the role of counter-ion. First, we focus on the molar ratio as a key driving parameter. Known and yet un-known values from other quantities governing the colloidal properties of these systems such as structural surface charge, osmotic pressure, molecular segregation, rigidity, in plane colloidal interactions and melting transition are discussed. We include also recent results obtained on the interfacial and foaming properties of these systems. We will highlight the specificity of these self-assemblies leading to unusual macroscopic properties rich of robust applications. PMID- 24345731 TI - Microcapsule mechanics: from stability to function. AB - Microcapsules are reviewed with special emphasis on the relevance of controlled mechanical properties for functional aspects. At first, assembly strategies are presented that allow control over the decisive geometrical parameters, diameter and wall thickness, which both influence the capsule's mechanical performance. As one of the most powerful approaches the layer-by-layer technique is identified. Subsequently, ensemble and, in particular, single-capsule deformation techniques are discussed. The latter generally provide more in-depth information and cover the complete range of applicable forces from smaller than pN to N. In a theory chapter, we illustrate the physics of capsule deformation. The main focus is on thin shell theory, which provides a useful approximation for many deformation scenarios. Finally, we give an overview of applications and future perspectives where the specific design of mechanical properties turns microcapsules into (multi-)functional devices, enriching especially life sciences and material sciences. PMID- 24345732 TI - McBain and the centenary of the micelle. AB - In 1913, J.W. McBain introduced the word "micelle" into surface and colloid chemistry in the context of the association of surfactant molecules in aqueous solution. This article gives a biographic account of McBain, and reviews the early work on micellar aggregation, leading up to the pioneering ideas of G.S. Hartley who introduced the first model of the spherical micelle that we would recognise today. PMID- 24345733 TI - Sleep duration, but not insomnia, predicts the 2-year course of depressive and anxiety disorders. AB - OBJECTIVE: To examine the predictive role of insomnia and sleep duration on the 2 year course of depressive and anxiety disorders. METHOD: This study is a secondary data analysis based on data from the baseline (2004-2007) and 2-year assessment of the Netherlands Study of Depression and Anxiety. Participants were 1,069 individuals with DSM-IV-based depressive and/or anxiety disorders at baseline. Sleep measures included insomnia (Women's Health Initiative Insomnia Rating Scale score >= 9) and sleep duration (categorized as short [<= 6 hours], normal [7-9 hours], or long [>= 10 hours]). Outcome measures were persistence of DSM-IV depressive and anxiety disorders (current diagnosis at 2-year follow-up), time to remission, and clinical course trajectory of symptoms (early sustained remission, late remission/recurrence, and chronic course). Logistic regression analyses were adjusted for sociodemographic characteristics and chronic medical disorders, psychotropic medications, and severity of depressive and anxiety symptoms. RESULTS: The effect of insomnia on persistence of depressive and/or anxiety disorders (OR = 1.50; 95% CI, 1.16-1.94) was explained by severity of baseline depressive/anxiety symptoms (adjusted OR with severity = 1.04; 95% CI, 0.79-1.37). Long sleep duration was independently associated with persistence of depression/anxiety even after adjusting for severity of psychiatric symptoms (OR = 2.52; 95% CI, 1.27-4.99). For short sleep duration, the independent association with persistence of combined depression/anxiety showed a trend toward significance (OR = 1.32; 95% CI, 0.98-1.78), and a significant association for the persistence of depressive disorders (OR = 1.49; 95% CI, 1.11-2.00). Both short and long sleep duration were independently associated with a chronic course trajectory (short sleep: OR = 1.50; 95% CI, 1.04-2.16; long sleep: OR = 2.91, 95% CI, 1.22-6.93). DISCUSSION: Both short and long sleep duration-but not insomnia are important predictors of a chronic course, independent of symptom severity. It is to be determined whether treating these sleep conditions results in more favorable outcomes of depression and anxiety. PMID- 24345734 TI - Postnatal epithelium and mesenchyme stem/progenitor cells in bioengineered amelogenesis and dentinogenesis. AB - Rodent incisors provide a classic model for studying epithelial-mesenchymal interactions in development. However, postnatal stem/progenitor cells in rodent incisors have not been exploited for tooth regeneration. Here, we characterized postnatal rat incisor epithelium and mesenchyme stem/progenitor cells and found that they formed enamel- and dentin-like tissues in vivo. Epithelium and mesenchyme cells were harvested separately from the apical region of postnatal 4 5 day rat incisors. Epithelial and mesenchymal phenotypes were confirmed by immunocytochemistry, CFU assay and/or multi-lineage differentiation. CK14+, Sox2+ and Lgr5+ epithelium stem cells from the cervical loop enhanced amelogenin and ameloblastin expression upon BMP4 or FGF3 stimulation, signifying their differentiation towards ameloblast-like cells, whereas mesenchyme stem/progenitor cells upon BMP4, BMP7 and Wnt3a treatment robustly expressed Dspp, a hallmark of odontoblastic differentiation. We then control-released microencapsulated BMP4, BMP7 and Wnt3a in transplants of epithelium and mesenchyme stem/progenitor cells in the renal capsule of athymic mice in vivo. Enamel and dentin-like tissues were generated in two integrated layers with specific expression of amelogenin and ameloblastin in the newly formed, de novo enamel-like tissue, and DSP in dentin like tissue. These findings suggest that postnatal epithelium and mesenchyme stem/progenitor cells can be primed towards bioengineered tooth regeneration. PMID- 24345735 TI - Injectable, porous, and cell-responsive gelatin cryogels. AB - The performance of biomaterials-based therapies can be hindered by complications associated with surgical implant, motivating the development of materials systems that allow minimally invasive introduction into the host. In this study, we created cell-adhesive and degradable gelatin scaffolds that could be injected through a conventional needle while maintaining a predefined geometry and architecture. These scaffolds supported attachment, proliferation, and survival of cells in vitro and could be degraded by recombinant matrix metalloproteinase-2 and -9. Prefabricated gelatin cryogels rapidly resumed their original shape when injected subcutaneously into mice and elicited only a minor host response following injection. Controlled release of granulocyte-macrophage colony stimulating factor from gelatin cryogels resulted in complete infiltration of the scaffold by immune cells and promoted matrix metalloproteinase production leading to cell-mediated degradation of the cryogel matrix. These findings suggest that gelatin cryogels could serve as a cell-responsive platform for biomaterial-based therapy. PMID- 24345736 TI - A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. AB - Targeted drug delivery vehicles with low immunogenicity and toxicity are needed for cancer therapy. Here we show that exosomes, endogenous nano-sized membrane vesicles secreted by most cell types, can deliver chemotherapeutics such as doxorubicin (Dox) to tumor tissue in BALB/c nude mice. To reduce immunogenicity and toxicity, mouse immature dendritic cells (imDCs) were used for exosome production. Tumor targeting was facilitated by engineering the imDCs to express a well-characterized exosomal membrane protein (Lamp2b) fused to alphav integrin specific iRGD peptide (CRGDKGPDC). Purified exosomes from imDCs were loaded with Dox via electroporation, with an encapsulation efficiency of up to 20%. iRGD exosomes showed highly efficient targeting and Dox delivery to alphav integrin positive breast cancer cells in vitro as demonstrated by confocal imaging and flow cytometry. Intravenously injected targeted exosomes delivered Dox specifically to tumor tissues, leading to inhibition of tumor growth without overt toxicity. Our results suggest that exosomes modified by targeting ligands can be used therapeutically for the delivery of Dox to tumors, thus having great potential value for clinical applications. PMID- 24345737 TI - Quorum sensing inhibitory activities of surface immobilized antibacterial dihydropyrrolones via click chemistry. AB - Device-related infection remains a major barrier to the use of biomaterial implants as life-saving devices. This study aims to examine the effectiveness and mechanism of action of surface attached dihydropyrrolones (DHPs), a quorum sensing (QS) inhibitor, against bacterial colonization. DHPs were covalently attached on glass surfaces via copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) click reaction. The covalent attachment of DHP surfaces was confirmed by X-ray photoelectron spectroscopy (XPS) and contact angle measurements, and the antimicrobial efficacy of the DHP coatings was assessed by confocal laser scanning microscopy (CLSM) and image analysis. The results demonstrated that covalently bound DHP compounds are effective in reducing the adhesion by up to 97% (p < 0.05) for both Pseudomonas aeruginosa and Staphylococcus aureus. Furthermore, using the green fluorescent protein (Gfp) based reporter technology, it is demonstrated that surface attached DHPs were able to repress the expression of a lasB-gfp reporter fusion of P. aeruginosa by 72% (p < 0.001) without affecting cell viability. This demonstrates the ability of the covalently bound QS inhibitor to inhibit QS and suggests the existence of a membrane-based pathway(s) for QS inhibition. Hence, strategies based on incorporation of QS inhibitors such as DHPs represent a potential approach for prevention of device-related infections. PMID- 24345738 TI - Pharmacological targeting of p53 through RITA is an effective antitumoral strategy for malignant pleural mesothelioma. AB - Malignant mesothelioma, a very aggressive tumor associated to asbestos exposure, is expected to increase in incidence, and unfortunately, no curative modality exists. Reactivation of p53 is a new attractive antitumoral strategy. p53 is rarely mutated in mesothelioma, but it is inactivated in most tumors by the lack of p14(ARF). Here, we evaluated the feasibility of this approach in pleural mesothelioma by testing RITA and nutlin-3, two molecules able to restore p53 function through a different mechanism, on a panel of mesothelioma cell lines representing the epithelioid (NCI-H28, NCI-H2452, IST-MES 2), biphasic (MSTO 211H), and sarcomatoid (NCI-H2052) histotypes compared with the normal mesothelial HMC-hTERT. RITA triggered robust caspase-dependent apoptosis specifically in epithelioid and biphasic mesothelioma cell lines, both through wild-type and mutant p53, concomitant to p21 downregulation. Conversely, nutlin-3 induced a p21-dependent growth arrest, rather than apoptosis, and was slightly toxic on HMC-hTERT. Interestingly, we identified a previously undetected point mutation of p53 (p.Arg249Ser) in IST-MES 2, and showed that RITA is also able to reactivate this p53 mutant protein and its apoptotic function. RITA reduced tumor growth in a MSTO-211H-derived xenograft model of mesothelioma and synergized with cisplatin, which is the mainstay of treatment for this tumor. Our data indicate that reactivation of p53 and concomitant p21 downregulation effectively induce cell death in mesothelioma, a tumor characterized by a high intrinsic resistance to apoptosis. Altogether, our findings provide the preclinical framework supporting the use of p53-reactivating agents alone, or in combination regimens, to improve the outcome of patients with mesothelioma. PMID- 24345739 TI - Ruptured mycobacterial aneurysm of the carotid artery. AB - Mycotic aneurysms resulting from intravesical bacillus Calmette-Guerin (BCG) treatment are exceptionally rare. We report on the case of a 73-year-old man who underwent intravesical therapy of BCG for bladder carcinoma and developed a right neck mass. A carotid pseudoaneurysm within a fibrotic mass was noted on surgical exploration. Radical resection was performed followed by a polytetrafluoroethylene interposition graft. Final pathology revealed necrotizing granulomas and multinucleated giant cells concerning for tuberculoma. Intravesicular BCG immunotherapy is an accepted treatment for patients with urothelial carcinoma. Carotid aneurysms are exceptionally rare in this setting and should prompt evaluation for systemic tuberculoid dissemination. PMID- 24345740 TI - Plastic bronchitis: symptomatic improvement after pulmonary arterial stenting in four patients with Fontan circulation. AB - Plastic bronchitis is a severe complication after a Fontan procedure, with an estimated incidence around 1-2% and poor prognosis. We present the cases of four patients with plastic bronchitis after a total cavopulmonary connection with a stenosis of the left pulmonary artery that was stented successfully. In three of the four patients, symptoms improved after catheter intervention in combination with pulmonary vasodilator and inhalative treatment. PMID- 24345741 TI - Optimal starting block configuration in sprint running; a comparison of biological and prosthetic legs. AB - In the 2012 Paralympic 100 m and 200 m finals, 86% of athletes with a unilateral amputation placed their unaffected leg on the front starting block. Can this preference be explained biomechanically? We measured the biomechanical effects of starting block configuration for seven nonamputee sprinters and nine athletes with a unilateral amputation. Each subject performed six starts, alternating between their usual and unusual starting block configurations. When sprinters with an amputation placed their unaffected leg on the front block, they developed 6% greater mean resultant combined force compared with the opposite configuration (1.38 +/- 0.06 vs 1.30 +/- 0.11 BW, P = .015). However, because of a more vertical push angle, horizontal acceleration performance was equivalent between starting block configurations. We then used force data from each sprinter with an amputation to calculate the hypothetical starting mechanics for a virtual nonamputee (two unaffected legs) and a virtual bilateral amputee (two affected legs). Accelerations of virtual bilateral amputees were 15% slower compared with athletes with a unilateral amputation, which in turn were 11% slower than virtual nonamputees. Our biomechanical data do not explain the starting block configuration preference but they do explain the starting performance differences observed between nonamputee athletes and those with leg amputations. PMID- 24345742 TI - The epidemic of extended-spectrum-beta-lactamase-producing Escherichia coli ST131 is driven by a single highly pathogenic subclone, H30-Rx. AB - The Escherichia coli sequence type 131 (ST131) clone is notorious for extraintestinal infections, fluoroquinolone resistance, and extended-spectrum beta-lactamase (ESBL) production, attributable to a CTX-M-15-encoding mobile element. Here, we applied pulsed-field gel electrophoresis (PFGE) and whole genome sequencing to reconstruct the evolutionary history of the ST131 clone. PFGE-based cluster analyses suggested that both fluoroquinolone resistance and ESBL production had been acquired by multiple ST131 sublineages through independent genetic events. In contrast, the more robust whole-genome-sequence based phylogenomic analysis revealed that fluoroquinolone resistance was confined almost entirely to a single, rapidly expanding ST131 subclone, designated H30-R. Strikingly, 91% of the CTX-M-15-producing isolates also belonged to a single, well-defined clade nested within H30-R, which was named H30-Rx due to its more extensive resistance. Despite its tight clonal relationship with H30Rx, the CTX-M 15 mobile element was inserted variably in plasmid and chromosomal locations within the H30-Rx genome. Screening of a large collection of recent clinical E. coli isolates both confirmed the global clonal expansion of H30-Rx and revealed its disproportionate association with sepsis (relative risk, 7.5; P < 0.001). Together, these results suggest that the high prevalence of CTX-M-15 production among ST131 isolates is due primarily to the expansion of a single, highly virulent subclone, H30-Rx. IMPORTANCE: We applied an advanced genomic approach to study the recent evolutionary history of one of the most important Escherichia coli strains in circulation today. This strain, called sequence type 131 (ST131), causes multidrug-resistant bladder, kidney, and bloodstream infections around the world. The rising prevalence of antibiotic resistance in E. coli is making these infections more difficult to treat and is leading to increased mortality. Past studies suggested that many different ST131 strains gained resistance to extended spectrum cephalosporins independently. In contrast, our research indicates that most extended-spectrum-cephalosporin-resistant ST131 strains belong to a single highly pathogenic subclone, called H30-Rx. The clonal nature of H30-Rx may provide opportunities for vaccine or transmission prevention-based control strategies, which could gain importance as H30-Rx and other extraintestinal pathogenic E. coli subclones become resistant to our best antibiotics. PMID- 24345743 TI - Role of endothelial cell septin 7 in the endocytosis of Candida albicans. AB - Candida albicans invades endothelial cells by binding to N-cadherin and other cell surface receptors. This binding induces rearrangement of endothelial cell actin microfilaments, which results in the formation of pseudopods that surround the organism and pull it into the endothelial cell. Here, we investigated the role of endothelial cell septin 7 (SEPT7) in the endocytosis of C. albicans hyphae. Using confocal microscopy, we determined that SEPT7 accumulated with N cadherin and actin microfilaments around C. albicans as it was endocytosed by endothelial cells. Affinity purification studies indicated that a complex containing N-cadherin and SEPT7 was recruited by C. albicans and that formation of this complex around C. albicans was mediated by the fungal Als3 and Ssa1 invasins. Knockdown of N-cadherin by small interfering RNA (siRNA) reduced recruitment of SEPT7 to C. albicans, suggesting that N-cadherin functions as a link between SEPT7 and the fungus. Also, depolymerization of actin microfilaments with cytochalasin D decreased the association between SEPT7 and N-cadherin and inhibited recruitment of both SEPT7 and N-cadherin to C. albicans, indicating the necessity of an intact cytoskeleton in the functional interaction between SEPT7 and N-cadherin. Importantly, knockdown of SEPT7 decreased accumulation of N cadherin around C. albicans in intact endothelial cells and reduced binding of N cadherin to this organism, as revealed by the affinity purification assay. Furthermore, SEPT7 knockdown significantly inhibited the endocytosis of C. albicans. Therefore, in response to C. albicans infection, SEPT7 forms a complex with endothelial cell N-cadherin, is required for normal accumulation of N cadherin around C. albicans hyphae, and is necessary for maximal endocytosis of the organism. IMPORTANCE: During hematogenously disseminated infection, Candida albicans invades the endothelial cell lining of the blood vessels to invade the deep tissues. C. albicans can invade endothelial cells by inducing its own endocytosis, which is triggered when the C. albicans Als3 and Ssa1 invasins bind to N-cadherin on the endothelial cell surface. How this binding induces endocytosis is incompletely understood. Septins are intracellular GTP-binding proteins that influence the function and localization of cell surface proteins. We found that C. albicans Als3 and Ssa1 bind to a complex containing N-cadherin and septin 7, which in turn interacts with endothelial cell microfilaments, thereby inducing endocytosis of the organism. The key role of septin 7 in governing receptor-mediated endocytosis is likely relevant to host cell invasion by other microbial pathogens, in addition to C. albicans. PMID- 24345746 TI - How the double spherules of infectious bronchitis virus impact our understanding of RNA virus replicative organelles. AB - Powered by advances in electron tomography, recent studies have extended our understanding of how viruses construct "replication factories" inside infected cells. Their function, however, remains an area of speculation with important implications for human health. It is clear from these studies that whatever their purpose, organelle structure is dynamic (M. Ulasli, M. H. Verheije, C. A. de Haan, and F. Reggiori, Cell. Microbiol. 12:844-861, 2010) and intricate (K. Knoops, M. Kikkert, S. H. Worm, J. C. Zevenhoven-Dobbe, Y. van der Meer, et al., PLOS Biol. 6:e226, 2008). But by concentrating on medically important viruses, these studies have failed to take advantage of the genetic variation inherent in a family of viruses that is as diverse as the archaea, bacteria, and eukaryotes combined (C. Lauber, J. J. Goeman, M. del Carmen Parquet, P. T. Nga, E. J. Snijder, et al., PLOS Pathog. 9:e1003500, 2013). In this climate, Maier et al. (H. J. Maier, P. C. Hawes, E. M. Cottam, J. Mantell, P. Verkade, et al., mBio 4:e00801-13, 2013) explored the replicative structures formed by an avian coronavirus that appears to have diverged at an early point in coronavirus evolution and shed light on controversial aspects of viral biology. PMID- 24345744 TI - Emergence of the epidemic methicillin-resistant Staphylococcus aureus strain USA300 coincides with horizontal transfer of the arginine catabolic mobile element and speG-mediated adaptations for survival on skin. AB - The arginine catabolic mobile element (ACME) is the largest genomic region distinguishing epidemic USA300 strains of methicillin-resistant Staphylococcus aureus (MRSA) from other S. aureus strains. However, the functional relevance of ACME to infection and disease has remained unclear. Using phylogenetic analysis, we have shown that the modular segments of ACME were assembled into a single genetic locus in Staphylococcus epidermidis and then horizontally transferred to the common ancestor of USA300 strains in an extremely recent event. Acquisition of one ACME gene, speG, allowed USA300 strains to withstand levels of polyamines (e.g., spermidine) produced in skin that are toxic to other closely related S. aureus strains. speG-mediated polyamine tolerance also enhanced biofilm formation, adherence to fibrinogen/fibronectin, and resistance to antibiotic and keratinocyte-mediated killing. We suggest that these properties gave USA300 a major selective advantage during skin infection and colonization, contributing to the extraordinary evolutionary success of this clone. IMPORTANCE: Over the past 15 years, methicillin-resistant Staphylococcus aureus (MRSA) has become a major public health problem. It is likely that adaptations in specific MRSA lineages (e.g., USA300) drove the spread of MRSA across the United States and allowed it to replace other, less-virulent S. aureus strains. We suggest that one major factor in the evolutionary success of MRSA may have been the acquisition of a gene (speG) that allows S. aureus to evade the toxicity of polyamines (e.g., spermidine and spermine) that are produced in human skin. Polyamine tolerance likely gave MRSA multiple fitness advantages, including the formation of more robust biofilms, increased adherence to host tissues, and resistance to antibiotics and killing by human skin cells. PMID- 24345747 TI - Cytochrome bd oxidase and hydrogen peroxide resistance in Mycobacterium tuberculosis. PMID- 24345748 TI - Oral cadmium in mice carrying 5 versus 2 copies of the Slc39a8 gene: comparison of uptake, distribution, metal content, and toxicity. AB - The highly conserved human and mouse SLC39A8 gene encodes the divalent cation/bicarbonate symporter ZIP8 expressed ubiquitously in most cell types. Our bacterial artificial chromosome-transgenic BTZIP8-3 line has 3 additional copies of the Slc39a8 gene in addition to its constitutive diploid pair found in wild type (WT) mice. In liver, kidney, lung, testis, gastrointestinal tract, and brain, BTZIP8-3 mice are known to express ~2.5 times greater amounts of ZIP8, compared with WT mice. Herein we administered cadmium chloride (CdCl2) in drinking water (100 mg/L through week 2, 200 mg/L through week 4, 400 mg/L through week 8, 800 mg/L through week 12, and 1600 mg/L through week 20, when the experiment was concluded). We postulated that Cd uptake and distribution--and, therefore, toxicity in certain tissues--would be enhanced in BTZIP8-3, compared with WT mice. BTZIP8-3 and WT groups ingested comparable amounts of Cd. Compared with WT, BTZIP8-3 mice showed tissue specific: increases in Cd, zinc, and manganese content and decreases in calcium content. Both Cd-exposed BTZIP8-3 and WT were similar in lower urinary pH; increased plasma alanine and aspartate aminotransferase activities; elevated iron and copper content in liver, kidney, lung, and testis; and higher blood urea nitrogen and kidney weight. Histological changes in liver, kidney, lung, and testis were minimal. In summary, at the daily oral Cd exposures chosen for this study, 5 versus 2 Slc39a8 gene copies result in no differences in Cd toxicity but do cause differences in tissue-specific content of Cd, zinc, manganese, calcium, iron, and copper. PMID- 24345749 TI - Reproductive toxicity evaluation of the dental resin monomer triethylene glycol dimethacrylate (CASRN 109-16-0) in mice. AB - The reproductive toxicity potential of the resin monomer triethylene glycol dimethacrylate (TEGDMA; Chemical Abstracts Service Registry Number 109-16-0) was investigated in male and female Crl:CD1(ICR) mice, 4 dosage groups, 25 mice/sex/group. Formulations of TEGDMA (0, 0.01, 0.1, or 1.0 mg/kg/d) in reverse osmosis-processed deionized water were intubated once daily beginning 28 days before cohabitation and continuing through mating (males) or through gestation day 17 (females). The following parameters were evaluated: viability, clinical signs, body weights, estrous cyclicity, necropsy observations, organ weights, sperm concentration/motility/morphology, cesarean-sectioning and litter observations, and histopathological evaluation of select tissues. No deaths or clinical signs related to TEGDMA occurred. No significant changes in male and female body weights and body weight gains were recorded for any of the administered dosages of TEGMDA. All mating and fertility parameters and all litter and fetal data were considered to be unaffected by dosages of TEGMDA as high as 1 mg/kg/d. Gross or histopathologic tissue changes attributable to the test article were not observed. Reproductive and developmental no observed adverse effect levels (NOAELs) for TEGMDA were 1.0 mg/kg/d, the highest dose tested. Comparison of conservatively estimated TEGDMA exposures from dental treatments to the NOAEL of 1.0 mg/kg/d identified in this study indicates margins of exposure of at least 120- to 3000-fold depending on the exposure scenario. The results of this study support the continued safe use of TEGDMA in polymeric dental products applied according to the manufacturers' instructions. PMID- 24345750 TI - Monoclonal B-cell lymphocytosis in healthy blood donors: an unexpectedly common finding. AB - Circulating monoclonal B cells may be detected in healthy adults, a condition called monoclonal B-cell lymphocytosis (MBL). MBL has also been identified in donated blood, but no systematic study of blood donors has been reported. Using sensitive and specific laboratory methods, we detected MBL in 149 (7.1%; 95% confidence interval, 6.0% to 8.3%) of 2098 unique donors ages 45 years or older in a Midwestern US regional blood center between 2010 and 2011. Most of the 149 donors had low-count MBL, including 99 chronic lymphocytic leukemia-like (66.4%), 22 atypical (14.8%), and 19 CD5(-) (12.8%) immunophenotypes. However, 5 donors (3.4%) had B-cell clonal counts above 500 cells per uL, including 3 with 1693 to 2887 cells per uL; the clone accounted for nearly all their circulating B cells. Four donors (2.7%) had 2 distinct MBL clones. Of 51 MBL samples in which immunoglobulin heavy chain (IGH)V-D-J genotypes could be determined, 71% and 29% used IGHV3- and IGHV4-family genes, respectively. Sequencing revealed 82% with somatic hypermutation, whereas 18% had >98% germ-line identity, including 5 with entirely germ-line sequences. In conclusion, MBL prevalence is much higher in blood donors than previously reported, and although uncommon, the presence of high-count MBL warrants further investigations to define the biological fate of the transfused cells in recipients. PMID- 24345751 TI - Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. AB - Bosutinib is an oral, dual SRC/ABL tyrosine kinase inhibitor (TKI) with clinical activity in Philadelphia chromosome-positive (Ph(+)) leukemia. We assessed the safety and tolerability of bosutinib 500 mg per day in a phase 1/2 study in chronic-phase (CP) chronic myeloid leukemia (CML) or advanced Ph(+) leukemia following resistance/intolerance to imatinib and possibly other TKIs. Patient cohorts included second-line CP CML (n = 286), third-/fourth-line CP CML (n = 118), and advanced leukemia (n = 166). Median bosutinib duration was 11.1 (range, 0.03-83.4) months. Treatment-emergent adverse events (TEAEs) in each cohort were primarily gastrointestinal (diarrhea [86%/83%/74%], nausea [46%/48%/48%], and vomiting [37%/38%/43%]). Diarrhea presented early, with few (8%) patients experiencing grade 3/4 events; dose reduction due to diarrhea occurred in 6% of affected patients. Grade 3/4 myelosuppression TEAEs were reported in 41% of patients; among affected patients, 46% were managed with bosutinib interruption and 32% with dose reduction. Alanine aminotransferase elevation TEAEs occurred in 17% of patients (grade 3/4, 7%); among patients managed with dose interruption, bosutinib rechallenge was successful in 74%. Bosutinib demonstrated acceptable safety with manageable toxicities in Ph(+) leukemia. This trial (NCT00261846) was registered at www.ClinicalTrials.gov (this manuscript is based on a different data snapshot from that in ClinicalTrials.gov). PMID- 24345752 TI - A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. AB - The genetics of angioimmunoblastic T-cell lymphoma (AITL) are very poorly understood. We defined the mutational landscape of AITL across 219 genes in 85 cases from the United States and Europe. We identified >=2 mutations in 34 genes, nearly all of which were not previously implicated in AITL. These included loss of-function mutations in TP53 (n = 4), ETV6 (n = 3), CCND3 (n = 2), and EP300 (n = 5), as well as gain-of-function mutations in JAK2 (n = 2) and STAT3 (n = 4). TET2 was mutated in 65 (76%) AITLs, including 43 that harbored 2 or 3 TET2 mutations. DNMT3A mutations occurred in 28 (33%) AITLs; 100% of these also harbored TET2 mutations (P < .0001). Seventeen AITLs harbored IDH2 R172 substitutions, including 15 with TET2 mutations. In summary, AITL is characterized by high frequencies of overlapping mutations in epigenetic modifiers and targetable mutations in a subset of cases. PMID- 24345754 TI - Human mesenchymal stromal cells deliver systemic oncolytic measles virus to treat acute lymphoblastic leukemia in the presence of humoral immunity. AB - Clinical trials of oncolytic attenuated measles virus (MV) are ongoing, but successful systemic delivery in immune individuals remains a major challenge. We demonstrated high-titer anti-MV antibody in 16 adults with acute lymphoblastic leukemia (ALL) following treatments including numerous immunosuppressive drugs. To resolve this challenge, human bone marrow-derived mesenchymal stromal cells (BM-MSCs) were used to efficiently deliver MV in a systemic xenograft model of precursor B-lineage-ALL. BM-MSCs were successfully loaded with MV ex vivo, and MV was amplified intracellularly, without toxicity. Live cell confocal imaging demonstrated a viral hand-off between BM-MSCs and ALL targets in the presence of antibody. In a murine model of disseminated ALL, successful MV treatment (judged by bioluminescence quantification and survival) was completely abrogated by passive immunization with high-titer human anti-MV antibody. Importantly, no such abrogation was seen in immunized mice receiving MV delivered by BM-MSCs. These data support the use of BM-MSCs as cellular carriers for MV in patients with ALL. PMID- 24345753 TI - Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. AB - About a quarter of patients with severe aplastic anemia remain pancytopenic despite immunosuppressive therapy. We have previously demonstrated that eltrombopag has efficacy in this setting with 44% (11/25) of patients having clinically significant hematologic responses. We now report safety and efficacy data on a further 18 patients and long-term follow-up on the entire cohort of 43 patients. The overall response rate was 17 of 43 patients (40%) at 3 to 4 months, including tri- and bilineage responses. The majority of patients who remained on eltrombopag in an extension study (14/17) continued to show improvement, and 7 eventually had significant increases in neutrophil, red cell, and platelet lineages. Five patients with robust near-normalization of blood counts had drug discontinued at a median of 28.5 months after entry (range, 9-37 months), and all maintained stable counts a median of 13 months (range, 1-15 months) off eltrombopag. Eight patients, including 6 nonresponders and 2 responders, developed new cytogenetic abnormalities on eltrombopag, including 5 with chromosome 7 loss or partial deletion. None evolved to acute myeloid leukemia to date. Eltrombopag is efficacious in a subset of patients with aplastic anemia refractory to immunosuppressive therapy, with frequent multilineage responses and maintenance of normalized hematopoiesis off treatment. This study is registered at www.clinicaltrials.gov as #NCT00922883. PMID- 24345755 TI - Growth differentiating factor 15 enhances the tumor-initiating and self-renewal potential of multiple myeloma cells. AB - Disease relapse remains a major factor limiting the survival of cancer patients. In the plasma cell malignancy multiple myeloma (MM), nearly all patients ultimately succumb to disease relapse and progression despite new therapies that have improved remission rates. Tumor regrowth indicates that clonogenic growth potential is continually maintained, but the determinants of self-renewal in MM are not well understood. Normal stem cells are regulated by extrinsic niche factors, and the tumor microenvironment (TME) may similarly influence tumor cell clonogenic growth and self-renewal. Growth differentiation factor 15 (GDF15) is aberrantly secreted by bone marrow stromal cells (BMSCs) in MM. We found that GDF15 is produced by BMSCs after direct contact with plasma cells and enhances the tumor-initiating potential and self-renewal of MM cells in a protein kinase B and SRY (sex-determining region Y)-box-dependent manner. Moreover, GDF15 induces the expansion of MM tumor-initiating cells (TICs), and changes in the serum levels of GDF15 were associated with changes in the frequency of clonogenic MM cells and the progression-free survival of MM patients. These findings demonstrate that GDF15 plays a critical role in mediating the interaction among mature tumor cells, the TME, and TICs, and strategies targeting GDF15 may affect long-term clinical outcomes in MM. PMID- 24345757 TI - Meta-analytic findings of the relation between maternal prenatal stress and anxiety and child cognitive outcome. AB - OBJECTIVE: Different studies have revealed mixed findings regarding the relation between maternal prenatal stress or anxiety (MPSA) and early child cognitive outcome. Different methodological considerations may be linked to the absence of clear support for this hypothesized link. The purpose of this article was to conduct a meta-analysis of this relation while considering the following as potential moderators: (1) pregnancy trimester during which MPSA was assessed, (2) type of MPSA assessment (life events, pregnancy related, subjective assessments), and (3) research design (retrospective or prospective). Other moderators were also examined: child age at assessment and the year of publication. METHOD: Eleven studies were identified (N = 5903) that examined the relation between MPSA and early child cognitive outcome. RESULTS: A small effect size of r = -.05 was found for this relation. The effect size varied across studies and was significantly moderated by the manner in which MPSA was operationalized (events, subjective assessment of stress or pregnancy-related stress or anxiety) and by whether MPSA assessment took place before or after infant birth. Greater relations to child cognitive outcome were found for postnatal event-based indicators of MPSA. CONCLUSION: The relation between MPSA and child cognitive outcome seems to be present, but low. Moreover, it is affected by the specific choices made by researchers in the manner in which constructs are operationalized. PMID- 24345756 TI - The evolution of cellular deficiency in GATA2 mutation. AB - Constitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS), and acute myeloid leukemia. In this study, we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency (DCML deficiency) with elevated Fms-like tyrosine kinase 3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Emberger syndrome, monocytopenia with Mycobacterium avium complex (MonoMAC), and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils, and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frameshift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors, and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56(bright) NK cells, naive T cells, and accumulation of terminally differentiated NK and CD8(+) memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision-making. PMID- 24345758 TI - A randomized, double-blind, placebo-controlled study of ziprasidone monotherapy in bipolar disorder with co-occurring lifetime panic or generalized anxiety disorder. AB - OBJECTIVE: Bipolar disorder often co-occurs with anxiety disorders. Evidence suggests that second-generation antipsychotics (SGAs) may be useful in treating both conditions. This study examined the efficacy of ziprasidone in the treatment of these disorders. METHOD: This 3-site, randomized, double-blind, placebo controlled, parallel group, 8-week trial of ziprasidone monotherapy examined 49 subjects with bipolar disorder and lifetime panic disorder (with or without agoraphobia) or generalized anxiety disorder (GAD) experiencing moderately severe anxiety symptoms at entrance into the study. Both bipolar disorder and anxiety diagnoses were based on DSM-IV-TR criteria. Patients were screened and randomized from June 25, 2010, through August 23, 2011. Primary outcome measures were the Clinical Global Impressions-21 Anxiety Scale (CGI-21 Anxiety) and the Sheehan Disability Scale (SDS), with secondary measures monitoring anxiety and mood symptoms. RESULTS: Last-observation-carried-forward analyses demonstrated that patients in the ziprasidone group did not improve significantly more than those in the placebo group on the CGI-21 Anxiety (F1 = 0.34; P = .564) or SDS (F1 = 0.26; P = .611). Secondary analysis using hierarchical linear modeling found similar results (CGI-21 Anxiety: F1 = 1.82; P = .178; and SDS: F1 = 0.70; P = .408). Regardless of group, time in the study was associated with significant decrease in anxiety (F1 = 11.08; P = .001) and total disability (F1 = 26.16; P < .001). Patients in the ziprasidone group showed a greater increase in abnormal involuntary movement, and 81.8% (n = 9) of the subjects who withdrew from the study due to adverse events, serious adverse events, or side effects were in the ziprasidone group. CONCLUSIONS: Results suggest that ziprasidone monotherapy was not associated with a clinically significant improvement in anxiety symptoms or improved function for patients with bipolar disorder, lifetime panic disorder or GAD, and concurrent moderately severe anxiety symptoms, and it was associated with a more negative side-effect profile relative to placebo. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01172652. PMID- 24345759 TI - Association between first-trimester placental volume and birth weight. AB - OBJECTIVE: To estimate the correlation between first-trimester placental volume, birth weight, small-for-gestational-age (SGA), and preeclampsia. METHODS: A prospective study of women with singleton pregnancy at 11-13 weeks of gestation was conducted. First-trimester placental volume was measured using three dimensional ultrasound and reported as multiple of median (MoM) for gestational age. Participants were followed until delivery where birth weight, placental weight, and occurrence of preeclampsia were collected. Non-parametric analyses were performed. RESULTS: We reached a complete follow-up for 543 eligible women. First-trimester placental volume was significantly correlated with birth weight (correlation coefficient: 0.18; p < 0.0001) and placental weight (cc: 0.22; p < 0.0001) adjusted for gestational age. First-trimester placental volume was smaller in women who delivered SGA neonates (median MoM: 0.79; interquartile range: 0.62-1.00; p < 0.001) and greater in women who delivered large-for gestational-age neonates (median MoM: 1.13; 0.95-1.49; p < 0.001) when compared to women with neonates between the 10th and 90th percentile (median MoM: 1.00; 0.81-1.25). First-trimester placental volume was not associated with the risk of preeclampsia (cc: 0.01; p = 0.87). CONCLUSION: First-trimester placental volume is strongly associated with fetal and placental growth. However, we did not observe a correlation between placental volume and the risk of preeclampsia. PMID- 24345760 TI - Tyk2 is a therapeutic target for psoriasis-like skin inflammation. AB - Tyrosine kinase 2 (Tyk2), a member of the Jak kinase family, mediates signals triggered by various cytokines, which are related to the pathogenesis of psoriasis. In this study, we investigated the role of Tyk2 in IL-23-induced psoriasis-like skin inflammation. Tyk2(-/-) mice when injected with IL-23 showed significantly reduced ear skin swelling with epidermal hyperplasia and inflammatory cell infiltration compared with wild-type mice. In addition, Tyk2 deficiency reduced production of pro-inflammatory cytokines and psoriasis relevant anti-microbial peptides. More noteworthy is that Tyk2 directly regulated IL-22-dependent inflammation and epidermal hyperplasia. Taken together with the inhibition of IL-23-induced inflammation by treatment with neutralizing antibodies against IL-17 or IL-22, Tyk2 participates in both IL-23 and IL-22 signal transduction to mediate psoriasis-like skin inflammation. On the basis of these findings, we demonstrated for the first time that a small-molecule Tyk2 inhibitor significantly inhibited IL-23-induced inflammation and cytokine production in the skin. These observations demonstrate the important role of Tyk2 in experimental skin inflammation and indicate the therapeutic potential of Tyk2 inhibition in human psoriasis. PMID- 24345761 TI - Microstructural changes of the nucleus accumbens due to increase of estradiol level during menstrual cycle contribute to recurrent manic episodes--a single case study. AB - We examined a rapid-cycling bipolar disorder patient who demonstrated manic episode regularly at around day 7 of the menstrual cycle. We hypothesize that gonadal hormones may induce a state-dependent change in cerebral microstructure and function. Following this hypothesis, the serum levels of estradiol and progesterone were analyzed and diffusion tensor imaging data were examined between the manic and euthymic states of the patient. Estradiol levels increased in the late follicular phase at manic state when compared to the luteal or early follicular phase at euthymic state. DTI results showed that the patient had increased fractional anisotropy values at manic state in the bilateral nucleus accumbens (NAc) and its connected areas, which is a major projection field of the mesolimbic dopamine (DA) system, perhaps reflecting microstructural changes due to neuronal activation related to manic episodes. According to these results, we consider that the mesolimbic DA system of this patient has hypersensitivity to estradiol, and elevation of the estradiol level increases the activity of the dopaminergic system, which in turn may contribute to recurrent manic episodes. Our findings provide a clue for understanding how fluctuations in gonadal hormone may amplify or ameliorate the symptomatology of psychiatric disorders related to the menstrual cycle. PMID- 24345762 TI - Reflections about death in the surgical simulation environment. PMID- 24345763 TI - Morphological variability of the P-wave for premature envision of paroxysmal atrial fibrillation events. AB - The present work introduces the first study on the P-wave morphological variability two hours preceding the onset of paroxysmal atrial fibrillation (PAF). The development of non-invasive methods able to track P-wave alterations over time is a clinically relevant tool to anticipate as much as possible the envision of a new PAF episode. This information is essential for further improvement of preventive and patient-tailored treatment strategies, which could avert the loss of sinus rhythm. In this way, risks for the patients could be minimized and their quality of life improved. Recently, the P-wave morphological analysis is drawing increasing attention because differences in morphology can reflect different atrial activation patterns. Indeed, the P-wave morphology study has recently proved to be useful for determining the presence of an underlying pathophysiological condition in patients prone to atrial fibrillation. However, the P-wave morphology variability over time has not been studied yet. In this respect, the present work puts forward some parameters related to the P-wave shape and energy with the ability to quantify non-invasively the notable atrial conduction alterations preceding the onset of PAF. Results showed that P-wave fragmentation and area presented higher variability over time as the onset of PAF approximates. By properly combining these indices, an average global accuracy of 86.33% was achieved to discern between electrocardiogram segments from healthy subjects, far from a PAF episode and less than one hour close to a PAF episode. As a consequence, the P-wave morphology long-term analysis seems to be a useful tool for the non-invasive envision of PAF onset with a reasonable anticipation. Nonetheless, further research is required to corroborate this finding and to validate the capability of the proposed P-wave metrics in the earlier prediction of PAF onset. PMID- 24345764 TI - Innovative modifications to Rose Bengal plate test enhance its specificity, sensitivity and predictive value in the diagnosis of brucellosis. AB - Current agglutination tests occasionally yield false results. Superagglutination test reduced false results, had higher sensitivity (95.88%) and negative predictive value (95.83%) than Rose Bengal plate test (RBPT), Standard Tube Agglutination test (STAT), ELISA, and Complement Fixation test and specificity (89.32%) and positive predictive value (89.42%) higher than RBPT and STAT. PMID- 24345765 TI - Adult tissue sources for new beta cells. AB - The diabetes pandemic incurs extraordinary public health and financial costs that are projected to expand for the foreseeable future. Consequently, the development of definitive therapies for diabetes is a priority. Currently, a wide spectrum of therapeutic strategies-from implantable insulin delivery devices to transplantation-based cell replacement therapy, to beta-cell regeneration-focus on replacing the lost insulin-producing capacity of individuals with diabetes. Among these, beta-cell regeneration remains promising but heretofore unproved. Indeed, recent experimental work has uncovered surprising biology that underscores the potential therapeutic benefit of beta-cell regeneration. These studies have elucidated a variety of sources for the endogenous production of new beta cells from existing cells. First, beta cells, long thought to be postmitotic, have demonstrated the potential for regenerative capacity. Second, the presence of pancreatic facultative endocrine progenitor cells has been established. Third, the malleability of cellular identity has availed the possibility of generating beta cells from other differentiated cell types. Here, we review the exciting developments surrounding endogenous sources of beta-cell production and consider the potential of realizing a regenerative therapy for diabetes from adult tissues. PMID- 24345766 TI - Coupling energy homeostasis with a mechanism to support plasticity in brain trauma. AB - Metabolic dysfunction occurring after traumatic brain injury (TBI) is an important risk factor for the development of psychiatric illness. In the present study, we utilized an omega-3 diet during early life as a metabolic preconditioning to alter the course of TBI during adulthood. TBI animals under omega-3 deficiency were more prone to alterations in energy homeostasis (adenosine monophosphate-activated protein kinase; AMPK phosphorylation and cytochrome C oxidase II; COII levels) and mitochondrial biogenesis (peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PGC-1alpha and mitochondrial transcription factor A; TFAM). A similar response was found for brain-derived neurotrophic factor (BDNF) and its signaling through tropomyosin receptor kinase B (TrkB). The results from in vitro studies showed that 7,8 dihydroxyflavone (7,8-DHF), a TrkB receptor agonist, upregulates the levels of biogenesis activator PGC-1alpha, and CREB phosphorylation in neuroblastoma cells suggesting that BDNF-TrkB signaling is pivotal for engaging signals related to synaptic plasticity and energy metabolism. The treatment with 7,8-DHF elevated the mitochondrial respiratory capacity, which emphasizes the role of BDNF-TrkB signaling as mitochondrial bioenergetics stimulator. Omega-3 deficiency worsened the effects of TBI on anxiety-like behavior and potentiated a reduction of anxiolytic neuropeptide Y1 receptor (NPY1R). These results highlight the action of metabolic preconditioning for building long-term neuronal resilience against TBI incurred during adulthood. Overall, the results emphasize the interactive action of metabolic and plasticity signals for supporting neurological health. PMID- 24345767 TI - Relationship between disease severity and quality of life and assessment of health care utilization and cost for ulcerative colitis in Australia: a cross sectional, observational study. AB - BACKGROUND & AIMS: The burden of ulcerative colitis (UC) in relation to disease severity is not well documented. This study quantitatively evaluated the relationship between disease activity and quality of life (QoL), as well as health care utilization, cost, and work-related impairment associated with UC in an Australian population. METHODS: A cross-sectional, noninterventional, observational study was performed in patients with a wide range of disease severity recruited during routine specialist consultations. Evaluations included the Assessment of Quality of Life-8-dimension (AQoL-8D), EuroQol 5-dimension, 5 level (EQ-5D-5L), the disease-specific Inflammatory Bowel Disease Questionnaire (IBDQ), and the Work Productivity and Activity Impairment (WPAI) instrument. The 3-item Partial Mayo Score was used to assess disease severity. Health care resource utilization was assessed by chart review and patient questionnaires. RESULTS: In 175 patients, mean (SD) AQoL-8D and EQ-5D-5L scores were greater for patients in remission (0.80 [0.19] and 0.81 [0.18], respectively) than for patients with active disease (0.70 [0.20] and 0.72 [0.19], respectively, both Ps<0.001). IBDQ correlated with both AQoL-8D (r=0.73; P<0.0001) and EQ-5D-5L (0.69; P<0.0001). Mean 3-month UC-related health care cost per patient was AUD $2914 (SD=$3447 [mean for patients in remission=$1970; mild disease=$3736; moderate/severe disease=$4162]). Patients in remission had the least work and activity impairment. CONCLUSIONS: More severe UC disease was associated with poorer QoL. Substantial health care utilization, costs, and work productivity impairments were found in this sample of patients with UC. Moreover, greater disease activity was associated with greater health care costs and impairment in work productivity and daily activities. PMID- 24345769 TI - Standardized cine-loop documentation in abdominal ultrasound facilitates offline image interpretation. AB - BACKGROUND: One of the main disadvantages of conventional ultrasound is its operator dependency, which might impede the reproducibility of the sonographic findings. A new approach with cine-loops and standardized scan protocols can overcome this drawback. PURPOSE: To compare abdominal ultrasound findings of immediate bedside reading by performing radiologist with offline reading by a non performing radiologist, using standardized cine-loop sequences. MATERIAL AND METHODS: Over a 6-month period, three radiologists performed 140 dynamic ultrasound organ-based examinations in 43 consecutive outpatients. Examination protocols were standardized and included predefined probe position and sequences of short cine-loops of the liver, gallbladder, pancreas, kidneys, and urine bladder, covering the organs completely in two planes. After bedside examinations, the studies were reviewed and read out immediately by the performing radiologist. Image quality was registered from 1 (no diagnostic value) to 5 (excellent cine-loop quality). Offline reading was performed blinded by a radiologist who had not performed the examination. Bedside and offline reading were compared with each other and with consensus results. RESULTS: In 140 examinations, consensus reading revealed 21 cases with renal disorders, 17 cases with liver and bile pathology, and four cases with bladder pathology. Overall inter-observer agreement was 0.73 (95% CI 0.61-0.91), with lowest agreement for findings of the urine bladder (0.36) and highest agreement in liver examinations (0.90). Disagreements between the two readings were seen in nine kidneys, three bladder examinations, one pancreas and bile system examinations each, and in one liver, giving a total number of mismatches of 11%. Nearly all cases of mismatch were of minor clinical significance. The median image quality was 3 (range, 2-5) with most examinations deemed a quality of 3. Compared to consensus reading, overall accuracy was 96% for bedside reading and 94% for offline reading. CONCLUSION: Standardized cine-loop documentation enables accurate offline reading in abdominal ultrasound and shows high agreement with immediate bedside reading. PMID- 24345768 TI - Impact of beta-blockade premedication on image quality of ECG-gated thoracic aorta CT angiography. AB - BACKGROUND: Thoracic aortic aneurysm is one of the most common aorta pathologies worldwide, which is commonly evaluated by computed tomography angiography (CTA). One of the routine methods to improve the image quality of CTA is heart rate reduction prior to study by beta-blockade administration. PURPOSE: To assess the effect of beta-blockade on image quality of the ascending aorta in electrocardiography (ECG)-gated dual-source CTA (DSCTA) images. MATERIAL AND METHODS: In this retrospective study, ECG-gated thoracic aorta CTA images of 40 patients without beta-blocker administration were compared with ECG-gated images of 40 patients with beta-blockade. Images of the aorta were analyzed objectively and subjectively at three levels: sinus of Valsalva (sinus), sinotubular junction (STJ), and mid ascending aorta (MAA). Quantitative sharpness index (SI) and signal-to-noise ratio (SNR) were calculated and two radiologists evaluated the image quality using a 3-point scale. RESULTS: Mean heart rate in beta-blocker and non-beta-blocker groups was 61.7 beats per minute (bpm) (range, 58.1-63.9 bpm) and 72.9 bpm (range, 69.3-84.1 bpm), respectively (P < 0.05). Aorta wall SI, SNR, and subjective grading were comparable between the two groups at all three levels (P > 0.05). CONCLUSION: Beta-blocker premedication may not be necessary for imaging of ascending aorta with ECG-gated DSCTA. PMID- 24345770 TI - Intraindividual movement variability within the 5 m water polo shot. AB - The purpose of this study was to explore movement variability of throwing arm and ball release parameters during the water polo shot and to compare variability between successful (hit) and unsuccessful (miss) outcomes. Seven injury free, subelite, females completed 10 trials of the 5 m water polo penalty shot. Intraindividual coefficient of variation percentage (CV%) values were calculated for elbow and wrist angular displacement, wrist linear velocity and ball release parameters (height, angle and velocity). Coordination variability (elbow/wrist angular displacement) was calculated as the CV% of the mean cross-correlation coefficient. Elbow and wrist displacement variability decreased to 80% of throwing time then increased toward release. Wrist linear velocity variability reduced toward release. Individual CV% values ranged between 1.6% and 23.5% (all trials), 0.4% and 20.6% (hit), and 0.4% and 27.1% (miss). Ball release height and velocity variability were low (< 12%; all trials) whereas release angle variability was high (>27%; all trials). Cross-correlation results were inconclusive. Roles of the elbow and wrist in production of stable ball release height and velocity and control of the highly variable release angle in the water polo shot are discussed and suggested for further study. Optimal levels of variability warrant future investigation. PMID- 24345771 TI - Unravelling the biodiversity of nanoscale signatures of spider silk fibres. AB - Living organisms are masters at designing outstanding self-assembled nanostructures through a hierarchical organization of modular proteins. Protein based biopolymers improved and selected by the driving forces of molecular evolution are among the most impressive archetypes of nanomaterials. One of these biomacromolecules is the myriad of compound fibroins of spider silks, which combine surprisingly high tensile strength with great elasticity. However, no consensus on the nano-organization of spider silk fibres has been reached. Here we explore the biodiversity of spider silk fibres, focusing on nanoscale characterization with high-resolution atomic force microscopy. Our results reveal an evolution of the nanoroughness, nanostiffness, nanoviscoelastic, nanotribological and nanoelectric organization of microfibres, even when they share similar sizes and shapes. These features are related to unique aspects of their molecular structures. The results show that combined nanoscale analyses of spider silks may enable the screening of appropriate motifs for bioengineering synthetic fibres from recombinant proteins. PMID- 24345772 TI - Osteosarcoma treatment - where do we stand? A state of the art review. AB - Long-term outcome for patients with high-grade osteosarcoma has improved with the addition of systemic chemotherapy, but subsequent progress has been less marked. Modern, multiagent, dose-intensive chemotherapy in conjunction with surgery achieves a 5-year event-free survival of 60-70% in extremity localized, non metastatic disease. A major, as yet unsolved, problem is the poor prognosis for metastatic relapse or recurrence, and for patients with axial disease. This article reviews the current state of the art of systemic osteosarcoma therapy by focusing on the experiences of cooperative osteosarcoma groups. Also, we shed light on questions and challenges posed by the aggressiveness of the tumor, and we consider potential future directions that may be critical to progress in the prognosis of high-grade osteosarcoma. PMID- 24345773 TI - The multi-xenobiotic resistance (MXR) efflux activity in hemocytes of Mytilus edulis is mediated by an ATP binding cassette transporter of class C (ABCC) principally inducible in eosinophilic granulocytes. AB - In marine and estuarine species, immunotoxic and/or immunomodulatory mechanisms are the crossroad of interactions between xenobiotics, microorganisms and physicochemical variations of the environment. In mussels, immunity relies exclusively on innate responses carried out by cells collectively called hemocytes and found in the open hemolymphatic circulatory system of these organisms. However, hemocytes do not form a homogenous population of immune cells since distinct subtypes of mussel blood cells can be distinguished by cytochemistry, flow cytometry or cell motility analysis. Previous studies have also shown that these cells are able to efflux xenobiotics by means of ATP binding cassette (ABC) transporter activities conferring a multixenobiotic resistance (MXR) phenotype. ABC transporters corresponding to vertebrate class B/P-glycoprotein (P-gp) and to class C/multidrug resistance related protein (MRP) are characterized in Mytilidae. Herein, we have investigated the relative contributions of ABCB- and ABCC-mediated efflux within the different hemocyte subpopulations of Mytilus edulis mussels, collected from areas differentially impacted by chemical contaminants in Normandy (France). RT-PCR analyses provide evidence for the presence of ABCB and ABCC transporters transcripts in hemocytes. Immunodetection of ABCB/P-gp with the monoclonal antibody UIC2 in living hemocytes revealed that expression was restricted to granular structures of spread cells. Efflux transporter activities, with calcein-AM as fluorescent probe, were measured by combining flow cytometry to accurate Coulter cell size measurements in order to get a cell-volume normalized fluorescence concentration. In these conditions, basal fluorescence levels were higher in hemocytes originating from Yport (control site) than in cells collected from the harbor of Le Havre, where mussels are more exposed to with persistent pollutants. By using specific ABCB/P-gp (verapamil, PSC833, zosuquidar) and ABCC/MRP (MK571) blockers, we show that MXR activity is only carried out by MRP-type transporters in M. edulis hemocytes. In addition, cell-type-gated flow cytometry and calculation of the MXR activity factor indicate that ABCC-efflux activity is higher and more inducible in eosinophilic granulocytes than in other hemocyte subtypes. We conclude that, in the hemocytes of M. edulis, MXR phenotype is mediated by an ABCC/MRP-type transporter activity principally supported by eosinophilic granulocytes. A role for ABC transporters in hemocyte migration is discussed. PMID- 24345774 TI - Influence of somatic state on cardiovascular measurements in pregnancy. AB - Normal pregnancy causes marked changes in cardiac and haemodynamic function but there is continuing debate about the patterns of 'normal' change. We believe that this lack of consensus is in large part caused by inappropriate assessment conditions. This study aimed to assess physiological data obtained from pregnant women during multiple steady-states and during between-state changes. The study was a longitudinal characterization of apparently healthy pregnant women aged >18 years with assessments at three antenatal stages (12-16, 26-28 and 34-36 weeks) and at 12 weeks following birth. Cardiovascular and heart rate variability (HRV) measures were quantified non-invasively during a range of states including postural manoeuvre, exercise and respiratory regulation. Cardiovascular and HRV variables were influenced by pregnancy in specific ways: (1) steady-state values were influenced differently to state-change responses; (2) cardiac output (CO) increased progressively throughout pregnancy in all states except supine rest; (3) the DeltaCO response to the supine-standing manoeuvre was particularly sensitive to pregnancy stage; (4) blood pressure was unaffected by pregnancy; (6) DeltaCO and DeltaSBP (systolic blood pressure) were enhanced from mid-pregnancy onwards; (7) DeltaHRV responses to state changes were markedly and progressively influenced by pregnancy. This study indicates that cardiovascular function in pregnant women is best quantified during at least one physical state change (in particular during the supine-to-standing manoeuvre) and that assessment during supine rest is inadequate for quantifying antenatal physiological function. PMID- 24345776 TI - Micro-chipping horses: animal identification and beyond. PMID- 24345777 TI - Effects of shoeing on intra- and inter-limb coordination and movement consistency in Icelandic horses at walk, tolt and trot. AB - To enhance expressiveness of forelimb movement and improve the four-beat rhythm of the tolt, Icelandic horses are commonly ridden with excessively high and long hooves. The aim of this study was to objectively assess the effect of shoeing on intra- and inter-limb coordination and limb movement consistency (inter-stride variability) at walk, tolt and trot. Thirteen sound and fit Icelandic horses accustomed to exercise with a rider on a treadmill were assessed with long and high hooves commonly used for competition (S(H)) and with the hooves trimmed according to the standards of normal shoeing (S(N)). Limb timing variables were extracted from the four vertical ground reaction force curves measured with an instrumented treadmill. Measurements were taken at walk and at two tolting and trotting speeds. High hooves with long toes reduced stride rate and increased breakover duration. At the tolt, the footfall rhythm showed less tendency to lateral couplets. Movement consistency of the walk remained unchanged, whereas, at the tolt, stride-to-stride variability of selected time parameters increased in SH and/or at the higher velocity. At the faster trotting speed, variability of hind limb duty factor decreased, whereas variability of contralateral step duration in the forelimb increased. High hooves with long toes improve the clearness of the four-beat footfall rhythm of the tolt, but disturb the movement consistency of the gait. The prolonged breakover duration observed in all gaits may have negative implications for the health of the palmar structures of the distal foot. PMID- 24345775 TI - Dysregulation of glucocorticoid receptor co-factors FKBP5, BAG1 and PTGES3 in prefrontal cortex in psychotic illness. AB - Molecular abnormalities within the glucocorticoid receptor (GR) stress signaling pathway may confer, or reflect, susceptibility to stress in schizophrenia and bipolar disorder, but the extent of such abnormalities in the brain is not known. Using RNA-Seq and qPCR in two postmortem cohorts totaling 55 schizophrenia, 34 bipolar disorder and 55 control individuals, we identified increased FKBP5 and PTGES3 mRNA expression, and decreased BAG1 mRNA expression, in the prefrontal cortex in schizophrenia cases relative to controls (68.0% [p < 0.001], 26.0% [p < 0.01] and 12.1% [p < 0.05] respectively). We also observed increased FKBP5 and decreased BAG1 mRNA expression in bipolar disorder (47.5% [p < 0.05] and 14.9% [p < 0.005]). There were no diagnostic differences in steady-state FKBP51 protein levels, nor in HSPA1A, HSP90AA1, DNAJB1 or HSPB1 mRNA levels. GR, co-factor and chaperone mRNA levels were strongly correlated. These results reveal coordinated cortical dysregulation of FKBP5, PTGES3, BAG1 and GR genes within the glucocorticoid signaling pathway in psychotic illness. PMID- 24345778 TI - Canine superficial bacterial folliculitis: current understanding of its etiology, diagnosis and treatment. AB - Superficial bacterial folliculitis (SBF) is more common in the dog than other mammalian species. Until recently, a successful outcome in cases of canine SBF was possible by administering a potentiated amoxicillin, a first generation cephalosporin or a potentiated sulfonamide. Unfortunately, this predictable susceptibility has changed, because methicillin resistant Staphylococcus pseudintermedius (MRSP) and Staphylococcus aureus (MRSA) are becoming more prevalent in canine SBF cases. The increasing frequency of multidrug resistance complicates the selection of antimicrobial therapy. Antimicrobial agents that were once rarely used in cases of canine SBF, such as amikacin, rifampicin and chloramphenicol, are becoming the drugs of choice, based on bacterial culture and susceptibility testing. Furthermore, changes in antimicrobial susceptibility have helped to re-emphasize the importance of a multimodal approach to treatment of the disease, including topical therapy. Due to the increasing frequency of identification of highly resistant Staphylococcus spp., topical antimicrobial therapy, including the use of diluted sodium hypochlorite (bleach), is becoming necessary to successfully treat some cases of canine SBF. Other important antiseptics that can be used include chlorhexidine, benzoyl peroxide, ethyl lactate, triclosan and boric acid/acetic acid. This review discusses the diagnostic and therapeutic management of canine SBF, with a special emphasis on treating methicillin resistant staphylococcal infections. PMID- 24345779 TI - Bovine viral diarrhoea: a playground for virologists and a target for eradication. PMID- 24345781 TI - Intraoperative epicardial ultrasound probe for visualization of embedded coronary arteries: a novel approach. AB - The identification of coronary anatomy at the time of cardiac revascularization can be problematic. Preoperative studies (ie, coronary angiography) can aid in the mapping of the coronary anatomy. However, there remain a select few patients with intramyocardial coronaries that provide challenges for surgical dissection during revascularization. Probing the visible portion of the coronary artery, intraoperative cine angiography, thermal angiography, and epicardial Doppler probes have been used to identify the coronary anatomy intraoperatively. Aggressive surgical maneuvers can result in damage and increased time on cardiopulmonary bypass. Previous studies have used epicardial echocardiography on patients undergoing off-pump coronary artery bypass grafting. We report 2 cases in patients undergoing cardiac revascularization on cardiopulmonary bypass where the use of a high-frequency epicardial ultrasound probe facilitated the identification of the embedded coronary arteries. We describe a technique of using antegrade and retrograde cardioplegia administration sequentially to locate the coronary arteries. Easy availability and familiar technology make the epicardial Doppler probe an attractive tool for the identification of embedded coronary arteries. PMID- 24345780 TI - Noteworthy articles in 2013 for cardiothoracic anesthesiologists. AB - In 2013, the field of cardiothoracic anesthesiology has continued to grow at the same astounding rate as in previous years. It has become increasingly difficult for practicing anesthesiologists to stay current on impactful publications related to our exciting subspecialty. The scientific output has expanded to such a great extent that following the literature in specialty journals barely scrapes the surface of available knowledge. With the recent emphasis on teamwork spanning multiple medical specialties in the care for complex patients, the door has opened for our research to be presented in nontraditional, nonanesthesiology venues. In this review, we have selected a small sample of noteworthy contributions to the field of cardiothoracic and vascular anesthesiology published in 2013 with potential impact on our clinical practice. PMID- 24345782 TI - Detection of the ovarian cancer biomarker CA-125 using chemiluminescence resonance energy transfer to graphene quantum dots. AB - An immunoassay has been developed for the detection of the ovarian cancer biomarker CA-125 by utilizing the chemiluminescence resonance energy transfer to graphene quantum dots. This biosensor shows a wide linear range from 0.1 U mL(-1) to 600 U mL(-1) with a limit of detection of 0.05 U mL(-1) for CA-125 in a buffer solution. PMID- 24345783 TI - Higher ambulatory blood pressure at 18 years in adolescents born less than 28 weeks' gestation in the 1990s compared with term controls. AB - OBJECTIVES: Adult preterm survivors from the 1980s have higher blood pressure (BP) than term controls. Survival rates of extremely preterm (gestational age<28 weeks; EP) infants born after 1990 have increased, but whether they still have higher BP than term controls is unknown. This study compared the BP of contemporary EP survivors with term controls in late adolescence. METHODS: All EP adolescents and matched term controls born in 1991-92 in Victoria, Australia, were enrolled in a longitudinal study. At age 18 years, 24-h ambulatory BP was measured. Average BP was compared between EP and term groups, and predictors of BP in EP adolescents were examined. RESULTS: BP data were obtained from 136 EP patients and 120 controls. EP patients on average had higher systolic, diastolic and mean BP than controls. The mean systolic difference over 24 h was 3.2 mmHg [95% confidence interval (CI) 0.1-6.4], 3.9 mmHg [95% CI 0.7-7.2] when awake, and 2.0 mmHg (95% CI 1.4-5.5) when asleep. Male sex and change in weight SD score from birth to 2 years were predictive of SBP (regression coefficients 6.2 (95% CI 1.8-10.6), P=0.006) and 2.0 (95% CI 0.2-3.8), P=0.032), respectively). SBP at age 8 was associated with BP at age 18 years. CONCLUSION: Late adolescent EP survivors of the modern era have higher BP compared with term controls. This highlights the importance of long-term cardiovascular surveillance for this increasing group into adulthood. PMID- 24345784 TI - Investigation of the mass distribution of a detailed seated male finite element model. AB - Accurate mass distribution in computational human body models is essential for proper kinematic and kinetic simulations. The purpose of this study was to investigate the mass distribution of a 50th percentile male (M50) full body finite element model (FEM) in the seated position. The FEM was partitioned into 10 segments, using segment planes constructed from bony landmarks per the methods described in previous research studies. Body segment masses and centers of gravity (CGs) of the FEM were compared with values found from these studies, which unlike the present work assumed homogeneous body density. Segment masses compared well to literature while CGs showed an average deviation of 6.0% to 7.0% when normalized by regional characteristic lengths. The discrete mass distribution of the FEM appears to affect the mass and CGs of some segments, particularly those with low-density soft tissues. The locations of the segment CGs are provided in local coordinate systems, thus facilitating comparison with other full body FEMs and human surrogates. The model provides insights into the effects of inhomogeneous mass on the location of body segment CGs. PMID- 24345785 TI - Targeting lipid esterases in mycobacteria grown under different physiological conditions using activity-based profiling with tetrahydrolipstatin (THL). AB - Tetrahydrolipstatin (THL) is bactericidal but its precise target spectrum is poorly characterized. Here, we used a THL analog and activity-based protein profiling to identify target proteins after enrichment from whole cell lysates of Mycobacterium bovis Bacillus Calmette-Guerin cultured under replicating and non replicating conditions. THL targets alpha/beta-hydrolases, including many lipid esterases (LipD, G, H, I, M, N, O, V, W, and TesA). Target protein concentrations and total esterase activity correlated inversely with cellular triacylglycerol upon entry into and exit from non-replicating conditions. Cellular overexpression of lipH and tesA led to decreased THL susceptibility thus providing functional validation. Our results define the target spectrum of THL in a biological species with particularly diverse lipid metabolic pathways. We furthermore derive a conceptual approach that demonstrates the use of such THL probes for the characterization of substrate recognition by lipases and related enzymes. PMID- 24345787 TI - Epigenetics in asthma and allergy. AB - PURPOSE OF REVIEW: Epigenetic mechanisms such as DNA methylation, histone modification and microRNA control the accessibility of the genome and manage gene transcription in response to the environment in a heritable fashion. Recent evidence suggests that these mechanisms play a role in allergy and asthma. RECENT FINDINGS: Here, we give an overview on recent developments in the field of asthma and allergy epigenetics with a special focus on the role of DNA methylation in these diseases, where finally, first pilot studies investigating differences in methylation pattern in patients have been published. Although these studies have to be interpreted with caution, it seems that methylation is affected by environmental stimuli such as prenatal smoke exposure and farming environments, whereas asthma status is associated with change in methylation in early childhood. SUMMARY: Early stage data from population studies indicate a role of methylation differences in asthma and allergy, whereas the exact impact of these epigenetic mechanisms on disease development needs to be elucidated further. PMID- 24345786 TI - Linkage of oxidative stress and mitochondrial dysfunctions to spontaneous culture degeneration in Aspergillus nidulans. AB - Filamentous fungi including mushrooms frequently and spontaneously degenerate during subsequent culture maintenance on artificial media, which shows the loss or reduction abilities of asexual sporulation, sexuality, fruiting, and production of secondary metabolites, thus leading to economic losses during mass production. To better understand the underlying mechanisms of fungal degeneration, the model fungus Aspergillus nidulans was employed in this study for comprehensive analyses. First, linkage of oxidative stress to culture degeneration was evident in A. nidulans. Taken together with the verifications of cell biology and biochemical data, a comparative mitochondrial proteome analysis revealed that, unlike the healthy wild type, a spontaneous fluffy sector culture of A. nidulans demonstrated the characteristics of mitochondrial dysfunctions. Relative to the wild type, the features of cytochrome c release, calcium overload and up-regulation of apoptosis inducing factors evident in sector mitochondria suggested a linkage of fungal degeneration to cell apoptosis. However, the sector culture could still be maintained for generations without the signs of growth arrest. Up-regulation of the heat shock protein chaperones, anti-apoptotic factors and DNA repair proteins in the sector could account for the compromise in cell death. The results of this study not only shed new lights on the mechanisms of spontaneous degeneration of fungal cultures but will also provide alternative biomarkers to monitor fungal culture degeneration. PMID- 24345788 TI - Mechanisms of cough. AB - PURPOSE OF REVIEW: To review recent developments in the mechanisms of chronic cough. RECENT FINDINGS: Although cough prevalence is similar across the world, there are significant regional differences in the diseases associated with cough. This may represent regional differences in diet, environmental exposure, and diagnostic assessment and labelling. Cough can be reliably measured using several validated questionnaires and objective tools that monitor cough frequency and cough reflex sensitivity. Cough with eosinophilic bronchitis responds to anti inflammatory therapy with corticosteroids and montelukast. The absence of airway hyperresponsiveness may be because of the release of a bronchoprotective mediator, prostaglandin E2. Cough with neutrophilic bronchitis is associated with rhinitis and gastroesophageal reflux disease. Laryngeal hypersensitivity (LHS) is an important new concept that explains cough mechanisms, identifies potentially new pharmacotherapies that target neural pathways and also transient receptor channels, and demonstrates how behavioural therapies can be effective in refractory cough. The concept also explains symptoms in a variety of related syndromes such as vocal cord dysfunction. SUMMARY: New insights into cough mechanisms that focus on LHS help explain cough symptoms and the place of effective therapies including speech pathology intervention and neuromodulators. PMID- 24345789 TI - A free cysteine prolongs the half-life of a homing peptide and improves its tumor penetrating activity. AB - The accessibility of extravascular tumor tissue to drugs is critical for therapeutic efficacy. We previously described a tumor-targeting peptide (iRGD) that elicits active transport of drugs and macromolecules (covalently coupled or co-administered) across the vascular wall into tumor tissue. Short peptides (iRGD is a 9-amino acid cyclic peptide) generally have a plasma half-life measured in minutes. Since short half-life limits the window of activity obtained with a bolus injection of iRGD, we explored to extend the half-life of the peptide. We show here that addition of a cysteine residue prolongs the plasma half-life of iRGD and increases the accumulation of the peptide in tumors. This modification prolongs the activity of iRGD in inducing macromolecular extravasation and leads to greater drug accumulation in tumors than is obtained with the unmodified peptide. This effect is mediated by covalent binding of iRGD to plasma albumin through a disulfide bond. Our study provides a simple strategy to improve peptide pharmacokinetics and activity. Applied to RGD, it provides a means to increase the entry of therapeutic agents into tumors. PMID- 24345791 TI - Hydrogen activation with perfluorinated organoboranes: 1,2,3 tris(pentafluorophenyl)-4,5,6,7-tetrafluoro-1-boraindene. AB - The perfluorinated boraindene was synthesized and fully characterized. Both computational and crystallographic data show that is antiaromatic. Compound was shown to react reversibly with H2 and to catalyse the hydrogenation of cyclohexene. The mechanism of catalysis was probed experimentally and computationally. PMID- 24345792 TI - Etiology and outcome of hydrops fetalis. PMID- 24345790 TI - Hunting for clinical translation with innate-like immune cells and their receptors. AB - Allogeneic stem cell transplantation (allo-SCT) has so far been the most effective immunotherapy for hematological malignancies. However, it is becoming increasingly clear that the immunotherapeutic concepts underlying allo-SCT as well as the traditional dissection of the immune system into innate and adaptive arms need substantial refinement. More and more cell types migrate into the interface between innate and adaptive immunity, creating new terms such as innate like lymphocytes. These innate-like cells, which include natural killer (NK) cells and gammadeltaT cells, could provide unique advantages to therapeutic interventions aimed at treating hematological malignancies, including protection against tumor relapse and viral infections without causing harmful graft-versus host disease (GVHD). Recent molecular and conceptual insights into these subpopulations have opened new avenues to exploit their exciting features for the development of new compounds and to revisit current therapeutic standards in the treatment of hematological cancers. This review therefore aims to discuss the rapid progress in the understanding of molecular mechanisms by which NK cells and gammadeltaT cells recognize malignancies and viral infections, and the value of this increasing knowledge to complement the battle against life-threatening complications of current strategies to treat cancer. PMID- 24345793 TI - Supraphysiologic doses of levothyroxine as adjunctive therapy in bipolar depression: a randomized, double-blind, placebo-controlled study. AB - OBJECTIVE: Suboptimal availability of circulating thyroid hormones may contribute to the high rate of treatment failures in bipolar disorder. This study tested the efficacy of adjunctive treatment with supraphysiologic doses of levothyroxine in patients with bipolar depression and the hypothesis that women would display a better outcome compared to men. METHOD: The aims of this multicenter, 6-week, double-blind, randomized, placebo-controlled fixed-dose (300 MUg/d) trial conducted from 2004 to 2009 were to assess efficacy and tolerability of levothyroxine adjunctive to continuing treatment with mood stabilizer and/or antidepressant medication for patients with bipolar I or II disorder, currently depressed (DSM-IV), and to investigate gender differences in treatment response. The primary efficacy variable was mean change in Hamilton Depression Rating Scale (HDRS) score. RESULTS: Of 74 patients enrolled in the study, 62 (35 with bipolar I; mean age = 44.9 years) were randomized. Mean change in HDRS score from randomization to week 6 was larger in the levothyroxine group compared to the placebo group, with a 2.7-point difference (decline of -7.8 [38.3%] vs -5.1 [25.5%]; last-observation-carried-forward analysis). The course of HDRS scores over time from randomization to week 6 was significantly different between groups at week 4 (P = .046) but not at the end of the placebo-controlled phase (P = .198). The secondary analysis of women (n = 32) revealed a significant difference between groups in mean change in HDRS score (-16.6% placebo vs -42.4% levothyroxine, P = .018). A mixed-effects model for repeated-measures analysis showed a significant between-group difference in HDRS score (6.8, P = .012) for women. High thyroid-stimulating hormone levels, indicating suboptimal levels of circulating thyroid hormones, were predictive for positive treatment outcome in women treated with levothyroxine in a linear regression model (F3 = 3.47; P = .05). DISCUSSION: This trial demonstrated that patients treated with levothyroxine did numerically better than those treated with placebo; however, the study failed to detect a statistically significant difference between the 2 groups in the primary outcome measure due to a high placebo response rate. Previous findings that women show better improvement in depression scores with levothyroxine compared to men were confirmed. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01528839. PMID- 24345794 TI - Evaluation of the use of Classical Nucleation Theory for predicting intestinal crystalline precipitation of two weakly basic BSC class II drugs. AB - The aim of this work was to evaluate an in vitro-in silico approach for prediction of small intestinal crystalline precipitation and drug absorption of two weakly basic model BCS class II drugs, AZD0865 and mebendazole. The crystallization rates were investigated in an in vitro method using simulated gastric and intestinal media, and the result was modeled by using Classical Nucleation Theory (CNT). The effect of varying in vitro parameters (initial drug concentration, rate of mixing gastric and intestinal fluid, stirring and filtration) on the interfacial tension gamma, being a key parameter in CNT, was investigated. The initial drug concentration had the most significant effect on gamma for both substances tested, although gamma is a fundamental parameter independent of concentration according to CNT. In the subsequent in silico prediction of drug absorption, by use of a Compartmental and Transit intestinal model, an empirical approach was used where gamma was allowed to vary with simulated small intestinal concentrations. The in silico predictions were compared to published human in vivo plasma drug concentration data for different doses of AZD0865 and dog intestinal drug concentrations, amount precipitated in intestine and plasma concentrations for mebendazole. The results showed that lack of significant crystallization effects on absorption in man of the model drug AZD0865 up to doses of 4 mg/kg could be predicted which was in accordance with in vivo data. Mebendazole intestinal precipitation in canines was also well described by the model, where mean predicted amount precipitated was 136% (range 111-164%) of measured solid amount, and mean predicted intestinal concentration was 94% (range 59-147%) of measured concentration. In conclusion, the in vitro-in silico approach can be used for predictions of absorption effects of crystallization, but the model could benefit from further development work on the theoretical crystallization model and in vitro experimental design. PMID- 24345795 TI - Preparation and characterization of amorphous amphotericin B nanoparticles for oral administration through liquid antisolvent precipitation. AB - We prepared amphotericin B (AmB) nanoparticles through liquid antisolvent precipitation (LAP) and by freeze-drying to improve the solubility of AmB for oral administration. The LAP was optimized through a single-factor experiment. We determined the effects of surfactants and their concentration, the stirring time, the precipitation temperature, the stirring intensity, the drug concentration and the volume ratio of antisolvent to solvent on the mean particle size (MPS) of the AmB nanoparticles. Increased stirring intensity and precipitation time favored AmB nanoparticles with smaller MPS, but precipitation times exceeding 30 min did not further reduce the MPS. Increased Tween-80 concentration and the drug concentration decreased the MPS of the AmB nanoparticles. Increased precipitation temperature and antisolvent to solvent volume ratio initially decreased the MPS of the AmB nanoparticles, which increased thereafter. Optimum conditions produced AmB nanoparticles with an MPS of 135.1 nm. The AmB nanoparticles were characterized through scanning electron microscopy (SEM), mass spectrometry (MS), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermal gravimetric analysis (TG), solvent residue, drug purity test, and dissolution testing. The analyses indicated that the chemical structure of AmB remained unchanged in the nanoparticles, but the structure was changed from crystalline to amorphous. The residual DMSO in the nanoparticles was 0.24% less than the standard set by the International Conference on Harmonization limit for class III solvents. The AmB nanoparticles exhibited 2.1 times faster dissolution rates and 13 times equilibrium solubility compared with the raw drug. The detection results indicate that the AmB nanoparticles potentially improved the oral absorption of AmB. PMID- 24345796 TI - Cell type and transfection reagent-dependent effects on viability, cell content, cell cycle and inflammation of RNAi in human primary mesenchymal cells. AB - The application of RNA interference (RNAi) has great therapeutic potential for degenerative diseases of cartilaginous tissues by means of fine tuning the phenotype of cells used for regeneration. However, possible non-specific effects of transfection per se might be relevant for future clinical application. In the current study, we selected two synthetic transfection reagents, a cationic lipid based commercial reagent Lipofectamine RNAiMAX and polyethylenimine (PEI), and two naturally-derived transfection reagents, namely the polysaccharides chitosan (98% deacetylation) and hyaluronic acid (20% amidation), for siRNA delivery into primary mesenchymal cells including nucleus pulposus cells, articular chondrocytes and mesenchymal stem cells (MSCs). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an endogenous model gene to evaluate the extent of silencing by 20 nM or 200 nM siRNA at day 3 and day 6 post-transfection. In addition to silencing efficiency, non-specific effects such as cytotoxicity, change in DNA content and differentiation potential of cells were evaluated. Among the four transfection reagents, the commercial liposome-based agent was the most efficient reagent for siRNA delivery at 20 nM siRNA, followed by chitosan. Transfection using cationic liposomes, chitosan and PEI showed some decrease in viability and DNA content to varying degrees that was dependent on the siRNA dose and cell type evaluated, but independent of GAPDH knockdown. Some effects on DNA content were not accompanied by concomitant changes in viability. However, changes in expression of marker genes for cell cycle inhibition or progression, such as p21 and PCNA, could not explain the changes in DNA content. Interestingly, aspecific upregulation of GAPDH activity was found, which was limited to cartilaginous cells. In conclusion, non-specific effects should not be overlooked in the application of RNAi for mesenchymal cell transfection and may need to be overcome for its effective therapeutic application. PMID- 24345798 TI - The management of abdominal contour defects following TRAM flap breast reconstruction. AB - BACKGROUND: Incisional hernia can develop following breast reconstruction with abdominal tissue regardless of technique, and the management is often challenging. OBJECTIVES: The authors characterize hernias following transverse rectus abdominis musculocutaneous (TRAM) flap procedures and evaluate outcomes of different strategies for repair. METHODS: All patients who underwent repair of a TRAM-related hernia or bulge between 2003 and 2011 at a single institution were retrospectively reviewed. A minimum of 2 years' follow-up was required for inclusion in this series. Outcomes of different techniques for repair were compared and risk factors for hernia recurrence identified. RESULTS: Forty-three patients underwent repair of a TRAM-related hernia or bulge, most often with mesh (74.4%, n=32). At a mean overall follow-up of 5.2 years, 9 patients (20.9%) developed recurrent hernia or bulge. Compared to primary suture closure, the use of mesh was protective against recurrence (odds ratio, 0.05; 95% confidence interval, 0.00-0.65; P=.02), with the best results observed with fascial closure and underlay mesh reinforcement. CONCLUSIONS: Incisional hernia following TRAM flap breast reconstruction can be a challenging problem. Attention to surgical technique and the use of mesh minimize the risk of recurrence. PMID- 24345797 TI - Autophagy activation reduces renal tubular injury induced by urinary proteins. AB - Autophagy is shown to be beneficial for renal tubular injury caused by nephrotoxic drugs. To investigate whether autophagy could protect renal tubular epithelial cells (TECs) from injury induced by urinary proteins, we studied the activity and action of autophagy in TECs after urinary protein overload in vivo and in vitro. We found that autophagic vacuoles increased in TECs from patients with minimal change nephrotic syndrome (MCNS) and rat models with severe proteinuria induced by cationic BSA. In HK-2 cells, exposure to urinary proteins extracted from patients with MCNS led to a significant increase in autophagosome and autolysosome formation and decrease in SQSTM1/p62 protein level. Urinary protein addition also induced lysosomal turnover of LC3-II and perinuclear clustering of lysosomes. These changes were mediated by a reactive oxygen species (ROS)-dependent mechanism. Furthermore, pretreatment of HK-2 cells with rapamycin reduced the production of LCN2/NGAL and HAVCR1/KIM-1 and the level of apoptosis induced by urinary proteins. In contrast, blocking autophagy with chloroquine or BECN1 siRNAs exerted an opposite effect. Similar results were also observed in animal models with proteinuria after treatments with rapamycin and chloroquine. Taken together, our results indicated an increase in autophagic flux, which mounts an adaptive response in TECs after urinary protein overload. PMID- 24345800 TI - Characterization of the work-time relationship during cross-country ski ergometry. AB - The purpose of this study was to examine the validity and reliability of estimated parameters of the work-time relationship during cross-country ski ergometry using the traditional multi-trial critical power (CP) test and a 3 min 'all-out' test (3MT). Fourteen recreationally active male participants (mean +/- SD; age: 22.14 +/- 2.85 yrs; height: 177.09 +/- 6.57 cm; weight: 85.68 +/- 13.56 kg) completed three testing visits. All testing was conducted using an upper-body ergometer (SkiErg, Concept2, Inc., Morrisville, VT). A graded exercise test was used to determined maximal oxygen uptake (VO2peak). Two separate 3MT sessions were used to determine oxygen uptake (VO23MT), end-test power (EP), work above end-test power (WEP) and end stroke rate (ESR). Additionally, three time trials completed in a single day at simulated distances of 300 m, 650 m and 1000 m were used to estimate CP, W' and critical stroke rate (CSR). VO2peak (3.65 +/- 0.50 l . min(-1)) and VO23MT (3.59 +/- 0.4 l . min(-1)) were not significantly different (p = 0.162). Intraclass correlation coefficients for EP, WEP and ESR were 0.809, 0.611 and 0.783, respectively. EP (148 +/- 33 W) and CP (157 +/- 49 W), were not significantly different between the testing methodologies (p = 0.290) and were highly correlated (r = 0.780). WEP (8.4 +/- 3.0 kJ) and W' (8.3 +/- 3.0 kJ) were similar (p = 0.947) but not related (r = 0.119), while ESR (45 +/- 7 spm) and CSR (47 +/- 7 spm) values were not significantly different (p = 0.238) and moderately correlated (r = 0.498). The 3MT using ski ergometry was shown to produce concurrently valid results with the traditional multi-trial CP test for CP and CSR, but not W', and elicited similar maximal oxygen uptake values when compared to a graded exercise test. PMID- 24345801 TI - Noise properties of reconstructed images in a kilo-voltage on-board imaging system with iterative reconstruction techniques: a phantom study. AB - X-ray computed tomography (CT) images obtained with a kilo-voltage (kV) on-board imaging (OBI) system improve the accuracy of patient setup and treatment planning. The use of iterative reconstruction techniques (IRTs) for CT imaging can also reduce radiation dose compared to analytic reconstruction techniques. Despite these improvements, the image quality varies with IRTs, and the noise structure of reconstructed images can be distorted by IRTs. In this study, the noise properties and spatial resolution of the images reconstructed by IRTs were evaluated in terms of conventional noise metrics, high-order statistics, noise spectral density (NSD) and modulation transfer function (MTF) at different radiation doses. A kV OBI system mounted on a Varian Trilogy machine and a CATPHAN600 phantom were used to obtain projections, and the projections were reconstructed by Feldkamp (FDK), algebraic reconstruction technique (ART), maximum-likelihood expectation-maximization (MLEM) and total variation (TV) minimization algorithms. The reconstructed images were compared according to mean, standard deviation, skewness, kurtosis, NSD and MTF at different radiation doses. The results demonstrated that the noise properties and spatial resolution of reconstructed images depend on the type of IRT and the radiation dose. The noise structures are altered by IRTs and can be characterized by high-order statistics and NSD, as well as conventional noise metrics. In conclusion, high order statistics and NSD should be considered in order to provide detailed information for the images reconstructed by IRTs. Also, trade-off among noise properties, spatial resolution and contrast is important to optimize image quality obtained using IRTs. PMID- 24345802 TI - REG3gamma-deficient mice have altered mucus distribution and increased mucosal inflammatory responses to the microbiota and enteric pathogens in the ileum. AB - REG3gamma is considered to have a protective role against infection with Gram positive bacteria due to its bactericidal activity, but evidence from in vivo studies is lacking. We generated a REG3gamma(-/-) mouse, and investigated the effect of lack of REG3gamma on intestinal mucus distribution, spatial compartmentalization of bacteria, and expression of innate immunity genes. Infection studies were also performed with Gram-positive and Gram-negative pathogens to investigate the antimicrobial role of REG3gamma. REG3gamma(-/-) mice display altered mucus distribution, increased bacterial contact with the epithelium, and elevated inflammatory markers in the ileum without histological evidence of pathology. Infection response pathway genes were differentially expressed in both Listeria monocytogenes and Salmonella enteritidis infected REG3gamma(-/-) and wild-type (wt) mice. Higher amounts of myeloperoxidase and interleukin-22 transcripts were present in the ileal mucosa of REG3gamma(-/-) than wt mice, but translocation to the organs was unaffected. We concluded that REG3gamma has a protective role against mucosal infection with pathogenic Listeria and Salmonella in vivo. REG3gamma is equally distributed throughout the mucus and its absence results in increased epithelial contact with the microbiota resulting in low-grade inflammation. REG3gamma can bind to Gram-negative and Gram positive bacteria and influence mucus distribution in the ileum, properties which may contribute to mucosal protection. PMID- 24345803 TI - Crucial role of Plexin C1 for pulmonary inflammation and survival during lung injury. AB - Acute pulmonary inflammation during lung injury is initiated by the migration of neutrophils into the alveolar space. The severity of these inflammatory changes within the pulmonary tissue determines the severity of lung injury and ultimately patient outcome. Recent work has demonstrated that the guidance protein Semaphorin 7A propagates the infiltration of neutrophils into an hypoxic tissue site, yet the role of its target receptor Plexin C1 (PLXNC1) during lung injury is to date unknown. We demonstrate here that PLXNC1(+) neutrophils are present within the alveolar space and that PLXNC1 is induced in vitro and in vivo during lung injury. In a model of high-pressure ventilation PLXNC1(-/-) animals show decreased signs of alveolar inflammation and improved survival compared with wild type controls. Studies employing chimeric animals identified the hematopoietic expression of PLXNC1 to be of crucial importance for the observed results. Functional inhibition of PLXNC1 resulted in improved survival and ameliorated the signs of inflammation within the lung. Furthermore, the injection of a peptide binding to PLXNC1 resulted in improved survival and attenuated pulmonary inflammation. As such we demonstrate here, that previously unknown PLXNC1 holds significant importance for degree of pulmonary inflammation and determines outcome during experimental lung injury. PMID- 24345804 TI - Hypertrophy of infected Peyer's patches arises from global, interferon-receptor, and CD69-independent shutdown of lymphocyte egress. AB - Lymphoid organ hypertrophy is a hallmark of localized infection. During the inflammatory response, massive changes in lymphocyte recirculation and turnover boost lymphoid organ cellularity. Intriguingly, the exact nature of these changes remains undefined to date. Here, we report that hypertrophy of Salmonella infected Peyer's patches (PPs) ensues from a global "shutdown" of lymphocyte egress, which traps recirculating lymphocytes in PPs. Surprisingly, infection induced lymphocyte sequestration did not require previously proposed mediators of lymphoid organ shutdown including type I interferon receptor and CD69. In contrast, following T-cell receptor-mediated priming, CD69 was essential to selectively block CD4(+) effector T-cell egress. Our findings segregate two distinct lymphocyte sequestration mechanisms, which differentially rely on intrinsic modulation of lymphocyte egress capacity and inflammation-induced changes in the lymphoid organ environment. PMID- 24345805 TI - Transmigrated neutrophils in the intestinal lumen engage ICAM-1 to regulate the epithelial barrier and neutrophil recruitment. AB - Neutrophil (PMN) transepithelial migration (TEM) and accumulation in luminal spaces is a hallmark of mucosal inflammation. TEM has been extensively modeled; however, the functional consequences and molecular basis of PMN interactions with luminal epithelial ligands are not clear. Here we report that cytokine-induced expression of a PMN ligand, intercellular adhesion molecule-1 (ICAM-1), exclusively on the luminal (apical) membrane of the intestinal epithelium results in accumulation and enhanced motility of transmigrated PMN on the apical epithelial surface. Using complementary in-vitro and in-vivo approaches, we demonstrate that ligation of epithelial ICAM-1 by PMN or with specific antibodies results in myosin light-chain kinase-dependent increases in epithelial permeability that are associated with enhanced PMN TEM. Effects of ICAM-1 ligation on epithelial permeability and PMN migration in vivo were blocked after intraluminal addition of peptides derived from the cytoplasmic domain of ICAM-1. These findings provide new evidence for functional interactions between PMN and epithelial cells after migration into the intestinal lumen. Although such interactions may aid in clearance of invading microorganisms by promoting PMN recruitment, engagement of ICAM-1 under pathologic conditions would increase accumulation of epithelial-associated PMN, thus contributing to mucosal injury as observed in conditions, including ulcerative colitis. PMID- 24345807 TI - Secondary analyses from a randomized clinical trial: age as the key prognostic factor in endometrial carcinoma. PMID- 24345809 TI - [Investing in knowledge for the future]. PMID- 24345806 TI - Cilia and coordination of signaling networks during heart development. AB - Primary cilia are unique sensory organelles that coordinate a wide variety of different signaling pathways to control cellular processes during development and in tissue homeostasis. Defects in function or assembly of these antenna-like structures are therefore associated with a broad range of developmental disorders and diseases called ciliopathies. Recent studies have indicated a major role of different populations of cilia, including nodal and cardiac primary cilia, in coordinating heart development, and defects in these cilia are associated with congenital heart disease. Here, we present an overview of the role of nodal and cardiac primary cilia in heart development. PMID- 24345808 TI - Heparin-binding EGF-like growth factor (HB-EGF) therapy for intestinal injury: Application and future prospects. AB - Throughout the past 20 years, we have been investigating the potential therapeutic roles of heparin-binding EGF-like growth factor (HB-EGF), a member of the epidermal growth factor family, in various models of intestinal injury including necrotizing enterocolitis (NEC), intestinal ischemia/reperfusion (I/R) injury, and hemorrhagic shock and resuscitation (HS/R). Our studies have demonstrated that HB-EGF acts as an effective mitogen, a restitution-inducing reagent, a cellular trophic factor, an anti-apoptotic protein and a vasodilator, via its effects on various cell types in the intestine. In the current paper, we have reviewed the application and therapeutic effects of HB-EGF in three classic animal models of intestinal injury, with particular emphasis on its protection of the intestines from NEC. Additionally, we have summarized the protective functions of HB-EGF on various target cells in the intestine. Lastly, we have provided a brief discussion focusing on the future development of HB-EGF clinical applications for the treatment of various forms of intestinal injury including NEC. PMID- 24345810 TI - [Occupational needlestick injuries in hospitals]. PMID- 24345811 TI - [Epidemiology of needlesticks at Landspitali University Hospital during the years 1986-2011. A descriptive study]. AB - INTRODUCTION: Needlesticks, bodyfluid exposure and bites (incident) put healthcare workers (HCWs) at risk of hepatitis B, C and HIV particularly if patients are infected (high risk incident). The risk of infection is greatest from bore-hollow needles. The aim of the study was to describe the epidemiology of reported incidents and evaluate underreporting by HCWs at Landspitali University Hospital (LUH). METHODS: A retrospective descriptive study of reported incidents during 1986-2011. The ratio of incidents was calculated according to the HCWs age and profession and distribution by source and wards. The ratio of high risk incidents and vaccination status against HBV at time of incident was determined as well as underreporting during 01.01.2005-31.12.2011. RESULTS: At least 4089 incidents occured during the study period but 3587 were reported and blood samples taken from 2578 patients. Approximately a third of the incidents were associated with non-compliance with standard precaution and 54,7% of needlesticks were associated with bore-hollow needles. Few reports came from physicians and medical students (17,9%). During the study period 50,3% HCWs were vaccinated against HBV at time of incident. High risk incidents were 94 (2.6%), mostly related to hepatitis C (64,9%). Two HCWs became infected with HCV. During 2005-2011 underreporting was estimated to be 28,0%. CONCLUSION: Improved education of standard precaution when handling needles and sharps at LUH may reduce the number of incidents. Introduction of safety-needles and safety-devices may greatly reduce needlesticks as a large number of incidents were associated with hollow needles. Improved HBV vaccination among HCWs and reporting incidents should be encouraged. PMID- 24345812 TI - [Incidence and management of ectopic pregnancy in Iceland 2000-2009]. AB - INTRODUCTION: Ectopic pregnancy can be life-threatening. Its treatment has changed radically during the last two decades. The study objective was to evaluate incidence and treatment of ectopic pregnancy in the Icelandic population during the decade 2000-2009. MATERIAL AND METHODS: Information was collected about all diagnosed cases, place and method of treatment and admissions. The annual incidence was calculated with reference to number of pregnancies (n/1000), number of women aged 15-44 years (n/10 000) and by 5-year age groups, comparing the periods 2000-2004 and 2005-2009. RESULTS: The number of ectopic pregnancies during these 10 years was 836, or 444 during the years 2000-2004 and 392 during 2005-2009. The average annual incidence was 15.6/1000 pregnancies and 12.9/10 000 women. There was an annual incidence reduction from 17.3 to 14.1/1000 pregnancies (p<0.01) and 14.1 to 11.7/10 000 women (p<0.01). Surgery was the primary treatment for 94.9% of women, methotrexate in 3.2% and expectant management in 1.9%. Surgical management decreased from 98.0% to 91.3% between 5-year periods as medical treatment increased (0.4% to 6.4%; p<0.0001). The proportion of laparoscopic procedures increased from 80.5% to 91.1% (p<0.0001). In the university referral hospital this changed from 91.3% to 98.1% (p<0.001) and in rural hospitals from 44.0% to 69.3% (p<0.001). Mean hospital stay after open surgery was 3.2 days, but 0.9 days after laparoscopy. CONCLUSIONS: The incidence reduction of ectopic pregnancy is comparable to the development in neighbouring countries. Management has changed with increased use of laparoscopic surgery, medical and expectant treatment. PMID- 24345813 TI - [Eosinophilic esophagitis in children. Two case reports]. AB - Eosiniophilic Esophagitis (EoE) is a relatively new disease which was first reported in 1978 but increasingly diagnosed in the last 15 years. Initially EoE was mainly described in children but later also recognized in adults. In infants it presents as a food refusal, failure to thrive and vomiting. In older children and adults symptoms include chest pain dysphagia, oesophageal food impaction and even strictures on endoscopy. The etiology of EoE is often food allergy. Diagnosis is made on biopsies from the oesophagus and by excluding other causes of eosophageal eosinophilia. It is treated by eliminating the offending food groups or using local corticosteroids. We describe different presentation of eosinophilic esophagitis in two children and discuss diagnosis and treatment. PMID- 24345814 TI - Consequences of childhood sexual abuse for health and well-being: gender similarities and differences. AB - AIMS: Analyse gender similarities and differences in the consequences of childhood sexual abuse for health and well-being. METHODS: Comparative analysis of 28 in-depth interviews with 14 purposefully chosen participants, seven women and seven men, who had experienced childhood sexual abuse; two interviews were conducted with each participant. RESULTS: The participants expressed a journey of deep and silent suffering which seems, for them, to be endless and almost unbearable. All of them have suffered from complex health problems since childhood. A gender difference was shown in the tendency of women to internalize their emotional pain while the men had a tendency to externalize it. CONCLUSIONS: It is important for health professionals to be aware of the symptoms and consequences of child sexual abuse in order to provide support, appropriate care and treatment for the survivors. Finally, preventive and long lasting public health measures have to be taken in order to prevent children from experiencing such serious trauma. PMID- 24345815 TI - Effects of CYP2C19 and P450 oxidoreductase polymorphisms on the population pharmacokinetics of clobazam and N-desmethylclobazam in japanese patients with epilepsy. AB - BACKGROUND: Clobazam (CLB) is a 1,5-benzodiazepine with antiepileptic properties. More than 70% of administered CLB is dealkylated to yield N-desmethylclobazam (N CLB), a pharmacologically active metabolite, by cytochrome P450 (CYP) 3A4 and CYP2C19. The subsequent inactivation of N-CLB is primarily catalyzed by CYP2C19. Meanwhile, P450 oxidoreductase (POR) is the obligatory electron donor to all microsomal CYP enzymes. The aim of this study was to evaluate the impact of the CYP2C19 and POR genotypes on the pharmacokinetic parameters of CLB and N-CLB. METHODS: This retrospective study included 85 Japanese patients with epilepsy who were treated with CLB. CYP2C19*2, *3, and P450 oxidoreductase (POR) *28 (rs1057868C>T) polymorphisms were evaluated. A total of 128 steady-state concentrations for both CLB and N-CLB were collected from the patients. A nonlinear mixed-effects model identified the pharmacokinetics of CLB and N-CLB; the covariates included CYP2C19 and POR genotypes, weight, gender, daily CLB dose, and coadministered antiepileptic drugs. RESULTS: Among the 85 patients, the allele frequencies of CYP2C19*2, CYP2C19*3, and POR*28 were 27.6%, 12.9%, and 41.2%, respectively. A one-compartment model with first-order absorption and/or elimination showed that the clearance of CLB and N-CLB was significantly lower by 18.1% and 84.9%, respectively, in the CYP2C19 poor metabolizers compared with the homozygous extensive metabolizers. The CLB clearance was 44% higher in subjects homozygous for the POR*28 T allele than in those homozygous for the POR*28 C allele, although the genotypes did not affect the N-CLB clearance. The concomitant use of phenobarbital, phenytoin, and zonisamide significantly affected the CLB clearance, whereas that of carbamazepine, phenytoin, and valproic acid affected the N-CLB clearance. The weight also significantly influenced the CLB clearance and volume of distribution of both CLB and N-CLB. CONCLUSIONS: Our results showed that the CYP2C19 and/or POR genotypes have an impact on the CLB and/or N-CLB clearance. These results suggest that determining the CYP2C19 and/or POR genotypes is helpful for obtaining appropriate serum CLB and N-CLB concentrations and preventing an overdose when starting CLB therapy. PMID- 24345816 TI - Birth characteristics and risk of lymphoma in young children. AB - BACKGROUND: Lymphoma is the third most common childhood malignancy and comprises two types, Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). The etiology of pediatric lymphomas is largely unknown, but has been suggested to have prenatal origins. METHODS: In this population-based study, California birth certificates were identified for 478 lymphoma cases diagnosed in children 0-5 years of age between 1988 and 2007; 208,015 controls frequency-matched by birth year were randomly selected from California birth records. RESULTS: Compared to non Hispanic whites, Hispanic children had an increased risk of HL (odds ratio (OR) and 95% confidence interval (CI) 2.43 [1.14, 5.17]), and in particular, were diagnosed more often with the mixed cellularity subtype. For all types of lymphoma, we observed an about twofold risk increase with indicators for high risk pregnancies including tocolysis, fetopelvic disproportion and previous preterm birth. NHL risk doubled with the complication premature rupture of membranes (OR and 95% CI 2.18 [1.12, 4.25]) and HL with meconium staining of amniotic fluids (OR and 95% CI 2.55 [1.01, 6.43]). CONCLUSION: These data support previously reported associations between Hispanic ethnicity and HL and suggest that pregnancy related factors, such as intra-uterine infections and factors associated with preterm labor, may be involved in lymphoma pathogenesis. PMID- 24345817 TI - Innovative drugs to treat depression: did animal models fail to be predictive or did clinical trials fail to detect effects? AB - Over recent decades, encouraging preclinical evidence using rodent models pointed to innovative pharmacological targets to treat major depressive disorder. However, subsequent clinical trials have failed to show convincing results. Two explanations for these rather disappointing results can be put forward, either animal models of psychiatric disorders have failed to predict the clinical effectiveness of treatments or clinical trials have failed to detect the effects of these new drugs. A careful analysis of the literature reveals that both statements are true. Indeed, in some cases, clinical efficacy has been predicted on the basis of inappropriate animal models, although the contrary is also true, as some clinical trials have not targeted the appropriate dose or clinical population. On the one hand, refinement of animal models requires using species that have better homological validity, designing models that rely on experimental manipulations inducing pathological features, and trying to model subtypes of depression. On the other hand, clinical research should consider carefully the results from preclinical studies, in order to study these compounds at the correct dose, in the appropriate psychiatric nosological entity or symptomatology, in relevant subpopulations of patients characterized by specific biomarkers. To achieve these goals, translational research has to strengthen the dialogue between basic and clinical science. PMID- 24345818 TI - Subjective, physiological, and cognitive responses to intravenous nicotine: effects of sex and menstrual cycle phase. AB - Nicotine dependence is a serious public health concern. Optimal treatment of nicotine dependence will require greater understanding of the mechanisms that contribute to the maintenance of smoking behaviors. A growing literature indicates sex and menstrual phase differences in responses to nicotine. The aim of this study was to assess sex and menstrual phase influences on a broad range of measures of nicotine response including subjective drug effects, cognition, physiological responses, and symptoms of withdrawal, craving, and affect. Using a well-established intravenous nicotine paradigm and biochemical confirmation of overnight abstinence and menstrual cycle phase, analyses were performed to compare sex (age 18-50 years; 115 male and 45 female) and menstrual cycle phase (29 follicular and 16 luteal) effects. Females had diminished subjective drug effects of, but greater physiological responses to, nicotine administration. Luteal-phase females showed diminished subjective drug effects and better cognition relative to follicular-phase women. These findings offer candidate mechanisms through which the luteal phase, wherein progesterone is dominant relative to estradiol, may be protective against vulnerability to smoking. PMID- 24345820 TI - Early urban impact on Mediterranean coastal environments. AB - A common belief is that, unlike today, ancient urban areas developed in a sustainable way within the environmental limits of local natural resources and the ecosystem's capacity to respond. This long-held paradigm is based on a weak knowledge of the processes underpinning the emergence of urban life and the rise of an urban-adapted environment in and beyond city boundaries. Here, we report a 6000-year record of environmental changes around the port city of Akko (Acre), Israel, to analyse ecological processes and patterns stemming from the emergence and growth of urban life. We show that early urban development deeply transformed pre-existing ecosystems, swiftly leading to an urban environment already governed by its own ecological rules and this, since the emergence of the cities. PMID- 24345819 TI - Cannabinoid receptor activation shifts temporally engendered patterns of dopamine release. AB - The ability to discern temporally pertinent environmental events is essential for the generation of adaptive behavior in conventional tasks, and our overall survival. Cannabinoids are thought to disrupt temporally controlled behaviors by interfering with dedicated brain timing networks. Cannabinoids also increase dopamine release within the mesolimbic system, a neural pathway generally implicated in timing behavior. Timing can be assessed using fixed-interval (FI) schedules, which reinforce behavior on the basis of time. To date, it remains unknown how cannabinoids modulate dopamine release when responding under FI conditions, and for that matter, how subsecond dopamine release is related to time in these tasks. In the present study, we hypothesized that cannabinoids would accelerate timing behavior in an FI task while concurrently augmenting a temporally relevant pattern of dopamine release. To assess this possibility, we measured subsecond dopamine concentrations in the nucleus accumbens while mice responded for food under the influence of the cannabinoid agonist WIN 55,212-2 in an FI task. Our data reveal that accumbal dopamine concentrations decrease proportionally to interval duration--suggesting that dopamine encodes time in FI tasks. We further demonstrate that WIN 55,212-2 dose-dependently increases dopamine release and accelerates a temporal behavioral response pattern in a CB1 receptor-dependent manner--suggesting that cannabinoid receptor activation modifies timing behavior, in part, by augmenting time-engendered patterns of dopamine release. Additional investigation uncovered a specific role for endogenous cannabinoid tone in timing behavior, as elevations in 2 arachidonoylglycerol, but not anandamide, significantly accelerated the temporal response pattern in a manner akin to WIN 55,212-2. PMID- 24345821 TI - Fluorescent protein-imprinted polymers capable of signal transduction of specific binding events prepared by a site-directed two-step post-imprinting modification. AB - Protein recognition polymers capable of highly specific transduction of protein binding events into fluorescence change were prepared by molecular imprinting in conjunction with a newly developed two-step post-imprinting chemical modification of functional groups located within the protein recognition cavity. PMID- 24345822 TI - Relating rejection of trace organic contaminants to membrane properties in forward osmosis: measurements, modelling and implications. AB - This study elucidates the relationship between membrane properties and the rejection of trace organic contaminants (TrOCs) in forward osmosis (FO). An asymmetric cellulose triacetate (CTA) and a thin-film composite (TFC) polyamide FO membrane were used for this investigation. The effective average pore radius (rp), selective barrier thickness over porosity parameter (l/epsilon), surface charge, support layer structural parameter (S), pure water permeability coefficient (A) and salt (NaCl) permeability coefficient (B) of the two membranes were systematically characterised. Results show that measured rejection of TrOCs as a function of permeate water flux can be well described by the pore hindrance transport model. This observation represents the first successful application of this model, which was developed for pressure-driven nanofiltration, to an osmotically-driven membrane process. The rejection of charged TrOCs by the CTA and TFC membranes was high and was governed by both electrostatic repulsion and steric hindrance. The TFC membrane exhibited higher rejection of neutral TrOCs with low molecular weight than the CTA membrane, although the estimated pore size of the TFC membrane (0.42 nm) was slightly larger than that of the CTA membrane (0.37 nm). This higher rejection of neutral TrOCs by the TFC membrane is likely attributed to its active layer properties, namely a more effective active layer structure, as indicated by a larger l/epsilon parameter, and pore hydration induced by the negative surface charge. PMID- 24345823 TI - Changes in matrix metalloproteinase-9 levels during progression of atrial fibrillation. AB - OBJECTIVES: To observe levels of matrix metalloproteinase (MMP)-9 and evaluate their significance in various stages of idiopathic atrial fibrillation (AF). METHODS: Patients with idiopathic AF were recruited into this prospective study and classified into one of three groups according to stage of disease progression: paroxysmal AF; persistent AF; permanent AF. Healthy individuals were enrolled as control subjects. Serum levels of MMP-9 in all four groups were determined using a double-antibody sandwich enzyme-linked immunosorbent assay. RESULTS: Each AF group included 25 patients; 40 healthy individuals were included as controls. MMP-9 levels in the three AF groups were significantly higher than in the control group: 168.72 +/- 25.970, 201.36 +/- 31.26 and 253.20 +/- 22.99 ng/ml for the paroxysmal, persistent and permanent AF groups respectively, versus 76.80 +/- 14.90 ng/ml for the control group. MMP-9 levels increased with idiopathic AF disease progression (P < 0.05). CONCLUSIONS: An elevated MMP-9 level appears to be associated with a diagnosis of AF. MMP-9 levels appear to increase in relation to the stage of idiopathic AF progression. PMID- 24345824 TI - Mental health among left-behind preschool-aged children: preliminary survey of its status and associated risk factors in rural China. AB - OBJECTIVE: A large proportion of preschoolers have been left behind due to parental migration in rural China. We conducted a preliminary cross-sectional survey to investigate the mental health of these left-behind preschool-aged children (LBPC) and associated risk factors. METHODS: A total of 750 LBPC, comprising 217 and 433 children left behind as a result of migration of either or both parents, respectively, and 100 controls were enrolled from two counties in Anhui province, China. Their caregivers completed questionnaires on demographics, the Family Support Scale, the Parenting Self-efficacy Scale and the Preschool aged Child Mental Health Scale. RESULTS: There were no significant differences in mental outcomes among the three groups. However, male LBPC who were younger, fostered by caregivers with lower levels of life satisfaction and parenting efficacy, and came from poorer families with less social support, experienced more mental health problems than other children. CONCLUSIONS: LBPC did not have worse mental well-being than their control counterparts, but some subpopulations were at potential risk of mental health problems compared with other LBPC. More research on other underlying factors and strategies to prevent the development of psychopathology is urgently needed. PMID- 24345825 TI - Preoperative fluorodeoxyglucose positron emission tomography-computed tomography in papillary thyroid cancer: a futile exercise. PMID- 24345826 TI - Lower fructose intake may help protect against development of nonalcoholic fatty liver in adolescents with obesity. AB - OBJECTIVES: Although obesity is a major risk factor for nonalcoholic fatty liver (NAFL), not all individuals with obesity develop the condition, suggesting that other factors such as diet may also contribute to NAFL development. We evaluated associations between fructose and total sugar intake and subsequent diagnosis of NAFL in adolescents with obesity and without obesity in a population-based cohort. METHODS: Adolescents participating in the Western Australian Pregnancy Cohort (Raine) Study completed 3-day food records and body mass index measurement at age 14 years. At age 17 years, participants underwent abdominal ultrasound to determine NAFL status. Multivariable logistic regression models were used to analyse associations between energy-adjusted fructose and total sugar intake and NAFL status. Food diaries and liver assessments were completed for 592 adolescents. RESULTS: The prevalence of NAFL at age 17 was 12.8% for the total group and 50% for adolescents with obesity. Fructose intake did not significantly differ between adolescents with or without NAFL in our cohort as a whole. Among adolescents with obesity, those without NAFL had significantly lower energy adjusted fructose intake at age 14 years compared with those with NAFL (mean +/- standard deviation [SD] 38.8 +/- 19.8 g/day, vs 55.7 +/- 14.4 g/day, P = 0.02). Energy-adjusted fructose intake was independently associated with NAFL in adolescents with obesity (OR [odds ratio] 1.09, 95% CI 1.01-1.19, P = 0.03) after the adjustment for confounding factors. Energy-adjusted total sugar intake showed less significance (OR 1.03, 95% CI 0.999-1.07, P = 0.06). No significant associations were observed in other body mass index categories. CONCLUSIONS: Lower fructose consumption in adolescents with obesity at 14 years is associated with a decreased risk of NAFL at 17 years. Fructose rather than overall sugar intake may be more physiologically relevant in this association. PMID- 24345828 TI - EEG abnormalities are associated with increased risk of transplant or poor outcome in children with acute liver failure. AB - OBJECTIVES: There are limited data on the incidence of seizures and utility of brain imaging and electroencephalogram (EEG) to predict outcome of children with acute liver failure (ALF). We investigated the association between hepatic encephalopathy (HE) scores, abnormal EEG or neuroimaging, and short-term outcome. METHODS: Single-center retrospective observational study of infants and children with ALF who underwent continuous EEG monitoring and brain imaging within 24 hours of admission to the intensive care unit (ICU). RESULTS: A total of 19 patients with ALF with a mean age of 6.8 +/- 1.5 years were evaluated. The majority of cases (74%) were indeterminate. Of the total, 10 patients (53%) survived to discharge without liver transplant (LT), 5 (26%) received LT, and 4 (21%) died without LT. Seizures occurred in only 2 cases (19%). Patients who had an abnormal EEG on admission (n = 7) were significantly more likely to die or require LT (P < 0.05, Fisher exact test). Patients with either an admission HE score <= 2, or liver injury unit score <222, combined with a normal or mildly abnormal EEG were more likely to survive without LT. Neuroimaging was normal in the majority of cases (87%) and was not associated with outcome. CONCLUSIONS: Children with a moderate or severe abnormality of EEG background on admission were significantly more likely to require LT or to die. Children with an HE score <= 2, and a normal or only mildly abnormal EEG, were significantly more likely to survive without needing LT. These findings are an initial step toward distinguishing patients with ALF who may recover spontaneously from those who will require LT. PMID- 24345829 TI - An Unusual Case of Pale Stools. PMID- 24345827 TI - Fat-soluble vitamins in cystic fibrosis and pancreatic insufficiency: efficacy of a nutrition intervention. AB - OBJECTIVES: The aim of the study was to assess the impact of LYM-X-SORB (LXS), an organized lipid matrix that has been shown to be absorbable without pancreatic enzyme therapy on fat-soluble vitamin status in children with cystic fibrosis (CF) and pancreatic insufficiency (PI). METHODS: Children with CF and PI were randomized to daily LXS or an isocaloric placebo comparison supplement for 12 months. Serum vitamins A (retinol), D (25-hydroxyvitamin D[25D]), E (alpha tocopherol, alpha-tocopherol:cholesterol ratio), and K (percentage of undercarboxylated osteocalcin [%ucOC] and plasma proteins induced by vitamin K absence factor II [PIVKA II]) were assessed at baseline and 12 months. Dietary intake was determined using 3-day weighed food records and supplemental vitamin intake by a comprehensive questionnaire. RESULTS: A total of 58 subjects (32 boys, age 10.3 +/- 2.9 years [mean +/- standard deviation]) with complete serum vitamin, dietary and supplemental vitamin data were analyzed. After adjusting for dietary and supplemental vitamin intake, serum retinol increased 3.0 +/- 1.4 MUg/dL (coefficient +/- standard error) (adjusted R2 = 0.02, P = 0.03) and vitamin K status improved as demonstrated by a decreased percentage of undercarboxylated osteocalcin of -6.0% +/- 1.6% by 12 months (adjusted R2 = 0.15, P < 0.001). These changes occurred in both the LXS and placebo comparison groups. No changes in serum 25D or alpha-tocopherol were detected. Both nutrition interventions increased caloric intake a mean of 83 +/- 666 kcal/day by 12 months. CONCLUSIONS: Vitamins A and K status improved, whereas vitamins D and E status was unchanged during 12 months of LXS and isocaloric placebo comparison supplement in children with CF and PI. PMID- 24345830 TI - Lubiprostone in pediatric functional constipation. PMID- 24345831 TI - Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN. AB - BACKGROUND: Constipation is a pediatric problem commonly encountered by many health care workers in primary, secondary, and tertiary care. To assist medical care providers in the evaluation and management of children with functional constipation, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition were charged with the task of developing a uniform document of evidence-based guidelines. METHODS: Nine clinical questions addressing diagnostic, therapeutic, and prognostic topics were formulated. A systematic literature search was performed from inception to October 2011 using Embase, MEDLINE, the Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials, and PsychInfo databases. The approach of the Grading of Recommendations Assessment, Development and Evaluation was applied to evaluate outcomes. For therapeutic questions, quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation system. Grading the quality of evidence for the other questions was performed according to the classification system of the Oxford Centre for Evidence-Based Medicine. During 3 consensus meetings, all recommendations were discussed and finalized. The group members voted on each recommendation, using the nominal voting technique. Expert opinion was used where no randomized controlled trials were available to support the recommendation. RESULTS: This evidence-based guideline provides recommendations for the evaluation and treatment of children with functional constipation to standardize and improve their quality of care. In addition, 2 algorithms were developed, one for the infants <6 months of age and the other for older infants and children. CONCLUSIONS: This document is intended to be used in daily practice and as a basis for further clinical research. Large well-designed clinical trials are necessary with regard to diagnostic evaluation and treatment. PMID- 24345834 TI - Dietary docosahexaenoic acid supplementation in children with autism. AB - OBJECTIVE: The aim of the study was to determine whether docosahexaenoic acid (DHA) supplementation improves the behavior of children with autism. METHODS: A group of 3- to 10-year-old children with autism were randomized in a double-blind fashion to receive a supplement containing 200 mg of DHA or a placebo for 6 months. The parents and the investigator completed the Clinical Global Impressions-Improvement scale to rate changes in core symptoms of autism after 3 and 6 months. The parents completed the Child Development Inventory and the Aberrant Behavior Checklist, and both parents and teachers completed the Behavior Assessment Scale for Children (BASC) at enrollment and after 6 months. RESULTS: A total of 48 children (40 [83%] boys, mean age [standard deviation] 6.1 [2.0] years) were enrolled; 24 received DHA and 24 placebo. Despite a median 431% increase in total plasma DHA levels after 6 months, the DHA group was not rated as improved in core symptoms of autism compared to the placebo group on the CGI I. Based on the analysis of covariance models adjusted for the baseline rating scores, parents (but not teachers) provided a higher average rating of social skills on the BASC for the children in the placebo group compared to the DHA group (P = 0.04), and teachers (but not parents) provided a higher average rating of functional communication on the BASC for the children in the DHA group compared to the placebo group (P = 0.02). CONCLUSIONS: Dietary DHA supplementation of 200 mg/day for 6 months does not improve the core symptoms of autism. Our results may have been limited by inadequate sample size. PMID- 24345835 TI - Maternal-fetal transmission of hepatitis C infection: what is so special about babies? AB - Children with hepatitis C virus infection often differ from adults regarding the rate of viral clearance, duration of infection, and the progression to cirrhosis. In the pediatric population, vertical transmission of hepatitis C virus infection from mother to infant is the most common route of infection. In the present review, we explore the factors that may influence the natural history of hepatitis C virus infection in children who acquire the infection through maternal-fetal transmission. There is particular focus on how viral diversity and the infant immune system may affect viral transmission. An enhanced understanding of maternal-fetal transmission of hepatitis C virus infection has the potential to affect effective drug and vaccine development for both children and adults. PMID- 24345837 TI - Does calretinin immunohistochemistry reduce inconclusive diagnosis in rectal biopsies for Hirschsprung disease? AB - Many difficulties occur during the evaluation of rectal biopsies for the diagnosis of Hirschsprung disease. We investigated whether the introduction of calretinin (CR) immunohistochemistry in a diagnostic panel could decrease the rate of inconclusive results. Data from 82 patients undergoing rectal biopsies before and after CR introduction were analyzed. Inconclusive results were obtained in 17 of 45 rectal biopsies (37.8%) in the series of cases before CR introduction and in 5 of 42 rectal biopsies (11.9%) in the series of cases after CR (P < 0.006). The inclusion of CR in the histopathologic panel may improve the diagnostic accuracy of Hirschsprung disease. PMID- 24345838 TI - Hepatitis C Virus-Autoimmune Hepatitis Overlap Syndrome in an Adolescent. PMID- 24345836 TI - Depression subtypes in pediatric inflammatory bowel disease. AB - OBJECTIVE: The association between inflammatory bowel disease (IBD) and depression provides a unique opportunity to understand the relation between systemic inflammation and depressive symptom profiles. METHODS: Youth (n = 226) ages 9 to 17 years with comorbid IBD and depression underwent psychiatric assessment and evaluation of IBD activity. Latent profile analysis (LPA) identified depressive subgroups based on similar responses to the Children's Depression Rating Scale-Revised. Demographic factors, depression severity, anxiety, IBD activity, inflammatory markers, IBD-related medications, and illness perception were evaluated as predictors of profile membership. RESULTS: Mean age was 14.3 years; 75% had Crohn disease; 31% were taking systemic corticosteroids. Mean depressive severity was moderate, whereas IBD activity, which reflects inflammation, was mild. LPA identified 3 subgroups: Profile-1 (mild, 75%) had diverse low-grade depressive symptoms and highest quality of life; Profile-2 (somatic, 19%) had severe fatigue, appetite change, anhedonia, decreased motor activity, and depressed mood with concurrent high-dose steroid therapy and the highest IBD activity; and Profile-3 (cognitive, 6%) had the highest rates of self reported depressive symptoms, ostomy placements, and anxiety with IBD symptoms in the relative absence of inflammation. CONCLUSIONS: Evidence was found for 3 depression profiles in youth with IBD and depression. Our analyses determined that patients with predominantly somatic or cognitive symptoms of depression comprised 25% of our cohort. These findings may be used to design subgroup specific interventions for depression in adolescents with IBD and other physical illnesses associated with systemic inflammation. PMID- 24345839 TI - Question of an infectious etiology or contribution to the pathogenesis of infantile hypertrophic pyloric stenosis. AB - Infantile hypertrophic pyloric stenosis is a concerning cause of nonbilious vomiting in the neonatal population. Although a number of etiological theories exist, its exact cause remains nebulous. The question of an infectious etiology (or contribution) has been previously examined in case reports and case series, with recent support through suggestions of seasonality and familial aggregation with unclear inheritance patterns. The present review discusses the published literature regarding infectious etiologies of infantile hypertrophic pyloric stenosis. Furthermore, it attempts to demonstrate that newer research regarding an NOS1 genetic etiology does not exclude, but rather can be consistent with, an infectious etiology. PMID- 24345840 TI - Dextranomer hyaluronic acid copolymer effects on gastroesophageal junction. AB - OBJECTIVE: The outcomes of fundoplication for gastroesophageal reflux disease are suboptimal in many children, and alternatives are clearly needed. Dextranomer hyaluronic acid (DxHA) copolymer, an agent with proven efficacy in vesicoureteral reflux, was studied with respect to its effects on the gastroesophageal junction (GEJ). METHODS: Twelve New Zealand white rabbits underwent measurement of lower esophageal sphincter pressure followed by laparotomy and injection into the muscular layer of the GEJ (controls, 1.0 mL saline; low-dose DxHA [0.5 mL]; high dose DxHA [1.0 mL]). After a 12-week survival period, the animals underwent manometry, sacrifice, and necropsy. Organs were examined histologically by pathologists blinded to the injection delivered. RESULTS: All animals survived. Weight gain was equal in the 3 groups. There was no significant difference in mean lower esophageal sphincter pressure from baseline in any group (control 2.3 mmHg [95% confidence interval, CI -3.3 to 7.9]; low-dose group 3.2 mmHg [95% CI 0.8 to 7.2]; high-dose group -4.0 mmHg [95% CI -18.95 to 10.95]). Histologically, DxHA injection produced an intramural implant, with a foreign body giant cell reaction, and fibroblastic infiltration with collagen deposition. High-dose injection did not consistently result in a qualitative increase in the magnitude of the reaction. There was no mucosal injury or luminal stenosis. CONCLUSIONS: In this first study evaluating the effects of DxHA injection at the GEJ, a histologic bulking effect was observed without obvious functional complications. The agent may have a role in the treatment of gastroesophageal reflux disease. PMID- 24345841 TI - Gastrointestinal Langerhans cell histiocytosis. PMID- 24345842 TI - Chronic functional constipation in children: adherence and factors associated with drug treatment. AB - OBJECTIVE: The aim of the present study was to evaluate the treatment adherence of children with chronic functional constipation. METHODS: The present study is a prospective and longitudinal study realized at a pediatric gastroenterology clinic of a Brazilian University Hospital, between August 2009 and October 2011. Rome III criteria and the Bristol Stool Scale were used to define constipation and to characterize feces, respectively. Drug treatment was prescribed for patients according to the protocols previously standardized in the clinic. Specific questionnaires, containing questions related to 1 dependent variable and independent variables were completed in the first and sixth months of the treatment. Independent variables related to the patients, their caregivers, the disease itself, and the therapeutic plan were analyzed and compared with the dependent variable (adherence to the treatment). Adherence was considered when the patient returned with >75% of the prescribed medicine containers empty. RESULTS: Fifty children participated in both the first and sixth months of treatment. The mean age of the sample was 77.6 +/- 43.8 months and the mean age of the onset of symptoms was 18.8 +/- 27.9 months. The adherence rate was 38% in the first month and 30% in the sixth month. Patients who were treated with polyethylene glycol had greater adherence than patients who were prescribed other laxatives, with statistical significance in the second moment of the study (P = 0.19 and P = 0.04, respectively). CONCLUSIONS: The study showed low adherence rates to drug treatment of constipation in children. It is necessary to seek new strategies to increase treatment adherence, while avoiding complications and reducing costs. PMID- 24345844 TI - Pyogenic Liver Abscess Masquerading as a Hepatic Neoplasm. PMID- 24345843 TI - Increased prevalence of eosinophilic gastrointestinal disorders in pediatric PTEN hamartoma tumor syndromes. AB - OBJECTIVES: The PTEN hamartoma tumor syndromes (PHTSs) are a collection of disorders caused by germline mutations of the tumor suppressor gene PTEN. Eosinophilic gastrointestinal disorders (EGIDs) are rare diseases characterized by food-induced, eosinophil-dominant inflammation in various segments of the gastrointestinal tract. On the basis of our clinical observations of several patients with EGID-PHTS, we investigated whether there is an association between these 2 disorders. METHODS: The Cincinnati Children's Hospital Medical Center (CCHMC) Informatics for Integrating Biology and the Bedside (i2b2) warehouse was queried for the years 2007 to 2012 using International Classification of Diseases 9 codes for PTEN-related diseases; the results were cross-referenced with participants enrolled in the Cincinnati Center for Eosinophilic Disorder's EGID database to identify patients with both disorders. In an effort to replicate our findings, the Cleveland Clinic Genomic Medicine Institute PTEN database was queried for cases between 2005 and 2012. Inclusion criteria were age <= 18 years, history of PHTS, and an esophagogastroduodenoscopy (EGD) and/or colonoscopy with at least 1 histologic EGID diagnosis confirmed by a CCHMC pathologist. The Pearson chi(2) test was used to determine the odds of EGID enrichment in PHTS. RESULTS: Of the 1,058,260 CCHMC distinct patients identified by the i2b2 search, 53 had clinical diagnoses suggestive of PHTS. Thirteen of the 53 had PTEN mutations, with 8 of 13 (62%) having had an EGD and/or colonoscopy. Five of the 8 had confirmed EGID. At the Cleveland Clinic, 3 of 75 patients (3/4 who had EGD and/or colonoscopy) with PHTS had confirmed EGID. CCHMC i2b2 query data showed a substantial enrichment of EGIDs in PHTSs (odds ratio 272; confidence interval 89 831, P < 0.0001). An EGID prevalence estimate from the i2b2 query supported a marked enrichment of EGIDs in PHTSs in the Cleveland Clinic database (P < 0.0001). Among the 8 subjects with EGIDs and PHTSs, the age at EGID and PHTS diagnosis was 7.6 +/- 3.2 and 7.9 +/- 5.8 years, respectively. Patients with EGID PHTS had excess eosinophils in biopsies of the esophagus (75%), stomach (38%), and colon (13%), with a notable presence of eosinophil-rich gastrointestinal polyposis (88%). CONCLUSIONS: EGID is a previously unrecognized comorbid disease in pediatric patients with PHTS. These data suggest a potential role of PTEN in contributing to EGID susceptibility. PMID- 24345845 TI - Energy requirements for maintenance and growth in 3- to 4-year-olds may be overestimated by existing equations. AB - OBJECTIVES: To give appropriate dietary advice to preschool children, an estimation of their energy requirements for both maintenance and activity is needed. We compared energy requirements for maintenance, measured by indirect calorimetry against existing equations predicting these requirements in 3- to 4 year-old children. METHODS: In 30 children (age 3.4 +/- 0.3) from the GECKO Drenthe cohort, height, weight, evening sleeping metabolic rate (SMR) (by indirect calorimetry), fat mass (FM), and fat-free mass (FFM) (by isotope dilution) were measured. For 25 children, a valid evening SMR was available as a measure for energy used for maintenance and growth. This SMR was compared with existing equations (Schofield, FAO/WHO/UNU, Oxford and Harris-Benedict). Correlations among SMR and weight, height, FM, and FFM were also calculated. RESULTS: From the existing equations, significant higher values, ranging from 58 to 144 kcal/day, were calculated for the BMR compared with the measured SMR results, indicating 8% to 19% overestimation. This overestimation is higher at lower ranges of energy requirement. SMR was positively related to weight (r = 0.488, P = 0.013), height (r = 0.499, P = 0.011), and FFM (r = 0.482, P = 0.027), but not to FM (r = 0.211, P = 0.358). CONCLUSIONS: Existing equations show higher values for the energy used for maintenance in young children compared to the results of our measurements of the SMR. Energy used for maintenance is correlated with FFM and not with FM. PMID- 24345846 TI - A 4-polymorphism risk score predicts steatohepatitis in children with nonalcoholic fatty liver disease. AB - OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in industrialized countries in adults and children, following the trail of the epidemic diffusion of obesity. Nonalcoholic steatohepatitis (NASH) is a potentially serious form of NAFLD linked with a significant increase in overall and liver-related morbidity and mortality. Because diagnosis still requires liver biopsy, there is urgent need of developing noninvasive early markers. The aim of the present study was to assess whether the simultaneous detection of genetic risk factors could predict NASH. METHOD: We enrolled 152 untreated, consecutive obese children and adolescents with biopsy proven NAFLD and increased liver enzymes. The PNPLA3 rs738409 C>G (I148 M), SOD2 rs4880 C>T, KLF6 rs3750861 G>A, and LPIN1 rs13412852 C>T polymorphisms were detected by Taqman assays. RESULTS: A multivariate logistic model based on the genetic risk factors significantly predicted NASH (area under the receiver operating characteristic curve [AUC] 0.75, 95% confidence interval [CI] 0.67 0.82, P < 0.0001), performing better than a clinical risk score identified at stepwise regression based on age, aspartate aminotransferase levels, and diastolic blood pressure (AUC 0.66, 95% CI 0.57-0.75). A single cutoff value of the genetic risk score had 90% sensitivity and 36% specificity for NASH. A risk score combining the clinical and genetic risk factors resulted in an AUC of 0.80 (95% CI 0.73-0.87). CONCLUSIONS: A score based on genetic risk factors significantly predicts NASH in obese children with increased liver enzymes, representing a proof-of-principle that genetic scores may be useful to predict long-term outcomes of the disease and guide clinical management. PMID- 24345847 TI - Structure-property relationships based on Hammett constants in cyclometalated iridium(III) complexes: their application to the design of a fluorine-free FIrPic like emitter. AB - While phosphorescent cyclometalated iridium(iii) complexes have been widely studied, only correlations between oxidation potential EOX and Hammett constant sigma, and between the redox gap (DeltaEREDOX = EOX-ERED) and emission or absorption wavelength (lambdaabs, lambdaem) have been reported. We present now a quantitative model based on Hammett parameters that rationalizes the effect of the substituents on the properties of cyclometalated iridium(iii) complexes. This simple model allows predicting the apparent redox potentials as well as the electrochemical gap of homoleptic complexes based on phenylpyridine ligands with good accuracy. In particular, the model accounts for the unequal effect of the substituents on both the HOMO and the LUMO energy levels. Consequently, the model is used to anticipate the emission maxima of the corresponding complexes with improved reliability. We demonstrate in a series of phenylpyridine emitters that electron-donating groups can effectively replace electron-withdrawing substituents on the orthometallated phenyl to induce a blue shift of the emission. This result is in contrast with the common approach that uses fluorine to blue shift the emission maximum. Finally, as a proof of concept, we used electron-donating substituents to design a new fluorine-free complex, referred to as EB343, matching the various properties, namely oxidation and reduction potentials, electrochemical gap and emission profile, of the standard sky-blue emitter FIrPic. PMID- 24345848 TI - Safer sex negotiation and its association with condom use among clients of female sex workers in Bangladesh. AB - This study examines safer sex negotiation and its association with condom use among clients of female sex workers (FSWs) in Bangladesh. Data were collected from 484 FSWs living in Dhaka city following a convenient sampling procedure. Overall, 47% of the clients were suggested to use condom during last sexual intercourse and 21% did so. Both bivariate and multivariable binary logistic regression analyses yielded significantly increased risk of negotiation for safer sex with clients among FSWs with higher education. The power bargaining significantly (P < .001) increased the risk of condom use by 2.15 times (95% confidence interval = 1.28-3.59). The odds of condom use were significantly higher among the FSWs with higher education, unmarried, hotel-based, and among those with higher level of HIV/AIDS-related knowledge. The Bangladeshi FSWs have little control over their profession. HIV prevention programs should aim to encourage FSWs through information, education, and communication program to insist on condom use among clients. PMID- 24345849 TI - A simple route to azaborinylphosphines: isoelectronic B-N analogues of arylphosphine ligands. AB - Azaborinylphosphines are readily prepared by the reaction of silylphosphines with a chloroborane under mild conditions; they are shown to contain P-B bonds that are sufficiently robust to allow these ligands to be used in homogeneous catalysis. PMID- 24345850 TI - Male microchimerism and survival among women. AB - BACKGROUND: During pregnancy, woman and fetus exchange small quantities of cells, and their persistence at later times is termed microchimerism. Microchimerism is known to substantially impact on women's later health. This study examined the survival of women according to male microchimerism status. METHODS: Male microchimerism presence, measured as Y chromosome in peripheral blood samples, was determined in 272 women from the large Danish Diet, Cancer and Health cohort when aged 50-64 years during 1993-97. Women were followed up for cause-specific death in national Danish registers until the end of 2009. Survival was analysed using Cox regression. RESULTS: A total of 190 women (70%) were male microchimerism positive. During follow-up 21 women died, of whom 11 (52%) were male microchimerism positive at enrolment and 10 were negative. Of the 21 deaths, 13 (62%) were due to cancer and 5 (24%) were due to cardiovascular disease. Male microchimerism presence was associated with a reduced hazard ratio of all-cause mortality of 0.42 (95% CI 0.17-1.03). The hazard ratio of death from cancer and cardiovascular disease was 0.24 (95% CI 0.08-0.79) and 1.66 (95% CI 0.18-15.48), respectively, among male microchimerism positive compared with negative women. CONCLUSIONS: Although the biological mechanisms are not precisely known, male microchimerism presence in peripheral blood of women is associated with substantially improved survival in women. The results also indicate that the association with male microchimerism may vary between different causes of death. PMID- 24345852 TI - Fluids in acute respiratory distress syndrome: pros and cons. AB - PURPOSE OF REVIEW: Fluid resuscitation in acute respiratory distress syndrome (ARDS) is not well documented. Clinical evidence comes from studies in critically ill patients, but these patients respond differently to fluids depending on the presence or absence of sepsis. RECENT FINDINGS: Clinical trials have shown adverse effects on kidney and hemostatic functions and trends toward increased mortality after hydroxyethyl starch infusion. Although well conducted, the methodology deserves attention concerning the infused volume, hemodynamic goals and the presence of septic and nonseptic patients. Small single-center studies have shown beneficial results associated with colloidal molecules through innovative methodological apparatus. Ongoing clinical trials allied to retrospective and prospective trials may favor the introduction of albumin in the critically ill population. SUMMARY: In order to evaluate the pros and cons of using fluids in ARDS patients, it is important to carefully analyze the latest trials. Recent studies have emphasized the importance of better understanding endothelial pathophysiology during fluid management in ARDS patients. Certainly, further studies analyzing fluid strategies in septic and nonseptic ARDS patients are needed. PMID- 24345851 TI - Systematic evaluation of environmental and behavioural factors associated with all-cause mortality in the United States national health and nutrition examination survey. AB - BACKGROUND: Environmental and behavioural factors are thought to contribute to all-cause mortality. Here, we develop a method to systematically screen and validate the potential independent contributions to all-cause mortality of 249 environmental and behavioural factors in the National Health and Nutrition Examination Survey (NHANES). METHODS: We used Cox proportional hazards regression to associate 249 factors with all-cause mortality while adjusting for sociodemographic factors on data in the 1999-2000 and 2001-02 surveys (median 5.5 follow-up years). We controlled for multiple comparisons with the false discovery rate (FDR) and validated significant findings in the 2003-04 survey (median 2.8 follow-up years). We selected 249 factors from a set of all possible factors based on their presence in both the 1999-2002 and 2003-04 surveys and linkage with at least 20 deceased participants. We evaluated the correlation pattern of validated factors and built a multivariable model to identify their independent contribution to mortality. RESULTS: We identified seven environmental and behavioural factors associated with all-cause mortality, including serum and urinary cadmium, serum lycopene levels, smoking (3-level factor) and physical activity. In a multivariable model, only physical activity, past smoking, smoking in participant's home and lycopene were independently associated with mortality. These three factors explained 2.1% of the variance of all-cause mortality after adjusting for demographic and socio-economic factors. CONCLUSIONS: Our association study suggests that, of the set of 249 factors in NHANES, physical activity, smoking, serum lycopene and serum/urinary cadmium are associated with all-cause mortality as identified in previous studies and after controlling for multiple hypotheses and validation in an independent survey. Whereas other NHANES factors may be associated with mortality, they may require larger cohorts with longer time of follow-up to detect. It is possible to use a systematic association study to prioritize risk factors for further investigation. PMID- 24345853 TI - Addressing concerns about the inclusion of premenstrual dysphoric disorder in DSM 5. AB - OBJECTIVE: Inclusion of premenstrual dysphoric disorder (PMDD) into the main text of the DSM has been a point of controversy for many years. The purpose of this article is to address the main concerns raised by opponents to its inclusion. Concerns are presented and countered in turn. LITERATURE SEARCH: To identify the most prevalent arguments against inclusion of PMDD, we searched MEDLINE (1966 2012), PsycINFO (1930-2012), the Internet, and reference lists of identified articles during September 1-17, 2012, using the keywords PMDD, premenstrual syndrome (PMS), DSM, DSM-5, concerns, controversy, women, political power, workforce, courts, and history. The search was restricted to English-language publications. A total of 55 articles were identified and included. The most pressing arguments against inclusion were grouped by similarity and addressed if they were reported 5 or more times. Our review of the sources yielded 38 concerns regarding PMDD; 6 concerns were reported at least 5 times and are addressed in this article. DISCUSSION: Evidence culled from historical and legal trends does not support the alleged societal use of PMS to harm women (eg, keeping women out of the workforce or using PMS against women in child custody disputes). Further, current epidemiologic research has answered all of the methodology criticisms of opponents. Studies have confirmed the existence of PMDD worldwide. The involvement of pharmaceutical companies in research has been questioned. However, irrespective of the level of association with industry, current research on PMDD has consistent results: PMDD exists in a minority of women. CONCLUSIONS: Historically, the pain and suffering of women have been dismissed, minimized, and negated. Similarly, women with PMDD have often had their experience invalidated. With the preponderance of evidence in its favor, PMDD has been placed in the main text of the DSM-5, opening the door for affected women to receive the attention full diagnostic status provides. PMID- 24345854 TI - Sonochemical preparation of carbon spheres. AB - Spherical morphology of carbon with 150-400 nm size is produced by sonication (480 kHz, 2.5 W) of toluene with water under ambient conditions. Medium range of frequency and weak power of ultrasound is found to be the appropriate conditions for preparing the carbon spheres. Morphological and structural analysis of the product is carried out with TEM, SEM, elemental analysis, TGA, and FT-IR spectroscopy. PMID- 24345855 TI - Folate conjugated silk fibroin nanocarriers for targeted drug delivery. AB - Disease treatment processes mainly focus on the development of nontoxic, biodegradable, non-immunogenic, biocompatible materials capable of controlled and long-term release of biomolecules. In this work silk protein fibroin from non mulberry tropical tasar silkworm, Antheraea mylitta, is used to prepare nanoparticles as a drug delivery system. Folate is a vitamin, which is brought into healthy and cancerous cells by folate receptors. The efficiency of silk fibroin-folate nanoparticles loaded with anticancer drug doxorubicin was evaluated by analysing the cell viability, proliferation and endocytosis. Consequently the effects of pro-inflammatory responses by cytokines such as TNF alpha, IL-1beta and nitric oxide were checked by stimulating the macrophages with folate conjugated silk fibroin nanoparticles. The fibroin-folate nanocarriers are nontoxic, easily taken up by cells and capable of sustained drug release. Nanoparticles loaded with anticancer drug doxorubicin target cancer cells. The results show that silk fibroin-folate nanoparticles may serve as promising nanocarriers for different biomedical and nanotechnology applications in cancer research. PMID- 24345856 TI - A tumor-promoting mechanism mediated by retrotransposon-encoded reverse transcriptase is active in human transformed cell lines. AB - LINE-1 elements make up the most abundant retrotransposon family in the human genome. Full-length LINE-1 elements encode a reverse transcriptase (RT) activity required for their own retrotranpsosition as well as that of non-autonomous Alu elements. LINE-1 are poorly expressed in normal cells and abundantly in cancer cells. Decreasing RT activity in cancer cells, by either LINE-1-specific RNA interference, or by RT inhibitory drugs, was previously found to reduce proliferation and promote differentiation and to antagonize tumor growth in animal models. Here we have investigated how RT exerts these global regulatory functions. We report that the RT inhibitor efavirenz (EFV) selectively downregulates proliferation of transformed cell lines, while exerting only mild effects on non-transformed cells; this differential sensitivity matches a differential RT abundance, which is high in the former and undetectable in the latter. Using CsCl density gradients, we selectively identify Alu and LINE-1 containing DNA:RNA hybrid molecules in cancer but not in normal cells. Remarkably, hybrid molecules fail to form in tumor cells treated with EFV under the same conditions that repress proliferation and induce the reprogramming of expression profiles of coding genes, microRNAs (miRNAs) and ultraconserved regions (UCRs). The RT-sensitive miRNAs and UCRs are significantly associated with Alu sequences. The results suggest that LINE-1-encoded RT governs the balance between single-stranded and double-stranded RNA production. In cancer cells the abundant RT reverse-transcribes retroelement-derived mRNAs forming RNA:DNA hybrids. We propose that this impairs the formation of double-stranded RNAs and the ensuing production of small regulatory RNAs, with a direct impact on gene expression. RT inhibition restores the 'normal' small RNA profile and the regulatory networks that depend on them. Thus, the retrotransposon-encoded RT drives a previously unrecognized mechanism crucial to the transformed state in tumor cells. PMID- 24345857 TI - A novel technique for muscle onset detection using surface EMG signals without removal of ECG artifacts. AB - Surface electromyography (EMG) signal from trunk muscles is often contaminated by electrocardiography (ECG) artifacts. This study presents a novel method for muscle activity onset detection by processing surface EMG against ECG artifacts. The method does not require removal of ECG artifacts from raw surface EMG signals. Instead, it applies the sample entropy (SampEn) analysis to highlight EMG activity and suppress ECG artifacts in the signal complexity domain. A SampEn threshold can then be determined for detection of muscle activity. The performance of the proposed method was examined with different SampEn analysis window lengths, using a series of combinations of 'clean' experimental EMG and ECG recordings over a wide range of signal to noise ratios (SNRs) from -10 to 10 dB. For all the examined SNRs, the window length of 128 ms yielded the best performance among all the tested lengths. Compared with the conventional amplitude thresholding and integrated profile methods, the SampEn analysis based method achieved significantly better performance, demonstrated as the shortest average latency or error among the three methods (p < 0.001 for any of the examined SNRs except 10 dB). PMID- 24345859 TI - Methylmercury production in and export from agricultural wetlands in California, USA: the need to account for physical transport processes into and out of the root zone. AB - Concentration and mass balance analyses were used to quantify methylmercury (MeHg) loads from conventional (white) rice, wild rice, and fallowed fields in northern California's Yolo Bypass. These analyses were standardized against chloride to distinguish transport pathways and net ecosystem production (NEP). During summer, chloride loads were both exported with surface water and moved into the root zone at a 2:1 ratio. MeHg and dissolved organic carbon (DOC) behaved similarly with surface water and root zone exports at ~3:1 ratio. These trends reversed in winter with DOC, MeHg, and chloride moving from the root zone to surface waters at rates opposite and exceeding summertime root zone fluxes. These trends suggest that summer transpiration advectively moves constituents from surface water into the root zone, and winter diffusion, driven by concentration gradients, subsequently releases those constituents into surface waters. The results challenge a number of paradigms regarding MeHg. Specifically, biogeochemical conditions favoring microbial MeHg production do not necessarily translate to synchronous surface water exports; MeHg may be preserved in the soils allowing for release at a later time; and plants play a role in both biogeochemistry and transport. Our calculations show that NEP of MeHg occurred during both summer irrigation and winter flooding. Wild rice wet harvesting and winter flooding of white rice fields were specific practices that increased MeHg export, both presumably related to increased labile organic carbon and disturbance. Outflow management during these times could reduce MeHg exports. Standardizing MeHg outflow:inflow concentration ratios against natural tracers (e.g. chloride, EC) provides a simple tool to identify NEP periods. Summer MeHg exports averaged 0.2 to 1 MUg m(-2) for the different agricultural wetland fields, depending upon flood duration. Average winter MeHg exports were estimated at 0.3 MUg m(-2). These exports are within the range reported for other shallow aquatic systems. PMID- 24345860 TI - Health risks from the exposure of children to As, Se, Pb and other heavy metals near the largest coking plant in China. AB - Coking influences environmental quality and poses high risks to human health as large amounts of heavy metals and metalloids are emitted into the environment from coal during the coking process. Health risks depend heavily on multi-pathway and element-specific exposures, which have, unfortunately, been rarely studied. In this study, children's health risks and exposure levels to As, Se, and heavy metals (Pb, Cd, Cr, Ni, Co, Zn, Cu, Mn, V and Sb) in the water, soil, dust, air and locally produced food were studied based on field sampling and questionnaire based surveys around the largest coking area in China. Human blood samples were collected and analyzed to indicate the exposure levels. The non-carcinogenic risks to children mainly resulted from Cr, Mn, Pb, As and Sb, the levels of which were 3 to 10 times higher than the acceptable levels (1.0*10(-6)). The carcinogenic risks to children were 30 to 200 times higher than the safe level (1.0*10(-6)-1.0*10(-4)), which could be attributed to Cr, As and Ni pollution. The estimated risks mainly came from the pathway involving the ingestion of locally produced food, accounting for more than 85% in total for most elements. For As, the food ingestion and air inhalation exposure pathways both contributed approximately 50%, respectively. The high risks in this study highlight the attention paid to the health of children who live in the vicinity of coking activities and the importance of site-specific multi-pathway health risk assessments and food safety to protect potentially exposed children. PMID- 24345861 TI - Assessment of sediment quality in Avicennia marina-dominated embayments of Sydney Estuary: the potential use of pneumatophores (aerial roots) as a bio-indicator of trace metal contamination. AB - Currently, coastal intertidal environments are under stress from increased contaminant loads due to urbanization and other anthropogenic disturbances. Mangrove habitats are abundant in tropical and sub-topical intertidal zones and frequently act as a metal bio-filter in estuarine systems. Mangrove reforestation is often considered as one of the management options to protect estuarine-marine habitats. The main objective of the present investigation was to assess the bio indicator potential of Avicennia marina by determining heavy metal concentrations in pneumatophore (aerial root) tissues and ambient sediments from Sydney Estuary (Australia). We collected mangrove sediments and pneumatophores in fifteen locations covering five major embayments of the estuary for a detailed biogeochemical investigation. Metal concentrations in sediment were mostly above Australian interim sediment quality guidelines (ISQG)-Low and in few instances above ISQG-High values. Enrichment factors (EFs >6, especially of Cu, Pb and Zn) suggest "very severe" modification of sediment in Sydney Estuary in all but one embayment which was mainly due to rapid changes in land use in connection with urbanization. High bio-concentration factors (BCFs) were observed for Cu and Ni in comparison with other metals (i.e., As, Cd, Co, Cr, Pb and Zn). A strong, positive relationship between metals in sediments and pneumatophores suggests potential use of these tissues as a bio-indicator of estuarine contamination and that metals are entering the biotic environment. The study further highlights a positive role of mangroves in sequestering metals from sediments and the water column and thus protecting estuarine environments from pollution. PMID- 24345862 TI - Spatial and temporal distribution of Cryptosporidium and Giardia in a drinking water resource: implications for monitoring and risk assessment. AB - Because of their significant public health impact, waterborne Cryptosporidium and Giardia have been monitored in surface water in order to assess microbial quality of water bodies used for drinking water production and/or for recreational purposes. In this context, sampling strategy is of key importance and should be representative enough to appropriately assess the related microbial risk. This, however, requires sound knowledge on the behaviour of both pathogens in water. In the present study, the spatial and temporal distribution of Cryptosporidium and Giardia was explored in the rural Upper-Sure watershed used for drinking water production in Luxembourg. By subdividing it into three compartments including (i) sub-catchments, (ii) the Sure River fed by the sub-catchments and (iii) the Upper Sure reservoir fed by the Sure River, parasite distribution was assessed using sampling designs adapted to the hydro-dynamic characteristics of the respective compartments. Results highlighted the high spatial and temporal variability in parasite distribution at watershed scale, as well as the prevalence of Giardia over Cryptosporidium. Besides land use features and catchment characteristics, hydro-climatology appeared to be a major driver of parasite behaviour in the watershed. It introduced a seasonal trend in their occurrence, highest densities being detected during the wet season. Peaks of contamination triggered out by rainfall-induced runoff were further observed in the three compartments. In the Sure River, Cryptosporidium and Giardia fluxes peaked at 10(9) and 10(10) (oo)cysts.d(-1), respectively, and were discharged into the drinking water reservoir, where they underwent a 2 to 3 log10 removal rate. Despite this, parasite fluxes entering the drinking water treatment plant were still high (10(6) to 10(7) (oo)cysts.d(-1)) and stressed on the need for improved watershed management upstream the water treatment barrier. The catchment-wide analysis described here constitutes a valuable tool for assessment of catchment microbial dynamics, especially within the framework of Water Safety Plans. PMID- 24345863 TI - Performance of a biological deoxygenation process for ships' ballast water treatment under very cold water conditions. AB - Water deoxygenation is listed among the promising on-board treatment technologies to treat ships' ballast waters to reduce the risk of species transfer. We assessed the performance of a yeast-based bioreactive deoxygenation process in very cold water (<2 degrees C) and determined the potential toxicity of the residual treated waters. Experiments using two treatment levels (0.5% and 1% v/v) were conducted in large-volume (4.5m(3)) tanks over 19 days at mean temperature of 1.5 degrees C. Time to hypoxia varied between 10.3 and 16 days, being slightly higher than the predicted time of 9.8 days from previous empirical relationships. Water deoxygenation was achieved when yeast density exceeded 5*10(5) viable cellsmL(-1) and variation in time to hypoxia was mainly explained by difference in yeast growth. There was no oxycline and no significant difference in yeast density over the 2-m deep water column. Results from six bioassays indicated weak toxic response of treated waters at the 1.0% level, but no potential toxic response at the 0.5% treatment level. Results confirmed that the potential application of a yeast-based deoxygenation process for treating ships' ballast waters extended over the range of water temperature typically encountered during most shipping operational conditions. Time to reach full deoxygenation may however be limiting for universal application of this treatment which should be preferably used for ships making longer voyages in cold environments. There was no evidence that biological deoxygenation at low temperature did increase toxicity risk of treated waters to impede their disposal at the time of discharge. PMID- 24345864 TI - Assessment of current dietary intake of organochlorine contaminants and polycyclic aromatic hydrocarbons in killer whales (Orcinus orca) through direct determination in a group of whales in captivity. AB - We determined the levels of 16 polycyclic aromatic hydrocarbons (PAHs), 19 organochlorine pesticides (OCPs) and 18 polychlorinated biphenyls (PCBs) in the plasma of captive adult killer whales and in their food. The goal of this research was the assessment of the dietary exposure of killer whales to these pollutants to gain insight on what is the actual magnitude of the exposure in this species, which is considered among the most contaminated in the planet. Plasma median ?OCP and ?PCB contents were 3150.3 and 7985.9 ng g(-1)l.w., respectively. A total of 78.9% of the PCBs were marker-PCBs, and 21.1% were dioxin-like PCBs (6688.7 pg g(-1)l.w. dioxin toxic equivalents). This is the first report of the blood levels of PAHs in killer whales, and their median value was 1023.1 ng g(-1)l.w. In parallel, we also determined the levels of these contaminants in the fish species that are used to feed these animals to estimate the orcas' average daily dietary intake of pollutants. All the contaminants in the fish were detected in the plasma of the killer whales, and proportionality between the intake and the blood levels was observed in all the animals. The calculated intake was extremely high for certain contaminants, which is a concern, giving a glimpse of what possibly occurs in the wild, where exposure to these contaminants can be even higher. Therefore, although many of these chemicals have been banned for decades, even today, the levels of these chemicals could reach very toxic concentrations in the tissues of these endangered animals because of their diet. PMID- 24345865 TI - Influence of Polyethylene Glycol Lipid Desorption Rates on Pharmacokinetics and Pharmacodynamics of siRNA Lipid Nanoparticles. AB - Lipid nanoparticles (LNPs) encapsulating short interfering RNAs that target hepatic genes are advancing through clinical trials, and early results indicate the excellent gene silencing observed in rodents and nonhuman primates also translates to humans. This success has motivated research to identify ways to further advance this delivery platform. Here, we characterize the polyethylene glycol lipid (PEG-lipid) components, which are required to control the self assembly process during formation of lipid particles, but can negatively affect delivery to hepatocytes and hepatic gene silencing in vivo. The rate of transfer from LNPs to plasma lipoproteins in vivo is measured for three PEG-lipids with dialkyl chains 14, 16, and 18 carbons long. We show that 1.5 mol % PEG-lipid represents a threshold concentration at which the chain length exerts a minimal effect on hepatic gene silencing but can still modify LNPs pharmacokinetics and biodistribution. Increasing the concentration to 2.5 and 3.5 mol % substantially compromises hepatocyte gene knockdown for PEG-lipids with distearyl (C18) chains but has little impact for shorter dimyristyl (C14) chains. These data are discussed with respect to RNA delivery and the different rates at which the steric barrier disassociates from LNPs in vivo.Molecular Therapy-Nucleic Acids (2013) 2, e139; doi:10.1038/mtna.2013.66; published online 17 December 2013. PMID- 24345866 TI - Long-chain omega 3 fatty acids: molecular bases of potential antioxidant actions. AB - Several lines of investigation are being developed to assess the impact of polyunsaturated fatty acids, namely those of the omega 3 series, intake on oxidative stress. Keeping in mind that there might be a dose-response relation, in vivo and in vitro data strongly suggest that omega 3 fatty acids might act as anti- rather than pro-oxidant in several cells such as vascular cells, hence diminishing inflammation, oxidative stress, and, in turn, the risk of atherosclerosis and degenerative disorders such as cardiovascular disease. PMID- 24345867 TI - Water-mediated inclusion of benzoates and tosylates inside the bambusuril macrocycle. AB - A supramolecular complex between benzoates and a bambusuril crystallizes out immediately after mixing in chloroform but only in the presence of residual water molecules. In this complex each of the two portals of the macrocycle is occupied by one benzoate. Carboxylate groups are connected through hydrogen bonding interactions with one molecule of water positioned between them in the center of the bambusuril cavity. Similar water assisted host-guest behavior was also observed when tosylates instead of benzoates were used. PMID- 24345868 TI - Outcomes in ethnic minority renal transplant recipients receiving everolimus versus mycophenolate: comparative risk assessment results from a pooled analysis. AB - BACKGROUND: Everolimus (EVR) has demonstrated good efficacy after renal transplantation. Racial disparities in clinical outcomes after de novo renal transplantation are well documented; whether the efficacy of EVR varies based on recipient ethnicity is unknown. We conducted a comparative risk assessment of EVR by ethnicity. METHODS: Data on 2004 renal transplant recipients from three EVR studies were pooled to identify the impact of ethnicity on efficacy outcomes across EVR dosing groups and control groups. Ethnic groups compared were African Americans, non-U.S. blacks, Asians, Hispanics, and Caucasians. EVR groups received either 1.5 or 3 mg per day, with either standard-dose cyclosporine or reduced-dose cyclosporine. Control groups received mycophenolic acid (MPA) with standard-dose cyclosporine. Composite efficacy failure endpoint was graft loss, death, biopsy-proven acute rejection, or lost to follow-up. Adjusted odds ratios were calculated using a logistic regression model. RESULTS: The proportion of renal transplant recipients who met the composite endpoint was African Americans (46%), non-U.S. black (35%), Caucasian (31%), Hispanic (28%), and Asian (25%). The odds of meeting the composite endpoint were significantly (P=0.0001) greater for African Americans versus Caucasians but did not differ among the other ethnic groups (ethnic groups were only compared with Caucasians). EVR and MPA were associated with similar efficacy among each of the ethnic groups. CONCLUSION: In this pooled data analysis in more than 2000 renal transplant recipients, EVR versus MPA resulted in similar composite endpoint incidence events across ethnicities. Consistent with previously published data, African Americans had poorer clinical outcomes. EVR is efficacious regardless of ethnicity. PMID- 24345869 TI - Narrow energy gap between triplet and singlet excited states of Sn2+ in borate glass. AB - Transparent inorganic luminescent materials have attracted considerable scientific and industrial attention recently because of their high chemical durability and formability. However, photoluminescence dynamics of ns(2)-type ions in oxide glasses has not been well examined, even though they can exhibit high quantum efficiency. We report on the emission property of Sn(2+)-doped strontium borate glasses. Photoluminescence dynamics studies show that the peak energy of the emission spectrum changes with time because of site distribution of emission centre in glass. It is also found that the emission decay of the present glass consists of two processes: a faster S1-S0 transition and a slower T1-S0 relaxation, and also that the energy difference between T1 and S1 states was found to be much smaller than that of (Sn, Sr)B6O10 crystals. We emphasize that the narrow energy gap between the S1 and T1 states provides the glass phosphor a high quantum efficiency, comparable to commercial crystalline phosphors. PMID- 24345870 TI - Evaporation from open microchannel grooves. AB - The evaporation of water from open u-shaped microchannel grooves was investigated with particular emphasis on the roles of channel width and air flow conditions. Given the small dimensions of the microchannels, all measurements were conducted in a range where convection and diffusion are of equal importance and known correlations for the calculation of mass transfer coefficients cannot be applied. The evaporation rates were measured using a new optical method and a gravimetric method. Both measurement methods yielded mass transfer coefficients that are in agreement with each other. The observed relation between mass transfer coefficient, air velocity and channel width vastly differs from the predictions obtained from macroscopic structures. With respect to diagnostic devices we conclude that analyte concentration in an open microchannel groove strongly increases even within short times due to the evaporation process and we show that wider channels are more favourable in terms of minimizing the relative evaporation rate. PMID- 24345871 TI - Relative performance of the two hands in simple and choice reaction time tasks. AB - There is evidence that the left hemisphere is more competent for motor control than the right hemisphere. This study investigated whether this hemispheric asymmetry is expressed in the latency/duration of sequential responses performed by the left and/or right hands. Thirty-two right-handed young adults (16 males, 16 females; 18-25 years old) were tested in a simple or choice reaction time task. They responded to a left and/or right visual target by moving their left and/or right middle fingers between two keys on each side of the midline. Right hand reaction time did not differ from left hand reaction time. Submovement times were longer for the right hand than the left hand when the response was bilateral. Pause times were shorter for the right hand than the left hand, both when the responses were unilateral or bilateral. Reaction time results indicate that the putatively more efficient response preparation by the left hemisphere motor mechanisms is not expressed behaviorally. Submovement time and pause time results indicate that the putatively more efficient response execution by the left hemisphere motor mechanisms is expressed behaviorally. In the case of the submovements, the less efficient motor control of the left hand would be compensated by a more intense attention to this hand. PMID- 24345873 TI - Laboratory animal: biological reagent or living being? AB - The duties of humans toward non-human animals and their rights in society have been debated for a long time. However, a discussion on the terminology used for the identification of laboratory animals is usually not considered, although the employment of inadequate terminology may generate disastrous consequences for the animals before, during, and after the experiment. This study intends to defend the use of appropriate terminology, call attention to an unethical attitude of certain professionals when dealing with experimental animals, and also propose operational mechanisms, which allow for those distortions to be corrected. PMID- 24345872 TI - ChIP-seq analysis of histone H3K9 trimethylation in peripheral blood mononuclear cells of membranous nephropathy patients. AB - Membranous nephropathy (MN), characterized by the presence of diffuse thickening of the glomerular basement membrane and subepithelial in situ immune complex disposition, is the most common cause of idiopathic nephrotic syndrome in adults, with an incidence of 5-10 per million per year. A number of studies have confirmed the relevance of several experimental insights to the pathogenesis of human MN, but the specific biomarkers of MN have not been fully elucidated. As a result, our knowledge of the alterations in histone methylation in MN is unclear. We used chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) to analyze the variations in a methylated histone (H3K9me3) in peripheral blood mononuclear cells from 10 MN patients and 10 healthy subjects. There were 108 genes with significantly different expression in the MN patients compared with the normal controls. In MN patients, significantly increased activity was seen in 75 H3K9me3 genes, and decreased activity was seen in 33, compared with healthy subjects. Five positive genes, DiGeorge syndrome critical region gene 6 (DGCR6), sorting nexin 16 (SNX16), contactin 4 (CNTN4), baculoviral IAP repeat containing 3 (BIRC3), and baculoviral IAP repeat containing 2 (BIRC2), were selected and quantified. There were alterations of H3K9me3 in MN patients. These may be candidates to help explain pathogenesis in MN patients. Such novel findings show that H3K9me3 may be a potential biomarker or promising target for epigenetic-based MN therapies. PMID- 24345874 TI - RNAi-mediated knockdown of FANCF suppresses cell proliferation, migration, invasion, and drug resistance potential of breast cancer cells. AB - Fanconi anemia complementation group F protein (FANCF) is a key factor, which maintains the function of FA/BRCA, a DNA damage response pathway. However, the functional role of FANCF in breast cancer has not been elucidated. We performed a specific FANCF-shRNA knockdown of endogenous FANCF in vitro. Cell viability was measured with a CCK-8 assay. DNA damage was assessed with an alkaline comet assay. Apoptosis, cell cycle, and drug accumulation were measured by flow cytometry. The expression levels of protein were determined by Western blot using specific antibodies. Based on these results, we used cell migration and invasion assays to demonstrate a crucial role for FANCF in those processes. FANCF shRNA effectively inhibited expression of FANCF. We found that proliferation of FANCF knockdown breast cancer cells (MCF-7 and MDA-MB-435S) was significantly inhibited, with cell cycle arrest in the S phase, induction of apoptosis, and DNA fragmentation. Inhibition of FANCF also resulted in decreased cell migration and invasion. In addition, FANCF knockdown enhanced sensitivity to doxorubicin in breast cancer cells. These results suggest that FANCF may be a potential target for molecular, therapeutic intervention in breast cancer. PMID- 24345875 TI - Role of Notch signaling in the mammalian heart. AB - Notch signaling is an evolutionarily ancient, highly conserved pathway important for deciding cell fate, cellular development, differentiation, proliferation, apoptosis, adhesion, and epithelial-to-mesenchymal transition. Notch signaling is also critical in mammalian cardiogenesis, as mutations in this signaling pathway are linked to human congenital heart disease. Furthermore, Notch signaling can repair myocardial injury by promoting myocardial regeneration, protecting ischemic myocardium, inducing angiogenesis, and negatively regulating cardiac fibroblast-myofibroblast transformation. This review provides an update on the known roles of Notch signaling in the mammalian heart. The goal is to assist in developing strategies to influence Notch signaling and optimize myocardial injury repair. PMID- 24345877 TI - Quality of prescribing in Belgian nursing homes: an electronic assessment of the medication chart. AB - OBJECTIVE: To develop a computerized assessment tool for monitoring the quality of prescribing in Belgian nursing homes. DESIGN: In a observational cross sectional study of the medication charts of nursing home residents, potentially inappropriate medication (PIM) was investigated using three scoring systems for the elderly (Beers, ACOVE, BEDNURS) complemented with a list of drug-drug interactions. SETTING: A representative stratified sample of Belgian nursing homes (n = 76). PARTICIPANTS: A random sample of nursing home residents with a complete data set (n = 1730) excluding palliative care patients. MAIN OUTCOME MEASURE: A combination of PIM scores to assess inappropriate, under- and overprescribing. RESULTS: Included residents had a mean age of 85, 78% were female. They used a mean of 7.1 chronic medications. Most PIMs were detected by the application of the ACOVE criteria for underprescribing with 58% of patients having at least one PIM. Using the BEDNURS and the Beers criteria, at least one PIM was noticed in 56 and 27% of patients, respectively. Patients' characteristics showing a positive relationship with the PIM score were age, female gender, amount of clinical and nursing care problems, number of prescriptions and the use of psychotropic drugs (multiple regression analysis R(2) = 0.332). CONCLUSIONS: In Belgian nursing homes, the observed high level of drug utilization was associated with potentially inappropriate prescribing. The development of a combined assessment tool and the implementation of a computerized monitoring system of PIMs is highly recommended to improve the quality of prescribing. PMID- 24345878 TI - Risk factors for filicide and homicide: 36-year national matched cohort study. AB - OBJECTIVE: To identify specific risk factors for filicide, parental killing of one's own children. METHOD: A nationwide matched cohort study of filicides, including filicide-suicide, was conducted in Sweden 1973-2008 (N = 151). We linked longitudinal national registry data on offender psychiatric and neurologic morbidity (ICD codes), suicide attempts, traumatic injury, and previous criminality. We compared filicide offenders and their children to age- and sex matched general population controls and their children. To compare homicide perpetrator subtypes, parallel analyses were made with nonfilicide homicide offenders (N = 3,979) and matched controls. RESULTS: History of major psychiatric disorder, defined as psychotic, affective, or personality disorder, was more common among filicide perpetrators even after adjusting for socioeconomic factors and other potential perpetrator and child confounders (adjusted odds ratio [AOR] = 8.6; 95% CI, 3.7-20.0). Substance misuse was not an independent risk factor, whereas prior suicide attempt conferred a marked increase of filicide risk (AOR = 11.6; 95% CI, 4.0-33.3). Multiple birth was the only child risk factor for filicide that was significant (AOR = 4.8; 95% CI, 1.3-17.6) in multivariate analyses. Overall, nonfilicide homicide offenders exhibited similar risk factors as filicide perpetrators; additionally, substance misuse and violent crime were significantly more frequent and suicide attempt less common (nonoverlapping 95% CIs) than in filicide offenders. CONCLUSIONS: Major psychiatric disorder and previous suicide attempt were strong independent risk factors of filicide; however, substance misuse and prior violent crime were less common than among nonfilicide homicide offenders. Filicide prevention attempts should focus major psychiatric disorder and suicidal behavior in particularly strained parents, instead of more general risk factors for interpersonal violence such as substance misuse. PMID- 24345879 TI - Anthropomorphic bias found in typically developing children is not found in children with autistic spectrum disorder. AB - The anthropomorphic bias describes the finding that the perceived naturalness of a biological motion decreases as the human-likeness of a computer-animated agent increases. To investigate the anthropomorphic bias in autistic children, human or cartoon characters were presented with biological and artificial motions side by side on a touchscreen. Children were required to touch one that would grow while the other would disappear, implicitly rewarding their choice. Only typically developing controls depicted the expected preference for biological motion when rendered with human, but not cartoon, characters. Despite performing the task to report a preference, children with autism depicted neither normal nor reversed anthropomorphic bias, suggesting that they are not sensitive to the congruence of form and motion information when observing computer-animated agents' actions. PMID- 24345876 TI - Microbicidal effects of alpha- and theta-defensins against antibiotic-resistant Staphylococcus aureus and Pseudomonas aeruginosa. AB - Antibiotic-resistant bacterial pathogens threaten public health. Because many antibiotics target specific bacterial enzymes or reactions, corresponding genes may mutate under selection and lead to antibiotic resistance. Accordingly, antimicrobials that selectively target overall microbial cell integrity may offer alternative approaches to therapeutic design. Naturally occurring mammalian alpha and theta-defensins are potent, non-toxic microbicides that may be useful for treating infections by antibiotic-resistant pathogens because certain defensin peptides disrupt bacterial, but not mammalian, cell membranes. To test this concept, clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), including vancomycin heteroresistant strains, and ciprofloxacin-resistant Pseudomonas aeruginosa (Cip(R)-PA) were tested for sensitivity to alpha-defensins Crp-4, RMAD-4 and HNPs 1-3, and to RTD-1, macaque theta-defensin-1. In vitro, 3 MUM Crp-4, RMAD-4 and RTD-1 reduced MRSA cell survival by 99%, regardless of vancomycin susceptibility. For PA clinical isolates that differ in fluoroquinolone resistance and virulence phenotype, peptide efficacy was independent of strain ciprofloxacin resistance, site of isolation or virulence factor expression. Thus, Crp-4, RMAD-4 and RTD-1 are effective in vitro antimicrobials against clinical isolates of MRSA and Cip(R)-PA, perhaps providing templates for development of alpha- and theta-defensin-based microbicides against antibiotic resistant or virulent infectious agents. PMID- 24345880 TI - Dynamics of tissue shrinkage during ablative temperature exposures. AB - There is a lack of studies that examine the dynamics of heat-induced shrinkage of organ tissues. Clinical procedures such as radiofrequency ablation, microwave ablation or high-intensity focused ultrasound, use heat to treat diseases such as cancer and cardiac arrhythmia. When heat is applied to tissues, shrinkage occurs due to protein denaturation, dehydration and contraction of collagen at temperatures greater 50 degrees C. This is particularly relevant for image guided procedures such as tumor ablation, where pre- and post-treatment images are compared and any changes in dimensions must be considered to avoid misinterpretations of the treatment outcome. We present data from ex vivo, isothermal shrinkage tests in porcine liver tissue, where axial changes in tissue length were recorded during 15 min of heating to temperatures between 60 and 95 degrees C. A mathematical model was developed to accurately describe the time and temperature-dependent shrinkage behavior. The shrinkage dynamics had the same characteristics independent of temperature; the estimated relative shrinkage, adjusted for time since death, after 15 min heating to temperatures of 60, 65, 75, 85 and 95 degrees C, was 12.3, 13.8, 16.6, 19.2 and 21.7%, respectively. Our results demonstrate the shrinkage dynamics of organ tissues, and suggest the importance of considering tissue shrinkage for thermal ablative treatments. PMID- 24345881 TI - Pediatric myelodysplastic syndromes: they do exist! AB - One of the most common hematologic malignancies in adults, myelodysplastic syndrome (MDS) is a heterogenous group of clonal disorders characterized by peripheral cytopenia(s) and normal or hypercellular bone marrow with dysplasia in >=1 blood cell lineages. MDS frequently evolves to secondary acute myeloid leukemia with poor prognosis. Although uncommon among pediatric hematologic malignancies, both de novo and secondary MDS occur in children and may be the first presentation of an inherited bone marrow failure syndrome. Unlike its adult counterpart, pediatric MDS is more frequently associated with hypocellular bone marrow and monosomy 7. Refractory cytopenia is more typical than refractory anemia, as seen in the elderly. Its recognition and management can be quite challenging and requires the expertise of an experienced hematopathologist. In this review, we describe the epidemiology, genetics, and clinical spectrum of pediatric MDS along with its diagnostic and therapeutic challenges. We also compare and contrast pediatric and adult MDS. PMID- 24345882 TI - Neurocognitive and neuroradiologic central nervous system late effects in children treated on Pediatric Oncology Group (POG) P9605 (standard risk) and P9201 (lesser risk) acute lymphoblastic leukemia protocols (ACCL0131): a methotrexate consequence? A report from the Children's Oncology Group. AB - Concerns about long-term methotrexate (MTX) neurotoxicity in the 1990s led to modifications in intrathecal (IT) therapy, leucovorin rescue, and frequency of systemic MTX administration in children with acute lymphoblastic leukemia. In this study, neurocognitive outcomes and neuroradiologic evidence of leukoencephalopathy were compared in children treated with intense central nervous system (CNS)-directed therapy (P9605) versus those receiving fewer CNS directed treatment days during intensive consolidation (P9201). A total of 66 children from 16 Pediatric Oncology Group institutions with "standard-risk" acute lymphoblastic leukemia, 1.00 to 9.99 years at diagnosis, without evidence of CNS leukemia at diagnosis were enrolled on ACCL0131: 28 from P9201 and 38 from P9605. Magnetic resonance imaging scans and standard neuropsychological tests were performed >=2.6 years after the end of treatment. Significantly more P9605 patients developed leukoencephalopathy compared with P9201 patients (68%, 95% confidence interval 49%-83% vs. 22%, 95% confidence interval 5%-44%; P=0.001) identified as late as 7.7 years after the end of treatment. Overall, 40% of patients scored <85 on either Verbal or Performance IQ. Children on both studies had significant attention problems, but P9605 children scored below average on more neurocognitive measures than those treated on P9201 (82%, 14/17 measures vs. 24%, 4/17 measures). This supports ongoing concerns about intensive MTX exposure as a major contributor to CNS late effects. PMID- 24345883 TI - The polycomb group protein EZH2 is a novel therapeutic target in tongue cancer. AB - EZH2, a core member of the Polycomb Repressor Complex 2 (PRC2), mediates transcriptional silencing by catalyzing the trimethylation of histone 3 lysine 27 (H3K27), which plays key roles in cancer initiation and progression. Here, we investigated the expression pattern and biological roles of EZH2 in tongue tumorigenesis by loss-of-function assays using small interference RNA and EZH2 inhibitor DZNep. Also we determined the therapeutic efficiency of DZNep against tongue cancer in vivo. We found that aberrantly overexpressed EZH2 was associated with pathological grade, cervical nodes metastasis and Ki-67 expression in tongue cancers. Elevated EZH2 correlated with shorter overall survival and showed significant and independent prognostic importance in patients with tongue cancer. Both genetic and pharmacological depletion of EZH2 inhibited cell proliferation, migration, invasion and colony formation and decreased CD44+ subpopulation probably in part through modulating p16, p21 and E-caherin. Moreover, DZNep enhanced the anticancer effects of 5-Fluorouracil. Furthermore, intratumoral EZH2 inhibition induced by DZNep intraperitoneal administration significantly attenuated tumor growth in a tongue cancer xenograft model. Taken together, our results indicate that EZH2 serves as a key driver with multiple oncogenic functions during tongue tumorigenesis and a new biomarker for tongue cancer diagnosis and prognostic prediction. These findings open up possibilities for therapeutic intervention against EZH2 in tongue cancer. PMID- 24345885 TI - Percentage of the population at high risk of osteoporotic fracture in South Korea: analysis of the 2010 Fifth Korean National Health and Nutrition Examination survey data. AB - Osteoporosis and high-risk osteopenia (high-risk of osteoporotic fractures) are highly prevalent in South Korean postmenopausal women and men aged 50 years and over. INTRODUCTION: This study determined the percentages of the population at high risk of osteoporotic fractures according to the World Health Organization (WHO) criteria and the Fracture Risk Assessment (FRAX) model. METHODS: Data collected from the 2010 Fifth Korean National Health and Nutrition Examination Survey, a cross-sectional survey of the general South Korean general population, were analyzed. The percentages of the population with high-risk osteopenia according to the US National Osteoporosis Foundation (NOF) and Japanese treatment guidelines were subsequently determined and compared. RESULTS: Based on the WHO criteria and FRAX model, 37.7% of the menopausal women and 12.7% of the men aged 50 years and older are at high risk of osteoporotic fracture. According to the Japanese and NOF guidelines, 10.9 (10.6% of men and 11.2% of women) and 10.7% (10.6% of men and 10.9% of women), respectively, of the study population with osteopenia are at high risk of fracture. By age group, 49.3% of Korean women aged 55 years and older, 67.7% of Korean women aged 65 years and older, and 33.5% of Korean men aged 75 years and older are at high risk. CONCLUSION: As a very large percentage of the South Korean postmenopausal population has osteoporosis or high risk osteopenia, greater effort at identifying and treating this population should be expended to prevent osteoporotic fracture. PMID- 24345887 TI - Towards personalized care in IBD. AB - The expanding knowledge of the role of genetic variants involved in the susceptibility to IBD heralds an era of disease categorization beyond Crohn's disease and ulcerative colitis. A more robust molecular definition of the spectrum of IBD subtypes is likely to be based on specific molecular pathways that determine not only disease susceptibility but also disease characteristics such as location, natural history and therapeutic response. Evolving diagnostic panels for IBD will include clinical variables and genetic markers as well as other indicators of gene function and interaction with environmental factors, such as the microbiome. Multimodal algorithms that combine clinical, serologic and genetic information are likely to be useful in predicting disease course. Variation in IBD-susceptibility and drug-related pathway genes seems to influence the response to anti-TNF therapy. Furthermore, gene expression signatures and composite models have both shown promise as predictors of therapeutic response. Ultimately, models based on combinations of genotype and gene expression data with clinical, biochemical, serological, and microbiome data for clinically meaningful subgroups of patients should permit the development of tools for individualized risk stratification and treatment selection. PMID- 24345886 TI - The effects of once-weekly teriparatide on hip structure and biomechanical properties assessed by CT. AB - SUMMARY: Once-weekly administration of 56.5 MUg teriparatide improved cortical bone parameters and biomechanical parameters at the proximal femur by CT geometry analysis. INTRODUCTION: The aim of this study was to evaluate the effects of weekly administration of teriparatide [human PTH (1-34)] on bone geometry, volumetric bone mineral density (vBMD), and parameters of bone strength at the proximal femur which were longitudinally investigated using computed tomography (CT). METHODS: The subjects were a subgroup of a recent, randomly assigned, double-blind study (578 subjects) comparing the anti-fracture efficacy of a once weekly subcutaneous injection of 56.5 MUg teriparatide with placebo (TOWER trial). RESULTS: Sixty-six ambulatory postmenopausal women with osteoporosis were enrolled at 15 study sites having multi-detector row CT, and included women injected with teriparatide (n = 29, 74.2 +/- 5.1 years) or with placebo (n = 37, 74.8 +/- 5.3 years). CT data were obtained at baseline and follow-up scans were performed at 48 and 72 weeks. The data were analyzed to obtain cross-sectional densitometric, geometric, and biomechanical parameters including the section modulus (SM) and buckling ratio (BR) of the femoral neck, inter-trochanter, and femoral shaft. We found that once-weekly teriparatide increased cortical thickness/cross-sectional area (CSA) and total area, and improved biomechanical properties (i.e., decreasing BR) at the femoral neck and shaft. Teriparatide did not change the cortical perimeter. CONCLUSIONS: Our longitudinal analysis of proximal femur geometry by CT revealed that once-weekly administration of 56.5 MUg teriparatide improved cortical bone parameters at the femoral neck and shaft and also improved biomechanical parameters. PMID- 24345884 TI - Selective anti-cancer agents as anti-aging drugs. AB - Recent groundbreaking discoveries have revealed that IGF-1, Ras, MEK, AMPK, TSC1/2, FOXO, PI3K, mTOR, S6K, and NFkappaB are involved in the aging process. This is remarkable because the same signaling molecules, oncoproteins and tumor suppressors, are well-known targets for cancer therapy. Furthermore, anti-cancer drugs aimed at some of these targets have been already developed. This arsenal could be potentially employed for anti-aging interventions (given that similar signaling molecules are involved in both cancer and aging). In cancer, intrinsic and acquired resistance, tumor heterogeneity, adaptation, and genetic instability of cancer cells all hinder cancer-directed therapy. But for anti-aging applications, these hurdles are irrelevant. For example, since anti-aging interventions should be aimed at normal postmitotic cells, no selection for resistance is expected. At low doses, certain agents may decelerate aging and age related diseases. Importantly, deceleration of aging can in turn postpone cancer, which is an age-related disease. PMID- 24345888 TI - Clinical effects of Helicobacter pylori outside the stomach. AB - The discovery of Helicobacter pylori infection in the stomach could be considered as one of the most important events of modern gastroenterology. Understanding of the natural history of many disorders of the upper gastrointestinal tract, including chronic gastritis, peptic ulcer disease, gastric cancer and MALT lymphoma, was altered by this discovery. Interestingly, epidemiological studies have also revealed a correlation between H. pylori infection and some diseases localized outside the stomach, especially those characterized by persistent and low-grade systemic inflammation. Of note, H. pylori has an important role in iron deficiency anaemia, idiopathic thrombocytopenic purpura and vitamin B12 deficiency. Moreover, the association of this bacterial pathogen with many other diseases, including hepatobiliary, pancreatic, cardiovascular and neurodegenerative disorders is currently under investigation. In this Review, we summarize the results of the most important studies performed to date surrounding the association of H. pylori infection with extragastric diseases, as well as the strength of the evidence. We also provide information concerning bacterial-host interactions and the mechanisms implicated in the pathogenesis of each of these extragastric diseases. PMID- 24345889 TI - Colorectal cancer: targeting self-renewal of cancer stem cells in colorectal cancer-a future treatment option? PMID- 24345890 TI - Clinical implications of ageing for the management of IBD. AB - As the global population ages, the number of older people (>=65 years) living with IBD is expected to increase. IBD therapeutics have advanced considerably over the past few decades with the introduction of multiple steroid-sparing agents as well as numerous clinical trials that have tested new therapeutic targets. However, the current paradigms for IBD management might not be directly translatable to older patients with IBD. Age-related factors such as immunodeficiency relative to younger patients, comorbidity, polypharmacy and diminished physical reserve directly or indirectly affect the natural history of their disease. This Review highlights how these age-associated variables can affect older patients with IBD and also illustrates the multiple gaps in our current knowledge of IBD in the elderly. PMID- 24345891 TI - IBD across the age spectrum: is it the same disease? AB - IBD is a chronic disorder with disease onset ranging from early childhood to beyond the sixth decade of life. The factors that determine the age of onset currently remain unexplained. Is timing of occurrence a random event or is it indicative of different pathophysiological pathways leading to different phenotypes across the age spectrum? Over the past decade, several studies have suggested that the characteristics and natural history of IBD seem to be different according to age of onset. This heterogeneity suggests that the respective contributions of genetics, host immune system and environment to the aetiology and phenotype of Crohn's disease and ulcerative colitis are different across ages. Critical reviews that focus on differences characterizing IBD between age groups are scarce. Therefore, this Review updates the knowledge of the differences in epidemiology, clinical characteristics, and natural history of paediatric, adult and elderly-onset IBD. In addition, potential differences in host-gene-microbial interactions according to age are highlighted. PMID- 24345892 TI - Development and validation of a low-cost, portable and wireless gait assessment tool. AB - BACKGROUND: Performing gait analysis in a clinical setting can often be challenging due to time, cost and the availability of sophisticated three dimensional (3D) gait analysis systems. This study has developed and tested a portable wireless gait assessment tool (wi-GAT) to address these challenges. AIM: To investigate the concurrent validity of the wi-GAT in measuring spatio-temporal gait parameters such as stride length, stride duration, cadence, double support time (DST), stance and swing time compared to a 3D Vicon motion analysis system. METHODS: Ten healthy volunteers participated in the study (age range 23-30 years). Spatio-temporal gait parameters were recorded simultaneously by the Vicon and the wi-GAT systems as each subject walked at their self-selected speed. RESULTS: The stride length and duration, cadence, stance duration and walking speed recorded using the wi-GAT showed strong agreement with those same parameters recorded by the Vicon (ICC of 0.94-0.996). A difference between the systems in registering "toe off" resulted in less agreement (ICC of 0.299-0.847) in gait parameters such as %stance and %swing and DST. DISCUSSION AND CONCLUSION: The study demonstrated good concurrent validity for the wi-GAT system. The wi-GAT has the potential to be a useful assessment tool for clinicians. PMID- 24345893 TI - Facile assembly of n-SnO(2) nanobelts-p-NiO heterojunctions with enhanced ultraviolet photoresponse. AB - We present a highly transparent heterojunction photodiode by precisely aligning n type SnO2 nanobelts on top of a p-type NiO thin film. This p-n junction diode demonstrates stable rectifying characteristics as well as greatly enhanced ultraviolet photoresponse, which exhibits an ultrahigh photosensitivity of up to 10(5) with accelerated response speed under reverse bias. PMID- 24345895 TI - Disparities in liver transplantation: the association between donor quality and recipient race/ethnicity and sex. AB - BACKGROUND: We aimed to examine the association between recipient race/ethnicity and sex, donor liver quality, and liver transplant graft survival. METHODS: Adult non-status 1 liver recipients transplanted between March 1, 2002, and December 31, 2008, were identified using Scientific Registry of Transplant Recipients data. The factors of interest were recipient race/ethnicity and sex. Donor risk index (DRI) was used as a donor quality measure. Logistic regression was used to assess the association between race/ethnicity and sex in relation to the transplantation of low-quality (high DRI) or high-quality (low DRI) livers. Cox regression was used to assess the association between race/ethnicity and sex and liver graft failure risk, accounting for DRI. RESULTS: Hispanics were 21% more likely to receive low-quality grafts compared to whites (odds ratio [OR]=1.21, P=0.002). Women had greater odds of receiving a low-quality graft compared to men (OR=1.24, P<0.0001). Despite adjustment for donor quality, African American recipients still had higher graft failure rates compared to whites (hazard ratio [HR]=1.28, P<0.001). Hispanics (HR=0.89, P=0.023) had significantly lower graft failure rates compared to whites despite higher odds of receiving a higher DRI graft. Using an interaction model of DRI and race/ethnicity, we found that the impact of DRI on graft failure rates was significantly reduced for African Americans compared to whites (P=0.02). CONCLUSIONS: This study shows that while liver graft quality differed significantly by recipient race/ethnicity and sex, donor selection practices do not seem to be the dominant factor responsible for worse liver transplant outcomes for minority recipients. PMID- 24345897 TI - Correction. PMID- 24345896 TI - Pretransplant CD8 T-cell response to IE-1 discriminates seropositive kidney recipients at risk of developing CMV infection posttransplant. AB - BACKGROUND: Cytomegalovirus (CMV) infection is an ongoing clinical problem in solid-organ transplantation (SOT). Pretransplant CMV serology is currently the only tool for assessing the risk of CMV infection, although cellular immune responses driven by CMV-specific CD4 and CD8 T lymphocytes are important for controlling viral replication. Therefore, the analysis of CMV-specific T cells may be useful for estimating the risk of infection. METHODS: This is a prospective study of patients with kidney transplants and no prophylactic treatment for CMV replication. CD4 and CD8 T-cell responses to the major CMV pp65 and IE-1 antigens in 15 seropositive patients at intermediate risk of CMV infection were investigated, according to current algorithms. Intracellular flow cytometry was employed to determine IFN-gamma production as a functional readout. The response was analyzed in pretransplant samples and prospectively at 1 and 6 months and at 1 year posttransplant. RESULTS: It was observed that the CD8 responses to IE-1 antigen were practically absent pretransplant in patients who developed CMV infection posttransplant. Within the group of patients free of infection, CD8 responses to IE-1 were detected more frequently and were significantly higher (P=0.0083). In a receiver operating characteristics curve analysis (AUC=0.929; P=0.010; 95% CI: 0.078-1.0), low CD8 responses to IE-1 (<=0.05%) pretransplant predicted the development of CMV infection under the immunosuppressive regime after transplant with 100% specificity and 85.7% sensitivity. CONCLUSIONS: Assessment of IE-1-specific CD8 T-cell frequencies pretransplant may be a useful tool for identifying seropositive SOT patients at risk of developing CMV infection posttransplant. PMID- 24345898 TI - Which factors influence decisions to transfer and treat patients with acute intracerebral haemorrhage and which are associated with prognosis? A retrospective cohort study. AB - OBJECTIVES: To identify factors associated with the decision to transfer and/or operate on patients with intracerebral haemorrhage (ICH) at a UK regional neurosurgical centre and test whether these decisions were associated with patient survival. DESIGN: Retrospective cohort study. SETTING: 14 acute and specialist hospitals served by the neurosurgical unit at Salford Royal NHS Foundation Trust, Salford, UK. PARTICIPANTS: All patients referred acutely to neurosurgery from January 2008 to October 2010. OUTCOME MEASURES: Primary outcome was survival and secondary outcomes were transfer to the neurosurgical centre and acute neurosurgery. RESULTS: We obtained clinical data from 1364 consecutive spontaneous patients with ICH and 1175 cases were included in the final analysis. 140 (12%) patients were transferred and 75 (6%) had surgery. In a multifactorial analysis, the decision to transfer was more likely with younger age, women, brainstem and cerebellar location and larger haematomas. Risk of death in the following year was higher with advancing age, lower Glasgow Coma Scale, larger haematomas, brainstem ICH and intraventricular haemorrhage. The transferred patients had a lower risk of death relative to those remaining at the referring centre whether they had surgery (HR 0.46, 95% CI 0.32 to 0.67) or not (HR 0.41, 95% CI 0.22 to 0.73). Acute management decisions were included in the regression model for the 227 patients under either stroke medicine or neurosurgery at the neurosurgical centre and early do-not-resuscitate orders accounted for much of the observed difference, independently associated with an increased risk of death (HR 4.8, 95% CI 2.7 to 8.6). CONCLUSIONS: The clear association between transfer to a specialist centre and survival, independent of established prognostic factors, suggests aggressive supportive care at a specialist centre may improve survival in ICH and warrants further investigation in prospective studies. PMID- 24345899 TI - Investigating the cost-effectiveness of health information technologies: a systematic review protocol. AB - INTRODUCTION: There is a need to develop new, more cost-effective models of healthcare and in this vein there is a considerable international interest in exploiting the potential offered by major developments in health information technologies (HITs). Very substantial investments are, as a result, now being made globally, but these still probably only represent a fraction of the investments needed if healthcare is to make the transition from the paper to the digital era. Investing greater resources is, however, inherently challenging and unpopular at a time of financial austerity and this is furthermore complicated by the thus far variable evidence of health benefits and demonstrable short-term to medium-term returns associated with investments in HITs. OBJECTIVES: Building on our related systematic overviews investigating the impact of HITs, we now seek to estimate the cost-effectiveness of HITs and as a secondary aim to identify potentially transferable lessons in relation to how to realise returns on investments in these technologies. METHODS: We will conduct a systematic review to identify the empirical evidence base surrounding the return on investments from implementing HITs. Two reviewers will independently search major international databases for published, unpublished and on-going experimental and quasi-experimental studies of interest published during the period 1990-2013. These searches of bibliographic databases will be supplemented by contacting an international panel of experts. There will be no restriction on the language of publication of studies. Studies will be critically appraised using the Critical Appraisal Skills Programme (CASP) Economic Evaluations checklist. In view of the anticipated heterogeneity in intervention investigated, study design and health system contexts, we will undertake a descriptive, narrative and interpretative synthesis of data. ETHICS AND DISSEMINATION: Ethical approval is not required. RESULTS: These will be presented in one manuscript. The protocol is registered with the International Prospective Register for Systematic Reviews (PROSPERO) CRD42013005294. PMID- 24345900 TI - Association between reduced stillbirth rates in England and regional uptake of accreditation training in customised fetal growth assessment. AB - OBJECTIVE: To assess the effect that accreditation training in fetal growth surveillance and evidence-based protocols had on stillbirth rates in England and Wales. DESIGN: Analysis of mortality data from Office of National Statistics. SETTING: England and Wales, including three National Health Service (NHS) regions (West Midlands, North East and Yorkshire and the Humber) which between 2008 and 2011 implemented training programmes in customised fetal growth assessment. POPULATION: Live births and stillbirths in England and Wales between 2007 and 2012. MAIN OUTCOME MEASURE: Stillbirth. RESULTS: There was a significant downward trend (p=0.03) in stillbirth rates between 2007 and 2012 in England to 4.81/1000, the lowest rate recorded since adoption of the current stillbirth definition in 1992. This drop was due to downward trends in each of the three English regions with high uptake of accreditation training, and led in turn to the lowest stillbirth rates on record in each of these regions. In contrast, there was no significant change in stillbirth rates in the remaining English regions and Wales, where uptake of training had been low. The three regions responsible for the record drop in national stillbirth rates made up less than a quarter (24.7%) of all births in England. The fall in stillbirth rate was most pronounced in the West Midlands, which had the most intensive training programme, from the preceding average baseline of 5.73/1000 in 2000-2007 to 4.47/1000 in 2012, a 22% drop which is equivalent to 92 fewer deaths a year. Extrapolated to the whole of the UK, this would amount to over 1000 fewer stillbirths each year. CONCLUSIONS: A training and accreditation programme in customised fetal growth assessment with evidence-based protocols was associated with a reduction in stillbirths in high uptake areas and resulted in a national drop in stillbirth rates to their lowest level in 20 years. PMID- 24345901 TI - Mobile phone text messages for improving adherence to antiretroviral therapy (ART): an individual patient data meta-analysis of randomised trials. AB - OBJECTIVES: Our objectives were to analyse the effects of text messaging versus usual care in improving adherence to antiretroviral therapy (ART) in people living with HIV using individual patient data meta-analysis. Adjusted, sensitivity and subgroup analyses were conducted. SETTING: 3 randomised controlled trials conducted between 2010 and 2012 in rural and urban centres in Cameroon and Kenya (two studies) were used. PARTICIPANTS: A total of 1166 participants were included in this analysis (Cameroon=200; Kenya=428 and 538). PRIMARY AND SECONDARY OUTCOMES: The primary outcome was adherence to ART >95%. The secondary outcomes were mortality, losses to follow-up, transfers and withdrawals. RESULTS: Text messaging improved adherence to ART (OR 1.38; 95% CIs 1.08 to 1.78; p=0.012), even after adjustment for baseline covariates (OR 1.46; 95% CI 1.13 to 1.88; p=0.004). Primary education (compared with no formal education) was associated with a greater intervention effect on adherence (OR 1.65; 95% CI 1.10 to 2.48; p=0.016) and also showed a significant subgroup effect (p=0.039). In sensitivity analysis, our findings were robust to a modified threshold of adherence, multiple imputation for missing data and aggregate level data pooling, but not to fixed-effects meta-analyses using generalised estimation equations. There was a significant subgroup effect for long weekly (p=0.037), short weekly text messages (p=0.014) and interactive messaging (p=0.010). Text messaging did not significantly affect any of the secondary outcomes. CONCLUSIONS: Text messaging has a significant effect on adherence to ART, and this effect is influenced by level of education, gender, timing (weekly vs daily) and interactivity. We recommend the use of interactive weekly text messaging to improve adherence to ART, which is most effective in those with at least a primary level of education. PMID- 24345902 TI - A proposed model for prediction of survival based on a follow-up study in unresectable pancreatic cancer. AB - OBJECTIVES: To define an easy-to-use model for prediction of survival time in patients with unresectable pancreatic cancer in order to optimise patient' care. DESIGN: An observational retrospective study on patients with unresectable pancreatic cancer. The initial radiographs at presentation of symptoms were reviewed and the maximum diameter of the primary tumour was determined. The occurrence of liver metastases and performance status that determines initiation of chemotherapy was also used in the regression analysis to identify prognostic subgroups. SETTING: County hospital in south-east of Sweden. POPULATION: Consecutive patients with unresectable pancreatic cancer who were diagnosed between January 2003 and May 2010 (n=132). MAIN OUTCOME MEASURES: Statistical analyses were performed using Stata V.13. Survival time was assessed with Kaplan Meier analysis, log-rank test for equality of survivor functions and Cox regression for calculation of individual hazard based on tumour diameter, presence of liver metastases and initiation of chemotherapy treatment according to patient performance status. RESULTS: The individual hazard was log h=0.357 tumour size+1.181 liver metastases-0.989 performance status/chemotherapy. Three prognostic groups could be defined: a low-risk group with a median survival time of 6.7 (IQR 9.7) months, a medium-risk group with a median survival time of 4.5 (IQR 4.5) months and a high-risk group with a median survival time of 1.2 (IQR 1.7) months. CONCLUSIONS: The maximum diameter of the primary tumour and the presence of liver metastases found at the X-ray examination of patients with pancreatic cancer, in conjunction with whether or not chemotherapy is initiated according to performance status, predict the survival time for patients who do not undergo surgical resection. The findings result in an easy-to-use model for predicting the survival time. PMID- 24345903 TI - The Oxford Renal (OxRen) cross-sectional study of chronic kidney disease in the UK. AB - INTRODUCTION: Chronic kidney disease (CKD) diagnosed with objective measures of kidney damage and function has been recognised as a major public health burden. Independent of age, sex, ethnicity and comorbidity, strong associations exist between cardiovascular disease, mortality, morbidity and CKD, defined by reduced glomerular filtration rate and increased urinary albumin excretion. Detection of CKD within the population is therefore a priority for health systems. METHODS AND ANALYSIS: 15 000 patients aged 60 years or over meeting the inclusion criteria will be invited to the study. Recruitment will be stratified to represent the distribution of socioeconomic position in the UK general population. Patients will be excluded if terminally ill (expected survival <1 year), or if they have received a solid organ transplant. Patients will attend up to two screening visits, to determine if they have CKD, followed by an assessment visit where demographic and physiological parameters will be recorded alongside questionnaires on exercise, diet, cognitive assessment and quality of life. Blood and urine specimens will be taken for immediate routine assays as well as for freezing pending peptide and genetic studies. Patients will have office and home blood pressure measurements as well as pulse wave velocity assessment. Healthcare costs of screening and subsequent monitoring will be calculated. ETHICS AND DISSEMINATION: The protocol and related documents have been approved by NRES Committee South Central-Oxford B-Reference 13/SC/0020. PMID- 24345904 TI - The effect of iron and zinc supplementation and its discontinuation on liver antioxidant status in rats fed deficient diets. AB - PURPOSE: The aim was to investigate the effect of iron or combined iron/zinc supplementation on rat liver antioxidant status. METHODS: The 6-week male Wistar rats were examined in 3 stages: (1) 4-week adaptation to the diets (C-control AIN 93M diet, D-iron deficient and R-with 50% reduction in all vitamin and mineral amounts); (2) 4-week supplementation with the same regimen enriched with tenfold more iron or iron/zinc; (3) 2-week post-supplementation period (the same diets as in the stage I). RESULTS: Combined iron/zinc supplementation similarly to iron supplementation alone significantly (p values <= 0.05) increased the iron content in the liver in D and R rats after stages II and III. Moreover, iron/zinc supplementation compared to iron supplementation alone significantly decreased the liver concentration of 8-isoprostane (after stage II in D and after stage III in R rats), protein carbonyl groups (only after stage III in R rats) and 8 hydroxy-2-deoxyguanosine (after stage II in R and after stage III in D and R rats). In rats fed R-type of diets after stage II hepatic superoxide dismutase (SOD) and catalase (CAT) activity, but not glutathione peroxidation activity and total antioxidant capacity, was lower in iron and iron/zinc supplemented than in non-supplemented rats, whereas after stage III in iron/zinc supplemented SOD was lower and CAT activity was higher in comparison with non-supplemented and iron supplemented rats. CONCLUSIONS: The simultaneous iron/zinc supplementation can protect liver against peroxidative damage induced by high doses of iron during and after the intervention in rats fed iron-deficient diet and diet with reduced amounts of vitamins and minerals. The post-intervention observation is relevant because the effect may be delayed and visible only after this period. PMID- 24345905 TI - Effect of dexmedetomidine on lung ischemia-reperfusion injury. AB - Dexmedetomidine, a specific selective alpha2-adrenergic agonist, does not only have the characteristics of being a sedative and analgesic, but also exhibits a protective role in brain ischemia-reperfusion injury and inhibits the inflammation in animals with sepsis. The objective of the present study was to investigate whether dexmedetomidine is capable of attenuating rat pulmonary damage induced by ischemia-reperfusion injury, which is a type of acute sterile lung injury. Sprague-Dawley rats were randomly assigned into six groups: The sham operated (sham) group, the lung ischemia-reperfusion (I/R) group, intravenous injection of dexmedetomidine 2.5 ug/kg/h (Dex2.5) or 5 ug/kg/h (Dex5) for 1 h prior to ischemia, combination of alpha2-adrenergic antagonist yohimbine prior to dexmedetomidine pre-treatment (Dex+Yoh) and pre-administration of yohimbine alone (Yoh) prior to ischemia. Lung injury was assessed by the histopathological changes, arterial blood gas, wet/dry (w/d) weight ratio and myeloperoxidase (MPO) activity of the lung. The concentration of tumor necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) in bronchoalveolar lavage fluid (BALF) was measured by an enzyme-linked immunosorbent assay. The expression of toll-like receptor-4 (TLR4) and myeloid differentiation factor 88 (MyD88) mRNA in the lung were determined by quantitative PCR, and phosphorylated levels of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK)1/2 were determined by western blotting. Pre-treatment with dexmedetomidine significantly reduced the lung injury, w/d weight ratio and MPO activity, and decreased the concentration of TNF alpha, IL-6 and MCP-1 in BALF compared with the I/R group. The expression of TLR4 and MyD88 mRNA and the levels of phosphorylated JNK and ERK1/2 in the lung tissue were markedly downregulated by intravenous injection of dexmedetomidne for 1 h prior to lung I/R. The protective effects of dexmedetomidine on the lung were not completely reversed by the alpha2-adrenergic antagonist, yohimbine. Pre-treatment with dexmedetomidine is capable of reducing pulmonary damage and inhibiting sterile inflammation induced by lung I/R injury. TLR4/MyD88/mitogen-activated protein kinase (MAPK) signaling is involved in the protective mechanism of dexmedetomidine through alpha2-adrenoceptor independence. PMID- 24345906 TI - Utilization and control of bioactuators across multiple length scales. AB - In this review, we summarize the recent developments in the emerging field of bioactuators across a multitude of length scales. First, we discuss the use and control of biomolecules as nanoscale actuators. Molecular motors, such as DNA, kinesin, myosin, and F1-ATPase, have been shown to exert forces in the range between 1 pN to 45 pN. Second, we discuss the use and control of single and small clusters of cells to power microscale devices. Microorganisms, such as flagellated bacteria, protozoa, and algae, can naturally swim at speeds between 20 MUm s(-1) to 2 mm s(-1) and produce thrust forces between 0.3 pN to 200 pN. Individual and clustered mammalian cells, such as cardiac and skeletal cells, can produce even higher contractile forces between 80 nN to 3.5 MUN. Finally, we discuss the use and control of 2D- and 3D-assembled muscle tissues and muscle tissue explants as bioactuators to power devices. Depending on the size, composition, and organization of these hierarchical tissue constructs, contractile forces have been demonstrated to produce between 25 MUN to 1.18 mN. PMID- 24345907 TI - Whole transcriptome organisation in the dehydrated supraoptic nucleus. AB - The supraoptic nucleus (SON) is part of the central osmotic circuitry that synthesises the hormone vasopressin (Avp) and transports it to terminals in the posterior lobe of the pituitary. Following osmotic stress such as dehydration, this tissue undergoes morphological, electrical and transcriptional changes to facilitate the appropriate regulation and release of Avp into the circulation where it conserves water at the level of the kidney. Here, the organisation of the whole transcriptome following dehydration is modelled to fit Zipf's law, a natural power law that holds true for all natural languages, that states if the frequency of word usage is plotted against its rank, then the log linear regression of this is -1. We have applied this model to our previously published euhydrated and dehydrated SON data to observe this trend and how it changes following dehydration. In accordance with other studies, our whole transcriptome data fit well with this model in the euhydrated SON microarrays, but interestingly, fit better in the dehydrated arrays. This trend was observed in a subset of differentially regulated genes and also following network reconstruction using a third-party database that mines public data. We make use of language as a metaphor that helps us philosophise about the role of the whole transcriptome in providing a suitable environment for the delivery of Avp following a survival threat like dehydration. PMID- 24345908 TI - Addressing conflicts of interest in the research paper: a societal demand in contemporary science? AB - In the last decade, dialogue between science and society has found a forum in an increasing number of publications on topics such as public engagement with science and public trust in science. Concerning the latter, issues that include cases of research misconduct, accountability in research, and conflicts of interest (COIs) have shaped global discussions on the communication of science. In the publication setting, the perception that hiding COIs and/or not managing them well may affect public trust in the research record has grown among editors. We conducted a search for editorials addressing COIs between 1989 and 2011, using four major databases: Medline/PubMed, Embase, Scopus, and Web of Knowledge. We explored the content of these editorials and the relationship they established between COIs and the public trust in science. Our results demonstrate that the relationship between disclosure of COIs and public trust in science has become a major concern among editors. We, thus, argue that COIs should be discussed more openly and frequently in graduate courses in the sciences, around the globe, not only in biomedical but also in non-biomedical areas. This is a critical issue in contemporary science, as graduate students are the future voices and decision makers of the research community. Therefore, COIs, especially in the broader context of science and society, merit closer attention from policymakers, researchers, and educators. At times of great expectations for public engagement with science, mishandling of COIs may have undesirable consequences for public engagement with science and confidence in the scientific endeavor. PMID- 24345909 TI - Lipid peroxidation, detoxification capacity, and genome damage in mice after transplacental exposure to pharmaceutical drugs. AB - Data on genome damage, lipid peroxidation, and levels of glutathione peroxidase (GPX) in newborns after transplacental exposure to xenobiotics are rare and insufficient for risk assessment. The aim of the current study was to analyze, in an animal model, transplacental genotoxicity, lipid peroxidation, and detoxification disturbances caused by the following drugs commonly prescribed to pregnant women: paracetamol, fluconazole, 5-nitrofurantoin, and sodium valproate. Genome damage in dams and their newborn pups transplacentally exposed to these drugs was investigated using the in vivo micronucleus (MN) assay. The drugs were administered to dams intraperitoneally in three consecutive daily doses between days 12 and 14 of pregnancy. The results were correlated, with detoxification capacity of the newborn pups measured by the levels of GPX in blood and lipid peroxidation in liver measured by malondialdehyde (HPLC-MDA) levels. Sodium valproate and 5-nitrofurantoin significantly increased MN frequency in pregnant dams. A significant increase in the MN frequency of newborn pups was detected for all drugs tested. This paper also provides reference levels of MDA in newborn pups, according to which all drugs tested significantly lowered MDA levels of newborn pups, while blood GPX activity dropped significantly only after exposure to paracetamol. The GPX reduction reflected systemic oxidative stress, which is known to occur with paracetamol treatment. The reduction of MDA in the liver is suggested to be an unspecific metabolic reaction to the drugs that express cytotoxic, in particular hepatotoxic, effects associated with oxidative stress and lipid peroxidation. PMID- 24345910 TI - The N-terminal 33 amino acid domain of Siva-1 is sufficient for nuclear localization. AB - Siva-1 induces apoptosis in multiple pathological processes and plays an important role in the suppression of tumor metastasis, protein degradation, and other functions. Although many studies have demonstrated that Siva-1 functions in the cytoplasm, a few have found that Siva-1 can relocate to the nucleus. In this study, we found that the first 33 amino acid residues of Siva-1 are required for its nuclear localization. Further study demonstrated that the green fluorescent protein can be imported into the nucleus after fusion with these 33 amino acid residues. Other Siva-1 regions and domains showed less effect on Siva-1 nuclear localization. By site-mutagenesis of all of these 33 amino acid residues, we found that mutants of the first 1-18 amino acids affected Siva-1 nuclear compartmentalization but could not complete this localization independently. In summary, we demonstrated that the N-terminal 33 amino acid residues were sufficient for Siva-1 nuclear localization, but the mechanism of this translocation needs additional investigation. PMID- 24345911 TI - Association between the c.910A>G genetic variant of the XRCC1 gene and susceptibility to esophageal cancer in the Chinese Han population. AB - Esophageal cancer (EC) is a common malignancy worldwide. The X-ray repair cross complementing 1 gene (XRCC1) is one of the most important candidate genes for influencing susceptibility to EC. This study aimed to investigate the effect of XRCC1 genetic variants on susceptibility to EC. A total of 383 EC patients (males: 239, females: 144, mean age: 56.62) and 387 cancer-free controls (males: 251, females: 136, mean age: 58.23) were enrolled in this study. The c.910A>G genetic variant of the XRCC1 gene was determined by polymerase chain reaction restriction fragment length polymorphism and DNA sequencing methods. The allele and genotype frequencies indicated statistical differences between EC patients and cancer-free controls. The c.910A>G genetic variant was statistically associated with increased susceptibility to EC [GG vs AA: odds ratio (OR)=1.79, 95% confidence interval (CI)=1.12-2.86, P=0.014; GG vs AG/AA: OR=1.76, 95%CI=1.13 2.75, P=0.013; G vs A: OR=1.25, 95%CI=1.01-1.55, P=0.041]. The allele G and genotype GG could contribute to the increased susceptibility to EC. Our findings suggest that the c.910A>G genetic variant is associated with susceptibility to EC in the Chinese Han population, and might be used as a molecular marker for detecting susceptibility to EC. PMID- 24345912 TI - Effect of chronic ethanol consumption in female rats subjected to experimental sepsis. AB - The objective of this research was to evaluate the interference of ethanol consumption by female rats with cytokines involved in the sepsis process and its correlation with mortality, the main outcome of sepsis. Female Wistar rats in estrus phase were evaluated in three experiments. Experiment 1 (n=40) was performed to determine survival rates. Experiment 2 (n=69) was designed for biochemical analysis, measurement of cytokine and estrogen levels before and after sepsis, and experiment 3 (n=10) was performed to evaluate bacterial growth by colony counts of peritoneal fluid. In all experiments, treated animals were exposed to a 10% ethanol/water solution (v/v) as the single drinking source, while untreated animals were given tap water. After 4 weeks, sepsis was induced in the rats by ip injection of feces. In experiment 1, mortality in ethanol exposed animals was delayed compared with those that drank water (48 h; P=0.0001). Experiment 2 showed increased tumor necrosis factor alpha (TNF-alpha) and decreased interleukin-6 (IL-6) and macrophage migration inhibitory factor in septic animals exposed to ethanol compared to septic animals not exposed. Sepsis also increased TNF-alpha and IL-6 levels in both ethanol- and water-exposed groups. Biochemical analysis showed higher creatinine, alanine aminotransferase and aspartate aminotransferase and decreased glucose levels in septic animals that were exposed to ethanol. In experiment 3, septic animals exposed to ethanol showed decreased numbers of colony-forming units than septic animals exposed to water. These results suggest that ethanol consumption delays the mortality of female rats in estrus phase after sepsis induction. Female characteristics, most probably sex hormones, may be involved in cytokine expression. PMID- 24345913 TI - Effect of penehyclidine hydrochloride on beta-arrestin-1 expression in lipopolysaccharide-induced human pulmonary microvascular endothelial cells. AB - beta-arrestins are expressed proteins that were first described, and are well known, as negative regulators of G protein-coupled receptor signaling. Penehyclidine hydrochloride (PHC) is a new anti-cholinergic drug that can inhibit biomembrane lipid peroxidation, and decrease cytokines and oxyradicals. However, to date, no reports on the effects of PHC on beta-arrestin-1 in cells have been published. The aim of this study was to investigate the effect of PHC on beta arrestin-1 expression in lipopolysaccharide (LPS)-induced human pulmonary microvascular endothelial cells (HPMEC). Cultured HPMEC were pretreated with PHC, followed by LPS treatment. Muscarinic receptor mRNAs were assayed by real-time quantitative PCR. Cell viability was assayed by the methyl thiazolyl tetrazolium (MTT) conversion test. The dose and time effects of PHC on beta-arrestin-1 expression in LPS-induced HPMEC were determined by Western blot analysis. Cell malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were measured. It was found that the M3 receptor was the one most highly expressed, and was activated 5 min after LPS challenge. Furthermore, 2 MUg/mL PHC significantly upregulated expression of beta-arrestin-1 within 10 to 15 min. Compared with the control group, MDA levels in cells were remarkably increased and SOD activities were significantly decreased in LPS pretreated cells, while PHC markedly decreased MDA levels and increased SOD activities. We conclude that PHC attenuated ROS injury by upregulating beta-arrestin-1 expression, thereby implicating a mechanism by which PHC may exert its protective effects against LPS induced pulmonary microvascular endothelial cell injury. PMID- 24345914 TI - Adrenomedullin and adrenotensin regulate collagen synthesis and proliferation in pulmonary arterial smooth muscle cells. AB - To understand the pathophysiological mechanisms of pulmonary arterial smooth muscle cell (PASMC) proliferation and extracellular-matrix accumulation in the development of pulmonary hypertension and remodeling, this study determined the effects of different doses of adrenomedullin (ADM) and adrenotensin (ADT) on PASMC proliferation and collagen synthesis. The objective was to investigate whether extracellular signal-regulated kinase (ERK1/2) signaling was involved in ADM- and ADT-stimulated proliferation of PASMCs in 4-week-old male Wistar rats (body weight: 100-150 g, n=10). The proliferation of PASMCs was examined by 5 bromo-2-deoxyuridine incorporation. A cell growth curve was generated by the Cell Counting Kit-8 method. Expression of collagen I, collagen III, and phosphorylated ERK1/2 (p-ERK1/2) was evaluated by immunofluorescence. The effects of different concentrations of ADM and ADT on collagen I, collagen III, and p-ERK1/2 protein expression were determined by immunoblotting. We also investigated the effect of PD98059 inhibition on the expression of p-ERK1/2 protein by immunoblotting. ADM dose-dependently decreased cell proliferation, whereas ADT dose-dependently increased it; and ADM and ADT inhibited each other with respect to their effects on the proliferation of PASMCs. Consistent with these results, the expression of collagen I, collagen III, and p-ERK1/2 in rat PASMCs decreased after exposure to ADM but was upregulated after exposure to ADT. PD98059 significantly inhibited the downregulation by ADM and the upregulation by ADT of p-ERK1/2 expression. We conclude that ADM inhibited, and ADT stimulated, ERK1/2 signaling in rat PASMCs to regulate cell proliferation and collagen expression. PMID- 24345915 TI - Estragole blocks neuronal excitability by direct inhibition of Na+ channels. AB - Estragole is a volatile terpenoid, which occurs naturally as a constituent of the essential oils of many plants. It has several pharmacological and biological activities. The objective of the present study was to investigate the mechanism of action of estragole on neuronal excitability. Intact and dissociated dorsal root ganglion neurons of rats were used to record action potential and Na+ currents with intracellular and patch-clamp techniques, respectively. Estragole blocked the generation of action potentials in cells with or without inflexions on their descendant (repolarization) phase (Ninf and N0 neurons, respectively) in a concentration-dependent manner. The resting potentials and input resistances of Ninf and N0 cells were not altered by estragole (2, 4, and 6 mM). Estragole also inhibited total Na+ current and tetrodotoxin-resistant Na+ current in a concentration-dependent manner (IC50 of 3.2 and 3.6 mM, respectively). Kinetic analysis of Na+ current in the presence of 4 mM estragole showed a statistically significant reduction of fast and slow inactivation time constants, indicating an acceleration of the inactivation process. These data demonstrate that estragole blocks neuronal excitability by direct inhibition of Na+ channel conductance activation. This action of estragole is likely to be relevant to the understanding of the mechanisms of several pharmacological effects of this substance. PMID- 24345916 TI - Molecular adjuvant interleukin-33 enhances the antifertility effect of Lagurus lagurus zona pellucida 3 DNA vaccine administered by the mucosal route. AB - It has been shown that cytokines can act as molecular adjuvant to enhance the immune response induced by DNA vaccines, but it is unknown whether interleukin 33 (IL-33) can enhance the immunocontraceptive effect induced by DNA vaccines. In the present study, we explored the effects of murine IL-33 on infertility induced by Lagurus lagurus zona pellucida 3 (Lzp3) contraceptive DNA vaccine administered by the mucosal route. Plasmid pcD-Lzp3 and plasmid pcD-mIL-33 were encapsulated with chitosan to generate the nanoparticle chi-(pcD-Lzp3+pcD-mIL-33) as the DNA vaccine. Sixty female ICR mice, divided into 5 groups (n=12/group), were intranasally immunized on days 0, 14, 28, and 42. After intranasal immunization, the anti-LZP3-specific IgG in serum and IgA in vaginal secretions and feces were determined by ELISA. The results showed that chi-(pcD-Lzp3+pcD-mIL-33) co immunization induced the highest levels of serum IgG, secreted mucosal IgA, and T cell proliferation. Importantly, mice co-immunized with chi-(pcD-Lzp3+pcD-mIL-33) had the lowest birth rate and mean litter size, which correlated with high levels of antibodies. Ovaries from infertile female mice co-immunized with chi-(pcD Lzp3+pcD-mIL-33) showed abnormal development of ovarian follicles, indicated by atretic follicles and loss of oocytes. Our results demonstrated that intranasal delivery of the molecular adjuvant mIL-33 with chi-pcD-Lzp3 significantly increased infertility by enhancing both systemic and mucosal immune responses. Therefore, chi-(pcD-Lzp3+pcD-mIL-33) co-immunization could be a strategy for controlling the population of wild animal pests. PMID- 24345917 TI - Capecitabine maintenance therapy in patients with recurrent or metastatic breast cancer. AB - Our objective was to investigate the efficacy and safety of capecitabine maintenance therapy (CMT) after capecitabine-based combination chemotherapy in patients with metastatic breast cancer. The clinical data of 139 metastatic breast cancer patients treated from March 2008 to May 2012 with capecitabine based combination chemotherapy were retrospectively analyzed. When initial disease control was achieved by the combination chemotherapy, we used CMT for 50 patients, while 37 patients were treated with a different (non-CMT) maintenance therapy. We compared time to progression (TTP), objective response rate, disease control rate, clinical benefit rate, and safety of the two groups, and a sub group analysis was performed according to pathological characteristics. Sixty four percent of the patients received a median of six cycles of a docetaxel+capecitabine combination chemotherapy regimen (range 1-45); the median TTP (MTTP) for the complete treatment was 9.43 months (95%CI=8.38-10.48 months) for the CMT group and 4.5 months (95%CI=4.22-4.78 months; P=0.004) for the non CMT group. The MTTPs for the maintenance therapies administered after the initial capecitabine combined chemotherapy were 4.11 months (95%CI=3.34-4.87 months) for the CMT group and 2.0 months (95%CI=1.63-2.38 months) for the non-CMT group. Gastrointestinal side effects, decreased white blood cells and palmar-plantar erythrodysesthesia were the main adverse reactions experienced with the combination chemotherapies, CMT and non-CMT treatments. No significant differences in the incidence of adverse reactions were detected in the CMT and non-CMT patients. After initial disease control was achieved with the capecitabine-based combination chemotherapy, CMT can significantly prolong TTP rates with a favorable safety profile. PMID- 24345918 TI - Screening for spinal stenosis in achondroplastic patients undergoing limb lengthening. AB - The need for a screening programme for spinal stenosis in children with achondroplasia undergoing limb lengthening was identified in a tertiary limb reconstruction service. The aim of this study was to evaluate whether screening would identify the 'at risk' group. A total of 26 achondroplastic patients underwent our screening programme. Canal diameters were measured by MRI. Neurosurgical interventions were recorded. Of the patients, 13 had severe foramen magnum narrowing. Six patients required single or multiple surgical decompressions. We identified female sex, delayed milestones and a tight cervicomedullary junction as high risks. We stress upon the importance of developing a nationalized screening programme with guidelines to identify a high risk group. PMID- 24345920 TI - BRAF fusions define a distinct molecular subset of melanomas with potential sensitivity to MEK inhibition. AB - PURPOSE: Recurrent "driver" mutations at specific loci in BRAF, NRAS, KIT, GNAQ, and GNA11 define clinically relevant molecular subsets of melanoma, but more than 30% are "pan-negative" for these recurrent mutations. We sought to identify additional potential drivers in "pan-negative" melanoma. EXPERIMENTAL DESIGN: Using a targeted next-generation sequencing (NGS) assay (FoundationOneTM) and targeted RNA sequencing, we identified a novel PAPSS1-BRAF fusion in a "pan negative" melanoma. We then analyzed NGS data from 51 additional melanomas genotyped by FoundationOneTM, as well as melanoma RNA, whole-genome and whole exome sequencing data in The Cancer Genome Atlas (TCGA), to determine the potential frequency of BRAF fusions in melanoma. We characterized the signaling properties of confirmed molecular alterations by ectopic expression of engineered cDNAs in 293H cells. RESULTS: Activation of the mitogen-activated protein kinase (MAPK) pathway in cells by ectopic expression of PAPSS1-BRAF was abrogated by mitogen-activated protein kinase kinase (MEK) inhibition but not by BRAF inhibition. NGS data analysis of 51 additional melanomas revealed a second BRAF fusion (TRIM24-BRAF) in a "pan-negative" sample; MAPK signaling induced by TRIM24 BRAF was also MEK inhibitor sensitive. Through mining TCGA skin cutaneous melanoma dataset, we further identified two potential BRAF fusions in another 49 "pan-negative" cases. CONCLUSIONS: BRAF fusions define a new molecular subset of melanoma, potentially comprising 4% to 8% of "pan-negative" cases. Their presence may explain an unexpected clinical response to MEK inhibitor therapy or assist in selecting patients for MEK-directed therapy. PMID- 24345922 TI - Different patterns between mechanical and electrical activities: an approach to investigate gastric motility in a model of long-term diabetic rats. AB - The relationship between time-courses of mechanical and electrical events in longstanding diabetes was investigated in rats. Magnetic markers and electrodes were surgically implanted in the gastric serosa of male rats. Simultaneous recordings were obtained by AC biosusceptometry, electromyography and electrogastrography one, three and six months after injections of saline (control) or alloxan (diabetic). Frequency and amplitude of contraction, abnormal rhythmic index and half-bandwidth were obtained (ANOVA P < 0.05). Antral hypomotility and gastric motility instability were observed in the signal waveform of diabetic rats at the three time points of study. The mean frequency (4.4 +/- 0.4 cpm) was strictly similar, but the mechanical and electrical correlation was lowest for diabetics groups. Decreases in mechanical amplitude were observed for all diabetic groups compared with control; also the ranges of frequency were much wider in diabetes. The half-bandwidth increased since the first month in mechanical recordings and only after the third month in electrical. In diabetic animals, about 40% of gastric activity was abnormal (against 12% in control) and may reach 60% in the sixth month of mechanical recordings. The multi-instrumental approach showed a more substantial deterioration in mechanical activity and created an integrative view of gastric motility for longstanding diabetic model. PMID- 24345923 TI - An update on prevention and treatment of catheter-associated urinary tract infections. AB - PURPOSE OF REVIEW: Catheter-related urinary tract infections (UTIs) are among the most important nosocomial infections. This review summarizes the latest advances in the field of catheter care and the management of catheter-associated UTIs. RECENT FINDINGS: The most efficient methods to prevent catheter-associated UTIs are to avoid unnecessary catheterizations and to remove catheters as soon as possible. The use of different reminder systems and implementation of infection control programs can effectively decrease catheter-associated UTIs, although their introduction can be challenging. There is still no evidence to support the routine use of antimicrobial-impregnated catheters, but the use of hydrophilic coated catheters for clean intermittent catheterization can effectively reduce infections. Preliminary results with chlorhexidine-coated catheters are promising. In cases of serious catheter-associated UTI in patients with a history of previous antibiotic therapy or healthcare-associated bacteraemia, empirical antibiotic treatment should be initiated with activity against multiresistant uropathogens. Suprapubic catheterization is not superior to urethral catheters in terms of reducing the rate of catheter-related bacteriuria. SUMMARY: A technology to prevent catheter-associated UTIs is still not available; however, there are promising results with new approaches such as the use of reminder systems and infection control programs, which can effectively decrease the rate of catheter associated UTIs. There is evidence supporting the use of hydrophilic coated catheters for clean intermittent catheterization, but an optimal catheter material or coating still has to be developed. Evidence-based catheter management is crucial for every patient in need of a catheter. PMID- 24345924 TI - Strategies to manage the HIV epidemic in gay, bisexual, and other men who have sex with men. AB - PURPOSE OF REVIEW: HIV epidemic spread continues among gay, bisexual, and other MSM globally in 2013. These epidemics are occurring in rapidly shifting contexts among these men, which have important impacts on HIV spread, HIV programs, access to services and human rights. Current HIV prevention strategies are inadequate and are taken to insufficient scale to control HIV spread. RECENT FINDINGS: We reviewed recent reports on epidemiology, HIV prevention advances, human rights, and epidemic disease control among MSM to understand why HIV epidemics among these men remain poorly controlled. Network level factors appear to be critically important for HIV epidemic spread among MSM. The only new prevention technology with evidence for efficacy in this population, daily oral chemoprophylaxis (PrEP), has been little used, particularly in low and middle-income countries. SUMMARY: Much more vigorous prevention efforts are required, including the adaptation and expanded use of PrEP, if we are to reduce new infections among gay, bisexual and other MSM. PMID- 24345925 TI - Physical key-protected one-time pad. AB - We describe an encrypted communication principle that forms a secure link between two parties without electronically saving either of their keys. Instead, random cryptographic bits are kept safe within the unique mesoscopic randomness of two volumetric scattering materials. We demonstrate how a shared set of patterned optical probes can generate 10 gigabits of statistically verified randomness between a pair of unique 2 mm(3) scattering objects. This shared randomness is used to facilitate information-theoretically secure communication following a modified one-time pad protocol. Benefits of volumetric physical storage over electronic memory include the inability to probe, duplicate or selectively reset any bits without fundamentally altering the entire key space. Our ability to securely couple the randomness contained within two unique physical objects can extend to strengthen hardware required by a variety of cryptographic protocols, which is currently a critically weak link in the security pipeline of our increasingly mobile communication culture. PMID- 24345926 TI - Adult rat retinal ganglion cells and glia can be printed by piezoelectric inkjet printing. AB - We have investigated whether inkjet printing technology can be extended to print cells of the adult rat central nervous system (CNS), retinal ganglion cells (RGC) and glia, and the effects on survival and growth of these cells in culture, which is an important step in the development of tissue grafts for regenerative medicine, and may aid in the cure of blindness. We observed that RGC and glia can be successfully printed using a piezoelectric printer. Whilst inkjet printing reduced the cell population due to sedimentation within the printing system, imaging of the printhead nozzle, which is the area where the cells experience the greatest shear stress and rate, confirmed that there was no evidence of destruction or even significant distortion of the cells during jet ejection and drop formation. Importantly, the viability of the cells was not affected by the printing process. When we cultured the same number of printed and non-printed RGC/glial cells, there was no significant difference in cell survival and RGC neurite outgrowth. In addition, use of a glial substrate significantly increased RGC neurite outgrowth, and this effect was retained when the cells had been printed. In conclusion, printing of RGC and glia using a piezoelectric printhead does not adversely affect viability and survival/growth of the cells in culture. Importantly, printed glial cells retain their growth-promoting properties when used as a substrate, opening new avenues for printed CNS grafts in regenerative medicine. PMID- 24345928 TI - Laughing matter. PMID- 24345927 TI - Interorganelle interactions and inheritance patterns of nuclei and vacuoles in budding yeast meiosis. AB - Many of the mechanisms by which organelles are inherited by spores during meiosis are not well understood. Dramatic chromosome motion and bouquet formation are evolutionarily conserved characteristics of meiotic chromosomes. The budding yeast bouquet genes (NDJ1, MPS3, CSM4) mediate these movements via telomere attachment to the nuclear envelope (NE). Here, we report that during meiosis the NE is in direct contact with vacuoles via nucleus-vacuole junctions (NVJs). We show that in meiosis NVJs are assembled through the interaction of the outer NE protein Nvj1 and the vacuolar membrane protein Vac8. Notably, NVJs function as diffusion barriers that exclude the nuclear pore complexes, the bouquet protein Mps3 and NE-tethered telomeres from the outer nuclear membrane and nuclear ER, resulting in distorted NEs during early meiosis. An increase in NVJ area resulting from Nvj1-GFP overexpression produced a moderate bouquet mutant-like phenotype in wild-type cells. NVJs, as the vacuolar contact sites of the nucleus, were found to undergo scission alongside the NE during meiotic nuclear division. The zygotic NE and NVJs were partly segregated into 4 spores. Lastly, new NVJs were also revealed to be synthesized de novo to rejoin the zygotic NE with the newly synthesized vacuoles in the mature spores. In conclusion, our results revealed that budding yeast nuclei and vacuoles exhibit dynamic interorganelle interactions and different inheritance patterns in meiosis, and also suggested that nvj1Delta mutant cells may be useful to resolve the technical challenges pertaining to the isolation of intact nuclei for the biochemical study of meiotic nuclear proteins. PMID- 24345934 TI - Single-molecule chemistry: Knowing your neighbours. PMID- 24345935 TI - Biosynthesis: Non-stick natural products. PMID- 24345936 TI - Separated tandem catalysis: It's about time. PMID- 24345937 TI - Biophysical chemistry: Strength in numbers. PMID- 24345939 TI - Argon out of thin air. PMID- 24345940 TI - Molecular dynamics: A stitch in time. PMID- 24345941 TI - Cloud-based simulations on Google Exacycle reveal ligand modulation of GPCR activation pathways. AB - Simulations can provide tremendous insight into the atomistic details of biological mechanisms, but micro- to millisecond timescales are historically only accessible on dedicated supercomputers. We demonstrate that cloud computing is a viable alternative that brings long-timescale processes within reach of a broader community. We used Google's Exacycle cloud-computing platform to simulate two milliseconds of dynamics of a major drug target, the G-protein-coupled receptor beta2AR. Markov state models aggregate independent simulations into a single statistical model that is validated by previous computational and experimental results. Moreover, our models provide an atomistic description of the activation of a G-protein-coupled receptor and reveal multiple activation pathways. Agonists and inverse agonists interact differentially with these pathways, with profound implications for drug design. PMID- 24345942 TI - Temporal separation of catalytic activities allows anti-Markovnikov reductive functionalization of terminal alkynes. AB - There is currently great interest in the development of multistep catalytic processes in which one or several catalysts act sequentially to rapidly build complex molecular structures. Many enzymes--often the inspiration for new synthetic transformations--are capable of processing a single substrate through a chain of discrete, mechanistically distinct catalytic steps. Here, we describe an approach to emulate the efficiency of these natural reaction cascades within a synthetic catalyst by the temporal separation of catalytic activities. In this approach, a single catalyst exhibits multiple catalytic activities sequentially, allowing for the efficient processing of a substrate through a cascade pathway. Application of this design strategy has led to the development of a method to effect the anti-Markovnikov (linear-selective) reductive functionalization of terminal alkynes. The strategy of temporal separation may facilitate the development of other efficient synthetic reaction cascades. PMID- 24345944 TI - The aromatic ene reaction. AB - The ene reaction is a pericyclic process in which an alkene with an allylic hydrogen atom (the ene donor) reacts with a second unsaturated species (the enophile) to form a new product with a transposed pi-bond. The aromatic ene reaction, in which the alkene component is embedded in an aromatic ring, has only been reported in a few (four) instances and has proceeded in low yield (<=6%). Here, we show efficient aromatic ene reactions in which a thermally generated aryne intermediate engages a pendant m-alkylarene substituent to produce a dearomatized isotoluene, itself another versatile but rare reactive intermediate. Our experiments were guided by computational studies that revealed structural features conducive to the aromatic ene process. We proceeded to identify a cascade comprising three reactions: (1) hexadehydro-Diels-Alder (for aryne generation), (2) intramolecular aromatic ene and (3) bimolecular Alder ene. The power of this cascade is evident from the structural complexity of the final products, the considerable scope, and the overall efficiency of these multistage, reagent- and by-product-free, single-pot transformations. PMID- 24345945 TI - Controlling intramolecular hydrogen transfer in a porphycene molecule with single atoms or molecules located nearby. AB - Although the local environment of a molecule can play an important role in its chemistry, rarely has it been examined experimentally at the level of individual molecules. Here we report the precise control of intramolecular hydrogen-transfer (tautomerization) reactions in single molecules using scanning tunnelling microscopy. By placing, with atomic precision, a copper adatom close to a porphycene molecule, we found that the tautomerization rates could be tuned up and down in a controlled fashion, surprisingly also at rather large separations. Furthermore, we extended our study to molecular assemblies in which even the arrangement of the pyrrolic hydrogen atoms in the neighbouring molecule influences the tautomerization reaction in a given porphycene, with positive and negative cooperativity effects. Our results highlight the importance of controlling the environment of molecules with atomic precision and demonstrate the potential to regulate processes that occur in a single molecule. PMID- 24345943 TI - Oligomerization transforms human APOBEC3G from an efficient enzyme to a slowly dissociating nucleic acid-binding protein. AB - The human APOBEC3 proteins are a family of DNA-editing enzymes that play an important role in the innate immune response against retroviruses and retrotransposons. APOBEC3G is a member of this family that inhibits HIV-1 replication in the absence of the viral infectivity factor Vif. Inhibition of HIV replication occurs by both deamination of viral single-stranded DNA and a deamination-independent mechanism. Efficient deamination requires rapid binding to and dissociation from ssDNA. However, a relatively slow dissociation rate is required for the proposed deaminase-independent roadblock mechanism in which APOBEC3G binds the viral template strand and blocks reverse transcriptase catalysed DNA elongation. Here, we show that APOBEC3G initially binds ssDNA with rapid on-off rates and subsequently converts to a slowly dissociating mode. In contrast, an oligomerization-deficient APOBEC3G mutant did not exhibit a slow off rate. We propose that catalytically active monomers or dimers slowly oligomerize on the viral genome and inhibit reverse transcription. PMID- 24345946 TI - Ligand-enabled multiple absolute stereocontrol in metal-catalysed cycloaddition for construction of contiguous all-carbon quaternary stereocentres. AB - The development of a general catalytic method for the direct and stereoselective construction of contiguous all-carbon quaternary stereocentres remains a formidable challenge in chemical synthesis. Here, we report a highly enantio- and diastereoselective [3+2] annulation reaction of 5-vinyloxazolidinones and activated trisubstituted alkenes catalysed by a palladium complex bearing a newly devised phosphine ligand with a chiral ammonium salt component, which enables the single-step construction of three contiguous stereocentres, including vicinal all carbon quaternary stereocentres, in a five-membered heterocyclic framework. This stereoselective cycloaddition protocol relies on the remarkable ability of the chiral ligand to rigorously control the absolute stereochemistry of each chiral centre associated with the multiple bond-forming events, and provides a reliable catalytic process for the asymmetric synthesis of densely functionalized pyrrolidines. PMID- 24345947 TI - Calculations predict a stable molecular crystal of N8. AB - Nitrogen, one of the most abundant elements in nature, forms the highly stable N2 molecule in its elemental state. In contrast, polynitrogen compounds comprising only nitrogen atoms are rare, and no molecular crystal made of these compounds has been prepared. Here, we predict the existence of such a molecular solid, consisting of N8 molecules, that is metastable even at ambient pressure. In the solid state, the N8 monomers retain the same structure and bonding pattern as those they adopt in the gas phase. The interactions that bind N8 molecules together are weak van der Waals and electrostatic forces. The solid is, according to calculations, more stable than a previously reported polymeric nitrogen solid, including at low pressure (below 20 GPa). The structure and properties of the N8 molecular crystal are discussed and a possible preparation strategy is suggested. PMID- 24345948 TI - Biogenetically inspired synthesis and skeletal diversification of indole alkaloids. AB - To access architecturally complex natural products, chemists usually devise a customized synthetic strategy for constructing a single target skeleton. In contrast, biosynthetic assembly lines often employ divergent intramolecular cyclizations of a polyunsaturated common intermediate to produce diverse arrays of scaffolds. With the aim of integrating such biogenetic strategies, we show the development of an artificial divergent assembly line generating unprecedented numbers of scaffold variations of terpenoid indole alkaloids. This approach not only allows practical access to multipotent intermediates, but also enables systematic diversification of skeletal, stereochemical and functional group properties without structural simplification of naturally occurring alkaloids. Three distinct modes of [4+2] cyclizations and two types of redox-mediated annulations provided divergent access to five skeletally distinct scaffolds involving iboga-, aspidosperma-, andranginine- and ngouniensine-type skeletons and a non-natural variant within six to nine steps from tryptamine. The efficiency of our approach was demonstrated by successful total syntheses of (+/ )-vincadifformine, (+/-)-andranginine and (-)-catharanthine. PMID- 24345949 TI - Discrimination of epimeric glycans and glycopeptides using IM-MS and its potential for carbohydrate sequencing. AB - Mass spectrometry is the primary analytical technique used to characterize the complex oligosaccharides that decorate cell surfaces. Monosaccharide building blocks are often simple epimers, which when combined produce diastereomeric glycoconjugates indistinguishable by mass spectrometry. Structure elucidation frequently relies on assumptions that biosynthetic pathways are highly conserved. Here, we show that biosynthetic enzymes can display unexpected promiscuity, with human glycosyltransferase pp-alpha-GanT2 able to utilize both uridine diphosphate N-acetylglucosamine and uridine diphosphate N-acetylgalactosamine, leading to the synthesis of epimeric glycopeptides in vitro. Ion-mobility mass spectrometry (IM MS) was used to separate these structures and, significantly, enabled characterization of the attached glycan based on the drift times of the monosaccharide product ions generated following collision-induced dissociation. Finally, ion-mobility mass spectrometry following fragmentation was used to determine the nature of both the reducing and non-reducing glycans of a series of epimeric disaccharides and the branched pentasaccharide Man3 glycan, demonstrating that this technique may prove useful for the sequencing of complex oligosaccharides. PMID- 24345950 TI - Visualization and selective chemical targeting of RNA G-quadruplex structures in the cytoplasm of human cells. AB - Following extensive evidence for the formation of four-stranded DNA G-quadruplex structures in vitro, DNA G-quadruplexes have been observed within human cells. Although chemically distinct, RNA can also fold in vitro into G-quadruplex structures that are highly stable because of the 2'-hydroxyl group. However, RNA G-quadruplexes have not yet been reported in cells. Here, we demonstrate the visualization of RNA G-quadruplex structures within the cytoplasm of human cells using a G-quadruplex structure-specific antibody. We also demonstrate that small molecules that bind to G-quadruplexes in vitro can trap endogenous RNA G quadruplexes when applied to cells. Furthermore, a small molecule that exhibits a preference for RNA G-quadruplexes rather than DNA G-quadruplexes in biophysical experiments also shows the same selectivity within a cellular context. Our findings provide substantive evidence for RNA G-quadruplex formation in the human transcriptome, and corroborate the selectivity and application of stabilizing ligands that target G-quadruplexes within a cellular context. PMID- 24345958 TI - Trauma at the hands of another: distinguishing PTSD patterns following intimate and nonintimate interpersonal and noninterpersonal trauma in a nationally representative sample. AB - OBJECTIVE: Interpersonal trauma and violence is currently considered a global public health emergency. However, studies have not differentiated between intimate interpersonal trauma and nonintimate interpersonal trauma in their impact on posttraumatic stress disorder (PTSD) symptomatology. This cross sectional study based on epidemiologic data examined the differential likelihoods of endorsing PTSD symptoms following 3 categories of trauma: noninterpersonal (eg, accidents, natural disasters), nonintimate interpersonal (physical assaults perpetrated by nonintimates), and intimate interpersonal (physical assaults perpetrated by intimates or caregivers and sexual assaults). METHOD: DSM-IV PTSD symptom data drawn from a weighted subsample (N = 1,012) of people reporting "most severe" reactions following one of the above types of trauma in the 2007 Australian National Survey of Mental Health and Well-Being (NSMHWB) were analyzed using binary logistic regression. RESULTS: Participants reporting intimate interpersonal compared with noninterpersonal trauma were significantly (P < .001) more likely to endorse core symptoms (intrusive reexperiencing, avoidance of reminders, hypervigilance, and startle response) of PTSD. The intimate interpersonal trauma group members were significantly more likely than the nonintimate interpersonal trauma group members to endorse distress at reminders (odds ratio [OR] = 3.2; P < .001; 99.7% CI, 1.3-7.9), avoiding thinking about the event (OR = 3.2; P < .001; 99.7% CI, 1.3-7.7), detachment from others (OR = 3.2; P < .001; 99.7% CI, 1.2-8.9), and restricted affect (OR = 4.1; P < .001; 99.7% CI, 1.5-11.3). Participants reporting nonintimate interpersonal and noninterpersonal traumas did not significantly differ except in endorsement of behavioral avoidance (OR = 2.8; P < .001; 99.7% CI, 1.2-6.6), hypervigilance (OR = 2.5; P = .002; 99.7% CI, 1.0-6.3), and exaggerated startle response (OR = 3.5; P < .001; 99.7% CI, 1.7-7.4). CONCLUSIONS: Survivors of intimate trauma appear to experience particularly severe intrusive memories and reminders of past trauma and suppression of emotional responsivity. The unique impact of interpersonal trauma, however, intimate or otherwise, compared with noninterpersonal trauma, is the experience of an environment as unsafe and unpredictable, due to the potential of human threat. Such findings have significant implications for the assessment of and interventions for survivors of interpersonal violence. PMID- 24345959 TI - X-ray irradiation-induced formation of luminescent silver clusters in nanoporous matrices. AB - We report the formation of luminescent silver clusters in zeolites by a fast, highly accurate, and controlled activation of silver ions entrapped in sodalite cages of LTA and FAU zeolites using high-brilliance soft X-rays. The activated luminescent samples were investigated by employing a combination of stationary and time-resolved spectroscopic techniques. PMID- 24345960 TI - Development of a canine model with diffuse hepatic vein obstruction (Budd-Chiari syndrome) via endovascular occlusion. AB - The aim of the present study was to develop a reliable and reproducible canine model to mimic human diffuse hepatic vein obstruction (Budd-Chiari syndrome, BCS). A total of 24 canines were divided into an experimental (n=18) and a control (n=6) group. Under the guidance of digital subtraction angiography, a balloon catheter was delivered to the target hepatic vein (the common trunk of the left hepatic and middle hepatic veins) via the right external jugular vein. The balloon was inflated to completely block the vessels. For the canines in the experimental group, a mixture of N-butyl-cyanoacrylate (NBCA) and lipiodol (3-5 ml) was injected via the balloon catheter. Canines in the control group were injected with equal volumes of normal saline. Liver function and pathology were examined at 4, 6 and 8 weeks following surgery. BCS was successfully established in all members of the experimental group and there were no serious complications in either group. The left and middle hepatic veins and common trunk were completely obstructed at 4, 6 and 8 weeks following surgery in the experimental group, while in the control group, the hepatic vein remained unobstructed at 4 weeks. There was hepatocyte congestion and edema at 4 weeks following surgery in the experimental group and the edema became aggravated following 6 weeks. At 8 weeks following surgery, there was necrosis of hepatocytes and significant thickening of the hepatic vein tunica intima in addition to an increased number of elastic fibers. In conclusion, the present study demonstrates that a reliable and reproducible canine model of BCS can be developed by endovascular obstruction of the hepatic vein. PMID- 24345963 TI - Reply to R. Erro and M. Tinazzi's "Functional (psychogenic) paroxysms: the diagnosis is in the eye of the beholder". PMID- 24345961 TI - Effect of lower limb preference on local muscular and vascular function. AB - Unilateral physical training can enhance muscular size and function as well as vascular function in the trained limb. In non-athletes, the preferred arm for use during unilateral tasks may exhibit greater muscular strength compared to the non preferred arm. It is unclear if lower limb preference affects lower limb vascular function or muscular endurance and power in recreationally active adults. To examine the effect of lower limb preference on quadriceps muscle size and function and on lower limb vascular function in middle-aged adults. Twenty (13 men, 7 women) recreationally-active middle-aged (55 +/- 7 yrs) adults underwent measurements of quadriceps muscle thickness, strength, mean power, endurance, and arterial stiffness, calf venous compliance, and calf blood flow in the preferred and non-preferred lower limb. The preferred limb exhibited greater calf vascular conductance (31.6 +/- 15.5 versus 25.8 +/- 13.0 units flow/mmHg; p = 0.011) compared to the non-preferred limb. The interlimb difference in calf vascular conductance was negatively related to weekly aerobic activity (hrs/week) (r = 0.521; p = 0.019). Lower limb preference affects calf blood flow but not quadriceps muscle size or function. Studies involving unilateral lower limb testing procedures in middle-aged individuals should consider standardizing the testing to either the preferred or non-preferred limb rather than the right or left limb. PMID- 24345964 TI - Tremor associated with Klinefelter syndrome--a case series and review of the literature. AB - BACKGROUND: Previous case series suggested a link between Klinefelter syndrome (KS) and essential tremor (ET) or an ET-like syndrome. METHODS: We investigated three KS-patients with tremor including tremor-analyzes and discuss our data in context to findings from a literature review. The clinical outcome after deep brain stimulation (DBS) is also reviewed. RESULTS: Tremor in KS is predominantly a postural and kinetic tremor that resembles ET. Our patients were further characterized by absent family history for tremor in first degree relatives, lack of subjective alcohol responsiveness inquired by history, and tremor onset in childhood. One of our patients and two cases from literature improved after DBS of the ventral intermediate nucleus (VIM) of the thalamus. CONCLUSIONS: Tremor in KS shares several features with ET. If other characteristics such as family history, alcohol responsiveness, and age at tremor onset may serve as discriminating factors from ET, needs to be further investigated. First observations suggest that VIM-DBS may be efficacious. PMID- 24345965 TI - A 1024-sample serum analyzer chip for cancer diagnostics. AB - We present a platform that combines microarrays and microfluidic techniques to measure four protein biomarkers in 1024 serum samples for a total of 4096 assays per device. Detection is based on a surface fluorescence sandwich immunoassay with a limit of detection of ~1 pM for most of the proteins measured: PSA, TNF alpha, IL-1beta, and IL-6. To validate the utility of our platform, we measured these four biomarkers in 20 clinical human serum samples, 10 from prostate cancer patients and 10 female and male controls. We compared the results of our platform to a conventional ELISA and found a good correlation between them. However, compared to a classical ELISA, our device reduces the total cost of reagents by 4 orders of magnitude while increasing throughput by 2 orders of magnitude. Overall, we demonstrate an integrated approach to perform low-cost and rapid quantification of protein biomarkers from over one thousand serum samples. This new high-throughput technology will have a significant impact on disease diagnosis and management. PMID- 24345966 TI - Exercises to activate the deeper abdominal wall muscles: the Lewit: a preliminary study. AB - The abdominal wall is a prime target for therapeutic exercises aimed to prevent and rehabilitate low back pain and to enhance performance training. This study examined the "Lewit," a corrective exercise prescribed for several purposes, which is performed lying supine in a crook-lying position and involves forceful breathing. Muscle activation and lumbar posture were compared with bracing the abdominal wall (stiffening) with robust effort and "hollowing" (attempting to draw in the wall toward the naval) with robust effort. Eight healthy male volunteers with 6 channels of electromyography were collected by means of surface electrode pairs of the rectus abdominis, external oblique, and internal oblique (IO) together with lumbar motion. The Lewit exercise caused higher muscle activity in the deeper abdominal wall muscles, in particular the IO and by default the transverse abdominis were activated at 54% maximum voluntary contractions (MVCs) on average and 84% MVC peak with no change in spine posture to maintain the elastic equilibrium of the lumbar spine. The Lewit is a deep oblique muscle activation exercise, and the activation levels are of a sufficient magnitude for training muscle engrams. This information will assist strength and conditioning coaches with program design decisions where this corrective abdominal exercise may be considered for clients who elevate the ribcage during strength exertions, or for clients targeting the deep obliques. PMID- 24345968 TI - Aerobic fitness ecological validity in elite soccer players: a metabolic power approach. AB - The aim of this study was to examine the association between match metabolic power (MP) categories and aerobic fitness in elite-level male soccer players. Seventeen male professional soccer players were tested for VO2max, maximal aerobic speed (MAS), VO2 at ventilatory threshold (VO2VT and %VO2VT), and speed at a selected blood lactate concentration (4 mmol.L(-1), V(L4)). Aerobic fitness tests were performed at the end of preseason and after 12 and 24 weeks during the championship. Aerobic fitness and MP variables were considered as mean of all seasonal testing and of 16 Championship home matches for all the calculations, respectively. Results showed that VO2max (from 0.55 to 0.68), MAS (from 0.52 to 0.72), VO2VT (from 0.72 to 0.83), %VO2maxVT (from 0.62 to 0.65), and V(L4) (from 0.56 to 0.73) were significantly (p < 0.05 to 0.001) large to very large associated with MP variables. These results provide evidence to the ecological validity of aerobic fitness in male professional soccer. Strength and conditioning professionals should consider aerobic fitness in their training program when dealing with professional male soccer players. The MP method resulted an interesting approach for tracking external load in male professional soccer players. PMID- 24345969 TI - Regression models of sprint, vertical jump, and change of direction performance. AB - It was the aim of the present study to expand on previous correlation analyses that have attempted to identify factors that influence performance of jumping, sprinting, and changing direction. This was achieved by using a regression approach to obtain linear models that combined anthropometric, strength, and other biomechanical variables. Thirty rugby union players participated in the study (age: 24.2 +/- 3.9 years; stature: 181.2 +/- 6.6 cm; mass: 94.2 +/- 11.1 kg). The athletes' ability to sprint, jump, and change direction was assessed using a 30-m sprint, vertical jump, and 505 agility test, respectively. Regression variables were collected during maximum strength tests (1 repetition maximum [1RM] deadlift and squat) and performance of fast velocity resistance exercises (deadlift and jump squat) using submaximum loads (10-70% 1RM). Force, velocity, power, and rate of force development (RFD) values were measured during fast velocity exercises with the greatest values produced across loads selected for further analysis. Anthropometric data, including lengths, widths, and girths were collected using a 3-dimensional body scanner. Potential regression variables were first identified using correlation analyses. Suitable variables were then regressed using a best subsets approach. Three factor models generally provided the most appropriate balance between explained variance and model complexity. Adjusted R values of 0.86, 0.82, and 0.67 were obtained for sprint, jump, and change of direction performance, respectively. Anthropometric measurements did not feature in any of the top models because of their strong association with body mass. For each performance measure, variance was best explained by relative maximum strength. Improvements in models were then obtained by including velocity and power values for jumping and sprinting performance, and by including RFD values for change of direction performance. PMID- 24345970 TI - Heart rate-running speed index may be an efficient method of monitoring endurance training adaptation. AB - The aim of this study was to investigate whether a novel heart rate (HR)-running speed index could be used in monitoring adaptation to endurance training. Forty five recreational runners underwent a 2-phased 28-week training regime. The first 14 weeks included basic endurance training, whereas the second 14 weeks were more intensive (increased volume and intensity). A maximal treadmill running test was performed in the beginning of the experiment, in the middle of basic endurance training, and at the end of each training period (PRE, WEEK 7, WEEK 14, and POST). The novel HR-running speed index was calculated from every continuous-type running exercise during the 28-week experiment based on exercise HR-running speed relation accompanied by individual information on resting and maximal HR and speed. The change in the novel index correlated significantly with the changes of peak running speed in the treadmill tests (r = 0.43-0.61, p < 0.01) and speed at respiratory compensation threshold (r = 0.35-0.39, p <= 0.05) during the experiment. The change in the index also correlated significantly (r = 0.49, p = 0.001) with relative changes in maximal oxygen uptake (in ml.kg.min). According to these findings, it seems that the novel index based on exercise HR and running speed may serve as a practical tool for daily monitoring of individual's training adaptation without the need to realize a maximal running test in laboratory conditions. PMID- 24345972 TI - Neuromuscular fatigue to power loading using a weight-stack device fitted with or without additional rubber band resistance. AB - The addition of a rubber band (RB) to traditional weight-based resistance may be beneficial regarding the deceleration phase common during explosive power actions with light weights. This would lead to greater force and muscle activity during the latter part of the movement, but this may influence the distribution of neuromuscular fatigue. Fifteen men performed 2 knee extension power loadings (5 * 5 * 40% of 1 repetition maximum [1RM]) using a typical weight-stack device without (WS) and with the addition of a RB (WS + RB) in a crossover design. Concentric contractions were performed as fast as possible, and analyzed for torque, velocity, power, and vastus lateralis and medialis surface electromyography (EMG) parameters over 20 degrees segments (range of motion, 60 180 degrees ) from throughout the loading. Additionally, maximum isometric knee extension was analyzed preloading and postloading for torque and EMG parameters, and for voluntary activation level using the twitch interpolation technique. Peak concentric power occurred at 100-120 degrees on both devices but was greater during WS + RB (p <= 0.05). Electromyographic amplitude was greater in WS at 80 120 degrees , p <= 0.05-0.01. Loading-induced reductions in peak concentric power (-12 +/- 8 vs. -4 +/- 10 kW, p <= 0.05) and voluntary activation level (-5.5 +/- 7 vs. -1.1 +/- 5%, p <= 0.05) were greater when using WS + RB. However, a greater reduction in root mean square of electromyography over 0-100 milliseconds was observed after WS (-31 +/- 22 vs. 10 +/- 26%, p < 0.05) accompanied by a large reduction in torque over 0-100 milliseconds. It seems that activation strategies, and consequently neuromuscular fatigue, during power loading could be modified through the addition of RB resistance. PMID- 24345973 TI - Autonomic modulation and its relation with body composition in swimmers. AB - This study compared autonomic modulation in swimmers and non-athletes in relation to body composition. A total of 28 athletes with a mean age of 19.7 +/- 2.9 years were evaluated who had at least 2 years of swimming training, trained approximately 7,000 m per day, with a frequency of 5 days per week, and who competed at national level. The control group was made up of 21 volunteers (23.0 +/- 2.5 years), who did not practice regular physical activity (<2 hours per week). Body composition was estimated using dual-energy x-ray absorptiometry, and autonomic modulation was assessed by heart rate variability (HRV). The results show that there were significant differences in autonomic modulation and body composition between the groups, and that the athletes had a higher overall variability (standard deviation of all normal intervals between consecutive heart beats [SDNN]: 78.1 [72.5-93.5] * 61.1 [56.4-75.7], p = 0.022) and greater autonomic balance (LF/HF: 0.96 [0.88-1.35] * 0.71 [0.56-0.93], p = 0.023), compared with the non-athletes, respectively. In addition, a moderate and positive relation was obtained between fat-free mass and the square root of the squared differences between consecutive heartbeat intervals (RMSSD: r = 0.526, p = 0.004 * r = 0.456, p = 0.038), (SDNN: r = 0.617, p = 0.001 * r = 0.571, p = 0.007) and low frequency (LFms: r = 0.517, p = 0.005 * r = 0.600, p = 0.004) in the athletes and non-athletes, respectively, without a correlation between fat mass (FM). The conclusion is that young highly trained swimmers had lower FM, increased fat-free mass, and better HRV than young adult non-athletes and suggests that a lower quantity of FM and, especially, a greater fat-free mass (FFM) are linked to better autonomic modulation. Thus, this study could contribute to coaches and trainers establishing greater performance by better autonomic modulation and greater quantity of FFM. PMID- 24345974 TI - Does an in-season detraining period affect the shoulder rotator cuff strength and balance of young swimmers? AB - Imbalance in shoulder rotator muscles is a well-documented problem in swimmers, and it is important to implement land-based strength training programs. Meanwhile, the effects of a detraining period on swimmers' shoulder rotator muscles are unknown. The purpose of this study was to analyze the effects of a strength training program and detraining on the strength and balance of shoulder rotator cuff muscles in young swimmers, despite the continuity of usual water training. An experimental group (n = 20) and a control group (n = 20) of young male swimmers with the same characteristics (age, body mass, height, training volume, and maturational state) were evaluated. In both groups, the peak torques of shoulder internal (IR) and external (ER) rotators were assessed during preseason, midseason (16 weeks), and postseason (32 weeks). The experimental group underwent a strength training regimen from baseline to 16 weeks and a detraining period from 16 to 32 weeks. Concentric action at 60 degrees .s-1 and 180 degrees .s-1 was measured using an isokinetic dynamometer. The ER/IR strength ratios were obtained. At 60 degrees .s-1, there were significant increments in IR strength and the ER/IR ratio in both shoulders. This trend was the same throughout the competitive season. The tendency was the same at 180 degrees .s-1 because training effects were noted primarily in IR and ER/IR ratios. Moreover, the absence of land-based strength training, from 16 to 32 weeks, revealed a reduction in the ER/IR ratio values in both shoulders. Our findings suggest that young swimmers' coaches should use dry-land strength training protocols, and that it is recommended that these should be conducted on a regular basis (during the whole season). PMID- 24345975 TI - The MARS for squat, countermovement, and standing long jump performance analyses: are measures reproducible? AB - Jump tests are often used to assess the effect of interventions because their outcomes are reported valid indicators of functional performance. In this study, we examined the reproducibility of performance parameters from 3 common jump tests obtained using the commercially available Kistler Measurement, Analysis and Reporting Software (MARS). On 2 separate days, 32 men performed 3 squat jumps (SJs), 3 countermovement jumps (CMJs), and 3 standing long jumps (LJs) on a Kistler force-plate. On both days, the performance measures from the best jump of each series were extracted using the MARS. Changes in the mean scores, intraclass correlation coefficients (ICCs), and coefficients of variations (CVs) were computed to quantify the between-day reproducibility of each parameter. Moreover, the reproducibility quantifiers specific to the 3 separate jumps were compared using nonparametric tests. Overall, an acceptable between-day reproducibility (mean +/- SD, ICC, and CV) of SJ (0.88 +/- 0.06 and 7.1 +/- 3.8%), CMJ (0.84 +/- 0.17 and 5.9 +/- 4.1%), and LJ (0.80 +/- 0.13 and 8.1 +/- 4.1%) measures was found using the MARS, except for parameters directly relating to the rate of force development (i.e., time to maximal force) and change in momentum during countermovement (i.e., negative force impulse) where reproducibility was lower. A greater proportion of the performance measures from the standing LJs had low ICCs and/or high CVs values most likely owing to the complex nature of the LJ test. Practitioners and researchers can use most of the jump test parameters from the MARS with confidence to quantify changes in the functional ability of individuals over time, except for those relating to the rate of force development or change in momentum during countermovement phases of jumps. PMID- 24345976 TI - Effect of body composition on respiratory compensation point during an incremental test. AB - Body mass (BM) and composition are considered to be significant determinants of aerobic endurance. The purpose of this study was to examine the influence of BM and its composition makeup on endurance performance. Thirty-nine men were divided into 3 groups of significantly different BM and mass composition: a control group, a group with high body fat (HBF), and a group with high lean body mass (HLBM). Participants in the HBF and HLBM groups had similar BM, which was significantly greater than observed in the control group. All participants performed an incremental treadmill test to volitional failure. Endurance performance was assessed on the basis of respiratory compensation point (RCP). The HBF and HLBM groups exceeded RCP at a much lower work intensity, expressed as %HRmax and %VO2max, compared with the control group. When considered relative to BM and lean body mass, oxygen consumption values at RCP were significantly less in the HBF and HLBM groups compared with the control group. Increased BM, regardless of its composition, substantially reduced aerobic endurance performance. Therefore, athletes and coaches should pay attention to not only the percentage of body fat but also to the amount of lean body mass because any gain may adversely affect aerobic endurance performance. PMID- 24345977 TI - Comparison of two-hand kettlebell exercise and graded treadmill walking: effectiveness as a stimulus for cardiorespiratory fitness. AB - Prevailing interest in the use of kettlebell (KB) exercises for rehabilitation and improvement of muscular strength has led to several recent studies, some suggesting that KB exercise may be useful for improvement of cardiorespiratory fitness. The purpose of this study was to determine whether KB exercise would produce similar cardiovascular stress to that of walking and thus provide an additional exercise mode for the improvement of cardiorespiratory fitness. It was hypothesized that a moderate-intensity, continuous KB protocol, would produce similar metabolic and cardiorespiratory responses as a brisk bout of graded treadmill (TM) walking, but greater rating of perceived exertion (RPE). Ten novice volunteers (5 men, 5 women) completed a preliminary session to determine body composition and VO2max and to familiarize participants with standardized KB exercise technique. Subsequently, they completed a 30-minute KB session that included 3 continuous 10-minute sets of 10 KB swings followed by 10 sumo deadlifts, with 3-minute rests between 10-minute exercise periods. The third session was a 30-minute TM regimen that began at the walking speed and 4% grade that matched the VO2 from the KB session and included 3-minute rest intervals after 10-minute TM exercise periods. VO2, respiratory exchange ratio, kcal.min, and blood pressure were similar for KB and moderate-intensity TM exercise, but RPE and heart rate were greater during KB exercise. Data indicate that a KB routine consisting of 2-hand swings and sumo deadlifts with 3-minute rest periods produces similar metabolic responses to those of a moderate-intensity TM walking protocol designed for the improvement of aerobic fitness. PMID- 24345978 TI - Surgical safety checklist is associated with improved operating room safety culture, reduced wound complications, and unplanned readmissions in a pilot study in neurosurgery. AB - BACKGROUND AND AIMS: The World Health Organization's surgical safety checklist is designed to improve adherence to operating room safety standards, and its use has been shown to reduce complications among surgical patients. The objective of our study was to assess the impact of the implementation of the checklist on safety related issues in the operating room and on postoperative adverse events in neurosurgery. MATERIAL AND METHODS: From structured questionnaires delivered to operating room personnel, answers were analyzed to evaluate communication and safety-related issues during 89 and 73 neurosurgical operations before and after the checklist implementation, respectively. From the analyzed operations, 83 and 67 patients, respectively, were included in a retrospective analysis of electronic patient records to compare the length of hospital stay, reported adverse events, and readmissions. In addition, the consistency of operating room documentation and patient records was assessed. RESULTS AND CONCLUSIONS: Communication between the surgeon and the anesthesiologist was enhanced, and safety-related issues were better covered when the checklist was used. Unplanned readmissions fell from 25% to 10% after the checklist implementation (p = 0.02). Wound complications decreased from 19% to 8% (p = 0.04). The consistency of documentation of the diagnosis and the procedure improved. The use of the checklist improved safety-related performance and, contemporarily, reduced numbers of wound complications, and readmissions were observed. PMID- 24345979 TI - Delay to surgery does not influence the pathological outcome of acute appendicitis. AB - INTRODUCTION: Emergency surgery is performed on patients with appendicitis in the belief that inflammation of the appendix may progress to necrosis and perforation. Many cases of appendicitis, however, resolve with conservative treatment, and necrotic appendicitis may represent a different disease rather than the end result of inflammation of the appendix. We wished to explore the relationship between the interval to surgery after admission to hospital with appendicitis and the proportion of patients developing necrosis. METHODS: Appendicectomy operations performed between 2005 and 2010 were reviewed. End points included age, sex, interval from admission to surgery, and final pathological diagnosis. RESULTS: A total of 2403 evaluable patients were identified (1266 females). Necrotic appendicitis occurred more commonly in children (17.5%) and the elderly (25.4%) compared with adults (10.5%). The median interval to surgery of patients with normal histology (17.1 h) was longer than the time to removal of inflamed (13 h) or necrotic (13.5 h) appendices (p < 0.001).The ratio of necrotic to inflamed appendicitis in the entire cohort was 0.24. Multivariate analysis reveals that necrosis of the appendix is more common in children and the elderly and that the proportion of patients with necrosis does not change with increasing interval to surgery. DISCUSSION: Our observations show that appendicitis is not more likely to lead to perforation if a short delay prior to surgery is allowed. In addition, our findings add weight to the increasing volume of data showing that necrosis of the appendix is a disease different from simple inflammation. PMID- 24345980 TI - Hip resurfacing arthroplasty versus large-diameter head metal-on-metal total hip arthroplasty: comparison of three designs from the Finnish Arthroplasty Register. AB - BACKGROUND AND AIMS: Large headed metal-on-metal total hip arthroplasty may produce more metal ions than hip resurfacing arthroplasty. Increased metal-ion levels may be associated with higher revision rates due to adverse reaction to metal debris. The purpose of our study was to compare the survivorship of three hip resurfacing arthroplasty designs with their analogous cementless large diameter head metal-on-metal total hip arthroplasties. MATERIAL AND METHODS: Based on data obtained from the Finnish Arthroplasty Register, the revision risks of three metal-on-metal hip resurfacing arthroplasty/total hip arthroplasty design couples performed during 2001-2011 were analyzed using the Cox regression model. RESULTS: In the Cox regression analysis for compared design pairs adjusted for age, gender, operated side, head size, diagnosis, and implant, there was no statistically significant difference in revision risk between ReCap hip resurfacing arthroplasty and Bimetric/ReCap total hip arthroplasty (risk ratio = 1.43, confidence interval = 0.95-2.14, p = 0.09) or between Birmingham hip resurfacing arthroplasty and Synergy/Birmingham hip resurfacing total hip arthroplasty (risk ratio = 1.35, confidence interval = 0.75-2.43, p = 0.31). However, the revision risk of Corail and Summit/articular surface replacement total hip arthroplasty (ASR HRA) was significantly increased compared to ASR HRA. (risk ratio = 0.73, confidence interval = 0.54-0.98, p = 0.04). CONCLUSION: We conclude that the short-term revision risk of large headed metal-on-metal total hip arthroplasties was not increased compared to analogous hip resurfacing arthroplasties in two out of three devices studied at a nationwide level. There may be implant-related factors having an effect on the success of single manufacturer devices. However, more information on the incidence of adverse soft tissue reactions in these patient cohorts is needed. PMID- 24345981 TI - Surgical management of gynecomastia: 20 years' experience. AB - BACKGROUND: Gynecomastia, breast hypertrophy in men, is a common finding. The diagnosis is clinical, and ancillary tests may be performed; however, there is no unanimity in the literature about their use or utility. The mainstay of management is conservative, with a minority of patients being operated on. The surgical treatment of gynecomastia is not restricted to one discipline and is performed by plastic, general, and pediatric surgeons. The aim of this study was to assess the experience treating gynecomastia in a university hospital and the practices of the different surgical disciplines in the diagnosis and surgical treatment of gynecomastia; this knowledge could be used for the formulation of guidelines and the allocation of health-care resources. METHODS: SETTING: a university medical center. DESIGN: A retrospective cohort study in which all records of patients operated on for gynecomastia over a 20-year period were retrieved. Data were obtained concerning patient demographics, responsible surgical discipline, the workup and etiology found, the surgical technique used, the occurrence of reoperations and revisions, and the use of pathological examination and its results. RESULTS: A total of 179 patients were treated. There was a difference between the patient groups operated on by the different disciplines regarding the indication, the workup, as well as in the operative techniques used. Plastic surgeons performed more bilateral operations than the other disciplines. Surgeons used more radiology and cytology testing. CONCLUSION: These results most probably represent differences in the population and pathologies treated. This is possibly due to a bias in the referrals by primary care physicians. PMID- 24345982 TI - Clinical outcome, echocardiographic assessment, neurohormonal and collagen turnover markers in low-fl ow severe aortic stenosis with high transvalvular gradient. AB - INTRODUCTION: Patients with severe aortic stenosis (AS), high mean gradient (HMG), and preserved left ventricular ejection fraction (LVEF) may present with paradoxical "low flow" (LF). OBJECTIVES: The aim of the study was to assess the potential effect of cardiac collagen metabolism on the HMG/LF phenomenon in patients with severe AS and to determine a clinical and echocardiographic pattern of these patients. PATIENTS AND METHODS: We assessed a clinical status of 89 patients, aged over 64 years, with severe AS, HMG, and preserved LVEF (>=50%). Cardiac structure and function as well as systemic arterial hemodynamics were assessed with echocardiography, conventional Doppler, and tissue Doppler imaging. Moreover, plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), procollagen III N-terminal propeptide (PIIINP), carboxyterminal telopeptide of collagen type I, matrix metallopeptidase 9, and inhibitor of matrix metalloproteinase type 1 were evaluated. We analyzed 2 groups of patients: with normal flow (stroke volume index [SVI], >=35 ml/m2; n = 70) and with LF (SVI, <35 ml/m2; n = 19). RESULTS: Patients with LF were older, had a larger left atrium and left atrial volume index, smaller aortic valve area, lower energy loss index, stroke work, mitral flow E velocity, mitral annular E' and S' velocities and systemic arterial compliance, higher relative left ventricular wall thickness, E/E', systemic arterial resistance and valvulo-arterial impedance. We observed a correlation between SVI and NT-proBNP, PIIINP, and selected parameters of cardiac structure and function. CONCLUSIONS: In patients with severe AS, HMG and preserved LVEF, the LF is related to a more severe obstruction, altered aortic hemodynamics, cardiac dysfunction, and higher blood levels of NT-proBNP. An inverse association between PIIINP and SVI may indicate enhanced tissue fibrosis as an underlying pathology. PMID- 24345983 TI - Health effects of sodium and potassium in humans. AB - PURPOSE OF REVIEW: Review new articles that clarify the health consequences of changes in dietary sodium and potassium and that characterize adherence to sodium and potassium intake guideline recommendations. RECENT FINDINGS: New clinical trials meta-analyses provide additional documentation of the blood pressure (BP) lowering effects of Na reduction and K supplement, with no adverse effects of Na reduction on cholesterol in steady-state settings. BP is the leading preventable risk factor for worldwide mortality and disability-adjusted life years. A preponderance of cohort studies has identified a direct relationship between dietary sodium and cardiovascular disease (CVD), specially stroke, and an inverse relationship between dietary potassium and CVD. However, these studies are of insufficient quality to support firm conclusions. Modeling studies of sodium reduction in the general population have identified an enormous potential for health benefits. Current intake of dietary sodium and potassium fails to meet guideline recommendations. SUMMARY: There is abundant evidence that a reduction in dietary sodium and increase in potassium intake decreases BP, incidence of hypertension, and morbidity and mortality from CVD. However, there is no credible evidence that existing policies have been effective in achieving population goals for dietary sodium and potassium intake in the USA. PMID- 24345984 TI - Gene-diet interaction and weight loss. AB - PURPOSE OF REVIEW: The purpose of this review is to summarize recent advances in investigations of dietary factors, genetic factors, and their interactive effects on obesity and weight loss. RECENT FINDINGS: Even with a tremendous body of research conducted, controversy still abounds regarding the relative effectiveness of various weight-loss diets. Recent advances in genome-wide association studies have made great strides in unraveling the genetic basis of regulation of body weight. In prospective cohorts, reproducible evidence is emerging to show interactions between genetic factors and dietary factors such as sugar-sweetened beverage on obesity. In randomized clinical trials, individuals' genotypes have also been found to modify diet interventions on weight loss, weight maintenance, and changes in related metabolic traits such as lipids, insulin resistance, and blood pressure. However, replication, functional exploration, and translation of the findings into personalized diet interventions remain the chief challenges. SUMMARY: Preliminary but promising data have emerged to lend support to gene-diet interaction in determining weight loss and maintenance; and studies in the area hold great promise to inform future personalized diet interventions on the reduction of obesity and related health problems. PMID- 24345986 TI - Sugar-sweetened beverages and body weight. AB - PURPOSE OF REVIEW: Given the high prevalence of obesity in the USA, much recent attention has focused on dietary strategies for weight control. Several medical and scientific societies currently recommend reducing consumption of sugar sweetened beverages (SSBs). However, the evidence base for a public health recommendation has been a topic of debate. The purpose of this review is not to underscore the debate but rather to consider how recently published data pertaining to SSBs contribute to the evidence base for preventing and treating obesity, with application to caring for patients. RECENT FINDINGS: Consumption of SSBs remains prevalent in the USA. Emerging data from epidemiological studies and clinical trials indicate that consumption contributes to positive energy balance and reducing consumption has beneficial effects on body weight. Some individuals may be more susceptible to the adverse effects of consuming SSBs owing to their ethnicity or genetic predisposition. Plausible physiological mechanisms link consumption of SSBs with weight control. SUMMARY: Available data provide an evidence base for counselling patients to reduce consumption of SSBs. Nevertheless, additional research is needed to strengthen the evidence base, particularly studies aimed at understanding susceptibility to the adverse effects of consuming SSBs on body weight and mechanisms for these effects. PMID- 24345985 TI - Macronutrient replacement options for saturated fat: effects on cardiovascular health. AB - PURPOSE OF REVIEW: The purpose of this review is to discuss macronutrient replacement options for saturated fatty acids (SFAs) to optimize cardiovascular disease (CVD) risk reduction. RECENT FINDINGS: Dietary recommendations advise decreasing SFAs. There is convincing evidence that replacing SFAs with unsaturated fat, both omega-6 and omega-3 polyunsaturated fatty acids, reduces CVD risk. Monounsaturated fatty acid substitution for SFAs also decreases CVD risk. Replacing SFAs with refined carbohydrate does little to alter CVD risk, whereas whole-grain CHO or lean protein substitutions beneficially affect CVD risk. SUMMARY: Modifying the macronutrient composition of the diet by replacing SFAs with unsaturated fatty acids, as well as lean protein and carbohydrate from whole grains, all lower CVD risk. Research is needed to identify food sources of macronutrients that optimize CVD risk reduction. PMID- 24345987 TI - Dyslipidemia, malnutrition, inflammation, cardiovascular disease and mortality in chronic kidney disease. AB - PURPOSE OF REVIEW: Dyslipidemia, malnutrition and inflammation are common in patients with chronic kidney disease (CKD) and are strongly associated with cardiovascular disease (CVD) and increased mortality. The epidemiology of dyslipidemia and its interactions with malnutrition and inflammation in CKD patients have been the subject of much interest in the past decade. Recent clinical trials have explored the effects of statins on CVD specifically in CKD patients. RECENT FINDINGS: Whereas the risk relationship between total cholesterol level and CVD morbidity and mortality is direct, strong and progressive in CKD patients without malnutrition and inflammation, it is inconsistent and often paradoxical in those with malnutrition and inflammation. Accumulating evidence demonstrates that statins reduce significantly the risk of CVD in CKD patients before the initiation of dialysis. However, the beneficial effect of statins in CKD patients on dialysis is uncertain. In CKD patients on dialysis, malnutrition and inflammation pose a higher risk for CVD than dyslipidemia. SUMMARY: In CKD patients, the risk of CVD associated to dyslipidemia is complex and is modified by malnutrition and inflammation. PMID- 24345988 TI - Non-nutritive sweeteners: evidence for benefit vs. risk. AB - PURPOSE OF REVIEW: Intake of added sugars in the American diet is high and has been linked to weight gain and adverse effects on glycemic control and diabetes. Several national health organizations recommend decreasing added sugars intake. Among the many strategies to consider to achieve this reduction is substitution with non-nutritive sweeteners (NNS - artificial sweeteners and stevia). The purpose of this review is to critically examine existing evidence for this strategy. RECENT FINDINGS: Short-term intervention studies suggest that NNS, when substituted for added sugars, may be useful in supporting energy intake reduction, and promoting glycemic control and weight management. However, the magnitude of effect in these studies has ranged from modest to null. Compensatory eating behaviors likely diminish, and in some cases negate, potential effects. Findings from longer-term observational studies that examine associations between NNS use and obesity or type 2 diabetes are potentially confounded by reverse causality. SUMMARY: Existing data are insufficient to clearly support or refute the effectiveness of substitution with NNS as a means of reducing added sugar intake. It is important to not lose sight of the impact of incorporating NNS containing beverages and foods on overall diet quality when assessing potential health benefits vs. risks. PMID- 24345989 TI - Updates on apolipoprotein CIII: fulfilling promise as a therapeutic target for hypertriglyceridemia and cardiovascular disease. AB - PURPOSE OF REVIEW: The lipid hypothesis of atherosclerosis is mainly predicated on the function of apolipoprotein (apo)B lipoproteins, which promote atherosclerosis, and apoA lipoproteins, which prevent it. However, accumulating evidence suggests causal roles of other apolipoproteins, abundant surface components of apoB and apoA lipoprotein, in promoting atherosclerosis and other metabolic diseases. This article reviews recent literature on one such apolipoprotein: apoCIII. RECENT FINDINGS: Population studies have consistently demonstrated that plasma apoCIII strongly predicts cardiovascular disease. ApoCIII's atherogenicity was traditionally attributed to hypertriglyceridemia because of its inhibition on the lipolysis of triglyceride-rich lipoproteins. Recent evidence expands this function and reveals apoCIII's key role in hepatic assembly and secretion of triglyceride-rich lipoproteins. In addition to these indirect atherogenic functions mediated through dyslipidemia, recent research discovers that apoCIII directly provoke proinflammatory responses in vascular cells, including monocytes and endothelial cells. These direct atherogenic effects are dependent on apoCIII. ApoCIII is also involved in pancreatic beta cell biology and contributes to type I diabetes. SUMMARY: Recent data further strengthen the theory that apoCIII exerts strong atherogenic functions through both indirect and direct mechanisms. Encouraging results from early stage clinical trials demonstrate that modulating apoCIII per se is a novel and potent therapeutic approach to managing dyslipidemia and cardiovascular disease risk. PMID- 24345990 TI - Update on cardiometabolic health effects of omega-3 fatty acids. AB - PURPOSE OF REVIEW: The fish fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may promote cardiometabolic health. This review summarizes the results of recent meta-analyses of prospective studies on cardiovascular diseases, diabetes type 2 and markers of atherosclerosis and thrombosis. RECENT FINDINGS: The results of recently published meta-analyses of prospective cohort studies showed that eating fish once a week was associated with a 16% lower risk of fatal coronary heart disease (CHD) and a 14% lower risk of stroke incidence, but was not related to heart failure. Fish consumption may be associated with a higher risk of diabetes in Western countries and a lower risk in Asian countries. Recent meta-analyses of randomized controlled trials showed that EPA-DHA supplementation reduced the risk of fatal CHD and sudden death by 10% of which the latter was not significant. Extra EPA-DHA did not reduce the risk of heart failure, stroke and cardiac arrhythmias. omega-3 fatty acid (FA) supplementation did reduce markers of ventricular fibrillation, inflammation and endothelial dysfunction and platelet aggregation. SUMMARY: There is strong evidence for a protective effect of omega-3 FA on fatal CHD and for some markers of atherosclerosis and thrombosis. Consistent results were not obtained for other vascular diseases and diabetes. omega-3 FA reduced markers of ventricular fibrillation but did not reduce the risk of atrial fibrillation. PMID- 24345991 TI - Against autonomy response. PMID- 24345992 TI - Comments on death, posthumous harm and bioethics. PMID- 24345993 TI - Moral bioenhancement is dangerous. PMID- 24345994 TI - Wait times and national health policy. AB - Many arguments against US healthcare reform appeal to facts about wait times, and wait times are also discussed in debates about national health policy in other industrialised countries. This paper points out that there are several different ways to measure wait times. We currently measure them in one way, and this paper describes an alternative. The most reasonable assessments of US and international health reforms need to rely on the alternative method, and so when critics of health reform rely on the standard method, their arguments are unsound. PMID- 24345995 TI - Taylor on posthumous organ procurement. PMID- 24345996 TI - Are we unfit for the future? PMID- 24345997 TI - Against autonomy? PMID- 24345998 TI - Ulnar polydactyly: long-term outcomes and cost-effectiveness of surgical clip application in the newborn. AB - BACKGROUND: Postaxial polydactyly type B (PAPD-B) refers to the nonfunctional, floppy extra digit on the ulnar border of the hand. Suture ligation is applied in the newborn unit if the base is narrow or pedunculated. However, wart-like scars, residual bumps, or neuromas are frequent complications. Wider-based extra digits are treated at a later age by surgical excision under general anesthesia. Surgical clip application expands the indications for PAPD treatment in the newborn unit or outpatient setting with lesser incidences of complications. DESIGN: A retrospective review identified 231 hands with PAPD-B in 132 newborns treated with surgical clips between January 1, 1996, and November 30, 2010, having a minimum of 2 years of follow-up. Medical records were queried for complications, revision procedures, and parent satisfaction. A relative cost survey compares the costs of surgical clips to surgery. CONCLUSIONS: In all, 16 extremities in 9 patients (7%) required surgical scar revision. No wound complications were noted. PMID- 24345999 TI - Fever in a returning traveler: the importance of a good history, physical examination, and focused laboratory testing. PMID- 24346000 TI - Involvement of alanine racemase in germination of Bacillus cereus spores lacking an intact exosporium. AB - The L-alanine mediated germination of food isolated Bacillus cereus DSA 1 spores, which lacked an intact exosporium, increased in the presence of D-cycloserine (DCS), which is an alanine racemase (Alr) inhibitor, reflecting the activity of the Alr enzyme, capable of converting L-alanine to the germination inhibitor D alanine. Proteomic analysis of the alkaline extracts of the spore proteins, which include exosporium and coat proteins, confirmed that Alr was present in the B. cereus DSA 1 spores and matched to that encoded by B. cereus ATCC 14579, whose spore germination was strongly affected by the block of conversion of L- to D alanine. Unlike ATCC 14579 spores, L-alanine germination of B. cereus DSA 1 spores was not affected by the preincubation with DCS, suggesting a lack of restriction in the reactant accessibility. PMID- 24346001 TI - Electrospun polyurethane-core and gelatin-shell coaxial fibre coatings for miniature implantable biosensors. AB - The aim of this study was to introduce bioactivity to the electrospun coating for implantable glucose biosensors. Coaxial fibre membranes having polyurethane as the core and gelatin as the shell were produced using a range of polyurethane concentrations (2, 4, 6 and 8% wt/v) while keeping gelatin concentration (10% wt/v) constant in 2,2,2-trifluoroethanol. The gelatin shell was stabilized using glutaraldehyde vapour. The formation of core-shell structure was confirmed using transmission/scanning electron microscopy and FTIR. The coaxial fibre membranes showed uniaxial tensile properties intermediate to that of the pure polyurethane and the gelatin fibre membranes. The gelatin shell increased hydrophilicity and glucose transport flux across the coaxial fibre membranes. The coaxial fibre membranes having small fibre diameter (541 nm) and a thick gelatin shell (52%) did not affect the sensor sensitivity, but decreased sensor's linearity in the long run. In contrast, thicker coaxial fibre membranes (1133 nm) having a thin gelatin shell (34%) maintained both sensitivity and linearity for the 84 days of the study period. To conclude, polyurethane-gelatin coaxial fibre membranes, due to their faster permeability to glucose, tailorable mechanical properties and bioactivity, are potential candidates for coatings to favourably modify the host responses to extend the reliable in vivo lifetime of implantable glucose biosensors. PMID- 24346002 TI - Loneliness mediates the relationship between internalised stigma and depression among patients with psychotic disorders. AB - BACKGROUND: Stigmatisation is a source of chronic stress and a major barrier to recovery for people with mental illnesses. The internalisation of stigma can have a negative impact on an individual's social relations and lead to feelings of loneliness and depression. AIM: This research is aimed at testing the hypothesis that the internalised stigma of mental illness contributes to the intensification of depressive symptoms indirectly, through its impact on feelings of loneliness. METHODS: A total of 110 individuals with diagnoses of psychotic disorders (International Classification of Diseases-10th Revision (ICD-10): F20-F29) were assessed with measures of internalised stigma, loneliness, depression, positive and negative symptoms and global functioning. The ordinary least squares regression was used for data analysis. RESULTS: After adding loneliness to the regression model, the initially significant impact of internalised stigma on depressive symptoms disappeared. As expected, loneliness proved to be a full mediator in the relationship between stigma and depression. CONCLUSION: The study findings provide useful insights into the mechanisms of the harmful effects of stigma on people with mental illness. Internalised stigma and loneliness should be considered important targets for interventions aiming to promote recovery. PMID- 24346003 TI - Bladder cancer: Always consider extravesical sites when BCG fails. PMID- 24346004 TI - Kidney cancer: Temsirolimus fails to expand its role in patients with mRCC. PMID- 24346005 TI - Can PDE5 inhibitors boost brain function? PMID- 24346006 TI - Thromboprophylaxis and bleeding diathesis in minimally invasive stone surgery. AB - With populations ageing and active treatment of urinary stones increasingly in demand, more patients with stones are presenting with an underlying bleeding disorder or need for regular thromboprophylaxis, by means of antiplatelet and other medication. A practical guide to thromboprophylaxis in the treatment of urinary tract lithiasis has not yet been established. Patients can be stratified according to levels of risk of arterial and venous thromboembolism, which influence the requirements for antiplatelet and anticoagulant medications, respectively. Patients should also be stratified according to their risk of bleeding. Consideration of the combined risks of bleeding and thromboembolism should determine the perioperative thromboprophylactic strategy. The choice of shockwave lithotripsy, percutaneous nephrolithotomy or ureteroscopy with laser lithotripsy for treatment of lithiasis should be determined with regard to these risks. Although ureteroscopy is the preferred method in high-risk patients, shockwave lithotripsy and percutaneous nephrolithotomy can be chosen when indicated, if appropriate guidelines are strictly followed. PMID- 24346009 TI - Bladder cancer: Tumour recurrence after radical nephroureterectomy for UTUC. PMID- 24346008 TI - Male urethral strictures and their management. AB - Male urethral stricture disease is prevalent and has a substantial impact on quality of life and health-care costs. Management of urethral strictures is complex and depends on the characteristics of the stricture. Data show that there is no difference between urethral dilation and internal urethrotomy in terms of long-term outcomes; success rates range widely from 8-80%, with long-term success rates of 20-30%. For both of these procedures, the risk of recurrence is greater for men with longer strictures, penile urethral strictures, multiple strictures, presence of infection, or history of prior procedures. Analysis has shown that repeated use of urethrotomy is not clinically effective or cost-effective in these patients. Long-term success rates are higher for surgical reconstruction with urethroplasty, with most studies showing success rates of 85-90%. Many techniques have been utilized for urethroplasty, depending on the location, length, and character of the stricture. Successful management of urethral strictures requires detailed knowledge of anatomy, pathophysiology, proper patient selection, and reconstructive techniques. PMID- 24346011 TI - Epidemiology: Largest national survey offers insight into sexual health in Britain. PMID- 24346012 TI - Surgery: Is indocyanine green dye useful in robotic surgery? PMID- 24346015 TI - Bladder cancer: Conditional survival after radical cystectomy. PMID- 24346016 TI - Kidney cancer: Tumour shrinkage of 10% is a reproducible measure in mRCC. PMID- 24346017 TI - Multiaxial high-modularity spinopelvis (HMSP) fixation device in neuromuscular scoliosis: a comparative study. AB - PURPOSE: To compare radiological and clinical results in patients operated for neuromuscular scoliosis with pelvic fixation using high-modularity spinopelvic screw (HMSP) designed by authors. METHODS: Of 54 patients with neuromuscular scoliosis, group 1 comprised of 27 patients with conventional pelvic fixation; and group 2 comprised of 27 patients using HMSP. Results were evaluated radiologically and functionally. We compared preoperative and postoperative complications, especially the loosening or breakage of spinopelvis fixation device, failure of fixation, and the change of shadow around the spinopelvis fixation device. RESULTS: There was no difference of correctional power, preoperative average Cobb's angle of each group was 79.8 and 75 to postoperative 30.2 and 28.3 (P < 0.05). Pelvic obliquity improved from average 18.3 degrees 8.9 degrees in group I and average 24.3 degrees -12.5 degrees in group II (P < 0.05). However, there was no difference between two groups (P > 0.05). Average blood loss was 2,698 ml in group 1 and 2,414.8 ml in group 2 (P > 0.05). Average operative time was 360 min in group 1 and 332 min in group 2 (P = 0.30). There was no difference found between two groups regarding gait and functional evaluation. On the all cases of group 1 and 2, the change of shadow around the spinopelvis fixation device was observed. There was one case of the fracture of spinopelvis fixation device in group I. CONCLUSION: There was no difference of Cobb's angle and correctional power between the groups using HMSP when compared with the group using standard spinopelvis fixation device. Therefore, HMSP can be used more effectively in case of neuromuscular scoliosis. PMID- 24346018 TI - Depletion of circulating blood NOS3 increases severity of myocardial infarction and left ventricular dysfunction. AB - Nitric oxide (NO) derived from endothelial NO synthase (NOS3) plays a central role in myocardial ischemia/reperfusion (I/R)-injury. Subsets of circulating blood cells, including red blood cells (RBCs), carry a NOS3 and contribute to blood pressure regulation and RBC nitrite/nitrate formation. We hypothesized that the circulating blood born NOS3 also modulates the severity of myocardial infarction in disease models. We cross-transplanted bone marrow in wild-type and NOS3(-/-) mice with wild-type mice, producing chimeras expressing NOS3 only in vascular endothelium (BC-/EC+) or in both blood cells and vascular endothelium (BC+/EC+). After 60-min closed-chest coronary occlusion followed by 24 h reperfusion, cardiac function, infarct size (IS), NOx levels, RBCs NO formation, RBC deformability, and vascular reactivity were assessed. At baseline, BC-/EC+ chimera had lower nitrite levels in blood plasma (BC-/EC+: 2.13 +/- 0.27 MUM vs. BC+/EC+ 3.17 +/- 0.29 MUM; *p < 0.05), reduced DAF FM associated fluorescence within RBCs (BC-/EC+: 538.4 +/- 12.8 mean fluorescence intensity (MFI) vs. BC+/EC+: 619.6 +/- 6.9 MFI; ***p < 0.001) and impaired erythrocyte deformability (BC-/EC+: 0.33 +/- 0.01 elongation index (EI) vs. BC+/EC+: 0.36 +/- 0.06 EI; *p < 0.05), while vascular reactivity remained unaffected. Area at risk did not differ, but infarct size was higher in BC-/EC+ (BC-/EC+: 26 +/- 3 %; BC+/EC+: 14 +/- 2 %; **p < 0.01), resulting in decreased ejection fraction (BC-/EC+ 46 +/- 2 % vs. BC+/EC+: 52 +/- 2 %; *p < 0.05) and increased end-systolic volume. Application of the NOS inhibitor S-ethylisothiourea hydrobromide was associated with larger infarct size in BC+/EC+, whereas infarct size in BC-/EC+ mice remained unaffected. Reduced infarct size, preserved cardiac function, NO levels in RBC and RBC deformability suggest a modulating role of circulating NOS3 in an acute model of myocardial I/R in chimeric mice. PMID- 24346019 TI - Antitumor activity of celecoxib, a selective cyclooxygenase-2 inhibitor, in medullary thyroid carcinoma. AB - The purpose of this study was to investigate the mechanisms of the antitumor effect of celecoxib (CXB) in the treatment of human medullary thyroid carcinoma (MTC). Human MTC TT cells were cultured with different concentrations (0, 20, 40, 60 umol/l) of CXB following 0-72 h in vitro. An MTT (3-[4,5-dimethylthiazol-2-yl] 2,5-diphenyltetrazolium bromide) assay was used to determine the growth inhibition of MTC in vitro. Flow cytometry was performed to analyze the cell cycle of TT cells. Levels of prostaglandin E2 (PGE2) were measured by enzyme linked immunosorbent assay (ELISA) method. The expression profile of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) was measured by western blot analysis. In the present study, it was identified that CXB inhibited TT cell proliferation and induced apoptosis in a dose- and time dependent manner. The cell cycle was arrested at G0/G1 and the percentage of cells in S phase was markedly decreased. The expression levels of PGE2 were inhibited by CXB. CXB effectively downregulated the expression of COX-2 and VEGF in a dose- and time-dependent manner. These data demonstrated that CXB inhibited the proliferation of MTC TT cells in vitro and thus may be effective as an antitumor therapy for human MTC. PMID- 24346022 TI - Publication of surgical outcomes-data: whose team are we on? PMID- 24346023 TI - Age-related changes in EEG power spectra in infants during sevoflurane wash-out. AB - BACKGROUND: Few electroencephalography (EEG) data are available in anaesthetized infants. This study aimed to identify EEG characteristics that might warn of awakening (AW) from sevoflurane anaesthesia in infants. METHODS: Twenty intubated infants [aged 39-77 weeks post-menstrual age (PMA)] were studied after surgery during sevoflurane wash-out. EEG was recorded at the end of surgery and throughout emergence. Changes in EEG time and frequency domains were described. RESULTS: At the end of surgery, mean end-tidal sevoflurane concentration was 2.3% (range 1.5-3.5) before wash-out and reduced to 0.3% (0.1-0.6) when AW began. On AW, movement artifacts made signals difficult to interpret. Before awakening, most power was within frequencies <=4 Hz, but trends over time were variable. Summated power in frequencies between 20 and 70 Hz was almost always <5 uV(2). During anaesthesia, there were two common power spectra: infants >52 weeks PMA had obvious summated power in the frequency range 5-20 Hz (P5-20 Hz) (mean 308, median 320, range 110-542 uV(2)), which decreased before awakening began [mean decrease 252 uV(2) (95% CI 153-351)], whereas younger infants had low P5-20 Hz throughout. P5-20 Hz during anaesthesia increased with age; power in this frequency band of ~100 uV(2) separated infants younger and older than 52 weeks PMA. CONCLUSIONS: During sevoflurane wash-out, decreasing P5-20 Hz might warn of impending AW in infants >3 months old, but not in younger infants. PMID- 24346021 TI - Association between neuraxial analgesia, cancer progression, and mortality after radical prostatectomy: a large, retrospective matched cohort study. AB - BACKGROUND: Systemic opioids are immunosuppressive, which could promote tumour recurrence. We, therefore, test the hypothesis that supplementing general anaesthesia with neuraxial analgesia improves long-term oncological outcomes in patients having radical prostatectomy for adenocarcinoma. METHODS: Patients who had general anaesthesia with neuraxial analgesia (n=1642) were matched 1:1 based on age, surgical year, pathological stage, Gleason scores, and presence of lymph node disease with those who had general anaesthesia only. Medical records were reviewed. Outcomes of interest were systemic cancer progression, recurrence, prostate cancer mortality, and all-cause mortality. Data were analysed using stratified proportional hazards regression, the Kaplan-Meier method, and log-rank tests. The median follow-up was 9 yr. RESULTS: After adjusting for comorbidities, positive surgical margins, and adjuvant hormonal and radiation therapies within 90 postoperative days, general anaesthesia only was associated with increased risk for systemic progression [hazard ratio (HR)=2.81, 95% confidence interval (CI) 1.31-6.05; P=0.008] and higher overall mortality (HR=1.32, 95% CI 1.00-1.74; P=0.047). Although not statistically significant, similar findings were observed for the outcome of prostate cancer deaths (adjusted HR=2.2, 95% CI 0.88-5.60; P=0.091). CONCLUSIONS: This large retrospective analysis suggests a possible beneficial effect of regional anaesthetic techniques on oncological outcomes after prostate surgery for cancer; however, these findings need to be confirmed (or refuted) in randomized trials. PMID- 24346025 TI - High-risk sex and displacement among refugees and surrounding populations in 10 countries: the need for integrating interventions. AB - INTRODUCTION: Between 2004 and 2012, the United Nations High Commissioner for Refugees conducted behavioural surveillance surveys in 27 separate communities in 10 countries. METHODS: Random systematic or two-stage cluster sampling was used among participants of age 15-49 years, using a modified standard questionnaire. We conducted descriptive data analysis and multivariable logistic regression to identify factors independently associated with multiple sexual partnerships. RESULTS: Of 27 sites surveyed comprising 24 219 individuals, 11 refugee and surrounding communities were paired. Recent displacement comprised less than 10% of participants. Visiting neighbouring communities varied from 8.6 to 74.4%. Multiple sexual partnerships varied from 2.7% in Sudan to 32.5% in Tanzania. Condom use during last sex was low in most of the communities (<5%). The prevalence of forced sex was similar in paired sites, with intimate partner violence being the most frequent, ranging between 1.0 and 4.6% in camps and 0.8 and 3.6% in communities, with the exception of Nepal (10.8 and 9.8%). Being away from home for more than 1 month and having lived in community for less than 12 months was associated with multiple partnerships in six and five of 16 sites, respectively. CONCLUSION: In the largest study of paired sites of refugees in protracted refugee camps and surrounding nationals, data showed no consistent difference in levels of risky sexual behaviour and there was much variation among the different groups. The prevention strategies should be targeted in a highly integrated manner for both the communities. Forced sex among women was reported at similar levels among refugees and nationals, with intimate partner violence being the most common. These findings should reduce stigma and discrimination against refugees. PMID- 24346024 TI - Surface topography regulates wnt signaling through control of primary cilia structure in mesenchymal stem cells. AB - The primary cilium regulates cellular signalling including influencing wnt sensitivity by sequestering beta-catenin within the ciliary compartment. Topographic regulation of intracellular actin-myosin tension can control stem cell fate of which wnt is an important mediator. We hypothesized that topography influences mesenchymal stem cell (MSC) wnt signaling through the regulation of primary cilia structure and function. MSCs cultured on grooves expressed elongated primary cilia, through reduced actin organization. siRNA inhibition of anterograde intraflagellar transport (IFT88) reduced cilia length and increased active nuclear beta-catenin. Conversely, increased primary cilia assembly in MSCs cultured on the grooves was associated with decreased levels of nuclear active beta-catenin, axin-2 induction and proliferation, in response to wnt3a. This negative regulation, on grooved topography, was reversed by siRNA to IFT88. This indicates that subtle regulation of IFT and associated cilia structure, tunes the wnt response controlling stem cell differentiation. PMID- 24346034 TI - Immunology: glyco-engineering 'super-self'. PMID- 24346036 TI - A new hemodynamic model shows that temporal perturbations of cerebral blood flow and metabolic rate of oxygen cannot be measured individually using functional near-infrared spectroscopy. AB - A recent dynamic model relates the functional near-infrared spectroscopy (fNIRS) measurements to hemodynamic and metabolic parameters. This note reports modified expressions of the new model in terms of cerebral blood volume (CBV), blood flow (CBF) and metabolic rate of oxygen (CMRO2). On the basis of these modified expressions, the new model reproduces known steady state relationships between hemoglobin concentration, CBF and CMRO2, and yields time-dependent relationships that describe transient changes. This new model allows for the translation of the fNIRS measurements into dynamic measures of DeltaCBV/CBV0 and the difference DeltaCBF/CBF0 - DeltaCMRO2/CMRO2|0, provided that some baseline physiological parameters and a relationship between overall, arterial and venous blood volume changes are assumed. PMID- 24346037 TI - Multiresolution imaging. AB - Imaging resolution has been standing as a core parameter in various applications of vision. Mostly, high resolutions are desirable or essential for many applications, e.g., in most remote sensing systems, and therefore much has been done to achieve a higher resolution of an image based on one or a series of images of relatively lower resolutions. On the other hand, lower resolutions are also preferred in some cases, e.g., for displaying images in a very small screen or interface. Accordingly, algorithms for image upsampling or downsampling have also been proposed. In the above algorithms, the downsampled or upsampled (super resolution) versions of the original image are often taken as test images to evaluate the performance of the algorithms. However, there is one important question left unanswered: whether the downsampled or upsampled versions of the original image can represent the low-resolution or high-resolution real images from a camera? To tackle this point, the following works are carried out: 1) a multiresolution camera is designed to simultaneously capture images in three different resolutions; 2) at a given resolution (i.e., image size), the relationship between a pair of images is studied, one gained via either downsampling or super-resolution, and the other is directly captured at this given resolution by an imaging device; and 3) the performance of the algorithms of super-resolution and image downsampling is evaluated by using the given image pairs. The key reason why we can effectively tackle the aforementioned issues is that the designed multiresolution imaging camera can provide us with real images of different resolutions, which builds a solid foundation for evaluating various algorithms and analyzing the images with different resolutions, which is very important for vision. PMID- 24346035 TI - The role of iron and reactive oxygen species in cell death. AB - The transition metal iron is essential for life, yet potentially toxic iron catalyzed reactive oxygen species (ROS) are unavoidable in an oxygen-rich environment. Iron and ROS are increasingly recognized as important initiators and mediators of cell death in a variety of organisms and pathological situations. Here, we review recent discoveries regarding the mechanism by which iron and ROS participate in cell death. We describe the different roles of iron in triggering cell death, targets of iron-dependent ROS that mediate cell death and a new form of iron-dependent cell death termed ferroptosis. Recent advances in understanding the role of iron and ROS in cell death offer unexpected surprises and suggest new therapeutic avenues to treat cancer, organ damage and degenerative disease. PMID- 24346038 TI - On-chip light sheet illumination enables diagnostic size and concentration measurements of membrane vesicles in biofluids. AB - Cell-derived membrane vesicles that are released in biofluids, like blood or saliva, are emerging as potential non-invasive biomarkers for diseases, such as cancer. Techniques capable of measuring the size and concentration of membrane vesicles directly in biofluids are urgently needed. Fluorescence single particle tracking microscopy has the potential of doing exactly that by labelling the membrane vesicles with a fluorescent label and analysing their Brownian motion in the biofluid. However, an unbound dye in the biofluid can cause high background intensity that strongly biases the fluorescence single particle tracking size and concentration measurements. While such background intensity can be avoided with light sheet illumination, current set-ups require specialty sample holders that are not compatible with high-throughput diagnostics. Here, a microfluidic chip with integrated light sheet illumination is reported, and accurate fluorescence single particle tracking size and concentration measurements of membrane vesicles in cell culture medium and in interstitial fluid collected from primary human breast tumours are demonstrated. PMID- 24346039 TI - Aetiology of infantile nystagmus. AB - PURPOSE OF REVIEW: Mechanisms underlying infantile nystagmus are unclear. The aim of this review is to outline recent developments in understanding the aetiology of infantile nystagmus. RECENT FINDINGS: There have been advances in understanding mechanisms underlying idiopathic infantile nystagmus, which has progressed through determining the role of the FRMD7 gene in controlling neurite outgrowth, and albinism, in which recent models have investigated the possibility of retinal miswiring leading to nystagmus. We also briefly review aetiology of infantile nystagmus in afferent visual deficits caused by ocular disease, and PAX6 mutations. Improved phenotypical characterization of all these infantile nystagmus subtypes has been achieved recently through high-resolution retinal imaging using optical coherence tomography. Several new hypotheses proposing common mechanisms that could underlie various infantile nystagmus subtypes are also highlighted. SUMMARY: Although there is still no consensus of opinion regarding the mechanisms causing infantile nystagmus, identification of new genes and determining their cellular function, phenotypical characterization of genetic subtypes, and improvements in animal models have significantly advanced our understanding of infantile nystagmus. These recent developments pave the way to achieving a much clearer picture of infantile nystagmus aetiology in the future. PMID- 24346040 TI - Self-plagiarism in scientific journals: an emerging discussion. PMID- 24346041 TI - Oral research in the world today. PMID- 24346042 TI - Effects of opioids on local anesthesia in the rat: a codeine and tramadol study. AB - Opioids are central analgesics that act on the CNS (central nervous system) and PNS (peripheral nervous system). We investigated the effects of codeine (COD) and tramadol (TRAM) on local anesthesia of the sciatic nerve. Eighty Wistar male rats received the following SC injections in the popliteal fossa: local anesthetic with epinephrine (LA); local anesthetic without vasoconstrictor (LA WV); COD; TRAM; LA + COD; LA + TRAM; COD 20 minutes prior to LA (COD 20' + LA) or TRAM 20 minutes prior to LA (TRAM 20' + LA). As a nociceptive function, the blockade was considered the absence of a paw withdraw reflex. As a motor function, it was the absence of claudication. As a proprioceptive function, it was the absence of hopping and tactile responses. All data were compared using repeated-measures analysis of variance (ANOVA). Opioids showed a significant increase in the level of anesthesia, and the blockade duration of LA + COD was greater than that of the remaining groups (p < 0.05). The associated use of opioids improved anesthesia efficacy. This could lead to a new perspective in controlling dental pain. PMID- 24346044 TI - Exponential growth of dental schools in Chile: effects on academic, economic and workforce issues. AB - In the last 30 years, Chile has undergone noteworthy economic development and an exponential growth in the access of its population to higher education. The aim of this paper was to review the changes in academic, economic and workforce issues that occurred as a consequence of the growth in supply of undergraduate dental vacancies between 1997 and 2011. Data collected from the Consejo de Educacion Superior - CES, Comision Nacional de Acreditacion - CNA, and Instituto Nacional de Estadisticas de Chile - INE included these variables: number of dental schools, school type (private or traditional, see explanation below), city where the school is located, entry vacancies, total student enrollment, admission scores, percentile rank of dentistry as a university career, tuition fees, accreditation status, and number of inhabitants. There was an exponential increase in dental schools in Chile (5 to 34) that occurred in association with the rise in tuition fees (US$ 3900 to US$ 9800), a deterioration in the academic level of dental students (650 to 550 points in admission scores) and a predicted 77.5% oversupply of dentists by 2025, according to WHO criteria. The exponential increase in dental schools in Chile brought about negative consequences, such as increasing career costs, deterioration in the academic level of dental students, and an oversupply of dentists, associated with lower incomes and possibly leading to unemployment. Additional research should be conducted to determine whether an increase in the number of dentists can improve the population's access to dental care and reduce the oral disease burden. PMID- 24346043 TI - Protective effect of calcium nanophosphate and CPP-ACP agents on enamel erosion. AB - The aim of this study was to assess the effect of different remineralizing agents on enamel microhardness (KHN) and surface topography after an erosive challenge. Forty-eight human enamel specimens (4 * 4 mm) were randomly assigned to 4 groups: control (no treatment), fluoride varnish, calcium nanophosphate paste and casein phosphopeptide-amorphous calcium phosphate paste (CPP-ACP). Both pastes were applied for 5 minutes, and fluoride varnish, for 24 h. Four daily erosive cycles of 5 minutes of immersion in a cola drink and 2 h in artificial saliva were conducted for 5 days. KHN readings were performed at baseline and after 5 days. The percentage of enamel hardness change (%KHN) was obtained after erosion. The surface topography was evaluated by atomic force microscopy (AFM). The data were tested using ANOVA, Tukey's and paired-T tests (p < 0.05). After an erosive challenge, there was no statistically significant difference between the control (96.8 +/- 11.4 KHN / 72.4 +/- 3.0%KHN) and the varnish (91.7 +/- 14.1 KHN / 73.4 +/- 5.5%KHN) groups. The nanophosphate group showed lower enamel hardness loss (187.2 +/- 27.9 / 49.0 +/- 7.9%KHN), compared with the CPP-ACP group (141.8 +/- 16.5 / 60.6 +/- 4.0%KHN), and both were statistically different from the varnish and the control groups. AFM images showed a rough surface for the control and the varnish groups, a non-homogeneous layer with globular irregularities for CPP-ACP, and a thick homogeneous layer for the nanophosphate group. None of the agents provided protection against the development of erosion; however, nanophosphate paste was able to reduce enamel surface softening after the erosive challenge. PMID- 24346045 TI - Endodontic filling removal procedure: an ex vivo comparative study between two rotary techniques. AB - In this study, we compared the ex vivo removal capacity of two endodontic rotary techniques and determined whether there was a significant quantitative difference in residual material when comparing root thirds. Forty extracted molars were used. The palatal roots were selected, and the canals were prepared using a step back technique and filled using a lateral condensation technique with gutta percha points and Endofill sealer. After two weeks of storage in a 0.9% saline solution at 37 oC in an oven, the specimens were divided into 2 groups of 20, with group 1 samples subjected to Gates-Glidden drills and group 2 samples subjected to the ProTaper retreatment System. Hedstroem files and eucalyptol solvent were used in both groups to complete the removal procedure. Then, the roots thirds were radiographed and the images were submitted to the NIH ImageJ program to measure the residual filling material in mm. Each root third was related to the total area of the root canals. The data were analyzed using Student's t test. There was a statistically significant difference between the two techniques as more filling material was removed by technique 2 (ProTaper) than technique 1 (Gates-Glidden drills, p < 0.05). The apical third had a greater amount of residual filling material than the cervical and middle thirds, and the difference was statistically significant (p < 0.05). None of the selected techniques removed all filling material, and the material was most difficult to remove from the apical third. The ProTaper files removed more material than the Gates-Glidden drills. PMID- 24346046 TI - Comparison of the hemolytic activity between C. albicans and non-albicans Candida species. AB - The ability to produce enzymes, such as hemolysins, is an important virulence factor for the genus Candida.The objective of this study was to compare the hemolytic activity between C. albicansand non-albicans Candida species. Fifty strains of Candida species, isolated from the oral cavity of patients infected with HIV were studied. The isolates included the following species: C. albicans, C. dubliniensis, C. glabrata, C. tropicalis, C. krusei, C. parapsilosis, C. dubliniensis, C. norvegensis, C. lusitaniae, and C. guilliermondii. Hemolysin production was evaluated on Sabouraud dextrose agar containing chloramphenicol, blood, and glucose. A loop-full of pure Candidaculture was spot-inoculated onto plates and incubated at 37 oC for 24 h in a 5% CO2 atmosphere. Hemolytic activity was defined as the formation of a translucent halo around the colonies. All C. albicansstrains that were studied produced hemolysins. Among the non-albicans Candidaspecies, 86% exhibited hemolytic activity. Only C. guilliermondiiand some C. parapsilosis isolates were negative for this enzyme. In conclusion, most non albicans Candidaspecies had a similar ability to produce hemolysins when compared to C. albicans. PMID- 24346047 TI - Morphometric evaluation of keratocystic odontogenic tumor before and after marsupialization. AB - The aim of the present study was the morphometric evaluation of the epithelial lining and fibrous capsule in histological specimens of keratocystic odontogenic tumors (KOTs) before and after marsupialization. Histological sections from six KOTs that had undergone marsupialization followed by enucleation were photographed. The thickness and features of the capsule and of the epithelial lining of the tumor were evaluated upon marsupialization and upon subsequent enucleation using Axion Vision software. The histological specimens taken upon marsupialization presented an epithelial lining that is typical of KOTs. After marsupialization, the enucleated specimens had a modified epithelial lining and a fibrous capsule that both presented a greater median thickness (p = 0.0277 and p = 0.0212, respectively), morphological changes, and significant enlargement. These modifications can facilitate full surgical treatment and may well be related to a low KOT recurrence rate. PMID- 24346048 TI - Evaluation of condyle defects using different reconstruction protocols of cone beam computed tomography. AB - This study was conducted to investigate how well cone-beam computed tomography (CBCT) can detect simulated cavitary defects in condyles, and to test the influence of the reconstruction protocols. Defects were created with spherical diamond burs (numbers 1013, 1016, 3017) in superior and/or posterior surfaces of twenty condyles. The condyles were scanned, and cross-sectional reconstructions were performed with nine different protocols, based on slice thickness (0.2, 0.6, 1.0 mm) and on the filters (original image, Sharpen Mild, S9) used. Two observers evaluated the defects, determining their presence and location. Statistical analysis was carried out using simple Kappa coefficient and McNemar's test to check inter- and intra-rater reliability. The chi-square test was used to compare the rater accuracy. Analysis of variance (Tukey's test) assessed the effect of the protocols used. Kappa values for inter- and intra-rater reliability demonstrate almost perfect agreement. The proportion of correct answers was significantly higher than that of errors for cavitary defects on both condyle surfaces (p < 0.01). Only in identifying the defects located on the posterior surface was it possible to observe the influence of the 1.0 mm protocol thickness and no filter, which showed a significantly lower value. Based on the results of the current study, the technique used was valid for identifying the existence of cavities in the condyle surface. However, the protocol of a 1.0 mm-thick slice and no filter proved to be the worst method for identifying the defects on the posterior surface. PMID- 24346049 TI - Classification of bifid mandibular canals using cone beam computed tomography. AB - The objective of this study was to classify the morphology of bifid mandibular canals and to evaluate their relationship with the roots of third molars, using cone beam computed tomography (CBCT) scans. The CBCT scans of 75 patients were analyzed and the bifurcations were classified according to Langlais et al. (1985). The relationship of bifurcation and third molars was established according to the following classification: class A--uninvolved, class B--close relationship, class C--intimate relationship and class D--absence of third molars. Data were submitted to descriptive statistics, and the results indicated that the patients' mean age was 48.2 (+/- 13.2) years. Unilateral bifurcation (Type 1) was the most frequent type (72.6%), followed by unilateral Type 2 (19.3%). Class D was the most frequent (57.33%), followed by class C (21.33%), class B (13.33%) and class A (8%). It could be concluded that most cases presented unilateral bifid mandibular canals extending to the third molar or adjacent regions, and when present, the roots seemed to be a continuation of the bifid mandibular canal. PMID- 24346050 TI - The influence of desensitizing dentifrices on pain induced by in-office bleaching. AB - The purpose of this study was to evaluate whether the use of desensitizing dentifrices used 15 days prior to and after in-office tooth bleaching could eliminate or reduce tooth sensitivity. After institutional review board approval and informed consent, 45 subjects were selected and divided into 3 groups according to the dentifrice selected: Colgate Total (CT), Colgate Sensitive Pro Relief (CS) or Sensodyne ProNamel (SP). The subjects used toothpaste and a toothbrush provided to them for 15 days prior to bleaching. They were then submitted to two in-office bleaching sessions (Whiteness HP Blue Calcium). Their tooth sensitivity was assessed using the Visual Analog Scale (VAS) for a week after each session. Their tooth shade alteration was measured with a Vitapan Classical shade guide to determine if the dentifrices could influence the effectiveness of the bleaching agent. The data were submitted to Wilcoxon, Kruskal-Wallis and Mann-Whitney tests (alpha = 0.05). The use of desensitizing dentifrices did not affect the bleaching efficacy. In regard to tooth sensitivity, there was a statistically significant difference between the results of the Control Group and Group T2 after the first session (p = 0.048). There was no statistically significant difference in the results for the other groups after the first session. In regard to the second session, there was no statistically significant difference in the results for all the groups. The use of a desensitizing dentifrice containing nitrate potassium reduced tooth sensitivity during the bleaching regimen. Dentifrices containing arginine and calcium carbonate did not reduce tooth sensitivity. Color change was not influenced by the dentifrices used. PMID- 24346051 TI - Surgical Management of Old Lower Cervical Dislocations With Locked Facet. AB - STUDY DESIGN: Prospective study. OBJECTIVE: To evaluate the role of the canal and vertebrae sagittal diameter (C/V) ratio in the treatment of old dislocations of the lower cervical spine. SUMMARY OF BACKGROUND DATA: Few studies have reported the management of old dislocations of the lower cervical spine. Conservative treatments including the use of a Halo vest, neck brace, and prolonged traction have been problematic. Operative treatment consisted of a primary or staged reduction and fusion using an anterior, posterior, or combined approach. METHODS: Fourteen consecutive patients with old dislocations of the lower cervical spine were included in this series. The preoperative C/V value was calculated based on the measurement on the neutral sagittal computed tomography at the most narrow place of the dislocated segments. Closed reduction was attempted in 9 patients with moderate stenosis (C/V>0.5). Five patients with severe stenosis (C/V<=0.5) were treated with a primary combined anterior and posterior operation. Patient's radiographic information, pain, and neurological function were assessed and recorded before and after surgery. RESULTS: Closed reduction followed by anterior cervical discectomy and fusion was performed in 3 of 9 patients with moderate stenosis. Eleven patients underwent circumferential release, posterior reduction, and fixation followed by anterior fusion. No severe complications were found. The average operative time was 138+/-43 minutes. The average blood loss was 239+/-140 mL. The postoperative C/V value was significantly increased. The neurological status improved at least one grade in all 13 neurologically impaired cases except for 2 who had complete spinal cord injuries. Bony fusion was obtained in all patients at 1-year follow-up. CONCLUSIONS: The C/V value plays an important role in determining surgical solutions for old lower cervical dislocations with locked facets. Favorable clinical outcomes can be achieved using closed reduction and surgical procedures with anterior or anterior plus posterior approaches. PMID- 24346052 TI - Lumbar fusion versus nonoperative management for treatment of discogenic low back pain: a systematic review and meta-analysis of randomized controlled trials. AB - STUDY DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs). OBJECTIVE: To evaluate the current evidence comparing lumbar fusion to nonoperative management for the treatment of chronic discogenic low back pain. BACKGROUND AND CONTEXT: Discogenic low back pain is a common and sometimes disabling condition. When the condition becomes chronic and intractable, spinal fusion may play a role. METHODS: A systematic review of the literature was conducted using the PubMed and CENTRAL databases. We included RCTs that compared lumbar fusion to nonoperative management for the treatment of adult patients with chronic discogenic low back pain. A meta-analysis was conducted to assess the improvement in back pain based on the Oswestry Disability Index (ODI). RESULTS: Five RCTs met our inclusion criteria. A total of 707 patients were divided into lumbar fusion (n=523) and conservative management (n=134). Although inclusion/exclusion criteria were relatively similar across studies, surgical techniques and conservative management protocols varied. The pooled mean difference in ODI (final ODI-initial ODI) between the nonoperative and lumbar fusion groups across all studies was -7.39 points (95% confidence interval: 20.26, 5.47) in favor of lumbar fusion, but this difference was not statistically significant (P=0.26). CONCLUSIONS: Despite the significant improvement in ODI in the lumbar fusion groups in 3 studies, pooled data revealed no significant difference when compared with the nonoperative group. Although there was an overall improvement of 7.39 points in the ODI in favor of lumbar fusion, it is unclear that this change in ODI would lead to a clinically significant difference. Prospective randomized trials comparing a specific surgical technique versus a structured physical therapy program may improve evidence quality. Until then, either operative intervention by lumbar fusion or nonoperative management and physical therapy remain 2 acceptable treatment methods for intractable low back pain. PMID- 24346053 TI - Bulb Syringe and Pulsed Irrigation: Which Is More Effective to Remove Bacteria in Spine Surgeries? AB - STUDY DESIGN: Retrospective study. OBJECTIVES: The aim of this study was to investigate the difference of efficacy between bulb syringe irrigation and pulsed irrigation in spinal surgeries. SUMMARY OF BACKGROUND: Pulsed irrigation has been used for more than half a century, especially in trauma surgeries. However, to the best of our knowledge, there has been no study as to the efficacy of pulsed irrigation in spinal surgeries so far. MATERIALS AND METHODS: The consecutive patients who underwent posterior lumbar interbody fusion for 6 months were investigated. Those who underwent surgeries during the first 3 months were irrigated by bulb syringe (group I) and those who underwent surgeries during the next 3 months were irrigated by pulsatile irrigator with 17 psi (group II). Sex, age, surgery time, amount of blood loss, whether associated with diabetes mellitus, smoking, and amount of irrigation solution were compared between the 2 groups to identify homogeneity. Normal saline was used. Intraoperative irrigations were performed 3 times as time elapsed. After the last irrigation, culture specimens were obtained from the muscle layer and intervertebral space. The culture results were compared between the 2 groups. RESULTS: There were 79 cases in group I and 59 cases in group II. In the homogeneity test, surgery time was longer (P=0.011) and amount of irrigation saline was larger (P=0.042) in group II. From the posterior muscle layer, bacteria were cultured in 8/79 cases (10.1%) in group I and 1/59 cases (1.6%) in group II. There was a significant difference between the 2 groups (P=0.046). And from the intervertebral space, it was cultured in 6/79 cases (7.6%) in group I and 5/59 cases (8.5%) in group II. There was no difference between the 2 groups (P=0.546). Staphylococcus epidermidis, Staphylococcus aureus, Staphylococcus hominis, and Staphylococcus saprophyticus were cultured in order of the frequency. CONCLUSIONS: Pulsed irrigation was more effective compared with bulb syringe irrigation in the posterior muscle layer. In the intervertebral space, however, both methods were insufficient to eradicate contaminated bacteria. PMID- 24346054 TI - Using a Combination of Intralaminar and Pedicular Screw Constructs for Enhancement of Spinal Stability and Maintenance of Correction in Patients With Sagittal Imbalance: Clinical Applications and Finite Element Analysis. AB - STUDY DESIGN: Case series and finite element analysis. OBJECTIVE: To report the clinical results of using intralaminar screw-rod (ILS) constructs as supplements to regular pedicle screw (PS) constructs in "high risk for implant failure" patients and to report the results of a finite element analysis (FEA) of this new instrumentation technique. SUMMARY OF BACKGROUND DATA: Despite advances in surgery and implantation techniques, osteoporosis, obesity, revision surgeries, and neuromuscular conditions (such as the Parkinson disease) are challenges against achieving solid arthrodesis and maintaining correction. Additional fixation strategies must be considered in these patients. There is only one study in the literature suggesting that ILS can be used as alternative anchor points and/or to increase fixation strength in conjunction with the PSs. MATERIALS AND METHODS: Five patients (3 male and 2 female) with mechanical comorbidities underwent PS+ILS to treat sagittal imbalance. In radiologic analysis, thoracic kyphosis, lumbar lordosis, and sagittal vertical axis were analyzed. FEA of ILS augmentation technique were carried out.Four different models were created: (1) the full-construct model with ILS+PS 2 levels above and below the osteotomy of T10; (2) only PS 2 levels above and below T10; (3) ILS+PS 1 level above and below the osteotomy; and (4) short-segment PS with only PSs 1 level above and below the osteotomy. The stress/load distributions on the implants in vertebrae were analyzed. RESULTS: The mean age of the patients included in this study was 41 years and the mean follow-up was 28.2 months. A total of 87 PSs and 39 ILSs were used. Both sagittal vertical axis and kyphosis angles showed significant improvements maintained at the latest follow-up. No pseudarthrosis or instrumentation failures were observed. FEA indicated that addition of ILS construct to a PS construct enabled decreased load bearing and increased implant life. CONCLUSIONS: Addition of an ILS construct to PS construct decreases osteotomy line deformation and reduces stress on pedicle fixation points, and the combination improves fixation stability over the conventional PS-rod technique. PMID- 24346056 TI - Novel palladium-catalyzed cascade carboxylative annulation to construct functionalized gamma-lactones in ionic liquids. AB - A novel palladium-catalyzed, one-pot, four-step cascade method has been developed to afford functionalized gamma-lactones in moderate to good yields. This novel and general methodology represents a rare instance of carbonylation of the C(sp(3))-palladium bond. PMID- 24346055 TI - Formation of bis(MU-tetrazolato)dinickel(II) complexes with N,N,O-donor Schiff bases via in situ 1,3-dipolar cyclo-additions: isolation of a novel bi-cyclic trinuclear nickel(II)-sodium(I)-nickel(II) complex. AB - A dinuclear and a novel bi-cyclic hetero trinuclear bis(MU-tetrazolato) bridged nickel(II) Schiff base complexes [Ni2(L(1))2(PTZ)2] (1) and [Ni2(L(2))2(PTZ)2Na(H2O)]ClO4.H2O (2) {where HL(1) = 2-((2 (dimethylamino)ethylimino)methyl)-6-methoxyphenol, HL(2) = 2-((2 (methylamino)ethylimino)methyl)-6-methoxyphenol and HPTZ = 5-(2 pyridyl)tetrazole} have been synthesized by in situ 1,3-dipolar cyclo-addition and characterized by spectral analysis, X-ray crystallography, and variable temperature magnetic susceptibility measurements. Both the complexes crystallize in monoclinic space group P2(1)/c. Both the complexes feature double MU-NN' tetrazolato bridged dinickel(II) structures, in which each nickel(II) is coordinated meridionally by a depronated terdentate Schiff base [(L(1))(-) for 1 and (L(2))(-) for 2] and two nitrogen atoms of the (PTZ)(-). A nitrogen atom from a symmetry related bridging (PTZ)(-) coordinates to complete the distorted octahedral geometry of nickel(II). The phenoxo and methoxo oxygen atoms from two [NiL(2)] units and a water molecule coordinate to a sodium(I) to form the unique bi-cyclic trinuclear nickel(II)-sodium(I)-nickel(II) core in complex 2. Very strong pi...pi stacking is observed in complex 2 to form a supramolecular chain. The variable-temperature (1.8-300 K) magnetic susceptibility measurements show the presence of anti-ferromagnetic coupling between two nickel(II) centers for both complexes with J = -2.14(1) cm(-1) (for 1) and J = -1.20(2) cm(-1) (for 2). To obtain a better understanding of the magnetic exchange mechanism, quantum mechanical (DFT) calculations have been performed. The calculated J values [J(theo) = -4.53 cm(-1) (for 1) and J(theo) = -2.48 cm(-1) (for 2)] are in agreement with the values obtained experimentally. PMID- 24346057 TI - Mycophenolate mofetil in liver transplantation: a review. AB - Liver transplantation is the only live-saving, curative treatment for various end stage liver diseases, and it has excellent survival rates. Mycophenolate mofetil is widely used as co-medication for immunosuppression after liver transplantation, especially to allow a sparing effect on calcineurin-inhibitors, thus reducing their numerous adverse effects. It improves both graft and patient survival. The properties of its active metabolite, mycophenolic acid, are diverse: inhibition of de novo purine synthesis and selective lymphocyte inhibition, anti-tumoral, antiviral, anti-angioneoplastic, and vasculoprotective mechanisms are described and summarized in this review. The most common adverse effects of mycophenolate mofetil are gastrointestinal complaints such as diarrhea, which often lead to dose-reduction or withdrawal of mycophenolate mofetil. A newer, enteric-coated formulation is available, which is meant to reduce the gastrointestinal adverse effects. Mycophenolate mofetil does not relevantly interact with other common drugs. The question of whether therapeutic drug monitoring allows optimized dosing strategies cannot be satisfyingly answered yet. The optimal partner-immunosuppressant seems to be tacrolimus, especially in low doses. This tutorial review provides an overview of recent studies exploring the role of mycophenolate mofetil in liver transplantation with regards to its development, mechanism of action, and actual controversies such as therapeutic drug monitoring or de novo malignancy after transplantation. PMID- 24346058 TI - Ginsenoside Rg1 reduces toxicity of fine particulate matter on human alveolar epithelial cells: a preliminary observation. AB - Fine particulate matter (PM2.5) is a significant environmental pollutant responsible for a number of human diseases. Ginsenoside Rg1 (Rg1) is likely to have the potential to relieve PM2.5-induced cell injury. The present study is designed to preliminarily observe the harmful effect of PM2.5 and the protective effect of Rg1 against PM2.5 on human A549 lung epithelial cells in vitro. The cytotoxic effects of the PM2.5 or Rg1 on A549 cells were measured by means of cell viability, and then exposure concentration of PM2.5 and pretreatment concentration of Rg1 used in the following assays were established. The A549 cells were pretreated with Rg1 for 1 h and then exposed to PM2.5 for 24 h. The levels of lactate dehydrogenase (LDH) in the cell culture supernatant and malondialdehyde (MDA) within the cells were assayed. The present results revealed that 200-1,200 ug/ml of PM2.5 decreased the viability of A549 cells significantly in a concentration-dependent manner; however, 50-400 ug/ml of Rg1 had no significant effect. Pretreatment with 100, 200 or 400 ug/ml Rg1 significantly diminished the 200 ug/ml PM2.5-induced A549 cell viability and decreased LDH leakage and MDA generation in a concentration-dependent manner. These results indicated that PM2.5 induced cell injury and Rg1, antagonized PM2.5-induced cell injury to a certain extent. PMID- 24346059 TI - Cannabinoid CB2 receptor immunolabelling in the healthy brain--still a live possibility. PMID- 24346060 TI - Paleontology at the "high table"? Popularization and disciplinary status in recent paleontology. AB - This paper examines the way in which paleontologists used "popular books" to call for a broader "expanded synthesis" of evolutionary biology. Beginning in the 1970s, a group of influential paleontologists, including Stephen Jay Gould, Niles Eldredge, David Raup, Steven Stanley, and others, aggressively promoted a new theoretical, evolutionary approach to the fossil record as an important revision of the existing synthetic view of Darwinism. This work had a transformative effect within the discipline of paleontology. However, by the 1980s, paleontologists began making their case to a wider audience, both within evolutionary biology, and to the general public. Many of their books-for example, Eldredge's provocatively-titled Unfinished Synthesis-explicitly argued that the received synthetic view of Darwinian evolution was incomplete, and that paleontological contributions such as punctuated equilibria, the hierarchical model of macroevolution, and the study of mass extinction dynamics offered a substantial corrective to evolutionary theory. This paper argues that books-far from being "mere popularizations" of scientific ideas-played an important role in disciplinary debates surrounding evolutionary theory during the 1980s, and in particular that paleontologists like Gould and Eldredge self-consciously adopted the book format because of the importance of that genre in the history of evolutionary biology. PMID- 24346061 TI - Multi-scale modeling of mycosubtilin lipopeptides at the air/water interface: structure and optical second harmonic generation. AB - Monolayers of the lipopeptide mycosubtilin are studied at the air/water interface. Their structure is investigated using molecular dynamics simulations. All-atom models suggest that the lipopeptide is flexible and aggregates at the interface. To achieve simulation times of several microseconds, a coarse-grained (CG) model based on the MARTINI force field was also used. These CG simulations describe the formation of half-micelles at the interface for surface densities up to 1 lipopeptide per nm(2). In these aggregates, the tyrosine side chain orientation is found to be constrained: on average, its main axis, as defined along the C-OH bond, aligns along the interface normal and points towards the air side. The origin of the optical second harmonic generation (SHG) from mycosubtilin monolayers at the air/water interface is also investigated. The molecular hyperpolarizability of the lipopeptide is obtained from quantum chemistry calculations. The tyrosine side chain contribution to the hyperpolarizability is found to be dominant. The orientation distribution of tyrosine, associated with a dominant hyperpolarizability component along the C-OH bond of the tyrosine, yields a ratio of the susceptibility elements chi((2))(ZZZ)/chi((2))(ZXX) consistent with the experimental measurements recently reported by M. N. Nasir et al. [Phys. Chem. Chem. Phys., 2013, 15, 19919]. PMID- 24346062 TI - GATA3 inhibits proliferation and induces expression of both early and late differentiation markers in keratinocytes of the human epidermis. AB - GATA3 belongs to the GATA transcription factor family and is a crucial regulator of lymphocyte differentiation. More recently, GATA3 was shown to be involved in skin cell lineage determination, in morphogenesis and maintenance of hair follicle keratinocytes as well as in epidermal barrier formation in mouse. In human, the potential role of GATA3 in the regulation of interfollicular epidermal homeostasis was still poorly explored. We thus investigated whether GATA3 could play a role in the regulation of proliferation and/or differentiation processes in human primary keratinocytes. We silenced the expression of GATA3 by small interfering RNA in either proliferating or differentiated human primary keratinocytes and analyzed the effect on cell proliferation and differentiation. We showed that GATA3 inhibition increased cell number, BrdU incorporation and expression of the proliferation markers PCNA and Ki67, demonstrating that GATA3 can inhibit keratinocyte proliferation. Moreover, GATA3 seems to be able to induce keratinocyte differentiation since its silencing leads to a decrease of both early and late differentiation markers such as Keratins 1 and 10, Involucrin and Loricrin. Our results demonstrate that GATA3 transcription factor inhibits proliferation and induces differentiation of primary keratinocytes, which suggest that it may regulate human interfollicular epidermal renewal. PMID- 24346063 TI - Maternal Ratings of the ADHD Symptoms: Subtypes Versus Severity in Clinic Referred Children and Adolescents. AB - OBJECTIVE: This study used confirmatory factor analysis (CFA), latent class analysis (LCA), and factor mixture model (FMM) to ascertain the best model for ADHD symptoms, as presented in the Strengths and Weaknesses of ADHD-Symptoms and Normal Behavior Scale (SWAN). METHOD: Mother ratings of the ADHD symptoms of 418 clinic-referred children and adolescents were obtained. RESULTS: The findings provided most support for an FMM with two classes (less severe inattention [IA] and hyperactivity/impulsivity [HI] symptoms and more severe IA/HI symptoms) and two factors (IA and HI) model. The more severe class had more individuals with the ADHD diagnosis, especially the combined type. CONCLUSION: The findings are discussed in relation to dimensional and categorical views of ADHD. PMID- 24346065 TI - Independent predictors for local recurrence following surgery for spinal metastasis. AB - BACKGROUND: Local recurrence of spinal metastasis after surgical resection is relatively common. We sought to determine risk factors and independent predictors for local recurrence after primary surgical resection of spinal metastasis. METHODS: Demographic and clinical variables were collected for patients who underwent surgery for spinal metastasis June 2005 to June 2011. Primary outcome of interest was local recurrence. Significant associations between covariates of interest and recurrence were identified using the chi-square test. Multivariable logistic regression models for recurrence risk were fit and adjusted for potential confounders. RESULTS: A total of 99 patients were analyzed. Mean time to metastatic recurrence was 9.8 months. Thirty-two patients (32.3 %) had local recurrence of metastatic disease following initial surgery. Patients who underwent radiotherapy had significantly higher recurrence rates than patients who did not (39.2 % vs. 12.0 %, respectively; P = 0.012). Patients with metastatic disease affecting more levels had significantly lower recurrence rates. On multivariate analysis, older age was an independent predictor of decreased likelihood of local recurrence. Melanoma was the only cancer type independently associated with higher risk for recurrence. Patients with recurrence had significantly higher 1- and 2-year survival rates than patients without recurrence. Median length of survival was longer in the recurrent group as well. CONCLUSIONS: Other than melanoma, covariates significantly associated with recurrence were factors likely associated with increased survival, including less-extensive spinal disease and radiotherapy. Thus, longer survival time following surgery likely results in a greater chance for local recurrence. As advancements in treatment provide prolonged survival, local recurrence rates will likely increase. PMID- 24346067 TI - Ultracompact (3 MUm) silicon slow-light optical modulator. AB - Wavelength-scale optical modulators are essential building blocks for future on chip optical interconnects. Any modulator design is a trade-off between bandwidth, size and fabrication complexity, size being particularly important as it determines capacitance and actuation energy. Here, we demonstrate an interesting alternative that is only 3 MUm long, only uses silicon on insulator (SOI) material and accommodates several nanometres of optical bandwidth at 1550 nm. The device is based on a photonic crystal waveguide: by combining the refractive index shift with slow-light enhanced absorption induced by free carrier injection, we achieve an operation bandwidth that significantly exceeds the shift of the bandedge. We compare a 3 MUm and an 80 MUm long modulator and surprisingly, the shorter device outperforms the longer one. Despite its small size, the device achieves an optical bandwidth as broad as 7 nm for an extinction ratio of 10 dB, and modulation times ranging between 500 ps and 100 ps. PMID- 24346066 TI - Detection of NDM-1-producing Enterobacteriaceae in Romania: report of the SENTRY Antimicrobial Surveillance Program. PMID- 24346068 TI - Breeding in peach, cherry and plum: from a tissue culture, genetic, transcriptomic and genomic perspective. AB - This review is an overview of traditional and modern breeding methodologies being used to develop new Prunus cultivars (stone fruits) with major emphasis on peach, sweet cherry and Japanese plum. To this end, common breeding tools used to produce seedlings, including in vitro culture tools, are discussed. Additionally, the mechanisms of inheritance of many important agronomical traits are described. Recent advances in stone fruit transcriptomics and genomic resources are providing an understanding of the molecular basis of phenotypic variability as well as the identification of allelic variants and molecular markers. These have potential applications for understanding the genetic diversity of the Prunus species, molecular marker-assisted selection and transgenesis. Simple Sequence Repeat (SSR) and Single Nucleotide Polymorphism (SNPs) molecular markers are described as useful tools to describe genetic diversity in peach, sweet cherry and Japanese plum. Additionally, the recently sequenced peach genome and the public release of the sweet cherry genome are discussed in terms of their applicability to breeding programs. PMID- 24346069 TI - Phytochemical profile and qualification of biological activity of an isolated fraction of Bellis perennis. AB - This study describes the isolation and identification of apigenin-7-O ghicopyranoside, a flavonoid isolated from the flowers of Bellis perennis L., Asteraceae, an species with a broad spectrum of biological activities. The in vitro antioxidant activity and the inhibition of the enzyme acetylcholinesterase were evaluated. The flavonoid showed strong in vitro antioxidant potential, because of the capacity of removal of hydroxyl radicals and nitric oxide, and also prevented the formation of thiobarbituric acid-reactive substances. These parameters were inhibited at the highest concentration of ApG at rates of 77.7%, 72% and 73.4%, respectively, in addition to inhibiting acetylcholinesterase, suggesting potential use in the treatment of neurodegenerative diseases. PMID- 24346070 TI - Prevalence of the 35delG mutation in the GJB2 gene in two samples of non syndromic deaf subjects from Chile. AB - Hearing loss is the most common inherited sensorial deficiency in humans; about 1 in 1000 children suffer from severe or profound hearing loss at birth. Mutations in the GJB2 gene are the most common cause of prelingual, non-syndromic autosomal recessive deafness in many populations; the c.35delG mutation is the most common in Caucasian populations. The frequency of the c.35delG mutation was estimated in two samples of deaf patients from Santiago, Chile. Unrelated non-syndromic sensorioneural deaf patients were examined: Group 1 consisted of 47 unrelated individuals with neurosensory deafness referred to the Chilean Cochlear Implant Program; Group 2 included 66 school children with prelingual deafness attending special education institutions for deaf people. Individuals with profound to moderate isolated neurosensory hearing loss with unknown etiology were included. The presence of the c.35delG mutation was evaluated by the allele-specific polymerase chain reaction method (PCR), and in some cases it was confirmed by direct DNA sequencing of the coding region of the GJB2 gene. Deaf relatives were present in 20.3% of the cases. We found 19.5% (22/113) patients with the c.35delG mutation, 6 of them homozygous; these rates are similar to frequencies found in other Latin American countries. PMID- 24346071 TI - Septin 7: actin cross-organization is required for axonal association of Schwann cells. AB - Myelin sheaths present two distinct domains: compacted myelin spirals and flanking non-compacted cytoplasmic channels, where lipid and protein segregation is established by unknown mechanisms. Septins, a conserved family of membrane and cytoskeletal interacting GTPases, form intracellular diffusion barriers during cell division and neurite extension and are expressed in myelinating cells. Septins, particularly septin 7 (Sept7), the central constituent of septin polymers, are associated with the cytoplasmic channels of myelinating cells. Here we show that Schwann cells deprived of Sept7 fail to wrap around axons from dorsal root ganglion neurons and exhibit disorganization of the actin cytoskeleton. Likewise, Sept7 distribution is dependent on microfilament but not microtubule organization. PMID- 24346072 TI - Intravenous administration of bone marrow-derived multipotent mesenchymal stromal cells has a neutral effect on obesity-induced diabetic cardiomyopathy. AB - Obesity is a major global health issue. Obese patients develop metabolic syndrome, which is a cluster of clinical features characterized by insulin resistance and dyslipidemia. Its cardiac manifestation, diabetic cardiomyopathy, leads to heart failure. Bone marrow-derived multipotent mesenchymal stromal cells, also referred to as mesenchymal stem cells (MSC) are envisioned as a therapeutic tool not only for cardiovascular diseases but also for other degenerative conditions. Our aim was to evaluate whether the intravenous administration of MSC modifies cardiac dysfunction in obese mice. To this end, C57BL/6 mice were fed a regular (normal) or high-fat diet (obese). Obese animals received the vehicle (obese), a single dose (obese + 1x MSC) or three doses (obese + 3x MSC) of 0.5x10(6) syngeneic MSC. Two to three months following MSC administration, cardiac function was assessed by cardiac catheterization, at basal condition and after a pharmacological stress. Compared to normal mice, obese mice presented hyperglycemia, hyperinsulinemia, hypercholesterolemia and cardiac dysfunction after stress condition. Exogenous MSC neither improved nor impaired this cardiac dysfunction. Thus, intravenous administration of MSC has neutral effect on obesity-induced diabetic cardiomyopathy. PMID- 24346073 TI - Lipids, proteins, phenolic composition, antioxidant and antibacterial activities of seeds of peanuts (Arachis hypogaea l) cultivated in Tunisia. AB - Fatty acid composition of peanut seed oil in four varieties cultivated in Tunisia showed that linoleic (C18:2), oleic (C18:1) and palmitic (C16) acids account for more than 84% for Chounfakhi and Massriya and for more than 85% of the total fatty acids of Trabilsia and Sinya seed oil respectively. Seed oil contents were significantly different (P <= 0.05) and did not exceed 48%. The study of total phenolics revealed that Chounfakhi contained more total phenolics (2.1 mg GAE/g DW), followed by the Massriya and Sinya cultivars (1.35 mg GAE/g DW for each); Trabilsia presented the lowest total phenolic content with 1 mg GAE/g DW. Considerable antiradical ability was found, especially in the Trabilsia peanut seed cultivar (IC50 = 1550 MUg/ml), the Massriya and Sinya cultivars had, respectively, 720 and 820 mg/ml IC50. In the Massriya variety the sterol fraction showed antibacterial activity against Listeria ivanovii, Listeria inocua, Pseudomonas aeruginosa, Staphylococus aureus, Enterococcus hirae and Bacillus cereus. PMID- 24346074 TI - Association between polymorphism of the G-protein beta3 subunit C825T and essential hypertension: an updated meta-analysis involving 36,802 subjects. AB - PURPOSE: The G-protein beta3-subunit gene C825T polymorphism (GNB3-C825T) has been reported to be associated with essential hypertension (EH), but results from previous studies are conflicting. The present study aimed at investigating the association between this polymorphism and risk of EH using a meta-analysis on the published studies. MATERIALS AND METHODS: PubMed, Embase, CBM (China Biological Medicine Database), Wanfang and VIP databases were searched to identify eligible studies published in English and Chinese before March 2013. Data were extracted using standardized methods. The association was assessed by the odds ratio (OR) with 95% confidence intervals (CI). Begg's test was used to measure publication bias. RESULTS: A total of 40 case-control studies containing 16,518 EH patients and 20,284 controls were involved in this meta-analysis. Overall, a significant association was found between GNB3 C825T polymorphism and risk of EH when all studies were pooled with a random-effects model for T versus C (OR=1.09, 95% CI: 1.04-1.19). In the subgroup analysis, the same association was found in overall Caucasian (T versus C, OR=1.16, 95% CI 1.08-1.24) and Chinese populations (TT versus CC, OR=1.23, 95% CI 1.06-1.57). No associations were detected between GNB3 C825T and the risk of EH overall in Asian and Japanese people. CONCLUSIONS: Meta analysis results suggest that the GNB3-C825T polymorphism is associated with risk of EH in the overall population, the Caucasians and the Chinese. The effect of the variants on the expression levels and the possible functional role of the variants in EH should be addressed in further studies. PMID- 24346076 TI - Reduction of lns-1 gene expression and tissue insulin levels in n5-STZ rats. AB - OBJECTIVE: The high global incidence of type 2 diabetes has challenged researchers to establish animal models that resemble the chronic stage observed in type 2 diabetes patients. One such model is induced by neonatal streptozotocin (n-STZ) administration to rat pups at 0, 2, or 5 days after birth. In this study, we assessed lns-1 gene expression and tissue insulin levels as well as serum concentration of glucose and insulin, insulin resistance, and histological changes of the islets of Langerhans in n5-STZ rats after 20-weeks post-induction. METHODS: Wistar rat pups were randomly distributed into a control group and a streptozotocin-induced group. Experimental induction involved a single intraperitoneal injection of streptozotocin (150 mg/kg) into neonates at five days after birth. RESULTS: At 20 weeks post-induction, streptozotocin-induced rats exhibited increased serum glucose levels, reduced serum insulin levels, impaired glucose metabolism and insulin resistance compared to control rats. Histologically, streptozotocin-induced rats exhibited atrophic islets, vacuolization, and significantly fewer insulin-positive cells. lns-1 gene expression was significantly decreased in n5-STZ rats in comparison to the control group. CONCLUSION: Our findings support that the n5-STZ model 20 weeks post-induction represents an appropriate experimental tool to study T2D and to evaluate novel therapeutic agents and targets that involve insulin gene expression and secretion, as well as complications caused by chronic diabetes. PMID- 24346075 TI - Galectin-8 binds to LFA-1, blocks its interaction with ICAM-1 and is counteracted by anti-Gal-8 autoantibodies isolated from lupus patients. AB - Galectin-8 belongs to a family of mammalian lectins that recognize glycoconjugates present on different cell surface components and modulate a variety of cellular processes. A role of Gal-8 in the immune system has been proposed based on its effects in immune cells, including T and B lymphocytes, as well as the presence of anti-Gal-8 autoantibodies in the prototypic autoimmune disease systemic lupus erythematosus (SLE). We have previously described that Gal 8 induces apoptosis in activated T cells interacting with certain beta1 integrins and this effect is counteracted by the anti-Gal-8 autoantibodies. Given that Gal 8 can potentially interact with several glycoproteins, here we analyzed the beta2 integrin Lymphocyte Function-Associated Antigen-1 (LFA-1), which is involved in leukocyte cell adhesion and immunological synapses. We show by GST-pull down assays that Gal-8 interacts with LFA-1 and this interaction is inhibited by anti Gal-8 autoantibodies isolated from SLE patients. In cell adhesion assays, Gal-8 precluded the interaction of LFA-1 with its ligand Intracellular Adhesion Molecule-1 (ICAM-1). These results suggest that Gal-8 can exert immunosuppressive action not only by inducing apoptosis in activated T cells but also by negatively modulating the crucial function of LFA-1 in the immune system, while function blocking autoantibodies counteract these effects. PMID- 24346077 TI - Fatty acid composition of Drosophila photoreceptor light-sensitive microvilli. AB - Phototransduction, the mechanism underlying the electrical response to light in photoreceptor cells, has been thoroughly investigated in Drosophila melanogaster, an essential model in signal transduction research. These cells present a highly specialized photosensitive membrane consisting of thousands of microvilli forming a prominent structure termed a rhabdomere. These microvilli encompass the phototransduction proteins, most of which are transmembrane and exclusively rhabdomeric. Rhabdomere membrane lipids play a crucial role in the activation of the transient receptor potential ionic channels (TRP and TRPL) responsible for initiating the photoresponse. Despite its importance, rhabdomere lipid composition has not been established. We developed a novel preparation enriched in rhabdomere membranes to perform a thorough characterization of the lipidomics of Drosophila rhabdomeres. Isolated eyes (500) were homogenized and subjected to a differential centrifugation protocol that generates a fraction enriched in rhabdomere membrane. Lipids extracted from this preparation were identified and quantified by gas chromatography coupled to mass spectrometry. We found an abundance of low sterol esters (C16:0, C18:0), highly abundant and diverse triglycerides, free fatty acids, a moderate variety of mono and diacyglycerols (C:16:0, 18:0, C18:1) and abundant phospholipids (principally C18:2). This preparation opens a new avenue for investigating essential aspects of phototransduction. PMID- 24346078 TI - Chronic Chagas disease: PCR-xenodiagnosis without previous microscopic observation is a useful tool to detect viable Trypanosoma cruzi. AB - We evaluate the elimination of the microscopic stage of conventional xenodiagnosis (XD) to optimize the parasitological diagnosis of Trypanosoma cruzi in chronic Chagas disease. To this purpose we applied under informed consent two XD cages to 150 Chilean chronic chagasic patients. The fecal samples (FS) of the triatomines at 30, 60 and 90 days post feeding were divided into two parts: in one a microscopic search for mobile trypomastigote and/or epimastigote forms was performed. In the other part, DNA extraction-purification for PCR directed to the conserved region of kDNA minicircles of trypanosomes (PCR-XD), without previous microscopic observation was done. An XD was considered positive when at least one mobile T. cruzi parasite in any one of three periods of incubation was observed, whereas PCR-XD was considered positive when the 330 bp band specific for T. cruzi was detected. 25 of 26 cases with positive conventional XD were PCR-XD positive (concordance 96.2%), whereas 85 of 124 cases with negative conventional XD were positive by PCR-XD (68.5%). Human chromosome 12 detected by Real-time PCR used as exogenous internal control of PCR-XD reaction allowed to discounting of PCR inhibition and false negative in 40 cases with negative PCR-XD. CONCLUSION: PCR XD performed without previous microscopic observation is a useful tool for detection of viable parasites with higher efficiency then conventional XD. PMID- 24346079 TI - Microdesiccates produced from normal human tears display four distinctive morphological components. AB - Desiccation of human tears on glass surfaces results in fern-like crystalloids. This phenomenon has been associated with tear normality (Tear Ferning Test, TFT) and is used as a diagnostic aid to evaluate patients with Dry-Eye disease. However, TFT is focused on the assessment of only a minor fraction of desiccated tear samples and considers only the relative abundance and density of fern-like crystalloids. The aim of this study was to characterize morphologically entire desiccated micro volumes of tears from healthy donors. Tear samples were collected from 23 healthy young adult volunteers. Tear aliquots (1-3 MUL) were allowed to dry on glass surfaces under ambient conditions of temperature (15-25 degrees C) and relative humidity (40-45%). Dry samples were analyzed by dark field microscopy. Morphometric data were acquired with Image J software. Tear volume was positively correlated with both area and time of desiccation. Morphological features of multiple microdesiccates produced from a single subject displayed striking similarities whereas tear microdesiccates from different healthy subjects displayed consistent differences but shared a common general design. This design may be mostly represented by the occurrence of four distinctive zones, named as zones I, II, III and Transition band. The main features of these zones are described. PMID- 24346081 TI - Letters to editor / erratum. PMID- 24346084 TI - Triggering cell death by nanographene oxide mediated hyperthermia. AB - Graphene oxide (GO) has been proposed as an hyperthermia agent for anticancer therapies due to its near-infrared (NIR) optical absorption ability which, with its small two-dimensional size, could have a unique performance when compared to that of any other nanoparticle. Nevertheless, attention should be given to the hyperthermia route and the kind of GO-cell interactions induced in the process. The hyperthermia laser irradiation parameters, such as exposure time and laser power, were investigated to control the temperature rise and consequent damage in the GOs containing cell culture medium. The type of cell damage produced was evaluated as a function of these parameters. The results showed that cell culture temperature (after irradiating cells with internalized GO) increases preferentially with laser power rather than with exposure time. Moreover, when laser power is increased, necrosis is the preferential cell death leading to an increase of cytokine release to the medium. PMID- 24346086 TI - Copolymer of poly(ethylene glycol) and poly(L-lysine) grafting polyethylenimine through a reducible disulfide linkage for siRNA delivery. AB - siRNA therapy research has primarily focused on the synthesis and development of effective siRNA delivery vectors with easy biodegradability and low toxicity. In the present study, we synthesized a ternary copolymer mPEG-b-PLL-g-(ss-lPEI), denoted as PLI, by introducing disulfide bond linkages to graft low molecular weight linear polyethylenimine (lPEI) to the block copolymer of poly(L-lysine) (PLL) and poly(ethylene glycol) (PEG) for siRNA delivery. The PLL block and disulfide linkage rendered the carrier biodegradability, while lPEI grafting brought about the proton buffering capacity for lysosomal siRNA release and low cationic toxicity. Conjugation of a single chain monoclonal antibody (Herceptin) to the carrier as a targeting ligand for the Her2/neu receptor significantly increased the transfection activity of the copolymer/siRNA nanocomplex (i.e. the polyplex) in Skov-3, a human ovarian cancer cell line. Determination of gene expression at both the mRNA and protein levels demonstrated that Her2-targeted delivery of siRNA (XIAP siRNA) effectively downregulated the targeted XIAP (X linked inhibitor of apoptosis protein) gene, resulting in enhanced cancer cell apoptosis and improved therapeutic efficacy in vitro and in vivo. The distinct features of low cytotoxicity, easy degradability, and high siRNA transfection efficiency make the copolymer a promising candidate for siRNA therapy in tumors. PMID- 24346088 TI - 18F-deoxyglucose uptake in stage I non-small-cell lung cancer: time to move to randomized trials. PMID- 24346089 TI - Lung cancer stem cell: fancy conceptual model of tumor biology or cornerstone of a forthcoming therapeutic breakthrough? AB - Cancer research has received a fresh impetus from the concept of cancer stem cell (CSC) which postulates the existence of a tumor cell population uniquely endowed with self-renewal capacity and therapy resistance. Despite recent progresses including targeted therapy, lung cancer treatment remains a challenge owing largely to disease recurrence. Providing a conceptual model of tumor resistance and disease relapse, the lung CSC has received extensive attention, leading to a flourishing literature and several ongoing clinical trials. In this study, we will discuss the data suggesting the existence of CSC in lung tumors and the potential clinical utility of CSCs as prognostic markers or cellular targets of new therapeutic strategies. We will also touch on the new fundamental developments of the CSC concept that ought to be considered if the integration of the CSC concept into clinical practice is to be successful and impact on lung cancer treatment. PMID- 24346091 TI - Transbronchial biopsy needle rinse solution used for comprehensive biomarker testing in patients with lung cancer. AB - INTRODUCTION: Although genetic information is essential for molecular targeted therapy for personalized medicine, tissue sampling for genetic analysis remains challenging. We investigated the utility of bronchoscopic sampling in non-small cell lung cancer (NSCLC) patients compared with conventional histological materials for multiple genetic analyses. METHODS: Patients with NSCLC proven by onsite cytological evaluation during bronchoscopic survey were eligible for this study. After conventional needle aspiration biopsy by flexible bronchofiberscopy of primary lesions or convex-probe endobronchial ultrasound of lymph nodes, the used needle was rinsed with saline, and the ultra-microsample (uMS) was used for cytological diagnosis and genetic analysis. Gene mutations and fusion genes were examined by high-resolution melting analysis and direct sequencing. The results from the uMS and those from conventional histological samples were compared. RESULTS: A total of 134 lesions (48 primary and 86 metastatic) were analyzed. Adenocarcinoma (n = 80), squamous-cell carcinoma (n = 43), and NSCLC (n = 11) samples were pathologically confirmed in histological cores; however, malignancies were detected in only 45 (34%) of the corresponding uMS. In 62 samples, genetic disorders, including epidermal growth factor receptor (n = 21), K-ras (n = 11), and BRAF mutations (n = 1); anaplastic lymphoma kinase (n = 5), receptor tyrosine kinase (n = 1), and RET fusion genes (n = 1); and silent mutations (n = 22), were identified. In total, 1474 molecular tests were performed, and 1464 tests (99.3%) were identical for both histological samples and uMS. CONCLUSION: Bronchoscopic uMS (biopsy needle rinsed fluids) are useful for multiple genetic examinations in NSCLC. PMID- 24346090 TI - Large-scale screening and molecular characterization of EML4-ALK fusion variants in archival non-small-cell lung cancer tumor specimens using quantitative reverse transcription polymerase chain reaction assays. AB - INTRODUCTION: The objective of this study was to identify and characterize echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase fusion (EML4-ALK+) cancers by variant-specific, quantitative reverse transcription polymerase chain reaction (RT-PCR) assays in a large cohort of North American non-small-cell lung cancer (NSCLC) patients. METHODS: We developed a panel of single and multiplex RT-PCR assays suitable for rapid and accurate detection of the eight most common EML4-ALK+ variants and ALK gene expression in archival formalin-fixed, paraffin-embedded NSCLC specimens. EGFR and KRAS genotyping and thymidylate synthase RNA level by RT-PCR assays were available in a subset of patients. RESULTS: Between December 2009 and September 2012, 7344 NSCLC specimens were tested. An EML4-ALK+ transcript was detected in 200 cases (2.7%), including 109 V1 (54.5%), 20 V2 (10.0%), 68 V3 (34.0%), and three V5a (1.5%) variants. Median age was 54.5 years (range, 23-89), and 104 patients (52.0%) were women. The great majority (n=188, 94.0%) of EML4-ALK+ NSCLC tumors had adenocarcinoma histology. ALK expression level varied significantly among different EML4-ALK+ variants and individual tumors. Only one case each of concurrent EGFR or KRAS mutation was detected. The median thymidylate synthase RNA level from 85 EML4-ALK+ cancers was significantly lower compared with that of EML4-ALK-negative lung adenocarcinomas (2.02 versus 3.29, respectively, p<0.001). CONCLUSIONS: This panel of variant-specific, quantitative RT-PCR assays detects common EML4-ALK+ variants as well as ALK gene expression level in archival formalin-fixed paraffin-embedded NSCLC specimens. These RT-PCR assays may be useful as an adjunct to the standard fluorescence in situ hybridization assay to better understand biologic variability and response patterns to anaplastic lymphoma kinase inhibitors. PMID- 24346092 TI - Putative stem cell markers in non-small-cell lung cancer: a clinicopathologic characterization. AB - INTRODUCTION: The cancer stem cell (CSC) theory postulates the existence of a distinct population of undifferentiated cells responsible for tumor initiation and maintenance. CSCs may be naturally resistant to the cytotoxic effect of radio chemotherapy because of slow cell cycling, lower proliferation, and increased expression of DNA repair and antiapoptosis genes. To date, a universal marker for CSCs has not been identified. Proposed CSC markers are expressed both by cancer cells as well as by benign stem cells. Although many putative CSC markers exist, a precise characterization for non-small-cell lung cancer (NSCLC) is lacking. METHODS: We explored the expression of multiple alleged stemness associated markers in 371 surgically resected NSCLCs. Extensive clinical data and a postoperative follow-up period of up to 15 years enabled detailed clinicopathological correlations. ABCG5, ALDH1, CD24, CD44, CD133, CD166, epithelial cell adhesion molecule epitopes (ESA, MOC-31, Ber-EP4), nestin, OCT4, and sex-determining region Y-box 2 were analyzed immunohistochemically by using a standardized tissue microarray platform. RESULTS: Sex-determining region Y-box 2, CD44, ABCG5, ALDH1, and nestin were associated with poorer tumor differentiation and/or an increased proliferation index. ALDH1, CD44, and SOX2 were frequently found in squamous cell carcinoma, whereas CD24, CD166, and epithelial cell adhesion molecule markers were encountered in adenocarcinomas. CD44 expression was an independent marker associated with better overall survival in squamous cell carcinoma and Ber-EP4 was associated with tumor recurrences. CONCLUSION: The expression and prognostic significance of CSC markers obviously varies depending on histologic NSCLC subtype. Importantly, our findings suggest that CD44 and Ber EP4 may be promising for ongoing targeted therapies in specific NSCLC subgroups. PMID- 24346093 TI - Erk/MAP kinase signaling pathway and neuroendocrine differentiation of non-small cell lung cancer. AB - INTRODUCTION: Almost all small-cell lung cancers (SCLC) and carcinoid tumors express neuroendocrine differentiation (NED), and 10% to 20% of non-small-cell lung cancers (NSCLC) are associated with NED. Although distinct clinical features and histology of SCLC and carcinoid tumors are well recognized, the clinical significance and the molecular basis of NED in NSCLC remain unclear. METHODS: To explore the potential molecular pathway involved in NED of NSCLC and its clinical relevance, we conducted investigations using an NSCLC cell line (NCI-H157) as a NED induction model, and explored the potential intracellular signal transduction pathways involved in NED of NSCLC. We confirmed our findings using activators versus inhibitors to these signal transduction pathways in vitro. We also performed immunohistochemical stains of phospho-Erk1/2 of lung cancer specimens known to have NED and explored its clinical relevance. RESULTS: We discovered that NED of NSCLC was associated with the activation of Erk1/2-mitogen-activated protein kinases (MAPK) signal transduction pathway, and the inhibition of the Akt signal transduction pathway. Using specific activator (Pb) and inhibitors (siRNA Erk1/2 and U0126) to the Erk1/2-MAP-kinase pathway, as well as the inhibitor (LY294002) to the Akt pathway, we found that Erk1/2-MAP-kinase activation was essential for NED of NCI-H157 cells. Staining of Erk1/2-MAP-kinase pathway revealed a high rate of positivity in NSCLC tumors with NED when compared with other neuroendocrine lung tumors. CONCLUSIONS: To our knowledge, our findings are the first to describe the potential involvement of Erk/MAPK signal transduction pathway of NSCLC in the association with NED. Further investigation of the Erk/MAPK signal transduction pathway of NSCLC may yield discoveries in identifying specific molecular targets for the treatment of NSCLC with NED. PMID- 24346094 TI - Maximum standardized uptake value on FDG-PET is a strong predictor of overall and disease-free survival for non-small-cell lung cancer patients after stereotactic body radiotherapy. AB - INTRODUCTION: The maximum standardized uptake value (SUVmax) on F fluorodeoxyglucose positron emission tomography is a predictor for overall survival (OS) in non-small-cell lung cancer (NSCLC) after resection. We investigated the association between SUVmax and outcomes in NSCLC after stereotactic body radiotherapy. METHODS: Between 2005 and 2012, 283 patients with early NSCLC (T1a-2N0M0) were treated with stereotactic body radiotherapy; the total doses were 40 to 60 Gy in five fractions. Patients who underwent staging F fluorodeoxyglucose positron emission tomography scans by a single scanner and were followed up for more than or who died within 6 months were eligible. The optimal threshold SUVmax was calculated for each outcome. Outcomes were analyzed using the Kaplan-Meier method and log-rank test. Prognostic significance was assessed by univariate and multivariate analyses. RESULTS: One hundred fifty-two patients were eligible. Median follow-up was 25.3 (range, 1.3-77.4) months. Local, regional, and distant recurrences, cancer-specific deaths, and deaths from other reasons occurred in 14, 11, 27, 21, and 31 patients, respectively. The optimal threshold SUVmax for local, regional, and distant recurrences, and disease-free survival (DFS), cancer-specific survival, and OS were 2.47 to 3.64. Outcomes of patients with SUVmax lower than each threshold were significantly better than those with higher SUVmax (all p<0.005): 3-year DFS rates were 93.0% versus 58.3% (p<0.001) and 3-year OS rates were 86.5% versus 42.2% (p<0.001), respectively. By multivariate analysis, higher SUVmax was a significantly worse predictor for DFS (p<0.01) and OS (p=0.04). CONCLUSIONS: SUVmax was a predictor for DFS and OS. A high SUVmax may be considered for intensive treatment to improve outcomes. PMID- 24346095 TI - Correlation between the size of the solid component on thin-section CT and the invasive component on pathology in small lung adenocarcinomas manifesting as ground-glass nodules. AB - INTRODUCTION: We aimed to evaluate the correlation between the size of the solid component on thin-section computed tomography (CT) and invasive component on pathology in small lung adenocarcinomas manifesting as subsolid nodules. METHODS: Fifty-nine subsolid nodules in 58 patients were evaluated. The maximum diameters of subsolid nodules and the solid component on CT were measured by two radiologists in three-dimensional (3D) and two-dimensional (2D) planes using in house software. In addition, the maximum diameters of the tumor and invasive component were measured on pathology by two pathologists. CT measurements were compared with pathologic measurements. RESULTS: There was a strong correlation between the size of the solid component on CT and invasive component on pathology, as well as the size of subsolid nodules and the tumor size (r = 0.82 0.87 for 3D measurement, 0.72-0.88 for 2D measurement; p < 0.0001). The size of subsolid nodules in 3D and 2D measurements was significantly larger than tumor size (p < 0.0001). In regard to measurement of the solid component, 3D measurements tended to be larger than the size of the invasive component whereas 2D measurement tended to be similar to the size of the invasive component. By applying a size criteria of solid component that was 3 mm or lesser in maximum diameter, preinvasive and minimally invasive adenocarcinoma was predicted with a specificity of 100% (28 of 28). CONCLUSION: We found a significant correlation between the size of the solid component on thin-section CT and the invasive component on pathology. PMID- 24346096 TI - Patient-reported neuropathy and taxane-associated symptoms in a phase 3 trial of nab-paclitaxel plus carboplatin versus solvent-based paclitaxel plus carboplatin for advanced non-small-cell lung cancer. AB - INTRODUCTION: nab-Paclitaxel (nab-P) is approved, in the United States, in combination with carboplatin for the first-line treatment of advanced non-small cell lung cancer, based on a randomized phase 3 trial of nab-P plus carboplatin (nab-P/C) versus solvent-based paclitaxel plus carboplatin (sb-P/C). This trial revealed a higher overall response rate (33% versus 25%; p = 0.005) and longer, but not statistically significant, overall and progression-free survival for nab P/C versus sb-P/C. In addition, nab-P/C demonstrated lower rates of grade 3 or higher peripheral neuropathy, myalgia, arthralgia, and neutropenia but higher rates of anemia and thrombocytopenia. This report analyzes patient and physician assessment of symptoms within this trial. METHODS: Patients completed the taxane subscale of the Functional Assessment of Cancer Therapy questionnaire, which focuses on taxane toxicity, including peripheral neuropathy and neurotoxicity. Mean baseline scores and changes from baseline are reported. Physicians also graded the severity of neuropathy at each patient visit using National Cancer Institute Common Toxicity Criteria. RESULTS: Patients receiving nab-P/C reported significantly less worsening of peripheral neuropathy (p < 0.001), pain (p < 0.001), and hearing loss (p = 0.002). Patient-reported edema was similar between the two treatment arms. In agreement with patient-reported symptoms, the results of a per-treatment cycle physician assessment of peripheral neuropathy also favored nab-P/C over sb-P/C (p < 0.001). CONCLUSION: In this trial of patients receiving first-line treatment for advanced non-small-cell lung cancer, nab-P/C was associated with statistically and clinically significant reductions in patient-reported neuropathy, neuropathic pain in the hands and feet, and hearing loss compared with sb-P/C. PMID- 24346097 TI - Clinical characteristics and treatment outcomes of lung adenocarcinomas with discrepant EGFR mutation testing results derived from PCR-direct sequencing and real-time PCR-based assays. AB - INTRODUCTION: Detection of epidermal growth factor receptor (EGFR) mutation has become the most critical molecular test in managing patients with advanced lung adenocarcinoma. Whether patients with discrepant EGFR mutation results determined by low- and high-sensitivity methods have different clinical outcomes with EGFR tyrosine kinase inhibitor (TKI) treatment needs to be further evaluated. METHODS: Genomic DNA from serial lung adenocarcinoma samples that were EGFR wild-type determined by direct sequencing (DS) were reanalyzed using Scorpion/Amplification Refractory Mutation System (ARMS). The outcomes with EGFR-TKI treatment among patients with discrepant EGFR mutation results between DS and Scorpion/ARMS versus patients with EGFR mutations detected by DS were studied. RESULTS: Of the 130 tumors studied, 28 (21.5%) were found to have EGFR mutations by Scorpion/ARMS. Discrepant EGFR mutation testing results were more common in samples from nonsmokers than in samples from smokers (30.7% versus 9.1%; p = 0.003) and in pleural than in nonpleural samples (62.5% versus 18.9%; p = 0.012). There was no significant difference in the abundance of cancer cells in region(s) selected for testing (26.2% in tumor cell percentage <=50 versus 16.9% in tumor cell percentage >50; p = 0.201). During EGFR-TKI treatment, the progression-free survival in patients with discrepant EGFR mutation results was similar to those with EGFR mutations detected by DS (median, 13.4 versus 10.9 months; p = 0.225). CONCLUSIONS: DS overlooked EGFR mutation in a significant number of lung adenocarcinoma patients. These patients could have obtained the same benefit from EGFR-TKI when a high-sensitivity method such as Scorpion/ARMS was applied. PMID- 24346098 TI - Preselection based on clinical characteristics in German non-small-cell lung cancer patients screened for EML4-ALK translocation. AB - BACKGROUND: The advent of multiple molecular targets in advanced non-small-cell lung cancer (NSCLC) has brought new treatments, but also new logistic and technical considerations, to the clinician. The small size of endoscopic biopsies and the increasing number of relevant but uncommon markers has increased the need for rational approaches to molecular testing. We present the results of clinical preselection before EML4-ALK testing in a German NSCLC cohort. METHODS: Patients with stage IV NSCLC were included. Clinicians were encouraged to consider screening epidermal growth factor receptor wild-type adenocarcinoma patients with a limited smoking history, relatively young age, or who had benefited from chemotherapy for a relatively long period. Break-apart fluorescence in situ hybridization using archived paraffin tissue was performed in a central facility. RESULTS: From April 2010 to September 2011 we included 61 patients: mean age 56.6 years, 41% women, 90% adenocarcinoma, 5% large-cell, and 5% squamous cell cancers. Only three patients had activating epidermal growth factor receptor mutations; 16.4% of patients were positive for EML4-ALK fusion. The anaplastic lymphoma kinase (ALK)-positive patients included 60% women, tended to be younger, had smoked less, and had received significantly more systemic therapy, on average 3.7 lines of treatment over 3 years, before ALK-testing compared with the ALK negative patients. Long periods of progression-free survival were experienced by ALK-positive patients treated with pemetrexed, vinorelbine, or cetuximab. CONCLUSIONS: EML4-ALK fusion is uncommon, reported in about 5% of NSCLC patients; however, clinical preselection increased the yield of testing to 16.4%. EML4-ALK positive patients seem to have distinct clinical features and show long responses to a number of systemic therapies. PMID- 24346099 TI - A brief report of 10-year trends in the use of stereotactic lung radiotherapy at a dutch academic medical center. AB - This report describes clinical trends in the use of stereotactic lung radiotherapy in a large single-institution program over the last 10 years. Changes in patient, tumor, and treatment characteristics are highlighted. PMID- 24346101 TI - Obatoclax mesylate, a pan-bcl-2 inhibitor, in combination with docetaxel in a phase 1/2 trial in relapsed non-small-cell lung cancer. AB - INTRODUCTION: The proapoptotic small-molecule pan-Bcl-2 inhibitor obatoclax mesylate (GX15-070) may enhance the cytotoxicity of chemotherapy in relapsed/refractory non-small-cell lung cancer (NSCLC). METHODS: Obatoclax was administered with docetaxel in patients with relapsed or refractory NSCLC- docetaxel as a 1-hour infusion on day 1 and obatoclax as a 24-hour infusion on days 1 and 2-every 3 weeks for up to eight cycles. Four dose levels were evaluated in phase 1 (level 1: docetaxel 55 mg/m * 1 and obatoclax 30 mg * 2; levels 2-4: docetaxel 75 mg/m and obatoclax 30 mg, 45 mg, or 60 mg * 2) to identify dose-limiting toxicity and a phase 2 dose. In phase 2, response and tolerability were evaluated. RESULTS: Eighteen patients were included in phase 1. Two dose-limiting toxicities occurred during cycle 1: one febrile neutropenia each at dose levels 3 and 4. Maximum tolerated dose was not reached; 32 patients (including 3 from phase 1) were treated in phase 2 with docetaxel 75 mg/m and obatoclax 60 mg (median 2 cycles). Three patients (11%) had partial responses in phase 2; two demonstrated stable disease lasting 12 weeks or more. Median duration of response was 4.8 months. Overall, median progression-free survival was 1.4 months. Neutropenia (31%), febrile neutropenia (16%), and dyspnea (19%) were the most common grade 3/4 adverse events observed. CONCLUSIONS: Combined obatoclax mesylate plus docetaxel is tolerable in patients with NSCLC, but response was minimal and neutropenia was a common adverse event. PMID- 24346100 TI - RET rearrangements in lung adenocarcinoma and radiation. AB - BACKGROUND: RET rearrangement, a hallmark of radiation-induced thyroid cancer, has been reported to occur in 1% of lung adenocarcinoma patients. Patients with this rearrangement tend to be younger and never smokers, raising a possibility of other causes, such as radiation. We hypothesized that RET chromosomal rearrangement may represent a genetic mechanism of radiation-induced lung cancer. METHODS: Two hundred forty-five consecutive primary lung adenocarcinomas without history of radiation and 38 lung adenocarcinoma patients with a history of therapeutic radiation for breast carcinoma or mediastinal Hodkgin lymphoma were tested for RET rearrangement by fluorescence in situ hybridization. Human lung adenocarcinoma cells (201T) were subjected to gamma radiation and tested for RET gene fusions by reverse transcriptase-polymerase chain reaction and Southern blot hybridization. RESULTS: We identified one case with RET rearrangement in the group without history of radiation (1 of 240; 0.4%) and two cases in the group with history of radiation (2 of 37; 5.4%; P=0.0436). Both these patients were women, who were former smokers with a history of breast carcinoma treated with surgery and radiation. Furthermore, we found that RET fusions could be directly induced in 201T human lung cells by exposure to 1 Gy of gamma radiation. All fusions identified were between RET and KIF5B genes, and no RET fusions to CCDC6 or NCOA4 genes, characteristic for thyroid cancer, were identified in the irradiated lung cells. CONCLUSION: RET fusions may represent a genetic mechanism of radiation-induced lung adenocarcinoma. PMID- 24346102 TI - Randomized, double-blind, phase II trial comparing gemcitabine-cisplatin plus the LTB4 antagonist LY293111 versus gemcitabine-cisplatin plus placebo in first-line non-small-cell lung cancer. AB - INTRODUCTION: In this phase II study, patients with stage IIIB/IV non-small-cell lung cancer were randomly assigned (1:1:1) to receive LY293111 (200 mg twice daily [200 LY293111] or 600 mg twice daily [600 LY293111]) or placebo for 7 days, followed by concurrent cisplatin (75 mg/m2; day 1) and gemcitabine (1250 mg/m2; days 1 and 8), every 21 days.The primary endpoint was progression-free survival, (PFS), with 75% power to detect 33% improvement compared with placebo (5 months). METHODS: Of 200 randomized patients, 195 were treated. Demographics were well balanced across treatment arms: 65% of the patients were men; median age was 62 years; 85% had stage IV disease; and patients had an Eastern Cooperative Oncology Group performance status of 0 (36%) or 1 (64%). RESULTS: The most frequent study drug-related toxicities were nausea, vomiting, and fatigue. Response rates were similar across treatment arms (200 LY293111: 20%; 600 LY293111: 25%; placebo: 31%). CONCLUSIONS: Median PFS (95% confidence interval) was not significantly different across treatment arms (200 LY293111: 4.6 months [3.2-5.0]; 600 LY293111: 5.6 months [4.1-6.8]; placebo: 6.0 months [5.2-7.5]). LY293111 combined with gemcitabine-cisplatin did not increase median PFS compared with placebo plus gemcitabine-cisplatin in patients with non-small-cell lung cancer. PMID- 24346103 TI - Resection of a giant neuroblastoma misdiagnosed as atypical mediastinal carcinoid. PMID- 24346104 TI - Unsuspected collision of synchronous lung adenocarcinomas: a potential cause of aberrant driver mutation profiles. PMID- 24346105 TI - Complete pathologic response in soft tissue sarcoma lung metastases with pazopanib. PMID- 24346106 TI - Consolidation chemotherapy after concurrent radiochemotherapy in locally advanced non-small-cell lung cancer may have been beneficial if we only knew where it have worked. PMID- 24346107 TI - Role of consolidation chemotherapy after concurrent chemo-radiotherapy in locally advanced non-small-cell lung cancer. PMID- 24346108 TI - Lung adenocarcinoma with ipsilateral pleural and breast metastases. PMID- 24346109 TI - Dendroaspis natriuretic peptide is degraded by a metalloproteinase in the rat kidney. AB - Our previous study demonstrated that the concentration of dendroaspis natriuretic peptide (DNP) was markedly higher than that of atrial NP (ANP) in rabbit plasma, indicating that DNP has a different metabolic rate from other NPs. Therefore, the metabolic characteristics of DNP in mammals require further analysis. The stabilities of NPs were determined by incubating 125I-labeled ANP, brain NP (BNP), C-type NP (CNP) and DNP at 37C for 1, 2 and 4 h, and analyzing their profiles by reversed-phase high-performance liquid chromatography. 125I-labeled ANP, BNP and CNP were quickly degraded in rat plasma, while 125I-labeled DNP was stable for 4 h. The relative stability of the peptides following incubation in rat plasma followed the rank order of: DNP>>>ANP>=BNP>>CNP. Organs were also examined for the degradation of DNP, including the spleen, kidney, liver, heart and lung. The physiological target organ for the degradation of DNP was observed to be the kidney. Furthermore, degradation of DNP in the kidney was attenuated by phenanthroline, a metalloproteinase inhibitor. Therefore, these results indicate that DNP has a longer stability in plasma and that it may have strong therapeutic applications in cardiac disease. PMID- 24346110 TI - Methylglyoxal concentrations differ in standard and washed neonatal packed red blood cells. AB - BACKGROUND: Preterm infants have a greater risk of necrotizing enterocolitis following transfusion. It is hypothesized that high glucose concentrations in red blood cell (RBC) preservatives lead to increased methylglyoxal (MG) metabolism, causing glycation-driven damage to transfused RBCs. Such changes to the RBCs could promote a proinflammatory state in transfusion recipients. METHODS: Standard and washed RBCs in Adsol-3, two common neonatal preparations, were studied. Consecutive measurements were performed of glucose, MG, reduced glutathione, glyoxalase I activity (GLO-I), and D-lactate, the stable end product of MG detoxification by glyoxalase enzymes over the 42-d storage period. RESULTS: RBC units consume glucose and produceD-lactate and MG during storage. In 28/30 units, the MG concentrations showed only small variations during storage. Two units had elevated MG levels (>10 pmol/mg Hb) during the first half of storage. Washing of the RBCs significantly reduced both MG and D-lactate. CONCLUSION: This study shows two patterns of MG metabolism in packed RBCs for neonatal transfusion and raises the possibility that RBC units with higher MG levels may have increased glycation-driven damage in the transfused RBCs. Whether transfused MG could trigger an inflammatory response such as necrotizing enterocolitis in preterm neonates and whether washing could prevent this require further study. PMID- 24346111 TI - Systemic glycerol decreases neonatal rabbit brain and cerebellar growth independent of intraventricular hemorrhage. AB - BACKGROUND: Cerebellar hypoplasia is a common problem in preterm infants and infants suffering from intraventricular hemorrhage (IVH). To evaluate the effects of IVH on cerebellar growth and development, we used a neonatal rabbit model of systemic glycerol to produce IVH. METHODS: New Zealand White rabbit kits were surgically delivered 2 d preterm and treated with intraperitoneal glycerol (3.25 6.5 g/kg). Controls were born at term. IVH was documented by ultrasonography. Brain volumes determined by magnetic resonance imaging, cerebellar foliation, proliferation (Ki-67), and Purkinje cell density were assessed at 2 wk of life. Tissue glycerol and glutathione concentrations were measured. RESULTS: Glycerol increased IVH, subarachnoid hemorrhages, and mortality in a dose-dependent manner. Total cerebellar volumes, cerebellar foliation, and cerebellar proliferation were decreased in a dose-dependent manner. Glycerol accumulated rapidly in blood, brain, and liver and was associated with increased glutathione concentration. All of these results were independent of IVH status. CONCLUSION: Cerebellar hypoplasia was induced after glycerol administration in a dose dependent manner. Given the rapid tissue accumulation of glycerol, dose-dependent decrease in brain growth, and lack of IVH effect on measured outcomes, we question the validity of this model because glycerol toxicity cannot be ruled out. A better physiological model of IVH is needed. PMID- 24346112 TI - Noninvasive measurements of hemodynamic transition directly after birth. AB - BACKGROUND: Cardiac output depends on stroke volume and heart rate (HR). Only HR is used to monitor hemodynamic transition. METHODS: In 24 term newborns born via cesarean section, HR and preductal blood pressure (BP) were measured. Also, using echocardiography, left ventricular dimensions and (Doppler derived) left ventricular output (LVO) were examined at 2, 5, and 10 min after birth. RESULTS: Mean (SD) HR and BP did not change with time (mean HR: 157 (21) bpm at 2 min, 154 (17) bpm at 5 min, and 155 (14) bpm at 10 min; mean BP: 51.2 (15.4) mm Hg at 2 min, 50.5 (11.7) mm Hg at 5 min, and 49.6 (9.5) mm Hg at 10 min). Left ventricular end-diastolic diameter increased from 2 to 5 min (14.3 (1.3) vs. 16.3 (1.7) mm; P < 0.001) and stabilized at 10 min (16.7 (1.4) mm). LVO increased between 2 and 5 min (151 (47) vs. 203 (55) ml/kg/min; P < 0.001) and stabilized at 10 min (201 (45) ml/kg/min). LVO increase was associated with rise in left ventricular stroke volume (r = 0.94; P < 0.001), not with rise in HR (r = 0.37; P value not significant). CONCLUSION: Left ventricular dimensions and LVO significantly increased the first 5 min after birth and stabilized at 10 min, whereas BP remained stable. LVO and left ventricular dimension increase are presumably due to increasing left ventricular preload resulting from pulmonary blood flow and ductal shunting increase. PMID- 24346113 TI - Definition and quantification of acute inflammatory white matter injury in the immature brain by MRI/MRS at high magnetic field. AB - BACKGROUND: Lipopolysaccharide (LPS) injection in the corpus callosum (CC) of rat pups results in diffuse white matter injury similar to the main neuropathology of preterm infants. The aim of this study was to characterize the structural and metabolic markers of acute inflammatory injury by high-field magnetic resonance imaging (MRI) magnetic resonance spectroscopy (MRS) in vivo. METHODS: Twenty-four hours after a 1-mg/kg injection of LPS in postnatal day 3 rat pups, diffusion tensor imaging and proton nuclear magnetic spectroscopy ((1)H NMR) were analyzed in conjunction to determine markers of cell death and inflammation using immunohistochemistry and gene expression. RESULTS: MRI and MRS in the CC revealed an increase in lactate and free lipids and a decrease of the apparent diffusion coefficient. Detailed evaluation of the CC showed a marked apoptotic response assessed by fractin expression. Interestingly, the degree of reduction in the apparent diffusion coefficient correlated strongly with the natural logarithm of fractin expression, in the same region of interest. LPS injection further resulted in increased activated microglia clustered in the cingulum, widespread astrogliosis, and increased expression of genes for interleukin (IL)-1, IL-6, and tumor necrosis factor. CONCLUSION: This model was able to reproduce the typical MRI hallmarks of acute diffuse white matter injury seen in preterm infants and allowed the evaluation of in vivo biomarkers of acute neuropathology after inflammatory challenge. PMID- 24346114 TI - Dexamphetamine effects on prepulse inhibition (PPI) and startle in healthy volunteers. AB - RATIONALE: Amphetamine challenge in rodent prepulse inhibition (PPI) studies has been used to model potential dopamine involvement in effects that may be relevant to schizophrenia, though similar studies in healthy humans have failed to report replicable or robust effects. OBJECTIVES: The present study investigated dexamphetamine effects on PPI in healthy humans with an increased dose and a range of startling stimulus intensities to determine participants' sensitivity and range of responses to the stimuli. METHODS: A randomised, placebo-controlled dexamphetamine (0.45 mg/kg, per os.), double-blind, counterbalanced, within subject design was used. PPI was measured in 64 participants across a range of startling stimulus intensities, during two attention set conditions (ATTEND and IGNORE). Startle magnitudes for pulse-alone and prepulse-pulse magnitudes were modelled using the startle reflex magnitude (sigmoid) function. Parameters were extracted from these fits, including the upper limit of the asymptote (maximum startle reflex capacity, R MAX), intensity threshold, stimulus intensity that elicits a half-maximal response (ES50) and the maximum rate of change of startle response magnitude to an increase in stimulus intensity. RESULTS: Dexamphetamine increased the threshold and ES50 of the response to pulse-alone trials in both sexes and reduced R MAX exclusively in females. Dexamphetamine modestly increased PPI of the R MAX across both attention conditions. PPI of R MAX was reduced during the ATTEND condition compared to the IGNORE condition. CONCLUSIONS: Results indicate that sex differences exist in motor, but not sensory, components of the startle reflex. Findings also reveal that administration of 0.45 mg/kg dexamphetamine to healthy humans does not mimic PPI effects observed in schizophrenia. PMID- 24346115 TI - Highly efficient and unidirectional energy transfer within a tightly self assembled host-guest multichromophoric array. AB - The coordination-driven synthesis of a rhomboid cavitand composed of two different Bodipys and its inclusion complex with 1,3,6,8-tetrasulfopyrene via ionic self-assembly was established by X-ray crystallography. Highly efficient and unidirectional intra-host and guest-to-host energy transfer was demonstrated by femtosecond fluorescence spectroscopy. PMID- 24346117 TI - Structural and computational insights into the versatility of cadmium binding to proteins. AB - Cadmium is a highly toxic group XII metal, similar to zinc and mercury. Unlike zinc, which is one of the most common metal cofactors in biology, cadmium is highly toxic. Many Zn(2+)-binding proteins can bind Cd(2+)-ions without significantly affecting their structures. Here, the protein data bank is analysed with regard to protein-cadmium interactions, which shows that cadmium can bind to a variety of ion binding sites in proteins. Statistical analysis of Cd(2+)-side chain interactions is compared with a similar analysis of other ions. This analysis reveals that with regard to amino acid side-chain preference, Cd(2+) is more similar to Mn(2+) than to Zn(2+) or Hg(2+). Finally, the interaction energies of three native metal binding proteins are calculated where Cd(2+) binds instead of Zn(2+), Ca(2+) or Cu(2+). The interaction energies are decomposed into individual components whose contributions are discussed. PMID- 24346116 TI - Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. AB - B-cell leukemia/lymphoma 2 (BCL-2) prevents commitment to programmed cell death at the mitochondrion. It remains a challenge to identify those tumors that are best treated by inhibition of BCL-2. Here, we demonstrate that acute myeloid leukemia (AML) cell lines, primary patient samples, and murine primary xenografts are very sensitive to treatment with the selective BCL-2 antagonist ABT-199. In primary patient cells, the median IC50 was approximately 10 nmol/L, and cell death occurred within 2 hours. Our ex vivo sensitivity results compare favorably with those observed for chronic lymphocytic leukemia, a disease for which ABT-199 has demonstrated consistent activity in clinical trials. Moreover, mitochondrial studies using BH3 profiling demonstrate activity at the mitochondrion that correlates well with cytotoxicity, supporting an on-target mitochondrial mechanism of action. Our protein and BH3 profiling studies provide promising tools that can be tested as predictive biomarkers in any clinical trial of ABT 199 in AML. PMID- 24346118 TI - Longitudinal pulmonary functional loss in cotton textile workers: a 5-year follow up study. AB - BACKGROUND: Occupational exposure to cotton dust causes several diseases affecting the lungs, but only limited information is available on effects of long term exposure. In this study, we aimed to evaluate longitudinal changes in selected parameters of pulmonary function in textile workers. MATERIAL AND METHODS: This prospective cohort study began with 196 textile workers in 2006 and was completed in 2011 with 49 workers. We used standardized tests for pulmonary function on participants on the first day of the workweek in June of 2006 and 2011. Environmental samples of cotton dust were gathered with a vertical elutriator. Loss of pulmonary function was assessed based on gender and smoking status. RESULTS: The mean number of years participants worked in the textile factory was 7.61 +/- 1.83 years, and the mean age was 35.3+5.8 years. The annual FEV1 loss of all workers was 53.2 ml, giving a ratio of annual FEV1 loss to baseline FEV1 of 1.4%. Pulmonary function parameters of all participants in 2011 were significantly lower than those in 2006 (for all, p<0.05). In both surveys, pulmonary function in current smokers was lower, but this difference was not significant (p>0.05). CONCLUSIONS: This study provides the first data on pulmonary functional loss in Turkish textile workers and supports the findings of other cohort studies that workers with long-term exposure to cotton dust may lose some pulmonary function. The ratio of annual FEV1 loss to baseline FEV1 appears to be a more accurate and comparable method than annual FEV1 loss for evaluating pulmonary functional loss. PMID- 24346119 TI - Optimization of competency in obstetrical emergencies: a role for simulation training. AB - PURPOSE: In obstetrical emergency situations, optimal management requires the immediate coordinated actions of a multi-disciplinary and multi-professional team. This study investigated the influence of simulation training on four specific skills: self-confidence, handling of emergency situation, knowledge of algorithms and team communication. METHODS: Clinical algorithms were first presented to the participants. Training for six emergency situations (shoulder dystocia, postpartum haemorrhage, pre-eclampsia, maternal basic life support, neonatal resuscitation and operative vaginal birth) was performed using high- and low-fidelity simulation mannequins. General impression of the simulation training and the four above-mentioned skills were evaluated anonymously through a self assessment questionnaire with a five-point Likert scale immediately after the training and 3 months later. RESULTS: From November 2010 to March 2012, 168 participants, distributed over six one-day courses, took part in the training. 156 participants returned the questionnaire directly after the course (92.9 %). The questionnaire return rate after 3 months was 36.3 %. The participants gave higher Likert scale answers for the questions on the four specific skills after 3 months compared to immediately after the course. The improvement was statistically significant (p <= 0.05) except for the question regarding team communication. CONCLUSION: Implementation of simulation training strengthens the professional competency. PMID- 24346120 TI - Detection of E6-AP as a potential therapeutic target in cervical specimen of HPV infected women. AB - PURPOSE: Silencing of HPV oncogenes or their human host client proteins using topically applied small interfering RNA (siRNA) may be an attractive nonsurgical strategy for CIN treatment. An exploratory clinical investigation was designed to evaluate E6-AP mRNA expression levels in different stages of cervical intraepithelial neoplasia and during the menstrual cycle. METHODS: In 38 premenopausal women aged 18-45 years referred to colposcopy clinic, analysis of serum hormones, cervical smears for cytology and HPV DNA, cervical biopsy, p16 immunohistochemistry and E6-AP mRNA expression levels in cervical smears and biopsies were performed. The intra-subject variability in E6-AP mRNA expression of vaginal smears was assessed and compared to cervical biopsy specimens. RESULTS: RNA of sufficient quantity and quality was available for E6-AP expression analysis from 97 % of the collected cervical smears and from 56 % of the collected biopsy samples. The normalized RNA levels from cervical smears were approximately tenfold higher compared to biopsies. There was little influence by the phase of the menstrual cycle or by CIN stage. Real-time PCR showed that the expression level of E6-AP is in a range (<28 C t) that would allow for detection of at least 100-fold modulation by a therapeutic agent (based on an assay LOD of C t = 36). CONCLUSIONS: Our findings suggest a potential therapeutic approach using E6-AP siRNA as a specific molecular target in cervical intraepithelial neoplasia. PMID- 24346121 TI - Chlamydia trachomatis infection: implications for HPV status and cervical cancer. AB - Genital Chlamydia trachomatis (CT) infections have been identified as a major health problem concern. CT is associated with adverse effect on women reproduction and also associated with cervical hypertrophy and induction of squamous metaplasia, providing a possible relationship with human papillomavirus (HPV) infection. Infection by high-risk HPV types is crucial to the pathogenesis of invasive cervical cancer (ICC), but other co-variants/cofactors must be present for the development of malignancy. CT biological effect may damage the mucosal barrier, improving HPV infection, or may interfere in immune response and viral clearance supporting the persistence of HPV infection. Moreover, CT-related chronic cervical inflammation, decrease of lower genital tract antigen-presenting cells, inhibition of cell-mediated immunity, and anti-apoptotic capacity may influence the natural history of HPV infection, namely persistence progression or resolution. Although several epidemiological studies have stated a positive association involving CT and HPV-related cervical neoplastic lesions and/or cervical cancer (CC), the specific role of this bacterium in the pathogenesis of cervical neoplasia has not been completely clarified. The present review summarizes several studies on CT role in cervical cancer and suggests future research directions on HPV and CT interaction. PMID- 24346122 TI - Immunohistochemical expression of p16 and HPV L1 capsid proteins as predictive markers in cervical lesions. AB - PURPOSE: Human papilloma virus (HPV) infection is the most important cause of cervical cancer, but only 2 % of cervical HPV infections will develop into cervical cancer. p16 INK4A has been introduced as a marker for HPV infection in cervix. HPV L1 capsid protein is also known to be associated with the productive phase of HPV infection; however, expression pattern in different HPV-associated cervical lesion and its correlation to p16 expression is not still well understood. The authors aimed to elucidate the relationship between L1 and p16 expression in cervical lesions. METHODS: Immunohistochemical studies using antibodies against L1 capsid and P16 proteins were carried out on 89 paraffin embedded tissue samples including 11 low-grade cervical intraepithelial neoplasias (CIN), 11 high-grade CINs, 20 cervical squamous cell carcinomas (SCC), eight cervical adenocarcinomas and 39 normal cervical tissues as a control group. RESULTS: L1 capsid protein was positive in 63.6 % of low-grade CINs and 9.1 % of high-grade CINs; while none of the cervical SCCs, adenocarcinomas or normal cervical tissues showed this marker. In contrast, p16 protein was positive in 81.8 % of low-grade CINs, 90.1 % of high-grade CINs, 90 % of SCCs, 75 % of adenocarcinomas and 10.25 % of normal cervical tissues (p value < 0.001). CONCLUSION: Despite the presence of interobserver variation in the histopathologic interpretation of cervical lesions, in more instances definite diagnosis is made by routine histopathological examination and these ancillary tests are supportive in follow-up of the patient. PMID- 24346123 TI - Acute colonic pseudo-obstruction after hysterectomy in a patient with Friedreich ataxia. AB - Acute colonic pseudo-obstruction is a rare complication of gynecological surgery. Despite the complete description of this condition, diagnosis remains difficult and is often delayed. Due to delay in diagnosis and existence of serious comorbid illnesses, morbidity and mortality approaches higher levels. Early recognition of signs and symptoms of this condition and prompt accurate management are vital to prevent serious mortality. Here, we report a case of acute colonic pseudo obstruction after total abdominal hysterectomy in a patient with known Friedreich ataxia. PMID- 24346124 TI - Effects of MACC1 siRNA on biological behaviors of HeLa. AB - PURPOSE: Metastasis-associated in colon cancer 1 (MACC1) has been shown to play a critical role in several types of cancer. The purposes of this study were to evaluate MACC1 expression in cervical cancer and determine role of MACC1 small interference RNA (siRNA) in the growth and progression of cervical cancer. METHODS: Immunohistochemical analysis of MACC1 expression was performed in different cervical lesion tissues. siRNA knockdown of MACC1 was performed. Cytoskeletal staining, RT-PCR, Western blot technology, transwell migration, MTT, and flow cytometry were used for identification of the functional roles of MACC1 siRNA in HeLa cells. RESULTS: Immunohistochemistry demonstrated that MACC1 overexpression was detected in cervical cancer tissues. MACC1 siRNA transfection remarkably affected HeLa cell biological behaviors. Expression of MACC1 in HeLa cells was significantly down-regulated by MACC1 siRNA. In addition, knockdown of MACC1 in HeLa cells caused a significant decrease in cell proliferation or migration, and increased cell apoptosis rate. Flow cytometry showed that MACC1 siRNA may inhibit cell proliferation by interfering with cell mitosis and cell cycle progression. CONCLUSIONS: These results suggest that MACC1 is a novel biomarker for cervical cancer diagnosis and a target for therapeutic interventions. Decreasing MACC1 expression by siRNA may prove to be an effective genetic therapy strategy. PMID- 24346126 TI - Using molecular profiles to tailor treatment in breast cancer: are they ready for prime time? AB - PURPOSE OF REVIEW: In this article, recent developments with molecular profiling in breast cancer and future directions will be highlighted. RECENT FINDINGS: Gene expression profiling revealed four major biologic subtypes that reflect intertumoral heterogeneity of breast cancer and have led to the development of prognostic tools to facilitate adequate treatment in early breast cancer. A number of commercially available prognostic tests have been introduced for implementation in clinical routine. Also, predictive tools and approaches to characterize molecular portraits of metastatic breast cancer in order to overcome treatment resistance have been investigated. Efforts to identify the quantity and quality of clonal selection and genomic variability through modern genomic profiling led successfully to new insights into targeted treatment with more effective drugs and the promise to overcome resistance. SUMMARY: Multigene approaches and novel microarray platforms such as the next-generation sequencing technology are feasible in clinical practice in order to assess the prognosis more precisely and to identify new molecular targets for developing more effective drugs in the near future. PMID- 24346127 TI - The renaissance of endocrine therapy in breast cancer. AB - PURPOSE OF REVIEW: Endocrine therapy for breast cancer has been the cornerstone of treatment for over a century since the discovery of the regressive effect of oophorectomy on 'cancer of the mamma' in 1896 by Beatson. Studies in the prevention and treatment of both early and metastatic breast cancer will be reviewed with a focus on recent large randomized clinical trials that may be practice changing. RECENT FINDINGS: Data from pivotal clinical trials that looked at the duration of adjuvant tamoxifen therapy in premenopausal women will be discussed. In addition, several recent clinical trials that address the optimal sequence of endocrine therapy and advances in the treatment of endocrine resistant metastatic disease will be reviewed. New findings from molecular studies that demonstrate targets in the endocrine axis and the role of aromatase inhibitors in the prevention setting will be highlighted. SUMMARY: Overall, these clinical trials show the benefit of aromatase inhibitors in the prevention setting, longer duration of tamoxifen in the adjuvant setting for premenopausal women, and new biologic agents with hormonal therapies. PMID- 24346128 TI - Triple-negative breast cancer: molecular subtypes and targeted therapy. AB - PURPOSE OF REVIEW: Triple-negative breast cancers (TNBCs), lacking estrogen receptor expression and human epidermal growth factor receptor 2 amplification, have no effective targeted therapy. Large-scale comprehensive genomic analyses have allowed stratification of TNBCs by molecular features. We will review the recent data regarding the classification of these poor prognosis cancers and the associated potential targeted treatment approaches. RECENT FINDINGS: TNBCs are a heterogeneous set of cancers characterized by a diverse set of gene-expression patterns and underlying genomic changes. Mutations in p53 are the only genomic alteration present in the majority of TNBCs. Other potential targetable alterations are only present in small subsets of TNBCs, and include defects in DNA repair present in BRCA1-mutant TNBCs and some sporadic TNBCs. Antiandrogens may be effective for TNBCs that express the androgen receptor and have luminal like gene-expression features. PI3KCA pathway inhibitors and HSP90 inhibitors may also be effective in a small fraction of TNBCs. SUMMARY: Robust methods to functionally classify TNBCs to determine vulnerable pathways are urgently needed to guide the development of clinical trials. It is quite possible that TNBCs, like non-small cell lung cancer, will be stratified into many individually rare cancer classes, each requiring a distinct treatment approach. PMID- 24346129 TI - Sequencing efforts help to refine the molecular classification of breast cancer. PMID- 24346125 TI - A review of signals used in sleep analysis. AB - This article presents a review of signals used for measuring physiology and activity during sleep and techniques for extracting information from these signals. We examine both clinical needs and biomedical signal processing approaches across a range of sensor types. Issues with recording and analysing the signals are discussed, together with their applicability to various clinical disorders. Both univariate and data fusion (exploiting the diverse characteristics of the primary recorded signals) approaches are discussed, together with a comparison of automated methods for analysing sleep. PMID- 24346130 TI - Eight-year update of a prospective study of wide excision alone for small low- or intermediate-grade ductal carcinoma in situ (DCIS). AB - Whether wide excision with margins >=1 cm is sufficient treatment for small low- or intermediate-grade ductal carcinoma in situ (DCIS) is unclear. This is an updated analysis of a phase II, single-arm, prospective trial testing this hypothesis. A total of 158 patients with low- or intermediate-grade DCIS who underwent wide excision alone (without radiation or tamoxifen) were entered onto the trial from 1995 to 2002. Entry criteria included mammographic extent <=2.5 cm, predominantly low or intermediate nuclear grade, and excision with final microscopic margins >=1 cm. Eight-year minimum potential follow-up was required for inclusion in the analysis; the final population comprised 143 patients. Cumulative incidence curves were generated to assess rates of local recurrence (LR) or other events. Median follow-up time was 11 years. Nineteen patients (13 %) had LR as a first event within 8 years. Thirteen LR (68 %) were DCIS only and six (32 %) were invasive. Fourteen (74 %) occurred in the original quadrant. The 10-year estimated cumulative incidence of LR was 15.6 %. The estimated annual percentage rate of LR was 1.9 % per patient-year. With longer follow-up, there remains a substantial and ongoing risk of LR in patients with favorable DCIS treated with wide excision margins without radiation. This information should be useful as patients and clinicians weigh the options of wide excision with and without radiation. PMID- 24346131 TI - Distinguishing between yield advances and yield plateaus in historical crop production trends. AB - Food security and land required for food production largely depend on rate of yield gain of major cereal crops. Previous projections of food security are often more optimistic than what historical yield trends would support. Many econometric projections of future food production assume compound rates of yield gain, which are not consistent with historical yield trends. Here we provide a framework to characterize past yield trends and show that linear trajectories adequately describe past yield trends, which means the relative rate of gain decreases over time. Furthermore, there is evidence of yield plateaus or abrupt decreases in rate of yield gain, including rice in eastern Asia and wheat in northwest Europe, which account for 31% of total global rice, wheat and maize production. Estimating future food production capacity would benefit from an analysis of past crop yield trends based on a robust statistical analysis framework that evaluates historical yield trajectories and plateaus. PMID- 24346132 TI - Atomic distribution and structural evolution of mesostructured PtRu nanoparticles electrodeposited on a microemulsion lyotropic liquid-crystalline template probed using EXAFS and XANES. AB - Mesostructured PtRu nanoparticles were electrochemically reduced from their metallic salts directed by a hexagonally packed microemulsion lyotropic liquid crystalline (MLLC) template. We investigated the structural evolution and atomic distribution of the MLLC-templated mesoporous PtRu nanoparticles (NPs) after electroreduction for varied duration using X-ray absorption near edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) spectroscopy, complemented by energy-dispersive X-ray spectroscopy (EDS) and field-emission transmission electron microscopy (FE-TEM). The XANES data at the Ru L2,3 and Pt L3 edges show predominantly metallic states of Ru and Pt in the PtRu NPs upon electroreduction. The reduction of Ru(3+) ions in RuCl3 into Ru atoms involves intermediate RuCl-containing complexes. A more rapid reduction of Pt precursors and a release of Ru atoms from Ru precursors in two steps upon electroreduction resulted in aggregation into PtRu nanoparticles, featuring a Pt-rich core, a Ru rich shell and a varied alloy extent of Ru, deduced from EXAFS data. The complementary results provide insight into the mechanism of growth and atomic distribution of mesostructured PtRu bimetallic nanoparticles from the use of the MLLC-type templates. PMID- 24346133 TI - A randomized placebo-controlled trial of an omega-3 fatty acid and vitamins E+C in schizophrenia. AB - Membrane lipid metabolism and redox regulation may be disturbed in schizophrenia. We examined the clinical effect of adding an omega-3 fatty acid and/or vitamins E+C to antipsychotics. It was hypothesized that lower baseline levels of polyunsaturated fatty acids (PUFAs) would predict more benefit from the add-on treatment. The trial had a multicenter, randomized, double-blind, placebo controlled 2 * 2 factorial design. Patients aged 18-39 years with schizophrenia or related psychoses were consecutively included at admission to psychiatric departments in Norway. They received active or placebo ethyl-eicosapentaenoate (EPA) 2 g day-1 and active or placebo vitamin E 364 mg day-1+vitamin C 1000 mg day-1 (vitamins) for 16 weeks. The main outcome measures were Positive and Negative Syndrome Scale (PANSS) total and subscales scores, analyzed by linear mixed models. Ninety-nine patients were included. At baseline, erythrocyte PUFA were measured in 97 subjects. Given separately, EPA and vitamins increased drop out rates, whereas when combined they did not differ from placebo. In low PUFA patients, EPA alone impaired the course of total PANSS (Cohen's d=0.29; P=0.03) and psychotic symptoms (d=0.40; P=0.003), especially persecutory delusions (d=0.48; P=0.0004). Vitamins alone impaired the course of psychotic symptoms (d= 0.37; P=0.005), especially persecutory delusions (d=0.47; P=0.0005). Adding vitamins to EPA neutralized the detrimental effect on psychosis (interaction d=0.31; P=0.02). In high PUFA patients, there were no significant effects of trial drugs on PANSS scales. In conclusion, given separately during an acute episode, EPA and vitamins E+C induce psychotic symptoms in patients with low levels of PUFA. Combined, these agents seem safe. PMID- 24346134 TI - All-trans retinoic acid-induced hypothalamus-pituitary-adrenal hyperactivity involves glucocorticoid receptor dysregulation. AB - Clinical reports have highlighted a role for retinoids in the etiology of mood disorders. Although we had shown that recruitment of the nuclear receptor retinoic acid receptor-alpha (RAR-alpha) to corticotropin-releasing hormone (CRH) promoter is implicated in activation of the hypothalamus-pituitary-adrenal (HPA) axis, further insight into how retinoids modulate HPA axis activity is lacking. Here we show that all-trans retinoic acid (RA)-induced HPA activation involves impairments in glucocorticoid receptor (GR) negative feedback. RA was applied to rats chronically through intracerebroventricular injection. A 19-day RA exposure induced potent HPA axis activation and typical depression-like behavior. Dexamethasone failed to suppress basal corticosterone (CORT) secretion, which is indicative of a disturbed GR negative feedback. In the hypothalamic paraventricular nucleus, increased CRH+ and c-fos+ cells were found while a negative R-2+/ER+ correlation was present between the number of RAR-alpha+ and GR+ cells. This was paralleled by increased RAR-alpha and decreased GR protein expression in the hypothalamus. Additional in vitro studies confirmed that RA abolished GR-mediated glucocorticoid-induced suppression of CRH expression, indicating a negative cross-talk between RAR-alpha and GR signaling pathways. Finally, the above changes could be rapidly normalized by treatment with GR antagonist mifepristone. We conclude that in addition to the 'classic' RAR-alpha mediated transcriptional control of CRH expression, disturbances in GR negative feedback constitute a novel pathway that underlies RA-induced HPA axis hyperactivity. The rapid normalization by mifepristone may be of potential clinical interest in this respect. PMID- 24346135 TI - Behavioral and neuroimaging evidence for overreliance on habit learning in alcohol-dependent patients. AB - Substance dependence is characterized by compulsive drug-taking despite negative consequences. Animal research suggests an underlying imbalance between goal directed and habitual action control with chronic drug use. However, this imbalance, and its associated neurophysiological mechanisms, has not yet been experimentally investigated in human drug abusers. The aim of the present study therefore was to assess the balance between goal-directed and habit-based learning and its neural correlates in abstinent alcohol-dependent (AD) patients. A total of 31 AD patients and 19 age, gender and education matched healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) during completion of an instrumental learning task designed to study the balance between goal-directed and habit learning. Task performance and task-related blood oxygen level-dependent activations in the brain were compared between AD patients and healthy matched controls. Findings were additionally associated with duration and severity of alcohol dependence. The results of this study provide evidence for an overreliance on stimulus-response habit learning in AD compared with HC, which was accompanied by decreased engagement of brain areas implicated in goal directed action (ventromedial prefrontal cortex and anterior putamen) and increased recruitment of brain areas implicated in habit learning (posterior putamen) in AD patients. In conclusion, this is the first human study to provide experimental evidence for a disturbed balance between goal-directed and habitual control by use of an instrumental learning task, and to directly implicate cortical dysfunction to overreliance on inflexible habits in AD patients. PMID- 24346137 TI - In-vitro biocompatibility and corrosion resistance of strontium incorporated TiO2 nanotube arrays for orthopaedic applications. AB - This article investigates the in-vitro biocompatibility and corrosion behaviour of strontium ion incorporated TiO2 nanotube arrays formed by anodization method for orthopaedic applications. The morphological studies were carried out using field emission scanning electron microscopy, atomic force microscopy, attenuated total reflectance fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy and thin film X-ray diffraction techniques. The morphological investigation indicated that the length and the average diameter of nanotube were 2.1 +/- 0.3 um and 110 +/- 4 nm, respectively. The wettability measurements showed that the TiO2 nanotube arrays have super wettability, as well as, strontium ion incorporated TiO2 nanotube arrays exhibited hydrophilic behaviour. Excellent in-vitro bioactivity was observed for TiO2 nanotube arrays with strontium ions. Electrochemical studies in Hank's solution showed that the TiO2 nanotube arrays with strontium ions have enhanced corrosion resistance. PMID- 24346136 TI - dcc orchestrates the development of the prefrontal cortex during adolescence and is altered in psychiatric patients. AB - Adolescence is a period of heightened susceptibility to psychiatric disorders of medial prefrontal cortex (mPFC) dysfunction and cognitive impairment. mPFC dopamine (DA) projections reach maturity only in early adulthood, when their control over cognition becomes fully functional. The mechanisms governing this protracted and unique development are unknown. Here we identify dcc as the first DA neuron gene to regulate mPFC connectivity during adolescence and dissect the mechanisms involved. Reduction or loss of dcc from DA neurons by Cre-lox recombination increased mPFC DA innervation. Underlying this was the presence of ectopic DA fibers that normally innervate non-cortical targets. Altered DA input changed the anatomy and electrophysiology of mPFC circuits, leading to enhanced cognitive flexibility. All phenotypes only emerged in adulthood. Using viral Cre, we demonstrated that dcc organizes mPFC wiring specifically during adolescence. Variations in DCC may determine differential predisposition to mPFC disorders in humans. Indeed, DCC expression is elevated in brains of antidepressant-free subjects who committed suicide. PMID- 24346139 TI - Nomegestrol acetate/estradiol hormonal oral contraceptive and breast cancer risk. AB - Combined hormonal contraceptives (CHCs) contain estrogen and progestin, which can stimulate estrogen-sensitive and/or progesterone-sensitive breast cancer growth. Until recently, ethinylestradiol had been almost the only estrogen used for decades, and its dose has been greatly reduced over time. The first generations of birth control pills contained approximately five times more estrogen and four times more progestin than the latest contraceptives. Newer CHCs also contain steroids that more closely mimic the physiological estradiol (E2) and progesterone effects. The newer CHC formulations are thus expected to have less influence on the breast, although it is very difficult to demonstrate any difference among the recent available preparations in human studies. Recently, nomegestrol acetate (NOMAC), a neutral, nonandrogenic, progesterone-like profile progestin, has become available in combination with the 'natural' estrogen, E2. According to the literature, NOMAC/E2 is expected to have either a lesser stimulating effect or a neutral effect on estrogen-sensitive breast cancers. We performed an analysis of the available studies and a bibliographical review. The endocrine and metabolic effects of NOMAC/E2 formulation might lead to a lesser breast tissue stimulation. The data reported, confirmed through clinical studies, should be considered when choosing a hormonal contraceptive, especially when breast stimulation is a concern. PMID- 24346140 TI - Optical properties and sensing in plexcitonic nanocavities: from simple molecular linkers to molecular aggregate layers. AB - We present a theoretical study of a metal-molecular aggregate hybrid system consisting of a strongly coupled dimer connected by molecules characterized by an excitonic transition. The plasmonic resonances of the metallic dimer interact with the molecular excitations giving rise to coupled plasmon-exciton states, so called plexcitons. We compare the differences in the optical response when the excitonic material is placed only as a linker in the plasmonic gap of the dimer and when the material is distributed as an aggregate layer covering the dimer entirely. We also explore the efficiency of plexcitons for localized surface plamon resonance (LSPR) sensing in both situations. The ordinary shift-based sensing is more efficient for dimers connected through molecular linkers, whereas intensity-based sensing is more effective when the molecular aggregate covers the entire nanostructure. These results can serve to design the chemistry of excitons around metallic nanoparticles. PMID- 24346138 TI - The potential role of kynurenines in Alzheimer's disease: pathomechanism and therapeutic possibilities by influencing the glutamate receptors. AB - The pathomechanism of neurodegenerative disorders still poses a challenge to neuroscientists, and continuous research is under way with the aim of attaining an understanding of the exact background of these devastating diseases. The pathomechanism of Alzheimer's disease (AD) is associated with characteristic neuropathological features such as extracellular amyloid-beta and intracellular tau deposition. Glutamate excitotoxicity and neuroinflammation are also factors that are known to contribute to the neurodegenerative process, but a cerebrovascular dysfunction has recently also been implicated in AD. Current therapeutic tools offer moderate symptomatic treatment, but fail to reduce disease progression. The kynurenine pathway (KP) has been implicated in the development of neurodegenerative processes, and alterations in the KP have been demonstrated in both acute and chronic neurological disorders. Kynurenines have been suggested to be involved in the regulation of neurotransmission and in immunological processes. Targeting the KP, therefore, offers a valuable strategic option for the attenuation of glutamatergic excitotoxicity, and for neuroprotection. PMID- 24346141 TI - Wnt5a, TLR2 and TLR4 are elevated in advanced human atherosclerotic lesions. AB - OBJECTIVE AND DESIGN: Atherosclerosis (ATH) is a chronic inflammatory disease that involves cascades of signaling events mediated by various effector proteins. Here we sought to determine if the expression of Wnt5a, a secreted glycoprotein, is altered in discrete regions of the arterial plaque. METHODS: Atherosclerotic plaque tissues from 14 human subjects undergoing elective carotid endarterectomy were used in this study. Immunohistochemistry and laser capture microdissection combined with quantitative real-time PCR were used to determine the expression of Wnt5a and Toll-like receptors (TLRs) in different sections of the arterial lesions. Atherosclerotic serum samples (n = 30) and serum from healthy subjects (n = 16) were quantified for Wnt5a using an enzyme-linked immunosorbent assay (ELISA). RESULTS: The data analysis revealed that Wnt5a transcripts and protein were elevated in advanced arterial lesions relative to less advanced arterial lesions; that Wnt5a expression correlated with the presence of TLR4 and TLR2 transcripts; and that the average amount of Wnt5a protein present in atherosclerotic patient serum was significantly higher compared to healthy controls. CONCLUSIONS: This study is the first to provide evidence that the expression of Wnt5a increases as the disease progresses to a more advanced stage, and that this expression is coincident with that of TLR2 and TLR4. In addition, we found that the average Wnt5a levels in the serum of atherosclerotic patients are elevated relative to healthy controls, which is consistent with the hypothesis that Wnt5a plays a role in ATH. PMID- 24346144 TI - Biomedical mass spectrometry. PMID- 24346143 TI - Study of the ESI and APCI interfaces for the UPLC-MS/MS analysis of pesticides in traditional Chinese herbal medicine. AB - In this work, 53 selected pesticides of different chemical groups were extracted from Chinese herbal medicines and determined by ultra-high-performance liquid chromatography (UHPLC)-tandem mass spectrometry (MS/MS) using both electrospray ionization (ESI) and atmospheric-pressure chemical ionization (APCI). Extracts were obtained using the acetonitrile-based quick, easy, cheap, effective, rugged, and safe (QuEChERS) sample preparation technique. Cleanup was performed by dispersive solid-phase extraction using primary secondary amine, graphitized carbon black, and octadecylsilane. Two atmospheric-pressure interfaces, ESI and APCI, were checked and compared. The validation study, including detection limits, linearity, and matrix effects, was conducted on fritillaria, radix ginseng, folium isatidis, semen persicae, and flos lonicerae in multiple reaction monitoring mode. These matrices represent a variety of plants used in traditional Chinese medicine. Fritillaria and radix ginseng were chosen as representatives for roots, folium isatidis was chosen as a representative for leaves, semen persicae was chosen as a representative for seeds, and flos lonicerae was chosen as a representative for flowers. The limits of detection for pesticides were lower in the UHPLC-ESI-MS/MS method than in the UHPLC-APCI-MS/MS method. Matrix effects on the two ionizations were evaluated for the five matrices. Soft signal enhancement in UHPLC-APCI-MS/MS and signal suppression in UHPLC-ESI-MS/MS were observed. PMID- 24346145 TI - It's all about Me: methyl-induced control of coordination stereochemistry by a flexible tridentate N,C,N' ligand. AB - A chiral, tridentate, pyridyl-functionalised NHC pro-ligand, S-L(Me)-H[PF6], has been prepared diastereoselectively via a five step synthesis starting from 1R,3S diamino-1,2,2-trimethylcyclopentane. The S prefix refers to the stereochemistry of a methyl substituted stereogenic carbon in one of the pyridyl arms which is generated by a stereoselective BH4(-) reduction of an imine precursor. The ligand has been coordinated to Rh(I) and Ir(I) to give trigonal bipyramidal complexes of the type [M(kappa(3)-N,C,N'-S-L(Me))(1,5-COD)]PF6 (M = Rh, Ir) as single diastereomers. A combination of spectroscopic and X-ray techniques confirm the stereoselective formation of the thermodynamically preferred endo,endo isomer. Similar reactions with R,S-L(Me)-H[PF6] gave a mixture of endo,endo-[M(kappa(3) N,C,N'-S-L(Me))(1,5-COD)](+) and exo,exo-[M(kappa(3)-N,C,N'-R-L(Me))(1,5 COD)](+). The absolute configuration at the metal is, therefore, solely dictated by the stereochemistry of the single methylpyridyl carbon. The observation of stereoselection extends to the square planar Ni(II) complex [Ni(delta-kappa(3) N,C,N'-S-L(Me))Cl](+) which is isolated as one (delta) of the two possible conformational isomers. DFT studies have been employed to explain the observed stereoselectivity with the configurations observed in the solid state being confirmed as those of lowest energy. PMID- 24346146 TI - Drug delivery without nanoparticle uptake: delivery by a kiss-and-run mechanism on the cell membrane. AB - Nearly all concepts of nanocarriers as drug delivery devices rely on intracellular uptake. Instead, we demonstrate an alternative concept for rapid and specific delivery of cargo by nanoparticles to TIP47+/ADRP+ lipid droplets. The model can serve as a novel strategy for the non-invasive delivery of drugs by releasing hydrophobic cargo, in our case a model dye, through a kiss-and-run mechanism between nanoparticles and the cell membrane. PMID- 24346147 TI - Robotic-assisted pancreas transplantation: where are we today? AB - PURPOSE OF REVIEW: To analyze the current status of robotic-assisted pancreas transplantation as a treatment option for diabetic patients. RECENT FINDINGS: Pancreas transplant recipients continue to suffer high rates of technical complications, including wound infections, fascial dehiscence, and postoperative ventral hernias. Robotic technology can potentially contribute to decreasing these dangerous complications and improve the postoperative course of pancreas transplantation. SUMMARY: Current literature on both robotic pancreas and robotic kidney transplant were reviewed in order to determine feasibility, safety, and efficacy of robotic pancreas transplantation. To date, only three cases of robotic pancreas transplantation, two of which were solely pancreas transplantation and one combined pancreas-kidney transplantation, have been reported in a single publication by an Italian group. Their preliminary data show that robotic pancreas transplantation is feasible and well tolerated. The authors believe that robotic pancreas transplantation could have a prominent role in lone pancreas transplantation performed in overweight recipients, in parallel to their experience with fully robotic kidney transplant in morbidly obese candidates. Broader experience with this innovative approach will be necessary to establish if robotic pancreas transplantation will be a beneficial option for diabetic patients needing beta-cell replacement. PMID- 24346148 TI - T-cell migration to vascularized organ allografts. AB - PURPOSE OF REVIEW: To review the classical paradigm of leukocyte migration and present new evidence that cognate antigen, and not signaling via Galphai-coupled chemokine receptors, drives the migration of effector and memory T cells into vascularized organ transplants. RECENT FINDINGS: Blocking Galphai function does not hinder integrin-dependent T-cell migration to heart and kidney allografts or significantly delay acute rejection. T-cell firm adhesion and transmigration is instead mediated by engagement of the T cell receptor for antigen (TCR) on antigen-specific (antidonor) T cells by cognate antigen presented by either graft endothelial cells or bone marrow-derived antigen-presenting cells that reach into the vascular lumen. Influx of bystander T cells is Galphai-dependent but occurs only if antigen-specific T cells are present. SUMMARY: Antigen-driven migration of effector and memory T cells sheds new light on the pathogenesis of transplant rejection and predicts that interrupting the TCR-triggered 'inside-out' signaling pathway, rather than that initiated by Galphai-coupled chemokine receptors, is a key approach to preventing rejection. PMID- 24346149 TI - Forensic evaluation of the AmpFlSTR Identifiler kit in nine Mexican native populations from the pre-Columbian Mesoamerican region. AB - Allele frequency distribution and forensic parameters of the AmpFlSTR Identifiler kit was determined in nine Mexican Amerindian populations based on 1,040 unrelated individuals from the pre-Columbian region known as Mesoamerica. Hardy Weinberg equilibrium was demonstrated for most of the short tandem repeats (STRs) in all nine populations. The power of discrimination and exclusion were higher than 0.99999 and 0.997942, respectively. In addition, a brief overview of the genetic relatedness and structure (F st = 2.62 %; p = 0.00000) between these populations is presented. PMID- 24346150 TI - Comparison of plantar pressure between flat and normal feet when crossing an obstacle at different heights. AB - OBJECTIVE: The purpose of this study is to compare the plantar foot pressure and the center of pressure (COP) pathway of normal and flat feet while crossing an obstacle at different heights. METHODS: Nineteen subjects (10 normal feet, 9 flat feet) participated in this study. The plantar foot surface was divided into the following seven regions for pressure measurement: two toe regions, three forefoot regions, one midfoot region, and one heel region. A one-way ANOVA with repeated measurements was used to compare the plantar foot pressure of normal and flat feet according to the obstacle height. RESULTS: The trend analysis showed a quadratic trend during level walking for the normal foot group, but a linear trend appeared as the obstacle height increased. In the flat foot group, the trend analysis showed a linear trend regardless of the obstacle height. In the 2nd-3rd metatarsal head region, the plantar pressure of the flat foot group increased more than the normal foot group as the obstacle height increased; however, in the 4th-5th metatarsal head region, the plantar pressure in flat feet was lower than in normal feet. In the heel region, the plantar pressure in both groups generally increased as the obstacle height increased, but the plantar pressure in the flat foot group was lower than in the normal foot group. CONCLUSION: We believe that, due to a loss of longitudinal arch, the COP path and plantar pressure of flat feet may be different from normal feet when crossing obstacles of different heights. PMID- 24346151 TI - Low-level laser therapy versus ultrasound therapy in the treatment of subacromial impingement syndrome: a randomized clinical trial. AB - OBJECTIVE: The aim of this study was to compare the effectiveness of low-level laser therapy and ultrasound therapy in the treatment of subacromial impingement syndrome. MATERIALS AND METHODS: Thirty one patients with subacromial impingement syndrome were randomly assigned to low-level laser therapy group (n=16) and ultrasound therapy group (n=15). Study participants received 10 treatment sessions of low-level laser therapy or ultrasound therapy over a period of two consecutive weeks (five days per week). Outcome measures (visual analogue pain scale, Shoulder Pain and Disability Index -SPADI-, patient's satisfactory level and sleep interference score) were assessed before treatment and at the 1st and 3rd months after treatment. All patients were analyzed by the intent-to-treat principle. RESULTS: Mean reduction in VAS pain, SPADI disability and sleep interference scores from baseline to after 1 month, and 3 months of treatment was statistically significant in both groups (P< 0.05). However, there was no significant difference in the mean change in VAS pain, SPADI disability and sleep interference scores between the two groups (P > 0.05). The mean level of patient satisfaction in group 1 at the first and third months after treatment was 72.45 +/- 23.45 mm and 71.50 +/- 16.54 mm, respectively. The mean level of patient satisfaction in group 2 at the first and third months after treatment was 70.38 +/- 21.52 mm and 72.09 +/- 13.42 mm, respectively. There was no significant difference in the mean level of patient satisfaction between the two groups (p > 0.05). CONCLUSIONS: The results suggest that efficacy of both treatments were comparable to each other in regarding reducing pain severity and functional disability in patients with subacromial impingement syndrome. Based on our findings, we conclude that low-level laser therapy may be considered as an effective alternative to ultrasound based therapy in patients with subacromial impingement syndrome especially ultrasound based therapy is contraindicated. PMID- 24346152 TI - Evaluation of joint findings with gait analysis in children with hemophilia. AB - BACKGROUNDS AND OBJECTIVES: Hemophilic arthropathy due to recurrent joint bleeding leads to physical, psychological and socioeconomic problems in children with hemophilia and reduces their quality of life. The purpose of this study was to evaluate joint damage through various parameters and to determine functional deterioration in the musculoskeletal system during walking using kinetic and kinematic gait analysis. MATERIAL AND METHOD: Physical examination and kinetic and kinematic gait analysis findings of 19 hemophilic patients aged 7-20 years were compared with those of age, sex and leg length matched controls. RESULTS: Stride time was longer in the hemophilia group (p=0.001) compared to the age matched healthy control group, while hip, knee and ankle joint rotation angles were more limited (p=0.001, p=0.035 and p=0.001, respectively). In the hemophilia group, the extensor moment of the knee joint in the stance phase was less than that in the control group (p=0.001). Stride time was longer in the severe hemophilia group compared to the mild-moderate hemophilia and control groups (p=0.011 and p=0.001, respectively). Rotation angle of the ankle was wider in the control group compared to the other two groups (p=0.001 for both). Rotation angle of the ankle joint was narrower in the severe hemophilia group compared to the others (p=0.001 for each). Extensor moment of the knee joint was greater in the control group compared to the other two groups (p=0.003 and p=0.001, respectively). Walking velocity was higher in the control group compared to the severe hemophilia group. CONCLUSION: Kinetic and kinematic gait analysis has the sensitivity to detect minimal changes in biomechanical parameters. Gait analysis can be used as a reliable method to detect early joint damage. PMID- 24346153 TI - Strength of hip muscle groups in sedentary women with patellofemoral pain syndrome. AB - OBJECTIVE: To compare the strength of hip muscle groups in sedentary women with bilateral patellofemoral pain syndrome (PFPS) with a matched control group of sedentary women without PFPS. METHODS: Twenty four women between 19 and 23 years of age (PFPS group, n=12; control group, n=12) participated in this study. Strength for all 6 hip muscle groups was measured bilaterally in all subjects using a stabilized Hand-held dynamometer. RESULTS: The hip musculature of sedentary women with bilateral PFPS was statistically weaker (range 31%-52%; p< 0.001) than that of the control group for all muscle groups. CONCLUSION: This study demonstrated a statistically significant weakness of hip muscle groups in sedentary women with PFPS. PMID- 24346154 TI - Topical distribution of initial paresis of the limbs to predict clinically relevant spasticity after ischemic stroke: a retrospective cohort study. AB - BACKGROUND: The degree of initial paresis relates to spasticity development in stroke patients. However, the importance of proximal and distal paresis in predicting spasticity after stroke is unclear. AIM: To investigate the role of topical distribution of initial limb paresis to predict clinically relevant spasticity in adults with stroke. DESIGN: Retrospective cohort study METHODS: Seventy-two first-ever ischemic stroke patients were examined. At the acute phase of illness, demographics and the European Stroke Scale motor items (maintenance of outstretched arm position, arm raising, wrist extension, grip strength, maintenance of outstretched leg position, leg flexion, foot dorsiflexion) were evaluated. At six months after the stroke onset, spasticity was assessed at the upper and lower limb with the modified Ashworth Scale. Clinically relevant spasticity was defined as modified Ashworth Scale >=3 (0-5). RESULTS: The degree of initial paresis of the proximal muscles of the upper limb and the distal muscles of the lower limb showed the strongest association and the best profile of sensitivity-specificity in predicting clinically relevant spasticity at the upper and lower limb, respectively. Younger age showed higher risk for developing clinically relevant spasticity in the upper limb. CONCLUSIONS: Our findings support the hypothesis that the initial degree of proximal paresis of the upper limb and distal paresis of the lower limb as well as age may be considered early predictors of clinically relevant spasticity in adults with ischemic stroke. CLINICAL REHABILITATION IMPACT: Our findings further improve the role of initial paresis as predictor of spasticity after stroke. PMID- 24346155 TI - High-dose atorvastatin reloading before percutaneous coronary intervention increased circulating endothelial progenitor cells and reduced inflammatory cytokine expression during the perioperative period. AB - OBJECTIVE: We investigated atorvastatin reloading effects on endothelial progenitor cell (EPC) count and inflammatory cytokine expression after percutaneous coronary intervention (PCI) in patients with stable angina pectoris who had previously received long-term statin treatments. METHODS: Patients with stable angina pectoris were treated with 80 mg atorvastatin 12 hours and 40 mg atorvastatin 2 hours before coronary angioplasty (n = 15) or preoperatively with 40 mg/d atorvastatin for 7 days (n = 15) or did not receive atorvastatin (n = 15). CD45-/133+/34+, CD45-/CD34+/kinase insert domain receptor (KDR)+, and CD45 /CD144+/KDR+ EPCs in the peripheral blood were determined by flow cytometry 1 hour before as well as 1 hour, 6 hours, and 24 hours after PCI. Soluble intercellular adhesion molecule 1 (sICAM-1), hypersensitive C-reactive protein (hCRP), and troponin-I (TnI) serum concentrations were analyzed immediately prior to and 24 hours after PCI. RESULTS: In the 40mg Atorvastatin and control groups, none of the analyzed EPC blood concentrations changed significantly from 1h before operation to 1h and 6 h postoperative values. In contrast, the number of circulating early differentiation stage EPCs CD45-/133+/34+ and CD45-/CD34+/ KDR+ raised significantly from 1 h preoperative values (57.3+/-9.3; 57.3 +/- 10.7) to 1 h postoperative ((74.4 +/- 11.4; 78.8 +/- 16.2), (p < 0.05)) and 6 h postoperative ((93 +/- 16.9; 99.7 +/- 11.9), (p < 0.05)) concentrations after coronary angioplasty in the 80mg Atorvastatin medication patients. In the control group, the sICAM-1 (174.55 +/- 38.91 vs 204.11 +/- 58.24) and hCRP (1.89 +/- 1.93 vs 9.0 +/- 11.1) serum concentrations at 24 hours after PCI were significantly elevated (P < .05) compared to preoperative values, whereas the increases in the 2 groups treated with atorvastatin were not significant. In addition, the rise in serum TnI concentration level from pre- to postoperative in the 80-mg (0.02 +/- 0.02 vs 0.09 +/- 0.08) and the 40-mg (0.01 +/- 0.03 vs 1.2 +/- 2.59) reloading groups was less than that of the controls (0.01 +/- 0.02 vs 1.75 +/- 3.09) (p < 0.05). CONCLUSION: Our results suggested that high-dose atorvastatin application before PCI triggered early EPC circulation. Furthermore, postoperative inflammatory cytokine sICAM-1 as well as hCRP serum levels were reduced, while postinterventional myocardial injury marker TnI elevations were inversely correlated with statin reloadings. PMID- 24346156 TI - A systematic review and meta-analysis of the effects of pycnogenol on plasma lipids. AB - BACKGROUND: Pycnogenol, the standardized flavonoid-rich extract from the bark of French maritime pine (Pinus pinaster Ait), has been shown to modify a number of cardiovascular risk factors. However, that Pycnogenol modulates plasma lipid levels is unclear due to the inconsistent findings. OBJECTIVE: To examine the impact of Pycnogenol on lipid profile through a meta-analysis of available controlled clinical trials. METHODS: Controlled trials assessing the effects of Pycnogenol on lipid parameters (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides) were identified by electronic search in Medline and Scopus. Weighed mean difference (WMD) and 95% confidence interval (CI) were calculated as effect size using random-effects meta-analysis. Sensitivity and meta-regression (for Pycnogenol dose and duration of supplementation) analyses were carried out using leave-one-out and unrestricted maximum likelihood methods, respectively. RESULTS: A total of 7 trials comprising 442 patients (226 in the Pycnogenol and 216 in the control group) were identified. Meta-analysis did not reveal any significant effect of Pycnogenol on lipid parameters: total cholesterol: WMD: 0.03 mmol/L, 95% CI: -0.34 to 0.28, P = .83; LDL-C: WMD: -0.07 mmol/L, 95% CI: 0.29 to 0.15, P = .54; HDL-C: WMD: 0.00 mmol/L, 95% CI: -0.04 to 0.05, P = .86; and triglycerides: WMD: 0.05 mmol/L, 95% CI: -0.12 to 0.23, P = .55. All these effect sizes were robust in sensitivity analyses. Apart from a dose-effect association for the effect of Pycnogenol on LDL-C, there was no other association between Pycnogenol dose or its duration of supplementation with changes in any of the lipid parameters. CONCLUSION: Current clinical evidence does not suggest any significant effect of Pycnogenol on fasting lipid profile. PMID- 24346157 TI - Concomitant resistance and early-breast cancer: should we change treatment strategies? AB - The dynamics of disease recurrence shows a bimodal pattern with a fairly broad dominant peak at about 1.5-2 years after surgery followed by a second peak at about 5 years. Nowadays, this clinical pattern is explained by assuming that primary breast tumours as well as their metastases have phases of both arrested (tumour dormancy) and active Gompertzian growth. Tumour dormancy at metastatic sites is currently ascribed to biological particularities of local tissue microenvironments that inhibit the growth of tumour cells. However, in some patients, tumour dormancy appears to also depend on the direct interplay between the primary tumour and those metastases, a biological phenomenon called "concomitant resistance". Concomitant resistance is related to three biological processes: concomitant immunity, tumour-induced angiogenesis and athrepsia. Concomitant resistance can explain the bimodal relapse pattern of breast cancer patients as well as many other clinical phenomena such as the better clinical outcome among patients surgically treated during the putative early luteal phase, or the worse clinical outcome of African-American premenopausal women. Any therapeutic interventions (even surgery) can affect concomitant resistance with the potential to induce a worse as well as a better clinical outcome. This should be taken into account when planning new treatment strategies. PMID- 24346159 TI - The promise of sonodynamic therapy. AB - Sonodynamic therapy is a potential cancer treatment modality that has been gaining support due to its effectiveness in both in vitro and in vivo studies. The therapeutic method combines ultrasonic irradiation with drugs known as sonosensitizers that amplify its ability to inflict preferential damage on malignant cells. This is based on the idea that ultrasonic waves have the ability to exhibit profound physical and chemical changes on cellular structure. The mechanisms by which ultrasound (US) disrupts cellular functioning can be further amplified when sonosensitizers are applied. Combining multiple sonosensitizers with US to create a substantial synergistic effect could be an effective method for destroying tumorigenic growths, while decreasing the likelihood of drug resistance. PMID- 24346160 TI - The dual functions of YAP-1 to promote and inhibit cell growth in human malignancy. AB - The major functions of Hippo (Hpo) signaling pathway are to control cell growth, proliferation, and apoptosis. As its important downstream player, yes-associated protein (YAP)-1 was originally found to promote cell proliferation and transformation. Overexpression of YAP-1 has been linked to tumor progression and worse survival in certain malignancies. However, it has been recently recognized as a tumor suppressor gene as well since it also induces apoptosis. Decreased or absent expression of YAP-1 is highly correlated with tumor progression and worse survival in other tumors such as breast cancer. It is clear that YAP-1 plays a dual role as oncogene and tumor suppressor gene in human oncogenesis, depending on the specific tissue type involved. Here, we reviewed the recent research on both the oncogenic and tumor suppressor function of YAP-1 and its significance in human malignancy. The clinical implication of YAP-1 expression in cancer prognosis and the development of targeted therapy will also be discussed. PMID- 24346158 TI - The non-coding transcriptome as a dynamic regulator of cancer metastasis. AB - Since the discovery of microRNAs, non-coding RNAs (NC-RNAs) have increasingly attracted the attention of cancer investigators. Two classes of NC-RNAs are emerging as putative metastasis-related genes: long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs). LncRNAs orchestrate metastatic progression through several mechanisms, including the interaction with epigenetic effectors, splicing control and generation of microRNA-like molecules. In contrast, snoRNAs have been long considered "housekeeping" genes with no relevant function in cancer. However, recent evidence challenges this assumption, indicating that some snoRNAs are deregulated in cancer cells and may play a specific role in metastasis. Interestingly, snoRNAs and lncRNAs share several mechanisms of action, and might synergize with protein-coding genes to generate a specific cellular phenotype. This evidence suggests that the current paradigm of metastatic progression is incomplete. We propose that NC-RNAs are organized in complex interactive networks which orchestrate cellular phenotypic plasticity. Since plasticity is critical for cancer cell metastasis, we suggest that a molecular interactome composed by both NC-RNAs and proteins orchestrates cancer metastasis. Interestingly, expression of lncRNAs and snoRNAs can be detected in biological fluids, making them potentially useful biomarkers. NC-RNA expression profiles in human neoplasms have been associated with patients' prognosis. SnoRNA and lncRNA silencing in pre-clinical models leads to cancer cell death and/or metastasis prevention, suggesting they can be investigated as novel therapeutic targets. Based on the literature to date, we critically discuss how the NC-RNA interactome can be explored and manipulated to generate more effective diagnostic, prognostic, and therapeutic strategies for metastatic neoplasms. PMID- 24346161 TI - KefB inhibits phagosomal acidification but its role is unrelated to M. tuberculosis survival in host. AB - kefB is annotated as a potassium/proton antiporter in M. tuberculosis. There have been divergent reports on the involvement of KefB in phagosomal maturation in M. bovis BCG and no investigation has been carried out on its role in M. tuberculosis, the pathogenic species responsible for causing tuberculosis. This study was taken up to ascertain the involvement of KefB in the growth of M. tuberculosis and its role in phagosomal maturation and survival of the pathogen in guinea pigs. Our findings show that kefB mutant of M. tuberculosis (MtbDeltakefB) was impaired i) for growth in high concentrations of potassium and ii) in arresting phagosomal acidification. However, the disruption of kefB had no adverse effect on the survival of M. tuberculosis in macrophages as well as in guinea pigs suggesting that the role of KefB in phagosomal acidification is unrelated to the survival of the pathogen in the host. PMID- 24346162 TI - The discovery of kimberlites in Antarctica extends the vast Gondwanan Cretaceous province. AB - Kimberlites are a volumetrically minor component of the Earth's volcanic record, but are very important as the major commercial source of diamonds and as the deepest samples of the Earth's mantle. They were predominantly emplaced from ~2,100 Ma to ~10 ka ago, into ancient, stable regions of continental crust (cratons), but are also known from continental rifts and mobile belts. Kimberlites have been reported from almost all major cratons on all continents except for Antarctica. Here we report the first bona fide Antarctic kimberlite occurrence, from the northern Prince Charles Mountains, emplaced during the reactivation of the Lambert Graben associated with rifting of India from Australia-Antarctica. The samples are texturally, mineralogically and geochemically typical of Group I kimberlites from more classical localities. Their ~120 Ma ages overlap with those of many kimberlites from other world-wide localities, extending a vast Cretaceous, Gondwanan kimberlite province, for the first time, into Antarctica. PMID- 24346163 TI - Interleaflet sliding in lipidic bilayers under shear flow: comparison of the gel and fluid phases using reversed non-equilibrium molecular dynamics simulations. AB - The friction between two rubbing surfaces lubricated by water can be diminished if they are coated with phospholipidic bilayers or brushes of polyelectrolytes. In the case of a coating by lipid membranes, the friction is lower when the lipids are in the gel phase rather than in the liquid phase. We investigated the response of fluid or gel bilayers to a mechanical load or under shear using non equilibrium molecular dynamics simulations (NEMD) to understand whether this difference could come from intermonolayer sliding. The system is composed of a single fully hydrated bilayer of coarse grained phospholipids under a parallel shear with vorticity parallel to the bilayer. In both the liquid and the gel phases, an intermonolayer slip was measured in the velocity profile. In the liquid phase this slip is proportional to the shear stress. In the tilted gel phase of our model the stress is not systematically linear and relaxes differently when the shear is in the direction of the tilt or perpendicular to it. The impact of surface tension (or load) on the friction is different for the liquid and gel phases, but grossly the slip remains of the same order of magnitude. PMID- 24346164 TI - Multilevel models for cost-effectiveness analyses that use cluster randomised trial data: An approach to model choice. AB - Multilevel models provide a flexible modelling framework for cost-effectiveness analyses that use cluster randomised trial data. However, there is a lack of guidance on how to choose the most appropriate multilevel models. This paper illustrates an approach for deciding what level of model complexity is warranted; in particular how best to accommodate complex variance-covariance structures, right-skewed costs and missing data. Our proposed models differ according to whether or not they allow individual-level variances and correlations to differ across treatment arms or clusters and by the assumed cost distribution (Normal, Gamma, Inverse Gaussian). The models are fitted by Markov chain Monte Carlo methods. Our approach to model choice is based on four main criteria: the characteristics of the data, model pre-specification informed by the previous literature, diagnostic plots and assessment of model appropriateness. This is illustrated by re-analysing a previous cost-effectiveness analysis that uses data from a cluster randomised trial. We find that the most useful criterion for model choice was the deviance information criterion, which distinguishes amongst models with alternative variance-covariance structures, as well as between those with different cost distributions. This strategy for model choice can help cost effectiveness analyses provide reliable inferences for policy-making when using cluster trials, including those with missing data. PMID- 24346165 TI - Rasch-family models are more valuable than score-based approaches for analysing longitudinal patient-reported outcomes with missing data. AB - The objective was to compare classical test theory and Rasch-family models derived from item response theory for the analysis of longitudinal patient reported outcomes data with possibly informative intermittent missing items. A simulation study was performed in order to assess and compare the performance of classical test theory and Rasch model in terms of bias, control of the type I error and power of the test of time effect. The type I error was controlled for classical test theory and Rasch model whether data were complete or some items were missing. Both methods were unbiased and displayed similar power with complete data. When items were missing, Rasch model remained unbiased and displayed higher power than classical test theory. Rasch model performed better than the classical test theory approach regarding the analysis of longitudinal patient-reported outcomes with possibly informative intermittent missing items mainly for power. This study highlights the interest of Rasch-based models in clinical research and epidemiology for the analysis of incomplete patient reported outcomes data. PMID- 24346166 TI - Use of auxiliary covariates in estimating a biomarker-adjusted treatment effect model with clinical trial data. AB - A biomarker-adjusted treatment effect (BATE) model describes the effect of one treatment versus another on a subpopulation of patients defined by a biomarker. Such a model can be estimated from clinical trial data without relying on additional modeling assumptions, and the estimator can be made more efficient by incorporating information on the main effect of the biomarker on the outcome of interest. Motivated by an HIV trial known as THRIVE, we consider the use of auxiliary covariates, which are usually available in clinical trials and have been used in overall treatment comparisons, in estimating a BATE model. Such covariates can be incorporated using an existing augmentation technique. For a specific type of estimating functions for difference-based BATE models, the optimal augmentation depends only on the joint main effects of marker and covariates. For a ratio-based BATE model, this result holds in special cases but not in general; however, simulation results suggest that the augmentation based on the joint main effects of marker and covariates is virtually equivalent to the theoretically optimal augmentation, especially when the augmentation terms are estimated from data. Application of these methods and results to the THRIVE data yields new insights on the utility of baseline CD4 cell count and viral load as predictive or treatment selection markers. PMID- 24346167 TI - Persistent postoperative pain and sensory changes following lymph node excision in melanoma patients: a topical review. AB - Studies on complications related to chronic nerve injury following sentinel lymph node biopsy (SLNB) and complete lymph node dissection (CLND) for melanoma are sparse. This review summarizes the existing literature on pain and neuropathic complications in melanoma patients undergoing SLNB with or without CLND. The Cochrane Central Register of Controlled Trials and the Embase and PubMed databases were searched. Full-text English language articles published before June 2013 were included. Prospective and retrospective studies assessing persistent (>1 month) sensory nerve injury, postoperative pain, neuropathic pain, and sensory disturbances following SLNB with or without CLND in melanoma patients were eligible. Nine studies (six prospective and three retrospective) including data for 3632 patients met our inclusion criteria. Outcome parameters were too heterogeneous to conduct a quantitative analysis, and few studies systematically evaluated pain and sensory abnormalities. Persistent postoperative pain was reported in 1-14% of patients following SLNB and in 6-34% following CLND and sensory abnormalities in 0.1-32 and 2-82%, respectively. In the one study that assessed the type of pain, neuropathic pain was suggested to explain persistent pain in 31-66% of patients with SLNB and 82-89% of patients with CLND. Sensory nerve-related complications in melanoma patients seem to be less pronounced following SLNB compared with CLND. Prospective observational studies are necessary to identify predictors of persistent pain, to evaluate the prevalence and impact of pain and sensory abnormalities, and to develop strategies for prevention of long-term complications. PMID- 24346168 TI - Lower prevalence of lymphatic metastasis and poorer survival of the sentinel node negative patients limit the prognostic value of sentinel node biopsy for head or neck melanomas. AB - Head or neck location of primary cutaneous melanomas has been described as an adverse prognostic factor, but this has to be reassessed after the introduction of sentinel lymph node (SLN) excision (SLNE). Descriptive statistics, Kaplan Meier estimates and Cox proportional hazard models were used to study retrospectively a population of 2302 consecutive melanoma patients from three German melanoma centres undergoing SLNE. Approximately 10% of the patients (N=237) had a primary melanoma located at the head or neck (HNM). In both the SLN positive and SLN-negative subpopulation, patients with HNM were significantly older, more frequently men and had thicker primaries compared with patients with tumours in other locations. The proportion of positive SLNs was lower in HNM compared with other locations of the primary (20 vs. 26%, P=0.048). The false negative rate was higher in HNM (17.5 vs. 8.4%, P=0.05). In patients with HNM, the SLN status was a significant factor for recurrence-free survival but not for overall survival. SLN-negative HNM patients had a significantly worse overall survival than the SLN negatives with primaries at other sites, whereas the prognosis of the SLN-positive patients was similar in both groups. The prevalence of lymph node metastases after SLNE is lower in patients with HNM compared with other melanoma locations. As a result, the prognostic information provided by the SLN for HNM seems less important. Decision making for SLNE in HNM should be carefully balanced considering the potential morbidity of the procedure. PMID- 24346169 TI - Crouzon syndrome: relationship of rectus muscle pulley location to pattern strabismus. AB - PURPOSE: Investigate the relationship between the extorsion of the rectus muscle pulleys and the V-pattern exotropia and "overelevation in adduction" observed in Crouzon syndrome. METHODS: Twenty children with Crouzon syndrome had assessment of eye alignment. The horizontal and vertical positions of the four rectus muscle pulleys were estimated from coronal CT images. Eye alignment was simulated in Orbit 1.8 software by shifting the corresponding location of the rectus muscle pulley array. RESULTS: Eleven of the 20 patients had a V-pattern exotropia with displacements of each rectus muscle pulley ranging from 2 to 7 mm. The remaining nine patients were orthotropic with <2 mm displacement of the rectus muscle pulleys. Simulated displacements (>2 mm) of either the horizontal or vertical rectus muscle pulleys produced a similar strabismus pattern. The amount of V pattern exotropia observed clinically was highly correlated with the amount predicted by pulley displacements in Orbit 1.8 (r(2) = 0.63; P < 0.0001). The displacement of vertical and horizontal rectus muscle pairs was significantly higher for patients having overelevation in adduction. CONCLUSIONS: Rotation of the four rectus muscle pulleys relative to the corresponding rotation planes of the globe changes the direction and magnitude of their active and passive pulling forces in a gaze-dependent manner. Extorsion of the horizontal and vertical rectus muscle pulleys in Orbit 1.8 reproduces the pattern strabismus observed in Crouzon syndrome. The high correlation between the predicted magnitude of the V pattern exotropia and observed exotropia indicates that extorsion of the rectus muscle pulleys primarily accounts for the pattern strabismus. PMID- 24346171 TI - Correction of the Crb1rd8 allele and retinal phenotype in C57BL/6N mice via TALEN mediated homology-directed repair. AB - PURPOSE: We directly corrected the mouse Crb1(rd8) gene mutation, which is present in many inbred laboratory strains derived from C57BL/6N and complicates genetic studies of retinal disease in mice. METHODS: Fertilized C57BL/6NJ oocytes were coinjected with mRNAs encoding a transcription activator-like effector nuclease (TALEN) targeting the Crb1(rd8) allele plus single-stranded oligonucleotides to correct the allele. The oligonucleotides included additional nucleotide changes to distinguish the corrected allele (Crb1(em1Mvw)) from wild type Crb1 and to minimize TALEN recutting. Oligonucleotide length, concentration of injected oligonucleotides and TALEN mRNAs were varied to optimize homology directed repair of the locus. Following microinjection, embryos were carried to term in pseudopregnant females. Correction efficiency was assessed by PCR analysis of the Crb1(em1Mvw) allele. Phenotypic correction was demonstrated by fundus imaging and optical coherence tomography of live mice, and by confocal fluorescence microscopy of retinal flat mounts. RESULTS: Under optimal conditions, homology-directed repair was observed in 27% (8/30) of live-born animals and showed minimal illegitimate recombination of donor DNA. However, extensive founder mosaicism was evident, emphasizing the need to analyze offspring of founder animals. Unlike C57BL/6NJ mice, which exhibited external limiting membrane fragmentation and regional retinal dysplasia, heterozygous Crb1(em1Mvw)/Crb1(rd8) mice showed a normal retinal phenotype. CONCLUSIONS: The C57BL/6NJ-Crb1(rd8) mutation and its associated retinal phenotypes were corrected efficiently by TALEN-mediated homology-directed repair. The C57BL/6NJ Crb1(em1Mvw) mice generated by this strategy will enhance ocular phenotyping efforts based on the C57BL/6N background, such as those implemented by the International Mouse Phenotyping Consortium (IMPC) project. PMID- 24346170 TI - Genetic evidence for role of carotenoids in age-related macular degeneration in the Carotenoids in Age-Related Eye Disease Study (CAREDS). AB - PURPOSE: We tested variants in genes related to lutein and zeaxanthin status for association with age-related macular degeneration (AMD) in the Carotenoids in Age Related Eye Disease Study (CAREDS). METHODS: Of 2005 CAREDS participants, 1663 were graded for AMD from fundus photography and genotyped for 424 single nucleotide polymorphisms (SNPs) from 24 candidate genes for carotenoid status. Of 337 AMD cases 91% had early or intermediate AMD. The SNPs were tested individually for association with AMD using logistic regression. A carotenoid related genetic risk model was built using backward selection and compared to existing AMD risk factors using the area under the receiver operating characteristic curve (AUC). RESULTS: A total of 24 variants from five genes (BCMO1, BCO2, NPCL1L1, ABCG8, and FADS2) not previously related to AMD and four genes related to AMD in previous studies (SCARB1, ABCA1, APOE, and ALDH3A2) were associated independently with AMD, after adjusting for age and ancestry. Variants in all genes (not always the identical SNPs) were associated with lutein and zeaxanthin in serum and/or macula, in this or other samples, except for BCO2 and FADS2. A genetic risk score including nine variants significantly (P = 0.002) discriminated between AMD cases and controls beyond age, smoking, CFH Y402H, and ARMS2 A69S. The odds ratio (95% confidence interval) for AMD among women in the highest versus lowest quintile for the risk score was 3.1 (2.0-4.9). CONCLUSIONS: Variants in genes related to lutein and zeaxanthin status were associated with AMD in CAREDS, adding to the body of evidence supporting a protective role of lutein and zeaxanthin in risk of AMD. PMID- 24346172 TI - Intersublaminar vascular plexus: the correlation of retinal blood vessels with functional sublaminae of the inner plexiform layer. AB - PURPOSE: Interactions between vasculature and neurons provide important insight into the function of the nervous system, as well as into neurological diseases wherein these interactions are disrupted. This study characterizes a previously unreported retinal vascular plexus and examines potential sites of neurovascular interaction. METHODS: Vascular, neuronal, and glial elements were visualized using immunohistochemical markers. The distribution of vascular layers was measured and compared across eccentricities. Intensity profiles were calculated from confocal image reconstructions to reveal the proximity of vasculature to neuronal and glial processes. RESULTS: Retinal vasculature forms a plexus that coincides with the dendritic processes of OFF cholinergic amacrine cells within the inner plexiform layer. Across eccentricities, this plexus comprises approximately 8% of the total length of horizontally running blood vessels in the retina. Processes of Muller glia and OFF cholinergic amacrine cells colocalize with the blood vessels that form the intersublaminar plexus. CONCLUSIONS: In the retina, vasculature lacks autonomic control, but shows efficient local regulation. Although the source of this regulation is unclear, these results suggest that cholinergic amacrine cells and Muller glia may interact with the intersublaminar plexus to influence vasomotor activity. This may indicate a key role in modulating reciprocal interactions between neuronal activity and blood flow. PMID- 24346173 TI - Vertical and oblique saccade disconjugacy in strabismus. AB - PURPOSE: Previous studies have shown that horizontal saccades are disconjugate in humans and monkeys with strabismus. The present study was designed to extend these results to vertical and oblique saccades. A major goal was to assess the conjugacy in terms of both amplitude and direction. METHODS: Saccadic eye movements were recorded binocularly in three adult monkeys. One had normal eye alignment, one had exotropia resulting from a bilateral medial rectus tenotomy in the first week of life, and one had esotropia resulting from prism rearing during the first 3 months of life. We assessed the conjugacy of saccades in various directions by comparing both amplitude and direction. RESULTS: Saccades in the strabismic monkeys were disconjugate in terms of both amplitude and direction. These effects were as large for vertical and oblique saccades as for horizontal ones. However, the pattern of disconjugacy often varied as a function of saccade direction. In some cases, saccades that appeared to be conjugate in terms of amplitude differed substantially when direction was taken into account. CONCLUSIONS: These data indicate that the assessment of saccade disconjugacy in strabismus may yield misleading results if direction is not considered. The complex pattern of disconjugacy suggests that strabismus is associated with substantial abnormalities within the circuitry controlling saccades. Neurophysiological studies are needed to identify the specific neural substrates for these behavioral effects. PMID- 24346174 TI - Reduced fluorescein angiography and fundus photography use in the management of neovascular macular degeneration and macular edema during the past decade. AB - PURPOSE: We assessed recent trends in the use of diagnostic testing for neovascular age-related macular degeneration (NVAMD) and macular edema (ME). METHODS: Claims data from a managed-care network were analyzed on patients with NVAMD (n = 22,954) or ME (n = 31,810) to assess the use of fluorescein angiography (FA), fundus photography (FP), and optical coherence tomography (OCT) from 2001 to 2009. Repeated-measures logistic regression was performed to compare patients' odds of undergoing these procedures in 2001, 2005, and 2009. In addition, the proportions of patients with an incident NVAMD or ME diagnosis in 2003 or 2008 who underwent FA, FP, and OCT were compared. RESULTS: From 2001 to 2009, among patients with NVAMD, the odds of undergoing OCT increased 23-fold, whereas the odds of receiving FA and FP decreased by 68% and 79%, respectively. Similar trends were observed for ME. From 2003 to 2008, the proportion of patients undergoing OCT within 1 year of initial diagnosis increased by 315% for NVAMD and by 143% for ME; the proportion undergoing OCT without FA within 1 year increased by 463% for NVAMD and by 216% for ME. CONCLUSIONS: Use of OCT increased dramatically during the past decade, whereas use of FA and FP declined considerably, suggesting that OCT may be replacing more traditional diagnostic testing in patients with NVAMD or ME. Future studies should evaluate whether this increased reliance on OCT instead of FA and FP affects patient outcomes. PMID- 24346175 TI - Driving with hemianopia: III. Detection of stationary and approaching pedestrians in a simulator. AB - PURPOSE: To compare blind-side detection performance of drivers with homonymous hemianopia (HH) for stationary and approaching pedestrians, initially appearing at small (4 degrees ) or large (14 degrees ) eccentricities in a driving simulator. While the stationary pedestrians did not represent an imminent threat, as their eccentricity increased rapidly as the vehicle advanced, the approaching pedestrians maintained a collision course with approximately constant eccentricity, walking or running, toward the travel lane as if to cross. METHODS: Twelve participants with complete HH and without spatial neglect pressed the horn whenever they detected a pedestrian while driving along predetermined routes in two driving simulator sessions. Miss rates and reaction times were analyzed for 52 stationary and 52 approaching pedestrians. RESULTS: Miss rates were higher and reaction times longer on the blind than the seeing side (P < 0.01). On the blind side, miss rates were lower for approaching than stationary pedestrians (16% vs. 29%, P = 0.01), especially at larger eccentricities (20% vs. 54%, P = 0.005), but reaction times for approaching pedestrians were longer (1.72 vs. 1.41 seconds; P = 0.03). Overall, the proportion of potential blind-side collisions (missed and late responses) was not different for the two paradigms (41% vs. 35%, P = 0.48), and significantly higher than for the seeing side (3%, P = 0.002). CONCLUSIONS: In a realistic pedestrian detection task, drivers with HH exhibited significant blind-side detection deficits. Even when approaching pedestrians were detected, responses were often too late to avoid a potential collision. PMID- 24346176 TI - Risk and protective factors for peer victimization: a 1-year follow-up study of urban American students. AB - This study examined whether internalizing problems, parental warmth and teacher support were associated with adolescents' experience of future peer victimization in school. Data were drawn from two rounds of the longitudinal Social and Health Assessment (SAHA). Study subjects comprised 593 US urban adolescents (aged 13.8 +/- 0.8 years; 56 % female). Results showed that there was a substantial degree of continuity in peer victimization over a 1-year period. The presence of internalizing (anxiety, depressive and somatic) symptoms at baseline was associated with an increased risk of peer victimization over time. Both parental warmth and teacher support were uniquely associated with a lower risk for peer victimization. Implications of these findings for prevention efforts are discussed. PMID- 24346178 TI - Practice guidelines for the perioperative management of patients with obstructive sleep apnea: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Management of patients with obstructive sleep apnea. PMID- 24346177 TI - Cardioprotection during diabetes: the role of mitochondrial DNA. AB - BACKGROUND: Diabetes alters mitochondrial bioenergetics and consequently disrupts cardioprotective signaling. The authors investigated whether mitochondrial DNA (mtDNA) modulates anesthetic preconditioning (APC) and cardiac susceptibility to ischemia-reperfusion injury by using two strains of rats, both sharing nuclear genome of type 2 diabetes mellitus (T2DN) rats and having distinct mitochondrial genomes of Wistar and fawn-hooded hypertensive (FHH) rat strains (T2DN(mtWistar) and T2DN(mtFHH), respectively). METHODS: Myocardial infarct size was measured in Wistar, T2DN(mtWistar), and T2DN(mtFHH) rats with or without APC (1.4% isoflurane) in the presence or absence of antioxidant N-acetylcysteine. Flavoprotein fluorescence intensity, a marker of mitochondrial redox state, 5 (and-6)-chloromethyl-2',7'-dichlorofluorescein fluorescence intensity, a marker of reactive oxygen species generation, and mitochondrial permeability transition pore opening were assessed in isolated rat ventricular cardiomyocytes with or without isoflurane (0.5 mmol/l). RESULTS: Myocardial infarct size was decreased by APC in Wistar and T2DN(mtWistar) rats (to 42 +/- 6%, n = 8; and 44 +/- 7%, n = 8; of risk area, respectively) compared with their respective controls (60 +/- 3%, n = 6; and 59 +/- 9%, n = 7), but not in T2DN(mtFHH) rats (60 +/- 2%, n = 8). N-acetylcysteine applied during isoflurane treatment restored APC in T2DN(mtFHH) (39 +/- 6%, n = 7; and 38 +/- 5%, n = 7; 150 and 75 mg/kg N-acetylcysteine, respectively), but abolished protection in control rats (54 +/- 8%, n = 6). Similar to the data on infarct size, APC delayed mitochondrial permeability transition pore opening in T2DN(mtWistar) but not in T2DN(mtFHH) cardiomyocytes. Isoflurane increased flavoprotein and 5-(and-6)-chloromethyl-2',7' dichlorofluorescein fluorescence intensity in all rat strains, with the greatest effect in T2DN(mtFHH) cardiomyocytes. CONCLUSION: Differences in the mitochondrial genome modulate isoflurane-induced generation of reactive oxygen species which translates into differential susceptibility to APC and ischemia reperfusion injury in diabetic rats. PMID- 24346179 TI - Colorimetric detection of microRNA miR-21 based on nanoplasmonic core-satellite assembly. AB - In order to detect microRNAs (miRNAs), we developed a colorimetric sensing method on the basis of the plasmonic coupling effect. Gold nanoplasmonic particles (GNPs) are assembled in a core-satellite configuration in the presence of target miRNA, inducing remarkable changes in the scattering color and spectra at the picomolar level with selectivity. PMID- 24346180 TI - Gender-specific changes in physical activity pattern in Iran: national surveillance of risk factors of non-communicable diseases (2007-2011). AB - OBJECTIVES: This study describes the gender-specific pattern of physical activity (PA) in Iran 2011. The 4-year changes in PA levels (domains) are also determined according to the Iran's national surveys conducted on 2007 and 2011. METHODS: Physical activity assessed based on the global physical activity questionnaire. In all, 4,121 (2007), and 7,436 (2011) adults were analyzed. RESULTS: Based on 2011 survey, 56.4 %, 39.2 %, and 74.4 % of participants were physically inactive at work, commuting and recreation, respectively. In all domains of PA, males showed a higher degree of activity (min/day) than females (P value <0.001). The overall prevalence of physical inactivity was increased from 15 % (2007) to 21.5 % (2011) (P value <0.001). Over the 4 years, a significant decline in total physical activity (MET * min/week) and the duration of commuting activity were noted in both genders. Work-related activity was dramatically decreased in females. However, the time spent in recreational activity remained relatively constant. CONCLUSIONS: This report indicating that the Iranian population, particularly females, have become less active during the survey period. Physical inactivity should receive more attention as a public health issue. PMID- 24346181 TI - Orthopedic aspects of collagen disorders. AB - PURPOSE OF REVIEW: The purpose of this article is to provide the pediatrician with a review of disorders that have the orthopedic manifestation of joint hypermobility. Hypermobility, also termed ligamentous laxity, may present in different parts of the body at different times throughout childhood and adolescence. It may be symptomatic or incidentally found on the physical examination. Many conditions that cause joint hypermobility resolve with nonoperative management, but occasionally operative intervention is required for the best patient outcome. RECENT FINDINGS: In addition, hypermobility may be associated with collagen disorders that affect vital organ systems. Recognition of hypermobility combined with a thorough patient evaluation may be the initial opportunity for the pediatrician to uncover disease that may be managed promptly. SUMMARY: Heightened awareness of subtle hypermobility or symptomatic joint laxity on physical examination facilitates optimal management and favorable outcomes in children with this condition. PMID- 24346182 TI - Core concepts in congenital melanocytic nevi and infantile hemangiomas. AB - PURPOSE OF REVIEW: Congenital melanocytic nevi (CMN) and infantile hemangiomas are commonly encountered in newborns and may present diagnostic and therapeutic dilemmas for medical practitioners. Herein, we review and discuss these two important clinical entities and focus on core issues and recent advances. RECENT FINDINGS: Melanoma risk for patients with CMN is greatest in infants with large CMN located on the trunk, CMN greater than 40 cm, and multiple satellite nevi. Recent histological and molecular findings have been described to assist in differentiating benign proliferative nodules arising in CMN from melanoma. Multiple CMN and associated neurological lesions have recently been shown to be due to a single postzygotic mutation in NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog]. Over the last several years, numerous advancements have occurred in redefining the clinical course of infantile hemangiomas, describing clinical syndromes associated with infantile hemangiomas and treating complicated infantile hemangiomas. The nonselective beta-blocker propranolol has become first line therapy for the treatment of complicated infantile hemangiomas. Topical timolol shows promise for the treatment of certain types of infantile hemangiomas. SUMMARY: Although most CMN and infantile hemangiomas do not require active intervention, understanding which lesions may impact the overall health of the infant assists in early intervention. This article touches on core concepts in the clinical evaluation and treatment of CMN and infantile hemangioma. PMID- 24346183 TI - Pediatric flatfoot: cause, epidemiology, assessment, and treatment. AB - PURPOSE OF REVIEW: The current review includes the most up to date literature on the cause, epidemiology, diagnosis, and treatment of pediatric flatfeet. RECENT FINDINGS: Recent systematic reviews concur that the evidence supporting the use of orthotics in pediatric flexible flatfeet is poor. Multiple studies have recently reported on the results of arthroereisis, yet these are mostly retrospective and do not include a comparative group or long-term follow up. Other options for symptomatic flatfeet may include osteotomies and/or fusions, but similarly high quality comparative studies are lacking. SUMMARY: Pediatric flatfeet range from the painless flexible normal variant of growth, to stiff or painful manifestations of tarsal coalition, collagen abnormalities, neurologic disease, or other underlying condition. Most children with flexible flatfeet do not have symptoms and do not require treatment. In symptomatic children, orthotics, osteotomies, or fusions may be considered. Arthroereisis has gained popularity in Europe, but has not been widely adopted in North America. Children with asymptomatic rigid flatfeet may not require treatment, whereas those with pain or functional deficits may benefit from orthotics, osteotomies, or fusions. A careful history, clinical exam, and selective diagnostic testing can be used to determine the appropriate treatment option for each child. PMID- 24346184 TI - Achieving high sensitivity in hybrid photodetectors based on an organic single crystal and an inorganic nanocrystal array. AB - We demonstrate an approach to enhance the photosensitivity of an organic single crystal photodetector by combining it with a nanocrystal (NC) array. A systematic study of the dependence of the photodetector performance on illumination wavelength and light power together with the charge carrier mobility reveals that charge separation at the single-crystal/CdSe NC interface and subsequent electron trapping in the CdSe NCs generates effective photoconductive gain by hole circulation through the high-mobility single crystal. As a result, the responsivity and specific detectivity reached values up to 50 A W(-1) and 2 * 10(9) cm Hz(1/2) W(-1), respectively. PMID- 24346186 TI - Risk and sub phenotype in Parkinson's disease. PMID- 24346185 TI - Phylogenetic applications of whole Y-chromosome sequences and the Near Eastern origin of Ashkenazi Levites. AB - Previous Y-chromosome studies have demonstrated that Ashkenazi Levites, members of a paternally inherited Jewish priestly caste, display a distinctive founder event within R1a, the most prevalent Y-chromosome haplogroup in Eastern Europe. Here we report the analysis of 16 whole R1 sequences and show that a set of 19 unique nucleotide substitutions defines the Ashkenazi R1a lineage. While our survey of one of these, M582, in 2,834 R1a samples reveals its absence in 922 Eastern Europeans, we show it is present in all sampled R1a Ashkenazi Levites, as well as in 33.8% of other R1a Ashkenazi Jewish males and 5.9% of 303 R1a Near Eastern males, where it shows considerably higher diversity. Moreover, the M582 lineage also occurs at low frequencies in non-Ashkenazi Jewish populations. In contrast to the previously suggested Eastern European origin for Ashkenazi Levites, the current data are indicative of a geographic source of the Levite founder lineage in the Near East and its likely presence among pre-Diaspora Hebrews. PMID- 24346188 TI - Resistance exercise increases endothelial progenitor cells and angiogenic factors. AB - INTRODUCTION: Bone marrow-derived endothelial progenitor cells (EPC) are involved in vascular growth and repair. They increase in the circulation after a single bout of aerobic exercise, potentially related to muscle ischemia. Muscular endurance resistance exercise (MERE) bouts also have the potential to induce muscle ischemia if appropriately structured. PURPOSE: The objective of this study is to determine the influence of a single bout of MERE on circulating EPC and related angiogenic factors. METHODS: Thirteen trained men age 22.4 +/- 0.5 yr (mean +/- SEM) performed a bout of MERE consisting of three sets of six exercises at participants' 15-repetition maximum without resting between repetitions or exercises. The MERE bout duration was 12.1 +/- 0.6 min. Blood lactate and HR were 11.9 +/- 0.9 mmol.L and 142 +/- 5 bpm, respectively, at the end of MERE. Blood was sampled preexercise and at 10 min, 2 h, and 24 h postexercise. RESULTS: Circulating EPC and serum concentrations of vascular endothelial growth factors (VEGF-A, VEGF-C, and VEGF-D), granulocyte colony stimulating factor, soluble Tie 2, soluble fms-like tyrosine kinase-1, and matrix metalloproteinases (MMP-1, MMP 2, MMP-3, MMP-9, and MMP-9) were higher (P < 0.05) in the postexercise period. Circulating EPC levels were unchanged at 10 min postexercise but higher at 2 h postexercise (P < 0.05). The concentration of most angiogenic factors and metalloproteinases were higher at 10 min postexercise (VEGF-A, +38%; VEGF-C, +40%; VEGF-D, +9%; soluble Tie-2, +15%; soluble fms-like tyrosine kinase-1, +24%; MMP-1, +62%; MMP-2, +3%; MMP-3, +54%; and MMP-9, +45%; all P < 0.05). Soluble E selectin was lower (P < 0.05) at 2 and 24 h postexercise, with endothelial microparticles and thrombomodulin unchanged. CONCLUSIONS: Short intense bouts of MERE can trigger increases in circulating EPC and related angiogenic factors, potentially contributing to vascular adaptation and vasculoprotection. PMID- 24346187 TI - Serum levels of trace elements and heavy metals in patients with acute hemorrhagic stroke. AB - Trace elements are essential components of biological structures, but alternatively, they can be toxic at concentrations beyond those necessary for their biological functions. Changes in the concentration of essential trace elements and heavy metals may affect acute hemorrhagic stroke. The aim of this study was to measure serum levels of essential trace elements [iron (Fe), zinc (Zn), manganese (Mn), copper (Cu), and magnesium (Mg)] and heavy metals [cobalt (Co), cadmium (Cd), and lead (Pb)] in patients with acute hemorrhagic stroke. Twenty-six patients with acute hemorrhagic stroke and 29 healthy controls were enrolled. Atomic absorption spectrophotometry (UNICAM-929) was used to measure serum Fe, Cu, Pb, Cd, Zn, Co, Mn and Mg concentrations. Serum Cd, Pb and Fe levels were significantly higher in patients with acute hemorrhagic stroke than controls (p < 0.001), while serum Cu, Zn, Mg and Mn levels were significantly lower (all p < 0.001). However, there was no significant difference between the groups with respect to serum Co levels (p > 0.05). We first demonstrate increased Cd, Pb, and Fe levels; and decreased Cu, Zn, Mg, and Mn levels in patients with acute hemorrhagic stroke. These findings may have diagnostic and prognostic value for acute hemorrhagic stroke. Further studies are required to elucidate the roles of trace elements and heavy metals in patients with acute hemorrhagic stroke. PMID- 24346189 TI - Force-velocity properties' contribution to bilateral deficit during ballistic push-off. AB - PURPOSE: The objective of this study is to quantify the contribution of the force velocity (F-v) properties to bilateral force deficit (BLD) in ballistic lower limb push-off and to relate it to individual F-v mechanical properties of the lower limbs. METHODS: The F-v relation was individually assessed from mechanical measurements for 14 subjects during maximal ballistic lower limb push-offs; its contribution to BLD was then investigated using a theoretical macroscopic approach, considering both the mechanical constraints of movement dynamics and the maximal external capabilities of the lower limb neuromuscular system. RESULTS: During ballistic lower limb push-off, the maximum force each lower limb can produce was lower during bilateral than unilateral actions, thus leading to a BLD of 36.7% +/- 5.7%. The decrease in force due to the F-v mechanical properties amounted to 19.9% +/- 3.6% of the force developed during BL push-offs, which represents a nonneural contribution to BLD of 43.5% +/- 9.1%. This contribution to BLD that cannot be attributed to changes in neural features was negatively correlated to the maximum unloaded extension velocity of the lower limb (r = 0.977, P < 0.001). CONCLUSION: During ballistic lower limb push-off, BLD is due to both neural alterations and F-v mechanical properties, the latter being associated with the change in movement velocity between bilateral and unilateral actions. The level of the contribution of the F-v properties depends on the individual F-v mechanical profile of the entire lower limb neuromuscular system: the more the F-v profile is oriented toward velocity capabilities, the lower the loss of force from unilateral to bilateral push-offs due to changes in movement velocity. PMID- 24346190 TI - Implementing exertional heat illness prevention strategies in US high school football. AB - PURPOSE: Approximately 6500 high school football athletes are treated annually for exertional heat illness (EHI). In 2009, the National Athletic Trainers Association (NATA)-led Inter-Association Task Force (NATA-IATF) released preseason heat acclimatization guidelines to help athletes become accustomed to environmental factors contributing to EHI. This study examines compliance with NATA-IATF guidelines and related EHI prevention strategies. METHODS: The study used a cross-sectional survey completed by 1142 certified athletic trainers (AT), which captured compliance with 17 NATA-IATF guidelines and EHI prevention strategies in high school football during the 2011 preseason. RESULTS: On average, AT reported football programs complying with 10.4 NATA-IATF guidelines (SD = 3.2); 29 AT (2.5%) reported compliance with all 17. Guidelines with the lowest compliance were as follows: "Single-practice days consisted of practice no more than three hours in length" (39.7%); and "During days 3-5 of acclimatization, only helmets and shoulder pads should be worn" (39.0%). An average of 7.6 EHI prevention strategies (SD = 2.5) were used. Common EHI prevention strategies were as follows: having ice bags/cooler available (98.5%) and having a policy with written instructions for initiating emergency medical service response (87.8%). Programs in states with mandated guidelines had higher levels of compliance with guidelines and greater prevalence of EHI prevention strategies. CONCLUSION: A low proportion of surveyed high school football programs fully complied with all 17 NATA-IATF guidelines. However, many EHI prevention strategies were voluntarily implemented. State-level mandated EHI prevention guidelines may increase compliance with recognized best practices recommendations. Ongoing longitudinal monitoring of compliance is also recommended. PMID- 24346192 TI - Editor's Note. PMID- 24346193 TI - Body and society in the Libro de la anathomia del hombre by Bernardino Montana de Monserrate: an anatomist's political dream. PMID- 24346191 TI - Fully anharmonic IR and Raman spectra of medium-size molecular systems: accuracy and interpretation. AB - Computation of full infrared (IR) and Raman spectra (including absolute intensities and transition energies) for medium- and large-sized molecular systems beyond the harmonic approximation is one of the most interesting challenges of contemporary computational chemistry. Contrary to common beliefs, low-order perturbation theory is able to deliver results of high accuracy (actually often better than those issuing from current direct dynamics approaches) provided that anharmonic resonances are properly managed. This perspective sketches the recent developments in our research group toward the development of a robust and user-friendly virtual spectrometer rooted in second order vibrational perturbation theory (VPT2) and usable also by non-specialists essentially as a black-box procedure. Several examples are explicitly worked out in order to illustrate the features of our computational tool together with the most important ongoing developments. PMID- 24346194 TI - Reflections on human embryo research: the debate in Portuguese ethics organizations. PMID- 24346195 TI - Reading about science in nineteenth century Brazil: Revista Popular , 1859-1862. AB - The aim of this text is to analyze how issues relating to the communication of science to the public were treated in a Brazilian periodical, Revista Popular , published by Livraria e Casa Editorial Garnier between 1859 and 1862. The science related sections are investigated, the prologues are analyzed, the topics included in the magazine's coverage of scientific commissions and expeditions around Brazil are examined, and the authors and editors are identified. The analysis indicates the importance of the periodical's role in divulging information about the potential development of a national science to a broader readership than those who had access to strictly intellectual circles. PMID- 24346197 TI - [Out of natural order: nature in discourses about cloning and stem cell research in Brazilian newspapers]. AB - Different conceptions of nature influence media coverage and public opinion about biotechnology. This study reports on a discourse analysis of the ideas about nature and what is natural expressed in Brazilian media coverage of cloning and stem cell research. In the discourse against this research, the biotechnologies in question are placed outside the natural order of things and deemed immoral. In the discourse of those who defend it, nature is portrayed as indifferent to the fate of humans or even cruel, or else a barrier to be overcome, while cloning and embryonic stem cells are naturalized and Dolly the sheep is anthropomorphized. The mythifying or transcendental representations of nature do not just influence public opinion, but also have ethical and political implications. PMID- 24346196 TI - Brazilian opinions about science and technology: the 'paradox' of the relation between information and attitudes. PMID- 24346198 TI - [Scientific controversies in Brazilian television journalism: the coverage of stem cell research onJornal Nacional]. AB - In 1998, stem cell research became a subject of heightened controversy. In Brazil, the polemic came to a head in 2008 when the Federal Supreme Court commenced a judicial review of the new Biosecurity Law because it permitted the use of human embryos in research. This study analyzes the coverage of human embryonic stem cell research on the national daily evening news show, Jornal Nacional . A positive tone is observed, marked by a focus on the potential benefits of the research and omission of its limitations and risks. The limited success rate thus far obtained from embryonic stem cell research and the risks of inducing the formation of tumors were omitted, intimating that the only barrier to new treatments and cures was the legislation. PMID- 24346199 TI - [The case of the 'lowlife': perceptions of danger and the prevention of disreputable behaviors in theRevista de Criminologia, Psiquiatria, Medicina Legal y Ciencias Afinesin Buenos Aires, 1914-1923]. AB - We analyze the construction of the notion of the 'lowlife' in the city of Buenos Aires in the Revista de Criminologia, Psiquiatria y Medicina Legal, from 1914 1923. We shall analyze the notion of 'lowlife', meaning behaviors situated in a border zone between crime and madness, from the point of view of prevention and perception of danger. The first way of analyzing the 'lowlife' examines institutional projects that were related to eugenics and that advocated preventive detention of dangerous people, 'alcoholists' and vagrants. The second involves identifying in moral and physical terms the kind of people who were targeted in the creation of intervention projects for those considered to be 'lowlifes', who could potentially damage the fabric of society in some way. PMID- 24346200 TI - [From miracle to dream come true: the rhetoric of hope and support for the medical profession in news items on transplants in Spain, 1900-1960]. AB - The article studies the building of public trust in transplants via a historico discursive analysis of media sources from 1900 to 1960 in Spain. Maintaining the 'rhetoric of hope' as the journalistic strategy for representing transplants, the initial discursive approach involved the image of the doctor as hero, and transplants as miraculous events. After corneal implants became widespread, transplants were presented as a dream come true thanks to the scientific and technical skills of expert physicians. Since the first news of kidney transplants, the press stressed the promise of a better future through science but reflecting a more cautious medical position and confidence that results could be quantified. PMID- 24346201 TI - ["I do not wish to be controversial": the arrival of the plague in Brazil; analysis of a controversy, 1899]. AB - This article analyzes a debate brought to the public arena by Jornal do Commercio newspaper in August and September 1899 involving two sanitation officials: Nuno de Andrade, Director-General of Public Health, and Jorge Pinto, Director of Hygiene and Public Welfare of the State of Rio de Janeiro. The issue in question was the measures taken by the federal government to prevent bubonic plague reaching Brazil from Porto, Portugal, where there was an epidemic. The theoretical framework for the analysis is Pierre Bourdieu's notion of field, and Bruno Latour's studies into scientific controversy. PMID- 24346202 TI - [Science, aesthetics and race: images and texts inO Brasil Medico, 1928-1945]. AB - This study addresses the formation of discourse about race and eugenics in texts and images published in O Brasil Medico, between 1928 and 1945. The documental analysis inspired on Foucault's theoretical and methodological perspectives, especially the concept of biopolitics, encountered references to the problems of eugenics amongst the Brazilian population, as well as a set of illustrations, mostly photographs of black people's bodies. A contradiction was identified, where a universalistic discourse about race was expressed at the same time that discourses about eugenics and biotypes revealed concerns about the degeneration of the formation of the Brazilian race. These discourses describe a Brazilian race with an idealized standard of physical and moral normality to serve as a model for the development and modernization of the nation. PMID- 24346203 TI - [War of Words:Revista Politecnicaand the construction of an idea of science in Sao Paulo, 1904-1917]. AB - This article discusses the role of the journal, Revista Politecnica in the creation of an idea of science in Sao Paulo during the first republican period in Brazil. Published by the students of the Escola Politecnica de Sao Paulo (Sao Paulo Polytechnic), which went through upheavals in its formative years, the periodical became a vehicle for the promotion and communication of an idea of science amongst the Sao Paulo elites at the time. It not only assured the institution a prominent position in the state, but also helped its consolidation as a national center of science, as opposed, for instance, to its main competitor, the Escola Politecnica do Rio de Janeiro (Rio de Janeiro Polytechnic). PMID- 24346204 TI - [Floriano de Lemos in theCorreio da Manhanewspaper, 1906-1965]. AB - This article covers the life and work of Rio de Janeiro-born doctor and journalist, Floriano de Lemos, bringing to light his extensive output as a columnist in the Correio da Manha newspaper, which had a significant impact on Brazilian history in the first half of the twentieth century. It presents recurring themes discussed by this intellectual - a figure who could be described as multifaceted and modern - as expressed in his column, "Scientific Chronicle", published every Sunday in the newspaper's literary supplement. It also analyzes Lemos's career, highlighting its historical significance not just because of its singularities, but primarily for what it reveals about the intellectual culture at the time. PMID- 24346206 TI - [Photography and its doubles: a picture on the wall]. AB - Hans Belting suggests that 'images are the nomads of media' because they set up and dismantle their camps every time new media appear. Whenever photography portrays another image (painting, TV screen) it plays out a chapter in this history. Photography has been the guardian of the paradoxes in the distance and tensions between image and world in modern times. This is why it now holds a central position in the debate about contemporary visuality. Our fate and the fate of images are somehow interconnected. The last generation of visual artists from the twentieth century sought to express the pain of virtualization; twenty first century photography is rediscovering the promise of a latent body in each image. PMID- 24346205 TI - [Have you eaten any DNA today? Science communication during Science and Technology Week in Brazil]. AB - During the first National Science and Technology Week held in 2004, science centers and museums, universities and schools engaged in activities with the idea of divulging science to the people. Demonstrations of the extraction of DNA from fruits were conducted in supermarkets in 11 Brazilian cities by two institutions, DNA Vai a Escola and Conselho de Informacao e Biotecnologia. This article describes the formation of a national network of people interested in communicating information about genetics to the lay public and the implementation of a low-cost science communication activity in different parts of the country simultaneously. It also analyzes the impact caused by this initiative and the perceptions of those involved in its organization. PMID- 24346207 TI - [The opening lesson in the course on history and geography given by Paul Vidal de la Blache at the Faculty of Nancy: reflections of a historian newly turned geographer]. AB - The aim of this presentation is to divulge the translation into Portuguese of the inaugural lesson given by French geographer Paul Vidal de la Blache at the Faculty of Nancy, given and published in 1873. This inaugural lesson already reveals the general principles proposed by the undisputed master of the French school of geography, which oriented French geography for many decades. A description is also given of the political and institutional context involving the institutionalization of modern geography in the last nineteenth century and the web of alliances and exchanges with historians, configuring an inheritance that Vidal de la Blache readily incorporated and transformed. PMID- 24346208 TI - [Programa de saude: a case of book censorship during the Brazilian military dictatorship]. AB - Some documents produced by the government during the Brazilian military dictatorship have been made available for reference, including censors' reports on television and radio programs, plays, films, songs, advertisements and printed matter. Of the 500 or so reports on books, there is one that vetoes Programa de saude: projetos e temas de higiene e saude, an educational work that proposed actions to help students understand their sanitary conditions and acquire knowledge about health and health-promoting habits in this area. The argument for vetoing it was that the information could fall into the hands of poorly trained teachers, who could distort its content, causing serious damage to Brazilian youth. In this report we see evidence of the obscurantist, elitist posture adopted by the Department of Censorship of Public Entertainment, which aimed to restrict the circulation of information and curb debate. PMID- 24346210 TI - [A black woman, her cells, and some challenges for research ethics]. PMID- 24346209 TI - [The magazineSaude em Debateas a source and object of study]. AB - This research note is about a study of Centro Brasileiro de Estudos da Saude (Brazilian Center for Health Studies, Cebes) and the sanitation reform movement conducted within the ambit of the History of Science and Public Health program at Casa de Oswaldo Cruz. The study focuses on Saude em Debate, the periodical published by Cebes, because of the importance it had during its ten-year existence. The use of the periodical in the research brought to light some issues concerning the participation of its members in the sanitation reform. It is shown how the use of the publication as a source and object of study in research in the area of health deserves broader investigation. PMID- 24346211 TI - [The institutional constitution of Museu Paraense]. PMID- 24346213 TI - [Peter Lund: between myth and history]. PMID- 24346212 TI - [On the endless incursions of Darwin in Brazil, Latin America and the world]. PMID- 24346214 TI - [The ideology and training of technical health workers in Brazil and Mercosur]. PMID- 24346215 TI - Early frontal structural and functional changes in mild white matter lesions relevant to cognitive decline. AB - White matter lesions (WMLs) are of considerable research interest because of their high prevalence and serious consequences, such as stroke and dementia. Most existing studies of WMLs have focused on severe WMLs, but mild WMLs, which are clinically and fundamentally significant, have been largely neglected. The present study is a comprehensive investigation on the injury pattern and on the anatomical, functional, and cognitive changes related to mild WMLs. These results may provide better understanding mild WMLs. Fifty-one human subjects with mild WMLs and 49 control participants completed serial neuropsychological tests and underwent a 3-T magnetic resonance imaging (MRI) scan that included diffusion tensor imaging, a resting-state functional MRI, and a structural MRI. We found declines in cognitive functions such as global function, executive function, and episodic memory in mild WMLs subjects. The white matter injuries in the mild WMLs subjects were mainly in the fibers that projected to frontal areas, while gray matter structures were relatively intact. The overall resting state function of the frontal area was significantly increased. The integrity of the neural fibers in the inferior fronto-occipital fasciculus and the inferior longitudinal fasciculus was significantly correlated with the cognitive scores in executive function and episodic memory in both the control and the mild WMLs group. These findings demonstrate that mild WMLs subjects exhibit abnormalities in both white matter structure and functional intrinsic brain activity and that such changes are related to several types of cognitive dysfunction. PMID- 24346216 TI - Activation of neuronal defense mechanisms in response to pathogenic factors triggering induction of amyloidosis in Alzheimer's disease. AB - We present a new model for etiology of Alzheimer's disease (AD) which postulates early involvement of specialized neuroprotective mechanisms in the pathology of AD. These neuroprotective mechanisms work in concert to regulate metabolic homeostasis in healthy neuronal cells, but contribute to the distinctive cytopathic phenotype of neuronal degeneration in AD. According to this model, two molecular/genetic hallmarks of AD, amyloid-beta (Abeta) deposition and tau hyperphosphorylation, are associated with neuronal mechanisms for dissipating thermal energy associated with high levels of protein synthesis in highly temperature-sensitive neuronal cells. Development of effective methods of AD treatment will require a better understanding of how this neuronal defense system is activated in response to cytopathological triggers in sporadic AD. The cause and effect link between synthesis and processing of amyloid-beta protein precursor (AbetaPP) and the AD terminal phenotype of neurofibrillary tangles and neuron loss involve the formation of Abeta peptides that accumulate as oligomers, cannot be controlled by neurons, and are toxic to the surrounding neuronal membranes. We analyze experimental and clinical studies that have investigated the correlation between phosphorylation of some transport proteins and increased synthesis of proteins in neurons. We also review the evidence related to the possibility that protein hyperphosphorylation may be a byproduct of energetic imbalances in AD cells associated with high levels of protein synthesis, and that activation of defense systems, through which energy-rich molecules are eliminated from the site of protein synthesis and are sequestered to the peripheral neuronal areas, may bring about some of the distinctive morphological features of AD. PMID- 24346217 TI - Stimulation of insulin signaling and inhibition of JNK-AP1 activation protect cells from amyloid-beta-induced signaling dysregulation and inflammatory response. AB - One of the hallmarks of Alzheimer's disease (AD) is the accumulation and deposition of amyloid-beta (Abeta) peptides in the brain and cerebral vasculature. Abeta evokes neuroinflammation and has been implicated in insulin signaling disruption and JNK-AP1 activation, contributing to AD neuropathologies including oxidative injury and vascular insufficiencies. In this study we aim to better understand the protective mechanisms of insulin signaling and JNK-AP1 inhibition on the adverse effects of Abeta. Four-hour treatment of hCMEC/D3, the immortalized human brain endothelial cells (iHBEC), with Abeta1-42 resulted in significant c-Jun phosphorylation, oxidative stress, and cell toxicity. Concurrent treatment with Abeta1-42 and insulin or Abeta1-42 and JNK inhibitor SP600125 significantly improved cell viability. Cytokine array on conditioned media showed that insulin and SP600125 strongly reduced all Abeta1-42-induced cytokines. ELISA confirmed the protective effect of insulin and SP600125 on Abeta induced expression of interleukin (IL)-8 and Growth related oncogene-alpha (Gro alpha). qRT-PCR revealed that insulin and SP600125 protected iHBEC from Abeta1-42 induced inflammatory gene expression. Transcription factor profiling showed that treatment of iHBEC with Abeta1-42, insulin, or SP600125 alone or in combination resulted in profound changes in modulating the activities of multiple transcription factors and relevant pathways, some of which were validated by western blot. Insulin treatment and JNK inhibition in vitro synergistically reduced c-Jun phosphorylation and thus JNK-AP1 signaling activation. The study suggests that activation of insulin and blocking of JNK-AP1 signaling inhibits Abeta-induced dysregulation of insulin signaling and inflammatory response. PMID- 24346218 TI - Accuracy of urinary AD7c-NTP for diagnosing Alzheimer's disease: a systematic review and meta-analysis. AB - BACKGROUND: Alzheimer-associated neuronal thread protein (AD7c-NTP) has been reported to have high diagnostic accuracy in patients with Alzheimer's disease (AD). OBJECTIVE: To determine the diagnostic accuracy of urinary AD7c-NTP for the diagnosis of AD in patients with suspected AD. METHODS: We searched MEDLINE (January 1950 to date) and other electronic databases (from inception to date) for diagnostic accuracy studies that compared urinary AD7c-NTP to the standard clinical diagnosis of AD. We conducted citation searches and screened the reference lists of included studies. Studies were assessed for methodological quality using QUADAS. Summary receiver operating characteristic curves were used to summarize overall test performance. RESULT: Nine studies met our inclusion criteria. The summary estimates of the urinary AD7c-NTP assay for probable or possible AD were as follows: SEN, 0.87 (95%CI: 0.80-0.91); SPE, 0.89 (95%CI: 0.87 0.91); PLR, 8.13 (95% CI: 6.60-10.02); and NLR, 0.15 (95% CI: 0.10-0.22). The four summary estimates of urinary AD7c-NTP assay for probable AD were 0.89 (95% CI: 0.86-0.92), 0.90 (95% CI: 0.88-0.92), 8.88 (95% CI: 7.09-11.12), and 0.12 (95% CI: 0.09-0.16), with no obvious heterogeneity. CONCLUSION: Urinary AD7c-NTP is a sensitive and specific test for the diagnosis of probable AD. However, whether urinary AD7c-NTP can be used as an early marker is still unknown. PMID- 24346219 TI - The complex insurance reimbursement landscape in reduction mammaplasty: how does the American plastic surgeon navigate it? AB - BACKGROUND: Reduction mammaplasty (RM) is generally thought of as a reconstructive procedure, frequently but variably reimbursed by third-party payers. The purpose of this study was to assess US plastic surgeons' opinions of and interactions with the insurance coverage environment surrounding the reimbursement of RM. METHODS: The RM policies of 15 regional and nationwide health insurance carriers were analyzed. A survey regarding RM was distributed to all members of the American Society of Plastic Surgeons and subsequently analyzed. RESULTS: Most insurance carriers require a minimum resection weight, a minimum age, and a conservative therapy trial. A total of 757 surgeons responded to our survey. Seventy-six percent of the respondents believe that only some RM procedures should be covered by insurance. Sixty-four percent feel that symptoms are the most important factor in the surgeon's determination of medical necessity. Fifty-seven percent state that a breast resection weight of 500 g or greater is required for coverage in their region. Seventy-one percent believe that this weight should be less than 500 g per breast. If the surgeon estimates that he/she will remove 500 g per breast, the minimum weight for coverage, 61% of the surgeons would have patients sign a statement of liability for payment. If the intraoperative resection weight is inadequate, 45.6% would not remove additional tissue, risking nonpayment; 32.7% would complete the procedure and inform the patient that payment is out-of-pocket. CONCLUSIONS: Insurance reimbursement for RM varies in approval by carrier. Surgeons believe that signs and symptoms of macromastia determine medical necessity, whereas insurance carriers place a larger emphasis on resection weights. PMID- 24346220 TI - Building surgical capacity in low-resource countries: a qualitative analysis of task shifting from surgeon volunteers' perspectives. AB - INTRODUCTION: Surgical volunteer organizations (SVOs) focus considerable resources on addressing the backlog of cases in low-resource countries. This model of service may perpetuate dependency. Efforts should focus on models that establish independence in providing surgical care. Independence could be achieved through surgical capacity building. However, there has been scant discussion in literature on SVO involvement in surgical capacity building. METHODS: Using qualitative methods, we evaluated the perspectives of surgeons with extensive volunteer experience in low-resource countries. We collected data through in depth interviews that centered on SVOs using task shifting as a tool for surgical capacity building. RESULTS: Some of the key themes from our analysis include the ethical ramifications of task shifting, the challenges of addressing technical and clinical education in capacity building for low-resource settings, and the allocation of limited volunteer resources toward surgical capacity building. CONCLUSION: These themes will be the foundation of subsequent studies that will focus on other stakeholders in surgical capacity building including host communities and SVO administrators. PMID- 24346221 TI - Risk factors in abdominal aortic aneurysm and in Polish population aortoiliac occlusive disease and differences between them [corrected]. AB - Abdominal aortic aneurysm (AAA) and aortoiliac occlusive disease (AIOD) are multifactorial vascular disorders caused by complex genetic and environmental factors. The purpose of this study was to define risk factors of AAA and AIOD in the Polish population and indicate differences between diseases. PMID- 24346222 TI - Financial coping strategies of mental health consumers: managing social benefits. AB - Mental health consumers depend on social benefits in the forms of supplemental security income and social security disability insurance for their livelihood. Although these programs pay meager benefits, little research has been undertaken into how this population makes ends meet. Using a qualitative approach, this study asks what are the financial coping strategies of mental health consumers? Seven approaches were identified: subsidies, cost-effective shopping, budgeting, prioritizing, technology, debt management, and saving money. Results illustrate the resourcefulness of mental health consumers in managing meager social benefits and highlight the need to strengthen community mental health efforts with financial capabilities education. PMID- 24346223 TI - Dialectical behavior therapy training to reduce clinical burnout in a public behavioral health system. AB - There is a risk of experiencing clinical burnout among therapists providing treatment to clients with borderline personality disorder (BPD), a complex, costly and difficult-to-treat psychiatric disorder. Dialectical behavior therapy (DBT) is an evidence-based treatment of BPD that has been widely disseminated. There is only one published study that has examined pre and post scores of burnout among clinicians who receive training in DBT, and none that have taken place within a public behavioral health system in the United States where resources for community-based agencies are limited and demands are high. The current study examined the rates of burnout among therapists treating clients with BPD within a large, urban public behavioral health system. The study included a sample of nine clinicians and showed significantly decreased scores of burnout after participants attended a series of DBT trainings over a period of 13 months. There were several key limitations to internal validity including the lack of a control group. Similar evaluations of training outcomes are needed to address the widespread occurrence of burnout among community-based clinicians providing treatment to clients with BPD in order to enhance the quality of patient care. PMID- 24346224 TI - Factor structure of the Internet Addiction Scale and its associations with psychiatric symptoms for Korean adolescents. AB - In this paper, we explore underlying factors of Internet Addiction Scale (IAS) and examine how the dimensions of the IAS relate to psychiatric symptoms in Korean adolescents. Exploratory factor analysis with a sample of N = 1,722 consisted of 13-15 year old Korean adolescents identified three distinctive factors of IAS and they were labeled 'time management', 'withdrawal behaviors' and 'neglect work'. Then, multiple regression models were applied to assess the association between each factor and eight psychological problems, which were evaluated by Youth Self Report. The overall IAS was significantly associated with Somatic, Immature, Thought, Attention, Delinquent and Aggressive behaviors. However, three factor scores showed different association patterns and indicated multidimensional aspects of problematic Internet use. PMID- 24346225 TI - Six-month outcomes of an integrated assertive community treatment team serving adults with complex behavioral health and housing needs. AB - Assertive community treatment (ACT) and integrated dual disorders treatment (IDDT) have individually proven effective for treatment of adults with complex behavioral health and housing needs. This study evaluated the effectiveness of an ACT team that delivered integrated care consistent with IDDT principles. Participants included 60 adults with a history of chronic homelessness and co occurring mental health and substance use disorders. Measures assessing mental health, substance use, and residential stability were completed at intake to the program and then 6 months later. Participants reported statistically significant improvements in mental health symptomatology and residential stability over time, although there were no changes in substance use. Findings support the effectiveness of the intervention for improving mental health and housing stability among adults with complex behavioral health and housing needs. Fidelity data support the notion that multiple evidence-based interventions can be integrated while still maintaining adequate fidelity to individual components. PMID- 24346226 TI - Checklist for anesthesiological process: analysis of risks. AB - BACKGROUND: Several methods are reported in the literature to analyze medically undesirable events during hospital care. Each method has several limitations, so no one has been defined as the standard tool to be able to detect failure during a medical process. The aim of this study was to compare an anesthesiological perioperative checklist with traditional Regional Incident Reporting (RIR) form in detecting and describing failures. METHODS: We analyzed RIR number of reports, seriousness and contributing factors. We also analyzed anesthesiological checklist data for: number of reports, seriousness of incident, contributing factors and distribution in macro-phases. RESULTS: We screened 2681 patients who underwent gynecological and obstetrical surgeries. RIR showed only the most harmful events in 0.4% of surgeries. Conversely, we recorded 135 failures with anesthesiological checklists (3.3%), of which 123 (91.1%) were solved. Categories of incident in checklists were: failures for medical device/equipment (N.=30, 22.2%), for treatment/procedures (N.=25, 18.5%), for clinical assessment (N.=22, 16.2%), for consent/communication (N.=19, 14%), for medication (N.=16, 11.8%) and for documentation (N.=8, 5.9%). Ninety-four failures (69.6%) resulted in no harm for the patient, 41 (30.3%) in reversible damage and there were no cases of permanent damage/death. Contributing factors in checklists were mainly related to team (43.7%), task factors (28.1%) and work environment (22.2%). Failures detected in macro-phases were related to: clinical assessment (31.8%), presurgical re-assessment (23.7%), preparation for anesthesia (30.3%), anesthesia conduction (8.8%) and awakening (5.1%). CONCLUSION: An anesthesiological checklist compared with traditional RIR provided a more sensible and complete framework for incident analysis during the perioperative period in patients undergoing gynecological and obstetrical surgeries. PMID- 24346227 TI - Pharmacological and clinical differences among transmucosal fentanyl formulations for the treatment of breakthrough cancer pain: a review article. AB - Breakthrough pain (BTP) is highly prevalent (59.2%) in chronic cancer patients and normally needs rescue treatments' with opioids when pain flares up. Transmucosal oral/nasal fentanyl formulations are commonly used in clinical practice. The different methods of release influence the pharmacokinetics and clinical properties of these formulations. The aim of this review was to assess and weigh these differences. Clinical trials comparing one transmucosal fentanyl with placebo or another active drug were included. We searched Medline for the last ten years and analyzed 13 studies, totaling 1447 patients. Clinical data on efficacy and safety were compared. In parallel, we report the differences in delivery systems, bioavailability, maximum plasma concentration (Cmax), plasma half-life, and time to reach Cmax (tmax). Considerable variability emerged between formulations. This suggests some considerations on the choice of the fentanyl formulation in the light of the BTP features in each clinical case. PMID- 24346228 TI - Hemoproteins-nickel foam hybrids as effective supercapacitors. AB - The immobilization of hemeproteins onto a nickel foam electrode was developed for the first time, and the electrode exhibits remarkable electrochemical performance with higher capacitance and stability compared to synthetic pseudocapacitors. PMID- 24346229 TI - Definition of K(trans) and FA thresholds for better assessment of experimental glioma using high-field MRI: a feasibility study. AB - PURPOSE: To define K(trans) and fractional anisotropy (FA) thresholds in correlation to histology for improved magnetic resonance imaging (MRI) tumor assessment in an animal model of brain glioma. METHODS: Twelve rats underwent 4.7 T MRI at day 10 after tumor implantation. Anatomical scans (T2, T1 at 8 min after double dose contrast application) as well as dynamic contrast-enhanced (DCE) imaging with calculation of K(trans) and diffusion tensor imaging (DTI) with calculation of FA were performed. T2- and T1-derived tumor volumes were calculated and thresholds for K(trans) and FA were defined for best MRI tumor assessment correlated to histology. RESULTS: Tumor volumes were 159 +/- 14 mm(3) (histology), 126 +/- 26 mm(3) (T1 with contrast, r=0.76), and 153 +/- 12 mm(3) (T2, r=0.84), respectively. K(trans)- and FA-derived tumor volumes were 160 +/- 16 mm(3) (for K(trans >= 0.04 min(-1), r=0.94), and 159 +/- 14 mm(3) (for FA L0.14, r=0.96), respectively. CONCLUSIONS: DCE-MRI and DTI with calculation of K(trans) and FA maps allow very precise brain glioma assessment comparable to histology if established thresholds for the given tumor model are used. PMID- 24346230 TI - Diversity, cold active enzymes and adaptation strategies of bacteria inhabiting glacier cryoconite holes of High Arctic. AB - Cryoconite holes have biogeochemical, ecological and biotechnological importance. This communication presents results on culturable psychrophilic bacterial diversity from cryoconite holes at Midre Lovenbreen (ML), Austre Broggerbreen (AB), and Vestre Broggerbreen (VB) glaciers. The culturable bacterial count ranged from 2.7 * 10(3) to 8.8 * 10(4) CFUs/g while the total bacterial numbers ranged from 5.07 * 10(5) to 1.50 * 10(6) cells at the three glaciers. A total of 35 morphologically distinct bacterial isolates were isolated. Based on 16S rRNA gene sequence data, the identified species belonged to eight genera namely Pseudomonas, Polaromonas, Micrococcus, Subtercola, Agreia, Leifsonia, Cryobacterium and Flavobacterium. The isolates varied in their growth temperature, NaCl tolerance, growth pH, enzyme activities, carbon utilization and antibiotic sensitivity tests. Fatty acid profiles indicate the predominance of branched fatty acids in the isolates. To the best of our knowledge, this is the first record of culturable bacterial communities and their characterization from glacier cryoconites from High Arctic. High amylase and protease activities expressed by Micrococcus sp. MLB-41 and amylase, protease and lipase activities expressed by Cryobacterium sp. MLB-32 provide a clue to the potential applications of these organisms. These cold-adapted enzymes may provide an opportunity for the prospect of biotechnology in Arctic. PMID- 24346232 TI - Homo- and heterometallic luminescent 2-D stilbene metal-organic frameworks. AB - Metal-organic frameworks (MOFs) can provide a matrix for the assembly of organic chromophores into well-defined geometries, allowing for tuning of the material properties and study of structure-property relationships. Here, we report on the effect of the coordinated metal ion on the luminescence properties of eight isostructural MOFs having the formula M(1)2M(2)L3(DMF)2 (M(1) = M(2) = Zn (1), Cd (2), Mn (3), Co (4); M(1) = Zn, M(2) = Cd (5), Mn (6), Co (7); M(1) = Co, M(2) = Mn (8); L = trans-4,4'-stilbene dicarboxylate), synthesized by reaction of the appropriate metal nitrate or mixtures of metal nitrates with LH2 in DMF. The crystal structures of 2, 3 and 5-8 were determined by X-ray diffraction to be composed of trinuclear metal clusters linked by stilbene dicarboxylate linkers in a paddlewheel geometry, extending to form a 2-D layered structure. In the mixed metal cases, the larger metal ion was found to occupy the octahedral site in the cluster while the smaller ion occupies the tetrahedral positions, suggesting a selective, ligand-directed assembly process for the mixed-metal species. Variable temperature magnetic measurements for paramagnetic MOFs 3 and 6-8 were consistent with the site occupancies determined crystallographically, and indicated weak intra-cluster antiferromagnetic coupling for 3 and 8. Comparison between the crystal structures of 2, 3 and 5-8 and those reported for 1 and 4 in the literature reveal close resemblances between linker environments, with important intermolecular stilbene-stilbene geometries that are comparable in all cases. Interestingly, pale-colored 1-3 and 5-7 display very similar emission profiles upon excitation at lambda(ex) = 350 nm, whereas dark-colored 4 and 8 do not exhibit detectable emission spectra. The bright, well-resolved luminescence of 1, 2 and 5 is ascribed to rigidification of the linker upon coordination to the d(10) metal ions, whereas the weaker emission observed for 3, 6 and 7 is presumably a result of quenching due to close proximity of the linker to one or more paramagnetic ions. Time-resolved measurements for 1, 2, 5 and 6 reveal biexponential emission decays, where the lifetime of the longer-lived state corresponds to observed variations in the nearest-neighbor cofacial stilbene stilbene distances in their crystal structures. For 3, a monoexponential decay with shorter lifetime was determined, indicating significant paramagnetic quenching of its emissive state. PMID- 24346231 TI - Activation of TREK-1 by morphine results in analgesia without adverse side effects. AB - Morphine is the gold-standard pain reliever for severe acute or chronic pain but it also produces adverse side effects that can alter the quality of life of patients and, in some rare cases, jeopardize the vital prognosis. Morphine elicits both therapeutic and adverse effects primarily through the same MU opioid receptor subtype, which makes it difficult to separate the two types of effects. Here we show that beneficial and deleterious effects of morphine are mediated through different signalling pathways downstream from MU opioid receptor. We demonstrate that the TREK-1 K(+) channel is a crucial contributor of morphine induced analgesia in mice, while it is not involved in morphine-induced constipation, respiratory depression and dependence-three main adverse effects of opioid analgesic therapy. These observations suggest that direct activation of the TREK-1 K(+) channel, acting downstream from the MU opioid receptor, might have strong analgesic effects without opioid-like adverse effects. PMID- 24346233 TI - A porous sodalite-type MOF based on tetrazolcarboxylate ligands and [Cu4Cl]7+ squares with open metal sites for gas sorption. AB - A porous sodalite-type metal-organic framework based on tetrazolcarboxylate ligands and [Cu4Cl](7+) squares was successfully synthesized, which exhibited permanent porosity and high adsorption abilities of H2, CO2 and organic chemical pollutants. PMID- 24346234 TI - Quartet analysis of putative horizontal gene transfer in Crenarchaeota. AB - Horizontal gene transfers (HGT) between four Crenarchaeota species (Metallosphaera cuprina Ar-4T, Acidianus hospitalis W1T, Vulcanisaeta moutnovskia 768-28T, and Pyrobaculum islandicum DSM 4184T) were investigated with quartet analysis. Strong support was found for individual genes that disagree with the phylogeny of the majority, implying genomic mosaicism. One such gene, a ferredoxin-related gene, was investigated further and incorporated into a larger phylogeny, which provided evidence for HGT of this gene from the Vulcanisaeta lineage to the Acidianus lineage. This is the first application of quartet analysis of HGT for the phylum Crenarchaeota. The results have shown that quartet analysis is a powerful technique to screen homologous sequences for putative HGTs and is useful in visually describing genomic mosaicism and HGT within four taxa. PMID- 24346235 TI - Early peripheral laser photocoagulation of nonperfused retina improves vision in patients with central retinal vein occlusion (Results of a proof of concept study). AB - BACKGROUND: To evaluate the effect of combination of ranibizumab and laser photocoagulation to peripheral retinal areas of nonperfusion in patients with non ischemic central retinal vein occlusion (CRVO) without neovascularizations. METHODS: This prospective, proof of concept study randomized 22 CRVO patients into two arms. The RL group (ranibizumab + laser; n = 10) received ranibizumab with additive laser photocoagulation; the control R group (n = 12) was treated with ranibizumab only. All patients received three initial monthly ranibizumab injections followed by PRN regimen. Changes in best corrected visual acuity (BCVA) and in central retinal thickness (CRT) were documented over 6 months. RESULTS: Median of BCVA improved in the RL group from 65 ETDRS letters (interquartile range IQR = 10 letters) at baseline to 70 (IQR = 23.2) letters at month 6. In the control group BCVA remained stable [baseline: 61 (IQR = 19.5) and month 6: 61 (IQR = 22) letters]. CRT decreased between baseline and final visit in the RL group from 547 (IQR = 513) MUm to 246.5 (IQR = 346.3) MUm, and in the control group from 637.5 (IQR = 344) MUm to 423 (IQR = 737) MUm. More pronounced improvements in BCVA were seen in the RL group (medians = 14 vs. 6.5 letters) although the observed group differences were not statistically significant due to small samples. CONCLUSIONS: The selective laser photocoagulation of peripheral areas of nonperfusion seems to lead to additional visual improvement in patients with CRVO. A larger replication trial is necessary to confirm the results of this proof of concept study. PMID- 24346237 TI - Treatment for locally advanced breast cancer: a global challenge, personalized medicine or both? AB - In this special issue of Current Opinion in Supportive and Palliative Care, we are delighted to bring together key, internationally recognized experts in the field of breast cancer care for a special issue on locally advanced breast cancer (LABC). To place this disease in context, we have deliberately tried to keep the chapter headings pertinent to the real world issues facing both patients and their healthcare providers. PMID- 24346236 TI - Frailty and prognosis in advanced heart failure. AB - PURPOSE OF REVIEW: The frailty syndrome is characterized by an increased vulnerability to physiologic stress. Frailty is distinct from disability and disease states; however, there is a strong relationship between frailty and heart failure and the pathophysiology's overlap. Heart failure exacerbations and hospitalizations likely accelerate the cycle of frailty. The following review summarizes the relationship between heart failure and frailty, and the utility of a frailty assessment in heart failure management. RECENT FINDINGS: A frailty assessment can help to stratify heart failure patients at high risk for adverse outcomes. Increasing availability of device therapies for patients with heart failure make prerisk assessment an important management strategy. SUMMARY: Furthermore, studies are necessary to understand the relationship between heart failure and frailty and to devise the best care strategies for these patients. PMID- 24346238 TI - Mental disturbances in Parkinson's disease and related disorders: the role of excitotoxins. AB - The pathomechanism behind the neurodegenerative process in Parkinson's disease involves damage to the dopaminergic and nondopaminergic systems with dysfunctioning of the dopaminergic-glutamatergic circuitry in the basal ganglional neural processing. Excitotoxicity may contribute markedly to neuronal damage and loss. Beside the cardinal motor signs of the disease, non-motor symptoms, including mental disturbances, are characteristic features of the clinical course. Affective or autonomic changes may precede motor symptoms. Neuroprotective drugs are not yet available. However, new modes of therapy targeting the defective dopaminergic-glutamatergic system might also be effective both for symptomatologic treatment and for neuroprotection. Alterations in the kynurenine pathway have been demonstrated in Parkinson's disease. Preclinical studies suggest that intervention in the kynurenine pathway may result in neuroprotection and additionally alleviate the symptoms through influencing the glutamatergic neurotransmission. PMID- 24346239 TI - Controlling nanomaterial synthesis, chemical reactions and self assembly in dynamic thin films. AB - Recent advances in continuous-flow processors, which integrate sustainability metrics including scalability, have established their utility in materials and chemical processing. In this review the spinning disc processor (SDP) and the related rotating tube processor (RTP), are highlighted in the use of highly sheared and micro-mixed dynamic thin films in gaining control over such processing for a wide range of applications. Both SDP and RTP have a number of control parameters beyond traditional batch processing which are effective in (i) manipulating the size, shape, defects, agglomeration, and precipitation of nanoparticles, as well as decorating preformed nano-structures, for a variety of inorganic and organic compounds, (ii) controlling chemical reactivity and selectivity including the formation of polymers, and (iii) disassembling self organised nano-structures, as a tool for probing macromolecular structure under shear conditions. PMID- 24346240 TI - Multi-frequency near-field scanning optical microscopy. AB - We demonstrate a new multi-frequency approach for mapping near-field optically induced forces with subwavelength spatial resolution. The concept relies on oscillating a scanning probe at two different frequencies. Oscillations at one frequency are driven electrically to provide positional feedback regulation. Modulations at another frequency are induced optically and are used to measure the mechanical action of the optical field on the probe. Because the measurement is based on locally detecting the force of the electromagnetic radiation acting on the probe, the new method does not require a photodetector to map the radiation distribution and, therefore, can provide true broadband detection of light with a single probe. PMID- 24346241 TI - Volumetric CT-based segmentation of NSCLC using 3D-Slicer. AB - Accurate volumetric assessment in non-small cell lung cancer (NSCLC) is critical for adequately informing treatments. In this study we assessed the clinical relevance of a semiautomatic computed tomography (CT)-based segmentation method using the competitive region-growing based algorithm, implemented in the free and public available 3D-Slicer software platform. We compared the 3D-Slicer segmented volumes by three independent observers, who segmented the primary tumour of 20 NSCLC patients twice, to manual slice-by-slice delineations of five physicians. Furthermore, we compared all tumour contours to the macroscopic diameter of the tumour in pathology, considered as the "gold standard". The 3D-Slicer segmented volumes demonstrated high agreement (overlap fractions > 0.90), lower volume variability (p = 0.0003) and smaller uncertainty areas (p = 0.0002), compared to manual slice-by-slice delineations. Furthermore, 3D-Slicer segmentations showed a strong correlation to pathology (r = 0.89, 95%CI, 0.81-0.94). Our results show that semiautomatic 3D-Slicer segmentations can be used for accurate contouring and are more stable than manual delineations. Therefore, 3D-Slicer can be employed as a starting point for treatment decisions or for high-throughput data mining research, such as Radiomics, where manual delineating often represent a time-consuming bottleneck. PMID- 24346242 TI - Ultrasound biomicroscopy (UBM) and scanning acoustic microscopy (SAM) for the assessment of hernia mesh integration: a comparison to standard histology in an experimental model. AB - BACKGROUND: Mesh integration is a key parameter for reliable and safe hernia repair. So far, its assessment is based on histology obtained from rare second look operations or experimental research. Therefore, non-invasive high-resolution imaging techniques would be of great value. Ultrasound biomicroscopy (UBM) and scanning acoustic microscopy (SAM) have shown potential in the imaging of hard and soft tissues. This experimental study compared the detection of mesh integration, foreign body reaction and scar formation in UBM/SAM with standard histology. MATERIALS AND METHODS: Ten titanized polypropylene meshes were implanted in rats in a model of onlay repair. 17 days postoperative animals were killed and samples were paraffin embedded for histology (H&E, Cresyl violet) or processed for postmortem UBM/SAM. The observation period was uneventful and meshes appeared well integrated. RESULTS: Relocation of neighboring cross sectional levels could easily be achieved with the 40-MHz UBM and granulation tissue could be distinguished from adjacent muscle tissue layers. The spatial resolution of approximately 8 MUm of the 200-MHz UBM system images was comparable to standard histology (2.5-5* magnification) and allowed a clear identification of mesh fibers and different tissue types, e.g., scar, fat, granulation, and muscle tissues, as well as vessels, abscedations, and foreign body giant cell clusters. CONCLUSION: This pilot study demonstrates the potential of high frequency ultrasound to assess hernia mesh integration non-invasively. Although the methods lack cell-specific information, tissue integration could reliably be assessed. The possibility of conducting UBM in vivo advocates this method as a guidance tool for the indication of second-look operations and subsequent elaborate histological analyses. PMID- 24346243 TI - Regeneration of full-thickness skin defects using umbilical cord blood stem cells loaded into modified porous scaffolds. AB - In this study, we have demonstrated the ability of cord blood (CB)-derived unrestricted somatic stem cells (USSCs) and chitosan-modified poly(3 hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) scaffold to promote skin regeneration. Afterward, the scaffolds were evaluated by structural, microscopic, physical, and mechanical assays and cell culture analyses. Results of structural, physical, and mechanical analyses also showed a good resilience and compliance with movement as a skin graft. Cellular experiments showed a better cell adhesion, growth, and proliferation inside the modified scaffolds compared with unmodified ones. In animal models with histological examinations, all groups, excluding the control group especially the groups treated with stem cells, exhibited the most pronounced effect on wound closure, with the statistically significant improvement in wound healing being seen at postoperative day 21. These data suggest that chitosan-modified PHBV scaffold loaded with CB-derived USSCs could significantly contribute to wound repair and be potentially used in the tissue engineering. PMID- 24346244 TI - Selecting optimal eggs and embryonic developmental stages of fathead minnow (Pimephales promelas) for early life-stage toxicity tests. AB - Aquaculture research has indicated that fish embryo hatching success and larval survival can sometimes be predicted by embryo characteristics, such as blastomere cleavage patterns. An analogous strategy of individual assessment of spawned eggs could also be used to improve the quality of toxicity tests using early life stages of fish where control-group survival determines experimental validity. Here we explored whether a simple method of assessing fathead minnow eggs and embryos for abnormalities could predict hatch success, and larval size at hatch, as indicators of embryo larval quality. Embryos were classified according to both their developmental stage and the presence of any abnormalities: uneven blastomere cleavage, atypical embryo size or shape, and the presence of inclusions in the yolk. Clutch size and fertilization rate did not predict embryo larval quality. Fewer abnormalities in embryos with <=32 cells correlated with longer larvae at hatch. Normal embryos were more likely to hatch successfully than abnormal embryos of the same clutch, but because abnormality rates were generally low, much of the variation in hatch success could not be attributed to visible embryo malformations. Blastomere symmetry may be a useful selection criterion in embryos <3 h postfertilization. Where toxicant exposures early in embryonic development are not required or possible, hatch success could be increased by using older embryos that have survived gastrulation. Purposeful selection of embryos with at least two blastomeres, blastomere symmetry, and few inclusions can improve control survival and improve the quality of any generated (sub)lethality data. In our laboratory, application of the egg-selection criteria significantly improved control group hatch success increasing it from a mean of 84.4 to 94.2%. PMID- 24346245 TI - Mobile uranium(IV)-bearing colloids in a mining-impacted wetland. AB - Tetravalent uranium is commonly assumed to form insoluble species, resulting in the immobilization of uranium under reducing conditions. Here we present the first report of mobile U(IV)-bearing colloids in the environment, bringing into question this common assumption. We investigate the mobility of uranium in a mining-impacted wetland in France harbouring uranium concentrations of up to 14,000 p.p.m. As an apparent release of uranium into the stream passing through the wetland was observable, we examine soil and porewater composition as a function of depth to assess the geochemical conditions leading to this release. The analyses show the presence of U(IV) in soil as a non-crystalline species bound to amorphous Al-P-Fe-Si aggregates, and in porewater, as a distinct species associated with Fe and organic matter colloids. These results demonstrate the lability of U(IV) in these soils and its association with mobile porewater colloids that are ultimately released into surface water. PMID- 24346246 TI - How to produce white light in a single-phase host? AB - White light-emitting diodes (WLEDs) as new solid-state light sources have a greatly promising application in the field of lighting and display. So far much effort has been devoted to exploring novel luminescent materials for WLEDs. Currently the major challenges in WLEDs are to achieve high luminous efficacy, high chromatic stability, brilliant color-rending properties, and price competitiveness against fluorescent lamps, which rely critically on the phosphor properties. In recent years, numerous efforts have been made to develop single phase white-light-emitting phosphors for near-ultraviolet or ultraviolet excitation to solve the above challenges with certain achievements. This review article highlights the current methods to realize the white light emission in a single-phase host, including: (1) doping a single rare earth ion (Eu(3+), Eu(2+) or Dy(3+)) into appropriate single-phase hosts; (2) co-doping various luminescent ions with different emissions into a single matrix simultaneously, such as Tm(3+)/Tb(3+)/Eu(3+), Tm(3+)/Dy(3+), Yb(3+)/Er(3+)/Tm(3+)etc.; (3) codoping different ions in one host to control emission color via energy transfer processes; and (4) controlling the concentration of the defect and reaction conditions of defect-related luminescent materials. PMID- 24346247 TI - New facile enantio- and diastereo-selective syntheses of (-)-triptonide and (-) triptolide. AB - A novel formal asymmetric synthesis of (-)-triptonide and (-)-triptolide, featuring a new alternative access to their known key intermediate 4, has been achieved through two synthetic routes in 9 steps with 13.6% total yield and 10 steps with 18.5% overall yield, respectively. This synthesis is scalable and hence has high potential for application to further synthetic elaboration and biologic investigation on such natural products. PMID- 24346248 TI - Neurosteroids and brain aging. AB - Patients with Alzheimer's disease (AD) or dementia are increasing in numbers as the population worldwide ages. Mid-life psychological stress, psychosocial stress and post-traumatic stress disorder have been shown to cause cognitive dysfunction and lead to increased risk for dementia. The mechanisms behind stress-induced AD or dementia are not known. Solid amyloid plaques in the affected brain tissues characterize AD. However, over the last decade it has been concluded that the level of soluble beta-amyloid proteins (Abeta) are reliable diagnostic markers as they correlate to cognitive performance while plaques do not. The soluble Abeta accumulate intracellularly and disturb the synaptic function. In addition, it has been shown that the levels of intracellular Abeta depend on neuronal activity. Previous studies in animal models have shown that deceased neuronal activity cause increased levels of Abeta inside neurons and cognitive decline. Allopregnanolone is produced in the brain at stress. It enhances the activity of the GABAergic neurotransmission and affects neuronal activities. In a series of studies using in transgenic Alzheimer's disease model, we have shown that chronically elevated levels of allopregnanolone accelerated AD development. After a period of exposure to chronically elevated levels of allopregnanolone, impaired learning and memory pattern occurred in the AD mice. Accordingly, increased levels of beta-amyloids were also observed in AD mice. We have also demonstrated that high levels of beta-amyloids corresponded to dysfunction among brain synapses. This was seen after a period of chronically elevated levels of allopregnanolone, but not after placebo treatment. This effect of allopregnanolone treatment was identified early in the disease development when AD mice normally have intact memory function. This review covers a wide topic of neurosteroids and brain aging, and provides insight on the mechanisms behind stress-induced AD or dementia. PMID- 24346249 TI - Hormone replacement therapy in menopause and in premature ovarian insufficiency. AB - Menopause is defined by world health organization (WHO) as the permanent cessation of menstruating resulting from a loss of ovarian follicular activity, after one year of amenorrhea. It signifies the last menstrual cycle and the end of women's fertile and reproductive life. The average age for a women to undergo menopause is 51 years; unlike menarche, whose average age has decreased over the past decades, the age of menopause has remained unchanged. We can distinguish: 1) premenopause, the time interval leading up to menopause; 2) climacteric, the time interval between the reproductive e non-reproductive life; 3) premature menopause, that occurs in 1% of women. Menopause can also be induced iatrogenically as a result of surgery, medical therapy, chemotherapy and radiotherapy. Beyond the life the number of oocytes falls until there are no more suitable follicles for reproduction and the menopause ensues. At the same time, the ability of the ovary to produce hormones falls, leading to an increasing pulsatile release of FSH in order to stimulate the ovary to produce oestrogens. Menopause is characterized by different symptoms such as hot flushes, night sweats, dispareunia, prolapse, vulval itching due to vaginal atrophy and dryness, urinary incontinence, dysuria, and also the psychological aspects don't should be underestimated because of many women suffer of depression, mood instability, insomnia, fatigue and decreased libido. Long term symptoms include osteoporosis, cardiovascular and neuro-degenerative diseases. The main aim of different treatments was symptoms relief. Pharmacological agents and psychological support represent the goal for menopause treatment. PMID- 24346250 TI - Selective estrogen modulators in menopause. AB - Hypoestrogenism is the primary etiologic factor for osteoporosis and related fractures, as well as for a number of clinical symptoms that can reduce the quality of life in postmenopausal women. Alternative to classical hormone replacement therapy (HRT) are needed for women that cannot or don't want to be treated with hormones. Selective estrogen receptor modulators (SERMs) are compounds that lack the steroid structure of estrogens, but interact with estrogen receptors (ERs) as agonists or antagonists depending on the target tissue. Tamoxifen, the first generation of SERMs, has been used for decades in the primary prevention and treatment of breast cancer. Tamoxifen exerts positive estrogenic effect on bone protecting bone mineral density (BMD). However, tamoxifen acts as agonist also on the endometrium, leading to an increased risk of endometrial hyperplasia and cancer. In addition, tamoxifen administration is associated with significantly increased risks of stroke, venous thromboembolism, including both deep-vein thrombosis and pulmonary emboli. Thus, these actions, in addition to the increased risk of and hot flushes, prevent the use of tamoxifen for the prevention of osteoporosis. Further generations of SERM, Raloxifene and bazedoxifene were developed for the prevention and treatment of postmenopausal osteoporosis and are now licensed for this indication. In addition. Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer. On the other hand, the available data indicate that Bazedoxifene exerts a greater anti fracture activity than Raloxifene. At variance of tamoxifen, both raloxifene and bazedoxifene reduce the risk of endometrial hyperplasia and cancer. However, they are associated with a significant increase the risks of venous thromboembolic events. Although raloxifene and Bazedoxifene prevent postmenopausal osteoporosis, they have not been associated with reductions in climacteric symptoms, particularly hot flushes. In order to find a new approach for menopausal management, SERMs have been combined with estrogens, creating a tissue selective estrogen complex (TSEC) to achieve a favorable clinical profile based on the blended tissue selective activity profiles of the components. Bazedoxifene in association with conjugated estrogens (BZA/CE) is the first TSEC evaluated in an extensive clinical program. BZA/CE administration decreases bone turnover, with an increase in lumbar spine and total hip BMD. The magnitude of these effects are similar to those exerted by HRT and greater than that observed with Raloxifene and Bazedoxifene alone. In addition, BZA/CE significantly reduced the severity and frequency of hot flushes and improved measures of vaginal atrophy and quality of-life scores, including that for sleep likewise HRT. BZA/CE administration prevents endometrial proliferation, with high rates of amenorrhea over one year. Taken together, all the available data indicate that BZA/CE combination is effective and safe for the treatment for climacteric women, improving the overall quality of life, while protecting the skeleton. The high amenorrhea rate may increase compliance, avoiding the bleedings and side effects related to progestin administration. Further studies are needed to evaluate the ultimate effects of BZA/CE combination on clinical outcomes, such as CVD events, breast and endometrial cancer. PMID- 24346251 TI - Individualizing hormone-therapy according to cardiovascular risk. AB - Many women, including those with risk factors for cardiovascular disease (CVD), may desire the benefits associated with hormone therapy including protection from progression of CVD, osteoporotic fractures, urogenital atrophy, skin loss, dementia, and a reduction in overall mortality. Before initiating or continuing therapy, it is important to consider an accurate risk benefit analysis in all women. Importantly, when considering initiation of hormone replacement, it is important to consider a woman's age, number of years since her menopause, and a number of cardiovascular risk factors. Women with positive risk factors are at increased risk for hormone therapy, especially related to the initiation of high dose oral therapy. Use of low dose transdermal hormone therapy can reduce these risks. For women with a recent cardiovascular event, current thromboembolic disease, long-standing immobilization, or severe peripheral arterial disease, hormone replacement is generally not recommended. There is growing consensus that the benefit to risk profile for hormone therapy is high for healthy, low-risk women initiating therapy within 10 years of menopause or under age 60. However, special considerations are needed for women who are outside those boundaries or for those that have risk factors for cardiovascular disease. PMID- 24346253 TI - Assessment of postpartum perineal pain after vaginal delivery: prevalence, severity and determinants. A prospective observational study. AB - AIM: Perineal pain is present, after birth, in almost all (95-100%) women who have experienced perineal trauma. It has been shown that women with spontaneous vaginal delivery and minimal or absent perineal trauma will have better recoveries: less pain, more tonic perineal muscles, improved sexual function and lower rates of depression. The purpose of the present study was to prospectively assess the prevalence of perineal pain in a population of women with vaginal birth at term and physiological single newborn. METHODS: Pain assessment was performed using two subjective scales: the Verbal Numeric Scale (VNS) of 11 points and the Verbal Rating Score (VRS) of 4 points. Data collection period ran from the first postnatal day until 6 months after delivery, with two intermediate measurements at 1 and 7 weeks after birth. RESULTS: The study enrolled 451 women: 239 primiparous and 212 multiparous, with a response rate of 92% at 6 months. The prevalence of pain was found 88.2% in the first day postpartum, 62.3% one week after birth, 8.0% at seven weeks and 0.7% at six months. With regard to the resumption of sexual activity at 6 months postpartum, a dyspareunia rate of 27% was observed in the Episiotomy group (OR 5.72, P<0.001). CONCLUSION: The study found that an increase in the extent of trauma is associated with the highest scores in the self-assessment of perceived pain, with long term persistent symptoms. Furthermore, the presence of an episiotomy is a conditioning factor for the sexual function after childbirth (OR 0.43, P<0.001). PMID- 24346252 TI - Ovarian adrenal interactions during the menopausal transition. AB - Observations over the past decade using longitudinal data reveal a gender specific shift in adrenal steroid production. This shift is represented by an increase in the circulating concentrations of delta 5 steroids in 85% of all women and is initiated only after the menopausal transition has begun. While the associated rise in the major adrenal androgen, dehydroepiandrosterone sulfate (DHEAS), is modest, the parallel rises in dehydroepiandrosteone (DHEA) and androstenediol (Adiol) are much more robust. These increases in circulating steroid concentrations are qualitatively similar on average between ethnicities but quantitatively different between individual women. Both circulating testosterone (T) and androstenedione (Adione) also rise concomitantly but modestly by comparison. This phenomenon presents a new and provocative aspect to the endocrine foundations of the menopausal transition and may provide important clues to understanding the fundamentals of mid-aged women's healthy aging, particularly an explanation for the wide diversity in phenotypes observed during the MT as well as their different responses to hormone replacement therapies. Experimental studies using the nonhuman primate animal model show an acute adrenal response to human chorionic gonadotropin (hCG) challenge as well as the presence of luteinizing hormone receptors (LHR) in their adrenal cortices. These experimental results support the concept that LHRs are recruited to the adrenal cortices of mid-aged women that subsequently function to respond to increasing circulating LH to shunt pregnenolone metabolites towards the delta 5 pathway. Future investigations are required to determine the relationship of these changes in adrenal function to symptoms and health outcomes of mid-aged women. PMID- 24346254 TI - Dermasilk(r) briefs in recurrent vulvovaginal candidosis. An alternative option in long-lasting disease. AB - AIM: Recurrent vulvovaginal candidosis (RVVC) can be a long-lasting disease; some patients refuse one of the most used treatment based on the assumption of oral fluconazole and resort to self-medication, risking poor control of symptoms and the development of local side effects. The aim of the study is to compare underwear made of Dermasilk(r), a pure fibroin fabric bonded with a permanent antimicrobial protection, with cotton placebo briefs to see whether it would be a useful tool in the management of RVVC in patients not receiving oral or topical antimycotic treatment. METHODS: A double-blind, randomized study was carried out on 30 women who had a long-term history of RVVC with mild to moderate symptoms. The patients were randomly divided into two groups and instructed to use either white cotton placebo briefs (CT group) or Dermasilk(r) briefs (DS group) for 6 months. RESULTS: All vulvovaginal symptoms and signs showed a statistically significant improvement in the DS group compared with the CT group (P<0.001) at the follow-up visits after 3 and 6 months. The number of flares of vulvovaginal symptoms was significantly lower in the DS group compared to the CT group (24 episodes versus 68 episodes during the 6-month study, P<0.001). CONCLUSION: In the absence of both topical and oral antimycotics, Dermasilk(r) briefs appear to be a useful tool, in reducing the signs and symptoms and the episodes of vulvovaginal discomfort in patients suffering from RVVC. PMID- 24346255 TI - [Topical treatment of vaginal infections by the association of metronidazole clotrimazole]. AB - Vaginal infections are one of the most gynecological frequently diseases observed and with significant psychological and clinical implications. Their pharmacological treatment may require different options, but even today, scientific literature and international guidelines recommend the use of metronidazole for the treatment of bacterial vaginosis (BV) and trichomoniasis, and the clotrimazole for fungal infections from Candida (VVC). In this contest, the topical association of clotrimazole-metronidazole (vaginal pessaries, cream and douches) represents a current reference treatment for these types of infections with a number of important pharmacological properties. This combination allows an effective activity against to a broad spectrum of pathogens (bacterial, fungal and protozoan), a feature particularly relevant in the case of mixed infections. Furthermore it allows a synergistic action that improve the therapeutic abilities of the individual components, a reduction of the spontaneous resistance of some microorganisms and the activity against symptoms and signs of vaginal inflammation with maintaining the vaginal ecosystem, since they have no activity against endogenous lactobacilli. Finally, recent studies have shown the ability of the topical association of metronidazole-clotrimazole to inhibit the in vitro phenotypic switching of Candida albicans, and its effectiveness against Recurrent Vulvovaginal Candidiasis (RVVC). PMID- 24346257 TI - Gold catalysed synthesis of 3-alkoxyfurans at room temperature. AB - Synthetically important 3-alkoxyfurans can be prepared efficiently via treatment of acetal-containing propargylic alcohols (obtained from the addition of 3,3 diethoxypropyne to aldehydes) with 2 mol% gold catalyst in an alcohol solvent at room temperature. The resulting furans show useful reactivity in a variety of subsequent transformations. PMID- 24346256 TI - Contributing factors to VEP grating acuity deficit and inter-ocular acuity difference in children with cerebral visual impairment. AB - PURPOSE: To investigate contributing factors to visual evoked potential (VEP) grating acuity deficit (GAD) and inter-ocular acuity difference (IAD) measured by sweep-VEPs in children with cerebral visual impairment (CVI). METHODS: VEP GAD was calculated for the better acuity eye by subtracting acuity thresholds from mean normal VEP grating acuity according to norms from our own laboratory. Deficits were categorized as mild (0.17 <= deficit < 0.40 log units), moderate (0.40 <= deficit < 0.70 log units) or severe (deficit >=0.70 log units). Maximum acceptable IAD was 0.10 log units. RESULTS: A group of 115 children (66 males-57 %) with ages ranging from 1.2 to 166.5 months (median = 17.7) was examined. VEP GAD ranged from 0.17 to 1.28 log units (mean = 0.68 +/- 0.27; median = 0.71), and it was mild in 23 (20 %) children, moderate in 32 (28 %) and severe in 60 (52 %). Severe deficit was significantly associated with older age and anti-seizure drug therapy. IAD ranged from 0 to 0.49 log units (mean = 0.06 +/- 0.08; median = 0.04) and was acceptable in 96 (83 %) children. Children with strabismus and nystagmus had IAD significantly larger compared to children with orthoposition. CONCLUSION: In a large cohort of children with CVI, variable severity of VEP GAD was found, with more than half of the children with severe deficits. Older children and those under anti-seizure therapy were at higher risk for larger deficits. Strabismus and nystagmus provided larger IADs. These results should be taken into account on the clinical management of children with this leading cause of bilateral visual impairment. PMID- 24346258 TI - The effects of dietary restriction and aging on amyloid precursor protein and presenilin-1 mRNA and protein expression in rat brain. AB - The objective of this study was to examine the effects of aging and long-term dietary restriction (DR) on the level of amyloid precursor protein (APP) and presenilin-1 (PS-1), proteins that are critically involved in Alzheimer's disease. Changes in mRNA and protein expression were assessed by real-time PCR and western blot analysis during aging and long-term DR in the cortex and hippocampus of 6-, 12-, 18-, and 24-month-old rats. Prominent regional changes in expression were observed in response to aging and DR. Although the hippocampus displayed significant alterations in APP mRNA and protein expression and no significant changes in PS-1 expression, an opposite pattern was observed in the cortex. DR counteracted the age-related changes in APP mRNA expression in both structures of old animals. The observed DR-induced increase in mRNA levels in the hippocampus was accompanied by an increase in the level of full-length protein APP. These results indicate that although both structures are very sensitive to aging, a specific spatial pattern of changes in APP and PS-1 occurs during aging. Furthermore, these findings provide evidence that DR can affect APP and PS-1 expression in a manner consistent with its proposed 'antiaging' effect. PMID- 24346259 TI - Long-term total sleep deprivation reduces thalamic gray matter volume in healthy men. AB - Sleep loss can alter extrinsic, task-related functional MRI signals involved in attention, memory, and executive function. However, the effects of sleep loss on brain structure have not been well characterized. Recent studies with patients with sleep disorders and animal models have demonstrated reduction of regional brain structure in the hippocampus and thalamus. In this study, using T1-weighted MRI, we examined the change of regional gray matter volume in healthy adults after long-term total sleep deprivation (~72 h). Regional volume changes were explored using voxel-based morphometry with a paired two-sample t-test. The results revealed significant loss of gray matter volume in the thalamus but not in the hippocampus. No overall decrease in whole brain gray matter volume was noted after sleep deprivation. As expected, sleep deprivation significantly reduced visual vigilance as assessed by the continuous performance test, and this decrease was correlated significantly with reduced regional gray matter volume in thalamic regions. This study provides the first evidence for sleep loss-related changes in gray matter in the healthy adult brain. PMID- 24346260 TI - Eye-hand coordination in on-line visuomotor adjustments. AB - When we perform a visually guided reaching action, the brain coordinates our hand and eye movements. Eye-hand coordination has been examined widely, but it remains unclear whether the hand and eye motor systems are coordinated during on-line visuomotor adjustments induced by a target jump during a reaching movement. As such quick motor responses are required when we interact with dynamic environments, eye and hand movements could be coordinated even during on-line motor control. Here, we examine the relationship between online hand adjustment and saccadic eye movement. In contrast to the well-known temporal order of eye and hand initiations where the hand follows the eyes, we found that on-line hand adjustment was initiated before the saccade onset. Despite this order reversal, a correlation between hand and saccade latencies was observed, suggesting that the hand motor system is not independent of eye control even when the hand response was induced before the saccade. Moreover, the latency of the hand adjustment with saccadic eye movement was significantly shorter than that with eye fixation. This hand latency modulation cannot be ascribed to any changes of visual or oculomotor reafferent information as the saccade was not yet initiated when the hand adjustment started. Taken together, the hand motor system would receive preparation signals rather than reafference signals of saccadic eye movements to provide quick manual adjustments of the goal-directed eye-hand movements. PMID- 24346261 TI - Tuning the oriented deposition of gold nanorods on patterned substrates. AB - The controlled patterning of anisotropic gold nanoparticles is of crucial importance for many applications related to their optical properties. In this paper, we report that gold nanorods prepared by a seed-mediated synthesis protocol (without any further functionalization) can be selectively deposited on hydrophilic parts of hydrophobic-hydrophilic contrast patterned substrates. We have seen that, when nanorods with lengths much smaller than the width of the hydrophilic stripe are used, they disperse on these stripes with random orientation and tunable uniform particle separation. However, for nanorods having lengths comparable to the width of the hydrophilic stripes, confinement-induced alignment occurs. We observe that different interactions governing the assembly forces can be modulated by controlling the concentration of assembling nanorods and the width of the hydrophilic stripes, leading to markedly different degrees of alignment. Our strategy can be replicated for other anisotropic nanoparticles to produce well-controlled patterning of these nanoentities on surfaces. PMID- 24346262 TI - Direct measurement of the biphoton Wigner function through two-photon interference. AB - The Hong-Ou-Mandel (HOM) experiment was a benchmark in quantum optics, evidencing the non-classical nature of photon pairs, later generalized to quantum systems with either bosonic or fermionic statistics. We show that a simple modification in the well-known and widely used HOM experiment provides the direct measurement of the Wigner function. We apply our results to one of the most reliable quantum systems, consisting of biphotons generated by parametric down conversion. A consequence of our results is that a negative value of the Wigner function is a sufficient condition for non-gaussian entanglement between two photons. In the general case, the Wigner function provides all the required information to infer entanglement using well known necessary and sufficient criteria. The present work offers a new vision of the HOM experiment that further develops its possibilities to realize fundamental tests of quantum mechanics using simple optical set-ups. PMID- 24346263 TI - Subcellular localization of NAPE-PLD and DAGL-alpha in the ventromedial nucleus of the hypothalamus by a preembedding immunogold method. AB - The hypothalamus and the endocannabinoid system are important players in the regulation of energy homeostasis. In a previous study, we described the ultrastructural distribution of CB1 receptors in GABAergic and glutamatergic synaptic terminals of the dorsomedial region of the ventromedial nucleus of the hypothalamus (VMH). However, the specific localization of the enzymes responsible for the synthesis of the two main endocannabinoids in the hypothalamus is not known. The objective of this study was to investigate the precise subcellular distribution of N-arachidonoylphospatidylethanolamine phospholipase D (NAPE-PLD) and diacylglycerol lipase alpha (DAGL-alpha) in the dorsomedial VMH of wild-type mice by a high resolution immunogold electron microscopy technique. Knock-out mice for each enzyme were used to validate the specificity of the antibodies. NAPE-PLD was localized presynaptically and postsynaptically but showed a preferential distribution in dendrites. DAGL-alpha was mostly postsynaptic in dendrites and dendritic spines. These anatomical results contribute to a better understanding of the endocannabinoid modulation in the VMH nucleus. Furthermore, they support the idea that the dorsomedial VMH displays the necessary machinery for the endocannabinoid-mediated modulation of synaptic transmission of brain circuitries that regulate important hypothalamic functions such as feeding behaviors. PMID- 24346264 TI - Upper limb musculoskeletal complaints among technicians working in a diagnostic tuberculosis laboratory: two case reports. AB - Upper limb musculoskeletal complaints are common among certain health professionals. We report two cases, both involving technicians working in a diagnostic tuberculosis laboratory in Hong Kong. A work process evaluation suggest that the need to repeatedly open and close small bottles, as well as to work for prolonged periods of time in confined areas, could be related to the workers' clinical presentation. The cases are also compatible with the diagnosis of repetitive strain injury (RSI) of the upper limb, but this term is not commonly used nowadays because of various definitional issues. A review of the various diagnostic issues in RSI is presented. PMID- 24346265 TI - An onsite ergonomics assessment for risk of work-related musculoskeletal disorders among cooks in a Chinese restaurant. AB - This article is a case presentation of an onsite ergonomic assessment of the risk factors for work-related musculoskeletal disorders (WMSDs) among three cooks working at a medium-sized Chinese restaurant in Hong Kong. The weight of workload was measured during the onsite assessment and the Ovako Working Posture Analysis System (OWAS), Rapid Upper Limb Assessment (RULA), and National Institute of Occupational Safety and Health (NIOSH) lifting equation used to assess the risk of WMSDs. The results showed that these cooks usually had to hold utensils for extended periods of time, toss woks, and barbecue meat, all of which demanded a lot of repetitive movements of the upper limbs. Future research is needed on the implementation of effective prevention measures, including administrative and ergonomic controls, to reduce the problems within this industry associated with such high-risk tasks. PMID- 24346266 TI - Development of the Chinese version of the Quick Exposure Check (CQEC). AB - BACKGROUND: Work-related musculoskeletal disorders (WMSDs) are a major public health concern. There has been a strong demand from occupational safety and health agencies and operators to develop simple tools for risk assessment and management of WMSDs. The Quick Exposure Check (QEC) was designed to assess exposure to WMSDs risk factors affecting the back, shoulder/upper arm, wrist/hand, and the neck. It is a valuable observational ergonomic assessment tool, suitable for field-based assessment. OBJECTIVE: This study set out to translate, culturally adapt, and validate a Chinese version of the Quick Exposure Check (CQEC), an observational tool used to assess exposure to physical and psychosocial workplace risk factors for the development of WMSDs in different body sites. METHODS: The CQEC was translated from its original English version using a forward- and back-translation approach. Content validity was examined by an expert panel and expert committee using item- and scale-level content validity indices. The intra-class correlation coefficient (ICC) was used to analyze the inter-rater reliability of the observer's assessment, with kappa statistics and percentage agreements used to estimate the test-retest reliability of the worker's assessment of individual items. RESULTS: The CQEC demonstrated an excellent scale-level content validity index (S-CVI > 0.90). The ICC lay between 0.71 and 0.97, indicating good inter-rater reliability. Test-retest reliability showed substantial agreement between the two measurement occasions for most of the items (kappa=0.68 to 1, percentage agreement=76 to 100%) capturing exposure to risk factors. CONCLUSIONS: The CQEC is a valid and reliable tool that can be used to calculate levels of exposure to risk factors for WMSDs. PMID- 24346267 TI - The FITS model office ergonomics program: a model for best practice. AB - BACKGROUD: An effective office ergonomics program can predict positive results in reducing musculoskeletal injury rates, enhancing productivity, and improving staff well-being and job satisfaction. OBJECTIVE: Its objective is to provide a systematic solution to manage the potential risk of musculoskeletal disorders among computer users in an office setting. A FITS Model office ergonomics program is developed. METHODS: The FITS Model Office Ergonomics Program has been developed which draws on the legislative requirements for promoting the health and safety of workers using computers for extended periods as well as previous research findings. The Model is developed according to the practical industrial knowledge in ergonomics, occupational health and safety management, and human resources management in Hong Kong and overseas. RESULTS: This paper proposes a comprehensive office ergonomics program, the FITS Model, which considers (1) Furniture Evaluation and Selection; (2) Individual Workstation Assessment; (3) Training and Education; (4) Stretching Exercises and Rest Break as elements of an effective program. CONCLUSION: An experienced ergonomics practitioner should be included in the program design and implementation. Through the FITS Model Office Ergonomics Program, the risk of musculoskeletal disorders among computer users can be eliminated or minimized, and workplace health and safety and employees' wellness enhanced. PMID- 24346268 TI - Living the chocolate dream. PMID- 24346270 TI - When your life and career just "click". PMID- 24346271 TI - Effects of text enhancements on the differentiation performance of orthographically similar drug names. AB - BACKGROUND: Orthographically similar drug names create confusion errors and pose a potential threat to medication safety. Enhancing the differing letters in similar drug names is one possible way to address the problem. OBJECTIVE: This study investigated the effects of text enhancement methods(tall man, bold face, larger lowercase, and red lettering with lowercase as the comparison group) and orthographic similarity (referred to the extent to which the letters that made up the two names in a pair were similar to each other) on the differentiation performance of look-alike drug names. METHODS: Sixty individuals from a university and its affiliated hospital participated in the differentiation test in which they determined whether the two drug names in each of the 120 confusable name pairs were the same or different. Outcome measures were response time and proportion of correct responses. RESULTS: Using larger lowercase and red lettering resulted in significantly shorter response times. Drug names that were more similar to each other led to significantly longer response times. Text enhancement and orthographic similarity did not have impact on proportion of correct responses. CONCLUSIONS: Our study provides additional support for the use of text enhancement to emphasize the differences between medicines with names that look alike. PMID- 24346272 TI - Private primary care physicians' perspectives on factors affecting the adoption of electronic medical records: a qualitative pre-implementation study. AB - BACKGROUND: Use of electronic medical records (EMR) has the potential to offer quality and safety benefits, but without the adoption of the technology, the benefits will not be realized. OBJECTIVE: This study aimed to identify the factors perceived as relevant by private physicians when considering EMR adoption. METHODS: A qualitative pre-implementation study was conducted using semi-structured, face to face interviews to explore the perspectives of physicians (n=16) operating in private clinics on the factors affecting their adoption of EMR. A multilevel, work system approach and the immersion/crystallization data analysis technique guided the researchers in examining the data, identifying patterns and key themes, and extracting representative quotes to illustrate these themes. RESULTS: The major factors associated with EMR adoption, which relate to the five categories of a work system, were system usefulness; user interface design; technical support; cost; system reliability; the privacy, confidentiality, and security of patient information; physical space in the clinic; data migration process; adverse work related factors; and the computer and systems skills of physicians. CONCLUSIONS: Pre-implementation identification of factors important to adoption can allow system developers to focus proactively on these factors when developing the system and its implementation strategies, to maximize the likelihood of successful introduction. PMID- 24346273 TI - Issues about home computer workstations and primary school children in Hong Kong: a pilot study. AB - BACKGROUND: All around the world, there is a rising trend of computer use among young children especially at home; yet the computer furniture is usually not designed specifically for children's use. In Hong Kong, this creates an even greater problem as most people live in very small apartments in high-rise buildings. Most of the past research literature is focused on computer use in children in the school environment and not about the home setting. OBJECTIVE: The present pilot study aimed to examine ergonomic issues in children's use of computers at home in Hong Kong, which has some unique home environmental issues. PARTICIPANTS: Fifteen children (six male, nine female) aged 8-11 years and their parents were recruited by convenience sampling. METHODS: Participants were asked to provide information on their computer use habits and related musculoskeletal symptoms. Participants were photographed when sitting at the computer workstation in their usual postures and joint angles were measured. RESULTS: The participants used computers frequently for less than two hours daily and the majority shared their workstations with other family members. Computer furniture was designed more for adult use and a mismatch of furniture and body size was found. Ergonomic issues included inappropriate positioning of the display screen, keyboard, and mouse, as well as lack of forearm support and suitable backrest. These led to awkward or constrained postures while some postural problems may be habitual. Three participants reported neck and shoulder discomfort in the past 12 months and 4 reported computer-related discomfort. CONCLUSIONS: Inappropriate computer workstation settings may have adverse effects on children's postures. More research on workstation setup at home, where children may use their computers the most, is needed. PMID- 24346274 TI - Lessons from the trenches: how to make self-employment work for people with disabilities. PMID- 24346275 TI - Public transport accessibility for wheelchair users: a perspective from macro ergonomic design. AB - BACKGROUND: Considering the current experience of Persons with Disabilities (PWD) seeking to join the labor market as well as improve their quality of life, full accessibility is an important tool to enable their integration into society. OBJECTIVE: The primary objective of this study was to identify ergonomics and accessibility issues faced by wheelchair users and persons with mobility alterations when using public transport, from a user perspective. METHODS: This was an observational, descriptive study, with a quantitative approach to data analysis and discussion. The study sample comprised 30 wheelchair-bound public transport users, and was drawn from the membership of LEME - Associacao dos Lesados Medulares de Novo Hamburgo (Novo Hamburgo Spinal Injury Victims' Association). Data were collected by means of an open-ended interview, which guided questionnaire development, and direct field observations conducted during bus rides. RESULTS: Results indicate that the primary issues are the quality of services offered, particularly the schedule and number of accessible vehicles, and the lack of trained employees to aid wheelchair users. CONCLUSIONS: The paper also identifies issues related to accessibility and safety, both when accessing vehicles and during transportation. PMID- 24346276 TI - Willingness to work with people with disabilities in future Brazilian professionals. AB - BACKGROUND: The Quota Law in Brazil determines that the organizations with over 100 workers must hire people with disabilities. OBJECTIVE: The aim of this investigation was to verify the willingness of future professionals to work with people with disabilities. PARTICIPANTS: A survey was conducted with 341 Brazilian university students. METHODS: The following factors were taken into account: the Quota Law favorability (attitude); the conceptions about disability (beliefs); the evaluation of consequences (positive or negative) which the individual attributes to the fact of working with people with disabilities; and the perception of the level of difficulty to insert these people (beliefs about control). RESULTS: Three patterns of willingness have been identified: willingness guided by the focus on the disability; willingness guided by the instrumental focus; and willingness guided towards accessibility. It has also been verified that these forms of willingness were associated to the perception of difficulties in inserting people with disabilities. CONCLUSIONS: These results empirically reinforce the fact that part of the difficulties in inserting people with disabilities is found in the social environment and conditions, suggesting that these aspects need to be taken into account in the studies on attitudes towards people with disabilities. PMID- 24346277 TI - Workplace adaptation to people with disabilities at construction industry in Brazil. AB - BACKGROUND: Despite the attempts to include people with disabilities at work, the number of such people seeking employment and of those receiving job opportunities remains low. OBJECTIVE: The objective was to evaluate the construction jobs of bricklayer, carpenter, steel fixer, painter, laborer 1, laborer 2 and foreman on the construction site of a water supply network so as to determine the profile of workers with disabilities who could perform these jobs and what adaptations are needed. METHODS: The methods used were: direct observation of the activities and the environment, interviews with staff on the site, and a video and photographic record of the tasks, while the software ErgoDis/IBV was used to analyze the jobs. RESULTS: it was found that workers with hearing impairments could perform the activities without any adaptations to the job, while for individuals whose leg or foot had been amputated, some adjustments would be needed. CONCLUSIONS: Thus, by the knowledge of the task, the physical, intellectual and organizational demands of jobs and knowing the functional capabilities of workers with disabilities, reasonable adaptation to work environments can be carried out adequately. To achieve this goal, it is important that this be done through an integration of a multidisciplinary team, which involves the areas of occupational safety and ergonomics. PMID- 24346278 TI - Toward a deeper understanding of the willingness to seek help: the case of teleworkers. AB - BACKGROUND: Employees frequently do not engage in help-seeking due to the associated social costs. Despite the importance of help-seeking, little research has been done to explore factors affecting whether individuals will or will not engage in help-seeking at work, and existing research has thus far not addressed help seeking in the telework context. OBJECTIVE: This paper expands the current literature on help-seeking by exploring this behavior in the context of teleworkers and develops propositions regarding how aspects of virtual work environments will help determine teleworkers' willingness to engage in help seeking behavior. METHODS: This article presents a review with critical analysis and integration of selected telework and help-seeking literatures. RESULTS: Grounded in the literature on inequity/indebtedness and the literature on threats to self-esteem, theoretically-derived research propositions are developed that help shed insights into help seeking behaviors in the telework context. These research propositions encompass media presence and the teleworker's perceived opportunity for reciprocation, and their associated impacts on the perceived cost of seeking help. CONCLUSION: The proposed research propositions provide practitioners and researchers a means to be better able to assess telework applications and prevent unintended effects. Through such systematic understanding of how telework alters the perceived cost of seeking help and the teleworker's willingness to seek help, telework may be further improved to contribute to more effective and productive individuals and organizations. PMID- 24346279 TI - Telework rationale and implementation for people with disabilities: considerations for employer policymaking. AB - BACKGROUND: Telework has been promoted as a viable workplace accommodation for people with disabilities since the 1990s, when information and communication technologies (ICT) had developed sufficiently to facilitate its widespread adoption. This initial research and accompanying policy recommendations were prescriptive in nature and frequently aimed at employers. OBJECTIVE: This article adds to existing policy models for facilitating successful telework outcomes for people with disabilities. Drawing upon two studies by the Rehabilitation Engineering Research Center on Workplace Accommodations, we expound on employee side considerations in the implementation of telework. METHODS: Our policy model utilizes established typologies for policy evaluation to develop a process model that considers rationales and implementation factors for telework among people with physical disabilities. RESULTS: Telework may be used as an accommodation for disability, but employee rationales for telework are more complex, involving work life balance, strategies for pain and fatigue not formally recognized as disability, and expediency in travel and transportation. Implementation of telework as a component of workplace operations is similarly multifaceted, involving non-technology accommodations to realize job restructuring left incomplete by telework. CONCLUSIONS: Our model grounds new empirical research in this area. We also renew our call for additional research on effective telework practices for people with disabilities. PMID- 24346281 TI - Genomic structural variations contribute to trait improvement during whole-genome shuffling of yeast. AB - Whole-genome shuffling (WGS) is a powerful technology of improving the complex traits of many microorganisms. However, the molecular mechanisms underlying the altered phenotypes in isolates were less clarified. Isolates with significantly enhanced stress tolerance and ethanol titer under very-high-gravity conditions were obtained after WGS of the bioethanol Saccharomyces cerevisiae strain ZTW1. Karyotype analysis and RT-qPCR showed that chromosomal rearrangement occurred frequently in genome shuffling. Thus, the phenotypic effects of genomic structural variations were determined in this study. RNA-Seq and physiological analyses revealed the diverse transcription pattern and physiological status of the isolate S3-110 and ZTW1. Our observations suggest that the improved stress tolerance of S3-110 can be largely attributed to the copy number variations in large DNA regions, which would adjust the ploidy of yeast cells and expression levels of certain genes involved in stress response. Overall, this work not only constructed shuffled S. cerevisiae strains that have potential industrial applications but also provided novel insights into the molecular mechanisms of WGS and enhanced our knowledge on this useful breeding strategy. PMID- 24346280 TI - Effects of low-fat and high-fat meals on steady-state pharmacokinetics of lapatinib in patients with advanced solid tumours. AB - AIM: To quantify the effect of food on the systemic exposure of lapatinib at steady state when administered 1 h before and after meals, and to observe the safety and tolerability of lapatinib under these conditions in patients with advanced solid tumours. METHODS: This was a three-treatment, randomised, three sequence cross-over study. Lapatinib was administered 1 h after a low- [B] or a high-fat [C] meal and systemic exposure was compared with that obtained following administration 1 h before a low-fat meal [A]. RESULTS: In total, 25 patients were included, of whom 12 were evaluable for the pharmacokinetic analysis. Both low fat and high-fat meals affected lapatinib exposure. Lapatinib AUC0-24 increased following lapatinib administration 1 h after a low-fat meal by 1.80-fold (90 % CI: 1.37-2.37) and after a high-fat meal by 2.61-fold (90 % CI: 1.98-3.43). Lapatinib Cmax increased following lapatinib administration 1 h after a low-fat meal by 1.90-fold (90 % CI: 1.49-2.43) and after a high-fat meal by 2.66-fold (90 % CI: 2.08-3.41). The most commonly occurring treatment-related toxicity was diarrhoea (8/25, 32 % CTCAE grade 1 and 2/25, 8 % grade 2) and one treatment related grade >= 3 event occurred (fatigue grade 3, 4 %). CONCLUSIONS: Both low fat and high-fat food consumed 1 h before lapatinib administration increased lapatinib systemic exposure compared with lapatinib administration 1 h before a low-fat meal. In order to administer lapatinib in a fasted state, it is advised to administer the drug 1 h before a meal. PMID- 24346282 TI - Comparative genomic and transcriptomic analyses of NaCl-tolerant Staphylococcus sp. OJ82 isolated from fermented seafood. AB - Bacteria belonging to the Staphylococcus genus reside in various natural environments; however, only disease-associated Staphylococcus strains have received attention while ecological function and physiologies of non-pathogenic strains were often neglected. Because high level of tolerance against NaCl is a common trait of Staphylococcus, we investigated the characteristics of halotolerance in Staphylococcus sp. OJ82 isolated from fermented seafood containing a high concentration of NaCl. Among the 292 isolates screened, OJ82 showed the highest beta-galactosidase and extracellular protease activities under high-salt conditions. Comparative genomic analysis with other Staphylococcus strains showed that (a) replication origins are highly conserved, (b) the OJ82 strain has a high number of amino acid transport- and metabolism-related genes, and (c) OJ82 has many unique proteins (15 %) and 12 prophage-related genomic islands. RNA-seq analysis under high-salt conditions showed that genes involved in cell membranes, transport, osmotic stress, ATP synthesis, and translation are highly expressed. OJ82 may use the ribulose monophosphate pathway to detoxify some toxic intermediates under high-salt conditions. Six new and three known non coding small RNAs of the OJ82 strain were also found in the RNA-seq analysis. Genomic and transcriptomic analyses identified target beta-galactosidase and extracellular protease. Interestingly, the OJ82 strain became resistant to bacteriocin produced by the Bacillus strain only under high-salt conditions. Our data showed that the OJ82 strain adapted to high-salt conditions by expressing core cellular processes (translation, ATP production) and defense genes (membrane synthesis, compatible solute transports, ribulose monophosphate pathway) could survive bacteriocin exposure under high-salt conditions. PMID- 24346283 TI - Epigenetic silencing of miRNA-9 is associated with HES1 oncogenic activity and poor prognosis of medulloblastoma. AB - BACKGROUND: microRNA-9 is a key regulator of neuronal development aberrantly expressed in brain malignancies, including medulloblastoma. The mechanisms by which microRNA-9 contributes to medulloblastoma pathogenesis remain unclear, and factors that regulate this process have not been delineated. METHODS: Expression and methylation status of microRNA-9 in medulloblastoma cell lines and primary samples were analysed. The association of microRNA-9 expression with medulloblastoma patients' clinical outcome was assessed, and the impact of microRNA-9 restoration was functionally validated in medulloblastoma cells. RESULTS: microRNA-9 expression is repressed in a large subset of MB samples compared with normal fetal cerebellum. Low microRNA-9 expression correlates significantly with the diagnosis of unfavourable histopathological variants and with poor clinical outcome. microRNA-9 silencing occurs via cancer-specific CpG island hypermethylation. HES1 was identified as a direct target of microRNA-9 in medulloblastoma, and restoration of microRNA-9 was shown to trigger cell cycle arrest, to inhibit clonal growth and to promote medulloblastoma cell differentiation. CONCLUSIONS: microRNA-9 is a methylation-silenced tumour suppressor that could be a potential candidate predictive marker for poor prognosis of medulloblastoma. Loss of microRNA-9 may confer a proliferative advantage to tumour cells, and it could possibly contribute to disease pathogenesis. Thus, re-expression of microRNA-9 may constitute a novel epigenetic regulation strategy against medulloblastoma. PMID- 24346284 TI - Akt/Ezrin Tyr353/NF-kappaB pathway regulates EGF-induced EMT and metastasis in tongue squamous cell carcinoma. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) is a crucial programme in cancer metastasis. Epidermal growth factor (EGF) is a key inducer of EMT, and Ezrin has an important role in this process. However, how Ezrin is activated and whether it mediates EGF-induced EMT in tongue squamous cell carcinomas (TSCCs) through activating NF-kappaB remains obscure. METHODS: We used two TSCC cell lines as a cell model to study invasion and EMT in vitro, and used nude mice xenografts model to evaluate metastasis of TSCC cells. Finally, we evaluated the level of pEzrin Tyr353, nuclear p65 and EMT markers in TSCC clinical samples. RESULTS: Ezrin Tyr353 was phosphorylated through Akt (but not ERK1/2, ROCK1) pathway, and lead to the activation of NF-kappaB in EGF-treated TSCC cells. Akt and NF-kappaB inhibitors blocked EGF-induced EMT, and suppressed invasion and migration of TSCC cells. In vivo, silencing Ezrin significantly suppressed EGF enhanced metastasis of TSCC xenografts. Finally, high levels of expression of pEzrin Tyr353, nuclear p65, vimentin and low level of expression of E-cadherin were correlated with cancer metastasis and poor patient prognosis. CONCLUSION: Our data suggest that Akt/Ezrin Tyr353/NF-kappaB pathway regulates EGF-induced EMT and metastasis inTSCC, and Ezrin may serve as a therapeutic target to reverse EMT in tongue cancers and prevent TSCC progression. PMID- 24346285 TI - BOADICEA breast cancer risk prediction model: updates to cancer incidences, tumour pathology and web interface. AB - BACKGROUND: The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction model that is used to compute probabilities of carrying mutations in the high-risk breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, and to estimate the future risks of developing breast or ovarian cancer. In this paper, we describe updates to the BOADICEA model that extend its capabilities, make it easier to use in a clinical setting and yield more accurate predictions. METHODS: We describe: (1) updates to the statistical model to include cancer incidences from multiple populations; (2) updates to the distributions of tumour pathology characteristics using new data on BRCA1 and BRCA2 mutation carriers and women with breast cancer from the general population; (3) improvements to the computational efficiency of the algorithm so that risk calculations now run substantially faster; and (4) updates to the model's web interface to accommodate these new features and to make it easier to use in a clinical setting. RESULTS: We present results derived using the updated model, and demonstrate that the changes have a significant impact on risk predictions. CONCLUSION: All updates have been implemented in a new version of the BOADICEA web interface that is now available for general use: http://ccge.medschl.cam.ac.uk/boadicea/. PMID- 24346286 TI - Role of HER3 expression and PTEN loss in patients with HER2-overexpressing metastatic breast cancer (MBC) who received taxane plus trastuzumab treatment. AB - BACKGROUND: The aim of this study was to investigate the role of human epidermal growth factor receptor (HER3) and PTEN expression in patients with HER2 overexpressing metastatic breast cancer (MBC). METHODS: One hundred twenty-five MBC patients who were treated with taxane plus trastuzumab chemotherapy as first line therapy were included in this analysis. Immunohistochemical (IHC) staining with HER3 and PTEN antibodies were conducted retrospectively. RESULTS: Patients who had negative HER3 staining (62.4%) had a better progression-free survival (PFS) than did those who had positive HER3 staining (P=0.001; median PFS, 21 vs 11 months). Patients who had a PTEN score >20 (78.1%) showed longer PFS than did those with a PTEN score <=20 (P=0.006; median PFS, 13 vs 9 months). Patients who had a PTEN score >20 exhibited a longer overall survival (OS) than did those with a PTEN score <=20 (P=0.005; median OS, 48 vs 25 months). HER3 negativity and PTEN loss were identified as independent risk factors for PFS. PTEN loss was identified as an independent risk factor for OS. CONCLUSION: HER3 and PTEN expressions may be predictive markers, and PTEN expression may be a predictive and prognostic biomarker for trastuzumab treatment in HER2-positive MBCs. PMID- 24346287 TI - HBx mutants differentially affect the activation of hypoxia-inducible factor 1alpha in hepatocellular carcinoma. AB - BACKGROUND: Mutations in HBx gene are frequently found in HBV-associated hepatocellular carcinoma (HCC). Activation of hypoxia-inducible factor-1alpha (HIF-1alpha) contributes to HCC development and progression. Wild-type HBx has been demonstrated to activate HIF-1alpha, but the effect of HBx mutations on HIF 1alpha has not been elucidated. METHODS: HBx mutations were identified by gene sequencing in 101 HCC tissues. Representative HBx mutants were cloned and transfected into HCC cells. Expression and activation of HIF-1alpha were analysed by western blot and luciferase assays, respectively. The relationship between HBx mutants and HIF-1alpha expression in HCC tissues was also evaluated. RESULTS: The dual mutations K130M/V131I enhanced the functionality of HBx as they upregulated the expression and transcriptional activity of HIF-1alpha. The C-terminal truncations and deletion mutations, however, weakened the ability of HBx to upregulate HIF-1alpha. Meanwhile, the C-terminus was further found to be essential for the stability and transactivation of HBx. In the HCC tissues, there was a positive association between the HBx mutants and HIF-1alpha expression. CONCLUSION: Different mutations of HBx exert differentiated effects on the functionality of HIF-1alpha, however, the overall activity of HBx mutants appears to increase the expression and transcriptional activity of HIF-1alpha. PMID- 24346288 TI - Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction. AB - BACKGROUND: Interleukin-6 (IL-6) has an important role in cancer progression, and high levels of plasma IL-6 are correlated with a poor prognosis in a variety of cancers. It has also been reported that tumour stromal fibroblasts are necessary for steps in cancer progression, such as angiogenesis. There have been few reports of a correlation between fibroblast actions and IL-6 levels. In this study, we examined the correlation between cancer stromal fibroblasts and IL-6 and the utility of IL-6 as a therapeutic target in human colon cancer. METHODS: The expression levels of IL-6 and VEGF of fibroblasts and cancer cell lines were evaluated using real-time PCR and ELISA. The anti-angiogenic effect of inhibiting IL-6 signalling was measured in an angiogenesis model and animal experiment. RESULTS: We demonstrate that stromal fibroblasts isolated from colon cancer produced significant amounts of IL-6 and that colon cancer cells enhanced IL-6 production by stromal fibroblasts. Moreover, IL-6 enhanced VEGF production by fibroblasts, thereby inducing angiogenesis. In vivo, anti-IL6 receptor antibody targeting stromal tissue showed greater anti-tumour activity than did anti-IL6 receptor antibody targeting xenografted cancer cells. CONCLUSION: Cancer stromal fibroblasts were an important source of IL-6 in colon cancer. IL-6 produced by activated fibroblasts induced tumour angiogenesis by stimulating adjacent stromal fibroblasts. The relationship between IL-6 and stromal fibroblasts offers new approaches to cancer therapy. PMID- 24346289 TI - Restricted access to standard or high fat chow alters sensitivity of rats to the 5-HT(2A/2C) receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane. AB - Feeding conditions can impact sensitivity to drugs acting on dopamine receptors; less is known about the impact of feeding conditions on the effects of drugs acting on serotonin (5-HT) receptors. This study examined the effects of feeding conditions on sensitivity to the direct-acting 5-HT(2A/2C) receptor agonist 1 (2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM; 0.1-3.2 mg/kg) and the direct acting dopamine D3/D2 receptor agonist quinpirole (0.0032-0.32 mg/kg). Male Sprague-Dawley rats had free access (11 weeks), followed by restricted access (6 weeks), to high fat (34.3%, n=8) or standard (5.7% fat; n=7) chow. Rats eating high fat chow became insulin resistant and gained more weight than rats eating standard chow. Free access to high fat chow did not alter sensitivity to DOM induced head twitch but increased sensitivity to quinpirole-induced yawning. Restricting access to high fat or standard chow shifted the DOM-induced head twitch dose-response curve to the right and shifted the quinpirole-induced yawning dose-response curve downward in both groups of rats. Some drugs of abuse and many therapeutic drugs act on 5-HT and dopamine systems; these results show that feeding conditions impact sensitivity to drugs acting on these systems, thereby possibly affecting vulnerability to abuse, as well as the therapeutic effectiveness of drugs. PMID- 24346290 TI - Blockade of CB1 receptors prevents retention of extinction but does not increase low preincubated conditioned fear in the fear incubation procedure. AB - We recently developed a procedure to study fear incubation, in which rats given 100 tone-shock pairings over 10 days show low fear 2 days after conditioned fear training and high fear after 30 days. Notably, fear 2 days after 10 sessions of fear conditioning is lower than fear seen 2 days after a single session of fear conditioning, suggesting that fear is suppressed. Here, we investigate the potential role of CB1 receptor activation by endocannabinoids in this fear suppression. We subjected rats to 10 days of fear conditioning and then administered systemic injections of the CB1 receptor antagonist SR141716 before a conditioned fear test was conducted 2 days later under extinction conditions. A second test was conducted without any injections on the following day (3 days after training) to examine retention of fear extinction. SR141716 injections did not increase fear expression 2 days after extended fear conditioning or affect within-session extinction; however, it impaired retention of between-session fear extinction in the day 3 test. These data suggest that CB1 receptor activation does not suppress fear soon after extended fear conditioning in the fear incubation task. The data also add to the existing literature on the role of CB1 receptors in extinction of conditioned fear. PMID- 24346291 TI - Efficacy of the Pilates method for pain and disability in patients with chronic nonspecific low back pain: a systematic review with meta-analysis. AB - OBJECTIVE: To systematically review the available evidence on the efficacy of the Pilates method in patients with chronic nonspecific low back pain. METHOD: Searches were performed in MEDLINE, EMBASE, PEDro, SciELO, LILACS, CINAHL and CENTRAL in March 2013. Randomized controlled trials that tested the effectiveness of the Pilates method (against a nontreatment group, minimal intervention or other types of interventions) in adults with chronic low back pain were included regardless the language of publication. The outcome data were extracted from the eligible studies and were combined using a meta-analysis approach. RESULTS: The searches identified a total of 1,545 articles. From these, eight trials were considered eligible, and seven trials were combined in the meta-analysis. The comparison groups were as follows: Pilates versus other types of exercises (n=2 trials), and Pilates versus no treatment group or minimal intervention (n=4 trials) for short term pain; Pilates versus minimal intervention for short-term disability (n=4).We determined that Pilates was not better than other types of exercises for reducing pain intensity. However, Pilates was better than a minimal intervention for reducing short-term pain and disability (pain: pooled mean difference=1.6 points; 95% CI 1.4 to 1.8; disability: pooled mean difference=5.2 points; 95% CI 4.3 to 6.1). CONCLUSIONS: Pilates was better than a minimal intervention for reducing pain and disability in patients with chronic low back pain. Pilates was not better than other types of exercise for short-term pain reduction. PMID- 24346292 TI - Effect of upper extremity proprioceptive neuromuscular facilitation combined with elastic resistance bands on respiratory muscle strength: a randomized controlled trial. AB - BACKGROUND: Elastic resistance bands (ERB) combined with proprioceptive neuromuscular facilitation (PNF) are often used in resistance muscle training programs, which have potential effects on peripheral muscle strength. However, the effects of the combination of ERB and PNF on respiratory muscle strength warrant further investigation. OBJECTIVES: The assessment of the effects of PNF combined with ERB on respiratory muscle strength. METHOD: Twenty healthy, right handed females were included. Subjects were randomized to either the resistance training program group (TG, n=10) or the control group (CG, n=10). Maximal expiratory pressure (MEP) and inspiratory pressure (MIP) were measured before and after four weeks of an upper extremity resistance training program. The training protocol consisted of upper extremity PNF combined with ERB, with resistance selected from 1 repetition maximum protocol. RESULTS: PNF combined with ERB showed significant increases in MIP and MEP (p<0.05). In addition, there were significant differences between the TG and CG regarding ?MIP (p=0.01) and ?MEP (p=0.04). CONCLUSIONS: PNF combined with ERB can have a positive impact on respiratory muscle strength. These results may be useful with respect to cardiopulmonary chronic diseases that are associated with reduced respiratory muscle strength. PMID- 24346293 TI - Comparison of motor and cognitive performance of children attending public and private day care centers. AB - BACKGROUND: Given that environmental factors, such as the school environment, can influence child development, more attention should be paid to the development of children attending day care centers. OBJECTIVE: To determine whether there are differences in the gross motor, fine motor, or cognitive performances of children between 1 and 3 years-old of similar socioeconomic status attending public and private day care centers full time. METHOD: Participants were divided into 2 groups, 1 of children attending public day care centers (69 children) and another of children attending private day care centers (47 children). All children were healthy and regularly attended day care full time for over 4 months. To assess cognitive, gross and fine motor performance, the Bayley Scales of Infant and Toddler Development III was used. The Mann-Whitney test was used for comparative analyses between groups of children between 13 and 24 months, 25 and 41 months, and 13 and 41 months. RESULTS: Children in public day care centers exhibited lower scores on the cognitive development scale beginning at 13 months old. The fine and gross motor performance scores were lower in children over the age of 25 months attending public centers. Maternal education was not related to the performance of children in either group. CONCLUSION: The scores of cognitive performance as well as fine and gross motor performance of children of similar socioeconomic status who attend public day care centers are lower than children attending private daycare centers. PMID- 24346294 TI - Translation, cultural adaptation and evaluation of the psychometric properties of the Falls Risk Awareness Questionnaire (FRAQ): FRAQ-Brazil. AB - OBJECTIVE: This study aimed to translate and culturally adapt the Falls Risk Awareness Questionnaire (FRAQ) for the elderly Brazilian population as well as to evaluate the internal consistency and reliability of this instrument. METHOD: The study used internationally accepted guidelines for the cross-cultural adaptation process. The questionnaire in its final Portuguese version was then applied to 120 elderly people to assess the measurement properties. The participants were interviewed twice in the first assessment (examiners 1 and 2 at an interval of 30 to 60 minutes) and again after 2 to 7 days by examiner 1. The internal consistency was assessed with Cronbach' s alpha coefficient. To evaluate the reliability of the intra- and inter-evaluators, the Kappa coefficient for categorical variables was used; for numeric variables, the intra-class correlation coefficient (2-way mixed model) and the respective 95% confidence intervals were used in addition to the concordance test of Bland and Altman. RESULTS: The Brazilian version of the FRAQ was obtained while maintaining a semantic, idiomatic, cultural and conceptual equivalence. The internal consistency was alpha=0.95, while for intra-examiner reliability, an intrarater correlation coefficient (ICC-3,1) of 0.91 was obtained with an intra-class correlation Kappa coefficient of 0.89 and a Bland and Altman mean difference (bias) of -0.52. Regarding the inter-examiner reliability, the ICC=0.78, Kappa=0.76 and bias=0.12. CONCLUSIONS: The translation and cultural adaptation of the FRAQ for the elderly Brazilian population was successfully performed. The instrument demonstrated excellent reliability and internal consistency, thus making it useful for assessing the perception of the risk of a fall among elderly Brazilians. PMID- 24346295 TI - Effect of early treatment with transcutaneous electrical diaphragmatic stimulation (TEDS) on pulmonary inflammation induced by bleomycin. AB - BACKGROUND: Bleomycin (B) is an antineoplastic drug that has pulmonary fibrosis as a side effect. There are few experimental studies about the effects of physical therapy treatment in this case. OBJECTIVE: The objective was to study rat lungs treated with B and precocious intervention by transcutaneous electrical diaphragmatic stimulation (TEDS). METHOD: Wistar rats were divided into 4 groups (n=5): a control group (C); a stimulated group (TEDS); a group treated with a single dose of B (intratracheally, 2.5 mg/kg) (B); and a group treated with B and electric stimulation (B + TEDS). After the B instillation, the electrical stimulation was applied for 7 days, for a duration of 20 minutes. Lung fragments were histologically processed with hematoxylin and eosin (HE) and 8-isoprostane PGF2alpha (8-iso-PGF2alpha). The density of the alveolar area was determined by planimetry, the inflammatory profile was defined by the number of cells, and the level of oxidative stress in the pulmonary tissue was evaluated by 8-iso PGF2alpha. For statistical analysis of the data, the Shapiro-Wilk test was used, followed by a one-way ANOVA with the post-hoc Bonferroni test (p <= 0.05). RESULTS: The B group exhibited a significant reduction in the area density, and the acute treatment with B + TEDS prevented this reduction. There were increased numbers of fibroblasts, leukocytes, and macrophages in the B group, as well as increased lipid peroxidation, which was observed only in this group. CONCLUSION: B promoted a reduction in the alveolar density area, thereby inducing the inflammatory process and increasing the production of free radicals. These effects were minimized by the application of TEDS at the initial treatment stage. PMID- 24346296 TI - Identification and agreement of first turn point by mathematical analysis applied to heart rate, carbon dioxide output and electromyography. AB - BACKGROUND: The second heart rate (HR) turn point has been extensively studied, however there are few studies determining the first HR turn point. Also, the use of mathematical and statistical models for determining changes in dynamic characteristics of physiological variables during an incremental cardiopulmonary test has been suggested. OBJECTIVES: To determine the first turn point by analysis of HR, surface electromyography (sEMG), and carbon dioxide output (VCO2) using two mathematical models and to compare the results to those of the visual method. METHOD: Ten sedentary middle-aged men (53.9 +/- 3.2 years old) were submitted to cardiopulmonary exercise testing on an electromagnetic cycle ergometer until exhaustion. Ventilatory variables, HR, and sEMG of the vastus lateralis were obtained in real time. Three methods were used to determine the first turn point: 1) visual analysis based on loss of parallelism between VCO2 and oxygen uptake (VO2); 2) the linear-linear model, based on fitting the curves to the set of VCO2 data (Lin-LinVCO2); 3) a bi-segmental linear regression of Hinkley's algorithm applied to HR (HMM-HR), VCO2 (HMM-VCO2), and sEMG data (HMM RMS). RESULTS: There were no differences between workload, HR, and ventilatory variable values at the first ventilatory turn point as determined by the five studied parameters (p>0.05). The Bland-Altman plot showed an even distribution of the visual analysis method with Lin-LinVCO2, HMM-HR, HMM-VCO2, and HMM-RMS. CONCLUSION: The proposed mathematical models were effective in determining the first turn point since they detected the linear pattern change and the deflection point of VCO2, HR responses, and sEMG. PMID- 24346297 TI - A combined solid- and solution-phase approach provides convenient access to analogues of the calcium-dependent lipopeptide antibiotics. AB - The calcium-dependent lipopeptide antibiotics represent a promising new class of antimicrobials for use in combating drug-resistant bacteria. At present, daptomycin is the only such lipopeptide used clinically and displays potent antimicrobial activity against a number of pathogenic Gram-positive bacteria. Given the increasing need for new antibiotics, practical synthetic access to unnatural analogues of daptomycin and related antimicrobial lipopeptides is of value. We here report an efficient synthetic route combining solid- and solution phase techniques that allows for the rapid preparation of daptomycin analogues. Using this approach, four such analogues, including two enantiomeric variants, were synthesized and their antimicrobial activities and hydrolytic stabilities evaluated. PMID- 24346298 TI - Transmetalation of self-assembled, supramolecular complexes. AB - Substituting one metal for another in inorganic and organometallic systems is a proven strategy for synthesizing complex molecules, and in some cases, provides the only route to a particular system. The multivalent nature of the coordination in metal-ligand assemblies lends itself more readily to some types of transmetalation. For instance, a binding site can open up for exchange without greatly effecting the many other interactions holding the structure together. In addition to exchanging the metal and altering the local binding environment, transmetalation in supramolecular systems can also lead to substantial changes in the nature of the secondary and tertiary structure of a larger assembly. In this tutorial review we will cover discrete supramolecular assemblies in which metals are exchanged. First we will address fully formed structures where direct substitution replaces one type of metal for another without changing the overall supramolecular assembly. We will then address systems where the disruptive exchange of one metal for another leads to a larger change in the supramolecular assembly. When possible we have tried to highlight systems that use supramolecular self-assembly in tandem with transmetalation to synthesize new structures not accessible through a more direct approach. At the end of this review, we highlight the use of transmetalation in self-assembled aqueous inorganic clusters and discuss the consequences for material science applications. PMID- 24346300 TI - An unruptured aneurysm of the posterior inferior cerebellar artery presenting with meningitis. PMID- 24346301 TI - Advice for NP advocacy associations. PMID- 24346305 TI - 26th Annual Legislative Update: progress for APRN authority to practice. AB - Healthcare access and delivery continues to grow in the United States as advanced practice registered nurses (APRNs) work through the legislative and regulatory process to enact and amend current statutes and regulations in individual states. PMID- 24346307 TI - A cadmium TCNQ-based semiconductor with versatile binding modes and non-integer redox states. AB - The 3-D coordination polymer with the basic formula Cd2(TCNQ)3.5(H2O)2 is the first instance of the coexistence of the bridging modes MU2, MU3 and MU4 for TCNQ in one network. Single crystal measurements revealed the compound to be a good semiconductor with a room temperature conductivity of 5.8 * 10(-3) S cm(-1). PMID- 24346308 TI - Ultra-high aspect ratio Si nanowires fabricated with plasma etching: plasma processing, mechanical stability analysis against adhesion and capillary forces and oleophobicity. AB - Room-temperature deep Si etching using time-multiplexed deep reactive ion etching (DRIE) processes is investigated to fabricate ultra-high aspect ratio Si nanowires (SiNWs) perpendicular to the silicon substrate. Nanopatterning is achieved using either top-down techniques (e.g. electron beam lithography) or colloidal polystyrene (PS) sphere self-assembly. The latter is a faster and more economical method if imperfections in diameter and position can be tolerated. We demonstrate wire radii from below 100 nm to several micrometers, and aspect ratios (ARs) above 100:1 with etching rates above 1 MUm min(-1) using classical mass flow controllers with pulsing rise times of seconds. The mechanical stability of these nanowires is studied theoretically and experimentally against adhesion and capillary forces. It is shown that above ARs of the order of 50:1 for spacing 1 MUm, SiNWs tend to bend due to adhesion forces between them. Such large adhesion forces are due to the high surface energy of silicon. Wetting the SiNWs with water and drying also gives rise to capillary forces. We find that capillary forces may be less important for SiNW collapse/bending compared to adhesion forces of dry SiNWs, contrary to what is observed for polymeric nanowires/nanopillars which have a much lower surface energy compared to silicon. Finally we show that SiNW arrays have oleophobic and superoleophobic properties, i.e. they exhibit excellent anti-wetting properties for a wide range of liquids and oils due to the re-entrant profile produced by the DRIE process and the well designed spacing. PMID- 24346309 TI - Functional multi-band THz meta-foils. AB - In this paper, we present the first experimental demonstration of double- and triple-band negative refraction index meta-foils in the terahertz (THz) region. Multi-band meta-foils constructed by multi-cell S-string resonators in a single structure exhibit simultaneously negative permittivity and negative permeability responses at multiple frequencies. The phenomena are confirmed by numerical simulations and Fourier transform infrared spectroscopy measurements. The flexible, freestanding multi-band meta-foils provide a promising candidate for the development of multi-frequency THz materials and devices. PMID- 24346310 TI - An analytical data inversion method for Magnetic Circular Dichroism spectra dominated by the "B-term". AB - A simple procedure is developed enabling the analytical inversion of an (unpolarized) absorption spectrum combined with a Magnetic Circular Dichroism (MCD) spectrum to resolve two overlapping bands of orthogonal polarization. This method is appropriate when (i) the overlapping transitions are well isolated from other bands, and (ii) when their electronic spacing is large enough so that the "A-term" and "C-term" contributions to the MCD spectrum can be ignored and hence only the "B-term" contribution need be considered. We apply this procedure to assign the Q-band system of chlorophylls, though similar challenges also commonly arise throughout both conventional and X-ray MCD (XMCD) spectroscopy. Analytical data inversion has not previously been possible as the inversion process is two fold underdetermined. We show that the assumptions of isolated spectra and "B term" dominance yields one generally valid constraint, leaving only one quantity unspecified by the experimental data. For some systems, an approximation leading to equal but opposite sign B-term magnitudes of the two components may be reasonable, but for chlorophyllides we find this constraint to be inappropriate. Instead, we constrain a bounded variable controlling the relative absorption strengths. Derived spectral bandshapes of the individual components are shown to be insensitive to its particular value, allowing weak spectral components of one polarization overlapped by intense components of the other to be immediately exposed. This is demonstrated for the chlorophylls, molecules for which the failure to detect such weak features historically led to incorrect proposals for the Q-band assignments. PMID- 24346311 TI - Aluminum induces cross-resistance of potato to Phytophthora infestans. AB - The phenomenon of cross-resistance allows plants to acquire resistance to a broad range of stresses after previous exposure to one specific factor. Although this stress-response relationship has been known for decades, the sequence of events that underpin cross-resistance remains unknown. Our experiments revealed that susceptible potato (Solanum tuberosum L. cv. Bintje) undergoing aluminum (Al) stress at the root level showed enhanced defense responses correlated with reduced disease symptoms after leaf inoculation with Phytophthora infestans. The protection capacity of Al to subsequent stress was associated with the local accumulation of H2O2 in roots and systemic activation of salicylic acid (SA) and nitric oxide (NO) dependent pathways. The most crucial Al-mediated changes involved coding of NO message in an enhanced S-nitrosothiol formation in leaves tuned with an abundant SNOs accumulation in the main vein of leaves. Al-induced distal NO generation was correlated with the overexpression of PR-2 and PR-3 at both mRNA and protein activity levels. In turn, after contact with a pathogen we observed early up-regulation of SA-mediated defense genes, e.g. PR1, PR-2, PR-3 and PAL, and subsequent disease limitation. Taken together Al exposure induced distal changes in the biochemical stress imprint, facilitating more effective responses to a subsequent pathogen attack. PMID- 24346312 TI - Neuroimaging findings in 41 low-functioning children with autism spectrum disorder: a single-center experience. AB - The data on the rate of brain imaging abnormalities in autistic spectrum disorders are still inconsistent. A recent study on patients with high functioning autism found that approximately 90% of children had normal magnetic resonance imaging (MRI) scans whereas an unexpected high rate of MRI abnormalities was reported in 77 nonsyndromic autistic children with or without intellectual disability. The aim of this study was to evaluate the prevalence of neuroradiologic findings in low-functioning autistic children compared to controls matched for age. Minor brain abnormalities were found in 44% of patients and 22% of controls. Our main result is the high rate of mega cisterna magna in autistic patients. High rate of minor neuroradiologic abnormalities in low functioning autistic patients could contribute to the research about the various endophenotypes and complete the clinical assessment of children with autistic spectrum disorder and intellectual disability. PMID- 24346313 TI - Insights into cerebrospinal fluid and cerebral blood flows in infants and young children. AB - This study investigates the craniospinal flows of blood and cerebrospinal fluid using phase-contrast magnetic resonance imaging (MRI) on 23 control neonates and infants (5 d-68 mo old). Mean arterial cerebral blood flow increased with age of infant from 180 mL/min after birth to 1330 mL/min around 6 years of age. This corresponds to 51 mL/min/100 g and 95 mL/min/100 g, respectively. Cervical cerebrospinal fluid stroke volume increased from 38 * 10(-3) mL to 752 * 10(-3) mL per cardiac cycle. After arterial systolic blood inflow, we observed a delay of the venous outflow that was always preceded by cerebrospinal fluid flushing out through the spinal canal. These results highlighted the importance of compliance of the spinal compartment and the interaction of blood and cerebrospinal fluid dynamics. The capacity of the spinal compartment to receive intracranial cerebrospinal fluid in presence of fontanels was demonstrated. We provide reference values to understand the physiology of cerebrospinal fluid and cerebral blood. PMID- 24346314 TI - Pediatric bell palsy: the time is ripe for a clinical trial. PMID- 24346315 TI - Isolated cerebellar involvement in vitamin B12 deficiency: a case report. AB - Deficiency of vitamin B12 causes megaloblastic anemia and nervous system demyelination. Structures affected in the nervous system include spinal cord, cranial and peripheral nerves, and brain white matter. A 9-year-old boy presented with knuckle hyperpigmentation and oral ulcers for 3 years, pallor and easy fatigability for 6 months, gait abnormalities for 3 months, and abnormal speech and behavioral abnormalities for 3 days. On examination, he had physical signs of megaloblastic anemia, mood swings with intermittent hallucinations, and features of cerebellar impairment. Blood investigations revealed megaloblastic anemia, and pernicious anemia was ruled out. Brain magnetic resonance imaging (MRI) revealed bilateral cerebellar signal changes. He received treatment for vitamin B12 deficiency and appropriate nutritional counseling. Three months later, he showed significant clinical and radiologic resolution. To our knowledge, isolated cerebellar involvement as the sole neurologic manifestation of vitamin B12 deficiency has not been described previously in children. PMID- 24346316 TI - What do patients and families want from a child neurology consultation? AB - Understanding what patients and their parents want is essential to plan appropriate patient-centered care. Questionnaires were distributed to 500 consecutive children and parents seen for their first pediatric neurology consultation. Both patients and their families answered questions about their expectations of the consultation, their level of worry, and the Penn State Worry Questionnaire. The 5 most important issues for the parents were to get information, to work with the doctor to manage the problem, to have questions answered, to find out what was wrong, and to discuss the impact on the child's life. The children had very similar priorities. The 5 least important concerns for parents were to get a prescription, blood tests, to talk to others with similar problems, to get a radiograph/computed tomography/magnetic resonance imaging (MRI) and to be told nothing is wrong. The pediatric neurologists did well in anticipating these priorities but had more difficulty appreciating parent and patient level of worry. PMID- 24346318 TI - The promised land. PMID- 24346317 TI - Origin and assessment of groundwater pollution and associated health risk: a case study in an industrial park, northwest China. AB - Groundwater quality which relates closely to human health has become as important as its quantity due to the demand for safe water. In the present study, an entropy-weighted fuzzy water quality index (WQI) has been proposed for performing groundwater quality assessment in and around an industrial park, northwest China, where domestic water requirements are solely met by groundwater. The human health risk was assessed with the model recommended by the United States Environmental Protection Agency. In addition, the sources of major ions and main contaminants were also analyzed. The study shows that groundwater in the study area has been contaminated conjunctively by natural processes and industrial and agricultural activities. Nitrate, manganese (Mn), fluoride, total dissolved solids, total hardness and sulfate are major contaminants influencing groundwater quality. Nitrate and heavy metals such as Mn are mainly affected by human agricultural activities and industrial production, while other contaminants are mainly originated from mineral weathering and water-rock interactions. The results of water quality assessment suggest that half of the groundwater samples collected are of medium quality thus require pretreatment before human consumption. The mean health risk caused by the consumption of contaminated groundwater in the area is 8.42 * 10(-5) per year which surpasses the maximum acceptable level (5 * 10(-5) per year) recommended by the International Commission on Radiologic Protection. The entropy-weighted fuzzy WQI proposed in this study can not only assign proper weights to parameters but also treat uncertainties associated with water quality classification. This study will be of interest to international environmentalists and hydrogeologists. It will also be useful in regional groundwater management and protection. PMID- 24346321 TI - Halide impact on emission of mononuclear copper(I) complexes with pyrazolylpyrimidine and triphenylphosphine. AB - A series of mononuclear heteroleptic copper(I) halide complexes, [CuL(PPh3)X] (X = Cl, Br, I), based on 4-(3,5-diphenyl-1H-pyrazol-1-yl)-6-(piperidin-1 yl)pyrimidine (L) and triphenylphosphine, have been synthesized by reaction between CuX (X = Cl, Br, I), L and PPh3 in a molar ratio of 1/1/1 in MeCN solutions. The copper atom, showing the distorted tetrahedral environment, is bound by the N,N-chelating ligand L, triphenylphosphine and a halide ion. The complexes [CuL(PPh3)Cl] and [CuL(PPh3)Br] are isostructural. In CH2Cl2 solutions, L and the complexes [CuL(PPh3)X] (X = Cl, Br, I) display a luminescence band with lambda(max) = 377 nm and a lifetime of 1.9 ns (ligand-based luminescence (LL*)). However, the complex [CuL(PPh3)I] has an additional weak luminescence band with lambda(max) = 681 nm and a lifetime of 96 ns of (3)MLCT origin. In the solid state, L shows the splitting of the luminescence band to lambda(max) = 365 and 384 nm and a slight increase of the lifetime to 2.66 ns. Solid samples of the complexes [CuL(PPh3)X] demonstrate (3)MLCT luminescence bands at 620 nm (X = Cl), 605 nm (X = Br) and 559 nm (X = I) with lifetimes in the range 3.6-11.2 MUs, whereas the LL* band (377 nm) is absent. Quantum yields and rate constants of radiative and nonradiative processes were determined in CH2Cl2 solutions and in the solid state for all complexes. The luminescence quantum yield and lifetimes for the solid samples increase in the order [CuL(PPh3)Cl] < [CuL(PPh3)Br] < [CuL(PPh3)I]. This is due to the increase of radiative decay and simultaneous suppression of nonradiative decay. The complex [CuL(PPh3)I] shows a high quantum yield of 29.4% and an excited state lifetime of 11.2 MUs. PMID- 24346322 TI - A multiyear assessment of hookah use prevalence among Florida high school students. AB - INTRODUCTION: The purpose of this study was to assess the prevalence of hookah use among Florida high school students over time. Alternative tobacco products, including hookah, pose a public health threat to tobacco prevention efforts, especially among adolescents. METHODS: Florida Youth Tobacco Survey data, representing all public high school students in the state, were analyzed to assess the prevalence of lifetime and current hookah use and were compared by demographic groups. Multiple years of data (2007-2012) were examined to assess changes over time. RESULTS: During the past 6 years, there was an increase in lifetime hookah use among Florida high school students. While males remained at a higher rate overall, female adolescents increased at a faster rate. Hispanic and non-Hispanic White respondents reported increased trends as well. Current use trends did not change over 4 years, remaining at about 8%. CONCLUSIONS: Hookah is a new tobacco product in the United States that appears attractive to youth, with dramatic increases among the state population. While cigarette use among youth is declining in Florida, the increasing uptake of alternative tobacco products may lessen the overall public health gains for tobacco use. There is a need for continued monitoring of hookah use among the adolescent population, for both prevention and cessation efforts as well as policy interventions to address this emerging trend. PMID- 24346324 TI - Ten polymorphic microsatellite loci developed from Triplophysa anterodorsalis. PMID- 24346325 TI - Cross-species amplification of microsatellites in genera Megalobrama and Parabramis. PMID- 24346326 TI - Development of polymorphic microsatellite loci for the tomato leaf miner, Tuta absoluta (Lepidoptera: Gelechiidae). PMID- 24346327 TI - Discovery and characterization of a first set of polymorphic microsatellite markers in red crab (Charybdis feriatus). PMID- 24346328 TI - Isolation and characterization of twenty-nine novel EST-SSR markers in Siniperca undulata. PMID- 24346329 TI - Development and characterization of microsatellite markers for Dysoxylum binectariferum, a medicinally important tree species in Western Ghats, India. PMID- 24346330 TI - Isolation and characterization of microsatellite loci for Phragmites australis. PMID- 24346331 TI - Identification of novel microsatellite markers for Saraca asoca, a medicinally important tree species in India. PMID- 24346332 TI - Identification of novel polymorphic microsatellite loci in the endangered Chinese sucker (Myxocyprinus asiaticus). PMID- 24346333 TI - Identification of twelve polymorphic microsatellite loci in the golden apple snail Pomacea canaliculata. PMID- 24346334 TI - Phototargeting human periodontal pathogens in vivo. AB - The effects of blue light at 455 nm were investigated on the bacterial composition of human dental plaque in vivo. Eleven subjects who refrained from brushing for 3 days before and during phototherapy participated in the study. Light with a power density of 70 mW/cm(2) was applied to the buccal surfaces of premolar and molar teeth on one side of the mouth twice daily for 2 min over a period of 4 days. Dental plaque was harvested at baseline and again at the end of 4 days from eight posterior teeth on both the exposed side and unexposed sides of the mouth. Microbiological changes were monitored by checkerboard DNA probe analysis of 40 periodontal bacteria. The proportions of black-pigmented species Porphyromonas gingivalis and Prevotella intermedia were significantly reduced on the exposed side from their original proportions by 25 and 56 %, respectively, while no change was observed to the unexposed side. Five other species showed the greatest proportional reduction of the light-exposed side relative to the unexposed side. These species were Streptococcus intermedius, Fusobacterium nucleatum ss. vincentii, Fusobacterium nucleatum ss. polymorphum, Fusobacterium periodonticum, and Capnocytophaga sputigena. At the same time, the percentage of gingival areas scored as being red decreased on the side exposed to light from 48 to 42 %, whereas the percentage scored as red increased on the unexposed side from 53 to 56 %. No adverse effects were found or reported in this study. The present study proposes a new method to modify the ecosystem in dental plaque by phototherapy and introduces a new avenue of prophylactic treatment for periodontal diseases. PMID- 24346335 TI - Effects of low-level laser therapy on orthodontics: rate of tooth movement, pain, and release of RANKL and OPG in GCF. AB - The aim of the study was evaluate tooth movement, receptor activator of nuclear factor KB ligand (RANKL), osteoprotegerin (OPG), and RANKL/OPG ratio in gingival crevicular fluid (GCF) in compression side and pain level during initial orthodontic tooth treatment to determine the efficacy of low-level laser therapy (LLLT). Ten volunteers who required fixed appliance positioned from the upper first premolars to upper first molars were selected. For each patient, the upper first premolar of the quadrant 1 was chosen to be irradiated with a laser diode at 670 nm, 200 mW, and 6.37 W/cm(2), applied on the distal, buccal, and lingual sides during 9 min on days 0, 1, 2, 3, 4, and 7. The same procedure was applied in the first premolar of the contralateral quadrant inserting the tip but without laser emission. Samples of GCF from the compression side of the upper first premolars to distalize were collected at baseline and after 2, 7, 30, and 45 days posttreatment for determination of RANKL and OPG by enzyme-linked immunosorbent assay. In addition, tooth movement was assessed by scanning models and pain intensity was assessed using a visual analog scale. There was improvement in the parameters studied (pain, tooth movement, levels of RANKL in GCF, and RANKL/OPG ratio) in the laser group when compared to the control group, although differences were not statistically significant. The accumulated retraction of the upper premolar at 30 days was higher in the laser group, and this difference was statistically significant between groups. LLLT delivered in repeated doses (six times in the initial 2 weeks) leads in some extent to a slight orthodontical improvement. PMID- 24346337 TI - A local reference frame for describing the proximal human femur: application in clinical settings. AB - OBJECTIVE: The conventional reference frame for the femur has limited relevance for the planning of hip surgery as the femoral neck axis, a crucial reference for surgeons, has to be independently derived. The purpose of this study is to develop and validate a reliable frame of reference for the proximal femur that can be applied in clinical settings. MATERIALS AND METHODS: Ten three-dimensional models of femurs were obtained. An iterative method was developed to find the femoral neck axis (X-axis). A second axis was also created from the lesser trochanter to the piriformis fossa (LTPF). The origin was defined as the femoral head centre. The cross product of the neck and LTPF axes provided the Z-axis and the third axis (Y-axis) was perpendicular to the other two. Intra-/inter investigator reliability was assessed on the ten femur models; ten times by one investigator and twice by three investigators respectively. The results were then compared with the conventional reference frame using landmarks on the distal femur. RESULTS: The femoral neck and LTPF axes had mean intra-/inter-investigator angle differences of 0.5 degrees (SD 0.4 degrees ) and 0.7 degrees (SD 0.5 degrees ), and 0.8 degrees (SD 0.5 degrees ) and 0.9 degrees (SD 0.6 degrees ) respectively while the variations of the X-, Y- and Z- axes were SD 0.6 degrees , 0.7 degrees and 0.5 degrees . CONCLUSIONS: A reliable method of obtaining the three-dimensional proximal femoral frame was developed, using the femoral neck axis, with greater relevance to clinical settings, preoperative planning and accurate assessment of procedures post-operatively. PMID- 24346338 TI - What has imaging contributed to the epidemiological understanding of osteoarthritis? PMID- 24346339 TI - Two-dimensional carbon topological insulators superior to graphene. AB - Graphene was the first material predicted to realize a topological insulator (TI), but unfortunately the gap is unobservably small due to carbon's weak spin orbital coupling (SOC). Based on first-principles calculations, we propose a stable sp-sp(2) hybrid carbon network as a graphene analog whose electronic band structures in proximity of the Fermi level are characterized by Dirac cones. We demonstrate that this unique carbon framework has topologically nontrivial electronic structures with the Z2 topological invariant of v = 1 which is quite promising for hosting the quantum spin Hall effect (QSHE) in an experimentally accessible low temperature regime (<7 K). This provides a viable approach for searching for new TIs in 2D carbon allotropes. PMID- 24346340 TI - Photoacoustic spectroscopy of surface adsorbed molecules using a nanostructured coupled resonator array. AB - A rapid method of obtaining photoacoustic spectroscopic signals for trace amounts of surface adsorbed molecules using a nanostructured coupled resonator array is described. Explosive molecules adsorbed on a nanoporous anodic aluminum oxide cantilever, which has hexagonally ordered nanowells with diameters and well-to well distances of 35 nm and 100 nm, respectively, are excited using pulsed infrared (IR) light with a frequency matching the common mode resonance frequency of the coupled resonator. The common mode resonance amplitudes of the coupled resonator as a function of illuminating IR wavelength present a photoacoustic IR absorption spectrum representing the chemical signatures of the adsorbed explosive molecules. In addition, the mass of the adsorbed molecules as an orthogonal signal for quantitative analysis is determined by measuring the variation of the localized, individual mode resonance frequency of a cantilever on the array. The limit of detection of the ternary mixture of explosive molecules (1:1:1 of trinitrotoluene (TNT), cyclotrimethylene trinitramine (RDX) and pentaerythritol tetranitrate (PETN)) is estimated to be ~ 100 ng cm(-2). These multi-modal signals enable us to perform quantitative and rapid chemical sensing and analysis in ambient conditions. PMID- 24346341 TI - Non-covalent self assembly controls the relaxivity of magnetically active guests. AB - The relaxivity of a magnetically responsive Gd complex can be controlled by non covalent molecular recognition with a water-soluble deep cavitand. Lowered relaxivity is conferred by a self-assembled micellar "off state", and the contrast can be regenerated by addition of a superior guest. PMID- 24346343 TI - Physical activity and gastric cancer: so what? An epidemiologist's confession. AB - Epidemiologists, like many scientists, tend to become specialized and focused on a particular disease, even though behavioral risk factors such as physical activity have effects across many diseases. This commentary is a personal reflection by an epidemiologist on the shortcomings of this disease-oriented approach to prevention. PMID- 24346342 TI - Postnatal muscle modification by myogenic factors modulates neuropathology and survival in an ALS mouse model. AB - MyoD and myogenin are myogenic transcription factors preferentially expressed in adult fast and slow muscles, respectively. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder in which motor neuron loss is accompanied by muscle denervation and paralysis. Studies suggest that muscle phenotype may influence ALS disease progression. Here we demonstrate that myogenin gene transfer into muscle supports spinal cord motor neuron survival and muscle endplate innervation in the G93A SOD1 fALS mice. On the other hand, MyoD gene transfer decreases survival and enhances motor neuron degeneration and muscle denervation. Although an increase in motor neuron count is associated with increased succinic dehydrogenase staining in the muscle, muscle overexpression of PGC-1alpha does not improve survival or motor function. Our study suggests that postnatal muscle modification influences disease progression and demonstrates that the muscle expression of myogenic and metabolic regulators differentially impacts neuropathology associated with disease progression in the G93A SOD1 fALS mouse model. PMID- 24346344 TI - Preventive effects of NSAIDs, NO-NSAIDs, and NSAIDs plus difluoromethylornithine in a chemically induced urinary bladder cancer model. AB - Urinary bladder cancer prevention studies were performed with the nonsteroidal anti-inflammatory drugs (NSAID) naproxen (a standard NSAID with a good cardiovascular profile), sulindac, and their nitric oxide (NO) derivatives. In addition, the effects of the ornithine decarboxylase inhibitor, difluoromethylornithine (DFMO), alone or combined with a suboptimal dose of naproxen or sulindac was examined. Agents were evaluated at their human equivalent doses (HED), as well as at lower doses. In the hydroxybutyl(butyl)nitrosamine (OH-BBN) model of urinary bladder cancer, naproxen (400 or 75 ppm) and sulindac (400 ppm) reduced the incidence of large bladder cancers by 82%, 68%, and 44%, respectively, when the agents were initially given 3 months after the final dose of the carcinogen; microscopic cancers already existed. NO-naproxen was highly effective, whereas NO-sulindac was inactive. To further compare naproxen and NO-naproxen, we examined their effects on gene expression in rat livers following a 7-day exposure. Limited, but similar, gene expression changes in the liver were induced by both agents, implying that the primary effects of both are mediated by the parent NSAID. When agents were initiated 2 weeks after the last administration of OH-BBN, DFMO at 1,000 ppm had limited activity, a low dose of naproxen (75 ppm) and sulindac (150 ppm) were highly and marginally effective. Combining DFMO with suboptimal doses of naproxen had minimal effects, whereas the combination of DMFO and sulindac was more active than either agent alone. Thus, naproxen and NO-naproxen were highly effective, whereas sulindac was moderately effective in the OH-BBN model at their HEDs. PMID- 24346346 TI - Principles of phosphorescent organic light emitting devices. AB - Organic light-emitting device (OLED) technology has found numerous applications in the development of solid state lighting, flat panel displays and flexible screens. These applications are already commercialized in mobile phones and TV sets. White OLEDs are of especial importance for lighting; they now use multilayer combinations of organic and elementoorganic dyes which emit various colors in the red, green and blue parts of the visible spectrum. At the same time the stability of phosphorescent blue emitters is still a major challenge for OLED applications. In this review we highlight the basic principles and the main mechanisms behind phosphorescent light emission of various classes of photofunctional OLED materials, like organic polymers and oligomers, electron and hole transport molecules, elementoorganic complexes with heavy metal central ions, and clarify connections between the main features of electronic structure and the photo-physical properties of the phosphorescent OLED materials. PMID- 24346345 TI - Application of SNP microarrays to the genome-wide analysis of chromosomal instability in premalignant airway lesions. AB - Chromosomal instability is central to the process of carcinogenesis. The genome wide detection of somatic chromosomal alterations (SCA) in small premalignant lesions remains challenging because sample heterogeneity dilutes the aberrant cell information. To overcome this hurdle, we focused on the B allele frequency data from single-nucleotide polymorphism microarrays (SNP arrays). The difference of allelic fractions between paired tumor and normal samples from the same patient (delta-theta) provides a simple but sensitive detection of SCA in the affected tissue. We applied the delta-theta approach to small, heterogeneous clinical specimens, including endobronchial biopsies and brushings. Regions identified by delta-theta were validated by FISH and quantitative PCR in heterogeneous samples. Distinctive genomic variations were successfully detected across the whole genome in all invasive cancer cases (6 of 6), carcinoma in situ (3 of 3), and high-grade dysplasia (severe or moderate; 3 of 11). Not only well described SCAs in lung squamous cell carcinoma, but also several novel chromosomal alterations were frequently found across the preinvasive dysplastic cases. Within these novel regions, losses of putative tumor suppressors (RNF20 and SSBP2) and an amplification of RASGRP3 gene with oncogenic activity were observed. Widespread sampling of the airway during bronchoscopy demonstrated that field cancerization reflected by SCAs at multiple sites was detectable. SNP arrays combined with delta-theta analysis can detect SCAs in heterogeneous clinical sample and expand our ability to assess genomic instability in the airway epithelium as a biomarker of lung cancer risk. PMID- 24346347 TI - Physicochemical properties and mineral contents of seven different date fruit (Phoenix dactylifera L.) varieties growing from Saudi Arabia. AB - The date (Phoenix dactylifera L.) fruits (Soukari, Soulag, Barhi, Khulas, Rozaiz, Soughi and Monaif) were evaluated with respect to some physical and chemical properties. While crude protein contents of fruits change between 1.51% (Soulag) to 2.41% (Soughi), crude fibre contents ranged between 1.91% (Soukari) to 3.90% (Barhi). Vitamin C contents of date samples changed between 971.82 mg/kg (Soughi) to 1,453.15 mg/kg (Barhi). Antioxidant activity of date fruits ranged from 80.07 IC50 (Soukari) to 81.21 IC50 (Soulag). The highest phenolic content was found in Khulas with a mean value of 198 mg GAE/100 g. Energy values of date fruits ranged from 3,725 kcal/kg (Soulag) to 3,870 kcal/kg (Soukari). Sucrose contents of date fruits changed between 1.02% (Soulag) to 55.71% (Soukari). Mineral contents of several date fruits were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES). Date samples contain potassium at a range between 7,468 mg/kg (Khulas) to 9,619 mg/kg (Soulag). Phosphorus contents of fruits were found between 1,848 mg/kg (Soulag) to 3,066 mg/kg (Rozaiz) and followed by magnesium and calcium. The highest Zn (9.33 mg/kg), Cu (4.27 mg/kg) and Mn (3.26 mg/kg) were found in Rozaiz, Soukari and Barhi samples, respectively. PMID- 24346348 TI - Determination of exposure to lead of subjects from southwestern Poland by human hair analysis. AB - The aim of the present work was to investigate the exposure to lead from various sources by investigation of mineral composition of human scalp hair. The research was carried out on hair sampled from 267 young adults living in Wroclaw (southwest Poland). The effect of the place of residence, diet, and lifestyle on lead content in hair was examined by inductively coupled plasma optical emission spectrometry (ICP-OES). Lead was determined at the wavelength 220.353 nm. These outcomes were reached by linking the results of lead level in hair with the results of questionnaire survey. The mean lead level in hair of the whole examined population was 2.01 +/- 2.10 mg kg(-1). Lead can enter the human body mainly by inhalation and gastrointestinal absorption. It was found that consuming cheese, fish, and lettuce caused increased level of lead in hair. On the other hand, drinking of milk, tea, coffee, or lemon resulted in decreased content of lead in hair. Additional source of exposure to lead could be cigarette smoking, distance to the traffic road, painting the walls, amalgam filling. Based on the results, it can be concluded that exposure to lead can occur mainly from eating habits and environmental exposure. PMID- 24346351 TI - Virgin ant queens mate with their own sons to avoid failure at colony foundation. AB - Mother-son mating (oedipal mating) is practically non-existent in social Hymenoptera, as queens typically avoid inbreeding, mate only early in life and do not mate again after having begun to lay eggs. In the ant genus Cardiocondyla mating occurs among sib in the natal nests. Sex ratios are extremely female biased and young queens face the risk of remaining without mating partners. Here, we show that virgin queens of Cardiocondyla argyrotricha produce sons from their own unfertilized eggs and later mate with them to produce female offspring from fertilized eggs. Oedipal mating may allow C. argyrotricha queens to found new colonies when no mating partners are available and thus maintains their unusual life history combining monogyny, mating in the nest, and low male production. Our result indicates that a trait that sporadically occurs in solitary haplodiploid animals may evolve also in social Hymenoptera under appropriate ecological and social conditions. PMID- 24346349 TI - Polycyclic aromatic hydrocarbons (PAHs) in surface sediments from the Bizerte Lagoon, Tunisia: levels, sources, and toxicological significance. AB - To assess the status of polycyclic aromatic hydrocarbon (PAH) contamination in sediments from the Bizerte Lagoon (northern Tunisia), 18 surface sediment samples were collected in March 2011 and analyzed for 14 US Environmental Protection Agency priority PAHs by high-performance liquid chromatography. The total concentrations of the 14 PAHs (SigmaPAHs) ranged from 16.9 to 394.1 ng g(-1) dry weight (dw) with a mean concentration of 85.5 ng g(-1) dw. Compared with other lagoons, coasts, and bays in the world, the concentrations of PAHs in surface sediments of the Bizerte Lagoon are low to moderate. The PAHs' composition pattern was dominated by the presence of four-ring PAHs (45.8 %) followed by five ring (26.8 %) and three-ring PAHs (12.7 %). The PAH source analysis suggested that the main origin of PAHs in the sediments of the lagoon was mainly from pyrolytic sources. According to the numerical effect-based sediment quality guidelines of the USA, the levels of PAHs in the Bizerte Lagoon should not exert adverse biological effects. The total benzo[a]pyrene toxicity equivalent values calculated for the samples varied from 3.1 to 53.7 ng g(-1) dw with an average of 10.6 ng g(-1) dw. PMID- 24346350 TI - Effectors of animal and plant pathogens use a common domain to bind host phosphoinositides. AB - Bacterial Type III Secretion Systems deliver effectors into host cells to manipulate cellular processes to the advantage of the pathogen. Many host targets of these effectors are found on membranes. Therefore, to identify their targets, effectors often use specialized membrane-localization domains to localize to appropriate host membranes. However, the molecular mechanisms used by many domains are unknown. Here we identify a conserved bacterial phosphoinositide binding domain (BPD) that is found in functionally diverse Type III effectors of both plant and animal pathogens. We show that members of the BPD family functionally bind phosphoinositides and mediate localization to host membranes. Moreover, NMR studies reveal that the BPD of the newly identified Vibrio parahaemolyticus Type III effector VopR is unfolded in solution, but folds into a specific structure upon binding its ligand phosphatidylinositol-(4,5) bisphosphate. Thus, our findings suggest a possible mechanism for promoting refolding of Type III effectors after delivery into host cells. PMID- 24346352 TI - Carbene complexes of phosphorus(V) fluorides substituted with perfluoroalkyl groups synthesized by oxidative addition. Cleavage of the complexes reveals a new synthetic protocol for ionic liquids. AB - The crystal structures of the previously reported 2,2-difluoro-1,3 dimethylimidazolidine and its acyclic analog were determined by in situ crystallization. Both liquid fluorinating agents have recently been introduced as potent precursors for the synthesis of p-block element carbene complexes. These fluorine compounds were compared with chloro-amidinium chlorides, which are already established carbene precursors. The chlorides were characterized as ion pairs and contrasted to the previous interpretation as charge-transfer complexes between carbene and dichlorine. Furthermore, the two precursors are used for the synthesis of a series of new carbene complexes of phosphorus(v) fluorides substituted with perfluoroalkyl-groups. These unusually stable hexacoordinate phosphorus(v) complexes were treated with anhydrous hydrogen fluoride to yield imidazolium phosphates. This procedure allows the synthesis of salts used as ionic liquids in high yield and high purity. PMID- 24346353 TI - Vibrational spectroscopic studies and DFT calculations on NaCH3CO2(aq) and CH3COOH(aq). AB - Aqueous solutions of sodium acetate, NaCH3CO2, and acetic acid, CH3COOH, were studied using Raman and infrared spectroscopy. The spectra were recorded over a large concentration range, in the terahertz region and up to 4000 cm(-1). In the isotropic Raman spectrum in R-format, a polarized band at 189 cm(-1) was assigned to the nu1Na-O stretch of the hydrated Na(+)-ion and a shoulder at 245 cm(-1) to the restricted translation band, nusO-H...O* of the hydrated acetate ion, CH3CO2( )(aq). The CH3CO2(-)(aq) and the hydrated acetic acid, CH3COOH(aq), possess pseudo Cs symmetry. Geometrical parameters for the species in the gas phase and for CH3CO2(-)(aq) and CH3COOH(aq) are reported. Characteristic bands for CH3CO2( )(aq) and CH3COOH(aq) were assigned under the guidance of the DFT vibrational frequency calculations and discussed in detail. In aqueous NaCH3CO2 solutions, at high concentrations, no contact ion pairs could be detected, but instead solvent separated ion pairs were found. In LiCH3CO2(aq), however, contact ion pairs are formed which is indicated by the appearance of a shoulder at 939 cm(-1) and the shift of the symmetric stretching mode of the -CO2(-) group to higher wavenumbers. PMID- 24346354 TI - Assessment of changes in membrane properties of platelets from patients with chronic myeloid leukaemia in different stages of the disease. AB - Patients with chronic myeloproliferative leukemia (CML) have frequent haemorrhage and/or thrombosis in their medical history. The mechanisms of these major and life-threatening complications remain unclear. Membrane organization influences many of the unique cellular functions and is strongly correlated, among other factors, to the membrane lipid composition; it may be evaluated by following up the membrane fluidity and aggregation properties of the platelet. In this study, we evaluated the platelet aggregation, the expression of platelet surface receptors, the membrane fluidity (as evaluated by fluorescence anisotropy) and its correlation to reactive oxygen species (ROS) production, in patients with chronic myeloid leukaemia (CML). It was found that the patients in accelerated and blastic phase of CML present an altered platelet aggregation response to all reagents except for ristocetin as compared with chronic phase group, which shows only epinephrine-altered response. We also found that BCR/ABL transcript leads to higher levels of ROS in accelerated and blastic CML phases. Patients without molecular remission have lower platelet membrane fluidity. We obtained a positive correlation between ROS level and membrane fluorescence anisotropy changes. The CD41 expression was decreased in CML patients and P selectin expression was found to be higher in these patients than in healthy volunteers. Platelets of CML patients have altered aggregation parameters in accelerated and blastic phases, in which BCR/ABL transcript level is increased. The increased level of ROS in CML patients without molecular remission is associated with a decrease in fluidity of platelet membrane and expression of CD41/CD61 receptors. These findings may contribute to understanding the mechanism of the altered platelet response reported in CML patients. PMID- 24346355 TI - Patients with risk factors have higher plasma levels of lysophosphatidic acid: a promising surrogate marker for blood platelet activation. AB - Although basic medical studies have shown that lysophosphatidic acid (LPA) has an important relationship to activated blood platelets, we know little about this from clinical experience. This pilot study examined plasma LPA levels in patients with a risk of thrombotic events and evaluated the effects of aspirin on plasma LPA levels. In this basically cross-sectional study, we recruited 1352 patients with either hypertension or hyperlipidemia and 670 controls without any risk factors. Patients with risk factors had significantly higher plasma LPA levels than controls, the mean of LPA = 3.12 +/- 2.24 vs. 2.57 +/- 1.96 MUmol/l, P < 0.001. The patients who had been taking aspirin had relatively lower plasma LPA levels compared with those who did not take aspirin, chi = 43.8, odds ratio (OR) [95% confidence interval (CI)] = 2.76 (2.03-3.75). For the hypertension group, chi = 23.1, OR (95% CI) = 3.44 (2.03-5.82), P < 0.001; for the hyperlipidemia group, chi = 22.9, OR (95% CI) = 2.53 (1.72-3.74), P < 0.001. Patients with a risk factor had higher plasma LPA levels compared with controls. Administration of aspirin may decrease elevated plasma LPA levels. This pilot clinical observation indicates that plasma LPA is worth to be studied further. PMID- 24346357 TI - Histone deacetylase activity and brain-derived neurotrophic factor (BDNF) levels in a pharmacological model of mania. AB - OBJECTIVE: In the present study, we aimed to examine the effects of repeated D amphetamine (AMPH) exposure, a well-accepted animal model of acute mania in bipolar disorder (BD), and histone deacetylase (HDAC) inhibitors on locomotor behavior and HDAC activity in the prefrontal cortex (PFC) and peripheral blood mononuclear cells (PBMCs) of rats. Moreover, we aimed to assess brain-derived neurotrophic factor (BDNF) protein and mRNA levels in these samples. METHODS: We treated adult male Wistar rats with 2 mg/kg AMPH or saline intraperitoneally for 14 days. Between the 8th and 14th days, rats also received 47.5 mg/kg lithium (Li), 200 mg/kg sodium valproate (VPT), 2 mg/kg sodium butyrate (SB), or saline. We evaluated locomotor activity in the open-field task and assessed HDAC activity in the PFC and PBMCs, and BDNF levels in the PFC and plasma. RESULTS: AMPH significantly increased locomotor activity, which was reversed by all drugs. This hyperactivity was associated with increased HDAC activity in the PFC, which was partially reversed by Li, VPT, and SB. No differences were found in BDNF levels. CONCLUSION: Repeated AMPH administration increases HDAC activity in the PFC without altering BDNF levels. The partial reversal of HDAC increase by Li, VPT, and SB may account for their ability to reverse AMPH-induced hyperactivity. PMID- 24346358 TI - Religious beliefs and alcohol control policies: a Brazilian nationwide study. AB - OBJECTIVE: The connection between lower alcohol use and religiousness has been extensively examined. Nevertheless, few studies have assessed how religion and religiousness influence public policies. The present study seeks to understand the influence of religious beliefs on attitudes toward alcohol use. METHODS: A door-to-door, nationwide, multistage population-based survey was carried out. Self-reported religiousness, religious attendance, and attitudes toward use of alcohol policies (such as approval of public health interventions, attitudes about drinking and driving, and attitudes toward other alcohol problems and their harmful effects) were examined. Multiple logistic regression was used to control for confounders and to assess explanatory variables. RESULTS: The sample was composed of 3,007 participants; 57.3% were female and mean age was 35.7 years. Religiousness was generally associated with more negative attitudes toward alcohol, such as limiting hours of sale (p , 0.01), not having alcohol available in corner shops (p , 0.01), prohibiting alcohol advertisements on TV (p , 0.01), raising the legal drinking age (p , 0.01), and raising taxes on alcohol (p , 0.05). Higher religious attendance was associated with less alcohol problems (OR: 0.61, 95%CI 0.40-0.91, p = 0.017), and self-reported religiousness was associated with less harmful effects of drinking (OR: 0.61, 95%CI 0.43-0.88, p = 0.009). CONCLUSIONS: Those with high levels of religiousness support more restrictive alcohol policies. These findings corroborate previous studies showing that religious people consume less alcohol and have fewer alcohol-related problems. PMID- 24346359 TI - Facile synthesis of ultra-small hybrid silica spheres for enhanced penetration in 3D glioma spheroids. AB - A facile approach has been developed to prepare ultra-small hybrid silica spheres with a diameter of ~10 nm, which show highly enhanced penetration ability in 3D glioma spheroids compared to conventional mesoporous silica nanoparticles. PMID- 24346363 TI - Let's talk about it: arranging a family conference. PMID- 24346364 TI - None shall pass...without answering the call bell. PMID- 24346365 TI - Postdeployment: a military nurse's journey. AB - BACKGROUND: Although being deployed gives military nurses opportunities for personal and professional growth, their psychological equilibrium is often strained more than they thought imaginable. Limited research has focused on how soldiers and families cope with the disappointment of the postdeployment phase, which can result from unrealistic expectations. RESEARCH QUESTIONS: Military nurses were asked these questions about the postdeployment phase. 1. How do you describe your experience? 2. What's the meaning of the experience? 3. What strategies influenced your return to personal and professional roles? METHOD: The researcher conducted a qualitative study by interviewing 10 military nurses, then re-presented a narrative of what many nurses experience after returning home from deployment. RESULTS: Seven themes emerged describing these nurses' experience and its meaning. Application to nursing practice: Several strategies were developed for future nurses to manage postdeployment periods. CONCLUSIONS: Conducting narrative inquiry contributes to the use of the qualitative method in nursing research. Healthcare professionals' increased knowledge and sensitivity can help them recognize the issues and challenges military nurses may face after returning home. PMID- 24346368 TI - Patient education series. Flu vaccines. PMID- 24346370 TI - When nurses become the students. PMID- 24346371 TI - How to meet the challenges of correctional nursing. PMID- 24346372 TI - Preventing migraine headache in adults. PMID- 24346373 TI - TeamSTEPPS makes strides for better communication. PMID- 24346374 TI - The fungus among us: Aspergillus. PMID- 24346375 TI - Using nimodipine for patients with aneurysmal subarachnoid hemorrhage. PMID- 24346378 TI - The mechanism of transforming diamond nanowires to carbon nanostructures. AB - The transformation of diamond nanowires (DNWs) with different diameters and geometries upon heating is investigated with density-functional-based tight binding molecular dynamics. DNWs of {100} and {111} oriented cross-section with projected average line density between 7 and 20 atoms A(-1) transform into carbon nanotubes (CNTs) under gradual heating up to 3500-4000 K. DNWs with projected average line density larger than 25 atoms A(-1) transform into double-wall CNTs. The route of transformation into CNTs clearly exhibits three stages, with the intriguing intermediate structural motif of a carbon nanoscroll (CNS). Moreover, the morphology plays an important role in the transformation involving the CNS as one important intermediate motif to form CNTs. When starting with [Formula: see text] oriented DNWs with a square cross-section consisting of two {111} facets facing each other, one interesting structure with 'nano-bookshelf' shape emerges: a number of graphene 'shelves' located inside the CNT, bonding to the CNT walls with sp(3) hybridized atoms. The nano-bookshelf structures exist in a wide range of temperatures up to 3,000 K. The further transformation from nano-bookshelf structures depends on the strength of the joints connecting shelves with CNT walls. Notably, the nano-bookshelf structure can evolve into two end products: one is CNT via the CNS pathway, the other is graphene transformed directly from the nano-bookshelf structure at high temperature. This work sheds light on the microscopic insight of carbon nanostructure formation mechanisms with the featured motifs highlighted in the pathways. PMID- 24346377 TI - An endoscopic-assisted technique for retrosellar access during the extended retrosigmoid approach: a cadaveric feasibility study and quantitative analysis of retrosellar working area. AB - The retrosigmoid approach has been advocated for certain petroclival tumors but provides limited access to any retrosellar extension of tumor, necessitating a two-stage operation. Our purpose was to demonstrate preliminary feasibility of an endoscopic-assisted technique to provide retrosellar access during the extended retrosigmoid approach and compare microscopic and endoscopic retrosellar working area. Standard retrosigmoid craniectomy and partial petrosectomy respecting inner ear structures were performed on six embalmed cadaveric heads. Two balloons were inflated to simulate a 15 mm petroclival tumor. Retrosellar clival and brainstem working area and ipsilateral oculomotor nerve and posterior cerebral artery (PCA) working distance were measured using the endoscope and microscope. Artificial tumors were implanted and resected using the endoscopic-assisted technique to assess feasibility. The endoscope provided significantly greater mean working area/distance on the clivus (201.6 vs 114.8 mm(2), p < 0.01), brainstem (223.5 vs 121.2 mm(2), p < 0.01), ipsilateral oculomotor nerve (10.8 vs 6.4 mm, p < 0.01), and ipsilateral PCA (13.7 vs 8.9 mm, p = 0.01). Petrous dissection to create a 10 * 10 mm working channel and artificial tumor resection was feasible in all dissections. The superior petrosal vein required ligation in 9 (75%) cases. Air cells were exposed in 1 (8%) case. The described endoscopic-assisted technique can provide retrosellar access during the extended retrosigmoid approach to access petroclival tumors with retrosellar extension. Risks include superior petrosal vein sacrifice, bleeding that can impair visualization, injury to the trigeminal nerve during endoscopic insertion/manipulation or injury to the brainstem while working in the medial limits of exposure. Further work is necessary to determine clinical feasibility, safety, and efficacy. PMID- 24346379 TI - Paracetamol to close the patent ductus arteriosus: From serendipity toward evidence based medicine. PMID- 24346380 TI - Association of B12 deficiency and clinical neuropathy with metformin use in type 2 diabetes patients. AB - CONTEXT: Long-term metformin use has been hypothesized to cause B12 deficiency and neuropathy in Type 2 diabetes patients. However, there is a paucity of Indian data regarding the same. AIM: To compare the prevalence of B12 deficiency and peripheral neuropathy in patients with Type 2 diabetes mellitus treated with or without metformin. MATERIALS AND METHODS: We recruited patients with Type 2 diabetes and divided them into metformin exposed and nonmetformin exposed groups. We measured baseline demographic variables like age, sex, vegetarian status, and HbA1c levels in both groups. We compared vitamin B12 levels and severity of peripheral neuropathy (using Toronto Clinical Scoring System (TCSS)) in both groups. Definite B12 deficiency was defined as B12 <150 pg/ml and possible B12 deficiency as <220 pg/ml. The difference in vitamin B12 levels and TCSS was calculated in both groups using independent samples t-test. Spearman's rank correlation between cumulative metformin use and B12 level was calculated. Odds ratio of vitamin B12 deficiency in metformin exposed group was also estimated. RESULTS: Mean serum B12 levels was significantly lower in metformin exposed group (n=84) compared with nonmetformin exposed group (n=52) (410+/-230.7 versus 549.2+/-244.7, P=0.0011). Mean neuropathy score was significantly higher in metformin exposed group. (5.72+/-2.04 versus 4.62+/-2.12, P=0.0064). Odds ratio for possible B12 deficiency was 4.45 (95% CI 1.24-15.97). There was significant negative correlation between cumulative metformin dose and vitamin B12 level (r= 0.68, P<0.0001). CONCLUSION: Metformin use is associated with vitamin B12 deficiency and clinical neuropathy in Type 2 diabetes patients. PMID- 24346381 TI - Does first line antiretroviral therapy increase the prevalence of cardiovascular risk factors in Indian patients?: A cross sectional study. AB - CONTEXT: Antiretroviral therapy (ART) is associated with a myriad of metabolic complications which are potential cardiovascular risk factors. Early detection of these risk factors could help in alleviating morbidity and mortality in human immunodeficiency virus (HIV) infected patients on ART. AIMS: To study the prevalence of cardiovascular risk factors in patients on a combination of nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTIs (NNRTIs) - the standard combination first line ART regimen used in tertiary referral center. SETTINGS AND DESIGN: The prevalence of cardiovascular risk factors in HIV infected subjects with stage 1t disease on standard first line ART for at least 1 year, HIV infected subjects with stage 1 disease and not on ART and HIV negative subjects was assessed. The study was a cross-sectional study design. MATERIALS AND METHODS: Basic demographic data was collected and patients were examined for anthropometric data and blood was collected for analysis of blood glucose, serum lipids, and fasting insulin levels. STATISTICAL ANALYSIS: Chi-square test was used to calculate significance. Statistical Package for Social Sciences (SPSS) software version 16.0 was used for data analysis. RESULTS: The prevalence of hypercholesterolemia and hypertriglyceridemia was higher in the patients on ART when compared to patients not on ART (P<0.001). There was no difference in the prevalence of abnormal glycemic status, obesity, abdominal obesity, insulin resistance, and hyperinsulinemia between patients on ART and those not on ART. CONCLUSIONS: First line ART is associated with increased prevalence of dyslipidemia. Early detection and treatment of dyslipidemia should help in reducing the cardiovascular morbidity in patients on ART. PMID- 24346382 TI - Risk factors for delirium and inpatient mortality with delirium. AB - BACKGROUND: There is limited on the risk factors and mortality in patients with delirium from India. AIM: This study aimed to evaluate the risk factors associated with delirium and inpatient mortality rates of patients diagnosed with delirium by psychiatry consultation liaison services. MATERIALS AND METHODS: Three hundred and thirty-one patients diagnosed as delirium by the psychiatry consultation liaison services were examined on standardized instruments: Delirium Rating Scale Revised 98 version (DRS-R-98), amended Delirium Motor Symptom Scale (DMSS), Delirium Etiology Checklist (DEC), Charlson Comorbidity index, and a checklist for assessment of risk factors. RESULTS: More than three medications as a risk factor and metabolic/endocrine disturbances as cause were observed to play largest role in development of delirium. The inpatient mortality rate was 12.4%. Compared to the survivor group, those who died were more likely to be young (<65 years), had significantly high rate of alcohol dependence and were more frequently restrained prior to development of delirium; of these only age <65 years and use of restraints emerged as the significant predictors of mortality in regression analysis. CONCLUSION: Age and use of restraints appears to be an important predictor mortality in patients with delirium. PMID- 24346383 TI - Do geriatrics require dose titration for antidiabetic agents? AB - OBJECTIVE: To evaluate the antidiabetic drug dosage differences between geriatric and nongeriatric diabetics with reference to duration of disease and creatinine clearance (Crcl). MATERIALS AND METHODS: Prospective study conducted for 6 months in a tertiary care hospital. Patients with type 2 diabetes mellitus were grouped into geriatric (age >=60 years) and nongeriatric (age <60 years). Patients' demographic data, duration of diabetes, medication, and serum creatinine were recorded. Crcl was calculated using Cockcroft-Gault formula. Doses of sulfonylureas (SU) were converted into equivalent doses, taking glibenclamide as standard. Univariate analysis was done for comparison of drug doses between groups. RESULT: A total of 320 geriatric and 157 nongeriatric diabetics completed the study. The duration of diabetes and Crcl adjusted dose reduction of glibenclamide (mean dose: Geriatrics 7.2+/-0.4 mg, nongeriatrics 9.6+/-0.7 mg; P=0.01) and gliclazide (mean dose: Geriatrics 85.5+/-11.5 mg, nongeriatrics 115.3+/-32.7 mg; P=0.42) was 25%, glimepiride (mean dose: Geriatrics 1.62+/-0.13 mg, nongeriatrics 2.1+/-0.18 mg; P=0.06) was 22%. Glipizide did not require dose reduction. Mean converted equivalent dose of sulfonylurea monotherapy was significantly lower in geriatrics than nongeriatrics (3.2+/-0.5 vs 6.4+/-1.02 mg; P=0.01) and showed 50% dose reduction. Mean dose of metformin was lower in geriatrics (901+/-32.2 mg vs 946.7+/-45.8 mg; P=0.45) and showed 5% reduction in dosage. There was no difference in the mean drug doses of thiazolidinediones and insulin between the groups. CONCLUSION: A substantial dose reduction of glibenclamide (25%), gliclazide (25%), glimepiride (22%), and metformin (5%) in geriatrics compared to nongeriatrics was observed. Smaller dosage formulations like 0.75 mg glibenclamide, 0.5 mg glimepiride, 20 mg gliclazide, and 250 mg metformin may be of value in geriatric diabetic practice. PMID- 24346384 TI - Preinduction incentive spirometry versus deep breathing to improve apnea tolerance during induction of anesthesia in patients of abdominal sepsis: A randomized trial. AB - BACKGROUND: Abdominal sepsis is associated with varied degree of hypoxemia and atelactasis in the lung and can enhance the onset of desaturation of arterial blood during apnea. AIMS: This study looked at methods to improve safety margin of apnea during induction of anesthesia in these high-risk patients. SETTINGS AND DESIGN: It was a randomized, single blind study on adult patients presenting for emergency laparotomy due to peritonitis in a university teaching hospital setting. MATERIALS AND METHODS: In group 1 (IS) (n = 32), three sessions of incentive spirometry (IS) were performed within one hour before induction of anesthesia. In group 2 (DB) (n = 34), patients were subjected to deep breathing sessions in a similar manner. All patients received preoxygenation (100%) by mask for 3 min, followed by rapid-sequence induction of anesthesia using fentanyl, thiopental, and suxamethonium and endotracheal intubation. Patients were subjected to a period of apnea by keeping the end of the endotracheal tube open to air till they developed 95% hemoglobin saturation (SpO 2) by pulse oxymetry. Positive pressure ventilation was resumed at the end. We observed for hemodynamic changes, apnea time, and SpO 2 (100%) recovery time on resuming ventilation. Arterial blood gas samples were taken before intervention, after IS or DB, after preoxygenation, and at the end of apnea. STATISTICAL ANALYSIS USED: One-way analysis of variance (ANOVA), X 2 test, Kaplan-Meier graph, and log-rank tests were applied to compare the two study groups. RESULTS: Oxygenation level in group 1 (265 +/- 76.7 mmHg) patients was significantly (P < 0.001) higher than in group 2 (221 +/- 61.8 mmHg)at the end of preoxygenation. The apnea time (median: lower bound - upper bound Confidence Interval apnea time) (272:240-279 s) in group 1 (IS) patients was significantly higher P < 0.05) than in group 2 (180:163-209 s) patients. Saturation recovery time (35:34-46 s) in group 1 (IS) patients was also quicker than in group 2 patients (48:44-58 s). CONCLUSIONS: IS in the preoperative period is superior to deep breathing sessions for improving apnea tolerance during induction of anesthesia in abdominal sepsis patients. PMID- 24346385 TI - Utilization of operating room time in a cancer hospital. AB - BACKGROUND: Appropriate usage of operating room (OR) time can improve efficiency of utilization of resources and help to decrease surgical waiting lists. AIMS: This study was conducted to evaluate the pattern of usage of OR time in a tertiary referral cancer hospital. SETTING AND DESIGN: This was a prospective audit carried out over 2 months in 11 major ORs in a cancer hospital. MATERIALS AND METHODS: OR anesthesiologists filled a standard form for all patients undergoing elective surgery and documented the following times: entry into OR, start of anesthesia, handover to surgeon, incision, start of reversal, end of anesthesia, and shifting out of patient. STATISTICAL ANALYSIS: Median time utilized for various OR processes was calculated. RESULTS: An average of two surgeries were performed per OR session (828 surgeries in 407 OR sessions). Anesthesia and surgery-related processes contributed to 17% and 79%, respectively, of total OR time, with turnover time between cases accounting for the remaining 4%. Fifteen percent (60 out of 407) OR sessions started more than 10 min later than the planned start time, and 17% (70 of 407) of OR sessions ended more than 2 h after the scheduled finish time. An anesthesia procedure room was utilized in only 15% of cases where it could potentially have been used. CONCLUSION: This audit identified patterns of OR usage in a cancer hospital and helped to detect areas of inefficient utilization. Anesthesia-related processes contributed to 17% of the total OR time. PMID- 24346386 TI - Genetic instability in urinary bladder cancer: An evolving hallmark. AB - Bladder cancer is a major health-care concern. A successful treatment of bladder cancer depends on its early diagnosis at the initial stage. Genetic instability is an essential early step toward the development of bladder cancer. This instability is found more often at the chromosomal level than at the nucleotide level. Microsatellite and chromosomal instability markers can be used as a prognostic marker for screening bladder cancer. Bladder cancer can be distinguished in two different categories according to genetic instability: Cancers with chromosomal level instability and cancers with nucleotide level instability. Deoxyribonucleic acid (DNA) mismatch repair (MMR) system and its correlation with other biologic pathway, both are essential to understand the basic mechanisms of cancer development. Microsatellite instability occurs due to defects in DNA MMR genes, including human mutL homolog 1 and human mutL homolog 2. Chromosomal alterations including deletions on chromosome 3, 8, 9, 11, 13, 17 have been detected in bladder cancer. In the current review, the most recent literature of genetic instability in urinary bladder cancer has been summarized. PMID- 24346387 TI - Renal angioplasty for atherosclerotic renal artery stenosis: Cardiologist's perspective. AB - Atherosclerotic renal artery stenosis (ARAS) is frequently associated with concomitant coronary and peripheral arterial disease with a significant impact on cardiovascular morbidity and mortality. Renal angioplasty of ARAS is more challenging because of increased incidence of technical failures, complications, and restenosis; while there is barely perceptible control of hypertension and only marginal improvement in renal function. This is because most of the patient population in recent randomized trials had unmanifested or clinically silent renovascular disease. Manifestations of RAS should be looked for and incorporated in the management plan particularly before deciding for revascularization. In the absence of clinical manifestation like renovascular hypertension, ischemic nephropathy, left ventricular failure, or unstable coronary syndromes; mere presence of RAS is analogous to presence of concomitant peripheral arterial disease which increases risk of adverse coronary events. Dormant-RAS in the absence of any manifestations can be managed with masterly inactivity. Chronological sequence of events and clinical condition of the patient help in decision making by identifying progressive renovascular disease. Selecting patients for renal artery stenting who actually will benefit from revascularization shall also decrease the unnecessary complications inherent with any interventional procedure. The present review is an attempt to analyze the current view on the diagnostic and management issues more specifically about the need and rationale behind angioplasty. PMID- 24346388 TI - "DREEM" comes true - Students' perceptions of educational environment in an Indian medical school. AB - BACKGROUND: The accomplishment and contentment of students depends upon their educational environment. Very few studies in India have looked at the impact of educational environment on students, there are few such studies in our country despite having a large number of medical schools. OBJECTIVE: This study was performed to assess the undergraduate students' perceptions of medical education in general and educational environment in our medical school in particular. MATERIALS AND METHODS: The Dundee Ready Education Environment Measure (DREEM), a validated inventory was distributed among undergraduate students in final Bachelor of Medicine and Bachelor of Surgery (MBBS) (2010-2011) and students who were undergoing internship (2010-2011) and various scores were calculated and the means were compared using Mann-Whitney test. RESULTS: The mean total DREEM score was found to be 121.5/200 for final MBBS students (n = 115) and 118.4/200 (n = 109) for the internship batch students. There was no statistically significant difference between the scores of the two batches. The overall DREEM score for our Medical School during the academic year 2010-2011 (for the final MBBS and internship batch) was 120/200 (n = 224), which showed that the students' perceptions were more positive. CONCLUSION: The study showed that the students' perception of the educational environment was positive. There was no statistically significant difference between the scores of the two batches (final MBBS and internship). This study helped us to introspect and identify remediable areas in the educational environment of our medical school and hence we could suggest some measures to modify them. PMID- 24346389 TI - Fatal acute pancreatitis in a patient with visceral leishmaniasis during miltefosine treatment. AB - Pancreatitis is a known side effect of the once commonly used drug, sodium stibogluconate, for treatment of visceral leishmaniasis (VL). In India, miltefosine has recently been introduced as the first-line drug. Its side effects include loose motions, vomiting, and teratogenicity. We report here a case of a 41-year-old parasitologically confirmed male case of VL, who developed acute pancreatitis during treatment with miltefosine. On the 13 th day of treatment, he presented with abdominal pain and vomiting. The biochemical, hematological, and radiological features were suggestive of acute pancreatitis. The patient was put on conservative treatment for pancreatitis at the specialized center but succumbed to renal failure and septicaemia. PMID- 24346390 TI - Marine stingray injuries to the extremities: Series of three cases with emphasis on imaging. AB - Stingray injuries are usually reported from coastal regions. The injury is caused by the tail spine of the stingray, which can penetrate deep into the soft tissues, and the venom in the tail can cause extensive tissue damage. Imaging plays a very important role in patients with stingray injuries, especially to detect the presence of retained foreign bodies and its complications. We present three cases of stingray injuries to the extremities, with a special emphasis on radiographic findings. Embedded foreign bodies that were radiographically visualized were removed in two of the patients (one patient was discharged at request and was lost to follow-up). We also discuss the types of injuries, clinical presentation, importance of imaging and management considerations in stingray injuries. PMID- 24346391 TI - Oral paracetamol in treatment of closure of patent ductus arteriosus in preterm neonates. AB - We herewith report a case series of six premature neonates with hemodynamically significant paten ductus successfully treated with oral paracetamol. This is a first case series describing the use of oral paracetamol treatment patent ductus in preterm neonates from India. Further prospective randomized-controlled trials are needed to evaluate the efficacy and safety of oral paracetamol in the treatment of patent ductus in preterm neonates. PMID- 24346392 TI - Ruptured ectopic pregnancy associated with tubal schistosomiasis. AB - Endemic in major parts of Africa and Middle East, Schistosoma haematobium is a common cause of recurrent urogenital infections and obstetric complications such as spontaneous abortions, ectopic pregnancies, and low birth weight babies. The involvement of fallopian tubes is not rare in endemic areas and may predispose to ectopic pregnancy and infertility. Indian subcontinent is a very lowrisk region for schistosoma infection. Tubal schistosomiasis is not exceptional in endemic zones, but is rarely found in India. The species most often isolated is S. haematobium. Contamination occurs via vascular anastomoses between the bladder and the genital organs. We report a case of tubal schistosomiasis presenting as ruptured ectopic pregnancy discovered on a surgical specimen after salpingectomy. PMID- 24346393 TI - Recurrent hypoglycemia...: A less well-known presentation of Sheehan's syndrome. AB - Sheehan's syndrome is a rare cause of recurrent hypoglycemia. We present a case of a middle aged woman who presented with recurrent life threatening hypoglycemia. Based on a past history of severe post partum hemmorhage and a clinical picture of myxedema and secondary amennorhea, laboratory and neuroimaging was undertaken to confirm a diagnosis of Sheehan's syndrome. The patient responded to treatment with thyroxine and steroids in replacement doses. The case report emphasises the importance of early suspicion and management of this easily missed and treatable condition. PMID- 24346394 TI - Isolated familial pneumothorax in a Taiwanese family with Birt-Hogg-Dube syndrome. AB - Primary spontaneous pneumothorax usually occurs as a sporadic event, but may be clustered in certain families with an underlying inherited disorder. Birt-Hogg Dubiota (BHD) syndrome is a rare autosomal dominant disease accounting for familial pneumothorax. BHD syndrome, caused by mutation of the folliculin gene, is characterized by skin fibrofolliculoma, pulmonary cysts, pneumothorax, and renal cancer. We describe a BHD-affected Taiwanese family with clinical and genetic study. A rare mutation of the folliculin gene was detected in the patient and members with pulmonary cysts or pneumothorax, but no skin or renal lesions were found. This mutation was reported in a Taiwanese family and might indicate a pneumothorax-predominant phenotype. Isolated pneumothorax is an uncommon initial presentation of BHD syndrome. Family history should be carefully reviewed when managing a patient with pneumothorax. PMID- 24346395 TI - Erdheim-Chester disease: A clinical and radiological masquerade. PMID- 24346396 TI - Urticaria and hydropneumothorax as an exceptional cause of ruptured hydatid cyst of lung. PMID- 24346398 TI - Soy milk toxicity: Additional concern. PMID- 24346397 TI - A rare cause of intraoperative nasogastric tube obstruction. PMID- 24346399 TI - Hyperkalemia due to fertilizer (N:P:K) poisoning. PMID- 24346400 TI - An uncommon cause of chest pain with electrocardiographic changes. PMID- 24346401 TI - Pachydermodactyly does not need rheumatologic work-up. PMID- 24346402 TI - Cardiotoxicity in OPC poisoning: Time to think differential diagnosis. PMID- 24346403 TI - Challenges in the diagnosis and treatment of a case of acute intermittent porphyria in India. PMID- 24346404 TI - Thyroid storm: An early clinical diagnosis and multidrug approach to therapy. PMID- 24346405 TI - Clues to non-organic sensory symptoms in neurology. PMID- 24346406 TI - Respiratory Hoover's sign. PMID- 24346407 TI - Eschar in scrub typhus: A valuable clue to the diagnosis. PMID- 24346408 TI - Methodological aspects in the use of scoring and multivariable logistic regression as predictive model. PMID- 24346409 TI - Methemoglobinemia following ingestion of a weedicide. PMID- 24346410 TI - Combination of ultrasonographic supraclavicular block and general anaesthesia for arthroscopic shoulder surgery in a patient with haemophilia A. PMID- 24346411 TI - Comments on Wale et al. : Combined (99)mTc-methoxyisobutylisonitrile scintigraphy and fine-needle aspiration cytology offers an accurate and potentially cost effective investigative strategy for the assessment of solitary or dominant thyroid nodules. PMID- 24346412 TI - Combined (99m)Tc-methoxyisobutylisonitrile scintigraphy and fine-needle aspiration cytology offers an accurate and potentially cost-effective investigative strategy for the assessment of solitary or dominant thyroid nodules: reply to comments by Riazi et al. PMID- 24346413 TI - (18)F-FDG PET/CT scan in malignant priapism with diffuse pulmonary adenocarcinoma metastatic invasion of both corpus spongiosum and cavernosum. PMID- 24346414 TI - Semiautomatic methods for segmentation of the proliferative tumour volume on sequential FLT PET/CT images in head and neck carcinomas and their relation to clinical outcome. AB - PURPOSE: Radiotherapy of head and neck cancer induces changes in tumour cell proliferation during treatment, which can be depicted by the PET tracer (18)F fluorothymidine (FLT). In this study, three advanced semiautomatic PET segmentation methods for delineation of the proliferative tumour volume (PV) before and during (chemo)radiotherapy were compared and related to clinical outcome. METHODS: The study group comprised 46 patients with 48 squamous cell carcinomas of the head and neck, treated with accelerated (chemo)radiotherapy, who underwent FLT PET/CT prior to treatment and in the 2nd and 4th week of therapy. Primary gross tumour volumes were visually delineated on CT images (GTV CT). PVs were visually determined on all PET scans (PV VIS). The following semiautomatic segmentation methods were applied to sequential PET scans: background-subtracted relative-threshold level (PV RTL), a gradient-based method using the watershed transform algorithm and hierarchical clustering analysis (PV W&C), and a fuzzy locally adaptive Bayesian algorithm (PV FLAB). RESULTS: Pretreatment PV VIS correlated best with PV FLAB and GTV CT. Correlations with PV RTL and PV W&C were weaker although statistically significant. During treatment, the PV VIS, PV W&C and PV FLAB significant decreased over time with the steepest decline over time for PV FLAB. Among these advanced segmentation methods, PV FLAB was the most robust in segmenting volumes in the third scan (67 % of tumours as compared to 40 % for PV W&C and 27 % for PV RTL). A decrease in PV FLAB above the median between the pretreatment scan and the scan obtained in the 4th week was associated with better disease-free survival (4 years 90 % versus 53 %). CONCLUSION: In patients with head and neck cancer, FLAB proved to be the best performing method for segmentation of the PV on repeat FLT PET/CT scans during (chemo)radiotherapy. This may potentially facilitate radiation dose adaptation to changing PV. PMID- 24346415 TI - Protocol requirements and diagnostic value of PET/MR imaging for liver metastasis detection. AB - PURPOSE: To compare the accuracy of PET/MR imaging with that of FDG PET/CT and to determine the MR sequences necessary for the detection of liver metastasis using a trimodality PET/CT/MR set-up. METHODS: Included in this single-centre IRB approved study were 55 patients (22 women, age 61 +/- 11 years) with suspected liver metastases from gastrointestinal cancer. Imaging using a trimodality PET/CT/MR set-up (time-of-flight PET/CT and 3-T whole-body MR imager) comprised PET, low-dose CT, contrast-enhanced (CE) CT of the abdomen, and MR with T1-W/T2 W, diffusion-weighted (DWI), and dynamic CE imaging. Two readers evaluated the following image sets for liver metastasis: PET/CT (set A), PET/CECT (B), PET/MR including T1-W/T2-W (C), T1-W/T2-W with either DWI (D) or CE imaging (E), and a combination (F). The accuracy of each image set was determined by receiver operating characteristic analysis using image set B as the standard of reference. RESULTS: Of 120 liver lesions in 21/55 patients (38%), 79 (66%) were considered malignant, and 63/79 (80%) showed abnormal FDG uptake. Accuracies were 0.937 (95% CI 89.5 - 97.9%) for image set A, 1.00 (95% CI 99.9 - 100.0%) for set C, 0.998 (95% CI 99.4 - 100.0%) for set D, 0.997 (95% CI 99.3 - 100.0%) for set E, and 0.995 (95% CI 99.0 - 100.0%) for set F. Differences were significant for image sets D - F (P < 0.05) when including lesions without abnormal FDG uptake. As shown by follow-up imaging after 50 - 177 days, the use of image sets D and both sets E and F led to the detection of metastases in one and three patients, respectively, and further metastases in the contralateral lobe in two patients negative on PET/CECT (P = 0.06). CONCLUSION: PET/MR imaging with T1-W/T2-W sequences results in similar diagnostic accuracy for the detection of liver metastases to PET/CECT. To significantly improve the characterization of liver lesions, we recommend the use of dynamic CE imaging sequences. PET/MR imaging has a diagnostic impact on clinical decision making. PMID- 24346416 TI - 11C-choline PET/CT detects the site of relapse in the majority of prostate cancer patients showing biochemical recurrence after EBRT. AB - PURPOSE: The aim of this retrospective study was to evaluate the usefulness and the detection rate of (11)C-choline PET/CT in a population of patients with prostate cancer (PC), exclusively treated with external beam radiotherapy (EBRT) as primary treatment, who showed biochemical relapse. MATERIALS AND METHODS: We enrolled 140 patients showing a serum PSA level >2 ng/mL (mean 8.6 ng/mL, median 5 ng/mL, range 2 - 60 ng/mL). All patients had been treated with EBRT to the prostate gland and prostatic fossa with doses ranging from 70 to 76 Gy in low risk patients (T1/T2 and/or serum PSA <10 ng/mL) and escalating to >76 Gy (range 76 - 81 Gy) in high-risk patients (T3/T4 and/or serum PSA >10 ng/mL). Of the 140 patients, 53 were receiving androgen deprivation therapy at the time of the scan. All positive (11)C-choline PET/CT findings were validated by transrectal ultrasound-guided biopsy or at least 12 months of follow-up with contrast enhanced CT, MR, bone scintigraphy or a repeated (11)C-choline PET/CT scan. The relationships between the detection rate of (11)C-choline PET/CT and the factors PSA level, PSA kinetics, Gleason score, age, time to relapse and SUV max in patients with positive findings were analysed. RESULTS: (11)C-Choline PET/CT detected the site of relapse in 123 of the 140 patients with a detection rate of 87.8 % (46 patients showed local relapse, 31 showed local and distant relapse, and 46 showed only distant relapse). In patients with relapse the mean serum PSA level was 9.08 ng/mL (median 5.1 ng/mL, range 2 - 60 ng/mL), the mean PSA doubling time was 5.6 months (median 3.5 months, range 0.4 - 48 months), and the mean PSA velocity was 15 ng/mL/year (median 8.8 ng/mL/year, range 0.4 - 87 ng/mL/year). Of the 123 patients with relapse, 77 (62.6 %) showed distant relapse with/without local relapse, and of these 77, 31 (40.2 %) showed oligometastatic disease (one or two distant lesions: lymph node lesions only in 16, bone lesions only in 14, and lymph node lesions and bone lesions in 1). In univariate and multivariate analyses PSA kinetics was the only variable affecting (11)C-choline PET/CT detection rate. A significant correlation between PSA kinetics and site of recurrence (local relapse only vs. distant metastasis) was also observed. CONCLUSION: The detection rate of (11)C-choline PET/CT in patients with PC showing biochemical recurrence after EBRT as primary treatment is relatively high (87.8 %). (11)C-Choline PET/CT was able to detect extraprostatic disease in the 62.6 % of patients. Considering this high detection rate, (11)C-choline PET/CT could have clinical usefulness in the management of these PC patients, but this should be confirmed in future studies. PMID- 24346418 TI - Highly sensitive hot electron bolometer based on disordered graphene. AB - A bolometer is a device that makes an electrical resistive response to the electromagnetic radiation resulted from a raise of temperature due to heating. The combination of the extremely weak electron-phonon interactions along with its small electron heat capacity makes graphene an ideal material for applications in ultra-fast and sensitive hot electron bolometer. However, a major issue is that the resistance of pristine graphene weakly depends on the electronic temperature. We propose using disordered graphene to obtain a strongly temperature dependent resistance. The measured electrical responsivity of the disordered graphene bolometer reaches 6 * 10(6) V/W at 1.5 K, corresponding to an optical responsivity of 1.6 * 10(5) V/W. The deduced electrical noise equivalent power is 1.2 fW/?Hz, corresponding to the optical noise equivalent power of 44 fW/?Hz. The minimal device structure and no requirement for high mobility graphene make a step forward towards the applications of graphene hot electron bolometers. PMID- 24346419 TI - Molecular mobility on graphene nanoribbons. AB - Graphene nanoribbons (GNRs) have been proposed to be used as nanoscale mass conveyor highways. However, how factors such as edge confinement, edge rippling, ribbon twisting, and thermal fluctuations affect the mobility of admolecules on GNRs for such application remains unknown. Using molecular dynamics (MD) simulations, we address these issues by investigating the surface mobility of a physisorbed C60 admolecule on pristine GNRs. We show that the absorption energy and edge energy barrier of a GNR are able to keep and confine the admolecule motion only on one side of the GNR. The twisting of narrow GNRs in combination with thermal fluctuations causes the admolecule to move in a helical trajectory, and thus markedly affects its mobility. As the GNR width increases, its twisting is gradually inhibited, and the motion of the admolecule becomes planar. A comparison between the results from our MD simulations and those from the confined Langevin model indicates that the distinct behavior of molecular mobility on narrow GNRs is due to their twisting rather than geometrical confinement. These findings shed light on the important factors that control the characteristics of the GNR-based mass transport highways. PMID- 24346420 TI - Overexpression of an isoprenyl diphosphate synthase in spruce leads to unexpected terpene diversion products that function in plant defense. AB - Spruce (Picea spp.) and other conifers employ terpenoid-based oleoresin as part of their defense against herbivores and pathogens. The short-chain isoprenyl diphosphate synthases (IDS) are situated at critical branch points in terpene biosynthesis, producing the precursors of the different terpenoid classes. To determine the role of IDS and to create altered terpene phenotypes for assessing the defensive role of terpenoids, we overexpressed a bifunctional spruce IDS, a geranyl diphosphate and geranylgeranyl diphosphate synthase in white spruce (Picea glauca) saplings. While transcript level (350-fold), enzyme activity level (7-fold), and in planta geranyl diphosphate and geranylgeranyl diphosphate levels (4- to 8-fold) were significantly increased in the needles of transgenic plants, there was no increase in the major monoterpenes and diterpene acids of the resin and no change in primary isoprenoids, such as sterols, chlorophylls, and carotenoids. Instead, large amounts of geranylgeranyl fatty acid esters, known from various gymnosperm and angiosperm plant species, accumulated in needles and were shown to act defensively in reducing the performance of larvae of the nun moth (Lymantria monacha), a conifer pest in Eurasia. These results show the impact of overexpression of an IDS and the defensive role of an unexpected accumulation product of terpenoid biosynthesis with the potential for a broader function in plant protection. PMID- 24346422 TI - Response to "CYP2C9 polymorphism is not a major determinant of bosentan exposure in healthy volunteers". PMID- 24346421 TI - Vasopressin antagonists for patients with acute heart failure: interpreting new clinical and translational data. PMID- 24346423 TI - Simon in action: the effect of spatial congruency on grasping trajectories. AB - The Simon effect, one of the well-known stimulus-response compatibility effects, is usually explained as an expression of a conflict that occurs at the response selection stage. Here, we extended previous findings to provide evidence for post response selection expression of the Simon effect. Following a presentation of a visual stimulus, participants grasped one of two objects that differed slightly in size. The results showed that visual stimulus congruency modulated grasping trajectories. Particularly, movements were more lateralized in congruent trials. This lateralization decreased as reaction time (RT) increased and therefore this effect could not be fully dissociated from the response selection stage. However, size sensitivity, as measured by the time taken to reach the maximum grip aperture between the fingers, was decreased for incongruent trials, unrelated to RT. This finding provides novel evidence for an independent expression of the Simon effect in post-response selection stages. Overall, our findings extend previous studies and demonstrate that the spatial conflict evoked by the Simon task encompasses several components and independently affects response selection stages as well as other components of motor execution. PMID- 24346425 TI - Ophthalmic complications among cases of head trauma in north-eastern Iran. AB - The aim of this study was to investigate the prevalence and pattern of ocular complications in patients with head trauma admitted to the main trauma centre in north-eastern Iran. A total of 459 head-injured patients (36.56 +/- 19.30 years of age) with at least one ocular manifestation were recruited. Each individual patient was examined by a neurosurgeon and an ophthalmologist to confirm the type of ocular complication. In addition, all patients were analysed for age, gender, and cause of head injury in addition to the ophthalmic and neurosurgical examinations. Of the 459 patients, 142 (31 %) were female and 317 (69 %) were male. The maximum rate of ocular complications was during the third decade of life and minimum during childhood and in the elderly (>71 years) population. The leading cause of head trauma was motor vehicle accidents, predominant in male adults aged 21-40 years. Ocular complications observed were classified into three major groups: soft-tissue injuries to the globe and adnexae (n = 434), orbital complications (n = 45) and neuro-ophthalmic complications (n = 152). In conclusion, our data provides a useful estimation of the rate and pattern of ocular complications among patients with head injuries seen in trauma centres in north-eastern Iran. Understanding the pattern of ocular complications helps us to design more appropriate preventive methods. PMID- 24346424 TI - On methodological standards in training and transfer experiments. AB - The past two decades have seen a tremendous surge in scientific interest in the extent to which certain types of training-be it aerobic, athletic, musical, video game, or brain trainer-can result in general enhancements in cognitive function. While there are certainly active debates regarding the results in these domains, what is perhaps more pressing is the fact that key aspects of methodology remain unsettled. Here we discuss a few of these areas including expectation effects, test-retest effects, the size of the cognitive test battery, the selection of control groups, group assignment methods, difficulties in comparing results across studies, and in interpreting null results. Specifically, our goal is to highlight points of contention as well as areas where the most commonly utilized methods could be improved upon. Furthermore, because each of the sub-areas above (aerobic training through brain training) share strong similarities in goal, theoretical framework, and experimental approach, we seek to discuss these issues from a general perspective that considers each as members of the same broad "training" domain. PMID- 24346426 TI - [Insomnia--state of the science]. AB - Diagnostic systems such as the international classification of diseases (ICD-10) or the diagnostic and statistical manual of mental disorders (DSM IV) have frequently been criticized as not adequately reflecting the complexity and heterogeneity of insomnia. Progress was made through the introduction of the international classification of sleep disorders (ICSD-2) and the research diagnostic criteria (RDC). The DSM-5 introduced the new category of insomnia disorder, thus relinquishing the traditional dichotomy of primary versus secondary insomnia. Recent basic research indicates that genetic and epigenetic factors are involved in the etiology of insomnia; the so-called three P model (i.e. predisposing, precipitating and perpetuating factors) and the hyperarousal concept have gained much attention in trying to explain the pathophysiology of insomnia. With respect to the cognitive-behavioral therapy of insomnia (CBT-I), a plethora of empirical evidence supports the first-line character of this type of treatment for insomnia. Unfortunately, CBT-I is still administered to only a minority of afflicted patients, probably due to a lack of resources in the healthcare system. As a consequence, stepped-care models to improve insomnia therapy encompass self-help programs, internet-based treatment avenues, community centered activities (specially trained nurses) and as a last resort medical specialists/psychotherapists and sleep experts to deal with insomnia. PMID- 24346427 TI - [Hypnotics--state of the science]. AB - This article provides an overview of the indications and effects of sleep inducing drugs. Pharmacological treatment should only be considered in cases of insufficient response to non-pharmacological interventions. Benzodiazepines and benzodiazepine receptor agonists are indicated for the short-term treatment of acute insomnia. Due to the risk of tolerance and dependency, sedative antihistamines and antidepressants are widely used as long-term hypnotics. Other substances, including herbal compounds and melatonin have few side effects; however, the therapeutic efficacy is very limited. Currently, long-term data on the efficacy and tolerability of sleep-inducing substances are lacking. Specifically in cases of non-response to first line treatment, extended psychiatric and somatic evaluation and treatment of associated disorders are recommended. PMID- 24346428 TI - [Therapeutic drug monitoring in psychiatry. A brief summary of the new consensus paper by the task force on TDM of the AGNP]. AB - In October 2011 the Task Force Therapeutic Drug Monitoring of the Association for Neuropsychopharmacology and Pharmacopsychiatry (AGNP) published an update (Pharmacopsychiatry 2011, 44: 195-235) of the first version of the consensus paper on therapeutic drug monitoring (TDM) published in 2004. This article summarizes the essential statements to make them accessible to a wider readership in German speaking countries. PMID- 24346429 TI - [Evaluation of outpatient aftercare of forensic patients (S 63 StGB) in North Rhine-Westphalia, Germany]. AB - BACKGROUND: The quality and success of the aftercare treatment of forensic patients (S 63 StGB, Penal Code) are not only of concern to therapists and law courts dealing with the question of potentially dangerous behavior; apart from politicians and the general public it is also a matter of interest for workers in general and community psychiatry. METHODS: In an evaluation of forensic patients who were discharged from confinement (SS 67d 2, 6 and 67b StGB) into aftercare treatment between 2002 and 2006 in North Rhine-Westphalia, it was possible to collect data on recidivism from a total of 225 patients after an average follow up period of 4.4 years. Apart from gathering statistics concerning case history, diagnosis, offence committed and resulting confinement, a dynamic analysis of how they coped in differing day to day situations was carried out with 115 of the discharged patients. RESULTS: The frequency of offence recidivism by patients who were professionally accompanied throughout the aftercare period was significantly lower in comparison to earlier studies (without specialist supervision), particularly the number of sexual offences and violent crimes (7 from 225 - 3.1 %) were noticeably reduced. By comparing patients who reoffended with those showing socially acceptable behavior it was possible to determine specific features of protection and risk characteristics. CONCLUSIONS: Low offence recidivism indicated a high degree of aftercare effectiveness but there is room for improvement and further development in the existing system. The postdischarge prognosis factors and the typical pitfalls found in the study should be adequately taken into account in order to improve risk management in the aftercare setting and therefore subsequently ameliorate the chances of discharge for long neglected problematic patient groups, in particular patients with personality disorders involved in sexual offences. PMID- 24346430 TI - Heterovalent cation substitutional doping for quantum dot homojunction solar cells. AB - Colloidal quantum dots have emerged as a material platform for low-cost high performance optoelectronics. At the heart of optoelectronic devices lies the formation of a junction, which requires the intimate contact of n-type and p-type semiconductors. Doping in bulk semiconductors has been largely deployed for many decades, yet electronically active doping in quantum dots has remained a challenge and the demonstration of robust functional optoelectronic devices had thus far been elusive. Here we report an optoelectronic device, a quantum dot homojunction solar cell, based on heterovalent cation substitution. We used PbS quantum dots as a reference material, which is a p-type semiconductor, and we employed Bi-doping to transform it into an n-type semiconductor. We then combined the two layers into a homojunction device operating as a solar cell robustly under ambient air conditions with power conversion efficiency of 2.7%. PMID- 24346432 TI - Glioblastoma cell enrichment is critical for analysis of phosphorylated drug targets and proteomic-genomic correlations. AB - The quality of cancer genomic and proteomic data relies upon the quality of the clinical specimens examined. Here, we show that data derived from non microdissected glioblastoma multiforme tumor tissue is either masked or not accurate, producing correlations between genomic and proteomic data that lead to false classifications for therapeutic stratification. We analyzed the level of 133 key signaling proteins and phosphoproteins in laser capture microdissected (LCM) primary tumors from a study set of tissues used for the Cancer Genome Atlas (TCGA) profiling efforts, comparing the results to tissue-matched, nontumor cell enriched lysates from adjacent sections. Among the analytes, 44%, including targets for clinically important inhibitors, such as phosphorylated mTOR, AKT, STAT1, VEGFR2, or BCL2, differed between matched tumor cell-enriched and nonenriched specimens (even in tumor sections with 90% tumor cell content). While total EGFR protein levels were higher in tumors with EGFR mutations, regardless of tumor cell enrichment, EGFR phosphorylation was increased only in LCM-enriched tumor specimens carrying EGFR mutations. Phosphorylated and total PTEN, which is highly expressed in normal brain, was reduced only in LCM-enriched tumor specimens with either PTEN mutation or loss in PTEN copy number, with no differences observed in non-microdissected samples. These results were confirmed in an independent, non-microdissected, publicly available protein data set from the TCGA database. Our findings highlight the necessity for careful upfront cellular enrichment in biospecimens that form the basis for targeted therapy selection and for molecular characterization efforts such as TCGA. PMID- 24346434 TI - Self-promoted post-synthetic modification of metal-ligand M(2)L(3) mesocates. AB - Reactive alcohol functionality has been incorporated into a self-assembled M2L3 mesocate. Post-synthetic modification of this complex with suitable isocyanates is not only possible, but is self-catalyzed by multiple internal hydrogen bonds from the self-assembly. As the metal-ligand coordination is reversible at elevated temperature, the isomeric distribution of product changes upon reaction, due to the different steric bulk conferred on the assembly after the modification. PMID- 24346435 TI - Validation of the A&D BP UA-651 device for home blood pressure measurement according to the European Society of Hypertension International Protocol revision 2010. AB - The objective of this study was to determine the accuracy of the A&D BP UA-651 device for home blood pressure (BP) measurement according to the International Protocol of the European Society of Hypertension. Device evaluation was carried out in 33 patients. The mean age of the patients was 48.3+/-15.5 years, the mean systolic BP was 138.3+/-24.9 mmHg (range 90-180), the mean diastolic BP was 88.3+/-13.8 mmHg (range 60-108), and the mean arm circumference was 28.6+/-3.4 cm (range 23-36). The protocol requirements were followed precisely. The device passed all requirements, fulfilling the standards of the protocol. On average, the device underestimated the systolic BP by 0.4+/-4.4 mmHg and diastolic BP by 1.3+/-3.5 mmHg. The device-observer discrepancies were unrelated to patients' clinical characteristics. These data show that the A&D BP UA-651 device fulfilled the requirements for validation by the International Protocol and can be recommended for clinical use in the adult population. PMID- 24346431 TI - Collagen signaling enhances tumor progression after anti-VEGF therapy in a murine model of pancreatic ductal adenocarcinoma. AB - There is growing evidence that antiangiogenic therapy stimulates cancer cell invasion and metastasis. However, the underlying molecular mechanisms responsible for these changes have not been fully defined. Here, we report that anti-VEGF therapy promotes local invasion and metastasis by inducing collagen signaling in cancer cells. We show that chronic VEGF inhibition in a genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDA) induces hypoxia, a less differentiated mesenchymal-like tumor cell phenotype, TGF-beta expression, and collagen deposition and signaling. In addition, we show that collagen signaling is critical for protumorigenic activity of TGF-beta in vitro. To further model the impact of collagen signaling in tumors, we evaluated PDA in mice lacking Sparc, a protein that reduces collagen binding to cell surface receptors. Importantly, we show that loss of Sparc increases collagen signaling and tumor progression. Together, these findings suggest that collagen actively promotes PDA spread and that enhanced disease progression associated with anti-VEGF therapy can arise from elevated extracellular matrix-mediated signaling. PMID- 24346436 TI - Measurement with an automated oscillometric wrist device with position sensor leads to lower values than measurements obtained with an automated oscillometric arm device from the same manufacturer in elderly persons. AB - OBJECTIVE: Home blood pressure (BP) monitoring is recommended by several clinical guidelines and has been shown to be feasible in elderly persons. Wrist manometers have recently been proposed for such home BP measurement, but their accuracy has not been previously assessed in elderly patients. METHODS: Forty-eight participants (33 women and 15 men, mean age 81.3+/-8.0 years) had their BP measured with a wrist device with position sensor and an arm device in random order in a sitting position. RESULTS: Average BP measurements were consistently lower with the wrist than arm device for systolic BP (120.1+/-2.2 vs. 130.5+/-2.2 mmHg, P<0.001, means+/-SD) and diastolic BP (66.0+/-1.3 vs. 69.7+/-1.3 mmHg, P<0.001). Moreover, a 10 mmHg or greater difference between the arm and wrist device was observed in 54.2 and 18.8% of systolic and diastolic measures, respectively. CONCLUSION: Compared with the arm device, the wrist device with position sensor systematically underestimated systolic as well as diastolic BP. The magnitude of the difference is clinically significant and questions the use of the wrist device to monitor BP in elderly persons. This study points to the need to validate BP measuring devices in all age groups, including in elderly persons. PMID- 24346437 TI - Internationalization: new challenges for the development of science in nursing and health care. PMID- 24346438 TI - [Women working at university restaurants: life and work conditions and gender based violence]. AB - This is an exploratory and descriptive study with a quantitative approach that aimed to understand the social production and reproduction processes of women working at university restaurants and the occurrence and the magnitude of gender based violence committed against them by their intimate partners. The data were collected through semi-structured interviews. The analysis categories used were social production and reproduction, gender and gender-based violence. The interviewees held a subordinate social position during the productive and reproductive periods of their lives. Approximately 70% reported having experienced gender-based violence from an intimate partner (66% psychological violence, 36.3% physical violence and 28.6% sexual violence). Most of the health problems resulting from violence were related to mental health. The results indicate that the situation requires immediate interventions, mostly guided by the instrumentalization of these women and the support by the state and the university as appropriate to address violence. PMID- 24346439 TI - [Maternal mortality from hemorrhage in the State of Santa Catarina, Brazil]. AB - Hemorrhage represents a set of causes that focuses on women during the pregnancy and puerperal period, and that, with improper attention, results in death. The authors aimed to analyze maternal deaths related to hemorrhage that occurred in the state of Santa Catarina, Brazil. The data were obtained from the Mortality Information System and Live Births Information System from the Brazilian Ministry of Health. This was a descriptive study, in which 491 maternal deaths that occurred in the period 1997-2010 were analyzed. Of these, 61 were related to hemorrhage, corresponding to 12.42%; postpartum hemorrhage was the most prevalent cause, with 26 deaths, followed by placental abruption with 15, representing 67.21% of the cases. The maternal mortality from hemorrhage is a public health problem in the state of Santa Catarina, due to its high prevalence and the fact that its underlying causes are preventable. PMID- 24346440 TI - [Care in a birth center according to the recommendations of the World Health Organization]. AB - Birth centers are maternal care models that use appropriate technology when providing care to birthing women. This descriptive study aimed to characterize intrapartum care in a freestanding birth center, in light of the practices recommended by the World Health Organization (WHO), with 1,079 assisted births from 2006 to 2009 in the Sapopemba Birth Center, Sao Paulo, Brazil. Results included the use of intermittent auscultation (mean=7 controls); maternal positions during delivery: semi-sitting (82.3%), side-lying (16.0%), other positions (1.7%), oral intake (95.6%); companionship (93.3%); exposure to up to three vaginal examinations (85.4%), shower bathing (84.0%), walking (68.0%), massage (60.1%), exercising with a Swiss ball (51.7%); amniotomy (53.4%), oxytocin use during the first (31.0%) and second stages of labor (25.8%), bath immersion (29.3%) and episiotomy (14.1%). In this birth center, care providers used practices recommended by the WHO, although some practices might have been applied less frequently. PMID- 24346441 TI - [Human milk for neonatal pain relief during ophthalmoscopy]. AB - Ophthalmoscopy performed for the early diagnosis of retinopathy of prematurity (ROP) is painful for preterm infants, thus necessitating interventions for minimizing pain. The present study aimed to establish the effectiveness of human milk, compared with sucrose, for pain relief in premature infants subjected to ophthalmoscopy for the early diagnosis of ROP. This investigation was a pilot, quasi-experimental study conducted with 14 premature infants admitted to the neonatal intensive care unit (NICU) of a university hospital. Comparison between the groups did not yield a statistically significant difference relative to the crying time, salivary cortisol, or heart rate (HR). Human milk appears to be as effective as sucrose in relieving acute pain associated with ophthalmoscopy. The study's limitations included its small sample size and lack of randomization. Experimental investigations with greater sample power should be performed to reinforce the evidence found in the present study. PMID- 24346442 TI - [Intraclass reliability of the Alberta Infant Motor Scale in the Brazilian version]. AB - This study had as its objective to analyze the intraclass reliability of the Alberta Infant Motor Scale (AIMS), in the Brazilian version, in preterm and term infants. It was a methodological study, conducted from November 2009 to April 2010, with 50 children receiving care in two public institutions in Fortaleza, Ceara, Brazil. Children were grouped according to gestational age as preterm and term, and evaluated by three evaluators in the communication laboratory of a public institution or at home. The intraclass correlation indices for the categories prone, supine, sitting and standing ranged from 0.553 to 0.952; most remained above 0.800, except for the standing category of the third evaluator, in which the index was 0.553. As for the total score and percentile, rates ranged from 0.843 to 0.954. The scale proved to be a reliable instrument for assessing gross motor performance of Brazilian children, particularly in Ceara, regardless of gestational age at birth. PMID- 24346443 TI - [Creation and validation of an instrument to identify nursing activities in pediatric wards: information for determining workload]. AB - The aim of this study was to develop and validate an instrument for identifying nursing activities performed in a pediatric ward and to provide a basis for defining the workload of these units. The instrument was developed by selecting the activities relevant to pediatric nursing from the Nursing Intervention Classification and then submitting them to a panel of judges for validation. The panel considered the selected activities relevant and representative of pediatric nursing practice. Now that representative activities for the nursing workload have been identified, we envision new studies to verify their usefulness in practice. Determining the amount of time each activity takes to perform will help to develop a system for measuring the workloads of nursing teams in pediatric wards. PMID- 24346444 TI - [Process and results of the development of an ICNP(r) Catalogue for Cancer Pain]. AB - This was a methodological study conducted to describe the process and results of the development of an International Classification for Nursing Practice (ICNP(r)) Catalogue for Cancer Pain. According to the International Council of Nurses (ICN), this catalogue contains a subset of nursing diagnoses, outcomes, and interventions to document the implementation of the nursing process in cancer patients. This catalogue was developed in several steps according to the guidelines recommended by the ICN. As a result, 68 statements on nursing diagnoses/outcomes were obtained, which were classified according to the theoretical model for nursing care related to cancer pain into physical (28), psychological (29), and sociocultural and spiritual (11) aspects. A total of 116 corresponding nursing interventions were obtained. The proposed ICNP(r) Catalogue for Cancer Pain aims to provide safe and systematic orientation to nurses who work in this field, thus improving the quality of patient care and facilitating the performance of the nursing process. PMID- 24346445 TI - [Nursing diagnoses and outcomes related to the circulatory-system terms (ICNP(r)) represented in an ontology]. AB - The aim of the present study was to develop titles of Nursing Diagnoses and Outcomes (ND/NO) through the relationship between the terms of the Focus axis, limited to the Circulatory System Process, and the terms of other ICNP(r) axes and to integrate these terms into an ontology. Titles were developed linking 17 terms of the focus axis, which were evaluated by expert nurses in five Brazilian cities. Titles whose use concordance was above 0.80 were included in the ontology. In total, 89 titles for ND/NO were supported in the literature, and 19 were not supported; 37 were assessed as eligible for use in healthcare practice and were included in the ontology. The construction of ND/NO titles based on the ICNP(r) and using a formal representation of knowledge is a task that requires deepening concepts used for nursing and adequate classification revisions. The elaborated titles will facilitate the composition of diagnostics that are more consistent with practice. PMID- 24346446 TI - [Content validation of the dimensions constituting non-adherence to treatment of arterial hypertension]. AB - The objective of the study was to validate the content of the dimensions that constituted nonadherence to treatment of arterial systemic hypertension. It was a methodological study of content validation. Initially an integrative review was conducted that demonstrated four dimensions of nonadherence: person, disease/treatment, health service, and environment. Definitions of these dimensions were evaluated by 17 professionals, who were specialists in the area, including: nurses, pharmacists and physicians. The Content Validity Index was calculated for each dimension (IVCi) and the set of the dimensions (IVCt), and the binomial test was conducted. The results permitted the validation of the dimensions with an IVCt of 0.88, demonstrating reasonable systematic comprehension of the phenomena of nonadherence. PMID- 24346447 TI - Validity and reliability of a questionnaire on knowledge of cardiovascular risk factors for use in Brazil. AB - Using a sample of patients with coronary artery disease, this methodological study aimed to conduct a cross-cultural adaptation and validation of a questionnaire on knowledge of cardiovascular risk factors (Q-FARCS), lifestyle changes, and treatment adherence for use in Brazil. The questionnaire has three scales: general knowledge of risk factors (RFs); specific knowledge of these RFs; and lifestyle changes achieved. Cross-cultural adaptation included translation, synthesis, back-translation, expert committee review, and pretesting. Face and content validity, reliability, and construct validity were measured. Cronbach's alpha for the total sample (n = 240) was 0.75. Assessment of psychometric properties revealed adequate face and content validity, and the construct revealed seven components. It was concluded that the Brazilian version of Q-FARCS had adequate reliability and validity for the assessment of knowledge of cardiovascular RFs. PMID- 24346448 TI - [Impact of the disease: acceptability, ceiling and floor effects and reliability of an instrument on heart failure]. AB - This study evaluated the acceptability, ceiling/floor effects, and the reliability of the instrument for measuring the Impact of the Disease on the Daily Life of Patients with Valvular Disease (IDCV) when applied to 135 patients with heart failure (HF). Acceptability was evaluated by the percentage of unanswered items and by the proportion of patients who responded to all items; the ceiling/floor effects by the percentage of patients who scored in the top of 10% best and worst results of the scale, respectively. Reliability was estimated by internal consistency (Cronbach's alpha coefficient) and stability of the measure (intraclass correlation coefficient - ICC). All patients responded to all items. Ceiling/floor effects evidenced were of moderate magnitude. The Cronbach's alpha was satisfactory for the majority of the domains and ICC> 0.90 in all the domains. The IDCV proved to be an easy to understand questionnaire, with evidence of reliability in patients with HF. PMID- 24346449 TI - [Improving patient safety: how and why incidences occur in nursing care]. AB - The present investigation was a cross-sectional, quantitative research study analyzing incidents associated with nursing care using a root-cause methodological analysis. The study was conducted in a public hospital intensive care unit (ICU) in Santiago de Chile and investigated 18 incidents related to nursing care that occurred from January to March of 2012. The sample was composed of six cases involving medications and the self-removal of therapeutic devices. The contributing factors were related to the tasks and technology, the professional work team, the patients, and the environment. The analysis confirmed that the cases presented with similar contributing factors, thereby indicating that the vulnerable aspects of the system are primarily responsible for the incidence occurrence. We conclude that root-cause analysis facilitates the identification of these vulnerable points. Proactive management in system-error prevention is made possible by recommendations. PMID- 24346450 TI - [Usage analysis of the Nursing Activities Score in two Spanish ICUS]. AB - The aim of this study was to analyze the discourse of health managers on aspects related to delay in tuberculosis diagnosis. This was a qualitative research study, conducted with 16 Family Health Unit managers. The empirical data were obtained through semi-structured interviews. The analysis was based on the theoretical framework of the French school of discourse analysis. According to the managers' statements, the delay in tuberculosis diagnosis is related to patient and health service aspects. As for patient aspects, managers report fear, prejudice and lack of information as factors that may promote a delayed diagnosis. Regarding health service aspects, structural problems and lack of professional skills were reported. The discourse of managers should be considered to qualify tuberculosis control actions and to prevent delays in diagnosis. PMID- 24346451 TI - [Comfort of the patient's family in an Intensive Care Unit related to welcoming]. AB - This study aimed to identify the level of comfort of families of patients in a critical health condition related to the welcoming practices performed by the hospital staff. Interviews were conducted with 250 relatives in hospitals of the state Bahia, using a Likert scale. Data were analyzed as percentages and quartiles. For nine of the 12 statements of the scale, most relatives scored their comfort level between very and totally comfortable, median of 4,revealing kindness, tranquility and friendly communication with family members. More than half of the sample scored its level as not at all to more or less comfortable, median of 3, for statements about demonstration of interest towards the relative by the staff and flexible visiting of the patient. The necessity of greater interest of the team in the condition and needs of the family was observed. Promoting comfort from the dimension of welcoming demands interdisciplinary actions grounded in humanistic philosophy, in which the nurse has an important role to play. PMID- 24346452 TI - [Use of health services by residents at a seniors-only living facility]. AB - The objective of the study was to compare the use of medical and dental services by seniors residing at a seniors-only living facility and in the general community. It was a quantitative study, among 50 residents of the living facility and 173 in the general community. The data were collected between November 2011 and February 2012 through a questionnaire, and subjected to statistical analysis. Performance of clinical exams and satisfaction with health services was greater among seniors living in the general community; however, physical therapy treatment was more common among those living in the facility. The use of medical and dental services showed a statistically significant difference. The seniors in both groups need oral health monitoring and those living in the facility also require coverage by the Family Health Strategy. The presence of professionals with the right profile to adequately serve residents and the network of available services are determining factors for the success of this new housing policy. PMID- 24346454 TI - [Patients' knowledge of diabetes five years after the end of an educational program]. AB - We present a cross-sectional study that aims to describe the sociodemographic and clinical conditions of individuals with diabetes mellitus and to analyze their knowledge of treatment five years after the end of an educational program in which they took part. In 2010, 40 individuals who had participated in a diabetes educational program for 12 months in 2005 at a primary care service were interviewed. A form was used for data collection that included their knowledge of the notion, physiopathology, and treatment of the disease; exercise; nutrition; foot care; self-monitoring of capillary blood glucose at home; hypoglycemia; chronic complications; special situations; and family support. The results showed that the volunteers incorporated the information about the notion, physiopathology, and treatment of the disease; exercise; foot care; self monitoring; care associated with hypoglycemia; chronic complications; and special situations. In contrast, nutrition and family support require further reinforcement. It is concluded that five years after the end of the educational program, the participants kept most of the information provided. PMID- 24346453 TI - [Burden in family caregivers of the elderly: prevalence and association with characteristics of the elderly and the caregivers]. AB - A cross-sectional, epidemiological study aimed to estimate the prevalence of burden among family caregivers of impaired elderly residents in the city of Joao Pessoa, and to identify associations between the mean burden and social and demographic characteristics of the elderly and the caregivers. A total number of 240 elderly residents in a previously drawn census tract participated in this research. The sample was composed of 52 elderly and their caregivers. For data collection, a questionnaire was applied with questions on social and demographic characteristics of elderly and caregivers, and the Burden Interview Scale was used. Results showed a high prevalence of burden among caregivers (84.6%), in which a statistically significant association was found with the following characteristics: retired elderly, elderly as head of family, spousal caregivers, and caregivers with less education. The findings of this study may contribute to the development of activities focused on formal and emotional support for the caregivers. PMID- 24346455 TI - [Evaluation of patients with stroke monitored by home care programs]. AB - The purpose of this study was to evaluate the patient with a stroke in home treatment, investigating physical capacity, mental status and anthropometric analysis. This was a cross-sectional study conducted in Fortaleza/CE, from January to April of 2010. Sixty-one individuals monitored by a home care program of three tertiary hospitals were investigated, through interviews and the application of scales. The majority of individuals encountered were female (59%), elderly, bedridden, with a low educational level, a history of other stroke, a high degree of dependence for basic (73.8%) and instrumental (80.3 %) activities of daily living, and a low cognitive level (95.1%). Individuals also presented with tracheostomy, gastric feeding and urinary catheter, difficulty hearing, speaking, chewing, swallowing, and those making daily use of various medications. It was concluded that home care by nurses is an alternative for care of those individuals with a stroke. PMID- 24346456 TI - [Ability for self-care and its association with sociodemographic factors of people with spinal cord injury]. AB - This study aimed to verify the association between self-care ability and sociodemographic factors of people with spinal cord injury (SCI). It was a cross sectional study, conducted in 2012, in all 58 Basic Health Units of Natal/RN, Brazil. Seventy-three subjects completed a sociodemographic form and Self-Care Agency Scale. Statistical analyses were performed using SPSS,including Cronbach's Alpha, Chi-square, Fisher's and contingency coefficient tests. The Cronbach's alpha was 0.788. The result verified that sex (p = 0.028), religion (p <0.001), education (p = 0.046), current age (p = 0.027), SCI time (p = 0.020) and the SCI type (p = 0.012) were variables associated with self-care ability of the subjects. It was concluded that sociodemographic factors may interfere with the self-care ability of persons with SCI, and nurses should consider this aspect during the execution of the nursing process. PMID- 24346457 TI - [Development of assistive technology for the visually impaired: use of the male condom]. AB - The objectives were to develop and evaluate an assistive technology for the use of the male condom by visually impaired men. It was a technology development study with the participation of seven subjects. Three workshops were performed between April and May of 2010; they were all filmed and the statements of the participants were transcribed and analyzed by content. Three categories were established: Sexuality of the visually impaired; Utilization of the text, For avoiding STDs, condoms we will use, divided in two subcategories, Concept discussion and Text evaluation; and Construction of a simple penile prosthesis. The knowledge transmitted related to STD, the utilization of the condom on the penile prosthesis made by the subjects themselves, and the interaction during the workshops were effective factors for the study. In the context of sexual health, the necessity of developing works involving the visually impaired was noted, addressing sexually transmitted diseases and focusing on the use of the condom by this population. PMID- 24346458 TI - [The discourse of health managers on aspects related to the delay in tuberculosis diagnosis]. AB - The aim of this study was to analyze the discourse of health managers on aspects related to delay in tuberculosis diagnosis. This was a qualitative research study, conducted with 16 Family Health Unit managers. The empirical data were obtained through semi-structured interviews. The analysis was based on the theoretical framework of the French school of discourse analysis. According to the managers' statements, the delay in tuberculosis diagnosis is related to patient and health service aspects. As for patient aspects, managers report fear, prejudice and lack of information as factors that may promote a delayed diagnosis. Regarding health service aspects, structural problems and lack of professional skills were reported. The discourse of managers should be considered to qualify tuberculosis control actions and to prevent delays in diagnosis. PMID- 24346459 TI - [Knowledge and attitudes of nurses towards alcohol and related problems: the impact of an educational intervention]. AB - An exploratory study of quasi-experimental approach that aimed to verify the impact of an educational intervention on attitudes and knowledge of nurses towards alcohol use and associated problems. The sample included 185 nurses, divided into two groups: 84 submitted to a training course and formed the experimental group. Data were collected through a knowledge survey and an attitude scale. The attitudes of the participants of both groups were positive. There were no significant differences between groups in relation to knowledge. The strongest predictors of positive attitudes were possessed preparation to act with chemical dependents (OR = 2.18), "have received increased workload during graduation on the theme, 'alcohol and other drugs'" (OR = 1.70), and "completed graduate school" (OR = 2.59). The educational intervention had a positive impact on the attitudes of nurses towards alcoholics, work and interpersonal relationships with such clientele. PMID- 24346460 TI - [Work-related stress according to the Demand-Control Model and Minor Psychic Disorder in nursing workers]. AB - This was a cross-sectional study that aimed to assess the association between work-related stress according to the Demand-Control Model, and the occurrence of Minor Psychic Disorder (MPD) in nursing workers. The participants were 335 professionals, out of which 245 were nursing technicians, aged predominantly between 20 and 40 years. Data were collected using the Job Stress Scale and the Self-Reporting Questionnaire-20. The analysis was performed using descriptive and analytical statistics. The prevalence of suspected MPD was 20.6%. Workers classified in the quadrants active job and high strain of the Demand-Control Model presented higher potential for developing MPD compared with those classified in the quadrant low strain. In conclusion, stress affects the mental health of workers and the aspects related to high psychological demands and high control still require further insight in order to understand their influence on the disease processes of nursing workers. PMID- 24346461 TI - [Stress among nurses: an examination of salivary cortisol levels on work and day off]. AB - The present study evaluates the use of salivary cortisol concentration as a physiological index of the stress level among nurses on their work day and day off and correlates it with the questionnaire used to measure occupational stress in nurses (Inventario de Estresse em Enfermeiros - IEE). This is a comparative, cross-sectional descriptive study in which sociodemographic data, IEE results and salivary cortisol levels were used. Fifty-seven nurses participated in the study (80.7% females and a mean age of 37.1 years old). The IEE average score was 124.5. The average cortisol level was 564.1 ng/m on work day and 354.1 ng/mL on day off. Nurses who had double workdays presented high values of salivary cortisol during the work day (638.1 ng/mL). In conclusion, salivary cortisol identified the nurses' stress level, and differences were found between a work day and day off. On the nurses' day off, their salivary cortisol levels and stress scores were lower. PMID- 24346462 TI - [Attitudes, knowledge, and opinions regarding mental health among undergraduate nursing students]. AB - A cross-sectional study involving 235 subjects was conducted in 2011 to compare the opinions of nursing students regarding mental illness and related care practices at two institutions in the state of Parana, Brazil. Following approval by the ethics committee, data collection was initiated using an instrument containing questions regarding the importance of personal characteristics, knowledge of mental health, and the Opinions about Mental Illness (OMI) scale. Statistical analyses, including the Mann-Whitney test, Chi-squared test, and Spearman correlation at , were performed using SPSSv.15. The students exhibited significantly different characteristics only for Benevolence. Regarding the importance of knowledge about mental health, in comparison with students from the State University of Londrina (Universidade Estadual de Londrina - UEL), students at the State University of Maringa (Universidade Estadual de Maringa - UEM) considered psychological aspects more comprehensively than technical knowledge. We conclude that there are differences between students at these institutions in terms of knowledge and the factor Benevolence. Further studies are necessary to identify the underlying causes of such differences. PMID- 24346463 TI - [Political-ethical skill development in nursing undergraduates]. AB - This research aimed to identify political-ethical skills developed in a training process compatible with the expected profile set by the National Curriculum Guidelines for the Undergraduate Nursing Degree. A case study was conducted with units represented by 32 former students from a particular religious teaching institution who already were in the job market. The content of the interviews was analyzed using the thematic analysis technique, which resulted in the following categories: "Political-ethical skills in the formative process" and "Political ethical skills as a product of the educational process." From the former students' perspective, these categories reinforced the social role of the nurse and the need for students to be reflective, understanding and participative in the transformation of society. PMID- 24346464 TI - [Expansion of undergraduate courses in nursing: dilemmas and contradictions facing the labor market]. AB - We sought to analyze, from the perspective of professors and students, the reasons and consequences of the expansion of undergraduate courses in nursing, discussing the dilemmas and the contradictions confronting the labor market. It was a qualitative study with data obtained from focus groups, conducted in 18 undergraduate nursing courses in the state of Minas Gerais, during the period of February to October of 2011. The narratives were submitted to critical discourse analysis. The results indicated that the education of the nurse was permeated by insecurity as to the future integration into the labor market. The insecurity translates into dilemmas that referred to employability and the precariousness of the working conditions. In this context, employment in the family health strategy emerges as a mirage. One glimpses the need for a political agenda with the purpose of discussion about education, the labor market and the determinants of these processes. PMID- 24346465 TI - [Edith Magalhaes Fraenkel: the greatest figure of Brazilian nursing]. AB - The present study aimed to describe and analyze the career of Edith Magalhaes Fraenkel and her important legacy to Brazilian nursing. The methodology chosen was a documentary analysis of her areas of participation based on documents of the Historical Cultural Center of Iberian-American School of Nursing of the University of Sao Paulo (Universidade de Sao Paulo, USP) and in the Rectory of the same University. The following thematic topics were categorized: preparation for leadership, moving to Sao Paulo, creation of the School of Nursing of USP, event organization, and unique developments at the end of her career. We conclude that Mrs. Edith Fraenkel is the most important figure of Brazilian nursing, thanks to her immeasurable work as a leader of the profession, nationally and internationally. PMID- 24346466 TI - [The use of the quality model of Parasuraman, Zeithaml and Berry in health services]. AB - This is an article about the theoretical model for assessing quality in health services proposed by Parasuraman, Zheitaml and Berry, in order to measure the degree of satisfaction of users. This model is based on the analysis of expectations and perceptions of users of health services, by means of five dimensions: tangibility, reliability, responsiveness, assurance and empathy. From the difference between what is expected by the user and the service offered, gaps or shortcomings are derived that may be the main obstacle for users to perceive the provision of such services with quality. It was observed that the use of the psychometric scale called Service Quality (SERVQUAL) in some studies about satisfaction, obtained very favorable results in the institutions in which it was employed. The analysis revealed the need to improve the existing models of evaluation, as well as the importance of measuring user satisfaction in health institutions. PMID- 24346467 TI - [The strategic impact of clinical practice guidelines in nursing on the managerial function of supervision]. AB - Clinical practice guidelines in nursing (CPG-N) are tools that allow the necessary knowledge that frequently remains specialist-internalised to be made explicit. These tools are a complement to risk adjustment systems (RAS), reinforcing their effectiveness and permitting a rationalisation of healthcare costs. This theoretical study defends the importance of building and using CPG-Ns as instruments to support the figure of the nursing supervisor in order to optimise the implementation of R&D and hospital quality strategies, enabling clinical excellence in nursing processes and cost-efficient reallocation of economic resources through their linear integration with SARs. PMID- 24346468 TI - Protective effects of probiotic Lactobacillus rhamnosus IMC501 in mice treated with PhIP. AB - The aim of the present study was to investigate the antigenotoxic properties of the probiotic Lactobacillus rhamnosus IMC501; DNA damage was induced by one representative food mutagen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Mice were treated orally with suspensions of lactobacilli for 10 days before administration of food mutagen. During the treatment, the abundance of lactobacilli in feces, as assessed by qPCR analysis, increased, whereas beta glucuronidase and N-acetyl-beta-glucosaminidase activities decreased. The extent of DNA damage was measured in colon and liver cells by comet assay. In colonocytes, diet supplementation with IMC501 resulted in a significant inhibition of DNA damage induced by PhIP. The results obtained in this in vitro study suggest that Lactobacillus rhamnosus IMC501 used as a dietary supplement can provide a useful integration of antimutagen food components of the normal diet, which are generally lower than the protective level. PMID- 24346469 TI - Lycorine: a potential broad-spectrum agent against crop pathogenic fungi. AB - A screening test showed that lycorine exhibited significant antifungal activity against 24 pathogenic crop fungi at concentrations of 500 MUg/ml and 100 MUg/ml, respectively. Fusarium graminearum was selected for antifungal mechanism studies by observing its mycelial morphology and investigating the variations in its conductivity. In addition, the substance absorption and metabolism of F. graminearum were explored. The mechanism was revealed as being one by which lycorine destroyed the cellular membrane and further influenced substance absorption and cell metabolism. PMID- 24346470 TI - Development of a novel immunochromatographic assay for rapid detection of VanA ligase-producing vancomycin-resistant enterococci. AB - We developed a novel immunochromatographic assay (ICA) (EZ-Step VanA rapid kit; Dinona, Korea) for the detection of VanA ligase from vancomycin-resistant enterococci (VRE). Of eight monoclonal antibodies screened by ELISAs, the VanA ligase ICA constructed with 1H9 plus 3G11 showed the greatest reactivity. The detection limit of the kit was 6.3 * 10(6) CFU per test. Of 127 vancomycin resistant microorganisms, 100 vanA VRE were positive in the VanA ligase ICA, and 27 non-vanA vancomycin-resistant isolates were negative. These results were consistent with those of the PCR analyses. Thus, our ICA is a reliable and easy to-use immunological assay for detecting VanA-producing VRE in clinical laboratories. PMID- 24346471 TI - Use of in vivo-induced antigen technology to identify in vivo-expressed genes of Campylobacter jejuni during human infection. AB - Campylobacter jejuni is a prevalent foodborne pathogen worldwide. Human infection by C. jejuni primarily arises from contaminated poultry meats. Genes expressed in vivo may play an important role in the pathogenicity of C. jejuni. We applied an immunoscreening method, in vivo-induced antigen technology (IVIAT), to identify in vivo-induced genes during human infection by C. jejuni. An inducible expression library of genomic proteins was constructed from sequenced C. jejuni NCTC 11168 and was then screened using adsorbed, pooled human sera obtained from clinical patients. We successfully identified 24 unique genes expressed in vivo. These genes were implicated in metabolism, molecular biosynthesis, genetic information processing, transport, and other processes. We selected six genes with different functions to compare their expression levels in vivo and in vitro using real-time RT-PCR. The results showed that the selected six genes were significantly upregulated in vivo but not in vitro. In short, these identified in vivo-induced genes may contribute to human infection of C. jejuni, some of which may be meaningful vaccine candidate antigens or diagnosis serologic markers for campylobacteriosis. IVIAT may present a significant and efficient method for understanding the pathogenicity mechanism of Campylobacter and for finding targets for its prevention and control. PMID- 24346473 TI - Serum concentrations of cholesterol, apolipoprotein A-I and apolipoprotein B in a total of 1694 meat-eaters, fish-eaters, vegetarians and vegans. AB - BACKGROUND/OBJECTIVES: The objective of this study was to describe serum lipid concentrations, including apolipoproteins A-I and B, in different diet groups. SUBJECTS/METHODS: A cross-sectional analysis of a sample of 424 meat-eaters, 425 fish-eaters, 423 vegetarians and 422 vegans, matched on sex and age, from the European Prospective Investigation into Cancer and Nutrition-Oxford cohort. Serum concentrations of total, and high-density lipoprotein (HDL) cholesterol, as well as apolipoproteins A-I and B were measured, and serum non-HDL cholesterol was calculated. RESULTS: Vegans had the lowest body mass index (BMI) and the highest and lowest intakes of polyunsaturated and saturated fat, respectively. After adjustment for age, alcohol and physical activity, compared with meat-eaters, fish-eaters and vegetarians, serum concentrations of total and non-HDL cholesterol and apolipoprotein B were significantly lower in vegans. Serum apolipoprotein A-I concentrations did not differ between the diet groups. In males, the mean serum total cholesterol concentration was 0.87 mmol/l lower in vegans than in meat-eaters; after further adjustment for BMI this difference was 0.76 mmol/l. In females, the difference in total cholesterol between these two groups was 0.6 mmol/l, and after further adjustment for BMI was 0.55 mmol/l. [corrected]. CONCLUSIONS: In this study, which included a large number of vegans, serum total cholesterol and apolipoprotein B concentrations were lower in vegans compared with meat-eaters, fish-eaters and vegetarians. A small proportion of the observed differences in serum lipid concentrations was explained by differences in BMI, but a large proportion is most likely due to diet. PMID- 24346474 TI - Follow-up of bone mineral density and body composition in adolescents with restrictive anorexia nervosa: role of dual-energy X-ray absorptiometry. AB - BACKGROUND/OBJECTIVES: Restrictive Anorexia nervosa (ANR) is an eating disorder (ED) characterized by a low bone mineral content (BMC) and by an alteration in body composition (reduction and abnormal distribution of fat mass-FM and lean mass-LM). The aim of our study was to address whether bone and body composition changes could be influenced by hormonal status and sport in female adolescents with restrictive anorexia nervosa-ANR. SUBJECTS/METHODS: Prospective study on 79 adolescents with ANR submitted to Dual Energy X-Ray Absorptiometry-DXA at baseline-T0 and after 12 months-T12. Among the 46/79-58.2% patients that completed the study, we evaluated total and regional FM and LM%, as well as lumbar bone mineral density (BMD) and Z-score, linking them to clinical variables: menarche/amenorrhea/hormonal therapy and physical activity. RESULTS: At T0: body mass index (BMI)=16.4+/-1.4 kg/m2 with low levels of FM% (21.7+/-5.7) low BMC in 12/46-26.0% (mean Z-score: -1.21+/-1.27, with higher values related to physical activity-P=0.001). At T12: a significant increase in BMI-P=0.001, with LM reduction and FM increase (more evident in the trunk-P<0.001); regarding bone, no significant changes were observed, though a tendency in terms of improvement associated with resumption of menses. CONCLUSIONS: After 1 year, weight recovery was not associated with a reestablishment of bone values; by contrast, it was associated with an increase and a distortion in FM distribution, more evident in trunk region (potential and adjunctive risk factor for the relapse of the psychiatric condition). The complexity of these clinical findings suggested DXA, a low-dose and low-cost technique, in long-term monitoring of ANR patients. PMID- 24346475 TI - Trends in the prevalence of childhood overweight and obesity according to socioeconomic status: Spain, 1987-2007. AB - BACKGROUND/OBJECTIVES: To ascertain trends in the prevalence of overweight and obesity among Spanish children and adolescents according to the socioeconomic status of the family household and area of residence across the period 1987-2007. SUBJECTS/METHODS: For study purposes, data were drawn from the 1987, 1995, 1997, 2001 and 2007 Spanish National Health Surveys. Overweight and obesity were estimated on the basis of body mass index. The following indicators of socioeconomic status were used: educational level of primary household earner and per capita income of province of residence. The statistical significance of the trend in the prevalence of overweight and obesity was assessed for each category of socioeconomic status. The chi2 test for trend was used in the case of educational level and a linear regression in the case of per capita income of province of residence. RESULTS: Although the prevalence of overweight and obesity had levelled off among boys and girls aged 5 to 9 years, it nevertheless showed a significant upward trend among those aged 10 to 15 years from families whose primary household earner had a lower educational level. The prevalence of overweight among boys in this last group was 13.1% in 1987 and 31.5% in 2007. From 1997 onwards, the prevalence of overweight and obesity among boys and girls aged 10 to 15 years increased in both the richest and the remaining provinces, although the magnitude of this increase was greater in the latter. Specifically, in these provinces the prevalence increased from 18 to 28.9% over the period of study. CONCLUSIONS: The prevalence of overweight and obesity in the childhood population in Spain has stabilised, except among adolescents, whether from lower income families or lower-income areas, among whom a rising trend is in evidence. PMID- 24346476 TI - White light emission by a lanthanide doped Sm(III) framework constructed from 4 sulfobenzoate and 1H-imidazo[4,5-f][1,10]-phenanthroline. AB - The 2D isostructural lanthanide-organic frameworks [Ln(4-SBA)(IP)OH] . 1.5H2O (Ln = Sm 1, Eu, 2 Gd3 and Tb 4 ; 4-SBA = 4-sulfobenzoate and IP = 1H-imidazo[4,5 f][1,10]-phenanthroline) display different luminescent behavior. White light emission was realized by introducing single dopant Eu(III) and codopants Eu(III)/Gd(III) or Eu(III)/Tb(III) into the Sm(III) framework for the first time. PMID- 24346477 TI - Intraoperative migration of a foreign body within the tendon sheath of the flexor pollicis longus. PMID- 24346478 TI - The orf virus: a case report. PMID- 24346479 TI - Identification and mapping of a novel dominant resistance gene, TuRB07 to Turnip mosaic virus in Brassica rapa. AB - KEY MESSAGE: A novel dominant resistance gene, TuRB07, was found to confer resistance to an isolate of TuMV strain C4 in B. rapa line VC1 and mapped on the top of chromosome A06. The inheritance of resistance to Turnip mosaic virus in Brassica rapa was investigated by crossing the resistant line, VC1 with the susceptible line, SR5, and genotyping and phenotyping diverse progenies derived from this cross. Both a doubled haploid population, VCS3M-DH, an F2 and two BC1 (F1 * VC1 and F1 * SR5) populations were created. Population tests revealed that the resistance to the TuMV C4 isolate in B. rapa is controlled by a single dominant gene. This resistance gene, TuRB07 was positioned on the top of linkage group A06 of the B. rapa genome through bulk segregation analysis and fine mapping recombinants in three doubled haploid- and one backcross population using microsatellite markers developed from BAC end sequences. Within the region between the two closely linked markers flanking TuRB07, H132A24-s1, and KS10960, in the Chiifu reference genome, two genes encoding nucleotide-binding site and leucine-rich repeat proteins with a coiled-coil motif (CC-NBS-LRR), Bra018862 and Bra018863 were identified as candidate resistance genes. The gene Bra018862 is truncated, but the gene Bra018863 has all the domains to function. Furthermore, the analysis of structural variation using resequencing data of VC1 and SR5 revealed that Bra018863 might be a functional gene because the gene has no structural variation in the resistant line VC1 when compared with Chiifu, whereas at the other NBS-LRR genes large deletions were identified in the resistant line. Allelic differences of Bra018863 were found between VC1 and SR5, supporting the notion that this gene is a putative candidate gene for the virus resistance. PMID- 24346480 TI - Identification of the key stages for sex determination in the silkworm, Bombyx mori. AB - In general, the master switch gene for sex determination is expressed for a limited period during the early embryonic stage. To increase our understanding of the sex determination mechanism in Bombyx mori, it is important to understand when sex determination takes place. To examine the key stages for sex determination in this insect, we focused on the expression patterns of Bmdsx (a double-switch gene in the sex determination cascade of B. mori) and BmIMP (a gene expressed specifically in males involved in male-specific splicing of Bmdsx). Reverse transcription PCR (RT-PCR) analysis revealed that male-type Bmdsx expression was observed in females at 27 and 29 h after oviposition (hao), and finally disappeared at 32 hao. Moreover, BmIMP mRNA was also expressed in these females, and its expression level was comparable to that of the male-type Bmdsx mRNA. These results demonstrated that female embryos before 32 hao can show male type expression of Bmdsx and BmIMP, suggesting that sex determination occurs between 29 and 32 hao, which correspond to the developmental stages from the head lobe differentiation to spoon-shaped embryo stages. This also suggests that the master switch gene for sex determination of B. mori is expressed in females during this period and represses the male-specific mode of expression in sex determining genes. PMID- 24346481 TI - Shape-controlled synthesis of nanocarbons through direct conversion of carbon dioxide. AB - Morphology control of carbon-based nanomaterials (nanocarbons) is critical to practical applications because their physical and chemical properties are highly shape-dependent. The discovery of novel shaped nanocarbons stimulates new development in carbon science and technology. Based on direct reaction of CO2 with Mg metal, we achieved controlled synthesis of several different types of nanocarbons including mesoporous graphene, carbon nanotubes, and hollow carbon nanoboxes. The last one, to our knowledge, has not been previously reported to this date. The method described here allows effective control of the shape and dimensions of nanocarbons through manipulation of reaction temperature. The formation mechanism of nanocarbons is proposed. As a proof of concept, the synthesized nanocarbons are used for electrodes in symmetrical supercapacitors, which exhibit high capacitance and good cycling stability. The reported protocols are instructive to production of nanocarbons with controlled shape and dimensions which are much desirable for many practical applications. PMID- 24346483 TI - A strategic approach to recharging lithium-sulphur batteries for long cycle life. AB - The success of rechargeable lithium-ion batteries has brought indisputable convenience to human society for the past two decades. However, unlike commercialized intercalation cathodes, high-energy-density sulphur cathodes are still in the stage of research because of the unsatisfactory capacity retention and long-term cyclability. The capacity degradation over extended cycles originates from the soluble polysulphides gradually diffusing out of the cathode region. Here we report an applicable way to recharge lithium-sulphur cells by a simple charge operation control that offers tremendous improvement with various lithium-sulphur battery systems. Adjusting the charging condition leads to long cycle life (over 500 cycles) with excellent capacity retention (>99%) by inhibiting electrochemical reactions along with severe polysulphide dissolution. This charging strategy and understanding of the reactions in different discharge steps will advance progress in the development of lithium-sulphur batteries. PMID- 24346482 TI - Microglial proliferation in the brain of chronic alcoholics with hepatic encephalopathy. AB - Hepatic encephalopathy (HE) is a common complication of chronic alcoholism and patients show neurological symptoms ranging from mild cognitive dysfunction to coma and death. The HE brain is characterized by glial changes, including microglial activation, but the exact pathogenesis of HE is poorly understood. During a study investigating cell proliferation in the subventricular zone of chronic alcoholics, a single case with widespread proliferation throughout their adjacent grey and white matter was noted. This case also had concomitant HE raising the possibility that glial proliferation might be a pathological feature of the disease. In order to explore this possibility fixed postmortem human brain tissue from chronic alcoholics with cirrhosis and HE (n = 9), alcoholics without HE (n = 4) and controls (n = 4) were examined using immunohistochemistry and cytokine assays. In total, 4/9 HE cases had PCNA- and a second proliferative marker, Ki-67-positive cells throughout their brain and these cells co-stained with the microglial marker, Iba1. These cases were termed 'proliferative HE' (pHE). The microglia in pHEs displayed an activated morphology with hypertrophied cell bodies and short, thickened processes. In contrast, the microglia in white matter regions of the non-proliferative HE cases were less activated and appeared dystrophic. pHEs were also characterized by higher interleukin-6 levels and a slightly higher neuronal density . These findings suggest that microglial proliferation may form part of an early neuroprotective response in HE that ultimately fails to halt the course of the disease because underlying etiological factors such as high cerebral ammonia and systemic inflammation remain. PMID- 24346484 TI - Conductivity control of as-grown branched indium tin oxide nanowire networks. AB - Branched indium tin oxide (ITO) nanowire networks are promising candidates for transparent conductive oxide applications, such as optoelectronic electrodes, due to their high porosity. However, these branched networks also present new challenges in assessing conductivity. Conventional four-point probe techniques cannot separate the effect of porosity on the long-range conductivity from the intrinsic material conductivity. Here we compare the average nanoscale conductivity within the film measured by terahertz time-domain spectroscopy (THz TDS) to the film conductivity measured by four-point probe in a branched ITO nanowire network. Both techniques report conductivity increases with deposition flux rate from 0.5 to 3.0 nm s(-1), achieving a maximum of ~ 10 (Omega cm)(-1). Modeling the THz-TDS conductivity data using the Drude-Smith model allows us to distinguish between conductivity increases resulting from morphological changes and those resulting from the intrinsic properties of the ITO. In particular, the intrinsic material conductivity within the nanowires can be extracted, and is found to reach a maximum of ~ 3000 (Omega cm)(-1), comparable to bulk ITO. To determine the mechanism responsible for increasing conductivity with flux rate, we characterize dopant concentration and morphological changes (i.e., to branching behavior, nanowire diameter and nucleation layers). We propose that changes in the electron density, primarily due to changes in O-vacancy concentration at different flux rates, are responsible for the observed conductivity increase. This understanding will assist balancing structural and conductivity requirements in applications of transparent conductive oxide networks. PMID- 24346485 TI - A stable, mononuclear, cationic Pt(III) complex stabilised by bulky N heterocyclic carbenes. AB - The thermally stable, paramagnetic Pt(iii) complex [PtI2(IPr)2][BAr(F)] has been prepared by oxidation of the Pt(ii) complex [PtI2(IPr)2] with iodine in the presence of NaBAr(F). X-ray crystallographic studies revealed the mononuclear nature of this species with a square-planar geometry. EPR and DFT studies pointed out to a metal-centred radical. PMID- 24346486 TI - Development of an integrated support system for hereditary cancer and its impact on gynecologic services. AB - OBJECTIVE: Patients with hereditary cancer need an integrated support system. A recently launched project was evaluated in terms of its efficacy in screening patients with hereditary cancer at the gynecologic service. METHODS: The project team comprised gynecologists, surgeons, medical geneticists, and certified genetic counselors (CGCs) in our hospital. At the gynecologic service, a newly developed self-administered family history questionnaire (SAFHQ) was given to patients with ovarian, endometrial, or breast cancer as well as a history of multiple cancers. After an interview, a CGC constructed a pedigree and evaluated the risk for hereditary cancer. Patients at risk were recommended by a gynecologist to receive further genetic counseling at the Department of Genetics according to the modified Bethesda criteria, Amsterdam II criteria, and National Comprehensive Cancer Network (NCCN) guidelines 2012 for breast-ovarian cancer syndrome (HBOC). The numbers of newly screened patients were compared before and after the project launch. RESULTS: The SAFHQ was administered to 131 patients and 106 (81 %) pedigrees were constructed between August 2012 and July 2013. The number of newly screened patients according to the Bethesda criteria was 4 and 8 at 10 years before and 1 year after the project launch, respectively. Two and 31 patients met the NCCN criteria for HBOC excluding ovarian cancer alone, respectively, at these 2 time points. Of 54 patients who were recommended to undergo further counseling, 10 (19 %) visited the Department of Genetics. CONCLUSION: After the launch of an integrated support system, the number of patients with hereditary cancers who were screened increased. The gynecologic service played a pivotal role in patient and family care. PMID- 24346487 TI - Long-term oncological outcome in men with T3 prostate cancer: radical prostatectomy versus external-beam radiation therapy at a single institution. AB - BACKGROUND: This study was designed to compare the long-term oncological outcome of patients with clinical T3 (cT3) prostate cancer (PCA) treated with either radical prostatectomy (RP) or external-beam radiation therapy (EBRT) and to identify predictors of oncological outcomes. METHODS: A total of 231 patients with cT3 PCA underwent either RP (n = 112) or EBRT (n = 119). Local progression free (LPFS), distant metastasis-free (DMFS), cancer-specific (CSS), and overall survival curves were generated with the Kaplan-Meier method, and the differences in survival rates between the two groups were assessed with a log-rank test. Cox proportional stepwise multivariate analysis was used to assess the association of variables to the oncological outcomes. RESULTS: The median follow-up of the RP and EBRT groups was 93 and 85 months, respectively (p = 0.004).The 10-year LPFS, DMFS, and CSS rates were not statistically different between the two groups (90.2, 73.9, and 93.7 % in the RP group and 82.7, 88.2, and 85.1 % in the EBRT group; p = 0.25, 0.10, and 0.10, respectively). The Cox proportional multivariate analysis revealed that clinical T3b (cT3b) (p = 0.001) and a biopsy Gleason score of 7-10 (p = 0.043) were significant predictors of cancer-specific mortality and that cT3b was also a significant predictor of local progression and all-cause mortality. CONCLUSION: In cT3 PCA, both RP and EBRT provide an excellent long term oncological outcome. cT3b was the strongest predictor of oncological outcome for the patients with locally advanced PCA who underwent the definitive therapy. PMID- 24346489 TI - Cancer-related concerns among women with a new diagnosis of gynecological cancer: an exploration of age group differences. AB - OBJECTIVE: The study aimed to characterize cancer-related concerns among women with a new diagnosis of gynecological cancer from a developmental life stage perspective. The study compared the degree of cancer-related concern between young women (45 years or younger), middle age women (46-64 years), and older women (65 years or older). MATERIALS/METHODS: Data from women (N = 243) with a condition diagnosed as primary gynecological cancer who were participating in a randomized control trial were analyzed. Women completed a measure that assessed the degree of concern in 12 cancer-related domains (physical functioning, cancer treatment, emotional functioning, sexual functioning, disease progression/death, own well-being, partner well-being, relationship with spouse/partner, body image, relationship with others, employment, and finances). Multivariate comparisons were made between the 3 age groups on the cancer-related concerns. RESULTS: There were age group differences in overall cancer-related concern and specific cancer related domains. Young women reported the greatest cancer-related concern (P < 0.001). They reported greater concern over emotional functioning (P < 0.001) and sexual functioning (P < 0.001) compared to the middle- and older-age groups. Older women reported less concern over the impact of cancer on finances (P = 007). There were no differences between age groups in concern over physical impairment, cancer treatment, disease progression/death, own well-being, partner well-being, relationship with spouse/partner, body image, and relationship with others. CONCLUSIONS: Age may play an important role in the impact of a gynecological cancer diagnosis in domains of functioning, specifically emotional functioning, sexual functioning, and finances. Other cancer-related areas may represent more universal degree of impact. Professionals may benefit from considering the impact of cancer from a developmental life stage perspective. PMID- 24346490 TI - Coronal reformatted CT images contribute to the precise evaluation of the radiofrequency ablative margin for hepatocellular carcinoma. AB - OBJECTIVE: The purpose of the present study was to evaluate the usefulness of coronal reformatted images obtained from 64-slice multi-detector computed tomography to assess the ablative margin (AM) in hepatocellular carcinoma (HCC) treated with radio frequency ablation (RFA). METHODS: Ninety-five HCC nodules were analyzed in 66 HCC patients treated with RFA. Two radiologists and one hepatologist independently reviewed axial CT images with or without coronal reformatted images in HCC treated with RFA. Nodules were determined as AM sufficient (>=5 mm) or AM-insufficient (<5 mm). The level of interobserver agreement was measured using the weighted kappa test. The sensitivity, specificity, and positive and negative predictive values (NPVs) of an insufficient AM (<5 mm) to predict local recurrence were evaluated. RESULTS: The numbers of AM-sufficient nodules judged by readers 1-3 based on axial images and both axial and coronal images were 56, 49, and 58, and 47, 33, and 48, respectively. Excellent agreement and good to excellent agreement were obtained among the three readers on axial image readings and both axial and coronal image readings, respectively. The mean sensitivity, specificity, and positive and NPVs of an insufficient AM on axial images and both axial and coronal images to predict local recurrence were 64%, 60%, 17%, and 93%, and 95%, 50%, 20%, and 97%, respectively. CONCLUSIONS: Coronal reformatted CT images should be utilized to evaluate the AM in HCC treated with RFA in order to decrease the risk of local recurrence following treatment. PMID- 24346491 TI - Probing the photochemistry of chemisorbed oxygen on TiO2(110) with Kr and other co-adsorbates. AB - Weakly-bound atoms and molecules (Ar, Kr, Xe, CO, CH4, CO2, CH3OH, N2O, and N2) are used to probe the photochemical interactions of chemisorbed oxygen on rutile TiO2(110). Ultraviolet irradiation of chemisorbed oxygen co-adsorbed with the probe species leads to photon-stimulated desorption (PSD) of some of the probe species (e.g. Kr and CH4), but not others (e.g. CO2 and N2O). Without chemisorbed oxygen, the PSD yields of all the probe species are very low or not observed. Surprisingly, both chemisorbed O2 and oxygen adatoms, Oa, are photo-active for desorption of Kr and other weakly-bound species. To our knowledge, this is the first evidence for photo-activity of Oa on TiO2(110). The Kr PSD yield increases with increasing coverage of Kr and of chemisorbed oxygen. For Kr, the angular distribution of the photodesorbed atoms is approximately cosine. The Kr distribution is quite different from the angular distribution for the O2 PSD, which is sharply peaked along the surface normal. We propose that various forms of chemisorbed oxygen are excited by reactions with electrons and/or holes created in the TiO2 substrate by UV photon irradiation. The photo-excited oxygen collides with, and transfers energy to, neighboring co-adsorbed atoms or molecules. For co-adsorbates with a small enough binding energy to the substrate, desorption may result. The observed phenomenon provides a new tool for studying photochemical processes. PMID- 24346492 TI - School-aged functioning of children diagnosed with autism spectrum disorder before age three: parent-reported diagnostic, adaptive, medication, and school placement outcomes. AB - Eighty children with early autism spectrum disorder (ASD) diagnoses (under 36 months) were identified using a chart abstraction protocol applied to early intervention charts. Parents filled out questionnaires by mail when the children were school-aged (ages 6-16 years). Similar to previous studies, approximately 20% no longer had ASD diagnoses; the other participants were assigned to Moderate/Severe versus Mild ASD outcome groups. These three groups were compared across several variables, including diagnostic features and functional features including adaptive behavior, social experiences, medication use, and school placement. The findings expand our knowledge about outcomes in longitudinal studies of children with ASD, as well as provide support for using relatively indirect methods (chart review, parent questionnaire) to gather this type of information. PMID- 24346493 TI - Conventional versus image-based cardiovascular risk assessment in Korean adults. AB - OBJECTIVE: The aim of this study is to evaluate the difference between risk stratifications according to the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) guideline and the coronary artery calcium score (CACS) in a Korean population at an intermediate risk. PARTICIPANTS AND METHODS: A total of 7988 nondiabetic individuals underwent coronary computed tomography to measure coronary artery calcium. The discordantly higher risk group (DHRG) was defined as individuals whose CACS risk category was discordantly higher than their risk category according to the NCEP-ATP III guideline. RESULTS: Among all individuals at a low to moderate risk according to NCEP-ATP III, 9.4% were reclassified to the DHRG by CACS. In the multivariate regression analysis, age [odds ratio, 95% confidence interval (CI): 1.140 (1.123-1.158)], female sex [0.312 (0.208-0.469)], alcohol consumption [1.383 (1.142-1.676)], uric acid [1.079 (1.005-1.158)], hemoglobin A1c [1.716 (1.225-2.404)], fasting insulin [1.275 (1.056-1.539)], and systolic blood pressure [1.008 (1.001-1.016)] were associated independently with the DHRG. In a receiver-operating characteristic analysis, age had the largest area under the curve (AUC) compared with all of the aforementioned significant variables [AUC (95% CI): 0.724 (0.705-0.743)] for the DHRG. For every 5 years over 35 years of age, the risk of being in the DHRG increases by 1.95. CONCLUSION: This study indicates that the NCEP-ATP III guideline underestimates cardiovascular risk in about 10% of asymptomatic nondiabetic Korean individuals in the lower to moderate risk group, and the discrepancy in risk stratification between NCEP-ATP III and CACS is particularly prominent in older individuals. This suggests that an image-based risk assessment such as a coronary calcium scan should be considered for more accurate risk stratification. PMID- 24346494 TI - Compensatory enlargement of the left main coronary artery: insights from the PROSPECT study. AB - OBJECTIVES: Glagov proposed that remodeling delayed development of significant coronary artery stenoses until plaque occupied, on average, 40% of arterial area (40% plaque burden). The aim of the current study was to confirm the previously proposed concept of coronary remodeling as first described by Glagov who studied postmortem left main coronary arteries (LMCAs). METHODS: Using the in-vivo intravascular ultrasound data from the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study, we evaluated 552 LMCAs in 552 patients. RESULTS: External elastic membrane cross-sectional areas (CSAs) increased in proportion to the increase in plaque and media CSAs (r=0.61, P<0.0001), especially when the plaque burden was 20% or lower (r=0.88, P<0.0001). For more advanced atherosclerosis (>40% plaque burden), there was an inverse relationship between lumen CSA and plaque burden (r=-0.57, P<0.0001), whereas this relationship was weak in the presence of less than 40% plaque burden. The frequency of virtual histology derived thin-cap fibroatheroma increased with increasing plaque burden. In contrast, the frequency of pathological intimal thickening decreased. CONCLUSION: The previously proposed remodeling concept of Glagov was validated in vivo in the PROSPECT study patients. In addition, the present study suggested that plaque phenotype worsened with increasing LMCA plaque growth. PMID- 24346495 TI - Acute toxicity by water containing hexavalent or trivalent chromium in native Brazilian fish, Piaractus mesopotamicus: anatomopathological alterations and mortality. AB - This study evaluated the toxicity of hexavalent and trivalent compounds of chromium to the pacu, Piaractus mesopotamicus, in acute exposures of 96 h through mortality and histopathological responses. Hexavalent potassium dichromate was more toxic than trivalent compounds of chromium chloride, chromium oxide and chromium carbochelate. Sufficient mortalities occurred only with potassium dichromate to yield an LC50 value at 124.2 mg L(-1). Hexavalent chromium caused reversible and irreversible lesions, which may affect organ functionality. Histopathological evaluation showed that trivalent chromium caused lesions of lower severity. Pacu subjected to different concentrations of chromium carbochelate showed no histopathological changes in the kidneys, liver, skin and gills, being similar to those of the control fish. Among the three sources of Cr(3+), only chromium chloride at 200 mg L(-1) resulted in mortality, which reached 100 % within the first 18 h. These findings confirm that trivalent chromium, when administered within recommended levels, may be used safely in aquaculture. PMID- 24346497 TI - Patterns of genetic diversity reveal multiple introductions and recurrent founder effects during range expansion in invasive populations of Geranium carolinianum (Geraniaceae). AB - Genetic diversity, and thus the adaptive potential of invasive populations, is largely based on three factors: patterns of genetic diversity in the species' native range, the number and location of introductions and the number of founding individuals per introduction. Specifically, reductions in genetic diversity ('founder effects') should be stronger for species with low within-population diversity in their native range and few introductions of few individuals to the invasive range. We test these predictions with Geranium carolinianum, a winter annual herb native to North America and invasive in China. We measure the extent of founder effects using allozymes and microsatellites, and ask whether this is consistent with its colonization history and patterns of diversity in the native range. In the native range, genetic diversity is higher and structure is lower than expected based on life history traits. In China, our results provide evidence for multiple introductions near Nanjing, Jiangsu province, with subsequent range expansion to the west and south. Patterns of genetic diversity across China reveal weak founder effects that are driven largely by low-diversity populations at the expansion front, away from the introduction location. This suggests that reduced diversity in China has resulted from successive founder events during range expansion, and that the loss of genetic diversity in the Nanjing area was mitigated by multiple introductions from diverse source populations. This has implications for the future of G. carolinianum in China, as continued gene flow among populations should eventually increase genetic diversity within the more recently founded populations. PMID- 24346496 TI - Disparate molecular evolution of two types of repetitive DNAs in the genome of the grasshopper Eyprepocnemis plorans. AB - Wide arrays of repetitive DNA sequences form an important part of eukaryotic genomes. These repeats appear to evolve as coherent families, where repeats within a family are more similar to each other than to other orthologous representatives in related species. The continuous homogenization of repeats, through selective and non-selective processes, is termed concerted evolution. Ascertaining the level of variation between repeats is crucial to determining which evolutionary model best explains the homogenization observed for these sequences. Here, for the grasshopper Eyprepocnemis plorans, we present the analysis of intragenomic diversity for two repetitive DNA sequences (a satellite DNA (satDNA) and the 45S rDNA) resulting from the independent microdissection of several chromosomes. Our results show different homogenization patterns for these two kinds of paralogous DNA sequences, with a high between-chromosome structure for rDNA but no structure at all for the satDNA. This difference is puzzling, considering the adjacent localization of the two repetitive DNAs on paracentromeric regions in most chromosomes. The disparate homogenization patterns detected for these two repetitive DNA sequences suggest that several processes participate in the concerted evolution in E. plorans, and that these mechanisms might not work as genome-wide processes but rather as sequence specific ones. PMID- 24346498 TI - Relatedness severely impacts accuracy of marker-assisted selection for disease resistance in hybrid wheat. AB - The accuracy of genomic selection depends on the relatedness between the members of the set in which marker effects are estimated based on evaluation data and the types for which performance is predicted. Here, we investigate the impact of relatedness on the performance of marker-assisted selection for fungal disease resistance in hybrid wheat. A large and diverse mapping population of 1739 elite European winter wheat inbred lines and hybrids was evaluated for powdery mildew, leaf rust and stripe rust resistance in multi-location field trials and fingerprinted with 9 k and 90 k SNP arrays. Comparison of the accuracies of prediction achieved with data sets from the two marker arrays revealed a crucial role for a sufficiently high marker density in genome-wide association mapping. Cross-validation studies using test sets with varying degrees of relationship to the corresponding estimation sets revealed that close relatedness leads to a substantial increase in the proportion of total genotypic variance explained by the identified QTL and consequently to an overoptimistic judgment of the precision of marker-assisted selection. PMID- 24346499 TI - Sex linkage of nuclear-encoded mitochondrial genes. PMID- 24346501 TI - Therapeutic potential of Rb phosphorylation in atherosclerosis. PMID- 24346500 TI - Genome-wide signatures of population bottlenecks and diversifying selection in European wolves. AB - Genomic resources developed for domesticated species provide powerful tools for studying the evolutionary history of their wild relatives. Here we use 61K single nucleotide polymorphisms (SNPs) evenly spaced throughout the canine nuclear genome to analyse evolutionary relationships among the three largest European populations of grey wolves in comparison with other populations worldwide, and investigate genome-wide effects of demographic bottlenecks and signatures of selection. European wolves have a discontinuous range, with large and connected populations in Eastern Europe and relatively smaller, isolated populations in Italy and the Iberian Peninsula. Our results suggest a continuous decline in wolf numbers in Europe since the Late Pleistocene, and long-term isolation and bottlenecks in the Italian and Iberian populations following their divergence from the Eastern European population. The Italian and Iberian populations have low genetic variability and high linkage disequilibrium, but relatively few autozygous segments across the genome. This last characteristic clearly distinguishes them from populations that underwent recent drastic demographic declines or founder events, and implies long-term bottlenecks in these two populations. Although genetic drift due to spatial isolation and bottlenecks seems to be a major evolutionary force diversifying the European populations, we detected 35 loci that are putatively under diversifying selection. Two of these loci flank the canine platelet-derived growth factor gene, which affects bone growth and may influence differences in body size between wolf populations. This study demonstrates the power of population genomics for identifying genetic signals of demographic bottlenecks and detecting signatures of directional selection in bottlenecked populations, despite their low background variability. PMID- 24346502 TI - Surface electronic structure of the topological Kondo-insulator candidate correlated electron system SmB6. AB - The Kondo insulator SmB6 has long been known to exhibit low-temperature transport anomalies whose origin is of great interest. Here we uniquely access the surface electronic structure of the anomalous transport regime by combining state-of-the art laser and synchrotron-based angle-resolved photoemission techniques. We observe clear in-gap states (up to ~4 meV), whose temperature dependence is contingent on the Kondo gap formation. In addition, our observed in-gap Fermi surface oddness tied with the Kramers' point topology, their coexistence with the two-dimensional transport anomaly in the Kondo hybridization regime, as well as their robustness against thermal recycling, taken together, collectively provide strong evidence for protected surface metallicity with a Fermi surface whose topology is consistent with the theoretically predicted topological Fermi surface. Our observations of systematic surface electronic structure provide the fundamental electronic parameters for the anomalous Kondo ground state of correlated electron material SmB6. PMID- 24346503 TI - Electromagnetic limits to radiofrequency (RF) neuronal telemetry. AB - The viability of a radiofrequency (RF) telemetry channel for reporting individual neuron activity wirelessly from an embedded antenna to an external receiver is determined. Comparing the power at the transmitting antenna required for the desired Channel Capacity, to the maximum power that this antenna can dissipate in the body without altering or damaging surrounding tissue reveals the severe penalty incurred by miniaturization of the antenna. Using both Specific Absorption Rate (SAR) and thermal damage limits as constraints, and 300 Kbps as the required capacity for telemetry streams 100 ms in duration, the model shows that conventional antennas smaller than 0.1 mm could not support human neuronal telemetry to a remote receiver (1 m away.) Reducing the antenna to 10 microns in size to enable the monitoring of single human neuron signals to a receiver at the surface of the head would require operating with a channel capacity of only 0.3 bps. PMID- 24346504 TI - Effects of AlGaAs cladding layers on the luminescence of GaAs/GaAs1-xBix/GaAs heterostructures. AB - The structural and optical properties of GaAs1-xBix quantum wells (QWs) symmetrically clad by GaAs barriers with and without additional confining AlGaAs layers are studied. It is shown that a GaAs/GaAs1-xBix/GaAs QW with x ~ 4% and well width of ~ 4 nm grown by molecular beam epitaxy demonstrates efficient photoluminescence (PL) that becomes significantly more thermally stable when a cladding AlGaAs layer is added to the QW structure. The PL behavior for temperatures between 10 and 300 K and for excitation intensities varying by seven orders of magnitude can be well described in terms of the dynamics of excitons including carrier capture in the QW layer, thermal emission and diffusion into the cladding barriers. Understanding the role of these processes in the luminescence of dilute GaAs1-xBix QW structures facilitates the creation of highly efficient devices with reduced thermal sensitivity and low threshold current. PMID- 24346505 TI - Methanetrisamidines in coordination chemistry--syntheses, structures and CH-NH tautomerism. AB - Methanetrisamidines {HC[C(NR)NHR]3} (R = i-Pr 1a; Ph 1b) were reacted with different metal complexes. Reaction of 1a with NiCl2(H2O)6 occurred with protonation of 1a and formation of {[C(C(NHi-Pr)2)3](2+)[NiCl4](2-)} 2, whereas the reaction with CuCl gave [C(C(N(i-Pr)CuCl)NHi-Pr)2(C(NHi-Pr)2)] 3. The formation of 2 and 3, which contain the N-H tautomeric form of 1a, occurred with H-migration from carbon to nitrogen. In contrast, reactions of 1b with [M(NCMe)3(CO)3] (M = Cr, Mo, W) yielded octahedral complexes fac [M(CO)3CH(C(NHPh)NPh)3] (M = Cr 4a, Mo 4b, W 4c), in which the C-H tautomeric form is preserved. 1b is a rather strong sigma-donor ligand as was shown by IR spectroscopy. The structures of 2, 3 and 4a were determined by single crystal X ray diffraction. PMID- 24346506 TI - Comparison of the transfer of equal numbers of blastocysts versus cleavage-stage embryos after repeated failure of in vitro fertilization cycles. AB - PURPOSE: To evaluate the efficacy of blastocyst transfer in women with at least two previously unsuccessful in vitro fertilization-embryo transfer (IVF-ET) attempts. METHODS: Retrospective analysis of 238 couples (with previous implantation failures) had equal number (two) of cleavage-stage embryos (n = 143) or blastocysts (n = 95) transferred in the same IVF center. RESULTS: The clinical pregnancy rates and live-birth rates were similar in the cleavage-stage embryo transfer group and the blastocyst group (35.6% vs. 40% and 32.1% vs. 35.7%; p > 0.05, respectively). Miscarriage rates (9.8% vs. 10.5%) and multiple pregnancy rates (15.6% vs. 23.6%) did not differ. Although implantation rate was higher with blastocyst transfer than that with day 3 transfer, it did not reach to a statistical significance (24.7% and 19%, respectively, p > 0.05). CONCLUSION: Blastocyst transfer in ICSI cycles does not yield a better outcome than that obtained with cleavage-stage embryos in women who had unsuccessful IVF attempts previously. PMID- 24346507 TI - Relationship between HLA-G polymorphism and susceptibility to recurrent miscarriage: a meta-analysis of non-family-based studies. AB - PURPOSE: The HLA-G 14-bp insertion/deletion polymorphism had been inconsistently associated with recurrent miscarriage (RM) risk. We examined the association by performing a meta-analysis. METHODS: Eligible articles were searched in PubMed, EMBASE and CNKI without language limitation. We included all the articles about two or more miscarriages associated with HLA-G 14-bp polymorphism. The odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Statistical analyses were performed by the STATA10.0 software. RESULTS: 17 studies were included, representing 1786 cases and 1574 controls. The current meta-analysis showed that 14-bp polymorphism was not associated with RM risk in all genetic models and allele contrast(+14 bp vs. -14 bp: OR = 1.13; 95% CI, 0.96,1.32; +14 bp/+14 bp vs. -14 bp/-14 bp: OR = 1.16, 95% CI, 0.85, 1.59; +14 bp/-14 bp vs. -14 bp/-14 bp: OR = 1.21, 95% CI, 0.92,1.58; dominant model: OR = 1.33; 95% CI, 0.99,1.78; recessive model: OR = 1.06; 95% CI, 0.79,1.43). Moreover, a significant heterogeneity was evident across studies. On the other hand, the subgroup analysis demonstrated that there was a significant association between HLA-G 14-bp polymorphism and patients with three or more miscarriages(+14 bp vs. -14 bp: OR = 1.27; 95% CI, 1.04, 1.55; dominant model: OR = 1.52; 95% CI, 1.16, 1.99; and model +14 bp/-14 bp versus -14 bp/-14 bp: OR = 1.51; 95% CI, 1.15, 1.97;). CONCLUSIONS: Our comprehensive meta-analysis indicated that there was insufficient evidence to demonstrate a conclusive association between the HLA G 14-bp insertion/deletion polymorphism and the risk of RM. But HLA-G 14-bp insertion/deletion polymorphic variation was associated with RM risk in patients with three or more miscarriages. Larger and well-designed studies may eventually provide a better, comprehensive understanding of the association between the HLA G 14-bp insertion/deletion polymorphism and RM in the future. PMID- 24346508 TI - Multi-plate reconstruction for severe bicondylar tibial plateau fractures of young adults. AB - PURPOSE: This study was to evaluate clinical outcomes and complications following multi-plate reconstruction for treating severe bicondylar tibial plateau fractures of young adults. METHODS: Between September 2007 and February 2012, 26 patients with severe bicondylar tibial plateau fractures met inclusion criteria; they were treated using multi-plate technique through combined approaches. Patients received an average follow-up of 40.8 (range, 18-64) months, which included anteroposterior and lateral imaging, postoperative complications, range of motion and stability of the knee. The Rasmussen score was applied for functional and radiological evaluation. RESULTS: Three to five plates were used for reconstruction. No intra-operative complications occurred. Postoperative complications included bulge of hardware in four patients and superficial dehiscence in three cases in the anterolateral incision of which one developed to deep infection. There was no neurovascular damage, and no implant breakage or loosening. Hardware was removed partly or totally in 16 cases. The average Rasmussen score at final follow-up was 27.2 (range, 21-30) points for functional evaluation and 16.4 (range, 14-18) for radiology. CONCLUSIONS: Multi-plate reconstruction is a valid and safe method for treating severe bicondylar tibial plateau fractures of young adults. PMID- 24346509 TI - Cordycepin prevented IL-beta-induced expression of inflammatory mediators in human osteoarthritis chondrocytes. AB - PURPOSE: Cordycepin, a nucleoside derivative isolated from Cordyceps, has been reported to exert anti-inflammatory, antitumor, antidiabetic and renoprotective effects. Osteoarthritis (OA) is a degenerative joint disease with an inflammatory component that drives the degradation of cartilage extracellular matrix. This study aimed to assess the effects of cordycepin on human OA chondrocytes. METHODS: In this study, human OA chondrocytes were pretreated with cordycepin at 10, 50 or 100 MUM and subsequently stimulated with interleukin-1beta (IL-1beta) (5 ng/ml) for 24 h. Production of prostaglandin E2 (PGE2) and nitric oxide (NO) were evaluated by the Griess reaction and an enzyme-linked immunosorbent assay (ELISA). Gene expression of matrix metalloproteinase (MMP)-13, IL-6, inducible nitric oxide synthase (iNOS) and cyclo-oxygenase (COX-2) was measured by real time polymerase chain reaction (PCR). MMP-13 and IL-6 proteins in culture medium were determined using cytokine-specific ELISA. Western immunoblotting was used to analyse the iNOS and COX-2 protein production in culture medium. Nuclear factor kappa-B (NF-kappaB) activity regulation was explored using Western immunoblotting. RESULTS: Pretreatment with cordycepin significantly inhibited the production of PGE2 and NO induced by IL-1beta. Cordycepin also significantly decreased the IL-1beta-stimulated gene expression and production of MMP-13, IL-6, iNOS and COX-2 in OA chondrocytes. Pretreatment with cordycepin attenuated IL 1beta-induced activation of NF-kappaB by suppressing degradation of its inhibitory protein nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha (IkappaB-alpha) in the cytoplasm. CONCLUSIONS: We show for the first time the anti-inflammatory activity of cordycepin in human OA chondrocytes. Thus, with this unique profile of actions, cordycepin may prove to be a potentially attractive and new therapeutic/preventive agent for OA. PMID- 24346510 TI - Comment on Park et al.: High glucose-induced oxidative stress promotes autophagy through mitochondrial damage in rat notochordal cells. PMID- 24346511 TI - The effect of minimally displaced posterior malleolar fractures on decision making in minimally displaced lateral malleolus fractures. AB - PURPOSE: Despite the high incidence of cases of minimally displaced lateral or posterior malleolus ankle fractures, treatment guidelines are still an issue of controversy. The purpose of this study was to delineate treatment preferences among orthopaedic surgeons in these fractures with and without concomitant posterior malleolus fractures. We hypothesized that concomitant minimally displaced fractures of the posterior malleolus can shift treatment preference towards operative intervention. METHODS: A questionnaire-based study was conducted among orthopaedic surgeons attending the 2012 European Federation of National Associations of Orthopaedics and Traumatology Conference (EFORT) in Berlin, Germany. Treatment preferences were reported for minimally displaced lateral malleolus fractures seen on radiographs and were then compared with treatment preferences when computed tomography (CT) was added revealing a concomitant minimally displaced posterolateral fracture of the posterior malleolus. RESULTS: The cohort comprised 177 surgeons from all six continents. When radiographs showing a minimally displaced lateral malleolus fracture were presented, nonoperative management was indicated by 35 % (62) of participants, whereas 65 % (115) preferred operative intervention. After CT views were added showing an accompanying minimally displaced posterolateral posterior malleolus fracture, 79 % (140) suggested operative intervention and only 21 % (37) advocated nonoperative management (p = 0.03). CONCLUSIONS: Most surgeons prefer open reduction with internal fixation for minimally displaced lateral malleolar fractures. The presence of concomitant posterior malleolus fractures in these cases shifts treatment preference further towards open reduction with internal fixation. Because the posterior malleolus fragment might not be well delineated on standard ankle radiographs, a high index of suspicion is warranted, and the use of CT should be considered in these cases. PMID- 24346513 TI - Comment on Lan et al.: S-osteotomy with lengthening and then nailing compared with traditional Ilizarov method. PMID- 24346512 TI - Total knee arthroplasty at 15-17 years: does implant design affect outcome? AB - PURPOSE: A study was conducted to compare minimum 15-year survivorship and outcome of the Genesis I and II implants for total knee arthroplasty (TKA). METHODS: We retrospectively reviewed 245 consecutive TKA implanted between January 1995 and October 1997. Genesis I was implanted in 156 knees and Genesis II in 89 knees. RESULTS: At 15-17 years, 75 patients (31%) had died, 28 patients (11%) were lost to follow-up and 11 TKA were revised (4.6%), including ten Genesis I (6.4%) and one Genesis II (1.1%); 131 TKA (53%) were available for follow-up. Cumulative survivorship was 92.4% at 15.7 years. Survival in patients <69 years at surgery was lower (88.0%) compared with patients >=69 years (98.5%; p = 0.023). In patients <69 years, Genesis I survival (84.3%) was worse compared with Genesis II (97.1%) (p = 0.018). Polyethylene (PE) Insert thickness <=11 mm had significantly better survivorship (97.1%) compared with PE >11 mm (56.7%) (p < 0.0001) CONCLUSIONS: At a minimum of 15 years, the overall (92.4%) survivorship of Genesis TKA was good, with excellent (98.1%) survivorship of the Genesis II design. Revision rates were higher with Genesis I in the younger age group and with insert thickness >11 mm, possibly due to longer shelf life of less frequently used sizes. PMID- 24346514 TI - Postoperative change in medial meniscal length in concurrent all-inside meniscus repair with anterior cruciate ligament reconstruction. AB - PURPOSE: Meniscus repair can restore meniscal function that transfers the axial compressive force to circumferential tensile strain. However, few reports have investigated the relationship between concurrent meniscus repair with acute anterior cruciate ligament (ACL) reconstruction and postoperative meniscal position. This study aimed to evaluate medial meniscal size and clinical results in patients who underwent ACL reconstruction and concomitant all-inside medial meniscus repair. METHODS: Twenty patients underwent ACL reconstruction and concurrent medial meniscus repair of a peripheral longitudinal tear using the FasT-Fix meniscal repair device. Medial tibial plateau length (MTPL) and width (MTPW) were determined by radiographic images. We evaluated the Lysholm score, anteroposterior instability, meniscal healing and magnetic resonance imaging (MRI)-based medial meniscal length (MML) and width (MMW). Correlations between MRI-based meniscal size, radiographic measurement and height were investigated. RESULTS: All patients showed complete healing of the repaired meniscus in arthroscopic evaluation. However, one patient needed a subsequent meniscus repair during the follow-up period. Lysholm score and anteroposterior instability improved significantly. A better correlation was observed between MMW and MTPW than between MML and MTPL. Concurrent all-inside medial meniscus repair with ACL reconstruction significantly increased MML percentage (%MML) (100 MML/MTPL) but did not affect MMW percentage (%MMW) (100 MMW/MTPW). CONCLUSIONS: Concurrent all inside medial meniscus repair with ACL reconstruction had satisfactory clinical results. %MML was increased by concurrent medial meniscus repair without affecting %MMW. Our results suggest that medial meniscus repair associated with ACL reconstruction may restore meniscal function by adjusting the anteroposterior length of the torn medial meniscus. PMID- 24346515 TI - Impact of the tibial slope on range of motion after low-contact-stress, mobile bearing, total knee arthroplasty. AB - PURPOSE: The aim of this study was to analyse a possible correlation between the tibial slope and range of motion (ROM) after implantation of the low-contact stress (LCS), mobile-bearing, total knee arthroplasty (TKA) after a minimum follow-up of ten years. METHODS: Eighty-three TKAs in 66 patients were investigated in this retrospective correlation analysis at a minimum follow up of ten years. Out of these 66 patients, 50 were women (76%) and 16 (24%) were men. The average age of these patients at the time of the examination was 76 years [standard deviation (SD) 11 years, range 37-95 years]. A lateral X-ray was taken at follow-up in order to analyse the tibial slope with respect to inter- and intra-observer agreement. ROM was measured and correlated with the tibial slope. RESULTS: The mean active ROM was 96.1 degrees (SD 18.8) and the mean tibial slope after four measurements was 7.65 degrees (SD 4.23), with substantial inter and intra-observer agreement. We found no significant correlation between tibial slope and ROM in patients with a minimum follow-up of ten years [correlation 0.196 (p > 0.05) and 0.152, (p > 0.05), respectively]. CONCLUSIONS: Alteration of the tibial slope does not significantly influence ROM after implantation of the LCS TKA at a minimum follow-up of ten years. We conclude that the tibial slope is not the primary influencing factor for ROM in patients ten years after primary TKA and believe that it should not substantially be altered during surgery. PMID- 24346516 TI - Risk, harm and intervention: the case of child obesity. AB - In this paper we aim to demonstrate the enormous ethical complexity that is prevalent in child obesity cases. This complexity, we argue, favors a cautious approach. Against those perhaps inclined to blame neglectful parents, we argue that laying the blame for child obesity at the feet of parents is simplistic once the broader context is taken into account. We also show that parents not only enjoy important relational prerogatives worth defending, but that children, too, are beneficiaries of that relationship in ways difficult to match elsewhere. Finally, against the backdrop of growing public concern and pressure to intervene earlier in the life cycle, we examine the perhaps unintended stigmatizing effects that labeling and intervention can have and consider a number of risks and potential harms occasioned by state interventions in these cases. PMID- 24346517 TI - Care and prejudice: moving beyond mistrust in the care relationship with addicted patients. AB - Social representations of addiction and the resulting stigmatization have been widely described and studied in the literature, but their effects are no less problematic. These representations, which also occur in care settings, generate a climate of distrust which damages the therapeutic relationship, and its ethical quality. This article, combining clinical experience and an ethical stance, offers an original, innovating approach to the existence of distrust in care relationships in the area of addiction. Pragmatic approaches deriving from the human sciences and analytical philosophy provide an invitation to escape from the demanding climate of mistrust, and to take the gamble on trust so as to improve the quality of interactions between protagonists in care. In complementary fashion, a sociology of action can combat the disquiet generated by distrust through a new commitment to innovating forms of action. This "poetic" mode of action is legitimized by the reflection that backs it up, and by its presentation to peers qualified to approve it. Finally, continental moral philosophy underlines the importance of a carefully weighed commitment on the part of caregivers and addicted patients towards promises aiming to support a sincere care relationship, without damaging the therapeutic dynamic or the ethical quality by providing too many safety nets. This reflection is intended to achieve better identification of the clinical and ethical issues raised by mistrust, and inclusion of these aspects in the training of personnel and in care provision planning. PMID- 24346519 TI - Oropharyngeal decontamination with antiseptics to prevent ventilator-associated pneumonia: rethinking the benefits of povidone-iodine. PMID- 24346518 TI - Multiple in-hospital resuscitation efforts in the elderly. AB - OBJECTIVES: The objective of this study was to determine the characteristics and survival rates of patients receiving cardiopulmonary resuscitation more than once during a single hospitalization. DESIGN: We analyzed inpatient Medicare data from 1992 to 2005 identifying beneficiaries 65 years old and older who underwent cardiopulmonary resuscitation more than once during the same hospitalization. MEASUREMENTS: We examined patient and hospital characteristics, survival to hospital discharge, factors associated with survival to discharge, median survival, and discharge disposition. RESULTS: We analyzed data from 421,394 patients who underwent cardiopulmonary resuscitation during the study period. Four lakh thirteen thousand four hundred three patients received cardiopulmonary resuscitation once during a hospitalization and survival was 17.7% with median survival after discharge being 20.6 months. There were 7,991 patients who received cardiopulmonary resuscitation more than once during the same hospitalization; 8.8% survived the efforts, and median survival after leaving the hospital was 10.5 months. Patients who received more than one episode of cardiopulmonary resuscitation during a hospitalization were significantly less likely to go home after discharge. Greater age, black race, higher burden of chronic illness, and receiving cardiopulmonary resuscitation in a larger or metropolitan hospital were associated with lower survival among patients receiving cardiopulmonary resuscitation more than once. CONCLUSIONS: Undergoing multiple cardiopulmonary resuscitation events during a hospitalization is associated with substantially reduced short- and long-term survival compared with patients who undergo cardiopulmonary resuscitation once. This information may be useful to clinicians when discussing end-of-life care with patients and families of patients who have experienced return of spontaneous circulation following in hospital cardiopulmonary resuscitation but remain at risk for recurrent cardiac arrest. PMID- 24346520 TI - Right test, right time, right patient. PMID- 24346521 TI - The role of multivessel coronary intervention in ST-segment elevation myocardial infarction complicated by cardiogenic shock: have we reached a verdict? PMID- 24346522 TI - Your call is important to us. Do not put your medical emergency team on hold. PMID- 24346523 TI - Designing a better "nest": applicable to preventing hospital exposures to risk factors for acute respiratory distress syndrome or just retrospective study design? PMID- 24346524 TI - Intraoperative management and pressure ulcers: not where the problem lies? PMID- 24346526 TI - Intestinal glucose transport in the critically ill--eavesdropping on a dialogue. PMID- 24346525 TI - Pseudomonas aeruginosa virulence and antimicrobial resistance: two sides of the same coin? PMID- 24346527 TI - Building better bundles. PMID- 24346528 TI - How much sedation can those smart ventilators handle? Patient-ventilator synchrony revisited. PMID- 24346529 TI - Emergency trauma score... still not quite ready for prime time? PMID- 24346530 TI - "Only few find the way, some don't recognize it when they do ..."--can we "observe" causality? PMID- 24346531 TI - Epidermal necrolyis: a skin disease to take your breath away. PMID- 24346532 TI - Are we offtrack using propofol for sedation after traumatic brain injury? PMID- 24346533 TI - The brain beats the heart. PMID- 24346534 TI - A Framework for a Physician-Parent Follow-Up Meeting After a Child's Death in a PICU and why this family-centered care approach should interest us all. PMID- 24346535 TI - Critical care transition and prevention of ICU readmissions: a bridge over troubled waters. PMID- 24346536 TI - Hematin and neuroglobin: contenders for prevention and treatment of sepsis associated encephalopathy? PMID- 24346537 TI - Recombinant human annexin A5: a novel drug candidate for treatment of sepsis? PMID- 24346538 TI - Will the promise of drug-induced therapeutic hypothermia be fulfilled? PMID- 24346539 TI - Compartmentalization of lung injury--atelectasis versus overstretch. PMID- 24346540 TI - What are the relevant molecular routes in septic acute kidney injury? PMID- 24346541 TI - Does blast limb trauma constitute a multisystem critical illness? PMID- 24346542 TI - An official multi-society statement: ventilator-associated events: the new definition. PMID- 24346544 TI - Improved cardiac and neurologic outcomes with postresuscitation infusion of cannabinoid receptor agonist WIN55, 212-2 depend on hypothermia in a rat model of cardiac arrest. AB - OBJECTIVES: To investigate the mechanisms of improved myocardial and neurological function and survival following i.v. administration of cannabinoid receptor agonist, WIN55, 212-2 in a rat model of cardiac arrest. DESIGN: Prospective randomized controlled experimental study. SETTING: University-affiliated research institute. SUBJECTS: Thirty male Sprague-Dawley rats. INTERVENTIONS: Ventricular fibrillation was electrically induced in 30 male Sprague-Dawley rats weighing between 450 and 550 g. Cardiopulmonary resuscitation was initiated after 6 minutes of untreated ventricular fibrillation. The precordial compression was performed with a pneumatically driven mechanical chest compressor. No pharmacological agent was used during cardiopulmonary resuscitation. After 8 minutes of cardiopulmonary resuscitation, up to three 2-J defibrillations were attempted. The animals were then randomized into three groups: 1) WIN55, 212-2 hypothermia, 2) WIN55, 212-2 with normal body temperature, and 3) placebo control. Either WIN55, 212-2 (1.0 mg/kg/hr) or saline placebo was continuously infused for 2 hours. Except for the WIN55, 212-2 hypothermia group, the body temperature in the other two groups was maintained at 37.0 +/- 0.2 degrees C using an external heating lamp. Postresuscitation myocardial function was measured by echocardiogram. Neurological deficit scores and survival time were observed for up to 72 hours. MEASUREMENTS AND MAIN RESULTS: Blood temperatures decreased from 37 degrees C to 33 degrees C in 4 hours in animals in WIN55, 212-2 hypothermia group. Myocardial function, as measured by cardiac output, ejection fraction, and myocardial performance index, was significantly impaired in all animals after successful resuscitation when compared with the baseline values. There was a significant improvement in myocardial function in the animals treated with WIN55, 212-2 hypothermia beginning at 1 hour after start of infusion. However, no improvement was observed in the groups of WIN55, 212-2 with normal body temperature and placebo control. WIN55, 212-2 hypothermia group was associated with significantly improved neurologic deficit scores and survival time when compared with placebo control group and WIN55, 212-2 with normal body temperature group. CONCLUSIONS: In a rat model of cardiac arrest, better postresuscitation myocardial function, neurological deficit scores, and longer duration of survival were observed by the pharmacologically induced hypothermia with WIN55, 212-2. The improved outcomes of cardiopulmonary resuscitation following administration of WIN55, 212-2 appeared to be the results from its temperature reduction effects. PMID- 24346545 TI - Do-not-resuscitate: another effect of rapid response team. PMID- 24346546 TI - Does the association between a high body mass index and hospital mortality weigh "heavily" on the association between a low body mass index and hospital mortality? PMID- 24346547 TI - Association of body mass index with hospital mortality in ICU patients. PMID- 24346548 TI - The "obesity-mortality paradox" phenomenon in critically ill patients: one size does not fit all. PMID- 24346549 TI - The authors reply. PMID- 24346550 TI - Sleep patterns during long-term mechanical ventilation in tracheostomized patients in the ICU: do they matter? PMID- 24346551 TI - The authors reply. PMID- 24346552 TI - Evidence base for the use of corticosteroids in septic shock in children. PMID- 24346553 TI - The author replies. PMID- 24346554 TI - Does cecal ligation and puncture-induced murine sepsis cause lung injury or not? PMID- 24346555 TI - The authors reply. PMID- 24346556 TI - Towards a unified theory of health-disease: I. Health as a complex model-object. AB - Theory building is one of the most crucial challenges faced by basic, clinical and population research, which form the scientific foundations of health practices in contemporary societies. The objective of the study is to propose a Unified Theory of Health-Disease as a conceptual tool for modeling health-disease care in the light of complexity approaches. With this aim, the epistemological basis of theoretical work in the health field and concepts related to complexity theory as concerned to health problems are discussed. Secondly, the concepts of model-object, multi-planes of occurrence, modes of health and disease-illness sickness complex are introduced and integrated into a unified theoretical framework. Finally, in the light of recent epistemological developments, the concept of Health-Disease-Care Integrals is updated as a complex reference object fit for modeling health-related processes and phenomena. PMID- 24346557 TI - [Prevalence of trachoma in Brazilian schoolchildren]. AB - OBJECTIVE: To estimate the prevalence and describe the distribution of trachoma among schoolchildren in Brazilian municipalities. METHODS: Cross-sectional study, using cluster sampling, of the schoolchildren population of the Brazilian municipalities with Human Development Index - Municipal lower than the national average. This trachoma prevalence survey was conducted by the Ministry of Health, in the period 2002-2007. There were 119,531 schoolchildren selected from 2,270 schools located in 1,156 municipalities. The selected schoolchildren underwent an external ocular examination, with a magnifying glass (2.5X), to detect clinical signs of trachoma according to the WHO criteria. The prevalence of trachoma, by state and national level, and their respective 95% confidence intervals were estimated. Chi-square and Chi-square for trends tests were used to compare categorical variables. RESULTS: There were 6,030 cases of trachoma detected, resulting in a prevalence of 5.0% (95%CI 4.5;5.4). There was no significant difference between the sexes. The prevalence of trachoma was 8.2% among children under 5 years of age, decreasing among higher age groups (p < 0.01). There was a significant difference in prevalence between urban and rural areas, 4.3% versus 6.2% respectively (p < 0.01). Cases were detected in 901 municipalities (77.7% of the sample), in all regions of the country. In 36.8% of the selected municipalities, the prevalence was higher than 5%. CONCLUSIONS: The study shows that trachoma is a significant public health problem in Brazil, contradicting the belief that the disease had been controlled in the country. The survey provides a baseline for evaluating planned interventions aimed at achieving the goal of global certification of elimination of trachoma as a cause of blindness in Brazil by 2020. PMID- 24346558 TI - [Diabetes in hospital deliveries in public and private health system hospitals]. AB - OBJECTIVE: To analyze trends of diagnoses of diabetes mellitus in hospital deliveries. METHODS: Transversal study analyzing data on hospital deliveries for pregnant women living in Ribeirao Preto, SP, from 1998 to 2007. The data on diabetes mellitus in pregnancy were obtained from the Faculdade de Medicina de Ribeirao Preto of the Universidade de Sao Paulo Hospital Data Processing Center. The data analyzed were: age group, type of delivery (vaginal or cesarean), length of hospitalization and type of care: public (SUS) or private (private and supplemented health care). RESULTS: There was a 3.9 fold increase in the proportion of deliveries with a record of diabetes in relation to the total number of births (p = 0.01). This increase was of 4.5 times in deliveries in the public health care system (p = 0.01) and 3 times in private care. An increase in the presence of diabetes was observed in all age groups, proportionally larger in lower age groups. The frequency of cesarean delivery in pregnancies which recorded diabetes fell from 64.5% in 1998/1999 to 39.8% in 2006/2007 in the public system; in the private system the frequency remained over 90%. CONCLUSIONS: The presence of diabetes mellitus in hospital deliveries increased throughout the two year periods, despite a fall in the overall number of deliveries and an increase in the number of women of childbearing age living in Ribeirao Preto. This trend means that not only diagnosis and treatment, but also pre-pregnancy interventions which may reverse it are called for. PMID- 24346559 TI - Gender and racial inequalities in trends of oral cancer mortality in Sao Paulo, Brazil. AB - OBJECTIVE: To analyse recent trends in oral cancer mortality, focusing specifically on differences concerning gender and race. METHODS: Official information on deaths and population in the city of Sao Paulo, 2003 to 2009, were used to estimate mortality rates from oral cancer (C00 to C10, International Classification of Diseases, 10th Revision), adjusted for age and stratified by gender (females and males) and race (blacks and whites). The Prais-Winsten auto regression procedure was used to analyse the time series. RESULTS: During the study period, 8,505 individuals living in the city of Sao Paulo died of oral cancer. Rates increased for females (rate of yearly increase = 4.4%, 95%CI 1.4;7.5), and levelled off for men, which represents an inversion of previous trends among genders in the city. Increases were identified for blacks, with a high rate of yearly increase of 9.1% (95%CI 5.5;12.9), and levelled off for whites. Oral cancer mortality in blacks almost doubled during the study period, and surpassed mortality in whites for almost all categories. CONCLUSIONS: Mortality presented a higher increase among women than in men, and it doubled among backs. The surveillance of trends of oral cancer mortality across gender and racial groups may contribute to implementing socially appropriate health policies, which concurrently reduce the burden of disease and the attenuation of unfair, avoidable and unnecessary inequalities in health. PMID- 24346560 TI - [Cultural adaptation of the Brazilian version of the Godin-Shephard Leisure-Time Physical Activity Questionnaire]. AB - OBJECTIVE: To conduct the cultural adaptation of the Brazilian version of the Godin-Shephard Leisure-Time Physical Activity Questionnaire (GSLTPAQ) and to assess its content validity, practicability, acceptability and reliability. METHODS: The stages of translation, synthesis, back translation, expert committee review and pre-test were carried out, followed by the evaluation of the practicability, acceptability and reliability (test-retest). The judges assessed its semantic, idiomatic, conceptual, cultural and metabolic equivalences. The adapted version was submitted to the pre-test (n = 20), and test-retest (n = 80), in healthy individuals and in those suffering from cardiovascular disease in Limeira, SP, Southeastern Brazil, between 2010 and 2011. The proportion of agreement of the committee of judges was assessed using the Content Validity Index. Reliability was assessed by the criterion of stability, with 15 days between applications. Practicability was evaluated by the time spent interviewing and acceptability was estimated as the percentage of unanswered items and the proportion of patients who responded to all items. RESULTS: The translated version of the questionnaire showed evidence of appropriate semantic-idiomatic, conceptual, cultural and metabolic equivalence, with substitutions of several physical activities more appropriate to the Brazilian population. The practicability analysis showed short time needed for the application of the instrument (mean 3.0 minutes). As for acceptability, all patients answered 100% of the items. The test-retest analysis suggested that stability was good (Intraclass Correlation Coefficient value of 0.84). CONCLUSIONS: The Brazilian version of the questionnaire showed satisfactory measures of the qualities in question. Its application to diverse populations in future studies is recommended in order to provide robust measures of these qualities. PMID- 24346561 TI - [Validity study of the "Physical Activity Checklist" in children]. AB - OBJECTIVE: To assess the validity and operational equivalence of the "Physical Activity Checklist" in children. METHODS: This study complements the cross cultural adaptation of the Physical Activity Checklist Interview, conducted with 118 school children aged between seven and ten years old, enrolled from the second to the fifth grades of primary education in the city of Sao Paulo, SP, Southeastern Brazil, in 2009. The questionnaire enables the quantification of time spent in moderate and vigorous physical activities and sedentary activities and the total and weighted metabolic costs. The accelerometer was adopted as a criterion measure of physical activity. The variables total physical activity (counts/min) and time spent in moderate to vigorous physical activity were quantified. The concurrent validity was assessed by Pearson's correlation coefficient while the operational equivalence was assessed by data concerning the duration and evaluation of the interview. RESULTS: The values for the correlation coefficient between the results from the questionnaire and the accelerometer ranged from 0.34 to 0.40. It was found that LAF overestimates time spent doing moderate and vigorous physical activity when compared to the accelerometer. The average duration of the interviews was 24 minutes (minimum = 13 min, maximum = 41 min, sd = 5 min). The interview item showing the poorest result was the children's ability to estimate time (poor or fair in 24.8% of interviews). CONCLUSIONS: In relation to the original version, the questionnaire "Physical Activity Checklist" presents similar indices of concurrent validity and operational equivalence, confirming the appropriateness of the cross-cultural adaptation. PMID- 24346562 TI - Effects of irregular-shift work and physical activity on cardiovascular risk factors in truck drivers. AB - OBJECTIVE: To analyze the putative effect of type of shift and its interaction with leisure-time physical activity on cardiovascular risk factors in truck drivers. METHODS: A cross-sectional study was undertaken on 57 male truck drivers working at a transportation company, of whom 31 worked irregular shifts and 26 worked on the day-shift. Participants recorded their physical activity using the International Physical Activity Questionnaire along with measurements of blood pressure, body mass index and waist-hip ratio. Participants also provided a fasting blood sample for analysis of lipid-related outcomes. Data were analyzed using a factorial model which was covariate-controlled for age, smoking, work demand, control at work and social support. RESULTS: Most of the irregular-shift and day-shift workers worked more than 8 hours per day (67.7% and 73.1%, respectively). The mean duration of experience working the irregular schedule was 15.7 years. Day-shift workers had never engaged in irregular-shift work and had been working as a truck driver for 10.8 years on average. The irregular-shift drivers had lower work demand but less control compared to day-shift drivers (p < 0.05). Moderately-active irregular-shift workers had higher systolic and diastolic arterial pressures (143.7 and 93.2 mmHg, respectively) than moderately active day-shift workers (116 and 73.3 mmHg, respectively) (p < 0.05) as well as higher total cholesterol concentrations (232.1 and 145 mg/dl, respectively) (p = 0.01). Irrespective of their physical activity, irregular-shift drivers had higher total cholesterol and LDL-cholesterol concentrations (211.8 and 135.7 mg/dl, respectively) than day-shift workers (161.9 and 96.7 mg/dl, respectively (ANCOVA, p < 0.05). CONCLUSIONS: Truck drivers are exposed to cardiovascular risk factors due to the characteristics of the job, such as high work demand, long working hours and time in this profession, regardless of shift type or leisure time physical activity. PMID- 24346563 TI - [Screening for dependence in activities of daily living in the elderly: minimum set of questions]. AB - OBJECTIVE: To analyze non-redundant questions on independence in activities of daily living in the elderly, representing the spectrum of dependency. METHODS: Multicenter project with a probabilistic population sample of 5,371 elderly residents in Sao Paulo, SP, Rio de Janeiro, RJ, Fortaleza, CE and Bambui, MG in 2008. A household survey was carried out and a questionnaire with 20 activities of daily living applied for the elderly to self-assess the difficulty/need for help in performing them. The responses were analyzed according to: the prevalence of some kind of difficulty/need for help for each activities of daily living, the frequency of non-response, and the grouping of activities in factor analysis. RESULTS: The personal activities (e.g., dressing) have, on average, a low prevalence of difficulty or need for help, compared to instrumental activities (e.g., shopping), and have lower rates of non- response. In factor analysis it was possible to identify three factors grouping the activities of daily living: one relative to mobility (e.g., walking 100 m), another for personal needs (e.g., bathing) and one relative to what someone else can do for the elderly (e.g., washing clothes). The activities of daily living with the highest eigenvalues in each group were also analyzed in the light of the prevalence of reported need for help and the proportion of non response. Three activities of daily living were selected as representing the spectrum of dependency and being well understood by the elderly - getting out of bed, bathing and walking 100 m. CONCLUSIONS: With only three activities of daily living we can have a simple and reliable screening instrument capable of identifying elderly in need of help in daily life. Estimating demand for care on a daily basis is an important indicator for planning and administration of health services within the paradigm of chronic diseases and population aging. PMID- 24346564 TI - Effect of eliminating chronic diseases among elderly individuals. AB - OBJECTIVE: To determine whether the elimination of certain chronic diseases is capable of leading to the compression of morbidity among elderly individuals. METHODS: A population-based, cross-sectional study was carried out with official data for the city of Sao Paulo, Southeastern Brazil in 2000 and data from the SABE (Health, Wellbeing and Ageing) study. Sullivan's method was used to calculate disability-free life expectancy. Cause-deleted life tables were used to calculate the probabilities of death and disabilities with the elimination of health conditions. RESULTS: The largest gains in disability-free life expectancy, with the elimination of chronic illness, occurred in the female gender. Among individuals of a more advanced age, gains in disability-free life expectancy occurred as result of a relative compression of morbidity. Among men aged 75 years, all conditions studied, except heart disease and systemic arterial pressure, led to an absolute expansion of morbidity and, at the same time, to a relative compression of morbidity upon being eliminated. CONCLUSIONS: The elimination of chronic diseases in the elderly could lead to the compression of morbidity in elderly men and women. PMID- 24346565 TI - [Instrument to measure adherence in hypertensive patients: contribution of Item Response Theory]. AB - OBJECTIVE: To analyze, by means of "Item Response Theory", an instrument to measure adherence to t treatment for hypertension. METHODS: Analytical study with 406 hypertensive patients with associated complications seen in primary care in Fortaleza, CE, Northeastern Brazil, 2011 using "Item Response Theory". The stages were: dimensionality test, calibrating the items, processing data and creating a scale, analyzed using the gradual response model. A study of the dimensionality of the instrument was conducted by analyzing the polychoric correlation matrix and factor analysis of complete information. Multilog software was used to calibrate items and estimate the scores. RESULTS: Items relating to drug therapy are the most directly related to adherence while those relating to drug-free therapy need to be reworked because they have less psychometric information and low discrimination. The independence of items, the small number of levels in the scale and low explained variance in the adjustment of the models show the main weaknesses of the instrument analyzed. The "Item Response Theory" proved to be a relevant analysis technique because it evaluated respondents for adherence to treatment for hypertension, the level of difficulty of the items and their ability to discriminate between individuals with different levels of adherence, which generates a greater amount of information. CONCLUSIONS: The instrument analyzed is limited in measuring adherence to hypertension treatment, by analyzing the "Item Response Theory" of the item, and needs adjustment. The proper formulation of the items is important in order to accurately measure the desired latent trait. PMID- 24346566 TI - [Violence and mental suffering among men in primary health care]. AB - OBJECTIVE: To analyze the association between male mental health problems and violence experienced. METHODS: Cross sectional study with 477 males aged between 18 and 60, users of two primary healthcare centers in Sao Paulo, SP, Southeastern Brazil. The selection for the sample was based on a sequentiality criterion, according to the order of arrival of the users. Sociodemographic and health characteristics and reports of having experienced violence at any time and/or having witnessed violence in childhood were collected. Information was also collected on the use of mental health services and/or psychological complaints/diagnoses during consultation at medical clinics by reading medical records, to categorize the dependent variable "mental suffering". The variables were described as absolute and relative frequencies. The association was tested using a confirmatory Poisson model with robust variance adjusted for age, marital status, education, violence witnessed in childhood and psychoactive substance use. RESULTS: The prevalence of mental suffering was 29.4%. Mental suffering was associated with experiencing repeated physical and/or sexual violence (RP 1.75, 95%CI 1.13;2.72). The association with a single episode of violence lost significance after the inclusion of psychoactive substance use in the model. Analysis of the fraction attributable to repetitive physical and/or sexual violence for the mental suffering of the men, verified it as 30.4%. CONCLUSIONS: The relationship between violence and mental suffering, already highlighted in studies with women, is also relevant to men's health, drawing attention to the similar need of identification, in the health services, of situations of violence experienced by the male population. For men, this relationship was shown to be influenced by the presence of psychoactive substance use; a situation which must be dealt with, more and in a better way, by the health care service. PMID- 24346567 TI - [Adherence to healthy ways of life through counselling by health care professionals]. AB - OBJECTIVE: To estimate the prevalence of factors associated with adherence to healthy ways of life. METHODS: This is a cross-sectional study carried out with users aged over 19 from a primary health care unit in Belo Horizonte, MG, Southeastern Brazil, from 2009 to 2010. The sample was selected to estimate the proportion of people who adhere to healthy ways of life (healthy eating and physical activity) through counseling conducted by health care professionals, and associated socio-demographic, dietary and health factors. Additionally, the perceived benefits from the adherence to healthy ways of life and their possible barriers were verified. Descriptive analysis, univariate (Chi-square Test or Fisher's Exact) and multivariate by Poisson Regression were performed. RESULTS: Of the 417 users selected for the survey, only 40.8% received counseling, of which 50.9% demonstrated adherence. In multivariate Poisson regression, adherence was associated with the perception of food being healthy (PR = 1.67, 95%CI 1.15;2.43) and participation in the public service health campaigns(PR = 1.55, 95%CI 1.18;2.03). The main reported benefits of adherence were greater willingness and weight loss and, the most commonly reported barriers were difficulty of changing habits and lack of time. CONCLUSIONS: Adopting healthier lifestyles requires the proposing of strategies that promote adherence, as well as the participation of professionals in implementing counseling as a health promoting action that generates greater autonomy and quality of life among those involved, supported by policies and programs promoting health. PMID- 24346568 TI - [Evolution of the relative prices of food groups between 1939 and 2010 in the city of Sao Paulo, Southeastern Brazil]. AB - OBJECTIVE: To analyze the evolution of relative prices of food groups and its influence on public healthy eating policies. METHODS: Data from the municipality of Sao Paulo between 1939 and 2010 were analyzed based on calculating index numbers. Data from the Economic Researches Foundation Institute price database and weight structures (1939 to 1988) and from the Brazilian Institute of Geography and Statistics (1989 to 2010) were used to. The price database was organized, its consistency tested and prices were deflated using the consumer price index. Relative prices were calculated and associated to food categories and groups, according to the food pyramid guide adapted for the Brazilian population. The price indices for each group were calculated according to Laspeyres modified formula. The general food price index was compared with the indices for each food group and respective category: fresh food, processed food, beverages, meat, legumes, milk and eggs, cereals and root vegetables and eating out. RESULTS: Price indices for fat, oil, spices, sugars and sweets and processed food showed relative price reduction. Fresh food, such as fruit and vegetables, showed an increase in relative prices. Other food groups, such as cereals, flour and pasta, meat, milk and egg, showed a steadier long term trend in relative prices. CONCLUSIONS: The evolution of relative prices of food in the city of Sao Paulo demonstrates a negative trend towards healthy eating at household level in the long run. PMID- 24346569 TI - [Estimates of the prevalence of child malnutrition in Brazilian municipalities in 2006]. AB - OBJECTIVE: To estimate the prevalence of malnutrition in children for all Brazilian municipalities. METHODS: A multilevel logistic regression model was used to estimate the individual probability of malnutrition in 5,507 Brazilian municipalities in 2006, in terms of predictive factors grouped according to hierarchical levels. The response variable was child malnutrition (children aged from six to 59 months with height for age and sex below -2 z-scores, according to the World Health Organization standard). The predictive variables were determinants of malnutrition measured similarly by the National Demographics and Health Survey-2006 and the Sample from the 2000 Demographic Census. At level 1 (individual): sex and age, level 2 (household): socioeconomic variables, water and indoor plumbing, urban or rural area and level 3 (municipal): location of the municipality and coverage of the Family Health Strategy (FHS) in 2006. RESULTS: The study detected a statistically significant chance of malnutrition in male children, those living in households with two or more individuals per room, those belonging to the lowest quintiles of the socioeconomic score, those with three or more children under five in the household, those with no access to running water or located in the North. There was a negative dose-response association between FHS coverage and the chance of malnutrition (p = 0.007). FHS coverage in the municipality equal to or greater than 70% showed a 45% reduction in the chance of infant malnutrition. Estimates of the prevalence of child malnutrition show that most of the cities have the risk of malnutrition under control, very low or low. Risks of greater magnitude exist only in 158 municipalities in the North Region. CONCLUSIONS: Childhood malnutrition as a public health problem is concentrated in the cities of the North region, where FHS coverage is lower. A protective effect of FHS in relation to child malnutrition was found in the country as a whole, irrespective of other determinants of the problem. PMID- 24346570 TI - [Estimated sodium intake for the Brazilian population, 2008-2009]. AB - OBJECTIVE: To update estimates of sodium intake in Brazil. METHODS: We used data from the Brazilian Household Budget Survey of 2008-2009. Records of food purchases of households were converted into nutrients using food composition tables. Mean sodium availability per person per day and mean adjusted availability for a 2,000 kcal daily energy intake were calculated. The contribution of food groups to the total household sodium availability was calculated and compared to results estimated from the 2002-2003 Household Budget Survey. RESULTS: Mean daily sodium available for consumption in Brazilian households was 4.7 g per 2,000 kcal per day, thus still more than twice the recommended levels of intake for this nutrient. Although most of the sodium available for intake is derived from table salt or salt-based condiments (74.4%), the fraction derived from processed foods with added salt showed a strong linear increase with household income (12.3% of total sodium intake in the lower quintile of per capita income distribution and 27.0% in the upper quintile). There was a reduction in the contribution of salt and salt-based condiments (76.2% to 74.4%) and fresh or processed foods without added salt (6.6% to 4.8%) and an increase of processed foods with added salt (15.8% to 18.9%) and ready meals (1.4% to 1.6%), when compared to results estimated from the 2002-2003 Household Budget Survey. CONCLUSIONS: Sodium intake in Brazil remains at levels above the recommended maximum for this nutrient in all Brazilian macro regions and income strata. There was stability in the total household sodium availability, and an increase in the fraction from processed foods with addition of salt and ready meals, when comparing 2008-2009 with 2002-2003. PMID- 24346571 TI - [Public drinking water supply and egg laying by Aedes aegypti]. AB - OBJECTIVE: To evaluate the effect of the quality of publicly supplied water in domestic water tanks on egg laying by female Aedes aegypti. METHODS: Laboratory study on immature Ae. aegypti, collected from water-tanks in the municipality of Potim, SP, Southeastern Brazil. Each cage contained three types of water in which eggs could be laid: Three choice per test were simultaneously used to deposit the eggs, ovipositor (A) with water collected from a water tank in Taubate, ovipositor (B) with distilled water (control) and ovipositor (C) water collected from a water tank in the municipality of Potim. Physiochemical parameters were analyzed. The Kruskall-Wallis test was used to analyze the mean number of eggs in each water sample and the Dwass-Steel-Critchlow-Fligner test was used in making comparisons. To evaluate egg laying, an ovipositional activity index was adopted. RESULTS: A significant difference in the number of eggs was found between the liquid solutions tested (H = 45; p < 0.0001). The number of eggs found in water tank samples originating from deep wells (C), was statistically superior to water samples from water tanks originating from superficial wells (A) (p < 0.0001) and from the Control (C) p < 0.0001. There was no significant difference between the number of eggs in Control (B) and the surface water (A). In all three tests, the first position was the most productive in all tested solutions. Only water sample (C) produced a positive index (0.54), i.e., attractive to egg laying. CONCLUSIONS: Water quality influences egg laying by Aedes aegypti. The high concentrations of ammonium nitrate in public water supplies suggest that this chemical component was responsible for attracting pregnant female Aedes aegypti to lay eggs in these environments. PMID- 24346572 TI - Aedes aegypti entomological indices in an endemic area for dengue in Sao Paulo State, Brazil. AB - OBJECTIVE: To evaluate the most productive types of properties and containers for Aedes aegypti and the spatial distribution of entomological indices. METHODS: Between December 2006 and February 2007, the vector's immature forms were collected to obtain entomological indices in 9,875 properties in the Jaguare neighborhood of Sao Jose do Rio Preto, SP, Southeastern Brazil. In March and April 2007, a questionnaire about the conditions and characteristics of properties was administered. Logistic regression was used to identify variables associated with the presence of pupae at the properties. Indices calculated per block were combined with a geo-referenced map, and thematic maps of these indices were obtained using statistical interpolation. RESULTS: The properties inspected had the following Ae. aegypti indices: Breteau Index = 18.9, 3.7 larvae and 0.42 pupae per property, 5.2 containers harboring Ae. aegypti per hectare, 100.0 larvae and 11.6 pupae per hectare, and 1.3 larvae and 0.15 pupae per inhabitant. The presence of yards, gardens and animals was associated with the presence of pupae. CONCLUSIONS: Specific types of properties and containers that simultaneously had low frequencies among those positive for the vector and high participation in the productivity of larvae and pupae were not identified. The use of indices including larval and pupal counts does not provide further information beyond that obtained from the traditional Stegomyia indices in locations with characteristics similar to those of Sao Jose do Rio Preto. The indices calculated per area were found to be more accurate for the spatial assessment of infestation. The Ae. aegypti infestation levels exhibited extensive spatial variation, indicating that the assessment of infestation in micro areas is needed. PMID- 24346573 TI - [Occupational pesticide poisoning mortality, 2000-2009, Brazil]. AB - OBJECTIVE: To estimate the mortality rate due to occupational pesticide poisoning in Brazil. METHODS: Data on diagnoses of death from pesticide poisoning between 2000 and 2009 were obtained from the Mortality Information System. ICD-10 codes T60.0-T60.4, T60.8 and T60.9, Y18, X487 and Z578 as the main or secondary cause of death; data on work-related deaths were obtained from the death certificate, from the fields , and whether cases were agricultural workers. Homicides and suicides were excluded. To calculate mortality, the number of agricultural workers was obtained from the Brazilian Institute of Geography and Statistics, National System of Accounts estimates. RESULTS: There were 2,052 deaths recorded as caused by pesticide poisoning in Brazil, between 2000 and 2009, of which 36.2% (n = 743) had no occupation data. Of the remaining 1,309, 679 (51.9%) were agricultural workers. Mortality from occupational pesticide poisoning declined from 0.56/100.000 (2000 2001) to 0.39/100.000 (2008-2009) workers during the study period, and there was a larger decrease among men compared with women. Males had a higher mortality from this type of poisoning than women in all study years. Most deaths were caused by organophosphates and carbamate pesticides poisoning. During the study period the number of cases declined in all regions, except for the Northeast. CONCLUSIONS: Improvement in the quality of Death Certificate records is needed, particularly for occupation and the assessment of causes of death as work related, crucial for work injuries control and prevention programs. Special attention is required in the Northeast region. PMID- 24346574 TI - [Motorcycle accidents: comparison between the years 1998 and 2010 in Londrina, Southern Brazil]. AB - OBJECTIVE: To compare the characteristics of motorcycle accidents and victims attended by pre-hospital care services. METHODS: A cross-sectional study was carried out using data on pre-hospital care of motorcyclists who had been injured in traffic accidents in Londrina, PR, Southeastern Brazil, in 2010, whose results were compared with those of a similar study conducted in 1998. Paramedic assistance registration forms were used as source of data. The fleets of motorcycles and the population of both years were used for estimating risks of accidents occurring. The Chi-square test was used to compare the profiles of accidents and victims. RESULTS: In 1998 and in 2010, respectively, 1,576 and 3,968 motorcyclists were seen (increase of 151.8%). The rate of injured motorcyclists per 1,000 inhabitants rose from 396.4 to 783.1, and that of the victims per 1,000 motorcycles from 53.1 to 61.1. Changes (p < 0.05) in the profile of accidents were observed, with higher proportions of falls from motorcycles, accidents between motorcyclists and occurrence during mornings, and a reduction of those at weekends. Regarding the victims, higher proportions of women, drivers, and those aged 35 years or over were observed. There was a decrease in the relative frequency of positive breathalyser results and an increase in the prevalence of helmet use. A lower proportion of victims were classified with moderate/severe coma and trauma scores and sent to hospitals. The immediate fatality rate dropped from 1.2% to 0.6%. CONCLUSIONS: Changes in the profiles of accidents and victims were observed in the period. Despite an absolute and relative increase in the number of victims of motorcycle accidents, a proportionally lower severity of these accidents was observed. PMID- 24346575 TI - [Instruments in Brazilian Sign Language for assessing the quality of life of the deaf population]. AB - OBJECTIVE: To construct versions of the WHOQOL-BREF and WHOQOL-DIS instruments in Brazilian sign language to evaluate the Brazilian deaf population's quality of life. METHODS: The methodology proposed by the World Health Organization (WHOQOL BREF and WHOQOL-DIS) was used to construct instruments adapted to the deaf community using Brazilian Sign Language (Libras). The research for constructing the instrument took placein 13 phases: 1) creating the QUALITY OF LIFE sign; 2) developing the answer scales in Libras; 3) translation by a bilingual group; 4) synthesized version; 5) first back translation; 6) production of the version in Libras to be provided to the focal groups; 7) carrying out the Focal Groups; 8) review by a monolingual group; 9) revision by the bilingual group; 10) semantic/syntactic analysis and second back translation; 11) re-evaluation of the back translation by the bilingual group; 12) recording the version into the software; 13) developing the WHOQOL-BREF and WHOQOL-DIS software in Libras. RESULTS: Characteristics peculiar to the culture of the deaf population indicated the necessity of adapting the application methodology of focal groups composed of deaf people. The writing conventions of sign languages have not yet been consolidated, leading to difficulties in graphically registering the translation phases. Linguistics structures that caused major problems in translation were those that included idiomatic Portuguese expressions, for many of which there are no equivalent concepts between Portuguese and Libras. In the end, it was possible to create WHOQOL-BREF and WHOQOL-DIS software in Libras. CONCLUSIONS: The WHOQOL BREF and the WHOQOL-DIS in Libras will allow the deaf to express themselves about their quality of life in an autonomous way, making it possible to investigate these issues more accurately. PMID- 24346576 TI - [Fatality and hospitalization in hemodialysis patients in a health plan]. AB - OBJECTIVE: To analyze clinical outcomes of patients on hemodialysis linked to health care plan provider. METHODS: Cohort study of hemodialysis events in Belo Horizonte, MG, Southeastern Brazil, between 2004 and 2008, based on records from health care plan provider databases. The independent variables were: sex, age, time between first appointment with nephrologist and starting hemodialysis, type of first vascular access, diabetes mellitus, length of time spent in hospital/year of treatment and death. DEPENDENT VARIABLES: time between starting hemodialysis and death and length of time spent in hospital/year of treatment > 7.5 days. Statistical analysis was carried out using Pearson's Chi-squared test in the univariate analysis for the outcomes 'death' and 'length of time spent in hospital/year of treatment'; the Kaplan-Meier method was used to analyze survival; the Cox model and Poisson regression were used for risk of death and chance of length of time spent in hospital/year of treatment > 7.5 days. The Business Intelligence tool and Stata(r) 10.0 software were used to extract data. RESULTS: There were 311 patients on hemodialysis included in the study, with a mean age of 62 (sd 16.6 years), of whom 55.5% were male. Prevalence increased 160% during the period in question. Survival analysis showed a higher mortality among older patients, patients that did not consult a nephrologists, those whose first vascular access was using a temporary catheter, those with diabetes mellitus, those admitted to hospital within a month of beginning hemodialysis. The Cox model showed that a higher risk of death was associated with age, diabetes mellitus, not consulting a nephrologists and those that were hospitalized within a month of beginning hemodialysis. Greater length of time spent in hospital/year of treatment was not associated with sex or diabetes. According to Poisson regression, the variables were not significant. CONCLUSIONS: Assessment by a specialist before starting hemodialysis decreases the risk of death in cases of chronic kidney disease, whereas the presence of diabetes and being hospitalized within a month of beginning hemodialysis are markers of risk of death. PMID- 24346577 TI - [Food consumption and dietary factors involved in health and disease in Nikkeis: systematic review]. AB - OBJECTIVE: To analyze food consumption and dietary factors involved in the Nikkei population's health and disease processes METHODS: A systematic review of observational studies that described Nikkeis' food intake was carried out in electronic databases Lilacs, SciELO and PubMed/Medline databases, from 1997 to 2012. Initially, 137 titles and abstracts were analyzed, excluding intervention studies, those which only presented metabolite and vitamin plasma levels and those which did not meet the objective of this study. Of these, 38 studies were selected and evaluated using a method based on Downs & Black (1998), adapted for observational studies, leaving 33 studies to be analyzed. RESULTS: Few studies about Nikkei food intake were found outside of Hawaii, in the United States, and Sao Paulo (mainly in the city of Bauru) in Brazil. The total energy intake of Japanese-Brazilians had an elevated fat contribution, decreasing carbohydrate and protein intake. In the United States, the prevalence of Japanese-Americans who consumed high density energy food was elevated. The Niseis (children of immigrants) presented, on average, higher intake of Japanese food products, while the Sanseis (grandchildren of immigrants) showed more Westernized dietary habits. CONCLUSIONS: Although some Japanese food habits have been maintained, the Nikkeis' dietary intake reveals a high prevalence of typical Westernized food intake (high in processed food, fat and sodium, and poor in fiber), that may be contributing to the increasing development of chronic disease in this population. PMID- 24346578 TI - Proteomic analysis of the effect of diclazuril on second-generation merozoites of Eimeria tenella. AB - Diclazuril has long been used as an effective benzeneacetonitrile anticoccidial for the control of Eimeria tenella that causes coccidiosis. However, the molecular mechanism underlying the anticoccidial effects of diclazuril remains elusive. In this study, a proteomic analysis of the effect of diclazuril on second-generation merozoites of E. tenella was performed. Using two-dimensional gel electrophoresis and real-time quantitative polymerase chain reaction (RT PCR), 13 target proteins were found to be significantly affected by diclazuril treatment, with 11 of these proteins being identified as annotated proteins from E. tenella or other Apicomplexa parasites. These proteins contribute to various functions, including metabolism, protein synthesis, and host cell invasion. Using RT-PCR, we identified the potential pattern of transcriptional regulation induced by diclazuril, and we suggest some promising targets for the intervention of E. tenella infection. PMID- 24346579 TI - Minithoracotomy versus sternotomy for mitral surgery in patients with chronic renal impairment: a propensity-matched study. AB - OBJECTIVE: Compared with median sternotomy, a right thoracotomy (RT) approach to mitral surgery is associated with decreased postoperative acute renal failure. Therefore, we examined propensity-matched patients with chronic renal impairment to compare outcomes. METHODS: A retrospective review at a single institution identified patients who underwent mitral valve surgery from 1986 to 2010. After excluding patients who had procedures that were not usually performed through an RT approach, 2306 patients were identified. Of this group, we found 446 patients with preoperative creatinines of 1.3 mg/dL or greater. Using propensity score matching based on comorbidities, operative year, and surgeon, 90 matched patients in each group were included. RESULTS: There was no difference in the median year of operation. Postoperative mortality is 20% lower for the RT group (P = 0.037) using Mantel-Cox statistics. This greater survival in the RT group occurred early within the first year and was maintained on long-term follow-up. The RT approach was also associated with a Cox proportional hazard for mortality of 0.528 (P = 0.006). Incidence of postoperative complications with an RT approach was lower in terms of acute renal failure (10% vs 21%, P = 0.05), stroke (1% vs 9%, P = 0.017), and permanent pacemaker insertion (3% vs 11%, P = 0.044). Right thoracotomy was associated with lower chest tube outputs (503 vs 1333 mL, P < 0.001). CONCLUSIONS: The RT approach was associated with lower postoperative mortality and morbidity in patients with impaired renal function. The RT approach to the mitral valve may be preferred in this high-risk population. PMID- 24346580 TI - Outcome of patients treated with Engager transapical aortic valve implantation: one-year results of the feasibility study. AB - OBJECTIVE: The aim of this study was to investigate the short-term and midterm outcome of the Engager transcatheter aortic valve implantation (TAVI) system, a transapical self-expanding valve device with anatomic orientation. METHODS: Transapical aortic valve implantation with the Engager valve prosthesis was performed in 10 patients. Endpoints were defined according to the Valve Academic Research Consortium recommendations for reporting outcomes of TAVI in clinical trials. Follow-up has been completed after 30 days and 1 year. RESULTS: All patients underwent the implantation procedure successfully. No device-related or delivery system-related complications were observed. One patient died of non device-related reasons at postoperative day 23 in multiorgan failure. At 30-day follow-up, no more than mild transvalvular and paravalvular aortic regurgitation were seen. After 1 year, no transvalvular regurgitation was observed as assessed by transthoracic echocardiography. None of the patients had more than mild paravalvular leakage. The mean +/- SD gradient was 15.3 +/- 4.2 mm Hg. New York Heart Association class decreased one degree in mean and sustained until 1-year follow-up. No more patients died until 1-year follow-up. CONCLUSIONS: Application of the Engager TAVI system is safe and reliable. Prosthesis deployment in an anatomically correct position was facilitated by the design of the valve prosthesis and successful in all patients. No device-related or delivery system related complications occurred. Procedural, short-term, and midterm results up to 1 year concerning the aortic valve performance are promising, with stable mean gradients and low rates of even mild regurgitation. PMID- 24346581 TI - Implantable loop recorders after atrial ablation: patient compliance and data surveillance in clinical practice. AB - OBJECTIVE: Recent data suggest continuous monitoring by implanted loop recorder (ILR) to be the criterion standard for rhythm surveillance after atrial ablation. Studies describing patient compliance and pitfalls in the perioperative period are lacking. It was the aim of this study to evaluate patient compliance and time invested by physicians for obtaining data during the follow-up period after implanting an ILR. METHODS: We prospectively collected data of 70 consecutive patients undergoing concomitant cardiac surgery, atrial ablation, and implantation of an ILR. Patient compliance was calculated as the ratio of incoming/expected data transmission. We documented total time spent by physicians with preoperative and postoperative supervision. RESULTS: Between February 2012 and February 2013, a total of 70 patients had an ILR implanted; 49 of 70 patients were eligible for evaluation of data at 3-month follow-up. The ratio of incoming/expected data transmission was 12/49 (24%). The mean +/- SD time spent with ILR-related issues during hospital stay was 88 +/- 19 minutes. Assessment of incoming data and information of the patient and the general practitioner took 132 +/- 13 minutes per patient. Overall, a mean +/- SD of 220 +/- 16 minutes per patient was needed for appropriate data acquisition, from implantation to first data transmission. CONCLUSIONS: In the patients having an ILR after surgical atrial ablation, initial compliance regarding data transmission was low. A substantial time effort was necessary to obtain sufficient data on cardiac rhythm. Device-related complications were observed. Patient selection should therefore be handled with care. Beneficial therapeutic decisions can be expected only when reliable data are obtained by efficient management. PMID- 24346582 TI - Hiatal hernia repair with or without esophageal lengthening: is there a difference? AB - OBJECTIVE: The need for esophageal lengthening (EL) as part of hiatal hernia (HH) repair is perceived to elevate perioperative risk and provide functionally inferior outcomes. Our objectives were to determine the risk factors of undergoing EL and to compare outcomes between operations with and without EL. We hypothesized that operative and functional outcomes for HH repair were similar in patients whether they required EL or not. METHODS: We reviewed institutional experience with EL as part of HH repair. The patients underwent symptom evaluation before and after surgery using a validated tool. RESULTS: Between 1999 and 2009, a total of 375 patients underwent HH repair. The operative approach was thoracotomy, 153 (41%); laparotomy, 18 (5%); laparoscopy, 167 (44%); or combined, 37 (10%). Of these, 168 (45%) required EL. There was a higher need for thoracotomy in the patients undergoing EL (79/168 vs 74/207, chi = 4.88, P = 0.034). The incidence of perioperative complications (leak, pneumonia, ileus, respiratory failure, and bleeding) was similar between the groups. Sixty-five selected patients undergoing EL were compared with 63 patients with comparable demographics not requiring EL. In a well-validated questionnaire that assessed symptoms before and after surgery, the patients undergoing EL showed significant improvement in their heartburn (76.8%), dysphagia (67.6%), regurgitation (71.7%), chest pain (91.9%), and nausea (86.5%) (P < 0.05). The patients not undergoing EL also showed significant improvement in their heartburn (81.1%), dysphagia (71.1%), regurgitation (64.4%), chest pain (64.1%), and nausea (61.0%) (P < 0.05). Improvement in symptoms, the continued use of antacid medications, and overall surgery satisfaction score were statistically similar between the two groups. CONCLUSIONS: Operative and functional outcomes for HH repair with or without EL are acceptable and comparable. Thoracic surgeons should use EL without reservations for appropriate indications. PMID- 24346583 TI - Initial experience with intraventricular repair using CorMatrix extracellular matrix. AB - OBJECTIVE: Pericardial patches for intraventricular repair are limited by progressive calcification, thickening, and retraction. The aim of this study was to evaluate the safety of CorMatrix extracellular matrix (ECM) for intraventricular repair of mechanical complications of myocardial infarction (MI). METHODS: CorMatrix ECM is a novel material synthesized from decellularized porcine small intestinal submucosa. Between July 2011 and October 2012, a total of 11 consecutive patients with post-MI complications including ventricular aneurysm (n = 7), ventricular septal defect (VSD; n = 3), and both aneurysm and VSD (n = 1) underwent patch repair using CorMatrix ECM. Clinical follow-up and interval transthoracic echocardiography data were collected. RESULTS: Eleven patients underwent Dor or linear left ventricular aneurysm repair and/or patch VSD repair. There were two reoperations and one surgical mortality but no cases of CorMatrix ECM repair failures. The mean +/- SD clinical follow-up was 207 +/- 211 days, and the longest follow-up was 642 days, during which there was no readmission for any cardiac cause or death. The mean +/- SD transthoracic echocardiography follow-up was 176 +/- 220 days, which demonstrated integrity of CorMatrix ECM repair in all cases. CONCLUSIONS: In our series, CorMatrix ECM was a safe alternative for ventricular patch repair of mechanical complications after MI in the short-term. This series supports the continued study of the efficacy and the regenerative potential of this novel material for cardiac repair. PMID- 24346584 TI - Defining the learning curve for robotic-assisted endoscopic harvesting of the left internal mammary artery. AB - OBJECTIVE: Robotic-assisted techniques are continuing to cement their role in coronary surgery, particularly in facilitating the endoscopic harvesting of the left internal mammary artery (LIMA), regardless of how the subsequent bypass grafting is performed. As more surgeons attempt to become trained in robotic assisted procedures, we sought to better define the learning curve associated with robotic-assisted endoscopic LIMA harvest. METHODS: Between January 2011 and July 2012, a total of 77 patients underwent robotic-assisted minimally invasive direct coronary artery bypass surgery at our institution. The LIMA was harvested endoscopically in all patients, using standard robotic instruments, followed by direct grafting to anterior wall myocardial vessels via a small thoracotomy. Intraoperative times for various components of the procedure were collated and analyzed. RESULTS: The mean +/- SD time taken to insert and position the ports for the robotic instruments was 3.9 +/- 1.4 minutes. The mean +/- SD LIMA harvest time was 31.8 +/- 10.1 minutes, and the mean +/- SD total robotic time was 44.2 +/- 12.9 minutes. All time variables consistently continued to decrease as the experience of the operating surgeon increased, with the greatest magnitude of improvement being evident within the first 20 cases. The logarithmic learning curves for LIMA harvest time and total robot time during our entire experience were both calculated as 90%, correlating to an expected 10% improvement in performance for each doubling of cases completed. CONCLUSIONS: Coronary surgeons can rapidly become proficient in robotic-assisted endoscopic LIMA harvest, with significant improvement in operative times evident within the first 20 cases completed. These data may be useful in designing appropriate training programs for newer surgeons seeking to gain experience in robotic-assisted coronary surgery. PMID- 24346585 TI - Survival, predictive factors, and causes of mortality following transcatheter aortic valve implantation. AB - OBJECTIVE: Transcatheter aortic valve implantation (TAVI) is considered the standard of care for patients with severe symptomatic aortic stenosis unsuitable for surgery. However, short- and long-term mortality after TAVI are still relatively high. The aim of this study was to establish survival, predictive factors, and causes of mortality after TAVI at early and midterm follow-up. METHODS: Between December 2007 and May 2012, a total of 119 patients with symptomatic severe aortic stenosis underwent 121 TAVI procedures. The mean +/- SD age was 81 +/- 9 years, and 59% were men. The mean +/- SD logistic European System for Cardiac Operative Risk Evaluation was 22 +/- 15. Seventy-five patients (63%) were in New York Heart Association functional class III to IV. The transfemoral approach was used in 76% of the patients. One hundred ten patients (91%) had the CoreValve prosthesis, and 11 (9%) had an Edwards SAPIEN valve. Baseline characteristics, procedural complications, and outcomes were collected prospectively. Clinical outcomes were defined according to the Valve Academic Research Consortium criteria. Follow-up was completed for 100% of the patients at a median of 1.3 years (range, 0-4.5). RESULTS: The total number of deaths was 36 (30%). One-month mortality was 4.2%. Actuarial survival was 83.2%, 76.5%, and 68.2% at 1, 2, and 3 years, respectively. Acute kidney injury occurred in 12.3% of the patients, none of whom required dialysis during hospitalization. Twenty one patients (17.6%) had new conduction abnormalities that required permanent pacemaker implantation before hospital discharge. The incidence of major vascular injury and stroke was 2.4% and 4.1%, respectively. Survival was significantly adversely affected by preprocedural left ventricular dysfunction (P = 0.04), history of atrial fibrillation (P = 0.03), prior heart block (P < 0.01), and critical preoperative state (P < 0.01). Twelve (33%) of the 36 deaths were due to bronchopneumonia. In 12 (33%) of the 36 patients who died, mortality was related to cardiac causes. When a death occurred within the first 30 days, it was mainly cardiac in nature (80%). Twelve patients (34%) died because of a variety of other reasons such as pulmonary embolism, stroke, cancer, renal failure, and sepsis. CONCLUSIONS: Preprocedural left ventricular dysfunction, atrial fibrillation, and heart block are independent predictive factors of all-cause mortality. Early mortality was mainly cardiac in origin. Most of the late deaths were caused by noncardiac reasons, with bronchopneumonia being reported as the most common cause of late mortality. PMID- 24346586 TI - Design characteristics of a three-dimensional geometric aortic valve annuloplasty ring. AB - OBJECTIVE: A full geometric annuloplasty ring could facilitate aortic valve repair. The purpose of this report was to document the design of such a ring using mathematical analyses of normal human aortic valve computed tomographic angiograms. METHODS: One-millimeter axial slices of high-resolution computed tomographic angiograms from 11 normal aortic roots were used to generate high density x, y, and z coordinates of valve structures in Mathematica. Three dimensional least squares regression analyses of leaflet-sinus coordinates were used to assess geometry of aortic valve and root structures. RESULTS: Normal valve geometry could be represented as three leaflet-sinus general ellipsoids nested within an elliptical aortic root. Minor-major diameter ratio of the valve base was 0.60 +/- 0.07, and elliptical geometry extended vertically up the commissures. By contrast, leaflet-sinus horizontal circumferences were fairly circular (diameter ratios, 0.82-0.87), and the left coronary/noncoronary commissural post was located at the posterior base minor diameter-circumference junction, with the center of the right coronary leaflet opposite. Post location on the circumference was symmetrical, with a deviation of only +/-2% to +/-3% from 33.3% symmetry. Commissural posts flared outward by 5 to 10 degrees, and leaflet areas were statistically equivalent (P > 0.10). From end diastole to midsystole, the aortic root became less elliptical (diameter ratio increased by 0.15), but root area expanded minimally (less than +5%). A one-piece rigid annuloplasty ring was designed with 2:3 base ellipticality, three 10-degree outwardly flaring symmetrical posts, and post height = base circumference/2pi. CONCLUSIONS: A three-dimensional aortic annuloplasty ring was designed that could prove useful for enhancing applicability and stability of aortic valve repair. PMID- 24346587 TI - Epicardial surgical ligation of the left atrial appendage is safe, reproducible, and effective by transesophageal echocardiographic follow-up. AB - OBJECTIVE: The left atrial appendage (LAA) is the source of 90% of thrombi in patients with atrial fibrillation. Our double LAA ligation (LLAA) technique was shown to be 96% successful in a small study. However, the outcomes of these patients have yet to be compared with a set of nonligated patients. METHODS: From 2005 to 2012, a total of 808 patients received LAA using our double ligation technique using both a polydioxanone (PDS) II endosnare and a running 4-0 Prolene pledgeted suture. The 30-day outcomes of these patients were compared with that of nonligated patients. Fifty-six of the ligated patients had a postoperative transesophageal echocardiography (TEE). An echocardiographer reviewed the follow up TEEs for LAA remnant and/or residual flow into the LAA using color Doppler imaging. The patients with LAA flow and/or remnant depth of 1 cm or greater were deemed to have an unsuccessful exclusion. RESULTS: The ligated group had a trend of less postoperative atrial fibrillation (19.4% vs 22.9%, P = 0.07) and an overall significantly lower in-hospital mortality (0.7% vs 3.0%, P < 0.001) and lower 30-day mortality (0.7% vs 3.4%, P < 0.0001). The LAA was successfully excluded in 53 (94.7%) of the 56 patients with TEE. CONCLUSIONS: Double LAA ligation correlates with lower rates of in-hospital and 30-day mortality. This advantage comes without an increase in perioperative complications. This technique can easily be performed off or on pump, is very reproducible, and comes at a very low cost compared with LAA occlusion devices. Stroke has a multifactorial etiology; successful LLAA removes one potential source of thrombi perioperatively and in the long-term. PMID- 24346588 TI - Measurements of the evaporation and hygroscopic response of single fine-mode aerosol particles using a Bessel beam optical trap. AB - A single horizontally-propagating zeroth order Bessel laser beam with a counter propagating gas flow was used to confine single fine-mode aerosol particles over extended periods of time, during which process measurements were performed. Particle sizes were measured by the analysis of the angular variation of light scattered at 532 nm by a particle in the Bessel beam, using either a probe beam at 405 nm or 633 nm. The vapour pressures of glycerol and 1,2,6-hexanetriol particles were determined to be 7.5 +/- 2.6 mPa and 0.20 +/- 0.02 mPa respectively. The lower volatility of hexanetriol allowed better definition of the trapping environment relative humidity profile over the measurement time period, thus higher precision measurements were obtained compared to those for glycerol. The size evolution of a hexanetriol particle, as well as its refractive index at wavelengths 532 nm and 405 nm, were determined by modelling its position along the Bessel beam propagation length while collecting phase functions with the 405 nm probe beam. Measurements of the hygroscopic growth of sodium chloride and ammonium sulfate have been performed on particles as small as 350 nm in radius, with growth curves well described by widely used equilibrium state models. These are the smallest particles for which single-particle hygroscopicity has been measured and represent the first measurements of hygroscopicity on fine mode and near-accumulation mode aerosols, the size regimes bearing the most atmospheric relevance in terms of loading, light extinction and scattering. Finally, the technique is contrasted with other single particle and ensemble methods, and limitations are assessed. PMID- 24346589 TI - Synthesis of the 2-methylene analogue of the HRV 3C protease inhibitor thysanone (2-carbathysanone). AB - The Human Rhinovirus (HRV) is the major aetiological agent for the common cold, for which only symptomatic treatment is available. HRV maturation and replication is entirely dependent on the activity of a virally encoded 3C protease that represents an attractive target for the development of therapeutics to treat the common cold. Herein we report the synthesis and biological evaluation of the 2 methylene analogue of the HRV 3C protease inhibitor (-)-thysanone (1) namely 2 carbathysanone (2), in an attempt to decipher the structural features in the natural product that are responsible for the 3C protease activity. 2 Carbathysanone (2) (and related analogues (+/-)-cis-23, (+/-)-cis-30, (+/-)-31) did not inhibit HRV 3C protease, indicating that the lactol functionality present in (-)-thysanone (1) is a critical structural feature required for inhibition. PMID- 24346590 TI - A rapid synthesis of high aspect ratio copper nanowires for high-performance transparent conducting films. AB - This communication presents a way to produce copper nanowires with aspect ratios as high as 5700 in 30 min, and describes the growth processes responsible for their formation. These nanowires were used to make transparent conducting films with a transmittance >95% at a sheet resistance <100 Omega sq(-1). PMID- 24346592 TI - [Multilevel segmental interbody fusion versus vertebral body replacement: comparison of two operative methods]. AB - BACKGROUND: The surgical techniques of interbody fusion and vertebral body replacement represent two concurrent options for multilevel anterior decompression and arthrodesis of the cervical spine. PATIENTS AND METHODS: In a retrospective study the data from 61 patients who received either interbody fusion (n = 38) as anterior cervical discectomy and fusion (ACDF) or vertebral body replacement (n = 23) (as anterior cervical corpectomy and fusion (ACCF) because of degenerative disc disease of the cervical spine were collected. RESULTS: The clinical outcome was better at all time points in the patient group with ACDF than in those with ACCF but with no statistically significant differences. The operated segments showed a more rapid fusion progress after ACDF during the time course in comparison to ACCF; however, there was no relationship between the grade of fusion and the clinical result. CONCLUSION: In direct comparison multisegmental interbody fusion showed better results with respect to the clinical outcome and bony fusion with a lower rate of complications than vertebral body replacement. However, the differences did not reach statistical significance. PMID- 24346593 TI - Thromboembolic complications in childhood nephrotic syndrome: a clinical profile. AB - BACKGROUND: Thromboembolism is a rare life-threatening complication of childhood nephrotic syndrome. METHODS: We present the clinical profile and outcome of 34 children with 35 events of thromboembolic complications with nephrotic syndrome. RESULTS: Cerebral venous thrombosis (CVT) was the commonest complication seen in 11 (31.4 %) children followed by pulmonary thromboembolism and deep venous thrombosis in 9 (25.7 %) and 6 (16.6 %) children, respectively. Arterial thrombosis resulting in central nervous system infarcts was observed in 7 (20 %) children and 2 children had thrombosis of the peripheral arteries. Episodes were equal in steroid-resistant nephrotic syndrome and steroid-dependent nephrotic syndrome groups. Most of the thromboembolic complications occurred with relapse but 11.4 % of children developed intracranial thrombosis during remission. The most sensitive symptom of CVT was persistent headache while unexplained respiratory distress and hypoxemia pointed towards pulmonary thromboembolism. Hypoalbuminemia was seen in 82.8 % of children, while concurrent infection was seen in 31.4 %. Coexistence of genetic prothrombotic condition was identified and merits evaluation. Early heparin therapy followed by oral anticoagulants resulted in complete recovery in 91.1 % of children. Death occurred in 3 (8.5 %) children and autopsy revealed pulmonary thromboembolism in 2 children. CONCLUSION: Venous and arterial thrombotic complications can occur in children with nephrotic syndrome. A high index of suspicion is required as the clinical features may be subtle. Neuroimaging and angiographic techniques help in confirming diagnosis. Early aggressive heparin therapy followed by oral anticoagulants is necessary for a favorable outcome. PMID- 24346594 TI - Lack of long-term effects of high-dose inhaled beclomethasone for respiratory syncytial virus bronchiolitis: a randomized placebo-controlled trial. AB - BACKGROUND: Previously, we showed that high-dose early initiated inhaled corticosteroids during respiratory syncytial virus bronchiolitis partially and transiently prevents subsequent recurrent wheeze. Here, we study treatment effect on lung function at age 6. METHODS: This is a 6-year follow-up report of a randomized placebo-controlled trial, in which 185 infants hospitalized for respiratory syncytial virus bronchiolitis were treated with early initiated, high dose inhaled beclomethasone (n = 86) or placebo (n = 99) for 3 months. The primary outcome was forced expiratory volume in 1 second as percentage predicted. Secondary outcomes were bronchial hyperresponsiveness, physician-diagnosed asthma, hay fever and eczema. Possible toxicity was assessed by linear growth measurements. RESULTS: At age 6, no significant differences were found in mean forced expiratory volume in 1 second percentage predicted between beclomethasone treated and placebo-treated patients (91.4 vs. 93.4, mean difference 2.05 (95% confidence interval: -1.98 to 6.08). The proportion of bronchial hyperresponsiveness, physician-diagnosed asthma, parent reported hay fever and eczema was comparable between groups. There were no differences in linear growth. CONCLUSIONS: Early initiated prolonged treatment with high-dose inhaled beclomethasone during hospitalization for respiratory syncytial virus infection during infancy did not improve the long-term respiratory outcome, but was safe. PMID- 24346596 TI - Safety and immunogenicity of a toddler dose following an infant series of a hexavalent diphtheria, tetanus, acellular pertussis, inactivated poliovirus, Haemophilus influenzae type b, hepatitis B vaccine administered concurrently or at separate visits with a heptavalent pneumococcal conjugate vaccine. AB - BACKGROUND: Combination diphtheria-tetanus-5 component acellular pertussis inactivated poliovirus-Haemophilus influenzae b conjugate-hepatitis B vaccine (DTaP5-IPV-Hib-HepB) administered either concurrently with 7-valent pneumococcal conjugate vaccine (PCV7) or 1 month apart was generally safe and immunogenic at 2, 4 and 6 months of age. This study examined the effects of a booster dose at age 15 months. METHODS: Participants were randomized to DTaP5-IPV-Hib-HepB plus PCV7, DTaP5-IPV-Hib-HepB with PCV7 administered 1 month later or a pentavalent DTaP5-IPV/Hib plus HepB plus PCV7 at 15 months of age in a randomized, open label, phase IIb clinical trial. Immunogenicity endpoints were rates of seroresponse to pertussis toxoid, filamentous hemagglutinin, pertactin and fimbriae types 2 and 3; rates of seroprotection against (Hib) polyribosylribitol phosphate capsular polysaccharide, hepatitis B surface antigen, diphtheria toxoid, tetanus toxoid and poliovirus types 1, 2 and 3; and geometric mean titers to all vaccine antigens. Safety endpoints included solicited injection-site reactions and systemic and serious adverse events. RESULTS: Seroresponse/seroprotection rates for all antigens exceeded prespecified criteria in both groups that received the hexavalent DTaP5-IPV-Hib-HepB; in the group that received the currently licensed pentavalent vaccine, seroresponse/seroprotection rates exceeded the criteria for all antigens except filamentous hemagglutinin. Seroresponse rates were >=88.9% for pertussis antigens and seroprotection rates against polyribosylribitol phosphate capsular polysaccharide, hepatitis B surface antigen, diphtheria toxoid, tetanus toxoid and poliovirus antigens were >=95.1% in recipients of DTaP5-IPV-Hib-HepB. CONCLUSIONS: DTaP5-IPV-Hib-HepB administered concomitantly with PCV7 or 1 month apart at 15 months of age following the infant series was well-tolerated and elicited antibody responses to all vaccine antigens, with no significant interference from concomitant PCV7 administration (clinicaltrials.gov registration number NCT00362427). PMID- 24346597 TI - Common presentations of nontuberculous mycobacterial infections. PMID- 24346595 TI - Population pharmacokinetics of intravenous acyclovir in preterm and term infants. AB - BACKGROUND: Acyclovir is used to treat herpes infections in preterm and term infants; however, the influence of maturation on drug disposition and dosing requirements is poorly characterized in this population. METHODS: We administered intravenous acyclovir to preterm and term infants <31 days postnatal age and collected plasma samples. We performed a population pharmacokinetic analysis. The primary pharmacodynamic target was acyclovir concentration >=3 mg/L for >=50% of the dosing interval. The final model was simulated using infant data from a clinical database. RESULTS: The analysis included 28 infants (median 30 weeks gestation). Acyclovir pharmacokinetics was described by a 1-compartment model: clearance (L/h/kg) = 0.305 * [postmenstrual age (PMA)/31.3 weeks]. This equation predicts a 4.5-fold increase in clearance from 25 to 41 weeks PMA. With proposed dosing, the pharmacodynamic target was achieved in 91% of infants: 20 mg/kg every 12 hours in infants <30 weeks PMA; 20 mg/kg every 8 hours in infants 30 to <36 weeks PMA and 20 mg/kg every 6 hours in infants 36-41 weeks PMA. CONCLUSIONS: Acyclovir clearance increased with infant maturation. A dosing strategy based on PMA accounted for developmental changes in acyclovir disposition to achieve the surrogate pharmacodynamic target in many infants. PMID- 24346598 TI - Mycoplasma pneumoniae Infections in Childhood. PMID- 24346599 TI - Detection of NH1N1 influenza virus in nonrespiratory sites among children. AB - Among 20 children admitted with laboratory-confirmed influenza, viral RNA was detected in respiratory secretion, stool and blood in 19, 5 and 1 children, respectively. Gastrointestinal symptoms were common but were not associated with viral RNA in stool. nH1N1 viremia was detected, for the first time, in an immunocompetent child. PMID- 24346600 TI - Monoarticular coccidioidal synovitis in a pediatric patient. AB - Isolated monoarticular synovitis is a rare presentation of coccidioidal disease and has, to our knowledge, never previously been described in the English language pediatric literature. Coccidioidal seropositivity is increasing in incidence in the Southwestern United States. It is critical to rule out Coccidioides infection when evaluating arthritis in the context of residence in or travel to high prevalence areas, even in otherwise healthy patients and especially before administering biologic immunosuppressive therapy. PMID- 24346601 TI - Fever, rash, lymphadenopathy and painful scab in an 11-year-old girl. PMID- 24346602 TI - Ganciclovir for the treatment of congenital cytomegalovirus: what are the side effects? PMID- 24346603 TI - Neurotrichinosis in a pediatric patient. PMID- 24346604 TI - Measles vaccine strain from the skin rash of a DiGeorge patient receiving tumor necrosis factor inhibitor. PMID- 24346605 TI - Challenges with new rapid influenza diagnostic tests. PMID- 24346607 TI - The use of colistin in critically ill children in a pediatric intensive care unit. AB - BACKGROUND: Colistin is active against most multidrug-resistant, aerobic Gram negative bacteria. Because of the reported nephrotoxicity during the first years of use of colistin, there were concerns of its use in pediatrics where there was limited experience The aim of this study is to document the clinical characteristics and outcomes of use of colistin in pediatric patients at a pediatric intensive care unit in Turkey. METHODS: We reviewed the medical and laboratory records of 29 critically ill children who were treated with colistin for 38 courses between January 2011 and December 2011 at the Department of Pediatric Intensive Care Unit in Ankara University Medical School, Turkey. RESULTS: The median age was 17 months (range 3-217 months). Male-to-female ratio was 1:1.37. Ventilator-associated pneumonia (21 courses) was the leading diagnosis followed by catheter-related blood stream infection (6 courses), bacteremia (4 courses), ventriculoperitoneal shunt infection, peritonitis and pneumonia (1 course). The most commonly isolated microorganisms were Acinetobacter baumanni, Pseudomonas aeruginosa, Klebsiella pneumoniae, Serratia marcescens, Stenotrophomonas maltophilia, and Enterobacter cloacae. Two colistin formulations were used. Colimycin (Kocak Farma) was used in 21 colistin treatment episodes. The median dosage of colistin in this group was 5.0 mg/kg/d (2.3-5.6 mg/kg/d). Colomycin (Forest Laboratories) was used in 17 colistin treatment episodes. The median dosage of colistin in the second group was 75,000 International Unit/kg/d (50,000-80,000 International Unit/kg/d). Thirty colistin treatment episodes (79%) had a good or partial clinical response and 8 (21%) had a poor clinical response. Of the 8 colistin treatment episodes with poor clinical response, 3 were in the Colimycin group and 5 were in the Colomycin group. Ten patients died. There was no evidence of neurotoxicity in this study. Nephrotoxicity was observed in 1 patient but was not attributed to colistin because the patient had multiorgan failure at the same time. CONCLUSIONS: This study in a small cohort of patients suggests that the use of colistin in severe nosocomial infections caused by multidrug-resistant Gram-negative bacteria is well-tolerated and efficacious. PMID- 24346609 TI - Survey of consent practices in cluster randomized trials: improvements are needed in ethical conduct and reporting. AB - BACKGROUND: Informed consent procedures in cluster randomized trials (CRTs) are considerably more complicated than in individually randomized trials. In a CRT, the units of randomization, intervention, and observation may differ in a single trial; there can be multiple levels of participants (individual and cluster level); consent may be required separately for intervention and data collection; and there may be practical constraints to seeking informed consent, for example, due to cluster-level interventions or the sheer size of clusters. PURPOSE: We aimed to document consent practices at individual and cluster levels, assess the adequacy of reporting consent in trial publications, and assess associations with two trial characteristics that may influence consent requirements in CRTs: presence or absence of study interventions and presence or absence of data collection procedures at individual and cluster levels. METHODS: We reviewed a random sample of 300 CRTs published during 2000-2008. We sent survey questionnaires to 285 unique authors of these trials to gather detailed information about consent procedures used in each trial. RESULTS: In all, 182 authors (64%) responded. Overall, 93% (95% confidence interval (CI): 88.8%-96.6%) indicated that participant consent had been sought for some aspects of the study. Consent was less frequently sought for a study intervention (70% of respondents) than for data collection (88%). More than half of the respondents (52%) indicated that consent had been sought at both cluster and individual levels. There was strong evidence for under-reporting of consent in trial publications: only 63% of all trial publications reported that informed consent had been sought for some aspect of the study. The odds ratios (ORs) summarizing the association of the two trial characteristics with cluster-level participant consent were weak (OR = 1.17, p = 0.70 for presence of cluster-level study intervention and OR = 1.54, p = 0.29 for data collection); on the other hand, the ORs summarizing the associations with individual-level consent were strong (OR = 6.2, p < 0.0001 for presence of individual-level intervention and OR = 14.7, p < 0.0001 for data collection). LIMITATIONS: In all, 36% of authors did not respond to the survey; to the extent that consent practices in their trials were different than in respondents' trials, our results may be biased. CONCLUSIONS: There is a need for improvements in research practices in CRTs as well as their reporting. There may be a lack of clarity about consent requirements at the cluster level in particular. With the publication of the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials, researchers and research ethics committees now have access to comprehensive ethics guidelines specific to CRTs. PMID- 24346610 TI - Central and statistical data monitoring in the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2) trial. AB - Background The purpose of monitoring in clinical trials is to ensure the rights, safety, and well-being of trial patients and the accuracy of the trial data. In the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2) trial, which recruited over 20,000 adult trauma patients worldwide, the nature and extent of monitoring was based on a risk assessment undertaken before recruitment started. Purpose We report the methods used for central and statistical monitoring in the CRASH-2 trial and explain how central monitoring was used to target on-site investigations. Methods To ensure that trial participants met the inclusion criteria, we monitored event rates for the primary (death) and secondary outcomes (blood transfusion given). We monitored four quantitative variables (systolic blood pressure (SBP), heart rate (HR), respiratory rate, and capillary refill time) as indicators of the severity of bleeding. We used the coefficient of variation (CV) to identify sites with too much or too little variability. To ensure the accuracy of the data on side effects, we monitored thromboembolic events at each site. Sites with higher or lower than expected event rates were identified for further evaluation. Results A total of 274 sites recruited patients: 145 sites recruited >=20; patients, and 52 sites recruited >=100 patients. Sites with low case fatality and low blood transfusion rates were found to be including patients with relatively mild haemorrhage. One site with a high rate of thromboembolic events was found to be using clinical judgement alone. Measurements of SBP and HR varied by about one fifth of their average value, and capillary refill time measurements varied by around one-third of their average; between-site variation was lowest for blood pressure. Limitations A comparison of mean and median CV indicated that the distributions are slightly skewed to the right. Our simple approach to calculating 95% confidence intervals for the CV may be improved by using a logarithmic transformation of CV for each variable. Conclusions Central and statistical monitoring of data can be used to monitor clinical trials, particularly large, pragmatic, international trials where 100% on-site monitoring is neither necessary nor cost-effective. In the CRASH-2 trial, re-education about trial protocol and the development of guidance helped resolve the issues identified during monitoring. PMID- 24346608 TI - Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE): a pragmatic trial of complex treatment for a complex disorder. AB - BACKGROUND: Classic and second-generation antipsychotic mood stabilizers are recommended for treatment of bipolar disorder, yet there are no randomized comparative effectiveness studies that have examined the 'real-world' advantages and disadvantages of these medications. PURPOSE: We describe the strategic decisions in the design of the Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE). This article outlines the key issues and solutions the investigators faced in designing a clinical trial that would maximize generalizability and inform real-world clinical treatment of bipolar disorder. METHODS: Bipolar CHOICE was a 6-month, multi-site, prospective, randomized clinical trial of outpatients with bipolar disorder. This study compares the effectiveness of quetiapine versus lithium, each with adjunctive personalized treatments (APTs). The co-primary outcomes selected are the overall benefits and harms of the study medications (as measured by the Clinical Global Impression-Efficacy Index) and the Necessary Clinical Adjustments (a measure of the number of medication changes). Secondary outcomes are continuous measures of mood, the Framingham General Cardiovascular Risk Score, and the Longitudinal Interval Follow up Evaluation Range of Impaired Functioning Tool (LIFE-RIFT). RESULTS: The final study design consisted of a single-blind, randomized comparative effectiveness trial of quetiapine versus lithium, plus APT, across 10 sites. Other important study considerations included limited exclusion criteria to maximize generalizability, flexible dosing of APT medications to mimic real-world treatment, and an intent-to-treat analysis plan. In all, 482 participants were randomized to the study, and 364 completed the study. LIMITATIONS: The potential limitations of the study include the heterogeneity of APT, selection of study medications, lack of a placebo-control group, and participants' ability to pay for study medications. CONCLUSION: We expect that this study will inform our understanding of the benefits and harms of lithium, a classic mood stabilizer, compared to quetiapine, a second-generation antipsychotic with broad-spectrum activity in bipolar disorder, and will provide an example of a well-designed and well-conducted randomized comparative effectiveness clinical trial. PMID- 24346611 TI - Use of health plan combined with registry data to predict clinical trial recruitment. AB - BACKGROUND: Large pragmatic clinical trials (PCTs) are increasingly used to conduct comparative effectiveness research. In the context of planning a safety PCT of the live herpes zoster vaccine in rheumatoid arthritis (RA) patients aged >= 50 years receiving anti-tumor necrosis factor (TNF) therapy, we evaluated the use of health plan combined with registry data to assess the feasibility of recruiting the 4000 patients needed for the trial and to facilitate site selection. METHODS: Using national US data from Medicare, we identified older RA patients who received anti-TNF therapy in the last quarter of 2009. Extrapolations were made from the Medicare patient population to younger patients and those with other types of insurance using the Consortium of Rheumatology Researchers of North America (CORRONA) disease registry. Patients' treating rheumatologists were grouped into practices and sorted by size from the greatest to the least number of eligible patients. RESULTS: Approximately 50,000 RA patients receiving anti-TNF therapy were identified in the Medicare data, distributed across 1980 physician practices. After augmenting Medicare data with information from CORRONA and extrapolating to younger patients and those with other types of insurance, more than 12,000 potentially eligible study subjects were identified from the 50 largest rheumatology practices. CONCLUSION: Health plan and registry databases appear useful to assess feasibility of large pragmatic trials and to assist in selection of recruitment sites with the greatest number of potentially eligible patients. This novel approach is applicable to trials with simple inclusion/exclusion criteria that can be readily assessed in these data sources. PMID- 24346614 TI - Caring people who can change the world: you. PMID- 24346613 TI - Chitosan: a promising safe and immune-enhancing adjuvant for intranasal vaccines. AB - The nasal route is attractive for the delivery of vaccines in that it not only offers an easy to use, non-invasive, needle-free alternative to more conventional parenteral injection, but it also creates an opportunity to elicit both systemic and (crucially) mucosal immune responses which may increase the capability of controlling pathogens at the site of entry. Immune responses to "naked" antigens are often modest and it is widely accepted that incorporation of an adjuvant is a prerequisite for the achievement of clinically effective nasal vaccines. Many existing adjuvants are sub-optimal or unsuitable because of local toxicity or poor enhancement of immunogenicity. Chitosan, particularly chitosan salts, have now been used in several preclinical and clinical studies with good tolerability, excellent immune stimulation and positive clinical results across a number of infections. Particularly significant evidence supporting chitosan as an adjuvant for nasal vaccination comes from clinical investigations on a norovirus vaccine; this demonstrated the ability of chitosan (ChiSys(r)), when combined with monophosphoryl lipid, to evoke robust immunological responses and confer protective immunity following (enteral) norovirus challenge. This article summarizes the totality of the meaningful information (including key unpublished data) supporting the development of chitosan-adjuvanted vaccines. PMID- 24346612 TI - The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis. AB - MicroRNAs (miRNAs) regulate cardiovascular biology and disease, but the role of flow-sensitive microRNAs in atherosclerosis is still unclear. Here we identify miRNA-712 (miR-712) as a mechanosensitive miRNA upregulated by disturbed flow (d flow) in endothelial cells, in vitro and in vivo. We also show that miR-712 is derived from an unexpected source, pre-ribosomal RNA, in an exoribonuclease dependent but DiGeorge syndrome critical region 8 (DGCR8)-independent manner, suggesting that it is an atypical miRNA. Mechanistically, d-flow-induced miR-712 downregulates tissue inhibitor of metalloproteinase 3 (TIMP3) expression, which in turn activates the downstream matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs) and stimulate pro-atherogenic responses, endothelial inflammation and permeability. Furthermore, silencing miR-712 by anti miR-712 rescues TIMP3 expression and prevents atherosclerosis in murine models of atherosclerosis. Finally, we report that human miR-205 shares the same 'seed sequence' as murine-specific miR-712 and also targets TIMP3 in a flow-dependent manner. Targeting these mechanosensitive 'athero-miRs' may provide a new treatment paradigm in atherosclerosis. PMID- 24346615 TI - Dyspnea coping strategies in Korean immigrants with asthma or chronic obstructive pulmonary disease. AB - PURPOSE: Patients with lung disease develop coping strategies to relieve dyspnea. The coping strategies of Korean immigrants, however, are poorly understood. The purpose of this study was to describe the strategies that Korean immigrants with asthma or chronic obstructive pulmonary disease (COPD) use to cope with dyspnea and to compare similarities and differences in coping strategies between the two conditions. DESIGN: Outpatients with asthma (n = 25) or COPD (n = 48) participated in a cross-sectional descriptive study. METHOD: Open-ended questions and a structured instrument were used to describe coping strategies for dyspnea. Descriptive and inferential statistics were used to analyze the data. RESULTS: The most prevalent strategy was "I keep still or rest." Korean immigrants also used traditional therapies to manage dyspnea. CONCLUSIONS: Although the coping strategies of Korean immigrants were similar to those of other ethnic groups, they incorporated elements of Asian medical practice and herbs. This finding enables health care providers to better understand Korean immigrants' efforts to overcome dyspnea and to guide their patients' approach to coping. PMID- 24346617 TI - President's message: using adversity to create opportunity. PMID- 24346616 TI - Transcultural Nursing Scholar's corner: academic-practice partnerships. PMID- 24346619 TI - Impact of metabolic syndrome on the risk of atrial fibrillation recurrence after catheter ablation: systematic review and meta-analysis. AB - PURPOSE: The impact of metabolic syndrome (MetS) on recurrence of atrial fibrillation (AF) after catheter ablation remains uncertain. We conducted a meta analysis to summarize the relative risks (RR) of AF recurrence after catheter ablation in patients with vs. without MetS and its components. METHODS: Among 839 articles identified from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, we included 23 studies with a total of 12,924 patients (7,594 with paroxysmal AF and 5,330 with nonparoxysmal AF) for analysis. Five of these had complete information on MetS components. Variables assessed comprised study design and population characteristics, AF ablation methods, use of anti arrhythmic drugs, AF recurrence ascertainment methods, adjustment variables, and other quality indicators. RESULTS: Our meta-analysis found an elevated risk of AF recurrence after ablation in patients with vs. without MetS (pooled RR, 1.63; 95 % confidence interval (CI), 1.25-2.12). Among components of MetS, hypertension was a predictor of AF post-ablation recurrence in studies without adjustment for other MetS components (RR, 1.62; 95 % CI, 1.23-2.13) but not in those adjusting for two or more additional MetS components (RR, 1.03; 95 % CI, 0.88-1.20). There was a borderline association between overweight/obesity and AF recurrence after ablation (RR, 1.27; 95 % CI, 0.99-1.64). CONCLUSIONS: MetS is associated with an increased risk of AF recurrence after catheter ablation. Further study of the MetS and its components as determinants of AF risk could help refine patient selection and improve procedural outcomes. PMID- 24346621 TI - A perspective on the role of the extracellular matrix in progressive retinal degenerative disorders. AB - Progressive inherited retinal degenerative disorders (PIRDDs) are the leading cause of blindness in developed countries, with AMD and RP constituting the majority of PIRDDs. Currently, over 8 million Americans have PIRDDs, and that number is estimated to drastically increase by the end of this decade. Although a mutant protein is expressed starting early during retinal development in patients with PIRDDs, symptoms of retinal degeneration do not manifest until much later. Historically, research has focused on understanding the role a mutation has in the function of a protein and what role the mutant protein has in the disease process. However, it remains unknown why the disease, irrespective of the mutation, manifests clinically much later in life, while cellular indicators of disease (e.g., accumulation of toxic protein products and cell death) occur throughout early and middle life. Herein, we propose that there exists a time point at which the degenerative process is accelerated, leading to the appearance of clinical symptoms. This point is defined by structural disruptions of the extracellular matrix (ECM). Death of a critical number of ECM-maintaining mutant protein-expressing retinal cells contributes to that break point in the degenerative process. Therefore, it is important to understand the changes occurring at the ECM during PIRDDs and to take that into account when therapeutic approaches are designed. PMID- 24346622 TI - Nd3+ sensitized up/down converting dual-mode nanomaterials for efficient in-vitro and in-vivo bioimaging excited at 800 nm. AB - Core/shell1/shell2/shell3 structured NaGdF4:Nd/NaYF4/NaGdF4:Nd,Yb,Er/NaYF4 nanocrystals were well designed and synthesized, each of the parts assume respective role and work together to achieve dual-mode upconverting (UC) and downconverting (DC) luminescence upon the low heat effect 800-nm excitation. Nd(3+), Yb(3+), Er(3+) tri-doped NaGdF4:Nd,Yb,Er UC layer [NIR (800 nm)-to Visible (540 nm)] with a constitutional efficient 800 nm excitable property were achieved for the in-vitro bioimaging with low auto-fluorescence and photo-damage effects. Moreover, typical NIR (800 nm)-to-NIR (860-895 nm) DC luminescence of Nd(3+) has also been realized with this designed nanostructure. Due to the low heat effect, high penetration depth of the excitation and the high efficiency of the DC luminescence, the in-vivo high contrast DC imaging of a whole body nude mouse was achieved. We believe that such dual-mode luminescence NCs will open the door to engineering the excitation and emission wavelengths of NCs and will provide a new tool for a wide variety of applications in the fields of bioanalysis and biomedical. PMID- 24346623 TI - Weak C-H...N and C-H...F hydrogen bonds and internal rotation in pyridine-CH3F. AB - The pulsed-jet Fourier transform rotational spectra of 4 isotopologues have been recorded for the most stable conformation of the molecular cluster pyridine-CH3F. Two weak C-H...N and C-H...F hydrogen bonds link the two subunits of the complex. Structural information on the hydrogen bridges has been obtained. The internal rotation of the CH3F subunit around its symmetry axis splits all rotational transitions into two (A and E) well resolved component lines, leading to a V3 barrier height of 1.55(1) kJ mol(-1). PMID- 24346624 TI - Identification of BACH2 as a susceptibility gene for Graves' disease in the Chinese Han population based on a three-stage genome-wide association study. AB - The BACH2 gene regulates B cell differentiation and function and has been reported to be a shared susceptibility gene for several autoimmune diseases. Our previous genome-wide association study (GWAS) indicated that several single nucleotide polymorphisms (SNPs) in the BACH2 gene are associated with Graves' disease (GD) in the Chinese Han population; however, the association did not achieve genome-wide significance levels. Recently, this association of BACH2 with GD was confirmed in Caucasians in the UK population, but fine mapping in this region has not yet been reported. Here, we provide a refined analysis of a 331-kb region in the BACH2 gene, which harbors 359 SNPs, using GWAS data from 1,442 GD patients and 1,468 controls. The SNPs rs2474619 and rs9344996 were implied as the independent variants associated with GD by forward and two-locus logistic regression analysis. We genotyped eight out of 10 tagSNPs with P < 1 * 10(-3) in 3,508 GD patients and 3,209 controls, the results also showed that rs2474619 was independently associated with GD in the combined population from GWAS and the second stage (P = 1.81 * 10(-5)). The rs2474619 and rs9344996 were further genotyped in the third stage cohorts, and rs2474619 showed evidence of association with GD at genome-wide significance levels in the combined population (P = 3.28 * 10(-8), odds ratio = 1.13). The association of rs9344996 with GD can be explained by its linkage to rs2474619 in the combined population. Our study clearly demonstrated that BACH2 is a susceptibility gene for GD in the Chinese Han population and further supported rs2474619, in intron 2 of BACH2, is the best association signal with GD. However, the mechanism by which BACH2 confers increased risk of GD requires further study. PMID- 24346625 TI - Factors influencing further acupuncture usage and a more positive outcome in patients with osteoarthritis of the knee and the hip: a 3-year follow-up of a randomized pragmatic trial. AB - OBJECTIVE: Considering the chronicity of osteoarthritis-associated pain, we aimed to evaluate long-term outcome differences between patients who received immediate or delayed acupuncture in addition to usual care, and to identify predictors for further acupuncture usage and a better long-term outcome. MATERIALS AND METHODS: The Acupuncture in Routine Care study was an open-label randomized pragmatic trial. As adjunct to usual care patients (>40 y, clinical and radiologic diagnosis of primary osteoarthritis of the knee or hip, pain duration >6 mo) received either immediate acupuncture in the first 3 months or delayed acupuncture in the subsequent 3 months. After 36 months 613 of 632 patients were available and asked to complete follow-up questionnaires. Primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). RESULTS: A total of 500 (82%) of the contacted patients completed questionnaires. After 36 months the WOMAC Index did not differ significantly between groups (immediate acupuncture 36.53+/-26.19 vs. delayed acupuncture 38.24+/-25.54; P=0.420). Further acupuncture treatment during the follow-up period was reported by 202 patients and predicted by previous successful acupuncture treatment at baseline (odds ratio=2.5; 95% confidence interval, 1.6-3.9). Less osteoarthritis symptoms (WOMAC Index) after 36 months were predicted by being an acupuncture responder at 6 months (P<0.001), having higher school education (P=0.005), not wanting to use medications (P=0.016), and using additional therapies (P<=0.001 to P=0.025). DISCUSSION: No long-term outcome differences were found between patients who received immediate versus those who received delayed acupuncture treatment. Education level and additional therapies were identified as predictors for a better long-term outcome. PMID- 24346629 TI - Facile synthesis of 2-arylmethylindoles and 2-vinylic indoles through palladium catalyzed heteroannulations of 2-(2-propynyl)aniline and 2-(2 propynyl)tosylanilide. AB - A facile method for the general synthesis of 2-arylmethylindoles has been developed through the reaction of 2-(2-propynyl)aniline or 2-(2 propynyl)tosylanilide with aryl iodides in the presence of Pd(OAc)2, PPh3, and DBU. 2-(2-Propynyl)tosylanilide is found to be reactive also towards electron deficient alkenes in the presence of Pd(OAc)2 and sodium iodide under an oxygen atmosphere, providing easy access to 2-vinylic indoles which possess exclusive E stereochemistry in the side chain double bond. Operational simplicity, compatibility of the various functional groups, and ease of product formation are the hallmarks of these methods. A mechanism has been proposed to explain the product formation. PMID- 24346630 TI - The microbiology of bacterial peritonitis due to appendicitis in children. AB - AIM: The aim of this study was to investigate the microbiology of secondary bacterial peritonitis due to appendicitis and the appropriateness of current antimicrobial practice in one institution. METHODS: A 14-year retrospective single-centre study of 69 consecutive paediatric patients (age 1-14 years) with appendicitis-related peritonitis and positive peritoneal specimen cultures was conducted. Post-operative outcomes, microbiology and antibiotic susceptibility of peritoneal isolates were analysed in all patients. RESULTS: Escherichia coli was identified in 56/69 (81 %) peritoneal specimens; four isolates were resistant to amoxicillin-clavulanate, and one other isolate was resistant to gentamicin. Anaerobes were identified in 37/69 (54 %) peritoneal specimens; two anaerobic isolates were resistant to amoxicillin-clavulanate and one isolate was resistant to metronidazole. Pseudomonas aeruginosa was identified in 4/69 (6 %) peritoneal specimens, and all were susceptible to gentamicin. Streptococcal species (two Group F streptococci and three beta-haemolytic streptococci) were identified in 5/69 (7 %) specimens, and all were susceptible to amoxicillin-clavulanate. Combination therapy involving amoxicillin-clavulanate and aminoglycoside is appropriate empirical treatment in 68/69 (99 %) patients. Addition of metronidazole to this regime would provide 100 % initial empirical coverage. Inadequate initial empiric antibiotic treatment and the presence of amoxicillin clavulanate resistant E. coli were independent predictors of the post-operative infectious complications observed in 14/69 (20 %) patients. CONCLUSION: E. coli and mixed anaerobes are the predominant organisms identified in secondary peritonitis from appendicitis in children. Inadequate initial empirical antibiotic and amoxicillin-clavulanate resistant E. coli may contribute to increased post-operative infectious complications. This study provides evidence based information on choice of combination therapy for paediatric appendicitis related bacterial peritonitis. PMID- 24346631 TI - Surgical conditions account for the majority of admissions to three primary referral hospitals in rural Mozambique. AB - BACKGROUND: The World Health Organization has identified the primary referral hospital as its priority site for improving surgical care in low- and middle income countries. Little is known about the relative burden surgical patients place on health care facilities at this level. This research estimates the fraction of admissions due to surgical conditions at three hospitals in rural Mozambique. METHODS: Prospective data were collected on all inpatients at three primary referral hospitals in Mozambique during a 12-day period. We compared the number of surgical patients and their length of stay (LOS) to the patients admitted to the medicine, pediatric, and maternity wards. These findings were validated using retrospective data collected from one hospital from January to May 2012. RESULTS: Patients with surgical conditions (i.e., patients admitted to the surgical or maternity ward) accounted for 57.5 % of admissions and 48.0 % of patient-days. The majority of patients were admitted to the maternity ward (32.3 %). The other admissions were evenly distributed to the pediatric (22.5 %), medical (20.0 %), and surgical (25.2 %) wards. Compared to patients from the three other wards, surgical patients had longer average LOS (8.7 vs. 1.9-7.7 days) and a higher number of total patient-days (891 vs. 252-703 days). The most prevalent procedures were cesarean section (33.3 %) and laceration repair/wound care (11.8 %). CONCLUSIONS: Surgical conditions are the most common reason for admissions at three primary referral hospitals in rural Mozambique. These data suggest that surgical care is a major component of health care delivered at primary referral hospitals in Mozambique and likely other sub-Saharan African countries. PMID- 24346632 TI - Results of intraoperative neuromonitoring in thyroid surgery and preoperative vocal cord paralysis. AB - BACKGROUND: Systematic studies of intermittent intraoperative neuromonitoring (IONM) have shown that IONM enhances recurrent laryngeal nerve (RLN) identification via functional assessment, but does not significantly reduce rates of vocal cord (VC) paralysis (VCP). The reliability of functional nerve assessment depends on the preoperative integrity of VC mobility. The present study was therefore performed to analyze the validity of IONM in patients with pre-existing VC paralysis. METHODS: Of 8,128 patients, 285 (3.5 %) with preoperative VCP underwent thyroid surgery using standardized IONM of the RLN and vagus nerves (VNs). VC function was assessed by pre- and postoperative direct videolaryngoscopy. Quantitative parameters of IONM in patients with VCP were compared with IONM in patients with intact VC function. Clinical symptoms and surgical outcomes of patients with pre-existing VCP were analyzed. RESULTS: A total of 244 patients revealed negative, and 41 revealed positive IONM on the side of the VCP. VCP with positive IONM revealed significantly lower amplitudes of VN and RLN than intact VN (p = 0.010) and RLN (p = 0.011). Symptoms of patients with VCP included hoarseness (25 %), dyspnea (29 %), stridor (13 %), and dysphagia (13 %); 13 % were asymptomatic. New VCP occurred in five patients, ten needed tracheostomy for various reasons, and one patient died. CONCLUSIONS: Patients with pre-existing VCP revealed significantly reduced amplitude of ipsilateral VN and RLN, indicating retained nerve conductivity despite VC immobility. Preoperative laryngoscopy is therefore indispensable for reliable IONM and risk assessment, even in patients without voice abnormalities. PMID- 24346633 TI - Effect of torsional isomerization and inclusion complex formation with cucurbit[7]uril on the fluorescence of 6-methoxy-1-methylquinolinium. AB - Inclusion of 6-methoxy-1-methylquinolinium (C1MQ) in the cavity of cucurbit[7]uril (CB7) was studied by absorption, fluorescence, NMR and isothermal calorimetric methods in aqueous solution at 298 K. The free C1MQ exhibited dual exponential fluorescence decay kinetics due to the two torsional isomers differing in the orientation of the methoxy moiety relative to the heterocyclic ring. The enthalpy-driven encapsulation of the heterocycle in CB7 led to a very stable 1 : 1 complex with a binding constant of (2.0 +/- 0.4) * 10(6) M(-1). The rate of C1MQ-CB7 complex dissociation was found to be comparable to the NMR timescale. Because the methoxy moiety is oriented outward from the host, its s cis-s-trans isomerization is slightly affected by the confinement. Inclusion complex formation significantly slowed down the photoinduced electron transfer from I(-) and N3(-) to the singlet-excited C1MQ, but did not preclude the reaction because long distance electron transfer occurred through the wall of the CB7 macrocycle. Due to the large difference in the quenching rate constant for free and encapsulated forms, C1MQ is an excellent probe for the study of the inclusion of nonfluorescent compounds in CB7 in the presence of Cl(-) or Br(-). PMID- 24346634 TI - Saccharopolyspora ghardaiensis sp. nov., an extremely halophilic actinomycete isolated from Algerian Saharan soil. AB - A novel halophilic actinomycete, strain designated H53(T), was isolated from a Saharan soil sample collected from Chaabet Ntissa, Beni-isguen, Ghardaia (South of Algeria) and was characterized taxonomically by means of polyphasic approach. Optimal growth was found to occur at 30-35 degrees C, pH 6-7 and in the presence of 15-25% (w/v) NaCl. The strain was observed to produce abundant aerial mycelium, which formed long chains of rod-shaped spores at maturity, and well developed and fragmented substrate mycelium. The cell wall was determined to contain meso-diaminopimelic acid; the diagnostic whole-cell sugars were arabinose and galactose. The predominant menaquinones were found to be MK-9(H4) and MK 9(H6). The predominant cellular fatty acids were determined to be iso- and anteiso-C17:0, iso-C15:0, and cis9 iso-C17:1. The diagnostic phospholipid detected was phosphatidylcholine. The morphological and chemotaxonomic characteristics of the strain were consistent with those of members of the genus Saccharopolyspora. Phylogenetic analyses on the basis of the 16S ribosomal RNA (rRNA) gene sequence showed that this strain formed a distinct phyletic line within the radiation of the genus Saccharopolyspora. The 16S rRNA sequence similarities between strain H53(T) and other members of the genus Saccharopolyspora ranged from 92.1 to 94.3%. The DNA G+C content of strain H53(T) was 72.6%. The genotypic and phenotypic data showed that the strain H53(T) represents a novel species of the genus Saccharopolyspora, for which the name Saccharopolyspora ghardaiensis sp. nov. is proposed, with the type strain H53(T) (=DSM 45606(T)=CCUG 63370(T)=CECT 8304(T)). PMID- 24346635 TI - Selective anti-tumor activity of the novel fluoropyrimidine polymer F10 towards G48a orthotopic GBM tumors. AB - F10 is a novel anti-tumor agent with minimal systemic toxicity in vivo and which displays strong cytotoxicity towards glioblastoma (GBM) cells in vitro. Here we investigate the cytotoxicity of F10 towards GBM cells and evaluate the anti-tumor activity of locally-administered F10 towards an orthotopic xenograft model of GBM. The effects of F10 on thymidylate synthase (TS) inhibition and Topoisomerase 1 (Top1) cleavage complex formation were evaluated using TS activity assays and in vivo complex of enzyme bioassays. Cytotoxicity of F10 towards normal brain was evaluated using cortices from embryonic (day 18) mice. F10 displays minimal penetrance of the blood-brain barrier and was delivered by intra-cerebral (i.c.) administration and prospective anti-tumor response towards luciferase-expressing G48a human GBM tumors in nude mice was evaluated using IVIS imaging. Histological examination of tumor and normal brain tissue was used to assess the selectivity of anti-tumor activity. F10 is cytotoxic towards G48a, SNB-19, and U-251 MG GBM cells through dual targeting of TS and Top1. F10 is not toxic to murine primary neuronal cultures. F10 is well-tolerated upon i.c. administration and induces significant regression of G48a tumors that is dose-dependent. Histological analysis from F10-treated mice revealed tumors were essentially completely eradicated in F10-treated mice while vehicle-treated mice displayed substantial infiltration into normal tissue. F10 displays strong efficacy for GBM treatment with minimal toxicity upon i.c. administration establishing F10 as a promising drug-candidate for treating GBM in human patients. PMID- 24346636 TI - Point-of-care C-reactive protein testing to facilitate implementation of isoniazid preventive therapy for people living with HIV. AB - BACKGROUND: Symptom-based tuberculosis screening identifies less than one-third of eligible HIV-infected patients as candidates for isoniazid preventive therapy (IPT). We evaluated whether testing for C-reactive protein (CRP) improves patient selection for IPT. METHODS: We measured CRP levels (normal <10 mg/L) using a point-of-care (POC) assay on stored serum samples from HIV-infected Ugandan adults initiating antiretroviral therapy. We assessed diagnostic accuracy in reference to baseline tuberculosis status adjudicated by an expert committee and calculated net reclassification improvement to quantify the incremental discriminatory benefit of POC-CRP in determining IPT eligibility compared to the World Health Organization (WHO) symptom screen. RESULTS: Of 201 patients (median CD4 cell count, 137 cells/MUL; interquartile range, 83-206), 5 (2.5%) had tuberculosis. Compared to the WHO symptom screen, POC-CRP had similar sensitivity (100% vs. 80%, P = 0.30) but greater specificity (21% vs. 87%, P < 0.0001) for tuberculosis. If based on the WHO symptom screen, no patients with tuberculosis but only 42 of 196 patients without tuberculosis would have been considered IPT eligible. If POC-CRP were used instead, 1 patient with tuberculosis (reclassification of cases, -20%; P = 0.32) and 129 patients without tuberculosis (reclassification of noncases, +66%; P < 0.001) would have been reclassified as IPT eligible, a net reclassification improvement of 46% (P = 0.03). In addition, POC-CRP testing would have reduced the proportion of patients without active tuberculosis requiring confirmatory tuberculosis testing (87% vs. 21%, P < 0.0001). CONCLUSIONS: POC-CRP testing increased more than 4-fold the proportion of HIV-infected adults immediately identified as IPT eligible and decreased the proportion of patients requiring referral for further tuberculosis diagnostic testing. POC-CRP testing could substantially improve implementation of tuberculosis screening guidelines. PMID- 24346637 TI - The effects of boceprevir and telaprevir on the pharmacokinetics of maraviroc: an open-label, fixed-sequence study in healthy volunteers. AB - OBJECTIVE: To evaluate the effects of boceprevir (BOC) and telaprevir (TVR) on the pharmacokinetics (PK) of maraviroc (MVC) in healthy volunteers. METHODS: In this open-label, fixed-sequence study, 14 volunteers received MVC 150 mg twice daily alone for 5 days (period 1), followed by MVC + BOC 800 mg 3 times daily and MVC + TVR 750 mg 3 times daily, each for 10 days in periods 2 and 3, respectively, with a >=10-day wash-out. PK was analyzed on day 5 of period 1 and day 10 of periods 2 and 3. Safety was also assessed. RESULTS: Ratios of the adjusted geometric means (90% confidence intervals) for MVC area under the curve from predose to 12 hours, maximum plasma concentration, and plasma concentration at 12 hours were 3.02 (2.53 to 3.59), 3.33 (2.54 to 4.36), and 2.78 (2.40 to 3.23), respectively, for MVC + BOC versus MVC alone, and 9.49 (7.94 to 11.34), 7.81 (5.92 to 10.32), and 10.17 (8.73 to 11.85), respectively, for MVC + TVR versus MVC alone. PK profiles for MVC + BOC or TVR were consistent with historic values for BOC and TVR monotherapy. Adverse event incidence was higher with MVC + BOC and MVC + TVR versus MVC alone. Dysgeusia (50%) and pruritus (29%) occurred most commonly with MVC + BOC, and fatigue (46%) and headache (31%) with MVC + TVR. There were no serious adverse events. CONCLUSIONS: MVC exposures were significantly increased with BOC or TVR, therefore MVC should be dosed at 150 mg twice daily when coadministered with these newly approved hepatitis C protease inhibitors. No dose adjustment for BOC or TVR is warranted with MVC. MVC + BOC or TVR was generally well tolerated with no unexpected safety findings. PMID- 24346638 TI - Association of chronic cough and pulmonary function with 6-minute walk test performance in HIV infection. AB - OBJECTIVE: Chronic lung disease has been associated with greater impairment in self-reported physical function in HIV-infected patients. We sought to study this association using objective measures of physical function and pulmonary function. DESIGN: Baseline data from the Examinations of HIV Associated Lung Emphysema study, a multicenter observational cohort of HIV-infected and uninfected veterans. METHODS: We assessed the association between clinical, laboratory, and pulmonary function measures with 6-minute walk test (6-MWT). Multivariable linear regression models were generated to identify factors associated with 6-MWT performance. RESULTS: Three hundred forty participants completed 6-MWT (mean age 55 years), with 68% blacks, 94% men, and 62% current smokers. Overall, 180 (53%) were HIV-infected and 63 (19%) had spirometry-defined chronic obstructive pulmonary disease. In a multivariable model, age, current smoking, and obesity (body mass index > 30) were independently associated with lower 6-MWT performance, but HIV infection was not; there was a significant interaction between HIV and chronic cough, such that distance walked among HIV-infected participants with chronic cough was 51.76 m less (P = 0.04) compared with those without cough or HIV. Among HIV-infected participants, the forced expiratory volume in 1 second (FEV1, percent predicted), to a greater extent than total lung capacity or diffusing capacity, attenuated the association with chronic cough; decreased FEV1 was independently associated with lower 6-MWT performance in those with HIV. CONCLUSIONS: Older age, current smoking, and airflow limitation were important determinants of 6-MWT performance in the HIV-infected participants. These findings suggest that potential interventions to improve physical function may include early management of respiratory symptoms and airflow limitation. PMID- 24346640 TI - A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus emtricitabine/tenofovir DF for initial treatment of HIV-1 infection: analysis of week 144 results. PMID- 24346639 TI - Predictive value of anemia for tuberculosis in HIV-infected patients in Sub Saharan Africa: an indication for routine microbiological investigation using new rapid assays. AB - BACKGROUND: The relationship between anemia and undiagnosed tuberculosis (TB) in patients living with HIV in sub-Saharan Africa is incompletely defined. We assessed the prevalence of TB among those with HIV-related anemia and evaluated new means of rapid TB diagnosis. METHODS: Blood hemoglobin levels were measured in unselected antiretroviral treatment-naive patients in Cape Town, South Africa, and anemia was classified according to World Health Organization criteria. All patients were screened for TB by testing paired sputum samples using liquid culture (reference standard), fluorescence microscopy, and Xpert MTB/RIF. Urine samples were tested for lipoarabinomannan (LAM) using the Determine TB-LAM diagnostic assay. RESULTS: Of 602 adults screened, 485 had complete results. Normal hemoglobin levels were found in 44.5% (n = 216) of patients, and mild, moderate, or severe anemia were present in 24.9% (n = 121), 25.4% (n = 123) and 5.2% (n = 25) of patients, respectively. Culture-confirmed pulmonary TB was diagnosed in 8.8% (19/216) of those without anemia compared with 16.5% (20/121), 26.0% (32/123), and 40.0% (10/25) among those with mild, moderate, or severe anemia, respectively (P < 0.001). Anemia was a strong independent predictor of TB. The sensitivities of diagnostic assays were much higher among those with moderate/severe anemia compared with those with no/mild anemia using sputum microscopy (42.9% vs 15.4%), urine LAM (54.8% vs 0%), sputum microscopy plus urine LAM (71.4% vs 15.4%), and sputum Xpert (73.8% vs 41.0%) (P < 0.01 for all). CONCLUSIONS: A very high prevalence of undiagnosed TB was found in patients with moderate or severe anemia. Such patients should be prioritized for routine microbiological investigation using rapid diagnostic assays. PMID- 24346641 TI - Low alcohol consumption as a predictor of higher CD4+ cell count in HIV-treated patients: a french paradox or a proxy of healthy behaviors? The ANRS APROCO COPILOTE CO-08 cohort. PMID- 24346642 TI - The politics and epidemiology of transition: PEPFAR and AIDS in South Africa. PMID- 24346643 TI - Reply: To PMID 23892243. PMID- 24346644 TI - HIV infection deregulates the balance between regulatory T cells and IL-2 producing CD4 T cells by decreasing the expression of the IL-2 receptor in Treg. AB - Indexation of regulatory T cells (Treg) to the number of activated T cells constitutes a homeostatic mechanism ensuring that T-cell expansion remains under control. However, immune hyperactivation observed in HIV-infected patients suggests a possible dysfunction of this mechanism. Here we show that the Treg/IL 2-producing cells' balance is deeply disturbed in viremic HIV-infected patients. We found a lower expression of IL-2 receptor alpha on Treg from viremic patients. We confirmed in vitro that HIV infection of Treg downregulates IL-2 receptor alpha and phosphorylated STAT5. Our results argue for an impaired capacity of Treg to sense the expansion of activated T cells in HIV-infected patients that could contribute to the immune deregulation. PMID- 24346645 TI - Simultaneous imaging of protonated and deprotonated carbonylcyanide p trifluoromethoxyphenylhydrazone in live cells by Raman microscopy. AB - We report the simultaneous imaging of protonated and deprotonated forms of carbonylcyanide p-trifluoromethoxy-phenylhydrazone (FCCP) molecules in live cells by Raman microscopy. Nitriles, structure-sensitive Raman tags, are used to detect the two distinct molecular structures, demonstrating the potential of Raman microscopy for structure-based imaging of bioactive small molecules. PMID- 24346646 TI - What's new in Shock? January 2014. PMID- 24346648 TI - Will the next breakthrough for neuroprotection after cardiac arrest come out of thin air? PMID- 24346647 TI - A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury. AB - Given that the leading clinical conditions associated with acute kidney injury (AKI), namely, sepsis, major surgery, heart failure, and hypovolemia, are all associated with shock, it is tempting to attribute all AKI to ischemia on the basis of macrohemodynamic changes. However, an increasing body of evidence has suggested that in many patients, AKI can occur in the absence of overt signs of global renal hypoperfusion. Indeed, sepsis-induced AKI can occur in the setting of normal or even increased renal blood flow. Accordingly, renal injury may not be entirely explained solely on the basis of the classic paradigm of hypoperfusion, and thus other mechanisms must come into play. Herein, we put forward a "unifying theory" to explain the interplay between inflammation and oxidative stress, microvascular dysfunction, and the adaptive response of the tubular epithelial cell to the septic insult. We propose that this response is mostly adaptive in origin, that it is driven by mitochondria, and that it ultimately results in and explains the clinical phenotype of sepsis-induced AKI. PMID- 24346649 TI - Nutritional support in critically ill patients: enteral, parenteral, or not at all? PMID- 24346650 TI - Rumination mediates the association between cyber-victimization and depressive symptoms. AB - The current study examined the 3-week prospective associations between cyber victimization and both depressive symptoms and rumination. In addition, a mediation model was tested, wherein rumination mediated the association between cyber-victimization and depressive symptoms. Participants (N = 565 college-age young adults) completed online surveys at two time points 3 weeks apart. Results indicated that cyber-victimization was associated with increases in both depressive symptoms and rumination over time. Furthermore, results of the path analysis indicated that cyber-victimization was associated with increases in rumination over time, which were then associated with greater depressive symptoms, providing support for the proposed mediation effect for women, but not men. Findings extend previous correlational findings by demonstrating that cyber victimization is associated with increases in symptomatology over time. Findings also suggest that the negative consequences of cyber-victimization extend beyond mental health problems to maladaptive emotion regulation. In fact, rumination may be a mechanism through which cyber-victimization influences mental health problems, at least for women. Mental health professionals are encouraged to assess cyber-victimization as part of standard victimization assessments and to consider targeting maladaptive emotion regulation in addition to mental health problems in clients who have experienced cyber-victimization. PMID- 24346651 TI - Processes and patterns in gay, lesbian, and bisexual sexual assault: a multimethodological assessment. AB - Although prior research suggests that sexual minorities are at equivalent or greater risk of sexual assault compared with heterosexual women, few studies have examined simultaneously a broad array of assault types, the forms of force and pressure experienced, and the relative risks of experiencing different kinds of assault or force or pressure during an assault according to sex and sexual orientation. Moreover, very little is known about how subjective interpretations of assault may differ by sex and sexual orientation. We address these gaps using a multimethodological analysis of original survey data (N = 342) with a snowball oversample of sexual minority respondents. Quantitative results indicate that both sexual minority status and sex are predictive of increased assault risk of most assault types, but that most effects of sexual minority status are restricted to men. The probabilities of experiencing verbal pressure or physical force are largely uniform across categories. Qualitative analyses of open-ended questions suggest that men and women interpret the experience of assault differently, such that sexual minority men conceptualize their unwanted sexual experiences as "giving in" due to feelings of guilt or low self-worth, whereas women of all sexual orientations acquiesced because it was perceived to be easier or more practical than resisting. Theoretical implications and directions for future research are discussed. PMID- 24346653 TI - Energetics of disordered and ordered rare earth oxide-stabilized bismuth oxide ionic conductors. AB - Rare-earth stabilized bismuth oxides are known for their excellent ionic conductivity at intermediate temperatures. However, previous studies have shown that their conductivity deteriorates during extended heat treatments at 500-600 degrees C, although the fluorite phase is maintained. In this study, the enthalpies of formation of quenched and aged ytterbia- and dysprosia-stabilized bismuth oxides were measured using high-temperature oxide melt solution calorimetry in 3Na2O-4MoO3 solvent at 702 degrees C. While a modest energy difference (-2 to -3 kJ mol(-1)) drives the kinetically slow aging transformation in the ytterbia-stabilized system at moderate dopant contents, no energetic driving force is detectable in the dysprosia-stabilized system. Although the small magnitude of the exothermic ordering energy suggests extensive short range ordering in both the quenched and aged samples, the anion configuration specific to the aged samples is nevertheless responsible for the significant decrease in conductivity. PMID- 24346652 TI - The Role of Rumination in Elevating Perceived Stress in Posttraumatic Stress Disorder. AB - Rumination has been shown to be important in both the maintenance and severity of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Increased rumination has also been linked to perceptions of increased stress, which in turn are significantly associated with increased PTSD severity. The present study sought to examine this relationship in more detail by means of a mediation analysis. Forty-nine female survivors of interpersonal violence who met Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV TR) criteria for PTSD were administered the Clinician-Administered PTSD Scale (CAPS), the Ruminative Thought Style Questionnaire (RTS), the Perceived Stress Scale (PSS), and the Beck Depression Inventory-II (BDI-II). Results indicated that perceived stress mediates the relationship between rumination and PTSD, but did not do so after controlling for depression. Such results provide further evidence for the overlap between PTSD and MDD, and, in broader clinical practice, translate to a sharper focus on rumination and perceived stress as maintenance factors in both disorders. PMID- 24346654 TI - Global searches for microalgae and aquatic plants that can eliminate radioactive cesium, iodine and strontium from the radio-polluted aquatic environment: a bioremediation strategy. AB - The Fukushima 1 Nuclear Power Plant accident in March 2011 released an enormously high level of radionuclides into the environment, a total estimation of 6.3 * 1017 Bq represented by mainly radioactive Cs, Sr, and I. Because these radionuclides are biophilic, an urgent risk has arisen due to biological intake and subsequent food web contamination in the ecosystem. Thus, urgent elimination of radionuclides from the environment is necessary to prevent substantial radiopollution of organisms. In this study, we selected microalgae and aquatic plants that can efficiently eliminate these radionuclides from the environment. The ability of aquatic plants and algae was assessed by determining the elimination rate of radioactive Cs, Sr and I from culture medium and the accumulation capacity of radionuclides into single cells or whole bodies. Among 188 strains examined from microalgae, aquatic plants and unidentified algal species, we identified six, three and eight strains that can accumulate high levels of radioactive Cs, Sr and I from the medium, respectively. Notably, a novel eustigmatophycean unicellular algal strain, nak 9, showed the highest ability to eliminate radioactive Cs from the medium by cellular accumulation. Our results provide an important strategy for decreasing radiopollution in Fukushima area. PMID- 24346655 TI - Estimation of soil-to-plant transfer factors of radiocesium in 99 wild plant species grown in arable lands 1 year after the Fukushima 1 Nuclear Power Plant accident. AB - One year after the deposition of radionuclides from the Fukushima 1 Nuclear Power Plant (A formal name is Fukushima Daiichi Nuclear Power Station) in March 2011, radiocesium (134Cs, 137Cs) concentrations ([Cs]) were comprehensively investigated in the wild plants of 99 species most of which were annual or summer green perennial herbs and started to grow from April 2012 at the heavily contaminated fields of paddy (three study sites) and upland (one study site) in Fukushima Prefecture. The survey was conducted three times (April, July and October) in the year. In each site, soils (soil cores of 5-cm depth) and plants (aerial shoots) were collected for determination of [Cs] on a dry weight basis, and then the transfer factor (TF) of radiocesium from soil to plant ([Cs]plant/[Cs]soil) was estimated in each species. The [Cs] values of both soils and plants largely varied. However, some species exhibited relatively high TF values (more than 0.4) (e.g., Athyrium yokoscense, Dryopteris tokyoensis, and Cyperus brevifolius), while others exhibited almost negligible values (less than 0.01) (e.g., Salix miyabeana, Humulus scandens, and Elymus tsukushiensis). In addition, judging from the 11 species grown in both paddy and upland fields, TF values were generally higher in the paddy fields. The estimation of phytoextraction efficiency of soil radiocesium by weed communities in the paddy fields suggests that the weed community is not a practical candidate for phytoremediation technique. PMID- 24346656 TI - What's new in antimicrobial use and resistance in critically ill patients? PMID- 24346657 TI - Observation of possible topological in-gap surface states in the Kondo insulator SmB6 by photoemission. AB - SmB6, a well-known Kondo insulator, exhibits a transport anomaly at low temperature. This anomaly is usually attributed to states within the hybridization gap. Recent theoretical work and transport measurements suggest that these in-gap states could be ascribed to topological surface states, which would make SmB6 the first realization of topological Kondo insulator. Here by performing angle-resolved photoemission spectroscopy experiments, we directly observe several dispersive states within the hybridization gap of SmB6. These states show negligible kz dependence, which indicates their surface origin. Furthermore, we perform photoemission circular dichroism experiments, which suggest that the in-gap states possess chirality of the orbital angular momentum. These states vanish simultaneously with the hybridization gap at around 150 K. Together, these observations suggest the possible topological origin of the in gap states. PMID- 24346658 TI - Increasing Statistical Power in Mediation Models Without Increasing Sample Size. AB - Inadequate statistical power to detect treatment effects in health research is a problem that is compounded when testing for mediation. In general, the preferred strategy for increasing power is to increase the sample size, but there are many situations where additional participants cannot be recruited, necessitating the use of other methods to increase statistical power. Many of these other strategies, commonly applied to analysis of variance and multiple regression models, can be applied to mediation models with similar results. Additional predictors or blocking variables will increase or decrease statistical power, however, depending on whether these variables are related to the mediator, the outcome, or both. The effect of these two methods on the power for tests of mediation is illustrated through the use of simulations. Implications for health researchers using these methods are discussed. PMID- 24346659 TI - Autochthonous cases of schistosomiasis in children in Recife, Northeastern Brazil. AB - OBJECTIVE: Investigate breeding sites with host snails and autochthonous human cases of schistosomiasis. METHODS: Between July 2010 and September 2012 were performed: (1) malacological survey searching for breeding sites, collection and identification of Biomphalaria snails positive for Schistosoma mansoni in Recife, PE, Northeastern Brazil; (2) prevalence survey in 2,718 schoolchildren aged from seven to 14 years old to identify cases of schistosomiasis, clinical examination and ultrasound in positive cases of S. mansoni. The autochthony of the cases was investigated and the case were clinically evaluated. The cases and breeding sites were georeferenced and spatially described. RESULTS: The results identified 30 breeding with B. straminea, four of which were potential foci of transmission, as molecular testing identified snails with S. mansoni DNA. There were 14 children diagnosed with schistosomiasis, of which five were considered to be autochthonous cases of the disease. CONCLUSIONS: Urgent measures are required in order to avoid schistosomiasis becoming endemic to Recife, as has happened in other coastal areas of the state of Pernambuco. PMID- 24346660 TI - Introduction and expansion of human American visceral leishmaniasis in the state of Sao Paulo, Brazil, 1999-2011. AB - OBJECTIVE: To analyze the spread of human American visceral leishmaniasis and identify the key municipalities for developing surveillance and control activities. METHODS: The area of the study was composed of the 316 municipalities in the state of Sao Paulo belonging to the five health districts in which human American visceral leishmaniasis occurs, using data on autochthonous cases and deaths according to the reporting year and municipality in which the death occurred. The incidence, mortality and case fatality rates for each municipality and for the entire area were calculated. An empirical Bayes estimator was used to calculate the local Bayesian incidence and rates of mortality per municipality, and Kriging was used to visualize the spatial distribution of temperature and rainfall. RESULTS: A total of 73 municipalities with transmission of the disease were identified. Human American visceral leishmaniasis was first detected in areas with higher temperatures and lower rainfall, but it also spread in cooler and wetter areas. The expansion of human American visceral leishmaniasis occurred along a main axis of dissemination, from Northwest to Southeast, following the Marechal Rondon highway and the Bolivia-Brazil gas pipeline, and along a secondary axis that was derived from the main axis, which runs both North and South, following the highway network. Rates of incidence according to health district exhibit a peak, followed by a fall, except the Sao Jose do Rio Preto region. Higher concentrations of municipalities with high incidence and mortality rates were observed in the Aracatuba, Presidente Prudente and Marilia health districts. CONCLUSIONS: This study indicates possible determinants of the spread of disease, including the Marechal Rondon highway and the construction of the Bolivia-Brazil gas pipeline. Climatic factors seemed to play no role in the spread. The use of spatial analysis techniques allowed the municipalities where cases and deaths are possibly underreported to be identified, which indicated the municipalities which should be prioritized for the development of surveillance and control activities. PMID- 24346661 TI - Associated factors of depressive symptoms in the elderly: EpiFloripa study. AB - OBJECTIVE: To estimate the prevalence and associated factors of depressive symptoms in the elderly. METHODS: Cross-sectional population based epidemiological study (The EpiFloripa Elderly survey) was carried out in two stage clusters, census tracts and households, with 1.656 elderly individuals in Florianopolis, SC. The prevalence of depressive symptoms (outcome) was obtained using Geriatric Depression Scale (GDS-15) and its associations with socio demographic, health, behavioral and social variables were assessed. Crude and adjusted prevalence ratios (PR) with 95% confidence intervals were calculated using Poisson regression. RESULTS: Depressive symptoms were observed in 23.9% of the elderly individuals (95%CI 21.84;26.01). In the fi nal model, depressive symptoms were associated with: 5 to 8 years of schooling (PR = 1.50, 95%CI 1.08;2.08); one to four years of schooling (PR = 1.62, 95%CI 1.18;2.23) and no schooling (PR = 2.11, 95%CI 1.46;3.05); being in a worse financial condition than at the age of 50 (PR = 1.33, 95%CI 1.02;1.74); cognitive impairment (PR = 1.45, 95%CI 1.21;1.75); perceiving their health to be regular (PR = 1.95, 95%CI 1.47;2.60) or poor (PR = 2.64, 95%CI 1.82;3.83); functional dependence (PR =1.83, 95%CI 1.43;2.33) and chronic pain (PR = 1.35, 95%CI 1.10;1.67). Factors with protective effects were: being in the 70 to 79 year old age group (PR = 0.77, 95%CI 0.64;0.93); physical activity in leisure time (PR = 0.75, 95%CI 0.59;0.94); participation in social or religious groups (PR = 0.80, 95%CI 0.64;0.99) and having sexual relations (PR = 0.70, 95%CI 0.53;0.94). CONCLUSIONS: Adverse clinical situations, being socioeconomically disadvantaged and low social and sexual activity were associated with depressive symptoms in the elderly. PMID- 24346662 TI - Tele-care and tele-alarms for the elderly: preliminary experiences in Mexico. AB - OBJECTIVE: To analyze the effect of a pilot program of tele-assistance and tele alarms on the elderly's self-perception of health status and to identify the satisfaction with and acceptance of the program. METHODS: Cross-sectional study that included interviews with 378 elderly individuals, 294 caretakers/relatives and 53 health care professionals. The program was run in Mexico City in 2010. The variables were socio-demographic characteristics, self-rated health, satisfaction and acceptance of the program. The information was gathered through a standardized questionnaire. The statistical analysis included descriptive analysis and nonparametric tests. RESULTS: Significant effects on self-perception of health were observed, 6.17 (SD 17.9 p < 0.05) points above the average. The program was well received and accepted by the elderly, family caregivers and health professionals. CONCLUSIONS: The program helps to maintain or improve quality of life, allows preventive care and is an ideal means of providing psychosocial support to the elderly. PMID- 24346663 TI - Man, road and vehicle: risk factors associated with the severity of traffic accidents. AB - OBJECTIVE: To describe the main characteristics of victims, roads and vehicles involved in traffic accidents and the risk factors involved in accidents resulting in death. METHODS A non-concurrent cohort study of traffic accidents in Fortaleza, CE, Northeastern Brazil, in the period from January 2004 to December 2008. Data from the Fortaleza Traffic Accidents Information System, the Mortality Information System, the Hospital Information System and the State Traffic Department Driving Licenses and Vehicle database. Deterministic and probabilistic relationship techniques were used to integrate the databases. First, descriptive analysis of data relating to people, roads, vehicles and weather was carried out. In the investigation of risk factors for death by traffic accident, generalized linear models were used. The fit of the model was verified by likelihood ratio and ROC analysis. RESULTS There were 118,830 accidents recorded in the period. The most common types of accidents were crashes/collisions (78.1%), running over pedestrians (11.9%), colliding with a fixed obstacle (3.9%), and with motorcycles (18.1%). Deaths occurred in 1.4% of accidents. The factors that were independently associated with death by traffic accident in the final model were bicycles (OR = 21.2, 95%CI 16.1;27.8), running over pedestrians OR = 5.9 (95%CI 3.7;9.2), collision with a fixed obstacle (OR = 5.7, 95%CI 3.1;10.5) and accidents involving motorcyclists (OR = 3.5, 95%CI 2.6;4.6). The main contributing factors were a single person being involved (OR = 6.6, 95%CI 4.1;10.73), presence of unskilled drivers (OR = 4.1, 95%CI 2.9;5.5) a single vehicle (OR = 3.9, 95%CI 2,3;6,4), male (OR = 2.5, 95%CI 1.9;3.3), traffic on roads under federal jurisdiction (OR = 2.4, 95%CI 1.8;3.7), early morning hours (OR = 2.4, 95%CI 1.8;3.0), and Sundays (OR = 1.7, 95%CI 1.3;2.2), adjusted according to the log-binomial model. CONCLUSIONS Activities promoting the prevention of traffic accidents should primarily focus on accidents involving two wheeled vehicles that most often involves a single person, unskilled, male, at nighttime, on weekends and on roads where they travel at higher speeds. PMID- 24346664 TI - Influence of psychosocial factors on smoking cessation: longitudinal evidence from the Pro-Saude Study. AB - OBJECTIVE: To evaluate the incidence of smoking cessation and its association with psychosocial factors. METHODS: Data came from three consecutive waves of the Pro-Saude Study, a longitudinal study of non-faculty civil servants working at a university in Rio de Janeiro, Southeastern Brazil. Inclusion criteria were having participated in Phases 1 and 3 and being a smoker at baseline (Phase 1--1999). Those who had stopped smoking less than a year before the follow-up (Phase 3- 2007) were excluded. The final study population consisted of 661 employees (78% of those eligible). Relative risks (RR) of smoking cessation were evaluated through Poisson regression with robust variance. RESULTS: The cumulative incidence of smoking cessation in eight years of follow-up was 27.7%. Among the psychosocial factors evaluated in the multivariate analysis, only lack of experience of physical violence was associated with higher smoking cessation (RR = 1.67, 95%CI 1.09;2.55). CONCLUSIONS: The incidence of smoking cessation was high, and the fact that associations were not found with most factors evaluated suggests that much of the effect found is due to the impact of public policies implemented in Brazil over the past decades. The association between no exposure to violence and higher incidence of smoking cessation draws attention to the importance of this factor in tobacco control policies. PMID- 24346665 TI - Inequalities in self-rated oral health in adults. AB - OBJECTIVE: To investigate the link between self-rated oral health and socio demographic inequalities. METHODS: Cross-sectional study, carried out with 2,016 adults between 20 and 59 years of age in 2009, in Florianopolis, SC, Southern Brazil. We adopted a two-stage sampling design (census tracts and households). Data were collected through face-to-face interviews, conducted in the participants' households. The outcome was self-rated oral health. The exploratory variables were demographic characteristics, indicators of socioeconomic position, dental service utilization and adverse self-reported oral health conditions. Analysis was performed using multivariable poisson regression, which allowed the estimation of prevalence ratios and 95% confidence intervals. RESULTS: The prevalence of negative self-rated oral health was 33.2% (95%CI 29.8;36.6). In the adjusted analysis, being of an older age, self-classifying as light-skinned black, lower education, the most recent dental appointment being three years or more ago, attending public dental surgeries, having less than 10 natural teeth in at least one arch, self-reporting need for dental treatment, reporting dry mouth, and difficulty eating due to tooth problems were associated with negative self rated oral health. CONCLUSIONS: Self-rated oral health reflects social inequalities in health, and it is associated with low socioeconomic status, less frequent use of dental services and poorer self-reported oral health conditions. PMID- 24346666 TI - Adaptation and validation of WHODAS 2.0 in patients with musculoskeletal pain. AB - OBJECTIVE: To validate the Portuguese version of the World Health Organization Disability Assessment Schedule (WHODAS 2.0). METHODS: The original, 36 item version of the WHODAS 2.0, administered through an interview, was translated into Portuguese following international guidelines and tested on 9 participants from the general population. The Portuguese version was then administered to 204 patients with musculoskeletal pain. The patients' socio-demographic and health data were collected, as were the number of sites where they were experiencing pain and the intensity of that pain. The WHODAS 2.0 was administered again by a second interviewer within three days to determine its inter-rater reliability. Construct validity was assessed according to the ability of WHODAS 2.0 to discriminate between patients with different numbers of pain sites and the correlation between WHODAS 2.0 scores and pain intensity. Internal consistency was also assessed. RESULTS: The Portuguese version of the WHODAS 2.0 is easily understood and has good internal consistency (alpha = 0.84), as well as, very good inter-rater reliability (ICC = 0.95). In addition, it was able to detect statistically significant differences between patients with different numbers of pain sites (p < 0.01) and showed that higher levels of disability are associated with more intense pain (r = 0.44, p < 0.01), indicating that it has construct validity. CONCLUSIONS: The Portuguese version of the WHODAS 2.0 has shown to be reliable and valid when administered to patients with musculoskeletal pain. PMID- 24346667 TI - Epidemiology of medication use among the elderly in an urban area of Northeastern Brazil. AB - OBJECTIVE: To analyze medication use and associated factors among the elderly. METHODS: A population-based cross-sectional study was carried out with a sample of 400 elderly people aged over 60 living in the urban area covered by the Family Health Strategy program in Recife, Northeastern Brazil in 2009. Individuals were selected by systematic random sampling and household data were collected. Demographic, socio-economic, lifestyle factors including nutrition practices and health variables were evaluated. Medication use was the independent variable. Univariate and multivariate statistical analysis were performed. RESULTS: The prevalence of medication use was 85.5%. Polypharmacy (> 5 drugs) occurred in 11% of cases. Of the 951 drugs reported, 98.2% were prescribed by doctors and 21.6% were considered unsafe for the elderly. The most commonly prescribed groups were: cardiovascular drugs (42.9%), central nervous system agents (20.2%) and drugs with an effect on the digestive tract and metabolism (17.3%). The use of polypharmacy was associated with education (p = 0.008), self-reported health (p = 0.012), self-reported chronic disease (p = 0.000) and the number of doctor appointments per year (0.000). CONCLUSIONS: The results of this study indicate a high proportion of medication use among the elderly, including of those considered unsuitable, and inequality among groups of elderly individuals regarding the use of medication, when education, number of doctor appointments and self-reported health are considered. PMID- 24346668 TI - Obesity and dental caries: systematic review. AB - OBJECTIVE: Identifying, through a systematic literature review, evidence of a possible association between obesity and dental caries. METHODS: A search of articles published between 2005 and January 2012 was performed in the Medline/PubMed, LILACS and Web of Science databases. The quality of scientific evidence of the selected articles was assessed by the items proposed for observational studies in the Downs & Black instrument. RESULTS: Initially, 537 references were found; after checking the titles and abstracts by two independent researchers, twenty-eight articles were selected for complete reading. Ten of them that assessed the primary and/or permanent dentition observed a positive association between obesity and dental caries and one study found an inverse association. According to the Downs & Black classification, thirteen articles with good scientific evidence were found. CONCLUSIONS: The present review did not find sufficient evidence regarding the association between obesity and dental caries, and it did not clarify the possible role of diet and other possible effect modifiers on this association. PMID- 24346669 TI - Incremental yield of bronchial washing for diagnosing smear-negative pulmonary tuberculosis. AB - OBJECTIVE: To assess the increased diagnostic yield for pulmonary tuberculosis using bronchial washing cultures compared with sputum cultures. METHODS: Study conducted with 61 adults in Lima, Peru, from January 2006 to December 2007. The yield of sputum cultures was compared with the yield of acid-fast bacilli smears and cultures of bronchial washing for diagnosing pulmonary tuberculosis in suspected cases of clinical tuberculosis with negative acid fast bacilli sputum smears. RESULTS: Twenty seven (95%CI 32;58) of the cases were eventually diagnosed with smear-negative pulmonary tuberculosis. Bronchial washing samples detected 23 (95%CI 72;99) of the smear-negative pulmonary tuberculosis cases compared with 15 (95%CI 37;74) for sputum cultures (p = 0.02). The incremental diagnostic yield of acid fast bacilli smear and culture of bronchial washing specimens over sputum culture was 44% (95%CI 25;65). CONCLUSIONS: In function of the epidemiological context and the resources available, bronchoscopy should be deployed as part of a comprehensive work up that optimizes smear-negative pulmonary tuberculosis diagnosis and minimizes risk and costs. PMID- 24346670 TI - Coexistence of HIV-1 variants with dipeptidic insertion in the reverse transcriptase gene. AB - The aim of this communication was to describe the detection of the coexistence of HIV-1 variant with dipeptide insertion between codons 69 and 70 of reverse transcriptase. These variants were isolated from a 16-year-old male patient, undergoing treatment in the city of Marilia, SP, Southeastern Brazil. After confirmation of treatment failure, resistance to antiretroviral drugs testing was performed and two variants with the insertions of the aminoacids Ser-Gly/Ser-Ala at codon 69 of reverse transcriptase were detected, besides the T69S mutation. These insertions have low prevalence, have not been reported in situations of coexistence in Brazil and are related to multidrug resistance, which makes this epidemiological finding relevant. PMID- 24346671 TI - Measures of experience and scientometrics to evaluate the impact of scientific production. AB - "Experiencimetrics" is proposed as a measure of researchers' academic experience, to complement the existing measure, scientometrics, when evaluating expertise in research. The article is partly based on the author's scientific output, and explores the possibilities of analyzing impact from a qualitative perspective. A synthesis is produced, with possible implications for this analysis, highlighting some options for evaluating the impact of research and articles which are not limited to counting author's citations in order to calculate the impact factor. PMID- 24346672 TI - Challenges and perspectives of academic evaluation. AB - Academic evaluation has been an essential component of modern science since its inception, as science has moved away from personalized patronage toward its contemporary role as an essential enterprise of contemporary, democratic societies. In recent years, Brazil has experienced sustained growth in its scientific output, which is nowadays fully compatible with its status as a high middle-income country striving to become a fully developed, more equitable country in the years to come. Growth usually takes place amidst challenges and dilemmas and, in Brazil as elsewhere, academic evaluation is not exempt from such difficulties. In a large, profoundly heterogeneous country with a national evaluation system and nationwide on-line platforms disseminating information on the most disparate fields of knowledge, the main challenges refer to how to pay attention to detail without losing sight of comprehensiveness and how to handle social and regional diversity while preserving academic excellence as the fundamental benchmark. PMID- 24346673 TI - The challenge of assessing the impact of science beyond bibliometrics. AB - It is hoped that the knowledge produced by scientific research turns into concrete benefits (material or non-material). Bibliometrics, with its various indexes, became the reference of scientific evaluation as an "objective" measure of scientific impact. In Brazil, the evaluation system focused on CAPES has been of great importance for the development of postgraduate studies and research; however changes are necessary, among others, to its bibliometric approach. If we consider the area of health, the challenge of the Unified Health System (SUS) implies the search for scientifically sound alternatives, regarding questions ranging from diagnosis, cure and prevention of a variety of problems, to the organization of a macro-structure capable of giving broad and equal access to the resources required for improving the health of the population. The solutions require expertise and creativity on the part of the researchers and the expected products must include, but are not limited to scientific publications. PMID- 24346674 TI - Social class: concepts and operationalization models in health research. AB - This article discusses the use of the concept of class in health research, different sociological approaches to social stratification and class structure, and the explanatory potential of the class concept in studies on social determinants and health inequalities. It also elaborates on the operationalization models that have been developed for use in sociological, demographic, or health research, as well as the limitations and scope of these models. Four main operationalization models were highlighted: the model developed by Singer for studies on income distribution in Brazil and adapted by Barros for use in epidemiological research, the model of Bronfman and Tuiran to study the Mexican demographics census and adapted by Lombardi for epidemiological research, the model proposed by Goldthorpe for socioeconomic studies in the UK and adapted by the Spanish Society of Epidemiology, and the model proposed by Wright for research in sociology and political science, which has also been used in population surveys in health. In conclusion, each of the models presented is consistent with their underlying theoretical concept, precluding the selection of one model over the others. PMID- 24346675 TI - Increased contribution of ultra-processed food products in the Brazilian diet (1987-2009). AB - OBJECTIVE: To establish temporal trends in household food and drink consumption in Brazil, taking into account the extent and purpose of its industrial processing. METHODS: Data was obtained from Household Budget Surveys conducted in Brazil in 1987-1988, 1995-1996, 2002-2003 and 2008-2009. In all surveys, probabilistic samples of households in the metropolitan areas were studied and, for the last two surveys, the scope was national. The units of analysis were food purchases records of clusters of households. The purchased food items were divided according to the extent and purpose of their industrial processing into: 'in natura' or minimally processed foods, processed culinary ingredients and ready-to-consume, processed and ultra-processed food and drink products. The quantity of each item was converted into energy. For each survey, the daily availability of calories per capita and the caloric share of the food groups were estimated. For the national surveys, estimates were calculated by income quintiles. Temporal trends were assessed using linear regression models and difference of means tests. RESULTS: The caloric share of ready-to-consume products significantly increased between 2002-2003 and 2008-2009 (from 23.0% to 27.8% of total calories), mainly because of the increase in the consumption of ultra-processed products (20.8% to 25.4%). In the same period, there was a significant reduction in the caloric share of foods and culinary ingredients. The increase in the ultra-processed products caloric share occurred across all income quintiles. There was an uniform increase in the caloric share of ready-to-consume products in the metropolitan areas, mostly in place of ultra-processed products, accompanied by a decrease in the share of 'in natura' or minimally processed foods and culinary ingredients. CONCLUSIONS: The share of ultra-processed products significantly increased in the Brazilian diet, as seen in the metropolitan areas since the 1980s, and confirmed at a national level in the 2000s. PMID- 24346676 TI - Reducing the use of sugar in public schools: a randomized cluster trial. AB - OBJECTIVE: To test the efficacy of nutritional guidelines for school lunch cooks aiming to reduce added sugar in school meals and their own sugar intake. METHODS: A controlled randomized cluster trial was carried out in twenty public schools in the municipality of Niteroi in Rio de Janeiro, Southeastern Brazil, from March to December 2007. A nutrition educational program was implemented in the schools in question through messages, activities and printed educational materials encouraging reduced levels of added sugar in school meals and in the school lunch cooks' own intake. The reduced availability of added sugar in schools was evaluated using spreadsheets including data on the monthly use of food item supplies. The cooks' individual food intake was evaluated by a Food Frequency Questionnaire. Anthropometric measurements were taken according to standardized techniques and variation in weight was measured throughout the duration of the study. RESULTS: There was a more marked reduction in the intervention schools compared to the control schools (-6.0 kg versus 0.34 kg), but no statistically significant difference (p = 0.21), although the study power was low. Both groups of school lunch cooks showed a reduction in the consumption of sweets and sweetened beverages, but the difference in sugar intake was not statistically significant. Weight loss and a reduction in total energy consumption occurred in both groups, but the difference between them was not statistically significant, and there was no alteration in the percentages of adequacy of macronutrients in relation to energy consumption. CONCLUSIONS: The strategy of reducing the use and consumption of sugar by school lunch cooks from public schools could not be proved to be effective. PMID- 24346677 TI - Evaluation of the reliability and validity of the Brazilian Healthy Eating Index Revised. AB - OBJECTIVE: Evaluate validity and reliability of the Brazilian Healthy Eating Index Revised according to the psychometric properties. METHODS: Cross-sectional study of a random sample of 2,375 individuals of both sexes, aged 12 or older from the city of Sao Paulo, Southeastern Brazil, drawn from the Health Survey carried out in 2003. Information on the population characteristics was acquired using a questionnaire. Food intake was obtained using 24h Recall, used to calculate the Brazilian Healthy Eating Index Revised (BHEI-R). The following aspects were evaluated: (1) content validity, by comparing the components with the Dietary Guidelines for the Brazilian Population; (2) construct validity, factor analysis using principal components method and verifying whether the index can measure diet quality regardless of energy intake; (3) discriminating validity; and (4) the reliability of the BHEI-R by analyzing the internal consistency of the items using Cronbach's alpha coefficient. RESULTS: The correlations between the component scores and energy intake were weak (r < 0.30). Principal component analysis indicated the presence of four factors with eigenvalues > 1 that represented 67% of the index variance. The discriminating validity of the BHEI-R was observed by comparing the individuals by sex and smoking habit, and identifying statistically significant differences between the means of the components of the BHEI-R and the final score. The Cronbach's alpha value (alpha = 0.7) indicated the presence of internal consistency between the components of the BHEI-R. The SoFAAS component followed by the total fruit component and whole fruit component presented greater correlation with the final index scores. CONCLUSIONS: The Brazilian Healthy Eating Index Revised showed itself to be reliable and structurally valid when used to evaluate and monitor the diet quality of Brazilians. PMID- 24346678 TI - Incorporated antivirals for chronic hepatitis B in Brazil: a cost-effectiveness analysis. AB - OBJECTIVE: To evaluate the cost-effectiveness of different drug therapies for chronic hepatitis B in adult patients. METHODS: Using a Markov model, a hypothetical cohort of 40 years for HBeAg-positive or HBeAg-negative patients was constructed. Adefovir, entecavir, tenofovir and lamivudine (with rescue therapy in cases of viral resistance) were compared for treating adult patients with chronic hepatitis B undergoing treatment for the first time, with high levels of alanine aminotransferase, no evidence of cirrhosis and without HIV co-infection. Values for cost and effect were obtained from the literature, and expressed in effect on life years (LY). A discount rate of 5% was applied. Univariate sensitivity analysis was conducted to assess model uncertainties. RESULTS: Initial treatment with entecavir or tenofovir showed better clinical outcomes. The lowest cost-effectiveness ratio was for entecavir in HBeAg-positive patients (R$ 4,010.84/LY) and lamivudine for HBeAg-negative patients (R$ 6,205.08/LY). For HBeAg-negative patients, the incremental cost-effectiveness ratio of entecavir (R$ 14,101.05/LY) is below the threshold recommended by the World Health Organization. Sensitivity analysis showed that variation in the cost of drugs may make tenofovir a cost-effective alternative for both HBeAg-positive and HBeAg negative patients. CONCLUSIONS: Entecavir is the recommended alternative to start treating patients with chronic hepatitis B in Brazil. However, if there is a reduction in the cost of tenofovir, it can become a cost-effective alternative. PMID- 24346679 TI - Social determinants of health and the Brazilian Family Health Care Program in the city of Sao Paulo, Southeastern Brazil. AB - OBJECTIVE: To analyze the current status of the interventions related to social determinants of health conducted in the context of the brazilian family health program. METHODS: A case study using a mixed method approach based on a sequential explanatory strategy with 171 unit managers in the Family Health Care Program in the municipality of Sao Paulo, SP, Southeastern Brazil, in 2005/2006. Self-administered questionnaires were applied and semi-structured interviews and focus groups were conducted with a purposive sample of professionals involved in initiatives related to social determinants of health. Quantitative data were analyzed using descriptive statistics, multiple correspondence analysis, cluster analysis and correlation tests. Qualitative data were analyzed through content analysis and the creation of thematic categories. RESULTS: Despite the concentration of activities directed at disease care, the Family Health Care Program carries out various activities related to the social determination of health, encompassing the entire spectrum of health promotion approaches (biological, behavioral, psychological, social and structural) and all major social determinants of health described in the literature. There was a significant difference related to the scope of the determinants being worked on in the units according to the area of the city. The description of the activities revealed the fragility of the initiatives and a disconnection with the organizational structure of the Family Health Care Program. CONCLUSIONS: The quantity and variety of initiatives related to social determinants of health attests to the program's potential to deal with the social determination of health. On the other hand, the fluidity of objectives and the 'out of the ordinary/extraordinary' characterization of the described initiatives raises concern about its sustainability as an integral part of the program's current operational model. PMID- 24346680 TI - The need to establish a national patient safety program in Brazil. AB - The aim of the study was to promote reflection on the need to create a national incident notification system based on a brazilian patient safety program. Incidents in health care harm patients and encumber the health care system. Although a quality assessment program has been recently launched in health care institutions, the Brazilian Ministry of Health does not yet have a program which systematically assesses negative outcomes of health care. This article discusses the need to establish a national patient safety program in Brazil, aiming to promote a culture of patient safety and quality health care in the Brazilian Unified Health System. PMID- 24346681 TI - Prevalence of nutritional deficits among children under five years of age in Angola. AB - OBJECTIVE: To estimate the prevalence of nutritional deficiencies in Angolan children. METHODS: A cross-sectional population based study. World Health Organization (2006) criteria were used to classify nutritional state. RESULTS: A high prevalence of low height for age, weight for height and weight for age was observed (22%, 13% and 7%, respectively) among the children. CONCLUSIONS: Nutritional deficiencies in children represents a serious public health problem in Bom Jesus, Angola. PMID- 24346683 TI - Does size difference in allogeneic cancellous bone granules loaded with differentiated autologous cultured osteoblasts affect osteogenic potential? AB - We study the efficacy of bone regeneration by using two differently sized allogeneic cancellous bone granules loaded with autologous cultured osteoblasts in a rabbit model. Critical-sized bone defects of the radial shaft were made in 40 New Zealand White rabbits. Small allogeneic bone granules (150-300 MUm in diameter) loaded with cultured differentiated autologous osteoblasts were implanted into one forearm (SBG group) and large bone granules (500-710 MUm) loaded with osteoblasts were implanted into the forearm of the other side (LBG group). Radiographic evaluations were performed at 3, 6, 9 and 12 weeks and histology and micro-CT image analysis were carried out at 6 and 12 weeks post implantation. On radiographic evaluation, the LBG group showed a higher bone quantity index at 3 and 6 weeks post-implantation (P < 0.05) but statistical significance was lost at 9 and 12 weeks. The progression of biological processes of the SBG group was faster than that of the LBG group. On micro-CT image analysis, the LBG group revealed a higher total bone volume and surface area than the SBG group at 6 weeks (P < 0.05) but the difference decreased at 12 weeks and was without statistical significance. Histological evaluation also revealed faster progression of new bone formation and maturation in the SBG group. Thus, the two differently sized allogeneic bone granules loaded with co-cultured autologous osteoblasts show no differences in the amount of bone regeneration, although the SBG group exhibits faster progression of bone regeneration and remodeling. This method might therefore provide benefits, such as a short healing time and easy application in an injectable form, in a clinical setting. PMID- 24346684 TI - A NMR experiment for simultaneous correlations of valine and leucine/isoleucine methyls with carbonyl chemical shifts in proteins. AB - A methyl-detected 'out-and-back' NMR experiment for obtaining simultaneous correlations of methyl resonances of valine and isoleucine/leucine residues with backbone carbonyl chemical shifts, SIM-HMCM(CGCBCA)CO, is described. The developed pulse-scheme serves the purpose of convenience in recording a single data set for all Ile(delta1), Leu(delta) and Val(gamma) (ILV) methyl positions instead of acquiring two separate spectra selective for valine or leucine/isoleucine residues. The SIM-HMCM(CGCBCA)CO experiment can be used for ILV methyl assignments in moderately sized protein systems (up to ~100 kDa) where the backbone chemical shifts of (13)C(alpha), (13)Cbeta and (13)CO are known from prior NMR studies and where some losses in sensitivity can be tolerated for the sake of an overall reduction in NMR acquisition time. PMID- 24346685 TI - Bridge over troubled proline: assignment of intrinsically disordered proteins using (HCA)CON(CAN)H and (HCA)N(CA)CO(N)H experiments concomitantly with HNCO and i(HCA)CO(CA)NH. AB - NMR spectroscopy is by far the most versatile and information rich technique to study intrinsically disordered proteins (IDPs). While NMR is able to offer residue level information on structure and dynamics, assignment of chemical shift resonances in IDPs is not a straightforward process. Consequently, numerous pulse sequences and assignment protocols have been developed during past several years, targeted especially for the assignment of IDPs, including experiments that employ H(N), H(alpha) or (13)C detection combined with two to six indirectly detected dimensions. Here we propose two new HN-detection based pulse sequences, (HCA)CON(CAN)H and (HCA)N(CA)CO(N)H, that provide correlations with (1)H(N)(i - 1), (13)C'(i - 1) and (15)N(i), and (1)H(N)(i + 1), (13)C'(i) and (15)N(i) frequencies, respectively. Most importantly, they offer sequential links across the proline bridges and enable filling the single proline gaps during the assignment. We show that the novel experiments can efficiently complement the information available from existing HNCO and intraresidual i(HCA)CO(CA)NH pulse sequences and their concomitant usage enabled >95 % assignment of backbone resonances in cytoplasmic tail of adenosine receptor A2A in comparison to 73 % complete assignment using the HNCO/i(HCA)CO(CA)NH data alone. PMID- 24346686 TI - The future of cancer research: prevention, screening, vaccines, and tumor specific drug combos. AB - New cancer research strategies have developed very rapidly over the past five years, including extensive DNA sequencing of tumor and normal cells; use of highly sensitive cancer cell detection methods; vaccine development and tumor specific (designer) drugs. These developments have raised questions about where to concentrate efforts in the near future when establishing clinical trials, particularly important in an age of diminishing resources and during a period when competing strategies for cancer control are likely to overwhelm the opportunities for establishing large, effective clinical trials. In particular, it behooves the research community to be mindful of the inevitable, challenging obligation to responsibly choose between clinical trials that offer the credible hope of incremental advances vs. trials that are less traditional but may have revolutionary outcomes. PMID- 24346687 TI - Ultrathin Co3O4 nanosheet arrays with high supercapacitive performance. AB - Constructing nanostructures with desirable morphology and size is a critical issue for pursuing high performance electrode materials. Ultrathin Co3O4 nanosheet arrays, which are composed of well aligned uniform long-range (~5 MUm in length) and thin (~10 nm in thickness) nanosheets, with reasonable mass loading on Ni foam are prepared by a two-step hydrothermal reaction. As a supercapacitor electrode, a superior specific capacitance (~1782 F g(-1)) is obtained at current density of 1.8 A g(-1) (5 mA cm(-2)), much larger than that of the thicker nanostrucutures (~300 F g(-1)). The ultrathin nanosheet arrays electrode exhibits good rate capabilities, maintaining 51% of the initial capacity at current density of 30 mA cm(-2), and excellent long-term stability, remaining >90% of capacitance after 2000 cycles. Such high performance is attributed to the desirable morphologies, uniform architecture and high surface area. The results manifest that ultrathin Co3O4 nanosheet arrays are promising electrode material for supercapacitor in future application. PMID- 24346688 TI - How do I follow patients with early breast cancer after completing adjuvant therapy. AB - OPINION STATEMENT: With improvements in the detection and treatment of breast cancer, more women are surviving after diagnosis. Patients who complete adjuvant therapy require ongoing follow-up to manage toxicities, to detect recurrences early, and to provide ongoing physical and psychosocial support. Routine surveillance should be implemented, with attention to educating patients about symptoms of recurrence, such as weight loss, cough, and bone pain. An intensive surveillance strategy with the routine use of laboratory and radiographic studies does not improve outcomes and raises the cost of follow-up. Patients should have annual mammograms in conjunction with physical exam and history at appropriate intervals that increase the farther out patients are from treatment. Attention also should be focused on other routine health maintenance and cancer screening, such as colonoscopy, gynecologic examinations, and bone health/DEXA scans. In the early posttreatment period, medical oncologists are best equipped to follow these patients. However, as women live longer after a breast cancer diagnosis and treatment, transitioning care to a primary care physician or nurse practitioner is appropriate, provided these practitioners are educated about late treatment effects and managing side effects of treatment, which may continue as long as a decade. A multidisciplinary follow-up strategy with excellent communication between providers can ensure safe, convenient, and quality care to the growing population of breast cancer survivors. As the treatment of breast cancer evolves into personalized strategies based on the biologic characteristics of individual tumors, future studies will be needed to determine if a single surveillance strategy is sufficient or if individualized surveillance based on risk can improve outcomes and costs of long-term follow-up care. PMID- 24346689 TI - The acute-phase protein PTX3 is an essential mediator of glial scar formation and resolution of brain edema after ischemic injury. AB - Acute-phase proteins (APPs) are key effectors of the immune response and are routinely used as biomarkers in cerebrovascular diseases, but their role during brain inflammation remains largely unknown. Elevated circulating levels of the acute-phase protein pentraxin-3 (PTX3) are associated with worse outcome in stroke patients. Here we show that PTX3 is expressed in neurons and glia in response to cerebral ischemia, and that the proinflammatory cytokine interleukin 1 (IL-1) is a key driver of PTX3 expression in the brain after experimental stroke. Gene deletion of PTX3 had no significant effects on acute ischemic brain injury. In contrast, the absence of PTX3 strongly compromised blood-brain barrier integrity and resolution of brain edema during recovery after ischemic injury. Compromised resolution of brain edema in PTX3-deficient mice was associated with impaired glial scar formation and alterations in scar-associated extracellular matrix production. Our results suggest that PTX3 expression induced by proinflammatory signals after ischemic brain injury is a critical effector of edema resolution and glial scar formation. This highlights the potential role for inflammatory molecules in brain recovery after injury and identifies APPs, in particular PTX3, as important targets in ischemic stroke and possibly other brain inflammatory disorders. PMID- 24346690 TI - Rivaroxaban does not increase hemorrhage after thrombolysis in experimental ischemic stroke. AB - The management of acute ischemic stroke during anticoagulation with a novel oral anticoagulant (NOAC) is challenging because intravenous thrombolysis is contraindicated because of a putative increased risk of intracerebral hemorrhagic complications. We examined the risk of secondary postischemic hemorrhage after thrombolysis in rodents pretreated with rivaroxaban or warfarin. Mice were pretreated with either rivaroxaban (30 mg/kg), warfarin (target international normalized ratio 2 to 3) or vehicle. After 2 or 3 hours, middle cerebral artery occlusion (MCAO), mice received 9 mg/kg recombinant tissue plasminogen activator. Twenty-four hours after MCAO, secondary hemorrhage was quantified using a macroscopic hemorrhage score and hemoglobin spectrophotometry. Blood-brain barrier (BBB) permeability was measured by Evans Blue spectrofluorometry. To increase the validity of our findings, experiments were also performed using a thromboembolic model in anticoagulated rats. Infarct size did not differ among groups. Pretreatment with warfarin led to significantly more secondary hemorrhage compared with rivaroxaban and nonanticoagulated controls after 2- and 3-hour ischemia in mice as well as in rats. Blood-brain barrier permeability was significantly higher in the warfarin group compared with rivaroxaban and control. Thus, rivaroxaban in contrast to warfarin does not increase secondary hemorrhage after thrombolysis in experimental cerebral ischemia. Less effects of rivaroxaban on postischemic BBB permeability may account for this difference. PMID- 24346691 TI - The Wnt/planar cell polarity signaling pathway contributes to the integrity of tight junctions in brain endothelial cells. AB - Wnt morphogens released by neural precursor cells were recently reported to control blood-brain barrier (BBB) formation during development. Indeed, in mouse brain endothelial cells, activation of the Wnt/beta-catenin signaling pathway, also known as the canonical Wnt pathway, was shown to stabilize endothelial tight junctions (TJs) through transcriptional regulation of the expression of TJ proteins. Because Wnt proteins activate several distinct beta-catenin-dependent and independent signaling pathways, this study was designed to assess whether the noncanonical Wnt/Par/aPKC planar cell polarity (PCP) pathway might also control TJ integrity in brain endothelial cells. First we established, in the hCMEC/D3 human brain endothelial cell line, that the Par/aPKC PCP complex colocalizes with TJs and controls apicobasal polarization. Second, using an siRNA approach, we showed that the Par/aPKC PCP complex regulates TJ stability and reassembling after osmotic shock. Finally, we provided evidence that Wnt5a signals in hCMEC/D3 cells through activation of the Par/aPKC PCP complex, independently of the Wnt canonical beta-catenin-dependent pathway and significantly contributes to TJ integrity and endothelial apicobasal polarity. In conclusion, this study suggests that the Wnt/Par/aPKC PCP pathway, in addition to the Wnt/beta-catenin canonical pathway, is a key regulator of the BBB. PMID- 24346693 TI - Supramolecular assembly in a Janus-type urea system. AB - A pyrazolyl urea ligand adopts two possible conformations with the urea NH groups directed either outward or inward. Metal coordination enforces the outward conformation resulting in either anion complexation or self-association and hence extended supramolecular assemblies including a hexameric barrel that persists in solution. PMID- 24346692 TI - Effect of glutamine synthetase inhibition on brain and interorgan ammonia metabolism in bile duct ligated rats. AB - Ammonia has a key role in the development of hepatic encephalopathy (HE). In the brain, glutamine synthetase (GS) rapidly converts blood-borne ammonia into glutamine which in high concentrations may cause mitochondrial dysfunction and osmolytic brain edema. In astrocyte-neuron cocultures and brains of healthy rats, inhibition of GS by methionine sulfoximine (MSO) reduced glutamine synthesis and increased alanine synthesis. Here, we investigate effects of MSO on brain and interorgan ammonia metabolism in sham and bile duct ligated (BDL) rats. Concentrations of glutamine, glutamate, alanine, and aspartate and incorporation of (15)NH(4)(+) into these amino acids in brain, liver, muscle, kidney, and plasma were similar in sham and BDL rats treated with saline. Methionine sulfoximine reduced glutamine concentrations in liver, kidney, and plasma but not in brain and muscle; MSO reduced incorporation of (15)NH(4)(+) into glutamine in all tissues. It did not affect alanine concentrations in any of the tissues but plasma alanine concentration increased; incorporation of (15)NH(4)(+) into alanine was increased in brain in sham and BDL rats and in kidney in sham rats. It inhibited GS in all tissues examined but only in brain was an increased incorporation of (15)N-ammonia into alanine observed. Liver and kidney were important for metabolizing blood-borne ammonia. PMID- 24346694 TI - Developing with the community. PMID- 24346696 TI - How unique is the human neocortex? AB - The human cerebral cortex is generally considered the most complex organ, and is the structure that we hold responsible for the repertoire of behavior that distinguishes us from our closest living and extinct relatives. At a recent Company of Biologists Workshop, 'Evolution of the Human Neocortex: How Unique Are We?' held in September 2013, researchers considered new information from the fields of developmental biology, genetics, genomics, molecular biology and ethology to understand unique features of the human cerebral cortex and their developmental and evolutionary origin. PMID- 24346695 TI - Sphingosine 1-phosphate signalling. AB - Sphingosine 1-phosphate (S1P) is a lipid mediator formed by the metabolism of sphingomyelin. In vertebrates, S1P is secreted into the extracellular environment and signals via G protein-coupled S1P receptors to regulate cell-cell and cell matrix adhesion, and thereby influence cell migration, differentiation and survival. The expression and localization of S1P receptors is dynamically regulated and controls vascular development, vessel stability and immune cell trafficking. In addition, crucial events during embryogenesis, such as angiogenesis, cardiogenesis, limb development and neurogenesis, are regulated by S1P signalling. Here, and in the accompanying poster, we provide an overview of S1P signalling in development and in disease. PMID- 24346697 TI - The actin-binding protein profilin is required for germline stem cell maintenance and germ cell enclosure by somatic cyst cells. AB - Specialized microenvironments, or niches, provide signaling cues that regulate stem cell behavior. In the Drosophila testis, the JAK-STAT signaling pathway regulates germline stem cell (GSC) attachment to the apical hub and somatic cyst stem cell (CySC) identity. Here, we demonstrate that chickadee, the Drosophila gene that encodes profilin, is required cell autonomously to maintain GSCs, possibly facilitating localization or maintenance of E-cadherin to the GSC-hub cell interface. Germline specific overexpression of Adenomatous Polyposis Coli 2 (APC2) rescued GSC loss in chic hypomorphs, suggesting an additive role of APC2 and F-actin in maintaining the adherens junctions that anchor GSCs to the niche. In addition, loss of chic function in the soma resulted in failure of somatic cyst cells to maintain germ cell enclosure and overproliferation of transit amplifying spermatogonia. PMID- 24346699 TI - Purkinje cells and Bergmann glia are primary targets of the TRalpha1 thyroid hormone receptor during mouse cerebellum postnatal development. AB - Thyroid hormone is necessary for normal development of the central nervous system, as shown by the severe mental retardation syndrome affecting hypothyroid patients with low levels of active thyroid hormone. The postnatal defects observed in hypothyroid mouse cerebellum are recapitulated in mice heterozygous for a dominant-negative mutation of Thra, the gene encoding the ubiquitous TRalpha1 receptor. Using CRE/loxP-mediated conditional expression approach, we found that this mutation primarily alters the differentiation of Purkinje cells and Bergmann glia, two cerebellum-specific cell types. These primary defects indirectly affect cerebellum development in a global manner. Notably, the inward migration and terminal differentiation of granule cell precursors is impaired. Therefore, despite the broad distribution of its receptors, thyroid hormone targets few cell types that exert a predominant role in the network of cellular interactions that govern normal cerebellum maturation. PMID- 24346698 TI - p63 and Brg1 control developmentally regulated higher-order chromatin remodelling at the epidermal differentiation complex locus in epidermal progenitor cells. AB - Chromatin structural states and their remodelling, including higher-order chromatin folding and three-dimensional (3D) genome organisation, play an important role in the control of gene expression. The role of 3D genome organisation in the control and execution of lineage-specific transcription programmes during the development and differentiation of multipotent stem cells into specialised cell types remains poorly understood. Here, we show that substantial remodelling of the higher-order chromatin structure of the epidermal differentiation complex (EDC), a keratinocyte lineage-specific gene locus on mouse chromosome 3, occurs during epidermal morphogenesis. During epidermal development, the locus relocates away from the nuclear periphery towards the nuclear interior into a compartment enriched in SC35-positive nuclear speckles. Relocation of the EDC locus occurs prior to the full activation of EDC genes involved in controlling terminal keratinocyte differentiation and is a lineage specific, developmentally regulated event controlled by transcription factor p63, a master regulator of epidermal development. We also show that, in epidermal progenitor cells, p63 directly regulates the expression of the ATP-dependent chromatin remodeller Brg1, which binds to distinct domains within the EDC and is required for relocation of the EDC towards the nuclear interior. Furthermore, Brg1 also regulates gene expression within the EDC locus during epidermal morphogenesis. Thus, p63 and its direct target Brg1 play an essential role in remodelling the higher-order chromatin structure of the EDC and in the specific positioning of this locus within the landscape of the 3D nuclear space, as required for the efficient expression of EDC genes in epidermal progenitor cells during skin development. PMID- 24346700 TI - Premature dyad separation in meiosis II is the major segregation error with maternal age in mouse oocytes. AB - As women get older their oocytes become susceptible to chromosome mis segregation. This generates aneuploid embryos, leading to increased infertility and birth defects. Here we examined the provenance of aneuploidy by tracking chromosomes and their kinetochores in oocytes from young and aged mice. Changes consistent with chromosome cohesion deterioration were found with age, including increased interkinetochore distance and loss of the centromeric protector of cohesion SGO2 in metaphase II arrested (metII) eggs, as well as a rise in the number of weakly attached bivalents in meiosis I (MI) and lagging chromosomes at anaphase I. However, there were no MI errors in congression or biorientation. Instead, premature separation of dyads in meiosis II was the major segregation defect in aged eggs and these were associated with very low levels of SGO2. These data show that although considerable cohesion loss occurs during MI, its consequences are observed during meiosis II, when centromeric cohesion is needed to maintain dyad integrity. PMID- 24346701 TI - HTZ-1/H2A.z and MYS-1/MYST HAT act redundantly to maintain cell fates in somatic gonadal cells through repression of ceh-22 in C. elegans. AB - The stable maintenance of acquired cell fates is important during development and for maintaining tissue homeostasis. Although histone modification is one of the major strategies used by cells to maintain their fates, the mechanisms by which histone variants maintain cell fates are not well understood. In C. elegans, the acetylated-histone-H4 (AcH4)-binding protein BET-1 acts downstream of the MYST family histone acetyltransferases MYS-1 and MYS-2 to establish and maintain cell fates in multiple cell lineages. Here we show that, in the bet-1 pathway, the histone H2A variant HTZ-1/H2A.z and MYS-1 are required for the maintenance of cell fates in a redundant manner. BET-1 controlled the subnuclear localization of HTZ-1. HTZ-1 and MYS-1 maintained the fates of the somatic gonadal cells (SGCs) through the repression of a target, ceh-22/Nkx2.5, which induced the formation of the leader cells of the gonad. H3K27 demethylase, UTX-1, had an antagonistic effect relative to HTZ-1 in the regulation of ceh-22. Nuclear spot assay revealed that HTZ-1 localized to the ceh-22 locus in SGCs in an utx-1-dependent manner. We propose that HTZ-1 and MYS-1 repress ceh-22 when UTX-1 removes its silencing mark, H3K27 methylation on the ceh-22 locus, thereby maintaining the fates of SGCs. PMID- 24346702 TI - Cas9 effector-mediated regulation of transcription and differentiation in human pluripotent stem cells. AB - The identification of the trans-acting factors and cis-regulatory modules that are involved in human pluripotent stem cell (hPSC) maintenance and differentiation is necessary to dissect the operating regulatory networks in these processes and thereby identify nodes where signal input will direct desired cell fate decisions in vitro or in vivo. To deconvolute these networks, we established a method to influence the differentiation state of hPSCs with a CRISPR-associated catalytically inactive dCas9 fused to an effector domain. In human embryonic stem cells, we find that the dCas9 effectors can exert positive or negative regulation on the expression of developmentally relevant genes, which can influence cell differentiation status when impinging on a key node in the regulatory network that governs the cell state. This system provides a platform for the interrogation of the underlying regulators governing specific differentiation decisions, which can then be employed to direct cellular differentiation down desired pathways. PMID- 24346706 TI - Economic empowerment of impoverished IPV survivors: a review of best practice literature and implications for policy. AB - Best practices in advocating for economic empowerment of impoverished intimate partner violence (IPV) survivors require the comprehensive and holistic organization of program and service delivery systems. This article outlines the best practices literature that addresses IPV in the lives of impoverished women, as well as the literature that specifically examines the interventions to economically empower IPV survivors--whether impoverished or not. This article concludes with suggestions for policy makers on how to incorporate these best practices into the Violence Against Women Act and for practitioners to ensure a comprehensive approach to interventions for impoverished IPV survivors. PMID- 24346707 TI - Psychopathology among homicidally bereaved individuals: a systematic review. AB - In the literature on bereavement, claims are made that homicidal loss is associated with posttraumatic stress reactions, depression, and other severe mental health problems. It is surprising that only a few studies have investigated the nature and prevalence of emotional symptoms following homicidal bereavement and a reference to systematic, empirical research is seldom provided. This article reviews the available literature to investigate whether these claims have empirical evidence. Three databases were searched to identify relevant studies. This approach was supplemented with a bibliography search. Eligible studies included English-language peer-reviewed articles that assessed psychopathology in the homicidally bereaved, as defined in the Diagnostic and Statistical Manual of Mental Disorders. Of the 360 potentially relevant articles, 8 studies (13 references) met predefined inclusion criteria. Homicide-related psychopathology among the bereaved assessed in these studies includes posttraumatic stress disorder (PTSD), depression, complicated grief, and substance abuse. Prevalence of lifetime homicide-related PTSD varied from 19.1% to 71% across studies. Current PTSD varied between 5.2% and 6%. The reviewed literature was inconclusive regarding the course of symptoms over time and the severity of psychopathology among the homicidally bereaved, compared to individuals bereaved by other causes of death. A comparison of the nature and prevalence of psychopathology between studies was complicated by unequal sample sizes and type, recruitment strategy, study design, and time since loss. Limitations of the included studies are discussed, as well as implications for clinical practice, policy, and future research. PMID- 24346703 TI - Novel cardiovascular gene functions revealed via systematic phenotype prediction in zebrafish. AB - Comprehensive functional annotation of vertebrate genomes is fundamental to biological discovery. Reverse genetic screening has been highly useful for determination of gene function, but is untenable as a systematic approach in vertebrate model organisms given the number of surveyable genes and observable phenotypes. Unbiased prediction of gene-phenotype relationships offers a strategy to direct finite experimental resources towards likely phenotypes, thus maximizing de novo discovery of gene functions. Here we prioritized genes for phenotypic assay in zebrafish through machine learning, predicting the effect of loss of function of each of 15,106 zebrafish genes on 338 distinct embryonic anatomical processes. Focusing on cardiovascular phenotypes, the learning procedure predicted known knockdown and mutant phenotypes with high precision. In proof-of-concept studies we validated 16 high-confidence cardiac predictions using targeted morpholino knockdown and initial blinded phenotyping in embryonic zebrafish, confirming a significant enrichment for cardiac phenotypes as compared with morpholino controls. Subsequent detailed analyses of cardiac function confirmed these results, identifying novel physiological defects for 11 tested genes. Among these we identified tmem88a, a recently described attenuator of Wnt signaling, as a discrete regulator of the patterning of intercellular coupling in the zebrafish cardiac epithelium. Thus, we show that systematic prioritization in zebrafish can accelerate the pace of developmental gene function discovery. PMID- 24346708 TI - Topoisomerase IIbeta binding protein 1 c.*229C>T (rs115160714) gene polymorphism and endometrial cancer risk. AB - TopBP1 (topoisomerase IIbeta binding protein 1) protein is involved in DNA replication, DNA damage checkpoint response and transcriptional regulation. In this study we investigated whether alterations in the TopBP1 gene can influence the risk of endometrial cancer. We examined the association between five single nucleotide polymorphisms (rs185903567, rs116645643, rs115160714, rs116195487, and rs112843513) located in the 3'UTR region of the TopBP1 gene and endometrial cancer risk as well as allele-specific gene expression. One hundred twenty-one endometrial cancer patients were genotyped for these SNPs. Allele-specific TopBP1 mRNA and protein expressions were determined by real time PCR and western blotting methods, respectively. Only one SNP (rs115160714) showed an association with endometrial cancer. Compared to homozygous common allele carriers, heterozygous for the T variant had significantly increased risk of endometrial cancer [adjusted odds ratio (OR) = 5.59, 95 % confidence interval (CI): 1.96 15.91, p = 0.0003]. Mean TopBP1 mRNA and protein expression were higher in the individuals with the CT genotype. There was a significant association between the rs115160714 and tumor grade and FIGO classification. Most carriers of minor allele had a high grade tumors (G3) classified as FIGO III/IV. The results of our study raise a possibility that a genetic variation of TopBP1 may be implicated in the etiology of endometrial cancer. PMID- 24346709 TI - Successful discontinuation of eculizumab therapy in a patient with aHUS. PMID- 24346710 TI - Pulmonary manifestations of the pre-engraftment syndrome after umbilical cord blood transplantation. AB - Pre-engraftment syndrome (PES) is a condition occurring after umbilical cord blood transplantation (UCBT) characterized by fever and erythematous skin rash prior to neutrophil engraftment. We sought to determine the incidence and characterize the pulmonary manifestations of PES. A retrospective review of patients who underwent UCBT at the University of Kansas Medical Center over a 5 year period was performed. Data collected included patient baseline characteristics, presence of PES, pulmonary findings, treatments, and survival. Forty-four patients underwent UCBT with 22 of those patients developing PES. Full intensity myeloablative conditioning regimen was found to be a risk factor for development of PES. Of those 22 patients, 13 had resting hypoxemia. The most common radiographic findings included diffuse ground glass opacities with pleural effusions. Fifteen patients with PES received corticosteroids, of which 12 had improvement in fevers and rash. These patients had a trend toward worse mortality than those not receiving corticosteroids. There was a nonsignificant trend toward worse survival in patients with PES and hypoxemia compared to those without hypoxemia. PES is a common complication following cord blood transplantation, with hypoxemia being present in over half of patients with PES. Hypoxemia with PES and treatment with corticosteroids may portend a worse prognosis. PMID- 24346712 TI - Puerarin ameliorates 3-nitropropionic acid-induced neurotoxicity in rats: possible neuromodulation and antioxidant mechanisms. AB - Puerarin (daidzein-8-C-glucoside), a major isoflavone glycoside purified from Pueraria lobata, is well reported to have a neuroprotective effect primarily by the antioxidant mechanisms. This investigation was designed to evaluate the efficacy of Puerarin (Pur) to offset 3-nitropropionic acid (3-NP) induced neurotoxicity. Male Wistar strain rats were given 3-NP (20 mg/kg, s.c.) over five consecutive days, whereas Pur (200 mg/kg, i.p.) was administrated 30 min before 3 NP. Rats treated with 3-NP exhibited significant weight loss, reduction of the prepulse inhibition, locomotor hypoactivity and hypothermia. The striata, hippocampi and cortices of the 3-NP treated rats showed abnormal levels of neurotransmitters, oxidative damage and characteristic histopathological lesions. Treatment with Pur ahead of 3-NP, significantly prevented weight loss, PPI deficit, locomotor hypoactivity and hypothermia. Pur treatment blocked the 3-NP induced neurotransmitters abnormalities (GABA, DA, 5-HT and NE), and normalized the oxidative stress biomarkers (lipid peroxidation, reduced glutathione, glutathione peroxidase). Histopathological examination further affirmed Pur's neuroprotective effect against 3-NP-induced neurotoxicity. In conclusion, Pur protected the brain tissues from 3-NP induced neurotoxicity primarily by its neuromodulation and antioxidant effect. PMID- 24346714 TI - [As part of this process, working groups of researchers with expertise on chronic diseases were formed in many Brazilian universities]. PMID- 24346715 TI - [Setting up the longitudinal study for adult health (ELSA-Brasil]. PMID- 24346716 TI - [Participants recruitment in ELSA-Brasil (Brazilian Longitudinal Study for Adult Health)]. AB - OBJECTIVE: To present the recruitment and communication strategies of the ELSA Brasil (Estudo Longitudinal de Saude do Adulto - Brazilian Longitudinal Study for Adult Health). METHODS: The strategies were directed at dissemination, institutionalization and recruitment. The communication actions intended to promote the strengthening of a positive institutional image for the study, knowledge management and an effective dialogue with its target audience. An official website was created in order to communicate with different audiences, to disseminate scientific knowledge, and to contribute to consolidate the image of the study within society. RESULTS: We recruited 16,435 men and women, active employees and retirees of six public institutions of education and research, to constitute the cohort of 15,105 participants. The recruitment goals were fully achieved in the six centers, with a slight predominance of women and of younger adults, and slightly fewer employees with lower level of schooling. CONCLUSIONS: The strategies used were adequate and essential to the successful inclusion and participation of the employees. PMID- 24346717 TI - [Ethical issues in longitudinal studies: the case of ELSA-Brasil]. AB - The debate about ethics in research with human beings has historically emphasized experimental studies because of their greater potential to harm the subjects involved. However, observational studies also include risks and relevant questions to be discussed. This article aims to present and discuss the ethical aspects involved in the implementation of ELSA-Brasil, a longitudinal multicenter study, with public funding, in which the research subjects and investigators are employees of the same institutions. The procedures adopted to meet the ethical requirements and commitments are described, as well as the casuistics that guided the actions according to their guiding principles (beneficence, autonomy and social justice). We present some moral problems that required consideration of risks and benefits at the confluence with the study's objectives, and we conclude with comments on the peculiarities and the potential benefits of a longitudinal study. PMID- 24346713 TI - From FMRP function to potential therapies for fragile X syndrome. AB - Fragile X syndrome (FXS) is caused by mutations in the fragile X mental retardation 1 (FMR1) gene. Most FXS cases occur due to the expansion of the CGG trinucleotide repeats in the 5' un-translated region of FMR1, which leads to hypermethylation and in turn silences the expression of FMRP (fragile X mental retardation protein). Numerous studies have demonstrated that FMRP interacts with both coding and non-coding RNAs and represses protein synthesis at dendritic and synaptic locations. In the absence of FMRP, the basal protein translation is enhanced and not responsive to neuronal stimulation. The altered protein translation may contribute to functional abnormalities in certain aspects of synaptic plasticity and intracellular signaling triggered by Gq-coupled receptors. This review focuses on the current understanding of FMRP function and potential therapeutic strategies that are mainly based on the manipulation of FMRP targets and knowledge gained from FXS pathophysiology. PMID- 24346718 TI - [Questionnaire development in ELSA-Brasil: challenges of a multidimensional instrument]. AB - This article describes the development of the Brazilian Longitudinal Study for Adult Health (ELSA-Brasil) questionnaire. We first address the selection of topics whose contents have to cover the knowledge available on the complex causal network of outcomes and allow comparability with similar studies. Then we deal with the "translation and adaptation of measurement instruments" including neighborhood environment rating scales, depression and anxiety disorder rating scale and a food frequency questionnaire and discuss criteria that guided "theme block sequencing". And finally we focus on the practical importance of "pretesting and pilot studies". The ELSA may provide an original contribution regarding factors that cause or aggravate the outcomes of interest in the Brazilian population, as well as protective factors. PMID- 24346719 TI - [Routines of organization of clinical tests and interviews in the ELSA-Brasil investigation center]. AB - The ELSA-Brasil (Estudo Longitudinal de Saude do Adulto - Brazilian Longitudinal Study for Adult Health) is a prospective cohort study with extensive assessments throughout time. This article describes the routine of clinical tests and interviews performed with participants and the structuring of the Research Center physical space and teams. The ELSA-Brasil assumes that participants will be present at the Research Center to have the tests and interviews performed, according to standard protocols developed by this study. Considering the multiplicity of activities involved, each with specific needs for standardization, several predetermined orders of clinical tests and interviews were created. This ensured a high standard of quality in data collection without harm to participants' comfort. Each participant was previously assigned to a specific sequence of clinical tests and interviews with a predefined arrival time, mean length of stay of five to six hours and departure time. PMID- 24346720 TI - [Publications committee of a multicenter study and computerized support system- publiELSA]. AB - The publications committee of a multicenter study has the aim of organizing the proposals for articles, so as to ensure wide-ranging access to the data, quality and precedence. An online information and management system for study proposals (publiELSA) was developed, composed of three modules: (i) submission and approval of proposals; (ii) follow-up of approved proposals; and (iii) consolidated reports. The first module allows any interested party to search for and become acquainted with articles that have already been published or are in progress and submit new proposals. The approval process and data transfer to the researcher responsible is organized at this stage. In the second module, the aim is to monitor proposals approved until they are finally published. The third module enables searching for and viewing proposals and articles. The system has innovative characteristics, especially with regard to encouraging cooperation between different researchers, through circulation of information on each proposal submitted. In this manner, interaction between different viewpoints and experiences involved in the research is stimulated. PMID- 24346721 TI - [Medical assessments and measurements in ELSA-Brasil]. AB - The article describes assessments and measurements performed in the Brazilian Longitudinal Study for Adult Health (ELSA-Brasil). Some assessments including anthropometric assessment, casual blood pressure measurement, and ankle-brachial index have an established clinical application while others including pulse wave velocity, heart rate variability, and carotid intima-media thickness have no established application and do not have reference values for healthy Brazilian population but may be important predictors of cardiovascular outcomes. Blood pressure measurement following postural change maneuver was included in the ELSA Brasil because it has not been much tested in epidemiological studies. Innovative approaches were developed for assessing the ankle-brachial index using an automatic device instead of the mercury column to measure blood pressure and for assessing the anterior-posterior diameter of the right lobe of the liver by ultrasound for quantitative assessment of nonalcoholic fatty liver disease. All ELSA-Brasil subjects were younger (35 years or more) than those included in other cohorts studying subclinical atherosclerosis. The inclusion of younger individuals and a variety of assessments make the ELSA-Brasil a relevant epidemiology study nationwide and worldwide. PMID- 24346722 TI - [Logistics of collection and transportation of biological samples and the organization of the central laboratory in the ELSA-Brasil]. AB - The ELSA (Estudo Longitudinal de Saude do Adulto - Brazilian Longitudinal Study for Adult Health) is a multicenter cohort study which aims at the identification of risk factors associated with type 2 diabetes and cardiovascular diseases in the Brazilian population. The paper describes the strategies for the collection, processing, transportation, and quality control of blood and urine tests in the ELSA. The study decided to centralize the tests at one single laboratory. The processing of the samples was performed at the local laboratories, reducing the weight of the material to be transported, and diminishing the costs of transportation to the central laboratory at the Universidade de Sao Paulo Hospital. The study included tests for the evaluation of diabetes, insulin resistance, dyslipidemia, electrolyte abnormalities, thyroid hormones, uric acid, hepatic enzyme abnormalities, inflammation, and total blood cell count. In addition, leukocyte DNA, urine, plasma and serum samples were stored. The central laboratory performed approximately 375,000 tests. PMID- 24346723 TI - [Design and implementation of the ELSA-Brasil biobank: a prospective study in a Brazilian population]. AB - The Brazilian Longitudinal Study for Adult Health (ELSA-Brasil) is a multicenter prospective cohort of civil servants designed to assess the determinants of chronic diseases, especially cardiovascular diseases and type 2 diabetes. The present article describes the main design and implementation points of the ELSA Brasil biobank project. Economic, political, logistical and technological aspects of this study are characterized. Additionally, it discusses the final biorepository protocol and the facilities implemented to achieve this objective. The design and implementation process of the ELSA-Brasil biobank took three years to be performed. Both the central and local biobanks were built according to the best biorepository techniques, using different technological solutions for the distinct needs expected in this study. PMID- 24346724 TI - [ELSA-Brasil strategies for outcome identification, investigation and ascertainment]. AB - OBJECTIVE: The article describes the strategies adopted by the Brazilian Longitudinal Study for Adult Health (ELSA-Brasil) for participation and retention of subjects. This is key to ensure internal validity of longitudinal studies, and to identify, investigate, and ascertain outcomes of interest. METHODS: The follow up strategies include annual telephone contacts with new assessments and interviews every three to four years this approach aims to identify transient outcomes (reversible or not), permanent outcomes as well as complications related to the progression of major diseases--cardiovascular diseases and diabetes--to be studied. RESULTS: Telephone interviews are designed to monitor subjects' health status and to identify potential health-related events such as hospital admissions, medical visits or pre-selected medical procedures. Subjects are also encouraged to report to the ELSA-Brasil team any new health-related events. When a potential event is identified, a thorough investigation is carried out to collect relevant information about that event from medical records. All data are blinded and reviewed and analyzed by a medical expert committee. Incident outcome ascertainment follows well-established international criteria to ensure data comparability and avoid misclassification. In addition to these strategies, the occurrence of health-related events is also investigated through linkage of secondary databases, such as national mortality and hospital admission databases. CONCLUSIONS: Accurate identification of outcomes will allow to estimating their incidence in the study cohort and to investigate the effect of the exposures studied in the ELSA-Brasil at baseline and at its subsequent waves. PMID- 24346725 TI - [Challenges to implementation of the ECG reading center in ELSA-Brasil]. AB - Electrocardiography is an established low-cost method of cardiovascular assessment, utilized for decades large epidemiological studies. Nonetheless, its use in large epidemiological studies presents challenges, especially when seeking to develop a reading center. This article describes the process, difficulties and challenges of implementing an electrocardiogram reading center in Brazilian Longitudinal Study for Adult Health (ELSA-Brasil). Among the issues discussed, we have emphasized: the criteria for selection of the electrocardiography machine and the central for storage and management of the machines; the required personnel; the procedures for acquisition and transmission of electrocardiographs to the Reading Center; coding systems, with emphasis on the Minnesota code; ethical and practical issues regarding the delivery of reports to study participants; and aspects related to quality control. PMID- 24346726 TI - [Information management in multicenter studies: the Brazilian longitudinal study for adult health]. AB - Information management in large multicenter studies requires a specialized approach. The Estudo Longitudinal da Saude do Adulto (ELSA-Brasil - Brazilian Longitudinal Study for Adult Health) has created a Datacenter to enter and manage its data system. The aim of this paper is to describe the steps involved, including the information entry, transmission and management methods. A web system was developed in order to allow, in a safe and confidential way, online data entry, checking and editing, as well as the incorporation of data collected on paper. Additionally, a Picture Archiving and Communication System was implemented and customized for echocardiography and retinography. It stores the images received from the Investigation Centers and makes them available at the Reading Centers. Finally, data extraction and cleaning processes were developed to create databases in formats that enable analyses in multiple statistical packages. PMID- 24346727 TI - [Strategies and development of quality assurance and control in the ELSA-Brasil]. AB - The ELSA-Brasil (Estudo Longitudinal de Saude do Adulto - Brazilian Longitudinal Study for Adult Health) is a cohort study composed of 15,105 adults followed up in order to assess the development of chronic diseases, especially diabetes and cardiovascular disease. Its size, multicenter nature and the diversity of measurements required effective and efficient mechanisms of quality assurance and control. The main quality assurance activities (those developed before data collection) were: careful selection of research instruments, centralized training and certification, pretesting and pilot studies, and preparation of operation manuals for the procedures. Quality control activities (developed during data collection and processing) were performed more intensively at the beginning, when routines had not been established yet. The main quality control activities were: periodic observation of technicians, test-retest studies, data monitoring, network of supervisors, and cross visits. Data that estimate the reliability of the obtained information attest that the quality goals have been achieved. PMID- 24346728 TI - [Reproducibility of arterial pressure measured in the ELSA-Brasil with 24-hour pressure monitoring]. AB - OBJECTIVE: To determine the reproducibility of casual arterial pressure measurement and to confirm pressure diagnosis by monitoring of participants in the ELSA-Brasil (Estudo Longitudinal de Saude do Adulto - Brazilian Longitudinal Study for Adult Health). METHODS: Casual blood pressure was measured with an oscilometric device. A sub-sample of participants (N = 255) from Espirito Santo state (Southeastern Brazil) was reevaluated using the same methodology following one to ten weeks and, in addition, underwent arterial blood pressure monitoring. Diagnosis of hypertension used cut off points of 140/90 mmHg for casual pressure and 130/80 mmHg for arterial blood pressure monitoring. White coat hypertension was defined as the presence of hypertension in casual blood pressure and normal arterial blood pressure monitoring, and converse findings characterized masked hypertension. RESULTS: Data are from 230 participants that on the two occasions were free from antihypertensive medication (N1 = 153) or under the same antihypertensive regimen (N2 = 77). Normotension was confirmed by arterial blood pressure monitoring in 120 out of 134 participants of the N1 group. In N2, blood pressure control was confirmed by arterial blood pressure monitoring in 43 of 54 participants with controlled hypertension per casual blood pressure. Overall diagnostic concordance between casual blood pressure and arterial blood pressure monitoring was 78% (kappa = 0.44). In the N1 group, six subjects (4%) presented white coat hypertension, and 23 subjects (25%) presented with masked hypertension. CONCLUSIONS: Diagnostic concordance between casual blood pressure and arterial blood pressure monitoring was moderate. The rigorous standardization of casual blood pressure measurement adopted in the ELSA-Brasil study was able to reduce white coat hypertension. The high frequency of masked hypertension may suggest that pressure values obtained by arterial blood pressure monitoring indicate an elevated degree of stress at work. PMID- 24346729 TI - [Cross-cultural adaptation and reliability of measurements on self-reported neighborhood characteristics in ELSA-Brasil]. AB - OBJECTIVE: To describe the process involved in adapting scales for measuring neighborhood characteristics to Brazilian Portuguese. METHODS: The dimensions addressed were social cohesion, environment suitable for physical activity, availability of healthy foods, safety, perceived violence and victimization. The adaptation process involved assessment of equivalence between the original scales and the Portuguese versions. The test-retest reliability was assessed in a subsample of 261 participants from the Brazilian Longitudinal Study for Adult Health (ELSA-Brasil), who answered the same questionnaire on two different occasions, separated by an interval of 7 to 14 days. RESULTS: The aspects of equivalence assessed were shown to be adequate. The intraclass correlation coefficient ranged from 0.83 (95%CI 0.78;0.87) for Social Cohesion to 0.90 (95%CI 0.87;0.92) for Walking Environment. The scales showed internal consistency (Cronbach's alpha) ranging from 0.60 to 0.84. CONCLUSIONS: The measurements on self-reported neighborhood characteristics had very good reproducibility and good internal consistency (Cronbach's alpha). The results suggest that these scales can be used in studies involving Brazilian populations with characteristics similar to those of ELSA-Brasil. PMID- 24346731 TI - [Experience of importation of equipment for research in the ELSA-Brasil]. AB - OBJECTIVE: Policies that promote research in health were established in the last decade, developing the Brazilian scientific production. This development has not been accompanied by an improvement in the legal-institutional framework, thus hindering the development of research projects, including equipment importation activities. The present study aimed to analyze the equipment importation process for the Brazilian Longitudinal Study for Adult Health (ELSA-Brasil). METHODS: A case study was performed with data collected from internal ELSA-Brasil documents in five Investigation Centers and their respective supporting foundations. The following importation documents were analyzed: pulse wave velocity, bioimaging and retinography. Additionally, non-structured interviews with researchers and key informers were conducted in the foundations. Data were treated and organized into three stages: administrative-operational, exchange rate, and fiscal. Lengths of duration of these stages were calculated comparatively among centers. RESULTS: The need to standardize equipment in a multicenter study required a joint action of implementing institutions and foundations. Of all pieces of equipment analyzed, the first stage was administrative-operational, with a varying duration (minimum of eight, maximum of 101, and mean of 55 days) which was longer when legal opinions were included. The second stage was the exchange rate, which was longer than the former and did not pose any obstacles to the process (minimum of 11, maximum of 381, and mean of 196 days). The third stage was fiscal, which was the longest one (minimum of 43, maximum of 388, and mean of 215.5 days), due to the release of equipment without registration into the country. There were other factors that posed obstacles: inexperience of investigation centers and institutions in networking; inadequacy of the national legislation on scientific research particularities; and the lack of specialized professionals in scientific project management. CONCLUSIONS: The results show the slowness of the equipment importation process in Brazil, especially due to legal, bureaucratic and managerial obstacles. PMID- 24346730 TI - [Social capital in ELSA-Brasil: test-retest reliability of the Resource Generator scale]. AB - OBJECTIVE: To estimate the test-retest reliability of items of the Resource Generator scale for assessing social capital in the Brazilian Longitudinal Study for Adult Health (ELSA-Brasil). METHODS: The social capital was applied in a subsample of 281 participants from six ELSA investigation centers, on two occasions with an interval of seven to 14 days. The instrument consists of 31 items that represent concrete situations to evaluate the access to different types of resources. In addition, it evaluates the strength of ties (family, friends or acquaintances) for the available resources. Statistical analyses were performed through use of the kappa statistic (k) and prevalence-adjusted kappa (ka). RESULTS: A high frequency was found for social resources (above 50%). Regarding the presence or absence of resources, prevalence-adjusted reliability (ka) varied from 0.54 to 0.97. With regard to the source for the resource, the reliability estimates ranged from ka = 0.45 ("someone who has good contacts with the media") to ka = 0.86 ("someone who completed secondary education"). CONCLUSIONS: The scale presented adequate levels of reliability, which varied according to the type of resource. PMID- 24346733 TI - Topological structure dynamics revealing collective evolution in active nematics. AB - Topological defects frequently emerge in active matter like bacterial colonies, cytoskeleton extracts on substrates, self-propelled granular or colloidal layers and so on, but their dynamical properties and the relations to large-scale organization and fluctuations in these active systems are seldom touched. Here we reveal, through a simple model for active nematics using self-driven hard elliptic rods, that the excitation, annihilation and transportation of topological defects differ markedly from those in non-active media. These dynamical processes exhibit strong irreversibility in active nematics in the absence of detailed balance. Moreover, topological defects are the key factors in organizing large-scale dynamic structures and collective flows, resulting in multi-spatial temporal effects. These findings allow us to control the self organization of active matter through topological structures. PMID- 24346734 TI - Soccer injuries and recovery in Dutch male amateur soccer players: results of a prospective cohort study. AB - OBJECTIVE: To describe characteristics of outdoor soccer injury and recovery among Dutch soccer players. DESIGN: Prospective cohort study. SETTING: The 2009 2010 competitive season (33 weeks). PARTICIPANTS: Four hundred fifty-six Dutch male soccer players of 23 amateur teams. MAIN OUTCOME MEASURES: Coaches recorded individual exposure to all soccer activities. Paramedics or sports trainers collected information on the occurrence (e.g., location, type, circumstances) and consequences (eg, absenteeism, medical treatment) of injuries. RESULTS: In total, 424 time-loss injuries were sustained by 60% (n = 274) of the players, with 23% (n = 105) having more than 1 injury. This corresponds to an overall density of 9.6 (8.7-10.5) injuries per 1000 player hours; 3.9 (3.3-4.7) in training sessions and 20.4 (18.1-23.1) in soccer matches. Almost 30% (n = 123) of the injuries lasted for more than 1 month, 14% (n = 58) were reinjuries (causing longer absence than new injuries), and 54% (n = 230) of the injuries were given medical treatment. The most common diagnoses were muscle/tendon (38%) or joint/ligament injuries (23%) of the lower extremities. After regaining the ability to fully take part in soccer training or matches, 27.4% of the players (n = 116) still reported complaints. CONCLUSIONS: Two recommendations based on the above mentioned results are (1) prevention should primarily focus on these most common diagnoses and (2) players resuming soccer activities after an injury should be given special attention to resolve the remaining complaints and to prevent reinjuries. PMID- 24346735 TI - A mandated change in goalie pad width has no effect on ice hockey goaltender hip kinematics. AB - OBJECTIVE: To determine hip kinematics and ground impact forces of the butterfly movement in ice hockey goaltenders for the pre-2005/06 season pads (30.5 cm) versus the current regulation width pads (27.9 cm). DESIGN: Prospective laboratory controlled study. SETTING: Research Institute BioMotion Laboratory. PARTICIPANTS: Ten male ice hockey goaltenders at the Midget AA level or higher. ASSESSMENT OF RISK FACTORS: The participants performed butterfly motions wearing 3 different types of leg pads in a randomized order: own 27.9 cm, standard 27.9 cm, and standard 30.5 cm. In addition, this study investigated hip kinematics and ground impact forces in the pre-2005/06 season pads versus the current regulation width pads. MAIN OUTCOME MEASURES: Kinematics and kinetics were calculated using motion analysis software. RESULTS: The knee ground reaction force upon landing was 1.45 +/- 0.43 times the body weight. Hip internal rotation was reduced when goaltenders wore their own, previously "broken-in," set of pads as compared with the set of standard, new 27.9-cm pads (17.5 +/- 4.8 vs 20.1 +/- 4.8 degrees, respectively; P = 0.032). The recent mandated change in goalie pad from 30.5- to 27.9-cm width had no significant effect on hip kinematics. However, previously worn versus new pads did have an effect on hip kinematics. CONCLUSIONS: The butterfly movement placed ice hockey goaltenders' hips at their passive limits of hip internal rotation and involved knee forces 1.45 times the body weight. The recent mandated change in goalie pad from 30.5- to 27.9-cm width had no significant effect on hip kinematics. However, previously worn versus new pads did have an effect on hip kinematics. PMID- 24346736 TI - Comparison of tibial shaft ski fractures in children and adults. AB - OBJECTIVE: To examine whether child and adult skiers have different risk factors or mechanisms of injury for tibial shaft fractures. DESIGN: Descriptive epidemiological study. SETTING: Prospectively analyzed the epidemiologic factors, injury types, and injury mechanisms at Sumi Memorial Hospital. PATIENTS: This study analyzed information obtained from 276 patients with tibial fractures sustained during skiing between 2004 and 2012. MAIN OUTCOME MEASURES: We focused on 174 ski-related tibial shaft fractures with respect to the following factors: age, gender, laterality of fracture, skill level, mechanism of fracture (fall vs collision), scene of injury (steepness of slope), snow condition, and weather. Fracture pattern was graded according to Arbeitsgemeinschaft fur Osteosynthesefragen (AO) classification and mechanical direction [external (ER) or internal rotation (IR)]. RESULTS: Tibial shaft fractures were the most common in both children (89.3%) and adults (47.4%). There were no significant differences in gender, side of fracture, mechanism of fracture, snow condition, or weather between children and adults. Skill levels were significantly lower in children than in adults (P < 0.0001). Type A fractures were more dominant in children (73 cases, 72.3%) than in adults (39 cases, 53.4%). There was significantly more ER in children than in adults (P < 0.0001). Among children, female patients had significantly more IR than ER; in contrast, among adults, women were injured by ER. CONCLUSIONS: We found significant differences in some of these parameters, suggesting that child and adult skiers have different risk factors or mechanisms of injury for tibial shaft fractures. PMID- 24346737 TI - Early signs of osteoarthritis in professional ballet dancers: a preliminary study. AB - OBJECTIVE: To investigate a cohort of professional ballet dancers for evidence of early signs of osteoarthritis (OA). DESIGN: One radiologist and 1 orthopedic surgeon specialized in musculoskeletal disorders analyzed magnetic resonance imaging scans independently. SETTING: University Teaching Hospital. PARTICIPANTS: Fifteen professional ballet dancers (4 males and 11 females; age range, 19-36 years) experiencing chronic pain in the hip, knee, spine, ankle, or foot joints. MAIN OUTCOME MEASURES: Presence of osteophytes, subchondral sclerosis, joint space narrowing, cysts, and bone marrow changes; the Kellgren and Lawrence scale was used to quantify the knee OA. RESULTS: In the knee, there was thinning and irregularity of the articular cartilage over the medial femoral condyle and bone marrow changes within the lateral femoral condyle. In the hip, there was a loss of joint space and a frayed labrum with deep recess. The first metatarsophalangeal joint showed evidence of osteophytic development. CONCLUSIONS: Early signs of OA, in different joints, were present in a small but highly selected cohort of professional ballet dancers. In future, prospective studies among a number of ballet companies should control for medical and natural history alongside the visual analysis of images and plain radiographs to confirm these preliminary results. PMID- 24346738 TI - Creatine kinase levels during preseason camp in National Collegiate Athletic Association Division I football athletes. AB - OBJECTIVE: To investigate mean creatine kinase (CK) levels in National Collegiate Athletic Association (NCAA) Division I football athletes and the relationship between mean CK levels and demographic variables. DESIGN: Observational cohort. SETTING: NCAA Division I football program. PARTICIPANTS: NCAA Division I football athletes. INTERVENTIONS: Blood and urine samples were obtained from 32 athletes on the first (time 1), third (time 2), and seventh (time 3) days of football camp. MAIN OUTCOME MEASURES: Mean CK levels. The hypotheses were formulated before the data were collected. RESULTS: All urine samples tested negative for blood. Mean CK levels were 284.7 U/L at time 1, 1299.8 U/L at time 2, and 1562.4 U/L at time 3. The increases in means were statistically significant (P < 0.005 for all pairwise comparisons). Most demographic variables were not related to mean CK levels. The number of days in the precamp conditioning program was negatively associated with mean CK levels (P = 0.0284). CONCLUSIONS: Mean CK levels in NCAA Division I football athletes during camp were higher than the serological criteria for rhabdomyolysis commonly used in clinical practice. More data are needed to assess if the number of days of participation in precamp conditioning is related to lower CK levels in NCAA Division I football athletes during camp. PMID- 24346739 TI - Effect of micellar and sol-gel media on the spectral and kinetic properties of tetracycline and its complexes with Mg2+. AB - The spectroscopic and photophysical properties of the broad-spectrum antibiotic tetracycline (TC) and its Mg(2+) complexes were studied in organized media attained by means of three iso-structural quaternary ammonium surfactants able to self-assemble in water at low c.m.c. values, thus giving spherical micelles and sol-gel media upon increasing the concentration. Specific protonated forms of TC and its complexes were introduced in these micro-heterogeneous environments and then investigated through steady-state (both in absorption and emission) and pulsed (up to femtosecond resolution) spectroscopic techniques. Free TC showed minor spectral and kinetic variations while complexes remained unchanged in the presence of spherical micelles, meaning that TC is likely to be placed at the interface between the micelle and the bulk aqueous solution, without altering its bioactivity. Ultrafast transient absorption spectroscopy proved to be a powerful tool to gain deep insight into the distribution of the investigated species between the heterogeneous structure of sol-gel media. In fact, according to the polarity and net charge of free TC and its complexes, these species can be mostly found in the hydrophobic (intertwined worm-like micelles) or in the hydrophilic domains (basically aqueous pools) that the sol-gel is made up of. In the first case, the properties are dramatically altered (highly enhanced fluorescence and lengthened lifetime of the first singlet excited state up to the nanosecond time scale), leading to the improved traceability of the drug. PMID- 24346740 TI - Ischiofemoral impingement of the hip: a novel approach to treatment. AB - Ischiofemoral impingement (IFI) is an uncommon source of hip pain recently described in the non-surgical hip, associated with decreased space between the lesser trochanter and the ischium. There are no reports in the English literature of surgical treatment of this problem. We describe a case of IFI in a 19-year-old female who failed conservative management and underwent endoscopic surgical intervention to increase the space between her ischium and proximal femur. More than 2 years later, the patient is doing very well with an improvement of her iHOT score of 53 points to 85. PMID- 24346741 TI - Arthroscopic treatment of recurrent acetabulum osteoid osteoma. AB - In this case report, arthroscopic treatment of a recurrent osteoid osteoma in the posterior column of the pelvis extending to the acetabular fovea in a young adolescent is being presented. PMID- 24346742 TI - Commentary #1: Adaptive randomization. PMID- 24346744 TI - Prevalence and patterns of antipsychotic use in youth at the time of admission and discharge from an inpatient psychiatric facility. AB - The objective of this study was to examine the prevalence and patterns of antipsychotic use in children and adolescents at the time of admission and discharge from a tertiary care inpatient psychiatric facility. This retrospective analysis included all patients 18 years and younger, who were admitted and discharged from a child and adolescent tertiary care inpatient psychiatric facility between May 1, 2008 and December 31, 2009. Data for medications at admission were obtained using a province-wide network that links all pharmacies in British Columbia, Canada to a central set of data systems, whereas data for medications at discharge were obtained using the Department of Pharmacy's (British Columbia Children's Hospital, Vancouver, British Columbia, Canada) inpatient computer database. Apart from antipsychotics, overall drug use included antidepressants, mood stabilizers, benzodiazepines, anticholinergics, stimulants, and sleep medications. Referral and discharge diagnoses were also examined. During the study period, 335 patients were admitted and discharged from the tertiary care inpatient psychiatric facility. Significantly, more patients were prescribed with an antipsychotic at the time of discharge from hospital compared with that of the time when they were admitted to hospital (51.6% vs 30.7%; P < 0.0001). Antidepressants were most often coprescribed with an antipsychotic at admission and discharge (32.0% vs 42.2%, respectively) followed by attention deficit/hyperactivity disorder medications (22.3% vs 24.9% at admission and discharge, respectively) and anticonvulsants (19.4% vs 19.1% at admission and discharge, respectively). Whether the significant increase in antipsychotic use seen from the time of admission to discharge is solely attributed to clinical worsening or other variables requires further investigation. PMID- 24346745 TI - The effect of naltrexone on sleep parameters in healthy male volunteers. PMID- 24346746 TI - Delirium caused by a drug-drug interaction between bupropion and risperidone. PMID- 24346747 TI - Effects of CYP2C19 genetic polymorphisms on atomoxetine pharmacokinetics. AB - Atomoxetine is a selective norepinephrine reuptake inhibitor indicated for the treatment of attention-deficit/hyperactivity disorder. Atomoxetine metabolism is mediated by CYP2D6 and CYP2C19. This study aimed to investigate the effect of the CYP2C19 genetic polymorphism on the pharmacokinetics of atomoxetine and its metabolites, 4-hydroxyatomoxetine and N-desmethylatomoxetine. A single 40-mg oral dose of atomoxetine was administered to 40 subjects with different CYP2C19 genotypes (all participants carried the CYP2D6*1/*10 genotype). Concentrations of atomoxetine and its metabolites were analyzed using high-performance liquid chromatography with tandem mass spectrometry in plasma samples that were collected up to 24 hours after drug intake. For atomoxetine, the CYP2C19 poor metabolizer (PM) group showed significantly increased maximum plasma concentration and AUC0-infinity (area under the plasma concentration-time curve from 0 to infinity) and decreased apparent oral clearance compared with samples of the CYP2C19 extensive metabolizer (EM) and intermediate metabolizer (IM) groups (P < 0.001 for all). The half-life of atomoxetine in the CYP2C19PM group was also significantly longer than in the other genotype groups (P < 0.01 for CYP2C19EM and P < 0.05 for CYP2C19IM groups). The maximum plasma concentration and AUC 0-infinity of 4-hydroxyatomoxetine were significantly higher in the CYP2C19PM group compared with those in the CYP2C19EM and IM groups (P < 0.001 for CYP2C19EM and P < 0.05 for CYP2C19IM, respectively), whereas the corresponding values for N-desmethylatomoxetine in the CYP2C19PM group were significantly lower than those in the 2 genotype groups (P < 0.001 for both genotype groups). These results suggest that the genetic polymorphisms of CYP2C19 significantly affect the pharmacokinetics of atomoxetine. PMID- 24346748 TI - The genetic association of FTO variants with metabolic traits in patients with schizophrenia may be modified by antipsychotics. PMID- 24346749 TI - Effects of switching to once-daily modified-release methylphenidate from previous treatment with other psychostimulants in children and adolescents with ADHD: an observational study with clinician, parent, and teacher evaluations. PMID- 24346750 TI - Topiramate and compulsive buying disorder. PMID- 24346751 TI - Early improvement in depressive symptoms with desvenlafaxine 50 mg/d as a predictor of treatment success in patients with major depressive disorder. AB - OBJECTIVE: This post hoc analysis assessed the predictive value of improvement in depressive scores at early time points for treatment outcomes at week 8 in patients with major depressive disorder treated with desvenlafaxine 50 mg/d or placebo. METHODS: Pooled data from 6 double-blind, fixed-dose studies in adult patients with major depressive disorder. Patients were randomly assigned to desvenlafaxine or placebo. Primary end point was change in 17-item Hamilton Rating Scale for Depression (HAM-D17) scores from baseline to week 8 (or last observation carried forward). Optimal thresholds of improvement (percent change from baseline HAM-D17) at weeks 2 and 3 for predicting 4 levels of treatment success (>= 45%, >= 50%, and >= 65% decrease from baseline HAM-D17, HAM-D17 <= 7) at week 8 (last observation carried forward) were determined using receiver operating characteristic analysis. Odds ratios of the predictability of improvement thresholds were computed from a logistic regression model adjusting for significant baseline predictors. RESULTS: Desvenlafaxine 50 mg/d (n = 1207) had significantly greater rates of treatment success for each level of treatment success at 8 weeks compared with placebo (n = 1067). Optimal early improvement thresholds for weeks 2 (20%-30%) and 3 (28%-41%) were highly predictive of all 4 levels of treatment success after adjusting for significant baseline predictors (odds ratios, 0.951-0.960; all P < 0.0001). Negative predictive value of early improvement increased, and positive predictive value decreased, for increasingly stringent definitions of treatment success at week 8. CONCLUSIONS: Clinical observations of patients' early response to desvenlafaxine 50 mg/d may have clinical value in predicting treatment success and guiding patient management. PMID- 24346752 TI - Rapid tranquilization of severely agitated patients with schizophrenia spectrum disorders: a naturalistic, rater-blinded, randomized, controlled study with oral haloperidol, risperidone, and olanzapine. AB - INTRODUCTION: Agitation is a major problem in acute schizophrenia. Only a few studies have tested antipsychotic agents in severely agitated patients, mainly because of legal issues. Furthermore, most studies were limited to the first 24 hours. We aimed to investigate the efficacy of oral haloperidol, risperidone, and olanzapine in reducing psychotic agitation in severely agitated patients with schizophrenia or schizophreniform or schizoaffective disorder over 96 hours using a prospective, randomized, rater-blinded, controlled design within a naturalistic treatment regimen. METHODS: In total, 43 severely agitated patients at acute care psychiatric units were enrolled. Participants were randomly assigned to receive either daily haloperidol 15 mg, olanzapine 20 mg, or risperidone 2 to 6 mg over 5 days. Positive and Negative Syndrome Scale psychotic agitation subscale score was the primary outcome variable. A mixed-model analysis was applied. RESULTS: All drugs were effective for rapid tranquilization within 2 hours. Over 5 days, the course differed between agents (P < 0.001), but none was superior. Dropouts occurred only in the risperidone and olanzapine groups. Men responded better to treatment than did women during the initial 2 hours (P = 0.046) as well as over the 5-day course (P < 0.001). No difference between drug groups was observed regarding diazepam or biperiden use. CONCLUSIONS: Oral haloperidol, risperidone, and olanzapine seem to be suitable for treating acute severe psychotic agitation in schizophrenia spectrum disorders. Response to oral antipsychotics demonstrated a gender effect with poorer outcome in women throughout the study. PMID- 24346753 TI - Lack of efficacy of dextromethorphan in managing alcohol withdrawal: a preliminary report of a randomized, double-blind, placebo-controlled trial. AB - Alcohol withdrawal syndrome is associated with increased central N-methyl-D aspartate (NMDA) glutamate transmission. Medications that reduce glutamate release or block NMDA overactivation have shown efficacy for treating alcohol withdrawal syndrome. Dextromethorphan (DXM), a widely used antitussive drug, is a low-affinity, noncompetitive NMDA antagonist with potential neuroprotective properties. This study, using a randomized, double-blind, placebo-controlled study design, examined the benefit of DXM in the management of acute alcohol withdrawal. Alcohol-dependent patients admitted for detoxification treatment and experiencing moderate alcohol withdrawal, as measured by a score greater than 10 on the revised Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar), were randomly assigned to receive either DXM 360 mg/d or an identical placebo for 7 days in a double-blind manner. All subjects received a concurrent dose of lorazepam 2 mg along with the initial administration of DXM or placebo and were given additional lorazepam (1 mg) as a rescue medication according to the symptom triggered detoxification protocol. Outcome measures consisted of the mean total dose of lorazepam received, the sequential scores on the CIWA-Ar, and craving assessed by the Obsessive-Compulsive Drinking Scale. Forty subjects completed the study, 18 in the DXM group and 22 in the placebo group. We found that compared with placebo, DXM use was not associated with lower lorazepam doses to control alcohol withdrawal symptoms. The progression in CIWA-Ar and Obsessive-Compulsive Drinking Scale scores was also comparable between the 2 groups. Our preliminary results do not support the efficacy of high-dose DXM in reducing the need of benzodiazepines to treat withdrawal symptoms in alcohol-dependent patients. PMID- 24346754 TI - Antidepressants and gastrointestinal symptoms in the general Dutch adult population. AB - BACKGROUND: Gastrointestinal symptoms are frequently reported adverse effects of antidepressants, but antidepressants are also a treatment modality in functional gastrointestinal disorders. We aimed to assess the association between antidepressant use and gastrointestinal symptoms in the general adult population. METHODS: We assessed gastrointestinal symptoms, medication use, and comorbidity through structured questionnaires in randomly selected individuals. We compared presence of gastrointestinal symptoms in respondents who reported antidepressant use with those who did not. We used multivariable regression analysis to verify the association between antidepressant use and gastrointestinal symptoms. RESULTS: In total, 16,758 questionnaires were returned and eligible for analysis. Antidepressant use was reported by 701 respondents (4.2%). Gastrointestinal symptoms were more frequently reported by antidepressant users compared with nonusers (40% vs 25%, P < 0.01). This apparent association between antidepressant use and gastrointestinal symptoms did not remain after adjusting for demographic factors, comorbidity, and use of other medications (adjusted odds ratio, 0.94; 95% confidence interval, 0.74-1.18). CONCLUSIONS: In our cross-sectional population-based study, we did not find an association between antidepressant use and gastrointestinal symptoms. PMID- 24346755 TI - Assessing alcohol versus baclofen withdrawal syndrome in patients treated with baclofen for alcohol use disorder. AB - Baclofen is a gamma-aminobutyric acid B (GABA-B) receptor agonist that is approved for spasticity. Recently, the off-label use of baclofen for alcohol use disorder (AUD) has increased. However, baclofen is known to induce a neuroadaptation process, which may be identified by the occurrence of a specific baclofen withdrawal syndrome (BWS), that is, confusion, agitation, seizures, and delirium. The same set of symptoms characterizes alcohol withdrawal syndrome (AWS), which could lead to mistaking BWS for AWS in some situations. We report the cases of 3 patients under a chronic baclofen treatment for AUD. The patients emergently presented with a clinical state of confusion that was initially diagnosed and treated as AWS, with limited effect of benzodiazepines. Retrospectively, using a validated algorithm for assessing drug-induced withdrawal, we determined that all of these clinical cases were consistent with BWS. Both AWS and BWS should be considered in the case of acute confusion or delirium occurring in patients treated with baclofen for AUD. Moreover, further research should investigate to what extent GABA-A and GABA-B induce shared or distinct neuroadaptation processes and withdrawal syndromes. PMID- 24346756 TI - Body mass index, obesity, and psychopathology in patients with schizophrenia. AB - A number of studies have reported that patients with schizophrenia have a higher body mass index (BMI) than the general population. Few Asian studies have examined BMI in patients with schizophrenia. The aims of the current study were to evaluate the distribution of BMI and prevalence of obesity in a large sample of Chinese patients with schizophrenia (n = 973) and to examine the sociodemographic and clinical correlates of overweight (BMI >= 25 kg/m) and obesity (BMI >= 30 kg/m). There was a preponderance of patients who were overweight (58.7%) and obese (73.6%) as compared with control subjects. Regression modeling of clinical and symptom factors in schizophrenia patients revealed that females were almost twice as likely to be obese compared with males and patients with comorbid medical conditions were more likely to be obese compared with those who did not have a comorbid medical condition (odds ratio, 1.6). Those prescribed typical antipsychotic medications were 1.7 times more likely to be obese, whereas individuals prescribed with both typical and atypical antipsychotic medications were 2.2 times more likely to be obese as compared with those prescribed atypical antipsychotics. A significant predictor interaction for obesity was observed between sex and typical antipsychotics, sex and comorbid medical conditions, and years of education and comorbid medical conditions. The higher prevalence of obesity in patients with schizophrenia is a matter of clinical and public health concern; interventions to reduce weight to healthy levels would result in both improved health and quality of life among patients with schizophrenia. PMID- 24346757 TI - Effects of duloxetine on norepinephrine and serotonin transporter activity in healthy subjects. AB - Duloxetine selectively inhibits the serotonin (5-HT) and norepinephrine (NE) transporters (5-HTT and NET, respectively), as demonstrated in vitro and in preclinical studies; however, transporter inhibition has not been fully assessed in vivo at the approved dose of 60 mg/d. Here, the in vivo effects of dosing with duloxetine 60 mg once daily for 11 days in healthy subjects were assessed in 2 studies: (1) centrally (n = 11), by measuring concentrations of 5 hydroxyindoleacetic acid, 3,4-dihydroxyphenylglycol (DHPG), and NE in cerebrospinal fluid, and (2) versus escitalopram 20 mg/d (n = 32) in a 2-period crossover study by assessing the DeltaDHPG/DeltaNE ratio in plasma during orthostatic testing and by pharmacokinetic/pharmacodynamic modeling of reuptake inhibition using subjects' serum in cell lines expressing cloned human 5-HTT or NET. At steady state, duloxetine significantly reduced concentrations of DHPG and 5-hydroxyindoleacetic acid (P < 0.05), but not NE, in cerebrospinal fluid; DHPG was also decreased in plasma and urine. The DeltaDHPG/DeltaNE ratio in plasma decreased significantly more with duloxetine than escitalopram (65% and 21%, respectively; P < 0.0001). Ex vivo reuptake inhibition of 5-HTT was comparable (EC50 = 44.5 nM) for duloxetine and escitalopram, but duloxetine inhibited NET more potently (EC50 = 116 nM and 1044 nM, respectively). Maximal predicted reuptake inhibition for 5-HTT was 84% for duloxetine and 80% for escitalopram, and that for NET was 67% and 14%, respectively. In summary, duloxetine significantly affected 5-HT and NE turnover in the central nervous system and periphery; these effects presumably occurred via inhibition of reuptake by the 5 HTT and NET, as indicated by effects on functional reuptake inhibition ex vivo. PMID- 24346758 TI - Quetiapine and the need for a thorough QT/QTc study. PMID- 24346759 TI - Further orthometalated dinuclear palladium(III) compounds with bridging N,S-donor ligands. AB - New dinuclear palladium(III) compounds of general formula Pd2[(C6H4)PPh2]2[N S]2Cl2, N-S being 2-mercaptopyridinate, 3a; 2-mercapto-6-methylpyridinate, 3b; 2 quinolinethiolate, 3c; 2-mercaptopyrimidinate, 3d; 1-methyl-1H-imidazole-2 thiolate, 3e; 1-methyl-1H-benzimidazole-2-thiolate, 3f; 2 mercaptobenzothiazolate, 3g and 5-mercapto-1-methyltetrazolate, 3h have been obtained by oxidation with PhICl2 of the corresponding palladium(II) counterparts. The stability of the new compounds has been studied by (31)P NMR spectroscopy from 200 to 298 K. Compounds 3f-h were relatively stable until room temperature and they have been synthesized and characterized by (31)P, (1)H and (13)C NMR spectroscopy at 223 K. Compound 3h was also structurally characterized by single X-ray diffraction methods at 150 K showing a Pd-Pd distance of 2.6334(6) A. A topological charge density analysis has also been performed in order to obtain information on the nature of the bonding in these new palladium(II) and (III) compounds. The contribution of the sulphur p orbitals to the HOMO orbitals in the oxidized compounds allows greater stabilization. PMID- 24346761 TI - Public health need versus sales of antibacterial agents active against multidrug resistant bacteria: a historical perspective. PMID- 24346760 TI - Soy isoflavones and cellular mechanics. AB - Soy isoflavones are diphenolic compounds that are frequently used for alternative treatment of ageing symptoms in both genders. They operate at principally two hierarchical levels of functional organization - cellular and molecular, while these 'types' of action appear to have indefinite borders. Soy isoflavone action at the cellular level involves inter alia the effects on cell mechanics. This epigenetic and modular determinant of cell function and fate is defined by: the anchorage to extracellular matrix (ECM) and neighboring cells, cytoskeleton organization, membrane tension and vesicle trafficking. Soy isoflavones have been reported to: (i) generally fashion an inert cell phenotype in some cancers and enhance the cell anchorage in connective tissues, via the effects on ECM proteins, focal adhesion kinases-mediated events and matrix metalloproteinases inhibition; (ii) affect cytoskeleton integrity, the effects being related to Ca(2+) ions fluxes and involving cell retraction or differentiation/proliferation related variations in mechanical status; (iii) increase, remain "silent" or decrease membrane tension/fluidity, which depends on polarity and a number and arrangement of functional groups in applied isoflavone; (iv) provoke inhibitory effects on vesicle trafficking and exo-/endocytosis, which are usually followed by changed cell morphology. Here we present and discuss the abundance of effects arising from cells' "encounter" with soy isoflavones, focusing on different morphofunctional definers of cell mechanics. PMID- 24346763 TI - Selective decontamination of the oropharynx and the digestive tract, and antimicrobial resistance: a 4 year ecological study in 38 intensive care units in the Netherlands--authors' response. PMID- 24346762 TI - Effectiveness of neuraminidase inhibitors in preventing hospitalization during the H1N1 influenza pandemic in British Columbia, Canada. AB - OBJECTIVES: In British Columbia (BC), Canada, neuraminidase inhibitors (NIs) were publicly funded during the 2009 A(H1N1)pdm09 pandemic for treatment of high-risk patients and/or anyone with moderate-to-severe illness. We assessed antiviral effectiveness (AVE) against hospitalization in that context. METHODS: A population-based cohort study was conducted using linked administrative data. The cohort included all individuals living in BC during the study period (1 September to 31 December 2009) with a diagnostic code consistent with influenza or pandemic H1N1. The main study period pertained to the second-wave A(H1N1)pdm09 circulation (1 October to 31 December 2009), with sensitivity analyses around the more specific pandemic peak (18 October to 7 November). Exposure was defined by same day NI prescription. The main outcome was all-cause hospitalization within 14 days of the outpatient influenza diagnosis. Cox proportional hazards models assessed AVE with 1 : 1 propensity-score matching and covariate adjustment. RESULTS: After matching, there were 304/58,061 NI-exposed and 345/58,061 unexposed patients hospitalized during the main study period. The very young [<6 months (35.0; 95% CI 16.7-73.4)], the old [65-79 years (13.7; 95% CI 10.1-18.6)] and the very old [>=80 years (38.7; 95% CI 26.6-56.5)] had the highest hospitalization rate per 1000 patients overall. Fully adjusted AVE against all cause hospitalization during the main study period was 16% (95% CI 2%-28%), similar to the pandemic peak (15%; 95% CI -4%-30%). CONCLUSIONS: The use of NIs was associated with modest protection against hospitalization during the 2009 pandemic, but appeared underutilized in affected age groups with the highest hospitalization risk. PMID- 24346764 TI - Evaluation of power consumption of paddle wheel in an open raceway pond. AB - Open raceway ponds are widely adopted in microalgae cultivation. Paddle wheels consume the most part of power during the process of cultivation in open raceway ponds. The configuration of blades directly determines power consumption for paddle wheels. In this work, power consumption of four blades configurations was determined in a bench-scale open raceway pond of 2.2 m(2). The effect of blades configuration, the influence of filling levels from 5 to 15 cm and influence of rotational speeds from 7 to 15 r min(-1) on shaft power consumption (P(S)), fluid velocity (U(c)) and paddle wheel efficiency (eta) was investigated. Results demonstrated that flat blades were the most efficient configuration. Higher culture depth led to larger U(c), more P(s) and larger eta, especially when blades were not totally immerged in water. Under the same filling level and rotational speed, the value of P(S) decreases in the order: zigzagged, flat, forward-curved and back-curved, respectively. The zigzagged blades led to a larger U(c) at the culture depth of 5 cm, while flat and forward-curved blades drove a larger U(c) when culture depth was higher than 5 cm. The maximum value of eta was 0.50 with flat blades at 11 r min(-1) and 15 cm of culture depth. Empirical correlations of non-dimensional numbers related to operation parameters and blades geometry for four paddle wheel blades were also proposed. PMID- 24346765 TI - Study of chemical pretreatment and enzymatic saccharification for producing fermentable sugars from rice straw. AB - This study evaluated a cost-effective approach for the conversion of rice straw into fermentable sugars. The composition of rice straw pretreated with 1 % sulfuric acid or 1 % sodium hydroxide solution was compared to rice straw with no chemical pretreatment. Enzymatic saccharification experiments on non-pretreated rice straw (NPRS), pretreated rice straw (PRS), and pretreated rice straw with acid hydrolysate (PRSAH) were conducted in a series of batch reactors. The results indicated that pretreating the rice straw with dilute acid and base increased the cellulose content from 38 % to over 50 %. During enzymatic saccharification, straight aliphatic cellulose was hydrolyzed before branched hemicellulose, and glucose was the major hydrolysis product. The glucose yield was 0.52 g glucose/g for NPRS and was comparable to the yields of 0.50 g glucose/g for PRS and 0.58 g glucose/g for PRSAH. The hydrolysis of rice straw to produce glucose can be described by a first-order reaction with a rate constant of 0.0550 d(-1) for NPRS, 0.0653 d(-1) for PRSAH, and 0.0654 d(-1) for PRS. Overall, the production of fermentable sugars from ground rice straw will be more cost effective if the straw is not pretreated with chemicals. PMID- 24346766 TI - Early recurrence after liver resection for colorectal metastases: risk factors, prognosis, and treatment. A LiverMetSurvey-based study of 6,025 patients. AB - PURPOSE: The aims of this study were to assess the risk of early recurrence after liver resection for colorectal metastases (CRLM) and its prognostic value; identify early recurrence predictive factors; clarify the effect of perioperative chemotherapy on its occurrence; and elucidate the best early recurrence management. METHODS: Patients of the LiverMetSurvey registry who underwent complete liver resection (R0/R1) between 1998 and 2009 were reviewed. Early recurrence was defined as any recurrence that occurred within 6 months after resection. RESULTS: A total of 6,025 patients were included; 2,734 (45.4 %) had recurrence, including 639 (10.6 %) early recurrences. Early recurrence was mainly hepatic (59.5 vs. 54.4 % for late recurrences; p = 0.023). Independent risk factors of early recurrence were: T3-4 primary tumor (p = 0.0002); synchronous CRLM (p = 0.0001); >3 CRLM (p < 0.0001); 0-mm margin liver resection (p = 0.003); and associated intraoperative radiofrequency ablation (p = 0.0005). Response to preoperative chemotherapy (complete/partial) and administration of adjuvant chemotherapy reduced early recurrence risk (p = 0.003 and p < 0.0001, respectively). Intraoperative ultrasonography reduced hepatic early recurrence rate (p = 0.025). Early recurrence negatively affected prognosis: 5-year survival 26.9 versus 49.4 % for the late recurrence group (p < 0.0001, median follow-up 34.4 months). Overall, 234 (36.6 %) patients with early recurrence underwent re resection. These patients had survival rates higher than non-re-resected patients (5-year survival 47.2 vs. 8.9 %; p < 0.0001) and similar to re-resected patients for late recurrence (48.7 %). Chemotherapy before early recurrence resection improved later survival (5-year survival 61.5 vs. 43.7 %; p = 0.028). CONCLUSIONS: Early recurrence risk is enhanced for extensive disease after poor preoperative disease control and inadequate surgical treatment, but is reduced after adjuvant chemotherapy. Although early recurrence negatively affects prognosis, re-resection may restore better survival. Chemotherapy before early recurrence resection is advocated. PMID- 24346767 TI - Preoperative fasting: current practice and areas for improvement. AB - Preoperative fasting aims to increase patient safety by reducing the risk of adverse events during general anaesthesia. However, prolonged fasting may be associated with dehydration, hypoglycaemia and electrolyte imbalance as well as patient discomfort. We aimed to examine compliance with the current best practice guidelines in a large surgical unit and to identify areas for improvement. Adult patients undergoing elective and emergency general, orthopaedic, gynaecology and vascular surgery procedures in the Royal Infirmary of Edinburgh were surveyed over a 3-month period commencing November 2011. A standardised questionnaire was used to collect information on the duration of preoperative fasting and the advice administered by medical and nursing staff. 292 patients were included. Median fast from solids was 13.5 h for elective patients (IQR 11.5-16) and 17.38 h for emergency patients (IQR 13.68-28.5 h). Similarly, the median fast from fluids was 9.36 h for elective patients (IQR 5.38-12.75 h) and 12.97 h for emergency patients (IQR 8.5-16.22 h). The instructions that elective patients received contributed to prolonged fasting times. The median fast for elective patients fully compliant with fasting advice would be 10 h for solids (IQR 8.75 12 h) and 6.25 h (IQR 3.83-9.25 h) for clear fluids. Elective patients fasted for longer than recommended confirming that clinical practice is slow to change. The use of universal fasting instructions and patient choice are factors that unnecessarily prolong preoperative fasting, which however appears to be multifactorial. Service improvement by abbreviation of the observed fasting periods will rely on targeted staff education and effective clinical communication by provision of written information for both elective and emergency surgical patients. The routine use of preoperative nutritional supplements may need to be re-examined when further evidence is available. PMID- 24346769 TI - Short-term results of total ankle arthroplasty for end-stage ankle arthritis with severe varus deformity. AB - BACKGROUND: Many authors have reported that an ankle varus deformity more than 10 to 15 degrees may be the cause of failures in total ankle arthroplasty. Our study aim was to analyze short-term outcomes of total ankle arthroplasty with additional procedures accompanied by more than 20 degrees of varus deformity. METHODS: Among the patients who received total ankle arthroplasty for end-stage osteoarthritis between June 2006 and May 2012, 103 cases that were followed for more than 6 months were reviewed. Depending on the degree of varus deformity, 24 cases with more than 20 degrees of coronal deformity were allocated into group A, and 79 cases with less than 20 degrees were allocated into group B. Soft tissue balancing, bony realignment osteotomy, and subtalar arthrodesis were also performed intraoperatively. The American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale, visual analogue scale (VAS) for pain, and ankle range of motion (ROM) were analyzed preoperatively and postoperatively. Subjective satisfaction of the patients (excellent, good, fair, or poor) and complications (major or minor) were identified. RESULTS: The average AOFAS and VAS scores significantly improved in both groups (P < .001), but there was no significant difference between the groups. Patients' subjective satisfaction levels also improved in both groups. CONCLUSION: Short-term follow-up of total ankle arthroplasty, according to the degree of varus deformity, revealed clinically satisfactory progress in both groups without significant differences. There were no significant differences between the 2 groups in postoperative complications and early implant failures. LEVEL OF EVIDENCE: Level III, comparative series. PMID- 24346771 TI - Anticoagulant medication at time of needle biopsy for breast cancer in relation to risk of lymph node metastasis. AB - Anticoagulant treatment might enhance the natural defense against tumor cell dissemination caused by diagnostic needle biopsy by counteracting thrombocyte coating of such cells. To clarify whether women using anticoagulant treatment at the time of biopsy have a lower occurrence of lymph node metastasis, we conducted a nationwide Swedish cohort study of 26,528 female incident breast cancer patients in 2006-2011. Point risk ratio (RR) of risk of lymph node metastasis among users of anticoagulant treatment adjusted for age, T-stage, socioeconomic factors, and concomitant medication was RR = 0.94, (95% CI: 0.87-1.03), and lower in younger women (RR = 0.80, 95% CI 0.50-1.29). Although nonsignificant, these associations may underestimate a true negative association since women using anticoagulant treatment are likely to have more concomitant diseases, lead an unhealthier lifestyle, and have lower participation in mammography screening. These findings provide some support for the hypothesis that anticoagulant medications might counteract breast cancer spread caused by needle biopsy. PMID- 24346768 TI - Identifying potential cancer driver genes by genomic data integration. AB - Cancer is a genomic disease associated with a plethora of gene mutations resulting in a loss of control over vital cellular functions. Among these mutated genes, driver genes are defined as being causally linked to oncogenesis, while passenger genes are thought to be irrelevant for cancer development. With increasing numbers of large-scale genomic datasets available, integrating these genomic data to identify driver genes from aberration regions of cancer genomes becomes an important goal of cancer genome analysis and investigations into mechanisms responsible for cancer development. A computational method, MAXDRIVER, is proposed here to identify potential driver genes on the basis of copy number aberration (CNA) regions of cancer genomes, by integrating publicly available human genomic data. MAXDRIVER employs several optimization strategies to construct a heterogeneous network, by means of combining a fused gene functional similarity network, gene-disease associations and a disease phenotypic similarity network. MAXDRIVER was validated to effectively recall known associations among genes and cancers. Previously identified as well as novel driver genes were detected by scanning CNAs of breast cancer, melanoma and liver carcinoma. Three predicted driver genes (CDKN2A, AKT1, RNF139) were found common in these three cancers by comparative analysis. PMID- 24346774 TI - Patents: unite to conquer. PMID- 24346772 TI - Sialic acid level reflects the disturbances of glycosylation and acute-phase reaction in rheumatic diseases. AB - In the rheumatic diseases, the changes in the carbohydrate part of serum glycoproteins occur and these abnormalities can be monitored by serum level of total and free sialic acid. The aim of this study was to evaluate the total and free sialic acid level as a marker of inflammation activity (TSA) and the changes in glycosylation of blood glycoproteins (FSA) in rheumatoid arthritis (RA), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). Studies were carried out in 50 patients with RA, 24 with SLE and 32 with SSc. TSA concentration was measured with an enzymatic, colorimetric method and FSA with a thiobarbituric method. The serum levels of TSA in RA and SLE patients were significantly increased compared to controls and in RA patients were higher than that in SSc patients. The mean serum level of FSA in RA patients was significantly higher, but in SSc patients significantly lower than that in the controls, and in RA patients was significantly higher than in SLE and in SSc patients. All acute-phase proteins were changed: Positive acute-phase proteins were elevated, and the negative protein was decreased. The positive acute-phase proteins positively correlated with the levels of TSA and FSA in RA and SSc patients. In SLE patients, TSA positively correlated with haptoglobin and alpha1 antitrypsin. In RA patients, there was the positive correlation of TSA and FSA with DAS 28. The changes in the serum levels of TSA and FSA in the course of rheumatic diseases could reflect the abnormalities in glycosylation/sialylation patterns of glycoproteins induced by acute-phase response. PMID- 24346775 TI - Post-transplant anemia and associated risk factors: the impact of steroid-free therapy. AB - CONTEXT AND OBJECTIVE: The prevalence of post-renal transplant anemia (PTA) reported in the literature is variable and several factors contribute towards its pathophysiology. This study aimed to investigate the prevalence of PTA, its associated risk factors and the impact of therapy without steroids. DESIGN AND SETTING: Retrospective cohort study in a renal transplantation unit at a tertiary hospital. METHODS: Anemia was defined as hemoglobin (Hb) < 12 g/dl in female adult recipients and < 13 g/dl in males. Donor and recipient age and gender, type of donor, creatinine, delayed graft function, acute rejection, use of angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) and therapy without steroids were investigated as risk factors for PTA through multivariate logistical regression analysis. RESULTS: Evaluations were performed on 258 recipients (mean age: 38.8 years; 60.5% males; 35.7% did not receive steroids). Anemia was diagnosed in 38% of the patients (at the sixth month, M6), 28% (M12), 32% (M24) and 45% (at last follow up). Donor age > 50 years was associated with greater risks of PTA at M6 (odds ratio (OR) = 4.68) and M24 (OR = 6.57), as well as with therapy without steroids at M6 (OR = 2.96). Delayed graft function was independently associated with PTA at M6 (OR = 3.66) and M12 (OR = 2.85). CONCLUSION: The lowest prevalence of PTA was observed between M9 and M24 after renal transplantation. Delayed graft function, donor age and therapy without steroids were the most important factors associated with PTA. PMID- 24346776 TI - Relationship between blood donors' iron status and their age, body mass index and donation frequency. AB - CONTEXT AND OBJECTIVE: Regular blood donation may decrease body iron storage and lead to anemia. The aim here was to evaluate the iron status of Iranian male blood donors and the impact of age, body mass index (BMI) and donation frequency over one year, on iron status indices. DESIGN AND SETTING: Cross-sectional, descriptive and analytical study at Tehran Blood Transfusion Center, Tehran, Iran. METHODS: Between July and September 2011, 117 male blood donors were selected and divided into four groups according to their frequency of blood donation. Thirty male non-donors were also recruited as controls after adjusting for age, weight, height, smoking habits and monthly income. Iron status indices and some criteria such as general health and dietary measurements were determined among all subjects. RESULTS: The values of the iron-related parameters were significantly lower among donors than among non-donors. Only total iron binding capacity (TIBC) was found to be significantly higher among different donor groups than in the controls. A significant positive correlation was observed between age and serum ferritin (SF) only among the donors who had donated once within the preceding year. The iron status indices did not show any significant relationship with BMI among donors or non-donors. CONCLUSION: A donation frequency of more than twice a year had a significant influence on iron-related parameters. Therefore, without annual measurement of these parameters, further phlebotomies may lead to iron deficiency and donor rejection in the future. PMID- 24346777 TI - Clinical profile, common thrombophilia markers and risk factors in 85 young Indian patients with arterial thrombosis. AB - CONTEXT AND OBJECTIVE: Arterial thrombosis may occur consequent to hereditary thrombophilia and increased lipoprotein(a) [Lp(a)] and fibrinogen. Our aim was to study the prevalence of common thrombophilia markers in 85 consecutive cases of arterial thrombosis. DESIGN AND SETTING: A retrospective study was conducted from 85 consecutive young patients treated as outpatients or admitted due to stroke or myocardial infarction at a tertiary care hospital. METHODS: Eighty-five Indian patients (age < 45 years) presenting ischemic stroke (n = 48) or myocardial infarction (n = 37) and 50 controls were studied for seven thrombophilia markers including antithrombin (AT), factor V, protein C, protein S, activated protein C resistance (APC-R), fibrinogen and Lp(a). Functional assays for protein C, protein S, factor V and APC-R were performed using clotting-based methods. Semi quantitative estimation of fibrinogen was done using Clauss's method and Lp(a) using immunoturbidimetry. Statistical analysis was done using the Epi Info 6 software. RESULTS: Thirty-three samples (38.8%) tested positive for one or more thrombophilia markers. The three commonest abnormalities were elevated Lp(a) (20%), fibrinogen (17.6%) and low APC-R (14.2%). Low levels of protein C, protein S and AT were present in 4.7, 9.4 and 7% of the patients, respectively. Overall, the risk factor profile was: smoking (33%), positive family history (15.3%), hyperlipidemia (7%), hypertension, diabetes mellitus and obesity (2.3% each). CONCLUSIONS: An association was found between low levels of protein C, protein S and AT and arterial thrombosis, but only elevated fibrinogen levels, smoking, positive family history and hyperlipidemia showed statistical significance. PMID- 24346778 TI - Quantitative and qualitative analysis on the legislative production relating to healthcare in passage in the National Congress in the years 2007 and 2008. AB - CONTEXT AND OBJECTIVES: The Federal Constitution of 1988 allowed the National Congress to contribute towards formulation of new public policies. The objective of this study was to analyze the legislative production that dealt with health issues that was in passage in the National Congress between January 2007 and December 2008. DESIGN AND SETTING: Descriptive-exploratory cross-sectional study with quantitative and qualitative approaches, conducted in a federal university. METHODS: The analysis material for the study comprised 144 draft bills that were classified and subsequently randomly evaluated by 155 professionals working within the healthcare system. RESULTS: The analysis showed that the Workers' Party (PT) and Brazilian Democratic Movement Party (PMDB) were the parties that presented the largest proportions of the draft bills (12.5% and 11.1%); 25.4% of the draft bills were presented by congress members with academic qualifications within healthcare and only 1.4% of the draft bills became transformed into legal regulations. In questionnaire responses, 51.5% of the evaluators did not consider the draft bills to be viable, 40.6% did not consider them to be relevant and 52.5% said that if the draft bills were not approved it would not be harmful to Brazilian society. CONCLUSION: In analyzing the data from this study, it was noted that the legislative production relating to healthcare was low and the transformation rate from draft bill to legal regulation was negligible. The results from the evaluation showed that the quality of legislative production was impaired. PMID- 24346779 TI - Profile of patients attended as psychiatric emergencies at a university general hospital. AB - CONTEXT AND OBJECTIVE: The prevalence of psychiatric conditions in clinical settings is high, particularly in emergency services. This is a challenge for healthcare professionals and an essential element in the functioning of the mental health network. The objective here was to describe the sociodemographic and clinical profile and the practices among patients treated psychiatrically in the Emergency Unit. DESIGN AND SETTING: Descriptive and quantitative study, conducted at Hospital das Clinicas (HC), Universidade Estadual de Campinas (Unicamp). METHODS: Sociodemographic data, reasons for attendance, diagnostic hypotheses and practices were analyzed. RESULTS: Psychiatric staff attended 1,835 cases over the study period, corresponding to 1465 patients. The patients were predominantly women (53.7%) and white (79.6%); their mean age was 37 years and 41.3% lived with their parents. The commonest reasons for attendance were depressive symptoms (28.1%), agitation (23.6%) and problems with psychoactive substances (19.5%). The commonest diagnoses were psychoactive substance-related disorders (23%) and depressive disorders (18.5%). 31.6% of the patients were referred to healthcare centers and 29.2% to specialized outpatient clinics, while 8.2% were hospitalized. CONCLUSIONS: This study emphasizes that it is important for professionals working in emergency service to have information about the patients' profile and the main reasons that lead them to seek psychiatric care, and to establish a diagnosis that will allow proper management at the emergency service and case referral. PMID- 24346780 TI - Recurrence of cervical intraepithelial neoplasia in human immunodeficiency virus infected women treated by means of electrosurgical excision of the transformation zone (LLETZ) in Rio de Janeiro, Brazil. AB - CONTEXT AND OBJECTIVE: Human immunodeficiency virus (HIV)-infected women have higher incidence, prevalence, persistence and recurrence of pre-invasive cervical lesions (CIN II or III). The aim here was to investigate the risk of recurrence of CIN II/III among HIV-infected women (HIV+) and uninfected women in a cohort treated by means of large-loop excision of the transformation zone (LLETZ). DESIGN AND SETTING: Cohort study conducted at Instituto Fernandes Figueira/Fundacao Oswaldo Cruz (IFF/Fiocruz). METHODS: 60 HIV+ and 209 HIV negative patients were included in a cohort for follow-up after undergoing LLETZ to treat CIN II/III. A histopathological diagnosis of CIN II/III during the follow-up was taken to constitute recurrence. The following possible confounding variables were assessed: age at treatment and at end of follow-up; histological grade of intraepithelial disease treated; surgical margin involvement; adequacy of colposcopy during the follow-up; CD4+ lymphocyte count; HIV viral load; and type of antiretroviral therapy. RESULTS: Among the 60 HIV+ women, six showed recurrent disease during the follow-up. However, among the 209 HIV-negative women, seven showed a new precursor lesion. The relative risk of disease recurrence in the HIV+ women was 4.21 (95% CI = 1.42 to 12.43). The Kaplan-Meyer curve showed that the risk of recurrence was significantly higher among HIV+ women (log-rank test: P = 0.0111). CONCLUSION: The HIV+ women in our cohort presented a risk of CIN II/III recurrence at least 42% higher than among the HIV negative women. These patients should form part of a rigorous screening and follow-up protocol for identification and appropriate treatment of cervical cancer precursor lesions. PMID- 24346781 TI - Neuraxial anesthesia for orthopedic surgery: systematic review and meta-analysis of randomized clinical trials. AB - CONTEXT AND OBJECTIVE: Taking the outcome of mortality into consideration, there is controversy about the beneficial effects of neuraxial anesthesia for orthopedic surgery. The aim of this study was to compare the effectiveness and safety of neuraxial anesthesia versus general anesthesia for orthopedic surgery. DESIGN AND SETTING: Systematic review at Universidade Federal de Alagoas. METHODS: We searched the Cochrane Central Register of Controlled Trials (Issue 10, 2012), PubMed (1966 to November 2012), Lilacs (1982 to November 2012), SciELO, EMBASE (1974 to November 2012) and reference lists of the studies included. Only randomized controlled trials were included. RESULTS: Out of 5,032 titles and abstracts, 17 studies were included. There were no statistically significant differences in mortality (risk difference, RD: -0.01; 95% confidence interval, CI: -0.04 to 0.01; n = 1903), stroke (RD: 0.02; 95% CI: -0.04 to 0.08; n = 259), myocardial infarction (RD: -0.01; 95% CI: -0.04 to 0.02; n = 291), length of hospitalization (mean difference, -0.05; 95% CI: -0.69 to 0.58; n = 870), postoperative cognitive dysfunction (RD: 0.00; 95% CI: -0.04 to 0.05; n = 479) or pneumonia (odds ratio, 0.61; 95% CI: 0.25 to 1.49; n = 167). CONCLUSION: So far, the evidence available from the studies included is insufficient to prove that neuraxial anesthesia is more effective and safer than general anesthesia for orthopedic surgery. However, this systematic review does not rule out clinically important differences with regard to mortality, stroke, myocardial infarction, length of hospitalization, postoperative cognitive dysfunction or pneumonia. PMID- 24346782 TI - Transcranial direct-current stimulation induced in stroke patients with aphasia: a prospective experimental cohort study. AB - CONTEXT AND OBJECTIVE: Previous animal and human studies have shown that transcranial direct current stimulation can induce significant and lasting neuroplasticity and may improve language recovery in patients with aphasia. The objective of the study was to describe a cohort of patients with aphasia after stroke who were treated with transcranial direct current stimulation. DESIGN AND SETTING: Prospective cohort study developed in a public university hospital. METHODS: Nineteen patients with chronic aphasia received 10 transcranial direct current stimulation sessions lasting 20 minutes each on consecutive days, using a current of 2 mA. The anode was positioned over the supraorbital area and the cathode over the contralateral motor cortex. The following variables were analyzed before and after the 10 neuromodulation sessions: oral language comprehension, copying, dictation, reading, writing, naming and verbal fluency. RESULTS: There were no adverse effects in the study. We found statistically significant differences from before to after stimulation in relation to simple sentence comprehension (P = 0.034), naming (P = 0.041) and verbal fluency for names of animals (P = 0.038). Improved scores for performing these three tasks were seen after stimulation. CONCLUSIONS: We observed that excitability of the primary motor cortex through transcranial direct current stimulation was associated with effects on different aspects of language. This can contribute towards future testing in randomized controlled trials. PMID- 24346783 TI - A rare non-Robertsonian translocation involving chromosomes 15 and 21. AB - CONTEXT: Robertsonian translocations (RT) are among the most common balanced structural rearrangements in humans and comprise complete chromatin fusion of the long arm of two acrocentric chromosomes. Nevertheless, non-Robertsonian translocation involving these chromosomes is a rare event. CASE REPORT: We report a de novo unbalanced translocation involving chromosomes 15 and 21. The newborn was the daughter of a 29-year-old mother and a 42-year-old father. The couple was non-consanguineous. Clinical findings led to the diagnosis of Down syndrome (DS) with severe congenital heart defects (persistent arterial duct, and complete atrioventricular septal defect), as well as low birth length and weight (< 5th and < 10th percentile, respectively, based on specific measurement curves for DS). Conventional cytogenetic analysis revealed the karyotype 46,XX,der(15)(15pter -> 15q26.2::21q11.2 -> 21 qter). The translocation was confirmed by means of fluorescence in situ hybridization. The parents had normal karyotypes. CONCLUSIONS: Differently from RT, in our case a rare event occurred involving the distal segment of 15q and the proximal segment of 21q. Only two reports of this translocation, involving chromosomes 15 and 21 but different breakpoints, have been described so far. The association between 21q duplication and 15q deletion makes it difficult to separate the effect of each chromosome, but might also be responsible for increasing the growth retardation, as detected in our case. Cytogenetic analysis on DS patients is mandatory not only to confirm the diagnosis, but also to assess the risk of recurrence at genetic counseling, as well as to evaluate the contribution of other chromosome aberrations in the final phenotype. PMID- 24346784 TI - Rhabdomyolysis as a manifestation of clomipramine poisoning. AB - CONTEXT: Tricyclic antidepressive agents are widely used in suicide attempts and present a variety of deleterious effects. Rhabdomyolysis is a rare complication of such poisoning. CASE REPORT: A 55-year-old woman ingested 120 pills of 25 mg clomipramine in a suicide attempt two days before admission. After gastric lavage in another emergency department on the day of intake, 80 pills were removed. On admission to our department, she was disoriented, complaining of a dry mouth and tremors at the extremities. An electrocardiogram showed a sinus rhythm with narrow QRS complexes. Laboratory results showed high creatine phosphokinase (CK = 15,094 U/l on admission; normal range = 26 to 140 U/l), hypocalcemia, slightly increased serum transaminases and mild metabolic acidosis. The patient's medical history included depression with previous suicide attempts, obsessive-compulsive disorder, hypothyroidism and osteoporosis. She presented cardiac arrest with pulseless electric activity for seven minutes and afterwards, without sedation, showed continuous side-to-side eye movement. She developed refractory hypotension, with need for vasopressors. Ceftriaxone and clindamycin administration was started because of a hypothesis of bronchoaspiration. The patient remained unresponsive even without sedation, with continuous side-to-side eye movement and a decerebrate posture. She died two months later. Rhabdomyolysis is a very rare complication of poisoning due to tricyclic drugs. It had only previously been described after an overdose of cyclobenzaprine, which has a toxicity profile similar to tricyclic drugs. CONCLUSIONS: Although arrhythmia is the most important complication, rhabdomyolysis should be investigated in cases of clomipramine poisoning. PMID- 24346785 TI - Carotid intima-media thickness is a relatively inexpensive and favorable prognostic marker in patients with spondyloarthritis. PMID- 24346786 TI - Acupuncture for pain in endometriosis. PMID- 24346787 TI - Repetitive transcranial magnetic stimulation for improving function after stroke. PMID- 24346788 TI - Catalysis of glyceraldehyde synthesis by primary or secondary amino acids under prebiotic conditions as a function of pH. AB - The synthesis of an excess of D-glyceraldehyde by coupling glycolaldehyde with formaldehyde under prebiotic conditions is catalyzed by L amino acids having primary amino groups at acidic pH's, but at neutral or higher pH's they preferentially form L-glyceraldehyde. L Amino acids having secondary amino groups, such as proline, have the reverse preferences, affording excess L glyceraldehyde at low pH but excess D-glyceraldehyde at higher pHs. Detailed mechanistic proposals make these preferences understandable. The relevance of these findings to the origin of D sugars on prebiotic Earth is described. PMID- 24346789 TI - Fetal cell microchimerism in the maternal mouse spinal cord. AB - Fetal cell microchimerism refers to the persistence of fetal cells in the maternal tissues following pregnancy. It has been detected in peripheral organs and the brain, but its existence in the spinal cord has not been reported. Our aim was to detect fetal cell microchimerism in the spinal cord of maternal mice. C57BL/6 female mice were crossed with GFP transgenic male mice and sacrificed after their first or third delivery. GFP-positive cells, which were presumably from fetuses whose fathers were GFP transgenic, were detected in the spinal cord by fluorescence microscopy and immunohistochemistry. PCR was also performed to detect GFP DNA, which must come from GFP hemizygous fetuses. We found GFP positive cells and detectable GFP DNA in most of the maternal spinal cords. Twenty percent (1/5) of the mice that were only pregnant once had detectable fetal cells, while 80% (4/5) of those that were pregnant three times had detectable fetal cells. Some fetal cells, which not only emitted green fluorescence but also expressed NeuN, were detected in the spinal cords from maternal mice. These results indicate that fetal cells migrate into the spinal cord of a maternal mouse during and/or after the gestational period, and the fetal cells may differentiate into neurons in the spinal cord. PMID- 24346790 TI - Heavy metals partitioning in the Rodrigo de Freitas lagoon; larvicidal potential of a new essential oil against Aedes aegypti; and the socioeconomic impact of tourism due to wild dolphins provisioning. PMID- 24346792 TI - Evaluation of morpho-anatomical and chemical differences between varieties of the medicinal plant Casearia sylvestris Swartz. AB - Casearia sylvestris Swartz (Salicaceae) has been used in traditional medicine and its leaf extracts have been exhibited important pharmacological activities. The species presents morphological, chemical and genetic variation. Two varieties are considered due external morphological differences: C. sylvestris var. sylvestris and var. lingua. There are difficulties in definition of these varieties. The objective of this work is to evaluate chemical and morpho-anatomical differences between C. sylvestris varieties that can be applied in their distinction for pharmaceutical or botanical purposes. Transverse and paradermic sections of leaves were prepared for morpho-anatomical, histochemical and quantitative microscopy (stomatal and palisade index) analyses. Diterpene profiles of the specimens were obtained by HPLC-DAD and TLC. Morpho-anatomical analyses demonstrated significant differences between the varieties only in paradermic sections: var. sylvestris--polygonal epidermic cell walls and hypostomatic; var. lingua--rounded epidermic cell walls and amphistomatic. No differences were observed for stomatal index; palisade index was found 2.8 for var. lingua and 3.9 for var. sylvestris. Chromatographic analyses confirmed previous results demonstrating that diterpene profile in varieties differs, with predominance of these metabolites in var. sylvestris. In conclusion, this work indicates that chromatographic analysis besides morpho-anatomical analysis can be applied in distinction of C. sylvestris varieties. PMID- 24346793 TI - Environmental pathways and human exposure to manganese in southern Brazil. AB - The study of environmental pathways and human exposure to Manganese (Mn) in Southern Brazil was performed using two steps. The first step consisted of taking water samples from the surface of the Pardinho River. The average results from this technique showed a significant increase of pollutants, including increased levels of Mn, above the environmentally acceptable standard recommended by the Brazilian National Environment Council. Additionally, 64 soil samples were taken from areas with and without agricultural activity. Many results were above the mean crust and did not indicate significant differences of Mn levels between the sampled areas. For the second step, 12 families were selected and assessed for exposure to Mn in a region with high levels of Mn in the soil. Most of the analyzed foods contained amounts of Mn above the reference values, indicating that food can be an important source of exposure. The Mn content from the hair of most subjects studied was also high compared to reference values from non-exposed populations. Although the contamination appeared to come from a natural origin, the results found in the present study showed that the Mn levels present in the Pardinho River Basin are a relevant public health issue. PMID- 24346794 TI - The role of the humic substances in the fractioning of heavy metals in Rodrigo de Freitas lagoon, Rio de Janeiro--Brazil. AB - One of the main results of the processes related to urbanization is the contamination of the adjacent water bodies. Inserted in this context, the Rodrigo de Freitas lagoon is situated in the south zone of the city of Rio de Janeiro. This ecosystem receives several inputs containing all sorts of pollutants, including heavy metals. The present work aimed to study the partitioning of heavy metals in the sediments of Rodrigo de Freitas and the influence of organic matter in this fractionation dynamic. The results of these analyses presented the contents of organic matter as an important metal-capturing agent. Fractionation of organic matter resulted in a predominance of humine. Heavy metal partitioning showed that the metals bound by the water-soluble phase have no significant concentrations. Special features such as, reducing sediment, high levels of organic matter and fine grain size have transformed this ecosystem in an effective deposit of pollutants, where heavy metals are not available in easily reactive fractions. PMID- 24346795 TI - Pollen grain morphology of Fabaceae in the Special Protection Area (SPA) Pau-de Fruta, Diamantina, Minas Gerais, Brazil. AB - The presented paper considered the pollen morphology of thirteen species belonging to seven genera of the Fabaceae family occurring in the Pau-de-Fruta Special Protection Area (SPA), Diamantina, state of Minas Gerais, Brazil. The pollen grains of six species of Chamaecrista [C. cathartica (Mart.) H.S. Irwin & Barneby, C. debilis Vogel, C. flexuosa (L.) Greene, C. hedysaroides (Vogel) H.S. Irwin & Barneby, C. glandulosa (L.) Greene, and C. papillata H.S. Irwin & Barneby] have a similar morphology, characterized by three long colporated apertures with a central constriction. The species share specific morphological features regarding pollen size, endoaperture type (circular, lalongate or lolongate) and SEM ornamentation patterns of the exine (rugulate with perforations or perforate). Andira fraxinifolia Benth., Dalbergia miscolobium Benth, Galactia martii DC, Periandra mediterranea (Vell.) Taub., Senna rugosa (G.Don) H.S. Irwin & Barneby and Zornia diphylla (L.) Pers showed different pollen types in small to large size; oblate spheroidal to prolate form; colpus or colporus apertures; circular, lalongate or lolongate endoapertures and distinctive SEM ornamentation patterns of the exine (perforate, microreticulate, reticulate or rugulate with perforations). Only Stryphnodendron adstringens (Mart.) Coville presents polyads. The pollen morphology variation of these species allowed the Fabaceae family to be characterized as eurypalynous in the SPA Pau-de-Fruta. PMID- 24346796 TI - Polychlorinated biphenyl (PCB) congener concentrations in aquatic birds. Case study: Ilha Grande Bay, Rio de Janeiro, Brazil. AB - Livers from 108 birds found prostrate or dead in Ilha Grande Bay between 2005 and 2010 were analyzed for 16 PCB congeners (IUPAC numbers 8, 18, 28, 31, 52, 77, 101, 118, 126, 128, 138, 149, 153, 169, 170, and 180). The species analyzed were Egretta caerulea (Linnaeus 1758), Nycticorax nycticorax (Linnaeus 1758), Egretta thula (Molina 1782), and Ardea cocoi (Linnaeus 1766). The analysis were performed using Origin software (7.5, 2004) with a significant level of p<0.05. Data were checked for adherence to the standard assumptions of parametric tests using the Kolmogorov-Smirnov test for normality and the Levene's test for homogeneity of variances. This has revealed differences in concentration for some congeners. Results indicate relatively low PCBs contamination in aquatic birds, but it is implied the close relationship of environmental contamination, showing potential power of widespread biological and mutagenic adverse effects in trophic levels, and therefore, signalling risk to human health. PMID- 24346797 TI - Reproductive phenology in a riparian rainforest in the south of Santa Catarina state, Brazil. AB - Phenological studies assist in forest ecosystems comprehension and evaluation of resource availability for wildlife, as well as in improving the understanding of relationships between plants and their pollinators and dispersers. This study aims to describe the reproductive phenophases of riparian plant species and correlate them with climatic variables. The reproductive phenology was analyzed biweekly throughout one year, recording the absence or presence of flowers/fruits. The flowering phenophase occurred throughout the year, with an increase in number of species in blossom in October, November, and December. The flowering peak of the community was observed in November. The fruiting phenophase also occurred throughout the year and showed an increase of species fruiting in June with a slight decrease in August and September. The data obtained in this study, when compared with other studies in different Atlantic Rainforest areas, indicates a seasonal pattern for the flowering phenophase and a variation in fruit availability throughout the year as well as in the fruiting peaks. Therefore, studies that observe flowering and fruiting events in loco are of main importance because they provide information on reproductive seasons of species for use in environmental restoration projects and thus alleviate the situation of degradation of riparian forests. PMID- 24346798 TI - Is the secondary thickening in palms always diffuse? AB - Unlike other arboreal monocotyledons, the secondary growth of palms has for the past 100 years been described as diffuse. Solely cell enlargement and random parenchyma divisions, without the activity of a meristem, characterize such growth. Some previous works of the early 20th century have, however, mentioned the presence of a secondary meristem in the stems of palms, but this information was forgotten since then. Addressing to this question, we analysed palm stems of four species, with the aim to understand the possible presence of such secondary growth. We found that a meristematic band occurs between the cortex and the central cylinder and gives rise to new vascular bundles and parenchyma internally, producing parenchyma and fibres externally. It appears secondarily, i.e., it undergoes meristematic activity in the median and basal stem regions, far away from the apical region. In fact, a meristematic band is present and may be more common than currently believed, but uneasy to detect in certain palms for being restricted to specific regions of their stems. In conclusion, the diffuse secondary thickening is here shown not to be the only mechanism of secondary growth in palms. The presence of a meristem band in the stems of palms merits careful reconsideration. PMID- 24346799 TI - Fermentation characteristics in stirred-tank reactor of exopolysaccharides with hypolipidemic activity produced by Pleurotus geesteranus 5#. AB - In this study, the hypolipidemic effect of exopolysaccharides (EPS) from Pleurotus geesteranus 5# fermenting liquor by the optimal culture conditions in a 5-L stirred-tank reactor was investigated. The hypolipidemic effect of the polysaccharide, investigated in streptozotocin induced diabetic mice, decreased plasma glucose, total cholesterol and triacylglycerol concentrations by 17.1 %, 18.8 % and 12.0 %, respectively. The results of the present investigation strongly demonstrate the potential of this polysaccharide to prevent hyperglycemia in the experimental animals. Under optimal culture conditions, the maximum concentrations of mycelial and EPS were 22.63 g/L after 7 d cultivation and 11.09 g/L after 10 d, respectively. Furthermore, the morphological parameters (i.e. mean diameter, circularity, roughness and compactness) of the pellets and the broth viscosity were characterized. It was proved that compactness of the pellet morphology (R2=0.963, p<0.01) was significantly and positively determined with mycelial biomass. Moreover, mean diameter (R2=93.3, p<0.01) and broth viscosity (R2=0.950, p<0.01) were significantly and positively determined with EPS content. PMID- 24346800 TI - Standardization of a method to study angiogenesis in a mouse model. AB - In the adult organism, angiogenesis is restricted to a few physiological conditions. On the other hand, uncontrolled angiogenesis have often been associated to angiogenesis-dependent pathologies. A variety of animal models have been described to provide more quantitative analysis of in vivo angiogenesis and to characterize pro- and antiangiogenic molecules. However, it is still necessary to establish a quantitative, reproducible and specific method for studies of angiogenesis factors and inhibitors. This work aimed to standardize a method for the study of angiogenesis and to investigate the effects of thalidomide on angiogenesis. Sponges of 0.5 x 0.5 x 0.5 cm were implanted in the back of mice groups, control and experimental (thalidomide 200 mg/K/day by gavage). After seven days, the sponges were removed. The dosage of hemoglobin in sponge and in circulation was performed and the ratio between the values was tested using nonparametric Mann-Whitney test. Results have shown that sponge-induced angiogenesis quantitated by ratio between hemoglobin content in serum and in sponge is a helpful model for in vivo studies on angiogenesis. Moreover, it was observed that sponge-induced angiogenesis can be suppressed by thalidomide, corroborating to the validity of the standardized method. PMID- 24346801 TI - Tau, APP, NCT and BACE1 in lymphocytes through cognitively normal ageing and neuropathology. AB - Although Alzheimer's disease is a brain disorder, a number of peripheral alterations have been found in these patients; however, little is known about how the key genes involved in the pathophysiology express in peripheral cells such as lymphocytes during normal compared to neuropathological ageing. We analysed the expression of tau, of the amyloid precursor protein, of nicastrin and of the beta site APP cleaving enzyme genes by RT-PCR in lymphocytes from a small group of late-onset Alzheimer's disease patients, from aged patients suffering from neuropsychological conditions different from Alzheimer's and from cognitively healthy subjects divided in four groups by age. We also investigated correlations between gene expression and levels of blood pressure, glucose, total cholesterol and triglycerides as risk factors for Alzheimer's. Results show no tau expression in lymphocytes, a lack of detection of nicastrin expression in Alzheimer's patients and correlations between the medical conditions studied and gene expression in lymphocytes. We believe nicastrin gene expression in lymphocytes should be considered of interest for further analyses in a wider population to investigate whether it might represent a potential biomarker to differentiate Alzheimer's from other neuropsychological disorders. PMID- 24346802 TI - Evaluation of Bcl-2, Bcl-x and cleaved caspase-3 in malignant peripheral nerve sheath tumors and neurofibromas. AB - AIMS: To study the expression of Bcl-2, Bcl-x, as well the presence of cleaved caspase-3 in neurofibromas and malignant peripheral nerve sheath tumors. The expression of Bcl-2 and Bcl-x and the presence of cleaved caspase 3 were compared to clinicopathological features of malignant peripheral nerve sheath tumors and their impact on survival rates were also investigated. MATERIALS AND METHODS: The evaluation of Bcl-2, Bcl-x and cleaved caspase-3 was performed by immunohistochemistry using tissue microarrays in 28 malignant peripheral nerve sheath tumors and 38 neurofibromas. Immunoquantification was performed by computerized digital image analysis. CONCLUSIONS: Apoptosis is altered in neurofibromas and mainly in malignant peripheral nerve sheath tumors. High levels of cleaved caspase-3 are more common in tumors with more aggressive histological features and it is associated with lower disease free survival of patients with malignant peripheral nerve sheath tumors. PMID- 24346803 TI - Perception of local inhabitants regarding the socioeconomic impact of tourism focused on provisioning wild dolphins in Novo Airao, Central Amazon, Brazil. AB - Botos (Inia geoffrensis) are currently provisioned for use in tourist attractions in five sites in the Brazilian Amazon. Despite the known negative effects associated with human-wild dolphin interactions, this activity has been regulated and licensed in the Anavilhanas National Park in Novo Airao, Amazonas State, Brazil. We present an updated evaluation of the perception of the local community concerning the possible socioeconomic impacts of this tourism in Novo Airao. In April 2011, 45 interviews were conducted with inhabitants. A small segment of Novo Airao perceives currently itself as being economically dependent on the botos feeding tourism. Despite that, the economic benefits of this controversial activity apparently are not shared among most inhabitants, and botos feeding tourism is perceived as generating diverse negative effects. We conclude that if the activity was banned or modified into a less impacting tourist activity, this action would probably not majorly affect the lives of the general population. PMID- 24346805 TI - Emerging role of human basophil biology in health and disease. AB - Basophils have emerged in recent years as a small but potent subpopulation of leukocytes capable of bridging innate and adaptive immunity. They can be activated through IgE-dependent and IgE-independent mechanisms to release preformed mediators and to produce Th2 cytokines. In addition to their role in protective immunity to helminths, basophils are major participants in allergic reactions as diverse as anaphylaxis and immediate hypersensitivity reactions, late-phase hypersensitivity reactions, and delayed hypersensitivity reactions. Additionally, basophils have been implicated in the pathophysiology of autoimmune diseases such as lupus nephritis and rheumatoid arthritis, and the modulation of immune responses to bacterial infections, as well as being a feature of myelogenous leukemias. Distinct signals for activation, degranulation, transendothelial migration, and immune regulation are being defined, and demonstrate the important role of basophils in promoting a Th2 microenvironment. These mechanistic insights are driving innovative approaches for diagnostic testing and therapeutic targeting of basophils. PMID- 24346806 TI - An outcome evaluation of a New Zealand farm safety intervention: a historical cohort study. AB - BACKGROUND: There is limited evidence that farm safety-related interventions based solely on an educational element have an effect on injury rates. Our aim was to evaluate a New Zealand national educational program, FarmSafeTM Awareness, for its effect on injury rates. METHODS: We used a before-after design followed by a historical cohort study of sheep, beef, and dairy farmers/workers. The outcomes were work-related injuries, identified from workers compensation data. Cox regressions were used to compare intervention with matched control group rates. RESULTS: FarmSafeTM Awareness was associated with significantly higher rates of work-related injury, than matched controls. CONCLUSIONS: It is difficult to see how FarmSafeTM Awareness could be causing an increased rate of work related injury. We detected no reporting bias, and selection bias is likely to act in the opposite direction to the observed results. We conclude that there is no evidence that FarmSafeTM Awareness prevents farm injury. PMID- 24346807 TI - The PI3K/Akt and MAPK-ERK1/2 pathways are altered in STZ induced diabetic rat placentas. AB - Diabetic pregnancy is associated with complications such as early and late embryonic death, fetal growth disorders, placental abnormalities, and embryonal placental metabolic disorders. Excessive apoptosis and/or changes of proliferation mechanisms are seen as a major event in the pathogenesis of diabetes-induced embryonic death, placental weight and structural anomalies. Akt and ERK1/2 proteins are important for placental and fetal development associated with cellular proliferation and differentiation mechanisms. The mechanism underlying the placental growth regulatory effects of hyperglycemia have not been elucidated. Moreover, it is still not determined how Akt and ERK1/2 proteins related proliferation and apoptosis mechanisms are influenced by Streptozotocin (STZ) induced diabetic rat placental development. The aim of this study was to investigate the expression levels and spatio-temporal immunolocalizations of Akt, p-Akt, ERK1/2 and p-ERK1/2 proteins in normal and STZ-treated diabetic rat placental development. In order to compose the diabetic group, pregnant females were injected with a single dose of 40 mg/kg STZ intraperitonally seven days before their sacrifice at 12th, 14th, 16th, 18th and 20th day of their gestation. We found that maternal diabetic environment led to a decrease in ERK1/2 and Akt phosphorylation during rat placental development. It could be said that MAPK ERK1/2 and PI3K/Akt cell signaling pathways are affected from hyperglycemic conditions in rat placentas. In conclusion, hyperglycemia-induced placental and embryonal developmental abnormalities could be associated with reduction of Akt and ERK1/2 phosphorylation. PMID- 24346808 TI - Evaluation of the effects of anti-motion sickness drugs on subjective sleepiness and cognitive performance of healthy males. AB - This study aimed to investigate the clinical and cognitive side effects of baclofen (10 mg), meclizine (25 mg), dimenhydrinate (40 mg) plus cinnarizine (25 mg) and promethazine (25 mg) plus d-amphetamine (10 mg). The study had a double blind, placebo controlled, repeated measures design and was conducted on healthy male volunteers. The psychomotor vigilance test, the Sternberg working memory task, the implicit memory test and the automated Operation Span (Ospan) task were performed. The Stanford, the Karolinska and the Epworth Sleepiness scale determined the degree of sleepiness. The Profile of Mood States (POMS) evaluated mood states and adverse effects were reported on a 22-item questionnaire. Letter recalls and time for solving mathematical problems, recorded during the Ospan task, were impaired by baclofen and dimenhydrinate-cinnarizine respectively, suggesting an influence of these drugs on the working memory. Significant side effects for baclofen were: sleepiness, tiredness, blurred vision, concentration problems and dizziness whereas for dimenhydrinate-cinnarizine only sleepiness and blurred vision were reported. Meclizine decreased the accuracy on the Sternberg working memory task and thus seemed to affect short-term memory. A reported side effect was increased sleepiness. Promethazine plus d-amphetamine did not affect any of the tested cognitive functions. However, many side effects such as sleepiness, dry mouth, dizziness, vertigo, confusion, insomnia and tremors were reported. The results show that meclizine and dimenhydrinate combined with cinnarizine were the two drugs with the most acceptable combination of side effects. PMID- 24346809 TI - The impact of modern treatment principles may have eliminated lithium-induced renal failure. AB - We have previously shown that lithium can cause end-stage renal disease (ESRD): however, this serious side-effect of lithium in prophylactic treatment of mood disorders may reflect the treatment regime of the 1960s and 1970s. Today's modern treatment routines, intended to reduce or eliminate lithium-induced ESRD (Li ESRD), were introduced in Sweden in the early 1980s. The aim of the present study was to test the hypothesis that these routines have eliminated the risk of Li ESRD. We used the Swedish Renal Registry to identify patients on renal replacement therapy (RRT), treated with dialysis or renal transplantation, with suspected Li-ESRD in two regions of Sweden with altogether about three million inhabitants. We reviewed their medical records to verify the exposure to lithium treatment, the diagnosis of Li-ESRD and the date of starting the lithium treatment. We found 32 RRT patients in whom lithium treatment was the sole or main contributing cause of ESRD. The starting year of their lithium treatment was between 1965-1980 in all patients. No patient started lithium treatment later than 1980. Modern lithium treatment may have eliminated the risk of Li-ESRD. Our findings support the continued use of lithium as a safe drug for the long-term treatment of mood disorders. PMID- 24346810 TI - Endothelial nitric oxide synthetase genetic variants, metabolic syndrome and endothelial function in schizophrenia. AB - OBJECTIVE: The increasing rates of metabolic syndrome and cardiovascular disease in schizophrenia led to investigation into their causes, including atypical antipsychotics and pharmacogenetic variants. This study focused on the peripheral vasculature as a cardiovascular phenotype and the influence of atypical antipsychotics, the aberrant metabolism of nitric oxide caused by endothelial nitric oxide synthetase (eNOS) genetic variants and metabolic syndrome in a cross sectional sample of schizophrenia subjects. METHODS: Associations between eNOS genetic variants and endothelial function was assessed in a cohort of schizophrenia patients taking antipsychotic drugs, whom were undergoing a clinical assessment for endothelial function via the method of peripheral artery tonometry (RH-PAT), as well as metabolic syndrome criteria screening. Analyses were conducted on the entire cohort, then again after stratifying by metabolic syndrome, to investigate the effect of the eNOS variants and metabolic syndrome on endothelial functionality. RESULTS: We included 203 subjects with a mean age of 46 years. The cohort was 36% female, 36% had metabolic syndrome and 85% were currently using atypical antipsychotics. We found associations between the eNOS T 786C and worse endothelial functioning (lower RH-PAT values) only in schizophrenia patients without metabolic syndrome. CONCLUSIONS: Our results suggested that when schizophrenia patients progress to meet metabolic syndrome criteria, the genetic protection of the eNOS T-786C variant on endothelial function is no longer seen: Other factors of this pro-inflammatory state may be overriding this effect. The results of this study need replication and the factors driving endothelial dysfunction in patients with metabolic syndrome warrant further investigation. PMID- 24346811 TI - Changes in plasma concentrations of risperidone and 9-hydroxyrisperidone and the associated clinical effects during the switch from oral risperidone to extended release paliperidone tablets in patients with schizophrenia. AB - This study aimed to investigate changes in plasma concentrations of risperidone and 9-hydroxy-risperidone (9-OHR) and the associated clinical effects when switching from oral risperidone to extended-release (ER) paliperidone in patients with schizophrenia. This study included 25 patients with schizophrenia. Following a one-week screening period with a stable dose of risperidone, a six-week open label switch study from risperidone to extended-release paliperidone (paliperidone ER) was conducted. Efficacy and safety assessments were performed on Day 1 and at Weeks 1, 2, 4, and 6. Plasma levels of the active fractions of oral risperidone and paliperidone ER were measured on Day 1 and at Week 1, respectively. Plasma levels of the active moiety (risperidone plus 9-OHR) while taking risperidone (mean dose: 4.0 mg) were significantly higher than plasma levels of 9-OHR while taking 6 mg of paliperidone ER. For 12 subjects taking only 3 mg of risperidone, plasma concentrations of the active moiety of risperidone were also significantly higher than those of 9-OHR while taking 6 mg of paliperidone ER. The amount of reduction in plasma levels was correlated with a temporal deterioration of clinical symptoms. These findings suggest that for patients with schizophrenia taking 3 mg or more of risperidone, an initial switching dose of 6 mg of paliperidone ER may be relatively low in terms of subsequent plasma concentrations and the associated clinical response. PMID- 24346812 TI - Ureterovaginal fistula: a case series. AB - INTRODUCTION AND HYPOTHESIS: We describe the presentation, diagnosis, and management of ureterovaginal fistula over a 7-year period at a tertiary care center. METHODS: A retrospective review of ureterovaginal fistula cases between 2003 and 2011 was performed. Demographic information, antecedent event, symptoms, diagnostic modalities, and management strategies were reviewed. RESULTS: Nineteen ureterovaginal fistulas were identified during the 7-year study period. One fistula followed a repeat cesarean section and 18 fistulas followed a hysterectomy (9 total abdominal, 6 total laparoscopic, 3 vaginal hysterectomies). Ureteral injuries were not recognized in any of the patients at the time of index surgery. Computed tomography (CT) urography was the most commonly utilized diagnostic modality (58%). Primary non-surgical management with ureteral stents was attempted and successful in 5 out of 7 cases (71%). There were 14 total surgical repairs, including 2 cases in which stents were successfully placed, but the fistula persisted, and 6 additional cases where attempted stent placement failed. Surgical repair consisted of 10 ureteroneocystostomies performed via laparotomy and 4 performed laparoscopically, 3 of which were robotically assisted. CONCLUSIONS: Despite being uncommon, ureterovaginal fistula should remain in the differential diagnosis of new post-operative urinary incontinence after gynecological surgery. Conservative management with ureteral stent appears to be the best initial approach in selected patients, with a success rate of 71%. Minimally invasive approaches to performing ureteroneocystostomy have high success rates, comparable to those of open surgical repair. PMID- 24346813 TI - Posture and micturition: does it really matter how a woman sits on the toilet? AB - The position that we adopt to evacuate "waste matters" may potentially have an impact on the efficiency with which these are expelled. Proponents of squatting have eloquently described associated "health benefits" and have hinted that nonsquatters may be prone to urological, gynecological, and colorectal disorders. In this original piece of research, the effects of posture on micturition have been studied in various positions with interesting results. PMID- 24346814 TI - Effect of estrogen and ovariectomy on response of the female rabbit urinary bladder to two forms of in vitro oxidative stress. AB - INTRODUCTION AND HYPOTHESIS: There are several lower urinary tract dysfunctions (LUTD) that are more common in women than in men including incontinence, interstitial cystitis, and recurrent urinary tract infection. There is increasing evidence that these dysfunctions are associated with reduced blood flow, ischemia, hypoxia, and reperfusion resulting in free radical generation and oxidative damage. The goal of the current study was to determine if the level of circulating estrogen affects the response of the bladder muscle and mucosa to two in vitro models of oxidative stress: Incubation in the presence of hydrogen peroxide (H(2)O(2)) is the first model; the second is ischemia followed by reperfusion which results in the direct production of damaging free radicals. The motivation for this study is the current literature linking female-related LUTD with oxidative stress. METHODS: Eighteen female New Zealand white rabbits were divided into three groups: control, ovariectomized, and ovariectomized receiving continuous estrogen. Eight bladder strips from each of three rabbits per group were taken for in vitro ischemia/reperfusion (I/R) physiological experiments, while eight strips from the three remaining rabbit bladders per group were taken for in vitro H(2)O(2) experiments. All tissue was analyzed for total antioxidant activity (AA) and malondialdehyde (MDA) levels. In addition, the organ bath buffer was also analyzed for AA. RESULTS: In vitro H(2)O(2) was found to target the nerve, muscarinic receptor, and membrane equally causing more damage to bladder tissue than in vitro I/R. Ovariectomy resulted in lower contractility and higher lipid peroxidation. However, estrogen supplementation following ovariectomy protected the bladder against both models of oxidative stress by maintaining contractile responses to stimulation and decreasing lipid peroxidation. CONCLUSIONS: The primary conclusion from this study is high estrogen protects the bladder from oxidative stress, whereas low estrogen makes the bladder more susceptible. PMID- 24346815 TI - Enhancement of Achilles tendon repair mediated by matrix metalloproteinase inhibition via systemic administration of doxycycline. AB - Collagenases or matrix metalloproteinases (MMPs) have been shown to play an important role in the matrix degradation cascade associated with Achilles tendon rupture and disease. The goal of this study was to examine the effects of daily administration of doxycycline (Doxy) through oral gavage on MMP activity and on the repair quality of Achilles tendons in vivo. Our findings indicate that Achilles tendon transection resulted in increasing MMP-8 activity from 2 to 6 weeks post-injury, with peak increases in activity occurring at 4 weeks post injury. Doxy adiministration at clinically relevant serum concentrations was found to significantly inhibit MMP activity after continuous treatment for 4 weeks, but not for continuous administration for shorter durations (96 h or 2 weeks). Extended doxy administration was also associated with improved collagen fibril organization, and enhanced biomechanical properties (stiffness, ultimate tensile strength, maximum load to failure, and elastic toughness). Our findings indicate that a temporal delay exists between Achilles tendon transection and associated increases in MMP-8 activity in situ. Our findings suggest that inhibition of MMP-8 at its peak activity levels ameliorates fibrosis development and improves biomechanical properties of the Achilles tendon. PMID- 24346816 TI - Comparison of different material models to simulate 3-d breast deformations using finite element analysis. AB - Biomechanical breast modeling using finite element (FE) analysis to predict 3-D breast deformations is of interest for various biomedical applications. Currently no consensus of reliable magnitudes of mechanical breast tissue properties exists. We therefore applied 12 material properties proposed in the literature to FE simulation models derived from prone MRI breast datasets of 18 female volunteers. A gravity free starting position is computed with an iterative FE algorithm followed by the calculation of the upright position of the breast and then compared to the real breast geometry in standing position using corresponding 3-D surface scans to determine the accuracy of the simulation. Hyper-elastic constitutive models showed superior performance than linear elastic models which cannot exceed the linear Hookean domain. Within the group of applied hyper-elastic material models those proposed by Tanner et al. (Med Phys 33:1758 1769, 2006) and Rajagopal et al. (Acad Radiol 15:1425-1436, 2008) performed significantly (p < 0.01) better than other material models. The advantage of the method presented is its non-invasive character by combining 3-D volume and surface imaging with automated FE analysis. Thus, reliable biomechanical breast models based on the presented methods can be applied in future to derive patient specific material parameter sets to improve a wide range of healthcare applications. PMID- 24346817 TI - Unexplained chronic leukopenia treated with oral iron supplements. AB - CASE: A 67-year-old woman known to have iron deficiency anemia and persistent unexplained chronic leukopenia was cared for by our medical center for about 16 years. During this period she was examined thoroughly and diagnosed to have chronic idiopathic neutropenia (also known as chronic benign neutropenia). Her iron deficiency was attributed to nutritional factors and she was non-compliant with her oral iron supplements. The patient fully received her iron supplement medication by nursing staff for two and a half months during an unexpected prolonged hospital stay after her suffering an acute ischemic cerebrovascular accident. An astonishing outcome was that in addition to having her iron deficiency anemia treated, her long-term unexplained neutropenia was also corrected. CONCLUSION: Some patients diagnosed with chronic idiopathic neutropenia and clinically present as having unexplained chronic neutropenia might actually be suffering from a form of not yet described iron deficiency induced neutropenia. PMID- 24346818 TI - Evaluation of a controlled, national collaboration study on a clinical pharmacy service of screening for risk medications. AB - BACKGROUND: Risk medications are frequently associated with adverse events and hospitalisations. OBJECTIVE: To evaluate a risk medication screening service for in-patients at Danish hospitals. SETTING: Danish hospitals. METHODS: The study was designed as a controlled, prospective intervention study. Inpatients were screened for the use of five risk medications; anticoagulants, digoxin, methotrexate, NSAIDs and opioids, and during the intervention period recommendations were made by clinical pharmacists according to a standardized intervention scheme. The recommendations were discussed with the physician face to-face. MAIN OUTCOME MEASURE: Readmissions within 6 months after discharge. RESULTS: In total, 1,007 control and 775 intervention patients were included in the study. The study found that half of the patients (50 % during the control and 48 % during the intervention period) admitted to Danish hospitals were treated with at least one of the five selected risk medications, significantly more drug related problems (DRPs) were identified during the control period (1.7/patient during the control and 1.4/patient during the intervention period (p < 0.001)), and the acceptance rate of recommendations (62 %) was similar to medication management service studies in the literature (39-100 %). However, no impact on outcome measures was found. The majority (69 %) of the clinical pharmacists reported that they had increased their professional competences by participating in the study, and that a national clinical pharmacy study may be used in promoting and implementing a unique clinical pharmacy service throughout the country (67 %). CONCLUSION: The study showed that a national screening service for risk medications could help identify and address DRPs. Despite no impact on the selected outcome measures, it is likely that the screening service could be included in a medication management review with further focus on the individual patient to ensure positive outcomes, or that the screening service should be delivered to selected patients groups, who might have maximum benefit of the service. PMID- 24346819 TI - Non-small cell lung cancer treatment receipt and survival among African-Americans and whites in a rural area. AB - Data on racial disparities among lung cancer patients in rural areas are scarce. We examined differences in treatment receipt and survival among African-American (AA) and Non-Hispanic White (NHW) non-small cell lung cancer (NSCLC) patients residing in Southwest Georgia (SWGA)-a primarily rural 33-county area; population 700,000. Medical records for 934 SWGA NSCLC patients diagnosed in 2001-2003 were used to extract information on age, race, marital status, insurance coverage, comorbidities, and treatment. Information pertaining to socioeconomic status, urban/rural residence, and survival was obtained from the cancer registry. Multivariable logistic regression analyses examined the relation of various patient and disease characteristics to receipt of tumor-directed therapy. Cox regression models were used to assess determinants of survival. Treatment receipt was associated with age, marital status, comorbidities, and disease stage in most analyses. No associations were observed between race and either surgery [odds ratio (OR) 0.83, 95% confidence interval (CI) 0.49-1.39] or radiation (OR 0.72; 95% CI 0.52-1.00). NHW patients were more likely to receive no treatment at all (OR 1.50, 95% CI 1.01-2.23). There was no racial difference in survival (hazard ratio = 1.07, 95% CI 0.90-1.26). Effects of insurance and treatment on survival were most pronounced within 6 months post-diagnosis, but were attenuated over time. We found no evidence of racial disparities in survival and, in some analyses, a decreased likelihood of treatment receipt among NHW NSCLC patients compared to AA. The results from SWGA stand in contrast to studies that applied different methodologies and were conducted elsewhere. PMID- 24346821 TI - Effects of marketed antiepileptic drugs and placebo in the human photosensitivity screening protocol. AB - A study of epilepsy patients with a reproducible range of photoparoxysmal responses (PPR) (epileptiform discharges evoked by flashing lights) has been used as a "proof-of-concept" trial to determine if novel potential antiepileptic drugs (AEDs) should proceed in development. The standard design for this trial requires a 3-day inpatient stay and is single-blind. We evaluated two marketed and effective AEDs-one narrow-spectrum [carbamazepine (CBZ)], and one broad-spectrum [levetiracetam (LEV)]-using a novel double-blinded, cross-over outpatient version of the trial to detect acute drug effects of the two marketed AEDs on photosensitivity. We tested 6 patients with a known stable photosensitivity response, using single oral doses of CBZ 400 mg and LEV 1000 mg, compared to 2 test days with single placebo doses. Patients who received LEV had the lowest mean PPR (compared with placebo and CBZ). The mixed effect model showed a significant effect of LEV in all eye closure conditions (p < 0.001). There was no evidence of a significant change in PPR after CBZ or placebo treatment. In conclusion, LEV 1000 mg, but not CBZ 400 mg, was effective in suppressing photosensitivity within a 6-h period compared with placebo showing the ability of our novel photosensitivity trial design to demonstrate effects of broad-spectrum AEDs. We cannot confirm the ability of the photosensitivity trial to detect the narrow-spectrum AED CBZ in our design. The novel outpatient study design is feasible and is expected to reduce costs compared with previous methodology. PMID- 24346820 TI - Identification of streptococcal m-protein cardiopathogenic epitopes in experimental autoimmune valvulitis. AB - The M protein of rheumatogenic group A streptococci induces carditis and valvulitis in Lewis rats and may play a role in pathogenesis of rheumatic heart disease. To identify the epitopes of M5 protein that produce valvulitis, synthetic peptides spanning A, B, and C repeat regions contained within the extracellular domain of the streptococcal M5 protein were investigated. A repeat region peptides NT4, NT5/6, and NT7 induced valvulitis similar to the intact pepsin fragment of M5 protein. T cell lines from rats with valvulitis recognized M5 peptides NT5/6 and NT6. Passive transfer of an NT5/6-specific T cell line into naive rats produced valvulitis characterized by infiltration of CD4+ cells and upregulation of VCAM-1, while an NT6-specific T cell line did not target the valve. Our new data suggests that M protein-specific T cells may be important mediators of valvulitis in the Lewis rat model of rheumatic carditis. PMID- 24346822 TI - Expression of drebrin, an actin binding protein, in basal cell carcinoma, trichoblastoma and trichoepithelioma. AB - Drebrin, an F-actin binding protein, is known to play important roles in cell migration, synaptogenesis and neural plasticity. Although drebrin was long thought to be specific for neuronal cells, its expression has recently been reported in non-neuronal cells. As for skin-derived cells, drebrin was shown to be enriched at adhering junctions (AJs) in cultured primary keratinocytes and also be highly expressed in basal cell carcinoma (BCC) cells. Since BCC and two types of benign neoplasm, trichoblastoma and trichoepithelioma, are considered to derive from the same origin, follicular germinative cells, it is sometimes difficult to morphologically distinguish BCC from trichoblastoma and trichoepithelioma. In this study, we performed immunohistochemical staining of drebrin in BCC, trichoblastoma and trichoepithelioma, to examine whether drebrin could serve as a biomarker for BCC diagnosis. In western blotting, drebrin was detected highly and moderately in the lysates from a squamous cell carcinoma cell line, DJM-1, and normal human epidermis, respectively. In immunofluorescence analyses, drebrin was colocalized with markers of AJs and tight junctions in DJM 1 cells and detected at cell-cell junction areas of human normal epidermis tissue. We then examined the distribution patterns of drebrin in BCC, trichoblastoma and trichoepithelioma. In BCC tissues, intense and homogeneous drebrin expression was observed mainly at tumor cell-cell boundaries. In contrast, drebrin was stained only weakly and non-homogeneously in trichoblastoma and trichoepthelioma tissue samples. For differential diagnosis of BCC, drebrin may be a novel and useful marker. PMID- 24346823 TI - Multishot diffusion-weighted MR imaging features in acute trauma of spinal cord. AB - OBJECTIVES: To analyse diffusion-weighted MRI of acute spinal cord trauma and evaluate its diagnostic value. METHODS: Conventional MRI and multishot, navigator corrected DWI were performed in 20 patients with acute spinal cord trauma using 1.5-T MR within 72 h after the onset of trauma. RESULTS: Twenty cases were classified into four categories according to the characteristics of DWI: (1) Oedema type: ten cases presented with variable hyperintense areas within the spinal cord. There were significant differences in the apparent diffusion coefficients (ADCs) between lesions and unaffected regions (t = -7.621, P < 0.01). ADC values of lesions were markedly lower than those of normal areas. (2) Mixed type: six cases showed heterogeneously hyperintense areas due to a mixture of haemorrhage and oedema. (3) Haemorrhage type: two cases showed lesions as marked hypointensity due to intramedullary haemorrhage. (4) Compressed type (by epidural haemorrhage): one of the two cases showed an area of mild hyperintensity in the markedly compressed cord due to epidural haematoma. CONCLUSIONS: Muti-shot DWI of the spinal cord can help visualise and evaluate the injured spinal cord in the early stage, especially in distinguishing the cytotoxic oedema from vasogenic oedema. It can assist in detecting intramedullary haemorrhage and may have a potential role in the evaluation of compressed spinal cord. KEY POINTS: * Multishot, navigator-corrected diffusion-weighted MRI is helpful when evaluating spinal cord injury (SCI). * Four types of SCI may be classified according to the DWI characteristics. * DWI differentiates cytotoxic from vasogenic oedema, thereby determining the centre of SCI. * DWI can assist in detecting intramedullary haemorrhage. * DWI can help evaluate the degree of compressed spinal cord. PMID- 24346824 TI - Montelukast: a novel therapeutic option in eosinophilic peritonitis. AB - BACKGROUND: Eosinophilic peritonitis is a recognised complication of peritoneal dialysis and has an incompletely understood pathophysiology. Current treatment options, including change of dialysate, change of peritoneal dialysis modality, steroids or antihistamines, are supported only by case reports with a lack of controlled trials or evidence-based guidelines. Leukotrienes are proinflammatory arachidonic acid metabolites produced by leucocytes and are involved in eosinophil chemotaxis. Montelukast is an orally administered leukotriene receptor antagonist commonly used in managing childhood atopic illnesses and theoretically safe for use in patients with renal failure. CASE DIAGNOSIS AND TREATMENT: We describe the first reported case of recurrent, symptomatic, eosinophilic peritonitis in a 15-year-old girl successfully treated with leukotriene receptor antagonist montelukast after changes in dialysate and treatment with antihistamines failed to adequately control eosinophilic peritoneal infiltrates or symptoms. CONCLUSIONS: Current scientific understanding of leukotrienes and eosinophil migration suggest that montelukast may be a well-tolerated, safe and efficacious treatment for eosinophilic peritonitis complicating peritoneal dialysis. Further cases and comparative studies are required to develop an evidence base for treatment of this condition. PMID- 24346825 TI - Management, morbidity and mortality of COPD during an 11-year period: an observational retrospective epidemiological register study in Sweden (PATHOS). AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of the most common causes of mortality and a major contributor to morbidity. Longitudinal clinical practice data yielding information on the characteristics of the disease, its natural course, and management are limited. AIMS: To investigate and describe the COPD population from a nationwide perspective during an 11-year period (1999-2009) with a focus on management, co-morbidity, and mortality. METHODS: This observational retrospective epidemiological study linked electronic medical records data from patients with COPD in primary care to mandatory Swedish hospital, drug and Cause of Death registry data from 1999 to 2009 (PATHOS). RESULTS: A total of 21,361 patients with a COPD diagnosis were included (mean age 68.0 years, 53% females). The proportion of patients diagnosed in primary care increased from 59% in 1999 to 81% in 2009 and the mean age at diagnosis decreased from 73 to 66 years. The number of exacerbations decreased from 3.0 to 1.3 and COPD-related hospitalisations decreased from 1.02 to 0.20 per patient per year. Prescriptions of long-acting muscarinic antagonists and fixed combinations of inhaled corticosteroid/long-acting beta2-agonist inhalers increased from 0% to 36% and 37%, respectively. The most common co-morbidities were hypertension, heart failure, ischaemic heart disease, and diabetes. Overall life expectancy was 8.3+/-6.8 years shorter in patients with COPD than in the general population, and all- cause mortality was 3.5 times higher. CONCLUSIONS: Management of COPD in Sweden has improved during the 11-year study period. Despite this, patients with COPD have a substantially reduced life expectancy than the general population. PMID- 24346826 TI - Chronic disease co-morbidity of asthma and unscheduled asthma care among adults: results of the national telephone health interview survey German Health Update (GEDA) 2009 and 2010. AB - BACKGROUND: Co-morbidities may complicate the clinical management of chronic conditions such as asthma. AIMS: To quantify the strength of the relationship between asthma and other chronic diseases and to analyse whether co-morbidities contribute to unscheduled asthma care. METHODS: Data from two consecutive national telephone health interview surveys (GEDA 2009 and 2010) including a total of 43,312 adults (>18 years of age) were analysed. Persons with and without a current diagnosis of asthma were compared with respect to concurrent diagnoses (diabetes mellitus, hypertension, chronic heart failure, depression, osteoarthritis, stroke, coronary heart disease, and cancer). Logistic regression models were applied to assess the strength of the association between asthma and co-morbidities in the total study population and, among persons with asthma, between the number of co-morbidities and unscheduled inpatient (hospital admissions and/or emergency department admissions) or outpatient asthma care in the past 12 months. RESULTS: Overall, 5.3% (95% CI 5.0% to 5.6%) of adults reported current physician-diagnosed asthma. Asthma was significantly associated with most of the conditions considered and 18% of persons with asthma had three or more co-morbidities. Adjusted odds ratios (AOR) of unscheduled asthma care increased with numbers of conditions, with AOR 3.40 (95% CI 1.39 to 8.31) for unscheduled inpatient care and AOR 2.32 (95% CI 1.30 to 4.14) for unscheduled outpatient care comparing those with three or more co-morbidities versus those with none. CONCLUSIONS: The magnitude of chronic disease co-morbidity is substantial in asthma, is related to unscheduled asthma care, and implies a significant number of adults with asthma facing complex healthcare needs. PMID- 24346828 TI - Construction of DNA-polymer hybrids using intercalation interactions. AB - Reversible addition-fragmentation chain transfer (RAFT) polymerisation was used to produce a range of polymers terminated with an acridine group, which intercalates efficiently into dsDNA; the structure of the polymer determines the nature and strength of the interaction. Using a short 63 base pair dsDNA, discrete and well-defined DNA-polymer hybrid nanoparticles were formed, which were characterised by dynamic light scattering, small-angle X-ray scattering and atomic force microscopy. PMID- 24346827 TI - The role of obesity and obstructive sleep apnea in the pathogenesis and treatment of resistant hypertension. AB - The incidence of resistant hypertension, obesity, and obstructive sleep apnea (OSA), three highly prevalent conditions in the United States, is rising. Approximately one in three adults in the US has hypertension, and a significant proportion of these individuals have hypertension that is difficult to treat, or resistant. Obesity and OSA are well-established risk factors for resistant hypertension, a condition that portends significant cardiovascular risk. Awareness of the various mechanisms by which obesity and OSA impact systemic blood pressure is essential to better understand how best to effectively care for patients with resistant hypertension. In this review, we discuss the clinical and pathophysiologic associations between obesity, OSA, and resistant hypertension. Furthermore, we will explore the effect of continuous positive airway pressure therapy (CPAP) and other therapeutic interventions on blood pressure control in patients with resistant hypertension.Key Points* Obesity, obstructive sleep apnea, and resistant hypertension are highly prevalent conditions, with increasing overall incidence [1-3].* Both obesity and obstructive sleep apnea are independent risk factors for the development of resistant hypertension.* OSA is characterized by a physiologic cascade of collapse of the upper airway, which can lead to intermittent hypoxia, hypercapnia, significant negative intra-thoracic pressure, and increased SNS output.* Intermittent hypoxia leads to activation of the endothelin system [17, 18, 19*], which can lead to the development of resistant hypertension.* Intermittent hypoxia can lead to the over activation of the SNS, which can also contribute to the development of resistant hypertension [20, 21].* OSA leads to state of elevated adrenergic tone, which in turn may contribute to resistant hypertension [25-27].* OSA patients have a higher incidence of "non-dipping" of nocturnal systolic blood pressure, a marker of increased adrenergic tone. This potentially represents a risk factor for hypertensive end organ disease [31, 32].* The prevalence of OSA is significantly higher in patients predisposed to fluid accumulation: including kidney disease, heart failure and resistant hypertension [33].* Interventions (such as the daytime use of compression stocking) which reduce daytime lower extremity fluid accumulation can significantly reduce the severity of OSA, particularly in patients with comorbid resistant hypertension [35, 36].* CPAP therapy can significantly reduce blood pressure in patients with comorbid hypertension and OSA. The treatment effect is most pronounced in those with resistant hypertension and OSA [16**, 38-42]. PMID- 24346829 TI - Nrf2 activation in the liver of rats subjected to a preconditioning sub-chronic iron protocol. AB - Sub-chronic iron (Fe) administration induces liver oxidative stress upregulating cytoprotective mechanisms that may involve redox-sensitive nuclear factor erythroid 2-related factor 2 (Nrf2). We aimed to investigate whether Fe activates Nrf2, in relation to its negative regulator Kelch-like ECH associated protein 1 (Keap1), with consequent antioxidant enzyme induction. Sprague-Dawley rats received six Fe doses (50 mg kg(-1)) on alternate days or saline (controls), a protocol that abrogates ischemia-reperfusion liver injury. Liver reduced glutathione (GSH) content and Nrf2 (Western blot) were measured 24 h after each Fe dose. Increased hepatic Fe deposition (Perls staining) was paralleled by reversible GSH depletion and enhancements in nuclear Nrf2 content and in nuclear/cytosolic Nrf2 ratios. A similar profile was observed for heme oxygenase 1 (HO-1) and NADPH-quinone oxidoreductase 1 (NQO-1) contents, antioxidant enzymes that significantly correlated with nuclear/cytosolic Nrf2 ratios. Normalization of Fe-induced oxidative stress status occurred concomitantly with that of Nrf2 and with the Nrf2-dependent HO-1 and NQO-1 expression, which are associated with delayed enhancement in cytosolic Keap1 levels. This is in agreement with the significant inverse correlation of nuclear/cytosolic Nrf2 ratios with those of nuclear Keap1/Nrf2, suggesting a negative feed-back mechanism normalizing Nrf2 signaling. In conclusion, sub-chronic Fe administration leads to transient liver oxidative stress development and Nrf2 activation, as evidenced by early GSH depletion, enhanced nuclear Nrf2 protein levels, and HO-1 and NQO-1 induction, with late normalization of these changes being related to Keap1 upregulation. PMID- 24346830 TI - Gene expression related to oxidative stress in the heart of mice after intestinal ischemia. AB - BACKGROUND: Intestinal ischemia-reperfusion is a frequent clinical event associated to injury in distant organs, especially the heart. OBJECTIVE: To investigate the gene expression of oxidative stress and antioxidant defense in the heart of inbred mice subjected to intestinal ischemia and reperfusion (IR). METHODS: Twelve mice (C57BL/6) were assigned to: IR Group (GIR) with 60 minutes of superior mesenteric artery occlusion followed by 60 minutes of reperfusion; Control Group (CG) which underwent anesthesia and laparotomy without IR procedure and was observed for 120 minutes. Intestine and heart samples were processed using the RT-qPCR/Reverse transcriptase-quantitative Polymerase Chain Reaction method for the gene expression of 84 genes related to oxidative stress and oxidative defense (Student's "t" test, p<0.05). RESULTS: The intestinal tissue (GIR) was noted to have an up-regulation of 65 genes (74.71%) in comparison to normal tissue (CG), and 37 genes (44.04%) were hyper-expressed (greater than three times the threshold allowed by the algorithm). Regarding the remote effects of intestinal I/R in cardiac tissue an up-regulation of 28 genes (33.33%) was seen, but only eight genes (9.52%) were hyper-expressed three times above threshold. Four (7.14%) of these eight genes were expressed in both intestinal and cardiac tissues. Cardiomyocytes with smaller and pyknotic nuclei, rich in heterochromatin with rare nucleoli, indicating cardiac distress, were observed in the GIR. CONCLUSION: Intestinal I/R caused a statistically significant over expression of 8 genes associated with oxidative stress in remote myocardial tissue. PMID- 24346834 TI - Enzyme-transporter interplay in the formation and clearance of abundant metabolites of faldaprevir found in excreta but not in circulation. AB - Faldaprevir is a hepatitis C virus protease inhibitor that effectively reduces viral load in patients. Since faldaprevir exhibits slow metabolism in vitro and low clearance in vivo, metabolism was expected to be a minor clearance pathway. The human [(14)C] absorption, distribution, metabolism, and excretion study revealed that two monohydroxylated metabolites (M2a and M2b) were the most abundant excretory metabolites in feces, constituting 41% of the total administered dose. To deconvolute the formation and disposition of M2a and M2b in humans and determine why the minor change in structure [the addition of 16 atomic mass units (amu)] produced chemical entities that were excreted and were not present in the circulation, multiple in vitro test systems were used. The results from these in vitro studies clarified the formation and clearance of M2a and M2b. Faldaprevir is metabolized primarily in the liver by CYP3A4/5 to form M2a and M2b, which are also substrates of efflux transporters (P-glycoprotein and breast cancer resistance protein). The role of transporters is considered important for M2a and M2b as they demonstrate low permeability. It is proposed that both metabolites are efficiently excreted via bile into feces and do not enter the systemic circulation to an appreciable extent. If these metabolites permeate to blood, they can be readily taken up into hepatocytes from the circulation by uptake transporters (likely organic anion transporting polypeptides). These results highlight the critical role of drug-metabolizing enzymes and multiple transporters in the process of the formation and clearance of faldaprevir metabolites. Faldaprevir metabolism also provides an interesting case study for metabolites that are exclusively excreted in feces but are of clinical relevance. PMID- 24346835 TI - Understanding the transport properties of metabolites: case studies and considerations for drug development. AB - Recent analyses demonstrated that metabolites are unlikely to contribute significantly to clinical inhibition of cytochrome P450 (P450)-mediated drug metabolism, and that only ~2% of this type of drug interaction could not be predicted from the parent drug alone. Due to generally increased polarity and decreased permeability, metabolites are less likely to interact with P450s, but their disposition is instead more likely to involve transporters. This commentary presents case studies illustrating the potential importance of transporters as determinants of metabolite disposition, and as sites of drug interactions, which may alter drug efficacy and safety. Many of these examples are hydrophilic phase II conjugates involved in enterohepatic cycling, where modulation of transporter dependent disposition may alter pharmacokinetics/pharmacodynamics. The case studies suggest that characterization of metabolite disposition, toxicology, and pharmacology should not focus solely on metabolites with appreciable systemic exposure, but should take into consideration major excretory metabolites. A more thorough understanding of metabolite (phase I and II; circulating and excreted) transport properties during drug development may provide an improved understanding of complex drug-drug interactions (DDIs) that can alter drug and/or metabolite systemic and intracellular exposure. Knowledge and capability gaps remain in clinical translation of in vitro and animal data regarding metabolite disposition. To this end, useful experimental and modeling approaches are highlighted. Application of these tools may lead to a better understanding of metabolite victim and perpetrator DDI potential, and ultimately the establishment of approaches for prediction of pharmacodynamic and toxicodynamic consequences of metabolite transport modulation. PMID- 24346836 TI - Interaction of human arylamine N-acetyltransferase 1 with different nanomaterials. AB - Humans are exposed to nanoparticles in the environment as well as those in nanomaterials developed for biomedical applications. However, the safety and biologic effects of many nanoparticles remain to be elucidated. Over the past decade, our understanding of the interaction of proteins with various nanomaterials has grown. The protein corona can determine not only how nanoparticles interact with cells but also their biologic effects and toxicity. In this study, we describe the effects that several different classes of nanoparticles exert on the enzymatic activity of the cytosolic protein human arylamine N-acetyltransferase 1 (NAT1), a drug-metabolizing enzyme widely distributed in the body that is also responsible for the activation and detoxification of known carcinogens. We investigated three metal oxides (zinc oxide, titanium dioxide, and silicon dioxide), two synthetic clay nanoparticles (layered double hydroxide and layered silicate nanoparticles), and a self assembling thermo-responsive polymeric nanoparticle that differ in size and surface characteristics. We found that the different nanoparticles induced very different responses, ranging from inhibition to marked enhancement of enzyme activity. The layered silicates did not directly inactivate NAT1, but was found to enhance substrate-dependent inhibition. These differing effects demonstrate the multiplicity of nanoparticle-protein interactions and suggest that enzyme activity may be compromised in organs exposed to nanoparticles, such as the lungs or reticulo-endothelial system. PMID- 24346837 TI - Intramedullary fixation for lesser metatarsal osteotomy: a technical tip. PMID- 24346838 TI - A retrospective comparison of cost and efficiency of the medial double and dual incision triple arthrodeses. AB - While the medial double arthrodesis has gained significant popularity for hindfoot arthrodesis in recent years, much has been touted about the efficiency and cost savings of the procedure in comparison to its triple counterpart without any literature to reinforce this claim. The purpose of this retrospective study was to compare the hardware costs and operative time between the medial double and triple arthrodeses. A total of 276 patients (277 feet) were identified via CPT codes with 47 hindfoot cases (47 feet) meeting the inclusion criteria consisting of 21 medial double (6 males, 15 females) and 26 triple (8 males, 18 females) arthrodeses. No significant difference was noted in age, body mass index, gender, chronic steroid use, preoperative osteopenia/osteoporosis, tobacco abuse, surgical side, presence of diabetes, immune compromised state, kidney disease, rheumatoid arthritis, or liver disease. Mean medial double operative (OR) time 106 +/- 31 minutes (range = 73-201 minutes) with a procedure time of 84 +/- 29 minutes (range = 44-163 minutes) was identified versus an OR time of 127 +/- 23 minutes (range = 91-200 minutes) and procedure time of 104 +/- 23 minutes (range = 50-169 minutes) for the triple arthrodesis group. The mean fixation cost for the triple arthrodesis was found to be higher with the mean triple hardware cost $2932.75 +/- $736.60 (range = $1434.00 to $3980.00) against the medial double's $1197.59 +/- $635.57 (range = $463.20 to $2019.00). Both efficiency and cost were found to favor the medial double for hindfoot arthrodesis at a level of statistical significance level (P = .0028 for OR time, P = .0033 for procedure time, and P < .0001 for cost). PMID- 24346839 TI - Characterization of the divalent metal binding site of bacterial polysaccharide deacetylase using crystallography and quantum chemical calculations. AB - Peptidoglycan deacetlyase (HP0310, HpPgdA) from the gram-negative pathogen Helicobacter pylori, is the enzyme responsible for a peptidoglycan modification that counteracts the host immune response. In a recent study, we determined the crystallographic structure of the enzyme, which is a homo-tetramer (Shaik et al., PloS One 2011;6:e19207). The metal-binding site, which is essential for the enzyme's catalytic activity, is visible within the structure, but we were unable to identify the nature of the metal itself. In this study, we have obtained a higher-resolution crystal structure of the enzyme, which shows that the ion bound is, in fact, zinc. Analysis of the structure of the four sites, one per monomer, and quantum chemical calculations of models of the site in the presence of different divalent metal ions show an intrinsic preference for zinc, but also significant flexibility of the site so that binding of other ions can eventually occur. PMID- 24346840 TI - Health status sensed by the adult Latin American immigrant population in the city of Seville, Spain. AB - The immigrant population in Seville has grown over the last 10 years, most of which are Latin Americans. Our aim was to describe the health status perceived in this emerging population. In 2011, a cross-sectional study was performed on a representative sample of 190 Latin American immigrants between the ages of 25 and 44 years residing in Seville (Spain). The self-sensed health status was 18% excellent, 28% very good, 42% good, 11% regular, and 1% poor. The average number of days of satisfactory health status during the last month was 22. Statistically significant differences were found: (a) higher satisfactory perception of health in men than in women (30 vs. 9%) and (b) higher average number of days with excellent health in people with satisfactory perception than those with an unsatisfactory perception of their health status (23 and 15, respectively). Logistic regression, educational level, number of days of good health, and doing physical exercise were the variables that best explained the satisfactory perception of health status. Most people studied have a positive self-assessment of their health status, especially men, who engage in physical activity and those who have 3 and more weeks of good health per month. Our results permit us to support, to a large extent, the theory of the "healthy immigrant". PMID- 24346841 TI - Young mothers lack plans to receive preventive health care. AB - BACKGROUND: Despite their health vulnerability, multiple barriers to health care exist for adolescent mothers. This pilot study aimed to gain information regarding preventive health care intentions of young mothers following pregnancy. METHODS: We administered institutional review board-approved surveys to mothers aged 15 to 21 years at a local hospital where 75% of infants are born. Participants were questioned regarding current and intended use of health care. RESULTS: Results showed that only half of the young mothers identified a primary care provider (PCP) but more had seen some type of doctor in the 3 years preceding their pregnancy. White mothers were significantly more likely than Hispanic to have seen a physician prior to pregnancy; family physicians (FPs) were referenced most. Additionally, white and black mothers were significantly more likely than Hispanic mothers or mothers of other ethnicity to have received minor emergency care during pregnancy. While FPs were referenced most frequently, few mothers planned to see one for preventive care. Nearly half of participants planned to see their obstetrician/gynecologist (OBGYN) for routine yearly checkups. CONCLUSIONS: This research indicates a gap in health care for young mothers. Only half enter parenthood with a PCP, and once mothers, few plan to see a physician for preventive care. In this study, OBGYNs were identified most often for preventive health care. Therefore OBGYNs should provide comprehensive care to this population, or connect them with other PCPs. Furthermore, young mothers do plan on seeing FPs for acute health care, supporting previous recommendations that physicians use all visits to provide comprehensive care to adolescents. PMID- 24346842 TI - A novel mutation in SOX3 polyalanine tract: a case of Kabuki syndrome with combined pituitary hormone deficiency harboring double mutations in MLL2 and SOX3. AB - INTRODUCTION: Both duplications encompassing SOX3 and loss-of function mutations in SOX3 have been reported in a minor portion of X-linked isolated growth hormone deficiency (GHD) or combined pituitary hormone deficiency (CPHD) patients with or without mental retardation. PATIENTS AND METHODS: We report a Japanese male patient with molecularly confirmed Kabuki syndrome who was found to have CPHD. We analyzed all coding exons and flanking introns of currently known nine genes responsible for CPHD by PCR-based sequencing. RESULTS: In this CPHD patient, we identified a novel hemizygous 21-base pair deletion, resulting in the loss of 7 alanine residues from polyalanine (PA) tracts of SOX3. The clinically and endocrinologically normal mother of the patient carried the same deletion in a heterozygous manner. In vitro experiments showed that the del 7A SOX3 had increased transactivation of the HESX1 promoter. CONCLUSION: Our study provides additional evidence that deletion in PA tracts of SOX3 is associated with hypopituitarism. Female carriers of SOX3 PA tract deletions will show a broad phenotypic spectrum, ranging from clinically normal to CPHD. PMID- 24346843 TI - Costs analysis of laparoendoscopic, single-site laparoscopic and open surgery for cT1 renal masses in a European high-volume centre. AB - OBJECTIVE: To analyse intraoperative costs and healthcare reimbursements of partial/radical nephrectomy in open and minimal invasive surgery (MIS), as laparoscopy and laparoendoscopic single-site surgery (LESS), for the treatment of renal tumour. MATERIALS AND METHODS: In a non-randomized retrospective study, we selected 90 patients who underwent (01/2010-12/2011) partial and radical nephrectomy for clinical renal masses <=7 cm (cT1N0M0) and divided them into laparoscopic [laparoscopic partial nephrectomy (LPN), laparoscopic radical nephrectomy (LRN)], LESS [laparoendoscopic single-site partial nephrectomy (LESS PN), laparoendoscopic single-site radical nephrectomy (LESS-RN)] and open groups [open partial nephrectomy (OPN), open radical nephrectomy (ORN)]. Patients were matched for age, sex, body mass index, ASA score and tumour side. Primary endpoints were evaluation of intraoperative costs (general, laparoscopic, sutures, haemostatic agents, anaesthesia, and surgeon/nurses fee), total insurance and estimated daily reimbursement. RESULTS: MIS showed longer operative time (p <= .02) and shorter hospital stay (p <= .04). Total costs were higher (p <= .03) in MIS (LRN: 4,091.5 ; LPN: 4,390.4 ; LESS-RN: 3,866 ; and LESS-PN: 3,450 ) if compared with open (OPN: 2,216.8.8 , ORN: 1,606.4 ). Laparoscopic materials incised mainly in total costs of MIS (38 58.1 %). Reusable instruments reduced LESS laparoscopic costs (LESS-PN: 1,312.2 vs. LRN: 2,212.2 , p < .0001). Intraoperative frozen section and DJ ureteric stenting (general costs) (p <= .008) and haemostatic agents use (p <= .01) were higher in nephron sparing surgery (NSS), due to more frequent use of ancillary procedures necessary for a safe management of such an approach. Estimated anaesthesia costs and doctor/nurses fee were higher in MIS (p <= .02). Whereas total final reimbursements were comparable (p >= .8), estimated daily reimbursements were lower in MIS (p < .001) due to higher intraoperative costs and longer operative time. CONCLUSION: Well-known advantages offered by MIS/NSS face higher total intraoperative costs and 'paradoxical' reduced healthcare reimbursement. We believe that local health systems should consider a subclassification with different compensations, which will incentive NSS and MIS approaches. PMID- 24346846 TI - Yamadazyma ubonensis f.a., sp. nov., a novel xylitol-producing yeast species isolated in Thailand. AB - Three hundred and thirty-seven xylose-utilizing yeast strains were isolated from various natural samples. Among these, 68 strains produced xylitol in the range of 0.1-0.69 g xylitol/g xylose. Thirty-nine xylitol-producing strains were identified to be Candida tropicalis. Ten strains were found belonging to 14 known species in the genus Candida, Cyberlindnera, Meyerozyma, Pichia, Wickerhamomyces, Yamadazyma and Cryptococcus. Two strains were identified to be two Candida species and two strains (DMKU-XE142(T) and DMKU-XE332) were found to be a novel species. Strain DMKU-XE142(T) was isolated from tree bark and DMKU-XE332 was obtained from decaying plant leaf collected in Thailand. On the basis of morphological, biochemical, physiological and chemotaxonomic characteristics and sequence analysis of the D1/D2 region of the large subunit rRNA gene (LSU) and the internal transcribed spacer (ITS) region, the two strains were determined to represent a novel Yamadazyma species although formation of ascospores was not observed. The sequences of the D1/D2 region of the LSU rRNA gene and the ITS region of the two strains were identical but differed from Yamadazyma phyllophila, the closest species in terms of pairwise sequence similarity of the D1/D2 region, by 1.7 % nucleotide substitutions and 3.5 % nucleotide substitutions in the ITS region. The name Yamadazyma ubonensis f.a., sp. nov. is proposed (type strain is DMKU-XE142(T) = BCC 61020(T) = CBS 12859(T)). PMID- 24346847 TI - Maspin expression, subcellular localization and clinicopathological correlation in endometrial hyperplasia and endometrial adenocarcinoma. AB - Maspin expression in endometrial hyperplasia and endometrial endometrioid adenocarcinomas was assessed and its correlation with p53 and Ki67 expressions and clinical outcome, as well as its potential to distinguish typical from atypical endometrial hyperplasia, were assessed in this study. Histological sections from 114 cases of endometrial endometrioid adenocarcinoma, 75 cases of endometrial hyperplasia (typical and atypical), and 23 normal endometrial tissue samples were examined. The most representative hematoxylin-eosin slides were selected and 2-3 micron-thick sections were cut for immunohistochemical staining with maspin, p53, and Ki67 antibodies. While there was no maspin expression in normal endometrial cells, it was present in 14.5% of the patients with endometrial hyperplasia without atypia. Staining for maspin was positive in atypical hyperplasia and endometrial adenocarcinoma in, respectively, 45% and 49.1% of the cases studied. No statistically significant correlations were found between maspin and Ki-67 antibodies or p53 expression. Our findings showed that maspin expression, which generally correlates with a less aggressive behavior, is significantly higher in atypical hyperplasia and in endometrial endometrioid adenocarcinoma. Maspin positivity in endometrial hyperplasia could be used to identify pseudo-atypical hyperplasia and could be considered a potentially useful prognostic parameter in those cases in which adenocarcinomas are well differentiated. PMID- 24346848 TI - A time to weep and a time to laugh: humour in the nurse-patient relationship in an adult cancer setting. AB - PURPOSE: The literature highlights the value of humour in health-care settings. Humour impacts on the physiological, psychosocial and cognitive well-being of a person. The diagnosis of cancer is extremely stressful, and treatments are difficult. Patients and nurses may use humour as a coping mechanism to contend with the stresses caused directly or indirectly by cancer. This study investigated the use of humour during interactions between patients and nurses in an adult cancer ward. METHODS: This study used a modified ethnographic methodology that included fieldwork participant observation and informal interviews (n=30 h) and formal interviews (n=10). In total, 9 nurses and 12 patients participated in participant observation. From these, five nurses and five patients were interviewed. Data were analysed using thematic analysis. RESULTS: Findings highlighted the importance of humour in the nurse-patient relationship. Patients consciously use humour during nurse-patient interactions in an attempt to help nurses cope with the stress they encounter in clinical practice. Patients perceive having a sense of humour as a positive nurse attribute. Nurses expressed concerns regarding compromising professionalism when using humour and felt the need for guidance from senior staff. Constant assessment and reflection help ensure humour is used appropriately in the adult health-care setting. CONCLUSION: The benefits of humour are recognised by both adult cancer patients and nurses. A deeper understanding of patient and nurse perceptions of the use of humour can inform strategies for its therapeutic use in the clinical setting. PMID- 24346849 TI - Pharmacokinetic-pharmacodynamic evaluation of the major component astragaloside IV on the immunomodulatory effects of Yu-ping-feng prescription. AB - Yu-ping-feng decoction (YPF), a traditional Chinese medicine (TCM) prescription, is widely used to treat some respiratory tract diseases. This study was aimed to set up a pharmacokinetic-pharmacodynamic (PK-PD) model to assess dose-effect relationships for immunomodulatory effects of YPF in rats and to clarify compatibility mechanisms for TCM prescription system. Serum samples taken after YPF administration were tested on spleen cells of rats in vitro and proliferation ratio of spleen cells was used as end points to evaluate pharmacodynamic properties of immunoregulatory effects of YPF prescription. And with a HPLC-MS method, concentrations of Astragaloside IV (AS), a main component of YPF, were determined to achieve pharmacokinetic parameters after administration of a simplified prescription which is composed with AS, Atractylenolide I and Prim-O glucosylcimifugin which are representative components of YPF. A plot of serum AS concentrations versus time and effects showed that there was a correlated relationship between AS concentrations and effects of YPF, and the concentration response curve which was based on an E max model showed a counterclockwise hysteresis manner. A PK-PD model with Sheiner's method was used to describe time course of AS concentration in blood compartment and effect compartment, and main parameters with the PK-PD model were calculated. These results showed that there is a symmetry relationship between serum AS concentrations and responses of serum containing medicine of YPF prescription, which means that AS plays an important role in immunoregulatory effects of YPF. And the investigation on dose-effect relationships has displayed a feasible method to clarify mechanisms of combination for TCM prescriptions. PMID- 24346850 TI - Effects of silymarin on the pharmacokinetics of atorvastatin in diabetic rats. AB - The effect of silymarin (SMN) on the pharmacokinetics of atorvastatin in diabetic rats was evaluated. Male Wistar rats were assigned into two major groups and then sub-grouped according to the purposes of the study. The first major group was subdivided into three groups (n = 6) including control, non-treated diabetic and SMN-treated diabetic animals. In the first major group, metabolism of testosterone by the hepatic microsomes was studied. The second major group also was divided to three groups including atorvastatin-treated non-diabetic, atorvastatin-treated diabetic and diabetic animals which received both atorvastatin and SMN. To study the pharmacokinetics of atorvastatin, serum samples were collected at 0, 3, 6, 12 and 24 h after the atorvastatin administration. Pharmacokinetic parameters were calculated using non compartmental model. Streptozotocin-induced diabetes resulted in a remarkable induction of testosterone hydroxylation as the V max for 6beta hydroxytestosterone production in the diabetic rats (77.3 +/- 8.6 pM/min/mg) was significantly higher than that in the control animals (45.9 +/- 5.9 pM/min/mg). Moreover, SMN-treated animals showed a significant (P < 0.05) reduction of V max (59.4 +/- 6.1 pM/min/mg). Diabetes resulted in a significant reduction of AUC (control 6.98 +/- 0.58 vs diabetic rats 4.35 +/- 0.24 h mg/ml) and C max values (control 0.52 +/- 0.03 vs diabetic group 0.33 +/- 0.01 MUg/ml), while the SMN received group showed remarkable recovery of diabetes-reduced values of AUC and C max. These findings indicated that diabetes resulted in a significant up regulation of microsomal enzyme activities. Moreover, as SMN could significantly regulate the enzyme activities and consequently the atorvastatin pharmacokinetics in diabetic rats, its regulative effect in a combination therapy is concluded. PMID- 24346851 TI - Gender differences in pharmacokinetics of a combination tablet of niacin extended release/simvastatin in healthy Chinese volunteers. AB - The gender differences in pharmacokinetics of a combination tablet of niacin extended-release/simvastatin were evaluated in healthy Chinese volunteers. Thirty six healthy male and female volunteers were enrolled in the study receiving a single oral dose of niacin extended-release/simvastatin 1,000/20 mg. The results indicated that the systemic exposure of simvastatin hydroxy acid and the total urine excretion of niacin were significantly higher for females compared with those for males, and the T max of niacin in plasma was significantly shorter for males than that for females. There were no significant differences in the systemic exposure of simvastatin, niacin, and NUA in plasma between males and females. PMID- 24346854 TI - Elastic stiffness characterization using three-dimensional full-field deformation obtained with optical coherence tomography and digital volume correlation. AB - This paper presents a methodology for stiffness identification from depth resolved three-dimensional (3-D) full-field deformation fields. These were obtained by performing digital volume correlation on optical coherence tomography volume reconstructions of silicone rubber phantoms. The effect of noise and reconstruction uncertainties on the performance of the correlation algorithm was first evaluated through stationary and rigid body translation tests to give an indication of the minimum strain that can be reliably measured. The phantoms were then tested under tension, and the 3-D deformation fields were used to identify the elastic constitutive parameters using a 3-D manually defined virtual fields method. The identification results for the cases of uniform and heterogeneous strain fields were compared with those calculated analytically through the constant uniaxial stress assumption, showing good agreement. PMID- 24346852 TI - Evolving concepts and treatment strategies for cardiac allograft vasculopathy. AB - OPINION STATEMENT: The central event in the development of allograft vasculopathy is the inflammatory response to immune-mediated and nonimmune-mediated endothelial damage. This response is characterized by the release of inflammatory cytokines, upregulation of cell-surface adhesion molecules, and subsequent binding of leukocytes. Growth factors stimulate smooth muscle cell proliferation and circulating progenitor cells are recruited to sites of arterial injury leading to neointima formation. Because of its diffuse nature, intravascular ultrasound is more sensitive than angiography for early diagnosis. Proliferation signal inhibitors (PSIs) have the capacity to slow vasculopathy progression by inhibiting smooth muscle cell proliferation, but its side effects profile makes its use as a first line agent difficult. Retransplantation is still the only definitive therapy but is available only in selected cases. The current hope is that immunomodulation at the time of transplant could induce long-term tolerance and graft accommodation, leading to less vasculopathy. PMID- 24346853 TI - The Role of Treatment for Anemia as a Therapeutic Target in the Management of Chronic Heart Failure: Insights After RED-HF. AB - OPINION STATEMENT: Anemia is common in patients with heart failure (HF) and appears to be closely linked with HF prognosis. A variety of mechanisms have been implicated in the association between anemia and HF, and treatment of anemia as a therapeutic target in HF patients is gaining increased attention. Recently large randomized controlled trials of erythropoietin-stimulating agents (ESA) and intravenous iron supplementation therapy have been completed and shed light on treatment of anemia in HF patients. ESA therapy did not show improvement in clinical outcomes, but intravenous iron supplementation may be of benefit in improving HF symptoms. Anemia has been commonly reported in patients with chronic heart failure (HF) and its prevalence appears to be closely linked with the severity of HF. Furthermore, the presence of anemia in patients with HF has been consistently associated with poor prognosis. Despite an increasing number of studies evaluating the relationship between HF and anemia, the answer to whether anemia is simply a marker or a mediator of poor prognosis in HF patients remains uncertain. One approach to this pivotal question has been to investigate treatment for anemia as a therapeutic target in HF. PMID- 24346855 TI - Digital image correlation-based optical coherence elastography. AB - Optical coherence elastography (OCE) provides deformation or material properties, mapping of soft tissue. We aim to develop a robust speckle tracking OCE technique with improved resolution and accuracy. A digital image correlation (DIC)-based OCE technique was developed by combining an advanced DIC algorithm with optical coherence tomography (OCT). System calibration and measurement error evaluation demonstrated that this DIC-based OCE technique had a resolution of ~0.6 MUm displacement and <0.5% strain measurement in the axial scan direction. The measured displacement ranged from 0.6 to 150 MUm, obtained via phantom imaging. The capability of the DIC-based OCE technique, for differentiation of stiffness, was evaluated by imaging a candle gel phantom with an irregularly shaped stiff inclusion. OCE imaging of a chicken breast sample differentiated the fat, membrane, and muscle layers. Strain elastograms of an aneurysm sample showed heterogeneity of the tissue and clear contrast between the adventitia and media. These promising results demonstrated the capability of the DIC-based OCE for the characterization of the various components of the tissue sample. Further improvement of the system will be conducted to make this OCE technique a practical tool for measuring and differentiating material properties of soft tissue. PMID- 24346856 TI - Enhanced fluorescence diffuse optical tomography with indocyanine green encapsulating liposomes targeted to receptors for vascular endothelial growth factor in tumor vasculature. AB - To develop an indocyanine green (ICG) tracer with slower clearance kinetics, we explored ICG-encapsulating liposomes (Lip) in three different formulations: untargeted (Lip/ICG), targeted to vascular endothelial growth factor (VEGF) receptors (scVEGF-Lip/ICG) by the receptor-binding moiety single-chain VEGF (scVEGF), or decorated with inactivated scVEGF (inactive-Lip/ICG) that does not bind to VEGF receptors. Experiments were conducted with tumor-bearing mice that were placed in a scattering medium with tumors located at imaging depths of either 1.5 or 2.0 cm. Near-infrared fluorescence diffuse optical tomography that provides depth-resolved spatial distributions of fluorescence in tumor was used for the detection of postinjection fluorescent signals. All liposome-based tracers, as well as free ICG, were injected intravenously into mice in the amounts corresponding to 5 nmol of ICG/mouse, and the kinetics of increase and decrease of fluorescent signals in tumors were monitored. A signal from free ICG reached maximum at 15-min postinjection and then rapidly declined with t1/2 of ~20 min. The signals from untargeted Lip/ICG and inactive-Lip/ICG also reached maximum at 15-min postinjection, however, declined somewhat slower than free ICG with t1/2 of ~30 min. By contrast, a signal from targeted scVEGF-Lip/ICG grew slower than that of all other tracers, reaching maximum at 30-min postinjection and declined much slower than that of other tracers with t1/2 of ~90 min, providing a more extended observation window. Higher scVEGF-Lip/ICG tumor accumulation was further confirmed by the analysis of fluorescence on cryosections of tumors that were harvested from animals at 400 min after injection with different tracers. PMID- 24346857 TI - Phase II trial of sorafenib in advanced salivary adenoid cystic carcinoma of the head and neck. AB - BACKGROUND: There is a need to improve the systemic treatment of advanced adenoid cystic carcinoma (ACC). Response rates to chemotherapy are poor and preliminary investigations of molecularly targeted agents have been disappointing. In this study, we evaluate sorafenib, an oral multikinase inhibitor, which has an attractive targeting profile for this disease. METHODS: In a single-arm phase II trial, patients with unresectable locally recurrent and/or metastatic ACC were treated with sorafenib 400 mg bid. RESULTS: Twenty-three patients, median age 51 years, were recruited from 2009 to 2011. Median progression-free survival (PFS) and overall survival (OS) were 11.3 and 19.6 months, respectively. PFS at 6 and 12 months were 69.3% and 46.2%, respectively. Sorafenib was only reasonably well tolerated, and 13 patients (57%) experienced grade 3 toxicity. CONCLUSION: Sorafenib showed modest activity in ACC with a 12-month PFS of 46.2%. Sorafenib 400 mg bid was associated with significant toxicity and, taken together with limited effectiveness, cannot be enthusiastically recommended for further evaluation. PMID- 24346858 TI - Temperature-driven switching of water adhesion on organogel surface. AB - Temperature-driven switching of water adhesion is realized on a novel n paraffinswollen organogel by thermally controlling the transition of air/liquid/solid (ALS/ALLS) systems via the phasechange process of n-paraffin. The thermal control of both the water-drop sliding motion and the switching of the optical transparency shows potential applications in scientific research and daily life. PMID- 24346859 TI - Fish oil in comparison to folinic acid for protection against adverse effects of methotrexate chemotherapy on bone. AB - Methotrexate (MTX) chemotherapy is known to cause bone loss which lacks specific preventative treatments, although clinically folinic acid is often used to reduce MTX toxicity in soft tissues. This study investigated damaging effects of MTX injections (0.75 mg/kg/day for 5 days) in rats and potential protective benefits of fish oil (0.25, 0.5, or 0.75 ml/100 g/day) in comparison to folinic acid (0.75 mg/kg) in the tibial metaphysis. MTX treatment significantly reduced height of primary spongiosa and volume of trabecular bone while reducing density of osteoblasts. Consistently, MTX reduced osteogenic differentiation but increased adipogenesis of bone marrow stromal cells, accompanied by lower mRNA expression of osteogenic transcription factors Runx2 and Osx, but an up-regulation of adipogenesis-related genes FABP4 and PPAR-gamma. MTX also increased osteoclast density, bone marrow osteoclast formation, and mRNA expression of proinflammatory cytokines IL-1, IL-6, TNF-alpha, and RANKL/OPG ratio in bone. Fish oil (0.5 or 0.75 ml/100 g) or folinic acid supplementation preserved bone volume, osteoblast density, and osteogenic differentiation, and suppressed MTX-induced cytokine expression, osteoclastogenesis, and adipogenesis. Thus, fish oil at 0.5 ml/100 g or above is as effective as folinic acid in counteracting MTX-induced bone damage, conserving bone formation, suppressing resorption and marrow adiposity, suggesting its therapeutic potential in preventing bone loss during MTX chemotherapy. PMID- 24346860 TI - Assessing the exposure of lion tamarins (Leontopithecus spp.) to future climate change. AB - Understanding how biodiversity will respond to climate change is a major challenge in conservation science. Climatic changes are likely to impose serious threats to many organisms, especially those with narrow distribution ranges, small populations and low dispersal capacity. Lion tamarins (Leontopithecus spp.) are endangered primates endemic to Brazilian Atlantic Forest (BAF), and all four living species are typical examples of these aggravating conditions. Here, we integrate ecological niche modeling and GIS-based information about BAF remnants and protected areas to estimate the exposure (i.e., the extent of climate change predicted to be experienced by a species) of current suitable habitats to climate change for 2050 and 2080, and to evaluate the efficacy of existing reserves to protect climatically suitable areas. Niche models were built using Maxent and then projected onto seven global circulation models derived from the A1B climatic scenario. According to our projections, the occurrence area of L. caissara will be little exposed to climate change. Western populations of L. chrysomelas could be potentially exposed, while climatically suitable habitats will be maintained only in part of the eastern region. Protected areas that presently harbor large populations of L. chrysopygus and L. rosalia will not retain climatic suitability by 2080. Monitoring trends of exposed populations and protecting areas predicted to hold suitable conditions should be prioritized. Given the potential exposure of key lion tamarin populations, we stress the importance of conducting additional studies to assess other aspects of their vulnerability (i.e., sensitivity to climate and adaptive capacity) and, therefore, to provide a more solid framework for future management decisions in the context of climate change. PMID- 24346861 TI - Hypo-pigmenting effect of sesquiterpenes from Inula britannica in B16 melanoma cells. AB - During the course of screens to identify anti-melanogenic agents from natural resources, we found that the methanol extract of the dried flower of Inula britannica L. inhibited melanin synthesis in cultured melanoma cells stimulated with 3-isobutyl-1-methylxanthine (IBMX). A bioassay-guided isolation of the chloroform fraction of the I. britannica using an in vitro melanogenesis inhibition assay led to the isolation of sesquiterpenes, 1-O acetylbritannilactone (1), britannilactone (2) and neobritannilactone B (3). Compounds 1 and 2 significantly reduced melanin production in a dose-dependent manner with IC50 values of 13.3 and 15.5 MUM, respectively, whereas compound 3 was found to be cytotoxic. Compound 1 also inhibited the tyrosinase activity only in cell based-systems. Western blot analysis indicated that compound 1 inhibited melanogenesis by activating extracellular signal-regulated kinase (ERK) and Akt signaling and also inhibiting cAMP related binding protein, which regulates its downstream pathway, including tyrosinase, tyrosinase related protein-1 and TRP-2. These results demonstrated that compound 1, a major sesquiterpene from the flowers of I. britannica, exhibited anti-melanogenic activity by suppression of tyrosinase expression via ERK and Akt signaling. Taken together, our results suggest that these compounds may act as potent natural skin-lightening agents. PMID- 24346862 TI - Providing animal health services to the poor in Northern Ghana: rethinking the role of community animal health workers? AB - The Community Animal Health Workers (CAHWs) system has been promoted as an alternative solution to providing animal health services in marginal areas. Yet, access to quality animal health services still remains a fundamental problem for livestock dependent communities. This paper uses the concepts of accessibility, affordability, and transaction costs to examine the perceptions of livestock keepers about the various animal health service providers. The empirical analysis is based on a survey of 120 livestock-keeping households in the Tolon-Kumbungu and Savelugu-Nanton districts in the Northern Region of Ghana. A multinomial logit model was used to determine the factors that influence households' choice of alternative animal health service providers. The results show that the government para-vets are the most preferred type of animal health service providers while CAHWs are the least preferred. Reasons for this observation include high transaction costs and low performance resulting from limited training. In areas with few or no government para-vets, farmers have resorted to self-treatment or to selling sick animals for consumption, which has undesirable health implications. These practices also result in significant financial losses for farmers. This paper finds that the CAHWs' system is insufficient for providing quality animal health services to the rural poor in marginal areas. Therefore, market-smart alternative solutions requiring strong public sector engagement to support livestock farmers in marginal areas and setting minimum training standards for animal health service providers merit policy consideration. PMID- 24346863 TI - Statins inhibit tumor progression via an enhancer of zeste homolog 2-mediated epigenetic alteration in colorectal cancer. AB - While statin intake has been proven to reduce the risk of colorectal cancer (CRC), the mechanism of antitumor effects and clinical significance in survival benefits remain unclear. Statin-induced antiproliferative effects and its underlying mechanism were examined using six CRC cell lines. Statins except pravastatin showed antiproliferative effects (simvastatin >= fluvastatin > atorvastatin) even though both of simvastatin and pravastatin could activate mevalonate pathways, suggesting the statin-mediated antiproliferative effects depended on non-mevalonate pathway. Indeed, statin induced p27(KIP1) expression by downregulation of histone methyltransferase enhancer of zeste homolog 2 (EZH2), which acts as an epigenetic gene silencer. Additionally, the use of simvastatin plus classII histone deacetylase (HDAC) inhibitor (MC1568) induced further overexpression of p27(KIP1) by inhibiting HDAC5 induction originated from downregulated EZH2 in CRC cells and synergistically led to considerable antiproliferative effects. In the clinical setting, Statin intake (except pravastatin) displayed the downregulated EZH2 expression and inversely upregulated p27(KIP1) expression in the resected CRC by immunohistochemical staining and resulted in the significantly better prognoses both in overall survival (p = 0.02) and disease free survival (p < 0.01) compared to patients without statin intake. Statins may inhibit tumor progression via an EZH2-mediated epigenetic alteration, which results in survival benefits after resected CRC. Furthermore, statin plus classII HDAC inhibitor could be a novel anticancer therapy by their synergistic effects in CRC. PMID- 24346864 TI - Enema use among men who have sex with men: a behavioral epidemiologic study with implications for HIV/STI prevention. AB - Enema use or douching is a risk factor for HIV/STI in men who have sex with men (MSM). However, few studies have explored enema use practices. We examined the frequency of enema use, type of products used, and reasons to use and not to use before and after receptive anal sex in a large sample of MSM (N = 4,992) recruited from 16 U.S. cities. Through online surveys, we examined personal, behavioral, and environmental factors associated with enema use. Most (52 %) participants reported having douched at least once and 35 % reported douching within the last 3 months. While most (88 %) reported enema use before receptive anal sex, 28 % douched after receptive anal sex. Most participants (65 %) used water to douche, 24 % added salt, soap, and/or antibacterial products to water, and 30 % reported using commercially available products. Being a man of color, HIV-positive, diagnosed with an STI, identifying as "versatile" in sex, and having more than two unprotected sex partners were significantly associated with recent enema use. Douching behavior appears closely associated with HIV/STI risk. Douching with water may be a concern since it may increase HIV/STI infection by damaging the epithelium. Development and promotion of a non-damaging, non-water based enema specifically for use in anal sex are recommended. In addition, the seemingly contradictory recommendations that water-based lubricant is recommended for anal sex but water-based enemas are dangerous need to be reconciled into a single consistent message. PMID- 24346865 TI - Self-reported impulsivity, rather than sociosexuality, predicts women's preferences for masculine features in male faces. AB - Previous research has suggested that an individual's sociosexual orientation (i.e., their willingness to engage in sexual behavior outside of long-term relationships) may influence the qualities they find attractive in a potential mate. Results, however, have not been consistent and, moreover, studies have tended to draw from specific social groups. Here, we tested the relationship between sociosexuality and female's preferences for masculinity in male faces, using a diverse population. We furthermore investigated impulsivity alongside sociosexuality, as this trait has been suggested as a "root" cause of variation in sexual behavior (Cross, 2010) and thus may better explain variation in mate choice. Results showed a significant association between increases in both sociosexuality and two subcomponents of impulsivity and greater preferences for masculine male features. Regression analysis suggested that a subcomponent of impulsivity, namely lack of planning, was the primary determinant of preferences. We discuss the implications these results have for our understanding of female attraction to masculine features. PMID- 24346866 TI - The faking orgasm scale for women: psychometric properties. AB - The Faking Orgasm Scale for Women (FOS) was designed to assess women's self reported motives for faking orgasm during oral sex and sexual intercourse. Exploratory factor analysis (EFA) was conducted on the responses of 481 heterosexual undergraduate females (M age = 20.33 years, SD = 2.48). Results of the EFA revealed that the FOS-Sexual Intercourse Subscale was composed of four factors: (1) Altruistic Deceit, faking orgasm out of concern for a partner's feelings; (2) Fear and Insecurity, faking orgasm to avoid negative emotions associated with the sexual experience; (3) Elevated Arousal, a woman's attempt to increase her own arousal through faking orgasm; and (4) Sexual Adjournment, faking orgasm to end sex. The analysis of the FOS-Oral Sex Subscale yielded four factors: (1) Altruistic Deceit; (2) Insecure Avoidance, faking orgasm to avoid feelings of insecurity; (3) Elevated Arousal; and (4) Fear of Dysfunction, faking orgasm to cope with concerns of being abnormal. Each factor of the two subscales was found to have excellent internal consistency. Confirmatory factor analysis on a separate sample of 398 heterosexual female undergraduates (M age = 20.52 years, SD = 2.55) confirmed the factor structure of each subscale with excellent fit statistics. The FOS should allow researchers and clinicians to better understand why women fake orgasm. Deepening this understanding may serve future research examining sexual desire, satisfaction, and dysfunction as well as have applications in sex and couples' therapy. PMID- 24346867 TI - Extradyadic involvement and relationship dissolution in heterosexual women university students. AB - This study examined the role of extradyadic involvement (EDI) in heterosexual dating relationships among young adult females (N = 539). A considerable percentage of participants (36 %) reported that they had engaged in an extradyadic emotional or sexual relationship within the last 2 months. Results from logistic regression analyses supported the general hypothesis that emotional and sexual EDI were both significantly associated with relationship dissolution. These associations remained strong even after controlling for participants' age, relationship duration, and relationship quality. The findings also showed that the strength of the association between acts of emotional or sexual extradyadic behaviors and relationship dissolution was linked to relationship quality, gender of the actor, and type of EDI (emotional vs. sexual). Specifically, compared to participants who reported poor relationship quality, those who reported high relationship quality were more likely to end the partnership if they reported emotional or sexual EDI. Findings suggest that individuals in higher quality relationships appear to have considerably more to lose in their relationship when emotional or sexual EDI occurs. This, in part, may be because the more satisfactory the relationship the more disillusionment one may feel when betrayed by their romantic partner. Overall, the present findings underscore the multifaceted nature of the relationships between EDI and relationship dissolution. We call for more research that rigorously examines what contextual factors influence young adults in dating relationships to dissolve relationships following EDI. PMID- 24346868 TI - A case of paraneoplastic pemphigus associated with Castleman's disease. AB - We present a case of PNP associated with Castleman's Disease. We have also reviewed the literature and described the characteristics of the two associated diseases. Gene clonal rearrangement was done to help diagnosis. We used, in addition, stereotactic radiosurgery which, as far as we know, has never before been employed to treat PNP associated with Castleman's Disease. This produced a good response, suggesting that it might be a good alternative treatment for PNP associated with Castleman's Disease when it is too difficult to operate. PMID- 24346869 TI - Clinical and surgical therapeutic approach in erithema elevatum diutinum--case report. AB - Erythema elevatum diutinum is a rare chronic cutaneous vasculitis which usually affects adults. It is characterized by symmetrical and persistent papules, plaques, and nodules. These lesions are usually located on the extensor surfaces of the extremities. We report a case of erythema elevatum diutinum in which the association of dapsone and surgical excision promoted complete remission of skin lesions, providing a new approach to the treatments described in the literature. PMID- 24346870 TI - Extra ocular sebaceous adenocarcinoma in HIV-positive patient--case report. AB - Sebaceous adenocarcinoma is a rare adnexal tumor that can affect the skin and is divided into ocular, a more common form and extra ocular, of a rarer occurrence. We report the case of a patient diagnosed with Acquired Immune Deficiency Syndrome (AIDS) who developed an extra ocular, bulky and fast-growing sebaceous adenocarcinoma on the face. The literature has suggested that transplanted patients and HIV-positive patients have an excess risk for developing adnexal tumors, including sebaceous adenocarcinoma. PMID- 24346871 TI - Biological agents: investigation into leprosy and other infectious diseases before indication. AB - Biological agents are widely used for various immune-mediated diseases, with remarkable effectiveness in the treatment of rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease. However, attention needs to be drawn to the adverse effects of these therapies and the risk of reactivating underlying granulomatous infectious diseases such as tuberculosis, leprosy, syphilis, leishmaniasis, among others. The objective of this paper is to describe a case of leprosy in a patient with RA using anti-TNF alfa, demonstrating the need for systematic investigation of skin lesions suggestive of leprosy in patients who require rheumatoid arthritis therapeutic treatment, especially in endemic regions like Brazil. PMID- 24346872 TI - Exacerbation of recalcitrant cutaneous sarcoidosis with adalimumab--a paradoxical effect? A case report. AB - The paradoxical adverse effects of tumor necrosis factor-alpha (TNF-alpha) antagonists have been described frequently as a result of the widespread use of these drugs. Among the TNF-alpha blocking agents, few reports exist relating the use of adalimumab in cutaneous sarcoidosis, although all of them show good results. More recently, sarcoidosis onsets have been reported with various TNF alpha inhibitors. The current case is, to our knowledge, the first to describe the exacerbation of cutaneous lesions of sarcoidosis treated with adalimumab. PMID- 24346873 TI - Psoriatic scarring alopecia. AB - Psoriasis is a relatively frequent inflammatory dermatosis. Scarring alopecia due to scalp psoriasis was first reported in 1972, but few reports have been written since then, showing that this is a very rare complication of a common disorder. We report a young Brazilian woman with longstanding scalp psoriasis, which progressed to scaring alopecia. PMID- 24346874 TI - Primary systemic amyloidosis, acquired cutis laxa and cutaneous mucinosis in a patient with multiple myeloma. AB - A 57-year-old woman presented with periorbital ecchymoses, laxity in skin folds, polyneuropathy and bilateral carpal tunnel syndrome. A skin biopsy of the axillary lesion demonstrated fragmentation of elastic fibers, but with a negative von Kossa stain, consistent with cutis laxa. The diagnosis of primary systemic amyloidosis was made by the presence of amyloid material in the eyelid using histopathological techniques, besides this, the patient was also diagnosed with purpura, polyneuropathy, bilateral carpal tunnel syndrome and monoclonal gammopathy. She was diagnosed as suffering from multiple myeloma based on the finding of 40% plasma cells in the bone marrow, component M in the urine and anemia. The patient developed blisters with a clear content, confirmed as mucinosis by the histopathological exam. The final diagnoses were: primary systemic amyloidosis, acquired cutis laxa and mucinosis, all related to multiple myeloma. PMID- 24346875 TI - Analysis of mutations in the PIK3CA and FGFR3 genes in verrucous epidermal nevus. AB - Verrucous epidermal nevi are congenital hamartomas composed of keratinocytes and may occur alone or in association with developmental abnormalities. A close relationship between variations in the PIK3CA and FGFR3 genes and the appearance of nevi has been recently reported. Based on that, we performed molecular assays for the identification of E542K, E545G/K and H1047R mutations in the PIK3CA gene and of the R248C mutation in the FGFR3 gene. Interestingly, during the amplification process, we did not observe the PCR product of exon 9 of the PIK3CA gene, a region comprising amino acids 542-545. This strongly suggests the occurrence of a microdeletion of that region and indicates a possible allelic variant, which has not yet being described in the literature. PMID- 24346876 TI - Acral pseudolymphomatous angiokeratoma: case report and literature review. AB - The authors describe a case of a female patient with Acral Pseudolymphomatous Angiokeratoma of Children, known as APACHE. It is a rare benign cutaneous disease, of unknown etiology, characterized by multiple, asymptomatic erythematous-violaceous papules and nodules, usually located unilaterally with acral distribution. Today, this denomination is questionable, since there are published reports of this disease in adults and in different locations. Clinically, it is similar to an angiokeratoma, whereas hystologically, it corresponds to a distinct type of pseudolymphoma. The immunohistochemical study is required to distinguish APACHE from cutaneous lymphoma. PMID- 24346877 TI - Calciphylaxis: a rare but potentially fatal event of chronic kidney disease. Case report. AB - Calciphylaxis or calcific uremic arteriolopathy is a rare cutaneous-systemic disease occurring in patients with advanced chronic kidney disease. The classical clinical picture is that of a necrotic and progressive skin ulcer of reticular pattern, mostly in the lower legs and susceptible to local infection. It is a product of mural calcification and occlusion of cutaneous and sub-cutaneous arteries and arterioles. The authors report the case of a 73-year-old male patient in his late stage of renal disease presenting severe necrotic cutaneous ulcers on lower legs followed by local and systemic infection and death due to sepse after parathyroidectomy. PMID- 24346878 TI - Inguinal ulcerated sebaceous carcinoma: an unusual presentation. AB - Sebaceous carcinoma is a rare and aggressive skin tumor. It can be located in any area of the body, the most commonly involved area being the periorbital region. It does not entail a typical clinical presentation, which explains the often late diagnosis. The aim of this report is to outline the rarity of the disease and its atypical clinical description, since to this day, inguinal ulcers with clinical manifestation have not been reported. We present and discuss a case of sebaceous carcinoma with an unusual clinical presentation, in an elderly male patient. The precise approach to genital ulcers, as shown in this case, is a diagnostic challenge that requires a great deal of effort on the part of the clinician. PMID- 24346879 TI - Cowden Syndrome: report of a case and brief review of literature. AB - We present the case of a female patient with facial cutaneous lesions, a cobblestone-like pattern of the oral mucosa, and verruciform lesions on the hand since her youth. She reported a history of breast cancer, endometrial cancer, melanoma and multiple benign tumors and cysts. PTEN gene analysis was performed and confirmed Cowden Syndrome, a rare genodermatosis with an autosomal dominant pattern of inheritance, characterized by multiple hamartomas. The phosphatase and tensin homolog (PTEN) gene negatively regulates cell proliferation and cell cycle progression. Loss of PTEN function contributes to an increased risk of cancer. We emphasize the importance of early detection and accurate management of Cowden Syndrome. PMID- 24346880 TI - Cutaneous metastasis of colon adenocarcinoma: case report and review of the literature. AB - Skin metastases from colorectal carcinoma are rare and signal advanced disease. We present a case of an 80-year-old male with a large skin metastatic focus in the lower abdomen, a year after resection of a colonic adenocarcinoma. The patient had already finished receiving his first cycle of chemotherapy shortly before the discovery of the abdominal nodules and at the same period a chest X ray, revealed shadows at the base of the right lung. PMID- 24346881 TI - Carcinomatous degeneration of pilonidal cyst with sacrum destruction and invasion of the rectum. AB - Malignant degeneration of pilonidal cysts is rare. The most common histologic type is the squamous cell carcinoma, triggered by the chronic inflammatory process. The growth of the lesion is typically slow. The diagnosis must be early and the appropriate treatment is ample surgical resection, including the presacral fascia. In some cases, as the present one, the diagnosis is made at a stage when the disease has progressed and invaded adjacent structures. In these cases the surgery involves multiple organ resection. We report the case of a patient with carcinomatous degeneration of pilonidal cyst, with bulky disease that extended up to the wall of the rectum. The treatment was extended resection, sacrectomy and abominoperineal resection of the rectosigmoid with permanent colostomy. PMID- 24346882 TI - Congenital multiple clustered dermatofibroma and multiple eruptive dermatofibromas--unusual presentations of a common entity. AB - Dermatofibroma is one of the most common entities seen in dermatology clinical practice. Several clinical subtypes have nevertheless been described, all of them of uncommon occurrence. The authors present two rare clinical variants of dermatofibromas: congenital multiple clustered dermatofibroma (the presented case is the 4th congenital case to be reported so far) and multiple eruptive dermatofibromas developing in the setting of a Sjogren's syndrome. Since the uncommon subtypes may not be clinically evident, dermatologists should familiarize themselves with their main features and we advise a high level of clinical suspicion in order to reach the correct diagnosis. PMID- 24346883 TI - Linear IgA bullous dermatosis: report of an exuberant case. AB - Linear immunoglobulin A dermatosis is a rare autoimmune bullous disease, but the most common autoimmune bullous dermatosis in children. We report a typical exuberant case of linear IgA dermatosis in a ten-month old child, who showed good response to treatment with corticosteroids and dapsone. PMID- 24346884 TI - Vulvoperineal Crohn's disease responsive to metronidazole. AB - Crohn's disease is a multisystem chronic granulomatous inflammatory disease that primarily affects the gastrointestinal tract. In the majority of the cases, the cutaneous manifestations follow the intestinal disease, but occasionally dermatological lesions are the inaugural event and may constitute the only sign of the disease. Vulvoperineal involvement is rare, may precede bowel symptoms by months to years and may go unrecognized. Due to the paucity of reports of Crohn's disease at this location and in the absence of randomized trials, there are no standard treatments for the cutaneous disease. We describe the case of a 47 year old woman with vulvoperineal Crohn's disease without digestive involvement, that was successfully managed with metronidazole. PMID- 24346885 TI - Systemic sclerosis with keloidal nodules. AB - Nodular sclerosis is a rare form of presentation related to both systemic and localized forms of scleroderma. We describe the case of a patient with nodular sclerosis in order to alert the medical community to recognize this entity. PMID- 24346886 TI - Diffuse systemic sclerosis with bullous lesions without systemic manifestations. AB - Here, we describe an atypical case of systemic sclerosis in its diffuse cutaneous form with acute and rapid progression of the cutaneous condition, without any systemic manifestations and the infrequent formation of bullae, showing the importance of diagnosis and early treatment in such cases. This case also shows that special measures should be taken for bullous cutaneous lesions and ulcerations resulting from serious sclerosis, which are entry points and increase morbidity and risk of death. Other prognostic factors include age, ESR and renal and pulmonary involvement. Capillaroscopies can be useful predictors of greater severity of systemic scleroderma, revealing a greater link with systemic, rather than cutaneous, involvement. PMID- 24346887 TI - Eumycetoma by Madurella mycetomatis with 30 years of evolution: therapeutic challenge. AB - We report a case of eumycetoma by Madurella mycetomatis on the buttocks and thighs in an adult immunocompetent patient, diagnosed after 30 years of clinical development. He was treated over four years with fluconazol and itraconazol associated with five times surgical excisions of subcutaneous nodules. At the eighth year of follow-up, one nodule recurred on the right infragluteal region, which was excised surgically and has remained asymptomatic ever since. PMID- 24346888 TI - Phacomatosis pigmentovascularis type IIa--case report. AB - Phacomatosis Pigmentovascularis is a rare syndrome characterized by capillary malformation and pigmentary nevus. A case of a 2-year-old patient is reported, who presented extensive nevus flammeus and an aberrant Mongolian spot, without systemic disease, manifestations that allow us to classify this case as type IIa Phacomatosis Pigmentovascularis, according to Hasegawa's classification. PMID- 24346889 TI - Nodular fasciitis on the zygomatic region: a rare presentation. AB - Nodular fasciitis is a benign tumor, resulting from reactive proliferation composed of fibroblastic/myofibroblastic cells. Due to its rapid growth and high cellularity it may be mistaken for sarcoma. Despite the possibility of spontaneous regression, excision is the treatment of choice. A 24-year-old female patient presented with a nodule on the zygomatic region with 3 months of evolution. Excisional biopsy was performed. Histopathological examination associated with immunohistochemical markers HHF35, AML and Ki-67 allowed diagnostic confirmation. The main relevance of the case presented is its rare location, suggesting its inclusion among the differential diagnoses of tumor lesions on the face. PMID- 24346890 TI - Lucio's phenomenon. Case study of an exceptional response to treatment exclusively with multibacillary multidrug therapy. AB - Lucio's phenomenon represents a serious cutaneous necrotizing reaction, which can occur with Lucio's leprosy and also in other forms of lepromatous leprosy. The authors discuss the case of a 63-year-old male patient presenting with ulcers and necrotic cutaneous lesions on the limbs, torso and face, associated with recurring sinusitis, hoarseness and a weight loss of 25 kilos over the last year. Bacilloscopy of intradermal scrapings showed a bacilloscopic index of 5 and the histopathological findings were compatible with the diagnosis of Lucio's phenomenon. The chosen treatment was exclusively multibacillary multidrug therapy, resulting in important dermatological improvement after one month of therapy. The authors present an impressive case of Lucio's phenomenon with an exceptional response to treatment exclusively with multibacillary multidrug therapy. PMID- 24346891 TI - Granuloma faciale: a rare disease from a dermoscopy perspective. AB - The granuloma faciale is a rare and benign skin disease of unknown etiology, characterized by chronic leukocitoclastic vasculitis. It is characterized by skin lesions predominantly facial whose course is chronic and slowly progressive. The diagnosis is based on clinical features, histopathology and, more recently, in dermoscopy. We describe the case of a male patient, 40 years old, with a sarcoid lesion on the malar site, whose histopathological examination revealed a mixed inflammatory infiltrate with presence of Grenz zone. Dermoscopy revealed a pink background with white striations. The definitive diagnosis is made by histopathologic evaluation, and dermatoscopy can be helpful. It is known to be resistant to therapy, oral medications, intralesional and surgical procedures are options. PMID- 24346892 TI - Perforating granuloma annulare mimicking papulonecrotic tuberculid. AB - A case is reported of a patient presenting lymph node tuberculosis and cutaneous lesions resembling papulonecrotic tuberculid, but histologically compatible with perforating granuloma annulare and which responded satisfactorily to antituberculous therapy. This is probably one of the first reports of the association of perforating granuloma annulare and tuberculosis, and it is important therefore to highlight the relevance of this disorder in the differential diagnosis of papulonecrotic tuberculid and to raise the hypothesis that this entity should also be considered to be a variant of tuberculid. PMID- 24346893 TI - Indeterminate leprosy and lepromatous index case: four cases in the same family. AB - Leprosy is a chronic infectious disease caused by Mycobacterium leprae, which primarily affects the skin and peripheral nerves. Brazil remains as the country with the second largest number of cases in the world. We report the case of three patients diagnosed with indeterminate leprosy in the same family. Two patients were HIV positive. An active search led to the discovery of the index case. It was crucial to persist in the search of the index case. This report shows how important it is to teach physicians and the general population about the signs and symptoms of leprosy. Early diagnosis and treatment are necessary to prevent sequelae and to eliminate the disease as a public health problem. PMID- 24346894 TI - Borderline tuberculoid leprosy and type 1 leprosy reaction in a hepatitis C patient during treatment with interferon and ribavirin. AB - Hepatitis C is an inflammatory disease of the liver caused by a single-stranded RNA virus belonging to the Hepacivirus genus in the Flaviviridae family, called the hepatitis C virus. After initial infection, 70% to 85% of the patients develop chronic hepatitis C with hepatic fibrosis. In addition to specific liver changes, various extrahepatic manifestations have been associated with the hepatitis C virus infection or with medications used to treat the condition. We report the case of a patient with chronic hepatitis C who presented with the signs and symptoms of borderline tuberculoid leprosy and type 1 reaction four months after the start of treatment with a pegylated interferon/ribavirin combination. PMID- 24346895 TI - Tufted angioma in ear auricle: importance of the differential diagnosis. AB - Tufted angioma is an acquired vascular proliferation with specific histological characteristics. The most common clinical features are erythematous macules. It occurs predominantly in children and young adults, especially in the chest and neck. We report the case of a male patient, 12 years old, with an increased right ear auricle associated with erythematous macules and increased local temperature, referred with a diagnosis of lepromatous leprosy; however, this diagnosis was questioned. Histopathology was consistent with tufted angioma. PMID- 24346896 TI - Mosaic epidermolytic ichthyosis--case report. AB - Epidermolytic ichthyosis is a rare autosomal dominant disease that manifests at birth with fragile blisters and erosions that evolve into hyperkeratotic lesions associated or not with erythroderma. When the disease is associated with a mutation in cytokeratin 1, it may be related to hyperkeratosis of palms and soles, but this is not usually found when cytokeratin 10 is mutated. The disease can present in a mosaic form, due to post zygotic mutation of the gene involved, constituting an individual formed by two populations of genetically distinct cells - one carrier of the mutation and the other without it. We report a case of mosaic epidermolytic ichthyosis diagnosed in a female patient. PMID- 24346897 TI - Implantation of autologous fat globules in localized scleroderma and idiopathic lipoatrophy--report of five patients. AB - A large number of diseases may cause Atrophic skin disorders are caused by a large number of diseases, some of them idiopathic and others inflammatory, in which there is loss of volume of body segments. Localized scleroderma is a rare inflammatory dermatosis, manifested by atrophic skin and subcutaneous tissue alterations. Lipoatrophy may be genetically inherited or acquired as a result of panniculitis, HIV infections or aging. Many treatments have been proposed. Results vary in the acute inflammatory phase and are scarce when sclerosis and atrophy have already been established. This article describes four cases of localized facial scleroderma and one of facial idiopathic lipoatrophy treated with implantation of autologous fat globules extracted from the infragluteal groove, without utilization of cannula aspiration, with lasting results. PMID- 24346898 TI - Cutaneous leiomyomatosis in a mother and daughter. AB - A 34-year-old woman with no known medical history was evaluated for multiple painful brown nodules and papules on the anterior aspect of the trunk. She mentioned a history of similar cutaneous findings on her mother. Biopsies of three lesions revealed piloleiomyomata. Renal and adrenal ultrasound revealed an isolated simple cortical cyst, and pelvic and endovaginal ultrasound revealed two uterine myomata. The clinical diagnosis of hereditary leiomyomatosis and renal cell cancer was corroborated by the identification of a heterozygous variant on exon 5 of the fumarate hydratase gene (c.578C>T p.T193I). Identification of the tumor piloleiomyoma should alert the dermatologist to this rare genodermatosis, which is associated with an increased risk of renal cell tumors, demanding multidisciplinary follow-up, and personal and family counseling. PMID- 24346899 TI - Lymphocytoma cutis--case report. AB - We describe a clinical case involving a 62-year-old white male, diagnosed with lymphocytoma cutis (Spiegler-Fendt sarcoid) in the cephalic segment. The diagnosis was carried out by pathological study and confirmed by immunohistochemical panel: evidence of polyclonality. Phototherapy sessions were suggested as treatment (13 PUVA sessions, with an accumulated dose of 58.65 J/cm2 ). The improvement was partial. Thus, infiltration of triamcinolone was opted for (one intralesional infiltration every 3 weeks). After 5 sessions, satisfactory improvement was observed: regression of nearly all the lesions. PMID- 24346900 TI - Primary cutaneous anaplastic large-cell lymphoma--case report. AB - Primary cutaneous anaplastic large-cell lymphoma is part of the spectrum of CD30+ lymphoproliferative cutaneous processes, characterized by single or multifocal nodules that ulcerate, are autoregressive and recurrent. Extracutaneous dissemination may occur, especially to regional lymph nodes. Histology shows a diffuse, non-epidermotropic infiltrate , anaplastic large lymphoid cells of immunohistochemistry CD30+, CD4+, EMA-/+, ALK-, CD15- and TIA1-/+. Prognosis is good and does not depend on lymphatic invasion. Radiotherapy, removal of the lesion and/or low-dose methotrexate are the treatments of choice. The present study reports the case of a 57-year-old-woman presenting Primary cutaneous anaplastic large-cell lymphoma with multifocal lesions. The patient evolved with pulmonary involvement 7 years later. She showed a good response to the treatment with low-dose methotrexate prescribed weekly. PMID- 24346901 TI - Primary cutaneous centrofollicular lymphoma with a good response to radiotherapy. AB - Primary cutaneous lymphomas have different clinical behavior and prognosis than systemic lymphomas of similar histological subtype. About 30% of non-Hodgkin lymphomas involve extranodal tissues, the skin being the second most affected body organ after the gastrointestinal tract (approximately 18%). According to the EORTC (European Organization for Research and Treatment of Cancer) classification, the lymphoma centrofollicular is indolent, since the lesions increase in size slowly over the years and spread to extracutaneous sites is uncommon. Based on this, radiotherapy has been considered the treatment of choice by many studies. We present the case of a patient who had cutaneous centrofollicular scalp lymphoma for 1 year and showed good response to radiotherapy. PMID- 24346902 TI - Linear lichen planus in children--case report. AB - Lichen planus is an uncommon disease in children, and only 2 to 3% of affected patients are under twenty years of age. This dermatosis may appear in several clinical forms, which vary according to the morphology and distribution of lesions. In less than 0.2% of all lichen planus cases, the lesions are distributed along the lines of Blaschko, and is a variant called linear lichen planus. This is a case report of a patient aged two years and eight months, who presented keratotic violaceous papules, affecting the abdomen, buttocks and right thigh, distributed along the lines of Blaschko. Histopathological examination confirmed a diagnosis of linear lichen planus. PMID- 24346903 TI - Agminate lichen aureus. AB - Lichen aureus is a rare variant of pigmented purpura, with a chronic and benign course. It is generally asymptomatic and often occurs in the lower limbs, presenting as erythematous brownish, coppery or golden macules and/or papules. The diagnosis is based on clinical and histopathological findings. The dermatoscopic pattern has been considered a useful tool in diagnosis presumption. We describe a case with a confluent morphological pattern, called agminate lichen aureus. PMID- 24346904 TI - Lichen planus pigmentosus inversus. AB - Twenty-five year old male patient presenting with asymptomatic brown spots, on cervical, axillary, inguinal and popliteal regions, for the last nine months. Pathological examination showed hydropic degeneration of the basal layer, pigmentary incontinence and moderate inflammatory lymphocytic infiltrate in the dermis. Lichen planus pigmentosus inversus is a rare subtype of lichen planus characterized by hyperchromic, asymptomatic or mildly pruritic macules, measuring from millimeters to centimeters in diameter, with defined borders, affecting intertriginous areas, most commonly in the axillae and groin of Caucasian patients. It presents unique lichenoid histology. We report a case with typical clinical features, histology and evolution. PMID- 24346905 TI - Pyoderma gangrenosum with renal and splenic impairment--case report. AB - Pyoderma gangrenosum is an uncommon and recurrent neutrophilic dermatosis of unknown cause. The lesions usually start as tender sterile papulopustules or erythematous nodules that undergo necrosis followed by ulceration. The lower limbs are most commonly affected and around half of the cases are associated with systemic disorders. Although rare, cases of pyoderma gangrenosum with extramucocutaneous sterile neutrophilic infiltrate have been reported, with the lungs being the most commonly affected organ. We report a case of pyoderma gangrenosum with splenic and renal impairment. Pyoderma gangrenosum should be considered a multisystemic disease with classic cutaneous manifestations and potential involvement of internal organs. PMID- 24346906 TI - Subcutaneous fat necrosis of the newborn: clinical manifestations in two cases. AB - Subcutaneous fat necrosis of the newborn is an unusual form of panniculitis, with few cases described in medical literature. The disease affects newborns at term or post-term, with normal general health. We describe two cases of newborns affected by the disease. One of them already had lesions since birth. Also, we discuss the use of puncture for diagnostic assistance. PMID- 24346907 TI - Blastic plasmacytoid dendritic cell neoplasm. AB - Blastic plasmacytoid dendritic cell neoplasm is a rare and aggressive hematodermic neoplasia with frequent cutaneous involvement and leukemic dissemination. We report the case of a 76-year-old man with a 2 month history of violaceous nodules and a tumor with stony consistency, located on the head, and mandibular, cervical and supraclavicular lymphadenopathies. Multiple thoracic and abdominal adenopathies were identified on computerized tomography. Flow cytometry analysis of the skin, lymph node and bone marrow biopsies demonstrated the presence of plasmocytoid dendritic cell neoplastic precursor cells (CD4+, CD45+, CD56+ and CD123+ phenotype). After initial clinical and laboratorial complete remission with chemotherapy, the patient died due to relapse of the disease associated with the appearance of a cervical mass with medullary compromise. PMID- 24346908 TI - Optic neuritis due to immunobiologics: first Brazilian case report. AB - The change in immunological response obtained by immunobiologics has brought a new paradigm to the treatment of immune-mediated disorders. As a result of their efficacy, there is a positive impact on the quality of life of patients. However, severe side effects, such as demyelination of cerebral or peripheral nerves, have been reported. After review of literature using PubMed and MEDLINE data from 2000 to 2012, we identified the cases correlating the biological uniterms and optic neuritis. This article reports the first Brazilian optic neuritis case associated with the use of immunobiologics. This publication is justified by the rarity of the disease and atypical therapeutical evolution. PMID- 24346909 TI - Diffuse neurofibroma--an uncommon cause of alopecia. AB - Although infrequent, alopecia can be caused by benign cutaneous tumours. Neurofibromas are common benign tumors that originate in the peripheral nerve sheath. Diffuse neurofibroma is a rare variant of neurofibroma that is thought to occur mainly in the head and neck of children and young adults. Histology generally shows an infiltrative tumor, composed of spindle cells in the dermis and subcutaneous tissue. Despite being rare, malignant transformation has been reported. The association between diffuse neurofibromas and neurofibromatosis type 1 still remains to be determined since some authors question the low incidence usually described. We report the case of a 42-year-old man who had a diffuse neurofibroma on the scalp presenting as alopecic plaques. PMID- 24346910 TI - Congenital agminated melanocytic nevus--case report. AB - Agminated nevus is a cluster group of melanocytic nevi confined to a localized area of the body. There are many pigmented lesions described in the literature as agminated, such as blue nevi, multiple lentigines and Spitz nevi, but only a few cases of congenital agminated melanocytic nevi have been described. We report a case of a male child who presented with congenital agminated nevi, emphasizing the importance of physical examination, dermoscopy, histopathological evaluation, differential diagnosis and follow up to rule out the possibility of dysplastic or malignant changes. PMID- 24346911 TI - Pyoderma gangrenosum in a newborn--case report. AB - Pyoderma gangrenosum is a rare, inflammatory, chronic and recurrent disease of unknown etiology, characterized by noninfectious, necrotizing and painful cutaneous ulcers. Usually it affects adults aged between 25 and 54 years old and rarely children (less than 4%), in which it mainly affects the head, face, buttocks, genital and perianal region. The disease presents a quick response to systemic corticosteroids. We report a case of a newborn with hemorrhagic and necrotic ulcers, distributed in the abdomen, buttocks and genital region with rapid and effective response to oral prednisone. PMID- 24346912 TI - Pyoderma gangrenosum: skin grafting and hyperbaric oxygen as adjuvants in the treatment of a deep and extensive ulcer. AB - Pyoderma gangrenosum is a rare dermatosis of unknown etiology and variable clinical presentation. The disease is challenging for the medical staff, from the frequent diagnostic difficulties to the lack of scientific evidence with a good level to support the management of extensive and refractory cases. Our patient is a 50 year-old man with an extensive and deep ulcer on the left leg, which exemplifies the therapeutic difficulties inherent to the disease and who, fortunately, has progressed with excellent result after association of hyperbaric oxygen therapy and skin grafting to the immunosuppression therapy initially proposed. PMID- 24346913 TI - Porokeratosis of Mibelli--literature review and a case report. AB - Porokeratosis is a disorder of epidermal keratinization characterized by annular plaques with an atrophic center and hyperkeratotic edges, and includes a heterogeneous group of disorders that are mostly inherited in an autosomal dominant form. This report describes a 5 year-old female patient, with porokeratosis of Mibelli confirmed histopathologically. The rarity of this disorder, its clinical exuberance and the destructive character of the lesions, as well as the facial and mucosal involvements, unusual in this form of porokeratosis, and also its onset in early childhood motivated this report. PMID- 24346914 TI - Cutaneous protothecosis--case report. AB - Cutaneous protothecosis is a rare infection caused by achlorophyllic algae of the genus Prototheca. The lesions usually occur on exposed areas, related with trauma, in immunocompromised patients. The most common clinical presentation is a vesicobullous and ulcerative lesion with pustules and scabs, simulating bacterial, fungal or herpetic infections or eczema. The diagnosis is determined by agent identification through histopathology, culture and the carbohydrates assimilation test. The finding of morula-like spherules is characteristic of Prototheca sp. Its rarity and non-specific clinical aspect may difficult the disease diagnosis. We report a case of a diabetic patient, in chronic use of systemic corticosteroids, that developed a skin lesion after trauma to the right leg. PMID- 24346915 TI - Pustular psoriasis of pregnancy (impetigo herpetiformis)--case report. AB - Impetigo herpetiformis is a rare dermatosis of pregnancy with typical onset during the last trimester of pregnancy and rapid resolution in the postpartum period. Clinically and histologically, it is consistent with pustular psoriasis. This similarity has led some authors to name the disease "the pustular psoriasis of pregnancy". We report the case of a patient who developed impetigo herpetiformis in two successive pregnancies. PMID- 24346916 TI - Epidermodysplasia verruciformis in a young man with HIV since birth--case report. AB - Epidermodysplasia Verruciformis is a genodermatosis characterized by susceptibility to infection by specific HPV types (HPV 3/10 and beta-HPVs). It is considered to be the first model in human carcinogenesis induced by HPV. In this report we present a rare case of Epidermodysplasia Verruciformis associated with vertical transmission of HIV. Although most patients with HIV present infections by HPV virus, the frequency of Epidermodysplasia Verruciformis is no greater in patients with HIV because in EV there is a deficiency of specific cellular immunity to infection by some types of HPV, called HPV-related Epidermodysplasia Verruciformis. PMID- 24346917 TI - Sacroiliitis after use of oral isotretinoin--association with acne fulminans or adverse effect? AB - Acne fulminans is a rare and severe form of acne that may evolve from acne vulgaris, especially in male adolescents, or occur as an adverse effect of oral isotretinoin. Arthritis is a serious clinical manifestation when the musculoskeletal system is compromised by AF and has been reported as a rare adverse effect of isotretinoin. Involvement of the sacroiliac joints occurs in 21% of acne fulminans cases. We present the case of a 18-year-old male patient in whom acne fulminans evolved from acne vulgaris grade IV and after inflammation resolution started treatment with oral isotretinoin. Within a 30-day period of retinoid treatment he presented with back pain followed by rapid, progressive inability to deambulate. PMID- 24346918 TI - Systemic sarcoidosis induced by etanercept: first Brazilian case report. AB - The antagonists of tumor necrosis factor alpha (TNF-alpha) are increasingly being used in the treatment of inflammatory and autoimmune diseases. Several adverse effects of these drugs have been reported, including the paradoxical development of sarcoidosis, especially with the use of etanercept. We present the first Brazilian case report of systemic sarcoidosis induced by etanercept and a literature review. PMID- 24346919 TI - Classic Kaposi's sarcoma treated with elastic stockings and outpatient follow-up of a 90-year-old patient. AB - Kaposi's sarcoma is a multifactorial angioproliferative disorder. The herpes virus 8 human contributes to its pathogenesis, but it is uncertain whether these lesions are only reactive hyperplasia to the virus or neoplasia. Four clinical types are described: classic, endemic, iatrogenic and HIV-associated. Classic Kaposi's sarcoma has no standard staging or treatment protocols. Some studies have shown the use of compression stockings in the treatment of lymphedema associated with Kaposi's sarcoma. We report the case of a 90 year-old patient with classic Kaposi's sarcoma treated with compression stockings who showed a satisfactory response. PMID- 24346920 TI - Birt-Hogg-Dube syndrome. AB - A 45-year-old woman with a history of renal carcinoma was observed for facial, cervical and truncal flesh-colored papules. Relatives had similar skin findings and a brother had repeated episodes of pneumothorax. The computerized tomography scan revealed multiple cysts on both lungs. A skin biopsy revealed a perifollicular fibroma. The clinical diagnosis of Birt-Hogg-Dube syndrome (BHDS) was corroborated by identification of a novel frameshift c.573delGAinsT (p.G191fsX31) mutation in heterozygosity on exon 6 of the folliculin gene. The presence of multiple and typical benign hair follicle tumors highlights the role of the dermatologist in the diagnosis of this rare genodermatosis that is associated with an increased risk of renal cell cancer and pulmonary cysts, warranting personal and familial follow-up and counseling. PMID- 24346921 TI - Vohwinkel syndrome, ichthyosiform variant--by Camisa--case report. AB - Vohwinkel syndrome or keratoderma hereditaria mutilans is a rare autosomal dominant palmoplantar keratosis, which manifests in infants and becomes more evident in adulthood. Its mode of inheritance is autosomal dominant with mutation in loricrin and Connexin 26 genes. Patients with this mutation present hyperkeratosis of the palms and soles, constricting bands of the digits, usually on the fifth, and starfish-shaped hyperkeratosis on the dorsal aspects of the hands and feet. The disease mostly occurs in white women, where constricting fibrous bands appear on the digits and can lead to progressive strangulation and auto-amputation (pseudo-ain-hum).The authors report a rare case of a patient with a clinical ichthyosiform variant of Vohwinkel syndrome. PMID- 24346922 TI - Bazex syndrome. AB - Acrokeratosis Paraneoplastica or Bazex syndrome is a dermatologic manifestation usually associated with the diagnosis of squamous cell carcinoma of the upper aerodigestive tract. We report a case with exuberant clinical manifestations, exemplifying the typical cutaneous lesions in this rare syndrome, in a patient with squamous cell carcinoma of the esophagus. PMID- 24346923 TI - Sporadic Kindler syndrome with a novel mutation. AB - We report the case of a 28-year-old woman with Kindler syndrome, a rare form of epidermolysis bullosa. Clinically, since childhood, she had widespread pigmentary changes in her skin as well as photosensitivity and fragility of the skin and mucous membranes. The mucosal involvement led to an erosive stomatitis as well as esophageal, anal and vaginal stenoses, requiring surgical intervention. The diagnosis of Kindler syndrome was confirmed by DNA sequencing with compound heterozygosity for a nonsense/frameshift combination of mutations (p.Arg110X; p.Ala289GlyfsX7) in the FERMT1 gene. PMID- 24346924 TI - Allogeneic hematopoietic stem cell transplantation in mycosis fungoides. AB - Mycosis Fungoides is typically an indolent disease in early stages. However, approximately 30% of patients have advanced staged disease at presentation and 20% will develop it at some time. These patients have a poorer prognosis with a median survival of 2-4 years. The only curative option for mycosis fungoides may be hematopoietic allogeneic stem cell transplantation. We report the case of a patient with mycosis fungoides in an advanced stage (IIB), refractory to treatment options. She underwent allogeneic hematopoietic stem-cell transplantation (allo-HSCT). The patient remains in complete remission nineteen months after allo-HSCT. Allogeneic transplantation can alter the natural history of mycosis fungoides and should be considered in patients who have refractory disease or short-lived responses with standard therapies. PMID- 24346925 TI - Propranolol for treatment of infantile hemangiomas. AB - Infantile hemangioma is the most common vascular tumor in early childhood. Propranolol has been successfully used recently in a limited number of children with Infantile hemangioma. We present 6 cases of Infantile hemangioma, at a single dermatological center, which responded to oral propranolol with good results. PMID- 24346926 TI - Use of the bilobed flap in the pubic region after tumoral lesion excision. AB - Reconstruction of surgical defects in the pubic region is a challenge to any surgeon. Our goal was to demonstrate the use of the bilobed flap to reconstruct the pubic region skin after the excision of a recurrent HPV lesion, resistant to conventional treatments. In spite of its classical use in nasal reconstructions, the bilobed flap has applications in extranasal defects, with excellent functional and aesthetic results. PMID- 24346927 TI - Livedoid vasculopathy associated with peripheral neuropathy: a report of two cases. AB - Livedoid vasculopathy (LV) is a chronic and recurrent disease consisting of livedo reticularis and symmetric ulcerations, primarily located on the lower extremities, which heal slowly and leave an atrophic white scar ("atrophie blanche"). Neurological involvment is rare and presumed to be secondary to the ischemia from vascular thrombosis of the vasa nervorum. Laboratory evaluation is needed to exclude secondary causes such as hyper-coagulable states, autoimmune disorders and neoplasms. We present two patients with a rare association of peripheral neuropathy and LV, thereby highlighting the importance of a multidisciplinary approach to reach the correct diagnosis. PMID- 24346928 TI - A secure and efficient authentication and key agreement scheme based on ECC for telecare medicine information systems. AB - In the field of the Telecare Medicine Information System, recent researches have focused on consummating more convenient and secure healthcare delivery services for patients. In order to protect the sensitive information, various attempts such as access control have been proposed to safeguard patients' privacy in this system. However, these schemes suffered from some certain security defects and had costly consumption, which were not suitable for the telecare medicine information system. In this paper, based on the elliptic curve cryptography, we propose a secure and efficient two-factor mutual authentication and key agreement scheme to reduce the computational cost. Such a scheme enables to provide the patient anonymity by employing the dynamic identity. Compared with other related protocols, the security analysis and performance evaluation show that our scheme overcomes some well-known attacks and has a better performance in the telecare medicine information system. PMID- 24346929 TI - Smartphones and health promotion: a review of the evidence. AB - Communication via mobile phones has become an essential tool for health professionals. The latest generation of smartphones is comparable to computers, allowing the development of new applications in health field. This paper aims to describe the use of smartphones by health professionals and patients in the field of health promotion. We conducted a bibliographic search through Pubmed. Then, research results were analyzed critically in order to select the best experiences available. All searches were carried out on November 2012 and were not limited by date. Each item from the initial search was reviewed independently by members of the project team. Initial search returned 472 items with PubMed. After the removal of duplicates, 406 items were reviewed by all the members of the project team and 21 articles were identified as specifically centered on health promotion. In the nutrition field there are applications that allow to count calories and keep a food diary or more specific platforms for people with food allergies, while about physical activity many applications suggest exercises with measurement of sports statistics. Some applications deal with lifestyles suggestions and tips. Finally, some positive experiences are reported in the prevention of falls in elderly and of sexually-transmitted diseases. Smartphones are transforming the ways of communication but the lack of monitoring of contents, the digital divide, the confidentiality of data, the exclusion of the health professional from the management of patient, are the main risks related to their use. PMID- 24346930 TI - A collaboration tool based on SNOCAP-HET. AB - Health enabling technologies and ambient assisted living are important fields in biomedical informatics. In this context, a huge variety of analysis methods are applied. Neither is a suitable structuring of these methods available, nor is an aid known for selecting appropriate methods for a given set of data specifying a context and a problem. The goal of the present paper is to present a prototype of a semantic collaboration tool which is based on the Systematic Nomenclature for Contexts, Analysis Methods and Problems in Health-Enabling Technologies (SNOCAP HET). This tool can be seen as a first step towards an assistance system for decision support within SNOCAP-HET. We present aspects of the selection and modeling process of our tool and discuss its benefits and appealing tasks for further research. Moreover we present a number of already planned and some unspecified upcoming steps which should optimize SNOCAP-HET in the future. PMID- 24346931 TI - Smart environment as a service: three factor cloud based user authentication for telecare medical information system. AB - The Telecare Medical Information System (TMIS) provides a set of different medical services to the patient and medical practitioner. The patients and medical practitioners can easily connect to the services remotely from their own premises. There are several studies carried out to enhance and authenticate smartcard-based remote user authentication protocols for TMIS system. In this article, we propose a set of enhanced and authentic Three Factor (3FA) remote user authentication protocols utilizing a smartphone capability over a dynamic Cloud Computing (CC) environment. A user can access the TMIS services presented in the form of CC services using his smart device e.g. smartphone. Our framework transforms a smartphone to act as a unique and only identity required to access the TMIS system remotely. Methods, Protocols and Authentication techniques are proposed followed by security analysis and a performance analysis with the two recent authentication protocols proposed for the healthcare TMIS system. PMID- 24346932 TI - Systems, technology and the critical need for rigorous evaluation. PMID- 24346934 TI - 50 years ago ... PMID- 24346936 TI - Genomic imprinting--the struggle of the genders at the molecular level. AB - Genomic imprinting, the parent of origin-dependent expression of genes, has been discovered as a fascinating example of the control of gene expression by epigenetic processes in the human body. It affects about 100 genes, which are often involved in growth and development. In this Review, we discuss the mechanisms leading to the generation of gender-specific imprints in form of DNA methylation marks, their preservation during growth and development of the organism, and the processes that translate parental methylation marks into monoallelic gene expression. We discuss the gender-specific dimorphic nature of imprints from an evolutionary point of view and present the prevalent model that molecular imprinting mediates a conflict of interest between the parents that occurs in viviparous animals. Finally, we summarize the relevance of parental imprinting for human health. PMID- 24346937 TI - Unusual 14-electron fragments [Pd(eta(3) -Bi3-x Pbx )]((x+1)-) as pseudo lead atoms in closo-[Pd@Pd2 Pb10 Bi6 ](4-). AB - How to simplify a complex thing: A salt of the heaviest intermetalloid cluster known to date, [K([2.2.2]crypt)]4 [Pd@Pd2 Pb10 Bi6 ]?2 en, resulted from a reaction of [Pd(PPh3 )4 ] with [K([2.2.2]crypt)]2 (Pb2 Bi2 )?2 en in ethane-1,2 diamine (en). The electron number of the ternary intermetalloid anion accords with Wade-Mingos rules, as the [Pd(eta(3) -Bi3-x Pbx )]((x+1)-) (x=0, 1) 14 electron fragments formed in situ are isolobal with Pb atoms. PMID- 24346938 TI - Synthesis and biological evaluation of paleo-soraphens. AB - Synthesis can provide molecules such as paleo-soraphens A and B that are genetically encoded but not obtained from the natural source. Although it is unclear whether this is part of an evolutionary process or the consequence of the chemical synthesis, the biological evaluation of these genetically encoded natural products can shed light on how natural products are structurally optimized with respect to their biological profile. PMID- 24346939 TI - Asymmetric synthesis of pyrroloindolones by N-heterocyclic carbene catalyzed [2+3] annulation of alpha-chloroaldehydes with nitrovinylindoles. AB - NHC-enolate plus 3: N-heterocyclic carbenes (NHCs) serve as organocatalysts for the [2+3] annulation of nitrovinylindoles with alpha-chloroaldehydes via an intermediate azolium enolate. The method provides trans-disubstituted pyrroloindolones with good yields and excellent diastereo- and enantioselectivities. Further transformations lead to tetracyclic pyrrolo[1,2 a]indoles with potential psychotropic and other bioactivities. PMID- 24346940 TI - Three-dimensional N-doped graphene hydrogel/NiCo double hydroxide electrocatalysts for highly efficient oxygen evolution. AB - A highly hydrated structure was fabricated for catalyzing the oxygen evolution reaction (OER), which demonstrated significantly enhanced catalytic activity, favorable kinetics, and strong durability. The enhanced performance is correlated with the dual-active-site mechanism, and high hydrophilicity of the electrode can dramatically expedite the process of water oxidation into molecular oxygen. PMID- 24346941 TI - Controllable optical activity of gold nanorod and chiral quantum dot assemblies. AB - The optical coupling between Au nanorods (Au NRs) and chiral quantum dots (QDs) in assemblies is investigated by both experiment and theoretical calculations. The coupled optical activity in the visible-light region can be manipulated by changing either the aspect ratio of Au NRs or the size of QDs (left). PMID- 24346942 TI - [2+2+2] Cycloadditions of siloxy alkynes with 1,2-diazines: from reaction discovery to identification of an antiglycolytic chemotype. AB - Cycloaddition uncovered: The title reaction produces novel polycyclic compounds with high efficiency and excellent diastereoselectivity under mild reaction conditions. A small-molecule library, synthesized using this reaction, yielded a novel chemotype which inhibited glycolytic ATP production by blocking glucose uptake in CHO-K1 cells. DMF=N,N-dimethylformamide, Tf=trifluoromethanesulfonyl, TIPS=triisopropylsilyl. PMID- 24346943 TI - Low-overpotential water oxidation by a surface-bound ruthenium-chromophore ruthenium-catalyst assembly. AB - When anchored to nanoITO (indium tin oxide), the ruthenium chromophore-catalyst assembly shown acts as an electrocatalyst for water oxidation, with O2 evolution occurring at an overpotential of 230 mV in 0.1 M HClO4 . The potential response of the electrode points to 3 e(-) /2 H(+) oxidized [?Rua (III) ?Rub (IV) ?O](5+) as the active form of the assembly. PMID- 24346944 TI - Metal oxychlorides as cathode materials for chloride ion batteries. AB - A key challenge of chloride ion batteries is to develop cathode materials that are stable in the electrolytes. Metal oxychlorides are presented as such a cathode material. The electrochemical performance and the reaction mechanisms of the BiOCl and FeOCl cathode were investigated. Both cathodes showed reversible reactions, including a major conversion reaction and a minor intercalation process, by chloride ion transfer during cycling. PMID- 24346945 TI - Copper-free asymmetric allylic alkylation of trisubstituted cyclic allyl bromides using Grignard reagents. AB - AAA: The asymmetric allylic alkylation (AAA) of trisubstituted cyclic allyl bromides with Grignard reagents is catalytic (2 mol % of ligand) and regioselective (SN 2'/SN 2=91:9->100:0). The quaternary carbon centers are formed with good to high enantioselectivity (e.r.=81.5:19.5->96:4). PMID- 24346946 TI - Regiospecific N-heteroarylation of amidines for full-color-tunable boron difluoride dyes with mechanochromic luminescence. AB - Colors to dye for: Palladium-catalyzed regiospecific N-heteroarylations of amidines with 2-halo-N-heteroarenes leads to a structurally diverse library of BF2 /amidine-based complexes. These dyes not only present full-visible-color solid-state emissions with large Stokes shifts and high fluorescence quantum yields, but also exhibit a full-color-tunable mechanofluorochromic nature. PMID- 24346947 TI - Selective and sensitive chromofluorogenic detection of the sulfite anion in water using hydrophobic hybrid organic-inorganic silica nanoparticles. AB - In water and wine: Chromofluorogenic detection of the sulfite anion in pure water was accomplished by using a new hybrid organic-inorganic material that contained a probe entrapped in hydrophobic biomimetic cavities. This material was used for the detection of sulfite in red wine. PMID- 24346948 TI - One-pot tandem approach to spirocyclic oxindoles featuring adjacent spiro stereocenters. AB - All in a sequence: An organocatalyzed Morita-Baylis-Hillman (MBH)/bromination/[3+2] annulation sequence for highly stereoselective syntheses of bis(spirooxindole)s featuring adjacent spiro-stereocenters is described. The key step is an unprecedented catalytic asymmetric [3+2] annulation of isatin derived MBH adducts, containing a tetrasubstituted alkene moiety, with isatins. PMID- 24346949 TI - Two-dimensional hybrid nanosheets of tungsten disulfide and reduced graphene oxide as catalysts for enhanced hydrogen evolution. AB - Composite materials: Tungsten disulfide and WS2 /reduced graphene oxide (WS2 /rGO) nanosheets were fabricated by hydrothermal synthesis using tungsten chloride, thioacetamide, and graphene oxide (GO) as starting materials. The WS2 nanosheets are efficiently templated on the rGO layer. The WS2 /rGO hybrid nanosheets show much better electrocatalytic activity for the hydrogen evolution reaction than WS2 nanosheets alone. PMID- 24346950 TI - Hydrolytic conversion of a metal-organic polyhedron into a metal-organic framework. AB - Twist and release: The metal-organic polyhedron 1 synthesized from 5-(prop-2 ynyloxy)isophthalic acid and Cu(NO3 )2 ? 3 H2 O has a hydrophobic outer surface and a hydrophilic inner core. In an aqueous medium, the resulting polarity gradient led to the transformation of 1 into the 2D metal-organic framework 2. This unique phenomenon enabled the gradual release of entrapped drug molecules. PMID- 24346951 TI - Graphene oxide as a pathogen-revealing agent: sensing with a digital-like response. AB - Turned ON by a pathogen: A highly sensitive pathogen-detection system has been designed and evaluated for the sensing of E. coli bacteria in diverse matrices. It employs antibody-quantum dot (Ab-QD) probes and exploits the extraordinary two dimensional structure and fluorescence-quenching capabilities of graphene oxide. PMID- 24346952 TI - Breaking pseudo-symmetry in multiantennary complex N-glycans using lanthanide binding tags and NMR pseudo-contact shifts. AB - Controlling NMR shifts by lanthanides tagged to a "symmetrical" N-glycan reveals individual resonances for the residues of the otherwise identical A and B arms. This method provides a global perspective of conformational features and interactions in solution. PMID- 24346953 TI - Natural gas to fuels and chemicals: improved methane aromatization in an oxygen permeable membrane reactor. AB - Adding value with membranes: Improved methane aromatization was achieved by using an oxygen-permeable membrane. The resulting membrane reactor shows a superior methane conversion and a higher resistance towards catalyst deactivation. PMID- 24346954 TI - Challenges for a new year. PMID- 24346955 TI - Influence of experimental conditions on data variability in the liver comet assay. AB - The in vivo comet assay has increasingly been used for regulatory genotoxicity testing in recent years. While it has been demonstrated that the experimental execution of the assay, for example, electrophoresis or scoring, can have a strong impact on the results; little is known on how initial steps, that is, from tissue sampling during necropsy up to slide preparation, can influence the comet assay results. Therefore, we investigated which of the multitude of steps in processing the liver for the comet assay are most critical. All together eight parameters were assessed by using liver samples of untreated animals. In addition, two of those parameters (temperature and storage time of liver before embedding into agarose) were further investigated in animals given a single oral dose of ethyl methanesulfonate at dose levels of 50, 100, and 200 mg/kg, 3 hr prior to necropsy. The results showed that sample cooling emerged as the predominant influence factor, whereas variations in other elements of the procedure (e.g., size of the liver piece sampled, time needed to process the liver tissue post-mortem, agarose temperature, or time of lysis) seem to be of little relevance. Storing of liver samples of up to 6 hr under cooled conditions did not cause an increase in tail intensity. In contrast, storing the tissue at room temperature, resulted in a considerable time-dependent increase in comet parameters. PMID- 24346956 TI - Aripiprazole alone or in combination for acute mania. AB - BACKGROUND: Bipolar disorder is a mental disorder characterised by episodes of elevated or irritable mood (manic or hypomanic episodes) and episodes of low mood and loss of energy (depressive episodes). Drug treatment is the first-line treatment for acute mania with the initial aim of rapid control of agitation, aggression and dangerous behaviour. Aripiprazole, an atypical antipsychotic, is used in the treatment of mania both as monotherapy and combined with other medicines. The British Association of Psychopharmacology guidelines report that, in monotherapy placebo-controlled trials, the atypical antipsychotics, including aripiprazole, have been shown to be effective for acute manic or mixed episodes. OBJECTIVES: To assess the efficacy and tolerability of aripiprazole alone or in combination with other antimanic drug treatments, compared with placebo and other drug treatments, in alleviating acute symptoms of manic or mixed episodes. Other objectives include reviewing the acceptability of treatment with aripiprazole, investigating the adverse effects of aripiprazole treatment, and determining overall mortality rates among those receiving aripiprazole treatment. SEARCH METHODS: The Cochrane Depression, Anxiety and Neurosis Group's Specialised Register (CCDANCTR-Studies and CCDANCTR-References) was searched, all years to 31st July 2013. This register contains relevant randomised controlled trials from: The Cochrane Library (all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). We also searched Bristol-Myers Squibb clinical trials register, the World Health Organization (WHO) trials portal (ICTRP) and ClinicalTrials.gov (to August 2013). SELECTION CRITERIA: Randomised trials comparing aripiprazole versus placebo or other drugs in the treatment of acute manic or mixed episodes. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, including adverse effect data, from trial reports and assessed bias. The drug manufacturer or the trial authors were contacted for missing data. MAIN RESULTS: Ten studies (3340 participants) were included in the review. Seven studies compared aripiprazole monotherapy versus placebo (2239 participants); two of these included a third comparison arm-one study used lithium (485 participants) and the other used haloperidol (480 participants). Two studies compared aripiprazole as an adjunctive treatment to valproate or lithium versus placebo as an adjunctive treatment (754 participants), and one study compared aripiprazole versus haloperidol (347 participants). The overall risk of bias was unclear. A high dropout rate from most trials (> 20% for each intervention in eight of the trials) may have affected the estimates of relative efficacy. Evidence shows that aripiprazole was more effective than placebo in reducing manic symptoms in adults and children/adolescents at three and four weeks but not at six weeks (Young Mania Rating Scale (YMRS); mean difference (MD) at three weeks (random effects) -3.66, 95% confidence interval (CI) -5.82 to 2.05; six studies; N = 1819, moderate quality evidence) - a modest difference. Aripiprazole was compared with other drug treatments in three studies in adults lithium was used in one study and haloperidol in two studies. No statistically significant differences between aripiprazole and other drug treatments in reducing manic symptoms were noted at three weeks (YMRS MD at three weeks (random effects) 0.07, 95% CI -1.24 to 1.37; three studies; N = 972, moderate quality evidence) or at any other time point up to and including 12 weeks. Compared with placebo, aripiprazole caused more movement disorders, as measured on the Simpson Angus Scale (SAS), on the Barnes Akathisia Scale (BAS) and by participant reported akathisia (high quality evidence), with more people requiring treatment with anticholinergic medication (risk ratios (random effects) 3.28, 95% CI 1.82 to 5.91; two studies; N = 730, high quality evidence). Aripiprazole also led to more gastrointestinal disturbances (nausea (high quality evidence), and constipation) and caused more children/adolescents to have a prolactin level that fell below the lower limit of normal. Significant heterogeneity was present in the meta-analysis of movement disorders associated with aripiprazole and other treatments and was most likely due to the different side effect profiles of lithium and haloperidol. At the three-week time point, meta-analysis was not possible because of lack of data; however, at 12 weeks, haloperidol resulted in significantly more movement disorders than aripiprazole, as measured on the SAS, the BAS and the Abnormal Involuntary Movement Scale (AIMS) and by participant reported akathisia. By 12 weeks, investigators reported no difference between aripiprazole and lithium (SAS, BAS, AIMS), except in terms of participant reported akathisia (RR 2.97, 95% CI 1.37 to 6.43; one study; N = 313). AUTHORS' CONCLUSIONS: Aripiprazole is an effective treatment for mania in a population that includes adults, children and adolescents, although its use leads to gastrointestinal disturbances and movement disorders. Comparative trials with medicines other than haloperidol and lithium are few, so the precise place of aripiprazole in therapy remains unclear. PMID- 24346957 TI - Wound drains after incisional hernia repair. AB - BACKGROUND: Incisional hernias are caused by the failure of the wall of the abdomen to close after abdominal surgery, leaving a hole through which the viscera protrude. Incisional hernias are repaired by further surgery. Surgical drains are frequently inserted during hernia repair with the aim of facilitating fluid drainage and preventing complications. Traditional teaching has recommended the use of drains after incisional hernia repair other than for laparoscopic ventral hernia repair. More than 50% of open mesh repairs of ventral hernias have drains inserted. However, there is uncertainty as to whether drains are associated with benefits or harm to the patient. OBJECTIVES: To determine the effects on wound infection and other outcomes, of inserting a wound drain during surgery to repair incisional hernias, and, if possible, to determine the comparative effects of different types of wound drain after incisional hernia repair. SEARCH METHODS: In November 2013, for this fourth update we searched the Cochrane Wounds Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library, Ovid MEDLINE, Ovid EMBASE, and EBSCO CINAHL. SELECTION CRITERIA: We considered all randomised trials performed in adult patients who underwent incisional hernia repair and that compared using a drain with no drain. We also considered trials that compared different types of drain. DATA COLLECTION AND ANALYSIS: We extracted data on the characteristics of the trial, methodological quality of the trials, outcomes (e.g. infection and other wound complications) from each trial. For each outcome, we calculated the risk ratio (RR) with 95% confidence intervals (CI) and based on intention-to treat analysis. MAIN RESULTS: No new trials were identified by the updated searches. Only one trial was eligible for inclusion in the review with a total of 24 patients randomised to an electrified drain (12 patients) compared with a corrugated drain (12 patients). There were no statistically significant differences between the groups for wound infection or in the length of stay in hospital. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether wound drains after incisional hernia repair are associated with better or worse outcomes than no drains. PMID- 24346958 TI - [Pharmacokinetics of intravitreally administered VEGF inhibitors]. AB - BACKGROUND: In addition to topical, periocular and systemic administration, intravitreal injection has been established in recent years as an additional standard procedure for ophthalmological drug delivery. This route of administration is now most frequently used for the therapy of retinal diseases with vascular endothelial growth factor (VEGF) inhibitors. MATERIAL AND METHODS: A selective literature review and an analysis of own research data were carried out. RESULTS: Intravitreal administration achieves high drug concentrations in the target tissue while minimizing systemic drug exposure. Depending on properties such as molecular weight and binding capacity to the neonatal Fc receptor, intravitreally applied VEGF inhibitors can exhibit relevant differences in intraocular and systemic pharmacokinetics. Moreover, the pharmacokinetics can be affected by properties of the individual eye, such as ocular volume, vitreous liquefaction, and prior vitrectomy. CONCLUSIONS: Pharmacokinetics of intravitreally administered drugs determine both the duration of ocular effect and the degree of systemic exposure and are thus of clinical relevance with regard to the reinjection strategy and systemic safety. PMID- 24346959 TI - A survey of community pharmacists and final-year student pharmacists and their perception of psychotherapeutic agents. AB - INTRODUCTION: The World Health Organization has estimated that as many as 450 million people worldwide have mental disorders. More than 44 million people in the United States have a mental disorder annually, estimating the annual direct costs of mental illness to exceed US$69 billion. Psychotherapeutic agents are used to treat mental illnesses and improve quality of life. The purpose of the study is to assess the knowledge and knowledge perception of community pharmacists and final-year student pharmacists regarding psychotherapeutic agents dispensed to their community of patients with mental illness. METHODS: A survey was distributed to pharmacists and final-year student pharmacists regarding psychotherapeutic agents. RESULTS: In all, 100 pharmacists and 40 final-year student pharmacists completed the survey. Upon analysis of surveys returned by pharmacists, knowledge deficiency was assessed regarding anxiolytics and mood stabilizers. The analysis of student participant surveys demonstrated knowledge deficiency regarding antidepressants and anxiolytics. CONCLUSIONS: Final-year student pharmacists would benefit from the curricular incorporation of courses and advanced pharmacy practice experiences in Psychiatry. Community pharmacists caring for customers with psychiatric disorders should take advantage of continuing education series that highlight updates and new developments regarding psychotherapeutic agents in order to improve clinical outcomes of patients. PMID- 24346960 TI - Evidence for sequence scrambling and divergent H/D exchange reactions of doubly charged isobaric b-type fragment ions. AB - To date, only a limited number of reports are available on structural variants of multiply-charged b-fragment ions. We report on observed bimodal gas-phase hydrogen/deuterium exchange (HDX) reaction kinetics and patterns for substance P b10(2+) that point to presence of isomeric structures. We also compare HDX reactions, post-ion mobility/collision-induced dissociation (post-IM/CID), and sustained off-resonance irradiation-collision induced dissociation (SORI-CID) of substance P b10(2+) and a cyclic peptide with an identical amino acid (AA) sequence order to substance P b10. The observed HDX patterns and reaction kinetics and SORI-CID pattern for the doubly charged head-to-tail cyclized peptide were different from either of the presumed isomers of substance P b10(2+), suggesting that b10(2+) may not exist exclusively as a head-to-tail cyclized structure. Ultra-high mass measurement accuracy was used to assign identities of the observed SORI-CID fragment ions of substance P b10(2+); over 30% of the observed SORI-CID fragment ions from substance P b10(2+) had rearranged (scrambled) AA sequences. Moreover, post-IM/CID experiments revealed the presence of two conformer types for substance P b10(2+), whereas only one conformer type was observed for the head-to-tail cyclized peptide. We also show that AA sequence scrambling from CID of doubly-charged b-fragment ions is not unique to substance P b10(2+). PMID- 24346961 TI - Quality by design study of the direct analysis in real time mass spectrometry response. AB - A mass spectrometry method has been developed using the Quality by Design (QbD) principle. Direct analysis in real time mass spectrometry (DART-MS) was adopted to analyze a pharmaceutical preparation. A fishbone diagram for DART-MS and the Plackett-Burman design were utilized to evaluate the impact of a number of factors on the method performance. Multivariate regression and Pareto ranking analysis indicated that the temperature, determined distance, and sampler speed were statistically significant (P < 0.05). Furthermore, the Box-Behnken design combined with response surface analysis was then employed to study the relationships between these three factors and the quality of the DART-MS analysis. The analytical design space of DART-MS was thus constructed and its robustness was validated. In this presented approach, method performance was mathematically described as a composite desirability function of the critical quality attributes (CQAs). Two terms of method validation, including analytical repeatability and method robustness, were carried out at an operating work point. Finally, the validated method was successfully applied to the pharmaceutical quality assurance in different manufacturing batches. These results revealed that the QbD concept was practical in DART-MS method development. Meanwhile, the determined quality was controlled by the analytical design space. This presented strategy provided a tutorial to the development of a robust QbD-compliant mass spectrometry method for industrial quality control. PMID- 24346962 TI - The alpha-effect and competing mechanisms: the gas-phase reactions of microsolvated anions with methyl formate. AB - The enhanced reactivity of alpha-nucleophiles, which contain an electron lone pair adjacent to the reactive site, has been demonstrated in solution and in the gas phase and, recently, for the gas-phase S(N)2 reactions of the microsolvated HOO(-)(H2O) ion with methyl chloride. In the present work, we continue to explore the significance of microsolvation on the alpha-effect as we compare the gas phase reactivity of the microsolvated alpha-nucleophile HOO(-)(H2O) with that of microsolvated normal alkoxy nucleophiles, RO(-)(H2O), in reactions with methyl formate, where three competing reactions are possible. The results reveal enhanced reactivity of HOO(-)(H2O) towards methyl formate, and clearly demonstrate the presence of an overall alpha-effect for the reactions of the microsolvated alpha-nucleophile. The association of the nucleophiles with a single water molecule significantly lowers the degree of proton abstraction and increases the S(N)2 and B(AC)2 reactivity compared with the unsolvated analogs. HOO(-)(H2O) reacts with methyl formate exclusively via the B(AC)2 channel. While microsolvation lowers the overall reaction efficiency, it enhances the B(AC)2 reaction efficiency for all anions compared with the unsolvated analogs. This may be explained by participation of the solvent water molecule in the B(AC)2 reaction in a way that continuously stabilizes the negative charge throughout the reaction. PMID- 24346963 TI - Complication rate of neurogenic lower urinary tract dysfunction after spinal cord injury in Taiwan. AB - PURPOSE: In view of the limited information on neurogenic lower urinary tract dysfunction (NLUTD) after spinal cord injury (SCI) in the literature, this study aimed to investigate the complication rate of NLUTD after SCI and to describe the clinical management of NLUTD in Taiwan. METHODS: A cross-sectional study was conducted using the National Health Insurance Research Database of Taiwan from which patients newly diagnosed with SCI during 2006-2008 were extracted. Records of diagnosis, prescriptions, and procedures for patients were retrieved to identify NLUTD cases. The utilization of medical treatments including pharmacotherapy and procedures such as intermittent and indwelling catheters was analyzed. RESULTS: A total of 941 eligible SCI patients were identified, with a mean age of 48.4 (+/-18.5), of which 575 (61.1 %) were male, and 500 (53.1 %) were with cervical SCI. By the end of 1-year follow-up, 165 (17.5 %) had developed NLUTD. The characteristics were mostly similar between the NLUTD and non-NLUTD groups except in age and length of stay (LOS) in hospitals, where patients with NLUTD were 7.5 years old and had 2.15-month-longer LOS. Over 80 % of NLUTD patients received urinary catheterization, with approximately half also receiving pharmacotherapy. CONCLUSIONS: This is the first study using nationwide datasets to evaluate the overall complication rate of NLUTD associated with SCI, which is shown to be lower than previously reported. While various treatment options are available, urinary catheterization is the most common treatment for NLUTD. PMID- 24346964 TI - Dynamic hyperpolarized carbon-13 MR metabolic imaging of nonhuman primate brain. AB - PURPOSE: To investigate hyperpolarized (13) C metabolic imaging methods in the primate brain that can be translated into future clinical trials for patients with brain cancer. METHODS: (13) C coils and pulse sequences designed for use in humans were tested in phantoms. Dynamic (13) C data were obtained from a healthy cynomolgus monkey brain using the optimized (13) C coils and pulse sequences. The metabolite kinetics were estimated from two-dimensional localized (13) C dynamic imaging data from the nonhuman primate brain. RESULTS: Pyruvate and lactate signal were observed in both the brain and the surrounding tissues with the maximum signal-to-noise ratio of 218 and 29 for pyruvate and lactate, respectively. Apparent rate constants for the conversion of pyruvate to lactate and the ratio of lactate to pyruvate showed a difference between brain and surrounding tissues. CONCLUSION: The feasibility of using hyperpolarized [1-(13) C]-pyruvate for assessing in vivo metabolism in a healthy nonhuman primate brain was demonstrated using a hyperpolarized (13) C imaging experimental setup designed for studying patients with brain tumors. The kinetics of the metabolite conversion suggests that this approach may be useful in future studies of human neuropathology. PMID- 24346970 TI - Rooftops under snow: Gustave Caillebotte. PMID- 24346967 TI - Synergistic effect of lung tumor-associated dendritic cell-derived HB-EGF and CXCL5 on cancer progression. AB - The interaction between cancer cells and their microenvironment is a paradoxical cycle that exacerbates cancer progression and results in metastasis. Our study investigated the mechanism underlying the synergistic enhancement of release of soluble factors from tumor-associated dendritic cells and its effect on cancer development. The combination of HB-EGF (heparin-binding EGF-like growth factor) and CXCL5 (CXCL5/epithelial neutrophil-activating peptide-78) produced a strong synergistic effect on cancer proliferation, epithelial-mesenchymal transition, migration and invasion. CXCL5 not only potentiated the classical EGFR pathway and the AKT and ERK/RSK1/2 signaling pathways but also increased the phosphorylation of heat shock protein 27 (HSP27), which was slightly increased in A549 cells treated with either HB-EGF or CXCL5 only. Phosphorylated HSP27 stabilized sustained AKT activity by direct interaction, leading to enhanced tumor spheroid formation. Knockdown of HSP27 by shRNA decreased HB-EGF plus CXCL5-mediated tumor spheroid formation in a three-dimensional culture system, suggesting that AKT/HSP27 was required for HB-EGF/CXCL5-mediated cancer progression. Inhibiting RSK also reduces the modulation of c-Fos phosphorylation, Snail upregulation and cell migration by HB-EGF plus CXCL5, suggesting a synergistic effect of ERK/RSK and HB-EGF plus CXCL5 on cell migration. In mice, CXCL5 antibody synergistically enhances the efficiency of the tyrosine kinase inhibitor, gefitinib, without increasing its toxicity. These results provide evidence that elucidates potential cross-points between extracellular signals affecting lung cancer progression. Targeting CXCL5 may provide therapeutic benefits for lung cancer chemotherapy or immunotherapy. PMID- 24346971 TI - New law allows organ transplants from deceased HIV-infected donors to HIV infected recipients. PMID- 24346972 TI - Clinicians examine advances and challenges in improving quality of end-of-life care in the ICU. PMID- 24346973 TI - US registry for sudden death in the young launched by the NIH and CDC. PMID- 24346985 TI - Rethinking reanalysis. PMID- 24346986 TI - A piece of my mind. Recognizing pride. PMID- 24346987 TI - Medical communication companies and continuing medical education: clouding the sunshine? PMID- 24346989 TI - The effect of nonsurgical periodontal therapy on hemoglobin A1c levels in persons with type 2 diabetes and chronic periodontitis: a randomized clinical trial. AB - IMPORTANCE: Chronic periodontitis, a destructive inflammatory disorder of the supporting structures of the teeth, is prevalent in patients with diabetes. Limited evidence suggests that periodontal therapy may improve glycemic control. OBJECTIVE: To determine if nonsurgical periodontal treatment reduces levels of glycated hemoglobin (HbA1c) in persons with type 2 diabetes and moderate to advanced chronic periodontitis. DESIGN, SETTING, AND PARTICIPANTS: The Diabetes and Periodontal Therapy Trial (DPTT), a 6-month, single-masked, multicenter, randomized clinical trial. Participants had type 2 diabetes, were taking stable doses of medications, had HbA1c levels between 7% and less than 9%, and untreated chronic periodontitis. Five hundred fourteen participants were enrolled between November 2009 and March 2012 from diabetes and dental clinics and communities affiliated with 5 academic medical centers. INTERVENTIONS: The treatment group (n = 257) received scaling and root planing plus chlorhexidine oral rinse at baseline and supportive periodontal therapy at 3 and 6 months. The control group (n = 257) received no treatment for 6 months. MAIN OUTCOMES AND MEASURES: Difference in change in HbA1c level from baseline between groups at 6 months. Secondary outcomes included changes in probing pocket depths, clinical attachment loss, bleeding on probing, gingival index, fasting glucose level, and Homeostasis Model Assessment (HOMA2) score. RESULTS: Enrollment was stopped early because of futility. At 6 months, mean HbA1c levels in the periodontal therapy group increased 0.17% (SD, 1.0), compared with 0.11% (SD, 1.0) in the control group, with no significant difference between groups based on a linear regression model adjusting for clinical site (mean difference, -0.05% [95% CI, -0.23% to 0.12%]; P = .55). Periodontal measures improved in the treatment group compared with the control group at 6 months, with adjusted between-group differences of 0.28 mm (95% CI, 0.18 to 0.37) for probing depth, 0.25 mm (95% CI, 0.14 to 0.36) for clinical attachment loss, 13.1% (95% CI, 8.1% to 18.1%) for bleeding on probing, and 0.27 (95% CI, 0.17 to 0.37) for gingival index (P < .001 for all). CONCLUSIONS AND RELEVANCE: Nonsurgical periodontal therapy did not improve glycemic control in patients with type 2 diabetes and moderate to advanced chronic periodontitis. These findings do not support the use of nonsurgical periodontal treatment in patients with diabetes for the purpose of lowering levels of HbA1c. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00997178. PMID- 24346990 TI - Calcium-channel blocker-clarithromycin drug interactions and acute kidney injury. AB - IMPORTANCE: Calcium-channel blockers are metabolized by the cytochrome P450 3A4 (CYP3A4; EC 1.14.13.97) enzyme. Blood concentrations of these drugs may rise to harmful levels when CYP3A4 activity is inhibited. Clarithromycin is an inhibitor of CYP3A4 and azithromycin is not, which makes comparisons between these 2 macrolide antibiotics useful in assessing clinically important drug interactions. OBJECTIVE: To characterize the risk of acute adverse events following coprescription of clarithromycin compared with azithromycin in older adults taking a calcium-channel blocker. DESIGN, SETTING, AND PARTICIPANTS: Population based retrospective cohort study in Ontario, Canada, from 2003 through 2012 of older adults (mean age, 76 years) who were newly coprescribed clarithromycin (n = 96,226) or azithromycin (n = 94,083) while taking a calcium-channel blocker (amlodipine, felodipine, nifedipine, diltiazem, or verapamil). MAIN OUTCOMES AND MEASURES: Hospitalization with acute kidney injury (primary outcome) and hospitalization with hypotension and all-cause mortality (secondary outcomes examined separately). Outcomes were assessed within 30 days of a new coprescription. RESULTS: There were no differences in measured baseline characteristics between the clarithromycin and azithromycin groups. Amlodipine was the most commonly prescribed calcium-channel blocker (more than 50% of patients). Coprescribing clarithromycin vs azithromycin with a calcium-channel blocker was associated with a higher risk of hospitalization with acute kidney injury (420 patients of 96,226 taking clarithromycin [0.44%] vs 208 patients of 94,083 taking azithromycin [0.22%]; absolute risk increase, 0.22% [95% CI, 0.16% 0.27%]; odds ratio [OR], 1.98 [95% CI, 1.68-2.34]). In a subgroup analysis, the risk was highest with dihydropyridines, particularly nifedipine (OR, 5.33 [95% CI, 3.39-8.38]; absolute risk increase, 0.63% [95% CI, 0.49%-0.78%]). Coprescription with clarithromycin was also associated with a higher risk of hospitalization with hypotension (111 patients of 96,226 taking clarithromycin [0.12%] vs 68 patients of 94,083 taking azithromycin [0.07%]; absolute risk increase, 0.04% [95% CI, 0.02%-0.07%]; OR, 1.60 [95% CI, 1.18-2.16]) and all cause mortality (984 patients of 96,226 taking clarithromycin [1.02%] vs 555 patients of 94,083 taking azithromycin [0.59%]; absolute risk increase, 0.43% [95% CI, 0.35%-0.51%]; OR, 1.74 [95% CI, 1.57-1.93]). CONCLUSIONS AND RELEVANCE: Among older adults taking a calcium-channel blocker, concurrent use of clarithromycin compared with azithromycin was associated with a small but statistically significant greater 30-day risk of hospitalization with acute kidney injury. These findings support current safety warnings regarding concurrent use of CYP3A4 inhibitors and calcium-channel blockers. PMID- 24346991 TI - Medical communication companies and industry grants. AB - IMPORTANCE: Medical communication companies (MCCs) are among the most significant health care stakeholders, supported mainly by drug and device companies. How MCCs share or protect physicians' personal data requires greater transparency. OBJECTIVE: To explore the financial relationships between MCCs and drug and device companies, to describe the characteristics of the large MCCs, and to explore whether they accurately represent themselves to physicians. DESIGN: We combined data from the 2010 grant registries of 14 pharmaceutical and device companies; grouped recipients into categories such as MCCs, academic medical centers, disease-targeted advocacy organizations, and professional associations; and created a master list of 19,272 grants. MAIN OUTCOMES AND MEASURES: Determine the distribution of funds from drug and device companies to various entities and assess the characteristics of large MCCs. RESULTS: Of the 6493 recipients of more than $657 million grant awards from drug and device companies, 18 of 363 MCCs received 26%, academic medical centers received 21%, and disease-targeted organizations received 15%. For-profit MCCs received 77% of funds (208 of 363). Among the top 5% of MCCs, 14 of 18 were for-profit. All 18 offered continuing medical education: 14 offered live and 17 offered online CME courses. All required physicians to provide personal data. Ten stated that they shared information with unnamed third parties. Eight stated they did not share information, but almost all added exceptions. None required explicit physician consent to their sharing policies. CONCLUSIONS AND RELEVANCE: Medical communication companies receive substantial support from drug and device companies. Physicians who interact with MCCs should be aware that all require personal data from the physician and some share these data with unnamed third parties. PMID- 24346992 TI - Annular vesiculobullous eruption in a healthy young man. PMID- 24346993 TI - Patterns of accelerometer-assessed sedentary behavior in older women. PMID- 24346994 TI - Suicides among military personnel. PMID- 24346995 TI - Suicides among military personnel. PMID- 24346996 TI - Suicides among military personnel. PMID- 24346997 TI - Suicides among military personnel--reply. PMID- 24346998 TI - Online identities of physicians. PMID- 24346999 TI - Online identities of physicians--reply. PMID- 24347000 TI - Weight loss treatment in obese adults. PMID- 24347001 TI - Weight loss treatment in obese adults--reply. PMID- 24347003 TI - The resistance of various nerve-cells to anemia. PMID- 24347004 TI - JAMA patient page. Blood thinners. PMID- 24347005 TI - Lymphadenopathy: defining a palpable lymph node. AB - BACKGROUND: The threshold size required to detect lymphadenopathy via palpation has never been formally determined. The purpose of this study was to determine the threshold, sensitivity, and error of node palpation and how this changes with experience. METHODS: Lymphadenopathy models were created using polyvinyl alcohol cryogel (PVA-C) to mimic tissue tactility. Node diameter ranged from 0.5 to 4 cm. Study subjects were medical students, otolaryngology residents, and otolaryngology consultants. Each subject provided 22 estimates of size. Primary outcomes were the sensitivity, error (true vs estimated size), and threshold of palpation. RESULTS: Thirty subjects completed the study. Sensitivity was 60%, 74%, and 86% for students, residents, and consultants, respectively (p < .01). Error was 0.88 cm, 0.61 cm, and 0.57 cm, respectively (p < .05). Palpation threshold was 1.32 cm, 0.83 cm, and 0.75 cm, respectively (p < .05). All participants detected nodes >=2 cm, whereas consultants detected nodes >=1 cm. CONCLUSION: Experience is associated with decreased palpation threshold and error, and increased sensitivity. Educational interventions should target nodes <2 cm. PMID- 24347006 TI - Long term efficacy of an integrated neurological and vocational rehabilitation programme for young adults with acquired brain injury. AB - PURPOSE: To characterise and determine the pre-injury, injury and post-injury factors associated with vocational outcome 1-9 years post-discharge from a mixed therapy/educational/vocational rehabilitation (VR) residential programme. METHODS: 119 clients of working age when they acquired their brain injury and who had attended the centre between 2002 and 2011 were followed up at least 1 year post-discharge to determine their vocational outcome as part of an ongoing review/audit of the service. All clients had had a severe/very severe brain injury. Clients were classified as having a positive vocational outcome (working paid/voluntary, full/part-time or undertaking full or part-time vocationally related education) or negative vocational outcome (undertaking neither work nor education). RESULTS: Over half of the clients attained a positive vocational outcome. Length of time since discharge did not differ between those clients with a positive or negative vocational outcome. Vocational outcome was predicted by cognitive and motor ability at discharge, and gender. Together these variables correctly classified the vocational outcome of 76 % of the clients. CONCLUSION: Clients with severe/very severe brain injury can attain a positive vocational outcome following intensive neurorehabilitation consisting of traditional therapies in addition to educational and VR. PMID- 24347007 TI - The dilemma of refractory epileptic syndromes without structural lesions visible through conventional MRI. "Sight beyond sight": is it possible to trust what we cannot see? PMID- 24347008 TI - Rehabilitation in Parkinson's disease - the challenge to provide early and ongoing, evidence-based, patient-centred care. PMID- 24347009 TI - Investigation of magnetic resonance imaging texture analysis as an aid tool for characterization of refractory epilepsies. AB - Refractory epilepsies are syndromes for which therapies that employ two or more antiepileptic drugs, separately or in association, do not result in control of crisis. Patients may present focal cortical dysplasia or diffuse dysplasia and/or hippocampal atrophic alterations that may not be detectable by a simple visual analysis in magnetic resonance imaging. The aim of this study was to evaluate MRI texture in regions of interest located in the hippocampi, limbic association cortex and prefrontal cortex of 20 patients with refractory epilepsy and to compare them with the same areas in 20 healthy individuals, in order to find out if the texture parameters could be related to the presence of the disease. Of the 11 texture parameters calculated, three indicated the existence of statistically significant differences between the studied groups. Such findings suggest the possibility of this technique contributing to studies of refractory epilepsies. PMID- 24347010 TI - Syncope in patients with drug-resistant epilepsy without apparent cardiovascular disease. AB - Epilepsy and syncope are clinical conditions with high prevalence rates in the general population, and the differential diagnosis between them is difficult. Objective To assess the frequency of syncope in patients diagnosed with drug resistant epilepsy (DRE) without appa-rent heart disease, to investigate the relationship between clinical and electroencephalographic (EEG) changes, and to verify the role of the inclination test (IT). Method An open, prospective study from 2004 to 2006, including 35 consecutive patients from the Epilepsy Program of Hospital Universitario Clementino Fraga Filho who were diagnosed with DRE without apparent heart disease. Results The frequency of syncope was 25.7% (n=9), with a significant prevalence in women. Vasovagal syncope (VVS) was the most frequent diagnosis. Conclusion We found a significant association between syncope and the presence of autonomic symptoms (p=0.005). The IT plays an important role in the differential diagnosis of patients with DRE presenting with autonomic symptoms, regardless of EEG results and brain magnetic resonance imaging (MRI) abnormalities. PMID- 24347011 TI - Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs): an intriguing EEG phenomenon. AB - SIRPIDs, an acronym for stimulus-induced rhythmic, periodic, or ictal discharges, were first named in 2004. This is a pattern observed in continuous electroencephalogram (CEEG) consistently elicited by stimulation in comatose patients. The pathophysiology of SIRPIDs probably involves dysregulation of subcortico-cortical projections, particularly thalamocortical circuit, in a markedly abnormal brain with hyperexci-table cortex. This may explain some studies found an association of prolonged periodic epileptiform discharges (PEDs) activity and a higher incidence of concurrent electrographic seizures and SIRPIDs. An association of SIRPIDs and poor prognosis has already been described. However, it is not yet possible to assert whether these discharges can cause neuronal injury or if they are simply a marker of severe brain injury. Objective of this paper is to review clinical relevance and pathophysiology of SIRPIDs, as well as its role as a brain response in the critically ill patient. PMID- 24347012 TI - Quantitative EEG evaluation in patients with acute encephalopathy. AB - OBJECTIVE: To investigate the use of quantitative EEG (qEEG) in patients with acute encephalopathies (AEs) and EEG background abnormalities. METHOD: Patients were divided into favorable outcome (group A, 43 patients) and an unfavorable outcome (group B, 5 patients). EEGLAB software was used for the qEEG analysis. A graphic of the spectral power from all channels was generated for each participant. Statistical comparisons between the groups were performed. RESULTS: In group A, spectral analysis revealed spectral peaks (theta and alpha frequency bands) in 84% (38/45) of the patients. In group B, a spectral peak in the delta frequency range was detected in one patient. The remainder of the patients in both groups did not present spectral peaks. Statistical analysis showed lower frequencies recorded from the posterior electrodes in group B patients. CONCLUSION: qEEG may be useful in the evaluations of patients with AEs by assisting with the prognostic determination. PMID- 24347013 TI - Painful temporomandibular disorders, self reported tinnitus, and depression are highly associated. AB - OBJECTIVE: The aim of this study was to investigate the association among painful temporomandibular disorders (TMD), self reported tinnitus, and levels of depression. METHOD: The sample consisted of 224 individuals with ages ranges from 18 to 76 years. The Research Diagnostic Criteria for Temporomandibular Disorders Axis I were used to classify TMD and Axis II were used for self reported tinnitus, and to score the levels of depression. The odds ratio (OR) with 95% confidence interval (CI) was applied. RESULTS: The presence of painful TMD without tinnitus was significantly associated with moderate/severe levels of depression (OR=9.3, 95%; CI: 3.44-25.11). The concomitant presence of painful TMD and tinnitus self-report increased the magnitude of the association with moderate/severe levels of depression (OR=16.3, 95%; CI, 6.58-40.51). CONCLUSION: Painful temporomandibular disorders, high levels of depression, and self reported tinnitus are deeply associated. However, this association does not imply a causal relationship. PMID- 24347014 TI - Muscle strength and executive function as complementary parameters for the assessment of impairment in Parkinson's disease. AB - OBJECTIVE: To evaluate the relationship between the quantitative results of functional and cognitive performance of patients with Parkinson's disease (PD) and disease severity; and to study the relationship between patients' functional and cognitive capacity and motor impairment (Unified Parkinson's Disease Rating Scale - UPDRS III). METHOD: Twenty-nine subjects clinically diagnosed with PD were classified into three groups according to disease severity using the modified Hoehn and Yahr Scale (H&Y). They were submitted to functional (Senior Fitness Test) and neuropsychological tests. Stepwise regression analysis showed a significant association between H&Y and upper limb strength (r2 =0.30; p=0.005) and executive function (r2 =0.37; p=0.004). In relation to UPDRS III, there was a significant association between lower limb strength (r2 =0.27; p=0.010) and global cognitive status (r2 =0.24; p=0.024). CONCLUSION: The implementation of simple tests of functional capacity associated with neuropsychological testing can help to assess disease severity and motor impairment, and can be used to monitor the response to treatment in PD. PMID- 24347015 TI - Brazilian cross-cultural translation and adaptation of the "Questionnaire of Life Quality Specific for Myasthenia Gravis - 15 items". AB - OBJECTIVE: To translate and to perform the cross-cultural adaptation of the "Questionnaire of Life Quality Specific for Myasthenia Gravis - 15 items" (MG QOL15). METHOD: The original English version of the questionnaire was translated into Portuguese. This version was revised and translated back into English. Later, both English versions were compared and the divergences were corrected in the Portuguese text. At a second stage, ten patients with MG followed at the Neuromuscular Diseases Clinic from the University Hospital, Universidade Federal de Minas Gerais answered the questionnaire. The authors analyzed the difficulties and misunderstandings in the application of the questionnaire. RESULTS: The questions 8, 13 and 15 were considered difficult to understand and were modified in the final Portuguese version. Most patients (70%) had a total score above 25, and the statements 3, 8 and 9 showed the highest scores. CONCLUSION: The Brazilian version of the questionnaire MG-QOL15 seems to be a promising tool for the assessment of Brazilian patients with MG. PMID- 24347016 TI - Prevalence of amyotrophic lateral sclerosis in the city of Porto Alegre, in Southern Brazil. AB - OBJECTIVE: To determine the prevalence of amyotrophic lateral sclerosis (ALS) in the city of Porto Alegre, Brazil. METHOD: We conducted an extensive investigation in clinics and hospitals that provide specialized assistance to these patients, contacted neurologists and the regional association of people with ALS. RESULTS: On July 31, 2010, 70 patients were alive and diagnosed with amyotrophic lateral sclerosis. Considering the population living in the city in the same period (1,409,351), the estimated prevalence was 5.0 cases per 100,000 people (95% CI, 3.9-6.2), being higher for men (5.2/100,000 95% CI, 3.6-7.2) than for women (4.8/100,000 95% CI, 3.4-6.5). The prevalence increased with age peaking in the age group 70-79 years in both genders. CONCLUSION: The prevalence of ALS in the city of Porto Alegre is similar to that reported in other parts of the world. PMID- 24347017 TI - Asymmetric optic nerve sheath diameter as an outcome factor following cranioplasty in patients harboring the 'syndrome of the trephined'. AB - Decompressive craniectomy (DC) is gaining an increasing role in the neurosurgical treatment of intractable intracranial hypertension, but not without complications. A rare complication is the "syndrome of the trephined" (ST). It occurs when the forces of gravity overwhelm intracranial pressures, leading the brain to become sunken. OBJECTIVE: To determine the usefulness of asymmetric optic nerve sheath diameter (ONSD) as an outcome factor after cranioplasty. METHOD: We followed-up 5 patients submitted to DC and diagnosed with ST. All were submitted to brain MRI to calculate the ONSD. RESULTS: Only two patients presented an asymmetric ONSD, being ONSD larger at the site of craniectomy. Surprisingly these patients had a marked neurological improvement after cranioplasty. They became independent a week after and statistically earlier than others. CONCLUSION: It is presumed that the presence of an asymmetric ONSD in trephined patients is an independent factor of good outcome after cranioplasty. PMID- 24347018 TI - Referral to rehabilitation in Parkinson's disease: who, when and to what end? AB - The current state of evidence in non-pharmacological treatments amounts to an impending paradigm shift in neurology where physicians should be alerted that some rehabilitation interventions are already supported in current therapeutic guidelines. This manuscript aims to overview the best scientific data supporting referral to rehabilitation services in order to help physicians make the best use of the existing evidence for non-pharmacological treatments in the different stages of Parkinson's disease. PMID- 24347019 TI - Babinski's contributions to cerebellar symptomatology: building the basis of the neurological examination. AB - Several assumptions about the function of the cerebellum and semiotic signs have been described over the centuries. Among the long list of famous researchers who have provided a strong contribution and who have left their names on the highway of cerebellar research, Joseph Babinski appears as a prominent name. The description of various forms of cerebellar symptomatology was a major part of Babinski's work, and clinical terms that he introduced, namely hypermetry , diadochokinesia , and asynergy , remain part of contemporary clinical vocabulary. Babinski studied cerebellar signs in many patients and was able to conduct longitudinal studies that permitted him to understand the evolution of cerebellar dysfunction. Babinski contributions to cerebellar symptomatology continue to influence the most modern theories, including functional and neuropathological studies. PMID- 24347020 TI - Unilateral clear hairy tongue sign. PMID- 24347021 TI - Spinal cord atrophy in spinocerebellar ataxia type 1. PMID- 24347022 TI - Cardiac evaluation in a patient with epileptic seizures: a value of cardiac magnetic resonance imaging. PMID- 24347025 TI - Set shifting in children and adolescents with anorexia nervosa: an exploratory systematic review and meta-analysis. AB - OBJECTIVE: Set shifting inefficiencies in adults with anorexia nervosa (AN) are established, however the neurocognitive profile of children and adolescents with AN is less clear. This study aimed to provide a review of the literature. METHOD: Electronic databases were used to search for manuscripts. RESULTS: Meta-analysis was performed on seven studies using two neuropsychological tests (Trail Making Task, TMT; Wisconsin Card Sorting Task, WCST). The mean difference in outcome between AN and healthy control (HC) groups was standardized by calculating Cohen's d. Meta-analysis of TMT studies showed a nonsignificant negative, pooled standardized mean difference of -0.005 (95% C.I. -0.416 to 0.406, z = 0.02, p = .98). WCST studies revealed a nonsignificant pooled effect size of d = 0.196 (95% C.I. -0.091-0.483, z = 1.34, p = .18). Studies which did not allow for a calculation of effect size typically showed a nonsignificant, worse performance by the AN groups. DISCUSSION: The inefficiencies in set shifting that are apparent in the adult AN literature do not appear to be as pronounced in children. This may suggest that set shifting difficulties in adult AN are the result of starvation or indicative of longer duration of illness. Larger studies are needed to confirm these impressions. PMID- 24347026 TI - Unveiling benznidazole's mechanism of action through overexpression of DNA repair proteins in Trypanosoma cruzi. AB - Benznidazole (BZ) is the most commonly used drug for the treatment of Chagas disease. Although BZ is known to induce the formation of free radicals and electrophilic metabolites within the parasite Trypanosoma cruzi, its precise mechanisms of action are still elusive. Here, we analyzed the survival of T. cruzi exposed to BZ using genetically modified parasites overexpressing different DNA repair proteins. Our results indicate that BZ induces oxidation mainly in the nucleotide pool, as heterologous expression of the nucleotide pyrophosphohydrolase MutT (but not overexpression of the glycosylase TcOgg1) increased drug resistance in the parasite. In addition, electron microscopy indicated that BZ catalyzes the formation of double-stranded breaks in the parasite, as its genomic DNA undergoes extensive heterochromatin unpacking following exposure to the drug. Furthermore, the overexpression of proteins involved in the recombination-mediated DNA repair increased resistance to BZ, reinforcing the idea that the drug causes double-stranded breaks. Our results also show that the overexpression of mitochondrial DNA repair proteins increase parasite survival upon BZ exposure, indicating that the drug induces lesions in the mitochondrial DNA as well. These findings suggest that BZ preferentially oxidizes the nucleotide pool, and the extensive incorporation of oxidized nucleotides during DNA replication leads to potentially lethal double-stranded DNA breaks in T. cruzi DNA. PMID- 24347027 TI - Cell proliferation arrest and redox state status as part of different stages during senescence establishment in mouse fibroblasts. AB - Senescence phenotype can be achieved by multiple pathways. Most of them involve the activation of negative cell cycle regulators as well as a shift to an oxidative status. However, the exact participation of these events in senescence establishment and maintenance is not completely understood. In this study we investigated the content of three final cell cycle regulators, as well as the redox state in some critical points during the pre-senescent and the full senescent states. Our results highlight the existence of a critical pre-phase in senescent phenotype establishment, in which cell proliferation stops with the participation of the cell cycle inhibitors, and a second maintenance stage where the exacerbated pro-oxidant state inside the cell induces the physiological decline characteristic in senescent cells. PMID- 24347028 TI - Photo-crosslinkable PEG-based microribbons for forming 3D macroporous scaffolds with decoupled niche properties. AB - PEG-based microribbons are designed and fabricated as building blocks for constructing a 3D cell niche with independently tunable biochemical, mechanical, and topographical cues. This platform supports direct cell encapsulation, allows spatial patterning of biochemical cues, and may provide a valuable tool for facilitating the analyses of how interactive niche signaling regulates cell fate in three dimensions. PMID- 24347029 TI - Angewandte Chemie always new. PMID- 24347031 TI - Combination versus sequential single agent chemotherapy for metastatic breast cancer. AB - BACKGROUND: Combination chemotherapy can cause greater tumour cell kill if the drug dose is not compromised, while sequential single agent chemotherapy may allow for greater dose intensity and treatment time, potentially meaning greater benefit from each single agent. In addition, sequentially using single agents might cause less toxicity and impairment of quality of life, but it is not known whether this might compromise survival time. OBJECTIVES: To assess the effect of combination chemotherapy compared to the same drugs given sequentially in women with metastatic breast cancer. SEARCH METHODS: We searched the Cochrane Breast Cancer Group Specialised Register, using the search terms "advanced breast cancer" and "chemotherapy", MEDLINE and EMBASE on 31 October 2013. The World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov were also searched (22 March 2012). SELECTION CRITERIA: Randomised controlled trials of combination chemotherapy compared to the same drugs used sequentially in women with metastatic breast cancer in the first-, second- or third-line setting. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from published trials. Hazard ratios (HR) were derived from time-to-event outcomes where possible, and a fixed-effect model was used for meta-analysis. Response rates were analysed as dichotomous variables (risk ratios (RR)), and toxicity and quality of life data were extracted where available. MAIN RESULTS: Twelve trials reporting on nine treatment comparisons (2317 patients randomised) were identified. The majority of trials (10 trials) had an unclear or high risk of bias. Time-to-event data were collected for nine trials for overall survival and eight trials for progression-free survival. All 12 trials reported results for tumour response. In the 12 trials there were 1023 deaths in 2317 women randomised. There was no difference in overall survival, with an overall HR of 1.04 (95% confidence interval (CI) 0.93 to 1.16; P = 0.45), and no significant heterogeneity. This result was consistent in the four subgroups analysed (risk of bias, line of chemotherapy, type of schema of chemotherapy, and relative dose intensity). In particular, there was no difference in survival according to the type of schema of chemotherapy, that is whether chemotherapy was given on disease progression or after a set number of cycles. In the eight trials that reported progression-free survival, 678 women progressed out of the 886 women randomised. The combination arm had a higher risk of progression than the sequential arm (HR 1.16; 95% CI 1.03 to 1.31; P = 0.01) with no significant heterogeneity. This result was consistent in all subgroups. Overall tumour response rates were higher in the combination arm (RR 1.13; 95% CI 1.03 to 1.24; P = 0.008) but there was significant heterogeneity for this outcome across the trials. In the seven trials that reported treatment-related deaths, there was no significant difference between the two arms, although the CIs were very wide due to the small number of events (RR 1.53; 95% CI 0.71 to 3.29; P = 0.28). The risk of febrile neutropenia was higher in the combination arm (RR 1.32; 95% CI 1.06 to 1.65; P = 0.01). There was no statistically significant difference in the risk of neutropenia, nausea and vomiting, or treatment-related deaths. Overall quality of life showed no difference between the two groups, but only three trials reported this outcome. AUTHORS' CONCLUSIONS: Sequential single agent chemotherapy has a positive effect on progression-free survival, whereas combination chemotherapy has a higher response rate and a higher risk of febrile neutropenia in metastatic breast cancer. There is no difference in overall survival time between these treatment strategies, both overall and in the subgroups analysed. In particular, there was no difference in survival according to the schema of chemotherapy (giving chemotherapy on disease progression or after a set number of cycles) or according to the line of chemotherapy (first line versus second- or third-line). Generally this review supports the recommendations by international guidelines to use sequential monotherapy unless there is rapid disease progression. PMID- 24347030 TI - Cerebral vasospasm after aneurysmal subarachnoid hemorrhage and traumatic brain injury. AB - OPINION STATEMENT: Cerebral vasospasm (cVSP) consists of the vasoconstriction of large and small intracranial vessels which can lead to cerebral hypoperfusion, and in extreme cases, delayed ischemic deficits with stroke. While most commonly observed after aneurysmal subarachnoid hemorrhage (aSAH), cVSP can also occur after traumatic brain injury (TBI) as we have described in detail in this review. For the past decades, the research attention has focused on cVSP because of its association with delayed cerebral ischemia, which is the largest contributor of morbidity and mortality after aSAH. New discoveries in the cVSP pathophysiology involving multifactorial complex cascades and pathways pose new targets for therapeutic interventions in the prevention and treatment of cVSP. The goal of this review is to demonstrate the commonalities and differences in epidemiology and pathophysiology of both aSAH and TBI-associated cVSP, and highlight the more recently discovered pathways of cVSP. Finally, the latest cVSP surveillance methods and treatment options are illustrated. PMID- 24347032 TI - [Patient-centredness in rehabilitation : an overview on the current state of research]. AB - This article provides an overall perspective of the concept of patient centredness in health care. After discussing the social factors that significantly contribute to this topic, the authors refer to a definition by Mead and Bower in their understanding of patient-centredness. They distinguished five facets of patient-centredness, namely the biopsychosocial perspective, seeing the patient as an individual person, sharing power and responsibility (e.g. shared decision-making), consideration of the patient-treatment provider relationship and regarding the treatment provider as a person. The authors discuss why approaches employing patient-centred care seem particularly well-suited to a rehabilitation context and emphasize the value and benefit of patient-centred care. They describe those areas currently engaging the greatest research efforts in Germany by providing an overview of projects now being conducted in the funding priority for chronic illnesses and patient orientation. In the final chapter the authors consider the need for further research as well as the potential adverse side effects associated with intensified patient-centred care. PMID- 24347033 TI - Accidental dural puncture, postdural puncture headache, intrathecal catheters, and epidural blood patch: revisiting the old nemesis. AB - One of the controversial management options for accidental dural puncture in pregnant patients is the conversion of labor epidural analgesia to continuous spinal analgesia by threading the epidural catheter intrathecally. No clear consensus exists on how to best prevent severe headache from occurring after accidental dural puncture. To investigate whether the intrathecal placement of an epidural catheter following accidental dural puncture impacts the incidence of postdural puncture headache (PDPH) and the subsequent need for an epidural blood patch in parturients. A retrospective chart review of accidental dural puncture was performed at Hutzel Women's Hospital in Detroit, MI, USA for the years 2002 2010. Documented cases of accidental dural punctures (N = 238) were distributed into two groups based on their management: an intrathecal catheter (ITC) group in which the epidural catheter was inserted intrathecally and a non-intrathecal catheter (non-ITC) group that received the epidural catheter inserted at different levels of lumbar interspaces. The incidence of PDPH as well as the necessity for epidural blood patch was analyzed using two-tailed Fisher's exact test. In the non-ITC group, 99 (54 %) parturients developed PDPH in comparison to 20 (37 %) in the ITC [odds ratio (OR), 1.98; 95 % confidence interval (CI), 1.06 3.69; P = 0.03]. Fifty-seven (31 %) of 182 patients in the non-ITC group required an epidural blood patch (EBP) (data for 2 patients of 184 were missing). In contrast, 7 (13 %) of parturients in the ITC group required an EBP. The incidence of EBP was calculated in parturients who actually developed headache to be 57 of 99 (57 %) in the non-ITC group versus 7 of 20 (35 %) in the ITC group (OR, 2.52; 95 % CI, 0.92-6.68; P = 0.07). The insertion of an intrathecal catheter following accidental dural puncture decreases the incidence of PDPH but not the need for epidural blood patch in parturients. PMID- 24347034 TI - Plasma ropivacaine concentrations after ultrasound-guided transversus abdominis plane block for open retropubic prostatectomy. AB - PURPOSE: Ropivacaine-induced vasoconstriction may affect the early absorption speed of ropivacaine; however, the effects of dose on pharmacokinetics following transversus abdominis plane (TAP) block have not been studied. In this study, we have examined plasma ropivacaine concentrations following TAP block with various ropivacaine concentrations (0.25, 0.5, and 0.75 %). METHODS: With the approval of our University ethics committee and informed consent, 39 adult patients undergoing open retropubic prostatectomy were enrolled. Patients were randomly assigned to three groups (n = 13 each) receiving TAP block with 20 ml (10 ml each side) of different concentrations of ropivacaine. To determine plasma concentrations, blood samples were drawn before and 15, 30, 45, 60, 90, 120, and 180 min after completion of bilateral TAP blocks. Plasma ropivacaine concentrations were analyzed by gas chromatography with mass spectrometry. RESULTS: We found that the peak plasma concentrations (C(max)) increased dose dependently (0.41 +/- 0.14, 0.89 +/- 0.55, and 1.56 +/- 0.50 ug/ml), but the times to C(max) (23.0 +/- 15.8, 23.1 +/- 14.5, and 20.8 +/- 11.5 min) were not different between 0.25, 0.5, and 0.75 % ropivacaine doses, respectively. Terminal elimination half-life (t(1/2)), total body clearance (CL), and distribution volume (V(d)) were also not different among the three groups. CONCLUSION: Ropivacaine concentration did not alter pharmacokinetic profile following TAP blocks. PMID- 24347035 TI - Perioperative management of factor XI deficiency in a patient undergoing hip arthroplasty. AB - Factor XI deficiency, or hemophilia C, is a rare autosomal recessive bleeding disorder often diagnosed by inappropriate bleeding associated with trauma or a surgical procedure, and reports of anesthetic management of this disorder are rare. We experienced an 85-year-old man with femoral neck fracture who was diagnosed preoperatively with factor XI deficiency based on abnormally long activated partial thromboplastin time (APTT). He was scheduled for bipolar hip arthroplasty and was prepared for surgery by transfusion of fresh frozen plasma (FFP), instead of factor XI concentrates, which are not commercially available in Japan. Five units of FFP were transfused 6 days before surgery, and 10 units of FFP with 2 units of red concentrated cells (RCC) were used on the day of surgery. Transfusion of FFP shortened the APTT to a level sufficient to allow hemostasis, although not to within the normal range. Although the patient required transfusion of 2 units of RCC postoperatively, no bleeding complications occurred. For bipolar hip arthroplasty, transfusion of FFP produced sufficient hemostasis without the use of tranexamic acid, factor VII preparations, or desmopressin. PMID- 24347036 TI - Continued use of 1-in-X Risk communications is a systemic problem. PMID- 24347037 TI - Pneumococcal glomerulonephritis in a healthy child: a case report and literature review. AB - Pneumococcal glomerulonephritis is rarely described in the literature. We report a four-year-old boy who developed acute glomerulonephritis following pneumococcal bacteraemia and submandibular lymphadenitis, and review the published literature. Two weeks after developing acute glomerulonephritis, the patient developed bronchopneumonia with left pleural effusion. However, by the fourth week of admission, his renal function had normalised and lung involvement resolved. PMID- 24347038 TI - Multiple oesophago-respiratory fistulae: sequelae of pulmonary tuberculosis in retroviral infection. AB - Pulmonary tuberculosis (PTB) is a common infectious disease worldwide. However, mediastinal tuberculous lymphadenitis complicated by oesophageal involvement and oesophago-respiratory fistula is now uncommon due to improved anti-tuberculous regimes and better general awareness. The overall incidence of acquired oesophago respiratory fistula due to infection is low, and therefore, the lesion is not often a frontrunner in differential diagnosis. Still, tuberculous oesophago respiratory fistulae can potentially occur in patients with retroviral disease, as they tend to have atypical and more virulent manifestations. In this study, we report the case of multiple oesophago-respiratory fistulae in a patient with PTB and retroviral disease, and highlight the computed tomography features of these lesions as an atypical presentation of PTB in retroviral disease. Clinicians should suspect oesophago-respiratory fistulae if patients present with Ono's sign, and remain particularly vigilant for patients with underlying PTB and retroviral disease, as early diagnosis and treatment could help to reduce mortality. PMID- 24347039 TI - Hepatic tuberculosis: a rare cause of fluorodeoxyglucose hepatic superscan with background suppression on positron emission tomography. AB - Fluorodeoxyglucose (FDG) hepatic superscan refers to the diffuse intense uptake of 18F-FDG in the liver on positron emission tomography (PET), with reduced physiological activity in the brain and heart. The common causes include lymphoma and metastasis. In this case report, we describe the imaging features of tuberculosis as a rare cause of FDG hepatic superscan. PET imaging may be the only clue to a diagnosis of hepatic tuberculosis, as other imaging modalities may demonstrate only nonspecific hepatomegaly. It is important to consider this entity in the differential diagnosis of patients presenting with FDG hepatic superscan and proceed with liver biopsy for a definitive diagnosis. PMID- 24347040 TI - Convex gradient optimization for increased spatiotemporal resolution and improved accuracy in phase contrast MRI. AB - PURPOSE: To evaluate convex gradient optimization (CVX) for increased spatiotemporal resolution and improved accuracy for phase-contrast MRI (PC-MRI). METHODS: A conventional flow-compensated and flow-encoded (FCFE) PC-MRI sequence was compared with a CVX PC-MRI sequence using numerical simulations, flow phantom experiments, and in vivo experiments. Flow measurements within the ascending aorta, main pulmonary artery, and right/left pulmonary arteries of normal volunteers (N = 10) were acquired at 3T and analyzed using a conventional FCFE sequence and a CVX sequence with either higher spatial resolution or higher temporal resolution. All sequences mitigated chemical shift-induced phase errors and used equivalent breath-hold durations. RESULTS: Chemical shift-optimized PC MRI has increased sequence efficiency when using CVX, which can provide either higher spatial or higher temporal resolution compared with conventional FCFE PC MRI. Numerical simulations, flow phantom experiments, and in vivo experiments indicate that CVX measurements of total flow and peak velocity are increased and more accurate when compared with FCFE. CONCLUSION: CVX PC-MRI increases sequence efficiency while reducing chemical shift-induced phase errors. This can be used to provide either higher spatial or higher temporal resolution than conventional chemical shift-mitigated PC-MRI methods to provide more accurate measurements of blood flow and peak velocity. PMID- 24347041 TI - Fragment N2, a caspase-3-generated RasGAP fragment, inhibits breast cancer metastatic progression. AB - The p120 RasGAP protein negatively regulates Ras via its GAP domain. RasGAP carries several other domains that modulate several signaling molecules such as Rho. RasGAP is also a caspase-3 substrate. One of the caspase-3-generated RasGAP fragments, corresponding to amino acids 158-455 and called fragment N2, was previously reported to specifically sensitize cancer cells to death induced by various anticancer agents. Here, we show that fragment N2 inhibits migration in vitro and that it impairs metastatic progression of breast cancer to the lung. Hence, stress-activated caspase-3 might contribute to the suppression of metastasis through the generation of fragment N2. These results indicate that the activity borne by fragment N2 has a potential therapeutic relevance to counteract the metastatic process. PMID- 24347042 TI - Characterizing ensemble statistics: mean size is represented across multiple frames of reference. AB - The visual system represents the overall statistical, not individual, properties of sets. Here we tested the spatial nature of ensemble statistics. We used a mean size adaptation paradigm (Corbett et al. in Visual Cognition, 20, 211-231, 2012) to examine whether average size is encoded in multiple reference frames. We adapted observers to patches of small- and large-sized dots in opposite regions of the display (left/right or top/bottom) and then tested their perceptions of the sizes of single test dots presented in regions that corresponded to retinotopic, spatiotopic, and hemispheric coordinates within the adapting displays. We observed retinotopic, spatiotopic, and hemispheric adaptation aftereffects, such that participants perceived a test dot as being larger when it was presented in the area adapted to the patch of small dots than when it was presented in the area adapted to large dots. This aftereffect also transferred between eyes. Our results demonstrate that mean size is represented across multiple spatial frames of reference, supporting the proposal that ensemble statistics play a fundamental role in maintaining perceptual stability. PMID- 24347043 TI - Evidence behind FDA alerts for drugs with adverse cardiovascular effects: implications for clinical practice. AB - The U.S. Food and Drug Administration (FDA) periodically publishes Drug Safety Communications and Drug Alerts notifying health care practitioners and the general public of important information regarding drug therapies following FDA approval. These alerts can result in both positive and negative effects on patient care. Most clinical trials are not designed to detect long-term safety end points, and postmarketing surveillance along with patient reported events are often instrumental in signaling the potential harmful effect of a drug. Recently, many cardiovascular (CV) safety announcements have been released for FDA-approved drugs. Because a premature warning could discourage a much needed treatment or prompt a sudden discontinuation, it is essential to evaluate the evidence supporting these FDA alerts to provide effective patient care and to avoid unwarranted changes in therapy. Conversely, paying attention to these warnings in cases involving high-risk patients can prevent adverse effects and litigation. This article reviews the evidence behind recent FDA alerts for drugs with adverse CV effects and discusses the clinical practice implications. PMID- 24347044 TI - Distinct patterns of global promoter methylation in early stage chronic lymphocytic leukemia. AB - Genomic and epigenomic studies of chronic lymphocytic leukemia (CLL) are reshaping our understanding of the disease and have provided new perspectives for a more individualized diagnosis and new potential therapeutic targets. In this study, the global promoter methylation profile was determined in highly purified B-cells from 37 (Binet stage A) CLL patients, using high-resolution methylation microarrays (27,578 CpG). Overall, the methylation pattern correlated with the major biological (ZAP-70 and CD38), and molecular (IGHV mutation) markers, distinguishing CLL cases according to IGHV mutational status. Cell adhesion molecules were enriched in the signature of unmutated (UM) versus mutated (M-) CLL. Moreover, in M-CLL CpG hyper-methylation in three genes, including SPG20, was significantly anti-correlated with the corresponding gene expression level. Finally, the correlation between the methylation pattern and clinical parameters was investigated. Notably, out of 42 methyl-probes that were significantly associated with progression free survival (PFS), hyper-methylation of SPG20 was also positively associated with PFS. These data support the notion that epigenetic changes have clinical impact in CLL and may contribute to the identification of novel candidate disease-associated genes potentially useful to predict the clinical outcome of early stage CLL patients. PMID- 24347045 TI - Isolation and phylogenetic analysis of an orf virus from sheep in Makhdoom, India. AB - Orf (contagious ecthyma) is an exanthematic disease caused by a parapoxvirus and occurs primarily in sheep and goats with zoonotic implications. In the present investigation, an orf outbreak in the Muzzaffarnagari sheep flock at the Central Institute for Research on Goats (CIRG), Makhdoom, Mathura, Uttar Pradesh, India, was investigated. Primary goat testes cell culture was used for isolation of the orf virus (ORFV) for the first time. The identity of the virus was confirmed by amplification and sequence analysis of the major envelope glycoprotein (B2L) gene and named ORFV/sheep/India/2012/CIRG. On phylogenetic analysis of B2L protein gene, it clustered with the ORFV strains from China suggesting distinct ORFV strains are circulating in India. On comparison of nucleotide and deduced amino acid sequence analysis (n = 63), a unique 126S residue was observed in ORFV/sheep/India/2012/CIRG. On further sequence analysis (B2L) of different ORFV strains (n = 63), some conserved amino acid residues were identified as host specific (sheep, human, camel, takin, and musk ox) and have been summarized. PMID- 24347046 TI - Risk factors for revision within 10 years of total knee arthroplasty. AB - BACKGROUND: An in-depth understanding of risk factors for revision TKA is needed to minimize the burden of revision surgery. Previous studies indicate that hospital and community characteristics may influence outcomes after TKA, but a detailed investigation in a diverse population is warranted to identify opportunities for quality improvement. QUESTIONS/PURPOSES: We asked: (1) What is the frequency of revision TKA within 10 years of primary arthroplasty? (2) Which patient demographic factors are associated with revision within 10 years of TKA? (3) Which community and institutional characteristics are associated with revision within 10 years of TKA? METHODS: We identified 301,955 patients who underwent primary TKAs in New York or California from 1997 to 2005 from statewide databases. Identifier codes were used to determine whether they underwent revision TKA. Patient, community, and hospital characteristics were analyzed using multivariable regression modeling to determine predictors for revision. RESULTS: The frequency of revision was 4.0% at 5 years after the index arthroplasty and 8.9% at 9-years. Patients between 50 and 75 years old had a lower risk of revision than patients younger than 50 years (hazard ratio [HR], 0.47; 95% CI, 0.44, 0.50). Black patients were at increased risk for needing revision surgery (HR, 1.39; 95% CI, 1.29, 1.49) after adjustment for insurance type, poverty level, and education. Women (HR, 0.82; 95% CI, 0.79, 0.86) and Medicare recipients (HR, 0.82; 95% CI, 0.79, 0.86) were less likely to undergo revision surgery, whereas those from the most educated (HR, 1.09; 95% CI, 1.02, 1.16) and the poorest communities (HR, 1.08; 95% CI, 1.01, 1.15) had modest increases in risk of revision. Mid-volume hospitals (200-400 annual cases) had a reduction of early revision (HR, 0.91; 95% CI, 0.83, 0.99) compared with those performing less than 200 cases annually, whereas higher-volume hospitals (greater than 400 cases) showed little effect compared with low-volume hospitals. CONCLUSIONS: Patient, community, and institutional characteristics affect the risk for revision within 10 years of index TKA. These data can be used to develop process improvement and implant surveillance strategies among high-risk patients. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence. PMID- 24347047 TI - Effects of silver nanoparticles on oxidative DNA damage-repair as a function of p38 MAPK status: a comparative approach using human Jurkat T cells and the nematode Caenorhabditis elegans. AB - The large-scale use of silver nanoparticles (AgNPs) has raised concerns over potential impacts on the environment and human health. We previously reported that AgNP exposure causes an increase in reactive oxygen species, DNA damage, and induction of p38 MAPK and PMK-1 in Jurkat T cells and in Caenorhabditis elegans. To elucidate the underlying mechanisms of AgNP toxicity, here we evaluate the effects of AgNPs on oxidative DNA damage-repair (in human and C. elegans DNA glycosylases hOGG1, hNTH1, NTH-1, and 8-oxo-GTPases-hMTH1, NDX-4) and explore the role of p38 MAPK and PMK-1 in this process. Our comparative approach examined viability, gene expression, and enzyme activities in wild type (WT) and p38 MAPK knock-down (KD) Jurkat T cells (in vitro) and in WT and pmk-1 loss-of-function mutant strains of C. elegans (in vivo). The results suggest that p38 MAPK/PMK-1 plays protective role against AgNP-mediated toxicity, reduced viability and greater accumulation of 8OHdG was observed in AgNP-treated KD cells, and in pmk-1 mutant worms compared with their WT counterparts, respectively. Furthermore, dose dependent alterations in hOGG1, hMTH1, and NDX-4 expression and enzyme activity, and survival in ndx-4 mutant worms occurred following AgNP exposure. Interestingly, the absence or depletion of p38 MAPK/PMK-1 caused impaired and additive effects in AgNP-induced ndx-4(ok1003); pmk-1(RNAi) mutant survival, and hOGG1 and NDX-4 expression and enzyme activity, which may lead to higher accumulation of 8OHdG. Together, the results indicate that p38 MAPK/PMK-1 plays an important protective role in AgNP-induced oxidative DNA damage-repair which is conserved from C. elegans to humans. PMID- 24347048 TI - Effect of acute hexavalent chromium exposure on pituitary-thyroid axis of a freshwater fish, Channa punctatus (Bloch). AB - Acute exposure to hexavalent chromium (10 mg L(-1) , 20 mg L(-1) , and 40 mg L( 1) potassium dichromate for 96 h) dose-dependently affected the pituitary-thyroid axis of teleost, Channa punctatus. Significant hypertrophy of the thyroid follicle was observed in 20 mg L(-1) and 40 mg L(-1) groups; the follicular epithelium was however hypertrophied only in 40 mg L(-1) group. The colloid depletion in the lumen of thyroid follicle was evident in 20 mg L(-1) and 40 mg L(-1) groups. Serum thyroid hormones (thyroxine/T4 and triiodothyronine/T3) level increased significantly at both the higher doses. Increased immunointensity and significant hypertrophy of the pituitary thyrotrophs (anti TSHbeta-immunoreactive cells) was observed in both 20 mg L(-1) and 40 mg L(-1) chromium-exposed fish. The increased thyroid hormones secretion observed in this study might be an adaptive response of the pituitary-thyroid axis under acute chromium-induced stress condition to maintain homeostasis. The long-term Cr(VI) exposures, however, may lead to attenuation/exhaustion of the pituitary-thyroid axis and pose serious threat to fish health and affect their population. PMID- 24347049 TI - Direct amine-functionalisation of gamma-Fe2O3 nanoparticles. AB - A novel and simple preparation of amine-modified gamma-Fe2O3 nanoparticles is described. The presence of amine groups on the surface, instead of hydroxyl groups, will allow conjugation of biologically active molecules to the iron oxide nanoparticles without the need for a size increasing silica shell. Furthermore, the outer amine-layer increases the temperature of the gamma-Fe2O3 to alpha-Fe2O3 structural transition in a similar way to previously reported cationic substitutions. This may suggest the formation of an oxide-nitride outer layer. Re dispersion of the amine-modified gamma-Fe2O3 nanoparticles led to the preparation of stable ferrofluids. PMID- 24347050 TI - Computationally simple estimation and improved efficiency for special cases of double truncation. AB - Doubly truncated survival data arise when event times are observed only if they occur within subject specific intervals of times. Existing iterative estimation procedures for doubly truncated data are computationally intensive (Turnbull 38:290-295, 1976; Efron and Petrosian 94:824-825, 1999; Shen 62:835-853, 2010a). These procedures assume that the event time is independent of the truncation times, in the sample space that conforms to their requisite ordering. This type of independence is referred to as quasi-independence. In this paper we identify and consider two special cases of quasi-independence: complete quasi-independence and complete truncation dependence. For the case of complete quasi-independence, we derive the nonparametric maximum likelihood estimator in closed-form. For the case of complete truncation dependence, we derive a closed-form nonparametric estimator that requires some external information, and a semi-parametric maximum likelihood estimator that achieves improved efficiency relative to the standard nonparametric maximum likelihood estimator, in the absence of external information. We demonstrate the consistency and potentially improved efficiency of the estimators in simulation studies, and illustrate their use in application to studies of AIDS incubation and Parkinson's disease age of onset. PMID- 24347051 TI - Spatial quantitation of FISH signals in diploid versus aneuploid nuclei. AB - Fluorescence in situ hybridization (FISH) is the most widely used molecular technique to visualize chromosomal abnormalities. Here, we describe a novel 3D modeling approach to allow precise shape estimation and localization of FISH signals in the nucleus of human embryonic stem cells (hES) undergoing progressive but defined aneuploidy. The hES cell line WA09 acquires an extra copy of chromosome 12 in culture with increasing passages. Both diploid and aneuploid nuclei were analyzed to quantitate the differences in the localization of centromeric FISH signals for chromosome 12 as it transitions from euploidy to aneuploidy. We employed superquadric modeling primitives coupled with principal component analysis to determine the 3D position of FISH signals within the nucleus. A novel aspect of our modeling approach is that it allows comparison of FISH signals across multiple cells by normalizing the position of the centromeric signals relative to a reference landmark in oriented nuclei. Using this model we present evidence of changes in the relative positioning of centromeres in trisomy 12 cells when compared with diploid cells from the same population. Our analysis also suggests a significant change in the spatial distribution of at least one of the FISH signals in the aneuploid chromosome complements implicating that an overall change in centromere position may occur in trisomy-12 due to the addition of an extra chromosome. These studies underscore the unique utility of our modeling algorithms in quantifying FISH signals in three dimensions. PMID- 24347052 TI - Core-sheath carbon nanostructured fibers for efficient wire-shaped dye-sensitized solar cells. AB - A novel core-sheath carbon nanostructured fiber is created with high tensile strength, electrical conductivity, and electrocatalytic activity. In particular, the designed ribbon-like nanostructure on the outer surface favors the attachment and impregnation of a second functional phase that is critical for electronic devices. As a demonstration, novel wire-shaped dye-sensitized solar cells are produced with high energy conversion efficiencies up to 6.83%. PMID- 24347053 TI - New cancer cachexia rat model generated by implantation of a peritoneal dissemination-derived human stomach cancer cell line. AB - Cancer cachexia (CC), a syndrome characterized by anorexia and body weight loss due to low fat-free mass levels, including reduced musculature, markedly worsens patient quality of life. Although stomach cancer patients have the highest incidence of cachexia, few experimental models for the study of stomach CC have been established. Herein, we developed stomach CC animal models using nude rats subcutaneously implanted with two novel cell lines, i.e., MKN45c185, established from the human stomach cancer cell line MKN-45, and 85As2, derived from peritoneal dissemination of orthotopically implanted MKN45c185 cells in mice. Both CC models showed marked weight loss, anorexia, reduced musculature and muscle strength, increased inflammatory markers, and low plasma albumin levels; however, CC developed earlier and was more severe in rats implanted with 85As2 than in those implanted with MKN45cl85. Moreover, human leukemia inhibitory factor (LIF), a known cachectic factor, and hypothalamic orexigenic peptide mRNA levels increased in the models, whereas hypothalamic anorexigenic peptide mRNA levels decreased. Surgical removal of the tumor not only abolished cachexia symptoms but also reduced plasma LIF levels to below detectable limits. Importantly, oral administration of rikkunshito, a traditional Japanese medicine, substantially ameliorated CC-related anorexia and body composition changes. In summary, our novel peritoneal dissemination-derived 85As2 rat model developed severe cachexia, possibly caused by LIF from cancer cells, that was ameliorated by rikkunshito. This model should provide a useful tool for further study into the mechanisms and treatment of stomach CC. PMID- 24347055 TI - Placental mitochondrial content and function in intrauterine growth restriction and preeclampsia. AB - Intrauterine growth restriction (IUGR) and pregnancy hypertensive disorders such as preeclampsia (PE) associated with IUGR share a common placental phenotype called "placental insufficiency", originating in early gestation when high availability of energy is required. Here, we assess mitochondrial content and the expression and activity of respiratory chain complexes (RCC) in placental cells of these pathologies. We measured mitochondrial (mt)DNA and nuclear respiratory factor 1 (NRF1) expression in placental tissue and cytotrophoblast cells, gene and protein expressions of RCC (real-time PCR and Western blotting) and their oxygen consumption, using the innovative technique of high-resolution respirometry. We analyzed eight IUGR, six PE, and eight uncomplicated human pregnancies delivered by elective cesarean section. We found lower mRNA levels of complex II, III, and IV in IUGR cytotrophoblast cells but no differences at the protein level, suggesting a posttranscriptional compensatory regulation. mtDNA was increased in IUGR placentas. Both mtDNA and NRF1 expression were instead significantly lower in their isolated cytotrophoblast cells. Finally, cytotrophoblast RCC activity was significantly increased in placentas of IUGR fetuses. No significant differences were found in PE placentas. This study provides genuine new data into the complex physiology of placental oxygenation in IUGR fetuses. The higher mitochondrial content in IUGR placental tissue is reversed in cytotrophoblast cells, which instead present higher mitochondrial functionality. This suggests different mitochondrial content and activity depending on the placental cell lineage. Increased placental oxygen consumption might represent a limiting step in fetal growth restriction, preventing adequate oxygen delivery to the fetus. PMID- 24347054 TI - Dipeptidyl peptidase IV inhibitor lowers PPARgamma agonist-induced body weight gain by affecting food intake, fat mass, and beige/brown fat but not fluid retention. AB - Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists like pioglitazone (PGZ) are effective antidiabetic drugs, but they induce fluid retention and body weight (BW) gain. Dipeptidyl peptidase IV (DPP IV) inhibitors are antidiabetic drugs that enhance renal Na(+) and fluid excretion. Therefore, we examined whether the DPP IV inhibitor alogliptin (ALG) ameliorates PGZ-induced BW gain. Male Sv129 mice were treated with vehicle (repelleted diet), PGZ (220 mg/kg diet), ALG (300 mg/kg diet), or a combination of PGZ and ALG (PGZ + ALG) for 14 days. PGZ + ALG prevented the increase in BW observed with PGZ but did not attenuate the increase in body fluid content determined by bioimpedance spectroscopy (BIS). BIS revealed that ALG alone had no effect on fat mass (FM) but enhanced the FM-lowering effect of PGZ; MRI analysis confirmed the latter and showed reductions in visceral and inguinal subcutaneous (sc) white adipose tissue (WAT). ALG but not PGZ decreased food intake and plasma free fatty acid concentrations. Conversely, PGZ but not ALG increased mRNA expression of thermogenesis mediator uncoupling protein 1 in epididymal WAT. Adding ALG to PGZ treatment increased the abundance of multilocular cell islets in sc WAT, and PGZ + ALG increased the expression of brown-fat-like "beige" cell marker TMEM26 in sc WAT and interscapular brown adipose tissue and increased rectal temperature vs. vehicle. In summary, DPP IV inhibition did not attenuate PPARgamma agonist induced fluid retention but prevented BW gain by reducing FM. This involved ALG inhibition of food intake and was associated with food intake-independent synergistic effects of PPARgamma agonism and DPP-IV inhibition on beige/brown fat cells and thermogenesis. PMID- 24347056 TI - Validation of surrogate indexes of insulin sensitivity in acute phase of myocardial infarction based on euglycemic-hyperinsulinemic clamp. AB - The decrease in insulin sensitivity (IS) during myocardial infarction (MI) is recognized as a possible contributor to poor patient outcomes. Despite its potential relevance, a standardized and convenient IS assessment tool has yet to be established for said clinical scenarios. This study aimed to validate the accuracy of surrogate indexes in determining IS in acute MI patients by comparison with the gold standard reference method for measuring IS, the euglycemic-hyperinsulinemic clamp (EHC). We performed EHCs in 31 consecutive nondiabetic patients who were admitted within the first 24 h of symptoms of ST segment elevation MI. Patients with prior diagnosis of diabetes, use of hypoglycemic agents, or a glycosylated hemoglobin >=6.5% were excluded. EHCs were performed at the second day (D2) and sixth day (D6) post-MI. Basal (12-h fasting) blood samples from D2 and D6 were used to evaluate patient blood glucose and insulin levels. We then calculated the following surrogate indexes: homeostatic model assessment of insulin sensitivity (HOMA2S), homeostatic model assessment of insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI). The IS index measured by EHC (ISiclamp) was correlated to HOMA2S, HOMA IR, and QUICKI at D2 (r = 0.485, P = 0.009; r = -0.384, P = 0.048; r = 0.479, P = 0.01, respectively) and D6 (r = 0.621, P = 0.002; r = -0.576, P = 0.006; r = 0.626, P = 0.002, respectively). Receiver operator characteristic curves made for discrimination of ISiclamp above the median in D2 and D6 depicted areas under the curve of 0.740, 0.734, and 0.760 for HOMA2S, HOMA-IR, and QUICKI, respectively. Bland-Altman plots displayed no apparent systematic error for indexes, but a propensity for proportional error, particularly with HOMA-IR. Thus, based on EHC, these simple surrogate indexes are feasible for assessing IS during MI. PMID- 24347057 TI - Blockade of the cerebral aqueduct in rats provides evidence of antagonistic leptin responses in the forebrain and hindbrain. AB - Previously, we reported that low-dose leptin infusions into the fourth ventricle produced a small but significant increase in body fat. These data contrast with reports that injections of higher doses of leptin into the fourth ventricle inhibit food intake and weight gain. In this study, we tested whether exogenous leptin in the fourth ventricle opposed or contributed to weight loss caused by third ventricle leptin infusion by blocking diffusion of CSF from the third to the fourth ventricle. Male Sprague-Dawley rats received third ventricle infusions of PBS or 0.3 MUg leptin/24 h from miniosmotic pumps. After 4 days, rats received a 3-MUl cerebral aqueduct injection of saline or of thermogelling nanoparticles (hydrogel) that solidified at body temperature. Third ventricle leptin infusion inhibited food intake and caused weight loss. Blocking the aqueduct exaggerated the effect of leptin on food intake and weight loss but had no effect on the weight of PBS-infused rats. Leptin reduced both body fat and lean body mass but did not change energy expenditure. Blocking the aqueduct decreased expenditure of rats infused with PBS or leptin. Infusion of leptin into the third ventricle increased phosphorylated STAT3 in the VMHDM of the hypothalamus and the medial NTS in the hindbrain. Blocking the aqueduct did not change hypothalamic p-STAT3 but decreased p-STAT3 in the medial NTS. These results support previous observations that low-level activation of hindbrain leptin receptors has the potential to blunt the catabolic effects of leptin in the third ventricle. PMID- 24347058 TI - Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine. AB - UCP1-Tg mice with ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle (SM) are a model of improved substrate metabolism and increased longevity. Analysis of myokine expression showed an induction of fibroblast growth factor 21 (FGF21) in SM, resulting in approximately fivefold elevated circulating FGF21 in UCP1-Tg mice. Despite a reduced muscle mass, UCP1-Tg mice showed no evidence for a myopathy or muscle autophagy deficiency but an activation of integrated stress response (ISR; eIF2alpha/ATF4) in SM. Targeting mitochondrial function in vitro by treating C2C12 myoblasts with the uncoupler FCCP resulted in a dose-dependent activation of ISR, which was associated with increased expression of FGF21, which was also observed by treatment with respiratory chain inhibitors antimycin A and myxothiazol. The cofactor required for FGF21 action, beta-klotho, was expressed in white adipose tissue (WAT) of UCP1-Tg mice, which showed an increased browning of WAT similar to what occurred in altered adipocyte morphology, increased brown adipocyte markers (UCP1, CIDEA), lipolysis (HSL phosphorylation), and respiratory capacity. Importantly, treatment of primary white adipocytes with serum of transgenic mice resulted in increased UCP1 expression. Additionally, UCP1-Tg mice showed reduced body length through the suppressed IGF-I-GH axis and decreased bone mass. We conclude that the induction of FGF21 as a myokine is coupled to disturbance of mitochondrial function and ISR activation in SM. FGF21 released from SM has endocrine effects leading to increased browning of WAT and can explain the healthy metabolic phenotype of UCP1-Tg mice. These results confirm muscle as an important endocrine regulator of whole body metabolism. PMID- 24347059 TI - AICAR-induced activation of AMPK negatively regulates myotube hypertrophy through the HSP72-mediated pathway in C2C12 skeletal muscle cells. AB - 5'-AMP-activated protein kinase (AMPK) plays an important role as a negative regulator of skeletal muscle mass. However, the precise mechanism of AMPK mediated regulation of muscle mass is not fully clarified. Heat shock proteins (HSPs), stress-induced molecular chaperones, are related with skeletal muscle adaptation, but the association between AMPK and HSPs in skeletal muscle hypertrophy is unknown. Thus, we investigated whether AMPK regulates hypertrophy by mediating HSPs in C2C12 cells. The treatment with AICAR, a potent stimulator of AMPK, decreased 72-kDa HSP (HSP72) expression, whereas there were no changes in the expressions of 25-kDa HSP, 70-kDa heat shock cognate, and heat shock transcription factor 1 in myotubes. Protein content and diameter were less in the AICAR-treated myotubes in those without treatment. AICAR-induced suppression of myotube hypertrophy and HSP72 expression was attenuated in the siRNA-mediated AMPKalpha knockdown myotubes. AICAR increased microRNA (miR)-1, a modulator of HSP72, and the increase of miR-1 was not induced in AMPKalpha knockdown condition. Furthermore, siRNA-mediated HSP72 knockdown blocked AICAR-induced inhibition of myotube hypertrophy. AICAR upregulated the gene expression of muscle Ring-finger 1, and this alteration was suppressed in either AMPKalpha or HSP72 knockdown myotubes. The phosphorylation of p70 S6 kinase Thr(389) was downregulated by AICAR, whereas this was attenuated in AMPKalpha, but not in HSP72, knockdown myotubes. These results suggest that AMPK inhibits hypertrophy through, in part, an HSP72-associated mechanism via miR-1 and protein degradation pathways in skeletal muscle cells. PMID- 24347060 TI - Role of bone morphogenetic protein 4 in the differentiation of brown fat-like adipocytes. AB - There are two different types of fat present in mammals: white adipose tissue, the primary site of energy storage, and brown adipose tissue, which is specializes in energy expenditure. Factors that specify the developmental fate and function of brown fat are poorly understood. Bone morphogenic proteins (BMPs) play an important role in adipogenesis. While BMP4 is capable of triggering commitment of stem cells to the white adipocyte lineage, BMP7 triggers commitment of progenitor cells to a brown adipocyte lineage and activates brown adipogenesis. To investigate the differential effects of BMPs on the development of adipocytes, C3H10T1/2 pluripotent cells were pretreated with BMP4 and BMP7, followed by different adipogenic induction cocktails. Both BMP4 and BMP7 unexpectedly activated a full program of brown adipogenesis, including induction of the brown fat-defining marker uncoupling protein-1 (UCP1), increasing the expression of early regulators of brown fat fate PRDM16 (PR domain-containing 16) and induction of mitochondrial biogenesis and function. Implantation of BMP4 pretreated C3H10T1/2 cells into nude mice resulted in the development of adipose tissue depots containing UCP1-positive brown adipocytes. Interestingly, BMP4 could also induce brown fat-like adipocytes in both white and brown preadipocytes, thereby decreasing the classical brown adipocyte marker Zic1 and increasing the recently identified beige adipocyte marker TMEM26. The data indicate an important role for BMP4 in promoting brown adipocyte differentiation and thermogenesis in vivo and in vitro and offers a potentially new therapeutic approach for the treatment of obesity. PMID- 24347061 TI - Tolerance of an aerobic denitrifier (Pseudomonas stutzeri) to high O2 concentrations. AB - An aerobic denitrifier was isolated from activated sludge and the isolate possessed an average removal rate of 5.7 mg NO3 (-)-N l(-1) h(-1) without accumulation of NO2 (-)-N (less than 2.1 mg l(-1)). The average removal efficiency of nitrate was 93.7 % in 24 h, when the dissolved oxygen (DO) concentrations ranged from 3.2 to 17.5 mg l(-1). The activity of both nap (periplasmic nitrate reductase) and nir (nitrite reductase), whose corresponding genes (napA and nirS) were amplified by touchdown PCR, could be responsible for the tolerance of DO concentrations. Other three genes relating to narG, norB and nosZ were noted to involve in isolate strain. PMID- 24347063 TI - A good year. PMID- 24347062 TI - Pediatric temporal bone fractures: current trends and comparison of classification schemes. AB - OBJECTIVES: 1) Characterize the current presentation of pediatric temporal bone fractures, 2) compare two classification schemes for temporal bone fractures and illustrate complications in each fracture type. DESIGN: Retrospective medical record review. SETTING: Tertiary-care, academic children's hospital. PATIENTS: All children presenting from 1999 to 2009 with CT-proven temporal bone fracture and audiology examination with follow-up. INTERVENTION: All CT scans were reinterpreted by a dedicated head and neck radiologist. All fractures were characterized as otic capsule sparing (OCS) or otic capsule violating (OCV), as well as transverse (T) or longitudinal (L). OUTCOME: CT findings, mechanisms of injury, sensorineural hearing loss (SNHL), conductive hearing loss (CHL), and facial nerve injury (FNI). RESULTS: Seventy-one children met inclusion criteria. Fifty-four (76%) children had longitudinal fractures versus 17 (24%) with transverse fractures. Sixty-four (90%) had OCS versus 7 (10%) with OCV. The otic capsule was involved in 7.4% of longitudinal fractures and 17.6% of transverse fractures. Eleven (15%) had facial weakness, 72% of whom had a visualized fracture through the facial nerve course. SNHL was detected in 14 (20%) patients and CHL in 17(23.9%). All patients with fractures classified as both transverse and OCV had SNHL. The OCS versus OCV and T versus L classification schemes were directly compared for statistical significance in predicting SNHL, CHL, and FNI using the Fisher's exact test. Both OCS/OCV and T/L were predictors of SNHL (P = .0025 and P = .0143, respectively), but the OCS/OCV scheme was more accurate. Neither classification significantly predicted CHL or FNI (P = .787 versus .825; P = .705 vs. .755). CONCLUSIONS: In this pediatric series, approximately 75% of the fractures are longitudinal and 25% are transverse. The otic capsule is spared in 90% and violated in 10%. Both OCS/OCV and L/T classification schemes predict SNHL, but the OCV/OCS scheme is more accurate in this prediction. Although the negative predictive value of the two schemes is similar, the positive predictive value is higher with the OCS/OCV system. The presence of conductive hearing loss and facial nerve symptoms was not predicted by either classification system. PMID- 24347066 TI - The combination of chemotherapy and radiotherapy towards more efficient drug delivery. AB - Research on anticancer therapies has advanced significantly in recent years. New therapeutic platforms that can further improve the health of patients are still highly demanded. We propose the idea of combining regular chemotherapy with radiation therapy to minimize side effects as well as increase drug-delivery efficiency. In this Focus Review, we seek to provide an overview of recent advances that can combine chemotherapy and radiotherapy. We begin by reviewing the current state of systems that can combine chemotherapy and gamma radiation. Among them, diselenide-containing polymers are highlighted as sensitive drug delivery vehicles that can disassemble under gamma radiation. Then X-ray responsive materials as promising alternative systems are summarized, including X ray responsive drug-delivery vehicles, prodrugs that can be activated by X-rays, and radiation-site-targeting systems. Finally, we describe strategies that involve phototherapies. PMID- 24347067 TI - Chemoenzymatic routes to polyoxygenated cyclooctenones related to the Eastern hemisphere of the macrolactam tripartilactam. AB - Polyoxygenated cyclooctenones closely related to the enantiomeric form of the Eastern hemisphere of the structurally and biogenetically unusual macrolactam tripartilactam have been assembled from an enzymatically-derived and homochiral cis-1,2-dihydrocatechol. Key steps include the oxidative cleavage of the chlorinated double bond within a derivative of the starting cis-1,2 dihydrocatechol and a ring-closing metathesis reaction to establish the required eight-membered ring. PMID- 24347068 TI - Chemoselective hydrogenation of functionalized nitroarenes and imines by using carbon nanofiber-supported iridium nanoparticles. AB - The reaction of three types of carbon nanofibers (CNFs; platelet: CNF-P, tubular: CNF-T, herringbone: CNF-H) with Ir4(CO)12 in mesitylene at 165 degrees C provided the corresponding CNF-supported iridium nanoparticles, Ir/CNFs (Ir content=2.3-2.6 wt.%). Transmission electron microscopy (TEM) studies of these Ir/CNF samples revealed that size-controlled Ir nanoparticles (average particle size of 1.1-1.5 nm) existed on the CNFs. Among the three Ir/CNF samples, Ir/CNF-T showed an excellent catalytic activity and chemoselectivity towards hydrogenation of functionalized nitroarenes and imines; the corresponding aniline derivatives were obtained with high turnover numbers at ambient temperature under 10 tm of H2 , and the catalyst is reusable. Ir/CNF-T was also effective for the reductive N alkylation of anilines with carbonyl compounds. PMID- 24347069 TI - Photocontrolled intramolecular charge/energy transfer and fluorescence switching of tetraphenylethene-dithienylethene-perylenemonoimide triad with donor-bridge acceptor structure. AB - Photochromic 1,2-dithienylethene (DTE) derivatives with a high thermal stability and fatigue resistance are appealing for optical switching of fluorescence. Here, we introduce a donor-photochromic bridge-acceptor tetraphenylethene dithienylethene-perylenemonoimide (TPE-DTE-PMI) triad, in which TPE acts as the electron donor, PMI as the electron acceptor, and DTE as the photochromic bridge. In this system, the localized and intramolecular charge transfer emission of TPE DTE-PMI with various Stokes shifts have been observed due to the photoinduced intramolecular charge transfer in different solvents. Upon UV irradiation, the fluorescence quenching resulting from photochromic fluorescence resonance energy transfer in TPE-DTE-PMI has been demonstrated in solution and in solid films. The fluorescence on/off switching ratio in polymethylacrylate film exceeds 100, a value much higher than in polymethylmethacrylate film, thus indicating that the fluorescence switching is dependent on matrices. PMID- 24347070 TI - Hydrophobic variations of N-oxide amphiphiles for membrane protein manipulation: importance of non-hydrocarbon groups in the hydrophobic portion. AB - Amphipathic agents called detergents serve as membrane-mimetic systems to maintain the native structures of membrane proteins during their manipulation. However, membrane proteins solubilized in conventional detergents tend to undergo denaturation and aggregation, necessitating the development of novel amphipathic agents with enhanced properties. Here we describe several new amphiphiles that contain an N-oxide group as the hydrophilic portion. The new amphiphiles have been evaluated for the ability to solubilize and stabilize a fragile multi subunit assembly from biological membranes. We found that cholate-based agents were promising in supporting retention of the native protein quaternary structure, while deoxycholate-based amphiphiles were highly efficient in extracting/solubilizing the intact superassembly from the native membrane. Monitoring superassembly solubilization and stabilization as a function of variation in amphiphile structure led us to propose that a non-hydrocarbon moiety such as an amide, ether, or a hydroxy group present in the lipophilic regions can manifest distinctive effects in the context of membrane protein manipulation. PMID- 24347071 TI - Pyridinium-fused pyridinone: a novel "turn-on" fluorescent chemodosimeter for cyanide. AB - A new chemodosimeter based on pyridinium-fused pyridinone iodide (PI) has been obtained through a "clean reaction" method. This compound can detect CN(-) in aqueous solution with a high selectivity and rapid response. The detection of CN( ) occurs through the nucleophilic attack of CN(-) on the C=N bond, which induces the destruction of the pi-conjugation on the pyridinium ring. Support of this detection mechanism was obtained by (1)H NMR titration, HR-MS, and DFT calculations. Upon the addition of 10 equivalents CN(-) to a solution of PI in THF/H2 O (1:1, v/v), a 57-fold enhancement in fluorescence intensity was observed at the maximum emission wavelength of 457 nm. Meanwhile, the maximum absorption wavelength was also blue-shifted from 447 nm to 355 nm. Other common anions such as BF4(-), PF6(-), F(-), Cl(-), Br(-), I(-), H2PO4(-), ClO4(-), CH3 COO(-) , NO2 (-) , N3 (-) , and SCN(-) had little effect on the detection of CN(-). The response time of PI for CN(-) was less than 5 seconds. The detection limit was calculated to be 5.4*10(-8) M, which is lower than the maximum permission concentration in drinking water (1.9 MUM) set by the World Health Organization (WHO). PMID- 24347072 TI - Highly selective "turn-on" fluorescent and colorimetric sensing of fluoride ion using 2-(2-hydroxyphenyl)-2,3-dihydroquinolin-4(1H)-one based on excited-state proton transfer. AB - A simple, highly selective and sensitive colorimetric system for the detection of fluoride ion in an aqueous medium has been developed using 2-(2-hydroxyphenyl) 2,3-dihydroquinolin-4(1H)-one. This system allows selective "turn-on" fluorescence detection of fluoride ion, which is found to be dependent upon guest basicity. An excited-state proton transfer is proposed to be the signaling mechanism, which is rationalized by DFT and TD-DFT calculations. The present sensor can also be applied to detect fluoride levels in real water samples. PMID- 24347073 TI - Copper-catalyzed C-H bond direct chalcogenation of aromatic compounds leading to diaryl sulfides, selenides, and diselenides by using elemental sulfur and selenium as chalcogen sources under oxidative conditions. AB - The reactions of aromatic compounds and elemental chalcogens catalyzed by a copper salt with molecular oxygen as an oxidant were carried out. The reaction of 3-substituted imidazo[1,5-a]pyridines and elemental sulfur in the presence of CuTC (copper(I) thiophenecarboxylate) gave the corresponding bisimidazopyridyl sulfides in good to quantitative yields. The reaction proceeded even under aerobic oxidation conditions. The use of a polar solvent was crucial for the reaction, and DMSO (dimethyl sulfoxide) in particular stimulated the reaction. The reaction could be applied to common aromatic compounds, such as N-methyl indole and dialkyl anilines. The reaction of indole proceeded at the nucleophilic C3 position rather than at the acidic C2 position. In addition, the reaction of dialkyl anilines proceeded with an ortho, para orientation. The reactions of imidazopyridines and elemental selenium under similar conditions gave the corresponding bisimidazopyridyl diselenides along with bisimidazopyridyl monoselenides. The resulting diselenides were readily converted to the corresponding monoselenides with unreacted imidazopyridines under the same conditions. The reaction could be applied to the copolymerization of bifunctional bisimidazopyridines and elemental sulfur to give oligomeric copolymers in quantitative yield. PMID- 24347075 TI - Compositing amorphous TiO2 with N-doped carbon as high-rate anode materials for lithium-ion batteries. AB - Compositing amorphous TiO2 with nitrogen-doped carbon through Ti-N bonding to form an amorphous TiO2/N-doped carbon hybrid (denoted a-TiO2/C-N) has been achieved by a two-step hydrothermal-calcining method with hydrazine hydrate as an inhibitor and nitrogen source. The resultant a-TiO2/C-N hybrid has a surface area as high as 108 m(2) g(-1) and, when used as an anode material, exhibits a capacity as high as 290.0 mA h g(-1) at a current rate of 1 C and a reversible capacity over 156 mA h g(-1) at a current rate of 10 C after 100 cycles; these results are better than those found in most reports on crystalline TiO2 . This superior electrochemical performance could be ascribed to a combined effect of several factors, including the amorphous nature, porous structure, high surface area, and N-doped carbon. PMID- 24347074 TI - Gold nanorods with phase-changing polymer corona for remotely near-infrared triggered drug release. AB - Herein, we report a new drug-delivery system (DDS) that is comprised of a near infrared (NIR)-light-sensitive gold-nanorod (GNR) core and a phase-changing poly(epsilon-caprolactone)-b-poly(ethylene glycol) polymer corona (GNR@PCL-b PEG). The underlying mechanism of the drug-loading and triggered-release behaviors involves the entrapment of drug payloads among the PCL crystallites and a heat-induced phase change, respectively. A low premature release of the pre loaded doxorubicin was observed in PBS buffer (pH 7.4) at 37 degrees C (<10% of the entire payload after 48 h). However, release could be activated within 30 min by conventional heating at 50 degrees C, above the Tm of the crystalline PCL domain (43.5 degrees C), with about 60% release over the subsequent 42 h at 37 degrees C. The NIR-induced heating of an aqueous suspension of GNR@PCL-b-PEG under NIR irradiation (802 nm) was investigated in terms of the irradiation period, power, and concentration-dependent heating behavior, as well as the NIR induced shape-transformation of the GNR cores. Remotely NIR-triggered release was also explored upon NIR irradiation for 30 min and about 70% release was achieved in the following 42 h at 37 degrees C, with a mild warming (<4 degrees C) of the surroundings. The cytotoxicity of GNR@PCL-b-PEG against the mouse fibroblastic-like L929 cell-line was assessed by MTS assay and good compatibility was confirmed with a cell viability of over 90% after incubation for 72 h. The cellular uptake of GNR@PCL-b-PEG by melanoma MEL-5 cells was also confirmed, with an averaged uptake of 1250(+/-110) particles cell(-1) after incubation for 12 h (50 MUg mL(-1)). This GNR@PCL-b-PEG DDS is aimed at addressing the different requirements for therapeutic treatments and is envisaged to provide new insights into DDS targeting for remotely triggered release by NIR activation. PMID- 24347076 TI - High-performance dye-sensitized solar cells based on phenothiazine dyes containing double anchors and thiophene spacers. AB - A series of new push-pull phenothiazine-based dyes (HL1-HL4) featuring various pi spacers (thiophene, 3-hexylthiophene, 4-hexyl-2,2'-bithiophene) and double acceptors/anchors have been synthesized, characterized, and used as sensitizers for dye-sensitized solar cells (DSSCs). Among them, the best conversion efficiency (7.31%) reaches approximately 99% of the N719-based (7.38%) DSSCs fabricated and measured under similar conditions. The dyes with two anchors have more efficient interfacial charge generation and transport compared with their congeners with only single anchor. Incorporation of hexyl chains into the pi conjugated spacer of these double-anchoring dyes can efficiently suppress dye aggregation and reduce charge recombination. PMID- 24347077 TI - Inhaled corticosteroids and bone mineral density at school age: a follow-up study after early childhood wheezing. AB - OBJECTIVE: The aim of the study was to evaluate the association between previous use of ICS and bone mineral density (BMD) at school age in a cohort followed after early childhood wheezing. METHODS: As part of a prospective follow-up study after hospitalization for wheezing at <24 months of age, BMD was measured in 89 children at 12.3 (median) years of age. Data on ICS use were collected by interviewing the parents, and this was supplemented with data from patient records. Cumulative doses and the duration of ICS use were calculated. Areal BMD (BMDareal , g/cm(2) ) was measured by dual energy X-ray absorptiometry (DXA), and apparent volumetric BMD (aBMDvol , g/cm(3) ) was calculated, for the lumbar spine and femoral neck. Weight, height and pubertal stage were recorded. FINDINGS: Age, sex, and pubertal stage were significantly associated with BMDareal and aBMDvol of the lumbar spine and BMDareal of the femoral neck. The regular use of ICS for >6 months at age <6 years was associated with a lower BMD of the lumbar spine. A lower BMDareal and aBMDvol of the femoral neck were associated with higher cumulative doses of ICS at age 0-12.3 (median) years. The results were robust to adjustment for age, sex, pubertal stage, height, weight, and use of systemic steroids. CONCLUSION: ICS use during childhood may be related to a decrease in BMD at late school age. It is important to use the lowest possible ICS dose that maintains adequate asthma control. PMID- 24347085 TI - Variation in phenolic compounds, anthocyanins, and color in red wine treated with enzymatic extract of Kluyveromyces marxianus. AB - The effect of the addition of enzymatic extract of Kluyveromyces marxianus NRRL-Y 7571 during the maceration and fermentation steps of Cabernet Sauvignon wine production was evaluated. The results obtained in the analytical determinations of the wines showed levels within the limits established by legislation and similar to values found in other studies. The results show that by adding the enzyme to the red wines these showed color characteristics considered to be superior to those of the control wine and accelerated the extraction of phenolic compounds and anthocyanins. It was observed that by using the commercial enzyme preparation there was an increase of 15 % in polyphenol content compared to the control wine and an increase of 28 % when the crude enzyme extract was used. Anthocyanin content in the wine increased after treatment with the commercial enzyme preparation (10 %) and with the use of the crude enzymatic extract (22 %). Considering all comparison criteria, the K. marxianus enzymatic extract showed results statistically similar or superior to those obtained with the commercial enzyme preparation. PMID- 24347086 TI - Detecting and correcting partial errors: Evidence for efficient control without conscious access. AB - Appropriate reactions to erroneous actions are essential to keeping behavior adaptive. Erring, however, is not an all-or-none process: electromyographic (EMG) recordings of the responding muscles have revealed that covert incorrect response activations (termed "partial errors") occur on a proportion of overtly correct trials. The occurrence of such "partial errors" shows that incorrect response activations could be corrected online, before turning into overt errors. In the present study, we showed that, unlike overt errors, such "partial errors" are poorly consciously detected by participants, who could report only one third of their partial errors. Two parameters of the partial errors were found to predict detection: the surface of the incorrect EMG burst (larger for detected) and the correction time (between the incorrect and correct EMG onsets; longer for detected). These two parameters provided independent information. The correct(ive) responses associated with detected partial errors were larger than the "pure-correct" ones, and this increase was likely a consequence, rather than a cause, of the detection. The respective impacts of the two parameters predicting detection (incorrect surface and correction time), along with the underlying physiological processes subtending partial-error detection, are discussed. PMID- 24347087 TI - Management of faecal incontinence and constipation in adults with central neurological diseases. AB - BACKGROUND: People with central neurological disease or injury have a much higher risk of both faecal incontinence and constipation than the general population. There is often a fine line between the two symptoms, with any management intended to ameliorate one risking precipitating the other. Bowel problems are observed to be the cause of much anxiety and may reduce quality of life in these people. Current bowel management is largely empirical, with a limited research base. This is an update of a Cochrane review first published in 2001 and subsequently updated in 2003 and 2006. The review is relevant to individuals with any disease directly and chronically affecting the central nervous system (post-traumatic, degenerative, ischaemic or neoplastic), such as multiple sclerosis, spinal cord injury, cerebrovascular disease, Parkinson's disease and Alzheimer's disease. OBJECTIVES: To determine the effects of management strategies for faecal incontinence and constipation in people with a neurological disease or injury affecting the central nervous system. SEARCH METHODS: We searched the Cochrane Incontinence Group Trials Register (searched 8 June 2012), which includes searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and MEDLINE In-Process as well as handsearching of journals and conference proceedings; and all reference lists of relevant articles. SELECTION CRITERIA: Randomised and quasi-randomised trials evaluating any type of conservative or surgical intervention for the management of faecal incontinence and constipation in people with central neurological disease or injury were selected. Specific therapies for the treatment of neurological diseases that indirectly affect bowel dysfunction were also considered. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the risk of bias of eligible trials and independently extracted data from the included trials using a range of pre specified outcome measures. MAIN RESULTS: Twenty trials involving 902 people were included.Oral medicationsThere was evidence from individual small trials that people with Parkinson's disease had a statistically significant improvement in the number of bowel motions or successful bowel care routines per week when fibre (psyllium) (mean difference (MD) -2.2 bowel motions, 95% confidence interval (CI) -3.3 to -1.4) or oral laxative (isosmotic macrogol electrolyte solution) (MD 2.9 bowel motions per week, 95% CI 1.48 to 4.32) are used compared with placebo. One trial in people with spinal cord injury showed statistically significant improvement in total bowel care time comparing intramuscular neostigmine glycopyrrolate (anticholinesterase plus an anticholinergic drug) with placebo (MD 23.3 minutes, 95% CI 4.68 to 41.92).Five studies reported the use of cisapride and tegaserod in people with spinal cord injuries or Parkinson's disease. These drugs have since been withdrawn from the market due to adverse effects; as they are no longer available they have been removed from this review.Rectal stimulantsOne small trial in people with spinal cord injuries compared two bisacodyl suppositories, one polyethylene glycol-based (PGB) and one hydrogenated vegetable oil-based (HVB). The trial found that the PGB bisacodyl suppository significantly reduced the mean defaecation period (PGB 20 minutes versus HVB 36 minutes, P < 0.03) and mean total time for bowel care (PGB 43 minutes versus HVB 74.5 minutes, P < 0.01) compared with the HVB bisacodyl suppository.Physical interventionsThere was evidence from one small trial with 31 participants that abdominal massage statistically improved the number of bowel motions in people who had a stroke compared with no massage (MD 1.7 bowel motions per week, 95% CI 2.22 to 1.18). A small feasibility trial including 30 individuals with multiple sclerosis also found evidence to support the use of abdominal massage. Constipation scores were statistically better with the abdominal massage during treatment although this was not supported by a change in outcome measures (for example the neurogenic bowel dysfunction score).One small trial in people with spinal cord injury showed statistically significant improvement in total bowel care time using electrical stimulation of abdominal muscles compared with no electrical stimulation (MD 29.3 minutes, 95% CI 7.35 to 51.25).There was evidence from one trial with a low risk of bias that for people with spinal cord injury transanal irrigation, compared against conservative bowel care, statistically improved constipation scores, neurogenic bowel dysfunction score, faecal incontinence score and total time for bowel care (MD 27.4 minutes, 95% CI 7.96 to 46.84). Patients were also more satisfied with this method.Other interventionsIn one trial in stroke patients, there appeared to be a short term benefit (less than six months) to patients in terms of the number of bowel motions per week with a one-off educational intervention from nurses (a structured nurse assessment leading to targeted education versus routine care), but this did not persist at 12 months. A trial in individuals with spinal cord injury found that a stepwise protocol did not reduce the need for oral laxatives and manual evacuation of stool.Finally, one further trial reported in abstract form showed that oral carbonated water (rather than tap water) improved constipation scores in people who had had a stroke. AUTHORS' CONCLUSIONS: There is still remarkably little research on this common and, to patients, very significant issue of bowel management. The available evidence is almost uniformly of low methodological quality. The clinical significance of some of the research findings presented here is difficult to interpret, not least because each intervention has only been addressed in individual trials, against control rather than compared against each other, and the interventions are very different from each other.There was very limited evidence from individual trials in favour of a bulk-forming laxative (psyllium), an isosmotic macrogol laxative, abdominal massage, electrical stimulation and an anticholinesterase-anticholinergic drug combination (neostigmine-glycopyrrolate) compared to no treatment or controls. There was also evidence in favour of transanal irrigation (compared to conservative management), oral carbonated (rather than tap) water and abdominal massage with lifestyle advice (compared to lifestyle advice alone). However, these findings need to be confirmed by larger well-designed controlled trials which should include evaluation of the acceptability of the intervention to patients and the effect on their quality of life. PMID- 24347088 TI - Breathing exercises for dysfunctional breathing/hyperventilation syndrome in children. AB - BACKGROUND: Dysfunctional breathing is described as chronic or recurrent changes in breathing pattern causing respiratory and non-respiratory symptoms. It is an umbrella term that encompasses hyperventilation syndrome and vocal cord dysfunction. Dysfunctional breathing affects 10% of the general population. Symptoms include dyspnoea, chest tightness, sighing and chest pain which arise secondary to alterations in respiratory pattern and rate. Little is known about dysfunctional breathing in children. Preliminary data suggest 5.3% or more of children with asthma have dysfunctional breathing and that, unlike in adults, it is associated with poorer asthma control. It is not known what proportion of the general paediatric population is affected. Breathing training is recommended as a first-line treatment for adults with dysfunctional breathing (with or without asthma) but no similar recommendations are available for the management of children. As such, breathing retraining is adapted from adult regimens based on the age and ability of the child. OBJECTIVES: To determine whether breathing retraining in children with dysfunctional breathing has beneficial effects as measured by quality of life indices.To determine whether there are any adverse effects of breathing retraining in young people with dysfunctional breathing. SEARCH METHODS: We identified trials for consideration using both electronic and manual search strategies. We searched CENTRAL, MEDLINE and EMBASE. We searched the National Research Register (NRR) Archive, Health Services Research Projects in Progress (HSRProj), Current Controlled Trials register (incorporating the metaRegister of Controlled Trials and the International Standard Randomised Controlled Trial Number (ISRCTN) to identify research in progress and unpublished research. The latest search was undertaken in October 2013. SELECTION CRITERIA: We planned to include randomised, quasi-randomised or cluster-randomised controlled trials. We excluded observational studies, case studies and studies utilising a cross-over design. The cross-over design was considered inappropriate due to the purported long-lasting effects of breathing retraining. Children up to the age of 18 years with a clinical diagnosis of dysfunctional breathing were eligible for inclusion. We planned to include children with a primary diagnosis of asthma with the intention of undertaking a subgroup analysis. Children with symptoms secondary to cardiac or metabolic disease were excluded.We considered any type of breathing retraining exercise for inclusion in this review, such as breathing control, diaphragmatic breathing, yoga breathing, Buteyko breathing, biofeedback-guided breathing modification and yawn/sigh suppression. We considered programmes where exercises were either supervised (by parents or a health professional, or both) or unsupervised. We also considered relaxation techniques and acute episode management as long as it was clear that breathing exercises were a component of the intervention.Any intervention without breathing exercises or where breathing exercises were not key to the intervention were excluded. DATA COLLECTION AND ANALYSIS: We planned that two authors (NJB and MJ) would extract data independently using a standardised form. Any discrepancies would be resolved by consensus. Where agreement could not be reached a third review author (MLE) would have considered the paper. MAIN RESULTS: We identified 264 potential trials and reviews from the search. Following removal of duplicates, we screened 224 papers based on title and abstract. We retrieved six full-text papers and further evaluated them but they did not meet the inclusion criteria. There were, therefore, no studies suitable for inclusion in this review. AUTHORS' CONCLUSIONS: The results of this systematic review cannot inform clinical practice as no suitable trials were identified for inclusion. Therefore, it is currently unknown whether these interventions offer any added value in this patient group or whether specific types of breathing exercise demonstrate superiority over others. Given that breathing exercises are frequently used to treat dysfunctional breathing/hyperventilation syndrome, there is an urgent need for well-designed clinical trials in this area. Future trials should conform to the CONSORT statement for standards of reporting and use validated outcome measures. Trial reports should also ensure full disclosure of data for all important clinical outcomes. PMID- 24347089 TI - Effects of nanoparticle-encapsulated curcumin on arsenic-induced liver toxicity in rats. AB - We investigated the therapeutic effectiveness of the nanoparticle-encapsulated curcumin (CUR-NP) against sodium arsenite-induced hepatic oxidative damage in rats. The CUR-NP prepared by emulsion technique was spherical in shape with an encapsulation efficiency of 86.5%. The particle size ranged between 120 and 140 nm with the mean particle size being 130.8 nm. Rats were divided into five groups of six each. Group 1 served as control. Group 2 rats were exposed to sodium arsenite (25 ppm) daily through drinking water for 42 days. Groups 3, 4, and 5 were treated with arsenic as in group 2, however, they were administered, empty nanoparticles, curcumin (100 mg/kg bw) and CUR-NP (100 mg/kg bw), respectively, by oral gavage during the last 14 days of arsenic exposure. Arsenic increased the activities of serum alanine aminotransferase and aspartate aminotransferase and caused histological alterations in liver indicating hepatotoxicity. Arsenic increased lipid peroxidation, depleted reduced glutathione and decreased the activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase in liver. All these effects of arsenic were attenuated with both curcumin and CUR-NP. However, the magnitude of amelioration was more pronounced with CUR-NP. The results indicate that curcumin given in nano encapsulated form caused better amelioration than free curcumin. (c) 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 628-637, 2015. PMID- 24347090 TI - Understanding the continuum of maternal morbidity in Accra, Ghana. AB - The objective was to determine the levels of maternal morbidity from no complications to near miss and describe factors associated with different levels of morbidity. We conducted an observational study of all women delivering at a tertiary hospital in Accra, Ghana between October 2010 and March 2011. We examined the factors associated with the continuum of maternal outcomes in terms of severity using multinomial logistic regression. Data were extracted from women's maternal care files with the main outcome measures of no complications, non-life threatening complications, potentially life-threatening conditions (PLTC), and near miss as defined by World Health Organization. Our study includes 1,586 women with no complications, 1,205 women with non-life threatening complications, 516 women with PLTC, and 94 near-miss cases. All of the factors associated with PLTC and near-miss cases were similar. None of the socio demographic variables remained significant in the multivariate analysis comparing different levels of severe morbidity with no complications. Women with no complications shared similar characteristics with women who experienced non-life threatening complications. As compared to women who had no complications, women who had severe morbidity were significantly more likely to have had no antenatal care. Our results underline the concept that morbidity is a continuum and indicate that if the underlying causes of poor maternal health outcomes are addressed, it is likely that changes such as better access to antenatal care will improve health outcomes across the continuum of morbidity. However, by only monitoring near-miss cases and mortality, we underestimate the impact on women who will live with non-life threatening, yet serious maternal morbidities. PMID- 24347091 TI - The association between physical activity and maternal and neonatal outcomes: a prospective cohort. AB - Some evidence, but not enough to be conclusive, suggests that physical activity in pregnancy reduces the risk of perinatal complications. Our objective was to examine if physical activity in the year before pregnancy and in the first half of pregnancy is associated with maternal and neonatal outcomes. Associations between physical activity and maternal and neonatal outcomes were examined in a prospective cohort (n = 1,749) in Halifax, Canada. The Kaiser Physical Activity Survey, completed at approximately 20 weeks' gestation, requested information regarding physical activity during the year before the pregnancy and the first 20 weeks of pregnancy. Outcomes were assessed by medical chart review. Multiple logistic regression was used to estimate odds ratios (OR) with 95 % confidence intervals (CI). Women with prepregnancy physical activity levels in the middle and highest tertiles were more likely to have high gestational weight gain relative to women in the lowest tertile [OR (CI): 1.40 (1.06-1.85) and 1.57 (1.18 2.09), respectively]. Higher physical activity in the first half of pregnancy decreased the odds of delivering a macrosomic infant (p trend = 0.005). Associations were not observed between total physical activity and gestational diabetes, gestational hypertension, pre-eclampsia, preterm birth, and low birth weight. Physical activity before, but not in the first half of pregnancy, is associated with high gestational weight gain. Physical activity in the first half of pregnancy may reduce the occurrence of macrosomia without affecting preterm birth or low birth weight. PMID- 24347092 TI - Prevalence of overweight among women of childbearing age in Nepal: trends from 2001 to 2011 and associations with socio-demographic factors. AB - This study examined trends in overweight (body mass index, BMI >= 25.0 kg/m(2)) and underweight (BMI < 18.5 kg/m(2)) from 2001 to 2011 and associations between socio-demographic factors and overweight in 2011 among 15-49-year-old women in Nepal. Nationally representative cross-sectional data were used from three Demographic and Health Surveys conducted in Nepal in 2001 (n = 7,900), 2006 (n = 10,076) and 2011 (n = 5,873). Body weight and height were measured by trained personnel. Data on socio-demographic variables were obtained by interviewing the participants. The data were analysed using logistic regression models. The prevalence of underweight decreased from 26.6 to 18.1 % and the prevalence of overweight increased from 6.4 to 14.0 % between 2001 and 2011 (p < 0.001 for both, adjusted for age, parity and education). Both trends were more pronounced among the rural than the urban women. Although overweight was much more common in the urban (27.4 %) than in the rural areas (11.8 %) in 2011, the difference diminished substantially (odds ratio, OR, for being overweight in the urban vs. in the rural areas, 1.40, 95 % CI 1.15-1.70) when adjusted for other socio demographic variables. The strongest independent predictors of being overweight were higher relative wealth and advanced age. Overweight has become almost as common phenomenon as underweight among women in childbearing age in Nepal. The urban-rural differences have slightly narrowed and overweight is still related to a higher socio-economic status in this population. Strategies to prevent further increases in the prevalence of overweight should urgently be developed and implemented at all levels of the society. PMID- 24347093 TI - 3D multi-slab diffusion-weighted readout-segmented EPI with real-time cardiac reordered K-space acquisition. AB - PURPOSE: The aim of this study was to develop, implement, and demonstrate a three dimensional (3D) extension of the readout-segmented echo-planar imaging (rs-EPI) sequence for diffusion imaging. THEORY AND METHODS: Potential k-space acquisition schemes were assessed by simulating their associated spatial point spread functions. Motion-induced phase artifacts were also simulated to test navigator corrections and a real-time reordering of the k-space acquisition relative to the cardiac cycle. The cardiac reordering strategy preferentially chooses readout segments closer to the center of 3D k-space during diastole. Motion-induced phase artifacts were quantified by calculating the voxel-wise temporal variation in a set of repeated diffusion-weighted acquisitions. Based on the results of these simulations, a 2D navigated multi-slab rs-EPI sequence with real-time cardiac reordering was implemented. The multi-slab implementation enables signal-to-noise ratio-optimal repetition times of 1-2 s. RESULTS: Cardiac reordering was validated in simulations and in vivo using the multi-slab rs-EPI sequence. In comparisons with standard k-space acquisitions, cardiac reordering was shown to reduce the variability due to motion-induced phase artifacts by 30-50%. High resolution diffusion tensor imaging data acquired with the cardiac-reordered multi-slab rs-EPI sequence are presented. CONCLUSION: A 3D multi-slab rs-EPI sequence with cardiac reordering has been demonstrated in vivo and is shown to provide high-quality 3D diffusion-weighted data sets. PMID- 24347095 TI - Dolutegravir: a new integrase strand transfer inhibitor for the treatment of HIV. AB - The first two integrase strand transfer inhibitors (INSTIs) approved for treatment of patients infected with human immunodeficiency virus (HIV) were raltegravir and elvitegravir. Both raltegravir and elvitegravir are now guideline preferred agents as part of an antiretroviral regimen for treatment-naive patients. However, raltegravir is dosed twice/day. Elvitegravir is available in a single-tablet regimen and dosed once/day because it is administered with the pharmacokinetic booster cobicistat, a potent CYP3A4 inhibitor that can lead to clinically significant drug-drug interactions. In addition, raltegravir and elvitegravir have a low genetic barrier to resistance and are associated with cross-resistance. Dolutegravir is a new-generation INSTI administered once/day without a pharmacokinetic booster and can be coformulated in a single-tablet regimen. Phase III studies have demonstrated the efficacy and safety of dolutegravir for treatment-naive and treatment-experienced patients. Compared with other INSTIs, dolutegravir has a higher genetic barrier to resistance. Dolutegravir was approved by the U.S. Food and Drug Administration in August 2013 and joins raltegravir and elvitegravir as guideline-preferred agents for the management for HIV-infected treatment-naive patients. PMID- 24347096 TI - Treatment effect of coenzyme Q(10) and an antioxidant cocktail in fibroblasts of patients with Sanfilippo disease. AB - Coenzyme Q10 (CoQ10) plays a key role in the exchange of electrons in lysosomal membrane, which contributes to protons' translocation into the lumen and to the acidification of intra-lysosomal medium, which is essential for the proteolytic function of hydrolases responsible -when deficient- of a wide range of inherited lysosomal diseases such as Sanfilippo syndromes. Our aim was to evaluate whether treatment with CoQ10 or with an antioxidant cocktail (alpha-tocopherol, N acetylcysteine and alpha-lipoic acid) were able to ameliorate the biochemical phenotype in cultured fibroblasts of Sanfilippo patients. Basal CoQ10 was analyzed in fibroblasts and Sanfilippo A patients showed decreased basal levels. However, no dysfunction in the CoQ10 biosynthesis pathways was found, revealing for the first time a secondary CoQ10 deficiency in Sanfilippo A fibroblasts. Cultured fibroblasts from five patients affected by Sanfilippo A and B diseases were treated with CoQ10 and an antioxidant cocktail. Upon CoQ10 treatment, none of the Sanfilippo A fibroblasts increased their residual enzymatic activity, but the two Sanfilippo B cell lines showed a statistically significant increase of their residual activity. The antioxidant treatment had no effect on the residual activity in all tested cell lines. Moreover, one Sanfilippo A and two Sanfilippo B fibroblasts showed a statistically significant reduction of glycosaminoglycans accumulation both, after 50 MUmol/L CoQ10 and antioxidant treatment. Fibroblasts responsive to treatment enhanced their exocytosis levels. Our results are encouraging as some cellular alterations observed in Sanfilippo syndrome can be partially restored by CoQ10 or other antioxidant treatment in some patients. PMID- 24347098 TI - Conflict of interest and evaluation research: should we do effectiveness studies of our own educational programs? PMID- 24347097 TI - Optimized breast MRI functional tumor volume as a biomarker of recurrence-free survival following neoadjuvant chemotherapy. AB - PURPOSE: To evaluate optimal contrast kinetics thresholds for measuring functional tumor volume (FTV) by breast magnetic resonance imaging (MRI) for assessment of recurrence-free survival (RFS). MATERIALS AND METHODS: In this Institutional Review Board (IRB)-approved retrospective study of 64 patients (ages 29-72, median age of 48.6) undergoing neoadjuvant chemotherapy (NACT) for breast cancer, all patients underwent pre-MRI1 and postchemotherapy MRI4 of the breast. Tumor was defined as voxels meeting thresholds for early percent enhancement (PEthresh) and early-to-late signal enhancement ratio (SERthresh); and FTV (PEthresh, SERthresh) by summing all voxels meeting threshold criteria and minimum connectivity requirements. Ranges of PEthresh from 50% to 220% and SERthresh from 0.0 to 2.0 were evaluated. A Cox proportional hazard model determined associations between change in FTV over treatment and RFS at different PE and SER thresholds. RESULTS: The plot of hazard ratios for change in FTV from MRI1 to MRI4 showed a broad peak with the maximum hazard ratio and highest significance occurring at PE threshold of 70% and SER threshold of 1.0 (hazard ratio = 8.71, 95% confidence interval 2.86-25.5, P < 0.00015), indicating optimal model fit. CONCLUSION: Enhancement thresholds affect the ability of MRI tumor volume to predict RFS. The value is robust over a wide range of thresholds, supporting the use of FTV as a biomarker. PMID- 24347099 TI - The long-term impact of a performance improvement continuing medical education intervention on osteoporosis screening. AB - INTRODUCTION: The purpose of this study is to determine whether a performance improvement continuing medical education (PI CME) initiative that utilizes quality improvement (QI) principles is effective in producing sustainable change in practice to improve the screening of patients at risk for osteoporosis. METHODOLOGY: A health care center participated in a PI CME program designed to increase appropriate osteoporosis screening. There were eight 1-hour educational sessions for this activity over a 9-month period. Thirteen providers completed all 3 stages of the PI CME program. A variety of other clinicians, in addition to the 13 providers, participated in the educational sessions. Data were collected at the beginning and end of the PI CME activity and at three intervals during the 5 years after the completion of the activity. RESULTS: The percentage of tests for osteoporosis ordered and performed increased significantly from Stage A to Stage C of the PI CME activity and continued to increase after the completion of the PI CME activity. Follow-up data at 4 and 40 months (for ordering and performing osteoporosis screening) and 49 months (for performing the screening only) reflect the impact of the PI CME activity plus the continuing QI interventions. The percentage of BMD tests ordered continued to increase substantially over the post-PI CME periods: 4 and 40 months (F(3,46) = 4.04, p < .05). Similarly, the percentage of BMD tests performed continued to increase at 4, 40, and 49 months after the conclusion of the PI CME activity (F(4,55) = 12.55, p < .0001). DISCUSSION: The data indicate that PI CME utilizing QI principles can be effective in producing sustainable change in practice to improve the screening of patients at risk for osteoporosis. Further research is needed to determine the extent to which such changes can be directly attributed to this type of intervention. PMID- 24347100 TI - How is clinical reasoning developed, maintained, and objectively assessed? Views from expert internists and internal medicine interns. AB - INTRODUCTION: There is limited understanding of how clinical reasoning is developed, maintained, and objectively assessed. Using the theoretical lens of deliberate practice, we explored physicians' views on clinical reasoning. We compared responses from internists (faculty) and internal medicine interns, to identify potential qualitative and/or quantitative differences in how clinical reasoning is developed and maintained. METHODS: Participants' free-text comments regarding how clinical reasoning is developed, maintained, and objectively assessed were analyzed. Three investigators coded responses using a constant comparative, grounded theory approach. We also compared the frequencies of each theme between the 2 groups. RESULTS: Twenty-two faculty and 17 interns participated in this study. Faculty and intern themes for how clinical reasoning is developed, maintained, and objectively assessed were similar, but quantitative and qualitative differences emerged. Interrater reliability of themes was high (overall kappa: 0.92; range: 0.88-0.98). Only experts (faculty) mentioned the value of teaching for development and maintenance of clinical reasoning. Interns focused on knowledge acquisition activities and use of online resources. Experts and intern participants both struggled with how to best measure clinical reasoning; direct observation was rarely mentioned as a strategy. DISCUSSION: Consistent with our theoretical expectations, we found quantitative and qualitative differences in participants' responses, which have implications for teaching and assessment of clinical reasoning. By capturing the types of activities and their relative frequencies within and between these groups, this work adds to the deliberate practice literature. PMID- 24347101 TI - What do primary care practitioners want to know? A content analysis of questions asked at the point of care. AB - INTRODUCTION: Assessing physician needs to develop continuing medical education (CME) activities is an integral part of CME curriculum development. The purpose of the present study was to demonstrate the feasibility of identifying areas of perceived greatest needs for continuing medical education (CME) by using questions collected electronically at the point of care. METHODS: This study is a secondary analysis of the "Just-in-Time" (JIT) information librarian consultation service database of questions using quantitative content analysis methods. The original JIT project demonstrated the feasibility of a real-time librarian service for answering questions asked by primary care clinicians at the point of care using a Web-based platform or handheld device. Data were collected from 88 primary care practitioners in Ontario, Canada, from October 2005 to April 2006. Questions were answered in less than 15 minutes, enabling clinicians to use the answer during patient encounters. RESULTS: Description of type and frequency of questions asked, including the organ system on which the questions focused, was produced using 2 classification systems, the "taxonomy of generic clinical questions" (TGCQ), and the International Classification for Primary Care version 2 (ICPC-2). Of the original 1889 questions, 1871 (99.0%) were suitable for analysis. A total of 970 (52%) of questions related to therapy; of these, 671 (69.2%) addressed questions about drug therapy, representing 36% of all questions. Questions related to diagnosis (24.8%) and epidemiology (13.5%) were also common. Organ systems questions concerning musculoskeletal, endocrine, skin, cardiac, and digestive systems were asked more than other categories. DISCUSSION: Questions collected at the point of care provide a valuable and unique source of information on the true learning needs of practicing clinicians. The TGCQ classification allowed us to show that a majority of questions had to do with treatment, particularly drug treatment, whereas the use of the ICPC-2 classification illustrated the great variety of questions asked about the diverse conditions encountered in primary care. It is feasible to use electronically collected questions asked by primary care clinicians in clinical practice to categorize self-identified knowledge and practice needs. This could be used to inform the development of future learning activities. PMID- 24347102 TI - Improving collaborative care in managing eating disorders: a pilot study. AB - INTRODUCTION: The purpose of this pilot study was to evaluate the impact of a continuing interprofessional educational workshop focused on eating disorders in a rural area in Newfoundland and Labrador (NL), Canada. The pilot study helped determine if the eating disorder workshop was feasible for implementation to a broader audience. A conceptual model developed by our eating disorder team and described in the article guided this innovative program. METHODS: The intensive 2 day workshop was piloted in one community with 41 health and education professionals in attendance. A key element was the focus on creating and sustaining collaborative care for eating disorders. Participants completed pre post workshop measures of interprofessional attitudes and skills, self-reported knowledge, confidence, and intention to change practice (post questionnaire only). A 6-month follow-up survey measured self-reported practice change. RESULTS: There were significant positive changes in interprofessional attitudes and skills as well as knowledge and confidence in collaborative management of eating disorders. Post-workshop, 69% (n = 24/35) of participants indicated intention to change practice, and on follow-up, 7 of 10 respondents reported implementing changes in practice as a result of the workshop. Low response rate at follow-up was a limitation. DISCUSSION: Results support the impact of the workshop in improving knowledge, confidence, and attitudes toward collaboration and changing practice and the value of implementing the program province-wide. PMID- 24347103 TI - Preparing culture change agents for academic medicine in a multi-institutional consortium: the C - change learning action network. AB - INTRODUCTION: Research suggests an ongoing need for change in the culture of academic medicine. This article describes the structure, activities and evaluation of a culture change project: the C - Change Learning Action Network (LAN) and its impact on participants. The LAN was developed to create the experience of a culture that would prepare participants to facilitate a culture in academic medicine that would be more collaborative, inclusive, relational, and that supports the humanity and vitality of faculty. METHODS: Purposefully diverse faculty, leaders, and deans from 5 US medical schools convened in 2 1/2-day meetings biannually over 4 years. LAN meetings employed experiential, cognitive, and affective learning modes; innovative dialogue strategies; and reflective practice aimed at facilitating deep dialogue, relationship formation, collaboration, authenticity, and transformative learning to help members experience the desired culture. Robust aggregated qualitative and quantitative data collected from the 5 schools were used to inform and stimulate culture change plans. RESULTS: Quantitative and qualitative evaluation methods were used. Participants indicated that a safe, supportive, inclusive, collaborative culture was established in LAN and highly valued. LAN members reported a deepened understanding of organizational change, new and valued interpersonal connections, increased motivation and resilience, new skills and approaches, increased self awareness and personal growth, emotional connection to the issues of diversity and inclusion, and application of new learnings in their work. DISCUSSION: A carefully designed multi-institutional learning community can transform the way participants experience and view institutional culture. It can motivate and prepare them to be change agents in their own institutions. PMID- 24347104 TI - Using an intervention mapping framework to develop an online mental health continuing education program for pharmacy staff. AB - INTRODUCTION: Current mental health policy in Australia recognizes that ongoing mental health workforce development is crucial to mental health care reform. Community pharmacy staff are well placed to assist people with mental illness living in the community; however, staff require the knowledge and skills to do this competently and effectively. This article presents the systematic planning and development process and content of an education and training program for community pharmacy staff, using a program planning approach called intervention mapping. METHODS: The intervention mapping framework was used to guide development of an online continuing education program. Interviews with mental health consumers and carers (n = 285) and key stakeholders (n = 15), and a survey of pharmacy staff (n = 504) informed the needs assessment. Program objectives were identified specifying required attitudes, knowledge, skills, and confidence. These objectives were aligned with an education technique and delivery strategy. This was followed by development of an education program and comprehensive evaluation plan. The program was piloted face to face with 24 participants and then translated into an online program comprising eight 30-minute modules for pharmacists, 4 of which were also used for support staff. The evaluation plan provided for online participants (n ? 500) to be randomized into intervention (immediate access) or control groups (delayed training access). It included pre- and posttraining questionnaires and a reflective learning questionnaire for pharmacy staff and telephone interviews post pharmacy visit for consumers and carers. RESULTS: An online education program was developed to address mental health knowledge, attitudes, confidence, and skills required by pharmacy staff to work effectively with mental health consumers and carers. DISCUSSION: Intervention mapping provides a systematic and rigorous approach that can be used to develop a quality continuing education program for the health workforce. PMID- 24347106 TI - A community of practice for knowledge translation trainees: an innovative approach for learning and collaboration. AB - A growing number of researchers and trainees identify knowledge translation (KT) as their field of study or practice. Yet, KT educational and professional development opportunities and established KT networks remain relatively uncommon, making it challenging for trainees to develop the necessary skills, networks, and collaborations to optimally work in this area. The Knowledge Translation Trainee Collaborative is a trainee-initiated and trainee-led community of practice established by junior knowledge translation researchers and practitioners to: examine the diversity of knowledge translation research and practice, build networks with other knowledge translation trainees, and advance the field through knowledge generation activities. In this article, we describe how the collaborative serves as an innovative community of practice for continuing education and professional development in knowledge translation and present a logic model that provides a framework for designing an evaluation of its impact as a community of practice. The expectation is that formal and informal networking will lead to knowledge sharing and knowledge generation opportunities that improve individual members' competencies (eg, combination of skills, abilities, and knowledge) in knowledge translation research and practice and contribute to the development and advancement of the knowledge translation field. PMID- 24347105 TI - Core competencies for shared decision making training programs: insights from an international, interdisciplinary working group. AB - Shared decision making is now making inroads in health care professionals' continuing education curriculum, but there is no consensus on what core competencies are required by clinicians for effectively involving patients in health-related decisions. Ready-made programs for training clinicians in shared decision making are in high demand, but existing programs vary widely in their theoretical foundations, length, and content. An international, interdisciplinary group of 25 individuals met in 2012 to discuss theoretical approaches to making health-related decisions, compare notes on existing programs, take stock of stakeholders concerns, and deliberate on core competencies. This article summarizes the results of those discussions. Some participants believed that existing models already provide a sufficient conceptual basis for developing and implementing shared decision making competency-based training programs on a wide scale. Others argued that this would be premature as there is still no consensus on the definition of shared decision making or sufficient evidence to recommend specific competencies for implementing shared decision making. However, all participants agreed that there were 2 broad types of competencies that clinicians need for implementing shared decision making: relational competencies and risk communication competencies. Further multidisciplinary research could broaden and deepen our understanding of core competencies for shared decision making training. PMID- 24347107 TI - Error in formula by Salbach et al. PMID- 24347108 TI - Reply to Dr. Bland: despite error in formula, EPIC scale still precise. PMID- 24347109 TI - On the size evolution of monolayer-protected gold clusters during ligand place exchange reactions: the effect of solvents. AB - Ligand place-exchange (LPE) reactions are extensively applied for the post functionalization of monolayer-protected gold clusters (MPCs) by using excessive incoming ligands to displace initial ones. However, the modified MPCs are often enlarged or degraded; this results in ill-defined size-dependent properties. The growth of MPCs essentially involves an unprotected surface that is subsequently has gold atoms added or is fused with other gold cores owing to collision. Reported herein is a guideline for the selection of solvents to suppress unwanted MPC growth. Favorable solvents are those with significant affinity to gold or with low solubility for desorbed ligands because these properties retard LPE reactions and minimize the time available for unprotected gold cores. This finding provides a general and convenient approach to regulate the size of functionalized MPCs. PMID- 24347111 TI - Analysis of 320 gastroenteropancreatic neuroendocrine tumors identifies TS expression as independent biomarker for survival. AB - Thymidylate synthase (TS), a critical enzyme for DNA synthesis and repair, is both a potential tumor prognostic biomarker as well as a tumorigenic oncogene in animal models. We have now studied the clinical implications of TS expression in gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) and compared these results to other cell cycle biomarker genes. Protein tissue arrays were used to study TS, Ki-67, Rb, pRb, E2F1, p18, p21, p27 and menin expression in 320 human GEP-NETs samples. Immunohistochemical expression was correlated with univariate and multivariate predictors of survival utilizing Kaplan Meier and Cox proportional hazards models. Real time RT-PCR was used to validate these findings. We found that 78 of 320 GEP-NETs (24.4%) expressed TS. NETs arising in the colon, stomach and pancreas showed the highest expression of TS (47.4%, 42.6% and 37.3%, respectively), whereas NETs of the appendix, rectum and duodenum displayed low TS expression (3.3%, 12.9% and 15.4%, respectively). TS expression in GEP-NETs was associated with poorly differentiated endocrine carcinoma, angiolymphatic invasion, lymph node metastasis and distant metastasis (p < 0.05). Patients with TS-positive NETs had markedly worse outcomes than TS-negative NETs as shown by univariate (p < 0.001) and multivariate (p = 0.01) survival analyses. Expression of p18 predicted survival in TS-positive patients that received chemotherapy (p = 0.015). In conclusion, TS protein expression was an independent prognostic biomarker for GEP-NETs. The strong association of increased TS expression with aggressive disease and early death supports the role of TS as a cancer promoting agent in these tumors. PMID- 24347110 TI - Pentalinon andrieuxii root extract is effective in the topical treatment of cutaneous leishmaniasis caused by Leishmania mexicana. AB - Cutaneous leishmaniasis (CL) manifests as localized skin lesions, which lead to significant tissue destruction and disfigurement. In the Yucatan Peninsula, Mayan traditional healers use Pentalinon andrieuxii Muell.-Arg. (Apocynaceae) roots for the topical treatment of CL. Here, we studied the effect of P. andrieuxii root hexane extract (PARE) on the parasites and host cells in vitro and examined its efficacy in the topical treatment of CL caused by Leishmania mexicana. PARE exhibited potent antiparasitic activity in vitro against promastigotes as well as amastigotes residing in macrophages. Electron microscopy of PARE-treated parasites revealed direct membrane damage. PARE also activated nuclear factor kappaB and enhanced interferon-gamma receptor and MHC class II expression and TNF alpha production in macrophages. In addition, PARE induced production of the Th1 promoting cytokine IL-12 in dendritic cells as well as enhanced expression of the co-stimulatory molecules CD40, CD80, and CD86. In vivo studies showed that L. mexicana-infected mice treated by topical application of PARE resulted in the significant reduction in lesion size and parasite burden compared to controls. These findings indicate that PARE could be used as an alternative therapy for the topical treatment of CL. PMID- 24347113 TI - Visual similarity is stronger than semantic similarity in guiding visual search for numbers. AB - Using a visual search task, we explored how behavior is influenced by both visual and semantic information. We recorded participants' eye movements as they searched for a single target number in a search array of single-digit numbers (0 9). We examined the probability of fixating the various distractors as a function of two key dimensions: the visual similarity between the target and each distractor, and the semantic similarity (i.e., the numerical distance) between the target and each distractor. Visual similarity estimates were obtained using multidimensional scaling based on the independent observer similarity ratings. A linear mixed-effects model demonstrated that both visual and semantic similarity influenced the probability that distractors would be fixated. However, the visual similarity effect was substantially larger than the semantic similarity effect. We close by discussing the potential value of using this novel methodological approach and the implications for both simple and complex visual search displays. PMID- 24347114 TI - Natural history of five children with surfactant protein C mutations and interstitial lung disease. AB - Interstitial lung diseases in infants and children are uncommon and may be caused by specific inborn errors of surfactant metabolism. Five children with open lung biopsy diagnosed interstitial lung disease were followed (mean of 27.2 years) and evaluated for surfactant protein gene mutations. Four of the children were originally diagnosed as desquamative interstitial pneumonitis and one as chronic interstitial pneumonitis. All had good response to chloroquine or hydroxychloroquine treatment for periods of 7-38 months. Lung function tests, incremental exercise tests, and rentgenological studies were performed in the children. Surfactant protein gene mutations were searched in all the patients and in part of their families. Three of the patients, aged now 32, 29, and 37 years, feel well and have normal lung function, while two of the patients, both females, aged 28 and 37 years, conduct normal activities of daily living, have healthy children but have clinical, physiological and rentgenological evidence of restrictive lung disease. All five patients were found to have surfactant protein C gene (SFTPC) mutations, three of them with the most common mutation (p.I73T) and the other two with new mutations of surfactant protein C gene (p.I38F and p.V39L). We conclude that detection of surfactant protein mutations should be attempted in all children presenting with interstitial lung disease. Furthermore, treatment with hydroxychloroquine should be considered in children with SFTPC mutations. Prospective evaluation of hydroxychloroquine therapy in a greater number of patients is needed. PMID- 24347115 TI - Lessons from fractional flow reserve measurements in chronic total occlusion interventions. PMID- 24347116 TI - Sparrow self-expanding sirolimus-eluting stent: do we need a self-expanding coronary stent? PMID- 24347117 TI - Conservative management of left main dissection: breaking the taboo. PMID- 24347118 TI - Transplant coronary atherosclerosis: parallels with in-stent neoatherosclerosis. PMID- 24347119 TI - Look before (and after) you plug: moving slowly toward safer selection and management of patients at risk of device erosion. PMID- 24347120 TI - Arterial access for limb salvage for critical limb ischemia: how low (and how small) can we go? PMID- 24347121 TI - Closure for arterial access in balloon aortic valvuloplasty. PMID- 24347122 TI - Possible synergism of physical exercise and ghrelin-agonists in patients with cachexia associated with chronic heart failure. AB - The occurrence of cachexia of multifactorial etiology in chronic heart failure (CHF) is a common and underestimated condition that usually leads to poor outcome and low survival rates, with high direct and indirect costs for the Health Care System. Recently, a consensus definition on cachexia has been reached, leading to a growing interest by the scientific community in this condition, which characterizes the last phase of many chronic diseases (i.e., cancer, acquired immunodeficiency syndrome). The etiology of cachexia is multifactorial and the underlying pathophysiological mechanisms are essentially the following: anorexia and malnourishment; immune overactivity and systemic inflammation; and endocrine disorders (anabolic/catabolic imbalance and resistance to growth hormone). In this paper, we review the main pathophysiological mechanisms underlying CHF cachexia, focusing also on the broad spectrum of actions of ghrelin and ghrelin agonists, and their possible use in combination with physical exercise to contrast CHF cachexia. PMID- 24347123 TI - Introducing a multifaceted exercise intervention particular to older adults diagnosed with Parkinson's disease: a preliminary study. AB - BACKGROUND AND AIM: With a substantial increase in diagnosed Parkinson's disease, it is of great importance to examine tolerance and physical measures of evolving exercise interventions. Of particular importance, a multifaceted exercise intervention combining active-assisted cycling and resistance training to older adults diagnosed with Parkinson's disease is being assessed. METHODS: Fourteen older adults diagnosed with Parkinson's disease and ten healthy older adults (67.5 +/- 7.9 years of age) engaged in an 8-week, 24-session, multifaceted exercise protocol. The protocol consisted of both active-assisted cycling and resistance training. Tolerance was measured, as well as multiple indicators of health-related physical fitness. These indicators examined improvements in cardiovascular performance, muscular strength, muscular endurance, and flexibility. RESULTS: Twenty-two older adults and older adults diagnosed with Parkinson's disease tolerated the intervention by completing all 24 sessions. Repeated-measures analysis of variance demonstrated significant (P <= 0.003) improvements in cardiovascular performance, muscular strength, muscular endurance, and flexibility for both groups of individuals. DISCUSSION AND CONCLUSION: The multifaceted intervention is the first to combine both active assisted cycling and resistance training. The older adult and the older adult diagnosed with Parkinson's disease exhibited both tolerance and health-related improvements in physical fitness following the intervention. PMID- 24347124 TI - Myocardial perfusion imaging: lessons learned and work to be done. By the Editorial Team of the Journal. PMID- 24347127 TI - Role of imaging in the diagnosis and management of patients with cardiac amyloidosis: state of the art review and focus on emerging nuclear techniques. AB - Amyloidosis is an infiltrative disease characterized by deposition of amyloid fibrils within the extracellular tissue of one or multiple organs. Involvement of the heart, cardiac amyloidosis, is recognized as a common cause of restrictive cardiomyopathy and heart failure. The two major types of cardiac amyloidosis are cardiac amyloid light-chain (AL) and transthyretin-related cardiac amyloidosis (ATTR, mutant and wild types) (Nat Rev Cardiol 2010;7:398-408). While early recognition of cardiac amyloidosis is of major clinical importance, so is the ability to differentiate between subtypes. Indeed, both prognosis and therapeutic options vary drastically depending on the subtype. While endomyocardial biopsy with immunostaining is considered the gold standard, advances in imaging provide an attractive non-invasive alternative. Currently, electrocardiography, echocardiography, and cardiac magnetic resonance imaging are all used in the evaluation of cardiac amyloidosis with varying diagnostic and prognostic accuracy. Yet, none of these modalities can effectively differentiate the cardiac amyloid subtypes. Recent data with (99m)Tc-phosphate derivatives, previously used as bone seeking radioactive tracers, have shown promising results; these radiotracers selectively bind ATTR, but not AL subtype, and can differentiate subtypes with high diagnostic accuracy. This review will initially present the non-radionuclide imaging techniques and then focus on the radionuclide imaging techniques, particularly (99m)Tc-DPD and (99m)Tc-PYP, mechanism of action, performance and interpretation of the study, diagnostic accuracy, prognostic value, future clinical perspective, and outlook. PMID- 24347128 TI - Short and lifetime cardiovascular risk estimates: same wine, different bottles. Do we have the COURAGE to abandon risk scores? PMID- 24347129 TI - Correction of proton resonance frequency shift MR-thermometry errors caused by heat-induced magnetic susceptibility changes during high intensity focused ultrasound ablations in tissues containing fat. AB - PURPOSE: In this study, we aim to demonstrate the sensitivity of proton resonance frequency shift (PRFS) -based thermometry to heat-induced magnetic susceptibility changes and to present and evaluate a model-based correction procedure. THEORY AND METHODS: To demonstrate the expected temperature effect, field disturbances during high intensity focused ultrasound sonications were monitored in breast fat samples with a three-dimensional (3D) gradient echo sequence. To evaluate the correction procedure, the interface of tissue-mimicking ethylene glycol gel and fat was sonicated. During sonication, the temperature was monitored with a 2D dual flip angle multi-echo gradient echo sequence, allowing for PRFS-based relative and referenced temperature measurements in the gel and T1 -based temperature measurements in fat. The PRFS-based measurement in the gel was corrected by minimizing the discrepancy between the observed 2D temperature profile and the profile predicted by a 3D thermal model. RESULTS: The HIFU sonications of breast fat resulted in a magnetic field disturbance which completely disappeared after cooling. For the correction method, the 5th to 95th percentile interval of the PRFS-thermometry error in the gel decreased from 3.8 degrees C before correction to 2.0-2.3 degrees C after correction. CONCLUSION: This study has shown the effects of magnetic susceptibility changes induced by heating of breast fatty tissue samples. The resultant errors can be reduced by the use of a model-based correction procedure. PMID- 24347130 TI - The role of left inferior fronto-occipital fascicle in verbal perseveration: a brain electrostimulation mapping study. AB - The subcortical connectivity underlying verbal perseveration (VP) remains poorly understood. We have previously reported that intraoperative electrical stimulation of the caudate nucleus during awake surgery resulted in VP. Here, our purpose is to study the white matter pathway underlying VP using subcortical stimulation mapping in a series of patients who underwent glioma resection. Eleven patients with a left hemispheric low grade glioma were operated on while awake. Intraoperative direct electrical stimulation was used both at cortical and subcortical levels while the patients carried out motor and naming tasks during the resection. All patients experienced VP during electrical stimulation performed at the level of different subcortical locations, which corresponded in the 11 cases to different parts of the left inferior fronto-occipital fascicle. Perseveration persisted into the postoperative days, but resolved completely by three months.Our original findings provide further insight into the neuroanatomical basis of VP, by supporting the role of left inferior fronto occipital fascicle. Such data may have both fundamental and clinical implications. PMID- 24347131 TI - Retrograde mechanochemical ablation of the small saphenous vein for the treatment of a venous ulcer. AB - We present the first case of retrograde ablation of the small saphenous vein to treat active venous ulceration. A 73-year-old gentleman with complicated varicose veins of the left leg and a non-healing venous ulcer despite previous successful endovenous treatment to his left great saphenous vein underwent mechanochemical ablation of his small saphenous vein with the ClariVein(r) system, under local anaesthetic, using a retrograde cannulation technique. Post-operatively the patient had improved symptomatically and the ulcer size had reduced. This report highlights that patients with small saphenous vein incompetence and active ulceration can be treated successfully with retrograde mechanochemical ablation. PMID- 24347132 TI - Causes of successful medico-legal claims following amputation. AB - INTRODUCTION: The causes of successful medico-legal claims following amputation were reviewed. METHODS: A retrospective analysis of claims handled by the National Health Service Litigation Authority, from 2005 to August 2010, was performed. Under the Freedom of Information Act, the National Health Service Litigation Authority provided limited details on closed claims, settled with damages, following a search of their database with the term "amputation." No demographic data were provided. RESULTS: During this period, 174 claims were settled by the National Health Service Litigation Authority, who paid out more than L36.3 million. The causes of the claims were the need for a lower limb amputation due to a delay in the diagnosis and or treatment of arterial ischaemia (56), an iatrogenic injury (15), the development of preventable pressure sores (15), the delay and or failure to diagnose a limb malignancy (6) and the delay in the management of an infected pseudo-aneurysm (1). Complications following orthopaedic surgery resulted in 25 successful claims as did the delayed diagnosis or mismanagement of 10 lower limb fractures. Additional claims followed the amputation of the wrong toe (1), a retained foreign body (2), an unnecessary amputation (4), inadequate consent (4), failure to provide thrombo-prophylaxis following amputation resulting in death (2) and a diathermy burn injury during an amputation (1). Delay in the diagnosis of and/or failure to manage an injury or infection resulted in 21 upper limb amputations. There was insufficient information provided in the remaining 11 claims to determine how the claim related to an amputation procedure. The largest single payout for damages (L1.9 million) resulted from the failure to diagnose and treat a femoral artery injury following a road traffic accident leading to an eventual below knee amputation. CONCLUSION: Delays in the diagnosis and or treatment of arterial ischaemia were the commonest reasons for a settled claim. Lessons can be learnt from potentially preventable cases that can be incorporated in medical education and training programs with the aim of reducing both amputation rates and litigation costs. PMID- 24347133 TI - Rescue EVAR for ruptured AAA: Clinical success does not mean technical success. AB - We report a clinical evolution of a 85-years old male admitted to our Emergency Department for ruptured abdominal aortic aneurysm (rAAA). One month later a huge type I proximal endoleak was detected and corrected by proximal aortic extension. We decided to fix the stent-graft to the aortic wall using EndoAnchors. However, an asymptomatic type III endoleak due to controlateral limb disconnection was detected at the followed schedulated CT angio and corrected by a relining of the endograft. The patient is now in good clinical condition with no evidence of endoleaks at 1-year follow-up. PMID- 24347134 TI - Median nerve neuropraxia by a large false brachial artery aneurysm. AB - Peripheral nerve compression is a rare complication of an iatrogenic false brachial artery aneurysm. We present a 72-year-old patient with median nerve compression due to a false brachial artery aneurysm after removal of an arterial catheter. Surgical exclusion of the false aneurysm was performed in order to release traction of the median nerve. At 3-month assessment, moderate hand recovery in function and sensibility was noted. In the case of neuropraxia of the upper extremity, following a history of hospital stay and arterial lining or catheterization, compression due to pseudoaneurysm should be considered a probable cause directly at presentation. Early recognition and treatment is essential to avoid permanent neurological deficit. PMID- 24347135 TI - Temporal artery biopsy size does not matter. AB - This study aimed to clarify whether positive temporal artery biopsies had a greater sample length than negative biopsies in temporal arteritis. It has been suggested that biopsy length should be at least 1 cm to improve diagnostic accuracy. A retrospective review of 149 patients who had 151 temporal artery biopsies was conducted. Twenty biopsies were positive (13.3%), 124 negative (82.1%) and seven samples were insufficient (4.6%). There was no clinically significant difference in the mean biopsy size between positive (0.7 cm) and negative samples (0.65 cm) (t-test: p = .43 NS). Ninety-four patients fulfilled all three ACR criteria prior to biopsy (62.3%) and four patients (2.6%) changed ACR score from 2 to 3 after biopsy. Treatment should not be delayed in anticipation of the biopsy or withheld in the case of a negative biopsy if the patient's symptoms improve. PMID- 24347136 TI - Application of endovascular stent placement as a remedy for spontaneous isolated superior mesenteric artery dissection. AB - OBJECTIVES: To present our experience regarding endovascular stent placement for the treatment of spontaneous isolated superior mesenteric artery dissection (SISMAD) and to evaluate the safety and feasibility of the endovascular therapy. METHODS: The clinical data from six patients with SISMAD who underwent endovascular stent placement in two institutions from March 2010 to May 2012 were analyzed retrospectively. Four patients were implanted a self-expanding stent, and an additional stent was deployed in two of these patients after the first stent was implanted. One patient was subjected to a self-expanding stent implantation combined with coil embolization. The remaining patient underwent thrombectomy plus partial intimectomy 2 months before a balloon-expandable stent was implanted. RESULTS: All of the patients recuperated uneventfully without any reoccurrence of the symptoms in the follow-up period (range 12-38 months). Contrast-enhanced computer tomography scanning was performed 3 months after the procedure in all of the patients, and the images showed that the false lumen was nearly thrombosed and that the true lumen was maintained patent. CONCLUSIONS: Endovascular stent placement is a simple and safe alternative to aggressive surgery or uncertain observation. PMID- 24347137 TI - Hypothenar hammer syndrome and basilic bypass. AB - We report a case of hypothenar hammer syndrome. The case presents necessary diagnostic measures and discusses the etiology of this syndrome. Additionally, the case reviews treatments, which culminated in the eventual use of ulnar artery bypass with autogenous basilica vein to treat and resolve the ischemic fingers of the patient. PMID- 24347138 TI - Primary leiomyosarcoma of saphenous vein presenting as deep venous thrombosis. AB - Only a small number of venous leiomyosarcomas have been previously reported. Of these tumors, those of saphenous origin comprise a minority of cases. A 59-year old man presented with symptoms of deep vein thrombosis and was eventually diagnosed with primary leiomyosarcoma of great saphenous vein origin. The tumor was treated with primary resection and femoral vein reconstruction with autologous patch. Although extremely rare, saphenous leiomyosarcoma can present as deep vein thrombosis. Vascular tumors should be included in the differential diagnosis of atypical extremity swelling refractory to conventional deep vein thrombosis management. PMID- 24347139 TI - Case Study Interpretation - Fort Lauderdale: Case 1. PMID- 24347140 TI - Comparison of prescription drug costs in the United States and the United kingdom, part 4: antibiotics in young children. AB - OBJECTIVES: To compare the usage and cost of antibiotics in the United States and United Kingdom in children younger than 10 years. METHODS: A follow up of some 160,000 young children enrolled in U.S. private health insurance companies and an equal number in general practices in the United Kingdom in 2009, based on two prospectively designed and documented electronic medical databases. MAIN RESULTS: Percentage of young children in each country prescribed an antibiotic together with the estimated total annual cost. PRINCIPAL CONCLUSIONS: In the United States, ~75% of privately insured children were prescribed one or more antibiotics compared with an estimated 50% in the United Kingdom. The annual cost was more than five times higher in the United States compared with the United Kingdom The usage and cost of antibiotics in young privately insured children is far higher in the United States than in the United Kingdom, where the government pays the cost of prescription drugs. PMID- 24347141 TI - How should propranolol be initiated for infantile hemangiomas: inpatient versus outpatient? PMID- 24347142 TI - The Truth, the Whole Truth, and Nothing but the Ground-Truth: Methods to Advance Environmental Justice and Researcher-Community Partnerships. AB - Environmental justice advocates often argue that environmental hazards and their health effects vary by neighborhood, income, and race. To assess these patterns and advance preventive policy, their colleagues in the research world often use complex and methodologically sophisticated statistical and geospatial techniques. One way to bridge the gap between the technical work and the expert knowledge of local residents is through community-based participatory research strategies. We document how an environmental justice screening method was coupled with "ground truthing"-a project in which community members worked with researchers to collect data across six Los Angeles neighborhoods-which demonstrated the clustering of potentially hazardous facilities, high levels of air pollution, and elevated health risks. We discuss recommendations and implications for future research and collaborations between researchers and community-based organizations. PMID- 24347143 TI - The Effect of Exposure to Pro-Tobacco Advertising on Experimentation With Emerging Tobacco Products Among U.S. Adolescents. AB - INTRODUCTION: This study assessed the influence of exposure to pro-tobacco advertisements on experimentation with emerging tobacco products among U.S. adolescents aged >=9 years, in Grades 6 to 12. METHOD: Data were obtained from the 2011 National Youth Tobacco Survey. Multivariate logistic regression was used to measure the association between experimentation with snus and e-cigarettes and exposure to pro-tobacco advertisements from three sources: over the Internet, in newspapers/magazines, and at retail stores. RESULTS: After controlling for sociodemographic characteristics and current use of other tobacco products, the odds of experimenting with snus were 1.36 (95% confidence interval [CI] = 0.88 3.16), 2.03 (95% CI = 1.30-3.17), and 3.24 (95% CI = 2.07-5.07), among students exposed to one, two, or all three types of pro-tobacco advertisements, respectively, compared with those exposed to none. Similar results were obtained for e-cigarettes. CONCLUSION: Stronger restrictions on tobacco advertisements, in concert with increased tobacco taxes and warning about the dangers of tobacco, use may help reduce youth tobacco use. PMID- 24347144 TI - Circles of Care: Implementation and Evaluation of Support Teams for African Americans With Cancer. AB - BACKGROUND: Community-based peer support may help meet the practical, emotional, and spiritual needs of African Americans with advanced cancer. Support teams are a unique model of peer support for persons facing serious illness, but research is rare. This study sought to (a) implement new volunteer support teams for African Americans with advanced cancer in two distinct regions and (b) evaluate support teams' ability to improve support, awareness of services, and quality of life for these patients. METHODS: The study used a pre-post design. Community and academic partners collaborated to implement volunteer support teams and evaluate the intervention using pre-post surveys of volunteers and patients. Patients who declined support teams were also interviewed as a comparison group. RESULTS: Investigators enrolled and trained 130 volunteers who formed 25 support teams in two geographic regions. Volunteers supported 25 African American patients with advanced cancer (72%) or other diseases. After 2 months, patients with support teams reported fewer needs for practical, emotional, and spiritual support on a structured checklist. They more often communicated with someone about their cancer care needs (48% vs. 75%, p = .04), and were more aware of Hospice (4% vs. 25%, p = .04), but quality of life scores were unchanged. Comparison patients who refused a support team had fewer support needs at baseline and follow-up, suggesting that refusals were based on a lack of need. CONCLUSION: Coordinated volunteer support teams are a promising new model to provide peer support for African Americans facing cancer and other serious illnesses. Further testing in a pragmatic clinical trial is warranted. PMID- 24347145 TI - Differentiating Behavior Initiation and Maintenance: Theoretical Framework and Proof of Concept. AB - Although many interventions are effective for health behavior initiation, maintenance has proven elusive. Interventions targeting maintenance often extend the duration with which initiation content is delivered or the duration of follow up without intervention. We posit that health behavior initiation and maintenance require separate psychological processes and skills. To determine the value of operationalizing maintenance as a process separate from initiation, we conducted a pilot study of a telephone-delivered intervention to assist people in transitioning from behavior initiation to maintenance. Participants were 20 veterans who had initiated lifestyle changes during a randomized controlled trial of a cholesterol reduction intervention. After completing the randomized controlled trial, these participants were enrolled in the pilot maintenance intervention, which involved three monthly telephone calls from a nurse interventionist focusing on behavioral maintenance skills. To evaluate the feasibility and acceptability of this intervention, we assessed recruitment and retention rates as well as 4-month pre-post changes in health behaviors and associated psychological processes. We also conducted individual interviews with participants after study completion. Although not powered to detect significant changes, there was evidence of improvement in dietary intake and of maintenance of physical activity and low-density lipoprotein cholesterol during the 4-month maintenance study. Participants found it helpful to plan for relapses, self monitor, and obtain social support, but they had mixed reactions about reflecting on satisfaction with outcomes. Participants accepted the intervention and desired ongoing contact to maintain accountability. This pilot maintenance intervention warrants further evaluation in a randomized controlled trial. PMID- 24347146 TI - Measuring HIV/AIDS-Related Stigma Across South Africa: A Versatile and Multidimensional Scale. AB - Reducing HIV/AIDS-related stigma is critical in the fight against HIV/AIDS. Although national campaigns and prevention programs have been implemented across South Africa to address this critical concern, assessing the impact of these initiatives is difficult as it requires that measurement of HIV/AIDS-related stigma is uniform and comparable nationwide. The appropriateness of existing stigma measures for this task is unclear as measurement of HIV/AIDS-related stigma may be qualitatively different across South Africa's diverse population. The current study assesses a theoretically and culturally informed multidimensional, HIV/AIDS-related stigma scale for measurement invariance across a sample drawn from two culturally distinct South African provinces: Limpopo (n = 597) and Western Cape (n = 598). Results suggest measurement invariance across groups for the HIV/AIDS stigma scale, supporting the scale's integrity and appropriateness for use across diverse populations. PMID- 24347147 TI - Help Preferences Among Employees Who Wish to Change Health Behaviors. AB - OBJECTIVE: To examine the help preferences of employees in the Danish police who had acknowledged that they wished to change health behaviors. In addition, we explored whether preferences varied with age, gender, chronic health concerns, positive expectations of good health, and past experiences of in-house health promotion services (i.e., wellness service). METHODS: Respondents to an electronic questionnaire who acknowledged wishing to change health behaviors in relation to smoking (n = 845), alcohol (n = 684), eating (n = 4,431), and physical activity (n = 5,179) were asked to choose up to three help alternatives on a predefined list. RESULTS: In descending order, smokers preferred help from nicotine gum, no help, and help and support from family and friends. Alcohol consumers preferred no help or help and support from family and friends or "other" forms. Employees who wanted to change eating habits preferred a free fruit bowl, free nutritional guidance, and healthy food at work. Employees who wanted to change physical activity patterns preferred exercise at work, offers of free exercise, and exercise in a social/collegial context. CONCLUSION: Wishing to change health behaviors is not always accompanied by perceiving a need for assistance. The no-help option was selected fairly frequently and mostly in relation to alcohol and smoking. A fruit bowl was the most preferred option for help, followed by exercise at work and free exercise. Help from traditional health services was ranked low, possibly reflecting that they are primarily viewed as a solution for stopping disease rather than promoting health. PMID- 24347148 TI - Diagnostic accuracy of dynamic gadoxetic-acid-enhanced MRI and PET/CT compared in patients with liver metastases from neuroendocrine neoplasms. AB - PURPOSE: To evaluate the diagnostic accuracy of dynamic-contrast-enhanced (DCE) MRI in comparison to both (18)F-FDG- and (68)Ga-DOTATATE-PET/CT in patients with liver metastases of neuroendocrine neoplasms (NEN). MATERIALS AND METHODS: Thirty two patients with hepatic metastases from NEN were examined both in DCE-MRI and positron emission tomography/computed tomography (PET/CT), using either (18)F fluorodeoxyglucose ((18)F-FDG) or (68)Ga-DOTATATE as tracer. DCE-MRI was performed at 3 Tesla with Gd-EOB-DTPA acquiring 48 slices every 2.2 s for 5 min. Three regions of interest (ROIs) representing liver background and liver metastases were defined in fat-saturated T1w three-dimensional GRE MRI sequences in the hepatobiliary phase. Corresponding ROIs were then defined in the DCE-MRI- and in the PET/CT-dataset. Area under the curve (AUC) was calculated for the differentiation between metastases and liver background for DCE-MRI and PET-CT parameters. RESULTS: AUC was very high for SUVmean (mean standardized uptake value) derived from (68)Ga-DOTATATE- (AUC = 0.966), and (18)F-FDG-PET/CT (AUC = 0.989). For DCE-MRI parameters, arterial flow fraction and intracellular uptake fraction showed the highest AUCs (AUC = 0.826, AUC = 0.819, respectively). The combination of those two had an AUC of 0.949. The combination of DCE-MRI and PET CT parameters resulted in the highest AUC. CONCLUSION: Both PET/CT parameters and DCE-MRI perfusion parameters show a high diagnostic accuracy in the distinction between liver metastases and liver tissue. Our data suggest that both modalities provide complementary information. PMID- 24347149 TI - Evolving health care systems and approaches to maintenance of certification. PMID- 24347150 TI - Specialty board certification in the United States: issues and evidence. AB - BACKGROUND: The American Board of Medical Specialties (ABMS) certification and maintenance of certification (MOC) programs strive to provide the public with guidance about a physician's competence. This study summarizes the literature on the effectiveness of these programs. METHOD: A literature search was conducted for studies published between 1986 and April 2013 and limited to ABMS certification. A modified version of Kirkpatrick's 4 levels of program evaluation included the reaction of stakeholders to certification, the extent to which physicians are encouraged to improve, the relationship between performance in the programs and nonclinical external measures of physician competence, and the relationship of performance in the programs with clinical quality measures. RESULTS: Patients' and hospitals' value of board certification and physician participation in MOC are high. Physicians are conflicted as to whether the effort involved is worth its value. Self-reported evidence shows improvement in knowledge, practice infrastructure, communication with patients and peers, and clinical care. Certification performance is generally related to nonclinical external measures such as types of training, practice characteristics, demographics, and disciplinary actions. In general, physicians who are board certified provide better patient care, albeit the results have modest effect sizes and are not unequivocal. CONCLUSIONS: Certification boards should continuously try to improve their programs in response to feedback from stakeholders, changes in the way physicians practice, as well as the growth in the fields of measurement and technology. Keeping pace with these changes in a responsible and evidence-based way is important. PMID- 24347151 TI - The Royal College experience and plans for the maintenance of certification program. AB - The Royal College of Physicians and Surgeons of Canada, in 2001, implemented a mandatory maintenance of certification (MOC) program that is required for fellows to maintain membership and fellowship. Participation in the MOC program is one of the recognized pathways approved by provincial medical regulatory authorities in Canada by which specialists can demonstrate their commitment to continued competent performance in practice. This article traces the historical beginnings of the MOC program, highlighting the educational foundation and scientific evidence that influenced its philosophy, goals, and strategic priorities. The MOC program has evolved into a complex system of continuing professional development to facilitate and enable a "cultural shift'' in how we conceptualize and support the continuing professional development (CPD) of specialists. The MOC program is an educational strategy that supports a learning culture where specialists are able to design, implement and document their accomplishments from multiple learning activities to build evidence-informed practices. In the future, the MOC Program must evolve from assisting fellows to use effective educational resources "for credit" to enable fellows, leveraging a competency-based CPD model, to demonstrate their capacity to continuously improve practice. This will require innovative methods to capture learning and practice improvements in real time, integrate learning during the delivery of health care, expand automation of reporting strategies, and facilitate new sociocultural methods of emergent learning and practice change. Collectively, these directions will require a research agenda that will generate evidence for how transformative cultural change in continuing professional education of the profession can be realized. PMID- 24347152 TI - The United Kingdom's experience with and future plans for revalidation. AB - Assuring fitness to practice for doctors internationally is increasingly complex. In the United Kingdom, the General Medical Council (GMC) has recently launched revalidation, which has been designed to bring all doctors into a governed environment. Since December 2012, all doctors who wish to practice are required to submit and reflect on supporting documentation against a framework of best practice, Good Medical Practice. These documents are brought together in an annual appraisal. Evidence of practice includes clinical governance activities such as significant events, complaints and audits, continuing professional development and feedback from colleagues and patients. Revalidation has been designed to support professionalism and identify early doctors in difficulty to support their remediation and so assure patient safety. The appraiser decides annually if the doctor has met the standard which is shared with the most senior doctor in the area, the responsible officer (RO). The RO's role is to make a recommendation for revalidation every 5 years for each doctor to the GMC. Revalidation is unique in that it is national, compulsory, involves all doctors regardless of position or training, and is linked to the potentially performance moderating process of appraisal. However, it has a long and troubled history that is shaped by high-profile medical scandals and delays from the profession, the GMC, and the government. Revalidation has been complicated further by rhetoric around patient care and driving up standards but at the same time identifying poor performance. The GMC have responded by commissioning a national evaluation which is currently under development. PMID- 24347153 TI - Professionalism, career-long assessment, and the American Board of Medical Specialties' Maintenance of Certification: an introduction to this special supplement. PMID- 24347154 TI - Practicing physicians' needs for assessment and feedback as part of professional development. AB - Recently, more is being learned about the linkages among assessment, feedback, and continued learning and professional development. The purpose of this article is to explore these linkages and to understand how assessment and feedback can guide professional development and related practice change. It includes a brief review of conceptual models that guide learning and practice change in general, related to both formally structured continuing professional development (CPD) sessions and to self-directed individual activities, and draws on these to inform learning and change from assessment and feedback. However, evidence and theory show that using assessment and feedback for learning and change are not naturally intuitive activities. We propose a 4-phase facilitated reflective process for enabling engagement with assessment data and feedback and using it for learning and change, and explore the varied personal and contextual factors which are influential and require consideration. We end with practical implications and suggestions. PMID- 24347155 TI - Maintenance of certification, revalidation, and professional self-regulation. PMID- 24347156 TI - American Board of Medical Specialties Maintenance of Certification: theory and evidence regarding the current framework. AB - The American Board of Medical Specialties Maintenance of Certification Program (ABMS MOC) is designed to provide a comprehensive approach to physician lifelong learning, self-assessment, and quality improvement (QI) through its 4-part framework and coverage of the 6 competencies previously adopted by the ABMS and the Accreditation Council for Graduate Medical Education (ACGME). In this article, the theoretical rationale and exemplary empiric data regarding the MOC program and its individual parts are reviewed. The value of each part is considered in relation to 4 criteria about the relationship of the competencies addressed within that part to (1) patient outcomes, (2) physician performance, (3) validity of the assessment or educational methods utilized, and (4) learning or improvement potential. Overall, a sound theoretical rationale and a respectable evidence base exists to support the current structure and elements of the MOC program. However, it is incumbent on the ABMS and ABMS member boards to continue to examine their programs moving forward to assure the public and the profession that they are meeting expectations, are clinically relevant, and provide value to patients and participating physicians, and to refine and improve them as ongoing research indicates. PMID- 24347157 TI - An overview of plant volatile metabolomics, sample treatment and reporting considerations with emphasis on mechanical damage and biological control of weeds. AB - INTRODUCTION: The technology for the collection and analysis of plant-emitted volatiles for understanding chemical cues of plant-plant, plant-insect or plant microbe interactions has increased over the years. Consequently, the in situ collection, analysis and identification of volatiles are considered integral to elucidation of complex plant communications. Due to the complexity and range of emissions the conditions for consistent emission of volatiles are difficult to standardise. OBJECTIVE: To discuss: evaluation of emitted volatile metabolites as a means of screening potential target- and non-target weeds/plants for insect biological control agents; plant volatile metabolomics to analyse resultant data; importance of considering volatiles from damaged plants; and use of a database for reporting experimental conditions and results. METHOD: Recent literature relating to plant volatiles and plant volatile metabolomics are summarised to provide a basic understanding of how metabolomics can be applied to the study of plant volatiles. RESULTS: An overview of plant secondary metabolites, plant volatile metabolomics, analysis of plant volatile metabolomics data and the subsequent input into a database, the roles of plant volatiles, volatile emission as a function of treatment, and the application of plant volatile metabolomics to biological control of invasive weeds. CONCLUSION: It is recommended that in addition to a non-damaged treatment, plants be damaged prior to collecting volatiles to provide the greatest diversity of odours. For the model system provided, optimal volatile emission occurred when the leaf was punctured with a needle. Results stored in a database should include basic environmental conditions or treatments. PMID- 24347158 TI - Biogas plasticization coupled anaerobic digestion: the anaerobic pump stoichiometry. AB - This paper presents the stoichiometry section of a bioenergetics investigation into the biogas plasticization of wastewater sludge using the Anaerobic Pump (TAP). Three residue samples, an input substrate and two residual products, were collected from two side by side operated AD systems, a conventional continuous flow and stirred reactor, and TAP, and submitted for elemental and calorimetric analyses. The elemental compositions of the residues were fitted to a heterotrophic metabolism model [1] for both systems. To facilitate balanced stoichiometric models, a simple "cell" correction computation separates measured residual composites into "real" residual composition and cell growth (C5H7NO2) components. The elemental data and model results show that the TAP stage II residual composition (C1H0.065O0.0027N0.036) was nearly devoid of hydrogen and oxygen, leaving only fixed carbon and cells grown as the composition of the remaining mass. This quantitative evidence supports prior measurements of very high methane yields from TAP stage II reactor during steady-state experiments [2]. All performance parameters derived from the stoichiometric model(s) showed good agreement with measured steady-state averaged values. These findings are strong evidence that plasticization-disruption (TAP) cycle is the mechanism responsible for the observed increases in methane yield. The accuracy achieved by the stoichiometry models qualifies them for thermodynamic analysis to obtain potentials and bioconversion efficiencies. How applied pressure causes matrix conformation changes triggered by a functional consequence (plasticization and disruption) is this study's essential focus. PMID- 24347159 TI - Aqueous extract of Crataegus azarolus protects against DNA damage in human lymphoblast Cell K562 and enhances antioxidant activity. AB - The present study was carried out to characterize the cellular antioxidant effect of the aqueous extract of Crataegus azarolus and its antigenotoxic potential using human myelogenous cells, K562. The antioxidant capacity of this extract was evaluated by determining its cellular antioxidant activity (CAA) in K562 cells. Also, preceding antigenotoxicity assessment, its eventual genotoxicity property was investigated by evaluating its capacity to induce the DNA degradation of treated cell nuclei. As no genotoxicity was detected at different exposure times, its ability to protect cell DNA against H2O2 oxidative effect was investigated, using the "comet assay." It appears that 800 MUg/mL of extract inhibited the genotoxicity induced by H2O2 with a rate of 41.30 %, after 4 h of incubation. In addition, this extract revealed a significant cellular antioxidant capacity against the reactive oxygen species in K562 cells. PMID- 24347160 TI - Influence of forced internal air circulation on airflow distribution and heat transfer in a gas double-dynamic solid-state fermentation bioreactor. AB - Internal air circulation affects the temperature field distribution in a gas double-dynamic solid-state fermentation bioreactor (GDSFB). To enhance heat transfer through strengthening internal air circulation in a GDSFB, we put an air distribution plate (ADP) into the bioreactor and studied the effects of forced internal air circulation on airflow, heat transfer, and cellulase activity of Trichoderma viride L3. Results showed that ADP could help form a steady and uniform airflow distribution, and with gas-guide tubes, air reversal was formed inside the bioreactor, thus resulting in a smaller temperature difference between medium and air by enhancing convective heat transfer inside the bioreactor. Using an ADP of 5.35 % aperture ratio caused a 1 degrees C decrease in the average temperature difference during the solid-state fermentation process of T. viride L3. Meanwhile, the cellulase activity of T. viride L3 increased by 13.5 %. The best heat-transfer effect was attained when using an ADP of 5.35 % aperture ratio and setting the fan power to 125 V (4.81 W) in the gas double-dynamic solid-state fermentation (GDSF) process. An option of suitable aperture ratio and fan power may be conducive to ADPs' industrial amplification. PMID- 24347161 TI - Characterization and high level expression of acidic endoglucanase in Pichia pastoris. AB - Bioconversion of cellulosic material into glucose needs cellulase enzymes. One of the most important organisms that produces cellulases is Trichoderma reesei, whose cellulose enzymes are probably the most widely used in the industry. However, these enzymes are not stable enough at high pH and temperatures. The optimized synthetic endoglucanase II gene with Pichia pastoris codon preferences was secretary expressed in P. pastoris. Recombinant enzyme characterization showed maximum activity at pH 4.8 and temperature 75 degrees C, and it demonstrated increasing thermal stability in high temperature. The enzyme maintained its activity in a wide pH range from 3.5 to 6.5. The optimization of fermentation medium was carried out in shaking flasks. Recombinant protein expression at optimum conditions (pH 7, temperature 25 degrees C, and 1 % methanol induction) for 72 h demonstrated 2,358.8 U/ml endoglucanase activity units. To our knowledge, this is the highest acidic thermophilic endoglucanase activity that is reported in crude intracellular medium in P. pastoris. We conclude that P. pastoris is an appropriate host for high-level expression of optimized endoglucanase gene with improved thermal stability. PMID- 24347162 TI - Effects of isoflurane anesthesia on F-waves in the sciatic nerve of the adult rat. AB - INTRODUCTION: Nerve conduction studies provide insights into the functional consequences of axonal and myelin pathology in peripheral neuropathies. We investigated whether isoflurane inhalation anesthesia alters F-wave latencies and F-persistence in the sciatic nerve of adult rats. METHODS: Ten rats were investigated at 3 different isoflurane concentrations followed by ketamine xylazine injection anesthesia. To assess F-wave latencies, a stimulation paradigm was chosen to minimize H-reflex masking of F-waves. RESULTS: F-wave persistence rates were reduced with 3.5% isoflurane concentration at 4 and 10 Hz supramaximal stimulation and marginally reduced with 2.5% isoflurane when compared with ketamine-xylazine. F-wave amplitudes decreased progressively with rising stimulus frequency in all types of anesthesia and most at 3.5% isoflurane concentration. CONCLUSIONS: The type of anesthesia and the stimulus repetition rate have an impact on some F-wave parameters. Higher isoflurane concentrations and repetition rates are not recommended in experimental studies using rat neuropathy models where F-waves are of interest. PMID- 24347163 TI - Competition through dimerization between antiapoptotic and proapoptotic HS-1 associated protein X-1 (Hax-1). AB - Studies on Hax-1 have mainly focused on variant (v) 1, demonstrating its antiapoptotic properties. However, HAX1 is heavily spliced, generating structurally distinct isoforms. We sought to characterize the Hax-1 isoforms expressed in rat heart before and after insult. We confirmed the presence of at least four Hax-1 transcripts in healthy rat cardiac muscle. These exhibited differential expression before and after induction of myocardial infarction, with v2 being up-regulated 12-fold at the transcript level and 1.5-fold at the protein level post-insult. Contrary to antiapoptotic rat and human v1, overexpression of rat v2 or human v4 (the human homologue of rat v2) in epithelial cells exacerbated cell death by 30% following H2O2 treatment compared with control vector. Coexpression of rat v1 and v2 or human v1 and v4 neutralized the protective effects of rat and human v1 and the proapoptotic effects of rat v2 and human v4 by modulating cytochrome c release. This is, at least partly, mediated by the ability of Hax-1 proteins to form homotypic and heterotypic dimers with binding affinities ranging from ~3.8 nm for v1 dimers to ~97 nm for v1/v2 dimers. The minimal binding region supporting these interactions lies between amino acids 97-278, which are shared by nearly all Hax-1 proteins, indicating that additional factors regulate the preferential formation of Hax-1 homo- or heterodimers. Our studies are the first to show that Hax-1 is a family of anti- and proapoptotic regulators that may modulate cell survival and death through homo- or heterodimerization. PMID- 24347164 TI - Structural change in FtsZ Induced by intermolecular interactions between bound GTP and the T7 loop. AB - FtsZ is a prokaryotic homolog of tubulin and is a key molecule in bacterial cell division. FtsZ with bound GTP polymerizes into tubulin-like protofilaments. Upon polymerization, the T7 loop of one subunit is inserted into the nucleotide binding pocket of the second subunit, which results in GTP hydrolysis. Thus, the T7 loop is important for both polymerization and hydrolysis in the tubulin/FtsZ family. Although x-ray crystallography revealed both straight and curved conformations of tubulin, only a curved structure was known for FtsZ. Recently, however, FtsZ from Staphylococcus aureus has been shown to have a very different conformation from the canonical FtsZ structure. The present study was performed to investigate the structure of FtsZ from Staphylococcus aureus by mutagenesis experiments; the effects of amino acid changes in the T7 loop on the structure as well as on GTPase activity were studied. These analyses indicated that FtsZ changes its conformation suitable for polymerization and GTP hydrolysis by movement between N- and C-subdomains via intermolecular interactions between bound nucleotide and residues in the T7 loop. PMID- 24347165 TI - Glucocorticoids recruit Tgfbr3 and Smad1 to shift transforming growth factor-beta signaling from the Tgfbr1/Smad2/3 axis to the Acvrl1/Smad1 axis in lung fibroblasts. AB - Glucocorticoids represent the mainstay therapy for many lung diseases, providing outstanding management of asthma but performing surprisingly poorly in patients with acute respiratory distress syndrome, chronic obstructive pulmonary disease, lung fibrosis, and blunted lung development associated with bronchopulmonary dysplasia in preterm infants. TGF-beta is a pathogenic mediator of all four of these diseases, prompting us to explore glucocorticoid/TGF-beta signaling cross talk. Glucocorticoids, including dexamethasone, methylprednisolone, budesonide, and fluticasone, potentiated TGF-beta signaling by the Acvrl1/Smad1/5/8 signaling axis and blunted signaling by the Tgfbr1/Smad2/3 axis in NIH/3T3 cells, as well as primary lung fibroblasts, smooth muscle cells, and endothelial cells. Dexamethasone drove expression of the accessory type III TGF-beta receptor Tgfbr3, also called betaglycan. Tgfbr3 was demonstrated to be a "switch" that blunted Tgfbr1/Smad2/3 and potentiated Acvrl1/Smad1 signaling in lung fibroblasts. The Acvrl1/Smad1 axis, which was stimulated by dexamethasone, was active in lung fibroblasts and antagonized Tgfbr1/Smad2/3 signaling. Dexamethasone acted synergistically with TGF-beta to drive differentiation of primary lung fibroblasts to myofibroblasts, revealed by acquisition of smooth muscle actin and smooth muscle myosin, which are exclusively Smad1-dependent processes in fibroblasts. Administration of dexamethasone to live mice recapitulated these observations and revealed a lung-specific impact of dexamethasone on lung Tgfbr3 expression and phospho-Smad1 levels in vivo. These data point to an interesting and hitherto unknown impact of glucocorticoids on TGF-beta signaling in lung fibroblasts and other constituent cell types of the lung that may be relevant to lung physiology, as well as lung pathophysiology, in terms of drug/disease interactions. PMID- 24347166 TI - Crucial positively charged residues for ligand activation of the GPR35 receptor. AB - GPR35 is a G protein-coupled receptor expressed in the immune, gastrointestinal, and nervous systems in gastric carcinomas and is implicated in heart failure and pain perception. We investigated residues in GPR35 responsible for ligand activation and the receptor structure in the active state. GPR35 contains numerous positively charged amino acids that face into the binding pocket that cluster in two distinct receptor regions, TMH3-4-5-6 and TMH1-2-7. Computer modeling implicated TMH3-4-5-6 for activation by the GPR35 agonists zaprinast and pamoic acid. Mutation results for the TMH1-2-7 region of GPR35 showed no change in ligand efficacies at the K1.32A, R2.65A, R7.33A, and K7.40A mutants. However, mutation of arginine residues in the TMH3-4-5-6 region (R4.60, R6.58, R3.36, R(164), and R(167) in the EC2 loop) had effects on signaling for one or both agonists tested. R4.60A resulted in a total ablation of agonist-induced activation in both the beta-arrestin trafficking and ERK1/2 activation assays. R6.58A increased the potency of zaprinast 30-fold in the pERK assay. The R(167)A mutant decreased the potency of pamoic acid in the beta-arrestin trafficking assay. The R(164)A and R(164)L mutants decreased potencies of both agonists. Similar trends for R6.58A and R(167)A were observed in calcium responses. Computer modeling showed that the R6.58A mutant has additional interactions with zaprinast. R3.36A did not express on the cell surface but was trapped in the cytoplasm. The lack of surface expression of R3.36A was rescued by a GPR35 antagonist, CID2745687. These results clearly show that R4.60, R(164), R(167), and R6.58 play crucial roles in the agonist initiated activation of GPR35. PMID- 24347167 TI - Bidirectional control of postsynaptic density-95 (PSD-95) clustering by Huntingtin. AB - Huntington disease is associated with early alterations in corticostriatal synaptic function that precede cell death, and it is postulated that ameliorating such changes may delay clinical onset and/or prevent neurodegeneration. Although many of these synaptic alterations are thought to be attributable to a toxic gain of function of the mutant huntingtin protein, the role that nonpathogenic huntingtin (HTT) plays in synaptic function is relatively unexplored. Here, we compare the immunocytochemical localization of a major postsynaptic scaffolding protein, PSD-95, in striatal neurons from WT mice and mice overexpressing HTT with 18 glutamine repeats (YAC18, nonpathogenic). We found that HTT overexpression resulted in a palmitoylation- and BDNF-dependent increase in PSD 95 clustering at synaptic sites in striatal spiny projection neurons (SPNs) co cultured with cortical neurons. Surprisingly, the latter effect was mediated presynaptically, as HTT overexpression in cortical neurons alone was sufficient to increase PSD-95 clustering in the postsynaptic SPNs. In contrast, antisense oligonucleotide knockdown of HTT in WT co-cultures resulted in a significant reduction of PSD-95 clustering in SPNs. Notably, despite these bidirectional changes in PSD-95 clustering, we did not observe an alteration in basal electrophysiological measures of AMPA and NMDA receptors. Thus, unlike in previous studies in the hippocampus, enhanced or decreased PSD-95 clustering alone was insufficient to drive AMPA or NMDA receptors into or out of SPN synapses. In all, our results demonstrate that nonpathogenic HTT can indeed influence synaptic protein localization and uncover a novel role of HTT in PSD-95 distribution. PMID- 24347168 TI - Endoplasmic reticulum (ER) stress and hypoxia response pathways interact to potentiate hypoxia-inducible factor 1 (HIF-1) transcriptional activity on targets like vascular endothelial growth factor (VEGF). AB - Cells respond to suboptimal microenvironments by activating stress signaling pathways, like the unfolded protein response and hypoxia-induced transcription factors HIF-1/2, to restore homeostasis. Both cytoprotective pathways have been well studied in isolation at the biochemical and molecular levels. Mounting evidence reveals that they can be activated simultaneously in tumor cells and, likely, in other tissues experiencing inadequate microenvironments and that they share some transcriptional targets, like the proangiogenic factor VEGFA. However, the potential interaction between these pathways is poorly understood. Cell culture experiments revealed that as a consequence of unfolded protein response activation, ATF4 bound to the human VEGFA promoter and activated its transcription, whereas HIF-1 did so in response to hypoxia. When both pathways were activated together, VEGFA transcripts were induced to a higher level than when either stress was applied alone. Surprisingly, this was not due to the combined actions of the stress pathway-specific transcription factors. Instead, we found that endoplasmic reticulum stress potentiated HIF-1 activity to transactivate VEGF expression as well as another well characterized target, BNIP3. These data reveal an unexpected interaction between two important cytoprotective responses that are likely to have significant consequences in environmentally compromised tissues and tumor cells. PMID- 24347169 TI - Ninjurin1 deficiency attenuates susceptibility of experimental autoimmune encephalomyelitis in mice. AB - Ninjurin1 is a homotypic adhesion molecule that contributes to leukocyte trafficking in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. However, in vivo gene deficiency animal studies have not yet been done. Here, we constructed Ninjurin1 knock-out (KO) mice and investigated the role of Ninjurin1 on leukocyte trafficking under inflammation conditions such as EAE and endotoxin-induced uveitis. Ninjurin1 KO mice attenuated EAE susceptibility by reducing leukocyte recruitment into the injury regions of the spinal cord and showed less adhesion of leukocytes on inflamed retinal vessels in endotoxin-induced uveitis mice. Moreover, the administration of a custom-made antibody (Ab26-37) targeting the Ninjurin1 binding domain ameliorated the EAE symptoms, showing the contribution of its adhesion activity to leukocyte trafficking. In addition, we addressed the transendothelial migration (TEM) activity of bone marrow-derived macrophages and Raw264.7 cells according to the expression level of Ninjurin1. TEM activity was decreased in Ninjurin1 KO bone marrow-derived macrophages and siNinj1 Raw264.7 cells. Consistent with this, GFP-tagged mNinj1-overexpressing Raw264.7 cells increased their TEM activity. Taken together, we have clarified the contribution of Ninjurin1 to leukocyte trafficking in vivo and delineated its direct functions to TEM, emphasizing Ninjurin1 as a beneficial therapeutic target against inflammatory diseases such as multiple sclerosis. PMID- 24347170 TI - Ascorbate efflux as a new strategy for iron reduction and transport in plants. AB - Iron (Fe) is essential for virtually all living organisms. The identification of the chemical forms of iron (the speciation) circulating in and between cells is crucial to further understand the mechanisms of iron delivery to its final targets. Here we analyzed how iron is transported to the seeds by the chemical identification of iron complexes that are delivered to embryos, followed by the biochemical characterization of the transport of these complexes by the embryo, using the pea (Pisum sativum) as a model species. We have found that iron circulates as ferric complexes with citrate and malate (Fe(III)3Cit2Mal2, Fe(III)3Cit3Mal1, Fe(III)Cit2). Because dicotyledonous plants only transport ferrous iron, we checked whether embryos were capable of reducing iron of these complexes. Indeed, embryos did express a constitutively high ferric reduction activity. Surprisingly, iron(III) reduction is not catalyzed by the expected membrane-bound ferric reductase. Instead, embryos efflux high amounts of ascorbate that chemically reduce iron(III) from citrate-malate complexes. In vitro transport experiments on isolated embryos using radiolabeled (55)Fe demonstrated that this ascorbate-mediated reduction is an obligatory step for the uptake of iron(II). Moreover, the ascorbate efflux activity was also measured in Arabidopsis embryos, suggesting that this new iron transport system may be generic to dicotyledonous plants. Finally, in embryos of the ascorbate-deficient mutants vtc2-4, vtc5-1, and vtc5-2, the reducing activity and the iron concentration were reduced significantly. Taken together, our results identified a new iron transport mechanism in plants that could play a major role to control iron loading in seeds. PMID- 24347171 TI - The death-inducer obliterator 1 (Dido1) gene regulates embryonic stem cell self renewal. AB - The regulatory network of factors that center on master transcription factors such as Oct4, Nanog, and Sox2 help maintain embryonic stem (ES) cells and ensure their pluripotency. The target genes of these master transcription factors define the ES cell transcriptional landscape. In this study, we report our findings that Dido1, a target of canonical transcription factors such as Oct4, Sox2, and Nanog, plays an important role in regulating ES cell maintenance. We found that depletion of Dido1 in mouse ES cells led to differentiation, and ectopic expression of Dido1 inhibited differentiation induced by leukemia inhibitory factor withdrawal. We further demonstrated that whereas Nanog and Oct4 could occupy the Dido1 locus and promote its transcription, Dido1 could also target to the loci of pluripotency factors such as Nanog and Oct4 and positively regulate their expression. Through this feedback and feedforward loop, Dido1 is able to regulate self-renewal of mouse ES cells. PMID- 24347172 TI - The reverse gyrase from Pyrobaculum calidifontis, a novel extremely thermophilic DNA topoisomerase endowed with DNA unwinding and annealing activities. AB - Reverse gyrase is a DNA topoisomerase specific for hyperthermophilic bacteria and archaea. It catalyzes the peculiar ATP-dependent DNA-positive supercoiling reaction and might be involved in the physiological adaptation to high growth temperature. Reverse gyrase comprises an N-terminal ATPase and a C-terminal topoisomerase domain, which cooperate in enzyme activity, but details of its mechanism of action are still not clear. We present here a functional characterization of PcalRG, a novel reverse gyrase from the archaeon Pyrobaculum calidifontis. PcalRG is the most robust and processive reverse gyrase known to date; it is active over a wide range of conditions, including temperature, ionic strength, and ATP concentration. Moreover, it holds a strong ATP-inhibited DNA cleavage activity. Most important, PcalRG is able to induce ATP-dependent unwinding of synthetic Holliday junctions and ATP-stimulated annealing of unconstrained single-stranded oligonucleotides. Combined DNA unwinding and annealing activities are typical of certain helicases, but until now were shown for no other reverse gyrase. Our results suggest for the first time that a reverse gyrase shares not only structural but also functional features with evolutionary conserved helicase-topoisomerase complexes involved in genome stability. PMID- 24347173 TI - Fluorine-doped Fe(2)O(3) as high energy density electroactive material for hybrid supercapacitor applications. AB - Nanostructured alpha-Fe2 O3 with and without fluorine substitution were successfully obtained by a green route, that is, microwave irradiation. The hematite phase materials were evaluated as a high-performance electrode material in a hybrid supercapacitor configuration along with activated carbon (AC). The presence of fluorine was confirmed through X-ray photoelectron spectroscopy and transmission electron microscopy. Fluorine-doped Fe2 O3 (F-Fe2 O3 ) exhibits an enhanced pseudocapacitive performance compared to that of the bare hematite phase. The F-Fe2 O3 /AC cell delivered a specific capacitance of 71 F g(-1) at a current density of 2.25 A g(-1) and retained approximately 90 % of its initial capacitance after 15 000 cycles. Furthermore, the F-Fe2 O3 /AC cell showed a very high energy density of about 28 W h kg(-1) compared to bare hematite phase (~9 W h kg(-1) ). These data clearly reveal that the electrochemical performance of Fe2 O3 can be improved by fluorine doping, thereby dramatically improving the energy density of the system. PMID- 24347174 TI - Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes. AB - Emerging data indicate that gut-derived endotoxin (metabolic endotoxemia) may contribute to low-grade systemic inflammation in insulin-resistant states. Specific gut bacteria seem to serve as lipopolysaccharide (LPS) sources and several reports claim a role for increased intestinal permeability in the genesis of metabolic disorders. Therefore, we investigated the serum levels of LPS and zonulin (ZO-1, a marker of gut permeability) along with systemic levels of tumor necrosis factor-alpha (TNF-alpha) and Interleukin-6 (IL-6) in patients with type 2 diabetes mellitus (T2DM) compared to control subjects. Study subjects were recruited from the Chennai Urban Rural Epidemiology Study [CURES], Chennai, India. Study group (n = 45 each) comprised of a) subjects with normal glucose tolerance (NGT) and (b) patients with T2DM. LPS, ZO-1, TNF-alpha, and IL-6 levels were measured by ELISA. Serum levels of LPS [p < 0.05], LPS activity [p < 0.001], ZO-1 [p < 0.001], TNFalpha [p < 0.001], and IL-6 [p < 0.001] were significantly increased in patients with T2DM compared to control subjects. Pearson correlation analysis revealed that LPS activity was significantly and positively correlated with ZO-1, fasting plasma glucose, 2 h post glucose, HbA1c, serum triglycerides, TNF-alpha, IL-6, and negatively correlated with HDL cholesterol. Regression analysis showed that increased LPS levels were significantly associated with type 2 diabetes [odds ratio (OR) 13.43, 95 % CI 1.998-18.9; p = 0.003]. In Asian Indians who are considered highly insulin resistant, the circulatory LPS levels, LPS activity, and ZO-1 were significantly increased in patients with type 2 diabetes and showed positive correlation with inflammatory markers and poor glycemic/lipid control. PMID- 24347175 TI - Effects of gamma-irradiation on Na,K-ATPase in cardiac sarcolemma. AB - Previous studies showed that adverse effect of ionizing radiation on the cardiovascular system is beside other factors mostly mediated by reactive oxygen and nitrogen species, which deplete antioxidant stores. One of the structures highly sensitive to radicals is the Na,K-ATPase the main system responsible for extrusion of superfluous Na(+) out of the cell which utilizes the energy derived from ATP. The aim of present study was the investigation of functional properties of cardiac Na,K-ATPase in 20-week-old male rats 6 weeks after gamma-irradiation by a dose 25 Gy (IR). Irradiation induced decrease of systolic blood pressure from 133 in controls to 85 mmHg in IR group together with hypertrophy of right ventricle (RV) and hypotrophy of left ventricle (LV). When activating the cardiac Na,K-ATPase with substrate, its activity was lower in IR in the whole concentration range of ATP. Evaluation of kinetic parameters revealed a decrease of the maximum velocity (V max) by 40 % with no changes in the value of Michaelis Menten constant (K m). During activation with Na(+), we observed a decrease of the enzyme activity in hearts from IR at all tested Na(+) concentrations. The value of V max decreased by 38 %, and the concentration of Na(+) that gives half maximal reaction velocity (K Na) increased by 62 %. This impairment in the affinity of the Na(+)-binding site together with decreased number of active Na,K ATPase molecules, as indicated by lowered V max values, are probably responsible for the deteriorated efflux of the excessive Na(+) from the intracellular space in hearts of irradiated rats. PMID- 24347176 TI - Mitigation of postischemic cardiac contractile dysfunction by CaMKII inhibition: effects on programmed necrotic and apoptotic cell death. AB - While Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) has been suggested to be an important protein regulating heart function upon ischemia/reperfusion (I/R), the mechanisms responsible are not fully known. Furthermore, it is not known whether CaMKII activation can modulate necroptosis, a recently described form of programmed cell death. In order to investigate these issues, Langendroff perfused rat hearts were subjected to global ischemia and reperfusion, and CaMKII inhibition was achieved by adding the CaMKII inhibitor KN-93 (0.5 MUmol/dm(3)) to the perfusion solution before the induction of ischemia. Immunoblotting was used to detect changes in expression of proteins modulating both necroptotic and apoptotic cell death. CaMKII inhibition normalized I/R induced increases in expression of necroptotic RIP1 and caspase-8 along with proteins of the intrinsic apoptotic pathway, namely cytochrome c and caspase-9. In addition, it increased the Bcl-2/Bax ratio and reduced caspase-3 and cleaved PARP1 content suggesting reduction of cell death. These changes coexisted with improvement of postischemic contractile function. On the other hand, there was no correlation between levels of pT287-CaMKIIdelta and LVDP recovery after I/R. These results demonstrate for the first time that CaMKII inhibition may mitigate cardiac contractile dysfunction, at least partially, by limiting the contents of not only apoptotic, but also necroptotic proteins. Phosphorylation of CaMKII seems unlikely to determine the degree of postischemic recovery of contractile function. PMID- 24347177 TI - The activation of TLR7 regulates the expression of VEGF, TIMP1, MMP2, IL-6, and IL-15 in Hela cells. AB - Toll-like receptors (TLRs) play important roles in activation of immunoreaction and tumor development. Toll-like receptor 7 (TLR7), one of the TLRs binding with single-stranded RNA, activates intracellular pathways and stimulates the release of proinflammatory cytokines, chemokines. In this study, we investigated the impact of the TLR7-signaling pathway on the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP2), tissue inhibitor of metalloproteinase 1 (TIMP1), interleukin 6 (IL-6), and interleukin 15 (IL-15), which have been testified to refer to the immunomodulating and tumor progression. We confirmed that the TLR7 was expressed by Hela cells, despite the abundance was weak. Gardiquimod, one of the TLR7 ligands, can promote these five genes expression in varying degrees. After stimulating with gardiquimod, the expression of the IL-15V1, 3 increased about 4.5 times on RNA level, the other expression was only up-regulated about 2 times. We also discovered that gardiquimod could activate the MAPK/ERK- and PI3K/AKT-signaling pathways, and the specific inhibitors studies indicate that, the effect of gardiquimod on these genes expression is mainly or partially dependent on the activation of these two signaling pathways. To sum up, the activation of TLR7 signaling pathway may modulate some genes expression in Hela cells and may contribute to the pathogenesis of the cervical cancer. PMID- 24347178 TI - The C-terminal cytoplasmic portion of the NhaP2 cation-proton antiporter from Vibrio cholerae affects its activity and substrate affinity. AB - In this work, we report the phenotypic and biochemical effects of deleting the C terminal cytoplasmic portion of the NhaP2 cation/proton antiporter from Vibrio cholerae. While the deletion changed neither the expression nor targeting of the Vc-NhaP2 in an antiporter-less Escherichia coli strain, it resulted in a changed sensitivity of the host to sodium ions at neutral pH, indicating an altered Na(+) transport through the truncated variant. When assayed in inside-out sub-bacterial vesicles, the truncation was found to result in greatly reduced K(+)/H(+) and Na(+)/H(+) antiport activity at all pH values tested and a greater than fivefold decrease in the affinity for K(+) (measured as the apparent K m) at pH 7.5. Being expressed in trans in a strain of V. cholerae bearing a chromosomal nhaP2 deletion, the truncated nhaP2 gene was able to complement its inability to grow in potassium-rich medium at pH 6.0. Thus the residual K(+)/H(+) antiport activity associated with the truncated Vc-NhaP2 was still sufficient to protect cells from an over-accumulation of K(+) ions in the cytoplasm. The presented data suggest that while the cytoplasmic portion of Vc-NhaP2 is not involved in ion translocation directly, it is necessary for optimal activity and substrate binding of the Vc-NhaP2 antiporter. PMID- 24347179 TI - pT4 stage II and III colon cancers carry the worst prognosis in a nationwide survival analysis. Shepherd's local peritoneal involvement revisited. AB - The aim of this study is to clarify the prognostic importance of several well known but still debated pathological variables related to the survival of colon cancer patients. The study focuses on the definition and survival carried by the pT4 category and stage II where the presence of high-risk variables may determine whether or not adjuvant chemotherapy is administered. A retrospective nationwide study was carried out including all colon cancer patients that underwent resection in Iceland between 1990 and 2004 (n = 889). All histopathology was reassessed. Cancer-specific survival (CSS) and overall survival were analysed using Kaplan-Meier and Cox regression analysis. In stage II, the five-year CSS for pT4 was 50% (95% CI, 32-69%), which was the lowest survival observed in that stage. In stage III the five-year CSS was 30% (95% CI, 18-41%) and 37% (95% CI, 26-48%) for pT4 and pN2 tumors, respectively. Lymphatic invasion and differentiation had no prognostic value in stage II. The survival associated with pT4a versus pT4b depends on how these categories are defined with regard to Shepherd's local peritoneal involvement (LPI). In the present series, pT4 is a major indicator of poor prognosis in patients with stage II and III colon carcinoma. Four-tiered TNM or Dukes staging systems are insufficient by not taking this variable into account. Only Shepherd's LPI4 and a subgroup of LPI3 (i.e., borderline LPI3/LPI4) should qualify for the pT4a subcategory. The results do not support lymphatic invasion or poor differentiation as high-risk stage II variables. PMID- 24347180 TI - Increased risk of dementia in patients with osteoporosis: a population-based retrospective cohort analysis. AB - Osteoporosis is a common systemic skeletal disease that predominantly affects people older than 50 years and often co-occurs with dementia. The purpose of this study was to evaluate the risk of dementia in osteoporosis patients in Taiwan. Using data from Taiwan's National Health Insurance Research Database (NHIRD), we identified 23,941 patients with osteoporosis from 2000 to 2010 and 47,579 nonosteoporosis control patients, frequency-matched for age, sex, and index year, excluding patients with dementia at the baseline. We conducted univariate and multiple Cox proportional-hazards regression analyses to calculate the hazard ratios (HRs) and 95 % confidence intervals (CIs) of the association between osteoporosis and risk of dementia. After adjustment for potential risk factors, the osteoporosis patients exhibited 1.46-fold and 1.39-fold higher risk of dementia (95 % CI = 1.37-1.56) and Alzheimer's disease (95 % CI = 0.95-2.02), respectively, compared with the matched nonosteoporosis patients. We observed increased risk of dementia in both men and women with osteoporosis. The osteoporosis patients receiving bisphosphonate treatment or estrogen supplementation were associated with significantly lower risk of dementia compared with the osteoporosis patients who did not receive any treatment. Overall, our results suggest higher risks of dementia in osteoporosis patients than in nonosteoporosis patients. Osteoporosis could thus be considered an early risk factor for dementia. Future large-scale double-blind randomized clinical trials are required to clarify the role of medication in osteoporosis-related dementia. PMID- 24347181 TI - Genome-wide analysis of DNA methylation in an APP/PS1 mouse model of Alzheimer's disease. AB - To investigate aberrant genome-wide CpG methylation patterns in cortex brain tissue of APP/PS1 mice and as compared to controls, which allows for identification of novel disease-associated genes. This study investigates the genome-wide DNA methylation profiles of the cortex from APP/PS1 transgenic mice and control mice using the Roche NimbleGen chip platform. Functional analysis was then conducted by Ingenuity Pathways Analysis system. The methylated DNA fragments in the genome of each sample were enriched by MeDIP and the whole genome interrogations were hybridized to the Roche NimbleGen Human DNA Methylation 3x720 K CpG Island Plus RefSeq Promoter Array that cover 15,980 CpG islands and 20,404 reference gene promoter regions of the entire human genome. Analysis reveals 2346 CpG sites representing 485 unique genes as potentially associated with AD disease status pending confirmation in additional study. At the same time, these hyper-methylated genes display familial aggregation. An impairment of the transforming growth factor-beta1 (TGF-beta1) signaling pathway has been demonstrated to be specific to the AD brain and, particularly, to the early phase of the disease, supporting a role for epigenetic change of TGF-beta1 in AD pathology. In future research, we will focus on TGF-beta1, as it appeared to be the most promising candidate for AD. PMID- 24347182 TI - How to treat tumefactive demyelinating disease? AB - Glioma-like inflammatory demyelinating lesions can be found in patients with pre diagnosed multiple sclerosis, but they have also been described as an isolated disease entity. The initial diagnostic work-up usually includes a biopsy for histopathological analysis. However, even after unambiguous histopathologic classification, tumefactive lesions pose a therapeutic challenge. Until now, there have been no guidelines on how to treat patients with these rare and extreme lesion phenotypes. Here we report a patient with a relapsing unifocal tumefactive demyelinating lesion. The patient initially showed a good response to steroid treatment, with full clinical recovery. However, after relapse of the same lesion, recovery was incomplete. Although immunosuppression was initiated, the patient presented with subsequent further deterioration. Only maximal escalation of immunosuppression was able to stop the inflammatory activity. Due to the length of time of the step-wise escalation treatment however, the lengthy lesion activity led to irreversible tissue destruction and residual non-remitting disability. Early aggressive treatment with an induction therapy regimen might be more appropriate for these rare and often strongly disabling lesion subtypes. PMID- 24347183 TI - Does multiple sclerosis affect glucose tolerance? AB - Based on current literature, it is not clear if multiple sclerosis (MS) patients are at increased risk to develop impaired glucose tolerance (IGT). Eighty-one MS patients and 45 healthy controls (HC) performed an oral glucose tolerance test. IGT was defined as a fasting glucose concentration of 6.1-6.9 mmol/l and two-hour post-load glucose of 7.8-11.1 mmol/l. The prevalence of impaired fasting glucose concentrations (17% vs 2%) and IGT (11% vs 0%) was higher in MS patients than HC. Accordingly, the areas under the glucose and insulin curves were higher in MS patients. The current study demonstrates an elevated IGT-prevalence in MS. PMID- 24347184 TI - Changes in functional network centrality underlie cognitive dysfunction and physical disability in multiple sclerosis. AB - BACKGROUND: Cognitive dysfunction in multiple sclerosis (MS) has a large impact on the quality of life and is poorly understood. OBJECTIVE: The aim of this study was to investigate functional network integrity in MS, and relate this to cognitive dysfunction and physical disability. METHODS: Resting state fMRI scans were included of 128 MS patients and 50 controls. Eigenvector centrality mapping (ECM) was applied, a graph analysis technique that ranks the importance of brain regions based on their connectivity patterns. Significant ECM changes were related to physical disability and cognitive dysfunction. RESULTS: In MS patients, ECM values were increased in bilateral thalamus and posterior cingulate (PCC) areas, and decreased in sensorimotor and ventral stream areas. Sensorimotor ECM decreases were related to higher EDSS (rho = -0.24, p = 0.007), while ventral stream decreases were related to poorer average cognition (rho = 0.23, p = 0.009). The thalamus displayed increased connectivity to sensorimotor and ventral stream areas. CONCLUSION: In MS, areas in the ventral stream and sensorimotor cortex appear to become less central in the entire functional network of the brain, which is associated with clinico-cognitive dysfunction. The thalamus, however, displays increased connectivity with these areas. These findings may aid in further elucidating the function of functional reorganization processes in MS. PMID- 24347185 TI - Building highly functional interprofessional teams in our practices. PMID- 24347186 TI - Measuring team development in clinical care settings. AB - BACKGROUND AND OBJECTIVES: Our objective was to describe the psychometric properties of a measure of team development that can be used to assess and guide team functioning in health care settings. METHODS: The Team Development Measure (TDM) is a 31-item questionnaire constructed using the Rasch rating scale measurement model. We conducted an Mplus exploratory factor analysis using data collected from 1,194 individuals representing 120 different teams. Team size ranged from three to 39 members from rural and urban inpatient and ambulatory health care settings. Here we characterize the domains of teamness, while taking into account the development of teams over time. RESULTS: The TDM was found to have good psychometric properties with little measurement error and a Rasch person reliability of 0.95. Overall Cronbach's alpha was 0.97. An Mplus exploratory factor analysis combined with the stochastic nature of the Rasch model suggests a developmental sequence in building teams consisting of four sub domains with the following mean item difficulty scores: cohesion=40.5, standard deviation (SD)=2.68, communication=49.3 (SD=2.78), roles and goals=52.7 (SD=2.74), and team primacy=53.3 (SD=1.06). This pattern suggests cohesiveness is an initial element for team development, followed by communication, roles and goals clarity, and team primacy. CONCLUSIONS: We developed and tested a measure of team development that has strong psychometric properties. This tool could be used to study how team functioning affects clinical outcomes and as a quality improvement tool to improve team function. PMID- 24347187 TI - Satisfaction, early removal, and side effects associated with long-acting reversible contraception. AB - BACKGROUND AND OBJECTIVES: Although intrauterine devices (IUDs) and subdermal implants (SDI) are recommended as first-line contraception for the majority of women by the American College of Obstetrics and Gynecology, these methods of long acting reversible contraception (LARC) are underutilized. Some concerns regarding their use include cost of placement, side effects, and perception of frequent early removal. This study evaluated satisfaction with LARC, frequency, and reasons behind early removal in a family medicine setting. METHODS: Women > 18 years seen for placement of removal of an IUD or SDI were identified from billing data and surveyed via telephone to determine satisfaction and side effects with LARC. Additional demographic information was extracted from the electronic health record. RESULTS: Of the 132 respondents (response rate 61.4%), 58.3% had IUDs and 41.7% had SDIs placed. Early removal occurred in 24.2% of women, and 72.7% were satisfied with their contraceptive choice. Younger and nulliparous women were more likely to have an SDI placed, whereas older and multiparous women chose the IUD. Younger nulliparous women were less likely to have LARC removed early. Pain (more commonly reported with the IUD) and increased frequency in bleeding (more commonly reported with the SDI) were associated with early removal rates. CONCLUSIONS: Most women who received LARC were satisfied with their contraceptive choice, and only one in four had the LARC removed early. This is significantly better than continuation rates with other contraceptive methods. Younger, nulliparous women were good candidates for LARC, continuing their use more than older, multiparous women. Improved counseling regarding pain and changes in menstrual bleeding patterns may impact early removal of IUDs and SDIs, respectively. PMID- 24347188 TI - Measuring family physician identity: the development of a new instrument. AB - OBJECTIVE: Our objective was to describe the development and psychometric assessment of an instrument designed to assess family medicine identity in residency training sites and compare responses from physician faculty and residents. METHODS: We conducted 28 focus groups between 2007--2008, 14 with faculty and 14 with residents who were part of the Preparing Personal Physicians for Practice (P4) Project. The first 22 focus groups were exploratory, and the second six were confirmatory where we shared working variable statements scored using a 5-point Likert scale. We then administered the survey to 223 faculty and 147 residents who were part of the P4 Project, followed by a principal component (factor) analysis, retaining items that reflected domains with eigenvalues higher than 1.0. RESULTS: A total of 223 family physician faculty and 147 residents completed the identity survey. The item analysis extraction loadings ranged from 0.36 to 0.70. Based on item grouping patterns, five domains were reflected in the data: Patient/Family Relationships, Patient Advocacy, Career Flexibility, Balancing the Breadth and Depth in Practice, and Comprehensive Nature of Patient Care. Compared to residents, faculty conveyed stronger agreement about being comfortable balancing the breadth and depth of medical knowledge needed in practice and using a variety of approaches to supplement their medical knowledge about patient care compared to residents (90.6% versus 68.7% for breadth and depth, 95.9% versus 88.3 for using a variety of approaches). Compared to faculty, residents agreed more strongly that the ability to choose many options in how to build their practice appeals to them compared to faculty (89.1% versus 82.9%). CONCLUSIONS: We successfully developed and tested a survey designed to measure family medicine identity in residencies, with five domains. Survey item responses were different between residents and faculty, which indicates the instrument may be sensitive to important changes over time. PMID- 24347189 TI - Advancing geriatrics fellowship programs through a community-based residency network. AB - BACKGROUND AND OBJECTIVES: Our nation faces unprecedented challenges in caring for older adults. Geriatricians who provide care and teach geriatrics are underrepresented in the workforce, especially in non-metropolitan communities. In Michigan, geriatricians and geriatrics fellowship (GF) programs are clustered in the Southeast, suggesting that training site demographics may influence fellows' career location decisions. A project was undertaken at Michigan State University to determine if an established family medicine residency network (FMRN) could facilitate the accreditation of new GF programs in non-metropolitan communities, recruit fellows, and retain graduates to practice and teach in neighboring areas. METHODS: A team (department chair, appointed GF network director, site program directors, and education specialists) conducted participating site needs and readiness assessments, facilitated collaboration between GF programs, assisted with completion of new program applications, led development of a curriculum utilizing shared instructional resources and evaluation tools, and provided career counseling to fellows. RESULTS: Two GF programs were accredited and accepted applicants. Ongoing cooperative efforts resulted in the writing of a GF curriculum, organization of a joint Observed Structured Clinical Evaluation (OSCE), and monthly information-sharing teleconferences with program directors. Following training, graduates have chosen to practice in areas underserved by geriatricians in Michigan and elsewhere. CONCLUSIONS: Early experience with this model of GF development indicates that new fellowships can be established in community-based residencies that competitively recruit and train fellows who are inclined to practice in areas of greatest need. Creation of more non-metropolitan GF programs could provide a means to stabilize and redistribute the geriatrician workforce. PMID- 24347190 TI - Resident time in continuity practice. AB - BACKGROUND AND OBJECTIVES: Family medicine residents are required to maintain a continuity practice in an approved family medicine center (FMC) and achieve minimum targets for patient encounters. In the past, minimum periods of time in the FMC were defined in the program requirements, but these have now been replaced with target numbers of patient encounters. As residency programs come under increasing pressure to address service needs on patient care services, some program directors face requests by hospital administration to benchmark their requirements for resident schedules in the FMC against national standards. Since no such standards presently exist, the authors decided to determine the average frequency with which residents are currently scheduled in their FMC continuity practices in order to meet accreditation requirements. METHODS: Using the data set from the 2011 American Academy of Family Physicians (AAFP) annual residency census and residency directory questionnaire, the frequency of reported resident scheduling in the FMC continuity practice was extracted. Although the census itself achieves a 100% response rate, not all programs respond to all of the residency directory questions. In this case, for reported time in the FMC, an 84% (380 out of 450 programs) response rate was achieved. RESULTS: Family medicine residency programs currently schedule residents in their FMC continuity practice substantially more often than previously required. CONCLUSIONS: To meet current accreditation requirements, family medicine residency programs schedule residents in their FMC continuity practices more than previously required minimums. PMID- 24347192 TI - Come July. PMID- 24347191 TI - Responding to a changing nation: are faculty prepared for cross-cultural conversations and care? AB - BACKGROUND AND OBJECTIVES: The United States is becoming increasingly diverse. Health disparities continue with little improvement despite national policies and standards. Medical institutions are modifying their curricula; however, little is known about faculty attitudes and comfort in addressing cultural issues. The purpose of this study was to determine faculty attitudes, self-perceived levels of comfort and skill, and future knowledge needs pertaining to cultural competence. METHODS: A survey was administered to all clinical faculty at the University of Virginia School of Medicine. Survey questions addressed faculty attitudes and self-perceived levels of comfort and skill in dealing with cultural issues, as well as perceived need and interest in future cultural competence training. RESULTS: When considering each phase of education (medical school, residency, continuing medical education [CME]), fewer than 25% of the respondents reported receiving formal instruction in cultural competency in any given phase, although 93% felt that cultural competency training was important. Fifty-eight percent felt "very comfortable" caring for diverse patients, although this dropped to 30% when specifying limited English proficiency. The situation in which the highest percentage of respondents felt "not particularly comfortable" or "not at all comfortable" was breaking bad news to a patient's family first if this was more culturally appropriate (47%). Respondents felt most skilled in working with medical interpreters, apologizing for cross-cultural misunderstandings, and eliciting the patients' perspectives about their health and illness. Respondents felt the least skilled providing culturally sensitive end-of-life care and dealing with cross-cultural conflicts. CONCLUSIONS: Clinical faculty have received limited instruction on cultural competency, and the reported levels of comfort and skill in many challenging areas of multicultural health leave much room for improvement. Until faculty become more comfortable and are able to model and teach these behaviors to learners, positive responses to national policies in culturally competent care are likely to be limited. PMID- 24347193 TI - Combat mentoring. PMID- 24347194 TI - Building relationships-one patient at a time. PMID- 24347196 TI - Meta-analysis. PMID- 24347197 TI - Interdisciplinary family medicine. PMID- 24347198 TI - Current evidence for ART practice: the Cochrane of Cochranes on optimising outcomes. PMID- 24347199 TI - Advanced wound care therapies in non-healing lower extremity ulcers: high expectations, low evidence. PMID- 24347200 TI - Maternal obesity during pregnancy is associated with adult offspring cardiovascular morbidity and mortality but may represent confounding by other factors. PMID- 24347201 TI - History and physical examination provide little guidance on diagnosis of rotator cuff tears. PMID- 24347203 TI - Case Study Interpretation - Fort Lauderdale Case 2. PMID- 24347202 TI - P-113 peptide: New experimental evidences on its biological activity and conformational insights from molecular dynamics simulations. AB - In this article, we report novel and additional results, both experimental and computational, obtained in our laboratories on the peptide P-113. In particular, our experimental results indicate that this peptide is endowed with a high target cell selectivity towards yeast species, suggesting its potential development as a new drug against oral microbial infections. To provide additional structural insights, we performed several Molecular Dynamics simulations in different conditions. Results suggest that P-113 is a rather compact species presumably because of its highly charged state as emerged from the dramatic increase of internal fluctuation occurring upon point-mutation. The peptide turns out to adopt, in water, a beta-hairpin-like conformation and, in a more hydrophobic environment, is found to be in a (probably slow) equilibrium between alpha-helix and hairpin conformations. Complexation with Zn(2+) induces a drastic mechanical stabilization, which prevents any conformational organization of the peptide into a biologically active state. PMID- 24347204 TI - Detection of candidate tumor driver genes using a fully integrated Bayesian approach. AB - DNA copy number alterations (CNAs), including amplifications and deletions, can result in significant changes in gene expression and are closely related to the development and progression of many diseases, especially cancer. For example, CNA associated expression changes in certain genes (called candidate tumor driver genes) can alter the expression levels of many downstream genes through transcription regulation and cause cancer. Identification of such candidate tumor driver genes leads to discovery of novel therapeutic targets for personalized treatment of cancers. Several approaches have been developed for this purpose by using both copy number and gene expression data. In this study, we propose a Bayesian approach to identify candidate tumor driver genes, in which the copy number and gene expression data are modeled together, and the dependency between the two data types is modeled through conditional probabilities. The proposed joint modeling approach can identify CNA and differentially expressed genes simultaneously, leading to improved detection of candidate tumor driver genes and comprehensive understanding of underlying biological processes. We evaluated the proposed method in simulation studies, and then applied to a head and neck squamous cell carcinoma data set. Both simulation studies and data application show that the joint modeling approach can significantly improve the performance in identifying candidate tumor driver genes, when compared with other existing approaches. PMID- 24347205 TI - New Italian guidelines for malaria prophylaxis in travellers to endemic areas. AB - BACKGROUND AND METHODS: As a consequence of the rapid evolution of malaria prophylaxis recommendations throughout the world, the Italian Society of Tropical Medicine (SIMET-Societa Italiana di Medicina Tropicale) has set up a working group in charge of preparing a new national guideline. Other scientific societies interested in the topic were also involved in the project. RESULTS AND CONCLUSIONS: The group stated that awareness about malaria risk and characteristics, as well as protection from mosquito bites, are recommended for all travellers visiting malaria-endemic countries. The risk and benefit of malaria chemoprophylaxis must be carefully balanced before prescribing drugs: the disease-related risk must outweigh the possibility of drugs' side effects. As a general rule, malaria pills are the first choice for travellers to high-risk areas, such as sub-Saharan Africa, Eastern India, Myanmar, Eastern Indonesia, Papua New Guinea and, with some limitations, South-East Asia, and the Amazon part of Venezuela, Guyana and French Guyana. However, several other factors, such as itinerary, season, duration of trip, availability of insect bite protection, pre existing conditions and compliance, must be taken into account. In low-risk areas, stand-by emergency treatment is the first option. In minimal-risk areas and in Plasmodium vivax areas, a prompt diagnosis only is advised (Central America, South America outside the Amazon basin, Middle East, China, Thailand, Nepal). Recommendations may be modified when particular groups of travellers are concerned, such as long-term residents, visiting friends and relatives, patients with pre-existing conditions, pregnant women and children. PMID- 24347206 TI - Dynamic ultrasonic nebulisation extraction coupled with headspace ionic liquid based single-drop microextraction for the analysis of the essential oil in Forsythia suspensa. AB - INTRODUCTION: Ionic liquids have attracted much attention as an extraction solvent instead of traditional organic solvent in single-drop microextraction. However, non-volatile ionic liquids are difficult to couple with gas chromatography. Thus, the following injection system for the determination of organic compounds is described. OBJECTIVE: To establish an environmentally friendly, simple, and effective extraction method for preparation and analysis of the essential oil from aromatic plants. METHODS: The dynamic ultrasonic nebulisation extraction was coupled with headspace ionic liquid-based single-drop microextraction(UNE-HS/IL/SDME)for the extraction of essential oils from Forsythia suspense fruits. After 13 min of extraction for 50 mg sample, the extracts in ionic liquid were evaporated rapidly in the gas chromatography injector through a thermal desorption unit (5 s). The traditional extraction method was carried out for comparative study. RESULTS: The optimum conditions were: 3 MUL of 1-methyl-3-octylimidazolium hexafluorophosphate was selected as the extraction solvent, the sample amount was 50 mg, the flow rate of purging gas was 200 mL/min, the extraction time was 13 min, the injection volume was 2 MUL, and the thermal desorption temperature and time were 240 degrees C and 5 s respectively. Comparing with hydrodistillation (HD), the proposed method was environment friendly and efficient. CONCLUSION: The proposed method is environmentally friendly, time saving, with high efficiency and low consumption. It would extend the application range of the HS/SDME and would be useful especially for aromatic plants analysis. PMID- 24347207 TI - The role of thoracic trauma in inflammatory responses, apoptosis and bacterial translocation following multiple traumas. AB - BACKGROUND: Blunt chest trauma and its complications are commonly encountered in emergency medicine. Herein, we used a rat model to investigate the role of thoracic trauma in inflammation, apoptosis and bacterial translocation following multiple traumas. METHODS: Ninety Wistar rats were divided equally into nine groups. Rats underwent a standardized blunt thoracic and/or head trauma and were sacrificed 24 or 48 hours after the trauma. Specimens from various organs and blood samples were collected and quantitatively cultured for aerobic organisms. Interleukins, TNF-alpha, and MCP-1 levels were assessed in the sera and markers of apoptosis were detected in the lungs. RESULTS: Levels of interleukins, TNF alpha and MCP-1 in all of the groups undergoing trauma were significantly higher than those of the control group (p=0.001). Levels of apoptotic cells in the groups undergoing head and thoracic trauma (HTT) were significantly higher than those of the control group (p=0.009). Light microscopic evaluation indicated that damage in the HTT groups was significantly higher than that in the control group. The incidence of bacterial translocation was also significantly higher in the HTT groups (p=0.003). CONCLUSION: Multiple inflammatory mediators are activated in multiple traumas (including blunt thoracic trauma), which allow bacterial translocation and apoptotic processes to occur. Our results indicate that thoracic trauma plays a major role in post-traumatic bacterial translocation, inflammation, and apoptosis following multiple traumas. PMID- 24347208 TI - Hypertonic saline, normal saline or neither: which is best for uncontrolled hemorrhagic shock? An experimental study in goats. AB - BACKGROUND: To evaluate the effects of various fluids on uncontrolled hemorrhagic shock (UHS). Controversy exists over the appropriate doses and types of fluids for best treating UHS. This study evaluated the effects of hypertonic saline (HTS), normal saline (NS), and no fluid resuscitation (NFR) on UHS. METHODS: Thirty goats were anesthetized and underwent right leg ablation. The animals were randomly assigned to equal NFR, HTS, and NS groups. The following features of UHS were analyzed: hemoglobin, heart rate, blood loss, mean arterial pressure, bleeding time, and pH. Animals were sacrificed two hours after ablation. RESULTS: All of the goats who received HTS died within 60 minutes. Four goats in the NS group and one goat in the NFR group died within 120 minutes. The NFR group had significantly higher hemoglobin values than the NS and HTS groups at the end of the trial. Blood loss in the HTS group was greater than in the other two groups (p<0.05). The NS group had higher blood loss than the NFR group (p<0.05). Mean arterial pressure in the HTS group decreased sharply toward zero within the first 60 minutes. In the NFR and NS groups, mean arterial pressure was higher than in the HTS group (p<0.05), and remained constant at 60mmHg after 35 minutes. The NFR group had higher pH values compared to the other two groups (p<0.05). CONCLUSION: Our study demonstrated that HTS is not suitable for treating UHS when compared to NFR and NS. Goats treated with NFR had superior values for all UHS features, including hemoglobin, pH, blood pressure, and bleeding time, compared to those treated with HTS and NS. Pre-hospital field treatment with NS or HTS may worsen the condition until surgical repair is accomplished. PMID- 24347209 TI - Antioxidant and anti-inflammatory effects of curcumin against hepatorenal oxidative injury in an experimental sepsis model in rats. AB - BACKGROUND: To investigate the effects of curcumin, an antioxidant and anti inflammatory agent, on free oxygen radicals and lipid peroxidation in an experimental sepsis model, as well as to determine the role of curcumin in preventing hepatorenal tissue damage caused by sepsis. METHODS: The rats were randomly divided into three groups (n=8) as follows: control group (group 1); sepsis group (group 2); and sepsis + curcumin group (group 3). Sepsis was created using the cecal ligation and perforation (CLP) method. Curcumin was administered intraperitoneally (200 mg/kg) in two equal doses just after the perforation and at twelve hours post-perforation. RESULTS: Serum TNF-a and IL-1beta, and tissue MDA and MPO values were higher, whereas tissue GSH and Na+/K+-ATPase values were lower, in group 2 as compared to group 1. These values in group 3 were the inverse of those in group 2. As compared to group 1, histopathological evaluation of group 2 showed damaged hepatocytes, glomeruli, and tubules, whereas the damage was significantly reduced in group 3 as compared to group 2. CONCLUSION: The strong antioxidant and anti-inflammatory effects of curcumin against potential hepatorenal damage were shown using an experimental sepsis model in rats. PMID- 24347210 TI - Management of soft tissue extremity degloving injuries with full-thickness grafts obtained from the avulsed flap. AB - BACKGROUND: A "degloving injury" is referred to as seperation of cutaneous tissue from the deeper structures of the body. Although many methods have been defined to reform the tissue integrity; defatting and readaptation of the avulsed flap still comprises one of the most effective methods. METHODS: From 2000-2012, we treated a total of nine patients with avulsed extremities with defatting and readaptation of the same flap. The fat compartment of the flaps was removed and the skin was meshed. The patients were followed-up with for an average of 12 months (range: 8-18 months). RESULTS: Total closure of the defect and healing was achieved in seven patients. Although 30% of the total surface area of the graft was lost in one patient, and 10% in another, total epithelialization was achieved later with secondary grafting. CONCLUSION: Defatting, meshing and readaptation of the same flap to its original site is still a valuable option for avulsion injuries because of the relative ease of the procedure, shorter operative times, and usability of the procedure by general surgeons. This technique might be particularly important in places where a reconstructive plastic surgeon is not available. PMID- 24347211 TI - Functional outcomes after treatment of traumatic brachial plexus injuries: clinical study. AB - BACKGROUND: The aim of this study is to evaluate functional outcome and quality of life using statistically validated tools. METHODS: Participating patients were called and asked questions from the Short Form 36 (SF-36), the Disability of the Arm, Shoulder and Hand (DASH) questionnaire, a pain scale and an additional question on their satisfaction with surgery. RESULTS: A total of 33 patients were operated by a single surgeon (MI) between 1997 and 2010 at the Neurosurgery Department of Istanbul School of Medicine. Three of these patients refused to participate and three other patients were excluded, leaving 27 patients, with an average follow-up of 79,6 months, for review. The most common cause of traumatic brachial plexus injuries (TBPI) was motor vehicle accidents. Fourteen patients had isolated supraclavicular injuries and three patients had infraclavicular injuries. The remaining 10 patients' injuries were both supra- and infraclavicular. Avulsion was encountered in three patients. The patients who were operated within the first six months after trauma represented significantly better scores in DASH, SF-36 and pain scale. CONCLUSION: Statistically validated tests like DASH and SF-36 questionnaires are valuable tools for evaluating TBPI patients. Centers specialized in treating TBPI with surgery may use these tests pre- and postoperatively which lead to objective personalized evaluation of patients' subjective symptoms. PMID- 24347212 TI - Factors affecting mortality caused by falls from height. AB - BACKGROUND: Falls from height are among the most common trauma cases presenting to emergency departments and often cause mortality and morbidity. In the present study, we aimed to determine the factors that effectively reduce mortality caused by falls from height. METHODS: Data from 2252 trauma patients who presented to Dicle University Emergency Service between January 2005 and December 2008 due to falling from height in the Southeastern Anatolia region were retrospectively analyzed. We analyzed the parameters that are considered to have a positive effect on mortality, which included the following: month of fall; age; gender; etiology; place of fall; type of ground on which the patient fell; height of fall; intubation; hypotension; tachycardia; neck, head, thoracal, abdominal, pelvic, and extremity injuries; Glasgow Coma Score (GCS); Injury Severity Score (ISS); and Revised Trauma Score (RTS). RESULTS: There were 1435 males (63.7%) and 817 females (36.3%) included in the study. Two thousand thirty-one (94.6%) patients survived the fall while 121(5.4%) died. The mean age of the surviving patients was 15.55+/-18.60 years, while the patients who died had a mean age of 29.59+/-28.93 years. The mean height of the fall of the survivors' was 3.09 meters, and the mean height of the fall for those that died was 6.61+/-5.73 meters (p<0.001). CONCLUSION: The mean fatal height of the fall in falls from height is 6.61 m. Age, attempted suicide, height of fall, type of ground on which the patient fell, place of fall, and head, thoracic, and abdominal trauma are the primary factors affecting mortality caused by falls from height. PMID- 24347213 TI - An analysis of firearms-related deaths between 1993-2010: a retrospective study. AB - BACKGROUND: Firearm injuries (FI) are the most common cause of death among military personnel. In this study, postmortem examination and autopsy records of deaths resulting from firearm injuries recorded in the Department of Forensic Medicine of Gulhane Military Medical Academy between 1993-2010 were examined retrospectively. METHODS: We evaluated the characteristics of 153 firearm deaths accounting for 36.6% of all medical-legal autopsies. The cases included 152 men (99.3%) and 1 woman (0.7%). RESULTS: The mean age of the cases was 23.1 years (+/ 4.7; range, 20-43 years). The manner of death was determined in all cases with 41.8% of cases identified as suicide and 39.9% as homicide. The most common sites of firearm entrance wounds were the head and neck region (n=109, 71.2%), the chest (n=26, 17%), or the abdomen (n=14, 9.2%). The type of firearm was not clear in most cases. CONCLUSION: In conclusion, complete forensic and medical records will facilitate the rapid and accurate conclusion of the legal process and will enhance future retrospective studies. PMID- 24347214 TI - A new application technique of circular fixator for the treatment of open tibial fractures: circular fixator-hinge technique. AB - BACKGROUND: The purpose of this study is to present and validate a hinge-fixator technique for the treatment of open tibial fractures, which has advantages in application and the follow up period. METHODS: The technique was used in open tibia fractures of 14 adult patients. Using this method, initial anatomic reduction was achieved and temporary stability was obtained on the hinge-fixator after applications were completed. Patients' radiological and clinical results were analyzed using the Paley's criteria at the time of the last follow-up. RESULTS: Patients were brought in for followed up analysis over a 5.4 year period. According to Paley, two patients had 'good' and 12 patients had 'excellent' radiological results, while the functional result were excellent (n=13) and good (n=1), respectively. CONCLUSION: The hinge-fixator technique is a fast and easy method that contributes to shorter operation times, reduced radiation exposure, and more comfortable treatment periods. PMID- 24347215 TI - Cemented calcar replacement versus cementless hemiarthroplasty for unstable intertrochanteric femur fractures in the elderly. AB - BACKGROUND: Unstable intertrochanteric fractures remain a challenging problem in elderly individuals due to high failure rates associated with internal fixation. Hemiarthroplasty is one treatment option for intertrochanteric femur fractures in elderly patients. The aim of the present study was to compare the reliability of cementless and cemented hemiarthroplasty for unstable intertrochanteric femur fractures in elderly patients. METHODS: Elderly patients with AO type 31-A2 intertrochanteric femur fractures were treated with cemented (n=40) or cementless (n=46) hemiarthroplasty. Duration of surgery, amount of blood loss and blood transfusion, Harris hip scores, rate of loosening of the femoral component, duration of hospital stay after surgery and mortality rates were recorded. RESULTS: There were no significant differences between the groups in length of hospital stays, Harris hip scores, amount of blood transfusions, implant loosening and follow-up mortality rates. Walking ability was better in the cemented group in the early follow-up period. Duration of surgery, amount of blood loss and perioperative mortality rates were significantly lower in the cementless group than in the cemented group. CONCLUSION: Cementless hemiarthroplasty is a reliable treatment choice for unstable intertrochanteric femur fractures in elderly patients with early mobilization, acceptable functional results, low implant loosening rates, shorter surgery time, lesser blood loss and lower perioperative mortality rate. PMID- 24347216 TI - [Analysis of risk factors for the development of pediatric appendicitis]. AB - BACKGROUND: Appendicitis is the most common form of abdominal pain requiring surgery among children. This study evaluates the association of age, sex, seasonal, and familial factors with the histopathology of appendectomies. METHODS: 588 patients who underwent operations for acute appendicitis between 2009 and 2011 were included in this study. The patients were classified in one of three groups based on histopathological results: acute, perforated, and negative appendectomy. This study evaluates the association between age, sex, seasonal, and familial factors and the histopathological classification. RESULTS: The mean age of the patients was 11.8+/-3.26 years (range 1 to 16 years). Among these patients, appendicitis was 2.41 times more common in children greater than 10 years old. Appendicitis occurred 4.63 times more often among males than in females. Negative appendectomy occurred more often in children greater than 10 years of age. Appendicitis was associated with both seasonal factors and family history; however this association did not meet the threshold for statistical significance (p>0.05). DISCUSSION: The age and sex of the patient should be taken into account when considering appendicitis surgery to improve the accuracy of the diagnosis. In addition, the histopathology of appendicitis is influenced by familial and environmental factors. PMID- 24347217 TI - [Can increased intra-abdominal pressure (IAP) be treated more effectively with intravesical pressure measurement in high-risk patients?]. AB - BACKGROUND: Increased intra-abdominal pressure (IAP) can result in multiorgan failure. Trauma, mechanical bowel obstruction (MBO), abdominal wall defects (AWD) and fluid resuscitation in septic shock are conditions associated with a high risk of increased IAP in children. It may be possible to treat these conditions more effectively using intravesical pressure measurement. METHODS: This prospective study was performed between December 2009 and October 2010. Intravesical pressure (IVP) measurement was used to determine IAP. The presence of Intra-abdominal hypertension (IAP >12 mmHg) and abdominal compartment syndrome (IAP >15 mmHg + new organ dysfunction) was evaluated in all clinical decisions. RESULTS: IVP monitoring was applied in all patients with abdominal trauma (14), AWD (8), fluid resuscitation for septic shock (7), and MBO (6). A diagnosis of ACS was determined in 14% of trauma patients and required surgery. IAH/ACS occurred in 38% of AWD cases, which required closure. IAH occurred in 43% of patients undergoing fluid resuscitation for septic shock, requiring decompressive intervention. IAH/ACS occurred in 50 % of MBO patients, all of whom required surgery. DISCUSSION: IVP measurement is a useful method to identify candidates for surgical treatment in cases of trauma and MBO. Similarly, IVP monitoring can facilitate the closure of abdominal wall defects and the application of fluid resuscitation in septic shock. PMID- 24347218 TI - Iliopsoas hematoma due to muscular rupture following defibrillation. AB - We describe a 62 year old patient who presented with acute anterior ischemia and subsequently developed an iliopsoas hematoma. The patient was treated surgically due to rapid progression and femoral neuropathy, and the iliopsoas muscle rupture was diagnosed intraoperatively. The rupture was related to the external electrical defibrillation the patient had on admission. This was a rare case, and we hope the report would help to raise physicians' awareness regarding this complication and treatment. PMID- 24347219 TI - Trauma-associated bleeding from the bilateral internal iliac arteries resolved using angiographic embolization. AB - Pelvic fracture is associated with high mortality. The management of major pelvic injuries remains one of the most important issues in modern trauma care. A 39 year-old male patient presented at the emergency department after being hit with a 500 kg load. His general condition was average with unstable vital signs. Pelvic tomography revealed fractured bone structure, thickening secondary to hematoma in both iliopsoas muscles, and hemorrhage-related active extravasation in the left internal iliac trace. The patient's hemodynamics worsened despite fluid and blood replacement, and angiographic embolization was scheduled. Bilateral embolization of the iliac artery was performed. Control angiography confirmed that full embolization was established. The patient was monitored in intensive care, but expired after three days due to acute kidney failure, disseminated intravascular coagulation, and multi-organ failure. Angiographic embolization is a technique improves hemorrhage control in pelvic trauma but can also increase risk of complications such as ischemia and necrosis. PMID- 24347220 TI - A rare cause of acute appendicitis: an ingested foreign body. AB - Various kinds of foreign bodies causing appendicitis have been reported. However, a needle contained in the appendix is very rare, especially in adults. We report an unusual case of a twenty year old man who had ingested a needle ten days prior and presented with signs and symptoms of acute abdominal pain. An abdominal computed tomography scan revealed acute appendicitis. The patient was successfully treated with laparoscopic surgical intervention. In cases of a foreign body in the gastrointestinal tract that cannot be removed endoscopically, the emergence of non-specific symptoms may be early symptoms of acute problems in the abdomen. PMID- 24347221 TI - Acute intestinal obstruction secondary to left paraduodenal hernia: a case report. AB - Paraduodenal hernia, the most common type of internal herniation, is rare in the etiology of intestinal obstruction. Delayed diagnosis and surgical intervention may result in significant morbidity and mortality risk. This report presents a case of left paraduodenal hernia resulting in acute intestinal obstruction. A 43 year old male patient was admitted with a diagnosis of acute intestinal obstruction. A left paraduodenal hernia was identified by computed tomography findings of an encapsulated cluster of dilated small bowel loops occupying the left upper quadrant between the stomach and pancreas, and the presence of an engorged and displaced vascular pedicle at the orifice of the hernia. Upon further investigation, the dilated proximal jejunal segments were found in the left paraduodenal fossa, enclosed in a hernia sac. After reducing the intestinal segments to the abdominal cavity, the orifice of the hernia sac was closed by suturing to the retroperitoneum. Paraduodenal hernia should be considered as a possible etiology in cases of acute intestinal obstruction with unremarkable presentations. Physicians should be familiar with the demonstrative imaging findings of computed tomography of a paraduodenal hernia. Early surgical intervention is critical to prevent the significant morbidity and mortality associated with this condition. PMID- 24347222 TI - [Late presentation of posttraumatic pulmonary arteriovenous fistulea occlusion with septal occluder device]. AB - Posttraumatic pulmonary arteriovenous fistula is a rare complication of penetrating injury. Cases may remain asymptomatic for years prior to diagnosis. We present a case of pulmonary arteriovenous fistula related to a penetrating injury of the thorax 6 years previously that was occluded with a septal occluder device. Consistent use of CT or conventional catheter pulmonary angiography following penetrating injury to the thorax is essential to the early diagnosis of pulmonary arteriovenous fistula during the asymptomatic stage. Modern occlude devices facilitate the transcatheter approach as a viable alternative to surgery for the closure large, high pressure defects. PMID- 24347223 TI - [Removal of mediastinal foreign body (steel shot) using mediastinoscopy: case report]. AB - Morbidity and mortality is high in patients with gunshot wounds to the chest. Only in rare cases do foreign bodies persist in the thorax without significant pathology. At this study, we present a case in which steel shot was removed through the mediastinum using mediastinoscopy due to the risk of tracheal fistula. PMID- 24347224 TI - FiO2 predicts outcome in infants with respiratory syncytial virus-induced acute respiratory distress syndrome. AB - OBJECTIVE: Respiratory syncytial virus (RSV) infection can progress to acute respiratory distress syndrome (ARDS) in infants. ARDS is a life-threatening condition that is characterized by severe hypoxemia, defined as PaO(2)/FiO(2) ratio <300 mmHg. This ratio is used in many trials as the sole oxygenation criterion for ARDS. Recently, however, it has been shown in adults with ARDS that FiO(2), independently of the PaO(2)/FiO(2) ratio predicts mortality. Because epidemiology and outcome of ARDS differ strongly between children and adults, we determined if FiO(2) on admission (baseline FiO(2)) independently predicted the duration of mechanical ventilation (MV) and length of stay (LOS) in the pediatric intensive care unit (PICU) in infants with RSV-induced ARDS. DESIGN: Retrospective observational study. SETTING: A 14-bed pediatric intensive care unit. PATIENTS: One hundred twenty-nine mechanically ventilated infants with RSV induced ARDS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Independent predictors for outcome, including baseline FiO(2) and PEEP, were analyzed using the cox regression model. Endpoints were duration of MV and LOS in the PICU. A higher baseline FiO(2) was independently associated with a longer duration of MV (HR 0.12, CI 0.02-0.87, P = 0.036) and increased LOS in the PICU (HR 0.09, CI 0.01-0.57, P = 0.023). Neither baseline PEEP nor PaO(2)/FiO(2) ratio correlated with outcome. CONCLUSIONS: FiO(2) level independently predicted outcome in infants with RSV-induced ARDS, whereas both PEEP and the PaO(2)/FiO(2) ratio did not. This suggests that FiO(2) should be taken into account in defining disease severity in infants with RSV-induced ARDS. PMID- 24347225 TI - Parallel processes: using motivational interviewing as an implementation coaching strategy. AB - In addition to its clinical efficacy as a communication style for strengthening motivation and commitment to change, motivational interviewing (MI) has been hypothesized to be a potential tool for facilitating evidence-based practice adoption decisions. This paper reports on the rationale and content of MI-based implementation coaching Webinars that, as part of a larger active dissemination strategy, were found to be more effective than passive dissemination strategies at promoting adoption decisions among behavioral health and health providers and administrators. The Motivational Interviewing Treatment Integrity scale (MITI 3.1.1) was used to rate coaching Webinars from 17 community behavioral health organizations and 17 community health centers. The MITI coding system was found to be applicable to the coaching Webinars, and raters achieved high levels of agreement on global and behavior count measurements of fidelity to MI. Results revealed that implementation coaches maintained fidelity to the MI model, exceeding competency benchmarks for almost all measures. Findings suggest that it is feasible to implement MI as a coaching tool. PMID- 24347226 TI - Expression of far upstream element (FUSE) binding protein 1 in human glioma is correlated with c-Myc and cell proliferation. AB - Glioma is one of the most common type of primary intracranial tumor. Although great advances have been achieved in treatment of glioma, the underlying molecular mechanisms remain largely unknown. Previous studies demonstrated that FBP1 is a transcriptional regulator of c-Myc and acts as an important prognostic indicator in many cancers. Our study aimed to assess the expression and function of FBP1 in human glioma. Immunohistochemical and Western blot analysis were performed in human glioma and normal brain tissues. High FBP1 expression (located in cell nuclei) was observed in 70 samples and its level was correlated with the grade of malignancy. A strongly positive correlation was observed between FBP1 and c-Myc (P = 0.005) and Ki-67 expression (P = 0.009). In a multivariate analysis, high FBP1 and c-Myc expressions were showed to be associated with poor prognosis in glioma. While in vitro, following serum stimulation of starved U87MG cells, the expression of FBP1 was upregulated, as well as c-Myc and PCNA. Moreover, knockdown of FBP1 by siRNA transfection diminished the expression of c Myc and arrested cell growth at G1 phase. Collectively, our results shows that the expression of FBP1 is in close correlation with c-Myc level and cell proliferation in glioma and provides a potential strategy to develop FBP1 inhibitors as novel anti-tumor agents. PMID- 24347227 TI - Stromal alterations as quantitative optical biomarkers of epithelial tumor progression. AB - Stroma plays an important role during epithelial tumor progression. Probing stroma alteration may become an intrinsic indicator for evaluating epithelial tumor progression. In this review, we summarize our recent works on stromal alterations as quantitative optical biomarkers of epithelial tumor progression by use of nonlinear optical microscopy. PMID- 24347228 TI - Performance, egg quality traits, and serum metabolite concentrations of laying hens affected by dietary supplemental chromium picolinate and vitamin C under a heat-stress condition. AB - A 3 * 2 factorial experiment consisting three levels (0, 200, and 400 MUg/kg) of chromium (chromium picolinate) and two levels (0 and 250 mg/kg) of vitamin C was employed to evaluate the effects of these dietary supplements on performance, egg quality traits, and serum biochemical parameters of heat-stressed laying hens (Lohmann LSL-Lite) from 66 to 74 weeks of age. Feed intake increased when birds were given either 400 MUg/kg chromium or 250 mg/kg vitamin C (P < 0.05), but the birds that received both chromium and vitamin C consumed feed similar to those that received only chromium. Dietary treatments had no effect on egg production, egg mass, egg volume, feed conversion ratio, and body mass (P > 0.05). The birds that fed on diet with chromium or vitamin C produced eggs with higher shell mass and thickness compared to the control. Both eggshell mass and thickness decreased when vitamin C and chromium were supplemented simultaneously, and birds given the diet supplemented with 400 MUg/kg chromium and 250 mg/kg vitamin C had eggshell mass and thickness similar to those of the control group. The serum concentration of chromium increased due to increasing level of dietary chromium (P < 0.05). The birds that received diet with chromium and vitamin C had higher serum concentrations of chromium compared to those that received only chromium (P < 0.05). Similarly, the hens that received chromium and vitamin C had higher serum concentrations of calcium and phosphorus compared to the hens fed with other treatments (P < 0.05). The birds given with supplemental chromium exhibited lower serum glucose, total cholesterol, and triglycerides concentrations but higher serum albumin and total protein concentrations compared to the other groups (P < 0.05). PMID- 24347230 TI - It is not always necessary to do axillary dissection for T1 and T2 breast cancer- point. AB - Axillary lymph node dissection (ALND) has been a part of breast cancer management since the 1900s. The idea that axillary metastases do not require surgical removal is a repudiation of the Halstedian concept of breast cancer biology, yet multiple prospective randomized studies show that the incidence of nodal recurrence in patients not having ALND is substantially lower than expected, based on the incidence of axillary metastases in patients having ALND, and survival does not differ based on axillary treatment. Avoidance of axillary dissection significantly reduces the morbidity of breast cancer surgery. As the use of systemic therapy has increased and targeted therapies have become available, the incidence of axillary recurrence in patients not having dissection has decreased to approximately 1% at 5 years, making routine axillary dissection difficult to justify. ALND is no longer standard management for patients with T1 and T2, clinically node-negative cancers undergoing breast-conserving therapy and found to have a positive sentinel node, and can also be avoided in patients with these tumor features having mastectomy if the need for postmastectomy radiotherapy is clear with the finding of a positive sentinel node. PMID- 24347231 TI - It is not always necessary to do axillary dissection for T1 and T2 breast cancer- reply to point. PMID- 24347232 TI - The need for axillary lymph node dissection in T1/T2 breast cancer surgery- counterpoint. AB - For breast cancer patients, the role of the axillary lymph node dissection (ALND) in the management of clinically node negative breast cancer patient has shifted from routine, to selective, to increasingly rare. With the publication of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial results, some are ready to announce the time of death of this procedure. However, many questions remain regarding the design and statistical interpretation of the study, the treatments the patients actually received, and its applicability in clinical practice in light of other studies concerning regional management. Thus, the reports of the ALND's death may be greatly exaggerated. Careful acknowledgement of the study's strengths and shortcomings, and more recent trial data, suggest that although ALND may be safely avoided in a subset of sentinel lymph node positive, Z0011-eligible patients, others may require multidisciplinary review and consensus, and a careful conversation with the patient, before deciding it is not necessary. PMID- 24347233 TI - The need for axillary lymph node dissection in T1/T2 breast cancer surgery--reply to counterpoint. PMID- 24347235 TI - Quality of care: not hospital but operator volume of pacemaker implantations counts. AB - Literature about pacemaker (PM) implantations shows that several clinical and technical factors determine the short- and long-term complications after the intervention. Annual hospital volume, however, does not negatively affect complications in contrast with the cumulative experience of the operator. In view of this observation, the current required number of 20 to 30 first PM implantations for cardiology training does not match standards for quality of care. In addition, concentration of implants and replacement of pacemakers to a limited number of operators per hospital to comply with the increasing demands of patients and other parties has to be seriously considered. PMID- 24347236 TI - The lymphocyte/monocyte ratio predicts poor clinical outcome and improves the predictive accuracy in patients with soft tissue sarcomas. AB - Increasing evidence indicates the involvement of inflammation and coagulation in cancer progression and metastases. Inflammatory biomarkers hold great promise for improving the predictive ability of existing prognostic tools in cancer patients. In the present study, we investigated several inflammatory indices with regard to their prognostic relevance for predicting clinical outcome in soft tissue sarcoma (STS) patients. Three hundred and forty STS patients were divided into a training set (n = 170) and a validation set (n = 170). Besides well-established clinico pathological prognostic factors, we evaluated the prognostic value of the neutrophil/lymphocyte (N/L) ratio, the lymphocyte/monocyte (L/M) ratio and the platelet/lymphocyte (P/L) ratio using Kaplan-Meier curves and univariate as well as multivariate Cox regression models. Additionally, we developed a nomogram by supplementing the L/M ratio to the well-established Kattan nomogram and evaluated the predictive accuracy of this novel nomogram by applying calibration and Harrell's concordance index (c-index). In multivariate analysis, a low L/M ratio was significantly associated with decreased CSS and DFS (HR = 0.41, 95% CI = 0.18 0.97, p = 0.043; HR = 0.39, 95% CI = 0.16-0.91, p = 0.031, respectively) in the training set. Using the validation set for confirmation, we found also in multivariate analysis an independent value for CSS (HR = 0.33, 95% CI = 0.12 0.90, p = 0.03) and for DFS (HR = 0.36, 95% CI = 0.16-0.79, p = 0.01). The estimated c-index was 0.74 using the original Kattan nomogram and 0.78 when the L/M ratio was added. Our study reports for the first time that the pre-operative L/M ratio represents a novel independent prognostic factor for prediction the clinical outcome in STS patients. This easily determinable biomarker might be helpful in improved individual risk assessment. PMID- 24347237 TI - 3D multislab, multishot acquisition for fast, whole-brain MR elastography with high signal-to-noise efficiency. AB - PURPOSE: To develop an acquisition scheme for generating MR elastography (MRE) displacement data with whole-brain coverage, high spatial resolution, and adequate signal-to-noise ratio (SNR) in a short scan time. THEORY AND METHODS: A 3D multislab, multishot acquisition for whole-brain MRE with 2.0 mm isotropic spatial resolution is proposed. The multislab approach allowed for the use of short repetition time to achieve very high SNR efficiency. High SNR efficiency allowed for a reduced acquisition time of only 6 min while the minimum SNR needed for inversion was maintained. RESULTS: The mechanical property maps estimated from whole-brain displacement data with nonlinear inversion (NLI) demonstrated excellent agreement with neuroanatomical features, including the cerebellum and brainstem. A comparison with an equivalent 2D acquisition illustrated the improvement in SNR efficiency of the 3D multislab acquisition. The flexibility afforded by the high SNR efficiency allowed for higher resolution with a 1.6 mm isotropic voxel size, which generated higher estimates of brainstem stiffness compared with the 2.0 mm isotropic acquisition. CONCLUSION: The acquisition presented allows for the capture of whole-brain MRE displacement data in a short scan time, and may be used to generate local mechanical property estimates of neuroanatomical features throughout the brain. PMID- 24347238 TI - Bioengineering virus-like particles as vaccines. AB - Virus-like particle (VLP) technology seeks to harness the optimally tuned immunostimulatory properties of natural viruses while omitting the infectious trait. VLPs that assemble from a single protein have been shown to be safe and highly efficacious in humans, and highly profitable. VLPs emerging from basic research possess varying levels of complexity and comprise single or multiple proteins, with or without a lipid membrane. Complex VLP assembly is traditionally orchestrated within cells using black-box approaches, which are appropriate when knowledge and control over assembly are limited. Recovery challenges including those of adherent and intracellular contaminants must then be addressed. Recent commercial VLPs variously incorporate steps that include VLP in vitro assembly to address these problems robustly, but at the expense of process complexity. Increasing research activity and translation opportunity necessitate bioengineering advances and new bioprocessing modalities for efficient and cost effective production of VLPs. Emerging approaches are necessarily multi-scale and multi-disciplinary, encompassing diverse fields from computational design of molecules to new macro-scale purification materials. In this review, we highlight historical and emerging VLP vaccine approaches. We overview approaches that seek to specifically engineer a desirable immune response through modular VLP design, and those that seek to improve bioprocess efficiency through inhibition of intracellular assembly to allow optimal use of existing purification technologies prior to cell-free VLP assembly. Greater understanding of VLP assembly and increased interdisciplinary activity will see enormous progress in VLP technology over the coming decade, driven by clear translational opportunity. PMID- 24347239 TI - Tandem Dyes: Stability in cocktails and compensation considerations. AB - Background: The stability and performance of tandem conjugated antibodies can be impaired when stored in antisera cocktails (1,2). This, and the need for frequent re-compensation due to the possible spectral spill over variation between tandem lots, reduces the robustness of clinical flow cytometry panels that include tandems. Since tandems are required for standard 8-10 colour screens, further studies of the stability of tandems in cocktails and their spill over variability are warranted. Methods: The performance of PE- and APC-tandems stored in cocktails was tested on fresh bone marrow, preserved blood and lyophilised cell samples over 1-, 6- or 8-week periods respectively, and their spill over matrices were compared. The observed correction factor differences were used as the basis for analysing how the application of an incorrect compensation matrix could influence data interpretation. Results: Signal intensities and background fluorescence remained constant for all fluorochromes in the cocktails tested. Spill over correction factors for different PE-Cy7 mAbs did not exceed or were only marginally higher than those for non-tandem organic dye conjugated mAb. By applying the correction factor differences observed between tandem mAb lots to clinical data, it was found that the over and under compensation would not alter the clinical interpretation. Conclusions: Tandems can be safely stored and used in cocktails. However, each cocktail should be tested on relevant material prior to use. Exact compensation settings are a requirement for accurate data. Provided that careful evaluation of tandem compensation requirements is carried out, certain tandems may use a generic compensation matrix. (c) 2013 Clinical Cytometry Society. PMID- 24347240 TI - Survival of an infant with homozygous surfactant protein C (SFTPC) mutation. AB - Lung diseases caused by surfactant protein C (SFTPC) mutations are inherited as autosomal traits with variable penetrance and severity or as sporadic disease caused by a de novo mutation on one allele. Here, we report the case of a child surviving with a homozygous surfactant protein C mutation after aggressive clinical management unlike his six siblings who died in infancy. This presentation raises the suspicion of an autosomal recessive inheritance that is discussed in this report. PMID- 24347241 TI - Therapeutic glucocorticoid administration alters the diurnal pattern of dehydroepiandrosterone. AB - Significant alteration in hypothalamic-pituitary-adrenal function has been demonstrated in patients after short-term glucocorticoid therapy, but its impact on the circadian rhythm of steroid hormones has never been investigated. This study examined the effects of short-term prednisone administration on the diurnal patterns of dehydroepiandrosterone (DHEA) and testosterone. Saliva samples were collected from 11 healthy, physically active, male volunteers for DHEA and testosterone analysis, as follows: every 4 h from 0800 to 2000 h on 2 control days without medication, and after 1 week of oral therapeutic prednisone treatment (60 mg daily) (days 0-3). Overall, a diurnal decline in the two steroid hormones was observed on the control days. After short-term glucocorticoid administration, DHEA concentrations were significantly decreased with a complete disappearance of the DHEA diurnal pattern, which lasted 2 days post-treatment. No glucocorticoid effect was observed for testosterone. The results indicate that short-term prednisone treatment affects the circadian pattern of saliva DHEA but not testosterone in healthy active volunteers. Further studies are necessary to determine whether this alteration in DHEA circadian pattern has clinical consequences in patients with chronic glucocorticoid therapy. PMID- 24347242 TI - 4-phenylbutyric acid attenuates endoplasmic reticulum stress-mediated pancreatic beta-cell apoptosis in rats with streptozotocin-induced diabetes. AB - Endoplasmic reticulum stress (ERS) plays an important role in diabetes mellitus (DM), but the association between DM and ERS is unknown. We have previously shown that streptozotocin (STZ)-induced diabetes in rats is characterized by increased levels of ERS markers. Here, we tested whether the chemical chaperone 4 phenylbutyric acid (4-PBA) ameliorated ERS-associated apoptosis in pancreatic beta-cells in rats with STZ-induced diabetes. Male Sprague-Dawley rats were divided into 3 groups: control group, DM group, and DM model plus 4-PBA treatment group (4-PBA group). DM model rats were induced by injection of STZ (60 mg/kg) intraperitoneally, and 4-PBA was administered daily by gavage at a dose of 500 mg/kg body weight for 20 days. beta-cell apoptosis was higher in the DM group than in the control group. Moreover, the expression of caspase-3, Bax, and the ERS indicators Bip and CHOP was markedly elevated in the pancreas of rats in the DM group, whereas the expression of Bcl-2 was lower in these rats (P < 0.05). Blood glucose concentration in diabetic rats gradually decreased with 4-PBA treatment but remained higher at the end of the experiment compared to the concentration in control rats. Consistent with this, 4-PBA raised the fasting insulin level in diabetic rats; it also suppressed the expression of caspase-3, Bax, and ERS indicators but enhanced the expression of Bcl-2. In conclusion, 4 PBA protects pancreatic beta-cells from apoptosis in STZ-induced diabetes by attenuating the severity of ERS. PMID- 24347243 TI - 17beta-Estradiol regulates scavenger receptor class BI gene expression via protein kinase C in vascular endothelial cells. AB - High-density lipoprotein (HDL) mediates reverse cholesterol transport. In this process, the human homolog of the B class, type I scavenger receptor (SR-BI), CD36, and LIMPII analogous-1 (hSR-BI/CLA-1) facilitates the cellular uptake of cholesterol from HDL. In endothelial cells, HDL activates endothelial nitric oxide synthase (eNOS) via hSR-BI/CLA-1, and 17beta-estradiol (E2) modulates nitric oxide (NO) synthesis. In this study, we elucidated the effect of E2 on hSR BI/CLA-1 expression in human umbilical vein endothelial cells (HUVECs). HSR BI/CLA-1 expression was examined by real-time PCR, western blot analysis and reporter gene assay in HUVECs incubated with E2. eNOS activity was assessed by detection of phosphorylation (Ser 1179) of eNOS. We investigated the effect of the constitutively active form or dominant negative form of protein kinase C on hSR-BI/CLA-1 promoter activity. Our results showed that E2 increased the endogenous expression of hSR-BI/CLA-1. E2 also enhanced the activity of the hSR BI/CLA-1 promoter and the expression of its mRNA. However, bisindolylmaleimide I, an inhibitor of protein kinase C, blocked the stimulatory effect of E2 on hSR BI/CLA-1 promoter activity. Moreover, constitutively active PKC increased the activity of the hSR-BI/CLA-1 promoter, and a dominant-negative mutant of PKC prevented E2 from stimulating promoter activity. In cells treated with E2, HDL stimulated the phosphorylation of serine 1179 of eNOS in HUVECs. These results suggested that E2 upregulates the expression of the endothelial hSR-BI/CLA-1 via the PKC pathway, which may be a novel mechanism of the anti-atherosclerotic potential of E2 in vascular endothelial cells. PMID- 24347245 TI - Cardiac function in 10-year-old twins following different fetal therapies for twin-twin transfusion syndrome. AB - OBJECTIVES: To compare cardiac function at 10 years of age in four groups of monochorionic diamniotic (MCDA) twin pairs: uncomplicated MCDA twins (n = 6) (Group 1); twins that had had twin-twin transfusion syndrome (TTTS) managed by amnioreduction (TTTS-amnio, n = 9) (Group 2) or laser photocoagulation (TTTS laser, n = 10) (Group 3); and dichorionic diamniotic controls (DCDA, n = 6) (Group 4). METHODS: Echocardiograms optimizing apical four-chamber and short-axis left ventricular views were stored for offline speckle-tracking analysis, blinded to twin type. Myocardial long-axis shortening and lengthening velocities were measured using pulsed Doppler ultrasound at the cardiac base. M-mode measurements of fractional shortening (short axis) and maximal excursion of the atrioventricular annulus (four-chamber) were recorded. Syngo Vector Velocity Imaging software tracked left ventricular myocardial motion offline to produce free wall strain, strain rate and rotation. Intertwin pair and group differences were investigated using ANOVA. RESULTS: Cardiac measurements were within the normal ranges for 10-year-olds. No significant within-twin-pair and intergroup differences were found in current size, heart rates, strain or strain rate. Compared to DCDA controls, TTTS twins showed less cardiac rotation (TTTS-laser, P < 0.001 and TTTS-amnio, P = 0.054) with significant intertwin reduction in the ex recipient (TTTS-amnio, P = 0.006) and larger MCDA twins (P = 0.027) compared with their cotwins. A similar pattern was seen in left ventricular early diastolic mitral valve tissue velocity (MVE') in all monochorionic groups, but only achieving significance in TTTS-amnio twins (P = 0.037). Intrapair differences in rotation and MVE' were significantly different following treatment at Quintero stages III or IV. CONCLUSIONS: Within-twin-pair patterns of left ventricular rotation and diastolic function differ at 10 years of age in ex-recipients of TTTS twins treated with amnioreduction compared with those treated by laser photocoagulation and controls. . PMID- 24347246 TI - Identity and norms: the role of group membership in medical student wellbeing. AB - Medical students experience high levels of mental health problems, which can lead to poor academic performance, substance abuse and burnout. The current paper draws on social psychology to explore the factors underpinning wellbeing in medical students. From the literature it is evident that there is a strong association between group membership and wellbeing. There is also evidence, however, that when the norms of a group prescribe unhealthy behaviours, group members who identify strongly with the group are likely to engage in those behaviours. It was hypothesized that (a) there would be a positive relationship between identification and wellbeing in medical students, (b) perceptions of norms would be positively related to unhealthy behaviour which would be negatively related to wellbeing and (c) identification would be positively related to levels of norm-related unhealthy behaviour. Ninety-two Australian medical students completed measures of identification, endorsement of norms, own behaviour in relation to norms and three indicators of wellbeing. The results supported the first hypothesis and showed only partial support for the second, suggesting a primarily positive role of group processes in medical student wellbeing. The implications for interventions to improve wellbeing in medical schools and directions for future research are discussed. PMID- 24347244 TI - Serum prolidase enzyme activity and oxidative stress levels in patients with diabetic neuropathy. AB - Previous studies have suggested that prolidase and nitric oxide (NO) regulate many processes, such as collagen synthesis and matrix remodeling. Oxidative stress plays an important role in the development of microvascular complications in diabetic patients. Data on serum prolidase activity in patients with diabetes mellitus or diabetic neuropathy (DN) are limited and conflicting. The aim of this study was to measure serum prolidase activity, NO, total antioxidant status (TAS), and malondialdehyde (MDA) levels in patients with DN. Forty-five patients with DN and 40 healthy controls were enrolled. Serum prolidase activity, TAS, MDA, and NO levels were determined. Serum MDA and NO levels were significantly higher in DN patients than controls (p = 0.002, p = 0.001, respectively), while prolidase activity and TAS levels were lower (p = 0.003, p = 0.001, respectively). Prolidase activity was negatively correlated with NO and MDA (r = 0.911, p < 0.001; r = -0.905, p < 0.001, respectively), while positively correlated with TAS (r = 0.981, p < 0.001) in DN patients. The current study is the first showing the decreased serum prolidase enzyme activity. Our results suggest that decreased collagen turnover may occur in DN patients, who have increased oxidative stress and increased NO levels. Decreased prolidase activity seems to be associated with increased NO levels and oxidative stress along with decreased antioxidant levels in DN. Therefore, decreased prolidase activity may play a role in pathogenesis of DN. Prospective clinical studies are necessary to confirm these findings. PMID- 24347247 TI - Methods of designing two-stage winner trials with survival outcomes. AB - In drug development, especially for oncology studies, a recent proposal is to combine a costly phase II dose selection study with a subsequent phase III study into a single trial that compares the selected (winning) dose from the first stage with the control group. This design may also be used in phase III trials, in which the winning active treatment regimen, selected at the first stage, is compared with the control group at the second stage. This design is known as a two-stage winner design, as proposed by Shun et al. (2008) for continuous outcomes. Time-to-event data are often analyzed in oncology trials. In order to derive the critical value and power of this design, per Shun et al. (2008), it is essential to calculate the asymptotic covariance and correlation of the log-rank statistics for survival outcomes between the two stages. In this paper, we derive the asymptotic covariance and correlation, and provide additional approximate design parameters. Examples are given to illustrate the method, and simulations are performed to evaluate the veracity of these approximate design parameters. PMID- 24347248 TI - Clinical efficacy and safety of transcatheter closure of ruptured sinus of valsalva aneurysm. AB - OBJECTIVES: To evaluate the clinical efficacy and safety of transcatheter closure (TCC) in patients with ruptured sinus of Valsalva aneurysm (RSVA). BACKGROUND: RSVA is a rare cardiovascular disease with a varied clinical presentation. The clinical efficacy and safety of TCC for RSVA still remain an ongoing concern. METHODS: From January 2009 to March 2013, 22 patients with RSVA were selected for TCC. Intracardiac pressure and size of cardiac chamber were measured before and post TCC. All patients were followed up by transthoracic echocardiography at 1, 3, 6, 12 months after procedure. RESULTS: RSVA was successfully occluded in 20 patients (19 cases with Amplatzer duct occluder and one with muscular ventricular septal defect occluder). Aortic root angiography showed no shunt in 18 cases and a small residual shunt in two cases. The pressures in the right atrium, right ventricle, and pulmonary artery were significantly decreased after the procedure (P < 0.01), and the aortic pressure was elevated (P < 0.001). The internal diameters of the right atrium, left atrium, and left ventricle were also significantly declined after the procedure (P < 0.05). No complications were found after 18.5 +/- 6.5 (range 3-35) months follow-up. Two patients underwent acute surgical aortic valve replacement because of procedure-related aortic valve regurgitation. CONCLUSIONS: Our results indicate that TCC is a promising alternative therapy to surgery in appropriate patients with RSVA. However, rare but severe procedure-related complications should be considered in the risk assessment. PMID- 24347250 TI - Behavioral medicine in China: history, current status, and future development. AB - BACKGROUND: Behavioral medicine in China has developed quickly in the last three decades. PURPOSE: We briefly summarized the history, the main scope and achievements, and the future development of behavioral medicine in China. METHOD: We did a literature search and discussed with senior scholars in behavioral medicine in China. RESULTS: The concept and main scope of behavioral medicine in China have been developed largely in accordance with the international perspective. Research in behavioral medicine in China significantly contributed to the better understanding of the relationship between various health behavioral factors and psychosomatic disorders and possible mechanisms of this relationship. The following aspects will be the main areas to be further developed in behavioral medicine in China: (1) Basic theories of behavioral medicine and theoretical mechanisms of higher nervous activities in human behavior regulation. (2) Etiology, pathogenesis, and mechanisms of common diseases that are closely related to human lifestyle behaviors. (3) Assessment criteria for unhealthy and disease-related behaviors. (4) Behavioral therapy of psychosomatic disorders, and rehabilitation technologies of disability. (5) Application of major findings from research of behavioral medical science in clinical practice and in health promotion of the whole society. CONCLUSION: Behavioral medicine in China, as a multidisciplinary subject, plays a relevant role in preventing behavior-related psychosomatic diseases and in promoting health of the public. PMID- 24347249 TI - Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules. AB - Hypoxic conditions in prostate cancer (PCA) are associated with poor prognosis; however, precise mechanism/s through which hypoxia promotes malignant phenotype remains unclear. Here, we analyzed the role of exosomes from hypoxic PCA cells in enhancing the invasiveness and stemness of naive PCA cells, as well as in promoting cancer-associated fibroblast (CAF) phenotype in prostate stromal cells (PrSC). Human PCA LNCaP and PC3 cells were exposed to hypoxic (1% O2 ) or normoxic (21% O2 ) conditions, and exosomes secreted under hypoxic (Exo(Hypoxic) ) and normoxic (Exo(Normoxic) ) conditions were isolated from conditioned media. Nanoparticle tracking analysis revealed that Exo(Hypoxic) have smaller average size as compared to Exo(Normoxic) . Immunoblotting results showed a higher level of tetraspanins (CD63 and CD81), heat shock proteins (HSP90 and HSP70), and Annexin II in Exo(Hypoxic) compared to Exo(Normoxic) . Co-culturing with Exo(Hypoxic) increased the invasiveness and motility of naive LNCaP and PC3 cells, respectively. Exo(Hypoxic) also promoted prostasphere formation by both LNCaP and PC3 cells, and enhanced alpha-SMA (a CAF biomarker) expression in PrSC. Compared to Exo(Normoxic) , Exo(Hypoxic) showed higher metalloproteinases activity and increased level of diverse signaling molecules (TGF-beta2, TNF1alpha, IL6, TSG101, Akt, ILK1, and beta-catenin). Furthermore, proteome analysis revealed a higher number of proteins in Exo(Hypoxic) (160 proteins) compared to Exo(Normoxic) (62 proteins), primarily associated with the remodeling of epithelial adherens junction pathway. Importantly, Exo(Hypoxic) targeted the expression of adherens junction proteins in naive PC3 cells. These findings suggest that Exo(Hypoxic) are loaded with unique proteins that could enhance invasiveness, stemness, and induce microenvironment changes; thereby, promoting PCA aggressiveness. PMID- 24347251 TI - Mediation of smoking consumption on the association of perception of smoking risks with successful spontaneous smoking cessation. AB - BACKGROUND: The perception of smoking risks has positive and smoking consumption has negative effects on successful smoking cessation, but no information is now available for what is the role of smoking consumption on the relationship between perception of smoking risks and successful smoking cessation. PURPOSE: To assess the mediation of smoking amount on the association of perception of smoking risks with successful spontaneous smoking cessation. METHOD: A community-based case control study was conducted with 294 adult spontaneous successful smoking quitters who have been quitting smoking consecutively for more than 2 years as the cases, and 347 adult failed spontaneous smoking quitters who quitted but relapsed or have been quitting smoking continuously equal to or less than 2 years as the controls. The smoking amount was evaluated by pack-year that was categorized into tertiles and scored inversely. The score of perception of smoking risks was also categorized into tertiles. Propensity score as the covariate in the regression model was used to adjust the potential confounding. The total effect was decomposed into direct effect and indirect (mediating) effect by using logistic regression based on the KHB method proposed by Karlson, Holm, and Breen. The proportion of mediating effect among the total effect is calculated as the indirect effect divided by the total effect. RESULTS: After adjusting age, profession, education, marital status, and reasons for quitting smoking by using propensity score, the small mediating effect of smoking amount on the association of perception of smoking risks with successful spontaneous smoking cessation was observed, and the mediating effect of smoking amount was 23.75% among the total effect. The dose-response analysis showed that the mediating effect of smoking amount in the groups with middle and high score of perception of smoking risks were 10.15 and 37.84% among their total effect, respectively. CONCLUSION: This study reveals that smoking amount has only small mediating effect among the total effect of perception of smoking risks on the successful spontaneous smoking cessation; enhancing the smokers' perception of smoking risks could promote their attempt to reduce smoking, so as to increase the probability of successful smoking cessation. PMID- 24347252 TI - Exact Equations for SIR Epidemics on Tree Graphs. AB - We consider Markovian susceptible-infectious-removed (SIR) dynamics on time invariant weighted contact networks where the infection and removal processes are Poisson and where network links may be directed or undirected. We prove that a particular pair-based moment closure representation generates the expected infectious time series for networks with no cycles in the underlying graph. Moreover, this "deterministic" representation of the expected behaviour of a complex heterogeneous and finite Markovian system is straightforward to evaluate numerically. PMID- 24347253 TI - Travelling waves in hybrid chemotaxis models. AB - Hybrid models of chemotaxis combine agent-based models of cells with partial differential equation models of extracellular chemical signals. In this paper, travelling wave properties of hybrid models of bacterial chemotaxis are investigated. Bacteria are modelled using an agent-based (individual-based) approach with internal dynamics describing signal transduction. In addition to the chemotactic behaviour of the bacteria, the individual-based model also includes cell proliferation and death. Cells consume the extracellular nutrient field (chemoattractant), which is modelled using a partial differential equation. Mesoscopic and macroscopic equations representing the behaviour of the hybrid model are derived and the existence of travelling wave solutions for these models is established. It is shown that cell proliferation is necessary for the existence of non-transient (stationary) travelling waves in hybrid models. Additionally, a numerical comparison between the wave speeds of the continuum models and the hybrid models shows good agreement in the case of weak chemotaxis and qualitative agreement for the strong chemotaxis case. In the case of slow cell adaptation, we detect oscillating behaviour of the wave, which cannot be explained by mean-field approximations. PMID- 24347254 TI - Independent predictors of human milk receipt at neonatal intensive care unit discharge. AB - OBJECTIVE: The aim of this study is to construct a predictive model for very low birth weight (VLBW) infants' receipt of mother's own milk within 24 hours before neonatal intensive care unit (NICU) discharge. STUDY DESIGN: Vermont Oxford Network (VON) clinical data were analyzed retrospectively for VLBW infants admitted between 2002 and 2012 at an inner city, level IV NICU with a well established lactation program. Bivariate analyses compared infant characteristics between recipients and nonrecipients of human milk before 24 hours of NICU discharge. Independent predictors identified in the bivariate analyses (p <= 0.05), were eligible for inclusion into a multivariable logistic regression model. RESULTS: We observed a 60.4% human milk feeding rate at NICU discharge. Multiple independent maternal (black race and Hispanic ethnicity) and clinical factors (need for mechanical ventilation, patent ductus arteriosus, late-onset sepsis, or discharge to home on a cardiorespiratory monitor) positively predicted the outcome. CONCLUSIONS: Our results were inconsistent with previous studies and suggest that a strong NICU lactation program in combination with a community based peer counselor program may increase rates of human milk receipt among VLBW infants born to black/Hispanic mothers and those with more complicated neonatal courses. PMID- 24347255 TI - High aspartate aminotransferase level predicts poor neurodevelopmental outcome in infants with meconium aspiration syndrome. AB - OBJECTIVE: The aim of our study is to clarify the perinatal predictive factors of meconium aspiration syndrome (MAS) with neurodevelopmental delay (ND) in infants. MATERIALS AND METHODS: In this retrospective study, data were collected from the infants born between 1990 and 2008. They all had primary diagnosis of MAS. Multivariable analyzed perinatal predictive factors of MAS with ND. The developmental status of these infants was followed at least 2 years with the Wechsler Intelligence Scale for Children. RESULTS: A total of 114 surviving babies met the criteria of MAS. Six babies were defined as ND group. Lower 5 minute Apgar score and diastolic blood pressure were significantly related to the ND group. Elevated asparatate aminotransferase (AST), nucleated red blood cells, and white blood cells at the time of admission were significantly high in ND group. Furthermore, AST had area under the receiver operating characteristic curve of 0.879, (95% confidence interval: 0.801, 0.934), p < 0.0001. At 96 mg/dL, it had 83.33% sensitivity, 80.81% specificity, and negative predictive value of 98.8. Multivariable logistic regression analysis revealed AST was the only significant predictive factor for MAS with ND. CONCLUSION: Early intervention should be recommended in infants having MAS with high AST level at birth for improving their neurodevelopmental outcomes. PMID- 24347256 TI - Changes in premature infant mercury and lead blood levels after blood transfusions. AB - OBJECTIVE: To describe the blood level changes of mercury and lead after packed red blood cell (PRBC) transfusions in <= 750 g birth weight infants. STUDY DESIGN: Heavy metal blood levels were measured in infants in PRBC units on 1st, 4th, 5th, and 7th days (D1, D4, D5, and D7) of life and in urine on D1, D4, and D7. RESULTS: A total of 10 infants were enrolled with a mean birth weight of 632 +/- 72 g. Out of which nine infants received one or more PRBC transfusions, with an average of 2.9 +/- 2.5 transfusions per infant. Heavy metals were detected in all the transfusions. The average mercury level was 1.33 ug/L on D1 and 1.66 ug/L on D7, p > 0.05. The average lead level was 0.32 ug/dL on D1 and 0.56 ug/dL on D7, p > 0.05. Urinary mercury excretion increased in infants with no bowel movements. Urinary excretion of lead decreased over time as blood levels increased. CONCLUSIONS: After receiving blood transfusions, the blood levels of mercury and lead were maintained at the end of the 1st week of life. As there is no evidence of a proportionate increase in excretory amounts of these heavy metals, there is a concern that they are retained and potentially exert toxic effects. PMID- 24347258 TI - The adjusted effect of maternal body mass index, energy and macronutrient intakes during pregnancy, and gestational weight gain on body composition of full-term neonates. AB - OBJECTIVE: To evaluate the effect of prepregnancy body mass index (BMI), energy and macronutrient intakes during pregnancy, and gestational weight gain (GWG) on the body composition of full-term appropriate-for-gestational age neonates. STUDY DESIGN: This is a cross-sectional study of a systematically recruited convenience sample of mother-infant pairs. Food intake during pregnancy was assessed by food frequency questionnaire and its nutritional value by the Food Processor Plus (ESHA Research Inc, Salem, OR). Neonatal body composition was assessed both by anthropometry and air displacement plethysmography. Explanatory models for neonatal body composition were tested by multiple linear regression analysis. RESULTS: A total of 100 mother-infant pairs were included. Prepregnancy overweight was positively associated with offspring weight, weight/length, BMI, and fat-free mass in the whole sample; in males, it was also positively associated with midarm circumference, ponderal index, and fat mass. Higher energy intake from carbohydrate was positively associated with midarm circumference and weight/length in the whole sample. Higher GWG was positively associated with weight, length, and midarm circumference in females. CONCLUSION: Positive adjusted associations were found between both prepregnancy BMI and energy intake from carbohydrate and offspring body size in the whole sample. Positive adjusted associations were also found between prepregnancy overweight and adiposity in males, and between GWG and body size in females. PMID- 24347259 TI - The timing of adverse events with Foley catheter preinduction cervical ripening; implications for outpatient use. AB - OBJECTIVE: We sought to determine the rate and timing of adverse events that occur during preinduction cervical ripening using the Foley catheter before extrusion of the balloon and institution of oxytocin. STUDY DESIGN: Using electronic medical records, we identified all women who presented for preinduction cervical ripening using a Foley catheter with a term (>=37 weeks) singleton vertex live fetus from January 1, 2006, to June 14, 2009. Women were excluded if they had had a previous cesarean delivery, gestational hypertension or preeclampsia, pregestational diabetes, rupture of membranes before induction, fetal anomaly, or antepartum stillbirth. Outcomes were cesarean delivery for nonreassuring fetal tracing, vaginal bleeding, placental abruption, or intrapartum stillbirth occurring between 2 hours after Foley catheter placement and 6 am. RESULTS: Among 2,514 women, 1,905 met the inclusion criteria. No adverse outcomes were noted among term, singleton uncomplicated pregnancies receiving a Foley catheter for preinduction cervical ripening who met inclusion criteria (relative risk, 0.0; 95% confidence interval, 0.0-0.002). CONCLUSIONS: In a low-risk population, the use of the Foley catheter for preinduction cervical ripening was associated with no adverse outcomes. It appears to be a safe mechanism for cervical ripening and has the potential for use in the outpatient setting in a selected subset of women. PMID- 24347260 TI - Changes in fetal heart tracing characteristics after magnesium exposure. AB - OBJECTIVE: The aim of this study is to describe the changes in term fetal heart tracings after magnesium exposure. MATERIALS AND METHODS: This was a retrospective cohort study of consecutive women delivering at a gestational age of >= 37 weeks with severe preeclampsia, receiving magnesium for seizure prophylaxis. Overall 90 minutes of electronic fetal monitoring (30 before magnesium, 30 during magnesium bolus, and 30 during steady state infusion) was prospectively interpreted by formally trained and blinded research nurses using American Congress of Obstetricians and Gynecologists guidelines. Multivariable analyses were performed using generalized estimating equations, comparing preexposure patterns to bolus, and steady state. RESULTS: Out of the 238 women evaluated, an average decrease of 2.4 beats per minute (p = 0.02) was found after magnesium bolus. This persisted into the steady state (p < 0.01). Minimal/absent variability increased during bolus infusion (odds ratio [OR] 2.40, 95% confidence interval [CI] 1.10-5.62) but corrected by steady state (OR 1.44, 95% CI 0.76 2.80). There were no significant changes in the fetal heart rate (FHR) baseline < 120, tachycardia, or presence of accelerations or decelerations. CONCLUSION: Exposure to magnesium is associated with a transient decrease in variability and a clinically insignificant decrease in FHR baseline without an increased incidence in bradycardia or category change. PMID- 24347261 TI - Unintended extension of the lower segment uterine incision at cesarean delivery: a randomized comparison of sharp versus blunt techniques. AB - OBJECTIVE: This study compared two methods of expanding the uterine incision at the time of cesarean delivery, which is associated with the risk of unintended extension. STUDY DESIGN: This randomized trial included 1,076 women who underwent elective cesarean delivery. The primary outcome measure was the incidence of unintended extension related to the method used for expanding the uterine incision. RESULTS: Participants in both groups (blunt vs. sharp) had similar demographic and clinical characteristics. The incidence of unintended extension (8.8% vs. 4.8%; p = 0.009), mean estimated blood loss (853.67 +/- 42 mL vs. 664.80 +/- 38 mL; p = 0.001), and blood loss >1000 mL (11.4% vs. 6.8%; p = 0.009) was significantly higher in the sharp group compared with the blunt group. No difference in transfusions (7.5% vs. 6.3%; p = 0.440) or the need for additional supertonic agents (16% vs. 12.9%; p = 0.144) was noted. CONCLUSION: Sharp expansion of the uterine incision was related to a higher risk of unintended extension and maternal blood loss. Because blunt expansion is associated with a lower risk for unintended extension and maternal blood loss, it should be the first option during elective cesarean delivery. PMID- 24347257 TI - Adverse pregnancy outcomes among women with prior spontaneous or induced abortions. AB - OBJECTIVE: The aim of the article is to determine whether prior spontaneous abortion (SAB) or induced abortion (IAB), or the interpregnancy interval are associated with subsequent adverse pregnancy outcomes in nulliparous women. METHODS: We performed a secondary analysis of data collected from nulliparous women enrolled in a completed trial of vitamins C and E or placebo for preeclampsia prevention. Adjusted odds ratios (ORs) for maternal and fetal outcomes were determined for nulliparous women with prior SABs and IABs as compared with primigravid participants. RESULTS: Compared with primigravidas, women with one prior SAB were at increased risk for perinatal death (adj. OR, 1.5; 95% CI, 1.1-2.3) in subsequent pregnancies. Two or more SABs were associated with an increased risk for spontaneous preterm birth (PTB) (adj. OR, 2.6, 95% CI, 1.7-4.0), preterm premature rupture of membranes (PROM) (adj. OR, 2.9; 95% CI, 1.6-5.3), and perinatal death (adj. OR, 2.8; 95% CI, 1.5-5.3). Women with one previous IAB had higher rates of spontaneous PTB (adj. OR, 1.4; 95% CI, 1.0-1.9) and preterm PROM (OR, 2.0; 95% CI, 1.4-3.0). An interpregnancy interval less than 6 months after SAB was not associated with adverse outcomes. CONCLUSION: Nulliparous women with a history of SAB or IAB, especially multiple SABs, are at increased risk for adverse pregnancy outcomes. PMID- 24347263 TI - Depressed heart rate variability is associated with abnormal EEG, MRI, and death in neonates with hypoxic ischemic encephalopathy. AB - OBJECTIVE: Asphyxia can lead to autonomic nervous system dysfunction, including depressed heart rate variability (HRV). We tested the hypothesis that low HRV is associated with adverse short-term outcomes of abnormalities on electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) and death in neonates with hypoxic ischemic encephalopathy (HIE). STUDY DESIGN: Neonates undergoing hypothermia therapy for HIE underwent monitoring of HRV. HRV in the first day after birth and after hypothermia and rewarming (days 4-7) were analyzed in relation to death and severity of abnormal findings on EEG and MRI. RESULTS: A total of 37 neonates had data available in the first 24 hour after birth and 67 had data days 2 to 7. Depressed HRV was significantly associated with adverse outcomes of death or moderate-to-severe abnormalities on EEG or MRI. In the first 24 hours, the odds ratio (OR) of one or more adverse outcomes for every 10-millisecond decrease in HRV was 3.19 (95% CI, 1.3-7.8; p = 0.01). HRV improved over time but low HRV remained significantly associated with adverse outcomes days 4 to 7 (OR, 2.72; CI, 1.32-5.61; p < 0.01). CONCLUSIONS: Monitoring HRV, which is reflected in the heart rate characteristic index, may provide useful adjunct information on the severity of brain injury in infants with HIE. PMID- 24347262 TI - Medication use in the neonatal intensive care unit. AB - OBJECTIVE: The aim of the article is to provide an update on medication use in infants admitted to the neonatal intensive care unit (NICU) in the United States and examine how use has changed over time. STUDY DESIGN: We performed a retrospective review (2005-2010) of a large prospectively collected administrative database. RESULT: Medications most commonly administered during the study period were ampicillin, gentamicin, caffeine citrate, vancomycin, beractant, furosemide, fentanyl, dopamine, midazolam, and calfactant (56-681 exposures per 1,000 infants). Those with the greatest relative increase in use included azithromycin, sildenafil, and milrinone. Medications with the greatest relative decrease in use included theophylline, metoclopramide, and doxapram. CONCLUSION: Medication use in the NICU has changed substantially over time, and only 35% of the most commonly prescribed medications are Food and Drug Administration -approved in infants. PMID- 24347264 TI - In utero stem cell transplantation for radical treatment of osteogenesis imperfecta: perspectives and controversies. AB - Osteogenesis imperfecta (OI) is a lethal hereditary connective tissue disease that affects the synthesis of type I collagen. Current treatment options including surgical, physical, and medical treatment help to reduce pain, deformities, and rate of bone fracture. However, these choices are insufficient and are associated with many adverse effects. The development of stem cell therapy allows scientists to consider this option for radical treatment of many genetic diseases including OI. In utero stem cell transplantation provides a better opportunity for early prenatal intervention while the fetus is preimmune and before any permanent damage occurs. Few animal and human trials for treatment of OI have been published, and the results were promising but still controversial. Our objective is to review the available evidence and discuss the points of controversy including the parameters of treatment success and postnatal predictors of long-term treatment outcome. PMID- 24347265 TI - Simultaneous dual contrast weighting using double echo rapid acquisition with relaxation enhancement (RARE) imaging. AB - PURPOSE: This work proposes a dual contrast rapid acquisition with relaxation enhancement (RARE) variant (2in1-RARE), which provides simultaneous proton density (PD) and T2 * contrast in a single acquisition. THEORY AND METHODS: The underlying concept of 2in1-RARE is the strict separation of spin echoes and stimulated echoes. This approach offers independent weighting of spin echoes and stimulated echoes. 2in1-RARE was evaluated in phantoms including signal-to-noise ratio (SNR) and point spread function assessment. 2in1-RARE was benchmarked versus coherent RARE and a split-echo RARE variant. The applicability of 2in1 RARE for brain imaging was demonstrated in a small cohort of healthy subjects (n = 10) and, exemplary, a multiple sclerosis patient at 3 Tesla as a precursor to a broader clinical study. RESULTS: 2in1-RARE enables the simultaneous acquisition of dual contrast weighted images without any significant image degradation and without sacrificing SNR versus split-echo RARE. This translates into a factor of two speed gain over multi-contrast, sequential split-echo RARE. A 15% broadening of the point spread function was observed in 2in1-RARE. T1 relaxation effects during the mixing time can be neglected for brain tissue. CONCLUSION: 2in1-RARE offers simultaneous acquisition of images of anatomical (PD) and functional (T2 *) contrast. It presents an alternative to address scan time constraints frequently encountered during sequential acquisition of T2 * or PD-weighted RARE. PMID- 24347266 TI - Tumor-derived microparticles induce bone marrow-derived cell mobilization and tumor homing: a process regulated by osteopontin. AB - Acute chemotherapy can induce rapid bone-marrow derived pro-angiogenic cell (BMDC) mobilization and tumor homing, contributing to tumor regrowth. To study the contribution of tumor cells to tumor regrowth following therapy, we focused on tumor-derived microparticles (TMPs). EMT/6 murine-mammary carcinoma cells exposed to paclitaxel chemotherapy exhibited an increased number of TMPs and significantly altered their angiogenic properties. Similarly, breast cancer patients had increased levels of plasma MUC-1(+) TMPs following chemotherapy. In addition, TMPs from cells exposed to paclitaxel induced higher BMDC mobilization and colonization, but had no increased effect on angiogenesis in Matrigel plugs and tumors than TMPs from untreated cells. Since TMPs abundantly express osteopontin, a protein known to participate in BMDC trafficking, the impact of osteopontin-depleted TMPs on BMDC mobilization, colonization, and tumor angiogenesis was examined. Although EMT/6 tumors grown in mice inoculated with osteopontin-depleted TMPs had lower numbers of BMDC infiltration and microvessel density when compared with EMT/6 tumors grown in mice inoculated with wild-type TMPs, no significant difference in tumor growth was seen between the two groups. However, when BMDCs from paclitaxel-treated mice were injected into wild-type EMT/6-bearing mice, a substantial increase in tumor growth and BMDC infiltration was detected compared to osteopontin-depleted EMT/6-bearing mice injected with BMDCs from paclitaxel-treated mice. Collectively, our results suggest that osteopontin expressed by TMPs play an important role in BMDC mobilization and colonization of tumors, but is not sufficient to enhance the angiogenic activity in tumors. PMID- 24347267 TI - Influence of physical activity on T1 and T2* relaxation times of healthy Achilles tendons at 3T. AB - PURPOSE: To evaluate longitudinal (T1) and transverse (T2*) relaxation times at different Achilles tendon locations (insertion, mid-portion, and musculotendinous area) in a cohort of subjects with variable tendon straining activity, but without any signs of tendinopathy. MATERIALS AND METHODS: T1 and T2* relaxation times of the Achilles tendon were measured using an ultrashort echo time (UTE) imaging sequence with flip angle and echo time variation on a 3T whole-body clinical magnetic resonance (MR) scanner. Twenty-four tendons of 12 healthy volunteers and 18 tendons of nine healthy recreational long-distance runners (average weekly running distance of 47.4 +/- 5.3 km) were enrolled. RESULTS: Mean T1 values of the whole tendon showed no marked group differences, whereas T2* relaxation times of runners were significantly longer (mean percentage increase 15.7 +/- 4.9%; P = 0.0181) compared to controls. Regarding group differences for the investigated insertional, mid-portion, and musculotendinous area of the Achilles tendon, only the mid-portion of the Achilles tendon in the running group presented significantly longer T2* values (mean percentage increase 29.1 +/- 23.0%; P = 0.0420) in comparison to the control group. CONCLUSION: Prolonged T2* values especially in the mid-portion of the Achilles tendon of runners are likely to reflect an adaptation of the tendon microstructure to repetitive tendon straining activity. PMID- 24347268 TI - Controlled interfacial electron dynamics in highly efficient Zn2 SnO4 -based dye sensitized solar cells. AB - Among ternary oxides, Zn2 SnO4 (ZSO) is considered for dye-sensitized solar cells (DSSCs) because of its wide bandgap, high optical transmittance, and high electrical conductivity. However, ZSO-based DSSCs have a poor performance record owing largely to the absence of systematic efforts to enhance their performance. Herein, general strategies are proposed to improve the performance of ZSO-based DSSCs involving interfacial engineering/modification of the photoanode. A conformal ZSO thin film (blocking layer) deposited at the fluorine-doped tin oxide-electrolyte interface by pulsed laser deposition suppressed the back electron transfer effectively while maintaining a high optical transmittance, which resulted in a 22 % improvement in the short-circuit photocurrent density. Surface modification of ZSO nanoparticles (NPs) resulted in an ultrathin ZnO shell layer, a 9 % improvement in the open-circuit voltage, and a 4 % improvement in the fill factor because of the reduced electron recombination at the ZSO NPs electrolyte interface. The ZSO-based DSSCs exhibited a faster charge injection and electron transport than their TiO2 -based counterparts, and their superior properties were not inhibited by the ZnO shell layer, which indicates their feasibility for highly efficient DSSCs. Each interfacial engineering strategy could be applied to the ZSO-based DSSC independently to lead to an improved conversion efficiency of 6 %, a very high conversion efficiency for a non-TiO2 based DSSC. PMID- 24347269 TI - Metallic oxide nanoparticles stimulate blood coagulation independent of their surface charge. AB - Positively charged metallic oxides prevent blood coagulation whereas negatively charged metallic oxides are thrombogenic. This study was performed to examine whether this effect extends to metallic oxide nanoparticles. Oscillation shear rheometry was used to study the effect of zinc oxide and silicon dioxide nanoparticles on thrombus formation in human whole blood. Our data show that oscillation shear rheometry is a sensitive and robust technique to analyze thrombogenicity induced by nanoparticles. Blood without previous contact with nanoparticles had a clotting time (CT) of 16.7 +/- 1.0 min reaching a maximal clot strength (CS) of 16 +/- 14 Pa (G') after 30 min. ZnO nanoparticles (diameter 70 nm, +37 mV zeta-potential) at a concentration of 1 mg/mL prolonged CT to 20.8 +/- 3.6 min and provoked a weak clot (CS 1.5 +/- 1.0 Pa). However, at a lower concentration of 100 ug/mL the ZnO particles dramatically reduced CT to 6.0 +/- 0.5 min and increased CS to 171 +/- 63 Pa. This procoagulant effect decreased at lower concentrations reaching the detection limit at 10 ng/mL. SiO2 nanoparticles (diameter 232 nm, -28 mV zeta-potential) at high concentrations (1 mg/mL) reduced CT (2.1 +/- 0.2 min) and stimulated CS (249 +/- 59 Pa). Similar to ZnO particles, this procoagulant effect reached a detection limit at 10 ng/mL. Nanoparticles in high concentrations reproduce the surface charge effects on blood coagulation previously observed with large particles or solid metal oxides. However, nanoparticles with different surface charges equally well stimulate coagulation at lower concentrations. This stimulation may be an effect which is not directly related to the surface charge. PMID- 24347270 TI - Dielectrophoresis with 3D microelectrodes fabricated by surface tension assisted lithography. AB - This paper demonstrates the utilization of 3D semispherical shaped microelectrodes for dielectrophoretic manipulation of yeast cells. The semispherical microelectrodes are capable of producing strong electric field gradients, and in turn dielectrophoretic forces across a large area of channel cross-section. The semispherical shape of microelectrodes avoids the formation of undesired sharp electric fields along the structure and also minimizes the disturbance of the streamlines of nearby passing fluid. The advantage of semispherical microelectrodes over the planar microelectrodes is demonstrated in a series of numerical simulations and proof-of-concept experiments aimed toward immobilization of viable yeast cells. PMID- 24347271 TI - A novel condition for capillary electrophoretic analysis of reductively aminated saccharides without removal of excess reagents. AB - We have identified novel CE conditions for the separation of 7-amino-4 methylcoumarin-labeled monosaccharides and oligosaccharides from glycoproteins. Using a neutrally coated capillary and alkaline borate buffer containing hydroxypropylcellulose and ACN, saccharide derivatives form anionic borate complexes, which move from the cathode to the anode in an electric field and are detected near the anodic end. Excess labeling reagents and other fluorescent products remain at the cathodic end. Fluorimetric detection using an LED as a light source enables determination of monosaccharide derivatives with good linearity between at least 0.4 and 400 MUM, may correspond to 140 amol to 140 fmol. The lower LOD (S/N = 5) is only 80 nM in the sample solution (ca. 28 amol). The results were comparable to reported values using fluorometric detection LC. The method was also applied to the analysis of oligosaccharides that were enzymatically released from glycoproteins. Fine resolution enables profiling of glycans in glycoproteins. The applicability of the method was examined by applying it to other derivatives labeled with nonacidic tags such as ethyl p aminobenzoate- and 2-aminoacridone-labeled saccharides. PMID- 24347272 TI - An optimized method to extract poplar leaf proteins for two-dimensional gel electrophoresis guided by analysis of polysaccharides and phenolic compounds. AB - Commonly used methods for protein extraction from plant leaves, such as extraction with phenol or a combination of trichloroacetic acid and acetone, were ineffective for four tested cultivars of poplar. Moreover, multiple protocols for 2DE of the extracted proteins gave different results when protein profiles of relatively closely related plants were compared. Given that polycyclic compounds strongly hinder 2DE, we analyzed the impact of polyphenols and polysaccharides present in the plant tissues used for protein extraction, on the quality of 2DE protein profiles. Analysis of content of polyphenols and polysaccharides in leaves of poplar cultivars showed that even small differences in concentrations of analyzed metabolites accompany large differences between poplar cultivars when considering the susceptibility of samples to protein extraction for 2DE. High quality 2DE results were correlated with decreased amounts of polyphenols. Additional analysis using MS/MS suggested that only levels of total phenolics affected the results of 2DE. Soluble total nonstructural carbohydrates also had a negative effect, but the level of starch was not important. Finally, we present an optimized method for extraction of proteins from poplar leaves, which enables reliable comparative analysis of four different poplar cultivars, that is, "Eridano," "Villafranca," "NE-42," and "Luisa Avanzo," which have not yet been used for the proteomic studies. PMID- 24347277 TI - Replication-defective HSV-1 effectively targets trigeminal ganglion and inhibits viral pathopoiesis by mediating interferon gamma expression in SH-SY5Y cells. AB - It has been widely believed that recurrence of herpes simplex keratitis (HSK) is due to the reactivation of herpes simplex virus type 1 (HSV-1) from latent sites in trigeminal ganglion (TG). However, there are also not effective vectors which could target TG for therapy. Replication-defective HSV-1 vector (rdHSV-IFNgamma) was established by calcium phosphate co-transfection of complementing cells. We firstly infected rdHSV-IFNgamma to SH-SY5Y, and detected IFNgamma expression by western blot, evaluated 50 % cellular cytotoxicity (CC(50)) by ELISA. Antiviral activity of rdHSV-IFNgamma was examined by immunofluorescence and antiviral concentration of 50 % effectiveness (EC(50)) assay. The rdHSV-IFNgamma vector was immunized to Wistar rats to observe targeting function to TG. Kaplan-Meier survival analysis was utilized to assess security of rdHSV-IFNgamma. RT-PCR and immunohistochemistry assay were employed to detect rdHSV-IFNgamma localization in TG. Western blot was employed to detect IFNgamma expression. rdHSV-IFNgamma was successfully established, and performed an effective antiviral activity and higher security in SH-SY5Y. There were no significant differences of survival and corneal infection rate of rdHSV-IFNgamma immunized rats among groups (P > 0.05). RT-PCR and immunohistochemistry indicated that expression of glycoprotein D (gD) in TG could target TG and decreased following with times post immunization. Furthermore, IFNgamma was expressed effectively in TG tissues. Our findings indicated that established rdHSV-IFNgamma vector effectively transported therapeutic gene into TG tissues. The administration of replication-defective vector carrying therapeutic genes may become a promising tool in inhibition or reoccurrence of HSK in clinical. PMID- 24347278 TI - Surgical salvage of acute renal artery occlusion in the setting of a solitary kidney. AB - Management of acute renal artery occlusion in patients with a solitary kidney has a poorly defined prognosis. Loss of renal function is reported by some when acute warm ischemia reaches 2 hours. We report a unique case of a patient that had a 24 hour onset of anuria and acute renal failure upon arrival to the hospital. Nuclear imaging showed trace uptake of the right kidney, without evidence of excretion. Conventional digital subtraction angiography was performed; however, evidence of nephrogram or distal filling of the renal artery was not demonstrated. Secondary to conflicting studies, a computed tomography of the abdomen and pelvis with intravenous contrast revealed only minimal cortical perfusion despite complete occlusion of the previously grafted right renal artery. Patient was taken for urgent hepatorenal bypass surgery. Intraoperative return of urine output occurred immediately after completion of the bypass. Hemodialysis, which was required preoperatively, was stopped after <30 days of bypass procedure. Over 2 years following successful renal salvage, the patient has maintained a normal glomerular filtration rate and patency of her bypass by duplex follow-up. PMID- 24347279 TI - Endovascular management of a mobile thoracic aortic thrombus following recurrent distal thromboembolism: a case report and literature review. AB - Sources of lower extremity and visceral arterial thromboembolism most commonly include the heart and proximal aneurysmal disease. Infrequently, further workup of "cryptogenic" emboli will reveal a mural atheroma or thrombus of the descending thoracic aorta. Without prospective data, anticoagulation and open surgical thrombectomy with or without aortic replacement have been the standard approach. Presented is a case of a floating mural thrombus in the setting of superior mesenteric and femoral arterial thromboembolism that was effectively treated with endovascular stent graft exclusion. PMID- 24347280 TI - Statins promote residual aneurysm sac regression following endovascular aortic aneurysm repair. AB - BACKGROUND: Regression of the residual sac is indicative of successful endovascular aortic aneurysm (EVAR) repair. Using color duplex ultrasound (CDU), we monitored the residual aneurysm sac following EVAR and correlated sac behavior with perioperative risk factors. METHODS: Of 145 patients with EVAR, 106 (73.1%) patients between January 01, 2003, and July 01, 2010, had at least 2 consecutive postoperative scans and thus were eligible for inclusion. Mean (+/- standard deviation [SD]) CDU scans per person was 4.6 (+/- 1.4). All were conducted by the same technologist using a standard protocol on the same machine. Aneurysm sac change in centimeters and percentage terms was calculated. The presence or absence of an endoleak was also recorded. Change in aneurysm sac size was correlated with preoperative risk factors. FINDINGS: Mean sac size change at 1 month was a decrease of 0.24 cm, equating to a percentage change of 4.3%. At 7 months, the decrease was 0.59 cm (9.8%), at 12 months, 0.73 cm (12.4%), at 18 months 0.92 cm (15.8%), and at 36 months 1.0 cm (16.6%). Both univariate and multivariate analyses demonstrated that statin therapy (P = .002) was the only risk factor variable positively associated with aneurysm regression while the presence of an endoleak was inversely related to sac reduction (P = .01). INTERPRETATION: Maximum aneurysmal sac reduction seems to occur in the first year following endograft implantation. Statin therapy appears to be associated with an increased likelihood of sac regression following EVAR. Further investigation of the role of statins in the biology of abdominal aortic aneurysmal disease is warranted. PMID- 24347281 TI - Gender and outcomes of carotid artery interventions. AB - The benefits of carotid artery revascularization in women have been debated since the publication of large randomized clinical trials comparing carotid endarterectomy (CEA) to medical therapy. Institutional series have historically had an underrepresentation of women and/or have lacked power for adequate analysis. Recent evidence from large databases reveals possible gender-based differences in outcomes of carotid artery stenting versus CEA. In this review, we evaluated clinical articles from 1991 to 2012, using Pubmed and Web of Science, which addressed gender and outcomes of carotid artery revascularization procedures. Our goal was to determine whether gender is associated with adverse outcomes following carotid artery interventions in patients with carotid artery disease. PMID- 24347282 TI - Efficacy, safety, and tolerability of pantoprazole magnesium in the treatment of reflux symptoms in patients with gastroesophageal reflux disease (GERD): a prospective, multicenter, post-marketing observational study. AB - BACKGROUND: To improve proton pump inhibitor effects, pharmacological modifications have been developed such as the use of enantiomer molecules (e.g., S-omeprazole, S-pantoprazole, or dexlansoprazole), or addition of NaHCO3 (for an immediate release) or magnesium (with a lower absorption for a more sustained effect). OBJECTIVE: The objective of this study was to assess the efficacy, safety, and tolerability of pantoprazole magnesium 40 mg once daily for 4 weeks, on the relief of reflux symptoms in gastroesophageal reflux disease (GERD) patients. METHODS: A phase IV, open-label, prospective, multicenter study was designed. Patients included were prescribed pantoprazole magnesium 40 mg orally once daily for 28+/-2 days. All patients had a history of persistent or recurrent heartburn and/or acid regurgitation for at least 3 months. Effectiveness and tolerability data obtained from patients who completed a minimum of 4 weeks of pantoprazole magnesium treatment were considered for analysis. RESULTS: The account of baseline characteristics and demographics of GERD symptom intensity was made by analyzing the group of 4,343 patients that fulfilled all inclusion criteria; 54% were females (n=2,345) and 46% (n=1,998) males, with a mean age of 36.2+/-7.5 years. Severity of symptoms, assessed by the physician using the 4 point Likert scale, reduced by at least 80% from baseline intensity after treatment in the per protocol population. In the case of the intention-to-treat population, the improvement in symptom intensity was 73%. The number of patients that experienced any adverse events was 175/5,027 (3.48%). CONCLUSIONS: Pantoprazole magnesium is a safe, effective, and well-tolerated drug that significantly improves GERD symptoms. PMID- 24347283 TI - Three-dimensional structure of a sugar N-formyltransferase from Francisella tularensis. AB - N-formylated sugars have been observed on the O-antigens of such pathogenic Gram negative bacteria as Campylobacter jejuni and Francisella tularensis. Until recently, however, little was known regarding the overall molecular architectures of the N-formyltransferases that are required for the biosynthesis of these unusual sugars. Here we demonstrate that the protein encoded by the wbtj gene from F. tularensis is an N-formyltransferase that functions on dTDP-4-amino-4,6 dideoxy-d-glucose as its substrate. The enzyme, hereafter referred to as WbtJ, demonstrates a strict requirement for N(10) -formyltetrahydrofolate as its carbon source. In addition to the kinetic analysis, the three-dimensional structure of the enzyme was solved in the presence of dTDP-sugar ligands to a nominal resolution of 2.1 A. Each subunit of the dimeric enzyme is dominated by a "core" domain defined by Met 1 to Ser 185. This core motif harbors the active site residues. Following the core domain, the last 56 residues fold into two alpha helices and a beta-hairpin motif. The hairpin motif is responsible primarily for the subunit:subunit interface, which is characterized by a rather hydrophobic pocket. From the study presented here, it is now known that WbtJ functions on C 4' amino sugars. Another enzyme recently investigated in the laboratory, WlaRD, formylates only C-3' amino sugars. Strikingly, the quaternary structures of WbtJ and WlaRD are remarkably different. In addition, there are several significant variations in the side chains that line their active site pockets, which may be important for substrate specificity. Details concerning the kinetic and structural properties of WbtJ are presented. PMID- 24347284 TI - PIK3CA gene alterations in bladder cancer are frequent and associate with reduced recurrence in non-muscle invasive tumors. AB - Bladder cancer (BC) is the fifth most common cancer in the world, being the non muscle invasive tumors (NMIBC) the most frequent. NMIBC shows a very high frequency of recurrence and, in certain cases, tumor progression. The phosphatidylinositol 3-kinase (PI3K) pathway, which controls cell growth, tumorigenesis, cell invasion and drug response, is frequently activated in numerous human cancers, including BC, in part through alterations of PIK3CA gene. However, the significance of PIK3CA gene alterations with respect to clinicopathological characteristics, and in particular tumor recurrence and progression, remains elusive. Here, we analyzed the presence of mutations in FGFR3 and PIK3CA genes and copy number alterations of PIK3CA gene in bladder tumor and their correspondent paired normal samples from 87 patients. We observed an extremely high frequency of PIK3CA gene alterations (mutations, copy gains, or both) in tumor samples, affecting primarily T1 and T2 tumors. A significant number of normal tissues also showed mutations and copy gains, being coincident with those found in the corresponding tumor sample. In low-grade tumors PIK3CA mutations associated with FGFR3 mutations. Alterations in PIK3CA gene resulted in increased Akt activity in tumors. Interestingly, the presence of PIK3CA gene alterations, and in particular gene mutations, is significantly associated with reduced recurrence of NMIBC patients. Importantly, the presence of FGFR3 mutations may influence the clinical outcome of patients bearing alterations in PIK3CA gene, and increased recurrence was associated to FGFR3 mutated, PIK3CA wt tumors. These findings may have high relevance in terms of using PI3K-targeted therapies for BC treatment. PMID- 24347285 TI - Corticosteroids may favor proliferation of thoracic inflammatory myofibroblastic tumors. AB - Inflammatory myofibroblastic tumor (IMT) was thought to represent a benign post infectious or post-inflammatory process cured by surgical resection. However, reports of cases with an aggressive clinical course suggest the need for caution about the prognosis. The treatment of choice is a complete surgical resection, while medical treatment options are limited. Corticosteroid therapy has been used with some success in unresectable lesion. However, rapid progression of lung IMT after prednisone treatment has been reported, raising the hypothesis that corticosteroids may favor a tumultuous proliferation of this lesion, possibly through immunosuppression. We here report a similar observation and suggest that other mechanisms may be involved. A 5-year and 6-month-old boy presented with a 72 hr history of breathlessness, initially responsive to albuterol and prednisone. He represented 15 days later with increasing symptoms despite further prednisone treatment. CT chest scan showed a mass lesion in the tracheal lumen, which on biopsy was found to be an IMT. The possibility that prednisone may have an enhancing effect on IMT cell proliferation is demonstrated through IMT cell culture and discussed. PMID- 24347286 TI - MR and CEUS monitoring of patients with severe rheumatoid arthritis treated with biological agents: a preliminary study. AB - PURPOSE: This study was done to propose a study protocol for patients with rheumatoid arthritis (RA) treated with biological agents, by evaluating the contribution of contrast-enhanced magnetic resonance (CE-MR) imaging, a software programme that calculates the volume of synovitis on CE-MR images, and contrast enhanced ultrasound (CEUS). MATERIALS AND METHODS: Sixteen patients with RA receiving treatment with biologics were analysed. The patients underwent clinical examination, CE-MR imaging and CEUS on the same day. Images were postprocessed with the software and evaluated independently by three physicians in terms of RAMRIS (Rheumatoid Arthritis Magnetic Resonance Imaging Score), SAMIS (Simplified Rheumatoid Arthritis Magnetic Resonance Imaging Score) and CEUS grade. The techniques were correlated statistically. RESULTS: The RAMRIS and SAMIS scores were found to correlate statistically. CE-MR imaging correlated with the clinical data (p < 0.05), whereas CEUS did not. The data provided by the software did not correlate statistically with the other techniques. The most painful joint was consistently found to be the joint with most synovitis. CONCLUSIONS: CE-MR imaging may be used prior to treatment and for long-term follow-up. CEUS might be useful in the short-term follow-up, as it seems to provide an indication of the presence or absence of disease, though not of its severity. The software is a very useful tool that can supplement, but not replace, the other techniques. PMID- 24347287 TI - Activation of a positive feedback loop involving IL-6 and aromatase promotes intratumoral 17beta-estradiol biosynthesis in endometrial carcinoma microenvironment. AB - Tumor-stroma interactions contribute greatly to intratumoral estrogen biosynthesis in endometrial carcinoma, but the mechanisms involved remain largely unknown. Previous study demonstrated that intratumoral aromatase upregulation in stromal cells participated in this process, but the specific aromatase-regulators have not been reported. In the present study, we found that aromatase expression in intratumoral stroma, but not in tumor epithelium, correlated positively with interleukin 6 (IL-6) expression in cancer epithelial cells by immunohistochemistry, which was confirmed using laser capture microdissection/real-time reverse transcription-PCR. With stimulation by exogenous IL-6, aromarase expression was increased in stromal cells not but not in cancer cells. Aromatase mRNA levels in endometrial cancer cells were not influenced by cocultivation with intratumoral stromal cells. When cocultured with 17beta-estradiol (E2 )-treated cancer cells, aromatase mRNA in stromal cells was significantly elevated and increased IL-6 protein levels were detected in E2 treated culture medium. Next, we demonstrated that E2 -induced IL-6 production was through cooperation between estrogen receptor alpha and nuclear factor-kappa B. Furthermore, an IL-6 receptor blocking antibody could attenuate the upregulation of aromatase expression in stromal cells and the E2 concentration in coculture systems of cancer and stromal cells. The results were confirmed by an orthotopic nude endometrial carcinoma model in vivo. These studies elucidated the activation of a positive feedback loop, that is, IL-6 stimulated by E2 in endometrial cancer cells induced aromatase expression in stromal cells, promoting enhanced intratumoral E2 synthesis. Blocking of this tumor-stroma interaction may be a therapeutic strategy to overcome in situ estrogen biosynthesis in endometrial carcinoma. PMID- 24347288 TI - Total colonic aganglionosis: a 15-year single center experience. AB - PURPOSE: Total colonic aganglionosis (TCA) is a rare condition, which is challenging to manage. Outcome data are sparse. We aimed to review the demographics, treatment, and outcomes of TCA in our center. PATIENTS AND METHODS: A retrospective case note review of 15 years from a single center was undertaken. RESULTS: A total of nine patients (five male) were managed. Gestational age at birth was 39 weeks (range, 32.5-41 weeks). All patients were referred with distal intestinal obstruction at a median of day 2 (range, 1-6 days) of life. Two patients were managed with a long-term stoma. One died with persistent functional obstruction (despite a ganglionic stoma). Of the nine patients, seven patients underwent staged pull-through: three Soave, three Duhamel, and one Martin procedure with no short-term complications. All patients had at least one readmission with enterocolitis, diarrhea, or high stoma output. Further procedures were required in four of the seven patients. Only one child (older than 3 years) has achieved continence. Two children (both aged 8 years) requested reformation of a stoma to manage incontinence. CONCLUSION: In this series, we observed high morbidity and poor functional outcome, which should be anticipated in TCA. Patients with TCA have a high probability of requiring a long-term stoma and this should be considered as a management option. PMID- 24347289 TI - Para-axillary subcutaneous endoscopic approach in torticollis: tips and tricks in the surgical technique. AB - AIM: An obvious scar on the neck may appear following the open surgery for congenital muscular torticollis (CMT). The cosmetic result may displease the patient and the family. In this study, we describe a minimally invasive technique, para-axillary subcutaneous endoscopic approach (PASEA) in CMT. PATIENTS AND METHODS: A total of 11 children (seven girls and four boys with the age range between 1 and 15 years) were operated for torticollis by PASEA. All patients had facial asymmetry and head and neck postural abnormality. Following an incision at the ipsilateral para-axillary region, a subcutaneous cavernous working space is formed toward sternocleidomastoid (SCM) muscle. The muscle and fascia are cut by cautery under endoscopic vision. The patients had postoperative 2nd-week and 3rd-month visits. The incision scar, inspection, and palpation findings of the region, head posture, and shoulder position of the affected side were considered in evaluation of the cosmetic outcome. Preoperative and postoperative range of motion of the head and neck were compared for functional outcome. RESULTS: We preferred single incision surgery in our last two patients; the rest had double para-axillary incision for port insertion. Incomplete transection of the muscle was not observed. There was no serious complication. Postoperatively, head posture and shoulder elevation were corrected significantly. Range of motion of the head was improved. Postoperatively, all the patients had rotation capacity with more than 30 degrees. The range of postoperative flexion and extension movements was between 45 and 60 degrees. CONCLUSIONS: The open surgery techniques of CMT causes visible lifelong incision scar on the neck. PASEA leaves a cosmetically hidden scar in the axillary region. A single incision surgery is also possible. A well-formed cavernous working space is needed. External manual palpation, delicate dissection, and cutting of SCM muscle with cautery are the important components of the procedure. Surgeons having experience in pediatric minimal invasive surgery may consider PASEA as an alternative to the open approach in CMT. The surgeon should be familiar with surgical anatomy of the neck and must be highly competent in management of possible complications in the region. PMID- 24347290 TI - In vivo waveguide elastography: effects of neurodegeneration in patients with amyotrophic lateral sclerosis. AB - PURPOSE: Waveguide elastography (WGE) combines magnetic resonance elastography (MRE), diffusion tensor imaging (DTI), and anisotropic inversions for a determination of the elastic properties of white matter. Previously, the method evaluated the anisotropic elastic properties of the corticospinal tracts (CSTs) of healthy volunteers. Here, the sensitivity of WGE is tested for the detection of pathologic changes in a cohort of patients with Amyotrophic Lateral Sclerosis (ALS). METHODS: MRE and DTI were performed in 14 patients with ALS and 14 healthy, age-matched controls. A comparison was made between three components from WGE and the DTI metrics FA, MD, PD, and RD, for the detection of differences between patients and controls. It was hypothesized that the stiffness values in the CSTs of the patients would be significantly lower due to the known neurodegeneration associated with ALS. RESULTS: Two anisotropic shear moduli polarized parallel and perpendicular to the CSTs were significantly reduced in ALS patients (P < 0.0001), whereas the anisotropic longitudinal modulus polarized parallel to the CSTs showed no significant differences. CONCLUSION: The results of this study suggest a relatively high sensitivity of two anisotropic shear moduli as noninvasive metrics for the assessment of neuronal degeneration within the CSTs. PMID- 24347291 TI - A survey of aflatoxins in sesame seeds imported into Khorasan Province, Iran. AB - Sesame seed is one of the main nutrient substances which is used in the food industries of Khorasan Razavi, Iran. Because it is likely that stored sesame seeds are contaminated with mycotoxins, the levels of aflatoxins (AF) in five lots of imported sesame seeds before their distribution to the market were studied during one year. A total of 269 sub-samples were obtained from a total of 9,321 tons of sesame seeds from five importing companies. Aflatoxins at >1 MUg/kg were found in 50 % of all samples, but at low levels in most cases, which is illustrated by mean AFB1 and total AF levels of 1.25 +/- 3.70 and 1.43 +/- 4.38 MUg/kg, respectively. A few (1.9 %) samples exceeded the National Iranian Standard maximum accepted level for AFB1 (5 MUg/kg) or total AF (15 MUg/kg); the maximum total AF level found in one sample was 48 MUg/kg. The results indicate that the risk of a violative AF contamination in imported sesame seeds is not negligible but is currently relatively low. PMID- 24347292 TI - Texture-based classification of liver fibrosis using MRI. AB - PURPOSE: To investigate the ability of texture analysis of MRI images to stage liver fibrosis. Current noninvasive approaches for detecting liver fibrosis have limitations and cannot yet routinely replace biopsy for diagnosing significant fibrosis. MATERIALS AND METHODS: Forty-nine patients with a range of liver diseases and biopsy-confirmed fibrosis were enrolled in the study. For texture analysis all patients were scanned with a T2 -weighted, high-resolution, spin echo sequence and Haralick texture features applied. The area under the receiver operating characteristics curve (AUROC) was used to assess the diagnostic performance of the texture analysis. RESULTS: The best mean AUROC achieved for separating mild from severe fibrosis was 0.81. The inclusion of age, liver fat and liver R2 variables into the generalized linear model improved AUROC values for all comparisons, with the F0 versus F1-4 comparison the highest (0.91). CONCLUSION: Our results suggest that a combination of MRI measures, that include selected texture features from T2 -weighted images, may be a useful tool for excluding fibrosis in patients with liver disease. However, texture analysis of MRI performs only modestly when applied to the classification of patients in the mild and intermediate fibrosis stages. PMID- 24347293 TI - Artificial leaf goes simpler and more efficient for solar fuel generation. AB - Layer upon layer: Solar-to-fuel conversion through water splitting is among the most challenging and growing fields in present day science. Herein, a report is highlighted that successfully demonstrates an efficient photoanodic system utilizing simple and low-cost tungsten-doped bismuth vanadate on single- or double-junction amorphous silicon photovoltaic in a tandem configuration. PMID- 24347294 TI - Ferritin trends do not predict changes in total body iron in patients with transfusional iron overload. AB - Ferritin levels and trends are widely used to manage iron overload and assess the efficacy of prescribed iron chelation in patients with transfusional iron loading. A retrospective cohort study was conducted in 134 patients with transfusion-dependent anemia, over a period of up to 9 years. To determine whether the trends in ferritin adequately reflect the changes in total body iron, changes in ferritin between consecutive liver iron measurements by magnetic resonance imaging (MRI) were compared to changes in liver iron concentrations (LIC), a measure of total body iron. The time period between two consecutive LIC measurements was defined as a segment. Trends in ferritin were considered to predict the change in LIC within a segment if the change in one parameter was less than twofold that of the other, and was in the same direction. Using the exclusion criteria detailed in methods, the trends in ferritin were compared to changes in LIC in 358 segments. An agreement between ferritin trends and LIC changes was found in only 38% of the 358 segments examined. Furthermore, the change in ferritin was in opposite direction to that of LIC in 26% of the segments. Trends in ferritin were a worse predictor of changes in LIC in sickle cell disease than in thalassemia (P < 0.01). While ferritin is a convenient measure of iron status; ferritin trends were unable to predict changes in LIC in individual patients. Ferritin trends need to be interpreted with caution and confirmed by direct measurement of LIC. PMID- 24347295 TI - Horizontal comparative fluorescence two-dimensional gel electrophoresis for improved spot coordinate detection. AB - Vertical comparative 2D fluorescence gel electrophoresis (CoFGE) has recently been shown to increase the reproducibility of coordinate assignment for protein spots, in particular in singular experiments, which cannot be investigated using DIGE. The method applies a standardized marker grid formed by a set of purified proteins to the sample proteome in a conglomerate of 1DE, 2DE, and DIGE. Here, improvements are demonstrated by transferring CoFGE to horizontal 2DE. These include the elimination of the protein modification by residual acrylamide monomer unavoidable in vertical CoFGE, reduced buffer volumes, and highly efficient laboratory procedures. Spot patterns are well defined and can be easily analyzed using commercially available warping algorithms. With horizontal CoFGE also a correction for changes in pI was introduced using a third fluorescent dye. Horizontal CoFGE holds high promises in comparative proteomics. PMID- 24347296 TI - Poly-cyclodextrin functionalized porous bioceramics for local chemotherapy and anticancer bone reconstruction. AB - The progress in bone cancer surgery and multimodal treatment concept achieve only modest improvement in the overall survival, due to failure in clearing out residual cancer cells at the surgical margin and extreme side-effects of adjuvant postoperative treatments. Our study aims to propose a new method based on cyclodextrin polymer (polyCD) functionalized hydroxyapatite (HA) for achieving a high local drug concentration with a sustained release profile and a better control of residual malignant cells via local drug delivery and promotion of the reconstruction of bone defects. PolyCD, a versatile carrier for therapeutic molecules, can be incorporated into HA (bone regeneration scaffold) through thermal treatment. The parameters of polyCD treatment on the macroporous HA (porosity 65%) were characterized via thermogravimetric analysis. Good cytocompatibility of polyCD functionalized bioceramics was demonstrated on osteoblast cells by cell vitality assay. An antibiotic (gentamicin) and an anticancer agent (cisplatin) were respectively loaded on polyCD functionalized bioceramics for drug release test. The results show that polyCD functionalization leads to significantly improved drug loading quantity (30% more concerning gentamicin and twice more for cisplatin) and drug release duration (7 days longer concerning gentamicin and 3 days longer for cisplatin). Conclusively, this study offers a safe and reliable drug delivery system for bioceramic matrices, which can load anticancer agents (or/and antibiotics) to reduce local recurrence (or/and infection). PMID- 24347297 TI - Genetic variability and geographic typicality of Italian former Prosecco grape variety using PCR-derived molecular markers. AB - This study uses PCR-derived marker systems to investigate the extent and distribution of genetic variability of 80 Italian Prosecco accessions coming from Prosecco DOC area (north-east area of Italy). The studied samples include genotypes from Veneto and Friuli Venezia Giulia region. In order to verify the varietal identity of the samples, analyses based on 22 SSR loci were performed, and two grape varieties were found: Prosecco tondo and Prosecco lungo. In addition to microsatellite analysis, intra-varietal variability study was performed using AFLP, SAMPL, ISSR, and M-AFLP molecular markers. This molecular approach could discriminate different Prosecco tondo accessions coming from Treviso hills, from Veneto plain, from Friuli Venezia Giulia region, and from Padua hills (Serprina samples). As concerning Prosecco lungo variety, it was possible to discriminate molecularly the accessions from Veneto region and those from Friuli Venezia Giulia region. The molecular analysis allowed a distinction of the Prosecco genotypes on the basis of their geographic origins with plant specific markers able to differentiate all Prosecco accessions. In this paper, the studied grape variety is termed Prosecco and not Glera (which is the present name) because the sampled vineyards were established many years ago when the name of the variety was Prosecco. PMID- 24347298 TI - Getting stung by black scorpion Androctonus crassicauda: a case report. AB - Importance of the correct diagnosis in the correct early management of a scorpion stung patient by using antivenom is not emphasized, particularly when there are little evidences. A 65-year-old female was brought to our emergency department with the chief compliant of being stung by an unknown object 3 h earlier while traveling in an intercity bus. She became agitated and simultaneously experienced tachycardia, very severe generalized sweating, cold and wet extremities, bilateral diffuse crackle in the base of lungs, tachypnea, and lethargy. With the primitive diagnosis of myocardial infarction, scorpion sting was documented as the cause of this combined cholinergic and adrenergic syndrome after the scorpion was found in the patient's bed clothes. She dramatically responded to the administration of low dose of scorpion antivenom. This case dramatically responded to the antivenom administration, especially the cholinergic and sympathetic signs, pulmonary edema, and electrocardiographic changes were fully and almost immediately recovered. Scorpion antivenom may reverse life-threatening manifestations of scorpion envenomation if used early and in appropriate patients. PMID- 24347299 TI - Environmental toxins: alarming impacts of pesticides on male fertility. AB - This review comprehensively summarizes the effects of more than 15 mostly used pesticides on male reproductive physiology, as recent experimental and epidemiological research have indicated their alarming impact on overall human health. Mechanisms have described that pesticide exposure damages spermatozoa, alter Sertoli or Leydig cell function, both in vitro and in vivo and thus affects semen quality. But, the literature suggests a need for more intricate research in those pesticides that are defined as mutagens or carcinogens and directly affect the hypothalamic-pituitary-gonadal axis. This literature review also proposes specific solutions to overcome these health effects. PMID- 24347300 TI - Vasorelaxant effects of mercury on rat thoracic aorta: the nitric oxide signaling mechanism. AB - Mercury, a heavy metal, is widespread and persistent in the environment and has been elucidated as a possible risk factor in cardiovascular diseases. Mercury has been reported to selectively impair the nitric oxide (NO) pathway in the vascular endothelium as a consequence of oxidative stress. Conversely, mercury per se causes endothelium-dependent vasorelaxation at lower concentration via the NO pathway. Little is known about the effects of mercury per se on other endothelial mediators. To elucidate possible mechanisms involved in this action, isometric tension was measured in aortic rings precontracted with phenylephrine (10 uM) from Wistar rats. Responses to increasing concentrations of inorganic mercuric chloride (10(-12)-10(-5) M) were obtained in the presence and absence of endothelium. Inorganic mercury produced a biphasic response in endothelium-intact aortic rings and produced only vasoconstriction in endothelium-denuded aortic rings. To study the possible underlying mechanisms for the biphasic response of mercury, increasing concentrations of mercuric chloride (10(-12)-10(-5) M) were used before and after N(G)-nitro-L-arginine methyl ester (L-NAME (10(-4) M)), glybenclamide (10(-5) M), superoxide dismutase (10 U/ml) + catalase (100 U/ml), and nifedipine (10(-4) M) treatment. Results suggest that mercury produces endothelium-dependent relaxation at low concentration mediated by endothelial generated NO and endothelium-derived hyperpolarizing factor and endothelium independent contraction resulting from the blockade of L-type Ca(2+) channels by generation of free radicals. PMID- 24347301 TI - Mitochondrial dysfunction and respiratory chain defects in a rodent model of methotrexate-induced enteritis. AB - The efficacy of methotrexate (MTX), a widely used chemotherapeutic drug, is limited by its gastrointestinal toxicity and the mechanism of which is not clear. The present study investigates the possible role of mitochondrial damage in MTX induced enteritis. Small intestinal injury was induced in Wistar rats by the administration of 7 mg kg(-1) body wt. MTX intraperitoneally for 3 consecutive days. MTX administration resulted in severe small intestinal injury and extensive damage to enterocyte mitochondria. Respiratory control ratio, the single most useful and reliable test of mitochondrial function, and 3-(4,5-dimethylthiazol-2 yll)-2,5-diphenyltetrazolium bromide reduction, a measure of cell viability were significantly reduced in all the fractions of MTX-treated rat enterocytes. A massive decrease (nearly 70%) in the activities of complexes II and IV was also observed. The results of the present study suggest that MTX-induced damage to enterocyte mitochondria may play a critical role in enteritis. MTX-induced alteration in mitochondrial structure may cause its dysfunction and decreases the activities of the electron chain complexes. MTX-induced mitochondrial damage can result in reduced adenosine triphosphate synthesis, thereby interfering with nutrient absorption and enterocyte renewal. This derangement may contribute to malabsorption of nutrients, diarrhea, and weight loss seen in patients on MTX chemotherapy. PMID- 24347302 TI - Modulatory effects of L-carnitine on tamoxifen toxicity and oncolytic activity: in vivo study. AB - The aim of this study was to investigate the protective effect of L-carnitine (L CAR) in tamoxifen (TAM)-induced toxicity and antitumor activity. Adult female rats were randomly divided into four groups. Group I was served as control, groups II and III were treated with TAM (10 mg/kg, periorally) and L-CAR (300 mg/kg, intraperitoneally), respectively, while group IV was treated with both compounds. The treatment continued daily for 28 days. Administration of TAM resulted in significant increase in serum lipid profiles, liver enzymes, and bilirubin level. TAM produced a significant increase in lipid peroxides (LPO) level and nonsignificant change in nitrogen oxide (NO(x)) level accompanied with significant decrease in superoxide dismutase (SOD) activity of hepatic and uterus tissues and significant decrease in glutathione (GSH) content of uterus tissue. Administration of L-CAR for 1 h prior to TAM treatment decreased serum lipids and liver enzymes significantly and significantly increased SOD activity in liver and uterus tissues compared with TAM-treated group. Furthermore, it restored LPO and GSH levels and increased NO(x) level in uterus tissue. DNA fragmentation and the apoptotic marker, caspase-3, were not detected in the liver of all treated groups. Histopathologically, alterations in the liver and uterus structures after TAM treatment, which was attenuated after L-CAR administration. The antitumor effect and survival of the combined treatment of Ehrlich ascites carcinoma (EAC) bearing mice was less than each one alone. L-CAR interestingly increased survival rate of EAC-bearing mice more than TAM-treated group. In conclusion, L-CAR has beneficial effects regarding TAM toxicity; however, it interferes with its antitumor effect. PMID- 24347303 TI - The HBM domain: introducing bimodularity to bacterial sensing. AB - We have recently reported the three dimensional structure of the McpS chemoreceptor sensor domain in complex with its cognate ligands. The domain was characterized by a bimodular architecture, where ligand binding to each module caused a chemotactic response. This is a novel small molecule binding domain, which, however, is un-annotated in relevant databases. We report here the domain signature of the family of McpS-like sensor domains, which was termed helical bimodular (HBM) domain. The HBM domain was identified in Bacteria and Archaea and forms part of chemoreceptors and histidine kinases. The conservation of amino acids in the ligand binding sites of both modules suggests that HBM family members recognize similar ligands. PMID- 24347304 TI - [Public health services origins from the Nazi past]. PMID- 24347306 TI - Investigating the quantitative fidelity of prospectively undersampled chemical shift imaging in muscular dystrophy with compressed sensing and parallel imaging reconstruction. AB - PURPOSE: Fat fraction measurement in muscular dystrophy has an important role to play in future therapy trials. Undersampled data acquisition reconstructed by combined compressed sensing and parallel imaging (CS-PI) can potentially reduce trial cost and improve compliance. These benefits are only gained from prospectively undersampled acquisitions. METHODS: Eight patients with Becker muscular dystrophy were recruited and prospectively undersampled data at ratios of 3.65*, 4.94*, and 6.42* were acquired in addition to fully sampled data: equivalent coherent undersamplings were acquired for reconstruction with parallel imaging alone (PI). Fat fraction maps and maps of total signal were created using a combined compressed sensing/parallel imaging (CS-PI) reconstruction. RESULTS: The CS-PI reconstructions are of sufficient quality to allow muscle delineation at 3.65* and 4.94* undersampling but some muscles were obscured at 6.42*. When plotted against the fat fractions derived from fully sampled data, non significant bias and 95% limits of agreement of 1.58%, 2.17% and 2.41% were found for the three CS-PI reconstructions, while a 3.36* PI reconstruction yields 2.78%, 1.8 times worse than the equivalent CS-PI reconstruction. CONCLUSION: Prospective undersampling and CS-PI reconstruction of muscle fat fraction mapping can be used to accelerate muscle fat fraction measurement in muscular dystrophy. PMID- 24347307 TI - Raising-flap technique for outflow reconstruction in living donor liver transplantation. PMID- 24347308 TI - Outcomes of the Evidence-Based Pitocin Administration Checklist at a Tertiary Level Hospital. AB - Pitocin, a synthetic form of the hormone oxytocin, is a high-alert medication that heightens patient harm when used incorrectly. This investigation examined the outcomes of an evidence-based Pitocin administration checklist used for labor augmentation at a tertiary-level hospital. Data came from patient records. Using the Perinatal Trigger Tool, N = 372 clinical records (n = 194 prior to and n = 178 following checklist implementation) were reviewed. Checklist implementation resulted in statistically significant reductions in the duration of hospitalization (1.72 vs. 2.02 days, p = .0005), presence of meconium (23.7% vs. 6.7%, p < .001), maternal fevers (7.2% vs. 2.3%, p = .030), and episiotomies (8.8% vs. 1.7%, p = .002), and clinically important reduction in APGAR scores < 7 at 5 min (3.6%-0.6%, p = .069) and instrumented deliveries (11.9%-8.4%, p = .307). A universal Pitocin checklist implementation can improve birth outcomes and costs of care. PMID- 24347309 TI - Identification of the PKR nuclear interactome reveals roles in ribosome biogenesis, mRNA processing and cell division. AB - The double-strand RNA-dependent protein kinase, PKR, plays a central role in inflammatory/chronic stress-mediated pathologies such as cancer, diabetes, and neuro/muscular degenerative diseases. Although a significant amount of research has been conducted to elucidate the role of PKR signaling in the cytosol, only recently has attention been paid to the role of PKR in the nuclear compartment. Previously our group reported that phosphorylated forms of PKR are present in the nucleus of acute leukemic cell lines, representing a reservoir of active kinase that responds to stress. Using the CCRF-CEM acute T-cell leukemia cell line, a PKR-specific inhibitor, co-immunoprecipitation and a proteomics approach, which included affinity purified mass spectrometry analysis (AP/MS), we identified the proteins present in active and inactive PKR nuclear complexes. Of the proteins identified in the PKR complexes, sixty-nine (69) were specific to the active complex, while thirty-eight (38) were specific to the inactive complex. An additional thirteen (13) proteins associated specifically with both complexes. The majority of the proteins identified are involved in, ribosome biogenesis, RNA splicing, mRNA stability, gene expression, cell cycle, or chromatin organization, including several with known significance to normal hematopoiesis and/or hematological disease. In agreement with the AP/MS data, basal- or over expression of PKR under normal growth conditions favored cell proliferation in the tested cell lines, whereas pharmacological inhibition of PKR or shRNA mediated knock-down did not. PKR was also found to influence the isoform and the level of expression of the proto-oncogene MYC. PMID- 24347311 TI - Sternocleidomastoid muscle additionally innervated by the facial nerve: case report and review of the literature. AB - An aberrant nerve branch from the facial nerve, additionally to the accessory nerve and cervical rami C2 and C3, was observed innervating the sternocleidomastoid (SCM) muscle in a 75-year-old male cadaver. We consider that the anomaly occurred as the result of a fusion of the muscular compartment from the digastric and SCM muscles during development. The aberrant innervation may be the source of the misinterpretation of electromyographic findings. PMID- 24347310 TI - Changes in MR relaxation times of the meniscus with acute loading: an in vivo pilot study in knee osteoarthritis. AB - PURPOSE: To prospectively evaluate changes in T1rho and T2 relaxation times in the meniscal body with acute loading using MRI in osteoarthritic knees and to compare these findings with those of age-matched healthy controls. MATERIALS AND METHODS: Female subjects above 40 years of age with (N1 = 20) and without osteoarthritis (OA) (N2 = 10) were imaged on a 3 Tesla MR scanner using a custom made loading device. MR images were acquired, with the knee flexed at 20 degrees , with and without a compressive load of 50% of the subject's bodyweight. The subjects were categorized based on the radiographic evidence of OA. Three different zones (outer, middle, and inner) of meniscus body were defined (each occupying 1/3rd the width). After adjusting for age and body mass index in the general linear regression model, repeated measures analysis of variance was used to detect significant differences in T1rho and T2 with and without loading. RESULTS: In the unloaded condition, the average T1rho and T2 times were elevated in the outer and middle zones of the medial meniscus in OA subjects compared with the controls. In the loaded condition, T1rho and T2 times of the outer zone of the medial meniscus was significantly elevated in OA subjects compared with controls. Finally the change (from unloaded to loaded) was significantly higher in controls than OA subjects (15.1% versus 8.3%; P = 0.039 for DeltaT1rho , and 11.5% versus 6.9%, P = 0.049 for DeltaT2 ). CONCLUSION: These findings suggest that while the OA process appears to affect the relaxation times of all regions within the meniscus, it may affect some regions sooner or to a greater degree. Furthermore, the differences in the change in relaxation times between unloaded and loaded conditions may reveal evidence about load transmission failure of the outer zone of the medial meniscus in subjects with knee OA. It is possible that these metrics (DeltaT1rho and DeltaT2 ) may be valuable as an early biomechanical biomarker, which could be used to predict load transmission to the underlying articular cartilage. PMID- 24347312 TI - Single-incision laparoscopic common bile duct exploration with conventional instruments: an innovative technique and a comparative study. AB - BACKGROUND: Single-incision laparoscopic surgery developed rapidly in recent years. We introduce an innovative technique: single-incision laparoscopic common bile duct exploration (SILCBDE) with conventional instruments. A retrospective comparison between SILCBDE and standard laparoscopic common bile duct exploration (LCBDE) was analyzed. METHODS: Thirty-four patients who underwent LCBDE for choledocholithiasis in a period of 17 months were enrolled. Seventeen standard LCBDEs and 17 SILCBDEs were attempted. Simultaneous cholecystectomies were performed. RESULTS: The stone clearance rate was 94.1% (16 patients) in the standard LCBDE group and 100% in the SILCBDE group. There was no statistical difference in demographic distribution, clinical presentations, and operative results between the two groups, except the SILCBDE group had a higher rate of acute cholecystitis than the standard LCBDE group (76.5 vs. 35.3%; p < 0.05). One procedure (5.9%) in the SILCBDE group was converted to a four-incision transcystic LCBDE. The complication rate was 11.8% (two patients) in the standard LCBDE group and 5.9% (one patient) in the SILCBDE group. The average follow-up period was 4.2 months. CONCLUSION: SILCBDE is as safe and efficacious as standard LCBDE in experienced hands. Choledochoscope manipulation and bile duct repair are the key skills. Long-term follow-up and further prospective randomized trials are anticipated. PMID- 24347313 TI - Optimal management of the splenic vein at the time of venous resection for pancreatic cancer: importance of the inferior mesenteric vein. AB - BACKGROUND: Resection of the superior mesenteric vein (SMV)-portal vein (PV) splenic vein (SV) confluence during pancreatectomy for pancreatic cancer requires management of the SV. DISCUSSION: Simple SV ligation can result in sinistral portal hypertension if the inferior mesenteric vein (IMV) enters the confluence and is thereby resected, or if the IMV is insufficient to drain the SV. We describe herein three patients whose clinical course confirms the importance of the IMV decompressing the SV to avoid sinistral hypertension. PMID- 24347314 TI - Extraduodenal papillectomy: a feasible alternative method of total papillectomy. AB - Rational treatment for neoplasms of the duodenal papilla (NDPs) is still controversial, especially for early stage lesions. Total papillectomies are indicated in patients expected to have adenomas, adenocarcinoma in an adenoma, or mucosal adenocarcinomas with no lymph node metastases. However, the preoperative pathological evaluation of NDPs is still challenging and often inaccurate, mainly because of the complicated anatomical structures involved and the possibility of an adenocarcinoma in an adenoma. Herein, we introduce a new method of total papillectomy, the extraduodenal papillectomy (ExDP). In this method, papillectomy is undertaken from outside of the duodenum, instead of resection from the inside through a wide incision of the duodenal wall as is done in conventional transduodenal papillectomy (TDP). The advantages of ExDP are precise and deeper cutting of the sphincter and shorter exploration time of the tumor compared to conventional TDP. We demonstrate three representative patients, all of whom had an uneventful postoperative course. One of them subsequently underwent a pylorus preserving pancreatoduodenectomy after detailed postoperative pathological evaluation. Including that patient, no recurrence has occurred with 37-46 months of follow-up. In conclusion, ExDP is regarded as a "total biopsy" for early stage borderline lesions and a feasible, less demanding alternative method for the treatment of NDPs. PMID- 24347315 TI - Azurophilic granules in myeloma cells. PMID- 24347316 TI - Antihypertensive treatment and risk of atrial fibrillation: a nationwide study. AB - AIMS: To examine the associations between antihypertensive treatment with angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs), beta-blockers, diuretics, or calcium-antagonists, and risk of atrial fibrillation. We examined these associations using the entire Danish population from 1995 through 2010. METHODS AND RESULTS: Excluding medication used in atrial fibrillation, we matched individuals on ACEi monotherapy 1:1 with individuals on beta-blocker (n = 48 658), diuretic (n = 69 630), calcium-antagonist (n = 57 646), and ARB monotherapy (n = 20 158). Likewise, individuals on ARB monotherapy were matched 1:1 with individuals on beta-blocker (n = 20 566), diuretic (n = 20 832), calcium-antagonist (n = 20 232), and ACEi monotherapy (n = 20 158). All were free of atrial fibrillation and of predisposing diseases like heart failure, ischaemic heart disease, diabetes mellitus, and hyperthyroidism at baseline and none received any other antihypertensive medication. We studied risk of atrial fibrillation, and used risk of stroke, influenced by lowering blood pressure rather than renin-angiotensin system blockade per se, as an indicator of the importance of blood pressure lowering per se. Hazard ratios of atrial fibrillation for ACEi and ARB monotherapy were 0.12 (95% CI: 0.10-0.15) and 0.10 (0.07-0.14) compared with beta-blocker, 0.51 (0.44-0.59) and 0.43 (0.32-0.58) compared with diuretic, and 0.97 (0.81-1.16) and 0.78 (0.56-1.08) compared with calcium-antagonist monotherapy. Risk of stroke did not differ among the five antihypertensive medications. CONCLUSION: Use of ACEis and ARBs compared with beta-blockers and diuretics associates with a reduced risk of atrial fibrillation, but not stroke, within the limitations of a retrospective study reporting associations. This suggests that controlling activation of the renin angiotensin system in addition to controlling blood pressure is associated with a reduced risk of atrial fibrillation. PMID- 24347318 TI - The grey zone of truth. PMID- 24347317 TI - Complications after cardiac implantable electronic device implantations: an analysis of a complete, nationwide cohort in Denmark. AB - AIMS: Complications after cardiac implantable electronic device (CIED) treatment, including permanent pacemakers (PMs), cardiac resynchronization therapy devices with defibrillators (CRT-Ds) or without (CRT-Ps), and implantable cardioverter defibrillators (ICDs), are associated with increased patient morbidity, healthcare costs, and possibly increased mortality. METHODS AND RESULTS: Population-based cohort study in all Danish patients who underwent a CIED procedure from May 2010 to April 2011. Data on complications were gathered on review of all patient charts while baseline data were obtained from the Danish Pacemaker and ICD Register. Adjusted risk ratios (aRRs) with 95% confidence intervals were estimated using binary regression. The study population consisted of 5918 consecutive patients. A total of 562 patients (9.5%) experienced at least one complication. The risk of any complication was higher if the patient was a female (aRR 1.3; 1.1-1.6), underweight (aRR 1.5; 1.1-2.3), implanted in a centre with an annual volume <750 procedures (0-249 procedures: aRR 1.6; 1.1-2.2, 250 499: aRR 2.0; 1.6-2.7, 500-749: aRR 1.5; 1.2-1.8), received a dual-chamber ICD (aRR 2.0; 1.4-2.7) or CRT-D (aRR 2.6; 1.9-3.4), underwent system upgrade or lead revision (aRR 1.3; 1.0-1.7), had an operator with an annual volume <50 procedures (aRR 1.9; 1.4-2.6), or underwent an emergency, out-of-hours procedure (aRR 1.5; 1.0-2.3). CONCLUSION: CIED complications are more frequent than generally acknowledged. Both patient- and procedure-related predictors may identify patients with a particularly high risk of complications. This information should be taken into account both in individual patient treatment and in the planning of future organization of CIED treatment. PMID- 24347319 TI - Excluding a giant coronary aneurysm by implantation of a covered stent. PMID- 24347320 TI - Determination of nitrophenolic compounds from atmospheric particles using hollow fiber liquid-phase microextraction and capillary electrophoresis/mass spectrometry analysis. AB - A hollow-fiber liquid-phase microextraction method was developed to enrich nine nitrophenolic compounds from aqueous extracts of atmospheric aerosol particles. Analysis was performed by CE coupled with ESI MS. The BGE composition was optimized to a 20 mM ammonium acetate buffer at pH 9.7 containing 15% methanol v/v. Several extraction parameters (composition of organic liquid membrane, pH of acceptor phase, salting-out effect, extraction time) were investigated for their effect on the analyte recoveries. The donor phase consisted of a 1.8 mL sample solution kept at pH 2 while the acceptor phase was a 15 MUL 100 mM aqueous ammonia solution. Dihexyl ether served as supported liquid membrane. Low detection limits in the range of nanomole per liter were achieved. Recoveries of aqueous standard solutions were found to be between 11 and 90% with enrichment factors between 10 and 100. Interday and intraday repeatabilities were in an acceptable range for most compounds (6-15% and 7-10%, respectively) but somewhat higher for 4-nitrocatechol (59 and 48%) and 2-nitrophenol (17 and 35%). The developed method was found to be competitive with more established method and was successfully applied to samples of atmospheric particulate matter from field experiments. PMID- 24347321 TI - Porous graphene materials for advanced electrochemical energy storage and conversion devices. AB - Combining the advantages from both porous materials and graphene, porous graphene materials have attracted vast interests due to their large surface areas, unique porous structures, diversified compositions and excellent electronic conductivity. These unordinary features enable porous graphene materials to serve as key components in high-performance electrochemical energy storage and conversion devices such as lithium ion batteries, supercapacitors, and fuel cells. This progress report summarizes the typical fabrication methods for porous graphene materials with micro-, meso-, and macro-porous structures. The structure property relationships of these materials and their application in advanced electrochemical devices are also discussed. PMID- 24347322 TI - IGF-1 intranasal administration rescues Huntington's disease phenotypes in YAC128 mice. AB - Huntington's disease (HD) is an autosomal dominant disease caused by an expansion of CAG repeats in the gene encoding for huntingtin. Brain metabolic dysfunction and altered Akt signaling pathways have been associated with disease progression. Nevertheless, conflicting results persist regarding the role of insulin-like growth factor-1 (IGF-1)/Akt pathway in HD. While high plasma levels of IGF-1 correlated with cognitive decline in HD patients, other data showed protective effects of IGF-1 in HD striatal neurons and R6/2 mice. Thus, in the present study, we investigated motor phenotype, peripheral and central metabolic profile, and striatal and cortical signaling pathways in YAC128 mice subjected to intranasal administration of recombinant human IGF-1 (rhIGF-1) for 2 weeks, in order to promote IGF-1 delivery to the brain. We show that IGF-1 supplementation enhances IGF-1 cortical levels and improves motor activity and both peripheral and central metabolic abnormalities in YAC128 mice. Moreover, decreased Akt activation in HD mice brain was ameliorated following IGF-1 administration. Upregulation of Akt following rhIGF-1 treatment occurred concomitantly with increased phosphorylation of mutant huntingtin on Ser421. These data suggest that intranasal administration of rhIGF-1 ameliorates HD-associated glucose metabolic brain abnormalities and mice phenotype. PMID- 24347324 TI - Effect of erythromycin-doped calcium polyphosphate scaffold composite in a mouse pouch infection model. AB - We previously showed that strontium-doped calcium polyphosphate (SCPP) scaffold with poly(vinyl alcohol) (PVA) coating extended the impregnated erythromycin (EM) release. In this study, we examined the bactericidal effect of EM-doped SCPP (SCPP(EM) ) scaffolds with PVA coating in a Staphylococcus aureus (S. aureus) infected mouse pouch. SCPP scaffolds with or without 5% EM, and SCPP(EM) scaffolds coated with PVA (with or without 5% EM) were prepared. Scaffolds were implanted in the pouch of BALB/c mice, followed by inoculation of 1 * 10(3) colony-forming units of S. aureus. Mice were sacrificed 14 days after surgery. Pouch tissues and scaffolds were collected for histology, scanning electron microscopy, and microbiological analysis. In the absence of SCPP scaffolds, the pouch infection was eliminated by the host immune surveillance. In the presence of SCPP scaffolds, both the pouch tissues and scaffolds were infected, but SCPP(EM) scaffolds successfully inhibited bacterial growth. Although PVA coating of SCPP(EM) scaffolds enhanced bacterial growth, incorporation of EM into PVA coating inhibited growth. In conclusion, BALB/c mice were capable of eradicating a low grade S. aureus infection. SCPP protected S. aureus growth from host immune surveillance. Though PVA coating sustained EM release in vitro, it was unable to inhibit bacterial growth because PVA gel matrix provided a temporary shelter for bacteria to grow and slowed the EM release from SCPP scaffold. To guarantee a sufficient inhibition of bacterial growth at the initial stage, embedding EM or other antibiotics in the PVA coating is also essential. PMID- 24347325 TI - Endocrine disruptors differently influence estrogen receptor beta and androgen receptor in male and female rat VSMC. AB - Sex steroid hormones differently control the major physiological processes in male and female organisms. In particular, their effects on vascular smooth muscle cells (VSMCs) migration are at the root of sex/gender-related differences reported in the cardiovascular system. Several exogenous substances, defined endocrine disruptor chemicals (EDCs), could interfere with these androgen and estrogen effects; however, the sex/gender-related susceptibility of VSMC motility to EDCs is completely unknown. Here, the effect of naturally occurring (naringenin, Nar) and synthetic (bisphenol A, BPA) EDCs on male and female VSMC motility has been evaluated. 17beta-estradiol (E2, 0.1 nM-1 uM) induced a dose dependent inhibition of motility in female-derived VSMC. In contrast, neither dihydrotestosterone (DHT, 0.01-100 nM) nor the common precursor of sex steroid hormones, testosterone (Tes, 0.01-100 nM) modified male-derived VSMC motility. Estrogen receptor (ER) beta subtype-dependent activation of p38 was necessary for the E2 effect on cell motility. High BPA concentration prevented E2 effects in female-derived cells being without any effect in male-derived cells. Nar mimicked E2 effects on female-derived cells even in the presence of E2 or BPA. Intriguingly, Nar also inhibited the male-derived VSMC mobility. This latter effect was prevented by ERbeta inhibitor, but not by the androgen receptor (AR) inhibitor. As a whole, ERbeta-dependent signals in VSMC results more susceptible to the impact of EDCs than AR signals suggesting a possible high and overall susceptibility of female to EDCs. However, several male-derived cells, including VSMC, express ERbeta, which could also serve as target of EDC disruption in male organisms. PMID- 24347327 TI - Four dimensional spectral-spatial fat saturation pulse design. AB - PURPOSE: The conventional spectrally selective fat saturation pulse may perform poorly with inhomogeneous amplitude of static (polarizing) field (B0 ) and/or amplitude of (excitation) radiofrequency field (B1 ) fields. We propose a four dimensional spectral-spatial fat saturation pulse that is more robust to B0/B1 inhomogeneity and also shorter than the conventional fat saturation pulse. THEORY: The proposed pulse is tailored for local B0 inhomogeneity, which avoids the need of a sharp transition band in the spectral domain, so it improves both performance and pulse length. Furthermore, it can also compensate for B1 inhomogeneity. The pulse is designed sequentially by small-tip-angle approximation design and an automatic rescaling procedure. METHODS: The proposed method is compared to the conventional fat saturation in phantom experiments and in vivo knee imaging at 3 T for both single-channel and parallel excitation versions. RESULTS: Compared to the conventional method, the proposed method produces superior fat suppression in the presence of B0 and B1 inhomogeneity and reduces pulse length by up to half of the standard length. CONCLUSION: The proposed four dimensional spectral-spatial fat saturation suppresses fat more robustly with shorter pulse length than the conventional fat saturation in the presence of B0 and B1 inhomogeneity. PMID- 24347328 TI - Macrocyclic polyoxazoles as G-quadruplex ligands. AB - This review deals with recent progress in the synthesis and evaluation of our telomestatin-inspired macrocyclic polyoxazoles as G-quadruplex (G4) ligands. The hexaoxazole derivatives (6OTDs) interact with and stabilize G4-forming oligonucleotides, depending upon the character of the side chain functional groups. Cationic functional groups are particularly effective due to their secondary interaction with phosphate in the DNA backbone. On the other hand, heptaoxazole derivatives (7OTDs) showed potent G4-binding and stabilization activity regardless of the functional groups on the side chain. A caged G4 ligand, Y2Nv2-6OTD (7), and a fluorescent G4 ligand, L1BOD-7OTD (13), have been synthesized. PMID- 24347333 TI - Comparing various surgical delay methods with ischemic preconditioning in the rat TRAM flap model. AB - Both surgical delay and ischemic preconditioning (IP) have been shown to be effective in improving the survival of flaps. We used a variety of flap delay methods and IP to increase the surviving area of the transverse rectus abdominis musculocutaneous (TRAM) flap in rats, and the results are compared in between. A 6-* 3-cm-sized TRAM flap in 40 Wistar rats was allocated into five groups. Group 1: TRAM flap was elevated from nondominant pedicle, and the flap was sutured to the original bed. Group 2: Left superior deep epigastric vessels (SDEV) were cut; 1 week later, TRAM flap was elevated. Group 3: Only skin incision was done; 1 week later, TRAM flap was elevated. Group 4: Skin incision was done, and the left SDEV were cut; 1 week later, TRAM flap was elevated. Group 5: TRAM flap was elevated; IP was performed using three cycles of 10 minutes of repeated ischemia/reperfusion (I/R) periods, and the flap was sutured to the original bed. The surviving area of the flap was statistically significant between the control and groups 2, 4, and 5 (p < 0.001), and groups 4 and 2 were superior to group 5. Although preconditioning has been intensively studied for the last two decades and partly provided its beneficial effects in I/R injury, we determined the IP increased the surviving area of the TRAM flap but not effective as much as surgical delay method. PMID- 24347326 TI - Crystal structures of the fungal pathogen Aspergillus fumigatus protein farnesyltransferase complexed with substrates and inhibitors reveal features for antifungal drug design. AB - Species of the fungal genus Aspergillus are significant human and agricultural pathogens that are often refractory to existing antifungal treatments. Protein farnesyltransferase (FTase), a critical enzyme in eukaryotes, is an attractive potential target for antifungal drug discovery. We report high-resolution structures of A. fumigatus FTase (AfFTase) in complex with substrates and inhibitors. Comparison of structures with farnesyldiphosphate (FPP) bound in the absence or presence of peptide substrate, corresponding to successive steps in ordered substrate binding, revealed that the second substrate-binding step is accompanied by motions of a loop in the catalytic site. Re-examination of other FTase structures showed that this motion is conserved. The substrate- and product binding clefts in the AfFTase active site are wider than in human FTase (hFTase). Widening is a consequence of small shifts in the alpha-helices that comprise the majority of the FTase structure, which in turn arise from sequence variation in the hydrophobic core of the protein. These structural effects are key features that distinguish fungal FTases from hFTase. Their variation results in differences in steady-state enzyme kinetics and inhibitor interactions and presents opportunities for developing selective anti-fungal drugs by exploiting size differences in the active sites. We illustrate the latter by comparing the interaction of ED5 and Tipifarnib with hFTase and AfFTase. In AfFTase, the wider groove enables ED5 to bind in the presence of FPP, whereas in hFTase it binds only in the absence of substrate. Tipifarnib binds similarly to both enzymes but makes less extensive contacts in AfFTase with consequently weaker binding. PMID- 24347334 TI - Psychological and social consequences after reconstruction of upper extremity trauma: methods of detection and management. AB - Upper extremity trauma and resulting disability is a stressful event and can affect a patient's personality. Several studies have shown that this injury type has serious psychological and/or social consequences. We systematically reviewed the evidence on the consequences of disability after a complex trauma (combination of soft tissue, osseous, vascular, and nerve involvement) of the upper extremity. We tried to find out the potential crucial factors that could determine the final hand function. In addition, we considered the challenges that need to be addressed to eliminate the adverse or negative effects that arise from upper limb trauma. In the literature, there is a growing interest to study changes in patients' quality of life and return to work. Psychological morbidity is an important part of patients' perceived general health. These issues could play an important role in the final functional outcome of the therapy. An early identification and treatment of trauma-related distress in patients may prevent progression of psychological pathology and mitigate negative effects on general health status. It may be important to evaluate the amount of psychological distress when caring for patients with hand injuries. PMID- 24347336 TI - Can team-based medicine prescribe trust? PMID- 24347335 TI - Differential labour market impacts from disability onset. AB - We estimate the causal labour market impacts of disability onset by gender, age and education levels up to 4 years after onset using longitudinal data from the Household Income and Labour Dynamics Australia survey and difference-in difference propensity score matching techniques. We find lasting negative impacts on employment, especially full-time employment, which is due more to reduced movement into full-time employment than downshifting from full-time to part-time work following onset. Those without post-school education qualifications are particularly vulnerable to the impacts of onset and are more likely to be out of work and on income support than those with qualifications up to 4 years after onset, due in part because they have greater difficulty adjusting. PMID- 24347337 TI - Myocarditis with hypotonic-hyporesponsive episode after multiple vaccination. PMID- 24347338 TI - Vermiform appendix inside the sac: uncommon case of inguinal hernia. PMID- 24347339 TI - Blue rubber bleb nevus syndrome. PMID- 24347340 TI - Silk-molded flexible, ultrasensitive, and highly stable electronic skin for monitoring human physiological signals. AB - Flexible and transparent E-skin devices are achieved by combining silk-molded micro-patterned polydimethylsiloxane (PDMS) with single-walled carbon nanotube (SWNT) ultrathin films. The E-skin sensing device demonstrates superior sensitivity, a very low detectable pressure limit, a fast response time, and a high stability for the detection of superslight pressures, which may broaden their potential use as cost-effective wearable electronics for healthcare applications. PMID- 24347341 TI - Structure of the female gonoduct of the viviparous teleost Poecilia reticulata (Poeciliidae) during nongestation and gestation stages. AB - Female teleosts do not have oviducts because Mullerian ducts do not develop. Instead, the caudal region of the ovary, the gonoduct, connects to the exterior. Because of the lack of oviducts in viviparous teleosts, the embryos develop in the ovary, as an intraovarian gestation, unique in vertebrates. This is the first study to address the histology of the gonoduct in a viviparous teleost. The gonoduct of Poecilia reticulata was analyzed during previtellogenesis, vitellogenesis, and gestation. The gonoduct lacks germinal cells. From deep to superficial, the wall has simple cuboidal or columnar epithelium, loose connective tissue, longitudinal layer of smooth muscle, and visceral peritoneum. Cells of the immune system occur in the lumen and in the mucosa. The gonoduct was divided in three regions: 1) cephalic, 2) middle, and 3) caudal. At the initial part of each region, thin mucosal folds extend into the lumen. The cephalic region forms a tubular structure with light and irregular folds. The middle region has a wider lumen and is more irregular due to ventral invaginations and irregular and short mucosal folds; beneath the epithelium there are melano macrophage centers. The caudal region is delimited from the middle region by folds; however, they are thinner than these of the other regions. Ventral invaginations form exocrine glands, and the smooth muscle is thicker than in the other regions. During gestation, cells of the immune system are abundant; melano macrophage centers become larger and the glands exhibit desquamated cells. These observations suggest roles of the gonoduct in reducing the diameter of the lumen; receiving sperm during vitellogenesis; producing secretions, more abundant during vitellogenesis; and in immunological activity throughout the reproductive cycle. The ciliated epithelium and the thick muscle of the caudal region may be involved during birth. PMID- 24347343 TI - Taurine-induced fabrication of nano-architectured conducting polypyrrole on biomedical titanium. AB - In this article, taurine, one of the small biomolecules associated with bone metabolism, is firstly utilized to induce the fabrication of nano-architectured conducting polypyrrole (NCPPy) on biomedical titanium in diverse pH values of phosphate buffer solution (PBS). Accordingly, the possible mechanism for the fabrication of NCPPy is proposed, which is dependent on the states of polytaurine from the polymerization of taurine, i.e., the inability of forming polytaurine and unordered restricted space results in taurine-incorporated and polytaurine incorporated tightly packed nanoparticles (pH 6.2 and 8.0), respectively, and however, ordered restricted space constructed by polytaurine chains induces the fabrication of polytaurine-incorporated nanopillars (pH 6.8) and polytaurine incorporated nanowire networks (pH 7.4). PMID- 24347342 TI - Prohibitins role in cellular survival through Ras-Raf-MEK-ERK pathway. AB - Prohibitins are members of a highly conserved protein family containing the stomatin/prohibitin/flotillin/HflK/C (SPFH) domain (also known as the prohibitin [PHB] domain) found in unicellular eukaryotes, fungi, plants, animals, and humans. Two highly homologous members of prohibitins expressed in eukaryotes are prohibitin (PHB; B-cell receptor associated protein-32, BAP-32) and prohibitin 2/repressor of estrogen receptor activity (PHB2, REA, BAP-37). Both PHB and REA/PHB2 are ubiquitously expressed and are present in multiple cellular compartments including the mitochondria, nucleus, and the plasma membrane. Multiple functions have been attributed to the mitochondrial and nuclear PHB and PHB2/REA including cellular differentiation, anti-proliferation, and morphogenesis. One of the major functions of the prohibitins are in maintaining the functional integrity of the mitochondria and protecting cells from various stresses. In the present review, we focus on the recent research developments indicating that PHB and PHB2/REA are involved in maintaining cellular survival through the Ras-Raf-MEK-Erk pathway. Understanding the molecular mechanisms by which the intracellular signaling pathways utilize prohibitins in governing cellular survival is likely to result in development of therapeutic strategies to overcome various human pathological disorders such as diabetes, obesity, neurological diseases, inflammatory bowel disease, and cancer. PMID- 24347344 TI - Short sleep duration is associated with decreased serum leptin, increased energy intake and decreased diet quality in postmenopausal women. AB - OBJECTIVE: Short sleep duration induces hormonal perturbations contributing to hyperphagia, insulin resistance, and obesity. The majority of these studies are conducted in young adults. This analysis in a large (n = 769) sample of postmenopausal women (median age 63 years) sought to (a) confirm that sleep duration and sleep quality are negatively correlated with circulating leptin concentrations and (b) to examine the relationship between self-reported sleep, dietary energy intake, and diet quality, as well as, investigate the role of leptin in these associations. METHODS: Sleep duration/quality, insomnia, and dietary intake were determined via self-report. Blood samples were collected following an overnight fast to assess serum leptin concentration. All analyses were adjusted for total body fat mass. RESULTS: Women reporting <=6 hr sleep/night had lower serum leptin concentrations than those reporting >=8 hr sleep (P = 0.04). Furthermore, those with <=6 hr sleep/night reported higher dietary energy intake (P = 0.01) and lower diet quality (P = 0.04) than the reference group (7 hr sleep/night). Women sleeping >=8 hr also reported lower diet quality than the reference group (P = 0.02). Importantly, serum leptin did not confound these associations. CONCLUSIONS: These results provide evidence that sleep duration is inversely associated with serum leptin and dietary energy intake in postmenopausal women. PMID- 24347345 TI - Hydroxytyrosol attenuates tunicamycin-induced endoplasmic reticulum stress in human hepatocarcinoma cells. AB - SCOPE: Hydroxytyrosol (HT) is a phenolic compound peculiarly abundant in olives and it is being recognized as a protector of LDL from oxidation. In addition to lipid oxidation, one emerging risk factor for cardiovascular disease is ER stress. We tested the effect of HT on the modulation of ER stress in HepG2 cells. METHODS AND RESULTS: HepG2 cells were treated with 1 MUM and 5 MUM of HT and 100 MUM lipoic acid (LA) and glutathione-ethyl ester (GSH), for 24 h. Induction of the unfolded protein response (UPR) was initiated by treatment with 2 MUg/mL tunicamycin for 4 h. Real time RT-PCR analyses followed by Western blot and ELISA of different ER stress markers revealed that the protective activities of HT were superior to those of two known thiolic antioxidants, i.e., LA and GSH. CONCLUSION: Mounting evidence indicates the ER as an important target of dietary or pharmacological intervention. In this paper, we report the modulatory activities of physiological concentrations of HT toward ER stress and we shed some light on pathways alternative to the well-known antioxidant mechanisms, through which olive oil phenolics modulate cell signaling and could impact cardiovascular health and degenerative diseases. PMID- 24347346 TI - iHEA student competition 'Young Researchers in Health Economics'. PMID- 24347347 TI - Automatic cardiac LV segmentation in MRI using modified graph cuts with smoothness and interslice constraints. AB - PURPOSE: Magnetic resonance imaging (MRI), specifically late-enhanced MRI, is the standard clinical imaging protocol to assess cardiac viability. Segmentation of myocardial walls is a prerequisite for this assessment. Automatic and robust multisequence segmentation is required to support processing massive quantities of data. METHODS: A generic rule-based framework to automatically segment the left ventricle myocardium is presented here. We use intensity information, and include shape and interslice smoothness constraints, providing robustness to subject- and study-specific changes. Our automatic initialization considers the geometrical and appearance properties of the left ventricle, as well as interslice information. The segmentation algorithm uses a decoupled, modified graph cut approach with control points, providing a good balance between flexibility and robustness. RESULTS: The method was evaluated on late-enhanced MRI images from a 20-patient in-house database, and on cine-MRI images from a 15 patient open access database, both using as reference manually delineated contours. Segmentation agreement, measured using the Dice coefficient, was 0.81+/ 0.05 and 0.92+/-0.04 for late-enhanced MRI and cine-MRI, respectively. The method was also compared favorably to a three-dimensional Active Shape Model approach. CONCLUSION: The experimental validation with two magnetic resonance sequences demonstrates increased accuracy and versatility. PMID- 24347348 TI - Reply to the article Espinos JC, Turro R, Mata A, Cruz M, da Costa M, Villa V, Buchwald JN, Turro J. Early experience with the Incision less Operating PlatformTM (IOP) for the treatment of obesity: the Primary Obesity Surgery Endolumenal (POSE) procedure. Obes Surg. 2013;23:1375-83. PMID- 24347349 TI - Evolution of subclinical hypothyroidism and its relation with glucose and triglycerides levels in morbidly obese patients after undergoing sleeve gastrectomy as bariatric procedure. AB - BACKGROUND: There is an increased prevalence of subclinical hypothyroidism (SCH) in patients with obesity. It is unclear if this biochemical abnormality may be a secondary phenomenon of obesity or a real hypothyroid state. METHODS: A retrospective study of all the morbidly obese patients undergoing laparoscopic sleeve gastrectomy as bariatric procedure between October 2007 and November 2012 was performed. Weight loss, body mass index (BMI) and excess weight loss, baseline glucose, lipid profiles, and TSH levels were obtained before operation and postoperative determinations at 3, 6, and 12 months after surgery. RESULTS: Sixty patients were included. Prevalence of subclinical hypothyroidism was 16.7% preoperatively, 10% at 3 months, 3.3% at 6 months, and 1.7% at 12 months. A significant correlation could be established between TSH decrease and weight loss at 12 months (Pearson 0.603; p = 0.007). TSH decrease showed a significant correlation with glucose and glycated hemoglobin decrease from 6th month onwards. Referring to lipid profile, an association of TSH decrease with total cholesterol, LDL cholesterol, or HDL cholesterol could not be determined. A significant association between TSH decrease and triglycerides and cardiovascular risk index triglycerides/HDL cholesterol reductions could also be established 12 months after surgery. CONCLUSIONS: SCH is usually corrected after bariatric surgery, while there are no significant changes in total or LDL cholesterol. This suggests that, in morbidly obese subjects, SCH is, in most patients, just a consequence of the abnormal fat accumulation and not a real hypothyroid state. PMID- 24347350 TI - Management of anastomotic ulcers after Roux-en-Y gastric bypass: results of an international survey. AB - BACKGROUND: Anastomotic ulcers (AUs) after Roux-en-Y gastric bypass (RYGB) occur in up to 16% of patients. In an international survey among members of the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO), current preventative and therapeutic strategies in AU were analyzed. METHODS: An Internet-based survey was performed. RESULTS: One hundred eighty-nine surgeons completed the survey. Preoperative screening for Helicobacter pylori is performed by 65%. Eighty-eight percent of them prophylactically prescribe antacids for 3 months after surgery (interquartile range (IQR) 1-6). In case of AU, 99% of participants opt for proton pump inhibitors (PPIs) either alone (60%) or in combination with sucralfate (39%). After ulcer resolution, 52% continue PPI for 6 (3-6) months. In case of AU recurrence, 56% continue with conservative treatment. In contrast, 41% of them favor a renewal of the gastrojejunal anastomosis either combined with truncal vagotomy (18%) or with gastric remnant resection (13%), and only 2% choose to resect both gastric pouch and gastric remnant with subsequent reconstruction by esophagojejunostomy. In case of recurrence after surgical revision, 46% of participants opt again for a conservative approach, while 36% chose to redo the gastrojejunostomy once again. CONCLUSIONS: The majority of bariatric surgeons recommend preoperative screening and eradication of H. pylori as well as prophylactic use of PPI. If an AU is diagnosed, the role of PPI as a first-line treatment seems to be undisputed. However, dosage and duration of therapy remain unclear. In refractory AU, there is no consensus among bariatric surgeons whether conservative treatment or surgical revision should be performed. PMID- 24347351 TI - Prophylactic glycopyrrolate reduces hypotensive responses in elderly patients during spinal anesthesia: a randomized controlled trial. AB - BACKGROUND: Hypotension during spinal anesthesia is a serious complication in elderly patients. We evaluated the effect of glycopyrrolate on hypotensive responses in elderly patients undergoing spinal anesthesia. METHODS: Sixty-six patients older than 60 yr of age scheduled for elective surgery with spinal anesthesia were included in the study. They received either glycopyrrolate 0.2 mg (group G) or normal saline (group C) intramuscularly 15 min before spinal anesthesia. The following outcomes were evaluated after the induction of spinal anesthesia: the incidence of hypotension and bradycardia, the ephedrine requirement, mean arterial pressure, heart rate, and the incidence of nausea and vomiting. RESULTS: Twenty-three of 33 (70.0%) patients in group C experienced hypotension compared with nine of 33 (27.3%) patients in group G (difference = 42.7%; 95% confidence interval [CI]: 18.4 to 60.2; P = 0.001). The median [interquartile range] amount of ephedrine required was 5 [0-15] mg in group C compared with 0 [0-5] mg in group G (difference = 5.0 mg; 95% CI: 2.7 to 7.3; P = 0.001). Nine (27.3%) patients in group C experienced nausea and vomiting compared with 2 (6.1%) in group G (difference = 21.2%; 95% CI: 3.0 to 38.7; P = 0.044). Three (9.1%) patients in group C experienced bradycardia compared with 1 (3.0%) patient in group G (difference = 6.1%; 95% CI: -7.6 to 20.8; P = 0.613). CONCLUSION: Prophylactic intramuscular glycopyrrolate reduced the occurrence and severity of hypotensive responses, the requirement for ephedrine, and the incidence of nausea and vomiting in elderly patients undergoing spinal anesthesia. The trial was registered at the Clinical Research Information Service, Republic of Korea (KCT0000556). PMID- 24347352 TI - Delayed recovery post anesthesia: an atypical presentation of familial hemiplegic migraine. PMID- 24347354 TI - Review of a high-risk obstetric anesthesia antepartum consult clinic. PMID- 24347355 TI - Estimation of equivalent threshold currents using different pulse widths for the epidural stimulation test in a porcine model. AB - BACKGROUND: The epidural stimulation test can help detect if a catheter is correctly positioned in the epidural space. Previous studies showed that a current of up to 16 mA was required to elicit a motor response, but few peripheral nerve stimulators can produce a current this high. Manipulating pulse width can produce a positive response at a lower current. To clarify the effects of pulse width on the epidural stimulation test, we performed a single-blinded study in a porcine model to estimate the equivalent current needed at varying pulse widths. METHODS: After obtaining local ethics approval, an 18G insulated Tuohy needle was advanced into the epidural space at the lower lumbar spinal level, and a 20G stimulating epidural catheter was advanced 30 cm cephalad. A gradually increasing electrical current was applied, and a motor response was elicited at pulse widths of 0.1, 0.2, 0.3, 0.5, and 1 msec. This was followed by a 1-2 cm catheter withdrawal, and the process was repeated for a total of 15 locations per pig. RESULTS: Recorded threshold currents ranged from 0.36-9.5 mA at a pulse width of 0.2 msec. Our results show a linear relationship between threshold current and pulse width. CONCLUSIONS: In situations where different pulse widths are needed, the nomograms presented here may be useful to estimate the equivalent threshold current which is required to elicit a motor response according to previously published criteria for epidural stimulation tests. PMID- 24347356 TI - Liver remnant regeneration in donors after living donor liver transplantation: long-term follow-up using CT and MR imaging. AB - PURPOSE: To assess liver remnant volume regeneration and maintenance, and complications in the long-time follow-up of donors after living donor liver transplantation using CT and MRI. MATERIALS AND METHODS: 47 donors with a mean age of 33.5 years who donated liver tissue for transplantation and who were available for follow-up imaging were included in this retrospective study. Contrast-enhanced CT and MR studies were acquired for routine follow-up. Two observers evaluated pre- and postoperative images regarding anatomy and pathological findings. Volumes were manually measured on contrast-enhanced images in the portal venous phase, and potential postoperative complications were documented. Pre- and postoperative liver volumes were compared for evaluating liver remnant regeneration. RESULTS: 47 preoperative and 89 follow-up studies covered a period of 22.4 months (range: 1 - 84). After right liver lobe (RLL) donation, the mean liver remnant volume was 522.0 ml (+/- 144.0; 36.1 %; n = 18), after left lateral section (LLS) donation 1,121.7 ml (+/- 212.8; 79.9 %; n = 24), and after left liver lobe (LLL) donation 1,181.5 ml (+/- 279.5; 72.0 %; n = 5). Twelve months after donation, the liver remnant volume were 87.3 % (RLL; +/- 11.8; n = 11), 95.0 % (LS; +/- 11.6; n = 18), and 80.1 % (LLL; +/- 2.0; n = 2 LLL) of the preoperative total liver volume. Rapid initial regeneration and maintenance at 80 % of the preoperative liver volume were observed over the total follow-up period. Minor postoperative complications were found early in 4 patients. No severe or late complications or mortality occurred. CONCLUSION: Rapid regeneration of liver remnant volumes in all donors and volume maintenance over the long-term follow-up period of up to 84 months without severe or late complications are important observations for assessing the safety of LDLT donors. KEY POINTS: Liver remnant volumes of LDLT donors rapidly regenerated after donation and volumes were maintained over the long-term follow-up period of up to 84 months without severe or late complications. PMID- 24347357 TI - [Increased dyspnea after airbag rupture]. PMID- 24347358 TI - [Pulmonary differentiation -/ATRA syndrome within the scope of therapy of acute promyelocytic leukemia (APL)]. PMID- 24347359 TI - MRI-guided and CT-guided cervical nerve root infiltration therapy: a cost comparison. AB - PURPOSE: To evaluate and compare the costs of MRI-guided and CT-guided cervical nerve root infiltration for the minimally invasive treatment of radicular neck pain. MATERIALS AND METHODS: Between September 2009 and April 2012, 22 patients (9 men, 13 women; mean age: 48.2 years) underwent MRI-guided (1.0 Tesla, Panorama HFO, Philips) single-site periradicular cervical nerve root infiltration with 40 mg triamcinolone acetonide. A further 64 patients (34 men, 30 women; mean age: 50.3 years) were treated under CT fluoroscopic guidance (Somatom Definition 64, Siemens). The mean overall costs were calculated as the sum of the prorated costs of equipment use (purchase, depreciation, maintenance, and energy costs), personnel costs and expenditure for disposables that were identified for MRI- and CT-guided procedures. Additionally, the cost of ultrasound guidance was calculated. RESULTS: The mean intervention time was 24.9 min. (range: 12 - 36 min.) for MRI-guided infiltration and 19.7 min. (range: 5 - 54 min.) for CT guided infiltration. The average total costs per patient were EUR 240 for MRI guided interventions and EUR 124 for CT-guided interventions. These were (MRI/CT guidance) EUR 150/60 for equipment use, EUR 46/40 for personnel, and EUR 44/25 for disposables. The mean overall cost of ultrasound guidance was EUR 76. CONCLUSION: Cervical nerve root infiltration using MRI guidance is still about twice as expensive as infiltration using CT guidance. However, since it does not involve radiation exposure for patients and personnel, MRI-guided nerve root infiltration may become a promising alternative to the CT-guided procedure, especially since a further price decrease is expected for MRI devices and MR compatible disposables. In contrast, ultrasound remains the less expensive method for nerve root infiltration guidance. PMID- 24347360 TI - Comparison of 3D cube FLAIR with 2D FLAIR for multiple sclerosis imaging at 3 Tesla. AB - PURPOSE: Three-dimensional (3 D) MRI sequences allow improved spatial resolution with good signal and contrast properties as well as multiplanar reconstruction. We sought to compare Cube, a 3 D FLAIR sequence, to a standard 2 D FLAIR sequence in multiple sclerosis (MS) imaging. MATERIALS AND METHODS: Examinations were performed in the clinical routine on a 3.0 Tesla scanner. 12 patients with definite MS were included. Lesions with MS-typical properties on the images of Cube FLAIR and 2 D FLAIR sequences were counted and allocated to different brain regions. Signal-to-noise ratios (SNR) and contrast-to-noise ratios (CNR) were calculated. RESULTS: With 384 the overall number of lesions found with Cube FLAIR was significantly higher than with 2 D FLAIR (N = 221). The difference was mostly accounted for by supratentorial lesions (N = 372 vs. N = 216) while the infratentorial lesion counts were low in both sequences. SNRs and CNRs were significantly higher in CUBE FLAIR with the exception of the CNR of lesion to gray matter, which was not significantly different. CONCLUSION: Cube FLAIR showed a higher sensitivity for MS lesions compared to a 2 D FLAIR sequence. 3 D FLAIR might replace 2 D FLAIR sequences in MS imaging in the future. PMID- 24347361 TI - Facile synthesis of anatase TiO(2) quantum-dot/graphene-nanosheet composites with enhanced electrochemical performance for lithium-ion batteries. AB - A facile method to synthesize well-dispersed TiO2 quantum dots on graphene nanosheets (TiO2 -QDs/GNs) in a water-in-oil (W/O) emulsion system is reported. The TiO2 /graphene composites display high performance as an anode material for lithium-ion batteries (LIBs), such as having high reversible lithium storage capacity, high Coulombic efficiency, excellent cycling stability, and high rate capability. The excellent electrochemical performance and special structure of the composites thus offer a way to prepare novel graphene-based electrode materials for high-energy-density and high-power LIBs. PMID- 24347362 TI - Comprehensive integrated care for patients with sickle cell disease in a remote aboriginal tribal population in southern India. AB - BACKGROUND: Healthcare delivery for sickle cell disease (SCD) can be challenging, in low resource settings. We studied the feasibility of delivering comprehensive SCD care in a community-based network for remote, economically, and socially disadvantaged tribes in Gudalur, India. PROCEDURE: We reviewed medical records for all patients followed at the Gudalur Adivasi Hospital. We used published quality of care indicators to benchmark screening and routine healthcare maintenance. RESULTS: We screened 9,646 individuals (60.4%) under the age of 30 of a population of 25,000 individuals. Of 111 active patients with SCD, 71% have had at least one annual comprehensive clinic visit at a median visit interval of 57 days. We provided pneumococcal immunization and penicillin prophylaxis to 56 (50%) patients and HU to 68 (61%). Median spleen size was 1 cm (range 1-6 cm), mean was Hb 9.3 g/dl and we reported a mean of 0.7 painful episodes/year. Premature deaths occurred in 19 patients at a median age of 23 years due to acute chest syndrome, sepsis, severe anemia, stroke, mesenteric infarction, puerperal sepsis, or sudden unexplained death. Healthcare maintenance met 11 of 17 published SCD quality of care indicators. Average cost was 1,343 Indian Rupees (INR) (approximately US$ 25) per hospitalization and 173 INR (approximately US$ 4) per clinic visit. CONCLUSION: High quality comprehensive care for SCD can be delivered for a low income, aboriginal population in India through a community driven network of care. This model can serve as a template for healthcare delivery for SCD in low-income communities. PMID- 24347363 TI - Detection of colorectal cancer and adenomas by FDG-PET cancer screening program: results based on a nationwide Japanese survey. AB - PURPOSE: The aim of this study was to analyze the detection rate for CRC and adenomas for asymptomatic subjects in Japan by FDG-PET cancer screening program carried out between 2006 and 2009. METHODS: The "FDG-PET cancer screening program" included both PET and positron emission tomography with computed tomography (PET/CT) with or without other screening tests. A total of 154,783 asymptomatic subjects underwent FDG-PET cancer screening program; we analyzed the 1,808 cases with findings from any detection method that indicated suspected CRC. RESULTS: Among the 1,808 cases, the number of cases verified as CRC and adenoma was 394 and 679, respectively. The sensitivity and positive predictive value (PPV) of FDG-PET were 86.0 and 31.7% for CRC, and 63.6 and 63.8% for CRC and adenoma. The sensitivity and PPV of fecal occult blood test (FOBT) for CRC were lower than those of FDG-PET, but higher for adenoma. Therefore, FDG-PET and FOBT were complementary for screening for CRC, and CRC and adenoma. The majority of CRC detected by the FDG-PET imaging was UICC stage 0 or I, however, detection of smaller or less invasive cancer was limited. CONCLUSION: The FDG-PET screening program in Japan has detected CRC at an early stage and adenomas as premalignant lesions. A combination of FDG-PET and FOBT yields the best results if the intent is to detect either CRC or adenoma. However, it is absolutely clear that an FDG PET cancer screening program cannot detect all colon lesions. PMID- 24347364 TI - Sleep surgery and medical malpractice. AB - OBJECTIVES/HYPOTHESIS: To describe and analyze the causes and outcomes of lawsuits pertaining to sleep surgery to mitigate future litigation and improve physician education. STUDY DESIGN: A retrospective review of a publicly available database containing jury verdicts and settlements. METHODS: The LexisNexis MEGA Jury Verdicts and Settlements database was reviewed for all lawsuits including settlements and trial verdicts related to sleep surgery. Data including type of surgery performed, plaintiff allegation, nature of injury, outcomes, and indemnities were collected and analyzed. RESULTS: Fifty-one cases met the inclusion criteria. Of these, 30 were decided by a jury, nine were settled out of court, and 10 were resolved by other means. Overall, 57% of known outcomes favored the defendant. The most common surgery performed was tonsillectomy (57%), followed by uvulopalatopharyngoplasty (45%), adenoidectomy (31%), and septoplasty (31%). No difference was found between outcomes when comparing the most common injuries cited, including wrongful death (P = .572), airway compromise (P = .376), and drug reaction (P = .443). If failure to recognize a complication (P = .034) or delay in diagnosis (P = .026) was a component of the legal allegations, the outcome significantly favored the plaintiff. The median settlement ($545,000) and plaintiff award ($1.45 million) were not significantly different (P = .13). CONCLUSIONS: The majority of outcomes favored the defendant. Type of injury did not predict outcome. Failure to recognize complications and delay in diagnosis strongly predicted a verdict in favor of the plaintiff. LEVEL OF EVIDENCE: 2c. PMID- 24347365 TI - Role of the extracellular matrix in whole organ engineering. AB - End-stage organ failure is a devastating problem with limited therapeutic options. The definitive treatment is orthotropic transplantation, however, there exists a severe shortage of viable donor organs, and this shortage is worsening with an aging demographic and as the number of new cases of organ failure increases. Patients fortunate enough to receive a transplant are required to receive immunosuppressive therapies and can face transplant rejection. The emerging concept of organ engineering may offer a new hope for these patients. Researchers in the field of regenerative medicine and tissue engineering are using three-dimensional whole organ scaffolds composed of allogeneic or xenogeneic extracellular matrix (ECM) for engineering functional tissue suitable for transplantation. Perfusion decellularization is an approach that generates native ECM scaffolds with intact 3D anatomical architecture and vasculature. Decellularized organs provide the ideal transplantable scaffold with all the necessary microstructure and extracellular cues for cell attachment, differentiation, vascularization, and function. The present manuscript will review the role of the ECM in normal development, the concept of ECM tissue specificity, and the effect of processing methods on eventual clinical outcomes. An overview of existing challenges and future directions will also be discussed. PMID- 24347366 TI - Dental patterning in the earliest sharks: Implications for tooth evolution. AB - Doliodus problematicus is the oldest known fossil shark-like fish with an almost intact dentition (Emsian, Lower Devonian, c. 397Ma). We provide a detailed description of the teeth and dentition in D. problematicus, based on tomographic analysis of NBMG 10127 (New Brunswick Museum, Canada). Comparisons with modern shark dentitions suggest that Doliodus was a ram-feeding predator with a dentition adapted to seizing and disabling prey. Doliodus provides several clues about the early evolution of the "shark-like" dentition in chondrichthyans and also raises new questions about the evolution of oral teeth in jawed vertebrates. As in modern sharks, teeth in Doliodus were replaced in a linguo-labial sequence within tooth families at fixed positions along the jaws (12-14 tooth families per jaw quadrant in NBMG 10127). Doliodus teeth were replaced much more slowly than in modern sharks. Nevertheless, its tooth formation was apparently as highly organized as in modern elasmobranchs, in which future tooth positions are indicated by synchronized expression of shh at fixed loci within the dental epithelium. Comparable dental arrays are absent in osteichthyans, placoderms, and many "acanthodians"; a "shark-like" dentition, therefore, may be a synapomorphy of chondrichthyans and gnathostomes such as Ptomacanthus. The upper anterior teeth in Doliodus were not attached to the palatoquadrates, but were instead supported by the ethmoid region of the prechordal basicranium, as in some other Paleozoic taxa (e.g., Triodus, Ptomacanthus). This suggests that the chondrichthyan dental lamina was originally associated with prechordal basicranial cartilage as well as jaw cartilage, and that the modern elasmobranch condition (in which the oral dentition is confined to the jaws) is phylogenetically advanced. Thus, oral tooth development in modern elasmobranchs does not provide a complete developmental model for chondrichthyans or gnathostomes. PMID- 24347367 TI - The linea aspera: a virtual case study testing emergence of form and function. AB - The linea aspera (LA) forms a characteristic ridge along the posterior aspect of the human femur. Absent in youth, the LA emerges during early puberty and becomes more prominent with advancing age. Pauwels, a pioneer of mechanobiology, hypothesized that the LA forms in the precise location where axial intracortical stresses are greatest, effectively "stiffening" the femur in bending. This study reassesses the mechanical role of the LA in virtual models of human femora, accounting for increasing prominence of the LA at juvenile, young adult and aged stages. Using finite element analysis, peak stresses and the relationship between the LA, neutral axis and centroidal axes (CAs) are evaluated for cross-sections along the mid-diaphysis of the virtual femora. Additionally, the relationship between LA and CAs is studied in anatomical cross-sections from Pauwels' manuscript as well as aged cadaveric donors, indicating that his conclusion may have been stymied by lack of modern computational methods. The results of the current study do not support a mechanical role of the LA as its emergence results in less than a 3% decrease in peak stress, while increasing prominence of the LA also serves to rotate CAs away from calculated stress field, implicating a less "bone centric" view of form and function. PMID- 24347368 TI - Directing self-assembly of nanoscopic cylindrical diblock brush terpolymers into films with desired spatial orientations: expansion of chemical composition scope. AB - Diblock brush terpolymers (DBTs) with different fluorinated methacrylate-based block segments are synthesized through sequential ring-opening metathesis polymerizations and are used to prepare polymer thin films with predictable film thicknesses. These DBTs exhibit preferable substrate vertical alignments within the films, induced by the relatively lower surface energy of the fluorinated structural components, together with the overall cylindrical morphology of the brush architecture. PMID- 24347369 TI - Modeling intention to participate in face-to-face and online lung cancer support groups. AB - BACKGROUND: Lung cancer patients and survivors are significantly less likely to use support groups than those with other cancers. In this study, we evaluated the utility and specificity of the Behavioral Model for Vulnerable Populations for modeling intention to participate in face-to-face (F2F) and online lung cancer support groups. METHODS: Adults diagnosed with lung cancer (n = 230) completed measures assessing predisposing, enabling, and need factors associated with intention to use support services. RESULTS: Intention to join a F2F support group (found among 36.4% of survivors) was associated with positive attitude about F2F support groups, fewer perceived time constraints, less travel time from the clinic, and not having enough social support. Intention to join an online support group (34% of survivors) was associated with having more positive attitudes about online support, greater use of avoidance coping strategies, more comfort using computers, and fewer perceived time constraints. Demographics, medical history, health status, and psychological status were not associated with intention to join either type of group. CONCLUSIONS: Reducing barriers to participation and addressing attitudes about support services may be the most effective ways to increase utilization of lung cancer support services. PMID- 24347370 TI - A ranking of diffusion MRI compartment models with in vivo human brain data. AB - PURPOSE: Diffusion magnetic resonance imaging (MRI) microstructure imaging provides a unique noninvasive probe into tissue microstructure. The technique relies on biophysically motivated mathematical models, relating microscopic tissue features to the magnetic resonance (MR) signal. This work aims to determine which compartment models of diffusion MRI are best at describing measurements from in vivo human brain white matter. METHODS: Recent work shows that three compartment models, designed to capture intra-axonal, extracellular, and isotropically restricted diffusion, best explain multi-b-value data sets from fixed rat corpus callosum. We extend this investigation to in vivo by using a live human subject on a clinical scanner. The analysis compares models of one, two, and three compartments and ranks their ability to explain the measured data. We enhance the original methodology to further evaluate the stability of the ranking. RESULTS: As with fixed tissue, three compartment models explain the data best. However, a clearer hierarchical structure and simpler models emerge. We also find that splitting the scanning into shorter sessions has little effect on the ranking of models, and that the results are broadly reproducible across sessions. CONCLUSION: Three compartments are required to explain diffusion MR measurements from in vivo corpus callosum, which informs the choice of model for microstructure imaging applications in the brain. PMID- 24347371 TI - Altered human gut dendritic cell properties in ulcerative colitis are reversed by Lactobacillus plantarum extracellular encrypted peptide STp. AB - SCOPE: The human/microbiota cross-talk is partially mediated by bacteria-derived peptides like Serine-Threonine peptide (STp), which is resistant to gut proteolysis, is found in the human healthy colon and induces regulatory properties on gut dendritic cells (DCs); here we characterized human gut DC in ulcerative colitis (UC) patients and studied the effect of STp on their properties. METHODS AND RESULTS: Human colonic DC from healthy controls and UC patients were isolated, conditioned for 24 h +/- STp and characterized by flow cytometry, immunohistochemistry, and electron microscopy. Expression of immature DC markers DC-SIGN and ILT3, and Toll-like receptors were increased on gut UC-DC. Langerin (involved in phagocytosis), lymph node homing marker CCR7, and activation markers CD40/CD80/CD86 were decreased in UC. Gut DC had restricted stimulatory capacity for T-cells in UC. Conditioning of DC with STp in vitro reduced Toll-like receptor expression, increased CD40 and CD80 expression, and restored their stimulatory capacity. CONCLUSION: Colonic DCs display an abnormal immature phenotype in UC, which was partially restored following STp treatment. Bacteria-derived metabolites, like STp, seem to have a role in gut homeostasis that is missing in UC so they might lead a new era of probiotic products setting the basis for nondrug dietary therapy in inflammatory bowel disease. PMID- 24347372 TI - Autophagy during early stages contributes to bovine viral diarrhea virus replication in MDBK cells. AB - Autophagy (or autophagocytosis) is an essential and precise control process by which cells degrade unnecessary or dysfunctional cellular components or organelles in the cytoplasm in response to nutrient depletion, exogenous pathogens, or other stimuli. This process results in the removal of damaged or surplus organelles and macromolecular complexes via a lysosome-dependent mechanism. Bovine viral diarrhea virus (BVDV) is a ssRNA virus of the Flaviviridae family (genus Pestivirus). BVDV infection results in major economic losses due to poor reproductive performance and poor calf performance in cattle herds. In our previous studies, we have shown that BVDV NADL infection significantly increases autophagy in MDBK cells. To further define the interactions between autophagy and BVDV infection, we investigated the effects of autophagy on the replication of BVDV NADL. The findings showed that autophagy was inhibited by treatment with 3-methyladenine (3-MA) or wortmannin and that the knockdown of LC3 and Beclin1 using lentivirus-mediated RNA interference (RNAi) suppressed BVDV NADL replication. In contrast, the findings showed the replication of BVDV NADL was significantly increased by treatment with the autophagy inducer rapamycin within 18 h post-infection (pi). However, the mRNA levels of BVDV NADL 5'UTRs showed a downward trend after 18 h pi, and this effect was reversed by chloroquine treatment. Therefore, we inferred that infection with BVDV NADL increases autophagy, which in turn favors BVDV NADL replication at early stages. PMID- 24347373 TI - MALDI mass spectrometry imaging of 1-methyl-4-phenylpyridinium (MPP+) in mouse brain. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting ~1% of the population older than 60 years. The administration of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice is one of the most widely used approach to elucidate the mechanisms of cell death involved in PD. Its toxicity is attributed to its active metabolite 1-methyl-4 phenylpyridinium (MPP(+)). However, the magnitude of the PD-like neurodegeneration induced by MPTP depends on many variables, including the route of administration. Different groups, including us, demonstrated that intranasal (i.n.) administration of MPTP constitutes a new route of toxin delivery to the brain that mimics environmental exposure to neurotoxins. In particular, our previous data showed that mice submitted to acute i.n. MPTP administration displayed a significant decrease of striatal dopamine (DA) and a loss of dopaminergic (DA) neurons in the substantia nigra pars compacta. However, little is known about the timing and the anatomical distribution of MPP(+) after i.n. MPTP administration in mice. In the present study, C57BL/6J mice received one dose of i.n. MPTP (1 mg/nostril) and were sacrificed at two different times after the administration. Using matrix-assisted laser desorption-ionization mass spectrometry imaging, a new technique for the detection of endogenous unlabeled molecules in tissue sections, we showed for the first time the MPP(+) anatomical distribution in different brain regions. We demonstrated that the toxin first reached almost all the brain areas; however, in a second time MPP(+) remained highly concentrated in the olfactory bulb, the basal ganglia, the ventral mesencephalon, and the locus coeruleus, regions differently affected in PD. PMID- 24347375 TI - DNA-mediated construction of hollow upconversion nanoparticles for protein harvesting and near-infrared light triggered release. AB - A simple DNA-mediated solvothermal method has been developed for the construction of well-defined hollow UNPs that can be used for a new paradigm to realize NIR light-controlled non-invasive protein release. In vitro studies show that the UNPs are capable of the transportation of enzyme into living cells. Intracellular NIR triggers the release of enzymes with high spatial and temporal precision and the released enzyme also retains its biological activity. PMID- 24347374 TI - Enhanced mossy fiber sprouting and synapse formation in organotypic hippocampal cultures following transient domoic acid excitotoxicity. AB - We have previously reported evidence of BDNF upregulation and increased neurogenesis in rat organotypic hippocampal slice cultures (OHSC) after a transient excitotoxic injury to the hippocampal CA1 area induced by low concentrations of the AMPA/kainate receptor agonist domoic acid (DOM). The changes observed in OHSC were consistent with observations in vivo, where low concentrations of DOM administered to rats during perinatal development caused increased BDNF and TrkB expression in the resulting adult animals. The in vivo low dose-DOM treatment also results in permanent alterations in hippocampal structure and function, including abnormal formation of dentate granule cell axons projecting to area CA3 (mossy fiber sprouting). Our objective in the current study is to determine if low concentrations of DOM induce mossy fiber sprouting and/or synaptogenesis in OHSC in order to facilitate future studies on the mechanisms of structural hippocampal plasticity induced by DOM. We report herein that application of a low concentration of DOM (2 MUM) for 24 h followed by recovery induced a significant increase in the expression of the mossy fiber marker ZnT3 that progressed over time in culture. The DOM insult (2 MUM, 24 h) also resulted in a significant upregulation of both the presynaptic marker synaptophysin and the postsynaptic marker PSD-95. All of the observed effects were fully antagonized by co-administration of the AMPA/kainate antagonists CNQX or NBQX but only partly by the NMDA antagonist CPP and not by the calcium channel blocker nifedipine. We conclude that exposure of OHSC to concentrations of DOM below those required to induce permanent neurotoxicity can induce a progressive change in hippocampal structure that can effectively model DOM effects in vivo. PMID- 24347376 TI - Health-related quality of life in children and young adults with post-thrombotic syndrome: results from a cross-sectional study. AB - OBJECTIVE: While post-thrombotic syndrome (PTS) is increasingly recognized in children with a history of deep vein thrombosis (DVT), its impact on the health related quality of life (HRQoL) is unknown. Our objective was to evaluate the association between the PTS and HRQoL by surveying a cohort of patients treated at our institution for DVT. MATERIALS/METHODS: All unique pediatric patients (0 18 years) treated for a DVT at the Mayo Clinic during the 15-year period, 1995 2009 were identified. A previously validated PTS survey instrument and age appropriate Pediatric Quality of Life inventory, version 4 (PedsQL 4.0) were mailed to eligible patients. Linear regression models were fit to compare the HRQoL scores between PTS groups (none, mild, moderate/severe), after adjusting for the presence of potential covariates. RESULTS: Of the 90 respondents, 65 (72%) reported signs and/or symptoms of PTS. Mean age (+/- SD) at DVT diagnosis and survey completion were 12.8 (+/- 6.1) and 19.3 (+/- 7.7) years, respectively. Self-report PedsQL 4.0 module was completed by 79 patients, and 34 guardians completed the parent-proxy module. Patients with moderate to severe PTS reported significantly worse total HRQoL score (mean +/- SD, 71.3 +/- 13.4) as compared to patients with mild PTS (84.8 +/- 14.2) and no PTS (83.4 +/- 14) (P = 0.001). CONCLUSION: Moderate to severe PTS has a significant impact on self-reported HRQoL as measured using the generic PedsQL 4.0. Further research is warranted to develop a venous disease-specific quality of life measure for children with a history of DVT. PMID- 24347377 TI - Venous thrombosis in rare or unusual sites: a diagnostic challenge. AB - Venous thrombosis usually involves the veins of the limbs, most frequently the leg veins. All other venous districts may sometimes be affected by the thrombotic process. Sometimes, the thrombotic occlusion of the veins of a given region show typical signs and symptoms. In other cases, the picture may not be clear and a high degree of clinical suspicion is needed for a correct approach to patient diagnosis and management. Thrombosis of retinal and jugular veins, right heart thrombosis including thrombosis of coronary sinus and thrombosis of the azygos system may be included in this group. In addition, thromboses of umbilical, renal, ovarian, spermatic, and iliac veins also require attention. Finally, the dorsal veins of the penis may also be affected by thrombotic events. The main clinical features of these thromboses are reviewed herein with suggestions for a correct diagnostic approach. The importance of sonography and of other imaging techniques is emphasized. A prompt diagnosis is of paramount importance as most of these thromboses in rare or unusual sites may still cause severe systemic complications (pulmonary embolism, sepsis, and heart failure). PMID- 24347378 TI - 2-Bromo-6-[(18) F]fluoropyridine: two-step fluorine-18 radiolabelling via transition metal-mediated chemistry. AB - Novel radiolabelling methods are important for the development of new tracers for positron emission tomography. Direct nucleophilic fluorination of aromatic rings with [(18) F]fluoride is limited to activated substrates, restricting the application of this approach. Inspired by transition metal-mediated transformations, a fluorine-18 synthon was prepared to supplement the radiolabelling methods available for molecules unsuitable for direct labelling. 2 Bromo-6-[(18) F]fluoropyridine (denoted [(18) F]1) was prepared in high yield, and palladium-mediated cross-coupling reactions were exemplified. High incorporation of fluoride and efficient cross-coupling reactions demonstrate that compound [(18) F]1 holds promise as a new synthon for construction of fluorine-18 labelled molecules via transition metal-mediated reactions. PMID- 24347379 TI - Care, compounded: researchers delve into reasons behind pregnancy-associated breast cancer. PMID- 24347382 TI - Progression-free survival: does a correlation with survival justify its role as a surrogate clinical endpoint? PMID- 24347383 TI - Breast cancer presentation and diagnostic delays in young women. AB - BACKGROUND: Young women may experience delays in diagnosis of breast cancer, and these delays may contribute to poorer outcomes. METHODS: In a prospective, multicenter cohort study, women recently diagnosed with breast cancer at age <=40 years were surveyed regarding their initial signs or symptoms of cancer and delays in diagnosis. Self delay was defined as >=90 days between the first sign or symptom and a patient's first visit to consult a health care provider. Care delay was defined as >=90 days between that first visit and the diagnosis of breast cancer. In a medical record review, tumor characteristics were assessed, including disease stage. Univariate and multivariate models were used to assess for predictors of self delay, care delay, and advanced stage in the self-detected subset. RESULTS: In 585 eligible participants, the first sign or symptom of cancer was a self-detected breast abnormality for 80%, a clinical breast examination abnormality for 6%, an imaging abnormality for 12%, and a systemic symptom for 1%. Among women with self-detected cancers, 17% reported a self delay, and 12% reported a care delay. Self delays were associated with poorer financial status (P = 0.01). Among young women with self-detected breast cancers, care delay was associated at trend level (P = .06) with higher stage in multivariate modeling. CONCLUSIONS: Most young women detect their own breast cancers, and most do not experience long delays before diagnosis. Women with fewer financial resources are more likely to delay seeking medical attention for a self-detected breast abnormality. PMID- 24347384 TI - Progression-free survival as a surrogate endpoint of overall survival in patients with metastatic renal cell carcinoma. AB - BACKGROUND: The current study was conducted to investigate the dependence between progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) and to explore whether PFS can be used as an intermediate endpoint of OS in this patient population. METHODS: A total of 1381 patients from 2 prospective phase 3 trials (Cancer and Leukemia Group B [CALGB] 90206 and AVOREN) of interferon-alpha with or without bevacizumab were analyzed. Both trials recruited previously untreated patients with clear cell mRCC with an Eastern Cooperative Oncology Group performance status of 0 to 2; adequate bone marrow, hepatic, cardiac, and renal function; and controlled blood pressure. The CALGB study served as the training data set, and the AVOREN study served as the testing data set. The dependence between PFS and OS was investigated using the Kendall tau for bivariate time-to-event endpoints. RESULTS: In the training data set, the median OS times among patients who experienced progressive disease at 3 months or 6 months were 6 months and 8 months, respectively, compared with 25 months and 30 months, respectively, (P < .001) in patients who did not develop disease progress. The adjusted hazard ratios (HR) were 2.6 (P < .0001) and 2.8 (P < .0001), respectively, for patients who did and did not progress at 3 months or 6 months. The dependence between PFS and OS was 0.53. These associations were confirmed in the testing data set. CONCLUSIONS: In patients with mRCC who were treated with interferon-alpha with or without bevacizumab, the PFS at 3 months and 6 months was found to be predictive of OS. A high dependence between PFS and OS was observed, suggesting that PFS may be used as a surrogate endpoint for OS. Although this is a novel observation for RCC, these findings require validation in patients with mRCC who are treated with other targeted agents. PMID- 24347385 TI - Otolaryngologist-assisted fluoroscopic-guided nasogastric tube placement in the postoperative laryngectomy patient. PMID- 24347386 TI - Ontogenetic study of allometric variation in Homo and Pan mandibles. AB - Investigating ontogenetic variation and allometry in the mandible can provide valuable insight and aid in addressing questions related to the ontogeny of the skull. Here, patterns of ontogenetic shape change and allometric trajectories were examined in the mandible of 187 sub-adult and adult humans, bonobos, and chimpanzees. Procrustes-based geometric morphometrics was employed to quantify and analyze mandibular form. Thirty three-dimensional landmarks were used to capture the overall morphology of the mandible, and the landmarks were analyzed as a whole and subdivided into separate anterior and posterior units. Principal component analyses in Procrustes shape-space and form-space, and multivariate regressions were used to examine patterns of ontogenetic and allometric shape change. Results suggest that humans are distinct from Pan both in their mandibular morphology, particularly in the anterior-alveolar region, and direction of allometric trajectory. Chimpanzees and bonobos have parallel ontogenetic trajectories, but also show differences in mandibular shape. Species specific features and adult mandibular shape are established before or by the eruption of the deciduous dentition. This suggests that developmental processes prior to deciduous teeth eruption have a stronger effect establishing taxa specific phenotypes than later postnatal effects. This additionally implies that divergent trajectories between Pan and Homo do not contribute much to the adult mandibular shape after deciduous teeth eruption. Separate analyses of the anterior-alveolar region and ascending ramus show that these regions are semi independent in their developmental pattern of shape change and allometry. This implies that allometric variation and ontogenetic shape change in the hominoid mandible is decoupled. PMID- 24347387 TI - Early retirement and non-employment after breast cancer. AB - OBJECTIVE: This study examined whether workplace support, sociodemographic factors and co-morbidity are associated with early retirement or non-employment due to other reasons among breast cancer survivors. We also compared quality of life and chronic symptoms (pain, fatigue, anxiety and depression) among employed, retired and other non-employed breast cancer survivors. METHODS: We identified breast cancer survivors diagnosed between 1997 and 2002 from either a hospital or a cancer registry in Denmark, Finland, Iceland and Norway (NOCWO study). All patients had been treated with curative intent. Information on employment, co morbidity and support was collected via a questionnaire. The sample included 1111 working-aged cancer-free survivors who had been employed at the time of diagnosis. We used multinomial logistic regression models to analyse the association of various determinants with early retirement and other non employment (due to unemployment, subsidized employment or being a homemaker). RESULTS: Low education, low physical quality of life, co-morbidity and pain were associated with both early retirement and other non-employment after cancer. Other non-employed survivors also rated their mental quality of life as lower and experienced anxiety and fatigue more often than all the other survivors. Moreover, they reported a lower level of supervisor support after their diagnosis than the employed survivors. Retired survivors more often reported weak support from colleagues. CONCLUSIONS: Differences in ill health and functional status between various groups of non-employed cancer survivors need to be considered when planning policy measures for improving the labour market participation of this population and preventing their early withdrawal from working life. PMID- 24347388 TI - Phosphorylation of PRAS40-Thr246 involved in renal lipid accumulation of diabetes. AB - Lipid accumulation of kidney is a threat to renal physiological function of diabetes. The previous studies on diabetic nephropathy have demonstrated that activated Akt was involved in renal lipogenesis through enhancing transcription factor SREBP-1. PRAS40 is one of the downstream targets of activated Akt that was reported to involve in lipid metabolism in hepatic cells. However, it is still not clear whether PRAS40 is also involved in the renal lipogenesis of diabetes. Our study revealed that phosphorylation of PRAS40-Thr246 known as inactivated style increased in renal tubular cells of diabetic rats accompanied with over expression of phospho-Akt, SREBP-1, and ADRP. In addition, in vitro experiment also found that high glucose enhanced expression of phospho-PRAS40-Thr246 followed by increased SREBP-1 and lipid droplets in HKC cells. After treated with LY294002, high glucose-induced HKC cells showed decreased phospho-PRAS40-Thr246, phospho-Akt-Ser473, and SREBP-1. Furthermore, wild type PRAS40 vector-caused increased phospho-PRAS40-Thr246 exaggerated lipid deposits in high glucose treated HKC cells, which was effectively prevented in cells transfected with mutant PRAS40 vector (T246A). These above data suggested that phosphorylation of PRAS40-Thr246 mediated abnormal lipid metabolism in kidney of diabetes and might be the potential target for treating lipogenesis of diabetic nephropathy. PMID- 24347393 TI - Juvenile play experience does not affect nicotine sensitization and voluntary consumption of nicotine in adult rats. AB - Juvenile play experiences promote behavioral flexibility in rats. If other early positive experiences, such as tactile stimulation, are given prior to exposure to psychostimulants, the behavioral response to the drug is attenuated. The objective of the present study was to determine if the experience of juvenile play behavior would attenuate the response to nicotine. Two experiments were conducted: (1) behavioral sensitization to nicotine exposure, and (2) voluntary consumption of nicotine. For both experiments, rats were reared either with three same-sex peers (play group) or one adult (no play group) during their juvenile period. Then, as adults, half of each group was exposed to repeated injections of nicotine and the other half to saline. Prior play experience had no effect on behavioral sensitization or on voluntary consumption of nicotine. It remains to be determined whether juvenile experience with play influences the rewarding properties of nicotine in social contexts as adults. PMID- 24347394 TI - High--valent technetium chemistry-new opportunities for radiopharmaceutical developments. AB - The rich coordination chemistry of (99m) Tc distinguishes this radiometal from other radiolabels applied for single-photon emission computed tomography (SPECT) or positron emission tomography (PET). This potential should be used to create novel opportunities for the development of effective imaging probes. In this context, the field of high-valent technetium chemistry has received much interest. It has been shown that fac-{(99m) TcO3 }(+) complexes are potential new synthons for radiopharmaceutical developments, due to their unique physicochemical properties and unprecedented reactivity. In this article, recent developments and the 'state of the art' in this field of technetium chemistry will be reviewed comprehensively. PMID- 24347395 TI - Sarcoglycan complex in human normal and pathological prostatic tissue: an immunohistochemical and RT-PCR study. AB - The sarcoglycan complex is a trans-membrane system playing a key role in mechano signaling the connection from the cytoskeleton to the extracellular matrix. While b-, d-, and e-sarcoglycans are widely distributed, g- and a-sarcoglycans are expressed exclusively in skeletal and cardiac muscle. Insufficient data are available on the distribution of sarcoglycans in nonmuscular tissue. In the present study, we used immunohistochemical and RT-PCR techniques to study the sarcoglycans also in normal human glandular tissue, a type of tissue never studied in relation to the sarcoglycan complex, with the aim of verifying the real wider distribution of this complex. To understand the role of sarcoglycans, we tested specimens collected from patients affected by benign prostatic hyperplasia and adenocarcinoma. For the first time, our results showed that all sarcoglycans are detectable in normal samples both in epithelial and in myoepithelial cells; in pathological prostate, sarcoglycans appeared severely reduced in number or were absent. These data demonstrated that all sarcoglycans have a wider distribution suggesting a new unknown role for these proteins. The decreased number of sarcoglycans, containing cadherin domain homologs in samples of prostate affected by hyperplasia, and the absence of proteins in prostate biopsies, in cases affected by adenocarcinoma, could be responsible for the loss of adhesion between epithelial cells, which in turn facilitates the progression of benign tumors and the invasive potential of malignant tumors. PMID- 24347396 TI - Application of polyglycerol coating to plasmid DNA lipoplex for the evasion of the accelerated blood clearance phenomenon in nucleic acid delivery. AB - Cationic liposomes (CLs) have shown promise as nonviral delivery systems. To achieve in vivo stability and long circulation, most liposomes are modified with hydrophilic polymer polyethylene glycol (PEG). However, we have reported that repeated administration of PEG-coated CLs containing plasmid DNA (pDNA; PEGylated lipoplexes) induces what is referred to as "the accelerated blood clearance (ABC) phenomenon" and, consequently, subsequently administered lipoplexes lose their prolonged circulation characteristics. Anti-PEG IgM produced in response to the first dose of PEG-coated pDNA-lipoplexes (PEG-DCL) has proven to be a major cause of the ABC phenomenon. In this study, to evade and/or attenuate this unexpected immune response, we modified the surface of a lipoplex with polyglycerol (PG) derived lipid. The PG-coated pDNA-lipoplex (PG-DCL) attenuated the production of anti-polymer IgM, whereas PEG-coated pDNA-lipoplex (PEG-DCL) did not. In addition, a second dose of PG-DCL maintained the accumulation level in the tumor tissue of a tumor-bearing mouse model, comparable to that of the first dose, whereas the tumor accumulation level of a second dose of PEG-DCL was significantly compromised, compared with the first dose of PEG-DCL. Our results indicate that surface modification of lipoplex with PG represents a viable means for the attenuation, and/or evasion, of the ABC phenomenon that is encountered upon repeated administrations of nucleic acids containing PEG-coated nanocarriers. PMID- 24347397 TI - Dual-scaled porous nitrocellulose membranes with underwater superoleophobicity for highly efficient oil/water separation. AB - Large-area dual-scaled porous nitrocellulose (p-NC) membranes are fabricated by a facile, inexpensive and scalable perforating approach. These p-NC membranes show stable superhydrophilicity in air and underwater superoleophobicity. The p-NC membranes with intrinsic nanopores and array of microscale perforated pores could selectively and efficiently separate water from various oil/water mixtures with high efficiency (>99%) rapidly. PMID- 24347398 TI - Diastereotopic splitting in the 13C NMR spectra of sulfur homofullerenes and methanofullerenes with chiral fragments. AB - Using gauge-invariant atomic orbital PBE/3zeta quantum chemistry approach, (13)C NMR chemical shifts and diastereotopic splittings of sp(2) fullerenyl carbons of a number of sulfur homofullerenes and methanofullerenes have been predicted and discussed. An anisochrony of fullerene carbons is caused by a chiral center of attached moieties. Clearly distinguishable diastereotopic pairs (from 8 to 11) of fullerenyl carbons of homofullerenes were observed. Unambiguous assignments of (13)C NMR chemical shifts were performed, and diastereotopic splittings of methanofullerenes were observed for alpha, beta and gamma to a functionalization site. PMID- 24347399 TI - 13C and 15N CP/MAS, 1H-15N SCT CP/MAS and FTIR spectroscopy as tools for qualitative detection of the presence of zwitterionic and non-ionic forms of ansa macrolide 3-formylrifamycin SV and its derivatives in solid state. AB - (13)C, (15)N CP/MAS, including (1)H-(13)C and (1)H-(15)N short contact time CP/MAS experiments, and FTIR methods were applied for detailed structural characterization of ansa-macrolides as 3-formylrifamycin SV (1) and its derivatives (2-6) in crystal and in powder forms. Although HPLC chromatograms for 2/CH3 OH and 2/CH3 CCl3 were the same for rifampicin crystals dissolved in respective solvents, the UV-vis data recorded for them were different in 300-375 nm region. Detailed solid state (13)C and (15)N CP/MAS NMR and FTIR studies revealed that rifampicin (2), in contrast to 3-formylrifamycin SV (1) and its amino derivatives (3-6), can occur in pure non-ionic or zwitterionic forms in crystal and in pure these forms or a mixture of them in a powder. Multinuclear CP/MAS and FTIR studies demonstrated also that 3-6 derivatives were present exclusively in pure zwitterionic forms, both in powder and in crystal. On the basis of the solid state NMR and FTIR studies, two conformers of 3 formylrifamycin SV were detected in powder form due to the different orientations of carbonyl group of amide moiety. The PM6 molecular modeling at the semi empirical level of theory, allowed visualization the most energetically favorable non-ionic and zwitterionic forms of 1-6 antibiotics, strongly stabilized via intramolecular H-bonds. FTIR studies indicated that the originally adopted forms of these type antibiotics in crystal or in powder are stable in standard laboratory conditions in time. The results presented point to the fact that because of a possible presence of two forms of rifampicin (compound 2), quantification of the content of this antibiotic in relevant pharmaceuticals needs caution. PMID- 24347400 TI - Structure elucidation and NMR assignments of two unusual xanthones from Lomatogonium carinthiacum (Wulf) Reichb. AB - Two new unusual xanthones, 5-O-beta-d-glucopyranosyl-1,3,8-trihydroxy-5,6,7,8 tetrahydroxanthone (1) and 1,3,5,8-tetrahydroxy-5,6,7,8-tetrahydroxanthone (2), were isolated from Lomatogonium carinthiacum (Wulf) Reichb. Their structures were elucidated on the basis of spectroscopic methods including UV, IR, ESI-MS, 1D NMR, and 2D NMR. PMID- 24347401 TI - They still grieve-a nationwide follow-up of young adults 2-9 years after losing a sibling to cancer. AB - OBJECTIVES: The aims of this study were to assess the prevalence of unresolved grief in bereaved young adult siblings and examine possible contributing factors. METHODS: The study was a Swedish population-based study of young adults who had lost a brother or sister to cancer, 2-9 years earlier. Of 240 eligible siblings, 174 (73%) completed a study-specific questionnaire. This study focused on whether the respondents had worked through their grief over the sibling's death and to what extent. RESULTS: A majority (54%) of siblings stated that they had worked through their grief either 'not at all' or 'to some extent' at the time of investigation. In multiple regression analyses with unresolved grief as the dependent variable, 21% of the variance was explained by lack of social support and shorter time since loss. CONCLUSION: The majority of bereaved young adults had not worked through their grief over the sibling's death. A small group of siblings reported that they had not worked through their grief at all, which may be an indicator of prolonged grief. Lack of social support and more recent loss were associated with not having worked through the grief over the sibling's death. PMID- 24347402 TI - Identification of risk factors for an unsuccessful transition from pediatric to adult sickle cell disease care. AB - BACKGROUND: A successful transition from pediatric to adult sickle cell disease (SCD) care is paramount to continued improvements in survival. In order to enhance transition success, our pediatric SCD transition process was modified to include combined adult and pediatric provider clinics that incorporated participation by our local SCD community-based organization. All children ages 16 and over participated in this newly-formed transition program. PROCEDURE: After 5 years of implementation of the modified SCD transition program, we retrospectively studied clinical and non-clinical risk factors for an unsuccessful transition. Risk factor categories studied included patient demographics, transition clinic attendance, and disease severity. RESULTS: Thirty two percent of patients did not transition successfully. Demographic factors such as gender, race, and type of insurance did not influence transition outcome, although travel distance to the adult SCD center was an identifiable risk factor for an unsuccessful transition. While transition clinic attendance rate did not affect transition outcomes, older age at first modified combined transition clinic visit was a significant risk factor for lack of transition. Patients with clinical markers of milder disease severity (SC and Sbeta(+) genotypes and no chronic transfusion therapy) were at higher risk for an unsuccessful transition than patients with severe disease. CONCLUSIONS: We have identified several risk factors for lack of transition success which will allow us to modify our transition efforts going forward to capture this highest risk subset. PMID- 24347403 TI - In reference to "is nasopharyngoscopy necessary in adult-onset otitis media with effusion?". PMID- 24347404 TI - Characterization of a new model of thromboembolic stroke in C57 black/6J mice. AB - This study characterizes a new model of thromboembolic stroke of the middle cerebral artery in C57 black/6J mice, thus offering an opportunity to use the model for studying ischemic stroke in transgenic mice. Thromboembolic stroke was induced by local injection of either 1.5 or 3.0 UI of thrombin directly into the right MCA of C57 black/6J mice. Cerebral blood flow (CBF) velocity was measured continuously by laser Doppler flowmetry, which allowed documentation of both MCA occlusion and of spontaneous recanalization. After 24 h, all animals were euthanized. Cryosections were cut at 400-MUm intervals and silver stained with the high-contrast method for volumetric assessment of infarct size. Interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha), caspase-3 and hsp 70 protein levels were investigated by immunofluorescence. Thrombin injection resulted in clot formation in all animals. Cortical infarction occurred in 63% of the mice while 37% had a spontaneous MCA recanalization during the first 20 min following thrombin injection. In cases of successful MCA occlusion with consequent infarction, the clot was stable up to 2 h after formation. Subsequently, 20% recanalized spontaneously. Infarctions were restricted to the cortex with a mean lesion volume of 36 +/- 5 for 1.5 UI and 56 +/- 8 for 3.0 UI thrombin. Protein levels of IL-6, TNF-alpha, caspase-3, and hsp 70 were significantly increased after MCAO. The results demonstrate that the mouse thromboembolic stroke model produces cortical infarctions of consistent size in C57 black/6J mice, which is dependent upon the amount of thrombin used for clot formation. Spontaneous MCA recanalization occurs after 2 h of ischemia in 20% of mice. Thus, the thromboembolic model is an applicable stroke model for C57 black/6J mice, which mimics many of the features of human stroke, including spontaneous recanalization. However, strain differences between Swiss and C57 black/6J mice must be taken into account when using the model. PMID- 24347406 TI - Physical activity disparities in heterosexual and sexual minority youth ages 12 22 years old: roles of childhood gender nonconformity and athletic self-esteem. AB - BACKGROUND: Physical activity is an important health determinant. Little is known about sexual orientation differences in physical activity and their psychosocial determinants. PURPOSE: The aim of this study is to examine adolescent and young adult hours/week of moderate/vigorous physical activity (MVPA) and team sports participation by sexual orientation and investigate contributions of gender nonconformity and low athletic self-esteem to possible sexual orientation differences. METHODS: Analysis of data from 5,272 males and 7,507 females from 1999 to 2005 waves of the US Growing Up Today Study (ages 12-22 years). RESULTS: Sexual minorities (i.e., lesbian, gay, bisexual, mostly heterosexual) reported 1.21-2.62 h/week less MVPA (p < 0.01) and were 46-76 % less likely to participate in team sports than same-gender heterosexuals. Gender nonconformity and athletic self-esteem accounted for 46-100 % of sexual orientation MVPA differences. CONCLUSIONS: Physical activity contexts should be modified to welcome sexual minority males and females. Targeting intolerance of gender nonconformity and fostering athletic self-esteem may mitigate sexual orientation MVPA disparities. PMID- 24347407 TI - Psychosocial mediators of two community-based physical activity programs. AB - BACKGROUND: Previous findings are inconclusive regarding the mediators of physical activity behavior change. PURPOSE: To test self-efficacy and social support as mediators of Active Choices, a telephone-delivered physical activity intervention, and Active Living Every Day, a group-based physical activity intervention, implemented with midlife and older adults in community settings. METHODS: MacKinnon's product of coefficients was used to examine social support and self-efficacy as mediators of change in physical activity. The proportion of the total effect mediated was calculated. Each model controlled for age, gender, race (white vs. non-white), body mass index (BMI), and education (high school graduate or less vs. at least some college). RESULTS: Increases in self-efficacy mediated increases in physical activity among Active Choices (n = 709) and Active Living Every Day (n = 849) participants. For Active Living Every Day, increases in social support also mediated increases in physical activity in single mediator models. CONCLUSIONS: Increasing self-efficacy and social support may help increase physical activity levels in older adults. PMID- 24347405 TI - Sexual orientation and gender differences in markers of inflammation and immune functioning. AB - BACKGROUND: Sexual minorities have documented elevated risk factors that can lead to inflammation and poor immune functioning. PURPOSE: This study aims to investigate disparities in C-reactive protein (CRP) and Epstein-Barr virus (EBV) by gender and sexual orientation. METHODS: We used the National Longitudinal Study of Adolescent Health to examine disparities in CRP (N = 11,462) and EBV (N = 11,812). RESULTS: Among heterosexuals, women had higher levels of CRP and EBV than men. However, sexual minority men had higher levels of CRP and EBV than heterosexual men and sexual minority women. Lesbians had lower levels of CRP than heterosexual women. CONCLUSIONS: Gender differences in CRP and EBV found between men and women who identify as 100 % heterosexual were reversed among sexual minorities and not explained by known risk factors (e.g., victimization, alcohol and tobacco use, and body mass index). More nuanced approaches to addressing gender differences in sexual orientation health disparities that include measures of gender nonconformity and minority stress are needed. PMID- 24347408 TI - A comprehensive study of named entity recognition in Chinese clinical text. AB - OBJECTIVE: Named entity recognition (NER) is one of the fundamental tasks in natural language processing. In the medical domain, there have been a number of studies on NER in English clinical notes; however, very limited NER research has been carried out on clinical notes written in Chinese. The goal of this study was to systematically investigate features and machine learning algorithms for NER in Chinese clinical text. MATERIALS AND METHODS: We randomly selected 400 admission notes and 400 discharge summaries from Peking Union Medical College Hospital in China. For each note, four types of entity-clinical problems, procedures, laboratory test, and medications-were annotated according to a predefined guideline. Two-thirds of the 400 notes were used to train the NER systems and one third for testing. We investigated the effects of different types of feature including bag-of-characters, word segmentation, part-of-speech, and section information, and different machine learning algorithms including conditional random fields (CRF), support vector machines (SVM), maximum entropy (ME), and structural SVM (SSVM) on the Chinese clinical NER task. All classifiers were trained on the training dataset and evaluated on the test set, and micro-averaged precision, recall, and F-measure were reported. RESULTS: Our evaluation on the independent test set showed that most types of feature were beneficial to Chinese NER systems, although the improvements were limited. The system achieved the highest performance by combining word segmentation and section information, indicating that these two types of feature complement each other. When the same types of optimized feature were used, CRF and SSVM outperformed SVM and ME. More specifically, SSVM achieved the highest performance of the four algorithms, with F-measures of 93.51% and 90.01% for admission notes and discharge summaries, respectively. PMID- 24347409 TI - [Management of dislocated radial head fractures with biodegradable implants]. AB - BACKGROUND: The Mason classification is used for radial head fractures. Mason type I fractures are managed by a functional conservative treatment of no loading for six weeks. Mason II fractures with a displacement greater than 10 degrees or a depression of greater than 2 millimeters are treated with open reduction and use of biodegradable implants constructed of polylactide. These implants have the advantage of maintaining the joint surface by placement beneath the surface of the articular cartilage. Furthermore, the implants can be placed from various positions through the articular surface and are therefore more versatile than other modes of open reduction. METHOD: The OP technique in Mason II radial head fracture is demonstrated in a video for the example of a 31-year-old male patient. RESULTS: 35 patients were treated using the new polylactide pins (Polypin(r)). Average follow-up for 34 patients was 38 months. 31 patients with Mason type II fractures presented with a score of 96 out of 100 using the Broberg Morrey score. CT scans were performed after 18 and 24 months in all patients. One first degree asymptomatic osteolysis was observed at 18 months which was reduced at 24 months. Two years later the pins were not visible on conventional X-rays. CT scans at 5 years revealed the implants to be in various levels of resorption and bony regrowth. CONCLUSION: Dislocated radial head fractures can be treated with good results with biodegradable implants. PMID- 24347410 TI - [Editorial for the Journal of Orthopaedic and Trauma Surgery]. PMID- 24347411 TI - [Medium- to long-term follow-up after anterior cruciate ligament rupture and repair in healing response technique]. AB - BACKGROUND: Healing response (HR) is an all-arthroscopic technique for treatment of acute proximal anterior cruciate ligament (ACL) tears within 6 weeks after injury. By means of arthroscopically controlled microfracture holes in the native femoral attachment and perforations of the ACL itself the exit of stem cells and growth factors is induced and the ligament can heal into its native attachment zone. The purpose of the study was to document medium- to long-term results after 5 years or longer following the healing response (HR) procedure. The aim of our study was to show that HR is a treatment option for acute proximal ACL tears. MATERIAL AND METHODS: Between 2004 and 2007 126 patients were treated in healing response technique in our hospital. Patients with a complete proximal ACL tear and operation within 6 weeks of initial injury were included in this study. Patients who had complex knee injuries with multidirectional instability, ACL rerupture, contralateral ACL reconstruction, contralateral ACL rupture or knee replacement and cartilage repair procedures (AMIC, MACT, OATS) were excluded. 43 (23 women/20 men; mean age at time of surgery 36.6 years +/- 11.6; range: 16 to 66 years) of 89 eligible patients received clinical follow-up up to 8 years after surgery (mean: 6.3 years). Lysholm score, Tegner activity score, a modified IKDC 2000 knee examination form and an individually created questionnaire were used for evaluation. Furthermore, range of motion, muscle circumference of the lower limb and the anterior tibial translation were measured with a KT-1000 arthrometerTM (MEDmetric(r) Corporation, San Diego, USA). RESULTS: 15.1 % of all patients showed a primary insufficiency after HR. 24.6 % of the 126 patients required subsequent ACL reconstruction up to the time of data collection. The 43 patients who received clinical follow-up showed a mean Lysholm score of 92 +/- 8.9 points. 72 % reached their original level of activity in the Tegner activity score. According to the IKDC evaluation system 90.7 % of all patients were grade A. 93 % did not show muscles atrophies of the lower limb. There were no limitations in range of motion. Mean side-to-side difference in the KT-1000 manual-maximum displacement test measurements was 1.3 mm +/- 1.6 mm. 97.7 % patients had a normal or nearly normal knee function and 86 % rated the overall treatment as good to very good. CONCLUSION: Patients with good clinical results 6 to 12 weeks after HR show even in the medium- to long-term follow-up good clinical outcomes as well as objective stability. In selected cases HR is an alternative treatment option for acute, proximal ACL ruptures. When indicating an HR procedure, it should be taken into consideration that up to 15 % of all patients could have a primary insufficiency. PMID- 24347412 TI - [Intraoperative damage to the medial collateral ligament (MCL) - what is to be done?]. AB - BACKGROUND: Intraoperative damage to the medial collateral ligament is a rather rare condition given only scant attention in the literature. Observing international medical journals (over the recent years), one finds very few case histories. What is more, these case histories vary significantly with regards to their approaches to the problem at hand. MATERIAL AND METHODS: This survey lists essential publications and case histories in question and - following their analysis and in light of the fairly low number of respective cases - attempts to create a 'treatment algorithm'. RESULTS: Approaches to treatment vary considerably throughout the medical literature. Reasons are the localisation of the actual damage, pertaining to the medial collateral ligament as well as surgeons' aptitudes and preferences with regards to hinged or constraint implants. Eventually, there are five different treatment options: (i) solely conservative treatment by means of an orthesis; (ii) primary reconstruction of the medial collateral ligament; (iii) medial collateral ligament augmentation; (iv) inlay elevation and lateral release procedure; and (v) a higher degree of coupling regarding the TKA. CONCLUSION: It is strongly advised to refrain from conducting a release at the femoral origin of the medial collateral ligament. In stages, a tibial release should be carried out strictly subperiostally. A high expenditure of energy during tension examination needs to be utterly avoided. Reconstruction of the femoral origin/insertion can be carried out rather safely, while reconstruction of the tibial origin/insertion is more complicated due to the more complex anatomic line-up/constellation. Likewise, the reconstruction of the median ligament portion is considerably more difficult; in this case, the application of a primary suture or augmentation by use of the semitendinosus or quadriceps tendon are recommended. In addition, the temporary application of an orthesis is recommended regardless. In any case, a higher degree of coupling should be considered as a fallback. Introduced is an algorithm which differentiates the ligament damage location. PMID- 24347413 TI - [Characteristics in treatment of the hip in patients with Down syndrome]. AB - BACKGROUND: The treatment of hip instability in patients with Down syndrome is challenging. We have performed different pelvic osteotomies and corrections at the proximal femur for this indication. This retrospective study was conducted to evaluate the clinical and radiological outcome of each intervention. MATERIAL AND METHODS: All in all, 166 patients with Down syndrome were treated at our orthopaedic department in the observation period. Problems related to the hip joint were diagnosed in 63 of those patients. Only patients who underwent surgery were included in this study. The charts and X-rays of these 31 patients were evaluated with respect to the following parameters: incidence of the hip problem, concomitant diseases, temporal progress, kind of operation method and date, duration of stay in the hospital, after-care, follow-on surgery related to complications, AC angle, CE angle, ACM angle, CCD angle, index of migration according to Reimers, classification of Bauer and Kerschbauer and general morphology of the femoral head. The group was compared with an age-matched group of 21 patients with hip dysplasia. Those patients underwent the same sort of operation in the same year. RESULTS: In the Morbus Down group, we performed surgery for preservation of the hip in 49 cases. This included 13 osteotomies according to Chiari, 11 triple osteotomies according to Tonnis, 10 corrections by femoral varus derotation osteotomy, 8 pelvic osteotomies according to Pemberton, 5 pelvic osteotomies according to Salter and 2 open reductions of the hip. With respect to the moment of surgery, we detected three peaks of age. There was no difference in course of disease and quantity of complications between the groups. Satisfactory results concerning clinical and radiological outcome were achieved predominantly by complete redirectional acetabular osteotomies. Half of the patients who were solely treated by femoral varus derotation osteotomy needed follow-on surgery in the form of pelvic osteotomy. Comparison of preoperative and postoperative range of motion of the hip joint between groups detected capsular insufficiency, increased ligamentous laxity and muscular hypotonia in patients with Down syndrome. Comparison of pelvic radiographs demonstrated significant improvement concerning measured angles in both groups. Preoperative values with respect to AC angle and CE angle were demonstrated to be lower in the hip dysplasia group (p < 0.01); whereas values for ACM angle were comparable between groups. CONCLUSION: Hypermobility and secondary dislocation of the hip joint is a common problem in patients with Down syndrome, which often requires surgical intervention at an early stage. According to our data and clinical results we suggest a complete redirectional acetabular osteotomy in combination with capsular plication for treatment of this challenging condition. PMID- 24347414 TI - [Treatment of septic arthritis of the hip in children and adolescents]. AB - GOAL: Irrigation of the hip joint by hip arthrotomy represents the standard treatment for septic arthritis of the hip in childhood and adolescence. Arthroscopic lavages for treating a septic knee, elbow, ankle and glenohumeral joints are well established, but have only reached little acceptance in the therapy of septic hip arthritis in children. The goal of this study is to evaluate the advantages of the minimally invasive arthroscopic high-volume lavage for septic hip arthritis with regards to treatment safety and complication frequency. PATIENTS AND METHODS: 20 children aged 6.4 years on average (2-14 years) with obvious signs of septic arthritis of the hip proven clinically and by blood tests were arthroscopically treated in a 2-portal technique. In a prone position on a standard table the patient had the arthroscopic lavage procedure followed by insertion of a Redon tube. In all cases a histological sample and a bacterial swab were taken. A traction table was not used. In three children there was a stage I according to Stutz and Gachter, in thirteen a stage II and in four patients a stage III. Because of a concomitant femoral neck osteomyelitis in three cases and an osteomyelitis of the os pubis in a single patient, PMMA mini chains were locally administered. The histological samples were reported as purulent in 16 and as non-specific synovitis in four patients. In ten children a positive bacterial result was given, with Staphylococcus aureus found in 7 cases and single cases with Meningococci, Salmonella and Staphylococcus warneri. All patients received an intravenous antibiotic treatment for 14 days followed by four weeks of oral antibiotics. RESULTS: 16 out of 20 children were sufficiently treated by one single arthroscopic lavage. In three cases with additional osteomyelitis a secondary procedure was needed for removal of the antibiotic chain. During follow-up after an average of 2.9 years 19 of 20 children demonstrated a free range of hip joint motion and a full sporting activity without any restrictions. One girl with stage III arthritis and a preoperative duration of symptoms of seven days developed a femoral head necrosis and chondrolysis with hip joint subluxation. The other 19 patients regained an excellent Harris hip score at follow-up, whereas the girl only produced moderate score values. So, 19 children had an unrestricted function of their hips on the same activity level as before. CONCLUSION: The 2-portal hip arthroscopy with high volume lavage represents a safe and minimally invasive method in order to successfully treat septic arthritis of the hip and concomitant femoral neck osteomyelitis in children and adolescents. This technique leads to a very low morbidity offering all advantages of arthroscopic procedures. The use of cannulated instruments through well established safe portals makes this arthroscopic lavage procedure a simple and easily adoptable technique. PMID- 24347415 TI - [Fibromyalgia syndrome - updated s3 guidelines]. AB - Patients with chronic widespread pain often present with musculo-skeletal pain and therefore often initially contact an orthopaedist. For these patients fibromyalgia syndrome is an important differential diagnosis. Recommendations for the diagnosis of and therapy for fibromyalgia syndrome based on the recent German S3 guidelines for fibromyalgia syndrome (AWMF registration number 041/004) are outlined in this paper. These guidelines were developed under the coordination of the German interdisciplinary association for pain management DIVS and two patient support groups. The history of a typical symptom complex and the exclusion of relevant somatic causes for the pain are epecially relevant for the diagnosis of fibromyalgia syndrome. Besides the exclusion of relevant orthopaedic causes for the pain, psycho-social aspects should always be evaluated. According to the modified ACR criteria 2010, chronic widespread pain and accompanying sleep disturbances and a physical as well as mental state of exhaustion lead to the diagnosis of fibromyalgia syndrome. It is not mandatory to check tender points (ACR 1990 criteria). A graduated treatment approach depending on the severity level of the fibromyalgia syndrome in the individual patient is recommended. Active treatment options (aerobic training, meditative movement therapies, strength training) should be preferred to any drug therapy in the long-term treatment of fibromyalgia. If indicated, amitryptiline or duloxetine may be used to treat accompanying depressive or generalised anxiety disorder. Muscle relaxant medication, non-steroidal anti-inflammatory drugs and strong opioids should be avoided. The multimodal pain therapy considering all psycho-social aspects is a promising treatment option for fibromyalgia syndrome of moderate to high severity. PMID- 24347416 TI - [Logbook of learning targets for special educational skills in orthopaedic and trauma surgery for undergraduate medical training]. AB - INTRODUCTION: The changes in medical licensing regulations introduced in Germany in 2012 require the development of specific catalogues, termed logbooks, that define the practical skills medical students should acquire in different specialties. In conjunction with another change in medical education, which allows medical students to freely select any German university hospital or academic teaching hospital for their one-year internship, these catalogues are a prerequisite for ensuring comparable training standards throughout Germany. The German licensing regulations provide no details regarding the contents or form of the logbooks but only mention a "training programme" in very general terms. A logbook is commonly understood to define clear learning objectives to be accomplished during a specified interval (4 months). The conference of German medical faculties proposed a basic logbook for compulsory training modules (surgery and internal medicine) that is intended to serve as a model (formally and contentwise) for those who develop similar catalogues for elective training modules. Here we present our logbook for an elective training module in orthopaedic surgery and traumatology. MATERIAL AND METHOD: The logbook presented here is based on the catalogue of learning outcomes in orthopaedic surgery and traumatology developed by an expert board of the medical teaching study group of the German Society of Orthopaedic Surgery and Traumatology (DGOU) in 2011. The objectives defined for the one-year internship are of necessity divided into orthopaedic surgery and traumatology skills that must be acquired by all medical students and those that are optional (compulsory and elective modules). Using a set of predefined criteria, the authors developed the catalogue of learning outcomes (logbook) presented here. The catalogue outlines the competencies to be acquired in an elective orthopaedic surgery and traumatology module, leaving it to each medical faculty to work out the details. Where applicable, comprehensive skills across a number of (compulsory and elective modules) learning objectives are arranged in such a way that they can be taught at different levels of complexity. RESULTS: The logbook covers 15 skill domains from different specific components of orthopaedic surgery and traumatology. Where these skills overlap with those also required in compulsory modules (e.g., surgery), the required level of complexity may be lower for students in the elective module. The text is supplemented by figures with synopses of the major issues and summaries for easy reference. CONCLUSION: With the recent changes in German licensing regulations for physicians, it has become necessary to set up a logbook of uniform learning outcomes to assist medical students and their teachers alike. The authors have developed such a logbook of elective training modules in orthopaedic surgery and traumatology to be taught during the one-year undergraduate internship of German medical students. PMID- 24347417 TI - [Radiofrequency kyphoplasty combined with posterior fixation in the treatment of burst fractures]. AB - PURPOSE: Radiofrequency kyphoplasty is an advancement of the balloon kyphoplasty and offers comparable results with a shorter operation time and a lower risk of cement leakage. This prospective study investigates the outcome of radiofrequency kyphoplasty in combination with posterior fixation by a cement-augmented screw system. Accordingly, statistical analyses of the treatment data were performed. MATERIALS AND METHODS: 19 patients (mean age: 74.5 +/- 7.2 years) with osteoporotic vertebral burst fractures were included in the study. All of them required a surgical intervention for treating the fracture. Thereby, the vertebrae were augmented by radiofrequency kyphoplasty and a posterior fixation by cement-augmentable screws was performed. To evaluate the effectiveness and safety of the procedure, pain was measured with the visual analog scale (VAS) and functional impairment was analysed by measuring the Oswestry disability index (ODI). Furthermore, a radiographic analysis of the anterior and medial height of the vertebrae and the degree of kyphosis were undertaken. All data were recorded preoperatively, 3 to 4 days postoperatively, 3 months postoperatively and 6 months postoperatively and any additionally occurring cement leakage was documented. RESULTS: The treatment showed a significant reduction of pain and improvement of the functional impairment at the 3 to 4 days postoperative evaluation (pVAS < 0.001, pODI < 0.001). The further follow-ups demonstrated an ongoing improvement of the VAS and ODI from each measurement to the next (pVAS_post-3 M < 0.001, pVAS_3 M-6 M = 0.17, pODI_post-3 M < 0.001, pODI_3 M-6 M = 0.004). The height of the vertebrae was significantly improved after the surgery (p_anterior < 0.001, p_medial < 0.001) and reduced slightly from follow up to follow-up, but still remained higher than the preoperative value. The degree of kyphosis was also significantly improved after the surgery (p < 0.001), whereby a significant deterioration was shown at the following examinations (p_post-3 M = 0.023, p_3 M-6 M = 0.016). But even as the height decreased the degree of kyphosis was still improved in relation to the preoperative values. During the surgery cement leakage occurred in 3 cases (15.79 %). CONCLUSION: Radiofrequency kyphoplasty is a safe and effective procedure for the treatment of vertebral compression fractures in combination with the use of posterior fixation by cement-augmentable screws with an acceptable rate of cement leakage. PMID- 24347418 TI - [Scaphoid fractures and pseudarthrosis of the scaphoid]. AB - Scaphoid fractures are by 80 % the most common fractures of the carpal bones. Detection and treatment can be delayed due to only slight clinical symptoms, which are often shown by acute injuries of the scaphoid. Pseudarthrosis of the scaphoid developing arthrosis of the wrist or even a carpal collapse can be the consequence. An in-depth clinical examination and adequate radiological diagnostics are essential for the detection and the treatment of scaphoid fractures. A primary examination by CT scan is obligatory. The classification of Krimmer/Herbert in the CT is used to subdivide the scaphoid fractures. Depending on the appearance of the fracture a conservative or surgical approach is indicated. All stable fractures of the scaphoid can be treated conservatively. In all forms of unstable scaphoid fractures surgery is recommended. Different ways of surgical approaches and osteosyntheses are described. Pseudarthrosis of the scaphoid should be surgically reconstructed with osteosynthesis in combination with bone graft to prevent a carpal collapse. PMID- 24347420 TI - Cortical photothrombotic infarcts impair the recall of previously acquired memories but spare the formation of new ones. AB - BACKGROUND AND PURPOSE: Despite a high incidence of poststroke dementia, there is no specific treatment for this condition. Because the evaluation of poststroke cognitive deficits in animal models of stroke is exceedingly challenging, the preclinical evaluation of candidate drugs is limited. We aimed to explore the impact of small cortical photothrombotic strokes on poststroke cognition, thereby assessing the suitability of this experimental stroke model for the investigation of cognitive impairment after stroke. METHODS: Photothrombotic cortical infarcts were induced in 19 adult male Wistar rats. Nineteen sham-operated animals served as controls. Using the Morris water maze, we analyzed the impact of photothrombotic stroke on both the acquisition of new memories and the recall of previously acquired memories. The cylinder test, the adhesive tape removal test, and the rotarod test were performed to investigate sensorimotor deficits. RESULTS: Photothrombotic stroke significantly impaired the recall of previously acquired memories (P<0.05), whereas the acquisition of new memories remained largely intact. The analysis of the animals' swimming speed in the water maze and the rotarod test showed no confounding motor impairments after photothrombotic stroke. The adhesive tape removal test and the cylinder test revealed mild sensorimotor deficits in lesioned animals (P<0.05). CONCLUSIONS: Photothrombotic cortical infarcts impair the recall of memories acquired before stroke, whereas the formation of new memories remains unimpaired. The observed deficits in the water maze are not confounded by disturbed motor functions. Overall, experimental photothrombotic strokes are well suited for the investigation of specific cognitive impairments after stroke. PMID- 24347423 TI - Diffusion-weighted image and fluid-attenuated inversion recovery image mismatch: unclear-onset versus clear-onset stroke. AB - BACKGROUND AND PURPOSE: Mismatch in lesion visibility between diffusion-weighted image and fluid-attenuated inversion recovery image (DWI-FLAIR mismatch) has been proposed as a biomarker for the estimation of ischemic lesion age. The actual onset in some patients with unclear-onset stroke (UnCOS) may be close to the first-found abnormal time. We hypothesized that patients with UnCOS within a particular time window might have a similar DWI-FLAIR mismatch profile with patients with clear-onset stroke (COS). METHODS: Patients who underwent MRI within 6 hours from first-found abnormal time were recruited retrospectively. Clinical characteristics and the proportion of DWI-FLAIR and perfusion-weighted image-DWI mismatch in each time window were compared between UnCOS and COS. RESULTS: The final analysis included 259 patients (114 with UnCOS and 145 with COS). Patients with UnCOS were older and had more severe stroke at baseline. Risk factors, stroke subtypes, and perfusion-weighted image-DWI mismatch did not differ between the 2 groups. The proportion of patients with DWI-FLAIR mismatch in UnCOS did not differ from COS within 2 hours of first-found abnormal time (50.0% versus 51.5%; P=0.92), but it was significantly lower in UnCOS than in COS at 2 to 3 hours (16.1% versus 44.4%; P=0.02), 3 to 4 hours (13.8% versus 36.4%; P=0.04), and 4 to 5 hours (5.6% versus 29.6%; P=0.05). CONCLUSIONS: The proportion of DWI-FLAIR mismatch in UnCOS within the first 2 hours from first found abnormal time was similar with COS, but it sharply decreased beyond 2 hours. These data suggest that patients with UnCOS within 2 hours of symptom detection may be good candidates for multimodal imaging-based thrombolysis. PMID- 24347422 TI - Carotid stenting: is there an operator effect? A pooled analysis from the carotid stenting trialists' collaboration. AB - BACKGROUND AND PURPOSE: Randomized clinical trials show higher 30-day risk of stroke or death after carotid artery stenting compared with surgery. We examined whether operator experience is associated with 30-day risk of stroke or death in the Carotid Stenting Trialists' Collaboration database. METHODS: The Carotid Stenting Trialists' Collaboration is a pooled individual patient database including all patients recruited in 3 randomized trials of stenting versus endarterectomy for symptomatic carotid stenosis (Endarterectomy Versus Angioplasty in patients with Symptomatic Severe Carotid Stenosis trial, Stent Protected Angioplasty versus Carotid Endarterectomy trial, and International Carotid Stenting Study). Lifetime carotid artery stenting experience, lifetime experience in stenting procedures excluding the carotid, and annual number of procedures performed within the trial (in-trial volume), divided into tertiles, were used to measure operator experience. The outcome event was the occurrence of any stroke or death within 30 days of the procedure. The analysis was done per protocol. RESULTS: Among 1546 patients who underwent carotid artery stenting, 120 (7.8%) had a stroke or death within 30 days of the procedure. The 30-day risk of stroke or death did not differ according to operator lifetime carotid artery stenting experience (P=0.8) or operator lifetime stenting experience excluding the carotid (P=0.7). In contrast, the 30-day risk of stroke or death was significantly higher in patients treated by operators with low (mean <=3.2 procedures/y; risk 10.1%; adjusted risk ratio=2.30 [1.36-3.87]) and intermediate annual in-trial volumes (3.2-5.6 procedures/y; 8.4%; adjusted risk ratio=1.93 [1.14-3.27]) compared with patients treated by high annual in-trial volume operators (>5.6 procedures/y; 5.1%). CONCLUSIONS: Carotid stenting should only be performed by operators with annual procedure volume >=6 cases per year. PMID- 24347424 TI - Reperfusion injury on magnetic resonance imaging after carotid revascularization. AB - BACKGROUND AND PURPOSE: Reperfusion injury can be revealed as delayed gadolinium enhancement in the subarachnoid space on a fluid-attenuated inversion recovery image, which is designated as a hyperintense acute reperfusion marker (HARM). We sought to investigate the occurrence and predictors of HARM and its association with new ischemic infarcts after carotid revascularization. METHODS: Forty-five patients who underwent carotid endarterectomy or stenting were prospectively enrolled. Diffusion-weighted imaging and fluid-attenuated inversion recovery were performed before and 24 hours after the procedures. Postprocedural fluid attenuated inversion recovery was done after intravenous gadolinium injection. RESULTS: HARM was observed in 8 (17.8%) patients. Of these, 4 patients showed neurological deterioration associated with HARM. These symptomatic HARMs disappeared on follow-up magnetic resonance imaging. Patients with symptomatic HARM were older (P=0.010) and had more frequent leukoaraiosis (P=0.012) and higher postprocedural systolic blood pressure (P=0.025) than those without. New brain infarcts on postprocedural diffusion-weighted imaging were identified in 13 (28.9%) patients. HARM was not associated with new infarcts. CONCLUSIONS: HARM after carotid revascularization is not uncommon. Symptomatic HARM was associated with old age, underlying leukoaraiosis, and postprocedural high blood pressure. PMID- 24347425 TI - Diagnosis of endocrine disease: Biochemical diagnosis of phaeochromocytoma and paraganglioma. AB - Adrenal phaechromocytomas and extra-adrenal sympathetic paragangliomas (PPGLs) are rare neuroendocrine tumours, characterised by production of the catecholamines: noradrenaline, adrenaline and dopamine. Tumoural secretion of catecholamines determines their clinical presentation which is highly variable among patients. Up to 10-15% of patients present entirely asymptomatic and in 5% of all adrenal incidentalomas a PPGL is found. Therefore, prompt diagnosis of PPGL remains a challenge for every clinician. Early consideration of the presence of a PPGL is of utmost importance, because missing the diagnosis can be devastating due to potential lethal cardiovascular complications of disease. First step in diagnosis is proper biochemical analysis to confirm or refute the presence of excess production of catecholamines or their metabolites. Biochemical testing is not only indicated in symptomatic patients but also in asymptomatic patients with adrenal incidentalomas or identified genetic predispositions. Measurements of metanephrines in plasma or urine offer the best diagnostic performance and are the tests of first choice. Paying attention to sampling conditions, patient preparation and use of interfering medications is important, as these factors can largely influence test results. When initial test results are inconclusive, additional tests can be performed, such as the clonidine suppression test. Test results can also be used for estimation of tumour size or prediction of tumour location and underlying genotype. Furthermore, tumoural production of 3-methoxytyramine is associated with presence of an underlying SDHB mutation and may be a biomarker of malignancy. PMID- 24347426 TI - Effects of raloxifene and estrogen on bioactive IGF1 in GH-deficient women. AB - CONTEXT: GH action is attenuated by estrogens and selective estrogen receptor modulators (SERMs) administered orally. During GH therapy in hypopituitary women, co-treatment with raloxifene, a SERM, induced a smaller gain in lean body mass (LBM) compared with estrogen, despite an equal reduction in IGF1. As a higher IGF binding protein-3 (IGFBP3) level was observed with raloxifene co-treatment, we hypothesize that an increase in IGFBP3 reduced IGF1 bioactivity causing the attenuated anabolic effect. OBJECTIVE: To assess the effects of 17beta-estradiol (E2) and raloxifene on bioactive IGF1. DESIGN: In study 1, 12 GH-deficient (GHD) women were randomized to raloxifene 120 mg/day or E2 4 mg/day for 1 month. In study 2, 16 GHD women were randomized to 1 month GH treatment alone (0.5 mg/day) and in combination with raloxifene (60 mg/day) or E2 (2 mg/day). We measured bioactive IGF1, immunoreactive IGF1 and IGF2, and IGFBP3 immunoreactivity and fragmentation. RESULTS: Raloxifene and estrogen suppressed (P<0.05) total IGF1 equally in GHD and GH-replaced hypopituitary women. In GHD patients, neither raloxifene nor estrogen affected bioactive IGF1. GH significantly increased IGF1 bioactivity, an effect attenuated by co-treatment with raloxifene (Delta -23 +/- 7%, P<0.01) and estrogen (Delta -26 +/- 3%, P=0.06). Total IGF1 correlated (r(2)=0.54, P<0.001) with bioactive IGF1, which represented 3.1 +/- 0.2% of the total IGF1, irrespective of the treatments. Total IGF2 was unchanged by raloxifene and estrogen treatment. IGFBP3 was significantly higher during raloxifene administration, whereas no differences in IGFBP3 fragmentation were observed. CONCLUSION: Raloxifene effect on bioactive IGF1 is similar to that of estrogen despite higher IGFBP3 levels during raloxifene administration. We conclude that the observed different effects on LBM between raloxifene and estrogen treatments cannot be explained by differences in IGF1 bioactivity. PMID- 24347427 TI - Mass-array screening of frequent mutations in cancers reveals RB1 alterations in aggressive adrenocortical carcinomas. AB - CONTEXT: Adrenocortical carcinoma (ACC) is a rare disease with a poor overall outcome. Transcriptome analysis identified two groups of ACCs with different prognosis. In aggressive ACCs, somatic mutations of the tumor suppressor gene TP53 and the proto-oncogene beta-catenin are detected in 50% of cases. For the remaining aggressive ACCs and for the group with a better prognosis, molecular alterations are unknown. OBJECTIVE: To identify new molecular actors driving adrenal tumorigenesis. EXPERIMENTAL DESIGN: Analysis by mass array of 374 mutations among 32 common oncogenes or tumor suppressor genes was performed on the tumoral DNA of 26 ACCs, using Sequenom OncoCarta Panels. RESULTS: Four mutations were identified, two previously known beta-catenin mutations and one alteration in two other genes: JAK3 and retinoblastoma gene (RB1). The JAK3 alteration was found in leukocyte DNA and therefore considered as a polymorphism and not a somatic event. The full RB1 tumor suppressor gene was subsequently sequenced in a cohort of 49 ACCs (26 ACCs from the 'OncoCarta cohort' and 23 other ACCs): three somatic mutations were identified, all in the poor-outcome ACC group. By immunohistochemistry, a loss of the retinoblastoma protein (pRb) was found exclusively in aggressive ACCs in 27% of cases (seven out of 26), three of them with an inactivating RB1 mutation. Among the seven pRb-negative ACCs, five had an allele loss at the RB1 locus. CONCLUSIONS: Parallel analysis of somatic mutations among known cancer genes allowed us to identify RB1 as a new actor in aggressive ACCs. These results suggest a prognostic significance of pRb expression loss in ACCs. PMID- 24347428 TI - Plasma levels of pentraxin-3, an inflammatory protein involved in fertility, are reduced in women with polycystic ovary syndrome. AB - OBJECTIVE: Pentraxin-3 (PTX3), like C-reactive protein (CRP), is an acute-phase protein that belongs to the pentraxin superfamily. Moreover, it is expressed in the cumulus oophorus and appears to be involved in female fertility. The aim of the present study was to assess whether PTX3 levels are altered in polycystic ovary syndrome (PCOS) women and whether they show any relationship with the main features of these subjects. DESIGN: A cross-sectional study was conducted at the outpatient clinic of an academic centre. METHODS: A total of 66 women affected with PCOS and 51 healthy controls were studied. Plasma PTX3 and serum CRP were measured by ELISA. Androgens were measured by liquid chromatography-mass spectrometry and free testosterone was measured by equilibrium dialysis. In PCOS women, insulin sensitivity was assessed by the glucose clamp technique. RESULTS: Adjusting for age and BMI, plasma PTX3 was reduced in PCOS women (P=0.036), in contrast with serum CRP, which was increased (P=0.004). In multiple regression analysis, serum androgens and other endocrine and ovarian features of PCOS were predictors of PTX3 levels, whereas body fat was the main independent predictor of CRP concentrations. CONCLUSIONS: Plasma PTX3 levels were reduced in PCOS women and independently associated with hyperandrogenism and other endocrine and ovarian features of PCOS. PMID- 24347429 TI - The inverse electron demand Diels-Alder click reaction in radiochemistry. AB - The inverse electron-demand Diels-Alder (IEDDA) cycloaddition between 1,2,4,5 tetrazines and strained alkene dienophiles is an emergent variety of catalyst free 'click' chemistry that has the potential to have a transformational impact on the synthesis and development of radiopharmaceuticals. The ligation is selective, rapid, high-yielding, clean, and bioorthogonal and, since its advent in 2008, has been employed in a wide variety of chemical settings. In radiochemistry, the reaction has proven particularly useful with (18) F and has already been utilized to create a number of (18) F-labeled agents, including the PARP1-targeting small molecule (18) F-AZD2281, the alphav beta3 integrin targeting peptide (18) F-RGD, and the GLP-1-targeting peptide (18) F-exendin. The inherent flexibility of the ligation has also been applied to the construction of radiometal-based probes, specifically the development of a modular strategy for the synthesis of radioimmunoconjugates that effectively eliminates variability in the construction of these agents. Further, the exceptional speed and biorthogonality of the reaction have made it especially promising in the realm of in vivo pretargeted imaging and therapy, and pretargeted imaging strategies based on the isotopes (111) In, (18) F, and (64) Cu have already proven capable of producing images with high tumor contrast and low levels of uptake in background, nontarget organs. Ultimately, the characteristics of inverse electron-demand Diels-Alder click chemistry make it almost uniquely well-suited for radiochemistry, and although the field is young, this ligation has the potential to make a tremendous impact on the synthesis, development, and study of novel radiopharmaceuticals. PMID- 24347430 TI - Prognostic value of the proliferation marker Ki-67 in laryngeal carcinoma: results of the accelerated radiotherapy with carbogen breathing and nicotinamide phase III randomized trial. AB - BACKGROUND: The prognostic and predictive value of the proliferation marker Ki-67 was investigated in a randomized trial comparing accelerated radiotherapy with carbogen breathing and nicotinamide (ARCON) to accelerated radiotherapy in laryngeal carcinoma. METHODS: Labeling index of Ki-67 (Li Ki-67) in immunohistochemically stained biopsies and the colocalization with carbonic anhydrase IX (CAIX) were related to tumor control and patient survival. RESULTS: On average, node-positive patients had a higher Li Ki-67 (median 14% vs 8%; p < .01). In patients with a high Li Ki-67, the 5-year regional control and metastases-free survival were 79% versus 96% (p < .01) and 71% versus 88% (p = .05) for accelerated radiotherapy and ARCON, respectively. The 5-year local control and disease-specific survival were not significantly different. Patients with low Ki-67 expression had an excellent outcome with accelerated radiotherapy alone. CONCLUSION: Patients with laryngeal carcinomas with high proliferative activity are at increased risk of regional and distant metastases formation. This risk can be reduced by treatment with ARCON. PMID- 24347431 TI - Use of the mouse ear vesicant model to evaluate the effectiveness of ebselen as a countermeasure to the nitrogen mustard mechlorethamine. AB - Previous studies in this and other laboratories have demonstrated that ebselen (EB-1), an organoselenium compound, spares cells from mechlorethamine (HN2) toxicity in vitro. In the present study, the hypothesis that EB-1 will reduce dermal toxicity of HN2 in vivo is put forward and found to have merit. Using the mouse ear vesicant model (MEVM), HN2, applied topically, showed a dose-dependent effect upon ear swelling and thickness 24 h after treatment; whereas tissue injury consistent with vesication was observed at the higher test doses of HN2 (>= 0.250 umol per ear). To examine HN2 countermeasure activity using the MEVM, either hydrocortisone (HC), as a positive control, or EB-1, the test countermeasure, was administered as three topical treatments 15 min, 4 and 8 h after HN2 exposure. Using this approach, both HC and EB-1 were found to reduce tissue swelling associated with HN2 toxicity 24 h after exposure to the vesicant. Taken together, these data demonstrate for the first time the effectiveness of EB 1 as a vesicant countermeasure in a relevant in vivo model. PMID- 24347432 TI - Postnatal change in sulcal length asymmetry in cerebrum of cynomolgus monkeys (Macaca fascicularis). AB - The purpose of this study was to determine the timing of the onset of adult-type sulcal length asymmetry during postnatal development of the male cynomolgus monkey cerebrum. The monkey brain has already reached adult size by 3 months of age, although the body weight only represents 1/8 of the adult body weight by that time. The fronto-occipital length and the cerebral width also reached adult levels by that postnatal age with no left/right bias. Consistently, lengths of the major primary sulci reached adult levels by 3 months of age, and then decreased slightly in sexually mature monkeys (4-6.5 years of age). Asymmetry quotient analysis showed that sulcal length asymmetry patterns gradually changed during postnatal development. The male adult pattern of sulcal length asymmetry was acquired after 24 months of age. In particular, age-dependent rightward lateralization of the arcuate sulcal length was revealed during cerebral maturation by three-way ANOVA. The results suggest that the regional difference in cerebral maturation from adolescence to young adulthood modifies the sulcal morphology with characteristic asymmetric patterns in male cynomolgus monkeys. PMID- 24347433 TI - Simultaneous detection of three antiviral and four antibiotic compounds in source separated urine with liquid chromatography. AB - An analytical method for the simultaneous screening of three antiviral agents (nevirapine, zidovudine, lamivudine), four antibiotics (sulfamethoxazole, trimethoprim, ciprofloxacin, rifampicin) and one reference compound (carbamazepine) in human urine was developed. Separation was achieved with a Kinetex XB-C18 (75 * 4.6 mm, 2.6 MUm) column after the extraction of pharmaceuticals from urine with SPE. Gradient elution with a mobile phase consisting of acetonitrile and 10 mM KH2 PO4 (pH 2.5), and diode array detection with monitoring at 210 and 264 nm was applied. The developed method was validated in terms of selectivity, linearity, stability and sensitivity. Repeatability (n = 3) and between-day precision (n = 3) revealed RSD <5%. The detection limits were estimated as 0.02-0.54 g/L (depending on compound). The method was validated for human urine and successfully applied to the simultaneous quantification of selected compounds. Strata-X cartridges provided good recoveries ranging from 81 to 109%. The limits of detection for urine varied between 0.04 and 1.61 g/L. The method is suitable for the fast determination of selected pharmaceuticals from source-separated urine samples for further environmental risk assessment and degradation potential evaluation. It provides a way to enhance safe nutrient recycling from wastewater streams and promotes the safe use of urine as fertiliser. PMID- 24347434 TI - Influence of health-insurance access and hospital retention policies on childhood cancer treatment in Kenya. AB - BACKGROUND: Kenyan national policies for public hospitals dictate that patients are retained on hospital wards until their hospital bills are paid, but this payment process differs for patients with or without access to National Hospital Insurance Fund (NHIF) at diagnosis. Whether these differences impact treatment outcomes has not been described. Our study explores whether childhood cancer treatment outcomes in Kenya are influenced by health-insurance status and hospital retention policies. PROCEDURE: This study combined retrospective review of medical records with an illustrative case report. We identified children diagnosed with malignancies at a large Kenyan academic hospital between 2007 and 2009, their treatment outcomes, and health-insurance status at diagnosis. RESULTS: Between 2007 and 2009, 222 children were diagnosed with malignancies. Among 180 patients with documented treatment outcome, 54% abandoned treatment, 22% had treatment-related death, 4% progressive/relapsed disease, and 19% event free survival. Health-insurance status at diagnosis was recorded in 148 children: 23% had NHIF and 77% had no NHIF. For children whose families had NHIF compared with those who did not, the relative risk for treatment abandonment relative to event-free survival was significantly smaller (relative-risk ratio = 0.31, 95% CI = 0.12-0.81, P = 0.016). The case report illustrates difficulties that Kenyan families might face when their child is diagnosed with cancer, has no NHIF, and is retained in hospital. CONCLUSIONS: Children with NHIF at diagnosis had significantly lower chance of abandoning treatment and higher chance of survival. Childhood cancer treatment outcomes could be improved by interventions that prevent treatment abandonment and improve access to NHIF. Hospital retention of patients over unpaid medical bills must stop. PMID- 24347435 TI - An easy and effective method to modulate molecular energy level of the polymer based on benzodithiophene for the application in polymer solar cells. AB - Attaching meta-alkoxy-phenyl groups as conjugated side chains is an easy and effective way to modulate the molecular energy level of D-A polymer for photovoltaic application, and the polymer solar cells based on the polymer consisting meta-alkoxy-phenyl groups as conjugated side chain, PBT-OP, shows an enhanced open circuit voltage and thus higher efficiency of 7.50%, under the illumination of AM 1.5G, 100 mW/cm(2) . PMID- 24347436 TI - Un Abrazo Para La Familia: an evidenced-based rehabilitation approach in providing cancer education to low-SES Hispanic co-survivors. AB - We discuss Un Abrazo Para La Familia as an effective, rehabilitation-informed evidence-based model of education, information-sharing, and skill teaching for use with low-income Hispanic co-survivors of cancer. Over 2 years, 120 co survivors participated in the intervention. The majority of participants (96 %) were women and all but one reported being Hispanic. Both in years 1 and 2, we followed the same pre- and post-intervention evaluation design. Based on pre- and post-intervention assessments of cancer-related knowledge and self-efficacy, the percentage of questions answered correctly about cancer significantly increased for co-survivors. Self-efficacy significantly increased as well. Using item analysis, we explored skill teaching as a mechanism for the effective delivery of Un Abrazo and recommend the use of promotoras in providing the intervention. Of the 12 cancer knowledge items resulting in statistically significant increases of cancer knowledge, 5 were taught via interactive skill teaching. Given the projected rise in the incidence of cancer in Hispanic populations, coupled with the fact that people from low-income backgrounds face unique challenges in cancer prevention and management, implications of the Un Abrazo model for future research and policy regarding cancer and families are considered. PMID- 24347437 TI - Olfactory neuroblastoma: a 35-year experience and suggested follow-up protocol. AB - OBJECTIVES/HYPOTHESIS: To validate a follow-up protocol based on the long-term outcomes and recurrence rates in patients who have undergone surgical treatment for olfactory neuroblastoma. METHODS: A prospective review of all patients treated for olfactory neuroblastoma at our institution over a 35-year period. RESULTS: Ninety-five patients were treated from 1978 to 2013, with craniofacial (65 patients) or endoscopic resection (30 patients). Duration of follow-up ranged from 1 to 309 months (mean, 88.66 months). Fifty-six patients were alive and well, and 13 were alive with recurrent disease. Twenty-one patients had died of disease, and three had died of intercurrent disease. Overall survival was 83.4% at 5 years and 76.1% at 10 years. Disease-free survival at 5 years was 80% and at 10 years was 62.8%. A Cox regression analysis showed orbital extension and intracranial involvement to be significant independent factors affecting outcome. Local and regional recurrence occurred after an average of 49 months but with a range of 3 to 233 months. CONCLUSIONS: In our series, olfactory neuroblastoma most commonly recurred within the first 4 years but can recur very late, after 19.4 years in one case. There is currently no universally accepted follow-up regime, but even late recurrence is eminently treatable. We therefore propose a protocol for lifelong follow-up with both clinical examination and serial imaging, including the neck and entire intracranial compartment. LEVEL OF EVIDENCE: 4. PMID- 24347438 TI - Pamidronate attenuates muscle loss after pediatric burn injury. AB - Children who are burned >40% total body surface area lose significant quantities of both bone and muscle mass because of acute bone resorption, inflammation, and endogenous glucocorticoid production, which result in negative nitrogen balance. Because administration of the bisphosphonate pamidronate within 10 days of the burn injury completely prevents the bone loss, we asked whether muscle protein balance was altered by the preservation of bone. We reviewed the results from 17 burned pediatric subjects previously enrolled in a double-blind randomized controlled study of pamidronate in the prevention of post-burn bone loss and who were concurrently evaluated for muscle protein synthesis and breakdown by stable isotope infusion studies during the acute hospitalization. We found a significantly lower fractional protein synthesis rate (FSR) in the pamidronate group and a correspondingly lower rate of appearance of the amino acid tracer in venous blood, suggesting lower muscle protein turnover. Moreover, net protein balance (synthesis minus breakdown) was positive in the subjects receiving pamidronate and negative in those receiving placebo. Muscle fiber diameter was significantly greater in the pamidronate subjects and leg strength at 9 months post-burn was not different between subjects who received pamidronate and normal physically fit age-matched children studied in our lab. Leg strength in burned subjects who served as controls tended to be weaker, although not significantly so. If substantiated by a larger study, these results suggest that bone may have a paracrine mechanism to preserve muscle and this finding may have implications for the treatment of sarcopenia in the elderly. PMID- 24347439 TI - Single molecule mechanical manipulation for studying biological properties of proteins, DNA, and sugars. AB - For over 20 years there has been immense biological insight gained using single molecule mechanical measurements to understand properties of biomolecules. This review outlines the field of single molecule mechanics studies and focuses on the manipulation of proteins, DNA, and sugars by single molecule force spectroscopy (SMFS) by atomic force microscopy (AFM). The methods and examples of SMFS by AFM are illustrated using recent advances in protein science including titin elasticity, mechanical unfolding and refolding of alpha-helical repeat proteins, mechanoenzymatics of thioredoxin and titin kinase, and intermolecular interactions of P-selectin complexes. The possibilities of SMFS to investigate the mechanics of other biopolymers like double- and single-stranded DNA and forced-induced conformational changes in sugars are also discussed. Finally, SMFS and its application to biological processes, like DNA replication, packing and transcription, and DNA methylation are illustrated. These measurements provide a unique and integral part of the development of our knowledge of biochemistry and molecular mechanics. PMID- 24347440 TI - Effects of 2 different swallowing exercise regimens during organ-preservation therapies for head and neck cancers on swallowing function. AB - BACKGROUND: This study investigated the effects of 2 different swallowing exercise regimens performed during radiation therapy with/without chemotherapy on swallowing function. METHODS: Fifty patients were recruited prospectively to 2 groups (the exercise group, n = 26 and the repetitive swallow group, n = 24). Functional Oral Intake Scale (FOIS) scores and percutaneous endoscopic gastrostomy (PEG) placements were compared at posttreatment and at 3 months. RESULTS: The exercise group eliminated significantly more PEG tubes at 3 months posttreatment compared to the swallow group (16% vs 50%). Among patients who received both radiation and chemotherapy, the exercise group had significantly less PEG tubes immediately posttreatment as well as 3 months posttreatment (35% and 10%), compared to the swallow group (69% and 50%). CONCLUSION: Findings indicate significant benefits of the exercise group's exercise regimen in reducing PEG dependence and oral intake difficulties. PMID- 24347441 TI - Divergent coverage, frequency and costs of organised and opportunistic Pap testing in Finland. AB - We evaluated the overall coverage, frequency and costs of Pap testing by screening modality and health care provider in Finland. Information about Pap testing in the Finnish female population of 2.7 million was obtained from nationwide population-based registry data. Among women aged 25-69 years, 87% had had a Pap test taken within or outside the organised programme at least once during the last 5 years and half of those screened in the organised programme had also had at least one Pap test taken outside the programme. Of the annual average of 530,000 Pap tests taken, 84% were taken for screening purposes and 16% as follow-up. Forty percent of the 446,000 annual screening tests were taken in the organised programme, 55% as opportunistic tests in public primary or student health care or by private providers and 5% in public secondary health care. One fifth of all opportunistic screening Pap tests were taken from women aged <25. The voluminous opportunistic Pap testing in public primary health care was concentrated in young women aged 25-29 whereas the bulk of opportunistic testing in private health occurred in age groups eligible for organised screening. The total cost of all screening Pap tests was ?22.4 million, of which 71% incurred in opportunistic screening. Of the 84,000 annual follow-up Pap tests and their ?8.3 million total costs, ~60% incurred in organised screening or in secondary health care. PMID- 24347442 TI - Combination of S-adenosylhomocysteine and scriptaid, a non-toxic epigenetic modifying reagent, modulates the reprogramming of bovine somatic-cell nuclear transfer embryos. AB - The goal of this study was to improve the development of bovine somatic-cell nuclear transfer (SCNT) embryos by optimizing the combination of DNA methyltransferases inhibitor S-adenosylhomocysteine (SAH) and histone deacetylase inhibitor Scriptaid (SPD). A. 4 * 4-factor design of different drug combinations (0, 0.75, 1.0, and 1.5 mM SAH and 0, 5, 250, and 500 nM SPD) was used to identify an optimal combination of 0.75 mM SAH and 250 nM SPD that improved the developmental competence of bovine SCNT embryos. Further experiments using this combination revealed that methylation levels of CpG islands near exon 1 of the pluripotent gene SOX2; the epigenetic-related gene HDAC3 and DNMT3a; imprinted genes XIST and PEG3; as well as apoptosis-related genes BCL2 and BAX were returned to levels similar to those of in vitro fertilized (IVF) embryo after treatment, which also normalized transcript levels for these genes. This combination also returned global DNA methylation to a normal level, correcting H4K12ac levels while enhancing H3K9ac levels. Thus, the combined application of 0.75 mM SAH and 250 nM SPD can significantly improve the reprogramming of bovine SCNT embryos by stabilizing how embryos utilize their genomes. PMID- 24347443 TI - Polycyclic aromatic hydrocarbons as test probes to investigate the retention behavior of 1,3-alternate calix[4]arene silica-bonded stationary phases. AB - A series of polycyclic aromatic hydrocarbons (PAHs) of different size and shape has been used to characterize the chromatographic behavior of five calix[4]arene stationary phases in 1,3-alternate conformation synthesized in our laboratory. The selection of linear, four-ring nonlinear, and five-ring PAHs gave data on selectivity changes across range of the calix[4]arene columns. Retention of the 12 aromatic solutes has been evaluated at various methanol contents in the mobile phase (70-100% v/v) and column temperatures (20-45 degrees C). The thermodynamic parameters underlying the retention mechanisms revealed that each of the five calix[4]arene columns exhibited variation in selectivity and retention of PAHs caused by enthalpy and entropy effects. The calixarene stationary phases substituted with electron-withdrawing groups exhibit enhanced selectivity toward PAHs in comparison to the rest of the investigated columns. The observed divergences are due to differences in solute-stationary phase interactions and originate in pi-pi and pi-electron transfer specific to the analytes and the type of calix[4]arene functionalization at the upper rim, as well as steric and sorption phenomena. PMID- 24347444 TI - Impact of hyperthermia on pharmacokinetics of intraperitoneal mitomycin C in rats investigated by microdialysis. AB - BACKGROUND AND OBJECTIVES: Patients with peritoneal surface malignancies are treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, commonly using mitomycin C (MMC). The purpose of this study was to investigate impact of hyperthermia on pharmacokinetics of intraperitoneal MMC. METHODS: In 14 athymic nude male rats, microdialysis (MD) probes were implanted in jugular vein (V), hind leg muscle (M) and extraperitoneal space (XP). Probes were calibrated by retrodialysis. Intraperitonal chemotherapy perfusion (IPEC) was administered over 90 min with MMC 5 mg/kg and saline 0.9% 500 ml/kg at 35 and 41 degrees C, defining the normothermic (NG) and hyperthermic groups (HG), respectively. MD and peritoneal perfusion fluid (PPF) samples were collected at 10 min intervals to determine MMC concentration. RESULTS: Time-concentration curves were virtually parallel between temperature groups, with equal peak concentrations (uM) of 0.3 (V), 0.7 (XP) and 0.3 (M). The following area under time-concentration curve (AUC) ratios were calculated: AUC PPF/AUC V were 69 in NG and 79 in HG (P = 0.54); AUC XP/AUC V were 2.7 in NG and 2.6 in HG (P = 0.90). CONCLUSIONS: IPEC provides high intraperitoneal MMC concentration and increased bioavailability in extraperitoneal tissue, combined with low systemic absorption. Hyperthermia at 41 degrees C did not modify MMC pharmacokinetics. PMID- 24347446 TI - Waffle Y technique: pCONus for tandem bifurcation aneurysms of the middle cerebral artery. AB - Broad based bifurcation aneurysms are challenging. Various endovascular techniques aim at stabilizing the coil package in the aneurysm. Among these, the waffle cone technique provides a viable alternative to Y stenting in selected cases, incorporating a less complex delivery, and the reduced inherent risk of a single stenting procedure compared with the use of two stents in Y configuration. Unlike conventional stents, the distal end of the new pCONus device opens like a blossoming flower inside of the aneurysm to facilitate the waffle cone technique. In a case with tandem unruptured broad based middle cerebral artery bifurcation aneurysms, the complex anatomical challenge was resolved by a unique combination of both techniques: two pCONus deployed in Y configuration, offering stable neck coverage for coiling both aneurysms. The angiographic results with complete occlusion of both aneurysms and the uneventful clinical course at 90 days with continued daily administration of dual antiplatelet therapy are encouraging. PMID- 24347445 TI - Tbx4 interacts with the short stature homeobox gene Shox2 in limb development. AB - BACKGROUND: The short stature homeodomain transcription factors SHOX and SHOX2 play key roles in limb formation. To gain more insight into genes regulated by Shox2 during limb development, we analyzed expression profiles of WT and Shox2-/- mouse embryonic limbs and identified the T-Box transcription factor Tbx4 as a potential downstream target. Tbx4 is known to exert essential functions in skeletal and muscular hindlimb development. In humans, haploinsufficiency of TBX4 causes small patella syndrome, a skeletal dysplasia characterized by anomalies of the knee, pelvis, and foot. RESULTS: Here, we demonstrate an inhibitory regulatory effect of Shox2 on Tbx4 specifically in the forelimbs. We also show that Tbx4 activates Shox2 expression in fore- and hindlimbs, suggesting Shox2 as a feedback modulator of Tbx4. Using EMSA studies, we find that Tbx4/TBX4 is able to bind to distinct T-box binding sites within the mouse and human Shox2/SHOX2 promoter. CONCLUSIONS: Our data identifies Tbx4 as a novel transcriptional activator of Shox2 during murine fore- and hindlimb development. Tbx4 is also regulated by Shox2 specifically in the forelimb bud possibly via a feedback mechanism. These data extend our understanding of the role and regulation of Tbx4 and Shox2 in limb development and limb associated diseases. PMID- 24347447 TI - Renal cell carcinoma metastasis to the cerebellopontine cistern: intraoperative Onyx embolization via direct needle puncture. AB - We report a rare case of a renal cell carcinoma (RCC) metastasis occupying the cerebellopontine and cerebellomedullary cisterns, and describe an alternative strategy for embolizing hypervascular intracranial tumors. A middle aged patient with a distant history of RCC presented with headaches, nausea, and vomiting, and was found to have an enhancing mass in the left cerebellopontine and cerebellopontine cisterns. The initial surgical resection was aborted due to excessive bleeding. After an unsuccessful attempt at intra-arterial embolization, the patient returned to the operating room and the tumor was devascularized by direct needle puncture Onyx embolization under biplane fluoroscopy. The devascularized tumor was then successfully dissected from the brainstem and adherent lower cranial nerves. In properly selected cases, open surgical direct needle puncture embolization of intracranial vascular tumors under biplane fluoroscopy is a viable alternative devascularization method. PMID- 24347448 TI - Optic pathway infarct after Onyx HD 500 aneurysm embolization: visual pathway ischemia from superior hypophyseal artery occlusion. AB - We report a case of visual deterioration after Onyx HD 500 embolization of a left 7 mm superior hypophyseal artery (SHA) aneurysm. After the procedure, the patient experienced a right incongruous homonymous hemianopia, and MRI showed an infarct of the ipsilateral optic chiasm/tract but no evidence of aneurysm mass effect or embolic cortical infarcts. The optic pathway ischemia is believed to be secondary to Onyx penetration and occlusion of an SHA branch near the aneurysm neck. Caution is advised when using liquid embolic agents to treat SHA aneurysms as SHA occlusion may lead to visual deficits. PMID- 24347449 TI - Contact dermatitis due to methyl methacrylate: uncommon and unwanted entity for dentists. PMID- 24347450 TI - Doxycycline and suicidality. AB - A case series outlining three young individuals with no history of mental disorder who were treated for skin conditions with doxycycline, but developed suicidal ideation with an outcome of suicide in two of the cases. One of these individuals had CYP2C19*2 heterozygote genotype associated with a diminished cytochrome p450 enzyme activity and two of his siblings had developed severe anxiety previously while on doxycycline. Another had previously developed mood difficulties on a lower dose of doxycycline which resolved after discontinuation. In the third individual, a discontinuation of doxycycline has led to the resolution of symptoms without the need for psychotropic medications. PMID- 24347451 TI - White-blue pyelocalyceal cyst with hydrotic glomerulonephritis. AB - A 5-month-old male infant presented with a 15 day history of distension of abdomen. On clinical examination, a soft lump was palpable in the left lumbar region. Radiological findings suggested an enlarged non-functional left kidney with ureteropelvic adhesive obstruction. The left renal mass was excised and submitted for histopathological examination. The excised renal mass was cystic with its wall partly white and partly blue. Gross and histopathological findings were diagnostic of a white-blue pyelocalyceal cyst with hydrotic glomerulonephritis. This entity needs to be differentiated from a large number of other cystic diseases of the kidney. Intrauterine screening and diagnosis may be significant for a possible early intrauterine uro-laparoscopic recanalisation of the pyeloureteral obstruction to save the affected kidney. PMID- 24347452 TI - Isolated duodenal varices as the initial presentation of hepatocellular carcinoma. AB - Duodenal varices are an uncommon, life-threatening cause of acute gastrointestinal (GI) bleeding commonly caused by portal hypertension. Though generally regarded as a complication of advanced cirrhosis and portal hypertension, often overlooked is that in about 2.7% of cases, it can be the first presenting symptom of advanced hepatocellular carcinoma (HCC). We report a case of an isolated, duodenal variceal bleeding as the first clinical manifestation of HCC, complicated by portal venous thrombosis. Diagnosis of HCC was established by a markedly elevated alpha-fetoprotein, hepatitis B surface and core antibody positivity and consistent radiological findings. Although not the first choice, variceal bleeding was successfully arrested with endoclips. The patient thereafter declined further evaluation and unsurprisingly died within a few weeks from a massive GI bleed. An initial bleed from a duodenal varix often confers a poor prognosis. Patients with HCC who present with variceal bleeding reportedly have a median survival of 71 days. PMID- 24347453 TI - Calcifications afloat: bad omens in maxillary sinus augmentation. PMID- 24347454 TI - Iris retractors: the saviours in cataract surgery for cataract in lens coloboma. AB - A 67-year-old woman presented with features of bilateral cataract and lens coloboma. The lens coloboma was from 1 to 8 o'clock and from 5 to 9 o'clock positions in right and left eye, respectively. With some modifications, phacoemulsification was performed in both eyes at an interval of 1 month. A smaller (4.5 mm) anterior capsulorrhexis was made due to poor peripheral lenticular support. Three iris retractors were used to stabilise anterior capsulorrhexis margin to the limbus. Phacoemulsification was performed by direct chop technique under low phacodynamics. A capsular tension ring was placed in a bag followed by tangential cortical clean up and implantation of a foldable intraocular lens (IOL). One month following surgery, both eyes had a visual acuity of 20/20 with a stable IOL. This case report highlights the rarest malformation of the lens with cataract and its successful management by phacoemulsification using iris retractors as capsule supporting device. PMID- 24347455 TI - Spontaneous bilateral compartment syndrome in a HIV-positive patient. AB - Spontaneous bilateral compartment syndrome is a very rare condition but one which requires swift diagnosis and urgent surgical decompression by fasciotomies in order to achieve the best outcome. We present the case of a 31-year-old HIV positive man. The case highlights the perils of being sidetracked by an atypical clinical history instead of acting on the classical clinical examination findings. We will discuss the presentation and management of this patient, review the literature and highlight the key learning points. The most important learning point being that no matter how atypical the history, if a patient presents with limb pain out of proportion to the injury (with or without pain on passive stretch), sensory changes and a loss of motor power, then a diagnosis of acute compartment syndrome must be considered. PMID- 24347456 TI - Prospects for enhancement of targeted radionuclide therapy of cancer using ultrasound. AB - Ultrasound-mediated drug delivery is a promising means of enhancing delivery, distribution and effectiveness of drugs within tumours. In this review, prospects for exploiting ultrasound to improve the tumour delivery and distribution of radiolabelled antibodies for radioimmunotherapy and to overcome barriers imposed by tumour microenvironment are discussed. PMID- 24347457 TI - Development of hollow fiber-supported liquid-phase microextraction and HPLC-DAD method for the determination of pyrethroid metabolites in human and rat urine. AB - A simple hollow fiber liquid-phase microextraction method for the determination of synthetic pyrethroid metabolites, 3-phenoxybenzoic acid and 4-hydroxy-3 phenoxybenzoic acid, in human and rat urine was developed and validated. A polypropylene hollow fiber tightly fitted onto a Nylon rod and impregnated with organic solvent served as a disposable extraction device. Desorption of analytes was carried out in NaOH solution, analyzed further by gradient HPLC and diode array detection method. Important factors were identified using Taguchi OA16 (4(5) ) orthogonal array design and further optimized using univariate approach. The optimum method performance was observed when 1 mL of urine hydrolyzed with 0.2 mL of concentrated HCl was further supplemented with 100 mg of NaCl and extracted for 120 min into dihexyl ether immobilized in the pores of the hollow fiber. Metabolites were desorbed into 0.1 mL of 0.1 M NaOH for another 120 min. Limits of detection and quantitation of 15 and 50 ng/mL were obtained for both analytes. Relative standard deviations of 1.6-12.6% over the linear range (50 10,000 ng/mL, r > 0.9906) were observed. Intra- and inter-day accuracies of the method ranged from 98.3 to 109.5% and from 93.3 to 110.9%, respectively. The optimized method was applied to the analysis of real urine samples collected from rats exposed orally to cypermethrin. PMID- 24347458 TI - [Preparation and in-vitro analysis of a polyethylenimine coating on hernia meshes]. AB - BACKGROUND: Certain coatings such as titanium may improve the biocompatibility of hernia meshes. The coating with biopolymers such as polyethylenimine (PEI) can also improve the material characteristics of implants. This approach has, however, not yet been explored. Thus, it was the aim of the present work to clarify if and how hernia meshes with their three-dimensional structure can be successfully coated with PEI and with which technique this coating can be best analysed. METHODS: Commercially available meshes made from polypropylene, polyester and ePTFE have been coated with PEI. The coating was analysed via cell proliferation test (mouse fibroblasts), electron microscopy, X-ray photoelectron spectroscopy (XPS) and fluorescence microscopy. Cell viability and cytotoxicity were tested by the MTT test. RESULTS: With the PEI surface modification, mouse fibroblasts grow faster and in greater numbers on the mesh surface. XPS as well as fluorescence microscopy show weaknesses in their applicability and meaningfulness because of the three-dimensional mesh structure while XPS showed overall better results. Optical proof in the electron microscope after cell fixation was not unambiguously accomplished with the techniques used here. In the MTT test, no cellular damage from the PEI coating was detected after 24 hours. CONCLUSION: The present results show for the first time that PEI coating of hernia meshes is possible and effective. The PEI coating can be achieved in a fast and cost-efficient way. Further investigations are necessary with respect to coating quality and cytotoxicity before such a coating may be used in the clinical routine. In conclusion, PEI is a promising polymer that warrants further research as a coating for medical implants. PMID- 24347459 TI - Voice outcomes following laser cordectomy for early glottic cancer: a physical model investigation. AB - OBJECTIVES/HYPOTHESIS: The voice effects following laser cordectomy for early glottic cancer are poorly described. We investigated the voice outcomes of subligamentous cordectomy of progressive anterior-posterior extent of excision. STUDY DESIGN: Physical phonatory modeling. METHODS: The influence of vocal fold surgical defects and corresponding scar was experimentally investigated using a self-oscillating physical model of the vocal folds and compared with the baseline model without defects or scar. RESULTS: Results showed that increasing anterior posterior extent of resection increased phonation threshold pressure and flow rate and reduced excitation of high-order harmonics, resulting in a more breathy and rough voice production. However, it was found that voice production was improved with the placement of scar, which increased both excitation of high order harmonics and the harmonic-to-noise ratio. CONCLUSIONS: Although large anterior-posterior surgical resections resulted in progressive impact on vocal measures, a limited excision of the vocal fold cover surprisingly demonstrated minimal voice changes. Further investigations are required to define the acceptable extent of surgical resection that may result in optimal voice outcomes. PMID- 24347460 TI - Benefits and harms of roflumilast in moderate to severe COPD. AB - BACKGROUND: Roflumilast, a phosphodiesterase 4 inhibitor, has been approved for the prevention of chronic obstructive pulmonary disease (COPD) exacerbations. It is unclear which patients will have a favourable benefit-harm balance with roflumilast. Our aim was to quantitatively assess the benefits and harms of roflumilast (500 ug/day) compared with placebo. METHODS: We used summary data released by the US Food and Drug Administration to estimate the treatment effects of roflumilast. Data from trials and observational studies were used to estimate the baseline risks for COPD exacerbations and gastrointestinal, neurological and psychiatric harms associated with roflumilast. Using simulation, we calculated the probability that roflumilast provides net benefit. We examined the impacts of different baseline risks for exacerbations and the severity of exacerbations, and varied weights (ie, relative importance) for outcomes and treated death as a competing risk in the analyses. RESULTS: The probability that roflumilast provides net benefit approximates 0% across different age categories of men and women with varying baseline risks for exacerbations. Using different weights for outcomes did not change the probability that roflumilast provides a net benefit. Only in the sensitivity analysis restricted to the prevention of severe exacerbations was there a probability of >50% that roflumilast provides a net benefit if the baseline risk of having at least one severe exacerbation per year exceeds 22%. CONCLUSIONS: Our results suggest that roflumilast only provides a net benefit to patients at a high risk of severe exacerbations. Guideline developers should consider different recommendations for patients with COPD at different baseline risks for exacerbations. PMID- 24347461 TI - Defective IL-10 expression and in vitro steroid-induced IL-17A in paediatric severe therapy-resistant asthma. AB - BACKGROUND: Understanding of immune mechanisms underpinning asthma has emerged from studies in adults. It is increasingly recognised, both immunologically and in the development of novel therapies, that adult responses cannot be used accurately to predict those of children. METHODS: Using a well-defined paediatric cohort of severe therapy-resistant asthma (STRA) patients, we investigated cytokine profiles in the airway by analysis of bronchoalveolar lavage fluid. The in vitro capacity of peripheral blood mononuclear cells (PBMCs) for cytokine production was also assessed following polyclonal T cell activation in culture, in the absence or presence of dexamethasone and 1alpha,25-dihydroxyvitamin D3. RESULTS: Children with both moderate and STRA had significantly diminished levels of anti-inflammatory interleukin (IL)-10 in airway lavage samples when compared with non-asthmatic controls (p<0.001). Their PBMCs also demonstrated significantly impaired capacity to secrete IL-10 in culture (p<0.001). Dexamethasone regulated the balance between PBMC IL-10 and IL-13 production, increasing IL-10 secretion (p<0.001) and decreasing IL-13 (p<0.001) but unexpectedly enhanced IL-17A production in all groups-most strikingly in the STRA cohort (p<0.001). The inclusion of the active form of vitamin D, 1alpha,25 dihydroxyvitamin D3, in culture enhanced dexamethasone-induced IL-10 (p<0.05) without marked effects on IL-13 or IL-17A production. Furthermore, systemic vitamin D status directly correlated with airway IL-10 (r=0.6, p<0.01). CONCLUSIONS: These findings demonstrate reduced peripheral and local IL-10 synthesis in paediatric asthma, and support therapeutic augmentation of low circulating vitamin D in severe, difficult-to-treat asthma, in order to correct impaired IL-10 levels. Conversely, steroids enhanced IL-17A levels, and therefore any steroid-sparing properties of vitamin D may have additional benefit in STRA. PMID- 24347462 TI - Time to disease progression in children with relapsed or refractory neuroblastoma treated with ABT-751: a report from the Children's Oncology Group (ANBL0621). AB - BACKGROUND: ABT-751, an orally bioavailable sulfonamide binds the colchicine site of beta-tubulin and inhibits microtubule polymerization. Prior phase I studies established the recommended dose in children with solid tumors as 200 mg/m(2) PO daily * 7 days every 21 days and subjects with neuroblastoma experienced prolonged stable disease. We conducted a phase 2 study (NCT00436852) in children and adolescents with progressive neuroblastoma to determine if ABT-751 prolonged the time to progression (TTP) compared to a hypothesized standard based on a historical control population. PROCEDURE: Children and adolescents (n = 91) with a median (range) age 7.7 (2.3-21.5) years and progressive neuroblastoma were enrolled and stratified by disease status into disease measureable by CT/MRI (n = 47) or disease assessable by (123) I-metaiodobenzylguanine scintigraphy (MIBG, n = 44). Response was evaluated using RECIST for measureable disease and the Curie score for MIBG-avid disease. RESULTS: ABT-751 was well tolerated. The objective response rate was 7%. The median TTP was 42 days (95% CI: 36, 56) in the measureable disease stratum and 45 days (95% CI: 42, 85) in the MIBG-avid disease stratum. TTP was similar to the historical control group (n = 136, median TTP 42 days). For the combined strata (n = 91), 1-year progression free survival (PFS) was 13 +/- 4% and overall survival (OS) was 48 +/- 5%. CONCLUSIONS: The low objective response rate and failure to prolong TTP indicate that ABT-751 is not sufficiently active to warrant further development for neuroblastoma. However, this trial demonstrates the utility of TTP as the primary endpoint in phase 2 trials in children and adolescents with neuroblastoma. PMID- 24347463 TI - Understanding and manipulating sucrose phloem loading, unloading, metabolism, and signalling to enhance crop yield and food security. AB - Sucrose is produced in, and translocated from, photosynthetically active leaves (sources) to support non-photosynthetic tissues (sinks), such as developing seeds, fruits, and tubers. Different plants can utilize distinct mechanisms to transport sucrose into the phloem sieve tubes in source leaves. While phloem loading mechanisms have been extensively studied in dicot plants, there is less information about phloem loading in monocots. Maize and rice are major dietary staples, which have previously been proposed to use different cellular routes to transport sucrose from photosynthetic cells into the translocation stream. The anatomical, physiological, and genetic evidence supporting these conflicting hypotheses is examined. Upon entering sink cells, sucrose often is degraded into hexoses for a wide range of metabolic and storage processes, including biosynthesis of starch, protein, and cellulose, which are all major constituents for food, fibre, and fuel. Sucrose, glucose, fructose, and their derivate, trehalose-6-phosphate, also serve as signalling molecules to regulate gene expression either directly or through cross-talk with other signalling pathways. As such, sugar transport and metabolism play pivotal roles in plant development and realization of crop yield that needs to be increased substantially to meet the projected population demand in the foreseeable future. This review will discuss the current understanding of the control of carbon partitioning from the cellular to whole-plant levels, focusing on (i) the pathways employed for phloem loading in source leaves, particularly in grasses, and the routes used in sink organs for phloem unloading; (ii) the transporter proteins responsible for sugar efflux and influx across plasma membranes; and (iii) the key enzymes regulating sucrose metabolism, signalling, and utilization. Examples of how sugar transport and metabolism can be manipulated to improve crop productivity and stress tolerance are discussed. PMID- 24347464 TI - Transcription factor-mediated cell-to-cell signalling in plants. AB - Plant cells utilize mobile transcription factors to transmit intercellular signals when they perceive environmental stimuli or initiate developmental programmes. Studies on these novel cell-to-cell signals have accumulated multiple pieces of evidence showing that non-cell-autonomous transcription factors play pivotal roles in most processes related to the formation and development of plant organs. Recent studies have explored the evolution of mobile transcription factors and proposed mechanisms for their trafficking through plasmodesmata, where a selective system exists to facilitate this process. Mobile transcription factors contribute to the diversity of the intercellular signalling network, which is also established by peptides, hormones, and RNAs. Crosstalk between mobile transcription factors and other intercellular molecules leads to the development of complex biological signalling networks in plants. The regulation of plasmodesmata appears to have been another major step in controlling the intercellular trafficking of transcription factors based on studies of many plasmodesmal components. Furthermore, diverse omics approaches are being successfully applied to explore a large number of candidate transcription factors as mobile signals in plants. Here, we review these fascinating discoveries to integrate current knowledge of non-cell-autonomous transcription factors. PMID- 24347465 TI - Visualization of the actin cytoskeleton: different F-actin-binding probes tell different stories. AB - The actin cytoskeleton is necessary for cell viability and plays crucial roles in cell motility, endocytosis, growth, and cytokinesis. Hence visualization of dynamic changes in F-actin distribution in vivo is of central importance in cell biology. This has been accomplished by the development of fluorescent protein fusions to actin itself or to various actin-binding proteins, actin cross-linking proteins, and their respective actin-binding domains (ABDs). Although these protein fusions have been shown to bind to F-actin in vivo, we show that the fluorescent protein used for visualization changes the subset of F-actin labeled by an F-actin ABD probe. Further, different amino acid linkers between the fluorescent protein and ABD induced a similar change in localization. Although different linkers and fluorescent proteins can alter the subset of actin bound by a particular ABD, in most cases, the fusion protein did not label all of a cell's F-actin all of the time. Even LimEDeltacoil and GFP-actin, which have been used extensively for cytoskeletal visualization, were highly variable in the subsets of actin that they labeled. Lifeact, conversely, clearly labeled cortical F-actin as well as F-actin in the anterior pseudopods of motile cells and in macropinocytotic cups. We conclude that Lifeact most accurately labels F-actin and is the best currently available probe for visualization of dynamic changes in F-actin networks. PMID- 24347466 TI - Microcavity-embedded, colour-tuneable, transparent organic solar cells. AB - In this work microcavity-capped colour-tuneable SMOSCs are evaluated. By adopting a microcavity-structured cathode with optical spacer layers of different thicknesses fabricated in a Ag/NPB/Ag structure, the transmission spectra of complete devices can be tuned over the entire visible-light region (400-750 nm). The fabricated semitransparent colour-tuneable solar cells show an average efficiency of 4.78% under 1-sun illumination. PMID- 24347467 TI - Knowledge, attitudes and behaviour regarding nutrition and dietary intake of seventh-grade students in rural areas of Mi Yun County, Beijing, China. AB - OBJECTIVES: To investigate the knowledge, attitudes and behaviour of seventh grade students regarding nutrition and dietary intake, to collect data that would facilitate the design and implementation of interventions aimed at promoting good nutrition in adolescents via the school and to contribute to the improvement of adolescents' health in rural regions. METHODS: This was a descriptive, cross sectional study in which a 27-item, self-administered, structured questionnaire, designed in Chinese, was administered to seventh-grade students attending one of three rural middle schools, chosen randomly from 15 middle schools, in Mi Yun County, Beijing. RESULTS: In terms of nutrition knowledge, 84.5 % of respondents had scores of between 3 and 7. Based on our analysis of the completed questionnaires, during the 7 days preceding completion of the questionnaire 43.6 % of respondents had eaten fresh fruit at least once per day, 71.3 % had eaten vegetables at least once per day, 22.3 % had consumed at least one glass of milk (or soy milk or yogurt) each day and 68.6 % had eaten breakfast every day. In total, 95.2 % of respondents thought nutrition was very important or important to their health, and 94.2 % thought it was very important or important to develop healthy dietary habits. Of the respondents, 52.7 % thought good food quality was the most important aspect of nutrition and dietary intake and 62.2 % thought food safety was the most important aspect. CONCLUSIONS: Based on the results of our survey we suggest their should be continuous efforts to teach adolescents in rural areas of China about various aspects of good nutrition, to encourage diversity in their choice of breakfasts, to guarantee food safety and to improve food quality. PMID- 24347468 TI - Association between mobile phone use and depressed mood in Japanese adolescents: a cross-sectional study. AB - OBJECTIVES: Mobile phones are commonly used by adolescents. The aim of this study was to clarify associations between duration of mobile phone use and psychological mood in high school students. METHODS: This cross-sectional study included 2,785 high school students in Niigata, Japan. A self-administered questionnaire was used to elicit information on sex, school year, hours of mobile phone use, psychological mood status, and possible confounders. Psychological mood outcomes were evaluated with the Mood Inventory, developed and validated in 1994, which includes five subcomponents with total scores ranging from 8 to 32 (higher score indicates stronger feeling): "Tension and excitement," "Refreshing mood," "Fatigue," "Depressed mood," and "Anxious mood." Analysis of covariance with Bonferroni's multiple comparison was used to compare mean values among quartiles of hours of mobile phone use. RESULTS: Among the respondents, mean mobile phone use per week was 24 (median 18) h. Long-duration mobile phone use was associated with female students, no participation in sports club activities, early mobile phone use, and fewer hours spent sleeping (all P < 0.001). Overall associations between hours of mobile phone use and total scores were significant for "Depressed mood" (P for trend = 0.005), "Tension and excitement" (P for trend <0.001), and "Fatigue" (P for trend < 0.001). Total scores for "Depressed mood," "Tension and excitement," and "Fatigue" of the fourth quartile (>=33 h/week) of mobile phone use were significantly higher than for other quartiles (all P < 0.05). CONCLUSIONS: Increased duration of mobile phone use is associated with unfavorable psychological mood, in particular, a depressed mood. Decreasing mobile phone use may help maintain appropriate mental health in very long duration users. PMID- 24347469 TI - MiR-335-5p promotes chondrogenesis in mouse mesenchymal stem cells and is regulated through two positive feedback loops. AB - Chondrogenic differentiation of mesenchymal stem cells (MSCs) is regulated by many factors and signal pathways, including transcription factors such as Sox9 and microRNAs. MiR-335-5p has been previously reported to regulate osteogenic and adipogenic differentiations of MSCs, but its role in chondrogenic differentiation of MSC remains unknown. In this study, we found that miR-335-5p and its host gene Mest are co-expressed and greatly upregulated during mouse MSCs (mMSCs) chondrogenesis. Overexpression of miR-335-5p in mMSCs increased expression of chondrogenic marker genes. Molecular mechanism explorations revealed that miR-335 5p targets Daam1 and ROCK1, a set of negative regulators of Sox9; Sox9 downregulates the expression of miR-29a and 29b, both negative regulators of Mest expression, thus forming a positive loop from miR-335-5p to Sox9 to Mest/miR-335 5p. In addition, miR-335-5p targets DKK1 during mMSC chondrogenic differentiation to increase beta-catenin/TCF activity, which leads to increased level of Mest transcription. These data showed miR-335-5p positively regulates MSC chondrogenesis, and two positive feedback loops are identified for the expression of miR-335-5p and its host gene Mest during the early phase of mMSC chondrogenic differentiation. PMID- 24347470 TI - Definitive radiotherapy for cervical esophageal cancer. AB - BACKGROUND: The role of contemporary radiotherapy (RT) has not yet been elucidated, mainly because of the low incidence of cervical esophageal cancer. The purpose of this study was to analyze the outcome in patients with cervical esophageal cancer treated with definitive RT. METHODS: A total of 115 patients with cervical esophageal cancer treated with definitive RT during January 2001 through April 2012 in our center were analyzed. Eighty patients received RT alone and 35 patients received concurrent chemoradiotherapy with cisplatin administered either weekly (30 mg/m2) or every 3 weeks (80 mg/m2). RESULTS: The median follow up time was 17.1 months. For all patients, the overall 2-year local failure-free survival (LFFS), regional failure-free survival (RFFS), distant failure-free survival (DFFS), and overall survival (OS) rate was 68.3%, 83.3%, 75.7%, and 47.6%, respectively. CONCLUSION: Definitive RT accomplished a satisfactory local control rate and contributed to organ preservation for patients with cervical esophageal cancer. 2015. PMID- 24347472 TI - Skp2 regulates androgen receptor through ubiquitin-mediated degradation independent of Akt/mTOR pathways in prostate cancer. AB - BACKGROUND: The intervention of advanced prostate cancer (PCa) in patients has been commonly depending on androgen deprivation therapy. Despite of tremendous research efforts, however, molecular mechanisms on AR regulation remain poorly understood, particularly for castration resistant prostate cancer (CRPC). Targeting AR and associated factors is considered an effective strategy in PCa treatment. METHODS: Human prostate cancer cells were used in this study. Manipulations of Skp2 expression were achieved by Skp2 shRNA/siRNA or overexpression of plasmids. Dual luciferase reporter assay was applied for AR activity assessment. Western blot, ubiquitination assay, immunoprecipitation, and immunofluorescence were applied to detect the proteins. RESULTS: Our results demonstrated that Skp2 directly involves the regulation of AR expression through ubiquitination-mediated degradation. Skp2 interacted with AR protein in PCa cells, and enforced expression of Skp2 resulted in a decreased level and activity of AR. By contrast, Skp2 knockdown increased the protein accumulation and activity of AR. Importantly, changes of AR contributed by Skp2 led to subsequent alterations of PSA level in PCa cells. AR ubiquitination was significantly increased upon Skp2 overexpression but greatly reduced upon Skp2 knockdown. AR mutant at K847R abrogated Skp2-mediated ubiquitination of AR. NVP-BEZ235, a dual PI3K/mTOR inhibitor, remarkably inhibited Skp2 level with a striking elevation of AR. CONCLUSIONS: The results indicate that Skp2 is an E3 ligase for proteasome dependent AR degradation, and K847 on AR is the recognition site for Skp2 mediated ubiquitination. Our findings reveal an essential role of Skp2 in AR signaling. PMID- 24347473 TI - Preparation of magnetic hydroxyapatite clusters and their application in the enrichment of phosphopeptides. AB - A novel strategy for the effective enrichment of phosphopeptides based on magnetic hydro-xyapatite (HAp) clusters was developed in the current study. The structure of HAp ensures its probable separation capability, including cation exchange with P-sites (negatively charged pairs of crystal phosphates), calcium coordination, anion exchange with C-sites (positively charged pairs of crystal calcium ions). The prepared magnetic HAp clusters showed good performance on the efficient enrichment of phosphopeptides from the digestion mixture of beta-casein and BSA. Compared to commercial HAp particles, the magnetic HAp clusters exhibited better selectivity toward phosphopeptides. In addition, the use of magnetic material greatly simplified the enrichment procedure, which avoided the tedious centrifugation steps in a typical phosphopeptides enrichment protocol. Finally, the material was successfully applied in the enrichment of phosphopeptides from human serum. Taken together, the efficient enrichment of the phosphopeptides by the easily prepared magnetic HAp clusters demonstrated a rapid and convenient strategy for the purification of phosphopeptides from complex samples, which may facilitate protein phosphorylation studies. PMID- 24347477 TI - One step forward in the quest for evidence of the efficacy of cognitive rehabilitation in multiple sclerosis. PMID- 24347474 TI - Chelators for copper radionuclides in positron emission tomography radiopharmaceuticals. AB - The development of chelating agents for copper radionuclides in positron emission tomography radiopharmaceuticals has been a highly active and important area of study in recent years. The rapid evolution of chelators has resulted in highly specific copper chelators that can be readily conjugated to biomolecules and efficiently radiolabeled to form stable complexes in vivo. Chelators are not only designed for conjugation to monovalent biomolecules but also for incorporation into multivalent targeting ligands such as theranostic nanoparticles. These advancements have strengthened the role of copper radionuclides in the fields of nuclear medicine and molecular imaging. This review emphasizes developments of new copper chelators that have most greatly advanced the field of copper-based radiopharmaceuticals over the past 5 years. PMID- 24347478 TI - Clinical commentary. PMID- 24347475 TI - Transplant versus resection for the management of hepatocellular carcinoma meeting Milan Criteria in the MELD exception era at a single institution in a UNOS region with short wait times. AB - BACKGROUND: Management of hepatocellular carcinoma (HCC) in the Model for End Stage Liver Disease (MELD) exception era remains regionally variable. Outcomes were compared for patients undergoing transplant versus resection at a single institution in a UNOS region with short wait times for organ availability. METHODS: All patients who underwent resection of HCC from January 2000 to August 2012 and patients who underwent transplant post-January 2006, during the Milan Criteria (MC)-based MELD exception policy for HCC, were identified. Primary outcomes were overall survival (OS) and recurrence-free survival (RFS). RESULTS: Two hundred fifty-seven patients were analyzed, of whom 131 underwent transplant and 126 underwent resection. All transplant patients met MC; 45 (36%) resection patients met MC. Median follow-up time was 30 months. Median wait time to transplant was 55 days; no patients dropped off the waitlist while awaiting an organ. Among patients meeting MC, transplant demonstrated significantly greater 5 year OS (65.7% vs. 43.8%; P = 0.005) and RFS (85.3% vs. 22.7%; P < 0.001) versus resection. For patients with hepatitis C, transplant (n = 87) demonstrated significantly improved 5-year outcomes compared to patients meeting MC who underwent resection (n = 21; OS: 63.5% vs. 23.3%; P = 0.001; RFS: 83.5% vs. 23.7%; P < 0.001). CONCLUSION: In a region with short waitlist times for organ availability, liver transplant is associated with improved survival compared to resection for HCC within MC and should be considered for all patients meeting MC, particularly those with hepatitis C. PMID- 24347479 TI - The role of vascular endothelial growth factor and vascular stability in diseases of the ear. AB - OBJECTIVES/HYPOTHESIS: Vascular endothelial growth factor (VEGF) is a critical mediator of vascular permeability and angiogenesis and likely plays an important role in cochlear function and hearing. This review highlights the role of VEGF in hearing loss associated with vestibular schwannomas, otitis media with effusion, and sensorineural hearing loss. STUDY DESIGN: PubMed literature review. METHODS: A review of the literature was conducted to determine the role of VEGF in diseases affecting hearing. RESULTS: Therapeutic efficacy has been demonstrated for the anti-VEGF agent bevacizumab in vestibular schwannomas, with tumor size reduction and hearing improvement in patients with neurofibromatosis type 2. The loss of functional Merlin, the protein product of the nf2 gene, results in a decrease in expression of the anti-angiogenic protein SEMA3F through a Rac-1 dependent mechanism, allowing VEGF to promote angiogenesis. Bevacizumab may therefore restore the angiogenic balance through inhibiting the relative increase in VEGF. Many of the clinical findings of otitis media with effusion can be reproduced by delivery of recombinant VEGF through transtympanic injection or submucosal osmotic pump. VEGF receptor inhibitors have been demonstrated to improve hearing in an animal model of otitis media with effusion. VEGF affects both the inner ear damage and repair processes in sensorineural hearing loss. CONCLUSIONS: VEGF has an important role in vestibular schwannomas, otitis media with effusion, and sensorineural hearing loss. PMID- 24347480 TI - Response Re: Evaluation of renal function after successful treatment for unilateral, non-syndromic Wilms tumor. PMID- 24347481 TI - Nonsurgical intra-operative blood management strategies for total hip arthroplasty. AB - The substantial blood loss that can occur during total hip arthroplasty frequently requires allogeneic transfusions. Both allogeneic transfusions and post-operative anemia are causes of increased morbidity, cardiovascular risks, and length of stay. This anemia can also lead to decreased vigor, suboptimal rehabilitation, and lowered quality of life in patients undergoing total hip arthroplasty. The aim of this review was to analyze recent evidence on nonsurgical intra-operative blood management strategies utilized for total hip arthroplasty. Specifically, we evaluated the use of fibrin sealants, desmopressin, acute normovolemic hemodilution, hypotensive anesthesia, blood salvage, and peri-operative normothermia. No single strategy has been shown to provide superior results over another in reducing the need for allogeneic transfusions. However, a combination of the above blood management strategies may further result in reduced blood loss over one strategy. Larger prospective randomized studies comparing the individual strategies, as well as their combination, are needed to develop the best algorithm that can be the most effective and safe for intra-operative blood management in total hip arthroplasty. PMID- 24347482 TI - Blood management strategies for total hip arthroplasty in Jehovah's witness patients. AB - Total hip arthroplasty is associated with extensive blood loss, which is often corrected using allogeneic blood transfusions. However, Jehovah's Witnesses often refuse allogeneic blood transfusions or certain types of autologous blood transfusions due to their religious beliefs. This may represent a tremendous challenge for the orthopaedic surgeon and their team. Performing a total hip arthroplasty on a Jehovah's Witness patient requires a well-trained group of physicians willing to pre-operatively optimize the patient, attempt to minimize the blood loss during the surgery, adequately manage the post-operative period, and be aware of which of the life-saving strategies can be used in these patients during an emergency situation. Ultimately, physicians should be prepared to deal with marked blood loss and respect the patients' wishes, values, and beliefs. This review focuses on studies where primary or revision total hip arthroplasty was performed in Jehovah's Witness patients. Therefore, we will illustrate that with a prepared team and an optimized patient, it is potentially quite safe to perform total hip arthroplasties in Jehovah's Witness patients. PMID- 24347483 TI - Surgical Intra-operative Blood Management Strategies for Total Hip Arthroplasty. AB - This section will complement other recent review articles of blood conservation in total hip arthroplasty. The purpose of this review was to provide a broad overview, as well as to evaluate the recent evidence on surgical intra-operative blood management strategies utilized for total hip arthroplasty. In this section, we specifically evaluated the use of bipolar sealants, patient positioning, wound compression, computer-assisted surgery, minimally invasive surgical approach, and cemented versus noncemented prostheses. PMID- 24347484 TI - Post-operative blood management strategies for total hip arthroplasty. AB - Total hip arthroplasty is increasing in incidence due to our aging population. However, this procedure has a high potential for increased blood loss, with allogeneic blood transfusions commonly used. However, due to potential transfusion-related risks such as immunosuppression or infections, attempts have been made to reduce the amount of blood loss and minimize transfusions. Therefore, our aim was to provide a broad overview of the widely used methods for reducing post-operative blood loss after total hip arthroplasty. These include antifibrinolytic agents, autologous blood transfusion drains, avoiding the use of drains, and modifications in drainage techniques. In addition, lowering the transfusion threshold is another method used to decrease the rates of allogeneic blood transfusion. Current evidence suggests that the use of some of these strategies-either alone, or in combination-may reduce the amount of blood loss and the need for allogeneic transfusions. However, further research is needed to create new, more standardized guidelines. PMID- 24347485 TI - Transforming growth factor-beta1 signaling blockade attenuates gastric cancer cell-induced peritoneal mesothelial cell fibrosis and alleviates peritoneal dissemination both in vitro and in vivo. AB - Peritoneal dissemination is the most frequent metastatic pattern of advanced gastric cancer and the main cause of death in gastric cancer patients. Transforming growth factor-beta1 (TGF- beta1), one of the most potent fibrotic stimuli for human peritoneal mesothelial cells, has been shown to play an important role in this process. In this study, we investigated the effect of TGF- beta1 signaling blockade in gastric cancer cell (GCC)-induced human peritoneal mesothelial cell (HPMC) fibrosis. HPMCs were cocultured with the high TGF- beta1 expressing GCC line SGC-7901 and various TGF- beta1 signaling inhibitors or SGC 7901 transfected with TGF-beta1-specific siRNA. HPMC fibrosis was monitored on the basis of morphology. Expression of the epithelial cell marker, E-cadherin, and the mesenchymal marker, alpha-smooth muscle actin (alpha-SMA), was evaluated by Western blotting and immunofluorescence confocal imaging. GCC adhesion to HPMC was also assayed. In nude mouse tumor model, the peritoneal fibrotic status was monitored by immunofluorescent confocal imaging and Masson's trichrome staining; formation of metastatic nodular and ascites fluid was also evaluated. Our study demonstrated that GCC expressing high levels of TGF-beta1 induced HMPC fibrosis, which is characterized by both upregulation of E-cadherin and downregulation of alpha-SMA. Furthermore, HPMC monolayers fibrosis was reversed by TGF- beta1 signaling blockade. In vivo, the TGF- beta1 receptor inhibitor SB-431542 partially attenuated early-stage gastric cancer peritoneal dissemination (GCPD). In conclusion, our study confirms the significance of TGFbeta1 signaling blockade in attenuating GCPD and may provide a therapeutic target for clinical therapy. PMID- 24347486 TI - Study of circulating antibodies against CD25 and FOXP3 in breast cancer. AB - Our recent work suggests that circulating levels of anti-CD25 and anti-FOXP3 antibodies were significantly increased in patients with either lung cancer or esophageal cancer. To confirm if these two autoantibodies are specific for certain types of malignant tumors, the present work was thus undertaken to examine an alteration of anti-CD25 and anti-FOXP3 IgG levels in breast cancer. A total of 152 patients with breast cancer and 112 control subjects were recruited in this study. The levels of circulating anti-CD25 and anti-FOXP3 IgG antibodies were tested using an in-house enzyme-linked immunosorbent assay (ELISA). Student's t test showed no significant differences in the levels of either anti CD25 IgG or anti-FOXP3 IgG between patients with breast cancer and control subjects, although patients at stage I had increased levels of anti-CD25 IgG compared with control subjects (t = 2.11, P = 0.037); there was no significant association of the anti-FOXP3 IgG levels with stages of breast cancer. In conclusion, circulating IgG autoantibody to CD25 instead of FOXP3 may be a potential biomarker for early diagnosis of breast cancer but further investigation remains needed to replicate this initial finding. PMID- 24347487 TI - Allergic conditions reduce the risk of glioma: a meta-analysis based on 128,936 subjects. AB - Many studies have investigated the association between the allergic conditions and the risk of glioma. However, the evidence is inadequate to draw robust conclusions because most studies were generally small and conducted in heterogeneous populations. To shed light on these inconclusive findings, we conducted a meta-analysis of studies relating the allergic conditions to the risk of glioma. We identified the relevant studies by searching ISI Web of Science, PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI) databases, and Wanfang database by October 2013. We included studies that reported odds ratio (OR) or hazard ratio (HR) with its 95% confidence interval (CI) for the association between the allergic condition and the risk of glioma. Eighteen independent publications, with 9,986 glioma cases and 118,950 controls, were included. Our results showed that allergic condition was reversely associated with the risk of glioma (OR = 0.78, 95% CI 0.73-0.83, P < 0.001). The results of our meta-analysis indicated that allergic conditions significantly reduce the risk of glioma. PMID- 24347488 TI - Xeroderma pigmentosum complementation group D (XPD) gene polymorphisms contribute to bladder cancer risk: a meta-analysis. AB - Numerous epidemiological studies have been conducted to investigate the association between Xeroderma pigmentosum complementation group D (XPD) Asp312Asn (rs1799793 G > A) and Lys751Gln (rs13181 A > C) polymorphisms and bladder cancer risk; however, the conclusions remain controversial. With this in mind, we performed this meta-analysis with 11 studies including 3,797 cases and 5,094 controls for Asp312Asn and 21 studies including 6,360 cases and 7,894 controls for Lys751Gln polymorphism. We searched available literatures from PubMed, Embase, and CBM databases. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the associations. Moreover, to validate biological plausibility of our findings, the effects of these two polymorphisms on XPD gene expression within three ethnicities was determine by gene expression analysis based on imputed genotypes from HapMap. Overall, the variant allele of Asp312Asn polymorphism was associated with an increased risk of bladder cancer (Asn/Asn vs. Asp/Asp: OR = 1.51, 95% CI = 1.19-1.91; Asp/Asn vs. Asp/Asp: OR = 1.23, 95% CI = 1.12-1.35; recessive model: OR = 1.33, 95% CI = 1.10 1.61; dominant model: OR = 1.32, 95% CI = 1.14-1.52; and allele comparing: OR = 1.26, 95% CI = 1.11-1.42). We found the Lys751Gln was associated with increased bladder cancer risk only under the recessive model (OR = 1.14, 95% CI = 1.01 1.29). Stratification analyses demonstrated an increased risk for Asians and hospital-based studies under all genetic models while only under the dominant model for Caucasians as to the Asp312Asn polymorphism and for Caucasians under the recessive model as to the Lys751Gln polymorphism. We also found the Asp312Asn polymorphism can significantly influence mRNA expression levels among Asians and Caucasians, and the Lys751Gln polymorphism has a similar effect for Caucasians. Despite some limitations, this meta-analysis suggests that polymorphisms in XPD gene may contribute to bladder cancer susceptibility. These findings need further validation by large well-designed prospective studies. PMID- 24347489 TI - Axl gene knockdown inhibits the metastasis properties of hepatocellular carcinoma via PI3K/Akt-PAK1 signal pathway. AB - The objective of this study is to clarify the possible role and mechanism of Axl in the tumorigenicity and metastasis process of hepatocellular carcinoma. The mRNA and protein expression levels of Axl in MHCC97-H and MHCC97-L cell lines were evaluated by real-time PCR and Western blot analysis. The key factor of phosphatidylinositol-3-kinase (PI3K)/Akt-p21-activated kinases-1 (PAK1) signaling pathway was studied after Axl expression was downregulated by shRNA. Finally, we analyzed the expression status of Axl protein expression in hepatocellular carcinoma tissues and its relationship with the prognosis of hepatocellular carcinoma. Axl was observed to be higher expressed in MHCC97-H cell lines compared to MHCC97-L cell lines. The downregulation of Axl in MHCC97-H cell lines resulted in the inhibition of the invasion ability of MHCC97-H cells both in vitro and in vivo. Interestingly, blocking PI3K/Akt signaling pathway by LY294002 or Akt siRNA could remarkably inhibit the PAK1 activation and cell invasion. Finally, the Axl protein expression was positively correlated with differentiation, lymph node metastasis, and clinical stage in patients with hepatocellular carcinoma patients (all P < 0.01). These findings suggest that Axl can also regulate the metastasis process of hepatocellular carcinoma and may serve as a new prognostic marker and therapeutic target for treating hepatocellular carcinoma metastasis. PMID- 24347490 TI - USP28 is a potential prognostic marker for bladder cancer. AB - This study was conducted to analyze the expression of the ubiquitin-specific protease Usp28 and assess its clinical significance in human bladder cancer. mRNA and protein expression levels of Usp28 were determined by real-time polymerase chain reaction (PCR) and Western blot in 24 paired bladder cancers and the adjacent non-cancerous tissues. In addition, the expression of Usp28 protein in 186 bladder cancers was also determined by immunohistochemistry. The relationship between expression of Usp28 and clinico-pathologic features and prognosis was finally evaluated. Usp28 was expressed at a higher level in bladder cancers compared to adjacent non-cancerous tissues at both the mRNA and protein levels in 24 paired samples (all P < 0.01). In immunohistochemical examination, 78 (41.9%) of 186 cases displayed low Usp28 expression in cancerous tissues, whereas 108 (58.1%) cases displayed high Usp28 expression. In the universal analysis, Usp28 correlated strongly with histopathological grade, clinical stage, tumor number and recurrence rate (P = 0.0001, 0.0001, 0.0001 and 0.0051, respectively), but did not correlate with gender or age (P = 0.5588 and 0.6574). After multiple analysis of the above factors and consideration of confounding factors, tumor number, histological grade, clinical stage, and recurrence were related to Usp28 expression (P = 0.001, 0.001, 0.001 and 0.001, respectively). Finally, Usp28 expression was indentified as a independent predictors of survival (P = 0.001). Usp28 protein expression is potentially valuable in prognostic evaluation of bladder cancer. PMID- 24347492 TI - Effect of number and ratio of positive lymph nodes in hypopharyngeal cancer. AB - BACKGROUND: The number and ratio of positive lymph nodes are important prognostic factors in gastric cancer, but there is little data reported in hypopharyngeal cancer. METHODS: Medical data from 81 patients with hypopharyngeal cancer undergoing radical hypopharyngectomy and cervical lymph node dissection were reviewed. RESULTS: The median survival time was 84, 54, 30, and 13 months in patients with N0, N1, N2, and N3, respectively, and 84, 51, and 17 months with positive lymph node ratios (N ratio) 0, <10%, and >10%, respectively. Of the 24 N1 patients, the 20 patients that had an N ratio <10% had a better prognosis than the 4 patients with an N ratio >10%. Similar data was seen for the N2 patients. Tumor (T) classification, adjuvant therapy, and N ratio were independent prognostic factors in multivariate analysis. CONCLUSION: The positive lymph node ratio is complementary to the current N classification system. PMID- 24347491 TI - Regorafenib (BAY 73-4506): antitumor and antimetastatic activities in preclinical models of colorectal cancer. AB - Regorafenib, a novel multikinase inhibitor, has recently demonstrated overall survival benefits in metastatic colorectal cancer (CRC) patients. Our study aimed to gain further insight into the molecular mechanisms of regorafenib and to assess its potential in combination therapy. Regorafenib was tested alone and in combination with irinotecan in patient-derived (PD) CRC models and a murine CRC liver metastasis model. Mechanism of action was investigated using in vitro functional assays, immunohistochemistry and correlation with CRC-related oncogenes. Regorafenib demonstrated significant inhibition of growth-factor mediated vascular endothelial growth factor receptor (VEGFR) 2 and VEGFR3 autophosphorylation, and intracellular VEGFR3 signaling in human umbilical vascular endothelial cells (HuVECs) and lymphatic endothelial cells (LECs), and also blocked migration of LECs. Furthermore, regorafenib inhibited proliferation in 19 of 25 human CRC cell lines and markedly slowed tumor growth in five of seven PD xenograft models. Combination of regorafenib with irinotecan significantly delayed tumor growth after extended treatment in four xenograft models. Reduced CD31 staining indicates that the antiangiogenic effects of regorafenib contribute to its antitumor activity. Finally, regorafenib significantly delayed disease progression in a murine CRC liver metastasis model by inhibiting the growth of established liver metastases and preventing the formation of new metastases in other organs. In addition, our results suggest that regorafenib displays antimetastatic activity, which may contribute to its efficacy in patients with metastatic CRC. Combination of regorafenib and irinotecan demonstrated an increased antitumor effect and could provide a future treatment option for CRC patients. PMID- 24347493 TI - Differential replication of two porcine parvovirus strains in bovine cell lines ensues from initial DNA processing and NS1 expression. AB - Porcine parvovirus (PPV) is a small DNA virus with restricted coding capacity. The 5 kb genome expresses three major non-structural proteins (NS1, NS2 and SAT), and two structural proteins (VP1 and VP2). These few viral proteins are pleiotropic and interact with cellular components throughout viral replication. In this regard, very few cell lines have been shown to replicate the virus efficiently. Cell lines were established from a primary culture of bovine cells that allowed allotropic variants of PPV to be distinguished. Three cell lines were differentially sensitive to infection by two prototype PPV strains, NADL-2 and Kresse. In the first cell line (D10), infection was restricted early in the infectious cycle and was not productive. Infection of the second cell line (G11) was 1000 times less efficient with the NADL-2 strain compared with porcine cells, while production of infectious virus of the Kresse strain was barely detectable. Restriction points in these cells were the initial generation of DNA replication intermediates and NS1 production. Infection with chimeras between NADL-2 and Kresse showed that residues outside the previously described allotropic determinant were also partially responsible for the restriction to Kresse replication in G11 cells. F4 cells were permissive to both strains, although genome replication and infectious virus production were lower than in the porcine cells used for comparison. These results highlight the dependent nature of parvovirus tropism on host factors and suggest that cells from a non-host origin can fully support a productive infection by both strains. PMID- 24347494 TI - Comparative ultrastructural characterization of African horse sickness virus infected mammalian and insect cells reveals a novel potential virus release mechanism from insect cells. AB - African horse sickness virus (AHSV) is an arbovirus capable of successfully replicating in both its mammalian host and insect vector. Where mammalian cells show a severe cytopathic effect (CPE) following AHSV infection, insect cells display no CPE. These differences in cell death could be linked to the method of viral release, i.e. lytic or non-lytic, that predominates in a specific cell type. Active release of AHSV, or any related orbivirus, has, however, not yet been documented from insect cells. We applied an integrated microscopy approach to compare the nanomechanical and morphological response of mammalian and insect cells to AHSV infection. Atomic force microscopy revealed plasma membrane destabilization, integrity loss and structural deformation of the entire surface of infected mammalian cells. Infected insect cells, in contrast, showed no morphological differences from mock-infected cells other than an increased incidence of circular cavities present on the cell surface. Transmission electron microscopy imaging identified a novel large vesicle-like compartment within infected insect cells, not present in mammalian cells, containing viral proteins and virus particles. Extracellular clusters of aggregated virus particles were visualized adjacent to infected insect cells with intact plasma membranes. We propose that foreign material is accumulated within these vesicles and that their subsequent fusion with the cell membrane releases entrapped viruses, thereby facilitating a non-lytic virus release mechanism different from the budding previously observed in mammalian cells. This insect cell-specific defence mechanism contributes to the lack of cell damage observed in AHSV-infected insect cells. PMID- 24347495 TI - Synthesis of a covalent monolayer sheet by photochemical anthracene dimerization at the air/water interface and its mechanical characterization by AFM indentation. AB - Covalent monolayer sheets in 2 hours: spreading of threefold anthracene-equipped shape-persistent and amphiphilic monomers at the air/water interface followed by a short photochemical treatment provides access to infinitely sized, strictly monolayered, covalent sheets with in-plane elastic modulus in the range of 19 N/m. PMID- 24347496 TI - Early influences on child satiety-responsiveness: the role of weaning style. AB - BACKGROUND: Nutrition during infancy may have a long-term impact upon weight gain and eating style. How infants are introduced to solid foods may be important. Traditionally, infants are introduced to solid foods via spoon-feeding of purees. However, baby-led weaning advocates allowing infants to self-feed foods in their whole form. Advocates suggest this may promote healthy eating styles, but evidence is sparse. The aim of the current study was to compare child eating behaviour at 18-24 months between infants weaned using a traditional weaning approach and those weaned using a baby-led weaning style. METHODS: Two hundred ninety-eight mothers with an infant aged 18-24 months completed a longitudinal, self-report questionnaire. In Phase One, mothers with an infant aged 6-12 months reported breastfeeding duration, timing of solid foods, weaning style (baby-led or standard) and maternal control, measured using the Child Feeding Questionnaire. At 18-24 months, post-partum mothers completed a follow-up questionnaire examining child eating style (satiety-responsiveness, food responsiveness, fussiness, enjoyment of food) and reported child weight. RESULTS: Infants weaned using a baby-led approach were significantly more satiety responsive and less likely to be overweight compared with those weaned using a standard approach. This was independent of breastfeeding duration, timing of introduction to complementary foods and maternal control. CONCLUSIONS: A baby-led weaning approach may encourage greater satiety-responsiveness and healthy weight gain trajectories in infants. However, the limitations of a self-report correlational study are noted. Further research using randomized controlled trial is needed. PMID- 24347497 TI - Anomalous hypertrophied muscle band in LV mimicking LV mass. PMID- 24347498 TI - Intramuscular lipoma of the abductor digiti minimi mimicking intramuscular haemangioma. AB - Intramuscular lipoma of the foot is rarely reported. We reported a case of intramuscular lipoma of the abductor digiti minimi mimicking intramuscular haemangioma in clinical and MR findings. PMID- 24347499 TI - Strategy for preventing hepatitis B reactivation in patients with resolved hepatitis B virus infection after rituximab-containing chemotherapy. PMID- 24347500 TI - After the dawn beckons: a soft awakening to an awful day. PMID- 24347501 TI - Raptors and primate evolution. AB - Most scholars agree that avoiding predators is a central concern of lemurs, monkeys, and apes. However, given uncertainties about the frequency with which primates actually become prey, the selective importance of predation in primate evolution continues to be debated. Some argue that primates are often killed by predators, while others maintain that such events are relatively rare. Some authors have contended that predation's influence on primate sociality has been trivial; others counter that predation need not occur often to be a powerful selective force. Given the challenges of documenting events that can be ephemeral and irregular, we are unlikely ever to amass the volume of systematic, comparative data we have on such topics as feeding, social dynamics, or locomotor behavior. Nevertheless, a steady accumulation of field observations, insight gained from natural experiments, and novel taphonomic analyses have enhanced understanding of how primates interact with several predators, especially raptors, the subject of this review. PMID- 24347503 TI - Grandmothers and the evolution of human longevity: a review of findings and future directions. AB - Women and female great apes both continue giving birth into their forties, but not beyond. However humans live much longer than other apes do. Even in hunting and gathering societies, where the mortality rate is high, adult life spans average twice those of chimpanzees, which become decrepit during their fertile years and rarely survive them. Since women usually remain healthy through and beyond childbearing age, human communities include substantial proportions of economically productive postmenopausal women. A grandmother hypothesis(8-12) may explain why greater longevity evolved in our lineage while female fertility still ends at ancestral ages. This hypothesis has implications for the evolution of a wide array of human features. Here we review some history of the hypothesis, recent findings, and questions for ongoing research. PMID- 24347504 TI - From forest fires to fisheries management: anthropology, conservation biology, and historical ecology. AB - Human-environmental relationships have long been of interest to a variety of scientists, including ecologists, biologists, anthropologists, and many others. In anthropology, this interest was especially prevalent among cultural ecologists of the 1970s and earlier, who tended to explain culture as the result of techno environmental constraints. More recently researchers have used historical ecology, an approach that focuses on the long-term dialectical relationship between humans and their environments, as well as long-term prehuman ecological datasets. An important contribution of anthropology to historical ecology is that anthropological datasets dealing with ethnohistory, traditional ecological knowledge, and human skeletal analysis, as well as archeological datasets on faunal and floral remains, artifacts, geochemistry, and stratigraphic analysis, provide a deep time perspective (across decades, centuries, and millennia) on the evolution of ecosystems and the place of people in those larger systems. Historical ecological data also have an applied component that can provide important information on the relative abundances of flora and fauna, changes in biogeography, alternations in food webs, landscape evolution, and much more. PMID- 24347507 TI - Screening of xanthine oxidase inhibitors in complex mixtures using online HPLC coupled with postcolumn fluorescence-based biochemical detection. AB - Xanthine oxidase (XO) catalyzes the metabolism of hypoxanthine and xanthine to uric acid, the overproduction and/or underexcretion of which could cause the incidence of hyperuricemia such as gout. Herein, the inhibition of XO is recognized as one of the therapeutic approaches to treat gout. In the present study, an off-line fluorescence-based microplate method was first developed for an XO assay in which the enzyme converted pterin to its fluorescent metabolite isoxanthopterin. Then, a postcolumn continuous XO assay as a means of bioactivity assessment was coupled to HPLC separation to establish the online HPLC with diode array detection, biochemical detection, and MS/MS system for the screening of XO inhibitors. The availability of the online system was first tested with a positive drug, allopurinol, a well-known XO inhibitor, and subsequent analysis of Scutellaria baicalensis extract showed that two main bioactive compounds with XO inhibitory activities were observed, indicating that the developed online system was applicable to complex mixtures. PMID- 24347508 TI - Complementary histological and genomic analyses reveal marked differences in the developmental trajectories of ovaries in Siberian hamsters raised in long- and short-day lengths. AB - Siberian hamsters (Phodopus sungorus) delay sexual development when raised in short-day (SD; 10 hr light: 14 hr dark) conditions, which leads to delayed onset of estrous cycles and ovulations as compared to females raised in long-day (LD; 16 hr light: 8 hr dark) conditions. In addition to the absence of pre-ovulatory follicles and corpora lutea, the ovaries of SD-reared Siberian hamsters are characterized by an abundance of hypertrophied granulosa cells (HGCs) that surround atretic oocytes. To determine the age at which the histology of LD and SD ovaries first diverge, including the initial appearance of HGCs in SD conditions, we examined hamster ovaries histologically at 1, 2, 3, 4, 6, 8, 10, and 12 weeks of age. After identifying subtle differences in LD and SD ovarian histology at 4 weeks of age, we searched for differences in ovarian gene expression at 3 and 8 weeks of age, which correspond to the ages when ovarian histology do not differ (3 weeks) versus the earliest age when HGCs were observed (8 weeks). At 3 weeks, only 14 genes were differentially expressed in LD and SD ovaries, whereas 183 genes were differentially expressed at 8 weeks. Overall, our findings demonstrate that ovarian development under SD conditions is not simply arrested at an early stage of LD development, but rather utilizes a developmental path that is distinct from that used in LD ovaries. PMID- 24347506 TI - Association of serum uric acid and incident nonspine fractures in elderly men: the Osteoporotic Fractures in Men (MrOS) study. AB - Uric acid (UA) is produced from purines by the enzyme xanthine oxidase, and elevated levels may cause arthritis and kidney stones. Conversely, UA also appears to function as an antioxidant and may protect against the oxidative stress associated with aging and disease. We performed a prospective fracture case-cohort study to understand the relation of UA and fracture risk in older men enrolled in the Osteoporotic Fractures in Men (MrOS) study. In the cohort of 5994 men aged 65 years and older attending the baseline MrOS examination, we evaluated a subgroup 1680 men in a case-cohort study design. The analytic group included 387 men with incident nonspine fractures (73 hip) and a random sample of 1383. Serum UA was measured in baseline serum samples. Modified proportional hazards models that account for case-cohort study design were used to estimate the relative hazards (RH) of hip and nonspine fracture in men for serum UA. Models were adjusted for age, race, clinic site, body mass index, vitamin D, parathyroid hormone, walking speed, Physical Activity Scale for the Elderly (PASE) score, frailty, and total. Subjects with incident nonspine fractures were older, had lower total hip bone mineral density (BMD), and higher serum phosphorus. There was an 18% decreased risk of nonspine fractures (95% confidence interval [CI] 0.71-0.93; p = 0.003) per 1 SD increase of baseline serum and 34% decreased risk of nonspine fractures in quartile 4 of UA versus quartiles 1, 2, and 3 (95% CI 0.49-0.89; p = 0.028) compared with nonfracture cases after multivariate adjustment. Hip fractures were not significantly associated with UA. Total hip BMD was significantly higher in the group of men with high UA levels compared with lower UA levels and increased linearly across quartiles of UA after multivariate adjustment (p for trend = 0.002). In summary, higher serum UA levels were associated with a reduction in risk of incident nonspine fractures but not hip fractures and higher hip BMD. PMID- 24347509 TI - A chemotherapy only therapeutic approach to pediatric Hodgkin lymphoma: AHOPCA LH 1999. AB - BACKGROUND: AHOPCA is a collaborative group that designs uniform treatment regimens (protocols) for children diagnosed with cancer in Central America. Based on a preliminary report from one of the AHOPCA centers, AHOPCA adopted a treatment regimen to maintain a good event-free survival (EFS) as well as eliminate radiation therapy from the treatment of children with Hodgkin lymphoma. PROCEDURE: Newly diagnosed patients with histologically proven Hodgkin lymphoma were staged according to the Ann Arbor classification and divided into favorable (stage I, stage IIA, and IIIA) and unfavorable (stage IIB, IIIB, and IV) groups. Subjects classified as group 1 (favorable) were treated with six 28-day cycles of chemotherapy (COPP/COPP +/- ABV). Subjects classified as group 2 (unfavorable) were treated with eight 28-day cycles of COPP/ABV chemotherapy. RESULTS: Of 269 patients registered, 216 were eligible for evaluation. The mean age at diagnosis was 7.5 years with a male to female ratio of 3.7-1. The predominant histology was nodular sclerosis (44%) but with a relatively high proportion of mixed cellularity (35.2%) The EFS at 5 and 10 years was 71% and 68%, respectively. There was a 14% rate of abandonment of therapy. CONCLUSION: This treatment regimen for children with Hodgkin lymphoma, when applied as a multi-institutional regimen, had poorer outcome than our previously reported preliminary data and was inferior to the EFS reported in high-income countries. The major contributor adversely affecting EFS in this report is abandonment of therapy. Given these results, AHOPCA initiated a concerted effort to decrease abandonment of therapy. PMID- 24347511 TI - Relational coherence in ambiguous and unambiguous relational networks. AB - Clinical theories often appeal to general cognitive styles in explaining psychopathology, but without describing in detail how the patterns are formed. In the present investigation, two experiments were conducted to examine how individuals respond to ambiguous relational networks. In both experiments, the participants learned two 3-stimulus networks (A1 LESS THAN B1, A1 GREATER THAN C1 and A2 GREATER THAN B2, C2 LESS THAN A2). Participants were presented with test trials to examine if they classified the combinatorial relations (B1 <-> C1 and B2 <-> C2) as SAME or DIFFERENT and as GREATER THAN or LESS THAN. Although the B C combinatorial relation in Network 1 is derivable in a readily coherent way (B1 GREATER THAN C1 and thus also B1 DIFFERENT C1), in Network 2 the combinatorial relation is ambiguous. When participants were required to specify the Network 2 B C relation as either SAME or DIFFERENT, those who chose DIFFERENT, also consistently chose B2 as either GREATER THAN or LESS THAN C2. Conversely, those who classified the B-C relation as SAME were inconsistent within themselves in choosing B2 as GREATER THAN or LESS THAN C2. In Experiment 2, nonarbitrary multiple exemplar pretraining was used to bias SAME versus DIFFERENT as a response for ambiguous combinatorial relations. In accord with the pattern seen in Experiment 1, those biased toward DIFFERENT consistently chose a comparative relation between B2 and C2 while those biased toward SAME were inconsistent in their comparative choices. The findings provide support for the importance of history and coherence in establishing patterns of responding to ambiguous relational networks, providing a beginning behavioral model of cognitive styles and errors. PMID- 24347512 TI - Measurement of the effect of playground surface materials on hand impact forces during upper limb fall arrests. AB - Distal radius fractures are common on playgrounds. Yet current guidelines for the selection of playground surface materials are based only on protection against fall-related head injuries. We conducted "torso release" experiments to determine how common playground surface materials affect impact force applied to the hand during upper limb fall arrests. Trials were acquired for falls onto a rigid surface, and onto five common playground surface materials: engineered wood fiber, gravel, mulch, rubber tile, and sand. Measures were acquired for arm angles of 20 and 40 degrees from the vertical. Playground surface materials influenced the peak resultant and vertical force (P<.001), but not the peak horizontal force (P=.159). When compared with the rigid condition, peak resultant force was reduced 17% by sand (from 1039 to 864 N), 16% by gravel, 7% by mulch, 5% by engineered wood fiber, and 2% by rubber tile. The best performing surface provided only a 17% reduction in peak resultant force. These results help to explain the lack of convincing evidence from clinical studies on the effectiveness of playground surface materials in preventing distal radius fractures during playground falls, and highlight the need to develop playground surface materials that provide improved protection against these injuries. PMID- 24347510 TI - Analysis of CD34+ cell collection using two mobilization regimens for newly diagnosed multiple myeloma patients reveals the separate impact of mobilization and collection variables. AB - Mobilization regimens for CD34+ cells have generally been judged successful based on the number of cells collected without evaluating mobilization separately from collection. Using retrospective data for patients who collected CD34+ cells on Total Therapy protocols 3a/3b (VTD-PACE) and Total Therapy 4/5 using a novel regimen that added low dose melphalan to VTD-PACE (MVTD-PACE), we analyzed mobilization and collection variables separately. A significant difference favoring MVDT-PACE was found in mean CD34+ cells/uL on day 2 of collection and in mean ratio of CD34+ cells/uL on day 2 to day 1. However, because apheresis variables and growth factor dose during collection were manipulated to optimize individual collections, the two regimens were not significantly different when the mean total CD34+ cells *10(6) /kg collected was compared. Thus, when evaluating a chemotherapy regimen or new growth factor for mobilization, it is important to realize that total CD34+ cells collected is dependent on both mobilization and collection variables. PMID- 24347513 TI - Diffusion-weighted imaging in head and neck squamous cell carcinomas: a systematic review. AB - BACKGROUND: The purpose of this study was for us to review diagnostic accuracy of diffusion-weighted imaging (DWI) in primary head and neck squamous cell carcinomas (HNSCCs), detection of metastatic lymph nodes, and recurrences. METHODS: A systematic review for studies concerning DWI was performed. RESULTS: Ten studies fulfilled inclusion criteria. All studies showed significant higher "apparent diffusion coefficient" (ADC) in benign compared to malignant lesions. ADC thresholds for optimal discrimination varied. In detection of primary HNSCC, the accuracy of DWI ranged from 66% to 86%. In metastatic lymph nodes, the accuracy of DWI was 85% to 91% and the negative predictive value (NPV) was higher than 91%. For recurrences, the accuracy of DWI was 78% to 100% and the NPV ranged from 77% to 100%. CONCLUSION: DWI showed consistent high accuracy and high NPV. However, available literature is sparse and varying ADC thresholds were reported. Compared to current imaging techniques, DWI showed the most potential in lymph node staging and detection of recurrences. PMID- 24347514 TI - Comprehensive metagenomic analysis of glioblastoma reveals absence of known virus despite antiviral-like type I interferon gene response. AB - Glioblastoma is a deadly malignant brain tumor and one of the most incurable forms of cancer in need of new therapeutic targets. As some cancers are known to be caused by a virus, the discovery of viruses could open the possibility to treat, and perhaps prevent, such a disease. Although an association with viruses such as cytomegalovirus or Simian virus 40 has been strongly suggested, involvement of these and other viruses in the initiation and/or propagation of glioblastoma remains vague, controversial and warrants elucidation. To exhaustively address the association of virus and glioblastoma, we developed and validated a robust metagenomic approach to analyze patient biopsies via high throughput sequencing, a sensitive tool for virus screening. In addition to traditional clinical diagnostics, glioblastoma biopsies were deep-sequenced and analyzed with a multistage computational pipeline to identify known or potentially discover unknown viruses. In contrast to the studies reporting the presence of viral signatures in glioblastoma, no common or recurring active viruses were detected, despite finding an antiviral-like type I interferon response in some specimens. Our findings highlight a discrete and non-specific viral signature and uncharacterized short RNA sequences in glioblastoma. This study provides new insights into glioblastoma pathogenesis and defines a general methodology that can be used for high-resolution virus screening and discovery in human cancers. PMID- 24347516 TI - Simultaneous stereoselective detection of chiral fungicides in soil by LC-MS/MS with fast sample preparation. AB - An enantioselective method was developed for the simultaneous detection of five chiral fungicides in soil, including fenbuconazole (1), tetraconazole (2), nuarimol (3), triticonazole (4), and simeconazole (5) by LC-MS/MS on a chiral stationary phase of cellulose tris-(3-chloro-4-methylphenylcarbamate) with a gradient elution. A new multifunctional filter was designed to simplify the QuEChERS (where QuEChERS is quick, easy, cheap, effective, rugged, and safe) method by simultaneous cleanup and filtration when the sample extracts were directly passed through it. Good linearities (R2 > 0.9980) were obtained in the range 0.005-2.5 mg/L, and the recovery rates were 77.4-103.6% with RSDs of 0.7 12.2% for intraday precision and 1.2-11.0% for interday precision. The LODs and LOQs for all enantiomers were in the range 0.1-0.2 and 0.25-0.5 MUg/kg, respectively. The analysis of the incubated soil suggests that this method is reliable and practical for the stereoselective detection of chiral fungicides. PMID- 24347515 TI - Scratching the surface: actin' and other roles for the C-terminal Eps15 homology domain protein, EHD2. AB - The C-terminal Eps15 homology domain-containing (EHD) proteins participate in multiple aspects of endocytic membrane trafficking. Of the four mammalian EHD proteins, EHD2 appears to be the most disparate, both in terms of sequence homology, and in subcellular localization/function. Since its initial description as a plasma membrane-associated protein, the precise function of EHD2 has remained enigmatic. Various reports have suggested roles for EHD2 at the plasma membrane, within the endocytic transport system, and even in the nucleus. For example, EHD2 facilitates membrane fusion/repair in muscle cells. Recently the focus has shifted to the role of EHD2 in regulating caveolae. Indeed, EHD2 is highly expressed in tissues rich in caveolae, including fat, muscle and blood vessels. This review highlights cumulative evidence linking EHD2 to actin-rich structures at the plasma membrane, where the plasma membrane-associated phospholipid phosphatidylinositol 4,5-bisphosphate controls EHD2 recruitment. Herein we examine the key pathways where EHD2 might function, and address its potential involvement in these processes. PMID- 24347517 TI - The effect of obstructive sleep apnea on olfactory functions. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to investigate the effect of obstructive sleep apnea (OSA) on the parameters of olfactory functions (odor threshold, odor discrimination, and odor identification tests) for orthonasal olfaction, retronasal olfactory testing, and olfactory bulb (OB) volumes. STUDY DESIGN: Prospective clinical study. METHODS: This study was carried out in 78 volunteers between the ages of 20 and 60 years. The mean age of the patients was 46 +/- 10.1 years. Patients were divided into three groups according to polysomnography results: 1) a control group, 2) a mild to moderate OSA group, and 3) a severe OSA group. Clinical features of the participants were evaluated with the Epworth Sleepiness Scale. Orthonasal and retronasal olfactory testing were performed with Sniffin' Sticks olfactory testing and retronasal olfactory testing, respectively. Olfactory bulb volumes were measured by planimetric manual contouring on magnetic resonance imaging (MRI). RESULTS: The current investigation produced four major findings: 1) The apnea-hypopnea index had a significant and strong negative correlation with odor threshold scores and odor discrimination scores; 2) The apnea-hypopnea index was significantly negatively correlated with odor identification score and both right and left OB volumes; 3) retronasal olfactory scores were not significantly affected by OSA; and 4) continuous O2 saturation had a significant positive correlation on orthonasal olfactory functions, particularly the odor threshold and discrimination scores. CONCLUSIONS: This study demonstrated that OSA had significant negative effects on all orthonasal olfactory tasks, especially on threshold and discrimination. MRI also revealed volumetric shrinkage of OB volumes. PMID- 24347518 TI - Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. AB - BACKGROUND: PAM50 is a 50-gene test that is designed to identify intrinsic breast cancer subtypes and generate a Risk of Recurrence (ROR) score. It has been developed to be carried out in qualified routine hospital pathology laboratories. PATIENTS AND METHODS: One thousand four hundred seventy-eight postmenopausal women with estrogen receptor (ER)+ early breast cancer (EBC) treated with tamoxifen or tamoxifen followed by anastrozole from the prospective randomized ABCSG-8 trial were entered into this study. Patients did not receive adjuvant chemotherapy. RNA was extracted from paraffin blocks and analyzed using the PAM50 test. Both intrinsic subtype (luminal A/B, HER2-enriched, basal-like) and ROR score were calculated. The primary analysis was designed to test whether the continuous ROR score adds prognostic value in predicting distant recurrence (DR) over and above standard clinical variables. RESULTS: In all tested subgroups, ROR score significantly adds prognostic information to the clinical predictor (P<0.0001). PAM50 assigns an intrinsic subtype to all cases, and the luminal A cohort had a significantly lower ROR at 10 years compared with Luminal B (P<0.0001). Significant and clinically relevant discrimination between low- and high-risk groups occurred also within all tested subgroups. CONCLUSION(S): The results of the primary analysis, in combination with recently published results from the ATAC trial, constitute Level 1 evidence for clinical validity of the PAM50 test for predicting the risk of DR in postmenopausal women with ER+ EBC. A 10-year metastasis risk of <3.5% in the ROR low category makes it unlikely that additional chemotherapy would improve this outcome-this finding could help to avoid unwarranted overtreatment. CLINICAL TRIAL NUMBER: ABCSG 8: NCT00291759. PMID- 24347519 TI - Epirubicin and docetaxel with or without capecitabine as neoadjuvant treatment for early breast cancer: final results of a randomized phase III study (ABCSG 24). AB - BACKGROUND: This randomized phase III trial compared pathologic complete response (pCR) rates of early breast cancer (EBC) following neoadjuvant epirubicin docetaxel (ED)+/-capecitabine (C), and evaluated the addition of trastuzumab in HER2-positive tumors. PATIENTS AND METHODS: Patients with invasive breast cancer (except T4d) were randomly assigned to receive six 3-weekly cycles of ED (both 75 mg/m2)+/-C (1000 mg/m2, twice daily, days 1-14). Patients with HER2-positive disease were further randomized to receive trastuzumab (8 mg/kg, then 6 mg/kg every 3 weeks) or not. Primary end point: pCR rate at the time of surgery. RESULTS: Five hundred thirty-six patients were randomized to ED (n=266) or EDC (n=270); 93 patients were further randomized to trastuzumab (n=44) or not (n=49). pCR rate was significantly increased with EDC (23.0% versus 15.4% ED, P=0.027), and nonsignificantly further increased with trastuzumab (38.6% EDC versus 26.5% ED, P=0.212). Rates of axillary node involvement at surgery and breast conservation were improved with EDC versus ED, but not significantly; the addition of trastuzumab had no further impact. Hormone receptor status, tumor size, grade, and C (all P<=0.035) were independent prognostic factors for pCR. Trastuzumab added to ED+/-C significantly increased the number of serious adverse events (35 versus 18; P=0.020), mainly due to infusion-related reactions. CONCLUSION: These findings show that the integration of C into a neoadjuvant taxane-/anthracycline-based regimen is a feasible, safe, and effective treatment option, with incorporation of trastuzumab in HER2-positive disease. CLINICAL TRIAL NUMBER: NCT00309556, www.clinicaltrials.gov. PMID- 24347520 TI - Efficacy of short-term psychodynamic psychotherapy (STPP) with depressed breast cancer patients: results of a randomized controlled multicenter trial. AB - BACKGROUND: There is a lack of trials of psychodynamic treatments of depression in breast cancer patients. The purpose of this trial was to determine the efficacy of short-term psychodynamic psychotherapy (STPP) in non-metastatic breast cancer patients diagnosed with depression, one of the most frequent mental comorbidities of breast cancer. PATIENTS AND METHODS: In a multicenter prospective trial, 157 breast cancer patients with comorbid depression were randomized to either individual STPP (intervention group, N=78) or 'treatment as usual' (control group, TAU, N=79). As our primary outcome measure, we hypothesized a higher rate of remission defined as no diagnosis of depression (Structured Clinical Interview for DSM-IV) and reduction in depression score by at least 2 points (Hospital Anxiety and Depression Scale, HADS-D) in STPP versus TAU at treatment termination. Secondary outcomes mainly refer to quality of life (QoL). RESULTS: In the intention to treat (ITT) analysis, 44% of the STPP group achieved highly significantly more remission than TAU (23%). STPP treatment (OR=7.64; P<0.001) was the strongest predictor for remission post-treatment; time was also significant (OR=0.96; P<0.05). A high effect favoring STPP (d=0.82) was observed for the HADS-D score post-treatment (secondary outcome). Regarding further secondary outcomes (QoL), analyses of covariance yielded main effects for group (favoring STPP with an effect size of at least d=0.5) for global QoL, role, emotional and social functioning, pain, treatment side-effects, breast symptoms and upset by hair loss. CONCLUSIONS: STPP is an effective treatment of a broad range of depressive conditions in breast cancer patients improving depression and functional QoL. Findings are limited by the drop-out rate (~1/3) and delayed post treatment assessments. Future trials may consider stepped-care approaches, tailored to patients' needs and requirements in the acute treatment phase. PMID- 24347521 TI - Cost-effectiveness of an Internet-based treatment program for stress urinary incontinence. AB - AIMS: To perform a deterministic cost-utility analysis, from a 1-year societal perspective, of two treatment programs for stress urinary incontinence (SUI) without face-to-face contact: one Internet-based and one sent by post. The treatments were compared with each other and with no treatment. METHODS: We performed this economic evaluation alongside a randomized controlled trial. The study included 250 women aged 18-70, with SUI >= 1 time/week, who were randomized to 3 months of pelvic floor muscle training via either an Internet-based program including e-mail support from an urotherapist (n = 124) or a program sent by post (n = 126). Recruitment was web-based, and participants were self-assessed with validated questionnaires and 2-day bladder diaries, supplemented by a telephone interview with a urotherapist. Treatment costs were continuously registered. Data on participants' time for training, incontinence aids, and laundry were collected at baseline, 4 months, and 1 year. We also measured quality of life with the condition-specific questionnaire ICIQ-LUTSqol, and calculated the quality adjusted life-years (QALYs) gained. Baseline data remained unchanged for the no treatment option. Sensitivity analysis was performed. RESULTS: Compared to the postal program, the extra cost per QALY for the Internet-based program ranged from 200? to 7,253?, indicating greater QALY-gains at similar or slightly higher costs. Compared to no treatment, the extra cost per QALY for the Internet-based program ranged from 10,022? to 38,921?, indicating greater QALY-gains at higher, but probably acceptable costs. CONCLUSION: An Internet-based treatment for SUI is a new, cost-effective treatment alternative. PMID- 24347522 TI - A network approach to diagnostic biomarkers in progressive supranuclear palsy. AB - Diagnosis of progressive supranuclear palsy (PSP) remains challenging because of the clinical overlap with Parkinson's disease (PD). To date, disease-specific biomarkers have yet to be identified. In the absence of reliable biomarkers, we used an integrated network approach to identify genes and related biological pathways associated with PSP. We tested a highly ranked gene in cellular whole blood samples from 122 patients enrolled in the Prognostic Biomarker Study. Biological and functional analysis identified 13 modules related to activation of leukocytes and lymphocytes, protein dephosphorylation, and phosphatase activity. Integration of these results with those from microarrays identified ptpn1 as a potential biomarker for PSP. Assessment of biomarker performance revealed that ptpn1 could be used to distinguish PSP patients from PD patients with 86% diagnostic accuracy. Ptpn1 may be a diagnostic marker useful for distinguishing PSP and PD. Further evaluation in a larger well-characterized prospective study is warranted. PMID- 24347523 TI - Extremely obese children respond better than extremely obese adolescents to lifestyle interventions. AB - What is already known about this subject Lifestyle intervention is regarded as therapy of choice in obese children and adolescents. It is unclear whether extremely obese children and adolescents respond to lifestyle intervention. What this study adds Extremely obese children respond better than obese children to a lifestyle intervention. In contrast, most extremely obese adolescents achieved no weight loss in lifestyle intervention suggesting that other treatment approaches are needed for them. BACKGROUND: There are conflicting results of treating extreme obesity in childhood by lifestyle interventions in the literature. METHODS: We analysed the outcome of a 1-year lifestyle intervention in an intention-to-treat approach in 1291 children (mean age 11.0 +/- 2.5 years, mean body mass index [BMI] 27.5 +/- 4.7 kg m(-2), 55.8% female, 62.4% obese, 37.6% extremely obese (defined by BMI-SDS >2.3) at end of intervention and 1 year later. RESULTS: The mean BMI-SDS reduction was -0.20 +/- 0.32 at end of intervention and -0.14 +/- 0.37 1 year after end of intervention compared to baseline (comparing intervention vs. 1 year later P = 0.010). Extremely obese children <=10 years demonstrated a significantly greater BMI-SDS reduction than obese children <=10 years (-0.24 +/- 0.38 vs. -0.16 +/- 0.38, P = 0.021). Extremely obese adolescents >10 years demonstrated a significantly lower BMI-SDS reduction compared to obese adolescents >10 years (-0.05 +/- 0.30 vs. -0.15 +/- 0.39, P < 0.001). Comparing the BMI-SDS reduction between obese children <10 years and >10 years revealed no significant difference (P = 0.195) in contrast to the comparison between extremely obese children <10 years and >10 years (P < 0.001). The same findings were observed in the follow-up period after the end of intervention. CONCLUSIONS: Our study demonstrated an encouraging effect of lifestyle intervention in extremely obese children <=10 years at the end of intervention and 1 year later, but only a limited effect in extremely obese adolescents >10 years. PMID- 24347524 TI - Artificial ion channels regulating light-induced ionic currents in photoelectrical conversion systems. AB - Artificial ion channels are introduced into a photosystem II photoelectrical conversion system to mimic the photocurrent regulating of the natural PSII energy system on the thylakoid membrane. In the composite system, PSII complexes act as pumps to convert light into currents and artificial ion channels act as valves to regulate light-induced ionic currents. PMID- 24347525 TI - How does met regulate the survival/apoptosis balance? PMID- 24347526 TI - Editorial: Basic and translational research on stimulus-stimulus relations. PMID- 24347527 TI - Interleukin-4 regulates lipid metabolism by inhibiting adipogenesis and promoting lipolysis. AB - Long-term cytokine-mediated inflammation is a risk factor for obesity and type 2 diabetes mellitus (T2DM). Our previous studies reveal significant associations between promoter single nucleotide polymorphisms (SNPs) of interleukin (IL)-4 and T2DM, as well as between SNPs in genes encoding IL-4/IL-4 receptor and high density lipoproteins. Our animal study reveals that IL-4 regulates glucose/lipid metabolism by promoting glucose tolerance and inhibiting lipid deposits. The above results strongly suggest the involvement of IL-4 in energy homeostasis. In the present study, we focus on examining the regulatory mechanism of IL-4 to lipid metabolism. Our results show that IL-4 inhibits adipogenesis by downregulating the expression of peroxisome proliferator-activated receptor-gamma and CCAAT/enhancer-binding protein-alpha. Additionally, IL-4 promotes lipolysis by enhancing the activity and translocation of hormone sensitive lipase (HSL) in mature adipocytes, which suggests that IL-4 plays a pro-lipolytic role in lipid metabolism by boosting HSL activity. Our results demonstrate that IL-4 harbors pro-lipolysis capacity by inhibiting adipocyte differentiation and lipid accumulation as well as by promoting lipolysis in mature adipocytes to decrease lipid deposits. The above findings uncover the novel roles of IL-4 in lipid metabolism and provide new insights into the interactions among cytokine/immune responses, insulin sensitivity, and metabolism. PMID- 24347529 TI - Nutrition optimization prior to surgery. AB - Optimization of metabolic state prior to major surgery leads to improved surgical outcomes. Nutrition screening protocols should be implemented in the preoperative evaluation, possibly as part of a bundle. Strategies to minimize hyperglycemia and insulin resistance by aggressive preoperative nutrition and carbohydrate loading may promote maintenance of a perioperative anabolic state, improving healing, reducing complications, and shortening the time to recovery of bowel function and hospital discharge. Short courses of preoperative immune-modulating formulas, using combinations of arginine, omega-3 fatty acids, and other nutrients, have been associated with improved surgical outcomes. These immune modulating nutrients are key elements of metabolic pathways that promote attenuation of the metabolic response to stress and improve both wound healing and immune function. Patients with severe malnutrition and gastrointestinal dysfunction may benefit from preoperative parenteral nutrition. Continuation of feeding through the intraoperative period for severely stressed hypermetabolic patients undergoing nongastrointestinal surgery is another strategy to optimize metabolic state and reduce prolonged nutrition deficits. In this paper, we review the importance of preoperative nutrition and strategies for effective preoperative nutrition optimization. PMID- 24347528 TI - High density lipoproteins improve insulin sensitivity in high-fat diet-fed mice by suppressing hepatic inflammation. AB - Obesity-induced liver inflammation can drive insulin resistance. HDL has anti inflammatory properties, so we hypothesized that low levels of HDL would perpetuate inflammatory responses in the liver and that HDL treatment would suppress liver inflammation and insulin resistance. The aim of this study was to investigate the effects of lipid-free apoAI on hepatic inflammation and insulin resistance in mice. We also investigated apoAI as a component of reconstituted HDLs (rHDLs) in hepatocytes to confirm results we observed in vivo. To test our hypothesis, C57BL/6 mice were fed a high-fat diet (HFD) for 16 weeks and administered either saline or lipid-free apoAI. Injections of lipid-free apoAI twice a week for 2 or 4 weeks with lipid-free apoAI resulted in: i) improved insulin sensitivity associated with decreased systemic and hepatic inflammation; ii) suppression of hepatic mRNA expression for key transcriptional regulators of lipogenic gene expression; and iii) suppression of nuclear factor kappaB (NF kappaB) activation. Human hepatoma HuH-7 cells exposed to rHDLs showed suppressed TNFalpha-induced NF-kappaB activation, correlating with decreased NF-kappaB target gene expression. We conclude that apoAI suppresses liver inflammation in HFD mice and improves insulin resistance via a mechanism that involves a downregulation of NF-kappaB activation. PMID- 24347530 TI - Going with the flow or swimming against the tide: should children with central venous catheters swim? AB - Children who require long-term parenteral nutrition (PN) have central venous catheters (CVCs) in place to allow the safe and effective infusion of life sustaining fluids and nutrition. Many consider recreational swimming to be a common part of childhood, but for some, the risk may outweigh the benefit. Children with CVCs may be at increased risk of exit site, tunnel, and catheter related bloodstream infections (CRBSIs) if these catheters are immersed in water. The purpose of this review is to evaluate the current literature regarding the risk of infection for patients with CVCs who swim and determine if there is consensus among home PN (HPN) programs on this controversial issue. A total 45 articles were reviewed and 16 pediatric HPN programs were surveyed regarding swimming and CVCs. Due to the limited data available, a firm recommendation cannot be made. Recreational water associated outbreaks are well documented in the general public, as is the presence of human pathogens even in chlorinated swimming pools. As a medical team, practitioners can provide information and education regarding the potential risk, but ultimately the decision lies with the parents. If the parents decide swimming is worth the risk, they are encouraged to use products designed for this use and to change their child's dressing immediately after swimming. Due to our experience with a fatal event immediately after swimming, we continue to strongly discourage patients with CVCs from swimming. Further large and well-designed studies regarding the risk of swimming with a CVC are needed to make a strong, evidence-based recommendation. PMID- 24347531 TI - Quality of life analysis during transition from stationary to portable infusion pump in home parenteral nutrition patients: a Canadian experience. AB - BACKGROUND: Quality of life (QOL) of patients receiving home parenteral nutrition (HPN) may be impacted by device technology. Historically, our HPN patients used pole-mounted pumps which can hinder activities and affect QOL. METHODS: Patients receiving HPN with a pole-mounted pump completed Short Form 36 (SF-36(r)) and pump-specific questionnaires. Patients were then enrolled in a 2-month prospective crossover open study. Patients were randomized to use a pole-mounted pump or a portable pump. After 1 month, each arm crossed over. Measurements were repeated at 4 and 8 weeks. RESULTS: Participants included 5 males, 15 females; age 52.8 +/- 3.3 (mean +/- SEM) years; 50% had short bowel syndrome; received HPN for 83.3 +/- 15.9 months; infused HPN over 11.2 +/- 0.3 hours/day; 4.3 +/- 0.4 days/week. Portable pump users scored 53.75 +/- 5.64, 61.25 +/- 6.14, and 40.31 +/- 4.94 in SF-36v2 physical, social, and health vitality, respectively, while the stationary pump users scored 45.50 +/- 4.82, 55.00 +/- 5.97, and 35.31 +/- 4.63, respectively (NS). They reported ease of movement between rooms (4.11 +/- 0.21 vs 1.44 +/- 0.20; P = .001); when traveling (5.00 +/- 0.00 vs 3.00 +/- 0.45; P < .02) (1 = very difficult, 5 = very easy); 5.0% were sleep disturbed with the portable compared to 42.1% with pole-mounted pump (P < .04). Overall, patients were significantly happier with the portable vs pole-mounted pump (4.53 +/- 0.19 vs 2.68 +/- 0.22; P < .001) (1 = very unhappy, 5 = very happy). CONCLUSION: Our HPN patients reported improved happiness and satisfaction regarding ease of use and function with a portable vs pole-mounted pump. PMID- 24347533 TI - Shank-rearfoot joint coupling with chronic ankle instability. AB - Chronic ankle instability (CAI) results in longstanding symptoms and subjective feelings of "giving way" following initial ankle sprain. Our purpose was to identify differences in joint coupling and variability between shank internal/external rotation and rearfoot inversion/eversion throughout the gait cycle of CAI subjects and healthy controls. Twenty-eight young adults participated (CAI, n = 15, control, n = 13). Kinematics were collected while walking and jogging on a treadmill. A vector coding method in which direction (theta) and magnitude of the angle-angle relationship and stride-to-stride variability (VCV) in shank-rearfoot coupling were calculated. In walking, the CAI group demonstrated lower theta, indicating a greater proportion of rearfoot-to shank motion, compared with the control group in early and late swing. The CAI group had higher magnitude, indicating greater combined motion between the two segments, in early swing, but lower magnitude, indicating less combined motion, during late swing. The CAI group also had lower VCV measures, indicating less stride-to-stride variability during stance. In jogging, the CAI group had lower theta measures than the control group during stance and swing. Differences in shank-rearfoot coupling of the CAI group may be related to changes in sensorimotor control and lead to further instances of instability. PMID- 24347532 TI - Serum prognostic biomarkers in head and neck cancer patients. AB - OBJECTIVES/HYPOTHESIS: A reliable estimate of survival is important as it may impact treatment choice. The objective of this study is to identify serum autoantibody biomarkers that can be used to improve prognostication for patients affected with head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: Prospective cohort study. METHODS: A panel of 130 serum biomarkers, previously selected for cancer detection using microarray-based serological profiling and specialized bioinformatics, were evaluated for their potential as prognostic biomarkers in a cohort of 119 HNSCC patients followed for up to 12.7 years. A biomarker was considered positive if its reactivity to the particular patient's serum was greater than one standard deviation above the mean reactivity to sera from the other 118 patients, using a leave-one-out cross-validation model. Survival curves were estimated according to the Kaplan-Meier method, and statistically significant differences in survival were examined using the log rank test. Independent prognostic biomarkers were identified following analysis using multivariate Cox proportional hazards models. RESULTS: Poor overall survival was associated with African Americans (hazard ratio [HR] for death = 2.61; 95% confidence interval [CI]: 1.58-4.33; P = .000), advanced stage (HR = 2.79; 95% CI: 1.40-5.57; P = .004), and recurrent disease (HR = 6.66; 95% CI: 2.54-17.44; P = .000). On multivariable Cox analysis adjusted for covariates (race and stage), six of the 130 markers evaluated were found to be independent prognosticators of overall survival. CONCLUSIONS: The results shown here are promising and demonstrate the potential use of serum biomarkers for prognostication in HNSCC patients. Further clinical trials to include larger samples of patients across multiple centers may be warranted. PMID- 24347534 TI - Effects of 3-hydroxyflavone on the cellular and molecular characteristics of bovine embryos produced by somatic-cell nuclear transfer. AB - This study aimed to investigate the effects of 3-hydroxyflavone, a natural antioxidant pigment enriched in vegetables, on the developmental cellular and molecular characteristics of bovine somatic-cell nuclear transfer (SCNT) embryos. There were no significant differences in the cleavage rate at 48 hr of culture or in the inner cell mass (ICM)-to-trophectoderm (TE) ratio between 3-hydroxyflavone addition and untreated (control) groups (P > 0.05). 3-hydroxyflavone (20 uM) did, however, increase the cleavage rate at 24 hr of culture and the blastocyst formation rate on Days 6 and 7 (P < 0.05); decrease the levels of intracellular reactive oxygen species in two-, four-, and eight-cell stage embryos (P < 0.05); increase H3K9ac levels in two- and four-cell stages (P < 0.05); increase the total cell number; and decrease the apoptosis index in Day-7 blastocysts. Furthermore, the addition of 3-hydroxyflavone resulted in lower expression of the stress-related gene HSP70.1 and pro-apoptotic gene BAX, as well as higher expression of the anti-apoptotic gene BCL-xL and pluripotency-related genes OCT4 and SOX2 in Day-7 blastocysts produced by SCNT (P < 0.05). The addition of 3 hydroxyflavone during in vitro culture thus exerted beneficial effects on preimplantation development of bovine SCNT embryos both at the cellular and molecular levels. PMID- 24347535 TI - Thermosensitive molecularly imprinted hydrogel cross-linked with N-malely chitosan for the recognition and separation of BSA. AB - A novel temperature-sensitive molecularly imprinted hydrogel composed of N isopropylacrylamide and acrylamide has been prepared by using free-radical polymerization and was cross-linked by modified water-soluble N-maley chitosan in aqueous solution. BSA (pI 4.9, MW 66.0 kDa) was used as the template protein. The produced hydrogels were characterized by environmental SEM to reveal the microcosmic morphology. A microporous structure was only found in the imprinted hydrogel, while no obvious microporous structure was found in nonimprinted hydrogels. The lower critical solution temperature of the hydrogels was 34 degrees C, and the optimal binding conditions were tested, namely, the adsorption equilibrium time of 6 h and initial BSA concentration of 1.0 mg/mL. The adsorption capacity Qmax was determined by Langmuir isotherm plots and was 5.72 mg/g for imprinted hydrogel and 1.18 mg/g for nonimprinted hydrogels. A separation factor (beta) of 4 was obtained when bovine hemoglobin (pI 6.9, MW 64.0 kDa) was selected as the particular reference protein. Molecular weights and pIs were chosen to investigate the selectivity of the hydrogels. It was shown that the shape memory and the size effect were the major factors for the recognition. This imprinted hydrogel was used to specifically adsorb the BSA from the protein mixture. PMID- 24347536 TI - Activation of hedgehog signaling during fracture repair enhances osteoblastic dependent matrix formation. AB - Fracture repair is a well orchestrated process involving various cell types and signaling molecules. The hedgehog signaling pathway is activated in chondrocytes during fracture repair and is known to regulate chondrogenesis however, its role in osteoblasts during injury is yet unknown. In this study we observed tibial fracture repair in mice in which hedgehog signaling was modulated through genetic alterations of the pathway activator, smoothened. Levels of the hedgehog target genes Gli1 and Ptch1 in wildtype mice were upregulated in fracture calluses throughout the repair process. Forced activation of the hedgehog pathway in ubiquitous fashion resulted in increased matrix deposition in the fracture callus. Interestingly, inhibition in chondrocytes did not alter the fracture repair phenotype, while activation of hedgehog in osteoblasts was a requirement for normal fracture repair. In vitro, transcript levels of Gli1 and Ptch1 were elevated during osteoblastogenesis. Activation of hedgehog signaling positively affected osteoblastic differentiation and mineralization as detected using alkaline phosphatase and Von Kossa staining and Alp and Col1 expression. Here we show that the hedgehog signaling pathway plays a critical role in osteoblasts during fracture repair: inhibition of the pathway in osteoblasts leads to decreased matrix at the fracture site while activation increased matrix deposition. PMID- 24347537 TI - Survival outcomes of patients with temporal bone squamous cell carcinoma with different invasion patterns. AB - BACKGROUND: The correlation between the survival rate and various invasion patterns of patients with temporal bone squamous cell carcinoma (SCC) is unclear. This study was performed to compare the survival outcomes of these patients to disclose the correlation. METHODS: The cases of 39 patients with temporal bone SCC who underwent surgery between January 2004 and December 2012 were reviewed. RESULTS: The 2-year overall survival rate was 56.9%, and it was 22.3% for patients with stage IV disease, and 100% for patients with stage I-III disease. Patients with parotid invasion (n = 11), temporomandibular joint (TMJ) involvement (n = 8), and middle ear surgery (n = 7) before temporal bone malignancies were diagnosed had poor survival with statistical difference. CONCLUSION: Patients with parotid gland, TMJ involvement, and previous middle ear surgery for chronic otitis media had poor outcomes. PMID- 24347538 TI - New methods of preventing neurodegeneration? Lessons from prion diseases. PMID- 24347540 TI - Two-dimensional Si nanosheets with local hexagonal structure on a MoS(2) surface. AB - The structural and electronic properties of a Si nanosheet (NS) grown onto a MoS2 substrate by means of molecular beam epitaxy are assessed. Epitaxially grown Si is shown to adapt to the trigonal prismatic surface lattice of MoS2 by forming two-dimensional nanodomains. The Si layer structure is distinguished from the underlying MoS2 surface structure. The local electronic properties of the Si nanosheet are dictated by the atomistic arrangement of the layer and unlike the MoS2 hosting substrate they are qualified by a gap-less density of states. PMID- 24347539 TI - Binge eating, binge eating disorder and loss of control eating: effects on weight outcomes after bariatric surgery. AB - There is increasing evidence that patients who have problems with binge eating (BE) or BE disorder (BED) are quite common among the severely obese, including bariatric surgery candidates. The literature suggests that in many cases such eating behaviours improve after bariatric surgery, although this is not uniformly true. The current paper reviews the data on the development of BE, BED and loss of control (LOC) eating after bariatric surgery and the impact of these problems on long-term weight outcome. A search was made of various databases regarding evidence of BE, BED and LOC eating post-operatively in bariatric surgery patients. The data extracted from the literature suggests that 15 research studies have now examined this question. Fourteen of the available 15 studies suggest that the development of problems with BE, BED or LOC eating post bariatric surgery is associated with less weight loss and/or more weight regain post-bariatric surgery. These data suggests that it is important to identify individuals at high risk for these problems, to follow them post-operatively, and, if appropriate interventions can be developed if such behaviours occur in order to maximize weight loss outcomes. PMID- 24347541 TI - Characterizing the nature of home care work and occupational hazards: a developmental intervention study. AB - BACKGROUND: Home care (HC) aide is the fastest growing occupation, yet job hazards are under-studied. This study documents the context of HC aide work, characterizes occupational safety and health (OSH) hazards, and identifies preventive interventions using qualitative methods. METHODS: We conducted 12 focus groups among aides and 26 in-depth interviews comprising 15 HC agency, union, and insurance company representatives as well as 11 HC recipients in Massachusetts. All focus groups and interviews were audio-recorded, transcribed, and coded with NVIVO software. RESULTS: Major OSH concerns were musculoskeletal disorders from client care tasks and verbal abuse. Performing tasks beyond specified job duties may be an OSH risk factor. HC aides' safety and clients' safety are closely linked. Client handling devices, client evaluation, care plan development, and training are key interventions for both aides' and clients' safety. CONCLUSIONS: Promoting OSH in HC is essential for maintaining a viable workforce. PMID- 24347542 TI - Labeling of the pathogenic bacterium Staphylococcus aureus with gold or ferric oxide-core nanoparticles highlights new capabilities for investigation of host pathogen interactions. AB - Throughout the world, infections caused by bacteria such as Staphylococcus aureus are a major cause of morbidity and mortality. In order to gain some understanding of the complicated physiological link between host and pathogen, modern techniques such as confocal microscopy and sophisticated OMICs technologies are suitable. However, labeling of pathogens such as S. aureus with green fluorescent protein, for example, or the generation of a reliable antibody, which are prerequisites for the application of reproducible isolation techniques, does not always succeed. Here, we present a universal approach for monitoring pathogen traffic after internalization into host cells by fluorescence microscopy and for isolation of bacteria from host-pathogen interaction assays using gold or ferric oxide-core, poly(vinyl alcohol) coated, and fluorescence-labeled nanoparticles (NP). The incubation of S. aureus HG001 with those NP had only minor effects on the bacterial growth in vitro. Quantitative proteome analysis after 24 h of NP incubation revealed that presence of NP provoked only marginal changes in the proteome pattern. The method presented enabled us to investigate the behavior of S. aureus HG001 during infection of S9 human epithelial cells by means of fluorescence microscopy and proteomics using magnetic separation or cell sorting. PMID- 24347543 TI - Spatial dilemmas of diffusible public goods. AB - The emergence of cooperation is a central question in evolutionary biology. Microorganisms often cooperate by producing a chemical resource (a public good) that benefits other cells. The sharing of public goods depends on their diffusion through space. Previous theory suggests that spatial structure can promote evolution of cooperation, but the diffusion of public goods introduces new phenomena that must be modeled explicitly. We develop an approach where colony geometry and public good diffusion are described by graphs. We find that the success of cooperation depends on a simple relation between the benefits and costs of the public good, the amount retained by a producer, and the average amount retained by each of the producer's neighbors. These quantities are derived as analytic functions of the graph topology and diffusion rate. In general, cooperation is favored for small diffusion rates, low colony dimensionality, and small rates of decay of the public good. DOI: http://dx.doi.org/10.7554/eLife.01169.001. PMID- 24347544 TI - Bone morphogenic protein signalling suppresses differentiation of pluripotent cells by maintaining expression of E-Cadherin. AB - Bone morphogenic protein (BMP) signalling contributes towards maintenance of pluripotency and favours mesodermal over neural fates upon differentiation, but the mechanisms by which BMP controls differentiation are not well understood. We report that BMP regulates differentiation by blocking downregulation of Cdh1, an event that accompanies the earliest stages of neural and mesodermal differentiation. We find that loss of Cdh1 is a limiting requirement for differentiation of pluripotent cells, and that experimental suppression of Cdh1 activity rescues the BMP-imposed block to differentiation. We further show that BMP acts prior to and independently of Cdh1 to prime pluripotent cells for mesoderm differentiation, thus helping to reinforce the block to neural differentiation. We conclude that differentiation depends not only on exposure to appropriate extrinsic cues but also on morphogenetic events that control receptivity to those differentiation cues, and we explain how a key pluripotency signal, BMP, feeds into this control mechanism. DOI: http://dx.doi.org/10.7554/eLife.01197.001. PMID- 24347545 TI - A new topology of the HK97-like fold revealed in Bordetella bacteriophage by cryoEM at 3.5 A resolution. AB - Bacteriophage BPP-1 infects and kills Bordetella species that cause whooping cough. Its diversity-generating retroelement (DGR) provides a naturally occurring phage-display system, but engineering efforts are hampered without atomic structures. Here, we report a cryo electron microscopy structure of the BPP-1 head at 3.5 A resolution. Our atomic model shows two of the three protein folds representing major viral lineages: jellyroll for its cement protein (CP) and HK97 like ('Johnson') for its major capsid protein (MCP). Strikingly, the fold topology of MCP is permuted non-circularly from the Johnson fold topology previously seen in viral and cellular proteins. We illustrate that the new topology is likely the only feasible alternative of the old topology. beta-sheet augmentation and electrostatic interactions contribute to the formation of non covalent chainmail in BPP-1, unlike covalent inter-protein linkages of the HK97 chainmail. Despite these complex interactions, the termini of both CP and MCP are ideally positioned for DGR-based phage-display engineering. DOI: http://dx.doi.org/10.7554/eLife.01299.001. PMID- 24347546 TI - c-di-GMP heterogeneity is generated by the chemotaxis machinery to regulate flagellar motility. AB - Individual cell heterogeneity is commonly observed within populations, although its molecular basis is largely unknown. Previously, using FRET-based microscopy, we observed heterogeneity in cellular c-di-GMP levels. In this study, we show that c-di-GMP heterogeneity in Pseudomonas aeruginosa is promoted by a specific phosphodiesterase partitioned after cell division. We found that subcellular localization and reduction of c-di-GMP levels by this phosphodiesterase is dependent on the histidine kinase component of the chemotaxis machinery, CheA, and its phosphorylation state. Therefore, individual cell heterogeneity in c-di GMP concentrations is regulated by the activity and the asymmetrical inheritance of the chemotaxis organelle after cell division. c-di-GMP heterogeneity results in a diversity of motility behaviors. The generation of diverse intracellular concentrations of c-di-GMP by asymmetric partitioning is likely important to the success and survival of bacterial populations within the environment by allowing a variety of motility behaviors. DOI: http://dx.doi.org/10.7554/eLife.01402.001. PMID- 24347547 TI - The genomic landscape of meiotic crossovers and gene conversions in Arabidopsis thaliana. AB - Knowledge of the exact distribution of meiotic crossovers (COs) and gene conversions (GCs) is essential for understanding many aspects of population genetics and evolution, from haplotype structure and long-distance genetic linkage to the generation of new allelic variants of genes. To this end, we resequenced the four products of 13 meiotic tetrads along with 10 doubled haploids derived from Arabidopsis thaliana hybrids. GC detection through short reads has previously been confounded by genomic rearrangements. Rigid filtering for misaligned reads allowed GC identification at high accuracy and revealed an ~80-kb transposition, which undergoes copy-number changes mediated by meiotic recombination. Non-crossover associated GCs were extremely rare most likely due to their short average length of ~25-50 bp, which is significantly shorter than the length of CO-associated GCs. Overall, recombination preferentially targeted non-methylated nucleosome-free regions at gene promoters, which showed significant enrichment of two sequence motifs. DOI: http://dx.doi.org/10.7554/eLife.01426.001. PMID- 24347548 TI - Frizzled3 controls axonal development in distinct populations of cranial and spinal motor neurons. AB - Disruption of the Frizzled3 (Fz3) gene leads to defects in axonal growth in the VII(th) and XII(th) cranial motor nerves, the phrenic nerve, and the dorsal motor nerve in fore- and hindlimbs. In Fz3(-/-) limbs, dorsal axons stall at a precise location in the nerve plexus, and, in contrast to the phenotypes of several other axon path-finding mutants, Fz3(-/-) dorsal axons do not reroute to other trajectories. Affected motor neurons undergo cell death 2 days prior to the normal wave of developmental cell death that coincides with innervation of muscle targets, providing in vivo evidence for the idea that developing neurons with long-range axons are programmed to die unless their axons arrive at intermediate targets on schedule. These experiments implicate planar cell polarity (PCP) signaling in motor axon growth and they highlight the question of how PCP proteins, which form cell-cell complexes in epithelia, function in the dynamic context of axonal growth. DOI: http://dx.doi.org/10.7554/eLife.01482.001. PMID- 24347549 TI - A serine sensor for multicellularity in a bacterium. AB - We report the discovery of a simple environmental sensing mechanism for biofilm formation in the bacterium Bacillus subtilis that operates without the involvement of a dedicated RNA or protein. Certain serine codons, the four TCN codons, in the gene for the biofilm repressor SinR caused a lowering of SinR levels under biofilm-inducing conditions. Synonymous substitutions of these TCN codons with AGC or AGT impaired biofilm formation and gene expression. Conversely, switching AGC or AGT to TCN codons upregulated biofilm formation. Genome-wide ribosome profiling showed that ribosome density was higher at UCN codons than at AGC or AGU during biofilm formation. Serine starvation recapitulated the effect of biofilm-inducing conditions on ribosome occupancy and SinR production. As serine is one of the first amino acids to be exhausted at the end of exponential phase growth, reduced translation speed at serine codons may be exploited by other microbes in adapting to stationary phase. DOI: http://dx.doi.org/10.7554/eLife.01501.001. PMID- 24347550 TI - Ready, set, differentiate! AB - The expression of E-Cadherin, a protein best known for its role in cell adhesion, regulates the onset of embryonic differentiation. PMID- 24347551 TI - How to survive a nerve-wracking journey. AB - When the axons that carry signals to muscles are growing, they rely on help from Frizzled3-a protein that is known to perform a number of other important functions in cells-to reach their final destination. PMID- 24347552 TI - Gene expression profiling in true interval breast cancer reveals overactivation of the mTOR signaling pathway. AB - BACKGROUND: The development and progression of true interval breast cancers (tumors that truly appear after a negative screening mammogram) is known to be different from screen-detected cancers. However, the worse clinical behavior of true interval cancers is not fully understood from a biologic basis. We described the differential patterns of gene expression through microarray analysis in true interval and screen-detected cancers. METHODS: An unsupervised exploratory gene expression profile analysis was performed on 10 samples (true interval cancers = 5; screen-detected cancers = 5) using Affymetrix Human Gene 1.0ST arrays and interpreted by Ingenuity Pathway Analysis. Differential expression of selected genes was confirmed in a validation series of 91 tumors (n = 12; n = 79) by immunohistochemistry and in 24 tumors (n = 8; n = 16) by reverse transcription quantitative PCR (RT-qPCR), in true interval and screen-detected cancers, respectively. RESULTS: Exploratory gene expression analysis identified 1,060 differentially expressed genes (unadjusted P < 0.05) between study groups. On the basis of biologic implications, four genes were further validated: ceruloplasmin (CP) and ribosomal protein S6 kinase, 70 kDa, polypeptide 2 (RPS6KB2), both upregulated in true interval cancers; and phosphatase and tensin homolog (PTEN) and transforming growth factor beta receptor III (TGFBR3), downregulated in true interval cancers. Their differential expression was confirmed by RT-qPCR and immunohistochemistry, consistent with mTOR pathway overexpression in true interval cancers. CONCLUSIONS: True interval and screen-detected cancers show differential expression profile both at gene and protein levels. The mTOR signaling is significantly upregulated in true interval cancers, suggesting this pathway may mediate their aggressiveness. IMPACT: Linking epidemiologic factors and mTOR activation may be the basis for future personalized screening strategies in women at risk of true interval cancers. PMID- 24347553 TI - Muscle contributions to elbow joint rotational stiffness in preparation for sudden external arm perturbations. AB - Understanding joint stiffness and stability is beneficial for assessing injury risk. The purpose of this study was to examine joint rotational stiffness for individual muscles contributing to elbow joint stability. Fifteen male participants maintained combinations of three body orientations (standing, supine, sitting) and three hand preloads (no load, solid tube, fluid filled tube) while a device imposed a sudden elbow extension. Elbow angle and activity from nine muscles were inputs to a biomechanical model to determine relative contributions to elbow joint rotational stiffness, reported as percent of total stiffness. A body orientation by preload interaction was evident for most muscles (P<.001). Brachioradialis had the largest change in contribution while standing (no load, 18.5%; solid, 23.8%; fluid, 26.3%). Across trials, the greatest contributions were brachialis (30.4+/-1.9%) and brachioradialis (21.7+/-2.2%). Contributions from the forearm muscles and triceps were 5.5+/-0.6% and 9.2+/ 1.9%, respectively. Contributions increased at time points closer to the perturbation (baseline to anticipatory), indicating increased neuromuscular response to resist rotation. This study quantified muscle contributions that resist elbow perturbations, found that forearm muscles contribute marginally and showed that orientation and preload should be considered when evaluating elbow joint stiffness and safety. PMID- 24347554 TI - Separation of xanthines in hydro-organic and polar-organic elution modes on a titania stationary phase. AB - Hydrophilic interaction LC was investigated in hydro-organic and nonaqueous elution modes on a titania column by using a set of N-methyl xanthines as neutral polar probes. To get information regarding the mechanisms that are behind the discrimination of these analytes in hydrophilic interaction, we focused our study on the type and amount of organic modifier as a critical yet rarely explored mobile phase parameter. Several alcohols such as methanol, ethanol, and isopropanol were studied as substitutes to acetonitrile in hydro-organic elution mode. Compared to silica, the investigation of the eluotropic series of these alcohols on titania highlighted a different implication in the retention mechanism of the xanthine derivatives. At low amounts of protic solvents, the adsorption mainly characterized the retention of analytes on bare silica; whereas mixed interactions including adsorption and ligand exchange were identified on native titania. To investigate the peculiar behavior of alcohols on the metal oxide, methanol, ethanol, and ethylene glycol were tested in replacement of water in polar-organic elution mode. Distinctive effects on the chromatographic retention and selectivity of xanthines were noticed for the dihydric alcohol, which was found to be a stronger eluting component than water on titania. PMID- 24347555 TI - Airways obstruction and pulmonary capillary blood volume in children with sickle cell disease. PMID- 24347556 TI - The influence of intensity and duration of a painful conditioning stimulation on conditioned pain modulation in volunteers. AB - BACKGROUND AND METHOD: The aim was to investigate influence from variations in intensity of a painful conditioning stimulation (CS) on early (0-6 min) and prolonged (6-12 min) conditioned pain modulation (CPM) in volunteers during concurrent exposure to test stimuli (TS). CS was applied to either forearm using painful heat with an intensity of 2/10 and 5/10, respectively, rated on a 0-10 numerical pain rating scale. At a second session, CS with an intensity of 7/10 was applied to the arm using a tourniquet. Threshold and suprathreshold painful heat and pressure as well as painful repeated monofilament pricking (RMP) were assessed as TS. RESULTS: Regardless of TS, there was no significant difference in the magnitude of CPM within the same stimulus modality during the various intensities and phases of the CS. Significant modulation of heat pain thresholds (HPTs) was found during the early phase at 5/10 and 7/10, but not at 2/10. Only at 5/10 the prolonged CS resulted in a significant additional increase in HPT. During the early CS phase, CPM of suprathreshold heat pain was found at 2/10 and 5/10. The prolonged CS resulted in a significant additional temperature increase at 5/10. Only during the early phase significant CPM of pressure pain thresholds were found for all three pain intensities in conjunction with a significant CPM of suprathreshold pressure pain at 5/10. There was no CPM of RMP. CONCLUSION: The CS intensity and the duration of CPM modulated pain sensitivity differentially across TS modalities. PMID- 24347557 TI - Injury classification agreement in linked Bureau of Labor Statistics and Workers' Compensation data. AB - BACKGROUND: Estimates of select occupational injuries and illnesses often differ across data sources. We explored agreement in injury classifications and the impact of differences on case estimates among records reported to multiple data sources. METHODS: We linked cases reported in the Bureau of Labor Statistics (BLS) annual Survey of Occupational Injuries and Illnesses (SOII) to Washington State workers' compensation (WC) claims and evaluated agreement in injury characteristics coded in each data source according to the same occupational injury and illness classification system. RESULTS: Agreement between data sources was greatest for body part and lowest for event or exposure. Agreement on nature of injury varied by condition. WC-assigned injury codes estimated 94% more amputations than SOII-assigned codes while SOII-assigned codes estimated 34% more work-related MSD cases. CONCLUSIONS: Accounting for classification differences may improve case ascertainment within individual data sources and help align injury and illness estimates derived from different data sources. PMID- 24347558 TI - Editorial: Epidemiologic approaches to women's health. PMID- 24347559 TI - Transcriptomic study of the red palm weevil Rhynchophorus ferrugineus embryogenesis. AB - The red palm weevil (RPW), Rhynchophorus ferrugineus (Coleoptera: Curculionidae), is an invasive, concealed and destructive tissue borer, and it becomes a lethal pest of the palm family of plants and has been reported to attack 20 palm species around the globe. Here we report a systematic transcriptomic study on embryogenesis of RPW, where we analyze the transcriptomes across five developmental stages of RPW embryogenesis, involving four embryonic stages (E1, E2, E3 and E4) and one larval stage (L1). Using the RNA-seq and next-generation platforms, we generated 80 to 91 million reads for each library and assemble 22 532 genes that are expressed at different embryonic stages. Among the total transcripts from the five embryonic development stages, we found that 30.45 % are differentially expressed, 10.10 % show stage-specificity and even a larger fraction, 62.88 %, exhibit constitutive expression in all the stages. We also analyzes the expression dynamics of several conserved signaling pathways (such as Hedgehog, JAK-STAT, Notch, TGF-beta, Ras/MAPK and Wnt), as well as key developmental genes, including those related to apoptosis, axis formation, Hox complex, neurogenesis and segmentation. The datasets provide an essential resource for gene annotation and RPW functional genomics, including studies by using tools and concepts from multiple disciplines, such as development, physiology, biochemistry, molecular biology and genetics. PMID- 24347560 TI - DENND1B gene variants associate with elevated exhaled nitric oxide in healthy high-risk neonates. AB - RATIONALE OF THE STUDY: Increased neonatal fraction of exhaled nitric oxide (FeNO) is associated with lung symptoms early in life, while predictors of neonatal FeNO levels are unknown. The objective of this study was to investigate perinatal and genetic predictors of FeNO in healthy at-risk neonates. METHODS: FeNO was measured during sedation by single-breath and tidal-breathing techniques in 253 one-month-old neonates from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC2000 ) birth cohort. The risk factor analyses included genetic variants in DENND1B, Filaggrin, and ORMDL3; anthropometrics; demographics; socioeconomics; paternal atopy; maternal smoking, and mother's consumption of paracetamol and antibiotics during 3rd trimester; and neonatal bacterial airway colonization. RESULTS: FeNO values measured by the single-breath versus tidal breathing technique yielded slightly higher values (median, 21.0 ppb; range, 2.0 74.0 ppb vs. 16.0 ppb; 1.0-67.0 ppb; P<0.0001) with increasing differences conditional on increasing FeNO values (P<0.0001). The multivariable analysis including all risk factors showed that the DENND1B rs2786098 C allele was associated with increasing levels of FeNO (additive model; +2.30 ppb per C allele; 95% CI, 0.10-5.00 ppb; P=0.04) and that children of atopic fathers had elevated FeNO (+2.90 ppb; 95% CI, 0.38-5.43 ppb; P=0.02). We did not detect association between the remaining risk factors and neonatal FeNO levels. CONCLUSION: Increased FeNO in healthy newborns seems strongly influenced by genetics including father's atopy and child's variants in the DENND1B locus at chromosome 1q31.3. PMID- 24347561 TI - Dried bonito dashi: a preferred fish broth without postoral reward actions in mice. AB - The flavor of dashi, the broth prepared from dried bonito tuna, is attractive to humans and rodents. The present experiments examined the ability of dashi to serve as an oral and/or postoral rewarding stimulus for conditioned flavor preferences in mice. In Experiment 1, C57BL/6J (B6) mice were infused intragastrically with dashi when they consumed a conditioned stimulus (CS)+ flavor and with water when they drank a CS- flavor on alternate days. Postoral dashi did not condition a CS+ preference. The combined effects of oral and postoral dashi exposure were examined in Experiment 2, in which B6 mice consumed a CS+ flavored dashi solution and CS- flavored water on alternate days. The mice did not prefer the CS+ to CS- when both flavors were presented in water. Yet, the B6 mice in both experiments preferred dashi to water in oral tests. Experiment 3 showed that taste-impaired Trpm5 knockout (KO) mice did not learn to prefer dashi after exposure to it, in contrast to previous findings with the umami prototype monosodium glutamate. This was not due to an inability to taste dashi, because Trpm5 KO mice learned a strong preference for dashi after it was mixed with glucose. The impact of dashi on reward may largely reflect an enhancement of association of oral and postoral effects of food. PMID- 24347562 TI - Lower extremity kinematics of a single-leg squat with an orthotic in male and female collegiate athletes. AB - Kinematic differences have been linked to the gender discrepancies seen in knee injuries. A medially posted orthotic decreases frontal and transverse plane motions in the lower extremity during ambulation, squatting and landing. This study investigated the effect of a medial post on amount and timing of lower extremity motions during a single-leg squat in male and female athletes. We hypothesized there would be differences in these kinematic variables dependent upon sex and post conditions. Twenty male and female athletes performed single leg squats with and without a five degree full-length medial post. Maximum joint angles were analyzed using a two-way, repeated-measures analysis of variance to determine if the differences created by post condition were statistically significant, whether there were gender differences, or interactions. Differences in maximum motion values and the time at which they occurred were found between men and women at the hip, knee and ankle. The post decreased all frontal plane measures in both sexes and resulted in earlier attainment of maximum ankle eversion and delayed maximum knee valgus. A medially posted orthotic may be beneficial not only in limiting motion, but in affecting the time in which stressful motions occur. PMID- 24347563 TI - Socially induced placebo analgesia: a comparison of a pre-recorded versus live face-to-face observation. AB - BACKGROUND: Recently, it has been shown that live, face-to-face social observation induces marked placebo analgesia. Despite the phenomenal growth of video sharing platforms, the potential analgesic effects of video-based social observation are largely unknown. This study compared video-based and live social observation induced placebo analgesia and whether there was a similar relationship between analgesic responses and empathy traits for both conditions. METHODS: Here, we compared placebo analgesia in four groups: social observation through a video (SOV group), social observation in person (SOP group), verbal suggestion alone (VS group) and a natural history group (NH group). The SOV and SOP groups underwent a placebo treatment and painful stimuli following respectively a video-based and live observation of a demonstrator showing analgesic effects when the painful stimuli were paired to a green light but not a red light. The VS group received painful stimuli after they had been verbally instructed to expect less pain after the green light. The NH group received painful stimuli, but was told nothing about the meaning of the lights. Individual pain reports and empathy traits were measured. RESULTS: We found that video-based observation induced substantial placebo analgesic responses that were of similar magnitude to live observation. Notably, the analgesic scores were strongly correlated with empathetic concern in the live observation group but not in the video replay group. CONCLUSIONS: These findings add evidence that placebo analgesia can be induced by social observation and that empathy interacts with these effects in a context-dependent manner. PMID- 24347564 TI - A screen for bacterial endosymbionts in the model organisms Tribolium castaneum, T. confusum, Callosobruchus maculatus, and related species. AB - Reproductive parasites such as Wolbachia are extremely widespread amongst the arthropods and can have a large influence over the reproduction and fitness of their hosts. Undetected infections could thus confound the results of a wide range of studies that focus on aspects of host behavior, reproduction, fitness, and degrees of reproductive isolation. This potential problem has already been underlined by work investigating the incidence of Wolbachia infections in stocks of the model system Drosophila melanogaster. Here we survey a range of lab stocks of further commonly used model arthropods, focusing especially on the flour beetles Tribolium castaneum and Tribolium confusum, the cowpea weevil Callosobruchus maculatus and related species (Coleoptera: Tenebrionidae and Bruchidae). These species are widespread stored product pests so knowledge of infections with symbionts further has potential use in informing biocontrol measures. Beetles were assessed for infection with 3 known microbial reproductive parasites: Wolbachia, Rickettsia, Spiroplasma. Infections with some of these microbes were found in some of the lab stocks studied, although overall infections were relatively rare. The consequences of finding infections in these or other species and the type of previous studies likely to be affected most are discussed. PMID- 24347565 TI - Sensitivity of joint kinematics and kinetics to different pose estimation algorithms and joint constraints in the elderly. AB - The purpose of this research was to study the sensitivity of lower limb joint kinematics and kinetics, calculated during different functional tasks (walking, stair descent and stair ascent) in a sample of older adults, to different pose estimation algorithms and models' joint constraints. Three models were developed and optimized differently: in one model, each segment had 6 degrees of freedom (segment optimization, SO), while in the other two, global optimization (GO) was used, with different joint constraints: (1) GO, allowing all joint rotations; (2) GOR, allowing three rotations at the hip, one at the knee (flexion/extension) and two at the ankle (dorsi/plantar flexion and eversion/inversion). The results showed that joint angles are more sensitive to the model's constraints than joint moments and, the more restrictive the model, the higher the differences between models, especially for the frontal and transverse planes (max. RMS difference during gait: 11.7 degrees (64%) vs 0.12 N.m/kg (35.4%). In addition, except for knee abduction/adduction angle, differences between SO and GO models were relatively low. Since GO avoids the nonanatomical dislocations sometimes observed in SO, choosing this model seems to be reasonable for future studies with a similar sample and study design. PMID- 24347566 TI - Influence of dorsiflexion shoes on jump performance. AB - The goal of dorsiflexion sports shoes is to increase jumping capacity by means of a lower position of the heel in relation to the forefoot which results in additional stretching of the ankle plantar flexors. The aim of this study was to compare a dorsiflexion sports shoe model with two conventional sports shoe models in a countermovement jump test. The sample consisted of 35 participants who performed a countermovement jump test on a force platform wearing the three models of shoes. There were significant differences in the way force was manifested (P<0.05) in the countermovement jump test, with a decrease in the velocity of the center of gravity and an increase in force at peak power and mean force in the concentric phase. Moreover, peak power was reached earlier with the dorsiflexion sports shoe model. The drop of the center of gravity was increased in CS1 in contrast to the dorsiflexion sports shoe model (P<.05). However, the dorsiflexion sports shoes were not effective for improving either peak power or jump height (P>.05). Although force manifestation and jump kinetics differ between dorsiflexion shoes and conventional sports shoes, jump performance was similar. PMID- 24347567 TI - NAMPT (visfatin), a direct target of hypoxia-inducible factor-2alpha, is an essential catabolic regulator of osteoarthritis. AB - OBJECTIVE: Hypoxia-inducible factor 2alpha (HIF-2alpha), encoded by Epas1, causes osteoarthritic cartilage destruction by regulating the expression of matrix degrading enzymes. We undertook this study to explore the role of nicotinamide phosphoribosyltransferase (NAMPT or visfatin) in HIF-2alpha-mediated osteoarthritic cartilage destruction. METHODS: The expression of HIF-2alpha, NAMPT and matrix-degrading enzymes was determined at the mRNA and protein levels in human osteoarthritis (OA) cartilage, mouse experimental OA cartilage and primary cultured mouse chondrocytes. Experimental OA in mice was induced by destabilisation of the medial meniscus (DMM) surgery or intra-articular injection of Ad-Epas1 or Ad-Nampt in wild-type, Epas1(+/-), Epas1(fl/fl);Col2a1-Cre and Col2a1-Nampt transgenic (TG) mice. Primary cultured mouse chondrocytes were treated with recombinant NAMPT protein or were infected with adenoviruses. RESULTS: We found that the Nampt gene is a direct target of HIF-2alpha in articular chondrocytes and OA cartilage. NAMPT protein, in turn, increased mRNA levels and activities of MMP3, MMP12 and MMP13 in chondrocytes, an action that was necessary for HIF-2alpha-induced expression of catabolic enzymes. Gain-of function studies (intra-articular injection of Ad-Nampt; Col2a1-Nampt TG mice) and loss-of-function studies (intra-articular injection of the NAMPT inhibitor FK866) demonstrated that NAMPT is an essential catabolic regulator of osteoarthritic cartilage destruction caused by HIF-2alpha or DMM surgery. CONCLUSIONS: Our findings indicate that NAMPT, whose corresponding gene is a direct target of HIF-2alpha, plays an essential catabolic role in OA pathogenesis and acts as a crucial mediator of osteoarthritic cartilage destruction caused by HIF-2alpha or DMM surgery. PMID- 24347568 TI - Use of statins is associated with a lower prevalence of generalised osteoarthritis. PMID- 24347569 TI - Efficacy and safety of belimumab in primary Sjogren's syndrome: results of the BELISS open-label phase II study. AB - BACKGROUND: Increased expression of B cell activating factor (BAFF or B lymphocyte stimulator) may explain the B cell activation characteristic of primary Sjogren's syndrome (pSS). OBJECTIVES: To evaluate the efficacy and safety of belimumab, targeting BAFF, in patients with pSS. METHODS: Patients were included in this bi-centric prospective 1-year open-label trial if they fulfilled American European Consensus group criteria, were anti-Sjogren's syndrome A positive and had current systemic complications or salivary gland enlargement, or early disease (<5 years), or biomarkers of B cell activation. They received belimumab, 10 mg/kg, at weeks 0, 2 and 4 and then every 4 weeks to week 24. The primary end-point, assessed at week 28, was improvement in two of five items: reduction in >=30% in dryness score on a visual analogue scale (VAS), >=30% in fatigue VAS score, >=30% in VAS pain score, >=30% in systemic activity VAS assessed by the physician and/or >25% improvement in any B cell activation biomarker values. RESULTS: Among 30 patients included, the primary end-point was achieved in 18 (60%). The mean (SD) European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index decreased from 8.8 (7.4) to 6.3 (6.6) (p=0.0015) and EULAR) Sjogren's Syndrome Patient Reported Index from 6.4 (1.1) to 5.6 (2.0) (p=0.0174). The mean dryness, fatigue and pain VAS varied from 7.8 (1.8) to 6.2 (2.9) (p=0.0021), 6.9 (1.8) to 6.0 (2.2) (p=0.0606) and 4.6 (2.6) to 4.7 (2.4) (p=0.89), respectively. Salivary flow and Schirmer's test did not change. CONCLUSIONS: These encouraging results justify future randomised controlled trials of belimumab in a selected target population of pSS patients most likely to benefit from treatment. PMID- 24347570 TI - Association between childhood overweight measures and adulthood knee pain, stiffness and dysfunction: a 25-year cohort study. AB - OBJECTIVE: To describe the associations between overweight measures in childhood and knee pain, stiffness and dysfunction among adults 25 years later. METHODS: Subjects broadly representative of the Australian population (n=449, aged 31-41 years, female 48%) were selected from the Australian Schools Health and Fitness Survey of 1985. Height, weight and knee injury were recorded and knee pain was assessed using the Western Ontario and McMaster Universities osteoarthritis index (WOMAC). Childhood height, weight and knee injury had been measured according to standard protocols 25 years earlier and body mass index (BMI) and percentage overweight were calculated. RESULTS: The prevalence of knee pain was 34% and overweight in childhood and adulthood was 7% and 48%, respectively. Overall, there were no significant associations between childhood overweight measures and total WOMAC knee pain, stiffness and dysfunction scores in adulthood. However, in men, overweight in childhood was associated with adulthood WOMAC pain (relative risk (RR) 1.72, 95% CI 1.11 to 2.69) and childhood weight and BMI were associated with WOMAC stiffness and dysfunction. Childhood weight, BMI and overweight were all associated with the presence of adulthood walking knee pain in men and the whole sample. Most of these associations were independent of adult overweight measures. Subjects who were overweight in both childhood and adult life had a significant increase in the risk and prevalence of adulthood walking pain (RR=2.42, 95% CI 1.06 to 5.53). CONCLUSIONS: Childhood overweight measures were significantly associated with adulthood knee mechanical joint pain, stiffness and dysfunction among men, independent of adult overweight, suggesting that childhood overweight may lead to later knee symptoms in men. PMID- 24347571 TI - Defining criteria for high disease activity in juvenile idiopathic arthritis based on the juvenile arthritis disease activity score. AB - OBJECTIVE: To determine cutoff values for defining the state of high disease activity (HDA) in juvenile idiopathic arthritis (JIA) using the Juvenile Arthritis Disease Activity Score (JADAS). METHODS: For the selection of cutoff values, data from a clinical database including 609 patients were used. Optimal cutoff values were determined against external criteria by calculating the 25th and 10th centile of cumulative score distribution and through receiver operating characteristic curve analysis. External criteria were based on the therapeutic decision made by the attending doctor. Cross-validation was performed using five patient samples that included 1421 patients. RESULTS: The optimal cutoff values were those obtained through the 90% fixed sensitivity method. The selected JADAS cutoff values were the following: 4.2 and 8.5 for JADAS27 in oligoarthritis and polyarthritis, respectively; 4.2 and 10.5 for both JADAS10 and JADAS71 in oligoarthritis and polyarthritis, respectively. In cross-validation analyses, the cutoff values showed strong ability to discriminate between different levels of American College of Rheumatology paediatric response in two clinical trials and could predict worse functional and radiographic outcome. CONCLUSIONS: Cutoff values for classifying HDA in JIA using the JADAS were developed. In cross validation analyses, they proved to have good construct and discriminant validity and ability to predict disease outcome. PMID- 24347572 TI - Genetic variation in VTCN1 (B7-H4) is associated with course of disease in juvenile idiopathic arthritis. AB - OBJECTIVE: The course of disease in juvenile idiopathic arthritis (JIA) is unpredictable with episodes of activity and remission. In order to identify predictive factors, 93 SNPs, JIA subtype, age at onset and ANA status were studied in relation to disease course. METHODS: Genetic and clinical parameters were analysed in a cohort of 272 Caucasian patients with persistent oligoarthritis (n=129), extended oligoarthritis (n=57) and rheumatoid factor negative polyarthritis (n=86). Categories of disease course (remitting (n=65), intermediate (n=96) and unremitting (n=111)) were designed based on the cumulative time spent in active disease in the first 2 years. RESULTS: Univariate analysis revealed association of the course of disease with JIA subtype (p=5.7*10(-5)) and three SNPs; VTCN1 rs10 923 223 (p=4.4*10(-5)), VTCN1 rs12 046 117 (p=0.017) and CDK6 rs42 041 (p=0.038). In a subsequent multivariate ordinal logistic regression analysis, VTCN1 rs10 923 223 (OR 0.41, 95%-CI 0.26 to 0.63) and JIA subtype (OR 3.8, 95%-CI 2.0 to 7.2; OR 2.5, 95%-CI 1.4 to 4.2, for extended oligoarthritis and RF-negative polyarthritis vs persistent oligoarthritis, respectively) were the strongest independent factors for course of disease. CONCLUSIONS: This study provides evidence that VTCN1, encoding B7-H4, is associated with course of disease in selected subtypes of JIA. VTCN1 might be useful in predicting the course of disease. PMID- 24347573 TI - Children's sleep patterns from 0 to 9 years: Australian population longitudinal study. AB - OBJECTIVE: To provide accurate population normative data documenting cross sectional, age-specific sleep patterns in Australian children aged 0-9 years. DESIGN AND SETTING: The first three waves of the nationally representative Longitudinal Study of Australian Children, comprising two cohorts recruited in 2004 at ages 0-1 years (n=5107) and 4-5 years (n=4983), and assessed biennially. PARTICIPANTS: Children with analysable sleep data for at least one wave. MEASURES: At every wave, parents prospectively completed 24-h time-use diaries for a randomly selected week or weekend day. 'Sleeping, napping' was one of the 26 precoded activities recorded in 15-min time intervals. RESULTS: From 0 to 9 years of age, 24-h sleep duration fell from a mean peak of 14 (SD 2.2) h at 4-6 months to 10 (SD 1.9) h at 9 years, mainly due to progressively later mean sleep onset time from 20:00 (SD 75 min) to 21:00 (SD 60 min) and declining length of day sleep from 3.0 (SD 1.7) h to 0.03 (SD 0.2) h. Number and duration of night wakings also fell. By primary school, wake and sleep onset times were markedly later on weekend days. The most striking feature of the centile charts is the huge variation at all ages in sleep duration, sleep onset time and, especially, wake time in this normal population. CONCLUSIONS: Parents and professionals can use these new centile charts to judge normalcy of children's sleep. In future research, these population parameters will now be used to empirically determine optimal child sleep patterns for child and parent outcomes like mental and physical health. PMID- 24347575 TI - The evolution of neurorehabilitation and neural repair. PMID- 24347574 TI - Childhood vaccination coverage by ethnicity within London between 2006/2007 and 2010/2011. AB - OBJECTIVES: To assess childhood vaccination coverage at first, second and fifth birthdays by ethnicity in London between 2006/2007 and 2010/2011 and identify factors relating to lower coverage. DESIGN: Data concerning receipt of diphtheria containing vaccines were extracted from child health information systems (CHISs) and sent to the Health Protection Agency. SETTING: Nine London Primary Care Trusts (PCTs). PARTICIPANTS: Records for 315 381 children born April 2001-March 2010. MAIN OUTCOME MEASURES: Receipt of a full primary course of diphtheria containing vaccines at first and second birthdays, and a primary course and preschool booster at fifth birthday. RESULTS: Consistently good vaccine coverage of the primary course (>88% at first birthday, >89% at second birthday) was achieved across the five largest ethnic groups. Coverage of the preschool booster at fifth birthday was >65% across the five largest ethnic groups. Lowest coverage was observed in smaller ethnic groups. Deprivation was not a strong indicator of coverage overall, and for most ethnic groups there was no relationship between deprivation and coverage. Coverage was significantly lower in children not assigned to a general practitioner practice in the CHIS. CONCLUSIONS: Smaller, less well-established ethnic groups within a PCT may require specific targeting to ensure children are fully immunised and to improve record keeping. Unregistered children need particular attention and may be missed by current scheduling processes in London. In order to monitor the impact of the current National Health Service (NHS) reorganisation on inequalities in access to healthcare data on country of birth, in addition to ethnicity, should be available for analysis. PMID- 24347576 TI - Compressive biological sequence analysis and archival in the era of high throughput sequencing technologies. AB - High-throughput sequencing technologies produce large collections of data, mainly DNA sequences with additional information, requiring the design of efficient and effective methodologies for both their compression and storage. In this context, we first provide a classification of the main techniques that have been proposed, according to three specific research directions that have emerged from the literature and, for each, we provide an overview of the current techniques. Finally, to make this review useful to researchers and technicians applying the existing software and tools, we include a synopsis of the main characteristics of the described approaches, including details on their implementation and availability. Performance of the various methods is also highlighted, although the state of the art does not lend itself to a consistent and coherent comparison among all the methods presented here. PMID- 24347578 TI - Interventions designed to reduce sedentary behaviours in young people: a review of reviews. AB - BACKGROUND: Leisure time is increasingly spent in sedentary pursuits such as screen-viewing (eg, television/DVD viewing and computer use), motorised travel, school/work and sitting-based socialising (eg, social media and chatting). Sedentary screen time, particularly TV, appears to play an important role in the aetiology of obesity due to its co-occurrence with other unhealthy behaviours such as snacking on energy-dense foods, low levels of physical activity and inadequate sleep. More information is needed on how to reduce sedentary behaviours. Most interventions have focused on young people and a number of systematic reviews exist on this topic. OBJECTIVE: To synthesise systematic reviews and meta-analyses of interventions aimed at decreasing sedentary behaviours among children and adolescents. METHODS: Papers were located from computerised and manual searches. Included articles were English language systematic reviews or meta-analyses of interventions aiming at reducing sedentary behaviour in children (<11 years) and adolescents (12-18 years). RESULTS: Ten papers met the inclusion criteria and were analysed. All reviews concluded some level of effectiveness in reducing time spent in sedentary behaviour. When an effect size was reported, there was a small but significant reduction in sedentary time (highest effect size=-0.29; CI -0.35 to -0.22). Moderator analyses showed a trend favouring interventions with children younger than 6 years. Effective strategies include the involvement of family, behavioural interventions and electronic TV monitoring devices. CONCLUSIONS: Results from systematic reviews and meta-analyses show that interventions to reduce children's sedentary behaviour have a small but significant effect. Future research should expand these findings examining interventions targeting different types of sedentary behaviours and the effectiveness of specific behaviour change techniques across different contexts and settings. PMID- 24347577 TI - Fetal striatal grafting slows motor and cognitive decline of Huntington's disease. AB - OBJECTIVE: To assess the clinical effect of caudate-putaminal transplantation of fetal striatal tissue in Huntington's disease (HD). METHODS: We carried out a follow-up study on 10 HD transplanted patients and 16 HD not-transplanted patients. All patients were evaluated with the Unified HD Rating Scale (UHDRS) whose change in motor, cognitive, behavioural and functional capacity total scores were considered as outcome measures. Grafted patients also received morphological and molecular neuroimaging. RESULTS: Patients were followed-up from disease onset for a total of 309.3 person-years (minimum 5.3, median 11.2 years, maximum 21.6 years). UHDRS scores have been available since 2004 (median time of 5.7 years since onset, minimum zero, maximum 17.2 years). Median post transplantation follow-up was 4.3 years, minimum 2.8, maximum 5.1 years. Adjusted post-transplantation motor score deterioration rate was reduced compared to the pretransplantation period, and to that of not-transplanted patients by 0.9 unit/years (95% CI 0.2 to 1.6). Cognitive score deterioration was reduced of 2.7 unit/years (95% CI 0.1 to 5.3). For grafted patients the 2-year post transplantation [(18)F]fluorodeoxyglucose positron emission tomography (PET) showed striatal/cortical metabolic increase compared to the presurgical evaluation; 4-year post-transplantation PET values were slightly decreased, but remained higher than preoperatively. [(123)I]iodobenzamide single photon emission CT demonstrated an increase in striatal D2-receptor density during postgrafting follow-up. CONCLUSIONS: Grafted patients experienced a milder clinical course with less pronounced motor/cognitive decline and associated brain metabolism improvement. Life-time follow-up may ultimately clarify whether transplantation permanently modifies the natural course of the disease, allowing longer sojourn time at less severe clinical stage, and improvement of overall survival. PMID- 24347580 TI - Dr Anne Szarewski: 1 September 1959-24 August 2013. PMID- 24347581 TI - The barrier to abortion is politics. PMID- 24347583 TI - "I honestly didn't know that I could": the rise and rise of in-pharmacy sexual and reproductive health guidance. PMID- 24347584 TI - The birth of mankind. PMID- 24347585 TI - Reproductive Health Matters. PMID- 24347586 TI - Comment on 'vasectomy: replacing the preoperative outpatient appointment with a DVD'. PMID- 24347587 TI - Comment on 'vasectomy: replacing the preoperative outpatient appointment with a DVD': authors' response. PMID- 24347588 TI - Comment on 'embracing post-fertilisation methods of family planning: a call to action'. PMID- 24347589 TI - Comment on 'Embracing post-fertilisation methods of family planning: a call to action': authors' response. PMID- 24347590 TI - Not all IUDs fit in young nulliparous and adolescent women. PMID- 24347591 TI - HPV knowledge and vaccine acceptability in Appalachian Tennessee and Kentucky, USA. PMID- 24347592 TI - Comment on 'infections post-Nexplanon(R) insertion'. PMID- 24347594 TI - A systematic review of symptomatic diagnosis of lung cancer. AB - BACKGROUND: Lung cancer (LC) is often diagnosed late when curative intervention is no longer viable. However, current referral guidelines (e.g. UK National Institute for Health and Care Excellence guidelines) for suspected LC are based on a weak evidence base. Aim. The purpose of this systematic review is to identify symptoms that are independently associated with LC and to identify the key methodological issues relating to symptomatic diagnosis research in LC. METHODS: Medline, Ovid and Cumulative Index to Nursing and Allied Health Literature were searched for the period between 1946 and 2012 using the MeSH terms 'lung cancer' and 'symptom*'. Quality of each paper was assessed using Scottish Intercollegiate Guidelines Network and Consolidated Criteria for Reporting Qualitative Research Checklists and checked by a second and third reviewer. RESULTS: Evidence regarding the diagnostic values of most symptoms was inconclusive; haemoptysis was the only symptom consistently indicated as a predictor of LC. Generally, evidence was weakened by methodological issues such as the lack of standardized data collection (recording bias) and the lack of comparability of findings across the different studies that extend beyond the spectrum of disease. Qualitative studies indicated that patients with LC experienced symptoms months before diagnosis but did not interpret them as serious enough to seek health care. Therefore, early LC symptoms might be under represented in primary care clinical notes. CONCLUSION: Current evidence is insufficient to suggest a symptom profile for LC across the disease stages, nor can it be concluded that classical LC symptoms are predictors of LC apart from, perhaps, haemoptysis. Prospective studies are now needed that systematically record symptoms and explore their predictive values for LC diagnosis. PMID- 24347595 TI - Atrial tachycardia after ablation of persistent atrial fibrillation: is it us or them? PMID- 24347596 TI - Unipolar electrogram morphology to assess lesion formation during catheter ablation of atrial fibrillation: successful translation into clinical practice. PMID- 24347597 TI - Deliberate epicardial catheter ablation lesions: making outside contact. PMID- 24347598 TI - Wave-mapping as a guide for ablation of atrial fibrillation: a daydream? PMID- 24347599 TI - Who should receive the subcutaneous implanted defibrillator?: The subcutaneous implantable cardioverter defibrillator (ICD) should be considered in all ICD patients who do not require pacing. PMID- 24347600 TI - Who should receive the subcutaneous implanted defibrillator?: Timing is not right to replace the transvenous implantable cardioverter defibrillator. PMID- 24347601 TI - Letter by Morris et al regarding article, "Low heart rates predict incident atrial fibrillation in healthy middle-aged men" by Grundvold et al. PMID- 24347602 TI - Response to Letter by Morris et al regarding article, "Low heart rates predict incident atrial fibrillation in healthy middle-aged men" by Grundvold et al. PMID- 24347603 TI - New diagnostic and therapeutic approaches to treat ventricular tachycardias originating at the summit of the left ventricle: role of merged hemodynamic-MRI and alternative ablation sources. PMID- 24347604 TI - Similia similibus curantur. PMID- 24347605 TI - Bundle branch reentrant ventricular tachycardia with wide and narrow QRS morphology. PMID- 24347606 TI - Bundles branch reentry. PMID- 24347607 TI - Fundamental concepts in electrophysiology in cases and reviews. PMID- 24347608 TI - Carbon ion radiotherapy of human lung cancer attenuates HIF-1 signaling and acts with considerably enhanced therapeutic efficiency. AB - Carbon ion irradiation is an emerging therapeutic option for various tumor entities. Radiation resistance of solid tumors toward photon irradiation is caused by attenuation of DNA damage in less oxygenated tumor areas and by increased hypoxia-inducible factor (HIF)-1 signaling. Carbon ion irradiation acts independently of oxygen; however, the role of HIF-1 is unclear. We analyzed the effect of HIF-1 signaling after carbon ions in comparison to photons by using biological equivalent radiation doses in a human non-small-cell cancer model. The studies were performed in cultured A549 and H1299 cell lines and in A549 xenografts. Knockdown of HIF-1alpha in vivo combined with photon irradiation delayed tumor growth (23 vs. 13 d; P<0.05). Photon irradiation induced HIF-1alpha and target genes, predominantly in oxygenated cells (1.6-fold; P<0.05), with subsequent enhanced tumor angiogenesis (1.7-fold; P<0.05). These effects were not observed after carbon ion irradiation. Micro-DNA array analysis indicated that photons, but not carbon ions, significantly induced components of the mTOR (mammalian target of rapamycin) pathway (gene set enrichment analysis; P<0.01) as relevant for HIF-1alpha induction. After carbon ion irradiation in vivo, we observed substantially decreased HIF-1alpha levels (8.9-fold; P<0.01) and drastically delayed tumor growth (P<0.01), an important finding that indicates a higher relative biological effectiveness (RBE) than anticipated from the cell survival data. Taken together, the evidence showed that carbon ions mediate an improved therapeutic effectiveness without tumor-promoting HIF-1 signaling. PMID- 24347609 TI - Mechanosensing through focal adhesion-anchored intermediate filaments. AB - Integrin-based mechanotransduction involves a complex focal adhesion (FA) associated machinery that is able to detect and respond to forces exerted either through components of the extracellular matrix or the intracellular contractile actomyosin network. Here, we show a hitherto unrecognized regulatory role of vimentin intermediate filaments (IFs) in this process. By studying fibroblasts in which vimentin IFs were decoupled from FAs, either because of vimentin deficiency (V0) or loss of vimentin network anchorage due to deficiency in the cytolinker protein plectin (P0), we demonstrate attenuated activation of the major mechanosensor molecule FAK and its downstream targets Src, ERK1/2, and p38, as well as an up-regulation of the compensatory feedback loop acting on RhoA and myosin light chain. In line with these findings, we show strongly reduced FA turnover rates in P0 fibroblasts combined with impaired directional migration, formation of protrusions, and up-regulation of "stretched" high-affinity integrin complexes. By exploiting tension-independent conditions, we were able to mechanistically link these defects to diminished cytoskeletal tension in both P0 and V0 cells. Our data provide important new insights into molecular mechanisms underlying cytoskeleton-regulated mechanosensing, a feature that is fundamental for controlled cell movement and tumor progression. PMID- 24347610 TI - In situ intracellular calcium oscillations in osteocytes in intact mouse long bones under dynamic mechanical loading. AB - Osteocytes have been hypothesized to be the major mechanosensors in bone. How in situ osteocytes respond to mechanical stimuli is still unclear because of technical difficulties. In vitro studies have shown that osteocytes exhibited unique calcium (Ca(2+)) oscillations to fluid shear. However, whether this mechanotransduction phenomenon holds for in situ osteocytes embedded within a mineralized bone matrix under dynamic loading remains unknown. Using a novel synchronized loading/imaging technique, we successfully visualized in real time and quantified Ca(2+) responses in osteocytes and bone surface cells in situ under controlled dynamic loading on intact mouse tibia. The resultant fluid induced shear stress on the osteocyte in the lacunocanalicular system (LCS) was also quantified. Osteocytes, but not surface cells, displayed repetitive Ca(2+) spikes in response to dynamic loading, with spike frequency and magnitude dependent on load magnitude, tissue strain, and shear stress in the LCS. The Ca(2+) oscillations were significantly reduced by endoplasmic reticulum (ER) depletion and P2 purinergic receptor (P2R)/phospholipase C (PLC) inhibition. This study provides direct evidence that osteocytes respond to in situ mechanical loading by Ca(2+) oscillations, which are dependent on the P2R/PLC/inositol trisphosphate/ER pathway. This study develops a novel approach in skeletal mechanobiology and also advances our fundamental knowledge of bone mechanotransduction. PMID- 24347611 TI - Dystrophin insufficiency causes selective muscle histopathology and loss of dystrophin-glycoprotein complex assembly in pig skeletal muscle. AB - The purpose of this investigation was to determine the extent to which dystrophin insufficiency caused histomorphological changes in a novel pig model of Becker muscular dystrophy. In our procedures, we used a combination of biochemical approaches, including quantitative PCR and Western blots, along with a histological analysis using standard and immunohistological measures. We found that 8-wk-old male affected pigs had a 70% reduction in dystrophin protein abundance in the diaphragm, psoas major, and longissimus lumborum and a 5-fold increase in serum creatine kinase activity compared with healthy male littermates. Dystrophin insufficiency in the diaphragm and the longissimus resulted in muscle histopathology with disorganized fibrosis that often colocalized with fatty infiltration but not the psoas. Affected animals also had an 80-85% reduction in alpha-sarcoglycan localization in these muscles, indicating compromised assembly of the dystrophin glycoprotein complex. Controls used in this study were 4 healthy male littermates, as they are most closely related to the affected animals. We concluded that pigs with insufficient dystrophin protein expression have a phenotype consistent with human dystrophinopathy patients. Given that and their similarity in body size and physiology to humans, we further conclude that this pig line is an appropriate translational model for dystrophinopathies. PMID- 24347612 TI - A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes. AB - RNA molecules transmit the information encoded in the genome and generally reflect its content. Adenosine-to-inosine (A-to-I) RNA editing by ADAR proteins converts a genomically encoded adenosine into inosine. It is known that most RNA editing in human takes place in the primate-specific Alu sequences, but the extent of this phenomenon and its effect on transcriptome diversity are not yet clear. Here, we analyzed large-scale RNA-seq data and detected ~1.6 million editing sites. As detection sensitivity increases with sequencing coverage, we performed ultradeep sequencing of selected Alu sequences and showed that the scope of editing is much larger than anticipated. We found that virtually all adenosines within Alu repeats that form double-stranded RNA undergo A-to-I editing, although most sites exhibit editing at only low levels (<1%). Moreover, using high coverage sequencing, we observed editing of transcripts resulting from residual antisense expression, doubling the number of edited sites in the human genome. Based on bioinformatic analyses and deep targeted sequencing, we estimate that there are over 100 million human Alu RNA editing sites, located in the majority of human genes. These findings set the stage for exploring how this primate-specific massive diversification of the transcriptome is utilized. PMID- 24347614 TI - Exercise training reverses unparallel downregulation of MaxiK channel alpha- and beta1-subunit to enhance vascular function in aging mesenteric arteries. AB - This study was designed to determine the effects of aerobic exercise training on aging-associated selective changes of the function and expression of the large conductance Ca(2+)-activated K(+) (MaxiK) channels in mesenteric arteries. Male Wistar rats aged 19-21 months were randomly assigned to sedentary (O-SED) and exercise-trained groups (O-EX). Two-month-old rats were used as Young control. Addition of iberiotoxin (10(-8) M) increased the norepinephrine-induced arterial contraction in all three groups, with the greatest enhancement being in Young and the least in O-SED. Patch clamp study revealed the characteristics of aging on MaxiK channel function in mesenteric arteries, mainly including (a) decrease of iberiotoxin-sensitive whole-cell K(+) current, (b) decrease of open probability and Ca(2+)/voltage sensitivity of single MaxiK channel, and (c) reduction of tamoxifen-induced MaxiK activation. After exercise training, all of these changes were markedly inhibited. Western blotting revealed that the protein expression of MaxiK was significantly reduced with aging and the suppression of beta1-subunit was larger than that of alpha-subunit, although exercise training diminished this alteration. Taken together, aerobic exercise training reverses the aging-related unparallel downregulation of MaxiK alpha- and beta1-subunit expression on mesenteric arteries, which partly underlies the beneficial effect of exercise on restoring aging-associated reduction in mesenteric artery vasodilatory properties. PMID- 24347616 TI - Arrhythmogenic right ventricular cardiomyopathy: growing evidence for complex inheritance. PMID- 24347613 TI - A heart that beats for 500 years: age-related changes in cardiac proteasome activity, oxidative protein damage and expression of heat shock proteins, inflammatory factors, and mitochondrial complexes in Arctica islandica, the longest-living noncolonial animal. AB - Study of negligibly senescent animals may provide clues that lead to better understanding of the cardiac aging process. To elucidate mechanisms of successful cardiac aging, we investigated age-related changes in proteasome activity, oxidative protein damage and expression of heat shock proteins, inflammatory factors, and mitochondrial complexes in the heart of the ocean quahog Arctica islandica, the longest-lived noncolonial animal (maximum life span potential: 508 years). We found that in the heart of A. islandica the level of oxidatively damaged proteins did not change significantly up to 120 years of age. No significant aging-induced changes were observed in caspase-like and trypsin-like proteasome activity. Chymotrypsin-like proteasome activity showed a significant early-life decline, then it remained stable for up to 182 years. No significant relationship was observed between the extent of protein ubiquitination and age. In the heart of A. islandica, an early-life decline in expression of HSP90 and five mitochondrial electron transport chain complexes was observed. We found significant age-related increases in the expression of three cytokine-like mediators (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha) in the heart of A. islandica. Collectively, in extremely long-lived molluscs, maintenance of protein homeostasis likely contributes to the preservation of cardiac function. Our data also support the concept that low-grade chronic inflammation in the cardiovascular system is a universal feature of the aging process, which is also manifest in invertebrates. PMID- 24347617 TI - Expanding the genetic spectrum of hypertrophic cardiomyopathy: X marks the spot. PMID- 24347618 TI - Genome-wide linkage approach yields novel early onset myocardial infarction locus in East Asians. PMID- 24347619 TI - Translation of genetics research to clinical medicine: the National Heart, Lung, and Blood Institute perspective. PMID- 24347620 TI - A repair tool-(c)kit for the injured heart. PMID- 24347621 TI - Salt, immune function, and the risk of autoimmune diseases. PMID- 24347623 TI - Homogeneous nuclear background for mitochondrial cline in northern range of Notochthamalus scabrosus. AB - A mitochondrial cline along the Chilean coast in the barnacle Notochthamalus scabrosus suggests a species history of transient allopatry and secondary contact. However, previous studies of nuclear sequence divergence suggested population genetic homogeneity across northern and central Chile. Here, we collect single-nucleotide polymorphism data from pooled population samples sequenced with restriction site-associated DNA sequencing procedures, confirm these data with the use of a GoldenGate array, and identify a discordance between population genetic patterns in the nuclear and mitochondrial genomes. This discordance was noted in previous work on this species, but here it is confirmed that the nuclear genome exhibits only slight phylogeographic variation across 3000 km of coastline, in the presence of a strong and statistically significant mitochondrial cline. There are nevertheless markers (approximately 5% of nuclear single-nucleotide polymorphisms) exhibiting cytonuclear disequilibrium relative to mitotype. Although these data confirm our previous explorations of this species, it is likely that some of the nuclear genomic diversity of this species has yet to be explored, as comparison with other barnacle phylogeography studies suggest that a divergence of similar magnitude should be found in the nuclear genome somewhere else in the species range. PMID- 24347622 TI - Identification of suppressors of mbk-2/DYRK by whole-genome sequencing. AB - Screening for suppressor mutations is a powerful method to isolate genes that function in a common pathway or process. Because suppressor mutations often do not have phenotypes on their own, cloning of suppressor loci can be challenging. A method combining whole-genome sequencing (WGS) and single nucleotide polymorphism (SNP) mapping (WGS/SNP mapping) was developed to identify mutations with visible phenotypes in C. elegans. We show here that WGS/SNP mapping is an efficient method to map suppressor mutations without the need for previous phenotypic characterization. Using RNA-mediated interference to test candidate loci identified by WGS/SNP mapping, we identified 10 extragenic and six intragenic suppressors of mbk-2, a DYRK family kinase required for the transition from oocyte to zygote. Remarkably, seven suppressors are mutations in cell-cycle regulators that extend the timing of the oocyte-to-zygote transition. PMID- 24347624 TI - Genetic architecture of contemporary adaptation to biotic invasions: quantitative trait locus mapping of beak reduction in soapberry bugs. AB - Biological invasions can result in new selection pressures driven by the establishment of new biotic interactions. The response of exotic and native species to selection depends critically on the genetic architecture of ecologically relevant traits. In the Florida peninsula, the soapberry bug (Jadera haematoloma) has colonized the recently introduced Chinese flametree, Koelreuteria elegans, as a host plant. Driven by feeding efficiency, the populations associated with this new host have differentiated into a new bug ecomorph characterized by short beaks more appropriate for feeding on the flattened pods of the Chinese flametree. In this study, we have generated a three generation pedigree from crossing the long-beaked and short-beaked ecomorphs to construct a de novo linkage map and to locate putative quantitative trait locus (QTL) controlling beak length and body size in J. haematoloma. Using amplified fragment-length polymorphism markers and a two-way pseudo-testcross design, we have produced two parental maps in six linkage groups, covering the known number of chromosomes. QTL analysis revealed one significant QTL for beak length on a maternal linkage group and the corresponding paternal linkage group. Three QTL were found for body size. Through single marker regression analysis, nine single markers that could not be placed on the map were also found to be significantly associated with one or both of the two traits. Interestingly, the most significant body size QTL co-localized with the beak length QTL, suggesting linkage disequilibrium or pleiotropic effects of related traits. Our results suggest an oligogenic control of beak length. PMID- 24347625 TI - Genomic characterization of the mouse ribosomal DNA locus. AB - The transcription of rRNA is critical to all living cells and is tightly controlled at the level of chromatin structure. Although the widespread adoption of genomic technologies including chromatin immunoprecipitation with massively parallel short-read sequencing (ChIP-seq) has allowed for the interrogation of chromatin structure on a genome-wide scale, until recently rDNA has not been analyzed by this technique. We extended genomic analysis of rDNA to mouse (Mus musculus), in which rDNA is similar in structure but highly divergent in sequence compared with human rDNA. Comparison of rDNA histone marks between mouse embryonic stem cells (mESCs) and more differentiated mouse cell types revealed differences between pluripotent and differentiated states. We also observed substantial divergence in rDNA histone modification patterns between mESCs and human embryonic stem cells (hESCs). Surprisingly, we found that the pluripotency factor OCT4 was bound to rDNA in similar patterns in mESCs and hESCs. Extending this analysis, we found that an additional 17 pluripotency-associated factors were bound to rDNA in mESCs, suggesting novel modes of rDNA regulation in pluripotent cells. Taken together, our results provide a detailed view of rDNA chromatin structure in an important model system and enable high-resolution comparison of rDNA regulation between mouse and human. PMID- 24347626 TI - Extensive use of RNA-binding proteins in Drosophila sensory neuron dendrite morphogenesis. AB - The large number of RNA-binding proteins and translation factors encoded in the Drosophila and other metazoan genomes predicts widespread use of post transcriptional regulation in cellular and developmental processes. Previous studies identified roles for several RNA-binding proteins in dendrite branching morphogenesis of Drosophila larval sensory neurons. To determine the larger contribution of post-transcriptional gene regulation to neuronal morphogenesis, we conducted an RNA interference screen to identify additional Drosophila proteins annotated as either RNA-binding proteins or translation factors that function in producing the complex dendritic trees of larval class IV dendritic arborization neurons. We identified 88 genes encoding such proteins whose knockdown resulted in aberrant dendritic morphology, including alterations in dendritic branch number, branch length, field size, and patterning of the dendritic tree. In particular, splicing and translation initiation factors were associated with distinct and characteristic phenotypes, suggesting that different morphogenetic events are best controlled at specific steps in post transcriptional messenger RNA metabolism. Many of the factors identified in the screen have been implicated in controlling the subcellular distributions and translation of maternal messenger RNAs; thus, common post-transcriptional regulatory strategies may be used in neurogenesis and in the generation of asymmetry in the female germline and embryo. PMID- 24347627 TI - Heterosis is prevalent among domesticated but not wild strains of Saccharomyces cerevisiae. AB - Crosses between inbred but unrelated individuals often result in an increased fitness of the progeny. This phenomenon is known as heterosis and has been reported for wild and domesticated populations of plants and animals. Analysis of heterosis is often hindered by the fact that the genetic relatedness between analyzed organisms is only approximately known. We studied a collection of Saccharomyces cerevisiae isolates from wild and human-created habitats whose genomes were sequenced and thus their relatedness was fully known. We reasoned that if these strains accumulated different deleterious mutations at an approximately constant rate, then heterosis should be most visible in F1 heterozygotes from the least related parents. We found that heterosis was substantial and positively correlated with sequence divergence, but only in domesticated strains. More than 80% of the heterozygous hybrids were more fit than expected from the mean of their homozygous parents, and approximately three quarters of those exceeded even the fittest parent. Our results support the notion that domestication brings about relaxation of selection and accumulation of deleterious mutations. However, other factors may have contributed as well. In particular, the observed build-up of genetic load might be facilitated by a decrease, and not increase, in the rate of inbreeding. PMID- 24347628 TI - Multigenic natural variation underlies Caenorhabditis elegans olfactory preference for the bacterial pathogen Serratia marcescens. AB - The nematode Caenorhabditis elegans can use olfaction to discriminate among different kinds of bacteria, its major food source. We asked how natural genetic variation contributes to choice behavior, focusing on differences in olfactory preference behavior between two wild-type C. elegans strains. The laboratory strain N2 strongly prefers the odor of Serratia marcescens, a soil bacterium that is pathogenic to C. elegans, to the odor of Escherichia coli, a commonly used laboratory food source. The divergent Hawaiian strain CB4856 has a weaker attraction to Serratia than the N2 strain, and this behavioral difference has a complex genetic basis. At least three quantitative trait loci (QTLs) from the CB4856 Hawaii strain (HW) with large effect sizes lead to reduced Serratia preference when introgressed into an N2 genetic background. These loci interact and have epistatic interactions with at least two antagonistic QTLs from HW that increase Serratia preference. The complex genetic architecture of this C. elegans trait is reminiscent of the architecture of mammalian metabolic and behavioral traits. PMID- 24347629 TI - Genome-wide association study of periodontal health measured by probing depth in adults ages 18-49 years. AB - The etiology of chronic periodontitis clearly includes a heritable component. Our purpose was to perform a small exploratory genome-wide association study in adults ages 18-49 years to nominate genes associated with periodontal disease related phenotypes for future consideration. Full-mouth periodontal pocket depth probing was performed on participants (N = 673), with affected status defined as two or more sextants with probing depths of 5.5 mm or greater. Two variations of this phenotype that differed in how missing teeth were treated were used in analysis. More than 1.2 million genetic markers across the genome were genotyped or imputed and tested for genetic association. We identified ten suggestive loci (p-value <= 1E-5), including genes/loci that have been previously implicated in chronic periodontitis: LAMA2, HAS2, CDH2, ESR1, and the genomic region on chromosome 14q21-22 between SOS2 and NIN. Moreover, we nominated novel loci not previously implicated in chronic periodontitis or related pathways, including the regions 3p22 near OSBPL10 (a lipid receptor implicated in hyperlipidemia), 4p15 near HSP90AB2P (a heat shock pseudogene), 11p15 near GVINP1 (a GTPase pseudogene), 14q31 near SEL1L (an intracellular transporter), and 18q12 in FHOD3 (an actin cytoskeleton regulator). Replication of these results in additional samples is needed. This is one of the first research efforts to identify genetic polymorphisms associated with chronic periodontitis-related phenotypes by the genome-wide association study approach. Though small, efforts such this are needed in order to nominate novel genes and generate new hypotheses for exploration and testing in future studies. PMID- 24347631 TI - Horizontal gene transfer can rescue prokaryotes from Muller's ratchet: benefit of DNA from dead cells and population subdivision. AB - Horizontal gene transfer (HGT) is a major factor in the evolution of prokaryotes. An intriguing question is whether HGT is maintained during evolution of prokaryotes owing to its adaptive value or is a byproduct of selection driven by other factors such as consumption of extracellular DNA (eDNA) as a nutrient. One hypothesis posits that HGT can restore genes inactivated by mutations and thereby prevent stochastic, irreversible deterioration of genomes in finite populations known as Muller's ratchet. To examine this hypothesis, we developed a population genetic model of prokaryotes undergoing HGT via homologous recombination. Analysis of this model indicates that HGT can prevent the operation of Muller's ratchet even when the source of transferred genes is eDNA that comes from dead cells and on average carries more deleterious mutations than the DNA of recipient live cells. Moreover, if HGT is sufficiently frequent and eDNA diffusion sufficiently rapid, a subdivided population is shown to be more resistant to Muller's ratchet than an undivided population of an equal overall size. Thus, to maintain genomic information in the face of Muller's ratchet, it is more advantageous to partition individuals into multiple subpopulations and let them "cross-reference" each other's genetic information through HGT than to collect all individuals in one population and thereby maximize the efficacy of natural selection. Taken together, the results suggest that HGT could be an important condition for the long-term maintenance of genomic information in prokaryotes through the prevention of Muller's ratchet. PMID- 24347630 TI - Global analysis of serine/threonine and tyrosine protein phosphatase catalytic subunit genes in Neurospora crassa reveals interplay between phosphatases and the p38 mitogen-activated protein kinase. AB - Protein phosphatases are integral components of the cellular signaling machinery in eukaryotes, regulating diverse aspects of growth and development. The genome of the filamentous fungus and model organism Neurospora crassa encodes catalytic subunits for 30 protein phosphatase genes. In this study, we have characterized 24 viable N. crassa phosphatase catalytic subunit knockout mutants for phenotypes during growth, asexual development, and sexual development. We found that 91% of the mutants had defects in at least one of these traits, whereas 29% possessed phenotypes in all three. Chemical sensitivity screens were conducted to reveal additional phenotypes for the mutants. This resulted in the identification of at least one chemical sensitivity phenotype for 17 phosphatase knockout mutants, including novel chemical sensitivities for two phosphatase mutants lacking a growth or developmental phenotype. Hence, chemical sensitivity or growth/developmental phenotype was observed for all 24 viable mutants. We investigated p38 mitogen-activated protein kinase (MAPK) phosphorylation profiles in the phosphatase mutants and identified nine potential candidates for regulators of the p38 MAPK. We demonstrated that the PP2C class phosphatase pph-8 (NCU04600) is an important regulator of female sexual development in N. crassa. In addition, we showed that the Deltacsp-6 (DeltaNCU08380) mutant exhibits a phenotype similar to the previously identified conidial separation mutants, Deltacsp-1 and Deltacsp-2, that lack transcription factors important for regulation of conidiation and the circadian clock. PMID- 24347633 TI - Glycoxidative damage to human DNA: Neo-antigenic epitopes on DNA molecule could be a possible reason for autoimmune response in type 1 diabetes. AB - Advanced glycation end-products (AGEs) are known to be mutagenic, diabetogenic and vascular disease risk factors. Methylglyoxal (MG) is a dicarbonyl species that reacts with biological macromolecule (proteins, DNA and lipids) to give AGEs. Nonenzymatic glycation of MG with lysine (Lys) in the presence of copper (Cu(2+)) is reported to generate reactive oxygen species (ROS) capable of causing DNA damage. We show that DNA modification in MG-Lys-Cu(2+) system results in the generation of strand breaks, base modification, hyperchromicity and increased fluorescence intensity. Superoxide generation in the MG-Lys system was found to be significantly higher when compared with that in the MG and Lys alone. Moreover, d-penicillamine and pyridoxal phosphate significantly inhibited the formation of glycation products. The presence of a major DNA glycation adduct, N(2)-carboxyethyl-2'-deoxyguanosine (CEdG), was detected by high performance liquid chromatography (HPLC) and confirmed by nuclear magnetic resonance (NMR). As reported earlier, modified DNA (MG-Lys-Cu(2+)-DNA) was highly immunogenic in experimental animals. Furthermore, induced anti-MG-Lys-Cu(2+)-DNA antibodies were effective probe for detecting glycoxidative lesions in human genomic DNA of type I diabetes patients. Our results clearly imply that interaction of MG-Lys and Cu(2+) leads to the formation of AGEs and also the production of potent ROS, capable of causing DNA damage, thereby playing an important role in diabetes mellitus. PMID- 24347634 TI - Cumulative latency advance underlies fast visual processing in desynchronized brain state. AB - Fast sensory processing is vital for the animal to efficiently respond to the changing environment. This is usually achieved when the animal is vigilant, as reflected by cortical desynchronization. However, the neural substrate for such fast processing remains unclear. Here, we report that neurons in rat primary visual cortex (V1) exhibited shorter response latency in the desynchronized state than in the synchronized state. In vivo whole-cell recording from the same V1 neurons undergoing the two states showed that both the resting and visually evoked conductances were higher in the desynchronized state. Such conductance increases of single V1 neurons shorten the response latency by elevating the membrane potential closer to the firing threshold and reducing the membrane time constant, but the effects only account for a small fraction of the observed latency advance. Simultaneous recordings in lateral geniculate nucleus (LGN) and V1 revealed that LGN neurons also exhibited latency advance, with a degree smaller than that of V1 neurons. Furthermore, latency advance in V1 increased across successive cortical layers. Thus, latency advance accumulates along various stages of the visual pathway, likely due to a global increase of membrane conductance in the desynchronized state. This cumulative effect may lead to a dramatic shortening of response latency for neurons in higher visual cortex and play a critical role in fast processing for vigilant animals. PMID- 24347632 TI - Large-scale quality analysis of published ChIP-seq data. AB - ChIP-seq has become the primary method for identifying in vivo protein-DNA interactions on a genome-wide scale, with nearly 800 publications involving the technique appearing in PubMed as of December 2012. Individually and in aggregate, these data are an important and information-rich resource. However, uncertainties about data quality confound their use by the wider research community. Recently, the Encyclopedia of DNA Elements (ENCODE) project developed and applied metrics to objectively measure ChIP-seq data quality. The ENCODE quality analysis was useful for flagging datasets for closer inspection, eliminating or replacing poor data, and for driving changes in experimental pipelines. There had been no similarly systematic quality analysis of the large and disparate body of published ChIP-seq profiles. Here, we report a uniform analysis of vertebrate transcription factor ChIP-seq datasets in the Gene Expression Omnibus (GEO) repository as of April 1, 2012. The majority (55%) of datasets scored as being highly successful, but a substantial minority (20%) were of apparently poor quality, and another ~25% were of intermediate quality. We discuss how different uses of ChIP-seq data are affected by specific aspects of data quality, and we highlight exceptional instances for which the metric values should not be taken at face value. Unexpectedly, we discovered that a significant subset of control datasets (i.e., no immunoprecipitation and mock immunoprecipitation samples) display an enrichment structure similar to successful ChIP-seq data. This can, in turn, affect peak calling and data interpretation. Published datasets identified here as high-quality comprise a large group that users can draw on for large scale integrated analysis. In the future, ChIP-seq quality assessment similar to that used here could guide experimentalists at early stages in a study, provide useful input in the publication process, and be used to stratify ChIP-seq data for different community-wide uses. PMID- 24347635 TI - Covalent EGFR inhibitor analysis reveals importance of reversible interactions to potency and mechanisms of drug resistance. AB - Covalent inhibition is a reemerging paradigm in kinase drug design, but the roles of inhibitor binding affinity and chemical reactivity in overall potency are not well-understood. To characterize the underlying molecular processes at a microscopic level and determine the appropriate kinetic constants, specialized experimental design and advanced numerical integration of differential equations are developed. Previously uncharacterized investigational covalent drugs reported here are shown to be extremely effective epidermal growth factor receptor (EGFR) inhibitors (kinact/Ki in the range 10(5)-10(7) M(-1)s(-1)), despite their low specific reactivity (kinact <= 2.1 * 10(-3) s(-1)), which is compensated for by high binding affinities (Ki < 1 nM). For inhibitors relying on reactivity to achieve potency, noncovalent enzyme-inhibitor complex partitioning between inhibitor dissociation and bond formation is central. Interestingly, reversible binding affinity of EGFR covalent inhibitors is highly correlated with antitumor cell potency. Furthermore, cellular potency for a subset of covalent inhibitors can be accounted for solely through reversible interactions. One reversible interaction is between EGFR-Cys797 nucleophile and the inhibitor's reactive group, which may also contribute to drug resistance. Because covalent inhibitors target a cysteine residue, the effects of its oxidation on enzyme catalysis and inhibitor pharmacology are characterized. Oxidation of the EGFR cysteine nucleophile does not alter catalysis but has widely varied effects on inhibitor potency depending on the EGFR context (e.g., oncogenic mutations), type of oxidation (sulfinylation or glutathiolation), and inhibitor architecture. These methods, parameters, and insights provide a rational framework for assessing and designing effective covalent inhibitors. PMID- 24347637 TI - Identification of secreted bacterial proteins by noncanonical amino acid tagging. AB - Pathogenic microbes have evolved complex secretion systems to deliver virulence factors into host cells. Identification of these factors is critical for understanding the infection process. We report a powerful and versatile approach to the selective labeling and identification of secreted pathogen proteins. Selective labeling of microbial proteins is accomplished via translational incorporation of azidonorleucine (Anl), a methionine surrogate that requires a mutant form of the methionyl-tRNA synthetase for activation. Secreted pathogen proteins containing Anl can be tagged by azide-alkyne cycloaddition and enriched by affinity purification. Application of the method to analysis of the type III secretion system of the human pathogen Yersinia enterocolitica enabled efficient identification of secreted proteins, identification of distinct secretion profiles for intracellular and extracellular bacteria, and determination of the order of substrate injection into host cells. This approach should be widely useful for the identification of virulence factors in microbial pathogens and the development of potential new targets for antimicrobial therapy. PMID- 24347638 TI - Salmonella exploits NLRP12-dependent innate immune signaling to suppress host defenses during infection. AB - The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 12 (NLRP12) plays a protective role in intestinal inflammation and carcinogenesis, but the physiological function of this NLR during microbial infection is largely unexplored. Salmonella enterica serovar Typhimurium (S. typhimurium) is a leading cause of food poisoning worldwide. Here, we show that NLRP12-deficient mice were highly resistant to S. typhimurium infection. Salmonella-infected macrophages induced NLRP12-dependent inhibition of NF-kappaB and ERK activation by suppressing phosphorylation of IkappaBalpha and ERK. NLRP12 mediated down-regulation of proinflammatory and antimicrobial molecules prevented efficient clearance of bacterial burden, highlighting a role for NLRP12 as a negative regulator of innate immune signaling during salmonellosis. These results underscore a signaling pathway defined by NLRP12-mediated dampening of host immune defenses that could be exploited by S. typhimurium to persist and survive in the host. PMID- 24347639 TI - Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. AB - The cellular response to highly genotoxic DNA double-strand breaks (DSBs) involves the exquisite coordination of multiple signaling and repair factors. Here, we conducted a functional RNAi screen and identified BAP1 as a deubiquitinase required for efficient assembly of the homologous recombination (HR) factors BRCA1 and RAD51 at ionizing radiation (IR) -induced foci. BAP1 is a chromatin-associated protein frequently inactivated in cancers of various tissues. To further investigate the role of BAP1 in DSB repair, we used a gene targeting approach to knockout (KO) this deubiquitinase in chicken DT40 cells. We show that BAP1-deficient cells are (i) sensitive to IR and other agents that induce DSBs, (ii) defective in HR-mediated immunoglobulin gene conversion, and (iii) exhibit an increased frequency of chromosomal breaks after IR treatment. We also show that BAP1 is recruited to chromatin in the proximity of a single site specific I-SceI-induced DSB. Finally, we identified six IR-induced phosphorylation sites in BAP1 and showed that mutation of these residues inhibits BAP1 recruitment to DSB sites. We also found that both BAP1 catalytic activity and its phosphorylation are critical for promoting DNA repair and cellular recovery from DNA damage. Our data reveal an important role for BAP1 in DSB repair by HR, thereby providing a possible molecular basis for its tumor suppressor function. PMID- 24347641 TI - The elephant, the blind, and the intersectoral intercomparison of climate impacts. PMID- 24347640 TI - Dual-modality gene reporter for in vivo imaging. AB - The ability to track cells and their patterns of gene expression in living organisms can increase our understanding of tissue development and disease. Gene reporters for bioluminescence, fluorescence, radionuclide, and magnetic resonance imaging (MRI) have been described but these suffer variously from limited depth penetration, spatial resolution, and sensitivity. We describe here a gene reporter, based on the organic anion transporting protein Oatp1a1, which mediates uptake of a clinically approved, Gd(3+)-based, hepatotrophic contrast agent (gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid). Cells expressing the reporter showed readily reversible, intense, and positive contrast (up to 7.8 fold signal enhancement) in T1-weighted magnetic resonance images acquired in vivo. The maximum signal enhancement obtained so far is more than double that produced by MRI gene reporters described previously. Exchanging the Gd(3+) ion for the radionuclide, (111)In, also allowed detection by single-photon emission computed tomography, thus combining the spatial resolution of MRI with the sensitivity of radionuclide imaging. PMID- 24347642 TI - A Cdc42- and Rac-interactive binding (CRIB) domain mediates functions of coronin. AB - The Cdc42- and Rac-interactive binding motif (CRIB) of coronin binds to Rho GTPases with a preference for GDP-loaded Rac. Mutation of the Cdc42- and Rac interactive binding motif abrogates Rac binding. This results in increased 1evels of activated Rac in coronin-deficient Dictyostelium cells (corA(-)), which impacts myosin II assembly. corA(-) cells show increased accumulation of myosin II in the cortex of growth-phase cells. Myosin II assembly is regulated by myosin heavy chain kinase-mediated phosphorylation of its tail. Kinase activity depends on the activation state of the p21-activated kinase a. The myosin II defect of corA(-) mutant is alleviated by dominant-negative p21-activated kinase a. It is rescued by wild-type coronin, whereas coronin carrying a mutated Cdc42- and Rac interactive binding motif failed to rescue the myosin defect in corA(-) mutant cells. Ectopically expressed myosin heavy chain kinases affinity purified from corA(-) cells show reduced kinase activity. We propose that coronin through its affinity for GDP-Rac regulates the availability of GTP-Rac for activation of downstream effectors. PMID- 24347645 TI - Absence of splash singularities for surface quasi-geostrophic sharp fronts and the Muskat problem. AB - In this paper, for both the sharp front surface quasi-geostrophic equation and the Muskat problem, we rule out the "splash singularity" blow-up scenario; in other words, we prove that the contours evolving from either of these systems cannot intersect at a single point while the free boundary remains smooth. Splash singularities have been shown to hold for the free boundary incompressible Euler equation in the form of the water waves contour evolution problem. Our result confirms the numerical simulations in earlier work, in which it was shown that the curvature blows up because the contours collapse at a point. Here, we prove that maintaining control of the curvature will remove the possibility of pointwise interphase collapse. Another conclusion that we provide is a better understanding of earlier work in which squirt singularities are ruled out; in this case, a positive volume of fluid between the contours cannot be ejected in finite time. PMID- 24347646 TI - Greenland Pt anomaly may point to noncataclysmic Cape York meteorite entry. PMID- 24347643 TI - Spontaneous slow replication fork progression elicits mitosis alterations in homologous recombination-deficient mammalian cells. AB - Homologous recombination deficient (HR(-)) mammalian cells spontaneously display reduced replication fork (RF) movement and mitotic extra centrosomes. We show here that these cells present a complex mitotic phenotype, including prolonged metaphase arrest, anaphase bridges, and multipolar segregations. We then asked whether the replication and the mitotic phenotypes are interdependent. First, we determined low doses of hydroxyurea that did not affect the cell cycle distribution or activate CHK1 phosphorylation but did slow the replication fork movement of wild-type cells to the same level than in HR(-) cells. Remarkably, these low hydroxyurea doses generated the same mitotic defects (and to the same extent) in wild-type cells as observed in unchallenged HR(-) cells. Reciprocally, supplying nucleotide precursors to HR(-) cells suppressed both their replication deceleration and mitotic extra centrosome phenotypes. Therefore, subtle replication stress that escapes to surveillance pathways and, thus, fails to prevent cells from entering mitosis alters metaphase progression and centrosome number, resulting in multipolar mitosis. Importantly, multipolar mitosis results in global unbalanced chromosome segregation involving the whole genome, even fully replicated chromosomes. These data highlight the cross-talk between chromosome replication and segregation, and the importance of HR at the interface of these two processes for protection against general genome instability. PMID- 24347647 TI - Development of a Croatian version of the US Hospital Survey on Patient Safety Culture questionnaire: dimensionality and psychometric properties. AB - BACKGROUND: The Hospital Survey on Patient Safety Culture (HSOPSC), originally developed in the USA, is used worldwide to assess patient safety culture in hospitals. A limited number of studies have provided data on psychometric properties outside of the US healthcare system. Our aim was to determine if all 12 dimensions of the US HSOPSC were applicable, valid and reliable to Croatian healthcare workers. METHODS: The study was conducted from September 2010 to April 2011. Questions were translated into Croatian and then translated back into English. The questionnaires (ie, the Croatian translation of the US HSOPSC) were distributed in unmarked envelopes along with a consent form to all the doctors and nurses in four Croatian hospitals. The responses were analysed using explorative factor analyses, reliability testing, and confirmatory factor analyses. RESULTS: The study included 561 healthcare workers in four Croatian hospitals--a response rate of 32.69%. Our results are similar to the original US sample, but with some differences: 11 dimensions with acceptable reliability scores were identified by exploratory factor analysis compared with the original 12 in the US sample; five of 12 dimensions had a Cronbach's alpha higher than 0.7, suggesting a reasonable fit to the original US HSOPSC; the dimensions 'Staffing' and 'Organisational learning--continuous improvement' were found to have a Cronbach's alpha <0.6. The use of confirmatory factor analysis confirmed a good fit to the original US model. CONCLUSIONS: Results show that the Croatian translation of the US HSOPSC is compatible in 11 of the original 12 dimensions. Results suggest that for the purposes of research in Croatia, the dimensions 'Staffing', 'Communication openness', and 'Organisational learning-continuous improvement' should be revised. For example, the use of question A7 ('We use more agency/temporary staff than is best for patient care') in the context of European healthcare systems should be adapted or removed for the Croatian version of the US HSOPSC questionnaire. PMID- 24347648 TI - Deterioration following craniectomy. PMID- 24347649 TI - Oral antibiotics at discharge for children with acute osteomyelitis: a rapid cycle improvement project. AB - BACKGROUND: Substantial evidence demonstrates comparable cure rates for oral versus intravenous therapy for routine osteomyelitis. Evidence adoption is often slow and in our centre virtually all patients with osteomyelitis were discharged on intravenous therapy. OBJECTIVE: For patients with acute osteomyelitis admitted to the hospital medicine service, we aimed to increase the proportion of cases discharged on oral antibiotics to at least 70%. METHODS: The setting for our observational time series study was a large academic children's hospital. The model for improvement and plan-do-study-act cycles were used to test, refine and implement interventions identified through our key driver diagram. Our multifaceted intervention included a shared decision-making tool, an order set in our electronic health record, and education to faculty and trainees. We also included an identify and mitigate intervention to target providers caring for children with osteomyelitis in near-real time and reinforce the evidence-based recommendations. Data were analysed on an annotated g-chart of osteomyelitis cases between patients discharged on intravenous antibiotics. Structured chart review was used to identify treatment failures as well as length of stay and hospital charges in preintervention and postintervention groups. RESULTS: The osteomyelitis cases between patients discharged on intravenous antibiotics increased from a median of 0 preintervention to a maximum of 9 cases following our identify and mitigate intervention. The direction and magnitude of successive improvements observed satisfied criteria for special cause variation. Improvement has been sustained for 1 year. Treatment failure and complications were uncommon in preintervention and postintervention phases. No significant differences in length of stay or charges were detected. CONCLUSIONS: Even for uncommon conditions, rapid and sustained evidence adoption is possible using quality improvement methods. PMID- 24347651 TI - Effect of locally applied transforming growth factor Beta3 on wound healing and stenosis development in tracheal surgery. AB - BACKGROUND: Tracheal stenosis constitutes one of the most frequently seen problems in thoracic surgery. Although many treatment modalities to prevent fibroblast proliferation, angiogenesis, or inflammation that causes tracheal stenosis have been attempted, an effective method has not yet been found. In this study, a transforming growth factor beta3 (TGF-beta3)/chitosan combination was used for this purpose. METHODS: A slow-release preparation containing a thin layer of TGF-beta3 with a chitosan base was made. Thirty albino Wistar rats were divided into 3 groups. A full-layer vertical incision was made in the anterior side of the trachea of each rat between the second and fifth tracheal rings. The tracheal incision was sutured. Group A was evaluated as the control group. In Group B, a chitosan-based film was placed on the incision line. In Group C, a slow-release TGF-beta3/chitosan-coated substance was placed on the incision line. The rats were killed on day 30, and their tracheas were excised by cutting between the lower edge of the thyroid cartilage and the upper edge of the sixth tracheal ring together with the esophagus. Epithelialization, fibroblast proliferation, angiogenesis, inflammation, and collagen levels were evaluated histopathologically by the same histopathologist. RESULTS: Statistically significant differences were not found among the 3 groups. Cold abscesses were observed at the incision sites in both the TGF-beta/chitosan and chitosan groups. These were thought to have formed due to the chitosan. CONCLUSIONS: As this was the first experiment in the literature to use this type of TGF-beta3 formulation, we intend to change the formulation and perform this study again with a different TGF-beta3/chitosan preparation. PMID- 24347650 TI - Caring for critically ill children in the community: a needs assessment. AB - OBJECTIVE: The goal of this study was to identify barriers and facilitators to the optimal management of critically ill children who present initially to community hospitals and how best to support the needs of front-line healthcare providers in these settings prior to transfer to the regional academic paediatric health sciences centre. METHODS: A qualitative needs assessment was performed in five community hospitals targeting healthcare providers in leadership and front line roles who could discuss their experiences of managing critically ill children that had presented to their institutions. Focused individual and focus group interviews of physicians, nurses and respiratory therapists from the participating hospitals were conducted and analysed to identify common themes. RESULTS: Five community hospitals participated in the study with a total of 57 participants and included 36 registered nurses, 4 respiratory therapists, 13 community hospital physicians and 4 paediatric intensive care specialists. Most participants did not report seeing more than one critically ill child per month. The management of very young paediatric patients was reported as a greater source of anxiety than patients presenting in cardiac arrest and despite being more frequently reported, respiratory conditions were identified as the most anxiety provoking and having the greatest educational need. The care required for a single critically ill child was often reported to render the emergency department staff incapable of meeting other patient care needs and was influenced by staffing resources, physical layout and access to proper equipment. Increased comfort and management ability was attributed to previous real-world experience and support from content experts in dealing with acutely ill children. Participants did not use web-based best practice guidelines. CONCLUSIONS: This study identifies the need to fully understand the management realities of front line caregivers of critically ill children in community hospital settings. We demonstrate the need to focus on the management of younger paediatric patients, technical skills development, practice of acute situations with less than optimal staffing resources, and access to facilitated real-world experiences with appropriate supervision and mentoring. Passive interventions such as web-based guidelines should not be used in isolation but as a support to ongoing exposure and engagement by content experts. PMID- 24347652 TI - Hyperinflation on chest radiograph as a marker of low adherence to positive airway pressure therapy in the overlap syndrome. AB - BACKGROUND: Positive airway pressure (PAP) in subjects with both obstructive sleep apnea and COPD reduces the risk of pulmonary hypertension, death, and hospitalizations from COPD exacerbations, but adherence to the intervention is low, similar to the experience with noninvasive ventilation in stable COPD. We sought to assess whether hyperinflation on chest radiographs contributes to low adherence to PAP therapy in the overlap syndrome. METHODS: Records of patients with a listed diagnosis of COPD at the time of polysomnography were reviewed. Overlap syndrome was diagnosed when COPD was clinically confirmed with spirometry showing a fixed airway obstruction and when the apnea-hypopnea index was >= 5. Hyperinflation was evaluated by a review of the right diaphragm height on a lateral chest radiograph. Adherence was assessed clinically or through device download at a 3-month follow-up, and later adherence was assessed by telephone interviews. A receiver operating curve was used to determine whether diaphragm height was associated with adherence. RESULTS: Twenty-one of 41 subjects (51%) were considered adherent to PAP therapy at the 3-month visit. Adherent subjects were more overweight compared with non-adherent subjects (body mass index of 36.0 +/- 5.7 vs 32.0 +/- 5.7 kg/m(2), P = .03), sleepier at the onset (Epworth sleepiness scale score of 13.0 +/- 5.8 vs 9.4 +/- 5.4, P < .05), and less likely to have hyperinflation as defined by a right diaphragm height <= 2.45 cm (33% vs 65%, P = .04). The body mass index and initial sleepiness no longer predicted adherence beyond 3 months, but 35% of subjects with a right diaphragm height <= 2.45 cm were adherent beyond 3 months compared with 75% of those with a right diaphragm height > 2.45 cm (P = .04 by Fisher exact test). CONCLUSIONS: Hyperinflation is associated with decreased adherence to PAP therapy in the overlap syndrome. PMID- 24347653 TI - Percutaneous coronary interventions in ST-segment-elevation myocardial infarction: shifting paradigms and future perspectives. PMID- 24347654 TI - Transcatheter aortic valve replacement in patients with aortic stenosis and left ventricular dysfunction: patient selection counts more than ever! PMID- 24347655 TI - Neurological injury after transcatheter aortic valve implantation: are the trees falling silently or is our hearing impaired? PMID- 24347656 TI - Standardized hyperemic stress for fractional flow reserve. PMID- 24347657 TI - Assessment and impact of the human coronary collateral circulation on myocardial ischemia and outcome. PMID- 24347658 TI - Aortopulmonary fistula after transcatheter pulmonary valve replacement. PMID- 24347661 TI - Changes in geographic variation in the use of percutaneous coronary intervention for stable ischemic heart disease after publication of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial. AB - BACKGROUND: Clinical uncertainty is cited as a cause of geographic variation. However, little is known about the effect of comparative effectiveness research on variation. We examined whether geographic variation in the use of percutaneous coronary intervention (PCI) for stable ischemic heart disease (SIHD) declined after publication of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial. METHODS AND RESULTS: We examined changes in utilization and geographic variation in 67 hospital referral regions using the State Inpatient Databases. We compared age- and sex-adjusted rates of PCI for SIHD before (2006) and after (2008) publication of the COURAGE trial and compared those with contemporaneous changes in PCI volume for acute coronary syndrome. A total of 272,659 PCIs for SIHD from 526 hospitals were included in the analysis. After the publication of the COURAGE trial, PCI volume for SIHD declined by 25% (P<0.001) and decreased by 12% for acute coronary syndrome (P<0.001). This was predominantly attributable to changes in hospital referral regions with the highest levels of utilization pre-COURAGE trial (35% decline in the highest tertile versus 18% in the lowest). As measured by the systematic component of variation, there was substantial geographic variation in the use of PCI for SIHD preceding the publication of the COURAGE trial. Variation declined by 28% (0.53 versus 0.40) after publication, but geographic variation remained higher for SIHD than acute coronary syndrome (0.40 versus 0.17). CONCLUSIONS: There was a substantial decline in the use of and geographic variation in PCI for SIHD after the publication of the COURAGE trial. However, geographic variation in the use of PCI for SIHD remained high. PMID- 24347662 TI - Women in cardiology: introspection into the under-representation. PMID- 24347663 TI - Prognostic value of plasma neutrophil gelatinase-associated lipocalin for mortality in patients with heart failure. AB - BACKGROUND: In patients with heart failure, renal dysfunction is associated with a poor outcome. We aimed to assess the prognostic value of plasma neutrophil gelatinase-associated lipocalin (NGAL), a novel marker of renal tubular damage, in patients with heart failure with or without renal dysfunction, and compare it with 2 frequently used biomarkers of chronic kidney disease. METHODS AND RESULTS: Plasma NGAL, estimated glomerular filtration rate (eGFR), and cystatin C were assessed in 562 patients with heart failure. Chronic kidney disease was defined as eGFR<60 mL/min per 1.73 m2. Outcome was all-cause mortality at 36 months. Mean age was 71+/-11 years, 61% were men, and 97% were in New York Heart Association functional class II/III. Mean baseline eGFR was 54+/-20 mL/min per 1.73 m2, mean cystatin C was 11.2 (7.7-16.2) mg/L, and median plasma NGAL was 85 (60-123) ng/mL. Higher plasma NGAL levels were independently associated with an increased risk of all-cause mortality, in patients with and without chronic kidney disease (hazard ratio [per SD increase in log NGAL]=1.45 [1.22-1.72]; P<0.001 and hazard ratio=1.51 [1.06-2.16]; P=0.023, respectively). Similarly, both in patients with high and low cystatin C (median cut-off), higher plasma NGAL levels were independently associated with an increased risk of all-cause mortality. Moreover, when NGAL was entered in the multivariable risk prediction model, eGFR (P=0.616) and cystatin C (P=0.937) were no longer associated with mortality. CONCLUSIONS: Plasma NGAL predicts mortality in patients with heart failure, both in patients with and without chronic kidney disease and is a stronger predictor for mortality than the established renal function indices eGFR and cystatin C. PMID- 24347664 TI - Left atrial volume and the benefit of cardiac resynchronization therapy in the MADIT-CRT trial. AB - BACKGROUND: Left atrial volume (LAV) is an important marker of heart failure (HF) severity. We hypothesized that LAV independently correlates with clinical outcomes in patients who receive cardiac resynchronization therapy with a defibrillator (CRT-D) and can be used for improved risk assessment in this population. METHODS AND RESULTS: The benefit of CRT-D versus defibrillator-only therapy in reducing the risk of HF or death was assessed by LAV (dichotomized at the upper quartile>52 mL/m2) among 1785 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study. Landmark analysis was used to evaluate the relationship between LAV response to CRT-D and subsequent clinical outcomes. Multivariable analysis showed that patients with a higher baseline LAV experienced 69% (P<0.001) and 59% (P=0.02) increased hazard for HF or death and for all-cause mortality, respectively, independently of baseline left ventricular volume. CRT-D was associated with a significant reduction in LAV compared with defibrillator only therapy (-28% versus -10%, respectively; P<0.001). Landmark analysis showed that after CRT-D implantation each 1% reduction in LAV was independently associated with a corresponding 4% reduction in the hazard of subsequent HF or death (P<0.001). The assessment of LAV change after CRT implantation improved prediction of clinical response to the device compared with assessment of the corresponding changes in left ventricular volume. CONCLUSIONS: LAV is an independent correlate of clinical outcomes in mildly symptomatic HF patients treated with CRT-D. CRT exerts pronounced reverse remodeling effects on the left atrium that independently correlate with improved clinical outcomes after device implantation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271. PMID- 24347665 TI - Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase. AB - RATIONALE: Aortic stiffening commonly occurs in hypertension and further elevates systolic pressure. Hypertension is also associated with vascular inflammation and increased mechanical stretch. The interplay between inflammation, mechanical stretch, and aortic stiffening in hypertension remains undefined. OBJECTIVE: Our aim was to determine the role of inflammation and mechanical stretch in aortic stiffening. METHODS AND RESULTS: Chronic angiotensin II infusion caused marked aortic adventitial collagen deposition, as quantified by Masson trichrome blue staining and biochemically by hydroxyproline content, in wild-type but not in recombination activating gene-1-deficient mice. Aortic compliance, defined by ex vivo measurements of stress-strain curves, was reduced by chronic angiotensin II infusion in wild-type mice (P<0.01) but not in recombination activating gene-1 deficient mice (P<0.05). Adoptive transfer of T-cells to recombination activating gene-1-deficient mice restored aortic collagen deposition and stiffness to values observed in wild-type mice. Mice lacking the T-cell-derived cytokine interleukin 17a were also protected against aortic stiffening. In additional studies, we found that blood pressure normalization by treatment with hydralazine and hydrochlorothiazide prevented angiotensin II-induced vascular T-cell infiltration, aortic stiffening, and collagen deposition. Finally, we found that mechanical stretch induces the expression of collagen 1alpha1, 3alpha1, and 5a1 in cultured aortic fibroblasts in a p38 mitogen-activated protein kinase dependent fashion, and that inhibition of p38 prevented angiotensin II-induced aortic stiffening in vivo. Interleukin 17a also induced collagen 3a1 expression via the activation of p38 mitogen-activated protein kinase. CONCLUSIONS: Our data define a pathway in which inflammation and mechanical stretch lead to vascular inflammation that promotes collagen deposition. The resultant increase in aortic stiffness likely further worsens systolic hypertension and its attendant end organ damage. PMID- 24347666 TI - Racism and Health I: Pathways and Scientific Evidence. AB - This article reviews the scientific research that indicates that despite marked declines in public support for negative racial attitudes in the United States, racism, in its multiple forms, remains embedded in American society. The focus of the article is on the review of empirical research that suggests that racism adversely affects the health of non-dominant racial populations in multiple ways. First, institutional racism developed policies and procedures that have reduced access to housing, neighborhood and educational quality, employment opportunities and other desirable resources in society. Second, cultural racism, at the societal and individual level, negatively affects economic status and health by creating a policy environment hostile to egalitarian policies, triggering negative stereotypes and discrimination that are pathogenic and fostering health damaging psychological responses such as stereotype threat and internalized racism. Finally, a large and growing body of evidence indicates that experiences of racial discrimination are an important type of psychosocial stressor that can lead to adverse changes in health status and altered behavioural patterns that increase health risks. PMID- 24347668 TI - A Note on Comparing the Power of Test Statistics at Low Significance Levels. AB - It is an obvious fact that the power of a test statistic is dependent upon the significance (alpha) level at which the test is performed. It is perhaps a less obvious fact that the relative performance of two statistics in terms of power is also a function of the alpha level. Through numerous personal discussions, we have noted that even some competent statisticians have the mistaken intuition that relative power comparisons at traditional levels such as alpha = 0.05 will be roughly similar to relative power comparisons at very low levels, such as the level alpha = 5 * 10-8, which is commonly used in genome-wide association studies. In this brief note, we demonstrate that this notion is in fact quite wrong, especially with respect to comparing tests with differing degrees of freedom. In fact, at very low alpha levels the cost of additional degrees of freedom is often comparatively low. Thus we recommend that statisticians exercise caution when interpreting the results of power comparison studies which use alpha levels that will not be used in practice. PMID- 24347667 TI - Racism and Health II: A Needed Research Agenda for Effective Interventions. AB - This article reviews the empirical evidence that suggests that there is a solid foundation for more systematic research attention to the ways in which interventions that seek to reduce the multiple dimensions of racism can improve health and reduce disparities in health. First, research reveals that policies and procedures that seek to reduce institutional racism by improving neighborhood and educational quality and enhancing access to additional income, employment opportunities and other desirable resources can improve health. Second, research is reviewed that shows that there is the potential to improve health through interventions that can reduce cultural racism at the societal and individual level. Finally, research is presented that suggests that the adverse consequences of racism on health can be reduced through policies that maximize the health enhancing capacities of medical care, address the social factors that initiate and sustain risk behaviors and empower individuals and communities to take control of their lives and health. Directions for future research are outlined. PMID- 24347669 TI - Parasitoid infestation changes female mating preferences. AB - Females often adjust their mating preference to environmental and social conditions. This plasticity of preference can be adaptive for females and can have important consequences for the evolution of male traits. While predation and parasitism are widespread, their effects on female preferences have rarely been investigated. Females of the cricket Gryllus lineaticeps are parasitized by the parasitoid fly Ormia ochracea. Infestation with fly larvae substantially reduces female life span and thus reproductive opportunities of the cricket. Both female G. lineaticeps and flies orient to male song and both prefer male songs with faster chirp rates to songs with slower chirp rates. We tested the effect of parasitic infestation on female responsiveness to male song and female chirp rate preferences. The proportion of individuals responding to male songs did not differ between infested and control females. Control females preferred intermediate chirp rates to slow chirp rates and did not discriminate between fast and intermediate chirp rates. In contrast, infested females showed no preferences in the choice trials, indicating reduced chirp rate selectivity. This plasticity in female preferences may be adaptive; parasitized females may have a higher probability of reproducing before they are killed by the parasitoids if they are less selective (i.e. there will be a larger pool of males considered acceptable). The change in preferences suggests relaxed selection on male chirp rate during times of parasitism. PMID- 24347670 TI - Well, Now, Okey Dokey: English Discourse Markers in Spanish Language Medical Consultations. AB - The purpose of this paper is to examine use of English discourse markers in otherwise Spanish language consultations. Data is derived from an audio-recorded corpus of Spanish language consultations that took place in a small community clinic in the United States as well as post-consultation interviews with patients and providers. Through quantification of the use of discourse makers in the corpus and discourse analysis of transcripts, we demonstrate that English speaking dominant medical providers use English discourse markers more frequently and with a broader range of functions than do Spanish-speaking dominant medical providers and patients. We argue that such use of English discourse markers serves to exacerbate the power relationship between providers and patients even though the use of English discourse markers does not cause overt miscommunication in the ongoing interaction. Implications for providers who use a second language in their medical consultations are discussed. PMID- 24347671 TI - Nitroxide-Functionalized Graphene Oxide from Graphite Oxide. AB - A facile method for preparing functionalized graphene oxide single layers with nitroxide groups is reported herein. Highly oxidized graphite oxide (GO=90.6%) was obtained, slightly modifying an improved Hummer's method. Oxoammonium salts (OS) were investigated to introduce nitroxide groups to GO, resulting in a one step functionalization and exfoliation. The mechanisms of functionalization/exfoliation are proposed, where the oxidation of aromatic alcohols to ketone groups, and the formation of alkoxyamine species are suggested. Two kinds of functionalized graphene oxide layers (GOFT1 and GOFT2) were obtained by controlling the amount of OS added. GOFT1 and GOFT2 exhibited a high interlayer spacing (d0001 = 1.12nm), which was determined by X-ray diffraction. The presence of new chemical bonds C-N (~9.5 %) and O-O (~4.3 %) from nitroxide attached onto graphene layers were observed by X-ray photoelectron spectroscopy. Single-layers of GOFT1 were observed by HRTEM, exhibiting amorphous and crystalline zones at a 50:50 ratio; in contrast, layers of GOFT2 exhibited a fully amorphous surface. Fingerprint of GOFT1 single layers was obtained by electron diffraction at several tilts. Finally, the potential use of these materials within Nylon 6 matrices was investigated, where an unusual simultaneous increase in tensile stress, tensile strain and Young's modulus was observed. PMID- 24347672 TI - Coaxial electrohydrodynamic atomization process for production of polymeric composite microspheres. AB - Polymeric composite microspheres consisting of a poly(D,L-lactic-co-glycolic acid) (PLGA) core surrounded by a poly(D,L-lactic acid) (PDLLA) shell layer were successfully fabricated by coaxial electrohydrodynamic atomization (CEHDA) process. Process conditions, including nozzle voltage and polymer solution flow rates, as well as solution parameters, such as polymer concentrations, were investigated to ensure the formation of composite microspheres with a doxorubicin loaded PLGA core surrounded by a relatively drug-free PDLLA shell layer. Various microsphere formulations were fabricated and characterized in terms of their drug distribution, encapsulation efficiency and in vitro release. Numerical simulation of CEHDA process was performed based on a computational fluid dynamics (CFD) model in Fluent by employing the process conditions and fluid properties used in the experiments. The simulation results were compared with the experimental work to illustrate the capability of the CFD model to predict the production of consistent compound droplets, and hence, the expected core-shell structured microspheres. PMID- 24347673 TI - Analyses of mineral specific surface area and hydroxyl substitution for intact bone. AB - Bone minerals possess two primary hydrogen sources: hydroxide ions in the nanocrystalline core and structural water in the amorphous surface layer. In order to accurately measure their concentrations using hydrogen to phosphorus cross polarization NMR spectroscopy, it is necessary to analyze the dependence of signal intensities on serial contact times, namely, cross polarization kinetics. A reliable protocol is developed to iteratively decompose the severely overlapped spectra and to analyze the cross-polarization kinetics, leading to measurement of hydroxyl and structural water concentrations. Structural water concentration is used to estimate mineral specific surface area and nanocrystal thickness for intact bone. PMID- 24347674 TI - Identity, Stress, and Resilience in Lesbians, Gay Men, and Bisexuals of Color. AB - The author addresses two issues raised in Moradi, DeBlaere, and Huang's Major Contribution to this issue: the intersection of racial/ethnic and lesbian, gay, and bisexual (LGB) identities and the question of stress and resilience. The author expands on Moradi et al.'s work, hoping to encourage further research. On the intersection of identities, the author notes that LGB identities among people of color have been construed as different from the identities of White LGB persons, purportedly because of an inherent conflict between racial/ethnic and gay identities. The author suggests that contrary to this, LGB people of color can have positive racial/ethnic and LGB identities. On the question of stress and resilience, hypotheses have suggested that compared with White LGB individuals, LGB people of color have both more stress and more resilience. The author addresses the competing hypotheses within the larger perspective of minority stress theory, noting that the study of stress and resilience among LGB people of color is relevant to core questions about social stress as a cause of mental disorders. PMID- 24347675 TI - Deforestation Drivers: Population, Migration, and Tropical Land Use. PMID- 24347676 TI - Resolution Properties of a Prototype Continuous Miniature Crystal Element (cMiCE) Scanner. AB - Continuous miniature crystal element (cMiCE) detectors are a potentially lower cost alternative for high resolution discrete crystal PET detector designs. We report on performance characteristics of a prototype PET scanner consisting of two cMiCE detector modules. Each cMiCE detector is comprised of a 50 * 50 * 8 mm3 LYSO crystal coupled to a 64 channel multi-anode PMT. The cMiCE detectors use a statistics-based positioning method based upon maximum likelihood estimation for event positioning. By this method, cMiCE detectors can also provide some depth of interaction event positioning information. For the prototype scanner, the cMiCE detectors were positioned across from one another on a horizontal gantry with a detector spacing of 10.7 cm. Full tomographic data were collected and reconstructed using single slice rebinning and filtered back projection with no smoothing. The average image resolutions in X (radial), Y (transverse) and Z (axial) were 1.05 +/- 0.08 mm, 0.99 +/- 0.07 mm, 1.24 +/- 0.31 mm FWHM. These initial imaging results from a prototype imaging system demonstrate the outstanding image resolution performance that can be achieved using the potentially lower cost cMiCE detectors. PMID- 24347678 TI - Movement between Mexico and Canada: Analysis of a New Migration Stream. AB - In this analysis we use data from the Mexican Migration Project to contrast processes of Mexican migration to Canada and the United States. All migrants to Canada entered through the Seasonal Agricultural Worker Program and consistent with program criteria, migration there is strongly predicted by marital status and number of dependents, yielding a migrant population that is made up of males of prime labor-force age who are married and have multiple children at home. In contrast, the vast majority of migrants to the United States are undocumented and thus self-selected without regard to marital status or parenthood. Migration to the United States is strongly predicted by age, and migration probabilities display the age curve classically associated with labor migration. Within countries of destination, migrants to Canada enjoy superior labor market outcomes compared with those to the United States, with higher wages and more compact work schedules that yield higher earnings and shorter periods away from families compared with undocumented migrants to the United States. Labor migration to Canada also tends to operate as a circular flow with considerable repeat migration whereas undocumented migrants to the United States do not come and go so regularly, as crossing the Mexico-U.S. border has become increasingly difficult and costly. PMID- 24347677 TI - Finding Optimized Conditions of Slit-Slat and Multislit-Slat Collimation for Breast Imaging. AB - In order to develop a breast-imaging system for Single Photon Emission Computed Tomography (SPECT) using slit-slat and multislit-slat collimators, we searched for optimized geometric parameters of the collimators. For this study, we employed two independent metrics to validate each result: 1) Signal to Noise Ratio (SNR) based on the Cramer-Rao lower Bound (CRB) and 2) contrast at the same noise level from an ensemble. We calculated SNR values using forward-projection data of an anthropomorphic digital phantom containing two lesions in the breast (one at the chest wall and the other at the center) with a simulated slit-slat collimator as a function of the collimator's geometric parameters. We also calculated contrast values from reconstructed images with noise. Based on the results from the slit-slat case, we investigated angular range, SNR, and contrast for the multislit-slat. We saw similar trends of the two metrics. One interesting property of the multislit-slat is that the imaging performance depends on the orientation of the field of view (FOV) of the side slits. When we compared the metric values for the slit-slat and multislit-slat, improvement was seen only when the lesion was in the FOV of the side slits. Therefore, tuning the parameters of the multislit-slat to optimally detect lesions at the chest wall might be a sensible option since the slit-slat already provides good image quality for center and superficial lesions. PMID- 24347679 TI - Narrative versus Non-narrative: The Role of Identification, Transportation and Emotion in Reducing Health Disparities. AB - This research empirically tests whether using a fictional narrative produces a greater impact on health-related knowledge, attitudes, and behavioral intention than presenting the identical information in a more traditional, nonfiction, non narrative format. European American, Mexican American, and African American women (N = 758) were surveyed before and after viewing either a narrative or non narrative cervical cancer-related film. The narrative was more effective in increasing cervical cancer-related knowledge and attitudes. Moreover, in response to the narrative featuring Latinas, Mexican Americans were most transported, identified most with the characters, and experienced the strongest emotions. Regressions revealed that transportation, identification with specific characters, and emotion each contributed to shifts in knowledge, attitudes, and behavioral intentions. Thus, narrative formats may provide a valuable tool in reducing health disparities. PMID- 24347681 TI - Locomotion concerns with moral usefulness: When liberals endorse binding moral foundations. AB - Moral Foundations Theory has provided a framework for understanding the endorsement of different moral beliefs. Our research investigated whether there are other reasons to endorse moral foundations in addition to epistemic concerns; specifically, the perceived social usefulness of moral foundations. In Study 1, we demonstrate that those showing stronger locomotion concerns for controlling movement tend toward a higher endorsement of binding foundations, and that this effect is stronger among political liberals who otherwise do not typically endorse these foundations. In Study 2, we show that priming participants with assessment concerns (emphasizing truth) rather than locomotion concerns (emphasizing control) reduces the response variance among liberals and also removes the association between locomotion and the binding foundations. In Study 3, we directly ask participants to focus on moral truth versus moral usefulness, with moral truth replicating the Study 2 effect of assessment priming, and moral usefulness replicating the effect of locomotion priming. PMID- 24347680 TI - A Bidirectional Coupling Procedure Applied to Multiscale Respiratory Modeling. AB - In this study, we present a novel multiscale computational framework for efficiently linking multiple lower-dimensional models describing the distal lung mechanics to imaging-based 3D computational fluid dynamics (CFD) models of the upper pulmonary airways in order to incorporate physiologically appropriate outlet boundary conditions. The framework is an extension of the Modified Newton's Method with nonlinear Krylov accelerator developed by Carlson and Miller [1, 2, 3]. Our extensions include the retention of subspace information over multiple timesteps, and a special correction at the end of a timestep that allows for corrections to be accepted with verified low residual with as little as a single residual evaluation per timestep on average. In the case of a single residual evaluation per timestep, the method has zero additional computational cost compared to uncoupled or unidirectionally coupled simulations. We expect these enhancements to be generally applicable to other multiscale coupling applications where timestepping occurs. In addition we have developed a "pressure drop" residual which allows for stable coupling of flows between a 3D incompressible CFD application and another (lower-dimensional) fluid system. We expect this residual to also be useful for coupling non-respiratory incompressible fluid applications, such as multiscale simulations involving blood flow. The lower-dimensional models that are considered in this study are sets of simple ordinary differential equations (ODEs) representing the compliant mechanics of symmetric human pulmonary airway trees. To validate the method, we compare the predictions of hybrid CFD-ODE models against an ODE-only model of pulmonary airflow in an idealized geometry. Subsequently, we couple multiple sets of ODEs describing the distal lung to an imaging-based human lung geometry. Boundary conditions in these models consist of atmospheric pressure at the mouth and intrapleural pressure applied to the multiple sets of ODEs. In both the simplified geometry and in the imaging-based geometry, the performance of the method was comparable to that of monolithic schemes, in most cases requiring only a single CFD evaluation per time step. Thus, this new accelerator allows us to begin combining pulmonary CFD models with lower-dimensional models of pulmonary mechanics with little computational overhead. Moreover, because the CFD and lower dimensional models are totally separate, this framework affords great flexibility in terms of the type and breadth of the adopted lower-dimensional model, allowing the biomedical researcher to appropriately focus on model design. Research funded by the National Heart and Blood Institute Award 1RO1HL073598. PMID- 24347682 TI - Gender Differences in Cognition among Older Adults in China. AB - In this paper, we model gender differences in cognitive ability in China using a new sample of middle-aged and older Chinese respondents. Modeled after the American Health and Retirement Study (HRS), the CHARLS Pilot survey respondents are 45 years and older in two quite distinct provinces-Zhejiang, a high-growth industrialized province on the East Coast, and Gansu, a largely agricultural and poor province in the West-in a sense new and old China. Our cognition measures proxy for two different dimensions of adult cognition-episodic memory and intact mental status. On both measures, Chinese women score much lower than do Chinese men, a gender difference that grows among older Chinese cohorts. We relate both these cognition scores to schooling, urban residence, family and community levels of economic resources, and height. We find that cognition is more closely related to mean community resources than to family resources, especially for women, suggesting that in traditional poor Chinese communities there are strong economic incentives to favor boys at the expense of girls. We also find that these gender differences in cognitive ability have been steadily decreasing across birth cohorts as the economy of China grew rapidly. Among cohorts of young adults in China, there is no longer any gender disparity in cognitive ability. This parallels the situation in the United States where cognition scores of adult women actually exceed those of adult men. PMID- 24347684 TI - Self-Healing of Unentangled Polymer Networks with Reversible Bonds. AB - Self-healing polymeric materials are systems that after damage can revert to their original state with full or partial recovery of mechanical strength. Using scaling theory we study a simple model of autonomic self-healing of unentangled polymer networks. In this model one of the two end monomers of each polymer chain is fixed in space mimicking dangling chains attachment to a polymer network, while the sticky monomer at the other end of each chain can form pairwise reversible bond with the sticky end of another chain. We study the reaction kinetics of reversible bonds in this simple model and analyze the different stages in the self-repair process. The formation of bridges and the recovery of the material strength across the fractured interface during the healing period occur appreciably faster after shorter waiting time, during which the fractured surfaces are kept apart. We observe the slowest formation of bridges for self adhesion after bringing into contact two bare surfaces with equilibrium (very low) density of open stickers in comparison with self-healing. The primary role of anomalous diffusion in material self-repair for short waiting times is established, while at long waiting times the recovery of bonds across fractured interface is due to hopping diffusion of stickers between different bonded partners. Acceleration in bridge formation for self-healing compared to self adhesion is due to excess non-equilibrium concentration of open stickers. Full recovery of reversible bonds across fractured interface (formation of bridges) occurs after appreciably longer time than the equilibration time of the concentration of reversible bonds in the bulk. PMID- 24347683 TI - Repeated Cocaine Experience Facilitates Sucrose-Reinforced Operant Responding in Enriched and Isolated Rats. AB - The purpose of the present experiment was to determine whether repeated cocaine exposure differentially affects sucrose-reinforced operant responding in rats raised in an enriched condition (EC) or an isolated condition (IC). Specifically, the performance of EC and IC rats pressing a lever for sucrose under a high fixed ratio schedule (FR 30) prior to and after 10 days of exposure to cocaine (15 mg/kg, i.p.) or saline was compared. Regardless of rearing condition, rats repeatedly exposed to cocaine had shorter reacquisition latencies to complete a sucrose-reinforced FR 30 task than saline controls. The results suggest that cocaine exposure may have cross-sensitized both EC and IC rats to the reinforcing effects of sucrose or sucrose-associated cues, thus facilitating reacquisition of operant responding. PMID- 24347685 TI - Is DNA a Good Model Polymer? AB - The details surrounding the cross-over from wormlike-specific to universal polymeric behavior has been the subject of debate and confusion even for the simple case of a dilute, unconfined wormlike chain. We have directly computed the polymer size, form factor, free energy and Kirkwood diffusivity for unconfined wormlike chains as a function of molecular weight, focusing on persistence lengths and effective widths that represent single-stranded and double-stranded DNA in a high ionic strength buffer. To do so, we use a chain-growth Monte Carlo algorithm, the Pruned-Enriched Rosenbluth Method (PERM), which allows us to estimate equilibrium and near-equilibrium dynamic properties of wormlike chains over an extremely large range of contour lengths. From our calculations, we find that very large DNA chains (~ 1,000,000 base pairs depending on the choice of size metric) are required to reach flexible, swollen non-draining coils. Furthermore, our results indicate that the commonly used model polymer lambda-DNA (48,500 base pairs) does not exhibit "ideal" scaling, but exists in the middle of the transition to long-chain behavior. We subsequently conclude that typical DNA used in experiments are too short to serve as an accurate model of long-chain, universal polymer behavior. PMID- 24347686 TI - Architecture-Induced Size Asymmetry and Effective Interactions of Ring Polymers: Simulation and Theory. AB - We investigate, by means of Monte Carlo simulations, the role of ring architecture and topology on the relative sizes of two interacting polymers as a function of the distance between their centers-of-mass. As a general rule, polymers swell as they approach each other, irrespectively of their topologies. For each mutual separation, two identical linear polymers adopt the same average size. However, unknotted rings at close separations adopt different sizes, with the small one being "nested" within the large one over long time intervals, exchanging their roles in the course of the simulation. For two rings of different architectures and identical polymerization degree, the knotted one is always smaller, penetrating the unknotted one. On the basis of these observations, we propose a phenomenological theory for the effective interactions between rings, modeling them as unequal-sized penetrable spheres. This simple approximation provides a good description of the simulation results. In particular, it rationalizes the non-Gaussian shape and the short-distance plateau observed in the effective potential between unknotted ring polymers and pairs of unequal-sized unknotted/knotted ones. Our results demonstrate the crucial role of the architecture on both the effective interactions and the molecular size for strongly interpenetrating polymers. PMID- 24347689 TI - A Combined Multiple-SLED Broadband Light Source at 1300 nm for High Resolution Optical Coherence Tomography. AB - We demonstrate a compact, inexpensive, and reliable fiber-coupled light source with broad bandwidth and sufficient power at 1300 nm for high resolution optical coherence tomography (OCT) imaging in real-time applications. By combining four superluminescent diodes (SLEDs) with different central wavelengths, the light source has a bandwidth of 145 nm centered at 1325 nm with over 10 mW of power. OCT images of an excised stage 30 embryonic chick heart acquired with our combined SLED light source (<5 MUm axial resolution in tissue) are compared with images obtained with a single SLED source (~10 MUm axial resolution in tissue). The high resolution OCT system with the combined SLED light source provides better image quality (smaller speckle noise) and a greater ability to observe fine structures in the embryonic heart. PMID- 24347690 TI - Of Elections and Emeritus Memberships. PMID- 24347691 TI - Enhanced Religiosity Following Illness? Assessing Evidence of Religious Consolation Among Black and White Americans. AB - This study assesses variation among Black and White Americans in the impact of ill-health on public and subjective religiosity. It is the first longitudinal assessment of race-based variation in "religious consolation." The under-explored consolation thesis anticipates ill-health influencing religiosity rather than the reverse, with religiosity functioning as a coping resource marshaled by the ill. Effects across races of physical ill-health indicators (chronic illnesses and impaired functioning) on religiosity outcomes are the main focus; but across-race variation in psychological distress-induced "consolation" is also assessed. Findings yield only limited evidence of consolation in each race, and restricted variation across races: Change in impaired functioning slightly enhances Whites' subjective religiosity; but that effect does not significantly eclipse the impact among Blacks. There is no evidence of physical illness-induced consolation among Blacks; and the proposition that Blacks are more inclined toward consolation than Whites is affirmed only for psychological distress. There are no signs in either race that consolation is intensified by aging or higher religiosity, and no significant across-race differentials in effects of these illness-age and illness religiosity interactions on subsequent religiosity. The multi-population model utilizes Americans' Changing Lives data. PMID- 24347692 TI - CmlI is an N-oxygenase in the biosynthesis of chloramphenicol. AB - The N-oxygenation of an amine group is one of the steps in the biosynthesis of the antibiotic chloramphenicol. The non-heme di-iron enzyme CmlI was identified as the enzyme catalyzing this reaction through bioinformatics studies and reconstitution of enzymatic activity. In vitro reconstitution was achieved using phenazine methosulfate and NADH as electron mediators, while in vivo activity was demonstrated in Escherichia coli using two substrates. Kinetic analysis showed a biphasic behavior of the enzyme. Oxidized hydroxylamine and nitroso compounds in the reaction were detected both in vitro and in vivo based on LC-MS. The active site metal was confirmed to be iron based on a ferrozine assay. These findings provide new insights into the biosynthesis of chloramphenicol and could lead to further development of CmlI as a useful biocatalyst. PMID- 24347693 TI - (1-bromovinyl)-MIDA boronate: a readily accessible and highly versatile building block for small molecule synthesis. PMID- 24347694 TI - Iterative Reducible Ligation to form Homogeneous Penicillamine Cross-linked Polypeptides. AB - The syntheses of homogeneous penicillamine disulfide cross-linked polypeptides are reported. Dodecapeptides containing N-terminal, C-terminal, or N- and C terminal Pen were serially ligated into 36 amino acid polypeptides linked through Cys-Pen, Pen-Cys or Pen-Pen disulfide bonds. Critical to the syntheses was the incorporation of thiazolidine masked Cys and Pen as the N-terminal residues and selective hydrolysis with silver trifluoromethanesulfonate in acidic aqueous conditions to generate a free thiol for subsequent ligation. This approach allows the synthesis of homogeneous disulfide cross-linked polypeptides that have different reductive stabilities and have application in gene delivery by undergoing a tempered reductive triggered release of DNA. PMID- 24347695 TI - Three-step synthesis of an annulated beta-carboline via palladium catalysis. AB - The synthesis of beta-carbolines is a mature field, yet new methods are desirable to introduce new functionality onto the core scaffold. We describe the incorporation of an additional fused ring onto the beta-carboline via a novel palladium-catalyzed, one-pot Sonogashira coupling/intramolecular [2+2+2] cyclization. This method generates three rings in one flask and produces an annulated beta-carboline in 80% yield. A preliminary mechanistic study into the sequence of events is described, which confirms an unprecedented catalytic role for palladium. PMID- 24347697 TI - Human resources for universal health coverage: from evidence to policy and action. PMID- 24347698 TI - Investing in human resources for health: the need for a paradigm shift. PMID- 24347700 TI - Beyond clinical skills: key capacities needed for universal health coverage. PMID- 24347699 TI - Human resources for universal health coverage: leadership needed. PMID- 24347702 TI - More midwives needed to improve maternal and newborn survival. AB - Retention of midwives, especially in rural areas, is a major challenge for many countries, one that threatens to negate all the hard work and resources invested in their training. Priya Shetty reports. PMID- 24347703 TI - Funding, flexible management needed for Brazil's health worker gaps. Interview by Claudia Jurberg. AB - Last month the first Cuban physicians arrived in Brazil under a new government programme to work in underserved parts of the country, both rural and urban. Francisco Eduardo de Campos tells Claudia Jurberg why the Mais Medicos (More Physicians) programme is necessary. PMID- 24347704 TI - Health worker remuneration in WHO Member States. AB - OBJECTIVE: To present the available data on the money spent by Member States of the World Health Organization (WHO) on remunerating health workers in the public and private sectors. METHODS: Data on government and total expenditure on health worker remuneration were obtained through a review of official documents in WHO's Global Health Expenditure Database and directly from country officials and country official web sites. Such data are presented in this paper, by World Bank country income groups, in millions of national currency units per calendar year for salaried and non-salaried health workers. They are presented as a share of gross domestic product (GDP), total health expenditure and general government health expenditure. The average yearly change in remuneration (i.e. compound annual growth rate) between 2000 and 2012 as a function of these parameters was also assessed. FINDINGS: On average, payments to health workers of all types accounted for more than one third of total health expenditure across countries. Such payments have grown faster than countries' GDPs but less rapidly than total health expenditure and general government health expenditure. Remuneration of health workers, on the other hand, has grown faster than that of other types of workers. CONCLUSION: As they seek to attain universal health coverage (UHC), countries will need to devote an increasing proportion of their GDPs to health and health worker remuneration. However, the fraction of total health expenditure devoted to paying health workers seems to be declining, partly because the pursuit of UHC calls for strengthening the health system as a whole. PMID- 24347705 TI - Monitoring the implementation of the WHO Global Code of Practice on the International Recruitment of Health Personnel. AB - OBJECTIVE: To present the findings of the first round of monitoring of the global implementation of the WHO Global Code of Practice on the International Recruitment of Health Personnel ("the Code"), a voluntary code adopted in 2010 by all 193 Member States of the World Health Organization (WHO). METHODS: WHO requested that its Member States designate a national authority for facilitating information exchange on health personnel migration and the implementation of the Code. Each designated authority was then sent a cross-sectional survey with 15 questions on a range of topics pertaining to the 10 articles included in the Code. FINDINGS: A national authority was designated by 85 countries. Only 56 countries reported on the status of Code implementation. Of these, 37 had taken steps towards implementing the Code, primarily by engaging relevant stakeholders. In 90% of countries, migrant health professionals reportedly enjoy the same legal rights and responsibilities as domestically trained health personnel. In the context of the Code, cooperation in the area of health workforce development goes beyond migration-related issues. An international comparative information base on health workforce mobility is needed but can only be developed through a collaborative, multi-partnered approach. CONCLUSION: Reporting on the implementation of the Code has been suboptimal in all but one WHO region. Greater collaboration among state and non-state actors is needed to raise awareness of the Code and reinforce its relevance as a potent framework for policy dialogue on ways to address the health workforce crisis. PMID- 24347706 TI - Quality of care provided by mid-level health workers: systematic review and meta analysis. AB - OBJECTIVE: To assess the effectiveness of care provided by mid-level health workers. METHODS: Experimental and observational studies comparing mid-level health workers and higher level health workers were identified by a systematic review of the scientific literature. The quality of the evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria and data were analysed using Review Manager. FINDINGS: Fifty-three studies, mostly from high-income countries and conducted at tertiary care facilities, were identified. In general, there was no difference between the effectiveness of care provided by mid-level health workers in the areas of maternal and child health and communicable and noncommunicable diseases and that provided by higher level health workers. However, the rates of episiotomy and analgesia use were significantly lower in women giving birth who received care from midwives alone than in those who received care from doctors working in teams with midwives, and women were significantly more satisfied with care from midwives. Overall, the quality of the evidence was low or very low. The search also identified six observational studies, all from Africa, that compared care from clinical officers, surgical technicians or non-physician clinicians with care from doctors. Outcomes were generally similar. CONCLUSION: No difference between the effectiveness of care provided by mid-level health workers and that provided by higher level health workers was found. However, the quality of the evidence was low. There is a need for studies with a high methodological quality, particularly in Africa - the region with the greatest shortage of health workers. PMID- 24347707 TI - Early implementation of WHO recommendations for the retention of health workers in remote and rural areas. AB - The maldistribution of health workers between urban and rural areas is a policy concern in virtually all countries. It prevents equitable access to health services, can contribute to increased health-care costs and underutilization of health professional skills in urban areas, and is a barrier to universal health coverage. To address this long-standing concern, the World Health Organization (WHO) has issued global recommendations to improve the rural recruitment and retention of the health workforce. This paper presents experiences with local and regional adaptation and adoption of WHO recommendations. It highlights challenges and lessons learnt in implementation in two countries - the Lao People's Democratic Republic and South Africa - and provides a broader perspective in two regions - Asia and Europe. At country level, the use of the recommendations facilitated a more structured and focused policy dialogue, which resulted in the development and adoption of more relevant and evidence-based policies. At regional level, the recommendations sparked a more sustained effort for cross country policy assessment and joint learning. There is a need for impact assessment and evaluation that focus on the links between the rural availability of health workers and universal health coverage. The effects of any health financing reforms on incentive structures for health workers will also have to be assessed if the central role of more equitably distributed health workers in achieving universal health coverage is to be supported. PMID- 24347708 TI - Why do health labour market forces matter? AB - Human resources for health have been recognized as essential to the development of responsive and effective health systems. Low- and middle-income countries seeking to achieve universal health coverage face human resource constraints - whether in the form of health worker shortages, maldistribution of workers or poor worker performance - that seriously undermine their ability to achieve well functioning health systems. Although much has been written about the human resource crisis in the health sector, labour economic frameworks have seldom been applied to analyse the situation and little is known or understood about the operation of labour markets in low- and middle-income countries. Traditional approaches to addressing human resource constraints have focused on workforce planning: estimating health workforce requirements based on a country's epidemiological and demographic profile and scaling up education and training capacities to narrow the gap between the "needed" number of health workers and the existing number. However, this approach neglects other important factors that influence human resource capacity, including labour market dynamics and the behavioural responses and preferences of the health workers themselves. This paper describes how labour market analysis can contribute to a better understanding of the factors behind human resource constraints in the health sector and to a more effective design of policies and interventions to address them. The premise is that a better understanding of the impact of health policies on health labour markets, and subsequently on the employment conditions of health workers, would be helpful in identifying an effective strategy towards the progressive attainment of universal health coverage. PMID- 24347709 TI - Community health workers for universal health-care coverage: from fragmentation to synergy. AB - To achieve universal health coverage, health systems will have to reach into every community, including the poorest and hardest to access. Since Alma-Ata, inconsistent support of community health workers (CHWs) and failure to integrate them into the health system have impeded full realization of their potential contribution in the context of primary health care. Scaling up and maintaining CHW programmes is fraught with a host of challenges: poor planning; multiple competing actors with little coordination; fragmented, disease-specific training; donor-driven management and funding; tenuous linkage with the health system; poor coordination, supervision and support, and under-recognition of CHWs' contribution. The current drive towards universal health coverage (UHC) presents an opportunity to enhance people's access to health services and their trust, demand and use of such services through CHWs. For their potential to be fully realized, however, CHWs will need to be better integrated into national health care systems in terms of employment, supervision, support and career development. Partners at the global, national and district levels will have to harmonize and synchronize their engagement in CHW support while maintaining enough flexibility for programmes to innovate and respond to local needs. Strong leadership from the public sector will be needed to facilitate alignment with national policy frameworks and country-led coordination and to achieve synergies and accountability, universal coverage and sustainability. In moving towards UHC, much can be gained by investing in building CHWs' skills and supporting them as valued members of the health team. Stand-alone investments in CHWs are no shortcut to progress. PMID- 24347710 TI - Human resources for health and universal health coverage: fostering equity and effective coverage. AB - Achieving universal health coverage (UHC) involves distributing resources, especially human resources for health (HRH), to match population needs. This paper explores the policy lessons on HRH from four countries that have achieved sustained improvements in UHC: Brazil, Ghana, Mexico and Thailand. Its purpose is to inform global policy and financial commitments on HRH in support of UHC. The paper reports on country experiences using an analytical framework that examines effective coverage in relation to the availability, accessibility, acceptability and quality (AAAQ) of HRH. The AAAQ dimensions make it possible to perform tracing analysis on HRH policy actions since 1990 in the four countries of interest in relation to national trends in workforce numbers and population mortality rates. The findings inform key principles for evidence-based decision making on HRH in support of UHC. First, HRH are critical to the expansion of health service coverage and the package of benefits; second, HRH strategies in each of the AAAQ dimensions collectively support achievements in effective coverage; and third, success is achieved through partnerships involving health and non-health actors. Facing the unprecedented health and development challenges that affect all countries and transforming HRH evidence into policy and practice must be at the heart of UHC and the post-2015 development agenda. It is a political imperative requiring national commitment and leadership to maximize the impact of available financial and human resources, and improve healthy life expectancy, with the recognition that improvements in health care are enabled by a health workforce that is fit for purpose. PMID- 24347711 TI - Strengthening human resources for health through multisectoral approaches and leadership: the case of Cameroon. AB - PROBLEM: Cameroon has a severe shortage of human resources for health (HRH) and those that are available are concentrated in urban areas. APPROACH: As the result of a national emergency plan for the years 2006-2008, innovative strategies and a multisectoral partnership - led by the Ministry of Public Health and supported by diverse national and international organizations - were developed to address the shortages and maldistribution of HRH in Cameroon. LOCAL SETTING: At the time that the emergency plan was developed, Cameroon had health services of poor quality, an imbalance between HRH training and employment, a maldistribution of HRH between urban and rural areas and a poor allocation of financial resources for HRH. It also lacked an accreditation system for use in the training of health workers. RELEVANT CHANGES: Between 2007 and 2009, the number of active health workers in Cameroon increased by 36%, several new institutions for higher education in health care and training schools for paramedical staff and midwives were opened, and a national strategy for universal health coverage was developed. LESSONS LEARNT: In the improvement of HRH, strong leadership is needed to ensure effective coordination and communication between the many different stakeholders. A national process of coordination and facilitation can produce a consensus-based view of the main HRH challenges. Once these challenges have been identified, the stakeholders can plan appropriate interventions that are coordinated, evidence based and coherent. PMID- 24347712 TI - Strengthening human resources for health through information, coordination and accountability mechanisms: the case of the Sudan. AB - PROBLEM: Human resources for health (HRH) in the Sudan were limited by shortages and the maldistribution of health workers, poor management, service fragmentation, poor retention of health workers in rural areas, and a weak health information system. APPROACH: A "country coordination and facilitation" process was implemented to strengthen the national HRH observatory, provide a coordination platform for key stakeholders, catalyse policy support and HRH planning, harmonize the mobilization of resources, strengthen HRH managerial structures, establish new training institutions and scale up the training of community health workers. LOCAL SETTING: The national government of the Sudan sanctioned state-level governance of the health system but many states lacked coherent HRH plans and policies. A paucity of training institutions constrained HRH production and the adequate and equitable deployment of health workers in rural areas. RELEVANT CHANGES: The country coordination and facilitation process prompted the establishment of a robust HRH information system and the development of the technical capacities and tools necessary for data analysis and evidence based participatory decision-making and action. LESSONS LEARNT: The success of the country coordination and facilitation process was substantiated by the stakeholders' coordinated support, which was built on solid evidence of the challenges in HRH and shared accountability in the planning and implementation of responses to those challenges. The support led to political commitment and the mobilization of resources for HRH. The leadership that was promoted and the educational institutions that were opened should facilitate the training, deployment and retention of the health workers needed to achieve universal health coverage. PMID- 24347713 TI - Health workforce contributions to health system development: a platform for universal health coverage. AB - PROBLEM: In the 1970s, Thailand was a low-income country with poor health indicators and low health service coverage. The local health infrastructure was especially weak. APPROACH: In the 1980s, measures were initiated to reduce geographical barriers to health service access, improve the health infrastructure at the district level, make essential medicines more widely available and develop a competent, committed health workforce willing to service rural areas. To ensure service accessibility, financial risk protection schemes were expanded. LOCAL SETTING: In Thailand, district hospitals were practically non-existent in the 1960s. Expansion of primary health care (PHC), especially in poor rural areas, was considered essential for attaining universal health coverage (UHC). Nationwide reforms led to important changes in a few decades. RELEVANT CHANGES: Over the past 30 years, the availability and distribution of health workers, as well as their skills and competencies, have greatly improved, along with national health indicators. Between 1980 and 2000 coverage with maternal and child health services increased substantially. By 2002, Thailand had attained UHC. Overall health system development, particularly an expanded health workforce, resulted in a functioning PHC system. LESSONS LEARNT: A competent, committed health workforce helped strengthen the PHC system at the district level. Keeping the policy focus on the development of human resources for health (HRH) for an extended period was essential, together with a holistic approach to the development of HRH, characterized by the integration of different kinds of HRH interventions and the linking of these interventions with broader efforts to strengthen other health system domains. PMID- 24347715 TI - Health workforce indicators: let's get real. PMID- 24347714 TI - Tackling health workforce challenges to universal health coverage: setting targets and measuring progress. AB - Human resources for health (HRH) will have to be strengthened if universal health coverage (UHC) is to be achieved. Existing health workforce benchmarks focus exclusively on the density of physicians, nurses and midwives and were developed with the objective of attaining relatively high coverage of skilled birth attendance and other essential health services of relevance to the health Millennium Development Goals (MDGs). However, the attainment of UHC will depend not only on the availability of adequate numbers of health workers, but also on the distribution, quality and performance of the available health workforce. In addition, as noncommunicable diseases grow in relative importance, the inputs required from health workers are changing. New, broader health-workforce benchmarks - and a corresponding monitoring framework - therefore need to be developed and included in the agenda for UHC to catalyse attention and investment in this critical area of health systems. The new benchmarks need to reflect the more diverse composition of the health workforce and the participation of community health workers and mid-level health workers, and they must capture the multifaceted nature and complexities of HRH development, including equity in accessibility, sex composition and quality. PMID- 24347716 TI - Towards universal health coverage: a health workforce fit for purpose and practice. PMID- 24347717 TI - Health workforce benchmarks for universal health coverage and sustainable development. PMID- 24347718 TI - Empowering patients and strengthening communities for real health workforce and funding targets. PMID- 24347719 TI - Leveraging information technology to bridge the health workforce gap. PMID- 24347720 TI - A comprehensive health labour market framework for universal health coverage. PMID- 24347721 TI - Can human resources for health in the context of noncommunicable disease control be a lever for health system changes? PMID- 24347725 TI - Public health management of mass gatherings: the Saudi Arabian experience with MERS-CoV. PMID- 24347724 TI - Knowledge is power; information is liberation. PMID- 24347727 TI - Push for palliative care stokes debate. AB - With the ageing of populations and a heavy burden of noncommunicable diseases around the world, there is a high but unmet demand for palliative care in many countries. Gary Humphreys reports. PMID- 24347728 TI - The joy of facts and figures by Fiona Fleck. AB - Hans Rosling tells Fiona Fleck why it's easy to make health statistics interesting but difficult to persuade people to accept a fact-based view of the world. PMID- 24347729 TI - Frequent exposure to suboptimal temperatures in vaccine cold-chain system in India: results of temperature monitoring in 10 states. AB - OBJECTIVE: To estimate the proportion of time the vaccines in the cold-chain system in India are exposed to temperatures of < 0 or > 8 degrees C. METHODS: In each of 10 states, the largest district and the one most distant from the state capital were selected for study. Four boxes, each containing an electronic temperature recorder and two vials of diphtheria, pertussis and tetanus vaccine, were placed in the state or regional vaccine store for each study state. Two of these boxes were then shipped - one per facility - towards the two most peripheral health facilities where vaccine was stored in each study district. The boxes were shipped, handled and stored as if they were routine vaccine supplies. FINDINGS: In state, regional and district vaccine stores and peripheral health facilities, respectively, the temperatures in the boxes exceeded 8 degrees C for 14.3%, 13.2%, 8.3% and 14.7% of their combined storage times and fell below 0 degrees C for 1.5%, 0.2%, 0.6% and 10.5% of these times. The boxes also spent about 18% and 7% of their combined times in transit at < 0 and > 8 degrees C, respectively. In shake tests conducted at the end of the study, two thirds of the vaccine vials in the boxes showed evidence of freezing. CONCLUSION: While exposure to temperatures above 8 degrees C occurred at every level of vaccine storage, exposure to subzero temperatures was only frequent during vaccine storage at peripheral facilities and vaccine transportation. Systematic efforts are needed to improve temperature monitoring in the cold-chain system in India. PMID- 24347730 TI - Trends in caesarean delivery by country and wealth quintile: cross-sectional surveys in southern Asia and sub-Saharan Africa. AB - OBJECTIVE: To examine temporal trends in caesarean delivery rates in southern Asia and sub-Saharan Africa, by country and wealth quintile. METHODS: Cross sectional data were extracted from the results of 80 Demographic and Health Surveys conducted in 26 countries in southern Asia or sub-Saharan Africa. Caesarean delivery rates were evaluated - as percentages of the deliveries that ended in live births - for each wealth quintile in each survey. The annual rates recorded for each country were then compared to see if they had increased over time. FINDINGS: Caesarean delivery rates had risen over time in all but 6 study countries but were consistently found to be lower than 5% in 18 of the countries and 10% or less in the other eight countries. Among the poorest 20% of the population, caesarean sections accounted for less than 1% and less than 2% of deliveries in 12 and 21 of the study countries, respectively. In each of 11 countries, the caesarean delivery rate in the poorest 40% of the population remained under 1%. In Chad, Ethiopia, Guinea, Madagascar, Mali, Mozambique, Niger and Nigeria, the rate remained under 1% in the poorest 80%. Compared with the 22 African study countries, the four study countries in southern Asia experienced a much greater rise in their caesarean delivery rates over time. However, the rates recorded among the poorest quintile in each of these countries consistently fell below 2%. CONCLUSION: Caesarean delivery rates among large sections of the population in sub-Saharan Africa are very low, probably because of poor access to such surgery. PMID- 24347731 TI - Monitoring service delivery for universal health coverage: the Service Availability and Readiness Assessment. AB - OBJECTIVE: To describe the Service Availability and Readiness Assessment (SARA) and the results of its implementation in six countries across three continents. METHODS: The SARA is a comprehensive approach for assessing and monitoring health service availability and the readiness of facilities to deliver health-care interventions, with a standardized set of indicators that cover all main programmes. Standardized data-collection instruments are used to gather information on a defined set of selected tracer items from public and private health facilities through a facility sample survey or census. Results from assessments in six countries are shown. FINDINGS: The results highlight important gaps in service delivery that are obstacles to universal access to health services. Considerable variation was found within and across countries in the distribution of health facility infrastructure and workforce and in the types of services offered. Weaknesses in laboratory diagnostic capacities and gaps in essential medicines and commodities were common across all countries. CONCLUSION: The SARA fills an important information gap in monitoring health system performance and universal health coverage by providing objective and regular information on all major health programmes that feeds into country planning cycles. PMID- 24347732 TI - Management of children exposed to Mycobacterium tuberculosis: a public health evaluation in West Java, Indonesia. AB - OBJECTIVE: To investigate qualitatively and quantitatively the performance of a programme for managing the child contacts of adult tuberculosis patients in Indonesia. METHODS: A public health evaluation framework was used to assess gaps in a child contact management programme at a lung clinic. Targets for programme performance indicators were derived from established programme indicator targets, the scientific literature and expert opinion. Compliance with tuberculosis screening, the initiation of isoniazid preventive therapy in children younger than 5 years, the accuracy of tuberculosis diagnosis and adherence to preventive therapy were assessed in 755 child contacts in two cohorts. In addition, 22 primary caregivers and 34 clinic staff were interviewed to evaluate knowledge and acceptance of child contact management. The cost to caregivers was recorded. Gaps between observed and target indicator values were quantified. FINDINGS: THE GAPS BETWEEN OBSERVED AND TARGET PERFORMANCE INDICATORS WERE: 82% for screening compliance; 64 to 100% for diagnostic accuracy, 50% for the initiation of preventive therapy, 54% for adherence to therapy and 50% for costs. Many staff did not have adequate knowledge of, or an appropriate attitude towards, child contact management, especially regarding isoniazid preventive therapy. Caregivers had good knowledge of screening but not of preventive therapy and had difficulty travelling to the clinic and paying costs. CONCLUSION: The study identified widespread gaps in the performance of a child contact management system in Indonesia, all of which appear amenable to intervention. The public health evaluation framework used could be applied in other settings where child contact management is failing. PMID- 24347733 TI - The impact of rural health system reform on hospitalization rates in the Islamic Republic of Iran: an interrupted time series. AB - OBJECTIVE: To assess the effects on hospital utilization rates of a major health system reform - a family physician programme and a social protection scheme - undertaken in rural areas of the Islamic Republic of Iran in 2005. METHODS: A "tracer" province that was not a patient referral hub was selected for the collection of monthly hospitalization data over a period of about 10 years, beginning two years before the rural health system reform (the "intervention") began. An interrupted time series analysis was conducted and segmented regression analysis was used to assess the immediate and gradual effects of the intervention on hospitalization rates in an intervention group composed of rural residents and a comparison group composed of urban residents primarily. FINDINGS: Before the intervention, the hospitalization rate in the rural population was significantly lower than in the comparison group. Although there was no significant increase or decline in hospitalization rates in the intervention or comparison group before the intervention, after the intervention a significant increase in the hospitalization rate - of 4.6 hospitalizations per 100 000 insured persons per month on average - was noted in the intervention group (P < 0.001). The monthly increase in the hospitalization rate continued for over a year and stabilized thereafter. No increase in the hospitalization rate was observed in the comparison group. CONCLUSION: The primary health-care programme instituted as part of the health system reform process has increased access to hospital care in a population that formerly underutilized hospital services. It has not reduced hospitalizations or hospitalization-related expenditure. PMID- 24347734 TI - The ethics of feedback of HIV test results in population-based surveys of HIV infection. AB - Population-based disease prevalence surveys raise ethical questions, including whether participants should be routinely told their test results. Ethical guidelines call for informing survey participants of any clinically relevant finding to enable appropriate management. However, in anonymous surveys of human immunodeficiency virus (HIV) infection, participants can "opt out" of being given their test results or are offered the chance to undergo voluntary HIV testing in local counselling and testing services. This is aimed at minimizing survey participation bias. Those who opt out of being given their HIV test results and who do not seek their results miss the opportunity to receive life-saving antiretroviral therapy. The justification for HIV surveys without routine feedback of results to participants is based on a public health utility argument: that the benefits of more rigorous survey methods - reduced participation bias - outweigh the benefits to individuals of knowing their HIV status. However, people with HIV infection have a strong immediate interest in knowing their HIV status. In consideration of the ethical value of showing respect for people and thereby alleviating suffering, an argument based on public health utility is not an appropriate justification. In anonymous HIV surveys as well as other prevalence surveys of treatable conditions in any setting, participation should be on the basis of routine individual feedback of results as an integral part of fully informed participation. Ensuring that surveys are ethically sound may stimulate participation, increase a broader uptake of HIV testing and reduce stigmatization of people who are HIV-positive. PMID- 24347735 TI - Rapid monitoring in vaccination campaigns during emergencies: the post-earthquake campaign in Haiti. AB - PROBLEM: The earthquake that struck Haiti in January 2010 caused 1.5 million people to be displaced to temporary camps. The Haitian Ministry of Public Health and Population and global immunization partners developed a plan to deliver vaccines to those residing in these camps. A strategy was needed to determine whether the immunization targets set for the campaign were achieved. APPROACH: Following the vaccination campaign, staff from the Ministry of Public Health and Population interviewed convenience samples of households - in specific predetermined locations in each of the camps - regarding receipt of the emergency vaccinations. A camp was targeted for "mop-up vaccination" - i.e. repeat mass vaccination - if more than 25% of the children aged 9 months to 7 years in the sample were found not to have received the emergency vaccinations. LOCAL SETTING: Rapid monitoring was implemented in camps located in the Port-au-Prince metropolitan area. Camps that housed more than 5000 people were monitored first. RELEVANT CHANGES: By the end of March 2010, 72 (23%) of the 310 vaccinated camps had been monitored. Although 32 (44%) of the monitored camps were targeted for mop-up vaccination, only six of them had received such repeat mass vaccination when checked several weeks after monitoring. LESSONS LEARNT: Rapid monitoring was only marginally beneficial in achieving immunization targets in the temporary camps in Port-au-Prince. More research is needed to evaluate the utility of conventional rapid monitoring, as well as other strategies, during post-disaster vaccination campaigns that involve mobile populations, particularly when there is little capacity to conduct repeat mass vaccination. PMID- 24347736 TI - Local production of WHO-recommended alcohol-based handrubs: feasibility, advantages, barriers and costs. AB - PROBLEM: Reduction of health-care-associated infections in low- and middle-income countries is hampered by inadequate supplies of soap and water and the lack or high cost of alcohol-based handrubs (ABHs). APPROACH: In 2005, the World Health Organization (WHO) developed and tested two formulations for ABHs that were suitable for production in health-care facilities. In 2011, the feasibility, advantages and costs of the local production of the two formulations - and the barriers to such production - were evaluated in an online survey. LOCAL SETTING: The survey included 34 health-care facilities and 5 private companies in 29 countries. RELEVANT CHANGES: Local production of one of the WHO formulations was feasible in every participating site. Twenty-one (54%) of the sites had replaced a previously used ABH with one of the WHO formulations. In 32 sites, the WHO formulation that had been produced was well tolerated and accepted by health-care workers. The WHO formulations were found to be less expensive than marketed ABHs. Barriers to local production included difficulty in identifying staff with adequate skills, the need for staff training, and constraints in ingredient and dispenser procurement. LESSONS LEARNT: The WHO formulations can be easily produced locally at low cost. They are well tolerated and accepted by health-care workers. Potential barriers to their local production - such as their smell and problems in the procurement of ingredients and dispensers and in performing quality control - require further investigation. PMID- 24347737 TI - Aggression and Rule-breaking: Heritability and stability of antisocial behavior problems in childhood and adolescence. AB - PURPOSE: This twin study examined the structure of genetic and environmental influences on aggression and rule-breaking in order to examine change and stability across the span of childhood to mid-adolescence. METHODS: Behavioral assessments were conducted at two time points: age 9-10 years and 14-15 years. Using behavioral genetics biometric modeling, the longitudinal structure of influences was investigated. RESULTS: Aggression and rule-breaking were found to be influenced by a latent common factor of antisocial behavior (ASB) within each wave of data collection. The childhood-age common factor of ASB was influenced by 41% genetics, 40% shared environment and 19% nonshared environment. In adolescence, 41% of influences on the common factor were novel and entirely genetic, while the remainder of influences were stable across time. Additionally, both aggression and rule-breaking within each wave were found to have unique influences not common across subscales or across waves, highlighting specificity of influences on different problem behaviors at both ages. CONCLUSIONS: This research sheds light on the commonality of influences on etiology of different forms of antisocial behavior, and suggests future directions for research into intervention for antisocial behavior problems in youth, such as investigation of adolescence-specific environmental influences on the development of antisocial behavior problems. PMID- 24347738 TI - What Causes BDD: Research Findings and a Proposed Model. PMID- 24347739 TI - Optimism and Resources: Effects on Each Other and on Health over 10 Years. AB - Dispositional optimism may be associated with growth of social and status resources by virtue of optimists' greater persistence and better performance. Conversely, resource growth may give people a more positive view of their future and increase optimism. Changes in dispositional optimism and resources over 10 years were examined in former law students (N = 61). More optimistic first-year law students made more money 10 years later, but income did not predict later optimism. More optimistic students did not have larger social networks 10 years later, but increases in social network size predicted increased optimism. These changes predicted mental and physical health. Dispositional optimism was less stable than many personality traits (r = .35), potentially because it is responsive to resource change. PMID- 24347740 TI - Disentangling leaf area and environmental effects on the response of the net ecosystem CO2 exchange to diffuse radiation. AB - There is an ongoing discussion about why the net ecosystem CO2 exchange (NEE) of some ecosystems is less sensitive to diffuse radiation than others and about the role other environmental factors play in determining the response of NEE to diffuse radiation. Using a six-year data set from a temperate mountain grassland in Austria we show that differences between ecosystems may be reconciled based on their green area index (GAI; square meter green plant area per square meter ground area) - the sensitivity to diffuse radiation increasing with GAI. Our data suggest diffuse radiation to have a negligible influence on NEE below a GAI of 2 m2 m-2. Changes in air/soil temperature and air humidity concurrent with the fraction of diffuse radiation were found to amplify the sensitivity of the investigated temperate mountain grassland ecosystem to diffuse radiation. PMID- 24347741 TI - The Experience of Discrimination and Black-White Health Disparities in Medical Care. AB - The current study of Black patients focuses on how discrimination contributes to racial disparities in health. The authors used a longitudinal methodology to study how perceived past discrimination affects reactions to medical interactions and adherence to physician recommendations. In addition, they explored whether these reactions and/or adherence mediate the relationship between discrimination and patients' health. The participants in this study were 156 Black patients of low socioeconomic status at a primary care clinic. Patients completed questionnaires on their current health, past adherence, and perceived past discrimination. Then, they saw a physician and rated their reactions to the visit. Four and 16 weeks later they reported on their adherence to physician recommendations and overall health. Perceived discrimination was significantly and negatively associated with patient health, reactions to the physician, and adherence. Path analyses indicated that adherence mediated the relationship between discrimination and patient health, but patient reactions to the interaction did not. PMID- 24347742 TI - Ionization effects in molecular depth profiling of trehalose films using buckminsterfullerene (C60) cluster ions. AB - Salts play a mysterious role in desorption mass spectrometry, especially in biological samples.[1] We used trehalose films doped with a peptide as a well defined model system to investigate the ionization effects in organic molecular depth profiling. Sodium salts at 1% level were added into the solution used to produce the trehalose films, and depth profiles were obtained with a C60 ion source. The results show that the protonated molecular ion signal from the peptide and the quasimolecular ion signal of trehalose are significantly suppressed by the addition of salts, whereas the signals representing salt clusters and salt adducts of trehalose are formed in both positive and negative modes. The formation of protonated molecular ions is found to correlate with the ratio between protonated and bare water ions, suggesting that the latter can be used as an indicator for the accumulation of protons liberated by the ion bombardment. In experiments where no salt was added, it is shown that the surface variation of the protonated molecular ion signal strongly depends upon the water content of the trehalose film. PMID- 24347743 TI - Fundamental studies of molecular depth profiling using organic delta layers as model systems. AB - Alternating Langmuir-Blodgett multilayers of barium arachidate (AA) and barium dimyristoyl phosphatidate (DMPA) were used to elucidate the factors that control depth resolution in molecular depth profiling experiments. More specifically, thin (4.4 nm) layers of DMPA were embedded in relatively thick (~50 nm) multilayer stacks of AA, resulting in a well-defined delta-layer model system closely resembling a biological membrane. This system was subjected to a three dimensional imaging depth profile analysis using a focused buckminsterfullerene (C60) cluster ion beam. The depth response function measured in these experiments exhibits similar features as those determined in inorganic depth profiling: namely, an asymmetric shape with quasi-exponential leading and trailing edges and a central Gaussian peak. The magnitude of the corresponding characteristic rise and decay lengths is found to be 5 and 16 nm, respectively, while the total half width of the response function characterizing the apparent depth resolution was about 29 nm. Ion-induced mixing is proposed to be largely responsible for the broadening, rather than topography, as determined by atomic force microscopy. PMID- 24347744 TI - Retrospective sputter depth profiling using 3D mass spectral imaging. AB - A molecular multilayer stack composed of alternating Langmuir-Blodgett films was analyzed by ToF-SIMS imaging in combination with intermediate sputter erosion using a focused C60+ cluster ion beam. From the resulting dataset, depth profiles of any desired lateral portion of the analyzed field-of-view can be extracted in retrospect, allowing the influence of the gating area on the apparent depth resolution to be assessed. In a similar way, the observed degradation of depth resolution with increasing depth of the analyzed interface can be analyzed in order to determine the 'intrinsic' depth resolution of the method. PMID- 24347745 TI - Temperature effects in the sputtering of a molecular solid by energetic atomic and cluster projectiles. AB - Temperature effects in the sputtering of an organic molecule were investigated by subjecting a well defined film of coronene to Au1 and C60 primary ions at 100 and 300 K. Strong field photoionization of the sputtered neutral flux was employed to monitor the change in flight time and kinetic energy distributions of intact and fragmented species. PMID- 24347746 TI - New spectral vegetation indices based on the near-infrared shoulder wavelengths for remote detection of grassland phytomass. AB - This article examines the possibility of exploiting ground reflectance in the near-infrared (NIR) for monitoring grassland phytomass on a temporal basis. Three new spectral vegetation indices (infrared slope index, ISI; normalized infrared difference index, NIDI; and normalized difference structural index, NDSI), which are based on the reflectance values in the H25 (863-881 nm) and the H18 (745-751 nm) Chris Proba (mode 5) bands, are proposed. Ground measurements of hyperspectral reflectance and phytomass were made at six grassland sites in the Italian and Austrian mountains using a hand-held spectroradiometer. At full canopy cover, strong saturation was observed for many traditional vegetation indices (normalized difference vegetation index (NDVI), modified simple ratio (MSR), enhanced vegetation index (EVI), enhanced vegetation index 2 (EVI 2), renormalized difference vegetation index (RDVI), wide dynamic range vegetation index (WDRVI)). Conversely, ISI and NDSI were linearly related to grassland phytomass with negligible inter-annual variability. The relationships between both ISI and NDSI and phytomass were however site specific. The WinSail model indicated that this was mostly due to grassland species composition and background reflectance. Further studies are needed to confirm the usefulness of these indices (e.g. using multispectral specific sensors) for monitoring vegetation structural biophysical variables in other ecosystem types and to test these relationships with aircraft and satellite sensors data. For grassland ecosystems, we conclude that ISI and NDSI hold great promise for non destructively monitoring the temporal variability of grassland phytomass. PMID- 24347747 TI - beta-Pyrazino-fused tetrarylporphyrins. AB - A novel method for the preparation of beta-fused porphyrin dyads was developed that exploits a one-pot reaction of 2,3-diaminoporphyrins with diethyl oxalate. This approach provides good yields of the zinc beta-fused dyad and the corresponding free-base, opening the way for preparation of several metal derivatives to permit modulation of optoelectronic characteristics for commercial applications. PMID- 24347748 TI - Engaging Teenagers with Science Through Comics. PMID- 24347749 TI - Structural Nested Cumulative Failure Time Models to Estimate the Effects of Interventions. AB - In the presence of time-varying confounders affected by prior treatment, standard statistical methods for failure time analysis may be biased. Methods that correctly adjust for this type of covariate include the parametric g-formula, inverse probability weighted estimation of marginal structural Cox proportional hazards models, and g-estimation of structural nested accelerated failure time models. In this article, we propose a novel method to estimate the causal effect of a time-dependent treatment on failure in the presence of informative right censoring and time-dependent confounders that may be affected by past treatment: g-estimation of structural nested cumulative failure time models (SNCFTMs). An SNCFTM considers the conditional effect of a final treatment at time m on the outcome at each later time k by modeling the ratio of two counterfactual cumulative risks at time k under treatment regimes that differ only at time m. Inverse probability weights are used to adjust for informative censoring. We also present a procedure that, under certain "no-interaction" conditions, uses the g estimates of the model parameters to calculate unconditional cumulative risks under nondynamic (static) treatment regimes. The procedure is illustrated with an example using data from a longitudinal cohort study, in which the "treatments" are healthy behaviors and the outcome is coronary heart disease. PMID- 24347750 TI - Defining the Low End of Primate Social Complexity: The Social Organization of the Nocturnal White-Footed Sportive Lemur (Lepilemur leucopus). AB - Whereas other species of sportive lemurs (genus Lepilemur) have been described as living in dispersed pairs, which are characterized by spatial overlap but a lack of affinity or affiliation between one adult male and female, existing reports on the social organization of the white-footed sportive lemur (Lepilemur leucopus) are conflicting, describing them as either living in dispersed one-male multifemale systems or pairs. We conducted this study in the spiny forest of Berenty Reserve, southern Madagascar, to clarify the social organization and to characterize the level of social complexity of this species. We combined 1530 h of radio-telemetry and behavioral observations over a period of 1 yr to describe the spatiotemporal stability, size, and interindividual overlap of individual home ranges as well as interindividual cohesiveness. Results revealed low intra- and high intersexual home range overlap. Although most of the social units identified consisted of dispersed pairs (N = 5), males were associated with two adult females in two cases. Furthermore, members of a social unit were never observed to groom each other or to share a daytime sleeping site, and Hutchinson's and Doncaster's dynamic interaction tests indicated active avoidance between pair partners. Low cohesiveness together with extremely low rates of social interactions therefore arguably places Lepilemur leucopus at the low end of primate social complexity. PMID- 24347751 TI - Within-person variability in state anxiety across adulthood: Magnitude and associations with between-person characteristics. AB - Across domains of functioning, research has shown substantial within-person variability in a number of different types of variables from one measurement occasion to another. Using data obtained from a large sample (n = 784, 18-97 years) at three separate occasions, we examined properties and correlates of short-term variability in a construct that by definition is prone to fluctuations, namely state anxiety. Our results revealed that participants exhibited sizeable across-occasion variation in state anxiety. The magnitude of variability was unrelated to age, but was associated with a number of individual difference characteristics such as self-reported health, aspects of personality, well-being, and cognition. However, after taking into account mean-level differences in state anxiety, evidence for unique associations of variability was minimal. PMID- 24347752 TI - Natural and constrained language production as a function of age and cognitive abilities. AB - Although it is often claimed that verbal abilities are relatively well maintained across the adult lifespan, certain aspects of language production have been found to exhibit cross-sectional differences and longitudinal declines. In the current project age-related differences in controlled and naturalistic elicited language production tasks were examined within the context of a reference battery of cognitive abilities in a moderately large sample of individuals aged 18-90. The results provide support for age-related increases in lexical sophistication and diversity at the discourse level, and declines in grammatical complexity in controlled and naturalistic contexts. Further, age-related decreases in facility with complex grammatical constructions in controlled sentence production were statistically independent of the cognitive abilities assessed in this project. PMID- 24347754 TI - Promoting Relationship Building and Connection: Adapting an Evidence-Based Parenting Program for Families Involved in the Child Welfare System. AB - The high needs of youth involved in the child welfare system and the poor long term outcomes of former foster youth represent a significant systemic challenge. As part of a process to adapt an evidence-based parenting program for a child welfare population, we conducted a series of focus groups with child welfare staff, foster caregivers, and young adults who were involved in the foster system as teens. From these focus groups we learned that, although there is a need for evidence-based parenting programs for families involved in the child welfare setting, one of the significant barriers to program implementation is the lack of meaningful connection between caregivers and youth in their care. We will provide an in-depth discussion on the proposed adaptations to make Staying Connected more relevant for foster families, including the addition of skills training to help overcome some of the barriers to connection. Staying Connected holds the promise of cultivating more supportive home environments that have the capacity to nurture youths' healthy development, including the avoidance of high-risk behaviors. PMID- 24347753 TI - Morphological structure in the Arabic mental lexicon: Parallels between standard and dialectal Arabic. AB - The Arabic language is acquired by its native speakers both as a regional spoken Arabic dialect, acquired in early childhood as a first language, and as the more formal variety known as Modern Standard Arabic (MSA), typically acquired later in childhood. These varieties of Arabic show a range of linguistic similarities and differences. Since previous psycholinguistic research in Arabic has primarily used MSA, it remains to be established whether the same cognitive properties hold for the dialects. Here we focus on the morphological level, and ask whether roots and word patterns play similar or different roles in MSA and in the regional dialect known as Southern Tunisian Arabic (STA). In two intra-modal auditory auditory priming experiments, we found similar results with strong priming effects for roots and patterns in both varieties. Despite differences in the timing and nature of the acquisition of MSA and STA, root and word pattern priming was clearly distinguishable from form-based and semantic-based priming in both varieties. The implication of these results for theories of Arabic diglossia and theories of morphological processing are discussed. PMID- 24347755 TI - Discrimination hurts, but mindfulness may help: Trait mindfulness moderates the relationship between perceived discrimination and depressive symptoms. AB - Discriminatory experiences are not only momentarily distressing, but can also increase risk for lasting physical and psychological problems. Specifically, significantly higher rates of depression and depressive symptoms are reported among people who are frequently the target of prejudice. Given the gravity of this problem, this research focuses on an individual difference, trait mindfulness, as a protective factor in the association between discrimination and depressive symptoms. In a community sample of 605 individuals, trait mindfulness dampens the relationship between perceived discrimination and depressive symptoms. Additionally, mindfulness provides benefits above and beyond those of positive emotions. Trait mindfulness may thus operate as a protective individual difference for targets of discrimination. PMID- 24347756 TI - Personality and facial morphology: Links to assertiveness and neuroticism in capuchins (Sapajus [Cebus] apella). AB - Personality has important links to health, social status, and life history outcomes (e.g. longevity and reproductive success). Human facial morphology appears to signal aspects of one's personality to others, raising questions about the evolutionary origins of such associations (e.g. signals of mate quality). Studies in non-human primates may help to achieve this goal: for instance, facial width-to-height ratio (fWHR) in the male face has been associated with dominance not only in humans but also in capuchin monkeys. Here we test the association of personality (assertiveness, openness, attentiveness, neuroticism, and sociability) with fWHR, face width/lower-face height, and lower face/face height ratio in 64 capuchins (Sapajus apella). In a structural model of personality and facial metrics, fWHR was associated with assertiveness, while lower face/face height ratio was associated with neuroticism (erratic vs. stable behaviour) and attentiveness (helpfulness vs. distractibility). Facial morphology thus appears to associate with three personality domains, which may act as a signal of status in capuchins. PMID- 24347758 TI - Limits of Spatial Resolution for Thermography and Other Non-destructive Imaging Methods Based on Diffusion Waves. AB - In this work the measured variable, such as temperature, is a random variable showing fluctuations. The loss of information caused by diffusion waves in non destructive testing can be described by stochastic processes. In non-destructive imaging, the information about the spatial pattern of a samples interior has to be transferred to the sample surface by certain waves, e.g., thermal waves. At the sample surface these waves can be detected and the interior structure is reconstructed from the measured signals. The amount of information about the interior of the sample, which can be gained from the detected waves on the sample surface, is essentially influenced by the propagation from its excitation to the surface. Diffusion causes entropy production and information loss for the propagating waves. Mandelis has developed a unifying framework for treating diverse diffusion-related periodic phenomena under the global mathematical label of diffusion-wave fields, such as thermal waves. Thermography uses the time dependent diffusion of heat (either pulsed or modulated periodically) which goes along with entropy production and a loss of information. Several attempts have been made to compensate for this diffusive effect to get a higher resolution for the reconstructed images of the samples interior. In this work it is shown that fluctuations limit this compensation. Therefore, the spatial resolution for non destructive imaging at a certain depth is also limited by theory. PMID- 24347757 TI - Parent Predictors of Changes in Child Behavior Problems. AB - The present study examined whether ineffective discipline, single parent status, social support, parent involvement, and parent depression predicted changes in preschoolers' (N = 129) behavior problems. This study also evaluated whether child sex and ethnicity moderated the relationships between these variables and changes in problem behavior. Parents completed questionnaires at the beginning of the study, and parent, teacher, and observational ratings of children's behavior problems were collected twice during the school year. Parents' own social support predicted improvement for boys and parent depression was associated with worsening symptoms for girls. Single parenthood and parent involvement predicted changes in behavior problems for the sample as a whole. Several significant ethnic differences emerged, highlighting the importance of considering cultural context in studies of parenting and child externalizing behavior. PMID- 24347759 TI - Chronotherapeutics: a hype or future of chronopharmacology? PMID- 24347760 TI - Zonisamide: a review of the clinical and experimental evidence for its use in Parkinson's disease. AB - The limitations of currently available therapies in addressing the non motor symptoms of Parkinson's disease (PD) have egged on the search for newer options. Zonisamide has been in use for epilepsy and it was serendipitously found to improve the symptoms of PD in a patient who had both epilepsy and PD. Thereafter, various trials were designed to assess the use of zonisamide in PD. The present article investigates the evidence for use of zonisamide in PD from the various clinical trials that were designed to address this issue. Furthermore, the article also summarizes the various mechanisms of its use in PD as described in various animal experiments. A search protocol was designed with predefined inclusion and exclusion criteria. The databases searched were Pubmed, Ovid medline, Cochrane and clinicaltrials.gov. The data thus generated, was fed into a predesigned format. Most of the clinical trials on zonisamide in PD have come from Japan. Most of these trials used the changes in the Unified Parkinson's Disease Rating Scale (UPDRS) score as the endpoints and the most conclusive evidence is for a dose of 25-50 mg, which caused a change in UPDRS part III (motor symptoms). These patients were on levodopa and other drugs used for PD during the trials. One of the clinical trials conducted in Spain investigates the use of zonisamide in impulse control disorders among 15 patients of PD. Among the many mechanisms postulated, a reduction in levodopa induced quinone formation, protection against mitochondrial impairment and an increase in astroglial cysteine transport, an inhibition of microglial activation, monoamine oxidase-B (MAO-B) inhibition, an increased dopamine release and blockade of calcium channels are the most cited. There is evidence for use of zonisamide in PD in addition to levodopa and other therapies for control of motor symptoms. For now, the evidence for its use in control of non motor symptoms in PD is not enough and needs to be investigated further. PMID- 24347761 TI - The effect of Chinese medicine Pu-Ren-Dan on pancreatic angiogenesis in high fat diet/streptozotocin-induced diabetic rats. AB - OBJECTIVES: The islet vascular system is critical for beta-cell function. This study investigated the antidiabetic effect of the Chinese Pu-Ren-Dan (PRD) recipe by regulating the pancreatic angiogenic factors in T2DM rats. MATERIALS METHODS: High fat diet/streptozotocin-induced obese type-2 diabetes mellitus rats were developed and treated with PRD for 4 weeks. Then glucolipid metabolism, insulin secretion, pancreatic blood flow, ultrastructure of islet beta-cell, histological changes of islet and protein expressions of pancreatic angiogenic factors were investigated. RESULTS: PRD-reduced T2DM rats' body weight and blood glucose level resisted the lipid metabolism disturbance, and ameliorated the insulin resistance and beta-cell function. In addition, the histological and morphological studies proved that PRD could maintain the normal distribution of endocrine cell in islet and normal ultrastructure of beta cell. An increased pancreatic blood flow was observed after the PRD treatment. In the investigation of pancreatic angiogenic factors, PRD inhibited the decreased expression of VEGF and Ang-1, and reversed the reduction of VEGFR2 and Tie2 phosphorylation in T2DM rats; the Ang-2 and TGFbeta expression were up-regulated by PRD while PKC was activated; endostatin and angiostatin were down-regulated by PRD. CONCLUSIONS: The results suggest that increasing VEGF expression, regulating VEGF/VEGFR2 signaling, stimulating Ang 1/Tie-2 signaling pathway, and inhibiting PKC-TGFbeta signaling and antiangiogenic factors might be the underlying mechanism of PRD's antidiabetic effect. PMID- 24347762 TI - Withania somnifera ameliorates lead-induced augmentation of adrenergic response in rat portal vein. AB - OBJECTIVES: Present study was undertaken to elucidate the ameliorating potential of Withania somnifera root extract (WRE) against lead-induced augmentation of adrenergic response in rat portal vein. MATERIALS AND METHODS: In-vitro studies were conducted on effect of lead alone and lead+WRE on rat-isolated portal vein while in-vivo studies were done in three groups of 12 rats each; Group-II and III received 0.5% lead acetate and 1.0% WRE + 0.5% lead acetate, respectively, in drinking water for 12 weeks whereas group-I served as control. Adrenaline and noradrenaline levels in brain and blood were determined by HPLC assay while vascular reactivity of portal vein to lead and WRE was determined by measuring the isometric tension. RESULTS: Following in-vitro exposure, lead did not alter the contractile effect of phenylephrine. In-vivo studies revealed that contractile effect of lead on portal vein was significantly potentiated and it was antagonized by prazosin (10(-7) M) and WRE (1%). WRE treatment significantly reduced elevated blood noradrenaline (37.80%) and restored noradrenaline level in brain (39.39%) in lead-exposed animals. These values were almost comparable to the control group. But it failed to significantly affect the blood and brain adrenaline levels. CONCLUSIONS: Results suggest that following pre-exposure of rats to WRE, lead-induced augmentation of alpha 1-adrenoceptors mediated response was reversed possibly by regulating catecholamine release from nerve endings. Thus, WRE may be useful in therapeutic management of lead-induced hypertension. PMID- 24347763 TI - Evaluation of antiangiogenic and antiproliferative potential of the organic extract of green algae Chlorella pyrenoidosa. AB - OBJECTIVE: algae isolates obtained from fresh and marine resources could be one of the richest sources of novel bioactive secondary metabolites expected to have pharmaceutical significance for new drug development. This study was conducted to evaluate the antiangiogenic and antiproliferative activity of Chlorella pyrenoidosa in experimental models of angiogenesis and by MTT assay. MATERIALS AND METHODS: lyophilized extract of C. pyrenoidosa was extracted using dichloromethane/methanol (2:1), concentrated and vacuum evaporated to obtain the dried extract. The crude extract was evaluated in the vascular endothelial growth factor (VEGF)-induced angiogenesis in in ovo chick chorioallantoic membrane assay (CAM) at various concentrations (n = 8) using thalidomide and normal saline as positive and untreated control groups, respectively. The crude extract was also subjected to the antiangiogenic activity in the silver nitrate/potassium nitrate cautery model of corneal neovascularization (CN) in rats where topical bevacizumab was used as a positive control. The vasculature was photographed and blood vessel density was quantified using Aphelion imaging software. The extract was also evaluated for its anti proliferative activity by microculture tetrazolium test (MTT) assay using HeLa cancer cell line (ATCC). RESULTS: VEGF increased the blood vessel density by 220% as compared to normal and thalidomide treatment decreased it to 67.2% in in ovo assay. In the in-vivo CN model, the mean neovascular density in the control group, the C. pyrenoidosa extract and bevacizumab group were found to be 100%, 59.02%, and 32.20%, respectively. The Chlorella pyrenoidosa extract negatively affected the viability of HeLa cells. An IC50 value of the extract was 570 MUg/ml, respectively. CONCLUSION: a significant antiangiogenic activity was observed against VEGF-induced neovascularization and antiproliferative activity by MTT assay. In this study, it could be attributed that the activity may be due to the presence of secondary metabolites in the C. pyrenoidosa extract. PMID- 24347764 TI - Neuroprotective activity of gossypin from Hibiscus vitifolius against global cerebral ischemia model in rats. AB - OBJECTIVES: The objective of this study is to evaluate the neuroprotective effect of gossypin (isolated from Hibiscus vitifolius) against global cerebral ischemia/reperfusion (I/R) injury-induced oxidative stress in rats. MATERIALS AND METHODS: Sprague Dawlet rats of wither gender were used in the study. Evaluation of cerbroprotective activity of bioflavonoid gossypin (in 5, 10 and 20 mg/kg oral doses) isolated from H. vitifolius was carried out by using the global cerebral I/R model by bilateral carotid artery occlusion for 30 min, followed by 24 h reperfusion. The antioxidant enzymatic and non-enzymatic levels were estimated along with histopathological studies. RESULT: Gossypin showed dose-dependent neuroprotective activity by significant decrease in lipid peroxidation (P < 0.001) and increase in the superoxide dismutase, catalase, glutathione and total thiol levels in gossypin treated groups when compared to control group. Cerebral infarction area was markedly reduced in gossypin treated groups when compared to control group. CONCLUSION: Gossypin showed potent neuroprotective activity against global cerebral I/R injury-induced oxidative stress in rats. PMID- 24347765 TI - Effect of melatonin and gabapentin on anxiety and pain associated with retrobulbar eye block for cataract surgery: a randomized double-blind study. AB - OBJECTIVES: To compare the effect of melatonin and gabapentin on anxiety, pain, sedation scores, and satisfaction of surgeon in patients of cataract surgery. MATERIALS AND METHODS: One hundred thirty patients aged between 35 and 85 years scheduled for cataract surgery were randomly allocated to three study groups to receive melatonin (6 mg), gabapentin (600 mg) or placebo 90 min before arrival in the operating room. Pain, anxiety, and sedation scores during block and surgery as well as the surgeon's satisfaction with the surgery were assessed. RESULTS: Anxiety scores decreased significantly in melatonin and gabapentin groups compared to the placebo group after premedication and extended to early postoperative period. The level of anxiety showed no statistically significant difference between melatonin and gabapentin groups at any time of measurement. There were significant differences between the pain scores during retrobulbar placement in gabapentin versus placebo (95% CI 3 to 4; P = 0.001) and melatonin (95% CI 3 to 4; P = 0.040) groups. Also, there were significant differences between the sedation scores during retrobulbar placement in gabapentin and placebo groups (95% CI 2 to 2.5; P = 0.046). The difference in sedation scores during retrobulbar placement in melatonin versus gabapentin and placebo groups was not significant. Neither the intraoperative pain scores nor the postoperative pain scores were different between the three groups. The surgeon reported similar quality of operation conditions during surgery for the three study groups. CONCLUSION: The level of anxiety was significantly lower with both anxiolytic drugs compared to placebo. Furthermore, gabapentin decreased the pain and improved the sedation scores only during retrobulbar placement compared to the placebo. PMID- 24347766 TI - Development of a teaching module for parenteral drug administration and objective structured practical examination stations in pharmacology. AB - OBJECTIVES: Safe parenteral drug administration includes preparation of safe medication for administration. Training medical students is crucial to minimize medication administration errors. The study aims to develop a module to teach drug preparation skills and to develop objective structured practical examination (OSPE) stations to assess these skills. Students' perceptions regarding the module were also assessed. MATERIALS AND METHODS: A module was developed to teach following skills to 2(nd) year medical students: Aspiration of a drug from the ampule, aspiration of the drug from the vial, aspiration of the drug in powdered form from vial (reconstitution), and setting up an intravenous (IV) infusion. A randomized case control study design was used to establish the validity of OSPE stations. Student volunteers were grouped into case (n = 20) and control groups (n = 20) by simple randomization. The test group watched videos of skills and received demonstration of skills and a practice session before OSPE, whereas the control group watched videos before the OSPE and received demonstration and a practice session only after the OSPE. Each student was assessed by two faculty members during OSPE using a validated checklist. Mean OSPE scores of control and test groups were compared using independent samples t-test. Interrater reliability and concurrent validity of stations were analyzed using interclass correlation coefficient (ICC) and Pearson correlation, respectively. Students' responses were expressed as median and interquartile range. RESULTS: The response rate in the questionnaire was 100%. Significant difference between mean scores (P < 0.05) of test and control groups revealed fulfillment of construct validity of OSPE stations. Interrater reliability (ICC > 0.7) and concurrent validity (r value > 7) of all the stations was high. Perceptions revealed acceptability of module and OSPE stations by students (median 4, scale 1-5). CONCLUSIONS: A module to teach drug preparation skills was developed and along with valid and reliable OSPE stations that were acceptable to students. The study demonstrated that students acquire better skills through teaching than merely watching these skills in videos. PMID- 24347767 TI - Sucrose-induced analgesia in mice: role of nitric oxide and opioid receptor mediated system. AB - BACKGROUND: The mechanism of action of sweet substance-induced analgesia is thought to involve activation of the endogenous opioid system. The nitric oxide (NO) pathway has a pivotal role in pain modulation of analgesic compounds such as opioids. OBJECTIVES: We investigated the role of NO and the opioid receptor mediated system in the analgesic effect of sucrose ingestion in mice. MATERIALS AND METHODS: We evaluated the effect of intraperitoneal administration of 10 mg/kg of NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME) and 20 mg/kg of opioid receptor antagonist, naltrexone on the tail flick response in sucrose ingesting mice. RESULTS: Sucrose ingestion for 12 days induced a statistically significant increase in the latency of tail flick response which was unmodified by L-NAME, but partially inhibited by naltrexone administration. CONCLUSIONS: Sucrose-induced nociception may be explained by facilitating the release of endogenous opioid peptides. Contrary to some previously studied pain models, the NO/cyclic guanosine monophosphate (cGMP) pathway had no role in thermal hyperalgesia in our study. We recommend further studies on the involvement of NO in other animals and pain models. PMID- 24347768 TI - Reversal of multidrug resistance by 5,5'-dimethoxylariciresinol-4-O-beta-D glucoside in doxorubicin-resistant human leukemia K562/DOX. AB - OBJECTIVE: The objective of this study was to investigate the reversal effects of 5,5'-dimethoxylariciresinol-4'-O-beta-D-glucoside (DMAG) extracted from traditional Chinese medicines Mahonia on multidrug resistance (MDR) of human leukemia cells to chemotherapeutic agents. MATERIALS AND METHODS: MTT(3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed to determine the effect of DMAG on doxorubicin sensitivity to K562/DOX cells. Propidium iodide /Hoechst 33342 double staining assay was used to investigate the effect of DMAG on doxorubicin-induced cellular apoptosis. Intracellular accumulation of doxorubicin and rhodamine 123 assay were performed to evaluate the effect of DMAG on drugs efflux activity of P-glycoprotein. RESULTS: DMAG significantly enhanced the doxorubicin cytotoxicity to K562/DOX cells. In the presence of 1.0 MUM of DMAG, the IC50 of doxorubicin decreased from 34.93 +/- 1.37 MUM to 12.51 +/- 1.28 MUM. DMAG of 1.0 MUM significantly enhanced doxorubicin-induced cell apoptosis in K562/DOX cells and the enhancement was time dependent. A significant increase in accumulation of doxorubicin in the presence of DMAG was observed. After treatment of the K562/DOX cells for 1 h with 15.0 MUM doxorubicin alone, the fluorescence intensity was 33093.12. With the addition of 1.0 MUM of DMAG, the fluorescence intensity of doxorubicin was 2.3-fold higher. A significant increase of accumulation of rhodamine 123 in the presence of DMAG was also observed. With the addition of 1.0 MUM of DMAG, the fluorescence intensity was increased by 49.11% compared with rhodamine 123 alone. CONCLUSION: DMAG was shown to effectively enhance chemosensitivity of resistant cells, which makes it might be a suitable candidate for potential MDR-reversing agents. PMID- 24347769 TI - Use of potentially inappropriate medications in hospitalized elderly at a teaching hospital: a comparison between Beers 2003 and 2012 criteria. AB - OBJECTIVES: To detect the prevalence and pattern of use of Potentially inappropriate medications (PIMs) in hospitalized elderly patients of a tertiary care teaching hospital using Beers 2012 criteria and to compare the same with Beers 2003 criteria. MATERIALS AND METHODS: Prescriptions of the elderly patients aged 65 years and above were collected from the medicine ward and analyzed. PIMs were identified with help of Beers 2003 and Beers 2012 criteria and comparison was made between the two criteria. Predictors associated with use of PIM were identified using bivariate and multivariate logistic regression analysis. RESULTS: A total of 210 patients received 2,267 drugs. According to Beers 2003 criteria, 60 (28.57%) elderly patients received at least one PIM and 2.9% drugs were prescribed inappropriately. According to Beers 2012 criteria, 84 (40%) elderly received at least one PIM while 22 (10.47%) received multiple PIMs and about 5% drugs were prescribed inappropriately. The most commonly prescribed PIM was mineral oil-liquid paraffin (30, 14.3%) followed by spironolactone (25, 11.9%), digoxin (19, 9%), and benzodiazepines (14, 6.7%). There was a significant association between the number of patients receiving more than six drugs and the use of PIMs (P < 0.01). Use of more than 10 drugs was a significant predictor for use of PIMs in the elderly. CONCLUSION: The study shows high prevalence of prescribing PIMs in hospitalized elderly patients. Beers 2012 criteria are more effective in identifying PIMs than Beers 2003 criteria. PMID- 24347770 TI - Parenteral polymyxins: assessing efficacy and safety in critically ill patients with renal dysfunction. AB - OBJECTIVES: Studies have established the effectiveness and safety of polymyxins in treating multidrug resistant (MDR) pathogens. However, the challenge is whether these nephrotoxic drugs can be administered in compromised renal states. The present study was undertaken to establish their role in such patients. The effectiveness and nephrotoxicity of polymyxins in critically ill-patients harboring MDR Gram-negative bacteria with already compromised renal functions was compared with those with normal renal functions. MATERIALS AND METHODS: This retrospective cohort study (March 2008-March 2010) was conducted in the intensive care unit of a tertiary care hospital. A total of 48 eligible critically ill patients receiving polymyxins were enrolled. A comparison was carried out (length of stay in hospital, mortality, renal function) between patients with acute kidney injury (AKI, n = 18; defined by the RIFLE classification) and patients with normal renal function (non-AKI, n = 30). RESULTS: Patients with baseline AKI had a significantly higher adjusted mortality rate at admission when compared with the non-AKI group. At the end of therapy with polymyxins, 26.66% non-AKI patients developed renal dysfunction while 38.88% of patients in the AKI group had worsening of renal function (P = 0.006). However, there was no significant difference in the length of hospital stay (23.9 +/- 13.24 vs. 30.5 +/- 22.50; P = 0.406) and overall mortality (44.4% vs. 36.7%; P = 0.76) between two groups. CONCLUSION: Polymyxins can be administered in AKI patients with favorable results provided used judiciously with strict monitoring of renal functions, dose modification according to creatinine clearance and aggressive fluid management. PMID- 24347771 TI - Granulocyte-colony stimulating factor improves Parkinson's disease associated with co-morbid depression: an experimental exploratory study. AB - INTRODUCTION: The present study was designed to evaluate the effect of granulocyte-colony stimulating factor (G-CSF) in the treatment of Parkinson's disease (PD), the second most common neurodegenerative disease characterized by muscle and movement disorder, often associated with depression. PD is very difficult to treat. Hence, the present study was aimed to evaluate the effect of G-CSF in PD associated with depression. MATERIALS AND METHODS: Adult Wistar male rats weighing about 180-250 g were selected and divided into five groups in parallel designed method namely; control group (n = 5); sham operated group (n = 5); Vehicle group (n = 5); G-CSF group (70 MUg/kg, s.c.) (n = 5) and L-DOPA group (n = 5). The rats were treated with 6-hydroxydopamine (6-OHDA) on day 0 and then treatment was continued for 14 day of L-DOPA/carbidopa, whereas G-CSF (70 MUg/kg, s.c.) was given from day 1 to 6. Thereafter, adhesive removal and forced swim tests were conducted to evaluate the behavioral outcome of G-CSF treatment. The finding was correlated and analyzed with Nissl staining findings for the final conclusion. RESULTS: The behavioral parameters were assessed and found to be ameliorate the symptoms of Parkinson's and reduced the depression like behavior in PD. The histological findings were supported the behavioral findings and showed pathological improvement. CONCLUSION: As a preliminary work, the present study first time suggested that G-CSF have a potential role in PD and associated depression. PMID- 24347772 TI - An evaluation of knowledge of pharmacovigilance among nurses and midwives in Turkey. AB - This study aimed to evaluate the awareness of nurse/midwives regarding pharmacovigilance as well as their knowledge and experience in identifying and reporting adverse reactions of drugs. Nurse/midwives (n = 329), working in four state hospitals, were provided a questionnaire with a view of identifying their knowledge and skills pertaining to pharmacovigilance. Around 45% of the participants claimed to have knowledge of pharmacovigilance but only 23.3% of them could define it correctly. Although 24.3% of the participants acknowledged that adverse reactions should be reported to a centre, only 1.2% of them named this centre (Turkey Pharmacovigilance Centre-TUFAM). The present study indicates that nurse/midwives have insufficient knowledge of pharmacovigilance practices. Hence, it is essential to include pharmacovigilance training in their undergraduate and graduate education programs, and to promote reporting of adverse reactions. PMID- 24347773 TI - Prevention of injection pain due to propofol by dezocine: a comparison with lidocaine. AB - OBJECTIVES: The aim of this study was to investigate the efficacy of dezocine (DEZ) versus placebo control (CON) and 2% lidocaine (LID) in prevention of injection pain due to DEZ. MATERIALS AND METHODS: A prospective randomized double blind, placebo-CON study was conducted in 75 adults, American Society of Anesthesiologists physical status I or II, scheduled to undergo an elective surgery. A total of 25 patients were randomly assigned to one of the three groups, thus CON, group LID and group DEZ. The groups received either 2 ml of normal saline or 2 ml 2% LID or 2 mg/2 ml DEZ, respectively, as pre-treatment. Propofol was injected 1 min later. A blinded researcher assessed the patient's pain level using a four point verbal rating scale. RESULTS: Less patients experienced pain due to propofol injection in the LID (40%) and DEZ (28%) groups compared with the CON (84%) group (P < 0.05). Six patients (24%) in the CON group reported severe pain during propofol injection but none in the other two groups. CONCLUSION: Pre-treatment with DEZ decreases propofol injection pain as effectively as LID. PMID- 24347774 TI - A comparative study to evaluate efficacy, safety and cost-effectiveness between Whitfield's ointment + oral fluconazole versus topical 1% butenafine in tinea infections of skin. AB - AIMS AND OBJECTIVES: The aim of this study is to compare the efficacy, safety and cost-effectiveness of topical Whitfield's ointment plus oral fluconazole with topical 1% butenafine in tinea infections of the skin. MATERIALS AND METHODS: Patients were randomly allocated to the two treatment groups and advised to apply either agent topically twice-a-day for 4 weeks on the lesions and fluconazole (150 mg) was administered once a week for 4 weeks in the study group applying Whitfield's ointment. Patients were followed-up at an interval of 10 days for clinical score and global evaluation response was assessed at baseline and during each follow-up. RESULTS: Out of 120 patients enrolled in the study 103 completed the study. Patients treated with Whitfield's ointment and oral fluconazole reduced mean sign and symptom score from 8.81 +/- 0.82 to 0.18 +/- 0.59 while butenafine treated patients reduced it from 8.88 +/- 0.53 to 0.31 +/- 0.67 at the end of the treatment. Nearly, 98% patients were completely cleared of the lesion on the 3(rd) follow-up with both treatments. CONCLUSION: Whitfield's ointment with oral fluconazole is as efficacious, safe and cost-effective as compared with 1% butenafine in tinea infections of the skin. PMID- 24347775 TI - Levofloxacin and furazolidone induced toxic epidermal necrosis. AB - Toxic epidermal necrolysis (TEN), also known as Lyell's syndrome, is a severe cutaneous drug reaction with a high mortality. Immune response is the possible cause in its pathogenesis. Levofloxacin is one of the most commonly used quinolones and has been reported to cause of TEN. On the other hand, furazolidone was proposed to augment the action of immediate hypersensitivity of levofloxacin by its cytotoxic effect and by the generation of free radicals. Here, we present a case of TEN where, levofloxacin and furazolidone were the probable cause of these adverse drug reactions. PMID- 24347776 TI - Allopurinol induced erythroderma. AB - Allopurinol, a widely prescribed urate lowering agent is responsible for various adverse drug reactions, including erythroderma. A 45-year-old male patient was admitted with the complaints of fever, redness and scaling all over the body after 3-4 weeks of allopurinol treatment for asymptomatic hyperuricemia. Elevated liver enzymes were detected in his blood analysis. Skin biopsy was consistent with drug induced erythroderma. Allopurinol was stopped and steroids were started. Patient improved over a period of 2 weeks. PMID- 24347777 TI - Sodium valproate induced priapism in an adult with bipolar affective disorder. AB - Priapism is defined as a prolonged and persistent, painful erection of the penis without sexual stimulation or arousal. There have been a few case report of priapism resulting from the use of antipsychotics. In our case, a 48-year-old male patient with a bipolar affective disorder was experiencing recurrent priapism with sodium valproate. The condition was found to resolve on stopping sodium valproate. There are no known case reports of similar complication with sodium valproate alone. PMID- 24347778 TI - Pott's disease and hypercalcemia in a patient with rheumatoid arthritis receiving methotrexate monotherapy. AB - Methotrexate (MTX) may have adverse effects on multiple organs and system. A few cases of pulmonary tuberculosis in-patients with rheumatoid arthritis (RA) while receiving MTX monotherapy has been reported in the literature. We submit a case of vertebral tuberculosis with hypercalcemia in a patient receiving MTX monotherapy. Patient with RA taking MTX for 15 years developed pancytopenia, skin necrosis, tuberculous spondylodiscitis and hypercalcemia. The present case showed adverse effects of MTX therapy may occur even after years of continuous treatment. Due to pancytopenia in older patients, life-threatening tuberculosis at unusual sites may develop. PMID- 24347779 TI - A rare case of imatinib-induced erythroderma. AB - Imatinib, a specific tyrosine kinase inhibitor is a newer anticancer agent, which has shown excellent efficacy in managing chronic myeloid leukemia. It is generally well tolerated with few side effects. Most commonly reported adverse events are maculopapular eruptions and periorbital edema. Severe adverse reactions are seen in 5% of patients. Exfoliative dermatitis has been very rarely reported with this drug. We report a case of a 52-year-old male who initially presented with a maculopapular rash and developed erythroderma on continuation of the drug. PMID- 24347780 TI - Phenytoin-induced cerebellar atrophy in an epileptic boy. AB - Epilepsy is an important health problem due to its high prevalence and potential for causing long-term morbidity. It is commonly treated in children with phenytoin sodium. It has wide pharmacokinetic variability and a narrow therapeutic range that leads to toxicity. Here, we report a case of phenytoin induced cerebellar atrophy in a 16-year-old epileptic boy who presented to the hospital with a viral infection. PMID- 24347781 TI - Pregabalin-induced self-harm behavior. AB - Antiepileptic Drugs (AEDs) such as lamotrigine, gabapentin, and oxcarbazepine may have the potential to increase the risk of self-harm or suicidal behavior. We report a case of pregabalin-induced self-inflicted multiple injuries on forearm after its continuous use. This is an interesting adverse drug reaction (ADR) that is rare, unusual, and potentially serious. PMID- 24347782 TI - Piperazine citrate induced myoclonus in a child. PMID- 24347783 TI - Drug safety guidelines: are they effective? PMID- 24347784 TI - Fatal anaphylactic reaction to iron sucrose in pregnancy: iron-induced Kounis syndrome? PMID- 24347785 TI - The smoked drum. PMID- 24347787 TI - A practical workflow for making anatomical atlases for biological research. AB - The anatomical atlas has been at the intersection of science and art for centuries. These atlases are essential to biological research, but high-quality atlases are often scarce. Recent advances in imaging technology have made high quality 3D atlases possible. However, until now there has been a lack of practical workflows using standard tools to generate atlases from images of biological samples. With certain adaptations, CG artists' workflow and tools, traditionally used in the film industry, are practical for building high-quality biological atlases. Researchers have developed a workflow for generating a 3D anatomical atlas using accessible artists' tools. They used this workflow to build a mouse limb atlas for studying the musculoskeletal system's development. This research aims to raise the awareness of using artists' tools in scientific research and promote interdisciplinary collaborations between artists and scientists. This video (http://youtu.be/g61C-nia9ms) demonstrates a workflow for creating an anatomical atlas. PMID- 24347788 TI - Electrophilic C-H Borylation and Related Reactions of B-H Boron Cations. AB - Catalytic procedures are described for aminedirected borylation of aliphatic and aromatic tertiary amine boranes. Sequential double borylation is observed in cases where two or more C-H bonds are available that allow 5-center or 6-center intramolecular borylation. The HNTf2 catalyzed borylation of benzylamine boranes provides a practical means for the synthesis of ortho-substituted arylboronic acid derivatives, suitable for Suzuki-Miyaura cross-coupling applications. PMID- 24347786 TI - Slave systems in verbal short-term memory. AB - BACKGROUND: The model of performance in short-term memory (STM) tasks that has been most influential in cognitive neuropsychological work on deficits of STM is the "working memory" model mainly associated with the work of Alan Baddeley and his colleagues. AIM: This paper reviews the model. We examine the development of this theory in studies that account for STM performances in normal (non-brain damaged) individuals, and then review the application of this theory to neuropsychological cases and specifications, modifications, and extensions of the theory that have been suggested on the basis of these cases. Our approach is to identify the major phenomena that have been discussed and to examine selected papers dealing with those phenomena in some detail. MAIN CONTRIBUTION: The main contribution is a review of the WM model that includes both normative and neuropsychological data. CONCLUSIONS: We conclude that the WM model has many inconsistencies and empirical inadequacies, and that cognitive neuropsychologists might benefit from considering other models when they attempt to describe and explain patients' performances on STM tasks. PMID- 24347789 TI - Lewis Base Activation of Lewis Acids - Group 13. In Situ Generation and Reaction of Borenium Ions. AB - A variety of Lewis bases were combined with 9-BBN-NTf2 to establish the requirements for the generation of borenium cations. Five different types of behavior were found, but the most interesting was the combination of Et3N, DABCO, 2,6-lutidine, or Ph3P=S which formed borenium ions exclusively even in sub- or superstoichiometric quantities. The 9-BBN borenium ion complex of 2,6-lutidine was found to rapidly catalyze the hydrosilylation of a variety of ketones in the presence of Et3SiH. Preliminary mechanistic experiments suggest that the reduction involves borenium ion activation of Et3SiH and not the ketone. PMID- 24347794 TI - FAS and FASL gene polymorphisms are not associated with hepatitis B virus infection based on a case-control study in a Brazilian population. AB - OBJECTIVE: This study investigated the association of the single nucleotide polymorphisms (SNPs) in the FAS and FASL genes with the outcome of hepatitis B virus (HBV) infection. METHODS: Blood samples were collected from 116 HBV infected patients at the Hospital of the Santa Casa de Misericordia Foundation (Belem, PA, Brazil). Seronegative individuals were used as controls. DNA samples were extracted from the leukocytes and assayed using the polymerase chain reaction (PCR) followed by RFLP analysis with restriction endonucleases. RESULTS: The frequencies of the mutant genotypes for -670FAS (GG), Ivs2nt-124FASL (GG), Ivs3nt-169FASL (DeltaT/DeltaT), and -844FASL (TT) were higher in the HBV patients, and the FAS-1377AA genotype was more frequent in the control group; however, the differences between the allele and genotype frequencies were not statistically significant. When the HBV patient population was divided into two groups (inactive carriers and active chronic hepatitis patients), the mutant genotypes were found to be more prevalent in the active chronic hepatitis group with respect to the FAS gene polymorphisms; however, this difference was not statistically significant. CONCLUSIONS: The results suggest that the polymorphisms in FAS and FASL genes are not associated with HBV infection or even with the natural history of the infection in the Brazilian Amazon region. PMID- 24347795 TI - Circulating autoantibodies to LGALS3BP: a novel biomarker for cancer. AB - PURPOSE: Circulating autoantibodies have been extensively investigated as possible markers for early diagnosis of cancer. The present study was carried out to investigate whether anti-LGALS3BP IgG autoantibodies could be classified as a biomarker for malignant tumors. METHODS: An in-house developed enzyme-linked immunosorbent assay was used to detect autoantibodies to LGALS3BP in sera from 71 patients with various types of cancers and 54 healthy subjects matched by age and gender. RESULTS: Patients with cancer have significant higher circulating levels of anti-LGALS3BP antibodies as compared to control subjects (P < 0.001). The test has a sensitivity of 33% and a specificity of 98%. CONCLUSIONS: Anti-LGALS3BP IgG autoantibodies are a promising biomarker for malignant tumors and could play a role in the development of a multimarker assay for the early detection of cancer. PMID- 24347797 TI - CD14 gene variants and their importance for childhood croup, atopy, and asthma. AB - BACKGROUND: The CD14 gene has an important role in the detection of inflammatory provoking pathogens and in the ensuing signaling of the innate immune response. We assessed the role of CD14 C-159T, G-1359T in the expression of asthma, croup, and allergy in Canadian school children of ages 6 to 14 years. METHODS: Children attending schools in a rural community participated in a cross-sectional survey of respiratory health. Following consent, we conducted clinical assessments to collect buccal swabs for genotyping and perform skin prick testing (SPT) to determine atopic status. Genotyping and SPT results were available for 533 and 499 children, respectively. Separate multivariable analyses that included both polymorphisms were conducted for each phenotype. RESULTS: The prevalence of asthma, allergy, and croup was 18.6%, 22.4%, and 6.6%, respectively. Children with the T/T variant of CD14 G-1359T were more likely to have physician diagnosed asthma (26.8%). Children with C/C variant of CD14 C-159T had a significantly lower prevalence of croup (2.6%). Haplotype analyses of the two CD14 polymorphisms showed that individuals with the T|T haplotype combination were significantly more likely to have asthma (P = 0.014). CONCLUSIONS: In this study, CD14 variants are important for the expression of croup and asthma but not atopy. PMID- 24347796 TI - Adiposity measurements by BMI, skinfolds and dual energy X-ray absorptiometry in relation to risk markers for cardiovascular disease and diabetes in adult males. AB - BACKGROUND: Choice of adiposity measure may be important in the evaluation of relationships between adiposity and risk markers for cardiovascular disease and diabetes. AIM: We explored the strengths of risk marker associations with BMI, a simple measure of adiposity, and with measures provided by skinfold thicknesses and dual energy X-ray absorptiometry (DXA). SUBJECTS AND METHODS: We evaluated in three subgroups of white males (n = 156-349), participating in a health screening program, the strengths of relationship between measures of total and regional adiposity and risk markers relating to blood pressure, lipids and lipoproteins, insulin sensitivity, and subclinical inflammation. RESULTS: Independent of age, smoking, alcohol intake, and exercise, the strongest correlations with adiposity measures were seen with serum triglyceride concentrations and indices of insulin sensitivity, with strengths of association showing little difference between BMI and skinfold and DXA measures of total and percent body fat (R = 0.20-0.46, P < 0.01). Significant but weaker associations with adiposity were seen for serum HDL cholesterol and only relatively inconsistent associations with adiposity for total and LDL cholesterol and indices of subclinical inflammation. CONCLUSIONS: BMI can account for variation in risk markers in white males as well as more sophisticated measures derived from skinfold thickness measurements or DXA scanning. PMID- 24347801 TI - Indigenous Principles of Wild Harvest and Management: An Ojibway Community as a Case Study. PMID- 24347800 TI - Future Scenarios as a Research Tool: Investigating Climate Change Impacts, Adaptation Options and Outcomes for the Great Barrier Reef, Australia. AB - Climate change is a significant future driver of change in coastal social ecological systems. Our knowledge of impacts, adaptation options, and possible outcomes for marine environments and coastal industries is expanding, but remains limited and uncertain. Alternative scenarios are a way to explore potential futures under a range of conditions. We developed four alternative future scenarios for the Great Barrier Reef and its fishing and tourism industries positing moderate and more extreme (2-3 degrees C above pre-industrial temperatures) warming for 2050 and contrasting 'limited' and 'ideal' ecological and social adaptation. We presented these scenarios to representatives of key stakeholder groups to assess the perceived viability of different social adaptation options to deliver desirable outcomes under varied contexts. PMID- 24347799 TI - Risk factors for mortality in hemodialysis patients: two-year follow-up study. AB - BACKGROUND: End-stage renal disease (ESRD) patients under hemodialysis (HD) have high mortality rate. Inflammation, dyslipidemia, disturbances in erythropoiesis, iron metabolism, endothelial function, and nutritional status have been reported in these patients. Our aim was to identify any significant association of death with these disturbances, by performing a two-year follow-up study. METHODS AND RESULTS: A large set of data was obtained from 189 HD patients (55.0% male; 66.4 +/- 13.9 years old), including hematological data, lipid profile, iron metabolism, nutritional, inflammatory, and endothelial (dys)function markers, and dialysis adequacy. RESULTS: 35 patients (18.5%) died along the follow-up period. Our data showed that the type of vascular access, C-reactive protein (CRP), and triglycerides (TG) are significant predictors of death. The risk of death was higher in patients using central venous catheter (CVC) (Hazard ratio [HR] = 3.03, 95% CI = 1.49-6.13), with higher CRP levels (fourth quartile), compared with those with lower levels (first quartile) (HR = 17.3, 95% CI = 2.40-124.9). Patients with higher TG levels (fourth quartile) presented a lower risk of death, compared with those with the lower TG levels (first quartile) (HR = 0.18, 95% CI = 0.05-0.58). CONCLUSIONS: The use of CVC, high CRP, and low TG values seem to be independent risk factors for mortality in HD patients. PMID- 24347802 TI - Fast Censored Linear Regression. AB - Weighted log-rank estimating function has become a standard estimation method for the censored linear regression model, or the accelerated failure time model. Well established statistically, the estimator defined as a consistent root has, however, rather poor computational properties because the estimating function is neither continuous nor, in general, monotone. We propose a computationally efficient estimator through an asymptotics-guided Newton algorithm, in which censored quantile regression methods are tailored to yield an initial consistent estimate and a consistent derivative estimate of the limiting estimating function. We also develop fast interval estimation with a new proposal for sandwich variance estimation. The proposed estimator is asymptotically equivalent to the consistent root estimator and barely distinguishable in samples of practical size. However, computation time is typically reduced by two to three orders of magnitude for point estimation alone. Illustrations with clinical applications are provided. PMID- 24347798 TI - Oxidative stress-related biomarkers in essential hypertension and ischemia reperfusion myocardial damage. AB - Cardiovascular diseases are a leading cause of mortality and morbidity worldwide, with hypertension being a major risk factor. Numerous studies support the contribution of reactive oxygen and nitrogen species in the pathogenesis of hypertension, as well as other pathologies associated with ischemia/reperfusion. However, the validation of oxidative stress-related biomarkers in these settings is still lacking and novel association of these biomarkers and other biomarkers such as endothelial progenitor cells, endothelial microparticles, and ischemia modified albumin, is just emerging. Oxidative stress has been suggested as a pathogenic factor and therapeutic target in early stages of essential hypertension. Systolic and diastolic blood pressure correlated positively with plasma F2-isoprostane levels and negatively with total antioxidant capacity of plasma in hypertensive and normotensive patients. Cardiac surgery with extracorporeal circulation causes an ischemia/reperfusion event associated with increased lipid peroxidation and protein carbonylation, two biomarkers associated with oxidative damage of cardiac tissue. An enhancement of the antioxidant defense system should contribute to ameliorating functional and structural abnormalities derived from this metabolic impairment. However, data have to be validated with the analysis of the appropriate oxidative stress and/or nitrosative stress biomarkers. PMID- 24347806 TI - A numerical method for solving a stochastic inverse problem for parameters. AB - We review recent work (Briedt et al., 2011., 2012) on a new approach to the formulation and solution of the stochastic inverse parameter determination problem, i.e. determine the random variation of input parameters to a map that matches specified random variation in the output of the map, and then apply the various aspects of this method to the interesting Brusselator model. In this approach, the problem is formulated as an inverse problem for an integral equation using the Law of Total Probability. The solution method employs two steps: (1) we construct a systematic method for approximating set-valued inverse solutions and (2) we construct a computational approach to compute a measure theoretic approximation of the probability measure on the input space imparted by the approximate set-valued inverse that solves the inverse problem. In addition to convergence analysis, we carry out an a posteriori error analysis on the computed probability distribution that takes into account all sources of stochastic and deterministic error. PMID- 24347803 TI - Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, CSD, sensitization and modulation of pain. AB - Scientific evidence support the notion that migraine pathophysiology involves inherited alteration of brain excitability, intracranial arterial dilatation, recurrent activation and sensitization of the trigeminovascular pathway, and consequential structural and functional changes in genetically susceptible individuals. Evidence of altered brain excitability emerged from clinical and preclinical investigation of sensory auras, ictal and interictal hypersensitivity to visual, auditory and olfactory stimulation, and reduced activation of descending inhibitory pain pathways. Data supporting the activation and sensitization of the trigeminovascular system include the progressive development of cephalic and whole-body cutaneous allodynia during a migraine attack. Also, structural and functional alterations include the presence of subcortical white mater lesions, thickening of cortical areas involved in processing sensory information, and cortical neuroplastic changes induced by cortical spreading depression. Here, we review recent anatomical data on the trigeminovascular pathway and its activation by cortical spreading depression, a novel understanding of the neural substrate of migraine-type photophobia, and modulation of the trigeminovascular pathway by the brainstem, hypothalamus and cortex. PMID- 24347807 TI - Volatile pheromone signalling in Drosophila. AB - Once captured by the antenna, 11-cis vaccenyl acetate (cVA) binds to an extracellular binding protein called LUSH that undergoes a conformational shift upon cVA binding. The stable LUSH-cVA complex is the activating ligand for pheromone receptors present on the dendrites of the aT1 neurones, comprising the only neurones that detect cVA pheromone. This mechanism explains the single molecule sensitivity of insect pheromone detection systems. The receptor that recognizes activated LUSH consists of a complex of several proteins, including Or67d, a member of the tuning odourant receptor family, Orco, a co-receptor ion channel, and SNMP, a CD36 homologue that may be an inhibitory subunit. In addition, genetic screens and reconstitution experiments reveal additional factors that are important for pheromone detection. Identification and functional dissection of these factors in Drosophila melanogaster Meigen should permit the identification of homologous factors in pathogenic insects and agricultural pests, which, in turn, may be viable candidates for novel classes of compounds to control populations of target insect species without impacting beneficial species. PMID- 24347808 TI - Evaluation of a Frequentist Hierarchical Model to Estimate Prevalence when sampling from a large geographic area using Pool Screening. AB - We present a frequentist Bernoulli-Beta hierarchical model to relax the constant prevalence assumption underlying the traditional prevalence estimation approach based on pooled data. This assumption is called into question when sampling from a large geographic area. Pool screening is a method that combines individual items into pools. Each pool will either test positive (at least one of the items is positive) or negative (all items are negative). Pool screening is commonly applied to the study of tropical diseases where pools consist of vectors (e.g. black flies) that can transmit the disease. The goal is to estimate the proportion of infected vectors. Intermediate estimators (model parameters) and estimators of ultimate interest (pertaining to prevalence) are evaluated by standard measures of merit, such as bias, variance and mean squared error making extensive use of expansions. Using the hierarchical model an investigator can determine the probability of the prevalence being below a prespecified threshold value, a value at which no reemergence of the disease is expected. An investigation into the least biased choice of the alpha parameter in the Beta (alpha, beta) prevalence distribution leads to the choice of alpha = 1. PMID- 24347809 TI - Ecosystem-scale biosphere-atmosphere interactions of a hemiboreal mixed forest stand at Jarvselja, Estonia. AB - During two measurement campaigns, from August to September 2008 and 2009, we quantified the major ecosystem fluxes in a hemiboreal forest ecosystem in Jarvselja, Estonia. The main aim of this study was to separate the ecosystem flux components and gain insight into the performance of a multi-species multi-layered tree stand. Carbon dioxide and water vapor fluxes were measured using the eddy covariance method above and below the canopy in conjunction with the microclimate. Leaf and soil contributions were quantified separately by cuvette and chamber measurements, including fluxes of carbon dioxide, water vapor, nitrogen oxides, nitrous oxide, methane, ozone, sulfur dioxide, and biogenic volatile organic compounds (isoprene and monoterpenes). The latter have been as well characterized for monoterpenes in detail. Based on measured atmospheric trace gas concentrations, the flux tower site can be characterized as remote and rural with low anthropogenic disturbances. Our results presented here encourage future experimental efforts to be directed towards year round integrated biosphere-atmosphere measurements and development of process-oriented models of forest-atmosphere exchange taking the special case of a multi-layered and multi species tree stand into account. As climate change likely leads to spatial extension of hemiboreal forest ecosystems a deep understanding of the processes and interactions therein is needed to foster management and mitigation strategies. PMID- 24347810 TI - A synchronized particle image velocimetry and infrared thermography technique applied to an acoustic streaming flow. AB - Subsurface coherent structures and surface temperatures are investigated using simultaneous measurements of particle image velocimetry (PIV) and infrared (IR) thermography. Results for coherent structures from acoustic streaming and associated heating transfer in a rectangular tank with an acoustic horn mounted horizontally at the sidewall are presented. An observed vortex pair develops and propagates in the direction along the centerline of the horn. From the PIV velocity field data, distinct kinematic regions are found with the Lagrangian coherent structure (LCS) method. The implications of this analysis with respect to heat transfer and related sonochemical applications are discussed. PMID- 24347805 TI - The fundamental unit of pain is the cell. AB - The molecular/genetic era has seen the discovery of a staggering number of molecules implicated in pain mechanisms [18,35,61,69,96,133,150,202,224]. This has stimulated pharmaceutical and biotechnology companies to invest billions of dollars to develop drugs that enhance or inhibit the function of many these molecules. Unfortunately this effort has provided a remarkably small return on this investment. Inevitably, transformative progress in this field will require a better understanding of the functional links among the ever-growing ranks of "pain molecules," as well as their links with an even larger number of molecules with which they interact. Importantly, all of these molecules exist side-by-side, within a functional unit, the cell, and its adjacent matrix of extracellular molecules. To paraphrase a recent editorial in Science magazine [223], although we live in the Golden age of Genetics, the fundamental unit of biology is still arguably the cell, and the cell is the critical structural and functional setting in which the function of pain-related molecules must be understood. This review summarizes our current understanding of the nociceptor as a cell-biological unit that responds to a variety of extracellular inputs with a complex and highly organized interaction of signaling molecules. We also discuss the insights that this approach is providing into peripheral mechanisms of chronic pain and sex dependence in pain. PMID- 24347811 TI - Smartphone-Based, Self-Administered Intervention System for Alcohol Use Disorders: Theory and Empirical Evidence Basis. AB - Advances in mobile technology provide an opportunity to deliver in-the-moment interventions to individuals with alcohol use disorders, yet availability of effective "apps" that deliver evidence-based interventions is scarce. We developed an immediately available, portable, smartphone-based intervention system whose purpose is to provide stand-alone, self-administered assessment and intervention. In this paper, we describe how theory and empirical evidence, combined with smartphone functionality contributed to the construction of a user friendly, engaging alcohol intervention. With translation in mind, we discuss how we selected appropriate intervention components including assessments, feedback and tools, that work together to produce the hypothesized outcomes. PMID- 24347812 TI - An individual differences analysis of memory control. AB - Performance on a wide variety of memory tasks can be hypothesized to be influenced by processes associated with controlling the contents of memory. In this project 328 adults ranging from 18 to 93 years of age performed six tasks (e.g., multiple trial recall with an interpolated interference list, directed forgetting, proactive interference, and retrieval inhibition) postulated to yield measures of the effectiveness of memory control. Although most of the patterns from earlier studies were replicated, only a few of the measures of memory control were reliable at the level of individual differences. Furthermore, the memory control measures had very weak relations with the age of the participant. Analyses examining the relations between established cognitive abilities and variables from the experimental tasks revealed that most of the variables were related only to episodic memory ability. PMID- 24347813 TI - Synonyms Provide Semantic Preview Benefit in English. AB - While orthographic and phonological preview benefits in reading are uncontroversial (see Schotter, Angele, & Rayner, 2012 for a review), researchers have debated the existence of semantic preview benefit with positive evidence in Chinese and German, but no support in English. Two experiments, using the gazecontingent boundary paradigm (Rayner, 1975), show that semantic preview benefit can be observed in English when the preview and target are synonyms (share the same or highly similar meaning, e.g., curlers-rollers). However, no semantic preview benefit was observed for semantic associates (e.g., curlers styling). These different preview conditions represent different degrees to which the meaning of the sentence changes when the preview is replaced by the target. When this continuous variable (determined by a norming procedure) was used as the predictor in the analyses, there was a significant relationship between it and all reading time measures, suggesting that similarity in meaning between what is accessed parafoveally and what is processed foveally may be an important influence on the presence of semantic preview benefit. Why synonyms provide semantic preview benefit in reading English is discussed in relation to (1) previous failures to find semantic preview benefit in English and (2) the fact that semantic preview benefit is observed in other languages even for non synonymous words. Semantic preview benefit is argued to depend on several factors attentional resources, depth of orthography, and degree of similarity between preview and target. PMID- 24347814 TI - Differential-associative processing or example elaboration: Which strategy is best for learning the definitions of related and unrelated concepts? AB - Definitions of related concepts (e.g., genotype-phenotype) are prevalent in introductory classes. Consequently, it is important that educators and students know which strategy(s) work best for learning them. This study showed that a new comparative elaboration strategy, called differential-associative processing, was better for learning definitions of related concepts than was an integrative elaborative strategy, called example elaboration. This outcome occurred even though example elaboration was administered in a naturalistic way (Experiment 1) and students spent more time in the example elaboration condition learning (Experiments 1, 2, 3), and generating pieces of information about the concepts (Experiments 2 and 3). Further, with unrelated concepts (morpheme-fluid intelligence), performance was similar regardless if students used differential associative processing or example elaboration (Experiment 3). Taken as a whole, these results suggest that differential-associative processing is better than example elaboration for learning definitions of related concepts and is as good as example elaboration for learning definitions of unrelated concepts. PMID- 24347815 TI - The Quality of Toddler Child Care and Cognitive Skills at 24 Months: Propensity Score Analysis Results from the ECLS-B. AB - Over half of the toddlers in the U.S. experience routine nonparental care, but much less is known about early care than about preschool care. This study analyzed 2-year-old child care and child outcome data from the nationally representative ECLS-B sample of children born in 2001. At two-years of age, 51% of children experienced exclusive parental care, 18% relative care, 15% family child care, and 16% center care. More children in nonparental care were in medium quality care (61%) than in high quality (26%) or low quality (13%) care. Low income children were more likely than non-low income children to be cared for by their parents and, when in care, were more often in lower quality care. The impact of toddler care quality on cognitive skills was estimated using propensity score adjustments to account for potential selection confounds due to family and child characteristics. Children's cognitive scores were higher in high or medium quality care than in low quality care, but no evidence emerged suggesting that poverty moderated the quality effects. Nevertheless, this suggests that increasing the proportion of low-income children in high quality care could reduce the achievement gap because low-income children are very unlikely to experience high quality care. PMID- 24347816 TI - WHEN DOES IMPROVING HEALTH RAISE GDP? AB - We assess quantitatively the effect of exogenous health improvements on output per capita. Our simulation model allows for a direct effect of health on worker productivity, as well as indirect effects that run through schooling, the size and age-structure of the population, capital accumulation, and crowding of fixed natural resources. The model is parameterized using a combination of microeconomic estimates, data on demographics, disease burdens, and natural resource income in developing countries, and standard components of quantitative macroeconomic theory. We consider both changes in general health, proxied by improvements in life expectancy, and changes in the prevalence of two particular diseases: malaria and tuberculosis. We find that the effects of health improvements on income per capita are substantially lower than those that are often quoted by policy-makers, and may not emerge at all for three decades or more after the initial improvement in health. The results suggest that proponents of efforts to improve health in developing countries should rely on humanitarian rather than economic arguments. PMID- 24347817 TI - Evidence for a Syndemic in Aging HIV-positive Gay, Bisexual, and Other MSM: Implications for a Holistic Approach to Prevention and Healthcare. AB - The theory of syndemics has been widely applied in HIV prevention studies of gay, bisexual, and other MSM over the last decade. Our investigation is the first to consider the applicability of the theory in a sample of aging (ages 50 and over) HIV-positive MSM, which is a growing population in the United States. A sample of 199 men were actively recruited and assessed in terms of mental health and drug use burden, as well as sexual risk behaviors. Bivariate and multivariable analyses indicate a high level of association between psychosocial burdens (i.e., drug use and mental health) and same-sex unprotected sexual behaviors, providing initial support for the applicability of the theory of syndemics to this population. Further support can be seen in participants' narratives. Findings suggest the mutually reinforcing nature of drug use, psychiatric disorders, and unprotected sexual behavior in older, HIV-positive, gay, bisexual, and other MSM, highlighting the need for holistic strategies to prevention and care among this population of older and sexually active individuals. In short, the generation of gay men who came of age in the late 1970s and 1980s, "the AIDS Generation," are continuing to mature such that further efforts must be enacted to meet the multidimensional nature of these men's physical, mental, and sexual health needs. PMID- 24347818 TI - MORE AND LESS THAN EQUAL: How Men Factor in the Reproductive Equation. AB - In both social science and medicine, research on reproduction generally focuses on women. In this article, we examine how men's reproductive contributions are understood. We develop an analytic framework that brings together Cynthia Daniels' conceptualization of reproductive masculinity (2006) with a staged view of reproduction, where the stages include the period before conception, conception, gestation, and birth. Drawing on data from two medical sites that are oriented to the period before pregnancy (preconception health care and sperm banks), we examine how gendered knowledge about reproduction produces different reproductive equations in different stages of the reproductive process. We conclude with a new research agenda that emerges from rethinking the role of men and masculinity in reproduction. PMID- 24347819 TI - Singing in the face of death: male banded wrens sing more to playback in their last breeding season. AB - Investment in signalling is subject to multiple trade-offs that vary with life stage, leading to a complex relationship between survival and trait expression. We show a negative relationship between survival and song rate in response to simulated territorial intrusion in male banded wrens (Thryophilus pleurostictus), and test several explanations for this association. (1) Male age failed to explain the association: though age affected song rate in a cross-sectional analysis, longitudinal analysis showed that individuals did not increase their song rate as they got older. Reconciling these results suggests differential selection against young males that respond to intrusion with low song rates. (2) Mortality costs of high song rates did not appear to explain the negative relationship between song rate and survival because, though song rate in response to playback was condition-dependent, high song rates in a different context did not appear to impose mortality costs. (3) High levels of territorial pressure may have increased mortality, but were not associated with high song rates in response to playback. (4) Since song rates did not increase with age, but tended to increase only in the last year of life, we tentatively suggest that the negative relationship between song rate and survival could represent a terminal investment in territorial defence by males in their final breeding season, though further work is needed to confirm this conclusion. PMID- 24347820 TI - Quasi-balanced two-wave mixing interferometer for remote ultrasound detection. AB - We present an improved detection scheme for a two-wave mixing interferometer with a Bi12SiO20 crystal. The proposed detection scheme allows quasi-balanced detection of ultrasonic signals whereby electrical disturbances are suppressed. Quasi-balancing is achieved by changing the polarity of the high voltage at the photorefractive crystal, leading to an inversion of the optical interference signal, in combination with inversion of the detector signal using a signal inverter before the data acquisition device. The polarity of the high voltage is changed by utilizing an H-bridge consisting of five high-voltage relays. Microcontrollers are used to synchronize the reversion of the high voltage at the photorefractive crystal and the inversion of the measured signals. We demonstrate remote measurement of ultrasonic waves and shown that electrical disturbances are suppressed using the quasi-balanced mode. PMID- 24347821 TI - Circulating C19MC microRNAs in preeclampsia, gestational hypertension, and fetal growth restriction. AB - The objective of the study was to identify the profile of circulating C19MC microRNAs (miR-516-5p, miR-517*, miR-518b, miR-520a*, miR-520h, miR-525, and miR 526a) in patients with established preeclampsia (n = 63), fetal growth restriction (n = 27), and gestational hypertension (n = 23). We examined the correlation between plasmatic concentrations and expression levels of microRNAs and the severity of the disease with respect to clinical signs, requirements for the delivery, and Doppler ultrasound parameters. Using absolute and relative quantification approaches, increased extracellular C19MC microRNA levels (miR-516 5p, P = 0.037, P = 0.009; miR-517*, P = 0.033, P = 0.043; miR-520a*, P = 0.001, P = 0.009; miR-525, P = 0.026, P = 0.01; miR-526a, P = 0.03, P = 0.035) were detected in patients with preeclampsia. The association analysis pointed to no relationship between C19MC microRNA plasmatic concentrations and expression profile and identified risk factors for a poorer perinatal outcome. However, the dependence between the levels of plasmatic C19MC microRNAs and the pulsatility index in the middle cerebral artery and the values of cerebroplacental ratio was demonstrated. The study brought the interesting finding that the upregulation of miR-516-5p, miR-517*, miR-520a*, miR-525, and miR-526a is a characteristic phenomenon of established preeclampsia. PMID- 24347822 TI - Dose-dependent anti-inflammatory and neuroprotective effects of an alphanubeta3 integrin-binding peptide. AB - Previous studies have shown that prevention of leukocyte infiltration by targeting integrins involved in transendothelial migration may suppress the clinical and pathological features of neuroinflammatory disease. This study was designed to investigate the effects of C16, an alphanubeta3 integrin-binding peptide, in an acute experimental allergic encephalomyelitis (EAE) rat model. Multiple histological and immunohistochemical staining, electron microscopy observation, ELISA assay, Western blot, and magnetic resonance imaging (MRI) were employed to assess the degree of inflammation, axonal loss, neuronal apoptosis, white matter demyelination, and extent of gliosis in the brain and spinal cord of differently treated EAE models. The results showed that C16 treatment could inhibit extensive leukocyte and macrophage accumulation and infiltration and reduce cytokine tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN gamma) expression levels. A significantly lower clinical score at the peak time of disease was also demonstrated in the C16 treated group. Moreover, astrogliosis, demyelination, neuronal death, and axonal loss were all alleviated in C16 treated EAE animals, which may be attributed to the improvement of microenvironment. The data suggests that C16 peptide may act as a protective agent by attenuating inflammatory progression and thus affecting the expression of some proinflammatory cytokines during neuroinflammatory disease. PMID- 24347823 TI - Plasma levels of IL-17, VEGF, and adrenomedullin and S-cone dysfunction of the retina in children and adolescents without signs of retinopathy and with varied duration of diabetes. AB - The study objective was to assess chosen biochemical parameters of blood and bioelectric function of the retina in patients with T1DM. The study group consisted of 41 patients with T1DM with no signs of diabetic retinopathy. The control group included 21 pediatric patients. We performed (1) S-cone ERG testing with retina response stimulation in both eyes at the luminance of 0.1, 0.2, and 0.5 (cd * s/m(2)) with the 440 nm blue flash and light application of the amber background (300 ph cd/m(2), 495 nm wavelength), (2) anthropometric measurements, (3) biochemical investigations: IL-17, VEGF, and ADM by the ELISA method. A comparison of the ERG results with biochemical investigations indicates a likely correlation between the worsening of retinal bioelectric function and VEGF levels growing with diabetes duration. We showed a negative correlation between ADM and HbA1c and described possible causes of ADM reduction observed in subgroup I. We demonstrated the presence of bioelectric retinal dysfunction already before the diagnosis of diabetic retinopathy, which provides new possibilities in the diagnosis of preclinical chronic complications of diabetes. The changes observed in the levels of IL-17, ADM, and VEGF suggest their involvement in the diabetic pathogenesis of eye diseases. PMID- 24347824 TI - Heat shock proteins 60 and 70 specific proinflammatory and cytotoxic response of CD4+CD28null cells in chronic kidney disease. AB - BACKGROUND: CD4(+)CD28(null) T cells are expanded in peripheral blood of patients with chronic kidney disease and associated with subclinical atherosclerosis. However, triggers for the oligoclonal expansion and activation of these cells are not clear. METHODS: We investigated twenty-five stage V-IV chronic kidney disease (CKD) patients and eight healthy subjects (HC). Peripheral mononuclear cells were isolated and incubated with heat shock protein- (HSP) 60 and 70. CD4(+)CD28(null) and CD4(+)CD28(+) cells were sorted by flowcytometry and antigen specific response was assessed by the mRNA and protein expression of interferon (IFN) gamma, perforin, and granzyme B using qRT-PCR and Elispot. RESULTS: The basal mRNA expression of IFN-gamma, perforin, and granzyme B in CD4(+)CD28(null) cells was higher in subjects with CKD compared to that in HC (P < 0.0001). Subjects with CKD also showed expression of IFN-gamma, perforin, and granzyme B in the CD4(+)CD28(+) subset, but this was much weaker than that seen in the CD4(+)CD28(null) population (P < 0.0001). We did not note the expression of these molecules at mRNA or protein level in either subset of CD4 cells in HC. After incubation with HSP60 and HSP70, CD4(+)CD28(null) cells showed increased expression at mRNA (P < 0.001) and protein level (P < 0.001). CD4(+)CD28(+) cells also showed a weak increase in expression. No antigen-specific response was noted in HC. CONCLUSION: These data show that CD4(+)CD28(null) cells in subjects with CKD react with HSP60 and HSP70 by upregulating the expression of IFN-gamma, perforin and granzyme B. Increased circulating level of HSP60 and HSP70 might play a role in initiation and/or progression of atherosclerosis in CKD subjects through perturbation of CD4(+)CD28(null) cells. PMID- 24347825 TI - Body mass index: a risk factor for retinopathy in type 2 diabetic patients. AB - The aim of the study was to investigate whether body mass index (BMI) independently or in correlation with other risk factors is associated with diabetic retinopathy (DR) progression. The study included 545 patients with type 2 diabetes. According to DR status, they were divided into three groups: group 1 (no retinopathy; n = 296), group 2 (mild/moderate nonproliferative DR; n = 118), and group 3 (severe/very severe NPDR or proliferative DR; n = 131). Patients without DR were younger than those with signs of retinopathy at time of diabetes onset whilst diabetes duration was longer in groups with severe NPDR and PDR. DR progression was correlated with diabetes duration, BMI, HbA1c, hypertension, and cholesterol. Statistical analyses showed that the progression of retinopathy increased significantly with higher BMI (gr. 1: 26.50 +/- 2.70, gr. 2: 28.11 +/- 3.00, gr. 3: 28.69 +/- 2.50; P < 0.01). We observed a significant deterioration of HbA1c and a significant increase in cholesterol and hypertension with an increase in BMI. Correlation between BMI and triglycerides was not significant. Thus, BMI in correlation with HbA1c cholesterol and hypertension appears to be associated with the progression of DR in type 2 diabetes and may serve as a predictive factor for the development of this important cause of visual loss in developed countries. PMID- 24347827 TI - NF-kappaB inhibition after cecal ligation and puncture reduces sepsis-associated lung injury without altering bacterial host defense. AB - INTRODUCTION: Since the NF-kappaB pathway regulates both inflammation and host defense, it is uncertain whether interventions targeting NF-kappaB would be beneficial in sepsis. Based on the kinetics of the innate immune response, we postulated that selective NF-kappaB inhibition during a defined time period after the onset of sepsis would reduce acute lung injury without compromising bacterial host defense. METHODS: Mice underwent cecal ligation and puncture (CLP). An NF kappaB inhibitor, BMS-345541 (50 ug/g mice), was administered by peroral gavage beginning 2 hours after CLP and repeated at 6 hour intervals for 2 additional doses. RESULTS: Mice treated with BMS-345541 after CLP showed reduced neutrophilic alveolitis and lower levels of KC in bronchoalveolar lavage fluid compared to mice treated with CLP+vehicle. In addition, mice treated with CLP+BMS had minimal histological evidence of lung injury and normal wet-dry ratios, indicating protection from acute lung injury. Treatment with the NF-kappaB inhibitor did not affect the ability of cultured macrophages to phagocytose bacteria and did not alter bacterial colony counts in blood, lung tissue, or peritoneal fluid at 24 hours after CLP. While BMS-345541 treatment did not alter mortality after CLP, our results showed a trend towards improved survival. CONCLUSION: Transiently blocking NF-kappaB activity after the onset of CLP induced sepsis can effectively reduce acute lung injury in mice without compromising bacterial host defense or survival after CLP. PMID- 24347826 TI - Hyperoxia exacerbates postnatal inflammation-induced lung injury in neonatal BRP 39 null mutant mice promoting the M1 macrophage phenotype. AB - RATIONALE: Hyperoxia exposure to developing lungs-critical in the pathogenesis of bronchopulmonary dysplasia-may augment lung inflammation by inhibiting anti inflammatory mediators in alveolar macrophages. OBJECTIVE: We sought to determine the O2-induced effects on the polarization of macrophages and the role of anti inflammatory BRP-39 in macrophage phenotype and neonatal lung injury. METHODS: We used RAW264.7, peritoneal, and bone marrow derived macrophages for polarization (M1/M2) studies. For in vivo studies, wild-type (WT) and BRP-39(-/-) mice received continuous exposure to 21% O2 (control mice) or 100% O2 from postnatal (PN) 1 to PN7 days, along with intranasal lipopolysaccharide (LPS) administered on alternate days (PN2, -4, and -6). Lung histology, bronchoalveolar lavage (BAL) cell counts, BAL protein, and cytokines measurements were performed. MEASUREMENTS AND MAIN RESULTS: Hyperoxia differentially contributed to macrophage polarization by enhancing LPS induced M1 and inhibiting interleukin-4 induced M2 phenotype. BRP-39 absence led to further enhancement of the hyperoxia and LPS induced M1 phenotype. In addition, BRP-39(-/-) mice were significantly more sensitive to LPS plus hyperoxia induced lung injury and mortality compared to WT mice. CONCLUSIONS: These findings collectively indicate that BRP-39 is involved in repressing the M1 proinflammatory phenotype in hyperoxia, thereby deactivating inflammatory responses in macrophages and preventing neonatal lung injury. PMID- 24347828 TI - Poly (ADP-ribose) polymerase mediates diabetes-induced retinal neuropathy. AB - Retinal neuropathy is an early event in the development of diabetic retinopathy. One of the potential enzymes that are activated by oxidative stress in the diabetic retina is poly (ADP-ribose) polymerase (PARP). We investigated the effect of the PARP inhibitor 1,5-isoquinolinediol on the expression of the neurodegeneration mediators and markers in the retinas of diabetic rats. After two weeks of streptozotocin-induced diabetes, rats were treated with 1,5 isoquinolinediol (3 mg/kg/day). After 4 weeks of diabetes, the retinas were harvested and the levels of reactive oxygen species (ROS) were determined fluorometrically and the expressions of PARP, phosporylated-ERK1/2, BDNF, synaptophysin, glutamine synthetase (GS), and caspase-3 were determined by Western blot analysis. Retinal levels of ROS, PARP-1/2, phosphorylated ERK1/2, and cleaved caspase-3 were significantly increased, whereas the expressions of BDNF synaptophysin and GS were significantly decreased in the retinas of diabetic rats, compared to nondiabetic rats. Administration of 1,5-isoquinolinediol did not affect the metabolic status of the diabetic rats, but it significantly attenuated diabetes-induced upregulation of PARP, ROS, ERK1/2 phosphorylation, and cleaved caspase-3 and downregulation of BDNF, synaptophysin, and GS. These findings suggest a beneficial effect of the PARP inhibitor in increasing neurotrophic support and ameliorating early retinal neuropathy induced by diabetes. PMID- 24347829 TI - Systemic treatments for noninfectious vitreous inflammation. AB - Vitreous inflammation, or vitritis, may result from many causes, including both infectious and noninfectious, including rheumatologic and autoimmune processes. Vitritis is commonly vision threatening and has serious sequelae. Treatment is frequently challenging, but, today, there are multiple methods of systemic treatment for vitritis. These categories include corticosteroids, antimetabolites, alkylating agents, T-cell inhibitors/calcineurin inhibitors, and biologic agents. These treatment categories were reviewed last year, but, even over the course of just a year, many therapies have made progress, as we have learned more about their indications and efficacy. We discuss here discoveries made over the past year on both existing and new drugs, as well as reviewing mechanisms of action, clinical dosages, specific conditions that are treated, adverse effects, and usual course of treatment for each class of therapy. PMID- 24347830 TI - Myeloperoxidase-dependent LDL modifications in bloodstream are mainly predicted by angiotensin II, adiponectin, and myeloperoxidase activity: a cross-sectional study in men. AB - The present paradigm of atherogenesis proposes that low density lipoproteins (LDLs) are trapped in subendothelial space of the vascular wall where they are oxidized. Previously, we showed that oxidation is not restricted to the subendothelial location. Myeloperoxidase (MPO), an enzyme secreted by neutrophils and macrophages, can modify LDL (Mox-LDL) at the surface of endothelial cells. In addition we observed that the activation of the endothelial cells by angiotensin II amplifies this process. We suggested that induction of the NADPH oxidase complex was a major step in the oxidative process. Based on these data, we asked whether there was an independent association, in 121 patients, between NADPH oxidase modulators, such as angiotensin II, adiponectin, and levels of circulating Mox-LDL. Our observations suggest that the combination of blood angiotensin II, MPO activity, and adiponectin explains, at least partially, serum Mox-LDL levels. PMID- 24347832 TI - Oxidized LDL in inflammation: from bench to bedside. PMID- 24347831 TI - Follistatin-like 1: a potential mediator of inflammation in obesity. AB - Obesity is associated with a state of chronic low-grade inflammation, which contributes to insulin resistance and type 2 diabetes. However, the molecular mechanisms that link obesity to inflammation are not fully understood. Follistatin-like 1 (FSTL1) is a novel proinflammatory cytokine that is expressed in adipose tissue and secreted by preadipocytes/adipocytes. We aimed to test whether FSTL1 could have a role in obesity-induced inflammation and insulin resistance. It was found that FSTL1 expression was markedly decreased during differentiation of 3T3-L1 preadipocytes but reinduced by TNF-alpha. Furthermore, a significant increase in FSTL1 levels was observed in adipose tissue of obese ob/ob mice, as well as in serum of overweight/obese subjects. Mechanistic studies revealed that FSTL1 induced inflammatory responses in both 3T3-L1 adipocytes and RAW264.7 macrophages. The expression of proinflammatory mediators including IL-6, TNF-alpha, and MCP-1 was upregulated by recombinant FSTL1 in a dose-dependent manner, paralleled with activation of the IKKbeta-NFkappaB and JNK signaling pathways in the two cell lines. Moreover, FSTL1 impaired insulin signaling in 3T3 L1 adipocytes, as revealed by attenuated phosphorylation of both Akt and IRS-1 in response to insulin stimulation. Together, our results suggest that FSTL1 is a potential mediator of inflammation and insulin resistance in obesity. PMID- 24347833 TI - A possible role for CD8+ T lymphocytes in the cell-mediated pathogenesis of pemphigus vulgaris. AB - Pemphigus vulgaris (PV) is an autoimmune blistering disease whose pathogenesis involves both humoral and cell-mediated immune response. Though the pathogenetic role of autoantibodies directed against desmoglein 3 is certain, a number of other factors have been suggested to determine acantholysis in PV. In this study we examined the possible role of CD8+ T cells in the development of acantholysis by a passive transfer of PV autoantibodies using CD8 deficient mice, and we also studied the inflammatory infiltrate of PV skin lesions by immunohistochemical staining. The results of the immunohistochemical staining to study the expression of CD3, CD4, and CD8 in PV skin lesions showed that CD4+ are more expressed than CD8+ in the inflammatory infiltrate of PV lesions, confirming the data of the previous literature. The passive transfer study showed a lower incidence of pemphigus in the group of CD8 deficient mice compared to the control one of wild type mice. These results suggest that CD8+ T cells may play a role in the pathogenesis of PV, perhaps through the Fas/FasL pathway. PMID- 24347834 TI - Mediators of inflammation as targets for chronic pain treatment. PMID- 24347835 TI - Insulin therapy with personal insulin pumps and early angiopathy in children with type 1 diabetes mellitus. AB - OBJECTIVE: Assessment of the effect of a treatment method change from multiple daily insulin injection (MDI) to continuous subcutaneous insulin infusion (CSII) on the development of early angiopathy in children with T1DM with or without retinopathy. METHODS: The study pump group involved 32 diabetic children aged 14.8, with the initial HbA1c level of 8.3%, previously treated by MDI. The patients were examined before pump insertion and after 3 and 6 months of CSII. We assessed HbA1c level, carotid artery intima-media thickness (c-IMT), and flow mediated dilatation (FMD) of the brachial artery. The pump group was compared to a group of eight teenagers with diagnosed nonproliferative retinopathy, treated with MDI. RESULTS: HbA1c in the entire group was found to improve in the second and in the third examination. During 6 months of CSII, FMD increased and IMT decreased. Retinopathic adolescents had significantly thicker IMT and lower FMD compared to baseline results of the pump group. Treatment intensification in the retinopathy-free children enhanced these differences. CONCLUSIONS: CSII is associated with lower IMT and higher FMD. Whether on the long-run CSII is superior to MDI to delay the occurrence of diabetes late complications remains to be explained. PMID- 24347836 TI - Histopathological implications of Aspergillus infection in lung. AB - This paper opens with a discussion on the significance of invasive fungal infections in advanced contemporary medicine, with an emphasis on the intractability of disease management and the difficulties of diagnosis. This is followed by a discussion concerning classification, histopathological features, and pathophysiology. While it has been largely accepted that Aspergillus species is recognized by cellular receptors and attacked by neutrophils, the radiological and macroscopic findings linking infection with neutropenia remain unconfirmed. In an effort to gain a better understanding of the pathophysiology and pathogenesis of invasive aspergillosis, we wish to emphasize the utility of radiological and histopathological examinations since these can provide detailed information on the extremely complex interaction between the causative microbes and tissue responses. A review of noninvasive or semi-invasive aspergillosis is also provided, with particular emphasis on chronic necrotizing pulmonary aspergillosis, which is recognized as a transition form of simple pulmonary aspergilloma and invasive pulmonary aspergillosis, although few findings have been reported in this area. PMID- 24347837 TI - E. coli endotoxin modulates the expression of Sirtuin proteins in PBMC in humans. AB - BACKGROUND: Sirtuin (SIRT) proteins are class I histone deacetylases displaying gene regulatory functions in inflammatory, cancer, and metabolic diseases. These SIRT actions involve the nuclear factor kappa B and its inhibitor I kappa B pathway. However, the regulation of SIRT in vivo is still unclear. MATERIAL AND METHODS: In a human endotoxemia model, 20 healthy male subjects received an intravenous bolus of 2 ng/kg body weight Escherichia coli endotoxin (LPS). SIRT expression was investigated in peripheral blood mononuclear cells (PBMC) with qPCR and Western blot before and 3 hours, 6 hours, and 24 hours after LPS challenge. Additionally, SIRT regulation was studied in vitro in cultivated PBMC after incubation with 20 ng/mL LPS. RESULTS: A downregulation by >40% of SIRT1 mRNA was detectable 3 hours after LPS and of SIRT3 mRNA 6 hours after LPS. SIRT3, IkappaBalpha, and IkappaB-beta protein expressions were decreased 3 and 6 hours after LPS. SIRT2 mRNA or protein expression did not change following LPS. These findings were consistent in vitro and associated with augmented phosphorylation of IkappaB-beta. DISCUSSION: In this E. coli endotoxemia model, SIRT1 and SIRT3 mRNA expressions in PBMC in humans were reduced after LPS challenge. This suggests that SIRT may represent an inflammatory target protein in vivo. PMID- 24347838 TI - Clearance of apoptotic cells by macrophages induces regulatory phenotype and involves stimulation of CD36 and platelet-activating factor receptor. AB - Phagocytosis of apoptotic cells (efferocytosis) induces macrophage differentiation towards a regulatory phenotype (IL-10(high)/IL-12p40(low)). CD36 is involved in the recognition of apoptotic cells (AC), and we have shown that the platelet-activating factor receptor (PAFR) is also involved. Here, we investigated the contribution of PAFR and CD36 to efferocytosis and to the establishment of a regulatory macrophage phenotype. Mice bone marrow-derived macrophages were cocultured with apoptotic thymocytes, and the phagocytic index was determined. Blockage of PAFR with antagonists or CD36 with specific antibodies inhibited the phagocytosis of AC (~70-80%). Using immunoprecipitation and confocal microscopy, we showed that efferocytosis increased the CD36 and PAFR colocalisation in the macrophage plasma membrane; PAFR and CD36 coimmunoprecipitated with flotillin-1, a constitutive lipid raft protein, and disruption of these membrane microdomains by methyl-beta-cyclodextrin reduced AC phagocytosis. Efferocytosis induced a pattern of cytokine production, IL 10(high)/IL-12p40(low), that is, characteristic of a regulatory phenotype. LPS potentiated the efferocytosis-induced production of IL-10, and this was prevented by blocking PAFR or CD36. It can be concluded that phagocytosis of apoptotic cells engages CD36 and PAFR, possibly in lipid rafts, and this is required for optimal efferocytosis and the establishment of the macrophage regulatory phenotype. PMID- 24347840 TI - Message from the president, Indian chest society. PMID- 24347839 TI - Sample size estimation for alternating logistic regressions analysis of multilevel randomized community trials of under-age drinking. AB - Under-age drinking is an enormous public health issue in the USA. Evidence that community level structures may impact on under-age drinking has led to a proliferation of efforts to change the environment surrounding the use of alcohol. Although the focus of these efforts is to reduce drinking by individual youths, environmental interventions are typically implemented at the community level with entire communities randomized to the same intervention condition. A distinct feature of these trials is the tendency of the behaviours of individuals residing in the same community to be more alike than that of others residing in different communities, which is herein called 'clustering'. Statistical analyses and sample size calculations must account for this clustering to avoid type I errors and to ensure an appropriately powered trial. Clustering itself may also be of scientific interest. We consider the alternating logistic regressions procedure within the population-averaged modelling framework to estimate the effect of a law enforcement intervention on the prevalence of under-age drinking behaviours while modelling the clustering at multiple levels, e.g. within communities and within neighbourhoods nested within communities, by using pairwise odds ratios. We then derive sample size formulae for estimating intervention effects when planning a post-test-only or repeated cross-sectional community-randomized trial using the alternating logistic regressions procedure. PMID- 24347841 TI - Message from the hon. Secretary, Indian chest society. PMID- 24347842 TI - From the Editor's Desk. PMID- 24347843 TI - Voicing the natural way. PMID- 24347844 TI - Voice recognition is here comma like it or not period. AB - Voice recognition (VR) technology needs improvement, but is as integral to the current practice of radiology as Radiology Information Systems and Picture Archival and Communication Systems. In the 1990s, the radiology community gave VR technology a rather lukewarm reception, but since then it has emerged as the predominant method of radiology reporting in the United States. In this article, we examine how VR technology works, outline the positive and negative aspects of VR technology on work flow, identify common VR transcription errors and review the discussion on VR adoption in the recent literature. We add to the discussion our personal experiences in an international teleradiology group. PMID- 24347845 TI - MRI brain in monohalomethane toxic encephalopathy: A case report. AB - Monohalomethanes are alkylating agents that have been used as methylating agents, laboratory reagents, refrigerants, aerosol propellants, pesticides, fumigants, fire-extinguishing agents, anesthetics, degreasers, blowing agents for plastic foams, and chemical intermediates. Compounds in this group are methyl chloride, methyl bromide, methyl iodide (MI), and methyl fluoride. MI is a colorless volatile liquid used as a methylating agent to manufacture a few pharmaceuticals and is also used as a fumigative insecticide. It is a rare intoxicant. Neurotoxicity is known with both acute and chronic exposure to MI. We present the characteristic magnetic resonance imaging (MRI) brain findings in a patient who developed neuropsychiatric symptoms weeks after occupational exposure to excessive doses of MI. PMID- 24347846 TI - Call-Fleming syndrome. AB - Call-Fleming syndrome is a part of reversible cerebral vasoconstriction syndrome (RCVS) group and is thought to be of idiopathic origin. It is classically described to be having multisegmental, focal vasospasms in the cerebral arteries. It is characterized clinically by the sudden onset of severe headache, classically described as thunderclap headache, with or without associated neurological deficits. The importance of it lies in that it is a potentially reversible cause of this clinical presentation, unlike its other counterparts, aneurysmal subarachnoid hemorrhage (SAH) or vasculitis. PMID- 24347847 TI - Cavernous hemangioma located at the foramen of Monro: Radiopathological correlation. AB - Intraventricular cavernous hemangiomas are rare. Amongst them, cavernomas located at the foramen of Monro are of greater interest because of their rare location, varied symptoms, and often association with hydrocephalus. We present a rare case of cavernous hemangioma located at foramen of Monro, with its radiopathological confirmation. PMID- 24347848 TI - Herniation of spinal cord into nerve root avulsion pseudomeningocele: A rare cause of delayed progressive neurological deficit. AB - We present a patient with old traumatic right brachial plexus injury, who developed progressive neurological deterioration 4 years after the initial injury. On magnetic resonance imaging (MRI), herniation of the upper dorsal cord was noted into a post-traumatic pseudomeningocele. Though the herniation of cord into a post-traumatic pseudomeningocele is very rare, it should be suspected in cases of delayed progressive myelopathy. A three dimensional (3-D) T2-weighted sequence such as Sampling Perfection with Application optimized Contrasts using different flip angle Evolution (SPACE) or constructive interference in steady state (CISS) provides optimal visualization of the herniated cord and helps in surgical planning. PMID- 24347849 TI - Pseudoaneurysm of internal carotid artery after carotid body tumor excision. AB - The common causes of pseudoaneurysms of internal carotid artery (ICA) in the neck are penetrating trauma, head and neck surgeries, carotid endarterectomies, infiltrating metastatic lymph nodes and neoplasms. We report a young male patient who presented with a swelling in left upper neck diagnosed as carotid body tumor with ultrasonography and magnetic resonance imaging. Subadventitial excision of the tumor was done. The patient developed dense right hemiplegia in the immediate postoperative period. Doppler study of neck revealed left ICA dissection with partial thrombosis of the lumen. Computed tomography of the brain revealed nonhemorrhagic left capsuloganglionic infarct and he was managed conservatively with heparin. Follow-up Doppler study done 2 weeks later revealed pseudoaneurysm of the ICA. Attempts to obliterate the pseudoaneurysm by interventional procedures failed due to the narrow neck of the pseudoaneurysm. Heparin was stopped and patient was maintained only on oral aspirin. Doppler study repeated 1 week later showed spontaneous thrombosis of the pseudoaneurysm with good flow in the distal ICA. To the best of our knowledge, only one case of pseudo pseudoaneurysm complicating surgical resection of carotid body tumor has been reported so far The etiology, imaging features, and treatment options of pseudoaneurysms are discussed. PMID- 24347850 TI - Imaging features of rhinosporidiosis on contrast CT. AB - CONTEXT: Rhinosporidiosis is a chronic granulomatous disease endemic in certain regions of India. Computed tomography (CT) imaging appearances of rhinosporidiosis have not been previously described in the literature. AIMS: To study imaging features in rhinosporidiosis with contrast-enhanced CT and elucidate its role in the evaluation of this disease. MATERIALS AND METHODS: Sixteen patients with pathologically proven rhinosporidiosis were included in the study. Contrast-enhanced CT images were analyzed retrospectively and imaging findings were correlated with surgical and histopathologic findings. RESULTS: A total of 29 lesions were found and evaluated. On contrast-enhanced CT, rhinosporidiosis was seen as moderately enhancing lobulated or irregular soft tissue mass lesions in the nasal cavity (n = 13), lesions arising in nasal cavity and extending through choana into nasopharynx (n = 5), pedunculated polypoidal lesions arising from the nasopharyngeal wall (n = 5), oropharyngeal wall (n = 2), larynx (n = 1), bronchus (n = 1), skin and subcutaneous tissue (n = 2). The inferior nasal cavity comprising nasal floor, inferior turbinate, and inferior meatus was the most common site of involvement (n = 13). Surrounding bone involvement was seen in the form of rarefaction (n = 6), partial (n = 3) or complete erosion (n = 3) of inferior turbinate, thinning of medial maxillary wall (n = 2), and septal erosion (n = 2). Nasolacrimal duct involvement was seen in four cases. CONCLUSIONS: Contrast-enhanced CT has an important role in delineating the site and extent of the disease, as well as the involvement of surrounding bone, nasolacrimal duct and tracheobronchial tree. This provides a useful roadmap prior to surgery. PMID- 24347851 TI - Role of dual-energy contrast-enhanced digital mammography as a problem-solving tool in dense breasts: A case report. AB - Breast density is strongly and independently related to the risk of breast cancer. Women with very dense breasts may have up to five times higher chances of developing malignancy as compared to those with less breast density. Detecting lesions in extremely dense or heterogeneous breasts on screening mammogram can be difficult. We report a case of incidental bilateral breast malignancy in an asymptomatic patient in whom mammogram and screening ultrasound were equivocal. PMID- 24347852 TI - Variations of celiac axis, common hepatic artery and its branches in 600 patients. AB - PURPOSE: To evaluate the spectrum of celiac axis, common hepatic artery (CHA), right, left, middle hepatic artery and gastroduodenal artery variations by using spiral computed tomography (CT). MATERIALS AND METHODS: A retrospective review of Multidetector CT (MDCT) abdominal angiography scans was performed in patients sent for various liver and other abdominal pathologies between January 2012 and February 2013. A total of 600 patients were evaluated. Definitions of CHA, ambiguous celiac axis, course and division patterns of CHA, replaced hepatic artery, accessory hepatic artery and middle hepatic artery were used as proposed by Song et al., Covey et al., and Wang et al. The pattern of the aortic origin of branches of celiac axis, common hepatic artery and its branches was analyzed. RESULTS: Six types of celiac axis anatomic variations were identified in our study. A total of 546 of the 600 patients had a normal celiac axis anatomy. Anatomic variations were seen in 5.5% of patients. Ambiguous anatomy was seen in 3.5% of the patients. CHA originated from celiac axis in 95.83% of the patients. Variations in anatomic origin of CHA were seen in 8 patients. Ambiguous dual pathway was seen in 4 patients. Normal Sp-preportal course of CHA was identified in 97.78% of cases, Sp-retroportal course in 7 patients, Tp-preportal course in 2, Tp-retroportal in 1, Ip-preportal in 1 and through Ligamentum venosum in 2 patients. Normal origin of RHA from HAP was seen in 79.6% patients. Replaced origin of RHA was seen in 15.16% cases and Accessory origin of RHA was seen in 5.16% cases. LHA originated from HAP in 81.5% patients. Replaced LHA origin was seen in 10.8% cases and Accessory LHA origin seen in 7.6% cases. MHA originated from RHA in 41.3% patients, LHA in 27.83% and from CHA in 4.5% cases. Origin of MHA could not be defined in 26.3% of patients. GDA originated from CHA in 97.6% of patients, from celiac axis in 1.6%, from RHA in 0.33% in patients. Trifurcation of CHA was seen in 7.16% and quadrifurcation of CHA in 2.16%. CONCLUSION: CT Angiography is a safe and highly sensitive and accurate modality for evaluation of arterial anatomy and its variants. PMID- 24347853 TI - CT imaging findings and endovascular management of isolated spontaneous dissecting aneurysm of celiac artery. AB - Isolated spontaneous dissecting aneurysm of celiac artery without concomitant involvement of aorta is a rare entity and only a few cases are reported in the literature. More cases are being detected recently with greater advancements in CT technology. Clinicians and emergency physicians should be aware of this condition and should include it in the differential diagnosis of patients who present with refractory postprandial epigastric pain, particularly in middle-aged men. We present a case of a 45-year-old male with isolated spontaneous dissecting celiac artery aneurysm, with special emphasis on CT findings and the role of endovascular management. PMID- 24347854 TI - Extrahepatic biliary atresia with choledochal cyst: Prenatal MRI predicted and post natally confirmed: A case report. AB - Extrahepatic biliary atresia (EHBA) is an uncommon cause of neonatal jaundice. Antenatal Magnetic Resonance Imaging (MRI) diagnosis of EHBA has not been published to the best of our knowledge till date. EHBA with cystic component is likely to be mistaken for choledochal cyst. A case that was antenatally predicted and postnatally confirmed by surgery and histopathology is being reported. All imaging signs are analyzed herewith. Imaging helps in the prediction of EHBA and also helps in early postnatal surgical referral which in turn improves the results of Kasai's portoenterostomy. PMID- 24347855 TI - Herlyn-Werner-Wunderlich syndrome presenting with infertility: Role of MRI in diagnosis. AB - Herlyn-Werner-Wunderlich syndrome (HWWS), characterized by uterus didelphys, obstructed hemivagina, and ipsilateral renal agenesis, is an uncommon combined Mullerian and mesonephric duct anomaly, and its presentation in adulthood is even rarer. We report here a 22-year-old female presenting with primary infertility where magnetic resonance imaging (MRI) suggested the diagnosis of HWWS with endometriosis. In a patient of infertility with endometriosis and unilateral renal agenesis, diagnosis of HWWS should be suspected and MRI is the investigation of choice for such anomalies. PMID- 24347856 TI - MR imaging of carcinoma cervix. AB - Cervical cancer is a common gynecological malignancy and a frequent cause of death. Patient outcome depends on tumor stage, size, nodal status, and histological grade. Correct tumor staging is important to decide the the treatment strategy. Magnetic Resonance Imaging is accepted as a preferred imaging modality to assess the prognostic factors. PMID- 24347857 TI - Transrectal ultrasound-guided aspiration in the management of prostatic abscess: A single-center experience. AB - OBJECTIVES: The safety and efficacy of transrectal ultrasound (TRUS) guided aspiration of prostatic abscess (PA) is known. The objective of this study is to describe a treatment algorithm for management of PA with TRUS-guided aspiration, emphasizing on indications and factors predicting the treatment outcome. MATERIALS AND METHODS: After the institutional review board approval was obtained, a retrospective study was done of all patients suspected with PA on digital rectal examination (DRE) and confirmed on TRUS. An 18-gauge two-part needle was used for aspiration. The real-time TRUS-guided aspiration of PA was done in the longitudinal axis. The aspiration of pus and the sequential collapse of cavity was seen "real time." A suprapubic catheter was placed, if the patient had urinary retention, persistent dysuria, and/or severe lower urinary tract symptoms (LUTS). Success was defined as complete resolution of the abscess and/or symptoms. RESULTS: Forty-eight patients were studied with PA, with a mean age of 54.6 +/- 14.6 (range 26-79) years. The DRE diagnosed PA in 22 (45.83%) patients, while abdominal sonography diagnosed PA in 13 (27.08%) patients. TRUS revealed a hypoechoic area with internal echoes in all 48 (100%) patients. The diagnosis was confirmed in all 48 cases with aspiration. The mean size of the lesion was 3.2 +/ 1.2 (range 1.5-8) cm. Mean volume aspirated was 10.2 ml (range 2.5-30 ml). Complete resolution after first aspiration was observed in 20 (41.66%) patients. An average of 4.1 (range 1-7) aspirations was required for complete resolution which was seen in 41 patients (85.42%). Seven (14.58%) patients required transurethral resection (deroofing) of the abscess cavity. We formulated a treatment algorithm based on the above findings. CONCLUSION: The proposed algorithm based on our experience suggests that patients with PA larger than 2 cm with severe LUTS and/or leukocytosis benefit from TRUS-guided aspiration. In addition, these patients are benefitted from urinary drainage (either perurethral or suprapubic). The algorithm also suggests that if two attempts of TRUS aspiration fail, these patients benefit from transurethral drainage. PMID- 24347858 TI - Rare complications of cesarean scar. AB - Cesarean scar pregnancy (CSP) and cesarean scar dehiscence (CSD) are the most dreaded complications of cesarean scar (CS). As the incidence of CS is increasing worldwide, so is the incidence of CSP, especially in cases with assisted reproduction techniques. It is of utmost importance to diagnose CSP in the early first trimester, as it can lead to myometrial rupture with fatal outcome. On the other hand, CSD may be encountered during pregnancy or in the postpartum period. CSD in the postpartum period is very rare and can cause secondary postpartum hemorrhage (PPH) leading to increased maternal morbidity or even death if not diagnosed and managed promptly. Both complications can be diagnosed on ultrasonography (USG) and confirmed on magnetic resonance imaging (MRI). These two conditions carry high morbidity and mortality. In this article, we highlight the role of imaging in the early diagnosis and management of these conditions. PMID- 24347859 TI - Increased fetal endocardial echogenicity mimicking endocardial fibroelastosis following maternal organophosphorus poisoning and its complete regression in utero. AB - Fetal endocardial fibroelastosis (EFE) has been diagnosed by antenatal ultrasonography in the past few years. A typical case of isolated endocardial fibroelastosis is illustrated here, in a fetus of 22 weeks of gestational age exposed to maternal organophosphorus poisoning at 20 weeks. No other structural cardiac or other systemic anomalies were detected in this fetus. The abnormal fetal echocardiographic features mimicking endocardial fibroelastosis completely regressed after 14 weeks and a normal full-term baby was delivered. Postnatal echocardiogram showed normal cardiac parameters. The diagnostic features mimicking EFE following maternal organophosphorus poisoning at 20 weeks of gestational age and the subsequent complete reversal of these changes after 14 weeks of diagnosis are reported for the first time in the literature. PMID- 24347860 TI - Validation of the global reference for fetal weight and birth weight percentiles. AB - The objective of this study was to evaluate whether the global reference curves adapted on the basis of WHO data for India and the Hadlock reference curves fit the population in India and to validate the reference curves. The data were retrieved retrospectively from the records of women registration for antenatal care at a charitable maternity hospital in Mumbai, India. All pregnancies were dated on CRL obtained before 14 weeks. Births before 34(th) week were excluded. The expected frequencies of birth weights below the 1(st), 5(th), 10(th), 50(th), 90(th), 95(th) and 99(th) centiles from three reference ranges were compared with observed frequencies. It was found that the WHO generic reference adapted to India significantly underpredicted the birth weights and that the Hadlock reference ranges significantly overpredicted the birth weights. The use of generic reference adapted to Sri Lanka showed a better fit to the observed data. We concluded that global reference curves adapted on the basis of WHO data for India and the Hadlock reference ranges do not fit all the population in India and the charts need validation. Reference charts modified on the basis of data for Sri Lankan population show a better fit to the observed data, and therefore are more appropriate for use in clinical practice in South India. PMID- 24347861 TI - High-resolution ultrasound imaging of cutaneous lesions. AB - High-resolution variable frequency ultrasound imaging is increasingly being used in the noninvasive evaluation of various cutaneous diseases. It plays a complimentary role to physical examination in the assessment of cutaneous lesions. It is the only imaging modality useful in the evaluation of superficial cutaneous lesions that are too small to be evaluated on computed tomography (CT) or magnetic resonance imaging (MRI) and is helpful in reducing invasive procedures like biopsies and fine needle aspirations. In this article, we seek to describe the relevance and basic principles of cutaneous ultrasound, imaging findings of normal skin, current applications of high-resolution ultrasound in the diagnosis and management of various dermatological conditions, along with the features of some commonly encountered lesions. PMID- 24347862 TI - Unilateral sternocostoclavicular hyperostosis in a patient with ankylosing spondylitis: A case report with color Doppler ultrasonogram findings. AB - Sternocostoclavicular hyperostosis is a chronic inflammatory disorder affecting the sternoclavicular joint and upper ribs. There is a strong association with seronegative spondyloarthropathy in which bilateral involvement is common. Ultrasonography and Color Doppler findings of this entity have not been described previously, to the best of our knowledge. We describe the findings in a patient of ankylosing spondylitis who was referred for unilateral sternoclavicular joint swelling. PMID- 24347863 TI - Thermography in ocular inflammation. AB - BACKGROUND AND OBJECTIVES: The purpose of this study was to evaluate ocular inflammatory and non-inflammatory conditions using commercially available thermal camera. MATERIALS AND METHODS: A non-contact thermographic camera (FLIR P 620) was used to take thermal pictures of seven cases of ocular inflammation, two cases of non-inflammatory ocular pathology, and one healthy subject with mild refractive error only. Ocular inflammatory cases included five cases of scleritis, one case of postoperative anterior uveitis, and a case of meibomian gland dysfunction with keratitis (MGD-keratitis). Non-inflammatory conditions included a case of conjunctival benign reactive lymphoid hyperplasia (BRLH) and a case of central serous chorio-retinopathy. Thermal and non-thermal photographs were taken, and using analyzing software, the ocular surface temperature was calculated. RESULTS: Patient with fresh episode of scleritis revealed high temperature. Eyes with MGD-keratitis depicted lower temperature in clinically more affected eye. Conjunctival BRLH showed a cold lesion on thermography at the site of involvement, in contrast to cases of scleritis with similar clinical presentation. CONCLUSION: Ocular thermal imaging is an underutilized diagnostic tool which can be used to distinguish inflammatory ocular conditions from non inflammatory conditions. It can also be utilized in the evaluation of tear film in dry eye syndrome. Its applications should be further explored in uveitis and other ocular disorders. Dedicated "ocular thermographic" camera is today's need of the hour. PMID- 24347864 TI - Research in pediatric surgery: Indian scenario. PMID- 24347865 TI - Endoscopic treatment of vesico-ureteral reflux: Experience of 99 ureteric moieties. AB - AIMS: To study the outcome of endoscopic hyaluronic acid/dextranomer injection in patients with vesico-ureteric reflux (VUR). MATERIALS AND METHODS: Sixty-three children were evaluated with a median follow up of 18 months (12-55 months) before injecting hyaluronic acid/dextranomer in a total of 99 ureteric moieties. Median age at presentation was 24 months (6-72 months). Primary VUR was the main presenting diagnosis in 60%. Patients were monitored for urinary tract infection (UTI), glomerular filtration rate (GFR), renal scarring, persistence, or appearance of contra-lateral reflux. RESULTS: Grade III VUR was the most common (38%) followed by Grade IV (24%), Grade V (17%), Grade II (14%), and Grade I (7%). Most common cause for VUR was Primary (60%), followed by posterior urethral valve (PUV) (19%), bladder exstrophy (5%), anorectal malformation (ARM), epispadias, and duplex system. Analysis of patients characteristics at presentation revealed renal scarring (40%), split renal functions <35% (35%), recurrent UTI (15%), GFR <50 ml/min/1.73 m(2) (15%), serum creatinine >1.4 mg/dL (10%). Complete resolution (100%) of Grade I and Grade II VUR was achieved after single injection. For Grade III VUR, single injection resolved reflux in 85.5% ureters, 100% resolution was seen after 2(nd) injection. In Grade IV VUR, 1(st) injection resolved VUR in 83.3% ureters, 95.8% ureters were reflux free after 2(nd) injection, and 100% resolution was seen after 3(rd) injection. In Grade V VUR, 94% ureters showed absent reflux after three injections. CONCLUSION: Hyaluronic acid/dextranomer injection holds promise even in higher grades of VUR. PMID- 24347866 TI - A survey of musculoskeletal and aesthetic abnormalities after thoracotomy in pediatric patients. AB - OBJECTIVE: To study the incidence and type of musculoskeletal and aesthetic abnormalities after thoracotomy in children. MATERIALS AND METHODS: Children below 12 years of age who had undergone thoracotomy for any condition and have at least 2 years follow up were included in the study. Detailed assessment of the patients included: history and general examination, clinical examination of chest and musculoskeletal system, X-ray chest including bilateral shoulders [antero posterior (AP), lateral, oblique], X-ray whole spine (AP, lateral, right and left side bending AP view). RESULTS: Fifty-two pateints were recruited. The incidences of various clinically and radiologically assessed musculoskeletal and aesthetic abnormalities observed were: winging of scapula (5.7%), ipsilateral elevation of shoulder (5.7%), fixation of skin cicatrix to bony thorax (7.7%), maldevelopment of pectoral muscles (11.5%), asymmetry of the level of nipples (1.9%), rib fusion (5.7%), crowding of ribs (9.6%), mediastinal shift (3.8%), decreased space available for lungs (3.8%), Scoliosis with Cobb's angle >10(0) (1.9%). CONCLUSIONS: The incidences of musculoskeletal and aesthetic abnormalities after posterolateral thoracotomies in children were low. Longer follow up of patients after thoracotomy is needed to pick up these abnormalities as the children grow. PMID- 24347867 TI - Plasma renin activity: An early marker of progressive renal disease in posterior urethral valves. AB - INTRODUCTION: A significant number of children with posterior urethral valves (PUV) develop chronic renal failure (CRF) due to activation of the renin angiotensin system (RAS). We investigated the role of plasma renin activity (PRA) in these cases and sought to establish a relationship between the accepted criteria of renal damage and PRA. AIMS AND OBJECTIVES: The aim of this study is to establish the relationship between PRA and CRF. MATERIALS AND METHODS: The records of 250 patients with PUV were reviewed. Multiple linear regression analysis was used to assess correlations between PRA, grade of reflux, presence of scars and raised creatinine and decrease in glomerular filtration rates (GFR). A P < 0.5 was considered as significant. RESULTS: A total of 58 patients were included. Their mean age was 16 years, range 5.3-24.2 years, mean follow-up period was 12.6 +/- 3.6 years. At diagnosis, 22/58 (38%) patients were in CRF and 36/58 (62%) patients had normal renal function (RF). The mean PRA after treatment was higher in those who developed CRF than in those with normal RF (12.6 +/- 10.2 vs. 34.6 +/- 14.2 ng/ml/24 h, P = 0.02). Mean GFR at 1 year of age were 48 +/- 9.8 ml/min/1.73 m(2) and 86 +/- 12.5 ml/min/1.73 m(2) respectively (P = 0.005). PRA correlated negatively with GFR, t = -2.816. CONFIDENCE INTERVAL: P = 0. 007. In the temporal plot over a period of 14 years, a rise in PRA preceded the fall in GFR in patients who developed CRF. CONCLUSIONS: This study shows that RAS is activated earlier in kidneys susceptible to damage. PRA could be investigated as a marker for the early detection and prevention of ongoing renal damage. PMID- 24347868 TI - Congenital double duodenal diaphragms in an infant. AB - Duodenal stenosis usually occurs in isolation and has a variable presentation in infancy due to partial obstruction. An unusual case of congenital double duodenal diaphragms in an infant presenting as failure to thrive has been described and pertinent literature has been reviewed herein. Excision of webs with double Heineke-Mikulicz closure was performed. PMID- 24347869 TI - Neonatal segmental enteritis due to cow's milk allergy. AB - Cow's milk protein allergy (CMPA) typically presents with persistent diarrhea or dysentery, vomiting and bleeding per rectum in young infants. CMPA is reported to mimic Hirschsprung's disease and malrotation. We report, a neonate who presented with recurrent attacks of segmental enteritis due to CMPA and the last episode presented with signs of peritonitis. He improved dramatically after elimination of cow's milk from his diet. CMPA should be considered in artificially fed babies with surgical abdomen and atypical clinical signs and symptoms. PMID- 24347870 TI - Single piece artificial urinary sphincter for secondary incontinence following successful repair of post traumatic urethral injury. AB - Post traumatic urethral injury is uncommon in children. The management of this condition is dependent on the severity of injury. Initial suprapubic cystostomy with delayed repair is the conventional treatment. Successful reconstruction of urethral injury may be followed by urethral stricture, incontinence, impotence, and retrograde ejaculation. Successful repair of post traumatic urethral injury followed by secondary incontinence in children has not been well addressed in literature. We report the management of one such child, with satisfactory outcome with implantation of a new model of single piece artificial urinary sphincter in the bulbar urethra by perineal approach. PMID- 24347871 TI - Malrotation with midgut volvulus associated with perforated ileal duplication. AB - Duplication of the alimentary tract is an important surgical condition. It may occur anywhere in the gastrointestinal tract. An important complication of this entity is perforation of the normal or abnormal gut. Malrotation with midgut volvulus can be a surgical emergency. We present a patient, who presented as malrotation with midgut volvulus associated with perforated ileal duplication. The patient was successfully managed. PMID- 24347872 TI - Hydatid cyst within a choledochal cyst. AB - A 5 year 4 months old male child presenting with pain abdomen and jaundice was diagnosed to have type 1 choledochal cyst on ultrasonography and magnetic resonance cholangio pancreatography. On exploration, the cystic dilatation of common bile duct was found to have a hydatid cyst (HC) inside it. The per operative findings were confirmed by histopathology. Association of HC within a choledochal cyst is extremely rare and has been reported only twice before in the available English literature. PMID- 24347873 TI - Multiple magnet ingestion: An uncommon cause of peritonitis. AB - Foreign body ingestion is common in infants and young children and they pass spontaneously in most of the cases. Magnetic foreign bodies, though not very common, require early intervention to avoid severe gastrointestinal complications. We report a case of multiple magnet ingestion who presented with peritonitis. PMID- 24347874 TI - Mediastinal hemangioma: Masquerading as pleural effusion. AB - We present a rare case of mediastinal hemangioma in a 4-year-old child. The child presented with cough and fever and the chest radiograph revealed right pleural effusion. On further work-up with chest computed tomography mediastinal cystic mass occupying the right hemithorax was identified. The cystic mass was resected completely through a right thoracotomy. Histopathological examination established the final diagnosis of mediastinal capillary hemangioma. PMID- 24347875 TI - Report of a malignant melanoma arising in a small congenital nevus in a 3-year old child. PMID- 24347876 TI - Bowel perforation due to retained enema nozzle in a patient of anorectal malformation. PMID- 24347877 TI - Research to knowledge. PMID- 24347878 TI - Clinical and radiographic evaluation of single-visit and multi-visit endodontic treatment of teeth with periapical pathology: An in vivo study. AB - OBJECTIVES: To compare and evaluate the clinical symptoms and radiographic evidence of periapical healing after endodontic treatment of teeth with periapical pathology when completed in one-visit or two-visits with ApexCal paste at 3, 6, and 12 months. MATERIALS AND METHODS: A total of 57 patients requiring root canal treatment on 64 single rooted teeth with periapical pathology preoperatively were included. The teeth were assigned randomly into two groups and treated according to standardized protocol. The teeth in group I (n = 34) were obturated at the first visit, while those in group II (n = 30) were medicated with ApexCal paste, and obturated in a second visit 7 days later. Patients were recalled at intervals of 3, 6, and 12 months to evaluate the treated teeth both clinically and radiographically for periapical healing. RESULTS: Mann - Whitney U test showed no difference between groups I and II. Wilcoxon signed rank test showed significant decrease in mean periapical index (PAI) scores within both groups during 12 months evaluation. The level of significance used was P < 0.05. CONCLUSIONS: Both groups exhibited equally favorable healing at 12 months, with no statistically significant differences between groups I and II. PMID- 24347879 TI - Sealing ability of three single-cone obturation systems: An in-vitro glucose leakage study. AB - AIM: The aim of this study is to compare the corono-apical sealing ability of three single-cone obturation systems using a glucose leakage model. MATERIALS AND METHODS: A total of 90 extracted maxillary single rooted teeth were selected and their crowns were cut. The root canal of each sample was instrumented using a rotary crown down technique and then divided into four experimental (n = 20 each) and two control groups (n = 5 each). Samples in the experimental groups were filled as follows: Group 1, cold lateral condensation using Gutta-percha/AH Plus; Group 2, single-cone Gutta-percha and AH Plus; Group 3, single-cone Gutta percha/and GuttaFlow2; Group 4, single-cone Resilon/RealSeal SE after 7 days, the sealing ability of root canal fillings was tested at different time intervals using glucose leakage model. Glucose leakage values were measured using a spectrophotometer and statistically analyzed. RESULTS: The four experimental groups presented significantly different glucose leakage values at all test periods (P < 0.05). At the end of the observation period, the cumulative glucose leakage values of Groups 3 and 4 were significantly lower than those of Groups 1 and 2 (P < 0.05). CONCLUSION: Gutta-percha/GuttaFlow2 or Resilon/RealSeal SE combinations provided the superior sealing ability over the lateral condensation technique. PMID- 24347880 TI - Evaluation of mineral trioxide aggregate as root canal sealer: A clinical study. AB - AIM: The aim of this study was to compare the clinical and radiological outcome of mineral trioxide aggregate (MTA) or epoxy resin as a root canal sealer compared with zinc oxide eugenol sealer. MATERIALS AND METHODS: 45 single rooted teeth with periapical index Score 2 or more were allotted to three groups with 15 teeth in each group. Root canal treatment was performed in two visits and obturated with Gutta-percha as obturating material and zinc oxide eugenol as sealer in Group 1, epoxy resin as sealer in Group 2 and MTA mixed with propylene glycol as sealer in Group 3. Visual analog scale, periapical index and VixWin digital Pro image analysis software were used for evaluation. The quantitative data was analyzed by t-test and analysis of variance. Ordinal data was analyzed by Wilcoxon's signed rank test, Mann-Whitney and Kruskall-Wallis test. RESULTS: Results suggested that there exists no statistically significant difference in clinical or radiological outcome of root canal therapy with three different types of sealers used in this study. CONCLUSIONS: MTA could be used as a root canal sealer with equal effectiveness compared with epoxy resin and zinc oxide eugenol sealers. Further long-term studies should be carried out to prove the effectiveness. PMID- 24347881 TI - The effect of various primers on shear bond strength of zirconia ceramic and resin composite. AB - AIMS: To determine the in vitro shear bond strengths (SBS) of zirconia ceramic to resin composite after various primer treatments. MATERIALS AND METHODS: Forty zirconia ceramic (Zeno, Wieland Dental) specimens (10 mm in diameter and 2 mm thick) were prepared, sandblasted with 50 MUm alumina, and divided into four groups (n = 10). Three experimental groups were surface treated with three primers; CP (RelyX Ceramic Primer, 3M ESPE), AP (Alloy Primer, Kuraray Medical), and MP (Monobond Plus, Ivoclar Vivadent AG). One group was not treated and served as the control. All specimens were bonded to a resin composite (Filtek Supreme XT, 3M ESPE) cylinder with an adhesive system (Adper Scotchbond Multi-Purpose Plus Adhesive, 3M ESPE) and then stored in 100% humidity at 37 degrees C for 24 h before SBS testing in a universal testing machine. Mean SBS (MPa) were analyzed with one-way analysis of variance (ANOVA) and the Tukey's Honestly Significant Difference (HSD) test (alpha = 0.05). RESULTS: Group AP yielded the highest mean and standard deviation (SD) value of SBS (16.8 +/- 2.5 MPa) and Group C presented the lowest mean and SD value (15.4 +/- 1.6 MPa). The SBS did not differ significantly among the groups (P = 0.079). CONCLUSIONS: Within the limitations of this study, the SBS values between zirconia ceramic to resin composite using various primers and untreated surface were not significantly different. PMID- 24347882 TI - Marginal sealing ability of silorane and methacrylate resin composites in class II cavities: A scanning electron microscopic study. AB - AIM AND OBJECTIVES: To comparatively evaluate the microleakage and microgap formation along the gingival margin in class II cavities restored with silorane resin composite and methacrylate resin composite with and without flowable resin liner. MATERIALS AND METHODS: Sixty human mandibular premolars were distributed into three groups, each group containing 20 teeth (n = 20). Mesial (subgroup A) and distal (subgroup B) box cavities were prepared with gingival margin above and below cemento enamel junction (CEJ), respectively, in each tooth and restored as follows - Group I - Silorane resin composite with self-etch primer and bond (Filtek P90, 3M ESPE MN, USA). Group II - Methacrylate resin composite (Filtek P60, 3M ESPE MN, USA) and self-etch adhesive (Adper Easy one, 3M ESPE MN, USA). Group III - Methacrylate resin composite with self-etch adhesive and a flowable resin liner (Filtek Z350 XT, 3M ESPE MN, USA). The teeth were thermocycled and immersed in 50% silver nitrate solution before sectioning. The specimens were observed under scanning electron microscope for dye penetration and microgap formation. The data was subjected to statistical analysis using Kruskal-Wallis test and Mann-Whitney U test using SPSS version 18. RESULTS: Subgroup A in all the three groups showed significantly less microleakage and microgap formation compared to subgroup B with P < 0.05. Intergroup comparison of subgroup A did not show statistically significant difference, whereas subgroup B showed statistically significant difference for microleakage between group I and group II (P = 0.003), group III and group II (P = 0.002). CONCLUSION: Silorane resin composite and methacrylate resin with liner showed significantly less microleakage in class II cavities along the gingival margin placed below CEJ compared to methacrylate resin without liner. All the study groups showed less microleakage and microgap formation along the gingival margin placed above CEJ. PMID- 24347883 TI - Comparative evaluation of the efficacy of three different irrigation devices in removal of debris from root canal at two different levels: An in vitro study. AB - AIM: The purpose of this in vitro study was to evaluate the cleaning efficacy of NaviTip, Max-i-Probe and Endovac in removal of debris from the root canal at 1.5 and 3.5 mm from the apex. MATERIALS AND METHODS: Forty single-rooted teeth were divided into four groups according to the root canal irrigation system (EndoVac, NaviTip, Max-i-Probe, and control). Instrumentation was done using ProFile 0.06 taper series to MAF #40. Root canals were irrigated after each file size with 1 ml of 5% NaOCl. For final irrigation 5 ml of 5% NaOCl and 17% ethylenediaminetetraacetic acid (EDTA) was used. Each group was irrigated with a different irrigation device. Four micron thick serial sections were prepared at 1.5 and 3.5 mm from the apical level and photographs were taken for the analysis. The influence of the irrigation system was evaluated using a one-way analysis of variance (ANOVA) test and unpaired t-test (P < 0.05). RESULTS: Endovac showed significantly least amount of mean percentage debris followed by Max-i-probe and NaviTip at both levels (P < 0.05). In all the experimental groups, significantly less amount of mean percentage debris was seen at 3.5 mm level than at 1.5 mm level (P < 0.05). However, the difference was statistically insignificant in case of Endovac irrigation system group. CONCLUSIONS: Amongst all the experimental groups, Endovac removed significantly more debris followed by Max-i-probe and NaviTip at both levels. PMID- 24347884 TI - Evaluation of immediate and delayed post space preparation on sealing ability of Resilon-Epiphany and Gutta percha-AH plus sealer. AB - AIM: To evaluate the influence of immediate and delayed post space preparation on sealing ability of Resilon-Epiphany and Gutta percha-AH plus. MATERIALS AND METHODS: Eighty extracted permanent maxillary central and lateral incisors were decoronated. Roots canals were prepared and obturated. Samples were divided into four groups depending on the time of post space preparation and obturated material. Group I and II: Immediate and delayed post space preparation respectively with Gutta percha/AH plus as obturating material. Group III and IV: Immediate and delayed post space preparation with Resilon/Epiphany as the obturating material. The samples were kept in methylene blue dye, sectioned and then measured under stereomicroscope and studied under SEM. STATISTICAL ANALYSIS: The data was subjected to statistical analysis using unpaired t-test. RESULTS: There was significant difference found between immediate and delayed post space preparation in Resilon-Epiphany group (P = 0.0109) as well as in AH plus-GP group (<0.0001). Difference in the sealing ability of the two materials was seen in delayed group (P = 0.0202). No statistically significant result was found between the two obturating materials when post space was prepared immediately (P = 0.0875). CONCLUSION: Within the limitations of this study, there was significantly less leakage when post space is prepared immediately in both the groups. Resilon-Epiphany shows better results when post space is delayed amongst the two whereas in immediate post space preparation there is no significant difference. PMID- 24347885 TI - Configuration of the inferior alveolar canal as detected by cone beam computed tomography. AB - AIMS: The aim of this study is to evaluate the course of the inferior alveolar canal (IAC) including its frequently seen variations in relation to root apices and the cortices of the mandible at fixed pre-determined anatomic reference points using cone beam volumetric computed tomography (CBVCT). MATERIAL AND METHODS: This retrospective study utilized CBVCT images from 44 patients to obtain quantifiable data to localize the IAC. Measurements to the IAC were made from the buccal and lingual cortical plates (BCP/LCP), inferior border of the mandible and the root apices of the mandibular posterior teeth and canine. Descriptive analysis was used to map out the course of the IAC. RESULTS: IACs were noted to course superiorly toward the root apices from the second molar to the first premolar and closer to the buccal cortical plate anteriorly. The canal was closest to the LCP at the level of the second molar. In 32.95% of the cases, the canal was seen at the level of the canine. CONCLUSIONS: This study indicates that caution needs to be exercised during endodontic surgical procedures in the mandible even at the level of the canine. CBVCT seems to provide an optimal, low dose, 3D imaging modality to help address the complexities in canal configuration. PMID- 24347886 TI - Dentinal defects before and after rotary root canal instrumentation with three different obturation techniques and two obturating materials. AB - AIM: To evaluate the role of rotary root canal instrumentation followed by obturation with three different techniques and two different materials on the incidence of dentinal defects. MATERIALS AND METHODS: One hundred and sixty mandibular premolars were divided into eight groups (n = 20). Group I was left untreated and served as control. The other seven groups were prepared with profile rotary instruments till #40.06 taper. After preparation, group II was left unfilled, groups III, IV, and V were obturated with Gutta-percha and AH Plus sealer using passive technique, lateral compaction and warm vertical compaction, respectively. Groups VI, VII, and VIII were obturated with Resilon and Realseal sealer using passive technique, lateral compaction, and warm vertical compaction, respectively. Roots were then sectioned at 3, 6, and 9 mm from the apex and inspected under a stereomicroscope (50*) for dentinal defects. Chi-square test was performed to compare the incidence of dentinal defects between the groups (P < 0.05). RESULTS: The unprepared control group had no dentinal defects. The instrumentation group (group II) and the obturation group (groups III-VIII) showed significantly more defects than the uninstrumented control group (group I) (P < 0.001). There was no significant difference between the root canal obturating techniques (group III-VIII) when compared with the instrumentation group (group II). On inter group comparison among the obturation groups the number of defects after lateral compaction with Gutta-percha (group IV) was significantly larger than passive Gutta-percha obturation (group III) (P < 0.05). CONCLUSIONS: The results suggest that root canal instrumentation significantly influenced the incidence of dentinal defects or fracture. Dentinal defects were more significantly attributed to the role of root canal instrumentation rather than the type of obturation technique or material. Lateral compaction with Gutta percha significantly produces more defects than passive Gutta-percha obturation. PMID- 24347887 TI - Effect of dietary solvents on the strength of nanocomposite, compomer, glass ionomer cement: An in-vitro study. AB - BACKGROUND: Intraoral degradation of resin restorative materials involves both mechanical and chemical factors. Thus, an in vitro study was conducted to compare the strength of nanocomposite to commonly used esthetic restorative materials in simulated in vivo conditions. AIM: The aim of this study was to determine the influence of dietary solvents on the strength of nanocomposite and other esthetic restorative materials. MATERIALS AND METHODS: Three test groups (nanocomposite, compomer and glass ionomer cement) each containing 60 pre-conditioned samples, divided into four subgroups of 15 samples each and conditioned in different dietary solvents, were subjected to shear punch test in custom designed shear punch apparatus in Instron Universal Testing Machine. STATISTICAL ANALYSIS: Descriptive statistics, one way analysis of variance (ANOVA), paired t-test were implied. RESULTS: One-way ANOVA revealed nanocomposite to bear most shear punch strength post-conditioning, as compared with the other two test materials. CONCLUSION: Nanocomposite yielded better strength than the other two test materials, indicating its universal application as a restorative material. PMID- 24347888 TI - Comparison of antimicrobial efficacy of propolis, Morinda citrifolia, Azadirachta indica (Neem) and 5% sodium hypochlorite on Candida albicans biofilm formed on tooth substrate: An in-vitro study. AB - INTRODUCTION: Endodontic infections are polymicrobial in nature. Candida albicans is the most common fungus isolated from failed endodontic cases. The constant increase in antibiotic resistant strains and side-effects caused by synthetic drugs has prompted researchers to look for herbal alternatives such as propolis, Morinda citrifolia and Azadirachta indica (Neem) etc., since, the gold standard for irrigation, i.e., sodium hypochlorite has many disadvantages. MATERIALS AND METHODS: Extracted human mandibular premolars were biomechanically prepared, vertically sectioned, placed in tissue culture wells exposing the root canal surface to C. albicans grown on Sabouraud Dextrose Agar to form a biofilm. At the end of 2 days, all groups were treated with test solutions and control for 10 min and evaluated for Candida growth and number of colony forming units. The readings were subjected to statistical analysis using analysis of variance and post hoc Tukey tests. RESULTS: Sodium hypochlorite and propolis groups exhibited highest antimicrobial efficacy against C. albicans with no statistically significant difference. It was followed by the A. indica (Neem) group. M. citrifolia had limited antifungal action followed by the negative control group of saline. CONCLUSION: According to the results of this study, propolis can be used as an effective antifungal agent similar to that of sodium hypochlorite, although long term in vivo studies are warranted. PMID- 24347889 TI - Influence of preheating the bonding agent of a conventional three-step adhesive system and the light activated resin cement on dentin bond strength. AB - AIMS: to evaluate the influence of preheating the bonding agent (Scotchbond Multipurpose Adhesive/3M ESPE) and the light-activated resin cement (RelyX Venner/3M ESPE) on dentin microtensile bond strength. MATERIALS AND METHODS: The exposed flat dentin surface of 40 human third molars were randomly distributed into four groups for cementation (SR Adoro/Ivoclar Vivadent) (n = 10): G1-bond and resin cement, both at room temperature (22 degrees C), G2-bond preheated to 58 degrees C and cement at room temperature (22 degrees C), G3-bond at room temperature (22 degrees C) and the cement preheated to 58 degrees C, G4-bond preheated to 58 degrees C and cement preheated to 58 degrees C. Sticks of dentin/block set measuring approximately 1 mm(2) were obtained and used for the microtensile bond strength test. All sticks had their failure mode classified. STATISTICAL ANALYSIS USED: Factorial analysis of variance was applied, 2 * 2 (bond * cement) (P < 0.05). RESULTS: Preheating the bonding agent (P = 0.8411) or the cement (P = 0.7155), yielded no significant difference. The interaction bond * cement was not significant (P = 0.9389). CONCLUSIONS: Preheating the bond and/or the light-activated resin cement did not influence dentin bond strength or fracture failure mode. PMID- 24347890 TI - Comparative evaluation of intracanal sealing ability of mineral trioxide aggregate and glass ionomer cement: An in vitro study. AB - AIMS: The purpose of this study was to compare the sealing ability of Mineral Trioxide Aggregate (MTA) and Glass Ionomer Cement (GIC) when used over gutta percha as intracanal sealing materials. The study also evaluated the sealing ability of Zinc oxide eugenol (ZOE) cement and Acroseal sealer. MATERIALS AND METHODS: Teeth were obturated with gutta-percha using sealer ZOE (group A, C, D) and Acroseal (group B). The groups were further divided into 2 subgroups (15 premolars each) on the basis of intracanal sealing material used: GIC subgroups (A1, B1) and MTA in subgroups (A2, B2). The clearing technique was used in this study for leakage evaluation. Seventy mandibular premolars were prepared using step-back technique and divided into experimental groups A and B (30 premolars each) and the positive and negative control groups C and D (5 premolars each). STATISTICAL ANALYSIS USED: Coronal microleakage was determined under stereomicroscope using 15X magnification. Data was statistically analyzed using one-way ANOVA followed by Post-Hoc Multiple comparison (Bonferroni). RESULTS: MTA group leaked significantly less than GIC group (P < 0.05). Acroseal exhibited better sealing ability than ZOE sealer. Teeth with no intracanal barrier showed almost complete leakage. CONCLUSIONS: MTA may be preferred over GIC as an intracanal barrier. PMID- 24347891 TI - An in-vivo comparative evaluation of two herbal extracts Emblica officinalis and Terminalia Chebula with chlorhexidine as an anticaries agent: A preliminary study. AB - AIM: To compare the effect of 20% aqueous extract of Terminalia chebula and Emblica officinallis with chlorhexidine as an anticaries mouthwash - an in vivo study. METHODOLOGY: 20% aqueous extract of Terminalia chebula and Emblica officinalis were prepared. Forty five high caries risk patients were divided into group 1,2,3 [ n=15]and asked to rinse with 20% aqueous extract of Terminalia chebula and Emblica officinalis, 0.2% Chlorhexidine for 40 seconds respectively. Salivary samples were collected for pH, buffering capacity before and after rinsing at repeated intervals of 10, 30,60 and 90 minutes and except for microbial analysis for which it was collected before and 90 minutes after rinsing. The pH and the buffering capacity analysis was done using chairside kit and percentage of reduction of Streptococcus mutans and Lactobacillus were tabulated and statistically analyzed. RESULTS: For salivary pH, Group 2 showed the highest peak value followed by group 1. For salivary buffering capacity, there was no significant difference between any of the groups. For microbial count, highest percentage of reduction was seen in group 2 followed by group 1 and 3. However group 3 was more efficient at 90 minutes followed by group 1 and group 2. CONCLUSION: The aqueous extract of Embilica officinalis extract and Terminalia chebula was more effective anticaries mouthwash but with less time of action than chlorhexidine. PMID- 24347892 TI - Evaluation of micro-shear bond strength of resin modified glass-ionomer to composite resins using various bonding systems. AB - AIM: The aim was to compare the micro-shear bond strength between composite and resin-modified glass-ionomer (RMGI) by different adhesive systems. MATERIALS AND METHODS: A total of 16 discs of RMGI with a diameter of 15 mm and a thickness of 2 mm were randomly divided into four groups (n = 4). Four cylinders of composite resin (z250) were bonded to the RMGI discs with Single Bond, Clearfil SE Bond and Clearfil S3 Bond in Groups 1-3, respectively. The fourth group was the control. Samples were tested by a mechanical testing machine with a strain rate of 0.5 mm/min. Failure mode was assessed under a stereo-microscope. RESULTS: The means of micro-shear bond strength values for Groups 1-4 were 14.45, 23.49, 16.23 and 5.46 MPa, respectively. Using a bonding agent significantly increased micro-shear bond strength (P = 0.0001). CONCLUSION: Micro-shear bond strength of RMGI to composite increased significantly with the use of adhesive resin. The bond strength of RMGI to composite resin could vary depending upon the type of adhesive system used. PMID- 24347893 TI - An in vitro comparison of root canal length determination by DentaPort ZX and iPex apex locators. AB - AIM: THE AIM OF THE PRESENT STUDY IS TO EVALUATE AND TO COMPARE THE ACCURACY OF TWO ELECTRONIC APEX LOCATORS (EALS): DentaPort ZX and iPex, at a position 0.5 mm short of the apical foramen. MATERIALS AND METHODS: Thirty single-rooted, mandibular premolar teeth were selected. Standard access cavities were prepared and the actual length (AL) was calculated. The samples were then embedded in alginate and the electronic measurements were determined and recorded. RESULTS: The results obtained showed that in determining the root canal length with a tolerance level of +/-0.5 mm, i.e., AL +/- 0.5 mm, DentaPort ZX was accurate in 93.3% of the samples and iPex was accurate in 90% of the samples at a position 0.5 mm short of the apical foramen. CONCLUSION: A strong correlation was seen between the two electronic methods and AL and also in between the two EALs, showing the possibility of their use to measure the root canal length. No statistically significant difference was found between both the apex locators. PMID- 24347894 TI - Surface geometry of various nanofiller composites using different polishing systems: A comparative study. AB - AIM: This in vitro study assessed the surface quality of three nanoparticle composites with four commercially available polishing systems. MATERIALS AND METHODS: A total of 180 specimens (10 * 2 mm) were prepared in metal molds using three nanocomposites, Filtek Z-350 XT, Ceram-X Mono, and Tetric N-Ceram. Sixty specimens of each material were then randomly assigned to five study groups. Control specimens were left untreated and the remaining specimens were subjected to polishing with SpinBrite, CompoMaster, AstroPol, and SofLex polishing systems. Average roughness (Ra) and average ten-point roughness (Rz) were calculated using Perthometer, and the data were analyzed by two-way analysis of variance (ANOVA) and post-hoc Tukey's tests. RESULTS: For all the materials, the roughest surfaces were observed for control specimens, with no statistically significant differences between the material groups. For Filtek Z-350 XT, the decrease in surface roughness after two-step polishing was insignificant. For Ceram-X, SpinBrite specimens showed similar degree of roughness as control specimens. For Tetric N-Ceram, no significant decrease in roughness was observed after one-step polishing. Two-way ANOVA (interaction of subgroups and groups) did not show a significant association with the outcome. CONCLUSIONS: For nanofilled composites (Filtek Z-350 XT), the surface roughness decreased with the increase in number of polishing steps, whereas one-step and multi-step polishing procedures produced similar quality of smoothness for nanohybrid composites (Ceram-X, Tetric N Ceram). Ra and Rz values of surface roughness are a function of type of finishing/polishing only. PMID- 24347895 TI - In vitro evaluation of the effect of two finishing and polishing systems on four esthetic restorative materials. AB - AIM: To determine the surface roughness of esthetic restorative materials after finishing and polishing. MATERIALS AND METHODS: All 60 specimens were divided into four groups. Group I: Nanocomposite, Z 350 XT (3M ESPE, USA); Group II: Microhybrid composite, Z 250 (3M ESPE, USA); Group III: Compomer, Dyract XP (LD Caulk/Dentsply, USA); and Group IV: Resin modified glass ionomer cement (GIC), Fuji II LC (GC, Japan). Each group was again divided into three subgroups. Subgroup A: Sof-Lex (3M ESPE); Subgroup B: Super-Snap Rainbow finishing and polishing kit (Shofu INC, Japan); and Subgroup C: Control Mylar strip. Surface roughness was determined by Perthen Perthometer S6P profilometer. RESULT: Filtek Z350 XT showed minimum surface roughness followed by Filtek Z250, Dyract XT and Fuji II LC. Super-Snap exhibited less surface roughness than Sof-Lex polishing systems. STATISTICAL ANALYSIS: One-way analysis of variance (ANOVA) followed by multiple post hoc comparisons using least square difference method and unpaired t test was used. CONCLUSION: Filtek Z350 XT with Mylar strip exhibited least surface roughness. PMID- 24347896 TI - Comparative outcome of revascularization in bilateral, non-vital, immature maxillary anterior teeth supplemented with or without platelet rich plasma: A case series. AB - Loss of pulp vitality in an immature permanent tooth arrests root development. This leads to tooth with open apex and weak lateral dentinal walls. Management of such necrotic teeth with immature roots poses several treatment challenges. The documented study was performed to evaluate and compare apexogenesis induced by revascularization, with and without platelet rich plasma (PRP) in non-vital, immature anterior teeth. Three patients having bilateral, non-vital, immature maxillary central incisors with apical periodontitis were recruited after institutional ethical clearance. Subsequent to chemo-mechanical preparation, revascularization with and without PRP was randomly induced in either of the tooth. The cases were followed-up clinically and radiographically at 6 and 12 months. There was a marked difference in periapical healing, apical closure and dentinal wall thickening of teeth treated by revascularization with PRP. PMID- 24347897 TI - Management of a large periapical lesion using Biodentine(TM) as retrograde restoration with eighteen months evident follow up. AB - Injury to anterior teeth is a common event. It requires a treatment approach that assures the complete biologic healing and functional restoration of the tooth or teeth involved. A cystic lesion, which is unable to heal nonsurgically, heals well with surgical intervention and use of mineral trioxide aggregate (MTA) as retrograde filling has been reported in literature. Another material with largely improved handling properties; Biodentine(TM) (Septodont, St. Maurdes Fosses, France) was introduced in 2011. It is a calcium silicate based material and manufacturers claim that it can be used for crown and root dentin repair treatment, repair of perforations or resorptions, apexification, and root end fillings. This article presents a case report of surgical management of a large cystic lesion using Biodentine(TM) as retrograde filling material which has not been reported in literature so far. Eighteen months radiographic follow-up exhibited completely healed cystic lesion. PMID- 24347898 TI - Endodontic management of a four rooted retained primary maxillary second molar. AB - The presence of accessory roots is rare in the primary dentition. Complete knowledge and understanding of tooth anatomy is essential to carry out high quality dental treatment with excellent outcome. In addition, the persistent primary tooth and its missing permanent successor in the dental arch pose several hurdles in front of the clinician due to doubtful survival of primary tooth. In this paper, highlights the root canal treatment of a rarest four rooted retained primary maxillary second molar. PMID- 24347899 TI - Role of mineral trioxide aggregate in management of external root resorption. AB - External root resorption (ERR) is a lytic process occurring in the cementum or cementum and dentin of the roots of teeth. Here we report a case of inflammatory ERR in a mandibular right molar in a 22-year-old male patient with history of incomplete root canal treatment with the same. Considering the biological properties of mineral trioxide aggregate cement, especially its alkalinity and sustained calcium hydroxide release, this material was used for the treatment of ERR, followed by permanent prosthesis. The clinical and radiographic follow-up for 24 months revealed that treated teeth were functional, the progression of the ERR had ceased, the resorptive area were replaced with newly formed bone and periapical radiolucencies was healed. PMID- 24347900 TI - An unusual occurrence of bilaterally geminated mandibular second premolars resulting in premolar molarization: A case report. AB - Gemination refers to an attempt by a single tooth bud to divide, with a resultant formation of either a large tooth with a bifid crown or two completely divided teeth throughout the crown and root. This report describes a rare case of bilateral gemination of permanent mandibular second premolar tooth giving rise to molarization of premolars. The mesiodistal width of these teeth is similar to mandibular molars, but the cervicoocclusal width is lesser than that of the molar tooth. This paper also discusses the potential orthodontic, periodontal, and endodontic complications of premolar molarization. PMID- 24347901 TI - Who is Responsible for this Entire Hustle Bustle: Let's Put on the 'Blue Hat'. PMID- 24347902 TI - Significance of the development of a cardiovascular disease surveillance and reporting system in India. AB - Cardiovascular disease (CVD) is the single largest cause of global morbidity and mortality and is the leading cause of death in the Indian subcontinent projected to contribute to deaths expected to double by 2015. The social and economic impact of these staggering projections highlight the need for a centralized effort to monitor and evaluate behavioral and physiological risk factors for CVD. Limited evidence on existing surveillance systems suggest that the key to an effective monitoring and evaluation (M and E) program for CVD surveillance in India relies upon the World Health Organization's STEP-wise model. Key recommendations for the Ministry of Health include the development of a national CVD surveillance program with expertise and a quality-improvement mechanism to receive continuous input from similar surveillance programs in likeminded countries. Structure of the surveillance system would include; (1) the development of process measures for CVD risk factor' based surveillance M and E systems for early detection of CVD at the local-level, (2) the development of trigger based data reporting responsibilities to State-based monitoring teams including incentives for accuracy in data reporting and the use of data-driven evidence to target risk specific intervention and prevention on Central Government monitoring teams with reporting feedback to the State and local-levels and (3) the creation of health policy to require the use of data to target risk specific prevention for intervention and developing local technical capacity. Such a system would provide significant cost and social benefits, presenting an evidence based data driven cost-effective business case for scale-up and potential use in areas comprising similar demographics. Future research should focus on the inclusion of a systematic critique of the reported data for the challenges to surveillance systems in India and the examination of the effect of an incentivized reporting system on the states. Further inquiry into the types of reporting and lessons from other countries' surveillance programs with alternative strategies to a national approach should address potential imitations at the ground or peripheral levels. PMID- 24347903 TI - Palliative radiotherapy in locally advanced head and neck cancer after failure of induction chemotherapy: comparison of two fractionation schemes. AB - CONTEXT: Among patients with locally advanced head and neck squamous cell cancers (LAHNSCC), the prognosis after nonresponse or progression despite induction chemotherapy (IC) is dismal, and further treatment is often palliative in intent. Given that nonresponse to chemotherapy could indicate subsequent radioresistance, we intended to assess the outcomes with two different fractionation schemes. AIMS: To compare the outcomes of two fractionation schemes- 'standard' (consisting 3GyX5 daily fractions for 2 consecutive weeks) versus 'hybrid' (6GyX3 fractions on alternate days during the 1(st) week, followed by 2GyX5 daily fractions in the 2(nd) week). SETTINGS AND DESIGN: Prospective randomized controlled two-arm unblinded trial. MATERIALS AND METHODS: Patients with locally advanced oropharyngeal, laryngeal, and hypopharyngeal cancers treated with a minimum of two cycles of taxane, platinum, and fluorouracil-based IC were eligible if residual disease volume amounted <30 cm(3). Kaplan-Meier survival curves were compared by the log-rank test. Response rates were compared using the unpaired t-test. Quality of life (QOL) was measured via patient reported questionnaires. RESULTS: Of the initially enrolled 51 patients, 45 patients (24 from standard arm, and 21 from the hybrid arm) were eligible for analysis. Despite being underpowered to attain statistical significance, there still seemed to be a trend towards improvement in progression-free (Hazard ratio (HR) for progression: 0.5966; 95% CI 0.3216-1.1066) and overall survival (HR for death: 0.6062; 95% CI 0.2676-1.3734) with the hybrid arm when compared to the standard arm. Benefits were also observed with regards to response rates and QOL. Rate of complications were similar in both arms. CONCLUSIONS: In comparison to the routinely used palliative fractionation scheme of 30 Gray (Gy) in 10 fractions (Fr), the use of hybrid fractionation which integrates hypofractionation in the 1(st) week, followed by conventional fractionation in the 2(nd) week, could possibly offer better response rates, QOL increments, and potential survival benefits among LAHNSCC patients even after failing to respond to IC. PMID- 24347904 TI - Psychiatric morbidity, pain perception, and functional status of chronic pain patients in palliative care. AB - CONTEXT: Psychological factors, such as that exist when we experience pain, can profoundly alter the strength of pain perception. AIM: The study aims to estimate the prevalence of psychiatric disorders, and its association with perception of pain and functional status in chronic patients in palliative care. MATERIALS AND METHODS: The sample was selected via simple randomisation and post consent were assessed using (1) a semi- structured questionnaire to elicit socio-demographic information and medical data (2) Brief Pain Inventory (3) ICD-10 Symptom Checklist (4) ICD-10-Diagnostic Criteria for Research (DCR) (5) Montgomery Asberg Depression Rating Scale (MADRS) (6) Covi Anxiety Rating Scale (7) Karnofsky Performance Status Scale. Data was analysed using independent sample t test and chi square test. RESULTS: The psychiatric morbidity was 67% with depression and adjustment disorders being the major diagnosis. There was a significant association between psychiatric morbidity pain variables (P = 0.000). Psychiatric morbidity significantly impaired activity, mood, working, walk, sleep, relationship, and enjoyment. There was no association between aetiology of pain, type of cancer, treatment for primary condition and treatment for pain and psychiatric morbidity. The functional status of cancer patients was also poorer in patients with psychiatric morbidity (P = 0.008). CONCLUSION: There is a high prevalence of psychiatric illness in chronic pain patients of any aetiology. Psychiatric morbidity is associated with increased pain perception, impairment in activity and poor functional status. PMID- 24347905 TI - A Prospective, Non-interventional Study of Assessment and Treatment Adequacy of Pain in the Emergency Department of a Tertiary Care Cancer Hospital. AB - INTRODUCTION: Pain is the most common reason for emergency department (ED) visits by the cancer patients. Treatment inconsistency and inadequacy are reported worldwide in the management of ED pain. We conducted a non-interventional observational study of 100 patients visiting ED with moderate to severe pain in a tertiary care cancer center. AIMS: The goal of this study was to describe the characteristics of pain and its treatment by oncologists in ED. MATERIALS AND METHODS: Management of 100 adult patients with complaints of moderate to severe pain was observed by the investigator in ED. Treatment was provided by the doctors of respective oncological services. Later, patients were interviewed by the investigator to collect data about the details of their pain and treatment adequacy. RESULTS: On arrival to ED, about 65% patients reported severe pain, however no formal pain assessment was performed and no patient received strong opioids. Poor compliance for prescribed analgesic medications was noted in a large number of patients (31%), primarily due to suboptimal pain relief and lack of awareness. Protocol based analgesic treatment was non-existent in ED. Majority of patients remained in significant pain after 30 min of analgesic administration and 24% patients could never achieve more than 50% pain relief at the time of discharge. CONCLUSION: Due to lack of formal pain assessment and laid down protocols, suboptimal pain management is commonly prevalent in ED. Use of strong opioids continues to be scarce in management of severe pain. There is a need to formulate pain management protocols for ED pain. PMID- 24347906 TI - Evaluation of Socio-demographic Factors for Non-compliance to Treatment in Locally Advanced Cases of Cancer Cervix in a Rural Medical College Hospital in India. AB - INTRODUCTION: Carcinoma cervix is a leading cause of cancer in India. However, majority of the patients face a problem of not being able to complete the treatment. AIM: This study was an attempt to find out the important causes of this non-compliance to treatment in a rural Medical College Hospital where majority of the cancer cases are of cervical cancer. RESULTS: Out of 144 patients studied over 2 years 88 cases could not complete the treatment. The study revealed that due old age 58.33% cases were defaulters, having many children at home meant a burden to 76.92% cases and 63.89% cases had a problem of not been able to travel a far distance of more than 100 km from home to hospital for treatment. CONCLUSION: These were the important factors of non-compliance and suggested more important than the issues of literacy and poor socio-economic status. PMID- 24347907 TI - Physiological and psychosocial stressors among hemodialysis patients in educational hospitals of northern iran. AB - BACKGROUND AND AIMS: The hemodialysis (HD) patients are experiencing high biopsychosocial stress on all levels. Therefore, this study was designed to survey on physiologic and psychosocial stressors among HD patients in two educational hospitals of Northern Iran. MATERIALS AND METHODS: This cross sectional study included 80 HD patients who were referred to Khomeini and Fatemeh Zahra hospitals in Mazandaran (Northern Iran) during the year 2011. Data were collected using a demographic information record sheet and Baldree Hemodialysis Stress Scale. FINDING: THE FOLLOWING PHYSIOLOGIC STRESSORS WERE NOTED: Fatigue (51.25%), limited time and places for enjoyment (46.25%), and physical activation limitation (32.5%). Similarly the following psychosocial stressors were observed: Fistula (58.75%), limitation of drinking water (47.5%), low quality of life (47.5%), travelling difficulties to the dialysis center (45%), treatment cost (41.5%), and low life expectancy. The stress level was high in women who were married, younger, less dialysis vintage, and belonged to a low education level. CONCLUSION: This study reports that HD patients have with significant physical and psychosocial problems and they need education, family, and social supports. PMID- 24347909 TI - Randomized Controlled Trial in Advance Stage Breast Cancer Patients for the Effectiveness on Stress Marker and Pain through Sudarshan Kriya and Pranayam. AB - OBJECTIVE: The objective of this study is to examine the effect of a cognitive, behavioral stress management module of Sudarshan Kriya (SK) and P on levels of serum cortisol and pain among the women suffering from advanced stage breast cancer. MATERIALS AND METHODS: Participants (n = 147) were screened and randomized to receive standard care (n = 69) versus standard along with SK and Pranayam (P) intervention (n = 78) imparted in one 18 hrs workshop spread during 3 days. Participants were expected to practice it at home 20 min daily as adjuvant to standard pharmacological treatment for pain. RESULTS: There was a significant difference in blood cortisol levels after 3 months of practice of SK and P. Mean blood levels in the intervention arm were 341.2 ng/ml against 549.2 ng/ml in the control arm (P <= 0.002). Pain perception in comparison to control arm reduced by 3 points in SK and P arm on 0-10 verbal scale of pain. CONCLUSION: SK and P is an effective intervention in reducing stress and pain among advance stage patients of breast cancer. PMID- 24347908 TI - An Exploratory Analysis of Levels of Evidence for Articles Published in Indian Journal of Palliative Care in the years 2010-2011. AB - CONTEXT: Indian Journal of Palliative Care (IJPC) provides a comprehensive multidisciplinary evidence base for an evidence-informed clinical decision making. AIMS: To analyze the levels of evidence of articles published in IJPC in the years 2010-2011. SETTINGS AND DESIGN: Systematic review of palliative care journals. MATERIALS AND METHODS: Systematic review of articles was done and was scored according to Center for Evidence-Based Medicine levels of evidence into any of the five grades. The articles were categorized based upon article type, number of authors, study approach, age focus, population focus, disease focus, goals of care, domains of care, models of care, and year of publication. STATISTICAL ANALYSIS USED: All descriptive analysis was done using frequencies and percentiles, and association between all categorical variables was done using Chi-square test at 95% confidence interval (CI) using Statistical Package for Social Sciences (SPSS) version 16 for Windows (SPSS Inc, Chicago, IL). RESULTS: There was a greater prevalence of low level evidence (level 4: n = 46, 51%; level 5: n = 35, 39%) among the 90 selected articles, and article type (original articles with higher level of evidence, P = 0.000), article approach (analytical studies with higher level of evidence, P = 0.000), domains of palliative care (practice-related studies with higher level of evidence, P = 0.000) and models of care (biological or psychosocial model with higher level of evidence, P = 0.044) had a significant association with the grade of levels of evidence. Association with other factors was not statistically significant (P < 0.05). CONCLUSIONS: The levels of research evidence for palliative care provided by articles published in IJPC were predominantly level 4 and level 5, and there is scope for more high quality evidence to inform palliative care decisions in the developing countries. PMID- 24347910 TI - Baseline Demographic Profile and General Health Influencing the Post-Radiotherapy Health Related Quality-of-Life in Women with Gynaecological Malignancy Treated with Pelvic Irradiation. AB - BACKGROUND: Cancer specific survival and quality-of-life (QOL) assessment are important in evaluating cancer treatment outcomes. Baseline demographic profiles have significant effects on follow-up health related QOL (HRQOL) and affect the outcome of treatments. MATERIALS AND METHODS: Post-operative gynaecological cancer patients required adjuvant pelvic radiation enrolled longitudinal assessment study. Patients had completed the short form-36 (SF-36) questionnaire before the adjuvant radiotherapy and functional assessments of cancer therapy general module at 6(th) month's follow-up period to assess the HRQOL. Baseline variables were race, age, body mass index (BMI), education, marital status, type of surgery, physical composite scores (PCS) and mental composite scores (MCS) summary scores of the SF-36. Univariate and multivariate regression analysis used to determine the influence of these variables on post-radiotherapy HRQOL domains. RESULTS: Baseline PCS, MCS, age, education and marital status had positively correlation with post-radiotherapy HRQOL while higher BMI had a negative impact in univariate analysis. In multivariate regression analysis, education and MCS had a positive correlation while higher BMI had a negative correlation with HRQOL domains. CONCLUSION: Enhance our ability to detect demographic variables and modify those factors and develops new treatment aimed at improving all aspect of gynaecological cancer including good QOL. PMID- 24347911 TI - Palliative radiation in primary squamous cell carcinoma of thyroid: a rare case report. AB - Primary squamous cell carcinoma of the thyroid is an extremely rare neoplasm with aggressive behavior. Until date, only around 60 cases have been reported in the literature. Primary treatment of the patient is radical surgery. With optimum treatment survival is not more than 6 months in this aggressive malignancy. However in our patient surgery it was not possible because of unresectability of the mass due to encroachment of major vessels. Hence, we have delivered radiotherapy alone, with which effective palliation could be achieved and patient is leading a good quality-of-life for last 1 year. PMID- 24347912 TI - High-level Evidence Exists for Low-level Laser Therapy on Chemoradiotherapy induced Oral Mucositis in Cancer Survivors. PMID- 24347913 TI - Healthcare professionals' fear of death and dying: implications for palliative care. PMID- 24347914 TI - Systematic reviews on palliative sedation: what do they tell us? PMID- 24347916 TI - Rasayans and non-rasayans herbs: Future immunodrug - Targets. AB - Ayurvedic therapeutics describes vast number of medicinal herbs used as "Vyadhirodhak Chamatav" that has enlightened the application of herbs used as corner stone in various diseases especially those modulating the immune system. Ayurveda literature comprises of rasayana and non-rasayana herbs. Materia Medica entirely enriched with enormous data of rasayana medicinal herbs acting as immunomodulators in existence. However, as such there is no specific review of literature available for non-Rasayana herbs that have immense potential as immunomodulators. This review article empowers data on non-rasayana medicinal herbs as promising future target for immunotherapy. PMID- 24347915 TI - Plants and phytochemicals for Huntington's disease. AB - Huntington's disease (HD) is a neurodegenerative disorder characterized by progressive motor dysfunction, including chorea and dystonia, emotional disturbances, memory, and weight loss. The medium spiny neurons of striatum and cortex are mainly effected in HD. Various hypotheses, including molecular genetics, oxidative stress, excitotoxicity, metabolic dysfunction, and mitochondrial impairment have been proposed to explain the pathogenesis of neuronal dysfunction and cell death. Despite no treatment is available to fully stop the progression of the disease, there are treatments available to help control the chorea. The present review deals with brief pathophysiology of the disease, plants and phytochemicals that have shown beneficial effects against HD like symptoms. The literature for the current review was collected using various databases such as Science direct, Pubmed, Scopus, Sci-finder, Google Scholar, and Cochrane database with a defined search strategy. PMID- 24347917 TI - In vitro techniques to assess the proficiency of skin care cosmetic formulations. AB - Cosmetics comprising either natural or synthetic components are used almost regularly and universally in different forms to enhance the beauty. The utmost disclosure of human membrane to sunlight and environmental pollution results in the exhibition of free radical, that react with deoxyribonucleic acid, proteins and fatty acids, causation oxidative destruction dysfunction of the antioxidant system. In skin, the formation of reactive oxygen species leads to skin diseases, predominantly cutaneous malignancies, immunosuppression, wrinkles, aging, etc., The human organism fosters a barrier practice against the destructive action of free radicals, comprising mostly of vitamins, carotenoids and enzymes. Cosmetic products are the best option to reduce skin disorders such as hyper pigmentation, skin aging, skin wrinkling and rough skin texture, etc., Hence in this review, we conferred various in vitro methods that are used for the development of novel cosmetic formulation. There is an expanding fascinate employing in vitro techniques because they are less time consuming, more cost-effective and lessen the participation of human volunteers. PMID- 24347918 TI - Natural proteins: Sources, isolation, characterization and applications. AB - Worldwide, plant protein contributes substantially as a food resource because it contains essential amino acids for meeting human physiological requirements. However, many versatile plant proteins are used as medicinal agents as they are produced by using molecular tools of biotechnology. Proteins can be obtained from plants, animals and microorganism cells. The abundant economical proteins can be obtained from plant seeds. These natural proteins are obtained by isolation procedures depending on the physicochemical properties of proteins. Isolation and purification of single protein from cells containing mixtures of unrelated proteins is achievable due to the physical and chemical attributes of proteins. The following characteristics are unique to each protein: Amino acid composition, sequence, subunit structures, size, shape, net charge, isoelectric point, solubility, heat stability and hydrophobicity. Based on these properties, various methods of isolation exist, like salting out and isoionic precipitation. Purification of proteins is quiet challenging and, therefore, several approaches like sodium dodecyl sulfate gel electrophoresis and chromatography are available. Characterization of proteins can be performed by mass spectrometry/liquid chromatography-mass spectrometry (LC-MS). The amino acid sequence of a protein can be detected by using tandem mass spectrometry. In this article, a review has been made on the sources, isolation, purification and characterization of natural proteins. PMID- 24347919 TI - Thymoquinone in the clinical treatment of cancer: Fact or fiction? AB - Thymoquinone (TQ) is the bioactive phytochemical constituent of the seeds oil of Nigella sativa. In vitro and in vivo research has thoroughly investigated the anticancer effects of TQ against several cancer cell lines and animal models. As a result, a considerable amount of information has been generated from research thus providing a better understanding of the anti-proliferating activity of this compound. Therefore, it is appropriate that TQ should move from testing on the bench to clinical experiments. The purpose of this review is to highlight the potential of TQ as an anticancer agent and the chances of this compound in the clinical treatment of cancer, with special attention on breast cancer treatment. PMID- 24347920 TI - Cholinesterase inhibitors from botanicals. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease, wherein a progressive loss of cholinergic synapses occurs in hippocampus and neocortex. Decreased concentration of the neurotransmitter, acetylcholine (ACh), appears to be critical element in the development of dementia, and the most appropriate therapeutic approach to treat AD and other form of dementia is to restore acetylcholine levels by inhibiting both major form of cholinesterase: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Consequently, researches have focused their attention towards finding cholinesterase inhibitors from natural products. A large number of such inhibitors have been isolated from medicinal plants. This review presents a comprehensive account of the advances in field of cholinesterase inhibitor phytoconstituents. The structures of some important phytoconstituents (collected through www.Chemspider.com) are also presented and the scope for future research is discussed. PMID- 24347921 TI - Oleandrin: A cardiac glycosides with potent cytotoxicity. AB - Cardiac glycosides are used in the treatment of congestive heart failure and arrhythmia. Current trend shows use of some cardiac glycosides in the treatment of proliferative diseases, which includes cancer. Nerium oleander L. is an important Chinese folk medicine having well proven cardio protective and cytotoxic effect. Oleandrin (a toxic cardiac glycoside of N. oleander L.) inhibits the activity of nuclear factor kappa-light-chain-enhancer of activated B chain (NF-kappaB) in various cultured cell lines (U937, CaOV3, human epithelial cells and T cells) as well as it induces programmed cell death in PC3 cell line culture. The mechanism of action includes improved cellular export of fibroblast growth factor-2, induction of apoptosis through Fas gene expression in tumor cells, formation of superoxide radicals that cause tumor cell injury through mitochondrial disruption, inhibition of interleukin-8 that mediates tumorigenesis and induction of tumor cell autophagy. The present review focuses the applicability of oleandrin in cancer treatment and concerned future perspective in the area. PMID- 24347922 TI - Onosma L.: A review of phytochemistry and ethnopharmacology. AB - The genus Onosma L. (Boraginaceae) includes about 150 species distributed world wide in which only about 75 plants has been described for its morphology and less than 10 plants for their chemical constituents and clinical potential. The phytochemical reports of this genus revels that it comprise mainly aliphatic ketones, lipids, naphthazarins, alkaloids, phenolic compounds, naphthoquinones, flavones while most important are shikonins and onosmins. The plants are traditionally used as laxative, anthelmintic and for alexipharmic effects. The plants are also equally use in eye, blood diseases, bronchitis, abdominal pain, stangury, thirst, itch, lecoderma, fever, wounds, burns, piles and urinary calculi. The flowers of various plants are prescribed as stimulants, cardiotonic, in body swelling while leaves are used as purgative and in cutaneous eruptions. The roots are used for coloring food stuffs, oils and dying wool and in medicinal preparations. This review emphasizes the distribution, morphology, phytochemical constituents, ethnopharmacology, which may help in future research. PMID- 24347923 TI - Camellia sinensis (Tea): Implications and role in preventing dental decay. AB - Tea is one of the most commonly consumed beverages with bioactive compounds like polyphenols-flavonoids-catechins, which are thought to be responsible for the health benefits that have traditionally been attributed to the tea. These compounds have multi-dimensional effects such as antibacterial action, inhibitory action on the bacterial and salivary amylase and inhibition of acid production. This article outlines the possible role of these compounds coupled with the presence of high fluoride content in tea to exhibit an anticariogenic effect. PMID- 24347924 TI - Review on Sphaeranthus indicus Linn. (Kottaikkarantai). AB - Sphaeranthus indicus Linn. is from the aroma family Asteraceae. It is also known with other synonyms such as Munditika, Mundi, Shravana, Bhikshu, Tapodhana, Mahashravani, Shravanahva, Shravanashirshaka. It is abundantly distributed in damp areas in plains and also as a weed in the rice fields. In the Indian system of medicine, the plant as a whole plant or its different anatomical parts viz., leaf, stem, bark, root, flower and seed are widely used for curing many diseases. The plant is bitter, stomachic, restorative, alterative, pectoral, demulcent and externally soothing. The whole plant and its anatomical parts have been reported with different types of secondary metabolites which include eudesmanolides, sesquiterpenoids, sesquiterpene lactones, sesquiterpene acids, flavone glycosides, flavonoid C-glycosides, isoflavone glycoside, sterols, sterol glycoside, alkaloid, peptide alkaloids, amino acids and sugars. The essential oils obtained from the flowers and whole plants were analyzed by different authors and reported the presence of many monoterpene hydrocarbons, oxygenated monoterpenes, sesquiterpene hydrocarbons and oxygenated sesquiterpenes. The whole plants, its isolated secondary metabolites and different anatomical parts have been reported for ovicidal, antifeedant, anthelmintic, antimicrobial, antiviral, macrofilaricidal, larvicidal, analgesic, antipyretic, hepatoprotective, antitussive, wound healing, bronchodilatory, mast cell stabilizing activity, anxiolytic, neuroleptic, immunomodulatory, anti-diabetic, antihyperlipidemic and antioxidant, antioxidant, central nervous system depressant, anti-arthritic, nephroprotective, anticonvulsant activities and many other activities. It is also effective on psoriasis. In the present paper, the plant is reviewed for its phytochemical and pharmacological reports in detail. PMID- 24347925 TI - Biological activities and chemical constituents of some mangrove species from Sundarban estuary: An overview. AB - This review represents the studies performed on some beneficial mangrove plants such as Ceriops decandra, Xylocarpus granatum, Xylocarpus moluccensis, Excoecaria agallocha, Sarcolobus globosus, Sonneratia caseolaris and Acanthus ilicifolius from the Sundarban estuary spanning India and Bangladesh with regard to their biological activities and chemical investigations till date. Sundarban is the largest single chunk of mangrove forest in the world. The forest is a source of livelihood to numerous people of the region. Several of its plant species have very large applications in the traditional folk medicine; various parts of these plants are used by the local people as cure for various ailments. Despite such enormous potential, remarkably few reports are available on these species regarding their biological activities and the active principles responsible for such activities. Though some chemical studies have been made on the mangrove plants of this estuary, reports pertaining to their activity-structure relationship are few in number. An attempt has been made in this review to increase the awareness for the medicinal significance as well as conservation and utilization of these mangrove species as natural rich sources of novel bioactive agents. PMID- 24347926 TI - A review on phytochemistry and ethnopharmacological aspects of genus Calendula. AB - This review includes 84 references on the genus Calendula (Asteraceae) and comprises ethnopharmacology, morphology and microscopy, phytoconstituents, pharmacological reports, clinical studies and toxicology of the prominent species of Calendula. Triterpene alcohols, triterpene saponins, flavonoids, carotenoids and polysaccharides constitute major classes of phytoconstituents of the genus. A few species of this genus have medicinal value, among these Calendula officinalis Linn., has been traditionally used in the treatment of various skin tumors, dermatological lesions, ulcers, swellings and nervous disorders as well as almost 200 cosmetic formulations, i.e., creams, lotions, shampoos. Despite a long tradition of use of some species, the genus has not been explored properly. In the concluding part, the future scope of Calendula species has been emphasized with a view to establish their multifarious biological activities and mode of action. PMID- 24347927 TI - The genus Vitex: A review. AB - The review includes 161 references on the genus Vitex, and comprises ethnopharmacology, morphology and microscopy, phytoconstituents, pharmacological reports, clinical studies, and toxicology of the prominent species of Vitex. Essential oils, flavonoids, iridoid glycosides, diterpenoides and ligans constitute major classes of phytoconstituents of the genus. A few species of this genus have medicinal value, among these, leaves and fruits of V. agnus-castus Linn. (Verbenaceae) has been traditionally used in treatment of women complaints. V. agnus-castus has also been included in herbal remedies, which are in clinical use to regulate the menstrual cycle, reduce premenstrual symptom tension and anxiety, treat some menopausal symptoms as well as to treat hormonally induced acne. Despite a long tradition of use of some species, the genus has not been explored properly. In the concluding part, the future scope of Vitex species has been emphasized with a view to establish their multifarious biological activities and mode of action. PMID- 24347929 TI - From the Editor's desk. PMID- 24347928 TI - Pharmacological and therapeutic effects of Peganum harmala and its main alkaloids. AB - Wild Syrian rue (Peganum harmala L. family Zygophyllaceae) is well-known in Iran and various parts of this plant including, its seeds, bark, and root have been used as folk medicine. Recent years of research has demonstrated different pharmacological and therapeutic effects of P. harmala and its active alkaloids, especially harmine and harmaline. Analytical studies on the chemical composition of the plant show that the most important constituents of this plant are beta carboline alkaloids such as harmalol, harmaline, and harmine. Harmine is the most studied among these naturally occurring alkaloids. In addition to P. harmala (Syrian rue), these beta-carbolines are present in many other plants such as Banisteria caapi and are used for the treatment of different diseases. This article reviews the traditional uses and pharmacological effects of total extract and individual active alkaloids of P. harmala (Syrian rue). PMID- 24347930 TI - Hyperprolactinemia. AB - Prolactin (PRL) is an anterior pituitary hormone which has its principle physiological action in initiation and maintenance of lactation. In human reproduction, pathological hyperprolactinemia most commonly presents as an ovulatory disorder and is often associated with secondary amenorrhea or oligomenorrhea. Galactorrhea, a typical symptom of hyperprolactinemia, occurs in less than half the cases. Out of the causes of hyperprolactinemia, pituitary tumors may be responsible for almost 50% of cases and need to be investigated especially in the absence of history of drug induced hyperprolactinemia. In women with hyperprolactinemic amenorrhea one important consequence of estrogen deficiency is osteoporosis, which deserves specific therapeutic consideration. Problem in diagnosing and treating hyperprolactinemia is the occurrence of the 'big big molecule of prolactin' that is biologically inactive (called macroprolactinemia), but detected by the same radioimmunoassay as the biologically active prolactin. This may explain many cases of very high prolactin levels sometimes found in normally ovulating women and do not require any treatment. Dopamine agonist is the mainstay of treatment. However, presence of a pituitary macroadenoma may require surgical or radiological management. PMID- 24347931 TI - A clinical appraisal of the genetic basis in unexplained male infertility. AB - Unexplained male infertility (UMI), the inability to reproduce despite having a normal sexual history, physical exam and semen analysis, can have a genetic origin. Currently, few diagnostic tools are available for detecting such genetic abnormalities. Karyotyping and fluorescence in situ hybridization (FISH) are respectively used for chromosomal alterations in somatic cells and sperm aneuploidy assessment. Gene sequencing and mutational analysis have been introduced for identifying specific mutations and polymorphisms. Other approaches to the molecular evaluation of spermatozoa are under investigation, including array comparative genomic hybridization and whole-genome sequencing and non coding ribonucleic acid arrays. Although treating cytogenetic abnormalities and genetic aberrations is still out of reach, the integration of these novel techniques may unravel hidden genetic defects in UMI. Finally, a deeper understanding of the sperm epigenome might allow the development of therapies based on epigenome modifications. This review focuses on the genetic basis of UMI and highlights the current and future methods for the evaluation of genetic defects as they relate to UMI. Review of the literature was carried out using ScienceDirect, OVID, PubMed and MedLine search engines. PMID- 24347932 TI - Transfer of spontaneously hatching or hatched blastocyst yields better pregnancy rates than expanded blastocyst transfer. AB - CONTEXT: Blastocyst stage embryo transfer (ET) has become routine practice in recent years. However, probably due to limitations of assisted hatching techniques, expanded blastocyst transfer (EBT) is still the preferred mode. Inexplicably, not much consideration has been given to spontaneously hatching/hatched blastocyst transfer (SHBT). AIM: This study aimed to investigate developmental potential of spontaneously hatching/hatched blastocyst against EBT in in vitro fertilization (IVF) cycles. SETTINGS AND DESIGN: Prospective study of 146 women undergoing their first IVF- ET cycle. SUBJECTS AND METHODS: On the basis of blastocyst status, women were classified into SHBT and EBT groups. Intracytoplasmic sperm injection cycles were excluded to remove male factor bias. Implantation rate (IR), clinical pregnancy rate, and live birth rate were the main outcome measures. STATISTICAL ANALYSIS: Graph-pad Prism 5 statistical package. RESULTS: SHBT group showed significantly higher blastocyst formation rate (53.3 +/- 17.5 vs. 43.1 +/- 14.5%, P = 0.0098), top-quality blastocysts (71.8 vs. 53.7%, P = 0.0436), IR (43.6 vs. 27.9%, P = 0.0408), pregnancy rate (59.4 vs. 45.1%, P = 0.0173), and live birth rate (36.8 vs. 22.8%, P = 0.003) compared to EBT group. Multiple pregnancy rates remained comparable between the two groups. Implantation correlated strongly with top-quality blastocysts (Pearson, r = 0.4441) in SHBT group, while the correlation was nonsignificant in EBT group. CONCLUSION: Extending culture of expanded blastocysts by a few hours to allow transfer of spontaneously hatching/hatched blastocysts gives higher implantation and pregnancy rates with no added risk of multiple gestations. Spontaneously hatching/hatched blastocysts have a better potential to implant and develop into a positive pregnancy. PMID- 24347933 TI - Ultrasound diagnosis of adenomyosis, leiomyoma, or combined with histopathological correlation. AB - OBJECTIVE: To evaluate the accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the diagnosis of adenomyosis, leiomyoma, or combined adenomyosis and leiomyoma by the use of transvaginal ultrasonography (TVS) compared to the histopathological findings. SUBJECTS AND METHODS: This is a retrospective study of patients with a preoperative TVS diagnosis of adenomyosis, leiomyoma, or combined. Patients diagnosed with adenomyosis or combined adenomyosis and leiomyoma via TVS underwent hysterectomy. Symptomatic patients diagnosed with adenomyosis and leiomyoma via TVS underwent myomectomy with excision of the surrounding myometrium which contained possible adenomyosis. Following surgery, a histopathological examination was performed by the hospital pathologists. The microscopic diagnosis of the specimen was recorded. RESULTS: TVS diagnosis of adenomyosis was sensitive but not specific. TVS was sensitive, specific, and accurate in the diagnosis of leiomyoma and combined adenomyosis and leiomyoma. CONCLUSION: This study demonstrated that TVS is a valuable noninvasive method that should be utilized in the diagnosis of leiomyoma and combined adenomyosis and leiomyoma. TVS is sensitive, but is not specific in the diagnosis of adenomyosis only. PMID- 24347934 TI - Anthropometric, clinical, and metabolic comparisons of the four Rotterdam PCOS phenotypes: A prospective study of PCOS women. AB - AIMS: 1. To study the distribution of various Rotterdam classified phenotypes of polycystic ovarian syndrome (PCOS) women, in our population. 2. To compare the four phenotypes with respect to anthropometric, clinical, and metabolic parameters. 3. To report the prevalence of insulin resistance (IR) and metabolic syndrome in these women. SETTINGS AND DESIGN: Private practice, Prospective cross sectional comparative study. MATERIALS AND METHODS: Women attending gynecology outpatient with the primary complains of irregular menses and/or infertility were evaluated. Each of them underwent detailed clinical examination, transvaginal sonography, and biochemical and hormonal assays. Four hundred and ten women with a clinical diagnosis of PCOS based on Rotterdam criteria were included in the study. The four phenotypes were 1) PCO complete, that is oligo/anovulation (O) + polycystic ovaries (P) + hyperandrogenism (H) 2) P + O, 3) P + H, and 4) O + H. All women were also evaluated for metabolic syndrome (American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI), modified Adult Treatment Panel (ATP) III 2005 guidelines) and IR (homeostatic model assessment IR (HOMA-IR)). STATISTICAL ANALYSIS: Statistical Package for Social Sciences (SPSS) version 18. RESULTS: Largest group was PCOS complete (65.6%) followed by P + O (22.2%); H + O (11.2%); and P + H (0.9%). Overall prevalence of metabolic syndrome was 35.07%. Hyperandrogenic phenotyptes; H + O (50%) and P + H + O (37.04%), had significantly higher prevalence of metabolic syndrome than normoandrogenic P + O phenotype (10%) (P <= 0.001). Body mass index (BMI) >= 25 (P = 0.0004; odds ratio (OR) = 3.07 (1.6574-5.7108, 95% CI)), waist circumference (WC) >= 80 cm (P = 0.001; OR = 3.68 (1.6807-8.0737, 95% CI)) and family history of diabetes (P = 0.019; OR 1.82 (1.1008-3.0194, 95% CI)), were strongly associated with the presence of metabolic syndrome. The overall prevalence of IR in PCOS women was 30.44% (HOMA-IR cutoff >= 3.8) and 34.94% (HOMA-IR cutoff >= 3.5). CONCLUSIONS: The prevalence of metabolic syndrome and IR was 35.07 and 30.44%, respectively. The hyperandrogenic phenotypes have significantly higher metabolic morbidity compared to normoandrgenic phenotype. BMI > 25, WC >= 80 cm, and family history of diabetes carry the highest risk for developing metabolic syndrome. PMID- 24347935 TI - Impact of socio-economic status on ovarian reserve markers. AB - BACKGROUND: Fertility rates have started declining in India in the last few decades. The total fertility rate, which was 3.5 in 93-94 declined to 2.5 in 2005 6. Researchers attribute this fertility transition to concomitant socio-economic development. Decreasing ovarian reserve is an important contributor for age related infertility. OBJECTIVES: The objective of this study was to assess the association of ovarian reserve with socio-economic status (SES) with the available clinical ovarian reserve markers in reproductive age women. MATERIALS AND METHODS: A total of 160 married women in the age group of 20-35 years, belonging to all three socio-economic strata were assessed for ovarian reserve using the clinical ovarian reserve parameters Antimullerian hormone (AMH), Antral follicle count (AFC) and follicular stimulating hormone (FSH). Analysis of variance was used to see the association of ovarian reserve with SES. RESULTS: Both the ovarian parameters AMH and AFC have shown a significant association with SES (P = 0.000 for AMH and P = 0.023 for AFC). The association between FSH and SES was not significant (P = 0.147). CONCLUSIONS: Higher SES in this study was seen to be associated with better ovarian reserve as assessed by the available clinical ovarian reserve markers. PMID- 24347938 TI - Finding relief at the end of the (Carpal) tunnel: Electrophysiological clues. PMID- 24347937 TI - Role of early serum beta human chorionic gonadotropin measurement in predicting multiple pregnancy and pregnancy wastage in an in vitro ET fertilization cycle. AB - OBJECTIVE: This study was performed to assess the prognostic value of serum beta human chorionic gonadotropin (betahCG), measured on day 14 post embryo transfer (ET) for predicting multiple gestation and pregnancy wastage in women undergoing in vitro fertilization ET (IVF-ET). MATERIALS AND METHODS: This retrospective study was performed between May 2009 and November 2012. Out of the 181 women who conceived, 168 were included and the remaining 13 were excluded as their pregnancy was biochemical. Serum betahCG was measured using a chemiluminescent enzyme immunometric assay. The predictive values of serum betahCG for establishing multiple pregnancy and pregnancy wastages were calculated by receiver operating characteristic (ROC) curve analysis. Median values of serum betahCG and outcome of all pregnancies were compared. RESULTS: Out of the 168 patients who conceived after IVF treatment, 114 (68%) were viable pregnancies (delivered/ongoing). Among the viable pregnancies, 97 (85%) had a successful pregnancy outcome and the remaining 17 patients are ongoing pregnancies. Median values of betahCG (625 IU/L) among viable pregnancies was significantly (P < 0.05) higher than that of nonviable pregnancies (174 IU/L). The median values of betahCG for singleton (502 IU/L), twins (1093 IU/L), and triplets (2160 IU/L) was statistically significant (P < 0.05). Using ROC curve it was predicted that for a value of betahCG at 375 IU/L, the sensitivity of viable pregnancy was 65% and specificity of viable pregnancy was also 65%, with positive and negative predictive values of 65 and 68%, respectively. Similarly for multiple pregnancy and pregnancy wastage the predictive values of betahCG were 808 and 375 IU/L, respectively; while the sensitivity and specificity is more than 65% each. CONCLUSION: betahCG cutoff values determined on day 14 post ET by ROC curve analysis are useful in discriminating between multiple pregnancy and pregnancy losses. The cutoff value might aid in the prognosis, clinical management, and counseling of the IVF patients. PMID- 24347939 TI - Belief and brain. PMID- 24347936 TI - Comparative multiplex analysis of cytokines, chemokines and growth factors in follicular fluid of normoresponder women undergoing ovum donation with gonadotropin-releasing hormone agonist versus gonadotropin-releasing hormone antagonist protocols. AB - BACKGROUND: Conflicting results were yielded about the superiority of gonadotropin-releasing hormone agonist (GnRH-a) versus gonadotropin-releasing hormone antagonist (GnRH-ant) protocols used in ovarian stimulation in in vitro fertilization (IVF) set-up. Reports also indicate that any single specific individual marker in follicular fluid collected at the time of oocyte retrieval bears inconclusive value as a predictor of oocyte quality. AIMS: Simultaneous analyses of large numbers of cytokines, chemokines and growth factors in ovarian follicular fluid and perifollicular vascularity in both protocols for ovarian stimulation in IVF program to address the above mentioned lacunae. SETTINGS AND DESIGNS: Normoresponder women (n = 45) were subjected to either GnRH-a (Group 1; n = 23) or GnRH-ant (Group 2; n = 22) for ovarian stimulation in IVF clinics. MATERIALS AND METHODS: The fluid samples of dominant follicles collected at oocyte retrieval from women in Group 1 (GnRH-a; n = 20) and Group 2 (GnRH-ant; n = 16) were used for simultaneous quantitative assays of 48 cytokines. Perifollicular vascularity was assessed by Doppler hemodynamics to assess the ovarian vascular response in all participants in Groups 1 and 2. RESULTS: Despite demographic and reproductive parameters studied remained comparable, higher follicular fluid concentration of interleukins, IL-3 (P < 0.01), IL12p70 (P < 0.05) and vascular endothelial growth factor (P < 0.01), P4 (P < 0.05) and pulsatility index (P < 0.04) along with a lower number of oocytes in metaphase II stage (P < 0.03) was observed in Group 2 compared with Group 1. GnRH-a protocol appeared to be superior to GnRH-ant protocol for ovarian stimulation in normoresponder women. PMID- 24347940 TI - Cerebral venous and sinus thrombosis. PMID- 24347941 TI - Etiological beliefs of patients with neurological disorders attending a tertiary care center: A cross-sectional study. AB - BACKGROUND: The understanding and management of neurological disorders is undergoing revolutionary changes over the last three decades in the background of ever increasing advances in medical technologies, diagnostic techniques, therapeutic processes and, molecular and genetic medicine. The fruits of these advances can reach patients only if the psychosocial hurdles in their delivery are identified, acknowledged and addressed. AIM: To explore the beliefs and practices of patients with neurological disorders in a tertiary care center in the eastern Nepal. MATERIALS AND METHODS: One hundred patients attending neurology/medicine outpatient for neurological disorders were interviewed about their beliefs regarding the triggering factors, causation and treatment-seeking behavior particularly from traditional healers. RESULT: Of the 100 patients (49 males, 51 females) recruited in the study, 51% expressed having 'no idea' about their illness. Only 20% patients gave medically congruent explanation for their illness. Psychological factors were attributed as triggering factors by 16% of patients, of which two-thirds were females. Chance, destiny and 'jadu tona' topped the list of triggering factors. Forty-four percent patients had sought help of traditional faith healers ('Dhami Jhakri') before seeking medical help. Traditional faith healers were approached by patients irrespective of their educational background. Fifty-nine percent of patients who first sought traditional faith healers, believed in 'jadu-tona'. Of those interviewed, 16% were planning to go to a faith healer in near future. CONCLUSION: The beliefs of patients with neurological disorders frequently do not conform to current medical opinion. There is need for greater communication and education of patients by their treating physicians. PMID- 24347942 TI - Depression and sleep disturbances in patients with multiple sclerosis and correlation with associated fatigue. AB - OBJECTIVE: To observe prevalence of depression and sleep disturbances in multiple sclerosis (MS) patients and their correlation with associated fatigue. STUDY DESIGN AND SETTING: Prospective observation study in a university tertiary research hospital in India. MATERIALS AND METHODS: Thirty-one patients (6 male and 25 female) with definite MS (McDonald's criteria) presented in out patient/admitted in the department of neurology (between February 2010 and December 2011) were included in the study. Depression was assessed using Beck's Depression Inventory (BDI). Sleep quality was assessed using Pittsburg Sleep Quality Index (PSQI). Disease severity was evaluated using the Kurtzke's expanded disability status scale (EDSS). Fatigue was assessed using Krupp's fatigue severity scale (FSS). We tried to observe correlation of depression and sleep disturbance with associated fatigue in MS patients. RESULTS: The age of patients varied between 16 and 50 years (30.1 +/- 9.1). The mean age at first symptom was 25.2 +/- 6.4 years (range 14-39 years). The prevalence of sleep disturbance and depression was 51.6% (16/31) each and fatigue 58.1% (18/31) in the study group. The PSQI scores were significantly greater in the patients with fatigue as compared with those without fatigue indicating poorer sleep quality is associated with fatigue in MS (P = 0.005). The BDI scores were also significantly higher in the fatigue group showing that severity of depression also strongly correlated with fatigue (P = 0.001). CONCLUSIONS: Depression and sleep disturbance in patients with MS is significantly correlated with associated fatigue. PMID- 24347943 TI - Reliability of motor parameters for follow-up after local steroid injection in carpal tunnel syndrome. AB - BACKGROUND: Local steroid injection is one of the treatment modalities for carpal tunnel syndrome (CTS). Symptomatic and electrophysiological improvement has been previously documented. The electrophysiological parameter, which represents the most consistent change after local steroid injection, is not well-known. OBJECTIVE: The objective of this study was to evaluate the changes in electrophysiological parameters 1 month after local steroid injection and to determine the parameter that is able to depict improvement across the severity spectrum of CTS. MATERIALS AND METHODS: Forty-seven patients (27 with bilateral disease, 74 hands totally) were included. The electrophysiological parameters studied at baseline included sensory onset latency, sensory nerve action potential amplitude, sensory conduction velocity (CV), distal motor latency, compound muscle action potential amplitude and motor CV. All patients were injected with 40 mg triamcinalone at the wrist. After 1 month, symptomatic improvement from baseline was documented using visual analog score of 100. Electrophysiology was repeated. Paired t tests were done between baseline electrophysiology parameters and those obtained 1 month after steroid injection for significant improvement. Subgroup analyses were performed in hands with mild to moderate (Grade 3 or less by Bland's classification) and severe disease (Grades 4 and 5). RESULTS: All patients showed a symptomatic improvement. Distal motor latency showed most consistent improvement irrespective of the severity of CTS. In mild to moderate CTS (Grade 3 or less of the classification given by Bland) sensory parameters were recordable and showed significant improvement in addition to distal motor latency. In the subcategory of severe CTS (Grades 4 and 5 of Bland) where sensory parameters are not recordable distal motor latency and the motor CV showed a significant improvement. CONCLUSION: One month after local steroid injection among the electrophysiological parameters studied distal motor latencies showed most consistent and recordable improvement across the severity spectrum of CTS. This can be used as a single objective parameter to follow-up patients after a local steroid injection to document improvement or relapse. They can also be considered as objective parameter to follow-up patients after surgery. PMID- 24347944 TI - Commentary. PMID- 24347945 TI - Commentary. PMID- 24347946 TI - Nursing students' attitude towards suicide attempters: A study from rural part of Northern India. AB - CONTEXT: Majority of health professionals have unfavorable attitudes towards patients presenting with self-harm, which further compromises their willingness and outcome of care. AIMS: To assess the nursing students' attitudes toward suicide attempters. SETTINGS AND DESIGN: Cross-sectional study was conducted in two nursing colleges of north India. MATERIAL AND METHODS: Three hundred and eight nursing students were recruited through total enumeration method from May to June 2012. 'Suicide opinion questionnaire' was administered to assess their attitudes towards suicide attempters. STATISTICAL ANALYSIS USED: Descriptive statistics was employed with Statistical Package for Social Sciences version 14.0 for Windows. RESULTS: Majority were single females, from urban locality, with the mean age of 20 years. Only minority had previous exposure to suicide prevention programs and management of such cases. Majority of students agreed for mental illness, disturbed family life, and depression as major push to attempt suicide. They held favorable attitude for half of the attitudinal statement, but they were uncertain for rest half of the statements. CONCLUSIONS: They generally had favorable attitude towards suicide attempters. Their uncertain response highlights the need for enhancing educational exposure of nursing students and new staff at the earliest opportunity, to carve their favorable attitude towards patients presenting with self-harm. PMID- 24347947 TI - Intelligence quotient is associated with epilepsy in children with intellectual disability in India. AB - BACKGROUND: Epilepsy is a disorder that is commonly found in people with intellectual disability (ID). The prevalence of epilepsy increases with the severity of ID. The objective of this study was to determine if there is an association between intelligence quotient (IQ) and epilepsy in children with ID. MATERIALS AND METHODS: A total of 262 children, aged 3-18 years, with ID were identified as part of a community-based rehabilitation project. These children were examined for epilepsy and diagnosed by a psychiatrist and physicians based on results of electroencephalogram tests. A Spearman's correlation (rho) was used to determine if there was an association between IQ scores and the occurrence of epilepsy. X(2) statistics used to examine the relationship of epilepsy with gender, socioeconomic status, population type, severity of ID, family history of mental illness, mental retardation, epilepsy, and coexisting disorder. RESULTS: Spearman's rho -0.605 demonstrates inverse association of IQ with epilepsy. X(2) demonstrates statistically significant association (P < 0.05) with gender, severity of ID, cerebral palsy, behavior problems, and family history of mental illness, mental retardation, and epilepsy. CONCLUSIONS: Lower IQ score in children with ID has association with occurrence of epilepsy. Epilepsy is also found highly associated with male gender and lower age. PMID- 24347948 TI - What is next after transfer of care from hospital to home for stroke patients? Evaluation of a community stroke care service based in a primary care clinic. AB - CONTEXT: Poststroke care in developing countries is inundated with poor concordance and scarce specialist stroke care providers. A primary care-driven health service is an option to ensure optimal care to poststroke patients residing at home in the community. AIMS: We assessed outcomes of a pilot long term stroke care clinic which combined secondary prevention and rehabilitation at community level. SETTINGS AND DESIGN: A prospective observational study of stroke patients treated between 2008 and 2010 at a primary care teaching facility. SUBJECTS AND METHODS: Analysis of patients was done at initial contact and at 1 year post treatment. Clinical outcomes included stroke risk factor(s) control, depression according to Patient Health Questionnaire (PHQ9), and level of independence using Barthel Index (BI). STATISTICAL ANALYSIS USED: Differences in means between baseline and post treatment were compared using paired t-tests or Wilcoxon-signed rank test. Significance level was set at 0.05. RESULTS: Ninety one patients were analyzed. Their mean age was 62.9 [standard deviation (SD) 10.9] years, mean stroke episodes were 1.30 (SD 0.5). The median interval between acute stroke and first contact with the clinic 4.0 (interquartile range 9.0) months. Mean systolic blood pressure decreased by 9.7 mmHg (t = 2.79, P = 0.007), while mean diastolic blood pressure remained unchanged at 80mmHg (z = 1.87, P = 0.06). Neurorehabilitation treatment was given to 84.6% of the patients. Median BI increased from 81 (range: 2-100) to 90.5 (range: 27-100) (Z = 2.34, P = 0.01). Median PHQ9 scores decreased from 4.0 (range: 0-22) to 3.0 (range: 0-19) though the change was not significant (Z= -0.744, P = 0.457). CONCLUSIONS: Primary care driven long-term stroke care services yield favorable outcomes for blood pressure control and functional level. PMID- 24347949 TI - The "Skull Flap" a new conceived device for decompressive craniectomy experimental study on dogs to evaluate the safety and efficacy in reducing intracranial pressure and subsequent impact on brain perfusion. AB - BACKGROUND: Decompressive craniectomy (DC) is a procedure performed increasingly often in current neurosurgical practice. Significant perioperative morbidity may be associated to this procedure because of the large skull defect; also, later closure of the skull defect (cranioplasty) may be associated to post-operative morbidity as much as any other reconstructive operation. The authors present a newly conceived/developed device: The "Skull Flap" (SF). This system, placed at the time of the craniectomy, offers the possibility to provide cranial reconstruction sparing patients a second operation. In other words, DC and cranioplasty essentially take place at the same time and in addition, patients retain their own bone flap. The current study conducted on animal models, represents the logical continuation of a prior recent study, realized on cadaver specimens, to assess the efficacy and safety of this recently developed device. MATERIALS AND METHODS: This is an experimental pilot study on dogs to assess both safety and efficacy of the SF device. Two groups of experimental raised intracranial pressure animal models underwent DC; in the first group of dogs, the bone flap was left in raised position above the skull defect using the SF device; on the second group the flap was discarded. All dogs underwent transcranial Doppler (TCD) to assess brain perfusion. Head computed tomography (CT) scan to determine flap position was also obtained in the group in which the SF device was placed. RESULTS: SF has proved to be a strong fixation device that allows satisfactory brain decompression by keeping the bone flap elevated from the swollen brain; later on, the SF allows cranial reconstruction in a simple way without requiring a second staged operation. In addition, it is relevant to note that brain perfusion was measured and found to be better in the group receiving the SF (while the flap being in a raised as well as in its natural position) comparing to the other group. CONCLUSION: The SF device has proved to be very easy to place, well-adaptable to a different type of flaps and ultimately very effective in maintaining satisfactory brain decompression and later on, making easy bone flap repositioning after brain swelling has subsided. PMID- 24347951 TI - Kummell's disease - uncommon or underreported disease: A clinicopathological account of a case and review of literature. AB - Kummell's disease is a rare form of vertebral body osteonecrosis, which develops as a delayed post-traumatic event. It is infrequently reported in literature and to the best of our knowledge, has not been reported from India. We describe the clinical, radiological, and pathological features of a case occurring in a 60 year-old man and relevant brief review of the literature of this rare disease. Its close resemblance to more commonly occurring bony tuberculosis poses a diagnostic dilemma particularly in developing country like India, where tuberculosis is endemic. Awareness of this entity, though rare, is essential to avoid unnecessary diagnostic work up and treatment. PMID- 24347952 TI - Commentary. PMID- 24347950 TI - Cerebral sinus venous thrombosis. AB - Cerebral sinus venous thrombosis (CSVT) is a rare phenomenon that can be seen with some frequency in young patients. CSVT is a multifactorial condition with gender-related specific causes, with a wide clinical presentation, the leading causes differ between developed and developing countries, converting CSVT in a condition characterized by a highly variable clinical spectra, difficult diagnosis, variable etiologies and prognosis that requires fine medical skills and a high suspicious index. Patients who presents with CSVT should underwent to CT-scan venography (CVT) and to the proper inquiry of the generating cause. This disease can affect the cerebral venous drainage and related anatomical structure. The symptoms may appear in relation to increased intracranial pressure imitating a pseudotumorcerebri. Prognosis depends on the early detection. Correcting the cause, generally the complications can be prevented. Mortality trends have diminished, and with the new technologies, surely it will continue. This work aims to review current knowledge about CSVT including its pathogenesis, etiology, clinical manifestations, diagnosis, and treatment. PMID- 24347953 TI - Commentary. PMID- 24347954 TI - A case of multiple myeloma presenting as scalp swelling with intracranial extension. AB - Multiple myeloma is a malignant neoplasm of bone marrow affecting plasma cells. It is usually detected in skull bone with characteristic features of multiple punched-out lesions. Its presentation as a solitary scalp swelling with underlying skull bone erosion and intracranial extension is very rare. A 35-year old female presented to us with complains of rapidly growing left-side scalp swelling with right-side paresis and simple partial seizure of right upper limb. Local examination, X-ray skull, CT scan, and MRI of brain were suggestive of a malignant lesion. Near total excision of lesion was done. Histopathological study was suggestive of plasmacytoma of skull. Bone marrow study further confirmed it as a case of multiple myeloma. Cases presenting with solitary osteolytic skull lesions, possibility of plasmacytoma, or multiple myeloma should be kept in mind. PMID- 24347955 TI - Commentary. PMID- 24347956 TI - Late onset of atypical paroxysmal non-kinesigenic dyskinesia with remote history of Graves' disease. AB - Paroxysmal non-kinesigenic dyskinesia (PNKD) is a rare hyperkinetic movement disorder and falls under the category of paroxysmal movement disorders. In this condition, episodes are spontaneous, involuntary, and involve dystonic posturing with choreic and ballistic movements. Attacks last for minutes to hours and rarely occur more than once per day. Attacks are not typically triggered by sudden movement, but may be brought on by alcohol, caffeine, stress, fatigue, or chocolate. We report a patient with multiple atypical features of PNKD. She had a 7-year history of this condition with onset at the age of 59, and a remote history of Graves' disease requiring total thyroidectomy. The frequency of attacks in our case ranged from five to six times a day to a minimum of twice per week, and the duration of episode was short, lasting not more than 2 min. Typically, PNKDs occur at a much younger age and have longer attack durations with low frequency. Administering clonazepam worked to reduce her symptoms, although majority of previous research suggests that pharmacological interventions have poor outcomes. PMID- 24347957 TI - Commentary. PMID- 24347958 TI - Giant cystic intradural extramedullary pilocytic astrocytoma of Cauda equina. AB - Astrocytomas of Conus-Cauda equina region are rare. Astrocytomas, which are intramedullary tumors, may rarely have an extramedullary component. However, primary intradural extramedullary astrocytomas are extremely rare, with very few cases reported in the literature. We describe a giant extramedullary pilocytic astrocytoma of Cauda equina in a 20-year-old male. To the best of our knowledge, this is the first report of such a case in the available literature. This case highlights the fact that astrocytomas can be primarily extramedullary and emphasizes the need to consider pilocytic astrocytoma in the differential diagnosis of cystic Cauda equina tumors. PMID- 24347959 TI - Posterior approach for giant S1 neurofibroma in Von Recklinghausen's disease: Is total resection realistic? AB - Bilateral sacral neurofibromas are uncommonly seen in neurofibromatosis type 1 (NF1) also known as Von Recklinghausen's disease. They often grow to enormous dimensions before detection owing to bone scalloping. Resections of "giant" S1 neurofibromas are difficult due to the limitations of operative window in sacrum and critical functions associated with S1 nerve root. We report a case of bilateral S1 neurofibromas in a patient of NF1 where she had a giant left-sided neurofibroma with extensive bone erosion and a small fusiform neurofibroma on the right side. The tumor was excised completely on the left and near totally on the right side via posterior approach. There were no postoperative neurological deficits and the patient recovered well. Usually, complete excision harbors the chances of postoperative neurological deficits due to the eloquence of the nerve root involved and complete resection without significant morbidity seems unrealistic. However, excision of giant ones may not result in grave deficits always if the patient is neurologically intact before surgery. Also, in selected patients, only posterior approach may suffice for giant neurofibromas with extensive bone scalloping and complete removal can be attempted successfully despite narrow corridors. PMID- 24347960 TI - Commentary. PMID- 24347961 TI - Disseminated neurocysticercosis presenting as affective mood disorder with chronic tension type headache. AB - Neurocysticercosis is a common parasitic infection in India presenting usually with seizues, headache, focal neurological deficits. Neurocysticercosis presenting as a psychiatric illness is rare. Disseminated cysticercosis with involvement of central nervous system and head and neck muscles is rare even in endemic areas. We present a case of disseminated cysticercosis, which presented with chronic tension type headache and affective mood disorder. Treatment with cysticidal drugs led to complete remission of psychiatric complaints. In endemic areas history suggestive of mood disorder should not be used as supportive evidence of a primary headache syndome like tension type headche without ruling out secondary causes. Making an early diagnosis can prevent morbidity. PMID- 24347962 TI - Vitamin D deficiency rickets presenting as pseudotumor cerebri. AB - Pseudotumor cerebri is a condition of elevated intracranial pressure in the absence of clinical, laboratory or radiological evidence of an intracranial space occupying lesion. Various associations with pseudotumor cerebri have been made in literature. We report the case of a five-month-old female infant with vitamin D deficiency rickets, who presented with pseudotumor cerebri. Her cerebrospinal fluid examination was normal, with a high opening pressure of 330 mmH2O. Her computed tomography scan was normal. After lumbar puncture the anterior fontanelle came at level. Her investigations revealed vitamin D deficiency. She was started on acetazolamide, calcitriol sachets, and calcium supplements. She became asymptomatic in three days and was discharged. Through this case we wish to highlight this unusual presentation of vitamin D deficiency rickets appearing as pseudotumor cerebri. PMID- 24347963 TI - Acute traumatic orbital encephalocele: A case report with review of literature. AB - Orbital roof fractures after a blunt injury are an uncommon complication of trauma. Traumatic encephaloceles in the orbital cavity are even rarer, with only 15 cases published till date. Raised intraorbital pressure leading to irreversible damage to the optic nerve can be prevented by early diagnosis and management. Orbital computed tomography (CT) with thin axial and coronal sections is helpful in trauma patients with a concurrent orbital trauma. Decompression of the orbital roof is the key step in surgical treatment and should be performed in every case. Repairing the orbital roof has to be performed to avoid transmission of variation in the intracranial pressure to the orbit. We present a case of traumatic orbital encephalocele who underwent surgical treatment via a frontobasal approach with evacuation of the contused herniated brain and reconstruction of the orbital roof using temporalis fascia which is readily available in contrast to costly materials like titanium mesh, screws, bone powder, fibrin glue, and so on, which are not easily available in every hospital. Rapid resolution of proptosis and visual symptoms along with excellent cosmetic outcome was seen at follow-ups after three and nine months. We emphasize the early diagnosis of this rare condition and also emergency treatment to prevent permanent visual loss as well as to achieve good cosmetic results. PMID- 24347964 TI - Using the head as a mould for cranioplasty with methylmethacrylate. AB - Methacrylate is a valuable tool to the neurosurgeon, even though it is currently being replaced by custom bone. During cranioplasty in the absence of custom bone, which is preformed based on the patients imaging, one has to make a cast to cover the cranial defect with or without the use of a mould. A good artificial skull outline is necessary for prevention of implant extrusion and acceptable cosmetic outcome. Using the patients head as a mould is a simple, cheap, and useful technique. An incision is made, and either a craniectomy or an attempt at skull elevation or separation of the scalp from dura is done based on the indication for the cranioplasty. The methacrylate monomer is mixed with its solvent. It is placed in between a sliced glove and then thinned out. Several layers of drapes are placed on the patients head, the acrylate which is in between the gloves is then placed on the drapes. As soon as it starts setting and the required shape obtained, it is removed and place on the sterile tray. It is then anchored and the wound closed. This technique produces good cosmetic outcome. However, the head must be properly protected from the risk of burns from the exothermic reaction. The technique is described in a 40-year-old driver who had a compound depressed skull fracture. He had a methylmethacrylate cranioplasty in the 9(th) week post trauma after allowing for wound healing. We recommend that this technique may be used in centers where custom bone is either too expensive or not available during cranioplasty in order to obtain a good outcome. PMID- 24347965 TI - Erratum. PMID- 24347966 TI - Reduction in global burden of stroke in underserved areas. PMID- 24347967 TI - Bilateral cystic glioblastoma multiforme. PMID- 24347968 TI - Ethylene glycol toxic encephalopathy. PMID- 24347969 TI - Commentary. PMID- 24347970 TI - Parasympathetic overactivity: A manifestation of temporal lobe epilepsy. PMID- 24347971 TI - Injection nerve palsy: What's to blame? PMID- 24347972 TI - Author's response. PMID- 24347973 TI - Pharmacovigilance in Calabria (Italy): Local experiences resonate international relevance. PMID- 24347974 TI - Vertigo/dizziness as a Drugs' adverse reaction. AB - INTRODUCTION: Vertigo, dizziness, and nausea encompass a spectrum of balance related symptoms caused by a variety of etiologies. Balance is affected by many systems: Proprioceptive pathways and visual, cerebellar, vestibulocochlear, and vascular / vasovagal systems. Vertigo is a subtype of dizziness, in which a subject, as a result to a dysfunction of the vestibular system, improperly experiments the perception of motion. The most useful clinical subdivision is to categorize vertigo into true vertigo and pseudovertigo, whereas from a pathophysiological point of view, vertigo can be classified into central, peripheral, and psychogenic. It is not easy to identify the cause of vertigo since the patients often are not able to precisely describe their symptoms. An impressive list of drugs may cause vertigo or dizziness. MATERIALS AND METHODS: The aim of the present study was to analyze the data extracted from the reporting cards of the ADRs (adverse drug reactions), received at our Pharmacovigilance Regional Center (Calabria, Italy) in 2012. In particular, the data concerning the occurrence of vertigo and dizziness, after taking certain classes of drugs, have been considered. RESULTS: Our results show that, among the side-effects of different classes of drugs such as anti-convulsants, anti-hypertensives, antibiotics, anti-depressants, anti-psychotics, and anti-inflammatory, also vertigo or dizziness are included. CONCLUSIONS: Spontaneous reports of vertigo or dizziness, as side-effect of certain drugs, received at our Pharmacovigilance Center, represented the 5% of all reports in 2012. Considering the high incidence of such an ADR for several drugs' classes, it can be speculated that under reporting also affect vertigo and dizziness. Despite the fact that these ADRs might not represent a direct threaten for life, indirectly they can cause secondary damage to patients such as falls, fractures etc. Balance should be accurately monitored during drug use and particularly in fragile patients. PMID- 24347975 TI - Safety and efficacy of generic drugs with respect to brand formulation. AB - Generic drugs are equivalent to the brand formulation if they have the same active substance, the same pharmaceutical form and the same therapeutic indications and a similar bioequivalence respect to the reference medicinal product. The use of generic drugs is indicated from many countries in order to reduce medication price. However some points, such as bioequivalence and the role of excipients, may be clarified regarding the clinical efficacy and safety during the switch from brand to generic formulations. In conclusion, the use of generic drugs could be related with an increased days of disease (time to relapse) or might lead to a therapeutic failure; on the other hand, a higher drug concentration might expose patients to an increased risk of dose-dependent side effects. PMID- 24347976 TI - Pharmacovigilance in Italy: An overview. AB - INTRODUCTION: Spontaneous reporting of adverse drug reactions (ADRs) is the basis of pharmacovigilance. In fact, ADRs are associated with a high degree of morbidity and mortality. However, underreporting by all healthcare professionals remains the major problem in Italy and in the rest of the world. The dissemination of pharmacovigilance knowledge among Italian healthcare professionals, and the new pharmacovigilance regulations may promote the early detection and reporting of ADRs. This review examines the legislative framework concerning the pharmacovigilance in Italy. MATERIALS AND METHODS: The information was collected from scientific articles and the websites of the Italian Ministry of Health and the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA). RESULTS: The pharmacovigilance system, both in Italy and Europe, has undergone profound changes. European legislation on pharmacovigilance has been changed in 2010 according to the EU Regulation 1235/2010 and Directive 2010/84/EU. Basically, the changes tend to increase the efficiency, speed and transparency of pharmacovigilance activities. The new Regulation (1235/2010) and the Directive (2010/84/EU) aim to strengthen the system of pharmacovigilance, establish more precisely who is obliged to do what, and allow faster and easier circulation and retrieval of information about ADRs. CONCLUSION: A greater knowledge on what is the Italian pharmacovigilance legislation will be useful to improve the status of ADRs reporting and spread the culture of spontaneous reporting. PMID- 24347977 TI - Abatacept in psoriatic arthritis: Case report and short review. AB - Psoriatic arthritis (PsA) is a chronic inflammatory disease affecting about 6-10% of patients with cutaneous psoriasis. According to current knowledge, activated T cells seem to play a pivotal role in the pathogenesis of both psoriasis and PsA. Abatacept is a novel biologic agent selectively designed to interfere with T cells co-stimulation. Structurally, it is a soluble, fully human fusion protein consisting of the extracellular domain of CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) linked to a modified Fc portion of human IgG1. Abatacept is now approved as a first-line treatment for rheumatoid arthritis (RA), but preliminary data disclose a potential role of abatacept in the treatment of other autoimmune diseases. In this article, we report a case of successful treatment with abatacept of a psoriatic arthritis patients who developed adverse drug reactions (ADRs) to medication commonly used in PsA, including three different anti-TNF-alpha agents. In addition, we review the scientific evidences supporting a possible role of abatacept in treatment of patients with psoriasis and PsA and the paradox of abatacept-induced psoriasis. PMID- 24347978 TI - Pharmacovigilance in pharmaceutical companies: An overview. AB - Pharmacovigilance is responsible for monitoring the safety of medicines in normal clinical use and during clinical trials. In the light of the experience acquired and following an assessment by the Commission of the Union system of pharmacovigilance, it has become clear that it is necessary to take measures in order to improve the operation of Union law on the pharmacovigilance of medicinal products for human use. Regulation (EU) No 1235/2010 and Directive 2010/84/EU introduced new legislation on pharmacovigilance. The marketing authorization holder should be responsible for continuously monitoring the safety of its medicinal products for human use, for informing the authorities of any changes that might have an impact on the marketing authorization, and for ensuring that the product information is kept up-to-date. Marketing authorization holders (MAH) record all suspected adverse reactions occurring in the European Union or in the third countries, and which are brought to their attention spontaneously by the patients or their health care, or occurring in the context of post-authorization study. For all medicinal products is mandatory to maintain a pharmacovigilance system master file (PSMF). According to the Legislative Decree 219/2006 the MAH must submit to the competent authorities the information on suspected adverse reactions of a medicinal product, in form of a periodic safety update reports (PSURs). PMID- 24347979 TI - Anti-vascular endothelial growth factor drugs safety and efficacy in ophthalmic diseases. AB - Macular degeneration is the leading cause of blindness in developed countries. In the treatment of neovascular age-related macular degeneration, vascular endothelial growth factor (VEGF) has emerged as a key target for therapy. The intravitreal injection of anti-VEGF drugs has been widely employed to reduce the disease progression and improve the visual outcomes of the affected patients. However, each intravitreal inoculation poses a risk of several complications as infection, inflammation, endophthalmitis, intraocular inflammation, increase of intraocular pressure and vitreous hemorrhage. This short review evaluates the efficacy and the incidence of adverse drug reactions related to intravitreal administration of the main anti-VEGF drugs actually available: Bevacizumab, ranibizumab and aflibercept. PMID- 24347980 TI - Pharmacovigilance and the italian medicines agency. AB - The new European Union (EU) regulations on pharmacovigilance require that the national systems are strengthened in order to fit the new requirements. The Italian Pharmacovigilance System, coordinated by the Italian Medicines Agency (AIFA), is made by local and regional structures. In 2007, a program for funding active pharmacovigilance projects in the Italian Regions was established by the National law. The AIFA is responsible for the preparation of guidelines aimed at the identification of research areas and for the approval of the projects submitted by the regions. In April 2012, the AIFA started a program of visits at the regional pharmacovigilance centers (RPCs), aimed at monitoring their performances, evaluating the quality of the activities in order to understand the main differences and discrepancies and with a view to start a program of harmonization of the procedures in place. The outcome of the visits program highlighted major differences among the quality management systems of the various centers; hence, AIFA has decided to launch an initiative to promote in the next months the harmonization of procedures. The synergy among AIFA, regional structures, RPCs, and local structure responsible for pharmacovigilance is needed in order to establish a robust pharmacovigilance system working in full compliance with the provisions of the new EU legislation. PMID- 24347981 TI - Informatics applied to pharmacovigilance: Future perspectives. AB - Spontaneous adverse drugs reaction (ADRs) reporting represents a precious resource for control and information about the drug's safety and pharmacovigilance. The current reporting system is mainly based on handwritten forms and later manually loaded into a national electronic database by few local pharmacovigilance centers. This reporting system is complicated for both reporters and pharmacovigilance centers which often avoid reporting ADRs for several reasons such as the lack of data on the report. The reporting system might be implemented by improving online platform for ADRs upload; this could allow inspecting all ADRs loaded. Currently, the database is only accessible by the Italian Medicine Agency (AIFA) and local pharmacovigilance centers; neither reporters nor other healthcare professionals can access the database. Finally, it would be right to implement pharmacovigilance centers with specific professional figures qualified in the pharmacovigilance to support both citizens and reporters on various aspects of ADRs reporting. PMID- 24347982 TI - Retrospective evaluation of adverse drug reactions induced by antihypertensive treatment. AB - The use of cardiovascular drugs is related to the development of adverse drug reactions (ADRs) in about 24% of the patients in the Cardiovascular Care Unit. Here, we evaluated the ADRs in patients treated with antihypertensive drugs. The study was conducted in two phases: In the first phase, we performed a retrospective study on clinical records of Clinical Divisions (i.e., Internal Medicine Operative Unit and Geriatric Operative Unit) from January 1, 2012 to December 31, 2012. Moreover from January 1, 2013 to March 30, 2013 we performed a prospective study on the outpatients attending the Emergency Department (ED) of the Pugliese-Ciaccio Hospital of Catanzaro, by conducting patient interviews after their informed consent was obtained. The association between a drug and ADR was evaluated using the Naranjo scale. We recorded 72 ADRs in the Clinical Divisions and six in the ED, and these were more frequent in women. Using the Naranjo score, we showed a probable association in 92% of these reactions and a possible association in 8%. The most vulnerable age group involved in ADRs was that of the elderly patients. In conclusion, our results indicate that antihypertensive drugs may be able to induce the development of ADRs, particularly in elderly women receiving multiple drug treatment. Therefore, it is important to motivate the healthcare providers to understand their role and responsibility in the detection, management, documentation, and reporting of ADRs, as also all the essential activities for optimizing patient safety. PMID- 24347983 TI - A questionnaire-based study in Calabria on the knowledge of off-label drugs in pediatrics. AB - Off-label use is very common among pediatricians, and the main cause is attributable to the lack of drugs specifically designed and marketed for children in different age groups. In this study, we evaluated, through a questionnaire, the knowledge of off-label drugs in pediatrics. Furthermore, we made a directory of 28 off-label drugs most commonly used by pediatricians in agreement with data obtained from Italian Agency for drugs (AIFA) referred to the law no. 648/1996; 180 pediatricians referred to the Italian Society of Pediatrics Calabrian section were asked to complete an online anonymous questionnaire. Eighty five (47.3%) of these completed the anonymous questionnaire, 40% revealed that they used off label drugs "sometimes"; generally, drugs were used off-label for age and to treat respiratory diseases. For 75 pediatricians (88%) the information about the risk/benefit of off-label drugs is inadequate and 63 pediatricians (74%) did not have a good knowledge about this practice. In conclusion, the knowledge of off label drugs is very low in pediatricians; more information about off-label drugs could be useful in order to improve the appropriateness of drugs' prescription and to reduce the development of side effects and improving drug safety. PMID- 24347984 TI - Pharmacovigilance and drug safety in Calabria (Italy): 2012 adverse events analysis. AB - INTRODUCTION: Pharmacovigilance (PV) is designed to monitor drugs continuously after their commercialization, assessing and improving their safety profile. The main objective is to increase the spontaneous reporting of adverse drug reactions (ADRs), in order to have a wide variety of information. The Italian Drug Agency (Agenzia Italiana del Farmaco [AIFA]) is financing several projects to increase reporting. In Calabria, a PV information center has been created in 2010. MATERIALS AND METHODS: We obtained data using the database of the National Health Information System AIFA relatively to Italy and Calabria in the year 2012. Descriptive statistics were performed to analyze the ADRs. RESULTS: A total number of 461 ADRs have been reported in the year 2012 with an increase of 234% compared with 2011 (138 reports). Hospital doctors are the main source of this reporting (51.62%). Sorafenib (Nexavar((r))), the combination of amoxicillin/clavulanic acid and ketoprofen represent the drugs most frequently reported causing adverse reactions. Adverse events in female patients (61.83%) were more frequently reported, whereas the age groups "41-65" (39.07%) and "over 65" (27.9%) were the most affected. CONCLUSIONS: Calabria has had a positive increase in the number of ADRs reported, although it has not yet reached the gold standard set by World Health Organization (about 600 reports), the data have shown that PV culture is making inroads in this region and that PV projects stimulating and increasing PV knowledge are needed. PMID- 24347985 TI - Annual report on adverse events related with vaccines use in Calabria (Italy): 2012. AB - Vaccines are administered to large population of healthy individuals, particularly to millions of infants every year, through national immunization programs. Although vaccines represent a good defense against some infectious diseases, their administration may be related with the development of adverse vaccine events (AVEs); therefore their use is continually monitored to detect these side effects. In the presents work, we reported the suspected AVEs recorded in 2012 in Calabria, Italy. We performed a retrospective study on report forms of patients that developed AVEs in Calabria from January 1, 2012 to December 31, 2012. Naranjo score was used to evaluate the association between AVEs and vaccines and only suspected AVEs definable as certain, probable, or possible were included in this analysis. During the study period, we evaluated 461 records of adverse drug reactions (ADRs) and 18 (3.9%) were probably induced by vaccination. AVEs were common in females (almost 77.7%) and in children aged 0-3 years. The largest number of non-serious AVEs involved "skin and subcutaneous tissue disorders" and "general disorders and administration site conditions." In conclusion, we documented that in Calabria the total number of AVEs is very low and it may be useful to increase the pharmacovigilance culture in order to evaluate the safety of these products in large populations. PMID- 24347986 TI - Limitations and obstacles of the spontaneous adverse drugs reactions reporting: Two "challenging" case reports. AB - INTRODUCTION: Nowadays, based on several epidemiological data, iatrogenic disease is an emerging public health problem, especially in industrialized countries. Adverse drugs reactions (ADRs) are extremely common and, therefore, clinically, socially, and economically worthy of attention. Spontaneous reporting system for suspected ADRs represents the cornerstone of the pharmacovigilance, because it allows rapid detection of potential alarm signals related to drugs use. However, spontaneous reporting system shows several limitations, which are mainly related to under-reporting. In this paper, we describe two particular case reports, which emphasize some reasons of under-reporting and other common criticisms of spontaneous reporting systems. MATERIALS AND METHODS: We performed a computer aided search of Medline, PubMed, Embase, Cochrane library databases, national and international databases of suspected ADRs reports in order to identify previous published case reports and spontaneous reports about the ADRs reviewed in this paper, and to examine the role of suspected drugs in the pathogenesis of the described adverse reactions. RESULTS: First, we reported a case of tizanidine induced hemorrhagic cystitis. In the second case report, we presented an episode of asthma exacerbation after taking bimatoprost. Through the review of these two cases, we highlighted some common criticisms of spontaneous reporting systems: under-reporting and false causality attribution. DISCUSSION AND CONCLUSION: Healthcare workers sometimes do not report ADRs because it is challenging to establish with certainty the causal relationship between drug and adverse reaction; however, according to a key principle of pharmacovigilance, it is always better to report even a suspicion to generate an alarm in the interest of protecting public health. PMID- 24347987 TI - Pharmacovigilance in Asia. AB - An increase in drug safety concerns in recent years with some high profile drug withdrawals have led to raising the bar by various stakeholders more importantly by the regulatory authorities. The number of Adverse Drug Reactions (ADRs) reported have also resulted in an increase in the volume of data handled and to understand pharmacovigilance a high level of expertise is required to rapidly detect drug risks as well as to defend the product against an inappropriate removal. Proactive pharmacovigilance throughout the product life cycle is the way forward and the future direction for drug safety in Asia. It has been a constant challenge to standardize pharmacovigilance in Asia, in the context of clinical trials and post-marketing pharmacovigilance due to varied geaographical, cultural and medical practices in these regioon. While major advancements of the discipline of pharmacovigilance have taken place in the West, not much has been achieved in Asian countries, though several attempts have been taken. However, with more clinical trials and clinical research activity being conducted in the Asian continent, there is an immense need to understand and implement pharmacovigilance. For this to happen, the mind set of people working in regulatory agencies, the Pharmaceutical companies, prescribers and patients/consumers need to change. PMID- 24347988 TI - Clinical and economic burden of adverse drug reactions. AB - Adverse drug reactions (ADRs) are unwanted drug effects that have considerable economic as well as clinical costs as they often lead to hospital admission, prolongation of hospital stay and emergency department visits. Randomized controlled trials (RCTs) are the main premarketing methods used to detect and quantify ADRs but these have several limitations, such as limited study sample size and limited heterogeneity due to the exclusion of the frailest patients. In addition, ADRs due to inappropriate medication use occur often in the real world of clinical practice but not in RCTs. Postmarketing drug safety monitoring through pharmacovigilance activities, including mining of spontaneous reporting and carrying out observational prospective cohort or retrospective database studies, allow longer follow-up periods of patients with a much wider range of characteristics, providing valuable means for ADR detection, quantification and where possible reduction, reducing healthcare costs in the process. Overall, pharmacovigilance is aimed at identifying drug safety signals as early as possible, thus minimizing potential clinical and economic consequences of ADRs. The goal of this review is to explore the epidemiology and the costs of ADRs in routine care. PMID- 24347989 TI - Management of dermatologic toxicities associated with monoclonal antibody epidermal growth factor receptor inhibitors: A case review. AB - INTRODUCTION: The epidermal growth factor receptor inhibitors (EGFRIs), cetuximab and panitumumab, represent an effective treatment option for patients affected by metastatic colorectal cancer (mCRC); furthermore, they are relatively devoid of systemic toxicities, which are commonly observed with standard cytotoxic chemotherapy. However, the majority of patients treated with these monoclonal antibodies (mAbs), will experience dermatologic toxicities, most notably the papulopustular skin rash, which can impact quality-of-life and affect adherence to therapy. This paper reviews the most recent practices in the management of skin rash related to anti-epidermal growth factor receptor (EGFR) mAbs, cetuximab and panitumumab, in the treatment of mCRC. MATERIALS AND METHODS: We reviewed relevant literature regarding dermatologic toxicities associated with anti-EGFR mAbs in order to give important indications about prevention and reactive treatment of skin rash. RESULTS: Two case reports were presented to show how skin rash could hamper mAb EGFRIs use in clinical practice, underscoring the need of implementing a comprehensive management strategy of skin toxicity in order to promote patients' compliance with anti-EGFR therapy and maintain quality-of-life. Based on randomized data, recent guidelines established by the Multinational Association for Supportive Care in Cancer Skin Toxicity Study Group suggest that prophylactic use of oral doxycycline or minocycline reduces the risk and severity of skin rash, improving clinical outcomes. CONCLUSIONS: At the start of treatment with cetuximab and panitumumab, the proper patient education about the skin rash associated with these mAbs and the implementation of a pre-emptive, comprehensive skin toxicity program significantly contribute to improve adherence to therapy, optimize anti-EGFR therapy and maintain quality-of-life. PMID- 24347990 TI - Nexavar((r))-related adverse reactions: Calabrian (Italy) experience for sorafenib exposition in 2012. AB - Hepatocellular carcinoma (HCC) remains a major global health problem and Calabria in the south of Italy is not an exception. Sorafenib is the first and only Food and Drug Administration approved drug for the treatment of advanced HCC and it is currently under intensive monitoring by the Health Authorities in Italy Agenzia Italiana del Farmaco. This general report has been developed with the aim of briefly reviewing the data found in the reports of adverse reactions (ADRs) collected in Calabria in 2012 for sorafenib treated patients. Extrapolated data have highlighted some differences between the adverse drug reactions reported in patients younger or older than 70 years and other important differences with the current approved leaflet. Several limitations might be present in data analysis form spontaneous reporting, however, the relevance of reporting ADRs (dermatitis, asthenia, vomiting, etc.) for the early identification of drug related signals has to be underlined. PMID- 24347991 TI - A possible case of natalizumab-dependent suicide attempt: A brief review about drugs and suicide. AB - beta-Interferon therapy is known to be a potential trigger of suicidal behavior, but this effect has not been previously reported for other multiple sclerosis (MS) treatments, such as, natalizumab. Here we report the case history of a 32 year-old woman affected by relapsing-remitting MS, who attempted suicide during natalizumab treatment. This case suggests that a suicidal ideation might be a rare side effect of natalizumab. Nevertheless, this case represents the first evidence of the new adverse drug reaction related to natalizumab treatment. We should alert clinicians to be aware of the possibility of paradoxical activation of suicidality during its therapeutic use. The main purpose of the present article is to use this case to review the possible relationship between suicidal behavior and drugs. PMID- 24347992 TI - Corticosteroid-related central nervous system side effects. AB - Corticosteroids have been used since the 50s as anti-inflammatory and immunosuppressive drugs for the treatment of several pathologies such as asthma, allergy, rheumatoid arthritis, and dermatological disorders. Corticosteroids have three principal mechanisms of action: 1) inhibit the synthesis of inflammatory proteins blocking NF-kB, 2) induce the expression of anti-inflammatory proteins by IkB and MAPK phosphatase I, and 3) inhibit 5-lipoxygenase and cyclooxygenase 2. The efficacy of glucocorticoids in alleviating inflammatory disorders results from the pleiotropic effects of the glucocorticoid receptors on multiple signaling pathways. However, they have adverse effects: Growth retardation in children, immunosuppression, hypertension, hyperglycemia, inhibition of wound repair, osteoporosis, metabolic disturbances, glaucoma, and cataracts. Less is known about psychiatric or side effects on central nervous system, as catatonia, decreased concentration, agitation, insomnia, and abnormal behaviors, which are also often underestimated in clinical practice. The aim of this review is to highlight the correlation between the administration of corticosteroids and CNS adverse effects, giving a useful guide for prescribers including a more careful assessment of risk factors and encourage the use of safer doses of this class of drugs. PMID- 24347993 TI - The safety of ketoprofen in different ages. AB - Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID), which acts by blocking cyclooxygenase (COX 1 and 2), an enzyme involved in the production of prostaglandins, messengers in the development of inflammation. All NSAIDs reduce signs of inflammation by blocking this enzyme and therefore prostaglandin production. In Calabria, 3.69% of adverse drug reactions (ADRs) reported in the National Network of Pharmacovigilance concerns the use of ketoprofen; only in one case in which the patient was under the age of 12 years, hospitalization was required for severe episode of pancreatitis. In Italy, Ketoprofen is the 6(th) drug for ADRs incidence (560 ADRs in the year 2012, of which, 31% are severe). Despite the high rate of spontaneous reporting, it must be considered that ketoprofen is one of the most used NSAIDs; therefore, as it happens for other commonly used drugs (eg, amoxicillin), the total number of ADRs should be related to the therapeutic use. However, it remains the problem of fragile patients (eg, children) and the safety of the drug in different ages. This paper presents a retrospective study on 2012 ADRs reviewing literature on the safety of ketoprofen in the elderly, children, and during pregnancy. PMID- 24347994 TI - Multivariate spatial nonparametric modelling via kernel processes mixing. AB - In this paper we develop a nonparametric multivariate spatial model that avoids specifying a Gaussian distribution for spatial random effects. Our nonparametric model extends the stick-breaking (SB) prior of Sethuraman (1994), which is frequently used in Bayesian modelling to capture uncertainty in the parametric form of an outcome. The stick-breaking prior is extended here to the spatial setting by assigning each location a different, unknown distribution, and smoothing the distributions in space with a series of space-dependent kernel functions that have a space-varying bandwidth parameter. This results in a flexible non-stationary spatial model, as different kernel functions lead to different relationships between the distributions at nearby locations. This approach is the first to allow both the probabilities and the point mass values of the SB prior to depend on space. Thus, there is no need for replications and we obtain a continuous process in the limit. We extend the model to the multivariate setting by having for each process a different kernel function, but sharing the location of the kernel knots across the different processes. The resulting covariance for the multivariate process is in general nonstationary and nonseparable. The modelling framework proposed here is also computationally efficient because it avoids inverting large matrices and calculating determinants, which often hinders the spatial analysis of large data sets. We study the theoretical properties of the proposed multivariate spatial process. The methods are illustrated using simulated examples and an air pollution application to model components of fine particulate matter. PMID- 24347995 TI - Correlates of individual, and age-related, differences in short-term learning. AB - Latent growth models were applied to data on multitrial verbal and spatial learning tasks from two independent studies. Although significant individual differences in both initial level of performance and subsequent learning were found in both tasks, age differences were found only in mean initial level, and not in mean learning. In neither task was fluid or crystallized intelligence associated with learning. Although there were moderate correlations among the level parameters across the verbal and spatial tasks, the learning parameters were not significantly correlated with one another across task modalities. These results are inconsistent with the existence of a general (e.g., material independent) learning ability. PMID- 24347996 TI - Associations between household responsibilities and academic competencies in the context of education accessibility in Zambia. AB - The relationship between education and socioeconomic status has been demonstrated in studies of the developed and the developing world, yet there are communities in which schooling is either not available to all children or not a preferred activity for all children. In this study, we investigated the differences between children in-school and out-of-school in rural and peri-urban communities of Zambia. As expected, we found that the children in-school performed higher in domains of adaptive behavior and on assessments of academic achievement (i.e., mathematics, reading). Somewhat unexpectedly, however, when controlling for socioeconomic status, home responsibilities (i.e., chores, work) were a positive predictor for the performance of the children out-of-school, but a negative predictor for the children in-school. The relationship between home responsibilities and academic performance may be bidirectional and differential; for example, our findings allow for the hypothesis that for in-school children chores take time away from the studies, but for out-of-school children they provide some limited mathematics exposure. PMID- 24347998 TI - Effects of age and experience on contest behavior in the burying beetle, Nicrophorus vespilloides. AB - Contest behavior forms an important part of reproductive investment. Life-history theory predicts that as individuals age and their residual reproductive value decreases, they should increase investment in contest behavior. However, other factors such as social experience may also be important in determining age related variation in contest behavior. To understand how selection acts on contest behavior over an individual's lifetime, it is therefore important to tease apart the effects of age per se from other factors that may vary with age. Here, we independently manipulate male age and social experience to examine their effects on male contest behavior in the burying beetle Nicrophorus vespilloides. We found that social experience, but not age, influenced male contest behavior but that these changes in behavior did not alter contest outcomes. Male size (relative to his opponent) was overwhelmingly the most important factor determining contest outcome. Our results suggest that in systems with high variation in fighting ability among males, there may be little opportunity for selection to act on factors that influence contest outcomes by altering motivation to win. PMID- 24347997 TI - Biparental incubation patterns in a high-Arctic breeding shorebird: how do pairs divide their duties? AB - In biparental species, parents may be in conflict over how much they invest into their offspring. To understand this conflict, parental care needs to be accurately measured, something rarely done. Here, we quantitatively describe the outcome of parental conflict in terms of quality, amount, and timing of incubation throughout the 21-day incubation period in a population of semipalmated sandpipers (Calidris pusilla) breeding under continuous daylight in the high Arctic. Incubation quality, measured by egg temperature and incubation constancy, showed no marked difference between the sexes. The amount of incubation, measured as length of incubation bouts, was on average 51min longer per bout for females (11.5h) than for males (10.7h), at first glance suggesting that females invested more than males. However, this difference may have been offset by sex differences in the timing of incubation; females were more often off nest during the warmer period of the day, when foraging conditions were presumably better. Overall, the daily timing of incubation shifted over the incubation period (e.g., for female incubation from evening-night to night morning) and over the season, but varied considerably among pairs. At one extreme, pairs shared the amount of incubation equally, but one parent always incubated during the colder part of the day; at the other extreme, pairs shifted the start of incubation bouts between days so that each parent experienced similar conditions across the incubation period. Our results highlight how the simultaneous consideration of different aspects of care across time allows sex specific investment to be more accurately quantified. PMID- 24347999 TI - Construct Validation of the Self-Efficacy Teaching and Knowledge Instrument for Science Teachers-Revised (SETAKIST-R): Lessons Learned. AB - Described herein is the academic lineage and independent validation of the Self Efficacy Teaching and Knowledge Instrument for Science Teachers-Revised (SETAKIST R). Data from 334 K-12 science teachers were analyzed using Partial Credit Rasch models. Principal components analysis on the person-item residuals suggest two latent dimensions: Knowledge and Teaching Self-Efficacies. Item-fit statistics were used to select items for each subscale. Person and item separation (reliability) indices were quite low, and we noted disordered response patterns on the person-item maps that revealed problems with item content and/or scaling for both subscales. These issues include the presence of: verbal negatives, ambiguous modifiers, counter-intuitive scaling, and an "undecided/uncertain" option. The SETAKIST-R, in its current form, cannot be recommended as a measure of science teacher self-efficacy. PMID- 24348000 TI - Promoting the Positive Development of Boys in High-Poverty Neighborhoods: Evidence From Four Anti-Poverty Experiments. AB - This study uses geocoded address data and information about parent's economic behavior and children's development from four random-assignment welfare and anti poverty experiments conducted during the 1990s. We find that the impacts of these welfare and anti-poverty programs on boys' and girls' developmental outcomes during the transition to early adolescence differ as a function of neighborhood poverty levels. The strongest positive impacts of these programs are among boys who lived in high-poverty neighborhoods at the time their parents enrolled in the studies, with smaller or non-statistically significant effects for boys in lower poverty neighborhoods and for girls across all neighborhoods. This research informs our understanding of how neighborhood context and child gender may interact with employment-based policies to affect children's well-being. PMID- 24348001 TI - Associations of Mothers' Friendship Quality with Adolescents' Friendship Quality and Emotional Adjustment. AB - Little research has examined the association of parents' friendships with adolescent's well-being, perhaps because the association was considered too distal. However, developmental theories suggest that contexts in which parents, but not their children, are situated may be related to child development (Bronfenbrenner, 1979; 1986). The current work examined associations between the quality of mothers' own friendships and their adolescent children's friendship quality and emotional adjustment. Fifth-, eighth-, and eleventh-graders (N = 172) whose mothers' friendships were characterized by conflict and antagonism reported having friendships that were high in negative friendship qualities as well as elevated internalizing symptoms. These associations held after controlling for mother-child relationship quality, suggesting that mothers' friendships may have a unique association with adolescents' adjustment. PMID- 24348002 TI - Do Market Incentives Crowd Out Charitable Giving? AB - Donations and volunteerism can be conceived as market transactions with a zero explicit price. However, evidence suggests people may not view zero as just another price when it comes to pro-social behavior. Thus, while markets might be expected to increase the supply of assets available to those in need, some worry such financial incentives will crowd out altruistic giving. This paper reports laboratory experiments directly investigating the degree to which market incentives crowd out large, discrete charitable donations in a setting related to deceased organ donation. The results suggest markets increase the supply of assets available to those in need. However, as some critics fear, market incentives disproportionately influence the relatively poor. PMID- 24348003 TI - Effect of Visuo-Motor Co-location on 3D Fitts' Task Performance in Physical and Virtual Environments. AB - : Given the ease that humans have with using a keyboard and mouse in typical, non colocated computer interaction, many studies have investigated the value of co locating the visual field and motor workspaces using immersive display modalities. Significant understanding has been gained by previous work comparing physical tasks against virtual tasks, visuo-motor co-location versus non colocation, and even visuo-motor rotational misalignments in virtual environments (VEs). However, few studies have explored all of these paradigms in context with each other and it is difficult to perform inter-study comparisons because of the variation in tested motor tasks. Therefore, using a stereoscopic fish tank display setup, the goal for the current study was to characterize human performance of a 3D Fitts' point-to-point reaching task using a stylus-based haptic interface in the physical, co-located/non-colocated, and rotated VE visualization conditions.Five performance measures - throughput, initial movement error, corrective movements, and peak velocity - were measured and used to evaluate task performance. These measures were studied in 22 subjects (11 male, 11 female, ages 20-32) performing a 3D variant of Fitts' serial task under 10 task conditions: physical, co-located VE, non-colocated VE, and rotated VEs from 45-315 degrees in 45 degrees increments. HYPOTHESES: All performance measures in the co-located VE were expected to reflect significantly reduced task performance over the real condition, but also reflect increased performance over the non-colocated VE condition. For rotational misalignments, all performance measures were expected to reflect highest performance at 0 degrees , reduce to lowest performance at 90 degrees and rise again to a local maximum at 180 degrees (symmetric about 0 degrees ). RESULTS: All performance measures showed that the co-located VE condition resulted in significantly lower task performance than the physical condition and higher mean performance than the non-colocated VE condition, but the difference was not statistically significant. Also, rotation misalignments showed that task performance were mostly reduced to minimums at 90 degrees , 135 degrees , and 225 degrees . We conclude that co-located VEs may not significantly improve point-to-point reaching performance over non-colocated VEs. Also, visual rotations of +/-45 degrees affected throughput, efficiency, peak velocity, and initial movement error, but the number of corrective movements were not affected until +/-90 degrees . PMID- 24348004 TI - An Improved Formulation of Hybrid Model Predictive Control With Application to Production-Inventory Systems. AB - We consider an improved model predictive control (MPC) formulation for linear hybrid systems described by mixed logical dynamical (MLD) models. The algorithm relies on a multiple-degree-of-freedom parametrization that enables the user to adjust the speed of setpoint tracking, measured disturbance rejection and unmeasured disturbance rejection independently in the closed-loop system. Consequently, controller tuning is more flexible and intuitive than relying on objective function weights (such as move suppression) traditionally used in MPC schemes. The controller formulation is motivated by the needs of non-traditional control applications that are suitably described by hybrid production-inventory systems. Two applications are considered in this paper: adaptive, time-varying interventions in behavioral health, and inventory management in supply chains under conditions of limited capacity. In the adaptive intervention application, a hypothetical intervention inspired by the Fast Track program, a real-life preventive intervention for reducing conduct disorder in at-risk children, is examined. In the inventory management application, the ability of the algorithm to judiciously alter production capacity under conditions of varying demand is presented. These case studies demonstrate that MPC for hybrid systems can be tuned for desired performance under demanding conditions involving noise and uncertainty. PMID- 24348005 TI - Robust and Efficient Regularized Boosting Using Total Bregman Divergence. AB - Boosting is a well known machine learning technique used to improve the performance of weak learners and has been successfully applied to computer vision, medical image analysis, computational biology and other fields. A critical step in boosting algorithms involves update of the data sample distribution, however, most existing boosting algorithms use updating mechanisms that lead to overfitting and instabilities during evolution of the distribution which in turn results in classification inaccuracies. Regularized boosting has been proposed in literature as a means to overcome these difficulties. In this paper, we propose a novel total Bregman divergence (tBD) regularized LPBoost, termed tBRLPBoost. tBD is a recently proposed divergence in literature, which is statistically robust and we prove that tBRLPBoost requires a constant number of iterations to learn a strong classifier and hence is computationally more efficient compared to other regularized Boosting algorithms. Also, unlike other boosting methods that are only effective on a handful of datasets, tBRLPBoost works well on a variety of datasets. We present results of testing our algorithm on many public domain databases and comparisons to several other state-of-the-art methods. Numerical results show that the proposed algorithm has much improved performance in efficiency and accuracy over other methods. PMID- 24348006 TI - Beliefs and expectancies in legal decision making: an introduction to the Special Issue. AB - This introduction describes what the co-editors believe readers can expect in this Special Issue. After beliefs and expectancies are defined, examples of how these constructs influence human thought, feeling, and behavior in legal settings are considered. Brief synopses are provided for the Special Issue papers on beliefs and expectancies regarding alibis, children's testimony behavior, eyewitness testimony, confessions, sexual assault victims, judges' decisions in child protection cases, and attorneys' beliefs about jurors' perceptions of juvenile offender culpability. Areas for future research are identified, and readers are encouraged to discover new ways that beliefs and expectancies operate in the legal system. PMID- 24348008 TI - Prejudice-Related Events and Traumatic Stress Among Heterosexuals and Lesbians, Gay Men and Bisexuals. AB - This mixed-methods study examined associations between prejudice events and posttraumatic stress disorder (PTSD) among 382 lesbians, gays, and bisexuals (LGB) and 126 heterosexuals. Using the Composite International Diagnostic Interview, we assessed PTSD but relaxed Criterion A1, that is, allowed prejudice events that did not involve threat to life or physical integrity to also qualify as traumatic. First, we tested whether exposure to prejudice events differed with respect to sexual orientation and race. White LGBs were more likely than White heterosexuals to encounter a prejudice event, but Black and Latino LGBs were no more likely than White LGBs to experience a prejudice event. Second, we used qualitative analysis to examine the prejudice events that precipitated relaxed Criterion A1 PTSD among 8 participants. Two specific themes emerged: the need to make major changes and compromised sense of safety and security following exposure to the prejudice event. PMID- 24348009 TI - A comprehensive phylogenetic analysis of deadenylases. AB - Deadenylases catalyze the shortening of the poly(A) tail at the messenger ribonucleic acid (mRNA) 3'-end in eukaryotes. Therefore, these enzymes influence mRNA decay, and constitute a major emerging group of promising anti-cancer pharmacological targets. Herein, we conducted full phylogenetic analyses of the deadenylase homologs in all available genomes in an effort to investigate evolutionary relationships between the deadenylase families and to identify invariant residues, which probably play key roles in the function of deadenylation across species. Our study includes both major Asp-Glu-Asp-Asp (DEDD) and exonuclease-endonuclease-phospatase (EEP) deadenylase superfamilies. The phylogenetic analysis has provided us with important information regarding conserved and invariant deadenylase amino acids across species. Knowledge of the phylogenetic properties and evolution of the domain of deadenylases provides the foundation for the targeted drug design in the pharmaceutical industry and modern exonuclease anti-cancer scientific research. PMID- 24348007 TI - Genetic screen of African Americans with Fuchs endothelial corneal dystrophy. AB - PURPOSE: Fuchs endothelial corneal dystrophy (FECD) is a genetically heterogeneous disorder that has been primarily studied in patients of European or Asian ancestry. Given the sparse literature on African Americans with FECD, we sought to characterize the genetic variation in three known FECD candidate genes in African American patients with FECD. METHODS: Over an 8-year period, we enrolled 47 African American probands with FECD. All participants were clinically examined with slit-lamp biomicroscopy, and when corneal tissue specimens were available, histopathologic confirmation of the clinical diagnosis was obtained. The coding regions of known FECD susceptibility genes collagen, type VIII, alpha 2 (COL8A2); solute carrier family 4, sodium borate transporter, member 11 (SLC4A11); and zinc finger E-box binding homeobox 1 (ZEB1 [also known as TCF8]) were Sanger sequenced in the 47 probands using DNA isolated from blood samples. RESULTS: Twenty-two coding variants were detected across the COL8A2, SLC4A11, and ZEB1 genes; six were nonsynonymous variants. Three novel coding variants were detected: a synonymous variant each in COL8A2 and SLC4A11 and one nonsynonymous variant in ZEB1 (p.P559S), which is predicted to be benign and tolerated, thus making its physiologic consequence uncertain. CONCLUSIONS: Variation in the COL8A2, SLC4A11, and ZEB1 genes is present in only a small fraction of our African American cases and as such does not appear to significantly contribute to the genetic risk of FECD in African Americans. This observation is on par with findings from previous sequencing studies involving European or Asian ancestry patients with FECD. PMID- 24348010 TI - Vitrectomy in double-perforation gunshot injury. AB - OBJECTIVE: This study sought to evaluate the result of pars plana vitrectomy in patients with gunshot wounds involving double perforation. METHODS: This was a retrospective, noncomparative, interventional case series. RESULTS: Eighteen patients (18 eyes) with double-perforation gunshot injuries were treated from February 2010 to March 2012. The group included 16 men (88%) and two women (11%); the mean age was 24 (15-33) years. In each case, vitrectomy was scheduled 1-6 weeks after repair of the entrance site. Associated retinal detachments were observed in two eyes (11%), retinal incarceration was observed surrounding the exit site in three eyes (16%), and retention of an intraocular foreign body was observed in two cases. After a follow-up period of 8 +/- 2 months, two eyes (11%) had achieved visual acuity (VA) of 0.5, nine eyes (50%) had achieved VA between 0.5 and 0.1, and seven eyes (38%) had achieved VA between 0.1 and hand movement. The main reasons for functional failure (VA 0.1 to hand movement) were macular dragging (due to fibrosis at the exit site near the macula) in seven cases (38%), submacular hemorrhage in four cases (22%), and epimacular fibrosis in five cases (27%). All cases developed postoperative exotropia. One case (5%) developed postoperative hemorrhage. No cases exhibited signs of postoperative redetachment. CONCLUSION: The outcome of pars plana vitrectomy in cases with double perforations is variable. Factors including the surgeon's skill level, the time to surgery, and the efficacy of the intraocular tamponade affect the postoperative outcome. PMID- 24348012 TI - Diabetic papillopathy with macular edema treated with intravitreal ranibizumab. AB - We report a case of diabetic papillopathy that demonstrated a resolution of optic disk swelling and rapid visual recovery when intravitreal ranibizumab was administered. A 51-year-old male presented with acute painless visual loss in his right eye. His vision was 20/320 in the right eye and 20/50 in the left eye. Fundus examination of the right eye showed nonproliferative diabetic retinopathy with macular edema and a swollen optic disk. Fluorescein angiography showed dye leakage from the right optic disk. Optical coherent tomography revealed a significant increase in retinal nerve fiber-layer thickness. Magnetic resonance imaging of the brain was normal. The patient received a single intravitreal ranibizumab (0.5 mg) injection. Two weeks following injection, there was marked regression of the disk swelling and improvement of macular edema, with vision improving to 20/100. Three months following injection, there was complete resolution of the optic disk swelling. No further treatment was required. PMID- 24348011 TI - Comparison of high-resolution Scheimpflug and high-frequency ultrasound biomicroscopy to anterior-segment OCT corneal thickness measurements. AB - BACKGROUND: The purpose of this study was to compare and correlate central corneal thickness in healthy, nonoperated eyes with three advanced anterior segment imaging systems: a high-resolution Scheimpflug tomography camera (Oculyzer II), a spectral-domain anterior-segment optical coherence tomography (AS-OCT) system, and a high-frequency ultrasound biomicroscopy (HF-UBM) system. METHODS: Fifty eyes randomly selected from 50 patients were included in the study. Inclusion criteria were healthy, nonoperated eyes examined consecutively by the same examiner. Corneal imaging was performed by three different methods, ie, Oculyzer II, spectral-domain AS-OCT, and FH-UBM. Central corneal thickness measurements were compared using scatter diagrams, Bland-Altman plots (with bias and 95% confidence intervals), and two-paired analysis. RESULTS: The coefficient of determination (r (2)) between the Oculyzer II and AS-OCT measurements was 0.895. Likewise, the coefficient was 0.893 between the Oculyzer II and HF-UBM and 0.830 between the AS-OCT and HF-UBM. The trend line coefficients of linearity were 0.925 between the Oculyzer II and the AS-OCT, 1.006 between the Oculyzer II and HF-UBM, and 0.841 between the AS-OCT and HF-UBM. The differences in average corneal thickness between the three pairs of CCT measurements were -6.86 MUm between the Oculyzer II and HF-UBM, -12.20 MUm between the AS-OCT and Oculyzer II, and +19.06 MUm between the HF-UBM and AS-OCT. CONCLUSION: The three methods used for corneal thickness measurement are highly correlated. Compared with the Scheimplug and ultrasound devices, the AS-OCT appears to report a more accurate, but overally thinner corneal pachymetry. PMID- 24348013 TI - First case of fungal keratitis caused by Pestalotiopsis clavispora. AB - PURPOSE: To report the isolation of Pestalotiopsis clavispora from the cornea of a patient with recurrent keratitis. CASE REPORT: A 73-year-old male gardener presented with conjunctival injection and an oval infiltrate with feathery margins in the temporal half of the cornea in the right eye. His ocular history in the right eye included cataract surgery, five episodes of herpes simplex keratitis, three glaucoma surgeries, and bullous keratopathy. He had been treated with corticosteroids for years. Light microscopy of corneal scrapings revealed a filamentous fungus, and fungal keratitis was diagnosed. Treatment with topical voriconazole and pimaricin ointment was commenced. One month later, the infiltrate resolved. The antifungal agents were discontinued 7 months later, and keratitis relapsed 4 days after the discontinuation. The fungus was isolated and identified by molecular techniques as P. clavispora. Based on the results of antifungal susceptibility testing, treatment with topical and intravenous micafungin was initiated. The corneal infiltrate resolved 1 month after the relapse. CONCLUSION: Molecular identification of the pathogen, and antifungal susceptibility testing, are useful in treating patients with fungal keratitis caused by a rare human pathogen. PMID- 24348014 TI - Simplified local anesthesia technique for external dacryocystorhinostomy without nasal packing: a new technique and pilot study outcome. AB - BACKGROUND: The purpose of this paper is to describe a simplified local anesthesia technique for external dacryocystorhinostomy (EXT-DCR). METHODS: In this pilot, retrospective, noncomparative, interventional case series, 448 patients (480 eyes) underwent EXT-DCR using a simplified local anesthesia technique. Nasal mucosal anesthesia was achieved using combined application of 6 mL of oxymetazoline 0.025% nasal spray and lidocaine 1% in the same spray bottle, without any packing of the nose with either pledgets or ribbon gauze. Local infiltration anesthesia consisted of subcutaneous injection of a 7 mL mixture of 2% lidocaine with 1:100,000 epinephrine injected on the flat side of the nose beneath the incision site, in addition to a second medial peribulbar injection (3 mL, 2% lidocaine without epinephrine). RESULTS: Successful unilateral or bilateral EXT-DCR was achieved in 432/448 patients (96.4%). Four patients could not tolerate the procedure under local anesthesia and were converted to general anesthesia. Four patients required additional local anesthetic injections because of intolerable pain. Heavy sedation was essential in eight uncooperative patients because surgical manipulation was impossible. The remaining patients tolerated the procedure well. The intraoperative bleeding rate was very low except in one patient. Mean operative time was 16 minutes. Severe postoperative epistaxis was observed in four patients. Temporary anosmia developed in one patient. CONCLUSION: Our simplified local anesthesia approach of EXT-DCR is convenient for the patient because it avoids unnecessary nasal packing. It is also safe and effective, as evidenced by the high rate of successful completion of the procedure without conversion to general anesthesia or the need for supplemental local anesthesia. PMID- 24348015 TI - Glistenings in hydrophobic acrylic intraocular lenses do affect visual function. PMID- 24348016 TI - Ocular cysticercosis in a 32-year-old man in Abuja: ultrasonic features as an aid in diagnosis. AB - We report the case of a 32-year-old man suffering from intraocular cysticercosis, with special emphasis on the use of B-scan ultrasound in the diagnosis and management of the condition. An 8000 B-Scan Scanmate was used to obtain the ultrasound images. The patient had worked on a pig farm a few years before presentation. He presented with shadows seen in the right eye. Binocular indirect ophthalmoscopy revealed that he had a choroidal detachment in the right eye inferotemporally. B-scan ultrasound revealed a subretinal subchoroidal cyst with a thick wall containing well defined intracystic echogenic entities representing scolices, and an associated retinal detachment. These findings appear to be pathognomonic. Excision of the cyst through a trans-scleral approach revealed a yellowish serous fluid, with scolices of cysticercus later confirmed histologically. B-scan ultrasound is extremely useful in the diagnosis of ocular cysticercosis and the findings can be pathognomonic. PMID- 24348017 TI - Lessons learned from peginesatide in the treatment of anemia associated with chronic kidney disease in patients on dialysis. AB - Peginesatide is the newest erythropoietin-stimulating agent (ESA) in the quest for the ideal treatment of anemia in chronic kidney disease (CKD) patients. Reduced frequency of administration along with a possibly lower cost as a result of simpler manufacturing techniques compared with other available agents makes peginesatide a highly desirable product in the competitive ESA market. Peginesatide is noninferior to the other ESAs, and has a good safety profile in patients on hemodialysis. The higher rates of adverse cardiovascular events reported in CKD patients not on dialysis in the recent Phase III studies require further, better planned, studies. Peginesatide had to be withdrawn from the market in the US after some reports of hypersensitivity reactions to the drug. This is a setback, but the scientific advances gained as a result of this product development can be used to develop other, newer products. PMID- 24348018 TI - Conversion to generic cyclosporine A in stable chronic patients after heart transplantation. AB - BACKGROUND: Cyclosporine A (CSA) is a narrow therapeutic index drug. Available CSA products differ in the constitution of their emulsion. To compare intra individual differences after a conversion to a generic CSA, a retrospective single-center study was initiated. METHODS: Twenty adult stable chronic (>24 months post heart transplant) recipients were included in the present retrospective study. These patients were previously switched from Sandimmune Neoral(r) to the generic CSA (Equoral(r)) according to the patients' preference during the clinical routine. Dose-normalized trough levels (DNL) and trough levels (C0) at 8 months, 4 months, and 2 weeks before the switch were retrospectively compared with the corresponding values at 2 weeks, 4 months, and 8 months after the switch to the generic CSA. Additionally, changes in the routine laboratory parameters, the number of treated rejection episodes, and the adherence to the CSA target levels were compared. RESULTS: The mean DNL (adapted to the daily CSA dose in mg) was 0.71+/-0.26 (ng/mL)/mg on Neoral therapy; on Equoral it was 0.68+/-0.23 (ng/mL)/mg, (P=0.38). In comparison to the CSA daily dose prior to the conversion, at postconversion, no significant changes of CSA daily dose were observed (Neoral 140.67+/-39.81 mg versus Equoral 134.58+/-41.61 mg; P=0.13). No rejection episodes requiring therapy occurred prior to or postconversion (P=0.99). Additionally, no statistically significant changes of routine laboratory parameters regarding the Modification of Diet in Renal Disease or hematological parameters were seen (all P=not significant). No adverse events after the conversion were observed. CONCLUSION: This study in chronic and stable HTx patients demonstrated no statistically significant differences in the CSA DNL after a conversion to generic CSA (Equoral). The generic CSA was generally well tolerated. We concluded that a conversion from Neoral to Equoral is safe and clinically feasible in this distinct patient population. However, multiple switches between different generic immunosuppressants must especially be avoided in the interest of patient safety, and close follow-up examinations must be warranted. PMID- 24348019 TI - Combined letrozole and clomiphene versus letrozole and clomiphene alone in infertile patients with polycystic ovary syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of childbearing age (6.8%-18%), is among the most common causes of infertility due to ovulation factors, and accounts for 55%-70% of infertility cases caused by chronic anovulation. In this study, we used a combination of letrozole and clomiphene in patients resistant to both drugs individually, and studied the effects of this combination in ovulation and pregnancy in resistant PCOS patients. METHODS: The study population included infertile couples diagnosed as PCOS in the wife. The women used clomiphene for at least six cycles in order to ovulate after failure to form the dominant follicle, and were then put on letrozole for four cycles. Patients who were unable to form the dominant follicle were enrolled on letrozole and clomiphene combination therapy. RESULTS: One hundred enrolled patients underwent 257 cycles of a combination of letrozole and clomiphene, in which 213 were able to form the dominant follicle (82.9%) and 44 were unable to do so (17.1%). The number of mature follicles was 2.3+/-1.1. The mean endometrial thickness in patients on the day of human chorionic gonadotropin administration was 8.17+/-1.3 mm. The pregnancy rate was 42%. CONCLUSION: According to the results of this study, it can be proposed that in PCOS patients resistant to clomiphene and letrozole used as single agents, a combination of the two drugs can be administered before using more aggressive treatment that may have severe complications or surgery. This combination may also be used as a first-line therapy to induce ovulation in severe cases of PCOS in order to save time and expense. PMID- 24348020 TI - Atomoxetine affects transcription/translation of the NMDA receptor and the norepinephrine transporter in the rat brain--an in vivo study. AB - Attention-deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder. The norepinephrine transporter (NET) inhibitor atomoxetine, the first nonstimulant drug licensed for ADHD treatment, also acts as an N-methyl-D-aspartate receptor (NMDAR) antagonist. The compound's effects on gene expression and protein levels of NET and NMDAR subunits (1, 2A, and 2B) are unknown. Therefore, adolescent Sprague Dawley rats were treated with atomoxetine (3 mg/kg, intraperitoneal injection [i.p.]) or saline (0.9%, i.p.) for 21 consecutive days on postnatal days (PND) 21-41. In humans, atomoxetine's earliest clinical therapeutic effects emerge after 2-3 weeks. Material from prefrontal cortex, striatum (STR), mesencephalon (MES), and hippocampus (HC) was analyzed either directly after treatment (PND 42) or 2 months after termination of treatment (PND 101) to assess the compound's long-term effects. In rat brains analyzed immediately after treatment, protein analysis exhibited decreased levels of the NET in HC, and NMDAR subunit 2B in both STR and HC; the transcript levels were unaltered. In rat brains probed 2 months after final atomoxetine exposure, messenger RNA analysis also revealed significantly reduced levels of genes coding for NMDAR subunits in MES and STR. NMDAR protein levels were reduced in STR and HC. Furthermore, the levels of two SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, synaptophysin and synaptosomal associated protein 25, were also significantly altered in both treatment groups. This in vivo study detected atomoxetine's effects beyond NET inhibition. Taken together, these data reveal that atomoxetine seems to decrease glutamatergic transmission in a brain region-specific manner. Long-term data show that the compound's impact is not due to an acute pharmacological effect but lasts or even amplifies after a drug-free period of 2 months, leading to altered development of synaptic composition. These alterations might contribute to atomoxetine's clinical effects in the treatment of ADHD, a neurodevelopmental disorder in which synaptic processes and especially a dysregulated glutamatergic metabolism seem to be involved. PMID- 24348021 TI - P-glycoprotein alters blood-brain barrier penetration of antiepileptic drugs in rats with medically intractable epilepsy. AB - P-glycoprotein is one of the earliest known multidrug transporters and plays an important role in resistance to chemotherapeutic drugs. In this study, we detected levels of P-glycoprotein and its mRNA expression in a rat brain model of medically intractable epilepsy established by amygdala kindling and drug selection. We investigated whether inhibition of P-glycoprotein affects the concentration of antiepileptic drugs in cortical extracellular fluid. We found that levels of P-glycoprotein and its mRNA expression were upregulated in epileptic cerebral tissue compared with cerebral tissue from normal rats. The concentrations of two antiepileptic drugs, carbamazepine and phenytoin, were very low in the cortical extracellular fluid of rats with medically intractable epilepsy, and were restored after blockade of P-glycoprotein by verapamil. These results show that increased P-glycoprotein levels alter the ability of carbamazepine and phenytoin to penetrate the blood-brain barrier and reduce the concentrations of these agents in extracellular cortical fluid. High P glycoprotein levels may be involved in resistance to antiepileptic drugs in medically intractable epilepsy. PMID- 24348022 TI - Development and characterization of gastroretentive sustained-release formulation by combination of swelling and mucoadhesive approach: a mechanistic study. AB - BACKGROUND: Acyclovir has pharmacokinetic limitations, including poor oral bioavailability of 15%-30%, high variability, and short elimination half-life of 2.3 hours. These limitations necessitate frequent administration of acyclovir, up to five times daily, leading to poor patient compliance, which in turn leads to a reduction in therapeutic efficacy and development of resistance. METHODS: A gastroretentive sustained-release (GR) formulation of acyclovir, based on a combination of swelling and mucoadhesive mechanisms, has been developed. Composition has been optimized after evaluation of different polymers, carbomer, polyethylene oxide, and sodium alginate alone and/or in combination. GR formulations were characterized for in-process quality-control tests, drug release and release rate kinetics, similarity factor analysis, swelling index, and matrix erosion. RESULTS: A formulation containing a combination of carbomer and polyethylene oxide had the highest similarity of drug release compared with a target drug-release profile obtained by pharmacokinetic simulations. The measurement of mucoadhesive strength, carried out with a texture analyzer, showed that the mucoadhesive strength of the GR formulation was significantly higher than that of the immediate-release (IR) tablet. The optimized GR formulation was found to be retained in the upper part of the gastrointestinal tract for 480 minutes; the IR tablet was retained for only 90 minutes as measured using a gastrointestinal retention study in albino rabbits. The GR formulation was also found to maintain more sustained plasma concentrations than the IR tablet. Mean residence time of the GR formulation was 7 hours versus 3.3 hours for the IR formulation. The relative bioavailability of the GR formulation was 261% of the IR formulation. CONCLUSION: The GR formulation of acyclovir, based on swelling and mucoadhesive mechanisms, has prolonged retention in the upper gastrointestinal tract, sustained in vitro drug release, prolonged in vivo absorption, and better bioavailability than the IR formulation. Such a formulation would improve patient compliance and increase the efficacy of therapy. PMID- 24348023 TI - Review of the rational use and adverse reactions to human serum albumin in the People's Republic of China. AB - Human serum albumin (HSA) is an ideal natural colloid that has been widely used in clinical practice for supplemental albumin or as a plasma substitute during therapeutic plasma exchanges to redress hypoproteinemia. However, a paucity of well-designed clinical trials, a lack of a clear cut survival benefit, and frequent case reports of adverse drug reaction (ADR) make the use of HSA controversial. This study aims to review and to comment on the reported ADRs of HSA in the People's Republic of China, so as to provide the basis for rational HSA use in clinical settings. Data on the ADR case reports from HSA administration between January 1990 and December 2012 available from the China National Knowledge Infrastructure (CNKI) database, Wanfang data (WF), and Chinese Biomedical Literature (CBM) were reviewed. The reasons for using HSA, the types of ADRs, the causality of ADRs and the rationality for HSA administration were extracted and analyzed. In total, 61 cases of ADR reports were identified of which the primary disease of patients using HSA was malignant tumor (34.42%). The primary ADR was anaphylaxis (59.02%). Of the 61 cases, 30 were caused by irrational use of HSA. The most common irrational use was off-label use (56.67%), followed by inappropriate infusion rate. Therefore, we conclude that to avoid the occurrence of ADRs, guidelines for using HSA are needed to guarantee its rational use and HSA should be used strictly according to these guidelines. In addition, medical staff, including clinical pharmacists and nurses, should pay more attention to the patients who inject HSA to ensure its safe use in the clinic. PMID- 24348024 TI - Three Dimensional Structure Prediction of Fatty Acid Binding Site on Human Transmembrane Receptor CD36. AB - CD36 is an integral membrane protein which is thought to have a hairpin-like structure with alpha-helices at the C and N terminals projecting through the membrane as well as a larger extracellular loop. This receptor interacts with a number of ligands including oxidized low density lipoprotein and long chain fatty acids (LCFAs). It is also implicated in lipid metabolism and heart diseases. It is therefore important to determine the 3D structure of the CD36 site involved in lipid binding. In this study, we predict the 3D structure of the fatty acid (FA) binding site [127-279 aa] of the CD36 receptor based on homology modeling with X ray structure of Human Muscle Fatty Acid Binding Protein (PDB code: 1HMT). Qualitative and quantitative analysis of the resulting model suggests that this model was reliable and stable, taking in consideration over 97.8% of the residues in the most favored regions as well as the significant overall quality factor. Protein analysis, which relied on the secondary structure prediction of the target sequence and the comparison of 1HMT and CD36 [127-279 aa] secondary structures, led to the determination of the amino acid sequence consensus. These results also led to the identification of the functional sites on CD36 and revealed the presence of residues which may play a major role during ligand protein interactions. PMID- 24348025 TI - Evolution of cardiovascular risk factors and ischemic heart disease in an elderly urban Romanian population over the course of 1 year. AB - BACKGROUND: Romania has some of the highest mortality figures in the world attributable to ischemic heart disease and stroke among both men and women. OBJECTIVES: To assess the changes in cardiovascular risk factors and ischemic heart disease in a group of subjects over 65 years of age during 1 year in an urban community of Romania. MATERIALS AND METHODS: We studied 515 subjects (264 women and 251 men) with a mean age of 73.41+/-6.44 years, followed up over the course of 1 year in order to determine the changes that occurred in cardiovascular risk factors and in the evolution of ischemic heart disease. At the beginning and after 1 year, we determined the following parameters: anthropometric measurements, blood pressure, smoking status, lipid profile (total cholesterol, triglycerides, high-density lipid cholesterol, low-density lipid cholesterol), fasting plasma glucose, and the presence of ischemic heart disease. RESULTS: There were no differences between the first and second assessments concerning the incidence of smoking (12.3% versus (vs) 12.5%), obesity (25% vs 26%), diabetes mellitus (19% vs 22.9%), or hypertension (88.2% vs 92.2%). Statistically significant differences were recorded regarding dyslipidemia (40.6% vs 30.3%, P<0.001). Cholesterol median values decreased (204 mg/dL vs 194 mg/dL, P=0.003), while median concentrations of plasma glucose increased (101 mg/dL vs 105 mg/dL, P<0.05). At the same time, we noted a higher incidence of ischemic heart disease (51.65% vs 63%). CONCLUSION: Our data show that in subjects over 65 years of age, cardiovascular disease occurs more often in women, but with certain features that should be taken into account. In addition, we point out the importance of reducing cardiovascular risk factors. However, we should not expect a major decrease or improvement in cardiovascular risk factors with such a short follow-up. Such results will be achieved only through long-term interventions. PMID- 24348026 TI - Fall-related admissions after fast-track total hip and knee arthroplasty - cause of concern or consequence of success? AB - BACKGROUND: Total hip (THA) and knee arthroplasty (TKA) are common procedures in elderly persons, who are at potential increased risk of postoperative fall due to loss of muscle strength and impaired balance. Fast-track surgery with early mobilization and opioid-sparing analgesia have improved outcomes after these procedures, but early mobilization and short hospitalization length of stay (LOS) could potentially increase the risk of falls after discharge. We investigated injuries, circumstances, and the timing of fall-related hospital admissions 90 days after fasttrack THA and TKA. METHODS: This was a prospective, descriptive multicenter study on fall-related hospital admissions, in 5145 elective fast track THA and TKA patients, with complete 90-day follow up through the Danish National Patient registry and medical charts. RESULTS: Of 83 (1.6%) fall-related hospital admissions, 43 (51.8%) were treated in the Emergency Room and 40 (48.2%) were admitted to a regular ward. The median LOS after surgery was 3 days (interquartile range [IQR]: 2-3) in fallers versus (vs) 2 days (IQR: 2-3) (P=0.022) in patients without falls. Injuries were classified as "none" or minor in 39.8%, moderate in 9.6%, and major in 50.6%. Most falls (54.8%) occurred within 1 month of discharge. Falls due to physical activity (12.0%) and extrinsic factors (14.5%) occurred later than did surgery-related falls (73.5%), contributing to 40% of all falls >30 days after discharge. In multivariate analysis, age (odds ratio [OR]: 1.05; 95% confidence interval [CI]: 1.0-1.08) (P=0.001), living alone (OR: 2.09; 95% CI: 1.20-3.62) (P=0.009), and psychiatric disease (OR: 2.80; 95% CI: 1.42-5.50) (P=0.001) were associated with surgery related falls, whereas the use of a walking aid (OR: 1.20; 95% CI: 0.67-2.16) (P=0.544) and LOS <=4 days (OR:1.19; 95% CI: 0.52-1.28) (P=0.680) was not. CONCLUSION: Hospital admissions due to falls are most frequent within the first month after fast-track THA and TKA. The overall incidence of surgery-related falls amongst these patients is low, declines after the first month, and is related to patient characteristics rather than short LOS. The effect of interventions aimed at surgery-related falls should focus on the first 30 days after surgery and differentiate between the causes of falling. PMID- 24348027 TI - Overall and abdominal obesity indicators had different association with central arterial stiffness and hemodynamics independent of age, sex, blood pressure, glucose, and lipids in Chinese community-dwelling adults. AB - OBJECTIVE: Limited large sample studies have specially compared overall and abdominal obesity in relation to central arterial stiffness and hemodynamics in community-dwelling adults, especially in the People's Republic of China. This study aimed to compare the relationship between an overall obesity indicator (body mass index [BMI]), an abdominal obesity index (waist circumference [WC]), and central arterial stiffness and hemodynamics, independent of age, sex, blood pressure, glucose, and lipids, in Chinese community-dwelling adults. METHODS: For 2,624 adults in this study, anthropometric indices, such as BMI and WC, were measured. Central arterial stiffness was assessed by carotid-femoral pulse wave velocity (cfPWV). Central hemodynamics was represented by central pulse pressure (cPP). RESULTS: Both overall and abdominally obese adults were older, with significantly higher cfPWV, cPP, peripheral pulse pressure (pPP), fasting blood glucose (FBG), and low-density lipoprotein-cholesterol (LDL-C), and significantly lower high-density lipoprotein-cholesterol (HDL-C). After adjusting for age and sex, both the overall and abdominally obese individuals had independently higher pPP, FBG, and LDL-C levels, and lower HDL-C level. The overall obese individuals had independently higher cPP, but not cfPWV, after adjusting for age and sex, while the abdominally obese individuals had independently higher cfPWV, but not cPP. After adjusting for age, sex, pPP, FBG, LDL-C, and HDL-C, WC, but not BMI, was independently correlated with cfPWV, and BMI, but not WC, was independently associated with cPP. Age, sex, pPP, FBG, and HDL-C levels have independent association with cfPWV. Age, sex, pPP, but not FBG and HDL-C levels, have independent association with cPP. CONCLUSION: The abdominal obesity index (WC), rather than the overall obesity indicator (BMI), was related to central arterial stiffness, independent of age, sex, blood pressure, glucose and lipids, while the overall obesity indicator (BMI), rather than the abdominal obesity indicator (WC), was independently correlated with central hemodynamics. Age, sex, and blood pressure were independently associated with central arterial stiffness and hemodynamics, but blood glucose and lipids were independently associated with central arterial stiffness, rather than hemodynamics. PMID- 24348028 TI - Rates, variability, and associated factors of polypharmacy in nursing home patients. AB - OBJECTIVES: To determine the rate and variability of polypharmacy in nursing home (NH) residents and investigate its relationship to age, sex, functional status, length of stay, and comorbidities. METHODS: We conducted a cross sectional, multicenter study that included six nursing homes. Demographic, clinical characteristics, Charlson comorbidity index (CCI), the number and classes of chronic medications, rate of polypharmacy >5 drugs (per day) and polypharmacy >7 drugs (per day) were recorded. RESULTS: Nine hundred and ninety-three residents were included; 750 (75.5%) fully dependent residents and 243 (24.5%) mobile demented residents requiring institutional care. The mean age was 85.04+/-7.55 (65-108) years. The mean rates of polypharmacy >5 drugs and polypharmacy >7 drugs were 42.6% and 18.6%, respectively. Differences in polypharmacy >5 drugs and polypharmacy >7 drugs were observed in NHs 24.7%-56% and 4.9%-30.4%, respectively (P<0.001). Mean number of chronic drugs per resident was 5.14+/-2.60 from 3.81+/ 2.24 to 5.95+/-2.73 (P<0.001). No differences in polypharmacy were found between sex and fully dependent versus mobile demented residents. The most common medications taken were for gastrointestinal, neurological, and cardiovascular disorders. Regression analysis revealed four independent variables for polypharmacy >5 drugs: groups aged 75-84 and >85 relative to 65-74, odds ratio (OR) 0.46 (95% confidence interval [CI] 0.27-0.78) P=0.004, OR 0.35 (95% confidence interval 0.19-0.53), respectively, P<0.001; length of stay >2 years, OR 0.51 (95% CI 0.36-0.73) P<0.001; CCI, OR 1.58 (95% CI 1.42-1.75) P<0.001; and feeding tube versus normal feeding, OR 0.27 (95% CI 0.12-0.60) P=0.001. CONCLUSION: Rates of polypharmacy in NHs are high with significant variability. Variability rates of polypharmacy, distinct residents' characteristics, and excessive use of certain drug groups may indicate that a decrease in medication is potentially feasible. PMID- 24348029 TI - Effect of 6 months of whole body vibration on lumbar spine bone density in postmenopausal women: a randomized controlled trial. AB - BACKGROUND: The issue of osteoporosis-induced fractures has attracted the world's attention. Postmenopausal women are particularly at risk for this type of fracture. The nonmedicinal intervention for postmenopausal women is mainly exercise. Whole body vibration (WBV) is a simple and convenient exercise. There have been some studies investigating the effect of WBV on osteoporosis; however, the intervention models and results are different. This study mainly investigated the effect of high-frequency and high-magnitude WBV on the bone mineral density (BMD) of the lumbar spine in postmenopausal women. METHODS: This study randomized 28 postmenopausal women into either the WBV group or the control group for a 6 month trial. The WBV group received an intervention of high-frequency (30 Hz) and high-magnitude (3.2 g) WBV in a natural full-standing posture for 5 minutes, three times per week, at a sports center. Dual-energy X-ray absorptiometry was used to measure the lumbar BMD of the two groups before and after the intervention. RESULTS: Six months later, the BMD of the WBV group had significantly increased by 2.032% (P=0.047), while that of the control group had decreased by 0.046% (P=0.188). The comparison between the two groups showed that the BMD of the WBV group had increased significantly (P=0.016). CONCLUSION: This study found that 6 months of high-frequency and high-magnitude WBV yielded significant benefits to the BMD of the lumbar spine in postmenopausal women, and could therefore be provided as an alternative exercise. PMID- 24348030 TI - Over diagnosis of chronic obstructive pulmonary disease in an underserved patient population. AB - INTRODUCTION: While cross-national studies have documented rates of chronic obstructive pulmonary disease (COPD) misdiagnosis among patients in primary care, US studies are scarce. Studies investigating diagnosis among uninsured patients are lacking. OBJECTIVE: The purpose of this study is to identify patients who are over diagnosed and thus, mistreated, for COPD in a federally qualified health center. METHODS: A descriptive study was conducted for a retrospective cohort from February 2011 to June 2012. Spirometry was performed by trained personnel following American Thoracic Society recommendations. Patients were referred for spirometry to confirm previous COPD diagnosis or to assess uncontrolled COPD symptoms. Airway obstruction was defined as a forced expiratory volume in the first second of expiration (FEV1) to forced vital capacity ratio less than 0.7. Reversibility was defined as a postbronchodilator increase in FEV1 greater than 200 mL and greater than 12%. RESULTS: Eighty patients treated for a previous diagnosis of COPD (n = 72) or on anticholinergic inhalers (n = 8) with no COPD diagnosis were evaluated. The average age was 52.9 years; 71% were uninsured. Only 17.5% (14/80) of patients reported previous spirometry. Spirometry revealed that 42.5% had no obstruction, 22.5% had reversible obstruction, and 35% had non reversible obstruction. CONCLUSION: Symptoms and smoking history are insufficient to diagnose COPD. Prevalence of COPD over diagnosis among uninsured patient populations may be higher than previously reported. Confirming previous COPD diagnosis with spirometry is essential to avoid unnecessary and potentially harmful treatment. PMID- 24348031 TI - Risk assessment of readmissions following an initial COPD-related hospitalization. AB - BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (COPD) is a leading cause of hospitalizations and readmissions in the US. Reducing the frequency of hospital readmission is a high priority of US health care organizations and government agencies. This study evaluated the risk factors associated with readmissions among commercially insured adults aged 40-65 years in the US who were hospitalized for COPD. METHODS: This retrospective cohort study used anonymized claims data from the Truven Health MarketScan(r) Commercial Claims and Encounters database. The patients included were aged 40-65 years, had an index hospitalization with a primary diagnosis of COPD between July 1, 2008 and June 30, 2010 (continuously enrolled 12 months before and after), and were alive at hospital discharge. Patients with cystic fibrosis or tuberculosis or who were transferred to another inpatient facility after hospital discharge were excluded. All readmissions regardless of diagnosis, and separately a subset of all readmissions that had COPD as a primary or secondary diagnosis (COPD related), were examined. Univariate descriptive statistics and multivariable regression methods were used. RESULTS: Of the 18,568 patients with index COPD hospitalizations, 6,095 (32.83%) met the eligibility criteria. Of those, 503 (8.25%) were readmitted within the first 30 days post-index hospitalization and 2,527 (41.46%) within the first year (COPD-related 340 [5.58%] and 1,681 [27.58%], respectively). The median time to the first readmission post initial discharge was 4.0 months, with a mean of 5.0 +/- 3.4 months. Multivariable regression analyses showed that comorbid conditions and health care utilization in the pre-index period were significant predictors for readmission both 30 and 90 days following index hospitalization. CONCLUSION: A relatively high readmission rate was observed for patients aged 40-65 years. The results suggest that attention to patient comorbidities and pre-index/index health care service utilization may help identify hospitalized COPD patients at higher risk for readmission. PMID- 24348032 TI - Impact of night-time symptoms in COPD: a real-world study in five European countries. AB - BACKGROUND: Sleep quality is often poor in patients with chronic obstructive pulmonary disease (COPD). A cross-sectional European survey investigated the prevalence of night-time symptoms in COPD to evaluate the level of disconnect between physician and patient perceptions of the presence of night-time symptoms, and to compare the characteristics of patients with and without night-time symptoms. METHODS: A total of 251 primary care physicians and 251 respiratory specialists completed record forms on 2,807 patients with COPD. The forms captured information on patient demographics, lung function, COPD severity, and symptoms. Patients completed questionnaires on the time of day when their COPD symptoms bothered them, and the impact of COPD on their ability to get up in the morning and on sleep. Data were compared between groups (those with and without night-time symptoms) using t-tests or Wilcoxon signed rank tests. The kappa statistic was used to assess the level of disconnect between physician and patient perceptions of the impact of night-time symptoms. RESULTS: Most patients (78%) reported night-time disturbance. Patients with night-time symptoms experienced more daytime breathlessness (mean modified Medical Research Council dyspnea scale score 2.4 versus 1.1) and exacerbations in the previous 12 months (mean 1.7 versus 0.4), and received more maintenance therapy (mean of 2.8 versus 2.3 products) than those without. Concordance between the frequency of physician reported (67.9% of patients) and patient-reported (68.5% of patients) night-time symptoms was good. Physicians significantly underestimated the impact of COPD on the patient's ability to get up in the morning and on sleep (fair-moderate agreement). Physician-reported night-time symptoms were present for 41.2% of patients who could be categorized by Global initiative for chronic Obstructive Lung Disease (GOLD) group (n=937), increasing from 20.9% of those in the low-risk group to 77.4% of those in the high-riskgroup. CONCLUSION: Patients with COPD experience night-time symptoms regardless of GOLD group, that impact on their ability to get up in the morning and on their sleep quality. PMID- 24348033 TI - Use of a care bundle in the emergency department for acute exacerbations of chronic obstructive pulmonary disease: a feasibility study. AB - AIM: To determine the efficacy and usefulness of a chronic obstructive pulmonary disease (COPD) care bundle designed for the initial management of acute exacerbations of COPD and to assess whether it improves quality of care and provides better outcomes. INTRODUCTION: The level of care provided in the emergency department (ED) for COPD exacerbations varies greatly, and there is a need for a more systematic, consistent, evidence-based quality improvement approach to improve outcomes and costs. METHODS: A prospective before and after study was carried out in a university teaching hospital. Fifty consecutive patients were identified in the ED with COPD exacerbations and their management was reviewed. Following the education of ED staff and the implementation of a COPD care bundle, the outcome for 51 consecutive patients was analyzed. This COPD care bundle consisted of ten elements considered essential to the management of COPD exacerbations and was scored 0-10 according to the number of items on the checklist implemented correctly. RESULTS: Following implementation, the mean bundle score out of 10 improved from 4.6 to 7 (P<0.001). There was a significant decrease in the unnecessary use of intravenous corticosteroids from 60% to 32% (P=0.003) and also a marked improvement in the use of oxygen therapy, with appropriate treatment increasing from 76% to 96% (P=0.003). Prophylaxis for venous thromboembolism also improved from 54% to 73% (P=0.054). The 30-day readmission rate did not significantly improve. CONCLUSION: The use of a bundle improves the delivery of care for COPD exacerbations in the ED. There is more appropriate use of therapeutic interventions, especially oxygen therapy and intravenous corticosteroids. PMID- 24348034 TI - Biosensor based on tyrosinase immobilized on a single-walled carbon nanotube modified glassy carbon electrode for detection of epinephrine. AB - A biosensor comprising tyrosinase immobilized on a single-walled carbon nanotube modified glassy carbon electrode has been developed. The sensitive element, ie, tyrosinase, was immobilized using a drop-and-dry method followed by cross linking. Tyrosinase maintained high bioactivity on this nanomaterial, catalyzing the oxidation of epinephrine to epinephrine-quinone, which was electrochemically reduced (-0.07 V versus Ag/AgCl) on the biosensor surface. Under optimum conditions, the biosensor showed a linear response in the range of 10-110 MUM. The limit of detection was calculated to be 2.54 MUM with a correlation coefficient of 0.977. The repeatability, expressed as the relative standard deviation for five consecutive determinations of 10(-5) M epinephrine solution was 3.4%. A good correlation was obtained between results obtained by the biosensor and those obtained by ultraviolet spectrophotometric methods. PMID- 24348036 TI - Human neural progenitor cells retain viability, phenotype, proliferation, and lineage differentiation when labeled with a novel iron oxide nanoparticle, Molday ION Rhodamine B. AB - Ultrasmall superparamagnetic iron-oxide particles (USPIOs) loaded into stem cells have been suggested as a way to track stem cell transplantation with magnetic resonance imaging, but the labeling, and post-labeling proliferation, viability, differentiation, and retention of USPIOs within the stem cells have yet to be determined for each type of stem cell and for each type of USPIO. Molday ION Rhodamine BTM (BioPAL, Worcester, MA, USA) (MIRB) has been shown to be a USPIO labeling agent for mesenchymal stem cells, glial progenitor cells, and stem cell lines. In this study, we have evaluated MIRB labeling in human neuroprogenitor cells and found that human neuroprogenitor cells are effectively labeled with MIRB without use of transfection reagents. Viability, proliferation, and differentiation properties are unchanged between MIRB-labeled neuroprogenitors cells and unlabeled cells. Moreover, MIRB-labeled human neuroprogenitor cells can be frozen, thawed, and replated without loss of MIRB or even without loss of their intrinsic biology. Overall, those results show that MIRB has advantageous properties that can be used for cell-based therapy. PMID- 24348035 TI - The effects of poly L-lactic acid nanofiber scaffold on mouse spermatogonial stem cell culture. AB - INTRODUCTION: A 3D-nanofiber scaffold acts in a similar way to the extracellular matrix (ECM)/basement membrane that enhances the proliferation and self-renewal of stem cells. The goal of the present study was to investigate the effects of a poly L-lactic acid (PLLA) nanofiber scaffold on frozen-thawed neonate mouse spermatogonial stem cells (SSCs) and testis tissues. METHODS: The isolated spermatogonial cells were divided into six culture groups: (1) fresh spermatogonial cells, (2) fresh spermatogonial cells seeded onto PLLA, (3) frozen thawed spermatogonial cells, (4) frozen-thawed spermatogonial cells seeded onto PLLA, (5) spermatogonial cells obtained from frozen-thawed testis tissue, and (6) spermatogonial cells obtained from frozen-thawed testis tissue seeded onto PLLA. Spermatogonial cells and testis fragments were cryopreserved and cultured for 3 weeks. Cluster assay was performed during the culture. The presence of spermatogonial cells in the culture was determined by a reverse transcriptase polymerase chain reaction for spermatogonial markers (Oct4, GFRalpha-1, PLZF, Mvh(VASA), Itgalpha6, and Itgbeta1), as well as the ultrastructural study of cell clusters and SSCs transplantation to a recipient azoospermic mouse. The significance of the data was analyzed using the repeated measures and analysis of variance. RESULTS: The findings indicated that the spermatogonial cells seeded on PLLA significantly increased in vitro spermatogonial cell cluster formations in comparison with the control groups (culture of SSCs not seeded on PLLA) (P<=0.001). The viability rate for the frozen cells after thawing was 63.00% +/- 3.56%. This number decreased significantly (40.00% +/- 0.82%) in spermatogonial cells obtained from the frozen-thawed testis tissue. Both groups, however, showed in vitro cluster formation. Although the expression of spermatogonial markers was maintained after 3 weeks of culture, there was a significant downregulation for some spermatogonial genes in the experimental groups compared with those of the control groups. Furthermore, transplantation assay and transmission electron microscopy studies suggested the presence of SSCs among the cultured cells. CONCLUSION: Although PLLA can increase the in vitro cluster formation of neonate fresh and frozen-thawed spermatogonial cells, it may also cause them to differentiate during cultivation. The study therefore has implications for SSCs proliferation and germ cell differentiation in vitro. PMID- 24348037 TI - Heuristic modeling of macromolecule release from PLGA microspheres. AB - Dissolution of protein macromolecules from poly(lactic-co-glycolic acid) (PLGA) particles is a complex process and still not fully understood. As such, there are difficulties in obtaining a predictive model that could be of fundamental significance in design, development, and optimization for medical applications and toxicity evaluation of PLGA-based multiparticulate dosage form. In the present study, two models with comparable goodness of fit were proposed for the prediction of the macromolecule dissolution profile from PLGA micro- and nanoparticles. In both cases, heuristic techniques, such as artificial neural networks (ANNs), feature selection, and genetic programming were employed. Feature selection provided by fscaret package and sensitivity analysis performed by ANNs reduced the original input vector from a total of 300 input variables to 21, 17, 16, and eleven; to achieve a better insight into generalization error, two cut-off points for every method was proposed. The best ANNs model results were obtained by monotone multi-layer perceptron neural network (MON-MLP) networks with a root-mean-square error (RMSE) of 15.4, and the input vector consisted of eleven inputs. The complicated classical equation derived from a database consisting of 17 inputs was able to yield a better generalization error (RMSE) of 14.3. The equation was characterized by four parameters, thus feasible (applicable) to standard nonlinear regression techniques. Heuristic modeling led to the ANN model describing macromolecules release profiles from PLGA microspheres with good predictive efficiency. Moreover genetic programming technique resulted in classical equation with comparable predictability to the ANN model. PMID- 24348038 TI - Immobilized transferrin Fe3O4@SiO2 nanoparticle with high doxorubicin loading for dual-targeted tumor drug delivery. AB - Transferrin (Tf) was immobilized onto Fe3O4@SiO2 nanoparticles with high doxorubicin (DOX) loading (TfDMP), for dual targeting of cancer, by chemically coupling both Tf and DOX with dual-function magnetic nanoparticles (DMPs) using a multi-armed crosslinker, poly-L-glutamic acid. With high trapping efficiency for magnetic targeting, TfDMP exhibits a Tf receptor-targeting function. Moreover, the DOX loading percentage of TfDMP is high, and can be controlled by adjusting the reactant ratio. TfDMP presents a narrow size distribution, and is sensitive to pH for drug release. Compared with DOX-coupled DMP without Tf modification (DDMP), TfDMP exhibits enhanced uptake by Tf receptor-expressing tumor cells, and displays stronger cancer cell cytotoxicity. This study provides an efficient method for the dual-targeted delivery of therapeutic agents to tumors, with controlled low carrier toxicity and high efficiency. PMID- 24348039 TI - Evaluating the potential of poly(beta-amino ester) nanoparticles for reprogramming human fibroblasts to become induced pluripotent stem cells. AB - BACKGROUND: Gene delivery can potentially be used as a therapeutic for treating genetic diseases, including neurodegenerative diseases, as well as an enabling technology for regenerative medicine. A central challenge in many gene delivery applications is having a safe and effective delivery method. We evaluated the use of a biodegradable poly(beta-amino ester) nanoparticle-based nonviral protocol and compared this with an electroporation-based approach to deliver episomal plasmids encoding reprogramming factors for generation of human induced pluripotent stem cells (hiPSCs) from human fibroblasts. METHODS: A polymer library was screened to identify the polymers most promising for gene delivery to human fibroblasts. Feeder-independent culturing protocols were developed for nanoparticle-based and electroporation-based reprogramming. The cells reprogrammed by both polymeric nanoparticle-based and electroporation-based nonviral methods were characterized by analysis of pluripotency markers and karyotypic stability. The hiPSC-like cells were further differentiated toward the neural lineage to test their potential for neurodegenerative retinal disease modeling. RESULTS: 1-(3-aminopropyl)-4-methylpiperazine end-terminated poly(1,4 butanediol diacry-late-co-4-amino-1-butanol) polymer (B4S4E7) self-assembled with plasmid DNA to form nanoparticles that were more effective than leading commercially available reagents, including Lipofectamine(r) 2000, FuGENE(r) HD, and 25 kDa branched polyethylenimine, for nonviral gene transfer. B4S4E7 nanoparticles showed effective gene delivery to IMR-90 human primary fibroblasts and to dermal fibroblasts derived from a patient with retinitis pigmentosa, and enabled coexpression of exogenously delivered genes, as is needed for reprogramming. The karyotypically normal hiPSC-like cells generated by conventional electroporation, but not by poly(beta-amino ester) reprogramming, could be differentiated toward the neuronal lineage, specifically pseudostratified optic cups. CONCLUSION: This study shows that certain nonviral reprogramming methods may not necessarily be safer than viral approaches and that maximizing exogenous gene expression of reprogramming factors is not sufficient to ensure successful reprogramming. PMID- 24348040 TI - Why it is time to develop the use of cognitive event-related potentials in the treatment of psychiatric diseases. AB - The relapse rate for many psychiatric disorders is staggeringly high, indicating that treatment methods combining psychotherapy with neuropharmacological interventions are not entirely effective. Therefore, in psychiatry, there is a current push to develop alternatives to psychotherapy and medication-based approaches. Cognitive deficits have gained considerable importance in the field as critical features of mental illness, and it is now believed that they might represent valid therapeutic targets. Indeed, an increase in cognitive skills has been shown to have a long-lasting, positive impact on the patients' quality of life and their clinical symptoms. We hereby present four principal arguments supporting the use of event-related potentials (ERP) that are derived from electroencephalography, which allow the identification of specific neurocognitive deficiencies in patients. These arguments could assist psychiatrists in the development of individualized, targeted therapy, as well as a follow-up and rehabilitation plan specific to each patient's deficit. Furthermore, they can be used as a tool to assess the possible benefits of combination therapy, consisting of medication, psychotherapy, and "ERP-oriented cognitive rehabilitation". Using this strategy, specific cognitive interventions could be planned based on each patient's needs, for an "individualized" or "personalized" therapy, which may have the potential to reduce relapse rates for many psychiatric disorders. The implementation of such a combined approach would require intense collaboration between psychiatry departments, clinical neurophysiology laboratories, and neuropsychological rehabilitation centers. PMID- 24348041 TI - Influence of cerebellar stereotactic stimulation on left-right electrodermal information transference in a patient with cerebral palsy. AB - BACKGROUND AND OBJECTIVES: Recent evidence indicates that cerebral palsy is connected to specific autonomic dysregulation between sympathetic and parasympathetic efferent pathways, likely linked to hemispheric influences. These findings suggest a hypothesis that contralateral interhemispheric disinhibition, which may occur on various levels of brain processing including motor functions, could be linked to specific functional dysregulation and structural lesions, which may play a specific role in the modulation of autonomic functions and lead to autonomic dysregulation in cerebral palsy. METHOD: With the aim of comparing autonomic functions as they relate to interhemispheric modulatory influences during therapeutically indicated stereotactic cerebellar stimulation, we have performed bilateral electrodermal activity measurement and calculations of pointwise transinformation (PTI) in a patient with cerebral palsy. Measurement was performed during therapeutic deep cerebellar stimulation in two cerebellar areas in anterior cerebellar lobe-culmen (left electrode) and central lobule superior cerebellar peduncle (right electrode). RESULTS: The results indicate that information transference (PTI) is able to distinguish the states related to specific cerebellar stimulations and that lowest levels of the PTI have been found during stimulation of the central lobule-superior cerebellar peduncle (electrode deepest contact 1), indicating a significantly increased level of inhibition between the left and right sides. CONCLUSION: The results may present potentially useful clinical findings indicating that increased PTI calculated from electrodermal activity could indirectly indicate disinhibitory activity as a possible indicator of a failure of interhemispheric communication that could explain some specific pathogenetic mechanisms in cerebral palsy. Nevertheless, these results need detailed confirmation in further research, as well as reliable clinical evaluation of their usefulness in the therapy of cerebral palsy. PMID- 24348042 TI - Pseudobulbar affect: prevalence and management. AB - Pseudobulbar affect (PBA) may occur in association with a variety of neurological diseases, and so may be encountered in the setting of amyotrophic lateral sclerosis, extrapyramidal and cerebellar disorders, multiple sclerosis, traumatic brain injury, Alzheimer's disease, stroke, and brain tumors. The psychological consequences and the impact on social interactions may be substantial. Although it is most commonly misidentified as a mood disorder, particularly depression or a bipolar disorder, there are characteristic features that can be recognized clinically or assessed by validated scales, resulting in accurate identification of PBA, and thus permitting proper management and treatment. Mechanistically, PBA is a disinhibition syndrome in which pathways involving serotonin and glutamate are disrupted. This knowledge has permitted effective treatment for many years with antidepressants, particularly tricyclic antidepressants and selective serotonin reuptake inhibitors. A recent therapeutic breakthrough occurred with the approval by the Food and Drug Administration of a dextromethorphan/quinidine combination as being safe and effective for treatment of PBA. Side effect profiles and contraindications differ for the various treatment options, and the clinician must be familiar with these when choosing the best therapy for an individual, particularly elderly patients and those with multiple comorbidities and concomitant medications. PMID- 24348044 TI - Serum lipid profile and correlates in newly presenting Nigerians with arterial hypertension. AB - BACKGROUND: Arterial hypertension and dyslipidemia are modifiable cardiovascular risk factors. The multiplicative effect of these risk factors may worsen the atherogenic index of an individual. The objective of this study was to determine the pattern and prevalence of dyslipidemia in newly presenting Nigerians with arterial hypertension, as well as determine some of its correlates. METHODS: This cross-sectional study compared 115 newly presenting, age- and sex-matched individuals with arterial hypertension with 115 normotensive individuals. Fasting lipids, total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and fasting plasma glucose were estimated. RESULTS: Patients with arterial hypertension had higher body mass index (t=7.64; P=0.000), TC (t=2.95; P=0.006), and HDL-C (t= 5.18; P=0.000). The most common dyslipidemia was low HDL-C, found in both the hypertensive (44.3%) and normotensive (20.9%) patients. The prevalence of dyslipidemia in hypertensives and controls was 64% and 39%, respectively. In hypertensive patients, TC correlated positively to diastolic blood pressure (r=0.218; P=0.0019). Other positive correlates include LDL-C and age (r=0.217; P=0.020) and fasting plasma glucose (r=0.202; P=0.030) and body mass index (r=0.209; P=0.025). Among normotensive controls, TC correlated positively with LDL-C (r=0.63; P=0.000) but correlated negatively with tri glycerides (r=-0.30; P=0.001). CONCLUSION: Lipid abnormalities are common in newly presenting Nigerians with arterial hypertension. Screening of these risk factors, promotion of healthy lifestyle, and the institution of therapy is desirable to reduce their multiplicative effects. PMID- 24348045 TI - The GAIN Short Screener (GSS) as a Predictor of Future Arrest or Incarceration Among Youth Presenting to Substance Use Disorder (SUD) Treatment. AB - The National Institutes of Health (NIH) data harmonization project on existing measures (www.phenx.org) has recommended the Global Appraisal of Individual Needs (GAIN)-Short Screener (GSS) as one of the most reliable, valid, efficient, and inexpensive general behavioral health screeners to quickly identify people with internalizing and externalizing mental health disorders, substance use disorders, and crime/violence problems. The present study examined how well the four GSS screeners and their sum predict future arrest or incarceration among individuals entering treatment for a substance use disorder. Using a cross-validation design, a diverse sample of 6,815 youth with substance use disorders was split into a development sample and a validation sample. Overall, results found the GSS's crime and violence screener (CVScr) and the substance disorder screener (SDScr) to be the two best predictors of arrest/incarceration within the 12 months following treatment intake. Additionally, we found that these screeners could be used to categorize individuals into three groups (low risk, moderate risk, high risk) and this simplified classification had good predictive validity (Area Under the Curve = 0.601). In sum, the GSS's predictive validity was similar to other instruments that have been developed to predict risk for recidivism; however, the GSS takes only a fraction of the time to collect (ie, approximately 2-3 minutes for just these two screeners). PMID- 24348043 TI - Vitamin E tocotrienol supplementation improves lipid profiles in chronic hemodialysis patients. AB - PURPOSE: Chronic hemodialysis patients experience accelerated atherosclerosis contributed to by dyslipidemia, inflammation, and an impaired antioxidant system. Vitamin E tocotrienols possess anti-inflammatory and antioxidant properties. However, the impact of dietary intervention with Vitamin E tocotrienols is unknown in this population. PATIENTS AND METHODS: A randomized, double-blind, placebo-controlled, parallel trial was conducted in 81 patients undergoing chronic hemodialysis. Subjects were provided daily with capsules containing either vitamin E tocotrienol-rich fraction (TRF) (180 mg tocotrienols, 40 mg tocopherols) or placebo (0.48 mg tocotrienols, 0.88 mg tocopherols). Endpoints included measurements of inflammatory markers (C-reactive protein and interleukin 6), oxidative status (total antioxidant power and malondialdehyde), lipid profiles (plasma total cholesterol, triacylglycerols, and high-density lipoprotein cholesterol), as well as cholesteryl-ester transfer protein activity and apolipoprotein A1. RESULTS: TRF supplementation did not impact any nutritional, inflammatory, or oxidative status biomarkers over time when compared with the baseline within the group (one-way repeated measures analysis of variance) or when compared with the placebo group at a particular time point (independent t-test). However, the TRF supplemented group showed improvement in lipid profiles after 12 and 16 weeks of intervention when compared with placebo at the respective time points. Normalized plasma triacylglycerols (cf baseline) in the TRF group were reduced by 33 mg/dL (P=0.032) and 36 mg/dL (P=0.072) after 12 and 16 weeks of intervention but no significant improvement was seen in the placebo group. Similarly, normalized plasma high-density lipoprotein cholesterol was higher (P<0.05) in the TRF group as compared with placebo at both week 12 and week 16. The changes in the TRF group at week 12 and week 16 were associated with higher plasma apolipoprotein A1 concentration (P<0.02) and lower cholesteryl ester transfer protein activity (P<0.001). CONCLUSION: TRF supplementation improved lipid profiles in this study of maintenance hemodialysis patients. A multi-centered trial is warranted to confirm these observations. PMID- 24348046 TI - Synchronous BRAF(V600E) and MEK inhibition leads to superior control of murine melanoma by limiting MEK inhibitor induced skin toxicity. AB - The BRAF inhibitor (BRAFi) treatment has led to impressive responses in BRAF(V600E) mutation-positive melanomas, but responses are not durable in many patients. As most of the BRAFi escape mechanisms involve ERK reactivation, combinations with MEK inhibitors (MEKi) are currently tested to improve BRAFi mediated response durations. Additionally, such a combination is expected to reduce MEKi-induced skin toxicities, as these drugs are thought to have antagonistic effects on ERK activation in keratinocytes. However, preclinical in vivo data exploring the combination of BRAFi and MEKi to achieve improved tumor control in the absence of skin toxicities are limited. Using a murine Tyr::CreER(T2);Pten(LoxP/LoxP);Braf(CA/+) melanoma model, we have determined the effect of BRAFi and MEKi treatment and their combination on melanoma control and occurrence of adverse events. We found that the MEKi dosed beyond the maximum tolerable dose (MTD) led to stronger control of tumor growth than did the BRAFi, but mice had to be removed from treatment because of skin toxicity. The combination of BRAFi and MEKi reduced MEKi-associated skin toxicity. This allowed high and long-term dosing of the MEKi, resulting in long-term tumor control. In contrast to previous hypotheses, the addition of a BRAFi did not restore the MEKi mediated downregulation of pERK1/2 in skin cells. Our data describe, for the first time, the alleviation of MEKi-mediated dose-limiting toxicity by addition of a BRAFi in a mouse melanoma model. Additional clinical Phase I studies should be implemented to explore MEKi dosing beyond the single drug MTD in combination with BRAFi. PMID- 24348047 TI - Intraoperative radiotherapy in stage IIB adenocarcinoma of the uterine cervix: a retrospective study. AB - OBJECTIVES: Adenocarcinoma (AC) of the uterine cervix has a poor prognosis and is usually fatal. The aim of this study was to evaluate the clinical outcome and toxicity of intraoperative electron beam radiation therapy (IOERT) in advanced AC. METHODS: Twenty-seven women were treated with IOERT. Surgery consisted of gross negative surgical margins in 19 patients, positive surgical margins in two patients, and close surgical margins in six patients. Twenty-three patients received chemotherapy. RESULTS: The 5-year overall survival and disease-free survival rates were 21/27 (77.8%) and 19/27 (70.4%), respectively. A significantly better survival rate was found in patients with AC compared to patients with adenosquamous carcinoma. Tumor recurrence and metastasis were observed in seven patients (25.9%). No central failure occurred whether or not the resection margins were positive. Two (7.4%) patients developed peripheral neurotoxicity. CONCLUSION: IOERT plus surgery may be feasible and effective with a low risk of toxicity, even in patients with positive resection margins. PMID- 24348048 TI - Gemcitabine and carboplatin demonstrate synergistic cytotoxicity in cervical cancer cells by inhibiting DNA synthesis and increasing cell apoptosis. AB - BACKGROUND: The present study aims to investigate the subunit expression and enzyme activity of ribonucleotide reductase in cervical cancer patients, and detect the combined effect of the ribonucleotide reductase inhibitor gemcitabine and the chemotherapeutic agent carboplatin on cervical cancer cell lines. METHODS: Using quantitative reverse transcription polymerase chain reaction, Western blotting, and cytidine 5'-diphosphate reduction assays, we tested the expression and activity of ribonucleotide reductase in cervical cancer patients. The antitumor activity of gemcitabine and/or carboplatin treatments to SiHa and CaSki human cervical cancer cell lines were assessed by Cell Counting Kit-8 viability assay, EdU incorporation assay, immunofluorescence assay, flow cytometry assay, and Western blotting methods. Additionally, synergistic efficacy was quantitatively analyzed using a combination index based on the Chou-Talalay method. RESULTS: The mRNA levels of three ribonucleotide reductase subunits were all upregulated in the cervical cancer tissues compared with normal tissues (P<0.0001). Consistently, the protein expression and enzyme activity of ribonucleotide reductase were also increased in the cervical cancer tissues. Interestingly, gemcitabine inhibited DNA synthesis and carboplatin induced DNA damage. Further, the combined drug regime had a significant synergistic effect on inhibiting cervical cancer cell viability (log10[combination index] <0) via enhanced DNA damage and cell apoptosis. CONCLUSION: The expression and activity of ribonucleotide reductase was increased in cervical cancer. Our study demonstrated the synergistic cytotoxicity of gemcitabine and carboplatin, through inhibiting DNA synthesis and increasing cell apoptosis in cervical cancer cell lines. This evidence might provide a rational clue of their combined application to improve cervical cancer treatment. PMID- 24348049 TI - The potential for targeting extracellular LOX proteins in human malignancy. AB - The extracellular matrix (ECM) is the physical scaffold where cells are organized into tissues and organs. The ECM may be modified during cancer to allow and promote proliferation, invasion, and metastasis. The family of lysyl oxidase (LOX) enzymes cross-links collagens and elastin and, therefore, is a central player in ECM deposition and maturation. Extensive research has revealed how the LOX proteins participate in every stage of cancer progression, and two family members, LOX and LOX-like 2, have been linked to metastasis, the final stage of cancer responsible for over 90% of cancer patient deaths. However, LOX biosynthesis results in by-product with antiproliferative properties in certain cancers, and LOX enzymes may have different effects depending on the molecular network in which they are active. Therefore, the design of therapies targeting the LOX family needs to be guided by the molecular makeup of the individual disease and will probably require other agents to act on both the LOX enzymes and their associated network. PMID- 24348050 TI - Signal transduction molecule patterns indicating potential glioblastoma therapy approaches. AB - PURPOSE: The expression of an array of signaling molecules, along with the assessment of real-time cell proliferation, has been performed in U87 glioma cell line and in patients' glioblastoma established cell cultures in order to provide a better understanding of cellular and molecular events involved in glioblastoma pathogenesis. Experimental therapy was performed using a phosphatidylinositol-3' kinase (PI3K) inhibitor. PATIENTS AND METHODS: xMAP technology was employed to assess expression levels of several signal transduction molecules and real-time xCELLigence platform for cell behavior. RESULTS: PI3K inhibition induced the most significant effects on global signaling pathways in patient-derived cell cultures, especially on members of the mitogen-activated protein-kinase family, P70S6 serine-threonine kinase, and cAMP response element-binding protein expression and further prevented tumor cell proliferation. CONCLUSION: The PI3K pathway might be a prime target for glioblastoma treatment. PMID- 24348051 TI - Metastatic colorectal cancer first-line treatment with bevacizumab: the impact of K-ras mutation. AB - BACKGROUND: Bevacizumab plus chemotherapy prolongs progression-free survival (PFS) and overall survival (OS) in metastatic colorectal cancer (mCRC). Although there is strong evidence to suggest that the mutational status of the K-ras oncogene has a role as a predictive factor for activity in patients treated with cetuximab and panitumumab, few data have been obtained in patients treated with bevacizumab. We conducted an additional retrospective analysis to investigate the prognostic value of K-ras mutation relative to mCRC first-line treatment with bevacizumab. MATERIALS AND METHODS: A total of 108 patients were retrospectively reviewed. K-ras status was assessed in the overall population by sequencing. Statistical association for PFS and OS was analyzed using the Kaplan-Meier method, and the prognostic role of K-ras was determined using the logrank test. RESULTS: Median PFS was 10 months both for patients with wild-type (WT) K-ras and mutated (MT) K-ras (hazard ratio [HR] 0.94, P=0.75); neither difference in median OS was significant (27 months WT K-ras versus 26 months MT K-ras, HR 0.92; P=0.70). A further analysis was carried out in the two groups according to metastatic sites. No statistically significant difference in terms of PFS and OS was demonstrated between WT K-ras and MT K-ras with liver metastases only and in those with extrahepatic disease. CONCLUSION: Although further study is required, our results seem to confirm that K-ras mutation does not have a prognostic role in mCRC patients receiving first-line treatment with bevacizumab. PMID- 24348052 TI - Sequential treatment of tyrosine kinase inhibitors and chemotherapy for EGFR mutated non-small cell lung cancer: a meta-analysis of Phase III trials. AB - BACKGROUND: This aim of this study was to compare the efficacy of first-line tyrosine kinase inhibitor therapy followed, upon progression, by chemotherapy with the reverse sequence in patients with EGFR-mutated non-small cell lung cancer (NSCLC) in terms of overall survival. METHODS: We performed a meta analysis of studies that met the following criteria: Phase III clinical trial comparing the sequencing of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors with chemotherapy in the treatment of advanced EGFR-mutated NSCLC; activating mutations reported; and availability of hazard ratio estimates with 95% confidence intervals (CIs) for overall survival. RESULTS: Six clinical trials were included in this study. The pooled hazard ratio for overall survival of the EGFR-mutated population that completed sequential treatment was 1.03 (95% CI 0.86-1.22, P=0.776). There was no statistically significant heterogeneity between the studies (tau(2) =0; I(2)=0, 95% CI 0-0.37, P=0.548). Evidence of marked publication bias for the two treatment sequences was insufficient (P=0.145). CONCLUSION: In patients with advanced NSCLC and activating EGFR mutations, first-line chemotherapy followed upon progression by a tyrosine kinase inhibitor was not inferior in terms of overall survival compared with the inverse sequence. This may serve as an indication that chemotherapy could be employed initially if mutation testing results are unavailable. PMID- 24348054 TI - The beta-lactamase inhibitor avibactam (NXL104) does not induce ampC beta lactamase in Enterobacter cloacae. AB - Induction of ampC beta-lactamase expression can often compromise antibiotic treatment and is triggered by several beta-lactams (such as cefoxitin and imipenem) and by the beta-lactamase inhibitor clavulanic acid. The novel beta lactamase inhibitor avibactam (NXL104) is a potent inhibitor of both class A and class C enzymes. The potential of avibactam for induction of ampC expression in Enterobacter cloacae was investigated by ampC messenger ribonucleic acid quantitation. Cefoxitin and clavulanic acid were confirmed as ampC inducers, whereas avibactam was found to exert no effect on ampC expression. Thus, avibactam is unlikely to diminish the activity of any partner beta-lactam antibiotic against AmpC-producing organisms. PMID- 24348053 TI - Ceftolozane/tazobactam: a novel antipseudomonal cephalosporin and beta-lactamase inhibitor combination. AB - The management of infections caused by multidrug-resistant Gram-negative bacteria, particularly Pseudomonas aeruginosa, continues to be a significant challenge to clinicians. Ceftolozane/tazobactam is a novel antibacterial and beta lactamase-inhibitor combination that has shown appreciable activity against wild type Enterobacteriaceae and potent activity against P. aeruginosa. Moreover, ceftolozane/tazobactam has not demonstrated cross-resistance to other antimicrobial classes, particularly those affected by extended-spectrum beta lactamases, AmpC beta-lactamase, a loss in porin channels, or the overexpression of efflux pumps in P. aeruginosa. Ceftolozane/tazobactam has completed two Phase II clinical trials in complicated intra-abdominal and complicated urinary tract infections. A Phase III, multicenter, prospective, randomized, open-label study has been initiated to evaluate the safety and efficacy of ceftolozane/tazobactam versus piperacillin/tazobactam for the treatment of ventilator-associated pneumonia. A Medline search of articles from inception to May 2013 and references for selected citations was conducted. Data from abstracts presented at conferences were also appraised. This article reviews the antimicrobial, pharmacokinetic, and pharmacodynamic profile of ceftolozane/tazobactam, and discusses its potential role in therapy. PMID- 24348055 TI - Comparison of the costs of nonoperative care to minimally invasive surgery for sacroiliac joint disruption and degenerative sacroiliitis in a United States Medicare population: potential economic implications of a new minimally-invasive technology. AB - INTRODUCTION: The economic burden associated with the treatment of low back pain (LBP) in the United States is significant. LBP caused by sacroiliac (SI) joint disruption/degenerative sacroiliitis is most commonly treated with nonoperative care and/or open SI joint surgery. New and effective minimally invasive surgery (MIS) options may offer potential cost savings to Medicare. METHODS: An economic model was developed to compare the costs of MIS treatment to nonoperative care for the treatment of SI joint disruption in the hospital inpatient setting in the US Medicare population. Lifetime cost savings (2012 US dollars) were estimated from the published literature and claims data. Costs included treatment, follow up, diagnostic testing, and retail pharmacy pain medication. Costs of SI joint disruption patients managed with nonoperative care were estimated from the 2005 2010 Medicare 5% Standard Analytic Files using primary International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes 720.2, 724.6, 739.4, 846.9, or 847.3. MIS fusion hospitalization cost was based on Diagnosis Related Group (DRG) payments of $46,700 (with major complications - DRG 459) and $27,800 (without major complications - DRG 460), weighted assuming 3.8% of patients have complications. MIS fusion professional fee was determined from the 2012 Medicare payment for Current Procedural Terminology code 27280, with an 82% fusion success rate and 1.8% revision rate. Outcomes were discounted by 3.0% per annum. RESULTS: The extrapolated lifetime cost of treating Medicare patients with MIS fusion was $48,185/patient compared to $51,543/patient for nonoperative care, resulting in a $660 million savings to Medicare (196,452 beneficiaries at $3,358 in savings/patient). Including those with ICD-9-CM code 721.3 (lumbosacral spondylosis) increased lifetime cost estimates (up to 478,764 beneficiaries at $8,692 in savings/patient). CONCLUSION: Treating Medicare beneficiaries with MIS fusion in the hospital inpatient setting could save Medicare $660 million over patients' lifetimes. PMID- 24348056 TI - Health economic evidence of 5% lidocaine medicated plaster in post-herpetic neuralgia. AB - BACKGROUND: Post-herpetic neuralgia (PHN) is the most common and most debilitating complication of herpes zoster, and involves considerable associated costs. OBJECTIVE: This paper presents results from nine health economic studies undertaken in eight European countries that compared lidocaine medicated plaster with gabapentin and/or pregabalin in PHN. It aims to support the increasing need for published cost-effectiveness data for health care decision-making processes in Europe. METHODS: All studies were based on a similar core Markov model with data derived from clinical trials, local Delphi panels, and official national price and tariff lists. The main outcome measure was cost per quality-adjusted life year gained; time without pain or intolerable adverse events was also included as a secondary outcome measure. All studies focused on an elderly population of patients with PHN who had insufficient pain relief with standard analgesics and could not tolerate or had contraindications to tricyclic antidepressants. RESULTS: Despite considerable differences in many of the variables used, the results showed remarkable similarity and suggested that use of lidocaine medicated plaster offered cost-savings in many of the countries studied, where it proved a highly cost-effective alternative to both gabapentin and pregabalin. CONCLUSION: Lidocaine medicated plaster is a cost-effective alternative to gabapentin and pregabalin in the treatment of PHN. These savings are largely the result of the superior safety profile of the lidocaine medicated plaster. PMID- 24348057 TI - C-QUALITY: cost and quality-of-life pharmacoeconomic analysis of antidepressants used in major depressive disorder in the regional Italian settings of Veneto and Sardinia. AB - BACKGROUND: Major depression is a commonly occurring, seriously impairing, and often recurrent mental disorder. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the treatments most commonly used for major depressive disorder. The objective of this study was to assess the cost-effectiveness of SSRIs and SNRIs in the treatment of major depressive disorder in two Italian regional settings, ie, Veneto and Sardinia. METHODS: A decision analytic model was adapted from the Swedish Dental and Pharmaceutical Benefits Agency to reflect current clinical practice in the treatment of major depressive disorder in the most significant Italian regions. This adaptation was possible as a result of collaboration with an expert panel of Italian psychiatrists and health economists. The population comprised patients with a first diagnosis of major depressive disorder and initiating one SSRI or SNRI drug for the first time. The time frame used was 12 months. Efficacy and utility data for the model were retrieved from the literature and validated by the expert panel. Local data were used for resource utilization and for treatment costs based on the perspective of each regional health service. Scenario analyses and probabilistic sensitivity analyses were performed to test the robustness of the model. RESULTS: Base case analysis showed that escitalopram is associated with the largest health gain (in quality-adjusted life years) and a lower total cost at one year for Sardinia (except for sertraline, against which it was cost effective) and for Veneto, and therefore dominates the other treatment strategies, given that more quality-adjusted life years are achieved at a lower total cost. Scenario analyses and probabilistic sensitivity analyses support the robustness of the model. CONCLUSION: The results indicate that escitalopram is the most cost-effective pharmacologic treatment strategy for both regional health services compared with all SSRIs and all SNRIs used in the first-line treatment of major depressive disorder. PMID- 24348058 TI - Effects of a recreational physical activity and healthy habits orientation program, using an illustrated diary, on the cardiovascular risk profile of overweight and obese schoolchildren: a pilot study in a public school in Brasilia, Federal District, Brazil. AB - INTRODUCTION: Educative strategies need to be adopted to encourage the consumption of healthy foods and to promote physical activity in childhood and adolescence. The effects of recreational physical activity and a health-habit orientation program using an illustrated diary on the cardiovascular risk profile of overweight and obese children was investigated. METHODS: The weight and height of 314 schoolchildren aged between 9 and 11 years old, in a public school in Brasilia, Federal District, Brazil, were recorded. According to the body mass index (BMI) classification proposed by the World Health Organization, 84 were overweight or obese for their age and sex. Of these children, 34 (40%) participated in the study. Students were divided into two groups matched for sex, age, BMI, percent body fat (%BF): the intervention group (IG, n = 17) and the control group (CG, n = 17). The IG underwent a program of 10 weeks of exercise with recreational activities and health-habit orientation using an illustrated diary of habits, while no such interventions were used with the CG during the study period. Before and after the intervention, the children's weight, height, BMI, %BF, waist circumference (WC), maximum oxygen intake (VO2max), total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides, glucose, eating habits, and physical activity level (PAL) were assessed. In analyzing the data, we used descriptive statistics and paired and unpaired t-tests, using a significance level of 0.05. For assessment of dietary habits, a questionnaire, contingency tables, and the chi-squared test were used, with <0.05 set as the significance level. RESULTS: After 10 weeks of intervention, the IG showed a reduction in BMI (pre: 22.2 +/- 2.1 kg/m(2) versus [vs] post: 21.6 +/- 2.1 kg/m(2), P < 0.01); WC (pre: 70.1 +/- 6.1 cm vs post: 69.1 +/- 5.8 cm, P < 0.01); %BF (pre: 29.2% +/- 4.6% vs post: 28.0% +/- 4.8%, P < 0.01); systolic blood pressure (P < 0.01); VO2max (P = 0.014); TC (P < 0.01); LDL (P < 0.01); triglycerides (P < 0.01); and intake of candy (P < 0.01) and soda drinks (P < 0.01), while an increase in the consumption of fruit (P < 0.01) and PAL (P < 0.01) were observed. The CG did not show any change in the health parameters assessed. CONCLUSION: The program was effective in reducing risk factors for cardiovascular disease and the use of an illustrative diary may have been the key to this result, since students were motivated to change their poor eating habits and to increase their physical activity level. PMID- 24348059 TI - SGLT-2 inhibitors and their potential in the treatment of diabetes. AB - Diabetes remains a burgeoning global problem, necessitating ongoing efforts on the part of pharmaceutical and device manufacturers, patients, and society to curb the frightening trends in morbidity and mortality attributable to the malady. Since 1835 when phlorizin was discovered, sodium glucose co-transporter 2 (SGLT-2) inhibitors have rested tantalizingly on the horizon, promising a more physiological approach to glucose control. These agents lower glucose by enhancing its excretion by blocking reabsorption in the renal tubules, thus eliminating glucose from the body along with the molecules' attendant effects on caloric balance, plasma osmolality, and lipids. Consequently, SGLT-2 inhibitors improve glucose control to an extent comparable to other hypoglycemic agents while simultaneously reducing body weight, blood pressure, and cholesterol - an admirable portfolio. One agent, canagliflozin, has recently been approved by the US Food and Drug Administration (FDA) and two other agents have progressed through Phase III trials, including dapagliflozin and empagliflozin. Collectively, when used as monotherapy, these agents have demonstrated reductions in hemoglobin A1c (HbA1c), body weight, and blood pressure of -0.34% to -1.03%, 2.0 to -3.4 kg, and -1.7 to -6.4 mmHg/-0.3 to -2.6 mmHg (systolic blood pressure/diastolic blood pressure), respectively. SGLT-2 inhibitors have been well tolerated, with hypoglycemia (0.9% to 4.3%) occurring infrequently in clinical trials. Safety signals related to breast and bladder cancer have arisen with dapagliflozin, though these are unsubstantiated and likely ascribed to the presence of preexisting cancer. As these agents emerge, clinicians should embrace the addition to the formulary for treating type 2 diabetes, but must also weight the risk-benefit of this new class in deciding which patient types are most likely to benefit from their novel mechanism of action. PMID- 24348060 TI - The effects of diet- and diet plus exercise-induced weight loss on basal metabolic rate and acylated ghrelin in grade 1 obese subjects. AB - BACKGROUND: Diet and exercise are often prescribed as primary intervention regarding obesity-related disorders. Additionally, recent studies have shown beneficial effects of weight loss through diet and exercise in ghrelin concentrations in obese subjects. The aim of this study was to evaluate the effects of a 5% weight loss on lipid profile, resting metabolic rate (RMR), and acylated ghrelin (AG) using two different methods of intervention (diet or diet plus exercise). MATERIALS AND METHODS: Eighteen subjects (twelve women and six men) aged 20-40 years with a body mass index of 30-34.9 kg/m(2) (grade 1 obesity) were randomized into two intervention groups: diet (n=9) or diet plus exercise (n=9). Both groups underwent treatment until 5% of the initial body weight was lost. At baseline and upon completion, RMR and AG were analyzed. RESULTS: Both groups showed a significant decrease in body fat percentage and fat mass. The diet-plus-exercise group showed a decrease in AG (pre: 54.4+/-25.3 pg/mL and post: 33.2+/-19.1 pg/mL) and an increase in RMR (pre: 1,363+/-379 kcal/day, post: 1,633+/-223 kcal/day). CONCLUSION: These data suggest that diet plus exercise induced weight loss and had beneficial effects on AG concentration and RMR, essential factors to ensure the benefits of a weight-loss program. PMID- 24348061 TI - HbA1c for diagnosis of type 2 diabetes. Is there an optimal cut point to assess high risk of diabetes complications, and how well does the 6.5% cutoff perform? AB - Glycated hemoglobin (HbA1c) has recently been recommended for the diagnosis of type 2 diabetes mellitus (T2DM) by leading diabetes organizations and by the World Health Organization. The most important reason to define T2DM is to identify subjects with high risk of diabetes complications who may benefit from treatment. This review addresses two questions: 1) to assess from existing studies whether there is an optimal HbA1c threshold to predict diabetes complications and 2) to assess how well the recommended 6.5% cutoff of HbA1c predicts diabetes complications. HbA1c cutoffs derived from predominantly cross sectional studies on retinopathy differ widely from 5.2%-7.8%, and among other reasons, this is due to the heterogeneity of statistical methods and differences in the definition of retinopathy. From the few studies on other microvascular complications, HbA1c thresholds could not be identified. HbA1c cutoffs make less sense for the prediction of cardiovascular events (CVEs) because CVE risks depend on various strong risk factors (eg, hypertension, smoking); subjects with low HbA1c levels but high values of CVE risk factors were shown to be at higher CVE risk than subjects with high HbA1c levels and low values of CVE risk factors. However, the recommended 6.5% threshold distinguishes well between subjects with and subjects without retinopathy, and this distinction is particularly strong in severe retinopathy. Thus, in existing studies, the prevalence of any retinopathy was 2.5 to 4.5 times as high in persons with HbA1c-defined T2DM as in subjects with HbA1c <6.5%. To conclude, from existing studies, a consistent optimal HbA1c threshold for diabetes complications cannot be derived, and the recommended 6.5% threshold has mainly been brought about by convention rather than by having a consistent empirical basis. Nevertheless, the 6.5% threshold is suitable to detect subjects with prevalent retinopathy, which is the most diabetes specific complication. However, most of the studies on associations between HbA1c and microvascular diabetes complications are cross-sectional, and there is a need for longitudinal studies. PMID- 24348063 TI - Hyperuricemia and non-dipping blood pressure. PMID- 24348062 TI - Effects of dopamine on leptin release and leptin gene (OB) expression in adipocytes from obese and hypertensive patients. AB - BACKGROUND: A reduction of dopaminergic (DAergic) activity with increased prolactin levels has been found in obese and hypertensive patients, suggesting its involvement as a pathophysiological mechanism promoting hypertension. Similarly, leptin action increasing sympathetic activity has been proposed to be involved in mechanisms of hypertension. The aim of this study was to analyze the effects of DA, norepinephrine (NE), and prolactin on leptin release and leptin gene (OB) expression in adipocytes from obese and hypertensive patients. METHODS: Leptin release and OB gene expression were analyzed in cultured adipocytes from 16 obese and hypertensive patients treated with DA (0.001, 0.01, 0.1, and 1.0 MUmol/L), NE (1.0 MUmol/L), insulin (0.1 MUmol/L), and prolactin (1.0 MUmol/L), and from five nonobese and normotensive controls treated with DA (1 MUmol/L), NE (1 MUmol/L), insulin (0.1 MUmol/L), and prolactin (1.0 MUmol/L). RESULTS: A dose related reduction of leptin release and OB gene messenger ribonucleic acid expression under different doses of DA was observed in adipocytes from obese hypertensive patients. Whereas prolactin treatment elicited a significant increase of both leptin release and OB gene expression, NE reduced these parameters. Although similar effects of DA and NE were observed in adipocytes from controls, baseline values in controls were reduced to 20% of the value in adipocytes from obese hypertensive patients. CONCLUSION: These results suggest that DAergic deficiency contributes to metabolic disorders linked to hyperleptinemia in obese and hypertensive patients. PMID- 24348064 TI - Prevalence of hypertension in three rural communities of Ife North Local Government Area of Osun State, South West Nigeria. AB - BACKGROUND: The prevalence of hypertension is increasing rapidly in sub-Saharan Africa, but data are limited on hypertension prevalence. In addition, few population-based studies have been conducted recently in Nigeria on the prevalence and correlates of hypertension in both urban and rural communities. Therefore, we determined the prevalence of hypertension in adults in the three rural communities of Ipetumodu, Edunabon, and Moro, in South West Nigeria. MATERIALS AND METHODS: One thousand adults between 15 and 90 years of age were recruited into this cross-sectional study, over a 6-month period, using a multistage proportional stratified random sampling technique. Sociodemographic data and anthropometric variables were obtained, and resting blood pressure (BP) was measured using an electronic sphygmomanometer. Diagnosis of hypertension was based on the JNC VII guidelines, the WHO/ISH 1999 guidelines, and the BP threshold of 160/95 mmHg. RESULTS: Four hundred and eighty-six men (48.6%) men and 514 women (51.4%) participated in the study. Their mean age, weight, height, and body mass index were 32.3+/-14.7 years, 62+/-13 kg, 1.5+/-0.1 m, and 23.02 kg/m(2), respectively. The prevalence of hypertension, based on the 140/90 mmHg definition, was 26.4% (Male: 27.3%; Female: 25.4%). The prevalence of hypertension, based on the 160/95 mmHg definition, was 11.8% (Male: 13.5%; Female: 10.1%). There were significant positive correlations between BP and some anthropometric indicators of obesity. CONCLUSION: The prevalence of hypertension in the three rural communities was 26.4%, indicating a trend towards increasing prevalence of hypertension. There was also a significant positive correlation between anthropometric indicators of obesity and BP in this population. PMID- 24348065 TI - Telephone-based anticoagulation management in the homebound setting: a retrospective observational study. AB - BACKGROUND: Anticoagulation management is currently performed through anticoagulation clinics or self-managed with or without the help of medical services. Homebound patients are a unique population that cannot utilize anticoagulation clinics or self-testing. Telephone-based anticoagulation management could be an alternative to the traditional methods of monitoring warfarin in this subgroup. The objective of this retrospective, observational study is to investigate the feasibility of warfarin management in homebound patients. METHODS: This study was performed through the use of telephone-based adjustments of warfarin dose based on an international normalized ratio (INR) result. Four hundred forty-eight homebound patients referred to the anticoagulation clinic at Staten Island University Hospital were visited at home by a phlebotomist; a blood sample was drawn for initial laboratory testing. A nurse practitioner then called the patient or designated person to relay the INR result and to direct dosage adjustment. INR results and dosage changes were entered into an electronic medical record and analyzed statistically. RESULTS: The mean percentage of INR values in range was 58.39%. The mean time when the INR was in the therapeutic range was 62.75%. The percent of patients who were therapeutically controlled decreased as the number of medications increased. The complication rate was 4% per patient year, with an equal distribution between bleeding and clotting. These values compared favorably to other studies in which monitoring was performed through anticoagulation clinics or self-monitoring. The cost per visit at our anticoagulation clinic was found to be approximately $300 compared with $82 when utilizing our homebound service. CONCLUSION: Telephone based management of warfarin therapy in the homebound setting is feasible. It can lower the cost of health care expenditures compared to other modalities of anticoagulation management. PMID- 24348066 TI - The prevalence and reliability of self-reported penicillin allergy in a community hospital. AB - BACKGROUND: Penicillin (PCN) accounts for most cases of antibiotic allergies. Reported PCN allergy deprives the patient from this class of antibiotics and creates hesitancy in using other beta-lactam antibiotics. The aim of this study is to report the prevalence of self-reported PCN allergy among adult patients admitted to the hospital and to examine the probable validity of these reports. METHODS: A questionnaire was conducted among 192 patients with self-reported PCN allergy who were admitted to a community hospital between July 25, 2011 and January 25, 2012. Patients admitted with an infection and treated with a beta lactam were also followed until hospital discharge. RESULTS: The mean age of patients at the time of their self-reported allergic reaction was 20.3 years. The most common allergic symptoms reported in decreasing order of frequency were itchy rash, angioedema, and urticaria. Based on analysis of the questionnaires, 121 patients (63.0%) had probable PCN allergy, 54 (28.1%) had possible PCN allergy, and 17 (8.9%) were unlikely to have a PCN allergy. Fifty-one participants (26.6%) had self-reported subsequent exposure to PCN in their life. This subsequent exposure was well tolerated in 86.3% of the participants. Fifty participants (25.9%) had self-reported subsequent exposure to a first generation cephalosporin and it was well tolerated in 78.4% of them. CONCLUSION: Taking a detailed history from patients with self-reported PCN allergy can help to distinguish a true PCN allergy from a false positive report of allergy and hence allow clinicians to use this important class of antibiotics when truly indicated. PMID- 24348067 TI - Feasibility and analgesic efficacy of the transversus abdominis plane block after single-port laparoscopy in patients having bariatric surgery. AB - PURPOSE: The transversus abdominis plane (TAP) block is a technique increasingly used for analgesia after surgery on the anterior abdominal wall. We undertook this study to determine the feasibility and analgesic efficacy of ultrasound guided TAP blocks in morbidly obese patients. We describe the dermatomal spread of local anesthetic in TAP blocks administered, and test the hypothesis that TAP blocks decrease visual analog scale (VAS) scores. PATIENTS AND METHODS: After ethics committee approval and informed consent, 35 patients with body mass index >35 undergoing single-port sleeve gastrectomy (SPSG) were enrolled. All patients received balanced general anesthesia, followed by intravenous patient-controlled analgesia (IV-PCA; hydromorphone) postoperatively; all reported VAS >3 upon arrival to the recovery room. From the cohort of 35 patients having single-port laparoscopy (SPL), a sealed envelope method was used to randomly select ten patients to the TAP group and 25 patients to the control group. The ten patients in the TAP group received ultrasound-guided TAP blocks with 30 mL of 0.2% Ropivacaine injected bilaterally. The dermatomal distribution of the sensory block (by pinprick test) was recorded. VAS scores for the first 24 hours after surgery and opioid use were compared between the IV-PCA+TAP block and IV-PCA only groups. RESULTS: Sensory block ranged from T5-L1. Mean VAS pain scores decreased from 8 +/- 2 to 4 +/- 3 (P=0.04) within 30 minutes of TAP block administration. Compared with patients given IV-PCA only, significantly fewer patients who received TAP block had moderate or severe pain (VAS 4-10) after block administration at 6 hours and 12 hours post-surgery. However, cumulative consumption of hydromorphone at 24 hours after SPSG surgery was similar for both groups. CONCLUSION: Ultrasound-guided TAP blocks in morbidly obese patients are feasible and result in satisfactory analgesia following SPSG in the immediate postoperative period. PMID- 24348068 TI - Dengue: factors driving the emerging epidemic. PMID- 24348069 TI - Epidemiology of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis is a chronic fibrotic lung disease of unknown cause that occurs in adults and has a poor prognosis. Its epidemiology has been difficult to study because of its rarity and evolution in diagnostic and coding practices. Though uncommon, it is likely underappreciated both in terms of its occurrence (ie, incidence, prevalence) and public health impact (ie, health care costs and resource utilization). Incidence and mortality appear to be on the rise, and prevalence is expected to increase with the aging population. Potential risk factors include occupational and environmental exposures, tobacco smoking, gastroesophageal reflux, and genetic factors. An accurate understanding of its epidemiology is important, especially as novel therapies are emerging. PMID- 24348070 TI - Lifestyle factors among proton pump inhibitor users and nonusers: a cross sectional study in a population-based setting. AB - PURPOSE: Lifestyle factors may influence observed associations between proton pump inhibitor (PPI) usage and health outcomes. The aim of the study reported here was to examine characteristics and differences in lifestyle among PPI users and nonusers. METHODS: This cross-sectional study utilized data from a 2006 population-based health survey of 21,637 persons in the Central Danish Region. All persons using prescribed PPIs were identified through linkage to a population based prescription database. Biometric measures and prevalence of smoking, excessive alcohol consumption, diet, and physical exercise were analyzed, comparing PPI users with nonusers. RESULTS: Among 10,129 (46.8%) male and 11,508 (53.2%) female survey respondents, 1,356 (13.4%) males and 1,691 (14.7%) females reported ever use of PPIs. PPI users were more obese (16.7%) than nonusers (13.1%), with an age- and sex-standardized prevalence ratio (PR) of 1.3 (95% confidence interval [CI]: 1.2-1.4). The prevalence of smokers was also higher in the PPI group (26.2% vs 22.3% [PR =1.2, 95% CI: 1.1-1.3]), as was the prevalence of ex-smokers (41.0% vs 32.0% [PR =1.2, 95% CI: 1.1-1.2]). Unhealthy diet was slightly more common among PPI users than among nonusers (15.4% vs 13.0%), with a PR of 1.2 (95% CI: 1.1-1.3). Physical exercise level and alcohol consumption were similar in the two groups. Hospital-diagnosed comorbidity was observed in 35% of PPI users (a Charlson Comorbidity Index score of 1 or more) compared with only 15% among nonusers. CONCLUSION: PPI users are more obese, smoke more, and have significantly more comorbidities than PPI nonusers. These data are important when evaluating unmeasured confounding in observational studies of PPI effects. PMID- 24348071 TI - Patterns of 6-mercaptopurine and azathioprine maintenance therapy among a cohort of commercially insured individuals diagnosed with Crohn's disease in the United States. AB - BACKGROUND AND AIMS: Thiopurines, including 6-mercaptopurine (6-MP) and azathioprine (AZA), are the mainstay of maintenance therapy for Crohn's disease (CD). However, studies examining their effectiveness in routine practice among diverse patient populations are lacking. Among a cohort of new users of 6MP/AZA, we described treatment patterns and changes in subsequent therapy. METHODS: Using the Truven Health Analytics databases, we identified all individuals diagnosed with CD and initiating 6-MP/AZA monotherapy from 2001-2008 (n=3,657). We estimated the proportion of CD patients remaining on 6-MP/AZA monotherapy, using Kaplan-Meier methods, and identified predictors of treatment noncontinuation, using multivariable Cox regression. Among the "noncontinuers," we described subsequent patterns of maintenance therapy and summarized the diagnosis and procedure codes and prescription drug claims preceding treatment discontinuation. RESULTS: The 1-year 6-MP/AZA treatment continuation rate was 42%. Children (age <=18 years) and individuals with no prior anti-tumor necrosis factor (TNF) use were more likely to continue 6-MP/AZA, while those dispensed more (>4) outpatient prescriptions for any drug before initiation of 6-MP/AZA were less likely to continue maintenance treatment. Overall, 1,128 (39%) and 105 (4%) individuals experienced a clinical event potentially indicating active disease or 6-MP/AZA intolerance prior to discontinuation, respectively. Most patients discontinued therapy; among the remaining patients who failed to continue 6-MP/AZA, most augmented with an anti-TNF. CONCLUSION: Most patients initiating 6-MP/AZA monotherapy did not continue beyond 1 year. In contrast to trial evidence showing 1-year remission rates of 40%-80%, this study observed a lower effectiveness of 6 MP/AZA treatment, possibly due to differences in disease severity, patient demographics, comorbidity, adherence, and health care utilization. PMID- 24348072 TI - The risk of bleeding with duloxetine treatment in patients who use nonsteroidal anti-inflammatory drugs (NSAIDs): analysis of placebo-controlled trials and post marketing adverse event reports. AB - PURPOSE: To assess the safety of duloxetine with regards to bleeding-related events in patients who concomitantly did, versus did not, use nonsteroidal anti inflammatory drugs (NSAIDs), including aspirin. METHODS: Safety data from all placebo-controlled trials of duloxetine conducted between December 1993 and December 2010, and post-marketing reports from duloxetine-treated patients in the US Food and Drug Administration Adverse Event Reporting System (FAERS), were searched for bleeding-related treatment-emergent adverse events (TEAEs). The percentage of patients with bleeding-related TEAEs was summarized and compared between treatment groups in all the placebo-controlled studies. Differences between NSAID user and non-user subgroups from clinical trial data were analyzed by a logistic regression model that included therapy, NSAID use, and therapy-by NSAID subgroup interaction. In addition, to determine if higher duloxetine doses are associated with an increased incidence of bleeding-related TEAEs, and whether the use of concomitant NSAIDs might influence the dose effect if one exists, placebo-controlled clinical trials with duloxetine fixed doses of 60 mg, 120 mg, and placebo were analyzed. Also, the incidence of bleeding-related TEAEs reported for duloxetine alone was compared with the incidence in patients treated with duloxetine and concomitant NSAIDs. Finally, the number of bleeding-related cases reported for duloxetine in the FAERS database was compared with the numbers reported for all other drugs. RESULTS: Across duloxetine clinical trials, there was a significantly greater incidence of bleeding-related TEAEs in duloxetine- versus placebo-treated patients overall and also in those patients who did not take concomitant NSAIDS, but no significant difference was seen among those patients who did take concomitant NSAIDS. There was no significant difference in the incidence of bleeding-related TEAEs in the subset of patients treated with duloxetine 120 mg once daily versus those treated with 60 mg once daily regardless of concomitant NSAID use. The combination of duloxetine and NSAIDs was associated with a statistically significantly higher incidence of bleeding related TEAEs compared with duloxetine alone. A similarly higher incidence of bleeding-related TEAEs was seen in patients treated with placebo and concomitant NSAIDs compared with placebo alone. Bleeding-related TEAEs reported in the FAERS database were disproportionally more frequent for duloxetine taken with NSAIDs compared with the full FAERS background, but there was no difference in the reporting of bleeding-related TEAEs when the cases reported for duloxetine taken with NSAIDs were compared against the cases reported for NSAIDs alone. CONCLUSION: Concomitant use of NSAIDs was associated with a higher incidence of bleeding-related TEAEs in clinical trials regardless of whether patients were taking duloxetine or placebo; bleeding-related TEAEs did not appear to increase along with duloxetine dose regardless of NSAID use. In spontaneously reported post-marketing data, the combination of duloxetine and NSAID use was not associated with an increased reporting of bleeding-related events when compared to NSAID use alone. PMID- 24348073 TI - Poor immunological recovery among severely immunosuppressed antiretroviral therapy-naive Ugandans. AB - INTRODUCTION: CD4 T lymphocytes remain the surrogate measure for monitoring HIV progress in resource-limited settings. The absolute CD4 cell counts form the basis for antiretroviral therapy (ART) initiation and monitoring among HIV infected adults. However, the rate of CD4 cell change differs among patients, and the factors responsible are inadequately documented. OBJECTIVE: This study investigated the relationship between HIV severity and ART outcomes among ART naive Ugandans, with the primary outcome of complete immunological recovery among patients of different baseline CD4 counts. METHODS: Patients' records at two HIV/ART sites - the Joint Clinic Research Centre (JCRC) in the Kampala region and Mbarara Hospital in Western Uganda - were reviewed. Records of 426 patients - 68.3% female and 63.2% from JCRC - who initiated ART between 2002 and 2007 were included. HIV severity was based on baseline CD4 cell counts, with low counts considered as severe immunosuppression, while attaining 418 CD4 cells/MUL signified complete immunological recovery. Incidence rates of complete immunological recovery were calculated for, and compared between baseline CD4 cell categories: <50 with >=50, <100 with >=100, <200 with >=200, and >=200 with >=250 cells/MUL. RESULTS: The incidence of complete immunological recovery was 158 during 791.9 person-years of observation, and patients with baseline CD4 >= 200 cells/MUL reached the end point of immunological recovery 1.89 times faster than the patients with baseline CD4 < 200 cells/MUL. CD4 cell change also differed by time, sex, and site, with a faster increase observed during the first year of treatment. CD4 cell increase was faster among females, and among patients from Mbarara. CONCLUSION: Initiating ART at an advanced HIV stage was the main reason for poor immunological recovery among Ugandans. Earlier ART initiation might lead to better immunological responses. PMID- 24348074 TI - Intrauterine contraception after cesarean section and during lactation: a systematic review. AB - BACKGROUND: All postpartum women, including those who are breastfeeding or have had a cesarean section, appear potentially suited to intrauterine contraception, a long acting reversible contraceptive (LARC). Like any other method used after delivery, it should not interfere with lactation or be affected by cesarean section. STUDY DESIGN: We searched the MEDLINE, PubMed, Popline, Google Scholar, and Clinicaltrials.gov databases from January 1968 through to December 2012. Studies were included if they reported event rates in women who had a cesarean section and event rates and clinical outcomes in lactating women or their infants in the breastfeeding group. Summary odds ratios were not calculated because of the diverse methods of reporting event rates in the cesarean section group and the heterogeneity of the results in the breastfeeding group. RESULTS: We found 26 articles on event rates in interval and post-placental intrauterine device (IUD) use, and 18 on event rates and clinical outcomes in breastfeeding IUD users. Four prospective studies and one retrospective study showed an increased expulsion rate in interval insertion. There were 19 studies, of which five were controlled in post-placental IUD insertion after cesarean section. Four studies had expulsion rates of 10 or more per 100 woman-years of use and 15 expulsion rates below 10 per 100 woman-years of use. Three studies showed that event rates for lactating IUD users are the same as those for non-lactating users. Fifteen controlled studies showed that the IUD had no effect on milk production and seven of these showed no effect on infant growth. Pharmacovigilance databases report an increased rate of IUD perforations in lactating women, while the event rate studies report that insertion is generally easier and less painful than expected. These were uncontrolled reports. CONCLUSION: The IUD is a long-acting reversible method of contraception with expulsion rates of 5-15 per 100 woman-years of use when used as a post-placental method immediately after cesarean section. As an interval procedure (6 or more weeks after cesarean section) it appears to have a high expulsion rate (5% or higher) notably in older devices. The IUD does not affect breastfeeding and is easy to insert in these women, but appears to be associated with a higher perforation rate (>1 per 100). Providers should not be deterred from using this contraception method, especially in developing countries, but should be attentive to preventing these potential problems. PMID- 24348075 TI - Chronic khat (Catha edulis) and alcohol marginally alter complete blood counts, clinical chemistry, and testosterone in male rats. AB - INTRODUCTION: Khat (Catha edulis) is a recreational psychoactive drug with psychostimulant properties. While the use of this drug is widespread in eastern Africa, including the Horn of Africa, surveys and anecdotal data show that its use has become cosmopolitan, with users now living in Europe and North America as well. Recent data in Uganda suggest an increasing pattern of simultaneous khat and ethanol use particularly among young adults. However, the effects of this pattern of use remain largely unknown, even though long-term use of either drug alone is known to be harmful. The aim of this study was to examine the toxic effects of simultaneous chronic administration of khat and ethanol on hematological parameters, clinical chemistry, and testosterone in a rat model. METHODS: Adult male Sprague-Dawley rats were randomly assigned to one of six dose groups: 2 g/kg khat; 4 g/kg khat; 4 g/kg ethanol; combined khat and ethanol (4 g/kg each); control; and an untreated group. Treatments were given by gavage twice daily for 28 days, followed by determination of hematological parameters, blood clinical chemistry, and testosterone. RESULTS: Ethanol alone significantly reduced platelet counts compared to control-, untreated and low-dose khat-treated rats; conversely low-dose khat significantly increased both the hemoglobin and hematocrit values, while ethanol alone also significantly increased the hemoglobin value compared to controls. Simultaneous khat and ethanol administration per se did not produce more toxic consequences in chronic use than either drug alone. CONCLUSION: Chronic short-term khat use and ethanol dependence individually produce note-worthy effects on the blood, but not on clinical chemistry or testosterone. Chronic short-term combined khat and ethanol use does not produce more toxic effects compared to use of either drug alone. This provides an opportunity for appropriate clinical interventions to avert the chronic long-term effects that result from use of these drugs of abuse. PMID- 24348076 TI - Clinical utility of implantable neurostimulation devices in the treatment of chronic migraine. AB - Chronic migraine is a disabling disorder that is costly to individuals and society. Occipital nerve stimulation has been used to treat refractory cases of primary headache disorders including drug-resistant chronic cluster headaches and chronic migraine. The Food and Drug Administration (FDA) off-labeled application of equipment used for peripheral nerve (occipital) stimulation is borrowed from FDA-labeled spinal cord stimulation. Manufacturer-sponsored randomized trials include a feasibility study (ONSTIM-Medtronic) and a safety and efficacy study (St Jude). A non-industry sponsored prospective, randomized crossover study by Serra and Marchiotretto suggests improved quality of life and a significant reduction in medication use. Though preliminary studies suggest occipital nerve stimulation is safe and efficacious in treating chronic migraine headache, complication rates, including lead migration, lead fracture, and surgical site infections remain high. Further studies are needed to demonstrate long-term outcomes, while improved surgical techniques and site-specific equipment are needed to minimize complications. PMID- 24348077 TI - System for simultaneous measurements of bilaterally symmetrical acupoints multifrequency impedances. AB - Devices which can obtain comparable bilaterally symmetrical acupoints (BSA) multifrequency impedances (MFI) are often needed in the detection of the energy balance states of acupoints in traditional Chinese medicine. To satisfy these needs, a two-channel impedance measurement system has been introduced which is capable of accurately and simultaneously measuring BSA MFI. The system includes a set of five electrodes, two of which are injected with exciting current signal to synchronously and equally excite BSA; the other three electrodes are used as sensors to simultaneously sense the response signal from both sides. The system also includes a PC-based time-domain signal testing platform with arbitrary current waveform generation and three channels (one exciting current and two response voltages) simultaneously sampling, and a set of MFI simultaneously unbiased computing algorithms based on special odd multisine current signal input. Preliminary validating experiments suggest that the system allows accurate and synchronous measurement of BSA MFI at least in the frequency range of 10 Hz to 60 kHz, and the obtained BSA MFI are well comparable. PMID- 24348078 TI - Implantable cardioverter defibrillator and inappropriate therapy: "black box" examination yielded both human and technical causes. AB - We report on a 70-year-old male patient who was recipient of GEM III DR 7275 Cardioverter Defibrillator, and who presented with inappropriate shocks. The patient had a documented slow ventricular tachycardia (VT), and the device was programmed to detect VT at rates >100 bpm, fast VT (FVT, via VT) at rates >150 bpm, and ventricular fibrillation (VF) at rates >188 bpm. After detection of FVT, efficient therapy was delivered; however, this was immediately followed by multiple inappropriate therapies. Inappropriate therapies were discussed, with a focus on programming features. PMID- 24348079 TI - Lipoprotein glomerulopathy associated with a mutation in apolipoprotein e. AB - Lipoprotein glomerulopathy is a pathological condition characterized by lipid accumulation in the glomerular capillaries that has been associated with the presence of rare mutants of apolipoprotein E (ApoE). We describe a 51-year-old Italian patient presenting Type III hyperlipidemia and proteinuria in whom renal biopsy showed capillary ectasia and intraluminal lipid deposits, suggesting the diagnosis of lipoprotein glomerulopathy. The patient, who had elevated plasma ApoE level, was found to be heterozygous for a mutation in ApoE (Arg150Cys), designated apoEMODENA. This mutation induces the formation of ApoE dimers that are detectable under non-reducing conditions. Treatment with hypolipidemic drugs did not result in a complete remission of the proteinuria and was accompanied by a slow but progressive worsening of renal function with the persistence of intracapillary lipid thrombi. The introduction of low-density lipoprotein aphaeresis combined with a more aggressive lipid lowering and antihypertensive therapy resulted in the remission of proteinuria and a substantial improvement of renal function. Switching from low-density lipoprotein aphaeresis to plasma filtration did not result in an equivalent control of renal damage. The patient died of intracranial hemorrhage during an acute episode of malignant hypertension. PMID- 24348080 TI - Epidemiology of Primary Hyperparathyroidism and its Non-classical Manifestations in the City of Recife, Brazil. AB - Before the introduction of routine measurements of serum calcium in ambulatory services, PHTP (primary hyperparathyroidism) was symptomatic with classic bone disease (known as osteitis fibrosa cystica) nephrolithiasis, and acute neuropsychiatric syndrome with severe hypercalcemia. Currently, PHPT presents few unspecific symptoms. This cross-sectional study was conducted from December 1, 2007, through August 31, 2008 to estimate the prevalence of primary hyperparathyroidism and to describe the clinical and laboratory characteristics of patients receiving ambulatory care. From 4207 patients, we found a prevalence of PHTP of 0.78 (95% confidence interval [CI], 0.52-1.04) of which 81.8% were asymptomatic and 18.2% symptomatic. The female:male ratio was 7.2:1, and 89.7% of the women were postmenopausal. Mean age was 61.12 +/- 15.73 years, mean serum calcium was 10.63 +/- 1.33 mg/dL, and mean serum parathyroid hormone (PTH) was 182.48 +/- 326.51 pg/mL. We found a high prevalence of PHTP at reference centers and a high prevalence of hypertension and type 2 diabetes. PMID- 24348081 TI - Atypical mechanism of glucose modulation by colesevelam in patients with type 2 diabetes. AB - Colesevelam's glucose-lowering mechanism of action is not completely understood. Clinical trials of colesevelam suggest that its mechanism, and often adverse effects, differ from those of other oral antidiabetes drugs. Colesevelam does not affect insulin sensitivity (unlike thiazolidinediones), insulin secretion (unlike sulfonylureas and meglitinides), or early insulin response or glucagon (unlike dipeptidyl peptidase-4 inhibitors). Colesevelam may have some effect on glucose absorption, but likely via a different mechanism than alpha-glucosidase inhibitors. Colesevelam and metformin have similarities regarding hepatic glucose production, but divergent effects on gluconeogenesis versus glycogenolysis, suggesting differing mechanisms of drug action for improving glycemic control. Colesevelam is thought to be a portal glucagon-like peptide-1 (GLP-1) secretagogue with primarily hepatic effects. Bile acid binding by colesevelam leads to TGR5 activation, increased secretion of GLP-1 or other incretins, and inhibition of hepatic glycogenolysis. Colesevelam's mechanism of action appears to be atypical of other antidiabetes medications, making it a potentially suitable component of many combination regimens in the treatment of type 2 diabetes. PMID- 24348083 TI - An aftereffect of adaptation to mean size. AB - The visual system rapidly represents the mean size of sets of objects. Here, we investigated whether mean size is explicitly encoded by the visual system, along a single dimension like texture, numerosity, and other visual dimensions susceptible to adaptation. Observers adapted to two sets of dots with different mean sizes, presented simultaneously in opposite visual fields. After adaptation, two test patches replaced the adapting dot sets, and participants judged which test appeared to have the larger average dot diameter. They generally perceived the test that replaced the smaller mean size adapting set as being larger than the test that replaced the larger adapting set. This differential aftereffect held for single test dots (Experiment 2) and high-pass filtered displays (Experiment 3), and changed systematically as a function of the variance of the adapting dot sets (Experiment 4), providing additional support that mean size is adaptable, and therefore explicitly encoded dimension of visual scenes. PMID- 24348082 TI - Mothers' and Fathers' Negative Responsibility Attributions and Perceptions of Children's Problem Behavior. AB - Parents' negative responsibility attributions about their child's misbehavior are related to a perception that the child has more behavior problems. The current study used a dyadic framework to explore how mothers' and fathers' attributions relate to their own perceptions and to their partner's perceptions of the child's externalizing problems. Participants included 102 couples interviewed when children were 7 years old. Results confirmed that mothers reported more externalizing behavior problems in their children than did fathers, and fathers of boys reported more child behavior problems than fathers of girls. Dyadic analyses suggested that parents' negative responsibility attributions of the child's behavior were associated with greater perceptions of child externalizing problems on behalf of parents and their partners. PMID- 24348084 TI - The Neural Fate of Individual Item Representations in Visual Working Memory. PMID- 24348085 TI - Measuring eddy covariance fluxes of ozone with a slow-response analyser. AB - Ozone (O3) fluxes above a temperate mountain grassland were measured by means of the eddy covariance (EC) method using a slow-response O3 analyser. The resultant flux loss was corrected for by a series of transfer functions which model the various sources of high- and, in particular, low-pass filtering. The resulting correction factors varied on average between 1.7 and 3.5 during night and day time, respectively. A cospectral analysis confirmed the accuracy of this approach. O3 fluxes were characterised by a comparatively large random uncertainty, which during daytime typically amounted to 60 %. EC O3 fluxes were compared against O3 flux measurements made concurrently with the flux-gradient (FG) method. The two methods generally agreed well, except for a period between sun rise and early afternoon, when the FG method was suspected of being affected by the presence of photochemical sources/sinks. O3 flux magnitudes and deposition velocities determined with the EC method compared nicely with the available literature from grassland studies. We conclude that our understanding of the causes and consequences of various sources of flux loss (associated with any EC system) has sufficiently matured so that also less-than-ideal instrumentation may be used in EC flux applications, albeit at the cost of relatively large empirical corrections. PMID- 24348087 TI - A war over mental health professionalism: Scientology versus psychiatry. AB - Over 60 years ago, founder L. Ron Hubbard began what has become Scientology's greatest battle. Scientology emerged from Dianetics, which Hubbard hoped would replace the psychiatric profession. In this article, we discuss how Scientology attempted to position itself as a rival profession to psychiatry and the consequences of those attempts. Scientology's battle with psychiatry gained some success from the social conditions during which it emerged, but it continues in a time that has seen increasing success with various psychiatric treatments. As such, Scientology's direct influence on the psychiatric profession may be difficult to measure, but its actions have coincided with substantial challenges to psychiatry. PMID- 24348086 TI - Addressing extrema and censoring in pollutant and exposure data using mixture of normal distributions. AB - BACKGROUND: Volatile organic compounds (VOC), which include many hazardous chemicals, have been used extensively in personal, commercial and industrial products. Due to the variation in source emissions, differences in the settings and environmental conditions where exposures occur, and measurement issues, distributions of VOC concentrations can have multiple modes, heavy tails, and significant portions of data below the method detection limit (MDL). These issues challenge standard parametric distribution models needed to estimate the exposures, even after log-transformation of the data. METHODS: This paper considers mixture of distributions that can be directly applied to concentration and exposure data. Two types of mixture distributions are considered: the traditional finite mixture of normal distributions, and a semi-parametric Dirichlet process mixture (DPM) of normal distributions. Both methods are implemented for a sample data set obtained from the Relationship between Indoor, Outdoor and Personal Air (RIOPA) study. Performance is assessed based on goodness of-fit criteria that compare the closeness of the density estimates with the empirical density based on data. The goodness-of-fit for the proposed density estimation methods are evaluated by a comprehensive simulation study. RESULTS: The finite mixture of normals and DPM of normals have superior performance when compared to the single normal distribution fitted to log-transformed exposure data. The advantages of using these mixture distributions are more pronounced when exposure data have heavy tails or a large fraction of data below the MDL. Distributions from the DPM provided slightly better fits than the finite mixture of normals. Additionally, the DPM method avoids certain convergence issues associated with the finite mixture of normals, and adaptively selects the number of components. CONCLUSIONS: Compared to the finite mixture of normals, DPM of normals has advantages by characterizing uncertainty around the number of components, and by providing a formal assessment of uncertainty for all model parameters through the posterior distribution. The method adapts to a spectrum of departures from standard model assumptions and provides robust estimates of the exposure density even under censoring due to MDL. PMID- 24348088 TI - Large Covariance Estimation by Thresholding Principal Orthogonal Complements. AB - This paper deals with the estimation of a high-dimensional covariance with a conditional sparsity structure and fast-diverging eigenvalues. By assuming sparse error covariance matrix in an approximate factor model, we allow for the presence of some cross-sectional correlation even after taking out common but unobservable factors. We introduce the Principal Orthogonal complEment Thresholding (POET) method to explore such an approximate factor structure with sparsity. The POET estimator includes the sample covariance matrix, the factor-based covariance matrix (Fan, Fan, and Lv, 2008), the thresholding estimator (Bickel and Levina, 2008) and the adaptive thresholding estimator (Cai and Liu, 2011) as specific examples. We provide mathematical insights when the factor analysis is approximately the same as the principal component analysis for high-dimensional data. The rates of convergence of the sparse residual covariance matrix and the conditional sparse covariance matrix are studied under various norms. It is shown that the impact of estimating the unknown factors vanishes as the dimensionality increases. The uniform rates of convergence for the unobserved factors and their factor loadings are derived. The asymptotic results are also verified by extensive simulation studies. Finally, a real data application on portfolio allocation is presented. PMID- 24348089 TI - Piecing Together Cell-like Systems. AB - Several laboratories are pursuing the synthesis of cellular systems from different directions, including those that begin with simple chemicals to those that exploit existing cells. The methods that begin with nonliving components tend to focus on mimicking specific features of life, such as genomic replication, protein synthesis, sensory systems, and compartment formation, growth, and division. Conversely, the more prevalent synthetic biology approaches begin with something that is already alive and seek to impart new behavior on existing cells. Here we discuss advances in building cell-like systems that mimic key features of life with defined components. PMID- 24348090 TI - Interlaboratory comparison of size measurements on nanoparticles using nanoparticle tracking analysis (NTA). AB - One of the key challenges in the field of nanoparticle (NP) analysis is in producing reliable and reproducible characterisation data for nanomaterials. This study looks at the reproducibility using a relatively new, but rapidly adopted, technique, Nanoparticle Tracking Analysis (NTA) on a range of particle sizes and materials in several different media. It describes the protocol development and presents both the data and analysis of results obtained from 12 laboratories, mostly based in Europe, who are primarily QualityNano members. QualityNano is an EU FP7 funded Research Infrastructure that integrates 28 European analytical and experimental facilities in nanotechnology, medicine and natural sciences with the goal of developing and implementing best practice and quality in all aspects of nanosafety assessment. This study looks at both the development of the protocol and how this leads to highly reproducible results amongst participants. In this study, the parameter being measured is the modal particle size. PMID- 24348091 TI - Development of novel anti-Kv 11.1 antibody-conjugated PEG-TiO2 nanoparticles for targeting pancreatic ductal adenocarcinoma cells. AB - Titanium dioxide (TiO2) has been widely used in many nanotechnology areas including nanomedicine, where it could be proposed for the photodynamic and sonodynamic cancer therapies. However, TiO2 nanoformulations have been shown to be toxic for living cells. In this article, we report the development of a new delivery system, based on nontoxic TiO2 nanoparticles, further conjugated with a monoclonal antibody against a novel and easily accessible tumor marker, e.g., the Kv 11.1 potassium channel. We synthesized, by simple solvothermal method, dicarboxylic acid-terminated PEG TiO2 nanocrystals (PEG-TiO2 NPs). Anti-Kv 11.1 monoclonal antibodies (Kv 11.1-Mab) were further linked to the terminal carboxylic acid groups. Proper conjugation was confirmed by X-ray photoelectron spectroscopy analysis. Kv 11.1-Mab-PEG-TiO2 NPs efficiently recognized the specific Kv 11.1 antigen, both in vitro and in pancreatic ductal adenocarcinoma (PDAC) cells, which express the Kv 11.1 channel onto the plasma membrane. Both PEG TiO2 and Kv 11.1-Mab-PEG-TiO2 NPs were not cytotoxic, but only Kv 11.1-Mab PEG-TiO2 NPs were efficiently internalized into PDAC cells. Data gathered from this study may have further applications for the chemical design of nanostructures to be applied for therapeutic purposes in pancreatic cancer. PMID- 24348092 TI - Beyond the Divinyl Ketone: Innovations in the Generation and Nazarov Cyclization of Pentadienyl Cation Intermediates. AB - The requirement for new strategies for synthesizing five-membered carbocycles has driven an expansion in the study of the Nazarov cyclization. This renewed interest in the reaction has led to the discovery of several interesting new methods for generating the pentadienyl cation intermediate central to the cyclization. Methods reviewed include carbon-heteroatom ionization, functionalization of a double bond, nucleophilic addition, or electrocyclic ring opening. Additional variations employ unconventional substrates to produce novel pentacycles, such as the iso- and imino-Nazarov. Herein, we provide an overview of these unconventional, yet highly useful versions of the Nazarov cyclization. PMID- 24348093 TI - Close encounters of the third domain: the emerging genomic view of archaeal diversity and evolution. AB - The Archaea represent the so-called Third Domain of life, which has evolved in parallel with the Bacteria and which is implicated to have played a pivotal role in the emergence of the eukaryotic domain of life. Recent progress in genomic sequencing technologies and cultivation-independent methods has started to unearth a plethora of data of novel, uncultivated archaeal lineages. Here, we review how the availability of such genomic data has revealed several important insights into the diversity, ecological relevance, metabolic capacity, and the origin and evolution of the archaeal domain of life. PMID- 24348094 TI - The common ancestor of archaea and eukarya was not an archaeon. AB - It is often assumed that eukarya originated from archaea. This view has been recently supported by phylogenetic analyses in which eukarya are nested within archaea. Here, I argue that these analyses are not reliable, and I critically discuss archaeal ancestor scenarios, as well as fusion scenarios for the origin of eukaryotes. Based on recognized evolutionary trends toward reduction in archaea and toward complexity in eukarya, I suggest that their last common ancestor was more complex than modern archaea but simpler than modern eukaryotes (the bug in-between scenario). I propose that the ancestors of archaea (and bacteria) escaped protoeukaryotic predators by invading high temperature biotopes, triggering their reductive evolution toward the "prokaryotic" phenotype (the thermoreduction hypothesis). Intriguingly, whereas archaea and eukarya share many basic features at the molecular level, the archaeal mobilome resembles more the bacterial than the eukaryotic one. I suggest that selection of different parts of the ancestral virosphere at the onset of the three domains played a critical role in shaping their respective biology. Eukarya probably evolved toward complexity with the help of retroviruses and large DNA viruses, whereas similar selection pressure (thermoreduction) could explain why the archaeal and bacterial mobilomes somehow resemble each other. PMID- 24348096 TI - Recent Progress in Rett Syndrome and MeCP2 Dysfunction: Assessment of Potential Treatment Options. AB - Synaptic communication is highly regulated process of contact between cells allowing information to be stored and modified. Synaptic formation and maturation is the result of interactions between intrinsic genetic/molecular factors and the external environment to establish the communication in the brain. One disorder associated with faulty synapse communication is Rett Syndrome (RTT). RTT is the leading form of severe MR in females, affecting approximately 1:10,000 females worldwide, without predisposition to any particular racial or ethnic group. Mutations in MECP2, the gene encoding methyl-CpG-binding protein-2, have been identified in more than 95% of individuals with RTT. Birth and the milestones of early development appear to be normal in individuals with RTT until approximately 6-18 months when in the subsequent months and years that follows, physical, motor, and social-cognitive development enter a period of regression. The clinical management of these individuals is extremely multifaceted, relying on collaborations of specialists and researchers from many different fields. In this critical literature review, we provide an overview of Rett Syndrome, from patient to pathophysiology with a therapeutic summary of clinical trials in RTT and preclinical studies using mouse and cell models of RTT. PMID- 24348095 TI - Early Detection of Huntington Disease. AB - Huntington disease (HD) is a devastating illness, although its autosomal dominant genetic transmission allows a unique opportunity to study apparently healthy individuals before manifest disease. Attempts to study early disease are not unique in neurology (e.g., Mild Cognitive Impairment, Vascular Cognitive Impairment), but studying otherwise-healthy appearing individuals who will go on with nearly 99% certainty to manifest the symptoms of brain disease does provide distinct but valuable information about the true natural history of the disease. The field has witnessed an explosion of research examining possible early indicators of HD during what is now referred to as the "prodrome" of HD. A NIH study in its ninth year (PREDICT-HD) has offered a glimpse into the transition from an apparently healthy state to an obviously diseased state, and can serve as a model for many other genetic diseases, both neurological and non-neurological. PMID- 24348098 TI - The water balance of grassland ecosystems in the Austrian Alps. AB - The altitudinal variation of precipitation, evapotranspiration and runoff was quantified at 16 different grassland sites between 580 and 2550 m a.s.l. in the Austrian Alps. Along this altitudinal transect annual evapotranspiration decreased from roughly 690 mm at low elevation sites to 210 - 220 mm at the upper limit of the alpine grassland belt. A detailed analysis of the data showed that the observed reduction in the annual sum of evapotranspiration could be mainly explained by the altitudinal decline of the length of the snow free period (i.e. the vegetation period). Daily mean sums of evapotranspiration showed no altitudinal trend and averaged 2.2 mm d-1 independent of elevation, although the leaf area index, growing season mean air temperature, and vapour pressure deficit declined with increasing altitude. As precipitation increased with elevation, evapotranspiration seems to be of secondary importance when compared to runoff. Inter-annual variability of evapotranspiration was fairly low across contrasting dry and wet years (coefficient of variation = 7 %), indicating that even during dry years water availability was not limiting evapotranspiration. PMID- 24348099 TI - Tools of the Trade: Planned Missing Data Designs for Research in Cognitive Development. AB - Data collection can be the most time- and cost-intensive part of developmental research. This article describes some long-proposed but little-used research designs that have the potential to maximize data quality (reliability and validity) while minimizing research cost. In planned missing data designs, missing data are used strategically to improve the validity of data collection in one of two ways. Multi-form designs allow one to increase the number of measures assessed on each participant without increasing each participant's burden. Two method measurement designs allow one to reap the benefits of a cost-intensive gold-standard measure, using a larger sample size made possible by a rougher, cheaper measure. We explain each method using examples relevant to cognitive development research. With the use of analysis methods that produce unbiased results, planned missing data designs are an efficient way to manage cost, improve data quality, and reduce participant fatigue and practice effects. PMID- 24348097 TI - PTEN phosphatase-independent maintenance of glandular morphology in a predictive colorectal cancer model system. AB - Organotypic models may provide mechanistic insight into colorectal cancer (CRC) morphology. Three-dimensional (3D) colorectal gland formation is regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN) coupling of cell division cycle 42 (cdc42) to atypical protein kinase C (aPKC). This study investigated PTEN phosphatase-dependent and phosphatase-independent morphogenic functions in 3D models and assessed translational relevance in human studies. Isogenic PTEN-expressing or PTEN-deficient 3D colorectal cultures were used. In translational studies, apical aPKC activity readout was assessed against apical membrane (AM) orientation and gland morphology in 3D models and human CRC. We found that catalytically active or inactive PTEN constructs containing an intact C2 domain enhanced cdc42 activity, whereas mutants of the C2 domain calcium binding region 3 membrane-binding loop (M-CBR3) were ineffective. The isolated PTEN C2 domain (C2) accumulated in membrane fractions, but C2 M-CBR3 remained in cytosol. Transfection of C2 but not C2 M-CBR3 rescued defective AM orientation and 3D morphogenesis of PTEN-deficient Caco-2 cultures. The signal intensity of apical phospho-aPKC correlated with that of Na(+)/H(+) exchanger regulatory factor-1 (NHERF-1) in the 3D model. Apical NHERF-1 intensity thus provided readout of apical aPKC activity and associated with glandular morphology in the model system and human colon. Low apical NHERF-1 intensity in CRC associated with disruption of glandular architecture, high cancer grade, and metastatic dissemination. We conclude that the membrane-binding function of the catalytically inert PTEN C2 domain influences cdc42/aPKC-dependent AM dynamics and gland formation in a highly relevant 3D CRC morphogenesis model system. PMID- 24348100 TI - Estimation and Selection via Absolute Penalized Convex Minimization And Its Multistage Adaptive Applications. AB - The l1-penalized method, or the Lasso, has emerged as an important tool for the analysis of large data sets. Many important results have been obtained for the Lasso in linear regression which have led to a deeper understanding of high dimensional statistical problems. In this article, we consider a class of weighted l1-penalized estimators for convex loss functions of a general form, including the generalized linear models. We study the estimation, prediction, selection and sparsity properties of the weighted l1-penalized estimator in sparse, high-dimensional settings where the number of predictors p can be much larger than the sample size n. Adaptive Lasso is considered as a special case. A multistage method is developed to approximate concave regularized estimation by applying an adaptive Lasso recursively. We provide prediction and estimation oracle inequalities for single- and multi-stage estimators, a general selection consistency theorem, and an upper bound for the dimension of the Lasso estimator. Important models including the linear regression, logistic regression and log linear models are used throughout to illustrate the applications of the general results. PMID- 24348101 TI - Creating Mechanisms for Meaningful Collaboration Between Members of Urban Communities and University-Based HIV Prevention Researchers. AB - This article provides a description of a Community/University Collaborative Board, a formalized partnership between representatives from an inner-city community and university-based researchers. This Collaborative Board oversees a number of research projects focused on designing, delivering and testing family based HIV prevention and mental health focused programs to elementary and junior high school age youth and their families. The Collaborative Board consists of urban parents, school staff members, representatives from community-based agencies and university-based researchers. One research project, the CHAMP (Collaborative HIV prevention and Adolescent Mental health Project) Family Program Study, an urban, family-based HIV prevention project will be used to illustrate how the Collaborative Board oversees a community-based research study. The process of establishing a Collaborative Board, recruiting members and developing subcommittees is described within this article. Examples of specific issues addressed by the Collaborative Board within its subcommittees, Implementation, Finance, Welcome, Research, Grant writing, Curriculum, and Leadership, are detailed in this article along with lessons learned. PMID- 24348102 TI - The Persistence of Segregation in the 21st Century Metropolis. AB - The traditional black-white color line in the American metropolis is being replaced by a more complex pattern of color lines involving multiple groups with different racial and ethnic origins. The consequences are positive in some respects, but they do not overcome the continuing barriers to equal opportunity. The degree of segregation has receded from the near-apartheid that was created in the black ghettos of Northern cities in the middle decades of the last century. Yet the experience of segregation continues to impact blacks of all economic classes. Today's color lines also involve Hispanics and Asians. The multiethnic metropolis is fostering a degree of neighborhood diversity that used to be quite rare. At the same time all-minority areas, now including blacks, Hispanics, and sometimes Asians, continue to be reproduced, and the disparities in community resources between white and minority neighborhoods remain deeply entrenched. PMID- 24348104 TI - EEG Wave of the Future: The Video-EEG and fMRI Suite? PMID- 24348103 TI - Why is there still doubt to cut it out? AB - Surgical treatment for epilepsy has made tremendous strides in the past few decades as a result of advances in neurodiagnostics-particularly structural and functional neuroimaging-and improved surgical techniques. This has not only resulted in better outcomes with respect to epileptic seizures and quality of life, and reduced surgical morbidity and mortality, but it has also increased the population of patients now considered as surgical candidates, particularly in the pediatric age range, and enhanced cost-effectiveness sufficient to make surgical treatment available to countries with limited resources. Yet surgical treatment for epilepsy remains arguably the most underutilized of all accepted medical interventions. In the United States, less than 1% of patients with pharmacoresistant epilepsy are referred to epilepsy centers. Although the number of epilepsy surgery centers has increased appreciably over the past two decades, the number of therapeutic surgical procedures performed for epilepsy has not increased at all. For patients who are referred, the average delay from onset of epilepsy to surgery is more than 20 years-too late for many to avoid a lifetime of disability or premature death. Not only has there been no consistent message to convince neurologists and primary care physicians to refer patients for surgery, but the increase in epilepsy surgery centers in the United States has appeared to result in a divergence of approaches to surgical treatment. Efforts are still needed to further improve the safety and efficacy of surgical treatment, including the identification of biomarkers that can reliably determine the extent of the epileptogenic region; however, the greatest benefits would derive from increasing access for potential surgical candidates to epilepsy surgery facilities. Information is needed to determine why appropriate surgical referrals are not being made. Consensus conferences are necessary to resolve controversies that still exist regarding presurgical evaluation and surgical approaches. Standards should be established for certifying epilepsy centers as recommended by the Institute of Medicine's report on epilepsy. Finally, the epilepsy community should not be promoting epilepsy surgery per se but instead emphasize that epilepsy centers do more than epilepsy surgery, promoting the message: All patients with disabling pharmacoresistant seizures deserve evaluation by specialists at epilepsy centers who can provide a variety of advanced diagnostic and therapeutic services. PMID- 24348105 TI - Tuber or Not Tuber: The Question of Epileptogenic Lesions in Tuberous Sclerosis Complex (TSC). PMID- 24348106 TI - Women with epilepsy planning pregnancy: we can improve outcomes by improving care. PMID- 24348107 TI - Ghee whiz! The growing evidence for the benefits of the modified atkins diet. PMID- 24348108 TI - Hemispherectomy: the full half of the glass. PMID- 24348109 TI - Shocking new insights into the epileptic trait. PMID- 24348110 TI - Treatment of super-refractory status epilepticus: the sooner the better with less adverse effects. PMID- 24348111 TI - Chopping Out CHOP Chops the Fate of Neurons. PMID- 24348112 TI - Algal proteins illuminate epilepsy. PMID- 24348113 TI - Waking up the dormant dentate gyrus. PMID- 24348114 TI - Is focal cortical dysplasia an infectious disease? PMID- 24348116 TI - Submit Topics for 2014 IW and CIW Programs. PMID- 24348115 TI - Seizure-induced newborn neurons might not be so bad after all. PMID- 24348117 TI - Managing common complex symptomatic epilepsies: tumors and trauma: american epilepsy society - 2012 annual course summary. PMID- 24348118 TI - Seizures, Cerebral Shutdown, and SUDEP. AB - Several potential pathophysiologic phenomena, including "cerebral shutdown," are postulated to be responsible for SUDEP. Since the evidence for a seizure-related mechanism is strong, a poor understanding of the physiology of human seizure termination is a major handicap. However, rather than a failure of a single homeostatic mechanism, such as postictal arousal, it may be a "perfect storm" created by the lining up of a several factors that lead to death. PMID- 24348119 TI - Serotonin: The Anti-SuddenDeathAmine? AB - Sudden unexpected death in epilepsy (SUDEP) is an exceptionally difficult condition to study in humans. Therefore, translational research in animal models has been very important in defining pathophysiological mechanisms of death and identifying potential treatments. These models are helping define whether the primary mechanism of death is cardiac or respiratory. They have also identified a link to the serotonergic system of the brainstem; this, in turn, led to recognition that SUDEP and sudden infant death syndrome (SIDS) may share a common final pathway in the sequence of events that lead to death. PMID- 24348120 TI - "TOR"-ing Down the Dentate Gate in Temporal Lobe Epilepsy. PMID- 24348121 TI - The right cells, the right place, the right result: transplants to alleviate seizures take a step forward. PMID- 24348122 TI - Sudden unexpected death in dravet syndrome. PMID- 24348123 TI - Recipes for making human interneurons from stem cells require multiple factors, careful timing, and long maturation periods. PMID- 24348125 TI - Are HFOs Still UFOs? The Known and Unknown About High Frequency Oscillations in Epilepsy Surgery. PMID- 24348124 TI - Perampanel: a selective AMPA antagonist for treating seizures. AB - Perampanel is a selective, noncompetitive AMPA receptor antagonist that has recently been approved for treating localization-related epilepsy. This article reviews the pharmacology, clinical development, efficacy, and safety/tolerability of perampanel. PMID- 24348126 TI - Predicting seizures: are we there yet? PMID- 24348127 TI - Levetiracetam: more evidence of safety in pregnancy. PMID- 24348128 TI - In utero valproate exposure and autism: long suspected, finally proven. PMID- 24348129 TI - EEG and clinical features of childhood absence predict clinical outcomes. PMID- 24348130 TI - Cortical hyperexcitability: a new biomarker in generalized epilepsy syndromes. PMID- 24348131 TI - Serotonin and epilepsy: the story continues. PMID- 24348134 TI - Taking the "Pulse" of Our Society with Q-PULSE. PMID- 24348132 TI - Issues in Clinical Epileptology: A View from the Bench. A Festschrift in Honor of Philip A. Schwartzkroin, PhD. PMID- 24348135 TI - The Changing Face of Epileptology? Results of the Initial Q-PULSE Survey. PMID- 24348133 TI - Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the guideline development subcommittee of the american academy of neurology. AB - OBJECTIVE: To evaluate the evidence since the 1999 assessment regarding efficacy and safety of vagus nerve stimulation (VNS) for epilepsy, currently approved as adjunctive therapy for partial-onset seizures in patients >12 years. METHODS: We reviewed the literature and identified relevant published studies. We classified these studies according to the American Academy of Neurology evidence-based methodology. RESULTS: VNS is associated with a >50% seizure reduction in 55% (95% confidence interval [CI] 50%-59%) of 470 children with partial or generalized epilepsy (13 Class III studies). VNS is associated with a >50% seizure reduction in 55% (95% CI 46%-64%) of 113 patients with Lennox-Gastaut syndrome (LGS) (4 Class III studies). VNS is associated with an increase in >=50% seizure frequency reduction rates of ~7% from 1 to 5 years postim-plantation (2 Class III studies). VNS is associated with a significant improvement in standard mood scales in 31 adults with epilepsy (2 Class III studies). Infection risk at the VNS implantation site in children is increased relative to that in adults (odds ratio 3.4, 95% CI 1.0-11.2). VNS is possibly effective for seizures (both partial and generalized) in children, for LGS-associated seizures, and for mood problems in adults with epilepsy. VNS may have improved efficacy over time. RECOMMENDATIONS: VNS may be considered for seizures in children, for LGS-associated seizures, and for improving mood in adults with epilepsy (Level C). VNS may be considered to have improved efficacy over time (Level C). Children should be carefully monitored for site infection after VNS implantation. Neurology(r) 2013;81:1-7. PMID- 24348136 TI - An efficient and self-adapted approach to the sharpening of color images. AB - An efficient approach to the sharpening of color images is proposed in this paper. For this, the image to be sharpened is first transformed to the HSV color model, and then only the channel of Value will be used for the process of sharpening while the other channels are left unchanged. We then apply a proposed edge detector and low-pass filter to the channel of Value to pick out pixels around boundaries. After that, those pixels detected as around edges or boundaries are adjusted so that the boundary can be sharpened, and those nonedge pixels are kept unaltered. The increment or decrement magnitude that is to be added to those edge pixels is determined in an adaptive manner based on global statistics of the image and local statistics of the pixel to be sharpened. With the proposed approach, the discontinuities can be highlighted while most of the original information contained in the image can be retained. Finally, the adjusted channel of Value and that of Hue and Saturation will be integrated to get the sharpened color image. Extensive experiments on natural images will be given in this paper to highlight the effectiveness and efficiency of the proposed approach. PMID- 24348137 TI - An effective hybrid firefly algorithm with harmony search for global numerical optimization. AB - A hybrid metaheuristic approach by hybridizing harmony search (HS) and firefly algorithm (FA), namely, HS/FA, is proposed to solve function optimization. In HS/FA, the exploration of HS and the exploitation of FA are fully exerted, so HS/FA has a faster convergence speed than HS and FA. Also, top fireflies scheme is introduced to reduce running time, and HS is utilized to mutate between fireflies when updating fireflies. The HS/FA method is verified by various benchmarks. From the experiments, the implementation of HS/FA is better than the standard FA and other eight optimization methods. PMID- 24348138 TI - Root growth and enzymes related to the lignification of maize seedlings exposed to the allelochemical L-DOPA. AB - L-3,4-Dihydroxyphenylalanine (L-DOPA) is a known allelochemical exuded from the roots of velvet bean (Mucuna pruriens L. Fabaceae). In the current work, we analyzed the effects of L-DOPA on the growth, the activities of phenylalanine ammonia-lyase (PAL), tyrosine ammonia-lyase (TAL), and peroxidase (POD), and the contents of phenylalanine, tyrosine, and lignin in maize (Zea mays) roots. Three day-old seedlings were cultivated in nutrient solution with or without 0.1 to 2.0 mM L-DOPA in a growth chamber (25 degrees C, light/dark photoperiod of 12/12, and photon flux density of 280 MU mol m(-2) s(-1)) for 24 h. The results revealed that the growth (length and weight) of the roots, the PAL, TAL, and soluble and cell wall-bound POD activities decreased, while phenylalanine, tyrosine, and lignin contents increased after L-DOPA exposure. Together, these findings showed the susceptibility of maize to L-DOPA. In brief, these results suggest that the inhibition of PAL and TAL can accumulate phenylalanine and tyrosine, which contribute to enhanced lignin deposition in the cell wall followed by a reduction of maize root growth. PMID- 24348139 TI - Association of FAS and FAS ligand genes polymorphism and risk of systemic lupus erythematosus. AB - FAS/FASL pathway plays a critical role in maintaining peripheral immune tolerance; therefore, the apoptosis genes, Fas and Fas ligand (FasL), could be suitable candidate genes in human SLE susceptibility. MATERIALS AND METHODS: In this case-control study, 106 SLE patients and 149 sex, age, and ethnicity matched healthy controls were genotyped for the Fas A-670G and FasLC-844T polymorphisms by polymerase chain reaction-restriction fragment length polymorphism method (PCR RFLP). RESULTS: The frequency of -670AA genotype was significantly higher in SLE patients than control group and the risk of SLE was 2.1-fold greater in subjects with AA genotype (P=0.03). The frequency of -670A allele was significantly higher in SLE patients than in controls too (58% versus 49%, P=0.03). The -844CC genotype frequency was significantly higher in SLE patients than in healthy controls and the risk of SLE was 2.8-fold greater in these subjects (P=0.01). The C allele frequency was significantly higher in patients than in controls (69% versus 49%, P=0.001). Increased SLE risk was observed in individuals with combined effect of Fas-670AA and FasL-844CC genotypes (P=0.001). CONCLUSION: Fas 670AA and FasL-844CC genotypes were associated with SLE risk, and combined effect of -670AA and -844CC genotypes might increase SLE susceptibility. PMID- 24348140 TI - Drinking water fluoride levels for a city in northern Mexico (durango) determined using a direct electrochemical method and their potential effects on oral health. AB - Fluoride is ingested primarily through consuming drinking water. When drinking water contains fluoride concentrations>0.7 parts per million (ppm), consuming such water can be toxic to the human body; this toxicity is called "fluorosis." Therefore, it is critical to determine the fluoride concentrations in drinking water. The objective of this study was to determine the fluoride concentration in the drinking water of the city of Durango. The wells that supply the drinking water distribution system for the city of Durango were studied. One hundred eighty-nine (189) water samples were analyzed, and the fluoride concentration in each sample was quantified as established by the law NMX-AA-077-SCFI-2001. The fluoride concentrations in such samples varied between 2.22 and 7.23 ppm with a 4.313+/-1.318 ppm mean concentration. The highest values were observed in the northern area of the city, with a 5.001+/-2.669 ppm mean value. The samples produced values that exceeded the national standard for fluoride in drinking water. Chronic exposure to fluoride at such concentrations produces harmful health effects, the first sign of which is dental fluorosis. Therefore, it is essential that the government authorities implement water defluoridation programs and take preventative measures to reduce the ingestion of this toxic halogen. PMID- 24348141 TI - Deterministic sensing matrices in compressive sensing: a survey. AB - Compressive sensing is a sampling method which provides a new approach to efficient signal compression and recovery by exploiting the fact that a sparse signal can be suitably reconstructed from very few measurements. One of the most concerns in compressive sensing is the construction of the sensing matrices. While random sensing matrices have been widely studied, only a few deterministic sensing matrices have been considered. These matrices are highly desirable on structure which allows fast implementation with reduced storage requirements. In this paper, a survey of deterministic sensing matrices for compressive sensing is presented. We introduce a basic problem in compressive sensing and some disadvantage of the random sensing matrices. Some recent results on construction of the deterministic sensing matrices are discussed. PMID- 24348142 TI - Dynamic behavior for an SIRS model with nonlinear incidence rate and treatment. AB - This paper considers an SIRS model with nonlinear incidence rate and treatment. It is assumed that susceptible and infectious individuals have constant immigration rates. We investigate the existence of equilibrium and prove the global asymptotical stable results of the endemic equilibrium. We then obtained that the model undergoes a Hopf bifurcation and existences a limit cycle. Some numerical simulations are given to illustrate the analytical results. PMID- 24348143 TI - Quantification of the dental morphology of orangutans. AB - Orangutans are believed to have close biological affinities to humans. Teeth being the hardest tissue provide useful information on primate evolution. Furthermore, knowledge of the pulp chamber and root canal morphology is important for dental treatment. A female Bornean orangutan and a Sumatran male orangutan skull were available for this study. Both of their dentitions, comprising 50 teeth, were scanned employing the cone-beam computed tomography for both metrical and nonmetrical analyses. Measurements included tooth and crown length, root length, enamel covered crown height, root canal length (posterior teeth), length of pulpal space (anterior teeth), and root canal width. Nonmetrical parameters included number of canals per root, number of foramina in each root, and root canal morphology according to Vertucci's classification. It was found that the enamel covered crown height was the longest in the upper central incisors although the canine was the longest amongst the anterior teeth. Both the upper premolars were three-rooted while the lower second premolar of the Sumatran orangutan was two-rooted, with two foramina. The mandibular lateral incisors of the Bornean orangutan were longer than the central incisors, a feature similar to humans. In addition, secondary dentine deposition was noticed, a feature consistent with aged humans. PMID- 24348145 TI - Retracted: Recent advances in DENV receptors. PMID- 24348144 TI - Perceived barriers to healthy eating and physical activity among adolescents in seven Arab countries: a cross-cultural study. AB - OBJECTIVE: To highlight the perceived personal, social, and environmental barriers to healthy eating and physical activity among Arab adolescents. METHOD: A multistage stratified sampling method was used to select 4698 students aged 15 18 years (2240 males and 2458 females) from public schools. Seven Arab counties were included in the study, namely, Algeria, Jordan, Kuwait, Libya, Palestine, Syria, and the United Arab Emirates. Self-reported questionnaire was used to list the barriers to healthy eating and physical activity facing these adolescents. RESULTS: It was found that lack of information on healthy eating, lack of motivation to eat a healthy diet, and not having time to prepare or eat healthy food were the main barriers to healthy eating among both genders. For physical activity, the main barriers selected were lack of motivation to do physical activity, less support from teachers, and lack of time to do physical activity. In general, females faced more barriers to physical activity than males in all countries included. There were significant differences between males and females within each country and among countries for most barriers. CONCLUSION: Intervention programmes to combat obesity and other chronic noncommunicable diseases in the Arab world should include solutions to overcome the barriers to weight maintenance, particularly the sociocultural barriers to practising physical activity. PMID- 24348146 TI - Unstart coupling mechanism analysis of multiple-modules hypersonic inlet. AB - The combination of multiplemodules in parallel manner is an important way to achieve the much higher thrust of scramjet engine. For the multiple-modules scramjet engine, when inlet unstarted oscillatory flow appears in a single-module engine due to high backpressure, how to interact with each module by massflow spillage, and whether inlet unstart occurs in other modules are important issues. The unstarted flowfield and coupling characteristic for a three-module hypersonic inlet caused by center module II and side module III were, conducted respectively. The results indicate that the other two hypersonic inlets are forced into unstarted flow when unstarted phenomenon appears on a single-module hypersonic inlet due to high backpressure, and the reversed flow in the isolator dominates the formation, expansion, shrinkage, and disappearance of the vortexes, and thus, it is the major factor of unstart coupling of multiple-modules hypersonic inlet. The coupling effect among multiple modules makes hypersonic inlet be more likely unstarted. PMID- 24348147 TI - Thiol modification of psyllium husk mucilage and evaluation of its mucoadhesive applications. AB - Thiol functionalization of psyllium was carried out to enhance its mucoadhesive potential. Thiolation of psyllium was achieved by esterification with thioglycolic acid. Thiolation was observed to change the surface morphology of psyllium from fibrous to granular and result in a slight increase in the crystallinity and swelling. Thiolated psyllium was found to contain 3.282 m moles of thiol groups/g of the polymer. Mucoadhesive applications of thiolated psylium were explored by formulating gels using metronidazole as the model drug. On comparative evaluation thiolated psyllium gels showed 3-fold higher mucoadhesive strength than the psyllium gels as determined by modified physical balance using chicken buccal pouch. The results of in vitro release study revealed that thiolated psyllium gels provided a prolonged release of metronidazole. Further, the psyllium and thiolated psyllium gels were found to release the drug following first-order kinetics by combination of polymer relaxation and diffusion through the matrix. PMID- 24348148 TI - Exit, voice, and loyalty in the Italian public health service: macroeconomic and corporate implications. AB - The paper analyses how customers of public health organizations can express their dissatisfaction for the services offered to them. The main aim is to evaluate the effects that possible dissatisfaction of Italian public health service customers can have on public health organizations. We adopted the methodological scheme developed by Hirschman with exit, voice, and loyalty, considering the macroeconomic and corporate implications that it causes for Italian public health organizations. The study investigated the effects developed by exit of the patients on the system of financing of local health authorities considering both the corporate level of analysis and the macroeconomic level. As a result, local health authority management is encouraged to pay greater attention to the exit phenomena through the adoption of tools that promote loyalty, such as the promotion of voice, even if exit is not promoting, at a macroeconomic level, considerable attention to this phenomenon. PMID- 24348149 TI - Review of inflammatory bowel disease in China. AB - Inflammatory bowel disease mainly consisting of ulcerative colitis and Crohn's disease has been rising gradually during the last two decades in China. In this review article, we provide the latest epidemiological trends in incidence, prevalence, and mortality of IBD patients in China and summarize the risk factors and genetic susceptibility of Chinese IBD patients. We also compare these characteristics to those of IBD patients in Western countries. PMID- 24348150 TI - Overdiagnosis of bipolar disorder: a critical analysis of the literature. AB - Bipolar disorder (BD) is considered one of the most disabling mental conditions, with high rates of morbidity, disability, and premature death from suicide. Although BD is often misdiagnosed as major depressive disorder, some attention has recently been drawn to the possibility that BD could be overdiagnosed in some settings. The present paper focuses on a critical analysis of the overdiagnosis issue among bipolar patients. It includes a review of the available literature findings, followed by some recommendations aiming at optimizing the diagnosis of BD and increasing its reliability. PMID- 24348151 TI - Some new generalized difference spaces of nonabsolute type derived from the spaces l p and l infinity. AB - We introduce the sequence space lplambda(B) of none absolute type which is a p normed space and BK space in the cases 0[0, +infinity) is continuous. Firstly, by constructing a special cone, applying Guo-Krasnoselskii's fixed point theorem and Leggett-Williams fixed point theorem, some new existence criteria for fractional boundary value problem are established; secondly, by applying a new extension of Krasnoselskii's fixed point theorem, a sufficient condition is obtained for the existence of multiple positive solutions to the considered boundary value problem from its auxiliary problem. Finally, as applications, some illustrative examples are presented to support the main results. PMID- 24348163 TI - Abatement of azo dye from wastewater using bimetal-chitosan. AB - We introduce a new adsorbent, bimetallic chitosan particle (BCP) that is successfully synthesized and applied to remove the orange II dye from wastewater. The effects of pH, BCP quantity, and contact time are initially verified on the basis of the percentage of orange II removed from the wastewater. Experimental data reveal that the Cu/Mg bimetal and chitosan have a synergistic effect on the adsorption process of the adsorbate, where the dye adsorption by Cu/Mg bimetal, chitosan alone, and bimetal-chitosan is 10, 49, and 99.5%, respectively. The time required for the complete decolorization of orange II by 1 mg/L of BCP is 10 min. The Langmuir model is the best fit for the experimental data, which attains a maximum adsorption capacity of 384.6 mg/g. The consideration of the kinetic behavior indicates that the adsorption of orange II onto the BCP fits best with the pseudo-second-order and Elovich models. Further, the simulated azo dye wastewater can be effectively treated using a relatively low quantity of the adsorbent, 1 mg/L, within a short reaction time of 20 min. Overall, the use of BCP can be considered a promising method for eliminating the azo dye from wastewater effectively. PMID- 24348164 TI - Hands-off and hands-on casting consistency of amputee below knee sockets using magnetic resonance imaging. AB - Residual limb shape capturing (Casting) consistency has a great influence on the quality of socket fit. Magnetic Resonance Imaging was used to establish a reliable reference grid for intercast and intracast shape and volume consistency of two common casting methods, Hands-off and Hands-on. Residual limbs were cast for twelve people with a unilateral below knee amputation and scanned twice for each casting concept. Subsequently, all four volume images of each amputee were semiautomatically segmented and registered to a common coordinate system using the tibia and then the shape and volume differences were calculated. The results show that both casting methods have intra cast volume consistency and there is no significant volume difference between the two methods. Inter- and intracast mean volume differences were not clinically significant based on the volume of one sock criteria. Neither the Hands-off nor the Hands-on method resulted in a consistent residual limb shape as the coefficient of variation of shape differences was high. The resultant shape of the residual limb in the Hands-off casting was variable but the differences were not clinically significant. For the Hands-on casting, shape differences were equal to the maximum acceptable limit for a poor socket fit. PMID- 24348165 TI - A location selection policy of live virtual machine migration for power saving and load balancing. AB - Green cloud data center has become a research hotspot of virtualized cloud computing architecture. And load balancing has also been one of the most important goals in cloud data centers. Since live virtual machine (VM) migration technology is widely used and studied in cloud computing, we have focused on location selection (migration policy) of live VM migration for power saving and load balancing. We propose a novel approach MOGA-LS, which is a heuristic and self-adaptive multiobjective optimization algorithm based on the improved genetic algorithm (GA). This paper has presented the specific design and implementation of MOGA-LS such as the design of the genetic operators, fitness values, and elitism. We have introduced the Pareto dominance theory and the simulated annealing (SA) idea into MOGA-LS and have presented the specific process to get the final solution, and thus, the whole approach achieves a long-term efficient optimization for power saving and load balancing. The experimental results demonstrate that MOGA-LS evidently reduces the total incremental power consumption and better protects the performance of VM migration and achieves the balancing of system load compared with the existing research. It makes the result of live VM migration more high-effective and meaningful. PMID- 24348166 TI - Chemical, biochemical, and microbiological properties of soils from abandoned and extensively cultivated olive orchards. AB - The abandonment of olive orchards is a phenomenon of great importance triggered mainly by economic and social causes. The aim of this study was to investigate some chemical, biochemical, and microbiological properties in a soil of a southern olive grove abandoned for 25 years. In order to define the effect of the long-term land abandonment on soil properties, an adjacent olive grove managed according to extensive practices was taken as reference (essentially minimum tillage and no fertilization). Soil organic matter, total nitrogen, and pH were significantly higher in the abandoned olive grove due to the absence of tillage and the natural inputs of organic matter at high C/N ratio which, inter alia, increased the number of cellulolytic bacteria and stimulated the activity of beta -glucosidase, an indicator of a more advanced stage of soil evolution. The soil of the abandoned olive orchard showed a lower number of total bacteria and fungi and a lower microbial diversity, measured by means of the Biolog method, as a result of a sort of specialization trend towards low quality organic substrates. From this point of view, the extensive cultivation management seemed to not induce a disturbance to microbiological communities. PMID- 24348168 TI - Metal and precursor effect during 1-heptyne selective hydrogenation using an activated carbon as support. AB - Palladium, platinum, and ruthenium supported on activated carbon were used as catalysts for the selective hydrogenation of 1-heptyne, a terminal alkyne. All catalysts were characterized by temperature programmed reduction, X-ray diffraction, transmission electron microscopy, and X-ray photoelectron spectroscopy. TPR and XPS suggest that the metal in all catalysts is reduced after the pretreatment with H2 at 673 K. The TPR trace of the PdNRX catalyst shows that the support surface groups are greatly modified as a consequence of the use of HNO3 during the catalyst preparation. During the hydrogenation of 1 heptyne, both palladium catalysts were more active and selective than the platinum and ruthenium catalysts. The activity order of the catalysts is as follows: PdClRX>PdNRX>PtClRX?RuClRX. This superior performance of PdClRX was attributed in part to the total occupancy of the d electronic levels of the Pd metal that is supposed to promote the rupture of the H2 bond during the hydrogenation reaction. The activity differences between PdClRX and PdNRX catalysts could be attributed to a better accessibility of the substrate to the active sites, as a consequence of steric and electronic effects of the superficial support groups. The order for the selectivity to 1-heptene is as follows: PdClRX=PdNRX>RuClRX>PtClRX, and it can be mainly attributed to thermodynamic effects. PMID- 24348167 TI - Characterisation and in silico analysis of interleukin-4 cDNA of nilgai (Boselaphus tragocamelus) and Indian buffalo (Bubalus bubalis). AB - Interleukin-4 (IL-4) produced from Th2 cells modulates both innate and adaptive immune responses. It is a common belief that wild animals possess better immunity against diseases than domestic and laboratory animals; however, the immune system of wild animals is not fully explored yet. Therefore, a comparative study was designed to explore the wildlife immunity through characterisation of IL-4 cDNA of nilgai, a wild ruminant, and Indian buffalo, a domestic ruminant. Total RNA was extracted from peripheral blood mononuclear cells of nilgai and Indian buffalo and reverse transcribed into cDNA. Respective cDNA was further cloned and sequenced. Sequences were analysed in silico and compared with their homologues available at GenBank. The deduced 135 amino acid protein of nilgai IL-4 is 95.6% similar to that of Indian buffalo. N-linked glycosylation sequence, leader sequence, Cysteine residues in the signal peptide region, and 3' UTR of IL-4 were found to be conserved across species. Six nonsynonymous nucleotide substitutions were found in Indian buffalo compared to nilgai amino acid sequence. Tertiary structure of this protein in both species was modeled, and it was found that this protein falls under 4-helical cytokines superfamily and short chain cytokine family. Phylogenetic analysis revealed a single cluster of ruminants including both nilgai and Indian buffalo that was placed distinct from other nonruminant mammals. PMID- 24348169 TI - Angular transmittance analysis of a novel thermotropic material. AB - This paper uses inverse adding-doubling (IAD) method and Monte Carlo method for the simulation of the spectral angular transmittance of a novel kind of thermotropic material at different temperatures. The results show that the collimated light takes the major part at the beginning of the switching process and the scattered light is negligible. However, the scattered light increased to high above 80% of the total transmitted light with the largest angle distribution of scattered light about 30 degrees as temperature elevated. PMID- 24348170 TI - Laboratory diagnosis of human rabies: recent advances. AB - Rabies, an acute progressive, fatal encephalomyelitis, transmitted most commonly through the bite of a rabid animal, is responsible for an estimated 61,000 human deaths worldwide. The true disease burden and public health impact due to rabies remain underestimated due to lack of sensitive laboratory diagnostic methods. Rapid diagnosis of rabies can help initiate prompt infection control and public health measures, obviate the need for unnecessary treatment/medical tests, and assist in timely administration of pre- or postexposure prophylactic vaccination to family members and medical staff. Antemortem diagnosis of human rabies provides an impetus for clinicians to attempt experimental therapeutic approaches in some patients, especially after the reported survival of a few cases of human rabies. Traditional methods for antemortem and postmortem rabies diagnosis have several limitations. Recent advances in technology have led to the improvement or development of several diagnostic assays which include methods for rabies viral antigen and antibody detection and assays for viral nucleic acid detection and identification of specific biomarkers. These assays which complement traditional methods have the potential to revolutionize rabies diagnosis in future. PMID- 24348172 TI - Preliminary computational hemodynamics study of double aortic aneurysms under multistage surgical procedures: an idealised model study. AB - Double aortic aneurysm (DAA) falls under the category of multiple aortic aneurysms. Repair is generally done through staged surgery due to low invasiveness. In this approach, one aneurysm is cured per operation. Therefore, two operations are required for DAA. However, post-first-surgery rupture cases have been reported. Although the problems involved with managing staged surgery have been discussed for more than 30 years, investigation from a hemodynamic perspective has not been attempted. Hence, this is the first computational fluid dynamics approach to the DAA problem. Three idealized geometries were prepared: presurgery, thoracic aortic aneurysm (TAA) cured, and abdominal aortic aneurysm (AAA) cured. By applying identical boundary conditions for flow rate and pressure, the Navier-Stokes equation and continuity equations were solved under the Newtonian fluid assumption. Average pressure in TAA was increased by AAA repair. On the other hand, average pressure in AAA was decreased after TAA repair. Average wall shear stress was decreased at the peak in post-first-surgery models. However, the wave profile of TAA average wall shear stress was changed in the late systole phase after AAA repair. Since the average wall shear stress in the post-first-surgery models decreased and pressure at TAA after AAA repair increased, the TAA might be treated first to prevent rupture. PMID- 24348171 TI - Emerging paradigms in genomics-based crop improvement. AB - Next generation sequencing platforms and high-throughput genotyping assays have remarkably expedited the pace of development of genomic tools and resources for several crops. Complementing the technological developments, conceptual shifts have also been witnessed in designing experimental populations. Availability of second generation mapping populations encompassing multiple alleles, multiple traits, and extensive recombination events is radically changing the phenomenon of classical QTL mapping. Additionally, the rising molecular breeding approaches like marker assisted recurrent selection (MARS) that are able to harness several QTLs are of particular importance in obtaining a "designed" genotype carrying the most desirable combinations of favourable alleles. Furthermore, rapid generation of genome-wide marker data coupled with easy access to precise and accurate phenotypic screens enable large-scale exploitation of LD not only to discover novel QTLs via whole genome association scans but also to practise genomic estimated breeding value (GEBV)-based selection of genotypes. Given refinements being experienced in analytical methods and software tools, the multiparent populations will be the resource of choice to undertake genome wide association studies (GWAS), multiparent MARS, and genomic selection (GS). With this, it is envisioned that these high-throughput and high-power molecular breeding methods would greatly assist in exploiting the enormous potential underlying breeding by design approach to facilitate accelerated crop improvement. PMID- 24348173 TI - Evaluation of in vitro antioxidant properties of methanol and aqueous extracts of Parkinsonia aculeata L. leaves. AB - In the present study, methanol and aqueous extracts of Parkinsonia aculeata L. leaves were prepared and analyzed for phytochemical analysis and antioxidant potential in different in vitro assays. Antioxidant activity was studied using DPPH, CUPRAC, reducing power assay, deoxyribose degradation (site and nonsite specific), ferric reducing antioxidant potential (FRAP), ferric thiocyanate (FTC), thiobarbituric acid (TBA), and molybdate ion reduction, respectively. The total phenolic contents of the methanol and aqueous leaf extract were 39 mg GAE/g and 38 mg GAE/g, whereas flavonoid contents of these extracts were found to be 0.013 mg RE/g and 0.006 mg RE/g, respectively. From the two extracts, the methanol extract shows maximum inhibition (%) of 57.82%, 71.23%, 48.26%, 69.85%, and 52.78% in DPPH, nonsite- and site-specific, FTC, and TBA assays and absorbance of 0.669 and 0.241 in reducing power and CUPRAC assays at the highest concentration tested. UPLC analysis was done to determine the presence of various types of polyphenols present in plant extracts. PMID- 24348174 TI - Insights on the phytochemical profile (cyclopeptides) and biological activities of Calotropis procera latex organic fractions. AB - Calotropis procera is a medicinal plant whose pharmacological properties are associated with its latex. Here, the Calotropis procera latex fractions were investigated in an attempt to trace its phytochemical profile and measure its anti-inflammatory and toxicity activity. The crude latex was partitioned, yielding five fractions (49.4% hexane, 5.2% dichloromethane, 2.0% ethyl acetate, 2.1% n-butanol, and 41.1% aqueous). Phytochemical screening and spectroscopy analysis revealed that dichloromethane is the most chemically diverse fraction. Triterpenes were detected in both the hexane and dichloromethane fractions, while flavonoids were detected in the dichloromethane and ethyl acetate fractions. These fractions were cytotoxic to cancer cell lines (LD50 0.05 to 3.9 MU g/mL) and lethal to brine shrimp (LD50 10.9 to 65.7 MU g/mL). Reduced neutrophil migration in rats was observed in carrageenan-induced peritonitis for the dichloromethane (67%), ethyl acetate (56%), and aqueous (72%) fractions. A positive reaction with tolidine and ninhydrin suggested that cyclopeptides are in the ethyl acetate fraction. It is therefore concluded that Calotropis procera latex dichloromethane and ethyl acetate fractions exhibit both in vitro and in vivo activities as well as anti-inflammatory properties. Cyclopeptide detection is especially interesting because previous attempts to investigate these low molecular cyclic amino acid sequences in C. procera have failed. PMID- 24348175 TI - Studying the relationship between robustness against mutations in metabolic networks and lifestyle of organisms. AB - Robustness is the key feature of biological networks that enables living organisms to keep their homeostatic state and to survive against external and internal perturbations. Variations in environmental conditions or nutrients and intracellular changes such as genetic mutations have the potential to change stability and efficiency of an organism. Structural robustness helps biological systems to choose alternative routes of adaptation to varying conditions. In this study, in order to estimate the structural robustness in metabolic networks we presented a novel flux balance-based approach inspired by bond percolation theory. Fourteen in silico metabolic models were studied in this work in order to examine the possible relationship between the lifestyle of organisms and their metabolic robustness. The results of this study confirm that in organisms which are highly adapted to their environment robustness to mutations may decrease compared to other organisms. PMID- 24348176 TI - Effect of supplementation with antioxidants on the quality of bovine milk and meat production. AB - From a clinical point of view, oxidative stress (OS) is considered the primary cause of numerous metabolic processes in transition cow. Thus, the addition of antioxidants has been considered a palliative or preventive treatment. But beyond the clinical perspective, antioxidant supplementation provides an added value to the product obtained being either milk or meat. This paper reviews the beneficial aspects that provide antioxidant supplementation on quality of both products and that fit into the new concept that the consumer has a functional and healthy food. Our approach is from a veterinary standpoint, by reviewing the studies conducted to date and the new perspectives that are interesting and need to be studied in the following years. One of the highlights is that sustainable farming, one in which production is combined with animal health, also impacts positively on the quality of the final products, with beneficial antioxidant properties to human health. PMID- 24348177 TI - Application of three-dimensional imaging to the intestinal crypt organoids and biopsied intestinal tissues. AB - Two-dimensional (2D) histopathology is the standard analytical method for intestinal biopsied tissues; however, the role of 3-dimensional (3D) imaging system in the analysis of the intestinal tissues is unclear. The 3D structure of the crypt organoids from the intestinal stem cell culture and intestinal tissues from the donors and recipients after intestinal transplantation was observed using a 3D imaging system and compared with 2D histopathology and immunohistochemistry. The crypt organoids and intestinal tissues showed well defined 3D structures. The 3D images of the intestinal tissues with acute rejection revealed absence of villi and few crypts, which were consistent with the histopathological features. In the intestinal transplant for megacystis microcolon intestinal hypoperistalsis syndrome, the donor's intestinal tissues had well-developed nerve networks and interstitial cells of Cajal (ICCs) in the muscle layer, while the recipient's intestinal tissues had distorted nerve network and the ICCs were few and sparsely distributed, relative to those of the donor. The 3D images showed a clear spatial relationship between the microstructures of the small bowel and the features of graft rejection. In conclusion, integration of the 3D imaging and 2D histopathology provided a global view of the intestinal tissues from the transplant patients. PMID- 24348178 TI - PLZF expression during colorectal cancer development and in normal colorectal mucosa according to body size, as marker of colorectal cancer risk. AB - Promyelocytic leukemia zinc finger protein (PLZF) is a protein involved in various signaling, growth regulatory, and differentiation pathways, including development/function of some T cells. Here, we aimed at the detection of PLZF during colorectal carcinogenesis, using immunofluorescence, and at the evaluation of the colocalization of PLZF with CD2 and CD56 positive cells (T, gamma delta , NK, and NKT cells), using confocal-microscopy, along colorectal carcinogenesis, since its earliest stages, that is, dysplastic aberrant crypt foci (ACF). Furthermore, we analyzed PLZF in the normal colonic mucosa (NM) according to anthropometric parameters of the subject. NM exhibited strong CD56 fluorescent staining. This infiltration was lost in both ACF and colorectal carcinoma (CRC), while PLZF presence increased from NM to ACF and CRC. Strong association was found between CD56+ colonic mucosa cell infiltration and body mass index. Interestingly, an increased stromal PLZF-reactivity was present in NM of obese subjects. This study shows that overexpression of PLZF and exclusion of NK cells in dysplastic microenvironment are very early events in the stepwise sequence leading to CRC and that lower levels of CD56+ cells in NM, together with increased levels of PLZF+ cells, can be a reflection of colon cancer risk due to obesity. PMID- 24348179 TI - Ultrasound for the anesthesiologists: present and future. AB - Ultrasound is a safe, portable, relatively inexpensive, and easily accessible imaging modality, making it a useful diagnostic and monitoring tool in medicine. Anesthesiologists encounter a variety of emergent situations and may benefit from the application of such a rapid and accurate diagnostic tool in their routine practice. This paper reviews current and potential applications of ultrasound in anesthesiology in order to encourage anesthesiologists to learn and use this useful tool as an adjunct to physical examination. Ultrasound-guided peripheral nerve blockade and vascular access represent the most popular ultrasound applications in anesthesiology. Ultrasound has recently started to substitute for CT scans and fluoroscopy in many pain treatment procedures. Although the application of airway ultrasound is still limited, it has a promising future. Lung ultrasound is a well-established field in point-of-care medicine, and it could have a great impact if utilized in our ORs, as it may help in rapid and accurate diagnosis in many emergent situations. Optic nerve sheath diameter (ONSD) measurement and transcranial color coded duplex (TCCD) are relatively new neuroimaging modalities, which assess intracranial pressure and cerebral blood flow. Gastric ultrasound can be used for assessment of gastric content and diagnosis of full stomach. Focused transthoracic (TTE) and transesophageal (TEE) echocardiography facilitate the assessment of left and right ventricular function, cardiac valve abnormalities, and volume status as well as guiding cardiac resuscitation. Thus, there are multiple potential areas where ultrasound can play a significant role in guiding otherwise blind and invasive interventions, diagnosing critical conditions, and assessing for possible anatomic variations that may lead to plan modification. We suggest that ultrasound training should be part of any anesthesiology training program curriculum. PMID- 24348181 TI - Cure kinetics of epoxy nanocomposites affected by MWCNTs functionalization: a review. AB - The current paper provides an overview to emphasize the role of functionalization of multiwalled carbon nanotubes (MWCNTs) in manipulating cure kinetics of epoxy nanocomposites, which itself determines ultimate properties of the resulting compound. In this regard, the most commonly used functionalization schemes, that is, carboxylation and amidation, are thoroughly surveyed to highlight the role of functionalized nanotubes in controlling the rate of autocatalytic and vitrification kinetics. The current literature elucidates that the mechanism of curing in epoxy/MWCNTs nanocomposites remains almost unaffected by the functionalization of carbon nanotubes. On the other hand, early stage facilitation of autocatalytic reactions in the presence of MWCNTs bearing amine groups has been addressed by several researchers. When carboxylated nanotubes were used to modify MWCNTs, the rate of such reactions diminished as a consequence of heterogeneous dispersion within the epoxy matrix. At later stages of curing, however, the prolonged vitrification was seen to be dominant. Thus, the type of functional groups covalently located on the surface of MWCNTs directly affects the degree of polymer-nanotube interaction followed by enhancement of curing reaction. Our survey demonstrated that most widespread efforts ever made to represent multifarious surface-treated MWCNTs have not been directed towards preparation of epoxy nanocomposites, but they could result in property synergism. PMID- 24348180 TI - The ethanol extract of the inner bark of Caesalpinia pyramidalis (Tul.) reduces urinary bladder damage during cyclophosphamide-induced cystitis in rats. AB - Hemorrhagic cystitis (HC) is a common side effect of cyclophosphamide therapy, which deserves new therapeutic strategies, such as those based on natural products. The ethanol extract of the inner bark of Caesalpinia pyramidalis (Tul.) (EECp) possesses anti-inflammatory, antinociceptive, and antioxidant activities as previously showed by our group. We have investigated the effect of EECp on the cyclophosphamide-induced HC. Cystitis was induced in male Wistar rats by the injection of cyclophosphamide. These animals were pretreated with EECp (100-400 mg/kg), vehicle, or mesna. Myeloperoxidase activity and malondialdehyde formation were measured in urinary bladder and other tissues. Bladder edema and histopathological alterations and serum nitric oxide metabolites concentration NOx- were also evaluated. Treatment with EECp (100-400 mg/kg) or mesna impaired the increase of myeloperoxidase activity in urinary bladder and the serum NOx- induced by cyclophosphamide but did not reduce edema in this tissue, as did mesna. Total histological score was reduced by EECp (100 mg/kg). Lung myeloperoxidase activity, which was increased by cyclophosphamide, was decreased significantly by EECp (400 mg/kg). EECp also diminished the malondialdehyde formation in bladder, lung, and spleen, although these parameters were not affected by cyclophosphamide. These results indicate that EECp reduced urinary bladder damage during cyclophosphamide-induced HC in rats. PMID- 24348182 TI - Characterization of human colorectal cancer MDR1/P-gp Fab antibody. AB - In this study, the peptide sized 21 kDa covering P-gp transmembrane region was first prepared for generating a novel mouse monoclonal antibody Fab fragment with biological activity against multiple drug resistance protein P-gp21 by phage display technology. Phage-displayed antibody library prepared from mice spleen tissues was selected against the recombinant protein P-gp21 with five rounds of panning. A number of clones expressing Fab bound to P-gp21, showing neutralized activity in vitro, were isolated and screened by enzyme-linked immunosorbent assay based on its recognition properties to P-gp21 and human colorectal cancer tissue homogenate, resulting in identification of an optimal recombinant Fab clone (Number 29). Further characterization by recloning number 29 into an expression vector showed significant induction of the Fab antibody in the clone number 29 by Isopropyl beta-D-1-thiogalactopyranoside (IPTG). After purified by HiTrap Protein L, the specificity of the Fab antibody to P-gp21 was also confirmed. Not only was the targeted region of this monoclonal Fab antibody identified as a 16-peptide epitope (ALKDKKELEGSGKIAT) comprising residues 883-898 within the transmembrane (TM) domain of human P-gp, but also the binding ability with it was verified. The clinical implication of our results for development of personalized therapy of colorectal cancer will be further studied. PMID- 24348183 TI - Characterization of thermo- and detergent stable antigenic glycosylated cysteine protease of Euphorbia nivulia Buch.-Ham. and evaluation of its ecofriendly applications. AB - An antigenic glycosylated cysteine protease has been purified from the latex of Euphorbia nivulia Buch.-Ham. It exhibits remarkable protease activity in the presence of metal ions, oxidizing agents, organic solvents, and detergents. This enzyme showed potential role in leather processing industry due to its dehairing activity for animal hide without hydrolyzing fibrous proteins, producing, by this way, a better quality product. The enzyme can also be used for silver recovering from X-ray plates. In addition, the stability (temperature and surfactants) and hydrolysis of blood stain data also revealed its application in detergent industries. Agriculturally, this protease finds application in biocontrol process against the infectious management of root knot nematode, Meloidogyne incognita. Biologically, it shows noticeable wound healing, haemostatic and antibacterial activity. PMID- 24348184 TI - Predictors of delayed entry into medical care of children diagnosed with HIV infection: data from an HIV cohort study in India. AB - Data about the attrition before entry into care of children diagnosed with HIV in low- or middle-income countries are scarce. The aim of this study is to describe the attrition before engagement in HIV medical care in 523 children who were diagnosed with HIV from 2007 to 2012 in a cohort study in India. The cumulative incidence of children who entered into care was 87.2% at one year, but most children who did not enter into care within one year were lost to followup. The mortality before entry into care was low (1.3% at one year) and concentrated during the first three months after HIV diagnosis. Factors associated with delayed entry into care were being diagnosed after mother's HIV diagnosis, belonging to scheduled castes, age<18 months, female gender, and living >90 minutes from the HIV centre. Children whose parents were alive and were living in a rented house were at a higher risk of delayed entry into care than those who were living in an owned house. The results of this study can be used to improve the linkage between HIV testing and HIV care of children diagnosed with HIV in India. PMID- 24348186 TI - A fast algorithm for computing binomial coefficients modulo powers of two. AB - I present a new algorithm for computing binomial coefficients modulo 2N. The proposed method has an O(N3.Multiplication(N)+N4) preprocessing time, after which a binomial coefficient C(P, Q) with 0<=Q<=P<=2N-1 can be computed modulo 2N in O(N2.log(N).Multiplication(N)) time. Multiplication(N) denotes the time complexity of multiplying two N-bit numbers, which can range from O(N2) to O(N.log(N).log(log(N))) or better. Thus, the overall time complexity for evaluating M binomial coefficients C(P, Q) modulo 2N with 0<=Q<=P<=2N-1 is O((N3+M.N2.log(N)).Multiplication(N)+N4). After preprocessing, we can actually compute binomial coefficients modulo any 2R with R<=N. For larger values of P and Q, variations of Lucas' theorem must be used first in order to reduce the computation to the evaluation of multiple (O(log(P))) binomial coefficients C(P', Q') (or restricted types of factorials P'!) modulo 2N with 0<=Q'<=P'<=2N-1. PMID- 24348187 TI - Strong convergence of a monotone projection algorithm in a Banach space. AB - In this paper, a common solution problem is investigated based on a Bregman projection. Strong convergence of the monotone projection algorithm for monotone operators and bifunctions is obtained in a reflexive Banach space. PMID- 24348185 TI - Islet-1 immunoreactivity in the developing retina of Xenopus laevis. AB - The LIM-homeodomain transcription factor Islet1 (Isl1) has been widely used as a marker of neuronal differentiation in the developing visual system of different classes of vertebrates, including mammals, birds, reptiles, and fish. In the present study, we analyzed the spatial and temporal distribution of Isl1 immunoreactive cells during Xenopus laevis retinal development and its relation to the formation of the retinal layers, and in combination with different markers of cell differentiation. The earliest Isl1 expression appeared at St29-30 in the cell nuclei of sparse differentiating neuroblasts located in the vitreal surface of the undifferentiated retina. At St35-36, abundant Isl1-positive cells accumulated at the vitreal surface of the neuroepithelium. As development proceeded and through the postmetamorphic juveniles, Isl1 expression was identified in subpopulations of ganglion cells and in subsets of amacrine, bipolar, and horizontal cells. These data together suggest a possible role for Isl1 in the early differentiation and maintenance of different retinal cell types, and Isl1 can serve as a specific molecular marker for the study of retinal cell specification in X. laevis. PMID- 24348188 TI - On the relationship between multicast/broadcast throughput and resource utilizations in wireless mesh networks. AB - This paper deals with the problem of multicast/broadcast throughput in multi channel multi-radio wireless mesh networks that suffer from the resource constraints. We provide a formulation to capture the utilization of the network resources and derive analytical relationships for the network's throughput in terms of the node utilization, the channel utilization, and the number of transmissions. Our model relies on the on-demand quality of service multicast/broadcast sessions, where each admitted session creates a unique tree with a specific bandwidth. As an advantage, the derived relationships are independent of the type of tree built for each session and can be used for different protocols. The proposed formulation considers the channel assignment strategy and reflects both the wireless broadcast advantage and the interference constraint. We also offer a comprehensive discussion to evaluate the effects of load-balancing and number of transmissions on the network's throughput. Numerical results confirm the accuracy of the presented analysis. PMID- 24348189 TI - Water plasma functionalized CNTs/MnO2 composites for supercapacitors. AB - A water plasma treatment applied to vertically-aligned multiwall carbon nanotubes (CNTs) synthesized by plasma enhanced chemical vapour deposition gives rise to surface functionalization and purification of the CNTs, along with an improvement of their electrochemical properties. Additional increase of their charge storage capability is achieved by anodic deposition of manganese dioxide lining the surface of plasma-treated nanotubes. The morphology (nanoflower, layer, or needle like structure) and oxidation state of manganese oxide depend on the voltage window applied during charge-discharge measurements and are found to be key points for improved efficiency of capacitor devices. MnO2/CNTs nanocomposites exhibit an increase in their specific capacitance from 678 Fg(-1), for untreated CNTs, up to 750 Fg(-1), for water plasma-treated CNTs. PMID- 24348191 TI - Analytical analysis of motion separability. AB - Motion segmentation is an important task in computer vision and several practical approaches have already been developed. A common approach to motion segmentation is to use the optical flow and formulate the segmentation problem using a linear approximation of the brightness constancy constraints. Although there are numerous solutions to solve this problem and their accuracies and reliabilities have been studied, the exact definition of the segmentation problem, its theoretical feasibility and the conditions for successful motion segmentation are yet to be derived. This paper presents a simplified theoretical framework for the prediction of feasibility, of segmentation of a two-dimensional linear equation system. A statistical definition of a separable motion (structure) is presented and a relatively straightforward criterion for predicting the separability of two different motions in this framework is derived. The applicability of the proposed criterion for prediction of the existence of multiple motions in practice is examined using both synthetic and real image sequences. The prescribed separability criterion is useful in designing computer vision applications as it is solely based on the amount of relative motion and the scale of measurement noise. PMID- 24348190 TI - Phenotypes and genotypes of patients with pantothenate kinase-associated neurodegeneration in Asian and Caucasian populations: 2 cases and literature review. AB - OBJECTIVES: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare disease caused by pantothenate kinase 2 (PANK2, OMIM 606157) mutations. This study is aimed to investigate clinical presentations, pathologies, and genetics in patients with PKAN. METHODS: Two patients with PKAN were reported. We reviewed the literature to include additional 19 patients with PKAN in Eastern Asia. These patients were divided into classic and atypical groups by the age of onset. We compared the data on PKAN patients of Asian and Caucasian populations. RESULTS: We found iron deposits in the globus pallidus in our Patient 1 and a heterozygous truncating mutation (c.1408insT) in Patient 2. Literature review shows that generalized dystonia and bulbar signs are more common in classic PKAN patients, whereas segmental dystonia and tremors are more specific to atypical ones. Asian patients have less complex presentations--lower prevalence of pyramidal signs, mental impairment, and parkinsonism--than Caucasians. D378G in exon 3 is the most frequent mutation (28%) in Asians. CONCLUSIONS: Our study demonstrates that the distribution of dystonia is the major distinction between subgroups of PKAN. Caucasian patients have more complex presentations than Asians. Exon 3 and 4 are hot spots for screening PANK2 mutations in Asian patients. PMID- 24348192 TI - Air temperature change in the southern Tarim River Basin, China, 1964-2011. AB - The temperature data from 3 meteorological stations (Kashi, Ruoqiang, and Hotan) in the South of Tarim River Basin (STRB) during 1964-2011 were analyzed by Mann Kendall test and correlation analysis. The results from Mann-Kendall test show that the surface temperature (ST), 850 hPa temperature (T850), and 700 hPa temperature (T700) exhibited upward trends, while 300 hPa temperature (T300) revealed a downward trend. On the whole, the change rate of ST, T850, T700, and T300 was 0.26~0.46 degrees C/10a, 0.15~0.40 degrees C/10a, 0.03~0.10 degrees C/10a, and -0.38~-0.13 degrees C/10a, respectively. For the periods, ST and T850 declined during 1964-1997 and then rose during 1998-2011. T700 declined during 1964-2005 and then rose during 2006-2011, while T300 rose from 1964 to 1970s and then declined. The results from correlation analysis show that T850 and T700 positively correlated with ST (P<0.01) at the all three stations and there was a negative correlation between T300 and ST at Hotan (P<0.1), while the correlation is not significant at Kashi and Ruoqiang. The results indicate that there were gradient differences in the response of upper-air temperature (UT) to ST change. PMID- 24348194 TI - Fabrication of flexible piezoelectric PZT/fabric composite. AB - Flexible piezoelectric PZT/fabric composite material is pliable and tough in nature which is in a lack of traditional PZT patches. It has great application prospect in improving the sensitivity of sensor/actuator made by piezoelectric materials especially when they are used for curved surfaces or complicated conditions. In this paper, glass fiber cloth was adopted as carrier to grow PZT piezoelectric crystal particles by hydrothermal method, and the optimum conditions were studied. The results showed that the soft glass fiber cloth was an ideal kind of carrier. A large number of cubic-shaped PZT nanocrystallines grew firmly in the carrier with a dense and uniform distribution. The best hydrothermal condition was found to be pH 13, reaction time 24 h, and reaction temperature 200 degrees C. PMID- 24348195 TI - Donor-like surface traps on two-dimensional electron gas and current collapse of AlGaN/GaN HEMTs. AB - The effect of donor-like surface traps on two-dimensional electron gas (2DEG) and drain current collapse of AlGaN/GaN high electron mobility transistors (HEMTs) has been investigated in detail. The depletion of 2DEG by the donor-like surface states is shown. The drain current collapse is found to be more sensitive to the addition of positive surface charges. Surface trap states with higher energy levels result in weaker current collapse and faster collapse process. By adopting an optimized backside doping scheme, the electron density of 2DEG has been improved greatly and the current collapse has been greatly eliminated. These results give reference to the improvement in device performance of AlGaN/GaN HEMTs. PMID- 24348196 TI - Preparation of soft magnetic Fe-Ni-Pb-B alloy nanoparticles by room temperature solid-solid reaction. AB - The Fe-Ni-Pb-B alloy nanoparticles was prepared by a solid-solid chemical reaction of ferric trichloride, nickel chloride, lead acetate, and potassium borohydride powders at room temperature. The research results of the ICP and thermal analysis indicate that the resultants are composed of iron, nickel, lead, boron, and PVP, and the component of the alloy is connected with the mole ratio of potassium borohydride and the metal salts. The TEM images show that the resultants are ultrafine and spherical particles, and the particle size is about a diameter of 25 nm. The largest saturation magnetization value of the 21.18 emu g(-1) is obtained in the Fe-Ni-Pb-B alloy. The mechanism of the preparation reaction for the Fe-Ni-Pb-B multicomponent alloys is discussed. PMID- 24348193 TI - Pharmacological effects of active compounds on neurodegenerative disease with gastrodia and uncaria decoction, a commonly used poststroke decoction. AB - Neurodegenerative diseases refer to the selective loss of neuronal systems in patients. The diseases cause high morbidity and mortality to approximately 22 million people worldwide and the number is expected to be tripled by 2050. Up to now, there is no effective prevention and treatment for the neurodegenerative diseases. Although some of the clinical therapies target at slowing down the progression of symptoms of the diseases, the general effectiveness of the drugs has been far from satisfactory. Traditional Chinese medicine becomes popular alternative remedies as it has been practiced clinically for more than thousands of years in China. As neurodegenerative diseases are mediated through different pathways, herbal decoction with multiple herbs is used as an effective therapeutic approach to work on multiple targets. Gastrodia and Uncaria Decoction, a popular TCM decoction, has been used to treat stroke in China. The decoction contains compounds including alkaloids, flavonoids, iridoids, carotenoids, and natural phenols, which have been found to possess anti inflammatory, antioxidative, and antiapoptotic effects. In this review, we will summarize the recent publications of the pharmacological effects of these five groups of compounds. Understanding the mechanisms of action of these compounds may provide new treatment opportunities for the patients with neurodegenerative diseases. PMID- 24348197 TI - Some endpoint results for beta-generalized weak contractive multifunctions. AB - We introduce beta-generalized weak contractive multifunctions and give some results about endpoints of the multifunctions. Also, we give some results about role of a point in the existence of endpoints. PMID- 24348198 TI - Feature-based classification of amino acid substitutions outside conserved functional protein domains. AB - There are more than 500 amino acid substitutions in each human genome, and bioinformatics tools irreplaceably contribute to determination of their functional effects. We have developed feature-based algorithm for the detection of mutations outside conserved functional domains (CFDs) and compared its classification efficacy with the most commonly used phylogeny-based tools, PolyPhen-2 and SIFT. The new algorithm is based on the informational spectrum method (ISM), a feature-based technique, and statistical analysis. Our dataset contained neutral polymorphisms and mutations associated with myeloid malignancies from epigenetic regulators ASXL1, DNMT3A, EZH2, and TET2. PolyPhen-2 and SIFT had significantly lower accuracies in predicting the effects of amino acid substitutions outside CFDs than expected, with especially low sensitivity. On the other hand, only ISM algorithm showed statistically significant classification of these sequences. It outperformed PolyPhen-2 and SIFT by 15% and 13%, respectively. These results suggest that feature-based methods, like ISM, are more suitable for the classification of amino acid substitutions outside CFDs than phylogeny-based tools. PMID- 24348199 TI - Rural Poverty Dynamics and Refugee Communities in South Africa: A Spatial Temporal Model. AB - The assimilation of refugees into their host community economic structures is often problematic. The paper investigates the ability of refugees in rural South Africa to accumulate assets over time relative to their host community. Bayesian spatial-temporal modelling was employed to analyse a longitudinal database that indicated that the asset accumulation rate of former Mozambican refugee households was similar to their host community; however, they were unable to close the wealth gap. A series of geo-statistical wealth maps illustrate that there is a spatial element to the higher levels of absolute poverty in the former refugee villages. The primary reason for this is their physical location in drier conditions that are established further away from facilities and infrastructure. Neighbouring South African villages in close proximity, however, display lower levels of absolute poverty, suggesting that the spatial location of the refugees only partially explains their disadvantaged situation. In this regard, the results indicate that the wealth of former refugee households continues to be more compromised by higher mortality levels, poorer education, and less access to high-return employment opportunities. The long-term impact of low initial asset status appears to be perpetuated in this instance by difficulties in obtaining legal status in order to access state pensions, facilities, and opportunities. The usefulness of the results is that they can be used to sharpen the targeting of differentiated policy in a given geographical area for refugee communities in rural Africa. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 24348201 TI - No question about exciting questions in cell biology. AB - Although we have a good grasp of many important processes in cell biology, including knowledge of many molecules involved and how they interact with each other, we still do not understand most of the dynamical features that are the essence of living systems. Fortunately, we now have the ability to dissect biological systems in enough detail to understand their dynamics, including the use of mathematical models to account for past observations and predict future experiments. This deep level of mechanistic understanding should be our goal-not simply to satisfy our scientific curiosity, but also to understand the causes of disease well enough to predict risks, make early diagnoses, and treat effectively. Many big questions remain to be answered before we reach this goal of understanding cellular dynamics. PMID- 24348200 TI - Translational profiling of clock cells reveals circadianly synchronized protein synthesis. AB - Genome-wide studies of circadian transcription or mRNA translation have been hindered by the presence of heterogeneous cell populations in complex tissues such as the nervous system. We describe here the use of a Drosophila cell specific translational profiling approach to document the rhythmic "translatome" of neural clock cells for the first time in any organism. Unexpectedly, translation of most clock-regulated transcripts--as assayed by mRNA ribosome association--occurs at one of two predominant circadian phases, midday or mid night, times of behavioral quiescence; mRNAs encoding similar cellular functions are translated at the same time of day. Our analysis also indicates that fundamental cellular processes--metabolism, energy production, redox state (e.g., the thioredoxin system), cell growth, signaling and others--are rhythmically modulated within clock cells via synchronized protein synthesis. Our approach is validated by the identification of mRNAs known to exhibit circadian changes in abundance and the discovery of hundreds of novel mRNAs that show translational rhythms. This includes Tdc2, encoding a neurotransmitter synthetic enzyme, which we demonstrate is required within clock neurons for normal circadian locomotor activity. PMID- 24348202 TI - Addressing Trauma Among Women With Serious Addictive Disorders: Treatment Models, Program Factors, And Potential Mediators. AB - A large majority of women entering addiction treatment present significant symptoms of trauma related to physical or sexual abuse. Despite research indicating that trauma interventions are integral to women's successful recovery from addiction, many programs do not adequately address violence-related trauma. This chapter provides a review of the literature on trauma among women with addictive disorders and several manual based interventions developed to address co-occurring addiction and trauma-related disorders. One intervention, "Beyond Trauma," which has become increasingly popular among community based programs is described in detail. Beyond Trauma appears to have several advantages over other therapies for treating trauma and addiction in women, including 1) a theoretical foundation that draws on relational theory as a guide to the intervention, 2) a broad based approach that can be utilized by a variety of professional and paraprofessional staff members, 3) a focus that goes beyond treating women with a formal diagnosis of post traumatic stress disorder to include treatment for an array of symptoms and problems associated with trauma, and 4) gender-appropriate use of expressive arts in its curriculum. The chapter also discusses treatment program environment factors that may be critically important to treatment outcome for women: 1) whether the program is gender specific, 2) the degree of emphasis on peer involvement in recovery, 3) program recognition of the value of knowledge based recovery experience, 4) program facilitation of cohesion, 5) the empowerment of clients in decisions affecting the program and 6) skills training relevant to managing moods, relationships and a variety of problems that women face during recovery. Possible mechanisms of change for Beyond Trauma are explored with particular emphasis on the variety of ways the intervention attempts to impact problem areas experienced by women (e.g., mental health functioning self esteem and social support). Recommendations for future research in the treatment of trauma and addiction-related disorders in women are outlined. PMID- 24348204 TI - Artemisinin combination therapy: a good antimalarial, but is the dose right? PMID- 24348203 TI - Characterization of regional influenza seasonality patterns in China and implications for vaccination strategies: spatio-temporal modeling of surveillance data. AB - BACKGROUND: The complexity of influenza seasonal patterns in the inter-tropical zone impedes the establishment of effective routine immunization programs. China is a climatologically and economically diverse country, which has yet to establish a national influenza vaccination program. Here we characterize the diversity of influenza seasonality in China and make recommendations to guide future vaccination programs. METHODS AND FINDINGS: We compiled weekly reports of laboratory-confirmed influenza A and B infections from sentinel hospitals in cities representing 30 Chinese provinces, 2005-2011, and data on population demographics, mobility patterns, socio-economic, and climate factors. We applied linear regression models with harmonic terms to estimate influenza seasonal characteristics, including the amplitude of annual and semi-annual periodicities, their ratio, and peak timing. Hierarchical Bayesian modeling and hierarchical clustering were used to identify predictors of influenza seasonal characteristics and define epidemiologically-relevant regions. The annual periodicity of influenza A epidemics increased with latitude (mean amplitude of annual cycle standardized by mean incidence, 140% [95% CI 128%-151%] in the north versus 37% [95% CI 27%-47%] in the south, p<0.0001). Epidemics peaked in January-February in Northern China (latitude >=33 degrees N) and April-June in southernmost regions (latitude <27 degrees N). Provinces at intermediate latitudes experienced dominant semi-annual influenza A periodicity with peaks in January-February and June-August (periodicity ratio >0.6 in provinces located within 27.4 degrees N 31.3 degrees N, slope of latitudinal gradient with latitude -0.016 [95% CI -0.025 to -0.008], p<0.001). In contrast, influenza B activity predominated in colder months throughout most of China. Climate factors were the strongest predictors of influenza seasonality, including minimum temperature, hours of sunshine, and maximum rainfall. Our main study limitations include a short surveillance period and sparse influenza sampling in some of the southern provinces. CONCLUSIONS: Regional-specific influenza vaccination strategies would be optimal in China; in particular, annual campaigns should be initiated 4-6 months apart in Northern and Southern China. Influenza surveillance should be strengthened in mid-latitude provinces, given the complexity of seasonal patterns in this region. More broadly, our findings are consistent with the role of climatic factors on influenza transmission dynamics. Please see later in the article for the Editors' Summary. PMID- 24348205 TI - HIV-1 Protease and Substrate Coevolution Validates the Substrate Envelope As the Substrate Recognition Pattern. AB - Drug resistance of HIV-1 protease alters the balance in the molecular recognition events in favor of substrate processing versus inhibitor binding. To develop robust inhibitors targeting ensembles of drug-resistant variants, the code of this balance needs to be cracked. For this purpose, the principles governing the substrate recognition are required to be revealed. Previous crystallographic studies on the WT protease-substrate complexes showed that the substrates have a conserved consensus volume in the protease active site despite their low sequence homology. This consensus volume is termed as the substrate envelope. The substrate envelope was recently reevaluated by taking the substrate dynamics into account, and the dynamic substrate envelope was reported to better define the substrate specificity for HIV-1 protease. Drug resistance occurs mostly through mutations in the protease, occasionally accompanied by cleavage site mutations. In this study, three coevolved protease-substrate complexes (AP2VNC-p1V82A, LP1'Fp1-p6D30N/N88D, and SP3'Np1-p6D30N/N88D) were investigated for structural and dynamic properties by molecular modeling and dynamics simulations. The results show the substrate envelope is preserved by these cleavage site mutations in the presence of drug-resistance mutations in the protease, if not enhanced. This study on the conformational and mutational ensembles of protease-substrate complexes validates the substrate envelope as the substrate recognition motif for HIV-1 protease. The substrate envelope hypothesis allows for the elucidation of possible drug resistance mutation patterns in the polyprotein cleavage sites. PMID- 24348206 TI - High-Resolution Free-Energy Landscape Analysis of alpha-Helical Protein Folding: HP35 and Its Double Mutant. AB - The free-energy landscape can provide a quantitative description of folding dynamics, if determined as a function of an optimally chosen reaction coordinate. Here, we construct the optimal coordinate and the associated free-energy profile for all-helical proteins HP35 and its norleucine (Nle/Nle) double mutant, based on realistic equilibrium folding simulations [Piana et al. Proc. Natl. Acad. Sci. U.S.A.2012, 109, 17845]. From the obtained profiles, we directly determine such basic properties of folding dynamics as the configurations of the minima and transition states (TS), the formation of secondary structure and hydrophobic core during the folding process, the value of the pre-exponential factor and its relation to the transition path times, the relation between the autocorrelation times in TS and minima. We also present an investigation of the accuracy of the pre-exponential factor estimation based on the transition-path times. Four different estimations of the pre-exponential factor for both proteins give k0-1 values of approximately a few tens of nanoseconds. Our analysis gives detailed information about folding of the proteins and can serve as a rigorous common language for extensive comparison between experiment and simulation. PMID- 24348208 TI - Hypoxia and DNA repair. AB - Hypoxia is a characteristic feature of solid tumors and occurs very early in neoplastic development. Hypoxia transforms cell physiology in multiple ways, with profound changes in cell metabolism, cell growth, susceptibility to apoptosis, induction of angiogenesis, and increased motility. Over the past 20 years, our lab has determined that hypoxia also induces genetic instability. We have conducted a large series of experiments revealing that this instability occurs through the alteration of DNA repair pathways, including nucleotide excision repair, DNA mismatch repair, and homology dependent repair. Our work suggests that hypoxia, as a key component of solid tumors, can drive cancer progression through its impact on genomic integrity. However, the acquired changes in DNA repair that are induced by hypoxia may also render hypoxic cancer cells vulnerable to tailored strategies designed to exploit these changes. PMID- 24348209 TI - Investigations of homologous recombination pathways and their regulation. AB - The DNA double-strand break (DSB), arising from exposure to ionizing radiation or various chemotherapeutic agents or from replication fork collapse, is among the most dangerous of chromosomal lesions. DSBs are highly cytotoxic and can lead to translocations, deletions, duplications, or mutations if mishandled. DSBs are eliminated by either homologous recombination (HR), which uses a homologous template to guide accurate repair, or by nonhomologous end joining (NHEJ), which simply rejoins the two broken ends after damaged nucleotides have been removed. HR generates error-free repair products and is also required for generating chromosome arm crossovers between homologous chromosomes in meiotic cells. The HR reaction includes several distinct steps: resection of DNA ends, homologous DNA pairing, DNA synthesis, and processing of HR intermediates. Each occurs in a highly regulated fashion utilizing multiple protein factors. These steps are being elucidated using a combination of genetic tools, cell-based assays, and in vitro reconstitution with highly purified HR proteins. In this review, we summarize contributions from our laboratory at Yale University in understanding HR mechanisms in eukaryotic cells. PMID- 24348210 TI - Cellular roles of DNA polymerase beta. AB - Since its discovery and purification in 1971, DNA polymerase beta (Pol beta) is one of the most well-studied DNA polymerases. Pol beta is a key enzyme in the base excision repair (BER) pathway that functions in gap filling DNA synthesis subsequent to the excision of damaged DNA bases. A major focus of our studies is on the cellular roles of Pol beta. We have shown that germline and tumor associated variants of Pol beta catalyze aberrant BER that leads to genomic instability and cellular transformation. Our studies suggest that Pol beta is critical for the maintenance of genomic stability and that it is a tumor suppressor. We have also shown that Pol beta functions during Prophase I of meiosis. Pol beta localizes to the synaptonemal complex and is critical for removal of the Spo11 complex from the 5' ends of double-strand breaks. Studies with Pol beta mutant mice are currently being undertaken to more clearly understand the function of Pol beta during meiosis. In this review, we will highlight our contributions from our studies of Pol beta germline and cancer associated variants. PMID- 24348211 TI - Triplex-induced DNA damage response. AB - Cellular DNA damage response is critical to preserving genomic integrity following exposure to genotoxic stress. A complex series of networks and signaling pathways become activated after DNA damage and trigger the appropriate cellular response, including cell cycle arrest, DNA repair, and apoptosis. The response elicited is dependent upon the type and extent of damage sustained, with the ultimate goal of preventing propagation of the damaged DNA. A major focus of our studies is to determine the cellular pathways involved in processing damage induced by altered helical structures, specifically triplexes. Our lab has demonstrated that the TFIIH factor XPD occupies a central role in triggering apoptosis in response to triplex-induced DNA strand breaks. We have shown that XPD co-localizes with gammaH2AX, and its presence is required for the phosphorylation of H2AX tyrosine142, which stimulates the signaling pathway to recruit pro-apoptotic factors to the damage site. Herein, we examine the cellular pathways activated in response to triplex formation and discuss our finding that suggests that XPD-dependent apoptosis plays a role in preserving genomic integrity in the presence of excessive structurally induced DNA damage. PMID- 24348212 TI - BRCA2: one small step for DNA repair, one giant protein purified. AB - DNA damage, malfunctions in DNA repair, and genomic instability are processes that intersect at the crossroads of carcinogenesis. Underscoring the importance of DNA repair in breast and ovarian tumorigenesis is the familial inherited cancer predisposition gene BRCA2. The role of BRCA2 in DNA double-strand break repair was first revealed based on its interaction with RAD51, a central player in homologous recombination. The RAD51 protein forms a nucleoprotein filament on single-stranded DNA, invades a DNA duplex, and initiates a search for homology. Once a homologous DNA sequence is found, the DNA is used as a template for the high-fidelity repair of the DNA break. Many of the biochemical features that allow BRCA2 to choreograph the activities of RAD51 have been elucidated and include: targeting RAD51 to single-stranded DNA while inhibiting binding to dsDNA, reducing the ATPase activity of RAD51, and facilitating the displacement of the single-strand DNA binding protein, Replication Protein A. These reinforcing activities of BRCA2 culminate in the correct positioning of RAD51 onto a processed DNA double-strand break and initiate its faithful repair by homologous recombination. In this review, I will address current biochemical data concerning the BRCA2 protein and highlight unanswered questions regarding BRCA2 function in homologous recombination and cancer. PMID- 24348213 TI - Fanconi anemia: a signal transduction and DNA repair pathway. AB - Fanconi anemia (FA) is a fascinating, rare genetic disorder marked by congenital defects, bone marrow failure, and cancer susceptibility. Research in recent years has led to the elucidation of FA as a DNA repair disorder and involved multiple pathways as well as having wide applicability to common cancers, including breast, ovarian, and head and neck. This review will describe the clinical aspects of FA as well as the current state of its molecular pathophysiology. In particular, work from the Kupfer laboratory will be described that demonstrates how the FA pathway interacts with multiple DNA repair pathways, including the mismatch repair system and signal transduction pathway of the DNA damage response. PMID- 24348214 TI - Early days of DNA repair: discovery of nucleotide excision repair and homology dependent recombinational repair. AB - The discovery of nucleotide excision repair in 1964 showed that DNA could be repaired by a mechanism that removed the damaged section of a strand and replaced it accurately by using the remaining intact strand as the template. This result showed that DNA could be actively metabolized in a process that had no precedent. In 1968, experiments describing postreplication repair, a process dependent on homologous recombination, were reported. The authors of these papers were either at Yale University or had prior Yale connections. Here we recount some of the events leading to these discoveries and consider the impact on further research at Yale and elsewhere. PMID- 24348215 TI - DNA damage tolerance and a web of connections with DNA repair at Yale. AB - This short article summarizes some of the research carried out recently by my laboratory colleagues on the function of DNA polymerase zeta (polzeta) in mammalian cells. Some personal background is also described, relevant to research associations with Yale University and its continuing influence. Polzeta is involved in the bypass of many DNA lesions by translesion DNA synthesis and is responsible for the majority of DNA damage-induced point mutagenesis in mammalian cells (including human cells), as well as in yeast. We also found that the absence of this enzyme leads to gross chromosomal instability in mammalian cells and increased spontaneous tumorigenesis in mice. Recently, we discovered a further unexpectedly critical role for polzeta: it plays an essential role in allowing continued rapid proliferation of cells and tissues. These observations and others indicate that polzeta engages frequently during DNA replication to bypass and tolerate DNA lesions or unusual DNA structures that are barriers for the normal DNA replication machinery. PMID- 24348216 TI - The awakening of DNA repair at Yale. AB - As a graduate student with Professor Richard Setlow at Yale in the late 1950s, I studied the effects of ultraviolet and visible light on the syntheses of DNA, RNA, and protein in bacteria. I reflect upon my research in the Yale Biophysics Department, my subsequent postdoctoral experiences, and the eventual analyses in the laboratories of Setlow, Paul Howard-Flanders, and myself that constituted the discovery of the ubiquitous pathway of DNA excision repair in the early 1960s. I then offer a brief perspective on a few more recent developments in the burgeoning DNA repair field and their relationships to human disease. PMID- 24348217 TI - Nanotechnology in medicine: nanofilm biomaterials. AB - By interrogating nature at the length scale of important biological molecules (proteins, DNA), nanotechnology offers great promise to biomedicine. We review here our recent work on nanofilm biomaterials: "nanoscopically" thin, functional, polymer-based films serving as biocompatible interfaces. In one thrust, films containing carbon nanotubes are shown to be highly antimicrobial and, thus, to be promising as biomedical device materials inherently resistive to microbial infection. In another thrust, strategies are developed toward films of independently controllable bioactivity and mechanical rigidity - two key variables governing typical biological responses. PMID- 24348219 TI - How radiotherapy was historically used to treat pneumonia: could it be useful today? AB - X-ray therapy was used to treat pneumonia during the first half of the 20th century. Fifteen studies report that approximately 700 cases of bacterial (lobar and bronchopneumonia), sulfanilamide non-responsive, interstitial, and atypical pneumonia were effectively treated by low doses of X-rays, leading to disease resolution, based on clinical symptoms, objective disease biomarkers, and mortality incidence. The capacity of the X-ray treatment to reduce mortality was similar to serum therapy and sulfonamide treatment during the same time period. Studies with four experimental animal models (i.e., mice, guinea pig, cat, and dog) with bacterial and viral pneumonia supported the clinical findings. The mechanism by which the X-ray treatment acts upon pneumonia involves the induction of an anti-inflammatory phenotype that leads to a rapid reversal of clinical symptoms, facilitating disease resolution. The capacity of low doses of X-rays to suppress inflammatory responses is a significant new concept with widespread biomedical and therapeutic applications. PMID- 24348220 TI - Lost trust: a yellow fever patient response. AB - In the 19th century, yellow fever thrived in the tropical, urban trade centers along the American Gulf Coast. Industrializing and populated, New Orleans and Memphis made excellent habitats for the yellow fever-carrying Aedes aegypti mosquitoes and the virulence they imparted on their victims. Known for its jaundice and black, blood-filled vomit, the malady terrorized the region for decades, sometimes claiming tens of thousands of lives during the near annual summertime outbreaks. In response to the failing medical community, a small, pronounced population of sick and healthy laypeople openly criticized the efforts to rid the Gulf region of yellow jack. Utilizing newspapers and cartoons to vocalize their opinions, these critics doubted and mocked the medical community, contributing to the regional and seasonal dilemma yellow fever posed for the American South. These sentient expressions prove to be an early example of patient distrust toward caregivers, a current problem in clinical heath care. PMID- 24348218 TI - Microvascular targets for anti-fibrotic therapeutics. AB - Fibrosis is characterized by excessive extracellular matrix deposition and is the pathological outcome of repetitive tissue injury in many disorders. The accumulation of matrix disrupts the structure and function of the native tissue and can affect multiple organs including the lungs, heart, liver, and skin. Unfortunately, current therapies against the deadliest and most common fibrosis are ineffective. The pathogenesis of fibrosis is the result of aberrant wound healing, therefore, the microvasculature plays an important role, contributing through regulation of leukocyte recruitment, inflammation, and angiogenesis. Further exacerbating the condition, microvascular endothelial cells and pericytes can transdifferentiate into matrix depositing myofibroblasts. The contribution of the microvasculature to fibrotic progression makes its cellular components and acellular products attractive therapeutic targets. In this review, we examine many of the cytokine, matrix, and cellular microvascular components involved in fibrosis and discuss their potential as targets for fibrotic therapies with a particular focus on developing nanotechnologies. PMID- 24348221 TI - Near-peer teaching in a required third-year clerkship. AB - Students who teach less experienced students within the same educational program are known as near-peer teachers. A number of studies have shown that near-peers are effective teachers in preclinical courses such as anatomy and physical examination. We hypothesized that near-peers could also be effective teachers in a clinical clerkship. We report on a pilot study in which near-peers participated in a training session and then taught a brief problem-focused skills curriculum to third-year students during a required ambulatory medicine rotation. The clerkship students assigned high ratings to the near-peer teachers, both on an absolute scale and relative to faculty. The results suggest that including near peers as teachers in a clinical clerkship may be appropriate and that this concept deserves further investigation. PMID- 24348222 TI - Creating comprehensive, youth centered, culturally appropriate sex education: What do young gay, bisexual and questioning men want? AB - We examined young gay, bisexual and questioning men's (YGBQM) experiences with school-based sex education as they sought to learn about sex and sexual health, and their suggestions for improving same-sex education resources. Thematic analysis of 30 in-depth interviews with YGBQM (ages 18-24) underscored the discrepancies between the existing school-based sex education curricula and YGBQM's perceived sex education needs. Our results show that many youths' sexuality and same-sex sexual behaviors are excluded in sex education lessons; however, YGBQM noted that they sought out other resources (e.g., websites) to answer their questions. We discuss YGBQM's ideas for the creation of a sex and sexual health website that would be tailored for youth like themselves, including topics and features that an ideal website would contain. In addition, we present recommended changes to existing school-based sexual education curricula. PMID- 24348223 TI - Heterogeneity, mixing, and the spatial scales of mosquito-borne pathogen transmission. AB - The Ross-Macdonald model has dominated theory for mosquito-borne pathogen transmission dynamics and control for over a century. The model, like many other basic population models, makes the mathematically convenient assumption that populations are well mixed; i.e., that each mosquito is equally likely to bite any vertebrate host. This assumption raises questions about the validity and utility of current theory because it is in conflict with preponderant empirical evidence that transmission is heterogeneous. Here, we propose a new dynamic framework that is realistic enough to describe biological causes of heterogeneous transmission of mosquito-borne pathogens of humans, yet tractable enough to provide a basis for developing and improving general theory. The framework is based on the ecological context of mosquito blood meals and the fine-scale movements of individual mosquitoes and human hosts that give rise to heterogeneous transmission. Using this framework, we describe pathogen dispersion in terms of individual-level analogues of two classical quantities: vectorial capacity and the basic reproductive number, R0. Importantly, this framework explicitly accounts for three key components of overall heterogeneity in transmission: heterogeneous exposure, poor mixing, and finite host numbers. Using these tools, we propose two ways of characterizing the spatial scales of transmission--pathogen dispersion kernels and the evenness of mixing across scales of aggregation--and demonstrate the consequences of a model's choice of spatial scale for epidemic dynamics and for estimation of R0, both by a priori model formulas and by inference of the force of infection from time-series data. PMID- 24348224 TI - Next-generation sequence assembly: four stages of data processing and computational challenges. AB - Decoding DNA symbols using next-generation sequencers was a major breakthrough in genomic research. Despite the many advantages of next-generation sequencers, e.g., the high-throughput sequencing rate and relatively low cost of sequencing, the assembly of the reads produced by these sequencers still remains a major challenge. In this review, we address the basic framework of next-generation genome sequence assemblers, which comprises four basic stages: preprocessing filtering, a graph construction process, a graph simplification process, and postprocessing filtering. Here we discuss them as a framework of four stages for data analysis and processing and survey variety of techniques, algorithms, and software tools used during each stage. We also discuss the challenges that face current assemblers in the next-generation environment to determine the current state-of-the-art. We recommend a layered architecture approach for constructing a general assembler that can handle the sequences generated by different sequencing platforms. PMID- 24348225 TI - Epidemic spread on weighted networks. AB - The contact structure between hosts shapes disease spread. Most network-based models used in epidemiology tend to ignore heterogeneity in the weighting of contacts between two individuals. However, this assumption is known to be at odds with the data for many networks (e.g. sexual contact networks) and to have a critical influence on epidemics' behavior. One of the reasons why models usually ignore heterogeneity in transmission is that we currently lack tools to analyze weighted networks, such that most studies rely on numerical simulations. Here, we present a novel framework to estimate key epidemiological variables, such as the rate of early epidemic expansion (r0) and the basic reproductive ratio (R0), from joint probability distributions of number of partners (contacts) and number of interaction events through which contacts are weighted. These distributions are much easier to infer than the exact shape of the network, which makes the approach widely applicable. The framework also allows for a derivation of the full time course of epidemic prevalence and contact behaviour, which we validate with numerical simulations on networks. Overall, incorporating more realistic contact networks into epidemiological models can improve our understanding of the emergence and spread of infectious diseases. PMID- 24348226 TI - Metabolic constraint-based refinement of transcriptional regulatory networks. AB - There is a strong need for computational frameworks that integrate different biological processes and data-types to unravel cellular regulation. Current efforts to reconstruct transcriptional regulatory networks (TRNs) focus primarily on proximal data such as gene co-expression and transcription factor (TF) binding. While such approaches enable rapid reconstruction of TRNs, the overwhelming combinatorics of possible networks limits identification of mechanistic regulatory interactions. Utilizing growth phenotypes and systems level constraints to inform regulatory network reconstruction is an unmet challenge. We present our approach Gene Expression and Metabolism Integrated for Network Inference (GEMINI) that links a compendium of candidate regulatory interactions with the metabolic network to predict their systems-level effect on growth phenotypes. We then compare predictions with experimental phenotype data to select phenotype-consistent regulatory interactions. GEMINI makes use of the observation that only a small fraction of regulatory network states are compatible with a viable metabolic network, and outputs a regulatory network that is simultaneously consistent with the input genome-scale metabolic network model, gene expression data, and TF knockout phenotypes. GEMINI preferentially recalls gold-standard interactions (p-value = 10(-172)), significantly better than using gene expression alone. We applied GEMINI to create an integrated metabolic regulatory network model for Saccharomyces cerevisiae involving 25,000 regulatory interactions controlling 1597 metabolic reactions. The model quantitatively predicts TF knockout phenotypes in new conditions (p-value = 10(-14)) and revealed potential condition-specific regulatory mechanisms. Our results suggest that a metabolic constraint-based approach can be successfully used to help reconstruct TRNs from high-throughput data, and highlights the potential of using a biochemically-detailed mechanistic framework to integrate and reconcile inconsistencies across different data-types. The algorithm and associated data are available at https://sourceforge.net/projects/gemini-data/ PMID- 24348228 TI - Time scales in epigenetic dynamics and phenotypic heterogeneity of embryonic stem cells. AB - A remarkable feature of the self-renewing population of embryonic stem cells (ESCs) is their phenotypic heterogeneity: Nanog and other marker proteins of ESCs show large cell-to-cell variation in their expression level, which should significantly influence the differentiation process of individual cells. The molecular mechanism and biological implication of this heterogeneity, however, still remain elusive. We address this problem by constructing a model of the core gene-network of mouse ESCs. The model takes account of processes of binding/unbinding of transcription factors, formation/dissolution of transcription apparatus, and modification of histone code at each locus of genes in the network. These processes are hierarchically interrelated to each other forming the dynamical feedback loops. By simulating stochastic dynamics of this model, we show that the phenotypic heterogeneity of ESCs can be explained when the chromatin at the Nanog locus undergoes the large scale reorganization in formation/dissolution of transcription apparatus, which should have the timescale similar to the cell cycle period. With this slow transcriptional switching of Nanog, the simulated ESCs fluctuate among multiple transient states, which can trigger the differentiation into the lineage-specific cell states. From the simulated transitions among cell states, the epigenetic landscape underlying transitions is calculated. The slow Nanog switching gives rise to the wide basin of ESC states in the landscape. The bimodal Nanog distribution arising from the kinetic flow running through this ESC basin prevents transdifferentiation and promotes the definite decision of the cell fate. These results show that the distribution of timescales of the regulatory processes is decisively important to characterize the fluctuation of cells and their differentiation process. The analyses through the epigenetic landscape and the kinetic flow on the landscape should provide a guideline to engineer cell differentiation. PMID- 24348227 TI - Decipher the mechanisms of protein conformational changes induced by nucleotide binding through free-energy landscape analysis: ATP binding to Hsp70. AB - ATP regulates the function of many proteins in the cell by transducing its binding and hydrolysis energies into protein conformational changes by mechanisms which are challenging to identify at the atomic scale. Based on molecular dynamics (MD) simulations, a method is proposed to analyze the structural changes induced by ATP binding to a protein by computing the effective free-energy landscape (FEL) of a subset of its coordinates along its amino-acid sequence. The method is applied to characterize the mechanism by which the binding of ATP to the nucleotide-binding domain (NBD) of Hsp70 propagates a signal to its substrate binding domain (SBD). Unbiased MD simulations were performed for Hsp70-DnaK chaperone in nucleotide-free, ADP-bound and ATP-bound states. The simulations revealed that the SBD does not interact with the NBD for DnaK in its nucleotide free and ADP-bound states whereas the docking of the SBD was found in the ATP bound state. The docked state induced by ATP binding found in MD is an intermediate state between the initial nucleotide-free and final ATP-bound states of Hsp70. The analysis of the FEL projected along the amino-acid sequence permitted to identify a subset of 27 protein internal coordinates corresponding to a network of 91 key residues involved in the conformational change induced by ATP binding. Among the 91 residues, 26 are identified for the first time, whereas the others were shown relevant for the allosteric communication of Hsp70 s in several experiments and bioinformatics analysis. The FEL analysis revealed also the origin of the ATP-induced structural modifications of the SBD recently measured by Electron Paramagnetic Resonance. The pathway between the nucleotide free and the intermediate state of DnaK was extracted by applying principal component analysis to the subset of internal coordinates describing the transition. The methodology proposed is general and could be applied to analyze allosteric communication in other proteins. PMID- 24348229 TI - Amino acid changes in disease-associated variants differ radically from variants observed in the 1000 genomes project dataset. AB - The 1000 Genomes Project data provides a natural background dataset for amino acid germline mutations in humans. Since the direction of mutation is known, the amino acid exchange matrix generated from the observed nucleotide variants is asymmetric and the mutabilities of the different amino acids are very different. These differences predominantly reflect preferences for nucleotide mutations in the DNA (especially the high mutation rate of the CpG dinucleotide, which makes arginine mutability very much higher than other amino acids) rather than selection imposed by protein structure constraints, although there is evidence for the latter as well. The variants occur predominantly on the surface of proteins (82%), with a slight preference for sites which are more exposed and less well conserved than random. Mutations to functional residues occur about half as often as expected by chance. The disease-associated amino acid variant distributions in OMIM are radically different from those expected on the basis of the 1000 Genomes dataset. The disease-associated variants preferentially occur in more conserved sites, compared to 1000 Genomes mutations. Many of the amino acid exchange profiles appear to exhibit an anti-correlation, with common exchanges in one dataset being rare in the other. Disease-associated variants exhibit more extreme differences in amino acid size and hydrophobicity. More modelling of the mutational processes at the nucleotide level is needed, but these observations should contribute to an improved prediction of the effects of specific variants in humans. PMID- 24348230 TI - Forward and backward inference in spatial cognition. AB - This paper shows that the various computations underlying spatial cognition can be implemented using statistical inference in a single probabilistic model. Inference is implemented using a common set of 'lower-level' computations involving forward and backward inference over time. For example, to estimate where you are in a known environment, forward inference is used to optimally combine location estimates from path integration with those from sensory input. To decide which way to turn to reach a goal, forward inference is used to compute the likelihood of reaching that goal under each option. To work out which environment you are in, forward inference is used to compute the likelihood of sensory observations under the different hypotheses. For reaching sensory goals that require a chaining together of decisions, forward inference can be used to compute a state trajectory that will lead to that goal, and backward inference to refine the route and estimate control signals that produce the required trajectory. We propose that these computations are reflected in recent findings of pattern replay in the mammalian brain. Specifically, that theta sequences reflect decision making, theta flickering reflects model selection, and remote replay reflects route and motor planning. We also propose a mapping of the above computational processes onto lateral and medial entorhinal cortex and hippocampus. PMID- 24348231 TI - Modeling the afferent dynamics of the baroreflex control system. AB - In this study we develop a modeling framework for predicting baroreceptor firing rate as a function of blood pressure. We test models within this framework both quantitatively and qualitatively using data from rats. The models describe three components: arterial wall deformation, stimulation of mechanoreceptors located in the BR nerve-endings, and modulation of the action potential frequency. The three sub-systems are modeled individually following well-established biological principles. The first submodel, predicting arterial wall deformation, uses blood pressure as an input and outputs circumferential strain. The mechanoreceptor stimulation model, uses circumferential strain as an input, predicting receptor deformation as an output. Finally, the neural model takes receptor deformation as an input predicting the BR firing rate as an output. Our results show that nonlinear dependence of firing rate on pressure can be accounted for by taking into account the nonlinear elastic properties of the artery wall. This was observed when testing the models using multiple experiments with a single set of parameters. We find that to model the response to a square pressure stimulus, giving rise to post-excitatory depression, it is necessary to include an integrate-and-fire model, which allows the firing rate to cease when the stimulus falls below a given threshold. We show that our modeling framework in combination with sensitivity analysis and parameter estimation can be used to test and compare models. Finally, we demonstrate that our preferred model can exhibit all known dynamics and that it is advantageous to combine qualitative and quantitative analysis methods. PMID- 24348233 TI - Moving education forward, again! PMID- 24348232 TI - Ecological modeling from time-series inference: insight into dynamics and stability of intestinal microbiota. AB - The intestinal microbiota is a microbial ecosystem of crucial importance to human health. Understanding how the microbiota confers resistance against enteric pathogens and how antibiotics disrupt that resistance is key to the prevention and cure of intestinal infections. We present a novel method to infer microbial community ecology directly from time-resolved metagenomics. This method extends generalized Lotka-Volterra dynamics to account for external perturbations. Data from recent experiments on antibiotic-mediated Clostridium difficile infection is analyzed to quantify microbial interactions, commensal-pathogen interactions, and the effect of the antibiotic on the community. Stability analysis reveals that the microbiota is intrinsically stable, explaining how antibiotic perturbations and C. difficile inoculation can produce catastrophic shifts that persist even after removal of the perturbations. Importantly, the analysis suggests a subnetwork of bacterial groups implicated in protection against C. difficile. Due to its generality, our method can be applied to any high-resolution ecological time-series data to infer community structure and response to external stimuli. PMID- 24348234 TI - Education in computational biology today and tomorrow. PMID- 24348235 TI - Inferring developmental stage composition from gene expression in human malaria. AB - In the current era of malaria eradication, reducing transmission is critical. Assessment of transmissibility requires tools that can accurately identify the various developmental stages of the malaria parasite, particularly those required for transmission (sexual stages). Here, we present a method for estimating relative amounts of Plasmodium falciparum asexual and sexual stages from gene expression measurements. These are modeled using constrained linear regression to characterize stage-specific expression profiles within mixed-stage populations. The resulting profiles were analyzed functionally by gene set enrichment analysis (GSEA), confirming differentially active pathways such as increased mitochondrial activity and lipid metabolism during sexual development. We validated model predictions both from microarrays and from quantitative RT-PCR (qRT-PCR) measurements, based on the expression of a small set of key transcriptional markers. This sufficient marker set was identified by backward selection from the whole genome as available from expression arrays, targeting one sentinel marker per stage. The model as learned can be applied to any new microarray or qRT-PCR transcriptional measurement. We illustrate its use in vitro in inferring changes in stage distribution following stress and drug treatment and in vivo in identifying immature and mature sexual stage carriers within patient cohorts. We believe this approach will be a valuable resource for staging lab and field samples alike and will have wide applicability in epidemiological studies of malaria transmission. PMID- 24348236 TI - Exploring early stages of the chemical unfolding of proteins at the proteome scale. AB - After decades of using urea as denaturant, the kinetic role of this molecule in the unfolding process is still undefined: does urea actively induce protein unfolding or passively stabilize the unfolded state? By analyzing a set of 30 proteins (representative of all native folds) through extensive molecular dynamics simulations in denaturant (using a range of force-fields), we derived robust rules for urea unfolding that are valid at the proteome level. Irrespective of the protein fold, presence or absence of disulphide bridges, and secondary structure composition, urea concentrates in the first solvation shell of quasi-native proteins, but with a density lower than that of the fully unfolded state. The presence of urea does not alter the spontaneous vibration pattern of proteins. In fact, it reduces the magnitude of such vibrations, leading to a counterintuitive slow down of the atomic-motions that opposes unfolding. Urea stickiness and slow diffusion is, however, crucial for unfolding. Long residence urea molecules placed around the hydrophobic core are crucial to stabilize partially open structures generated by thermal fluctuations. Our simulations indicate that although urea does not favor the formation of partially open microstates, it is not a mere spectator of unfolding that simply displaces to the right of the folded <--> unfolded equilibrium. On the contrary, urea actively favors unfolding: it selects and stabilizes partially unfolded microstates, slowly driving the protein conformational ensemble far from the native one and also from the conformations sampled during thermal unfolding. PMID- 24348237 TI - GDI-mediated cell polarization in yeast provides precise spatial and temporal control of Cdc42 signaling. AB - Cell polarization is a prerequisite for essential processes such as cell migration, proliferation or differentiation. The yeast Saccharomyces cerevisiae under control of the GTPase Cdc42 is able to polarize without the help of cytoskeletal structures and spatial cues through a pathway depending on its guanine nucleotide dissociation inhibitor (GDI) Rdi1. To develop a fundamental understanding of yeast polarization we establish a detailed mechanistic model of GDI-mediated polarization. We show that GDI-mediated polarization provides precise spatial and temporal control of Cdc42 signaling and give experimental evidence for our findings. Cell cycle induced changes of Cdc42 regulation enhance positive feedback loops of active Cdc42 production, and thereby allow simultaneous switch-like regulation of focused polarity and Cdc42 activation. This regulation drives the direct formation of a unique polarity cluster with characteristic narrowing dynamics, as opposed to the previously proposed competition between transient clusters. As the key components of the studied system are conserved among eukaryotes, we expect our findings also to apply to cell polarization in other organisms. PMID- 24348239 TI - Aspergillus fumigatus--what makes the species a ubiquitous human fungal pathogen? PMID- 24348240 TI - Dual expression profile of type VI secretion system immunity genes protects pandemic Vibrio cholerae. AB - The Vibrio cholerae type VI secretion system (T6SS) assembles as a molecular syringe that injects toxic protein effectors into both eukaryotic and prokaryotic cells. We previously reported that the V. cholerae O37 serogroup strain V52 maintains a constitutively active T6SS to kill other Gram-negative bacteria while being immune to attack by kin bacteria. The pandemic O1 El Tor V. cholerae strain C6706 is T6SS-silent under laboratory conditions as it does not produce T6SS structural components and effectors, and fails to kill Escherichia coli prey. Yet, C6706 exhibits full resistance when approached by T6SS-active V52. These findings suggested that an active T6SS is not required for immunity against T6SS mediated virulence. Here, we describe a dual expression profile of the T6SS immunity protein-encoding genes tsiV1, tsiV2, and tsiV3 that provides pandemic V. cholerae strains with T6SS immunity and allows T6SS-silent strains to maintain immunity against attacks by T6SS-active bacterial neighbors. The dual expression profile allows transcription of the three genes encoding immunity proteins independently of other T6SS proteins encoded within the same operon. One of these immunity proteins, TsiV2, protects against the T6SS effector VasX which is encoded immediately upstream of tsiV2. VasX is a secreted, lipid-binding protein that we previously characterized with respect to T6SS-mediated virulence towards the social amoeba Dictyostelium discoideum. Our data suggest the presence of an internal promoter in the open reading frame of vasX that drives expression of the downstream gene tsiV2. Furthermore, VasX is shown to act in conjunction with VasW, an accessory protein to VasX, to compromise the inner membrane of prokaryotic target cells. The dual regulatory profile of the T6SS immunity protein-encoding genes tsiV1, tsiV2, and tsiV3 permits V. cholerae to tightly control T6SS gene expression while maintaining immunity to T6SS activity. PMID- 24348241 TI - Coronaviruses as DNA wannabes: a new model for the regulation of RNA virus replication fidelity. PMID- 24348243 TI - Innate lymphoid cells: new players in IL-17-mediated antifungal immunity. PMID- 24348242 TI - The type-specific neutralizing antibody response elicited by a dengue vaccine candidate is focused on two amino acids of the envelope protein. AB - Dengue viruses are mosquito-borne flaviviruses that circulate in nature as four distinct serotypes (DENV1-4). These emerging pathogens are responsible for more than 100 million human infections annually. Severe clinical manifestations of disease are predominantly associated with a secondary infection by a heterotypic DENV serotype. The increased risk of severe disease in DENV-sensitized populations significantly complicates vaccine development, as a vaccine must simultaneously confer protection against all four DENV serotypes. Eliciting a protective tetravalent neutralizing antibody response is a major goal of ongoing vaccine development efforts. However, a recent large clinical trial of a candidate live-attenuated DENV vaccine revealed low protective efficacy despite eliciting a neutralizing antibody response, highlighting the need for a better understanding of the humoral immune response against dengue infection. In this study, we sought to identify epitopes recognized by serotype-specific neutralizing antibodies elicited by monovalent DENV1 vaccination. We constructed a panel of over 50 DENV1 structural gene variants containing substitutions at surface-accessible residues of the envelope (E) protein to match the corresponding DENV2 sequence. Amino acids that contribute to recognition by serotype-specific neutralizing antibodies were identified as DENV mutants with reduced sensitivity to neutralization by DENV1 immune sera, but not cross reactive neutralizing antibodies elicited by DENV2 vaccination. We identified two mutations (E126K and E157K) that contribute significantly to type-specific recognition by polyclonal DENV1 immune sera. Longitudinal and cross-sectional analysis of sera from 24 participants of a phase I clinical study revealed a markedly reduced capacity to neutralize a E126K/E157K DENV1 variant. Sera from 77% of subjects recognized the E126K/E157K DENV1 variant and DENV2 equivalently (<3-fold difference). These data indicate the type-specific component of the DENV1 neutralizing antibody response to vaccination is strikingly focused on just two amino acids of the E protein. This study provides an important step towards deconvoluting the functional complexity of DENV serology following vaccination. PMID- 24348244 TI - Balancing stability and flexibility within the genome of the pathogen Cryptococcus neoformans. PMID- 24348245 TI - CRISPR-Cas immunity against phages: its effects on the evolution and survival of bacterial pathogens. PMID- 24348246 TI - Emerging functions for the Staphylococcus aureus RNome. AB - Staphylococcus aureus is a leading pathogen for animals and humans, not only being one of the most frequently isolated bacteria in hospital-associated infections but also causing diseases in the community. To coordinate the expression of its numerous virulence genes for growth and survival, S. aureus uses various signalling pathways that include two-component regulatory systems, transcription factors, and also around 250 regulatory RNAs. Biological roles have only been determined for a handful of these sRNAs, including cis, trans, and cis trans acting RNAs, some internally encoding small, functional peptides and others possessing dual or multiple functions. Here we put forward an inventory of these fascinating sRNAs; the proteins involved in their activities; and those involved in stress response, metabolisms, and virulence. PMID- 24348247 TI - LysM effectors: secreted proteins supporting fungal life. PMID- 24348248 TI - Tmprss2 is essential for influenza H1N1 virus pathogenesis in mice. AB - Annual influenza epidemics and occasional pandemics pose a severe threat to human health. Host cell factors required for viral spread but not for cellular survival are attractive targets for novel approaches to antiviral intervention. The cleavage activation of the influenza virus hemagglutinin (HA) by host cell proteases is essential for viral infectivity. However, it is unknown which proteases activate influenza viruses in mammals. Several candidates have been identified in cell culture studies, leading to the concept that influenza viruses can employ multiple enzymes to ensure their cleavage activation in the host. Here, we show that deletion of a single HA-activating protease gene, Tmprss2, in mice inhibits spread of mono-basic H1N1 influenza viruses, including the pandemic 2009 swine influenza virus. Lung pathology was strongly reduced and mutant mice were protected from weight loss, death and impairment of lung function. Also, after infection with mono-basic H3N2 influenza A virus body weight loss and survival was less severe in Tmprss2 mutant compared to wild type mice. As expected, Tmprss2-deficient mice were not protected from viral spread and pathology after infection with multi-basic H7N7 influenza A virus. In conclusion, these results identify TMPRSS2 as a host cell factor essential for viral spread and pathogenesis of mono-basic H1N1 and H3N2 influenza A viruses. PMID- 24348249 TI - Real-time imaging of the intracellular glutathione redox potential in the malaria parasite Plasmodium falciparum. AB - In the malaria parasite Plasmodium falciparum, the cellular redox potential influences signaling events, antioxidant defense, and mechanisms of drug action and resistance. Until now, the real-time determination of the redox potential in malaria parasites has been limited because conventional approaches disrupt sub cellular integrity. Using a glutathione biosensor comprising human glutaredoxin-1 linked to a redox-sensitive green fluorescent protein (hGrx1-roGFP2), we systematically characterized basal values and drug-induced changes in the cytosolic glutathione-dependent redox potential (EGSH) of drug-sensitive (3D7) and resistant (Dd2) P. falciparum parasites. Via confocal microscopy, we demonstrated that hGrx1-roGFP2 rapidly detects EGSH changes induced by oxidative and nitrosative stress. The cytosolic basal EGSH of 3D7 and Dd2 were estimated to be -314.2+/-3.1 mV and -313.9+/-3.4 mV, respectively, which is indicative of a highly reducing compartment. We furthermore monitored short-, medium-, and long term changes in EGSH after incubation with various redox-active compounds and antimalarial drugs. Interestingly, the redox cyclers methylene blue and pyocyanin rapidly changed the fluorescence ratio of hGrx1-roGFP2 in the cytosol of P. falciparum, which can, however, partially be explained by a direct interaction with the probe. In contrast, quinoline and artemisinin-based antimalarial drugs showed strong effects on the parasites' EGSH after longer incubation times (24 h). As tested for various conditions, these effects were accompanied by a drop in total glutathione concentrations determined in parallel with alternative methods. Notably, the effects were generally more pronounced in the chloroquine-sensitive 3D7 strain than in the resistant Dd2 strain. Based on these results hGrx1-roGFP2 can be recommended as a reliable and specific biosensor for real-time spatiotemporal monitoring of the intracellular EGSH in P. falciparum. Applying this technique in further studies will enhance our understanding of redox regulation and mechanisms of drug action and resistance in Plasmodium and might also stimulate redox research in other pathogens. PMID- 24348250 TI - Serotonergic chemosensory neurons modify the C. elegans immune response by regulating G-protein signaling in epithelial cells. AB - The nervous and immune systems influence each other, allowing animals to rapidly protect themselves from changes in their internal and external environment. However, the complex nature of these systems in mammals makes it difficult to determine how neuronal signaling influences the immune response. Here we show that serotonin, synthesized in Caenorhabditis elegans chemosensory neurons, modulates the immune response. Serotonin released from these cells acts, directly or indirectly, to regulate G-protein signaling in epithelial cells. Signaling in these cells is required for the immune response to infection by the natural pathogen Microbacterium nematophilum. Here we show that serotonin signaling suppresses the innate immune response and limits the rate of pathogen clearance. We show that C. elegans uses classical neurotransmitters to alter the immune response. Serotonin released from sensory neurons may function to modify the immune system in response to changes in the animal's external environment such as the availability, or quality, of food. PMID- 24348251 TI - Enterohemorrhagic Escherichia coli hemolysin employs outer membrane vesicles to target mitochondria and cause endothelial and epithelial apoptosis. AB - Enterohemorrhagic Escherichia coli (EHEC) strains cause diarrhea and hemolytic uremic syndrome resulting from toxin-mediated microvascular endothelial injury. EHEC hemolysin (EHEC-Hly), a member of the RTX (repeats-in-toxin) family, is an EHEC virulence factor of increasingly recognized importance. The toxin exists as free EHEC-Hly and as EHEC-Hly associated with outer membrane vesicles (OMVs) released by EHEC during growth. Whereas the free toxin is lytic towards human endothelium, the biological effects of the OMV-associated EHEC-Hly on microvascular endothelial and intestinal epithelial cells, which are the major targets during EHEC infection, are unknown. Using microscopic, biochemical, flow cytometry and functional analyses of human brain microvascular endothelial cells (HBMEC) and Caco-2 cells we demonstrate that OMV-associated EHEC-Hly does not lyse the target cells but triggers their apoptosis. The OMV-associated toxin is internalized by HBMEC and Caco-2 cells via dynamin-dependent endocytosis of OMVs and trafficked with OMVs into endo-lysosomal compartments. Upon endosome acidification and subsequent pH drop, EHEC-Hly is separated from OMVs, escapes from the lysosomes, most probably via its pore-forming activity, and targets mitochondria. This results in decrease of the mitochondrial transmembrane potential and translocation of cytochrome c to the cytosol, indicating EHEC-Hly mediated permeabilization of the mitochondrial membranes. Subsequent activation of caspase-9 and caspase-3 leads to apoptotic cell death as evidenced by DNA fragmentation and chromatin condensation in the intoxicated cells. The ability of OMV-associated EHEC-Hly to trigger the mitochondrial apoptotic pathway in human microvascular endothelial and intestinal epithelial cells indicates a novel mechanism of EHEC-Hly involvement in the pathogenesis of EHEC diseases. The OMV mediated intracellular delivery represents a newly recognized mechanism for a bacterial toxin to enter host cells in order to target mitochondria. PMID- 24348252 TI - The genetic basis of Escherichia coli pathoadaptation to macrophages. AB - Antagonistic interactions are likely important driving forces of the evolutionary process underlying bacterial genome complexity and diversity. We hypothesized that the ability of evolved bacteria to escape specific components of host innate immunity, such as phagocytosis and killing by macrophages (MPhi), is a critical trait relevant in the acquisition of bacterial virulence. Here, we used a combination of experimental evolution, phenotypic characterization, genome sequencing and mathematical modeling to address how fast, and through how many adaptive steps, a commensal Escherichia coli (E. coli) acquire this virulence trait. We show that when maintained in vitro under the selective pressure of host MPhi commensal E. coli can evolve, in less than 500 generations, virulent clones that escape phagocytosis and MPhi killing in vitro, while increasing their pathogenicity in vivo, as assessed in mice. This pathoadaptive process is driven by a mechanism involving the insertion of a single transposable element into the promoter region of the E. coli yrfF gene. Moreover, transposition of the IS186 element into the promoter of Lon gene, encoding an ATP-dependent serine protease, is likely to accelerate this pathoadaptive process. Competition between clones carrying distinct beneficial mutations dominates the dynamics of the pathoadaptive process, as suggested from a mathematical model, which reproduces the observed experimental dynamics of E. coli evolution towards virulence. In conclusion, we reveal a molecular mechanism explaining how a specific component of host innate immunity can modulate microbial evolution towards pathogenicity. PMID- 24348253 TI - Semen CD4+ T cells and macrophages are productively infected at all stages of SIV infection in macaques. AB - The mucosal events of HIV transmission have been extensively studied, but the role of infected cells present in the genital and rectal secretions, and in the semen, in particular, remains a matter of debate. As a prerequisite to a thorough in vivo investigation of the early transmission events through infected cells, we characterized in detail by multi-parameter flow cytometry the changes in macaque seminal leukocytes during SIVmac251 infection, focusing on T cells, macrophages and dendritic cells. Using immunocytofluorescence targeting SIV proteins and real time quantitative PCR targeting SIV DNA, we investigated the nature of the infected cells on sorted semen leukocytes from macaques at different stages of infection. Finally, we cocultured semen CD4(+) T cells and macrophages with a cell line permissive to SIV infection to assess their infectivity in vitro. We found that primary infection induced strong local inflammation, which was associated with an increase in the number of leukocytes in semen, both factors having the potential to favor cell-associated virus transmission. Semen CD4(+) T cells and macrophages were productively infected at all stages of infection and were infectious in vitro. Lymphocytes had a mucosal phenotype and expressed activation (CD69 & HLA-DR) and migration (CCR5, CXCR4, LFA-1) markers. CD69 expression was increased in semen T cells by SIV infection, at all stages of infection. Macrophages predominated at all stages and expressed CD4, CCR5, MAC-1 and LFA-1. Altogether, we demonstrated that semen contains the two major SIV target cells (CD4+ T cells and macrophages). Both cell types can be productively infected at all stages of SIV infection and are endowed with markers that may facilitate transmission of infection during sexual exposure. PMID- 24348254 TI - The malarial serine protease SUB1 plays an essential role in parasite liver stage development. AB - Transmission of the malaria parasite to its vertebrate host involves an obligatory exoerythrocytic stage in which extensive asexual replication of the parasite takes place in infected hepatocytes. The resulting liver schizont undergoes segmentation to produce thousands of daughter merozoites. These are released to initiate the blood stage life cycle, which causes all the pathology associated with the disease. Whilst elements of liver stage merozoite biology are similar to those in the much better-studied blood stage merozoites, little is known of the molecular players involved in liver stage merozoite production. To facilitate the study of liver stage biology we developed a strategy for the rapid production of complex conditional alleles by recombinase mediated engineering in Escherichia coli, which we used in combination with existing Plasmodium berghei deleter lines expressing Flp recombinase to study subtilisin-like protease 1 (SUB1), a conserved Plasmodium serine protease previously implicated in blood stage merozoite maturation and egress. We demonstrate that SUB1 is not required for the early stages of intrahepatic growth, but is essential for complete development of the liver stage schizont and for production of hepatic merozoites. Our results indicate that inhibitors of SUB1 could be used in prophylactic approaches to control or block the clinically silent pre-erythrocytic stage of the malaria parasite life cycle. PMID- 24348255 TI - Phagocytosis escape by a Staphylococcus aureus protein that connects complement and coagulation proteins at the bacterial surface. AB - Upon contact with human plasma, bacteria are rapidly recognized by the complement system that labels their surface for uptake and clearance by phagocytic cells. Staphylococcus aureus secretes the 16 kD Extracellular fibrinogen binding protein (Efb) that binds two different plasma proteins using separate domains: the Efb N terminus binds to fibrinogen, while the C-terminus binds complement C3. In this study, we show that Efb blocks phagocytosis of S. aureus by human neutrophils. In vitro, we demonstrate that Efb blocks phagocytosis in plasma and in human whole blood. Using a mouse peritonitis model we show that Efb effectively blocks phagocytosis in vivo, either as a purified protein or when produced endogenously by S. aureus. Mutational analysis revealed that Efb requires both its fibrinogen and complement binding residues for phagocytic escape. Using confocal and transmission electron microscopy we show that Efb attracts fibrinogen to the surface of complement-labeled S. aureus generating a 'capsule'-like shield. This thick layer of fibrinogen shields both surface-bound C3b and antibodies from recognition by phagocytic receptors. This information is critical for future vaccination attempts, since opsonizing antibodies may not function in the presence of Efb. Altogether we discover that Efb from S. aureus uniquely escapes phagocytosis by forming a bridge between a complement and coagulation protein. PMID- 24348256 TI - Placental syncytium forms a biophysical barrier against pathogen invasion. AB - Fetal syncytiotrophoblasts form a unique fused multinuclear surface that is bathed in maternal blood, and constitutes the main interface between fetus and mother. Syncytiotrophoblasts are exposed to pathogens circulating in maternal blood, and appear to have unique resistance mechanisms against microbial invasion. These are due in part to the lack of intercellular junctions and their receptors, the Achilles heel of polarized mononuclear epithelia. However, the syncytium is immune to receptor-independent invasion as well, suggesting additional general defense mechanisms against infection. The difficulty of maintaining and manipulating primary human syncytiotrophoblasts in culture makes it challenging to investigate the cellular and molecular basis of host defenses in this unique tissue. Here we present a novel system to study placental pathogenesis using murine trophoblast stem cells (mTSC) that can be differentiated into syncytiotrophoblasts and recapitulate human placental syncytium. Consistent with previous results in primary human organ cultures, murine syncytiotrophoblasts were found to be resistant to infection with Listeria monocytogenes via direct invasion and cell-to-cell spread. Atomic force microscopy of murine syncytiotrophoblasts demonstrated that these cells have a greater elastic modulus than mononuclear trophoblasts. Disruption of the unusually dense actin structure--a diffuse meshwork of microfilaments--with Cytochalasin D led to a decrease in its elastic modulus by 25%. This correlated with a small but significant increase in invasion of L. monocytogenes into murine and human syncytium. These results suggest that the syncytial actin cytoskeleton may form a general barrier against pathogen entry in humans and mice. Moreover, murine TSCs are a genetically tractable model system for the investigation of specific pathways in syncytial host defenses. PMID- 24348257 TI - Nodular inflammatory foci are sites of T cell priming and control of murine cytomegalovirus infection in the neonatal lung. AB - Neonates, including mice and humans, are highly susceptible to cytomegalovirus (CMV) infection. However, many aspects of neonatal CMV infections such as viral cell tropism, spatio-temporal distribution of the pathogen as well as genesis of antiviral immunity are unknown. With the use of reporter mutants of the murine cytomegalovirus (MCMV) we identified the lung as a primary target of mucosal infection in neonatal mice. Comparative analysis of neonatal and adult mice revealed a delayed control of virus replication in the neonatal lung mucosa explaining the pronounced systemic infection and disease in neonates. This phenomenon was supplemented by a delayed expansion of CD8(+) T cell clones recognizing the viral protein M45 in neonates. We detected viral infection at the single-cell level and observed myeloid cells forming "nodular inflammatory foci" (NIF) in the neonatal lung. Co-localization of infected cells within NIFs was associated with their disruption and clearance of the infection. By 2-photon microscopy, we characterized how neonatal antigen-presenting cells (APC) interacted with T cells and induced mature adaptive immune responses within such NIFs. We thus define NIFs of the neonatal lung as niches for prolonged MCMV replication and T cell priming but also as sites of infection control. PMID- 24348259 TI - Wolbachia variants induce differential protection to viruses in Drosophila melanogaster: a phenotypic and phylogenomic analysis. AB - Wolbachia are intracellular bacterial symbionts that are able to protect various insect hosts from viral infections. This tripartite interaction was initially described in Drosophila melanogaster carrying wMel, its natural Wolbachia strain. wMel has been shown to be genetically polymorphic and there has been a recent change in variant frequencies in natural populations. We have compared the antiviral protection conferred by different wMel variants, their titres and influence on host longevity, in a genetically identical D. melanogaster host. The phenotypes cluster the variants into two groups--wMelCS-like and wMel-like. wMelCS-like variants give stronger protection against Drosophila C virus and Flock House virus, reach higher titres and often shorten the host lifespan. We have sequenced and assembled the genomes of these Wolbachia, and shown that the two phenotypic groups are two monophyletic groups. We have also analysed a virulent and over-replicating variant, wMelPop, which protects D. melanogaster even better than the closely related wMelCS. We have found that a ~21 kb region of the genome, encoding eight genes, is amplified seven times in wMelPop and may be the cause of its phenotypes. Our results indicate that the more protective wMelCS-like variants, which sometimes have a cost, were replaced by the less protective but more benign wMel-like variants. This has resulted in a recent reduction in virus resistance in D. melanogaster in natural populations worldwide. Our work helps to understand the natural variation in wMel and its evolutionary dynamics, and inform the use of Wolbachia in arthropod-borne disease control. PMID- 24348260 TI - Role of tomato lipoxygenase D in wound-induced jasmonate biosynthesis and plant immunity to insect herbivores. AB - In response to insect attack and mechanical wounding, plants activate the expression of genes involved in various defense-related processes. A fascinating feature of these inducible defenses is their occurrence both locally at the wounding site and systemically in undamaged leaves throughout the plant. Wound inducible proteinase inhibitors (PIs) in tomato (Solanum lycopersicum) provide an attractive model to understand the signal transduction events leading from localized injury to the systemic expression of defense-related genes. Among the identified intercellular molecules in regulating systemic wound response of tomato are the peptide signal systemin and the oxylipin signal jasmonic acid (JA). The systemin/JA signaling pathway provides a unique opportunity to investigate, in a single experimental system, the mechanism by which peptide and oxylipin signals interact to coordinate plant systemic immunity. Here we describe the characterization of the tomato suppressor of prosystemin-mediated responses8 (spr8) mutant, which was isolated as a suppressor of (pro)systemin-mediated signaling. spr8 plants exhibit a series of JA-dependent immune deficiencies, including the inability to express wound-responsive genes, abnormal development of glandular trichomes, and severely compromised resistance to cotton bollworm (Helicoverpa armigera) and Botrytis cinerea. Map-based cloning studies demonstrate that the spr8 mutant phenotype results from a point mutation in the catalytic domain of TomLoxD, a chloroplast-localized lipoxygenase involved in JA biosynthesis. We present evidence that overexpression of TomLoxD leads to elevated wound-induced JA biosynthesis, increased expression of wound-responsive genes and, therefore, enhanced resistance to insect herbivory attack and necrotrophic pathogen infection. These results indicate that TomLoxD is involved in wound-induced JA biosynthesis and highlight the application potential of this gene for crop protection against insects and pathogens. PMID- 24348261 TI - An Lmx1b-miR135a2 regulatory circuit modulates Wnt1/Wnt signaling and determines the size of the midbrain dopaminergic progenitor pool. AB - MicroRNAs regulate gene expression in diverse physiological scenarios. Their role in the control of morphogen related signaling pathways has been less studied, particularly in the context of embryonic Central Nervous System (CNS) development. Here, we uncover a role for microRNAs in limiting the spatiotemporal range of morphogen expression and function. Wnt1 is a key morphogen in the embryonic midbrain, and directs proliferation, survival, patterning and neurogenesis. We reveal an autoregulatory negative feedback loop between the transcription factor Lmx1b and a newly characterized microRNA, miR135a2, which modulates the extent of Wnt1/Wnt signaling and the size of the dopamine progenitor domain. Conditional gain of function studies reveal that Lmx1b promotes Wnt1/Wnt signaling, and thereby increases midbrain size and dopamine progenitor allocation. Conditional removal of Lmx1b has the opposite effect, in that expansion of the dopamine progenitor domain is severely compromised. Next, we provide evidence that microRNAs are involved in restricting dopamine progenitor allocation. Conditional loss of Dicer1 in embryonic stem cells (ESCs) results in expanded Lmx1a/b+ progenitors. In contrast, forced elevation of miR135a2 during an early window in vivo phenocopies the Lmx1b conditional knockout. When En1::Cre, but not Shh::Cre or Nes::Cre, is used for recombination, the expansion of Lmx1a/b+ progenitors is selectively reduced. Bioinformatics and luciferase assay data suggests that miR135a2 targets Lmx1b and many genes in the Wnt signaling pathway, including Ccnd1, Gsk3b, and Tcf7l2. Consistent with this, we demonstrate that this mutant displays reductions in the size of the Lmx1b/Wnt1 domain and range of canonical Wnt signaling. We posit that microRNA modulation of the Lmx1b/Wnt axis in the early midbrain/isthmus could determine midbrain size and allocation of dopamine progenitors. Since canonical Wnt activity has recently been recognized as a key ingredient for programming ESCs towards a dopaminergic fate in vitro, these studies could impact the rational design of such protocols. PMID- 24348262 TI - Parathyroid-specific deletion of Klotho unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion. AB - Klotho acts as a co-receptor for and dictates tissue specificity of circulating FGF23. FGF23 inhibits PTH secretion, and reduced Klotho abundance is considered a pathogenic factor in renal secondary hyperparathyroidism. To dissect the role of parathyroid gland resident Klotho in health and disease, we generated mice with a parathyroid-specific Klotho deletion (PTH-KL(-/-)). PTH-KL(-/-) mice had a normal gross phenotype and survival; normal serum PTH and calcium; unaltered expression of the PTH gene in parathyroid tissue; and preserved PTH response and sensitivity to acute changes in serum calcium. Their PTH response to intravenous FGF23 delivery or renal failure did not differ compared to their wild-type littermates despite disrupted FGF23-induced activation of the MAPK/ERK pathway. Importantly, calcineurin-NFAT signaling, defined by increased MCIP1 level and nuclear localization of NFATC2, was constitutively activated in PTH-KL(-/-) mice. Treatment with the calcineurin-inhibitor cyclosporine A abolished FGF23-mediated PTH suppression in PTH-KL(-/-) mice whereas wild-type mice remained responsive. Similar results were observed in thyro-parathyroid explants ex vivo. Collectively, we present genetic and functional evidence for a novel, Klotho independent, calcineurin-mediated FGF23 signaling pathway in parathyroid glands that mediates suppression of PTH. The presence of Klotho-independent FGF23 effects in a Klotho-expressing target organ represents a paradigm shift in the conceptualization of FGF23 endocrine action. PMID- 24348263 TI - A global in vivo Drosophila RNAi screen identifies a key role of ceramide phosphoethanolamine for glial ensheathment of axons. AB - Glia are of vital importance for all complex nervous system. One of the many functions of glia is to insulate and provide trophic and metabolic support to axons. Here, using glial-specific RNAi knockdown in Drosophila, we silenced 6930 conserved genes in adult flies to identify essential genes and pathways. Among our screening hits, metabolic processes were highly represented, and genes involved in carbohydrate and lipid metabolic pathways appeared to be essential in glia. One critical pathway identified was de novo ceramide synthesis. Glial knockdown of lace, a subunit of the serine palmitoyltransferase associated with hereditary sensory and autonomic neuropathies in humans, resulted in ensheathment defects of peripheral nerves in Drosophila. A genetic dissection study combined with shotgun high-resolution mass spectrometry of lipids showed that levels of ceramide phosphoethanolamine are crucial for axonal ensheathment by glia. A detailed morphological and functional analysis demonstrated that the depletion of ceramide phosphoethanolamine resulted in axonal defasciculation, slowed spike propagation, and failure of wrapping glia to enwrap peripheral axons. Supplementing sphingosine into the diet rescued the neuropathy in flies. Thus, our RNAi study in Drosophila identifies a key role of ceramide phosphoethanolamine in wrapping of axons by glia. PMID- 24348264 TI - Tay bridge is a negative regulator of EGFR signalling and interacts with Erk and Mkp3 in the Drosophila melanogaster wing. AB - The regulation of Extracellular regulated kinase (Erk) activity is a key aspect of signalling by pathways activated by extracellular ligands acting through tyrosine kinase transmembrane receptors. In this process, participate proteins with kinase activity that phosphorylate and activate Erk, as well as different phosphatases that inactivate Erk by de-phosphorylation. The state of Erk phosphorylation affects not only its activity, but also its subcellular localization, defining the repertoire of Erk target proteins, and consequently, the cellular response to Erk. In this work, we characterise Tay bridge as a novel component of the EGFR/Erk signalling pathway. Tay bridge is a large nuclear protein with a domain of homology with human AUTS2, and was previously identified due to the neuronal phenotypes displayed by loss-of-function mutations. We show that Tay bridge antagonizes EGFR signalling in the Drosophila melanogaster wing disc and other tissues, and that the protein interacts with both Erk and Mkp3. We suggest that Tay bridge constitutes a novel element involved in the regulation of Erk activity, acting as a nuclear docking for Erk that retains this protein in an inactive form in the nucleus. PMID- 24348265 TI - Genetic recombination is targeted towards gene promoter regions in dogs. AB - The identification of the H3K4 trimethylase, PRDM9, as the gene responsible for recombination hotspot localization has provided considerable insight into the mechanisms by which recombination is initiated in mammals. However, uniquely amongst mammals, canids appear to lack a functional version of PRDM9 and may therefore provide a model for understanding recombination that occurs in the absence of PRDM9, and thus how PRDM9 functions to shape the recombination landscape. We have constructed a fine-scale genetic map from patterns of linkage disequilibrium assessed using high-throughput sequence data from 51 free-ranging dogs, Canis lupus familiaris. While broad-scale properties of recombination appear similar to other mammalian species, our fine-scale estimates indicate that canine highly elevated recombination rates are observed in the vicinity of CpG rich regions including gene promoter regions, but show little association with H3K4 trimethylation marks identified in spermatocytes. By comparison to genomic data from the Andean fox, Lycalopex culpaeus, we show that biased gene conversion is a plausible mechanism by which the high CpG content of the dog genome could have occurred. PMID- 24348266 TI - Alcohol-induced histone acetylation reveals a gene network involved in alcohol tolerance. AB - Sustained or repeated exposure to sedating drugs, such as alcohol, triggers homeostatic adaptations in the brain that lead to the development of drug tolerance and dependence. These adaptations involve long-term changes in the transcription of drug-responsive genes as well as an epigenetic restructuring of chromosomal regions that is thought to signal and maintain the altered transcriptional state. Alcohol-induced epigenetic changes have been shown to be important in the long-term adaptation that leads to alcohol tolerance and dependence endophenotypes. A major constraint impeding progress is that alcohol produces a surfeit of changes in gene expression, most of which may not make any meaningful contribution to the ethanol response under study. Here we used a novel genomic epigenetic approach to find genes relevant for functional alcohol tolerance by exploiting the commonalities of two chemically distinct alcohols. In Drosophila melanogaster, ethanol and benzyl alcohol induce mutual cross tolerance, indicating that they share a common mechanism for producing tolerance. We surveyed the genome-wide changes in histone acetylation that occur in response to these drugs. Each drug induces modifications in a large number of genes. The genes that respond similarly to either treatment, however, represent a subgroup enriched for genes important for the common tolerance response. Genes were functionally tested for behavioral tolerance to the sedative effects of ethanol and benzyl alcohol using mutant and inducible RNAi stocks. We identified a network of genes that are essential for the development of tolerance to sedation by alcohol. PMID- 24348267 TI - Expanding the marine virosphere using metagenomics. AB - Viruses infecting prokaryotic cells (phages) are the most abundant entities of the biosphere and contain a largely uncharted wealth of genomic diversity. They play a critical role in the biology of their hosts and in ecosystem functioning at large. The classical approaches studying phages require isolation from a pure culture of the host. Direct sequencing approaches have been hampered by the small amounts of phage DNA present in most natural habitats and the difficulty in applying meta-omic approaches, such as annotation of small reads and assembly. Serendipitously, it has been discovered that cellular metagenomes of highly productive ocean waters (the deep chlorophyll maximum) contain significant amounts of viral DNA derived from cells undergoing the lytic cycle. We have taken advantage of this phenomenon to retrieve metagenomic fosmids containing viral DNA from a Mediterranean deep chlorophyll maximum sample. This method allowed description of complete genomes of 208 new marine phages. The diversity of these genomes was remarkable, contributing 21 genomic groups of tailed bacteriophages of which 10 are completely new. Sequence based methods have allowed host assignment to many of them. These predicted hosts represent a wide variety of important marine prokaryotic microbes like members of SAR11 and SAR116 clades, Cyanobacteria and also the newly described low GC Actinobacteria. A metavirome constructed from the same habitat showed that many of the new phage genomes were abundantly represented. Furthermore, other available metaviromes also indicated that some of the new phages are globally distributed in low to medium latitude ocean waters. The availability of many genomes from the same sample allows a direct approach to viral population genomics confirming the remarkable mosaicism of phage genomes. PMID- 24348268 TI - MAN1B1 deficiency: an unexpected CDG-II. AB - Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, due to impaired protein and lipid glycosylation. In the present study, exome sequencing was used to identify MAN1B1 as the culprit gene in an unsolved CDG-II patient. Subsequently, 6 additional cases with MAN1B1-CDG were found. All individuals presented slight facial dysmorphism, psychomotor retardation and truncal obesity. Generally, MAN1B1 is believed to be an ER resident alpha-1,2 mannosidase acting as a key factor in glycoprotein quality control by targeting misfolded proteins for ER-associated degradation (ERAD). However, recent studies indicated a Golgi localization of the endogenous MAN1B1, suggesting a more complex role for MAN1B1 in quality control. We were able to confirm that MAN1B1 is indeed localized to the Golgi complex instead of the ER. Furthermore, we observed an altered Golgi morphology in all patients' cells, with marked dilatation and fragmentation. We hypothesize that part of the phenotype is associated to this Golgi disruption. In conclusion, we linked mutations in MAN1B1 to a Golgi glycosylation disorder. Additionally, our results support the recent findings on MAN1B1 localization. However, more work is needed to pinpoint the exact function of MAN1B1 in glycoprotein quality control, and to understand the pathophysiology of its deficiency. PMID- 24348269 TI - Sumoylated NHR-25/NR5A regulates cell fate during C. elegans vulval development. AB - Individual metazoan transcription factors (TFs) regulate distinct sets of genes depending on cell type and developmental or physiological context. The precise mechanisms by which regulatory information from ligands, genomic sequence elements, co-factors, and post-translational modifications are integrated by TFs remain challenging questions. Here, we examine how a single regulatory input, sumoylation, differentially modulates the activity of a conserved C. elegans nuclear hormone receptor, NHR-25, in different cell types. Through a combination of yeast two-hybrid analysis and in vitro biochemistry we identified the single C. elegans SUMO (SMO-1) as an NHR-25 interacting protein, and showed that NHR-25 is sumoylated on at least four lysines. Some of the sumoylation acceptor sites are in common with those of the NHR-25 mammalian orthologs SF-1 and LRH-1, demonstrating that sumoylation has been strongly conserved within the NR5A family. We showed that NHR-25 bound canonical SF-1 binding sequences to regulate transcription, and that NHR-25 activity was enhanced in vivo upon loss of sumoylation. Knockdown of smo-1 mimicked NHR-25 overexpression with respect to maintenance of the 3 degrees cell fate in vulval precursor cells (VPCs) during development. Importantly, however, overexpression of unsumoylatable alleles of NHR-25 revealed that NHR-25 sumoylation is critical for maintaining 3 degrees cell fate. Moreover, SUMO also conferred formation of a developmental time dependent NHR-25 concentration gradient across the VPCs. That is, accumulation of GFP-tagged NHR-25 was uniform across VPCs at the beginning of development, but as cells began dividing, a smo-1-dependent NHR-25 gradient formed with highest levels in 1 degrees fated VPCs, intermediate levels in 2 degrees fated VPCs, and low levels in 3 degrees fated VPCs. We conclude that sumoylation operates at multiple levels to affect NHR-25 activity in a highly coordinated spatial and temporal manner. PMID- 24348270 TI - A trans-acting protein effect causes severe eye malformation in the Mp mouse. AB - Mp is an irradiation-induced mouse mutation associated with microphthalmia, micropinna and hind limb syndactyly. We show that Mp is caused by a 660 kb balanced inversion on chromosome 18 producing reciprocal 3-prime gene fusion events involving Fbn2 and Isoc1. The Isoc1-Fbn2 fusion gene (Isoc1(Mp)) mRNA has a frameshift and early stop codon resulting in nonsense mediated decay. Homozygous deletions of Isoc1 do not support a significant developmental role for this gene. The Fbn2-Isoc1 fusion gene (Fbn2 (Mp)) predicted protein consists of the N-terminal Fibrillin-2 (amino acids 1-2646, exons 1-62) lacking the C terminal furin-cleavage site with a short out-of-frame extension encoded by the final exon of Isoc1. The Mp limb phenotype is consistent with that reported in Fbn2 null embryos. However, severe eye malformations, a defining feature of Mp, are not seen in Fbn2 null animals. Fibrillin-2(Mp) forms large fibrillar structures within the rough endoplasmic reticulum (rER) associated with an unfolded protein response and quantitative mass spectrometry shows a generalised defect in protein secretion in conditioned media from mutant cells. In the embryonic eye Fbn2 is expressed within the peripheral ciliary margin (CM). Mp embryos show reduced canonical Wnt-signalling in the CM - known to be essential for ciliary body development - and show subsequent aplasia of CM-derived structures. We propose that the Mp "worse-than-null" eye phenotype plausibly results from a failure in normal trafficking of proteins that are co-expressed with Fbn2 within the CM. The prediction of similar trans-acting protein effects will be an important challenge in the medical interpretation of human mutations from whole exome sequencing. PMID- 24348271 TI - Dual regulation of gene expression mediated by extended MAPK activation and salicylic acid contributes to robust innate immunity in Arabidopsis thaliana. AB - Network robustness is a crucial property of the plant immune signaling network because pathogens are under a strong selection pressure to perturb plant network components to dampen plant immune responses. Nevertheless, modulation of network robustness is an area of network biology that has rarely been explored. While two modes of plant immunity, Effector-Triggered Immunity (ETI) and Pattern-Triggered Immunity (PTI), extensively share signaling machinery, the network output is much more robust against perturbations during ETI than PTI, suggesting modulation of network robustness. Here, we report a molecular mechanism underlying the modulation of the network robustness in Arabidopsis thaliana. The salicylic acid (SA) signaling sector regulates a major portion of the plant immune response and is important in immunity against biotrophic and hemibiotrophic pathogens. In Arabidopsis, SA signaling was required for the proper regulation of the vast majority of SA-responsive genes during PTI. However, during ETI, regulation of most SA-responsive genes, including the canonical SA marker gene PR1, could be controlled by SA-independent mechanisms as well as by SA. The activation of the two immune-related MAPKs, MPK3 and MPK6, persisted for several hours during ETI but less than one hour during PTI. Sustained MAPK activation was sufficient to confer SA-independent regulation of most SA-responsive genes. Furthermore, the MPK3 and SA signaling sectors were compensatory to each other for inhibition of bacterial growth as well as for PR1 expression during ETI. These results indicate that the duration of the MAPK activation is a critical determinant for modulation of robustness of the immune signaling network. Our findings with the plant immune signaling network imply that the robustness level of a biological network can be modulated by the activities of network components. PMID- 24348272 TI - Histone methylation restrains the expression of subtype-specific genes during terminal neuronal differentiation in Caenorhabditis elegans. AB - Although epigenetic control of stem cell fate choice is well established, little is known about epigenetic regulation of terminal neuronal differentiation. We found that some differences among the subtypes of Caenorhabditis elegans VC neurons, particularly the expression of the transcription factor gene unc-4, require histone modification, most likely H3K9 methylation. An EGF signal from the vulva alleviated the epigenetic repression of unc-4 in vulval VC neurons but not the more distant nonvulval VC cells, which kept unc-4 silenced. Loss of the H3K9 methyltransferase MET-2 or H3K9me2/3 binding proteins HPL-2 and LIN-61 or a novel chromodomain protein CEC-3 caused ectopic unc-4 expression in all VC neurons. Downstream of the EGF signaling in vulval VC neurons, the transcription factor LIN-11 and histone demethylases removed the suppressive histone marks and derepressed unc-4. Behaviorally, expression of UNC-4 in all the VC neurons caused an imbalance in the egg-laying circuit. Thus, epigenetic mechanisms help establish subtype-specific gene expression, which are needed for optimal activity of a neural circuit. PMID- 24348273 TI - Ethylene promotes hypocotyl growth and HY5 degradation by enhancing the movement of COP1 to the nucleus in the light. AB - In the dark, etiolated seedlings display a long hypocotyl, the growth of which is rapidly inhibited when the seedlings are exposed to light. In contrast, the phytohormone ethylene prevents hypocotyl elongation in the dark but enhances its growth in the light. However, the mechanism by which light and ethylene signalling oppositely affect this process at the protein level is unclear. Here, we report that ethylene enhances the movement of constitutive photomorphogenesis 1 (COP1) to the nucleus where it mediates the degradation of long hypocotyl 5 (HY5), contributing to hypocotyl growth in the light. Our results indicate that HY5 is required for ethylene-promoted hypocotyl growth in the light, but not in the dark. Using genetic and biochemical analyses, we found that HY5 functions downstream of ethylene insensitive 3 (EIN3) for ethylene-promoted hypocotyl growth. Furthermore, the upstream regulation of HY5 stability by ethylene is COP1 dependent, and COP1 is genetically located downstream of EIN3, indicating that the COP1-HY5 complex integrates light and ethylene signalling downstream of EIN3. Importantly, the ethylene precursor 1-aminocyclopropane-1-carboxylate (ACC) enriched the nuclear localisation of COP1; however, this effect was dependent on EIN3 only in the presence of light, strongly suggesting that ethylene promotes the effects of light on the movement of COP1 from the cytoplasm to the nucleus. Thus, our investigation demonstrates that the COP1-HY5 complex is a novel integrator that plays an essential role in ethylene-promoted hypocotyl growth in the light. PMID- 24348276 TI - Uptake and distribution of cd in sweet maize grown on contaminated soils: a field scale study. AB - Maize is an economic crop that is also a candidate for use in phytoremediation in low-to-moderately Cd-contaminated soils, because the plant can accumulate high concentration of Cd in parts that are nonedible to humans while accumulating only a low concentration of Cd in the fruit. Maize cultivars CT38 and HZ were planted in field soils contaminated with Cd and nitrilotriacetic acid (NTA) was used to enhance the phytoextractive effect of the maize. Different organs of the plant were analyzed to identify the Cd sinks in the maize. A distinction was made between leaf sheath tissue and leaf lamina tissue. Cd concentrations decreased in the tissues in the following order: sheath > root > lamina > stem > fruit. The addition of NTA increased the amount of Cd absorbed but left the relative distribution of the metal among the plant organs essentially unchanged. The Cd in the fruit of maize was below the Chinese government's permitted concentration in coarse cereals. Therefore, this study shows that it is possible to conduct maize phytoremediation of Cd-contaminated soil while, at the same time, harvesting a crop, for subsequent consumption. PMID- 24348275 TI - A domesticated PiggyBac transposase interacts with heterochromatin and catalyzes reproducible DNA elimination in Tetrahymena. AB - The somatic genome of the ciliated protist Tetrahymena undergoes DNA elimination of defined sequences called internal eliminated sequences (IESs), which account for ~30% of the germline genome. During DNA elimination, IES regions are heterochromatinized and assembled into heterochromatin bodies in the developing somatic nucleus. The domesticated piggyBac transposase Tpb2p is essential for the formation of heterochromatin bodies and DNA elimination. In this study, we demonstrate that the activities of Tpb2p involved in forming heterochromatin bodies and executing DNA elimination are genetically separable. The cysteine-rich domain of Tpb2p, which interacts with the heterochromatin-specific histone modifications, is necessary for both heterochromatin body formation and DNA elimination, whereas the endonuclease activity of Tpb2p is only necessary for DNA elimination. Furthermore, we demonstrate that the endonuclease activity of Tpb2p in vitro and the endonuclease activity that executes DNA elimination in vivo have similar substrate sequence preferences. These results strongly indicate that Tpb2p is the endonuclease that directly catalyzes the excision of IESs and that the boundaries of IESs are at least partially determined by the combination of Tpb2p-heterochromatin interaction and relaxed sequence preference of the endonuclease activity of Tpb2p. PMID- 24348274 TI - The NuRD chromatin-remodeling enzyme CHD4 promotes embryonic vascular integrity by transcriptionally regulating extracellular matrix proteolysis. AB - The extracellular matrix (ECM) supports vascular integrity during embryonic development. Proteolytic degradation of ECM components is required for angiogenesis, but excessive ECM proteolysis causes blood vessel fragility and hemorrhage. Little is understood about how ECM proteolysis is transcriptionally regulated during embryonic vascular development. We now show that the NuRD ATP dependent chromatin-remodeling complex promotes vascular integrity by preventing excessive ECM proteolysis in vivo. Mice lacking endothelial CHD4--a catalytic subunit of NuRD complexes--died at midgestation from vascular rupture. ECM components surrounding rupture-prone vessels in Chd4 mutants were significantly downregulated prior to embryonic lethality. Using qPCR arrays, we found two critical mediators of ECM stability misregulated in mutant endothelial cells: the urokinase-type plasminogen activator receptor (uPAR or Plaur) was upregulated, and thrombospondin-1 (Thbs1) was downregulated. Chromatin immunoprecipitation assays showed that CHD4-containing NuRD complexes directly bound the promoters of these genes in endothelial cells. uPAR and THBS1 respectively promote and inhibit activation of the potent ECM protease plasmin, and we detected increased plasmin activity around rupture-prone vessels in Chd4 mutants. We rescued ECM components and vascular rupture in Chd4 mutants by genetically reducing urokinase (uPA or Plau), which cooperates with uPAR to activate plasmin. Our findings provide a novel mechanism by which a chromatin-remodeling enzyme regulates ECM stability to maintain vascular integrity during embryonic development. PMID- 24348277 TI - Long-term effects of the Moving to Opportunity residential mobility experiment on crime and delinquency. AB - OBJECTIVES: Using data from a randomized experiment, to examine whether moving youth out of areas of concentrated poverty, where a disproportionate amount of crime occurs, prevents involvement in crime. METHODS: We draw on new administrative data from the U.S. Department of Housing and Urban Development's Moving to Opportunity (MTO) experiment. MTO families were randomized into an experimental group offered a housing voucher that could only be used to move to a low-poverty neighborhood, a Section 8 housing group offered a standard housing voucher, and a control group. This paper focuses on MTO youth ages 15-25 in 2001 (n = 4,643) and analyzes intention to treat effects on neighborhood characteristics and criminal behavior (number of violent- and property-crime arrests) through 10 years after randomization. RESULTS: We find the offer of a housing voucher generates large improvements in neighborhood conditions that attenuate over time and initially generates substantial reductions in violent crime arrests and sizable increases in property-crime arrests for experimental group males. The crime effects attenuate over time along with differences in neighborhood conditions. CONCLUSIONS: Our findings suggest that criminal behavior is more strongly related to current neighborhood conditions (situational neighborhood effects) than to past neighborhood conditions (developmental neighborhood effects). The MTO design makes it difficult to determine which specific neighborhood characteristics are most important for criminal behavior. Our administrative data analyses could be affected by differences across areas in the likelihood that a crime results in an arrest. PMID- 24348278 TI - The complete targeted profile of the organic acid intermediates of the citric acid cycle using a single stable isotope dilution analysis, sodium borodeuteride reduction and selected ion monitoring GC/MS. AB - The quantitative profiling of the organic acid intermediates of the citric acid cycle (CAC) presents a challenge due to the lack of commercially available internal standards for all of the organic acid intermediates. We developed an analytical method that enables the quantitation of all the organic acids in the CAC in a single stable isotope dilution GC/MS analysis with deuterium-labeled analogs used as internal standards. The unstable alpha-keto acids are rapidly reduced with sodium borodeuteride to the corresponding stable alpha-deutero-alpha hydroxy acids and these, along with their unlabeled analogs and other CAC organic acid intermediates, are converted to their tert-butyldimethylsilyl derivatives. Selected ion monitoring is employed with electron ionization. We validated this method by treating an untransformed mouse mammary epithelial cell line with well known mitochondrial toxins affecting the electron transport chain and ATP synthase, which resulted in profound perturbations of the concentration of CAC intermediates. PMID- 24348280 TI - Electrocautery therapy combined with oral steroid administration for refractory corrosive esophageal stenosis prevents restenosis. AB - A 61-year-old female with refractory corrosive esophageal stenosis repeatedly underwent endoscopic balloon dilation at another hospital; however, no improvements were observed in the esophageal stenosis. Consequently, she had been on a liquid diet for the previous three years. She was admitted to our department for further treatment. A radial incision was made, by use of the SB knife Jr, for a pinhole-like stenosis in a short segment 39 cm from the incisor, and dilation was safely performed by use of a CRE balloon dilator. Subsequently, prednisolone was orally administered to prevent re-stenosis. This was followed by a favorable clinical course. PMID- 24348279 TI - Caregiver Burden in Fragile X Families. AB - Complex caregiving issues occur in multigenerational families carrying the fragile X mutation and premutation. The same family members may care for children or siblings with fragile X syndrome (FXS) and for elderly parents with fragile X associated tremor/ataxia syndrome (FXTAS). Family caregivers experience anxiety, depression, neglect of personal health care needs, employment difficulties, and loss of social support, leading to isolation and further psychiatric consequences. There is growing awareness of caregiver burden with regard to parents of children with FXS, but much less is known about the needs of informal caregivers of patients with FXTAS. In this paper, we review the available literature to date and provide suggestions for further exploration of caregivers' needs. Evidence-based strategies to address these needs are included. Many more research studies exploring caregiver burden in multigenerational fragile X families are needed, as well as studies aimed at investigating interventions and their impact on reduction. PMID- 24348281 TI - Society for microbial ecology, microbial ecology in health and disease, and the future. PMID- 24348282 TI - Impact factor went on a ventilator: Neither died nor buried. PMID- 24348283 TI - Tranexamic acid in obstetrics: Encouraging data in anemic parturients. PMID- 24348284 TI - A survey of the practice of regional anesthesia in Saudi Arabia. AB - OBJECTIVE: This survey aimed to assess both the extent of practice and need for training in regional anesthesia among anesthesiologists in Saudi Arabia in 2012. METHODS: We distributed an electronic survey among 382 anesthesiologists attending the bi-annual meetings of the Saudi Anesthetic Association, enquiring about their practice in regional anesthesia. Questions concerned the practice of regional anesthesia, use of ultrasound guidance, and the need for training workshops. RESULTS: The response rate of anesthetists was 55.2% with most of them were males and had mean age of 25-50 years. Most anesthesiologists (88.2%) were practicing regional anesthesia frequently in the operating rooms (75.3%) rather than designated block room. From the respondents, only 14.2% did fellowship in regional anesthesia, 21.8% and 18.5% were using ultrasound and nerve stimulation guidance, respectively, 11.4% received formal training, and 86.3% were willing to attend training workshops on regional anesthesia. There was a significant negative correlation between the ultrasound users and their institutional positions (r=-0.191) (P=0.026). CONCLUSIONS: We believe that more could be done to improve the practice of regional anesthesia in the Kingdom of Saudi Arabia, including the implementation of formal training and conduction of more frequent specialized courses/workshops in the field of regional anesthesia with special reference to ultrasound regional anesthesia blockade techniques. PMID- 24348285 TI - Clinical expertise in regional anesthesia: Anesthesiologists voice their need for formal training. PMID- 24348286 TI - Paravertebral block can attenuate cytokine response when it replaces general anesthesia for cancer breast surgeries. AB - CONTEXT: Cytokine release is a well-known response to surgery especially when it is linked to cancer. Paravertebral block (PVB) is the suitable regional anesthesia for breast surgery. AIM: We tested the effect of replacing general anesthesia (GA) with PVB on cytokine response during and after surgeries for cancer breast. SETTINGS AND DESIGN: Controlled randomized study. METHODS: Forty cancer breast patients were divided in two groups; Group I received PVB and Group II received GA during performance of unilateral breast surgery without axillary clearance. Plasma concentrations of interleukin (IL)-6, IL-10, IL-12 and interferon-gamma (IFN-gamma) were measured and IL-10/IFN-gamma were estimated in the following points; before starting PVB in Group I or induction of GA in Group II (Sample A), before skin incision (Sample B), at the end of procedure before shifting out of operating room (Sample C), 4-h post-operatively (Sample D) and 24 h post-operatively (Sample E). STATISTICAL ANALYSIS: unpaired Student t-test. RESULTS: IL-6 increased progressively in both groups with statistically significant lower levels in samples C and D in Group I. IL-10 levels showed progressive increasing in both groups without differences between groups. IL-12 showed progressive decrease in both groups with statistically significant higher levels in samples C and D in Group I. IFN-levels showed significantly higher levels in samples C and D in Group I. IL-10/IFN-gamma ratio was significantly lower in Group II in samples C and D. CONCLUSION: Replacing GA with PVB can attenuate cytokines response to cancer breast surgeries. PMID- 24348288 TI - Nonopioid versus opioid based general anesthesia technique for bariatric surgery: A randomized double-blind study. AB - OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of giving general anesthesia without the use of any opioids either systemic or intraperitoneal in bariatric surgery. METHODS: Prospective randomized controlled trial. Obese patients (body mass index >50 Kg/m(2)) undergoing laparoscopic sleeve gastrectomies were recruited and provided an informed signed consent. Patients were randomized using a computer generated randomization table to receive either opioid or non-opioid based anesthesia. The patient and the investigator scoring patient outcome after surgery were blinded to the anesthetic protocol. Primary outcomes were hemodynamics in the form of "heart rate, systolic, diastolic, and mean arterial blood pressure" on induction and 1/2 hourly thereafter. Pain monitoring through visual analog scale (VAS) 30 min after recovery, hourly for 2 h and every 4 h for 24 h was also recorded. Pain monitoring through VAS and post-operative nausea and vomiting 30 min after recovery were also recorded and finally patient satisfaction and acute pain nurse satisfaction. RESULTS: There was no difference in background characteristics in both groups. There were no statistically significant differences in different outcomes as heart rate, mean blood pressure, O2 saturation in different timings between groups at any of the determined eight time points but pain score and nurse satisfaction showed a trend to better performance with non-opioid treatment. CONCLUSION: Nonopioid based general anesthesia for Bariatric surgery is as effective as opioid one. There is no need to use opioids for such surgery especially that there was a trend to less pain in non-opioid anesthesia. PMID- 24348287 TI - Transoesophageal Doppler compared to central venous pressure for perioperative hemodynamic monitoring and fluid guidance in liver resection. AB - PURPOSE: Major hepatic resections may result in hemodynamic changes. Aim is to study transesophageal Doppler (TED) monitoring and fluid management in comparison to central venous pressure (CVP) monitoring. A follow-up comparative hospital based study. METHODS: 59 consecutive cirrhotic patients (CHILD A) undergoing major hepatotomy. CVP monitoring only (CVP group), (n=30) and TED (Doppler group), (n=29) with CVP transduced but not available on the monitor. Exclusion criteria include contra-indication for Doppler probe insertion or bleeding tendency. An attempt to reduce CVP during the resection in both groups with colloid restriction, but crystalloids infusion of 6 ml/kg/h was allowed to replace insensible loss. Post-resection colloids infusion were CVP guided in CVP group (5-10 mmHg) and corrected flow time (FTc) aortic guided in Doppler group (>0.4 s) blood products given according to the laboratory data. RESULTS: Using the FTc to guide Hydroxyethyl starch 130/0.4 significantly decreased intake in TED versus CVP (1.03 [0.49] versus 1.74 [0.41] Liter; P<0.05). Nausea, vomiting, and chest infection were less in TED with a shorter hospital stay (P<0.05). No correlation between FTc and CVP (r=0.24, P > 0.05). Cardiac index and stroke volume of TED increased post-resection compared to baseline, 3.0 (0.9) versus 3.6 (0.9) L/min/m(2), P<0.05; 67.1 (14.5) versus 76 (13.2) ml, P<0.05, respectively, associated with a decrease in systemic vascular resistance (SVR) 1142.7 (511) versus 835.4 (190.9) dynes.s/cm(5), P<0.05. No significant difference in arterial pressure and CVP between groups at any stage. CVP during resection in TED 6.4 (3.06) mmHg versus 6.1 (1.4) in CVP group, P=0.6. TED placement consumed less time than CVP (7.3 [1.5] min versus 13.2 [2.9], P<0.05). CONCLUSION: TED in comparison to the CVP monitoring was able to reduced colloids administration post resection, lower morbidity and shorten hospital stay. TED consumed less time to insert and was also able to present significant hemodynamic changes. Advanced surgical techniques of resection play a key role in reducing blood loss despite CVP more than 5 cm H2O. TED fluid management protocols during resection need to be developed. PMID- 24348289 TI - The effect of ketamine versus fentanyl on the incidence of emergence agitation after sevoflurane anesthesia in pediatric patients undergoing tonsillectomy with or without adenoidectomy. AB - BACKGROUND: Emergence agitation (EA) has been documented as a common side-effect of sevoflurane anesthesia. This prospective, randomized, double-blind, placebo controlled study was designed to compare the effects of ketamine versus fentanyl, administered 10 min before the end of surgery on the development of EA. METHODS: A total of 120 children aged 3-7 years of American Society of Anesthesiologists I II physical status were randomly assigned to one of three equal groups receiving either ketamine 0.5 mg/kg (Group K), fentanyl 1 MUg/kg (Group F) or saline (Group C) at 10 min before the end of surgery. Post-operative EA was assessed with Aono's four point scale. Recovery times, the post-operative pain and adverse reactions were assessed. RESULTS: There was no significant difference between the three groups regarding recovery and discharge times from post-anesthesia care unit. The incidence of EA was significantly low in Group K and Group F (15% and 17.5%, respectively) compared to the control group (42.5%), with no significant difference between Group K and Group F. There were no significant differences in Children's Hospital of Eastern Ontario Pain Scale between the three groups. The incidence of nausea or vomiting was significantly more in Group F compared to that in other two groups. However, no complications such as somnolence, oxygen desaturation or respiratory depression occurred during the study period and there were no episodes of hallucinations or bad dreams in the ketamine group. CONCLUSION: The intravenous administration of either ketamine 0.5 mg/kg or fentanyl 1 MUg/kg before the end of surgery in sevoflurane-anesthetized children undergoing tonsillectomy with or without adenoidectomy reduces the incidence of post-operative agitation without delaying emergence. PMID- 24348290 TI - Entropy-guided end-tidal desflurane concentration during living donor liver transplantation. AB - BACKGROUND: The three phases of living donor liver transplantation (LDLT) represent different liver conditions. The aim is to study the required end-tidal desflurane concentration (ET-Des) guided with entropy monitoring for the depth of anesthesia. METHODS: After the Ethics and Research Committee approval, 40 patients were included in this prospective study. Anesthesia was maintained with Desflurane-O2-air. State entropy (SE) and Response entropy (RE) were kept between 40 and 60. RESULTS: Age and Model for End-stage Liver Disease (MELD) score were 45+/-10 years and 15.43+/-3.92, respectively. ET-Des were significantly lower in the anhepatic phase (2.8+/-0.4%) than in the pre-anhepatic and neohepatic phases (3.3+/-0.3%, 3.47+/-0.3%, respectively, P<0.001). The SE and RE for pre anhepatic, anhepatic, and neohepatic phases were (45.6+/-3.7, 47.4+/-3.2), (44.7+/-2.1, 46.4+/-2.04), and (46.1+/-3.3, 47.9+/-3.3), respectively, with no significant changes between the phases, P > 0.05. Total operative time was 651+/ 88 minutes, and for each phase it was 276+/-11, 195+/-55, and 191+/-24 minutes, respectively. Significant changes were found in hemoglobin g/dl and hematocrit % between the three phases (10.28+/-1.5, 30.48+/-4.3), (9.45+/-1.34, 28.36+/-4.1), and (8.88+/-1.1, 26.63+/-3.5), P<0.05. The heart rate and mean blood pressures were stable despite the cardiac index demonstrated a significant reduction during the anhepatic phase (2.99+/-0.22) when compared to the pre-anhepatic and neohepatic phases (3.60+/-0.29) and (4.72+/-0.32), respectively, (P<0.05). There was a significant correlation between CI and ET-Des% (r=0.604, P<0.05). CONCLUSION: Inhalational anesthetic requirements differed from one phase to another during LDLT, with requirements being the least during the anhepatic phase. Monitoring of the anesthesia depth was required, to avoid excess administration, which could compromise the hemodynamics before the critical time of reperfusion. PMID- 24348291 TI - Comparison of unilateral spinal and continous spinal anesthesia for hip surgery in elderly patients. AB - BACKGROUND: Continous spinal anesthesia (CSA) and frequently unilateral spinal anesthesia (USpA) are usually preferred for lower extremity surgeries. In this study, we aimed to compare the effects of these anesthetic techniques, on hemodynamic parameters, quality of anesthesia and complications in elderly patients undergoing hip surgeries. METHODS: Forty patients aged 65 years and older, assigned to receive either CSA or USpA with 7.5 mg (1.5 cc) 0.5% hyperbaric bupivacaine initially. In CSA group, additional doses of 2.5 mg bupivacaine were applied until sensory block reach to T10. Maximum sensorial block level, time to reach the level of T10 (defined as onset time) and to regress to T12, hemodynamic parameters and ephedrine requirements were recorded peroperatively and during 2 h postoperatively. RESULTS: Hemodynamic parameters, ephedrine requirements and regression of sensory block by two levels were similar in two groups. The onset time of anesthesia was significantly longer in USpA group than CSA group. Neuraxial anesthesia had to be converted to general anesthesia in 5 patients (25%) in CSA group and 1 patient (5%) in USpA group. CONCLUSIONS: We conclude that both USpA and CSA techniques have similar effects in elderly high risk patients. On the other hand, USpA is more preferable for surgeries with shorter durations due to its low cost and high success rate. PMID- 24348292 TI - Causes of tracheal re-intubation after craniotomy: A prospective study. AB - BACKGROUND: Re-intubation of neurosurgical patients after a successful tracheal extubation in the operating room is not uncommon. However, no prospective study has ever addressed this concern. This study was aimed at analyzing various risk factors of re-intubation and its effect on patient outcome. METHODS: Patients aged between 18-60 yrs and of ASA physical status I and II undergoing elective craniotomies over a period of two yrs were included. A standard anesthetic technique using propofol, fentanyl, rocuronium, and isoflurane/sevoflurane was followed, in all these patients. 'Re-intubation' was defined as the necessity of tracheal intubation within 72 hrs of a planned extubation. Data were collected and analyzed employing standard statistical methods. RESULTS: One thousand eight hundred and fifty patients underwent elective craniotomy, of which 920 were included in this study. A total of 45 (4.9%) patients required re-intubation. Mean anesthesia duration and time of re-intubation were 6.3+/-1.8 and 24.6+/-21.9 hrs, respectively. The causes of re-intubation were neurological deterioration (55.6%), respiratory distress (22.2%), unmanageable respiratory secretion (13.3%), and seizures (8.9%). The most common post-operative radiological (CT scan) finding was residual tumor and edema (68.9%). Seventy-three percent of the re-intubated patients had satisfactory post-operative cough-reflex. The ICU and hospital stay, and Glasgow outcome scale at discharge were not significantly affected by different causes of re-intubation. CONCLUSION: Neurological deterioration is the most common cause of re-intubation following elective craniotomies owing to residual tumor and surrounding edema. A satisfactory cough reflex may not prevent subsequent re-intubation in post-craniotomy patients. PMID- 24348293 TI - Analyzing the effects of intra-operation video-clip display on hemodynamic and satisfaction of patients during lumbar discectomy under spinal anesthesia. AB - OBJECTIVE: Most neurosurgeons and anesthesiologists prefer the less invasive intervention for most surgeries; recently, the lumbar anesthesia is more popular method. In this study we have tried to distract the attention of the patients to their favorite video-clip instead of their surrounding operating room background to evaluate the hemodynamic as well as their satisfaction during the operation. METHODS: 80 patients who were scheduled for an elective one level discectomy under the regional spinal anesthesia enrolled in this prospective randomized clinical trial. The patients were randomized with sealed envelope method and each envelope was randomly assigned from this set of envelops to be either in case group one (video group) or control groups two (no audio and video and only head phone on their ears) group. In all patients, systolic and diastolic blood pressure, pulse rate and SPO2 were measured and recorded in the questionnaire charts. RESULTS: Of the 80 patients with Lumbar disk herniation, 53 patients were male and 27 female. The mean age for all patients was 44 year. Systolic and diastolic blood pressure at the end of surgery was significantly lower in video group (P=0.045 and 0.004). Systolic Blood pressure differences between 3(rd) and 5(th) and the end of the surgery with minute zero was significantly less in the video group. (P=0.025, 0.018 and 0.030). Diastolic blood pressure differences between 3(rd) and 5(th) and the end of the surgery with minute zero was significantly less in the video group.(P=0.051, 0.019 and 0.15). Pulse rate differences between first, 3(rd), 5(th) and exactly before leaving the recovery room with minute zero was significantly less in the video group. (P=0.015, 0.028, 0.030 and 0.008). CONCLUSION: According to our study, by displaying patient's favorite video clip during the surgical intervention we could highly reduce the patient's attention to what is happening in operating room and therefore, decrease their anxiety and stress. PMID- 24348294 TI - Evaluation of interadductor approach in neurolytic blockade of obturator nerve in spastic patients. AB - BACKGROUND: Spasticity is a syndrome associated with a persistent increase in involuntary reflex activity of a muscle in response to stretch. Adductor muscle spasticity is a common complication of spinal cord and brain injury. It needs to be treated if it interferes with activities of daily living and self-care. Obturator neurolytic blockade is one of the cost-effective therapeutic possibilities to treat spasticity of adductor group of muscles. In this study, we assessed the efficacy of interadductor approach in alleviating the spasticity. METHODS: Obturator neurolysis using 8-10 ml 6% phenol was given with the guidance of a peripheral nerve stimulator in 20 spastic patients. Technical evaluation included number of attempted needle insertions, time to accurate location of the nerve, depth of needle insertion, and success rate. Pain, spasticity, hip abduction range of motion (ROM), number of spasms, gait, and hygiene were evaluated at 1(st) hour, 24(th) hour, end of the 1(st) week, and in the 1(st), 2(nd), and 3(rd) months following the intervention. RESULTS: The success rate was 100% with mean time to accurate nerve location 4.9+/-2.06 min. Average depth of needle insertion was 2.91+/-0.32 cm. Compared with the scores measured immediately before the block, all studied parameters improved significantly. An increase in the Modified Ashworth Scale values was observed in the 2(nd) and 3(rd) months, but they did not reach their initial values. CONCLUSION: The interadductor approach proved to be accurate and fast, with a high success rate. Phenol blockade is an efficient and cost-effective technique in patients with adductor spasticity. It led to a decrease in spasticity and pain with an increase in the ROM of the hip and better hygiene, with an efficacy lasting for about 3 months. PMID- 24348295 TI - Comparative evaluation of two doses of tranexamic acid used prophylactically in anemic parturients for lower segment cesarean section: A double-blind randomized case control prospective trial. AB - BACKGROUND: Postpartum hemorrhage (PPH) and anemia thereafter can be a life threatening condition in parturients undergoing lower segment cesarean section (LSCS), especially when anemia is present. AIM: The objective of this study was to assess two doses of Tranexamic acid (TXA) in reducing intra operative blood loss and incidence of PPH, in terms of both efficacy and safety profiles, when used prophylactically. METHODS: A monocenter prospective case control double blind randomized study was carried out on a consecutive series of 90 anemic patients undergoing LSCS, with hemoglobin between 7-10 g percent. Three random groups were formed. Group T1 (n=30) received 10mg/kg TXA in 20 ml of 5% dextrose intravenously, while T2 group (n=30) received 15mg/kg. Group C (n=30) received a placebo. Drug was administered prophylactically 20 min before skin incision. Blood loss was measured from placental delivery up to 24 hours by method of weight and volume. STAISTICAL ANALYSIS: To compare quantitative data between two groups, t-test, and for more than two groups ANOVA was used. To compare the mean for non- parametric data between two groups Mann - Whitney test was used, while in case of more than two groups Kruskal - Wallis test was employed. Probability (p) value was considered significant when it was 0.05 or less. RESULTS: TXA significantly reduced blood loss in both the study groups. Mean total blood loss was 527.17+/-88.666 ml, 376.83+/-31.961ml and 261.17+/-56.777 ml in group C, T1, and T2 respectively. While reduction of blood loss in T1 group compared to control group was 146.34+/-56.32ml, it was 262+/-31.51ml in T2 group. Difference between T1 and T2 was 115.66+/-24.81ml, which was statistically significant (P<0.05). Postoperative blood loss was insignificant in all three groups. Pre- and post-operative hemoglobin levels differed significantly when compared to control group. Blood transfusion was needed in two patients in the control group, whereas no patient in groups T1 and T2 needed transfusion (P=0.02). No significant adverse effect was seen in all the three groups. CONCLUSION: Hence, TXA was found to be effective in reducing blood loss and transfusion in anemic parturients undergoing LSCS. 15mg/kg dose of TXA was more efficacious than the 10mg/kg dose and without any undue increase in adverse events. Postpartum anemia is a public health problem worldwide and TXA could prove to be a very useful drug to prevent blood loss and transfusions in patients undergoing LSCS, especially in the anemic subgroup. PMID- 24348296 TI - Ultrasound-guided rectus sheath block in children with umbilical hernia: Case series. AB - BACKGROUND: Umbilical hernia repair, a common day-case surgery procedure in children, is associated with a significant postoperative pain. The most popular peripheral nerve blocks used in umbilical hernia repair are rectus sheath infiltration and caudal block. The rectus sheath block may offer improved pain relief following umbilical hernia repair with no undesired effects such as lower limb motor weakness or urinary retention seen with caudal block which might delay discharge from the hospital. Ultrasound guidance of peripheral nerve blocks has reduced the number of complications and improved the quality of blocks. The aim of this case series is to assess the post rectus sheath block pain relief in pediatric patients coming for umbilical surgery. METHODS: Twenty two (22) children (age range: 1.5-8 years) scheduled for umbilical hernia repair were included in the study. Following the induction of general anesthesia, the ultrasonographic anatomy of the umbilical region was studied with a 5-16 MHz 50 mm linear probe. An ultrasound-guided posterior rectus sheath block of both rectus abdominis muscles (RMs) was performed (total of 44 punctures). An in-plain technique using Stimuplex A insulated facet tip needle 22G 50mm. Surgical conditions, intraoperative hemodynamic parameters, and postoperative analgesia by means of the modified CHEOPS scale were evaluated. RESULTS: ultrasonograghic visualization of the posterior sheath was possible in all patients. The ultrasound guided rectus sheath blockade provided sufficient analgesia in all children with no need for additional analgesia except for one patient who postoperatively required morphine 0.1 mg/kg intravenously. There were no complications. CONCLUSIONS: Ultrasound guidance enables performances of an effective rectus sheath block for umbilical hernia. Use of the Stimuplex A insulated facet tip needle 22G 50mm provides easy, less traumatic skin and rectus muscle penetration and satisfactory needle visualiza. PMID- 24348297 TI - Use of extraglottic airways in patients undergoing ambulatory laparoscopic surgery without the need for tracheal intubation. AB - BACKGROUND: Second generation extraglottic airway devices with gastric access and separate breathing channels have ushered in a new era where their use is increasingly prevalent in surgical patients who would have been traditionally intubated for general anesthesia. New innovations like the i-gel, which is constructed of a thermoplastic elastomer, provide an airtight seal around patient's perilaryngeal anatomy without the inflatable cuff mechanism found in the laryngeal mask airway supreme (LMAS). METHODS: We conducted a randomized controlled trial comparing the LMAS with the i-gel in 70 anesthetized paralyzed patients undergoing laparoscopic female sterilization. Our primary outcome measure was the oropharyngeal leak pressure (OLP). We studied secondary outcomes of successful first attempt insertion rates, time and ease of the airway and gastric tube insertion, leak fractions and pharyngeal morbidity. RESULTS: We found no difference in the OLP between LMAS and i-gel, 25.9 (4.2) versus 24.4 (4.3) s, P=0.153. Both devices had similar first attempt insertion rates (LMAS 94% vs. i-gel 91%) with similar ease and comparable times to achieve an effective airway, LMAS 14.7 (2.7) versus i-gel 16.5 (9.6) s, P=0.306, although gastric tube insertion was easier and faster for the LMAS, 7.9 (1.9) versus i-gel 14.8 (7.7) s, P<0.005. Intraoperatively, there was a significantly greater leak fraction with the i-gel of 0.06 (0.03) versus 0.04 (0.02) with the LMAS, P=0.013. Three patients (8.6%) with LMAS had mild sore throat; one patient (2.9%) had mucosal injury. No complications were documented in the i-gel group. CONCLUSIONS: Both these extraglottic airway devices offer similar OLPs, high insertion success rates at the first attempt with similar ease and insertion times (albeit longer gastric tube insertion with i-gel). Both provided effective ventilation despite a higher leak fraction with i-gel that was clinically inconsequential. PMID- 24348298 TI - Statins and succinylcholine interaction: A cause of concern for serious muscular damage in anesthesiology practice! AB - Statins are being extensively used in cardiac patient throughout the globe. Succinylcholine has been the mainstay of profound relaxation during induction and intubation of anesthesia for almost six decades now. The interactive properties of these drugs have been of major concern during routine anesthesiology practice in the last few years. However, no major research trial, prospective studies or meta-analysis are available, which can truly allay the fears of possible potential negative synergistic interactions between these two commonly used drugs. Whatever the evidence is available is hardly enough to support a positive outcome and the results have been drawn from observations of only few small studies. As a result, a continuous need among anesthesiologist fraternity is felt to arrive at a suitable inference, which can predict definite consequences of this synergistic interaction. The present article reviews some of the important observations of few handful studies which were carried out to observe any potential adverse interactions between succinylcholine and statins. PMID- 24348299 TI - Hypoglycaemia in anesthesiology practice: Diagnostic, preventive, and management strategies. AB - Diabetes mellitus has emerged as one of the fastest growing non communicable diseases worldwide. Management of diabetic patients during surgical and critically illness is of paramount challenge to anesthesiologist and intensivist. Among its major acute complications, hypoglycemia has been given lesser attention as compared to other major acute complications; diabetic ketoacidosis and hyperosmolar non ketotic coma. However, newer studies and literary evidence have established the serious concerns of morbidity and mortality, both long- and short term, related to hypoglycemia. basis. Invariably, diabetic patients are encountered in our daily routine practice of anesthesia. During fasting status as well as the perioperative period, it is hypoglycemia that is of high concern to anesthesiologist. Management has to be based on clinical, pharmacological, social, and psychological basis, so as to completely prevent the complications arising from an acute episode of hypoglycemia. This review aims to highlight various aspects of hypoglycemia and its management both from endocrine and anesthesia perspective. PMID- 24348300 TI - Spasticity - Pathogenesis, prevention and treatment strategies. AB - This review of the long-term management of spasticity addresses some of the clinical dilemmas in the management of patients with chronic disability. It is important for clinicians to have clear objectives in patient treatment and the available treatment strategies. The review reiterates the role of physical treatment in the management, and thereafter the maintenance of patients with spasticity. Spasticity is a physiological consequence of an injury to the nervous system. It is a complex problem which can cause profound disability, alone or in combination with the other features of an upper motor neuron syndrome, and can give rise to significant difficulties in the process of rehabilitation. This can be associated with profound restriction to activity and participation due to pain, weakness, and contractures. Optimum management is dependent on an understanding of its underlying physiology, an awareness of its natural history, an appreciation of the impact on the patient, and a comprehensive approach to minimizing that impact. The aim of this article is to highlight the importance, basic approach, and management options available to the general practitioner in such a complex condition. PMID- 24348301 TI - Anesthetic management of a patient with Marfan syndrome and severe aortic root dilatation undergoing cholecystectomy and partial hepatic resection. AB - Due to high mortality associated with aortic dissection, anesthetic management of patients with Marfan syndrome with severe aortic root dilation is a challenging situation. We describe the anesthetic management of a patient with Marfan syndrome with severe aortic root dilation, who required major surgery like cholecystectomy with partial liver resection under general anesthesia. A 47-year old female presented to pre-anesthetic clinic for cholecystectomy with partial hepatic resection for gall bladder carcinoma. Clinical features, transthoracic echocardiography and computed tomography of thorax supported a diagnosis of Marfan syndrome with severely dilated aortic root. Aortic dissection in patients with Marfan syndrome and severely dilated aortic root can be precipitated by major hemodynamic changes under anesthesia. Careful hemodynamic monitoring and avoidance of hemodynamic swings can prevent this life-threatening event. PMID- 24348302 TI - Inadvertent intrathecal injection of large dose magnesium sulfate. AB - The case is a 35-year-old man who underwent spinal anesthesia for emergency strangulated inguinal hernia repair. About five minutes after 3 ml intrathecal drug injection, the patient suffered respiratory distress, bradycardia, hypotension and loss of consciousness. The patient was rapidly intubated and crystalloid infusion and epinephrine drip were established. Thereafter, he was admitted in intensive care unit. Search for the cause revealed us that 3 ml of magnesium sulfate (50%) was injected mistakenly for spinal anesthesia. Two days later, he was extubated and on the fifth day, he was discharged from the hospital without an obvious evidence of complication. PMID- 24348303 TI - A child with xeroderma pigmentosum for excision of basal cell carcinoma. AB - Xeroderma pigmentosum (XP) is characterized by hypersensitivity to sunlight, ocular involvement, and progressive neurological complications. These manifestations are due to a cellular hypersensitivity to ultraviolet radiation leading to a defect in repair of DNA by the process of nucleotide excision repair. Basal cell carcinoma which is rare in children can occur with XP. Though the XP induced changes are predominately dermatologic, pose several challenges in anaesthetic management. Hence, we are reporting a 9-year-old child with XP scheduled for excision of basal cell carcinoma under general anaesthesia. PMID- 24348304 TI - Orbital exenteration under trigeminal block: An innovative method of regional anesthesia. AB - Orbital exenteration is a disfiguring operation involving the removal of the entire contents of the orbit, with or without the eyelids. It is widely felt that such extensive surgery can only be performed under general anesthesia. We report our experience with a patient who underwent orbitalexenteration under trigeminal block with intravenous sedation. A 68-year-old male patient was diagnosed to have orbital cellulitis (mucormycosis), uncontrolled diabetes mellitus, ischemic heart disease, dilated cardiomyopathy with severe left ventricular systolic dysfunction with severe pulmonary artery hypertension, and nephropathy. We decided to avoid general anesthesia for such a high-risk patient with many co-morbid illnesses. We gave trigeminal block using a 22-G spinal needle with local anesthetic solution of bupivacaine 0.5% by classic approach. A standard exenteration was performed and the patient tolerated the procedure well with no complications. PMID- 24348305 TI - Henna dye: A cause of erroneous pulse oximetry readings. AB - Pulse oximetry is a noninvasive and continuous monitoring of the pulsed saturation of hemoglobin oxygen. Because of its simplicity and usefulness, it is part of monitoring recommended for any anesthesia in the operating room. Different factors may limit the use of this monitoring. We report a case of difficulty monitoring by the presence of henna in a patient scheduled for general anesthesia in prone position. PMID- 24348306 TI - Is ketamine-propofol mixture (ketofol) an appropriate alternative induction agent for electroconvulsive therapy? PMID- 24348307 TI - Qualitative research in anesthesiology: An essential practice and need of the hour. PMID- 24348308 TI - Hemodynamically unstable atrial fibrillation after oral contrast dye instillation in a case of Boerhaave's syndrome. PMID- 24348309 TI - Anesthesia for a patient with thrombocytosis. PMID- 24348310 TI - Abnormal CVP waveform. PMID- 24348311 TI - Bifid uvula: Anesthetist don't take it lightly! PMID- 24348312 TI - Methanol toxicity following esmolol infusion in a post-operative case of pheochromocytoma resection. PMID- 24348313 TI - Anesthesia for feeding jejunostomy in a case of difficult airway: A novel approach. PMID- 24348314 TI - Intra-arterial induction for emergency intubation-Should we use? PMID- 24348315 TI - High altitude cerebral edema with a fatal outcome within 24 h of its onset: Shall acclimatization be made compulsory? PMID- 24348316 TI - Airway management for oral surgery in a patient with repaired cleft palate. PMID- 24348317 TI - Unethical practices in anesthetic research and publication: Clinical impact, consequences and preventive measures. PMID- 24348318 TI - Breathing circuit obstruction: An unusual case. PMID- 24348319 TI - Life-Threatening Gastrointestinal Mucosal Necrosis during Methotrexate Treatment for Rheumatoid Arthritis. AB - Methotrexate (MTX), a folic acid antagonist, is widely used in the treatment of neoplasms, psoriasis and rheumatoid arthritis. Despite its efficacy, MTX sometimes finds limited application because of its adverse effects, including renal or liver impairment, bone marrow toxicity and gastrointestinal mucosal injury. Intestinal mucositis, bleeding and peptic ulcers are well-known gastrointestinal adverse effects of MTX, although cases of fatal mucosal necrosis induced by MTX are extremely rare. Here, we report the case of an 82-year-old Japanese woman who developed severe gastrointestinal mucosal necrosis after 8 years of treatment with low-dose MTX (8 mg/week). In the drug lymphocyte stimulation test, MTX showed a strong positive reaction, with a stimulation index of 443% against normal controls. Physicians must be aware of potential drug induced adverse effects in patients with chronic diseases who are on long-term medication. PMID- 24348320 TI - Systemic Reactive Amyloidosis Associated with Castleman's Disease. AB - We report this case of secondary amyloidosis associated with Castleman's disease. A 51-year-old man presented with systemic symptoms of generalized weakness, fatigue, unintended weight loss, anorexia and progressively worsening abdominal distension. On examination he was found to have an indurated right-sided submandibular mass and tense ascites. He was found to have multiorgan dysfunction with deranged liver function tests and renal failure. Ascitic fluid analysis revealed evidence of spontaneous bacterial peritonitis. Biopsy of the submandibular mass revealed angiofollicular lymph node hyperplasia consistent with a diagnosis of Castleman's disease. A subsequent liver biopsy showed extensive deposition of amyloid protein. Bone marrow biopsy also showed the presence of amyloid and increased kappa light chain-restricted plasma cells. The patient was not considered a candidate for chemotherapy or solid organ transplantation in view of active sepsis and poor physical condition. Secondary systemic amyloidosis complicating Castleman's disease is very rare. Untreated secondary systemic amyloidosis often has a rapidly fatal course, such as seen in our patient. PMID- 24348321 TI - Fusobacterium liver abscess. AB - Fusobacterium is well characterized as an oropharyngeal pathogen that may induce a septic thrombophlebitis by direct extension of abscess into an adjacent neck vessel (Lemierre's syndrome); its potential for visceral abscess formation, however, remains under-recognized. A 65-year-old man with a recent history of multiple rim-enhancing liver lesions presented to the emergency room with fever and abdominal pain. Based on interval increase in the size of the lesions, abscess was suspected. A liver biopsy was performed, and although no organism could be identified on routine microscopy, Warthin-Starry stain revealed Gram negative bacilli consistent with an anaerobic Fusobacterium species as the underlying etiology of liver abscess formation. Subsequent anaerobic culture results confirmed the diagnosis. This case highlights the importance of consideration for Fusobacterium infection in the setting of liver abscess if anaerobic organisms have not yet been excluded on initial culture evaluation. PMID- 24348322 TI - Coil migration after transarterial coil embolization of a splenic artery pseudoaneurysm. AB - A 48-year-old man with a history of splenic artery pseudoaneurysm requiring transarterial embolization 3 months earlier presented to the emergency department with abdominal pain and fever. Computed tomography showed evidence of embolization coil fragments within the gastrointestinal tract. Upper endoscopy showed a large gastric ulcer with numerous embolization coils extruding into the gastric lumen. The patient underwent partial gastrectomy, distal pancreatectomy and resection of the splenic artery pseudoaneurysm. This case illustrates a rare delayed complication of transarterial embolization of a splenic artery pseudoaneurysm. PMID- 24348323 TI - The relationship between the age of onset of musical training and rhythm synchronization performance: validation of sensitive period effects. AB - A sensitive period associated with musical training has been proposed, suggesting the influence of musical training on the brain and behavior is strongest during the early years of childhood. Experiments from our laboratory have directly tested the sensitive period hypothesis for musical training by comparing musicians who began their training prior to age seven with those who began their training after age seven, while matching the two groups in terms of musical experience (Watanabe et al., 2007; Bailey and Penhune, 2010, 2012). Using this matching paradigm, the early-trained groups have demonstrated enhanced sensorimotor synchronization skills and associated differences in brain structure (Bailey et al., 2013; Steele et al., 2013). The current study takes a different approach to investigating the sensitive period hypothesis for musical training by examining a single large group of unmatched musicians (N = 77) and exploring the relationship between age of onset of musical training as a continuous variable and performance on the Rhythm Synchronization Task (RST), a previously used auditory-motor RST. Interestingly, age of onset was correlated with task performance for those who began training earlier, however, no such relationship was observed among those who began training in their later childhood years. In addition, years of formal training showed a similar pattern. However, individual working memory scores were predictive of task performance, regardless of age of onset of musical training. Overall, these results support the sensitive period hypothesis for musical training and suggest a non-linear relationship between age of onset of musical training and auditory-motor rhythm synchronization abilities, such that a relationship exists early in childhood but then plateaus later on in development, similar to maturational growth trajectories of brain regions implicated in playing music. PMID- 24348324 TI - Attention effects on the processing of task-relevant and task-irrelevant speech sounds and letters. AB - We used event-related brain potentials (ERPs) to study effects of selective attention on the processing of attended and unattended spoken syllables and letters. Participants were presented with syllables randomly occurring in the left or right ear and spoken by different voices and with a concurrent foveal stream of consonant letters written in darker or lighter fonts. During auditory phonological (AP) and non-phonological tasks, they responded to syllables in a designated ear starting with a vowel and spoken by female voices, respectively. These syllables occurred infrequently among standard syllables starting with a consonant and spoken by male voices. During visual phonological and non phonological tasks, they responded to consonant letters with names starting with a vowel and to letters written in dark fonts, respectively. These letters occurred infrequently among standard letters with names starting with a consonant and written in light fonts. To examine genuine effects of attention and task on ERPs not overlapped by ERPs associated with target processing or deviance detection, these effects were studied only in ERPs to auditory and visual standards. During selective listening to syllables in a designated ear, ERPs to the attended syllables were negatively displaced during both phonological and non phonological auditory tasks. Selective attention to letters elicited an early negative displacement and a subsequent positive displacement (Pd) of ERPs to attended letters being larger during the visual phonological than non phonological task suggesting a higher demand for attention during the visual phonological task. Active suppression of unattended speech during the AP and non phonological tasks and during the visual phonological tasks was suggested by a rejection positivity (RP) to unattended syllables. We also found evidence for suppression of the processing of task-irrelevant visual stimuli in visual ERPs during auditory tasks involving left-ear syllables. PMID- 24348325 TI - Nur transcription factors in stress and addiction. AB - The Nur transcription factors Nur77 (NGFI-B, NR4A1), Nurr1 (NR4A2), and Nor-1 (NR4A3) are a sub-family of orphan members of the nuclear receptor superfamily. These transcription factors are products of immediate early genes, whose expression is rapidly and transiently induced in the central nervous system by several types of stimuli. Nur factors are present throughout the hypothalamus pituitary-adrenal (HPA) axis where are prominently induced in response to stress. Drugs of abuse and stress also induce the expression of Nur factors in nuclei of the motivation/reward circuit of the brain, indicating their participation in the process of drug addiction and in non-hypothalamic responses to stress. Repeated use of addictive drugs and chronic stress induce long-lasting dysregulation of the brain motivation/reward circuit due to reprogramming of gene expression and enduring alterations in neuronal function. Here, we review the data supporting that Nur transcription factors are key players in the molecular basis of the dysregulation of neuronal circuits involved in chronic stress and addiction. PMID- 24348326 TI - Small non-coding RNAs add complexity to the RNA pathogenic mechanisms in trinucleotide repeat expansion diseases. AB - Trinucleotide-repeat expansion diseases (TREDs) are a group of inherited human genetic disorders normally involving late-onset neurological/neurodegenerative affectation. Trinucleotide-repeat expansions occur in coding and non-coding regions of unique genes that typically result in protein and RNA toxic gain of function, respectively. In polyglutamine (polyQ) disorders caused by an expanded CAG repeat in the coding region of specific genes, neuronal dysfunction has been traditionally linked to the long polyQ stretch. However, a number of evidences suggest a detrimental role of the expanded/mutant mRNA, which may contribute to cell function impairment. In this review we describe the mechanisms of RNA induced toxicity in TREDs with special focus in small-non-coding RNA pathogenic mechanisms and we summarize and comment on translational approaches targeting the expanded trinucleotide-repeat for disease modifying therapies. PMID- 24348328 TI - Comparative functional expression of nAChR subtypes in rodent DRG neurons. AB - We investigated the functional expression of nicotinic acetylcholine receptors (nAChRs) in heterogeneous populations of dissociated rat and mouse lumbar dorsal root ganglion (DRG) neurons by calcium imaging. By this experimental approach, it is possible to investigate the functional expression of multiple receptor and ion channel subtypes across more than 100 neuronal and glial cells simultaneously. Based on nAChR expression, DRG neurons could be divided into four subclasses: (1) neurons that express predominantly alpha3beta4 and alpha6beta4 nAChRs; (2) neurons that express predominantly alpha7 nAChRs; (3) neurons that express a combination of alpha3beta4/alpha6beta4 and alpha7 nAChRs; and (4) neurons that do not express nAChRs. In this comparative study, the same four neuronal subclasses were observed in mouse and rat DRG. However, the expression frequency differed between species: substantially more rat DRG neurons were in the first three subclasses than mouse DRG neurons, at all developmental time points tested in our study. Approximately 70-80% of rat DRG neurons expressed functional nAChRs, in contrast to only ~15-30% of mouse DRG neurons. Our study also demonstrated functional coupling between nAChRs, voltage-gated calcium channels, and mitochondrial Ca(2) (+) transport in discrete subsets of DRG neurons. In contrast to the expression of nAChRs in DRG neurons, we demonstrated that a subset of non neuronal DRG cells expressed muscarinic acetylcholine receptors and not nAChRs. The general approach to comparative cellular neurobiology outlined in this paper has the potential to better integrate molecular and systems neuroscience by uncovering the spectrum of neuronal subclasses present in a given cell population and the functionally integrated signaling components expressed in each subclass. PMID- 24348327 TI - Wnts in adult brain: from synaptic plasticity to cognitive deficiencies. AB - During development of the central nervous system the Wnt signaling pathway has been implicated in a wide spectrum of physiological processes, including neuronal connectivity and synapse formation. Wnt proteins and components of the Wnt pathway are expressed in the brain since early development to the adult life, however, little is known about its role in mature synapses. Here, we review evidences indicating that Wnt proteins participate in the remodeling of pre- and post-synaptic regions, thus modulating synaptic function. We include the most recent data in the literature showing that Wnts are constantly released in the brain to maintain the basal neural activity. Also, we review the evidences that involve components of the Wnt pathway in the development of neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling. Finally, we include the evidences that support a neuroprotective role of Wnt proteins in Alzheimer's disease. We postulate that deregulation in Wnt signaling might have a fundamental role in the origin of neurological diseases, by altering the synaptic function at stages where the phenotype is not yet established but when the cognitive decline starts. PMID- 24348330 TI - Four-dimensional multi-site photolysis of caged neurotransmitters. AB - Neurons receive thousands of synaptic inputs that are distributed in space and time. The systematic study of how neurons process these inputs requires a technique to stimulate multiple yet highly targeted points of interest along the neuron's dendritic tree. Three-dimensional multi-focal patterns produced via holographic projection combined with two-photon photolysis of caged compounds can provide for highly localized release of neurotransmitters within each diffraction limited focus, and in this way emulate simultaneous synaptic inputs to the neuron. However, this technique so far cannot achieve time-dependent stimulation patterns due to fundamental limitations of the hologram-encoding device and other factors that affect the consistency of controlled synaptic stimulation. Here, we report an advanced technique that enables the design and application of arbitrary spatio-temporal photostimulation patterns that resemble physiological synaptic inputs. By combining holographic projection with a programmable high-speed light switching array, we have overcome temporal limitations with holographic projection, allowing us to mimic distributed activation of synaptic inputs leading to action potential generation. Our experiments uniquely demonstrate multi-site two-photon glutamate uncaging in three dimensions with submillisecond temporal resolution. Implementing this approach opens up new prospects for studying neuronal synaptic integration in four dimensions. PMID- 24348329 TI - Signal processing by T-type calcium channel interactions in the cerebellum. AB - T-type calcium channels of the Cav3 family are unique among voltage-gated calcium channels due to their low activation voltage, rapid inactivation, and small single channel conductance. These special properties allow Cav3 calcium channels to regulate neuronal processing in the subthreshold voltage range. Here, we review two different subthreshold ion channel interactions involving Cav3 channels and explore the ability of these interactions to expand the functional roles of Cav3 channels. In cerebellar Purkinje cells, Cav3 and intermediate conductance calcium-activated potassium (IKCa) channels form a novel complex which creates a low voltage-activated, transient outward current capable of suppressing temporal summation of excitatory postsynaptic potentials (EPSPs). In large diameter neurons of the deep cerebellar nuclei, Cav3-mediated calcium current (I T) and hyperpolarization-activated cation current (I H) are activated during trains of inhibitory postsynaptic potentials. These currents have distinct, and yet synergistic, roles in the subthreshold domain with I T generating a rebound burst and I H controlling first spike latency and rebound spike precision. However, by shortening the membrane time constant the membrane returns towards resting value at a faster rate, allowing I H to increase the efficacy of I T and increase the range of burst frequencies that can be generated. The net effect of Cav3 channels thus depends on the channels with which they are paired. When expressed in a complex with a KCa channel, Cav3 channels reduce excitability when processing excitatory inputs. If functionally coupled with an HCN channel, the depolarizing effect of Cav3 channels is accentuated, allowing for efficient inversion of inhibitory inputs to generate a rebound burst output. Therefore, signal processing relies not only on the activity of individual subtypes of channels but also on complex interactions between ion channels whether based on a physical complex or by indirect effects on membrane properties. PMID- 24348332 TI - Mapping the pathophysiology of schizophrenia: interactions between multiple cellular pathways. PMID- 24348331 TI - Enhancement of ventricular-subventricular zone-derived neurogenesis and oligodendrogenesis by erythropoietin and its derivatives. AB - In the postnatal mammalian brain, stem cells in the ventricular-subventricular zone (V-SVZ) continuously generate neuronal and glial cells throughout life. Genetic labeling of cells of specific lineages have demonstrated that the V-SVZ is an important source of the neuroblasts and/or oligodendrocyte progenitor cells (OPCs) that migrate toward injured brain areas in response to several types of insult, including ischemia and demyelinating diseases. However, this spontaneous regeneration is insufficient for complete structural and functional restoration of the injured brain, so interventions to enhance these processes are sought for clinical applications. Erythropoietin (EPO), a clinically applied erythropoietic factor, is reported to have cytoprotective effects in various kinds of insult in the central nervous system. Moreover, recent studies suggest that EPO promotes the V-SVZ-derived neurogenesis and oligodendrogenesis. EPO increases the proliferation of progenitors in the V-SVZ and/or the migration and differentiation of their progenies in and around injured areas, depending on the dosage, timing, and duration of treatment, as well as the type of animal model used. On the other hand, EPO has undesirable side effects, including thrombotic complications. We recently demonstrated that a 2-week treatment with the EPO derivative asialo-EPO promotes the differentiation of V-SVZ-derived OPCs into myelin-forming mature oligodendrocytes in the injured white matter of neonatal mice without causing erythropoiesis. Here we present an overview of the multifaceted effects of EPO and its derivatives in the V-SVZ and discuss the possible applications of these molecules in regenerative medicine. PMID- 24348333 TI - Characterization of Wnt/beta-catenin and BMP/Smad signaling pathways in an in vitro model of amyotrophic lateral sclerosis. AB - Different pathways activated by morphogens of the early embryonic development, such as the Wnt and the Bone Morphogenetic Protein (BMP) ligands, are involved in diverse physiological and pathological conditions of the nervous system, including neurodegeneration. In this work, we have analyzed the endogenous activity of the canonical Wnt/beta-catenin and BMP/Smad-dependent pathways in an in vitro model of amyotrophic lateral sclerosis (ALS), given by motor neuron-like NSC34 cells stably expressing wild-type or G93A mutated forms of human Cu/Zn superoxide dismutase-1 (SOD1). As ALS-derived motor neurons, NSC34 cells expressing mutated hSOD1 show a decreased proliferation rate, are more susceptible to oxidation-induced cell death and display Golgi fragmentation. In addition, they display an impaired ability to induce the expression of the motor neuronal marker Hb9 and, consistently, to morphologically differentiate into a motor neuronal phenotype. Regarding signaling, our data show that the transcriptional activity associated to the Wnt/beta-catenin pathway is decreased, a finding possibly associated to the cytosolic aggregation of beta-catenin. In turn, the BMP-dependent phosphorylation of Smad1 and the transcriptional activation of the BMP/Smad pathway is increased in the pathologic model. Together, these findings suggest that Wnt/beta-catenin and the BMP-dependent pathways could play relevant roles in the neurodegeneration of motor neurons in the context of ALS. PMID- 24348334 TI - Redox environment is an intracellular factor to operate distinct pathways for aggregation of Cu,Zn-superoxide dismutase in amyotrophic lateral sclerosis. AB - Dominant mutations in Cu,Zn-superoxide dismutase (SOD1) cause a familial form of amyotrophic lateral sclerosis (fALS). Misfolding and aggregation of mutant SOD1 proteins are a pathological hallmark of SOD1-related fALS cases; however, the molecular mechanism of SOD1 aggregation remains controversial. Here, I have used E. coli as a model organism and shown multiple distinct pathways of SOD1 aggregation that are dependent upon its thiol-disulfide status. Overexpression of fALS-mutant SOD1s in the cytoplasm of E. coli BL21 and SHuffle(TM), where redox environment is reducing and oxidizing, respectively, resulted in the formation of insoluble aggregates with notable differences; a disulfide bond of SOD1 was completely reduced in BL21 or abnormally formed between SOD1 molecules in SHuffle(TM). Depending upon intracellular redox environment, therefore, mutant SOD1 is considered to misfold/aggregate through distinct pathways, which would be relevant in description of the pathological heterogeneity of SOD1-related fALS cases. PMID- 24348335 TI - Undifferentiated embryonic stem cells express ionotropic glutamate receptor mRNAs. AB - Ionotropic glutamate receptors (iGluRs) do not only mediate the majority of excitatory neurotransmission in the vertebrate CNS, but also modulate pre- and postnatal neurogenesis. Most of the studies on the developmental role of iGluRs are performed on neural progenitors and neural stem cells (NSCs). We took a step back in our study by examining the role of iGluRs in the earliest possible cell type, embryonic stem cells (ESCs), by looking at the mRNA expression of the major iGluR subfamilies in undifferentiated mouse ESCs. For that, we used two distinct murine ES cell lines, 46C ESCs and J1 ESCs. Regarding 46C ESCs, we found transcripts of kainate receptors (KARs) (GluK2 to GluK5), AMPA receptors (AMPARs) (GluA1, GluA3, and GluA4), and NMDA receptors (NMDARs) (GluN1, and GluN2A to GluN2D). Analysis of 46C-derived cells of later developmental stages, namely neuroepithelial precursor cells (NEPs) and NSCs, revealed that the mRNA expression of KARs is significantly upregulated in NEPs and, subsequently, downregulated in NSCs. However, we could not detect any protein expression of any of the KAR subunits present on the mRNA level either in ESCs, NEPs, or NSCs. Regarding AMPARs and NMDARs, GluN2A is weakly expressed at the protein level only in NSCs. Matching our findings for iGluRs, all three cell types were found to weakly express pre- and postsynaptic markers of glutamatergic synapses only at the mRNA level. Finally, we performed patch-clamp recordings of 46C ESCs and could not detect any current upon iGluR agonist application. Similar to 46C ESCs, J1 ESCs express KARs (GluK2 to GluK5), AMPARs (GluA3), and NMDARs (GluN1, and GluN2A to GluN2D) at the mRNA level, but these transcripts are not translated into receptor proteins either. Thus, we conclude that ESCs do not contain functional iGluRs, although they do express an almost complete set of iGluR subunit mRNAs. PMID- 24348336 TI - A role for the canonical nuclear factor-kappaB pathway in coupling neurotrophin induced differential survival of developing spiral ganglion neurons. AB - Neurotrophins are key players of neural development by controlling cell death programs. However, the signaling pathways that mediate their selective responses in different populations of neurons remain unclear. In the mammalian cochlea, sensory neurons differentiate perinatally into type I and II populations both expressing TrkB and TrkC, which bind respectively brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3). How these two neuronal populations respond differentially to these two neurotrophins remains unknown. Here, we report in rat the segregation of the nuclear factor-kappaB (NFkappaB) subunit p65 specifically within the type II population postnatally. Using dissociated cultures of embryonic and postnatal spiral ganglion neurons, we observed a specific requirement of NFkappaB for BDNF but not NT3-dependent neuronal survival during a particular postnatal time window that corresponds to a period of neuronal cell death and hair cell innervation refinement in the developing cochlea. Consistently, postnatal p65 knockout mice showed a specific decreased number in type II spiral ganglion neurons. Taken together, these results identify NFkappaB as a type II neuron-specific factor that participates in the selective survival effects of BDNF and NT3 signaling on developing spiral ganglion neurons. PMID- 24348337 TI - Molecular mechanisms driving homeostatic plasticity of neurotransmitter release. AB - Homeostatic plasticity is a process by which neurons adapt to the overall network activity to keep their firing rates in a reasonable range. At the cellular level this kind of plasticity comprises modulation of cellular excitability and tuning of synaptic strength. In this review we concentrate on presynaptic homeostatic plasticity controlling the efficacy of neurotransmitter release from presynaptic boutons. While morphological and electrophysiological approaches were successful to describe homeostatic plasticity-induced changes in the presynaptic architecture and function, cellular and molecular mechanisms underlying those modifications remained largely unknown for a long time. We summarize the latest progress made in the understanding of homeostasis-induced regulation of different steps of the synaptic vesicle cycle and the molecular machineries involved in this process. We particularly focus on the role of presynaptic scaffolding proteins, which functionally and spatially organize synaptic vesicle clusters, neurotransmitter release sites and the associated endocytic machinery. These proteins turned out to be major presynaptic substrates for remodeling during homeostatic plasticity. Finally, we discuss cellular processes and signaling pathways acting during homeostatic molecular remodeling and their potential involvement in the maladaptive plasticity occurring in multiple neuropathologic conditions such as neurodegeneration, epilepsy and neuropsychiatric disorders. PMID- 24348338 TI - Short duration waveforms recorded extracellularly from freely moving rats are representative of axonal activity. AB - While extracellular somatic action potentials from freely moving rats have been well characterized, axonal activity has not. We report direct extracellular tetrode recordings of putative axons whose principal feature is a short duration waveform (SDW) with an average peak-trough length less than 179 MUs. While SDW recordings using tetrodes have previously been treated as questionable or classified as cells, we hypothesize that they are representative of axonal activity. These waveforms have significantly shorter duration than somatic action potentials, are triphasic and are therefore similar to classic descriptions of microelectrode recordings in white matter and of in vitro action potential propagation along axons. We describe SDWs recorded from pure white-matter tracts including the alveus and corpus callosum. Recordings of several SDWs in the alveus exhibit grid-like firing patterns suggesting these axons carry spatial information from entorhinal cortical neurons. Finally, we locally injected the GABAA agonist Muscimol into layer CA1 of the hippocampus while simultaneously recording somatic activity and SDWs on the same tetrodes. The persistent activity of SDWs during Muscimol inactivation of somatic action potentials indicates that SDWs are representative of action potential propagation along axons projecting from more distal somata. This characterization is important as it illustrates the dangers of exclusively using spike duration as the sole determinant of unit type, particularly in the case of interneurons whose peak-trough times overlap with SDWs. It may also allow future studies to explore how axonal projections from disparate brain regions integrate spatial information in the hippocampus, and provide a basis for studying the effects of pharmaceutical agents on signal transmission in axons, and ultimately to aid in defining the potential role of axons in cognition. PMID- 24348339 TI - Classification of neocortical interneurons using affinity propagation. AB - In spite of over a century of research on cortical circuits, it is still unknown how many classes of cortical neurons exist. In fact, neuronal classification is a difficult problem because it is unclear how to designate a neuronal cell class and what are the best characteristics to define them. Recently, unsupervised classifications using cluster analysis based on morphological, physiological, or molecular characteristics, have provided quantitative and unbiased identification of distinct neuronal subtypes, when applied to selected datasets. However, better and more robust classification methods are needed for increasingly complex and larger datasets. Here, we explored the use of affinity propagation, a recently developed unsupervised classification algorithm imported from machine learning, which gives a representative example or exemplar for each cluster. As a case study, we applied affinity propagation to a test dataset of 337 interneurons belonging to four subtypes, previously identified based on morphological and physiological characteristics. We found that affinity propagation correctly classified most of the neurons in a blind, non-supervised manner. Affinity propagation outperformed Ward's method, a current standard clustering approach, in classifying the neurons into 4 subtypes. Affinity propagation could therefore be used in future studies to validly classify neurons, as a first step to help reverse engineer neural circuits. PMID- 24348343 TI - A perspective on terra incognita: uncovering the neuroanatomy of the human subcortex. AB - Recent exciting advancements in the field of in vivo neuroimaging allow for visualization of the living human brain with unprecedented anatomical detail. Large consortium studies will provide us with novel insights in the function and connectivity of the human brain. However, it is unlikely that the spatial resolution obtained using in vivo imaging will, in the near future, approximate the level of detail obtained in post-mortem anatomical studies. Initiatives such as the recently published Big Brain project (Amunts et al., 2013) herald a novel approach in post-mortem brain research. We feel that linking data from histological observations with in vivo imaging studies will greatly advance our understanding of the functional neuroanatomy of the human brain. PMID- 24348341 TI - Corticosterone rapidly increases thorns of CA3 neurons via synaptic/extranuclear glucocorticoid receptor in rat hippocampus. AB - Modulation of synapses under acute stress is attracting much attention. Exposure to acute stress induces corticosterone (CORT) secretion from the adrenal cortex, resulting in rapid increase of CORT levels in plasma and the hippocampus. We tried to test whether rapid CORT effects involve activation of essential kinases as non-genomic processes. We demonstrated rapid effects (~1 h) of CORT on the density of thorns, by imaging Lucifer Yellow-injected neurons in adult male rat hippocampal slices. Thorns of thorny excrescences of CA3 hippocampal neurons are post-synaptic regions whose presynaptic partners are mossy fiber terminals. The application of CORT at 100, 500, and 1000 nM induced a rapid increase in the density of thorns in the stratum lucidum of CA3 pyramidal neurons. Co administration of RU486, an antagonist of glucocorticoid receptor (GR), abolished the effect of CORT. Blocking a single kinase, including MAPK, PKA, or PKC, suppressed CORT-induced enhancement of thorn-genesis. On the other hand, GSK 3beta was not involved in the signaling of thorn-genesis. Blocking AMPA receptors suppressed the CORT effect. Expression of CA3 synaptic/extranuclear GR was demonstrated by immunogold electron microscopic analysis. From these results, stress levels of CORT (100-1000 nM) might drive the rapid thorn-genesis via synaptic/extranuclear GR and multiple kinase pathways, although a role of nuclear GRs cannot be completely excluded. PMID- 24348340 TI - Japanese studies on neural circuits and behavior of Caenorhabditis elegans. AB - The nematode Caenorhabditis elegans is an ideal organism for studying neural plasticity and animal behaviors. A total of 302 neurons of a C. elegans hermaphrodite have been classified into 118 neuronal groups. This simple neural circuit provides a solid basis for understanding the mechanisms of the brains of higher animals, including humans. Recent studies that employ modern imaging and manipulation techniques enable researchers to study the dynamic properties of nervous systems with great precision. Behavioral and molecular genetic analyses of this tiny animal have contributed greatly to the advancement of neural circuit research. Here, we will review the recent studies on the neural circuits of C. elegans that have been conducted in Japan. Several laboratories have established unique and clever methods to study the underlying neuronal substrates of behavioral regulation in C. elegans. The technological advances applied to studies of C. elegans have allowed new approaches for the studies of complex neural systems. Through reviewing the studies on the neuronal circuits of C. elegans in Japan, we will analyze and discuss the directions of neural circuit studies. PMID- 24348342 TI - GABAergic neurons in the preoptic area send direct inhibitory projections to orexin neurons. AB - Populations of neurons in the hypothalamic preoptic area (POA) fire rapidly during sleep, exhibiting sleep/waking state-dependent firing patterns that are the reciprocal of those observed in the arousal system. The majority of these preoptic "sleep-active" neurons contain the inhibitory neurotransmitter GABA. On the other hand, a population of neurons in the lateral hypothalamic area (LHA) contains orexins, which play an important role in the maintenance of wakefulness, and exhibit an excitatory influence on arousal-related neurons. It is important to know the anatomical and functional interactions between the POA sleep-active neurons and orexin neurons, both of which play important, but opposite roles in regulation of sleep/wakefulness states. In this study, we confirmed that specific pharmacogenetic stimulation of GABAergic neurons in the POA leads to an increase in the amount of non-rapid eye movement (NREM) sleep. We next examined direct connectivity between POA GABAergic neurons and orexin neurons using channelrhodopsin 2 (ChR2) as an anterograde tracer as well as an optogenetic tool. We expressed ChR2-eYFP selectively in GABAergic neurons in the POA by AAV mediated gene transfer, and examined the projection sites of ChR2-eYFP-expressing axons, and the effect of optogenetic stimulation of ChR2-eYFP on the activity of orexin neurons. We found that these neurons send widespread projections to wakefulness-related areas in the hypothalamus and brain stem, including the LHA where these fibers make close appositions to orexin neurons. Optogenetic stimulation of these fibers resulted in rapid inhibition of orexin neurons. These observations suggest direct connectivity between POA GABAergic neurons and orexin neurons. PMID- 24348344 TI - Music and emotion-a composer's perspective. AB - This article takes an experiential and anecdotal look at the daily lives and work of film composers as creators of music. It endeavors to work backwards from what practitioners of the art and craft of music do instinctively or unconsciously, and try to shine a light on it as a conscious process. It examines the role of the film composer in his task to convey an often complex set of emotions, and communicate with an immediacy and universality that often sit outside of common language. Through the experiences of the author, as well as interviews with composer colleagues, this explores both concrete and abstract ways in which music can bring meaning and magic to words and images, and as an underscore to our daily lives. PMID- 24348345 TI - Unilateral hearing during development: hemispheric specificity in plastic reorganizations. AB - The present study investigates the hemispheric contributions of neuronal reorganization following early single-sided hearing (unilateral deafness). The experiments were performed on ten cats from our colony of deaf white cats. Two were identified in early hearing screening as unilaterally congenitally deaf. The remaining eight were bilaterally congenitally deaf, unilaterally implanted at different ages with a cochlear implant. Implanted animals were chronically stimulated using a single-channel portable signal processor for two to five months. Microelectrode recordings were performed at the primary auditory cortex under stimulation at the hearing and deaf ear with bilateral cochlear implants. Local field potentials (LFPs) were compared at the cortex ipsilateral and contralateral to the hearing ear. The focus of the study was on the morphology and the onset latency of the LFPs. With respect to morphology of LFPs, pronounced hemisphere-specific effects were observed. Morphology of amplitude-normalized LFPs for stimulation of the deaf and the hearing ear was similar for responses recorded at the same hemisphere. However, when comparisons were performed between the hemispheres, the morphology was more dissimilar even though the same ear was stimulated. This demonstrates hemispheric specificity of some cortical adaptations irrespective of the ear stimulated. The results suggest a specific adaptation process at the hemisphere ipsilateral to the hearing ear, involving specific (down-regulated inhibitory) mechanisms not found in the contralateral hemisphere. Finally, onset latencies revealed that the sensitive period for the cortex ipsilateral to the hearing ear is shorter than that for the contralateral cortex. Unilateral hearing experience leads to a functionally-asymmetric brain with different neuronal reorganizations and different sensitive periods involved. PMID- 24348346 TI - Decomposition of abnormal free locomotor behavior in a rat model of Parkinson's disease. AB - Poverty of spontaneous movement, slowed execution and reduced amplitudes of movement (akinesia, brady- and hypokinesia) are cardinal motor manifestations of Parkinson's disease that can be modeled in experimental animals by brain lesions affecting midbrain dopaminergic neurons. Most behavioral investigations in experimental parkinsonism have employed short-term observation windows to assess motor impairments. We postulated that an analysis of longer-term free exploratory behavior could provide further insights into the complex fine structure of altered locomotor activity in parkinsonian animals. To this end, we video monitored 23 h of free locomotor behavior and extracted several behavioral measures before and after the expression of a severe parkinsonian phenotype following bilateral 6-hydroxydopamine (6-OHDA) lesions of the rat dopaminergic substantia nigra. Unbiased stereological cell counting verified the degree of midbrain tyrosine hydroxylase positive cell loss in the substantia nigra and ventral tegmental area. In line with previous reports, overall covered distance and maximal motion speed of lesioned animals were found to be significantly reduced compared to controls. Before lesion surgery, exploratory rat behavior exhibited a bimodal distribution of maximal speed values obtained for single movement episodes, corresponding to a "first" and "second gear" of motion. 6-OHDA injections significantly reduced the incidence of second gear motion episodes and also resulted in an abnormal prolongation of these fast motion events. Likewise, the spatial spread of such episodes was increased in 6-OHDA rats. The increase in curvature of motion tracks was increased in both lesioned and control animals. We conclude that the discrimination of distinct modes of motion by statistical decomposition of longer-term spontaneous locomotion provides useful insights into the fine structure of fluctuating motor functions in a rat analog of Parkinson's disease. PMID- 24348347 TI - Training changes processing of speech cues in older adults with hearing loss. AB - Aging results in a loss of sensory function, and the effects of hearing impairment can be especially devastating due to reduced communication ability. Older adults with hearing loss report that speech, especially in noisy backgrounds, is uncomfortably loud yet unclear. Hearing loss results in an unbalanced neural representation of speech: the slowly-varying envelope is enhanced, dominating representation in the auditory pathway and perceptual salience at the cost of the rapidly-varying fine structure. We hypothesized that older adults with hearing loss can be trained to compensate for these changes in central auditory processing through directed attention to behaviorally-relevant speech sounds. To that end, we evaluated the effects of auditory-cognitive training in older adults (ages 55-79) with normal hearing and hearing loss. After training, the auditory training group with hearing loss experienced a reduction in the neural representation of the speech envelope presented in noise, approaching levels observed in normal hearing older adults. No changes were noted in the control group. Importantly, changes in speech processing were accompanied by improvements in speech perception. Thus, central processing deficits associated with hearing loss may be partially remediated with training, resulting in real-life benefits for everyday communication. PMID- 24348348 TI - Harnessing electric potential: DLPFC tDCS induces widespread brain perfusion changes. PMID- 24348349 TI - Valproate reopens critical-period learning of absolute pitch. AB - Absolute pitch, the ability to identify or produce the pitch of a sound without a reference point, has a critical period, i.e., it can only be acquired early in life. However, research has shown that histone-deacetylase inhibitors (HDAC inhibitors) enable adult mice to establish perceptual preferences that are otherwise impossible to acquire after youth. In humans, we found that adult men who took valproate (VPA) (a HDAC inhibitor) learned to identify pitch significantly better than those taking placebo-evidence that VPA facilitated critical-period learning in the adult human brain. Importantly, this result was not due to a general change in cognitive function, but rather a specific effect on a sensory task associated with a critical-period. PMID- 24348350 TI - Stress modulates intestinal secretory immunoglobulin A. AB - Stress is a response of the central nervous system to environmental stimuli perceived as a threat to homeostasis. The stress response triggers the generation of neurotransmitters and hormones from the hypothalamus pituitary adrenal axis, sympathetic axis and brain gut axis, and in this way modulates the intestinal immune system. The effects of psychological stress on intestinal immunity have been investigated mostly with the restraint/immobilization rodent model, resulting in an up or down modulation of SIgA levels depending on the intensity and time of exposure to stress. SIgA is a protein complex formed by dimeric (dIgA) or polymeric IgA (pIgA) and the secretory component (SC), a peptide derived from the polymeric immunoglobulin receptor (pIgR). The latter receptor is a transmembrane protein expressed on the basolateral side of gut epithelial cells, where it uptakes dIgA or pIgA released by plasma cells in the lamina propria. As a result, the IgA-pIgR complex is formed and transported by vesicles to the apical side of epithelial cells. pIgR is then cleaved to release SIgA into the luminal secretions of gut. Down modulation of SIgA associated with stress can have negative repercussions on intestinal function and integrity. This can take the form of increased adhesion of pathogenic agents to the intestinal epithelium and/or an altered balance of inflammation leading to greater intestinal permeability. Most studies on the molecular and biochemical mechanisms involved in the stress response have focused on systemic immunity. The present review analyzes the impact of stress (mostly by restraint/immobilization, but also with mention of other models) on the generation of SIgA, pIgR and other humoral and cellular components involved in the intestinal immune response. Insights into these mechanisms could lead to better therapies for protecting against pathogenic agents and avoiding epithelial tissue damage by modulating intestinal inflammation. PMID- 24348351 TI - Polymorphisms of the OXTR gene explain why sales professionals love to help customers. AB - Polymorphisms of the OXTR gene affect people's social interaction styles in various social encounters: carriers of the OXTR GG, compared to the OXTR AA/AG in general, are more motivated to interact socially and detect social salience. We focus on sales professionals operating in knowledge intensive organizations. Study 1, with a sample of 141 sales people, shows that carriers of the OXTR GG allele, compared to the OXTR AA/AG allele, are more motivated to help customers than to manipulatively impose goods/services on them. Study 2, using genomic functional magnetic resonance imaging (fMRI) on a sample of 21 sales professionals processing facial pictures with different emotional valences, investigates key nuclei of social brain regions (SBRs). Compared to OXTR AA/AG carriers, OXTR GG carriers experience greater effective connectivity between SBRs of interest measured by Granger causality tests using univariate Haugh tests. In addition, the multivariate El-Himdi and Roy tests demonstrate that the amygdala, prefrontal cortex, and pars opercularis (inferior frontal gyrus) play key roles when processing emotional expressions. The bilateral amygdala and medial prefrontal cortex (mPFC) show significantly greater clout-influence on other brain regions-for GG allele carriers than non-carriers; likewise, the bilateral pars opercularis, left amygdala, and left mPFC are more receptive to activity in other brain regions among GG allele carriers than AG/AA allele carriers are. Thus, carriers of the OXTR GG allele are more sensitive to changes in emotional cues, enhancing social salience. To our knowledge, this is the first study on how insights from imaging genetics help understanding of the social motivation of people operating in a professional setting. PMID- 24348352 TI - Oscillatory interaction between amygdala and hippocampus coordinates behavioral modulation based on reward expectation. AB - The aim of this study is to examine how the amygdala and hippocampus interact for behavioral performance modulated by different Reward-expectations (REs). We simultaneously recorded neuronal spikes and local field potential from the basolateral amygdala and hippocampal CA1 while rats were performing a light-side discrimination task with different expectations of a high or low probability of reward delivery. Here, we report the following results. First, the rats actually modulated their behavioral performance on their expectations of a high or low probability of reward. Second, we found more neurons related to RE in the amygdala and more neurons related to task performance in the hippocampus. Third, a prominent increase in the coherence of high-frequency oscillations (HFOs) (90 150 Hz) between the amygdala and the hippocampus was present during high RE. Fourth, coherent HFOs during inter-trial intervals and theta coherence during trials had significant correlations with the behavioral goal-selection time. Finally, cross-frequency couplings of LFPs within and across the amygdala and hippocampus occurred during ITI. These results suggest that the amygdala and hippocampus have different functional roles in the present task with different REs, and the distinctive band of coherence between the amygdala and the hippocampus contributes to behavioral modulation on the basis of REs. We propose that the amygdala influences firing rates and the strength of synchronization of hippocampal neurons through coherent oscillation, which is a part of the mechanism of how reward expectations modulate goal-directed behavior. PMID- 24348353 TI - Skills development in infants: a possible role for widespread neurogenesis? PMID- 24348354 TI - Appetitive behavioral traits and stimulus intensity influence maintenance of conditioned fear. AB - INDIVIDUAL DIFFERENCES IN APPETITIVE LEARNING HAVE LONG BEEN REPORTED, AND GENERALLY DIVIDE INTO TWO CLASSES OF RESPONSES: cue- vs. reward-directed. The influence of cue- vs. reward-directed phenotypes on aversive cue processing, is less well understood. In the current study, we first categorized rats based on their predominant cue-directed orienting responses during appetitive Pavlovian conditioning. Then, we investigated the effect of phenotype on the latency to exit a familiar dark environment and enter an unfamiliar illuminated open field. Next, we examined whether the two phenotypes responded differently to a reconsolidation updating manipulation (retrieval+extinction) after fear conditioning. We report that the rats with a cue-directed ("orienting") phenotype differentially respond to the open field, and also to fear conditioning, depending on US-intensity. In addition, our findings suggest that, regardless of appetitive phenotype or shock intensity, extinction within the reconsolidation window prevents spontaneous recovery of fear. PMID- 24348355 TI - What motivates gambling behavior? Insight into dopamine's role. PMID- 24348356 TI - GluN2B-containing NMDA receptors and AMPA receptors in medial prefrontal cortex are necessary for odor span in rats. AB - Working memory is a type of short-term memory involved in the maintenance and manipulation of information essential for complex cognition. While memory span capacity has been extensively studied in humans as a measure of working memory, it has received considerably less attention in rodents. Our aim was to examine the role of the N-methyl-D-aspartate (NMDA) and alpha-Amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) glutamate receptors in odor span capacity using systemic injections or infusions of receptor antagonists into the medial prefrontal cortex (mPFC). Long Evans rats were trained on a well-characterized odor span task (OST). Initially, rats were trained to dig for a food reward in sand followed by training on a non-match to sample discrimination using sand scented with household spices. The rats were then required to perform a serial delayed non-match to sample procedure which was their odor span. Systemic injection of the broad spectrum NMDA receptor antagonist 3-(2-Carboxypiperazin-4 yl)propyl-1-phosphonic acid (CPP) (10 mg/kg) or the GluN2B-selective antagonist Ro 25-6981 (10 mg/kg but not 6 mg/kg) significantly reduced odor span capacity. Infusions of the GluN2B- selective antagonist Ro 25-6981 (2.5 MUg/hemisphere) into mPFC reduced span capacity, an effect that was nearly significant (p = 0.069). Infusions of the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3 dione (CNQX) (1.25 MUg/hemisphere) into mPFC reduced span capacity and latency for the rats to make a choice in the task. These results demonstrate span capacity in rats depends on ionotropic glutamate receptor activation in the mPFC. Further understanding of the circuitry underlying span capacity may aid in the novel therapeutic drug development for persons with working memory impairments as a result of disorders such as schizophrenia and Alzheimer's disease. PMID- 24348357 TI - Retraction: Episodic memory: a comparative approach. PMID- 24348359 TI - The functional anatomy of attention: a DCM study. AB - Recent formulations of attention-in terms of predictive coding-associate attentional gain with the expected precision of sensory information. Formal models of the Posner paradigm suggest that validity effects can be explained in a principled (Bayes optimal) fashion in terms of a cue-dependent setting of precision or gain on the sensory channels reporting anticipated target locations, which is updated selectively by invalid targets. This normative model is equipped with a biologically plausible process theory in the form of predictive coding, where precision is encoded by the gain of superficial pyramidal cells reporting prediction error. We used dynamic causal modeling to assess the evidence in magnetoencephalographic responses for cue-dependent and top-down updating of superficial pyramidal cell gain. Bayesian model comparison suggested that it is almost certain that differences in superficial pyramidal cells gain-and its top down modulation-contribute to observed responses; and we could be more than 80% certain that anticipatory effects on post-synaptic gain are limited to visual (extrastriate) sources. These empirical results speak to the role of attention in optimizing perceptual inference and its formulation in terms of predictive coding. PMID- 24348358 TI - Facets and mechanisms of adaptive pain behavior: predictive regulation and action. AB - Neural mechanisms underlying nociception and pain perception are considered to serve the ultimate goal of limiting tissue damage. However, since pain usually occurs in complex environments and situations that call for elaborate control over behavior, simple avoidance is insufficient to explain a range of mammalian pain responses, especially in the presence of competing goals. In this integrative review we propose a Predictive Regulation and Action (PRA) model of acute pain processing. It emphasizes evidence that the nervous system is organized to anticipate potential pain and to adjust behavior before the risk of tissue damage becomes critical. Regulatory processes occur on many levels, and can be dynamically influenced by local interactions or by modulation from other brain areas in the network. The PRA model centers on neural substrates supporting the predictive nature of pain processing, as well as on finely-calibrated yet versatile regulatory processes that ultimately affect behavior. We outline several operational categories of pain behavior, from spinally-mediated reflexes to adaptive voluntary action, situated at various neural levels. An implication is that neural processes that track potential tissue damage in terms of behavioral consequences are an integral part of pain perception. PMID- 24348360 TI - Navigating the complex path between the oxytocin receptor gene (OXTR) and cooperation: an endophenotype approach. AB - Although cooperation represents a core facet of human social behavior there exists considerable variability across people in terms of the tendency to cooperate. One factor that may contribute to individual differences in cooperation is a key gene within the oxytocin (OT) system, the OT reception gene (OXTR). In this article, we aim to bridge the gap between the OXTR gene and cooperation by using an endophenotype approach. We present evidence that the association between the OXTR gene and cooperation may in part be due to how the OXTR gene affects brain systems involved in emotion recognition, empathy/theory of mind, social communication and social reward seeking. There is evidence that the OXTR gene is associated with the functional anatomy of the amygdala, visual cortex (VC), anterior cingulate and superior temporal gyrus (STG). However, it is currently unknown how the OXTR gene may be linked to the functional anatomy of other relevant brain regions that include the fusiform gyrus (FG), superior temporal sulcus (STS), ventromedial prefrontal cortex (VMPFC), temporoparietal junction (TPJ) and nucleus accumbens (NAcc). We conclude by highlighting potential future research directions that may elucidate the path between OXTR and complex behaviors such as cooperation. PMID- 24348361 TI - Reading into neuronal oscillations in the visual system: implications for developmental dyslexia. AB - While phonological impairments are common in developmental dyslexia, there has recently been much debate as to whether there is a causal link between the phonological difficulties and the reading problem. An alternative suggestion has been gaining ground that the core deficit in dyslexia is in visual attentional mechanisms. If so, the visual aetiology may be at any of a number of sites along the afferent magnocellular pathway or in the dorsal cortical stream that are all essential for a visuo-spatial attentional feedback to the primary visual cortex. It has been suggested that the same circuits and pathways of top-down attention used for serial visual search are used for reading. Top-down signals from the dorsal parietal areas to primary visual cortex serially highlight cortical locations representing successive letters in a text before they can be recognized and concatenated into a word. We had shown in non-human primates that the mechanism of such a top-down feedback in a visual attention task uses synchronized neuronal oscillations at the lower end of the gamma frequency range. It is no coincidence that reading graphemes in a text also happens at the low gamma frequencies. The basic proposal here is that each cycle of gamma oscillation focuses an attentional spotlight on the primary visual cortical representation of just one or two letters before sequential recognition of letters and their concatenation into word strings. The timing, period, envelope, amplitude, and phase of the synchronized oscillations modulating the incoming signals in the striate cortex would have a profound influence on the accuracy and speed of reading. Thus, the general temporal sampling difficulties in dyslexic subjects may impact reading not necessarily by causing phonological deficits, but by affecting the spatio-temporal parsing of the visual input within the visual system before these signals are used for letter and word recognition. PMID- 24348362 TI - A new methodical approach in neuroscience: assessing inter-personal brain coupling using functional near-infrared imaging (fNIRI) hyperscanning. AB - Since the first demonstration of how to simultaneously measure brain activity using functional magnetic resonance imaging (fMRI) on two subjects about 10 years ago, a new paradigm in neuroscience is emerging: measuring brain activity from two or more people simultaneously, termed "hyperscanning". The hyperscanning approach has the potential to reveal inter-personal brain mechanisms underlying interaction-mediated brain-to-brain coupling. These mechanisms are engaged during real social interactions, and cannot be captured using single-subject recordings. In particular, functional near-infrared imaging (fNIRI) hyperscanning is a promising new method, offering a cost-effective, easy to apply and reliable technology to measure inter-personal interactions in a natural context. In this short review we report on fNIRI hyperscanning studies published so far and summarize opportunities and challenges for future studies. PMID- 24348363 TI - Age related changes in striatal resting state functional connectivity in autism. AB - Characterizing the nature of developmental change is critical to understanding the mechanisms that are impaired in complex neurodevelopment disorders such as autism spectrum disorder (ASD) and, pragmatically, may allow us to pinpoint periods of plasticity when interventions are particularly useful. Although aberrant brain development has long been theorized as a characteristic feature of ASD, the neural substrates have been difficult to characterize, in part due to a lack of developmental data and to performance confounds. To address these issues, we examined the development of intrinsic functional connectivity, with resting state fMRI from late childhood to early adulthood (8-36 years), using a seed based functional connectivity method with the striatal regions. Overall, we found that both groups show decreases in cortico-striatal circuits over age. However, when controlling for age, ASD participants showed increased connectivity with parietal cortex and decreased connectivity with prefrontal cortex relative to typically developed (TD) participants. In addition, ASD participants showed aberrant age-related connectivity with anterior aspects of cerebellum, and posterior temporal regions (e.g., fusiform gyrus, inferior and superior temporal gyri). In sum, we found prominent differences in the development of striatal connectivity in ASD, most notably, atypical development of connectivity in striatal networks that may underlie cognitive and social reward processing. Our findings highlight the need to identify the biological mechanisms of perturbations in brain reorganization over development, which may also help clarify discrepant findings in the literature. PMID- 24348364 TI - Brain mechanisms underlying the impact of attachment-related stress on social cognition. AB - Mentalizing, in particular the successful attribution of complex mental states to others, is crucial for navigating social interactions. This ability is highly influenced by external factors within one's daily life, such as stress. We investigated the impact of stress on the brain basis of mentalization in adults. Using a novel modification of the Reading the Mind in the Eyes Test (RMET-R) we compared the differential effects of two personalized stress induction procedures: a general stress induction (GSI) and an attachment-related stress induction (ASI). Participants performed the RMET-R at baseline and after each of the two inductions. Baseline results replicated and extended previous findings regarding the neural correlates of the RMET-R. Additionally, we identified brain regions associated with making complex age judgments from the same stimuli. Results after stress exposure showed that the ASI condition resulted in reduced mentalization-related activation in the left posterior superior temporal sulcus (STS), left inferior frontal gyrus and left temporoparietal junction (TPJ). Moreover, the left middle frontal gyrus and left anterior insula showed greater functional connectivity to the left posterior STS after the ASI. Our findings indicate that attachment-related stress has a unique effect on the neural correlates of mentalization. PMID- 24348365 TI - Using action observation to study superior motor performance: a pilot fMRI study. AB - The most efficient way to acquire motor skills may be through physical practice. Nevertheless, it has also been shown that action observation may improve motor performance. The aim of the present pilot study was to examine a potential action observation paradigm used to (1) capture the superior performance of expert athletes and (2) capture the underlying neural mechanisms of successful action observation in relation to task experience. We used functional magnetic resonance imaging to measure regional blood flow while presenting videos of a hockey player shooting a puck toward a hockey goal. The videos (a total of 120) where stopped at different time frames with different amount of information provided, creating a paradigm with three different levels of difficulty to decide the fate of a shot. Since this was only a pilot study, we first tested the paradigm behaviorally on six elite expert hockey players, five intermediate players, and six non-hockey playing controls. The results showed that expert hockey players were significantly (p < 0.05) more accurate on deciding the fate of the action compared to the others. Thus, it appears as if the paradigm can capture superior performance of expert athletes (aim 1). We then tested three of the hockey players and three of the controls on the same paradigm in the MRI scanner to investigate the underlying neural mechanisms of successful action anticipation. The imaging results showed that when expert hockey players observed and correctly anticipated situations, they recruited motor and temporal regions of the brain. Novices, on the other hand, relied on visual regions during observation and prefrontal regions during action decision. Thus, the results from the imaging data suggest that different networks of the brain are recruited depending on task experience (aim 2). In conclusion, depending on the level of motor skill of the observer, when correctly anticipating actions different neural systems will be recruited. PMID- 24348366 TI - Neural networks underlying affective states in a multimodal virtual environment: contributions to boredom. AB - The interaction of low perceptual stimulation or goal-directed behavior with a negative subjective evaluation may lead to boredom. This contribution to boredom may shed light on its neural correlates, which are poorly characterized so far. A video game served as simulation of free interactive behavior without interruption of the game's narrative. Thirteen male German volunteers played a first-person shooter game (Tactical Ops: Assault on Terror) during functional magnetic resonance imaging (fMRI). Two independent coders performed the time-based analysis of the audio-visual game content. Boredom was operationalized as interaction of prolonged absence of goal-directed behavior with lowered affect in the Positive and Negative Affect Schedule (PANAS). A decrease of positive affect (PA) correlated with response amplitudes in bilateral insular clusters extending into the amygdala to prolonged inactive phases in a game play and an increase in negative affect (NA) was associated with higher responses in bilateral ventromedial prefrontal cortex (vmPFC). Precuneus and hippocampus responses were negatively correlated with changes in NA. We describe for the first time neural contributions to boredom, using a video game as complex virtual environment. Further our study confirmed that PA and NA are separable constructs, reflected by distinct neural patterns. PA may be associated with afferent limbic activity whereas NA with affective control. PMID- 24348367 TI - Resolving the orthographic ambiguity during visual word recognition in Arabic: an event-related potential investigation. AB - The Arabic alphabetical orthographic system has various unique features that include the existence of emphatic phonemic letters. These represent several pairs of letters that share a phonological similarity and use the same parts of the articulation system. The phonological and articulatory similarities between these letters lead to spelling errors where the subject tends to produce a pseudohomophone (PHw) instead of the correct word. Here, we investigated whether or not the unique orthographic features of the written Arabic words modulate early orthographic processes. For this purpose, we analyzed event-related potentials (ERPs) collected from adult skilled readers during an orthographic decision task on real words and their corresponding PHw. The subjects' reaction times (RTs) were faster in words than in PHw. ERPs analysis revealed significant response differences between words and the PHw starting during the N170 and extending to the P2 component, with no difference during processing steps devoted to phonological and lexico-semantic processing. Amplitude and latency differences were found also during the P6 component which peaked earlier for words and where source localization indicated the involvement of the classical left language areas. Our findings replicate some of the previous findings on PHw processing and extend them to involve early orthographical processes. PMID- 24348368 TI - How culture influences perspective taking: differences in correction, not integration. AB - Individuals from East Asian (Chinese) backgrounds have been shown to exhibit greater sensitivity to a speaker's perspective than Western (U.S.) participants when resolving referentially ambiguous expressions. We show that this cultural difference does not reflect better integration of social information during language processing, but rather is the result of differential correction: in the earliest moments of referential processing, Chinese participants showed equivalent egocentric interference to Westerners, but managed to suppress the interference earlier and more effectively. A time-series analysis of visual-world eye-tracking data found that the two cultural groups diverged extremely late in processing, between 600 and 1400 ms after the onset of egocentric interference. We suggest that the early moments of referential processing reflect the operation of a universal stratum of processing that provides rapid ambiguity resolution at the cost of accuracy and flexibility. Late components, in contrast, reflect the mapping of outputs from referential processes to decision-making and action planning systems, allowing for a flexibility in responding that is molded by culturally specific demands. PMID- 24348370 TI - The impact of physical exercise on convergent and divergent thinking. AB - Anecdotal literature suggests that creative people sometimes use bodily movement to help overcome mental blocks and lack of inspiration. Several studies have shown that physical exercise may sometimes enhance creative thinking, but the evidence is still inconclusive. In this study we investigated whether creativity in convergent- and divergent-thinking tasks is affected by acute moderate and intense physical exercise in athletes (n = 48) and non-athletes (n = 48). Exercise interfered with divergent thinking in both groups. The impact on convergent thinking, the task that presumably required more cognitive control, depended on the training level: while in non-athletes performance was significantly impaired by exercise, athletes showed a benefit that approached significance. The findings suggest that acute exercise may affect both, divergent and convergent thinking. In particular, it seems to affect control-hungry tasks through exercise-induced "ego-depletion," which however is less pronounced in individuals with higher levels of physical fitness, presumably because of the automatization of movement control, fitness-related neuroenergetic benefits, or both. PMID- 24348371 TI - Expertise and processing distorted structure in chess. AB - A classic finding in research on human expertise and knowledge is that of enhanced memory for stimuli in a domain of expertise as compared to either stimuli outside that domain, or within-domain stimuli that have been degraded or distorted in some way. However, we do not understand how experts process degradation or distortion of stimuli within the expert domain (e.g., a face with the eyes, nose, and mouth in the wrong positions, or a chessboard with pieces placed randomly). Focusing on the domain of chess, we present new fMRI evidence that when experts view such distorted/within-domain stimuli, they engage an active search for structure-a kind of exploratory chunking-that involves a component of a prefrontal-parietal network linked to consciousness, attention and working memory. PMID- 24348372 TI - Patterns of interval correlations in neural oscillators with adaptation. AB - Neural firing is often subject to negative feedback by adaptation currents. These currents can induce strong correlations among the time intervals between spikes. Here we study analytically the interval correlations of a broad class of noisy neural oscillators with spike-triggered adaptation of arbitrary strength and time scale. Our weak-noise theory provides a general relation between the correlations and the phase-response curve (PRC) of the oscillator, proves anti-correlations between neighboring intervals for adapting neurons with type I PRC and identifies a single order parameter that determines the qualitative pattern of correlations. Monotonically decaying or oscillating correlation structures can be related to qualitatively different voltage traces after spiking, which can be explained by the phase plane geometry. At high firing rates, the long-term variability of the spike train associated with the cumulative interval correlations becomes small, independent of model details. Our results are verified by comparison with stochastic simulations of the exponential, leaky, and generalized integrate-and fire models with adaptation. PMID- 24348373 TI - Computational model of precision grip in Parkinson's disease: a utility based approach. AB - We propose a computational model of Precision Grip (PG) performance in normal subjects and Parkinson's Disease (PD) patients. Prior studies on grip force generation in PD patients show an increase in grip force during ON medication and an increase in the variability of the grip force during OFF medication (Ingvarsson et al., 1997; Fellows et al., 1998). Changes in grip force generation in dopamine-deficient PD conditions strongly suggest contribution of the Basal Ganglia, a deep brain system having a crucial role in translating dopamine signals to decision making. The present approach is to treat the problem of modeling grip force generation as a problem of action selection, which is one of the key functions of the Basal Ganglia. The model consists of two components: (1) the sensory-motor loop component, and (2) the Basal Ganglia component. The sensory-motor loop component converts a reference position and a reference grip force, into lift force and grip force profiles, respectively. These two forces cooperate in grip-lifting a load. The sensory-motor loop component also includes a plant model that represents the interaction between two fingers involved in PG, and the object to be lifted. The Basal Ganglia component is modeled using Reinforcement Learning with the significant difference that the action selection is performed using utility distribution instead of using purely Value-based distribution, thereby incorporating risk-based decision making. The proposed model is able to account for the PG results from normal and PD patients accurately (Ingvarsson et al., 1997; Fellows et al., 1998). To our knowledge the model is the first model of PG in PD conditions. PMID- 24348374 TI - The emergence of two anti-phase oscillatory neural populations in a computational model of the Parkinsonian globus pallidus. AB - Experiments in rodent models of Parkinson's disease have demonstrated a prominent increase of oscillatory firing patterns in neurons within the Parkinsonian globus pallidus (GP) which may underlie some of the motor symptoms of the disease. There are two main pathways from the cortex to GP: via the striatum and via the subthalamic nucleus (STN), but it is not known how these inputs sculpt the pathological pallidal firing patterns. To study this we developed a novel neural network model of conductance-based spiking pallidal neurons with cortex-modulated input from STN neurons. Our results support the hypothesis that entrainment occurs primarily via the subthalamic pathway. We find that as a result of the interplay between excitatory input from the STN and mutual inhibitory coupling between GP neurons, a homogeneous population of GP neurons demonstrates a self organizing dynamical behavior where two groups of neurons emerge: one spiking in phase with the cortical rhythm and the other in anti-phase. This finding mirrors what is seen in recordings from the GP of rodents that have had Parkinsonism induced via brain lesions. Our model also includes downregulation of Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels in response to burst firing of GP neurons, since this has been suggested as a possible mechanism for the emergence of Parkinsonian activity. We found that the downregulation of HCN channels provides even better correspondence with experimental data but that it is not essential in order for the two groups of oscillatory neurons to appear. We discuss how the influence of inhibitory striatal input will strengthen our results. PMID- 24348369 TI - Modulation of human corticospinal excitability by paired associative stimulation. AB - Paired Associative Stimulation (PAS) has come to prominence as a potential therapeutic intervention for the treatment of brain injury/disease, and as an experimental method with which to investigate Hebbian principles of neural plasticity in humans. Prototypically, a single electrical stimulus is directed to a peripheral nerve in advance of transcranial magnetic stimulation (TMS) delivered to the contralateral primary motor cortex (M1). Repeated pairing of the stimuli (i.e., association) over an extended period may increase or decrease the excitability of corticospinal projections from M1, in manner that depends on the interstimulus interval (ISI). It has been suggested that these effects represent a form of associative long-term potentiation (LTP) and depression (LTD) that bears resemblance to spike-timing dependent plasticity (STDP) as it has been elaborated in animal models. With a large body of empirical evidence having emerged since the cardinal features of PAS were first described, and in light of the variations from the original protocols that have been implemented, it is opportune to consider whether the phenomenology of PAS remains consistent with the characteristic features that were initially disclosed. This assessment necessarily has bearing upon interpretation of the effects of PAS in relation to the specific cellular pathways that are putatively engaged, including those that adhere to the rules of STDP. The balance of evidence suggests that the mechanisms that contribute to the LTP- and LTD-type responses to PAS differ depending on the precise nature of the induction protocol that is used. In addition to emphasizing the requirement for additional explanatory models, in the present analysis we highlight the key features of the PAS phenomenology that require interpretation. PMID- 24348376 TI - Learning in brain and machine-complexity, Godel, Aristotle. PMID- 24348375 TI - EEG theta and Mu oscillations during perception of human and robot actions. AB - The perception of others' actions supports important skills such as communication, intention understanding, and empathy. Are mechanisms of action processing in the human brain specifically tuned to process biological agents? Humanoid robots can perform recognizable actions, but can look and move differently from humans, and as such, can be used in experiments to address such questions. Here, we recorded EEG as participants viewed actions performed by three agents. In the Human condition, the agent had biological appearance and motion. The other two conditions featured a state-of-the-art robot in two different appearances: Android, which had biological appearance but mechanical motion, and Robot, which had mechanical appearance and motion. We explored whether sensorimotor mu (8-13 Hz) and frontal theta (4-8 Hz) activity exhibited selectivity for biological entities, in particular for whether the visual appearance and/or the motion of the observed agent was biological. Sensorimotor mu suppression has been linked to the motor simulation aspect of action processing (and the human mirror neuron system, MNS), and frontal theta to semantic and memory-related aspects. For all three agents, action observation induced significant attenuation in the power of mu oscillations, with no difference between agents. Thus, mu suppression, considered an index of MNS activity, does not appear to be selective for biological agents. Observation of the Robot resulted in greater frontal theta activity compared to the Android and the Human, whereas the latter two did not differ from each other. Frontal theta thus appears to be sensitive to visual appearance, suggesting agents that are not sufficiently biological in appearance may result in greater memory processing demands for the observer. Studies combining robotics and neuroscience such as this one can allow us to explore neural basis of action processing on the one hand, and inform the design of social robots on the other. PMID- 24348378 TI - Verrucous spitz nevus in a Japanese female. AB - A 23-year-old female presented with a reddish-brown dome-shaped hyperkeratotic nodule of 11 * 10 mm on the left lower leg. Dermoscopic examination demonstrated a prominent whitish scaly area with ring-like appearance, pinkish-white structureless areas, a few milia-like cysts, dotted and glomerular vessels, and light brown globules. The lesion was completely excised under the diagnosis of verruca vulgaris or dermatofibroma. Histopathological examination revealed a well circumscribed symmetric lesion with hyperkeratosis, acanthosis, and pseudohorn cysts. The lesion was composed of spindle-shaped and epithelioid melanocytes with large cytoplasm arranged in confluent nests surrounded by stromal fibrosis. Mitotic figures and Kamino bodies were absent. Moderate proliferation of capillaries was found in the papillary dermis. Immunohistochemical staining with melan-A or S-100 was positive for tumor cells, but the staining with HMB-45 was negative. Melan-A staining was weaker in the deeply situated cells than in the superficial ones, which is known as stratification. Finally, we made a diagnosis of verrucous Spitz nevus based on these findings. We should have been aware of the entity of verrucous Spitz nevus as a variant of Spitz nevus and its dermoscopic features in order to reach a correct diagnosis before excision. PMID- 24348377 TI - Self-assembled liposomal nanoparticles in photodynamic therapy. AB - Photodynamic therapy (PDT) employs the combination of non-toxic photosensitizers (PS) together with harmless visible light of the appropriate wavelength to produce reactive oxygen species that kill unwanted cells. Because many PS are hydrophobic molecules prone to aggregation, numerous drug delivery vehicles have been tested to solubilize these molecules, render them biocompatible and enhance the ease of administration after intravenous injection. The recent rise in nanotechnology has markedly expanded the range of these nanoparticulate delivery vehicles beyond the well-established liposomes and micelles. Self-assembled nanoparticles are formed by judicious choice of monomer building blocks that spontaneously form a well-oriented 3-dimensional structure that incorporates the PS when subjected to the appropriate conditions. This self-assembly process is governed by a subtle interplay of forces on the molecular level. This review will cover the state of the art in the preparation and use of self-assembled liposomal nanoparticles within the context of PDT. PMID- 24348379 TI - Scleromyxedema with subcutaneous nodules: successful treatment with thalidomide and intravenous immunoglobulin. AB - Scleromyxedema is a rare cutaneous mucinosis, usually presenting with generalized papular eruption and sclerodermoid induration, monoclonal gammopathy and systemic manifestations. An atypical clinical presentation with cutaneous and subcutaneous nodules has been reported rarely. In recent years, intravenous immunoglobulin (IVIg) appears to be the therapy of choice for scleromyxedema. Treatment experiences in atypical manifestations with mucinous nodules are limited to sporadic reports. We report the case of male patient with atypical scleromyxedema without underlying paraproteinemia, presenting with generalized papular and sclerodermoid skin eruption and multiple nodular mucinous lesions on the fingers and face as well as on the eyelids, and associated systemic symptoms. Complete regression of all cutaneous lesions and extracutaneous symptoms with sustained remission was achieved by combined treatment with thalidomide and IVIg. PMID- 24348380 TI - A case report of atypical scrotal leiomyoma. AB - Scrotal leiomyoma is a benign tumor derived from the scrotal dartos muscle; it is rare in clinical findings. The cause of the disease is not yet clear. Here, we present the case of a patient with no typical clinical features, but with some typical pathological changes. A middle-aged male patient saw a doctor for paroxysmal itching and burning of the scrotum. The physical examination revealed 3 * 5-cm(2), ill-defined, pink plaques, an uneven surface, and basal infiltration with pigmentation defects in the center. Pathology results showed dermal spindle cells in nodular hyperplasia. The nucleus was round at both ends, a perinuclear halo could be seen, and staining was positive for actin and negative for S100. Therefore, the diagnosis of scrotal myoma was made. PMID- 24348381 TI - Genital vulvar lichen sclerosus in monozygotic twin women: a case report and review of the literature. AB - Lichen sclerosus et atrophicus is a skin disease of multifactorial etiology which appears in patients with genetic or hormonal predisposition and autoimmune disease. Genetic predisposition is suggested by familial reports of the disease which involve twins, siblings, and mother-daughter/son series. This is a report of the occurrence of lichen sclerosus et atrophicus in monozygotic twin women, suggesting that inheritance is of relevance in the etiology of this disease. PMID- 24348382 TI - Paradoxical Reaction to Golimumab: Tumor Necrosis Factor alpha Inhibitor Inducing Psoriasis Pustulosa. AB - IMPORTANCE: Golimumab is a human monoclonal antibody, used for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Adverse reactions are increasing with this class of medication (tumor necrosis factor alpha inhibitors). OBSERVATIONS: The authors present a case of a female patient who presented with psoriasis pustulosa after the use of golimumab for rheumatoid arthritis. CONCLUSIONS AND RELEVANCE: Paradoxically, in this case, golimumab, which is used for psoriasis, induced the pustular form of this disease. We are observing an increasing number of patients who develop collateral effects with tumor necrosis factor alpha inhibitors, and the understanding of the mechanism of action and how these adverse reactions occur may contribute to avoid these sometimes severe situations. PMID- 24348383 TI - Adalimumab in recalcitrant severe psoriasis associated with atopic dermatitis. AB - Tumor necrosis factor-alpha inhibitors may induce various cutaneous side effects including eczematous-like lesions. The management of such side effects can be challenging. Herein, we report a case of a 55-year-old man who had a flare-up and subsequent improvement of atopic dermatitis during treatment of severe psoriasis with adalimumab. PMID- 24348384 TI - Allergic contact dermatitis induced by textile necklace. AB - Allergic contact dermatitis to textile dyes is considered to be a rare phenomenon. A recent review reported a prevalence of contact allergy to disperse dyes between 0.4 and 6.7%. The relevance of positive patch testing was not reported in all studies. Textile dye allergy is easily overlooked and is furthermore challenging to investigate as textile dyes are not labelled on clothing. In this report, we present a case of allergic contact dermatitis to a textile necklace. The patch test showed strong reactions to the necklace and the azo dyes Disperse Orange 1 and Disperse Yellow 3. Despite the European legislation and the reduced use of disperse dyes in Third World countries, disperse azo dyes still induce new cases of allergic contact dermatitis. PMID- 24348385 TI - Effects of a facial cream containing the minor alkaloid anatabine on improving the appearance of the skin in mild to moderate rosacea: an open-label case series study. AB - BACKGROUND: Current medical and scientific research indicates that rosacea, a chronic and often debilitating skin condition that primarily affects the central face, may be caused by an overactive or excessive inflammatory immune response. Regardless of etiology, the accompanying redness and inflammation is unsightly and difficult for the patient. Anatabine is an alkaloid from the plant family Solanaceae that has been shown in several preclinical studies to modulate proinflammatory signaling pathways. OBJECTIVE: A cream containing anatabine was developed and evaluated in an open-label case series study for safety and effects on the appearance of the skin in 10 patients with mild to moderate rosacea. METHODS: Patients applied the cream to the face twice daily for a period of 30 days. Patients and the study physician completed safety and efficacy assessments at study end. RESULTS: Results showed that 50% of the patients self-reported improvement in the appearance of their skin, and the physician noted improvement in 70% of the patients. Photographs taken before and after 30 days of cream use provide visual evidence of the improvement in several patients. There were no complications or adverse events reported by any of the patients in the study, indicating that the anatabine cream was safe and very well tolerated. CONCLUSION: The results of this open-label case series show that a facial cream containing anatabine can improve the appearance of the skin in patients with mild to moderate rosacea and suggest that a double-blind, vehicle-controlled trial in a larger number of subjects is warranted. PMID- 24348386 TI - Hyperpigmentation following Treatment of Frontal Fibrosing Alopecia. AB - INTRODUCTION: Frontal fibrosing alopecia (FFA) is a scarring alopecia characterized by progressive recession of the frontotemporal hairline. Current treatment is aimed at stopping progression, and the combination of dutasteride and pimecrolimus is the most effective therapy. Side effects associated with dutasteride are erectile dysfunction as well as breast tenderness and enlargement, while pimecrolimus produces a burning sensation. CASE REPORT: We present a 57-year-old postmenopausal female with a 3-year history of a scarring alopecic plaque in her frontotemporal region. Biopsy confirmed the diagnosis of FFA, and she was started on dutasteride 0.5 mg p.o. q.d., and later, topical pimecrolimus 1% b.i.d. was added. Eight months after initiating treatment, she showed hyperpigmentation on her metacarpophalangeal and interphalangeal joints, as well as on the cheeks and on the chin; dutasteride and pimecrolimus were discontinued. After 5 months of follow-up, her hyperpigmentation improved by 80% only by using photoprotection. CONCLUSION: Because of the variable clinical course of FFA, treatment is focused on halting its progression. Several therapeutic agents have been evaluated and the combination of dutasteride and pimecrolimus has shown a high response rate. There is no reported evidence of hyperpigmentation associated with this combination. PMID- 24348387 TI - Incidental discovery of testicular microlithiasis: what is the importance of ultrasound surveillance? Two case reports. AB - Many studies have demonstrated an association between diffuse bilateral testicular microlithiasis (TM) and gonadal and extragonadal germ cell tumors. Nevertheless, it is still uncertain whether ultrasound surveillance is really necessary in patients with TM in the absence of other risk factors such as previous testicular cancer, a history of cryptorchidism or testicular atrophy. We report the cases of a 33- and a 39-year-old man presenting with a retroperitoneal extragonadal tumor. The first patient underwent an MRI examination in order to rule out a lumbosacral hernia: MRI images showed no slipped disks but a voluminous retroperitoneal solid mass. The histological analysis revealed an immature teratoma. The second patient came to the emergency department complaining of abdominal pain, vomiting, weight loss and mild jaundice: ultrasound examination showed a large, ill-defined heterogeneous abdominal mass, confirmed by CT and MRI examination. The histology diagnosed a yolk sac tumor. In both patients, the testicular sonography was performed to rule out a focal lesion, but it displayed bilateral TM without a focal testicular mass. Based on our direct experience, we highlight the importance of annual ultrasonographic surveillance of the testis and the retroperitoneal space in patients with occasionally detected TM. PMID- 24348388 TI - Successful chemotherapy with Carboplatin and s-1 for thymic carcinoma: a case report. AB - Thymic carcinoma is a rare but aggressive neoplasm. Although there is no clearly optimal first- or second-line chemotherapy regimen for thymic carcinoma, platinum based chemotherapy has repeatedly been shown to be of benefit to patients with advanced thymic carcinoma. Some case reports have described S-1 as a novel agent with good activity against advanced thymic carcinoma. A 74-year-old female was diagnosed with thymic carcinoma complicated by pleural dissemination and pericardial effusion of carcinomatosa. She was treated with carboplatin on day 1 plus S-1 on days 1-14 in cycles repeated every 3 or 4 weeks. Four cycles of this regimen were administered, and a partial response was confirmed. There were no severe hematological or nonhematological toxicities, and no dose reduction was necessary. To our knowledge, this is the first report to demonstrate the efficacy of combination chemotherapy consisting of carboplatin and S-1 against thymic carcinoma. PMID- 24348389 TI - Early relapse of unresectable gallbladder cancer after discontinuation of gemcitabine monotherapy administered for 5 years in a patient who had complete response to the treatment. AB - The tumor shrinkage effect of gemcitabine is considered to be limited in cases of advanced gallbladder cancer, and there are few reports of complete response to gemcitabine therapy in patients with this cancer. Therefore, the treatment continuation strategy in these patients, after a complete response has been achieved, still remains to be established. Here, we present the case of a 77-year old patient with unresectable gallbladder cancer, who after showing complete response to gemcitabine monotherapy administered for 5 years, showed early relapse within only 11 months of discontinuation of the drug. Thus, it is necessary to establish a suitable treatment continuation strategy for patients who show complete response to gemcitabine treatment. PMID- 24348390 TI - A husband and a wife with simultaneous presentation of glioblastoma multiforme: a case report. AB - Glioblastoma multiforme (GBM) is the most lethal subtype of glioma, classified as a WHO grade 4 infiltrative glioma. The etiology of GBM remains unknown and risk factors can be identified only in a small minority. We report the synchronous occurrence of GBM in an otherwise unrelated married couple, i.e. a husband and his wife, who developed GBM within an interval of 1 month. No specific causative environmental factors were identified for both patients, and the genetic screens were negative for hereditary syndromes. Family history was negative for tumors, and no other incidence of cancer in either siblings, parents or other children was reported. An analysis of the couple's exposure to nonionizing electromagnetic fields and ionizing radiations revealed values within the normal ranges usually found in homes. Overall, conjugal tumors are rarely reported. However, the case reported herein raises important questions about possible etiologic factors. PMID- 24348391 TI - Growing teratoma syndrome of the ovary showing three patterns of metastasis: a case report. AB - Growing teratoma syndrome (GTS) is defined as metastatic masses during or after chemotherapy for germ cell tumors, which contain only mature teratoma components. The peritoneum of the pelvis and abdomen and the retroperitoneum are the most frequent sites of metastasis. We report a case of GTS of the ovary showing three patterns of metastasis: dissemination, lymphogenous metastasis, and hematogenous metastasis. The patient initially presented 5 years ago with a mixed germ cell tumor of the left ovary and positive cytology of ascites. After surgery and chemotherapy, mature teratomas recurred as pelvic peritoneal dissemination, a para-aortic lymph node mass, and a lung mass. Our case highlights the importance of long-term follow-up and a whole-body search. We think that our case is suggestive regarding the mechanism of critical GTS. PMID- 24348392 TI - Use of an Amplatzer Device for Endoscopic Closure of a Large Bronchopleural Fistula following Lobectomy for a Stage I Squamous Cell Carcinoma. AB - Bronchopleural fistulas can occur as a rare but severe complication after pulmonary resection. Established guidelines for the proper treatment of patients with bronchopleural fistulas do not exist. Apart from attempts to close the fistula, emphasis is placed on preventive measures, early treatment with antibiotics, drainage of the empyema and aggressive nutritional and rehabilitative support. For inoperable patients, endoscopic procedures are the only therapeutic option. Unfortunately, large (>8 mm) or central bronchopleural fistulas are usually not suitable for such endoscopic management. Recently, some groups have published a few case reports about a novel technique for the endobronchial closure of bronchopleural fistulas, using an Amplatzer device, originally designed for transcatheter closure of cardiac septal defects. We applied the same technique as a life-saving treatment in a ventilated patient who was considered inoperable due to a high oxygen need. The operation was successful. The patient could be weaned from ventilation and was eventually discharged from the hospital to a rehabilitation facility several weeks after the insertion of the device. Until now, endoscopic techniques have only been useful for the treatment of small, peripheral, bronchopleural fistulas and even then only as a bridge to surgery in high-risk surgical patients. In this case report, we demonstrate that the use of an Amplatzer device can expand the importance of endoscopic techniques in the treatment of bronchopleural fistulas. An Amplatzer device, for endobronchial closure, can indeed be administered for large and central bronchopleural fistulas. Moreover, it can be considered as a definite alternative to surgery in inoperable patients. PMID- 24348393 TI - Gastric and endobronchial metastases in a case of lobular breast cancer. AB - BACKGROUND: Invasive lobular carcinoma (ILC) is the second most common histological type of invasive breast carcinoma, preceded only by infiltrating ductal carcinoma, which has clinical, biological and molecular distinctions. These distinctions imply a different metastatic behavior between the histology of these 2 types of breast cancer. CASE PRESENTATION: We report the case of a 51 year-old woman with breast cancer with ILC histology, diagnosed at an early stage. In the course of her disease, recurrences in the gastric mucosa and endobronchial area occurred. The treatment she received is described herein. CONCLUSION: This is a case of ILC with unusual metastases. The absence of E cadherin is related to the carcinogenesis of ILC and probably to these patterns of metastasis as well. PMID- 24348394 TI - Presacral ganglioneuroma: diagnostic considerations and therapeutic strategy. AB - Presacral ganglioneuroma is an extremely rare tumor of neural crest origin. To the best of our knowledge, less than 20 cases have been reported previously. The present study reports on a presacral ganglioneuroma, 10.5 * 8 * 4 cm in size, that was found incidentally in a 35-year-old man with prior history of diverticulitis. He was admitted to our hospital due to lower left abdominal pain. Abdominal computed tomography and magnetic resonance imaging confirmed the extension of the lesion from the S2 level to the coccyx. The mass had low signal intensity on T1-weighted images and heterogeneous high signal intensity on T2 weighted images with no intraspinal or rectal extension. T2-weighted images demonstrated a compartmentalized solid tumor with cystic components. Complete tumor resection with free surgical margins was achieved using an abdominal approach. The patient remains asymptomatic 2 years after surgery. We emphasize on clinical features, radiologic appearance and surgical treatment of this rare entity. The clinical and pathologic features of previously reported studies are also briefly reviewed. PMID- 24348395 TI - Long survival of a small-cell lung cancer patient who received maintenance chemotherapy with irinotecan. AB - Lung cancer is the leading cause of cancer-related death worldwide. Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers. It is characterized by rapid tumor growth and early metastasis to multiple organs. Response to initial chemotherapy is generally good; however, the majority of patients develop recurrence and the prognosis of such patients is reportedly 2-4 months. Evolution of the treatment for SCLC has stagnated, and cisplatin + etoposide has been the standard chemotherapy for decades. Meanwhile, the combination of cisplatin + irinotecan has demonstrated equivalent efficacy to cisplatin + etoposide. Recently, maintenance chemotherapy has been extensively investigated in non-small-cell lung cancer (NSCLC), and is currently recommended as a standard treatment in clinical guidelines. On the contrary, a maintenance strategy has not been established for SCLC. Here, we describe an SCLC patient who received maintenance chemotherapy with irinotecan for more than 2 years after induction chemotherapy with cisplatin + irinotecan, and survived long term with no recurrence. PMID- 24348396 TI - A Case of Stage IV Non-Small Cell Lung Cancer Treated with Korean Medicine Therapy Alone. AB - This report presents a case that shows a significant anticancer effect of Korean medicine therapy (KMT). A 79-year-old man, who was diagnosed as stage IV non small cell lung cancer (NSCLC) in December 2012, was treated with KMT including intravenous pharmacopunctures and oral herbal medicine from February 22, 2013, until September 2013 without any surgical intervention, chemotherapy or radiotherapy. The intravenous pharmacopunctures were the wild ginseng pharmacopuncture, Cordyceps sinensis pharmacopuncture and Trichosanthes kirilowii pharmacopuncture. The oral herbal medicine used was soramdan, made of cultivated wild ginseng. The effectiveness of this therapy was evaluated with computed tomography and the Eastern Cooperative Oncology Group (ECOG) performance scale. The size of the tumor mass was markedly decreased and the ECOG performance scale was also improved. These results suggest that KMT alone can be an effective method to treat NSCLC. PMID- 24348397 TI - Esophageal gastrointestinal stromal tumors presenting as mediastinal mass. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and are predominant in the stomach and intestine but rare in the esophagus. Here, we report a case of esophageal GIST which presented as a mediastinal mass on chest X-ray and dyspnea. The case was initially diagnosed as leiomyosarcoma, which could create a diagnostic dilemma. Therefore, recognizing this uncommon presentation as a mediastinal mass with esophageal GIST is important in the differential diagnosis. PMID- 24348398 TI - Psychiatric Presentation of Frontotemporal Dementia Associated with Inclusion Body Myopathy due to the VCP Mutation (R155H) in a French Family. AB - INTRODUCTION: Inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD) is a rare late-onset autosomal dominant disorder due to a mutation of the valosin-containing protein (VCP) gene. CASE REPORT: We report the case of a patient who developed progressive weakness of the limbs in his fifties, until he was confined to a wheelchair. At that time, he developed acute behavioural changes including irritability, severe anxiety and major depression, which led to him being hospitalised in a psychiatric hospital. He also suffered from aphasia and executive function impairment, which helped us to diagnose a behavioural form of frontotemporal dementia (FTD). The diagnosis of IBMPFD due to a mutation in the VCP gene was confirmed by a genetic study of the VCP gene (R155H mutation). DISCUSSION: THE CLINICAL DIAGNOSIS OF IBMPFD IS SUGGESTED BY THE PRESENCE OF AT LEAST ONE OF THREE MAJOR MANIFESTATIONS AS FOLLOWS: inclusion body myopathy (mean onset at 42 years of age), Paget's disease of the bone and FTD (mean onset at 55 years of age). It is mostly the behavioural form of FTD (behavioural changes, executive dysfunction and aphasia). One interesting finding in our report is the predominance of the psychiatric symptoms at the beginning of the behavioural changes, which led to the diagnosis of FTD. The diagnosis of IBMPFD was confirmed by the genetic study: the R155H mutation found on exon 5 domain CDC48 is the most frequent of the 18 known mutations in the VCP gene. PMID- 24348399 TI - Multiple vascular accidents including rupture of a sinus of valsalva aneurysm, a minor ischemic stroke and intracranial arterial anomaly in a patient with systemic congenital abnormalities: a case report. AB - A 39-year-old man with a history of rupture of a sinus of Valsalva aneurysm experienced an ischemic stroke. Although the patient presented left-sided hemiparesis for a week, no abnormal signals were indicated on diffusion-weighted imaging with repeated magnetic resonance scans. Carotid ultrasound and cerebral angiography were conducted, and they revealed hypoplasty of the left internal carotid artery with a low-lying carotid bifurcation at the level of the C6 vertebra. In addition, he was diagnosed with intellectual disabilities, evaluated by the Wechsler Adult Intelligence Scale-III, and congenital velopharyngeal insufficiency. We herein present the first report of a patient with cardio cerebrovascular abnormalities, intellectual disabilities, and an otorhinolaryngological abnormality. PMID- 24348400 TI - Does intrathecal baclofen have a place in the treatment of painful spasms in friedreich ataxia? AB - We present the case of a 50-year-old female patient with Friedreich ataxia (FA) who was treated successfully with an intrathecal baclofen (ITB)-delivering pump for painful spasms. To our knowledge, this is the second reported case of FA where ITB relieved painful and disabling spasms. We suggest that ITB should be considered in the treatment of disabling spasms in patients with FA. PMID- 24348401 TI - Spontaneous Closure of a Full-Thickness Stage 2 Idiopathic Macular Hole without Posterior Vitreous Detachment. AB - OBJECTIVE: We report a 50-year-old female patient with a stage 2 idiopathic macular hole that closed spontaneously. METHOD: The case is presented on the basis of an observational case report. RESULTS: The stage 2 idiopathic macular hole closed spontaneously in 6 weeks with a lamellar defect in the outer retina due to the formation of the bridging retinal tissue, but without any evidence of the common mechanisms of spontaneous closure such as posterior vitreous detachment or epiretinal membrane formation. PMID- 24348402 TI - Recurrent annular peripheral choroidal detachment after trabeculectomy. AB - We report a challenging case of recurrent flat anterior chamber without hypotony after trabeculectomy in a 54-year-old Black male with a remote history of steroid treated polymyositis, cataract surgery, and uncontrolled open angle glaucoma. The patient presented with a flat chamber on postoperative day 11, but had a normal fundus exam and intraocular pressure (IOP). Flat chamber persisted despite treatment with cycloplegics, steroids, and a Healon injection into the anterior chamber. A transverse B-scan of the peripheral fundus revealed a shallow annular peripheral choroidal detachment. The suprachoroidal fluid was drained. The patient presented 3 days later with a recurrent flat chamber and an annular peripheral choroidal effusion. The fluid was removed and reinforcement of the scleral flap was performed with the resolution of the flat anterior chamber. A large corneal epithelial defect developed after the second drainage. The oral prednisone was tapered quickly and the topical steroid was decreased. One week later, his vision decreased to count fingers with severe corneal stromal edema and Descemet's membrane folds that improved to 20/50 within 24 h of resumption of the oral steroid and frequent topical steroid. The patient's visual acuity improved to 20/20 following a slow withdrawal of the oral and topical steroid. Eight months after surgery, the IOP was 15 mm Hg without glaucoma medication. The detection of a shallow anterior choroidal detachment by transverse B-scan is critical to making the correct diagnosis. Severe cornea edema can occur if the steroid is withdrawn too quickly. Thus, steroids should be tapered cautiously in steroid-dependent patients. PMID- 24348403 TI - Forme Fruste Keratoconus Imaging and Validation via Novel Multi-Spot Reflection Topography. AB - BACKGROUND/AIMS: This case report aims to evaluate safety, efficacy and applicability of anterior surface imaging in a patient with forme fruste keratoconus (FFKC) based on a novel multi-spot, multicolor light-emitting-diode (LED) tear film-reflection imaging technology. CASE DESCRIPTION: A 45-year-old male patient, clinically diagnosed with FFKC, with highly asymmetric manifestation between his eyes, was subjected to the multicolor-spot reflection topography. We investigated elevation and sagittal curvature maps comparatively with the multicolor-spot reflection topographer, a Placido topographer and a Scheimpflug imaging system. For the right eye, steep and flat keratometry values were 41.92 and 41.05 D with the multicolor spot-reflection topographer, 42.30 and 42.08 D with the Placido, and 41.95 and 41.19 D with the Scheimpflug system. For the left eye, steep and flat keratometry values were 41.86 and 41.19 D with the multicolor spot-reflection topographer, 42.06 and 41.66 D with the Placido topographer, and 41.96 and 41.66 D with the Scheimpflug camera. Average repeatability of the keratometry measurements was +/-0.35 D for the multicolor spot-reflection topographer, +/-0.30 D for the Placido, and +/-0.25 D for the Scheimpflug camera. Very good agreement between the instruments was demonstrated on the elevation and curvature maps. CONCLUSION: The ease of use and the comparable results offered by the multicolor spot-reflection topographer, in comparison to established Placido and Scheimpflug imaging, as well as the increased predictability that may be offered by the multicolor spot-reflection topographer, may hold promise for wider clinical application, such as screening of young adults for early keratoconus and, in a much wider perspective, potential candidates for laser corneal refractive surgery. PMID- 24348404 TI - Traumatic partial aniridia and cataract after iris-fixated foldable phakic intraocular lens implantation. AB - We present the first case of partial aniridia, traumatic cataract, and peripapillary subretinal hemorrhage after blunt trauma to an eye containing a foldable iris-fixated phakic intraocular lens (pIOL). Although the patient experienced visual loss because of considerable corneal astigmatism and a traumatic cataract, vision was recovered by a 2-stage primary corneal repair and cataract surgery with a toric intraocular lens. This case exhibits clinical manifestations that differ from previously reported trauma of a non-foldable iris fixated pIOL. A relatively small corneal incision and a large optic diameter of Artiflex pIOLs may prevent posttraumatic total expulsion of intraocular tissues and present different clinical features from the case of non-foldable pIOLs (Artisan). Although the extent of the damage is different, the possibility of aniridia and traumatic cataract exists in eyes with both foldable and non foldable iris-fixated pIOLs. PMID- 24348405 TI - Successful corticosteroid-sparing effect of rituximab in the treatment of refractory idiopathic orbital inflammatory disease. AB - Idiopathic orbital inflammatory disease (IOID) is an idiopathic inflammatory process within the orbit that can result in permanent visual impairment. Although high-dose oral corticosteroids are currently the mainstay of therapy, their long term usage can cause significant toxicity. We present a case of IOID that was successfully treated with the anti-CD20 monoclonal antibody rituximab following failed steroid sparing with conventional second-line immunosuppressive agents. PMID- 24348406 TI - Toric intraocular lens implantation for correction of astigmatism in cataract patients with corneal ectasia. AB - Our purpose was to examine the long-term efficacy of toric intraocular lens (IOL) implantation in cataract patients with high astigmatism due to corneal ectasia, who underwent phacoemulsification cataract surgery. Five eyes of 3 cataract patients with topographically stable keratoconus or pellucid macular degeneration (PMD), in which phacoemulsification with toric IOL implantation was used to correct high astigmatism, are reported. Objective and subjective refraction, visual acuity measurement and corneal topography were performed in all cases before and after cataract surgery. In all cases, there was a significant improvement in visual acuity, as well as refraction, which remained stable over time. Specifically, in subjective refraction, all patients achieved visual acuity from 7/10 to 9/10 with up to -2.50 cyl. Corneal topography also remained stable. Postoperative follow-up was 18-28 months. Cataract surgery with toric IOL implantation seems to be safe and effective in correcting astigmatism and improving visual function in cataract patients with topographically stable keratoconus or PMD. PMID- 24348407 TI - Mobius syndrome: surgical treatment for eyelid dysfunction. AB - INTRODUCTION: Mobius syndrome is a heterogeneous congenital disorder that is linked to bilateral palsies of the cranial nerves VI and VII, resulting in congenital facial paralysis sometimes associated with impaired ocular abduction. CASE REPORT: We present the case of a 44-year-old woman with Mobius syndrome and inferior recurrent keratitis secondary to scleral show in both eyes. We decided to use a cartilage graft from the ear in the inferior eyelid to avoid eyelid retraction and scleral show. DISCUSSION: Patients with Mobius syndrome have a severe dysfunction of their facial mimic. Their treatment must be individualized, depending on their age, clinical examination and symptoms. PMID- 24348408 TI - Macroaneurysm on the optic disc in a patient with aortic dissection. AB - PURPOSE: We report a case of macroaneurysm on the optic disc, a rare location, accompanied by vitreous hemorrhage in a patient with aortic dissection. METHODS: A 60-year-old female with a history of aortic dissection at the age of 51 presented with visual disturbance owing to vitreous hemorrhage in her right eye. During vitrectomy, we found a large macroaneurysm on the optic disc that was beating and oozing blood. However, the macroaneurysm was not treated. RESULTS: The macroaneurysm gradually shrunk, and the beating and oozing of blood disappeared accordingly. CONCLUSION: Up to now, there have been no reports of macroaneurysm on the optic disc in aortic dissection patients. The association between macroaneurysm on the optic disc and aortic dissection is unclear; therefore, additional case reports may be necessary. To the best of our knowledge, our case is the first one reported in the literature. PMID- 24348409 TI - A simple and easy method using rigid endoscope to detect iridocorneal and keratolenticular adhesions in peters' anomaly. AB - Peters' anomaly is characterized by a central corneal opacity with corresponding defects in the posterior stroma, Descemet's membrane, and endothelium. We present 2 cases that showed corneal opacity when examined by topical endoscopic imaging (TEI). Case 1 was a 20-day-old neonatal female who had a central corneal opacity in the left eye. TEI showed that the iris stroma was adhered toward the back of the opacified cornea. Case 2 was a 4-month-old male who had a bilateral corneal opacity. TEI revealed that both a keratolenticular adhesion and a surrounding iridocorneal adhesion were observed behind the area of corneal opacity. The patient was diagnosed as having Peters' anomaly with persistent fetal vasculature. This study demonstrates that TEI is a novel method capable of looking into an eye from only a small area of the clear cornea. PMID- 24348410 TI - Floating vitreous cyst: two clinical cases. AB - PURPOSE: To report two cases of solitary unilateral vitreous cyst. METHODS: A complete ocular examination, fundus photography, B-scan ultrasound and spectral domain optical coherence tomography were performed in both patients. RESULTS: The first patient (a 39-year-old man) presented with transient blurred vision in the right eye. The second patient (a 78-year-old man) reported transient blurred vision in the right eye when changing head position. He was referred to the Eye Hospital because of vitreomacular traction in the other eye. After examination, a diagnosis of vitreous cyst was made in both cases. CONCLUSIONS: Vitreous cysts are rare clinical findings. They can occur in normal eyes or in eyes with certain ocular pathologies. When a cyst floats into the visual axis area, it can disturb visual function; therefore, patients usually report transient blurring of vision. A prompt clinical examination is necessary for differentiating this rare condition. PMID- 24348411 TI - Patient-Reported Difference following Implantation of a Blue Light-Filtering Aspheric Intraocular Lens and a UV-Filtering Aspheric Intraocular Lens. AB - We report on a series of 6 patients who experienced yellow vision after uncomplicated cataract surgery in their second eye. In the first eye, an aspheric blue-light filtering intraocular lens (IOL) was implanted, followed by the implantation of a 1-Piece aspheric IOL in the second eye. The time between the surgeries ranged from 12 months to 3 years. The patients experienced noticeable differences between the yellow and the clear lens. It is suggested to avoid mixing blue light-filtering and UV-filtering IOLs in the same patient, particularly in those who have high expectations following cataract surgery. PMID- 24348412 TI - Intraocular Invasion of Adult T-Cell Leukemia Cells without Systemic Symptoms after Cataract Surgery. AB - Adult T-cell leukemia (ATL) is an aggressive lymphoid proliferation associated with the human T-lymphotropic virus type I (HTLV-I). The intraocular invasion of ATL is a rare event. A 75-year-old man without any systemic disease underwent uneventful cataract surgery of the right eye. On postoperative day 6, the patient presented with blurred vision due to severe vitreous opacity in the right eye. Analysis of the vitreous fluid revealed a suspected ATL infection based on the flow cytometric analysis. Moreover, cytological examination of the vitreous specimen revealed flower cell infiltration, and HTLV-1 DNA was detected by PCR analysis of the vitreous sample. Monoclonal T-cell receptor chain rearrangement was also detected by PCR. Thorough analysis of a vitreous sample is essential for vitrectomy in vitreous opacity of unknown cause. Flow cytometric, cytological, and PCR analysis of vitreous samples is beneficial for determining the cause of this kind of severe illness. PMID- 24348413 TI - Intracapsular lens extraction for the treatment of pupillary block glaucoma associated with anterior subluxation of the crystalline lens. AB - PURPOSE: To report a case of pupillary block glaucoma associated with spontaneous crystalline lens subluxation into the anterior chamber in a 34-year-old man. METHODS: Dry vitrectomy was performed for securing enough retrolental space, and an intracapsular lens extraction was then performed via a corneolimbal incision. Additional endothelial cell damage was avoided with an injection of viscoelastics and gentle extraction of the crystalline lens. After deepening of the anterior chamber, scleral fixation of the intraocular lens was performed with an ab externo technique. RESULTS: Two months after the operation, a well-fixated intraocular lens was observed and intraocular pressure was stable. The postoperative corneal astigmatism was -3.5 dpt, and the patient had a best corrected visual acuity of 20/25. Postoperative complications included decreased endothelial cell count and sector iris paralysis near the incision site. CONCLUSIONS: An anteriorly subluxated crystalline lens can cause pupillary block glaucoma in healthy young adults. To prevent intraoperative complications, intracapsular lens extraction with dry vitrectomy can be a good surgical option. The endothelial cell density should be closely monitored after surgery. PMID- 24348414 TI - Neuroretinitis with branch retinal artery occlusion in a 15-year-old female. AB - We report a case of Bartonella henselae neuroretinitis with significant disc and peripapillary edema, branch retinal artery occlusion without macula involvement and well preserved central vision. A 15-year-old female presented with loss of vision over 4 weeks in the left eye. She had a history of cat exposure, but a cat scratch, insect bite or conjunctivitis was not reported. An inferotemporal arcuate scotoma developed during the acute phase and persisted over the course of the follow-up. PMID- 24348415 TI - Methicillin-Resistant Staphylococcus aureus Keratitis after Descemet's Stripping Automated Endothelial Keratoplasty. AB - PURPOSE: We report a case of methicillin-resistant Staphylococcus aureus (MRSA) keratitis after Descemet's stripping automated endothelial keratoplasty (DSAEK). CASE REPORT: An 87-year-old woman who had undergone a DSAEK 4 months previously was referred to Tokushima University Hospital with a diagnosis of infectious keratitis after DSAEK. A white abscess and infiltration in the inferior cornea of the right eye were observed. We started an empiric therapy using topical levofloxacin and chloramphenicol on the basis of the microscopic findings of the corneal scraping concurrently with cultivation of the cornea. RESULTS: A strain of MRSA was isolated from the corneal sample. Although the strain was susceptible to chloramphenicol, it was resistant to quinolone. The keratitis improved rapidly due to empiric therapy, and topical steroids could be resumed 6 days after initiation of the empiric therapy. CONCLUSIONS: To our knowledge, this is the first case of MRSA keratitis, and the second case of bacterial keratitis, after DSAEK. MRSA keratitis can occur following uneventful DSAEK. The empiric therapy on the basis of results from a light microscopic examination of a Gram-stained corneal scraping and restarting topical steroids in the early stages of medication contributed to the good clinical course of this case. PMID- 24348416 TI - Washout allometric reference method (WARM) for parametric analysis of [(11)C]PIB in human brains. AB - Rapid clearance and disappearance of a tracer from the circulation challenges the determination of the tracer's binding potentials in brain (BP ND) by positron emission tomography (PET). This is the case for the analysis of the binding of radiolabeled [(11)C]Pittsburgh Compound B ([(11)C]PIB) to amyloid-beta (Abeta) plaques in brain of patients with Alzheimer's disease (AD). To resolve the issue of rapid clearance from the circulation, we here introduce the flow-independent Washout Allometric Reference Method (WARM) for the analysis of washout and binding of [(11)C]PIB in two groups of human subjects, healthy aged control subjects (HC), and patients suffering from AD, and we compare the results to the outcome of two conventional analysis methods. We also use the rapid initial clearance to obtain a surrogate measure of the rate of cerebral blood flow (CBF), as well as a method of identifying a suitable reference region directly from the [(11)C]PIB signal. The difference of average absolute CBF values between the AD and HC groups was highly significant (P < 0.003). The CBF measures were not significantly different between the groups when normalized to cerebellar gray matter flow. Thus, when flow differences confound conventional measures of [(11)C]PIB binding, the separate estimates of CBF and BP ND provide additional information about possible AD. The results demonstrate the importance of data driven estimation of CBF and BP ND, as well as reference region detection from the [(11)C]PIB signal. We conclude that the WARM method yields stable measures of BP ND with relative ease, using only integration for noise reduction and no model regression. The method accounts for relative flow differences in the brain tissue and yields a calibrated measure of absolute CBF directly from the [(11)C]PIB signal. Compared to conventional methods, WARM optimizes the Abeta plaque load discrimination between patients with AD and healthy controls (P = 0.009). PMID- 24348417 TI - Drive for consumption, craving, and connectivity in the visual cortex during the imagery of desired food. AB - There is considerable interest in understanding food cravings given the obesogenic environment of Western Society. In this paper we examine how the imagery of palatable foods affects cravings and functional connectivity in the visual cortex for people who differ on the power of food scale (PFS). Fourteen older, overweight/obese adults came to our laboratory on two different occasions. Both times they ate a controlled breakfast meal and then were restricted from eating for 2.5 h prior to scanning. On 1 day they consumed a BOOST((r)) liquid meal after the period of food restriction, whereas on the other day they only consumed water (NO BOOST((r)) condition). After these manipulations, they had an fMRI scan in which they were asked to image both neutral objects and their favorite snack foods; they also completed visual analog scales for craving, hunger, and the vividness of the imagery experiences. Irrespective of the BOOST((r)) manipulation, we observed marked increases in food cravings when older, overweight/obese adults created images of favorite foods in their minds as opposed to creating an image of neutral objects; however, the increase in food craving following the imagery of desired food was more pronounced among those scoring high than low on the PFS. Furthermore, local efficiency within the visual cortex when imaging desired food was higher for those scoring high as compared to low on the PFS. The active imagery of desired foods seemed to have overpowered the BOOST((r)) manipulation when evaluating connectivity in the visual cortex. PMID- 24348418 TI - Age-related changes in consolidation of perceptual and muscle-based learning of motor skills. AB - Improvements in motor sequence learning come about via goal-based learning of the sequence of visual stimuli and muscle-based learning of the sequence of movement responses. In young adults, consolidation of goal-based learning is observed after intervals of sleep but not following wake, whereas consolidation of muscle based learning is greater following intervals with wake compared to sleep. While the benefit of sleep on motor sequence learning has been shown to decline with age, how sleep contributes to consolidation of goal-based vs. muscle-based learning in older adults (OA) has not been disentangled. We trained young (n = 62) and older (n = 50) adults on a motor sequence learning task and re-tested learning following 12 h intervals containing overnight sleep or daytime wake. To probe consolidation of goal-based learning of the sequence, half of the participants were re-tested in a configuration in which the stimulus sequence was the same but, due to a shift in stimulus-response mapping, the movement response sequence differed. To probe consolidation of muscle-based learning, the remaining participants were tested in a configuration in which the stimulus sequence was novel, but now the sequence of movements used for responding was unchanged. In young adults, there was a significant condition (goal-based vs. muscle-based learning) by interval (sleep vs. wake) interaction, F(1,58) = 6.58, p = 0.013: goal-based learning tended to be greater following sleep compared to wake, t(29) = 1.47, p = 0.072. Conversely, muscle-based learning was greater following wake than sleep, t(29) = 2.11, p = 0.021. Unlike young adults, this interaction was not significant in OA, F(1,46) = 0.04, p = 0.84, nor was there a main effect of interval, F(1,46) = 1.14, p = 0.29. Thus, OA do not preferentially consolidate sequence learning over wake or sleep. PMID- 24348420 TI - Gene expression of muscarinic, tachykinin, and purinergic receptors in porcine bladder: comparison with cultured cells. AB - Urothelial cells, myofibroblasts, and smooth muscle cells are important cell types contributing to bladder function. Multiple receptors including muscarinic (M3/M5), tachykinin (NK1/NK2), and purinergic (P2X1/P2Y6) receptors are involved in bladder motor and sensory actions. Using female pig bladder, our aim was to differentiate between various cell types in bladder by genetic markers. We compared the molecular expression pattern between the fresh tissue layers and their cultured cell counterparts. We also examined responses to agonists for these receptors in cultured cells. Urothelial, suburothelial (myofibroblasts), and smooth muscle cells isolated from pig bladder were cultured (10-14 days) and identified by marker antibodies. Gene (mRNA) expression level was demonstrated by real-time PCR. The receptor expression pattern was very similar between suburothelium and detrusor, and higher than urothelium. The gene expression of all receptors decreased in culture compared with the fresh tissue, although the reduction in cultured urothelial cells appeared less significant compared to suburothelial and detrusor cells. Cultured myofibroblasts and detrusor cells did not contract in response to the agonists acetylcholine, neurokinin A, and beta,gamma-MeATP, up to concentrations of 0.1 and 1 mM. The significant reduction of M3, NK2, and P2X1 receptors under culture conditions may be associated with the unresponsiveness of cultured suburothelial and detrusor cells to their respective agonists. These results suggest that under culture conditions, bladder cells lose the receptors that are involved in contraction, as this function is no longer required. The study provides further evidence that cultured cells do not necessarily mimic the actions exerted by intact tissues. PMID- 24348421 TI - Cardioprotection by systemic dosing of thymosin beta four following ischemic myocardial injury. AB - Thymosin beta 4 (Tbeta4) was previously shown to reduce infarct size and improve contractile performance in chronic myocardial ischemic injury via two phases of action: an acute phase, just after injury, when Tbeta4 preserves ischemic myocardium via antiapoptotic or anti-inflammatory mechanisms; and a chronic phase, when Tbeta4 activates the growth of vascular or cardiac progenitor cells. In order to differentiate between the effects of Tbeta4 during the acute and during the chronic phases, and also in order to obtain detailed hemodynamic and biomarker data on the effects of Tbeta4 treatment suitable for use in clinical studies, we tested Tbeta4 in a rat model of chronic myocardial ischemia using two dosing regimens: short term dosing (Tbeta4 administered only during the first 3 days following injury), and long term dosing (Tbeta4 administered during the first 3 days following injury and also every third day until the end of the study). Tbeta4 administered throughout the study reduced infarct size and resulted in significant improvements in hemodynamic performance; however, chamber volumes and ejection fractions were not significantly improved. Tbeta4 administered only during the first 3 days following injury tended to reduce infarct size, chamber volumes and improve hemodynamic performance. Plasma biomarkers of myocyte injury were significantly reduced by Tbeta4 treatment during the acute injury period, and plasma ANP levels were significantly reduced in both dosing groups. Surprisingly, neither acute nor chronic Tbeta4 treatment significantly increased blood vessel density in peri-infarct regions. These results suggest the following: repeated dosing may be required to achieve clinically measureable improvements in cardiac function post-myocardial infarction (MI); improvement in cardiac function may be observed in the absence of a high degree of angiogenesis; and that plasma biomarkers of cardiac function and myocardial injury are sensitive pharmacodynamic biomarkers of the effects of Tbeta4. PMID- 24348419 TI - Controversies about the enhanced vulnerability of the adolescent brain to develop addiction. AB - Adolescence, defined as a transition phase toward autonomy and independence, is a natural time of learning and adjustment, particularly in the setting of long-term goals and personal aspirations. It also is a period of heightened sensation seeking, including risk taking and reckless behaviors, which is a major cause of morbidity and mortality among teenagers. Recent observations suggest that a relative immaturity in frontal cortical neural systems may underlie the adolescent propensity for uninhibited risk taking and hazardous behaviors. However, converging preclinical and clinical studies do not support a simple model of frontal cortical immaturity, and there is substantial evidence that adolescents engage in dangerous activities, including drug abuse, despite knowing and understanding the risks involved. Therefore, a current consensus considers that much brain development during adolescence occurs in brain regions and systems that are critically involved in the perception and evaluation of risk and reward, leading to important changes in social and affective processing. Hence, rather than naive, immature and vulnerable, the adolescent brain, particularly the prefrontal cortex, should be considered as prewired for expecting novel experiences. In this perspective, thrill seeking may not represent a danger but rather a window of opportunities permitting the development of cognitive control through multiple experiences. However, if the maturation of brain systems implicated in self-regulation is contextually dependent, it is important to understand which experiences matter most. In particular, it is essential to unveil the underpinning mechanisms by which recurrent adverse episodes of stress or unrestricted access to drugs can shape the adolescent brain and potentially trigger life-long maladaptive responses. PMID- 24348422 TI - Adult spinal cord ependymal layer: a promising pool of quiescent stem cells to treat spinal cord injury. AB - Spinal cord injury (SCI) is a major health burden and currently there is no effective medical intervention. Research performed over the last decade revealed that cells surrounding the central canal of the adult spinal cord and forming the ependymal layer acquire stem cell properties either in vitro or in response to injury. Following SCI activated ependymal cells generate progeny cells which migrate to the injury site but fail to produce the appropriate type of cells in sufficient number to limit the damage, rendering this physiological response mainly ineffective. Research is now focusing on the manipulation of ependymal cells to produce cells of the oligodendrocyte lineage which are primarily lost in such a situation leading to secondary neuronal degeneration. Thus, there is a need for a more focused approach to understand the molecular properties of adult ependymal cells in greater detail and develop effective strategies for guiding their response during SCI. PMID- 24348423 TI - Polarization of membrane associated proteins in the choroid plexus epithelium from normal and slc4a10 knockout mice. AB - The choroid plexus epithelium (CPE) has served as a model-epithelium for cell polarization and transport studies and plays a crucial role for cerebrospinal fluid (CSF) production. The normal luminal membrane expression of Na(+),K(+) ATPase, aquaporin-1 and Na(+)/H(+) exchanger 1 in the choroid plexus is severely affected by deletion of the slc4a10 gene that encodes the bicarbonate transporting protein Ncbe/NBCn2. The causes for these deviations from normal epithelial polarization and redistribution following specific gene knockout are unknown, but may be significant for basic epithelial cell biology. Therefore, a more comprehensive analysis of cell polarization in the choroid plexus is warranted. We find that the cytoskeleton in the choroid plexus contains alphaI-, alphaII-, betaI-, and betaII-spectrin isoforms along with the anchoring protein ankyrin-3, most of which are mainly localized in the luminal membrane domain. Furthermore, we find alpha-adducin localized near the plasma membranes globally, but with only faint expression in the luminal membrane domain. In slc4a10 knockout mice, the abundance of beta1 Na(+),K(+)-ATPase subunits in the luminal membrane is markedly reduced. Anion exchanger 2 abundance is increased in slc4a10 knockout and its anchor protein, alpha-adducin is almost exclusively found near the basolateral domain. The alphaI- and betaI-spectrin abundances are also decreased in the slc4a10 knockout, where the basolateral domain expression of alphaI-spectrin is exchanged for a strictly luminal domain localization. E cadherin expression is unchanged in the slc4a10 knockout, while small decreases in abundance are observed for its probable adaptor proteins, the catenins. Interestingly, the abundance of the tight junction protein claudin-2 is significantly reduced in the slc4a10 knockouts, which may critically affect paracellular transport in this epithelium. The observations allow the generation of new hypotheses on basic cell biological paradigms that can be tested experimentally in future studies. PMID- 24348424 TI - The interplay between stress and physical activity in the prevention and treatment of cardiovascular disease. PMID- 24348426 TI - Simple silicone chamber system for in vitro three-dimensional skeletal muscle tissue formation. AB - Bioengineering skeletal muscle often requires customized equipment and intricate casting techniques. One of the major hurdles when initially trying to establish in vitro tissue engineered muscle constructs is the lack of consistency across published methodology. Although this diversity allows for specialization according to specific research goals, lack of standardization hampers comparative efforts. Differences in cell type, number and density, variability in matrix and scaffold usage as well as inconsistency in the distance between and type of adhesion posts complicates initial establishment of the technique with confidence. We describe an inexpensive, but readily adaptable silicone chamber system for the generation of skeletal muscle constructs that can readily be standardized and used to elucidate myoblast behavior in a three-dimensional space. Muscle generation, regeneration and adaptation can also be investigated in this model, which is more advanced than differentiated myotubes. PMID- 24348427 TI - Assessing homing failure in honeybees exposed to pesticides: Guez's (2013) criticism illustrates pitfalls and challenges. PMID- 24348425 TI - Effects of exercise training on cardiovascular adrenergic system. AB - In heart failure (HF), exercise has been shown to modulate cardiac sympathetic hyperactivation which is one of the earliest features of neurohormonal derangement in this syndrome and correlates with adverse outcome. An important molecular alteration related to chronic sympathetic overstimulation in HF is represented by cardiac beta-adrenergic receptor (beta-AR) dysfunction. It has been demonstrated that exercise reverses beta-AR dysfunction by restoring cardiac receptor membrane density and G-protein-dependent adenylyl cyclase activation. In particular, several evidence indicate that exercise reduces levels of cardiac G protein coupled receptor kinase-2 (GRK2) which is known to be involved in both beta1-AR and beta2-AR dysregulation in HF. Similar alterations of beta-AR system have been described also in the senescent heart. It has also been demonstrated that exercise training restores adrenal GRK2/alpha-2AR/catecholamine (CA) production axis. At vascular level, exercise shows a therapeutic effect on age related impairment of vascular reactivity to adrenergic stimulation and restores beta-AR-dependent vasodilatation by increasing vascular beta-AR responsiveness and reducing endothelial GRK2 activity. Sympathetic nervous system overdrive is thought to account for >50% of all cases of hypertension and a lack of balance between parasympathetic and sympathetic modulation has been observed in hypertensive subjects. Non-pharmacological, lifestyle interventions have been associated with reductions in SNS overactivity and blood pressure in hypertension. Several evidence have highlighted the blood pressure lowering effects of aerobic endurance exercise in patients with hypertension and the significant reduction in sympathetic neural activity has been reported as one of the main mechanisms explaining the favorable effects of exercise on blood pressure control. PMID- 24348428 TI - Regulation of insect behavior via the insulin-signaling pathway. AB - The insulin/insulin-like growth factor signaling (IIS) pathway is well established as a critical regulator of growth and metabolic homeostasis across the animal kingdom. Insulin-like peptides (ILPs), the functional analogs of mammalian insulin, were initially discovered in the silkmoth Bombyx mori and subsequently identified in many other insect species. Initial research focused on the role of insulin signaling in metabolism, cell proliferation, development, reproduction and aging. More recently however, increasing attention has been given to the role of insulin in the regulation of neuronal function and behavior. Here we review the role of insulin signaling in two specific insect behaviors: feeding and locomotion. PMID- 24348430 TI - Mechanisms of auditory verbal hallucination in schizophrenia. AB - Recent work on the mechanisms underlying auditory verbal hallucination (AVH) has been heavily informed by self-monitoring accounts that postulate defects in an internal monitoring mechanism as the basis of AVH. A more neglected alternative is an account focusing on defects in auditory processing, namely a spontaneous activation account of auditory activity underlying AVH. Science is often aided by putting theories in competition. Accordingly, a discussion that systematically contrasts the two models of AVH can generate sharper questions that will lead to new avenues of investigation. In this paper, we provide such a theoretical discussion of the two models, drawing strong contrasts between them. We identify a set of challenges for the self-monitoring account and argue that the spontaneous activation account has much in favor of it and should be the default account. Our theoretical overview leads to new questions and issues regarding the explanation of AVH as a subjective phenomenon and its neural basis. Accordingly, we suggest a set of experimental strategies to dissect the underlying mechanisms of AVH in light of the two competing models. PMID- 24348431 TI - Identity Formation, Marijuana and "The Self": A Study of Cannabis Normalization among University Students. AB - Over the past half-century, as use of marijuana has become more widespread in Canadian society, there are indications of a normalizing process in societal reactions and experiences of use. Among other research avenues, these trends suggest a need for further exploration of young people's understandings of how they make the choice to use or not and how decisions relate to presentation of the self. This study draws on interviews with 30 undergraduates recruited from a larger online survey of respondents at the University of Guelph, ON, Canada. In probing their perceptions of the use of marijuana, we often found that trying/using "pot" was the default option, whereas choosing not to use required more conscious effort. With specific reference to Goffman's contribution to a situated understanding of the self, our findings are interpreted with emphasis on further theoretical development of the normalization thesis and on the role of marijuana in identity formation among persons in the process of transition to adulthood. PMID- 24348429 TI - Rare Genomic Variants Link Bipolar Disorder with Anxiety Disorders to CREB Regulated Intracellular Signaling Pathways. AB - Bipolar disorder is a common, complex, and severe psychiatric disorder with cyclical disturbances of mood and a high suicide rate. Here, we describe a family with four siblings, three affected females and one unaffected male. The disease course was characterized by early-onset bipolar disorder and co-morbid anxiety spectrum disorders that followed the onset of bipolar disorder. Genetic risk factors were suggested by the early onset of the disease, the severe disease course, including multiple suicide attempts, and lack of adverse prenatal or early life events. In particular, drug and alcohol abuse did not contribute to the disease onset. Exome sequencing identified very rare, heterozygous, and likely protein-damaging variants in eight brain-expressed genes: IQUB, JMJD1C, GADD45A, GOLGB1, PLSCR5, VRK2, MESDC2, and FGGY. The variants were shared among all three affected family members but absent in the unaffected sibling and in more than 200 controls. The genes encode proteins with significant regulatory roles in the ERK/MAPK and CREB-regulated intracellular signaling pathways. These pathways are central to neuronal and synaptic plasticity, cognition, affect regulation and response to chronic stress. In addition, proteins in these pathways are the target of commonly used mood-stabilizing drugs, such as tricyclic antidepressants, lithium, and valproic acid. The combination of multiple rare, damaging mutations in these central pathways could lead to reduced resilience and increased vulnerability to stressful life events. Our results support a new model for psychiatric disorders, in which multiple rare, damaging mutations in genes functionally related to a common signaling pathway contribute to the manifestation of bipolar disorder. PMID- 24348432 TI - Working memory capacity and psychotic-like experiences in a general population sample of adolescents and young adults. AB - Working memory (WM) impairment is a common feature in individuals with schizophrenia and high-risk for psychosis and a promising target for early intervention strategies. However, it is unclear to what extent WM impairment parallels specific behavioral symptoms along the psychosis continuum. To address this issue, the current study investigated the relation of WM capacity with psychotic-like experiences (PLEs) in a large Swedish population sample (N = 1012) of adolescents and young adults (M = 24.4 years, range 12-35). WM was assessed with two online computer tasks: a task where participants had to identify and remember the location of an odd shape and a task of remembering and following instructions. PLE scores were derived from a translated symptom questionnaire (Community Assessment of Psychic Experiences), which includes positive, negative, and depressive symptom scales. Positive and negative symptom scales were further subdivided into symptom clusters based on factor analyses. The results showed that low WM capacity was modestly associated with increased reports of bizarre experiences (BE) and depressive symptoms, after controlling for age, gender, and global symptom scores. Interestingly, when analyses were repeated for separate age groups, low WM was exclusively associated with a higher frequency of BE for young adults (20-27 years) and with depressive symptoms for older adults (28-35 years). These findings suggest that specific PLEs can be indicative of reduced WM capacity in early adulthood, which in turn may reflect an increased risk for psychosis and a greater need for targeted intervention. In contrast, during adolescence individual differences in cognitive development may influence the strength of the relationships and thereby mask potential vulnerabilities for psychopathology. PMID- 24348434 TI - Toward understanding social cues and signals in human-robot interaction: effects of robot gaze and proxemic behavior. AB - As robots are increasingly deployed in settings requiring social interaction, research is needed to examine the social signals perceived by humans when robots display certain social cues. In this paper, we report a study designed to examine how humans interpret social cues exhibited by robots. We first provide a brief overview of perspectives from social cognition in humans and how these processes are applicable to human-robot interaction (HRI). We then discuss the need to examine the relationship between social cues and signals as a function of the degree to which a robot is perceived as a socially present agent. We describe an experiment in which social cues were manipulated on an iRobot Ava(TM) mobile robotics platform in a hallway navigation scenario. Cues associated with the robot's proxemic behavior were found to significantly affect participant perceptions of the robot's social presence and emotional state while cues associated with the robot's gaze behavior were not found to be significant. Further, regardless of the proxemic behavior, participants attributed more social presence and emotional states to the robot over repeated interactions than when they first interacted with it. Generally, these results indicate the importance for HRI research to consider how social cues expressed by a robot can differentially affect perceptions of the robot's mental states and intentions. The discussion focuses on implications for the design of robotic systems and future directions for research on the relationship between social cues and signals. PMID- 24348433 TI - Narrative descriptions should replace grades and numerical ratings for clinical performance in medical education in the United States. AB - BACKGROUND: In medical education, evaluation of clinical performance is based almost universally on rating scales for defined aspects of performance and scores on examinations and checklists. Unfortunately, scores and grades do not capture progress and competence among learners in the complex tasks and roles required to practice medicine. While the literature suggests serious problems with the validity and reliability of ratings of clinical performance based on numerical scores, the critical issue is not that judgments about what is observed vary from rater to rater but that these judgments are lost when translated into numbers on a scale. As the Next Accreditation System of the Accreditation Council on Graduate Medical Education (ACGME) takes effect, medical educators have an opportunity to create new processes of evaluation to document and facilitate progress of medical learners in the required areas of competence. Proposal and initial experience: Narrative descriptions of learner performance in the clinical environment, gathered using a framework for observation that builds a shared understanding of competence among the faculty, promise to provide meaningful qualitative data closely linked to the work of physicians. With descriptions grouped in categories and matched to milestones, core faculty can place each learner along the milestones' continua of progress. This provides the foundation for meaningful feedback to facilitate the progress of each learner as well as documentation of progress toward competence. IMPLICATIONS: This narrative evaluation system addresses educational needs as well as the goals of the Next Accreditation System for explicitly documented progress. Educators at other levels of education and in other professions experience similar needs for authentic assessment and, with meaningful frameworks that describe roles and tasks, may also find useful a system built on descriptions of learner performance in actual work settings. CONCLUSIONS: We must place medical learning and assessment in the contexts and domains in which learners do clinical work. The approach proposed here for gathering qualitative performance data in different contexts and domains is one step along the road to moving learners toward competence and mastery. PMID- 24348435 TI - Numerical synesthesia is more than just a symbol-induced phenomenon. PMID- 24348436 TI - Lexical neighborhood effects in pseudoword spelling. AB - The general aim of this study is to contribute to a better understanding of the cognitive processes that underpin skilled adult spelling. More specifically, it investigates the influence of lexical neighbors on pseudo-word spelling with the goal of providing a more detailed account of the interaction between lexical and sublexical sources of knowledge in spelling. In prior research examining this topic, adult participants typically heard lists composed of both words and pseudo words and had to make a lexical decision to each stimulus before writing the pseudo-words. However, these priming paradigms are susceptible to strategic influence and may therefore not give a clear picture of the processes normally engaged in spelling unfamiliar words. In our two Experiments involving 71 French speaking literate adults, only pseudo-words were presented which participants were simply requested to write to dictation using the first spelling that came to mind. Unbeknownst to participants, pseudo-words varied according to whether they did or did not have a phonological word neighbor. Results revealed that low probability phoneme/grapheme mappings (e.g., /o/ -> aud in French) were used significantly more often in spelling pseudo-words with a close phonological lexical neighbor with that spelling (e.g., /krepo/ derived from "crapaud," /krapo/) than in spelling pseudo-words with no close neighbors (e.g., /fropo/). In addition, the strength of this lexical influence increased with the lexical frequency of the word neighbors as well as with their degree of phonetic overlap with the pseudo-word targets. These results indicate that information from lexical and sublexical processes is integrated in the course of spelling, and a specific theoretical account as to how such integration may occur is introduced. PMID- 24348437 TI - Using "Cinema Verite" (truthful cinema) to facilitate replication and accountability in psychological research(?). AB - To increase replication and accountability, it is proposed that researchers make audio/video recordings of laboratory protocols using currently available technologies, such as smart-phones. A detailed record of the procedure representing each experimental condition of the study design with simulated participants could then be posted on the internet and made accessible to researchers wanting more information about the procedures described in the research publication. Making recordings of all research participants a standard practice would be a greater challenge because of threats to internal validity and ethical concerns, however it is feasible and merits a broad discussion among researchers, professional societies, IRB's and funding organizations. PMID- 24348438 TI - Does interoceptive awareness affect the ability to regulate unfair treatment by others? AB - In this study we aimed to investigate how awareness of bodily responses, referred to as interoceptive awareness, influences decision-making in a social interactive context. Interoceptive awareness is thought to be crucial for adequate regulation of one's emotions. However, there is a dearth of studies that examine the association between interoceptive awareness and the ability to regulate emotions during interpersonal decision-making. Here, we quantified interoceptive awareness with a heartbeat detection task in which we measured the difference between subjective self-reports and an objective psychophysiological measurement of participant heart rates. Social decision-making was quantified using a two-round Ultimatum Game. Participants were asked to first reject or accept an unfair division of money proposed by a partner. In turn, participants could then make an offer on how to divide an amount of money with the same partner. Participants performed 20 rounds of the two-round Ultimatum Game twice, once during baseline condition and once while asked to reappraise emotional reactions when confronted with unfair offers from partners. Results showed that after reappraisal participants (1) accepted more unfair offers and (2) offered higher return divisions, as compared to baseline. With respect to interoceptive awareness, participants with better heartbeat detection scores tended to report less emotional involvement when they applied reappraisal while playing the Ultimatum Game. However, there was no reliably significant relationship between heartbeat detection and the acceptance of unfair offers. Similarly, heartbeat detection accuracy was not related to return offers made in the second round of the Ultimatum Game or the habitual use of emotion regulation. These preliminary findings suggest that the relationship between interoceptive awareness and behavioral changes due to emotion regulation in a social decision-making context appears to be complex. PMID- 24348439 TI - Sensory motor mechanisms unify psychology: the embodiment of culture. AB - Sensorimotor mechanisms can unify explanations at cognitive, social, and cultural levels. As an example, we review how anticipated motor effort is used by individuals and groups to judge distance: the greater the anticipated effort the greater the perceived distance. Anticipated motor effort can also be used to understand cultural differences. People with interdependent self- construals interact almost exclusively with in-group members, and hence there is little opportunity to tune their sensorimotor systems for interaction with out-group members. The result is that interactions with out-group members are expected to be difficult and out-group members are perceived as literally more distant. In two experiments we show (a) interdependent Americans, compared to independent Americans, see American confederates (in-group) as closer; (b) interdependent Arabs, compared to independent Arabs, perceive Arab confederates (in- group) as closer, whereas interdependent Americans perceive Arab confederates (out-group) as farther. These results demonstrate how the same embodied mechanism can seamlessly contribute to explanations at the cognitive, social, and cultural levels. PMID- 24348440 TI - Socio-emotional correlates of a schooldog-teacher-team in the classroom. AB - A growing number of teachers in Europe regularly take their dogs with them into the classroom. Limited research points at positive socio-emotional effects of this practice. In this study the effects of a schooldog-teacher-team on socioemotional experiences in school, depression and emotion regulation strategies were investigated in a classroom of third-graders (male n = 12, female n = 13), which had a schooldog present for 1 day per week in comparison with a control class (male n = 11, female n = 10). In contrast to the control class, the dog-class students reported a stronger improvement with regard to positive attitude toward school (repeated measures ANOVA; F = 10.769, df = 1, p = 0.002) and positive emotions related to learning (F = 4.479, df = 1, p = 0.042) over the course of the year. Since a prerequisite of all kinds of effective learning is a positive attitude and mood toward school and learning, the presence of a schooldog-teacher team thus has the potential to support learning. PMID- 24348441 TI - The relationship of sex and sexual orientation to self-esteem, body shape satisfaction, and eating disorder symptomatology. AB - There is increasing interest in understanding what role, if any, sex and sexual orientation play in body dissatisfaction, its correlates to distress, and its relationship to disordered eating. The goals of the present study were to examine: (a) differences in sex and sexual orientation in internalization of societal pressure to modify physical appearance, components of body image dissatisfaction, self-esteem, and eating disorder symptomatology and (b) whether the internalization-eating disorder symptomatology was mediated by the different components of body image dissatisfaction and low self-esteem. The present data support several key trends in the literature: men generally reported less body dissatisfaction, internalization of socio-cultural standards of beauty, drive for thinness, and disordered eating, but a greater drive for muscularity than women; results also indicated that different components of body image dissatisfaction and low self-esteem partially mediated the relationship between internalization and eating disorder symptomatology. Gay men reported significantly more body dissatisfaction, internalization, eating disorder symptomatology, drive for thinness, and drive for muscularity than heterosexual men. Compared to heterosexual women, lesbians reported increased drive for muscularity, lower self esteem, and lower internalization; however, they did not significantly differ on body dissatisfaction, drive for thinness or disordered eating. Correlation coefficients between body shape dissatisfaction and several aspects of mental distress were significantly larger for gay men than heterosexual men; the same coefficients did not differ between lesbian women and heterosexual women. Results of path analyses indicated that the relationship between internalization and disordered eating differs for gay and heterosexual men but not for lesbian and heterosexual women. These results call attention to lesbians as a generally understudied population. PMID- 24348442 TI - Modulating mind-wandering in dysphoria. AB - Depression is associated with significant difficulty staying "in the moment" as the mind tends to wander away from current activity to focus instead on personal concerns. Mind-wandering (MW) may in some instances be a precursor for depressive rumination, a thinking style believed to confer vulnerability to the likelihood and extent of depression. Thus, MW may be not only a consequence but also a cause of low mood. Identifying a paradigm that could modulate MW, particularly in depressed individuals, would allow future studies to test whether elevated rates of MW causally drive cognitive-affective features of depression, such as rumination and anhedonia. This study therefore explored the feasibility of using an existing task manipulation to modulate behavioral and self-report indices of MW in participants with varying levels of self-reported dysphoria. Participants completed two go/no-go tasks-the SART and a high target probability task-and measures of state and trait MW. The two tasks were identical in all respects apart from the lower probability of no-go targets on the SART, a feature considered to encourage mindless, or inattentive, responding. Across participants, errors of commission (a behavioral indicator of MW) were elevated on the SART relative to the high probability task, a pattern that was particularly pronounced in dysphoric participants. Dysphoric individuals furthermore reported elevated levels of MW, though the modulation of these subjective reports by task was present to a similar rather than greater extent in the dysphoric individuals. These findings provide encouraging preliminary support for the use of this paradigm as one that modulates MW in depressed individuals. The implications of these results and directions for future research are discussed. PMID- 24348443 TI - Rethinking the portrayal of deaf characters in children's picture books. PMID- 24348444 TI - The way we encounter reading material influences how frequently we mind wander. AB - We examined whether different encounters of reading material influence the likelihood of mind wandering, memory for the material, and the ratings of interest in the material. In a within-subjects design participants experienced three different reading encounters: (1) reading a passage aloud, (2) listening to a passage being read to them, and (3) reading a passage silently. Throughout each reading encounter probes were given in order to identify mind wandering. After finishing the passage participants also rated how interesting it was and completed a content recognition test. Results showed that reading aloud led to the least amount of mind wandering, while listening to the passage led to the most mind wandering. Listening to the passage was also associated with the poorest memory performance and the least interest in the material. Finally, within the silent reading and listening encounters we observed negative relations between mind wandering and both memory performance and interest in the material, replicating previous findings. Taken together, the present findings improve our understanding of the nature of mind wandering while reading, and have potentially important implications for readers seeking to take advantage of the convenience of audiobooks and podcasts. PMID- 24348445 TI - Understanding egorrhea from cultural-clinical psychology. AB - Based on his observations in Japanese clinical settings, Fujinawa (1972) conceptualized egorrhea syndrome, which includes symptoms such as erythrophobia, fear of eye-to-eye confrontation, olfactory reference syndrome, delusions of soliloquy, delusions of sleep talking, and thought broadcasting. The key feature of this syndrome is self-leakage, a perceived sense that one's personal internal information, such as feelings and thoughts, are leaking out. To reach a more comprehensive understanding of egorrhea, this paper aims to present general overview and reconsider the phenomenon of self-leakage using cultural-clinical psychology as a framework. First, the symptoms of egorrhea are reviewed in relation to other related psychopathologies such as social anxiety disorder (SAD) and taijin kyofusho (TKS), as well as schizophrenia. Second, a series of empirical studies conducted using Japanese non-clinical samples are summarized. The results of these studies form the basis for subsequent discussions, which incorporates the cultural-clinical psychology perspective proposed by Ryder et al. (2011). This paper ends with a general discussion regarding implications for research and clinical practice. PMID- 24348446 TI - Individuality in harpsichord performance: disentangling performer- and piece specific influences on interpretive choices. AB - Although a growing body of research has examined issues related to individuality in music performance, few studies have attempted to quantify markers of individuality that transcend pieces and musical styles. This study aims to identify such meta-markers by discriminating between influences linked to specific pieces or interpretive goals and performer-specific playing styles, using two complementary statistical approaches: linear mixed models (LMMs) to estimate fixed (piece and interpretation) and random (performer) effects, and similarity analyses to compare expressive profiles on a note-by-note basis across pieces and expressive parameters. Twelve professional harpsichordists recorded three pieces representative of the Baroque harpsichord repertoire, including three interpretations of one of these pieces, each emphasizing a different melodic line, on an instrument equipped with a MIDI console. Four expressive parameters were analyzed: articulation, note onset asynchrony, timing, and velocity. LMMs showed that piece-specific influences were much larger for articulation than for other parameters, for which performer-specific effects were predominant, and that piece-specific influences were generally larger than effects associated with interpretive goals. Some performers consistently deviated from the mean values for articulation and velocity across pieces and interpretations, suggesting that global measures of expressivity may in some cases constitute valid markers of artistic individuality. Similarity analyses detected significant associations among the magnitudes of the correlations between the expressive profiles of different performers. These associations were found both when comparing across parameters and within the same piece or interpretation, or on the same parameter and across pieces or interpretations. These findings suggest the existence of expressive meta-strategies that can manifest themselves across pieces, interpretive goals, or expressive devices. PMID- 24348447 TI - Sensory descriptors, hedonic perception and consumer's attitudes to Sangiovese red wine deriving from organically and conventionally grown grapes. AB - In recent years, produce obtained from organic farming methods (i.e., a system that minimizes pollution and avoids the use of synthetic fertilizers and pesticides) has rapidly increased in developed countries. This may be explained by the fact that organic food meets the standard requirements for quality and healthiness. Among organic products, wine has greatly attracted the interest of the consumers. In the present study, trained assessors and regular wine consumers were respectively required to identify the sensory properties (e.g., odor, taste, flavor, and mouthfeel sensations) and to evaluate the hedonic dimension of red wines deriving from organically and conventionally grown grapes. Results showed differences related mainly to taste (sour and bitter) and mouthfeel (astringent) sensations, with odor and flavor playing a minor role. However, these differences did not influence liking, as organic and conventional wines were hedonically comparable. Interestingly, 61% of respondents would be willing to pay more for organically produced wines, which suggests that environmentally sustainable practices related to wine quality have good market prospects. PMID- 24348448 TI - Erratum: Early ERP signature of hearing impairment in visual rhyme judgment. AB - [This corrects the article on p. 241 in vol. 4, PMID: 23653613.]. PMID- 24348449 TI - Staying and shifting patterns across IGT trials distinguish children with externalizing disorders from controls. AB - The Iowa Gambling Task (IGT) is the most widely instrument used in the assessment of affective decision-making in several populations with frontal impairment. The standard performance measure on the IGT is obtained by calculating the difference between the advantageous and the disadvantageous choices. This standard score does not allows the assessment of the use of different strategies to deal with contingencies of gain and losses across the task. This study aims to compare the standard score method used in IGT with a method that analyses the patterns of staying and shifting among different decks across the 100 choices, considering contingencies of choices with and without losses. We compared the IGT performance of 24 children with externalizing disorders (Attention Deficit Hyperactivity Disorder and Oppositional Defiant Disorder) and 24 healthy age-matched children. The analyses of the standard score across all blocks failed to show differences among children with externalizing disorders and control children. However, healthy children showed a pattern of shifting more from disadvantageous decks to advantageous decks and choosing more consecutive cards from the advantageous decks across all blocks, independently of the contingency of losses. On the other hand, children with externalizing disorders presented a pattern of shifting more from advantageous decks to disadvantageous ones in comparison to healthy children and repeatedly chose cards from the B deck across all blocks. This findings show that even though differences among groups might not be found when using the standard analyses, a different type of analysis might be able to show distinct strategies on the execution of the test. PMID- 24348451 TI - Erratum: Neural entrainment to rhythmically-presented auditory, visual and audio visual speech in children. AB - [This corrects the article on p. 216 in vol. 3, PMID: 22833726.]. PMID- 24348450 TI - Relationships between personality traits and attitudes toward the sense of smell. AB - Olfactory perception appears to be linked to personality traits. This study aimed to determine whether personality traits influence human attitudes toward sense of smell. Two-hundred participants' attitudes toward their senses of smell and their personality traits were measured using two self-administered questionnaires: the Importance of Olfaction Questionnaire and the Eysenck Personality Questionnaire Revised. Demographics and olfactory function were also assessed using a self administered questionnaire. Gender-induced differences were present in attitudes toward sense of smell. Women participants were more dependent than men participants on olfactory cues for daily decision-making. In addition, as participants evaluated their own olfactory functions more positively, they relied more on olfactory information in everyday life. To determine a relationship between personality traits and attitudes toward sense of smell, Spearman partial correlation analyses were conducted, with controlling the factors that might influence attitudes with respect to sense of smell (i.e., gender and self awareness of olfactory function) as covariates. Participants who scored high on the lie-scale (i.e., socially desirable and faking good), tended to use olfactory cues for daily decision-making related both to social communication and product purchase. In conclusion, our findings demonstrate a significant association between personality traits and attitudes toward sense of smell. PMID- 24348452 TI - A mid-level explanation for the venetian blind effect. PMID- 24348453 TI - Alexithymia and fibromyalgia: clinical evidence. AB - This review proposes a critical discussion of the latest studies investigating the presence of alexithymia in patients with fibromyalgia (FM) and its relation to other psychological disorders. The focus is on the most relevant literature exploring the relationship between FM, a chronic pain syndrome, and alexithymia, an affective dysregulation, largely observed in psychosomatic diseases. The articles were selected from the Medline/Pubmed database using the search terms "Fibromyalgia," "Alexithymia," and "Psychological Distress." Of the seven studies fulfilling these criteria, one found no differences between FM patients and the control group, four found significant differences, with higher levels of alexithymia in the FM sample, while two showed unclear results. Overall, the majority of findings highlighted the high prevalence of alexithymia in FM patients. Future studies should clarify the role of alexithymia in FM, paying attention to two principal aspects: the use, as a control group, of patients with chronic pain conditions but a low psychosomatic component, and the use of other measures, in addition to the Toronto Alexithymia Scale (TAS-20), to assess alexithymia. PMID- 24348454 TI - Influence of music on steroid hormones and the relationship between receptor polymorphisms and musical ability: a pilot study. AB - Studies have shown that music confers plasticity to the brain. In a preliminary pilot study, we examined the effect of music listening on steroid hormones and the relationship between steroid hormone receptor polymorphisms and musical ability. Twenty-one subjects (10 males and 11 females) were recruited and divided into musically talented and control groups. The subjects selected (1) music they preferred (chill-inducing music) and (2) music they did not like. Before and after the experiments, saliva was collected to measure the levels of steroid hormones such as testosterone, estradiol, and cortisol. DNA was also isolated from the saliva samples to determine the androgen receptor (AR) and arginine vasopressin receptor 1A genotypes. Advanced Measures of Music Audiation (AMMA) was used to determine the musical ability of the subjects. With both types of music, the cortisol levels decreased significantly in both sexes. The testosterone (T) levels declined in males when they listened to both types of music. In females, the T levels increased in those listening to chill-inducing music but declined when they listened to music they disliked. However, these differences were not significant. The 17-beta estradiol levels increased in males with both types of music, whereas the levels increased with chill-inducing music but declined with disliked music in females. The AMMA scores were higher for the short repeat length-type AR than for the long repeat length-type. Comparisons of AR polymorphisms and T levels before the experiments showed that the T levels were within the low range in the short repeat length-type group and there was a positive relationship with the repeat length, although it was not significant. This is the first study conducted in humans to analyze the relationships between the AR gene, T levels, and musical ability. PMID- 24348456 TI - No evidence for a role of competitive capabilities of adults in causing habitat segregation of diploid and hexaploid Senecio carniolicus (Asteracaeae). AB - Hexaploid individuals of Senecio carniolicus (Asteraceae) predominantly occur in dense swards while diploids prevail in open vegetation. We test whether this habitat segregation is due to differential responses to competition. Linear regression models were used to relate biomass and maximum leaf length of adults to vegetation cover within radii of 20 cm around target individuals. Biomass differed between ploidy levels, but was independent from vegetation cover in both cytotypes. Maximum leaf length of diploids increased with vegetation cover, but remained constant in hexaploids. This suggests that at the adult stage diploids respond to increasing competition by changes in plant architecture rather than changes in resource utilization, while hexaploids are unaffected by competition. Consequently, other factors, such as competitive interactions at earlier life stages, likely are responsible for habitat segregation of diploid and hexaploid S. carniolicus. PMID- 24348455 TI - Alterations in the sense of time, space, and body in the mindfulness-trained brain: a neurophenomenologically-guided MEG study. AB - Meditation practice can lead to what have been referred to as "altered states of consciousness."One of the phenomenological characteristics of these states is a joint alteration in the sense of time, space, and body. Here, we set out to study the unique experiences of alteration in the sense of time and space by collaborating with a select group of 12 long-term mindfulness meditation (MM) practitioners in a neurophenomenological setup, utilizing first-person data to guide the neural analyses. We hypothesized that the underlying neural activity accompanying alterations in the sense of time and space would be related to alterations in bodily processing. The participants were asked to volitionally bring about distinct states of "Timelessness" (outside time) and "Spacelessness" (outside space) while their brain activity was recorded by MEG. In order to rule out the involvement of attention, memory, or imagination, we used control states of "Then" (past) and "There" (another place). MEG sensors evidencing alterations in power values were identified, and the brain regions underlying these changes were estimated via spatial filtering (beamforming). Particularly, we searched for similar neural activity hypothesized to underlie both the state of "Timelessness" and "Spacelessness." The results were mostly confined to the theta band, and showed that: (1) the "Then"/"There" overlap yielded activity in regions related to autobiographic memory and imagery (right posterior parietal lobule (PPL), right precentral/middle frontal gyrus (MFG), bilateral precuneus); (2) "Timelessness"/"Spacelessness" conditions overlapped in a different network, related to alterations in the sense of the body (posterior cingulate, right temporoparietal junction (TPJ), cerebellum); and (3) phenomenologically-guided neural analyses enabled us to dissociate different levels of alterations in the sense of the body. This study illustrates the utility of employing experienced contemplative practitioners within a neurophenomenological setup for scientifically characterizing a self-induced altered sense of time, space and body, as well as the importance of theta activity in relation with these altered states. PMID- 24348457 TI - Sleep Apnea and Inflammation - Getting a Good Night's Sleep with Omega-3 Supplementation. AB - Obstructive sleep apnea (OSA) is a multifactorial sleep disorder associated with an increased risk of cardiovascular mortality and morbidity. Several mechanisms have been proposed to explain the association between OSA and cardiovascular dysfunction. One of the proposed mechanisms is an inflammatory response to OSA mediated by tumor necrosis factor (TNF-alpha). Patients with OSA have higher plasma, serum, and intracellular levels of TNF-alpha, which may be reduced after apnea treatment with continuous positive airway pressure (CPAP). Because TNF alpha plays an important role in OSA related cardiovascular morbidity, the present review aims to identify other preventive measures, in addition to CPAP, that may minimize the inflammatory process in OSA and consequently the risk of premature death due to cardiovascular dysfunction. Thus, we hypothesized that a nutritional immunology profile, i.e., supplementation with omega-3 fatty acids, may be valuable for individuals with OSA. PMID- 24348458 TI - The cell and molecular biology of neurodegenerative diseases: an overview. PMID- 24348459 TI - Neurobehavioral effects of levetiracetam in patients with traumatic brain injury. AB - Moderate to severe traumatic brain injury (TBI) is one of the leading causes of acquired epilepsy. Prophylaxis for seizures is the standard of care for individuals with moderate to severe injuries at risk for developing seizures, though relatively limited comparative data is available to guide clinicians in their choice of agents. There have however been experimental studies which demonstrate potential neuroprotective qualities of levetiracetam after TBI, and in turn there is hope that eventually such agents may improve neurobehavioral outcomes post-TBI. This mini-review summarizes the available studies and suggests areas for future studies. PMID- 24348460 TI - Endothelin Type A Receptor Genotype is a Determinant of Quantitative Traits of Metabolic Syndrome in Asian Hypertensive Families: A SAPPHIRe Study. AB - Co-heritability of hypertension and insulin resistance (IR) within families not only implies genetic susceptibility may be responsible for these complex traits but also suggests a rational that biological candidate genes for hypertension may serve as markers for features of the metabolic syndrome (MetS). Thus we determined whether the T323C polymorphism (rs5333) of endothelin type A (ETA) receptor, a predominant receptor evoking potent vasoconstrictive action of endothelin-1, contributes to susceptibility to IR-associated hypertension in 1694 subjects of Chinese and Japanese origins. Blood pressures (BPs) and biochemistries were measured. Fasting insulin level, insulin-resistance homeostasis model assessment (HOMAIR) score, and area under curve of insulin concentration (AUCINS) were selected for assessing insulin sensitivity. Genotypes were obtained by methods of polymerase chain reaction-restriction fragment length polymorphism. Foremost findings were that minor allele frequency of the T323C polymorphism was noticeable lower in our overall Asian subjects compared to multi national population reported in gene database; moreover both the genotypic and allelic frequencies of the polymorphism were significantly different between the two ethnic groups we studied. The genotype distributions at TT/TC/CC were 65, 31, 4% in Chinese and 51, 41, 8% in Japanese, respectively (p < 0.0001). Additionally, carriers of the C homozygote revealed characteristics of IR, namely significantly higher levels of fasting insulin, HOMAIR score, and AUCINS at 29.3, 35.3, and 39.3%, respectively, when compared to their counterparts with TT/TC genotypes in Chinese. Meanwhile, the CC genotype was associated with a higher level of high density lipoprotein cholesterol in Japanese. No association of the polymorphism with BP was observed. This study demonstrated for the first time that T323C polymorphism of ETA receptor gene was associated with an adverse insulin response in Chinese and a favorite atherogenic index in Japanese. PMID- 24348461 TI - The multiplicity of post-translational modifications in pro-opiomelanocortin derived peptides. AB - The precursor protein, pro-opiomelanocortin (POMC) undergoes extensive post translational processing in a tissue-specific manner to yield various biologically active peptides involved in diverse cellular functions. The recently developed method of matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) for direct tissue analysis has proved to be a powerful tool for investigating the distribution of peptides and proteins. In particular, topological mass spectrometry analysis using MALDI-MS can selectively provide a mass profile of the hormones included in cell secretory granules. An advantage of this technology is that it is possible to analyze a frozen thin slice section, avoiding an extraction procedure. Subsequently, tandem mass spectrometry (MS/MS) has a profound impact on addressing the modified residues in the hormone molecules. Based on these strategies with mass spectrometry, several interesting molecular forms of POMC-derived peptides have been found in the fish pituitary, such as novel sites of acetylation in alpha-melanocyte-stimulating hormone (MSH), hydroxylation of a proline residue in beta-MSH, and the phosphorylated form of corticotropin-like intermediate lobe peptide. PMID- 24348463 TI - Thrombospondin-1 Silencing Down-Regulates Integrin Expression Levels in Human Anaplastic Thyroid Cancer Cells with BRAF(V600E): New Insights in the Host Tissue Adaptation and Homeostasis of Tumor Microenvironment. AB - BACKGROUND AND RATIONALE: Anaplastic thyroid cancer (ATC) is characterized by pleomorphic cells, has a poor prognosis, is highly devastating disease, and is not curable. No reliable biomarkers of metastatic potential, helpful for early diagnosis of ATC and therapeutic response have been found yet. Thrombospondin-1 (TSP-1) plays a fundamental role in cancer progression by regulating cell stromal cross-talk in the tumor microenvironment. GOALS: Our goal was to understand whether TSP-1 could affect protein levels of its integrin receptors (e.g., ITGalpha3, alpha6, and beta1) and cell morphology in BRAF(V600E)-ATC cells in vitro and in vivo. EXPERIMENTAL DESIGN: Anaplastic thyroid cancer-derived cell cultures and western blotting were used to assess integrin protein expression upon TSP-1 silencing. Immunohistochemistry was performed on orthotopic primary human ATC and metastatic ATC in lung tissue to compare TSP-1 and integrin protein expression levels. RESULTS: TSP-1 knock-down down-regulates ITGalpha3, alpha6, and beta1 in BRAF(V600E)-human ATC cells. BRAF(V600E)-ATC cells with TSP-1 knock down were rounded compared to control cells, which displayed a spread morphology. TSP-1 knock-down also reduced TSP-1, ITGalpha3, alpha6, and beta1 protein expression levels in vivo in the ATC microenvironment, which is enriched in stromal and inflammatory cells. CONCLUSION: TSP-1 silencing causes changes in ITG levels and ATC cell morphology. The assessment of TSP-1 and ITG levels might contribute to earlier metastatic potential of BRAF(V600E)-positive aggressive thyroid cancers, and allow improved patient selection for clinical trials. PMID- 24348462 TI - Normal glucose metabolism in carnivores overlaps with diabetes pathology in non carnivores. AB - Carnivores, such as the dolphin and the domestic cat, have numerous adaptations that befit consumption of diets with high protein and fat content, with little carbohydrate content. Consequently, nutrient metabolism in carnivorous species differs substantially from that of non-carnivores. Important metabolic pathways known to differ between carnivores and non-carnivores are implicated in the development of diabetes and insulin resistance in non-carnivores: (1) the hepatic glucokinase (GCK) pathway is absent in healthy carnivores yet GCK deficiency may result in diabetes in rodents and humans, (2) healthy dolphins and cats are prone to periods of fasting hyperglycemia and exhibit insulin resistance, both of which are risk factors for diabetes in non-carnivores. Similarly, carnivores develop naturally occurring diseases such as hemochromatosis, fatty liver, obesity, and diabetes that have strong parallels with the same disorders in humans. Understanding how evolution, environment, diet, and domestication may play a role with nutrient metabolism in the dolphin and cat may also be relevant to human diabetes. PMID- 24348464 TI - Functional gene pyrosequencing and network analysis: an approach to examine the response of denitrifying bacteria to increased nitrogen supply in salt marsh sediments. AB - Functional gene pyrosequencing is emerging as a useful tool to examine the diversity and abundance of microbes that facilitate key biogeochemical processes. One such process, denitrification, is of particular importance because it converts fixed nitrate (NO(-) 3) to N2 gas, which returns to the atmosphere. In nitrogen limited salt marshes, removal of NO(-) 3 prior to entering adjacent waters helps prevent eutrophication. Understanding the dynamics of salt marsh microbial denitrification is thus imperative for the maintenance of healthy coastal ecosystems. We used pyrosequencing of the nirS gene to examine the denitrifying community response to fertilization in experimentally enriched marsh plots. A key challenge in the analysis of sequence data derived from pyrosequencing is understanding whether small differences in gene sequences are ecologically meaningful. We applied a novel approach from information theory to determine that the optimal similarity level for clustering DNA sequences into OTUs, while still capturing the ecological complexity of the system, was 88%. With this clustering, phylogenetic analysis yielded 6 dominant clades of denitrifiers, the largest of which, accounting for more than half of all the sequences collected, had no close cultured representatives. Of the 638 OTUs identified, only 11 were present in all plots and no single OTU was dominant. We did, however, find a large number of specialist OTUs that were present only in a single plot. The high degree of endemic OTUs, while accounting for a large proportion of the nirS diversity in the plots, were found in lower abundance than the generalist taxa. The proportion of specialist taxa increased with increasing supply of nutrients, suggesting that addition of fertilizer may create conditions that expand the niche space for denitrifying organisms and may enhance the genetic capacity for denitrification. PMID- 24348465 TI - Vibrio cholerae O1 epidemic variants in Angola: a retrospective study between 1992 and 2006. AB - Cholera is still a major public health concern in many African countries. In Angola, after a decade of absence, cholera reemerged in 1987, spreading throughout the country until 1996, with outbreaks recurring in a seasonal pattern. In 2006 Angola was hit by one of the most severe outbreaks of the last decade, with ca. 240,000 cases reported. We analyzed 21 clinical strains isolated between 1992 and 2006 from several provinces throughout the country: Benguela, Bengo, Luanda, Cuando Cubango, and Cabinda. We used two multiplex PCR assays to investigate discriminatory mobile genetic elements (MGE) [Integrative Conjugative Elements (ICEs), VSP-II, GI12, GI14, GI15, K, and TLC phages] and we compared the profiles obtained with those of different reference V. cholerae O1 variants (prototypical, altered, and hybrid), responsible for the ongoing 7th pandemic. We also tested the strains for the presence of specific VSP-II variants and for the presence of a genomic island (GI) (WASA-1), correlated with the transmission of seventh pandemic cholera from Africa to South America. Based on the presence/absence of the analyzed genetic elements, five novel profiles were detected in the epidemic strains circulating in the 1990s. The most frequent profiles, F and G, were characterized by the absence of ICEs and the three GIs tested, and the presence of GI WASA-1 and the WASA variant of the VSP-II island. Our results identified unexpected variability within the 1990s epidemic, showing different rearrangements in a dynamic part of the genome not present in the prototypical V. cholerae O1 N16961. Moreover the 2006 strains differed from the current pandemic V. cholerae O1 strain. Taken together, our results highlight the role of horizontal gene transfer (HGT) in diversifying the genetic background of V. cholerae within a single epidemic. PMID- 24348466 TI - Bespoke microbiome therapy to manage plant diseases. AB - Information gathered with advanced nucleotide sequencing technologies, small molecule detection systems and computational biology is revealing that a community of microbes and their genes, now termed "the microbiome," located in gut and rhizosphere, is responsible for maintaining the health of human beings and plants, respectively. Within the complete microbiome a "core-microbiome" exists that plays the pivotal role in well being of humans and plants. Recent studies in medicine have shown that an artificial mixture of bacteria representing the core gut microbiome of healthy person when transferred into gut of diseased person results in re-establishment of normal microflora in the latter leading to alleviation from diseased condition. In agriculture, though not exactly in similar manner as in medicine, success in plant disease management has been achieved through transfer of microbiome by mixing disease suppressive soils with disease conducive soils. A study more similar to artificial gut microbiome transfer in medical field has been recently reported in agriculture, in which transfer of microbiome via soil solutions (filtered and unfiltered) has shown ability to alleviate drought stress in Arabidopsis thaliana. However, the exact practice of transferring artificially cultivated core-microbiome as in medicine has not thus far been attempted in plant disease management. Nonetheless, as the gut and rhizosphere microbiome are known to share many common traits, there exists a good scope for accomplishing similar studies in agriculture. Based upon the information drawn from all recent works in microbiome studies of gut and rhizosphere, we propose that tailor-made core-microbiome transfer therapy can be a success in agriculture too and it could become a viable strategy for management of plant diseases in future. PMID- 24348467 TI - Gimme shelter: how Vibrio fischeri successfully navigates an animal's multiple environments. AB - Bacteria successfully colonize distinct niches because they can sense and appropriately respond to a variety of environmental signals. Of particular interest is how a bacterium negotiates the multiple, complex environments posed during successful infection of an animal host. One tractable model system to study how a bacterium manages a host's multiple environments is the symbiotic relationship between the marine bacterium, Vibrio fischeri, and its squid host, Euprymna scolopes. V. fischeri encounters many different host surroundings ranging from initial contact with the squid to ultimate colonization of a specialized organ known as the light organ. For example, upon recognition of the squid, V. fischeri forms a biofilm aggregate outside the light organ that is required for efficient colonization. The bacteria then disperse from this biofilm to enter the organ, where they are exposed to nitric oxide, a molecule that can act as both a signal and an antimicrobial. After successfully managing this potentially hostile environment, V. fischeri cells finally establish their niche in the deep crypts of the light organ where the bacteria bioluminesce in a pheromone-dependent fashion, a phenotype that E. scolopes utilizes for anti predation purposes. The mechanism by which V. fischeri manages these environments to outcompete all other bacterial species for colonization of E. scolopes is an important and intriguing question that will permit valuable insights into how a bacterium successfully associates with a host. This review focuses on specific molecular pathways that allow V. fischeri to establish this exquisite bacteria host interaction. PMID- 24348468 TI - Exploring the risks of phage application in the environment. AB - Interest in using bacteriophages to control the growth and spread of bacterial pathogens is being revived in the wake of widespread antibiotic resistance. However, little is known about the ecological effects that high concentrations of phages in the environment might have on natural microbial communities. We review the current evidence suggesting phage-mediated environmental perturbation, with a focus on agricultural examples, and describe the potential implications for human health and agriculture. Specifically, we examine the known and potential consequences of phage application in certain agricultural practices, discuss the risks of evolved bacterial resistance to phages, and question whether the future of phage therapy will emulate that of antibiotic treatment in terms of widespread resistance. Finally, we propose some basic precautions that could preclude such phenomena and highlight existing methods for tracking bacterial resistance to phage therapeutic agents. PMID- 24348469 TI - Methanogens at the top of the world: occurrence and potential activity of methanogens in newly deglaciated soils in high-altitude cold deserts in the Western Himalayas. AB - Methanogens typically occur in reduced anoxic environments. However, in recent studies it has been shown that many aerated upland soils, including desert soils also host active methanogens. Here we show that soil samples from high-altitude cold deserts in the western Himalayas (Ladakh, India) produce CH4 after incubation as slurry under anoxic conditions at rates comparable to those of hot desert soils. Samples of matured soil from three different vegetation belts (arid, steppe, and subnival) were compared with younger soils originating from frontal and lateral moraines of receding glaciers. While methanogenic rates were higher in the samples from matured soils, CH4 was also produced in the samples from the recently deglaciated moraines. In both young and matured soils, those covered by a biological soil crust (biocrust) were more active than their bare counterparts. Isotopic analysis showed that in both cases CH4 was initially produced from H2/CO2 but later mostly from acetate. Analysis of the archaeal community in the in situ soil samples revealed a clear dominance of sequences related to Thaumarchaeota, while the methanogenic community comprised only a minor fraction of the archaeal community. Similar to other aerated soils, the methanogenic community was comprised almost solely of the genera Methanosarcina and Methanocella, and possibly also Methanobacterium in some cases. Nevertheless, ~10(3) gdw(-1) soil methanogens were already present in the young moraine soil together with cyanobacteria. Our results demonstrate that Methanosarcina and Methanocella not only tolerate atmospheric oxygen but are also able to survive in these harsh cold environments. Their occurrence in newly deglaciated soils shows that they are early colonizers of desert soils, similar to cyanobacteria, and may play a role in the development of desert biocrusts. PMID- 24348470 TI - Biological CO2 conversion to acetate in subsurface coal-sand formation using a high-pressure reactor system. AB - Geological CO2 sequestration in unmineable subsurface oil/gas fields and coal formations has been proposed as a means of reducing anthropogenic greenhouse gasses in the atmosphere. However, the feasibility of injecting CO2 into subsurface depends upon a variety of geological and economic conditions, and the ecological consequences are largely unpredictable. In this study, we developed a new flow-through-type reactor system to examine potential geophysical, geochemical and microbiological impacts associated with CO2 injection by simulating in-situ pressure (0-100 MPa) and temperature (0-70 degrees C) conditions. Using the reactor system, anaerobic artificial fluid and CO2 (flow rate: 0.002 and 0.00001 ml/min, respectively) were continuously supplemented into a column comprised of bituminous coal and sand under a pore pressure of 40 MPa (confined pressure: 41 MPa) at 40 degrees C for 56 days. 16S rRNA gene analysis of the bacterial components showed distinct spatial separation of the predominant taxa in the coal and sand over the course of the experiment. Cultivation experiments using sub-sampled fluids revealed that some microbes survived, or were metabolically active, under CO2-rich conditions. However, no methanogens were activated during the experiment, even though hydrogenotrophic and methylotrophic methanogens were obtained from conventional batch-type cultivation at 20 degrees C. During the reactor experiment, the acetate and methanol concentration in the fluids increased while the delta(13)Cacetate, H2 and CO2 concentrations decreased, indicating the occurrence of homo-acetogenesis. 16S rRNA genes of homo-acetogenic spore-forming bacteria related to the genus Sporomusa were consistently detected from the sandstone after the reactor experiment. Our results suggest that the injection of CO2 into a natural coal sand formation preferentially stimulates homo-acetogenesis rather than methanogenesis, and that this process is accompanied by biogenic CO2 conversion to acetate. PMID- 24348471 TI - Desulfotomaculum spp. and related gram-positive sulfate-reducing bacteria in deep subsurface environments. AB - Gram-positive spore-forming sulfate reducers and particularly members of the genus Desulfotomaculum are commonly found in the subsurface biosphere by culture based and molecular approaches. Due to their metabolic versatility and their ability to persist as endospores. Desulfotomaculum spp. are well-adapted for colonizing environments through a slow sedimentation process. Because of their ability to grow autotrophically (H2/CO2) and produce sulfide or acetate, these microorganisms may play key roles in deep lithoautotrophic microbial communities. Available data about Desulfotomaculum spp. and related species from studies carried out from deep freshwater lakes, marine sediments, oligotrophic and organic rich deep geological settings are discussed in this review. PMID- 24348472 TI - Quantification of lincomycin resistance genes associated with lincomycin residues in waters and soils adjacent to representative swine farms in China. AB - Lincomycin is commonly used on swine farms for growth promotion as well as disease treatment and control. Consequently, lincomycin may accumulate in the environment adjacent to the swine farms in many ways, thereby influencing antibiotic resistance in the environment. Levels of lincomycin-resistance genes and lincomycin residues in water and soil samples collected from multiple sites near wastewater discharge areas were investigated in this study. Sixteen lincomycin-resistance and 16S rRNA genes were detected using real-time PCR. Three genes, lnu(F), erm(A), and erm(B), were detected in all water and soil samples except control samples. Lincomycin residues were determined by rapid resolution liquid chromatography-tandem mass spectrometry, with concentrations detected as high as 9.29 ng/mL in water and 0.97 ng/g in soil. A gradual reduction in the levels of lincomycin-resistance genes and lincomycin residues in the waters and soils were detected from multiple sites along the path of wastewater discharging to the surrounding environment from the swine farms. Significant correlations were found between levels of lincomycin-resistance genes in paired water and soil samples (r = 0.885, p = 0.019), and between lincomycin-resistance genes and lincomycin residues (r = 0.975, p < 0.01). This study emphasized the potential risk of dissemination of lincomycin-resistance genes such as lnu(F), erm(A), and erm(B), associated with lincomycin residues in surrounding environments adjacent to swine farms. PMID- 24348473 TI - Therapeutic use of dendritic cells to promote the extranodal priming of anti tumor immunity. AB - Ectopic lymphoid tissue, also known as tertiary lymphoid organs (TLO) develop adaptively within sites of chronic tissue inflammation, thereby allowing the host to efficiently crossprime specific immune effector cells within sites of disease. Recent evidence suggests that the presence of TLO in the tumor microenvironment (TME) predicts better overall survival. We will discuss the relevance of extranodal T cell priming within the TME as a means to effectively promote anti tumor immunity and the strategic use of dendritic cell (DC)-based therapies to reinforce this clinically preferred process in the cancer-bearing host. PMID- 24348475 TI - Adjuvants are Key Factors for the Development of Future Vaccines: Lessons from the Finlay Adjuvant Platform. AB - The development of effective vaccines against neglected diseases, especially those associated with poverty and social deprivation, is urgently needed. Modern vaccine technologies and a better understanding of the immune response have provided scientists with the tools for rational and safer design of subunit vaccines. Often, however, subunit vaccines do not elicit strong immune responses, highlighting the need to incorporate better adjuvants; this step therefore becomes a key factor for vaccine development. In this review we outline some key features of modern vaccinology that are linked with the development of better adjuvants. In line with the increased desire to obtain novel adjuvants for future vaccines, the Finlay Adjuvant Platform offers a novel approach for the development of new and effective adjuvants. The Finlay Adjuvants (AFs), AFPL (proteoliposome), and AFCo (cochleate), were initially designed for parenteral and mucosal applications, and constitute potent adjuvants for the induction of Th1 responses against several antigens. This review summarizes the status of the Finlay technology in producing promising adjuvants for unsolved-vaccine diseases including mucosal approaches and therapeutic vaccines. Ideas related to adjuvant classification, adjuvant selection, and their possible influence on innate recognition via multiple toll-like receptors are also discussed. PMID- 24348476 TI - NKT cells as an ideal anti-tumor immunotherapeutic. AB - Human natural killer T (NKT) cells are characterized by their expression of an invariant T cell antigen receptor alpha chain variable region encoded by a Valpha24Jalpha18 rearrangement. These NKT cells recognize alpha galactosylceramide (alpha-GalCer) in conjunction with the MHC class I-like CD1d molecule and bridge the innate and acquired immune systems to mediate efficient and augmented immune responses. A prime example of one such function is adjuvant activity: NKT cells augment anti-tumor responses because they can rapidly produce large amounts of IFN-gamma, which acts on NK cells to eliminate MHC negative tumors and also on CD8 cytotoxic T cells to kill MHC positive tumors. Thus, upon administration of alpha-GalCer-pulsed DCs, both MHC negative and positive tumor cells can be effectively eliminated, resulting in complete tumor eradication without tumor recurrence. Clinical trials have been completed in a cohort of 17 patients with advanced non-small cell lung cancers and 10 cases of head and neck tumors. Sixty percent of advanced lung cancer patients with high IFN-gamma production had significantly prolonged median survival times of 29.3 months with only the primary treatment. In the case of head and neck tumors, 10 patients who completed the trial all had stable disease or partial responses 5 weeks after the combination therapy of alpha-GalCer-DCs and activated NKT cells. We now focus on two potential powerful treatment options for the future. One is to establish artificial adjuvant vector cells containing tumor mRNA and alpha-GalCer/CD1d. This stimulates host NKT cells followed by DC maturation and NK cell activation but also induces tumor-specific long-term memory CD8 killer T cell responses, suppressing tumor metastasis even 1 year after the initial single injection. The other approach is to establish induced pluripotent stem (iPS) cells that can generate unlimited numbers of NKT cells with adjuvant activity. Such iPS-derived NKT cells produce IFN-gamma in vitro and in vivo upon stimulation with alpha GalCer/DCs, and mediated adjuvant effects, suppressing tumor growth in vivo. PMID- 24348477 TI - Inhibitory receptor signaling destabilizes immunological synapse formation in primary NK cells. AB - Upon engagement of their cognate class I major histocompatibility complex ligands, receptors containing immunotyrosine-based inhibitory motifs (ITIMs) transduce signals that block cytolytic and inflammatory responses. In this manner, ITIM-coupled receptors play a crucial role in maintaining natural killer (NK) cell tolerance toward normal, healthy tissue. A number of studies, mostly using immortalized NK cell lines, have demonstrated that ITIM signaling functions by disrupting the cytolytic immunological synapse formed between an NK cell and its target. However, more recent imaging experiments using primary NK cells have suggested that inhibitory receptor engagement does not antagonize contact formation, casting doubt on the hypothesis that ITIM signals destabilize the synapse. To resolve this issue, we analyzed primary NK cell activation and contact formation on supported lipid bilayers containing controlled combinations of activating and inhibitory ligands. Under these conditions, we observed that ITIM signaling clearly inhibited adhesion, cell arrest, and calcium influx, three hallmarks of synapse formation. These results are consistent with previous reports showing that inhibitory receptors deliver a "reverse stop" signal, and confirm that ITIM signaling functions at least in part by destabilizing cytolytic synapse formation. PMID- 24348474 TI - The gastrointestinal frontier: IgA and viruses. AB - Viral gastroenteritis is one of the leading causes of diseases that kill ~2.2 million people worldwide each year. IgA is one of the major immune effector products present in the gastrointestinal tract yet its importance in protection against gastrointestinal viral infections has been difficult to prove. In part this has been due to a lack of small and large animal models in which pathogenesis of and immunity to gastrointestinal viral infections is similar to that in humans. Much of what we have learned about the role of IgA in the intestinal immune response has been obtained from experimental animal models of rotavirus infection. Rotavirus-specific intestinal IgA appears to be one of the principle effectors of long term protection against rotavirus infection. Thus, there has been a focus on understanding the immunological pathways through which this virus-specific IgA is induced during infection. In addition, the experimental animal models of rotavirus infection provide excellent systems in which new areas of research on viral-specific intestinal IgA including the long term maintenance of viral-specific IgA. PMID- 24348478 TI - In the crosshairs: investigating lytic granules by high-resolution microscopy and electrophysiology. AB - Cytotoxic T lymphocytes (CTLs) form an integral part of the adaptive immune system. Their main function is to eliminate bacteria- and virus-infected target cells by releasing perforin and granzymes (the lethal hit) contained within lytic granules (LGs), at the CTL-target-cell interface [the immunological synapse (IS)]. The formation of the IS as well as the final events at the IS leading to target-cell death are both highly complex and dynamic processes. In this review we highlight and discuss three high-resolution techniques that have proven invaluable in the effort to decipher key features of the mechanism of CTL effector function and in particular lytic granule maturation and fusion. Correlative light and electron microscopy allows the correlation between organelle morphology and localization of particular proteins, while total internal reflection fluorescence microscopy (TIRFM) enables the study of lytic granule dynamics at the IS in real time. The combination of TIRFM with patch clamp membrane capacitance measurements finally provides a tool to quantify the size of fusing LGs at the IS. PMID- 24348481 TI - Clinical Implications of Co-Inhibitory Molecule Expression in the Tumor Microenvironment for DC Vaccination: A Game of Stop and Go. AB - The aim of therapeutic dendritic cell (DC) vaccines in cancer immunotherapy is to activate cytotoxic T cells to recognize and attack the tumor. T cell activation requires the interaction of the T cell receptor with a cognate major histocompatibility complex-peptide complex. Although initiated by antigen engagement, it is the complex balance between co-stimulatory and co-inhibitory signals on DCs that results in T cell activation or tolerance. Even when already activated, tumor-specific T cells can be neutralized by the expression of co inhibitory molecules on tumor cells. These and other immunosuppressive cues in the tumor microenvironment are major factors currently hampering the application of DC vaccination. In this review, we discuss recent data regarding the essential and complex role of co-inhibitory molecules in regulating the immune response within the tumor microenvironment. In particular, possible therapeutic intervention strategies aimed at reversing or neutralizing suppressive networks within the tumor microenvironment will be emphasized. Importantly, blocking co inhibitory molecule signaling, often referred to as immune checkpoint blockade, does not necessarily lead to an effective activation of tumor-specific T cells. Therefore, combination of checkpoint blockade with other immune potentiating therapeutic strategies, such as DC vaccination, might serve as a synergistic combination, capable of reversing effector T cells immunosuppression while at the same time increasing the efficacy of T cell-mediated immunotherapies. This will ultimately result in long-term anti-tumor immunity. PMID- 24348479 TI - The past, present, and future of immune repertoire biology - the rise of next generation repertoire analysis. AB - T and B cell repertoires are collections of lymphocytes, each characterized by its antigen-specific receptor. We review here classical technologies and analysis strategies developed to assess immunoglobulin (IG) and T cell receptor (TR) repertoire diversity, and describe recent advances in the field. First, we describe the broad range of available methodological tools developed in the past decades, each of which answering different questions and showing complementarity for progressive identification of the level of repertoire alterations: global overview of the diversity by flow cytometry, IG repertoire descriptions at the protein level for the identification of IG reactivities, IG/TR CDR3 spectratyping strategies, and related molecular quantification or dynamics of T/B cell differentiation. Additionally, we introduce the recent technological advances in molecular biology tools allowing deeper analysis of IG/TR diversity by next generation sequencing (NGS), offering systematic and comprehensive sequencing of IG/TR transcripts in a short amount of time. NGS provides several angles of analysis such as clonotype frequency, CDR3 diversity, CDR3 sequence analysis, V allele identification with a quantitative dimension, therefore requiring high throughput analysis tools development. In this line, we discuss the recent efforts made for nomenclature standardization and ontology development. We then present the variety of available statistical analysis and modeling approaches developed with regards to the various levels of diversity analysis, and reveal the increasing sophistication of those modeling approaches. To conclude, we provide some examples of recent mathematical modeling strategies and perspectives that illustrate the active rise of a "next-generation" of repertoire analysis. PMID- 24348483 TI - MicroRNAs: The Missing Link in the Biology of Graft-Versus-Host Disease? AB - Graft-versus-host disease (GVHD) is still the major complication of allogeneic hematopoietic stem cell transplantation. Despite extensive studies in understanding the pathophysiology of GVHD, its pathogenesis remains unclear. Recently, important functions of microRNAs have been demonstrated in various autoimmune diseases and cancers such as psoriasis and lymphoma. This review highlights the need to investigate the role of microRNAs in GVHD and hypothesizes that microRNAs may be one of the missing links in our understanding of GVHD, with the potential for novel therapeutics. PMID- 24348482 TI - The dark side of dendritic cells: development and exploitation of tolerogenic activity that favor tumor outgrowth and immune escape. AB - Dendritic cells (DC) play a central role in the regulation of the immune responses by providing the information needed to decide between tolerance, ignorance, or active responses. For this reason different therapies aim at manipulating DC to obtain the desired response, such as enhanced cell-mediated toxicity against tumor and infected cells or the induction of tolerance in autoimmunity and transplantation. In the last decade studies performed in these settings have started to identify (some) molecules/factors involved in the acquisition of a tolerogenic DC phenotype as well as the underlying mechanisms of their regulatory function on different immune cell populations. PMID- 24348484 TI - The importance of aboveground-belowground interactions on the evolution and maintenance of variation in plant defense traits. AB - Over the past two decades a growing body of empirical research has shown that many ecological processes are mediated by a complex array of indirect interactions occurring between rhizosphere-inhabiting organisms and those found on aboveground plant parts. Aboveground-belowground studies have thus far focused on elucidating processes and underlying mechanisms that mediate the behavior and performance of invertebrates in opposite ecosystem compartments. Less is known about genetic variation in plant traits such as defense as that may be driven by above- and belowground trophic interactions. For instance, although our understanding of genetic variation in aboveground plant traits and its effects on community-level interactions is well developed, little is known about the importance of aboveground-belowground interactions in driving this variation. Plant traits may have evolved in response to selection pressures from above- and below-ground interactions from antagonists and mutualists. Here, we discuss gaps in our understanding of genetic variation in plant-related traits as they relate to aboveground and belowground multitrophic interactions. When metabolic resources are limiting, multiple attacks by antagonists in both domains may lead to trade-offs. In nature, these trade-offs may critically depend upon their effects on plant fitness. Natural enemies of herbivores may also influence selection for different traits via top-down control. At larger scales these interactions may generate evolutionary "hotspots" where the expression of various plant traits is the result of strong reciprocal selection via direct and indirect interactions. The role of abiotic factors in driving genetic variation in plant traits is also discussed. PMID- 24348486 TI - Operation of trans-thylakoid thiol-metabolizing pathways in photosynthesis. AB - Thiol oxidation to disulfides and the reverse reaction, i.e., disulfide reduction to free thiols, are under the control of catalysts in vivo. Enzymatically assisted thiol-disulfide chemistry is required for the biogenesis of all energy transducing membrane systems. However, until recently, this had only been demonstrated for the bacterial plasma membrane. Long considered to be vacant, the thylakoid lumen has now moved to the forefront of photosynthesis research with the realization that its proteome is far more complicated than initially anticipated. Several lumenal proteins are known to be disulfide bonded in Arabidopsis, highlighting the importance of sulfhydryl oxidation in the thylakoid lumen. While disulfide reduction in the plastid stroma is known to activate several enzymatic activities, it appears that it is the reverse reaction, i.e., thiol oxidation that is required for the activity of several lumen-resident proteins. This paradigm for redox regulation in the thylakoid lumen has opened a new frontier for research in the field of photosynthesis. Of particular significance in this context is the discovery of trans-thylakoid redox pathways controlling disulfide bond formation and reduction, which are required for photosynthesis. PMID- 24348485 TI - Dissecting the integrative antioxidant and redox systems in plant mitochondria. Effect of stress and S-nitrosylation. AB - Mitochondrial respiration provides the energy needed to drive metabolic and transport processes in cells. Mitochondria are a significant site of reactive oxygen species (ROS) production in plant cells, and redox-system components obey fine regulation mechanisms that are essential in protecting the mitochondrial integrity. In addition to ROS, there are compelling indications that nitric oxide can be generated in this organelle by both reductive and oxidative pathways. ROS and reactive nitrogen species play a key role in signaling but they can also be deleterious via oxidation of macromolecules. The high production of ROS obligates mitochondria to be provided with a set of ROS scavenging mechanisms. The first line of mitochondrial antioxidants is composed of superoxide dismutase and the enzymes of the ascorbate-glutathione cycle, which are not only able to scavenge ROS but also to repair cell damage and possibly serve as redox sensors. The dithiol-disulfide exchanges form independent signaling nodes and act as antioxidant defense mechanisms as well as sensor proteins modulating redox signaling during development and stress adaptation. The presence of thioredoxin (Trx), peroxiredoxin (Prx) and sulfiredoxin (Srx) in the mitochondria has been recently reported. Cumulative results obtained from studies in salt stress models have demonstrated that these redox proteins play a significant role in the establishment of salt tolerance. The Trx/Prx/Srx system may be subjected to a fine regulated mechanism involving post-translational modifications, among which S-glutathionylation and S-nitrosylation seem to exhibit a critical role that is just beginning to be understood. This review summarizes our current knowledge in antioxidative systems in plant mitochondria, their interrelationships, mechanisms of compensation and some unresolved questions, with special focus on their response to abiotic stress. PMID- 24348488 TI - Desiccation tolerance in resurrection plants: new insights from transcriptome, proteome and metabolome analysis. AB - Most higher plants are unable to survive desiccation to an air-dried state. An exception is a small group of vascular angiosperm plants, termed resurrection plants. They have evolved unique mechanisms of desiccation tolerance and thus can tolerate severe water loss, and mostly adjust their water content with the relative humidity in the environment. Desiccation tolerance is a complex phenomenon and depends on the regulated expression of numerous genes during dehydration and subsequent rehydration. Most of the resurrection plants have a large genome and are difficult to transform which makes them unsuitable for genetic approaches. However, technical advances have made it possible to analyze changes in gene expression on a large-scale. These approaches together with comparative studies with non-desiccation tolerant plants provide novel insights into the molecular processes required for desiccation tolerance and will shed light on identification of orphan genes with unknown functions. Here, we review large-scale recent transcriptomic, proteomic, and metabolomic studies that have been performed in desiccation tolerant plants and discuss how these studies contribute to understanding the molecular basis of desiccation tolerance. PMID- 24348487 TI - The GIP gamma-tubulin complex-associated proteins are involved in nuclear architecture in Arabidopsis thaliana. AB - During interphase, the microtubular cytoskeleton of cycling plant cells is organized in both cortical and perinuclear arrays. Perinuclear microtubules (MTs) are nucleated from gamma-Tubulin Complexes (gamma-TuCs) located at the surface of the nucleus. The molecular mechanisms of gamma-TuC association to the nuclear envelope (NE) are currently unknown. The gamma-TuC Protein 3 (GCP3)-Interacting Protein 1 (GIP1) is the smallest gamma-TuC component identified so far. AtGIP1 and its homologous protein AtGIP2 participate in the localization of active gamma TuCs at interphasic and mitotic MT nucleation sites. Arabidopsis gip1gip2 mutants are impaired in establishing a fully functional mitotic spindle and exhibit severe developmental defects. In this study, gip1gip2 knock down mutants were further characterized at the cellular level. In addition to defects in both the localization of gamma-TuC core proteins and MT fiber robustness, gip1gip2 mutants exhibited a severe alteration of the nuclear shape associated with an abnormal distribution of the nuclear pore complexes. Simultaneously, they showed a misorganization of the inner nuclear membrane protein AtSUN1. Furthermore, AtGIP1 was identified as an interacting partner of AtTSA1 which was detected, like the AtGIP proteins, at the NE. These results provide the first evidence for the involvement of a gamma-TuC component in both nuclear shaping and NE organization. Functional hypotheses are discussed in order to propose a model for a GIP dependent nucleo-cytoplasmic continuum. PMID- 24348489 TI - Buffering growth variations against water deficits through timely carbon usage. AB - Water stresses reduce plant growth but there is no consensus on whether carbon metabolism has any role in this reduction. Sugar starvation resulting from stomatal closure is often proposed as a cause of growth impairment under long term or severe water deficits. However, growth decreases faster than photosynthesis in response to drought, leading to increased carbohydrate stores under short-term or moderate water deficits. Here, we addressed the question of the role of carbon availability on growth under moderate water deficits using two different systems. Firstly, we monitored the day/night pattern of leaf growth in Arabidopsis plants. We show that a moderate soil water deficit promotes leaf growth at night in mutants severely disrupted in their nighttime carbohydrate availability. This suggests that soil water deficit promotes carbon satiation. Secondly, we monitored the sub-hourly growth variations of clementine fruits in response to daily, natural fluctuations in air water deficit, and at contrasting source-sink balances obtained by defoliation. We show that high carbohydrate levels prevent excessive, hydraulic shrinkage of the fruit during days with high evaporative demand, most probably through osmotic adjustment. Together, our results contribute to the view that growing organs under moderate soil or air water deficit are not carbon starved, but use soluble carbohydrate in excess to partly release a hydromechanical limitation of growth. PMID- 24348490 TI - Contrasting xylem vessel constraints on hydraulic conductivity between native and non-native woody understory species. AB - We examined the hydraulic properties of 82 native and non-native woody species common to forests of Eastern North America, including several congeneric groups, representing a range of anatomical wood types. We observed smaller conduit diameters with greater frequency in non-native species, corresponding to lower calculated potential vulnerability to cavitation index. Non-native species exhibited higher vessel-grouping in metaxylem compared with native species, however, solitary vessels were more prevalent in secondary xylem. Higher frequency of solitary vessels in secondary xylem was related to a lower potential vulnerability index. We found no relationship between anatomical characteristics of xylem, origin of species and hydraulic conductivity, indicating that non native species did not exhibit advantageous hydraulic efficiency over native species. Our results confer anatomical advantages for non-native species under the potential for cavitation due to freezing, perhaps permitting extended growing seasons. PMID- 24348491 TI - Functional recapitulation of transitions in sexual systems by homeosis during the evolution of dioecy in Thalictrum. AB - Sexual systems are highly variable in flowering plants and an important contributor to floral diversity. The ranunculid genus Thalictrum is especially well-suited to study evolutionary transitions in sexual systems. Homeotic transformation of sexual organs (stamens and carpels) is a plausible mechanism for the transition from hermaphroditic to unisexual flowers in this lineage because flowers of dioecious species develop unisexually from inception. The single-copy gene PISTILLATA (PI) constitutes a likely candidate for rapid switches between stamen and carpel identity. Here, we first characterized the expression pattern of all B class genes in the dioecious species T. dioicum. As expected, all B class orthologs are expressed in stamens from the earliest stages. Certain AP3 lineages were also expressed late in sepal development. We then tested whether orthologs of PI could potentially control sexual system transitions in Thalictrum, by knocking-down their expression in T. dioicum and the hermaphroditic species T. thalictroides. In T. dioicum, we found that ThdPI 1/2 silencing caused stamen primordia to develop into carpels, resulting in male to female flower conversions. In T. thalictroides, we found that ThtPI silencing caused stamen primordia to develop into supernumerary carpels, resulting in hermaphroditic to female flower conversions. These phenotypes illustrate the ability for homeotic mutations to bring about sudden and potentially adaptive changes by altering the function of a single gene. We propose a two-step evolutionary model where transitions from hermaphroditic to unisexual plants in Thalictrum result from two independent mutations at a B class gene locus. Our PI knockdown experiments in T. thalictroides recapitulate the second step in this model: the evolution of female plants as a result of a loss-of-function mutation in a B class gene. PMID- 24348492 TI - Comparative profiling of miRNA expression in developing seeds of high linoleic and high oleic safflower (Carthamus tinctorius L.) plants. AB - Vegetable oils high in oleic acid are considered to be advantageous because of their better nutritional value and potential industrial applications. The oleic acid content in the classic safflower oil is normally 10-15% while a natural mutant (ol) accumulates elevated oleic acid up to 70% in seed oil. As a part of our investigation into the molecular features of the high oleic (HO) trait in safflower we have profiled the microRNA (miRNA) populations in developing safflower seeds expressing the ol allele in comparison to the wild type high linoleic (HL) safflower using deep sequencing technology. The small RNA populations of the mid-maturity developing embryos of homozygous ol HO and wild type HL safflower had a very similar size distribution pattern, however, only ~16.5% of the unique small RNAs were overlapping in these two genotypes. From these two small RNA populations we have found 55 known miRNAs and identified two candidate novel miRNA families to be likely unique to the developing safflower seeds. Target genes with conserved as well as novel functions were predicted for the conserved miRNAs. We have also identified 13 miRNAs differentially expressed between the HO and HL safflower genotypes. The results may lay a foundation for unraveling the miRNA-mediated molecular processes that regulate oleic acid accumulation in the HO safflower mutant and developmental processes in safflower embryos in general. PMID- 24348493 TI - Cellular iron homeostasis and metabolism in plant. PMID- 24348494 TI - The impact of high temperatures on Vitis vinifera cv. Semillon grapevine performance and berry ripening. AB - The heat event that occurred in many parts of Australia in 2009 was the worst on record for the past decade, with air temperatures exceeding 40( degrees )C for 14 days. Our aim was to assess the impacts of this heat event on vine performance, including ripening, yield, and gas exchange of Vitis vinifera cv. Semillon grown in a Riverina vineyard. To assess the affect of high temperatures on Semillon grapevines, the vines were covered with a protective layer to reduce radiant heating and were compared with vines exposed to ambient conditions. The heat event had major effects on ripening; reducing the rate of ripening by 50% and delaying harvest ripeness and causing a high incidence of berry shrivel and sunburn. Yield was not affected. Photosynthesis was reduced 35% by the heat event while transpiration increased nearly threefold and was accounted for by increased stomatal conductance. The conclusion of this study was that heat events delayed ripening in Semillon berries and caused a significant reduction in berry quality. Strategies to minimize the radiant load during heat events are required and this study has confirmed a protective layer can reduce canopy temperatures and enhance berry quality. PMID- 24348495 TI - Erratum: Iron biofortification and homeostasis in transgenic cassava roots expressing an algal iron assimilatory protein, FEA1. AB - [This corrects the article on p. 171 in vol. 3, PMID: 22993514.]. PMID- 24348497 TI - Importance of the hexagonal lipid phase in biological membrane organization. AB - Domains are present in every natural membrane. They are characterized by a distinctive protein and/or lipid composition. Their size is highly variable from the nano- to the micrometer scale. The domains confer specific properties to the membrane leading to original structure and function. The determinants leading to domain organization are therefore important but remain obscure. This review presents how the ability of lipids to organize into hexagonal II or lamellar phases can promote particular local structures within membranes. Since biological membranes are composed of a mixture of lipids, each with distinctive biophysical properties, lateral and transversal sorting of lipids can promote creation of domains inside the membrane through local modulation of the lipid phase. Lipid biophysical properties have been characterized for long based on in vitro analyses using non-natural lipid molecules; their re-examinations using natural lipids might open interesting perspectives on membrane architecture occurring in vivo in various cellular and physiological contexts. PMID- 24348496 TI - Reprogramming cells to study vacuolar development. AB - During vegetative and embryonic developmental transitions, plant cells are massively reorganized to support the activities that will take place during the subsequent developmental phase. Studying cellular and subcellular changes that occur during these short transitional periods can sometimes present challenges, especially when dealing with Arabidopsis thaliana embryo and seed tissues. As a complementary approach, cellular reprogramming can be used as a tool to study these cellular changes in another, more easily accessible, tissue type. To reprogram cells, genetic manipulation of particular regulatory factors that play critical roles in establishing or repressing the seed developmental program can be used to bring about a change of cell fate. During different developmental phases, vacuoles assume different functions and morphologies to respond to the changing needs of the cell. Lytic vacuoles (LVs) and protein storage vacuoles (PSVs) are the two main vacuole types found in flowering plants such as Arabidopsis. Although both are morphologically distinct and carry out unique functions, they also share some similar activities. As the co-existence of the two vacuole types is short-lived in plant cells, how they replace each other has been a long-standing curiosity. To study the LV to PSV transition, LEAFY COTYLEDON2, a key transcriptional regulator of seed development, was overexpressed in vegetative cells to activate the seed developmental program. At the cellular level, Arabidopsis leaf LVs were observed to convert to PSV-like organelles. This presents the opportunity for further research to elucidate the mechanism of LV to PSV transitions. Overall, this example demonstrates the potential usefulness of cellular reprogramming as a method to study cellular processes that occur during developmental transitions. PMID- 24348498 TI - Stroke types in rural and urban northern portugal: incidence and 7-year survival in a community-based study. AB - BACKGROUND/AIM: Differences in stroke incidence and mortality between regions could stem from differences in the incidence of particular stroke types and long term prognosis. The aim of this study was to investigate whether different risk profiles and stroke types underlie the difference in stroke incidence and patient long-term survival in rural and urban populations. METHODS: All suspected first ever-in-a-lifetime strokes occurring between October 1998 and September 2000 in 37,290 residents of rural municipalities and in 86,023 individuals living in the city of Porto were entered into a population-based registry. Standard definitions of stroke types and overlapping comprehensive sources of information were used for patient identification. Patients were examined by neurologists at 3 months, 1 year and 7 years after the index event. RESULTS: From a total of 688 patients included (226 in rural and 462 in urban areas), 76.2% had an ischaemic stroke (IS; 75.3 vs. 77.9%), 16.1% a primary intracerebral haemorrhage (PICH; 16.3 vs. 14.6%) and 3.3% a subarachnoid haemorrhage (SAH; 2.7 vs. 3.7%); in 4.4% (4.9 vs. 4.1%), the stroke type could not be determined. The annual incidence rate per 1,000 was 2.13 (95% CI, 1.95-2.31), 0.45 (95% CI, 0.37-0.53), 0.09 (95% CI, 0.06 0.14) and 0.12 (95% CI, 0.08-0.17), respectively. The age-specific rural/urban incidence rate ratios for IS in the youngest group (<55 years) was 0.27 (95% CI, 0.11-0.69), increasing to 1.47 (95% CI, 1.07-2.01) for those aged 65-74 years and to 1.87 (95% CI, 1.39-2.52) for those between 75 and 84 years. Rural compared to urban patients with an IS were predominantly men, had a prevalence ratio (PR) of 1.28 (95% CI, 1.05-1.56), were 65 years or older (PR = 1.18; 95% CI, 1.08-1.30) and had in general a lower prevalence of risk factors. There was no evidence of rural/urban differences in 28-day case fatality for the stroke types, although IS tended to be less fatal among urban patients (10.3 vs. 13.1%), whereas PICH (33.3 vs. 24.2%) and SAH (35.3 vs. 16.7%) were less fatal among rural patients. Independently of rural/urban residence, predictors of poor survival after the acute phase (28 days) were age >65 years (HR = 3.57; 95% CI, 2.6-4.9), diabetes (HR = 1.5; 95% CI, 1.2-1.9), ischaemic heart disease (HR = 1.8; 95% CI, 1.3-2.6), atrial fibrillation (HR = 1.5; 95% CI, 1.1-2.0) and smoking habits (HR = 1.6; 95% CI, 1.1-2.3). CONCLUSIONS: The age pattern of IS incidence marks the difference between rural and urban populations; the youngest urban and the oldest rural residents were at a higher risk. Although patients from rural areas were older, the relatively lower prevalence of simultaneously occurring risk and prognostic factors among them as well as the similar management of rural and urban patients may justify why rurality is not associated with long-term survival. PMID- 24348499 TI - Intravenous thrombolysis in a stroke patient receiving rivaroxaban. PMID- 24348500 TI - The effect of psychosocial support intervention on depression in patients with dementia and their family caregivers: an assessor-blinded randomized controlled trial. AB - BACKGROUND/AIM: A three-component tailored psychosocial 12-month assessor-blinded randomized controlled trial to reduce depression in people with dementia (PWD) and carers was conducted. METHODS: A total of 230 home-dwelling dyads of PWD and their carers were randomized to usual care or intervention consisting of three components over 12 months. Primary outcomes were the difference between the baseline and 12-month score on the Cornell Scale of Depression in Dementia (CSDD) in the PWD and on the Geriatric Depression Scale (GDS) in the carers. RESULTS: The intent-to-treat difference between the baseline and 12-month change score was not significant between the intervention and control groups for the CSDD (p = 0.95) or GDS (p = 0.82). CONCLUSIONS: The trial did not show a significant difference between usual care and the intervention on depressive symptoms in PWD or their family caregivers. (c) 2013 S. Karger AG, Basel. PMID- 24348501 TI - Cognitive activities and instrumental activity of daily living in older adults with mild cognitive impairment. AB - AIMS: This study aimed to identify differences in the implementation of cognitive activities and instrumental activities of daily living (IADLs) between healthy individuals and subjects with mild cognitive impairment (MCI). METHODS: The study included 2,498 cognitively healthy subjects (mean age, 71.2 +/- 5.1 years) and 809 MCI subjects (mean age, 71.8 +/- 5.4 years). The subjects were interviewed regarding their participation in cognitive activities and the implementation of IADLs. RESULTS: We found a significant association between participation in any cognitive activities (p < 0.001), using a bus or a train (p < 0.001), and MCI. After adjusting for covariates, cognitive activity of any type remained significantly associated with MCI (p < 0.005) but not with the implementation of IADLs. CONCLUSIONS: Our study revealed that greater participation in cognitive activity was associated with lower odds of MCI. Participation in cognitive activities may reflect differences between healthy and MCI subjects. To clarify the causal relationship between cognitive activities and MCI, further studies are required. PMID- 24348502 TI - Reliability and Validity of the Clinical Dementia Rating for Community-Living Elderly Subjects without an Informant. AB - BACKGROUND: The Clinical Dementia Rating (CDR) scale is widely used to assess cognitive impairment in Alzheimer's disease. It requires collateral information from a reliable informant who is not available in many instances. We adapted the original CDR scale for use with elderly subjects without an informant (CDR-NI) and evaluated its reliability and validity for assessing mild cognitive impairment (MCI) and dementia among community-dwelling elderly subjects. METHOD: At two consecutive visits 1 week apart, nurses trained in CDR assessment interviewed, observed and rated cognitive and functional performance according to a protocol in 90 elderly subjects with suboptimal cognitive performance [Mini Mental State Examination (MMSE) <26 and/or Montreal Cognitive Assessment (MOCA) <26] and without informants according to a protocol. CDR domains and global scores were assigned after the second visit based upon corroborative information from the subjects' responses to questions, role-play, and observed performance in specifically assigned tasks at home and within the community. RESULTS: The CDR-NI scores (0, 0.5, 1) showed good internal consistency (Crohnbach's alpha 0.83 0.84), inter-rater reliability (kappa 0.77-1.00 for six domains and 0.95 for global rating) and test-retest reliability (kappa 0.75-1.00 for six domains and 0.80 for global rating), good agreement (kappa 0.79) with the clinical assessment status of MCI (n = 37) and dementia (n = 4) and significant differences in the mean scores for MMSE, MOCA and Instrumental Activities of Daily Living (ANOVA global p < 0.001). CONCLUSION: Owing to the protocol of the interviews, assessments and structured observations gathered during the two visits, CDR-NI provides valid and reliable assessment of MCI and dementia in community-living elderly subjects without an informant. PMID- 24348503 TI - Optimization of the inclusion of Alzheimer's disease patients in international multicenter randomized trials: results of a national survey conducted in memory research centers in france. AB - INTRODUCTION: Since 2002, with the creation of Centers of Memory Resources and Research (CMRR), considerable progress has been made in France regarding the administrative and institutional framework within which Alzheimer's disease (AD) is managed. In this study, we explore three approaches that can help optimize the inclusion of patients in clinical trials related to AD. They are as follows: to assess communication concerning clinical trials on AD in French CMRR, to analyze the internal organization of these centers concerning the dynamics of inclusion, and to evaluate screening tools used. METHODS: A national, descriptive, cross sectional survey was conducted in all CMRR in France between May 1 and July 31, 2011, using a self-administered questionnaire. All investigators, subinvestigators and the relevant CMRR personnel were involved. RESULTS: A total of 75% of the CMRR participated, and about 30% of the physicians contacted responded positively to the survey. Only 50% reported having communicated with health care professionals at least once in the previous 3 months, and less than 50% had communicated occasionally with the general public. A total of 75% of those surveyed had a research group but only half of the groups were active, 50% of the physicians did not have a consultation time dedicated to study recruitment, and 75% of the respondents had a screening tool in their CMRR but over half of them were not satisfied with it. CONCLUSION: This investigation provides a basis for improving the screening of patients by both internal organizational development and adaptation of tools already available. Improvement requires promoting regular communication that is appropriate and targeted to health care professionals, smaller memory centers, associations and the public, and therefore, familiarizing the whole population with clinical research on AD. PMID- 24348505 TI - Neutrophil Gelatinase-Associated Lipocalin as a Biomarker of Acute Kidney Injury in Patients with Morbid Obesity Who Underwent Bariatric Surgery. AB - INTRODUCTION: Neutrophil gelatinase-associated lipocalin (NGAL) has been identified as a biomarker of acute kidney injury (AKI) that could contribute to early diagnosis and effective management of AKI. The purpose of this study was to evaluate NGAL as a predictive marker of AKI in patients with clinically severe obesity (BMI >50) who underwent biliopancreatic diversion surgery. PATIENTS AND METHODS: We prospectively studied 23 patients with clinically severe obesity who underwent biliopancreatic bypass surgery. NGAL was measured using chemiluminescent microparticle immunoassay in three urine samples collected from each patient before surgery (first sample), 2-6 h after surgery (second sample) and on the first postoperative day (third sample). RESULTS: Renal function was evaluated using serum creatinine values, which were 0.91 +/- 0.26 mg/dl before surgery, 0.87 +/- 0.31 mg/dl immediately after surgery and 0.92 +/- 0.62 mg/dl on the fifth postoperative day. During the immediate postoperative period, AKI was observed in 2 patients, one of whom required renal replacement therapy with hemodialysis. In both patients, urine NGAL increased within the first postoperative hours before the values of serum creatinine increased. CONCLUSION: Urine NGAL in patients with clinically severe obesity, which was surgically treated, might be a potential biomarker of early AKI detection. Further research is required in order to confirm these results observed in a small number of patients who developed postoperative AKI and make recommendations for predictive NGAL values in patients who underwent bariatric surgery. PMID- 24348504 TI - Predictors of institutionalization of dementia patients in mild and moderate stages: a 4-year prospective analysis. AB - BACKGROUND: Institutionalization is the most important milestone in the care of dementia patients. This study was aimed at identifying relevant predictors of institutionalization in a broad empirical context and interpreting them on the basis of the predictor model proposed by Luppa et al. [Dement Geriatr Cogn Disord 2008;26:65-78]. METHODS: At the start of this study, 357 patients with mild to moderate dementia were examined by their general practitioners, and a telephone interview was conducted with their caregivers. Four years later, the outcomes 'institutionalization' and 'death' were determined from health insurance data. Forty-one variables were examined for their predictive influence by univariate and multivariate Cox regression. RESULTS: The risk of institutionalization increased significantly (p <= 0.05) with older ages of patients [hazard ratio (HR) = 1.05] and caregivers (HR = 1.03), a higher educational level of the caregiver (HR = 1.83), greater use of community health services (HR = 1.59), greater caregiver burden (HR = 1.02), and when the caregiver and patient lived apart (HR = 1.97). CONCLUSION: The results show that there is a multifactorial influence on institutionalization of dementia patients by sociodemographic, health-related, and psychological aspects as well as the care situation, thus validating the predictor model by Luppa et al. [Dement Geriatr Cogn Disord 2008;26:65-78]. Caregiver burden was found to be the strongest predictor accessible to interventions. PMID- 24348506 TI - The Association between Fibroblast Growth Factor-23 and Vascular Calcification Is Mitigated by Inflammation Markers. AB - BACKGROUND: Fibroblast growth factor-23 (FGF-23) has been linked to vascular calcification, ventricular hypertrophy and mortality in chronic kidney disease (CKD), although these links may not be direct and independent. Similar grave outcomes are associated with inflammation and oxidative stress in CKD. Recently, accumulating evidence has linked components of phosphate homeostasis to inflammation and oxidative stress. The interaction between the triad of inflammation, FGF-23 and cardiovascular outcomes is underinvestigated. METHODS: We studied 65 patients with stage 5 CKD on hemodialysis. Serum levels of FGF-23, high-sensitivity C-reactive protein (hsCRP), endogenous soluble receptor of advanced glycation end products (esRAGE), advanced oxidation protein products (AOPP), parathormone, lipids, calcium and phosphorous were measured. The aortic calcification index (ACI) was determined using non-contrast CT scans of the abdominal aorta. RESULTS: FGF-23 was elevated (mean: 4,681 pg/ml, SD: 3,906) and correlated with hsCRP, esRAGE, AOPP, dialysis vintage and phosphorus in univariate analysis. In multiple regression analysis, hsCRP, AOPP and phosphorus but not esRAGE were all significantly correlated to FGF-23 (R2 = 0.7, p < 0.001). In univariate analysis, ACI correlated with hsCRP, esRAGE, FGF-23, dialysis vintage, systolic blood pressure (BP) and serum cholesterol. In multiple regression analysis not including inflammation markers, ACI was associated with FGF-23. However, inclusion of inflammation markers in another multiple regression analyses showed that ACI correlated with hsCRP, BP, dialysis vintage and esRAGE but not with FGF-23 (R2 = 0.65, p < 0.001). CONCLUSION: FGF-23 is strongly correlated to various markers of inflammation and oxidative stress in hemodialysis patients. The association between FGF-23 and vascular calcification was mitigated when corrected for inflammation markers. PMID- 24348507 TI - Adjusted Anion Gap Is Associated with Glomerular Filtration Rate Decline in Chronic Kidney Disease. AB - BACKGROUND: Metabolic acidosis is known to accelerate the progression of chronic kidney disease (CKD). However, whether undetermined anions as indicated by the adjusted anion gap (aAG) are associated with estimated glomerular filtration rate (eGFR) decline in patients with CKD is unclear. METHODS: Data from 42 patients with CKD (baseline eGFR, 7.1-52.0 ml/min/ 1.73 m2) without massive proteinuria (urinary protein-creatinine ratio, UPCR <3.5) were retrospectively analyzed. aAG was calculated from serum sodium, serum chloride, serum bicarbonate, serum albumin, serum potassium, serum calcium and serum phosphate. The association between the percentage of the 6-month change of eGFR (%DeltaeGFR/6m) and aAG was examined. RESULTS: The mean baseline eGFR was 27.5 +/- 11.1 ml/min/1.73 m2 and the mean %DeltaeGFR/6m was 13.8 +/- 10.3. UPCR and aAG were 1.13 +/- 0.93 and 9.48 +/- 1.88, respectively. %DeltaeGFR/6m was associated with aAG (r = 0.438, p < 0.005), but not with UPCR (r = 0.194, p = 0.218). In multivariate linear regression analyses, aAG remained significantly associated with %DeltaeGFR/6m (beta = 0.45, p < 0.01) after controlling for age, baseline eGFR, UPCR and HCO3- concentration. CONCLUSION: These data suggest that aAG appears to be associated with the progression of CKD. aAG might be an independent predictor of CKD progression. PMID- 24348508 TI - Impact of Growth Hormone on Cystatin C. AB - BACKGROUND: Cystatin C (CysC) is an alternative marker to creatinine for estimation of the glomerular filtration rate (GFR). Hormones such as thyroid hormones and glucocorticoids are known to have an impact on CysC. In this study, we examined the effect of growth hormone (GH) on CysC in patients with acromegaly undergoing transsphenoidal surgery. METHODS: Creatinine, CysC, GH and insulin like growth factor-1 (IGF-1) were determined in 24 patients with acromegaly before and following transsphenoidal surgery. Estimated GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula. RESULTS: In all patients, surgical debulking resulted in decreased clinical disease activity and declining GH/IGF-1 levels. Postoperatively, biochemical cure was documented in 20 out of 24 patients. Creatinine levels (mean +/- SEM) increased from 72 +/- 3 to 80 +/- 3 umol/l (p = 0.0004) and concurrently, estimated GFR decreased from 99 +/ 3 to 91 +/- 3 ml/min (p = 0.0008). In contrast to creatinine, CysC levels decreased from 0.72 +/- 0.02 to 0.68 +/- 0.02 mg/l (p = 0.0008). CONCLUSIONS: Our study provides strong evidence for discordant effects of GH on creatinine and CysC in patients with acromegaly undergoing transsphenoidal surgery, thus identifying another hormone that influences CysC independent of renal function. PMID- 24348509 TI - Blobology: exploring raw genome data for contaminants, symbionts and parasites using taxon-annotated GC-coverage plots. AB - Generating the raw data for a de novo genome assembly project for a target eukaryotic species is relatively easy. This democratization of access to large scale data has allowed many research teams to plan to assemble the genomes of non model organisms. These new genome targets are very different from the traditional, inbred, laboratory-reared model organisms. They are often small, and cannot be isolated free of their environment - whether ingested food, the surrounding host organism of parasites, or commensal and symbiotic organisms attached to or within the individuals sampled. Preparation of pure DNA originating from a single species can be technically impossible, but assembly of mixed-organism DNA can be difficult, as most genome assemblers perform poorly when faced with multiple genomes in different stoichiometries. This class of problem is common in metagenomic datasets that deliberately try to capture all the genomes present in an environment, but replicon assembly is not often the goal of such programs. Here we present an approach to extracting, from mixed DNA sequence data, subsets that correspond to single species' genomes and thus improving genome assembly. We use both numerical (proportion of GC bases and read coverage) and biological (best-matching sequence in annotated databases) indicators to aid partitioning of draft assembly contigs, and the reads that contribute to those contigs, into distinct bins that can then be subjected to rigorous, optimized assembly, through the use of taxon-annotated GC-coverage plots (TAGC plots). We also present Blobsplorer, a tool that aids exploration and selection of subsets from TAGC-annotated data. Partitioning the data in this way can rescue poorly assembled genomes, and reveal unexpected symbionts and commensals in eukaryotic genome projects. The TAGC plot pipeline script is available from https://github.com/blaxterlab/blobology, and the Blobsplorer tool from https://github.com/mojones/Blobsplorer. PMID- 24348510 TI - Aberrant epigenetic regulators control expansion of human CD34+ hematopoietic stem/progenitor cells. AB - Transcription is a tightly regulated process ensuring the proper expression of numerous genes regulating all aspects of cellular behavior. Transcription factors regulate multiple genes including other transcription factors that together control a highly complex gene network. The transcriptional machinery can be "hijacked" by oncogenic transcription factors, thereby leading to malignant cell transformation. Oncogenic transcription factors manipulate a variety of epigenetic control mechanisms to fulfill gene regulatory and cell transforming functions. These factors assemble epigenetic regulators at target gene promoter sequences, thereby disturbing physiological gene expression patterns. Retroviral vector technology and the availability of "healthy" human hematopoietic CD34+ progenitor cells enable the generation of pre-leukemic cell models for the analysis of aberrant human hematopoietic progenitor cell expansion mediated by leukemogenic transcription factors. This review summarizes recent findings regarding the mechanism by which leukemogenic gene products control human hematopoietic CD34+ progenitor cell expansion by disrupting the normal epigenetic program. PMID- 24348512 TI - Stem cells supporting other stem cells. AB - Adult stem cell therapies are increasingly prevalent for the treatment of damaged or diseased tissues, but most of the improvements observed to date are attributed to the ability of stem cells to produce paracrine factors that have a trophic effect on existing tissue cells, improving their functional capacity. It is now clear that this ability to produce trophic factors is a normal and necessary function for some stem cell populations. In vivo adult stem cells are thought to self-renew due to local signals from the microenvironment where they live, the niche. Several niches have now been identified which harbor multiple stem cell populations. In three of these niches - the Drosophila testis, the bulge of the mammalian hair follicle, and the mammalian bone marrow - one type of stem cell has been found to produce factors that contribute to the maintenance of a second stem cell population in the shared niche. In this review, I will examine the architecture of these three niches and discuss the molecular signals involved. Together, these examples establish a new paradigm for stem cell behavior, that stem cells can promote the maintenance of other stem cells. PMID- 24348514 TI - Erratum: Transcription and replication result in distinct epigenetic marks following repression of early gene expression. PMID- 24348511 TI - Regulation of the transcriptome by ER stress: non-canonical mechanisms and physiological consequences. AB - The mammalian unfolded protein response (UPR) is propagated by three ER-resident transmembrane proteins, each of which initiates a signaling cascade that ultimately culminates in production of a transcriptional activator. The UPR was originally characterized as a pathway for upregulating ER chaperones, and a comprehensive body of subsequent work has shown that protein synthesis, folding, oxidation, trafficking, and degradation are all transcriptionally enhanced by the UPR. However, the global reach of the UPR extends to genes involved in diverse physiological processes having seemingly little to do with ER protein folding, and this includes a substantial number of mRNAs that are suppressed by stress rather than stimulated. Through multiple non-canonical mechanisms emanating from each of the UPR pathways, the cell dynamically regulates transcription and mRNA degradation. Here we highlight these mechanisms and their increasingly appreciated impact on physiological processes. PMID- 24348513 TI - Epigenetic alteration and microRNA dysregulation in cancer. AB - MicroRNAs (miRNAs) play pivotal roles in numerous biological processes, and their dysregulation is a common feature of human cancer. Thanks to recent advances in the analysis of the cancer epigenome, we now know that epigenetic alterations, including aberrant DNA methylation and histone modifications, are major causes of miRNA dysregulation in cancer. Moreover, the list of miRNA genes silenced in association with CpG island hypermethylation is rapidly growing, and various oncogenic miRNAs are now known to be upregulated via DNA hypomethylation. Histone modifications also play important roles in the dysregulation of miRNAs, and histone deacetylation and gain of repressive histone marks are strongly associated with miRNA gene silencing. Conversely, miRNA dysregulation is causally related to epigenetic alterations in cancer. Thus aberrant methylation of miRNA genes is a potentially useful biomarker for detecting cancer and predicting its outcome. Given that many of the silenced miRNAs appear to act as tumor suppressors through the targeting of oncogenes, re-expression of the miRNAs could be an effective approach to cancer therapy, and unraveling the relationship between epigenetic alteration and miRNA dysregulation may lead to the discovery of new therapeutic targets. PMID- 24348515 TI - Gene genealogies for genetic association mapping, with application to Crohn's disease. AB - A gene genealogy describes relationships among haplotypes sampled from a population. Knowledge of the gene genealogy for a set of haplotypes is useful for estimation of population genetic parameters and it also has potential application in finding disease-predisposing genetic variants. As the true gene genealogy is unknown, Markov chain Monte Carlo (MCMC) approaches have been used to sample genealogies conditional on data at multiple genetic markers. We previously implemented an MCMC algorithm to sample from an approximation to the distribution of the gene genealogy conditional on haplotype data. Our approach samples ancestral trees, recombination and mutation rates at a genomic focal point. In this work, we describe how our sampler can be used to find disease-predisposing genetic variants in samples of cases and controls. We use a tree-based association statistic that quantifies the degree to which case haplotypes are more closely related to each other around the focal point than control haplotypes, without relying on a disease model. As the ancestral tree is a latent variable, so is the tree-based association statistic. We show how the sampler can be used to estimate the posterior distribution of the latent test statistic and corresponding latent p-values, which together comprise a fuzzy p-value. We illustrate the approach on a publicly-available dataset from a study of Crohn's disease that consists of genotypes at multiple SNP markers in a small genomic region. We estimate the posterior distribution of the tree-based association statistic and the recombination rate at multiple focal points in the region. Reassuringly, the posterior mean recombination rates estimated at the different focal points are consistent with previously published estimates. The tree-based association approach finds multiple sub-regions where the case haplotypes are more genetically related than the control haplotypes, and that there may be one or multiple disease-predisposing loci. PMID- 24348516 TI - The role of mesenchymal stem cells in cancer development. AB - The role of mesenchymal stem cells (MSCs) in cancer development is still controversial. MSCs may promote tumor progression through immune modulation, but other tumor suppressive effects of MSCs have also beendescribed. The discrepancy between these results may arise from issues related to different tissue sources, individual donor variability, and injection timing of MSCs. The expression of critical receptors such as Toll-like receptor is variable a teach time point of treatment, which may also determine the effects of MSCs on tumor progression. However, factors released from malignant cells, as well as surrounding tissues and the vasculature, are still regarded as a "black box. " Thus, it is still difficult to clarify the specific role of MSCs in cancer development. Whether MSCs support or suppress tumor progression is currently unclear, but it is clear that systemically administered MSCs can be recruited and migrate toward tumors. These findings are important because they can be used as a basis for initiating studies to explore the incorporation of engineered MSCs as novel anti-tumor carriers, for the development of tumor-targeted therapies. PMID- 24348517 TI - On protocols and measures for the validation of supervised methods for the inference of biological networks. AB - Networks provide a natural representation of molecular biology knowledge, in particular to model relationships between biological entities such as genes, proteins, drugs, or diseases. Because of the effort, the cost, or the lack of the experiments necessary for the elucidation of these networks, computational approaches for network inference have been frequently investigated in the literature. In this paper, we examine the assessment of supervised network inference. Supervised inference is based on machine learning techniques that infer the network from a training sample of known interacting and possibly non interacting entities and additional measurement data. While these methods are very effective, their reliable validation in silico poses a challenge, since both prediction and validation need to be performed on the basis of the same partially known network. Cross-validation techniques need to be specifically adapted to classification problems on pairs of objects. We perform a critical review and assessment of protocols and measures proposed in the literature and derive specific guidelines how to best exploit and evaluate machine learning techniques for network inference. Through theoretical considerations and in silico experiments, we analyze in depth how important factors influence the outcome of performance estimation. These factors include the amount of information available for the interacting entities, the sparsity and topology of biological networks, and the lack of experimentally verified non-interacting pairs. PMID- 24348518 TI - Discovering epistasis in large scale genetic association studies by exploiting graphics cards. AB - Despite the enormous investments made in collecting DNA samples and generating germline variation data across thousands of individuals in modern genome-wide association studies (GWAS), progress has been frustratingly slow in explaining much of the heritability in common disease. Today's paradigm of testing independent hypotheses on each single nucleotide polymorphism (SNP) marker is unlikely to adequately reflect the complex biological processes in disease risk. Alternatively, modeling risk as an ensemble of SNPs that act in concert in a pathway, and/or interact non-additively on log risk for example, may be a more sensible way to approach gene mapping in modern studies. Implementing such analyzes genome-wide can quickly become intractable due to the fact that even modest size SNP panels on modern genotype arrays (500k markers) pose a combinatorial nightmare, require tens of billions of models to be tested for evidence of interaction. In this article, we provide an in-depth analysis of programs that have been developed to explicitly overcome these enormous computational barriers through the use of processors on graphics cards known as Graphics Processing Units (GPU). We include tutorials on GPU technology, which will convey why they are growing in appeal with today's numerical scientists. One obvious advantage is the impressive density of microprocessor cores that are available on only a single GPU. Whereas high end servers feature up to 24 Intel or AMD CPU cores, the latest GPU offerings from nVidia feature over 2600 cores. Each compute node may be outfitted with up to 4 GPU devices. Success on GPUs varies across problems. However, epistasis screens fare well due to the high degree of parallelism exposed in these problems. Papers that we review routinely report GPU speedups of over two orders of magnitude (>100x) over standard CPU implementations. PMID- 24348519 TI - EMR-linked GWAS study: investigation of variation landscape of loci for body mass index in children. AB - Common variations at the loci harboring the fat mass and obesity gene (FTO), MC4R, and TMEM18 are consistently reported as being associated with obesity and body mass index (BMI) especially in adult population. In order to confirm this effect in pediatric population five European ancestry cohorts from pediatric eMERGE-II network (CCHMC-BCH) were evaluated. METHOD: Data on 5049 samples of European ancestry were obtained from the Electronic Medical Records (EMRs) of two large academic centers in five different genotyped cohorts. For all available samples, gender, age, height, and weight were collected and BMI was calculated. To account for age and sex differences in BMI, BMI z-scores were generated using 2000 Centers of Disease Control and Prevention (CDC) growth charts. A Genome-wide association study (GWAS) was performed with BMI z-score. After removing missing data and outliers based on principal components (PC) analyses, 2860 samples were used for the GWAS study. The association between each single nucleotide polymorphism (SNP) and BMI was tested using linear regression adjusting for age, gender, and PC by cohort. The effects of SNPs were modeled assuming additive, recessive, and dominant effects of the minor allele. Meta-analysis was conducted using a weighted z-score approach. RESULTS: The mean age of subjects was 9.8 years (range 2-19). The proportion of male subjects was 56%. In these cohorts, 14% of samples had a BMI >=95 and 28 >= 85%. Meta analyses produced a signal at 16q12 genomic region with the best result of p = 1.43 * 10(-) (7) [p (rec) = 7.34 * 10(-) (8)) for the SNP rs8050136 at the first intron of FTO gene (z = 5.26) and with no heterogeneity between cohorts (p = 0.77). Under a recessive model, another published SNP at this locus, rs1421085, generates the best result [z = 5.782, p (rec) = 8.21 * 10(-) (9)]. Imputation in this region using dense 1000 Genome and Hapmap CEU samples revealed 71 SNPs with p < 10(-) (6), all at the first intron of FTO locus. When hetero-geneity was permitted between cohorts, signals were also obtained in other previously identified loci, including MC4R (rs12964056, p = 6.87 * 10(-) (7), z = -4.98), cholecystokinin CCK (rs8192472, p = 1.33 * 10(-) (6), z = -4.85), Interleukin 15 (rs2099884, p = 1.27 * 10(-) (5), z = 4.34), low density lipoprotein receptor-related protein 1B [LRP1B (rs7583748, p = 0.00013, z = -3.81)] and near transmembrane protein 18 (TMEM18) (rs7561317, p = 0.001, z = -3.17). We also detected a novel locus at chromosome 3 at COL6A5 [best SNP = rs1542829, minor allele frequency (MAF) of 5% p = 4.35 * 10(-) (9), z = 5.89]. CONCLUSION: An EMR linked cohort study demonstrates that the BMI-Z measurements can be successfully extracted and linked to genomic data with meaningful confirmatory results. We verified the high prevalence of childhood rate of overweight and obesity in our cohort (28%). In addition, our data indicate that genetic variants in the first intron of FTO, a known adult genetic risk factor for BMI, are also robustly associated with BMI in pediatric population. PMID- 24348520 TI - Microrefugia and species persistence in the Galapagos highlands: a 26,000-year paleoecological perspective. AB - The Galapagos Islands are known to have experienced significant drought during the Quaternary. The loss of mesophytic upland habitats has been suggested to underlie the relatively lower endemism of upland compared with lowland plant assemblages. A fossil pollen record spanning the last 26,000 years from an upland bog on Santa Cruz Island, revealed the persistent presence of highland pollen and spore types during the last glacial maximum and a millennial-scale series of droughts in the mid Holocene. The absence of lowland taxa and presence of mesic taxa led to the conclusion that the highland flora of the Galapagos persisted during both these periods. The resiliency of the highland flora of the Galapagos to long-term drought contradicts an earlier hypothesis that an extinction of highland taxa occurred during the last glacial maximum and that rapid Holocene speciation created the modern plant assemblage within the last 10,000 years. Based on the palynological data, we suggest that, even during the height of glacial and Holocene droughts, cool sea-surface temperatures and strong trade wind activity would have promoted persistent ground level cloudiness that provided the necessary moisture inputs to maintain microrefugia for mesophytic plants. Although moist conditions were maintained, the lack of precipitation caused the loss of open water habitat during such events, and accounts for the known extinctions of species such as Azolla sp., and Elatine sp., while other moisture dependent taxa, i.e., Cyathea weatherbyana, persisted. PMID- 24348521 TI - Disruption of the expression and function of microRNAs in lung cancer as a result of epigenetic changes. AB - Two decades have passed since the discovery of microRNA (miRNA), which determines cell fate in nematodes. About one decade ago, the conservation of miRNA in humans was also discovered. At present, the loss of certain miRNAs and the overexpression of miRNAs have been demonstrated in many types of diseases, especially cancer. A key miRNA in lung cancer was reported soon after the initial discovery of a tumor-suppressive miRNA in a hematological malignancy. Various causes of miRNA disruption are known, including deletions, mutations, and epigenetic suppression as well as coding genes. The recent accumulation of knowledge regarding epigenetic transcriptional suppression has revealed the suppression of several miRNAs in lung cancer in response to epigenetic changes, such as H3K9 methylation prior to DNA methylation and H3K27 methylation independent of DNA methylation. In this review, recent knowledge of miRNA disruption in lung cancer as a result of epigenetic changes is discussed. Additionally, emerging cancer-specific changes in RNA editing and their impact on miRNA function are described. PMID- 24348522 TI - PTEN/PI3K and MAPK signaling in protection and pathology following CNS injuries. AB - Brain and spinal cord injuries initiate widespread temporal and spatial neurodegeneration, through both necrotic and programmed cell death mechanisms. Inflammation, reactive oxidation, excitotoxicity and cell-specific dysregulation of metabolic processes are instigated by traumatic insult and are main contributors to this cumulative damage. Successful treatments rely on prevention or reduction of the magnitude of disruption, and interfering with injurious cellular responses through modulation of signaling cascades is an effective approach. Two intracellular signaling pathways, the phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling cascades play various cellular roles under normal and pathological conditions. Activation of both pathways can influence anatomical and functional outcomes in multiple CNS disorders. However, some mechanisms involve inhibiting or enhancing one pathway or the other, or both, in propagating specific downstream effects. Though many intracellular mechanisms contribute to cell responses to insult, this review examines the evidence exploring PTEN/PI3K and MAPK signaling influence on pathology, neuroprotection, and repair and how these pathways may be targeted for advancing knowledge and improving neurological outcome after injury to the brain and spinal cord. PMID- 24348523 TI - The perinucleolar compartment associates with malignancy. AB - The perinucleolar compartment (PNC) is a unique nuclear substructure, forming predominantly in cancer cells both in vitro and in vivo. PNC prevalence (percentage of cells containing at least one PNC) has been found to positively correlate with disease progression in several cancers (breast, ovarian, and colon). While there is a clear association between PNCs and cancer, the molecular function of the PNC remains unclear. Here we summarize the current understanding of the association of PNCs with cancer and its possible functions in cancer cells. PMID- 24348524 TI - Eddy covariance VOC emission and deposition fluxes above grassland using PTR-TOF. AB - Eddy covariance (EC) is the preferable technique for flux measurements since it is the only direct flux determination method. It requires a continuum of high time resolution measurements (e.g. 5-20 Hz). For volatile organic compounds (VOC) soft ionization via proton transfer reaction has proven to be a quantitative method for real time mass spectrometry; here we use a proton transfer reaction time of flight mass spectrometer (PTR-TOF) for 10 Hz EC measurements of full mass spectra up to m/z 315. The mass resolution of the PTR-TOF enabled the identification of chemical formulas and separation of oxygenated and hydrocarbon species exhibiting the same nominal mass. We determined 481 ion mass peaks from ambient air concentration above a managed, temperate mountain grassland in Neustift, Stubai Valley, Austria. During harvesting we found significant fluxes of 18 compounds distributed over 43 ions, including protonated parent compounds, as well as their isotopes and fragments and VOC-H+ - water clusters. The dominant BVOC fluxes were methanol, acetaldehyde, ethanol, hexenal and other C6 leaf wound compounds, acetone, acetic acid, monoterpenes and sequiterpenes. The smallest reliable fluxes we determined were less than 0.1 nmol m-2 s-1, as in the case of sesquiterpene emissions from freshly cut grass. Terpenoids, including mono- and sesquiterpenes, were also deposited to the grassland before and after the harvesting. During cutting, total VOC emission fluxes up to 200 nmolC m-2 s-1 were measured. Methanol emissions accounted for half of the emissions of oxygenated VOCs and a third of the carbon of all measured VOC emissions during harvesting. PMID- 24348525 TI - Summertime elemental mercury exchange of temperate grasslands on an ecosystem scale. AB - In order to estimate the air-surface mercury exchange of grasslands in temperate climate regions, fluxes of gaseous elemental mercury (GEM) were measured at two sites in Switzerland and one in Austria during summer 2006. Two classic micrometeorological methods (aerodynamic and modified Bowen ratio) have been applied to estimate net GEM exchange rates and to determine the response of the GEM flux to changes in environmental conditions (e.g. heavy rain, summer ozone) on an ecosystem-scale. Both methods proved to be appropriate to estimate fluxes on time scales of a few hours and longer. Average dry deposition rates up to 4.3 ng m-2 h-1 and mean deposition velocities up to 0.10 cm s-1 were measured, which indicates that during the active vegetation period temperate grasslands are a small net sink for atmospheric mercury. With increasing ozone concentrations depletion of GEM was observed, but could not be quantified from the flux signal. Night-time deposition fluxes of GEM were measured and seem to be the result of mercury co-deposition with condensing water. Effects of grass cuts could also be observed, but were of minor magnitude. PMID- 24348526 TI - Comparison of User-Directed and Automatic Mapping of the Planned Isocenter to Treatment Space for Prostate IGRT. AB - Image-guided radiotherapy (IGRT), adaptive radiotherapy (ART), and online reoptimization rely on accurate mapping of the radiation beam isocenter(s) from planning to treatment space. This mapping involves rigid and/or nonrigid registration of planning (pCT) and intratreatment (tCT) CT images. The purpose of this study was to retrospectively compare a fully automatic approach, including a non-rigid step, against a user-directed rigid method implemented in a clinical IGRT protocol for prostate cancer. Isocenters resulting from automatic and clinical mappings were compared to reference isocenters carefully determined in each tCT. Comparison was based on displacements from the reference isocenters and prostate dose-volume histograms (DVHs). Ten patients with a total of 243 tCTs were investigated. Fully automatic registration was found to be as accurate as the clinical protocol but more precise for all patients. The average of the unsigned x, y, and z offsets and the standard deviations ( sigma ) of the signed offsets computed over all images were (avg. +/- sigma (mm)): 1.1 +/- 1.4, 1.8 +/- 2.3, 2.5 +/- 3.5 for the clinical protocol and 0.6 +/- 0.8, 1.1 +/- 1.5 and 1.1 +/- 1.4 for the automatic method. No failures or outliers from automatic mapping were observed, while 8 outliers occurred for the clinical protocol. PMID- 24348527 TI - An overview of Bayesian methods for neural spike train analysis. AB - Neural spike train analysis is an important task in computational neuroscience which aims to understand neural mechanisms and gain insights into neural circuits. With the advancement of multielectrode recording and imaging technologies, it has become increasingly demanding to develop statistical tools for analyzing large neuronal ensemble spike activity. Here we present a tutorial overview of Bayesian methods and their representative applications in neural spike train analysis, at both single neuron and population levels. On the theoretical side, we focus on various approximate Bayesian inference techniques as applied to latent state and parameter estimation. On the application side, the topics include spike sorting, tuning curve estimation, neural encoding and decoding, deconvolution of spike trains from calcium imaging signals, and inference of neuronal functional connectivity and synchrony. Some research challenges and opportunities for neural spike train analysis are discussed. PMID- 24348528 TI - New and safe treatment of food impacted in the esophagus: a single center experience of 100 consecutive cases. AB - Aim. Large food bits can get stuck in the esophagus and must be removed by endoscopy. In some cases, this can be difficult or unsafe. We describe a new and safe treatment for such patients. Materials and Methods. 100 consecutive patients were referred to Akershus University Hospital with impacted food in the esophagus. In 36 patients (36%), the food passed spontaneously. In 59 (92%) of the remaining 64 patients, the food was removed by endoscopic intervention. In the last five patients, endoscopic removal was judged difficult or unsafe. These patients received the new treatment: one capsule Creon 10000 IU dissolved in 30 mL of Coca-Cola administered by a nasooesophageal tube four times daily for 2-3 days. Results. Of the 59 patients treated with endoscopic procedure, complications occurred in four (7%): three bleedings and one perforation of the esophagus. In five patients treated with Coca-Cola and Creon, the food had either passed or was soft after 2-3 days and could easily be removed. Conclusion. The treatment of choice of impacted food in the esophagus is endoscopic removal. In cases where this is difficult, we recommend treatment with Coca-Cola and Creon for 2-3 days before complications occur. PMID- 24348529 TI - Parenteral nutrition-induced cholestasis in neonates: where does the problem lie? AB - Background. Parenteral nutrition (PN) is an effective method of nourishing the neonate who is unable to receive full enteral feeds. Cholestasis can be a complication of PN and can lead to severe liver damage. Aim. We describe our patient population and determine risk factors for developing PN cholestasis. Methods. Retrospective chart review of newborns admitted from January 2006 to May 2011 to the Neonatal Intensive Care Unit at our institution and received PN >14 days. Cholestasis was defined as serum conjugated bilirubin >50 MU mol/L. Results. Eighty-seven newborns were included; 18 (20.7%) developed PN cholestasis. The most frequent surgical condition for both groups was gastroschisis (8/87; 9.2%). No significant differences were found between the cholestasis and control groups for the following parameters: birth weight, gestational age, intrauterine growth restriction, Apgar scores, and day of life at initiation of enteral feeds. Duration of PN in days and dosage of carbohydrates in g/kg/day were significantly higher in the cholestasis group than the control group. Conclusion. PN-related cholestasis presented in one-fifth of neonates receiving PN for more than two weeks. Longer duration of PN and higher dosage of carbohydrates were independent risk factors for the development of PN cholestasis in this population. PMID- 24348531 TI - How to differentiate sites of gastrointestinal bleeding in patients with hematochezia by using clinical factors? AB - Hematochezia is one of common gastrointestinal complaint at the Emergency Department (ED). Causes may be due to upper (UGIB) or lower (LGIB) gastrointestinal tract bleeding. Here, clinical factors were studied to differentiate sites of bleeding in patients with hematochezia. All patients with an age of more than 18 years who were diagnosed with GIB at the ED, Ramathibodi Hospital, Thailand were enrolled. Patients who presented with hematochezia and received complete workups to identify causes of bleeding were studied and categorized as being in the UGIB or LGIB groups. There were 1,854 patients who presented with GIB at the ED. Of those, 76 patients presented with hematochezia; 30 patients were in the UGIB group, while 43 patients were in the LGIB group. Clinical variables between both groups were mostly comparable. Three clinical factors were significantly associated with UGIB causes in patients with hematochezia including systolic blood pressure, hematocrit level, and BUN/Cr ratio. The adjusted odds ratios for all three factors were 0.725 (per 5 mmHg increase), 0.751 (per 3% increase), and 1.11 (per unit increase). Physicians at the ED could use these clinical factors as a guide for further investigation in patients who presented with hematochezia. PMID- 24348532 TI - Prognostic Significance of DR-70 Levels in Dysplastic Colorectal Polyps. AB - Background. To investigate the relationship between DR-70 serum levels and dysplastic colon polyps. Materials and Methods. A total of 130 patients with adenomatous polyps detected by colonoscopy and divided into two groups including low versus high grade polyp, along with 50 healthy blood donors were included in the study. Blood samples from each participant were analyzed for serum CEA and DR 70 levels. Results. No statistically significant differences were observed between the two groups in terms of age or gender. The median DR-70 level was 0.5 MU g/mL in the healthy control group and 1.1 MU g/mL in group 1b (i.e., the high grade polyp) (P < 0.001). DR-70 was higher in group 1b as compared to group 1a (P < 0.001). However, the median DR-70 values for the low grade polyp group (i.e., group 1a) and the control group were similar (P = 0.067). In order to determine independent predictors of high grade dysplasia, CEA, DR-70, polyp size, and age parameters were subjected to multiple logistical regression analyses via the Enter method; the model was statistically significant (P < 0.001). Conclusions. DR-70, a marker used to measure FDP, which is generated by all major cancers, is a potential marker to identify patients with advanced adenomatous polyps, that is, precursors of colorectal cancer. PMID- 24348530 TI - Nutrition care for patients with weight regain after bariatric surgery. AB - Achieving optimal weight outcomes for patients with obesity is important to the management of their chronic disease. All interventions present risks for weight regain. Bariatric surgery is the most efficacious treatment, producing greater weight losses that are sustained over more time compared to lifestyle interventions. However, approximately 20-30% of patients do not achieve successful weight outcomes, and patients may experience a regain of 20-25% of their lost weight. This paper reviews several factors that influence weight regain after bariatric surgery, including type of surgery, food tolerance, energy requirements, drivers to eat, errors in estimating intake, adherence, food and beverage choices, and patient knowledge. A comprehensive multidisciplinary approach can provide the best care for patients with weight regain. Nutrition care by a registered dietitian is recommended for all bariatric surgery patients. Nutrition diagnoses and interventions are discussed. Regular monitoring of weight status and early intervention may help prevent significant weight regain. PMID- 24348533 TI - Preventive Effect of TU-100 on a Type-2 Model of Colitis in Mice: Possible Involvement of Enhancing Adrenomedullin in Intestinal Epithelial Cells. AB - Purpose. Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD), have histopathologically and immunologically different characteristics. We previously reported that a traditional Japanese medicine, daikenchuto (TU-100), ameliorated a trinitrobenzenesulfonic acid- (TNBS ) induced type-1 model colitis exhibiting histopathological features of CD through adrenomedullin (ADM) enhancement. Our current aims were to examine whether TU-100 ameliorates a type-2 model colitis that histologically resembles UC and identify the active ingredients. Methods. TU-100 was administered orally to mice with oxazolone- (OXN-) induced type-2 model colitis. The morbidity was evaluated by body weight loss and the macroscopic score of colonic lesions. ADM was quantified using an EIA kit. Results. TU-100 prevented weight loss and colon ulceration. ADM production by intestinal epithelial cells was increased by TU-100 addition. Screening to identify active ingredients showed that [6]-shogaol and hydroxy alpha -sanshool enhanced ADM production. Conclusions. TU-100 exerted a protective effect in OXN-induced type-2 model colitis, indicating that TU-100 may be a beneficial agent for treatment of UC. PMID- 24348534 TI - Helicobacter pylori Infection and Anemia in Taiwanese Adults. AB - Background. Chronic Helicobacter pylori infection and iron-deficiency anemia (IDA) are common in adults. Although the most common causes of IDA usually arise from the gastrointestinal tract, the association between chronic Helicobacter pylori infection and anemia remains unclear. Aim. To evaluate the association of chronic Helicobacter pylori infection and IDA. Materials and Methods. We enrolled 882 patients from January 2010 to April 2013. The status of Helicobacter pylori (H.p) infection was confirmed and blood samples from the same participants were taken on the same day to check the level of hemoglobin, serum iron, ferritin, and total iron-binding capacity (TIBC). Results. No significant difference was noted from the demographic data. The average level of hemoglobin (Hb) was not different between negative and positive groups, pos 13.57 g/dL versus neg 13.65 g/dL (P = 0.699). Although the levels of serum IDA related parameters were expected in positive group (lower serum iron and ferritin and higher TIBC) these differences did not reach statistical significance (P = 0.824 for iron, P = 0.360 for ferritin, and P = 0.252 for TIBC). Conclusion. Chronic Helicobacter pylori infection is not attributed to IDA. The levels of hemoglobin, serum iron and ferritin, and TIBC remain unaffected after chronic H.p infection. Large-scale clinical studies are needed to prove the association. PMID- 24348535 TI - International Consensus Diagnostic Criteria for Autoimmune Pancreatitis and Its Japanese Amendment Have Improved Diagnostic Ability over Existing Criteria. AB - Objectives. The recent International Consensus Diagnostic Criteria (ICDC) for autoimmune pancreatitis (AIP) and its Japanese amendment developed by the Japanese Pancreas Society (JPS 2011) may have overcome the drawbacks of earlier criteria and achieved a higher diagnostic ability for AIP. The aim of the present study is to evaluate this possibility and identify the underlying causes of this change. Methods. We compared the diagnostic abilities of the ICDC and JPS 2011 with those of the Japanese diagnostic criteria 2006 (JPS 2006), Korean diagnostic criteria (Korean), Asian diagnostic criteria (Asian), and HISORt diagnostic criteria in 110 patients with AIP and 31 patients with malignant pancreatic cancer. Results. The ICDC achieved the highest diagnostic ability in terms of accuracy (95.0%), followed by JPS 2011 (92.9%), Korean (92.2%), HISORt (88.7%), Asian (87.2%), and JPS 2006 (85.1%). Nearly all criteria systems exhibited a high specificity of 100%, indicating that the enhanced diagnostic ability of the ICDC and JPS 2011 likely stemmed from increased sensitivity brought about by inclusion of diagnostic items requiring no endoscopic retrograde pancreatography. The diagnostic ability of JPS 2011 was nearly equivalent to that of the ICDC. Conclusions. The ICDC and JPS 2011 have improved diagnostic ability as compared with earlier criteria sets because of an increase in sensitivity. PMID- 24348536 TI - Insulin Resistance Increases MRI-Estimated Pancreatic Fat in Nonalcoholic Fatty Liver Disease and Normal Controls. AB - Background. Ectopic fat deposition in the pancreas and its relationship with hepatic steatosis and insulin resistance have not been compared between patients with nonalcoholic fatty liver disease (NAFLD) and healthy controls. Aim. Using a novel magnetic resonance imaging (MRI) based biomarker, the proton-density-fat fraction (MRI-PDFF), we compared pancreatic fat content in patients with biopsy proven NAFLD to healthy controls and determined whether it is associated with insulin resistance and liver fat content. Methods. This nested case-control study was derived from two prospective studies including 43 patients with biopsy-proven NAFLD and 49 healthy controls who underwent biochemical testing and MRI. Results. Compared to healthy controls, patients with NAFLD had significantly higher pancreatic MRI-PDFF (3.6% versus 8.5%, P value <0.001), and these results remained consistent in multivariable-adjusted models including age, sex, body mass index, and diabetes (P value =0.03). We found a strong correlation between hepatic and pancreatic MRI-PDFF (Spearman correlation, P = 0.57, P value <0.001). Participants with increased insulin resistance determined by homeostatic-model-of insulin-resistance (HOMA-IR) greater than 2.5 had higher pancreatic (7.3% versus 4.5%, P value =0.015) and liver (13.5% versus 4.0%, P value <0.001) MRI-PDFF. Conclusion. Patients with NAFLD have greater pancreatic fat than normal controls. Insulin resistance is associated with liver and pancreatic fat accumulation. PMID- 24348537 TI - Management of open abdomen: single center experience. AB - Aim. The authors reviewed their experience in the management of open abdomen using the vacuum-assisted closure (VAC), in order to assess its morbidity, and the outcome of abdominal wall integrity. Methods. A retrospective review was performed using the trauma registry to identify patients undergoing temporary abdominal closure (TAC) either using Bogota Bag (BB) or VAC, from January 2006 to December 2012. Inclusion criteria were TAC and survival to definitive abdominal closure. Data collected included age, indication for TAC, number of operating room procedures, primary fascial closure rate, and complications. Results. During the study period, 156 patients required one type of TAC. Mean number of operations required in BB group was 3.04 as compared to 1.96 in VAC group (P = 0.006). Survival was significantly increased in the VAC group (P < 0.001). The difference in primary closure rates did not reach statistical significance (25% vs. 55%; P = 0.074). Complications were observed less frequently in the VAC group (P = 0.047). The mean time for fascial closure was 21 (+/-12) days in the BB group, as opposed to 6 (+/-3) days in the VAC group (P < 0.001). Conclusion. The vacuum assisted closure (VAC) has a significantly faster rate of closure, requires less number of operations, and is associated with a lower complication rate. PMID- 24348538 TI - Enterovesical fistulae: aetiology, imaging, and management. AB - Background and Study Objectives. Enterovesical fistula (EVF) is a devastating complication of a variety of inflammatory and neoplastic diseases. Radiological imaging plays a vital role in the diagnosis of EVF and is indispensable to gastroenterologists and surgeons for choosing the correct therapeutic option. This paper provides an overview of the diagnosis of enterovesical fistulae. The treatment of fistulae is also briefly discussed. Material and Methods. We performed a literature review by searching the Medline database for articles published from its inception until September 2013 based on clinical relevance. Electronic searches were limited to the keywords: "enterovesical fistula," "colovesical fistula" (CVF), "pelvic fistula", and "urinary fistula". Results. EVF is a rare pathology. Diverticulitis is the commonest aetiology. Over two thirds of affected patients describe pathognomonic features of pneumaturia, fecaluria, and recurrent urinary tract infections. Computed tomography is the modality of choice for the diagnosis of enterovesical fistulae as not only does it detect a fistula, but it also provides information about the surrounding anatomical structures. Conclusions. In the vast majority of cases, this condition is diagnosed because of unremitting urinary symptoms after gastroenterologist follow-up procedures for a diverticulitis or bowel inflammatory disease. Computed tomography is the most sensitive test for enterovesical fistula. PMID- 24348540 TI - Small intestinal tumours. AB - Objective. Balloon enteroscopy (BE) and capsule enteroscopy (CE) are enteroscopy methods that allow examination and treatment of the small bowel. Before the CE and BE era, the small intestine was difficult to access for investigation. Small intestinal tumours are infrequent conditions, but about half of them are malignant. Materials and Methods. A total of 303 BEs were performed in 179 patients. Oral insertion was performed in 240 and anal in 63 BEs. Indications for the procedure in our patients with small bowel tumours were anaemia and/or bleeding, obstruction, suspicion of carcinoid tumour, or suspicion of Peutz Jeghers syndrome. Results. In 50 of our 179 patients (28%), we diagnosed some small intestinal tumours: hamartomas in Peutz-Jeghers syndrome in 16 patients, adenocarcinoma in 7, lymphoma in 6, carcinoid tumour in 4, melanoma and stromal tumour in 3, adenoma, lipoma, and inflammatory polyps in 2, and granular cell tumour, cavernous lymphangioma, fibrolipoma, Cronkhite-Canada polyps, and metastatic involvement in individual cases. Conclusion. BE facilitates exploration and treatment of the small intestine. The procedure is generally safe and useful. BE and CE are essential modalities for the management of small intestinal diseases. PMID- 24348539 TI - Dominant fecal microbiota in newly diagnosed untreated inflammatory bowel disease patients. AB - Our knowledge about the microbiota associated with the onset of IBD is limited. The aim of our study was to investigate the correlation between IBD and the fecal microbiota for early diagnosed untreated patients. The fecal samples used were a part of the Inflammatory Bowel South-Eastern Norway II (IBSEN II) study and were collected from CD patients (n = 30), UC patients (n = 33), unclassified IBD (IBDU) patients (n = 3), and from a control group (n = 34). The bacteria associated with the fecal samples were analyzed using a direct 16S rRNA gene sequencing approach combined with a multivariate curve resolution (MCR) analysis. In addition, a 16S rRNA gene clone library was prepared for the construction of bacteria-specific gene-targeted single nucleotide primer extension (SNuPE) probes. The MCR analysis resulted in the recovery of five pure components of the dominant bacteria present: Escherichia/Shigella, Faecalibacterium, Bacteroides, and two components of unclassified Clostridiales. Escherichia/Shigella was found to be significantly increased in CD patients compared to control subjects, and Faecalibacterium was found to be significantly reduced in CD patients compared to both UC patients and control subjects. Furthermore, a SNuPE probe specific for Escherichia/Shigella showed a significant overrepresentation of Escherichia/Shigella in CD patients compared to control subjects. In conclusion, samples from CD patients exhibited an increase in Escherichia/Shigella and a decrease in Faecalibacterium indicating that the onset of the disease is associated with an increase in proinflammatory and a decrease in anti inflammatory bacteria. PMID- 24348541 TI - Mast Cells Positive to Tryptase and c-Kit Receptor Expressing Cells Correlates with Angiogenesis in Gastric Cancer Patients Surgically Treated. AB - Background. Angiogenesis is a complex process involved in both growth and progression of several human and animal tumours. Tryptase is a serin protease stored in mast cells granules, which plays a role in tumour angiogenesis. Mast cells (MCs) can release tryptase following c-Kit receptor (c-KitR) activation. Method. In a series of 25 gastric cancer patients with stage T3N2-3M0 (by AJCC for Gastric Cancer 7th Edition), immunohistochemistry and image analysis methods were employed to evaluate in the tumour tissue the correlation between the number of mast cells positive to tryptase (MCPT), c-KitR expressing cells (c-KitR-EC), and microvascular density (MVD). Results. Data demonstrated a positive correlation between MCPT, c-KitR-EC, and MVD to each other. In tumour tissue the mean number of MCPT was 15, the mean number of c-KitR-EC was 20, and the mean number of MVD was 20. The Pearson test correlating MCPT and MVD, c-KitR-EC and MVD was significantly (r = 0.64, P = 0.001; r = 0.66, P = 0.041, resp.). Conclusion. In this pilot study, we suggest that MCPT and c-KitR-EC play a role in gastric cancer angiogenesis, so we think that several c-KitR or tryptase inhibitors such as gabexate mesilate and nafamostat mesilate might be evaluated in clinical trials as a new antiangiogenetic approach. PMID- 24348542 TI - Surgical treatment for achalasia of the esophagus: laparoscopic heller myotomy. AB - Achalasia is an esophageal motility disorder that leads to dysphagia, chest pain, and weight loss. Its diagnosis is clinically suspected and is confirmed with esophageal manometry. Although pneumatic dilation has a role in the treatment of patients with achalasia, laparoscopic Heller myotomy is considered by many experts as the best treatment modality for most patients with newly diagnosed achalasia. This review will focus on the surgical treatment of achalasia, with special emphasis on laparoscopic Heller myotomy. We will also present a brief discussion of the evaluation of patients with persistent or recurrent symptoms after surgical treatment for achalasia and emerging technologies such as LESS, robot-assisted myotomy, and POEM. PMID- 24348543 TI - Clonality Analysis of Helicobacter pylori in Patients Isolated from Several Biopsy Specimens and Gastric Juice in a Japanese Urban Population by Random Amplified Polymorphic DNA Fingerprinting. AB - Background. The number of Helicobacter pylori clones infecting a single host has been discussed in numerous reports. The number has been suggested to vary depending on the regions in the world. Aim. The purpose of this study was to examine the number of clones infecting a single host in a Japanese urban population. Materials and Methods. Thirty-one Japanese patients undergoing upper gastrointestinal endoscopy were enrolled in this study. H. pylori isolates (total 104 strains) were obtained from biopsy specimens (antrum, corpus, and duodenum) and gastric juice. Clonal diversity was examined by the random amplified polymorphic DNA (RAPD) fingerprinting method. Results. The RAPD fingerprinting patterns of isolates from each patient were identical or very similar. And the isolates obtained from several patients with 5- to 9-year intervals showed identical or very similar RAPD patterns. Conclusion. Each Japanese individual of an urban population is predominantly infected with a single H. pylori clone. PMID- 24348544 TI - Transabdominal ultrasonography of the small bowel. AB - In the era of double balloon enteroscopy, capsule endoscopy, CT, and MRI enterography is transabdominal ultrasonography (TUS) underestimated method for evaluation of small bowel pathology. As often initial imagine method in abdominal complaints, nowadays has TUS much better diagnostic potential than two decades ago. High-resolution ultrasound probes with harmonic imaging significantly improve resolution of bowel wall in real time, with possibility to asses bowel peristalsis. Color flow doppler enables evaluation of intramural bowel vascularisation, pulse wave doppler helps to quantificate flow in coeliac and superior mesenteric arteries. Small intestine contrast ultrasonography with oral contrast fluid, as well as contrast enhanced ultrasonography with intravenous microbubble contrast also improves small bowel imaging. We present a review of small intestine pathology that should be detected during ultrasound examinations, discuss technical requirements, advantages and limitations of TUS, typical ultrasound signs of Crohn's disease, ileus, celiac disease, intussusception, infectious enteritis, tumours, ischemic and haemorrhagic conditions of small bowel. In the hands of experienced investigator, despite some significant limitations(obesity, meteorism), is transabdominal ultrasonography reliable, noninvasive and inexpensive alternative method to computerised tomography (CT) and magnetic resonance imaging (MRI) in small bowel examination. PMID- 24348545 TI - Improved outcome of biliary atresia with postoperative high-dose steroid. AB - Objective. The dosage, duration, and the benefits of high-dose steroid treatment and outcome in biliary atresia (BA) remain controversial. In this study, we evaluated the impact of high-dose steroid therapy on the outcome of BA after the Kasai procedure. Methods. Intravenous prednisolone administration was started 1 week after surgery, followed by 8 to 12 weeks of oral prednisolone. Total bilirubin (TB) levels (3, 6, and 12 months after surgery), early onset of cholangitis, and two-year native liver survival were evaluated. Results. 53.4%, 56.9%, and 58.1% of the patients in the high-dose steroid group were jaundice free 3, 6, and 12 months after surgery, respectively; these values were significantly higher than the 38.7%, 39.4%, and 43.3% of the low-dose steroid group. One year after surgery, the incidence of cholangitis in the high-dose group (32.0%) was lower than that in the low-dose group (48.0%). Infants with native liver in the high-dose group had a better two-year survival compared to those in the low-dose steroid group (53.7% versus 42.6%). Conclusions. The high dose steroid protocol can reduce the incidence of cholangitis, increase the jaundice-free rate, and improve two-year survival with native liver after the Kasai operation. PMID- 24348546 TI - A full bi-tensor neural tractography algorithm using the unscented Kalman filter. AB - We describe a technique that uses tractography to visualize neural pathways in human brains by extending an existing framework that uses overlapping Gaussian tensors to model the signal. At each point on the fiber, an unscented Kalman filter is used to find the most consistent direction as a mixture of previous estimates and of the local model. In our previous framework, the diffusion ellipsoid had a cylindrical shape, i.e., the diffusion tensor's second and third eigenvalues were identical. In this paper, we extend the tensor representation so that the diffusion tensor is represented by an arbitrary ellipsoid. Experiments on synthetic data show a reduction in the angular error at fiber crossings and branchings. Tests on in vivo data demonstrate the ability to trace fibers in areas containing crossings or branchings, and the tests also confirm the superiority of using a full tensor representation over the simplified model. PMID- 24348547 TI - Antioxidative properties and inhibition of key enzymes relevant to type-2 diabetes and hypertension by essential oils from black pepper. AB - The antioxidant properties and effect of essential oil of black pepper (Piper guineense) seeds on alpha -amylase, alpha -glucosidase (key enzymes linked to type-2 diabetes), and angiotensin-I converting enzyme (ACE) (key enzyme linked to hypertension) were assessed. The essential oil was obtained by hydrodistillation and dried with anhydrous Na2SO4, and the phenolic content, radical [1,1-diphenyl 2 picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) and nitric oxide (NO)] scavenging abilities as well as the ferric reducing antioxidant property (FRAP) and Fe(2+)-chelating ability of the essential oil were investigated. Furthermore, the effect on alpha -amylase, alpha -glucosidase, and ACE enzyme activities was also investigated. The characterization of the constituents was done using GC. The essential oil scavenged DPPH*, NO*, and ABTS* and chelated Fe(2+). alpha -Pinene, beta -pinene, cis-ocimene, myrcene, allo ocimene, and 1,8-cineole were among the constituents identified by GC. The essential oil inhibited alpha -amylase, alpha -glucosidase, and ACE enzyme activities in concentration-dependent manners, though exhibiting a stronger inhibition of alpha -glucosidase than alpha -amylase activities. Conclusively, the phenolic content, antioxidant activity, and inhibition of alpha -amylase, alpha -glucosidase, and angiotensin-1 converting enzyme activities by the essential oil extract of black pepper could be part of the mechanism by which the essential oil could manage and/or prevent type-2 diabetes and hypertension. PMID- 24348548 TI - Acetaldehyde content and oxidative stress in the deleterious effects of alcohol drinking on rat uterine horn. AB - After alcohol exposure through a standard Lieber and De Carli diet for 28 days, a severe atrophy in the rat uteirne horn was observed, accompanied by significant alterations in its epithelial cells. Microsomal pathway of acetaldehyde production was slightly increased. Hydroxyl radicals were detected in the cytosolic fraction, and this was attributed to participation of xanthine oxidoreductase. They were also observed in the microsomal fraction in the presence of NADPH generating system. No generation of 1-hydroxyethyl was evidenced. The t-butylhydroperoxide-induced chemiluminescence analysis of uterine horn homogenates revealed a significant increase in the chemiluminiscence emission due to ethanol exposure. In the animals repeatedly exposed to alcohol, sulfhydryl content from uterine horn proteins was decreased, but no significant changes were observed in the protein carbonyl content from the same samples. Minor but significant decreasing changes were observed in the GSH content accompanied by a tendency to decrease in the GSH/GSSG ratio. A highly significant finding was the diminished activity content of glutathione peroxidase. Results suggest that acetaldehyde accumulation plus the oxidative stress may play an additional effect to the alcohol-promoted hormonal changes in the uterus reported by others after chronic exposure to alcohol. PMID- 24348549 TI - Effect of Aqueous Stem Bark Extract of Khaya senegalensis on Some Biochemical, Haematological, and Histopathological Parameters of Rats. AB - The subchronic effect of aqueous stem bark extract of Khaya senegalensis on some biochemical, haematological, and histopathological parameters of rats was investigated. The rats were divided into six groups of five rats per group. Groups I to VI were administered graded doses of 0, 400, 800, 1200, 1600, and 2000 mg/kg bw, respectively. The result of study revealed that administration of the Khaya senegalensis for twenty-eight days at the experimental dose resulted in significant (P < 0.05) increase in urea, electrolytes (Na(+), K(+)), and creatinine levels. The extract also significantly (P < 0.05) increased serum activity of ALT, AST, and ALP. The levels of protein, albumin, and bilirubin were significantly changed when compared to their control values, but they were not dose dependent. The hematological indices assayed in this study were not significantly affected at the experimental dose when compared to the control values. Histological studies of the liver showed cellular degeneration and necrosis and bile duct hyperplasia and fibrosis with lymphocytic infiltration of the hepatocyte, providing supportive evidence for discussing the biochemical findings, indicative of functional derangement. The histological architecture of the kidney and that of the heart were however preserved. The result of this study indicates that the aqueous stem bark extract of K. senegalensis may affect the cellular integrity of vital organs of the body. PMID- 24348550 TI - Brown fat expresses adiponectin in humans. AB - The presence of brown adipose tissue (BAT) in humans is unclear. Pheochromocytomas (PHEO) are rare tumors of neuroectodermal origin which occur in 0.1-0.2% of patients with hypertension. We sought to evaluate the presence and activity of BAT surrounding adrenal PHEO in a well-studied sample of 11 patients who were diagnosed with PHEO and then underwent adrenalectomy. Areas of white fat (WAT) and BAT surrounding PHEO were obtained by Laser Capture Microdissection for analysis of uncoupling protein (UCP)-1 and adiponectin mRNA expression. Adiponectin and UCP-1 mRNA levels were significantly higher in BAT than in WAT (0.62 versus 0.15 and 362.4 versus 22.1, resp., P < 0.01 for both). Adiponectin mRNA levels significantly correlated with urinary metanephrines (r = 0.76, P < 0.01), vanilly mandelic acid (VMA) (r = 0.95, P < 0.01), and serum adiponectin levels (r = 0.95, P < 0.01). Serum adiponectin levels significantly decreased (24.2 +/- 2 MU g/mL versus 18 +/- 11 MU g/mL, P < 0.01) after adrenalectomy in PHEO subjects. This study provides the following findings: (1) BAT surrounding PHEO expresses adiponectin and UCP-1 mRNA, (2) expression of adiponectin mRNA is significantly higher in BAT than in WAT surrounding PHEO, and (3) catecholamines and serum adiponectin levels significantly correlate with BAT UCP-1 and adiponectin mRNA. PMID- 24348551 TI - Analyzing the role of receptor internalization in the regulation of melanin concentrating hormone signaling. AB - The regulation of appetite is complex, though our understanding of the process is improving. The potential role for the melanin-concentrating hormone (MCH) signaling pathway in the treatment of obesity is being explored by many. It was hypothesized that internalization of MCH receptors would act to potently desensitize cells to MCH. Despite potent desensitization of ERK signaling by MCH in BHK-570 cells, we were unable to observe MCH-mediated internalization of MCH receptor 1 (MCHR1) by fluorescence microscopy. A more quantitative approach using a cell-based ELISA indicated only 15% of receptors internalized, which is much lower than that reported in the literature. When beta-arrestins were overexpressed in our system, removal of receptors from the cell surface was facilitated and signaling to a leptin promoter was diminished, suggesting that internalization of MCHR1 is sensitive to cellular beta-arrestin levels. A dominant-negative GRK construct completely inhibited loss of receptors from the cell surface in response to MCH, suggesting that the internalization observed is phosphorylation-dependent. Since desensitization of MCH-mediated ERK signaling did not correlate with significant loss of MCHR1 from the cell surface, we hypothesize that in this model system regulation of MCH signaling may be the result of segregation of receptors from signaling components at the plasma membrane. PMID- 24348552 TI - Investigation of responsiveness to thyrotropin-releasing hormone in growth hormone-producing pituitary adenomas. AB - Objective. The aim of this study was to investigate how the paradoxical response of GH secretion to TRH changes according to tumor volumes. Methods. Patients with newly diagnosed acromegaly were classified as either TRH responders or nonresponders according to the results of a TRH stimulation test (TST), and their clinical characteristics were compared according to responsiveness to TRH and tumor volumes. Results. A total of 41 acromegalic patients who underwent the TST were included in this study. Between TRH responders and nonresponders, basal GH, IGF-I levels, peak GH levels, and tumor volume were not significantly different, but the between-group difference of GH levels remained near significant over the entire TST time. DeltaGHmax-min during the TST were significantly different according to the responsiveness to TRH. Peak GH levels and DeltaGHmax-min during the TST showed significantly positive correlations with tumor volume with higher levels in macroadenomas than in microadenomas. GH levels over the entire TST time also remained significantly higher in macroadenomas than in microadenomas. Conclusion. Our data demonstrated that the paradoxical response of GH secretion to TRH in GH-producing pituitary adenomas was not inversely correlated with tumor volumes. PMID- 24348553 TI - Trunk fat negatively influences skeletal and testicular functions in obese men: clinical implications for the aging male. AB - Osteocalcin (OSCA) seems to act as a negative regulator of energy metabolism and insulin sensitivity. Evidence from male rodents suggests that OSCA may also regulate testosterone (T) synthesis. Using a cross-sectional design, we evaluated OSCA, 25(OH) vitamin D, T, 17 beta -estradiol (E2), homeostasis model assessment of insulin resistance (HOMA-IR), and body composition in 86 obese (mean BMI = 34) male subjects (18-69 yr old). Independently from BMI, an inverse relationship between trunk fat percentage and plasma T (r (2) = -0.26, P < 0.01) and between HOMA-IR and OSCA levels (r (2) = -0.22, P < 0.005) was found. OSCA levels, as well as vitamin D, decreased significantly for higher BMI with significant differences above 35 (P < 0.01). A direct correlation between T and bone mineral density at lumbar (BMDL) and neck (BMDH) (P < 0.001, r (2) = -0.20; P < 0.001, r (2) = -0.24) was found, independently from age. An inverse correlation between E2 levels, BMDL, and BMDH (P < 0.001, r (2) = -0.20; P < 0.001, r (2) = -0.19) was observed. These data provide new evidences that a relationship between trunk fat mass, insulin sensitivity, OSCA and T synthesis occurs. This new relationship with skeletal health has relevant implications for the aging male, suggesting OSCA as a novel marker of metabolic and gonadal health status. PMID- 24348554 TI - Incidental thyroid carcinoma diagnosed after total thyroidectomy for benign thyroid diseases: incidence and association with thyroid disease type and laboratory markers. AB - Objective. Currently, total thyroidectomy (TT) is widely used to treat benign thyroid diseases and thyroid carcinoma. The differential diagnosis between benign and malignant thyroid disorders and the potential identification of thyroid microcarcinomas with biochemical markers remain controversial. This retrospective study aimed to estimate the prognostic validity of thyroid autoantibodies, thyroglobulin (Tg), and the thyroid disease type in diagnostic approaches regarding the co-existence of incidental thyroid carcinoma (ITC) with benign thyroid diseases. Methods. A cohort of 228 patients was treated with TT for benign thyroid disorders between 2005 and 2010. Thyroid autoantibodies and Tg were preoperatively estimated. Patients were classified according to the preoperative and histologically established diagnoses, and the median values of the biochemical markers were compared between the groups. Results. ITC was detected in 33/228 patients and almost exclusively in the presence of nontoxic thyroid disorders (P = 0.014). There were no statistically significant differences in the median values of the biochemical markers between the benign and malignant groups. There was also no significant association between ITC and chronic lymphocytic thyroiditis. Conclusions. The co-existence of ITC with benign and especially nontoxic thyroid diseases is significant, and treatment of these disorders with TT when indicated can lead to the identification and definitive cure of microcarcinomas. Further studies are required to establish precise markers with prognostic validity for TC diagnosis. PMID- 24348555 TI - Estrogen inhibits colon polyp formation by reducing angiogenesis in a carcinogen induced rat model. AB - Objective. To study the effects of estrogen on colon polyp formation, proliferation, and angiogenesis on a rat model of colon cancer induced by dimethylhydrazine (DMH). Methods. Thirty-six female ovariectomized (OVX) rats were randomly divided into 3 groups: (I) control group (administrated with vehicles weekly), (II) DMH group (administrated with DMH weekly), and (III) DMH + E2 group (administrated with DMH and 17beta-estradiol weekly). The incidence, volumes, and multiplicity of colon polyps in each group were evaluated. The microvessel density (MVD), the expressions of Proliferating Cell Nuclear Antigen (PCNA), and the expressions of HIF-1 alpha and VEGF in polyps were detected in each group. Results. Estrogen reduced the multiplicity, volumes, and the PCNA expressions of DMH-induced colon polyps. The MVD in DMH + E2 group was significantly lower than that in DMH group. Estrogen treatment decreased the HIF 1 alpha and VEGF expressions at both mRNA and protein level. Conclusion. Estrogen replacement was protective for ovariectomized rats from DMH-induced carcinogenesis, and one of the mechanisms for this was due to estrogen's inhibitive effects on blood vessel formation by downregulating VEGF and HIF-1 alpha expressions. PMID- 24348556 TI - Mitotane-induced hyperlipidemia: a retrospective cohort study. AB - Limited data are available about mitotane-nduced hyperlipidemia. We retrospectively analyzed lipid data in 38 patients with adrenocortical carcinoma (ACC) who received mitotane therapy with emphasis on HDL cholesterol (HDL-c) and clinical predictors of lipid changes. At baseline, the mean levels of HDL-c, LDL c, and triglycerides were 53.3 mg/dL, 114.4 mg/dL, and 149 mg/dL, respectively. HDL-c, LDL-c, and triglyceride concentrations significantly increased with mitotane therapy to a mean HDL peak (HDL-P) of 86.3 mg/dL (P < 0.001), a mean LDL peak of 160.1 mg/dL (P < 0.001), and a mean triglyceride peak (Tg-P) of 216.7 mg/dL (P = 0.042). HDL-P positively correlated with mitotane concentration (r = 0.52, P < 0.001), while LDL-P levels and Tg-P did not. Gender, body mass index, cortisol overproduction, baseline levels of HDL-c, and triglyceride did not predict change in HDL-c. Similar changes were noticed in subgroup analysis after excluding patients who were using lipid-lowering agents. In conclusion, in ACC patients, mitotane caused significant increases in HDL-c that may counteract the deleterious atherosclerotic effects of LDL-c and Tg rise. Understanding the mechanism of HDL change may lead to the discovery of novel HDL-c-elevating drugs. PMID- 24348557 TI - Potential mechanisms for racial and ethnic differences in antimullerian hormone and ovarian reserve. AB - Accumulating evidence suggests that reproductive potential and function may be different across racial and ethnic groups. Racial differences have been demonstrated in pubertal timing, infertility, outcomes after assisted reproductive technology (ART) treatment, and reproductive aging. Recently, racial differences have also been described in serum antimullerian hormone (AMH), a sensitive biomarker of ovarian reserve, supporting the notion that ovarian reserve differs between racial/ethnic groups. The existence of such racial/ethnic differences in ovarian reserve, as reflected by AMH, may have important clinical implications for reproductive endocrinologists. However, the mechanisms which may underlie such racial differences in ovarian reserve are unclear. Various genetic factors and environmental factors such as obesity, smoking, and vitamin D deficiency which have been shown to correlate with serum AMH levels and also display significant racial/ethnic variations are discussed in this review. Improving our understanding of racial differences in ovarian reserve and their underlying causes may be essential for infertility treatment in minority women and lead to better reproductive planning, improved treatment outcomes, and timely interventions which may prolong reproductive lifespan in these women. PMID- 24348559 TI - Comparing health promotion programs in public dental service of vantaa, Finland: a clinical trial in 6-36-month-old children. AB - Objective. The study assessed whether the new family-based programs in health promotion or the training of dental professionals had an impact on the colonization of mutans streptococci (MS) in young children. Material and Methods. The participants were children born in 2008 and inhabitants of Vantaa aged 24-36 months. The families with first-born children were invited to a questionnaire study. Vantaa was categorized into three matching areas, which were randomly assigned to different programs. New counseling methods were trained. The routine program used earlier served as the control group. The children born in 2006 served as a historic control. The outcome measure was the presence of MS. Statistical method was logistic regression. Results. Colonization of MS was found only in few children born in 2006 or 2008; 15% and 11%, respectively. Within the 2008 birth cohort, the addition of parental counseling did not improve the routine program. Instead, the father's advanced level of education (P = 0.044) and the child's reported the use of xylitol at least three times a day (P = 0.014) associated with negative MS scores. Conclusions. The routine program and training of the professionals seem to reduce the proportion of children with MS more than adding parental self-care to oral health programs. PMID- 24348558 TI - How Much Does AMH Really Vary in Normal Women? AB - Anti-Mullerian Hormone (AMH) is an ovarian hormone expressed in growing follicles that have undergone recruitment from the primordial follicle pool but have not yet been selected for dominance. It is considered an accurate marker of ovarian reserve, able to reflect the size of the ovarian follicular pool of a woman of reproductive age. In comparison to other hormonal biomarkers such as serum FSH, low intra- and intermenstrual cycle variability have been proposed for AMH. This review summarizes the knowledge regarding within-subject variability, with particular attention on AMH intracycle variability. Moreover the impact of ethnicity, body mass index, and smoking behaviour on AMH interindividual variability will be reviewed. Finally changes in AMH serum levels in two conditions of ovarian quiescence, namely contraceptives use and pregnancy, will be discussed. The present review aims at guiding researchers and clinicians in interpreting AMH values and fluctuations in various research and clinical scenarios. PMID- 24348560 TI - Management of internal root resorption on permanent teeth. AB - Internal root resorption (IRR) is a particular category of pulp disease characterized by the loss of dentine as a result of the action of clastic cells stimulated by pulpal inflammation. This review article explains the etiology, the prevalence of IRR, and, in addition to the clinical data, the contribution of the three-dimensional imaging (CBCT) to the diagnosis, the clinical decision, and the therapeutic management of IRR. The authors discussed the various therapeutic options including the orthograde or retrograde fillings of the root canal resorption area. Root canal treatment remains the treatment of choice of internal root resorption as it removes the granulation tissue and blood supply of the clastic cells. The authors describe with different clinical cases the modern endodontic techniques including optical aids, ultrasonic improvement of chemical debridement, and the use of alternative materials such as calcium silicate combined with thermoplastic filling (warm gutta-percha). In these conditions, the prognosis of the conservative treatment of internal resorptions, even if root walls are perforated, is good. PMID- 24348561 TI - Alternative splicing: role in cancer development and progression. PMID- 24348562 TI - Role of protein misfolding and proteostasis deficiency in protein misfolding diseases and aging. AB - The misfolding, aggregation, and tissue accumulation of proteins are common events in diverse chronic diseases, known as protein misfolding disorders. Many of these diseases are associated with aging, but the mechanism for this connection is unknown. Recent evidence has shown that the formation and accumulation of protein aggregates may be a process frequently occurring during normal aging, but it is unknown whether protein misfolding is a cause or a consequence of aging. To combat the formation of these misfolded aggregates cells have developed complex and complementary pathways aiming to maintain protein homeostasis. These protective pathways include the unfolded protein response, the ubiquitin proteasome system, autophagy, and the encapsulation of damaged proteins in aggresomes. In this paper we review the current knowledge on the role of protein misfolding in disease and aging as well as the implication of deficiencies in the proteostasis cellular pathways in these processes. It is likely that further understanding of the mechanisms involved in protein misfolding and the natural defense pathways may lead to novel strategies for treatment of age-dependent protein misfolding disorders and perhaps aging itself. PMID- 24348563 TI - The mitochondrial disulfide relay system: roles in oxidative protein folding and beyond. AB - Disulfide bond formation drives protein import of most proteins of the mitochondrial intermembrane space (IMS). The main components of this disulfide relay machinery are the oxidoreductase Mia40 and the sulfhydryl oxidase Erv1/ALR. Their precise functions have been elucidated in molecular detail for the yeast and human enzymes in vitro and in intact cells. However, we still lack knowledge on how Mia40 and Erv1/ALR impact cellular and organism physiology and whether they have functions beyond their role in disulfide bond formation. Here we summarize the principles of oxidation-dependent protein import mediated by the mitochondrial disulfide relay. We proceed by discussing recently described functions of Mia40 in the hypoxia response and of ALR in influencing mitochondrial morphology and its importance for tissue development and embryogenesis. We also include a discussion of the still mysterious function of Erv1/ALR in liver regeneration. PMID- 24348564 TI - Cysteine-10 on 17 beta -Hydroxysteroid Dehydrogenase 1 Has Stabilizing Interactions in the Cofactor Binding Region and Renders Sensitivity to Sulfhydryl Modifying Chemicals. AB - 17 beta -Hydroxysteroid dehydrogenase type 1 (17 beta -HSD1) catalyzes the conversion of estrone to the potent estrogen estradiol. 17 beta -HSD1 is highly expressed in breast and ovary tissues and represents a prognostic marker for the tumor progression and survival of patients with breast cancer and other estrogen dependent tumors. Therefore, the enzyme is considered a promising drug target against estrogen-dependent cancers. For the development of novel inhibitors, an improved understanding of the structure-function relationships is essential. In the present study, we examined the role of a cysteine residue, Cys(10), in the Rossmann-fold NADPH binding region, for 17 beta -HSD1 function and tested the sensitivity towards sulfhydryl modifying chemicals. 3D structure modeling revealed important interactions of Cys(10) with residues involved in the stabilization of amino acids of the NADPH binding pocket. Analysis of enzyme activity revealed that 17 beta -HSD1 was irreversibly inhibited by the sulfhydryl modifying agents N-ethylmaleimide (NEM) and dithiocarbamates. Preincubation with increasing concentrations of NADPH protected 17 beta -HSD1 from inhibition by these chemicals. Cys(10)Ser mutant 17 beta -HSD1 was partially protected from inhibition by NEM and dithiocarbamates, emphasizing the importance of Cys(10) in the cofactor binding region. Substitution of Cys(10) with serine resulted in a decreased protein half-life, without significantly altering kinetic properties. Despite the fact that Cys(10) on 17 beta -HSD1 seems to have limited potential as a target for new enzyme inhibitors, the present study provides new insight into the structure-function relationships of this enzyme. PMID- 24348566 TI - Agromyces arachidis sp. nov. Isolated from a Peanut (Arachis hypogaea) Crop Field. AB - A Gram-positive, yellowish bacterium strain AK-1(T) was isolated from soil sample collected from peanut (Arachis hypogaea) crop field and studied by using a polyphasic approach. The organism had morphological and chemotaxonomic properties consistent with its classification in the genus Agromyces. Phylogenetic analysis of the 16S rRNA gene sequence showed that strain AK-1(T) was closely related to Agromyces aurantiacus (98.6%) followed by Agromyces soli (98.3%), Agromyces tropicus (97.6%), Agromyces ulmi (97.3%), Agromyces flavus (97.2%), and Agromyces italicus (97.0%), whereas the sequence similarity values with respect to the other Agromyces species with validly published names were between 95.3 and 96.7 %. However, the DNA-DNA hybridization values obtained between strain AK-1(T) and other related strains were well below the threshold that is required for the proposal of a novel species. The DNA G + C content of the strain is 71.8 mol%. The above data in combination with the phenotypic distinctiveness of AK-1(T) clearly indicate that the strain represents a novel species, for which the name Agromyces arachidis sp. nov. is proposed. The type strain is AK-1(T) (=MTCC 10524(T) = JCM 19251(T)). PMID- 24348567 TI - Rheumatoid factor positivity is associated with increased joint destruction and upregulation of matrix metalloproteinase 9 and cathepsin k gene expression in the peripheral blood in rheumatoid arthritic patients treated with methotrexate. AB - We evaluated changes in gene expression of mTOR, p21, caspase-3, ULK1, TNF alpha , matrix metalloproteinase (MMP)-9, and cathepsin K in the whole blood of rheumatoid arthritic (RA) patients treated with methotrexate (MTX) in relation to their rheumatoid factor status, clinical, immunological, and radiological parameters, and therapeutic response after a 24-month follow-up. The study group consisted of 35 control subjects and 33 RA patients without previous history of MTX treatment. Gene expression was measured using real-time RT-PCR. Decreased disease activity in patients at the end of the study was associated with significant downregulation of TNF alpha expression. Downregulation of mTOR was observed in seronegative patients, while no significant changes in the expression of p21, ULK1, or caspase-3 were noted in any RA patients at the end of the study. The increase in erosion numbers observed in the seropositive patients at the end of the follow-up was accompanied by upregulation of MMP-9 and cathepsin K, while seronegative patients demonstrated an absence of significant changes in MMP-9 and cathepsin K expression and no increase in the erosion score. Our results suggest that increased expression of MMP-9 and cathepsin K genes in the peripheral blood might indicate higher bone tissue destruction activity in RA patients treated with methotrexate. The clinical study registration number is 0120.0810610. PMID- 24348568 TI - Myomectomy during Caesarean Birth in Fibroid-Endemic, Low-Resource Settings. AB - If myomectomy during caesarean delivery becomes a widespread practice, it could potentially eliminate multiple surgeries for both indications. However, many surgeons have been reluctant to adopt this policy without conclusive evidence demonstrating its safety. This study reviews the publications on caesarean myomectomy especially from the African Continent with respect to duration of surgery, blood loss, length of hospital stay, and blood transfusions. Judging from the lack of large studies on caesarean myomectomy, the proportion of surgeons who attempt the procedure is largely low because of concerns about its safety. However, most of the authors suggested that the complications and morbidity following caesarean myomectomy do not significantly differ from those occurring during caesarean section alone, while fertility is apparently not compromised by this treatment. With careful patient selection, adequate experience, and efficient haemostatic measures, the procedure does not appear as hazardous as was once thought. This piece of information is relevant for counseling women who request for the simultaneous removal of previously diagnosed fibroids during caesarean section. Staff and facilities for safe management of haemorrhage are a requisite for the procedure. Large randomized trials are needed to guide decisions as to the best clinical practice regarding myomectomy during caesarean delivery. PMID- 24348569 TI - The natural history of uterine leiomyomas: light and electron microscopic studies of fibroid phases, interstitial ischemia, inanosis, and reclamation. AB - We propose, and offer evidence to support, the concept that many uterine leiomyomas pursue a self-limited life cycle. This cycle can be arbitrarily divided on the basis of morphologic assessment of the collagen content into 4 phases: (1) proliferation, (2) proliferation and synthesis of collagen, (3) proliferation, synthesis of collagen, and early senescence, and (4) involution. Involution occurs as a result of both vascular and interstitial ischemia. Interstitial ischemia is the consequence of the excessive elaboration of collagen, resulting in reduced microvascular density, increased distance between myocytes and capillaries, nutritional deprivation, and myocyte atrophy. The end stage of this process is an involuted tumor with a predominance of collagen, little to no proliferative activity, myocyte atrophy, and myocyte cell death. Since many of the dying cells exhibit light microscopic and ultrastructural features that appear distinct from either necrosis or apoptosis, we refer to this process as inanosis, because it appears that nutritional deprivation, or inanition, is the underlying cause of cell death. The disposal of myocytes dying by inanosis also differs in that there is no phagocytic reaction, but rather an apparent dissolution of the cell, which might be viewed as a process of reclamation as the molecular contents are reclaimed and recycled. PMID- 24348565 TI - The role of s-nitrosylation and s-glutathionylation of protein disulphide isomerase in protein misfolding and neurodegeneration. AB - Neurodegenerative diseases involve the progressive loss of neurons, and a pathological hallmark is the presence of abnormal inclusions containing misfolded proteins. Although the precise molecular mechanisms triggering neurodegeneration remain unclear, endoplasmic reticulum (ER) stress, elevated oxidative and nitrosative stress, and protein misfolding are important features in pathogenesis. Protein disulphide isomerase (PDI) is the prototype of a family of molecular chaperones and foldases upregulated during ER stress that are increasingly implicated in neurodegenerative diseases. PDI catalyzes the rearrangement and formation of disulphide bonds, thus facilitating protein folding, and in neurodegeneration may act to ameliorate the burden of protein misfolding. However, an aberrant posttranslational modification of PDI, S nitrosylation, inhibits its protective function in these conditions. S nitrosylation is a redox-mediated modification that regulates protein function by covalent addition of nitric oxide- (NO-) containing groups to cysteine residues. Here, we discuss the evidence for abnormal S-nitrosylation of PDI (SNO-PDI) in neurodegeneration and how this may be linked to another aberrant modification of PDI, S-glutathionylation. Understanding the role of aberrant S-nitrosylation/S glutathionylation of PDI in the pathogenesis of neurodegenerative diseases may provide insights into novel therapeutic interventions in the future. PMID- 24348570 TI - Esophageal intramural pseudodiverticulosis: a rare endoscopic finding. AB - A 76-year-old woman, presenting with a 4-year history of progressive dysphagia, was submitted to endoscopic examination. The upper endoscopy revealed a proximal esophageal stricture and inflammatory mucosa associated with multiples small orifices in the esophageal wall, some of them fulfilled with white spots suggestive of fungal infection. This was a typical endoscopic finding of esophageal intramural pseudodiverticulosis, a benign and rare condition, related to chronic esophagitis and others comorbid states, such as gastroesophageal reflux disease or infectious esophagitis, diabetes mellitus, alcohol consumption, and achalasia. Dysphagia is the predominant symptom and can be accompanied by esophageal stricture in 80% to 90% of patients. The pathogenesis is unknown, and as the pseudodiverticulosis is an intramural finding, endoscopy biopsies are inconclusive. The main histological finding is dilation of the submucosal glands excretory ducts, probably obstructed by inflammatory cells. The treatment consists in management of the underlying diseases and symptoms relief. In this particular case, the patient was submitted to antifungal drugs followed by endoscopic dilation with thermoplastic bougies, with satisfactory improvement of dysphagia. PMID- 24348571 TI - Infliximab-Induced Hypothyroidism: A Novel Case and Postulations concerning the Mechanism. AB - We report a patient with cutaneous sarcoidosis who developed hypothyroidism following 17 months of infliximab therapy. To our knowledge, this is the first reported case of hypothyroidism following infliximab administration. While it is possible that the patient's hypothyroidism was unrelated to the use of infliximab, the time course and lack of alternative explanations make such an association plausible. We postulate that hypothyroidism in this patient may have been related to the development of autoantibodies to infliximab that triggered the development of an autoimmune thyroiditis. Regardless of the mechanism, we would encourage clinicians to keep the potential mechanisms of TNF-alpha in mind when treating patients with TNF-alpha antagonist medications. PMID- 24348572 TI - Kernohan's Notch: A Forgotten Cause of Hemiplegia-CT Scans Are Useful in This Diagnosis. AB - Hemiparesis ipsilateral to a cerebral lesion can be a false localizing sign. This is due to midline shift of the midbrain resulting in compression of the contralateral pyramidal fibers on the tough dural reflection tentorium cerebelli. This may result in partial or complete damage to these fibers. Since these fibers are destined to cross in the medulla and innervate the opposite side of the body, this causes hemiparesis ipsilateral to the site of cerebral lesion. Computed tomography (CT) scans have not been used to support the diagnosis of this entity until now. We report a 68-year-old woman with a subdural hematoma who developed ipsilateral hemiparesis without any other explanation (Kernohan's notch). The CT of the head showed evidence of compression of the midbrain contralateral to the hematoma and was useful in the diagnosis. The purpose of this report is to increase the awareness of this presentation and to emphasize the utility of CT scans to support the diagnosis. PMID- 24348573 TI - Pneumomediastinum Complicating Diabetic Ketoacidosis and Boerhaave's Syndrome. AB - An 18-year-old man presented with altered mental status. He was found to have diabetic ketoacidosis. Chest X-ray showed pneumomediastinum. After intubation for air-way protection, an oral-gastric tube was placed. A chest computed tomography scan showed the tip of the oral-gastric tube to be in the right hemithorax. The patient underwent a thoracotomy and was managed in the intensive care unit. Both diabetic ketoacidosis and Boerhaave's syndrome should be considered as possible causes of pneumomediastinum in a patient with similar presentation. Boerhaave's syndrome should be ruled out prior to the insertion of an oral-gastric tube to avoid further morbidities. PMID- 24348574 TI - Mixed acinar-neuroendocrine carcinoma of the pancreas with neuroendocrine predominance. AB - Background. Pancreatic tumors are rare and could arise from either the exocrine (ductal and acinar cells) or the endocrine (neuroendocrine cells) components of the pancreas. In some instances, the occurrence of pancreatic tumors comprising both acinar cells and neuroendocrine cells, with neuroendocrine cells making up more than 30% of the tumor, has been identified. This unique entity has been referred to as mixed acinar-neuroendocrine carcinoma (MANEC). Only about 20 such cases have been reported in the literature. Case Report. We report an interesting case of MANEC with neuroendocrine cell predominance in a woman presenting with epigastric pain secondary to a pancreatic mass with acinar and endocrine differentiation. She underwent surgical resection of the tumor and was offered adjuvant treatment chemotherapy with carboplatin, etoposide, and radiotherapy for positive tumor resection margins. Conclusions. Given the paucity of the cases of MANEC, continuous reporting of these cases when identified should be encouraged to aid oncologists in understanding the disease and help establish standardized management. PMID- 24348575 TI - Primary Cutaneous Vasculitis Masquerading as Drug Induced following Aspirin Desensitization. AB - Aspirin-exacerbated respiratory disease (AERD) is a well-known clinical condition. Aspirin desensitization followed by daily aspirin therapy is the treatment of choice. We report a challenging case of primary cutaneous vasculitis following aspirin desensitization in a patient with AERD. The vasculitis was likely suppressed with higher dose systemic steroid use to control asthma. Aspirin desensitization led to improved asthma control and steroid reduction, which led to manifestation of prior suppressed cutaneous vasculitis. In our case, there was no evidence of systemic involvement and the patient had a favorable outcome with appropriate therapy. PMID- 24348576 TI - Caesarean delivery complicated by unintentional subdural block and conversion disorder. AB - Combined spinal epidural (CSE) can provide excellent labor analgesia. Subdural block is also a potential but rare complication of attempted epidural placement during a CSE procedure, which may present as a block that is usually patchy in nature, with a component of sensory and/or motor deficit and a variable duration of action. In addition, a conversion disorder or a functional neurological disorder has been described with epidural and spinal anesthesia in obstetric patients. In this clinical report, we describe a 33-year-old G4P3 at 40 weeks gestation that received an unintentional subdural block as part of her labor analgesia and after an uneventful caesarean delivery presented with a conversion disorder. The rarity of the association between a subdural block and a conversion disorder complicated by the fact that the neurological deficit produced by the subdural block and that produced by a conversion disorder are similar in distribution made the clinical presentation and diagnosis a challenge for the obstetric anesthesia team. A functional neurological disorder of this nature complicating a subdural block in an obstetric anesthesia clinical practice has not been described so far. PMID- 24348577 TI - Tenon's Cyst Presenting as a Long-Term Complication following Incision Cataract Surgery. AB - Context. Tenon's cyst or conjunctival cyst formation is not uncommon late complication of traditional extracapsular cataract surgery; however, few reports are available in the literature. Aims. Large cystic swellings were clinically diagnosed as filtering blebs at the cataract incision site in two patients. The purpose of the case presentation is to discuss the factors leading to cyst formation, visual loss and cyst recurrence after its excision. Patients and Methods. Case 1. Sixty-one-year-old male patient presented with a bleb at superior limbal region in the right eye, two years after cataract surgery. Case 2. A giant bleb was found at the same region in the right eye of a 65-year-old male patient, eight years after cataract surgery. Results. Complete excision of the cyst was performed with conjunctival autograft in the first patient and followed up for two years. No recurrence of the cyst was observed. Internal wound gaping was seen on gonioscopy in the second patient. Conclusions. Unstable scleral tunnel could explain bleb formation in both the patients. Complete bleb excision with conjunctival auto-graft resulted in closure of the defect with no bleb recurrence during two-year follow-up. Over-filtration causing hypotonic maculopathy was the reason for decreased vision in the second case. PMID- 24348578 TI - Bisphosphonate Treatment in a Patient Affected by MPS IVA with Osteoporotic Phenotype. AB - Morquio A syndrome (Mucopolysaccharidosis type IVA) (MPS IVA) is a rare inherited metabolic disorder characterized by the defective degradation of keratan sulfate and chondroitin-6-sulfate. Classically, MPS IVA patients present with severe multisystemic involvement and have a short life expectancy. Attenuated forms with clinical features limited to minor skeletal abnormalities and short stature have also been described, sometimes associated to an early-onset osteoporotic phenotype. No treatment with allogenic bone marrow transplantation or gene therapy is currently available for Morquio A syndrome, and enzyme replacement therapy is under evaluation. We report a case of MPS IVA, who manifested tardily attenuated phenotype and significant bone mass reduction, which was treated with a bisphosphonate (BPN), resulting in an improvement of X-ray skeletal aspects and functional bone performance. We suggest that the use of bisphosphonates may be an interesting supportive therapeutic option for Morquio A patients with osteoporotic phenotype, but further studies involving more patients are necessary to confirm our findings. PMID- 24348579 TI - Dialysis and pregnancy in end stage kidney disease associated with lupus nephritis. AB - Female patients with systemic lupus erythematosus are often of childbearing age at diagnosis, and though fertility in these patients is similar to the general population, successful pregnancy remains a rare occurrence. This incidence is, however, increasing and the management of these high risk pregnancies is often further complicated by the patient's need for dialysis as a result of lupus nephritis (LN). We share our experience in managing two LN patients with successful pregnancies, one on automated peritoneal dialysis and the other on haemodialysis, as well as a review of cases in the literature. PMID- 24348580 TI - Differentiation of dental pulp stem cells into neuron-like cells in serum-free medium. AB - Dental pulp tissue contains dental pulp stem cells (DPSCs). Dental pulp cells (also known as dental pulp-derived mesenchymal stem cells) are capable of differentiating into multilineage cells including neuron-like cells. The aim of this study was to examine the capability of DPSCs to differentiate into neuron like cells without using any reagents or growth factors. DPSCs were isolated from teeth extracted from 6- to 8-week-old mice and maintained in complete medium. The cells from the fourth passage were induced to differentiate by culturing in medium without serum or growth factors. RT-PCR molecular analysis showed characteristics of Cd146(+) , Cd166(+) , and Cd31(-) in DPSCs, indicating that these cells are mesenchymal stem cells rather than hematopoietic stem cells. After 5 days of neuronal differentiation, the cells showed neuron-like morphological changes and expressed MAP2 protein. The activation of Nestin was observed at low level prior to differentiation and increased after 5 days of culture in differentiation medium, whereas Tub3 was activated only after 5 days of neuronal differentiation. The proliferation of the differentiated cells decreased in comparison to that of the control cells. Dental pulp stem cells are induced to differentiate into neuron-like cells when cultured in serum- and growth factor-free medium. PMID- 24348581 TI - Adaptive behavior in young children with neurofibromatosis type 1. AB - Neurofibromatosis-1 is the most common single gene disorder affecting 1 in 3000. In children, it is associated not only with physical features but also with attention and learning problems. Research has identified a downward shift in intellectual functioning as well, but to date, there are no published studies about the everyday adaptive behavior of children with NF1. In this study, parental reports of adaptive behavior of 61 children with NF1 ages 3 through 8 were compared to an unaffected contrast group (n = 55) that comprised siblings and community members. Significant group differences in adaptive skills were evident and were largely related to group differences in intellectual functioning. In a subsample of children with average-range intellectual functioning, group differences in parent-reported motor skills were apparent even after controlling statistically for group differences in intellectual functioning. The implications of the findings for the care of children with NF1 are discussed. PMID- 24348582 TI - The attitudes and intention to participate in hemoglobinopathy carrier screening in The Netherlands among individuals from Turkish, Moroccan, and Surinamese descent. AB - OBJECTIVE: To explore factors that influence intention to participate in hemoglobinopathy (HbP) carrier screening under Dutch subjects at risk, since HbP became more common in The Netherlands. METHOD: Structured interviews with 301 subjects from Turkish, Moroccan, or Surinamese ethnicity. RESULTS: Half of the participants were familiar with HbP, 27% with carrier screening. Only 55% correctly answered basic knowledge items. After balanced information, 83% percent of subjects express intention to participate in HbP carrier screening. Intention to participate was correlated with (1) anticipated negative feelings, (2) valuing a physician's advice, and (3) beliefs on significance of carrier screening. Risk perception was a significant determinant, while respondents were unaware of HbP as endemic in their country of birth. Respondents preferred screening before pregnancy and at cost < 50?. CONCLUSION: These findings show the importance of informing those at risk by tailored health education. We propose easy access at no costs for those willing to participate in HbP carrier screening. PMID- 24348583 TI - Leaf area controls on energy partitioning of a temperate mountain grassland. AB - Using a six year data set of eddy covariance flux measurements of sensible and latent heat, soil heat flux, net radiation, above-ground phytomass and meteorological driving forces energy partitioning was investigated at a temperate mountain grassland managed as a hay meadow in the Stubai Valley (Austria). The main findings of the study were: (i) Energy partitioning was dominated by latent heat, followed by sensible heat and the soil heat flux; (ii) When compared to standard environmental forcings, the amount of green plant matter, which due to three cuts varied considerably during the vegetation period, explained similar, and partially larger, fractions of the variability in energy partitioning; (iii) There were little, if any, indications of water stress effects on energy partitioning, despite reductions in soil water availability in combination with high evaporative demand, e.g. during the summer drought of 2003. PMID- 24348585 TI - Role of insulin in the type 2 diabetes therapy: past, present and future. AB - CONTEXT: Since 2006 a relevant number of therapeutical algorithms for the management of type 2 diabetes have been proposed, generating a lively debate in the scientific community, particularly on the ideal timing for introduction of insulin therapy and on which drug should be preferred as add-on therapy in patients failing to metformin. At the moment, there is no real consensus. The aim of the present review is to summarize established knowledge and areas for debate with respect to insulin therapy in type 2 diabetes. EVIDENCE ACQUISITION: In type 2 diabetic patients, insulin represents a therapy with a long and well established history, but, considering the modern insulin therapy, several points must be carefully examined. The role played by the introduction of insulin analogues, the choice of insulin regimens, the ongoing debate on insulin and cancer, the cardiovascular effects of insulin, the role of insulin on beta-cell protection and the actual clinical perspective in the treatment of the disease. Nevertheless, still many exciting expectations exist: the new insulin analogues, the technological options, the inhaled and oral insulin and the issue of transplantation. CONCLUSIONS: Although insulin is the more potent hypoglicemic agent, the availability of a wider spectrum of therapeutic agents, many of which are better tolerated than insulin, has reduced the field of application for insulin treatment; presently, insulin is used only in those who cannot maintain an adequate glycemic control with other drugs. Furthermore, a lively research activity is currently ongoing, in order to make insulin therapy even safer and simpler for patients. PMID- 24348584 TI - The role of estrogen in the treatment of men with schizophrenia. AB - Schizophrenia is a debilitating and pervasive mental illness with devastating effects on many aspects of psychological, cognitive and social wellbeing. Epidemiological and life-cycle data point to significant differences in the incidence and course of schizophrenia between men and women, suggesting that estrogen plays a "protective" role . Adjunctive estrogen therapy has been shown to be effective in enhancing the treatment of schizophrenia in women. In men, consideration of estrogen therapy has been impacted by concerns of feminisation, however, clinical trials using estrogen to treat prostate cancer, bone density loss and even aggression in men with dementia or traumatic brain injury, show estrogen to be a safe and effective therapy. Findings do, however, suggest that further exploration of a therapeutic role for adjunctive estradiol treatment in men with schizophrenia is warranted. The development of the new estrogen compounds - Selective Estrogen Receptor Modulators (SERMs) which do not cause feminisation - opens up the possibility of using a different type of estrogen for a longer period of time at higher doses. Estrogen could therefore prove to be an important component in the treatment of psychotic symptoms in men with schizophrenia. This review explains the scientific rationale behind the estrogen hypothesis and how it can be clinically utilised to address concerns unique to the care of men with schizophrenia. PMID- 24348586 TI - The effect of community-based education for lifestyle intervention on the prevalence of metabolic syndrome and its components: tehran lipid and glucose study. AB - BACKGROUND: It has been shown that life style modification may decrease the prevalence of metabolic syndrome, but this intervention has not been reported in community setting. OBJECTIVES: Effect of lifestyle modification on prevalence of metabolic syndrome and its components were assessed in an urban population. MATERIALS AND METHODS: In 6870 participants of Tehran Lipid and Glucose Study aged 20-74 years, the prevalence of metabolic syndrome and its components were measured before and after a 3.6 years interval. Lifestyle intervention was employed at a community level including 2961 individuals and also 3909 subjects which were recruited as controls. Logistic regression analysis was adjusted for age, sex and medications. RESULTS: After 3.6 years, the rise in the prevalence of metabolic syndrome was less prominent in intervention than control group (P < 0.002 for increase of metabolic syndrome prevalence between groups), with an OR of 0.84 (confidence interval 0.75-0.95). After intervention the prevalence of abdominal obesity, elevated fasting glucose levels, elevated triglyceride and low HDL cholesterol were more prominent in control group, as compared to intervention group. CONCLUSIONS: Community based lifestyle modifications in Tehranian adults delayed rise in the prevalence of metabolic syndrome and some of its components. PMID- 24348587 TI - Expression and Localization of Neuregulin-1 (Nrg1) and ErbB2/ErbB4 Receptors in Main Endocrine Organs of the Rhesus Monkey. AB - BACKGROUND: Although Neuregulin-1 (Nrg1)and its receptors have been indicated at the mRNA level in partial human endocrine organs and its functional roles have been evaluated in vitro, their morphological distribution in higher animals are not fully studied. The present research focused on expression of Nrg1 and its main receptors ErbB2 and ErbB4 in main endocrine organs of the rhesus monkey. MATERIALS AND METHODS: The morphological expression of Nrg1 and its receptors ErbB2 and ErbB4 as well as their potential co-localization were determined by double immunofluorescence in the pituitary, thyroid, parathyroid, pancreas and adrenal gland sample tissues. The expression level of Nrg1 on each sample was indexed by the fold of integrative fluorescence intensity (IFI) relative to that of one cortical tissue. RESULTS: Differential expression of Nrg1 and their cognate receptors ErbB2 and ErbB4 were found selectively expressed in endocrine organs we tested, with higher expression levels detected in the adrenal gland (AG) and pancreas. Co-localization of Nrg1 with either ErbB2 or ErbB4 was detected in AG, thyroid and parathyroid gland, and Nrg1 was only co-localized with ErbB4 in the islet cells of the pancreas. In the pituitary, adjacent localization of Nrg1 positive cells with ErbB4 positive cells were observed. CONCLUSIONS: This investigation morphologically profiles the differential expression of Nrg1 and its receptors ErbB2 and ErbB4 in the main endocrine organ structures, suggesting an autocrine or paracrine-directed Nrg1-ErbB signaling pathway in some of these structures. PMID- 24348588 TI - Effect of ethnicity, dietary intake and physical activity on plasma adiponectin concentrations among malaysian patients with type 2 diabetes mellitus. AB - BACKGROUND: The Malaysian Health and morbidity Survey (2006) reported the highest prevalence of type 2 diabetes mellitus (T2DM) among the Indian population compared to the Malay and Chinese populations. Many studies have supported the important role of adiponectin in insulin-sensitizing, which is associated with T2DM. These studies have raised a research question whether the variation in prevalence is related to the adiponectin concentrations or the lifestyle factors. OBJECTIVES: The purpose of this study is to determine whether the adiponectin concentrations differ between the Malay, Chinese and the Indian populations with T2DM. It is to investigate the association of adiponectin concentrations with ethnicity, dietary intake and physical activity too. MATERIALS AND METHODS: In this cross-sectional study, a total of 210 T2DM patients with mean (SD) age of 56.73 (10.23) years were recruited from Penang, Malaysia. Data on demographic background, medical history, anthropometry (weight, height, visceral fat, percentage of body fat and waist circumference), dietary intake (3 days 24 hours diet recall) and physical activity (International Physical Activity Questionnaire) were obtained accordingly. Plasma adiponectin and routine laboratory tests (fasting blood sugar, HbA1c, total cholesterol, LDL, HDL and triglyceride) were performed according to standard procedure. RESULTS: After adjustment for physical activity and dietary intakes, the Indian population had significantly lower adiponectin concentrations (P = 0.003) when compared with the Malay and the Chinese populations, The Indian population also had significantly higher value of HbA1c (P = 0.017) and significantly lower HDL (P = 0.013). Plasma adiponectin concentrations was significantly associated with ethnicity (P = 0.011), dietary carbohydrate (P = 0.003) and physical activity total MET score (P = 0.026), after medical history, age, sex, total cholesterol and visceral fat adjusted. However, dietary carbohydrate and physical activity did not show significantly difference among the various ethnic groups. CONCLUSIONS: In conclusion, lower concentration of adiponectin in the Indian population when compared with the Malay and the Chinese populations is not associated with lifestyle factors. The possibility of adiponectin gene polymorphism should be discussed further. PMID- 24348589 TI - Effects of nutrition education on levels of nutritional awareness of pregnant women in Western iran. AB - BACKGROUND: Maternal nutritional health, before and during pregnancy, influences the health status of herself and her developing fetus. Pregnancy is an important condition for improving nutritional knowledge. OBJECTIVES: The present study aimed at determining effects of nutrition education on levels of nutritional awareness of a representative group of pregnant women in Western Iran. PATIENTS AND METHODS: A quasi-experimental intervention was undertaken on a random sample of pregnant women (n = 100) attending urban health centers in Ilam city (western Iran) during the year 2011 for prenatal care. A nutritional education program containing two to four lessons was undertaken for small groups of between six to ten women. Nutritional knowledge was assessed before intervention (pretest) and followed by two posttests within three weeks interval. RESULTS: The awareness level of pregnant women about healthy nutrition was significantly increased from 3% before intervention to 31% after the nutritional education intervention (P < 0.001). This significant difference was independent from maternal characteristics of age and levels of literacy and in obese mothers in particular. CONCLUSIONS: A nutritional education intervention will have a positive effect on nutritional awareness of pregnant women. PMID- 24348590 TI - Is hypothyroidism and hypogonadism an issue after aneurysmal subarachnoid hemorrhage-an institutional experience? AB - BACKGROUND: The incidence of hypopituitarism in aneurysmal subarachnoid hemorrhage ranges from 0% to 45%. Also the screening for hypopituitarism in survivors of aneurysmal SAH is not a routine. This has led to a controversy in the management of such patients. OBJECTIVES: The aim of the study was to evaluate the endocrine profile of our patients who had presented with aneurysmal SAH. PATIENTS AND METHODS: This was a prospective study conducted over a period of three years in patients of aneurysmal subarachnoid hemorrhage. The serum samples for levels of free T4, free T3, TSH, prolactin, FSH, LH and testosterone were analyzed at the time of admission and at a follow-up period between 9-12 months. Patients with known endocrine abnormalities, liver or kidney disease and patients with hemodynamic abnormalities were excluded from the study. Abnormalities in levels were noted and a comparative analysis of the hormone levels between the 2 time periods was done. A total of 73 patients were enrolled in the study. RESULTS: Serum prolactin was raised in 17.80% (13/73) and FSH, LH and testosterone levels were reduced in 12.32% (9/73) of patients in the acute phase at admission. After 9 months follow-up, serum prolactin normalized in all except one patient and in all the males, testosterone level increased significantly. Two patients (3%) developed central hypothyroidism on follow-up. CONCLUSIONS: Chronic hypothyroidism and hypogonadism is not an issue in aneurysmal SAH patients. PMID- 24348591 TI - Liraglutide Improves the Survival of INS-1 Cells by Promoting Macroautophagy. AB - BACKGROUND: Type 2 diabetes mellitus (T2D) is a metabolic disease characterized by dysfunction of pancreatic beta cell and insulin resistance. Liraglutide, which has many special anti-diabetes biological effects, is found to inhibit beta cell death and ameliorate endoplasmic reticulum stress (ERs) induced by free fatty acid (FFA). Macroautophagy (hereafter referred to as autophagy) altered by FFA is also associated with the dysfunction or death of pancreatic beta cells. OBJECTIVES: We aim at proving that Liraglutide improves the survival of INS-1 cells by promoting autophagy. MATERIALS AND METHODS: Cell survival was assessed by CCK8 assay. The percentage of apoptotic cells was determined by flow cytometric assay after Annexin V-FITC/PI staining. Expression of LC3 was detected by western blotting. MDC staining and transmission electron microscopy (TEM) were used in the measurement of autophagy. RESULTS: Apoptosis induced by PA in INS-1 cells was significantly resolved after Liraglutide treatment. Simultaneously, autophagy was enhanced with the treatment of PA and Liraglutide. CONCLUSIONS: Liraglutide appears to protect INS-1 cells from apoptosis FFA-induced by promoting autophagy. CONCLUSIONS: These findings provide a novel role for GLP-1 analogue in preventing or treating with T2D. PMID- 24348593 TI - Leksell Gamma Knife : An Effective Non Invasive Treatment for Rare Case of Nelson's Syndrome. AB - Nelson's syndrome nowadays a rare entity results from an adrenocorticotropin (ACTH)-secreting pituitary adenoma in patients with refractory Cushing's disease after a therapeutic bilateral adrenal gland removal. We report a case of 25 year old female with cushing's disease who was initially managed with medical treatment, but in view of severe persistent hyper cortisol state was subjected to bilateral adrenalectomy following which she developed Nelson's syndrome after a gap of six years, which was difficult to diagnose because of limited investigations available. Patient was managed with stereotactic radiosurgery (gamma knife surgery). PMID- 24348592 TI - Coexistent Papillary Carcinoma of Thyroid and Hashimoto's Thyroiditis - Diagnosis on Fine Needle Aspiration Cytology. AB - Hashimoto's thyroiditis is associated with an increased risk of developing papillary carcinoma of thyroid. We hereby report a case of Hashimoto's thyroiditis with papillary carcinoma in a 45-year-old ear old female diagnosed on fine needle aspiration cytology (FNAC) which was later confirmed on histopathological examination .Such an occurrence, when both lesions are picked up on FNAC in a patient with no palpable thyroid nodule is rare. The case is presented here for its rarity. PMID- 24348595 TI - Demographic factors influencing consensus opinion on the recall for women screened by mobile mammography unit in taiwan. AB - BACKGROUND: The incidence of breast cancer has had a four-fold increase from 1980 to 2005 in Taiwan. Limited data have been available on mobile breast screening in the Taiwanese population since 2009. OBJECTIVES: This study aims at investigating the factors influencing consensus opinion on the recall for mobile breast screening in Taiwan. PATIENTS AND METHODS: The factors were categorized by individual health background, socioeconomic status and knowledge about breast screening. There were 502 questionnaires collected from Taiwanese women examined on mobile mammography screening vehicle. Data were then analyzed by SPSS 12 via analysis of variance (ANOVA), F-test, t-test or chi-square test. RESULTS: Strong participation was associated with a younger age, higher educational level, higher incomes, previous history of cancer, previous family history of cancer, one or two prior mammographies, more correct recognitions of mammography, recall rate, and breast cancer risk. If the false-positive result occurred, 83.9%, 81.9% and 77.3% of the women agreed or strongly agreed to participate in noninvasive and invasive testing and screening mammography, respectively. CONCLUSION: The policy makers should notify the importance of demographic factors affecting further examination for early detection of breast cancer in Taiwan. PMID- 24348594 TI - Comparing ovarian radiation doses in flat-panel and conventional angiography during uterine artery embolization: a randomized clinical trial. AB - BACKGROUND: Uterine artery embolization (UAE) is a minimally invasive procedure performed under fluoroscopy for the treatment of uterine fibroids and accompanied by radiation exposure. OBJECTIVES: To compare ovarian radiation doses during uterine artery embolization (UAE) in patients using conventional digital subtraction angiography (DSA) with those using digital flat-panel technology. PATIENTS AND METHODS: Thirty women who were candidates for UAE were randomly enrolled for one of the two angiographic systems. Ovarian doses were calculated according to in-vitro phantom study results using entrance and exit doses and were compared between the two groups. RESULTS: The mean right entrance dose was 1586+/-1221 mGy in the conventional and 522.3+/-400.1 mGy in the flat panel group (P=0.005). These figures were 1470+/-1170 mGy and 456+/-396 mGy, respectively for the left side (P=0.006). The mean right exit dose was 18.8+/-12.3 for the conventional and 9.4+/-6.4 mGy for the flat panel group (P=0.013). These figures were 16.7+/-11.3 and 10.2+/-7.2 mGy, respectively for the left side (P=0.06). The mean right ovarian dose was 139.9+/-92 in the conventional and 23.6+/-16.2 mGy in the flat panel group (P<0.0001). These figures were 101.7+/-77.6 and 24.6+/-16.9 mGy, respectively for the left side (P=0.002). CONCLUSION: Flat panel system can significantly reduce the ovarian radiation dose during UAE compared with conventional DSA. PMID- 24348596 TI - Interobserver and Intraobserver Agreement of Sonographic BIRADS Lexicon in the Assessment of Breast Masses. AB - BACKGROUND: BI-RADS was first developed in 1993 for mammography and in 2003 it was redesigned for ultrasonography (US). If the observer agreement is high, the method used in the classification of lesion would be reproducible. OBJECTIVES: The aim of this study is to evaluate the inter- and intraobserver agreement of sonographic BI-RADS lexicon in the categorization and feature characterization of nonpalpable breast lesions. PATIENTS AND METHODS: We included 223 patients with 245 nonpalpable breast lesions who underwent ultrasound-guided wire needle localization. Two radiologists retrospectively described each lesion using sonographic BI-RADS descriptors and final assessment. The observers were blinded to mammographic images, medical history and pathologic results. Inter- and intraobserver agreement was assessed using Kappa (kappa) agreement coefficient. RESULTS: The interobserver agreement for sonographic descriptors changed between fair and substantial. The highest agreement was detected for mass orientation (kappa=0.66). The lowest agreement was found in the margin (kappa=0.33). The interobserver agreement for BI-RADS final category was found as fair (kappa=0.35). The intraobserver agreement for sonographic descriptors changed between substantial and almost perfect. The intraobserver agreement of BI-RADS result category was found as substantial for observer 1 (kappa=0.64) and excellent for observer 2 (kappa=0.83). CONCLUSION: Our results demonstrated that each observer was self-consistent in interpreting US BI-RADS classification, while interobserver agreement was relatively poor. Although it has been ten years since the description of sonographic BI-RADS lexicon, further training and periodic performance evaluations would probably help to achieve better agreement among radiologists. PMID- 24348597 TI - Magnetic resonance spectroscopic findings of chronic lesions in two subtypes of multiple sclerosis: primary progressive versus relapsing remitting. AB - BACKGROUND: Multiple sclerosis (MS) is a highly prevalent cause of neurological disability and has different clinical subtypes with potentially different underlying pathologies. Differentiation of primary progressive multiple sclerosis (PPMS) from relapsing remitting multiple sclerosis (RRMS) could be difficult especially in its early phases. OBJECTIVES: We compared brain metabolite concentrations and ratios in patients with PPMS and RRMS by magnetic resonance spectroscopic imaging (MRSI). PATIENTS AND METHODS: Thirty patients with definite MS (15 with RRMS and 15 with PPMS) underwent MRSI and their non-enhancing lesion metabolites were measured. N-acetyl aspartate (NAA), Creatine (Cr), Choline (Cho), NAA/Cr and NAA/Cho were measured and compared between the two MS subtypes. RESULTS: When the two MS groups were compared together, we found that Cr was significantly increased (P value=0.008) and NAA/Cr was significantly decreased (P value=0.03) in non-enhancing lesions in PPMS compared with RRMS. There was no significant difference in NAA, Cho or NAA/Cho between the two MS subtypes. CONCLUSION: MRS is a potential way to differentiate PPMS and RRMS. PMID- 24348598 TI - Endovascular stent placement of juxtaanastomotic stenosis in native arteriovenous fistula after unsuccessful balloon angioplasty. AB - BACKGROUND: In hemodialysis patients, the most common problem in arteriovenous fistulas, as the best functional vascular access, is the juxtaanastomotic located lesions. Percutaneous transluminal angioplasty is accepted as the treatment method for juxtanastomotic lesions. OBJECTIVES: To assess juxtaanastomotic stent placement after insufficient balloon angioplasty in the treatment of autogenous radiocephalic or brachiocephalic fistula dysfunction. PATIENTS AND METHODS: Between July 2003 and June 2010, 20 hemodialysis patients with autogenous radiocephalic or brachiocephalic fistula dysfunction underwent stent placement for the lesion located at the juxtaanastomotic region. Indications for stent placement were insufficient balloon dilatation, early recurring stenosis, chronic organizing thrombus and vessel rupture. The Kaplan-Meier method was used to calculate the stent patency rates. All patients who had fistula dysfunction (thrombosis of hemodialysis access, difficult access cannulation, extremity pain due to thrombosis or decreased arterial access blood flow) were evaluated by color Doppler ultrasound. The stenoses were initially dilated with standard noncompliant balloons (3 to 10-mm in diameter). Dilatation was followed by high pressure (Blue Max, Boston Scientific) or cutting balloons (Boston Scientific), if the standard balloon failed to dilate the stenotic segment. RESULTS: Twenty one stents were applied. The anatomical and clinical success rate was 100%. Seventeen additional interventions were done for 11 (55%) patients due to stent thrombosis or stenosis during follow-up. Our 1- and 2-year secondary patency rates were 76.2% and 65.5%, respectively and were comparable to those after balloon angioplasty and surgical shunt revision. CONCLUSION: Metallic stent placement is a safe and effective procedure for salvage of native hemodialysis fistula after unsuccessful balloon angioplasty. PMID- 24348599 TI - Identification of Nasal Bone Fractures on Conventional Radiography and Facial CT: Comparison of the Diagnostic Accuracy in Different Imaging Modalities and Analysis of Interobserver Reliability. AB - BACKGROUND: There has been no study to compare the diagnostic accuracy of an experienced radiologist with a trainee in nasal bone fracture. OBJECTIVES: To compare the diagnostic accuracy between conventional radiography and computed tomography (CT) for the identification of nasal bone fractures and to evaluate the interobserver reliability between a staff radiologist and a trainee. PATIENTS AND METHODS: A total of 108 patients who underwent conventional radiography and CT after acute nasal trauma were included in this retrospective study. Two readers, a staff radiologist and a second-year resident, independently assessed the results of the imaging studies. RESULTS: Of the 108 patients, the presence of a nasal bone fracture was confirmed in 88 (81.5%) patients. The number of non depressed fractures was higher than the number of depressed fractures. In nine (10.2%) patients, nasal bone fractures were only identified on conventional radiography, including three depressed and six non-depressed fractures. CT was more accurate as compared to conventional radiography for the identification of nasal bone fractures as determined by both readers (P <0.05), all diagnostic indices of an experienced radiologist were similar to or higher than those of a trainee, and kappa statistics showed moderate agreement between the two diagnostic tools for both readers. There was no statistical difference in the assessment of interobserver reliability for both imaging modalities in the identification of nasal bone fractures. CONCLUSION: For the identification of nasal bone fractures, CT was significantly superior to conventional radiography. Although a staff radiologist showed better values in the identification of nasal bone fracture and differentiation between depressed and non-depressed fractures than a trainee, there was no statistically significant difference in the interpretation of conventional radiography and CT between a radiologist and a trainee. PMID- 24348600 TI - Palatine Tonsillar Metastasis of Small-Cell Neuroendocrine Carcinoma from the Lung Detected by FDG-PET/CT After Tonsillectomy: A Case Report. AB - Metastasis from a malignant tumor to the palatine tonsils is rare, accounting for only 0.8% of all tonsillar tumors, with only 100 cases reported in the English language literature. Various malignant lung carcinomas may metastasize to the tonsils. A few cases of tonsillar metastasis from neuroendocrine lung carcinoma have been reported. A 67-year-old female underwent a right tonsillectomy because of a sore throat and an enlarged right tonsil. The postoperative pathology showed right tonsillar small cell neuroendocrine carcinoma (SCNC). Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) demonstrated metabolic activity in the lower lobe of the right lung. In addition, hypermetabolic foci were noted in the lymph nodes of the right neck and mediastinum. A needle biopsy of the pulmonary mass showed SCNC. The patient received chemotherapy and died of multiple distant metastases after 6 months. This is the first report using PET/CT to evaluate tonsillar metastasis from lung SCNC. PMID- 24348601 TI - A rare case of rib osteoblastoma: imaging features and review of literature. AB - Osteoblastoma is a rare benign, but locally aggressive bone tumor with rare malignant transformation. It mostly affects the vertebral column and long bones. Radiographically, it is seen as an expansile, oval, sclerotic or lytic mass-like lesion with well-defined borders, although sometimes it may mimic a malignant tumor such as osteogenic sarcoma by its irregular borders. Herein, we report a case of osteoblastoma in a 22 year-old man with a long history of back and neck pain accompanied with neck stiffness. On the routine chest X-ray, the salient lesion appeared as an expansile, oval, sclerotic mass with well-defined borders and speckled calcification without any internal lucency and periosteal reaction, involving the posterolateral aspect of the first left thoracic rib, a rare anatomical site. Despite the unusual location, osteoblastoma should be considered in the differential diagnosis of a solitary rib lesion. PMID- 24348602 TI - Acute appendicitis presenting as unusual left upper quadrant pain. AB - Appendicitis is the most common abdominal disease that requires surgery in the emergency ward. It usually presents as right lower quadrant pain, but may rarely present as left upper quadrant (LUQ) pain due to congenital anatomical abnormalities of the intestine. We report a patient who complained of persistent LUQ abdominal pain and was finally diagnosed by computed tomography (CT) as congenital intestinal malrotation complicated with acute appendicitis. It is important to include acute appendicitis in the differential diagnosis of patients who complain of LUQ abdominal pain. Abdominal CT can provide significant information that is useful in preoperative diagnosis and determination of proper treatment. PMID- 24348603 TI - Urography and CT Features of Primary Small Cell Carcinoma of the Ureter: A Case Report. AB - Primary small cell carcinoma of the ureter is an extremely rare disease, only several cases have been reported worldwide so far. We report a 70-year-old woman who was examined with intravenous urography and abdominal computed tomography and was diagnosed as small cell carcinoma confirmed by pathology. We describe and discuss the urography and computed tomography findings of this case. PMID- 24348604 TI - Paraspinal and presacral extramedullary hematopoiesis: a rare manifestation of polycythemia vera. AB - Extramedullary hematopoiesis is characterized by the presence of hematopoietic tissue outside the bone marrow. Extrathoracic extramedullary hematopoiesis is a rare and usually asymptomatic condition. We report a case of a 38-year-old female with paraspinal and presacral extramedullary hematopoiesis with polycythemia vera. Clinical and laboratory evaluation, along with radiological and histopathological findings are described. The diagnosis of the disease was confirmed by CT-guided biopsy. Review of literature is presented. PMID- 24348605 TI - A case of neonatal urosepsis with multifocal osteoarthritis: could ultrasonography change the clinical course? AB - An eleven-day boy neonate with a fetal anamnesis of grade 1 bilateral hydronephrosis according to the grading of the Society for Fetal Urology (SFU), came to our attention for an acute osteoarthritis secondary to urosepsis. In the urological follow-up, a severe bilateral vesico-ureteral reflux (VUR) was diagnosed. An early post-natal, reno-vesicle ultrasound evaluation could have changed the clinical course of our patient. PMID- 24348606 TI - Different MRI signs in predicting the treatment efficacy of epidural blood patch in spontaneous intracranial hypotension: a case report. AB - The current mainstay of treatment in spontaneous intracranial hypotension (SIH) is an epidural blood patch (EBP). Although magnetic resonance imaging (MRI) has a well-established role in the diagnosis of SIH, imaging features regarding the treatment efficacy of EBP have rarely been discussed. We therefore sought to investigate and compare the sequential brain MRI studies before and after EBP by evaluating the changes of the following intracranial structures-the contour of the transverse dural sinus (TDS), tension of the pituitary stalk (or the infundibulum), and thickness of the dura mater. We found that the progressive reversals of these structures are predictive of an effective EBP. PMID- 24348607 TI - Well-differentiated intraosseous osteosarcoma in the sacrum: a case report. AB - Hereby we report a case of well-differentiated intraosseous osteosarcoma in the sacrum. A 32-year-old woman was admitted to our hospital with a low echo-level mass in the pelvis searched by ultrasound in a routine physical examination. Radiographically, the mass was misdiagnosed as a benign bony tumor originating from the sacrum. The tumor was completely resected and pathological diagnosis was intraosseous well-differentiated osteosarcoma. Twelve months after operation, the patient was well and there was no evidence of recurrence and distal metastasis. This is a peculiar case of well-differentiated osteosarcoma involving an unusual site of the sacrum. The radiographic appearance and the differential diagnosis are discussed. We consider that dense trabeculated-like bone within an intraosseous solid mass might be suggestive of a well-differentiated osteosarcoma that was valuable in guiding the treatment and prediction of its prognosis. Well differentiated osteosarcoma, although malignant, may be mistaken for a benign condition. Local excision has almost always been associated with recurrence. For this case, the patient had a wide excision and had no recurrence and metastasis. Therefore, it is very important to identify the radiological features and to distinguish this tumor from benign lesions and high-grade osteosarcomas before operation. PMID- 24348608 TI - Assessing the oldness and capacity of radiography and ultrasound equipments in tehran university of medical sciences. AB - BACKGROUND: Maintenance of imaging equipment is a very important part of the management of all medical imaging centers. OBJECTIVES: To assess the oldness and capacity of radiography and ultrasound equipment in Tehran University of Medical Sciences. MATERIALS AND METHODS: The study was performed in 16 hospitals, 4 faculties and three healthcare centers of Tehran University of Medical Sciences. We evaluated all the X-ray equipment (including the simple plain and dental, panorex, mammography, fluoroscopy and C-arm X-Ray devices) and also simple and Doppler ultrasound machines in terms of the type and usage of the device, production year, quantity of utilization, location, brand and current condition. RESULTS: Among fixed X-ray systems, 15 were currently in use, two were junk, two were damaged, and one was not utilized. The mean (SD) of the usage of these was 2151 (2230) cliche/month, and the mean (SD) of the oldness was 16.9 (13.6) years. The oldness of radiography equipment in our study was more than 20 years in 16, between 11 and 20 in 46, and less than 10 years in 76 devices. The mean (SD) usage (patients/month) of simple and color Doppler devices were 234.1 (365.2) and 597.5 (505.3), respectively. The oldness of ultrasonography equipment in our study was more than 11 years in 12 and less than 10 years in 55 devices. We found that 22 (15.9%) of the radiography systems and two (3%) of the ultrasonography systems had been used for more than 20 years. CONCLUSION: Radiology equipment in Tehran University of Medical Sciences have potential capacity, but they need repair, and better maintenance and management and application of standards for the imaging system needs organized supervisory mechanisms. PMID- 24348609 TI - Percutaneous liver biopsies guided with ultrasonography: a case series. AB - BACKGROUND: Although liver biopsy is an easy procedure for hospitalized patients and outpatients, some complications may occur. OBJECTIVES: To evaluate the efficiency, complications, safety and clinicopathological utility of ultrasonographic-guided percutaneous liver biopsy in diffuse liver disease. PATIENTS AND METHODS: In our retrospective study, we evaluated ultrasound assisted needle biopsies that were performed in outpatients from October 2006 to July 2010. The liver biopsies were performed following one-night fasting using the tru-cut biopsy gun (18-20 gauge) after marking the best seen and hypovascular part of the liver, distant enough from the adjacent organs. RESULTS: A total of 1018 patients were referred to our radiology department. Most of the patients had hepatitis B (60.6%). The biopsy specimens were recorded and sent to our pathology department for histopathological examination. CONCLUSION: According to the results of our series, percutaneous liver biopsy using the tru-cut biopsy gun guided by ultrasonography can be performed safely. We resolve that routine ultrasound of the puncture site is a quick, effective and safe procedure. The complication rate is very low. The US-assisted percutaneous liver biopsy should be used for all cases. PMID- 24348610 TI - Association between obstetric conjugate diameter measured by transabdominal ultrasonography during pregnancy and the type of delivery. AB - BACKGROUND: Normal morphological features of the maternal pelvis are an important prerequisite to vaginal delivery. OBJECTIVES: We aimed to evaluate the association between obstetric conjugate diameter (OCD) measured by ultrasonography and the type of delivery, vaginally (V) or by cesarean (C) section. PATIENTS AND METHODS: Pelvimetry was performed in 200 primigravid women for fetal cephalic presentation. The OCD was measured twice by transabdominal ultrasonography during 25-30 weeks and 30-35 weeks of pregnancy. RESULTS: The mean OCD of both sonographies in groups V and C was 125.51+/- 8.35 mm (105-144.5) and 112.99 +/- 8.53 mm (96-134.5), respectively, which was significantly lower in group C (P<0.001). The values of OCD between the first and second measurements were not different significantly (P=0.065). C-section was indicated in 65 (32.5%) mothers. The optimal cut-off point for the OCD in the prediction of vaginal delivery was >= 119.75 mm, with a sensitivity and specificity of 80% and 78.5%, respectively. CONCLUSION: The US measurement of OCD might be an accurate method that almost always remains constant during late pregnancy; it is easy to measure and might be confidentially employed for predicting C-section, but needs more precise studies to be used widely. PMID- 24348611 TI - Sella turcica-Its importance in orthodontics and craniofacial morphology. AB - The sella turcica is a structure which can be readily seen on lateral cephalometric radiographs and sella point is routinely traced for various cephalometric analyses. The search was carried out using the following key words (sella turcica, bridging of sella, size, shape of sella turcica) and with the following search engine (Pubmed, Cochrane, Google scholar). The morphology is very important for the cephalometric position of the reference point sella, not only for evaluating craniofacial morphology, but also when growth changes and orthodontic treatment results are to be evaluated. This makes it a good source of additional diagnostic information related to pathology of the pituitary gland, or to various syndromes that affect the craniofacial region. Clinicians should be familiar with the normal radiographic anatomy and morphologic variability of this area, in order to recognize and investigate deviations that may reflect pathological situations, even before these become clinically apparent. During embryological development, the sella turcica area is the key point for the migration of the neural crest cells to the frontonasal and maxillary developmental fields. The neural crest cells are involved in the formation and development of sella turcica and teeth. The size of sella turcica ranges from 4 to 12 mm for the vertical and 5 to 16 mm for the anteroposterior dimension. There are many classification systems regarding the shape of sella turcica. Majority of the studies show that about 67% of the subjects had normal appearance and about 33% showed variations. The prevalence of sella turcica bridging is high in class III malocclusions and dental anomalies. PMID- 24348612 TI - Biochemical markers in oral submucous fibrosis: A review and update. AB - Oral submucous fibrosis (OSMF) is a potentially malignant oral condition effectively linked to the causative habit of chewing areca nut. Since its first description in the 1950s, numerous epidemiological, biochemical, histological, and genetic studies have been reported. While most studies point out to the cause and effect of areca nut, co-additive factors are also implicated in the progression and malignant transformation of this condition. Biochemical investigations have concentrated on outlining such changes in the blood, serum or tissues of these patients and have given insights on the possible pathogenesis of OSMF. This article attempts to compile details of biochemical investigations in OSMF and summarize and infer on the findings. PMID- 24348614 TI - Clinico-pathological study of odontomas in 19 Libyan patients. AB - BACKGROUND: Odontomas are among the most common benign odontogenic tumors, which are mostly discovered in the first and second decades of life with no clear sex predilection. MATERIALS AND METHODS: The present retrospective study reviews the clinical, radiological, and the histopathological characteristics of odontomas in 19 Libyan patients seen during the last 18 years in our department. RESULTS: Most odontomas in our study were discovered when they obstruct a tooth from an eruption at its normal eruption time although a few cases were noticed on routine radiological examination of the region. Panoramic radiographs computed Tomography Scan of the area and the histopathological examination are helpful to elicit the diagnosis. Two cases in this series were found associating with dentigerous cyst and in another two cases the odontomas were seen erupting intraorally. CONCLUSION: Odontomas should be considered in the differential diagnosis of the mixed radioopaque radiolucent lesions, especially if they found obstructing the teeth from eruption. PMID- 24348613 TI - Dental abscess: A microbiological review. AB - Dental abscess is a frequently occurring infectious process known to the health practice. The fate of the infection depends on the virulence of the bacteria, host resistance factors, and regional anatomy. Serious consequences arising from the spread of a dental abscess lead to significant morbidity and mortality. Acute dental abscess is polymicrobial, comprising of strict anaerobes, such as anaerobic cocci, Prevotella, Fusobacterium species, and facultative anaerobes, such as viridans group streptococci and the Streptococcus anginosus group. Numerous novel, uncultivable and fastidious organisms have been identified as potential pathogens with the use of non-culture techniques. The majority of localized dental abscesses respond to surgical treatment while the use of antimicrobials is limited to severe spreading infections. There is a need for good-quality clinical trials of sufficient size to identify the ideal treatment. The microbiology of the acute dentoalveolar abscess and its treatment in the light of improved culture and diagnostic methods are reviewed. PMID- 24348615 TI - The effect of re-bonding using surface sealant or adhesive system on microleakage of class V resin composite restorations. AB - BACKGROUND: Microleakage is still one of the defects of resin composites that can lead to treatment failure; and re-bonding technique is one of the effective ways to reduce it. This study evaluated the effect of re-bonding with a surface sealant or a dentin adhesive on microleakage in class V microhybrid, nanohybrid, and packable composite restorations. MATERIALS AND METHODS: In this in vitro study, class V cavities with occlusal margins in enamel and cervical margins in dentin/cementum were prepared on the buccal and lingual surfaces of 54 extracted premolars. The prepared teeth were randomly assigned to three groups (3 group's Chi 18 teeth each), with each group being restored with microhybrid (Point 4); nanohybrid (Herculite XRV Ultra), and packable (Packable Premise) resin composite. Following finishing and polishing procedures, each group was randomly subdivided in to three subgroups (n = 12). The margins of two groups were both etched and re-bonded with surface sealant (Optiguard) or dentin adhesive (Opti Bond Solo Plus) and control group received no treatment. Specimens were thermocycled 1500 cycles, immersed in a methylene blue, sectioned, evaluated for microleakage using a stereomicroscope at a x 20 and scored on a scale of 0-3. Data were analyzed with Kruskal - Wallis, Mann - Whitney, and Wilcoxon tests (alpha = 0.05). RESULTS: There were no significant differences among the three resin composites tested, and also no significant differences among subgroups with the same surface treatment. Only the microhybrid and packable composite restorations sealed with Optiguard had significantly lower microleakage compared to the control subgroups at the occlusal margin. There were no significant differences between occlusal and cervical margins regarding the microleakage scores when compared to the control subgroups of microhybrid and packable composite restorations. CONCLUSION: The re-bonding technique could be considered as an advisable procedure in order to minimize microleakage and its effect might be material-dependent. PMID- 24348616 TI - Lateral ridge split and immediate implant placement in moderately resorbed alveolar ridges: How much is the added width? AB - BACKGROUND: Lateral ridge split technique is a way to solve the problem of the width in narrow ridges with adequate height. Simultaneous insertion of dental implants will considerably reduce the edentulism time. MATERIALS AND METHODS: Twenty-five patients who were managed with ridge splitting technique were enrolled. Thirty-eight locations in both jaws with near equal distribution in quadrants received 82 dental fixtures. Beta Tricalcium phosphate (Cerasorb((r)) ) was used as biomaterial to fill the intercortical space. Submerged implants were used and 3 months later healing caps were placed. Direct bone measurements before and after split were done with a Collis. Patients were clinically re-evaluated at least 6 months after implant loading. All the data were analyzed by Statistical Package for Social Sciences (SPSS) software version 11.5 (SPSS Inc, Chicago Illinois, USA). Frequency of edentulous spaces and pre/post operative bone width was analyzed. Paired t-test was used for statistical analysis. Difference was considered significant if P value was less than 0.05. RESULTS: Mean value for presplit width was 3.2 +/- 0.34 mm while post-split mean width was 5.57 +/- 0.49 mm. Mean gain in crest ridge after ridge splitting was 2 +/- 0.3 mm. Statistical analysis showed significant differences in width before and after operation ((P > 0.05). All implants (n = 82) survived and were in full function at follow up (at least 6 months after implant loading). CONCLUSION: Ridge splitting technique in both jaws showed the predictable outcomes, if appropriate cases selected and special attention paid to details; then the waiting time between surgery and beginning of prosthodontic treatment can be reduced to 3 month. PMID- 24348617 TI - The comparison of salivary level of estrogen and progesterone in 1(st) , 2(nd) and 3(rd) trimester in pregnant women with and without geographic tongue. AB - BACKGROUND: Geographic tongue (GT) was first reported as a wandering rash of the tongue in 1831; however, its etiopathogenesis remains unclear. Increased prevalence of GT has been documented in the pregnancy. The aim of this study was to compare the level of salivary estrogen and progesterone in pregnant women with and without GT. MATERIALS AND METHODS: This analytical-descriptive study consisted of 26 pregnant women (13 with GT, 13 without GT) with an age range between 18 years and 45 years. The estrogen and progesterone level was measured during 1(st) , 2(nd) and 3(rd) trimester of pregnancy. Saliva sampling was performed to determine the level of sex hormones. The samples were stored at -80 degrees C and determined by Eliza method. The results were analyzed by t-test and repeated measure ANOVA (alpha = 0.05). RESULTS: The mean level of estrogen for control and case group was 49.4and 52.33 in the 1(st) , 71.05 and 74.12 in the 2(nd) and 109.1 and 112.16 in the 3(rd) trimester respectively. The mean level of progesterone was 0.72 and 0.72 in the 1(st) , 1.14 and 1.21 in the 2(nd) and 1.3 and 1.28 in the 3(rd) trimester of pregnancy for the control and case groups respectively. Even though, there was no significant difference regarding the level of sex hormones between case and control groups (P < 0.05), but the difference between the level of these hormones during 3 trimesters of pregnancy was significant in each group (P = 0.001). CONCLUSION: The level of sex hormones is not the only etiologic factor of GT in pregnant women, but other factors such as genetic potential, human leukocyte antigen marker and stress may aggravate the incidence of this lesion. PMID- 24348618 TI - Gingivitis and periodontitis as a risk factor for stroke: A case-control study in the Iranian population. AB - BACKGROUND: Periodontitis and gingivitis are one of the most infectious diseases in human. Several studies have been carried out on dependence of periodontitis and stroke. The aim of this study was to investigate the gingivitis and periodontitis as a risk factor for stroke in Iranian population. MATERIALS AND METHODS: A case-control study was conducted on 100 patients suffering from stroke as case group, and 100 hospitalized patients as control group. The case group included 42 males and 58 females, and in control group there were 44 males and 56 females. Using a University of North Carolina-15 manual probe, the clinical attachment level, the distance between the cemento-enamel junction and the probed base of the periodontal pocket, were recorded by gingival and periodontal indexes. The data were analyzed by multiple logistic regressions, Chi-square test, Fisher's test, t-test, Man Whitney, and SPSS11.5 software program. P > 0.05 was considered as significant. RESULTS: The case group included 42 males and 58 females, and in control group 44 males and 56 females were included. In this investigation, the average of gingival index in men and women of case group was 1.22 +/- 0.55 and 1.31 +/- 0.55, respectively. This study showed that the average of gingival index in case group was more than control group. Periodontal index in both groups in men was more than women. The moderate and severe periodontitis in case group were more than that of control group (P = 0.003, P = 0.001). CONCLUSION: The result of this study shows that there is a significant relation between stroke and periodontal index; however, there isn't any significant relation between stroke and gingival index. PMID- 24348619 TI - Comparison of the efficacy of two anesthetic techniques of mandibular primary first molar: A randomized clinical trial. AB - BACKGROUND: The most common technique to anesthetize mandibular primary teeth is inferior alveolar (I.A) nerve block injection which induces a relatively sustained anesthesia and in turn may potentially traumatize soft-tissues. Therefore, the need of having an alternative technique of anesthesia with a shorter term but the same efficacy is reasonable. The aim of this study was a comparison of the efficacy of two anesthetic techniques of mandibular primary first molar. MATERIALS AND METHODS: In this randomized crossover clinical trial, 40 children with ages ranged from 5 years to 8 years whose mandibular primary first molars were eligible for pulpotomy, were selected and divided randomly into two groups. The right and left mandibular first molars of group A were anesthetized with infiltration and I. A nerve block techniques in the first and second sessions respectively. The left and right mandibular first molars of group B were anesthetized with I.A nerve block and infiltration techniques in the first and second sessions respectively. The severity of pain were measured and recorded according to sound-eye-motor scale by a certain person. Data was analyzed using Wilcoxon Signed Rank and Mann-Whitney U tests (P > 0.05). RESULTS: The severity of pain was lower in infiltration technique versus I.A nerve block. There were no significant differences between the severities of pain on pulpal exposure of two techniques. CONCLUSION: It seems that infiltration technique is more favorable to anesthetize the mandibular primary first molar compared to I.A nerve block. PMID- 24348620 TI - The effect of adjunctive low-dose doxycycline and licorice therapy on gingival crevicular fluid matrix metalloproteinase-8 levels in chronic periodontitis. AB - BACKGROUND: This study compared the effect of adjunctive low dose doxycycline and licorice on gingival crevicular fluid (GCF) matrix metalloproteinase-8 (MMP-8) levels in patients with chronic periodontitis. MATERIALS AND METHODS: In this in vivo, experimental study 39 patients with mild to moderate chronic periodontitis were selected. Samples of GCF were collected from three deepest pockets and MMP-8 concentration was measured. Patients were divided into three groups (n = 13). Groups were treated with doxycycline, licorice and placebo. Sampling and measurement of MMP-8 was repeated after 6 weeks. Data was analyzed by t-paired and ANOVA test. P > 0.001 was considered significant. RESULTS: The decrease in mean of MMP-8 concentration was higher in doxycycline and licorice group in comparison with the placebo group and the difference was statistically significant (P value > 0.001). The decrease in mean of MMP-8 concentration was higher in licorice group than doxycycline group, but the difference was not statistically significant. CONCLUSION: The present study showed that licorice extract can prevent the production of MMPs by host cells and can be as useful as antibiotics like doxycycline to cure periodontal and other inflammatory diseases. It must be added that no side-effects were observed in usage of licorice extract. PMID- 24348621 TI - The effect of ovalbumin on orthodontic induced root resorption. AB - BACKGROUND: This randomized trial was undertaken to investigate the effect of experimentally induced allergy on orthodontic induced root resorption. MATERIALS AND METHODS: A total of 30 Wistar rats were divided randomly into test and control groups. Starting from the first 3 days, the rats in the test group were injected intra-peritoneally by 2 mg ovalbumin as allergen and 0.5 mg Alume as adjuvant. Afterward only allergen was injected once a week. The control group was injected by normal saline. After 21 days, Wistar immunoglobulin E was measured and peripheral matured eosinophil was counted. A total of 50 g nickel-titanium closed coil spring was ligated between right incisor and first molar. All animals were sacrificed after 14 days. The mesial root of the right and left first molar was dissected in a horizontal plane. The specimens were divided into four groups considering whether force and/or ovalbumin was applied or not. Root resorption was measured and compared among these groups. Repeated measures analysis of variance (ANOVA), and Bonferoni tests were used to analyze the data. The level of significance was determined at 0.05. RESULTS: In general, the differences were insignificant (P < 0.05). As the only exception, the group in which both ovalbumin and force were applied had significantly more root resorption than the group in which neither force nor ovalbumin was applied (P > 0.001). CONCLUSION: Allergy may increase the susceptibility to root resorption. Application of light force, periodical monitoring of root resorption and control of allergy are advisable. PMID- 24348622 TI - Evaluation of orthodontic treatment need by patient-based methods compared with normative method. AB - BACKGROUND: A comprehensive system of assessing orthodontic need requires the integration of normative clinical measures with patient-based indicators. This study sought to discover weather an oral health-related quality of life measure or Aesthetic Component of Index of Orthodontic Treatment Need (AC-IOTN) could be used as a predictor of orthodontic treatment need. Factors affecting the judgment of patient and dentist about this need are discussed. MATERIALS AND METHODS: Oral examination on 597 Iranian students between 13 years and 18 years was done to reach the grade of Dental Health Component (DHC). The Child Oral Health Impact Profile (COHIP) and AC-IOTN were recorded. The diagnostic values of subjective tests were assessed. Multiple logistic regressions were applied to investigate the role of variables in the persons' perceptions. RESULTS: Half of the 570 eligible students did not need orthodontic treatment either on professional or self-assessment; 60% of patients with definite need had a distinct impact on their quality of life. The specificity of AC to detect the healthy persons was excellent (0.99) but its sensitivity was low (0.08). COHIP score gave a better sensitivity but its specificity was 50%. Caries experience, quality of life, father's education, and brushing habits were the factors relating to the same judgment of persons and dentists (P > 0.02). CONCLUSION: Regarding the discrepancies between two assessment methods, present instruments did not meet the predictor's competencies. The patient-based methods could not substitute the professional assessment, but by identification, the persons with higher impacts would benefit the prioritization process. PMID- 24348623 TI - Microleakage assessment of fissure sealant following fissurotomy bur or pumice prophylaxis use before etching. AB - BACKGROUND: A prolonged life of fissure sealant has always been the target for preventing caries in vulnerable newly erupted teeth. The use of preparatory techniques including bur introduction to the fissures is considered among such improving steps. MATERIALS AND METHODS: Ninety freshly extracted healthy maxillary premolar teeth were randomly selected for this investigation. Teeth were then divided into three fissure sealant preparatory groups of A: Fissurotomy bur + acid etch; B: Pumice prophylaxis + acid etch and C: Acid etch alone. Sealant was applied to the occlusal fissures of all specimens using a plastic instrument. This was to avoid any air trap under the sealant. Sample teeth were first thermocycled (1000 cycles, 20 s dwell time) and then coated with two layers of nail varnish leaving 2 mm around the sealant. This was then followed by immersion in basic fuchsin 3%. Processed teeth were sectioned longitudinally and examined under a stereomicroscope for microleakage assessment using a score of 0 3. Collected data was then subjected to Kruskall-Wallis Analysis of Variance and Mann-Whitney U-test. P > 0.05 was considered as significant. RESULTS: Teeth in fissurotomy bur and pumice prophylaxis groups had significantly reduced level of microleakage than those in acid etch alone (P = 0.005 and P = 0.003, respectively). CONCLUSION: Use of fissurotomy bur and pumice prophylaxis accompanied with acid etching appears to have a more successful reduction of microleakage than acid etch alone. PMID- 24348624 TI - Effect of low-level laser therapy on dental pain induced by separator force in orthodontic treatment. AB - BACKGROUND: Patients undergoing orthodontic treatment experience varying degrees of pain with separator insertion. A survey of patients' attitude towards orthodontic treatment revealed that pain was the most discouraging factor related to their treatment. Moreover, it was the highest ranking reason for wanting to discontinue care. The purpose of this study was to determine the effect of low level laser irradiation on dental pain induced by forces from separators in orthodontic treatment. MATERIALS AND METHODS: This study was an experimental clinical trial. Twenty-nine patients were recruited for this research. Low-level laser irradiation was applied on one half of the maxillary and mandibular arches for 5 days. The opposite half of the arches was considered the control group. Laser irradiation was applied for 30 seconds in the alveolar bone between the second premolars, first molars, and second molars. Pain perception was evaluated with a standardized questionnaire that was answered by patients before and after laser irradiation. Data was analyzed by Wilcoxon and Friedman test. P value <=0.05 was considered significant. RESULTS: The highest pain level was reported at day 1 following separator placement and decreased gradually until day 5. At day 4 and 5, the pain intensity was lower in the laser group than in the control group; however, this finding was not statistically significant. At day 1 and 3, the pain intensity was higher in the laser group than in the control group; however, it was not statistically significant. At day 2, the pain intensity was lower in the laser group than in the control group and was statistically significant. CONCLUSION: Our findings suggest that there is no statistically significant difference in pain by using low-level laser irradiation. PMID- 24348625 TI - In vivo biocompatibility of Resilon compared with gutta-percha in a pre-clinical model. AB - BACKGROUND: The aim of this study was to investigate in vivo biocompatibility of Resilon, compared with gutta-percha, at short and long-term following implantation in a rat subcutaneous implantation model. MATERIALS AND METHODS: Male Wistar rats were implanted subcutaneously with either Resilon or gutta percha or were sham controls. Tissues were harvested at 8 days or 60 days after implantation and were evaluated histologically for inflammation and fibrous encapsulation. The severity of histologic injury, scored on a scale of 0-4 and quantitative analysis of the capsule wall thickness were determined for statistical analysis. Data were analyzed by Student t-test, one-way analysis of variance, Kruskal-Wallis or Mann-Whitney's tests as appropriate. A value of P <= 0.05 was considered statistically significant. RESULTS: No behavioral changes or visible signs of physical impairment were observed at 8 days or 60 days post implantation. Histopathologic observation of the implanted sites at each time point showed that both Resilon and gutta-percha implants induced foreign body reaction, showing minimal to mild inflammatory reactions in most cases, which diminished significantly with time. Compared with gutta-percha, the capsule wall was thinner (P < 0.05) after Resilon implantation at day 8 and significantly (P = 0.01) thicker at day 60. In addition, capsule wall thickness showed a trend to increase with time after implantation in the Resilon groups (P < 0.05), opposed to the significant decrease (P = 0.016) observed after implantation in the gutta percha groups, suggesting lesser long-term biocompatibility of Resilon. CONCLUSION: Our findings validate Resilon as an in vivo biocompatible material. However, our data suggest that long-term biocompatibility of Resilon, despite validated, is inferior to that of gutta-percha control. PMID- 24348626 TI - Infant oral health: Knowledge, attitude and practices of parents in Udaipur, India. AB - BACKGROUND: The aim of this study was to assess the infant oral health (IOH) related knowledge, attitudes and practices (KAP) of parents in Udaipur, India. MATERIALS AND METHODS: A cross-sectional descriptive study was conducted among 470 parents visiting the Department of Pediatrics, Rabindranath Tagore Medical College and Hospital. A 32-item questionnaire covering socio-demographic characteristics and questions pertaining to KAP regarding IOH care was used to collect the data. Descriptive statistics, Student's t-test, one-way analysis of variance, and Scheffe's test were used for the statistical analysis (P <= 0.05). RESULTS: Majority of the parents had good knowledge regarding tooth eruption, but had a poor knowledge of cleaning (58.7%) and development of caries (48.5%). Parents in the age group of 25-30 years showed significantly higher mean knowledge (25.90 +/- 3.93), attitude (15.71 +/- 2.23), and practice (20.09 +/- 2.50) scores. Female parents showed a significantly higher mean knowledge (21.45 +/- 4.27) and attitude scores (14.97 +/- 2.15) than the male parents. CONCLUSION: Parent's knowledge on IOH care was inadequate. Health professionals, who are the first to come into contact with expectant and new mothers, need to disseminate appropriate and accurate information about oral health-care for infants. PMID- 24348627 TI - Clinical and radiological assessment of effects of long-term corticosteroid therapy on oral health. AB - BACKGROUND: Corticosteroids (Cs) are used widely for their anti-inflammatory and immunosuppressive properties. They have the potential to cause dramatic improvement as well as produce equally dramatic adverse effects. The clinical misuse like over prescription of the drug should be avoided. Long-term administration may cause many adverse effects leading to impaired oral health. Oral health is usually not considered during management of patients on long-term corticosteroid therapy. The aim of this study was to assess the oral health status and radiological changes in the jaw bones of the patients under long-term corticosteroid therapy. MATERIALS AND METHODS: Oral health of 100 patients under long-term corticosteroid therapy with a minimum of 3 months duration was compared with sex- and age-matched 100 healthy controls. The clinical examination included complete examination of the mouth and periodontal status. Radiographic evaluation of bone with the help of intra oral periapical radiograph and digital orthopantomograph and levels of serum calcium, alkaline phosphatase, and random blood sugar were assessed. 'Chi-square test', 'Kolmogorov-Smirnov test' and 'Mann Whitney U test' were used for statistical analysis. P > 0.05 was considered significant. RESULTS: Patients on steroids exhibited significantly higher levels of candidiasis and clinical attachment loss of the periodontal ligament, probing pocket depth. Bone density was significantly lower in the study group than that in the control group. Random blood glucose was significantly higher and significant lower levels of calcium were observed in patients on steroids. CONCLUSION: Long-term use of Cs may affect oral health adversely leading to candidiasis as well as impair bone metabolism leading to a considerable decrease in the mandibular bone mineral density. PMID- 24348628 TI - An unusual triad: Bilateral dilated odontoma, hypodontia and peg laterals. AB - The dilated odontoma is an infrequent developmental alteration that appears in any area of the dental arches and can affect deciduous, permanent and supernumerary tooth. Dens invaginatus is a developmental anomaly resulting from invagination of a portion of crown forming within the enamel organ during odontogenesis. The most extreme form of dens invaginatus is known as dilated odontoma. The aim of this case report is to present a rare case of bilateral dilated odontoma affecting a microdontic permanent lateral incisor in a 30 year old female patient with hypodontia and peglateral teeth with its clinical, radiological and histological features, which has yet been not reported. Bilateral presence of dilated odontoma is not a common occurrence, although a single tooth involvement in each case has been reported in the literature. PMID- 24348630 TI - Mucinous cystadenoma: A rare entity. AB - Cystadenoma is a rare benign salivary gland tumor that chiefly originates in the minor salivary glands as a cystic growth with papillary projections into the cystic lumen without the lymphoid element. It is further classified into two histopathological variants that have been recognized by World Health Organization as the papillary and the mucinous forms of cystadenoma. Clinically, it is difficult to differentiate from other benign minor salivary tumors and mucous retention phenomenon. Diagnosis is chiefly based on characteristics histological features. It is believed that the salivary gland tumors are difficult to diagnose and interpret because there are varied patterns of presentation. The study of salivary gland disorders has increased in leaps and bounds. The authors report a case of mucinous cystadenoma of the minor salivary gland on the hard palate, which is even rarest of the rarely reported cystadenomas of the minor salivary glands. PMID- 24348629 TI - Rapid, conservative, multidisciplinary miniscrew-assisted approach for treatment of mandibular fractures following plane crash. AB - Mandibular fractures are among the most common facial injuries. This case report demonstrates the efficacy of simultaneous usage of miniscrews and direct bonding techniques without open reduction in an extensive traumatized patient. A 25-year old girl with multiple injuries in the head and facial region 1 month after a plane crash accident was referred to manage the mandibular fractures. Due to the presence of multiple injuries, a conservative treatment of symphysiseal fracture was performed. In order to keep the fractured fragments of the mandible close together, the anterior teeth of the lower arch were tied by means of the orthodontic wire. Ten miniscrews were used to improve the anchorage units and also, settling the occlusion by means of light intermaxillary elastics. Following the active treatment, clinical and radiographic analysis showed satisfactory healing without any periodontal involvement of the teeth in the fracture line. PMID- 24348631 TI - Treatment strategy for guided tissue regeneration in various class II furcation defect: Case series. AB - Periodontal regeneration is a main aspect in the treatment of teeth affected by periodontitis. Periodontal regeneration in furcation areas is quite challenging, especially when it is in interproximal region. There are several techniques used alone or in combination considered to achieve periodontal regeneration, including the bone grafts or substitutes, guided tissue regeneration (GTR), root surface modification, and biological mediators. Many factors may account for variability in response to regenerative therapy in class II furcation. This case series describes the management of class II furcation defect in a mesial interproximal region of a maxillary tooth and other with a buccal class II furcation of mandibular tooth, with the help of surgical intervention including the GTR membrane and bone graft materials. This combined treatment resulted in healthy periodontium with a radiographic evidence of alveolar bone gain in both cases. This case series demonstrates that proper diagnosis, followed by removal of etiological factors and utilizing the combined treatment modalities will restore health and function of the tooth with the severe attachment loss. PMID- 24348632 TI - A procedure for recording and reproducing the cast position on a surveyor. PMID- 24348633 TI - Normal limit for serum alanine aminotransferase level and distribution of metabolic factors in old population of kalaleh, iran. AB - BACKGROUNDS: Normal or elevated values of serum alanine aminotransferase level (ALT) vary in different studies mostly related to characteristics of reference population including age, gender, body mass index, nonalcoholic fatty liver disease (NAFLD), and metabolic syndrome prevalence. OBJECTIVES: To measure upper normal limit (UNL) for serum ALT in an apparently healthy Iranian old population (which we had not sufficient data before this study), and its modulating factors. PATIENTS AND METHODS: All inhabitants (> 50 years old) of Kalaleh, Golestan, Iran (N = 1986) were invited to the study. ALT measurements were performed for all subjects using the same laboratory method. Upper limit of normal (ULN) ALT was calculated based on its 95th percentile in normal weight subjects. Modulating factors of ALT were determined by multivariate analysis. RESULTS: A total of 1309 subjects, with the mean age of 61.5 +/- 7.5 years were included. UNL of ALT was 18.8 U/L and 21.4 U/L in women and men, respectively. Based on univariate analysis, waist circumference (r = 0.124, P = 0.01), body mass index (r = 0.118, P = 0.01), triglyceride (r = 0.143, P = 0.01), and having metabolic syndrome (OR = 2.04) modulate ALT levels in men. Also triglyceride (r = 0.119, P = 0.01) modulates ALT levels in women. CONCLUSIONS: The calculated level for UNL of ALT is considerably far lower than previous accepted value. Age, gender, ethnicity, and metabolic factors should be accounted in future studies to determine normal ALT level. PMID- 24348634 TI - Evaluation of PCR-RFLP in the Pre-S Region as Molecular Method for Hepatitis B Virus Genotyping. AB - BACKGROUND: Hepatitis B virus (HBV) infection is a public health problem in developing countries. HBV genotypes play major role in the evolution of infection since they were involved in different clinical presentations and response to treatment. OBJECTIVES: This study was conducted to evaluate the efficiency of restriction fragment length polymorphism (RFLP) analysis for HBV genotyping. PATIENTS AND METHODS: We investigated 98 samples collected from patients chronically infected with HBV. HBV genotypes were determined by analysis of patterns obtained after amplification in Pre-S region and digestion of the amplicon by two endonucleases AvaII and DpnII. Obtained results were confirmed by partial sequencing in the same region. RESULTS: Two different HBV genotypes were detected in this study, Genotype D (in 95. 9%) and Genotype A (in 4.1%). Seventy four samples (75.5%) were successfully genotyped with RFLP analysis and all classified as genotype D. The remaining 24 samples (24.5%) which were un genotyped by RFLP analysis, were classified by partial sequencing of the pre-S region as HBV genotype D (20 samples, 20.4%) and genotype A (4 samples, 4.1%). Atypical profiles were significantly associated with advanced liver disease (P = 0.001) as well as older age (P < 0.05). CONCLUSIONS: Several previous studies used PCR-RFLP to genotype HBV; however, we showed the high risk to obtain atypical profiles, especially in advanced stages of chronic infection, with as results difficulties to genotype the virus. These profiles resulted from the accumulation of mutations during natural course of infection resulting in a modification in restriction sites for enzymes. So, we recommended completing the investigation by partial sequencing to confirm obtained results. PMID- 24348635 TI - Baseline high viral load and unfavorable patterns of alanine aminotransferase change predict virological relapse in patients with chronic hepatitis C genotype 1 or 2 obtaining rapid virological response during antiviral therapy. AB - BACKGROUND: Rapid virological response (RVR) strongly predicts sustained virological response (SVR) in patients with chronic hepatitis C (CHC), and abbreviates antiviral therapy in some patients. OBJECTIVES: To identify factors predicting virological relapse (VR) in CHC patients who attained RVR. PATIENTS AND METHODS: Medical records of 133 CHC patients with an RVR after completing 24 weeks of antiviral therapy (a combination of pegylated interferon-alpha and ribavirin) were analyzed. Baseline characteristics and on-treatment responses were compared between the patients with an SVR and those with VR. Patients with normal alanine aminotransferase (ALT) levels at weeks 4 and 12 and at the end-of treatment (EoT) and patients with elevated, but constantly decreasing, ALT levels were classified as having favorable patterns of ALT change. A trend of increasing ALT levels either between weeks 4 and 12 or between weeks 12 and EoT was classified as unfavorable. A high viral load (HVL) was defined as a baseline HCV RNA >= 600000 IU/mL. RESULTS: In total, 116 (87.2%) patients had a SVR and 14 (10.5%) had VR. The VR rates were comparable between patients with genotype-1 (13.1%) and genotype-2 infection (8.7%) (P = 0.572). Multivariate analysis revealed that HVL (P = 0.015; odds ratio [OR] = 14.754; 95% confidence interval (CI) = 1.671-130.240), and unfavorable ALT patterns (P = 0.039; OR = 4.397; 95% CI = 1.078-17.930) independently predicted VR. In subgroup analysis, low viral load (LVL) patients had a minimal VR rate (1.8%). Among the HVL patients, the VR rate of those using peg-IFN-alpha-2a was relatively low (9.1%). Patients using peg-IFN-alpha-2b had a slightly higher VR rate (23.8%; P = 0.128), and patients with favorable patterns of ALT changes had a lower VR rate (10.3%) compared to the 53.8% in patients with unfavorable ALT patterns (P = 0.005). CONCLUSIONS: In southern Taiwan, 24 weeks of antiviral therapy achieved a high SVR rate in patients with CHC attaining RVR, except in the subgroup of patients treated with peg-IFN-alpha-2b with HVL and on-treatment unfavorable ALT patterns. PMID- 24348637 TI - Substitution rtq267h of hepatitis B virus increases the weight of replication and Lamivudine resistance. AB - BACKGROUND: Nucleus(t)ide analogs (NAs), containing Lamivudine (LMV), adefovir dipivoxil (ADV), endeavor (ETV), telbivudine (LdT), and tenofovir (TDF) are widely used for the treatment of chronic hepatitis B (CHB), but long term anti Hepatitis B virus (HBV) therapy with NAs may give rise to the emergence of drug resistant viral mutants. OBJECTIVES: This study aimed to find and identify some new resistance mutations of HBV from the patients accepted anti-HBV therapy. PATIENTS AND METHODS: The reverse transcriptase (RT) coding region of HBV was PCR amplified using HBV DNA extracted from patients' blood samples and sequenced. RESULTS: Nineteen substitution mutations were detected. Among them, rtQ267H was often observed in patients receiving LMV administration. This LMV therapy-related mutation was introduced into HBV replication-competent plasmids. The in vitro susceptibility of both wild-type (WT) and mutant-type (MT) HBV to NAs was analyzed by Southern blot, and/or quantitative real-time PCR (qRT-PCR). The rtQ267H substitution enhanced HBV replication not merely in single-site mutation, but also in multisite mutations. The in vitro susceptibility analysis showed that the existence of rtQ267H in WT and LMV-resistant (LMVr) HBV were responsible for the reduced susceptibility to LMV to varying degrees, and enhanced HBV replication capacity. However, HBV harbored this substitution retained normal susceptibility to ADV, LdT, ETV, and TDF. CONCLUSIONS: The result suggested that rtQ267H is a potential adaptive mutation of HBV to LMV. PMID- 24348636 TI - The role of celiac disease in severity of liver disorders and effect of a gluten free diet on diseases improvement. AB - CONTEXT: Celiac disease (CD) is defined as a permanent intolerance to ingested gluten. The intolerance to gluten results in immune-mediated damage of small intestine mucosa manifested by villous atrophy and crypt hyperplasia. These abnormalities resolve with initiationa gluten-free diet. EVIDENCE ACQUISITION: PubMed, Ovid, and Google were searched for full text articles published between 1963 and 2012. The associated keywords were used, and papers described particularly the impact of celiac disease on severity of liver disorder were identified. RESULTS: Recently evidence has emerged revealingthat celiac disease not only is associated with small intestine abnormalities and malabsorption, but is also a multisystem disorder affecting other systems outside gastrointestinal tract, including musculo-skeletal, cardiovascular and nervous systems. Some correlations have been assumed between celiac and liver diseases. In particular, celiac disease is associated with changes in liver biochemistry and linked to alter the prognosis of other disorders. This review will concentrate on the effect of celiac disease and gluten-free diets on the severity of liver disorders. CONCLUSIONS: Although GFD effect on the progression of CD associated liver diseases is not well defined, it seems that GFD improves liver function tests in patients with a hypertransaminasemia. PMID- 24348638 TI - Serum iron markers in patients with chronic hepatitis C infection. AB - BACKGROUND: Patients with chronic hepatitis C (CHC) often have elevated serum iron markers, which may worsen liver injury. OBJECTIVES: The aim of this study was to investigate the possible correlations between iron metabolism serum markers, HCV viral load, and liver disease severity in treatment-naive patients with chronic hepatitis C infection. PATIENTS AND METHODS: Eighty five patients with untreated hepatitis C chronic infection were investigated. RESULTS: Twenty one patients (24.7%) had elevated serum iron levels, and 29 subjects (34.1%) had severe liver fibrosis. Significantly elevated levels of serum iron (P < 0.05) and ferritin (P < 0.001), associated with lower levels of TIBC (P < 0.05) were detected in patients with severe fibrosis compared to no/mild fibrosis. Severe necroinflammatory activity was also significantly correlated with serum iron (P < 0.001), TIBC (P < 0.05), and ferritin levels (P < 0.001). Using multiple linear regression analysis, serum levels of ferritin and transferrin were the independent variables selected as being good predictors for advanced fibrosis and severe necroinflammatory activity. No significant correlations were detected between HCV viral load and iron markers. CONCLUSIONS: This study revealed that serum iron markers (especially ferritin and transferrin) might be used as surrogate markers for both liver fibrosis and necroinflammatory activity.Patients with chronic hepatitis C (CHC) often have elevated serum iron markers, which may worsen liver injury. PMID- 24348639 TI - Hepatitis B: knowledge, vaccine situation and seroconversion of dentistry students of a public university. AB - BACKGROUND: Viral hepatitis B (VHB) is an occupational risk for dentists. It is necessary that dental students start clinical practice immunized with the vaccine, response monitored and informed about the means of transmission of the disease. Rarely, there are studies, which evaluate concomitantly knowledge of these academics and their vaccine situation. OBJECTIVES: To evaluate the knowledge about Hepatitis B, the vaccine situation and the immunization status of dental students and to investigate the probable correlation between the status of immunization, vaccination membership and adherence to the test of seroconversion and associated factors. PATIENTS AND METHODS: 189 students from the dentistry course at the Federal University of Piaui (UFPI) who attended from the 3rd to 9th period were invited to participate in the research. Their knowledge about HBV, attitude regarding protection and their vaccine situation were assessed through a self-administered form. Antibodies against surface antigens of Hepatitis B virus (Anti-HBs) and against the antigens of the virus nucleous of Hepatitis B (Anti HBc total) were measured qualitatively using the enzyme-linked immunosorbent assay (ELISA). RESULTS: Of the 179 students surveyed, 58.1% knew about the degree of virulence of the Hepatitis B virus (HBV). As to the means of transmission, 98.3% considered blood transmission, 82.6% plates and cutlery, 15.6% cough and 12.3% vertical transmission. Most students (87.4%) knew that they should take 3 doses of the vaccine and 62.2% completed the immunization schedule. A minority of students (48.6%) knew the about the Anti-HBs test and 5.6% took the test. Among the students who reported having taken three doses of the vaccine, 12.5% were not seroconverted. There was no significant correlation between the variables. CONCLUSIONS: Dental academics were unsure about the means of infection and prevention against HBV. Many of them had not completed the immunization scheme and did not have the test of seroconversion. The serological analysis revealed unprotection, even after students completed the vaccination schedule. PMID- 24348640 TI - The Relationship between Intestinal Motility and Interstitial Cells of Cajal in Nonalcoholic Fatty Liver Mice. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in western world. However, NAFLD shows an increasing trend in China every year, which has attracted the attention of national health authorities. The previous studies have shown that NAFLD caused severe gastrointestinal motor disorders, but little is known about the interstitial cells of Cajal (ICC) role in gastrointestinal motor disorders. OBJECTIVES: The aim of this study was to observe the ICC in jejunum of nonalcoholic fatty liver mice by immunohistochemistry and assessed the relationship between intestinal motility and ICC. MATERIALS AND METHODS: Thirty five Sprague-Dawley (SD) rats were randomly divided into nonalcoholic fatty liver (n = 25) and control groups (n = 10), rats were housed individually in cages and had free access to food and water, nonalcoholic fatty liver group was duplicated by high-fat diet (consisted of ordinary food, 20 g/kg cholesterol and 100 g/kg fat) feeding. Dextran blue 2000 was used to monitor the intestinal motility. The proximal small intestine was harvested to investigate the C-kit positive ICC. The hepatic tissue slices were used for pathological observation. RESULTS: Nonalcoholic fatty liver disease was successfully established. The intestinal motility in nonalcoholic fatty liver group (49.5 +/- 10.9) was weaker compared to the control group (57.3 +/- 8.9), P < 0.05. The rate of ICC also have shown statistically significant differences between nonalcoholic fatty liver (4.87 +/- 2.97/mm (2)) and control groups (6.54 +/- 3.13/mm (2)), P < 0.05. CONCLUSIONS: ICC may be related to the intestinal motility in nonalcoholic fatty liver mice. PMID- 24348642 TI - Liver Transplantation for Quality as well as Quantity of Life. PMID- 24348641 TI - Immunization of Mice by BCG Formulated HCV Core Protein Elicited Higher Th1 Oriented Responses Compared to Pluronic-F127 Copolymer. AB - BACKGROUND: A supreme vaccine for Hepatitis C virus (HCV) infection should elicit strong Th1-oriented cellular responses. In the absence of a Th1-specific adjuvant, immunizations by protein antigens generally induce Th2-type and weak cellular responses. OBJECTIVES: To evaluate the adjuvant effect of BCG in comparison with nonionic copolymer-Pluronic F127 (F127) as a classic adjuvant in the formulation of HCV core protein (HCVcp) as a candidate vaccine for induction of Th1 immune responses. MATERIALS AND METHODS: Expression of N-terminally His Tagged HCVcp (1-122) by pIVEX2.4a-core vector harboring the corresponding gene under the control of arabinose-inducible (araBAD) promoter was achieved in BL21 AI strain of E.coli and purified through application of nitrilotriacetic acid (Ni NTA) chromatography. Mice were immunized subcutaneously (s.c.) in base of the tail with 100 MUl of immunogen (F127+HCVcp or BCG+HCVcp; 5 MUgHCVcp/mouse/dose) or control formulations (PBS, BCG, F127) at weeks 0, 3, 6. Total and subtypes of IgG, as well as cellular immune responses (Proliferation, In vivo CTL and IFN gamma/IL-4 ELISpot assays against a strong and dominant H2-d restricted, CD8+ epitopic peptide, core 39-48; RRGPRLGVRA of HCVcp) were compared in each group of immunized animals. RESULTS: Expression and purification of core protein around the expected size (21 kDa) was confirmed by Western blotting. The HCVcp + BCG vaccinated mice showed significantly higher lymphocyte proliferation and IFN gamma production but lower levels of cell lysis (45% versus 62% in CTL assay) than the HCVcp+F127 immunized animals. "Besides, total anti-core IgG and IgG1 levels were significantly higher in HCVcp + F127 immunized mice as compared to HCVcp + BCG vaccinated animals, indicating relatively higher efficacy of F127 for the stimulation of humoral and Th2-oriented immune responses". CONCLUSIONS: Results showed that HCVcp + BCG induced a moderate CTL and mixed Th1/Th2 immune responses with higher levels of cell proliferation and IFN-gamma secretion, indicating that BCG may have a better outcome when formulated in HCVcp-based subunit vaccines. PMID- 24348643 TI - Liver transplant recipients quality of life instrument: development and psychometric testing. AB - BACKGROUND: Liver transplantation is a life-saving intervention for many patients with end-stage liver disease. In the past, evaluation of successful liver transplantation was based on patients' survival rate. However, in recent years this evaluation has been based on patients' quality of life. Various instruments have been developed to evaluate patients' quality of life. Nonetheless, scholars still believe that it is crucial to develop a standardized and disease specific instrument for evaluating the quality of life in liver transplant recipients. OBJECTIVES: The aim of this paper was to describe the development and psychometric testing process of a quality of life instrument specific to liver transplant recipients. MATERIALS AND METHODS: Initial items of this instrument were extracted from a conventional content analysis study, and then were completed with findings of related international literature. The face validity was assessed by interviewing with four liver transplant recipients, and the content validity was evaluated by eleven experts in the field of transplantation. The construct validity was achieved by involving 250 liver transplant recipients through exploratory factor analysis method, and reliability was calculated by Cronbach's alpha. RESULTS: Three main factors with 40 items were extracted from the exploratory factor analysis: Health Satisfaction, Concerns, and Complications. Reliability of the instrument was confirmed (alpha = 0.922). CONCLUSIONS: Given the special considerations regarding liver transplant recipients, this questionnaire is more accurate in evaluating the success of liver transplantation. PMID- 24348644 TI - Seroprevalence of hepatitis e among pregnant women in urmia, iran. AB - BACKGROUND: While hepatitis E virus (HEV) mostly causes self-limited disease in general population, it is more severe in pregnant women. OBJECTIVES: This study aimed to investigate the seroprevalence of anti-HEV IgG among a population of pregnant women in West Azerbaijan of Iran . PATIENTS AND METHODS: One hundred thirty six pregnant women referred to urban health centers of Urmia for pursuing pregnancy-related health services were enrolled in a descriptive, cross-sectional study. Anti-HEV IgG antibody was evaluated using enzyme-linked immunosorbent assay (enzyme-linked immunosorbent assay, ELISA; Dia.Pro; Diagnostic Bioprobes). RESULTS: Only five (3.6%) of 136 cases had positive results for anti-HEV IgG. There was no significant difference between age (P=0.88), and income level (P = 0.19) of the two seropositive and seronegative groups. All seropositive cases were from urban areas. CONCLUSIONS: The seroprevalence of anti-HEV IgG is low in the population of pregnant women in , similar to the rates reported from developed countries. Effective health services and provision of safe water supplies in Urmia may take role in this low prevalence rate. PMID- 24348645 TI - Impact of Pegylated Interferon-alfa-2a on Perforin Level in Patients With Chronic Hepatitis B; Preliminary Study. AB - BACKGROUND: Chronic hepatitis B is one of the most common causes of cirrhosis and hepatocellular toxicity in many countries, including Iran. Cytotoxic T lymphocyte (CTL) and Natural killer (NK) cells are the two of main cell populations considered as cytotoxic cells. One of the distinct pathways CTL and NK cells exert cytotoxicity is perforin/granzyme. After the cytotoxic cell/target cell junction, perforin is released from granules by exocytosis. Once it is anchored, perforin forms cylindrical pores through which granzymes and granulysin enter and induce apoptosis. OBJECTIVES: Large controlled trials have demonstrated the efficacy of PEG-IFN-alpha-2a in treatment of chronic hepatitis B. This study was aimed to examine whether the enhancement of cytotoxicity by PEG-IFN-alpha-2a is mainly due to the perforin pathway. PATIENTS AND METHODS: This research work was performed on 50 patients and five healthy people. Patients with chronic hepatitis B were further subdivided into two groups: patients with inactive chronic hepatitis B (carriers, n = 30), and those with active chronic hepatitis B who were under treatment with PEG-IFN-alfa-2a (n = 20) for minimum six and maximum 12 months. Serum perforin level was measured using ELISA method (CUSABIO Company), HBV viral load was assessed using COBAS Taq-man, and we used Elecsys hepatitis B surface antigen (HBs Ag) II quantitative assay method for HBs Ag determination. HBeAg was evaluated by ELISA method, and AST and ALT were measured by routine laboratorymethods. RESULTS: Based on the results obtained serum perforin level in healthy group was 0.64 ng/mL, the mean of serum perforin level in inactive HBs Ag carriers was 2.63ng/mL, and 4.63 ng/mL in patients with active chronic hepatitis B under treatment with PEG-IFN-alpha-2a. The mean of serum perforin level in patients with and without virologic response to treatment were 5.45 ng/mL,and 3.4 ng/mL respectively. Finally in patients with virologic response and seroconverted serum perforin level was 7.23 ng/mL. CONCLUSIONS: Based on our results higher perforin level in patients under treatment with PEG-IFN-alpha-2a, could be an indication of elevated cytotoxicity via perforin/granzyme pathway. PMID- 24348646 TI - Cholestasis and seizure due to lead toxicity: a case report. AB - INTRODUCTION: Lead poisoning is a major public health risk which may involve major organs. Recently, there have been reports of opioid adulteration with lead in Iran. The following case report is the first of its kind in that intrahepatic cholestasis due to lead toxicity has been described. CASE PRESENTATION: A 65-year old man presented to the emergency department with abdominal pain, abnormal liver function tests (cholestatic pattern), and normocytic anemia. He had been an opium user for 20 years. Clinical and preclinical findings including the bluish discoloration of periodontal tissues, or Burton's sign, and generalized ileus on abdominal x-ray led us to the possibility of lead poisoning. Lead levels were higher than normal (150 MUg/dL). Magnetic resonance cholangiopancreatography (MRCP) and abdominal ultrasound were performed to rule out extra hepatic causes of cholestasis. To evaluate the possibility of lead-induced hepatotoxicity, a liver biopsy was performed. Histological features of lead-induced hepatotoxity have rarely been described in humans. In this patient, focal canalicular cholestasis and mild portal inflammation were confirmed. Thus, treatment with ethylenediaminetetraacetic acid (EDTA) and British anti-lewisite (BAL) were initiated and continued for five days. The patient's liver function tests returned to their normal values, clinical findings including nausea, vomiting, and abdominal pain subsided, and the patient was discharged from the hospital in good condition. CONCLUSIONS: Lead toxicity should always be taken into account in cases of intrahepatic cholestasis with an unknown etiology, especially in a setting where opium abuse is common. PMID- 24348647 TI - Sexual Transmission of Hepatitis C Virus Between HIV Infected Subjects and Their Main Heterosexual Partners. AB - BACKGROUND: Overall, 60-70% of the hepatitis c virus (HCV) transmission routes is parenteral, and in 30-40% of the cases is unknown (e.g. sexual route). Knowing these routes in HIV infected dyads is very important due to clinical and methodological reasons. OBJECTIVES: The present study aimed to identify and quantitatively investigate HIV-infected individuals and their main heterosexual partners regarding the risk factors of HCV transmission. PATIENTS AND METHODS: One hundred sixty eight of 984 couples were chosen through random generated numbers using a computer program from behavioral consultation center in Shiraz, Iran. We used actor partner independent model (APIM) and multilevel analysis to assess multiple risk factors for HCV, while partitioning the source of risk at the individual and couple levels. RESULTS: Age of the index samples was 38.71 +/- 7 years, and 33.2 +/- 6.3 for their main heterosexual partners; the mean duration of sexual relationship for couples was 11.9 (median = 8.5) years. Multivariate analysis showed that actor risk factor of intravenous drug using (IDU) (AOR= 13.03; 95% CI: 3.9- 43.82) and actor cofactors of HIV positivity (AOR = 7.1; 95% CI: 1.37- 36.97), razor sharing (AOR = 4.81; 95% CI: 1.84- 12.55), sex (AOR = 8.83; 95% CI: 3.16- 24.87), and condom use in sexual activity with main partner (AOR = 0.15; 95% CI: 0.02- 0.44) were associated with actor HCV positivity. CONCLUSIONS: Health care providers need to pay special attention to sexual transmission of HCV among HIV-infected individuals, and should recommend control/preventive measures for HCV sexual transmission. PMID- 24348648 TI - Association of IL28B Polymorphisms With the Response to Peginterferon Plus Ribavirin Combined Therapy in Polish Patients Infected With HCV Genotype 1 and 4. AB - BACKGROUND: Three single nucleotide polymorphisms (SNPs) near interleukin-28B (IL 28B) gene were shown to be highly associated with treatment response (SVR) in patients with chronic hepatitis C virus (HCV) infection. There is limited data about the role of single and combined IL-28B polymorphisms in HCV-infected Polish population. OBJECTIVES: This study's aim was to determine predictability of three IL-28B gene polymorphisms and other known prognostic factors on the treatment response in HCV genotype 1 and 4 infected Polish patients. The effect of IL-28B polymorphisms on therapy was also compared with other known prognostic factors. PATIENTS AND METHODS: We genotyped IL-28B polymorphisms (rs12979860, rs12980275 and rs8099917) by polymerase chain reaction-based restriction fragment length polymorphism assay in a group of 293 patients from which a selected cohort of 174 treatment-naiev patients underwent treatment. RESULTS: We showed that rs12979860 CC [odds ratio (OR) = 4.6, P < 0.001], rs12980275 AA (OR = 2.9, P = 0.002) and rs8099917 TT (OR = 2.2, P = 0.016) genotypes were associated with successful treatment compared to the rs12979860 CT-TT, rs12980275 AG-GG and rs8099917 TG-GG, respectively. Patients bearing of IL-28B profile including the three favourable genotypes do not have much chance of a recovery (OR = 3.4, P = 0.002). Except for IL-28B polymorphisms, there was no association of SVR with any other pretreatment clinical data in analyzed group. The correlation of SNPs with other host and viral factors revealed association of favorable genotypes of IL-28B markers with high levels of alanine aminotransferase and baseline HCV viral load. CONCLUSIONS: IL-28B polymorphisms were the strongest pretreatment predictors of response to pegylated interferon and ribavirin in Polish patients chronically infected with HCV genotype 1 and 4. This study confirm the strongest impact of IL-28B rs12979860 on SVR, nevertheless rs12980275 AA seems to be more important than rs8099917 TT in predicting positive treatment response. PMID- 24348649 TI - A Better Quality of Life in Hemodialysis Patients With Viral Hepatitis: Is it a Reality? PMID- 24348650 TI - An Evaluation of Dentin's Effect on the Antifungal Activity of MTA Cements. AB - INTRODUCTION: The aim of this study was to evaluate the effect of dentin on the antifungal activity of gray and white-colored MTA (GMTA, WMTA) using a tube dilution test. MATERIALS AND METHODS: MTA preparations were tested freshly mixed and after 24h on Candida Albicans (CA). The experiment was performed in 24-well culture plates. Fifty wells were used and divided into four experimental groups (freshly-mixed WMTA, freshly-mixed WMTA plus dentin powder, freshly-mixed GMTA, and freshly-mixed GMTA plus dentin powder) of 10 wells each and control groups of five wells each. Plates of Sabouraud dextrose agar mixed with CA served as positive control and Sabouraud dextrose agar without CA served as negative control. Fresh inoculate of CA was prepared by growing an overnight culture from a stock culture. Aliquots of CA were then taken from the stock culture and plated on the agar compound of the experimental and positive control group. All plates were incubated at 37 degrees C for1h, 24h, and 72h. Growth of fungi was monitored daily by the presence of turbidity. Kruskal-Wallis test was used for statistical analysis. RESULTS: Results showed the inhibitory effect of dentin powder on the antifungal effect of MTA cements during 24h and 72h incubation periods, whereas, there was no significant difference between 1h incubation groups. CONCLUSION: The antifungal effect of freshly mixed MTA cements was decreased in the presence of dentin. PMID- 24348651 TI - SEM Study of Root Canal Walls Cleanliness after Ni-Ti Rotary and Hand Instrumentation. AB - INTRODUCTION: To compare the cleaning effectiveness of K3 and Race NiTi rotary systems with K-Flexo file instruments during the preparation of curved canals in extracted human teeth. MATERIALS AND METHODS: A total of 50 root canals of mandibular and maxillary molars with curvatures ranging between 25o and 35 o were divided in three groups of 15 each and 5 as negative control groups. Canals were prepared using a low torque control motor in two rotary groups according to manufacturer's instructions. Conventional Step back with S.S K files was the preparation technique in third group. The amount of debris and smear layer was quantified on the basis of a numerical evaluation scale. The data were statistically analyzed using Chi-Square and Likelihood Ratio tests. RESULTS: In general, no significant difference in terms of amount of debris were found among three groups, only in apical zones of Race and K-Flexo file groups a significant difference was detected (P=0.041). Race rotary system left significantly less smear layer than k-Flexo file in the middle (P=0.009) and apical thirds (P=0.012), respectively. K3 significantly achieved higher scores of cleanliness than K-Flexo file in apical third only (P=0.049). No significant difference between Race and K3 rotary groups for residual debris and formed smear layer was detected. CONCLUSION: Obtaining higher scores of cleanliness in various regions of the canals, crown down technique and the use of rotary instrumentation seem to be superior to conventional hand instrumentation with step back technique .No significant difference between K3 with three radial lands and Race with three cutting edges in terms of debris and smear layer formation was detected. PMID- 24348652 TI - An in-vitro evaluation of sealing ability of real seal using fluid filtration. AB - INTRODUCTION: The aim of this study was to compare the sealing ability of Real Seal (RS) and Gutta-percha (GP). MATERIALS AND METHODS: Forty nine extracted human maxillary central incisors were used. The coronal part of each tooth was removed, the root canal was prepared using the crown down technique and apical enlargement to rotary file # 40. The specimens were randomly divided in to 3 groups of 15 each and two control groups of 2 each. Group 1, was obturated with RS and group 2 and 3 were obturated with GP and AH26 sealer by lateral condensation technique. In group 1 and 3 the smear layer was removed by 5mL of 5.25% NaOCl and 3mL of 17% EDTA. Leakage of the obturated roots was measured using the fluid filtration technique. This method was done at 2 min intervals for 8 min. data were analyzed using ANOVA and Tukey tests. RESULTS: Statistical analysis indicated significant differences between groups 2 with 1 and 3. The most leakage value was observed in the group 2. CONCLUSION: Root canal filling with RS or GP in combination with smear layer removal showed better sealing. Therefore the smear layer has more effect one apical leakage than the obturation system. PMID- 24348653 TI - Pattern of Antibiotic Prescription among Dentists in Iran. AB - INTRODUCTION: This study examines the antibiotic prescription in dentists participated in 9(th) Congress of Iranian Association of Endodontists in Esfahan/2006. MATERIALS AND METHODS: A questionnaire for this cross sectional study was designed for evaluating the patterns of antibiotic prescription. It included some demographic information, clinical signs, and conditions in need for antibiotic and prophylactic prescription and their choices. Data was analyzed using Pearson's Chi-square test. RESULTS: High percentage of responders prescribe antibiotic for fever (78.2%) and diffuse swelling (85.1%). However, some situations such as acute pulpitis, chronic periapical lesions and marginal gingivitis were irrationally prescribed. CONCLUSION: This study showed a fairly good pattern of antibiotic prescription but it was far from ideal. PMID- 24348654 TI - Presence of Candida Albicans in Root Canal System of Teeth Requiring Endodontic Retreatment with and without Periapical Lesions. AB - INTRODUCTION: An important consideration in endodontic treatment is the elimination of microorganisms, including fungi, from the complex three- dimensional root canal system. Candida Albicans (CA) has a major role in endodontic treatment failure as the most important fungus isolated from the root canal system. The present study was carried out to evaluate the presence of CA in the teeth requiring endodontic retreatment, with or without periapical lesions. MATERIALS AND METHODS: This study was carried out on 60 root canals from human molars requiring endodontic retreatment. The root canals were randomly divided into two equal groups of 30 canals with versus without periapical lesions. Samples were collected from the root canals and cultured on MacConkey and blood agar culture media. The samples suspected of having CA were streaked on Sabouraud's Dextrose Agar (SDA) and evaluated under a light microscope. Data was analyzed and compared using Chi- square and Kappa tests. RESULTS: CA was found in 11 patients (36.7%) with periapical lesions. In the patients without periapical lesions only 4 samples demonstrated CA in the root canal systems (13.3%). The difference between the two groups as to the presence of CA was statistically significant (p<0.037). In addition, evaluation of salivary samples revealed 15 cases (50%) of CA presence in the patients with periapical lesions and 16 cases (53.3%) of CA in the patients without periapical lesions, demonstrating no statistically significant difference between the two groups. CONCLUSION: Considering the fact that the presence of CA in the root canal systems of teeth with periapical lesions was more noticeable and statistically significant compared to the teeth without periapical lesions, the elimination of this microorganism from the root canal system, using appropriate intracanal solutions and medications is of utmost importance. PMID- 24348655 TI - Analysis of anxiety scale and related elements in endodontic patients. AB - INTRODUCTION: Anxiety of patients is one of the problems in dentistry which are considered in recent years, and it prevents them from having a treatment out of stress. This study was conducted to specify anxiety prevalence and related elements among endodontic patients. MATERIALS AND METHODS: The study was conducted on 150 patients referred to Endodontic department of dental school of Islamic Azad University, using a cross sectional descriptive method in 2006. Using background characteristics, the patients were classified as a matter of age, sex, education and related factors such as previous dental visit, unfavorable experience in dental office, and the most prevalent cause of referring to dentist. In this regard, Dental Fear Survey (DFS), questionnaire was used and patients were divided in three groups of anxiety level. The results were analyzed using Chi-square and Fisher exact tests. RESULTS: The findings showed highest anxiety scales among dental office referents were statistically significant for age group of 20-30, women, and under diploma education (P<0.05). CONCLUSION: Improving the knowledge about causes of anxiety and its preventive methods are suggested to dentists. They should also provide treatments without annoyance and trauma. PMID- 24348656 TI - Maturogenesis of a complicated crown fracture: a case report with 8 years follow up. AB - This report describes a case of a 7 years old girl who suffered from complicated crown fracture of right mandibular central incisor because of a bicycle accident. For the tooth partial pulpotomy with calcium hydroxide, capping was performed in order to achieve apexogenesis and the tooth was restored with a double-seal of glass ionomer cement and composite resin. The patient was reviewed over 8 years. The tooth showed continued root development and complete apex formation. PMID- 24348657 TI - The promotion of mental health and the prevention of mental health problems in child and adolescent. AB - Improving mental health and reducing the burden of mental illness are complementary strategies which, along with the treatment and rehabilitation of people with mental disorders, significantly improve population health and well being. A Institute of Medicine report describes a range of interventions for mental disorders that included treatment and maintenance, reserving the term "prevention" for efforts that occur before onset of a diagnosable disorder. Mental health problems affect 10-20% of children and adolescents worldwide. Despite their relevance as a leading cause of health-related disability and their long lasting consequences, the mental health needs of children and adolescents are neglected. Early intervention can help reduce the significant impacts that children and adolescents with serious mental health problems may experience. Screening is the first step in early intervention, recognizing emotional and behavioral problems and providing help at an early stage. It is essential to implement early intervention in a sensitive and ethical manner to avoid any of the negative outcomes. PMID- 24348659 TI - Ureaplasma urealyticum or Ureaplasma parvum: what's the difference? PMID- 24348658 TI - Prevalence of rotavirus genotypes in South Korea in 1989-2009: implications for a nationwide rotavirus vaccine program. AB - The epidemiology of human group A rotavirus was analyzed by examining genotypic data acquired from 1989 to 2009 in South Korea. This information was derived from all the available published articles on rotavirus studies in South Korea, retrieved from both the PubMed and KoreaMed databases. Four common G types (G1, G2, G3, and G4) and three common P types (P[8], P[4], and P[6]) accounted for approximately 93% and 99% of the rotavirus reports, respectively. The G9 type was frequently detected after 2000, and because of this prevalence, it is considered to be the fifth most important G type rotavirus after the G1.G4 genotypes. Less common G types of the virus such as G12, G11, and G10 were detected in some geographic settings, and it is important to consider the context of these subtypes and their epidemiological significance. The P[9] virus genotype was observed in the study and has been discussed in many other studies; however, the P[3], P[10] and P[25] genotypes were rarely detected in the epidemiological research. In general, the distributions of the G and P genotypes showed temporal and geographical fluctuations, and a nationwide rotavirus vaccine program that targeted these genotypes demonstrated effectiveness in protecting against the circulating rotavirus strains. However, further analysis is needed to determine the true long-term effectiveness of these vaccines; the analysis should also consider the unexpected effects of vaccinations, such as vaccine-induced diseases, herd immunity, and changes in host susceptibilities. PMID- 24348660 TI - Serological investigation of Ureaplasma urealyticum in Korean preterm infants. AB - PURPOSE: Ureaplasma colonization is related with perinatal complications in preterm infants. Little is known about the difference in virulence among various Ureaplasma urealyticum serovars. The aim of this study was to determine U. urealyticum serovars of preterm infants in order to assess whether any of the serovars were associated with bronchopulmonary dysplasia (BPD). METHODS: Three hundred forty-four preterm infants with a gestational age less than 34 weeks admitted to Gangnam Severance Hospital neonatal intensive care unit from July 2011 to December 2012 were included in this study. Tracheal and gastric aspirations were conducted on infants to confirm Ureaplasma colonization. Ureaplasma colonization was confirmed in 9% of infants, of these, serovars were determined by real-time polymerase chain reaction. RESULTS: A total of 31 infants (gestational age, 29.3+/-3.1 weeks; birth weight, 1,170+/-790 g) were U. urealyticum positive. The Ureaplasma positive group treated for more days with oxygen and ventilation than the negative group (P<0.05). Histologic chorioamnionitis and moderate to severe BPD were more frequent in the Ureaplasma positive group than in the negative group (P<0.05). U. urealyticum isolates were either found to be a mixture of multiple serovars (32%), serovar 9 alone or combined with other serovars (39%), serovar 11 (26%), 2 (13%), 8 (10%), 10 (13%), and 13 (25%). No individual serovars were significantly associated with moderate to severe BPD and chorioamnionitis. CONCLUSION: This is the first study to describe the distribution of U. urealyticum serovars from Korean preterm infants. Ureaplasma-colonized infants showed higher incidence of BPD and chorioamnionitis. PMID- 24348661 TI - The effect of rhinovirus on airway inflammation in a murine asthma model. AB - PURPOSE: The aim of the present study was to investigate the differences in lower airway inflammatory immune responses, including cellular responses and responses in terms of inflammatory mediators in bronchoalveolar lavage fluid (BALF) and the airway, to rhinovirus (RV) infection on asthma exacerbation by comparing a control and a murine asthma model, with or without RV infection. METHODS: BALB/c mice were intraperitoneally injected with a crude extract of Dermatophagoides farinae (Df) or phosphate buffered saline (PBS) and were subsequently intranasally treated with a crude extract of Df or PBS. Airway responsiveness and cell infiltration, differential cell counts in BALF, and cytokine and chemokine concentrations in BALF were measured 24 hours after intranasal RV1B infection. RESULTS: RV infection increased the enhanced pause (Penh) in both the Df sensitized and challenged mice (Df mice) and PBS-treated mice (PBS mice) (P<0.05). Airway eosinophil infiltration increased in Df mice after RV infection (P<0.05). The levels of interleukin (IL) 13, tumor necrosis factor alpha, and regulated on activation, normal T cells expressed and secreted (RANTES) increased in response to RV infection in Df mice, but not in PBS mice (P<0.05). The level of IL-10 significantly decreased following RV infection in Df mice (P<0.05). CONCLUSION: Our findings suggest that the augmented induction of proinflammatory cytokines, Th2 cytokines, and chemokines that mediate an eosinophil response and the decreased induction of regulatory cytokines after RV infection may be important manifestations leading to airway inflammation with eosinophil infiltration and changes in airway responsiveness in the asthma model. PMID- 24348662 TI - Evaluation of risk for graft-versus-host disease in children who receive less than the full doses of mini-dose methotrexate for graft-versus-host disease prophylaxis in allogeneic hematopoietic stem cell transplantation. AB - PURPOSE: The use of cyclosporine and mini-dose methotrexate (MTX) is a common strategy for graft-versus-host disease (GVHD) prophylaxis in allogeneic transplants. We investigated whether patients who receive fewer than the planned MTX doses are at increased risk for GVHD. METHODS: The study cohort included 103 patients who received allogeneic transplants at the Department of Pediatrics of The Catholic University of Korea College of Medicine, from January 2010 to December 2011. MTX was administered on days 1, 3, 6, and 11 after transplant at a dose of 5 mg/m(2) each. Within the cohort, 76 patients (74%) received all 4 doses of MTX [MTX(4) group], while 27 patients (26%) received 0-3 doses [MTX(0-3) group]. RESULTS: Although there was no difference in neutrophil engraftment between the 2 groups, platelet engraftment was significantly faster in the MTX(4) group (median, 15 days), compared to the MTX(0-3) group (median, 25 days; P=0.034). The incidence of grades II-IV acute GVHD was not different between the MTX(4) and MTX(0-3) groups (P=0.417). In the multivariate study, human leukocyte antigen mismatch was the most significant factor causing grades II-IV acute GVHD (P=0.002), followed by female donor to male recipient transplant (P=0.034). No difference was found between the MTX(4) and MTX (0-3) groups regarding grades III IV acute GVHD, chronic GVHD, and disease-free survival. CONCLUSION: Our results indicate that deviations from the full dose schedule of MTX for GVHD prophylaxis do not lead to increased incidence of either acute or chronic GVHD. PMID- 24348663 TI - Liver abscess due to Klebsiella pneumoniae in a healthy 12-year-old boy. AB - Pyogenic liver abscess (PLA) is rare in healthy children. We report a case of PLA in an immunocompetent 12-year-old boy. Percutaneous catheter drainage was performed for the abscess. In addition, parenteral antibiotics were administered for 3 weeks. Klebsiella pneumoniae was detected in the culture of blood and drained fluid. Here, we present this case and a brief review of the literature on this subject. PMID- 24348664 TI - Stroke after percutaneous transhepatic variceal obliteration of esophageal varix in Caroli syndrome. AB - Here we present the case of an 11-year-old female patient diagnosed with Caroli syndrome, who had refractory esophageal varices. The patient had a history of recurrent bleeding from esophageal varices, which was treated with endoscopic variceal ligation thrice over a period of 2 years. However, the bleeding was not controlled. When the patient finally visited the Emergency Department, the hemoglobin level was 4.4 g/dL. Transhepatic intrajugular portosystemic shunt was unsuccessful. Subsequently, the patient underwent percutaneous transhepatic variceal obliteration. Twenty hours after this procedure, the patient complained of aphasia, dizziness, headache, and general weakness. Six hours later, the patient became drowsy and unresponsive to painful stimuli. Lipiodol particles used to embolize the coronary and posterior gastric veins might have passed into the systemic arterial circulation, and they were found to be lodged in the brain, kidney, lung, and stomach. There was no abnormality of the portal vein on portal venography, and blood flow to the azygos vein through the paravertebral and hemiazygos systems was found to drain to the systemic circulation on coronary venography. Contrast echocardiography showed no pulmonary arteriovenous fistula. Symptoms improved with conservative management, and the esophageal varices were found to have improved on esophagogastroduodenoscopy. PMID- 24348665 TI - Biopsy and mutation detection strategies in non-small cell lung cancer. AB - The emergence of new therapeutic agents for non-small cell lung cancer (NSCLC) implies that histologic subtyping and molecular predictive testing are now essential for therapeutic decisions. Histologic subtype predicts the efficacy and toxicity of some treatment agents, as do genetic alterations, which can be important predictive factors in treatment selection. Molecular markers, such as epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement, are the best predictors of response to specific tyrosine kinase inhibitor treatment agents. As the majority of patients with NSCLC present with unresectable disease, it is therefore crucial to optimize the use of tissue samples for diagnostic and predictive examinations, particularly for small biopsy and cytology specimens. Therefore, each institution needs to develop a diagnostic approach requiring close communication between the pulmonologist, radiologist, pathologist, and oncologist in order to preserve sufficient biopsy materials for molecular analysis as well as to ensure rapid diagnosis. Currently, personalized medicine in NSCLC is based on the histologic subtype and molecular status. This review summarizes strategies for tissue acquisition, histologic subtyping and molecular analysis for predictive testing in NSCLC. PMID- 24348666 TI - Molecular basis of drug resistance: epidermal growth factor receptor tyrosine kinase inhibitors and anaplastic lymphoma kinase inhibitors. AB - Over the past decade, several kinase inhibitors have been approved based on their clinical benefit in cancer patients. Unfortunately, in many cases, patients develop resistance to these agents via secondary mutations and alternative mechanisms. To date, several major mechanisms of acquired resistance, such as secondary mutation of the epidermal growth factor receptor (EGFR) gene, amplification of the MET gene and overexpression of hepatocyte growth factor, have been reported. This review describes the recent findings on the mechanisms of primary and acquired resistance to EGFR tyrosine kinase inhibitors and acquired resistance to anaplastic lymphoma kinase inhibitors, primarily focusing on non-small cell lung carcinoma. PMID- 24348667 TI - Increasing Recovery of Nontuberculous Mycobacteria from Respiratory Specimens over a 10-Year Period in a Tertiary Referral Hospital in South Korea. AB - BACKGROUND: The number of patients with pulmonary disease caused by nontuberculous mycobacteria (NTM) has been increasing worldwide. The aim of this study was to evaluate long-term trends in the NTM recovery rate from respiratory specimens over a 10-year period in a tertiary referral hospital in South Korea. METHODS: We retrospectively reviewed the records of mycobacterial cultures of respiratory specimens at Samsung Medical Center from January 2001 to December 2011. RESULTS: During the study period, 32,841 respiratory specimens from 10,563 patients were found to be culture-positive for mycobacteria. These included 12,619 (38%) Mycobacterium tuberculosis and 20,222 (62%) NTM isolates. The proportion of NTM among all positive mycobacterial cultures increased from 43% (548/1,283) in 2001 to 70% (3,341/4,800) in 2011 (p<0.001, test for trend). The recovery rate of NTM isolates from acid-fast bacilli smear-positive specimens increased from 9% (38/417) in 2001 to 64% (1,284/1,997) in 2011 (p<0.001, test for trend). The proportion of positive liquid cultures was higher for NTM than for M. tuberculosis (p<0.001). The most frequently isolated NTM were Mycobacterium avium-intracellulare complex (53%) and Mycobacterium abscessus massiliense complex (25%). CONCLUSION: The recovery rate of NTM from respiratory specimens in South Korea has increased steadily. PMID- 24348668 TI - Effect of Prunetin on TNF-alpha-Induced MUC5AC Mucin Gene Expression, Production, Degradation of IkappaB and Translocation of NF-kappaB p65 in Human Airway Epithelial Cells. AB - BACKGROUND: We investigated whether prunetin significantly affects tumor necrosis factor-alpha (TNF-alpha)-induced MUC5AC mucin gene expression, production, inhibitory kappa B (IkappaB) degradation and nuclear factor kappa B (NF-kappaB) p65 translocation in human airway epithelial cells. METHODS: Confluent NCI-H292 cells were pretreated with prunetin for 30 minutes and then stimulated with TNF alpha for 24 hours or the indicated periods. MUC5AC mucin gene expression and mucin protein production were measured by reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The effect of prunetin on TNF-alpha-induced degradation of IkappaB and translocation of NF kappaB p65 was investigated by western blot analysis. RESULTS: We found that incubation of NCI-H292 cells with prunetin significantly inhibited mucin production and down-regulated the MUC5AC gene expression induced by TNF-alpha. Prunetin inhibited TNF-alpha-induced degradation of IkappaB and translocation of NF-kappaB p65. CONCLUSION: This result suggests that prunetin inhibits the NF kappaB signaling pathway, which may explain its role in the inhibition of MUC5AC mucin gene expression and production regulated by the NF-kappaB signaling pathway. PMID- 24348669 TI - An unusual case of superior vena cava syndrome caused by the intravascular invasion of an invasive thymoma. AB - Superior vena cava syndrome (SVCS) is usually caused by extrinsic compression or invasion of the superior vena cava (SVC) by malignant tumors involving mediastinal structures. Although thymomas are well-known causes of SVCS, cases of SVCS caused by malignant thymomas protruding into adjacent vessels draining the SVC with thrombosis have been very rarely reported worldwide. We experienced a 39 year-old female patient with SVCS that developed after the direct invasion of the left brachiocephalic vein (LBCV) and SVC by an anterior mediastinal mass with a high maximum standardized uptake value on the chest computed tomography (CT) and positron emission tomography-CT. Based on these results, she underwent en bloc resection of the tumor, including removal of the involved vessels, and was eventually diagnosed as having a type B2 thymoma permeating into the LBCV and SVC. We present this case as a very rare form of SVCS caused by an invasive thymoma. PMID- 24348670 TI - Spontaneous regression of non-small cell lung cancer in a patient with idiopathic pulmonary fibrosis: a case report. AB - Treatment of lung cancer in patients with idiopathic pulmonary fibrosis (IPF) is difficult because the mortality rate after surgery or chemotherapy is high for these patients. Spontaneous regression of cancer is rare, especially in lung cancer. A 62-year-old man, previously diagnosed with IPF, presented with stage IIIC (T2N3M0) non-small cell lung cancer. About 4 months later, spontaneous regression of the primary tumor was observed without treatment. To the best of our knowledge, this is the first report of spontaneous regression of lung cancer in a patient with IPF. PMID- 24348671 TI - Spontaneous Splenic Rupture as a Paradoxical Reaction during Treatment for Splenic Tuberculosis. AB - This report describes a rare case of a patient with splenic tuberculosis (TB) who developed spontaneous splenic rupture after 10 weeks of antituberculous chemotherapy. The patient responded well to the antituberculous regimen prior to the spontaneous splenic rupture. We considered a paradoxical reaction as a cause of the splenic rupture. The patient underwent splenectomy and continuously received initial antituberculous drugs without change. To the best of our knowledge, this is the first report of spontaneous splenic rupture as a paradoxical reaction to antituberculous chemotherapy in an immunocompetent host with splenic TB. PMID- 24348672 TI - A case of bilateral giant bullae in young adult. AB - Giant bullae are large bullae occupying at least one-third of the hemithorax and surgical bullectomy is the treatment of choice. We report a case with symptomatic giant bullae which were resected successfully. A 35-year-old man presented with bilateral giant bullae that occupied almost the entire left hemithorax and a third of the right hemithorax. He was a current smoker with a 30 pack-year history and he presented with dyspnea on exertion. An elective surgical bullectomy was performed with video-assisted thoracoscopic surgery. The patient recovered without any adverse events and stayed well for 1 month after surgery. PMID- 24348673 TI - Haemophilus parasuis subunit vaccines based on native proteins with affinity to porcine transferrin prevent the expression of proinflammatory chemokines and cytokines in pigs. AB - The expression of chemokines (CCL-2 and CXCL-8) and cytokines (IL-1 alpha , IL-1 beta , IL-6, TNF- alpha , and IL-10) was evaluated by RT-qPCR in colostrum deprived pigs vaccinated and challenged with Haemophilus parasuis serovar 5. Two vaccines containing native proteins with affinity to porcine transferrin (NPAPTim and NPAPTit) were tested, along with two control groups: one inoculated with PBS instead of antigen (challenge group (CHG)), and another one nonimmunized and noninfected (blank group). The use of NPAPTim and NPAPTit resulted in complete protection against H. parasuis (no clinical signs and/or lesions), and both vaccines were capable of avoiding the expression of the proinflammatory molecules to levels similar to physiological values in blank group. However, overexpression of all proinflammatory molecules was observed in CHG group, mainly in the target infection tissues (brain, lungs, and spleen). High expression of CCL-2, CXCL-8, IL-1 alpha , IL-1 beta , and IL-6 can be considered one of the characteristics of H. parasuis infection by serovar 5. PMID- 24348674 TI - Modulatory effect of 1,25-dihydroxyvitamin D 3 on IL1 beta -induced RANKL, OPG, TNF alpha , and IL-6 expression in human rheumatoid synoviocyte MH7A. AB - Receptor activator of nuclear factor kappa B ligand (RANKL) plays a crucial role in the bone erosion of rheumatoid arthritis (RA) by prompting osteoclastogenesis. Considering that 1,25(OH)2D3 has been suggested as a potent inducer of RANKL expression, it should clarify whether vitamin D supplement could result in RANKL overexpression and thereby facilitate excessive osteoclastogenesis and bone resorption in RA. Here, we investigated modulatory effect of 1,25(OH)2D3 on the expression of RANKL and its decoy receptor osteoprotegerin (OPG) in an inflammatory condition of human rheumatoid synoviocyte MH7A. MH7A cells were stimulated with IL1 beta and then treated with different concentrations of 1,25(OH)2D3 for 48 h. A significantly elevated OPG/RANKL ratio and markedly decreased levels of IL-6 and TNF beta mRNA expression in cells and IL-6 protein in supernatants were observed in IL1 beta -induced MH7A in the presence of 1,25(OH)2D3 compared with those in the absence of it. Osteoclast formation was obviously decreased when RAW264.7 cells were treated with both 1,25(OH)2D3 and IL1 beta . In summary, although it has a biological function to induce RANKL expression, 1,25(OH)2D3 could upregulate OPG/RANKL ratio and mediate anti inflammatory action in an inflammatory milieu of synoviocyte, contributing to the inhibition of inflammation-induced osteoclastogenesis in RA. PMID- 24348675 TI - Effect of selective serotonin reuptake inhibitors and immunomodulator on cytokines levels: an alternative therapy for patients with major depressive disorder. AB - Major depressive disorder (MDD) is a psychiatric illness that presents as a deficit of serotonergic neurotransmission in the central nervous system. MDD patients also experience alterations in cortisol and cytokines levels. Treatment with selective serotonin reuptake inhibitors (SSRIs) is the first-line antidepressant regimen for MDD. The aim of this study was to determine the effect of a combination of SSRIs and an immunomodulator-human dialyzable leukocyte extract (hDLE)-on cortisol and cytokines levels. Patients received SSRIs or SSRIs plus hDLE. The proinflammatory cytokines IL-1 beta , IL-2, and IFN- gamma ; anti inflammatory cytokines IL-13 and IL-10; and 24-h urine cortisol were measured at weeks (W) 0, 5, 20, 36, and 52 of treatment. The reduction in cortisol levels in the SSRI-treated group was 30% until W52, in contrast, the combined treatment induced a 54% decrease at W36. The decline in cortisol in patients who were treated with SSRI plus hDLE correlated with reduction of anti-inflammatory cytokines and increases levels of proinflammatory cytokines at the study conclusion. These results suggest that the immune-stimulating activity of hDLE, in combination with SSRIs, restored the pro- and anti-inflammatory cytokine balance and cortisol levels in depressed patients versus those who were given SSRIs alone. PMID- 24348676 TI - Decreased CD127 expression on CD4+ T-cells and elevated frequencies of CD4+CD25+CD127- T-cells in children with long-lasting type 1 diabetes. AB - Pathobiology of type 1 diabetes (T1D) is predominantly associated with T-cell related actions. Homeostasis of majority of T-cells is critically dependent on signals mediated by CD127 (interleukin-7 receptor, IL-7R). In contrast, regulatory T-cells express very little CD127 and thereby may be delineated by CD4+CD25+CD127- phenotype. Here we aimed to analyze CD127 expression on CD4+ and CD8+ T-cells and enumerate CD4+CD25+CD127- T-cells in long-lasting T1D. T-cells were analyzed by flow cytometry and immunologic data were correlated with vascular, metabolic, and inflammatory parameters. We demonstrated significantly decreased CD127 levels on CD4+, but not CD8+, T cells in T1D pediatric patients. Interestingly, frequencies of CD4+CD25+CD127- T-cells were significantly enhanced in T1D children and correlated well with frequencies of CD34+CD144+ endothelial progenitor cells and CD4+CD25- T-cells. Levels of CD127 on both CD4+ and CD8+ T cells in T1D patients were not correlated to each other or HbA1C. Interestingly, however, CD127 levels on CD4+ T-cells were significantly correlated to frequencies of CD4+CD25+CD127- T-cells, whereas CD127 levels on CD8+ T-cells were significantly correlated to concentrations of VEGF and triglycerides. Our data indicate that CD127 expression is differentially modulated on CD4+ and CD8+ T cells in the course of T1D. Moreover, we demonstrated that, in contrast to recent onset T1D, long-lasting T1D is associated with enhancement of T-cells with regulatory phenotype. PMID- 24348677 TI - Selection of conserved epitopes from hepatitis C virus for pan-populational stimulation of T-cell responses. AB - The hepatitis C virus (HCV) is able to persist as a chronic infection, which can lead to cirrhosis and liver cancer. There is evidence that clearance of HCV is linked to strong responses by CD8 cytotoxic T lymphocytes (CTLs), suggesting that eliciting CTL responses against HCV through an epitope-based vaccine could prove an effective means of immunization. However, HCV genomic plasticity as well as the polymorphisms of HLA I molecules restricting CD8 T-cell responses challenges the selection of epitopes for a widely protective vaccine. Here, we devised an approach to overcome these limitations. From available databases, we first collected a set of 245 HCV-specific CD8 T-cell epitopes, all known to be targeted in the course of a natural infection in humans. After a sequence variability analysis, we next identified 17 highly invariant epitopes. Subsequently, we predicted the epitope HLA I binding profiles that determine their potential presentation and recognition. Finally, using the relevant HLA I-genetic frequencies, we identified various epitope subsets encompassing 6 conserved HCV specific CTL epitopes each predicted to elicit an effective T-cell response in any individual regardless of their HLA I background. We implemented this epitope selection approach for free public use at the EPISOPT web server. PMID- 24348678 TI - Modulation of LPS-induced CD4+ T-cell activation and apoptosis by antioxidants in untreated asymptomatic HIV infected participants: an in vitro study. AB - Persistent immune activation characterises HIV infection and is associated with depletion of CD4+ T-cells and increased risk of disease progression. Early loss of gut mucosal integrity results in the translocation of microbial products such as lipopolysaccharide (LPS) into the systemic circulation. This is an important source of on-going immune stimulation. The purpose of this study was to determine levels of CD4+ T-cell activation (%CD25 expression) and apoptosis (% annexin V/7 AAD) in asymptomatic, untreated HIV infection at baseline and after stimulation with LPS and incubation with or without vitamin C and N-acetylcysteine. LPS induced a significant (P < 0.03) increase in %CD25 expression, annexin V, and 7 AAD in HIV positive individuals. NAC in combination with vitamin C, significantly (P = 0.0018) reduced activation and early apoptosis of CD4+ T-cells to a greater degree than with either antioxidant alone. Certain combinations of antioxidants could be important in reducing the harmful effects of chronic immune activation and thereby limit CD4+ T-cell depletion. Importantly, we showed that CD4+ T-cells of the HIV positive group responded better to a combination of the antioxidants at this stage than those of the controls. Therefore, appropriate intervention at this asymptomatic stage could rescue the cells before repetitive activation results in the death of CD4+ T-cells. PMID- 24348679 TI - Impaired lymphocyte profile in schistosomiasis patients with periportal fibrosis. AB - The Th2 immune response in chronic schistosomiasis is associated with the development of periportal fibrosis. However, little is known about the phenotype and activation status of T cells in the process. Objective. To evaluate the profile of T cells in schistosomiasis patients with periportal fibrosis. Methods. It was a cross-sectional study, conducted in the village of Agua Preta, Bahia, Brazil, which included 37 subjects with periportal fibrosis determined by ultrasound. Peripheral blood mononuclear cells were obtained by the Ficcol hypaque gradient and the frequency of T cells expressing the surface markers CD28, CD69, CD25, and CTLA-4 was determined by flow cytometry. Results. The frequency of CD4(+)CD28(+) T lymphocytes was higher in individuals with moderate to severe fibrosis compared to patients with incipient fibrosis. We did not observe any significant difference in the frequency of CD4(+) T cells expressing CD69 among groups of individuals. There was also no significant difference in the frequency of CD8(+) T cells expressing CD28 or CD69 among the studied groups. Individuals with moderate to severe fibrosis presented a lower frequency of CD8(+) T cells, CD4(+)CD25(high) T cells, and CD4(+)CTLA-4(+) T cells when compared to patients without fibrosis or incipient fibrosis. The frequency of CD4(+)CD25(low) cells did not differ between groups. Conclusion. The high frequency of activated T cells coinciding with a low frequency of putative Treg cells may account for the development of periportal fibrosis in human schistosomiasis. PMID- 24348680 TI - Interferon alpha association with neuromyelitis optica. AB - Interferon-alpha (IFN- alpha ) has immunoregulatory functions in autoimmune inflammatory diseases. The goal of this study was to determine occurrence and clinical consequences of IFN- alpha in neuromyelitis optica (NMO) patients. Thirty-six NMO and 41 multiple sclerosis (MS) patients from a population-based retrospective case series were included. Expanded Disability Status Scale (EDSS) score and MRI findings determined disease activity. Linear regression was used to assess the effects of the level of IFN- alpha on disability (EDSS). IFN- alpha was determined by sensitive ELISA assays. IFN- alpha was detectable in sera from 9/36 NMO patients, significantly more often than in the MS group (2/41) (P = 0.0197). A higher frequency of IFN- alpha was observed in NMO patients with acute relapse compared to NMO patients in remission (P < 0.001) and compared to the MS patients with relapse (P = 0.010). In NMO patients, the levels of IFN- alpha were significantly associated with EDSS (P = 0.0062). It may be concluded that IFN- alpha was detectable in a subgroup of NMO patients. Association of IFN- alpha levels with clinical disease activity and severity suggests a role for IFN- alpha in disease perpetuation and may provide a plausible explanation for a negative effect of IFN-1 treatment in NMO patients. PMID- 24348681 TI - Potential immune modularly role of glycine in oral gingival inflammation. AB - Gingival epithelial cells (GECs) represent a physical barrier against bacteria and are involved in the processes of innate immunity. Recently, an anti inflammatory and immune-modulatory effect of the amino acid glycine has been demonstrated. However, there is only little information about the immune modulatory effects of glycine in oral tissues. This study aimed to investigate the existence and role of the glycine receptor in gingival tissue analyzing tissues/cells from extracted human molars via immunohistochemical analysis. In vitro, GECs were challenged by inflammatory conditions with IL-1 beta alone or in combination with glycine and analyzed for cytokine expression of IL6/IL8 via real time PCR. On protein level, the effect of nuclear translocalization of NF kappa B protein p65 was analyzed using immunofluorescence analysis. A distinct proof of the GlyR in oral gingival tissue and keratinocytes could be demonstrated. Isolated challenge of the keratinocytes with IL-1 beta as well as with glycine resulted in an upregulation of IL6 and IL8 mRNA expression and activation of NF kappa B pathway. The presence of glycine in combination with the inflammatory stimulus led to a significant decrease in inflammatory parameters. These results indicate a possible anti-inflammatory role of glycine in gingival inflammation and encourage further research on the utility of glycine in the prevention or therapy of inflammatory periodontitis. PMID- 24348682 TI - APACHE IV is superior to MELD scoring system in predicting prognosis in patients after orthotopic liver transplantation. AB - This study aims to compare the efficiency of APACHE IV with that of MELD scoring system for prediction of the risk of mortality risk after orthotopic liver transplantation (OLT). A retrospective cohort study was performed based on a total of 195 patients admitted to the ICU after orthotopic liver transplantation (OLT) between February 2006 and July 2009 in Guangzhou, China. APACHE IV and MELD scoring systems were used to predict the postoperative mortality after OLT. The area under the receiver operating characteristic curve (AUC) and the Hosmer Lemeshow C statistic were used to assess the discrimination and calibration of APACHE IV and MELD, respectively. Twenty-seven patients died during hospitalization with a mortality rate of 13.8%. The mean scores of APACHE IV and MELD were 42.32 +/- 21.95 and 18.09 +/- 10.55, respectively, and APACHE IV showed better discrimination than MELD; the areas under the receiver operating characteristic curve for APACHE IV and MELD were 0.937 and 0.694 (P < 0.05 for both models), which indicated that the prognostic value of APACHE IV was relatively high. Both models were well-calibrated (The Hosmer-Lemeshow C statistics were 1.568 and 6.818 for APACHE IV and MELD, resp.; P > 0.05 for both). The respective Youden indexes of APACHE IV, MELD, and combination of APACHE IV with MELD were 0.763, 0.430, and 0.545. The prognostic value of APACHE IV is high but still underestimates the overall hospital mortality, while the prognostic value of MELD is poor. The function of the APACHE IV is, thus, better than that of the MELD. PMID- 24348683 TI - Incidence and clinical significance of de novo donor specific antibodies after kidney transplantation. AB - Kidney transplantation has evolved over more than half a century and remarkable progress has been made in patient and graft outcomes. Despite these advances, chronic allograft dysfunction remains a major problem. Among other reasons, de novo formation of antibodies against donor human leukocyte antigens has been recognized as one of the major risk factors for reduced allograft survival. The type of treatment in the presence of donor specific antibodies (DSA) posttransplantation is largely related to the clinical syndrome the patient presents with at the time of detection. There is no consensus regarding the treatment of stable renal transplant recipients with circulating de novo DSA. On the contrast, in acute or chronic allograft dysfunction transplant centers use various protocols in order to reduce the amount of circulating DSA and achieve long-term graft survival. These protocols include removal of the antibodies by plasmapheresis, intravenous administration of immunoglobulin, or depletion of B cells with anti-CD20 monoclonal antibodies along with tacrolimus and mycophenolate mofetil. This review aims at the comprehension of the clinical correlations of de novo DSA in kidney transplant recipients, assessment of their prognostic value, and providing insights into the management of these patients. PMID- 24348684 TI - Tumor protective activity of CD4+ but not of CD8+ T cells in DNA-vaccinated mice challenged with bcr-abl-transformed cells. AB - In the recent past, it has repeatedly been reported that CD4 cells play an important role in the immunology of chronic myeloid leukaemia. It was therefore of interest to test their activity in an animal model using bcr-abl-transformed cells. BALB/c mice were four times immunized with a DNA vaccine carrying the bcr abl fusion gene. Two weeks after the last vaccine dose, the animals were challenged with syngeneic bcr-abl-transformed 12B1 cells which form solid tumors after subcutaneous administration. At the time of challenge, animals were treated with antibodies against the CD8+ T cells or CD4+ T cells. The efficacy of the depletion was monitored and found highly effective. All nonimmunized animals developed tumors. All animals untreated with the antibodies as well as those in which CD8+ T cells had been depleted, were fully protected against the challenge. On the other hand, almost all mice treated with anti-CD4+ antibody developed tumors. These results strongly suggested that the CD4+ T cells acted as effectors in the present system. PMID- 24348685 TI - TSLP: A Key Regulator of Asthma Pathogenesis. AB - Asthma is a complex disorder of the airways that is characterized by T helper type 2 (Th2) inflammation. The pleiotrophic cytokine TSLP has emerged as an important player involved in orchestrating the inflammation seen in asthma and other atopic diseases. Early research elucidated the role of TSLP on CD4+ T cells, and recent work has revealed the impact of TSLP on multiple cell types. Furthermore, TSLP plays an important role in the sequential progression of atopic dermatitis to asthma, clarifying the key role of TSLP in the pathogenesis of asthma, a finding with therapeutic implications. PMID- 24348686 TI - Premature guidance about whole-genome sequencing. PMID- 24348687 TI - Electroacupuncture-Induced Neuroprotection against Cerebral Ischemia in Rats: Role of the Dopamine D2 Receptor. AB - Background. Cerebral ischemia is known to produce brain damage and related behavioural deficits, including memory deficits and motor disorders. Evidence shows that EA significantly promotes recovery of neurological function and thus improves quality of life. Objective. Evidence exists for the involvement of catecholamines in human neuroplasticity. A better understanding of dopaminergic (DAergic) modulation in this process will be important. Methods. A total of 72 adult male Sprague-Dawley (SD) rats were divided into 6 groups: normal, model, EA, spiperone group, EA + spiperone group, and pergolide. The middle cerebral artery occlusion (MCAO) model was used in all 6 groups except the normal group. A behavioural assessment was conducted at 1, 3, 5, and 7 days after MCAO. The percent of brain infarct area was also determined 7 days after MCAO. Tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP-43) fluorescence double labeling was performed in the striatum. Results. In this study, we found that EA at Fengchi (GB20) acupoints resulted in marked improvements based on a behavioural assessment. Both TTC staining and GAP-43 immunofluorescence labeling results showed that EA treatment reduced ischemia injury and promoted neuroplasticity compared with the model group. The D2R-selective agonist, pergolide, showed similar results, but these results were reversed by the D2R selective antagonist, spiperone. We also found that there were more colocalization and expression of GAP-43 and TH in the EA and pergolide groups than those in the other groups. Conclusion. These results suggest that the neuroplasticity induced by EA was mediated by D2 autoreceptors in DAergic neurons. PMID- 24348688 TI - Insoluble fiber in young barley leaf suppresses the increment of postprandial blood glucose level by increasing the digesta viscosity. AB - Barley (Hordeum vulgare L.) is a well-known cereal plant. Young barley leaf is consumed as a popular green-colored drink, which is named "Aojiru" in Japan. We examined the effects of barley leaf powder (BLP) and insoluble fibers derived from BLP on postprandial blood glucose in rats and healthy Japanese volunteers. BLP and insoluble fibers derived from BLP suppressed the increment of postprandial blood glucose levels in rats (P < 0.01), and increased the viscosity of their digesta. The insoluble fibers present in BLP might play a role in controlling blood glucose level by increasing digesta viscosity. In human, BLP suppressed the increment of postprandial blood glucose level only in those which exhibited higher blood glucose levels after meals (P < 0.01). BLP might suppress the increment of postprandial blood glucose level by increasing digesta viscosity in both of rats and humans who require blood glucose monitoring. PMID- 24348689 TI - Effect of Nelumbo nucifera Petal Extracts on Lipase, Adipogenesis, Adipolysis, and Central Receptors of Obesity. AB - N. nucifera is one among the important medicinal plants assessed for its antiobesity action in various preclinical models. The present study was aimed at investigating the antiobesity effect of methanol and successive water extracts of petals of N. nucifera by studying its effect on adipogenesis, adipolysis, lipase, serotonin (5-HT2C), cannabinoid (CNR2), melanocyte concentrating hormone (MCHR1), and melanocortin (MC4R) receptors. Both methanol and successive water extracts of N. nucifera petals had an effect on inhibition of lipid storage in adipocytes and on increasing lipolysis. N. nucifera petal methanol extract exhibited the concentration-dependent inhibitory effect on lipase activity with an IC50 value of 47 ug/mL. N. nucifera petal extracts showed evident agonist and antagonist activity towards 5-HT2C and CNR2 receptors, respectively, while it showed no effect towards MCHR1 and MC4R receptors. Overall, methanol extract of N. nucifera petals showed better activity than successive water extract. PMID- 24348690 TI - Anti-Inflammatory Activity of Water-Soluble Polysaccharide of Agaricus blazei Murill on Ovariectomized Osteopenic Rats. AB - In the present study, we investigated the anti-inflammatory activity of water soluble polysaccharide of Agaricus blazei Murill (WSP-AbM) on ovariectomized osteopenic rats. The rats were administered orally WSP-AbM (200 mg/kg BW) for 8 weeks. Subsequent serum maleic dialdehyde (MDA) level, total antioxidant status (TAOS), nuclear factor kappa B (NF- kappa B) level, polymorphonuclear (PMN) cells level, interleukin-1 beta (IL-1 beta ) level, inducible nitric oxide synthase (iNOS) level, tumor necrosis factor- alpha (TNF- alpha ) level, adhesion molecule (ICAM-1), and cyclooxygenase-2 (COX-2) were determined by enzyme linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. WSP-AbM administration markedly (P < 0.05) decreased serum IL-1 beta and TNF- alpha levels and the expressions of ICAM-1, COX-2, and iNOS NF- kappa B compared with OVX rats. WSP-AbM administration alsomarkedly (P < 0.05) decreased PMN infiltration. In conclusion, we observed that WSP-AbM supplementation had anti inflammatory effects in a model of osteoporosis disease. PMID- 24348691 TI - Spiritual needs in patients suffering from fibromyalgia. AB - The objective of this study was to assess spiritual needs of patients with fibromyalgia syndrome (FMS) and to evaluate correlations with disease and health associated variables. Using a set of standardized questionnaires (i.e., Spiritual Needs Questionnaire, Fibromyalgia Impact Questionnaire, SF-36's Quality of Life, Brief Multidimensional Life Satisfaction Scale, etc.), we enrolled 141 patients (95% women, mean age 58 +/- 10 years). Here, needs for inner peace and giving/generativity scored the highest, while existential needs and religious needs scored lowest. Particularly inner peace needs and existential needs correlated with different domains of reduced mental health, particularly with anxiety, the intention to escape from illness, and psychosocial restrictions. Thirty-eight percent of the patients stated needs to be forgiven and nearly half to forgive someone from their past life. Therefore, the specific spiritual needs of patients with chronic diseases should be addressed in clinical care in order to identify potential therapeutic avenues to support and stabilize their psychoemotional situation. PMID- 24348692 TI - Effect of jeju water on blood glucose levels in diabetic patients: a randomized controlled trial. AB - Jeju water is the groundwater of Jeju Island, a volcanic island located in Republic of Korea. We investigated whether Jeju water improved glycemic control in patients with diabetes. This was a 12-week single-center, double-blind, randomized, and controlled trial. The subjects daily drank a liter of one of three kinds of water: two Jeju waters (S1 and S2) and Seoul tap water (SS). The primary outcome was the proportion of patients in the per-protocol (PP) population achieving glycated hemoglobin (HbA1c) < 7.0% at week 12. In total, 196 patients were randomized and analyzed in the intention-to-treat (ITT) population (66 consuming S1, 63 consuming S2, and 67 consuming SS); 146 patients were considered in the PP population. There were no significant differences in the primary outcomes of the groups consuming S1, S2, or SS. However, the percentage of patients achieving HbA1c < 8% was significantly higher in the S2 group than in the SS group. In the ITT population, the 12-week HbA1c and fructosamine levels were lower in the S1 group than in the SS group and the 4-, 8-, and 12-week fructosamine levels were lower in the S2 group than in the SS group. Although we failed to achieve the primary outcome, it is possible that the Jeju waters improve glycemic control compared with the Seoul tap water in diabetic patients. PMID- 24348693 TI - Bioinformatics analysis for the antirheumatic effects of huang-lian-jie-du-tang from a network perspective. AB - Huang-Lian-Jie-Du-Tang (HLJDT) is a classic TCM formula to clear "heat" and "poison" that exhibits antirheumatic activity. Here we investigated the therapeutic mechanisms of HLJDT at protein network level using bioinformatics approach. It was found that HLJDT shares 5 target proteins with 3 types of anti RA drugs, and several pathways in immune system and bone formation are significantly regulated by HLJDT's components, suggesting the therapeutic effect of HLJDT on RA. By defining an antirheumatic effect score to quantitatively measure the therapeutic effect, we found that the score of each HLJDT's component is very low, while the whole HLJDT achieves a much higher effect score, suggesting a synergistic effect of HLJDT achieved by its multiple components acting on multiple targets. At last, topological analysis on the RA-associated PPI network was conducted to illustrate key roles of HLJDT's target proteins on this network. Integrating our findings with TCM theory suggests that HLJDT targets on hub nodes and main pathway in the Hot ZENG network, and thus it could be applied as adjuvant treatment for Hot-ZENG-related RA. This study may facilitate our understanding of antirheumatic effect of HLJDT and it may suggest new approach for the study of TCM pharmacology. PMID- 24348694 TI - Manual acupuncture and laser acupuncture for autonomic regulations in rats: observation on heart rate variability and gastric motility. AB - This study focused on the effects of laser acupuncture (LA) and manual acupuncture (MA) at different acupoints on gastric motility and heart rate variability (HRV) simultaneously to elucidate the site specific effects of acupoints and the correlation between changes of gastric motility and low frequency/high frequency (LF/HF) ratio. Gastric motility and HRV were recorded before and during MA or LA. Stimulating PC-6 or ST-36 significantly enhanced gastric motility, while BL-21 caused no changes. In contrast, MA or LA at CV-12 significantly suppressed gastric motility. Stimulating PC-6 or ST-36 significantly increased heart rate (HR), while CV-12 or BL-21 induced no significant changes of HR. Stimulating PC-6 significantly increased LF/HF, while ST-36, CV-12, or BL-21 induced no significant effects. These results indicated that there was acupoint specificity in the effects of acupuncture on gastric motility and HRV. The stimulatory effect of MA and LA at PC-6 and ST-36 on HR was associated with sympathetic activity. The stimulatory effect of MA or LA at PC-6 or ST-36 on gastric motility was associated with vagal activity. Laser needle can be used as an alternative stimulation therapy. PMID- 24348695 TI - German psychiatrists' observation and interpretation of religiosity/spirituality. AB - The purpose of this study was to explore how contemporary German psychiatrists think about religiosity/spirituality (ReS) in regard to their therapies. We conducted an anonymous survey among the clinical staff of psychiatry and psychotherapy departments in German university hospitals and faith-based clinics in the same cities. Two main instruments were used, the Duke University Religion Index (DUREL) and the questionnaire from Curlin et al. "Religion and Spirituality in Medicine: Physicians' Perspectives." A total of 123 psychiatrists participated in this survey. However, due to incomplete responses, only 99 questionnaires from psychiatrists were analyzed. Results show that German psychiatrists positively experience the influence of ReS on patients' mental health. Psychiatrists' own ReS significantly influenced their interpretation of the effect of ReS on psychiatric patients as well as their attitude toward ReS in the clinical setting. The more religious psychiatrists are, the more they tend to observe a positive influence of ReS on mental health. In light of these results, psychiatrists should be aware of their own religious/spiritual characteristics and also reconsider their assumptions about professional neutrality and value openness. Furthermore, training programs on religious/spiritual issues and effective teamwork with chaplains are recommended. PMID- 24348696 TI - Establishment of an Experimental Breast Cancer ZHENG Model and Curative Effect Evaluation of Zuo-Jin Wan. AB - Herbal formulas based on the traditional Chinese medicine (TCM) syndrome (ZHENG) have been used as alternative treatments for breast cancer. However, there is a lack of the experimental animal ZHENG model for the evaluation of the herbal formulas. In this study, we have established 4T1 mouse breast cancer with Liver Fire Invading Stomach Syndrome model (4T1 LFISS mice) and investigated the effects of the herbal formula, Zuo-Jin Wan (ZJW). Our results showed that 4T1 LFISS mice have the features of LFISS including irritability, loss of appetite, yellow urine, chow, and a tail hot. Compared to untreated 4T1 LFISS mice, ZJW significantly reduced tumor weight and volume (P < 0.05), although it was weaker than Cisplatin. However, ZJW significantly increased the body weight and food intake of 4T1 LFISS mice and decreased serum ALT, AST, Cr, and BUN levels and ZHENG score (P < 0.05), while Cisplatin reduced the food intake, and body weight and increased serum ALT, AST, Cr, and BUN levels in 4T1 LFISS mice. Our study has provided a mouse breast cancer ZHENG model and showed that ZJW suppresses tumor growth and improves LFISS and kidney and liver functions in the 4T1 LFISS mice. PMID- 24348697 TI - Direct radiofrequency application improves pain and gait in collagenase-induced acute achilles tendon injury. AB - Radiofrequency (RF) is often used as a supplementary and alternative method to alleviate pain for chronic tendinopathy. Whether or how it would work for acute tendon injury is not addressed in the literatures. Through detailed pain and gait monitoring, we hypothesized that collagenase-induce acute tendinopathy model may be able to answer these questions. Gait parameters, including time, distance, and range of motion, were recorded and analyzed using a walking track equipped with a video-based system. Expression of substance P (SP), calcitonin gene related peptide (CGRP), and galanin were used as pain markers. Beta-III tubulin and Masson trichrome staining were used as to evaluate nerve sprouting, matrix tension, and degeneration in the tendon. Of fourteen analyzed parameters, RF significantly improved stance phase, step length, preswing, and intermediary toe spread of gait. Improved gait related to the expression of substance P, CGRP, and reduced nerve fiber sprouting and matrix tension, but not galanin. The study indicates that direct RF application may be a valuable approach to improve gait and pain in acute tendon injury. Altered gait parameters may be used as references to evaluate therapeutic outcomes of RF or other treatment plan for tendinopathy. PMID- 24348698 TI - Tropical protozoan diseases: natural product drug discovery and development. PMID- 24348699 TI - Subacute and Reproductive Oral Toxicity Assessment of the Hydroethanolic Extract of Jacaranda decurrens Roots in Adult Male Rats. AB - Jacaranda decurrens subsp. symmetrifoliolata Farias & Proenca (Bignoniaceae) is a species traditionally used for the treatment of inflammatory and infectious diseases. Previous findings from our group reported scientifically that J. decurrens has anti-inflammatory efficacy. However, more toxicological studies are needed to support and ensure its safe use. The present study was carried out to evaluate the toxic effects of a prolonged treatment with hydroethanolic root extract of J. decurrens (EJD) on hematological, biochemical, and reproductive parameters in adult male rats. The animals received by oral gavage 0; 250; 500; or 1000 mg/kg body weight of EJD for 28 days. After the treatment, biochemical, hematological, histopathological, and reproductive parameters were analyzed. The EJD treatment did not cause adverse effects on body weight gain, feed and water consumption, hematological and biochemical profiles, or histopathological analysis of liver and kidney. Similarly, there were no statistically significant differences in reproductive parameters, such as sperm production, number of sperm in the epididymis, and sperm morphology. These results demonstrate the absence of subacute toxicity as a result of the oral treatment with EJD for 28 days in adult male rats. However, other studies should be performed to evaluate the total safety of this plant. PMID- 24348700 TI - An exploratory survey of deqi sensation from the views and experiences of chinese patients and acupuncturists. AB - Deqi sensation is believed to be important in clinical efficacy according to TCM theory. The measuring method of Deqi sensation has significant implications for the result of research trials. This study makes an investigation on acupuncture experienced patients and expert acupuncturists in China and aims to find out the patient's needling sensations and acupuncturist's sensations which can be acceptable as descriptors of Deqi sensation, so as to provide foundation for more systematic and sensitive quantitative evaluation method of Deqi sensation. Results of this survey indicated that the Deqi sensation noted by both patient and acupuncturist is equally important to the treatment efficacy. It is found that there are some differences between the patients' real-life experience and the acupuncturists' expectations on patients' Deqi sensation. The "dull pain," "aching," "sore," "numb," "distended," "heavy," "electric," "throbbing," "warmness," "coolness," "spreading," and "radiating" can be considered as the main manifestations of Deqi sensations. The acupuncturists believed that Deqi sensations were mainly "pulling," "tight," and "throbbing." We suggest developing a questionnaire measuring the Deqi sensations which includes both the sensations of the patient and acupuncturist, and this would be very important and necessary for a better understanding of the relationship between Deqi sensation and acupuncture effects in future studies. PMID- 24348701 TI - Treatment of fibromyalgia syndrome: recommendations of recent evidence-based interdisciplinary guidelines with special emphasis on complementary and alternative therapies. AB - Objective. Current evidence indicates that there is no single ideal treatment for fibromyalgia syndrome (FMS). First choice treatment options remain debatable, especially concerning the importance of complementary and alternative medicine (CAM) treatments. Methods. Three evidence-based interdisciplinary guidelines on FMS in Canada, Germany, and Israel were compared for their first choice and CAM recommendations. Results. All three guidelines emphasized a patient-tailored approach according to the key symptoms. Aerobic exercise, cognitive behavioral therapy, and multicomponent therapy were first choice treatments. The guidelines differed in the grade of recommendation for drug treatment. Anticonvulsants (gabapentin, pregabalin) and serotonin noradrenaline reuptake inhibitors (duloxetine, milnacipran) were strongly recommended by the Canadian and the Israeli guidelines. These drugs received only a weak recommendation by the German guideline. In consideration of CAM-treatments, acupuncture, hypnosis/guided imagery, and Tai Chi were recommended by the German and Israeli guidelines. The Canadian guidelines did not recommend any CAM therapy. Discussion. Recent evidence-based interdisciplinary guidelines concur on the importance of treatment tailored to the individual patient and further emphasize the need of self management strategies (exercise, and psychological techniques). PMID- 24348702 TI - The sasang constitution as an independent risk factor for metabolic syndrome: propensity matching analysis. AB - THE SASANG CONSTITUTIONAL MEDICINE IS A TRADITIONAL KOREAN CUSTOMIZED MEDICINE THAT CLASSIFIES PEOPLE INTO FOUR TYPES: Tae-eumin (TE), Soyangin (SY), Soeumin (SE), and Taeyangin. The aim of this study was to show whether the Sasang Constitution (SC) could be an independent risk factor for the metabolic syndrome (MS). Totally, 3,334 subjects from 24 Korean medicine clinics participated in this study. A one-way ANOVA for the continuous variables and a chi-square test for the prevalence of MS were conducted. A logistic regression was conducted to calculate the propensity score and the odds ratios (ORs). The prevalence for MS in TE, SY, and SE was 50.6%, 30.9%, and 17.7% (P < 0.001) before matching, and 36.7%, 28.6% and 28.2% (P = 0.042) after matching, respectively. The TE was associated with an increased OR for MS compared with the SE and SY in both crude (OR 4.773, 95% CI 3.889-5.859, and OR 2.292, 95% CI 1.942-2.704, resp.) and matched groups (OR 1.476, 95% CI 1.043-2.089, and OR 1.452, 95% CI 1.026-2.053, resp.). This study reveals that the SC, especially the TE type, could be considered as a risk element for MS even in people with otherwise similar physical characteristics. PMID- 24348703 TI - In Vitro Antiproliferative Effect of Arthrocnemum indicum Extracts on Caco-2 Cancer Cells through Cell Cycle Control and Related Phenol LC-TOF-MS Identification. AB - This study aimed to determinate phenolic contents and antioxidant activities of the halophyte Arthrocnemum indicum shoot extracts. Moreover, the anticancer effect of this plant on human colon cancer cells and the likely underlying mechanisms were also investigated, and the major phenols were identified by LC ESI-TOF-MS. Results showed that shoot extracts had an antiproliferative effect of about 55% as compared to the control and were characterised by substantial total polyphenol content (19 mg GAE/g DW) and high antioxidant activity (IC50 = 40 MU g/mL for DPPH test). DAPI staining revealed that these extracts decrease DNA synthesis and reduce the proliferation of Caco-2 cells which were stopped at the G2/M phase. The changes in the cell-cycle-associated proteins (cyclin B1, p38, Erk1/2, Chk1, and Chk2) correlate with the changes in cell cycle distribution. Eight phenolic compounds were also identified. In conclusion, A. indicum showed interesting antioxidant capacities associated with a significant antiproliferative effect explained by a cell cycle blocking at the G2/M phase. Taken together, these data suggest that A. indicum could be a promising candidate species as a source of anticancer molecules. PMID- 24348704 TI - The Drinking Effect of Hydrogen Water on Atopic Dermatitis Induced by Dermatophagoides farinae Allergen in NC/Nga Mice. AB - Hydrogen water (HW) produced by electrolysis of water has characteristics of extremely low oxidation-reduction potential (ORP) value and high dissolved hydrogen (DH). It has been proved to have various beneficial effects including antioxidant and anti-inflammatory effects; however, HW effect on atopic dermatitis (AD), an inflammatory skin disorder, is poorly documented. In the present study, we examined the immunological effect of drinking HW on Dermatophagoides farinae-induced AD-like skin in NC/Nga mice. Mice were administered with HW and purified water (PW) for 25 days. We evaluated the serum concentration of pro-inflammatory (TNF- alpha ), Th1 (IFN- gamma , IL-2, and IL 12p70), Th2 (IL-4, IL-5, and IL-10), and cytokine expressed by both subsets (GM CSF) to assess their possible relationship to the severity of AD. The serum levels of cytokines such as IL-10, TNF- alpha , IL-12p70, and GM-CSF of mice administered with HW was significantly reduced as compared to PW group. The results suggest that HW affects allergic contact dermatitis through modulation of Th1 and Th2 responses in NC/Nga mice. This is the first note on the drinking effect of HW on AD, clinically implying a promising potential remedy for treatment of AD. PMID- 24348705 TI - The long-term effects of a kampo medicine, juzentaihoto, on maintenance of antibody titer in elderly people after influenza vaccination. AB - We have performed a broad-ranging analysis of the adjuvant effect of a Kampo medicine, juzentaihoto (JTT), on influenza vaccination in a multicenter randomized controlled trial. In this study, the enhancing effect of JTT on antibody titer after influenza vaccination was studied for 28 weeks in elderly people who were in the high-risk group for influenza infection. In total, 91 subjects over 65 years old were recruited from four long-term-care facilities located in Chiba, Gunma, and Toyama prefectures in Japan. Participants were randomly assigned to the JTT and the control groups. Blood samples were taken at 4 weeks before vaccination, at the time of vaccination, and then at 4, 8, 12, and 24 weeks after vaccination. The hemagglutination inhibition (HI) titers against A/California/7/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 were then manually measured. A significant increase in HI titer against H3N2 was observed at week 8 after vaccination in the JTT group compared with the control group (P = 0.0229), and the HI titer of the JTT group significantly increased from 4 to 24 weeks (P = 0.0468), compared with the control group. In conclusion, our results indicated that JTT increased and prolonged antibody production against A/Victoria/210/2009 (H3N2), in particular, after influenza vaccination. PMID- 24348706 TI - Electroacupuncture regulates apoptosis/proliferation of intramuscular interstitial cells of cajal and restores colonic motility in diabetic constipation rats. AB - Injury of interstitial cells of Cajal (ICC) is associated with gut dysmotility in diabetic rats. We have shown an acceleration of the colonic contractility by electroacupuncture stimulation (EAS). However, little is known about potential roles of EAS on colonic transit and ICC. In this study, we evaluate the effect of EAS on colonic transit and investigate whether apoptosis/proliferation of ICC was involved in regulative effect of EAS on colonic transit. Rats were randomly assigned to normal, diabetic, diabetic-plus-sham stimulation, diabetic-plus-low frequency stimulation, and diabetic-plus-high-frequency stimulation groups. Bead expulsion test was used for measuring the distal colonic transit. The Kit (ICC marker) was detected by western blot. Apoptotic ICC was detected by terminal dUTP nucleotide end labeling. Proliferating ICC was identified by Kit/Ki67 double immunofluorescent staining on whole mount preparations. Ultrastructure changes of ICC were studied using electron microscopy. Results showed that high-frequency stimulation significantly promoted colonic transit. Low- and high-frequency stimulation markedly rescued intramuscular ICC from apoptosis. Abundant proliferating intramuscular ICC was found in low- and high-frequency stimulation groups. Our results indicate that high-frequency EAS has stimulatory effect on the distal colonic transit, which may be mediated by downregulation of the apoptosis and upregulation of the proliferation of intramuscular ICC. PMID- 24348707 TI - Evaluation of anxiolytic-like effect of aqueous extract of asparagus stem in mice. AB - There are few studies on the neuropharmacological properties of asparagus, which was applied in Chinese traditional medicine as a tonic and heat-clearing agent. The present study was designed to investigate the anxiolytic-like activity of the aqueous extract of asparagus stem (AEAS) using elevated plus maze (EPM) and Vogel conflict tests (VCT) in mice. AEAS significantly increased the percentage of time spent in open arms in EPM, when compared with control group. In the Vogel conflict drinking test, the numbers of punished licks increased to 177% and 174% by the treatment of AEAS at the doses of 1.5 and 3.0 g/kg (250 and 500 mg sarsasapogenin per kilogram of body weight), compared with control group. The serum cortisol level decreased significantly, at the same time. In conclusion, these findings indicated that the aqueous extract of asparagus stem exhibited a strong anxiolytic-like effect at dose of 1.5 and 3.0 g/kg (250 and 500 mg sarsasapogenin per kilogram of body weight) in experimental models of anxiety and may be considered an alternative approach for the management of anxiety disorder. PMID- 24348708 TI - A network-based systematic study for the mechanism of the treatment of zhengs related to cough variant asthma. AB - Traditional Chinese medicine (TCM) has shown significant efficacy in the treatment of cough variant asthma (CVA), a special type of asthma. However, there is shortage of explanations for relevant mechanism of treatment. As Zhengs differentiation is a critical concept in TCM, it is necessary to explain the mechanism of treatment of Zhengs. Based on TCM clinical cases, this study illustrated the mechanism of the treatment of three remarkably relevant Zhengs for CVA: "FengXieFanFei," "FeiQiShiXuan", and "QiDaoLuanJi." To achieve this goal, five steps were carried out: (1) determining feature Zhengs and corresponding key herbs of CVA by analyses of clinical cases; (2) finding out potential targets of the key herbs and clustering them based on their functional annotations; (3) constructing an ingredient-herb network and an ingredient network; (4) identifying modules of the ingredient network; (5) illustrating the mechanism of the treatment by further mining the latent biological implications within each module. The systematic study reveals that the treatment of "FengXieFanFei," "FeiQiShiXuan," and "QiDaoLuanJi" has effects on the regulation of multiple bioprocesses by herbs containing different ingredients with functions of steroid metabolism regulation, airway inflammation, and ion conduction and transportation. This network-based systematic study will be a good way to boost the scientific understanding of mechanism of the treatment of Zhengs. PMID- 24348709 TI - Rosmarinic Acid and Its Methyl Ester as Antimicrobial Components of the Hydromethanolic Extract of Hyptis atrorubens Poit. (Lamiaceae). AB - Primary biological examination of four extracts of the leaves and stems of Hyptis atrorubens Poit. (Lamiaceae), a plant species used as an antimicrobial agent in Guadeloupe, allowed us to select the hydromethanolic extract of the stems for further studies. It was tested against 46 microorganisms in vitro. It was active against 29 microorganisms. The best antibacterial activity was found against bacteria, mostly Gram-positive ones. Bioautography enabled the isolation and identification of four antibacterial compounds from this plant: rosmarinic acid, methyl rosmarinate, isoquercetin, and hyperoside. The MIC and MBC values of these compounds and their combinations were determined against eight pathogenic bacteria. The best inhibitory and bactericidal activity was found for methyl rosmarinate (0.3 mg/mL). Nevertheless, the bactericidal power of rosmarinic acid was much faster in the time kill study. Synergistic effects were found when combining the active compounds. Finally, the inhibitory effects of the compounds were evaluated on the bacterial growth phases at two different temperatures. Our study demonstrated for the first time antimicrobial activity of Hyptis atrorubens with identification of the active compounds. It supports its traditional use in French West Indies. Although its active compounds need to be further evaluated in vivo, this work emphasizes plants as potent sources of new antimicrobial agents when resistance to antibiotics increases dramatically. PMID- 24348710 TI - Mushrooms and truffles: historical biofactories for complementary medicine in Africa and in the middle East. AB - The ethnopharmaceutical approach is important for the discovery and development of natural product research and requires a deep understanding not only of biometabolites discovery and profiling but also of cultural and social science. For millennia, epigeous macrofungi (mushrooms) and hypogeous macrofungi (truffles) were considered as precious food in many cultures based on their high nutritional value and characterized pleasant aroma. In African and Middle Eastern cultures, macrofungi have long history as high nutritional food and were widely applied in folk medicine. The purpose of this review is to summarize the available information related to the nutritional and medicinal value of African and Middle Eastern macrofungi and to highlight their application in complementary folk medicine in this part of the world. PMID- 24348711 TI - Yoga and rehabilitation: physical, psychological, and social. PMID- 24348713 TI - Icariin Augments Bone Formation and Reverses the Phenotypes of Osteoprotegerin Deficient Mice through the Activation of Wnt/ beta -Catenin-BMP Signaling. AB - Icariin has been mostly reported to enhance bone fracture healing and treat postmenopausal osteoporosis in ovariectomized animal model. As another novel animal model of osteoporosis, there is few publication about the effect of Icariin on osteoprotegerin-deficient mice. Therefore, the goal of this study is to find the effect on bone formation and underlying mechanisms of Icariin in osteoprotegerin (OPG) knockout (KO) mice. We found that Icariin significantly stimulated new bone formation after local injection over the surface of calvaria at the dose of 5 mg/kg per day. With this dose, Icariin was also capable of significantly reversing OPG-deficient-induced bone loss and bone strength reduction. Real-time PCR analysis showed that Icariin significantly upregulated the expression of BMP2, BMP4, RUNX2, OC, Wnt1, and Wnt3a in OPG KO mice. Icariin also significantly increased the expression of AXIN2, DKK1, TCF1, and LEF1, which are the direct target genes of beta -catenin signaling. The in vitro studies showed that Icariin induced osteoblast differentiation through the activation of Wnt/ beta -catenin-BMP signaling by in vitro deletion of the beta -catenin gene using beta -catenin(fx/fx) mice. Together, our findings demonstrate that Icariin significantly reverses the phenotypes of OPG-deficient mice through the activation of Wnt/ beta -catenin-BMP signaling. PMID- 24348715 TI - Polysaccharides-Rich Extract of Ganoderma lucidum (M.A. Curtis:Fr.) P. Karst Accelerates Wound Healing in Streptozotocin-Induced Diabetic Rats. AB - Ganoderma lucidum (M.A. Curtis:Fr.) P. Karst is a popular medicinal mushroom. Scientific reports had shown that the wound healing effects of G. lucidum were partly attributed to its rich polysaccharides. However, little attention has been paid to its potential effects on wounds associated with diabetes mellitus. In this study, we evaluated the wound healing activity of the hot aqueous extract of G. lucidum in streptozotocin-induced diabetic rats. The extract of G. lucidum was standardised based on chemical contents (w/w) of total polysaccharides (25.1%), ganoderic acid A (0.45%), and adenosine (0.069%). Six groups of six rats were experimentally wounded in the posterior neck region. Intrasite gel was used as a positive control and aqueous cream as the placebo. Topical application with 10% (w/w) of mushroom extract-incorporated aqueous cream was more effective than that with Intrasite gel in terms of wound closure. The antioxidant activity in serum of rats treated with aqueous extract of G. lucidum was significantly higher; whereas the oxidative protein products and lipid damage were lower when compared to those of the controls. These findings strongly support the beneficial effects of standardised aqueous extract of G. lucidum in accelerating wound healing in streptozotocin-induced diabetic rats. PMID- 24348714 TI - Recent Advances in Astragalus membranaceus Anti-Diabetic Research: Pharmacological Effects of Its Phytochemical Constituents. AB - The disease burden of diabetes mellitus is increasing throughout the world. The need for more potent drugs to complement the present anti-diabetic drugs has become an imperative. Astragalus membranaceus, a key component of most Chinese herbal anti-diabetic formulas, has been an important prospect for lead anti diabetic compounds. It has been progressively studied for its anti-diabetic properties. Ethnopharmacological studies have established its potential to alleviate diabetes mellitus. Recent studies have sought to relate its chemical constituents to types 1 and 2 diabetes mellitus. Its total polysaccharides, saponins, and flavonoids fractions and several isolated compounds have been the most studied. The total polysaccharides fraction demonstrated activity to both types 1 and 2 diabetes mellitus. This paper discusses the anti-diabetic effects and pharmacological action of the chemical constituents in relation to types 1 and 2 diabetes mellitus. PMID- 24348712 TI - Curcumin and diabetes: a systematic review. AB - Turmeric (Curcuma longa), a rhizomatous herbaceous perennial plant of the ginger family, has been used for the treatment of diabetes in Ayurvedic and traditional Chinese medicine. The active component of turmeric, curcumin, has caught attention as a potential treatment for diabetes and its complications primarily because it is a relatively safe and inexpensive drug that reduces glycemia and hyperlipidemia in rodent models of diabetes. Here, we review the recent literature on the applications of curcumin for glycemia and diabetes-related liver disorders, adipocyte dysfunction, neuropathy, nephropathy, vascular diseases, pancreatic disorders, and other complications, and we also discuss its antioxidant and anti-inflammatory properties. The applications of additional curcuminoid compounds for diabetes prevention and treatment are also included in this paper. Finally, we mention the approaches that are currently being sought to generate a "super curcumin" through improvement of the bioavailability to bring this promising natural product to the forefront of diabetes therapeutics. PMID- 24348716 TI - Activity-Guided Isolation of Bioactive Constituents with Antinociceptive Activity from Muntingia calabura L. Leaves Using the Formalin Test. AB - The present study was conducted to determine the antinociceptive potential of methanol extract of Muntingia calabura L. (MEMC) and to isolate and identify the bioactive compound(s) responsible for the observed antinociceptive activity. The MEMC and its partitions (petroleum ether (PEP), ethyl acetate (EAP), and aqueous (AQP) partitions), in the dose range of 100, 500, and 1000 mg/kg, were tested using the formalin-induced nociceptive test. The PEP, which exerted the most effective activity in the respective early and late phase, was further subjected to the fractionation procedures and yielded seven fractions (labelled A to G). These fractions were tested, at the dose of 300 mg/kg, together with distilled water or 10% DMSO (negative controls); morphine and aspirin (positive controls) for potential antinociceptive activity. Of all fractions, Fraction D showed the most significant antinociceptive activity, which is considered as equieffective to morphine or aspirin in the early or late phase, respectively. Further isolation and identification processes on fraction D led to the identification of three known and one new compounds, namely, 5-hydroxy-3,7,8-trimethoxyflavone (1), 3,7-dimethoxy-5-hydroyflavone (2), 2',4'-dihydroxy-3'-methoxychalcone (3), and calaburone (4). At the dose of 50 mg/kg, compound 3 exhibited the highest percentage of antinociceptive activity in both phases of the formalin test. In conclusion, the antinociceptive activity of MEMC involved, partly, the synergistic activation of the flavonoid types of compounds. PMID- 24348717 TI - Beneficial Effect of 7-O-Galloyl-D-sedoheptulose, a Polyphenol Isolated from Corni Fructus, against Diabetes-Induced Alterations in Kidney and Adipose Tissue of Type 2 Diabetic db/db Mice. AB - Traditional medicines are being focused on as possible treatments for diabetes and its complications because of their negligible toxic and/or side effects. In line with this, our group has reported that Corni Fructus, a traditional medicine considered exhibiting beneficial effects on liver and kidney functions, possessed an antidiabetic effect via ameliorating glucose-mediated metabolic disorders. To add to these findings, we screened the iridoid glycoside fraction containing morroniside and loganin, and low molecular weight polyphenol fraction containing 7-O-galloyl-d-sedoheptulose (GS) from Corni Fructus. To our knowledge, GS is a compound only detected in Corni Fructus, and its biological activity has been poorly understood until now. For these reasons, we examined whether GS has an ameliorative effect on diabetic changes using type 2 diabetic db/db mice. Our findings suggest that GS has a beneficial effect on the pathological state of the serum, kidney, and adipose tissue related to diabetic damage. PMID- 24348718 TI - Immunosuppression of the trimellitic anhydride-induced th2 response by novel nonanatural products mixture in mice. AB - Many natural dietary products prevent or cure allergic inflammation; however, the ability of mixtures of these natural medicinals to suppress allergic skin inflammation is unknown. We examined the inhibitory effects of nonanatural products mixture (NPM-9), which provides immunoregulatory activation, on Th2 mediated skin allergic inflammation. Oral administration of NPM-9 in mice reduced ear thickness and specific IgE production in trimellitic anhydride- (TMA-)induced contact hypersensitivity (CHS). NPM-9 also suppressed IL-4 and IL-1beta production in splenocytes but prevented only TMA-induced IL-1beta production in inflamed ears. To characterize the mechanism of this effect, we examined NPM-9 immunosuppression on an OVA-induced Th2 allergic state. Oral administration of NPM-9 inhibited Th2-mediated serum IgE overproduction. NPM-9 also downregulated the polarized Th2 response, whereas it upregulated Th1 response in splenocytes. These data suggest that NPM-9 may be a useful therapeutic agent for allergic inflammatory diseases through its suppression of the Th2-mediated allergic response. PMID- 24348720 TI - Evaluation of the effects of honey on acute-phase deep burn wounds. AB - This study aimed to clarify the effects of honey on acute-phase deep burn wounds. Two deep burn wounds were created on mice which were divided into four groups: no treatment, silver sulfadiazine, manuka honey, and Japanese acacia honey. Wound sizes were calculated as expanded wound areas and sampled 30 minutes and 1-4 days after wounding for histological observation. The wound sections were subjected to hematoxylin and eosin and immunohistological staining to detect necrotic cells, apoptotic cells, neutrophils, and macrophages. The no treatment group formed a scar. The redness around the wound edges in the silver sulfadiazine group was the most intense. All groups exhibited increased wound areas after wounding. The proportions of necrotic cells and the numbers of neutrophils in the manuka and acacia honey groups were lower than those in the no treatment and silver sulfadiazine groups until day 3; however, there were no significant differences between all groups on day 4. These results show that honey treatment on deep burn wounds cannot prevent wound progression. Moreover, comparing our observations with those of Jackson, there are some differences between humans and animals in this regard, and the zone of hyperemia and its surrounding area fall into necrosis, which contributes to burn wound progression. PMID- 24348719 TI - Citrus bergamia Risso Elevates Intracellular Ca (2+) in Human Vascular Endothelial Cells due to Release of Ca (2+) from Primary Intracellular Stores. AB - The purpose of the present study is to examine the effects of essential oil of Citrus bergamia Risso (bergamot, BEO) on intracellular Ca(2+) in human umbilical vein endothelial cells. Fura-2 fluorescence was used to examine changes in intracellular Ca(2+) concentration [Ca(2+)]i . In the presence of extracellular Ca(2+), BEO increased [Ca(2+)]i , which was partially inhibited by a nonselective Ca(2+) channel blocker La(3+). In Ca(2+)-free extracellular solutions, BEO increased [Ca(2+)]i in a concentration-dependent manner, suggesting that BEO mobilizes intracellular Ca(2+). BEO-induced [Ca(2+)]i increase was partially inhibited by a Ca(2+)-induced Ca(2+) release inhibitor dantrolene, a phospholipase C inhibitor U73122, and an inositol 1,4,5-triphosphate (IP3)-gated Ca(2+) channel blocker, 2-aminoethoxydiphenyl borane (2-APB). BEO also increased [Ca(2+)]i in the presence of carbonyl cyanide m-chlorophenylhydrazone, an inhibitor of mitochondrial Ca(2+) uptake. In addition, store-operated Ca(2+) entry (SOC) was potentiated by BEO. These results suggest that BEO mobilizes Ca(2+) from primary intracellular stores via Ca(2+)-induced and IP3-mediated Ca(2+) release and affect promotion of Ca(2+) influx, likely via an SOC mechanism. PMID- 24348721 TI - Shenqi fuzheng injection alleviates the transient worsening caused by steroids pulse therapy in treating myasthenia gravis. AB - Purpose. To evaluate the treatment effect and side effect of Shenqi Fuzheng Injection (SFI) on alleviating transient worsening of myasthenia gravis (MG) symptoms caused by high-dose steroids pulse therapy. Methods. Sixty-six consecutive patients with MG were randomly divided into two groups: the treatment group treated with SFI and methylprednisolone pulse therapy (MPT) and the control group treated with MPT alone. The severity of MG before, during, and after MPT and the duration of transient worsening (TW) were evaluated and compared with the clinical absolute scoring (AS) and relative scoring (RS) system. Results. Twenty nine patients experienced TW in each group. At TW, the AS was significantly increased (P < 0.000) in both groups compared with baseline data, with the AS increase in the treatment group (16.8 +/- 2) significantly smaller (P < 0.05) than in the control group (24.9 +/- 2.5). At the end of the treatment course, the AS for the treatment group was significantly decreased (7.5 +/- 0.9) compared with at TW, although no significant difference compared with the control (9.7 +/- 1.1). The TW lasted 1-6 days (mean 3.7) for the treatment group, significantly shorter (P < 0.05) than 2-12 days (mean 7.8) for the control. The RS for the treatment group at the end of treatment was 43.8%-100% (mean 76.8% +/- 2.6%), significantly better than the control group: 33.3%-100% (mean 67.2 +/- 3.6%). Slight side effects (18.75%) included maldigestion and rash in the treatment group. Conclusion. SFI has a better treatment effect and few side effects and can alleviate the severity and shorten the duration of the transient worsening of MG during steroids pulse therapy. PMID- 24348722 TI - Compassionate Love as a Predictor of Reduced HIV Disease Progression and Transmission Risk. AB - Objectives. This study examined if compassionate love (CL) predicts HIV disease progression and transmission risk. Scientific study of CL emerged with Underwood's working model of other-centered CL, defining five criteria: free choice, cognitive understanding, valuing/empowering, openness/receptivity for spirituality, and response of the heart. Method. This 10-year cohort study collected 6-monthly interviews/essays on coping with HIV and trauma of 177 people with HIV in South Florida. Secondary qualitative content analysis on other centered CL inductively added the component of CL towards self. Deductively, we coded the presence of the five criteria of CL and rated the benefit of CL for the recipient on a 6-point Likert scale. Growth-curve modeling (reduced to 4 years due to cohort effects) investigated if CL predicts CD4 slope (HIV disease progression) and cumulative viral load detection (transmission risk). Results. Valuing/empowering and cognitive understanding were the essential criteria for CL to confer long-term benefits. CL had a higher benefit for recipients if given out of free choice. High scores of CL towards self were reciprocal with receiving (93%) and giving (77%) other-centered CL. Conversely, those rated low on CL towards self were least likely to score high on receiving (38%) and giving (49%) other-centered CL. Growth-curve modeling showed that CL towards self predicted 4 year cumulative undetectable viral load (independent from sociocultural differences, substance use disorder, baseline CD4 and viral load). Those high versus low on CL self were 2.25 times more likely to have undetectable viral load at baseline and 1.49 times more likely to maintain undetectable viral load over time. CL towards self predicted CD4 preservation after controlling for differences in CL giving. Conclusions. CL towards self is potentially the seed of being expressive and receptive of CL. Health care professionals prepared to walk the extra mile for those who neglect and isolate themselves may break a vicious circle since those lacking CL self were least likely to receive CL from others. Future studies should examine whether any enhancement of CL towards self may translate into slower disease progression and reduction of transmission risk. PMID- 24348723 TI - A brief analysis of traditional chinese medical elongated needle therapy on acute spinal cord injury and its mechanism. AB - Acute spinal cord injury is one of the most common and complicated diseases among human spinal injury. We aimed to explore the effect of point-through-point acupuncture therapy with elongated needles on acute spinal cord injury in rabbits and its possible mechanism. Adult rabbits were randomly divided into a model group, elongated needle therapy group, and blank group. Immunohistochemical staining showed that the protein levels of Fas and caspase-3 in the model group were significantly higher than those in the blank group at each time point (P < 0.05) and significantly lower than those in the elongated needle therapy group on the 3rd and 5th days after operation (P < 0.05). RT-PCR showed that Fas and caspase-3 mRNA levels in the model group and elongated needle therapy group were significantly higher than those in the blank group (P < 0.05, 0.01). The mRNA levels of Fas and caspase-3 in the elongated needle therapy group were significantly lower than those in model group on the 3rd day (P < 0.05, 0.01). Therefore, we confirmed that elongated needle therapy has an obvious effect on acute spinal cord injury in rabbits. Its mechanism is made possible by inhibiting the expression of the Fas->caspase-3 cascade, thereby inhibiting cell apoptosis after spinal cord injury. PMID- 24348724 TI - Clinical effect of acupuncture on endemic skeletal fluorosis: a randomized controlled trial. AB - Objective. To evaluate the effect of acupuncture on endemic skeletal fluorosis (ESF) through the randomized controlled trial. Methods. Ninety-nine cases were divided into the treatment group (68 cases) and the control group (31 cases) randomly. Normal acupuncture combined with electroacupuncture was used in treatment group, while Caltrate with vitamin D tablets were applied in control group. After 2 courses, the VAS, urinary fluoride, serum calcium, and serum phosphate were evaluated before and after treatment. Results. Both of these two methods could relieve pain effectively and the effect of acupuncture was better (P < 0.05). In treatment group, the content of urinary fluoride after treatment was higher than before (P < 0.05), while the content of serum calcium and phosphate was lower (P < 0.05). Conclusion. The effect of acupuncture on relieving pain and promoting discharge of urinary fluoride is better than that of western medicine. Acupuncture can reduce the content of serum calcium and phosphate. PMID- 24348725 TI - What the iberian conquest bequeathed to us: the fruit trees introduced in argentine subtropic-their history and importance in present traditional medicine. AB - This contribution presents information about the history of introduction, establishment, and local appropriation of Eurasian fruit trees-species and varieties of the genera Prunus and Citrus-from 15th century in two rural areas of Northern Argentina. By means of an ethnobotanical and ethnohistorical approach, our study was aimed at analysing how this process influenced local medicine and the design of cultural landscape that they are still part of. As a first step, local diversity, knowledge, and management practices of these fruit tree species were surveyed. In a second moment, medicinal properties attributed to them were documented. A historical literature was consulted referring to different aspects on introduction of peaches and citric species into America and their uses in the past. The appropriation of these fruit-trees gave place to new applications and a particular status for introduced species that are seen as identitary and contribute to the definition of the communities and daily life landscapes. Besides, these plants, introduced in a relatively short period and with written record, allow the researcher to understand and to design landscape domestication, as a multidimensional result of physical, social, and symbolic environment. PMID- 24348726 TI - Greenselect phytosome for borderline metabolic syndrome. AB - The beneficial effects of Greenselect Phytosome, a proprietary lecithin formulation of a caffeine-free green tea catechin extract, were evaluated in a controlled registry study on 50 asymptomatic subjects borderline for metabolic syndrome factors and with increased plasma oxidative stress. After 24 weeks of intervention, improvement in weight, blood lipid profile, and blood pressure positioned 68% of subjects in the treatment arm out of the metabolic syndrome profile, while 80% of the subjects in the control group still remained in their initial borderline disease signature. Compared to the control (lifestyle and dietary changes alone), Greenselect Phytosome was especially effective for weight/waist changes. These results highlight the relevance of addressing multiple factors involved in the development of metabolic syndrome with a pleiotropic agent capable of improving the beneficial effects of lifestyle and dietary changes and foster the attainment of a globally improved health profile. PMID- 24348727 TI - Chinese herbal medicine for postinfectious cough: a systematic review of randomized controlled trials. AB - Chinese herbal medicine has been commonly used in the treatment of postinfectious cough. The aim of this review is to systematically evaluate the efficacy and safety of Chinese herbal medicine for postinfectious cough. An extensive search for RCTs was performed using multiple electronic databases, supplemented with a manual search. All studies included were confirmed with specific inclusion criteria. Methodological quality of each study was examined according to the Cochrane risk of bias assessment. Quality of evidence was evaluated using rating approach developed by GRADE working group. The literature search yielded 352 results, of which 12 RCTs satisfied the inclusion criteria, offering moderate-to high levels of evidence. Methodological quality was considered high in three trials, while in the other nine studies the unclear risk of bias was in the majority. Findings suggested that, compared with western conventional medicine or placebo, Chinese herbal medicine could effectively improve core symptoms of postinfectious cough, act better and have earlier antitussive effect, and enhance patients' quality of life. No serious adverse event was reported. PMID- 24348728 TI - Flavonoids Identified from Korean Scutellaria baicalensis Georgi Inhibit Inflammatory Signaling by Suppressing Activation of NF- kappa B and MAPK in RAW 264.7 Cells. AB - Scutellaria baicalensis Georgi has been used as traditional medicine for treating inflammatory diseases, hepatitis, tumors, and diarrhea in Asia. Hence, we investigated the anti-inflammatory effect and determined the molecular mechanism of action of flavonoids isolated from Korean S. baicalensis G. in lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages. A 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to examine cytotoxicity of the flavonoids at various concentrations of 10, 40, 70, and 100 ug/mL. No cytotoxicity was observed in RAW 264.7 cells at these concentrations. Furthermore, the flavonoids decreased production of inflammatory mediators such as inducible nitric oxide synthase, cyclooxygenase-2, interleukin 6, and tumor necrosis factor-alpha and inhibited phosphorylation of nuclear factor-kappa B (NF- kappa B) and mitogen-activated protein kinases (MAPKs) in LPS induced RAW 264.7 cells. Moreover, to identify the differentially expressed proteins in RAW 264.7 cells of the control, LPS-treated, and flavonoid-treated groups, two-dimensional gel electrophoresis and mass spectrometry were conducted. The identified proteins were involved in the inflammatory response and included PRKA anchor protein and heat shock protein 70 kD. These findings suggest that the flavonoids isolated from S. baicalensis G. might have anti-inflammatory effects that regulate the expression of inflammatory mediators by inhibiting the NF- kappa B signaling pathway via the MAPK signaling pathway in RAW 264.7 cells. PMID- 24348729 TI - Effectiveness of Interstitial Laser Acupuncture Depends upon Dosage: Experimental Results from Electrocardiographic and Electrocorticographic Recordings. AB - The purpose of this study was to evaluate the influence of the duration of interstitial laser acupuncture therapy effects on neurovegetative and neurobioelectrical parameters like heart rate (HR), heart rate variability (HRV), and electroencephalogram (EEG). We investigated 6 male Sprague-Dawley rats. They underwent 10 min, 20 min, and 30 min interstitial laser acupuncture (in randomized order, with a break of at least 30 min between the different measurement conditions) at the acupoint Neiguan. HR changed significantly only during 20 min red laser stimulation, whereas 10 and 30 min stimulation did not induce significant changes. HRV did not change significantly during any of the different durations; however, an increase was found during 20 min irradiation. Neither the LF/HF ratio of HRV nor the integrated EEG showed significant changes. In this study, it could be experimentally proved that some effects of laser acupuncture are time dependent, and therefore the dosage, as well known from theory, also depends on the time factor. We could especially demonstrate that different treatment times lead to different effects on neurovegetative and neurobioelectrical parameters. Further studies are needed to verify or refute these results. PMID- 24348730 TI - Effects of pretreatment with a combination of melatonin and electroacupuncture in a rat model of transient focal cerebral ischemia. AB - Both melatonin and electroacupuncture (EA) have been suggested to be effective treatments against stroke. However, it is unknown whether a combination of these two therapies could be beneficial against transient focal cerebral ischemia. The present study investigated the effects of pretreatment of a combination of melatonin and EA in a rat model of transient middle cerebral artery occlusion (MCAO). After pretreatment of melatonin plus EA (MEA), transient MCAO was induced for 90 minutes in male Sprague-Dawley (SD) rats. The neurological deficit score, brain infarct volume, cerebral edema ratio, neuronal inflammation, and apoptosis were evaluated 24 hours after transient MCAO. The expression of related inflammatory and apoptotic mediators in the brain was also investigated. The results showed that MEA improved neurological outcome, reduced brain infarct volume, and inhibited neuronal inflammation as well as apoptosis 24 hours after transient MCAO. The beneficial effects may derive from downregulation of proinflammatory and proapoptotic mediators and upregulation of antiapoptotic mediators. Thus, these results suggest a preventive effect of pretreatment of MEA on transient focal cerebral ischemia. PMID- 24348731 TI - Understanding Acupuncture Based on ZHENG Classification from System Perspective. AB - Acupuncture is an efficient therapy method originated in ancient China, the study of which based on ZHENG classification is a systematic research on understanding its complexity. The system perspective is contributed to understand the essence of phenomena, and, as the coming of the system biology era, broader technology platforms such as omics technologies were established for the objective study of traditional chinese medicine (TCM). Omics technologies could dynamically determine molecular components of various levels, which could achieve a systematic understanding of acupuncture by finding out the relationships of various response parts. After reviewing the literature of acupuncture studied by omics approaches, the following points were found. Firstly, with the help of omics approaches, acupuncture was found to be able to treat diseases by regulating the neuroendocrine immune (NEI) network and the change of which could reflect the global effect of acupuncture. Secondly, the global effect of acupuncture could reflect ZHENG information at certain structure and function levels, which might reveal the mechanism of Meridian and Acupoint Specificity. Furthermore, based on comprehensive ZHENG classification, omics researches could help us understand the action characteristics of acupoints and the molecular mechanisms of their synergistic effect. PMID- 24348732 TI - Tai chi chuan exercise for patients with cardiovascular disease. AB - Exercise training is the cornerstone of rehabilitation for patients with cardiovascular disease (CVD). Although high-intensity exercise has significant cardiovascular benefits, light-to-moderate intensity aerobic exercise also offers health benefits. With lower-intensity workouts, patients may be able to exercise for longer periods of time and increase the acceptance of exercise, particularly in unfit and elderly patients. Tai Chi Chuan (Tai Chi) is a traditional Chinese mind-body exercise. The exercise intensity of Tai Chi is light to moderate, depending on its training style, posture, and duration. Previous research has shown that Tai Chi enhances aerobic capacity, muscular strength, balance, and psychological well-being. Additionally, Tai Chi training has significant benefits for common cardiovascular risk factors, such as hypertension, diabetes mellitus, dyslipidemia, poor exercise capacity, endothelial dysfunction, and depression. Tai Chi is safe and effective in patients with acute myocardial infarction (AMI), coronary artery bypass grafting (CABG) surgery, congestive heart failure (HF), and stroke. In conclusion, Tai Chi has significant benefits to patients with cardiovascular disease, and it may be prescribed as an alternative exercise program for selected patients with CVD. PMID- 24348733 TI - Nonnegative mixed-norm convex optimization for mitotic cell detection in phase contrast microscopy. AB - This paper proposes a nonnegative mix-norm convex optimization method for mitotic cell detection. First, we apply an imaging model-based microscopy image segmentation method that exploits phase contrast optics to extract mitotic candidates in the input images. Then, a convex objective function regularized by mix-norm with nonnegative constraint is proposed to induce sparsity and consistence for discriminative representation of deformable objects in a sparse representation scheme. At last, a Support Vector Machine classifier is utilized for mitotic cell modeling and detection. This method can overcome the difficulty in feature formulation for deformable objects and is independent of tracking or temporal inference model. The comparison experiments demonstrate that the proposed method can produce competing results with the state-of-the-art methods. PMID- 24348734 TI - Regularized multidirections and multiscales anisotropic diffusion for sinogram restoration of low-dosed computed tomography. AB - Although most of existing anisotropic diffusion (AD) methods are supported by prefect mathematical theories, they still lead to smoothed edges and anatomy details (EADs). They are caused by not considering the discrete nature of digital signal. In order to improve the performance of AD in sinogram restoration of low dosed computed tomography (LDCT), we propose a new AD method, named regularized multidirections and multiscales anisotropic diffusion (RMDMS-AD), by extending AD to regularized AD (RAD) in multidirections and multiscales. Since the multidirections can reduce the discrete errors to the maximum extent, meanwhile multiscales and RAD make searching neighborhood of solution be as large as possible which can get more optimal solution to AD, the new proposed method can improve the performance of AD both in denoising and in stability of solution. Moreover, the discrete errors and ill-posed solutions occur mostly near the EADs; the RMDMS-AD will also preserve EADs well. Comparing the proposed new method to existing AD methods using real sinogram, the new method shows good performance in EADs preserving while denoising and suppressing artifacts. PMID- 24348735 TI - Lp-norm regularization in volumetric imaging of cardiac current sources. AB - Advances in computer vision have substantially improved our ability to analyze the structure and mechanics of the heart. In comparison, our ability to observe and analyze cardiac electrical activities is much limited. The progress to computationally reconstruct cardiac current sources from noninvasive voltage data sensed on the body surface has been hindered by the ill-posedness and the lack of a unique solution of the reconstruction problem. Common L2- and L1-norm regularizations tend to produce a solution that is either too diffused or too scattered to reflect the complex spatial structure of current source distribution in the heart. In this work, we propose a general regularization with Lp-norm (1 < p < 2) constraint to bridge the gap and balance between an overly smeared and overly focal solution in cardiac source reconstruction. In a set of phantom experiments, we demonstrate the superiority of the proposed Lp-norm method over its L1 and L2 counterparts in imaging cardiac current sources with increasing extents. Through computer-simulated and real-data experiments, we further demonstrate the feasibility of the proposed method in imaging the complex structure of excitation wavefront, as well as current sources distributed along the postinfarction scar border. This ability to preserve the spatial structure of source distribution is important for revealing the potential disruption to the normal heart excitation. PMID- 24348737 TI - A novel CT imaging system with adjacent double X-ray sources. AB - Current computed tomography (CT) scanners rotate fast to reduce motion artifact. X-ray tube must work in a high power to make the image clear under short exposure time. However, the life span of such a tube may be shortened. In this paper, we propose a novel double sources CT imaging system, which puts two of the same X ray sources closely with each other. The system is different from current dual source CT with orthogonal X-ray sources. In our system, each projection is taken twice by these two sources to enhance the exposure value and then recovered to a single source projection for image reconstruction. The proposed system can work like normal single source CT system, while halving down the working power for each tube. PMID- 24348736 TI - Fast and automatic ultrasound simulation from CT images. AB - Ultrasound is currently widely used in clinical diagnosis because of its fast and safe imaging principles. As the anatomical structures present in an ultrasound image are not as clear as CT or MRI. Physicians usually need advance clinical knowledge and experience to distinguish diseased tissues. Fast simulation of ultrasound provides a cost-effective way for the training and correlation of ultrasound and the anatomic structures. In this paper, a novel method is proposed for fast simulation of ultrasound from a CT image. A multiscale method is developed to enhance tubular structures so as to simulate the blood flow. The acoustic response of common tissues is generated by weighted integration of adjacent regions on the ultrasound propagation path in the CT image, from which parameters, including attenuation, reflection, scattering, and noise, are estimated simultaneously. The thin-plate spline interpolation method is employed to transform the simulation image between polar and rectangular coordinate systems. The Kaiser window function is utilized to produce integration and radial blurring effects of multiple transducer elements. Experimental results show that the developed method is very fast and effective, allowing realistic ultrasound to be fast generated. Given that the developed method is fully automatic, it can be utilized for ultrasound guided navigation in clinical practice and for training purpose. PMID- 24348738 TI - Vascular tree segmentation in medical images using Hessian-based multiscale filtering and level set method. AB - Vascular segmentation plays an important role in medical image analysis. A novel technique for the automatic extraction of vascular trees from 2D medical images is presented, which combines Hessian-based multiscale filtering and a modified level set method. In the proposed algorithm, the morphological top-hat transformation is firstly adopted to attenuate background. Then Hessian-based multiscale filtering is used to enhance vascular structures by combining Hessian matrix with Gaussian convolution to tune the filtering response to the specific scales. Because Gaussian convolution tends to blur vessel boundaries, which makes scale selection inaccurate, an improved level set method is finally proposed to extract vascular structures by introducing an external constrained term related to the standard deviation of Gaussian function into the traditional level set. Our approach was tested on synthetic images with vascular-like structures and 2D slices extracted from real 3D abdomen magnetic resonance angiography (MRA) images along the coronal plane. The segmentation rates for synthetic images are above 95%. The results for MRA images demonstrate that the proposed method can extract most of the vascular structures successfully and accurately in visualization. Therefore, the proposed method is effective for the vascular tree extraction in medical images. PMID- 24348739 TI - Modeling the chemoelectromechanical behavior of skeletal muscle using the parallel open-source software library OpenCMISS. AB - An extensible, flexible, multiscale, and multiphysics model for nonisometric skeletal muscle behavior is presented. The skeletal muscle chemoelectromechanical model is based on a bottom-up approach modeling the entire excitation-contraction pathway by strongly coupling a detailed biophysical model of a half-sarcomere to the propagation of action potentials along skeletal muscle fibers and linking cellular parameters to a transversely isotropic continuum-mechanical constitutive equation describing the overall mechanical behavior of skeletal muscle tissue. Since the multiscale model exhibits separable time scales, a special emphasis is placed on employing computationally efficient staggered solution schemes. Further, the implementation builds on the open-source software library OpenCMISS and uses state-of-the-art parallelization techniques taking advantage of the unique anatomical fiber architecture of skeletal muscles. OpenCMISS utilizes standardized data structures for geometrical aspects (FieldML) and cellular models (CellML). Both standards are designed to allow for a maximum flexibility, reproducibility, and extensibility. The results demonstrate the model's capability of simulating different aspects of nonisometric muscle contraction and efficiently simulating the chemoelectromechanical behavior in complex skeletal muscles such as the tibialis anterior muscle. PMID- 24348740 TI - Local temporal correlation common spatial patterns for single trial EEG classification during motor imagery. AB - Common spatial pattern (CSP) is one of the most popular and effective feature extraction methods for motor imagery-based brain-computer interface (BCI), but the inherent drawback of CSP is that the estimation of the covariance matrices is sensitive to noise. In this work, local temporal correlation (LTC) information was introduced to further improve the covariance matrices estimation (LTCCSP). Compared to the Euclidean distance used in a previous CSP variant named local temporal CSP (LTCSP), the correlation may be a more reasonable metric to measure the similarity of activated spatial patterns existing in motor imagery period. Numerical comparisons among CSP, LTCSP, and LTCCSP were quantitatively conducted on the simulated datasets by adding outliers to Dataset IVa of BCI Competition III and Dataset IIa of BCI Competition IV, respectively. Results showed that LTCCSP achieves the highest average classification accuracies in all the outliers occurrence frequencies. The application of the three methods to the EEG dataset recorded in our laboratory also demonstrated that LTCCSP achieves the highest average accuracy. The above results consistently indicate that LTCCSP would be a promising method for practical motor imagery BCI application. PMID- 24348741 TI - Power and stability properties of resampling-based multiple testing procedures with applications to gene oncology studies. AB - Resampling-based multiple testing procedures are widely used in genomic studies to identify differentially expressed genes and to conduct genome-wide association studies. However, the power and stability properties of these popular resampling based multiple testing procedures have not been extensively evaluated. Our study focuses on investigating the power and stability of seven resampling-based multiple testing procedures frequently used in high-throughput data analysis for small sample size data through simulations and gene oncology examples. The bootstrap single-step minP procedure and the bootstrap step-down minP procedure perform the best among all tested procedures, when sample size is as small as 3 in each group and either familywise error rate or false discovery rate control is desired. When sample size increases to 12 and false discovery rate control is desired, the permutation maxT procedure and the permutation minP procedure perform best. Our results provide guidance for high-throughput data analysis when sample size is small. PMID- 24348742 TI - Low-dose and scatter-free cone-beam CT imaging using a stationary beam blocker in a single scan: phantom studies. AB - Excessive imaging dose from repeated scans and poor image quality mainly due to scatter contamination are the two bottlenecks of cone-beam CT (CBCT) imaging. Compressed sensing (CS) reconstruction algorithms show promises in recovering faithful signals from low-dose projection data but do not serve well the needs of accurate CBCT imaging if effective scatter correction is not in place. Scatter can be accurately measured and removed using measurement-based methods. However, these approaches are considered unpractical in the conventional FDK reconstruction, due to the inevitable primary loss for scatter measurement. We combine measurement-based scatter correction and CS-based iterative reconstruction to generate scatter-free images from low-dose projections. We distribute blocked areas on the detector where primary signals are considered redundant in a full scan. Scatter distribution is estimated by interpolating/extrapolating measured scatter samples inside blocked areas. CS based iterative reconstruction is finally carried out on the undersampled data to obtain scatter-free and low-dose CBCT images. With only 25% of conventional full scan dose, our method reduces the average CT number error from 250 HU to 24 HU and increases the contrast by a factor of 2.1 on Catphan 600 phantom. On an anthropomorphic head phantom, the average CT number error is reduced from 224 HU to 10 HU in the central uniform area. PMID- 24348743 TI - Transformation of physical DVHs to radiobiologically equivalent ones in hypofractionated radiotherapy analyzing dosimetric and clinical parameters: a practical approach for routine clinical practice in radiation oncology. AB - PURPOSE: The purpose of this study was to transform DVHs from physical to radiobiological ones as well as to evaluate their reliability by correlations of dosimetric and clinical parameters for 50 patients with prostate cancer and 50 patients with breast cancer, who were submitted to Hypofractionated Radiotherapy. METHODS AND MATERIALS: To achieve this transformation, we used both the linear quadratic model (LQ model) and the Niemierko model. The outcome of radiobiological DVHs was correlated with acute toxicity score according to EORTC/RTOG criteria. RESULTS: Concerning the prostate radiotherapy, there was a significant correlation between RTOG acute rectal toxicity and D50 (P < 0.001) and V60 (P = 0.001) dosimetric parameters, calculated for alpha/beta = 10 Gy. Moreover, concerning the breast radiotherapy there was a significant correlation between RTOG skin toxicity and V(>=60) dosimetric parameter, calculated for both alpha/beta = 2.3 Gy (P < 0.001) and alpha/beta = 10 Gy (P < 0.001). The new tool seems reliable and user-friendly. CONCLUSIONS: Our proposed model seems user friendly. Its reliability in terms of agreement with the presented acute radiation induced toxicity was satisfactory. However, more patients are needed to extract safe conclusions. PMID- 24348744 TI - Mathematical modeling of the HIV/Kaposi's sarcoma coinfection dynamics in areas of high HIV prevalence. AB - We formulate a deterministic system of ordinary differential equations to quantify HAART treatment levels for patients co-infected with HIV and Kaposi's Sarcoma in a high HIV prevalence setting. A qualitative stability analysis of the equilibrium states is carried out and we find that the disease-free equilibrium is globally attracting whenever the reproductive number Rk < 1. A unique endemic equilibrium exists and is locally stable whenever Rk > 1. Therefore, reducing Rk to below unity should be the goal for disease eradication. Provision of HAART is shown to provide dual benefit of reducing HIV spread and the risk of acquiring another fatal disease for HIV/AIDS patients. By providing treatment to 10% of the HIV population, about 87% of the AIDS population acquire protection against coinfection with HIV and Kaposi's Sarcoma (KS). Most sub-Sahara African countries already have programmes in place to screen HIV. Our recommendation is that these programmes should be expanded to include testing for HHV-8 and KS counseling. PMID- 24348745 TI - Three-dimensional reconstruction of coronary arteries and its application in localization of coronary artery segments corresponding to myocardial segments identified by transthoracic echocardiography. AB - OBJECTIVES: To establish 3D models of coronary arteries (CA) and study their application in localization of CA segments identified by Transthoracic Echocardiography (TTE). METHODS: Sectional images of the heart collected from the first CVH dataset and contrast CT data were used to establish 3D models of the CA. Virtual dissection was performed on the 3D models to simulate the conventional sections of TTE. Then, we used 2D ultrasound, speckle tracking imaging (STI), and 2D ultrasound plus 3D CA models to diagnose 170 patients and compare the results to coronary angiography (CAG). RESULTS: 3D models of CA distinctly displayed both 3D structure and 2D sections of CA. This simulated TTE imaging in any plane and showed the CA segments that corresponded to 17 myocardial segments identified by TTE. The localization accuracy showed a significant difference between 2D ultrasound and 2D ultrasound plus 3D CA model in the severe stenosis group (P < 0.05) and in the mild-to-moderate stenosis group (P < 0.05). CONCLUSIONS: These innovative modeling techniques help clinicians identify the CA segments that correspond to myocardial segments typically shown in TTE sectional images, thereby increasing the accuracy of the TTE-based diagnosis of CHD. PMID- 24348747 TI - GPU-based block-wise nonlocal means denoising for 3D ultrasound images. AB - Speckle suppression plays an important role in improving ultrasound (US) image quality. While lots of algorithms have been proposed for 2D US image denoising with remarkable filtering quality, there is relatively less work done on 3D ultrasound speckle suppression, where the whole volume data rather than just one frame needs to be considered. Then, the most crucial problem with 3D US denoising is that the computational complexity increases tremendously. The nonlocal means (NLM) provides an effective method for speckle suppression in US images. In this paper, a programmable graphic-processor-unit- (GPU-) based fast NLM filter is proposed for 3D ultrasound speckle reduction. A Gamma distribution noise model, which is able to reliably capture image statistics for Log-compressed ultrasound images, was used for the 3D block-wise NLM filter on basis of Bayesian framework. The most significant aspect of our method was the adopting of powerful data parallel computing capability of GPU to improve the overall efficiency. Experimental results demonstrate that the proposed method can enormously accelerate the algorithm. PMID- 24348746 TI - A gradient boosting algorithm for survival analysis via direct optimization of concordance index. AB - Survival analysis focuses on modeling and predicting the time to an event of interest. Many statistical models have been proposed for survival analysis. They often impose strong assumptions on hazard functions, which describe how the risk of an event changes over time depending on covariates associated with each individual. In particular, the prevalent proportional hazards model assumes that covariates are multiplicatively related to the hazard. Here we propose a nonparametric model for survival analysis that does not explicitly assume particular forms of hazard functions. Our nonparametric model utilizes an ensemble of regression trees to determine how the hazard function varies according to the associated covariates. The ensemble model is trained using a gradient boosting method to optimize a smoothed approximation of the concordance index, which is one of the most widely used metrics in survival model performance evaluation. We implemented our model in a software package called GBMCI (gradient boosting machine for concordance index) and benchmarked the performance of our model against other popular survival models with a large-scale breast cancer prognosis dataset. Our experiment shows that GBMCI consistently outperforms other methods based on a number of covariate settings. GBMCI is implemented in R and is freely available online. PMID- 24348748 TI - Evaluation of treatment in the Smart Home IRIS in terms of functional independence and occupational performance and satisfaction. AB - The development of assistive technologies, home modifications, and smart homes has rapidly advanced in the last two decades. Health professionals have recognised the benefits of these technologies in improving individual's quality of life. The Smart Home IRIS was established in 2008 within the University Rehabilitation Institute in Ljubljana with the aim to enable persons with disabilities and elderly people to test various assistive technologies and technical solutions for their independent living. We investigated the effect of treatments in the Smart Home IRIS. A convenience sample of 59 persons with disabilities and elderly people (aged 24-81 years) who were treated in the Smart Home IRIS from April to December 2011 participated. Standardised instruments--the Canadian Occupational Performance Measure (COPM) and the Functional Independence Measure (FIM)--were administered at the first assessment in the Smart Home IRIS and at a second assessment at the participant's home after 6-12 months. All the outcomes statistically significantly improved from the first to the second assessment. The treatments in the Smart Home IRIS appeared to contribute to higher occupational performance and satisfaction with performance and higher functional independence of persons with disabilities and elderly people. PMID- 24348749 TI - A voxel-map quantitative analysis approach for atherosclerotic noncalcified plaques of the coronary artery tree. AB - Noncalcified plaques (NCPs) are associated with the presence of lipid-core plaques that are prone to rupture. Thus, it is important to detect and monitor the development of NCPs. Contrast-enhanced coronary Computed Tomography Angiography (CTA) is a potential imaging technique to identify atherosclerotic plaques in the whole coronary tree, but it fails to provide information about vessel walls. In order to overcome the limitations of coronary CTA and provide more meaningful quantitative information for percutaneous coronary intervention (PCI), we proposed a Voxel-Map based on mathematical morphology to quantitatively analyze the noncalcified plaques on a three-dimensional coronary artery wall model (3D-CAWM). This approach is a combination of Voxel-Map analysis techniques, plaque locating, and anatomical location related labeling, which show more detailed and comprehensive coronary tree wall visualization. PMID- 24348750 TI - InterRett, a model for international data collection in a rare genetic disorder. AB - Rett syndrome (RTT) is a rare genetic disorder within the autistic spectrum. This study compared socio-demographic, clinical and genetic characteristics of the international database, InterRett, and the population based Australian Rett syndrome database (ARSD). It also explored the strengths and limitations of InterRett in comparison with other studies. A literature review compared InterRett with RTT population-based and case-based studies of thirty or more cases that investigated genotype and/or phenotype relationships. Questionnaire data were used to determine case status and to investigate the comparability of InterRett and ARSD. Twenty four case series, five population based studies and a MECP2 mutation database were identified of which twenty one (70%) collected phenotype and genotype data. Only three studies were representative of their underlying case population and many had low numbers. Of one thousand one hundred and fourteen InterRett subjects, nine hundred and thirty five born after 1976 could be verified as Rett cases and compared with the two hundred and ninety five ARSD subjects. Although more InterRett families had higher education and occupation levels and their children were marginally less severe, the distribution of MECP2 mutation types was similar. The InterRett can be used with confidence to investigate genotype phenotype associations and clinical variation in RTT and provides an exemplary international model for other rare disorders. PMID- 24348752 TI - A Pocock approach to sequential meta-analysis of clinical trials. AB - Three recent papers have provided sequential methods for meta-analysis of two treatment randomized clinical trials. This paper provides an alternate approach that has three desirable features. First, when carried out prospectively (i.e., we only have the results up to the time of our current analysis), we do not require knowledge of the information fraction (the fraction of the total information that is available at each analysis). Second, the methods work even if the expected values of the effect sizes vary from study to study. Finally, our methods have easily interpretable metrics that make sense under changing effect sizes. Although the other published methods can be adapted to be "group sequential" (recommended), meaning that a set number and timing of looks are specified, rather than looking after every trial, ours can be used in both a continuous or group sequential manner. We provide an example on the role of probiotics in preventing necrotizing enterocolitis in preterm infants. PMID- 24348751 TI - Advances in Therapeutic Options for Gait and Balance in Parkinson's Disease. AB - There is a need to explore non-dopaminergic approaches to treating balance and gait problems in PD. There is emerging evidence on the role of cholinergic denervation of the PPN-thalamus system and falls in PD. Preliminary clinical trial data suggest that the subgroup of PD patients with frequent falls may be suitable candidates for future cholinergic augmentation clinical trials. Recent controlled clinical trials using methylphenidate have been unable to confirm earlier reports of improved gait in PD. Although progressive deterioration of axial motor symptoms occur with DBS of the STN or GPi, new preliminary research suggests that other surgical stimulation sites, such as the PPN, may have a potential benefit on gait and balance impairments in PD. Ongoing vigorous exercise and physical fitness should be highly encouraged to patients with PD who are at risk of physical deconditioning and fear of falling but effective anti fall physical therapy interventions remain an unmet clinical need. PMID- 24348753 TI - Photo-Reactive Nanogel as a Means to Tune Properties during Polymer Network Formation. AB - Photo-reactive nanogels with an integrated photoinitiator-based functionality were synthesized via a Reversible Addition-Fragmentation Chain Transfer (RAFT) process. Without additional free initiators, this nanogel is capable of radical generation and initiating polymerization of a secondary monomer (i.e. dimethacrylate) that infiltrates and disperses the nanogel particles. Due to the presence of RAFT functionality and the fact that all initiating sites are initially located within the nanogel structure, gelation can be delayed by sequencing the polymerization from the nanogel to the bulk matrix. During polymerization of a nanogel-filled resin system, a progressive delay of gelation conversion from about 2 % for conventional chain growth polymerization to 18 % for the same monomer containing 20 wt% nanogel additive was achieved. A significant delay of stress development was also observed with much lower final stress achieved with the nanogel-modified systems due to the change of network formation mechanics. Compared with the nanogel-free dimethacrylate control, which contained uniformly distributed free initiator, the flexural modulus and mechanical strength results were maintained for the photopolymers with nanogel contents greater than 10 wt%. There appears to be a critical interparticle spacing of the photo-reactive nanogel that provides effective photopolymerization while providing delayed gelation and substantial stress reduction. PMID- 24348754 TI - Human papillomavirus oncoproteins and apoptosis (Review). AB - The aim of this study was to review the literature and identify the association between human papillomavirus (HPV) oncoproteins and apoptosis. HPV-associated apoptosis may be primarily blocked by a number of oncoproteins, including E5, E6 and E7. E5 protein protects cells from tumor necrosis factor-associated apoptosis; the oncoprotein E6 predominantly inhibits apoptosis through the p53 pathway; and oncoprotein E7 is involved in apoptosis activation and inhibition. In addition, HPV oncoproteins are involved in activating or repressing the transcription of E6/E7. In conclusion, HPV oncoproteins, including E5, E6 and E7 protein, may interfere with apoptosis via certain regulatory principles. PMID- 24348755 TI - Pancreaticobiliary maljuction combining with pancreas divisum: Report of four cases. AB - Pancreaticobiliary maljunction (PBM) is an unusual anomalous condition in which the pancreatic duct and bile duct merge outside the duodenal wall and form a long common channel. Pancreas divisum (PD) is a congenital anomaly in which the dorsal and ventral pancreatic ducts fail to fuse. Endoscopic retrograde cholangiopancreatography (ERCP) is the gold standard for diagnosing PD and magnetic resonance cholangiopancreatography (MRCP) is the non-invasive choice. In this study, four cases of patients with unusual PBM in addition to PD are described. The patients presented with abdominal pain, which was caused by distal biliary stricture diagnosed by MRCP. The patients received ERCP and had a good prognosis. PMID- 24348757 TI - Mechanisms of the immunosuppressive effects of mouse adipose tissue-derived mesenchymal stromal cells on mouse alloreactively stimulated spleen cells. AB - The mechanisms of immunomodulation by mesenchymal stromal cells remain poorly understood. In this study, the effects of mouse adipose tissue-derived mesenchymal stromal cells (ASCs) on mouse spleen cells alloreactively stimulated by anti-CD3 and anti-CD28 antibody-coated (anti-CD3/CD28) beads were observed. Production of interferon-gamma by the anti-CD3/CD28 bead-stimulated spleen cells was significantly suppressed in co-culture with ASCs. However, an augmented intensity of CD69 on the stimulated spleen cells was not suppressed in the presence of ASCs. The immunosuppressive effects of ASCs were partially mediated by one or more soluble factors (26% suppression). However, the ASCs require cell cell contact in order to maximally exert suppression (88%). The suppressive effect of ASCs mediated by direct cell contact was partially reversed following knockdown of beta2 microglobulin, a component of the major histocompatibility complex (MHC) class I molecule, with siRNA. The results of the study demonstrated that ASCs have significant immune modulatory effects on alloreactively stimulated spleen cells. The effects of ASCs on spleen cells are dependent on soluble factor(s) and cell contact, which is mediated by the MHC class I complex on ASCs. PMID- 24348756 TI - Protective effect of the ultra-filtration extract from Xin Mai Jia on human aortic smooth muscle cell injury induced by hydrogen peroxide. AB - The aim of the present study was to explore whether an ultra-filtration extract from Xin Mai Jia (XMJ), a Chinese medicinal formulation, has a protective effect on human aortic smooth muscle cell (HASMC) injury models induced by hydrogen peroxide (H2O2), and to consider the mechanism and efficacy of the therapeutic action of XMJ on atherosclerosis. HASMCs were injured by H2O2 and then exposed to various concentrations of XMJ. The morphological changes, growth, proliferation, migration and cytokine release of HASMCs were detected using 2,3-bis-(2-methoxy-4 nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT), an enzyme-linked immunosorbent assay and a scratch adhesion test. H2O2 significantly promoted the proliferation of HASMCs. The ultra-filtration extract from XMJ was observed to significantly attenuate the morphological changes of injured HASMCs, reduce the expression levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), interleukin (IL)-1, IL-6 and nuclear factor (NF) kappaB, and increase the expression levels of matrix metalloproteinase (MMP)-2 and tissue inhibitor of metalloproteinase (TIMP). XMJ has clear anti-inflammatory and antioxidant effects, and significantly inhibits the proliferation and migration of HASMCs. PMID- 24348758 TI - Quantitative analysis of vascular calcification. AB - Vascular calcification is a prominent feature of atherosclerosis. The mineral composition and quantity within calcified arterial plaques remains unelucidated; therefore, the aim of this study was to analyze the mineral composition of such plaques. Calcified arterial plaques were obtained from patients with abdominal aortic aneurysms (AAAs) and carotid artery stenoses. Calcified aneurysmal plaques were obtained during the routine open repair of AAAs, while calcified carotid plaques were collected from patients who underwent carotid endarterectomy (CEA). Following the appropriate preparation of each sample, inductively coupled plasma atomic emission spectrometry (ICP-AES) was used to analyze the calcium and phosphate levels, while flame atomic absorption spectrometry (FAAS) was used to analyze the levels of iron and zinc. The levels of these mineral components were evaluated. In the aortic and carotid plaques, the mean calcium concentration was 9.83 and 11.94 wt.%, respectively, and the mean phosphate concentration was 4.31 and 6.08 wt.%, respectively. It was not possible to analyze the absolute concentration of iron in the carotid plaques due to the concentration being below the measurement limit. The zinc concentration was variable between samples. In conclusion, the main components of aortic and carotid plaques are calcium and phosphate. The mineral concentrations of the plaques in the present study may be used as reference values for further studies on vascular calcification. More studies are required to elucidate the correlation between the mineral components and vascular calcification. PMID- 24348759 TI - Efficacy of once or twice weekly administration of epoetin kappa in patients receiving hemodialysis: A retrospective study. AB - Several clinically approved recombinant erythropoietin (rEPO) preparations, such as epoetin-beta, epoetin-delta and the epoetin-alpha derivative, darbepoetin alpha, have been commercially produced. Since the expiration of patent protection, a number of novel rEPO biosimilars have been approved on the world market. In 2010, epoetin-kappa, which is biosimilar to epoetin-alpha, was clinically approved. Epoetin-kappa is a biopharmaceutical product that is based on serum-free media following master cell bank preparation. The present study analyzes the results obtained during a six-month observation period, in which the administration of epoetin-beta was switched to that of epoetin-kappa. In a cohort of patients receiving chronic dialysis, who were clinically in a state of relative calm and were in control of their renal anemia, it was possible to sustain good control of the anemia by reducing the frequency of the epoetin-beta administration from the conventional and empirically determined three times a week to twice a week, and further to once a week. Furthermore, the good control was maintained upon changing from the administration of epoetin-beta to that of epoetin-kappa. Moreover, three months subsequent to this switch, the degree of instability observed among the patients had decreased. Despite the fact that the situation following the changeover requires further investigation, it may be concluded that the results obtained in this study are indicative of the clinical equivalence and efficacy of epoetin-kappa. PMID- 24348760 TI - Null anticarcinogenic effect of silymarin on diethylnitrosamine-induced hepatocarcinogenesis in rats. AB - The aim of this study was to investigate the anticarcinogenic effects of silymarin in diethylnitrosamine (DEN)-induced hepatocarcinogenic rat models. Severe and mild models of hepatocellular carcinoma (HCC) were generated by the intraperitoneal administration of 40 mg/kg DEN once a week for 18 weeks and 100 mg/kg DEN every 2 weeks for 6 weeks in male Wistar rats, respectively. In the severe and mild models of HCC, the rats were treated with 0.1 and 0.5% silymarin for 18 weeks and with 0.1% silymarin for 5 weeks, respectively. Serum transaminase levels were not significantly decreased by the silymarin treatment in either model. Macroscopic and microscopic features indicated that the silymarin-containing formulations did not significantly inhibit the hepatic tumor formation induced by DEN. Furthermore, immunohistochemical and western blot analyses demonstrated that the expression levels of proliferating cell nuclear antigen and glutathione S-transferase P, which are hepatocarcinogenic markers, were not significantly modified by the silymarin treatment. These results indicate that silymarin may not be considered as a candidate agent against hepatocarcinogenesis. PMID- 24348762 TI - A comparison of oxytocin and carboprost tromethamine in the prevention of postpartum hemorrhage in high-risk patients undergoing cesarean delivery. AB - The aim of this study was to compare carboprost with oxytocin for the prevention of postpartum hemorrhage (PPH) in females with a high risk of PPH undergoing cesarean delivery. Patients were randomly divided into three groups that received different uterotonics (oxytocin, carboprost and oxytocin plus carboprost) during cesarean section, following the delivery of the infant. A total of 117 females (age range, 19-40 years) at 35-40 weeks gestation who delivered by cesarean between December, 2010 and May, 2012 were included in this study. There were 29 cases of twins, 12 cases of polyhydramnios, 23 cases of placenta previa and 53 cases of fetal macrosomia. There were 37 patients in the oxytocin group, 36 in the carboprost group and 44 in the oxytocin plus carboprost group. No significant differences were identified in maternal age, gravidity/parity, gestational age and reason for cesarean delivery between the three groups. The median blood loss in the oxytocin, carboprost and oxytocin plus carboprost groups was 610, 438 and 520 ml, respectively. The blood loss in the carboprost group was significantly lower than that in the oxytocin and oxytocin plus carboprost groups (both P<0.05). Vomiting occurred in eight patients from the carboprost group, two from the oxytocin group and two from the oxytocin plus carboprost group (P=0.036). Carboprost was more effective than oxytocin in preventing PPH in high-risk patients undergoing cesarean delivery. PMID- 24348761 TI - Pyrrolidine dithiocarbamate (PDTC) inhibits the overexpression of MCP-1 and attenuates microglial activation in the hippocampus of a pilocarpine-induced status epilepticus rat model. AB - The aim of this study was to investigate the effects of pyrrolidine dithiocarbamate (PDTC) on MCP-1 expression and microglial activation in the hippocampus of a rat model of pilocarpine (PILO)-induced status epilepticus (SE). Moreover, seizure susceptibility, frequency and severity as well as brain damage were analyzed and changes in behavior were recorded. Chemokine MCP-1 expression and microglial activation were detected by immunohistochemistry (IHC). Fluoro Jade C (FJC) and NeuN staining were used for the evaluation of tissue damage. Our results showed that although SE resulted in the upregulation of MCP-1 and microglial activation in the rat hippocampus 24 h after seizure onset, pretreatment with PDTC significantly inhibited the MCP-1 overexpression and attenuated the microglial activation. These effects were accompanied by neurodegenerative amelioration. To the best of our knowledge, these findings indicated for the first time that the activation of the nuclear factor-kappaB (NF kappaB) pathway may contribute to MCP-1 upregulation and microglial activation in the context of epilepsy. PDTC was also shown to exert anticonvulsant activity and to have a neuroprotective effect on the hippocampal CA1 and CA3 regions, potentially through attenuating microglial activation. PMID- 24348763 TI - A novel technique for central hepatectomy: Maintain the blood supply and biliary drainage on one side and the blood supply from the portal vein on the other. AB - Central hepatectomy is amongst the most difficult surgeries of liver tumors. For the routine local excision of a tumor, if the tumor has invaded the blood vessels or bile duct of the liver, then half of the liver or three lobes of the liver are resected. This results in two major drawbacks, one of which is that the residual hepatic lobe may not compensate for the damage, so it is not possible to perform conventional partial resection. The other is that the volume of normal liver tissue removed may be much more than the volume of tumor removed, causing substantial waste. In the present study, surgery was performed to resect a central liver tumor. In that surgery, the V segment and parts of the IV, VI and VIII segments were resected, and the blood supply and biliary drainage of the left hepatic lobe were kept intact. However, for the remaining VI, VII and VIII segments of the right hepatic lobe, only the blood supply from the portal vein was maintained and no arterial blood supply or biliary drainage was kept so that the patient had the opportunity to undergo radical resection and successful rehabilitation. The reason these opportunities may be possible is that the residual right liver is a temporary replacement therapy in the perioperative period. Therefore, for central hepatic tumors, particularly tumors that have invaded the neighboring bile ducts or blood vessels, if the blood supply and biliary drainage on one side is maintained and the blood supply to the other side from the portal vein is kept intact, then it is possible to perform radical resection. This provides a novel approach to the clinical resection of central liver tumors. PMID- 24348765 TI - Intractable epilepsy due to angiocentric glioma: A case report and minireview. AB - The aim of this case report and minireview was to investigate the diagnosis of and therapeutic approaches for angiocentric glioma (AG) and to summarize the clinical manifestations and the pathological and imaging characteristics of the disease. Intraoperative cortical electroencephalogram (ECoG) monitoring was performed to locate the epileptic foci in a child with AG who presented with intractable epilepsy, prior to the total resection of the tumor being performed under the microscope. The clinical features, imaging characteristics, intraoperative conditions, surgical methods and pathological results were analyzed and compared with the literature. The review revealed that to date, the clinical features of the 52 reported cases of AG (including this case) have been mainly characterized by epilepsy. High T2-weighted image (WI) and fluid attenuated inversion recovery (FLAIR) signals may be detected with magnetic resonance imaging (MRI) scanning of the cranium; however, no enhancement signals are detected by enhanced scanning. The prognosis following surgical resection is favorable. The lesions in the present case demonstrated clear boundaries with a central cystic affection accompanied by an arachnoid cyst on the left temporal pole. Pathological examination revealed that the lesion was positive for glial fibrillary acidic protein (GFAP), S-100 protein, vimentin, epithelial membrane antigen (EMA), cluster of differentiation 99 (CD99) and D2-40. The Ki-67/MIBk-1 labeling index was ~1%. In conclusion, AG exhibits characteristic features in imaging; however, its diagnosis depends on histopathological examination. The prognosis of total surgical resection is good and intraoperative ECoG may be used to assist positioning. PMID- 24348764 TI - Stimulation of the proliferation of human normal esophageal epithelial cells by fumonisin B1 and its mechanism. AB - Previous epidemiological studies have demonstrated a correlation between fumonisin B1 (FB1) and human esophageal cancer in China, Iran and South Africa. The purpose of this study was to investigate the effects of FB1 on the proliferation, cell-cycle and apoptosis of normal human esophageal epithelial cells (HEECs) and to explore the molecular mechanisms of these effects. The proliferation of HEECs treated with FB1 was assessed using a colorimetric assay, while analyses of the cell cycle and apoptosis were performed using flow cytometry and the measurement of the protein expressions of genes associated with the cell cycle was conducted using western blotting. The results showed that FB1 stimulated the proliferation of HEECs, decreased the percentage of cells in the G0/G1 phase and reduced apoptosis. The western blotting results showed that FB1 significantly increased the protein expression of cyclin D1 and significantly decreased the protein expression of cyclin E, p21 and p27. The results indicated that FB1 stimulated the proliferation of HEECs by affecting the cell cycle and apoptosis. This mechanism was associated with changes in cyclin D1, cyclin E, p21 and p27 expression. PMID- 24348766 TI - MEK inhibition reduces glial scar formation and promotes the recovery of sensorimotor function in rats following spinal cord injury. AB - The aim of this study was to investigate the effect of U0126 on the formation of glial scars following spinal cord injury (SCI) in a rat model. Ninety adult female Sprague-Dawley rats were divided randomly into sham injury (group I), SCI (group II) and U0126 treatment (group III) groups, and functional outcome was observed during the 4 weeks following the injury. The P1 and N1 latencies and P1 N1 amplitudes of somatosensory-evoked potentials (SEPs) were collected one day prior to surgery, on the day of surgery and 14 and 28 days postoperatively. The expression levels of glial fibrillary acidic protein (GFAP) and vimentin (Vim) were assessed 14 and 28 days post-injury. Treatment with U0126 significantly increased locomotor function from the second week until 4 weeks post-SCI. At 14 and 28 days subsequent to the injury, the number of cells that were positive for GFAP expression in the U0126-treated group was significantly reduced and the GFAP positive cells were observed to be smaller, with a reduced prominence and pale staining. Moreover, the area of glial scarring was smaller compared with that of the SCI controls. Inhibitors of MEK may reduce glial scar formation by suppressing the proliferation of astrocytes, and may improve hindlimb motor function. PMID- 24348767 TI - Analysis of mitochondrial transcription factor A SNPs in alcoholic cirrhosis. AB - Genetic susceptibility to alcoholic cirrhosis (AC) exists. We previously demonstrated hepatic mitochondrial DNA (mtDNA) damage in patients with AC compared with chronic alcoholics without cirrhosis. Mitochondrial transcription factor A (mtTFA) is central to mtDNA expression regulation and repair; however, it is unclear whether there are specific mtTFA single nucleotide polymorphisms (SNPs) in patients with AC and whether they affect mtDNA repair. In the present study, we screened mtTFA SNPs in patients with AC and analyzed their impact on the copy number of mtDNA in AC. A total of 50 patients with AC, 50 alcoholics without AC and 50 normal subjects were enrolled in the study. SNPs of full-length mtTFA were analyzed using the polymerase chain reaction (PCR) combined with gene sequencing. The hepatic mtTFA mRNA and mtDNA copy numbers were measured using quantitative PCR (qPCR), and mtTFA protein was measured using western blot analysis. A total of 18 mtTFA SNPs specific to patients with AC with frequencies >10% were identified. Two were located in the coding region and 16 were identified in non-coding regions. Conversely, there were five SNPs that were only present in patients with AC and normal subjects and had a frequency >10%. In the AC group, the hepatic mtTFA mRNA and protein levels were significantly lower than those in the other two groups. Moreover, the hepatic mtDNA copy number was significantly lower in the AC group than in the controls and alcoholics without AC. Based on these data, we conclude that AC-specific mtTFA SNPs may be responsible for the observed reductions in mtTFA mRNA, protein levels and mtDNA copy number and they may also increase the susceptibility to AC. PMID- 24348768 TI - Effects of Porphyromonas gingivalis lipopolysaccharide on osteoblast-osteoclast bidirectional EphB4-EphrinB2 signaling. AB - In bone remodeling, the Eph family is involved in regulating the process of osteoclast and osteoblast coordination in order to maintain bone homeostasis. In this study, the effects of Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) on the osteoblast-osteoclast bidirectional EphB4-EphrinB2 signaling were investigated. An osteoblast-osteoclast co-culture system was achieved successfully. Hence, direct contact and communication between osteoblasts and osteoclasts was permitted. Regarding the protein expression and gene expression of EphB4 and EphrinB2, it was shown that Pg-LPS increased the expression of EphB4 while inhibiting the expression of EphrinB2. Therefore, the results indicate that, when treated with Pg-LPS, the EphB4 receptor on osteoblasts and the EphrinB2 ligand on osteoclasts may generate bidirectional anti-osteoclastogenic and pro-osteoblastogenic signaling into respective cells and potentially facilitate the transition from bone resorption to bone formation. This study may contribute to the control of osteoblast differentiation and bone formation at remodeling, and possibly also modeling, sites. PMID- 24348770 TI - Solitary schwannoma of the sural nerve: An unusual clinical presentation. AB - Schwannomas may arise from any peripheral nerve containing Schwann cells. However, sural nerve schwannoma is extremely rare. In this study, a case of solitary schwannoma originating from the sural nerve in a 42-year-old male is presented. Physical examination revealed a 3-cm, elastic-hard, mobile, non-tender mass, while neurovascular examinations, including Tinel's sign, were normal. Magnetic resonance imaging revealed an oval-shaped subcutaneous mass with iso signal intensity relative to skeletal muscle on T1-weighted sequences. T2 weighted spectral presaturation with inversion recovery sequences showed higher signal intensity peripherally and lower signal intensity centrally, representing a target sign. Contrast-enhanced T1-weighted sequences demonstrated a marked central enhancement of the mass. The tumor was completely enucleated using an intracapsular technique. Histological examination confirmed the diagnosis of a schwannoma, consisting mainly of Antoni A tissue. The patient had no evidence of local recurrence and no neurological deficit at the final follow-up. Although rare, schwannoma should be considered in the differential diagnosis of a well defined, oval, subcutaneous mass in the posterior aspect of the lower leg. PMID- 24348769 TI - Correlation of fibrinogen-like protein 2 with disease progression in patients with severe acute pancreatitis. AB - It has recently been demonstrated that fibrinogen-like protein 2 (fgl2) is expressed on the surface of macrophages, T cells and endothelial cells and directly cleaves prothrombin to thrombin. The present study was designed to examine fgl2 expression in patients with severe acute pancreatitis (SAP) and its correlation with disease progression. Peripheral blood mononuclear cells (PBMCs) were isolated from 25 patients with SAP, 37 patients with mild acute pancreatitis (MAP) and 20 healthy volunteers as controls. Paraffin sections of pancreas were obtained from 18 postoperative patients with SAP between 2003 and 2012. Human fgl2 (hfgl2) gene expression was determined in the PBMCs by real-time PCR. A monoclonal antibody against hfgl2 was applied to detect hfgl2 protein expression in the pancreatic tissues as well as in the PBMCs by immunohistochemical staining. The levels of hfgl2 expression in the PBMCs from the 25 patients with SAP were markedly upregulated compared with the other groups, whereas no significant difference between the MAP group and healthy controls was observed. hfgl2 expression in the PBMCs and pancreatic tissues was detectable through using immunohistochemistry and was demonstrated to be specifically localized to the endothelium of microvessels and inflammatory infiltrative cells in the areas of acute focal, confluent necrosis. There were positive correlations between hfgl2 expression in the PBMCs and the severity of SAP, as indicated by scores of Ranson and Acute Physiology and Chronic Health Evaluation II. The results suggest that hfgl2 is involved in the pathogenesis of SAP and hfgl2 levels may serve as a biomarker during disease progression. PMID- 24348771 TI - Establishment and primary clinical application of competitive inhibition for measurement of augmenter of liver regeneration. AB - The aim of the present study was to establish a quantitative method for the measurement of serum human augmenter of liver regeneration (hALR) using competitive inhibition that is applicable in the clinic. A monoclonal antibody to hALR was used as the primary antibody and the pure hALR protein was used as a standard for competition with Eu3+-labeled hALR (Eu3+-hALR) to plot a standard curve. Serum samples from 90 patients with various liver diseases due to hepatitis B virus (HBV) infection were used for a competitive reaction with Eu3+ hALR. A regression analysis of the results was performed using the standard curve to calculate the serum concentration of hALR. The minimum detectable value using direct competitive measurement established by Eu3+-hALR was 1 ng/ml, with a positive linear correlation within the range of 200 ng/ml. In the sera of the 90 patients, the hALR level in the severe hepatitis group was the highest, followed by that in the acute hepatitis group. The serum hALR levels in the cirrhosis and chronic hepatitis groups were significantly higher compared with those in the normal control groups (P<0.01). The direct competitive measurement method of serum hALR established in the present study has high sensitivity, specificity, stability and reliability, meets clinical requirements and may be used as potential index in clinical tests. PMID- 24348772 TI - Intravenous immunoglobulin in the therapy of adult acute fulminant myocarditis: A retrospective study. AB - Acute fulminant myocarditis (AFM) is a serious heart disease with limited treatment. This observational retrospective study aimed to investigate whether intravenous immunoglobulin (IVIG) was able to improve left ventricular function and reduce the episodes of arrhythmia in adult patients with AFM. The medical records of all patients with AFM who were admitted to the Critical Care Unit of Guangdong General Hospital (Guangzhou, China) between January 2001 and December 2010 were reviewed. A cohort of 58 patients was included in the study. Of these 58, 32 patients were treated with IVIG (400 mg/kg per day) for five days, while the remaining patients did not receive IVIG therapy. The patients who received IVIG therapy had a higher left ventricular ejection fraction (LVEF) and a reduced left ventricular end-diastolic diameter (LVDD) compared with the non-IVIG therapy patients four weeks subsequent to the treatment (PLVEF=0.011 and PLVDD=0.048). The post-treatment incidence of ventricular tachycardia/ventricular fibrillation (VT/VF) and atrioventricular block (AVB) was reduced in the patients who received IVIG therapy compared with the baseline values (PVT/VF=0.025, PAVB=0.003); however, no significant differences were observed in the non-IVIG therapy patients (PVT/VF=0.564, PAVB=0.083) following treatment. There were two mortalities in the IVIG therapy group and seven in the non-IVIG therapy group (P=0.072). This retrospective study suggested that the use of IVIG for the treatment of AFM may be associated with improved left ventricular function and reduced episodes of fulminant arrhythmias. PMID- 24348773 TI - Thrombolytic and anticoagulant therapy for acute submassive pulmonary embolism. AB - This study aimed to compare the efficacy and safety of thrombolytic and anticoagulant therapy for acute submassive pulmonary embolism (PE). A retrospective evaluation was performed on 25 consecutive inpatients with acute submassive PE treated by thrombolytic therapy and 25 earlier consecutive inpatients with acute submassive PE treated by anticoagulant therapy. No statistically significant difference in clinical curative effect was identified between the thrombolysis and anticoagulation groups (P>0.05). Following 24 h of therapy, the improvement rates of dyspnea and revascularization in the thrombolysis group achieved statistical significance compared with those of the anticoagulation group (P<0.01 for each). The PO2 level of the thrombolysis group (81.18+/-5.66 mmHg) was notably higher than that of the anticoagulation group and the difference was statistically significant (P<0.01). The pulmonary arterial pressures of the thrombolysis group (51.21+/-6.86 mmHg) were significantly lower than those of the anticoagulation group (60.64+/-5.17 mmHg) (P<0.01). Furthermore, the difference between the hemorrhage rates of the two groups was statistically significant (P<0.05). Thrombolysis was shown to rapidly relieve dyspnea, reduce pulmonary arterial pressure and revascularize the embolized blood vessels. However, the hemorrhage rate of the thrombolysis group was higher than that of the anticoagulation group. The overall efficacies and fatality rates of the thrombolysis and anticoagulation groups were similar. PMID- 24348774 TI - Alpinetin activates the delta receptor instead of the kappa and MU receptor pathways to protect against rat myocardial cell apoptosis. AB - Alpinetin is a natural flavonoid that protects cells against fatal injury in ischemia-reperfusion. delta receptor activation protects myocardial cells from trauma; however, the mechanism is unknown. The aim of this study was to explore the function of alpinetin in delta receptor-mediated myocardial apoptosis. The myocardial cells of newly born rats were cultivated and myocardial apoptosis was induced by serum deprivation. The MTT method was used to evaluate cell viability and Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining was used to analyze apoptosis. The expression levels of opioid receptor mRNA and protein were tested using reverse transcription-polymerase reaction (RT-PCR) and western blot assays. In addition, an opioid receptor antagonist, as well as protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) inhibitors, were used to determine the inferred signaling pathway. The results showed that that alpinetin reduced the myocardial apoptosis induced by serum deprivation in a concentration-dependent manner. However, the protection conferred to the myocardial cells by alpinetin was blocked by the delta opioid receptor antagonist naltrindole, as well as by PKC and ERK inhibitors (GF109203X and U0126, respectively). In addition, it was shown that alpinetin was able to maintain the stability of the mitochondrial membrane potential, lower the level of intracytoplasmic cytochrome c and reduce Bax displacement from the cytoplasm to the mitochondria. It was concluded that alpinetin was able to activate delta receptors to induce the endogenous protection of myocardial cells via the PKC/ERK signaling pathway. PMID- 24348775 TI - Postconditioning with rosuvastatin reduces myocardial ischemia-reperfusion injury by inhibiting high mobility group box 1 protein expression. AB - High mobility group box 1 protein (HMGB1) plays an important role in myocardial ischemia-reperfusion (I/R) injury. Rosuvastatin (RS) preconditioning has been reported to reduce myocardial I/R injury. The aim of this study was to investigate whether postconditioning with RS is able to reduce myocardial I/R injury by inhibiting HMGB1 expression in rats. Anesthetized male rats were subjected to ischemia for 30 min and treated once with RS (10 mg/kg, i.v.) 5 min prior to reperfusion for 4 h. Lactate dehydrogenase (LDH), creatine kinase (CK) and superoxide dismutase (SOD) activities, malondialdehyde (MDA) levels and infarct size were measured. HMGB1 expression was assessed by immunoblotting. The results showed that RS postconditioning significantly decreased the infarct size and the activities of LDH and CK following 4 h reperfusion (all P<0.05). RS postconditioning also significantly inhibited the increase of MDA levels and the reduction of SOD activity (both P<0.05). RS postconditioning was able to significantly inhibit the HMGB1 expression induced by I/R. The present study suggested that postconditioning with RS reduces myocardial I/R injury, which may be associated with the inhibition of HMGB1 expression. PMID- 24348776 TI - A study exploring critical pathways in clear cell renal cell carcinoma. AB - Renal cell carcinoma (RCC) is the most lethal type of cancer in the urinary system and often presents as a metastatic disease. Furthermore, there are no effective treatments for the disease. Several studies based on gene expression profiling have been performed with the aim of gaining insights into the pathogenesis of RCC; however, few studies have investigated RCC at the pathway level to search for the possible pathways involved in clear cell RCC (CCRCC). In this study, gene set enrichment analysis (GSEA) was conducted on microarray datasets from CCRCC tissue. DAVID functional enrichment analysis was performed based on the dysregulated genes that were identified in a meta-analysis performed on the microarray datasets from CCRCC tissue. In GSEA, 17 down- and 12 upregulated pathways coexisted in six datasets. The majority of the upregulated pathways were associated with the immune system. In addition, 32 dysregulated pathways were obtained from DAVID functional enrichment analysis, based on the abnormal genes identified by meta-analysis. This study demonstrated that cross GSEA is a useful method for exploring the critical pathways involved CCRCC; however, an individual dataset with a small sample may introduce bias. A cross GSEA based on certain well-designed datasets may be required to further the progress made in this study, following the analysis of its results. PMID- 24348777 TI - Evaluation of the revised versus the simplified scoring system in patients with autoimmune hepatitis. AB - The aim of this study was to evaluate the simplified and revised scoring systems for the diagnosis of autoimmune hepatitis (AIH). Seventy-seven patients diagnosed with AIH via the revised scoring system were enrolled in this study. Statistical analysis was performed by means of the chi2 test and logistic regression analysis. A total of 39 patients with definite AIH and 38 patients with probable AIH were diagnosed by the revised scoring system, whereas among these 77 patients, the simplified scoring system classified nine cases as definite AIH, 39 as probable AIH and 29 without AIH. In this study, the parameters contributing to the discrepant diagnosis of AIH were compared using the revised and simplified systems. A chi2 test showed that antinuclear antibody (ANA) or smooth muscle antibody (SMA) titers were significantly lower in the patients with discrepant diagnoses (chi2=15.0, P=0.001). Logistic regression with backward selection revealed that for the discrepant diagnosis of patients, the presence of other concurrent autoimmune diseases [odds ratio (OR)=7.25; P=0.018; 95% confidence interval (CI), 1.41-37.29] was the only independent risk factor. In addition, the presence of anti-soluble liver antigen/liver-pancreas antigen (SLA/LP) or perinuclear antineutrophil cytoplasmic antibody (pANCA) (OR=0.12; P=0.022; 95% CI, 0.02-0.74), the level of immunoglobulin G (IgG) with 1-1.1 * Normal (N) (OR=0.02; P=0.044; 95% CI, 0.00-0.89) and ANA or SMA titers >=1:80 (OR=0.04; P=<0.001; 95% CI, 0.01-0.23) were three independent protective factors. In conclusion, the revised scoring system has a superior performance in the diagnosis of patients with AIH compared with the simplified scoring system. According to the simplified scoring system, other concurrent autoimmune diseases are the risk factor for the AIH diagnosis. PMID- 24348778 TI - Changes in monoclonal HLA-DR antigen expression in acute organophosphorus pesticide-poisoned patients. AB - The aim of this study was to investigate changes in human leukocyte antigen (HLA) DR expression of peripheral blood mononuclear cells (MNCs) in patients with acute organophosphorus pesticide poisoning (AOPP). HLA-DR antigen expression of peripheral blood MNCs was examined in 75 patients with AOPP, including 36 patients without multiple organ dysfunction syndrome (non-MODS) and 39 patients with multiple organ dysfunction syndrome (MODS), as well as in 30 healthy individuals using flow cytometry assay. The associations between HLA-DR antigen expression and certain parameters were analyzed, including acute physiology and chronic health evaluation II (APACHE II) score, serum cholinesterase (ChE) activity, cardiac troponin I (cTnI), cardiac enzymes, and liver and kidney function. The mean fluorescence intensity (MCF) of HLA-DR expression in the AOPP group (21.59+/-5.36) was significantly lower than that in the control group (27.85+/-4.86) (P<0.001). The MCF in the MODS group (18.17+/-4.23) was lower than that in the non-MODS group (25.15+/-6.15). In addition, the MCF of the deceased patients (15.29+/-3.97) was lower than that of the surviving patients (22.34+/ 2.76) (P<0.001). The MCF of patients with AOPP and MODS was positively correlated with serum ChE (P<0.01) and negatively correlated with the APACHE II score, creatine kinase isoenzyme, cTnI, lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen and serum creatinine (P<0.05). In conclusion, HLA-DR expression in patients with AOPP was significantly decreased compared with that in healthy individuals; HLA-DR expression may therefore be a good indicator for evaluating AOPP, MODS disease severity, immune function, efficacy of prognosis and prognosis. Examination of HLA-DR antigen expression may be of crucial clinical value. PMID- 24348779 TI - A case of veno-occlusive disease following liver transplantation. AB - The present case report describes the diagnosis and treatment of a patient with veno-occlusive disease (VOD) following liver transplantation. Combining the clinical data and relevant literature, the study aimed to consider the causes of VOD following liver transplantation, and the pathogenesis, clinical diagnosis and auxiliary examination features of VOD. A 42-year-old man who had a long history of taking traditional Chinese medicine (essential components unknown) underwent an orthotropic liver transplantation on January 14, 2011, due to small venous occlusion disease of the liver. The patient was treated with tacrolimus as an antirejection therapy following the surgery, and gradually developed right upper quadrant pain and fatigue. The examination results were consistent with the diagnostic standards for VOD. Following treatment with methylprednisolone, the patient was treated with alprostadil and Danhong injections. Forty days later, the patient's total bilirubin (TBIL) level was observed to have decreased significantly, the liver function had returned to normal and the ascites had decreased, but had not completely disappeared. The patient then underwent a transjugular intrahepatic portosystemic shunt (TIPS) procedure, following which the ascites were shown to have completely disappeared. PMID- 24348780 TI - Clinical features in different age groups of patients with autoimmune hepatitis. AB - The Chinese population are at an increased risk of autoimmune hepatitis (AIH). The aims of this study were to determine the demographic and clinical features of AIH in China. A total of 83 patients with AIH diagnosed by the revised scoring system were re-analyzed, and the clinical presentations among the different ages were compared. The patients were classified according to age at presentation. AIH occurred in patients aged <=30 years (9.6%), 31-39 years (10.8%), 40-49 years (16.9%), 50-59 years (31.3%) and >=60 years (31.3%). There were no differences in the form of the clinical presentation, concurrent autoimmune diseases, cirrhosis distribution and autoantibodies among the groups. However, patients aged >=60 years presented with higher levels of alkaline phosphatase (ALP) and gamma glutamyl transpeptidase (gamma-GT) compared with patients aged <=30 years (P=0.034, P=0.043, respectively), and patients aged 31-39 years had a significantly lower immunoglobulin G (IgG) level compared with those aged 50-59 years (P=0.049) and those aged >=60 years (P=0.012). By contrast, patients aged <=30 years had a significantly higher total bilirubin (TBIL) level compared with those aged 31-39 years (P=0.007), 50-59 years (P=0.002) and >=60 years (P=0.013). A substantial portion of patients with AIH were aged >60 years, indicating a poor liver-associated outcome under current management strategies. Elderly patients appeared to be more asymptomatic compared with the younger patients. PMID- 24348781 TI - Elevated NKT cell levels in adults with severe chronic immune thrombocytopenia. AB - The aim of this study was to investigate the frequency of circulating natural killer T (NKT) cells and regulatory T cells (Tregs), as well as serum cytokine profiles, in adult chronic primary immune thrombocytopenia (ITP). The frequency of circulating T cell receptor (TCR) Valpha24+Vbeta11+CD3+ NKT cells and CD4+CD25+CD127-/low Tregs was measured using multi-color flow cytometry. The serum concentrations of 11 cytokines were determined with a cytometric bead assay. The frequency of circulating NKT cells in patients with ITP was 0.13+/ 0.03%, whereas the frequency in healthy controls was 0.07+/-0.01% of CD3+ (P>0.05). However, the frequency of NKT cells in patients with ITP with platelet counts <=20*109/l (0.22+/-0.05%) was significantly higher than that in patients with platelet counts >20*109/l (0.05+/-0.01%; P<0.05) and that in healthy controls (0.07+/-0.01%; P<0.05). The frequency of peripheral Tregs was comparable between patients with ITP (3.97+/-0.44% of CD4+) and healthy controls (3.69+/ 0.31%; P>0.05). No significant differences were observed in the serum concentrations of 11 cytokines between patients with ITP and healthy controls, despite the fact that the serum levels of interleukin (IL)-12p70, IL-8, IL-4, interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha in patients with ITP were higher than those in the healthy controls. The platelet count was negatively correlated with the frequency of circulating NKT cells in chronic ITP. These results indicate that NKT cells may be involved in ITP with severe thrombocytopenia, and NKT and Tregs may be important in cytokine deregulation in chronic ITP. PMID- 24348782 TI - Correlation between the single nucleotide polymorphisms of the human phosphodiesterase 4D gene and the risk of cerebral infarction in the Uygur and Han ethnic groups of Xinjiang, China. AB - In this study, the correlation between the single nucleotide polymorphisms (SNPs) at rs2910829 and rs918592 in the phosphodiesterase 4D (PDE4D) gene and cerebral infarction in the Uygur and Han ethnic groups of Xinjiang, China were examined. The study population consisted of 373 Uygur and Han patients with cerebral infarction and 377 Uygur and Han control participants with no nervous system diseases. Polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP) and gene sequencing methods were used to assess the SNPs at the rs2910829 and rs918592 loci in the PDE4D gene. The differences in genotype and allele frequency distribution were compared between the two groups. The C allele frequency of the rs2910829 locus in the PDE4D gene of the cerebral infarction group (81.0%) was significantly higher than that of the control group (76.4%) (P<0.05). Furthermore, the A allele frequency of the rs918592 locus in the PDE4D gene in the Uygur cerebral infarction group was significantly higher than that of the Uygur control group (P<0.05). There were no significant differences in the genotype and allele frequency distributions between the Uygur and Han groups (P>0.05). The A allele of the rs918592 locus may be associated with the occurrence of cerebral infarction in the Uygur population. In addition, it was indicated that the C allele of the rs2910829 locus in the PDE4D gene confers susceptibility to cerebral infarction; however, no significant difference was identified between Uygur and Han patients with cerebral infarction. PMID- 24348783 TI - deltaEF1 upregulates CDK4 transcription via the E2-box element on the CDK4 promoter. AB - The zinc finger-homeodomain transcription factor, delta-crystallin enhancer factor 1 (deltaEF1) has been identified as a regulatory factor involved in the promotion of breast cancer cell proliferation via the downregulation of p21 and the upregulation of cyclin-dependent kinase-2 (CDK2) and CDK4 expression. However, the molecular mechanisms underlying the regulation of CDK4 expression by deltaEF1 have not yet been elucidated. The present study demonstrated that the ectopic expression of deltaEF1 in MDA-MB-231 breast cancer cells significantly increased the activity of the CDK4 promoter. Deletion of the E2-box (CACGTG), which is located at position -197/-191 on the human CDK4 promoter, significantly attenuated the activation of CDK4 transcription by deltaEF1. In addition, a CDK4 promoter-M construct was generated via site-directed mutagenesis of the E2-box on the human CDK4 promoter. Luciferase assay showed that the activation of CDK4 promoter-M activity by deltaEF1 was markedly decreased compared with the CDK4 promoter-0.4k promoter. Knockdown of deltaEF1 using RNA interference resulted in the inhibition of CDK4 promoter activity. These observations suggest that deltaEF1 upregulates CDK4 transcription via the E2-box element on the CDK4 promoter. PMID- 24348784 TI - Protective effect of Panax quinquefolium 20(S)-protopanaxadiol saponins, isolated from Pana quinquefolium, on permanent focal cerebral ischemic injury in rats. AB - Oxidative stress is significant in the pathogenesis of cerebral ischemia. Panax quinquefolium 20(S)-protopanaxadiol saponins (PQDS) have been demonstrated to exhibit a variety of biological effects in the cardiovascular system as a result of their antioxidant properties. However, little is known regarding the effect of PQDS on cerebral ischemia. The purpose of this study was to investigate whether PQDS exhibited protective effects against cerebral ischemia. A model of cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in Sprague-Dawley rats. Adult male rats were randomly divided into five groups: Sham, MCAO and PQDS treatment groups at doses of 12.5, 25.0 and 50.0 mg/kg. The effects of PQDS on neurological deficits, cerebral infarct area, brain water content, and the malondialdehyde (MDA) and Ca2+ levels and Na+-K+-ATPase and superoxide dismutase (SOD) activities in the brain tissue were analyzed, and the nitric oxide (NO) content and nitric oxide synthase (NOS) activity in the serum were evaluated. Moreover, the expression of Bcl-2 was analyzed using western blotting. Pretreatment with PQDS (25.0 and 50.0 mg/kg) significantly reduced the neurological deficit score, decreased the infarcted area and decreased the brain water content from 83.09 to 80.27% (P<0.05). In addition, PQDS pretreatment decreased the NOS activity and the NO levels in the serum compared with those in the MCAO group. Furthermore, pretreatment with PQDS (25.0 and 50.0 mg/kg) significantly increased the activities of SOD and Na+-K+-ATPase and decreased the levels of Ca2+ and MDA in the brain tissue (P<0.05) compared with those in the MCAO group. Pretreatment with PQDS (25.0 and 50.0 mg/kg) also increased the protein expression level of Bcl-2 compared with that in the MCAO group. The histopathological results demonstrated the protective effect of PQDS on ischemic injury. The results indicated that PQDS has protective effects against ischemic injury in rats. The mechanism may be associated with the inhibition of oxidative stress and apoptosis. PMID- 24348785 TI - Correlation between superoxide dismutase 1 and 2 polymorphisms and susceptibility to oral squamous cell carcinoma. AB - Oxidative stress is significant in numerous types of cancer. Tobacco smoke, an important risk factor for oral squamous cell carcinoma (OSCC), is able to generate reactive oxygen species (ROS) and cause oxidative DNA damage. Superoxide dismutase (SOD) is an endogenous antioxidant enzyme that is critical in limiting the oxidative burden effectively. The purpose of this study was to investigate the effects of the mitochondrial SOD2 and Cu/Zn enzyme SOD1 gene polymorphisms on the susceptibility to and clinicopathological characteristics of OSCC, as well as the synergistic effect between these gene polymorphisms and the well-known risk factor of tobacco consumption. Patients with clinically diagnosed OSCC (n=362) and healthy normal individuals (n=358) were investigated for four single nucleotide polymorphisms (SNPs; rs4880, rs5746136, rs1804450 and rs11556620) by polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing methods. Following adjustment for other confounders, no significant difference was observed in the rs5746136 SOD2 SNPs between the patients and controls. However, the incidence of the CT genotype of SOD2 SNP rs4880 was higher in the patients than in normal subjects in the additive model [CT vs. TT; P=0.045; adjusted odds ratio (AOR)=1.484; 95% confidence interval (CI), 1.009 2.182] and in the dominant model (CT/CC vs. TT; P=0.022; AOR=1.559; 95% CI, 1.067 2.278). For those who smoked, the incidence of the CT genotype of rs4880 increased markedly in the patients compared with the controls in the additive model (CT vs. TT; P=0.003; AOR=2.325; 95% CI, 1.330-4.064) and in the dominant model (CT/CC vs. TT; P=0.001; AOR=2.448; 95% CI, 1.417-4.230). For SOD1, polymorphisms at rs1804450 and rs11556620 were not present in any of the OSCC or control subjects. The results suggest that SOD2 rs4880 may be involved in the tumorigenesis of OSCC and may be useful as a genetic susceptibility marker for OSCC. PMID- 24348786 TI - Forsythiaside attenuates lipopolysaccharide-induced inflammatory responses in the bursa of Fabricius of chickens by downregulating the NF-kappaB signaling pathway. AB - Forsythiaside, a phenylethanoside product isolated from air-dried fruits of Forsythia suspensa, has been demonstrated to exhibit antioxidant, antibacterial and anti-inflammatory activities in vitro. However, its mechanism and the effects of lipopolysaccharide (LPS)-induced injury on the bursa of Fabricius (BF) of chickens are poorly understood. The present study aimed to investigate the anti inflammatory effects of forsythiaside on LPS-induced acute inflammation. In addition, the potential molecular mechanisms of forsythiaside were analyzed in the BF, a special immune organ in chickens. Forty 15-day-old chickens were randomly divided into control, LPS and LPS plus forsythiaside (30 or 60 mg/kg) groups (n=10 for each group). In the LPS plus forsythiaside (30 or 60 mg/kg) groups, the chickens were orally administered with forsythiaside at doses of 30 and 60 mg/kg for seven days. At 21 days old, the chickens were intravenously injected with 200 MUg/kg body weight LPS. Chickens in the control and LPS groups were only administered with vehicle or LPS, respectively, at day 21. At 3 h post injection, the body temperature and nitric oxide (NO) levels were analyzed. In addition, the levels and mRNA expression of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-1beta, and the mRNA expression of nuclear factor-kappaB (NF-kappaB), cyclooxygenase-2 (COX 2) and inducible NO synthase (iNOS), were examined in the BFs isolated from the chickens. The results revealed that forsythiaside was able to attenuate the LPS induced inflammatory responses in the BFs of the chickens. The mechanisms by which forsythiaside exerted its anti-inflammatory effect were found to correlate with the inhibition of IL-6, IL-1beta, TNF-alpha and COX-2 production, via the inactivation of NF-kappaB, indicating that the NF-kappaB-iNOS-NO signaling pathway may be important in this process. PMID- 24348787 TI - Clinicopathological features and prognosis of pseudomyxoma peritonei. AB - The aim of this study was to evaluate the effects of treatment and the factors influencing the postoperative recurrence and survival time for pseudomyxoma peritonei (PMP). A total of 39 patients with PMP who received treatment were analyzed in The General Hospital of PLA (Beijing, China) between 2002 and 2011. The patients received cytoreductive surgery (CRS) and 25 cases of PMP recurred. Seven patients received postoperative hyperthermic intraperitoneal chemoperfusion (HIPEC). The median follow-up was 40 months. There were eight mortalities in this period. The 5- and 10-year survival rates were 89.0 and 35.0%, respectively. The medians of overall survival (OS) and recurrence time were 37 and 4 months, respectively. Multivariate analyses revealed that pathological subtype was able to influence the recurrence (P=0.042) and OS (P=0.033) times, as an independent prognostic factor. HIPEC was significantly associated with postoperative recurrence time (P=0.017). Patients with disseminated peritoneal adenomucinosis had a more favorable prognosis. CRS combined with HIPEC was able to extend the postoperative recurrence time for patients with PMP. PMID- 24348788 TI - Apoptosis and p53 expression in the placental villi of females with unexplained recurrent spontaneous abortion. AB - The aim of this study was to explore the level of apoptosis and p53 expression in the placental villi of patients with unexplained recurrent spontaneous abortion (URSA). Fifty-three pregnant females with URSA and 32 pregnant females who required an induced abortion were selected as the subjects of this study. Placental villus tissues were collected from June 2010 to June 2012 and quantitative polymerase chain reaction (qPCR) and immunohistochemical analysis were performed to determine the mRNA and protein levels of p53 in the placental villus tissues. The level of apoptosis in the tissues was studied using terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) assay. The mRNA and protein expression levels of p53 in the URSA group were significantly higher than those in the control group (P<0.05). Furthermore, the levels of apoptosis were increased markedly in the URSA group compared with the control group (P<0.05). In conclusion, the placental villi of patients with URSA express a high level of p53, which may result in cell apoptosis and lead to recurrent spontaneous abortion. PMID- 24348789 TI - Role of nuclear factor of activated T cells 1 in the pathogenesis of osteoarthritis. AB - Osteoarthritis (OA) is the most common form of joint disease in middle-aged individuals and the elderly. Previous studies have shown that the overexpression of matrix-degrading proteinases and proinflammatory cytokines is associated with the degradation of osteoarthritic cartilage. However, the transcription factors involved remain unclear. The present study aimed to determine the expression levels of nuclear factor of activated T cells 1 (NFAT1), interleukin-1beta (IL 1beta) and tumor necrosis factor-alpha (TNF-alpha) in patients with OA, and to validate the role of NFAT1 in the pathogenesis of OA. The expression levels of NFAT1, IL-1beta and TNF-alpha in chondrocytes in the cartilage of patients with OA and healthy individuals were evaluated using western blot analysis. A luciferase reporter assay was performed to determine the activity of NFAT1 in primary human chondrocytes that were transfected with pNFAT1-luc plasmid and stimulated by IL-1beta. An enzyme-linked immunosorbent assay was performed to detect the levels of TNF-alpha, matrix metalloproteinase (MMP)-1, MMP-3 and MMP-9 in the supernatant of cultured chondrocytes in which the NFAT1 was silenced. The expression levels of NFAT1, IL-1beta and TNF-alpha in the cartilage of patients with OA were higher than those of the controls. IL-1beta induced the expression of NFAT1 in primary chondrocytes. The expression levels of TNF-alpha, MMP-1, -3 and -9 promoted by IL-1beta were decreased in NFAT1-silenced chondrocytes. In conclusion, NFAT1 may be important in the pathogenesis of OA and calcineurin-NFAT inhibitors may be potential effective agents for the treatment of OA. PMID- 24348790 TI - MDCT and MRI for the diagnosis of complex fractures of the tibial plateau: A case control study. AB - The aim of this study was to evaluate the clinical value of multidetector-row computed tomography (MDCT) and magnetic resonance imaging (MRI) in the diagnosis and treatment of complex fractures of the tibial plateau. A total of 71 patients with complex fractures of the tibial plateau (estimated Schatzker classifications III, V and VI) were included in this study. The X-ray, MDCT and MRI data obtained from the patients were analyzed. MDCT was the most sensitive method in the diagnosis of tibial articular surface collapse, cruciate ligament tibial avulsion fracture, degree of fracture comminution and degree of fracture displacement (P<0.01). MRI was the most sensitive method in the diagnosis of injuries of the cruciate and collateral ligaments, menisci and cartilage peeling of the articular surfaces (P<0.01). MDCT and MRI were demonstrated to be more sensitive than X rays for the diagnosis of insidious damage around the knee. PMID- 24348791 TI - Construction and identification of the recombinant plasmid pET30a-EgA31-Eg95 of Echinococcus granulosus. AB - To clone the Eg95 and EgA31 antigen genes into the prokaryotic expression plasmid pET30a-EgA31-Eg95, we expressed the recombinant protein EgA31-Eg95 and confirmed with western blot analysis. The total RNA was extracted from the protoscoleces of Echinococcus granulosus (E. granulosus) adult worms. The complementary DNA (cDNA) encoding the EgA31 antigen was amplified via quantitative real-time polymerase chain reaction (qPCR). The recombinant plasmid pET30a-EgA31 was used as a carrier and was connected with the Eg95 vector. The recombinant plasmid pET30a-EgA31-Eg95 was constructed and the fusion protein EgA31-Eg95 was detected using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The positive clone was the empty recombinant vector. The recombinant protein pET30a-EgA31-Eg95 was ~46 kDa, and the expressed product accounted for approximately 20% of the total soluble proteins. We successfully constructed the recombinant plasmid pET30a EgA31-Eg95 and expressed the recombinant protein EgA31-Eg95. The results may be the foundation of research on its immunogenicity in the future. PMID- 24348792 TI - UPLC-PDA determination of paeoniflorin in rat plasma following the oral administration of Radix Paeoniae Alba and its effects on rats with collagen induced arthritis. AB - Rheumatoid arthritis (RA) is a chronic disabling autoimmune disease with characteristics of chronic, progressive inflammatory joint synovial damage, which mainly encroaches upon the synovium of the joint. The use of traditional medicine to treat RA slows the development of RA to a certain extent; however, it often has numerous side-effects. Therefore, the focus of RA research is the identification of a new, safe and effective medicine. The aim of the present study was to use an ultra performance liquid chromatography and photo diode array (UPLC-PDA) method to detect the paeoniflorin component in a Radix Paeoniae Alba decoction and in rat plasma following the oral administration of Radix Paeoniae Alba decoction. In addition, the effects of paeoniflorin on collagen-induced arthritis (CIA) in rats were investigated. The results indicate that a UPLC-PDA method for determining the presence of paeoniflorin in the Radix Paeoniae Alba decoction was successfully established. The method was fast, simple, sensitive, precise and valid. Paeoniflorin was shown to be a bioactive component of the Radix Paeoniae Alba decoction that was absorbed into rat plasma. Paeoniflorin significantly improved the disease resistant ability of RA rats and reduced the levels of the inflammatory cytokines, IL-1beta and TNF-alpha, thereby inhibiting inflammation and bone erosion in the rats with CIA. The observations are likely to lay the foundation for further study of the mechanism of paeoniflorin in the treatment of RA. PMID- 24348793 TI - Combination of hearing screening and genetic screening for deafness susceptibility genes in newborns. AB - The aim of this study was to determine the clinical significance of the results of screening of newborn hearing and the incidence of deafness-susceptibility genes. One thousand newborn babies in the Handan Center Hospital (Handan, China) underwent screening of hearing and deafness-susceptibility genes. The first screening test was carried out using otoacoustic emissions (OAEs). Babies with hearing loss who failed to pass the initial screening were scheduled for rescreening at 42 days after birth. Cord blood was used for the screening of deafness-susceptibility genes, namely the GJB2, SLC26A4 and mitochondrial 12S rRNA (MTRNR1) genes. Among the 1,000 neonates that underwent the first hearing screening, 25 exhibited left-sided hearing loss, 21 exhibited right-sided hearing loss and 15 cases had binaural hearing loss. After rescreening 42 days later, only one of the initial 61 cases exhibited hearing loss under OAE testing. The neonatal deafness gene tests showed two cases with 1555A>G mutation and two cases with 1494C>T mutation of the MTRNR1 gene. In the SLC26A4 gene screening, four cases exhibited the heterozygous IVS7-2A>G mutation and one case exhibited heterozygous 1226G>A mutation. In the GJB2 gene screening, two cases exhibited the homozygous 427C>T mutation and 10 exhibited the heterozygous 235delC mutation. The genetic screening revealed 21 newborns with mutations in the three deafness-susceptibility genes. The overall carrier rate was 2.1% (21/1,000). The association of hearing and gene screening may be the promising screening strategy for the diagnosis of hearing loss. PMID- 24348794 TI - Effect of topiramate on interleukin 6 expression in the hippocampus of amygdala kindled epileptic rats. AB - The objective of this study was to analyze the changes in expression and the possible functions of interleukin-6 (IL-6) in electrical kindling of the basolateral amygdala (BLA) in epileptic rats. Bipolar electrodes were implanted into the BLA of Sprague-Dawley rats, and the rats were then subjected to chronic electrical stimulation through the electrodes to induce kindling. The seizure characteristics and behavioral changes of the rats were observed, and electroencephalograms were recorded during and following kindling. The IL-6 mRNA expression in the hippocampi of the rats was analyzed using semi-quantitative reverse transcription-polymerase chain reaction, and control and topiramate (TPM) treated groups were compared. The mean time-period required for kindling was 13.50+/-3.99 days, and the afterdischarge duration (ADD) measured between 21,450 and 119,720 msec. The expression of IL-6 mRNA was significantly upregulated in the kindled rats. TPM was able to depress the seizures and decrease the IL-6 level in the kindled rats. In conclusion, IL-6 mRNA was upregulated in the hippocampi of epileptic rats, and IL-6 may have participated in the process of kindling. PMID- 24348795 TI - Fucoidan induces caspase-dependent apoptosis in MC3 human mucoepidermoid carcinoma cells. AB - Fucoidan is a sulfated polysaccharide present in brown algae that has been identified to exhibit multiple biological effects. In this study, the apoptotic effects of fucoidan in MC3 human mucoepidermoid carcinoma (MEC) cells were investigated. The apoptotic effects of fucoidan on MC3 MEC cells were evaluated by cell proliferation assay, 4',6-diamidino-2-phenylindole staining and western blot analysis. The results showed that fucoidan decreased cell proliferation and induced caspase-dependent apoptosis in MC3 MEC cells. Fucoidan downregulated the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, whereas phospho-p38 mitogen-activated protein kinase or phospho-c-Jun NH2-terminal kinase (JNK) levels were not altered. In addition, fucoidan significantly decreased the expression levels of myeloid cell leukemia-1 (Mcl-1). These results suggest that fucoidan is able to modulate the ERK1/2 pathway and thereby regulate Mcl-1 protein expression and induce apoptosis in MC3 MEC cells. Therefore, fucoidan may be a promising agent for the treatment of human MEC. PMID- 24348796 TI - Evaluation of acoustic radiation force impulse imaging for the clinicopathological typing of renal fibrosis. AB - This study aimed to explore the assessment value of virtual touch quantization (VTQ) for the clinicopathological typing of renal fibrosis. The quantitative detection of 76 patients with nephropathy was performed using acoustic radiation force impulse imaging (ARFI). The extent of the renal fibrosis in each patient was confirmed using ultrasound-guided biopsy pathology. The VTQ values were compared with the degree of renal fibrosis in order to analyze the correlation between them. Patients were divided pathologically into four groups, as follows: non-fibrosis (n=14), mild fibrosis (n=40), moderate fibrosis (n=21) and severe fibrosis (n=1). Compared with the non-fibrosis group, the VTQ values of the mild and moderate fibrosis groups were significantly increased (P<0.01); however, there was no significant difference between the VTQ values of the mild and moderate fibrosis groups (P>0.05). According to the receiver operating characteristic (ROC) curve, a VTQ value of renal parenchyma of >1.67 m/sec was determined to be an indicator of renal fibrosis, with a sensitivity of 86.3% and a specificity of 83.3%. VTQ technology may be significant in the assessment of the extent of renal fibrosis. PMID- 24348797 TI - Expression of toll-like receptor 4 in maternal monocytes of patients with gestational diabetes mellitus. AB - Toll-like receptors (TLRs) are pattern recognition receptors and play an important role in innate immune responses and the occurrence of inflammatory disease. TLR4 is a member of the TLR family and its activation is capable of inducing inflammatory responses, reflecting a relationship between the innate and adaptive immune systems. However, whether TLR4 is expressed in patients with gestational diabetes mellitus (GDM) has not been elucidated. The aim of the present study was to investigate whether TLR4 is expressed in maternal peripheral blood monocytes of patients with GDM. A case-control study, using standard quantitative polymerase chain reaction and western blotting, was performed to assess the TLR4 expression in 30 females with GDM and 32 healthy pregnant females at similar gestational ages. Serum tumor necrosis factor (TNF)-alpha levels were assessed using ELISA in all the females. The TLR4 expression levels in the maternal peripheral blood monocytes and the serum TNF-alpha levels were increased in females with GDM compared with healthy pregnant females (P<0.05). Additionally, there was a positive correlation between the TLR4 expression level in peripheral blood monocytes and serum TNF-alpha levels in all the females. These results indicate that TLR4-mediated release of inflammatory cytokines may represent one factor leading to increased glucose levels in patients with GDM. In addition, TLR4 may be involved in the pathogenesis of GDM. PMID- 24348798 TI - Variations in NAG-1 expression of human gastric carcinoma and normal gastric tissues. AB - Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1), a member of the transforming growth factor beta (TGF-beta) superfamily, has been demonstrated to possess antitumorigenic and proapoptotic activities in gastric cancer cells. In the present study, the expression of NAG-1 was assessed in human gastric carcinoma, tumor-adjacent normal tissues and normal gastric mucosa, with the aim to investigate the role of NAG-1 in the carcinogenesis and development of gastric carcinoma. NAG-1 protein expression was evaluated using immunohistochemical staining, while the expression of NAG-1 mRNA was evaluated using reverse transcription-polymerase chain reaction. It was observed that adenocarcinoma tissues had a lower expression of NAG-1 than normal gastric tissues. Furthermore, moderately and well-differentiated adenocarcinoma tissues expressed more NAG-1 protein than the poorly differentiated adenocarcinoma tissues. The expression of NAG-1 protein in adenocarcinoma tissues did not correlate with tumor-node metastasis staging, infiltration degree or tumor size. The NAG-1 mRNA expression in adenocarcinoma tissues was also lower than that in normal gastric tissues. In conclusion, NAG-1 was poorly expressed in adenocarcinoma tissues and inversely correlated with the degree of tumor differentiation. These results indicate that NAG-1 may have an anti-oncogenic function in the carcinogenesis and development of gastric carcinoma, and that its attenuated or absent expression may lead to gastric carcinogenesis. PMID- 24348799 TI - In vitro studies on the cytotoxicity, and elastase and tyrosinase inhibitory activities of marigold (Tagetes erecta L.) flower extracts. AB - Marigold (Tagetes erecta L.) has long been used as a medicinal herb for a number of therapeutic activities. In the present study, the cytotoxicities of ethanol and ethyl acetate extracts of marigold flowers and their inhibitory effects on elastase and tyrosinase enzymes were investigated. An MTT assay was performed to measure the cytotoxicity of these two extracts on the H460 lung cancer and the Caco-2 colon cancer cell lines. An elastase assay kit, based on the digestion of a non-fluorescent elastin substrate to highly fluorescent fragments by elastase, was used for the elastase inhibition assay. Tyrosinase inhibition activity was investigated using the dopachrome method with L-3,4-dihydroxyphenylalanine (L DOPA) as a substrate. The data obtained in this study demonstrated that the extracts were nontoxic to H460 and Caco-2 cell lines. The elastase inhibition activities of ethanol (250 MUg/ml) and ethyl acetate (125 MUg/ml) extracts were found to be significantly higher than that of the negative control. The tyrosinase inhibition activities of ethanol and ethyl acetate extracts, in terms of the mean inhibition concentration (IC50), were 1,078 and 1,467 MUg/ml, respectively. To the best of our knowledge, the present study has demonstrated for the first time that marigold flower extracts possess tyrosinase inhibition activity. The activities of ethanol and ethyl acetate extracts of marigold flowers were investigated in vitro and indicated that these extracts possess useful properties that may be of interest for cosmetic development. PMID- 24348800 TI - Terson syndrome with no cerebral hemorrhage: A case report. AB - The present study reports the case of a 33-year-old male who presented with Terson syndrome with no cerebral hemorrhage secondary to traumatic brain injury (TBI). A computed tomography scan of the patient, who had sustained an impact injury to the right occipital region, showed no cerebral lesion. Ophthalmoscopy clearly demonstrated vitreous hemorrhage in both eye globes. Vitreous hemorrhage, which results from an abrupt increase in intracranial pressure (ICP), is associated with TBI. In this case, the visual disturbance was attributed to Terson syndrome secondary to TBI. Therefore, close ophthalmological and radiological evaluation is required in patients with TBI, in order to enable the diagnosis of Terson syndrome and an early vitrectomy. PMID- 24348801 TI - Baicalin protects the myocardium from reperfusion-induced damage in isolated rat hearts via the antioxidant and paracrine effect. AB - The aim of the present study was to investigate the protective effect of baicalin (BA) against ischemia-reperfusion (I/R) injury in isolated rat hearts. Sprague Dawley rat hearts were rapidly removed, mounted on a Langendorff apparatus and subjected to 30 min ischemia followed by 30 min reperfusion with Krebs-Henseleit (K-H) solution at 37 degrees C to establish the isolated I/R injury model. All animals (n=50) were randomly divided into five groups (n=10 in each): I, normal control; II, I/R; III, I/R plus 20 mg/kg BA; IV, I/R plus 40 mg/kg BA; and V, I/R plus 80 mg/kg BA. The degree of heart injury caused by the I/R was assessed by evaluating left ventricular function and by detecting the levels of lactate dehydrogenase (LDH) and creatine kinase (CK) in the coronary effluent and the myocardial superoxide dismutase (SOD) and malondialdehyde (MDA) levels in the isolated rat hearts. Myocardial infarct size and vascular density were assessed using histology and immunohistochemistry. The apoptotic cardiomyocytes were determined using flow cytometry (FCM). Compared with group II, the BA groups demonstrated improved left ventricular function, reduced CK and LDH release in the coronary effluent and increased SOD and MDA activity (P<0.05). Furthermore, histology and immunohistochemistry results showed that the infarct size was reduced and vessel density was augmented in the BA groups (P<0.01) compared with group II. The FCM results indicated that apoptosis was significantly lower in the BA groups than in group II (P<0.05) and that the protective effect was dose dependent. In conclusion, these results demonstrated that BA exerts a dose dependent protective effect on I/R injury in isolated rat hearts, the mechanisms of which may be associated with antioxidant and anti-apoptosis properties. To the best of our knowledge, this study is the first evaluation of the efficacy of BA in isolated rat hearts using histology and immunohistochemistry, providing a foundation for the use of BA in the treatment of acute myocardial infarction. PMID- 24348803 TI - Surgical treatment of a ventricular aneurysm in a patient with essential thrombocythemia complicated by acute myocardial infarction: A case report. AB - Essential thrombocythemia (ET) is a chronic clonal myeloproliferative disorder, which is often complicated by arterial or venous thrombosis and idiopathic bleeding diathesis. The present study reports a female patient with ET complicated by acute myocardial infarction, leading to ventricular aneurysm following interventional therapy for 3 years and a subsequent in-stent restenosis. Following careful examination, a ventricular aneurysm resection and coronary artery bypass graft were carried out. During this case, the monitoring and controlling of the platelet count, pre- and post-operatively, was extremely important for successful surgery. PMID- 24348804 TI - Correlation analysis between the rate of respiration in the root and the active components in licorice (Glycyrrhiza uralensis). AB - The aim of this study was to investigate the correlation between root respiration and the percentage of active components in licorice (Glycyrrhiza uralensis Fisch.), in order to provide a foundation for the regulation and modulation of the quality of G. uralensis. Respiration efflux of annual and biennial G. uralensis was determined using a Li-7000 CO2/H2O analyzer. The root systems were scanned at a resolution of 3,000 dpi using an Epson Expression 10000XL scanner. Root growth was determined by analyzing the scanned images using WinRHIZO version Pro2007d software and the rate of respiration in the root was subsequently calculated. In addition, the percentages of the five major active components in licorice, glycyrrhizic acid, glycyrrhizin, isoliquiritin, liquiritigenin and isoliquiritigenin, were detected using high-performance liquid chromatography (HPLC). The correlation between the root respiration and the percentage of the active components was investigated. Significant seasonal changes were observed in the rates of respiration of first and zero-class roots. In annual and biennial G. uralensis, the maximum and minimum values for rate of respiration were present in July (P<0.05) and November (P<0.05), respectively. The correlation coefficients between the five major active components and the rate of respiration were -0.304 (glycyrrhizin), -0.129 (liquiritigenin), -0.441 (glycyrrhizic acid; P<0.05), 0.471 (isoliquiritin; P<0.05) and 0.148 (isoliquiritigenin). The percentages of glycyrrhizic acid and isoliquiritin were significantly negatively correlated with the rate of respiration in annual and biennial G. uralensis. Understanding the correlation between the root rate of respiration and the active components in G. uralensis may be beneficial to ensuring the quality of cultivated G. uralensis. PMID- 24348802 TI - Grape seed extract attenuates arsenic-induced nephrotoxicity in rats. AB - Oxidative stress is a recognized factor in nephrotoxicity induced by chronic exposure to inorganic arsenic (As). Grape seed extract (GSE) possesses antioxidant properties. The present study was designed to evaluate the beneficial effects of GSE against arsenic-induced renal injury. Healthy, male Sprague-Dawley rats were exposed to As in drinking water (30 ppm) with or without GSE (100 mg/kg) for 12 months. The serum proinflammatory cytokine levels and mRNA expression levels of fibrogenic markers in the renal tissues were evaluated using enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively. The protein expression levels of nicotinamide adenine dinucleotide phosphate (NADPH) subunits, transforming growth factor-beta1 (TGF-beta1) and phosphorylated Smad2/3 (pSmad2/3) were assessed using western blot analysis. The results demonstrated that cotreatment with GSE significantly improved renal function, as demonstrated by the reductions in relative kidney weight (% of body weight) and blood urea nitrogen, and the increase in the creatinine clearance capacity. GSE attenuated the As-induced changes in the serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-1beta and the mRNA levels of TGF-beta1, alpha-smooth muscle actin (alpha-SMA), connective tissue growth factor (CTGF) and fibronectin (FN) in renal tissue. Furthermore, administration of GSE markedly reduced As-stimulated reactive oxygen species (ROS) production and Nox activity, as well as the protein expression levels of the NADPH subunits (Nox2, p47phox and Nox4). In addition, GSE cotreatment was correlated with a significant reduction in TGF-beta/Smad signaling, as demonstrated by the decreased protein levels of TGF-beta1 and pSmad2/3 in renal tissue. This study indicated that GSE may be a useful agent for the prevention of nephrotoxicity induced by chronic exposure to As. GSE may exert its effects through the suppression of Nox and inhibition of TGF-beta/Smad signaling activation. PMID- 24348805 TI - Potential beneficial effects of oral administration of isoflavones in patients with chronic mountain sickness. AB - Soy isoflavones (Ifs), which are natural phytoestrogens, have beneficial effects in cardiovascular disease. We have previously shown that genistein, the most active component of Ifs, inhibits pulmonary vascular structural remodeling and right ventricular hypertrophy induced by chronic hypoxia in male Wistar rats. This study aimed to evaluate the effects of Ifs on right ventricular and pulmonary hemodynamics in individuals with chronic mountain sickness (CMS). Twenty-eight male patients living on the Qinghai-Tibetan plateau (5,200 m) who were suffering from CMS were treated orally with Ifs (20 mg, twice daily) for 45 days. Physiological and plasma biochemical indices, hematology and echocardiography were investigated. It was observed that 45 days of treatment with Ifs significantly increased blood oxygen saturation and markedly decreased the CMS score and heart rate (all P<0.05) of the subjects. Following treatment with Ifs, hematocrit (P<0.05), hemoglobin concentration (P<0.01) and plasma levels of malondialdehyde (P<0.05) were significantly decreased, while plasma levels of nitric oxide (P<0.01) and the plasma activity of nitric oxide synthase (P<0.01) and superoxide dismutase (P<0.01) were markedly increased compared with the respective values obtained prior to treatment with Ifs. The echocardiography results showed that Ifs significantly decreased the main pulmonary artery diameter (P<0.05), right ventricular end-diastolic anteroposterior diameter (P<0.01), right ventricular end-diastolic trans diameter (P<0.01), right ventricular anterior wall (P<0.01) and right ventricular outflow tract (P<0.01). These results indicate the potential beneficial effects of Ifs in the reduction of excessive erythrocytosis, the alleviation of oxidative damage and the amelioration of right ventricular index and pulmonary hemodynamics in CMS. PMID- 24348806 TI - Correlation between matrix metalloproteinase expression and activation of the focal adhesion kinase signaling pathway in herpes stromal keratitis. AB - The present study aimed to investigate the correlation between matrix metalloproteinase-2 (MMP-2) expression and activation of the focal adhesion kinase (FAK) signaling pathway in herpes stromal keratitis (HSK). The cornea of 24 BALB/c mice was infected with herpes simplex virus type 1 (HSV-1) to construct a model of HSK. Six additional mice served as negative controls. Immunohistochemical staining was used to detect FAK expression levels. Human corneal epithelial (HCE) cells cultured in vitro were infected with HSV-1 and the expression levels of MMP-2, FAK and phosphorylated-FAK (p-FAK) in HCE cells were detected using reverse transcription-polymerase chain reaction (RT-PCR), western blot analysis and immunohistochemistry at 2, 20 and 40 h following infection. In the HSK rat model, the corneal epithelial cells appeared deranged and the number of neutrophils and FAK-positive cells was significantly increased compared with that of the negative control group (P<0.05). Repeated measures analysis of variance of RT-PCR showed no significant differences in MMP-2 and FAK mRNA expression levels in the infected cells at various time points, and no significant differences between infected cells and the negative control group were observed. There was no interaction between groups and time points. Pairwise comparisons showed that MMP-2 and FAK mRNA expression levels were significantly increased in virus-infected cells compared with those of the control group. Over time, MMP-2 and FAK mRNA expression levels did not differ significantly in virus infected cells or in control cells. Western blot analysis indicated no significant differences in p-FAK, FAK and MMP-2 expression levels between the infected and control cells at 2 h (P>0.05). Infected cells showed a significant increase in MMP-2 and p-FAK expression levels than that of the control cells at 20 and 40 h (P<0.05). p-FAK, FAK and MMP-2 expression levels in virus-infected cells at 2 h differed significantly from those at 20 and 40 h (P<0.05). Immunohistochemical staining results showed that a longer infection time was associated with an increased number of cells staining positive for MMP-2, FAK and p-FAK. Following HSV-1 infection of the corneal epithelium, the FAK signaling pathway was activated, resulting in increased secretion of MMP-2 in the corneal tissue and accelerated formation of corneal ulcers and necrotic lesions. PMID- 24348807 TI - Giant epidermal cyst in the posterior neck developing over 40 years: A case report. AB - Conventional epidermal cysts are generally small, slow-growing, non-tender, dome shaped lesions. An epidermal cyst is usually asymptomatic until it is infected or enlarged to the extent that it causes damage to adjacent anatomical structures. However, few cases of giant epidermal cysts in the neck have been reported. The present case reports a giant epidermal cyst in the posterior neck, which grew to an extremely large size for >40 years without inflammation or rupture, and was misdiagnosed as a large soft tissue neoplasm. The patient exhibited depression and developed social anxiety due to the negative cosmetic consequences of the large mass. The patient underwent excision of the mass. At the follow-up examination two years postoperatively, there were no local recurrence and the psychiatric symptoms of the patient were completely resolved. To the best of our knowledge, a giant epidermal cyst growing for >40 years has not previously been reported. PMID- 24348808 TI - Effect of 15-hydroxyprostaglandin dehydrogenase gene on the proliferation of gastric cancer cell murine forestomach carcinoma. AB - The aim of the present study was to construct the eukaryotic expression vector pcDNA3.1/15-PGDH. The vector was used to transfect mouse murine forestomach carcinoma (MFC) cancer cells and observe the effects of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) on the proliferation of MFC. pcDNA3.1/15-PGDH was constructed using gene recombination technology and the vector was used to transfect MFC cells to build a stable transfected cell strain. The expression levels of 15-PGDH in the transfected cells were detected using reverse transcription polymerase chain reaction. Optical Density (OD) values were determined using an MTT assay and used to draw cell growth curves. The effects of 15-PGDH on the proliferation of MFC were observed using a clone formation experiment. Following successful transfection by 15-PGDH, the relative expression levels of 15-PGDH in the MFC/15-PGDH cells were significantly higher (1.06+/ 0.08) (P<0.01) compared with the empty plasmid-transfected group (0.22+/-0.01) and the untransfected group (0.21+/-0.01). Following transfection by 15-PGDH, cell growth was markedly inhibited. The MTT results showed that on days 4, 6 and 8, the 15-PGDH-transfected group had a low OD on average, which was significantly different (P<0.05) from the empty plasmid-transfected group or the untransfected group. The 15-PGDH-transfected group had a plating efficiency of 18%, and compared with the untransfected group (63%) and the empty plasmid-transfected group (59%), clone formation was significantly inhibited (P<0.01). Results of the present study indicate that transfection by 15-PGDH may significantly inhibit the proliferation and clone formation of MFC cells. PMID- 24348809 TI - Insulin augments mechanical strain-induced ERK activation and cyclooxygenase-2 expression in MG63 cells through integrins. AB - Insulin has been proposed to be a positive regulator of osteoblast proliferation and bone formation. In vivo mechanical loading is essential for maintaining skeletal integrity and bone mass. Since insulin and mechanical force activate similar signaling pathways in osteoblasts, it was hypothesized that insulin may affect mechanical stimulation in osteoblasts. The present study tested the hypothesis that insulin augments mechanical strain-induced signaling and early gene expression in MG63 cells via activation of the extracellular signal regulated kinase (ERK) pathway and cyclooxygenase-2 (Cox-2) expression. Western blot analysis and quantitative polymerase chain reaction demonstrated respectively that insulin enhanced mechanical strain-induced ERK phosphorylation and Cox-2 expression levels in a dose-dependent manner. The effect of insulin on mechanical strain-induced Cox-2 expression was inhibited by blockade of the ERK pathway. In addition, echistatin, an inhibitor of integrin function, prevented the effects of insulin on mechanical strain-induced ERK phosphorylation and Cox-2 expression. The data obtained from this study suggested that insulin augments mechanical strain-induced Cox-2 expression levels via integrin-dependent activation of the ERK pathway in osteoblasts. PMID- 24348810 TI - Serum from patients with hepatitis E virus-related acute liver failure induces human liver cell apoptosis. AB - The pathogenesis of acute liver failure has not been fully elucidated. The present study investigated the effects of the serum from patients with hepatitis E virus (HEV)-related acute liver failure on human liver cell survival and apoptosis, and evaluated the protective effects of anti-lipopolysaccharide(LPS) antibody recognizing core polysaccharide against acute liver failure serum induced apoptosis. Serum was collected from patients with HEV-related acute liver failure. The levels of endotoxin (LPS) in the serum were measured using a quantitative tachypleus amebocyte lysate endotoxin detection kit with a chromogenic endpoint. Serum with a mean concentration of LPS was incubated with L02 human liver cells and the rate of apoptosis was detected by flow cytometry. The apoptotic rate was also evaluated in liver cells incubated with antibody and the HEV-related acute liver failure serum. The results indicated that the concentration of LPS in the serum of patients with HEV-related acute liver failure was 0.26+/-0.02 EU/ml, which was significantly higher than that of the control group (P<0.05). The rate of apoptosis in the human liver cells induced by acute liver failure serum was 5.83+/-0.42%, which was significantly increased compared with that in the cells treated with the serum of healthy individuals (P<0.05). The apoptotic rate of the cells incubated with antibody and the acute liver failure serum was 5.53+/-0.51%, which was lower than that of the cells incubated with acute liver failure serum alone (P>0.05). These results indicate that the serum of patients with HEV-related acute liver failure induces the apoptosis of human liver cells. LPS may be directly involved in the apoptosis of human liver cells. Moreover, the presence of the antibody did not significantly reduce the level of apoptosis of liver cells exposed to HEV-related acute liver failure serum. PMID- 24348812 TI - Prognostic factors associated with locally recurrent rectal cancer following primary surgery (Review). AB - Locally recurrent rectal cancer (LRRC) is defined as an intrapelvic recurrence following a primary rectal cancer resection, with or without distal metastasis. The treatment of LRRC remains a clinical challenge. LRRC has been regarded as an incurable disease state leading to a poor quality of life and a limited survival time. However, curative reoperations have proved beneficial for treating LRRC. A complete resection of recurrent tumors (R0 resection) allows the treatment to be curative rather than palliative, which is a milestone in medicine. In LRRC cases, the difficulty of achieving an R0 resection is associated with the post-operative prognosis and is affected by several clinical factors, including the staging of the local recurrence (LR), accompanying symptoms, patterns of tumors and combined therapy. The risk factors following primary surgery that lead to an increased rate of LR are summarized in this study, including the surgical, pathological and therapeutic factors. PMID- 24348813 TI - Analysis of the anticancer activity of curcuminoids, thiotryptophan and 4 phenoxyphenol derivatives. AB - Curcumin, a non-nutritive yellow pigment derived from the rhizome of Curcuma longa (turmeric), is considered to be an established nutraceutical with anticancer activity. Turmeric contains three principal components, curcumin, demethoxycurcumin and bisdemethoxycurcumin, of which curcumin is most abundant and potent. The concurrence of a high consumption of turmeric and a low incidence of prostate cancer in Asian countries may suggest a role for curcumin in chemoprevention. Curcumin has been identified to exhibit anti-inflammatory, anti oxidative and anticarcinogenic properties. Since the compound does not exhibit side effects, curcumin has been designated for several clinical trials as a treatment for human cancers. The pro-apototic, antioxidant and anti-inflammatory characteristics of curcumin are implicated in its anticancer activity, yet the mechanism of action of curcumin remains unknown. To achieve an effective pharmacological outcome, curcumin must reach and sustain appropriate levels at the site of action. However, the main disadvantage of curcumin is its high metabolic instability and poor aqueous solubility that limits its systemic bioavailability. To overcome this difficulty, the present study tested the anticancer activity of new curcumin-like compounds (E21cH and Q012095H). Also, the use of new medicaments requires an understanding of their pharmacokinetic profiles and targets. Thus, molecular modeling methods were used to identify the targets of curcumin and curcumin-like compounds compared with other anticancer drugs (Q012138 and Q012169AT), which were used as the controls. The present study identified several enzymes that are targeted by curcumin, aldo-keto reductase family 1 member B10 (AKR1B10), serine/threonine-protein kinase, protein kinase C, matrix metalloproteinase (MMP), cyclooxygenase and epidermal growth factor receptor, which were tested as targets for these anticancer chemicals. All the examined small compounds demonstrated anticancer activity in the in vitro experiments and may impact cancer cells by acting on AKR1B10, MMP-9 and their targets. PMID- 24348814 TI - Endoplasmic reticulum stress in diethylnitrosamine-induced rat liver cancer. AB - To analyze the significance of endoplasmic reticulum stress (ERS) in the development of diethylnitrosamine (DEN)-induced liver cancer in rats, critical regulatory factors in ERS signaling pathways were investigated in the present study. The results showed that the expression of ERS-related proteins gradually increased in the early and mid-term stages of carcinogenesis, while in the later stages, the expression of these proteins did not change significantly after reaching a peak. ERS is involved in DEN-induced rat liver injury, the proliferation of liver cells and the occurrence and development of liver cirrhosis. However, ERS did not affect hepatoma cell growth following the formation of rat liver cancer in the current study. PMID- 24348811 TI - Lentiviral vector-based therapy in head and neck cancer (Review). AB - Head and neck squamous cell carcinoma (HNSCC) is the sixth most common neoplasm worldwide. Despite advances in multimodality treatments involving surgery, radiation and chemotherapy, the five-year survival rate has remained at ~50% for the past 35 years. Therefore, the early detection of recurrent or persistent disease is extremely important. Replication-incompetent HIV-1-based lentiviral vectors have emerged as powerful and safe tools for gene delivery. Commonly, HNSCC is a locoregional disease that presents at or close to the body surface. Thus, HNSCC is amendable to intratumoral injections of gene therapy vectors aimed at correcting defects associated with tumor suppressor genes to induce the direct cytotoxicity of cancer cells or immune modulation to promote antitumor immunity. Current investigations analyzing HNSCC gene mutations and stem cell markers and the cancer immunoediting concept are creating exciting therapeutic opportunities for lentiviral and other gene transfer vectors. The present review reports specific examples of the current applications of lentiviral vectors in HNSCC. PMID- 24348815 TI - Inhibition of Annexin A2 gene transcription is a promising molecular target for hepatoma cell proliferation and metastasis. AB - Hepatocyte Annexin A2 (ANXA2) expression is associated with the progression and metastasis of hepatocellular carcinoma (HCC). Circulating ANXA2 levels in HCC patients are significantly higher compared with that of patients with benign liver disease. ANXA2 levels have been found to correlate with hepatitis B virus infection, extrahepatic metastasis and portal vein thrombus. By contrast, ANXA2 levels do not correlate with tumour size and AFP levels. However, the underlying mechanisms of ANXA2 remain obscure. The results of the current study identified that abnormalities in hepatic ANXA2 expression were localised to the cell membrane and cytoplasm of HCC tissues and mainly in the cytoplasm of para cancerous tissues. ANXA2 was overexpressed in MHCC97-H cells which have high metastatic potential. Following specific ANXA2-small hairpin RNA (shRNA) transfection in vitro, ANXA-2 was effectively inhibited and the S phase ratio of cells was 27.76%, compared with 36.14% in mock-treated cells. In addition, the invading cell ratio was reduced in the shRNA-treated group (52.16%) compared with the mock-treated group (86.14%). The growth and volume of xenograft tumours in vivo was significantly suppressed (P<0.05) in the shRNA group compared with that of the mock group, indicating that ANXA2 may be a novel and useful target for elucidating molecular mechanisms involving the proliferation and metastasis of HCC. PMID- 24348817 TI - Middle ear squamous papilloma: A report of four cases analyzed by HPV and EBV in situ hybridization. AB - Squamous papilloma involving the middle ear as a primary lesion is an extremely rare occurrence. The aims of the present study were to investigate the presence of human papilloma virus (HPV) and Epstein-Barr virus (EBV) infections in primary middle ear squamous papilloma and to describe the clinical and pathological features of the disease along with therapeutic strategies. A retrospective review was conducted of four patients with clinical and pathological diagnoses of middle ear squamous papilloma. In situ hybridization (ISH) for a wide range of HPV DNA subtypes and EBV-encoded RNA was performed in the tissue samples obtained from these patients. Only two cases of primary squamous papilloma in the middle ear have been previously reported in the English literature. These papillomas developed in males of ~60-years of age and otorrhea was the most frequent complaint. Premalignant changes were observed in two of the present cases and ISH of HPV and EBV was negative in all four cases. The results of the present study indicated that chronic inflammatory stimulation, not HPV and EBV infection, is involved in the occurrence of middle ear squamous papilloma and its malignant transformation. Radical surgery and long-term postoperative follow-up are recommended due to its malignant and recurrent potential. Further genetic investigations with additional new cases are required to clarify the pathogenesis of squamous papilloma involving the middle ear. PMID- 24348816 TI - NANOG expression correlates with differentiation, metastasis and resistance to preoperative adjuvant therapy in oral squamous cell carcinoma. AB - NANOG protein, a transcription factor expressed in embryonic stem cells, is overexpressed in tumor development. Although studies investigating the function of NANOG in cancer have shown that it plays several roles, such as in cell proliferation, invasion and metastasis, the overall function of NANOG in cancer cells has remained elusive. In the present study, NANOG expression in oral squamous cell carcinoma (OSCC) was examined to determine its potential clinical significance. The expression of NANOG protein was assessed in 60 patients with OSCC by immunohistochemistry, and its correlation with clinicopathological factors and metastasis was evaluated. NANOG protein levels in human OSCC cell lines were determined by western blotting and immunofluorescence staining. NANOG protein expression was identified in 52 cases (86.7%) and expression levels were higher in primary foci of poorly differentiated OSCC than in those of well differentiated OSCC, indicating that NANOG expression is associated with OSCC differentiation. Regardless of the differentiation levels of primary foci, NANOG expression levels in metastatic foci were extremely high. In addition, NANOG expression in metastatic foci was maintained at high levels following preoperative adjuvant therapy. Furthermore, NANOG protein was detected at an identical level in human OSCC cell lines. These data indicate that NANOG expressing OSCC cells tend to metastasize and that metastatic tumors expressing NANOG may be resistant to preoperative adjuvant therapy, including chemoradiation. Thus, assessment of NANOG expression may assist the strategy for treatment of OSCC metastasis. PMID- 24348818 TI - Complete remission of a reccurrent mesenteric liposarcoma with rare histological features following the administration of trabectedin. AB - The present study describes a rare case of a mesenteric liposarcoma that resulted in a complete remission (CR) following treatment with trabectedin (Yondelis(r)). The patient presented with abdominal pain and fever. An abdominal mass was identified that corresponded to a mixed-type high-grade mesenteric liposarcoma with wide areas of necrosis, areas of dedifferentiation and features of a leiomyosarcoma. Three months after the removal of the first mass, the patient underwent a second laparotomy, followed by treatment with doxorubicin and ifosfamide. Subsequently, the patient was started on therapy with trabectedin and a CR was noted following only four cycles of therapy. The best responses that are reported in the literature for cases of liposarcoma treated with trabectedin are mostly for liposarcomas of the myxoid/round cell type and are mainly partial responses. In the present study, trabectedin was used for the treatment of a mesenteric liposarcoma of mixed morphological features and a CR was achieved. PMID- 24348819 TI - Sustained complete response of hepatocellular carcinoma with portal vein tumor thrombus following discontinuation of sorafenib: A case report. AB - Hepatocellular carcinoma (HCC) is the third most common cause of cancer associated mortality worldwide. No effective treatment has been established for unresectable advanced HCC, and the prognosis is poor. Sorafenib is an oral multi targeted tyrosine kinase inhibitor for unresectable advanced HCC that significantly improves progression-free and overall survival. However, in the two large phase III clinical trials (the SHARP and Asia-Pacific trials), no cases of complete response (CR) were reported. The present study reports the case of a 68 year-old male with hepatitis C virus-related cirrhosis and multiple recurrent HCCs, with a tumor thrombus of the third portal vein following resection. The patient received 400 mg once daily (half the standard dose) of sorafenib for two years and achieved a CR. At the most recent follow-up examination at one year after the cessation of treatment, the patient was observed to be in remission without clinical or imaging evidence of disease recurrence. PMID- 24348820 TI - Occult neoplastic cells in lymph node sinuses and recurrence/metastasis of stage II/III gastric cancer. AB - In the present study, we investigated the correlation between the presence of occult neoplastic cells (ONCs) in lymph node sinuses and recurrence/metastasis of stage II/III gastric cancer in 164 patients who underwent radical curative resection. We calculated the five-year relapse-free survival rate (5Y-RFS) and five-year overall survival rate (5Y-OS) of the ONC(+) and ONC(-) groups. The 5Y RFS was 71.4% in the ONC(-) group and 47.5% in the ONC(+) group (P=0.003). The 5Y OS was 68.8 and 48.4%, respectively (P=0.008). ONCs were found in 34.8% of stage II patients and were also detected in 66.7% of stage III patients. For distinguishing between the recurrence and non-recurrence groups, the sensitivity of ONC(+) was 64.5% (40/62; P=0.003), the positive predictive value (PPV) was 49.4% (40/81), the specificity was 59.8% (61/102) and the negative predictive value (NPV) was 73.5% (61/83). This high sensitivity indicates that ONC positivity may be a significant indicator for high-risk patients in the early postoperative period, and a lack of ONCs may be a useful indicator for identifying low-risk patients, as patients without ONCs had a high NPV. PMID- 24348821 TI - Expression of p-Akt in ovarian serous carcinoma and its association with proliferation and apoptosis. AB - The aim of the present study was to determine the expression of p-Akt in ovarian serous carcinoma (OSC) and its association with proliferation and apoptosis. Paraffin-embedded tissues of patients aged between 35 and 64 years old without history of radiotherapy, chemotherapy and hormone therapy prior to surgery were collected. In total, samples included 12 ovarian serous cystadenomas (OSAs), 18 ovarian serous borderline tumors (OS-BTs) and 46 OSCs. Of the 46 OSC samples, 16 were well-differentiated, 20 were moderately differentiated and 10 were poorly differentiated, while 22 developed lymphatic metastases and 24 were metastasis free. An additional 10 paraffin-embedded normal ovarian tissues (NOTs) were used as controls. Streptavidin-peroxidase immunohistochemistry assays were used to investigate the expression of p-Akt and cyclin D1 in the collected samples. Compared with NOT, p-Akt expression in the OS-BT and OSC groups, as well as cyclin D1 expression in the OSA and OSC groups, was significantly elevated (P<0.05). Compared with the OSA group, p-Akt expression in the OSC group was significantly elevated (P<0.01) and reversely associated with tumor differentiation (P<0.01), whereas cyclin D1 expression showed no correlation with tumor differentiation (P>0.05). The expression of p-Akt, caspase-3 and cyclin D1 was positively associated with lymphatic metastasis (r=0.334; P=0.023). The expression of p-Akt gradually increased with carcinoma development and was associated with differentiation and metastasis of OSC, revealing that the activation of the PI3K/Akt signaling pathway is involved in the development of OSC. Furthermore, the expression of cyclin D1 gradually increased in the NOT, OSA, OS-BT and OSC groups and was associated with tumor metastasis. PMID- 24348822 TI - Signet-ring cell melanoma with sentinel lymph node metastasis: A case report with immunohistochemical analysis and review of the clinicopathological features. AB - Signet-ring cell melanoma is an extremely rare variant of malignant melanoma. A 68-year-old male presented with a black nodule on the left thigh. Histopathological examination revealed proliferation of sheet-like or variable sized nests of atypical melanocytes. Neoplastic cells showing signet-ring cell appearance, characterized by the presence of eccentrically located enlarged nuclei and abundant pale cytoplasm, were also present. Immunohistochemically, the tumor cells were positive for S-100 protein, vimentin and Melan-A. Moreover, mammalian target of rapamycin (mTOR) pathway proteins were diffusely expressed. The current case report presents the 21st reported case of signet-ring cell melanoma. Analyses of the clinicopathological features revealed that this disease commonly affects middle-aged males and the presence of metastatic signet-ring cell melanoma with an unknown primary tumor. Immunohistochemical analyses of melanocytic markers have been useful for establishing the diagnosis of this type of disease, however, HMB-45 is occasionally found to be negative. In addition, the present case report is the first to analyze the expression of mTOR pathway proteins, which are central proteins involved in carcinogenesis and its inhibitor has been proposed as a therapeutic target for various types of tumor. Therefore, the mTOR inhibitor may also be a potential candidate for the treatment of this type of tumor. PMID- 24348823 TI - Epigenetic silencing of checkpoint with fork-head associated and ring finger gene expression in esophageal cancer. AB - Checkpoint with fork-head associated and ring finger (CHFR) is a mitotic checkpoint gene with tumor-suppressor functions. Previous studies have described the hypermethylation of the CpG island in the promoter region as a key mechanism involved in silencing tumor suppressor genes. The epigenetic alterations regulating CHFR expression and the clinical significance of CHFR downregulation remain unclear. A total of 40 patients with esophageal squamous cell carcinoma who underwent primary resection were enrolled in this study. CHFR mRNA expression was quantified, followed by an evaluation of the methylation status using methylation-specific polymerase chain reaction (MSP) techniques in 29 patients. The correlation between CHFR expression and MSP status was then analyzed. In addition, the significance of CHFR expression was determined, with respect to clinicopathological features and overall survival. Aberrant hypermethylation of the CHFR gene was observed in 13 of 29 primary esophageal cancers. The CHFR expression levels of the methylated status samples was significantly lower than that of the unmethylated status samples (P=0.014). CHFR expression levels did not exhibit clinical significance with respect to the patient characteristics or overall survival. Hypermethylation of the CHFR gene is a common event in the development of primary esophageal cancer. CpG island hypermethylation of the promoter region in the CHFR gene is a key mechanism involved in silencing the CHFR gene in patients with esophageal cancer. PMID- 24348824 TI - Frizzled-2: A potential novel target for molecular pancreatic cancer therapy. AB - In the present study, pancreatic cancer cell proliferation was analyzed following the suppression of frizzled (Fz)2 expression. Reverse transcription polymerase chain reaction (PCR) was performed using RNA isolated from pancreatic cancer cell lines, PANC-1, NOR-P1, PK-45H, PK-1, PK-59, MIA-Paca2 and KP4. A surgical specimen of pancreatic cancer was immunostained with antibodies specific to Fz2. Cell proliferation assays were performed with MIA-Paca2 cells transfected with small interfering RNA (siRNA) or short hairpin RNA (shRNA) of Fz2. Fz2 was found to be expressed in all pancreatic cancer cell lines, with the exception of NOR P1. Immunostaining revealed that Fz2 was not expressed in normal pancreatic tissues, while it was expressed in pancreatic cancer cells. The expression levels of cyclin D1 were analyzed by quantitative PCR. The proliferation and expression of cyclin D1 were suppressed with the siRNA and shRNA of Fz2 in the MIA-Paca2 cells. Therefore, Fz2 is a potential target for the molecular therapy of pancreatic cancer. PMID- 24348825 TI - Primary bone marrow diffuse large B-cell lymphoma accompanying cold agglutinin disease: A case report with review of the literature. AB - Cold agglutinin disease (CAD) is a well-recognized complication of lymphoproliferative disorders. It has been previously recognized that cases of primary CAD frequently exhibit underlying malignant lymphoma in the bone marrow. Lymphoplasmacytic lymphoma is the most common subtype of malignant lymphoma; however, diffuse large B-cell lymphoma (DLBCL) has also been documented, albeit extremely rare. The current report presents a case of primary bone marrow DLBCL accompanying CAD. A 76-year-old male presented with fever and fatigue. Laboratory tests revealed anemia and elevated bilirubin and cold agglutinins with a titer of 8,192 at 4 degrees C. Bone marrow biopsy demonstrated DLBCL and systemic surveillance failed to detect tumorous lesions or lymphadenopathy. Following R THP-COP therapy, cold agglutinins titer was markedly decreased (by <4); however, malignant lymphoma relapsed and cold agglutinin levels increased again (4,096). This is the second documented case of primary bone marrow DLBCL accompanying CAD. Previously, malignant lymphoma exclusively involving the bone marrow, namely primary bone marrow lymphoma (PBML), has been recognized as a rare and aggressive subtype. The analyses of the present study revealed that the incidence of hemolytic anemia in primary bone marrow DLBCL may be high compared with conventional DLBCL. Therefore, additional analyses are required to clarify the clinicopathological features of PBML. PMID- 24348826 TI - Interaction of a CD44+ head and neck squamous cell carcinoma cell line with a stromal cell-derived factor-1-expressing supportive niche: An in vitro model. AB - The cancer stem cell (CSC) theory implies that CSCs are surrounded by supportive stromal cells, which are known as the CSC niche. Stromal cell-derived factor-1 (SDF-1) shows a multitude of functional effects in head and neck squamous cell carcinoma (HNSCC) cells, including migration and polarization. Therefore, the SDF 1-CXCR4 axis may be involved in the pathophysiology of the progression, recurrence and metastasis of malignant diseases of the head and neck. In the present study, the CD44+ HNSCC UM-SCC-11A cell line was used as a model for CSCs. The interaction between the UM-SCC-11A cells and the supportive microenvironmental cells, including fibrocytes, human umbilical vein endothelial cells (HUVECs) and human microvascular vein endothelial cells (HMVECs) was evaluated. All the cell types that were tested were shown to secrete different concentrations of SDF-1 into the surrounding culture medium [mean (m)fibro, 1243.3+/-156.2 pg/ml; mHMVEC, 1061.4+/-23.2 pg/ml; mHUVEC, 849.6+/-110.9 pg/ml]. The migration of the UM-SCC-11A cells towards the supportive cells was increased by a higher supply of SDF-1 (contrfibro, 315.23+/-61.55 MUm; mfibro, 477.73+/ 143.7 MUm; Pfibro=0.003; contrHMVEC, 123.41+/-66.68 MUm; mHMVEC, 249.04+/-111.95 MUm; PHMVEC=0.004; contrHUVEC, 189.7+/-93.26 MUm; mHUVEC, 260.82+/-161.58 MUm). The amount of the UM-SCC-11A cells that migrated towards the differentiated fibrocytes was significantly higher than that which migrated towards the HMVECs or HUVECs (Pfibro/HMVEC=2.12E-11; Pfibro/HUVEC=2.28E-5). Cell-cell interaction by podia formation of the UM-SCC-11A cells was observed in all the supportive cell types that were tested. Broadly based cell-cell contacts were observed. By contrast, digitiform podia formations presented by the UM-SCC-11A cells were determined using fluorescence microscopy. The SDF-1-CXCR4 axis is postulated to be a crucial pathway in the interaction between CSCs and their surrounding supportive cells. Understanding the cell-cell interactions in the CSC niche using in vitro models may aid in gaining further insight into these mechanisms and finding new strategies of therapy in this field. PMID- 24348827 TI - Treatment with Huisheng oral solution inhibits the development of pulmonary thromboembolism and metastasis in mice with Lewis lung carcinoma. AB - The aim of this study was to investigate whether Huisheng oral solution (HSOS) has an inhibitory effect on the development of pulmonary thrombosis and metastasis in mice with Lewis lung carcinoma (LLC), and to explore the possible mechanisms involved. A mouse model of LLC was developed, and model mice were divided into either a treatment group or a control group to undergo treatment with HSOS or normal saline. Normal mice treated with saline were used as normal controls. On day 25 after treatment, blood samples were drawn from the eyes of half the mice in each group to determine blood cell counts and plasma levels of D Dimer and vascular endothelial growth factor (VEGF), while heart blood samples were collected from the remaining mice to measure the rate of thrombin-induced platelet aggregation. For all mice, pathological analyses of the cerebrum, lung, mesentery, femoral vein, external iliac vein and spleen were performed. Tumors were weighed to assess the impact of HSOS treatment on tumor growth, and the number of thrombi, metastatic nodules and neovessels in the tumor tissue were counted. In addition, 24 normal New Zealand rabbits were divided into two groups and treated with either HSOS or normal saline to determine the rates of ADP-, collagen- or thrombin-induced platelet aggregation. Compared with the model group, HSOS treatment decreased the incidence of pulmonary thromboembolism and metastasis, the number of metastatic nodules, the plasma levels of D-dimer and VEGF, the rate of collagen-induced platelet aggregation in rabbits and the numbers of leukocytes and tumor neovessels (P<0.05 for all). It increased the thymus and spleen coefficients and the number of platelets (P<0.05 for all), but had no significant effect on thrombin-induced platelet aggregation in mice and rabbits, ADP-induced platelet aggregation in rabbits, or the number of red blood cells. The reduced rate of tumor growth was 9.7% in mice treated with HSOS. HSOS treatment effectively reduced the development of pulmonary thromboembolism and metastasis in mice bearing LLC via mechanisms possibly associated with ameliorating a blood hypercoagulable state, decreasing tumor angiogenesis and enhancing immunity. PMID- 24348828 TI - Correlation between TSP-1, TGF-beta and PPAR-gamma expression levels and glioma microvascular density. AB - Gliomas are the most common type of primary tumor in the central nervous system and are characterized by abundant capillary angiogenesis. It is important to study the underlying molecular mechanisms of angiogenesis in order to aid the identification of potential therapeutic targets. The aim of the current study was to investigate the expression levels of thrombospondin-1 (TSP-1), transforming growth factor-beta (TGF-beta) and peroxisome proliferator-activated receptor gamma (PPAR-gamma) in gliomas, and determine their relationships with angiogenesis. Immunohistochemical methods were used to detect TSP-1, TGF-beta and PPAR-gamma expression levels and to assess microvascular density (MVD) in 99 glioma tissue samples of various grades. The total positive expression rates of TSP-1 and PPAR-gamma were 78.4 and 94.1% in low-grade gliomas and 45.8 and 39.6% in high-grade gliomas. These values suggest that their expression negatively correlated with tumor grade. However, TGF-beta expression positively correlated with tumor grade; the total positive expression rate of TGF-beta in high-grade gliomas (93.8%) was significantly increased compared with that in low-grade gliomas (43.1%). The MVD in the low-grade group was 28+/-7.2 vessels/field, which was significantly lower than in the high-grade group (45+/-6.2 vessels/field). TSP-1 and PPAR-gamma expression levels were negatively correlated with MVD (P<0.05), while the TGF-beta expression level was positively correlated with MVD (P<0.05). These results indicate that the TSP-1, TGF-beta and PPAR-gamma expression levels in gliomas are correlated with MVD, which suggests that these proteins may be involved in the regulation of glioma angiogenesis. PMID- 24348829 TI - Knockdown of astrocyte elevated gene-1 inhibits growth through suppression of IL 6 secretion in HepG2 human hepatoma cells. AB - Astrocyte-elevated gene-1 (AEG-1) has been reported to be associated with cancer progression in various types of human cancers, including liver cancer. However, to date, the molecular mechanism of AEG-1 action on the growth of liver cancer cells has been poorly elucidated. The present study aimed to investigate the effect of AEG-1 on the proliferation and apoptosis of liver cancer cells and the role of IL-6 in this process using the HepG2 human hepatoma cell line. shRNAs targeting AEG-1 were used to silence the expression of AEG-1. The effects on cell growth were detected by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, colony formation and cell cycle assays. Apoptosis was analyzed by flow cytometry. The expression of IL-6 was examined by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, and the phosphorylation of Stat3 was detected by western blotting. AEG-1 knockdown was observed to induce cell proliferation inhibition and apoptosis through the suppression of IL-6 secretion. Stat3, a downstream target of IL-6 signaling, was suppressed in the AEG-1 silenced cells and target genes, including Bcl-2 and crystalin, alphaB, which are associated with cell survival, were downregulated. Overall, the findings suggest that aberrant AEG-1 expression promotes the growth of HepG2 liver cancer cells, contributing to the progression of liver cancer, which may partly be mediated by IL-6 signaling. PMID- 24348830 TI - Semi-automated evaluation of Ki-67 index in invasive ductal carcinoma of the breast. AB - A significant factor that affects the value of the Ki-67 proliferation index (IK) is the interpretation and implementation approach. This method is based on visual or automated methods to count tumor nuclei labeled with Ki-67 antigen, and is prone to errors. Detection of Ki-67 is a useful tool in breast cancer and contributes to its molecular classification. The current study proposes a method for the quantification of Ki-67-positive tumor nuclei, which allows for the determination of the exact IK value that is required for tumor stratification based on the proliferation rate. The IK was assessed in 81 successive cases of diagnosed invasive ductal breast carcinoma using a semi-automated method that accurately identifies positive tumor cell nuclei. This method prevents the inclusion of other possible positive cells, including lymphoid, normal epithelia and hyperplastic. In small specimens with increased cell density, where the nucleus/cytoplasm ratio is markedly in favor of the nucleus and the distance between nuclei is small, the method allows precise quantification of the nuclei, even when the limits between nuclei are difficult to identify. In addition, images may be stored in a database, including the assessments, and easily accessed when required. We hypothesize that the semi-automated method for counting nuclei offers the most accurate method of assessing the IK and avoids counting errors that may occur through other methods. PMID- 24348831 TI - Nucleosome-binding protein HMGN2 exhibits antitumor activity in oral squamous cell carcinoma. AB - Natural killer (NK) cells and cytolytic T lymphocytes (CTLs) serve as effectors in the antitumor response. High mobility group nucleosomal binding domain 2 (HMGN2) is a candidate effector molecule involved in CTL and NK cell function. In the current study, recombinant human HMGN2 was isolated and purified from transformed Escherichia coli. Tca8113 cells, an oral squamous cell carcinoma line, were treated with a variety of HMGN2 protein concentrations and cell growth was analyzed. HMGN2 significantly inhibited the growth of Tca8113 cells and was predicted to arrest cells in the S phase. Moreover, HMGN2 treatment increased the apoptosis rate of Tca8113 cells. Western blotting indicated the upregulation of p53 and Bax proteins, whereas Bcl-2 was significantly downregulated. In addition, caspase-3 was found to be activated. Furthermore, the HMGN2 protein may suppress the growth of Tca8113 cells in vivo. The results of the current study indicated that the HMGN2 protein may inhibit the growth of oral squamous cell carcinoma and HMGN2 may represent an antitumor effector molecule of CTL or NK cells. PMID- 24348832 TI - VX680 suppresses the growth of HepG2 cells and enhances the chemosensitivity to cisplatin. AB - VX680 is an Aurora A inhibitor. It has been reported to inhibit the growth of the HepG2 cell line in several studies. However, whether it enhances chemosensitivity to cisplatin remains unclear. In this study, the synergistic effect of VX680 and cisplatin on the proliferation of HepG2 cells was determined by MTT assay. The changes in cell apoptosis were detected by flow cytometry. Aurora A, Bcl-2 and p53 protein levels were analyzed by western blotting. This study demonstrated that VX680, cisplatin and a combination of the two inhibit the growth of HepG2 cells in a dose- and time-dependent manner. A synergistic effect was observed with the combined therapy. Moreover, the inhibitory effect of VX680 was positively correlated with the expression of Aurora A. The rate of apoptosis in the combined group was significantly higher compared with that of the VX680 and cisplatin groups. In addition, VX680 and cisplatin increased the expression of the p53 protein. Cisplatin reduced the expression of Bcl-2 protein, while VX680 did not. In the combined group, the expression of Bcl-2 and p53 changed significantly compared with the single drug group and control group. This study suggests that Aurora A may represent a valid target in hepatocellular carcinoma. We also demonstrated that the Aurora A inhibitor VX680 has a synergistic effect with cisplatin. PMID- 24348833 TI - Low dose of interferon-alpha improves the clinical outcomes of docetaxel in patients with castration-resistant prostate cancer: A pilot study. AB - The aim of this study was to test whether a low dose of interferon-alpha-2b (IFN alpha2b) enhances the clinical outcome of docetaxel (DXT) in patients with castration-resistant prostate cancer (CRPC). A prospective controlled trial of 40 CRPC patients receiving 5 mg of prednisone twice daily was conducted, where patients were randomly assigned to be administered 75 mg/m2 DXT plus 3 mIU/m2 IFN alpha2b (group A, n=20) or 75 mg/m2 DXT alone (group B, n=20). The prostate specific antigen (PSA) response, tumor response, progression-free survival (PFS) and overall survival (OS) were evaluated. There was no statistically significant difference in PSA response rate between groups A and B (65 vs. 47.4%, P=0.341). The tumor response rate in group A was significantly greater compared with that in group B (55 vs. 21.1%, P=0.048). The median PFS was longer in group A compared with that in group B (10 vs. 8 months, P=0.043). There was no statistically significant difference in median OS between the two groups (19 vs. 17 months, P=0.348), but one patient displayed a complete tumor response in group A. In groups A and B, transient grade 3 to 4 neutropenia was observed in nine and six patients, grade 3 to 4 anemia was observed in three and five patients, and grade 3 to 4 general fatigue was observed in four and one patient(s), respectively. The proportion of patients with grade 3 to 4 toxicity was not statistically different between the two groups. A low dosage of IFN-alpha2b may improve the antitumor activity of DXT with an acceptable toxicity profile in patients with CRPC. PMID- 24348834 TI - Expression of dedifferentiation markers and multilineage markers in U251 glioblastoma cells with silenced EGFR and FGFR genes. AB - Epithelial growth factor (EGF) and basic fibroblast growth factor (bFGF), and their receptors, epithelial growth factor receptor (EGFR) and bFGF receptor (bFGFR), are frequently overexpressed in high-grade gliomas. In the present study, the EGF and bFGF levels in U251 glioblastoma cell culture supernatants were determined by ELISA, and enhanced green fluorescent protein (EGFP)-labeled recombinant lentiviral expression vectors with small interfering RNA targeting the EGFR and bFGFR genes were constructed. The mRNA expression levels of EGFR, bFGFR, cluster of differentiation (CD)133, glial fibrillary acidic protein (GFAP), tubulin-beta3 (TUBB3) and myelin basic protein (MBP) were determined using quantitative polymerase chain reactions in U251 cells prior to and following silencing of the EGFR and/or bFGFR genes. Prior to silencing, the U251 cells secreted EGF and bFGF, and expressed EGFR, bFGFR, CD133, GFAP, TUBB3 and MBP mRNA. Subsequent to silencing the EGFR and/or bFGFR gene, CD133 mRNA expression decreased and GFAP and TUBB3 mRNA expression increased. Silencing the EGFR and FGFR genes acted synergistically to downregulate CD133 expression. The downregulation of CD133 mRNA expression and the upregulation of GFAP and TUBB3 mRNA expression were not significantly different when blocking the EGFR and FGFR pathways. These results indicate that autocrine or paracrine EGF and/or FGF mechanisms exist in U251 cells. Knocking down the EGFR and/or FGFR genes downregulates CD133 mRNA expression and facilitates glial and neuronal differentiation in U251 cells. PMID- 24348835 TI - Primary pleomorphic rhabdomyosarcoma of the adrenal gland in an adult: A case report. AB - A 61-year-old female was referred to The First Affiliated Hospital, College of Medicine, Zhejiang University (Hangzhou, China) due to a right adrenal tumor. A pre-operative transcutaneous fine-needle aspiration biopsy and right adrenalectomy were performed, and pathological analysis resulted in the diagnosis of pleomorphic rhabdomyosarcoma (RMS). Primary pleomorphic RMS of the adrenal gland in an adult is a rare condition. To the best of our knowledge, this is the first case of pleomorphic RMS of the adrenal gland in an adult diagnosed by light microscopy and immunohistochemical stains. PMID- 24348836 TI - Primary giant mediastinal synovial sarcoma of the neck: A case report and review of the literature. AB - Synovial sarcomas commonly occur in the soft tissue of the extremities, while a primary occurrence in the mediastinum is quite rare. The current study reports the case of an 11-year-old male who presented with a neck mass, which computed tomography showed was due to a giant mediastinal mass involving the thyroid gland. The tumor was resected by thoracotomy and diagnosed as monophasic synovial sarcoma by histopathology. The patient received adjuvant combination chemotherapy and radiation therapy following surgery. At the 3-month follow-up, no local tumor recurrence was found. The present case report highlights the significance of recognizing the unusual presentation and clinical manifestation of synovial sarcoma to aid clinical management. Written informed consent was obtained from the patient's family. PMID- 24348837 TI - Granulocytic sarcoma of the breast in acute myeloid leukemia: Two case reports. AB - Granulocytic sarcoma (GS) of the breast is extremely rare in patients with acute myeloid leukemia (AML) and therefore, is often misdiagnosed as lymphoma or other benign tumors. The current report presents two cases of GS of the breast, of which, one was considered to be a fibroma, as observed by fine-needle aspiration, and the other was misdiagnosed as lymphoma by frozen section. Previous literature that described the clinical and pathological characteristics, treatments and prognosis of GS of the breast in AML were reviewed. In addition to the treatment of mastectomy with/without radiotherapy, lumpectomy may also be received as a good treatment plan. PMID- 24348838 TI - Management of perivascular epithelioid cell tumor of the liver: A case report and review of the literature. AB - Perivascular epithelioid cell tumor (PEComa) is a rare tumor that originates from mesenchymal tissues. Cases of PEComa in the liver are extremely rare. The present study aimed to analyze the clinical features of PEComa in the liver and discuss its management. Here we report a 25-year-old female with multiple lesions of low density with poorly defined borders in the liver, as shown by a computed tomography (CT) scan. A partial hepatectomy was proceeded and PEComa was diagnosed by immunohistochemistry. No evidence of recurrence was observed during the one year follow-up. A total of 20 patients with hepatic PEComa, including one case from the present study and 19 cases that were reported in literature between June 2001 and December 2012, were reviewed and analyzed. The mean patient age was 43.4 years (range, 25-67 years) and the cases consisted of 18 female and two male patients. The tumor size ranged between 2.0*1.6 and 15.0*12.0 cm. Of the 20 patients, nine were asymptomatic and 11 had mild to significant complaints. Immunohistochemistry plays a key role in the diagnosis of PEComa. All the cases in this study were strongly positive for human melanoma black-45. A surgical resection is the gold standard for curative intent. All the patients underwent a surgical resection and none were administered perioperative chemotherapy or radiotherapy. In total, 13 of the 14 patients with follow-up information survived during the 8-36-month follow-up period and one patient succumbed due to recurrence two years after the surgery. PMID- 24348839 TI - Rectal adenocarcinoma metastatic to the tonsil; PET-CT observations with pathological confirmation: A case report. AB - Metastasis of rectal adenocarcinoma develops by lymphatic or hematogenous spread. The usual sites of metastasis from rectal adenocarcinoma include local and distant lymph nodes, the liver and the lungs. The current case report presents a unique case of a mass that was identified in the tonsil by positron emission tomography-computed tomography (PET-CT), indicating a metastasis from rectal adenocarcinoma. Metastatic tumor to the tonsil is extremely rare and to the best of our knowledge, no previous studies have reported a case of tonsil metastasis from rectal adenocarcinoma. PET-CT scanners represent an important evolution in technology that is helping to bring anatomical imaging togeother with functional imaging in cancer diagnosis and therapy. Written informed consent was obtained from the patient. PMID- 24348840 TI - Primary breast T-cell lymphoma, unspecified, treated with autologous peripheral blood stem cell transplantation: A case report and literature review. AB - The current study presents a case of primary T-cell lymphoma (PTBL), unspecified, in a 27-year-old female. The patient received chemotherapy [cyclophosphamide, epirubicin, vindesine and prednisolone (CHOP) and VP-16 plus CHOP (ECHOP)] and autologous peripheral blood stem cell transplantation, however, relapse occurred rapidly. The recurrent tumor exhibited increased levels of karyopyknosis and nuclear fragmentation and a higher Ki67 index compared with the primary tumor. No response to subsequent chemotherapy, including ECHOP and gemcitabine, dexamethasone and cisplatin, was observed. The patient succumbed to PTBL, unspecified, 18 months after the diagnosis. We hypothesize that autologous peripheral blood stem cell transplantation is ineffective for PTBL. PMID- 24348841 TI - Expression of gammaH2AX in various gastric pathologies and its association with Helicobacter pylori infection. AB - Phosphorylation of H2AX at Ser 139 (gammaH2AX) is a biomarker of DNA double strand breaks (DSBs). The present study aimed to explore the association between gammaH2AX levels and gastric pathology and Helicobacter pylori (H. pylori) infection. Gastric biopsies were obtained from 302 H. pylori-negative and positive patients, including those with chronic gastritis (CG), intestinal metaplasia (IM), dysplasia (Dys) and gastric cancer (GC). Proteins were extracted from five gastric epithelial cell lines and from 10 specimens of matched GC and adjacent normal tissues. The expression of gammaH2AX, a biomarker for the detection of DNA DSBs, in gastric tissues was detected by immunohistochemistry and western blotting. The expression of gammaH2AX progressively increased in tissues according to pathological stage from CG to Dys, but was slightly decreased in GC. H. pylori infection was associated with increased gammaH2AX expression, IM and Dys. Overexpression of gammaH2AX in GC was found to correlate with tumor location, gross appearance, differentiation, depth of invasion, TNM stage and lymph node metastasis. The results indicated that DSBs appear to be an early molecular event in gastric carcinogenesis, which may be associated with H. pylori infection. Moreover, immunohistochemical staining of gammaH2AX was found to correlate with a number of clinicopathological characteristics. The expression of gammaH2AX may serve as a valuable biomarker for the diagnosis and progression of GC. PMID- 24348842 TI - Requirement for a standardised definition of advanced gastric cancer. AB - Each year, ~988,000 new cases of stomach cancer are reported worldwide. Uniformity for the definition of advanced gastric cancer (AGC) is required to ensure the improved management of patients. Various classifications do actually exist for gastric cancer, but the classification determined by lesion depth is extremely important, as it has been shown to correlate with patient prognosis; for example, early gastric cancer (EGC) has a favourable prognosis when compared with AGC. In the literature, the definition of EGC is clear, however, there is heterogeneity in the definition of AGC. In the current study, all parameters of the TNM classification for AGC reported in each previous study were individually analysed. It was necessary to perform a comprehensive systematic literature search of all previous studies that have reported a definition of ACG to guarantee homogeneity in the assessment of surgical outcome. It must be understood that the term 'advanced gastric cancer' may implicate a number of stages of disease, and studies must highlight the exact clinical TNM stages used for evaluation of the study. PMID- 24348843 TI - Icotinib combined with rapamycin in a renal transplant recipient with epidermal growth factor receptor-mutated non-small cell lung cancer: A case report. AB - As kidney transplant recipients are at increased risk of developing cancer, regular monitoring should be undertaken to monitor the balance between immunosuppression and graft function and to identify malignancy. The present study reports the outcome of the treatment of adenocarcinoma of the lung (T1aN0M1a, stage IV) using the molecular-targeted therapy, icotinib, in a 66-year old male renal transplant patient receiving rapamycin and prednisolone as ongoing renal immunosuppressive therapy. An initial partial response to icotinib was achieved, and graft function remained good. However, the patient subsequently developed interstitial pneumonitis. The plasma concentrations of rapamycin and icotinib were within the normal ranges, which excluded the possibility of a pharmacokinetic drug interaction and indicated that the interstitial pneumonitis was likely to be associated with the side-effects of icotinib. Drug therapy was discontinued and the patient underwent a segmentectomy. Tacrolimus was administered for ongoing renal graft immunosuppression. To the best of our knowledge, this is the first report of the concomitant administration of icotinib and rapamycin in post-transplant de novo lung cancer. It is also the first report of interstitial pneumonitis associated with icotinib in a post-transplant patient. PMID- 24348844 TI - Treatment outcomes in relapsed acute promyelocytic leukemia patients initially treated with all-trans retinoic acid and arsenic compound-based combined therapies. AB - Contemporary combined therapies that include the use of all-trans retinoic acid (ATRA) and arsenic compounds have reduced relapse rates from ~50 to <10% in acute promyelocytic leukemia (APL) patients, however relapse treatment remains controversial. Treatment outcomes in relapsed patients with APL previously treated with combined ATRA + arsenic compound therapy were investigated. A retrospective, observational study was conducted of 25 patients with APL (male to female ratio, 17:8; mean age, 36.4+/-10.3 years) exhibiting first-time relapse following combined ATRA + arsenic compound therapy. These patients were subsequently treated with secondary ATRA + arsenic compound therapy, salvage chemotherapy, monoclonal antibody therapy or intrathecal chemotherapy, between January 1994 and December 2010. The overall remission rate, duration of remission and toxic effects were assessed. Patient outcomes included mortality during secondary induction therapy (6/25, 24.0%); complete recovery from central nervous system (CNS) relapse following intrathecal chemotherapy (1/25, 4.0%); complete remission following ATRA + arsenic compound therapy (10/25, 40.0%), chemotherapy (3/25, 12.0%) and targeted therapy (1/25, 4.0%); and non-remission (NR) following ATRA + arsenic compound therapy (4/25, 16%). Four (16.0%) patients were subsequently treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT), two of which remained disease-free at the end of the study period and two of which succumbed to the disease. Secondary bone marrow and CNS relapse occurred in 14 (56.0%) patients and one (4.0%) patient, respectively. ATRA + arsenic compound-based combination therapy was effective in re-inducing morphological remission in relapsed patients with APL with previous exposure to ATRA + arsenic compounds, producing low molecular remission rates and high risk of secondary relapse. Furthermore, investigation of early allo-HSCT is required to determine its potential as a therapeutic option for re-inducing morphological remission in relapsed patients with APL with previous exposure to ATRA + arsenic compounds. PMID- 24348845 TI - microRNA-106a modulates cisplatin sensitivity by targeting PDCD4 in human ovarian cancer cells. AB - microRNAs (miRNAs/miRs) are a cluster of short non-protein coding RNAs that negatively regulate gene expression, which is involved in fundamental cellular processes, including the response of tumor cells to chemotherapeutic agents. The present study investigated the role of miR-106a in the development of drug resistance in ovarian cancer cells. The expression of miR-106a in the ovarian cancer OVCAR3 cell line and the cisplatin (CDDP)-resistant ovarian cancer OVCAR3/CIS cell line was detected using stem-loop quantitative (q)PCR. The OVCAR3 and OVCAR3/CIS cells were transfected with mimics or inhibitors of miR-106a or with negative control (NC) RNA using lipofectamine 2000. Luciferase reporter assays were used to determine whether PDCD4 was a direct target of miR-106a in the OVCAR3 cells. The expression levels of the PDCD4 proteins were assessed using qRT-PCR and western blotting, respectively. Drug sensitivity was analyzed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, while apoptosis was determined by fluorescence-activating cell sorting analysis. The expression levels of miR-106a were upregulated in the CDDP-resistant ovarian cancer OVCAR3/CIS cell line compared with the parental OVCAR3 cell line. However, the PDCD4 protein levels were decreased in the OVCAR3/CIS cells compared with the OVCAR3 cells. The luciferase reporter assays revealed that PDCD4 was a direct miR 106a target in the OVCAR3 cells. Transfection of the OVCAR3/CIS cells with inhibitors of miR-106a enhanced the sensitivity of the OVCAR3/CIS cells to CDDP and increased CDDP-induced apoptosis. The expression of the PDCD4 protein and the sensitivity to CDDP was decreased in the OVCAR3 cells that were transfected with the mimics of miR-106a. The knockdown of PDCD4 expression using PDCD4-specific siRNAs in the OVCAR3 cells demonstrated that PDCD4 is a key signaling molecule in OVCAR3 cell CDDP-induced resistance. miR-106a may be involved in the development of drug resistance and the regulation of PDCD4 expression, at least in part, by modulating CDDP-induced apoptosis in ovarian cancer cells. PMID- 24348846 TI - Paxillin expression is closely linked to the pathogenesis, progression and prognosis of gastric carcinomas. AB - Paxillin encodes a focal adhesion-associated protein and is involved in the progression and aggressive phenotypes of malignancies through its interactions with the actin cytoskeleton and key signal transduction oncogenes. The present study aimed to investigate the clinicopathological and prognostic significance of paxillin in gastric cancer. The expression of paxillin was evaluated using tissue microarrays of gastric adjacent non-cancerous mucosa, adenoma and carcinoma specimens by immunohistochemistry. Paxillin expression was compared against clinicopathological parameters and the survival time of the patients. Paxillin was highly expressed in gastric adenoma compared with that in non-neoplastic mucosa and carcinoma (P<0.05). Paxillin expression was lower in the younger carcinoma patients compared with that in the elder carcinoma patients (P<0.05). Paxillin expression was negatively correlated with tumor size, depth of invasion and lymph node metastasis, but not with patient gender, lymphatic or venous invasion, or TNM staging (P>0.05). Higher paxillin expression was observed in intestinal-type compared with diffuse-type carcinoma (P<0.05). Kaplan-Meier analysis indicated a positive association between paxillin expression and cumulative survival rate in all, advanced and intestinal-type carcinoma patients (P<0.05). Multivariate analysis using the Cox proportional hazards model indicated that patient age, depth of invasion, lymphatic invasion, lymph node metastasis, TNM staging and Lauren classification were independent prognostic factors for all gastric carcinomas (P<0.05). Aberrant paxillin expression may be involved in the growth, invasion, metastasis and differentiation of gastric carcinoma. Altered paxillin expression may, therefore, be employed as an indicator of pathobiological behaviors and prognosis of gastric carcinomas. PMID- 24348847 TI - Ultrasonography, X-ray and CT imaging findings of a giant pericardial lipoma: Imaging diagnosis and review of the literature. AB - Pericardial lipomas are rare and mostly asymptomatic tumors, which are usually detected incidentally during physical examination. The present study describes a case of giant pericardial lipoma that was diagnosed by surgical pathology. The study also describe the X-ray, magnetic resonance imaging, and the distinguish of the pericardial lipomas. The study also describes the ultrasonography, X-ray, computed tomography and magnetic resonance imaging findings of the tumor, and a review of the literature of cardiac lipoma, to help increase awareness of the tumor and selection of the correct imaging method for diagnosis. PMID- 24348848 TI - Primary yolk sac tumour of the urinary bladder: A case report and review of the literature. AB - We present a case of rare primary yolk sac tumour of the urinary bladder in adulthood. A 31-year-old female patient presented with a history of chronic ketamine abuse, which has not previously been shown to be associated with malignancy development. The final diagnosis was established only after radical cystectomy. A computed tomography (CT) scan showed paraaortic lymph node metastasis. The patient was treated with systemic chemotherapy. A review of the literature revealed that surgical excision and cisplatin-based chemotherapy remain to be the standard of care for extragonadal yolk sac tumours. PMID- 24348850 TI - Body mass index can affect gastrointestinal and genitourinary toxicity in patients with prostate cancer treated with external beam radiation therapy. AB - The aim of the present study was to determine the impact of obesity on radiation induced gastrointestinal (GI) and genitourinary (GU) toxicity. The cases of 54 patients with prostate cancer, treated with three-dimensional conformal radiation therapy (RT), were reviewed. For each patient, the body mass index (BMI), distance between the prostate and rectum (D) on a computerised tomography scan and the dosimetric parameters of the rectum and bladder in the planning data of RT, were analyzed. GI and GU toxicity was assessed during and following RT. The results of the patients with a BMI of <25 (lower BMI) were compared with those of the patients with a BMI of >=25 (higher BMI). The higher BMI group exhibited significantly lower doses of V60 and V65 in the rectum than the lower BMI group. No significant differences were found in D and bladder doses between the two groups. The incidence of acute GI and GU toxicity and late GI and GU toxicity were 41.7, 19.4, 35.3 and 5.7% in the lower BMI group, respectively, and 27.8, 27.8, 5.9 and 35.3% in the higher BMI group, respectively. In addition, a significant difference was found in the incidence of late GU toxicity between the two groups. Among patients who underwent RT for prostate cancer, those with higher BMIs had a tendency to show lower incidences of GI toxicity and higher incidences of GU toxicity than patients with lower BMIs. To conclude, an increased effort must be made to reduce rectal doses in patients with lower BMIs. Conversely, increased care for GU toxicity must be provided for overweight patients. PMID- 24348851 TI - Downregulation of ERK signaling impairs U2OS osteosarcoma cell migration in collagen matrix by suppressing MMP9 production. AB - The present study investigated the role of extracellular signal-regulated kinase (ERK) activation in the migratory phenotype of human U2OS osteosarcoma (OS) cells in a collagen matrix. The activation of ERK was inhibited by PD98059, a specific inhibitor of ERK kinase. Additionally, no significant differences were observed in the adhesion and proliferation of the cells with or without PD98059 treatment in collagen-coated dishes. The migratory capacity of the U2OS cells was then examined in non-coated and collagen-coated dishes, and the results depicted that collagen I enhanced the migration of the U2OS cells, the effect of which was significantly blocked by the treatment of the cells with PD98059. Furthermore, enhanced gene and protein expression of matrix metalloproteinase 9 (MMP9), but not MMP2, was observed to be involved in the enhanced migratory phenotype of the U20S cells in the collagen-coated plates. This effect was partially abolished by the treatment of the cells in the collagen-coated dishes with ERK inhibitor. Collectively, the data demonstrate that ERK signaling is important for the migration of U2OS cells through the extracellular matrix (ECM), which is comprised mostly of collagen, by enhancing MMP9 production. These results may contribute to the regulation of MMP9 production in metastatic OS. PMID- 24348849 TI - Histone deacetylase inhibitor, valproic acid, radiosensitizes the C6 glioma cell line in vitro. AB - Valproic acid (VPA) is a well-tolerated drug that is used to treat seizure disorders and that has recently been shown to inhibit histone deacetylase. The present study investigated the effects of VPA on the radiosensitization of the rat C6 glioma cell line in vitro. To select an appropriate treatment concentration and time, MTT and flow cytometry assays were performed to measure the inhibitory effects of VPA at various concentrations and incubation time points. The radiosensitizing effect of VPA was determined using clonogenic experiments. VPA- and radiation-induced C6 apoptosis was analyzed using quantitative polymerase chain reaction and western blot analysis. Cell proliferation was significantly inhibited by VPA in a time- and dose-dependent manner (P<0.05). VPA enhanced radiation-induced C6 cell death and there was clear inhibition of clonogenic formation [sensitizer enhancement ratio (SER), 1.30]. This effect was closely associated with the concentration of VPA. VPA treatment decreased the mRNA and protein levels of Bcl-2, whereas increased changes were detected with Bax. At a concentration of 0.5 mmol/l, VPA had a low toxicity and enhanced the radiosensitization of the C6 cells. VPA may radiosensitize glioma cells by inhibiting cellular proliferation and inducing apoptosis by regulating apoptosis-related molecular changes. PMID- 24348852 TI - Atypical imaging observations of branchial cleft cysts. AB - The aim of the present study was to assess the atypical imaging manifestations of branchial cleft cysts (BCCs) confirmed by pathology. Computerized tomography (CT) or magnetic resonance imaging (MRI) of 17 BCC cases were reviewed. The imaging features, including laterality, location, border, attenuation and internal architecture, were evaluated. All 17 cases were second BCCs, including 5 cases of Bailey type I classification cysts and 12 cases of type II classification cysts. The atypical imaging features included signal and morphological abnormalities. The abnormal signal intensities were caused by intracapsular bleeding (n=2) or solidification of cystic fluid (n=2). Intracystic hemorrhaging revealed homogeneous hyperintensity on T1-weighted image (T1WI) and T2-weighted image (T2WI). Solidification of cystic fluid revealed slightly homogeneous hyperintensity compared with muscle on T1WI and homogeneous hypointensity on T2WI without enhancement. The aberrant morphology mainly presented as thickening of the cystic wall (n=13). Thickened walls of BCCs with ill- (n=5) or well- (n=8) defined borders were observed in 13 patients. In 3 patients, significant enhancement was identified following intravenous gadolinium administration (n=4). When with atypical CT or MRI features are presented, the typical location of BCCs can help in the diagnosis, as it is located at the lateral portion of the neck adjacent to the anterior border of the mandibular angle or sternocleidomastoid muscle. The atypical observations, including variable signals, imply that the cystic content has changed. Thickened walls indicate inflammation or cancerous tendency and patients with ill-defined margins, vascular involvement or lymphadenopathy atelectasis indicate malignant conversion. PMID- 24348853 TI - First case report of an intracortical lipoma in an adult tibia. AB - The current case report describes an adult male with an intracortical lipoma accompanied by cystic changes in the tibial diaphysis. To the best of our knowledge, intracortical lipoma in an adult tibia has not been previously described. An anteroposterior radiograph of the tibia revealed an osteolytic lesion on the diaphysis. Magnetic resonance imaging and computed tomography revealed that the lesion was located in the cortex and consisted of fat and cyst tissue. Surgical excision of the lesion confirmed diagnosis of an intracortical lipoma. PMID- 24348854 TI - Significance of thymidylate synthase expression for resistance to pemetrexed in pulmonary adenocarcinoma. AB - Pemetrexed (PEM), a multi-targeted antifolate, has promising clinical activity in non-squamous non-small cell lung cancer. However, the majority of patients eventually acquire resistance to PEM. To evaluate the resistant mechanisms, the A549 lung adenocarcinoma cell line was exposed to stepwise increasing PEM concentrations of 1.6, 6.4 and 16 MUM to establish three PEM-resistant lung cancer cell lines, A549/PEM-1.6, -6.4 and -16. Growth inhibition was determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Expression of the genes encoding thymidylate synthase (TS), reduced folate carrier (RFC) and folypoly-gamma-glutamate synthetase (FPGS) were analyzed by quantitative real-time reverse transcription polymerase chain reaction. The three A549 cell lines showed more resistance to PEM (3.7-, 17.3- and 38.0-fold, respectively) compared with that of the parental cell line, which also showed cross-resistance to cisplatin, but not to docetaxel, vinorelbine and 5 Fluorouracil (5-FU). TS gene expression was significantly increased in three PEM resistant cells, relative to that of the parental cells, in a PEM dose-dependent manner. Knockdown of TS expression with siRNA enhanced the cytotoxicity of PEM in A549/PEM-16 cells. By contrast, the levels of RFC and FPGS gene expression in A549/PEM-1.6 and -6.4 cells were significantly decreased, whereas the levels of the two genes were restored in A549/PEM-16 cells. In summary, PEM-resistant A549 cells remained sensitive to docetaxel, vinorelbine and 5-FU. TS expression appeared to be associated with resistance to PEM, which may be a predictive marker for PEM sensitivity in lung adenocarcinoma. PMID- 24348855 TI - Overexpression of Pygopus-2 is required for canonical Wnt activation in human lung cancer. AB - Lung cancer is the most common cause of cancer-related mortality worldwide. It is necessary to improve the understanding of the molecular mechanisms involved in lung cancer in order to develop more effective therapeutics for the treatment of this fatal disease. The canonical Wnt signaling pathway has been known to be important in a number of cancer types, including lung cancer. Pygopus (Pygo) is a recently identified downstream component of the Wnt signaling pathway required for beta-catenin/T-cell factor (TCF)-dependent transcription. However, the role of Pygo in lung cancer remains to be elucidated. The present study showed that Pygo2 is overexpressed in human lung cancer tissue samples and cell lines. Expression levels of Pygo2 were found to correlate with cytosolic beta-catenin protein levels in the samples examined. Co-immunofluorescent staining showed that Pygo2 protein accumulated in the nuclei and colocalized with nuclear beta-catenin in lung cancer cell lines expressing Pygo2. To investigate the functional importance of the Pygo2 overexpression in lung cancer, short hairpin RNA (shRNA) was used to knockdown Pygo2 mRNA in lung cancer cells expressing the gene. Pygo2 shRNA was observed to inhibit cell proliferation and decrease beta-catenin/TCF dependent transcriptional activity in vitro. Furthermore, Pygo2 shRNA significantly suppressed lung cancer xenograft models in vivo (P<0.05). These results suggested that Pygo2 is a putative therapeutic target for human lung cancer and overexpression of Pygo2 may be important for aberrant Wnt activation in lung cancer. PMID- 24348856 TI - hTERT promoter activity identifies osteosarcoma cells with increased EMT characteristics. AB - Epithelial-mesenchymal transition (EMT) is a critical step in order for epithelial-derived malignancies to metastasize, however, its role in mesenchymal derived tumors, i.e., osteosarcoma, remains unclear. Cancer stem cells (CSCs) are enriched with cells that undergo EMT. The activity of telomerase is maintained in normal stem cells and a number of malignant tumors. The current study observed the heterogeneity of telomerase activity among individual osteosarcoma cells. We hypothesized that telomerase-positive (TELpos) cells are enriched for stem cell like and EMT properties. A human telomerase reverse transcriptase (hTERT) promoter-reporter was applied to assess the telomerase activity of individual MG63 osteosarcoma cells and sort them into TELpos and telomerase-negative (TELneg) subpopulations. It was found that the TELpos cells exhibited an enhanced ability to form sarcospheres in vitro. In addition, TELpos cells exhibited a higher expression of vimentin, accompanied by an increased long/short axis ratio. A panel of EMT-related genes was evaluated by quantitative PCR and western blot analysis, and were found to be significantly upregulated in TELpos cells. Next, the in vitro migration capacity was examined by Transwell assay, which confirmed that TELpos cells are more prone to migration (2.6 fold). The results of the present study support the concept that EMT also applies to mesenchymal-derived osteosarcoma and draws a connection between telomerase and EMT characteristics. PMID- 24348857 TI - Sarcomatoid (spindle cell) carcinoma of the pancreas: A case report and review of the literature. AB - Sarcomatoid (spindle cell) carcinoma of the pancreas is a rare, high-grade epithelial malignancy composed predominantly or exclusively of spindle cells demonstrating evidence of epithelial derivation, but no features indicative of a specific line of mesenchymal differentiation. The current study presents the case of an 85-year-old Caucasian male with a tumor mass in the body of the pancreas. The individual subsequently underwent a distal pancreatectomy, splenectomy and partial gastrectomy. Microscopic examination of the 3.3-cm mass located in the body of the pancreas revealed a small, but high-grade, adenocarcinomatous component that blended imperceptibly with malignant spindle cells. No light microscopic or immunohistochemical evidence of specific mesenchymal differentiation was identified, and the spindle cells, as in the case of the carcinoma, were diffusely keratin-positive. Sarcomatoid (spindle cell) carcinoma defined in this way rarely presents in the pancreas, with, to the best of our knowledge, only six cases reported in the English literature. PMID- 24348858 TI - Antitumor activities of Juemingzi (Cassia tora L.) on Balb/c sarcoma 180-injected mice. AB - The antitumor activity of Juemingzi (Cassia tora L.) was investigated in mice that were fed various concentrations of the compound. Although mice fed a low concentration (50 mg/kg b.w.) of Juemingzi exhibited a high tumor weight, the higher feeding concentrations (100 and 200 mg/kg b.w.) were associated with lower weight tumors. The growth rate of mouse splenocytes that were treated with 200 mg/kg b.w. Juemingzi was determined using a 3-(4,5-dimethyl-2-thiazolyl)-2,5 diphenyltetrazolium bromide assay. This rate of proliferation was higher than that achieved with 100 and 50 mg/kg b.w. Juemingzi treatment by fetal bovine serum, lipopolysaccharide or concanavalin A. Compared with the lower concentrations of Juemingzi treatment, 200 mg/kg b.w. Juemingzi significantly (P<0.05) reduced aspartate aminotransferase, alanine transaminase and blood urea nitrogen levels. A high concentration of Juemingzi (200 mg/kg b.w.) significantly (P<0.05) increased the levels of tumor necrosis factor-alpha and interleukin 1beta cytokines compared with those of the mice that were treated with 100 and 50 mg/kg b.w. Juemingzi. PMID- 24348859 TI - Effect of epidermal growth factor receptor status on the outcomes of patients with metastatic gastric cancer: A pilot study. AB - The expression of epidermal growth factor receptor (EGFR) has been linked to clinical outcome in several solid tumors. However, the clinical significance of EGFR (c-erbB1) in gastric cancer remains unclear. The present study was designed to detect the clinical implications of EGFR in the Turkish population. Paraffin embedded tissue microarrays containing gastric cancer tissue were obtained from 30 patients. EGFR expression was detected using immunohistochemistry. The correlation of this biomarker to the clinicopathological features and survival of patients with gastric cancer was studied. The overall positivity rate of EGFR was 63.3%. EGFR expression was significantly correlated with an improved progression free survival (PFS) and overall survival (OS) rate (P=0.039 and 0.01, respectively). EGFR expression is a good prognostic marker for patients with gastric cancer. PMID- 24348860 TI - Safety and efficacy of radiation and chemoradiation in patients over 70 years old with inoperable esophageal squamous cell carcinoma. AB - The aim of the present study was to perform a retrospective analysis to investigate the outcome and toxicity of radiation (RT) and chemoradiation (CRT) in elderly, inoperable patients >70 years old. Between 2003 and 2012, 1,024 patients with squamous cell carcinoma (SCC) of the esophagus were treated at the Department of Thoracic Cancer, West China Hospital (Chengdu, China). Of these patients, 37 were >70 years old and had not undergone surgery, and were selected for analysis. Of these 37 patients, CRT had been administered to 20 (54%). Actuarial survival rates were determined by the Kaplan-Meier method. The one-year survival rate in the CRT group (n=20) was 85%, while 35% of patients in the RT group (n=17) survived for more than one year. The overall and progression-free survival in the CRT group versus the RT group were 17 months [95% confidence interval (CI), 11.861-22.139] versus eight months (95% CI, 6.674-9.326) (P=0.013) and 14 months (95% CI, 9.617-18.383) versus five months (95% CI, 2.311-7.689) (P=0.01), respectively. Patients irradiated with a dose of >50 Gy exhibited an improved survival rate compared with patients who received a dose of <=50 Gy (18 vs. 14 months; P=0.049). Furthermore, patients with an Eastern Cooperative Oncology Group (ECOG) score of <=1 had an improved prognosis compared with those with an ECOG score of 2 (14 vs. seven months; P=0.006). The two regimens were well-tolerated and there were no therapy-associated mortalities. The current retrospective study indicated that patients of >70 years old with inoperable esophageal SCC and a good ECOG score exhibit comparably better safety levels with CRT and improved survival rates compared with RT alone. PMID- 24348861 TI - A giant aneurysmal bone cyst of the rib: Case report. AB - An aneurysmal bone cyst (ABC) is a benign tumor of the skeletal system, which most frequently occurs in long bones. An ABC arising from the rib is extremely rare and it is difficult to distinguish from other types of rib tumors. The present study describes an unusual case of a large ABC in the rib of a 17-year old male. The entity is discussed with particular emphasis on the clinicopathological features, differential diagnosis and treatment. Due to difficulties in the pre-operative diagnosis, a possible diagnosis of ABC should be made aware when confronting an expansile rib mass. An en bloc resection of the mass and the affected portion of the rib is mandatory to obtain a satisfactory outcome. PMID- 24348862 TI - microRNA-32 inhibits the proliferation and invasion of the SGC-7901 gastric cancer cell line in vitro. AB - microRNAs (miRNAs) are a class of endogenously expressed, small non-coding RNAs, which suppress their target mRNAs at the post-transcriptional level. miRNAs play key roles in tumor metastasis. The aim of the present study was to investigate the expression of miRNA-32 (miR-32) on the biological behavior of the human gastric cancer cell line, SGC-7901. SGC-7901 cells were transfected with miR-32 mimic, miR-32-inhibitor and empty plasmid vectors using LipofectamineTM 2000. The expression of GFP was observed by fluorescent microscopy and miR-32 gene expression was detected by quantitative polymerase chain reaction. The cell counting kit-8 assay was performed to evaluate the effect of miR-32 expression on cell proliferation in vitro. Alterations in the migration and metastatic potential of SGC-7901 cells, prior to and following miR-32 gene transfection, were assayed by cell chemotactic migration and invasion tests. The results of the current study showed that the proliferation rate of the transfected SGC-7901 cells overexpressing miR-32 is reduced and cell chemotactic migration and invasion potentials is markedly reduced following miR-32-mimic transfection (P<0.05). In addition, the results demonstrated that overexpression of miR-32 greatly inhibits the proliferation and decreases the migration and invasion capabilities of SGC-7901 cells in vitro. PMID- 24348863 TI - Multiple microvenular hemangioma: A case report. AB - The current study reports a case of multiple microvenular hemangioma (MH). A 35 year-old male presented with dark red maculopapules on the trunk and limbs that had been apparent for 5 years. The number of lesions exceeded 100 in total. A histological examination demonstrated multiple, irregular, branching venules in the dermis, without any endothelial atypia. On immunohistochemical analysis of the vascular structures, the endothelial cells stained positive for CD31, CD34 and factor VIII, and the perivascular cells stained positive for SMA and HHF-35. These observations were consistent with a diagnosis of MH, and should be differentiated from the most common differential diagnosis of patch-stage Kaposi's sarcoma. There was no clear effect following topical application of recombinant human interferon alpha-2b gel. PMID- 24348864 TI - Prognostic role of BRCA1 mutation in patients with triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is proposed to be an immunohistochemical surrogate of the basal-like breast cancer subtype. In spite of the relative chemosensitivity of this cancer subtype, it is characterized by aggressive clinical behavior; therefore, a further subclassification of TNBC is required to develop new targeted treatment. In previous studies, a strong correlation between BRCA1 mutation-associated tumors and TNBC has been identified. The aim of the present study was to investigate the prognostic significance of carrying two germline BRCA1 founder mutations (4153delA and 5382insC) in patients with TNBC in the Latvian population. A total of 78 consecutive BRCA1 mutation-negative and 38 BRCA1 mutation-positive invasive TNBC patients in stage I-IV with no history of ovarian or other primary advanced cancers, who had undergone definitive surgery and genetic testing between 2005 and 2011, were deemed eligible for study. Relapse rates and breast cancer-specific survival (BCS) outcomes were compared between mutation carriers and non-carriers. Univariate and multivariate analyses Cox proportional-hazards models were used to compute independent predictors of survival outcomes. No statistically significant differences were identified in relation to tumor size, T stage, stage, Ki-67 status and tumor differentiation grade between the two groups. The median follow-up period was 36 months for mutation carriers and 41 months for non-carriers. A higher proportion of BRCA1 mutation non-carriers experienced distant recurrence compared with that of mutation carriers (P<0.03). BRCA1 mutation carriers had a significantly higher BCS than non-carriers (94.9 vs. 76.9%; P<0.02). In the univariate analyses, BRCA1 positive status was associated with decreased risk of distant recurrence (HR, 0.228; 95% Cl, 0.052-0.997; P<0.049) and breast cancer-specific mortality (HR, 0.209; 95% Cl, 0.048-0.902; P<0.036). In the multivariate analysis Cox proportional-hazards model, BRCA1-positive status was an independent favorable prognostic factor for distant recurrence-free survival (HR, 3.301; 95% Cl, 1.102 9.893; P<0.033). In conclusion, results of the present study demonstrate that positive BRCA1 founder mutation status in TNBC, with no evidence of ovarian or other cancer type in advanced stage, significantly improves prognosis. PMID- 24348865 TI - Renal myopericytoma: A case report with a literature review. AB - Myopericytoma is a rare neoplasm that generally arises from the skin and superficial soft tissues of distal extremities, and is particularly rare in the visceral organs. The current report presents a case of giant myopericytoma showing kidney involvement, which is extremely rare. A 39-year-old male presented to the Department of Urology with a 2-month history of a painless and palpable mass in the region of the left abdomen. Unenhanced computed tomography revealed a 9*10*18-cm3 mass that was heterogeneous with central lower density. The patient underwent radical nephrectomy, including lymphadenectomy, without adjuvant therapy. The tumor was composed of spindle-shaped myoid cells with a concentric arrangement and showed immunoreactivity for smooth muscle actin and cluster of differentiation (CD)10, and had a Ki-67 index of <1%; however, staining was negative for CD34, desmin, S-100 protein, cytokeratin, human melanoma black (HMB) 45, B-cell lymphoma (Bcl)-2 and CD99. Routine follow-up revealed no local or distant metastatic signs of reccurrence for 20 months. The present report shows that renal myopericytoma may be a benign tumor, and surgical excision without adjuvant therapy may be the only potentially curative treatment approach. PMID- 24348866 TI - Computed tomography-guided core needle biopsy of lung lesions: Diagnostic yield and correlation between factors and complications. AB - The aim of the present study was to determine the diagnostic accuracy of computed tomography (CT)-guided core needle biopsy (CNB) and to retrospectively analyze the correlation between the factors and complications of the procedure. Between January 2009 and June 2010, CNB was performed on 345 lung lesions in 343 patients. These patients were then followed up for at least two years. The sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of the CNB diagnoses were calculated. The correlation between factors, such as smoking, positoin and maximal diameter, and the complications of pneumothorax and hemorrhage was analyzed by chi2 test. The sensitivity, specificity, accuracy, PPV and NPV of the CNB diagnoses were 97.3, 100, 97.7, 100 and 87.7%, respectively. A statistically significant correlation was found between pneumothorax and the factors of smoking (P=0.015) and position (P<0.01) and length of the needle in the normal parenchyma (P=0.011), as well as between hemorrhage and the maximal diameter (P=0.005) and length of the needle in the normal parenchyma (P<0.01) and the frequency of needle adjustments (P<0.01). A CT-guided core needle biopsy of the lung lesions provides a high diagnostic yield. Smoking, the decubitus position and a longer length of the needle in the normal parenchyma were found to represent risk factors for a pneumothorax. In addition, a small diameter and longer length of the needle in the normal parenchyma and a more frequent adjustment of the needle were poor predictive factors of hemorrhage. PMID- 24348867 TI - Polydatin inhibits growth of lung cancer cells by inducing apoptosis and causing cell cycle arrest. AB - Polydatin (PD), a small natural compound from Polygonum cuspidatum, has a number of biological functions. However, the anticancer activity of PD has been poorly investigated. In the present study, thiazolyl blue tetrazolium bromide assay was used to evaluate the inhibitory effect of PD on cell growth. Cell cycle distribution and apoptosis were investigated by flow cytometry. In addition, the expression of several proteins associated with apoptosis and cell cycle were analyzed by western blot analysis. The results demonstrated that PD significantly inhibits the proliferation of A549 and NCI-H1975 lung cancer cell lines and causes dose-dependent apoptosis. Cell cycle analysis revealed that PD induces S phase cell cycle arrest. Western blot analysis showed that the expression of Bcl 2 decreased as that of Bax increased, and the expression of cyclin D1 was also suppressed. The results suggest that PD has potential therapeutic applications in the treatment of lung cancer. PMID- 24348869 TI - Predicting ICU admissions from attempted suicide presentations at an Emergency Department in Central Queensland. AB - BACKGROUND: Emergency medicine physicians and psychiatric staff face a challenging job in risk stratifying patients presenting with suicide attempts to predict which patients need intensive care unit admission, hospital admission or can be discharged with psychiatry follow up. AIMS: This study aims to analyse patients who were admitted to the intensive care unit or regular ward for suicide attempt, and the methods they employed in a rural Australian base hospital. METHOD: We conducted a retrospective analysis of patients who presented with suicide attempts to the Rockhampton Base Hospital Emergency Department, Queensland Australia from 1 September 2007 to 31 August 2009. Multivariate logistic regression was undertaken to identify risk factors for ICU and regular ward admission, and predictors of suicide method. RESULTS: There were 570 patients presenting with suicide attempts, 74 of which were repeat suicide attempts. There was a 10- fold increase in the odds of intensive care unit or ICU admission (CI 1.45-81.9, p=0.02) for patients who presented with drug overdose. Increased age (OR=1.02, 95 per cent CI 1.00-1.03, p=0.05), drug overdose (OR=2.69, 95 per cent CI 1.37-5.29, p=0.004), and previous suicide attempt (OR=1.53, 95 per cent CI 1.03-2.28, p=0.03) were significantly correlated with hospital admission. Male patients (OR=2.76, 95 per cent CI 1.43-5.30, p=0.002) and Aboriginal patients (OR=3.38, 95 per cent CI 1.42-8.05, p=0.006) were more likely to choose hanging as a suicide method. CONCLUSION: We identified drug overdose as a strong predictor of ICU admission, while age, drug overdose and history of previous suicide attempts predict hospital admission. We recommend reviewing physician practices, especially safe medication, in suicide risk patients. Our study also highlights the need for continued close collaboration by acute care and community mental health providers for quality improvement. PMID- 24348868 TI - MAGNETIC NANOPARTICLE HYPERTHERMIA IN CANCER TREATMENT. AB - The activation of magnetic nanoparticles (mNPs) by an alternating magnetic field (AMF) is currently being explored as technique for targeted therapeutic heating of tumors. Various types of superparamagnetic and ferromagnetic particles, with different coatings and targeting agents, allow for tumor site and type specificity. Magnetic nanoparticle hyperthermia is also being studied as an adjuvant to conventional chemotherapy and radiation therapy. This review provides an introduction to some of the relevant biology and materials science involved in the technical development and current and future use of mNP hyperthermia as clinical cancer therapy. PMID- 24348870 TI - Why are organisations that provide healthcare services fuzzy? AB - BACKGROUND: Healthcare organisations are an enigma to many people inand outside the service. Organisational fuzziness is a common state, characterised by a lack of clarity, lack of awareness, lack of organisational knowledge, and the reliance on practice and custom instead of transparency. AIMS: The objective of this study was to obtain a better understanding of what causes this fuzziness and provide an actionable description of fuzzy organisations. Such a description is essential to managing and preventing organisational fuzziness. METHOD: We used a longitudinal case study in an integrated healthand social care organisation to obtain a thorough understanding of how the organisation functions. These indepth insights allowed the identification of three generators of fuzziness. RESULTS: We found that the three main generators of organisational fuzziness are change, informal organisation and complexity. Organisational fuzziness is thus partly due to the inherent complexities of human systems. However, also continuous change and the inability of the system to adapt its formal structures resulted in structures deteriorating or no longer being appropriate. CONCLUSION: Existing approaches to explain unclear or absent structures in healthcare organisations by describing these organisations as complex adaptive systems (CAS) are too simplistic. While aspects relating to people and their interactions are indeed complex, fuzziness of structural aspects are often the result of continuous change and insufficient organisational capacity to adapt to it. PMID- 24348871 TI - Why drug shortages are an ethical issue. AB - Drug shortages are a growing problem in developed countries. To some extent they are the result of technical and organisational failures, but to view drug shortages simply as technical and economic phenomena is to miss the fact that they are also ethical and political issues. This observation is important because it highlights both the moral and political imperative to respond to drug shortages as vigorously as possible, and the need for those addressing shortages to do so in ethically and politically sophisticated ways. This brief article outlines the ethical issues that need to be considered by anyone attempting to understand or address drug shortages. PMID- 24348872 TI - Clinical profile and visual outcome of ocular injuries in a rural area of western India. AB - BACKGROUND: Ocular trauma is a major cause of visual impairment and morbidity worldwide. AIMS: To identify the various type of ocular injury in a rural area, determine the presence of any associated visual damage and assess the final visual outcome after treatment. METHOD: Hospital-based, prospective study conducted over a period of two years. A total of 60 patients of ocular trauma were included. RESULTS: Ocular injuries were more commonly seen in adult (55 per cent) patients who were associated with agricultural work (43.33 per cent). They were more common in male patients (71.67 per cent). Closed globe injury (68.33 per cent) was more common than open globe injury (31.67 per cent). Both in open and closed globe injuries, the commonest object causing injury was a wooden stick. Just 26.7 per cent of the patients had a visual acuity better than 6/60 at presentation; while after completed treatment at two months follow-up, 68.3 per cent had best corrected visual acuity better than 6/60. CONCLUSION: Agricultural trauma is an important cause of monocular blindness in rural India. The visual outcome depends upon the site and size of the injury and the extent of the ocular damage. PMID- 24348873 TI - Enablers of and barriers to making healthy change during pregnancy in overweight and obese women. AB - BACKGROUND: High Body Mass Index (BMI) during pregnancy is associated with an increased risk of adverse health outcomes. Making healthy change during pregnancy is beneficial, especially for overweight and obese women. AIMS: The aim of this study was to explore the barriers and enablers identified by overweight and obese women that preclude and facilitate making healthy change during pregnancy. METHOD: Twenty-six women who were overweight or obese during pregnancy were interviewed at 28 weeks gestational age. Interviews were transcribed verbatim and the analysis is based on the thematic analysis methodology. RESULTS: The core concept of "being pregnant" indicated women consider this specific time as both a reason not to make healthy change as well as a motivation for change. Overweight and obese women cited the following barriers to making healthy change during pregnancy: physiological (e.g. pregnancy complications and tiredness); emotional (e.g. preference and mood); cognitive (e.g. lack knowledge); interpersonal (e.g. lack support); and environmental (e.g. availability of healthy choice). Similar enablers were identified by overweight and obese women: physiological (e.g. relief of pregnancy symptoms); emotional (e.g. approval and commitment); cognitive (e.g. knowledge and belief); interpersonal (e.g. family support); and environmental (e.g. help from others). More barriers than enablers were given, indicating that women were more sensitive to barriers than the enablers for making healthy change. Factors viewed by some women as barriers were viewed as enablers by others. CONCLUSION: When designing interventions to promote healthy eating and physical activity during pregnancy, individually focused interventions must be implemented in conjunction with environmental-level interventions to facilitate behaviour change. PMID- 24348875 TI - Lipid-dependent and -independent regulation of nuclear envelope disassembly. PMID- 24348876 TI - JOCB Bulletin. PMID- 24348874 TI - Recent progress in tissue optical clearing. AB - Tissue optical clearing technique provides a prospective solution for the application of advanced optical methods in life sciences. This paper gives a review of recent developments in tissue optical clearing techniques. The physical, molecular and physiological mechanisms of tissue optical clearing are overviewed and discussed. Various methods for enhancing penetration of optical clearing agents into tissue, such as physical methods, chemical-penetration enhancers and combination of physical and chemical methods are introduced. Combining the tissue optical clearing technique with advanced microscopy image or labeling technique, applications for 3D microstructure of whole tissues such as brain and central nervous system with unprecedented resolution are demonstrated. Moreover, the difference in diffusion and/or clearing ability of selected agents in healthy versus pathological tissues can provide a highly sensitive indicator of the tissue health/pathology condition. Finally, recent advances in optical clearing of soft or hard tissue for in vivo imaging and phototherapy are introduced. [Formula: see text]. PMID- 24348877 TI - Substrate Stiffness Regulates PDGF-Induced Circular Dorsal Ruffle Formation Through MLCK. AB - As atherosclerosis progresses, vascular smooth muscle cells (VSMCs) invade from the medial layer into the intimal layer and proliferate, contributing to atherosclerotic plaque formation. This migration is stimulated in part by platelet-derived growth factor (PDGF), which is released by endothelial cells and inflammatory cells, and vessel stiffening, which occurs with age and atherosclerosis progression. PDGF induces the formation of circular dorsal ruffles (CDRs), actin-based structures associated with increased cell motility. Here we show that mechanical changes in matrix stiffness enhance the formation of CDRs in VSMCs in response to PDGF stimulation. Our data indicate that matrix stiffness increases cellular contractility, and that intracellular pre-stress is necessary for robust CDR formation. When treated with agonists that promote contractility, cells increase CDR formation, whereas agonists that inhibit contractility lead to decreased CDR formation. Substrate stiffness promotes CDR formation in response to PDGF by upregulating Src activity through myosin light chain kinase. Together, these data indicate that vessel stiffening accompanying atherogenesis may exacerbate VSMC response to PDGF leading to CDR formation. PMID- 24348879 TI - Improved Convolutive and Under-Determined Blind Audio Source Separation with MRF Smoothing. AB - Convolutive and under-determined blind audio source separation from noisy recordings is a challenging problem. Several computational strategies have been proposed to address this problem. This study is concerned with several modifications to the expectation-minimization-based algorithm, which iteratively estimates the mixing and source parameters. This strategy assumes that any entry in each source spectrogram is modeled using superimposed Gaussian components, which are mutually and individually independent across frequency and time bins. In our approach, we resolve this issue by considering a locally smooth temporal and frequency structure in the power source spectrograms. Local smoothness is enforced by incorporating a Gibbs prior in the complete data likelihood function, which models the interactions between neighboring spectrogram bins using a Markov random field. Simulations using audio files derived from stereo audio source separation evaluation campaign 2008 demonstrate high efficiency with the proposed improvement. PMID- 24348878 TI - Analytic study of three-dimensional single cell migration with and without proteolytic enzymes. AB - Cell motility is a fundamental physiological process that regulates cellular fate in healthy and diseased systems. Cells cultured in 3D environments often exhibit biphasic dependence of migration speed with cell adhesion. Much is not understood about this very common behavior. A phenomenological model for 3D single-cell migration that exhibits biphasic behavior and highlights the important role of steric hindrance is developed and studied analytically. Changes in the biphasic behavior in the presence of proteolytic enzymes are investigated. Our methods produce a framework to determine analytic formulae for the mean cell speed, allowing general statements in terms of parameters to be explored, which will be useful when interpreting future experimental results. Our formula for mean cell speed as a function of ligand concentration generalizes and extends previous computational models that have shown good agreement with in vitro experiments. PMID- 24348880 TI - Network Based Prediction Model for Genomics Data Analysis. AB - Biological networks, such as genetic regulatory networks and protein interaction networks, provide important information for studying gene/protein activities. In this paper, we propose a new method, NetBoosting, for incorporating a priori biological network information in analyzing high dimensional genomics data. Specially, we are interested in constructing prediction models for disease phenotypes of interest based on genomics data, and at the same time identifying disease susceptible genes. We employ the gradient descent boosting procedure to build an additive tree model and propose a new algorithm to utilize the network structure in fitting small tree weak learners. We illustrate by simulation studies and a real data example that, by making use of the network information, NetBoosting outperforms a few existing methods in terms of accuracy of prediction and variable selection. PMID- 24348881 TI - Comparative Study of Continuous and Pulsatile Left Ventricular Assist Devices on Hemodynamics of a Pediatric End-to-Side Anastomotic Graft. AB - Although there are many studies that focus on understanding the consequence of pumping mode (continuous vs. pulsatile) associated with ventricular assist devices (VADs) on pediatric vascular pulsatility, the impact on local hemodynamics has been largely ignored. Hence, we compare not only the hemodynamic parameters indicative of pulsatility but also the local flow fields in the aorta and the great vessels originating from the aortic arch. A physiologic graft anastomotic model is constructed based on a pediatric, patient specific, aorta with a graft attached on the ascending aorta. The flow is simulated using a previously validated second-order accurate Navier-Stokes flow solver based upon a finite volume approach. The major findings are: (1) pulsatile support provides a greater degree of vascular pulsatility when compared to continuous support, which, however, is still 20% less than pulsatility in the healthy aorta; (2) pulsatile support increases the flow in the great vessels, while continuous support decreases it; (3) complete VAD support results in turbulence in the aorta, with maximum principal Reynolds stresses for pulsatile support and continuous support of 7081 and 249 dyn/cm2, respectively; (4) complete pulsatile support results in a significant increase in predicted hemolysis in the aorta; and (5) pulsatile support causes both higher time-averaged wall shear stresses (WSS) and oscillatory shear indices (OSI) in the aorta than does continuous support. These findings will help to identify the risk of graft failure for pediatric patients with pulsatile and continuous VADs. PMID- 24348882 TI - The effect of grid resolution on estimates of the burden of ozone and fine particulate matter on premature mortality in the United States. AB - Assessments of human health impacts associated with outdoor air pollution often use air quality models to represent exposure, but involve uncertainties due to coarse model resolution. Here we quantify how estimates of mortality in the United States attributable to ozone (O3) and fine particulate matter (PM2.5) at coarse resolution differ from those at finer resolution. Using the finest modeled concentrations (12 km), we estimate that 66,000 (95% CI, 39,300 - 84,500) all cause and 21,400 (5,600 - 34,200) respiratory deaths per year are attributable to PM2.5 and O3 concentrations above low-concentration thresholds, respectively. Using model results at 36 km resolution gives mortality burdens that are 11% higher for PM2.5 and 12% higher for O3 than the 12 km estimates, suggesting a modest positive bias. We also scale modeled concentrations at 12 km to coarser resolutions by simple averaging, and repeat the mortality assessment at multiple resolutions from 24 to 408 km, including the resolutions of global models; in doing so, we account for the effect of resolution on population exposure. Coarse grid resolutions produce mortality estimates that are substantially biased low for PM2.5 (30-40% lower than the 12 km estimate at >250 km resolution), but less than 6% higher for O3 at any resolution. Mortality estimates for primary PM2.5 species show greater bias at coarse resolution than secondary species. These results suggest that coarse resolution global models (>100 km) are likely biased low for PM2.5 health effects. For ozone, biases due to coarse resolution may be much smaller, and the effect on modeled chemistry likely dominates. PMID- 24348883 TI - The speakers' bureau system: a form of peer selling. AB - In the speakers' bureau system, physicians are recruited and trained by pharmaceutical, biotechnology, and medical device companies to deliver information about products to other physicians, in exchange for a fee. Using publicly available disclosures, we assessed the thesis that speakers' bureau involvement is not a feature of academic medicine in Canada, by estimating the prevalence of participation in speakers' bureaus among Canadian faculty in one medical specialty, cardiology. We analyzed the relevant features of an actual contract made public by the physician addressee and applied the Canadian Medical Association (CMA) guidelines on physician-industry relations to participation in a speakers' bureau. We argue that speakers' bureau participation constitutes a form of peer selling that should be understood to contravene the prohibition on product endorsement in the CMA Code of Ethics. Academic medical institutions, in conjunction with regulatory colleges, should continue and strengthen their policies to address participation in speakers' bureaus. PMID- 24348884 TI - Multispecialty physician networks in Ontario. AB - BACKGROUND: Large multispecialty physician group practices, with a central role for primary care practitioners, have been shown to achieve high-quality, low-cost care for patients with chronic disease. We assessed the extent to which informal multispecialty physician networks in Ontario could be identified by using health administrative data to exploit natural linkages among patients, physicians, and hospitals based on existing patient flow. METHODS: We linked each Ontario resident to his or her usual provider of primary care over the period from fiscal year 2008/2009 to fiscal year 2010/2011. We linked each specialist to the hospital where he or she performed the most inpatient services. We linked each primary care physician to the hospital where most of his or her ambulatory patients were admitted for non-maternal medical care. Each resident was then linked to the same hospital as his or her usual provider of primary care. We computed "loyalty" as the proportion of care to network residents provided by physicians and hospitals within their network. Smaller clusters were aggregated to create networks based on a minimum population size, distance, and loyalty. Networks were not constrained geographically. RESULTS: We identified 78 multispecialty physician networks, comprising 12,410 primary care physicians, 14,687 specialists, and 175 acute care hospitals serving a total of 12,917,178 people. Median network size was 134,723 residents, 125 primary care physicians, and 143 specialists. Virtually all eligible residents were linked to a usual provider of primary care and to a network. Most specialists (93.5%) and primary care physicians (98.2%) were linked to a hospital. Median network physician loyalty was 68.4% for all physician visits and 81.1% for primary care visits. Median non-maternal admission loyalty was 67.4%. Urban networks had lower loyalties and were less self-contained but had more health care resources. INTERPRETATION: We demonstrated the feasibility of identifying informal multispecialty physician networks in Ontario on the basis of patterns of health care-seeking behaviour. Networks were reasonably self-contained, in that individual residents received most of their care from providers within their respective networks. Formal constitution of networks could foster accountability for efficient, integrated care through care management tools and quality improvement, the ideas behind "accountable care organizations." PMID- 24348886 TI - Herpes zoster as a marker of underlying malignancy. AB - BACKGROUND: Both herpes zoster and malignancy are associated with immunosuppression. However, the association between herpes zoster and the subsequent diagnosis of malignancy is unclear. We undertook this study to assess whether a diagnosis of herpes zoster is a risk factor for subsequent malignancy. METHODS: For this matched retrospective cohort study, a physician billing database was used to identify individuals 18 years of age or older with a diagnosis of herpes zoster and no prior diagnosis of cancer or HIV infection. Individuals with a herpes zoster diagnosis were matched one-to-one to individuals without a herpes zoster diagnosis, and both groups were examined for up to 5 years for diagnosis of cancer. RESULTS: A total of 542,575 individuals with a diagnosis of herpes zoster were identified. Compared with matched controls, these patients were more likely (p < 0.001) to have a history of myocardial infarction, asthma, congestive heart failure, chronic obstructive pulmonary disease, diabetes mellitus, and hypertension. The incidence of cancer was significantly greater among individuals with herpes zoster than among those without herpes zoster, for both men and women and across all time intervals studied (up to 5 years). The greatest adjusted hazard ratio was seen 180 days after a herpes zoster diagnosis (1.19, 95% confidence interval 1.12-1.25); the hazard ratio decreased as the time from herpes zoster diagnosis increased. Lymphoma was the type of cancer with the greatest relative increase in incidence following diagnosis of herpes zoster. INTERPRETATION: There is a risk of malignancy following an episode of herpes zoster in both men and women and in all age groups 18 years and over. The risk is greatest during the first 180 days following the diagnosis of herpes zoster. PMID- 24348885 TI - Probiotics for the prevention of antibiotic-associated diarrhea and Clostridium difficile infection among hospitalized patients: systematic review and meta analysis. AB - BACKGROUND: Antibiotic-associated diarrhea (AAD) and Clostridium difficile infection (CDI) are associated with high morbidity, mortality, and health care costs. Probiotics may mitigate the existing disease burden. We performed a systematic review and meta-analysis to evaluate the efficacy of co-administration of probiotics with antibiotics in preventing these adverse outcomes in adult inpatients. METHODS: Systematic searches of MEDLINE (1946 to May 2012), Embase (1980 to May 2012), and the Cochrane Central Register of Controlled Trials were undertaken on May 31, 2012, to identify relevant publications. We searched for randomized controlled trials, published in English, of adult inpatients who were receiving antibiotics and who were randomly assigned to co-administration of probiotics or usual care, with or without the use of placebo. Studies were included if they reported on AAD or CDI (or both) as outcomes. Data for predetermined criteria evaluating study characteristics, methods, and risk of bias were extracted. Trials were given a global rating of good, fair, or poor by at least 2 reviewers. Meta-analyses were performed using a random-effects model, and pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated. RESULTS: Sixteen trials met the criteria for inclusion in this review. Four studies were of good quality, 5 were of fair quality, and 7 were of poor quality. Pooled analyses revealed significant reductions in the risks of AAD (RR 0.61, 95% CI 0.47 to 0.79) and CDI (RR 0.37, 95% CI 0.22 to 0.61) among patients randomly assigned to co-administration of probiotics. The number needed to treat for benefit was 11 (95% CI 8 to 20) for AAD and 14 (95% CI 9 to 50) for CDI. With subgroup analysis, significant reductions in rates of both AAD and CDI were retained in the subgroups of good-quality trials, the trials assessing a primarily Lactobacillus-based probiotic formulation, and the trials for which the follow-up period was less than 4 weeks. INTERPRETATION: Probiotics used concurrently with antibiotics reduce the risk of AAD and CDI. PMID- 24348887 TI - Severe Hypoxia: Consequences to Neural Stem Cells and Neurons. AB - BACKGROUND: Multiple neurological diseases result from a pathological hypoxia in the brain, resulting in various motor, sensory or cognitive sequelae. Understanding the response of neural stem cells (NSCs) and differentiated neurons to hypoxia will help better treat such diseases. METHODS: We exposed mouse embryonic primary neurons (PN) and neural stem cells to 1% O2 in vitro. RESULTS: Both cell types survived and retained their immunocyto-chemical markers, and neurons showed no obvious morphological changes. Microarray analysis showed that the number of genes with significantly altered expression levels was almost five fold higher in NSCs compared to PN. NSCs displayed a clear block in G1/S phase of the cell cycle and a number of down-regulated cytokine genes. Various growth factors (e.g. neural growth factor, prolactin), involved in survival and proliferation, genes of the Notch pathway, and genes involved in glial differentiation, and cell-matrix adhesion were up-regulated. PN displayed a down regulation of a number of genes involved in neuron-specific functions, in particular, transmitter-related (e.g. synaptic transmission, neurotransmitter transport and release, learning, adult behavior). CONCLUSIONS: We conclude that hypoxia 1-down-regulates genes involved in multiple neuronal functions which can negatively impact learning and memory; 2-induces a cell cycle block in NSCs; 3 can precondition NSC towards a particular differentiation potential while maintaining them fully undifferentiated. PMID- 24348888 TI - PAX3-FKHR regulates the expression of pleiotrophin to mediate motility in alveolar rhabdomyosarcoma cells. AB - More than 80% of the aggressive alveolar rhabdomyosarcoma (ARMSs) harbor a PAX3 FKHR fusion transcription factor, which regulates cell motility and promotes metastasis. Our hypothesis is that PAX3-FKHR regulates cell motility by regulating the expression of its transcriptional targets that are also its downstream effectors, which if identified, may lead to novel therapeutic approaches for treating ARMS. Here we report that PAX3-FKHR regulates the expression of pleiotrophin (PTN) by binding specifically to a paired-box domain binding-site in the PTN promoter, indicating that PTN is a transcriptional target of PAX3-FKHR. Significantly, we show that PTN regulates ARMS cell motility. Taken together, we have identified PTN as a novel transcriptional target of PAX3-FKHR that promotes ARMS cell motility. PTN may be a novel therapeutic target for the treatment of ARMS. PMID- 24348889 TI - Light-addressable measurements of cellular oxygen consumption rates in microwell arrays based on phase-based phosphorescence lifetime detection. AB - A digital light modulation system that utilizes a modified commercial digital micromirror device (DMD) projector, which is equipped with a UV light-emitting diode as a light modulation source, has been developed to spatially direct excited light toward a microwell array device to detect the oxygen consumption rate (OCR) of single cells via phase-based phosphorescence lifetime detection. The microwell array device is composed of a combination of two components: an array of glass microwells containing Pt(II) octaethylporphine (PtOEP) as the oxygen-sensitive luminescent layer and a microfluidic module with pneumatically actuated glass lids set above the microwells to controllably seal the microwells of interest. By controlling the illumination pattern on the DMD, the modulated excitation light can be spatially projected to only excite the sealed microwell for cellular OCR measurements. The OCR of baby hamster kidney-21 fibroblast cells cultivated on the PtOEP layer within a sealed microwell has been successfully measured at 104 +/- 2.96 amol s(-1) cell(-1). Repeatable and consistent measurements indicate that the oxygen measurements did not adversely affect the physiological state of the measured cells. The OCR of the cells exhibited a good linear relationship with the diameter of the microwells, ranging from 400 to 1000 MUm and containing approximately 480 to 1200 cells within a microwell. In addition, the OCR variation of single cells in situ infected by Dengue virus with a different multiplicity of infection was also successfully measured in real time. This proposed platform provides the potential for a wide range of biological applications in cell-based biosensing, toxicology, and drug discovery. PMID- 24348890 TI - Analysis of a laminar-flow diffusional mixer for directed self-assembly of liposomes. AB - The present work describes the operation and simulation of a microfluidic laminar flow mixer. Diffusive mixing takes place between a core solution containing lipids in ethanol and a sheath solution containing aqueous buffer, leading to self assembly of liposomes. Present device architecture hydrodynamically focuses the lipid solution into a cylindrical core positioned at the center of a microfluidic channel of 125 * 125-MUm(2) cross-section. Use of the device produces liposomes in the size range of 100-300 nm, with larger liposomes forming at greater ionic strength in the sheath solution and at lower lipid concentration in the core solution. Finite element simulations compute the concentration distributions of solutes at axial distances of greater than 100 channel widths. These simulations reduce computation time and enable computation at long axial distances by utilizing long hexahedral elements in the axial flow region and fine tetrahedral elements in the hydrodynamic focusing region. Present meshing technique is generally useful for simulation of long microfluidic channels and is fully implementable using comsol Multiphysics. Confocal microscopy provides experimental validation of the simulations using fluorescent solutions containing fluorescein or enhanced green fluorescent protein. PMID- 24348891 TI - Cylindrical glass nanocapillaries patterned via coarse lithography (>1 MUm) for biomicrofluidic applications. AB - We demonstrate a new method of fabricating in-plane cylindrical glass nanocapillaries (<100 nm) that does not require advanced patterning techniques but the standard coarse photolithography (>1 MUm). These nanocapillaries are self enclosed optically transparent and highly regular over large areas. Our method involves structuring MUm-scale rectangular trenches in silicon, sealing the trenches into enclosed triangular channels by depositing phosphosilicate glass, and then transforming the channels into cylindrical capillaries through shape transformation by the reflow of annealed glass layer. Extended anneal has the structures shrunk into nanocapillaries preserving their cylindrical shape. Nanocapillaries ~50 nm in diameter and effective stretching of digested lambda phage DNA in them are demonstrated. PMID- 24348892 TI - Erratum: "Electro-entropic excluded volume effects on DNA looping and relaxation in nanochannels" [Biomicrofluidics 7, 054119 (2013)]. AB - [This corrects the article on p. 054119 in vol. 7.]. PMID- 24348893 TI - Penalized Regression and Risk Prediction in Genome-Wide Association Studies. AB - An important task in personalized medicine is to predict disease risk based on a person's genome, e.g. on a large number of single-nucleotide polymorphisms (SNPs). Genome-wide association studies (GWAS) make SNP and phenotype data available to researchers. A critical question for researchers is how to best predict disease risk. Penalized regression equipped with variable selection, such as LASSO and SCAD, is deemed to be promising in this setting. However, the sparsity assumption taken by the LASSO, SCAD and many other penalized regression techniques may not be applicable here: it is now hypothesized that many common diseases are associated with many SNPs with small to moderate effects. In this article, we use the GWAS data from the Wellcome Trust Case Control Consortium (WTCCC) to investigate the performance of various unpenalized and penalized regression approaches under true sparse or non-sparse models. We find that in general penalized regression outperformed unpenalized regression; SCAD, TLP and LASSO performed best for sparse models, while elastic net regression was the winner, followed by ridge, TLP and LASSO, for non-sparse models. PMID- 24348896 TI - March of the titans: the locomotor capabilities of sauropod dinosaurs. PMID- 24348895 TI - DNA barcoding the Canadian Arctic flora: core plastid barcodes (rbcL + matK) for 490 vascular plant species. AB - Accurate identification of Arctic plant species is critical for understanding potential climate-induced changes in their diversity and distributions. To facilitate rapid identification we generated DNA barcodes for the core plastid barcode loci (rbcL and matK) for 490 vascular plant species, representing nearly half of the Canadian Arctic flora and 93% of the flora of the Canadian Arctic Archipelago. Sequence recovery was higher for rbcL than matK (93% and 81%), and rbcL was easier to recover than matK from herbarium specimens (92% and 77%). Distance-based and sequence-similarity analyses of combined rbcL + matK data discriminate 97% of genera, 56% of species, and 7% of infraspecific taxa. There is a significant negative correlation between the number of species sampled per genus and the percent species resolution per genus. We characterize barcode variation in detail in the ten largest genera sampled (Carex, Draba, Festuca, Pedicularis, Poa, Potentilla, Puccinellia, Ranunculus, Salix, and Saxifraga) in the context of their phylogenetic relationships and taxonomy. Discrimination with the core barcode loci in these genera ranges from 0% in Salix to 85% in Carex. Haplotype variation in multiple genera does not correspond to species boundaries, including Taraxacum, in which the distribution of plastid haplotypes among Arctic species is consistent with plastid variation documented in non-Arctic species. Introgression of Poa glauca plastid DNA into multiple individuals of P. hartzii is problematic for identification of these species with DNA barcodes. Of three supplementary barcode loci (psbA-trnH, psbK-psbI, atpF-atpH) collected for a subset of Poa and Puccinellia species, only atpF-atpH improved discrimination in Puccinellia, compared with rbcL and matK. Variation in matK in Vaccinium uliginosum and rbcL in Saxifraga oppositifolia corresponds to variation in other loci used to characterize the phylogeographic histories of these Arctic-alpine species. PMID- 24348899 TI - Using a search engine-based mutually reinforcing approach to assess the semantic relatedness of biomedical terms. AB - BACKGROUND: Determining the semantic relatedness of two biomedical terms is an important task for many text-mining applications in the biomedical field. Previous studies, such as those using ontology-based and corpus-based approaches, measured semantic relatedness by using information from the structure of biomedical literature, but these methods are limited by the small size of training resources. To increase the size of training datasets, the outputs of search engines have been used extensively to analyze the lexical patterns of biomedical terms. METHODOLOGY/PRINCIPAL FINDINGS: In this work, we propose the Mutually Reinforcing Lexical Pattern Ranking (ReLPR) algorithm for learning and exploring the lexical patterns of synonym pairs in biomedical text. ReLPR employs lexical patterns and their pattern containers to assess the semantic relatedness of biomedical terms. By combining sentence structures and the linking activities between containers and lexical patterns, our algorithm can explore the correlation between two biomedical terms. CONCLUSIONS/SIGNIFICANCE: The average correlation coefficient of the ReLPR algorithm was 0.82 for various datasets. The results of the ReLPR algorithm were significantly superior to those of previous methods. PMID- 24348898 TI - Identification of unstable network modules reveals disease modules associated with the progression of Alzheimer's disease. AB - Alzheimer's disease (AD), the most common cause of dementia, is associated with aging, and it leads to neuron death. Deposits of amyloid beta and aberrantly phosphorylated tau protein are known as pathological hallmarks of AD, but the underlying mechanisms have not yet been revealed. A high-throughput gene expression analysis previously showed that differentially expressed genes accompanying the progression of AD were more down-regulated than up-regulated in the later stages of AD. This suggested that the molecular networks and their constituent modules collapsed along with AD progression. In this study, by using gene expression profiles and protein interaction networks (PINs), we identified the PINs expressed in three brain regions: the entorhinal cortex (EC), hippocampus (HIP) and superior frontal gyrus (SFG). Dividing the expressed PINs into modules, we examined the stability of the modules with AD progression and with normal aging. We found that in the AD modules, the constituent proteins, interactions and cellular functions were not maintained between consecutive stages through all brain regions. Interestingly, the modules were collapsed with AD progression, specifically in the EC region. By identifying the modules that were affected by AD pathology, we found the transcriptional regulation-associated modules that interact with the proteasome-associated module via UCHL5 hub protein, which is a deubiquitinating enzyme. Considering PINs as a system made of network modules, we found that the modules relevant to the transcriptional regulation are disrupted in the EC region, which affects the ubiquitin-proteasome system. PMID- 24348900 TI - Transcriptional activation of the cholecystokinin gene by DJ-1 through interaction of DJ-1 with RREB1 and the effect of DJ-1 on the cholecystokinin level in mice. AB - DJ-1 is an oncogene and also causative gene for familial Parkinson's disease. DJ 1 has multiple functions, including transcriptional regulation. DJ-1 acts as a coactivator that binds to various transcription factors, resulting in stimulation or repression of the expression of their target genes. In this study, we found that the cholecystokinin (CCK) gene is a transcriptional target gene for DJ-1. CCK is a peptide hormone and plays roles in contraction of the gallbladder and in promotion of secretion of pancreatic fluid. CCK is co-localized with dopamine in the substantia nigra to regulate release of dopamine. Reduced expression of CCK mRNA was observed in DJ-1-knockdown cells. The Ras-responsive element (RRE) and Sp1 site were essential for promoter activity, and DJ-1 stimulated promoter activity by binding to RRE-binding protein 1 (RREBP1). The complex of DJ-1 with RREB1 but not with Sp1 bound to the RRE. Furthermore, the reduced CCK level in the serum from DJ-1-knockout mice compared to that from wild-type mice was observed. This is the first report showing that DJ-1 participates in peptide hormone synthesis. PMID- 24348901 TI - Identification of three antiviral inhibitors against Japanese encephalitis virus from library of pharmacologically active compounds 1280. AB - Japanese encephalitis virus (JEV) can cause severe central nervous disease with a high mortality rate. There is no antiviral drug available for JEV-specific treatment. In this study, a cytopathic-effect-based, high-throughput screening assay was developed and applied to screen JEV inhibitors from Library of Pharmacologically Active Compounds 1280. The antiviral effects of three hit compounds including FGIN-1-27, cilnidipine, and niclosamide were evaluated in cells by western blotting, indirect immunofluorescence assay, and plaque reduction assay. A time-of-addition assay proved that all three compounds inhibited JEV at the stage of replication. The EC50s of FGIN-1-27, cilnidipine, and niclosamide were 3.21, 6.52, and 5.80 uM, respectively, while the selectivity indexes were 38.79, 30.67, and 7.49. FGIN-1-27 and cilnidipine have high efficiency and selectivity against JEV. This study provided two JEV antiviral inhibitors as candidates for treatment of JEV infection. PMID- 24348902 TI - Measuring the reliability of picture story exercises like the TAT. AB - As frequently reported, psychometric assessments on Picture Story Exercises, especially variations of the Thematic Apperception Test, mostly reveal inadequate scores for internal consistency. We demonstrate that the reason for this apparent shortcoming is not caused by the coding system itself but from the incorrect use of internal consistency coefficients, especially Cronbach's alpha. This problem could be eliminated by using the category-scores as items instead of the picture scores. In addition to a theoretical explanation we prove mathematically why the use of category-scores produces an adequate internal consistency estimation and examine our idea empirically with the origin data set of the Thematic Apperception Test by Heckhausen and two additional data sets. We found generally higher values when using the category-scores as items instead of picture-scores. From an empirical and theoretical point of view, the estimated reliability is also superior to each category within a picture as item measuring. When comparing our suggestion with a multifaceted Rasch-model we provide evidence that our procedure better fits the underlying principles of PSE. PMID- 24348904 TI - Early re-do surgery for glioblastoma is a feasible and safe strategy to achieve complete resection of enhancing tumor. AB - BACKGROUND: Complete resection of enhancing tumor as assessed by early (<72 hours) postoperative MRI is regarded as the optimal result in glioblastoma surgery. As yet, there is no consensus on standard procedure if post-operative imaging reveals unintended tumor remnants. OBJECTIVE: The current study evaluated the feasibility and safety of an early re-do surgery aimed at completing resections with the aid of 5-ALA fluorescence and neuronavigation after detection of enhancing tumor remnants on post-operative MRI. METHODS: From October 2008 to October 2012 a single center institutional protocol offered a second surgery within one week to patients with unintentional incomplete glioblastoma resection. We report on the feasibility of the use 5-ALA fluorescence guidance, the extent of resection (EOR) rates and complications of early re-do surgery. RESULTS: Nine of 151 patients (6%) with glioblastoma resections had an unintentional tumor remnant with a volume >0.175 cm(3). 5-ALA guided re-do surgery completed the resection (CRET) in all patients without causing neurological deficits, infections or other complications. Patients who underwent a re-do surgery remained hospitalized between surgeries, resulting in a mean length of hospital stay of 11 days (range 7-15), compared to 9 days for single surgery (range 3-23; p=0.147). CONCLUSION: Our early re-do protocol led to complete resection of all enhancing tumor in all cases without any new neurological deficits and thus provides a similar oncological result as intraoperative MRI (iMRI). The repeated use of 5-ALA induced fluorescence, used for identification of small remnants, remains highly sensitive and specific in the setting of re-do surgery. Early re do surgery is a feasible and safe strategy to complete unintended subtotal resections. PMID- 24348903 TI - A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma. AB - Chemotherapy induces apoptosis and tumor regression primarily through activation of p53-mediated transcription. Neuroblastoma is a p53 wild type malignancy at diagnosis and repression of p53 signaling plays an important role in its pathogenesis. Recently developed small molecule inhibitors of the MDM2-p53 interaction are able to overcome this repression and potently activate p53 dependent apoptosis in malignancies with intact p53 downstream signaling. We used the small molecule MDM2 inhibitor, Nutlin-3a, to determine the p53 drug response signature in neuroblastoma cells. In addition to p53 mediated apoptotic signatures, GSEA and pathway analysis identified a set of p53-repressed genes that were reciprocally over-expressed in neuroblastoma patients with the worst overall outcome in multiple clinical cohorts. Multifactorial regression analysis identified a subset of four genes (CHAF1A, RRM2, MCM3, and MCM6) whose expression together strongly predicted overall and event-free survival (p<0.0001). The expression of these four genes was then validated by quantitative PCR in a large independent clinical cohort. Our findings further support the concept that oncogene-driven transcriptional networks opposing p53 activation are essential for the aggressive behavior and poor response to therapy of high-risk neuroblastoma. PMID- 24348905 TI - Food availability and maternal immunization affect transfer and persistence of maternal antibodies in nestling pigeons. AB - The ability of mothers to transfer antibodies (Abs) to their young and the temporal persistence of maternal Abs in offspring constitute important life history traits that can impact the evolution of host-parasite interactions. Here, we examined the effects of food availability and parental immunization on the transfer and persistence of maternal antibodies in nestling pigeons (Columba livia). This species can transmit maternal Abs to offspring before hatching through the egg yolk and potentially after hatching through crop milk. However, the role of this postnatal substance in immunity remains elusive. We used a full cross-fostering design to disentangle the effects of food limitation and parental immunization both before and after hatching on the levels and persistence of maternal Abs in chicks. Parents were immunized via injection with keyhole limpet hemocyanin antigens. Using an immunoassay that specifically detected the IgY antibodies that are known to be transmitted via the yolk, we found that the levels of anti-KLH Abs in newly hatched chicks were positively correlated with the levels of anti-KLH Abs in the blood of their biological mothers. However, this correlation was not present between chicks and their foster parents, suggesting limited IgY transfer via crop milk to the chick's bloodstream. Interestingly, biological mothers subjected to food limitation during egg laying transferred significantly fewer specific maternal Abs, which suggests that the transfer of antibodies might be costly for them. In addition, the persistence of maternal Abs in a chick's bloodstream was not affected by food limitation or the foster parents' anti-KLH Ab levels; it was only affected by the initial level of maternal anti-KLH Abs that were present in newly hatched chicks. These results suggest that the maternal transfer of Abs could be costly but that their persistence in an offspring's bloodstream may not necessarily be affected by environmental conditions. PMID- 24348906 TI - Negative node count improvement prognostic prediction of the seventh edition of the TNM classification for gastric cancer. AB - OBJECTIVE: To demonstrate that the seventh edition of the tumor-node-metastasis (TNM) classification for gastric cancer (GC) should be updated with the number of negative lymph nodes for the improvement of its prognostic prediction accuracy. METHODS: Clinicopathological data of 769 GC patients who underwent curative gastrectomy with lymphadenectomy between 1997 and 2006 were retrospectively analyzed to demonstrate the superiority of prognostic efficiency of the seventh edition of the TNM classification, which can be improved by combining the number of negative lymph nodes. RESULTS: With the Cox regression multivariate analysis, the seventh edition of the TNM classification, the number of negative nodes, the type of gastrectomy, and the depth of tumor invasion (T stage) were identified as independent factors for predicting the overall survival of GC patients. Furthermore, we confirmed that the T stage-N stage-number of negative lymph nodes metastasis (TNnM) classification is the most appropriate prognostic predictor of GC patients by using case-control matched fashion and multinominal logistic regression. Finally, we were able to clarify that TNnM classification may provide more precise survival differences among the different TNM sub-stages of GC by using the measure of agreement (Kappa coefficient), the McNemar value, the Akaike information criterion, and the Bayesian Information Criterion compared with the seventh edition of the TNM classification. CONCLUSION: The number of negative nodes, as an important prognostic predictor of GC, can improve the prognostic prediction efficiency of the seventh edition of the TNM classification for GC, which should be recommended for conventional clinical applications. PMID- 24348907 TI - iTRAQ-based proteomic analysis of polyploid giant cancer cells and budding progeny cells reveals several distinct pathways for ovarian cancer development. AB - Polyploid giant cancer cells (PGCCs) are a morphologically distinct subgroup of human tumor cells with increased nuclear size or multiple nuclei, but they are generally considered unimportant because they are presumed to be nondividing and thus nonviable. We have recently shown that these large cancer cells are not only viable but also can divide asymmetrically and yield progeny cancer cells with cancer stem-like properties via budding division. To further understand the molecular events involved in the regulation of PGCCs and the generation of their progeny cancer cells, we comparatively analyzed the proteomic profiles of PGCCs, PGCCs with budding daughter cells, and regular control cancer cells from the HEY and SKOv3 human ovarian cancer cell lines with and without CoCl2. We used a high throughput iTRAQ-based proteomic methodology coupled with liquid chromatography electrospray ionization tandem mass spectroscopy to determine the differentiated regulated proteins. We performed Western blotting and immunohistochemical analyses to validate the differences in the expression patterns of a variety of proteins between PGCCs or budding PGCCs and regular cancer cells identified by iTRAQ approach and also a selected group of proteins from the literature. The differentially regulated proteins included proteins involved in response to hypoxia, stem cell generation, chromatin remodeling, cell-cycle regulation, and invasion and metastasis. In particular, we found that HIF-1alpha and its known target STC1 are upregulated in PGCCs. In addition, we found that a panel of stem cell-regulating factors and epithelial-to-mesenchymal transition regulatory transcription factors were upregulated in budding PGCCs, whereas expression of the histone 1 family of nucleosomal linker proteins was consistently lower in PGCCs than in control cells. Thus, proteomic expression patterns provide valuable insight into the underlying mechanisms of PGCC formation and the relationship between PGCCs and cancer stem cells in patients with ovarian cancers. PMID- 24348908 TI - Distinct optical chemistry of dissolved organic matter in urban pond ecosystems. AB - Urbanization has the potential to dramatically alter the biogeochemistry of receiving freshwater ecosystems. We examined the optical chemistry of dissolved organic matter (DOM) in forty-five urban ponds across southern Ontario, Canada to examine whether optical characteristics in these relatively new ecosystems are distinct from other freshwater systems. Dissolved organic carbon (DOC) concentrations ranged from 2 to 16 mg C L(-1) across the ponds with an average value of 5.3 mg C L(-1). Excitation-emission matrix (EEM) spectroscopy and parallel factor analysis (PARAFAC) modelling showed urban pond DOM to be characterized by microbial-like and, less importantly, by terrestrial derived humic-like components. The relatively transparent, non-humic DOM in urban ponds was more similar to that found in open water, lake ecosystems than to rivers or wetlands. After irradiation equivalent to 1.7 days of natural solar radiation, DOC concentrations, on average, decreased by 38% and UV absorbance decreased by 25%. Irradiation decreased the relative abundances of terrestrial humic-like components and increased protein-like aspects of the DOM pool. These findings suggest that high internal production and/or prolonged exposure to sunlight exerts a distinct and significant influence on the chemistry of urban pond DOM, which likely reduces its chemical similarity with upstream sources. These properties of urban pond DOM may alter its biogeochemical role in these relatively novel aquatic ecosystems. PMID- 24348909 TI - Trying to move your unseen static arm modulates visually-evoked kinesthetic illusion. AB - Although kinesthesia is known to largely depend on afferent inflow, recent data suggest that central signals originating from volitional control (efferent outflow) could also be involved and interact with the former to build up a coherent percept. Evidence derives from both clinical and experimental observations where vision, which is of primary importance in kinesthesia, was systematically precluded. The purpose of the present experiment was to assess the role of volitional effort in kinesthesia when visual information is available. Participants (n=20) produced isometric contraction (10-20% of maximal voluntary force) of their right arm while their left arm, which image was reflected in a mirror, either was passively moved into flexion/extension by a motorized manipulandum, or remained static. The contraction of the right arm was either congruent with or opposite to the passive displacements of the left arm. Results revealed that in most trials, kinesthetic illusions were visually driven, and their occurrence and intensity were modulated by whether volitional effort was congruent or not with visual signals. These results confirm the impact of volitional effort in kinesthesia and demonstrate for the first time that these signals interact with visual afferents to offer a coherent and unified percept. PMID- 24348910 TI - Transcriptional regulation of two conceptus interferon tau genes expressed in Japanese black cattle during peri-implantation period. AB - Interferon tau (IFNT), produced by the mononuclear trophectoderm, signals the process of maternal recognition of pregnancy in ruminants. However, its expression in vivo and its transcriptional regulation are not yet well characterized. Objectives of this study were to determine conceptus IFNT gene isoforms expressed in the bovine uterus and to identify differences in promoter sequences of IFNT genes that differ in their expression. RNA-seq data analysis of bovine conceptuses on days 17, 20, and 22 (day 0 = day of estrus) detected the expression of two IFNT transcripts, IFNT1 and IFNTc1, which were indeed classified into the IFNT gene clade. RNA-seq and quantitative RT-PCR analyses also revealed that the expression levels of both IFNT mRNAs were highest on day 17, and then decreased on days 20 and 22. Bovine ear-derived fibroblast (EF) cells, a model system commonly used for bovine IFNT gene transcription study in this laboratory, were cotransfected with luciferase reporter constructs carrying upstream (positions -637 to +51) regions of IFNT1 or IFNTc1 gene and various transcription factor expression plasmids including CDX2, AP-1 (Jun) and ETS2. CDX2, either alone or with the other transcription factors, markedly increased luciferase activity. The upstream regions of IFNT1 and IFNTc1 loci were then serially deleted or point-mutated at potential CDX-, AP-1-, and ETS-binding sites. Compared to the wild-type constructs, deletion or mutation at CDX2 or ETS2 binding sites similarly reduced the luciferase activities of IFNT1- or IFNTc1 promoter constructs. However, with the AP-1 site mutated construct, IFNT1- and IFNTc1-reporters behaved differently. These results suggest that two forms of bovine conceptus IFNT genes are expressed in utero and their transcriptional regulations differ. PMID- 24348911 TI - Associations between lifetime traumatic events and subsequent chronic physical conditions: a cross-national, cross-sectional study. AB - BACKGROUND: Associations between lifetime traumatic event (LTE) exposures and subsequent physical ill-health are well established but it has remained unclear whether these are explained by PTSD or other mental disorders. This study examined this question and investigated whether associations varied by type and number of LTEs, across physical condition outcomes, or across countries. METHODS: Cross-sectional, face-to-face household surveys of adults (18+) were conducted in 14 countries (n = 38, 051). The Composite International Diagnostic Interview assessed lifetime LTEs and DSM-IV mental disorders. Chronic physical conditions were ascertained by self-report of physician's diagnosis and year of diagnosis or onset. Survival analyses estimated associations between the number and type of LTEs with the subsequent onset of 11 physical conditions, with and without adjustment for mental disorders. FINDINGS: A dose-response association was found between increasing number of LTEs and odds of any physical condition onset (OR 1.5 [95% CI: 1.4-1.5] for 1 LTE; 2.1 [2.0-2.3] for 5+ LTEs), independent of all mental disorders. Associations did not vary greatly by type of LTE (except for combat and other war experience), nor across countries. A history of 1 LTE was associated with 7/11 of the physical conditions (ORs 1.3 [1.2-1.5] to 1.7 [1.4 2.0]) and a history of 5+ LTEs was associated with 9/11 physical conditions (ORs 1.8 [1.3-2.4] to 3.6 [2.0-6.5]), the exceptions being cancer and stroke. CONCLUSIONS: Traumatic events are associated with adverse downstream effects on physical health, independent of PTSD and other mental disorders. Although the associations are modest they have public health implications due to the high prevalence of traumatic events and the range of common physical conditions affected. The effects of traumatic stress are a concern for all medical professionals and researchers, not just mental health specialists. PMID- 24348912 TI - Modulation of intracellular calcium waves and triggered activities by mitochondrial ca flux in mouse cardiomyocytes. AB - Recent studies have suggested that mitochondria may play important roles in the Ca(2+) homeostasis of cardiac myocytes. However, it is still unclear if mitochondrial Ca(2+) flux can regulate the generation of Ca(2+) waves (CaWs) and triggered activities in cardiac myocytes. In the present study, intracellular/cytosolic Ca(2+) (Cai (2+)) was imaged in Fluo-4-AM loaded mouse ventricular myocytes. Spontaneous sarcoplasmic reticulum (SR) Ca(2+) release and CaWs were induced in the presence of high (4 mM) external Ca(2+) (Cao (2+)). The protonophore carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP) reversibly raised basal Cai (2+) levels even after depletion of SR Ca(2+) in the absence of Cao (2+) , suggesting Ca(2+) release from mitochondria. FCCP at 0.01 - 0.1 uM partially depolarized the mitochondrial membrane potential (Deltapsi m ) and increased the frequency and amplitude of CaWs in a dose-dependent manner. Simultaneous recording of cell membrane potentials showed the augmentation of delayed afterdepolarization amplitudes and frequencies, and induction of triggered action potentials. The effect of FCCP on CaWs was mimicked by antimycin A (an electron transport chain inhibitor disrupting Deltapsi m ) or Ru360 (a mitochondrial Ca(2+) uniporter inhibitor), but not by oligomycin (an ATP synthase inhibitor) or iodoacetic acid (a glycolytic inhibitor), excluding the contribution of intracellular ATP levels. The effects of FCCP on CaWs were counteracted by the mitochondrial permeability transition pore blocker cyclosporine A, or the mitochondrial Ca(2+) uniporter activator kaempferol. Our results suggest that mitochondrial Ca(2+) release and uptake exquisitely control the local Ca(2+) level in the micro-domain near SR ryanodine receptors and play an important role in regulation of intracellular CaWs and arrhythmogenesis. PMID- 24348913 TI - Deterministic diffusion fiber tracking improved by quantitative anisotropy. AB - Diffusion MRI tractography has emerged as a useful and popular tool for mapping connections between brain regions. In this study, we examined the performance of quantitative anisotropy (QA) in facilitating deterministic fiber tracking. Two phantom studies were conducted. The first phantom study examined the susceptibility of fractional anisotropy (FA), generalized factional anisotropy (GFA), and QA to various partial volume effects. The second phantom study examined the spatial resolution of the FA-aided, GFA-aided, and QA-aided tractographies. An in vivo study was conducted to track the arcuate fasciculus, and two neurosurgeons blind to the acquisition and analysis settings were invited to identify false tracks. The performance of QA in assisting fiber tracking was compared with FA, GFA, and anatomical information from T1-weighted images. Our first phantom study showed that QA is less sensitive to the partial volume effects of crossing fibers and free water, suggesting that it is a robust index. The second phantom study showed that the QA-aided tractography has better resolution than the FA-aided and GFA-aided tractography. Our in vivo study further showed that the QA-aided tractography outperforms the FA-aided, GFA aided, and anatomy-aided tractographies. In the shell scheme (HARDI), the FA aided, GFA-aided, and anatomy-aided tractographies have 30.7%, 32.6%, and 24.45% of the false tracks, respectively, while the QA-aided tractography has 16.2%. In the grid scheme (DSI), the FA-aided, GFA-aided, and anatomy-aided tractographies have 12.3%, 9.0%, and 10.93% of the false tracks, respectively, while the QA aided tractography has 4.43%. The QA-aided deterministic fiber tracking may assist fiber tracking studies and facilitate the advancement of human connectomics. PMID- 24348914 TI - The transcriptomics of glucocorticoid receptor signaling in developing zebrafish. AB - Cortisol is the primary corticosteroid in teleosts that is released in response to stressor activation of the hypothalamus-pituitary-interrenal axis. The target tissue action of this hormone is primarily mediated by the intracellular glucocorticoid receptor (GR), a ligand-bound transcription factor. In developing zebrafish (Danio rerio) embryos, GR transcripts and cortisol are maternally deposited into the oocyte prior to fertilization and influence early embryogenesis. To better understand of the molecular mechanisms involved, we investigated changes in the developmental transcriptome prior to hatch, in response to morpholino oligonucleotide knockdown of GR using the Agilent zebrafish microarray platform. A total of 1313 and 836 mRNA transcripts were significantly changed at 24 and 36 hours post fertilization (hpf), respectively. Functional analysis revealed numerous developmental processes under GR regulation, including neurogenesis, eye development, skeletal and cardiac muscle formation. Together, this study underscores a critical role for glucocorticoid signaling in programming molecular events essential for zebrafish development. PMID- 24348915 TI - Effect of artificial selection on runs of homozygosity in u.s. Holstein cattle. AB - The intensive selection programs for milk made possible by mass artificial insemination increased the similarity among the genomes of North American (NA) Holsteins tremendously since the 1960s. This migration of elite alleles has caused certain regions of the genome to have runs of homozygosity (ROH) occasionally spanning millions of continuous base pairs at a specific locus. In this study, genome signatures of artificial selection in NA Holsteins born between 1953 and 2008 were identified by comparing changes in ROH between three distinct groups under different selective pressure for milk production. The ROH regions were also used to estimate the inbreeding coefficients. The comparisons of genomic autozygosity between groups selected or unselected since 1964 for milk production revealed significant differences with respect to overall ROH frequency and distribution. These results indicate selection has increased overall autozygosity across the genome, whereas the autozygosity in an unselected line has not changed significantly across most of the chromosomes. In addition, ROH distribution was more variable across the genomes of selected animals in comparison to a more even ROH distribution for unselected animals. Further analysis of genome-wide autozygosity changes and the association between traits and haplotypes identified more than 40 genomic regions under selection on several chromosomes (Chr) including Chr 2, 7, 16 and 20. Many of these selection signatures corresponded to quantitative trait loci for milk, fat, and protein yield previously found in contemporary Holsteins. PMID- 24348916 TI - Antigenic and genetic diversity of human enterovirus 71 from 2009 to 2012, Taiwan. AB - Different subgenogroups of enterovirus 71 (EV-71) have caused numerous outbreaks of hand, foot, and mouth disease worldwide, especially in the Asia-Pacific region. During the development of a vaccine against EV-71, the genetic and antigenic diversities of EV-71 isolates from Taiwan were analyzed by phylogenetic analyses and neutralization tests. The results showed that the dominant genogroups had changed twice, from B to C and from C to B, between 2009 and 2012. The subgenogroup B5 (B5b cluster) was dominant in 2008-2009 but was replaced by subgenogroup C4 in 2010-2011. From the end of 2011 to 2012, the re-emerging subgenogroup B5 (B5c cluster) was identified as the dominant subgenogroup of EV 71 outbreaks, and subgenogroups C2 and C4 were detected in sporadic cases. Interestingly, the amino acid substitution at position 145 in the VP1 gene was observed in some strains isolated from patients with acute flaccid paralysis. Furthermore, thirty-five strains and their corresponding serum samples were used to analyze the cross-protections and antigenic diversities among different subgenogroups (C4a, C5, B4, B5b, B5c, and C2-like) of EV-71. Evident antigenic diversity existed only for the C2-like subgenogroup, which was not effectively neutralized by other serum samples. In contrast, the anti-C2-like serum sample showed broad cross-reactivity against all other subgenogroups. Therefore, these results may provide valuable information for the selection of EV-71 vaccine candidates and the evolution of EV-71 subgenogroups in Taiwan from 2009 to 2012. PMID- 24348918 TI - New paleocene sepiid coleoids (cephalopoda) from Egypt: evolutionary significance and origin of the sepiid 'rostrum'. AB - New coleoid cephalopods, assignable to the order Sepiida, are recorded from the Selandian/Thanetian boundary interval (Middle to Upper Paleocene transition, c. 59.2 Ma) along the southeastern margin (Toshka Lakes) of the Western Desert in Egypt. The two genera recognised, Aegyptosaepia n. gen. and ?Anomalosaepia Weaver and Ciampaglio, are placed in the families Belosaepiidae and ?Anomalosaepiidae, respectively. They constitute the oldest record to date of sepiids with a 'rostrum-like' prong. In addition, a third, generically and specifically indeterminate coleoid is represented by a single rostrum-like find. The taxonomic assignment of the material is based on apical parts (as preserved), i.e., guard, apical prong (or 'rostrum-like' structure), phragmocone and (remains of) protoconch, plus shell mineralogy. We here confirm the shell of early sepiids to have been bimineralic, i.e., composed of both calcite and aragonite. Aegyptosaepia lugeri n. gen., n. sp. reveals some similarities to later species of Belosaepia, in particular the possession of a distinct prong. General features of the phragmocone and protoconch of the new form are similar to both Belocurta (Middle Danian [Lower Paleocene]) and Belosaepia (Eocene). However, breviconic coiling and the presence of a longer ventral conotheca indicate closer ties with late Maastrichtian-Middle Danian Ceratisepia. In this respect, Aegyptosaepia n. gen. constitutes a link between Ceratisepia and the Eocene Belosaepia. The occurrence of the new genus near the Selandian/Thanetian boundary suggests an earlier origin of belosaepiids, during the early to Middle Paleocene. These earliest known belosaepiids may have originated in the Tethyan Realm. From northeast Africa, they subsequently spread to western India, the Arabian Plate and, probably via the Mediterranean region, to Europe and North America. PMID- 24348919 TI - Light suppresses sporulation and epidemics of Peronospora belbahrii. AB - Peronospora belbahrii is a biotrophic oomycete attacking sweet basil. It propagates asexually by producing spores on dichotomously branched sporophores emerging from leaf stomata. Sporulation occurs when infected plants are incubated for at least 7.5h in the dark in moisture-saturated atmosphere at 10-27 degrees C. Exposure to light suppresses spore formation but allows sporophores to emerge from stomata. Incandescent or CW fluorescent light of 3.5 or 6 umoles.m(2).s(-1) respectively, caused 100% inhibition of spore formation on lower leaf surface even when only the upper leaf surface was exposed to light. The inhibitory effect of light failed to translocate from an illuminated part of a leaf to a shaded part of the same leaf. Inhibition of sporulation by light was temperature dependent. Light was fully inhibitory at 15-27 degrees C but not at 10 degrees C, suggesting that enzyme(s) activity and/or photoreceptor protein re-arrangement induced by light occur at >=15 degrees C. DCMU or paraquat could not abolish light inhibition, indicating that photosystem I and photosystem II are not involved. Narrow band led illumination showed that red light (lambdamax 625 nm) was most inhibitory and blue light (lambdamax 440 nm) was least inhibitory, suggesting that inhibition in P. belbahrii, unlike other oomycetes, operates via a red light photoreceptor. Nocturnal illumination of basil in the field (4-10 umoles.m(2).s(-1) from 7pm to 7am) suppressed sporulation of P. belbahrii and reduced epidemics of downy mildew, thus reducing the need for fungicide applications. This is the first report on red light inhibition of sporulation in oomycetes and on the practical application of light for disease control in the field. PMID- 24348917 TI - Stress responses of the industrial workhorse Bacillus licheniformis to osmotic challenges. AB - The Gram-positive endospore-forming bacterium Bacillus licheniformis can be found widely in nature and it is exploited in industrial processes for the manufacturing of antibiotics, specialty chemicals, and enzymes. Both in its varied natural habitats and in industrial settings, B. licheniformis cells will be exposed to increases in the external osmolarity, conditions that trigger water efflux, impair turgor, cause the cessation of growth, and negatively affect the productivity of cell factories in biotechnological processes. We have taken here both systems-wide and targeted physiological approaches to unravel the core of the osmostress responses of B. licheniformis. Cells were suddenly subjected to an osmotic upshift of considerable magnitude (with 1 M NaCl), and their transcriptional profile was then recorded in a time-resolved fashion on a genome wide scale. A bioinformatics cluster analysis was used to group the osmotically up-regulated genes into categories that are functionally associated with the synthesis and import of osmostress-relieving compounds (compatible solutes), the SigB-controlled general stress response, and genes whose functional annotation suggests that salt stress triggers secondary oxidative stress responses in B. licheniformis. The data set focusing on the transcriptional profile of B. licheniformis was enriched by proteomics aimed at identifying those proteins that were accumulated by the cells through increased biosynthesis in response to osmotic stress. Furthermore, these global approaches were augmented by a set of experiments that addressed the synthesis of the compatible solutes proline and glycine betaine and assessed the growth-enhancing effects of various osmoprotectants. Combined, our data provide a blueprint of the cellular adjustment processes of B. licheniformis to both sudden and sustained osmotic stress. PMID- 24348920 TI - Attenuation of eph receptor kinase activation in cancer cells by coexpressed ephrin ligands. AB - The Eph receptor tyrosine kinases mediate juxtacrine signals by interacting "in trans" with ligands anchored to the surface of neighboring cells via a GPI-anchor (ephrin-As) or a transmembrane segment (ephrin-Bs), which leads to receptor clustering and increased kinase activity. Additionally, soluble forms of the ephrin-A ligands released from the cell surface by matrix metalloproteases can also activate EphA receptor signaling. Besides these trans interactions, recent studies have revealed that Eph receptors and ephrins coexpressed in neurons can also engage in lateral "cis" associations that attenuate receptor activation by ephrins in trans with critical functional consequences. Despite the importance of the Eph/ephrin system in tumorigenesis, Eph receptor-ephrin cis interactions have not been previously investigated in cancer cells. Here we show that in cancer cells, coexpressed ephrin-A3 can inhibit the ability of EphA2 and EphA3 to bind ephrins in trans and become activated, while ephrin-B2 can inhibit not only EphB4 but also EphA3. The cis inhibition of EphA3 by ephrin-B2 implies that in some cases ephrins that cannot activate a particular Eph receptor in trans can nevertheless inhibit its signaling ability through cis association. We also found that an EphA3 mutation identified in lung cancer enhances cis interaction with ephrin-A3. These results suggest a novel mechanism that may contribute to cancer pathogenesis by attenuating the tumor suppressing effects of Eph receptor signaling pathways activated by ephrins in trans. PMID- 24348921 TI - The Panhandle formed by influenza A and C virus NS non-coding regions determines NS segment expression. AB - Exchange of the extremities of the NS segment of type A and C influenza viruses in reverse genetics systems was used to assess their putative role in type specificity. Restoration of each specific proximal panhandle was mandatory to allow the rescue of viruses with heterotypic extremities. Moreover, the transcription level of the modified segment seemed to be directly affected by the distal panhandle strength. PMID- 24348922 TI - Systems approaches to animal disease surveillance and resource allocation: methodological frameworks for behavioral analysis. AB - While demands for animal disease surveillance systems are growing, there has been little applied research that has examined the interactions between resource allocation, cost-effectiveness, and behavioral considerations of actors throughout the livestock supply chain in a surveillance system context. These interactions are important as feedbacks between surveillance decisions and disease evolution may be modulated by their contextual drivers, influencing the cost-effectiveness of a given surveillance system. This paper identifies a number of key behavioral aspects involved in animal health surveillance systems and reviews some novel methodologies for their analysis. A generic framework for analysis is discussed, with exemplar results provided to demonstrate the utility of such an approach in guiding better disease control and surveillance decisions. PMID- 24348983 TI - Absence of suction feeding ichthyosaurs and its implications for triassic mesopelagic paleoecology. AB - Mesozoic marine reptiles and modern marine mammals are often considered ecological analogs, but the extent of their similarity is largely unknown. Particularly important is the presence/absence of deep-diving suction feeders among Mesozoic marine reptiles because this would indicate the establishment of mesopelagic cephalopod and fish communities in the Mesozoic. A recent study suggested that diverse suction feeders, resembling the extant beaked whales, evolved among ichthyosaurs in the Triassic. However, this hypothesis has not been tested quantitatively. We examined four osteological features of jawed vertebrates that are closely linked to the mechanism of suction feeding, namely hyoid corpus ossification/calcification, hyobranchial apparatus robustness, mandibular bluntness, and mandibular pressure concentration index. Measurements were taken from 18 species of Triassic and Early Jurassic ichthyosaurs, including the presumed suction feeders. Statistical comparisons with extant sharks and marine mammals of known diets suggest that ichthyosaurian hyobranchial bones are significantly more slender than in suction-feeding sharks or cetaceans but similar to those of ram-feeding sharks. Most importantly, an ossified hyoid corpus to which hyoid retractor muscles attach is unknown in all but one ichthyosaur, whereas a strong integration of the ossified corpus and cornua of the hyobranchial apparatus has been identified in the literature as an important feature of suction feeders. Also, ichthyosaurian mandibles do not narrow rapidly to allow high suction pressure concentration within the oral cavity, unlike in beaked whales or sperm whales. In conclusion, it is most likely that Triassic and Early Jurassic ichthyosaurs were 'ram-feeders', without any beaked-whale-like suction feeder among them. When combined with the inferred inability for dim light vision in relevant Triassic ichthyosaurs, the fossil record of ichthyosaurs does not suggest the establishment of modern-style mesopelagic animal communities in the Triassic. This new interpretation matches the fossil record of coleoids, which indicates the absence of soft-bodied deepwater species in the Triassic. PMID- 24348984 TI - ReacKnock: identifying reaction deletion strategies for microbial strain optimization based on genome-scale metabolic network. AB - Gene knockout has been used as a common strategy to improve microbial strains for producing chemicals. Several algorithms are available to predict the target reactions to be deleted. Most of them apply mixed integer bi-level linear programming (MIBLP) based on metabolic networks, and use duality theory to transform bi-level optimization problem of large-scale MIBLP to single-level programming. However, the validity of the transformation was not proved. Solution of MIBLP depends on the structure of inner problem. If the inner problem is continuous, Karush-Kuhn-Tucker (KKT) method can be used to reformulate the MIBLP to a single-level one. We adopt KKT technique in our algorithm ReacKnock to attack the intractable problem of the solution of MIBLP, demonstrated with the genome-scale metabolic network model of E. coli for producing various chemicals such as succinate, ethanol, threonine and etc. Compared to the previous methods, our algorithm is fast, stable and reliable to find the optimal solutions for all the chemical products tested, and able to provide all the alternative deletion strategies which lead to the same industrial objective. PMID- 24348986 TI - Multiple Sclerosis in the Mount Etna region: possible role of volcanogenic trace elements. AB - BACKGROUND: Trace elements have been hypothesised to be involved in the pathogenesis of Multiple Sclerosis and volcanic degassing is the major natural sources of trace elements. Both incidence of Multiple Sclerosis in Catania and volcanic activity of Mount Etna have been significantly increased during the last 30 years. Due to prevailing trade winds direction, volcanic gases from Etna summit craters are mostly blown towards the eastern and southern sectors of the volcano. OBJECTIVE: To evaluate the possible association between Multiple Sclerosis and exposure to volcanogenic trace elements. METHODS: We evaluated prevalence and incidence of Multiple Sclerosis in four communities (47,234 inhabitants) located in the eastern flank and in two communities (52,210 inhabitants) located in the western flank of Mount Etna, respectively the most and least exposed area to crater gas emissions. RESULTS: A higher prevalence was found in the population of the eastern flank compared to the population of the western one (137.6/100,000 versus 94.3/100,000; p-value 0.04). We found a borderline significantly higher incidence risk during the incidence study period (1980-2009) in the population of the eastern flank 4.6/100,000 (95% CI 3.1-5.9), compared with the western population 3.2/100,000 (95% CI 2.4-4.2) with a RR of 1.41 (95% CI 0.97-2.05; p-value 0.06). Incidence risks have increased over the time in both populations reaching a peak of 6.4/100,000 in the eastern flank and of 4.4/100.000 in the western flank during 2000-2009. CONCLUSION: We found a higher prevalence and incidence of Multiple Sclerosis among populations living in the eastern flank of Mount Etna. According to our data a possible role of TE cannot be ruled out as possible co-factor in the MS pathogenesis. However larger epidemiological study are needed to confirm this hypothesis. PMID- 24348985 TI - Risk of severe upper gastrointestinal complications among oral bisphosphonate users. AB - BACKGROUND: Oral bisphosphonates (BPs) are the primary agents for the treatment of osteoporosis. Although BPs are generally well tolerated, serious gastrointestinal adverse events have been observed. AIM: To assess the risk of severe upper gastrointestinal complications (UGIC) among BP users by means of a large study based on a network of Italian healthcare utilization databases. METHODS: A nested case-control study was carried out by including 110,220 patients aged 45 years or older who, from 2003 until 2005, were treated with oral BPs. Cases were the 862 patients who experienced the outcome (hospitalization for UGIC) until 2007. Up to 20 controls were randomly selected for each case. Conditional logistic regression model was used to estimate odds ratio (OR) associated with current use of BPs after adjusting for several covariates. A set of sensitivity analyses was performed in order to account for sources of systematic uncertainty. RESULTS: The adjusted OR for current use of BPs with respect to past use was 0.94 (95% CI 0.81 to 1.08). There was no evidence that this risk changed either with BP type and regimen, or concurrent use of other drugs or previous hospitalizations. CONCLUSIONS: No evidence was found that current use of BPs increases the risk of severe upper gastrointestinal complications compared to past use. PMID- 24348988 TI - Association between gestational weight gain and postpartum diabetes: evidence from a community based large cohort study. AB - We have investigated the prospective association between excess gestational weight gain (GWG) and development of diabetes by 21 years post-partum using a community-based large prospective cohort study in Brisbane, Australia. There were 3386 mothers for whom complete data were available on GWG, pre-pregnancy BMI and self-reported diabetes 21 years post-partum. We used The Institute of Medicine (IOM) definition to categorize GWG as inadequate, adequate and excessive. We found 839 (25.78%) mothers gained inadequate weight, 1,353 (39.96%) had adequate weight gain and 1,194 (35.26%) had gained excessive weight during pregnancy. At 21 years post-partum, 8.40% of mothers self-reported a diagnosis of diabetes made by their doctor. In the age adjusted model, we found mothers who gained excess weight during pregnancy were 1.47 (1.11,1.94) times more likely to experience diabetes at 21 years post-partum compared to the mothers who gained adequate weight. This association was not explained by the potential confounders including maternal age, parity, education, race, smoking, TV watching and exercise. However, this association was mediated by the current BMI. There was no association for the women who had normal BMI before pregnancy and gained excess weight during pregnancy. The findings of this study suggest that women who gain excess weight during pregnancy are at greater risk of being diagnosed with diabetes in later life. This relationship is likely mediated through the pathway of post-partum weight-retention and obesity. This study adds evidence to the argument that excessive GWG during pregnancy for overweight mothers has long term maternal health implications. PMID- 24348987 TI - Site-specific keloid fibroblasts alter the behaviour of normal skin and normal scar fibroblasts through paracrine signalling. AB - Keloid disease (KD) is an abnormal cutaneous fibroproliferative disorder of unknown aetiopathogenesis. Keloid fibroblasts (KF) are implicated as mediators of elevated extracellular matrix deposition. Aberrant secretory behaviour by KF relative to normal skin fibroblasts (NF) may influence the disease state. To date, no previous reports exist on the ability of site-specific KF to induce fibrotic-like phenotypic changes in NF or normal scar fibroblasts (NS) by paracrine mechanisms. Therefore, the aim of this study was to investigate the influence of conditioned media from site-specific KF on the cellular and molecular behaviour of both NF and NS enabled by paracrine mechanisms. Conditioned media was collected from cultured primary fibroblasts during a proliferative log phase of growth including: NF, NS, peri-lesional keloid fibroblasts (PKF) and intra-lesional keloid fibroblasts (IKF). Conditioned media was used to grow NF, NS, PKF and IKF cells over 240 hrs. Cellular behavior was monitored through real time cell analysis (RTCA), proliferation rates and migration in a scratch wound assay. Fibrosis-associated marker expression was determined at both protein and gene level. PKF conditioned media treatment of both NF and NS elicited enhanced cell proliferation, spreading and viability as measured in real time over 240 hrs versus control conditioned media. Following PKF and IKF media treatments up to 240 hrs, both NF and NS showed significantly elevated proliferation rates (p<0.03) and migration in a scratch wound assay (p<0.04). Concomitant up-regulation of collagen I, fibronectin, alpha-SMA, PAI-1, TGF-beta and CTGF (p<0.03) protein expression were also observed. Corresponding qRT-PCR analysis supported these findings (P<0.03). In all cases, conditioned media from growing marginal PKF elicited the strongest effects. In conclusion, primary NF and NS cells treated with PKF or IKF conditioned media exhibit enhanced expression of fibrosis-associated molecular markers and increased cellular activity as a result of keloid fibroblast-derived paracrine factors. PMID- 24348989 TI - Baseline levels and temporal stability of 27 multiplexed serum cytokine concentrations in healthy subjects. AB - BACKGROUND: Cytokines are humoral molecules that elicit regulatory function in immunologic pathways. The level and type of cytokine production has become critical in distinguishing physiologic from pathologic immune conditions. Cytokine profiling has become an important biomarker discovery tool in monitoring of the immune system. However, the variations in cytokine levels in individual subjects over time in healthy individuals have not been extensively studied. In this study, we use multiplex bead arrays to evaluate 27 analytes in paired serum samples taken seven days apart from 144 healthy individuals in order to assess variations over a short time period. METHODS: Fluorescent bead-based immunoassay (Luminex) was used to measure 27 analytes in serum samples. Measurements were performed on matched samples from 144 healthy donors. To assess inter-plate variability, one arbitrarily selected serum sample was analyzed on each of the first ten plates as bridge sample. RESULTS: Using the bridge sample, we showed minimal inter-plate variations in the measurement of most analytes. In measurement of cytokines from the 144 patients at two time points, we found that three cytokines (IL-2, IL-15 and GM-CSF) were undetectable and five analytes (RANTES, MCP-1, VEGF, MIP-1beta and PDGF-BB) showed significant difference in concentrations at Day 0 compared to Day 7. CONCLUSIONS: The current study demonstrated higher variations in cytokine levels among individuals than were observed for samples obtained one week apart from identical donors. These data suggest that a serum sample from each subject for use as a baseline measurement is a better control for clinical trials rather than sera from a paired cohort. PMID- 24348992 TI - Human-assisted spread of a maladaptive behavior in a critically endangered bird. AB - Conservation management often focuses on counteracting the adverse effects of human activities on threatened populations. However, conservation measures may unintentionally relax selection by allowing the 'survival of the not-so-fit', increasing the risk of fixation of maladaptive traits. Here, we report such a case in the critically-endangered Chatham Island black robin (Petroica traversi) which, in 1980, was reduced to a single breeding pair. Following this bottleneck, some females were observed to lay eggs on the rims of their nests. Rim eggs left in place always failed to hatch. To expedite population recovery, rim eggs were repositioned inside nests, yielding viable hatchlings. Repositioning resulted in rapid growth of the black robin population, but by 1989 over 50% of all females were laying rim eggs. We used an exceptional, species-wide pedigree to consider both recessive and dominant models of inheritance over all plausible founder genotype combinations at a biallelic and possibly sex-linked locus. The pattern of rim laying is best fitted as an autosomal dominant Mendelian trait. Using a phenotype permutation test we could also reject the null hypothesis of non heritability for this trait in favour of our best-fitting model of heritability. Data collected after intervention ceased shows that the frequency of rim laying has strongly declined, and that this trait is maladaptive. This episode yields an important lesson for conservation biology: fixation of maladaptive traits could render small threatened populations completely dependent on humans for reproduction, irreversibly compromising the long term viability of populations humanity seeks to conserve. PMID- 24348990 TI - Essential function of dynamin in the invasive properties and actin architecture of v-Src induced podosomes/invadosomes. AB - The large GTPase dynamin plays a key role in endocytosis but is also localized at numerous actin rich sites. We investigated dynamin functions at podosomes/invadosomes, actin-based cellular adhesion structures implicated in tissue invasion. Podosomes/invadosomes are constituted of long F-actin bundles perpendicular to the substratum (actin cores), connected to randomly arranged F actin fibers parallel to the substratum (actin cloud). We show here that dynamin depletion in v-Src-transformed fibroblasts triggers a massive disorganization of podosomes/invadosomes (isolated or in rosettes), with a corresponding inhibition of their invasive properties. The action of dynamin at podosomes/invadosomes requires a functional full-length protein, suggesting that the effects of dynamin at these sites and in membrane remodelling during endocytosis are mediated by similar mechanisms. In order to determine direct effect of dynamin depletion on invadosome, an optogenetic approach based on the photosensitizer KillerRed was developed. Acute dynamin photo-inactivation leads to a very rapid disorganization of invadosome without affecting focal adhesions. Dynamin therefore is a key regulator of the architecture of actin in podosomes/invadosomes. PMID- 24348991 TI - Individual differences in brain structure and resting brain function underlie cognitive styles: evidence from the Embedded Figures Test. AB - Cognitive styles can be characterized as individual differences in the way people perceive, think, solve problems, learn, and relate to others. Field dependence/independence (FDI) is an important and widely studied dimension of cognitive styles. Although functional imaging studies have investigated the brain activation of FDI cognitive styles, the combined structural and functional correlates with individual differences in a large sample have never been investigated. In the present study, we investigated the neural correlates of individual differences in FDI cognitive styles by analyzing the correlations between Embedded Figures Test (EFT) score and structural neuroimaging data [regional gray matter volume (rGMV) was assessed using voxel-based morphometry (VBM)]/functional neuroimaging data [resting-brain functions were measured by amplitude of low-frequency fluctuation (ALFF)] throughout the whole brain. Results showed that the increased rGMV in the left inferior parietal lobule (IPL) was associated with the EFT score, which might be the structural basis of effective local processing. Additionally, a significant positive correlation between ALFF and EFT score was found in the fronto-parietal network, including the left inferior parietal lobule (IPL) and the medial prefrontal cortex (mPFC). We speculated that the left IPL might be associated with superior feature identification, and mPFC might be related to cognitive inhibition of global processing bias. These results suggested that the underlying neuroanatomical and functional bases were linked to the individual differences in FDI cognitive styles and emphasized the important contribution of superior local processing ability and cognitive inhibition to field-independent style. PMID- 24348993 TI - Mortality attributable to influenza in England and Wales prior to, during and after the 2009 pandemic. AB - Very different influenza seasons have been observed from 2008/09-2011/12 in England and Wales, with the reported burden varying overall and by age group. The objective of this study was to estimate the impact of influenza on all-cause and cause-specific mortality during this period. Age-specific generalised linear regression models fitted with an identity link were developed, modelling weekly influenza activity through multiplying clinical influenza-like illness consultation rates with proportion of samples positive for influenza A or B. To adjust for confounding factors, a similar activity indicator was calculated for Respiratory Syncytial Virus. Extreme temperature and seasonal trend were controlled for. Following a severe influenza season in 2008/09 in 65+yr olds (estimated excess of 13,058 influenza A all-cause deaths), attributed all-cause mortality was not significant during the 2009 pandemic in this age group and comparatively low levels of influenza A mortality were seen in post-pandemic seasons. The age shift of the burden of seasonal influenza from the elderly to young adults during the pandemic continued into 2010/11; a comparatively larger impact was seen with the same circulating A(H1N1)pdm09 strain, with the burden of influenza A all-cause excess mortality in 15-64 yr olds the largest reported during 2008/09-2011/12 (436 deaths in 15-44 yr olds and 1,274 in 45-64 yr olds). On average, 76% of seasonal influenza A all-age attributable deaths had a cardiovascular or respiratory cause recorded (average of 5,849 influenza A deaths per season), with nearly a quarter reported for other causes (average of 1,770 influenza A deaths per season), highlighting the importance of all-cause as well as cause-specific estimates. No significant influenza B attributable mortality was detected by season, cause or age group. This analysis forms part of the preparatory work to establish a routine mortality monitoring system ahead of introduction of the UK universal childhood seasonal influenza vaccination programme in 2013/14. PMID- 24348994 TI - Topic structure affects semantic integration: evidence from event-related potentials. AB - This study investigated whether semantic integration in discourse context could be influenced by topic structure using event-related brain potentials. Participants read discourses in which the last sentence contained a critical word that was either congruent or incongruent with the topic established in the first sentence. The intervening sentences between the first and the last sentence of the discourse either maintained or shifted the original topic. Results showed that incongruent words in topic-maintained discourses elicited an N400 effect that was broadly distributed over the scalp while those in topic-shifted discourses elicited an N400 effect that was lateralized to the right hemisphere and localized over central and posterior areas. Moreover, a late positivity effect was only elicited by incongruent words in topic-shifted discourses, but not in topic-maintained discourses. This suggests an important role for discourse structure in semantic integration, such that compared with topic-maintained discourses, the complexity of discourse structure in topic-shifted condition reduces the initial stage of semantic integration and enhances the later stage in which a mental representation is updated. PMID- 24348995 TI - Antibiotic stewardship ward rounds and a dedicated prescription chart reduce antibiotic consumption and pharmacy costs without affecting inpatient mortality or re-admission rates. AB - BACKGROUND: Antibiotic consumption is a major driver of bacterial resistance. To address the increasing burden of multi-drug resistant bacterial infections, antibiotic stewardship programmes are promoted worldwide to rationalize antibiotic prescribing and conserve remaining antibiotics. Few studies have been reported from developing countries and none from Africa that report on an intervention based approach with outcomes that include morbidity and mortality. METHODS: An antibiotic prescription chart and weekly antibiotic stewardship ward round was introduced into two medical wards of an academic teaching hospital in South Africa between January-December 2012. Electronic pharmacy records were used to collect the volume and cost of antibiotics used, the patient database was analysed to determine inpatient mortality and 30-day re-admission rates, and laboratory records to determine use of infection-related tests. Outcomes were compared to a control period, January-December 2011. RESULTS: During the intervention period, 475.8 defined daily doses were prescribed per 1000 inpatient days compared to 592.0 defined daily doses/1000 inpatient days during the control period. This represents a 19.6% decrease in volume with a cost reduction of 35% of the pharmacy's antibiotic budget. There was a concomitant increase in laboratory tests driven by requests for procalcitonin. There was no difference in inpatient mortality or 30-day readmission rate during the control and intervention periods. CONCLUSIONS: Introduction of antibiotic stewardship ward rounds and a dedicated prescription chart in a developing country setting can achieve reduction in antibiotic consumption without harm to patients. Increased laboratory costs should be anticipated when introducing an antibiotic stewardship program. PMID- 24348996 TI - Mechanisms of hemagglutinin targeted influenza virus neutralization. AB - Human monoclonal antibodies have been identified which neutralize broad spectra of influenza A or B viruses. Here, we dissect the mechanisms by which such antibodies interfere with infectivity. We distinguish four mechanisms that link the conserved hemagglutinin (HA) epitopes of broadly neutralizing antibodies to critical processes in the viral life cycle. HA-stem binding antibodies can act intracellularly by blocking fusion between the viral and endosomal membranes and extracellularly by preventing the proteolytic activation of HA. HA-head binding antibodies prevent viral attachment and release. These insights into newly identified ways by which the human immune system can interfere with influenza virus infection may aid the development of novel universal vaccines and antivirals. PMID- 24348997 TI - A small RNA encoded in the Rv2660c locus of Mycobacterium tuberculosis is induced during starvation and infection. AB - Enhanced transcription of the Rv2660c locus in response to starvation of Mycobacterium tuberculosis H37Rv encouraged addition of the predicted Rv2660c protein to an improved vaccine formulation. Using strand-specific RNA sequencing, we show that the up-regulated transcript is in fact a small RNA encoded on the opposite strand to the annotated Rv2660c. The transcript originates within a prophage and is expressed only in strains that carry PhiRv2. The small RNA contains both host and phage sequences and provides a useful biomarker to monitor bacterial starvation during infection and/or non-replicating persistence. Using different approaches we do not find any evidence of Rv2660c at the level of mRNA or protein. Further efforts to understand the mechanism by which Rv2660c improves efficacy of the H56 vaccine are likely to provide insights into the pathology and immunology of tuberculosis. PMID- 24348998 TI - Genetic analysis of low BMI phenotype in the Utah Population Database. AB - The low body mass index (BMI) phenotype of less than 18.5 has been linked to medical and psychological morbidity as well as increased mortality risk. Although genetic factors have been shown to influence BMI across the entire BMI, the contribution of genetic factors to the low BMI phenotype is unclear. We hypothesized genetic factors would contribute to risk of a low BMI phenotype. To test this hypothesis, we conducted a genealogy data analysis using height and weight measurements from driver's license data from the Utah Population Data Base. The Genealogical Index of Familiality (GIF) test and relative risk in relatives were used to examine evidence for excess relatedness among individuals with the low BMI phenotype. The overall GIF test for excess relatedness in the low BMI phenotype showed a significant excess over expected (GIF 4.47 for all cases versus 4.10 for controls, overall empirical p-value<0.001). The significant excess relatedness was still observed when close relationships were ignored, supporting a specific genetic contribution rather than only a family environmental effect. This study supports a specific genetic contribution in the risk for the low BMI phenotype. Better understanding of the genetic contribution to low BMI holds promise for weight regulation and potentially for novel strategies in the treatment of leanness and obesity. PMID- 24348999 TI - Zoos through the lens of the IUCN Red List: a global metapopulation approach to support conservation breeding programs. AB - Given current extinction trends, the number of species requiring conservation breeding programs (CBPs) is likely to increase dramatically. To inform CBP policies for threatened terrestrial vertebrates, we evaluated the number and representation of threatened vertebrate species on the IUCN Red List held in the ISIS zoo network and estimated the complexity of their management as metapopulations. Our results show that 695 of the 3,955 (23%) terrestrial vertebrate species in ISIS zoos are threatened. Only two of the 59 taxonomic orders show a higher proportion of threatened species in ISIS zoos than would be expected if species were selected at random. In addition, for most taxa, the management of a zoo metapopulation of more than 250 individuals will require the coordination of a cluster of 11 to 24 ISIS zoos within a radius of 2,000 km. Thus, in the zoo network, the representation of species that may require CBPs is currently low and the spatial distribution of these zoo populations makes management difficult. Although the zoo community may have the will and the logistical potential to contribute to conservation actions, including CBPs, to do so will require greater collaboration between zoos and other institutions, alongside the development of international agreements that facilitate cross border movement of zoo animals. To maximize the effectiveness of integrated conservation actions that include CBPs, it is fundamental that the non-zoo conservation community acknowledges and integrates the expertise and facilities of zoos where it can be helpful. PMID- 24349000 TI - Strong genetic influence on a UK nationwide test of educational achievement at the end of compulsory education at age 16. AB - We have previously shown that individual differences in educational achievement are highly heritable in the early and middle school years in the UK. The objective of the present study was to investigate whether similarly high heritability is found at the end of compulsory education (age 16) for the UK-wide examination, called the General Certificate of Secondary Education (GCSE). In a national twin sample of 11,117 16-year-olds, heritability was substantial for overall GCSE performance for compulsory core subjects (58%) as well as for each of them individually: English (52%), mathematics (55%) and science (58%). In contrast, the overall effects of shared environment, which includes all family and school influences shared by members of twin pairs growing up in the same family and attending the same school, accounts for about 36% of the variance of mean GCSE scores. The significance of these findings is that individual differences in educational achievement at the end of compulsory education are not primarily an index of the quality of teachers or schools: much more of the variance of GCSE scores can be attributed to genetics than to school or family environment. We suggest a model of education that recognizes the important role of genetics. Rather than a passive model of schooling as instruction (instruere, 'to build in'), we propose an active model of education (educare, 'to bring out') in which children create their own educational experiences in part on the basis of their genetic propensities, which supports the trend towards personalized learning. PMID- 24349001 TI - Dissociated neurons and glial cells derived from rat inferior colliculi after digestion with papain. AB - The formation of gliosis around implant electrodes for deep brain stimulation impairs electrode-tissue interaction. Unspecific growth of glial tissue around the electrodes can be hindered by altering physicochemical material properties. However, in vitro screening of neural tissue-material interaction requires an adequate cell culture system. No adequate model for cells dissociated from the inferior colliculus (IC) has been described and was thus the aim of this study. Therefore, IC were isolated from neonatal rats (P3_5) and a dissociated cell culture was established. In screening experiments using four dissociation methods (Neural Tissue Dissociation Kit [NTDK] T, NTDK P; NTDK PN, and a validated protocol for the dissociation of spiral ganglion neurons [SGN]), the optimal media, and seeding densities were identified. Thereafter, a dissociation protocol containing only the proteolytic enzymes of interest (trypsin or papain) was tested. For analysis, cells were fixed and immunolabeled using glial- and neuron specific antibodies. Adhesion and survival of dissociated neurons and glial cells isolated from the IC were demonstrated in all experimental settings. Hence, preservation of type-specific cytoarchitecture with sufficient neuronal networks only occurred in cultures dissociated with NTDK P, NTDK PN, and fresh prepared papain solution. However, cultures obtained after dissociation with papain, seeded at a density of 2*10(4) cells/well and cultivated with Neuro Medium for 6 days reliably revealed the highest neuronal yield with excellent cytoarchitecture of neurons and glial cells. The herein described dissociated culture can be utilized as in vitro model to screen interactions between cells of the IC and surface modifications of the electrode. PMID- 24349002 TI - Sialylation and muscle performance: sialic acid is a marker of muscle ageing. AB - Sialic acids (Sia) are widely expressed as terminal monosaccharides on eukaryotic glycoconjugates. They are involved in many cellular functions, such as cell-cell interaction and signal recognition. The key enzyme of sialic acid biosynthesis is the bifunctional UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE), which catalyses the first two steps of Sia biosynthesis in the cytosol. In this study we analysed sialylation of muscles in wild type (C57Bl/6 GNE (+/+)) and heterozygous GNE-deficient (C57Bl/6 GNE (+/-)) mice. We measured a significantly lower performance in the initial weeks of a treadmill exercise in C57Bl/6 GNE (+/-) mice compared to wild type C57Bl/6 GNE (+/+) animals. Membrane bound Sia of C57Bl/6 GNE (+/-) mice were reduced by 33-53% at week 24 and by 12 15% at week 80 in comparison to C57Bl/6 GNE (+/+) mice. Interestingly, membrane bound Sia concentration increased with age of the mice by 16-46% in C57Bl/6 GNE (+/+), but by 87-207% in C57Bl/6 GNE (+/-). Furthermore we could identify specific morphological changes in aged muscles. Here we propose that increased Sia concentrations in muscles are a characteristic feature of ageing and could be used as a marker for age-related changes in muscle. PMID- 24349003 TI - Vaginal immunization to elicit primary T-cell activation and dissemination. AB - Primary T-cell activation at mucosal sites is of utmost importance for the development of vaccination strategies. T-cell priming after vaginal immunization, with ovalbumin and CpG oligodeoxynucleotide adjuvant as model vaccine formulation, was studied in vivo in hormone-synchronized mice and compared to the one induced by the nasal route. Twenty-four hours after both vaginal or nasal immunization, antigen-loaded dendritic cells were detected within the respective draining lymph nodes. Vaginal immunization elicited a strong recruitment of antigen-specific CD4(+) T cells into draining lymph nodes that was more rapid than the one observed following nasal immunization. T-cell clonal expansion was first detected in iliac lymph nodes, draining the genital tract, and proliferated T cells disseminated towards distal lymph nodes and spleen similarly to what observed following nasal immunization. T cells were indeed activated by the antigen encounter and acquired homing molecules essential to disseminate towards distal lymphoid organs as confirmed by the modulation of CD45RB, CD69, CD44 and CD62L marker expression. A multi-type Galton Watson branching process, previously used for in vitro analysis of T-cell proliferation, was applied to model in vivo CFSE proliferation data in draining lymph nodes 57 hours following immunization, in order to calculate the probabilistic decision of a cell to enter in division, rest in quiescence or migrate/die. The modelling analysis indicated that the probability of a cell to proliferate was higher following vaginal than nasal immunization. All together these data show that vaginal immunization, despite the absence of an organized mucosal associated inductive site in the genital tract, is very efficient in priming antigen-specific CD4(+) T cells and inducing their dissemination from draining lymph nodes towards distal lymphoid organs. PMID- 24349004 TI - ESAT-6 (EsxA) and TB10.4 (EsxH) based vaccines for pre- and post-exposure tuberculosis vaccination. AB - The ESX systems from Mycobacterium tuberculosis are responsible for the secretion of highly immunogenic proteins of key importance for bacterial survival and growth. The two prototypic proteins, ESAT-6 (EsxA from ESX-1) and TB10.4 (EsxH from ESX-3) share a lot of characteristics regarding genome organization, size, antigenic properties, and vaccine potential but the two molecules clearly have very different roles in bacterial physiology. To further investigate the role of ESAT-6 and TB10.4 as preventive and post-exposure tuberculosis vaccines, we evaluated four different fusion-protein vaccines; H1, H4, H56 and H28, that differ only in these two components. We found that all of these vaccines give rise to protection in a conventional prophylactic vaccination model. In contrast, only the ESAT-6-containing vaccines resulted in significant protection against reactivation, when administered post-exposure. This difference in post-exposure activity did not correlate with a difference in gene expression during infection or a differential magnitude or quality of the vaccine-specific CD4 T cells induced by ESAT-6 versus TB10.4-containing vaccines. The post-exposure effect of the ESAT-6 based vaccines was found to be influenced by the infectious load at the time-point of vaccination and was abolished in chronically infected animals with high bacterial loads at the onset of vaccination. Our data demonstrate that there are specific requirements for the immune system to target an already established tuberculosis infection and that ESAT-6 has a unique potential in post exposure vaccination strategies. PMID- 24349005 TI - Phylogenetic relatedness of circulating HIV-1C variants in Mochudi, Botswana. AB - BACKGROUND: Determining patterns of HIV transmission is increasingly important for the most efficient use of modern prevention interventions. HIV phylogeny can provide a better understanding of the mechanisms underlying HIV transmission networks in communities. METHODS: To reconstruct the structure and dynamics of a local HIV/AIDS epidemic, the phylogenetic relatedness of HIV-1 subtype C env sequences obtained from 785 HIV-infected community residents in the northeastern sector of Mochudi, Botswana, during 2010-2013 was estimated. The genotyping coverage was estimated at 44%. Clusters were defined based on relatedness of HIV 1C env sequences and bootstrap support of splits. RESULTS: The overall proportion of clustered HIV-1C env sequences was 19.1% (95% CI 17.5% to 20.8%). The proportion of clustered sequences from Mochudi was significantly higher than the proportion of non-Mochudi sequences that clustered, 27.0% vs. 14.7% (p = 5.8E-12; Fisher exact test). The majority of clustered Mochudi sequences (90.1%; 95% CI 85.1% to 93.6%) were found in the Mochudi-unique clusters. None of the sequences from Mochudi clustered with any of the 1,244 non-Botswana HIV-1C sequences. At least 83 distinct HIV-1C variants, or chains of HIV transmission, in Mochudi were enumerated, and their sequence signatures were reconstructed. Seven of 20 genotyped seroconverters were found in 7 distinct clusters. CONCLUSIONS: The study provides essential characteristics of the HIV transmission network in a community in Botswana, suggests the importance of high sampling coverage, and highlights the need for broad HIV genotyping to determine the spread of community unique and community-mixed viral variants circulating in local epidemics. The proposed methodology of cluster analysis enumerates circulating HIV variants and can work well for surveillance of HIV transmission networks. HIV genotyping at the community level can help to optimize and balance HIV prevention strategies in trials and combined intervention packages. PMID- 24349006 TI - Breast cancer mortality vs. exercise and breast size in runners and walkers. AB - PURPOSE: Identify predictors of breast cancer mortality in women who exercised below (<7.5 metabolic equivalent hours/week, MET-hours/wk), at (7.5 to 12.5 MET hours/wk), or above (>=12.5 MET-hours/wk) recommended levels. METHODS: Cox proportional hazard analyses of baseline pre-diagnosis MET-hours/wk vs. breast cancer mortality adjusted for follow-up age, race, baseline menopause, and estrogen and oral contraceptive use in 79,124 women (32,872 walkers, 46,252 runners) from the National Walkers' and Runners' Health Studies. RESULTS: One hundred eleven women (57 walkers, 54 runners) died from breast cancer during the 11-year follow-up. The decline in mortality in women who exercised >=7.5 MET hours/wk was not different for walking and running (P = 0.34), so running and walking energy expenditures were combined. The risk for breast cancer mortality was 41.5% lower for >=7.5 vs. <7.5 MET-hours/wk (HR: 0.585, 95%CI: 0.382 to 0.924, P = 0.02), which persisted when adjusted for BMI (HR: 0.584, 95%CI: 0.368 to 0.956, P = 0.03). Other than age and menopause, baseline bra cup size was the strongest predictor of breast cancer mortality, i.e., 57.9% risk increase per cup size when adjusted for MET-hours/wk and the other covariates (HR: 1.579, 95%CI: 1.268 to 1.966, P<0.0001), and 70.4% greater when further adjusted for BMI (HR: 1.704, 95%CI: 1.344 to 2.156, P = 10(-5)). Breast cancer mortality was 4.0-fold greater (HR: 3.980, 95%CI: 1.894 to 9.412, P = 0.0001) for C-cup, and 4.7-fold greater (HR: 4.668, 95%CI: 1.963 to 11.980, P = 0.0004) for >=D-cup vs. A-cup when adjusted for BMI and other covariates. Adjustment for cup size and BMI did not eliminate the association between breast cancer mortality and >=7.5 MET hour/wk walked or run (HR: 0.615, 95%CI: 0.389 to 1.004, P = 0.05). CONCLUSION: Breast cancer mortality decreased in association with both meeting the exercise recommendations and smaller breast volume. PMID- 24349007 TI - Performance of rapid point-of-care and laboratory tests for acute and established HIV infection in San Francisco. AB - BACKGROUND: Current laboratory and point-of-care tests for HIV detect different analytes and use different sample types. Some have fast turnaround times (<1 hour). We investigated how HIV test choice could impact case finding by testing programs. METHODS: We analyzed 21,234 consecutive HIV tests with venous blood obtained by San Francisco HIV testing programs from 2003 to 2008. For a subset, oral fluid (n = 6446) or fingerstick blood (n = 8127) samples were also obtained for rapid testing. In all cases, HIV status was determined using an HIV antibody plus-RNA test algorithm. We assessed how the screening antibody tests performed individually versus the gold standard of the full algorithm. We then evaluated the potential ability of other tests (including new tests) to detect more cases, by re-testing all specimens that had negative/discrepant antibody results on initial screening. FINDINGS: The antibody-RNA algorithm identified 58 acute and 703 established HIV infection cases. 1(st)-generation (Vironostika) and 3(rd) generation (Genetic Systems) immunoassays had 92 and 96 percent sensitivity, respectively. The Oraquick rapid test had clinical sensitivity of only 86 percent on oral fluid samples, but 92 percent on finger-stick blood. Newer 4(th) generation, antigen-antibody combo rapid immunoassay (ARCHITECT) detected HIV in 87 percent of all the acute cases that had been missed by one of the previous screening assays. A point-of-care 4(th) generation antigen-antibody combo rapid test (Determine) detected about 54 percent of such acute cases. CONCLUSIONS: Our study suggests that some rapid antibody blood tests will give similar case detection to laboratory antibody tests, but that oral fluid testing greatly reduces ability to detect HIV. New 4(th)-generation combo tests can detect the majority of acute infections detectable by HIV RNA but with rapid results. Using these tests as a primary screening assay in high-risk HIV testing programs could reduce or eliminate the need for HIV RNA testing. PMID- 24349008 TI - The alpha and Delta isoforms of CREB1 are required to maintain normal pulmonary vascular resistance. AB - Chronic hypoxia causes pulmonary hypertension associated with structural alterations in pulmonary vessels and sustained vasoconstriction. The transcriptional mechanisms responsible for these distinctive changes are unclear. We have previously reported that CREB1 is activated in the lung in response to alveolar hypoxia but not in other organs. To directly investigate the role of alpha and Delta isoforms of CREB1 in the regulation of pulmonary vascular resistance we examined the responses of mice in which these isoforms of CREB1 had been inactivated by gene mutation, leaving only the beta isoform intact (CREB(alphaDelta) mice). Here we report that expression of CREB regulated genes was altered in the lungs of CREB(alphaDelta) mice. CREB(alphaDelta) mice had greater pulmonary vascular resistance than wild types, both basally in normoxia and following exposure to hypoxic conditions for three weeks. There was no difference in rho kinase mediated vasoconstriction between CREB(alphaDelta) and wild type mice. Stereological analysis of pulmonary vascular structure showed characteristic wall thickening and lumen reduction in hypoxic wild-type mice, with similar changes observed in CREB(alphaDelta). CREB(alphaDelta) mice had larger lungs with reduced epithelial surface density suggesting increased pulmonary compliance. These findings show that alpha and Delta isoforms of CREB1 regulate homeostatic gene expression in the lung and that normal activity of these isoforms is essential to maintain low pulmonary vascular resistance in both normoxic and hypoxic conditions and to maintain the normal alveolar structure. Interventions that enhance the actions of alpha and Delta isoforms of CREB1 warrant further investigation in hypoxic lung diseases. PMID- 24349009 TI - Insulin protects apoptotic cardiomyocytes from hypoxia/reoxygenation injury through the sphingosine kinase/sphingosine 1-phosphate axis. AB - OBJECTIVE: Experimental and clinical studies have shown that administration of insulin during reperfusion is cardioprotective, but the mechanisms underlying this effect are still unknown. In this study, the ability of insulin to protect apoptotic cardiomyocytes from hypoxia/reoxygenation injury using the sphingosine kinase/sphingosine 1-phosphate axis was investigated. METHODS AND RESULTS: Rat cardiomyocytes were isolated and subjected to hypoxia and reoxygenation. [gamma 32P] ATP was used to assess sphingosine kinase activity. Insulin was found to increase sphingosine kinase activity. Immunocytochemistry and Western blot analysis showed changes in the subcellular location of sphingosine kinase 1 from cytosol to the membrane in cardiomyocytes. Insulin caused cardiomyocytes to accumulate of S1P in a dose-dependent manner. FRET efficiency showed that insulin also transactivates the S1P1 receptor. TUNEL staining showed that administration of insulin during reoxygenation could to reduce the rate of reoxygenation-induced apoptosis, which is a requirement for SphK 1 activity. It also reduced the rate of activation of the S1P receptor and inhibited hypoxia/reoxygenation-induced cell death in cardiomyocytes. CONCLUSION: The sphingosine kinase 1/sphingosine 1 phosphate/S1P receptor axis is one pathway through which insulin protects rat cardiomyocytes from apoptosis induced by hypoxia/reoxygenation injury. PMID- 24349010 TI - Predicting survival after liver transplantation based on pre-transplant MELD score: a systematic review of the literature. AB - The model for end-stage liver disease (MELD) score is used to stratify candidates for liver transplantation based on objective measures of disease severity. MELD has been validated as a predictor of wait-list mortality in transplantation candidates and has been postulated as a predictor of post-transplant survival. The purpose of this study was to examine the predictive value of the pre transplantation MELD score on post-transplant survival from relevant existing studies. A systematic review and critical appraisal was performed using Cochrane guidelines. PubMed, the Cochrane Library, Embase, and Web of Science were searched for articles published in the English language since 2005 using a structured search strategy. There were 3058 discrete citations identified and screened for possible inclusion. Any study examining the relationship between pre transplant MELD and post-transplant survival in the general transplant population was included. Thirty-seven studies met these criteria and were included in the review. Studies were all case series that typically involved stratified analyses of survival by MELD. They represented 15 countries and a total of 53,691 patients. There was significant clinical heterogeneity in patient populations across studies, which precluded performance of a meta-analysis. In 15 studies, no statistically significant association between MELD and post-transplant survival was found. In the remaining 22, some association was found. Eleven studies also measured predictive ability with c-statistics. Values were below 0.7 in all but two studies, suggesting poor predictive value. In summary, while the majority of studies reported an association between pre-transplantation MELD score and post transplant survival, they represented a low level of evidence. Therefore, their findings should be interpreted conservatively. PMID- 24349011 TI - Capsular types of Klebsiella pneumoniae revisited by wzc sequencing. AB - Capsule is an important virulence factor in bacteria. A total of 78 capsular types have been identified in Klebsiella pneumoniae. However, there are limitations in current typing methods. We report here the development of a new genotyping method based on amplification of the variable regions of the wzc gene. Fragments corresponding to the variable region of wzc were amplified and sequenced from 76 documented capsular types of reference or clinical strains. The remaining two capsular types (reference strains K15 and K50) lacked amplifiable wzc genes and were proven to be acapsular. Strains with the same capsular type exhibited ?94% DNA sequence identity across the variable region (CD1-VR2-CD2) of wzc. Strains with distinct K types exhibited <80% DNA sequence identity across this region, with the exception of three pairs of strains: K22/K37, K9/K45, and K52/K79. Strains K22 and K37 shared identical capsular polysaccharide synthesis (cps) genes except for one gene with a difference at a single base which resulted in frameshift mutation. The wzc sequences of K9 and K45 exhibited high DNA sequence similarity but possessed different genes in their cps clusters. K52 and K79 exhibited 89% wzc DNA sequence identity but were readily distinguished from each other at the DNA level; in contrast, strains with the same capsular type as K52 exhibited 100% wzc sequence identity. A total of 29 strains from patients with bacteremia were typed by the wzc system. wzc DNA sequences confirmed the documented capsular type for twenty-eight of these clinical isolates; the remaining strain likely represents a new capsular type. Thus, the wzc genotyping system is a simple and useful method for capsular typing of K. pneumoniae. PMID- 24349012 TI - TLR2 ligands induce NF-kappaB activation from endosomal compartments of human monocytes. AB - Localization of Toll-like receptors (TLR) in subcellular organelles is a major strategy to regulate innate immune responses. While TLR4, a cell-surface receptor, signals from both the plasma membrane and endosomal compartments, less is known about the functional role of endosomal trafficking upon TLR2 signaling. Here we show that the bacterial TLR2 ligands Pam3CSK4 and LTA activate NF-kappaB dependent signaling from endosomal compartments in human monocytes and in a NF kappaB sensitive reporter cell line, despite the expression of TLR2 at the cell surface. Further analyses indicate that TLR2-induced NF-kappaB activation is controlled by a clathrin/dynamin-dependent endocytosis mechanism, in which CD14 serves as an important upstream regulator. These findings establish that internalization of cell-surface TLR2 into endosomal compartments is required for NF-kappaB activation. These observations further demonstrate the need of endocytosis in the activation and regulation of TLR2-dependent signaling pathways. PMID- 24349013 TI - Long range linkage disequilibrium across the human genome. AB - Long-range linkage disequilibria (LRLD) between sites that are widely separated on chromosomes may suggest that population admixture, epistatic selection, or other evolutionary forces are at work. We quantified patterns of LRLD on a chromosome-wide level in the YRI population of the HapMap dataset of single nucleotide polymorphisms (SNPs). We calculated the disequilibrium between all pairs of SNPs on each chromosome (a total of >2*10(11) values) and evaluated significance of overall disequilibrium using randomization. The results show an excess of associations between pairs of distant sites (separated by >0.25 cM) on all of the 22 autosomes. We discuss possible explanations for this observation. PMID- 24349014 TI - Patients' & healthcare professionals' values regarding true- & false-positive diagnosis when colorectal cancer screening by CT colonography: discrete choice experiment. AB - PURPOSE: To establish the relative weighting given by patients and healthcare professionals to gains in diagnostic sensitivity versus loss of specificity when using CT colonography (CTC) for colorectal cancer screening. MATERIALS AND METHODS: Following ethical approval and informed consent, 75 patients and 50 healthcare professionals undertook a discrete choice experiment in which they chose between "standard" CTC and "enhanced" CTC that raised diagnostic sensitivity 10% for either cancer or polyps in exchange for varying levels of specificity. We established the relative increase in false-positive diagnoses participants traded for an increase in true-positive diagnoses. RESULTS: Data from 122 participants were analysed. There were 30 (25%) non-traders for the cancer scenario and 20 (16%) for the polyp scenario. For cancer, the 10% gain in sensitivity was traded up to a median 45% (IQR 25 to >85) drop in specificity, equating to 2250 (IQR 1250 to >4250) additional false-positives per additional true-positive cancer, at 0.2% prevalence. For polyps, the figure was 15% (IQR 7.5 to 55), equating to 6 (IQR 3 to 22) additional false-positives per additional true-positive polyp, at 25% prevalence. Tipping points were significantly higher for patients than professionals for both cancer (85 vs 25, p<0.001) and polyps (55 vs 15, p<0.001). Patients were willing to pay significantly more for increased sensitivity for cancer (p = 0.021). CONCLUSION: When screening for colorectal cancer, patients and professionals believe gains in true-positive diagnoses are worth much more than the negative consequences of a corresponding rise in false-positives. Evaluation of screening tests should account for this. PMID- 24349015 TI - Resource competition may lead to effective treatment of antibiotic resistant infections. AB - Drug resistance is a common problem in the fight against infectious diseases. Recent studies have shown conditions (which we call antiR) that select against resistant strains. However, no specific drug administration strategies based on this property exist yet. Here, we mathematically compare growth of resistant versus sensitive strains under different treatments (no drugs, antibiotic, and antiR), and show how a precisely timed combination of treatments may help defeat resistant strains. Our analysis is based on a previously developed model of infection and immunity in which a costly plasmid confers antibiotic resistance. As expected, antibiotic treatment increases the frequency of the resistant strain, while the plasmid cost causes a reduction of resistance in the absence of antibiotic selection. Our analysis suggests that this reduction occurs under competition for limited resources. Based on this model, we estimate treatment schedules that would lead to a complete elimination of both sensitive and resistant strains. In particular, we derive an analytical expression for the rate of resistance loss, and hence for the time necessary to turn a resistant infection into sensitive (tclear). This time depends on the experimentally measurable rates of pathogen division, growth and plasmid loss. Finally, we estimated tclear for a specific case, using available empirical data, and found that resistance may be lost up to 15 times faster under antiR treatment when compared to a no treatment regime. This strategy may be particularly suitable to treat chronic infection. Finally, our analysis suggests that accounting explicitly for a resistance-decaying rate may drastically change predicted outcomes in host-population models. PMID- 24349016 TI - Automated identification and location analysis of marked stem cells colonies in optical microscopy images. AB - Embryonic stem cells (ESCs) are characterized by two remarkable peculiarities: the capacity to propagate as undifferentiated cells (self-renewal) and the ability to differentiate in ectoderm, endoderm, and mesoderm derivatives (pluripotency). Although the majority of ESCs divide without losing the pluripotency, it has become evident that ESC cultures consists of multiple cell populations highlighted by the expression of early germ lineage markers during spontaneous differentiation. Hence, the identification and characterization of ESCs subpopulations represents an efficient approach to improve the comprehension of correlation between gene expression and cell specification status. To study markers of ESCs heterogeneity, we developed an analysis pipeline which can automatically process images of stem cell colonies in optical microscopy. The question we try to address is to find out the statistically significant preferred locations of the marked cells. We tested our algorithm on a set of images of stem cell colonies to analyze the expression pattern of the Zscan4 gene, which was an elite candidate gene to be studied because it is specifically expressed in subpopulation of ESCs. To validate the proposed method we analyzed the behavior of control genes whose pattern had been associated to biological status such as differentiation (EndoA), pluripotency (Pou5f1), and pluripotency fluctuation (Nanog). We found that Zscan4 is not uniformly expressed inside a stem cell colony, and that it tends to be expressed towards the center of the colony, moreover cells expressing Zscan4 cluster each other. This is of significant importance because it allows us to hypothesize a biological status where the cells expressing Zscan4 are preferably associated to the inner of colonies suggesting pluripotent cell status features, and the clustering between themselves suggests either a colony paracrine effect or an early phase of cell specification through proliferation. Also, the analysis on the control genes showed that they behave as expected. PMID- 24349017 TI - Forgiver triumphs in alternating Prisoner's Dilemma. AB - Cooperative behavior, where one individual incurs a cost to help another, is a wide spread phenomenon. Here we study direct reciprocity in the context of the alternating Prisoner's Dilemma. We consider all strategies that can be implemented by one and two-state automata. We calculate the payoff matrix of all pairwise encounters in the presence of noise. We explore deterministic selection dynamics with and without mutation. Using different error rates and payoff values, we observe convergence to a small number of distinct equilibria. Two of them are uncooperative strict Nash equilibria representing always-defect (ALLD) and Grim. The third equilibrium is mixed and represents a cooperative alliance of several strategies, dominated by a strategy which we call Forgiver. Forgiver cooperates whenever the opponent has cooperated; it defects once when the opponent has defected, but subsequently Forgiver attempts to re-establish cooperation even if the opponent has defected again. Forgiver is not an evolutionarily stable strategy, but the alliance, which it rules, is asymptotically stable. For a wide range of parameter values the most commonly observed outcome is convergence to the mixed equilibrium, dominated by Forgiver. Our results show that although forgiving might incur a short-term loss it can lead to a long-term gain. Forgiveness facilitates stable cooperation in the presence of exploitation and noise. PMID- 24349018 TI - The good, the bad, and the ugly: agonistic behaviour in juvenile crocodilians. AB - We examined agonistic behaviour in seven species of hatchling and juvenile crocodilians held in small groups (N = 4) under similar laboratory conditions. Agonistic interactions occurred in all seven species, typically involved two individuals, were short in duration (5-15 seconds), and occurred between 1600 2200 h in open water. The nature and extent of agonistic interactions, the behaviours displayed, and the level of conspecific tolerance varied among species. Discrete postures, non-contact and contact movements are described. Three of these were species-specific: push downs by C. johnstoni; inflated tail sweeping by C. novaeguineae; and, side head striking combined with tail wagging by C. porosus. The two long-snouted species (C. johnstoni and G. gangeticus) avoided contact involving the head and often raised the head up out of the way during agonistic interactions. Several behaviours not associated with aggression are also described, including snout rubbing, raising the head up high while at rest, and the use of vocalizations. The two most aggressive species (C. porosus, C. novaeguineae) appeared to form dominance hierarchies, whereas the less aggressive species did not. Interspecific differences in agonistic behaviour may reflect evolutionary divergence associated with morphology, ecology, general life history and responses to interspecific conflict in areas where multiple species have co-existed. Understanding species-specific traits in agonistic behaviour and social tolerance has implications for the controlled raising of different species of hatchlings for conservation, management or production purposes. PMID- 24349019 TI - Modulatory effects of spectral energy contrasts on lateral inhibition in the human auditory cortex: an MEG study. AB - We investigated the modulation of lateral inhibition in the human auditory cortex by means of magnetoencephalography (MEG). In the first experiment, five acoustic masking stimuli (MS), consisting of noise passing through a digital notch filter which was centered at 1 kHz, were presented. The spectral energy contrasts of four MS were modified systematically by either amplifying or attenuating the edge frequency bands around the notch (EFB) by 30 dB. Additionally, the width of EFB amplification/attenuation was varied (3/8 or 7/8 octave on each side of the notch). N1m and auditory steady state responses (ASSR), evoked by a test stimulus with a carrier frequency of 1 kHz, were evaluated. A consistent dependence of N1m responses upon the preceding MS was observed. The minimal N1m source strength was found in the narrowest amplified EFB condition, representing pronounced lateral inhibition of neurons with characteristic frequencies corresponding to the center frequency of the notch (NOTCH CF) in secondary auditory cortical areas. We tested in a second experiment whether an even narrower bandwidth of EFB amplification would result in further enhanced lateral inhibition of the NOTCH CF. Here three MS were presented, two of which were modified by amplifying 1/8 or 1/24 octave EFB width around the notch. We found that N1m responses were again significantly smaller in both amplified EFB conditions as compared to the NFN condition. To our knowledge, this is the first study demonstrating that the energy and width of the EFB around the notch modulate lateral inhibition in human secondary auditory cortical areas. Because it is assumed that chronic tinnitus is caused by a lack of lateral inhibition, these new insights could be used as a tool for further improvement of tinnitus treatments focusing on the lateral inhibition of neurons corresponding to the tinnitus frequency, such as the tailor-made notched music training. PMID- 24349021 TI - Analysis of the spatial organization of molecules with robust statistics. AB - One major question in molecular biology is whether the spatial distribution of observed molecules is random or organized in clusters. Indeed, this analysis gives information about molecules' interactions and physical interplay with their environment. The standard tool for analyzing molecules' distribution statistically is the Ripley's K function, which tests spatial randomness through the computation of its critical quantiles. However, quantiles' computation is very cumbersome, hindering its use. Here, we present an analytical expression of these quantiles, leading to a fast and robust statistical test, and we derive the characteristic clusters' size from the maxima of the Ripley's K function. Subsequently, we analyze the spatial organization of endocytic spots at the cell membrane and we report that clathrin spots are randomly distributed while clathrin-independent spots are organized in clusters with a radius of 2 MUm, which suggests distinct physical mechanisms and cellular functions for each pathway. PMID- 24349020 TI - Increased firing irregularity as an emergent property of neural-state transition in monkey prefrontal cortex. AB - Flexible behaviors are organized by complex neural networks in the prefrontal cortex. Recent studies have suggested that such networks exhibit multiple dynamical states, and can switch rapidly from one state to another. In many complex systems such as the brain, the early-warning signals that may predict whether a critical threshold for state transitions is approaching are extremely difficult to detect. We hypothesized that increases in firing irregularity are a crucial measure for predicting state transitions in the underlying neuronal circuits of the prefrontal cortex. We used both experimental and theoretical approaches to test this hypothesis. Experimentally, we analyzed activities of neurons in the prefrontal cortex while monkeys performed a maze task that required them to perform actions to reach a goal. We observed increased firing irregularity before the activity changed to encode goal-to-action information. Theoretically, we constructed theoretical generic neural networks and demonstrated that changes in neuronal gain on functional connectivity resulted in a loss of stability and an altered state of the networks, accompanied by increased firing irregularity. These results suggest that assessing the temporal pattern of neuronal fluctuations provides important clues regarding the state stability of the prefrontal network. We also introduce a novel scheme that the prefrontal cortex functions in a metastable state near the critical point of bifurcation. According to this scheme, firing irregularity in the prefrontal cortex indicates that the system is about to change its state and the flow of information in a flexible manner, which is essential for executive functions. This metastable and/or critical dynamical state of the prefrontal cortex may account for distractibility and loss of flexibility in the prefrontal cortex in major mental illnesses such as schizophrenia. PMID- 24349022 TI - Epoxy fatty acids and inhibition of the soluble epoxide hydrolase selectively modulate GABA mediated neurotransmission to delay onset of seizures. AB - In the brain, seizures lead to release of large amounts of polyunsaturated fatty acids including arachidonic acid (ARA). ARA is a substrate for three major enzymatic routes of metabolism by cyclooxygenase, lipoxygenase and cytochrome P450 enzymes. These enzymes convert ARA to potent lipid mediators including prostanoids, leukotrienes and epoxyeicosatrienoic acids (EETs). The prostanoids and leukotrienes are largely pro-inflammatory molecules that sensitize neurons whereas EETs are anti-inflammatory and reduce the excitability of neurons. Recent evidence suggests a GABA-related mode of action potentially mediated by neurosteroids. Here we tested this hypothesis using models of chemically induced seizures. The level of EETs in the brain was modulated by inhibiting the soluble epoxide hydrolase (sEH), the major enzyme that metabolizes EETs to inactive molecules, by genetic deletion of sEH and by direct administration of EETs into the brain. All three approaches delayed onset of seizures instigated by GABA antagonists but not seizures through other mechanisms. Inhibition of neurosteroid synthesis by finasteride partially blocked the anticonvulsant effects of sEH inhibitors while the efficacy of an inactive dose of neurosteroid allopregnanolone was enhanced by sEH inhibition. Consistent with earlier findings, levels of prostanoids in the brain were elevated. In contrast, levels of bioactive EpFAs were decreased following seizures. Overall these results demonstrate that EETs are natural molecules which suppress the tonic component of seizure related excitability through modulating the GABA activity and that exploration of the EET mediated signaling in the brain could yield alternative approaches to treat convulsive disorders. PMID- 24349023 TI - Ubiquitin-specific peptidase 5, a target molecule of vialinin A, is a key molecule of TNF-alpha production in RBL-2H3 cells. AB - Tumor necrosis factor alpha (TNF-alpha), a central mediator of the inflammatory response, is released from basophilic cells and other cells in response to a variety of proinflammatory stimuli. Vialinin A is a potent inhibitor of TNF-alpha production and is released from RBL-2H3 cells. Ubiquitin-specific peptidase 5 (USP5), a deubiquitinating enzyme, was identified as a target molecule of vialinin A and its enzymatic activity was inhibited by vialinin A. Here we report production of TNF-alpha is decreased in USP5 siRNA-knockdown RBL-2H3 cells, compared with control cells. The finding of the present study strongly suggests that USP5 is one of the essential molecules for the production of TNF-alpha in RBL-2H3. PMID- 24349024 TI - Lanternfish (Myctophidae) zoogeography off eastern Australia: a comparison with physicochemical biogeography. AB - In this first attempt to model the distributions of a mesopelagic fish family at this scale in the eastern Australian region (10 degrees S to 57 degrees S), lanternfish species occurrence data spanning a period from 1928 to 2010 were modelled against environmental covariates. This involved: (1) data collation and taxonomic quality checking, (2) classification of trawls into "horizontal" (presence-absence) and "oblique" (presence-only) types, and classification of vertical migration patterns using existing literature and the species occurrence database, (3) binomial GAMs using presence-absence data for representative temperate, subtropical and tropical species to examine depth interactions with environmental covariates and refine the selection of environmental layers for presence-only MAXENT models, (4) Presence-only MAXENT modelling using data from all trawls and the reduced environmental layers, and (5) Multivariate analysis (area-wise and species-wise) of the resulting matrix of logistic score by geographic pixel. We test the hypothesis that major fronts in the region (Tasman Front, Subtropical Convergence, Subantarctic Front) represent zoogeographic boundaries. A four-region zoogeographic scheme is hypothesised: Coral Sea region, Subtropical Lower Water region, Subtropical Convergence/South Tasman region and Subantarctic region. The Tasman Front, Subtropical Convergence and Subantarctic Front represented zoogeographic boundaries. An additional boundary at ~25 degrees S (coined the 'Capricorn' boundary) was adopted to delineate the Coral Sea from Subtropical Lower Water regions. Lanternfish zoogeographic regions are congruent with some aspects of two prevailing physicochemical biogeographic schema in the region, but neither of these schema alone accurately predicts lanternfish distributions. As lanternfishes integrate vertical ocean processes, the hypothesised lanternfish zoogeography may represent a useful model for a generalised pelagic biogeography that should be tested for other oceanic groups. PMID- 24349026 TI - Fluctuation analysis: can estimates be trusted? AB - The estimation of mutation rates and relative fitnesses in fluctuation analysis is based on the unrealistic hypothesis that the single-cell times to division are exponentially distributed. Using the classical Luria-Delbruck distribution outside its modelling hypotheses induces an important bias on the estimation of the relative fitness. The model is extended here to any division time distribution. Mutant counts follow a generalization of the Luria-Delbruck distribution, which depends on the mean number of mutations, the relative fitness of normal cells compared to mutants, and the division time distribution of mutant cells. Empirical probability generating function techniques yield precise estimates both of the mean number of mutations and the relative fitness of normal cells compared to mutants. In the case where no information is available on the division time distribution, it is shown that the estimation procedure using constant division times yields more reliable results. Numerical results both on observed and simulated data are reported. PMID- 24349025 TI - Family poverty affects the rate of human infant brain growth. AB - Living in poverty places children at very high risk for problems across a variety of domains, including schooling, behavioral regulation, and health. Aspects of cognitive functioning, such as information processing, may underlie these kinds of problems. How might poverty affect the brain functions underlying these cognitive processes? Here, we address this question by observing and analyzing repeated measures of brain development of young children between five months and four years of age from economically diverse backgrounds (n = 77). In doing so, we have the opportunity to observe changes in brain growth as children begin to experience the effects of poverty. These children underwent MRI scanning, with subjects completing between 1 and 7 scans longitudinally. Two hundred and three MRI scans were divided into different tissue types using a novel image processing algorithm specifically designed to analyze brain data from young infants. Total gray, white, and cerebral (summation of total gray and white matter) volumes were examined along with volumes of the frontal, parietal, temporal, and occipital lobes. Infants from low-income families had lower volumes of gray matter, tissue critical for processing of information and execution of actions. These differences were found for both the frontal and parietal lobes. No differences were detected in white matter, temporal lobe volumes, or occipital lobe volumes. In addition, differences in brain growth were found to vary with socioeconomic status (SES), with children from lower-income households having slower trajectories of growth during infancy and early childhood. Volumetric differences were associated with the emergence of disruptive behavioral problems. PMID- 24349028 TI - Oculomotor examination of the weapon focus effect: does a gun automatically engage visual attention? AB - BACKGROUND: A person is less likely to be accurately remembered if they appear in a visual scene with a gun, a result that has been termed the weapon focus effect (WFE). Explanations of the WFE argue that weapons engage attention because they are unusual and/or threatening, which causes encoding deficits for the other items in the visual scene. Previous WFE research has always embedded the weapon and nonweapon objects within a larger context that provides information about an actor's intention to use the object. As such, it is currently unknown whether a gun automatically engages attention to a greater extent than other objects independent of the context in which it is presented. METHOD: Reflexive responding to a gun compared to other objects was examined in two experiments. Experiment 1 employed a prosaccade gap-overlap paradigm, whereby participants looked toward a peripheral target, and Experiment 2 employed an antisaccade gap-overlap paradigm, whereby participants looked away from a peripheral target. In both experiments, the peripheral target was a gun or a nonthreatening object (i.e., a tomato or pocket watch). We also controlled how unexpected the targets were and compared saccadic reaction times across types of objects. RESULTS: A gun was not found to differentially engage attention compared to the unexpected object (i.e., a pocket watch). Some evidence was found (Experiment 2) that both the gun and the unexpected object engaged attention to a greater extent compared the expected object (i.e., a tomato). CONCLUSION: An image of a gun did not engage attention to a larger extent than images of other types of objects (i.e., a pocket watch or tomato). The results suggest that context may be an important determinant of WFE. The extent to which an object is threatening may depend on the larger context in which it is presented. PMID- 24349027 TI - In vivo pharmacological evaluations of novel olanzapine analogues in rats: a potential new avenue for the treatment of schizophrenia. AB - Olanzapine (Olz) is one of the most effective antipsychotic drugs commonly used for treating schizophrenia. Unfortunately, Olz administration is associated with severe weight gain and metabolic disturbances. Both patients and clinicians are highly interested in the development of new antipsychotics which are as effective as atypical antipsychotics but which have a lower propensity to induce metabolic side effects. In the present study, we examined two new derivatives of Olz; OlzEt (2-ethyl-4-(4'-methylpiperazin-1'-yl)-10Hbenzo[b]thieno[2,3-e][1,4]diazepine), and OlzHomo (2-ethyl-4-(4'-methyl-1',4'-diazepan-1'-yl)-10H-benzo[b]thieno[2,3-e] [1,4]diazepine), for their tendency to induce weight gain in rats. Weight gain and metabolic changes were measured in female Sprague Dawley rats. Animals were treated orally with Olz, OlzEt, OlzHomo (3 or 6 mg/kg/day), or vehicle (n = 8), three times daily at eight-hour intervals for 5 weeks. Furthermore, a phencyclidine (PCP)-treated rat model was used to examine the prevention of PCP induced hyperlocomotor activity relevant for schizophrenia therapy. Male Sprague Dawley rats were pre-treated with a single dose (3 mg/kg/day) of Olz, OlzEt, OlzHomo, or vehicle (n = 12), for 2 weeks. Locomotor activity was recorded following a subcutaneous injection with either saline or PCP (10 mg/kg). Olz was found to induce weight gain, hyperphagia, visceral fat accumulation, and metabolic changes associated with reduced histamatergic H1 receptor density in the hypothalamus of treated rats. In contrast, OlzEt and OlzHomo presented promising antipsychotic effects, which did not induce weight gain or fat deposition in the treated animals. Behavioural analysis showed OlzEt to attenuate PCP-induced hyperactivity to a level similar to that of Olz; however, OlzHomo showed a lower propensity to inhibit these stereotyped behaviours. Our data suggest that the therapeutic effectiveness of OlzHomo may be delivered at a higher dose than that of Olz and OlzEt. Overall, OlzEt and OlzHomo may offer a better pharmacological profile than Olz for treating patients with schizophrenia. Clinical trials are needed to test this hypothesis. PMID- 24349029 TI - Optimal caliper width for propensity score matching of three treatment groups: a Monte Carlo study. AB - Propensity score matching is a method to reduce bias in non-randomized and observational studies. Propensity score matching is mainly applied to two treatment groups rather than multiple treatment groups, because some key issues affecting its application to multiple treatment groups remain unsolved, such as the matching distance, the assessment of balance in baseline variables, and the choice of optimal caliper width. The primary objective of this study was to compare propensity score matching methods using different calipers and to choose the optimal caliper width for use with three treatment groups. The authors used caliper widths from 0.1 to 0.8 of the pooled standard deviation of the logit of the propensity score, in increments of 0.1. The balance in baseline variables was assessed by standardized difference. The matching ratio, relative bias, and mean squared error (MSE) of the estimate between groups in different propensity score matched samples were also reported. The results of Monte Carlo simulations indicate that matching using a caliper width of 0.2 of the pooled standard deviation of the logit of the propensity score affords superior performance in the estimation of treatment effects. This study provides practical solutions for the application of propensity score matching of three treatment groups. PMID- 24349030 TI - A genetic deconstruction of neurocognitive traits in schizophrenia and bipolar disorder. AB - BACKGROUND: Impairments in cognitive functions are common in patients suffering from psychiatric disorders, such as schizophrenia and bipolar disorder. Cognitive traits have been proposed as useful for understanding the biological and genetic mechanisms implicated in cognitive function in healthy individuals and in the dysfunction observed in psychiatric disorders. METHODS: Sets of genes associated with a range of cognitive functions often impaired in schizophrenia and bipolar disorder were generated from a genome-wide association study (GWAS) on a sample comprising 670 healthy Norwegian adults who were phenotyped for a broad battery of cognitive tests. These gene sets were then tested for enrichment of association in GWASs of schizophrenia and bipolar disorder. The GWAS data was derived from three independent single-centre schizophrenia samples, three independent single-centre bipolar disorder samples, and the multi-centre schizophrenia and bipolar disorder samples from the Psychiatric Genomics Consortium. RESULTS: The strongest enrichments were observed for visuospatial attention and verbal abilities sets in bipolar disorder. Delayed verbal memory was also enriched in one sample of bipolar disorder. For schizophrenia, the strongest evidence of enrichment was observed for the sets of genes associated with performance in a colour-word interference test and for sets associated with memory learning slope. CONCLUSIONS: Our results are consistent with the increasing evidence that cognitive functions share genetic factors with schizophrenia and bipolar disorder. Our data provides evidence that genetic studies using polygenic and pleiotropic models can be used to link specific cognitive functions with psychiatric disorders. PMID- 24349031 TI - Immunization of Chlamydia pneumoniae (Cpn)-infected Apob(tm2Sgy)Ldlr(tm1Her)/J mice with a combined peptide of Cpn significantly reduces atherosclerotic lesion development. AB - OBJECTIVE: To investigate the antigenic effect of a peptide containing two epitopes of Chlamydia pneumoniae (Cpn) on atherosclerotic lesion formation in mice infected with Cpn. MATERIALS AND METHODS: Six-week-old Apob(tm2Sgy)Ldlr(tm1Her)/J mice were immunized using a repetitive immunization multiple-sites strategy with KLH-conjugated peptides derived from the major outer membrane protein and the putative outer membrane protein 5 of Cpn. Mice were fed a high-fat diet and infected with Cpn twice during the 10-week diet period. Lesions were evaluated histologically; local and systemic immune responses were analyzed by immunohistochemistry of aorta samples and cytokine measurements in plasma samples and splenocyte supernatants. RESULTS: Mice immunized with the combined Cpn peptide showed a greater reduction in lesion size compared to mice immunized with either epitope alone [54.7% vs 39.8% or 41.72%] and was also associated with a significant decrease in lesion area in descending aortas compared with those in controls (88.9% for combined Cpn peptide, 81.9% for MOMP peptide and 75.7% for Omp5, respectively). This effect was associated with a shift in the cellular composition of plaques towards decreased inflammatory cell and increased regulatory T-cell content. Additionally, the effect was also connected with decreased secretion of proinflammatory cytokines and increased production of anti-inflammatory cytokines demonstrated in plasma and in supernatant on stimulated spleen cells. CONCLUSIONS: Atherosclerotic lesion formation may be promoted by Cpn infection in the presence of a high-fat diet, and reduced by immunization with the combined Cpn peptide. The combined peptide has more potential than either epitope alone in reducing atherosclerotic lesion development through Treg expansion. PMID- 24349032 TI - Structure of a highly conserved domain of Rock1 required for Shroom-mediated regulation of cell morphology. AB - Rho-associated coiled coil containing protein kinase (Rho-kinase or Rock) is a well-defined determinant of actin organization and dynamics in most animal cells characterized to date. One of the primary effectors of Rock is non-muscle myosin II. Activation of Rock results in increased contractility of myosin II and subsequent changes in actin architecture and cell morphology. The regulation of Rock is thought to occur via autoinhibition of the kinase domain via intramolecular interactions between the N-terminus and the C-terminus of the kinase. This autoinhibited state can be relieved via proteolytic cleavage, binding of lipids to a Pleckstrin Homology domain near the C-terminus, or binding of GTP-bound RhoA to the central coiled-coil region of Rock. Recent work has identified the Shroom family of proteins as an additional regulator of Rock either at the level of cellular distribution or catalytic activity or both. The Shroom-Rock complex is conserved in most animals and is essential for the formation of the neural tube, eye, and gut in vertebrates. To address the mechanism by which Shroom and Rock interact, we have solved the structure of the coiled-coil region of Rock that binds to Shroom proteins. Consistent with other observations, the Shroom binding domain is a parallel coiled-coil dimer. Using biochemical approaches, we have identified a large patch of residues that contribute to Shrm binding. Their orientation suggests that there may be two independent Shrm binding sites on opposing faces of the coiled-coil region of Rock. Finally, we show that the binding surface is essential for Rock colocalization with Shroom and for Shroom-mediated changes in cell morphology. PMID- 24349034 TI - Patterns of Saccharina latissima recruitment. AB - The lack of recovery in Norwegian populations of the kelp Saccharina latissima (Linnaeus) C. E. Lane, C. Mayes, Druehl & G. W. Saunders after a large-scale disturbance that occurred sometime between the late 1990s and early 2000s has raised considerable concerns. Kelp forests are areas of high production that serve as habitats for numerous species, and their continued absence may represent the loss of an entire ecosystem. Some S. latissima populations remain as scattered patches within the affected areas, but today, most of the areas are completely devoid of kelp. The question is if natural recolonization by kelp and the reestablishment of the associated ecosystem is possible. Previous studies indicate that a high degree of reproductive synchrony in macrophytes has a positive effect on their potential for dispersal and on the connectivity between populations, but little is known about the patterns of recruitment in Norwegian S. latissima. More is, however, known about the development of fertile tissue (sori) on adult individuals, which is easily observed. The present study investigated the degree of coupling between the appearance of sori and the recruitment on clean artificial substrate beneath adult specimens. The pattern of recruitment was linked to the retreat of visible sori (i.e. spore release) and a seasonal component unrelated to the fertility of the adults. The formation and the retreat of visible sori are processes that seem synchronized along the south coast of Norway, and the link between sori development and recruitment may therefore suggest that the potential for S. latissima dispersal is relatively large. These results support the notion that the production and dispersal of viable spores is unlikely to be the bottleneck preventing recolonization in the south of Norway, but studies over larger temporal and spatial scales are still needed to confirm this hypothesis. PMID- 24349033 TI - Screening and identification of six serum microRNAs as novel potential combination biomarkers for pulmonary tuberculosis diagnosis. AB - BACKGROUND: It is very difficult to prevent pulmonary tuberculosis (TB) due to the lack of specific and diagnostic markers, which could lead to a high incidence of pulmonary TB. We screened the differentially expressed serum microRNAs (miRNAs) as potential biomarkers for the diagnosis of pulmonary TB. METHODS: In this study, serum miRNAs were screened using the Solexa sequencing method as the potential biomarkers for the diagnosis of pulmonary TB. The stem-loop quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assay was used to verify differentially expressed serum miRNAs. The receiver operating characteristic (ROC) curve and logistic regression model were used to analyze the sensitivity and specificity of the single miRNA and a combination of miRNAs for diagnosis, respectively. Using the predicted target genes, we constructed the regulatory networks of miRNAs and genes that were related to pulmonary TB. RESULTS: The Solexa sequencing data showed that 91 serum miRNAs were differentially expressed in pulmonary TB patients, compared to healthy controls. Following qRT-PCR confirmation, six serum miRNAs (hsa-miR-378, hsa-miR-483-5p, hsa-miR-22, hsa-miR-29c, hsa-miR-101 and hsa-miR-320b) showed significant difference among pulmonary TB patients, healthy controls (P<0.001) and differential diagnosis groups (including patients with pneumonia, lung cancer and chronic obstructive pulmonary disease) (P<0.05). The logistic regression analysis of a combination of six serum miRNAs revealed that the sensitivity and the specificity of TB diagnosis were 95.0% and 91.8% respectively. The miRNAs-gene regulatory networks revealed that several miRNAs may regulate some target genes involved in immune pathways and participate in the pathogenesis of pulmonary TB. CONCLUSION: Our study suggests that a combination of six serum miRNAs have great potential to serve as non-invasive biomarkers of pulmonary TB. PMID- 24349035 TI - Predicting protein-protein interaction by the mirrortree method: possibilities and limitations. AB - Molecular co-evolution analysis as a sequence-only based method has been used to predict protein-protein interactions. In co-evolution analysis, Pearson's correlation within the mirrortree method is a well-known way of quantifying the correlation between protein pairs. Here we studied the mirrortree method on both known interacting protein pairs and sets of presumed non-interacting protein pairs, to evaluate the utility of this correlation analysis method for predicting protein-protein interactions within eukaryotes. We varied metrics for computing evolutionary distance and evolutionary span of the species analyzed. We found the differences between co-evolutionary correlation scores of the interacting and non interacting proteins, normalized for evolutionary span, to be significantly predictive for proteins conserved over a wide range of eukaryotic clades (from mammals to fungi). On the other hand, for narrower ranges of evolutionary span, the predictive power was much weaker. PMID- 24349036 TI - Unhealthy days and quality of life in Irish patients with diabetes. AB - OBJECTIVES: To study the determinants of health-related quality of life (HRQoL) in Irish patients with diabetes using the Centres for Disease Controls' (CDC's) 'Unhealthy Days' summary measure and to assesses the agreement between this generic HRQoL measure and the disease-specific Audit of Diabetes Dependant Quality of Life (ADDQoL) measure. RESEARCH DESIGN AND METHODS: Data were analysed from the Diabetes Quality of Life Study, a cross-sectional study of 1,456 people with diabetes in Ireland (71% response rate). Unhealthy days were assessed using the CDC's 'Unhealthy days' summary measure. Quality of life (QoL) was also assessed using the ADDQoL measure. Analyses were conducted primarily using logistic regression. The agreement between the two QoL instruments was measured using the kappa co-efficient. RESULTS: Participants reported a median of 2 unhealthy days per month. In multivariate analyses, female gender (P = 0.001), insulin use (P = 0.030), diabetes complications (P = <0.001) were significantly associated with more unhealthy days. Older patients had fewer unhealthy days per month (P = 0.003). Agreement between the two measures of QoL (unhealthy days measure and ADDQoL) was poor, Kappa = 0.234. CONCLUSIONS: The findings highlight the determinants of HRQoL in patients with diabetes using a generic HRQoL summary measure. The 'Unhealthy Days' and the ADDQoL have poor agreement, therefore the 'Unhealthy Days' summary measure may be assessing a different construct. Nonetheless, this study demonstrates that the generic 'Unhealthy Days' summary measure can be used to detect determinants of HRQoL in patients with diabetes. PMID- 24349037 TI - Curcumin intake affects miRNA signature in murine melanoma with mmu-miR-205-5p most significantly altered. AB - Melanoma is the most aggressive form of skin cancer with estimated 48,000 deaths per year worldwide. The polyphenol curcumin derived from the plant Curcuma longa is well known for its anti-inflammatory and anti-cancerogenic properties. Accordingly, dietary intake of this compound may be suitable for melanoma prevention. However, how this compound affects basic cellular mechanisms in developing melanoma still remains elusive. Therefore, the aim of this study was to investigate for the first time the impact of oral curcumin administration on the miRNA signature of engrafting melanoma. For this purpose, the effects of a 4% curcumin diet were tested on melanoma, which were established by injection of murine B78H1 cells in the flank of C57BL/6 mice. Curcumin diet or standard chow (control) was administered two weeks prior to injection of tumor cells until termination of the experiment. High throughput chip-based array analysis was deployed to detect alterations in the miRNA signature of the tumors. Curcumin treatment significantly reduced the growth of the flank tumors. Furthermore the miRNA expression signature in tumors was substantially altered by curcumin intake with mmu-miR-205-5p over 100 times higher expressed when compared to controls. The expression levels of identified key miRNAs in the tumor samples were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). A comparable expression pattern of these miRNAs was also detected in other curcumin treated melanoma cell lines under in vitro conditions. Putative targets of curcumin-induced up-regulated miRNAs were enriched in 'o-glycan biosynthesis', 'endoplasmatic reticulum protein processing' and different cancer-related pathways. Western Blot analyses revealed that of these targets anti-apoptotic B cell CLL/lymphoma 2 (Bcl-2) and proliferating cell nuclear antigen (PCNA) were significantly down-regulated in curcumin-treated tumors. These findings demonstrate a profound alteration of the miRNA expression signature in engrafting curcumin-treated melanoma with mmu-miR-205-5p being up-regulated most significantly. PMID- 24349038 TI - CT morphometric analysis to determine the anatomical basis for the use of transpedicular screws during reconstruction and fixations of anterior cervical vertebrae. AB - BACKGROUND: Accurate placement of pedicle screw during Anterior Transpedicular Screw fixation (ATPS) in cervical spine depends on accurate anatomical knowledge of the vertebrae. However, little is known of the morphometric characteristics of cervical vertebrae in Chinese population. METHODS: Three-dimensional reconstructions of CT images were performed for 80 cases. The anatomic data and screw fixation parameters for ATPS fixation were measured using the Mimics software. FINDINGS: The overall mean OPW, OPH and PAL ranged from 5.81 to 7.49 mm, 7.77 to 8.69 mm, and 33.40 to 31.13 mm separately, and SPA was 93.54 to 109.36 degrees from C3 to C6, 104.99 degrees at C7, whereas, 49.00 to 32.26 degrees from C4 to C7, 46.79 degrees at C3 (TPA). Dl/rSIP had an increasing trend away from upper endplate with mean value from 1.87 to 5.83 mm. Dl/rTIP was located at the lateral portion of the anterior cortex of vertebrae for C3 to C5 and ipsilateral for C6 to C7 with mean value from -2.70 to -3.00 mm, and 0.17 to 3.18 mm. The entrance points for pedicular screw insertion for C3 to C5 and C6 to C7 were recommended -2~-3 mm and 0-4 mm from the median sagittal plane, respectively, 1-4 mm and 5-6 mm from the upper endplate, with TPA being 46.79 49.00 degrees and 40.89-32.26 degrees, respectively, and SPA being 93.54-106.69 degrees and 109.36-104.99 degrees, respectively. The pedicle screw insertion diameter was recommended 3.5 mm (C3 and C4), 4.0 mm (C5 to C7), and the pedicle axial length was 21-24 mm for C3 to C7 for both genders. However, the ATPS insertion in C3 should be individualized given its relatively small anatomical dimensions. CONCLUSIONS: The data provided a morphometric basis for the ATPS fixation technique in lower cervical fixation. It will help in preoperative planning and execution of this surgery. PMID- 24349039 TI - Tumor versus stromal cells in culture--survival of the fittest? AB - Two of the signature genetic events that occur in human gliomas, EGFR amplification and IDH mutation, are poorly represented in experimental models in vitro. EGFR amplification, for example, occurs in 40 to 50% of GBM, and yet, EGFR amplification is rarely preserved in cell cultures derived from human tumors. To analyze the fate of EGFR amplified and IDH mutated cells in culture, we followed the development over time of cultures derived from human xenografts in nude rats enriched for tumor cells with EGFR amplification and of cultures derived from patient samples with IDH mutations, in serum monolayer and spheroid suspension culture, under serum and serum free conditions. We observed under serum monolayer conditions, that nestin positive or nestin and SMA double positive rat stromal cells outgrew EGFR amplified tumor cells, while serum spheroid cultures preserved tumor cells with EGFR amplification. Serum free suspension culture exhibited a more variable cell composition in that the resultant cell populations were either predominantly nestin/SOX2 co-expressing rat stromal cells or human tumor cells, or a mixture of both. The selection for nestin/SMA positive stromal cells under serum monolayer conditions was also consistently observed in human oligodendrogliomas and oligoastrocytomas with IDH mutations. Our results highlight for the first time that serum monolayer conditions can select for stromal cells instead of tumor cells in certain brain tumor subtypes. This result has an important impact on the establishment of new tumor cell cultures from brain tumors and raises the question of the proper conditions for the growth of the tumor cell populations of interest. PMID- 24349040 TI - Complex variation in measures of general intelligence and cognitive change. AB - Combining information from multiple SNPs may capture a greater amount of genetic variation than from the sum of individual SNP effects and help identifying missing heritability. Regions may capture variation from multiple common variants of small effect, multiple rare variants or a combination of both. We describe regional heritability mapping of human cognition. Measures of crystallised (gc) and fluid intelligence (gf) in late adulthood (64-79 years) were available for 1806 individuals genotyped for 549,692 autosomal single nucleotide polymorphisms (SNPs). The same individuals were tested at age 11, enabling us the rare opportunity to measure cognitive change across most of their lifespan. 547,750 SNPs ranked by position are divided into 10, 908 overlapping regions of 101 SNPs to estimate the genetic variance each region explains, an approach that resembles classical linkage methods. We also estimate the genetic variation explained by individual autosomes and by SNPs within genes. Empirical significance thresholds are estimated separately for each trait from whole genome scans of 500 permutated data sets. The 5% significance threshold for the likelihood ratio test of a single region ranged from 17-17.5 for the three traits. This is the equivalent to nominal significance under the expectation of a chi-squared distribution (between 1 df and 0) of P<1.44*10(-5). These thresholds indicate that the distribution of the likelihood ratio test from this type of variance component analysis should be estimated empirically. Furthermore, we show that estimates of variation explained by these regions can be grossly overestimated. After applying permutation thresholds, a region for gf on chromosome 5 spanning the PRRC1 gene is significant at a genome-wide 10% empirical threshold. Analysis of gene methylation on the temporal cortex provides support for the association of PRRC1 and fluid intelligence (P = 0.004), and provides a prime candidate gene for high throughput sequencing of these uniquely informative cohorts. PMID- 24349041 TI - The three subtypes of tick-borne encephalitis virus induce encephalitis in a natural host, the bank vole (Myodes glareolus). AB - Tick-borne encephalitis virus (TBEV) infects bank voles (Myodes glareolus) in nature, but the relevance of rodents for TBEV transmission and maintenance is unclear. We infected colonized bank voles subcutaneously to study and compare the infection kinetics, acute infection, and potential viral persistence of the three known TBEV subtypes: European (TBEV-Eur), Siberian (TBEV-Sib) and Far Eastern (TBEV-FE). All strains representing the three subtypes were infective and highly neurotropic. They induced (meningo)encephalitis in some of the animals, however most of the cases did not present with apparent clinical symptoms. TBEV-RNA was cleared significantly slower from the brain as compared to other organs studied. Supporting our earlier findings in natural rodent populations, TBEV-RNA could be detected in the brain for up to 168 days post infection, but we could not demonstrate infectivity by cell culture isolation. Throughout all time points post infection, RNA of the TBEV-FE was detected significantly more often than RNA of the other two strains in all organs studied. TBEV-FE also induced prolonged viremia, indicating distinctive kinetics in rodents in comparison to the other two subtypes. This study shows that bank voles can develop a neuroinvasive TBEV infection with persistence of viral RNA in brain, and mount an anti-TBEV IgG response. The findings also provide further evidence that bank voles can serve as sentinels for TBEV endemicity. PMID- 24349042 TI - Norisoboldine suppresses VEGF-induced endothelial cell migration via the cAMP-PKA NF-kappaB/Notch1 pathway. AB - The migration of endothelial cells has been regarded as a potential target for the treatment of angiogenesis-related diseases. Previously, we demonstrated that norisoboldine (NOR), an alkaloid compound isolated from Radix Linderae, can significantly suppress synovial angiogenesis by selectively inhibiting endothelial cell migration. In this study, we evaluated the importance of various pathways in VEGF-induced endothelial cell migration using specific inhibitor. VEGF-induced endothelial cell migration and sprouting were significantly inhibited by H-89 (an inhibitor of protein kinase A (PKA)) but not by inhibitors of other pathways. NOR markedly suppressed VEGF-induced intracytoplasmic cAMP production and PKA activation and thereby down-regulated the activation of downstream components of the PKA pathway, including enzymes (src, VASP and eNOS) and the transcription factor NF-kappaB. Moreover, the transcription activation potential of NF-kappaB, which is related to IkappaBalpha phosphorylation and the disruption of the p65/IkappaBalpha complex, was reduced by NOR. Meanwhile, NOR selectively inhibited the expression of p-p65 (ser276) but not p-p65 (ser536) or PKAc, indicating that PKAc participates in the regulation of NF-kappaB by NOR. Co immunoprecipitation and immunofluorescence assays confirmed that NOR inhibited the formation of the PKAc/p65 complex and thereby decreased p65 (ser276) phosphorylation to prevent p65 binding to DNA. Docking models indicated that the affinity of NOR for PKA was higher than that of the original PKA ligand. Moreover, the fact that H-89 improved Notch1 activation, but DAPT (an inhibitor of Notch) failed to affect PKA activation, suggested that PKA may act on upstream of Notch1. In conclusion, the inhibitory effects of NOR on endothelial cell migration can be attributed to its modulation of the PKA pathway, especially on the processes of p65/IkappaBalpha complex disruption and PKAc/p65 complex formation. These results suggest that NOR inhibit VEGF-induced endothelial cell migration via a cAMP-PKA-NF-kappaB/Notch1 signaling pathway. PMID- 24349043 TI - Nifedipine treatment reduces resting calcium concentration, oxidative and apoptotic gene expression, and improves muscle function in dystrophic mdx mice. AB - Duchenne Muscular Dystrophy (DMD) is a recessive X-linked genetic disease, caused by mutations in the gene encoding dystrophin. DMD is characterized in humans and in mdx mice by a severe and progressive destruction of muscle fibers, inflammation, oxidative/nitrosative stress, and cell death. In mdx muscle fibers, we have shown that basal ATP release is increased and that extracellular ATP stimulation is pro-apoptotic. In normal fibers, depolarization-induced ATP release is blocked by nifedipine, leading us to study the potential therapeutic effect of nifedipine in mdx muscles and its relation with extracellular ATP signaling. Acute exposure to nifedipine (10 uM) decreased [Ca(2+)]r, NF-kappaB activity and iNOS expression in mdx myotubes. In addition, 6-week-old mdx mice were treated with daily intraperitoneal injections of nifedipine, 1 mg/Kg for 1 week. This treatment lowered the [Ca(2+)]r measured in vivo in the mdx vastus lateralis. We demonstrated that extracellular ATP levels were higher in adult mdx flexor digitorum brevis (FDB) fibers and can be significantly reduced after 1 week of treatment with nifedipine. Interestingly, acute treatment of mdx FDB fibers with apyrase, an enzyme that completely degrades extracellular ATP to AMP, reduced [Ca(2+)]r to a similar extent as was seen in FDB fibers after 1-week of nifedipine treatment. Moreover, we demonstrated that nifedipine treatment reduced mRNA levels of pro-oxidative/nitrosative (iNOS and gp91(phox)/p47(phox) NOX2 subunits) and pro-apoptotic (Bax) genes in mdx diaphragm muscles and lowered serum creatine kinase (CK) levels. In addition, nifedipine treatment increased muscle strength assessed by the inverted grip-hanging test and exercise tolerance measured with forced swimming test in mdx mice. We hypothesize that nifedipine reduces basal ATP release, thereby decreasing purinergic receptor activation, which in turn reduces [Ca(2+)]r in mdx skeletal muscle cells. The results in this work open new perspectives towards possible targets for pharmacological approaches to treat DMD. PMID- 24349044 TI - Second language as an exemptor from sociocultural norms. Emotion-Related Language Choice revisited. AB - Bilinguals often switch languages depending on what they are saying. According to the Emotion-Related Language Choice theory, they find their second language an easier medium of conveying content which evokes strong emotions. The first language carries too much emotional power, which can be threatening for the speaker. In a covert experiment, bilingual Polish students translated texts brimming with expletives from Polish into English and vice versa. In the Polish translations, the swear word equivalents used were weaker than in the source text; in the English translations, they were stronger than in the original. These results corroborate the ERLC theory. However, the effect was only observed for ethnophaulisms, i.e. expletives directed at social groups. It turns out that the main factor triggering the language choice in bilinguals is not necessarily the different emotional power of both languages, but social and cultural norms. PMID- 24349045 TI - Indigenous burning as conservation practice: neotropical savanna recovery amid agribusiness deforestation in Central Brazil. AB - International efforts to address climate change by reducing tropical deforestation increasingly rely on indigenous reserves as conservation units and indigenous peoples as strategic partners. Considered win-win situations where global conservation measures also contribute to cultural preservation, such alliances also frame indigenous peoples in diverse ecological settings with the responsibility to offset global carbon budgets through fire suppression based on the presumed positive value of non-alteration of tropical landscapes. Anthropogenic fire associated with indigenous ceremonial and collective hunting practices in the Neotropical savannas (cerrado) of Central Brazil is routinely represented in public and scientific conservation discourse as a cause of deforestation and increased CO2 emissions despite a lack of supporting evidence. We evaluate this claim for the Xavante people of Pimentel Barbosa Indigenous Reserve, Brazil. Building upon 23 years of longitudinal interdisciplinary research in the area, we used multi-temporal spatial analyses to compare land cover change under indigenous and agribusiness management over the last four decades (1973-2010) and quantify the contemporary Xavante burning regime contributing to observed patterns based on a four year sample at the end of this sequence (2007-2010). The overall proportion of deforested land remained stable inside the reserve (0.6%) but increased sharply outside (1.5% to 26.0%). Vegetation recovery occurred where reserve boundary adjustments transferred lands previously deforested by agribusiness to indigenous management. Periodic traditional burning by the Xavante had a large spatial distribution but repeated burning in consecutive years was restricted. Our results suggest a need to reassess overreaching conservation narratives about the purported destructiveness of indigenous anthropogenic fire in the cerrado. The real challenge to conservation in the fire-adapted cerrado biome is the long-term sustainability of indigenous lands and other tropical conservation islands increasingly subsumed by agribusiness expansion rather than the localized subsistence practices of indigenous and other traditional peoples. PMID- 24349047 TI - Mother knows best: occurrence and associations of resighted humpback whales suggest maternally derived fidelity to a Southern Hemisphere coastal feeding ground. AB - Site fidelity is common among migratory cetaceans, including humpback whales (Megaptera novaeangliae). In the Northern Hemisphere it has been found that fidelity to humpback whale feeding grounds is transferred maternally but this has never been shown for the species in the Southern Hemisphere. We examined this in a unique feeding area off west South Africa using resighting data of 68 individually identified humpback whales by means of photographic (tail flukes and dorsal fins) and/or molecular methods (microsatellite genotyping) over an 18 year span. We found short-term association patterns and recurrent visits typical of other feeding grounds. Males and females had different seasonality of attendance. Significant female-dominated presence corresponded to timing of an expected influx of females on their southward migration from the breeding ground: firstly non-nursing (possibly pregnant) females in mid-spring, and mothers and calves in mid-to late summer. The potential benefit of this mid-latitude feeding area for females is illustrated by a record of a cow with known age of at least 23 years that produced calves in three consecutive years, each of which survived to at least six months of age: the first record of successful post-partum ovulation for this species in the Southern Hemisphere. We recorded association of a weaned calf with its mother, and a recurring association between a non-lactating female and male over more than two years. Moreover, three animals first identified as calves returned to the same area in subsequent years, sometimes on the same day as their mothers. This, together with numerous Parent-Offspring relations detected genetically among and between resighted and non-resighted whales is strongly suggestive of maternally derived site fidelity at a small spatial scale by a small sub-population of humpback whales. PMID- 24349046 TI - Synthesis of lipid mediators during UVB-induced inflammatory hyperalgesia in rats and mice. AB - Peripheral sensitization during inflammatory pain is mediated by a variety of endogenous proalgesic mediators including a number of oxidized lipids, some of which serve endogenous modulators of sensory TRP-channels. These lipids are eicosanoids of the arachidonic acid and linoleic acid pathway, as well as lysophophatidic acids (LPAs). However, their regulation pattern during inflammatory pain and their contribution to peripheral sensitization is still unclear. Here, we used the UVB-model for inflammatory pain to investigate alterations of lipid concentrations at the site of inflammation, the dorsal root ganglia (DRGs) as well as the spinal dorsal horn and quantified 21 lipid species from five different lipid families at the peak of inflammation 48 hours post irradiation. We found that known proinflammatory lipids as well as lipids with unknown roles in inflammatory pain to be strongly increased in the skin, whereas surprisingly little changes of lipid levels were seen in DRGs or the dorsal horn. Importantly, although there are profound differences between the number of cytochrome (CYP) genes between mice and rats, CYP-derived lipids were regulated similarly in both species. Since TRPV1 agonists such as LPA 18?1, 9- and 13-HODE, 5- and 12-HETE were elevated in the skin, they may contribute to thermal hyperalgesia and mechanical allodynia during UVB-induced inflammatory pain. These results may explain why some studies show relatively weak analgesic effects of cyclooxygenase inhibitors in UVB-induced skin inflammation, as they do not inhibit synthesis of other proalgesic lipids such as LPA 18?1, 9-and 13-HODE and HETEs. PMID- 24349048 TI - Aphotic N2 fixation in the Eastern Tropical South Pacific Ocean. AB - We examined rates of N2 fixation from the surface to 2000 m depth in the Eastern Tropical South Pacific (ETSP) during El Nino (2010) and La Nina (2011). Replicated vertical profiles performed under oxygen-free conditions show that N2 fixation takes place both in euphotic and aphotic waters, with rates reaching 155 to 509 umol N m(-2) d(-1) in 2010 and 24+/-14 to 118+/-87 umol N m(-2) d(-1) in 2011. In the aphotic layers, volumetric N2 fixation rates were relatively low (<1.00 nmol N L(-1) d(-1)), but when integrated over the whole aphotic layer, they accounted for 87-90% of total rates (euphotic+aphotic) for the two cruises. Phylogenetic studies performed in microcosms experiments confirm the presence of diazotrophs in the deep waters of the Oxygen Minimum Zone (OMZ), which were comprised of non-cyanobacterial diazotrophs affiliated with nifH clusters 1K (predominantly comprised of alpha-proteobacteria), 1G (predominantly comprised of gamma-proteobacteria), and 3 (sulfate reducing genera of the delta-proteobacteria and Clostridium spp., Vibrio spp.). Organic and inorganic nutrient addition bioassays revealed that amino acids significantly stimulated N2 fixation in the core of the OMZ at all stations tested and as did simple carbohydrates at stations located nearest the coast of Peru/Chile. The episodic supply of these substrates from upper layers are hypothesized to explain the observed variability of N2 fixation in the ETSP. PMID- 24349049 TI - Social environment influences performance in a cognitive task in natural variants of the foraging gene. AB - In Drosophila melanogaster, natural genetic variation in the foraging gene affects the foraging behaviour of larval and adult flies, larval reward learning, adult visual learning, and adult aversive training tasks. Sitters (for(s)) are more sedentary and aggregate within food patches whereas rovers (for(R)) have greater movement within and between food patches, suggesting that these natural variants are likely to experience different social environments. We hypothesized that social context would differentially influence rover and sitter behaviour in a cognitive task. We measured adult rover and sitter performance in a classical olfactory training test in groups and alone. All flies were reared in groups, but fly training and testing were done alone and in groups. Sitters trained and tested in a group had significantly higher learning performances compared to sitters trained and tested alone. Rovers performed similarly when trained and tested alone and in a group. In other words, rovers learning ability is independent of group training and testing. This suggests that sitters may be more sensitive to the social context than rovers. These differences in learning performance can be altered by pharmacological manipulations of PKG activity levels, the foraging (for) gene's gene product. Learning and memory is also affected by the type of social interaction (being in a group of the same strain or in a group of a different strain) in rovers, but not in sitters. These results suggest that for mediates social learning and memory in D. melanogaster. PMID- 24349050 TI - Observational cohort study of ventricular arrhythmia in adults with Marfan syndrome caused by FBN1 mutations. AB - BACKGROUND: Marfan syndrome is associated with ventricular arrhythmia but risk factors including FBN1 mutation characteristics require elucidation. METHODS AND RESULTS: We performed an observational cohort study of 80 consecutive adults (30 men, 50 women aged 42+/-15 years) with Marfan syndrome caused by FBN1 mutations. We assessed ventricular arrhythmia on baseline ambulatory electrocardiography as >10 premature ventricular complexes per hour (>10 PVC/h), as ventricular couplets (Couplet), or as non-sustained ventricular tachycardia (nsVT), and during 31+/-18 months of follow-up as ventricular tachycardia (VT) events (VTE) such as sudden cardiac death (SCD), and sustained ventricular tachycardia (sVT). We identified >10 PVC/h in 28 (35%), Couplet/nsVT in 32 (40%), and VTE in 6 patients (8%), including 3 with SCD (4%). PVC>10/h, Couplet/nsVT, and VTE exhibited increased N terminal pro-brain natriuretic peptide serum levels(P<.001). All arrhythmias related to increased NT-proBNP (P<.001), where PVC>10/h and Couplet/nsVT also related to increased indexed end-systolic LV diameters (P = .024 and P = .020), to moderate mitral valve regurgitation (P = .018 and P = .003), and to prolonged QTc intervals (P = .001 and P = .006), respectively. Moreover, VTE related to mutations in exons 24-32 (P = .021). Kaplan-Meier analysis corroborated an association of VTE with increased NT-proBNP (P<.001) and with mutations in exons 24-32 (P<.001). CONCLUSIONS: Marfan syndrome with causative FBN1 mutations is associated with an increased risk for arrhythmia, and affected persons may require life-long monitoring. Ventricular arrhythmia on electrocardiography, signs of myocardial dysfunction and mutations in exons 24-32 may be risk factors of VTE. PMID- 24349051 TI - Experimental differentiation of intraocular masses using ultrahigh-field magnetic resonance imaging--a case series. AB - PURPOSE: The case reports presented here were compiled to demonstrate the potential for improved diagnosis and monitoring of disease progress of intraocular lesions using ultrahigh-field magnetic resonance microscopy (MRM) at 7.1 Tesla. METHODS: High-resolution ex vivo ocular magnetic resonance (MR) images were acquired on an ultrahigh-field MR system (7.1 Tesla, ClinScan, Bruker BioScan, Germany) using a 2-channel coil with 4 coil elements and T2-weighted turbo spin echo (TSE) sequences of human eyes enucleated because of different intraocular lesions. Imaging parameters were: 40*40 mm field of view, 512*512 matrix, and 700 um slice thickness. The results were correlated with in vivo ultrasound and histology of the enucleated eyes. RESULTS: Imaging was performed in enucleated eyes with choroidal melanoma, malignant melanoma of iris and ciliary body with scleral perforation, ciliary body melanoma, intraocular metastasis of esophageal cancer, subretinal bleeding in the presence of perforated corneal ulcer, hemorrhagic choroidal detachment, and premature retinopathy with phthisis and ossification of bulbar structures. MR imaging allowed differentiation between solid and cystic tumor components. In case of hemorrhage, fluid-fluid levels were identified. Melanin and calcifications caused significant hypointensity. Microstructural features of eye lesions identified by MRM were confirmed by histology. CONCLUSION: This study demonstrates the potential of MRM for the visualization and differential diagnosis of intraocular lesions. At present, the narrow bore of the magnet still limits the use of this technology in humans in vivo. Further advances in ultrahigh-field MR imaging will permit visualization of tumor extent and evaluation of nonclassified intraocular structures in the near future. PMID- 24349052 TI - Phase 2a study of ataluren-mediated dystrophin production in patients with nonsense mutation Duchenne muscular dystrophy. AB - BACKGROUND: Approximately 13% of boys with Duchenne muscular dystrophy (DMD) have a nonsense mutation in the dystrophin gene, resulting in a premature stop codon in the corresponding mRNA and failure to generate a functional protein. Ataluren (PTC124) enables ribosomal readthrough of premature stop codons, leading to production of full-length, functional proteins. METHODS: This Phase 2a open label, sequential dose-ranging trial recruited 38 boys with nonsense mutation DMD. The first cohort (n = 6) received ataluren three times per day at morning, midday, and evening doses of 4, 4, and 8 mg/kg; the second cohort (n = 20) was dosed at 10, 10, 20 mg/kg; and the third cohort (n = 12) was dosed at 20, 20, 40 mg/kg. Treatment duration was 28 days. Change in full-length dystrophin expression, as assessed by immunostaining in pre- and post-treatment muscle biopsy specimens, was the primary endpoint. FINDINGS: Twenty three of 38 (61%) subjects demonstrated increases in post-treatment dystrophin expression in a quantitative analysis assessing the ratio of dystrophin/spectrin. A qualitative analysis also showed positive changes in dystrophin expression. Expression was not associated with nonsense mutation type or exon location. Ataluren trough plasma concentrations active in the mdx mouse model were consistently achieved at the mid- and high- dose levels in participants. Ataluren was generally well tolerated. INTERPRETATION: Ataluren showed activity and safety in this short-term study, supporting evaluation of ataluren 10, 10, 20 mg/kg and 20, 20, 40 mg/kg in a Phase 2b, double-blind, long-term study in nonsense mutation DMD. TRIAL REGISTRATION: ClinicalTrials.gov NCT00264888. PMID- 24349054 TI - No correlation between PNPLA3 rs738409 genotype and fatty liver and hepatic cirrhosis in Japanese patients with HCV. AB - BACKGROUND: Hepatitis C virus (HCV) infection is associated with the development of cirrhosis and hepatocellular carcinoma and is also related to fatty change of the liver. Variation in patatin-like phospholipase domain-containing 3 (PNPLA3) gene is associated with disease progression in nonalcoholic fatty liver disease (NAFLD). Recent reports have suggested that PNPLA3, IL28B and TLR4-associated single nucleotide polymorphisms (SNPs) may have an impact on hepatic steatosis or fibrosis in patients with chronic HCV infection. METHODS AND FINDINGS: Four SNPs (PNPLA3 rs738409, TLR4 rs4986790, TLR4 rs4986791, IL28B rs8099917) were identified in Japanese patients infected with HCV. We examined the association between the distribution of these SNP alleles and fatty change of the liver or existence of hepatic cirrhosis diagnosed by ultrasonography, one of the widely accessible and easy-to-use methods. PNPLA3 rs738409 G-allele and IL28B rs 8099917 minor allele were found in 70.0% and 31.1%, respectively. These two TLR4 SNPs were uniform in Japanese. Fatty change of the liver developed independent of the abscence of hepatic cirrhosis on sonographic findings and younger age. Hepatic cirrhosis was associated with a higher aspartate aminotransferase/platelet ratio index (APRI), no fatty change of the liver, higher BMI and higher AFP levels. No association between PNPLA3 rs738409/IL28B rs8099917 genotypes and hepatic steatosis or liver fibrosis was observed. CONCLUSIONS: According to ultrasound examinations, no association between PNPLA3 rs738409 genotype and fatty change of the liver or hepatic cirrhosis was found in Japanese patients infected with HCV. Together, our results suggested that the mechanism of hepatic steatosis underlying HCV infection might differ from that of NAFLD and should be explored. PMID- 24349053 TI - Assessing early access to care and child survival during a health system strengthening intervention in Mali: a repeated cross sectional survey. AB - BACKGROUND: In 2012, 6.6 million children under age five died worldwide, most from diseases with known means of prevention and treatment. A delivery gap persists between well-validated methods for child survival and equitable, timely access to those methods. We measured early child health care access, morbidity, and mortality over the course of a health system strengthening model intervention in Yirimadjo, Mali. The intervention included Community Health Worker active case finding, user fee removal, infrastructure development, community mobilization, and prevention programming. METHODS AND FINDINGS: We conducted four household surveys using a cluster-based, population-weighted sampling methodology at baseline and at 12, 24, and 36 months. We defined our outcomes as the percentage of children initiating an effective antimalarial within 24 hours of symptom onset, the percentage of children reported to be febrile within the previous two weeks, and the under-five child mortality rate. We compared prevalence of febrile illness and treatment using chi-square statistics, and estimated and compared under-five mortality rates using Cox proportional hazard regression. There was a statistically significant difference in under-five mortality between the 2008 and 2011 surveys; in 2011, the hazard of under-five mortality in the intervention area was one tenth that of baseline (HR 0.10, p<0.0001). After three years of the intervention, the prevalence of febrile illness among children under five was significantly lower, from 38.2% at baseline to 23.3% in 2011 (PR = 0.61, p = 0.0009). The percentage of children starting an effective antimalarial within 24 hours of symptom onset was nearly twice that reported at baseline (PR = 1.89, p = 0.0195). CONCLUSIONS: Community-based health systems strengthening may facilitate early access to prevention and care and may provide a means for improving child survival. PMID- 24349055 TI - Non-invasive bioluminescence imaging to monitor the immunological control of a plasmablastic lymphoma-like B cell neoplasia after hematopoietic cell transplantation. AB - To promote cancer research and to develop innovative therapies, refined pre clinical mouse tumor models that mimic the actual disease in humans are of dire need. A number of neoplasms along the B cell lineage are commonly initiated by a translocation recombining c-myc with the immunoglobulin heavy-chain gene locus. The translocation is modeled in the C.129S1-Igha(tm1(Myc)Janz)/J mouse which has been previously engineered to express c-myc under the control of the endogenous IgH promoter. This transgenic mouse exhibits B cell hyperplasia and develops diverse B cell tumors. We have isolated tumor cells from the spleen of a C.129S1 Igha(tm1(Myc)Janz)/J mouse that spontaneously developed a plasmablastic lymphoma like disease. These cells were cultured, transduced to express eGFP and firefly luciferase, and gave rise to a highly aggressive, transplantable B cell lymphoma cell line, termed IM380. This model bears several advantages over other models as it is genetically induced and mimics the translocation that is detectable in a number of human B cell lymphomas. The growth of the tumor cells, their dissemination, and response to treatment within immunocompetent hosts can be imaged non-invasively in vivo due to their expression of firefly luciferase. IM380 cells are radioresistant in vivo and mice with established tumors can be allogeneically transplanted to analyze graft-versus-tumor effects of transplanted T cells. Allogeneic hematopoietic stem cell transplantation of tumor-bearing mice results in prolonged survival. These traits make the IM380 model very valuable for the study of B cell lymphoma pathophysiology and for the development of innovative cancer therapies. PMID- 24349056 TI - CXCL10 gene promoter polymorphism -1447A>G correlates with plasma CXCL10 levels and is associated with male susceptibility to cerebral malaria. AB - The risk factors for cerebral malaria (CM) and the wide variation in clinical manifestations of malaria are poorly understood. Recent studies indicate that interferon gamma inducible chemokine, CXCL10, is a strong predictor of both human and experimental cerebral malaria. Increased plasma and cerebrospinal fluid levels of CXCL10 were tightly associated with fatal CM in Indian and Ghanaian patients. In the present study, we hypothesized that in a subset of malaria patients, CM susceptibility is associated with variation in CXCL10 expression. We determined whether polymorphisms in the CXCL10 gene promoter region played a role in the clinical status of malaria patients and addressed the genetic basis of CXCL10 expression during malaria infection. Following extensive bioinformatics analyses, two reported single nucleotide polymorphisms in the CXCL10 promoter ( 135G>A [rs56061981] and -1447A>G [rs4508917]) were identified among 66 CM and 69 non-CM Indian patients using PCR-restriction fragment length polymorphism assay. Individuals with the -1447(A/G) genotype were susceptible to CM (adjusted odds ratio [AOR] = 2.60, 95% CI = 1.51-5.85, p = 0.021). In addition, individuals with the -1447(A/G) genotype had significantly higher plasma CXCL10 levels than individuals with the -1447(A/A) genotype. Stratifying patients according to gender, the observed association of CM with over expression of CXCL10 were more pronounced in males than in female patients (AOR = 5.47, 95% CI = 1.34-22.29, p = 0.018). Furthermore, -135G>A polymorphism conferred a decreased risk of CM among males (AOR = 0.19, 95% CI = 0.05-0.78, p = 0.021). Polymorphisms in the CXCL10 gene promoter sequence were associated with increased CXCL10 production, which is linked to severity of CM. These results suggest that the -1447A>G polymorphism in CXCL10 gene promoter could be partly responsible for the reported variation underlying severity of CM outcomes particularly in males. PMID- 24349057 TI - Sperm associated antigen 9 plays an important role in bladder transitional cell carcinoma. AB - BACKGROUND: Majority of bladder cancer deaths are caused due to transitional cell carcinoma (TCC) which is the most prevalent and chemoresistant malignancy of urinary bladder. Therefore, we analyzed the role of Sperm associated antigen 9 (SPAG9) in bladder TCC. METHODOLOGY AND FINDINGS: We examined SPAG9 expression and humoral response in 125 bladder TCC patients. Four bladder cancer cell lines were assessed for SPAG9 expression. In addition, we investigated the effect of SPAG9 ablation on cellular proliferation, cell cycle, migration and invasion in UM-UC-3 bladder cancer cells by employing gene silencing approach. Our SPAG9 gene and protein expression analysis revealed SPAG9 expression in 81% of bladder TCC tissue specimens. High SPAG9 expression (>60% SPAG9 positive cells) was found to be significantly associated with superficial non-muscle invasive stage (P = 0.042) and low grade tumors (P = 0.002) suggesting SPAG9 putative role in early spread and tumorigenesis. Humoral response against SPAG9 was observed in 95% of patients found positive for SPAG9 expression. All four bladder cancer cell lines revealed SPAG9 expression. In addition, SPAG9 gene silencing in UM-UC-3 cells resulted in induction of G0-G1 arrest characterized by up-regulation of p16 and p21 and consequent down-regulation of cyclin E, cyclin D and cyclin B, CDK4 and CDK1. Further, SPAG9 gene silencing also resulted in reduction in cellular growth, and migration and invasion ability of cancer cells in vitro. CONCLUSIONS: Collectively, our data in clinical specimens indicated that SPAG9 is potential biomarker and therapeutic target for bladder TCC. PMID- 24349058 TI - Eucommia ulmoides Oliver extract, aucubin, and geniposide enhance lysosomal activity to regulate ER stress and hepatic lipid accumulation. AB - Eucommia ulmoides Oliver is a natural product widely used as a dietary supplement and medicinal plant. Here, we examined the potential regulatory effects of Eucommia ulmoides Oliver extracts (EUE) on hepatic dyslipidemia and its related mechanisms by in vitro and in vivo studies. EUE and its two active constituents, aucubin and geniposide, inhibited palmitate-induced endoplasmic reticulum (ER) stress, reducing hepatic lipid accumulation through secretion of apolipoprotein B and associated triglycerides and cholesterol in human HepG2 hepatocytes. To determine how EUE diminishes the ER stress response, lysosomal and proteasomal protein degradation activities were analyzed. Although proteasomal activity was not affected, lysosomal enzyme activities including V-ATPase were significantly increased by EUE as well as aucubin and geniposide in HepG2 cells. Treatment with the V-ATPase inhibitor, bafilomycin, reversed the inhibition of ER stress, secretion of apolipoprotein B, and hepatic lipid accumulation induced by EUE or its component, aucubin or geniposide. In addition, EUE was determined to regulate hepatic dyslipidemia by enhancing lysosomal activity and to regulate ER stress in rats fed a high-fat diet. Together, these results suggest that EUE and its active components enhance lysosomal activity, resulting in decreased ER stress and hepatic dyslipidemia. PMID- 24349059 TI - Exercise protects against diet-induced insulin resistance through downregulation of protein kinase Cbeta in mice. AB - Physical exercise is an important and effective therapy for diabetes. However, its underlying mechanism is not fully understood. Protein kinase Cbeta (PKCbeta) has been suggested to be involved in the pathogenesis of obesity and insulin resistance, but the role of PKCbeta in exercise-induced improvements in insulin resistance is completely unknown. In this study, we evaluated the involvement of PKCbeta in exercise-attenuated insulin resistance in high-fat diet (HFD)-fed mice. PKCbeta(-/-) and wild-type mice were fed a HFD with or without exercise training. PKC protein expression, body and tissue weight change, glucose and insulin tolerance, metabolic rate, mitochondria size and number, adipose inflammation, and AKT activation were determined to evaluate insulin sensitivity and metabolic changes after intervention. PKCbeta expression decreased in both skeletal muscle and liver tissue after exercise. Exercise and PKCbeta deficiency can alleviate HFD-induced insulin resistance, as evidenced by improved insulin tolerance. In addition, fat accumulation and mitochondrial dysfunction induced by HFD were also ameliorated by both exercise and PKCbeta deficiency. On the other hand, exercise had little effect on PKCbeta(-/-) mice. Further, our data indicated improved activation of AKT, the downstream signal molecule of insulin, in skeletal muscle and liver of exercised mice, whereas PKCbeta deficiency blunted the difference between sedentary and exercised mice. These results suggest that downregulation of PKCbeta contributes to exercise-induced improvement of insulin resistance in HFD-fed mice. PMID- 24349060 TI - Recovery after work: the role of work beliefs in the unwinding process. AB - According to the Effort-Recovery model, mental or physical detachment from work is an important mechanism of work related recovery, as delayed recovery has been associated with range of negative health symptoms. In this paper, we examine whether recovery from work (in the form of mentally disengagement from work) is affected by the concept of 'work ethic', which refers to beliefs workers hold about their work and leisure and the effects of experiencing interruptions at work. Two indices of post-work recovery were utilized: problem solving pondering and psychological detachment. The study was conducted with 310 participants employed from diverse occupational sectors. Main effects of positive and negative appraisal of work interruption and beliefs were analysed using mediated and moderated regression analysis on problem-solving pondering and detachment. Weakened belief in wasted time as a partial mediator, reduced problem-solving pondering post work when interruptions were appraised as positive, and a high evaluation of leisure partially mediated problem-solving pondering when interruptions were appraised as positive. The results also showed that a high evaluation of centrality of work and leisure moderated the effect of negative appraisal of work interruption on elevated problem-solving pondering. Positive appraisal of work interruption was related to problem-solving pondering, and the strength of this association was further moderated by a strong belief in delay of gratification. In addition, employees' positive appraisal of work interruption was related to work detachment, and the strength of this association was further moderated by strong beliefs in hard work and self-reliance. These findings are discussed in terms of their theoretical and practical implications for employees who are strongly influenced by such work beliefs. PMID- 24349061 TI - Ex vivo pathomechanics of the canine Pond-Nuki model. AB - BACKGROUND: Transection of the canine cranial cruciate ligament (CCL) is a well established osteoarthritis (OA) model. The effect of CCL loss on contact pressure and joint alignment has not been quantified for stifle loading in standing. The purposes of the study were to measure femorotibial contact areas and stresses and joint alignment following transection of the CCL in an ex vivo model. We hypothesized that transection of the CCL would lead to abnormal kinematics, as well as alterations in contact mechanics of the femorotibial joint. METHODOLOGY/PRINCIPAL FINDINGS: Eight canine hindlimbs were tested in a servo hydraulic materials testing machine using a custom made femoral jig. Contact area and pressure measurements, and femorotibial rotations and translations were measured in the normal and the CCL-deficient stifle in both standing and deep flexion angles. We found that at standing angle, transection of the CCL caused cranial translation and internal rotation of the tibia with a concurrent caudal shift of the contact area, an increase in peak pressure and a decrease in contact area. These changes were not noted in deep flexion. At standing, loss of CCL caused a redistribution of the joint pressure, with the caudal region of the compartment being overloaded and the rest of the joint being underloaded. CONCLUSION: In the Pond-Nuki model alterations in joint alignment are correlated with shifting of the contact points to infrequently loaded areas of the tibial plateau. The results of this study suggest that this cadaveric Pond-Nuki model simulates the biomechanical changes previously reported in the in-vivo Pond-Nuki model. PMID- 24349062 TI - Chromosomal characterization of the three subgenomes in the polyploids of Hordeum murinum L.: new insight into the evolution of this complex. AB - Hordeum murinum L. is a species complex composed of related taxa, including the subspecies glaucum, murinum and leporinum. However, the phylogenetic relationships between the different taxa and their cytotypes, and the origin of the polyploid forms, remain points of controversy. The present work reports a comparative karyotype analysis of seven accessions of the H. murinum complex representing all subspecies and cytotypes. The karyotypes were determined by examining the distribution of the repetitive Triticeae DNA sequences pTa71, pTa794, pSc119.2, pAs1 and pHch950, the simple sequence repeats (SSRs) (AG)10, (AAC)5, (AAG)5, (ACT)5, (ATC)5, and (CCCTAAA)3 via in situ hybridization. The chromosomes of the three subgenomes involved in the polyploids were identified. All tetraploids of all subspecies shared the same two subgenomes (thus suggesting them to in fact belong to the same taxon), the result of hybridization between two diploid ancestors. One of the subgenomes present in all tetraploids of all subspecies was found to be very similar (though not identical) to the chromosome complement of the diploid glaucum. The hexaploid form of leporinum came about through a cross between a tetraploid and a third diploid form. Exclusively bivalent associations among homologous chromosomes were observed when analyzing pollen mother cells of tetraploid taxa. In conclusion, the present results identify all the individual chromosomes within the H. murinum complex, reveal its genome structure and phylogeny, and explain the appearance of the different cytotypes. Three cryptic species are proposed according to ploidy level that may deserve full taxonomic recognition. PMID- 24349064 TI - A model of self-organizing head-centered visual responses in primate parietal areas. AB - We present a hypothesis for how head-centered visual representations in primate parietal areas could self-organize through visually-guided learning, and test this hypothesis using a neural network model. The model consists of a competitive output layer of neurons that receives afferent synaptic connections from a population of input neurons with eye position gain modulated retinal receptive fields. The synaptic connections in the model are trained with an associative trace learning rule which has the effect of encouraging output neurons to learn to respond to subsets of input patterns that tend to occur close together in time. This network architecture and synaptic learning rule is hypothesized to promote the development of head-centered output neurons during periods of time when the head remains fixed while the eyes move. This hypothesis is demonstrated to be feasible, and each of the core model components described is tested and found to be individually necessary for successful self-organization. PMID- 24349063 TI - Abnormal organization of white matter network in patients with no dementia after ischemic stroke. AB - Structural changes after ischemic stroke could affect information communication extensively in the brain network. It is likely that the defects in the white matter (WM) network play a key role in information interchange. In this study, we used graph theoretical analysis to examine potential organization alteration in the WM network architecture derived from diffusion tensor images from subjects with no dementia and experienced stroke in the past 5.4-14.8 months (N = 47, Mini Mental Screening Examination, MMSE range 18-30), compared with a normal control group with 44 age and gender-matched healthy volunteers (MMSE range 26-30). Region-wise connectivity was derived from fiber connection density of 90 different cortical and subcortical parcellations across the whole brain. Both normal controls and patients with chronic stroke exhibited efficient small-world properties in their WM structural networks. Compared with normal controls, topological efficiency was basically unaltered in the patients with chronic stroke, as reflected by unchanged local and global clustering coefficient, characteristic path length, and regional efficiency. No significant difference in hub distribution was found between normal control and patient groups. Patients with chronic stroke, however, were found to have reduced betweenness centrality and predominantly located in the orbitofrontal cortex, whereas increased betweenness centrality and vulnerability were observed in parietal-occipital cortex. The National Institutes of Health Stroke Scale (NIHSS) score of patient is correlated with the betweenness centrality of right pallidum and local clustering coefficient of left superior occipital gyrus. Our findings suggest that patients with chronic stroke still exhibit efficient small-world organization and unaltered topological efficiency, with altered topology at orbitofrontal cortex and parietal-occipital cortex in the overall structural network. Findings from this study could help in understanding the mechanism of cognitive impairment and functional compensation occurred in patients with chronic stroke. PMID- 24349065 TI - SRComp: short read sequence compression using burstsort and Elias omega coding. AB - Next-generation sequencing (NGS) technologies permit the rapid production of vast amounts of data at low cost. Economical data storage and transmission hence becomes an increasingly important challenge for NGS experiments. In this paper, we introduce a new non-reference based read sequence compression tool called SRComp. It works by first employing a fast string-sorting algorithm called burstsort to sort read sequences in lexicographical order and then Elias omega based integer coding to encode the sorted read sequences. SRComp has been benchmarked on four large NGS datasets, where experimental results show that it can run 5-35 times faster than current state-of-the-art read sequence compression tools such as BEETL and SCALCE, while retaining comparable compression efficiency for large collections of short read sequences. SRComp is a read sequence compression tool that is particularly valuable in certain applications where compression time is of major concern. PMID- 24349066 TI - Dispersion estimation and its effect on test performance in RNA-seq data analysis: a simulation-based comparison of methods. AB - A central goal of RNA sequencing (RNA-seq) experiments is to detect differentially expressed genes. In the ubiquitous negative binomial model for RNA seq data, each gene is given a dispersion parameter, and correctly estimating these dispersion parameters is vital to detecting differential expression. Since the dispersions control the variances of the gene counts, underestimation may lead to false discovery, while overestimation may lower the rate of true detection. After briefly reviewing several popular dispersion estimation methods, this article describes a simulation study that compares them in terms of point estimation and the effect on the performance of tests for differential expression. The methods that maximize the test performance are the ones that use a moderate degree of dispersion shrinkage: the DSS, Tagwise wqCML, and Tagwise APL. In practical RNA-seq data analysis, we recommend using one of these moderate shrinkage methods with the QLShrink test in QuasiSeq R package. PMID- 24349067 TI - Preliminary evidence that anodal transcranial direct current stimulation enhances time to task failure of a sustained submaximal contraction. AB - The purpose of this study was to determine whether anodal transcranial direct current stimulation (tDCS) delivered while performing a sustained submaximal contraction would increase time to task failure (TTF) compared to sham stimulation. Healthy volunteers (n = 18) performed two fatiguing contractions at 20% of maximum strength with the elbow flexors on separate occasions. During fatigue task performance, either anodal or sham stimulation was delivered to the motor cortex for up to 20 minutes. Transcranial magnetic stimulation (TMS) was used to assess changes in cortical excitability during stimulation. There was no systematic effect of the anodal tDCS stimulation on TTF for the entire subject set (n = 18; p = 0.64). Accordingly, a posteriori subjects were divided into two tDCS-time groups: Full-Time (n = 8), where TTF occurred prior to the termination of tDCS, and Part-Time (n = 10), where TTF extended after tDCS terminated. The TTF for the Full-Time group was 31% longer with anodal tDCS compared to sham (p = 0.04), whereas TTF for the Part-Time group did not differ (p = 0.81). Therefore, the remainder of our analysis addressed the Full-Time group. With anodal tDCS, the amount of muscle fatigue was 6% greater at task failure (p = 0.05) and the amount of time the Full-Time group performed the task at an RPE between 8-10 ("very hard") increased by 38% (p = 0.04) compared to sham. There was no difference in measures of cortical excitability between stimulation conditions (p = 0.90). That the targeted delivery of anodal tDCS during task performance both increased TTF and the amount of muscle fatigue in a subset of subjects suggests that augmenting cortical excitability with tDCS enhanced descending drive to the spinal motorpool to recruit more motor units. The results also suggest that the application of tDCS during performance of fatiguing activity has the potential to bolster the capacity to exercise under conditions required to derive benefits due to overload. PMID- 24349068 TI - Gene expression analysis of PTEN positive glioblastoma stem cells identifies DUB3 and Wee1 modulation in a cell differentiation model. AB - The term astrocytoma defines a quite heterogeneous group of neoplastic diseases that collectively represent the most frequent brain tumors in humans. Among them, glioblastoma multiforme represents the most malignant form and its associated prognosis is one of the poorest among tumors of the central nervous system. It has been demonstrated that a small population of tumor cells, isolated from the brain neoplastic tissue, can reproduce the parental tumor when transplanted in immunodeficient mouse. These tumor initiating cells are supposed to be involved in cancer development and progression and possess stem cell-like features; like their normal counterpart, these cells remain quiescent until they are committed to differentiation. Many studies have shown that the role of the tumor suppressor protein PTEN in cell cycle progression is fundamental for tumor dynamics: in low grade gliomas, PTEN contributes to maintain cells in G1 while the loss of its activity is frequently observed in high grade gliomas. The mechanisms underlying the above described PTEN activity have been studied in many tumors, but those involved in the maintenance of tumor initiating cells quiescence remain to be investigated in more detail. The aim of the present study is to shed light on the role of PTEN pathway on cell cycle regulation in Glioblastoma stem cells, through a cell differentiation model. Our results suggest the existence of a molecular mechanism, that involves DUB3 and WEE1 gene products in the regulation of Cdc25a, as functional effector of the PTEN/Akt pathway. PMID- 24349069 TI - Confocal comparison of corneal reinnervation after small incision lenticule extraction (SMILE) and femtosecond laser in situ keratomileusis (FS-LASIK). AB - PURPOSE: To evaluate corneal reinnervation, and the corresponding corneal sensitivity and keratocyte density after small incision lenticule extraction (SMILE) and femtosecond laser in situ keratomileusis (FS-LASIK). METHODS: In this prospective, non-randomized observational study, 18 patients (32 eyes) received SMILE surgery, and 22 patients (42 eyes) received FS-LASIK surgery to correct myopia. The corneal subbasal nerve density and microscopic morphological changes in corneal architecture were evaluated by confocal microscopy prior to surgery and at 1 week, 1 month, 3 months, and 6 months after surgery. A correlation analysis was performed between subbasal corneal nerve density and the corresponding keratocyte density and corneal sensitivity. RESULTS: The decrease in subbasal nerve density was less severe in SMILE-treated eyes than in FS-LASIK treated eyes at 1 week (P = 0.0147), 1 month (P = 0.0243), and 3 months (P = 0.0498), but no difference was detected at the 6-month visit (P = 0.5277). The subbasal nerve density correlated positively with central corneal sensitivity in both groups (r = 0.416, P<0.0001, and r = 0.2567, P = 0.0038 for SMILE group and FS-LASIK group, respectively). The SMILE-treated eyes have a lower risk of developing peripheral empty space with epithelial cells filling in (P = 0.0005). CONCLUSIONS: The decrease in subbasal nerve fiber density was less severe in the SMILE group than the FS-LASIK group in the first 3 months following the surgeries. The subbasal nerve density was correlated with central corneal sensitivity. PMID- 24349070 TI - Hierarchical self-organization of non-cooperating individuals. AB - Hierarchy is one of the most conspicuous features of numerous natural, technological and social systems. The underlying structures are typically complex and their most relevant organizational principle is the ordering of the ties among the units they are made of according to a network displaying hierarchical features. In spite of the abundant presence of hierarchy no quantitative theoretical interpretation of the origins of a multi-level, knowledge-based social network exists. Here we introduce an approach which is capable of reproducing the emergence of a multi-levelled network structure based on the plausible assumption that the individuals (representing the nodes of the network) can make the right estimate about the state of their changing environment to a varying degree. Our model accounts for a fundamental feature of knowledge-based organizations: the less capable individuals tend to follow those who are better at solving the problems they all face. We find that relatively simple rules lead to hierarchical self-organization and the specific structures we obtain possess the two, perhaps most important features of complex systems: a simultaneous presence of adaptability and stability. In addition, the performance (success score) of the emerging networks is significantly higher than the average expected score of the individuals without letting them copy the decisions of the others. The results of our calculations are in agreement with a related experiment and can be useful from the point of designing the optimal conditions for constructing a given complex social structure as well as understanding the hierarchical organization of such biological structures of major importance as the regulatory pathways or the dynamics of neural networks. PMID- 24349071 TI - The prognostic value of phosphorylated AKT expression in non-small cell lung cancer: a meta-analysis. AB - OBJECTIVES: Phosphorylated AKT (p-AKT), constitutive activation of AKT, is a potentially interesting prognostic marker and therapeutic target in non-small cell lung cancer (NSCLC). However, the available results of p-AKT expression in NSCLC are heterogeneous. Therefore, a meta-analysis of published researches investigating the prognostic relevance of p-AKT expression in patients with NSCLC was performed. MATERIALS AND METHODS: A literature search via PubMed, EMBASE and CNKI (China National Knowledge Infrastructure) databases was conducted. Data from eligible studies were extracted and included into meta-analysis using a random effects model. RESULTS: A total of 1049 patients from nine studies were included in the meta-analysis. Nine studies investigated the relationship between p-AKT expression and overall survival using univariate analysis, and five of these undertook multivariate analysis. The pooled hazard ratio (HR) for overall survival was 1.49 (95% confidence interval (CI): 1.01-2.20) by univariate analysis and 1.02 (95% CI: 0.54-1.95) by multivariate analysis. CONCLUSION: Our study shows that positive expression of p-AKT is associated with poor prognosis in patients with NSCLC. However, adequately designed prospective studies need to perform. PMID- 24349073 TI - Estimation of the horizon in photographed outdoor scenes by human and machine. AB - We present three experiments on horizon estimation. In Experiment 1 we verify the human ability to estimate the horizon in static images from only visual input. Estimates are given without time constraints with emphasis on precision. The resulting estimates are used as baseline to evaluate horizon estimates from early visual processes. Stimuli are presented for only 153 ms and then masked to purge visual short-term memory and enforcing estimates to rely on early processes, only. The high agreement between estimates and the lack of a training effect shows that enough information about viewpoint is extracted in the first few hundred milliseconds to make accurate horizon estimation possible. In Experiment 3 we investigate several strategies to estimate the horizon in the computer and compare human with machine "behavior" for different image manipulations and image scene types. PMID- 24349072 TI - Voluntary running in young adult mice reduces anxiety-like behavior and increases the accumulation of bioactive lipids in the cerebral cortex. AB - Combinatorial therapies using voluntary exercise and diet supplementation with polyunsaturated fatty acids have synergistic effects benefiting brain function and behavior. Here, we assessed the effects of voluntary exercise on anxiety-like behavior and on total FA accumulation within three brain regions: cortex, hippocampus, and cerebellum of running versus sedentary young adult male C57/BL6J mice. The running group was subjected to one month of voluntary exercise in their home cages, while the sedentary group was kept in their home cages without access to a running wheel. Elevated plus maze (EPM), several behavioral postures and two risk assessment behaviors (RABs) were then measured in both animal groups followed immediately by blood samplings for assessment of corticosterone levels. Brains were then dissected for non-targeted lipidomic analysis of selected brain regions using gas chromatography coupled to mass spectrometry (GC/MS). Results showed that mice in the running group, when examined in the EPM, displayed significantly lower anxiety-like behavior, higher exploratory and risky behaviors, compared to sedentary mice. Notably, we found no differences in blood corticosterone levels between the two groups, suggesting that the different EPM and RAB behaviors were not related to reduced physiological stress in the running mice. Lipidomics analysis revealed a region-specific cortical decrease of the saturated FA: palmitate (C16:0) and a concomitant increase of polyunsaturated FA, arachidonic acid (AA, omega 6-C20: 4) and docosahexaenoic acid (DHA, omega 3-C22: 6), in running mice compared to sedentary controls. Finally, we found that running mice, as opposed to sedentary animals, showed significantly enhanced cortical expression of phospholipase A2 (PLA2) protein, a signaling molecule required in the production of both AA and DHA. In summary, our data support the anxiolytic effects of exercise and provide insights into the molecular processes modulated by exercise that may lead to its beneficial effects on mood. PMID- 24349074 TI - De-etiolation of wheat seedling leaves: cross talk between heme oxygenase/carbon monoxide and nitric oxide. AB - Greening of etiolated plants is predominantly stimulated by light but the complete molecular mechanism is still unknown. Multiple studies currently focus on the important physiological effects of heme oxygenase (HO)/carbon monoxide (CO) in plants. In this report, firstly, the role of HO/CO in light-induced de etiolation process was investigated. We discovered that light could significantly increase HO activities, HO-1 gene expression, CO release, and chlorophyll accumulation, all of which were sensitive to zinc protoporphyrin (ZnPPIX), the potent inhibitor of HO-1, respectively. Both HO-1 inducer hematin (H) and CO aqueous solution were able to relieve etiolation in wheat seedling leaves under completely darkness by up-regulating endogenous HO/CO system, so as nitric oxide (NO) donor sodium nitroprusside (SNP) did. Similarly, endogenous NO production was also boost in response to light, SNP, hematin and CO aqueous solution in wheat seedling leaves. Additionally, the restoration of chlorophyll contents was blocked, when the inhibitor of mammalian nitric oxide synthase N(G)-nitro-L arginine methylester hydrochloride (L-NAME) or the specific scavenger of NO 2-(4 carboxyphenyl)-4, 4, 5, 5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt (cPTIO) was added, respectively. Furthermore, the inducible effects of light were different from those of SNP, hematin, and CO on Pfr accumulation and PHYA transcripts. However, all of sodium nitroprusside (SNP), hematin, and CO could accelerate NO emission, which suggested that HO/CO in wheat seedlings de etiolation under dark-light transition may have a cross talk with NO. PMID- 24349075 TI - Impact of a combined high cholesterol diet and high glucose environment on vasculature. AB - AIMS: Vascular complications are the leading cause of mortality and morbidity in patients with diabetes. However, proper animal models of diabetic vasculopathy that recapitulate the accelerated progression of vascular lesions in human are unavailable. In the present study, we developed a zebrafish model of diabetic vascular complications and the methodology for quantifying vascular lesion formation real-time in the living diabetic zebrafish. METHODS AND RESULTS: Wild type zebrafish (AB) and transgenic zebrafish lines of fli1:EGFP, lyz:EGFP, gata1:dsRed, double transgenic zebrafish of gata1:dsRed/fli1:EGFP were exposed to high cholesterol diet and 3% glucose (HCD-HG) for 10 days. The zebrafish model with HCD-HG treatment was characterized by significantly increased tissue levels of insulin, glucagon, glucose, total triglyceride and cholesterol. Confocal microscopic analysis further revealed that the diabetic larvae developed clearly thickened endothelial layers, distinct perivascular lipid depositions, substantial accumulations of inflammatory cells in the injured vasculature, and a decreased velocity of blood flow. Moreover, the vascular abnormalities were improved by the treatment of pioglitazone and metformin. CONCLUSION: A combination of high cholesterol diet and high glucose exposure induces a rapid onset of vascular complications in zebrafish similar to the early atherosclerotic vascular injuries in mammalian diabetic models, suggesting that zebrafish may be used as a novel animal model for diabetic vasculopathy. PMID- 24349076 TI - Telomere length correlations among somatic tissues in adult zebra finches. AB - Telomeres are repetitive non coding DNA sequences located at the end of eukaryotic chromosomes, which maintain the integrity of the genome by hiding the chromosome ends from being recognised as double stranded breaks. Telomeres are emerging as biomarkers for ageing and survival, and are susceptible to reflect different individual life history trajectories. In particular, the telomere length with which one starts in life has been shown to be linked with individual life-long survival, suggesting that telomere dynamics can be a proxy for individual fitness and thereby be implicated in evolutionary trade-offs. As a consequence, an increasing number of studies were conducted on telomeres in the fields of ecology and evolutionary biology, in which telomere length was almost exclusively measured from blood samples. However, not only do the number of repeats of the telomeric sequences vary among species, but also within species with great inter-individual telomere lengths variability with age, tissues, and chromosomes. This raises the issue of the exact biological meaning of telomere measurement in blood cells and stimulated the study of the correlation of telomere lengths among tissues over age. By measuring telomere length in adult zebra finches (Taeniopygia guttata) in different somatic tissues displaying variable cell turnovers (bone marrow, brain, spleen, pectoral muscle, heart, liver and in red blood cells), we checked that the measure of telomere length in red blood cells is related to telomere lengths in the other tissues. Here we show significant relationships between the telomere lengths of red blood cells and several somatic tissues at adulthood. As red blood cells are easily accessible and suitable for the longitudinal monitoring of the individual rate of telomere loss, our study confirms that telomere length measured in red blood cells could serve as a surrogate for telomere length in the whole avian organism. PMID- 24349077 TI - Serum interleukin-18 levels are associated with physical activity in Japanese men. AB - OBJECTIVE: To investigate the link between serum interleukin-18 (IL-18) levels and physical activity in Japanese men. METHODS: A total of 81 men (45.7+/-17.6 years old) was enrolled in this cross-sectional investigation study. We assessed anthropometric and body composition parameters. Serum IL-18 levels, physical activity by uniaxial accelerometers, peak oxygen uptake and metabolic risk parameters were also evaluated. RESULTS: Serum IL-18 levels were 179.4+/-84.7 pg/mL. Physical activity evaluated by Sigma[metabolic equivalents * h per week (METs?h/w)]was significantly and negatively correlated with serum IL-18 levels (r = -0.252, p = 0.0235). These associations remained even after adjusting for age, peak oxygen uptake and other confounding factors. CONCLUSION: Serum IL-18 levels were closely associated with physical activity independent of peak oxygen uptake in Japanese men. PMID- 24349078 TI - Choriocapillaris and choroidal microvasculature imaging with ultrahigh speed OCT angiography. AB - We demonstrate in vivo choriocapillaris and choroidal microvasculature imaging in normal human subjects using optical coherence tomography (OCT). An ultrahigh speed swept source OCT prototype at 1060 nm wavelengths with a 400 kHz A-scan rate is developed for three-dimensional ultrahigh speed imaging of the posterior eye. OCT angiography is used to image three-dimensional vascular structure without the need for exogenous fluorophores by detecting erythrocyte motion contrast between OCT intensity cross-sectional images acquired rapidly and repeatedly from the same location on the retina. En face OCT angiograms of the choriocapillaris and choroidal vasculature are visualized by acquiring cross sectional OCT angiograms volumetrically via raster scanning and segmenting the three-dimensional angiographic data at multiple depths below the retinal pigment epithelium (RPE). Fine microvasculature of the choriocapillaris, as well as tightly packed networks of feeding arterioles and draining venules, can be visualized at different en face depths. Panoramic ultra-wide field stitched OCT angiograms of the choriocapillaris spanning ~32 mm on the retina show distinct vascular structures at different fundus locations. Isolated smaller fields at the central fovea and ~6 mm nasal to the fovea at the depths of the choriocapillaris and Sattler's layer show vasculature structures consistent with established architectural morphology from histological and electron micrograph corrosion casting studies. Choriocapillaris imaging was performed in eight healthy volunteers with OCT angiograms successfully acquired from all subjects. These results demonstrate the feasibility of ultrahigh speed OCT for in vivo dye-free choriocapillaris and choroidal vasculature imaging, in addition to conventional structural imaging. PMID- 24349079 TI - Detection of tissue factor antigen and coagulation activity in coronary artery thrombi isolated from patients with ST-segment elevation acute myocardial infarction. AB - INTRODUCTION: Although ruptured atherosclerotic plaques have been extensively analyzed, the composition of thrombi causing arterial occlusion in patients with ST-segment elevation acute myocardial infarction has been less thoroughly investigated. We sought to investigate whether coagulant active tissue factor can be retrieved in thrombi of patients with STEMI undergoing primary percutaneous coronary intervention. METHODS: Nineteen patients with ST-segment elevation acute myocardial infarction referred for primary percutaneous coronary intervention were enrolled in this study. Coronary thrombi aspirated from coronary arteries were routinely processed for paraffin embedding and histological evaluation (4 patients) or immediately snap frozen for evaluation of tissue factor activity using a modified aPTT test (15 patients). Immunoprecipitation followed by immunoblotting was also performed in 12 patients. RESULTS: Thrombi aspirated from coronary arteries showed large and irregular areas of tissue factor staining within platelet aggregates, and in close contact with inflammatory cells. Some platelet aggregates stained positive for tissue factor, whereas others did not. Monocytes consistently stained strongly for tissue factor, neutrophils had a more variable and irregular tissue factor staining, and red blood cells did not demonstrate staining for tissue factor. Median clotting time of plasma samples containing homogenized thrombi incubated with a monoclonal antibody that specifically inhibits tissue factor-mediated coagulation activity (mAb 5G9) were significantly longer than their respective controls (88.9 seconds versus 76.5 seconds, respectively; p<0.001). Tissue factor was also identified by immunoprecipitation in 10 patients, with significant variability among band intensities. CONCLUSIONS: Active tissue factor is present in coronary artery thrombi of patients with ST-segment elevation acute myocardial infarction, suggesting that it contributes to activate the coagulation cascade ensuing in coronary thrombosis. PMID- 24349081 TI - Northern hemisphere glaciation during the globally warm early Late Pliocene. AB - The early Late Pliocene (3.6 to ~3.0 million years ago) is the last extended interval in Earth's history when atmospheric CO2 concentrations were comparable to today's and global climate was warmer. Yet a severe global glaciation during marine isotope stage (MIS) M2 interrupted this phase of global warmth ~3.30 million years ago, and is seen as a premature attempt of the climate system to establish an ice-age world. Here we propose a conceptual model for the glaciation and deglaciation of MIS M2 based on geochemical and palynological records from five marine sediment cores along a Caribbean to eastern North Atlantic transect. Our records show that increased Pacific-to-Atlantic flow via the Central American Seaway weakened the North Atlantic Current and attendant northward heat transport prior to MIS M2. The consequent cooling of the northern high latitude oceans permitted expansion of the continental ice sheets during MIS M2, despite near modern atmospheric CO2 concentrations. Sea level drop during this glaciation halted the inflow of Pacific water to the Atlantic via the Central American Seaway, allowing the build-up of a Caribbean Warm Pool. Once this warm pool was large enough, the Gulf Stream-North Atlantic Current system was reinvigorated, leading to significant northward heat transport that terminated the glaciation. Before and after MIS M2, heat transport via the North Atlantic Current was crucial in maintaining warm climates comparable to those predicted for the end of this century. PMID- 24349080 TI - Mechanistic phenotypes: an aggregative phenotyping strategy to identify disease mechanisms using GWAS data. AB - A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF<0.1) non-synonymous SNPs (nsSNPs) associated with "mechanistic phenotypes", comprised of collections of related diagnoses. We studied two mechanistic phenotypes: (1) thrombosis, evaluated in a population of 1,655 African Americans; and (2) four groupings of cancer diagnoses, evaluated in 3,009 white European Americans. We tested associations between nsSNPs represented on GWAS platforms and mechanistic phenotypes ascertained from electronic medical records (EMRs), and sought enrichment in functional ontologies across the top-ranked associations. We used a two-step analytic approach whereby nsSNPs were first sorted by the strength of their association with a phenotype. We tested associations using two reverse genetic models and standard additive and recessive models. In the second step, we employed a hypothesis-free ontological enrichment analysis using the sorted nsSNPs to identify functional mechanisms underlying the diagnoses comprising the mechanistic phenotypes. The thrombosis phenotype was solely associated with ontologies related to blood coagulation (Fisher's p = 0.0001, FDR p = 0.03), driven by the F5, P2RY12 and F2RL2 genes. For the cancer phenotypes, the reverse genetics models were enriched in DNA repair functions (p = 2*10-5, FDR p = 0.03) (POLG/FANCI, SLX4/FANCP, XRCC1, BRCA1, FANCA, CHD1L) while the additive model showed enrichment related to chromatid segregation (p = 4*10-6, FDR p = 0.005) (KIF25, PINX1). We were able to replicate nsSNP associations for POLG/FANCI, BRCA1, FANCA and CHD1L in independent data sets. Mechanism-oriented phenotyping using collections of EMR-derived diagnoses can elucidate fundamental disease mechanisms. PMID- 24349082 TI - Cartilage-specific overexpression of ERRgamma results in Chondrodysplasia and reduced chondrocyte proliferation. AB - While the role of estrogen receptor-related receptor alpha (ERRalpha) in chondrogenesis has been investigated, the involvement of ERR gamma (ERRgamma) has not been determined. To assess the effect of increased ERRgamma activity on cartilage development in vivo, we generated two transgenic (Tg) lines overexpressing ERRgamma2 via a chondrocyte-specific promoter; the two lines exhibited ~3 and ~5 fold increased ERRgamma2 protein expression respectively in E14.5 Tg versus wild type (WT) limbs. On postnatal day seven (P7), we observed a 4-10% reduction in the size of the craniofacial, axial and appendicular skeletons in Tg versus WT mice. The reduction in bone length was already present at birth and did not appear to involve bones that are derived via intramembranous bone formation as the bones of the calvaria, clavicle, and the mandible developed normally. Histological analysis of P7 growth plates revealed a reduction in the length of the Tg versus WT growth plate, the majority of which was attributable to a reduced proliferative zone. The reduced proliferative zone paralleled a decrease in the number of Ki67-positive proliferating cells, with no significant change in apoptosis, and was accompanied by large cell-free swaths of cartilage matrix, which extended through multiple zones of the growth plate. Using a bioinformatics approach, we identified known chondrogenesis-associated genes with at least one predicted ERR binding site in their proximal promoters, as well as cell cycle regulators known to be regulated by ERRgamma. Of the genes identified, Col2al, Agg, Pth1r, and Cdkn1b (p27) were significantly upregulated, suggesting that ERRgamma2 negatively regulates chondrocyte proliferation and positively regulates matrix synthesis to coordinate growth plate height and organization. PMID- 24349083 TI - Wild ungulates as disseminators of Shiga toxin-producing Escherichia coli in urban areas. AB - BACKGROUND: In 2008, children playing on a soccer field in Colorado were sickened with a strain of Shiga toxin-producing Escherichia coli (STEC) O157:H7, which was ultimately linked to feces from wild Rocky Mountain elk. We addressed whether wild cervids were a potential source of STEC infections in humans and whether STEC was ubiquitous throughout wild cervid populations in Colorado. METHODOLOGY/PRINCIPAL FINDINGS: We collected 483 fecal samples from Rocky Mountain elk and mule deer in urban and non-urban areas. Samples testing positive for STEC were higher in urban (11.0%) than non-urban (1.6%) areas. Elk fecal samples in urban areas had a much higher probability of containing STEC, which increased in both urban and non-urban areas as maximum daily temperature increased. Of the STEC-positive samples, 25% contained stx1 strains, 34.3% contained stx2, and 13% contained both stx1 and stx2. Additionally, eaeA genes were detected in 54.1% of the positive samples. Serotypes O103, and O146 were found in elk and deer feces, which also have the potential to cause human illness. CONCLUSIONS/SIGNIFICANCE: The high incidence of stx2 strains combined with eaeA and E-hyl genes that we found in wild cervid feces is associated with severe human disease, such as hemolytic uremic syndrome. This is of concern because there is a very close physical interface between elk and humans in urban areas that we sampled. In addition, we found a strong relationship between ambient temperature and incidence of STEC in elk feces, suggesting a higher incidence of STEC in elk feces in public areas on warmer days, which in turn may increase the likelihood that people will come in contact with infected feces. These concerns also have implications to other urban areas where high densities of coexisting wild cervids and humans interact on a regular basis. PMID- 24349084 TI - Cellular microRNA miR-181b inhibits replication of mink enteritis virus by repression of non-structural protein 1 translation. AB - Mink enteritis virus (MEV) is one of the most important viral pathogens in the mink industry. Recent studies have showed that microRNAs (miRNAs), small noncoding RNAs of length ranging from 18-23 nucleotides (nt) participate in host pathogen interaction networks; however, whether or not miRNAs are involved in MEV infection has not been reported. Our study revealed that miRNA miR-181b inhibited replication of MEV in the feline kidney (F81) cell line by targeting the MEV non structural protein 1 (NS1) messenger RNA (mRNA) coding region, resulting in NS1 translational repression, while MEV infection reduced miR-181b expression. This is the first description of cellular miRNAs modulating MEV infection in F81 cells, providing further insight into the mechanisms of viral infection, and may be useful in development of naturally-occurring miRNAs antiviral strategies. PMID- 24349085 TI - Transglutaminase 2 contributes to apoptosis induction in Jurkat T cells by modulating Ca2+ homeostasis via cross-linking RAP1GDS1. AB - BACKGROUND: Transglutaminase 2 (TG2) is a protein cross-linking enzyme known to be associated with the in vivo apoptosis program of T cells. However, its role in the T cell apoptosis program was not investigated yet. RESULTS: Here we report that timed overexpression of both the wild type (wt) and the cross-linking mutant of TG2 induced apoptosis in Jurkat T cells, the wt being more effective. Part of TG2 colocalised with mitochondria. WtTG2-induced apoptosis was characterized by enhanced mitochondrial Ca(2+) uptake. Ca(2+)-activated wtTG2 cross-linked RAP1, GTP-GDP dissociation stimulator 1, an unusual guanine exchange factor acting on various small GTPases, to induce a yet uncharacterized signaling pathway that was able to promote the Ca(2+) release from the endoplasmic reticulum via both Ins3P and ryanodine sensitive receptors leading to a consequently enhanced mitochondrial Ca(2+)uptake. CONCLUSIONS: Our data indicate that TG2 might act as a Ca(2+) sensor to amplify endoplasmic reticulum-derived Ca(2+) signals to enhance mitochondria Ca(2+) uptake. Since enhanced mitochondrial Ca(2+) levels were previously shown to sensitize mitochondria for various apoptotic signals, our data demonstrate a novel mechanism through which TG2 can contribute to the induction of apoptosis in certain cell types. Since, as compared to knock out cells, physiological levels of TG2 affected Ca(2+) signals in mouse embryonic fibroblasts similar to Jurkat cells, our data might indicate a more general role of TG2 in the regulation of mitochondrial Ca(2+) homeostasis. PMID- 24349087 TI - Effect of site level environmental variables, spatial autocorrelation and sampling intensity on arthropod communities in an ancient temperate lowland woodland area. AB - The interaction of arthropods with the environment and the management of their populations is a focus of the ecological agenda. Spatial autocorrelation and under-sampling may generate bias and, when they are ignored, it is hard to determine if results can in any way be trusted. Arthropod communities were studied during two seasons and using two methods: window and panel traps, in an area of ancient temperate lowland woodland of Zebracka (Czech Republic). The composition of arthropod communities was studied focusing on four site level variables (canopy openness, diameter in the breast height and height of tree, and water distance) and finally analysed using two approaches: with and without effects of spatial autocorrelation. I found that the proportion of variance explained by space cannot be ignored (~20% in both years). Potential bias in analyses of the response of arthropods to site level variables without including spatial co-variables is well illustrated by redundancy analyses. Inclusion of space led to more accurate results, as water distance and tree diameter were significant, showing approximately the same ratio of explained variance and direction in both seasons. Results without spatial co-variables were much more disordered and were difficult to explain. This study showed that neglecting the effects of spatial autocorrelation could lead to wrong conclusions in site level studies and, furthermore, that inclusion of space may lead to more accurate and unambiguous outcomes. Rarefactions showed that lower sampling intensity, when appropriately designed, can produce sufficient results without exploitation of the environment. PMID- 24349086 TI - Effect of alpha linolenic acid supplementation on serum prostate specific antigen (PSA): results from the alpha omega trial. AB - BACKGROUND: Alpha linolenic acid (ALA) is the major omega-3 fatty acid in the diet. Evidence on health effects of ALA is not conclusive, but some observational studies found an increased risk of prostate cancer with higher intake of ALA. We examined the effect of ALA supplementation on serum concentrations of prostate specific antigen (PSA), a biomarker for prostate cancer. METHODS: The Alpha Omega Trial (ClinicalTrials.gov Identifier: NCT00127452) was a double-blind, placebo controlled trial of ALA and the fish fatty acids eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) on the recurrence of cardiovascular disease, using a 2*2 factorial design. Blood was collected at the start and the end of the intervention period. The present analysis included 1622 patients with a history of a myocardial infarction, aged 60-80 years with an initial PSA concentration <4 ng/mL. They received either 2 g per day of ALA or placebo in margarine spreads for 40 months. T-tests and logistic regression were used to assess the effects of ALA supplementation on changes in serum PSA (both continuously and as a dichotomous outcome, cut-off point: >4 ng/mL). FINDINGS: Mean serum PSA increased by 0.42 ng/mL on placebo (n = 815) and by 0.52 ng/mL on ALA (n = 807), a difference of 0.10 (95% confidence interval: -0.02 to 0.22) ng/mL (P = 0.12). The odds ratio for PSA rising above 4 ng/mL on ALA versus placebo was 1.15 (95% CI: 0.84-1.58). INTERPRETATION: An additional amount of 2 g of ALA per day increased PSA by 0.10 ng/mL, but the confidence interval ranged from -0.02 to 0.22 ng/mL and included no effect. Therefore, more studies are needed to establish whether or not ALA intake has a clinically significant effect on PSA or prostate cancer. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov; Identifier: NCT00127452. URL: http://www.clinicaltrials.gov/ct2/show/NCT00127452. PMID- 24349088 TI - Reconstructing coherent networks from electroencephalography and magnetoencephalography with reduced contamination from volume conduction or magnetic field spread. AB - Volume conduction (VC) and magnetic field spread (MFS) induce spurious correlations between EEG/MEG sensors, such that the estimation of functional networks from scalp recordings is inaccurate. Imaginary coherency [1] reduces VC/MFS artefacts between sensors by assuming that instantaneous interactions are caused predominantly by VC/MFS and do not contribute to the imaginary part of the cross-spectral densities (CSDs). We propose an adaptation of the dynamic imaging of coherent sources (DICS) [2] - a method for reconstructing the CSDs between sources, and subsequently inferring functional connectivity based on coherences between those sources. Firstly, we reformulate the principle of imaginary coherency by performing an eigenvector decomposition of the imaginary part of the CSD to estimate the power that only contributes to the non-zero phase-lagged (NZPL) interactions. Secondly, we construct an NZPL-optimised spatial filter with two a priori assumptions: (1) that only NZPL interactions exist at the source level and (2) the NZPL CSD at the sensor level is a good approximation of the projected source NZPL CSDs. We compare the performance of the NZPL method to the standard method by reconstructing a coherent network from simulated EEG/MEG recordings. We demonstrate that, as long as there are phase differences between the sources, the NZPL method reliably detects the underlying networks from EEG and MEG. We show that the method is also robust to very small phase lags, noise from phase jitter, and is less sensitive to regularisation parameters. The method is applied to a human dataset to infer parts of a coherent network underpinning face recognition. PMID- 24349089 TI - Hypothalamic GPR40 signaling activated by free long chain fatty acids suppresses CFA-induced inflammatory chronic pain. AB - GPR40 has been reported to be activated by long-chain fatty acids, such as docosahexaenoic acid (DHA). However, reports studying functional role of GPR40 in the brain are lacking. The present study focused on the relationship between pain regulation and GPR40, investigating the functional roles of hypothalamic GPR40 during chronic pain caused using a complete Freund's adjuvant (CFA)-induced inflammatory chronic pain mouse model. GPR40 protein expression in the hypothalamus was transiently increased at day 7, but not at days 1, 3 and 14, after CFA injection. GPR40 was co-localized with NeuN, a neuron marker, but not with glial fibrillary acidic protein (GFAP), an astrocyte marker. At day 1 after CFA injection, GFAP protein expression was markedly increased in the hypothalamus. These increases were significantly inhibited by the intracerebroventricular injection of flavopiridol (15 nmol), a cyclin-dependent kinase inhibitor, depending on the decreases in both the increment of GPR40 protein expression and the induction of mechanical allodynia and thermal hyperalgesia at day 7 after CFA injection. Furthermore, the level of DHA in the hypothalamus tissue was significantly increased in a flavopiridol reversible manner at day 1, but not at day 7, after CFA injection. The intracerebroventricular injection of DHA (50 ug) and GW9508 (1.0 ug), a GPR40 selective agonist, significantly reduced mechanical allodynia and thermal hyperalgesia at day 7, but not at day 1, after CFA injection. These effects were inhibited by intracerebroventricular pretreatment with GW1100 (10 ug), a GPR40 antagonist. The protein expression of GPR40 was colocalized with that of beta endorphin and proopiomelanocortin, and a single intracerebroventricular injection of GW9508 (1.0 ug) significantly increased the number of neurons double-stained for c-Fos and proopiomelanocortin in the arcuate nucleus of the hypothalamus. Our findings suggest that hypothalamic GPR40 activated by free long chain fatty acids might have an important role in this pain control system. PMID- 24349090 TI - Ribbon synapse plasticity in the cochleae of Guinea pigs after noise-induced silent damage. AB - Noise exposure at low levels or low doses can damage hair cell afferent ribbon synapses without causing permanent threshold shifts. In contrast to reports in the mouse cochleae, initial damage to ribbon synapses in the cochleae of guinea pigs is largely repairable. In the present study, we further investigated the repair process in ribbon synapses in guinea pigs after similar noise exposure. In the control samples, a small portion of afferent synapses lacked synaptic ribbons, suggesting the co-existence of conventional no-ribbon and ribbon synapses. The loss and recovery of hair cell ribbons and post-synaptic densities (PSDs) occurred in parallel, but the recovery was not complete, resulting in a permanent loss of less than 10% synapses. During the repair process, ribbons were temporally separated from the PSDs. A plastic interaction between ribbons and postsynaptic terminals may be involved in the reestablishment of synaptic contact between ribbons and PSDs, as shown by location changes in both structures. Synapse repair was associated with a breakdown in temporal processing, as reflected by poorer responses in the compound action potential (CAP) of auditory nerves to time-stress signals. Thus, deterioration in temporal processing originated from the cochlea. This deterioration developed with the recovery in hearing threshold and ribbon synapse counts, suggesting that the repaired synapses had deficits in temporal processing. PMID- 24349091 TI - Influence of post-traumatic stress disorder on neuroinflammation and cell proliferation in a rat model of traumatic brain injury. AB - Long-term consequences of traumatic brain injury (TBI) are closely associated with the development of severe psychiatric disorders, such as post-traumatic stress disorder (PTSD), yet preclinical studies on pathological changes after combined TBI with PTSD are lacking. In the present in vivo study, we assessed chronic neuroinflammation, neuronal cell loss, cell proliferation and neuronal differentiation in specific brain regions of adult Sprague-Dawley male rats following controlled cortical impact model of moderate TBI with or without exposure to PTSD. Eight weeks post-TBI, stereology-based histological analyses revealed no significant differences between sham and PTSD alone treatment across all brain regions examined, whereas significant exacerbation of OX6-positive activated microglial cells in the striatum, thalamus, and cerebral peduncle, but not cerebellum, in animals that received TBI alone and combined TBI-PTSD compared with PTSD alone and sham treatment. Additional immunohistochemical results revealed a significant loss of CA3 pyramidal neurons in the hippocampus of TBI alone and TBI-PTSD compared to PTSD alone and sham treatment. Further examination of neurogenic niches revealed a significant downregulation of Ki67-positive proliferating cells, but not DCX-positive neuronally migrating cells in the neurogenic subgranular zone and subventricular zone for both TBI alone and TBI PTSD compared to PTSD alone and sham treatment. Comparisons of levels of neuroinflammation and neurogenesis between TBI alone and TBI+PTSD revealed that PTSD did not exacerbate the neuropathological hallmarks of TBI. These results indicate a progressive deterioration of the TBI brain, which, under the conditions of the present approach, was not intensified by PTSD, at least within our time window and within the examined areas of the brain. Although the PTSD manipulation employed here did not exacerbate the pathological effects of TBI, the observed long-term inflammation and suppressed cell proliferation may evolve into more severe neurodegenerative diseases and psychiatric disorders currently being recognized in traumatized TBI patients. PMID- 24349092 TI - Association of ideal cardiovascular metrics and serum high-sensitivity C-reactive protein in hypertensive population. AB - Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP) are associated with increased risk of cardiovascular disease. However, ideal cardiovascular health indicates lower risk of cardiovascular disease. This study aimed to investigate the effect of ideal cardiovascular health behaviors and health factors on hs-CRP levels among a hypertensive population. From 2006 to 2007, a cross-sectional study was conducted to survey 41,476 hypertensive subjects among the employees of Kailuan Corporation. Data from unified questionnaires and blood biochemical examinations were collected. The effects of ideal cardiovascular health behaviors and health factors on hs-CRP levels were evaluated through multivariate logistic regression analysis. A negative correlation was observed between hs-CRP levels and the number of ideal cardiovascular health metrics. The mean hs-CRP levels of subjects with zero to one, two, three, and four to six ideal cardiovascular health metrics were 1.11, 0.96, 0.90, and 0.80 mg/L, respectively (P<0.01). Multivariate logistic regression analysis revealed that after adjustment for sex, age, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and other risk factors, the risks for subjects with two, three, and four to six ideal health metrics with serum hs-CRP >3 mg/L were lower than those with zero to one ideal health metrics, with corresponding odd ratios of 0.86 (95%CI: 0.79-0.93, P<0.01), 0.76 (95%CI: 0.69-0.83, P<0.01), and 0.68 (95%CI: 0.64-0.75, P<0.01), respectively. This finding suggests that ideal cardiovascular health behaviors and health factors were related to decreased hs-CRP levels in a hypertensive population. CLINICAL TRIAL REGISTRATION: UNIQUE IDENTIFIER: ChiCTR-TNC-11001489. PMID- 24349093 TI - Determining a clinically relevant strategy for bone tissue engineering: an "all in-one" study in nude mice. AB - PURPOSE: Autologous bone grafting (BG) remains the standard reconstruction strategy for large craniofacial defects. Calcium phosphate (CaP) biomaterials, such as biphasic calcium phosphate (BCP), do not yield consistent results when used alone and must then be combined with cells through bone tissue engineering (BTE). In this context, total bone marrow (TBM) and bone marrow-derived mesenchymal stem cells (MSC) are the primary sources of cellular material used with biomaterials. However, several other BTE strategies exist, including the use of growth factors, various scaffolds, and MSC isolated from different tissues. Thus, clinicians might be unsure as to which method offers patients the most benefit. For this reason, the aim of this study was to compare eight clinically relevant BTE methods in an "all-in-one" study. METHODS: We used a transgenic rat strain expressing green fluorescent protein (GFP), from which BG, TBM, and MSC were harvested. Progenitor cells were then mixed with CaP materials and implanted subcutaneously into nude mice. After eight weeks, bone formation was evaluated by histology and scanning electron microscopy, and GFP-expressing cells were tracked with photon fluorescence microscopy. RESULTS/CONCLUSIONS: Bone formation was observed in only four groups. These included CaP materials mixed with BG or TBM, in which abundant de novo bone was formed, and BCP mixed with committed cells grown in two- and three-dimensions, which yielded limited bone formation. Fluorescence microscopy revealed that only the TBM and BG groups were positive for GFP expressing-cells, suggesting that these donor cells were still present in the host and contributed to the formation of bone. Since the TBM-based procedure does not require bone harvest or cell culture techniques, but provides abundant de novo bone formation, we recommend consideration of this strategy for clinical applications. PMID- 24349094 TI - Downregulation of cellular protective factors of rumen epithelium in goats fed high energy diet. AB - Energy-rich diets can challenge metabolic and protective functions of the rumen epithelial cells, but the underlying factors are unclear. This study sought to evaluate proteomic changes of the rumen epithelium in goats fed a low, medium, or high energy diet. Expression of protein changes were compared by two-dimensional differential gel electrophoresis followed by protein identification with matrix assisted laser desorption ionisation tandem time-of-flight mass spectrometry. Of about 2,000 spots commonly detected in all gels, 64 spots were significantly regulated, which were traced back to 24 unique proteins. Interestingly, the expression profiles of several chaperone proteins with important cellular protective functions such as heat shock cognate 71 kDa protein, peroxiredoxin-6, serpin H1, protein disulfide-isomerase, and selenium-binding protein were collectively downregulated in response to high dietary energy supply. Similar regulation patterns were obtained for some other proteins involved in transport or metabolic functions. In contrast, metabolic enzymes like retinal dehydrogenase 1 and ATP synthase subunit beta, mitochondrial precursor were upregulated in response to high energy diet. Lower expressions of chaperone proteins in the rumen epithelial cells in response to high energy supply may suggest that these cells were less protected against the potentially harmful rumen toxic compounds, which might have consequences for rumen and systemic health. Our findings also suggest that energy-rich diets and the resulting acidotic insult may render rumen epithelial cells more vulnerable to cellular damage by attenuating their cell defense system, hence facilitating the impairment of rumen barrier function, typically observed in energy-rich fed ruminants. PMID- 24349095 TI - Caring across boundaries versus keeping boundaries intact: links between moral values and interpersonal orientations. AB - Prior work has established robust diversity in the extent to which different moral values are endorsed. Some people focus on values related to caring and fairness, whereas others assign additional moral weight to ingroup loyalty, respect for authority and established hierarchies, and purity concerns. Five studies explore associations between endorsement of distinct moral values and a suite of interpersonal orientations: Machiavellianism, prosocial resource distribution, Social Dominance Orientation, and reported likelihood of helping and not helping kin and close friends versus acquaintances and neighbors. We found that Machiavellianism (Studies 1, 3, 4, 5) (e.g., amorality, controlling and status-seeking behaviors) and Social Dominance Orientation (Study 4) were negatively associated with caring values, and positively associated with valuation of authority. Those higher in caring values were more likely to choose prosocial resource distributions (Studies 2, 3, 4) and to report reduced likelihood of failing to help kin/close friends or acquaintances (Study 4). Finally, greater likelihood of helping acquaintances was positively associated with all moral values tested except authority values (Study 4). The current work offers a novel approach to characterizing moral values and reveals a striking divergence between two kinds of moral values in particular: caring values and authority values. Caring values were positively linked with prosociality and negatively associated with Machiavellianism, whereas authority values were positively associated with Machiavellianism and Social Dominance Orientation. PMID- 24349096 TI - Swing-out of the beta3 hybrid domain is required for alphaIIbbeta3 priming and normal cytoskeletal reorganization, but not adhesion to immobilized fibrinogen. AB - Structural and functional analyses of integrin alphaIIbbeta3 has implicated swing out motion of the beta3 hybrid domain in alphaIIbbeta3 activation and ligand binding. Using data from targeted molecular dynamics (TMD) simulations, we engineered two disulfide-bonded mutant receptors designed to limit swing-out (XS O). XS-O mutants cannot bind the high Mr ligand fibrinogen in the presence of an activating mAb or after introducing mutations into the alphaIIb subunit designed to simulate inside-out signaling. They also have reduced capacity to be "primed" to bind fibrinogen by pretreatment with eptifibatide. They can, however, bind the small RGD venom protein kistrin. Despite their inability to bind soluble fibrinogen, the XS-O mutants can support adhesion to immobilized fibrinogen, although such adhesion does not initiate outside-in signaling leading to normal cytoskeletal reorganization. Collectively, our data further define the biologic role of beta3 hybrid domain swing-out in both soluble and immobilized high Mr ligand binding, as well as in priming and outside-in signaling. We also infer that swing-out is likely to be a downstream effect of receptor extension. PMID- 24349097 TI - Effects of direct Renin inhibition on myocardial fibrosis and cardiac fibroblast function. AB - Myocardial fibrosis, a major pathophysiologic substrate of heart failure with preserved ejection fraction (HFPEF), is modulated by multiple pathways including the renin-angiotensin system. Direct renin inhibition is a promising anti fibrotic therapy since it attenuates the pro-fibrotic effects of renin in addition to that of other effectors of the renin-angiotensin cascade. Here we show that the oral renin inhibitor aliskiren has direct effects on collagen metabolism in cardiac fibroblasts and prevented myocardial collagen deposition in a non-hypertrophic mouse model of myocardial fibrosis. Adult mice were fed hyperhomocysteinemia-inducing diet to induce myocardial fibrosis and treated concomitantly with either vehicle or aliskiren for 12 weeks. Blood pressure and plasma angiotensin II levels were normal in control and hyperhomocysteinemic mice and reduced to levels lower than observed in the control group in the groups treated with aliskiren. Homocysteine-induced myocardial matrix gene expression and fibrosis were also prevented by aliskiren. In vitro studies using adult rat cardiac fibroblasts also showed that aliskiren attenuated the pro-fibrotic pattern of matrix gene and protein expression induced by D,L, homocysteine. Both in vivo and in vitro studies demonstrated that the Akt pathway was activated by homocysteine, and that treatment with aliskiren attenuated Akt activation. In conclusion, aliskiren as mono-therapy has potent and direct effects on myocardial matrix turnover and beneficial effects on diastolic function. PMID- 24349098 TI - Elevated plasma SPARC levels are associated with insulin resistance, dyslipidemia, and inflammation in gestational diabetes mellitus. AB - OBJECTIVE: Recent studies suggested that secreted protein acidic and rich in cysteine (SPARC), a novel adipokine, is a key player in the pathology of obesity and type 2 diabetes. We aimed to determine whether concentrations of SPARC were altered in patients with gestational diabetes mellitus (GDM) compared to normal glucose tolerance (NGT) controls and to investigate the relationships between SPARC and metabolic parameters in pregnant women. DESIGN/METHODS: Cross-sectional study of 120 pregnant women with GDM and 60 controls with NGT, in a university hospital setting. Plasma levels of SPARC, adiponectin, fibroblast growth factor 21 (FGF21), insulin and proinsulin were determined by ELISA. RESULTS: GDM women had higher SPARC and lower adiponectin than NGT subjects; no difference was found in FGF21. SPARC levels were the lowest in subjects in the third tertile of insulin sensitivity index (ISIOGTT) and correlated positively with pre-pregnant BMI, insulin and 3 h glucose during 100-g OGTT, HOMA-IR, fasting proinsulin, hsCRP and white blood cells count, and negatively with ISIOGTT, when adjusting for gestational age. Triglyceride (TG), Apolipoprotein A1, apolipoprotein B and lipoprotein (a) correlated with SPARC in partial Pearson correlation. Correlations between SPARC with adiponectin, systolic blood pressure and TG were marginally significant in partial Spearman correlation analysis. In multivariate regression analysis, SPARC was an independent negative indicator of ISIOGTT. CONCLUSIONS: SPARC levels are correlated significantly with inflammation and may also be correlated with dyslipidemia and represent an independent determinant of insulin resistance in late pregnancy, indicating a potential role of SPARC in the pathophysiology of GDM. PMID- 24349099 TI - Expression and biological activity of the cystine knot bioinsecticide PA1b (Pea Albumin 1 Subunit b). AB - The PA1b (Pea Albumin 1, subunit b) peptide is an entomotoxin extract from Legume seeds with lethal activity on several insect pests, such as mosquitoes, some aphids and cereal weevils. This 37 amino-acid cysteine-rich peptide has been, until now, obtained by biochemical purification or chemical synthesis. In this paper, we present our results for the transient production of the peptide in Nicotiana benthamiana by agro-infiltration, with a yield of about 35 ug/g of fresh leaves and maximum production 8 days after infiltration. PA1b is part of the PA1 gene which, after post-translational modifications, encodes two peptides (PA1b and PA1a). We show that transforming tobacco with the PA1b cDNA alone does not result in production of the toxin and, in fact, the entire cDNA is necessary, raising the question of the role of PA1a. We constructed a PA1-cassette, allowing for the quick "cut/paste" of different PA1b mutants within a conserved PA1 cDNA. This cassette enabled us to produce the six isoforms of PA1b which exist in pea seeds. Biological tests revealed that all the isoforms display similar activity, with the exception of one which is inactive. The lack of activity in this isoform led us to conclude that the amphiphilic nature of the peptide is necessary for activity. The possible applications of this expression system for other cysteine rich biomolecules are discussed. PMID- 24349100 TI - Location and dynamics of the immunodominant CD8 T cell response to SIVDeltanef immunization and SIVmac251 vaginal challenge. AB - Live-attenuated SIV vaccines (LAVs) have been the most effective to date in preventing or partially controlling infection by wild-type SIV in non-human primate models of HIV-1 transmission to women acting by mechanisms of protection that are not well understood. To gain insights into mechanisms of protection by LAVs that could aid development of effective vaccines to prevent HIV-1 transmission to women, we used in situ tetramer staining to determine whether increased densities or changes in the local distribution of SIV-specific CD8 T cells correlated with the maturation of SIVDeltanef vaccine-induced protection prior to and after intra-vaginal challenge with wild-type SIVmac251. We evaluated the immunodominant Mamu-A1*001:01/Gag (CM9) and Mamu-A1*001:01/Tat (SL8) epitope response in genital and lymphoid tissues, and found that tetramer+ cells were present at all time points examined. In the cervical vaginal tissues, most tetramer+ cells were distributed diffusely throughout the lamina propria or co localized with other CD8 T cells within lymphoid aggregates. The distribution and densities of the tetramer+ cells at the portal of entry did not correlate with the maturation of protection or change after challenge. Given these findings, we discuss the possibility that changes in other aspects of the immune system, including the quality of the resident population of virus-specific effector CD8 T cells could contribute to maturation of protection, as well as the potential for vaccine strategies that further increase the size and quality of this effector population to prevent HIV-1 transmission. PMID- 24349102 TI - Awareness and learning in participatory noise sensing. AB - The development of ICT infrastructures has facilitated the emergence of new paradigms for looking at society and the environment over the last few years. Participatory environmental sensing, i.e. directly involving citizens in environmental monitoring, is one example, which is hoped to encourage learning and enhance awareness of environmental issues. In this paper, an analysis of the behaviour of individuals involved in noise sensing is presented. Citizens have been involved in noise measuring activities through the WideNoise smartphone application. This application has been designed to record both objective (noise samples) and subjective (opinions, feelings) data. The application has been open to be used freely by anyone and has been widely employed worldwide. In addition, several test cases have been organised in European countries. Based on the information submitted by users, an analysis of emerging awareness and learning is performed. The data show that changes in the way the environment is perceived after repeated usage of the application do appear. Specifically, users learn how to recognise different noise levels they are exposed to. Additionally, the subjective data collected indicate an increased user involvement in time and a categorisation effect between pleasant and less pleasant environments. PMID- 24349101 TI - Insights from zebrafish and mouse models on the activity and safety of ar turmerone as a potential drug candidate for the treatment of epilepsy. AB - In a previous study, we uncovered the anticonvulsant properties of turmeric oil and its sesquiterpenoids (ar-turmerone, alpha-, beta-turmerone and alpha atlantone) in both zebrafish and mouse models of chemically-induced seizures using pentylenetetrazole (PTZ). In this follow-up study, we aimed at evaluating the anticonvulsant activity of ar-turmerone further. A more in-depth anticonvulsant evaluation of ar-turmerone was therefore carried out in the i.v. PTZ and 6-Hz mouse models. The potential toxic effects of ar-turmerone were evaluated using the beam walking test to assess mouse motor function and balance. In addition, determination of the concentration-time profile of ar-turmerone was carried out for a more extended evaluation of its bioavailability in the mouse brain. Ar-turmerone displayed anticonvulsant properties in both acute seizure models in mice and modulated the expression patterns of two seizure-related genes (c-fos and brain-derived neurotrophic factor [bdnf]) in zebrafish. Importantly, no effects on motor function and balance were observed in mice after treatment with ar-turmerone even after administering a dose 500-fold higher than the effective dose in the 6-Hz model. In addition, quantification of its concentration in mouse brains revealed rapid absorption after i.p. administration, capacity to cross the BBB and long-term brain residence. Hence, our results provide additional information on the anticonvulsant properties of ar turmerone and support further evaluation towards elucidating its mechanism of action, bioavailability, toxicity and potential clinical application. PMID- 24349103 TI - The simplest integrated multicellular organism unveiled. AB - Volvocine green algae represent the "evolutionary time machine" model lineage for studying multicellularity, because they encompass the whole range of evolutionary transition of multicellularity from unicellular Chlamydomonas to >500-celled Volvox. Multicellular volvocalean species including Gonium pectorale and Volvox carteri generally have several common morphological features to survive as integrated multicellular organisms such as "rotational asymmetry of cells" so that the cells become components of the individual and "cytoplasmic bridges between protoplasts in developing embryos" to maintain the species-specific form of the multicellular individual before secretion of new extracellular matrix (ECM). However, these morphological features have not been studied in the four celled colonial volvocine species Tetrabaena socialis that is positioned in the most basal lineage within the colonial or multicellular volvocine greens. Here we established synchronous cultures of T. socialis and carried out immunofluorescence microscopic and ultrastructural observations to elucidate these two morphological attributes. Based on immunofluorescence microscopy, four cells of the mature T. socialis colony were identical in morphology but had rotational asymmetry in arrangement of microtubular rootlets and separation of basal bodies like G. pectorale and V. carteri. Ultrastructural observations clearly confirmed the presence of cytoplasmic bridges between protoplasts in developing embryos of T. socialis even after the formation of new flagella in each daughter protoplast within the parental ECM. Therefore, these two morphological attributes might have evolved in the common four-celled ancestor of the colonial volvocine algae and contributed to the further increase in cell number and complexity of the multicellular individuals of this model lineage. T. socialis is one of the simplest integrated multicellular organisms in which four identical cells constitute the individual. PMID- 24349104 TI - Pathogenicity of a microsporidium isolate from the diamondback moth against Noctuid moths: characterization and implications for microbiological pest management. AB - BACKGROUND: Due to problems with chemical control, there is increasing interest in the use of microsporidia for control of lepidopteran pests. However, there have been few studies to evaluate the susceptibility of exotic species to microsporidia from indigenous Lepidoptera. METHODOLOGY/PRINCIPAL FINDINGS: We investigated some biological characteristics of the microsporidian parasite isolated from wild Plutella xylostella (PX) and evaluated its pathogenicity on the laboratory responses of sympatric invasive and resident noctuid moths. There were significant differences in spore size and morphology between PX and Spodoptera litura (SL) isolates. Spores of PX isolate were ovocylindrical, while those of SL were oval. PX spores were 1.05 times longer than those of SL, which in turn were 1.49 times wider than those of the PX. The timing of infection peaks was much shorter in SL and resulted in earlier larval death. There were no noticeable differences in amplicon size (two DNA fragments were each about 1200 base pairs in length). Phylogenetic analysis revealed that the small subunit (SSU) rRNA gene sequences of the two isolates shared a clade with Nosema/Vairimorpha sequences. The absence of octospores in infected spodopteran tissues suggested that PX and SL spores are closely related to Nosema plutellae and N. bombycis, respectively. Both SL and S. exigua (SE) exhibited susceptibility to the PX isolate infection, but showed different infection patterns. Tissular infection was more diverse in the former and resulted in much greater spore production and larval mortality. Microsporidium-infected larvae pupated among both infected and control larvae, but adult emergence occurred only in the second group. CONCLUSION/SIGNIFICANCE: The PX isolate infection prevented completion of development of most leafworm and beet armyworm larvae. The ability of the microsporidian isolate to severely infect and kill larvae of both native and introduced spodopterans makes it a valuable candidate for biocontrol against lepidopteran pests. PMID- 24349105 TI - A noise level prediction method based on electro-mechanical frequency response function for capacitors. AB - The capacitors in high-voltage direct-current (HVDC) converter stations radiate a lot of audible noise which can reach higher than 100 dB. The existing noise level prediction methods are not satisfying enough. In this paper, a new noise level prediction method is proposed based on a frequency response function considering both electrical and mechanical characteristics of capacitors. The electro mechanical frequency response function (EMFRF) is defined as the frequency domain quotient of the vibration response and the squared capacitor voltage, and it is obtained from impulse current experiment. Under given excitations, the vibration response of the capacitor tank is the product of EMFRF and the square of the given capacitor voltage in frequency domain, and the radiated audible noise is calculated by structure acoustic coupling formulas. The noise level under the same excitations is also measured in laboratory, and the results are compared with the prediction. The comparison proves that the noise prediction method is effective. PMID- 24349106 TI - Recipe for a busy bee: microRNAs in Honey Bee caste determination. AB - Social caste determination in the honey bee is assumed to be determined by the dietary status of the young larvae and translated into physiological and epigenetic changes through nutrient-sensing pathways. We have employed Illumina/Solexa sequencing to examine the small RNA content in the bee larval food, and show that worker jelly is enriched in miRNA complexity and abundance relative to royal jelly. The miRNA levels in worker jelly were 7-215 fold higher than in royal jelly, and both jellies showed dynamic changes in miRNA content during the 4(th) to 6(th) day of larval development. Adding specific miRNAs to royal jelly elicited significant changes in queen larval mRNA expression and morphological characters of the emerging adult queen bee. We propose that miRNAs in the nurse bee secretions constitute an additional element in the regulatory control of caste determination in the honey bee. PMID- 24349107 TI - Inhibition of DNA glycosylases via small molecule purine analogs. AB - Following the formation of oxidatively-induced DNA damage, several DNA glycosylases are required to initiate repair of the base lesions that are formed. Recently, NEIL1 and other DNA glycosylases, including OGG1 and NTH1 were identified as potential targets in combination chemotherapeutic strategies. The potential therapeutic benefit for the inhibition of DNA glycosylases was validated by demonstrating synthetic lethality with drugs that are commonly used to limit DNA replication through dNTP pool depletion via inhibition of thymidylate synthetase and dihydrofolate reductase. Additionally, NEIL1 associated synthetic lethality has been achieved in combination with Fanconi anemia, group G. As a prelude to the development of strategies to exploit the potential benefits of DNA glycosylase inhibition, it was necessary to develop a reliable high-throughput screening protocol for this class of enzymes. Using NEIL1 as the proof-of-principle glycosylase, a fluorescence-based assay was developed that utilizes incision of site-specifically modified oligodeoxynucleotides to detect enzymatic activity. This assay was miniaturized to a 1536-well format and used to screen small molecule libraries for inhibitors of the combined glycosylase/AP lyase activities. Among the top hits of these screens were several purine analogs, whose postulated presence in the active site of NEIL1 was consistent with the paradigm of NEIL1 recognition and excision of damaged purines. Although a subset of these small molecules could inhibit other DNA glycosylases that excise oxidatively-induced DNA adducts, they could not inhibit a pyrimidine dimer-specific glycosylase. PMID- 24349108 TI - Selection of osteoprogenitors from the jaw periosteum by a specific animal-free culture medium. AB - The goal of our research work is to establish mesenchymal osteoprogenitors derived from human jaw periosteum for tissue engineering applications in oral and maxillofacial surgery. For future autologous and/or allogeneic transplantations, some issues must be addressed. On the one hand, animal-free culture conditions have yet to be established. On the other hand, attempts should be undertaken to shorten the in vitro culturing process efficiently. The aim of the present study is to compare and analyze the phenotype of osteoprogenitors from the jaw periosteum under normal FCS-containing and animal-free culture conditions. Therefore, we analyzed the proliferation rates of MesenCult-XF medium (MC-) in comparison to DMEM-cultured JPCs. Whereas jaw periosteal cells (JPCs) show relatively slow proliferation rates and a fibroblastoid shape under DMEM culture conditions, MC-cultured JPCs diminished their cell size significantly and proliferated rapidly. By live-monitoring measurements of adhesion and proliferation, we made an interesting observation: whereas the proliferation of the MSCA-1(+) subpopulation and the unseparated cell fraction were favored by the animal-free culture medium, the proliferation of the MSCA-1(-) subpopulation seemed to be repressed under these conditions. The alkaline phosphatase expression pattern showed similar results under both culture conditions. Comparison of the mineralization capacity revealed an earlier formation of calcium-phosphate precipitates under MC culture conditions; however, the mineralization capacity of the DMEM-cultured cells seemed to be higher. We conclude that the tested animal-free medium is suitable for the in vitro expansion and even for the specific selection of osteoprogenitor cells derived from the jaw periosteum. PMID- 24349109 TI - Expression and functional relevance of cannabinoid receptor 1 in Hodgkin lymphoma. AB - BACKGROUND: Cannabinoid receptor 1 (CB1) is expressed in certain types of malignancies. An analysis of CB1 expression and function in Hodgkin lymphoma (HL), one of the most frequent lymphomas, was not performed to date. DESIGN AND METHODS: We examined the distribution of CB1 protein in primary cases of HL. Using lymphoma derived cell lines, the role of CB1 signaling on cell survival was investigated. RESULTS: A predominant expression of CB1 was found in Hodgkin-Reed Sternberg cells in a vast majority of classical HL cases. The HL cell lines L428, L540 and KM-H2 showed strong CB1-abundance and displayed a dose-dependent decline of viability under CB1 inhibition with AM251. Further, application of AM251 led to decrease of constitutively active NFkappaB/p65, a crucial survival factor of HRS-cells, and was followed by elevation of apoptotic markers in HL cells. CONCLUSIONS: The present study identifies CB1 as a feature of HL, which might serve as a potential selective target in the treatment of Hodgkin lymphoma. PMID- 24349110 TI - Analyzing kernel matrices for the identification of differentially expressed genes. AB - One of the most important applications of microarray data is the class prediction of biological samples. For this purpose, statistical tests have often been applied to identify the differentially expressed genes (DEGs), followed by the employment of the state-of-the-art learning machines including the Support Vector Machines (SVM) in particular. The SVM is a typical sample-based classifier whose performance comes down to how discriminant samples are. However, DEGs identified by statistical tests are not guaranteed to result in a training dataset composed of discriminant samples. To tackle this problem, a novel gene ranking method namely the Kernel Matrix Gene Selection (KMGS) is proposed. The rationale of the method, which roots in the fundamental ideas of the SVM algorithm, is described. The notion of ''the separability of a sample'' which is estimated by performing [Formula: see text]-like statistics on each column of the kernel matrix, is first introduced. The separability of a classification problem is then measured, from which the significance of a specific gene is deduced. Also described is a method of Kernel Matrix Sequential Forward Selection (KMSFS) which shares the KMGS method's essential ideas but proceeds in a greedy manner. On three public microarray datasets, our proposed algorithms achieved noticeably competitive performance in terms of the B.632+ error rate. PMID- 24349111 TI - Metarhizium anisopliae pathogenesis of mosquito larvae: a verdict of accidental death. AB - Metarhizium anisopliae, a fungal pathogen of terrestrial arthropods, kills the aquatic larvae of Aedes aegypti, the vector of dengue and yellow fever. The fungus kills without adhering to the host cuticle. Ingested conidia also fail to germinate and are expelled in fecal pellets. This study investigates the mechanism by which this fungus adapted to terrestrial hosts kills aquatic mosquito larvae. Genes associated with the M. anisopliae early pathogenic response (proteinases Pr1 and Pr2, and adhesins, Mad1 and Mad2) are upregulated in the presence of larvae, but the established infection process observed in terrestrial hosts does not progress and insecticidal destruxins were not detected. Protease inhibitors reduce larval mortality indicating the importance of proteases in the host interaction. The Ae. aegypti immune response to M. anisopliae appears limited, whilst the oxidative stress response gene encoding for thiol peroxidase is upregulated. Cecropin and Hsp70 genes are downregulated as larval death occurs, and insect mortality appears to be linked to autolysis through caspase activity regulated by Hsp70 and inhibited, in infected larvae, by protease inhibitors. Evidence is presented that a traditional host-pathogen response does not occur as the species have not evolved to interact. M. anisopliae retains pre-formed pathogenic determinants which mediate host mortality, but unlike true aquatic fungal pathogens, does not recognise and colonise the larval host. PMID- 24349112 TI - Appraisal of space words and allocation of emotion words in bodily space. AB - The body-specificity hypothesis (BSH) predicts that right-handers and left handers allocate positive and negative concepts differently on the horizontal plane, i.e., while left-handers allocate negative concepts on the right-hand side of their bodily space, right-handers allocate such concepts to the left-hand side. Similar research shows that people, in general, tend to allocate positive and negative concepts in upper and lower areas, respectively, in relation to the vertical plane. Further research shows a higher salience of the vertical plane over the horizontal plane in the performance of sensorimotor tasks. The aim of the paper is to examine whether there should be a dominance of the vertical plane over the horizontal plane, not only at a sensorimotor level but also at a conceptual level. In Experiment 1, various participants from diverse linguistic backgrounds were asked to rate the words "up", "down", "left", and "right". In Experiment 2, right-handed participants from two linguistic backgrounds were asked to allocate emotion words into a square grid divided into four boxes of equal areas. Results suggest that the vertical plane is more salient than the horizontal plane regarding the allocation of emotion words and positively valenced words were placed in upper locations whereas negatively-valenced words were placed in lower locations. Together, the results lend support to the BSH while also suggesting a higher saliency of the vertical plane over the horizontal plane in the allocation of valenced words. PMID- 24349114 TI - Extended daily dialysis in acute kidney injury patients: metabolic and fluid control and risk factors for death. AB - Intermittent hemodialysis (IHD) and continuous renal replacement therapies (CRRT) are used as Acute Kidney Injury (AKI) therapy and have certain advantages and disadvantages. Extended daily dialysis (EDD) has emerged as an alternative to CRRT in the management of hemodynamically unstable AKI patients, mainly in developed countries. OBJECTIVES: We hypothesized that EDD is a safe option for AKI treatment and aimed to describe metabolic and fluid control of AKI patients undergoing EDD and identify complications and risk factors associated with death. STUDY SELECTION: This is an observational and retrospective study describing introduction of EDD at our institution. A total of 231 hemodynamically unstable AKI patients (noradrenalin dose between 0.3 and 1.0 ucg/kg/min) were assigned to 1367 EDD session. EDD consisted of 6-8 h of HD 6 days a week, with blood flow of 200 ml/min, dialysate flows of 300 ml/min. DATA SYNTHESIS: Mean age was 60.6+/ 15.8 years, 97.4% of patients were in the intensive care unit, and sepsis was the main etiology of AKI (76.2). BUN and creatinine levels stabilized after four sessions at around 38 and 2.4 mg/dl, respectively. Fluid balance decreased progressively and stabilized around zero after five sessions. Weekly delivered Kt/V was 5.94+/-0.7. Hypotension and filter clotting occurred in 47.5 and 12.4% of treatment session, respectively. Regarding AKI outcome, 22.5% of patients presented renal function recovery, 5.6% of patients remained on dialysis after 30 days, and 71.9% of patients died. Age and focus abdominal sepsis were identified as risk factors for death. Urine output and negative fluid balance were identified as protective factors. CONCLUSIONS: EDD is effective for AKI patients, allowing adequate metabolic and fluid control. Age, focus abdominal sepsis, and lower urine output as well as positive fluid balance after two EDD sessions were associated significantly with death. PMID- 24349115 TI - Emergence of Streptococcus pyogenes emm102 causing toxic shock syndrome in Southern Taiwan during 2005-2012. AB - BACKGROUND: Streptococcal toxic shock syndrome (STSS) is an uncommon but life threatening disease caused by Streptococcus pyogenes. METHODS: To understand the clinical and molecular characteristics of STSS, we analyzed clinical data and explored the emm types, superantigen genes, and pulsed-field gel electrophoresis of causative S. pyogenes isolates obtained between 2005 and 2012. RESULTS: In total, 53 patients with STSS were included in this study. The median age of the patients was 57 years (range: 9-83 years), and 81.1% were male. The most prevalent underlying disease was diabetes mellitus (45.3%). Skin and soft-tissue infection accounted for 86.8% of STSS. The overall mortality rate was 32.1%. Underlying diseases had no statistical impact on mortality. A total of 19 different emm types were identified. The most prevalent emm type was emm102 (18.9%), followed by emm11 (17%), emm1 (11.3%), emm87 (9.4%), and emm89 (7.5%). There was no statistically significant association between emm type and a fatal outcome. Among the superantigen genes, speB was the most frequently detected one (92.5%), followed by smeZ (90.6%), speG (81.1%), speC (39.6%), and speF (39.6%). The majority of emm102 strains were found to have speB, speC, speG, and smeZ. The presence of speG was negatively associated with a fatal outcome (P = 0.045). CONCLUSIONS: Our surveillance revealed the emergence of uncommon emm types, particularly emm102, causing STSS in southern Taiwan. Characterization of clinical, epidemiological, and molecular characteristics of STSS will improve our understanding of this life-threatening disease. PMID- 24349113 TI - A quantitative comparison of human HT-1080 fibrosarcoma cells and primary human dermal fibroblasts identifies a 3D migration mechanism with properties unique to the transformed phenotype. AB - Here, we describe an engineering approach to quantitatively compare migration, morphologies, and adhesion for tumorigenic human fibrosarcoma cells (HT-1080s) and primary human dermal fibroblasts (hDFs) with the aim of identifying distinguishing properties of the transformed phenotype. Relative adhesiveness was quantified using self-assembled monolayer (SAM) arrays and proteolytic 3 dimensional (3D) migration was investigated using matrix metalloproteinase (MMP) degradable poly(ethylene glycol) (PEG) hydrogels ("synthetic extracellular matrix" or "synthetic ECM"). In synthetic ECM, hDFs were characterized by vinculin-containing features on the tips of protrusions, multipolar morphologies, and organized actomyosin filaments. In contrast, HT-1080s were characterized by diffuse vinculin expression, pronounced beta1-integrin on the tips of protrusions, a cortically-organized F-actin cytoskeleton, and quantitatively more rounded morphologies, decreased adhesiveness, and increased directional motility compared to hDFs. Further, HT-1080s were characterized by contractility-dependent motility, pronounced blebbing, and cortical contraction waves or constriction rings, while quantified 3D motility was similar in matrices with a wide range of biochemical and biophysical properties (including collagen) despite substantial morphological changes. While HT-1080s were distinct from hDFs for each of the 2D and 3D properties investigated, several features were similar to WM239a melanoma cells, including rounded, proteolytic migration modes, cortical F-actin organization, and prominent uropod-like structures enriched with beta1-integrin, F-actin, and melanoma cell adhesion molecule (MCAM/CD146/MUC18). Importantly, many of the features observed for HT-1080s were analogous to cellular changes induced by transformation, including cell rounding, a disorganized F-actin cytoskeleton, altered organization of focal adhesion proteins, and a weakly adherent phenotype. Based on our results, we propose that HT-1080s migrate in synthetic ECM with functional properties that are a direct consequence of their transformed phenotype. PMID- 24349116 TI - Urinary immunoglobulin G to albumin ratio and N-Acetyl-Beta-D-Glucosaminidase as early predictors of therapeutic response in ANCA-associated glomerulonephritis. AB - BACKGROUND: The aim of our study was to evaluate the prognostic value of glomerular and tubular proteinuria and tubular enzymuria as early indicators of therapeutic response to induction therapy with i.v. pulse cyclophosphamide (CyC) and methylprednisolone (MP) in patients with antineutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis. METHODS AND FINDINGS: An observational single-center study was conducted in 30 patients with ANCA-associated glomerulonephritis. Patients were divided into subgroups with good or poor response to CyC therapy according to clinical and laboratory parameters. The diagnosis of ANCA-associated glomerulonephritis was based on the Chapel-Hill disease definitions. Good response to induction therapy was significantly associated with higher absolute values of urine N-acetyl-beta-D-glucosaminidase (NAG) to creatinine ratio (above 14.83 microcat/mol) and urine immunoglobulin G (IgG) to albumin ratio (above 0.09) at the time of diagnosis, while albuminuria or proteinuria did not have any early predictive value. The remission of renal disease was anticipated as early as 3 months after introduction of induction therapy in patients with reduction of urine NAG to creatinine ratio below the baseline value and in patients with at least 24% rise in eGFR. CONCLUSIONS: Urine IgG to albumin and urine NAG to creatinine ratio are better early predictors of treatment response in patients with ANCA-associated glomerulonephritis than proteinuria or albuminuria. PMID- 24349117 TI - The Muller-Lyer illusion in ant foraging. AB - The Muller-Lyer illusion is a classical geometric illusion in which the apparent (perceived) length of a line depends on whether the line terminates in an arrow tail or arrowhead. This effect may be caused by economic compensation for the gap between the physical stimulus and visual fields. Here, we show that the Muller Lyer illusion can also be produced by the foraging patterns of garden ants (Lasius niger) and that the pattern obtained can be explained by a simple, asynchronously updated foraging ant model. Our results suggest that the geometric illusion may be a byproduct of the foraging process, in which local interactions underlying efficient exploitation can also give rise to global exploration, and that visual information processing in human could implement similar modulation between local efficient processing and widespread computation. PMID- 24349118 TI - Systems biology analysis of Brucella infected Peyer's patch reveals rapid invasion with modest transient perturbations of the host transcriptome. AB - Brucella melitensis causes the most severe and acute symptoms of all Brucella species in human beings and infects hosts primarily through the oral route. The epithelium covering domed villi of jejunal-ileal Peyer's patches is an important site of entry for several pathogens, including Brucella. Here, we use the calf ligated ileal loop model to study temporal in vivo Brucella-infected host molecular and morphological responses. Our results document Brucella bacteremia occurring within 30 min after intraluminal inoculation of the ileum without histopathologic traces of lesions. Based on a system biology Dynamic Bayesian Network modeling approach (DBN) of microarray data, a very early transient perturbation of the host enteric transcriptome was associated with the initial host response to Brucella contact that is rapidly averted allowing invasion and dissemination. A detailed analysis revealed active expression of Syndecan 2, Integrin alpha L and Integrin beta 2 genes, which may favor initial Brucella adhesion. Also, two intestinal barrier-related pathways (Tight Junction and Trefoil Factors Initiated Mucosal Healing) were significantly repressed in the early stage of infection, suggesting subversion of mucosal epithelial barrier function to facilitate Brucella transepithelial migration. Simultaneously, the strong activation of the innate immune response pathways would suggest that the host mounts an appropriate protective immune response; however, the expression of the two key genes that encode innate immunity anti-Brucella cytokines such as TNF alpha and IL12p40 were not significantly changed throughout the study. Furthermore, the defective expression of Toll-Like Receptor Signaling pathways may partially explain the lack of proinflammatory cytokine production and consequently the absence of morphologically detectable inflammation at the site of infection. Cumulatively, our results indicate that the in vivo pathogenesis of the early infectious process of Brucella is primarily accomplished by compromising the mucosal immune barrier and subverting critical immune response mechanisms. PMID- 24349119 TI - Health benefits of reducing sugar-sweetened beverage intake in high risk populations of California: results from the cardiovascular disease (CVD) policy model. AB - BACKGROUND: Consumption of sugar-sweetened beverage (SSB) has risen over the past two decades, with over 10 million Californians drinking one or more SSB per day. High SSB intake is associated with risk of type 2 diabetes, obesity, hypertension, and coronary heart disease (CHD). Reduction of SSB intake and the potential impact on health outcomes in California and among racial, ethnic, and low-income sub-groups has not been quantified. METHODS: We projected the impact of reduced SSB consumption on health outcomes among all Californians and California subpopulations from 2013 to 2022. We used the CVD Policy Model - CA, an established computer simulation of diabetes and heart disease adapted to California. We modeled a reduction in SSB intake by 10-20% as has been projected to result from proposed penny-per-ounce excise tax on SSB and modeled varying effects of this reduction on health parameters including body mass index, blood pressure, and diabetes risk. We projected avoided cases of diabetes and CHD, and associated health care cost savings in 2012 US dollars. RESULTS: Over the next decade, a 10-20% SSB consumption reduction is projected to result in a 1.8-3.4% decline in the new cases of diabetes and an additional drop of 0.5-1% in incident CHD cases and 0.5-0.9% in total myocardial infarctions. The greatest reductions are expected in African Americans, Mexican Americans, and those with limited income regardless of race and ethnicity. This reduction in SSB consumption is projected to yield $320-620 million in medical cost savings associated with diabetes cases averted and an additional savings of $14-27 million in diabetes related CHD costs avoided. CONCLUSIONS: A reduction of SSB consumption could yield substantial population health benefits and cost savings for California. In particular, racial, ethnic, and low-income subgroups of California could reap the greatest health benefits. PMID- 24349120 TI - Global expression profiling of low temperature induced genes in the chilling tolerant japonica rice Jumli Marshi. AB - Low temperature is a key factor that limits growth and productivity of many important agronomical crops worldwide. Rice (Oryza sativa L.) is negatively affected already at temperatures below +10 degrees C and is therefore denoted as chilling sensitive. However, chilling tolerant rice cultivars exist and can be commercially cultivated at altitudes up to 3,050 meters with temperatures reaching as low as +4 degrees C. In this work, the global transcriptional response to cold stress (+4 degrees C) was studied in the Nepalese highland variety Jumli Marshi (spp. japonica) and 4,636 genes were identified as significantly differentially expressed within 24 hours of cold stress. Comparison with previously published microarray data from one chilling tolerant and two sensitive rice cultivars identified 182 genes differentially expressed (DE) upon cold stress in all four rice cultivars and 511 genes DE only in the chilling tolerant rice. Promoter analysis of the 182 genes suggests a complex cross-talk between ABRE and CBF regulons. Promoter analysis of the 511 genes identified over represented ABRE motifs but not DRE motifs, suggesting a role for ABA signaling in cold tolerance. Moreover, 2,101 genes were DE in Jumli Marshi alone. By chromosomal localization analysis, 473 of these cold responsive genes were located within 13 different QTLs previously identified as cold associated. PMID- 24349121 TI - DNA methylation of IGF2DMR and H19 is associated with fetal and infant growth: the generation R study. AB - Changes in epigenetic programming of embryonic growth genes during pregnancy seem to affect fetal growth. Therefore, in a population-based prospective birth cohort in the Netherlands, we examined associations between fetal and infant growth and DNA methylation of IGF2DMR, H19 and MTHFR. For this study, we selected 69 case children born small-for-gestational age (SGA, birth weight <-2SDS) and 471 control children. Fetal growth was assessed with serial ultrasound measurements. Information on birth outcomes was retrieved from medical records. Infant weight was assessed at three and six months. Methylation was assessed in DNA extracted from umbilical cord white blood cells. Analyses were performed using linear mixed models with DNA methylation as dependent variable. The DNA methylation levels of IGF2DMR and H19 in the control group were, median (90% range), 53.6% (44.5-61.6) and 30.0% (25.6-34.2) and in the SGA group 52.0% (43.9-60.9) and 30.5% (23.9 32.9), respectively. The MTHFR region was found to be hypomethylated with limited variability in the control and SGA group, 2.5% (1.4-4.0) and 2.4% (1.5-3.8), respectively. SGA was associated with lower IGF2DMR DNA methylation (beta = 1.07, 95% CI -1.93; -0.21, P-value = 0.015), but not with H19 methylation. A weight gain in the first three months after birth was associated with lower IGF2DMR DNA methylation (beta = -0.53, 95% CI -0.91; -0.16, P-value = 0.005). Genetic variants in the IGF2/H19 locus were associated with IGF2DMR DNA methylation (P-value<0.05), but not with H19 methylation. Furthermore, our results suggest a possibility of mediation of DNA methylation in the association between the genetic variants and SGA. To conclude, IGF2DMR and H19 DNA methylation is associated with fetal and infant growth. PMID- 24349122 TI - Neural processes underlying the"same"-"different" judgment of two simultaneously presented objects--an EEG study. AB - The present study investigated the neural processes underlying "same" and "different" judgments for two simultaneously presented objects, that varied on one or both, of two dimensions: color and shape. Participants judged whether or not the two objects were "same" or "different" on either the color dimension (color task) or the shape dimension (shape task). The unattended irrelevant dimension of the objects was either congruent (same-same; different-different) or incongruent (same-different). ERP data showed a main effect of color congruency in the time window 190-260 ms post-stimulus presentation and a main effect of shape congruency in the time window 220-280 ms post-stimulus presentation in both color and shape tasks. The interaction between color and shape congruency in the ERP data occurred in a later time window than the two main effects, indicating that mismatches in task-relevant and task-irrelevant dimensions were processed automatically and independently before a response was selected. The fact that the interference of the task-irrelevant dimension occurred after mismatch detection, supports a confluence model of processing. PMID- 24349123 TI - Benign and malignant renal cells are differentially inhibited during prolonged organ preservation. AB - The worry of potential residual renal cancer cells in donor kidney after resection of small renal cancer impedes the extensive use of such controversial donor source. To explore the impacts of organ preservation process on the survival of renal cancer cells, we detected cell proliferation and viability of benign and malignant renal cell lines and clinical renal samples after treated with simulated organ preservation process. It was found that the viability and proliferation of malignant renal cells are inhibited much more than that of benign renal cells during prolonged organ preservation. The inhibition of proliferation in benign renal cells is fully reversible, while in malignant renal cancer cells is not fully reversible after a certain time. So potential residual renal cancer cells could be partly inhibited and eliminated by organ preservation process. PMID- 24349125 TI - When whole-genome alignments just won't work: kSNP v2 software for alignment-free SNP discovery and phylogenetics of hundreds of microbial genomes. AB - Effective use of rapid and inexpensive whole genome sequencing for microbes requires fast, memory efficient bioinformatics tools for sequence comparison. The kSNP v2 software finds single nucleotide polymorphisms (SNPs) in whole genome data. kSNP v2 has numerous improvements over kSNP v1 including SNP gene annotation; better scaling for draft genomes available as assembled contigs or raw, unassembled reads; a tool to identify the optimal value of k; distribution of packages of executables for Linux and Mac OS X for ease of installation and user-friendly use; and a detailed User Guide. SNP discovery is based on k-mer analysis, and requires no multiple sequence alignment or the selection of a single reference genome. Most target sets with hundreds of genomes complete in minutes to hours. SNP phylogenies are built by maximum likelihood, parsimony, and distance, based on all SNPs, only core SNPs, or SNPs present in some intermediate user-specified fraction of targets. The SNP-based trees that result are consistent with known taxonomy. kSNP v2 can handle many gigabases of sequence in a single run, and if one or more annotated genomes are included in the target set, SNPs are annotated with protein coding and other information (UTRs, etc.) from Genbank file(s). We demonstrate application of kSNP v2 on sets of viral and bacterial genomes, and discuss in detail analysis of a set of 68 finished E. coli and Shigella genomes and a set of the same genomes to which have been added 47 assemblies and four "raw read" genomes of H104:H4 strains from the recent European E. coli outbreak that resulted in both bloody diarrhea and hemolytic uremic syndrome (HUS), and caused at least 50 deaths. PMID- 24349124 TI - Phosphorylation of mitogen- and stress-activated protein kinase-1 in astrocytic inflammation: a possible role in inhibiting production of inflammatory cytokines. AB - PURPOSE: It is generally accepted that inflammation has a role in the progression of many central nervous system (CNS) diseases, although the mechanisms through which this occurs remain unclear. Among mitogen-activated protein kinase (MAPK) targets, mitogen- and stress-activated protein kinase (MSK1) has been thought to be involved in the pathology of inflammatory gene expression. In this study, the roles of MSK1 activation in neuroinflammation were investigated. METHODS: The bacterial lipopolysaccharide (LPS)-induced brain injury model was performed on Sprague-Dawley rats. The dynamic expression changes and the cellular location of p-MSK1 in the brain cortex were detected by Western blot and immunofluorescence staining. The synthesis of inflammatory cytokines in astrocytes was detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Phosphorylated MSK1 (p-MSK1 Thr-581) was induced significantly after intracerebral injection of LPS into the lateral ventricles of the rat brain. Specific upregulation of p-MSK1 in astrocytes was also observed in inflamed cerebral cortex. At 1 day after LPS stimulation, iNOS, TNFalpha expression, and the astrocyte marker glial fibrillary acidic protein (GFAP) were increased significantly. Also, in vitro studies indicated that the upregulation of p-MSK1 (Thr-581) may be involved in the subsequent astrocyte inflammatory process, following LPS challenge. Using an enzyme-linked immunosorbent assay (ELISA), it was confirmed that treatment with LPS in primary astrocytes stimulated the synthesis of inflammatory cytokines, through MAPKs signaling pathways. In cultured primary astrocytes, both knock-down of total MSK1 by small interfering RNAs (siRNA) or specific mutation of Thr-581 resulted in higher production of certain cytokines, such as TNFalpha and IL-6. CONCLUSIONS: Collectively, these results suggest that MSK1 phosphorylation is associated with the regulation of LPS-induced brain injury and possibly acts as a negative regulator of inflammation. PMID- 24349126 TI - MHC class II expression in human basophils: induction and lack of functional significance. AB - The antigen-presenting abilities of basophils and their role in initiating a Th2 phenotype is a topic of current controversy. We aimed to determine whether human basophils can be induced to express MHC Class II and act as antigen presenting cells for T cell stimulation. Isolated human basophils were exposed to a panel of cytokines and TLR-ligands and assessed for MHC Class II expression. MHC Class II was expressed in up to 17% of isolated basophils following incubation with a combination of IL-3, IFN-gamma and GM-CSF for 72 hours. Costimulatory molecules (CD80 and CD86) were expressed at very low levels after stimulation. Gene expression analysis of MHC Class II-positive basophils confirmed up-regulation of HLA-DR, HLA-DM, CD74 and Cathepsin S. However, MHC Class II expressing basophils were incapable of inducing antigen-specific T cell activation or proliferation. This is the first report of significant cytokine-induced MHC Class II up regulation, at both RNA and protein level, in isolated human basophils. By testing stimulation with relevant T cell epitope peptide as well as whole antigen, the failure of MHC Class II expressing basophils to induce T cell response was shown not to be solely due to inefficient antigen uptake and/or processing. PMID- 24349127 TI - Artemisinin analogues as potent inhibitors of in vitro hepatitis C virus replication. AB - We reported previously that Artemisinin (ART), a widely used anti-malarial drug, is an inhibitor of in vitro HCV subgenomic replicon replication. We here demonstrate that ART exerts its antiviral activity also in hepatoma cells infected with full length infectious HCV JFH-1. We identified a number of ART analogues that are up to 10-fold more potent and selective as in vitro inhibitors of HCV replication than ART. The iron donor Hemin only marginally potentiates the anti-HCV activity of ART in HCV-infected cultures. Carbon-centered radicals have been shown to be critical for the anti-malarial activity of ART. We demonstrate that carbon-centered radicals-trapping (the so-called TEMPO) compounds only marginally affect the anti-HCV activity of ART. This provides evidence that carbon-centered radicals are not the main effectors of the anti-HCV activity of the Artemisinin. ART and analogues may possibly exert their anti-HCV activity by the induction of reactive oxygen species (ROS). The combined anti-HCV activity of ART or its analogues with L-N-Acetylcysteine (L-NAC) [a molecule that inhibits ROS generation] was studied. L-NAC significantly reduced the in vitro anti-HCV activity of ART and derivatives. Taken together, the in vitro anti-HCV activity of ART and analogues can, at least in part, be explained by the induction of ROS; carbon-centered radicals may not be important in the anti-HCV effect of these molecules. PMID- 24349128 TI - Differential network analysis applied to preoperative breast cancer chemotherapy response. AB - In silico approaches are increasingly considered to improve breast cancer treatment. One of these treatments, neoadjuvant TFAC chemotherapy, is used in cases where application of preoperative systemic therapy is indicated. Estimating response to treatment allows or improves clinical decision-making and this, in turn, may be based on a good understanding of the underlying molecular mechanisms. Ever increasing amounts of high throughput data become available for integration into functional networks. In this study, we applied our software tool ExprEssence to identify specific mechanisms relevant for TFAC therapy response, from a gene/protein interaction network. We contrasted the resulting active subnetwork to the subnetworks of two other such methods, OptDis and KeyPathwayMiner. We could show that the ExprEssence subnetwork is more related to the mechanistic functional principles of TFAC therapy than the subnetworks of the other two methods despite the simplicity of ExprEssence. We were able to validate our method by recovering known mechanisms and as an application example of our method, we identified a mechanism that may further explain the synergism between paclitaxel and doxorubicin in TFAC treatment: Paclitaxel may attenuate MELK gene expression, resulting in lower levels of its target MYBL2, already associated with doxorubicin synergism in hepatocellular carcinoma cell lines. We tested our hypothesis in three breast cancer cell lines, confirming it in part. In particular, the predicted effect on MYBL2 could be validated, and a synergistic effect of paclitaxel and doxorubicin could be demonstrated in the breast cancer cell lines SKBR3 and MCF-7. PMID- 24349129 TI - Molecular evidence for a thymus-independent partial T cell development in a FOXN1 /- athymic human fetus. AB - The thymus is the primary organ able to support T cell ontogeny, abrogated in FOXN1(-/-) human athymia. Although evidence indicates that in animal models T lymphocytes may differentiate at extrathymic sites, whether this process is really thymus-independent has still to be clarified. In an athymic FOXN1(-/-) fetus, in which we previously described a total blockage of CD4(+) and partial blockage of CD8(+) cell development, we investigated whether intestine could play a role as extrathymic site of T-lymphopoiesis in humans. We document the presence of few extrathymically developed T lymphocytes and the presence in the intestine of CD3(+) and CD8(+), but not of CD4(+) cells, a few of them exhibiting a CD45RA(+) naive phenotype. The expression of CD3epsilonepsilonpTalpha, RAG1 and RAG2 transcripts in the intestine and TCR gene rearrangement was also documented, thus indicating that in humans the partial T cell ontogeny occurring at extrathymic sites is a thymus- and FOXN1-independent process. PMID- 24349130 TI - Year of birth effects in the historical decline of tuberculosis mortality: a reconsideration. AB - Birth cohort patterns in mortality are often used to infer long-lasting impacts of early life conditions. One of the most widely accepted examples of a birth cohort effect is that of tuberculosis mortality before the late 1940s. However the evidential basis for claims of cohort-specific declines in tuberculosis mortality is very slight. Reanalysis of original or enhanced versions of datasets used previously to support claims of cohort effects in tuberculosis mortality indicated that: 1. where the initial decline in tuberculosis mortality occurred within the period of observation, onset of decline occurred simultaneously in many age groups, in a pattern indicative of 'period' not cohort-dependent effects. 2. there was little evidence of 'proportional hazard'-type cohort patterns in tuberculosis mortality for any female population studied. Therefore any mechanisms proposed to underlie this type of cohort pattern in male mortality must be sex-specific. 3. sex ratios of tuberculosis mortality at older ages peaked in cohorts born around 1900, and resembled cohort sex ratios of lung cancer mortality. This analysis indicates that age-specific patterns in the decline in tuberculosis mortality before 1950 are unlikely to reflect improvements in early life conditions. The patterns observed are generally more consistent with the influence of factors that reduced mortality simultaneously in most age groups. Additional influences, possibly smoking habits, impeded the decline of tuberculosis in older adult males, and produced the sex-specific shifts in age distributions of mortality that were previously interpreted as evidence of cohort-dependent mortality decline. PMID- 24349131 TI - Next generation sequencing analysis of human platelet PolyA+ mRNAs and rRNA depleted total RNA. AB - BACKGROUND: Platelets are small anucleate cells circulating in the blood vessels where they play a key role in hemostasis and thrombosis. Here, we compared platelet RNA-Seq results obtained from polyA+ mRNA and rRNA-depleted total RNA. MATERIALS AND METHODS: We used purified, CD45 depleted, human blood platelets collected by apheresis from three male and one female healthy blood donors. The Illumina HiSeq 2000 platform was employed to sequence cDNA converted either from oligo(dT) isolated polyA+ RNA or from rRNA-depleted total RNA. The reads were aligned to the GRCh37 reference assembly with the TopHat/Cufflinks alignment package using Ensembl annotations. A de novo assembly of the platelet transcriptome using the Trinity software package and RSEM was also performed. The bioinformatic tools HTSeq and DESeq from Bioconductor were employed for further statistical analyses of read counts. RESULTS: Consistent with previous findings our data suggests that mitochondrially expressed genes comprise a substantial fraction of the platelet transcriptome. We also identified high transcript levels for protein coding genes related to the cytoskeleton function, chemokine signaling, cell adhesion, aggregation, as well as receptor interaction between cells. Certain transcripts were particularly abundant in platelets compared with other cell and tissue types represented by RNA-Seq data from the Illumina Human Body Map 2.0 project. Irrespective of the different library preparation and sequencing protocols, there was good agreement between samples from the 4 individuals. Eighteen differentially expressed genes were identified in the two sexes at 10% false discovery rate using DESeq. CONCLUSION: The present data suggests that platelets may have a unique transcriptome profile characterized by a relative over-expression of mitochondrially encoded genes and also of genomic transcripts related to the cytoskeleton function, chemokine signaling and surface components compared with other cell and tissue types. The in vivo functional significance of the non-mitochondrial transcripts remains to be shown. PMID- 24349132 TI - A RabGAP regulates life-cycle duration via trimeric G-protein cascades in Dictyostelium discoideum. AB - BACKGROUND: The life-cycle of cellular slime molds comprises chronobiologically regulated processes. During the growth phase, the amoeboid cells proliferate at a definite rate. Upon starvation, they synthesize cAMP as both first and second messengers in signalling pathways and form aggregates, migrating slugs, and fruiting bodies, consisting of spores and stalk cells, within 24 h. In Dictyostelium discoideum, because most growth-specific events cease during development, proliferative and heterochronic mutations are not considered to be interrelated and no genetic factor governing the entire life-cycle duration has ever been identified. METHODOLOGY/PRINCIPAL FINDINGS: Using yeast 2-hybrid library screening, we isolated a Dictyostelium discoideum RabGAP, Dd Rbg-3, as a candidate molecule by which the Dictyostelium Galpha2 subunit directs its effects. Rab GTPase-activating protein, RabGAP, acts as a negative regulator of Rab small GTPases, which orchestrate the intracellular membrane trafficking involved in cell proliferation. Deletion mutants of Dd rbg-3 exhibited an increased growth rate and a shortened developmental period, while an overexpression mutant demonstrated the opposite effects. We also show that Dd Rbg 3 interacts with 2 Galpha subunits in an activity-dependent manner in vitro. Furthermore, both human and Caenorhabditis elegans rbg-3 homologs complemented the Dd rbg-3-deletion phenotype in D. discoideum, indicating that similar pathways may be generally conserved in multicellular organisms. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that Dd Rbg-3 acts as a key element regulating the duration of D. discoideum life-span potentially via trimeric G-protein cascades. PMID- 24349133 TI - A novel source of cultured podocytes. AB - Amniotic fluid is in continuity with multiple developing organ systems, including the kidney. Committed, but still stem-like cells from these organs may thus appear in amniotic fluid. We report having established for the first time a stem like cell population derived from human amniotic fluid and possessing characteristics of podocyte precursors. Using a method of triple positive selection we obtained a population of cells (hAKPC-P) that can be propagated in vitro for many passages without immortalization or genetic manipulation. Under specific culture conditions, these cells can be differentiated to mature podocytes. In this work we compared these cells with conditionally immortalized podocytes, the current gold standard for in vitro studies. After in vitro differentiation, both cell lines have similar expression of the major podocyte proteins, such as nephrin and type IV collagen, that are characteristic of mature functional podocytes. In addition, differentiated hAKPC-P respond to angiotensin II and the podocyte toxin, puromycin aminonucleoside, in a way typical of podocytes. In contrast to immortalized cells, hAKPC-P have a more nearly normal cell cycle regulation and a pronounced developmental pattern of specific protein expression, suggesting their suitability for studies of podocyte development for the first time in vitro. These novel progenitor cells appear to have several distinct advantages for studies of podocyte cell biology and potentially for translational therapies. PMID- 24349134 TI - Renal function can improve at any stage of chronic kidney disease. AB - INTRODUCTION: Even though renal function decline is considered relentless in chronic kidney disease (CKD), improvement has been shown in patients with hypertensive nephropathy. Whether this can occur in any type of nephropathy and at any stage is unknown as are the features of patients who improve. METHODS: We identified 406 patients in the NephroTest cohort with glomerular filtration rates (mGFR) measured by (51)Cr-EDTA clearance at least 3 times during at least 2 years of follow-up. Individual examination of mGFR trajectories by 4 independent nephrologists classified patients as improvers, defined as those showing a sustained mGFR increase, or nonimprovers. Twelve patients with erratic trajectories were excluded. Baseline data were compared between improvers and nonimprovers, as was the number of recommended therapeutic targets achieved over time (specifically, for systolic and diastolic blood pressure, proteinuria, and use of renin angiotensin system blockers). RESULTS: Measured GFR improved over time in 62 patients (15.3%). Their median mGFR slope was +1.88[IQR 1.38, 3.55] ml/min/year; it was -2.23[-3.9, -0.91] for the 332 nonimprovers. Improvers had various nephropathies, but not diabetic glomerulopathy or polycystic kidney disease. They did not differ from nonimprovers for age, sex, cardiovascular history, or CKD stage, but their urinary albumin excretion rate was lower. Improvers achieved significantly more recommended therapeutic targets (2.74+/ 0.87) than nonimprovers (2.44+/-0.80, p<0.01). They also had fewer CKD-related metabolic complications and a lower prevalence of 25OH-vitamin-D deficiency. CONCLUSION: GFR improvement is possible in CKD patients at any CKD stage through stage 4-5. It is noteworthy that this GFR improvement is associated with a decrease in the number of metabolic complications over time. PMID- 24349135 TI - Protection enhances community and habitat stability: evidence from a mediterranean marine protected area. AB - Rare evidences support that Marine Protected Areas (MPAs) enhance the stability of marine habitats and assemblages. Based on nine years of observation (2001 2009) inside and outside a well managed MPA, we assessed the potential of conservation and management actions to modify patterns of spatial and/or temporal variability of Posidonia oceanica meadows, the lower midlittoral and the shallow infralittoral rock assemblages. Significant differences in both temporal variations and spatial patterns were observed between protected and unprotected locations. A lower temporal variability in the protected vs. unprotected assemblages was found in the shallow infralittoral, demonstrating that, at least at local scale, protection can enhance community stability. Macrobenthos with long-lived and relatively slow-growing invertebrates and structurally complex algal forms were homogeneously distributed in space and went through little fluctuations in time. In contrast, a mosaic of disturbed patches featured unprotected locations, with small-scale shifts from macroalgal stands to barrens, and harsh temporal variations between the two states. Opposite patterns of spatial and temporal variability were found for the midlittoral assemblages. Despite an overall clear pattern of seagrass regression through time, protected meadows showed a significantly higher shoot density than unprotected ones, suggesting a higher resistance to local human activities. Our results support the assumption that the exclusion/management of human activities within MPAs enhance the stability of the structural components of protected marine systems, reverting or arresting threat-induced trajectories of change. PMID- 24349136 TI - Estimation of quasi-stiffness of the human hip in the stance phase of walking. AB - This work presents a framework for selection of subject-specific quasi-stiffness of hip orthoses and exoskeletons, and other devices that are intended to emulate the biological performance of this joint during walking. The hip joint exhibits linear moment-angular excursion behavior in both the extension and flexion stages of the resilient loading-unloading phase that consists of terminal stance and initial swing phases. Here, we establish statistical models that can closely estimate the slope of linear fits to the moment-angle graph of the hip in this phase, termed as the quasi-stiffness of the hip. Employing an inverse dynamics analysis, we identify a series of parameters that can capture the nearly linear hip quasi-stiffnesses in the resilient loading phase. We then employ regression analysis on experimental moment-angle data of 216 gait trials across 26 human adults walking over a wide range of gait speeds (0.75-2.63 m/s) to obtain a set of general-form statistical models that estimate the hip quasi-stiffnesses using body weight and height, gait speed, and hip excursion. We show that the general form models can closely estimate the hip quasi-stiffness in the extension (R(2) = 92%) and flexion portions (R(2) = 89%) of the resilient loading phase of the gait. We further simplify the general-form models and present a set of stature based models that can estimate the hip quasi-stiffness for the preferred gait speed using only body weight and height with an average error of 27% for the extension stage and 37% for the flexion stage. PMID- 24349137 TI - Hospital physicians' influence on gastrointestinal protection during treatment with non-steroidal anti-inflammatory drugs and acetylsalicylic acid and the impact on prescribing in primary care. AB - BACKGROUND: The aim of this study was to describe the use of gastrointestinal (GI) protection before, during and after hospitalisation for elderly patients using NSAID or low-dose ASA. METHODS: This study included all elderly patients (75+) admitted to hospital in the period of 1(st) April 2010 to 31(st) March 2011 at Odense University Hospital, Denmark, who were regular users of NSAID or low dose ASA before hospital admission, or had one of these drugs initiated during hospital stay. By using pharmacy dispensing data and a hospital-based pharmacoepidemiological database, the treatment strategy for the individual patients was followed across hospital stay. RESULTS: In total, 3,587 patients were included. Before hospital admission, 93 of 245 NSAID users (38.0%) and 597 of 1994 user of low-dose ASA (29.9%) had used GI protection. During hospital stay, use of GI protection increased to 75% and 33.9%, respectively. When hospital physicians initiated new treatment with NSAID or with low-dose ASA, 305 of 555 (55.0%) and 647 of 961 (67.3%) were initiated without concomitant use of GI protection. When hospital physicians initiated GI protection, 26.8-51.0% were continued in primary care after discharge. CONCLUSIONS: During hospital stay, the use of GI protection increases, but when new treatment with NSAIDs or low-dose ASA is initiated in hospital, the use of gastrointestinal protection is low. The low use of GI protection is carried on in primary care after discharge. PMID- 24349138 TI - Predicting future blood demand from thalassemia major patients in Hong Kong. AB - BACKGROUND: In Hong Kong, thalassemia major (TM) patients utilized up to 9.5% of blood supply in 2009. For long-term management of blood supply, we predicted the future blood demand of TM patients for the next 10 years. METHODS AND RESULTS: Annual individual transfusion data in 2005-2009 and demographic information of 381 TM patients were obtained from the Hong Kong Red Cross Blood Transfusion Service database. A generalized estimating equation (GEE) model was fitted to establish the potential relations of blood demand with age, sex, body weight, year of transfusion and splenectomy, accounted for within-patient correlation. The fitted model was used to predict future blood demand for the existing patients by accounting for expected change in body weight and mortality rate. We also predicted the number of new cases in the future based on age- and sex specific TM incidence and official population projections. Future blood demand was predicted by combining blood demand from the existing and new patients. Female (RR = 0.94, p = 0.006) and history of splenectomy (RR = 0.85, p<0.001) were significantly associated with lower blood demand, while age and weight had an inverted U-shape relation with maximal blood demand at around 24 years of age and 71.8 kg, respectively. We predicted that the total blood demand would increase 0.81% annually from 13,459 units in 2009 to 15,183 units in 2024, with new TM cases accounting for 31.7% of the overall blood demand in 2024. CONCLUSIONS: Our results showed that future annual blood demand from TM patients would steadily increase in the next 10 years. Reducing incidence of TM cases in the future (by improving public education, antenatal care, prenatal diagnosis) and minimizing blood use among existing TM cases (e.g. with hemopoietic stem cell transplantation) can help relieve the burden on management of future blood demand. PMID- 24349139 TI - Deciphering the complex distribution of human immunodeficiency virus type 1 subtypes among different cohorts in Northern Tanzania. AB - BACKGROUND: Increased understanding of the genetic diversity of HIV-1 is challenging but important in the development of an effective vaccine. We aimed to describe the distribution of HIV-1 subtypes in northern Tanzania among women enrolled in studies preparing for HIV-1 prevention trials (hospitality facility worker cohorts), and among men and women in an open cohort demographic surveillance system (Kisesa cohort). METHODS: The polymerase encompassing partial reverse transcriptase was sequenced and phylogenetic analysis performed and subtype determined. Questionnaires documented demographic data. We examined factors associated with subtype using multinomial logistic regression, adjusted for study, age, and sex. RESULTS: Among 140 individuals (125 women and 15 men), subtype A1 predominated (54, 39%), followed by C (46, 33%), D (25, 18%) and unique recombinant forms (URFs) (15, 11%). There was weak evidence to suggest different subtype frequencies by study (for example, 18% URFs in the Kisesa cohort versus 5-9% in the hospitality facility-worker cohorts; adjusted relative risk ratio (aRR) = 2.35 [95% CI 0.59,9.32]; global p = 0.09). Compared to men, women were less likely to have subtype D versus A (aRR = 0.12 [95% CI 0.02,0.76]; global p = 0.05). There was a trend to suggest lower relative risk of subtype D compared to A with older age (aRR = 0.44 [95% CI 0.23,0.85] per 10 years; global p = 0.05). CONCLUSIONS: We observed multiple subtypes, confirming the complex genetic diversity of HIV-1 strains circulating in northern Tanzania, and found some differences between cohorts and by age and sex. This has important implications for vaccine design and development, providing opportunity to determine vaccine efficacy in diverse HIV-1 strains. PMID- 24349141 TI - Modeling trends from North American breeding bird survey data: a spatially explicit approach. AB - Population trends, defined as interval-specific proportional changes in population size, are often used to help identify species of conservation interest. Efficient modeling of such trends depends on the consideration of the correlation of population changes with key spatial and environmental covariates. This can provide insights into causal mechanisms and allow spatially explicit summaries at scales that are of interest to management agencies. We expand the hierarchical modeling framework used in the North American Breeding Bird Survey (BBS) by developing a spatially explicit model of temporal trend using a conditional autoregressive (CAR) model. By adopting a formal spatial model for abundance, we produce spatially explicit abundance and trend estimates. Analyses based on large-scale geographic strata such as Bird Conservation Regions (BCR) can suffer from basic imbalances in spatial sampling. Our approach addresses this issue by providing an explicit weighting based on the fundamental sample allocation unit of the BBS. We applied the spatial model to three species from the BBS. Species have been chosen based upon their well-known population change patterns, which allows us to evaluate the quality of our model and the biological meaning of our estimates. We also compare our results with the ones obtained for BCRs using a nonspatial hierarchical model (Sauer and Link 2011). Globally, estimates for mean trends are consistent between the two approaches but spatial estimates provide much more precise trend estimates in regions on the edges of species ranges that were poorly estimated in non-spatial analyses. Incorporating a spatial component in the analysis not only allows us to obtain relevant and biologically meaningful estimates for population trends, but also enables us to provide a flexible framework in order to obtain trend estimates for any area. PMID- 24349140 TI - A metagenomic framework for the study of airborne microbial communities. AB - Understanding the microbial content of the air has important scientific, health, and economic implications. While studies have primarily characterized the taxonomic content of air samples by sequencing the 16S or 18S ribosomal RNA gene, direct analysis of the genomic content of airborne microorganisms has not been possible due to the extremely low density of biological material in airborne environments. We developed sampling and amplification methods to enable adequate DNA recovery to allow metagenomic profiling of air samples collected from indoor and outdoor environments. Air samples were collected from a large urban building, a medical center, a house, and a pier. Analyses of metagenomic data generated from these samples reveal airborne communities with a high degree of diversity and different genera abundance profiles. The identities of many of the taxonomic groups and protein families also allows for the identification of the likely sources of the sampled airborne bacteria. PMID- 24349143 TI - Incorrect citations give unfair credit to review authors in ecology journals. AB - The number of citations that papers receive has become significant in measuring researchers' scientific productivity, and such measurements are important when one seeks career opportunities and research funding. Skewed citation practices can thus have profound effects on academic careers. We investigated (i) how frequently authors misinterpret original information and (ii) how frequently authors inappropriately cite reviews instead of the articles upon which the reviews are based. To reach this aim, we carried a survey of ecology journals indexed in the Web of Science and assessed the appropriateness of citations of review papers. Reviews were significantly more often cited than regular articles. In addition, 22% of citations were inaccurate, and another 15% unfairly gave credit to the review authors for other scientists' ideas. These practices should be stopped, mainly through more open discussion among mentors, researchers and students. PMID- 24349142 TI - Hypoxic tumor environments exhibit disrupted collagen I fibers and low macromolecular transport. AB - Hypoxic tumor microenvironments result in an aggressive phenotype and resistance to therapy that lead to tumor progression, recurrence, and metastasis. While poor vascularization and the resultant inadequate drug delivery are known to contribute to drug resistance, the effect of hypoxia on molecular transport through the interstitium, and the role of the extracellular matrix (ECM) in mediating this transport are unexplored. The dense mesh of fibers present in the ECM can especially influence the movement of macromolecules. Collagen 1 (Col1) fibers form a key component of the ECM in breast cancers. Here we characterized the influence of hypoxia on macromolecular transport in tumors, and the role of Col1 fibers in mediating this transport using an MDA-MB-231 breast cancer xenograft model engineered to express red fluorescent protein under hypoxia. Magnetic resonance imaging of macromolecular transport was combined with second harmonic generation microscopy of Col1 fibers. Hypoxic tumor regions displayed significantly decreased Col1 fiber density and volume, as well as significantly lower macromolecular draining and pooling rates, than normoxic regions. Regions adjacent to severely hypoxic areas revealed higher deposition of Col1 fibers and increased macromolecular transport. These data suggest that Col1 fibers may facilitate macromolecular transport in tumors, and their reduction in hypoxic regions may reduce this transport. Decreased macromolecular transport in hypoxic regions may also contribute to poor drug delivery and tumor recurrence in hypoxic regions. High Col1 fiber density observed around hypoxic regions may facilitate the escape of aggressive cancer cells from hypoxic regions. PMID- 24349144 TI - Insertion of a specific fungal 3'-phosphoadenosine-5'-phosphatase motif into a plant homologue improves halotolerance and drought tolerance of plants. AB - Soil salinity and drought are among the most serious agricultural and environmental problems of today. Therefore, investigations of plant resistance to abiotic stress have received a lot of attention in recent years. In this study, we identified the complete coding sequence of a 3'-phosphoadenosine-5' phosphatase protein, ApHal2, from the halotolerant yeast Aureobasidium pullulans. Expression of the ApHAL2 gene in a Saccharomyces cerevisiae hal2 mutant complemented the mutant auxotrophy for methionine, and rescued the growth of the hal2 mutant in media with high NaCl concentrations. A 21-amino-acids-long region of the ApHal2 enzyme was inserted into the Arabidopsis thaliana homologue of Hal2, the SAL1 phosphatase. The inserted sequence included the META motif, which has previously been implicated in increased sodium tolerance of the Hal2 homologue from a related fungal species. Transgenic Arabidopsis plants overexpressing this modified SAL1 (mSAL1) showed improved halotolerance and drought tolerance. In a medium with an elevated salt concentration, mSAL1 expressing plants were twice as likely to have roots in a higher length category in comparison with the wild-type Arabidopsis and with plants overexpressing the native SAL1, and had 5% to 10% larger leaf surface area under moderate and severe salt stress, respectively. Similarly, after moderate drought exposure, the mSAL1 expressing plants showed 14% increased dry weight after revitalisation, with no increase in dry weight of the wild-type plants. With severe drought, plants overexpressing native SAL1 had the worst rehydration success, consistent with the recently proposed role of SAL1 in severe drought. This was not observed for plants expressing mSAL1. Therefore, the presence of this fungal META motif sequence is beneficial under conditions of increased salinity and moderate drought, and shows no drawbacks for plant survival under severe drought. This demonstrates that adaptations of extremotolerant fungi should be considered as a valuable resource for improving stress-tolerance in plant breeding in the future. PMID- 24349145 TI - The relationship between economic status, knowledge on dengue, risk perceptions and practices. AB - The reemergence of dengue as an important public health problem reflects the difficulties in sustaining vertically organized, effective, control programs and the need for community-based strategies for Aedes aegypti control that result in behavioral change. We aimed to disentangle the relationships between underlying determinants of dengue related practices. We conducted a cross-sectional study in 780 households in La Lisa, Havana, Cuba. A questionnaire and an observation guide were administrated to collect information on variables related to economic status, knowledge on dengue, risk perception and practices associated with Aedes aegypti breading sites. To test a conceptual model that hypothesized direct relationships among all these constructs, we first used Exploratory Factor Analysis with Principal Component Analysis to establish the relationship between observed variables and the underlying latent variables. Subsequently, we tested whether the observed data supported the conceptual model through Confirmatory Factor Analysis. Exploratory Factor Analysis indicated that the items measured could be reduced into five factors with an eigenvalue >1.0: Knowledge on dengue, Intradomiciliar risk practices, Peridomiciliar risk practices, Risk perception and Economic status. The proportion of the total variance in the data explained by these five factors was 74.3%. The Confirmatory Factor Analysis model differed from our hypothesized conceptual model. Only Knowledge on dengue had a significant, direct, positive, effect on Practices. There was also a direct association of Economic status with Knowledge on dengue, but not with Risk perception and Practices. Clarifying the relationship between direct and indirect determinants of dengue related practices contributes to a better understanding of the potential effect of Information Education and Communication on practices and on the reduction of Aedes aegypti breeding sites and provides inputs for designing a community based strategy for dengue control. PMID- 24349146 TI - Influence of lifestyle factors on mammographic density in postmenopausal women. AB - BACKGROUND: Mammographic density is a strong risk factor for breast cancer. Apart from hormone replacement therapy (HRT), little is known about lifestyle factors that influence breast density. METHODS: We examined the effect of smoking, alcohol and physical activity on mammographic density in a population-based sample of postmenopausal women without breast cancer. Lifestyle factors were assessed by a questionnaire and percentage and area measures of mammographic density were measured using computer-assisted software. General linear models were used to assess the association between lifestyle factors and mammographic density and effect modification by body mass index (BMI) and HRT was studied. RESULTS: Overall, alcohol intake was positively associated with percent mammographic density (P trend = 0.07). This association was modified by HRT use (P interaction = 0.06): increasing alcohol intake was associated with increasing percent density in current HRT users (P trend = 0.01) but not in non-current users (P trend = 0.82). A similar interaction between alcohol and HRT was found for the absolute dense area, with a positive association being present in current HRT users only (P interaction = 0.04). No differences in mammographic density were observed across categories of smoking and physical activity, neither overall nor in stratified analyses by BMI and HRT use. CONCLUSIONS: Increasing alcohol intake is associated with an increase in mammography density, whereas smoking and physical activity do not seem to influence density. The observed interaction between alcohol and HRT may pose an opportunity for HRT users to lower their mammographic density and breast cancer risk. PMID- 24349148 TI - Imported dengue cases, weather variation and autochthonous dengue incidence in Cairns, Australia. AB - BACKGROUND: Dengue fever (DF) outbreaks often arise from imported DF cases in Cairns, Australia. Few studies have incorporated imported DF cases in the estimation of the relationship between weather variability and incidence of autochthonous DF. The study aimed to examine the impact of weather variability on autochthonous DF infection after accounting for imported DF cases and then to explore the possibility of developing an empirical forecast system. METHODOLOGY/PRINCIPAL FINDS: Data on weather variables, notified DF cases (including those acquired locally and overseas), and population size in Cairns were supplied by the Australian Bureau of Meteorology, Queensland Health, and Australian Bureau of Statistics. A time-series negative-binomial hurdle model was used to assess the effects of imported DF cases and weather variability on autochthonous DF incidence. Our results showed that monthly autochthonous DF incidences were significantly associated with monthly imported DF cases (Relative Risk (RR):1.52; 95% confidence interval (CI): 1.01-2.28), monthly minimum temperature ((o)C) (RR: 2.28; 95% CI: 1.77-2.93), monthly relative humidity (%) (RR: 1.21; 95% CI: 1.06-1.37), monthly rainfall (mm) (RR: 0.50; 95% CI: 0.31 0.81) and monthly standard deviation of daily relative humidity (%) (RR: 1.27; 95% CI: 1.08-1.50). In the zero hurdle component, the occurrence of monthly autochthonous DF cases was significantly associated with monthly minimum temperature (Odds Ratio (OR): 1.64; 95% CI: 1.01-2.67). CONCLUSIONS/SIGNIFICANCE: Our research suggested that incidences of monthly autochthonous DF were strongly positively associated with monthly imported DF cases, local minimum temperature and inter-month relative humidity variability in Cairns. Moreover, DF outbreak in Cairns was driven by imported DF cases only under favourable seasons and weather conditions in the study. PMID- 24349147 TI - Healthy lifestyles reduce the incidence of chronic diseases and dementia: evidence from the Caerphilly cohort study. AB - BACKGROUND: Healthy lifestyles based on non-smoking, an acceptable BMI, a high fruit and vegetable intake, regular physical activity, and low/moderate alcohol intake, are associated with reductions in the incidence of certain chronic diseases, but to date there is limited evidence on cognitive function and dementia. METHODS: In 1979 healthy behaviours were recorded on 2,235 men aged 45 59 years in Caerphilly, UK. During the following 30 years incident diabetes, vascular disease, cancer and death were recorded, and in 2004 cognitive state was determined. FINDINGS: Men who followed four or five of the behaviours had an odds ratio (OR) and confidence intervals (CI) for diabetes, corrected for age and social class, of 0.50 (95% CI: 0.19, 1.31; P for trend with increasing numbers of healthy behaviours <0.0005). For vascular disease the OR was 0.50 (95% CI: 0.30, 0.84; P for trend <0.0005), and there was a delay in vascular disease events of up to 12 years. Cancer incidence was not significantly related to lifestyle although there was a reduction associated with non-smoking (OR: 0.65; 95% CI: 0.54, 0.79). All-cause mortality was reduced in men following four or five behaviours (OR 0.40; 95% CI: 0.24, 0.67; P for trend <0.005). After further adjustment for NART, the OR for men following four or five healthy behaviours was 0.36 (95% CI: 0.12, 1.09; P for trend <0.001) for cognitive impairment, and 0.36 (95% CI: 0.07, 1.99; P for trend <0.02) for dementia. The adoption of a healthy lifestyle by men was low and appears not to have changed during the subsequent 30 years, with under 1% of men following all five of the behaviours and 5% reporting four or more in 1979 and in 2009. INTERPRETATION: A healthy lifestyle is associated with increased disease-free survival and reduced cognitive impairment but the uptake remains low. PMID- 24349149 TI - Remote source document verification in two national clinical trials networks: a pilot study. AB - OBJECTIVE: Barriers to executing large-scale randomized controlled trials include costs, complexity, and regulatory requirements. We hypothesized that source document verification (SDV) via remote electronic monitoring is feasible. METHODS: Five hospitals from two NIH sponsored networks provided remote electronic access to study monitors. We evaluated pre-visit remote SDV compared to traditional on-site SDV using a randomized convenience sample of all study subjects due for a monitoring visit. The number of data values verified and the time to perform remote and on-site SDV was collected. RESULTS: Thirty-two study subjects were randomized to either remote SDV (N=16) or traditional on-site SDV (N=16). Technical capabilities, remote access policies and regulatory requirements varied widely across sites. In the adult network, only 14 of 2965 data values (0.47%) could not be located remotely. In the traditional on-site SDV arm, 3 of 2608 data values (0.12%) required coordinator help. In the pediatric network, all 198 data values in the remote SDV arm and all 183 data values in the on-site SDV arm were located. Although not statistically significant there was a consistent trend for more time consumed per data value (minutes +/- SD): Adult 0.50 +/- 0.17 min vs. 0.39 +/- 0.10 min (two-tailed t-test p=0.11); Pediatric 0.99 +/- 1.07 min vs. 0.56 +/- 0.61 min (p=0.37) and time per case report form: Adult: 4.60 +/- 1.42 min vs. 3.60 +/- 0.96 min (p=0.10); Pediatric: 11.64 +/- 7.54 min vs. 6.07 +/- 3.18 min (p=0.10) using remote SDV. CONCLUSIONS: Because each site had different policies, requirements, and technologies, a common approach to assimilating monitors into the access management system could not be implemented. Despite substantial technology differences, more than 99% of data values were successfully monitored remotely. This pilot study demonstrates the feasibility of remote monitoring and the need to develop consistent access policies for remote study monitoring. PMID- 24349150 TI - Source-sink estimates of genetic introgression show influence of hatchery strays on wild chum salmon populations in Prince William Sound, Alaska. AB - The extent to which stray, hatchery-reared salmon affect wild populations is much debated. Although experiments show that artificial breeding and culture influence the genetics of hatchery salmon, little is known about the interaction between hatchery and wild salmon in a natural setting. Here, we estimated historical and contemporary genetic population structures of chum salmon (Oncorhynchus keta) in Prince William Sound (PWS), Alaska, with 135 single nucleotide polymorphism (SNP) markers. Historical population structure was inferred from the analysis of DNA from fish scales, which had been archived since the late 1960's for several populations in PWS. Parallel analyses with microsatellites and a test based on Hardy-Weinberg proportions showed that about 50% of the fish-scale DNA was cross contaminated with DNA from other fish. These samples were removed from the analysis. We used a novel application of the classical source-sink model to compare SNP allele frequencies in these archived fish-scales (1964-1982) with frequencies in contemporary samples (2008-2010) and found a temporal shift toward hatchery allele frequencies in some wild populations. Other populations showed markedly less introgression, despite moderate amounts of hatchery straying. The extent of introgression may reflect similarities in spawning time and life history traits between hatchery and wild fish, or the degree that hybrids return to a natal spawning area. The source-sink model is a powerful means of detecting low levels of introgression over several generations. PMID- 24349152 TI - Reassessing morphological homologies in the early-divergent angiosperm Fenerivia (annonaceae) based on floral vascular anatomy: significance for interpreting putative homeotic mutations. AB - Fenerivia species (Annonaceae) are characterized by a prominent flange immediately below the perianth, which has been interpreted as synapomorphic for the genus. The homology of this flange is controversial: previous studies of Fenerivia heteropetala (an aberrant species, with 12 perianth parts in three whorls) have suggested that the flange may represent a vestigial calyx resulting from a disruption to the homeotic control of organ identity during floral development. Comparative data on floral vasculature in Fenerivia capuronii are presented to elucidate the homology of the flange in other Fenerivia species (which possess nine perianth parts in three whorls, typical of most Annonaceae). The flange in F. capuronii differs from that in F. heteropetala as it is unvascularized. It is nevertheless suggested that the flange is likely to be homologous, and that a homeotic mutation in the F. heteropetala lineage resulted in the formation of a vestigial but vascularized calyx that fused with the otherwise unvascularized flange. PMID- 24349151 TI - Tuberculous lymphadenitis in Northern Ethiopia: in a public health and microbiological perspectives. AB - BACKGROUND: The actual burden and causative agent of tuberculous lymphadenitis (TBLN) cases is not well known due to lack of strong surveillance system and diagnostic facilities in Ethiopia. This study was conducted to determine the prevalence of TBLN, its causative agent and risk factors for acquiring this infection. METHODS: A cross-sectional study was conducted from April to May 2012 at four main hospitals and one diagnostic clinic located in northern Ethiopia. Fine needle aspirates (FNAs) from TBLN suspects were taken for acid fast bacilli (AFB) microscopy, culture and molecular typing. RESULTS: Among 437 aspirates, culture yielded AFB in 226 (51.7%) of cases. Sixty one culture negative cases (30.5% of 200 cases) were positive by Xpert MTB/RIF test. Moreover, a rifampicin resistant AFB was detected from culture negative cases. The overall prevalence of FNAs positive TBLN cases was 65.8 %. The BacT/AlerT 3D system proved to be a more rapid method with higher recovery rate than Lowenstein-Jensen (L-J) and/or Gottsacker media (P<0.0001). Molecular typing identified all culture positive isolates as M.tuberculosis. The main risk factors for TBLN were pediatric age (OR 2.8, 95% CI, 1.09- 7.05) and cough (OR 2, 95%CI, 1.09-3.7). CONCLUSIONS: The results of this study revealed a high prevalence of TBLN in the study sites and that pediatric age and cough are key predictors of the disease. TBLN is an important public health problem that needs to be addressed in the area. It is important to note that MDR strains of TB could be involved and aetiological confirmation and drug sensitivity testing of TBLN isolates should be expanded. Further studies on the M.tuberculosis lineages, circulating strains and transmission dynamics, are recommended. PMID- 24349153 TI - TNFalpha signals via p66(Shc) to induce E-Selectin, promote leukocyte transmigration and enhance permeability in human endothelial cells. AB - Endothelial cells participate in inflammatory events leading to atherogenesis by regulating endothelial cell permeability via the expression of VE-Cadherin and beta-catenin and leukocyte recruitment via the expression of E-Selectins and other adhesion molecules. The protein p66(Shc) acts as a sensor/inducer of oxidative stress and may promote vascular dysfunction. The objective of this study was to investigate the role of p66(Shc) in tumor necrosis factor TNFalpha induced E-Selectin expression and function in human umbilical vein endothelial cells (HUVEC). Exposure of HUVEC to 50 ng/ml TNFalpha resulted in increased leukocyte transmigration through the endothelial monolayer and E-Selectin expression, in association with augmented phosphorylation of both p66(Shc) on Ser(36) and the stress kinase c-Jun NH2-terminal protein kinase (JNK)-1/2, and higher intracellular reactive oxygen species (ROS) levels. Overexpression of p66(Shc) in HUVEC resulted in enhanced p66(Shc) phosphorylation on Ser(36), increased ROS and E-Selectin levels, and amplified endothelial cell permeability and leukocyte transmigration through the HUVEC monolayer. Conversely, overexpression of a phosphorylation-defective p66(Shc) protein, in which Ser(36) was replaced by Ala, did not augment ROS and E-Selectin levels, nor modify cell permeability or leukocyte transmigration beyond those found in wild-type cells. Moreover, siRNA-mediated silencing of p66(Shc) resulted in marked reduction of E Selectin expression and leukocyte transmigration. In conclusion, p66(Shc) acts as a novel intermediate in the TNFalpha pathway mediating endothelial dysfunction, and its action requires JNK-dependent phosphorylation of p66(Shc) on Ser(36). PMID- 24349154 TI - The activation by glucose of liver membrane nitric oxide synthase in the synthesis and translocation of glucose transporter-4 in the production of insulin in the mice hepatocytes. AB - INTRODUCTION: Glucose has been reported to have an essential role in the synthesis and secretion of insulin in hepatocytes. As the efflux of glucose is facilitated from the liver cells into the circulation, the mechanism of transportation of glucose into the hepatocytes for the synthesis of insulin was investigated. METHODS: Grated liver suspension (GLS) was prepared by grating intact liver from adult mice by using a grater. Nitric oxide (NO) was measured by methemoglobin method. Glucose transporter-4 (Glut-4) was measured by immunoblot technique using Glut-4 antibody. RESULTS: Incubation of GLS with different amounts of glucose resulted in the uptake of glucose by the suspension with increased NO synthesis due to the stimulation of a glucose activated nitric oxide synthase that was present in the liver membrane. The inhibition of glucose induced NO synthesis resulted in the inhibition of glucose uptake. Glucose at 0.02M that maximally increased NO synthesis in the hepatocytes led to the translocation and increased synthesis of Glut-4 by 3.3 fold over the control that was inhibited by the inhibition of NO synthesis. The glucose induced NO synthesis was also found to result in the synthesis of insulin, in the presence of glucose due to the expression of both proinsulin genes I and II in the liver cells. CONCLUSION: It was concluded that glucose itself facilitated its own transportation in the liver cells both via Glut-4 and by the synthesis of NO which had an essential role for insulin synthesis in the presence of glucose in these cells. PMID- 24349155 TI - Brassinosteroids regulate plant growth through distinct signaling pathways in Selaginella and Arabidopsis. AB - Brassinosteroids (BRs) are growth-promoting steroid hormones that regulate diverse physiological processes in plants. Most BR biosynthetic enzymes belong to the cytochrome P450 (CYP) family. The gene encoding the ultimate step of BR biosynthesis in Arabidopsis likely evolved by gene duplication followed by functional specialization in a dicotyledonous plant-specific manner. To gain insight into the evolution of BRs, we performed a genomic reconstitution of Arabidopsis BR biosynthetic genes in an ancestral vascular plant, the lycophyte Selaginella moellendorffii. Selaginella contains four members of the CYP90 family that cluster together in the CYP85 clan. Similar to known BR biosynthetic genes, the Selaginella CYP90s exhibit eight or ten exons and Selaginella produces a putative BR biosynthetic intermediate. Therefore, we hypothesized that Selaginella CYP90 genes encode BR biosynthetic enzymes. In contrast to typical CYPs in Arabidopsis, Selaginella CYP90E2 and CYP90F1 do not possess amino terminal signal peptides, suggesting that they do not localize to the endoplasmic reticulum. In addition, one of the three putative CYP reductases (CPRs) that is required for CYP enzyme function co-localized with CYP90E2 and CYP90F1. Treatments with a BR biosynthetic inhibitor, propiconazole, and epi-brassinolide resulted in greatly retarded and increased growth, respectively. This suggests that BRs promote growth in Selaginella, as they do in Arabidopsis. However, BR signaling occurs through different pathways than in Arabidopsis. A sequence homologous to the Arabidopsis BR receptor BRI1 was absent in Selaginella, but downstream components, including BIN2, BSU1, and BZR1, were present. Thus, the mechanism that initiates BR signaling in Selaginella seems to differ from that in Arabidopsis. Our findings suggest that the basic physiological roles of BRs as growth-promoting hormones are conserved in both lycophytes and Arabidopsis; however, different BR molecules and BRI1-based membrane receptor complexes evolved in these plants. PMID- 24349157 TI - Chemical camouflage--a frog's strategy to co-exist with aggressive ants. AB - Whereas interspecific associations receive considerable attention in evolutionary, behavioural and ecological literature, the proximate bases for these associations are usually unknown. This in particular applies to associations between vertebrates with invertebrates. The West-African savanna frog Phrynomantis microps lives in the underground nest of ponerine ants (Paltothyreus tarsatus). The ants usually react highly aggressively when disturbed by fiercely stinging, but the frog is not attacked and lives unharmed among the ants. Herein we examined the proximate mechanisms for this unusual association. Experiments with termites and mealworms covered with the skin secretion of the frog revealed that specific chemical compounds seem to prevent the ants from stinging. By HPLC-fractionation of an aqueous solution of the frogs' skin secretion, two peptides of 1,029 and 1,143 Da were isolated and found to inhibit the aggressive behaviour of the ants. By de novo sequencing using tandem mass spectrometry, the amino acid sequence of both peptides consisting of a chain of 9 and 11 residues, respectively, was elucidated. Both peptides were synthesized and tested, and exhibited the same inhibitory properties as the original frog secretions. These novel peptides most likely act as an appeasement allomone and may serve as models for taming insect aggression. PMID- 24349156 TI - Functionally different pads on the same foot allow control of attachment: stick insects have load-sensitive "heel" pads for friction and shear-sensitive "toe" pads for adhesion. AB - Stick insects (Carausius morosus) have two distinct types of attachment pad per leg, tarsal "heel" pads (euplantulae) and a pre-tarsal "toe" pad (arolium). Here we show that these two pad types are specialised for fundamentally different functions. When standing upright, stick insects rested on their proximal euplantulae, while arolia were the only pads in surface contact when hanging upside down. Single-pad force measurements showed that the adhesion of euplantulae was extremely small, but friction forces strongly increased with normal load and coefficients of friction were [Formula: see text] 1. The pre tarsal arolium, in contrast, generated adhesion that strongly increased with pulling forces, allowing adhesion to be activated and deactivated by shear forces, which can be produced actively, or passively as a result of the insects' sprawled posture. The shear-sensitivity of the arolium was present even when corrected for contact area, and was independent of normal preloads covering nearly an order of magnitude. Attachment of both heel and toe pads is thus activated partly by the forces that arise passively in the situations in which they are used by the insects, ensuring safe attachment. Our results suggest that stick insect euplantulae are specialised "friction pads" that produce traction when pressed against the substrate, while arolia are "true" adhesive pads that stick to the substrate when activated by pulling forces. PMID- 24349158 TI - Mitochondrial DNA diversity of modern, ancient and wild sheep(Ovis gmelinii anatolica) from Turkey: new insights on the evolutionary history of sheep. AB - In the present study, to contribute to the understanding of the evolutionary history of sheep, the mitochondrial (mt) DNA polymorphisms occurring in modern Turkish native domestic (n = 628), modern wild (Ovis gmelinii anatolica) (n = 30) and ancient domestic sheep from Oylum Hoyuk in Kilis (n = 33) were examined comparatively with the accumulated data in the literature. The lengths (75 bp/76 bp) of the second and subsequent repeat units of the mtDNA control region (CR) sequences differentiated the five haplogroups (HPGs) observed in the domestic sheep into two genetic clusters as was already implied by other mtDNA markers: the first cluster being composed of HPGs A, B, D and the second cluster harboring HPGs C, E. To manifest genetic relatedness between wild Ovis gmelinii and domestic sheep haplogroups, their partial cytochrome B sequences were examined together on a median-joining network. The two parallel but wider aforementioned clusters were observed also on the network of Ovis gmelenii individuals, within which domestic haplogroups were embedded. The Ovis gmelinii wilds of the present day appeared to be distributed on two partially overlapping geographic areas parallel to the genetic clusters that they belong to (the first cluster being in the western part of the overall distribution). Thus, the analyses suggested that the domestic sheep may be the products of two maternally distinct ancestral Ovis gmelinii populations. Furthermore, Ovis gmelinii anatolica individuals exhibited a haplotype of HPG A (n = 22) and another haplotype (n = 8) from the second cluster which was not observed among the modern domestic sheep. HPG E, with the newly observed members (n = 11), showed signs of expansion. Studies of ancient and modern mtDNA suggest that HPG C frequency increased in the Southeast Anatolia from 6% to 22% some time after the beginning of the Hellenistic period, 500 years Before Common Era (BCE). PMID- 24349159 TI - Protocol for callus induction and somatic embryogenesis in Moso Bamboo. AB - Moso bamboo [Phyllostachys heterocycla var. pubescens (Mazel ex J. Houz.) Ohwi] is one of the most important forest crops in China and the rest of Asia. Although many sympodial bamboo tissue culture protocols have been established, there is no protocol available for plantlet regeneration as indicated by callus induction for monopodial bamboos, such as Moso bamboo. In the present report, embryogenic callus induction, embryoid development, and germination were established for Moso bamboo from zygotic seed embryos. Callus was initiated from zygotic embryos after 10-20 d culture on MS media supplemented with 4.0 mg/L 2, 4-D and 0.1 mg/L zeatin (ZT). About 50% of the explants produced calli, and nearly 15% of the calli were found to be embryogenic in nature. These embryogenic calli can be subcultured for proliferation in the Murashige and Skoog media (MS) supplemented with 0.5-2.0 mg/L 2, 4-D. These calli were found to have maintained their capacity for regeneration even after one year of subculture. The viable somatic embryoids regenerated in medium containing 5.0-7.0 mg/L ZT. Nearly 5% of the calli were found capable of regenerating into plantlets directly in MS medium containing 5.0 7.0 mg/L ZT. Root growth was more pronounced when the plantlets were transferred to medium containing 2.0 mg/L NAA. After 30 days of subculture, the plantlets were transferred to a greenhouse. PMID- 24349160 TI - A multistage gene normalization system integrating multiple effective methods. AB - Gene/protein recognition and normalization is an important preliminary step for many biological text mining tasks. In this paper, we present a multistage gene normalization system which consists of four major subtasks: pre-processing, dictionary matching, ambiguity resolution and filtering. For the first subtask, we apply the gene mention tagger developed in our earlier work, which achieves an F-score of 88.42% on the BioCreative II GM testing set. In the stage of dictionary matching, the exact matching and approximate matching between gene names and the EntrezGene lexicon have been combined. For the ambiguity resolution subtask, we propose a semantic similarity disambiguation method based on Munkres' Assignment Algorithm. At the last step, a filter based on Wikipedia has been built to remove the false positives. Experimental results show that the presented system can achieve an F-score of 90.1%, outperforming most of the state-of-the art systems. PMID- 24349161 TI - Negative emotion regulation in patients with posttraumatic stress disorder. AB - OBJECTIVE: To explore the neural mechanisms of negative emotion regulation in patients with post-traumatic stress disorder (PTSD). METHODS: Twenty PTSD patients and 20 healthy subjects were recruited. Event-related functional magnetic resonance imaging (fMRI) was used to investigate the modification of emotional responses to negative stimuli. Participants were required to regulate their emotional reactions according to the auditory regulation instructions via headphones, to maintain, enhance or diminish responses to negative stimuli during fMRI scans. RESULTS: The PTSD group showed poorer modification performance than the control group when diminishing responses to negative stimuli. On fMRI, the PTSD group showed decreased activation in the inferior frontal cortex, inferior parietal lobule, insula and putamen, and increased activation in posterior cingulate cortex and amygdala during up-regulation of negative emotion. Similar decreased activation regions were found during down-regulation of negative emotion, but no increased activation was found. CONCLUSION: Trauma exposure might impair the ability to down-regulate negative emotion. The present findings will improve our understanding of the neural mechanisms of emotion regulation underlying PTSD. PMID- 24349162 TI - New therapeutic approach: diphenyl diselenide reduces mitochondrial dysfunction in acetaminophen-induced acute liver failure. AB - The acute liver failure (ALF) induced by acetaminophen (APAP) is closely related to oxidative damage and depletion of hepatic glutathione, consequently changes in cell energy metabolism and mitochondrial dysfunction have been observed after APAP overdose. Diphenyl diselenide [(PhSe)2], a simple organoselenium compound with antioxidant properties, previously demonstrated to confer hepatoprotection. However, little is known about the protective mechanism on mitochondria. The main objective of this study was to investigate the effects (PhSe)2 to reduce mitochondrial dysfunction and, secondly, compare in the liver homogenate the hepatoprotective effects of the (PhSe)2 to the N-acetylcysteine (NAC) during APAP induced ALF to validate our model. Mice were injected intraperitoneal with APAP (600 mg/kg), (PhSe)2 (15.6 mg/kg), NAC (1200 mg/kg), APAP+(PhSe)2 or APAP+NAC, where the (PhSe)2 or NAC treatment were given 1 h following APAP. The liver was collected 4 h after overdose. The plasma alanine and aspartate aminotransferase activities increased after APAP administration. APAP caused a remarkable increase of oxidative stress markers (lipid peroxidation, reactive species and protein carbonylation) and decrease of the antioxidant defense in the liver homogenate and mitochondria. APAP caused a marked loss in the mitochondrial membrane potential, the mitochondrial ATPase activity, and the rate of mitochondrial oxygen consumption and increased the mitochondrial swelling. All these effects were significantly prevented by (PhSe)2. The effectiveness of (PhSe)2 was similar at a lower dose than NAC. In summary, (PhSe)2 provided a significant improvement to the mitochondrial redox homeostasis and the mitochondrial bioenergetics dysfunction caused by membrane permeability transition in the hepatotoxicity APAP induced. PMID- 24349163 TI - The network architecture of the Saccharomyces cerevisiae genome. AB - We propose a network-based approach for surmising the spatial organization of genomes from high-throughput interaction data. Our strategy is based on methods for inferring architectural features of networks. Specifically, we employ a community detection algorithm to partition networks of genomic interactions. These community partitions represent an intuitive interpretation of genomic organization from interaction data. Furthermore, they are able to recapitulate known aspects of the spatial organization of the Saccharomyces cerevisiae genome, such as the rosette conformation of the genome, the clustering of centromeres, as well as tRNAs, and telomeres. We also demonstrate that simple architectural features of genomic interaction networks, such as cliques, can give meaningful insight into the functional role of the spatial organization of the genome. We show that there is a correlation between inter-chromosomal clique size and replication timing, as well as cohesin enrichment. Together, our network-based approach represents an effective and intuitive framework for interpreting high throughput genomic interaction data. Importantly, there is a great potential for this strategy, given the rich literature and extensive set of existing tools in the field of network analysis. PMID- 24349165 TI - A collusion-resistant fingerprinting system for restricted distribution of digital documents. AB - Digital fingerprinting is a technique that consists of inserting the ID of an authorized user in the digital content that he requests. This technique has been mainly used to trace back pirate copies of multimedia content such as images, audio, and video. This study proposes the use of state-of-the-art digital fingerprinting techniques in the context of restricted distribution of digital documents. In particular, the system proposed by Kuribayashi for multimedia content is investigated. Extensive simulations show the robustness of the proposed system against average collusion attack. Perceptual transparency of the fingerprinted documents is also studied. Moreover, by using an efficient Fast Fourier Transform core and standard computer machines it is shown that the proposed system is suitable for real-world scenarios. PMID- 24349164 TI - Evaluation of cytotoxic and anti-inflammatory activities of extracts and lectins from Moringa oleifera seeds. AB - BACKGROUND: The extract from Moringa oleifera seeds is used worldwide, especially in rural areas of developing countries, to treat drinking water. M. oleifera seeds contain the lectins cmol and WSMoL, which are carbohydrate-binding proteins that are able to reduce water turbidity because of their coagulant activity. Studies investigating the ability of natural products to damage normal cells are essential for the safe use of these substances. This study evaluated the cytotoxic and anti-inflammatory properties of the aqueous seed extract, the extract used by population to treat water (named diluted seed extract in this work), and the isolated lectins cmol and WSMoL. METHODOLOGY/PRINCIPAL FINDINGS: The data showed that the aqueous seed extract and cmol were potentially cytotoxic to human peripheral blood mononuclear cells, while WSMoL and diluted seed extract were not cytotoxic. The M. oleifera aqueous seed extract and the lectins cmol and WSMoL were weakly/moderately cytotoxic to the NCI-H292, HT-29 and HEp-2 cancer cell lines and were not hemolytic to murine erythrocytes. Evaluation of acute toxicity in mice revealed that the aqueous seed extract (2.000 mg/kg) did not cause systemic toxicity. The aqueous seed extract, cmol and WSMoL (6.25 ug/mL) and diluted seed extract at 50 ug/mL exhibited anti-inflammatory activity on lipopolyssaccharide-stimulated murine macrophages by regulating the production of nitric oxide, TNF-alpha and IL-1beta. The aqueous seed extract reduced leukocyte migration in a mouse model of carrageenan-induced pleurisy; the myeloperoxidase activity and nitric oxide, TNF-alpha and IL-1beta levels were similarly reduced. Histological analysis of the lungs showed that the extract reduced the number of leukocytes. CONCLUSION/SIGNIFICANCE: This study shows that the extract prepared according to folk use and WSMoL may be non-toxic to mammalian cells; however, the aqueous seed extract and cmol may be cytotoxic to immune cells which may explain the immunosuppressive potential of the extract. PMID- 24349166 TI - Rapid induction of lipid droplets in Chlamydomonas reinhardtii and Chlorella vulgaris by Brefeldin A. AB - Algal lipids are the focus of intensive research because they are potential sources of biodiesel. However, most algae produce neutral lipids only under stress conditions. Here, we report that treatment with Brefeldin A (BFA), a chemical inducer of ER stress, rapidly triggers lipid droplet (LD) formation in two different microalgal species, Chlamydomonas reinhardtii and Chlorella vulgaris. LD staining using Nile red revealed that BFA-treated algal cells exhibited many more fluorescent bodies than control cells. Lipid analyses based on thin layer chromatography and gas chromatography revealed that the additional lipids formed upon BFA treatment were mainly triacylglycerols (TAGs). The increase in TAG accumulation was accompanied by a decrease in the betaine lipid diacylglyceryl N,N,N-trimethylhomoserine (DGTS), a major component of the extraplastidic membrane lipids in Chlamydomonas, suggesting that at least some of the TAGs were assembled from the degradation products of membrane lipids. Interestingly, BFA induced TAG accumulation in the Chlamydomonas cells regardless of the presence or absence of an acetate or nitrogen source in the medium. This effect of BFA in Chlamydomonas cells seems to be due to BFA-induced ER stress, as supported by the induction of three homologs of ER stress marker genes by the drug. Together, these results suggest that ER stress rapidly triggers TAG accumulation in two green microalgae, C. reinhardtii and C. vulgaris. A further investigation of the link between ER stress and TAG synthesis may yield an efficient means of producing biofuel from algae. PMID- 24349168 TI - Co-culture of human bronchial fibroblasts and CD4+ T cells increases Th17 cytokine signature. AB - BACKGROUND: Airway inflammation is an important characteristic of asthma and has been associated with airway remodelling and bronchial hyperreactivity. The mucosal microenvironment composed of structural cells and highly specialised extracellular matrix is able to amplify and promote inflammation. This microenvironment leads to the development and maintenance of a specific adaptive response characterized by Th2 and Th17. Bronchial fibroblasts produce multiple mediators that may play a role in maintaining and amplifying this response in asthma. OBJECTIVE: To investigate the role of bronchial fibroblasts obtained from asthmatic subjects and healthy controls in regulating Th17 response by creating a local micro-environment that promotes this response in the airways. METHODS: Human bronchial fibroblasts and CD4(+)T cells were isolated from atopic asthmatics and non-atopic healthy controls. CD4(+)T were co-cultured with bronchial fibroblasts of asthmatic subjects and healthy controls. RORc gene expression was detected by qPCR. Phosphorylated STAT-3 and RORgammat were evaluated by western blots. Th17 phenotype was measured by flow cytometry. IL-22, IL17, IL-6 TGF-beta and IL1-beta were assessed by qPCR and ELISA. RESULTS: Co culture of CD4(+)T cells with bronchial fibroblasts significantly stimulated RORc expression and induced a significant increase in Th17 cells as characterized by the percentage of IL-17(+)/CCR6(+) staining in asthmatic conditions. IL-17 and IL 22 were increased in both normal and asthmatic conditions with a significantly higher amount in asthmatics compared to controls. IL-6, IL-1beta, TGF-beta and IL 23 were significantly elevated in fibroblasts from asthmatic subjects upon co culture with CD4(+)T cells. IL-23 stimulates IL-6 and IL-1beta expression by bronchial fibroblasts. CONCLUSION: Interaction between bronchial fibroblasts and T cells seems to promote specifically Th17 cells profile in asthma. These results suggest that cellular interaction particularly between T cells and fibroblasts may play a pivotal role in the regulation of the inflammatory response in asthma. PMID- 24349167 TI - Carnosine's effect on amyloid fibril formation and induced cytotoxicity of lysozyme. AB - Carnosine, a common dipeptide in mammals, has previously been shown to dissemble alpha-crystallin amyloid fibrils. To date, the dipeptide's anti-fibrillogensis effect has not been thoroughly characterized in other proteins. For a more complete understanding of carnosine's mechanism of action in amyloid fibril inhibition, we have investigated the effect of the dipeptide on lysozyme fibril formation and induced cytotoxicity in human neuroblastoma SH-SY5Y cells. Our study demonstrates a positive correlation between the concentration and inhibitory effect of carnosine against lysozyme fibril formation. Molecular docking results show carnosine's mechanism of fibrillogenesis inhibition may be initiated by binding with the aggregation-prone region of the protein. The dipeptide attenuates the amyloid fibril-induced cytotoxicity of human neuronal cells by reducing both apoptotic and necrotic cell deaths. Our study provides solid support for carnosine's amyloid fibril inhibitory property and its effect against fibril-induced cytotoxicity in SH-SY5Y cells. The additional insights gained herein may pave way to the discovery of other small molecules that may exert similar effects against amyloid fibril formation and its associated neurodegenerative diseases. PMID- 24349169 TI - Rv0132c of Mycobacterium tuberculosis encodes a coenzyme F420-dependent hydroxymycolic acid dehydrogenase. AB - The ability of Mycobacterium tuberculosis to manipulate and evade human immune system is in part due to its extraordinarily complex cell wall. One of the key components of this cell wall is a family of lipids called mycolic acids. Oxygenation of mycolic acids generating methoxy- and ketomycolic acids enhances the pathogenic attributes of M. tuberculosis. Thus, the respective enzymes are of interest in the research on mycobacteria. The generation of methoxy- and ketomycolic acids proceeds through intermediary formation of hydroxymycolic acids. While the methyl transferase that generates methoxymycolic acids from hydroxymycolic acids is known, hydroxymycolic acids dehydrogenase that oxidizes hydroxymycolic acids to ketomycolic acids has been elusive. We found that hydroxymycolic acid dehydrogenase is encoded by the rv0132c gene and the enzyme utilizes F420, a deazaflavin coenzyme, as electron carrier, and accordingly we called it F420-dependent hydroxymycolic acid dehydrogenase. This is the first report on the involvement of F420 in the synthesis of a mycobacterial cell envelope. Also, F420-dependent hydroxymycolic acid dehydrogenase was inhibited by PA-824, and therefore, it is a previously unknown target for this new tuberculosis drug. PMID- 24349170 TI - Biomass partitioning and its relationship with the environmental factors at the alpine steppe in Northern Tibet. AB - Alpine steppe is considered to be the largest grassland type on the Tibetan Plateau. This grassland contributes to the global carbon cycle and is sensitive to climate changes. The allocation of biomass in an ecosystem affects plant growth and the overall functioning of the ecosystem. However, the mechanism by which plant biomass is allocated on the alpine steppe remains unclear. In this study, biomass allocation and its relationship to environmental factors on the alpine grassland were studied by a meta-analysis of 32 field sites across the alpine steppe of the northern Tibetan Plateau. We found that there is less above ground biomass (M A ) and below-ground biomass (M B ) in the alpine steppe than there is in alpine meadows and temperate grasslands. By contrast, the root-to shoot ratio (R:S) in the alpine steppe is higher than it is in alpine meadows and temperate grasslands. Although temperature maintained the biomass in the alpine steppe, precipitation was found to considerably influence M A , M B , and R:S, as shown by ordination space partitioning. After standardized major axis (SMA) analysis, we found that allocation of biomass on the alpine steppe is supported by the allometric biomass partitioning hypothesis rather than the isometric allocation hypothesis. Based on these results, we believe that M A and M B will decrease as a result of the increased aridity expected to occur in the future, which will reduce the landscape's capacity for carbon storage. PMID- 24349171 TI - Two randomized trials provide no consistent evidence for nonmusical cognitive benefits of brief preschool music enrichment. AB - Young children regularly engage in musical activities, but the effects of early music education on children's cognitive development are unknown. While some studies have found associations between musical training in childhood and later nonmusical cognitive outcomes, few randomized controlled trials (RCTs) have been employed to assess causal effects of music lessons on child cognition and no clear pattern of results has emerged. We conducted two RCTs with preschool children investigating the cognitive effects of a brief series of music classes, as compared to a similar but non-musical form of arts instruction (visual arts classes, Experiment 1) or to a no-treatment control (Experiment 2). Consistent with typical preschool arts enrichment programs, parents attended classes with their children, participating in a variety of developmentally appropriate arts activities. After six weeks of class, we assessed children's skills in four distinct cognitive areas in which older arts-trained students have been reported to excel: spatial-navigational reasoning, visual form analysis, numerical discrimination, and receptive vocabulary. We initially found that children from the music class showed greater spatial-navigational ability than did children from the visual arts class, while children from the visual arts class showed greater visual form analysis ability than children from the music class (Experiment 1). However, a partial replication attempt comparing music training to a no-treatment control failed to confirm these findings (Experiment 2), and the combined results of the two experiments were negative: overall, children provided with music classes performed no better than those with visual arts or no classes on any assessment. Our findings underscore the need for replication in RCTs, and suggest caution in interpreting the positive findings from past studies of cognitive effects of music instruction. PMID- 24349172 TI - Extramotor damage is associated with cognition in primary lateral sclerosis patients. AB - OBJECTIVES: This is a cross-sectional study aimed at investigating cognitive performances in patients with primary lateral sclerosis (PLS) and using diffusion tensor (DT) magnetic resonance imaging (MRI) to determine the topographical distribution of microstructural white matter (WM) damage in patients with or without cognitive deficits. METHODS: DT MRI scans were obtained from 21 PLS patients and 35 age- and sex-matched healthy controls. All PLS patients underwent a comprehensive neuropsychological battery. Tract-based-spatial-statistics (TBSS) was used to perform a whole-brain voxel-wise analysis of fractional anisotropy (FA), axial, radial (radD) and mean diffusivity (MD). RESULTS: Ten PLS patients had abnormal scores in at least one neuropsychological test (PLS with cognitive deficits, PLS-cd). Compared with healthy controls and cognitively unimpaired PLS patients (PLS-cu), PLS-cd cases showed decreased FA and increased MD and radD in the corticospinal tract (CST), corpus callosum, brainstem, anterior limb of internal capsule, superior and inferior longitudinal fasciculi, fornix, thalamic radiations, and parietal lobes, bilaterally. Compared with healthy controls, PLS cd patients showed further decreased FA and increased radD in the cerebellar WM, bilaterally. Compared with controls, PLS-cu patients showed decreased FA in the mid-body of corpus callosum. In PLS, executive and language test scores correlated with WM damage. CONCLUSIONS: This is the first study evaluating the relationship between cognitive performance and WM tract damage in PLS patients. PLS can be associated with a multi-domain cognitive impairment. WM damage to interhemispheric, limbic and major associative WM tracts seem to be the structural correlate of cognitive abnormalities in these patients. PMID- 24349173 TI - In silico, in vitro and in vivo analysis of binding affinity between N and C domains of Clostridium perfringens alpha toxin. AB - Clostridium perfringens alpha toxin/phospholipase C (CP-PLC) is one of the most potent bacterial toxins known to cause soft tissue infections like gas gangrene in humans and animals. It is the first bacterial toxin demonstrated to be an enzyme with phospholipase, sphingomyelinase and lecithinase activities. The toxin is comprised of an enzymatic N-domain and a binding C-domain interconnected by a flexible linker. The N-domain alone is non-toxic to mammalian cells, but incubation with C-domain restores the toxicity, the mechanism of which is still not elucidated. The objectives of the current study were to investigate the formation of a stable N and C-domain complex, to determine possible interactions between the two domains in silico and to characterize the in vitro and in vivo correlates of the interaction. To establish the existence of a stable N and C domain hybrid, in vitro pull down assay and dot-Far Western blotting assays were employed, where it was clearly revealed that the two domains bound to each other to form an intermediate. Using bioinformatics tools like MetaPPISP, PatchDock and FireDock, we predicted that the two domains may interact with each other through electrostatic interactions between at least six pairs of amino acids. This N and C-domains interacted with each other in 1:1 ratio and the hybrid lysed mouse erythrocytes in a slower kinetics when compared with wild type native Cp-PLC. BALB/c mice when challenged with N and C-domain hybrid demonstrated severe myonecrosis at the site of injection while no death was observed. Our results provide further insight into better understanding the mechanism for the toxicity of Cp-PLC N and C-domain mixture. PMID- 24349174 TI - Psychosocial functioning and intelligence both partly explain socioeconomic inequalities in premature death. A population-based male cohort study. AB - OBJECTIVE: The possible contributions of psychosocial functioning and intelligence differences to socioeconomic status (SES)-related inequalities in premature death were investigated. None of the previous studies focusing on inequalities in mortality has included measures of both psychosocial functioning and intelligence. METHODS: The study was based on a cohort of 49 321 men born 1949-1951 from the general community in Sweden. Data on psychosocial functioning and intelligence from military conscription at ~18 years of age were linked with register data on education, occupational class, and income at 35-39 years of age. Psychosocial functioning was rated by psychologists as a summary measure of differences in level of activity, power of initiative, independence, and emotional stability. Intelligence was measured through a multidimensional test. Causes of death between 40 and 57 years of age were followed in registers. RESULTS: The estimated inequalities in all-cause mortality by education and occupational class were attenuated with 32% (95% confidence interval: 20-45%) and 41% (29-52%) after adjustments for individual psychological differences; both psychosocial functioning and intelligence contributed to account for the inequalities. The inequalities in cardiovascular and injury mortality were attenuated by as much as 51% (24-76%) and 52% (35-68%) after the same adjustments, and the inequalities in alcohol-related mortality were attenuated by up to 33% (8-59%). Less of the inequalities were accounted for when those were measured by level of income, with which intelligence had a weaker correlation. The small SES-related inequalities in cancer mortality were not attenuated by adjustment for intelligence. CONCLUSIONS: Differences in psychosocial functioning and intelligence might both contribute to the explanation of observed SES-related inequalities in premature death, but the magnitude of their contributions likely varies with measure of socioeconomic status and cause of death. Both psychosocial functioning and intelligence should be considered in future studies. PMID- 24349175 TI - Ginkgo biloba extract individually inhibits JNK activation and induces c-Jun degradation in human chondrocytes: potential therapeutics for osteoarthritis. AB - Osteoarthritis (OA) is a common joint disorder with varying degrees of inflammation. The ideal anti-OA drug should have immunomodulatory effects while at the same time having limited or no toxicity. We examined the anti-inflammatory effects of Ginkgo biloba extract (EGb) in interleukin-1 (IL-1)-stimulated human chondrocytes. Chondrocytes were prepared from cartilage specimens taken from patients with osteoarthritis who had received total hip or total knee replacement. The concentrations of chemokines and the degree of cell migration were determined by ELISA and chemotaxis assays, respectively. The activation of inducible nitric oxide synthase (iNOS), mitogen-activated protein kinases (MAPKs), activator protein-1 (AP-1), and nuclear factor-kappaB (NF-kappaB) was determined by immunoblotting, immunohistochemistry, and electrophoretic mobility shift assay. We found that EGb inhibited IL-1-induced production of chemokines, which in turn resulted in attenuation of THP-1 cell migration toward EGb-treated cell culture medium. EGb also suppressed IL-1-stimulated iNOS expression and release of nitric oxide (NO). The EGb-mediated suppression of the iNOS-NO pathway correlated with the attenuation of activator protein-1 (AP-1) but not nuclear factor-kappaB (NF-kappaB) DNA-binding activity. Of the mitogen-activated protein kinases (MAPKs), EGb inhibited only c-Jun N-terminal kinase (JNK). Unexpectedly, EGb selectively caused degradation of c-Jun protein. Further investigation revealed that EGb-mediated c-Jun degradation was preceded by ubiquitination of c Jun and could be prevented by the proteosome inhibitor MG-132. The results imply that EGb protects against chondrocyte degeneration by inhibiting JNK activation and inducing ubiquitination-dependent c-Jun degradation. Although additional research is needed, our results suggest that EGb is a potential therapeutic agent for the treatment of OA. PMID- 24349177 TI - Effects of 'target' plant species body size on neighbourhood species richness and composition in old-field vegetation. AB - Competition is generally regarded as an important force in organizing the structure of vegetation, and evidence from several experimental studies of species mixtures suggests that larger mature plant size elicits a competitive advantage. However, these findings are at odds with the fact that large and small plant species generally coexist, and relatively smaller species are more common in virtually all plant communities. Here, we use replicates of ten relatively large old-field plant species to explore the competitive impact of target individual size on their surrounding neighbourhoods compared to nearby neighbourhoods of the same size that are not centred by a large target individual. While target individuals of the largest of our test species, Centaurea jacea L., had a strong impact on neighbouring species, in general, target species size was a weak predictor of the number of other resident species growing within its immediate neighbourhood, as well as the number of resident species that were reproductive. Thus, the presence of a large competitor did not restrict the ability of neighbouring species to reproduce. Lastly, target species size did not have any impact on the species size structure of neighbouring species; i.e. they did not restrict smaller, supposedly poorer competitors, from growing and reproducing close by. Taken together, these results provide no support for a size-advantage in competition restricting local species richness or the ability of small species to coexist and successfully reproduce in the immediate neighbourhood of a large species. PMID- 24349176 TI - Celecoxib-induced cytotoxic effect is potentiated by inhibition of autophagy in human urothelial carcinoma cells. AB - Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, can elicit anti-tumor effects in various malignancies. Here, we sought to clarify the role of autophagy in celecoxib-induced cytotoxicity in human urothelial carcinoma (UC) cells. The results shows celecoxib induced cellular stress response such as endoplasmic reticulum (ER) stress, phosopho-SAPK/JNK, and phosopho-c-Jun as well as autophagosome formation in UC cells. Inhibition of autophagy by 3-methyladenine (3-MA), bafilomycin A1 or ATG7 knockdown potentiated celecoxib-induced apoptosis. Up-regulation of autophagy by rapamycin or GFP-LC3B-transfection alleviated celecoxib-induced cytotoxicity in UC cells. Taken together, the inhibition of autophagy enhances therapeutic efficacy of celecoxib in UC cells, suggesting a novel therapeutic strategy against UC. PMID- 24349178 TI - Nephrogenic systemic fibrosis in Denmark--a nationwide investigation. AB - BACKGROUND: Nephrogenic systemic fibrosis is a debilitating and painful disorder with an increased stimulation of the connective tissue in the skin and systemic tissues. The disease is associated with exposure to gadolinium-based contrast agent used in magnetic resonance imaging in patients with renal impairment. METHODS: The prevalence of nephrogenic systemic fibrosis has so far never been determined at a national level. In 2009, Denmark was the first country to design a guideline for the tracing of nephrogenic systemic fibrosis patients. The aim of this paper is to communicate the main findings of this quest. RESULTS: The outcome of the nationwide investigation revealed that Denmark had 65 patients with nephrogenic systemic fibrosis and thereby the highest prevalence of nephrogenic systemic fibrosis worldwide with 65 per 5.6 million inhabitants, or 12 per million. CONCLUSIONS: The nationwide investigation in Denmark revealed the highest prevalence of NSF worldwide. This may be rooted in a high level of awareness of NSF both among doctors, politicians and, not least, the media, combined with the fact that a nationwide NSF investigation was initiated. PMID- 24349179 TI - Effects of ENSO and temporal rainfall variation on the dynamics of successional communities in old-field succession of a tropical dry forest. AB - The effects of temporal variation of rainfall on secondary succession of tropical dry ecosystems are poorly understood. We studied effects of inter-seasonal and inter-year rainfall variation on the dynamics of regenerative successional communities of a tropical dry forest in Mexico. We emphasized the effects caused by the severe El Nino Southern Oscillation (ENSO) occurred in 2005. We established permanent plots in sites representing a chronosequence of Pasture (abandoned pastures, 0-1 years fallow age), Early (3-5), Intermediate (8-12), and Old-Growth Forest categories (n = 3 per category). In total, 8210 shrubs and trees 10 to 100-cm height were identified, measured, and monitored over four years. Rates of plant recruitment, growth and mortality, and gain and loss of species were quantified per season (dry vs. rainy), year, and successional category, considering whole communities and separating seedlings from sprouts and shrubs from trees. Community rates changed with rainfall variation without almost any effect of successional stage. Mortality and species loss rates peaked during the ENSO year and the following year; however, after two rainy years mortality peaked in the rainy season. Such changes could result from the severe drought in the ENSO year, and of the outbreak of biotic agents during the following rainy years. Growth, recruitment and species gain rates were higher in the rainy season but they were significantly reduced after the ENSO year. Seedlings exhibited higher recruitment and mortality rate than sprouts, and shrubs showed higher recruitment than trees. ENSO strongly impacted both the dynamics and trajectory of succession, creating transient fluctuations in the abundance and species richness of the communities. Overall, there was a net decline in plant and species density in most successional stages along the years. Therefore, strong drought events have critical consequences for regeneration dynamics, delaying the successional process and modifying the resilience of these systems. PMID- 24349180 TI - Testing measurement invariance of the schizotypal personality questionnaire-brief scores across Spanish and Swiss adolescents. AB - BACKGROUND: Schizotypy is a complex construct intimately related to psychosis. Empirical evidence indicates that participants with high scores on schizotypal self-report are at a heightened risk for the later development of psychotic disorders. Schizotypal experiences represent the behavioural expression of liability for psychotic disorders. Previous factorial studies have shown that schizotypy is a multidimensional construct similar to that found in patients with schizophrenia. Specifically, using the Schizotypal Personality Questionnaire Brief (SPQ-B), the three-dimensional model has been widely replicated. However, there has been no in-depth investigation of whether the dimensional structure underlying the SPQ-B scores is invariant across countries. METHODS: The main goal of this study was to examine the measurement invariance of the SPQ-B scores across Spanish and Swiss adolescents. The final sample was made up of 261 Spanish participants (51.7% men; M = 16.04 years) and 241 Swiss participants (52.3% men; M = 15.94 years). RESULTS: The results indicated that Raine et al.'s three-factor model presented adequate goodness-of-fit indices. Moreover, the results supported the measurement invariance (configural and partial strong invariance) of the SPQ B scores across the two samples. Spanish participants scored higher on Interpersonal dimension than Swiss when latent means were compared. DISCUSSION: The study of measurement equivalence across countries provides preliminary evidence for the Raine et al.'s three-factor model and of the cross-cultural validity of the SPQ-B scores in adolescent population. Future studies should continue to examine the measurement invariance of the schizotypy and psychosis risk syndromes across cultures. PMID- 24349181 TI - Preserved excitatory-inhibitory balance of cortical synaptic inputs following deprived eye stimulation after a saturating period of monocular deprivation in rats. AB - Monocular deprivation (MD) during development leads to a dramatic loss of responsiveness through the deprived eye in primary visual cortical neurons, and to degraded spatial vision (amblyopia) in all species tested so far, including rodents. Such loss of responsiveness is accompanied since the beginning by a decreased excitatory drive from the thalamo-cortical inputs. However, in the thalamorecipient layer 4, inhibitory interneurons are initially unaffected by MD and their synapses onto pyramidal cells potentiate. It remains controversial whether ocular dominance plasticity similarly or differentially affects the excitatory and inhibitory synaptic conductances driven by visual stimulation of the deprived eye and impinging onto visual cortical pyramids, after a saturating period of MD. To address this issue, we isolated visually-driven excitatory and inhibitory conductances by in vivo whole-cell recordings from layer 4 regular spiking neurons in the primary visual cortex (V1) of juvenile rats. We found that a saturating period of MD comparably reduced visually-driven excitatory and inhibitory conductances driven by visual stimulation of the deprived eye. Also, the excitatory and inhibitory conductances underlying the synaptic responses driven by the ipsilateral, left open eye were similarly potentiated compared to controls. Multiunit recordings in layer 4 followed by spike sorting indicated that the suprathreshold loss of responsiveness and the MD-driven ocular preference shifts were similar for narrow spiking, putative inhibitory neurons and broad spiking, putative excitatory neurons. Thus, by the time the plastic response has reached a plateau, inhibitory circuits adjust to preserve the normal balance between excitation and inhibition in the cortical network of the main thalamorecipient layer. PMID- 24349183 TI - Evaluation and ranking of researchers--Bh Index. AB - Evaluation and ranking of every author is very crucial as it is widely used to evaluate the performance of the researcher. This article proposes a new method, called Bh-Index, to evaluate the researchers based on the publications and citations. The method is built on h-Index and only the h-core articles are taken into consideration. The method assigns value additions to those articles that receive significantly high citations in comparison to the h-Index of the researcher. It provides a wide range of values for a given h-Index and effective evaluation even for a short period. Use of Bh-Index along with the h-Index gives a powerful tool to evaluate the researchers. PMID- 24349182 TI - Geotemporal analysis of Neisseria meningitidis clones in the United States: 2000 2005. AB - BACKGROUND: The detection of meningococcal outbreaks relies on serogrouping and epidemiologic definitions. Advances in molecular epidemiology have improved the ability to distinguish unique Neisseria meningitidis strains, enabling the classification of isolates into clones. Around 98% of meningococcal cases in the United States are believed to be sporadic. METHODS: Meningococcal isolates from 9 Active Bacterial Core surveillance sites throughout the United States from 2000 through 2005 were classified according to serogroup, multilocus sequence typing, and outer membrane protein (porA, porB, and fetA) genotyping. Clones were defined as isolates that were indistinguishable according to this characterization. Case data were aggregated to the census tract level and all non-singleton clones were assessed for non-random spatial and temporal clustering using retrospective space time analyses with a discrete Poisson probability model. RESULTS: Among 1,062 geocoded cases with available isolates, 438 unique clones were identified, 78 of which had >=2 isolates. 702 cases were attributable to non-singleton clones, accounting for 66.0% of all geocoded cases. 32 statistically significant clusters comprised of 107 cases (10.1% of all geocoded cases) were identified. Clusters had the following attributes: included 2 to 11 cases; 1 day to 33 months duration; radius of 0 to 61.7 km; and attack rate of 0.7 to 57.8 cases per 100,000 population. Serogroups represented among the clusters were: B (n = 12 clusters, 45 cases), C (n = 11 clusters, 27 cases), and Y (n = 9 clusters, 35 cases); 20 clusters (62.5%) were caused by serogroups represented in meningococcal vaccines that are commercially available in the United States. CONCLUSIONS: Around 10% of meningococcal disease cases in the U.S. could be assigned to a geotemporal cluster. Molecular characterization of isolates, combined with geotemporal analysis, is a useful tool for understanding the spread of virulent meningococcal clones and patterns of transmission in populations. PMID- 24349185 TI - A comparison of methods to measure the magnetic moment of magnetotactic bacteria through analysis of their trajectories in external magnetic fields. AB - Magnetotactic bacteria possess organelles called magnetosomes that confer a magnetic moment on the cells, resulting in their partial alignment with external magnetic fields. Here we show that analysis of the trajectories of cells exposed to an external magnetic field can be used to measure the average magnetic dipole moment of a cell population in at least five different ways. We apply this analysis to movies of Magnetospirillum magneticum AMB-1 cells, and compare the values of the magnetic moment obtained in this way to that obtained by direct measurements of magnetosome dimension from electron micrographs. We find that methods relying on the viscous relaxation of the cell orientation give results comparable to that obtained by magnetosome measurements, whereas methods relying on statistical mechanics assumptions give systematically lower values of the magnetic moment. Since the observed distribution of magnetic moments in the population is not sufficient to explain this discrepancy, our results suggest that non-thermal random noise is present in the system, implying that a magnetotactic bacterial population should not be considered as similar to a paramagnetic material. PMID- 24349184 TI - Correlation of cytokine levels and microglial cell infiltration during retinal degeneration in RCS rats. AB - Microglial cells, which are immunocompetent cells, are involved in all diseases of the central nervous system. During their activation in various diseases, a variety of soluble factors are released. In the present study, the correlation between cytokine levels and microglial cell migration in the course of retinal degeneration of Royal College of Surgeons (RCS) rats was evaluated. MFG-E8 and CD11b were used to confirm the microglial cells. In the retina of RCS rats, the mRNA expression of seven genes (MFG-E8 and its integrins alphaupsilon and beta5, CD11b and the cytokines TNF-alpha, IL-1beta, and MCP-1) formed almost similar bimodal peak distributions, which were centred at P7 and P45 to P60. In contrast, in rdy rats, which comprised the control group, a unimodal peak distribution centred at P14 was observed. The gene expression accompanied the activation and migration of microglial cells from the inner to the outer layer of the retina during the process of degeneration. Principal component analysis and discriminant function analysis revealed that the expression of these seven genes, especially TNF-alpha and CD11b, positively correlated with retinal degeneration and microglial activity during retinal degeneration in RCS rats, but not in the control rats. Furthermore, linear regression analysis demonstrated a significant correlation between the expression of these genes and the activation of microglial cells in the dystrophic retina. Our findings suggest that the suppression of microglial cells and the blockade of their cytotoxic effects may constitute a novel therapeutic strategy for treating photoreceptor death in various retinal disorders. PMID- 24349187 TI - Effective classification and gene expression profiling for the Facioscapulohumeral Muscular Dystrophy. AB - The Facioscapulohumeral Muscular Dystrophy (FSHD) is an autosomal dominant neuromuscular disorder whose incidence is estimated in about one in 400,000 to one in 20,000. No effective therapeutic strategies are known to halt progression or reverse muscle weakness and atrophy. It is known that the FSHD is caused by modifications located within a D4ZA repeat array in the chromosome 4q, while recent advances have linked these modifications to the DUX4 gene. Unfortunately, the complete mechanisms responsible for the molecular pathogenesis and progressive muscle weakness still remain unknown. Although there are many studies addressing cancer databases from a machine learning perspective, there is no such precedent in the analysis of the FSHD. This study aims to fill this gap by analyzing two specific FSHD databases. A feature selection algorithm is used as the main engine to select genes promoting the highest possible classification capacity. The combination of feature selection and classification aims at obtaining simple models (in terms of very low numbers of genes) capable of good generalization, that may be associated with the disease. We show that the reported method is highly efficient in finding genes to discern between healthy cases (not affected by the FSHD) and FSHD cases, allowing the discovery of very parsimonious models that yield negligible repeated cross-validation error. These models in turn give rise to very simple decision procedures in the form of a decision tree. Current biological evidence regarding these genes shows that they are linked to skeletal muscle processes concerning specific human conditions. PMID- 24349186 TI - Four genotyping schemes for phylogenetic analysis of Pseudomonas aeruginosa: comparison of their congruence with multi-locus sequence typing. AB - Several molecular typing schemes have been proposed to differentiate among isolates and clonal groups, and hence establish epidemiological or phylogenetic links. It has been widely accepted that multi-locus sequence typing (MLST) is the gold standard for phylogenetic typing/long-term epidemiological surveillance, but other recently described methods may be easier to carry out, especially in settings with limited access to DNA sequencing. Comparing the performance of such techniques to MLST is therefore of relevance. A study was therefore carried out with a collection of P. aeruginosa strains (n = 133) typed by four typing schemes: MLST, multiple-locus variable number tandem repeat analysis (MLVA), pulsed-field gel electrophoresis (PFGE) and the commercial DiversiLab microbial typing system (DL). The aim of this study was to compare the results of each typing method with MLST. The Simpson's indices of diversity were 0.989, 0.980, 0.961 and 0.906 respectively for PFGE, MLVA, DL and MLST. The congruence between techniques was measured by the adjusted Wallace index (W): this coefficient indicates the probability that a pair of isolates which is assigned to the same type by one typing method is also typed as identical by the other. In this context, the congruence between techniques was recorded as follow: MLVA-type to predict MLST-type (93%), PFGE to MLST (92%), DL to MLST (64.2%), PFGE to MLVA (63.5%) and PFGE to DL (61.7%). Conversely, for all above combinations, prediction was very poor. The congruence was increased at the clonal complex (CC) level. MLST is regarded the gold standard for phylogenetic classification of bacteria, but is rather laborious to carry out in many settings. Our data suggest that MLVA can predict the MLST-type with high accuracy, and even higher when studying the clonal complex level. Of the studied three techniques MLVA was therefore the best surrogate method to predict MLST. PMID- 24349188 TI - Electrical vestibular stimulation after vestibular deafferentation and in vestibular schwannoma. AB - BACKGROUND: Vestibular reflexes, evoked by human electrical (galvanic) vestibular stimulation (EVS), are utilized to assess vestibular function and investigate its pathways. Our study aimed to investigate the electrically-evoked vestibulo-ocular reflex (eVOR) output after bilateral and unilateral vestibular deafferentations to determine the characteristics for interpreting unilateral lesions such as vestibular schwannomas. METHODS: EVOR was recorded with dual-search coils as binocular three-dimensional eye movements evoked by bipolar 100 ms-step at EVS intensities of [0.9, 2.5, 5.0, 7.5, 10.0] mA and unipolar 100 ms-step at 5 mA EVS intensity. Five bilateral vestibular deafferented (BVD), 12 unilateral vestibular deafferented (UVD), four unilateral vestibular schwannoma (UVS) patients and 17 healthy subjects were tested with bipolar EVS, and five UVDs with unipolar EVS. RESULTS: After BVD, bipolar EVS elicited no eVOR. After UVD, bipolar EVS of one functioning ear elicited bidirectional, excitatory eVOR to cathodal EVS with 9 ms latency and inhibitory eVOR to anodal EVS, opposite in direction, at half the amplitude with 12 ms latency, exhibiting an excitatory-inhibitory asymmetry. The eVOR patterns from UVS were consistent with responses from UVD confirming the vestibular loss on the lesion side. Unexpectedly, unipolar EVS of the UVD ear, instead of absent response, evoked one-third the bipolar eVOR while unipolar EVS of the functioning ear evoked half the bipolar response. CONCLUSIONS: The bidirectional eVOR evoked by bipolar EVS from UVD with an excitatory-inhibitory asymmetry and the 3 ms latency difference between normal and lesion side may be useful for detecting vestibular lesions such as UVS. We suggest that current spread could account for the small eVOR to 5 mA unipolar EVS of the UVD ear. PMID- 24349189 TI - Dendritic branch intersections are structurally regulated targets for efficient axonal wiring and synaptic clustering. AB - Synaptic clustering on dendritic branches enhances plasticity, input integration and neuronal firing. However, the mechanisms guiding axons to cluster synapses at appropriate sites along dendritic branches are poorly understood. We searched for such a mechanism by investigating the structural overlap between dendritic branches and axons in a simplified model of neuronal networks--the hippocampal cell culture. Using newly developed software, we converted images of meshes of overlapping axonal and dendrites into topological maps of intersections, enabling quantitative study of overlapping neuritic geometry at the resolution of single dendritic branch-to-branch and axon-to-branch crossings. Among dendro-dendritic crossing configurations, it was revealed that the orientations through which dendritic branches cross is a regulated attribute. While crossing angle distribution among branches thinner than 1 um appeared to be random, dendritic branches 1 um or wider showed a preference for crossing each other at angle ranges of either 50 degrees -70 degrees or 80 degrees -90 degrees . It was then found that the dendro-dendritic crossings themselves, as well as their selective angles, both affected the path of axonal growth. Axons displayed 4 fold stronger tendency to traverse within 2 um of dendro-dendritic intersections than at farther distances, probably to minimize wiring length. Moreover, almost 70% of the 50 degrees -70 degrees dendro-denritic crossings were traversed by axons from the obtuse angle's zone, whereas only 15% traversed through the acute angle's zone. By contrast, axons showed no orientation restriction when traversing 80 degrees -90 degrees crossings. When such traverse behavior was repeated by many axons, they converged in the vicinity of dendro-dendritic intersections, thereby clustering their synaptic connections. Thus, the vicinity of dendritic branch-to-branch crossings appears to be a regulated structure used by axons as a target for efficient wiring and as a preferred site for synaptic clustering. This synaptic clustering mechanism may enhance synaptic co-activity and plasticity. PMID- 24349190 TI - Is Switzerland suitable for the invasion of Aedes albopictus [corrected]? AB - BACKGROUND: Over the last 30 years, the Asian tiger mosquito, Aedes albopictus, has rapidly spread around the world. The European distribution comprises the Mediterranean basin with a first appearance in Switzerland in 2003. Early identification of the most suitable areas in Switzerland allowing progressive invasion by this species is considered crucial to suggest adequate surveillance and control plans. METHODOLOGY/PRINCIPAL FINDINGS: We identified the most suitable areas for invasion and establishment of Ae. albopictus in Switzerland. The potential distribution areas linked to the current climatic suitability were assessed using remotely sensed land surface temperature data recorded by the MODIS satellite sensors. Suitable areas for adult survival and overwintering of diapausing eggs were also identified for future climatic conditions, considering two different climate change scenarios (A1B, A2) for the periods 2020-2049 and 2045-2074. At present, the areas around Lake Geneva in western Switzerland provide suitable climatic conditions for Ae. albopictus. In northern Switzerland, parts of the Rhine valley, around Lake Constance, as well as the surroundings of Lake Neuchatel, appear to be suitable for the survival at least of adult Ae. albopictus. However, these areas are characterized by winters currently being too cold for survival and development of diapausing eggs. In southern Switzerland, Ae. albopictus is already well-established, especially in the Canton of Ticino. For the years 2020-2049, the predicted possible spread of the tiger mosquito does not differ significantly from its potential current distribution. However, important expansions are obtained if the period is extended to the years 2045 2074, when Ae. albopictus may invade large new areas. CONCLUSIONS/SIGNIFICANCE: Several parts of Switzerland provide suitable climatic conditions for invasion and establishment of Ae. albopictus. The current distribution and rapid spread in other European countries suggest that the tiger mosquito will colonize new areas in Switzerland in the near future. PMID- 24349191 TI - Risk of obstructive sleep apnea in Parkinson's disease: a meta-analysis. AB - STUDY OBJECTIVES: Sleep disorders are a common symptom of Parkinson's disease (PD) and they significantly impair the sleep quality of the PD patients. However, there is no conclusive evidence to support the relation between PD and the prevalence of obstructive sleep apnea (OSA). The purpose of this meta-analysis review is to evaluate the association between PD and the prevalence of OSA. METHODS: A comprehensive literature search was conducted on PubMed and Embase through July 2013. Only studies that referred to PD and the prevalence of OSA and that met the selection criteria were included in the analysis. The odds ratios (ORs) were used to evaluate the relationship of PD and the prevalence of OSA by the fixed-effect model. RESULTS: Five eligible studies were analyzed in this study including 322 cases and 6,361 controls. The pooled-analysis showed the OR to be 0.60 (95% confidence interval (CI): 0.44 to 0.81, P = 0.001) and I(2) = 0.0% (chi(2) = 3.90, P = 0.420) in the fixed-effect model. CONCLUSIONS: Although we only included five small sample studies that indicated high homogeneity in the heterogeneity test, the results suggest that there is a significant negative association between PD and the prevalence of OSA; PD patients generally have a reduced prevalence of OSA. According to our analysis, these results are primarily due to the lower BMI of PD patients when compared with the general population controls. PMID- 24349192 TI - Hepatitis C virus NS3/4A protease inhibits complement activation by cleaving complement component 4. AB - BACKGROUND: It has been hypothesized that persistent hepatitis C virus (HCV) infection is mediated in part by viral proteins that abrogate the host immune response, including the complement system, but the precise mechanisms are not well understood. We investigated whether HCV proteins are involved in the fragmentation of complement component 4 (C4), composed of subunits C4alpha, C4beta, and C4gamma, and the role of HCV proteins in complement activation. METHODS: Human C4 was incubated with HCV nonstructural (NS) 3/4A protease, core, or NS5. Samples were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and then subjected to peptide sequencing. The activity of the classical complement pathway was examined using an erythrocyte hemolysis assay. The cleavage pattern of C4 in NS3/4A-expressing and HCV-infected cells, respectively, was also examined. RESULTS: HCV NS3/4A protease cleaved C4gamma in a concentration-dependent manner, but viral core and NS5 did not. A specific inhibitor of NS3/4A protease reduced C4gamma cleavage. NS3/4A protease-mediated cleavage of C4 inhibited classical pathway activation, which was abrogated by a NS3/4A protease inhibitor. In addition, co-transfection of cells with C4 and wild type NS3/4A, but not a catalytic-site mutant of NS3/4A, produced cleaved C4gamma fragments. Such C4 processing, with a concomitant reduction in levels of full length C4gamma, was also observed in HCV-infected cells expressing C4. CONCLUSIONS: C4 is a novel cellular substrate of the HCV NS3/4A protease. Understanding disturbances in the complement system mediated by NS3/4A protease may provide new insights into the mechanisms underlying persistent HCV infection. PMID- 24349193 TI - Simultaneous in vitro characterisation of DNA deaminase function and associated DNA repair pathways. AB - During immunoglobulin (Ig) diversification, activation-induced deaminase (AID) initiates somatic hypermutation and class switch recombination by catalysing the conversion of cytosine to uracil. The synergy between AID and DNA repair pathways is fundamental for the introduction of mutations, however the molecular and biochemical mechanisms underlying this process are not fully elucidated. We describe a novel method to efficiently decipher the composition and activity of DNA repair pathways that are activated by AID-induced lesions. The in vitro resolution (IVR) assay combines AID based deamination and DNA repair activities from a cellular milieu in a single assay, thus avoiding synthetically created DNA lesions or genetic-based readouts. Recombinant GAL4-AID fusion protein is targeted to a plasmid containing GAL4 binding sites, allowing for controlled cytosine deamination within a substrate plasmid. Subsequently, the Xenopus laevis egg extract provides a source of DNA repair proteins and functional repair pathways. Our results demonstrated that DNA repair pathways which are in vitro activated by AID-induced lesions are reminiscent of those found during AID induced in vivo Ig diversification. The comparative ease of manipulation of this in vitro systems provides a new approach to dissect the complex DNA repair pathways acting on defined physiologically lesions, can be adapted to use with other DNA damaging proteins (e.g. APOBECs), and provide a means to develop and characterise pharmacological agents to inhibit these potentially oncogenic processes. PMID- 24349194 TI - Bisphenol-A impairs insulin action and up-regulates inflammatory pathways in human subcutaneous adipocytes and 3T3-L1 cells. AB - Current evidence indicates that chemical pollutants may interfere with the homeostatic control of nutrient metabolism, thereby contributing to the increased prevalence of metabolic disorders. Bisphenol-A (BPA) is a lipophilic compound contained in plastic which is considered a candidate for impairing energy and glucose metabolism. We have investigated the impact of low doses of BPA on adipocyte metabolic functions. Human adipocytes derived from subcutaneous adipose tissue and differentiated 3T3-L1 cells were incubated with BPA, in order to evaluate the effect on glucose utilization, insulin sensitivity and cytokine secretion. Treatment with 1 nM BPA significantly inhibited insulin-stimulated glucose utilization, without grossly interfering with adipocyte differentiation. Accordingly, mRNA levels of the adipogenic markers PPARgamma and GLUT4 were unchanged upon BPA exposure. BPA treatment also impaired insulin-activated receptor phosphorylation and signaling. Moreover, adipocyte incubation with BPA was accompanied by increased release of IL-6 and IFN-gamma, as assessed by multiplex ELISA assays, and by activation of JNK, STAT3 and NFkB pathways. Treatment of the cells with the JNK inhibitor SP600125 almost fully reverted BPA effect on insulin signaling and glucose utilization. In conclusion, low doses of BPA interfere with inflammatory/insulin signaling pathways, leading to impairment of adipose cell function. PMID- 24349195 TI - An internal ribosome entry site (IRES) mutant library for tuning expression level of multiple genes in mammalian cells. AB - A set of mutated Encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES) elements with varying strengths is generated by mutating the translation initiation codons of 10(th), 11(th), and 12(th) AUG to non-AUG triplets. They are able to control the relative expression of multiple genes over a wide range in mammalian cells in both transient and stable transfections. The relative strength of each IRES mutant remains similar in different mammalian cell lines and is not gene specific. The expressed proteins have correct molecular weights. Optimization of light chain over heavy chain expression by these IRES mutants enhances monoclonal antibody expression level and quality in stable transfections. Uses of this set of IRES mutants can be extended to other applications such as synthetic biology, investigating interactions between proteins and its complexes, cell engineering, multi-subunit protein production, gene therapy, and reprogramming of somatic cells into stem cells. PMID- 24349196 TI - Caveolin-1--a novel interacting partner of organic cation/carnitine transporter (Octn2): effect of protein kinase C on this interaction in rat astrocytes. AB - OCTN2--the Organic Cation Transporter Novel family member 2 (SLC22A5) is known to be a xenobiotic/drug transporter. It transports as well carnitine--a compound necessary for oxidation of fatty acids and mutations of its gene cause primary carnitine deficiency. Octn2 regulation by protein kinase C (PKC) was studied in rat astrocytes--cells in which beta-oxidation takes place in the brain. Activation of PKC with phorbol ester stimulated L-carnitine transport and increased cell surface presence of the transporter, although no PKC-specific phosphorylation of Octn2 could be detected. PKC activation resulted in an augmented Octn2 presence in cholesterol/sphingolipid-rich microdomains of plasma membrane (rafts) and increased co-precipitation of Octn2 with raft-proteins, caveolin-1 and flotillin-1. Deletion of potential caveolin-1 binding motifs pointed to amino acids 14-22 and 447-454 as the caveolin-1 binding sites within Octn2 sequence. A direct interaction of Octn2 with caveolin-1 in astrocytes upon PKC activation was detected by proximity ligation assay, while such an interaction was excluded in case of flotillin-1. Functioning of a multi-protein complex regulated by PKC has been postulated in rOctn2 trafficking to the cell surface, a process which could be important both under physiological conditions, when carnitine facilitates fatty acids catabolism and controls free Coenzyme A pool as well as in pathology, when transport of several drugs can induce secondary carnitine deficiency. PMID- 24349197 TI - Meta-analysis of long-term vitamin D supplementation on overall mortality. AB - INTRODUCTION: It has been suggested that vitamin D is effective to prevent mortality. However, there is no consistent conclusion that the effects of vitamin D supplementation on all-cause mortality are associated with duration of treatment. We conducted a meta-analysis regarding this issue in an effort to provide a more robust answer. METHODS: A comprehensive search in a number of databases, including MEDLINE, Embase and The Cochrane Central Register of Controlled Trials, was conducted for collecting randomized controlled trials (RCTs) on vitamin D supplementation preventing mortality. Two investigators independently screened the literature according to the inclusive and exclusive criteria and the relative data were extracted. Data analysis was performed by using Review Manager 5.0 software. RESULTS: Data from forty-two RCT s were included. Vitamin D therapy significantly decreased all-cause mortality with a duration of follow-up longer than 3 years with a RR (95% CI) of 0.94 (0.90-0.98). No benefit was seen in a shorter follow-up periods with a RR (95% CI) of 1.04 (0.97-1.12). Results remain robust after sensitivity analysis. The following subgroups of long-term follow-up had significantly fewer deaths: female only, participants with a mean age younger than 80, daily dose of 800 IU or less, participants with vitamin D insufficiency (baseline 25-hydroxyvitamin D level less than 50 nmol/L) and cholecalciferol therapy. In addition, the combination of vitamin D and calcium significantly reduced mortality and vitamin D alone also had a trend to decrease mortality in a longer time follow up. CONCLUSIONS: The data suggest that supplementation of vitamin D is effective in preventing overall mortality in a long-term treatment, whereas it is not significantly effective in a treatment duration shorter than 3 years. Future studies are needed to identify the efficacy of vitamin D on specific mortality, such as cancer and cardiovascular disease mortality in a long-term treatment duration. PMID- 24349198 TI - Dynamics and flexibility of human aromatase probed by FTIR and time resolved fluorescence spectroscopy. AB - Human aromatase (CYP19A1) is a steroidogenic cytochrome P450 converting androgens into estrogens. No ligand-free crystal structure of the enzyme is available to date. The crystal structure in complex with the substrate androstenedione and the steroidal inhibitor exemestane shows a very compact conformation of the enzyme, leaving unanswered questions on the conformational changes that must occur to allow access of the ligand to the active site. As H/D exchange kinetics followed by FTIR spectroscopy can provide information on the conformational changes in proteins where solvent accessibility is affected, here the amide I region was used to measure the exchange rates of the different elements of the secondary structure for aromatase in the ligand-free form and in the presence of the substrate androstenedione and the inhibitor anastrozole. Biphasic exponential functions were found to fit the H/D exchange data collected as a function of time. Two exchange rates were assigned to two populations of protons present in different flexible regions of the protein. The addition of the substrate androstenedione and the inhibitor anastrozole lowers the H/D exchange rates of the alpha-helices of the enzyme when compared to the ligand-free form. Furthermore, the presence of the inhibitor anastrozole lowers exchange rate constant (k1) for beta-sheets from 0.22+/-0.06 min(-1) for the inhibitor-bound enzyme to 0.12+/-0.02 min(-1) for the free protein. Dynamics effects localised in helix F were studied by time resolved fluorescence. The data demonstrate that the fluorescence lifetime component associated to Trp224 emission undergoes a shift toward longer lifetimes (from ~5.0 to ~5.5 ns) when the substrate or the inhibitor are present, suggesting slower dynamics in the presence of ligands. Together the results are consistent with different degrees of flexibility of the access channel and therefore different conformations adopted by the enzyme in the free, substrate- and inhibitor-bound forms. PMID- 24349199 TI - A prognostic gene signature for metastasis-free survival of triple negative breast cancer patients. AB - Although triple negative breast cancers (TNBC) are the most aggressive subtype of breast cancer, they currently lack targeted therapies. Because this classification still includes a heterogeneous collection of tumors, new tools to classify TNBCs are urgently required in order to improve our prognostic capability for high risk patients and predict response to therapy. We previously defined a gene expression signature, RKIP Pathway Metastasis Signature (RPMS), based upon a metastasis-suppressive signaling pathway initiated by Raf Kinase Inhibitory Protein (RKIP). We have now generated a new BACH1 Pathway Metastasis gene signature (BPMS) that utilizes targets of the metastasis regulator BACH1. Specifically, we substituted experimentally validated target genes to generate a new BACH1 metagene, developed an approach to optimize patient tumor stratification, and reduced the number of signature genes to 30. The BPMS significantly and selectively stratified metastasis-free survival in basal-like and, in particular, TNBC patients. In addition, the BPMS further stratified patients identified as having a good or poor prognosis by other signatures including the Mammaprint(r) and Oncotype(r) clinical tests. The BPMS is thus complementary to existing signatures and is a prognostic tool for high risk ER HER2- patients. We also demonstrate the potential clinical applicability of the BPMS as a single sample predictor. Together, these results reveal the potential of this pathway-based BPMS gene signature to identify high risk TNBC patients that can respond effectively to targeted therapy, and highlight BPMS genes as novel drug targets for therapeutic development. PMID- 24349200 TI - The 12 item Social and Economic Conservatism Scale (SECS). AB - Recent years have seen a surge in psychological research on the relationship between political ideology (particularly conservatism) and cognition, affect, behaviour, and even biology. Despite this flurry of investigation, however, there is as yet no accepted, validated, and widely used multi-item scale of conservatism that is concise, that is modern in its conceptualisation, and that includes both social and economic conservatism subscales. In this paper the 12 Item Social and Economic Conservatism Scale (SECS) is proposed and validated to help fill this gap. The SECS is suggested to be an important and useful tool for researchers working in political psychology. PMID- 24349201 TI - NEXN is a novel susceptibility gene for coronary artery disease in Han Chinese. AB - Coronary artery disease (CAD) is the leading cause of death and disability in the world. Genome-wide association studies have implicated the importance of the genetic contribution of vascular smooth muscle cells (VSMCs) function in CAD susceptibility. The aberrant phenotypic modulation of VSMC is responsible for the pathological vascular intima hyperplasia that is the hallmark for atherosclerotic morphology. NEXN is a muscle-specific F-actin binding protein and is regulated by inflammatory cytokines in VSMCs. Whether NEXN contributes to human vascular disorders is still unknown. In this study, we genotyped 5 SNPs, tagging all of the 17 common SNPs within 54 kilobases (kb) covering NEXN gene and its flanking region, in 1883 patients with CAD and 1973 healthy individuals from Han Chinese, and identified one SNP, rs1780050, which was strongly associated with CAD trait. The Bonferroni corrected P-value was 7.65*10(-5). The odds ratio (95% confidence interval) was 1.23 (1.12-1.36) with statistical power of 0.994. Functional analysis showed that NEXN promotes VSMC to a contractile phenotype in vitro and inhibits balloon-injury induced neointima formation in vivo. Further eQTL analysis demonstrated that the risk allele T of rs1780050 is associated with decreased expression of NEXN, thus contributing to a higher risk of CAD susceptibility in the population. This is, to our knowledge, the first study to identify NEXN as a novel CAD susceptibility gene with both genetic and functional evidence. PMID- 24349202 TI - Spatiotemporal analysis of predation by carabid beetles (Carabidae) on nematode infected and uninfected slugs in the field. AB - The dynamics of predation on parasites within prey has received relatively little attention despite the profound effects this is likely to have on both prey and parasite numbers and hence on biological control programmes where parasites are employed. The nematode Phasmarhabditis hermaphrodita is a commercially available biological agent against slugs. Predation on these slugs may, at the same time, result in intraguild predation on slug-parasitic nematodes. This study describes, for the first time, predation by carabid beetles on slugs and their nematode parasites on both spatial and temporal scales, using PCR-based methods. The highest nematode infection levels were found in the slugs Deroceras reticulatum and Arion silvaticus. Numbers of infected slugs decreased over time and no infected slugs were found four months after nematode application. The density of the most abundant slug, the invasive Arion vulgaris, was positively related to the activity-density of the carabid beetle, Carabus nemoralis. Predation on slugs was density and size related, with highest predation levels also on A. vulgaris. Predation on A. vulgaris decreased significantly in summer when these slugs were larger than one gram. Predation by C. nemoralis on slugs was opportunistic, without any preferences for specific species. Intraguild predation on the nematodes was low, suggesting that carabid beetles such as C. nemoralis probably do not have a significant impact on the success of biological control using P. hermaphrodita. PMID- 24349203 TI - Skeletal cell differentiation is enhanced by atmospheric dielectric barrier discharge plasma treatment. AB - Enhancing chondrogenic and osteogenic differentiation is of paramount importance in providing effective regenerative therapies and improving the rate of fracture healing. This study investigated the potential of non-thermal atmospheric dielectric barrier discharge plasma (NT-plasma) to enhance chondrocyte and osteoblast proliferation and differentiation. Although the exact mechanism by which NT-plasma interacts with cells is undefined, it is known that during treatment the atmosphere is ionized generating extracellular reactive oxygen and nitrogen species (ROS and RNS) and an electric field. Appropriate NT-plasma conditions were determined using lactate-dehydrogenase release, flow cytometric live/dead assay, flow cytometric cell cycle analysis, and Western blots to evaluate DNA damage and mitochondrial integrity. We observed that specific NT plasma conditions were required to prevent cell death, and that loss of pre osteoblastic cell viability was dependent on intracellular ROS and RNS production. To further investigate the involvement of intracellular ROS, fluorescent intracellular dyes Mitosox (superoxide) and dihydrorhodamine (peroxide) were used to assess onset and duration after NT-plasma treatment. Both intracellular superoxide and peroxide were found to increase immediately post NT plasma treatment. These increases were sustained for one hour but returned to control levels by 24 hr. Using the same treatment conditions, osteogenic differentiation by NT-plasma was assessed and compared to peroxide or osteogenic media containing beta-glycerolphosphate. Although both NT-plasma and peroxide induced differentiation-specific gene expression, neither was as effective as the osteogenic media. However, treatment of cells with NT-plasma after 24 hr in osteogenic or chondrogenic media significantly enhanced differentiation as compared to differentiation media alone. The results of this study show that NT plasma can selectively initiate and amplify ROS signaling to enhance differentiation, and suggest this technology could be used to enhance bone fusion and improve healing after skeletal injury. PMID- 24349204 TI - Variation in yield gap induced by nitrogen, phosphorus and potassium fertilizer in North China Plain. AB - A field experiment was conducted under a wheat-maize rotation system from 1990 to 2006 in North China Plain (NCP) to determine the effects of N, P and K on yield and yield gap. There were five treatments: NPK, PK, NK, NP and a control. Average wheat and maize yields were the highest in the NPK treatment, followed by those in the NP plots among all treatments. For wheat and maize yield, a significant increasing trend over time was found in the NPK-treated plots and a decreasing trend in the NK-treated plots. In the absence of N or P, wheat and maize yields were significantly lower than those in the NPK treatment. For both crops, the increasing rate of the yield gap was the highest in the P omission plots, i.e., 189.1 kg ha(-1) yr(-1) for wheat and 560.6 kg ha(-1) yr(-1) for maize. The cumulative omission of P fertilizer induced a deficit in the soil available N and extractable P concentrations for maize. The P fertilizer was more pivotal in long term wheat and maize growth and soil fertility conservation in NCP, although the N fertilizer input was important for both crops growth. The crop response to K fertilizers was much lower than that to N or P fertilizers, but for maize, the cumulative omission of K fertilizer decreased the yield by 26% and increased the yield gap at a rate of 322.7 kg ha(-1) yr(-1). The soil indigenous K supply was not sufficiently high to meet maize K requirement over a long period. The proper application of K fertilizers is necessary for maize production in the region. Thus, the appropriate application of N and P fertilizers for the growth of both crops, while regularly combining K fertilizers for maize growth, is absolutely necessary for sustainable crop production in the NCP. PMID- 24349205 TI - Association between oral health status and type 2 diabetes mellitus among Sudanese adults: a matched case-control study. AB - AIM: The purpose of this study was to compare the clinical and subjective oral health indicators of type 2 diabetic patients (T2DM) with age and gender matched non-diabetic controls. A second aim was to identify clinical and subjective oral health indicators that discriminate between well-controlled and poorly controlled T2DM patients as well as between patients with long and short duration of the disease. METHODS: A total of 457 individuals participated in the study (154 T2DM cases and 303 non-diabetic controls). The T2DM group was sub-divided according to metabolic control [(well-controlled: glycosylated haemoglobin test 8%), (poorly controlled: glycosylated haemoglobin test > 8%)] and according to duration of T2DM [(long duration: >10 years), (short duration: 10 years)]. Participants were interviewed using a structured questionnaire including socio-demographics, lifestyle and oral health related quality of life factors. The clinical examination comprised full mouth probing depths, plaque index, tooth mobility index, furcation involvement and coronal and root surface caries. RESULTS: The T2DM patients presented with more probing depths 4 mm, furcation involvement, tooth mobility, missing teeth, and oral impacts on daily performance (OIDP). The corresponding adjusted odds ratios and their 95% confidence intervals were 4.07 (1.74-9.49), 2.96 (1.36-6.45), 5.90 (2.26-15.39), 0.23 (0.08-0.63) and 3.46 (1.61 7.42), respectively. Moreover, the odds ratio was 2.60 (1.21-5.55) for the poorly controlled T2DM patients to have high levels of mobility index and 2.94 (1.24 6.94) for those with long duration of T2DM to have high decayed, missed and filled teeth (DMFT) values. CONCLUSION: This study revealed that chronic periodontitis, tooth mobility, furcation involvement and OIDP were more prevalent among T2DM patients compared to their non-diabetic controls. PMID- 24349207 TI - Dynamic source routing strategy for two-level flows on scale-free networks. AB - Packets transmitting in real communication networks such as the Internet can be classified as time-sensitive or time-insensitive. To better support the real-time and time-insensitive applications, we propose a two-level flow traffic model in which packets are labeled as level-1 or level-2, and those with level-1 have higher priority to be transmitted. In order to enhance the traffic capacity of the two-level flow traffic model, we expand the global dynamic routing strategy and propose a new dynamic source routing which supports no routing-flaps, high traffic capacity, and diverse traffic flows. As shown in this paper, the proposed dynamic source routing can significantly enhance the traffic capacity and quality of time-sensitive applications compared with the global shortest path routing strategy. PMID- 24349206 TI - The transcriptomic response of rat hepatic stellate cells to endotoxin: implications for hepatic inflammation and immune regulation. AB - With their location in the perisinusoidal space of Disse, hepatic stellate cells (HSCs) communicate with all of the liver cell types both by physical association (cell body as well as cytosolic processes penetrating into sinusoids through the endothelial fenestrations) and by producing several cytokines and chemokines. Bacterial lipopolysaccharide (LPS), circulating levels of which are elevated in liver diseases and transplantation, stimulates HSCs to produce increased amounts of cytokines and chemokines. Although recent research provides strong evidence for the role of HSCs in hepatic inflammation and immune regulation, the number of HSC-elaborated inflammatory and immune regulatory molecules may be much greater then known at the present time. Here we report time-dependent changes in the gene expression profile of inflammatory and immune-regulatory molecules in LPS stimulated rat HSCs, and their validation by biochemical analyses. LPS strongly up-regulated LPS-response elements (TLR2 and TLR7) but did not affect TLR4 and down-regulated TLR9. LPS also up-regulated genes in the MAPK, NFkappaB, STAT, SOCS, IRAK and interferon signaling pathways, numerous CC and CXC chemokines and IL17F. Interestingly, LPS modulated genes related to TGFbeta and HSC activation in a manner that would limit their activation and fibrogenic activity. The data indicate that LPS-stimulated HSCs become a major cell type in regulating hepatic inflammatory and immunological responses by altering expression of numerous relevant genes, and thus play a prominent role in hepatic pathophysiology including liver diseases and transplantation. PMID- 24349209 TI - A quantitative framework for flower phenotyping in cultivated carnation (Dianthus caryophyllus L.). AB - Most important breeding goals in ornamental crops are plant appearance and flower characteristics where selection is visually performed on direct offspring of crossings. We developed an image analysis toolbox for the acquisition of flower and petal images from cultivated carnation (Dianthus caryophyllus L.) that was validated by a detailed analysis of flower and petal size and shape in 78 commercial cultivars of D. caryophyllus, including 55 standard, 22 spray and 1 pot carnation cultivars. Correlation analyses allowed us to reduce the number of parameters accounting for the observed variation in flower and petal morphology. Convexity was used as a descriptor for the level of serration in flowers and petals. We used a landmark-based approach that allowed us to identify eight main principal components (PCs) accounting for most of the variance observed in petal shape. The effect and the strength of these PCs in standard and spray carnation cultivars are consistent with shared underlying mechanisms involved in the morphological diversification of petals in both subpopulations. Our results also indicate that neighbor-joining trees built with morphological data might infer certain phylogenetic relationships among carnation cultivars. Based on estimated broad-sense heritability values for some flower and petal features, different genetic determinants shall modulate the responses of flower and petal morphology to environmental cues in this species. We believe our image analysis toolbox could allow capturing flower variation in other species of high ornamental value. PMID- 24349208 TI - Hepatic crown-like structure: a unique histological feature in non-alcoholic steatohepatitis in mice and humans. AB - Although macrophages are thought to be crucial for the pathogenesis of chronic inflammatory diseases, how they are involved in disease progression from simple steatosis to non-alcoholic steatohepatitis (NASH) is poorly understood. Here we report the unique histological structure termed "hepatic crown-like structures (hCLS)" in the mouse model of human NASH; melanocortin-4 receptor deficient mice fed a Western diet. In hCLS, CD11c-positive macrophages aggregate to surround hepatocytes with large lipid droplets, which is similar to those described in obese adipose tissue. Histological analysis revealed that hCLS is closely associated with activated fibroblasts and collagen deposition. When treatment with clodronate liposomes effectively depletes macrophages scattered in the liver, with those in hCLS intact, hepatic expression of inflammatory and fibrogenic genes is unaffected, suggesting that hCLS is an important source of inflammation and fibrosis during the progression of NASH. Notably, the number of hCLS is positively correlated with the extent of liver fibrosis. We also observed increased number of hCLS in the liver of non-alcoholic fatty liver disease/NASH patients. Collectively, our data provide evidence that hCLS is involved in the development of hepatic inflammation and fibrosis, thereby suggesting its pathophysiologic role in disease progression from simple steatosis to NASH. PMID- 24349210 TI - YBX1 is a modulator of MIA/CD-RAP-dependent chondrogenesis. AB - MIA/CD-RAP is a small, secreted protein involved in cartilage differentiation and melanoma progression. We recently revealed that p54(nrb) acts as a mediator of MIA/CD-RAP action to promote chondrogenesis and the progression of malignant melanoma. As the molecular mechanism of MIA/CD-RAP action in cartilage has not been defined in detail until now, we aimed to understand the regulation of p54(nrb) transcription in chondrogenesis. We concentrated on the previously described MIA/CD-RAP-dependent regulatory region in the p54(nrb) promoter and characterized the transcriptional regulation of p54(nrb) by MIA/CD-RAP in cartilage. A series of truncated p54(nrb) promoter constructs and mutagenesis analysis revealed that the transcription factor YBX1, which has not been investigated in chondrogenesis thus far, is the mediator of MIA/CD-RAP dependent activation of p54(nrb) transcription. A systematic analysis of genes carrying this binding site in their promoter region revealed further potential MIA/CD-RAP regulated genes that have been implicated in cartilage differentiation. In summary, we described the effects of MIA/CD-RAP on transcriptional regulation in chondrocytes. Understanding the regulation of p54(nrb) via YBX1 contributes to the understanding of chondrogenesis. Uncovering new downstream effectors that function via the activation of YBX1 supports the important role of MIA/CD-RAP in these processes. PMID- 24349211 TI - Common neural mechanisms underlying reversal learning by reward and punishment. AB - Impairments in flexible goal-directed decisions, often examined by reversal learning, are associated with behavioral abnormalities characterized by impulsiveness and disinhibition. Although the lateral orbital frontal cortex (OFC) has been consistently implicated in reversal learning, it is still unclear whether this region is involved in negative feedback processing, behavioral control, or both, and whether reward and punishment might have different effects on lateral OFC involvement. Using a relatively large sample (N = 47), and a categorical learning task with either monetary reward or moderate electric shock as feedback, we found overlapping activations in the right lateral OFC (and adjacent insula) for reward and punishment reversal learning when comparing correct reversal trials with correct acquisition trials, whereas we found overlapping activations in the right dorsolateral prefrontal cortex (DLPFC) when negative feedback signaled contingency change. The right lateral OFC and DLPFC also showed greater sensitivity to punishment than did their left homologues, indicating an asymmetry in how punishment is processed. We propose that the right lateral OFC and anterior insula are important for transforming affective feedback to behavioral adjustment, whereas the right DLPFC is involved in higher level attention control. These results provide insight into the neural mechanisms of reversal learning and behavioral flexibility, which can be leveraged to understand risky behaviors among vulnerable populations. PMID- 24349212 TI - In vivo and in vitro characterization of the immune stimulating activity of the Neisserial porin PorB. AB - Vaccines play a vital role in modern medicine. The development of novel vaccines for emerging and resistant pathogens has been aided in recent years by the use of novel adjuvants in subunit vaccines. A deeper understanding of the molecular pathways behind adjuvanticity is required to better select immunostimulatory molecules for use in individual vaccines. To this end, we have undertaken a study of the essential signaling pathways involved in the innate and adaptive immune responses to the Neisseria meningitidis outer membrane protein Porin B (PorB). We have previously demonstrated that PorB is an agonist of Toll-Like Receptor 2 (TLR2) and acts as an adjuvant in vaccines for protein, carbohydrate and lipopolysaccharide antigens using murine models. Here we demonstrate NFkappaB translocation following stimulation with PorB only occurs in the presence of TLR2. IL-6 and TNF-alpha secretion was shown to be MAPK dependent. Surface expression of activation markers on macrophages, including CD40, CD69, and CD86, was increased following PorB stimulation in vitro. Interestingly, some upregulation of CD54 and CD69 was still observed in macrophages obtained from TLR2 KO mice, indicating a possible non-TLR2 mediated activation pathway induced by PorB. In a murine vaccination model, using ovalbumin as the antigen and PorB as the adjuvant, a decreased antigen-specific IgG production was observed in TLR2 KO mice; adjuvant-dependent increased IgG production was entirely ablated in MyD88 KO mice. These observations demonstrate the importance of the above pathways to the adjuvant activity of PorB. The potential TLR2 independent effect is currently being explored. PMID- 24349213 TI - The microenvironment-specific transformation of adult stem cells models malignant triton tumors. AB - Here, we demonstrated the differentiation potential of murine muscle-derived stem/progenitor cells (MDSPCs) toward myogenic, neuronal, and glial lineages. MDSPCs, following transplantation into a critical-sized sciatic nerve defect in mice, showed full regeneration with complete functional recovery of the injured peripheral nerve at 6 weeks post-implantation. However, several weeks after regeneration of the sciatic nerve, neoplastic growths were observed. The resulting tumors were malignant peripheral nerve sheath tumors (MPNSTs) with rhabdomyoblastic differentiation, expressing myogenic, neurogenic, and glial markers, common markers of human malignant triton tumors (MTTs). No signs of tumorigenesis were observed 17 weeks post-implantation of MDSPCs into the gastrocnemius muscles of dystrophic/mdx mice, or 1 year following subcutaneous or intravenous injection. While MDSPCs were not oncogenic in nature, the neoplasias were composed almost entirely of donor cells. Furthermore, cells isolated from the tumors were serially transplantable, generating tumors when reimplanted into mice. However, this transformation could be abrogated by differentiation of the cells toward the neurogenic lineage prior to implantation. These results establish that MDSPCs participated in the regeneration of the injured peripheral nerve but transformed in a microenvironment- and time-dependent manner, when they likely received concomitant neurogenic and myogenic differentiation signals. This microenvironment-specific transformation provides a useful mouse model for human MTTs and potentially some insight into the origins of this disease. PMID- 24349214 TI - A leaderless genome identified during persistent bovine coronavirus infection is associated with attenuation of gene expression. AB - The establishment of persistent viral infection is often associated with the selection of one or more mutant viruses. For example, it has been found that an intraleader open reading frame (ORF) in genomic and subgenomic mRNA (sgmRNA) molecules is selected during bovine coronavirus (BCoV) persistence which leads to translation attenuation of the downstream ORF. Here, we report the unexpected identification of leaderless genomes, in addition to leader-containing genomes, in a cell culture persistently infected with BCoV. The discovery was made by using a head-to-tail ligation method that examines genomic 5'-terminal sequences at different times postinfection. Functional analyses of the leaderless genomic RNA in a BCoV defective interfering (DI) RNA revealed that (1) the leaderless genome was able to serve as a template for the synthesis of negative-strand genome, although it cannot perform replicative positive-strand genomic RNA synthesis, and (2) the leaderless genome retained its function in translation and transcription, although the efficiency of these processes was impaired. Therefore, this previously unidentified leaderless genome is associated with the attenuation of genome expression. Whether the leaderless genome contributes to the establishment of persistent infection remains to be determined. PMID- 24349215 TI - The PS1 hairpin of Mcm3 is essential for viability and for DNA unwinding in vitro. AB - The pre-sensor 1 (PS1) hairpin is found in ring-shaped helicases of the AAA+ family (ATPases associated with a variety of cellular activities) of proteins and is implicated in DNA translocation during DNA unwinding of archaeal mini chromosome maintenance (MCM) and superfamily 3 viral replicative helicases. To determine whether the PS1 hairpin is required for the function of the eukaryotic replicative helicase, Mcm2-7 (also comprised of AAA+ proteins), we mutated the conserved lysine residue in the putative PS1 hairpin motif in each of the Saccharomyces cerevisiae Mcm2-7 subunits to alanine. Interestingly, only the PS1 hairpin of Mcm3 was essential for viability. While mutation of the PS1 hairpin in the remaining MCM subunits resulted in minimal phenotypes, with the exception of Mcm7 which showed slow growth under all conditions examined, the viable alleles were synthetic lethal with each other. Reconstituted Mcm2-7 containing Mcm3 with the PS1 mutation (Mcm3(K499A)) had severely decreased helicase activity. The lack of helicase activity provides a probable explanation for the inviability of the mcm3(K499A) strain. The ATPase activity of Mcm2-7(3K499A) was similar to the wild type complex, but its interaction with single-stranded DNA in an electrophoretic mobility shift assay and its associations in cells were subtly altered. Together, these findings indicate that the PS1 hairpins in the Mcm2-7 subunits have important and distinct functions, most evident by the essential nature of the Mcm3 PS1 hairpin in DNA unwinding. PMID- 24349216 TI - Syndromic surveillance using veterinary laboratory data: algorithm combination and customization of alerts. AB - BACKGROUND: Syndromic surveillance research has focused on two main themes: the search for data sources that can provide early disease detection; and the development of efficient algorithms that can detect potential outbreak signals. METHODS: This work combines three algorithms that have demonstrated solid performance in detecting simulated outbreak signals of varying shapes in time series of laboratory submissions counts. These are: the Shewhart control charts designed to detect sudden spikes in counts; the EWMA control charts developed to detect slow increasing outbreaks; and the Holt-Winters exponential smoothing, which can explicitly account for temporal effects in the data stream monitored. A scoring system to detect and report alarms using these algorithms in a complementary way is proposed. RESULTS: The use of multiple algorithms in parallel resulted in increased system sensitivity. Specificity was decreased in simulated data, but the number of false alarms per year when the approach was applied to real data was considered manageable (between 1 and 3 per year for each of ten syndromic groups monitored). The automated implementation of this approach, including a method for on-line filtering of potential outbreak signals is described. CONCLUSION: The developed system provides high sensitivity for detection of potential outbreak signals while also providing robustness and flexibility in establishing what signals constitute an alarm. This flexibility allows an analyst to customize the system for different syndromes. PMID- 24349217 TI - Colonisation and diversification of the Zenaida Dove (Zenaida aurita) in the Antilles: phylogeography, contemporary gene flow and morphological divergence. AB - Caribbean avifaunal biogeography has been mainly studied based on mitochondrial DNA. Here, we investigated both past and recent island differentiation and micro evolutionary changes in the Zenaida Dove (Zenaida aurita) based on combined information from one mitochondrial (Cytochrome c Oxydase subunit I, COI) and 13 microsatellite markers and four morphological characters. This Caribbean endemic and abundant species has a large distribution, and two subspecies are supposed to occur: Z. a. zenaida in the Greater Antilles (GA) and Z. a. aurita in the Lesser Antilles (LA). Doves were sampled on two GA islands (Puerto Rico and the British Virgin Islands) and six LA islands (Saint Barthelemy, Guadeloupe, Les Saintes, Martinique, Saint Lucia and Barbados). Eleven COI haplotypes were observed that could be assembled in two distinct lineages, with six specific to GA, four to LA, the remaining one occurring in all islands. However, the level of divergence between those two lineages was too moderate to fully corroborate the existence of two subspecies. Colonisation of the studied islands appeared to be a recent process. However, both phenotypic and microsatellite data suggest that differentiation is already under way between all of them, partly associated with the existence of limited gene flow. No isolation by distance was observed. Differentiation for morphological traits was more pronounced than for neutral markers. These results suggest that despite recent colonisation, genetic drift and/or restricted gene flow are promoting differentiation for neutral markers. Variation in selective pressures between islands may explain the observed phenotypic differentiation. PMID- 24349218 TI - Attenuation of CCl4-induced hepatic fibrosis in mice by vaccinating against TGF beta1. AB - Transforming growth factor beta1 (TGF-beta1) is the pivotal pro-fibrogenic cytokine in hepatic fibrosis. Reducing the over-produced expression of TGF-beta1 or blocking its signaling pathways is considered to be a promising therapeutic strategy for hepatic fibrosis. In this study, we evaluated the feasibility of attenuating hepatic fibrosis by vaccination against TGF-beta1 with TGF-beta1 kinoids. Two TGF-beta1 kinoid vaccines were prepared by cross-linking TGF-beta1 derived polypeptides (TGF-beta1(25)-[41-65] and TGF-beta1(30)-[83-112]) to keyhole limpet hemocyanin (KLH). Immunization with the two TGF-beta1 kinoids efficiently elicited the production of high-levels of TGF-beta1-specific antibodies against in BALB/c mice as tested by enzyme-linked immunosorbent assay (ELISA) and Western blotting. The antisera neutralized TGF-beta1-induced growth inhibition on mink lung epithelial cells (Mv1Lu) and attenuated TGF-beta1-induced Smad2/3 phosphorylation, alpha-SMA, collagen type 1 alpha 2 (COL1A2), plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteinase-1 (TIMP 1) expression in the rat hepatic stellate cell (HSC) line, HSC-T6. Vaccination against TGF-beta1 with the kinoids significantly suppressed CCl4-induced collagen deposition and the expression of alpha-SMA and desmin, attenuated hepatocyte apoptosis and accelerated hepatocyte proliferation in BALB/c mice. These results demonstrated that immunization with the TGF-beta1 kinoids efficiently attenuated CCl4-induced hepatic fibrosis and liver injury. Our study suggests that vaccination against TGF-beta1 might be developed into a feasible therapeutic approach for the treatment of chronic fibrotic liver diseases. PMID- 24349219 TI - KIAA1462, a coronary artery disease associated gene, is a candidate gene for late onset Alzheimer disease in APOE carriers. AB - Alzheimer disease (AD) is a devastating neurodegenerative disease affecting more than five million Americans. In this study, we have used updated genetic linkage data from chromosome 10 in combination with expression data from serial analysis of gene expression to choose a new set of thirteen candidate genes for genetic analysis in late onset Alzheimer disease (LOAD). Results in this study identify the KIAA1462 locus as a candidate locus for LOAD in APOE4 carriers. Two genes exist at this locus, KIAA1462, a gene associated with coronary artery disease, and "rokimi", encoding an untranslated spliced RNA The genetic architecture at this locus suggests that the gene product important in this association is either "rokimi", or a different isoform of KIAA1462 than the isoform that is important in cardiovascular disease. Expression data suggests that isoform f of KIAA1462 is a more attractive candidate for association with LOAD in APOE4 carriers than "rokimi" which had no detectable expression in brain. PMID- 24349220 TI - Human CD8+ T cells from TB pleurisy respond to four immunodominant epitopes in Mtb CFP10 restricted by HLA-B alleles. AB - CD8(+) T cells are essential for host defense to Mycobacterium tuberculosis (Mtb) infection and identification of CD8(+) T cell epitopes from Mtb is of importance for the development of effective peptide-based diagnostics and vaccines. We previously demonstrated that the secreted 10-KDa culture filtrate protein (CFP10) from Mtb is a potent CD8(+) T cell antigen but the repertoire and dominance pattern of human CD8 epitopes for CFP10 remained poorly characterized. In the present study, we undertook to define immunodominant CD8 epitopes involved in CFP10 using a panel of CFP10-derived 13-15 amino acid (aa) peptides overlapping by 11 aa. Four peptides in CFP10 were observed to induce significant CD8(+) T cell responses and we further determined the size of the epitopes involved in each individual peptide tested. Four 9 aa CD8 epitopes were finally identified and deleting a single amino acid from the N or C terminus of either peptide markedly reduced IFN-gamma production, suggesting that they are minimum of CD8 epitopes. In the individuals tested, each epitope represented a single immunodominant response in CD8(+) T cells. The epitope-specific CD8(+) T cells displayed effector or effector memory phenotypes and could upregulate the expression of CD107a/b upon antigen stimulation. In addition, we found that epitope-specific CD8(+) T cells shared biased usage of T cell receptor (TCR) variable region of beta chain (Vbeta) 12, 9, 7.2 or Vbeta4 chains. As judged from HLA-typing results and using bioinformatics technology for prediction of MHC binding affinity, we found that the epitope-specific CD8(+) T cells are all restricted by HLA-B alleles. Our findings suggest that the four epitopes in CFP10 recognized by CD8(+) T cells might be of importance for the development of Mtb peptide-based vaccines and for improved diagnosis of TB in humans. PMID- 24349221 TI - Phylogenetic evidence of long distance dispersal and transmission of piscine reovirus (PRV) between farmed and wild Atlantic salmon. AB - The extent and effect of disease interaction and pathogen exchange between wild and farmed fish populations is an ongoing debate and an area of research that is difficult to explore. The objective of this study was to investigate pathogen transmission between farmed and wild Atlantic salmon (Salmo salar L.) populations in Norway by means of molecular epidemiology. Piscine reovirus (PRV) was selected as the model organism as it is widely distributed in both farmed and wild Atlantic salmon in Norway, and because infection not necessarily will lead to mortality through development of disease. A matrix comprised of PRV protein coding sequences S1, S2 and S4 from wild, hatchery-reared and farmed Atlantic salmon in addition to one sea-trout (Salmo trutta L.) was examined. Phylogenetic analyses based on maximum likelihood and Bayesian inference indicate long distance transport of PRV and exchange of virus between populations. The results are discussed in the context of Atlantic salmon ecology and the structure of the Norwegian salmon industry. We conclude that the lack of a geographical pattern in the phylogenetic trees is caused by extensive exchange of PRV. In addition, the detailed topography of the trees indicates long distance transportation of PRV. Through its size, structure and infection status, the Atlantic salmon farming industry has the capacity to play a central role in both long distance transportation and transmission of pathogens. Despite extensive migration, wild salmon probably play a minor role as they are fewer in numbers, appear at lower densities and are less likely to be infected. An open question is the relationship between the PRV sequences found in marine fish and those originating from salmon. PMID- 24349222 TI - Soluble tumor necrosis factor related apoptosis inducing ligand level as a predictor of severity of sepsis and the risk of mortality in septic patients. AB - BACKGROUND: Tumor necrosis factor related apoptosis inducing ligand (TRAIL) as a member of the TNF gene superfamily induces apoptosis primarily in tumor cells. TRAIL also plays an important role in the modulation of inflammatory responses, especially in the process of immune paralysis. The aim of the present study was to examine soluble TRAIL (sTRAIL) levels in septic patients in an attempt to explore the association between sTRAIL level and the risk of mortality. METHODS: Plasma sTRAIL levels were detected by ELISA in 50 septic patients and 20 healthy volunteers. HLA-DR expression in monocytes was detected by flow cytometry. Selective biochemical parameters were recorded, and patients were monitored in a 28-day period for mortality. RESULTS: The mean plasma sTRAIL level in septic patients was significantly lower than that in healthy controls (16.9+/-8.3 vs. 68.3+/-8.6 pg/ml, P<0.01), and was significantly higher in 28-day survivors than those in non-survivors (19.4+/-9.8 vs. 13.9+/-4.7 pg/ml, P<0.05). Univariate analysis indicated that plasma sTRAIL level was positively correlated with monocyte and lymphocyte counts and HLA-DR expression level (r = 0.5, P<0.01; r = 0.3, P<0.05; r = 0.43, P<0.01, respectively). STRAIL level was negatively correlated with APACHE II score, BUN and age (r = -0.48, P<0.01; r = -0.29, P<0.05; r = -0.45, P<0.01, respectively). Multiple linear regression analysis indicated that the predictor of plasma soluble TRAIL level was HLA-DR expression (P<0.01). CONCLUSION: Low plasma sTRAIL levels were associated with immune paralysis and a high risk of mortality in patients with septic shock. sTRAIL may prove to be a potential biomarker of immune function and predict the survival of septic patients. PMID- 24349223 TI - Carbon storages in plantation ecosystems in sand source areas of north Beijing, China. AB - Afforestation is a mitigation option to reduce the increased atmospheric carbon dioxide levels as well as the predicted high possibility of climate change. In this paper, vegetation survey data, statistical database, National Forest Resource Inventory database, and allometric equations were used to estimate carbon density (carbon mass per hectare) and carbon storage, and identify the size and spatial distribution of forest carbon sinks in plantation ecosystems in sand source areas of north Beijing, China. From 2001 to the end of 2010, the forest areas increased more than 2.3 million ha, and total carbon storage in forest ecosystems was 173.02 Tg C, of which 82.80 percent was contained in soil in the top 0-100 cm layer. Younger forests have a large potential for enhancing carbon sequestration in terrestrial ecosystems than older ones. Regarding future afforestation efforts, it will be more effective to increase forest area and vegetation carbon density through selection of appropriate tree species and stand structure according to local climate and soil conditions, and application of proper forest management including land-shaping, artificial tending and fencing plantations. It would be also important to protect the organic carbon in surface soils during forest management. PMID- 24349224 TI - Evaluation of elevated mean pulmonary arterial pressure based on magnetic resonance 4D velocity mapping: comparison of visualization techniques. AB - PURPOSE: Three-dimensional (3D) magnetic resonance phase contrast imaging (PC MRI) allows non-invasive diagnosis of pulmonary hypertension (PH) and estimation of elevated mean pulmonary arterial pressure (mPAP) based on vortical motion of blood in the main pulmonary artery. The purpose of the present study was to compare the presence and duration of PH-associated vortices derived from different flow visualization techniques with special respect to their performance for non-invasive assessment of elevated mPAP and diagnosis of PH. METHODS: Fifty patients with suspected PH (23 patients with and 27 without PH) were investigated by right heart catheterization and time-resolved PC-MRI of the main pulmonary artery. PC-MRI data were visualized with dedicated prototype software, providing 3D vector, multi-planar reformatted (MPR) 2D vector, streamline, and particle trace representation of flow patterns. Persistence of PH-associated vortical blood flow (tvortex) was evaluated with all visualization techniques. Dependencies of tvortex on visualization techniques were analyzed by means of correlation and receiver operating characteristic (ROC) curve analysis. RESULTS: tvortex values from 3D vector visualization correlated strongly with those from other visualization techniques (r = 0.98, 0.98 and 0.97 for MPR, streamline and particle trace visualization, respectively). Areas under ROC curves for diagnosis of PH based on tvortex did not differ significantly and were 0.998 for 3D vector, MPR vector and particle trace visualization and 0.999 for streamline visualization. Correlations between elevated mPAP and tvortex in patients with PH were r = 0.96, 0.93, 0.95 and 0.92 for 3D vector, MPR vector, streamline and particle trace visualization, respectively. Corresponding standard deviations from the linear regression lines ranged between 3 and 4 mmHg. CONCLUSION: 3D vector, MPR vector, streamline as well as particle trace visualization of time resolved 3D PC-MRI data of the main pulmonary artery can be employed for accurate vortex-based diagnosis of PH and estimation of elevated mPAP. PMID- 24349225 TI - Safety, immunogenicity and duration of immunity elicited by an inactivated bovine ephemeral fever vaccine. AB - Bovine ephemeral fever (BEF) is an economically important viral vector-borne cattle disease. Several live-attenuated, inactivated and recombinant vaccines have been tested, demonstrating varying efficacy. However, to the best of our knowledge, duration of immunity conferred by an inactivated vaccine has never been reported. In the last decade, Israel has faced an increasing number of BEF outbreaks. The need for an effective vaccine compatible with strains circulating in the Middle East region led to the development of a MONTANIDETM ISA 206 VG (water-in-oil-in-water), inactivated vaccine based on a local strain. We tested the safety, immunogenicity and duration of immunity conferred by this vaccine. The induced neutralizing antibody (NA) response was followed for 493 days in 40 cows vaccinated by different protocols. The vaccine did not cause adverse reactions or a decrease in milk production. All cows [except 2 (6.7%) which did not respond to vaccination] showed a significant rise in NA titer of up to 1:256 following the second, third or fourth booster vaccination. Neutralizing antibody levels declined gradually to 1:16 up to 120 days post vaccination. This decline continued in cows vaccinated only twice, whereas cows vaccinated 3 or 4 times showed stable titers of approximately 1:16 for up to 267 days post vaccination. At least three vaccinations with the inactivated BEF vaccine were needed to confer long-lasting immunity. These results may have significant implications for the choice of vaccination protocol with inactivated BEF vaccines. Complementary challenge data should however be added to the above results in order to determine what is the minimal NA response conferring protection from clinical disease. PMID- 24349227 TI - The wallpaper effect: the contact hypothesis fails for minority group members who live in areas with a high proportion of majority group members. AB - We aim to provide one explanation for why the link between contact and prejudice is consistently less strong for minority group members than it is for majority group members. Specifically, we propose a "wallpaper effect" such that contact works to increase minority group members' positivity towards majority groups when they live in areas densely populated with other minority group members. Conversely, we suggest that when minority group members live in neighborhoods patterned with majority group faces (as is so often the case), contact will be less transformative. We test this assumption using a large sample of both New Zealander minority (Maori; N = 925) and majority (European; N = 3805) group members. In line with predictions, Maori who lived in minority dense neighborhoods showed the traditional association between contact and increased warmth towards New Zealander Europeans. This relationship, however, was weak or non-existent when they lived in primarily European neighborhoods. Contact effects in majority group members were unaffected by neighborhood composition. The interaction held when controlling for, and was not explained by: gender, income, experiences of harm, cognitions of race-based rejection, or realistic threat. We provide the first evidence to suggest that when it comes to minority group members' intergroup attitudes, contact with majority group members may be a relatively ineffective predictor unless the "wallpaper" of their lives is minority-dense. PMID- 24349226 TI - Sequential effects in judgements of attractiveness: the influences of face race and sex. AB - In perceptual decision-making, a person's response on a given trial is influenced by their response on the immediately preceding trial. This sequential effect was initially demonstrated in psychophysical tasks, but has now been found in more complex, real-world judgements. The similarity of the current and previous stimuli determines the nature of the effect, with more similar items producing assimilation in judgements, while less similarity can cause a contrast effect. Previous research found assimilation in ratings of facial attractiveness, and here, we investigated whether this effect is influenced by the social categories of the faces presented. Over three experiments, participants rated the attractiveness of own- (White) and other-race (Chinese) faces of both sexes that appeared successively. Through blocking trials by race (Experiment 1), sex (Experiment 2), or both dimensions (Experiment 3), we could examine how sequential judgements were altered by the salience of different social categories in face sequences. For sequences that varied in sex alone, own-race faces showed significantly less opposite-sex assimilation (male and female faces perceived as dissimilar), while other-race faces showed equal assimilation for opposite- and same-sex sequences (male and female faces were not differentiated). For sequences that varied in race alone, categorisation by race resulted in no opposite-race assimilation for either sex of face (White and Chinese faces perceived as dissimilar). For sequences that varied in both race and sex, same-category assimilation was significantly greater than opposite-category. Our results suggest that the race of a face represents a superordinate category relative to sex. These findings demonstrate the importance of social categories when considering sequential judgements of faces, and also highlight a novel approach for investigating how multiple social dimensions interact during decision-making. PMID- 24349228 TI - Predation limits spread of Didemnum vexillum into natural habitats from refuges on anthropogenic structures. AB - Non-indigenous species can dominate fouling assemblages on artificial structures in marine environments; however, the extent to which infected structures act as reservoirs for subsequent spread to natural habitats is poorly understood. Didemnum vexillum is one of few colonial ascidian species that is widely reported to be highly invasive in natural ecosystems, but which in New Zealand proliferates only on suspended structures. Experimental work revealed that D. vexillum established equally well on suspended artificial and natural substrata, and was able to overgrow suspended settlement plates that were completely covered in other cosmopolitan fouling species. Fragmentation led to a level of D. vexillum cover that was significantly greater than was achieved as a result of ambient larval recruitment. The species failed to establish following fragment transplants onto seabed cobbles and into beds of macroalgae. The establishment success of D. vexillum was greatest in summer compared with autumn, and on the underside of experimental settlement plates that were suspended off the seabed to avoid benthic predators. Where benthic predation pressure was reduced by caging, D. vexillum establishment success was broadly comparable to suspended treatments; by contrast, the species did not establish on the face-up aspect of uncaged plates. This study provides compelling evidence that benthic predation was a key mechanism that prevented D. vexillum's establishment in the cobble habitats of the study region. The widespread occurrence of D. vexillum on suspended anthropogenic structures is consistent with evidence for other sessile invertebrates that such habitats provide a refuge from benthic predation. For invasive species generally, anthropogenic structures are likely to be most important as propagule reservoirs for spread to natural habitats in situations where predation and other mechanisms do not limit their subsequent proliferation. PMID- 24349229 TI - Resistance to ROS1 inhibition mediated by EGFR pathway activation in non-small cell lung cancer. AB - The targeting of oncogenic 'driver' kinases with small molecule inhibitors has proven to be a highly effective therapeutic strategy in selected non-small cell lung cancer (NSCLC) patients. However, acquired resistance to targeted therapies invariably arises and is a major limitation to patient care. ROS1 fusion proteins are a recently described class of oncogenic driver, and NSCLC patients that express these fusions generally respond well to ROS1-targeted therapy. In this study, we sought to determine mechanisms of acquired resistance to ROS1 inhibition. To accomplish this, we analyzed tumor samples from a patient who initially responded to the ROS1 inhibitor crizotinib but eventually developed acquired resistance. In addition, we generated a ROS1 inhibition-resistant derivative of the initially sensitive NSCLC cell line HCC78. Previously described mechanisms of acquired resistance to tyrosine kinase inhibitors including target kinase-domain mutation, target copy number gain, epithelial-mesenchymal transition, and conversion to small cell lung cancer histology were found to not underlie resistance in the patient sample or resistant cell line. However, we did observe a switch in the control of growth and survival signaling pathways from ROS1 to EGFR in the resistant cell line. As a result of this switch, ROS1 inhibition-resistant HCC78 cells became sensitive to EGFR inhibition, an effect that was enhanced by co-treatment with a ROS1 inhibitor. Our results suggest that co-inhibition of ROS1 and EGFR may be an effective strategy to combat resistance to targeted therapy in some ROS1 fusion-positive NSCLC patients. PMID- 24349230 TI - TFpredict and SABINE: sequence-based prediction of structural and functional characteristics of transcription factors. AB - One of the key mechanisms of transcriptional control are the specific connections between transcription factors (TF) and cis-regulatory elements in gene promoters. The elucidation of these specific protein-DNA interactions is crucial to gain insights into the complex regulatory mechanisms and networks underlying the adaptation of organisms to dynamically changing environmental conditions. As experimental techniques for determining TF binding sites are expensive and mostly performed for selected TFs only, accurate computational approaches are needed to analyze transcriptional regulation in eukaryotes on a genome-wide level. We implemented a four-step classification workflow which for a given protein sequence (1) discriminates TFs from other proteins, (2) determines the structural superclass of TFs, (3) identifies the DNA-binding domains of TFs and (4) predicts their cis-acting DNA motif. While existing tools were extended and adapted for performing the latter two prediction steps, the first two steps are based on a novel numeric sequence representation which allows for combining existing knowledge from a BLAST scan with robust machine learning-based classification. By evaluation on a set of experimentally confirmed TFs and non-TFs, we demonstrate that our new protein sequence representation facilitates more reliable identification and structural classification of TFs than previously proposed sequence-derived features. The algorithms underlying our proposed methodology are implemented in the two complementary tools TFpredict and SABINE. The online and stand-alone versions of TFpredict and SABINE are freely available to academics at http://www.cogsys.cs.uni-tuebingen.de/software/TFpredict/ and http://www.cogsys.cs.uni-tuebingen.de/software/SABINE/. PMID- 24349232 TI - Bottom-water conditions in a marine basin after the Cretaceous-Paleogene impact event: timing the recovery of oxygen levels and productivity. AB - An ultra-high-resolution analysis of major and trace element contents from the Cretaceous-Paleogene boundary interval in the Caravaca section, southeast Spain, reveals a quick recovery of depositional conditions after the impact event. Enrichment/depletion profiles of redox sensitive elements indicate significant geochemical anomalies just within the boundary ejecta layer, supporting an instantaneous recovery--some 10(2) years--of pre-impact conditions in terms of oxygenation. Geochemical redox proxies point to oxygen levels comparable to those at the end of the Cretaceous shortly after impact, which is further evidenced by the contemporary macrobenthic colonization of opportunistic tracemakers. Recovery of the oxygen conditions was therefore several orders shorter than traditional proposals (10(4)-10(5) years), suggesting a probable rapid recovery of deep-sea ecosystems at bottom and in intermediate waters. PMID- 24349231 TI - Human host defense peptide LL-37 stimulates virulence factor production and adaptive resistance in Pseudomonas aeruginosa. AB - A multitude of different virulence factors as well as the ability to rapidly adapt to adverse environmental conditions are important features for the high pathogenicity of Pseudomonas aeruginosa. Both virulence and adaptive resistance are tightly controlled by a complex regulatory network and respond to external stimuli, such as host signals or antibiotic stress, in a highly specific manner. Here, we demonstrate that physiological concentrations of the human host defense peptide LL-37 promote virulence factor production as well as an adaptive resistance against fluoroquinolone and aminoglycoside antibiotics in P. aeruginosa PAO1. Microarray analyses of P. aeruginosa cells exposed to LL-37 revealed an upregulation of gene clusters involved in the production of quorum sensing molecules and secreted virulence factors (PQS, phenazine, hydrogen cyanide (HCN), elastase and rhamnolipids) and in lipopolysaccharide (LPS) modification as well as an induction of genes encoding multidrug efflux pumps MexCD-OprJ and MexGHI-OpmD. Accordingly, we detected significantly elevated levels of toxic metabolites and proteases in bacterial supernatants after LL-37 treatment. Pre-incubation of bacteria with LL-37 for 2 h led to a decreased susceptibility towards gentamicin and ciprofloxacin. Quantitative Realtime PCR results using a PAO1-pqsE mutant strain present evidence that the quinolone response protein and virulence regulator PqsE may be implicated in the regulation of the observed phenotype in response to LL-37. Further experiments with synthetic cationic antimicrobial peptides IDR-1018, 1037 and HHC-36 showed no induction of pqsE expression, suggesting a new role of PqsE as highly specific host stress sensor. PMID- 24349233 TI - Localization of microfibrillar-associated protein 4 (MFAP4) in human tissues: clinical evaluation of serum MFAP4 and its association with various cardiovascular conditions. AB - Microfibrillar-associated protein 4 (MFAP4) is located in the extracellular matrix (ECM). We sought to identify tissues with high levels of MFAP4 mRNA and MFAP4 protein expression. Moreover, we aimed to evaluate the significance of MFAP4 as a marker of cardiovascular disease (CVD) and to correlate MFAP4 with other known ECM markers, such as fibulin-1, osteoprotegerin (OPG), and osteopontin (OPN). Quantitative real-time PCR demonstrated that MFAP4 mRNA was more highly expressed in the heart, lung, and intestine than in other elastic tissues. Immunohistochemical studies demonstrated high levels of MFAP4 protein mainly at sites rich in elastic fibers and within blood vessels in all tissues investigated. The AlphaLISA technique was used to determine serum MFAP4 levels in a clinical cohort of 172 patients consisting of 5 matched groups with varying degrees of CVD: 1: patients with ST elevation myocardial infarction (STEMI), 2: patients with non-STEMI, 3: patients destined for vascular surgery because of various atherosclerotic diseases (stable atherosclerotic disease), 4: apparently healthy individuals with documented coronary artery calcification (CAC-positive), and 5: apparently healthy individuals without signs of coronary artery calcification (CAC-negative). Serum MFAP4 levels were significantly lower in patients with stable atherosclerotic disease than CAC-negative individuals (p<0.05). Furthermore, lower serum MFAP4 levels were present in patients with stable atherosclerotic disease compared with STEMI and non-STEMI patients (p<0.05). In patients with stable atherosclerotic disease, positive correlations between MFAP4 and both fibulin-1 (rho = 0.50; p = 0.0244) and OPG (rho = 0.62; p = 0.0014) were found. Together, these results indicate that MFAP4 is mainly located in elastic fibers and is highly expressed in blood vessels. The present study suggests that serum MFAP4 varies in groups of patients with different cardiovascular conditions. Further studies are warranted to describe the role of serum MFAP4 as a biomarker of stable atherosclerotic disease. PMID- 24349234 TI - Surgically induced interpregnancy weight loss and prevalence of overweight and obesity in offspring. AB - INTRODUCTION: According to the fetal overnutrition hypothesis, obesity in pregnancy predisposes the offspring to obesity. Previous studies have suggested that after biliopancreatic surgery for obesity, the offspring is less likely to be obese. This study aims to further compare the BMI development of children born before and after maternal surgical weight loss. METHOD: Women with at least one child born before and one child born after bariatric surgery were identified by record-linkage. Information about maternal BMI was extracted from medical records, as was information about the children's BMI from birth to 10 years of age. We retrieved BMI data at four years of age for 340 children, born to 223 women (164 children born before surgery (BS), 176 children born after surgery (AS)). We evaluated prevalence of overweight/obesity and mean BMI in children born BS and AS at the ages of four, six and ten using GEE regression models. For 71 families, where we had complete data on mother and both children, we used a fixed-effects regression model to explore the association between differences in maternal BMI in w10 of the pre- and post-operative pregnancies with siblings' BMI differences at age four. RESULTS: In no age group did we see a significantly reduced prevalence of overweight/obesity AS. For 10-year-old girls, the AS group had significantly higher rates of obesity. There was no association between differences in maternal BMI in early pregnancy and differences in siblings' BMI at four years of age (beta = -0.01, CI 95% = -0.11; 0.09). CONCLUSIONS: We have been unable to demonstrate any effect of bariatric surgery on weight development in offspring. It seems unlikely that restrictive bariatric surgery conveys a protective effect in offspring with regards to obesity. PMID- 24349235 TI - Prophage-mediated dynamics of 'Candidatus Liberibacter asiaticus' populations, the destructive bacterial pathogens of citrus huanglongbing. AB - Prophages are highly dynamic components in the bacterial genome and play an important role in intraspecies variations. There are at least two prophages in the chromosomes of Candidatus Liberibacter asiaticus' (Las) Floridian isolates. Las is both unculturable and the most prevalent species of Liberibacter pathogens that cause huanglongbing (HLB), a worldwide destructive disease of citrus. In this study, seven new prophage variants resulting from two hyper-variable regions were identified by screening clone libraries of infected citrus, periwinkle and psyllids. Among them, Types A and B share highly conserved sequences and localize within the two prophages, FP1 and FP2, respectively. Although Types B and C were abundant in all three libraries, Type A was much more abundant in the libraries from the Las-infected psyllids than from the Las-infected plants, and Type D was only identified in libraries from the infected host plants but not from the infected psyllids. Sequence analysis of these variants revealed that the variations may result from recombination and rearrangement events. Conventional PCR results using type-specific molecular markers indicated that A, B, C and D are the four most abundant types in Las-infected citrus and periwinkle. However, only three types, A, B and C are abundant in Las-infected psyllids. Typing results for Las-infected citrus field samples indicated that mixed populations of Las bacteria present in Floridian isolates, but only the Type D population was correlated with the blotchy mottle symptom. Extended cloning and sequencing of the Type D region revealed a third prophage/phage in the Las genome, which may derive from the recombination of FP1 and FP2. Dramatic variations in these prophage regions were also found among the global Las isolates. These results are the first to demonstrate the prophage/phage-mediated dynamics of Las populations in plant and insect hosts, and their correlation with insect transmission and disease development. PMID- 24349236 TI - Factors associated with failed treatment: an analysis of 121,744 women embarking on their first IVF cycles. AB - BACKGROUND: In-vitro fertilization (IVF) is the treatment of choice for unresolved infertility. It comprises a number of key steps, each of which has to be negotiated before the next is attempted, but the factors which are associated with failure at each stage have not been reported. METHODS AND FINDINGS: We analyzed anonymised national data on women undergoing their first fresh autologous IVF and intracytoplasmic sperm injection (ICSI) cycle in the United Kingdom between 2000 and 2007 to predict factors associated with overall lack of livebirth as well as the chance of non-progress at different stages of an IVF cycle. A total of 121,744 women were included in this analysis. Multivariable models underlined the importance of increased female age and duration of infertility, lack of previous pregnancy, and a diagnosis of tubal or male factor infertility in predicting the risk of not having a live birth in an IVF treatment. At each stage, a woman's chance of proceeding to the next stage of IVF treatment is affected by increased age and duration of infertility. The intention to use intra-cytoplasmic sperm injection (ICSI) is associated with a decreased risk of treatment failure in women starting an IVF cycle (RR 0.93, 99% CI 0.92, 0.94) but this association is reversed at a later stage once fertilisation has been confirmed (RR=1.01, 99%CI 1.00, 1.03). CONCLUSIONS: Female age is a key predictor of failure to have a livebirth following IVF as well as the risk of poor performance at each stage of treatment. While increased duration of infertility is also associated with worse outcomes at every stage, its impact appears to be less influential. Women embarking on ICSI treatment for male factor infertility have a lower chance of treatment failure but this does not appear to be due to increased chances of implantation of ICSI embryos. PMID- 24349237 TI - Procalcitonin levels predict acute kidney injury and prognosis in acute pancreatitis: a prospective study. AB - BACKGROUND: Acute kidney injury (AKI) has been proposed as a leading cause of mortality for acute pancreatitis (AP) patients admitted to the intensive care unit (ICU). This study investigated the predictive value of procalcitonin (PCT) for AKI development and relevant prognosis in patients with AP, and compared PCT's predictive power with that of other inflammation-related variables. METHODS: Between January 2011 and March 2013, we enrolled 305 cases with acute pancreatitis admitted to ICU. Serum levels of PCT, serum amyloid A (SAA), interleukin-6 (IL-6), and C reactive protein (CRP) were determined on admission. Serum PCT was tested in patients who developed AKI on the day of AKI occurrence and on either day 28 after occurrence (for survivors) or on the day of death (for those who died within 28 days). RESULTS: Serum PCT levels were 100-fold higher in the AKI group than in the non-AKI group on the day of ICU admission (p<0.05). The area under the receiver-operating characteristic (ROC) curve of PCT for predicting AKI was 0.986, which was superior to SAA, CRP, and IL-6 (p<0.05). ROC analysis revealed all variables tested had lower predictive performance for AKI prognosis. The average serum PCT level on day 28 (2.67 (0.89, 7.99) ng/ml) was significantly (p<0.0001) lower than on the day of AKI occurrence (43.71 (19.24,65.69) ng/ml) in survivors, but the serum PCT level on death (63.73 (34.22,94.30) ng/ml) was higher than on the day of AKI occurrence (37.55 (18.70,74.12) ng/ml) in non-survivors, although there was no significant difference between the two days in the latter group (p = 0.1365). CONCLUSION: Serum PCT is superior to CRP, IL-6, and SAA for predicting the development of AKI in patients with AP, and also can be used for dynamic evaluation of AKI prognosis. PMID- 24349238 TI - Local experience with extracorporeal membrane oxygenation in children with acute fulminant myocarditis. AB - To analyze the clinical effect of extracorporeal membrane oxygenation (ECMO) in children with acute fulminant myocarditis, we retrospectively analyzed the data of five children with acute fulminant myocarditis in the intensive care unit (ICU) at the Affiliated Children's Hospital, Zhejiang University from February 2009 to November 2012. The study group included two boys and three girls ranging in age from 9 to 13 years (median 10 years). Body weight ranged from 25 to 33 kg (mean 29.6 kg). They underwent extracorporeal membrane oxygenation (ECMO) through a venous-arterial ECMO model with an average ECMO supporting time of 89.8 h (40 142 h). Extracorporeal circulation was established in all five children. After treatment with ECMO, the heart rate, blood pressure, and oxygen saturation were greatly improved in the four children who survived. These four children were successfully weaned from ECMO and discharged from hospital machine-free, for a survival rate of 80% (4/5). One child died still dependent on the machine. Cause of death was irrecoverable cardiac function and multiple organ failure. Complications during ECMO included three cases of suture bleeding, one case of acute hemolytic renal failure and suture bleeding, and one case of hyperglycemia. During the follow-up period of 4-50 months, the four surviving children recovered with normal cardiac function and no abnormal functions of other organs. The application of ECMO in acute fulminant myocarditis, even in local centers that experience low incidence of this disease, remains an effective approach. Larger studies to determine optimal timing of placement on ECMO to guide local centers are warranted. PMID- 24349239 TI - Electrically conductive bulk composites through a contact-connected aggregate. AB - This paper introduces a concept that allows the creation of low-resistance composites using a network of compliant conductive aggregate units, connected through contact, embedded within the composite. Due to the straight-forward fabrication method of the aggregate, conductive composites can be created in nearly arbitrary shapes and sizes, with a lower bound near the length scale of the conductive cell used in the aggregate. The described instantiation involves aggregate cells that are approximately spherical copper coils-of-coils within a polymeric matrix, but the concept can be implemented with a wide range of conductor elements, cell geometries, and matrix materials due to its lack of reliance on specific material chemistries. The aggregate cell network provides a conductive pathway that can have orders of magnitude lower resistance than that of the matrix material--from 10(12) ohm-cm (approx.) for pure silicone rubber to as low as 1 ohm-cm for the silicone/copper composite at room temperature for the presented example. After describing the basic concept and key factors involved in its success, three methods of implementing the aggregate into a matrix are then addressed--unjammed packing, jammed packing, and pre-stressed jammed packing- with an analysis of the tradeoffs between increased stiffness and improved resistivity. PMID- 24349240 TI - Overexpression of small heat shock protein LimHSP16.45 in Arabidopsis enhances tolerance to abiotic stresses. AB - Small heat shock proteins (smHSPs) play important and extensive roles in plant defenses against abiotic stresses. We cloned a gene for a smHSP from the David Lily (Lilium davidii (E. H. Wilson) Raffill var. Willmottiae), which we named LimHSP16.45 based on its protein molecular weight. Its expression was induced by many kinds of abiotic stresses in both the lily and transgenic plants of Arabidopsis. Heterologous expression enhanced cell viability of the latter under high temperatures, high salt, and oxidative stress, and heat shock granules (HSGs) formed under heat or salinity treatment. Assays of enzymes showed that LimHSP16.45 overexpression was related to greater activity by superoxide dismutase and catalase in transgenic lines. Therefore, we conclude that heterologous expression can protect plants against abiotic stresses by preventing irreversible protein aggregation, and by scavenging cellular reactive oxygen species. PMID- 24349241 TI - A flexible approach for assessing functional landscape connectivity, with application to greater sage-grouse (Centrocercus urophasianus). AB - Connectivity of animal populations is an increasingly prominent concern in fragmented landscapes, yet existing methodological and conceptual approaches implicitly assume the presence of, or need for, discrete corridors. We tested this assumption by developing a flexible conceptual approach that does not assume, but allows for, the presence of discrete movement corridors. We quantified functional connectivity habitat for greater sage-grouse (Centrocercus urophasianus) across a large landscape in central western North America. We assigned sample locations to a movement state (encamped, traveling and relocating), and used Global Positioning System (GPS) location data and conditional logistic regression to estimate state-specific resource selection functions. Patterns of resource selection during different movement states reflected selection for sagebrush and general avoidance of rough topography and anthropogenic features. Distinct connectivity corridors were not common in the 5,625 km(2) study area. Rather, broad areas functioned as generally high or low quality connectivity habitat. A comprehensive map predicting the quality of connectivity habitat across the study area validated well based on a set of GPS locations from independent greater sage-grouse. The functional relationship between greater sage-grouse and the landscape did not always conform to the idea of a discrete corridor. A more flexible consideration of landscape connectivity may improve the efficacy of management actions by aligning those actions with the spatial patterns by which animals interact with the landscape. PMID- 24349242 TI - Attenuation of hyperlipidemia- and diabetes-induced early-stage apoptosis and late-stage renal dysfunction via administration of fibroblast growth factor-21 is associated with suppression of renal inflammation. AB - BACKGROUND: Lipotoxicity is a key feature of the pathogenesis of diabetic kidney disease, and is attributed to excessive lipid accumulation (hyperlipidemia). Increasing evidence suggests that fibroblast growth factor (FGF)21 has a crucial role in lipid metabolism under diabetic conditions. OBJECTIVE: The present study investigated whether FGF21 can prevent hyperlipidemia- or diabetes-induced renal damage, and if so, the possible mechanism. METHODS: Mice were injected with free fatty acids (FFAs, 10 mg/10 g body weight) or streptozotocin (150 mg/kg) to establish a lipotoxic model or type 1 diabetic model, respectively. Simultaneously the mice were treated with FGF21 (100 ug/kg) for 10 or 80 days. The kidney weight-to-tibia length ratio and renal function were assessed. Systematic and renal lipid levels were detected by ELISA and Oil Red O staining. Renal apoptosis was examined by TUNEL assay. Inflammation, oxidative stress, and fibrosis were assessed by Western blot. RESULTS: Acute FFA administration and chronic diabetes were associated with lower kidney-to-tibia length ratio, higher lipid levels, severe renal apoptosis and renal dysfunction. Obvious inflammation, oxidative stress and fibrosis also observed in the kidney of both mice models. Deletion of the fgf21 gene further enhanced the above pathological changes, which were significantly prevented by administration of exogenous FGF21. CONCLUSION: These results suggest that FFA administration and diabetes induced renal damage, which was further enhanced in FGF21 knock-out mice. Administration of FGF21 significantly prevented both FFA- and diabetes-induced renal damage partially by decreasing renal lipid accumulation and suppressing inflammation, oxidative stress, and fibrosis. PMID- 24349243 TI - An allosteric regulator of R7-RGS proteins influences light-evoked activity and glutamatergic waves in the inner retina. AB - In the outer retina, G protein-coupled receptor (GPCR) signaling mediates phototransduction and synaptic transmission between photoreceptors and ON bipolar cells. In contrast, the functions of modulatory GPCR signaling networks in the inner retina are less well understood. We addressed this question by determining the consequences of augmenting modulatory Gi/o signaling driven by endogenous transmitters. This was done by analyzing the effects of genetically ablating the R7 RGS-binding protein (R7BP), a membrane-targeting protein and positive allosteric modulator of R7-RGS (regulator of the G protein signaling 7) family that deactivates Gi/oalpha subunits. We found that R7BP is expressed highly in starburst amacrine cells and retinal ganglion cells (RGCs). As indicated by electroretinography and multielectrode array recordings of adult retina, ablation of R7BP preserved outer retina function, but altered the firing rate and latency of ON RGCs driven by rods and cones but not rods alone. In developing retina, R7BP ablation increased the burst duration of glutamatergic waves whereas cholinergic waves were unaffected. This effect on glutamatergic waves did not result in impaired segregation of RGC projections to eye-specific domains of the dorsal lateral geniculate nucleus. R7BP knockout mice exhibited normal spatial contrast sensitivity and visual acuity as assessed by optomotor reflexes. Taken together these findings indicate that R7BP-dependent regulation of R7-RGS proteins shapes specific aspects of light-evoked and spontaneous activity of RGCs in mature and developing retina. PMID- 24349244 TI - Four-month-old infants' long-term memory for a stressful social event. AB - Infants clearly show an early capacity for memory for inanimate emotionally neutral events. However, their memory for social stress events has received far less attention. The aim of the study was to investigate infants' memory for a stressful social event (i.e., maternal unresponsiveness during the Still-Face paradigm) after a 15-day recall interval using changes in behavioral responses and salivary post-stress cortisol reactivity as measures of memory. Thirty-seven infants were exposed to social stress two times (experimental condition); the first time when they were 4 months of age and second exposure after a 2 week interval. Infants in the control condition (N = 37) were exposed to social stress just one time, at the age corresponding to the second exposure for infants in the experimental condition (4 months plus 2 weeks). Given individual differences in infants' reactivity to social stress events, we categorized infants as increasers or decreasers based on their cortisol reactivity after their initial exposure to the stress of the maternal still-face. Infants in the experimental condition, both increasers and decreasers, showed a significant change in cortisol response after the second exposure to the maternal still-face, though change was different for each reactivity group. In contrast, age-matched infants with no prior exposure to the maternal still-face showed similar post-stress cortisol reactivity to the reactivity of the experimental infants at their first exposure. There were no behavioral differences between increasers and decreasers during the Still-Face paradigm and exposures to the social stress. Thus differences between the experimental and control groups' post-stress cortisol reactivity was associated with the experimental group having previous experience with the social stress. These findings indicate long-term memory for social stress in infants as young as 4 months of age. PMID- 24349245 TI - High nasopharyngeal carriage of non-vaccine serotypes in Western Australian aboriginal people following 10 years of pneumococcal conjugate vaccination. AB - BACKGROUND: Invasive pneumococcal disease (IPD) continues to occur at high rates among Australian Aboriginal people. The seven-valent pneumococcal conjugate vaccine (7vPCV) was given in a 2-4-6-month schedule from 2001, with a 23-valent pneumococcal polysaccharide vaccine (23vPPV) booster at 18 months, and replaced with 13vPCV in July 2011. Since carriage surveillance can supplement IPD surveillance, we have monitored pneumococcal carriage in western Australia (WA) since 2008 to assess the impact of the 10-year 7vPCV program. METHODS: We collected 1,500 nasopharyngeal specimens from Aboriginal people living in varied regions of WA from August 2008 until June 2011. Specimens were cultured on selective media. Pneumococcal isolates were serotyped by the quellung reaction. RESULTS: Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis were carried by 71.9%, 63.2% and 63.3% respectively of children <5 years of age, and 34.6%, 22.4% and 27.2% of people >=5 years. Of 43 pneumococcal serotypes identified, the most common were 19A, 16F and 6C in children <5 years, and 15B, 34 and 22F in older people. 7vPCV serotypes accounted for 14.5% of all serotypeable isolates, 13vPCV for 32.4% and 23vPPV for 49.9%, with little variation across all age groups. Serotypes 1 and 12F were rarely identified, despite causing recent IPD outbreaks in WA. Complete penicillin resistance (MIC >=2ug/ml) was found in 1.6% of serotype 19A (5.2%), 19F (4.9%) and 16F (3.2%) isolates and reduced penicillin susceptibility (MIC >=0.125ug/ml) in 24.9% of isolates, particularly 19F (92.7%), 19A (41.3%), 16F (29.0%). Multi-resistance to cotrimoxazole, tetracycline and erythromycin was found in 83.0% of 23F isolates. Among non-serotypeable isolates 76.0% had reduced susceptibility and 4.0% showed complete resistance to penicillin. CONCLUSIONS: Ten years after introduction of 7vPCV for Aboriginal Australian children, 7vPCV serotypes account for a small proportion of carried pneumococci. A large proportion of circulating serotypes are not covered by any currently licensed vaccine. PMID- 24349246 TI - The T309G MDM2 gene polymorphism is a novel risk factor for proliferative vitreoretinopathy. AB - Proliferative vitreoretinopathy (PVR) is still the major cause of failure in retinal detachment (RD) surgery. It is believed that down-regulation in the p53 pathway could be an important key in PVR pathogenesis. The purpose was to evaluate the impact of T309G MDM2 polymorphism (rs2279744) in PVR. Distribution of T309G MDM2 genotypes among European subjects undergoing RD surgery was evaluated. Proportions of genotypes between subsamples from different countries were analyzed. Also, a genetic interaction between rs2279744 in MDM2 and rs1042522 in p53 gene was analyzed. Significant differences were observed comparing MDM2 genotype frequencies at position 309 of intron 1 between cases (GG: 21.6%, TG: 54.5%, TT: 23.8%) and controls (GG: 7.3%, TG: 43.9%, TT: 48.7%). The proportions of genotypes between sub-samples from different countries showed a significant difference. Distribution of GG genotype revealed differences in Spain (35.1-53.0)/(22.6-32.9), Portugal (39.0-74.4)/(21.4-38.9), Netherlands (40.6-66.3)/(25.3-38.8) and UK (37.5-62.4)/(23.3-34.2). The OR of G carriers in the global sample was 5.9 (95% CI: 3.2 to 11.2). The OR of G carriers from Spain and Portugal was 5.4 (95% CI: 2.2-12.7), whereas in the UK and the Netherlands was 7.3 (95% CI: 2.8-19.1). Results indicate that the G allele of rs2279744 is associated with a higher risk of developing PVR in patients undergoing a RD surgery. Further studies are necessary to understand the role of this SNP in the development of PVR. PMID- 24349247 TI - Molecular mechanism of inhibition of the mitochondrial carnitine/acylcarnitine transporter by omeprazole revealed by proteoliposome assay, mutagenesis and bioinformatics. AB - The effect of omeprazole on the mitochondrial carnitine/acylcarnitine transporter has been studied in proteoliposomes. Externally added omeprazole inhibited the carnitine/carnitine antiport catalysed by the transporter. The inhibition was partially reversed by DTE indicating that it was caused by the covalent reaction of omeprazole with Cys residue(s). Inhibition of the C-less mutant transporter indicated also the occurrence of an alternative non-covalent mechanism. The IC50 of the inhibition of the WT and the C-less CACT by omeprazole were 5.4 uM and 29 uM, respectively. Inhibition kinetics showed non competitive inhibition of the WT and competitive inhibition of the C-less. The presence of carnitine or acylcarnitines during the incubation of the proteoliposomes with omeprazole increased the inhibition. Using site-directed Cys mutants it was demonstrated that C283 and C136 were essential for covalent inhibition. Molecular docking of omeprazole with CACT indicated the formation of both covalent interactions with C136 and C283 and non-covalent interactions in agreement with the experimental data. PMID- 24349248 TI - The prevention of diabetic cardiomyopathy by non-mitogenic acidic fibroblast growth factor is probably mediated by the suppression of oxidative stress and damage. AB - BACKGROUND: Emerging evidence showed the beneficial effect of acidic fibroblast growth factor (aFGF) on heart diseases. The present study investigated whether non-mitogenic aFGF (nm-aFGF) can prevent diabetic cardiomyopathy and the underlying mechanisms, if any. METHODOLOGY/PRINCIPAL FINDINGS: Type 1 diabetes was induced in mice by multiple intraperitoneal injections of low-dose streptozotocin. Hyperglycemic and age-matched control mice were treated with or without nm-aFGF at 10 ug/kg daily for 1 and 6 months. Blood pressure and cardiac function were assessed. Cardiac H9c2 cell, human microvascular endothelial cells, and rat cardiomyocytes were exposed to high glucose (25 mM) for mimicking an in vitro diabetic condition for mechanistic studies. Oxidative stress, DNA damage, cardiac hypertrophy and fibrosis were assessed by real-time qPCR, immunofluorescent staining, Western blotting, and pathological examination. Nm aFGF significantly prevented diabetes-induced hypertension and cardiac dysfunction at 6 months. Mechanistic studies demonstrated that nm-aFGF showed the similar preventive effect as the native aFGF on high glucose-induced oxidative stress (increase generation of reactive oxygen species) and damage (cellular DNA oxidation), cell hypertrophy, and fibrotic response (increased mRNA expression of fibronectin) in three kinds of cells. These in vitro findings were recaptured by examining the heart of the diabetic mice with and without nm-aFGF. CONCLUSIONS: These results suggest that nm-aFGF can prevent diabetic cardiomyopathy, probably through attenuation of cardiac oxidative stress, hypertrophy, and fibrosis. PMID- 24349249 TI - Incidence, predictive factors, and clinical outcomes of acute kidney injury after gastric surgery for gastric cancer. AB - BACKGROUND: Postoperative acute kidney injury (AKI), a serious surgical complication, is common after cardiac surgery; however, reports on AKI after noncardiac surgery are limited. We sought to determine the incidence and predictive factors of AKI after gastric surgery for gastric cancer and its effects on the clinical outcomes. METHODS: We conducted a retrospective study of 4718 patients with normal renal function who underwent partial or total gastrectomy for gastric cancer between June 2002 and December 2011. Postoperative AKI was defined by serum creatinine change, as per the Kidney Disease Improving Global Outcomes guideline. RESULTS: Of the 4718 patients, 679 (14.4%) developed AKI. Length of hospital stay, intensive care unit admission rates, and in hospital mortality rate (3.5% versus 0.2%) were significantly higher in patients with AKI than in those without. AKI was also associated with requirement of renal replacement therapy. Multivariate analysis revealed that male gender; hypertension; chronic obstructive pulmonary disease; hypoalbuminemia (<4 g/dl); use of diuretics, vasopressors, and contrast agents; and packed red blood cell transfusion were independent predictors for AKI after gastric surgery. Postoperative AKI and vasopressor use entailed a high risk of 3-month mortality after multiple adjustments. CONCLUSIONS: AKI was common after gastric surgery for gastric cancer and associated with adverse outcomes. We identified several factors associated with postoperative AKI; recognition of these predictive factors may help reduce the incidence of AKI after gastric surgery. Furthermore, postoperative AKI in patients with gastric cancer is an important risk factor for short-term mortality. PMID- 24349250 TI - A change in configuration of the calmodulin-KCNQ channel complex underlies Ca2+ dependent modulation of KCNQ channel activity. AB - All subtypes of KCNQ channel subunits (KCNQ1-5) require calmodulin as a co-factor for functional channels. It has been demonstrated that calmodulin plays a critical role in KCNQ channel trafficking as well as calcium-mediated current modulation. However, how calcium-bound calmodulin suppresses the M-current is not well understood. In this study, we investigated the molecular mechanism of KCNQ2 current suppression mediated by calcium-bound calmodulin. We show that calcium induced slow calmodulin dissociation from the KCNQ2 channel subunit. In contrast, in homomeric KCNQ3 channels, calcium facilitated calmodulin binding. We demonstrate that this difference in calmodulin binding was due to the unique cysteine residue in the KCNQ2 subunit at aa 527 in Helix B, which corresponds to an arginine residue in other KCNQ subunits including KCNQ3. In addition, a KCNQ2 channel associated protein AKAP79/150 (79 for human, 150 for rodent orthologs) also preferentially bound calcium-bound calmodulin. Therefore, the KCNQ2 channel complex was able to retain calcium-bound calmodulin either through the AKPA79/150 or KCNQ3 subunit. Functionally, increasing intracellular calcium by ionomycin suppressed currents generated by KCNQ2, KCNQ2(C527R) or heteromeric KCNQ2/KCNQ3 channels to an equivalent extent. This suggests that a change in the binding configuration, rather than dissociation of calmodulin, is responsible for KCNQ current suppression. Furthermore, we demonstrate that KCNQ current suppression was accompanied by reduced KCNQ affinity toward phosphatidylinositol 4,5 bisphosphate (PIP2) when assessed by a voltage-sensitive phosphatase, Ci-VSP. These results suggest that a rise in intracellular calcium induces a change in the configuration of CaM-KCNQ binding, which leads to the reduction of KCNQ affinity for PIP2 and subsequent current suppression. PMID- 24349251 TI - Effects of sustained sleep restriction on mitogen-stimulated cytokines, chemokines and T helper 1/ T helper 2 balance in humans. AB - BACKGROUND: Recent studies suggest that acute sleep deprivation disrupts cellular immune responses by shifting T helper (Th) cell activity towards a Th2 cytokine profile. Since little is known about more long-term effects, we investigated how five days of sleep restriction would affect pro-inflammatory, chemotactic, Th1- and Th2 cytokine secretion. METHODS: Nine healthy males participated in an experimental sleep protocol with two baseline sleep-wake cycles (sleep 23.00 07.00 h) followed by 5 days with restricted sleep (03.00-07.00 h). On the second baseline day and on the fifth day with restricted sleep, samples were drawn every third hour for determination of cytokines/chemokines (tumor necrosis factor alpha (TNF-alpha), interleukin (IL) -1beta, IL-2, IL-4 and monocyte chemoattractant protein-1 (MCP-1)) after in vitro stimulation of whole blood samples with the mitogen phytohemagglutinin (PHA). Also leukocyte numbers, mononuclear cells and cortisol were analysed. RESULTS: 5-days of sleep restriction affected PHA-induced immune responses in several ways. There was a general decrease of IL-2 production (p<.05). A shift in Th1/Th2 cytokine balance was also evident, as determined by a decrease in IL2/IL4 ratio. No other main effects of restricted sleep were shown. Two significant interactions showed that restricted sleep resulted in increased TNF-alpha and MCP-1 in the late evening and early night hours (p's<.05). In addition, all variables varied across the 24 h day. CONCLUSIONS: 5-days of sleep restriction is characterized by a shift towards Th2 activity (i.e. lower 1L-2/IL 4 ratio) which is similar to the effects of acute sleep deprivation and psychological stress. This may have implications for people suffering from conditions characterized by excessive Th2 activity like in allergic disease, such as asthma, for whom restricted sleep could have negative consequences. PMID- 24349253 TI - Computer-based image studies on tumor nests mathematical features of breast cancer and their clinical prognostic value. AB - BACKGROUND: The expending and invasive features of tumor nests could reflect the malignant biological behaviors of breast invasive ductal carcinoma. Useful information on cancer invasiveness hidden within tumor nests could be extracted and analyzed by computer image processing and big data analysis. METHODS: Tissue microarrays from invasive ductal carcinoma (n = 202) were first stained with cytokeratin by immunohistochemical method to clearly demarcate the tumor nests. Then an expert-aided computer analysis system was developed to study the mathematical and geometrical features of the tumor nests. Computer recognition system and imaging analysis software extracted tumor nests information, and mathematical features of tumor nests were calculated. The relationship between tumor nests mathematical parameters and patients' 5-year disease free survival was studied. RESULTS: There were 8 mathematical parameters extracted by expert aided computer analysis system. Three mathematical parameters (number, circularity and total perimeter) with area under curve >0.5 and 4 mathematical parameters (average area, average perimeter, total area/total perimeter, average (area/perimeter)) with area under curve <0.5 in ROC analysis were combined into integrated parameter 1 and integrated parameter 2, respectively. Multivariate analysis showed that integrated parameter 1 (P = 0.040) was independent prognostic factor of patients' 5-year disease free survival. The hazard risk ratio of integrated parameter 1 was 1.454 (HR 95% CI [1.017-2.078]), higher than that of N stage (HR 1.396, 95% CI [1.125-1.733]) and hormone receptor status (HR 0.575, 95% CI [0.353-0.936]), but lower than that of histological grading (HR 3.370, 95% CI [1.125-5.364]) and T stage (HR 1.610, 95% CI [1.026 -2.527]). CONCLUSIONS: This study indicated integrated parameter 1 of mathematical features (number, circularity and total perimeter) of tumor nests could be a useful parameter to predict the prognosis of early stage breast invasive ductal carcinoma. PMID- 24349252 TI - Molecular epidemiologic characterization of a clustering HCV infection caused by inappropriate medical care in Heyuan City of Guangdong, China. AB - BACKGROUND: From November 2011 to January 2012, a number of clustering cases of HCV infection were reported in Zijin County, Heyuan City, Guangdong, China. Most patients in the clustering cases suspected that they could be infected due to inappropriate medical care in the clinic located at the Xiangshui road. However, the molecular epidemiology of the clustering cases remains unknown. METHODOLOGY: The residents, living at Xiangshui Road, with HCV antibody positive reported from 2011 and 2012 were recruited. A survey of the HCV infected individuals from the clustering cases was conducted. Each participant underwent a questionnaire defining demographic characteristics and health care history. HCV serological test and viral load test were performed to confirm the infection status. Molecular phylogenetic analysis and Bayesian coalescence analysis were conducted to further confirm the HCV subtype distribution and to reconstruct the associated demographic history and time-scaled phylogeny among the clustering cases. PRINCIPAL FINDINGS: The molecular phylogenetic analysis revealed that only two HCV subtypes, 2a and 6a, were found among the clustering cases. There was no close HCV subtype evolutionary relation was observed among patients from the same family. The 6a cluster showed higher viral loads than the 2a cluster. In addition, the Bayesian skyline plot analysis showed that both the HCV 2a and 6a subtype infections among the Heyuan cases experienced an "expansion-diminishment expansion" featured dissemination. The 2a clustering infection occurred in 2004, and the 6a clustering cases originated in 2006. CONCLUSIONS: The molecular epidemiological characters imply that the inappropriate medical practices were possibly associated with the clustering HCV cases in Heyuan City during 2011, 2012. Latent HCV subtypes 2a and 6a infection may cause the prevalence and become a new public health issue in Guangdong, China. PMID- 24349254 TI - Discovery of potent broad spectrum antivirals derived from marine actinobacteria. AB - Natural products provide a vast array of chemical structures to explore in the discovery of new medicines. Although secondary metabolites produced by microbes have been developed to treat a variety of diseases, including bacterial and fungal infections, to date there has been limited investigation of natural products with antiviral activity. In this report, we used a phenotypic cell-based replicon assay coupled with an iterative biochemical fractionation process to identify, purify, and characterize antiviral compounds produced by marine microbes. We isolated a compound from Streptomyces kaviengensis, a novel actinomycetes isolated from marine sediments obtained off the coast of New Ireland, Papua New Guinea, which we identified as antimycin A1a. This compound displays potent activity against western equine encephalitis virus in cultured cells with half-maximal inhibitory concentrations of less than 4 nM and a selectivity index of greater than 550. Our efforts also revealed that several antimycin A analogues display antiviral activity, and mechanism of action studies confirmed that these Streptomyces-derived secondary metabolites function by inhibiting the cellular mitochondrial electron transport chain, thereby suppressing de novo pyrimidine synthesis. Furthermore, we found that antimycin A functions as a broad spectrum agent with activity against a wide range of RNA viruses in cultured cells, including members of the Togaviridae, Flaviviridae, Bunyaviridae, Picornaviridae, and Paramyxoviridae families. Finally, we demonstrate that antimycin A reduces central nervous system viral titers, improves clinical disease severity, and enhances survival in mice given a lethal challenge with western equine encephalitis virus. Our results provide conclusive validation for using natural product resources derived from marine microbes as source material for antiviral drug discovery, and they indicate that host mitochondrial electron transport is a viable target for the continued development of broadly active antiviral compounds. PMID- 24349255 TI - Endoplasmic reticulum stress contributes to Helicobacter pylori VacA-induced apoptosis. AB - Vacuolating cytotoxin A (VacA) is one of the important virulence factors produced by H. pylori. VacA induces apoptotic cell death, which is potentiated by ammonia. VacA also causes cell death by mitochondrial damage, via signaling pathways that are not fully defined. Our aim was to determine whether endoplasmic reticulum (ER) stress is associated with VacA-induced mitochondrial dysfunction and apoptosis. We found that C/EBP homologous protein (CHOP), a key signaling protein of ER stress-induced apoptosis, was transcriptionally up-regulated following incubation of gastric epithelial cells with VacA. The effect of VacA on CHOP induction was significantly enhanced by co-incubation with ammonium chloride. Phosphorylation of eukaryotic initiation factor 2 (eIF2)-alpha, which is known to occur downstream of the ER stress sensor PKR-like ER-localized eIF2-alpha kinase (PERK) and to regulate CHOP expression, was also observed following incubation with VacA in the presence of ammonium chloride. Knockdown of CHOP by siRNA resulted in inhibition of VacA-induced apoptosis. Further studies showed that silencing of the PERK gene with siRNA attenuated VacA-mediated phosphorylation of eIF2-alpha, CHOP induction, expression of BH3-only protein Bim and Bax activation, and cell death induced by VacA with ammonium chloride, indicating that ER stress may lead to mitochondrial dysfunction during VacA-induced toxicity. Activation of ER stress and up-regulation of BH3-only proteins were also observed in human H. pylori-infected gastric mucosa. Collectively, this study reveals a possible association between VacA-induced apoptosis in gastric epithelial cells, and activation of ER stress in H. pylori-positive gastric mucosa. PMID- 24349256 TI - Cerebral autoregulation is minimally influenced by the superior cervical ganglion in two- week-old lambs, and absent in preterm lambs immediately following delivery. AB - Cerebral vessels in the premature newborn brain are well supplied with adrenergic nerves, stemming from the superior cervical ganglia (SCG), but their role in regulation of blood flow remains uncertain. To test this function twelve premature or two-week-old lambs were instrumented with laser Doppler flow probes in the parietal cortices to measure changes in blood flow during changes in systemic blood pressure and electrical stimulation of the SCG. In lambs delivered prematurely at ~129 days gestation cerebral perfusion and driving pressure demonstrated a direct linear relationship throughout the physiologic range, indicating lack of autoregulation. In contrast, in lambs two-weeks of age, surgical removal of one SCG resulted in ipsilateral loss of autoregulation during pronounced hypertension. Electrical stimulation of one SCG elicited unilateral increases in cerebral resistance to blood flow in both pre-term and two-week-old lambs, indicating functioning neural pathways in the instrumented, anesthetized lambs. We conclude cerebral autoregulation is non-functional in preterm lambs following cesarean delivery. Adrenergic control of cerebral vascular resistance becomes effective in newborn lambs within two-weeks after birth but SCG-dependent autoregulation is essential only during pronounced hypertension, well above the normal range of blood pressure. PMID- 24349257 TI - Game-based e-learning is more effective than a conventional instructional method: a randomized controlled trial with third-year medical students. AB - BACKGROUND: When compared with more traditional instructional methods, Game-based e-learning (GbEl) promises a higher motivation of learners by presenting contents in an interactive, rule-based and competitive way. Most recent systematic reviews and meta-analysis of studies on Game-based learning and GbEl in the medical professions have shown limited effects of these instructional methods. OBJECTIVES: To compare the effectiveness on the learning outcome of a Game-based e-learning (GbEl) instruction with a conventional script-based instruction in the teaching of phase contrast microscopy urinalysis under routine training conditions of undergraduate medical students. METHODS: A randomized controlled trial was conducted with 145 medical students in their third year of training in the Department of Urology at the University Medical Center Freiburg, Germany. 82 subjects where allocated for training with an educational adventure-game (GbEl group) and 69 subjects for conventional training with a written script-based approach (script group). Learning outcome was measured with a 34 item single choice test. Students' attitudes were collected by a questionnaire regarding fun with the training, motivation to continue the training and self-assessment of acquired knowledge. RESULTS: The students in the GbEl group achieved significantly better results in the cognitive knowledge test than the students in the script group: the mean score was 28.6 for the GbEl group and 26.0 for the script group of a total of 34.0 points with a Cohen's d effect size of 0.71 (ITT analysis). Attitudes towards the recent learning experience were significantly more positive with GbEl. Students reported to have more fun while learning with the game when compared to the script-based approach. CONCLUSIONS: Game-based e learning is more effective than a script-based approach for the training of urinalysis in regard to cognitive learning outcome and has a high positive motivational impact on learning. Game-based e-learning can be used as an effective teaching method for self-instruction. PMID- 24349258 TI - Analysis of time-resolved gene expression measurements across individuals. AB - Genetic and environmental determinants of altered cellular function, disease state, and drug response are increasingly studied using time-resolved transcriptomic profiles. While it is widely acknowledged that the rate of biological processes may vary between individuals, data analysis approaches that go beyond evaluating differential expression of single genes have so far not taken this variability into account. To this end, we introduce here a robust multi-gene data analysis approach and evaluate it in a biomarker discovery scenario across four publicly available datasets. In our evaluation, existing methods perform surprisingly poorly on time-resolved data; only the approach taking the variability into account yields reproducible and biologically plausible results. Our results indicate the need to capture gene expression between potentially heterogeneous individuals at multiple time points, and highlight the importance of robust data analysis in the presence of heterogeneous gene expression responses. PMID- 24349259 TI - Investment into defensive traits by anuran prey (Lithobates pipiens) is mediated by the starvation-predation risk trade-off. AB - Prey can invest in a variety of defensive traits when balancing risk of predation against that of starvation. What remains unknown is the relative costs of different defensive traits and how prey reconcile investment into these traits when energetically limited. We tested the simple allocation model of prey defense, which predicts an additive effect of increasing predation risk and resource availability, resulting in the full deployment of defensive traits under conditions of high risk and resource saturation. We collected morphometric, developmental, and behavioural data in an experiment using dragonfly larvae (predator) and Northern leopard frog tadpoles (prey) subject to variable levels of food availability and predation risk. Larvae exposed to food restriction showed limited response to predation risk; larvae at food saturation altered behaviour, development, and growth in response to predation risk. Responses to risk varied through time, suggesting ontogeny may affect the deployment of particular defensive traits. The observed negative correlation between body size and activity level for food-restricted prey--and the absence of a similar response among adequately-fed prey--suggests that a trade-off exists between behavioural and growth responses when energy budgets are limited. Our research is the first to demonstrate how investment into these defensive traits is mediated along gradients of both predation risk and resource availability over time. The interactions we demonstrate between resource availability and risk level on deployment of inducible defenses provide evidence that both internal condition and extrinsic risk factors play a critical role in the production of inducible defenses over time. PMID- 24349260 TI - Opposing roles of PKA and EPAC in the cAMP-dependent regulation of schwann cell proliferation and differentiation [corrected]. AB - In Schwann cells (SCs), cyclic adenosine monophosphate (cAMP) not only induces differentiation into a myelinating SC-related phenotype, but also synergistically enhances the mitogenic action of growth factors such as neuregulin. To better understand the molecular mechanism by which cAMP exerts these apparently contradictory functions, we investigated the role of the two main effectors of cAMP, protein kinase A (PKA) and the exchange protein activated by cAMP (EPAC), on the proliferation and differentiation of both isolated and axon-related SCs. For these studies, a variety of PKA and EPAC agonists and antagonists were used, including pathway-selective analogs of cAMP and pharmacological inhibitors. Our studies indicated that the activity of PKA rather than EPAC was required for the adjuvant effect of cAMP on S-phase entry, whereas the activity of EPAC rather than PKA was required for SC differentiation and myelin formation. Even though selective EPAC activation had an overall anti-proliferative effect in SCs, it failed to drive the expression of Krox-20, a master regulator of myelination, and that of myelin-specific proteins and lipids, suggesting that EPAC activation was insufficient to drive a full differentiating response. Interestingly, inhibition of EPAC activity resulted in a drastic impairment of SC differentiation and myelin formation but not Krox-20 expression, which indicates an independent mechanism of Krox-20 regulation in response to cAMP. In conclusion, our data supports the idea that the outcome of cAMP signaling in SCs depends on the particular set of effectors activated. Whereas the mitogenic action of cAMP relies exclusively on PKA activity, the differentiating action of cAMP requires a PKA-independent (non-canonical) cAMP-specific pathway that is partially transduced by EPAC. PMID- 24349261 TI - A glycoprotein in shells of conspecifics induces larval settlement of the Pacific oyster Crassostrea gigas. AB - Settlement of larvae of Crassostrea gigas on shell chips (SC) prepared from shells of 11 different species of mollusks was investigated. Furthermore, the settlement inducing compound in the shell of C. gigas was extracted and subjected to various treatments to characterize the chemical cue. C. gigas larvae settled on SC of all species tested except on Patinopecten yessoensis and Atrina pinnata. In SC of species that induced C. gigas larvae to settle, settlement was proportionate to the amount of SC supplied to the larvae. When compared to C. gigas SC, all species except Crassostrea nippona showed lower settlement inducing activities, suggesting that the cue may be more abundant or in a more available form to the larvae in shells of conspecific and C. nippona than in other species. The settlement inducing activity of C. gigas SC remained intact after antibiotic treatment. Extraction of C. gigas SC with diethyl ether (Et2O-ex), ethanol (EtOH ex), and water (Aq-ex) did not induce larval settlement of C. gigas larvae. However, extraction of C. gigas SC with 2N of hydrochloric acid (HCl-ex) induced larval settlement that was at the same level as the SC. The settlement inducing compound in the HCl-ex was stable at 100 degrees C but was destroyed or degraded after pepsin, trypsin, PNGase F and trifluoromethanesulfonic acid treatments. This chemical cue eluted between the molecular mass range of 45 and 150 kDa after gel filtration and revealed a major band at 55 kDa on the SDS-PAGE gel after staining with Stains-all. Thus, a 55 kDa glycoprotein component in the organic matrix of C. gigas shells is hypothesized to be the chemical basis of larval settlement on conspecifics. PMID- 24349262 TI - Frequency of inappropriate medication prescription in hospitalized elderly patients in Italy. AB - BACKGROUND: Older people often need comprehensive treatment, including many medications, and polypharmacy is common. The aims of this cross-sectional investigation were to examine the potentially inappropriate medication during the hospitalization and to identify the factors that may influence such inappropriateness among elderly in Italy. METHODS: A sample of 605 individuals aged 65 years and older admitted in non-academic public acute care hospitals was randomly selected. Prescription of inappropriate medications were evaluated during the period from the day of admission to a randomly preselected day (index day). Beers Criteria were used to evaluate appropriateness. RESULTS: At least one potentially inappropriate medication prescription from the day of hospital admission to the index day has been observed in 188 patients (31.1%), and respectively 84.1% and 15.9% of them had received one or two inappropriate medications. A total of 15 medications was prescribed inappropriately to these 188 patients, for 215 times with a total of 1143 doses. The multivariate logistic regression analysis revealed that the significant predictors for having at least one potentially inappropriate medication prescription during the hospitalization were: patients having an elementary education level, a lower pre-admission performance-based measure of basic activities of daily living, having received an inappropriate drug before the hospitalization, a hospital stay in the general and in the specialties surgical wards, a longer length of hospital stay from the admission to the index day, and having received a higher number of drugs from the day of the hospital admission to the index day. The most prevalent inappropriate medications administered were ketorolac (27.4%), amiodarone (19.1%), and clonidine (11.2%). CONCLUSIONS: This study supports the need for clinical guidelines implementation to assist physicians in choosing the most appropriate drugs for the elderly and for effective education of all physicians. PMID- 24349263 TI - Phenotypic and genotypic characteristic of invasive pneumococcal isolates from both children and adult patients from a multicenter surveillance in China 2005 2011. AB - Streptococcus pneumoniae is an important pathogen in both children and the elderly, but previous studies in China have provided limited information about invasive pneumococcal disease (IPD). A total of 240 IPD S. pneumoniae strains (from 105 children and 135 adults) were collected from 12 cities in China in 2005 2011. Their phenotypes and genetic characteristics were analyzed. Streptococcus pneumoniae remained highly resistant to macrolides, tetracycline, and cotrimoxazole each year. Serotypes were assigned to the 240 isolates, and 19A (22.1%), 19F (21.7%), 14 (7.5%), 3 (7.1%), and 23F (5.4%) were the most prevalent, accounting for 63.8% of all strains. Serogroup 19 strains were significantly more common among children than among adults (58.7% vs 32.4%, respectively; P < 0.001). Serotypes 19F and 19A demonstrated higher resistance to beta-lactams and cephalosporins than the other serotypes. The coverage of PCV13 was superior to that calculated for PCV7 and PCV10 (77.9% vs 40.8% and 47.1%, respectively), and coverage was higher in children than in adults (85.6% vs 72.1%, respectively; P = 0.012). A multilocus sequence typing analysis revealed great diversity, with nine clonal complexes and 83 singletons among all the strains. Specifically, CC271 was more common in children, whereas singletons were more prevalent in adults. Among the serogroup 19 strains, 84.7% were ST271, ST320, or ST236, belonging to CC271. The homogeneous genetic background of 19F and 19A, together with the high resistance of these strains, suggests that clonal spread is responsible for the high prevalence of serogroup 19 in IPD. This is the first large study to investigate IPD strains in both children and adults in China. PMID- 24349264 TI - Comparison of ultra-conserved elements in drosophilids and vertebrates. AB - Metazoan genomes contain many ultra-conserved elements (UCEs), long sequences identical between distant species. In this study we identified UCEs in drosophilid and vertebrate species with a similar level of phylogenetic divergence measured at protein-coding regions, and demonstrated that both the length and number of UCEs are larger in vertebrates. The proportion of non-exonic UCEs declines in distant drosophilids whilst an opposite trend was observed in vertebrates. We generated a set of 2,126 Sophophora UCEs by merging elements identified in several drosophila species and compared these to the eutherian UCEs identified in placental mammals. In contrast to vertebrates, the Sophophora UCEs are depleted around transcription start sites. Analysis of 52,954 P-element, piggyBac and Minos insertions in the D. melanogaster genome revealed depletion of the P-element and piggyBac insertions in and around the Sophophora UCEs. We examined eleven fly strains with transposon insertions into the intergenic UCEs and identified associated phenotypes in five strains. Four insertions behave as recessive lethals, and in one case we observed a suppression of the marker gene within the transgene, presumably by silenced chromatin around the integration site. To confirm the lethality is caused by integration of transposons we performed a phenotype rescue experiment for two stocks and demonstrated that the excision of the transposons from the intergenic UCEs restores viability. Sequencing of DNA after the transposon excision in one fly strain with the restored viability revealed a 47 bp insertion at the original transposon integration site suggesting that the nature of the mutation is important for the appearance of the phenotype. Our results suggest that the UCEs in flies and vertebrates have both common and distinct features, and demonstrate that a significant proportion of intergenic drosophila UCEs are sensitive to disruption. PMID- 24349265 TI - Resistance to bleomycin in cancer cell lines is characterized by prolonged doubling time, reduced DNA damage and evasion of G2/M arrest and apoptosis. AB - BACKGROUND: To establish, characterize and elucidate potential mechanisms of acquired bleomycin (BLM) resistance using human cancer cell lines. Seven BLM resistant cell lines were established by exposure to escalating BLM concentrations over a period of 16-24 months. IC50 values and cell doubling times were quantified using a real time cytotoxicity assay. COMET and gamma-H2AX assays, cell cycle analysis, and apoptosis assessment further investigated the mechanisms of BLM resistance in these cell lines. RESULTS: Compared with parental cell lines, real time cytotoxicity assays revealed 7 to 49 fold increases in IC50 and a mean doubling time increase of 147 % (range 64 %-352%) in BLM-resistant sub clones (p<0.05 for both). Higher maintenance BLM concentrations were associated with higher IC50 and increased doubling times (p<0.05). Significantly reduced DNA damage (COMET and gamma-H2AX assays), G2/M arrest, and apoptosis (p<0.05 for each set of comparison) following high-dose acute BLM exposure was observed in resistant sub-clones, compared with their BLM-sensitive parental counterparts. Three weeks of BLM-free culturing resulted in a partial return to BLM sensitivity in 3/7 BLM-resistant sub-clones (p<0.05). CONCLUSION: Bleomycin resistance may be associated with reduced DNA damage after bleomycin exposure, resulting in reduced G2/M arrest, and reduced apoptosis. PMID- 24349266 TI - Changes in mitochondrial carriers exhibit stress-specific signatures in INS 1Ebeta-cells exposed to glucose versus fatty acids. AB - Chronic exposure of beta-cells to metabolic stresses impairs their function and potentially induces apoptosis. Mitochondria play a central role in coupling glucose metabolism to insulin secretion. However, little is known on mitochondrial responses to specific stresses; i.e. low versus high glucose, saturated versus unsaturated fatty acids, or oxidative stress. INS-1E cells were exposed for 3 days to 5.6 mM glucose, 25 mM glucose, 0.4 mM palmitate, and 0.4 mM oleate. Culture at standard 11.1 mM glucose served as no-stress control and transient oxidative stress (200 uM H2O2 for 10 min at day 0) served as positive stressful condition. Mito-array analyzed transcripts of 60 mitochondrion associated genes with special focus on members of the Slc25 family. Transcripts of interest were evaluated at the protein level by immunoblotting. Bioinformatics analyzed the expression profiles to delineate comprehensive networks. Chronic exposure to the different metabolic stresses impaired glucose-stimulated insulin secretion; revealing glucotoxicity and lipo-dysfunction. Both saturated and unsaturated fatty acids increased expression of the carnitine/acylcarnitine carrier CAC, whereas the citrate carrier CIC and energy sensor SIRT1 were specifically upregulated by palmitate and oleate, respectively. High glucose upregulated CIC, the dicarboxylate carrier DIC and glutamate carrier GC1. Conversely, it reduced expression of energy sensors (AMPK, SIRT1, SIRT4), metabolic genes, transcription factor PDX1, and anti-apoptotic Bcl2. This was associated with caspase-3 cleavage and cell death. Expression levels of GC1 and SIRT4 exhibited positive and negative glucose dose-response, respectively. Expression profiles of energy sensors and mitochondrial carriers were selectively modified by the different conditions, exhibiting stress-specific signatures. PMID- 24349267 TI - Recording of severe mental illness in United Kingdom primary care, 2000-2010. AB - BACKGROUND: There is increasing emphasis on primary care services for individuals with severe mental illnesses (SMI), including schizophrenia, bipolar disorder, and other non-organic psychotic disorders. However we lack information on how many people receive these different diagnoses in primary care. Primary care databases offer an opportunity to explore the recording of new SMI diagnoses in representative general practices. METHODS: We used data from The UK Health Improvement Network (THIN) primary care database including longitudinal patient records for individuals aged over 16 years from 437 general practices. We determined the annual GP recorded rate of first diagnosis of SMI by age, gender, social deprivation and urbanicity between 2000 and 2010. RESULTS: We identified 10,520 individuals with a first record of schizophrenia, bipolar disorder or other non-organic psychosis among 4,164,794 patients. This corresponded to a rate of first diagnosis of 46.4 per 100,000 person years at risk (PYAR) (95% CI 45.4 to 47.4) in the 16-65 age group. The rate of first record of schizophrenia was 9.2 per 100,000 PYAR (95% CI 8.7 to 9.6) in this age group, bipolar disorder was 15.0 per 100,000 PYAR (95% CI 14.4 to 15.5) and other non-organic psychotic disorder was 22.3 per 100,000 PYAR (95% CI 21.6 to 23.0). CONCLUSIONS: The rates of GP recorded SMI in primary care records were broadly comparable to incidence rates from previous epidemiological studies of SMI and show similar patterns by socio-demographic characteristics. However there were some differences by specific diagnoses. GPs may be recording rates that are higher than those used to commission services. PMID- 24349269 TI - Recreational boats and turtles: behavioral mismatches result in high rates of injury. AB - Recreational boats are a dominant feature of estuarine waters in the United States. Boat strike injury and mortality may have a detrimental effect on populations of diamondback terrapins (Malaclemys terrapin), a keystone species in estuarine ecosystems. In Barnegat Bay, New Jersey, 11% of terrapins (n = 2,644) have scars consistent with injuries from boats. Conservative estimates of injury rates from boats increased from 2006 to 2011. When exposed to playback recordings of approaching boat engines of varying sizes and speeds in situ, terrapins did not significantly change their behavior in response to sounds of boat engines of different sizes. The lack of behavioral response of terrapins to boat sounds helps explain high rates of injury and mortality of terrapins and may threaten the viability of terrapin populations. Boater education courses that discuss impacts of boats to wildlife, combined with closure of areas of high terrapin densities to boating, are necessary to protect terrapins and other aquatic species from injury and mortality caused by motorized boats. PMID- 24349268 TI - Antibody to mCLCA3 suppresses symptoms in a mouse model of asthma. AB - BACKGROUND: Asthma is a complex and heterogeneous chronic inflammatory disorder that is associated with mucous cell metaplasia and mucus hypersecretion. Functional genomic analysis indicates that mucous cell metaplasia and mucus hypersecretion depend on members of the calcium-activated chloride channel (CLCA) gene family. It has been reported that the inhibition of CLCAs could relieve the symptoms of asthma. Thus, the mCLCA3 antibody may be a promising strategy to treat allergic diseases such as asthma. METHODS: We constructed asthmatic mouse models of OVA-induced chronic airway inflammatory disorder to study the function of the mCLCA3 antibody. Airway inflammation was measured by HE staining; goblet cell hyperplasia and mucus hypersecretion were detected by PAS staining; muc5ac, IL-13, IFN-gamma levels in bronchoalveolar lavage fluid (BALF) were examined by ELISA; Goblet cell apoptosis was measured by TUNEL assay and alcian blue staining; mCLCA3, Bcl-2 and Bax expression were detected by RT-PCR, Western blotting and immunohistochemical analysis. RESULTS: In our study, mice treated with mCLCA3 antibody developed fewer pathological changes compared with control mice and asthmatic mice, including a remarkable reduction in airway inflammation, the number of goblet cells and mCLCA3 expression in lung tissue. The levels of muc5ac and IL-13 were significantly reduced in BALF. We also found that the rate of goblet cell apoptosis was increased after treatment with mCLCA3 antibody, which was accompanied by an increase in Bax levels and a decrease in Bcl-2 expression in goblet cells. CONCLUSIONS: Taken together, our results indicate that mCLCA3 antibody may have the potential as an effective pharmacotherapy for asthma. PMID- 24349270 TI - Immunomagnetic separation combined with polymerase chain reaction for the detection of Alicyclobacillus acidoterrestris in apple juice. AB - A combination of immunomagnetic separation (IMS) and polymerase chain reaction (PCR) was used to detect Alicyclobacillus acidoterrestris (A. acidoterrestris) in apple juice. The optimum technological parameters of the IMS system were investigated. The results indicated that the immunocapture reactions could be finished in 60 min and the quantity of IMPs used for IMS was 2.5 mg/mL. Then the combined IMS-PCR procedure was assessed by detecting A. acidoterrestris in apple juice samples. The agarose gel electrophoresis results of 20 different strains showed that the IMS-PCR procedure presented high specificity to the A. acidoterrestris. The sensitivity of the IMS-PCR was 2*10(1) CFU/mL and the total detection time was 3 to 4 h. Of the 78 naturally contaminated apple juice samples examined, the sensitivity, specificity and accuracy of IMS-PCR compared with the standardized pour plate method were 90.9%, 97.0% and 96.2%, respectively. The results exhibited that the developed IMS-PCR method will be a valuable tool for detecting A. acidoterrestris and improving food quality in juice samples. PMID- 24349271 TI - Prediction of severe disease in children with diarrhea in a resource-limited setting. AB - OBJECTIVE: To investigate the accuracy of three clinical scales for predicting severe disease (severe dehydration or death) in children with diarrhea in a resource-limited setting. METHODS: Participants included 178 children admitted to three Rwandan hospitals with diarrhea. A local physician or nurse assessed each child on arrival using the World Health Organization (WHO) severe dehydration scale and the Centers for Disease Control (CDC) scale. Children were weighed on arrival and daily until they achieved a stable weight, with a 10% increase between admission weight and stable weight considered severe dehydration. The Clinical Dehydration Scale was then constructed post-hoc using the data collected for the other two scales. Receiver Operator Characteristic (ROC) curves were constructed for each scale compared to the composite outcome of severe dehydration or death. RESULTS: The WHO severe dehydration scale, CDC scale, and Clinical Dehydration Scale had areas under the ROC curves (AUCs) of 0.72 (95% CI 0.60, 0.85), 0.73 (95% CI 0.62, 0.84), and 0.80 (95% CI 0.71, 0.89), respectively, in the full cohort. Only the Clinical Dehydration Scale was a significant predictor of severe disease when used in infants, with an AUC of 0.77 (95% CI 0.61, 0.93), and when used by nurses, with an AUC of 0.78 (95% CI 0.63, 0.93). CONCLUSIONS: While all three scales were moderate predictors of severe disease in children with diarrhea, scale accuracy varied based on provider training and age of the child. Future research should focus on developing or validating clinical tools that can be used accurately by nurses and other less skilled providers to assess all children with diarrhea in resource-limited settings. PMID- 24349272 TI - Efficient isolation of pure and functional mitochondria from mouse tissues using automated tissue disruption and enrichment with anti-TOM22 magnetic beads. AB - To better understand molecular mechanisms regulating changes in metabolism, as observed e.g. in diabetes or neuronal disorders, the function of mitochondria needs to be precisely determined. The usual isolation methods such as differential centrifugation result in isolates of highly variable quality and quantity. To fulfill the need of a reproducible isolation method from solid tissues, which is suitable to handle parallel samples simultaneously, we developed a protocol based on anti-TOM22 (translocase of outer mitochondrial membrane 22 homolog) antibody-coupled magnetic beads. To measure oxygen consumption rate in isolated mitochondria from various mouse tissues, a traditional Clark electrode and the high-throughput XF Extracellular Flux Analyzer were used. Furthermore, Western blots, transmission electron microscopic and proteomic studies were performed to analyze the purity and integrity of the mitochondrial preparations. Mitochondrial fractions isolated from liver, brain and skeletal muscle by anti-TOM22 magnetic beads showed oxygen consumption capacities comparable to previously reported values and little contamination with other organelles. The purity and quality of isolated mitochondria using anti TOM22 magnetic beads was compared to traditional differential centrifugation protocol in liver and the results indicated an obvious advantage of the magnetic beads method compared to the traditional differential centrifugation technique. PMID- 24349273 TI - Application of U/Th and 40Ar/39Ar dating to Orgnac 3, a Late Acheulean and Early Middle Palaeolithic site in Ardeche, France. AB - Refined radio-isotopic dating techniques have been applied to Orgnac 3, a Late Acheulean and Early Middle Palaeolithic site in France. Evidence of Levallois core technology appeared in level 4b in the middle of the sequence, became predominant in the upper horizons, and was best represented in uppermost level 1, making the site one of the oldest examples of Levallois technology. In our dating study, fourteen speleothem samples from levels 7, 6 and 5b, were U/Th-dated. Four pure calcite samples from the speleothem PL1 (levels 5b, 6) yield ages between 265 +/- 4 (PL1-3) and 312 +/- 15 (PL1-6) thousand years ago (ka). Three samples from the top of a second stalagmite, PL2, yield dates ranging from 288 +/- 10 ka (PL2-1) to 298 +/- 17 ka (PL2-3). Three samples from the base of PL2 (level 7) yield much younger U/Th dates between 267 and 283 ka. These dates show that the speleothems PL1 and PL2 are contemporaneous and formed during marine isotope stage (MIS) 9 and MIS 8. Volcanic minerals in level 2, the upper sequence, were dated by the (40)Ar/(39)Ar method, giving a weighted mean of 302.9 +/- 2.5 ka (2sigma) and an inverse isochron age of 302.9 +/- 5.9 ka (2sigma). Both (40)Ar/(39)Ar dating of volcanic sanidines and U/Th dating of relatively pure and dense cave calcites are known to be well established. The first parallel application of the two geochronometers to Orgnac 3 yields generally consistent results, which point to the reliability of the two methods. The difference between their age results is discussed. PMID- 24349274 TI - Rbt1 protein domains analysis in Candida albicans brings insights into hyphal surface modifications and Rbt1 potential role during adhesion and biofilm formation. AB - Cell wall proteins are central to the virulence of Candida albicans. Hwp1, Hwp2 and Rbt1 form a family of hypha-associated cell surface proteins. Hwp1 and Hwp2 have been involved in adhesion and other virulence traits but Rbt1 is still poorly characterized. To assess the role of Rbt1 in the interaction of C. albicans with biotic and abiotic surfaces independently of its morphological state, heterologous expression and promoter swap strategies were applied. The N terminal domain with features typical of the Flo11 superfamily was found to be essential for adhesiveness to polystyrene through an increase in cell surface hydrophobicity. A 42 amino acid-long domain localized in the central part of the protein was shown to enhance the aggregation function. We demonstrated that a VTTGVVVVT motif within the 42 amino acid domain displayed a high beta-aggregation potential and was responsible for cell-to-cell interactions by promoting the aggregation of hyphae. Finally, we showed through constitutive expression that while Rbt1 was directly accessible to antibodies in hyphae, it was not so in yeast. Similar results were obtained for another cell wall protein, namely Iff8, and suggested that modification of the cell wall structure between yeast and hyphae can regulate the extracellular accessibility of cell wall proteins independently of gene regulation. PMID- 24349275 TI - Myelopoietic efficacy of orlistat in murine hosts bearing T cell lymphoma: implication in macrophage differentiation and activation. AB - Orlistat, an inhibitor of fatty acid synthase (FASN), acts as an antitumor agent by blocking de novo fatty acid synthesis of tumor cells. Although, myelopoiesis also depends on de novo fatty acid synthesis, the effect of orlistat on differentiation of macrophages, which play a central role in host's antitumor defence, remains unexplored in a tumor-bearing host. Therefore, the present investigation was undertaken to examine the effect of orlistat administration on macrophage differentiation in a T cell lymphoma bearing host. Administration of orlistat (240 mg/kg/day/mice) to tumor-bearing mice resulted in a decline of tumor load accompanied by an augmentation of bone marrow cellularity and survival of bone marrow cells (BMC). The expression of apoptosis regulatory caspase-3, Bax and Bcl2 was modulated in the BMC of orlistat-administered tumor-bearing mice. Orlistat administration also resulted in an increase in serum level of IFN-gamma along with decreased TGF-beta and IL-10. BMC of orlistat-administered tumor bearing mice showed augmented differentiation into macrophages accompanied by enhanced expression of macrophage colony stimulating factor (M-CSF) and its receptor (M-CSFR). The macrophages differentiated from BMC of orlistat administered mice showed characteristic features of M1 macrophage phenotype confirmed by expression of CD11c, TLR-2, generation of reactive oxygen species, phagocytosis, tumor cell cytotoxicity, production of IL-1,TNF-alpha and nitric oxide. These novel findings indicate that orlistat could be useful to support myelopoesis in a tumor-bearing host. PMID- 24349276 TI - Biochemical, transcriptional and translational evidences of the phenol-meta degradation pathway by the hyperthermophilic Sulfolobus solfataricus 98/2. AB - Phenol is a widespread pollutant and a model molecule to study the biodegradation of monoaromatic compounds. After a first oxidation step leading to catechol in mesophilic and thermophilic microorganisms, two main routes have been identified depending on the cleavage of the aromatic ring: ortho involving a catechol 1,2 dioxygenase (C12D) and meta involving a catechol 2,3 dioxygenase (C23D). Our work aimed at elucidating the phenol-degradation pathway in the hyperthermophilic archaea Sulfolobus solfataricus 98/2. For this purpose, the strain was cultivated in a fermentor under different substrate and oxygenation conditions. Indeed, reducing dissolved-oxygen concentration allowed slowing down phenol catabolism (specific growth and phenol-consumption rates dropped 55% and 39%, respectively) and thus, evidencing intermediate accumulations in the broth. HPLC/Diode Array Detector and LC-MS analyses on culture samples at low dissolved-oxygen concentration (DOC = 0.06 mg x L(-1)) suggested, apart for catechol, the presence of 2-hydroxymuconic acid, 4-oxalocrotonate and 4-hydroxy-2-oxovalerate, three intermediates of the meta route. RT-PCR analysis on oxygenase-coding genes of S. solfataricus 98/2 showed that the gene coding for the C23D was expressed only on phenol. In 2D-DIGE/MALDI-TOF analysis, the C23D was found and identified only on phenol. This set of results allowed us concluding that S. solfataricus 98/2 degrade phenol through the meta route. PMID- 24349277 TI - Multiview locally linear embedding for effective medical image retrieval. AB - Content-based medical image retrieval continues to gain attention for its potential to assist radiological image interpretation and decision making. Many approaches have been proposed to improve the performance of medical image retrieval system, among which visual features such as SIFT, LBP, and intensity histogram play a critical role. Typically, these features are concatenated into a long vector to represent medical images, and thus traditional dimension reduction techniques such as locally linear embedding (LLE), principal component analysis (PCA), or laplacian eigenmaps (LE) can be employed to reduce the "curse of dimensionality". Though these approaches show promising performance for medical image retrieval, the feature-concatenating method ignores the fact that different features have distinct physical meanings. In this paper, we propose a new method called multiview locally linear embedding (MLLE) for medical image retrieval. Following the patch alignment framework, MLLE preserves the geometric structure of the local patch in each feature space according to the LLE criterion. To explore complementary properties among a range of features, MLLE assigns different weights to local patches from different feature spaces. Finally, MLLE employs global coordinate alignment and alternating optimization techniques to learn a smooth low-dimensional embedding from different features. To justify the effectiveness of MLLE for medical image retrieval, we compare it with conventional spectral embedding methods. We conduct experiments on a subset of the IRMA medical image data set. Evaluation results show that MLLE outperforms state-of-the-art dimension reduction methods. PMID- 24349278 TI - BP-ANN for fitting the temperature-germination model and its application in predicting sowing time and region for Bermudagrass. AB - Temperature is one of the most significant environmental factors that affects germination of grass seeds. Reliable prediction of the optimal temperature for seed germination is crucial for determining the suitable regions and favorable sowing timing for turf grass cultivation. In this study, a back-propagation artificial-neural-network-aided dual quintic equation (BP-ANN-QE) model was developed to improve the prediction of the optimal temperature for seed germination. This BP-ANN-QE model was used to determine optimal sowing times and suitable regions for three Cynodon dactylon cultivars (C. dactylon, 'Savannah' and 'Princess VII'). Prediction of the optimal temperature for these seeds was based on comprehensive germination tests using 36 day/night (high/low) temperature regimes (both ranging from 5/5 to 40/40 degrees C with 5 degrees C increments). Seed germination data from these temperature regimes were used to construct temperature-germination correlation models for estimating germination percentage with confidence intervals. Our tests revealed that the optimal high/low temperature regimes required for all the three bermudagrass cultivars are 30/5, 30/10, 35/5, 35/10, 35/15, 35/20, 40/15 and 40/20 degrees C; constant temperatures ranging from 5 to 40 degrees C inhibited the germination of all three cultivars. While comparing different simulating methods, including DQEM, Bisquare ANN-QE, and BP-ANN-QE in establishing temperature based germination percentage rules, we found that the R(2) values of germination prediction function could be significantly improved from about 0.6940-0.8177 (DQEM approach) to 0.9439-0.9813 (BP-ANN-QE). These results indicated that our BP-ANN-QE model has better performance than the rests of the compared models. Furthermore, data of the national temperature grids generated from monthly-average temperature for 25 years were fit into these functions and we were able to map the germination percentage of these C. dactylon cultivars in the national scale of China, and suggested the optimum sowing regions and times for them. PMID- 24349279 TI - Transformation of adaptation and gain rescaling along the whisker sensory pathway. AB - Neurons in all sensory systems have a remarkable ability to adapt their sensitivity to the statistical structure of the sensory signals to which they are tuned. In the barrel cortex, firing rate adapts to the variance of a whisker stimulus and neuronal sensitivity (gain) adjusts in inverse proportion to the stimulus standard deviation. To determine how adaptation might be transformed across the ascending lemniscal pathway, we measured the responses of single units in the first and last subcortical stages, the trigeminal ganglion (TRG) and ventral posterior medial thalamic nucleus (VPM), to controlled whisker stimulation in urethane-anesthetized rats. We probed adaptation using a filtered white noise stimulus that switched between low- and high-variance epochs. We found that the firing rate of both TRG and VPM neurons adapted to stimulus variance. By fitting the responses of each unit to a Linear-Nonlinear-Poisson model, we tested whether adaptation changed feature selectivity and/or sensitivity. We found that, whereas feature selectivity was unaffected by stimulus variance, units often exhibited a marked change in sensitivity. The extent of these sensitivity changes increased systematically along the pathway from TRG to barrel cortex. However, there was marked variability across units, especially in VPM. In sum, in the whisker system, the adaptation properties of subcortical neurons are surprisingly diverse. The significance of this diversity may be that it contributes to a rich population representation of whisker dynamics. PMID- 24349280 TI - Disconnection mechanism and regional cortical atrophy contribute to impaired processing of facial expressions and theory of mind in multiple sclerosis: a structural MRI study. AB - Successful socialization requires the ability of understanding of others' mental states. This ability called as mentalization (Theory of Mind) may become deficient and contribute to everyday life difficulties in multiple sclerosis. We aimed to explore the impact of brain pathology on mentalization performance in multiple sclerosis. Mentalization performance of 49 patients with multiple sclerosis was compared to 24 age- and gender matched healthy controls. T1- and T2 weighted three-dimensional brain MRI images were acquired at 3Tesla from patients with multiple sclerosis and 18 gender- and age matched healthy controls. We assessed overall brain cortical thickness in patients with multiple sclerosis and the scanned healthy controls, and measured the total and regional T1 and T2 white matter lesion volumes in patients with multiple sclerosis. Performances in tests of recognition of mental states and emotions from facial expressions and eye gazes correlated with both total T1-lesion load and regional T1-lesion load of association fiber tracts interconnecting cortical regions related to visual and emotion processing (genu and splenium of corpus callosum, right inferior longitudinal fasciculus, right inferior fronto-occipital fasciculus, uncinate fasciculus). Both of these tests showed correlations with specific cortical areas involved in emotion recognition from facial expressions (right and left fusiform face area, frontal eye filed), processing of emotions (right entorhinal cortex) and socially relevant information (left temporal pole). Thus, both disconnection mechanism due to white matter lesions and cortical thinning of specific brain areas may result in cognitive deficit in multiple sclerosis affecting emotion and mental state processing from facial expressions and contributing to everyday and social life difficulties of these patients. PMID- 24349281 TI - Mutation inactivation of Nijmegen breakage syndrome gene (NBS1) in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. AB - Nijmegen breakage syndrome (NBS) with NBS1 germ-line mutation is a human autosomal recessive disease characterized by genomic instability and enhanced cancer predisposition. The NBS1 gene codes for a protein, Nbs1(p95/Nibrin), involved in the processing/repair of DNA double-strand breaks. Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several genomic alterations. Recent studies have shown that heterozygous NBS1 mice exhibited a higher incidence of HCC than did wild-type mice. The objective of the present study is to assess whether NBS1 mutations play a role in the pathogenesis of human primary liver cancer, including HBV-associated HCC and intrahepatic cholangiocarcinoma (ICC). Eight missense NBS1 mutations were identified in six of 64 (9.4%) HCCs and two of 18 (11.1%) ICCs, whereas only one synonymous mutation was found in 89 control cases of cirrhosis and chronic hepatitis B. Analysis of the functional consequences of the identified NBS1 mutations in Mre11-binding domain showed loss of nuclear localization of Nbs1 partner Mre11, one of the hallmarks for Nbs1 deficiency, in one HCC and two ICCs with NBS1 mutations. Moreover, seven of the eight tumors with NBS1 mutations had at least one genetic alteration in the TP53 pathway, including TP53 mutation, MDM2 amplification, p14ARF homozygous deletion and promoter methylation, implying a synergistic effect of Nbs1 disruption and p53 inactivation. Our findings provide novel insight on the molecular pathogenesis of primary liver cancer characterized by mutation inactivation of NBS1, a DNA repair associated gene. PMID- 24349282 TI - Organic production enhances milk nutritional quality by shifting fatty acid composition: a United States-wide, 18-month study. AB - Over the last century, intakes of omega-6 (omega-6) fatty acids in Western diets have dramatically increased, while omega-3 (omega-3) intakes have fallen. Resulting omega-6/omega-3 intake ratios have risen to nutritionally undesirable levels, generally 10 to 15, compared to a possible optimal ratio near 2.3. We report results of the first large-scale, nationwide study of fatty acids in U.S. organic and conventional milk. Averaged over 12 months, organic milk contained 25% less omega-6 fatty acids and 62% more omega-3 fatty acids than conventional milk, yielding a 2.5-fold higher omega-6/omega-3 ratio in conventional compared to organic milk (5.77 vs. 2.28). All individual omega-3 fatty acid concentrations were higher in organic milk--alpha-linolenic acid (by 60%), eicosapentaenoic acid (32%), and docosapentaenoic acid (19%)--as was the concentration of conjugated linoleic acid (18%). We report mostly moderate regional and seasonal variability in milk fatty acid profiles. Hypothetical diets of adult women were modeled to assess milk fatty-acid-driven differences in overall dietary omega-6/omega-3 ratios. Diets varied according to three choices: high instead of moderate dairy consumption; organic vs. conventional dairy products; and reduced vs. typical consumption of omega-6 fatty acids. The three choices together would decrease the omega-6/omega-3 ratio among adult women by ~80% of the total decrease needed to reach a target ratio of 2.3, with relative impact "switch to low omega-6 foods" > "switch to organic dairy products" ~ "increase consumption of conventional dairy products." Based on recommended servings of dairy products and seafoods, dairy products supply far more alpha-linolenic acid than seafoods, about one-third as much eicosapentaenoic acid, and slightly more docosapentaenoic acid, but negligible docosahexaenoic acid. We conclude that consumers have viable options to reduce average omega-6/omega-3 intake ratios, thereby reducing or eliminating probable risk factors for a wide range of developmental and chronic health problems. PMID- 24349283 TI - Succession of ephemeral secondary forests and their limited role for the conservation of floristic diversity in a human-modified tropical landscape. AB - Both local- and landscape-scale processes drive succession of secondary forests in human-modified tropical landscapes. Nonetheless, until recently successional changes in composition and diversity have been predominantly studied at the patch level. Here, we used a unique dataset with 45 randomly selected sites across a mixed-use tropical landscape in central Panama to study forest succession simultaneously on local and landscape scales and across both life stages (seedling, sapling, juvenile and adult trees) and life forms (shrubs, trees, lianas, and palms). To understand the potential of these secondary forests to conserve tree species diversity, we also evaluated the diversity of species that can persist as viable metapopulations in a dynamic patchwork of short-lived successional forests, using different assumptions about the average relative size at reproductive maturity. We found a deterministic shift in the diversity and composition of the local plant communities as well as the metacommunity, driven by variation in the rate at which species recruited into and disappeared from the secondary forests across the landscape. Our results indicate that dispersal limitation and the successional niche operate simultaneously and shape successional dynamics of the metacommunity of these early secondary forests. A high diversity of plant species across the metacommunity of early secondary forests shows a potential for restoration of diverse forests through natural succession, when trees and fragments of older forests are maintained in the agricultural matrix and land is abandoned or set aside for a long period of time. On the other hand, during the first 32 years the number of species with mature sized individuals was a relatively small and strongly biased sub-sample of the total species pool. This implies that ephemeral secondary forests have a limited role in the long-term conservation of tree species diversity in human-modified tropical landscapes. PMID- 24349284 TI - Tuberculosis in migrant populations. A systematic review of the qualitative literature. AB - BACKGROUND: The re-emergence of tuberculosis (TB) in low-incidence countries and its disproportionate burden on immigrants is a public health concern posing specific social and ethical challenges. This review explores perceptions, knowledge, attitudes and treatment adherence behaviour relating to TB and their social implications as reported in the qualitative literature. METHODS: Systematic review in four electronic databases. Findings from thirty selected studies extracted, tabulated, compared and synthesized. FINDINGS: TB was attributed to many non-exclusive causes including air-born transmission of bacteria, genetics, malnutrition, excessive work, irresponsible lifestyles, casual contact with infected persons or objects; and exposure to low temperatures, dirt, stress and witchcraft. Perceived as curable but potentially lethal and highly contagious, there was confusion around a condition surrounded by fears. A range of economic, legislative, cultural, social and health system barriers could delay treatment seeking. Fears of deportation and having contacts traced could prevent individuals from seeking medical assistance. Once on treatment, family support and "the personal touch" of health providers emerged as key factors facilitating adherence. The concept of latent infection was difficult to comprehend and while TB screening was often seen as a socially responsible act, it could be perceived as discriminatory. Immigration and the infectiousness of TB mutually reinforced each another exacerbating stigma. This was further aggravated by indirect costs such as losing a job, being evicted by a landlord or not being able to attend school. CONCLUSIONS: Understanding immigrants' views of TB and the obstacles that they face when accessing the health system and adhering to a treatment programme-taking into consideration their previous experiences at countries of origin as well as the social, economic and legislative context in which they live at host countries- has an important role and should be considered in the design, evaluation and adaptation of programmes. PMID- 24349285 TI - The rhizosphere selects for particular groups of acidobacteria and verrucomicrobia. AB - There is a lack in our current understanding on the putative interactions of species of the phyla of Acidobacteria and Verrucomicrobia with plants. Moreover, progress in this area is seriously hampered by the recalcitrance of members of these phyla to grow as pure cultures. The purpose of this study was to investigate whether particular members of Acidobacteria and Verrucomicrobia are avid colonizers of the rhizosphere. Based on previous work, rhizosphere competence was demonstrated for the Verrucomicrobia subdivision 1 groups of Luteolibacter and Candidatus genus Rhizospheria and it was hypothesized that the rhizosphere is a common habitat for Acidobacteria subdivision 8 (class Holophagae). We assessed the population densities of Bacteria, Verrucomicrobia subdivision 1 groups Luteolibacter and Candidatus genus Rhizospheria and Acidobacteria subdivisions 1, 3, 4, 6 and Holophagae in bulk soil and in the rhizospheres of grass, potato and leek in the same field at different points in time using real-time quantitative PCR. Primers of all seven verrucomicrobial, acidobacterial and holophagal PCR systems were based on 16S rRNA gene sequences of cultivable representatives of the different groups. Luteolibacter, Candidatus genus Rhizospheria, subdivision 6 acidobacteria and Holophaga showed preferences for one or more rhizospheres. In particular, the Holophaga 16S rRNA gene number were more abundant in the leek rhizosphere than in bulk soil and the rhizospheres of grass and potato. Attraction to, and colonization of, leek roots by Holophagae strain CHC25 was further shown in an experimental microcosm set-up. In the light of this remarkable capacity, we propose to coin strain CHC25 Candidatus Porrumbacterium oxyphilus (class Holophagae, Phylum Acidobacteria), the first cultured representative with rhizosphere competence. PMID- 24349286 TI - Arabidopsis heterotrimeric G-proteins play a critical role in host and nonhost resistance against Pseudomonas syringae pathogens. AB - Heterotrimeric G-proteins have been proposed to be involved in many aspects of plant disease resistance but their precise role in mediating nonhost disease resistance is not well understood. We evaluated the roles of specific subunits of heterotrimeric G-proteins using knock-out mutants of Arabidopsis Galpha, Gbeta and Ggamma subunits in response to host and nonhost Pseudomonas pathogens. Plants lacking functional Galpha, Gbeta and Ggamma1Ggamma2 proteins displayed enhanced bacterial growth and disease susceptibility in response to host and nonhost pathogens. Mutations of single Ggamma subunits Ggamma1, Ggamma2 and Ggamma3 did not alter bacterial disease resistance. Some specificity of subunit usage was observed when comparing host pathogen versus nonhost pathogen. Overexpression of both Galpha and Gbeta led to reduced bacterial multiplication of nonhost pathogen P. syringae pv. tabaci whereas overexpression of Gbeta, but not of Galpha, resulted in reduced bacterial growth of host pathogen P. syringae pv. maculicola, compared to wild-type Col-0. Moreover, the regulation of stomatal aperture by bacterial pathogens was altered in Galpha and Gbeta mutants but not in any of the single or double Ggamma mutants. Taken together, these data substantiate the critical role of heterotrimeric G-proteins in plant innate immunity and stomatal modulation in response to P. syringae. PMID- 24349287 TI - Predicting early intrahepatic recurrence of hepatocellular carcinoma after microwave ablation using SELDI-TOF proteomic signature. AB - BACKGROUND/AIMS: Despite great progress in the treatment of hepatocellular carcinoma (HCC) over the last-decade, intrahepatic recurrence is still the most frequent serious adverse event after all the treatments including microwave ablation. This study aimed to predict early recurrence of HCC after microwave ablation using serum proteomic signature. METHODS: After curative microwave ablation of HCC, 86 patients were followed-up for 1 year. Serum samples were collected before microwave ablation. The mass spectra of proteins were generated using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). Serum samples from 50 patients were randomly selected as a training set and for biomarkers discovery and model development. The remaining serum samples were categorized for validation of the algorithm. RESULTS: According to preablation serum protein profiling obtained from the 50 HCC samples in the training set, nine significant differentially-expressed proteins were detected in the serum samples between recurrent and non-recurrent patients. Decision classification tree combined with three candidate proteins with m/z values of 7787, 6858 and 6646 was produced using Biomarker Patterns Software with sensitivity of 85.7% and specificity of 88.9% in the training set. When the SELDI marker pattern was tested with the blinded testing set, it yielded a sensitivity of 80.0%, a specificity of 88.5% and a positive predictive value of 86.1%. CONCLUSIONS: Differentially-expressed protein peaks in preablation serum screened by SELDI are associated with prognosis of HCC. The decision classification tree is a potential tool in predicting early intrahepatic recurrence in HCC patients after microwave ablation. PMID- 24349288 TI - A decline in HIV and syphilis epidemics in Chinese female sex workers (2000 2011): a systematic review and meta-analysis. AB - BACKGROUND: Female sex workers (FSWs) play an important role in transmitting HIV and syphilis from high-risk groups to the general population. However, the trends in HIV and syphilis epidemics in Chinese FSWs in the period after 2000 are unclear to date. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement was followed. Seven databases were searched for published peer-reviewed articles. The incidence of HIV and syphilis in FSWs in different time periods, provinces and workplaces in China were separately pooled by meta-analysis. Correlation analysis was conducted between HIV and syphilis incidence and study time, respectively. RESULTS: After 1,662 articles were screened, 190 published papers were included in the final analysis. Estimated HIV prevalence was 0.284% (95% CI: 0.080-0.488%) in the period 2000-2002, 0.211% (95% CI: 0.149-0.273%) in 2003-2005, 0.242% (95% CI: 0.190-0.294%) in 2006-2008 and 0.041% (95% CI: 0.024-0.058%) in 2009-2011. The corresponding syphilis prevalence was 9.669% (95% CI: 7.810-11.529%), 4.970% (95% CI: 4.384-5.556%), 4.404% (95% CI: 4.032-4.775%) and 3.169% (95% CI: 2.738-3.600%), respectively. Spearman rank correlation coefficients were -0.165 (p = 0.002) between HIV prevalence and study time, and -0.209 (p = 0.000) between syphilis prevalence and study time. The combined HIV prevalence was 0.318% (95% CI: 0.156-0.479%) in medium and high-tier workplaces and 0.393% (95% CI: 0.176-0.610%) in low-tier workplaces. The corresponding syphilis prevalence was 3.216% (95% CI: 2.192-4.240%) and 13.817% (95% CI: 10.589-17.044%), respectively. CONCLUSIONS: Our data suggested a decline in HIV and syphilis epidemics in FSWs in China on a national level during the study period (2000-2011). FSWs in low-tier workplaces should be given more attention in the future to ensure they are included in prevention programs for HIV and sexually transmitted diseases. PMID- 24349290 TI - Multiple transport-active binding sites are available for a single substrate on human P-glycoprotein (ABCB1). AB - P-glycoprotein (Pgp, ABCB1) is an ATP-Binding Cassette (ABC) transporter that is associated with the development of multidrug resistance in cancer cells. Pgp transports a variety of chemically dissimilar amphipathic compounds using the energy from ATP hydrolysis. In the present study, to elucidate the binding sites on Pgp for substrates and modulators, we employed site-directed mutagenesis, cell and membrane-based assays, molecular modeling and docking. We generated single, double and triple mutants with substitutions of the Y307, F343, Q725, F728, F978 and V982 residues at the proposed drug-binding site with cys in a cysless Pgp, and expressed them in insect and mammalian cells using a baculovirus expression system. All the mutant proteins were expressed at the cell surface to the same extent as the cysless wild-type Pgp. With substitution of three residues of the pocket (Y307, Q725 and V982) with cysteine in a cysless Pgp, QZ59S-SSS, cyclosporine A, tariquidar, valinomycin and FSBA lose the ability to inhibit the labeling of Pgp with a transport substrate, [(125)I]-Iodoarylazidoprazosin, indicating these drugs cannot bind at their primary binding sites. However, the drugs can modulate the ATP hydrolysis of the mutant Pgps, demonstrating that they bind at secondary sites. In addition, the transport of six fluorescent substrates in HeLa cells expressing triple mutant (Y307C/Q725C/V982C) Pgp is also not significantly altered, showing that substrates bound at secondary sites are still transported. The homology modeling of human Pgp and substrate and modulator docking studies support the biochemical and transport data. In aggregate, our results demonstrate that a large flexible pocket in the Pgp transmembrane domains is able to bind chemically diverse compounds. When residues of the primary drug binding site are mutated, substrates and modulators bind to secondary sites on the transporter and more than one transport-active binding site is available for each substrate. PMID- 24349289 TI - Reverse engineering the neuroblastoma regulatory network uncovers MAX as one of the master regulators of tumor progression. AB - Neuroblastoma is the most common extracranial tumor and a major cause of infant cancer mortality worldwide. Despite its importance, little is known about its molecular mechanisms. A striking feature of this tumor is its clinical heterogeneity. Possible outcomes range from aggressive invasion to other tissues, causing patient death, to spontaneous disease regression or differentiation into benign ganglioneuromas. Several efforts have been made in order to find tumor progression markers. In this work, we have reconstructed the neuroblastoma regulatory network using an information-theoretic approach in order to find genes involved in tumor progression and that could be used as outcome predictors or as therapeutic targets. We have queried the reconstructed neuroblastoma regulatory network using an aggressive neuroblastoma metastasis gene signature in order to find its master regulators (MRs). MRs expression profiles were then investigated in other neuroblastoma datasets so as to detect possible clinical significance. Our analysis pointed MAX as one of the MRs of neuroblastoma progression. We have found that higher MAX expression correlated with favorable patient outcomes. We have also found that MAX expression and protein levels were increased during neuroblastoma SH-SY5Y cells differentiation. We propose that MAX is involved in neuroblastoma progression, possibly increasing cell differentiation by means of regulating the availability of MYC:MAX heterodimers. This mechanism is consistent with the results found in our SH-SY5Y differentiation protocol, suggesting that MAX has a more central role in these cells differentiation than previously reported. Overexpression of MAX has been identified as anti-tumorigenic in other works, but, to our knowledge, this is the first time that the link between the expression of this gene and malignancy was verified under physiological conditions. PMID- 24349291 TI - Back from the brink: the Holocene history of the Carpathian barbel Barbus carpathicus. AB - As a result of specific adaptations and habitat preferences strongly rheophilic fish species may show high levels of endemism. Many temperate rheophilic fish species were subjected to a series of range contractions during the Pleistocene, and then successfully expanded during the Holocene, colonising previously abandoned areas. The Carpathian barbel (Barbus carpathicus Kotlik, Tsigenopoulos, Rab et Berrebi 2002) occurs in the montane streams in three basins of the main Central European rivers in the northern part of the Carpathian range. We used genetic variation within 3 mitochondrial and 9 microsatellite loci to determine a pattern of postglacial expansion in B. carpathicus. We found that overall genetic variation within the species is relatively low. Estimate of time to the most recent common ancestor (tMRCA) of mitochondrial sequences falls within the Holocene. The highest levels of genetic variation found in upper reaches of the Tisa river in the Danube basin suggest that glacial refugia were located in the south-eastern part of the species range. Our data suggest that the species crossed different watersheds at least six times as three genetically distinct groups (probably established in different expansion episodes) were found in northern part of the species range. Clines of genetic variation were observed in both the Danube and Vistula basins, which probably resulted from subsequent bottlenecks while colonizing successive habitats (south eastern populations) or due to the admixture of genetically diverse individuals to a previously uniform population (Vistula basin). Therefore, B. carpathicus underwent both demographic breakdowns and expansions during the Holocene, showing its distribution and demography are sensitive to environmental change. Our findings are important in the light of the current human-induced habitats alterations. PMID- 24349292 TI - The A930G polymorphism ofP22phox (CYBA) gene but not C242T variation is associated with hypertension: a meta-analysis. AB - BACKGROUND: Recently, it has been reported that the A930G and C242T polymorphisms within p22phox (CYBA) gene are involved in the pathogenesis of hypertension. However, the results remain controversial. Furthermore, no previous meta-analysis has been conducted to evaluate the relationship between the A930G and C242T polymorphisms and hypertension. Therefore, we performed this meta-analysis to clarify these controversies. OBJECTIVE AND METHODS: All of the included articles were retrieved from the PubMed and Embase databases, as well as the CNKI, CBM, Chongqing VIP and Wan Fang databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Odds ratios (OR) with corresponding 95% confidence intervals (CI) were used to assess the strength of the association. Accounting for heterogeneity, a fixed or random effects model was respectively adopted. Heterogeneity was checked using the Q test and the I(2) statistic. A cumulative meta-analysis was conducted to estimate the tendency of pooled OR. Funnel plots and Egger's tests were performed to test for possible publication bias. RESULTS: Five articles on A930G with 2003 cases/2434 controls and eight articles on C242T with 2644 cases/1967 controls were identified. A significant association of A930G polymorphisms with the risk of hypertension was found in the dominant model (OR=0.59, 95% CI: 0.38-0.92, p=0.021) and allelic model (OR=0.66, 95% CI: 0.46-0.95, p=0.024). In the stratified analysis, a significant association could be found among the hospital-based and population based studies. However, no evidence of a significant association of the C242T polymorphism with hypertension was found in the overall analysis and subgroup analysis. CONCLUSIONS: This meta-analysis indicates that the A930G polymorphism, but not the C242T variation, might be a protective factor for hypertension. PMID- 24349293 TI - The effectiveness of acupuncture in prevention and treatment of postoperative nausea and vomiting--a systematic review and meta-analysis. AB - BACKGROUND: Acupuncture therapy for preventive and treatment of postoperative nausea and vomiting(PONV), a condition which commonly present after anaesthesia and surgery is a subject of growing interest. OBJECTIVE: This paper included a systematic review and meta-analysis on the effect of different type of acupuncture and acupoint selection in PONV prevention and treatment. METHODS: Randomised controlled trials(RCTs) comparing acupuncture with non-acupuncture treatment were identified from databases PubMed, Cochrane, EBSCO, Ovid, CNKI and Wanfangdata. Meta-analysis on eligible studies was performed using fixed-effects model with RevMan 5.2. Results were expressed as RR for dichotomous data, with 95%CI. RESULTS: Thirty RCTs, 1276 patients (intervention) and 1258 patients (control) were identified. Meta-analysis showed that PC6 acupuncture significantly reduced the number of cases of early vomiting (postoperative 0-6h) (RR=0.36, 95%CI 0.19,0.71; P=0.003) and nausea (postoperative 0-24h) (RR=0.25, 95%CI 0.10,0.61; P=0.002), but not early nausea (postoperative 0-6h) (RR=0.64, 95%CI 0.34,1.19; P=0.150) and vomiting (postoperative 0-24h) (RR=0.82, 95%CI 0.48,1.38; P=0.450). PC6 acupressure significantly reduced the number of cases of nausea (RR=0.71, 95%CI 0.57,0.87; P=0.001) and vomiting (RR=0.62, 95%CI 0.49,0.80; P=0.000) at postoperative 0-24h. PC6 electro-acupoint stimulation significantly reduced the number of cases of nausea (RR=0.49, 95%CI 0.38,0.63; P<0.000) and vomiting (RR=0.50, 95%CI 0.36,0.70; P<0.000) at postoperative 0-24h. Stimulation of PC6 with other acupoint(s) significantly reduced the number of cases of nausea and vomiting (RR=0.29, 95%CI 0.17,0.49; P<0.000) at postoperative 0-24h. Stimulation of other acupoint(s)(non PC6) also significantly reduced the number of cases of nausea and vomiting (RR=0.63, 95%CI 0.49,0.81; P=0.000) at postoperative 0-24h. However, the quality of study was generally low in studies of PC6 combined with other acupoint(s) and other acupoint(s). Details of blinding were not reported in most reports. CONCLUSIONS: Besides PC6, PC6 combined with other acupoint(s) and other alternative acupoint(s) might be beneficial in prevention and treatment of PONV, the evidence justifies future high-quality studies. PMID- 24349295 TI - Modelling size-dependent cannibalism in barramundi Lates calcarifer: cannibalistic polyphenism and its implication to aquaculture. AB - This study quantified size-dependent cannibalism in barramundi Lates calcarifer through coupling a range of prey-predator pairs in a different range of fish sizes. Predictive models were developed using morphological traits with the alterative assumption of cannibalistic polyphenism. Predictive models were validated with the data from trials where cannibals were challenged with progressing increments of prey sizes. The experimental observations showed that cannibals of 25-131 mm total length could ingest the conspecific prey of 78-72% cannibal length. In the validation test, all predictive models underestimate the maximum ingestible prey size for cannibals of a similar size range. However, the model based on the maximal mouth width at opening closely matched the empirical observations, suggesting a certain degree of phenotypic plasticity of mouth size among cannibalistic individuals. Mouth size showed allometric growth comparing with body depth, resulting in a decreasing trend on the maximum size of ingestible prey as cannibals grow larger, which in parts explains why cannibalism in barramundi is frequently observed in the early developmental stage. Any barramundi has the potential to become a cannibal when the initial prey size was <50% of the cannibal body length, but fish could never become a cannibal when prey were >58% of their size, suggesting that 50% of size difference can be the threshold to initiate intracohort cannibalism in a barramundi population. Cannibalistic polyphenism was likely to occur in barramundi that had a cannibalistic history. An experienced cannibal would have a greater ability to stretch its mouth size to capture a much larger prey than the models predict. The awareness of cannibalistic polyphenism has important application in fish farming management to reduce cannibalism. PMID- 24349294 TI - Mortality among methadone maintenance clients in China: a six-year cohort study. AB - OBJECTIVE: To assess the overall mortality of methadone maintenance treatment (MMT) clients in China and its associated factors. METHODS: A total of 1,511 MMT clients, all of whom enrolled in China's first eight MMT clinics between March and December 2004, were included in this cohort study and followed for approximately six years, until June 2010. Mortality and its predictors were examined using Cox proportional hazards regression models. RESULTS: A total of 154 deaths were observed within 5,391 person-years (PY) of follow-up for an all cause mortality rate of 28.6 per 1,000 PY. The leading causes of death were drug overdose (33.8%), HIV/AIDS-unrelated disease (21.4%), and HIV/AIDS (16.9%). The all-cause mortality rate of clients engaged in MMT for one year or less was roughly three times that of clients who stayed in MMT for four years or more (14.0 vs. 4.6, p<0.0001), HIV-positive subjects was nearly four times mortality rate than that of HIV-negative individuals (28.1 vs.6.8, p<0.0001). ART-naive HIV positive subjects had approximately two times higher mortality rate than those receiving ART (31.2 vs. 17.3, <0.0001). After adjusting for confounding variables, we found that being male (HR = 1.63, CI: 1.03-2.57, p = 0.0355) and being HIV-positive (HR = 5.16, CI: 3.70-7.10, p<0.0001) were both associated with higher risk of death whereas increased durations of methadone treatment were associated with a lower risk of death (HR = 0.26, CI: 0.18-0.38, p<0.0001 for two to three years, HR = 0.08, CI: 0.05-0.14, p<0.0001 for four or more years). CONCLUSION: Overall mortality was high among MMT clients in China. Specific interventions aimed at decreasing mortality among MMT clients are needed. Our study supports the need for keeping client at MMT longer and for expanding ART coverage and suggests the potential benefits of integrated MMT and ART services for drug users in China. PMID- 24349296 TI - Identifying biologically meaningful hot-weather events using threshold temperatures that affect life-history. AB - Increases in the frequency, duration and intensity of heat waves are frequently evoked in climate change predictions. However, there is no universal definition of a heat wave. Recent, intense hot weather events have caused mass mortalities of birds, bats and even humans, making the definition and prediction of heat wave events that have the potential to impact populations of different species an urgent priority. One possible technique for defining biologically meaningful heat waves is to use threshold temperatures (T(thresh)) above which known fitness costs are incurred by species of interest. We set out to test the utility of this technique using T(thresh) values that, when exceeded, affect aspects of the fitness of two focal southern African bird species: the southern pied babbler Turdiodes bicolor (T(thresh) = 35.5 degrees C) and the common fiscal Lanius collaris (T(thresh) = 33 degrees C). We used these T(thresh) values to analyse trends in the frequency, duration and intensity of heat waves of magnitude relevant to the focal species, as well as the annual number of hot days (maximum air temperature > T(thresh)), in north-western South Africa between 1961 and 2010. Using this technique, we were able to show that, while all heat wave indices increased during the study period, most rapid increases for both species were in the annual number of hot days and in the maximum intensity (and therefore intensity variance) of biologically meaningful heat waves. Importantly, we also showed that warming trends were not uniform across the study area and that geographical patterns in warming allowed both areas of high risk and potential climate refugia to be identified. We discuss the implications of the trends we found for our focal species, and the utility of the T(thresh) technique as a conservation tool. PMID- 24349297 TI - Molecular evolution and diversity of Conus peptide toxins, as revealed by gene structure and intron sequence analyses. AB - Cone snails, which are predatory marine gastropods, produce a cocktail of venoms used for predation, defense and competition. The major venom component, conotoxin, has received significant attention because it is useful in neuroscience research, drug development and molecular diversity studies. In this study, we report the genomic characterization of nine conotoxin gene superfamilies from 18 Conus species and investigate the relationships among conotoxin gene structure, molecular evolution and diversity. The I1, I2, M, O2, O3, P, S, and T superfamily precursors all contain three exons and two introns, while A superfamily members contain two exons and one intron. The introns are conserved within a certain gene superfamily, and also conserved across different Conus species, but divergent among different superfamilies. The intronic sequences contain many simple repeat sequences and regulatory elements that may influence conotoxin gene expression. Furthermore, due to the unique gene structure of conotoxins, the base substitution rates and the number of positively selected sites vary greatly among exons. Many more point mutations and trinucleotide indels were observed in the mature peptide exon than in the other exons. In addition, the first example of alternative splicing in conotoxin genes was found. These results suggest that the diversity of conotoxin genes has been shaped by point mutations and indels, as well as rare gene recombination or alternative splicing events, and that the unique gene structures could have made a contribution to the evolution of conotoxin genes. PMID- 24349298 TI - Enhanced responses to tumor immunization following total body irradiation are time-dependent. AB - The development of successful cancer vaccines is contingent on the ability to induce effective and persistent anti-tumor immunity against self-antigens that do not typically elicit immune responses. In this study, we examine the effects of a non-myeloablative dose of total body irradiation on the ability of tumor-naive mice to respond to DNA vaccines against melanoma. We demonstrate that irradiation followed by lymphocyte infusion results in a dramatic increase in responsiveness to tumor vaccination, with augmentation of T cell responses to tumor antigens and tumor eradication. In irradiated mice, infused CD8(+) T cells expand in an environment that is relatively depleted in regulatory T cells, and this correlates with improved CD8(+) T cell functionality. We also observe an increase in the frequency of dendritic cells displaying an activated phenotype within lymphoid organs in the first 24 hours after irradiation. Intriguingly, both the relative decrease in regulatory T cells and increase in activated dendritic cells correspond with a brief window of augmented responsiveness to immunization. After this 24 hour window, the numbers of dendritic cells decline, as does the ability of mice to respond to immunizations. When immunizations are initiated within the period of augmented dendritic cell activation, mice develop anti-tumor responses that show increased durability as well as magnitude, and this approach leads to improved survival in experiments with mice bearing established tumors as well as in a spontaneous melanoma model. We conclude that irradiation can produce potent immune adjuvant effects independent of its ability to induce tumor ablation, and that the timing of immunization and lymphocyte infusion in the irradiated host are crucial for generating optimal anti-tumor immunity. Clinical strategies using these approaches must therefore optimize such parameters, as the correct timing of infusion and vaccination may mean the difference between an ineffective treatment and successful tumor eradication. PMID- 24349299 TI - Inhibitory effects of vinpocetine on the progression of atherosclerosis are mediated by Akt/NF-kappaB dependent mechanisms in apoE-/- mice. AB - BACKGROUND: Recent studies have found additional roles for vinpocetine, a potent phosphodiesterase type I inhibitor, in anti-proliferation and anti-inflammation of vascular smooth muscle cells and cancer cells via different mechanisms. In this study, we attempted to investigate whether vinpocetine protected against atherosclerotic development in apoE(-/-) mice and explore the underlying anti atherogenic mechanisms in macrophages. METHODOLOGY/PRINCIPAL FINDINGS: Vinpocetine markedly decreased atherosclerotic lesion size in apoE(-/-) mice measured by oil red O. Masson's trichrome staining and immunohistochemical analyses revealed that vinpocetine significantly increased the thickness of fibrous cap, reduced the size of lipid-rich necrotic core and attenuated inflammation. In vitro experiments exhibited a significant decrease in monocyte adhesion treated with vinpocetine. Further, active TNF-alpha, IL-6, monocyte chemoattractant protein-1 and matrix metalloproteinase-9 expression induced by ox LDL were attenuated by vinpocetine in a dose-dependent manner. Similarly, ox-LDL induced reactive oxygen species were significantly repressed by vinpocetine. Both western blot and luciferase activity assay showed that vinpocetine inhibited the enhanced Akt, IKKalpha/beta, IkappaBalpha phosphorylation and NF-kappaB activity induced by ox-LDL, and the inhibition of NF-kappaB activity was partly caused by Akt dephosphorylation. However, knockdown of PDE1B did not affect Akt, IKKalpha/beta and IkappaBalpha phosphorylation. CONCLUSIONS: These results suggest that vinpocetine exerts anti-atherogenic effects through inhibition of monocyte adhesion, oxidative stress and inflammatory response, which are mediated by Akt/NF-kappaB dependent pathway but independent of PDE1 blockade in macrophages. PMID- 24349300 TI - Population genetic structure of a microalgal species under expansion. AB - Biological invasions often cause major perturbations in the environment and are well studied among macroorganisms. Less is known about invasion by free-living microbes. Gonyostomum semen (Raphidophyceae) is a freshwater phytoplankton species that has increased in abundance in Northern Europe since the 1980's and has expanded its habitat range. In this study, we aimed to determine the genetic population structure of G. semen in Northern Europe and to what extent it reflects the species' recent expansion. We sampled lakes from 12 locations (11 lakes) in Norway, Sweden and Finland. Multiple strains from each location were genotyped using Amplified Fragment Length Polymorphism (AFLP). We found low differentiation between locations, and low gene diversity within each location. Moreover, there was an absence of genetic isolation with distance (Mantel test, p = 0.50). According to a Bayesian clustering method all the isolates belonged to the same genetic population. Together our data suggest the presence of one metapopulation and an overall low diversity, which is coherent with a recent expansion of G. semen. PMID- 24349301 TI - Quantitative phosphoproteomic analysis identifies activation of the RET and IGF 1R/IR signaling pathways in neuroblastoma. AB - Neuroblastoma is an embryonal tumor of childhood with a heterogenous clinical presentation that reflects differences in activation of complex biological signaling pathways. Protein phosphorylation is a key component of cellular signal transduction and plays a critical role in processes that control cancer cell growth and survival. We used shotgun LC/MS to compare phosphorylation between a human MYCN amplified neuroblastoma cell line (NB10), modeling a resistant tumor, and a human neural precursor cell line (NPC), modeling a normal baseline neural crest cell. 2181 unique phosphorylation sites representing 1171 proteins and 2598 phosphopeptides were found. Protein kinases accounted for 6% of the proteome, with a predominance of tyrosine kinases, supporting their prominent role in oncogenic signaling pathways. Highly abundant receptor tyrosine kinase (RTK) phosphopeptides in the NB10 cell line relative to the NPC cell line included RET, insulin-like growth factor 1 receptor/insulin receptor (IGF-1R/IR), and fibroblast growth factor receptor 1 (FGFR1). Multiple phosphorylated peptides from downstream mediators of the PI3K/AKT/mTOR and RAS pathways were also highly abundant in NB10 relative to NPC. Our analysis highlights the importance of RET, IGF-1R/IR and FGFR1 as RTKs in neuroblastoma and suggests a methodology that can be used to identify potential novel biological therapeutic targets. Furthermore, application of this previously unexploited technology in the clinic opens the possibility of providing a new wide-scale molecular signature to assess disease progression and prognosis. PMID- 24349302 TI - Quorum sensing and self-quorum quenching in the intracellular pathogen Brucellamelitensis. AB - Brucella quorum sensing has been described as an important regulatory system controlling crucial virulence determinants such as the VirB type IV secretion system and the flagellar genes. However, the basis of quorum sensing, namely the production of autoinducers in Brucella has been questioned. Here, we report data obtained from the use of a genetic tool allowing the in situ detection of long chain N-acyl-homoserine lactones (AHL) activity at single bacterium level in Brucella melitensis. These data are consistent with an intrinsic production of AHL by B. melitensis in low concentration both during in vitro growth and macrophage infection. Moreover, we identified a protein, named AibP, which is homologous to the AHL-acylases of various bacterial species. In vitro and during infection, expression of aibP coincided with a decrease in endogenous AHL activity within B. melitensis, suggesting that AibP could efficiently impair AHL accumulation. Furthermore, we showed that deletion of aibP in B. melitensis resulted in enhanced virB genes expression and VirB8 production as well as in a reduced flagellar genes expression and production of FlgE (hook protein) and FliC (flagellin) in vitro. Altogether, these results suggest that AHL-dependent quorum sensing and AHL-quorum quenching coexist in Brucella, at least to regulate its virulence. PMID- 24349303 TI - Molecular epidemiology of nontypeable Haemophilus influenzae causing community acquired pneumonia in adults. AB - Nontypeable Haemophilus influenzae (NTHi) is an opportunistic pathogen which causes a variety of respiratory infections. The objectives of the study were to determine its antimicrobial susceptibility, to characterize the beta-lactam resistance, and to establish a genetic characterization of NTHi isolates. Ninety five NTHi isolates were analyzed by pulsed field gel electrophoresis (PFGE) and multi locus sequence typing (MLST). Antimicrobial susceptibility was determined by microdilution, and the ftsI gene (encoding penicillin-binding protein 3, PBP3) was PCR amplified and sequenced. Thirty (31.6%) isolates were non-susceptible to ampicillin (MIC >= 2 mg/L), with 10 of them producing beta-lactamase type TEM-1 as a resistance mechanism. After ftsI sequencing, 39 (41.1%) isolates showed amino acid substitutions in PBP3, with Asn526 -> Lys being the most common (69.2%). Eighty-four patients were successfully treated with amoxicillin/clavulanic acid, ceftriaxone and levofloxacin. Eight patients died due either to aspiration or complication of their comorbidities. In conclusion, NTHi causing CAP in adults shows high genetic diversity and is associated with a high rate of reduced susceptibility to ampicillin due to alterations in PBP3. The analysis of treatment and outcomes demonstrated that NTHi strains with mutations in the ftsI gene could be successfully treated with ceftriaxone or fluoroquinolones. PMID- 24349304 TI - Four genetic polymorphisms of lymphotoxin-alpha gene and cancer risk: a systematic review and meta-analysis. AB - Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine that plays an important role in the inflammatory and immunologic response. Numerous studies have shown LTA polymorphisms as risk factors for cancers, but the results remain inconclusive. The goal of the present meta-analyses is to establish the associations between cancers and four LTA variants (rs1041981, rs2239704, rs2229094 and rs746868). A total of 30 case-control studies involving 58,649 participants were included in the current meta-analyses. Our results showed significant associations with increased cancer risk for rs1041981 (odd ratio (OR) = 1.15, 99% confidential interval (CI) = 1.07-1.25, P < 0.0001, I(2) = 12.2%), rs2239704 (OR = 1.08, 99% CI = 1.01-1.16, P = 0.021, I(2) = 0.0%) and rs2229094 (OR = 1.28, 99% CI = 1.09-1.50, P = 0.003, I(2) = 0.0%). No evidence was found for the association between rs746868 and cancer risk (OR = 1.01, 99% CI = 0.93 1.10, P = 0.771, I(2) = 0.0%). Subgroup meta-analysis suggested that rs2239704 was likely to increase the risk of hematological malignancy (OR = 1.10, 99% CI = 1.01-1.20, P = 0.023, I(2) = 0.0%), and rs2229094 was specific for the increased risk of adenocarcinoma (OR = 1.33, 99% CI = 1.11-1.59, P = 0.002, I(2) = 0.0%). In conclusion, our meta-analyses suggested that the LTA rs1041981, rs2239704 and rs2229094 polymorphisms contributed to the increased risk of cancers. Future functional studies were needed to clarify the mechanistic roles of the three variants in the cancer risk. PMID- 24349305 TI - Strain-independent increases of crystallin proteins in the retina of type 1 diabetic rats. AB - Diabetic retinopathy is the leading cause of vision loss in working-age individuals in the United States and is expected to continue growing with the increased prevalence of diabetes. Streptozotocin-induced hyperglycemia in rats is the most commonly used model for diabetic retinopathy. Previous studies have shown that this model can lead to different inflammatory changes in the retina depending on the strain of rat. Our previous work has shown that crystallin proteins, including members of the alpha- and beta/gamma-crystallin subfamilies, are upregulated in the STZ rat retina. Crystallin proteins have been implicated in a number of cellular processes, such as neuroprotection, non-native protein folding and vascular remodeling. In this current study, we have demonstrated that unlike other strain-dependent changes, such as inflammatory cytokines and growth factor levels, in the STZ rat, the protein upregulation of crystallins is consistent across the Brown Norway, Long-Evans and Sprague-Dawley rat strains in the context of diabetes. Taken together, these data illustrate the potential critical role played by crystallins, and especially alpha-crystallins, in the retina in the context of diabetes. PMID- 24349306 TI - Interleukin-encoding adenoviral vectors as genetic adjuvant for vaccination against retroviral infection. AB - Interleukins (IL) are cytokines with stimulatory and modulatory functions in the immune system. In this study, we have chosen interleukins which are involved in the enhancement of TH2 responses and B cell functions to analyze their potential to improve a prophylactic adenovirus-based anti-retroviral vaccine with regard to antibody and virus-specific CD4(+) T cell responses. Mice were vaccinated with an adenoviral vector which encodes and displays the Friend Virus (FV) surface envelope protein gp70 (Ad.pIXgp70) in combination with adenoviral vectors encoding the interleukins IL4, IL5, IL6, IL7 or IL23. Co-application of Ad.pIXgp70 with Ad.IL5, Ad.IL6 or Ad.IL23 resulted in improved protection with high control over FV-induced splenomegaly and reduced viral loads. Mice co immunized with adenoviral vectors encoding IL5 or IL23 showed increased neutralizing antibody responses while mice co-immunized with Ad.IL6 or Ad.IL23 showed improved FV-specific CD4(+) T cell responses compared to mice immunized with Ad.pIXgp70 alone. We show that the co-application of adenoviral vectors encoding specific interleukins is suitable to improve the vaccination efficacy of an anti-retroviral vaccine. Improved protection correlated with improved CD4(+) T cell responses and especially with higher neutralizing antibody titers. The co application of selected interleukin-encoding adenoviral vectors is a valuable tool for vaccination with regard to enhancement of antibody mediated immunity. PMID- 24349307 TI - Reconstitution of cholesterol-dependent vaginolysin into tethered phospholipid bilayers: implications for bioanalysis. AB - Functional reconstitution of the cholesterol-dependent cytolysin vaginolysin (VLY) from Gardnerella vaginalis into artificial tethered bilayer membranes (tBLMs) has been accomplished. The reconstitution of VLY was followed in real time by electrochemical impedance spectroscopy (EIS). Changes of the EIS parameters of the tBLMs upon exposure to VLY solutions were consistent with the formation of water-filled pores in the membranes. It was found that reconstitution of VLY is a strictly cholesterol-dependent, irreversible process. At a constant cholesterol concentration reconstitution of VLY occurred in a concentration-dependent manner, thus allowing the monitoring of VLY concentration and activity in vitro and opening possibilities for tBLM utilization in bioanalysis. EIS methodology allowed us to detect VLY down to 0.5 nM (28 ng/mL) concentration. Inactivation of VLY by certain amino acid substitutions led to noticeably lesser tBLM damage. Pre-incubation of VLY with the neutralizing monoclonal antibody 9B4 inactivated the VLY membrane damage in a concentration dependent manner, while the non-neutralizing antibody 21A5 exhibited no effect. These findings demonstrate the biological relevance of the interaction between VLY and the tBLM. The membrane-damaging interaction between VLY and tBLM was observed in the absence of the human CD59 receptor, known to strongly facilitate the hemolytic activity of VLY. Taken together, our study demonstrates the applicability of tBLMs as a bioanalytical platform for the detection of the activity of VLY and possibly other cholesterol-dependent cytolysins. PMID- 24349308 TI - TALE-PvuII fusion proteins--novel tools for gene targeting. AB - Zinc finger nucleases (ZFNs) consist of zinc fingers as DNA-binding module and the non-specific DNA-cleavage domain of the restriction endonuclease FokI as DNA cleavage module. This architecture is also used by TALE nucleases (TALENs), in which the DNA-binding modules of the ZFNs have been replaced by DNA-binding domains based on transcription activator like effector (TALE) proteins. Both TALENs and ZFNs are programmable nucleases which rely on the dimerization of FokI to induce double-strand DNA cleavage at the target site after recognition of the target DNA by the respective DNA-binding module. TALENs seem to have an advantage over ZFNs, as the assembly of TALE proteins is easier than that of ZFNs. Here, we present evidence that variant TALENs can be produced by replacing the catalytic domain of FokI with the restriction endonuclease PvuII. These fusion proteins recognize only the composite recognition site consisting of the target site of the TALE protein and the PvuII recognition sequence (addressed site), but not isolated TALE or PvuII recognition sites (unaddressed sites), even at high excess of protein over DNA and long incubation times. In vitro, their preference for an addressed over an unaddressed site is > 34,000-fold. Moreover, TALE-PvuII fusion proteins are active in cellula with minimal cytotoxicity. PMID- 24349309 TI - Exposure to atmospheric particulate matter enhances Th17 polarization through the aryl hydrocarbon receptor. AB - Lung diseases, including asthma, COPD, and other autoimmune lung pathologies are aggravated by exposure to particulate matter (PM) found in air pollution. IL-17 has been shown to exacerbate airway disease in animal models. As PM is known to contain aryl hydrocarbon receptor (AHR) ligands and the AHR has recently been shown to play a role in differentiation of Th17 T cells, the aim of this study was to determine whether exposure to PM could impact Th17 polarization in an AHR dependent manner. This study used both cell culture techniques and in vivo exposure in mice to examine the response of T cells to PM. Initially experiments were conducted with urban dust particles from a standard reference material, and ultimately repeated with freshly collected samples of diesel exhaust and cigarette smoke. The readout for the assays was increased T cell differentiation as indicated by increased generation of IL-17A in culture, and increased populations of IL-17 producing cells by intracellular flow cytometry. The data illustrate that Th17 polarization was significantly enhanced by addition of urban dust in a dose dependent fashion in cultures of wild-type but not AHR(-/-) mice. The data further suggest that polycyclic aromatic hydrocarbons played a primary role in this enhancement. There was both an increase of Th17 cell differentiation, and also an increase in the amount of IL-17 secreted by the cells. In summary, this paper identifies a novel mechanism whereby PM can directly act on the AHR in T cells, leading to enhanced Th17 differentiation. Further understanding of the molecular mechanisms responsible for pathologic Th17 differentiation and autoimmunity seen after exposure to pollution will allow direct targeting of proteins involved in AHR activation and function for treatment of PM exposures. PMID- 24349310 TI - CLCN1 mutations in Czech patients with myotonia congenita, in silico analysis of novel and known mutations in the human dimeric skeletal muscle chloride channel. AB - Myotonia congenita (MC) is a genetic disease caused by mutations in the skeletal muscle chloride channel gene (CLCN1) encoding the skeletal muscle chloride channel (ClC-1). Mutations of CLCN1 result in either autosomal dominant MC (Thomsen disease) or autosomal recessive MC (Becker disease). The ClC-1 protein is a homodimer with a separate ion pore within each monomer. Mutations causing recessive myotonia most likely affect properties of only the mutant monomer in the heterodimer, leaving the wild type monomer unaffected, while mutations causing dominant myotonia affect properties of both subunits in the heterodimer. Our study addresses two points: 1) molecular genetic diagnostics of MC by analysis of the CLCN1 gene and 2) structural analysis of mutations in the homology model of the human dimeric ClC-1 protein. In the first part, 34 different types of CLCN1 mutations were identified in 51 MC probands (14 mutations were new). In the second part, on the basis of the homology model we identified the amino acids which forming the dimer interface and those which form the Cl(-) ion pathway. In the literature, we searched for mutations of these amino acids for which functional analyses were performed to assess the correlation between localisation of a mutation and occurrence of a dominant negative effect (corresponding to dominant MC). This revealed that both types of mutations, with and without a dominant-negative effect, are localised at the dimer interface while solely mutations without a dominant-negative effect occur inside the chloride channel. This work is complemented by structural analysis of the homology model which provides elucidation of the effects of mutations, including a description of impacts of newly detected missense mutations. PMID- 24349311 TI - Is fluid overload more important than diabetes in renal progression in late chronic kidney disease? AB - Fluid overload is one of the major presentations in patients with late stage chronic kidney disease (CKD). Diabetes is the leading cause of renal failure, and progression of diabetic nephropathy has been associated with changes in extracellular fluid volume. The aim of the study was to assess the association of fluid overload and diabetes in commencing dialysis and rapid renal function decline (the slope of estimated glomerular filtration rate (eGFR) less than -3 ml/min per 1.73 m(2)/y) in 472 patients with stages 4-5 CKD. Fluid status was determined by bioimpedance spectroscopy method, Body Composition Monitor. The study population was further classified into four groups according to the median of relative hydration status (?HS =fluid overload/extracellular water) and the presence or absence of diabetes. The median level of relative hydration status was 7%. Among all patients, 207(43.9 %) were diabetic. 71 (15.0%) subjects had commencing dialysis, and 187 (39.6%) subjects presented rapid renal function decline during a median 17.3-month follow-up. Patients with fluid overload had a significantly increased risk for commencing dialysis and renal function decline independent of the presence or absence of diabetes. No significantly increased risk for renal progression was found between diabetes and non-diabetes in late CKD without fluid overload. In conclusion, fluid overload has a higher predictive value of an elevated risk for renal progression than diabetes in late CKD. PMID- 24349312 TI - C-terminus of the B-chain of relaxin-3 is important for receptor activity. AB - Human relaxin-3 is a neuropeptide that is structurally similar to human insulin with two chains (A and B) connected by three disulfide bonds. It is expressed primarily in the brain and has modulatory roles in stress and anxiety, feeding and metabolism, and arousal and behavioural activation. Structure-activity relationship studies have shown that relaxin-3 interacts with its cognate receptor RXFP3 primarily through its B-chain and that its A-chain does not have any functional role. In this study, we have investigated the effect of modification of the B-chain C-terminus on the binding and activity of the peptide. We have chemically synthesised and characterized H3 relaxin as C-termini acid (both A and B chains having free C-termini; native form) and amide forms (both chains' C-termini were amidated). We have confirmed that the acid form of the peptide is more potent than its amide form at both RXFP3 and RXFP4 receptors. We further investigated the effects of amidation at the C-terminus of individual chains. We report here for the first time that amidation at the C-terminus of the B-chain of H3 relaxin leads to significant drop in the binding and activity of the peptide at RXFP3/RXFP4 receptors. However, modification of the A-chain C terminus does not have any effect on the activity. We have confirmed using circular dichroism spectroscopy that there is no secondary structural change between the acid and amide form of the peptide, and it is likely that it is the local C-terminal carboxyl group orientation that is crucial for interacting with the receptors. PMID- 24349313 TI - Should physical activity recommendations be ethnicity-specific? Evidence from a cross-sectional study of South Asian and European men. AB - BACKGROUND: Expert bodies and health organisations recommend that adults undertake at least 150 min.week(-1) of moderate-intensity physical activity (MPA). However, the underpinning data largely emanate from studies of populations of European descent. It is unclear whether this level of activity is appropriate for other ethnic groups, particularly South Asians, who have increased cardio metabolic disease risk compared to Europeans. The aim of this study was to explore the level of MPA required in South Asians to confer a similar cardio metabolic risk profile to that observed in Europeans undertaking the currently recommended MPA level of 150 min.week(-1). METHODS: Seventy-five South Asian and 83 European men, aged 40-70, without cardiovascular disease or diabetes had fasted blood taken, blood pressure measured, physical activity assessed objectively (using accelerometry), and anthropometric measures made. Factor analysis was used to summarise measured risk biomarkers into underlying latent 'factors' for glycaemia, insulin resistance, lipid metabolism, blood pressure, and overall cardio-metabolic risk. Age-adjusted regression models were used to determine the equivalent level of MPA (in bouts of >= 10 minutes) in South Asians needed to elicit the same value in each factor as Europeans undertaking 150 min.week(-1) MPA. FINDINGS: For all factors, except blood pressure, equivalent MPA values in South Asians were significantly higher than 150 min.week(-1); the equivalent MPA value for the overall cardio-metabolic risk factor was 266 (95% CI 185-347) min.week(-1). CONCLUSIONS: South Asian men may need to undertake greater levels of MPA than Europeans to exhibit a similar cardio-metabolic risk profile, suggesting that a conceptual case can be made for ethnicity-specific physical activity guidance. Further study is needed to extend these findings to women and to replicate them prospectively in a larger cohort. PMID- 24349314 TI - Cost-effectiveness analysis of breast cancer control interventions in Peru. AB - OBJECTIVES: In Peru, a country with constrained health resources, breast cancer control is characterized by late stage treatment and poor survival. To support breast cancer control in Peru, this study aims to determine the cost effectiveness of different breast cancer control interventions relevant for the Peruvian context. METHODS: We performed a cost-effectiveness analysis (CEA) according to WHO-CHOICE guidelines, from a healthcare perspective. Different screening, early detection, palliative, and treatment interventions were evaluated using mathematical modeling. Effectiveness estimates were based on observational studies, modeling, and on information from Instituto Nacional de Enfermedades Neoplasicas (INEN). Resource utilizations and unit costs were based on estimates from INEN and observational studies. Cost-effectiveness estimates are in 2012 United States dollars (US$) per disability adjusted life year (DALY) averted. RESULTS: The current breast cancer program in Peru ($8,426 per DALY averted) could be improved through implementing triennial or biennial screening strategies. These strategies seem the most cost-effective in Peru, particularly when mobile mammography is applied (from $4,125 per DALY averted), or when both CBE screening and mammography screening are combined (from $4,239 per DALY averted). Triennially, these interventions costs between $63 million and $72 million per year. Late stage treatment, trastuzumab therapy and annual screening strategies are the least cost-effective. CONCLUSIONS: Our analysis suggests that breast cancer control in Peru should be oriented towards early detection through combining fixed and mobile mammography screening (age 45-69) triennially. However, a phased introduction of triennial CBE screening (age 40-69) with upfront FNA in non-urban settings, and both CBE (age 40-49) and fixed mammography screening (age 50-69) in urban settings, seems a more feasible option and is also cost-effective. The implementation of this intervention is only meaningful if awareness raising, diagnostic, referral, treatment and basic palliative services are simultaneously improved, and if financial and organizational barriers to these services are reduced. PMID- 24349315 TI - Design, synthesis of novel lipids as chemical permeation enhancers and development of nanoparticle system for transdermal drug delivery. AB - In the present study, we designed and developed novel lipids that include (Z)-1 (Octadec-9-en-1-yl)-pyrrolidine (Cy5T), 1, 1-Di-((Z)-octadec-9-en-1-yl)pyrrolidin 1-ium iodide (Cy5), (Z)-1-(Octadec-9-en-1-yl)-piperidine (Cy6T), and 1, 1-Di-((Z) octadec-9-en-1-yl) piperidin-1-ium iodide (Cy6) to enhance the transdermal permeation of some selected drugs. Firstly, we evaluated the transdermal permeation efficacies of these lipids as chemical permeation enhancers in vehicle formulations for melatonin, beta-estradiol, caffeine, alpha-MSH, and spantide using franz diffusion cells. Among them Cy5 lipid was determined to be the most efficient by increasing the transdermal permeation of melatonin, beta-estradiol, caffeine, alpha-MSH, and spantide by 1.5 to 3.26-fold more at the epidermal layer and 1.3 to 2.5-fold more at the dermal layer, in comparison to either NMP or OA. Hence we developed a nanoparticle system (cy5 lipid ethanol drug nanoparticles) to evaluate any further improvement in the drug penetration. Cy5 lipid formed uniformly sized nanoparticles ranging from 150-200 nm depending on the type of drug. Further, Cy5 based nanoparticle system significantly (p<0.05) increased the permeation of all the drugs in comparison to the lipid solution and standard permeation enhancers. There were about 1.54 to 22-fold more of drug retained in the dermis for the Cy5 based nanoparticles compared to OA/NMP standard enhancers and 3.87 to 66.67-fold more than lipid solution. In addition, epifluorescent microscopic analysis in rhodamine-PE permeation studies confirmed the superior permeation enhancement of LEDs (detection of fluorescence up to skin depth of 340 MUm) more than lipid solution, which revealed fluorescence up to skin depth of only 260 MUm. In summary the present findings demonstrate that i) cationic lipid with 5 membered amine heterocyclic ring has higher permeating efficacy than the 6 membered amine hertocyclic ring. ii) The nanoparticle system prepared with Cy5 showed significant (p<0.05) increase in the permeation of the drugs than the control penetration enhancers, oleic acid and NMP. PMID- 24349316 TI - Human L-ficolin, a recognition molecule of the lectin activation pathway of complement, activates complement by binding to pneumolysin, the major toxin of Streptococcus pneumoniae. AB - The complement system is an essential component of the immune response, providing a critical line of defense against different pathogens including S. pneumoniae. Complement is activated via three distinct pathways: the classical (CP), the alternative (AP) and the lectin pathway (LP). The role of Pneumolysin (PLY), a bacterial toxin released by S. pneumoniae, in triggering complement activation has been studied in vitro. Our results demonstrate that in both human and mouse sera complement was activated via the CP, initiated by direct binding of even non specific IgM and IgG3 to PLY. Absence of CP activity in C1q(-/-) mouse serum completely abolished any C3 deposition. However, C1q depleted human serum strongly opsonized PLY through abundant deposition of C3 activation products, indicating that the LP may have a vital role in activating the human complement system on PLY. We identified that human L-ficolin is the critical LP recognition molecule that drives LP activation on PLY, while all of the murine LP recognition components fail to bind and activate complement on PLY. This work elucidates the detailed interactions between PLY and complement and shows for the first time a specific role of the LP in PLY-mediated complement activation in human serum. PMID- 24349317 TI - Functional characterization of ECP-heparin interaction: a novel molecular model. AB - Human eosinophil cationic protein (ECP) and eosinophil derived neurotoxin (EDN) are two ribonuclease A (RNaseA) family members secreted by activated eosinophils. They share conserved catalytic triad and similar three dimensional structures. ECP and EDN are heparin binding proteins with diverse biological functions. We predicted a novel molecular model for ECP binding of heparin hexasaccharide (Hep6), [GlcNS(6S)-IdoA(2S)]3, and residues Gln(40), His(64) and Arg(105) were indicated as major contributions for the interaction. Interestingly, Gln(40) and His(64) on ECP formed a clamp-like structure to stabilize Hep6 in our model, which was not observed in the corresponding residues on EDN. To validate our prediction, mutant ECPs including ECP Q40A, H64A, R105A, and double mutant ECP Q40A/H64A were generated, and their binding affinity for heparins were measured by isothermal titration calorimetry (ITC). Weaker binding of ECP Q40A/H64A of all heparin variants suggested that Gln(40)-His(64) clamp contributed to ECP-heparin interaction significantly. Our in silico and in vitro data together demonstrate that ECP uses not only major heparin binding region but also use other surrounding residues to interact with heparin. Such correlation in sequence, structure, and function is a unique feature of only higher primate ECP, but not EDN. PMID- 24349318 TI - Urinary miR-29 correlates with albuminuria and carotid intima-media thickness in type 2 diabetes patients. AB - BACKGROUND: Cell-free microRNAs stably and abundantly exist in body fluids and emerging evidence suggests cell-free microRNAs as novel and non-invasive disease biomarker. Deregulation of miR-29 is involved in the pathogenesis of diabetic nephropathy and insulin resistance thus may be implicated in diabetic vascular complication. Therefore, we investigated the possibility of urinary miR-29 as biomarker for diabetic nephropathy and atherosclerosis in patients with type 2 diabetes. METHODS: 83 patients with type 2 diabetes were enrolled in this study, miR-29a, miR-29b and miR-29c levels in urine supernatant was determined by TaqMan qRT-PCR, and a synthetic cel-miR-39 was added to the urine as a spike-in control before miRNAs extraction. Urinary albumin excretion rate and urine albumin/creatinine ratio, funduscopy and carotid ultrasound were used for evaluation of diabetic vascular complication. The laboratory parameters indicating blood glucose level, renal function and serum lipids were also collected. RESULTS: Patients with albuminuria (n = 42, age 60.62 +/- 12.00 yrs) showed significantly higher comorbidity of diabetic retinopathy (p = 0.015) and higher levels of urinary miR-29a (p = 0.035) compared with those with normoalbuminuria (n = 41, age 58.54 +/- 14.40 yrs). There was no significant difference in urinary miR-29b (p = 0.148) or miR-29c level (p = 0.321) between groups. Urinary albumin excretion rate significantly correlated with urinary miR 29a level (r = 0.286, p = 0.016), while urinary miR-29b significantly correlated with carotid intima-media thickness (cIMT) (r = 0.286, p = 0.046). CONCLUSION: Urinary miR-29a correlated with albuminuria while urinary miR-29b correlated with carotid intima-media thickness (cIMT) in patients with type 2 diabetes. Therefore, they may have the potential to serve as alternative biomarker for diabetic nephropathy and atherosclerosis in type 2 diabetes. PMID- 24349319 TI - Horizontal gene acquisition of Liberibacter plant pathogens from a bacteriome confined endosymbiont of their psyllid vector. AB - he Asian citrus psyllid Diaphorina citri is a notorious agricultural pest that transmits the phloem-inhabiting alphaproteobacterial 'Candidatus Liberibacter asiaticus' and allied plant pathogens, which cause the devastating citrus disease called Huanglongbing or greening disease. D. citri harbors two distinct bacterial mutualists in the symbiotic organ called bacteriome: the betaproteobacterium 'Candidatus Profftella armatura' in the syncytial cytoplasm at the center of the bacteriome, and the gammaproteobacterium 'Candidatus Carsonella ruddii' in uninucleate bacteriocytes. Here we report that a putative amino acid transporter LysE of Profftella forms a highly supported clade with proteins of L. asiaticus, L. americanus, and L. solanacearum. L. crescens, the most basal Liberibacter lineage currently known, lacked the corresponding gene. The Profftella Liberibacter subclade of LysE formed a clade with proteins from betaproteobacteria of the order Burkholderiales, to which Profftella belongs. This phylogenetic pattern favors the hypothesis that the Liberibacter lineage acquired the gene from the Profftella lineage via horizontal gene transfer (HGT) after L. crescens diverged from other Liberibacter lineages. K A/K S analyses further supported the hypothesis that the genes encoded in the Liberibacter genomes are functional. These findings highlight the possible evolutionary importance of HGT between plant pathogens and their insect vector's symbionts that are confined in the symbiotic organ and seemingly sequestered from external microbial populations. PMID- 24349320 TI - Folate deficiency during early-mid pregnancy affects the skeletal muscle transcriptome of piglets from a reciprocal cross. AB - Folate deficiency (FD) during pregnancy can cause fetal intrauterine growth restriction in pigs, of which the skeletal dysplasia is a major manifestation. Factors influencing muscle development are very important in the formation of porcine meat quality trait. However, the effect of folate deficiency on skeletal muscle development and its molecular mechanisms are unknown. The objective of this study is to determine the effect of maternal folate deficiency on the skeletal muscle transcriptome of piglets from a reciprocal cross, in which full sibling Landrace (LR) and full-sibling Chinese local breed Laiwu (LW) pigs were used for reciprocal cross matings, and sows were fed either a folate deficient or a normal diet during early-mid gestation. In addition, the difference in the responsiveness of the piglets to folate deficiency during early-mid pregnancy between reciprocal cross groups was investigated. Longissimus dorsi (LD) muscle samples were collected from newborn piglets and a 4 * 44K Agilent porcine oligo microarray was used for transcriptome analysis of porcine LD muscle. The results showed that folate deficiency during early-mid pregnancy affected piglet body weight, LD muscle fiber number and content of intramuscular triglyceride. The microarray results indicated that 3154 genes were differentially expressed between folate deficient and normal piglets from the LR? * LW? cross, and 3885 differentially expressed genes (DEGs) in the ones from the LW? * LR? cross. From functional analyses, sow folate deficiency affected almost all biological processes in the progeny. Lipid metabolism-related genes and associated metabolic pathways were regulated extensively by folate deficiency, especially in LR? * LW? cross piglets. Most of the genes that are regulated by folate deficiency in the LD muscle of piglets were different between LR? * LW? and LW? * LR? crosses, suggesting some epigenetic effects of FD exist in genes underlying myogenesis and intramuscular fat deposition in piglets. PMID- 24349321 TI - Difference in protein expression profile and chemotherapy drugs response of different progression stages of LNCaP sublines and other human prostate cancer cells. AB - Androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, 80-90% of the patients who receive androgen ablation therapy ultimately develop recurrent tumors in 12-33 months after treatment with a median overall survival time of 1-2 years after relapse. LNCaP is a commonly used cell line established from a human lymph node metastatic lesion of prostatic adenocarcinoma. We previously established two relapsed androgen receptor (AR) rich androgen-independent LNCaP sublines 104-R1 (androgen depleted for 12 months) and 104-R2 cells (androgen depleted for 24 months) from AR-positive androgen dependent LNCaP 104-S cells. LNCaP 104-R1 and 104-R2 mimics the AR-positive hormone-refractory relapsed tumors in patients receiving androgen ablation therapy. Androgen treatment stimulates proliferation of 104-S cells, but causes growth inhibition and G1 cell cycle arrest in 104-R1 and 104-R2 cells. We investigated the protein expression profile difference between LNCaP 104-S vs. LNCaP 104-R1, 104-R2, PC-3, and DU-145 cells as well as examined the sensitivity of these prostate cancer cells to different chemotherapy drugs and small molecule inhibitors. Compared to 104-S cells, 104-R1 and 104-R2 cells express higher protein levels of AR, PSA, c-Myc, Skp2, BCL-2, P53, p-MDM2 S166, Rb, and p-Rb S807/811. The 104-R1 and 104-R2 cells express higher ratio of p-Akt S473/Akt, p EGFR/EGFR, and p-Src/Src, but lower ratio of p-ERK/ERK than 104-S cells. PC-3 and DU-145 cells express higher c-Myc, Skp2, Akt, Akt1, and phospho-EGFR but less phospho-Akt and phospho-ERK. Overexpression of Skp2 increased resistance of LNCaP cells to chemotherapy drugs. Paclitaxel, androgen, and inhibitors for PI3K/Akt, EGFR, Src, or Bcl-2 seem to be potential choices for treatment of advanced prostate cancers. Our study provides rationale for targeting Akt, EGFR, Src, Bcl 2, and AR signaling as a treatment for AR-positive relapsed prostate tumors after hormone therapy. PMID- 24349322 TI - First identification of "Brachyspira hampsonii" in wild European waterfowl. AB - Anseriformes deserve special attention in the epidemiology of Brachyspira spp. because diverse Anseriformes species have been described to act as highly efficient carriers of several Brachyspira spp. that can also infect livestock. The aim of this study was to investigate the prevalence and diversity of Brachyspira spp. in waterfowl that winter in Spain. Brachyspira spp. were isolated from 51 of the 205 faecal samples collected from graylag geese and mallards in the Villafafila Lagoons Nature Reserve (Northwestern Spain). The Brachyspira species identified through phenotyping, PCR and sequencing of the nox gene were B. pilosicoli (5.9%), B. alvinipulli (11.8%), "B. hampsonii" (19.6%), B. murdochii (23.5%) and B. innocens (39.2%). The most relevant finding of this study is the description of "B. hampsonii" in specimens from birds for the first time. Phylogenetic analysis of the nox gene sequences grouped all of the obtained "B. hampsonii" isolates into a cluster with Brachyspira strains previously identified by others as "B. hampsonii" and separated from other Brachyspira spp. isolates and reference strains. Additionally, this cluster was related to clades that grouped B. murdochii and B. innocens isolates. The identification of "B. hampsonii" was also achieved in 8 of the 10 isolates by sequencing the16S rRNA gene and tlyA gene. Regardless of the species identified, no antimicrobial resistance was observed in any of the enteropathogenic isolates recovered. This is the first description of "B. hampsonii" in European waterfowl, which might represent hosts that serve as natural reservoirs of this Brachyspira species. This finding indicates that this spirochete is not limited to North America, and its presence in wild birds in Europe poses a risk of transmission to livestock. PMID- 24349323 TI - An inducible expression system to measure rhodopsin transport in transgenic Xenopus rod outer segments. AB - We developed an inducible transgene expression system in Xenopus rod photoreceptors. Using a transgene containing mCherry fused to the carboxyl terminus of rhodopsin (Rho-mCherry), we characterized the displacement of rhodopsin (Rho) from the base to the tip of rod outer segment (OS) membranes. Quantitative confocal imaging of live rods showed very tight regulation of Rho mCherry expression, with undetectable expression in the absence of dexamethasone (Dex) and an average of 16.5 uM of Rho-mCherry peak concentration after induction for several days (equivalent to >150-fold increase). Using repetitive inductions, we found the axial rate of disk displacement to be 1.0 um/day for tadpoles at 20 degrees C in a 12 h dark /12 h light lighting cycle. The average distance to peak following Dex addition was 3.2 um, which is equivalent to ~3 days. Rods treated for longer times showed more variable expression patterns, with most showing a reduction in Rho-mCherry concentration after 3 days. Using a simple model, we find that stochastic variation in transgene expression can account for the shape of the induction response. PMID- 24349324 TI - A new in vitro model to study cellular responses after thermomechanical damage in monolayer cultures. AB - Although electrosurgical instruments are widely used in surgery to cut tissue layers or to achieve hemostasis by coagulation (electrocautery), only little information is available concerning the inflammatory or immune response towards the debris generated. Given the elevated local temperatures required for successful electrocautery, the remaining debris is likely to contain a plethora of compounds entirely novel to the intracorporal setting. A very common in vitro method to study cell migration after mechanical damage is the scratch assay, however, there is no established model for thermomechanical damage to characterise cellular reactions. In this study, we established a new in vitro model to investigate exposure to high temperature in a carefully controlled cell culture system. Heatable thermostat-controlled aluminium stamps were developed to induce local damage in primary human umbilical vein endothelial cells (HUVEC). The thermomechanical damage invoked is reproducibly locally confined, therefore allowing studies, under the same experimental conditions, of cells affected to various degrees as well as of unaffected cells. We show that the unaffected cells surrounding the thermomechanical damage zone are able to migrate into the damaged area, resulting in a complete closure of the 'wound' within 48 h. Initial studies have shown that there are significant morphological and biological differences in endothelial cells after thermomechanical damage compared to the mechanical damage inflicted by using the unheated stamp as a control. Accordingly, after thermomechanical damage, cell death as well as cell protection programs were activated. Mononuclear cells adhered in the area adjacent to thermomechanical damage, but not to the zone of mechanical damage. Therefore, our model can help to understand the differences in wound healing during the early phase of regeneration after thermomechanical vs. mechanical damage. Furthermore, this model lends itself to study the response of other cells, thus broadening the range of thermal injuries that can be analysed. PMID- 24349325 TI - Evaluation of current and new biomarkers in severe preeclampsia: a microarray approach reveals the VSIG4 gene as a potential blood biomarker. AB - Preeclampsia is a placental disease characterized by hypertension and proteinuria in pregnant women, and it is associated with a high maternal and neonatal morbidity. However, circulating biomarkers that are able to predict the prognosis of preeclampsia are lacking. Thirty-eight women were included in the current study. They consisted of 19 patients with preeclampsia (13 with severe preeclampsia and 6 with non-severe preeclampsia) and 19 gestational age-matched women with normal pregnancies as controls. We measured circulating factors that are associated with the coagulation pathway (including fibrinogen, fibronectin, factor VIII, antithrombin, protein S and protein C), endothelial activation (such as soluble endoglin and CD146), and the release of total and platelet-derived microparticles. These markers enabled us to discriminate the preeclampsia condition from a normal pregnancy but were not sufficient to distinguish severe from non-severe preeclampsia. We then used a microarray to study the transcriptional signature of blood samples. Preeclampsia patients exhibited a specific transcriptional program distinct from that of the control group of women. Interestingly, we also identified a severity-related transcriptional signature. Functional annotation of the upmodulated signature in severe preeclampsia highlighted two main functions related to "ribosome" and "complement". Finally, we identified 8 genes that were specifically upmodulated in severe preeclampsia compared with non-severe preeclampsia and the normotensive controls. Among these genes, we identified VSIG4 as a potential diagnostic marker of severe preeclampsia. The determination of this gene may improve the prognostic assessment of severe preeclampsia. PMID- 24349326 TI - Dipeptidyl peptidase IV inhibition activates CREB and improves islet vascularization through VEGF-A/VEGFR-2 signaling pathway. AB - Substitution of pancreatic islets is a potential therapy to treat diabetes and it depends on reconstitution of islet's capillary network. In this study, we addressed the question whether stabilization of Glucagon-Like-Peptide-1 (GLP-1) by inhibiting Dipeptidyl Peptidase-IV (DPP-IV) increases beta-cell mass by modulating vascularization. Mouse or porcine donor islets were implanted under kidney capsule of diabetic mice treated with DPP-IV inhibitor sitagliptin. Grafts were analyzed for insulin production, beta-cell proliferation and vascularization. In addition, the effect of sitagliptin on sprouting and Vascular Endothelial Growth Factor (VEGF)-A expression was examined ex vivo. The cAMP response element-binding (CREB) and VEGF-A/ Vascular Endothelial Growth Factor Receptor (VEGFR)-2 signaling pathway leading to islet vascularization was explored. Sitagliptin increased mean insulin content of islet grafts and area of insulin-positive tissue as well as beta-cell proliferation. Interestingly, sitagliptin treatment also markedly increased endothelial cell proliferation, microvessel density and blood flow. Finally, GLP-1 (7-36) stimulated sprouting and VEGF expression, which was significantly enhanced by sitagliptin- mediated inhibition of DPP-IV. Our in vivo data demonstrate that sitagliptin treatment phosphorylated CREB and induced islet vascularization through VEGF-A/VEGFR-2 signaling pathway. This study paves a new pathway for improvement of islet transplantation in treating diabetes mellitus. PMID- 24349327 TI - Helicobacter pylori genotypes associated with gastric histo-pathological damages in a Moroccan population. AB - H. pylori persistent infection induces chronic gastritis and is associated with peptic ulcer disease and gastric carcinoma development. The severity of these diseases is related to human's genetic diversity, H. pylori genetic variability and environmental factors. To identify the prevalence of histo-pathological damages caused by H. pylori infection in Moroccan population, and to determine their association to H. pylori genotypes, a prospective study has been conducted during 3 years on patients attending the gastroenterology department of Hassan II University Hospital (CHU) of Fez, Morocco. A total of 801 Moroccan adults' patients were recruited; H. pylori was diagnosed and genotyped by PCR in biopsy specimens and histological exam was performed. We found a high rate of glandular atrophy. Chronic inflammation, neutrophil activity and glandular atrophy showed statistically significant association with H. pylori infection. However, intestinal metaplasia was inversely associated to this infection and no association was observed with gastric cancer cases. A statistically significant association was found between intestinal metaplasia and vacAs1 and vac Am1 genotypes in patients aged 50 years and more but not in younger. This last genotype is also associated to gastric cancer. In this study, gastric cancer showed no significant association with H. pylori. Further studies are warranted to determine the role of other etiological agents such as Epstein-Barr virus, human papillomavirus and possibly environmental and dietetic factors in the occurrence of this pathology. PMID- 24349328 TI - Phthalates induce neurotoxicity affecting locomotor and thermotactic behaviors and AFD neurons through oxidative stress in Caenorhabditis elegans. AB - BACKGROUND: Phthalate esters are ubiquitous environmental contaminants and numerous organisms are thus exposed to various levels of phthalates in their natural habitat. Considering the critical, but limited, research on human neurobehavioral outcomes in association with phthalates exposure, we used the nematode Caenorhabditis elegans as an in vivo model to evaluate phthalates induced neurotoxicity and the possible associated mechanisms. PRINCIPAL FINDINGS: Exposure to phthalates (DEHP, DBP, and DIBP) at the examined concentrations induced behavioral defects, including changes in body bending, head thrashing, reversal frequency, and thermotaxis in C. elegans. Moreover, phthalates (DEHP, DBP, and DIBP) exposure caused toxicity, affecting the relative sizes of cell body fluorescent puncta, and relative intensities of cell bodies in AFD neurons. The mRNA levels of the majority of the genes (TTX-1, TAX-2, TAX-4, and CEH-14) that are required for the differentiation and function of AFD neurons were decreased upon DEHP exposure. Furthermore, phthalates (DEHP, DBP, and DIBP) exposure at the examined concentrations produced elevated intracellular reactive oxygen species (ROS) in C. elegans. Finally, pretreatment with the antioxidant ascorbic acid significantly lowered the intracellular ROS level, ameliorated the locomotor and thermotactic behavior defects, and protected the damage of AFD neurons by DEHP exposure. CONCLUSIONS: Our study suggests that oxidative stress plays a critical role in the phthalate esters-induced neurotoxic effects in C. elegans. PMID- 24349329 TI - A vaccine that co-targets tumor cells and cancer associated fibroblasts results in enhanced antitumor activity by inducing antigen spreading. AB - Dendritic cell (DC) vaccines targeting only cancer cells have produced limited antitumor activity in most clinical studies. Targeting cancer-associated fibroblasts (CAFs) in addition to cancer cells may enhance antitumor effects, since CAFs, the central component of the tumor stroma, directly support tumor growth and contribute to the immunosuppressive tumor microenvironment. To co target CAFs and tumor cells we developed a new compound DC vaccine that encodes an A20-specific shRNA to enhance DC function, and targets fibroblast activation protein (FAP) expressed in CAFs and the tumor antigen tyrosine-related protein (TRP)2 (DC-shA20-FAP-TRP2). DC-shA20-FAP-TRP2 vaccination induced robust FAP- and TRP2-specific T-cell responses, resulting in greater antitumor activity in the B16 melanoma model in comparison to monovalent vaccines or a vaccine encoding antigens and a control shRNA. DC-shA20-FAP-TRP2 vaccination enhanced tumor infiltration of CD8-positive T cells, and induced antigen-spreading resulting in potent antitumor activity. Thus, co-targeting of tumor cells and CAFs results in the induction of broad-based tumor-specific T-cell responses and has the potential to improve current vaccine approaches for cancer. PMID- 24349330 TI - Cortical mapping of mismatch negativity with deviance detection property in rat. AB - Mismatch Negativity (MMN) is an N-methyl-d-aspartic acid (NMDA)-mediated, negative deflection in human auditory evoked potentials in response to a cognitively discriminable change. MMN-like responses have been extensively investigated in animal models, but the existence of MMN equivalent is still controversial. In this study, we aimed to investigate how closely the putative MMN (MMNp) in rats exhibited the comparable properties of human MMN. We used a surface microelectrode array with a grid of 10 * 7 recording sites within an area of 4.5 * 3.0 mm to densely map evoked potentials in the auditory cortex of anesthetized rats under the oddball paradigm. Firstly, like human MMN, deviant stimuli elicited negative deflections in auditory evoked potentials following the positive middle-latency response, termed P1. Secondly, MMNp exhibited deviance detecting property, which could not be explained by simple stimulus specific adaptation (SSA). Thirdly, this MMNp occurred focally in the auditory cortex, including both the core and belt regions, while P1 activation focus was obtained in the core region, indicating that both P1 and MMNp are generated in the auditory cortex, yet the sources of these signals do not completely overlap. Fourthly, MMNp significantly decreased after the application of AP5 (D-(-)-2 amino-5-phosphonopentanoic acid), an antagonist at NMDA receptors. In stark contrast, AP5 affected neither P1 amplitude nor SSA of P1. These results provide compelling evidence that the MMNp we have examined in rats is functionally comparable to human MMN. The present work will stimulate translational research into MMN, which may help bridge the gap between electroencephalography (EEG)/magnetoencephalography (MEG) studies in humans and electrophysiological studies in animals. PMID- 24349331 TI - Infective endocarditis epidemiology over five decades: a systematic review. AB - AIMS: To Assess changes in infective endocarditis (IE) epidemiology over the last 5 decades. METHODS AND RESULTS: We searched the published literature using PubMed, MEDLINE, and EMBASE from inception until December 2011. DATA FROM: Einstein Medical Center, Philadelphia, PA were also included. Criteria for inclusion in this systematic review included studies with reported IE microbiology, IE definition, description of population studied, and time frame. Two authors independently extracted data and assessed manuscript quality. One hundred sixty studies (27,083 patients) met inclusion criteria. Among hospital based studies (n=142; 23,606 patients) staphylococcal IE percentage increased over time, with coagulase-negative staphylococcus (CNS) increasing over each of the last 5 decades (p<0.001) and Staphylococcus aureus (SA) in the last decade (21% to 30%; p<0.05). Streptococcus viridans (SV) and culture negative (CN) IE frequency decreased over time (p<0.001), while enterococcal IE increased in the last decade (p<0.01). Patient age and male predominance increased over time as well. In subgroup analysis, SA frequency increased in North America, but not the rest of the world. This was due, in part, to an increase in intravenous drug abuse IE in North America (p<0.001). Among population-based studies (n=18; 3,477 patients) no significant changes were found. CONCLUSION: Important changes occurred in IE epidemiology over the last half-century, especially in the last decade. Staphylococcal and enterococcal IE percentage increased while SV and CN IE decreased. Moreover, mean age at diagnosis increased together with male:female ratio. These changes should be considered at the time of decision-making in treatment of and prophylaxis for IE. PMID- 24349332 TI - Human Fanconi anemia complementation group a protein stimulates the 5' flap endonuclease activity of FEN1. AB - In eukaryotic cells, Flap endonuclease 1 (FEN1) is a major structure-specific endonuclease that processes 5' flapped structures during maturation of lagging strand DNA synthesis, long patch base excision repair, and rescue of stalled replication forks. Here we report that fanconi anemia complementation group A protein (FANCA), a protein that recognizes 5' flap structures and is involved in DNA repair and maintenance of replication forks, constantly stimulates FEN1 mediated incision of both DNA and RNA flaps. Kinetic analyses indicate that FANCA stimulates FEN1 by increasing the turnover rate of FEN1 and altering its substrate affinity. More importantly, six pathogenic FANCA mutants are significantly less efficient than the wild-type at stimulating FEN1 endonuclease activity, implicating that regulation of FEN1 by FANCA contributes to the maintenance of genomic stability. PMID- 24349333 TI - The effect of high intensity interval exercise on postprandial triacylglycerol and leukocyte activation--monitored for 48 h post exercise. AB - Postprandial phenomenon are thought to contribute to atherogenesis alongside activation of the immune system. A single bout of high intensity interval exercise attenuates postprandial triacylglycerol (TG), although the longevity and mechanisms underlying this observation are unknown. The aims of this study were to determine whether this attenuation in postprandial TG remained 2 days after high intensity interval exercise, to monitor markers of leukocyte activation and investigate the underlying mechanisms. Eight young men each completed two three day trials. On day 1: subjects rested (Control) or performed 5 x 30 s maximal sprints (high intensity interval exercise). On day 2 and 3 subjects consumed high fat meals for breakfast and 3 h later for lunch. Blood samples were taken at various times and analysed for TG, glucose and TG-rich lipoprotein (TRL)-bound LPL-dependent TRL-TG hydrolysis (LTTH). Flow cytometry was used to evaluate granulocyte, monocyte and lymphocyte CD11b and CD36 expression. On day 2 after high intensity interval exercise TG area under the curve was lower (P<0.05) (7.46 +/- 1.53 mmol/l/7h) compared to the control trial (9.47 +/- 3 .04 mmol/l/7h) with no differences during day 3 of the trial. LTTH activity was higher (P<0.05) after high intensity interval exercise, at 2 hours of day 2, compared to control. Granulocyte, monocyte and lymphocyte CD11b expression increased with time over day 2 and 3 of the study (P<0.0001). Lymphocyte and monocyte CD36 expression decreased with time over day 2 and 3 (P<0.05). There were no differences between trials in CD11b and CD36 expression on any leukocytes. A single session of high intensity interval exercise attenuated postprandial TG on day 2 of the study, with this effect abolished by day 3.The reduction in postprandial TG was associated with an increase in LTTH. High intensity interval exercise had no effect on postprandial responses of CD11b or CD36. PMID- 24349334 TI - Genetic and non-genetic determinants of raltegravir penetration into cerebrospinal fluid: a single arm pharmacokinetic study. AB - BACKGROUND: Antiretroviral drugs vary in their central nervous system penetration, with better penetration possibly conferring neurocognitive benefit during human immunodeficiency virus (HIV) therapy. The efflux transporter gene ABCB1 is expressed in the blood-brain barrier, and an ABCB1 variant (3435C -> T) has been reported to affect ABCB1 expression. The integrase inhibitor raltegravir is a substrate for ABCB1. We examined whether ABCB1 3435C -> T affects raltegravir disposition into cerebrospinal fluid (CSF), and explored associations with polymorphisms in other membrane transporter genes expressed in the blood brain barrier. METHODS: Forty healthy, HIV-negative adults of European descent (20 homozygous for ABCB1 3435 C/C, 20 homozygous for 3435 T/T, each group divided equally between males and females) were given raltegravir 400 mg twice daily for 7 days. With the final dose, plasma was collected for pharmacokinetic analysis at 9 timepoints over 12 hours, and CSF collected 4 hours post dose. RESULTS: The 4 hour CSF concentration correlated more strongly with 2-hour (r(2)=0.76, P=1.12 x 10(-11)) than 4-hour (r(2)=0.47, P=6.89 x 10(-6)) single timepoint plasma concentration, and correlated strongly with partial plasma area-under-the-curve values (AUC0-4h r(2)=0.86, P=5.15 x 10(-16)). There was no significant association between ABCB1 3435C -> T and ratios of CSF-to-plasma AUC or concentration (p>0.05 for each comparison). In exploratory analyses, CSF-to plasma ratios were not associated with 276 polymorphisms across 16 membrane transporter genes. CONCLUSIONS: Among HIV-negative adults, CSF raltegravir concentrations do not differ by ABCB1 3435C -> T genotype but strongly correlate with plasma exposure. TRIAL REGISTRATION: ClinicalTrials.gov NCT00729924 http://clinicaltrials.gov/show/NCT00729924. PMID- 24349335 TI - Acute and prolonged adverse effects of temperature on mortality from cardiovascular diseases. AB - BACKGROUND: Cardiovascular diseases are the leading causes of death worldwide, especially for developed countries. Elevated mortality from cardiovascular diseases has been shown related to extreme temperature. We thus assessed the risk of mortality from cerebrovascular diseases, heart diseases, and ischemic heart disease (IHD) in relation to temperature profiles in four subtropical metropolitans (Taipei, Taichung, Tainan, and Kaohsiung) from 1994 to 2007 in Taiwan. METHODS: Distributed lag non-linear models were applied to estimate the cumulative relative risks (RRs) with confidence intervals of cause-specific mortality associated with daily temperature from lag 0 to 20 days, and specific effect of extreme temperature episodes with PM10, NOx, and O3, and other potential confounders controlled. Estimates for cause-specific mortalities were then pooled by random-effect meta-analysis. RESULTS: Comparing to centered temperature at 27 degrees C, the cumulative 4-day (lag 0 to 3) risk of mortality was significantly elevated at 31 degrees C for cerebrovascular diseases (RR = 1.14; 95% CI: 1.00, 1.31) and heart diseases (RR = 1.22; 95% CI: 1.02, 1.46) , but not for IHD (RR = 1.09; 95% CI: 0.99, 1.21). To the other extreme, at 15 degrees C, the cumulative 21-day (lag 0 to 20) risk of mortality were also remarkably increased for cerebrovascular diseases, heart diseases, and IHD (RRs = 1.48 with 95% CI: 1.04, 2.12, 2.04 with 95% CI: 1.61, 2.58, and 1.62 with 95% CI: 1.30, 2.01, respectively). Mortality risks for cardiovascular diseases were generally highest on the present day (lag 0) of extreme heat. No particular finding was detected on prolonged extreme temperature event by pooling estimations for cause-specific mortality. CONCLUSIONS: Low temperature was associated with greater risk of mortality from cardiovascular diseases in comparison with that of high temperature. Adverse effects of extreme temperatures are acute at the beginning of exposure. PMID- 24349336 TI - Short-term azithromycin treatment promotes cornea allograft survival in the rat. AB - BACKGROUND: Any inflammatory response following corneal transplantation may induce rejection and irreversible graft failure. The purpose of this study is to analyze the anti-inflammatory effect of azithromycin (AZM) following experimental keratoplasty in rats. METHODS: Corneal transplants were performed between Fisher donor and Lewis-recipient rats. Recipients were postoperatively treated three times daily with AZM, miglyol, ofloxacin or dexamethasone eye drops. As an additional control, AZM was applied following syngeneic keratoplasty. Furthermore, short-term treatments with AZM for seven days perioperatively or with AZM only three days prior to the transplantation were compared to appropriate controls. All transplants were monitored clinically for opacity, edema, and vascularization. Infiltrating CD45(+), CD4(+), CD8(+), CD25(+), CD161(+) and CD163(+) cells were quantified via immunohistochemistry. RESULTS: AZM significantly promoted corneal graft survival compared with miglyol or ofloxacin treatment. This effect was comparable to topical dexamethasone. No adverse AZM effect was observed. Histology confirmed a significant reduction of infiltrating leukocytes. The short-term application of AZM for three days prior to transplantation or for seven days perioperatively reduced corneal graft rejection significantly compared with the controls. CONCLUSIONS: Along with antibiotic properties, topical AZM has a strong anti-inflammatory effect. Following keratoplasty, this effect is comparable to topical dexamethasone without the risk of steroid-induced adverse effects. Short-term treatment with AZM three days prior to the transplantation was sufficient to promote graft survival in the rat keratoplasty model. We therefore suggest further assessing the anti-inflammatory function of topical AZM following keratoplasty in humans. PMID- 24349337 TI - Transmural ultrasound imaging of thermal lesion and action potential changes in perfused canine cardiac wedge preparations by high intensity focused ultrasound ablation. AB - Intra-procedural imaging is important for guiding cardiac arrhythmia ablation. It is difficult to obtain intra-procedural correlation of thermal lesion formation with action potential (AP) changes in the transmural plane during ablation. This study tested parametric ultrasound imaging for transmural imaging of lesion and AP changes in high intensity focused ultrasound (HIFU) ablation using coronary perfused canine ventricular wedge preparations (n = 13). The preparations were paced from epi/endocardial surfaces and subjected to HIFU application (3.5 MHz, 11 Hz pulse-repetition-frequency, 70% duty cycle, duration 4 s, 3500 W/cm(2)), during which simultaneous optical mapping (1 kframes/s) using di-4-ANEPPS and ultrasound imaging (30 MHz) of the same transmural surface of the wedge were performed. Spatiotemporally correlated AP measurements and ultrasound imaging allowed quantification of the reduction of AP amplitude (APA), shortening of AP duration at 50% repolarization, AP triangulation, decrease of optical AP rise, and change of conduction velocity along tissue depth direction within and surrounding HIFU lesions. The threshold of irreversible change in APA correlating to lesions was determined to be 43 +/- 1% with a receiver operating characteristic (ROC) area under curve (AUC) of 0.96 +/- 0.01 (n = 13). Ultrasound imaging parameters such as integrated backscatter, Rayleigh (alpha) and log normal (sigma) parameters, cumulative extrema of sigma were tested, with the cumulative extrema of sigma performing the best in detecting lesion (ROC AUC 0.89 +/- 0.01, n = 13) and change of APA (ROC AUC 0.79 +/- 0.03, n = 13). In conclusion, characteristic tissue and AP changes in HIFU ablation were identified and spatiotemporally correlated using optical mapping and ultrasound imaging. Parametric ultrasound imaging using cumulative extrema of sigma can detect HIFU lesion and APA reduction. PMID- 24349338 TI - Structural characterization of a therapeutic anti-methamphetamine antibody fragment: oligomerization and binding of active metabolites. AB - Vaccines and monoclonal antibodies (mAb) for treatment of (+)-methamphetamine (METH) abuse are in late stage preclinical and early clinical trial phases, respectively. These immunotherapies work as pharmacokinetic antagonists, sequestering METH and its metabolites away from sites of action in the brain and reduce the rewarding and toxic effects of the drug. A key aspect of these immunotherapy strategies is the understanding of the subtle molecular interactions important for generating antibodies with high affinity and specificity for METH. We previously determined crystal structures of a high affinity anti-METH therapeutic single chain antibody fragment (scFv6H4, K(D) = 10 nM) in complex with METH and the (+) stereoisomer of 3,4 methylenedioxymethamphetamine (MDMA, or "ecstasy"). Here we report the crystal structure of scFv6H4 in homo-trimeric unbound (apo) form (2.60A), as well as monomeric forms in complex with two active metabolites; (+)-amphetamine (AMP, 2.38A) and (+)-4-hydroxy methamphetamine (p-OH-METH, 2.33A). The apo structure forms a trimer in the crystal lattice and it results in the formation of an intermolecular composite beta-sheet with a three-fold symmetry. We were also able to structurally characterize the coordination of the His-tags with Ni(2+). Two of the histidine residues of each C-terminal His-tag interact with Ni(2+) in an octahedral geometry. In the apo state the CDR loops of scFv6H4 form an open conformation of the binding pocket. Upon ligand binding, the CDR loops adopt a closed formation, encasing the drug almost completely. The structural information reported here elucidates key molecular interactions important in anti methamphetamine abuse immunotherapy. PMID- 24349339 TI - Loss of heterozygosity drives clonal diversity of Phytophthora capsici in China. AB - Phytophthora capsici causes significant loss to pepper (Capsicum annum) in China and our goal was to develop single nucleotide polymorphism (SNP) markers for P. capsici and characterize genetic diversity nationwide. Eighteen isolates of P. capsici from locations worldwide were re-sequenced and candidate nuclear and mitochondrial SNPs identified. From 2006 to 2012, 276 isolates of P. capsici were recovered from 136 locations in 27 provinces and genotyped using 45 nuclear and 2 mitochondrial SNPs. There were two main mitochondrial haplotypes and 95 multi locus genotypes (MLGs) identified. Genetic diversity was geographically structured with a high level of genotypic diversity in the north and on Hainan Island in the south, suggesting outcrossing contributes to diversity in these areas. The remaining areas of China are dominated by four clonal lineages that share mitochondrial haplotypes, are almost exclusively the A1 or A2 mating type and appear to exhibit extensive diversity based on loss of heterozygosity (LOH). Analysis of SNPs directly from infected peppers confirmed LOH in field populations. One clonal lineage is dominant throughout much of the country. The overall implications for long-lived genetically diverse clonal lineages amidst a widely dispersed sexual population are discussed. PMID- 24349340 TI - Predictors of acute respiratory distress syndrome in patients with paraquat intoxication. AB - INTRODUCTION: Paraquat poisoning is characterized by acute lung injury, pulmonary fibrosis, respiratory failure, and multi-organ failure, resulting in a high rate of mortality and morbidity. The objectives of this study were to identify predictors of acute respiratory distress syndrome (ARDS) in cases of paraquat poisoning and determine the association between these parameters. MATERIALS AND METHODS: In total, 187 patients were referred for management of intentional paraquat ingestion between 2000 and 2010. Demographic, clinical, and laboratory data were recorded. Sequential organ failure assessment (SOFA) and Acute Kidney Injury Network (AKIN) scores were collected, and predictors of ARDS were analyzed. RESULTS: The overall mortality rate for the entire population was 54% (101/187). Furthermore, the mortality rate was higher in the ARDS patients than in the non-ARDS patients (80% vs. 43.80%, P<0.001). Additionally, the ARDS patients not only had higher AKIN48-h scores (P<0.009), SOFA48-h scores (P<0.001), and time to ARDS/nadir PaO2 (P=0.008) but also suffered from lower nadir PaO2 (P<0.001), nadir AaDO2 (P<0.001), and nadir eGFR (P=0.001) compared to those in the non-ARDS patients. Moreover, pneumomediastinum episodes were more frequent in the ARDS patients than in the non-ARDS patients (P<0.001). A multivariate Cox regression model revealed that blood paraquat concentrations (P<0.001), SOFA48-h scores (P=0.001), and steroid and cyclophosphamide pulse therapies (P=0.024) were significant predictors of ARDS. The cumulative survival rates differed significantly (P<0.001) between patients with SOFA48-h scores <3 and SOFA48-h scores >=3, with a sensitivity of 95.8%, specificity of 58.4%, and overall correctness of 67.6%. Finally, the area under the receiver operating characteristic (AUROC) analysis showed that SOFA48-h scores (P<0.001) had a better discriminatory power than blood paraquat concentrations (P=0.01) for predicting ARDS. CONCLUSIONS: The analytical results indicate that SOFA48-h scores, blood paraquat concentrations, and steroid and cyclophosphamide pulse therapies are significantly associated with ARDS complications after paraquat intoxication. PMID- 24349341 TI - Development of a real-time microchip PCR system for portable plant disease diagnosis. AB - Rapid and accurate detection of plant pathogens in the field is crucial to prevent the proliferation of infected crops. Polymerase chain reaction (PCR) process is the most reliable and accepted method for plant pathogen diagnosis, however current conventional PCR machines are not portable and require additional post-processing steps to detect the amplified DNA (amplicon) of pathogens. Real time PCR can directly quantify the amplicon during the DNA amplification without the need for post processing, thus more suitable for field operations, however still takes time and require large instruments that are costly and not portable. Microchip PCR systems have emerged in the past decade to miniaturize conventional PCR systems and to reduce operation time and cost. Real-time microchip PCR systems have also emerged, but unfortunately all reported portable real-time microchip PCR systems require various auxiliary instruments. Here we present a stand-alone real-time microchip PCR system composed of a PCR reaction chamber microchip with integrated thin-film heater, a compact fluorescence detector to detect amplified DNA, a microcontroller to control the entire thermocycling operation with data acquisition capability, and a battery. The entire system is 25 * 16 * 8 cm(3) in size and 843 g in weight. The disposable microchip requires only 8-ul sample volume and a single PCR run consumes 110 mAh of power. A DNA extraction protocol, notably without the use of liquid nitrogen, chemicals, and other large lab equipment, was developed for field operations. The developed real time microchip PCR system and the DNA extraction protocol were used to successfully detect six different fungal and bacterial plant pathogens with 100% success rate to a detection limit of 5 ng/8 ul sample. PMID- 24349342 TI - Artificial sweeteners in a large Canadian river reflect human consumption in the watershed. AB - Artificial sweeteners have been widely incorporated in human food products for aid in weight loss regimes, dental health protection and dietary control of diabetes. Some of these widely used compounds can pass non-degraded through wastewater treatment systems and are subsequently discharged to groundwater and surface waters. Measurements of artificial sweeteners in rivers used for drinking water production are scarce. In order to determine the riverine concentrations of artificial sweeteners and their usefulness as a tracer of wastewater at the scale of an entire watershed, we analyzed samples from 23 sites along the entire length of the Grand River, a large river in Southern Ontario, Canada, that is impacted by agricultural activities and urban centres. Municipal water from household taps was also sampled from several cities within the Grand River Watershed. Cyclamate, saccharin, sucralose, and acesulfame were found in elevated concentrations despite high rates of biological activity, large daily cycles in dissolved oxygen and shallow river depth. The maximum concentrations that we measured for sucralose (21 ug/L), cyclamate (2.4 ug/L) [corrected], and saccharin (7.2 ug/L) are the highest reported concentrations of these compounds in surface waters to date anywhere in the world. Acesulfame persists at concentrations that are up to several orders of magnitude above the detection limit over a distance of 300 km and it behaves conservatively in the river, recording the wastewater contribution from the cumulative population in the basin. Acesulfame is a reliable wastewater effluent tracer in rivers. Furthermore, it can be used to assess rates of nutrient assimilation, track wastewater plume dilution, separate human and animal waste contributions and determine the relative persistence of emerging contaminants in impacted watersheds where multiple sources confound the usefulness of other tracers. The effects of artificial sweeteners on aquatic biota in rivers and in the downstream Great Lakes are largely unknown. PMID- 24349343 TI - An automated blur detection method for histological whole slide imaging. AB - Whole slide scanners are novel devices that enable high-resolution imaging of an entire histological slide. Furthermore, the imaging is achieved in only a few minutes, which enables image rendering of large-scale studies involving multiple immunohistochemistry biomarkers. Although whole slide imaging has improved considerably, locally poor focusing causes blurred regions of the image. These artifacts may strongly affect the quality of subsequent analyses, making a slide review process mandatory. This tedious and time-consuming task requires the scanner operator to carefully assess the virtual slide and to manually select new focus points. We propose a statistical learning method that provides early image quality feedback and automatically identifies regions of the image that require additional focus points. PMID- 24349344 TI - Enhanced expression of cystathionine beta-synthase and cystathionine gamma-lyase during acute cholecystitis-induced gallbladder inflammation. AB - BACKGROUND: Hydrogen sulfide (H2S) has recently been shown to play an important role in the digestive system, but the role of endogenous H2S produced locally in the gallbladder is unknown. The aim of this study was to investigate whether gallbladder possesses the enzymatic machinery to synthesize H2S, and whether H2S synthesis is changed in gallbladder inflammation during acute acalculous cholecystitis (AC). METHODS: Adult male guinea pigs underwent either a sham operation or common bile duct ligation (CBDL). One, two, or three days after CBDL, the animals were sacrificed separately. Hematoxylin and eosin-stained slides of gallbladder samples were scored for inflammation. H2S production rate in gallbladder tissue from each group was determined; immunohistochemistry and western blotting were used to determine expression levels of the H2S-producing enzymes cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE) in gallbladder. RESULTS: There was a progressive inflammatory response after CBDL. Immunohistochemistry analysis showed that CBS and CSE were expressed in the gallbladder epithelium, muscular layer, and blood vessels and that the expression increased progressively with increasing inflammation following CBDL. The expression of CBS protein as well as the H2S-production rate was significantly increased in the animals that underwent CBDL, compared to those that underwent the sham operation. CONCLUSIONS: Both CBS and CSE are expressed in gallbladder tissues. The expression of these enzymes, as well as H2S synthesis, was up regulated in the context of inflammation during AC. PMID- 24349345 TI - High transcript levels of vitamin D receptor are correlated with higher mRNA expression of human beta defensins and IL-10 in mucosa of HIV-1-exposed seronegative individuals. AB - Vitamin D (VitD) is an endogenous immunomodulator that could protect from HIV-1 infection reducing immune activation and inducing the expression of anti-HIV-1 peptides. To establish a correlation between VitD and natural resistance to HIV-1 infection, a case-control study using blood and mucosa samples of 58 HIV-1 exposed but seronegative (HESN) individuals, 43 HIV-1 seropositives (SPs) and 59 non-exposed healthy controls (HCs) was carried out. The VitD concentration in plasma was determined by ELISA, and mRNA relative units (RU) of VDR, IL-10, TGF beta, TNF-alpha and IL-1beta in peripheral blood mononuclear cells (PBMCs), oral and genital mucosa was quantified by qRT-PCR. mRNA levels of human beta-defensin (HBD) -2 and -3 were previously reported and used for correlations. Significantly higher levels of VitD were found in plasma as well as higher mRNA RU of VDR in PBMCs, and in genital mucosa from HESN compared to HCs. In addition, higher mRNA RU of TNF-alpha, IL-1beta and IL-10, and lower mRNA RU of TGF-beta were found in PBMC from HESNs compared to HCs. We also observed higher IL-10 mRNA RU in genital mucosa of HESNs compared to HCs, and the mRNA levels of TNF-alpha in oral and genital mucosa of SPs were higher compared to HESNs. Furthermore, positive correlations between VDR and IL-10 mRNA RU in PBMCs and genital mucosa of HESNs were found. Finally, HBD-2 and HBD-3 mRNA RU were positively correlated with VDR mRNA expression in oral mucosa from HESNs. These results suggest that high levels of VitD and its receptor are associated with natural resistance to HIV-1 infection. Up-regulation of the anti-inflammatory IL-10, and the induction of anti-HIV-1 defensins in mucosa might be part of the mechanisms involved in this association. However, further studies are required to define causal associations. PMID- 24349347 TI - Health information seeking partially mediated the association between socioeconomic status and self-rated health among Hong Kong Chinese. AB - BACKGROUND: Poor self-rated health (SRH) is socially patterned with health communication inequalities, arguably, serving as one mechanisms. This study investigated the effects of health information seeking on SRH, and its mediation effects on disparities in SRH. METHODS: We conducted probability-based telephone surveys administered over telephone in 2009, 2010/11 and 2012 to monitor health information use among 4553 Chinese adults in Hong Kong. Frequency of information seeking from television, radio, newspapers/magazines and Internet was dichotomised as <1 time/month and >= 1 time/month. Adjusted odds ratios (aOR) for poor SRH were calculated for health information seeking from different sources and socioeconomic status (education and income). Mediation effects of health information seeking on the association between SES and poor SRH was estimated. RESULTS: Poor SRH was associated with lower socioeconomic status (P for trend <0.001), and less than monthly health information seeking from newspapers/magazines (aOR = 1.23, 95% CI 1.07-1.42) and Internet (aOR = 1.13, 95% CI 0.98-1.31). Increasing combined frequency of health information seeking from newspapers/magazines and Internet was linearly associated with better SRH (P for trend <0.01). Health information seeking from these two sources contributed 9.2% and 7.9% of the total mediation effects of education and household income on poor SRH, respectively. CONCLUSIONS: Poor SRH was associated with lower socioeconomic status, and infrequent health information seeking from newspapers/magazines and Internet among Hong Kong Chinese. Disparities in SRH may be partially mediated by health information seeking from newspapers/magazines and Internet. PMID- 24349348 TI - Maternal investment in the swordtail fish Xiphophorus multilineatus: support for the differential allocation hypothesis. AB - The differential allocation hypothesis predicts that reproductive investment will be influenced by mate attractiveness, given a cost to reproduction and a tradeoff between current and future reproduction. We tested the differential allocation hypothesis in the swordtail fish Xiphophorus multilineatus, where males have genetically influenced (patroclinous inheritance) alternative mating tactics (ARTs) maintained by a tradeoff between being more attractive to females (mature later as larger courting males) and a higher probability of reaching sexual maturity (mature earlier as smaller sneaker males). Males in X. multilineatus do not provide parental care or other resources to the offspring. Allelic variation and copy number of the Mc4R gene on the Y-chromosome influences the size differences between males, however there is no variation in this gene on the X chromosome. Therefore, to determine if mothers invested more in offspring of the larger courter males, we examined age to sexual maturity for daughters. We confirmed a tradeoff between number of offspring and female offspring's age to sexual maturity, corroborating that there is a cost to reproduction. In addition, the ART of their fathers significantly influenced the age at which daughters reached sexual maturity, suggesting increased maternal investment to daughters of courter males. The differential allocation we detected was influenced by how long the wild-caught mother had been in the laboratory, as there was a brood order by father genotype (ART) interaction. These results suggest that females can adjust their reproductive investment strategy, and that differential allocation is context specific. We hypothesize that one of two aspects of laboratory conditions produced this shift: increased female condition due to higher quality diet, and/or assessment of future mating opportunities due to isolation from males. PMID- 24349346 TI - Nicotine elicits prolonged calcium signaling along ventral hippocampal axons. AB - Presynaptic nicotinic acetylcholine receptors (nAChRs) have long been implicated in the modulation of CNS circuits. We previously reported that brief exposure to low concentrations of nicotine induced sustained potentiation of glutamatergic transmission at ventral hippocampal (vHipp)-striatal synapses. Here, we exploited nAChR subtype-selective antagonists and agonists and alpha7*nAChR knockout mutant mice (alpha7-/-) to elucidate the signaling mechanisms underlying nAChR-mediated modulation of synaptic transmission. Using a combination of micro-slices culture from WT and alpha7-/-mice, calcium imaging, and immuno-histochemical techniques, we found that nicotine elicits localized and oscillatory increases in intracellular Ca(2+) along vHipp axons that persists for up to 30 minutes. The sustained phase of the nicotine-induced Ca(2+) response was blocked by alpha-BgTx but not by DHbetaE and was mimicked by alpha7*nAChR agonists but not by non alpha7*nAChR agonists. In vHipp slices from alpha7-/- mice, nicotine elicited only transient increases of axonal Ca(2+) signals and did not activate CaMKII. The sustained phase of the nicotine-induced Ca(2+) response required localized activation of CaMKII, phospholipase C, and IP3 receptor mediated Ca(2+)-induced Ca(2+) release (CICR). In conclusion, activation of presynaptic nAChRs by nicotine elicits Ca(2+) influx into the presynaptic axons, the sustained phase of the nicotine-induced Ca(2+) response requires that axonal alpha7*nAChR activate a downstream signaling network in the vHipp axons. PMID- 24349349 TI - Erythrina mulungu alkaloids are potent inhibitors of neuronal nicotinic receptor currents in mammalian cells. AB - Crude extracts and three isolated alkaloids from Erythrina mulungu plants have shown anxiolytic effects in different animal models. We investigated whether these alkaloids could affect nicotinic acetylcholine receptors and if they are selective for different central nervous system (CNS) subtypes. Screening experiments were performed using a single concentration of the alkaloid co applied with acetylcholine in whole cell patch-clamp recordings in three different cell models: (i) PC12 cells natively expressing alpha3* nicotinic acetylcholine receptors; (ii) cultured hippocampal neurons natively expressing alpha7* nicotinic acetylcholine receptors; and (iii) HEK 293 cells heterologoulsy expressing alpha4beta2 nicotinic acetylcholine receptors. For all three receptors, the percent inhibition of acetylcholine-activated currents by (+)-11a hydroxyerysotrine was the lowest, whereas (+)-erythravine and (+)-11a hydroxyerythravine inhibited the currents to a greater extent. For the latter two substances, we obtained concentration-response curves with a pre-application protocol for the alpha7* and alpha4beta2 nicotinic acetylcholine receptors. The IC50 obtained with (+)-erythravine and (+)-11a-hydroxyerythravine were 6 uM and 5 uM for the alpha7* receptors, and 13 nM and 4 nM for the alpha4beta2 receptors, respectively. Our data suggest that these Erythrina alkaloids may exert their behavioral effects through inhibition of CNS nicotinic acetylcholine receptors, particularly the alpha4beta2 subtype. PMID- 24349350 TI - Propofol protects against focal cerebral ischemia via inhibition of microglia mediated proinflammatory cytokines in a rat model of experimental stroke. AB - Ischemic stroke induces microglial activation and release of proinflammatory cytokines, contributing to the expansion of brain injury and poor clinical outcome. Propofol has been shown to ameliorate neuronal injury in a number of experimental studies, but the precise mechanisms involved in its neuroprotective effects remain unclear. We tested the hypothesis that propofol confers neuroprotection against focal ischemia by inhibiting microglia-mediated inflammatory response in a rat model of ischemic stroke. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h followed by 24 h of reperfusion. Propofol (50 mg/kg/h) or vehicle was infused intravenously at the onset of reperfusion for 30 minutes. In vehicle-treated rats, MCAO resulted in significant cerebral infarction, higher neurological deficit scores and decreased time on the rotarod compared with sham-operated rats. Propofol treatment reduced infarct volume and improved the neurological functions. In addition, molecular studies demonstrated that mRNA expression of microglial marker Cd68 and Emr1 was significantly increased, and mRNA and protein expressions of proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta and interleukin-6 were augmented in the peri-infarct cortical regions of vehicle-treated rats 24 h after MCAO. Immunohistochemical study revealed that number of total microglia and proportion of activated microglia in the peri-infarct cortical regions were markedly elevated. All of these findings were ameliorated in propofol-treated rats. Furthermore, vehicle-treated rats had higher plasma levels of interleukin-6 and C-reactive protein 24 h after MCAO, which were decreased after treatment with propofol. These results suggest that propofol protects against focal cerebral ischemia via inhibition of microglia-mediated proinflammatory cytokines. Propofol may be a promising therapeutic agent for the treatment of ischemic stroke and other neurodegenerative diseases associated with microglial activation. PMID- 24349351 TI - Bone mesenchymal stem cells contributed to the neointimal formation after arterial injury. AB - OBJECTIVES: Recent findings suggest that in response to repair-to-injury bone marrow mesenchymal stem cells (BMSCs) participate in the process of angiogenesis. It is unclear what role BMSCs play in the structure of the vessel wall. In present study, we aimed to determine whether BMSCs had the capacity of endothelial cells (ECs). METHODS: BMSCs were separated and cultured. FACS and RT PCR analysis confirmed the gene expression phenotype. The capacity of migration and adhesion and the ultrastructure of BMSCs were examined. The effect of BMSCs transplantation on the vascular repair was investigated in a murine carotid artery-injured model. RESULTS: BMSCs could express some markers and form the tube like structure. The migration and adhesion capacity of BMSCs increased significantly after stimulated. In addition, BMSCs had the intact cell junction. In vivo the local transfer of BMSCs differentiated into neo-endothelial cells in the injury model for carotid artery and contributed to the vascular remodeling. CONCLUSION: These results showed that BMSCs could contribute to neointimal formation for vascular lesion and might be associated with the differentiation into ECs, which indicated the important therapeutic implications for vascular diseases. PMID- 24349352 TI - NFBD1/MDC1 is phosphorylated by PLK1 and controls G2/M transition through the regulation of a TOPOIIalpha-mediated decatenation checkpoint. AB - Although it has been established that nuclear factor with BRCT domain 1/ mediator of the DNA damage checkpoint protein 1 (NFBD1/MDC1) is closely involved in DNA damage response, its possible contribution to the regulation of cell- cycle progression is unclear. In the present study, we have found for the first time that NFBD1 is phosphorylated by polo-like kinase 1 (PLK1) and has an important role in G2/M transition. Both NFBD1 and PLK1 are co-expressed in cellular nuclei throughout G2/M transition, and binding assays demonstrated direct interaction between NFBD1 and PLK1. Indeed, in vitro kinase reactions revealed that the PST domain of NFBD1 contains a potential amino acid sequence (845-DVTGEE-850) targeted by PLK1. Furthermore, enforced expression of GFP-PST but not GFP PST(T847A) where threonine at 847 was substituted by alanine inhibited the phosphorylation levels of histone H3, suggesting a defect of M phase entry. Because PLK1 has been implicated in promoting the G2/M transition, we reasoned that overexpressed PST might serve as a pseudosubstrate for PLK1 and thus interfere with phosphorylation of endogenous PLK1 substrates. Interestingly, siRNA-mediated knockdown of NFBD1 resulted in early M phase entry and accelerated M phase progression, raising the possibility that NFBD1 is a PLK1 substrate for regulating the G2/M transition. Moreover, the constitutive active form of PLK1(T210D) overcame the ICRF-193-induced decatenation checkpoint and inhibited the interaction between NFBD1 and topoisomerase IIalpha, but kinase-deficient PLK1 did not. Based on these observations, we propose that PLK1-mediated phosphorylation of NFBD1 is involved in the regulation of G2/M transition by recovering a decatenation checkpoint. PMID- 24349353 TI - A systematic review and meta-analysis of antibiotic-impregnated bone cement use in primary total hip or knee arthroplasty. AB - BACKGROUND: Antibiotic-impregnated bone cement (AIBC) has been widely used for the treatment of infected revision arthroplasty, but its routine use in primary total joint arthroplasty (TJA) remains considerably controversial. With this meta analysis of published randomized controlled trials, we intended to assess the antimicrobial efficacy and safety of AIBC for its prophylactic use in primary TJA. METHODS: A literature search was performed in MEDLINE, Embase, CBMdisc and the Cochrane Library until June, 2013. The studies were divided into two sub groups according to the type of the control group. Outcomes of interest included postoperative infection rates, radiographic outcomes and clinical joint score. Study quality was evaluated using the Jadad scale (five points). RESULTS: In total, eight studies were included, with a sample size of 6,381 arthroplasties. The overall pooled data demonstrated that, compared with the control (plain cement or systemic antibiotic), AIBC did not reveal an advantage in decreasing the rate of superficial infection (relative risk [RR] = 1.47; 95% CI, 1.13-1.91; P=0.004), while there were significant differences in deep infection rate between the AIBC and control group (RR = 0.41; 95% CI, 0.17-0.97; P=0.04). For the analysis of gentamicin and cefuroxime subgroups, the gentamicin was superior to the cefuroxime in reducing deep infection rate (P=0.0005 versus P= 0.10). However, no significant differences were found in their radiographic outcomes and clinical joint score. CONCLUSION: This meta-analysis had proven that the prophylactic use of AIBC could lower the deep infection rate in primary TJA, while AIBC did not show an improvement in reducing the superficial infection rate compared with the control. More sufficiently powered studies would be required to further evaluate the efficacy and safety of AIBC for primary TJA. PMID- 24349354 TI - Cardiac troponin I in non- acute coronary syndrome patients with chronic kidney disease. AB - OBJECTIVE: The aim of this study was to assess the results of troponin I (cTnI) in non- acute Coronary Syndrome (ACS) patients with chronic kidney disease (CKD). We also examined the risk factors for elevated cTnI in non-ACS patients with CKD and whether stage 5 CKD modifies the associations of elevated cTnI and the risk factors in non-ACS patients with CKD. METHODS: A retrospective study was performed. Logistic regression models were used. RESULTS: 293 non-ACS patients with CKD were included in the current study. 43.34% non-ACS patients with CKD have an elevated cTnI level and 5.12% have an elevated cTnT level in MI range. In CKD patients without ACS and heart failure, only 26.03% (38/146) patients have an elevated cTnT level. In adjusted analyses, age, diastolic blood pressure and congestive heart failure is associated with an elevated cTnI level in non-ACS patients with CKD. Congestive heart failure is associated with an elevated cTnI level in non-ACS patients with CKD (OR 2.30, 95% CI 1.08,4.88, P=0.03). Stage 5 CKD does not modify the association of congestive heart failure and an elevated cTnI level. CONCLUSION: 43.34% non-ACS patients with CKD and 26.03% CKD patients without ACS and congestive heart failure have an elevated cTnI level. Congestive heart failure is associated with an elevated cTnI level in non-ACS patients with CKD. Stage 5 CKD does not modify the association of congestive heart failure and an elevated cTnI level. PMID- 24349355 TI - Serum protein signatures differentiating autoimmune pancreatitis versus pancreatic cancer. AB - Autoimmune pancreatitis (AIP) is defined by characteristic lymphoplasmacytic infiltrate, ductal strictures and a pancreatic enlargement or mass that can mimic pancreatic cancer (PaCa). The distinction between this benign disease and pancreatic cancer can be challenging. However, an accurate diagnosis may pre-empt the misdiagnosis of cancer, allowing the appropriate medical treatment of AIP and, consequently, decreasing the number of unnecessary pancreatic resections. Mass spectrometry (MS) and two-dimensional differential gel electrophoresis (2D DIGE) have been applied to analyse serum protein alterations associated with AIP and PaCa, and to identify protein signatures indicative of the diseases. Patients' sera were immunodepleted from the 20 most prominent serum proteins prior to further 2D-DIGE and image analysis. The identity of the most discriminatory proteins detected, was performed by MS and ELISAs were applied to confirm their expression. Serum profiling data analysis with 2D-DIGE revealed 39 protein peaks able to discriminate between AIP and PaCa. Proteins were purified and further analysed by MALDI-TOF-MS. Peptide mass fingerprinting led to identification of eleven proteins. Among them apolipoprotein A-I, apolipoprotein A-II, transthyretin, and tetranectin were identified and found as 3.0-, 3.5-, 2-, and 1.6-fold decreased in PaCa sera, respectively, whereas haptoglobin and apolipoprotein E were found to be 3.8- and 1.6-fold elevated in PaCa sera. With the exception of haptoglobin the ELISA results of the identified proteins confirmed the 2D-DIGE image analysis characteristics. Integration of the identified serum proteins as AIP markers may have considerable potential to provide additional information for the diagnosis of AIP to choose the appropriate treatment. PMID- 24349356 TI - Disparities in HIV screening among pregnant women--El Salvador, 2011. AB - OBJECTIVES: To provide an accurate estimate of antenatal HIV screening and its determinants among pregnant women in El Salvador and help local authorities make informed decisions for targeted interventions around mother-to-child transmission (MTCT). METHODS: A total sample of 4,730 women aged 15-49 years were interviewed from a random sample of 3,625 households. We collected data on antenatal care services, including HIV screening, during last pregnancy through a pre established questionnaire. We used a backward elimination multivariate logistic regression model to examine the association between HIV screening and sociodemographic and health care-related factors. RESULTS: A total of 2,929 women were included in this analysis. About 98% of participants reported receiving antenatal care, but only 83% of these reported being screened for HIV. Screening was lower in geographic areas with higher HIV incidence and ranged from 69.1% among women who were not seen by a physician during antenatal care, to 93.7% among those who attended or completed college. Odds for screening varied also by age, employment status, household economic expenditure, possession of health care coverage, health care settings, and number of antenatal care visits. CONCLUSIONS: We found disparities in HIV screening during antenatal care at the environmental, social, demographic, and structural levels despite a high uptake of antenatal care in El Salvador. Our findings should urge health authorities to tailor and enhance current strategies implemented to eliminate MTCT and reduce inequities and HIV morbidity among women in El Salvador. PMID- 24349357 TI - The Wobbler mouse model of amyotrophic lateral sclerosis (ALS) displays hippocampal hyperexcitability, and reduced number of interneurons, but no presynaptic vesicle release impairments. AB - Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. It is a fatal degenerative disease, best recognized for its debilitating neuromuscular effects. ALS however also induces cognitive impairments in as many as 50% of affected individuals. Moreover, many ALS patients demonstrate cortical hyperexcitability, which has been shown to precede the onset of clinical symptoms. The wobbler mouse is a model of ALS, and like ALS patients the wobbler mouse displays cortical hyperexcitability. Here we investigated if the neocortical aberrations of the wobbler mouse also occur in the hippocampus. Consequently, we performed extracellular field excitatory postsynaptic potential recordings in the CA1 region of the hippocampus on acute brain slices from symptomatic (P45-P60) and presymptomatic (P17-P21) wobbler mice. Significant increased excitation of hippocampal synapses was revealed by leftward shifted input/output-curves in both symptomatic and presymptomatic wobbler mice, and substantiated by population spike occurrence analyses, demonstrating that the increased synaptic excitation precedes the onset of visible phenotypic symptoms in the mouse. Synaptic facilitation tested by paired-pulse facilitation and trains in wobbler and control mice showed no differences, suggesting the absence of presynaptic defects. Immunohistochemical staining revealed that symptomatic wobbler mice have a lower number of parvalbumin positive interneurons when compared to controls and presymptomatic mice. This study reveals that the wobbler mouse model of ALS exhibits hippocampal hyperexcitability. We suggest that the hyperexcitability could be caused by increased excitatory synaptic transmission and a concomitant reduced inhibition due to a decreased number of parvalbumin positive interneurons. Thus we substantiate that wobbler brain impairments are not confined to the motor cortex, but extend to the hippocampus. Importantly, we have revealed more details of the early pathophysiology in asymptomatic animals, and studies like the present may facilitate the development of novel treatment strategies for earlier intervention in ALS patients in the future. PMID- 24349358 TI - Male infertility workup needs additional testing of expressed prostatic secretion and/or post-massage urine. AB - The male factor accounts for almost 50% of infertility cases. Inflammation may reduce semen quality via several pathways, including oxidative stress (OxS). As male infertility routinely is assessed using semen analysis only, the possible presence of non-leukocytospermic asymptomatic inflammatory prostatitis may be overlooked. We compared local and systemic OxS levels in male partners of infertile couples with different inflammation patterns in their genital tract and/or oligospermia. Subjects (n=143) were grouped according to inflammation in their semen, expressed prostatic secretion (EPS), and/or post-massage urine (post M). Systemic (8-isoprostanes in urine) and local (diene conjugates and total antioxidant capacity in seminal plasma) OxS was measured The levels of OxS markers were significantly elevated in both severe inflammation groups- leukocytospermic men and subjects whose inflammation was limited only to EPS and/or post-M. Comparison between oligospermic and non-oligospermic men with genital tract inflammation, and oligozoospermic men with or without inflammation in the genital tract indicated that inflammation but not oligospermia status had significant impact on the measured OxS markers. Hence, a high leukocyte count in prostate-specific materials (EPS, post-M), even in absence of clear leukocytopsermia, is an important source of local and systemic OxS that may be associated with male infertility and affect general health. We suggest including the tests for detection of inflammation of the prostate into the workup of infertile men as was suggested in the WHO 1993 recommendation. PMID- 24349359 TI - Is obesity a risk factor for vaccine non-responsiveness? AB - Understanding the link between vaccine immunogenicity and efficacy is currently a major focus in HIV research. Consequently, recent developments in the HIV-1 vaccine field have led to a closer look at immune responses to known efficacious vaccines. We undertook a study to explore clinical predictors of vaccine efficacy following recombinant hepatitis B (rHBV) vaccination in a cohort of HIV uninfected, hepatitis B virus naive women living in a peri-urban setting in Cape Town. Our aim was to define host biological risk factors associated with lack of vaccine uptake. We found a significant association (p=0.009) between body mass index (BMI) and lack of vaccine-specific IgG titre (<10 mIU/mL). Obese individuals (BMI >= 30 kg/m(2)) were significantly more likely to be non responders following 2 rHBV vaccine doses (Adjusted Odds Ratio of 8.75; p=0.043). There was no observed association between vaccine responses and age, method of contraception or time from vaccination to antibody measurement. These data suggest that obesity-associated factors interfere with vaccine immunogenicity and possible efficacy. PMID- 24349360 TI - Assessment of health status in patients with newly diagnosed chronic obstructive pulmonary disease. AB - SUBJECT: Chronic obstructive pulmonary disease (COPD) is a common disease worldwide. This study aimed to investigate the health status of patients with newly diagnosed COPD. METHODS: A total of 45 healthy controls and 218 patients with newly diagnosed COPD were recruited. Pulmonary function test (PFT) values, COPD assessment test (CAT) scores, exacerbation history, and demographics were recorded. RESULTS: Forced expiratory volume in 1 s percent (FEV1%) predicted was significantly decreased and the CAT score was significantly increased in patients with COPD compared with healthy controls (P <0.001). Among the COPD patients, the most commonly reported respiratory symptoms were cough (86.7%), sputum (80.3%), and dyspnea (45%). A total of 86.2% patients were in the moderate or severe stage (spirometric classification) of COPD, and 71.5% were in Group C or Group D (combined assessment). A total of 33.9% of the patients had 2 or more exacerbations in the previous year. Nearly half of the patients (45.4%) had a high CAT score of >= 10. Patients with a history of more exacerbations had a higher CAT score. CONCLUSIONS: Most COPD patients were symptomatic and appeared to have moderate to severe airflow limitation or a high risk of exacerbation before definitely being diagnosed with COPD using the PFT. PMID- 24349361 TI - Association between the STK15 F31I polymorphism and cancer susceptibility: a meta analysis involving 43,626 subjects. AB - The association between the Serine/threonine kinase 15 (STK15) F31I polymorphism (rs2273535) and cancer susceptibility remains controversial. To further investigate this potential relationship, we conducted a comprehensive meta analysis of 27 published studies involving a total of 19,267 multiple cancer cases and 24,359 controls. Our results indicate statistical evidence of an association between the STK15 F31I polymorphism and the increased risk of overall cancer in four genetic models: AA vs. TA+TT, AA vs. TT, AA vs. TA, and A vs. T. In a stratified analysis by cancer type, there was an increased risk of breast cancer in four genetic models: AA vs. TA+TT, AA vs. TT, AA vs. TA, and A vs. T, as well as esophageal cancer in two genetic models: AA vs. TA+TT and AA vs. TA. In a stratified analysis by ethnicity, there was a significant increase in cancer risk among Asians, but not Caucasians, in four genetic models: AA vs. TA+TT, AA vs. TT, AA vs. TA and A vs. T. In addition, a stratified analysis by ethnicity in the breast cancer subgroup revealed a significant increase in cancer risk among Asians in two genetic models: AA vs. TA+TT and AA vs. TT, as well as among Caucasians in one genetic model: AA vs. TA. In summary, this meta-analysis demonstrates that the STK15 F31I polymorphism may be a risk factor for cancer. PMID- 24349362 TI - Age-related modifications to the magnitude and periodicity of neuromuscular noise. AB - BACKGROUND: Evaluation of task related outcomes within geriatric and fall-prone populations is essential not only for identification of neuromuscular deficits, but also for effective implementation of fall prevention strategies. As most tasks and activities of daily living are performed at submaximal force levels, restoration of muscle strength often does not produce the expected benefit in functional capacity. However, it is known that muscular control plays a key role in the performance of functional tasks, but it remains unclear to what degree muscular control and the associated neuromuscular noise (NmN) is age-related, particularly in the lower-extremities. OBJECTIVES: The aim of this study was to determine the effects of age and fall-pathology on the magnitude as well as the frequency of NmN during lower extremity force production. METHODS: Sixteen young healthy adults, as well as seventy elderly women (36 healthy, 34 elderly fallers), performed force production tests at moderate levels (15% of maximum voluntary isometric contractions). RESULTS: Elderly fallers exhibited the highest magnitude of NmN, while the highest frequency components of NmN tended to occur in the healthy elderly. Young subjects exhibited significantly more power in the low frequency ranges than either of the elderly groups, and had the lowest levels of NmN. CONCLUSION: These data suggest increased degeneration of muscular control through greater NmN in elderly fallers compared to healthy elderly or young subjects. This could possibly be associated with muscle atrophy and lower levels of motor unit synchronisation. PMID- 24349363 TI - S-1-based chemotherapy versus capecitabine-based chemotherapy as first-line treatment for advanced gastric carcinoma: a meta-analysis. AB - BACKGROUND: Although both oral fluoropyrimidines were reported effective and safe, doubts exist about whether S-1 or capecitabine is more advantageous in advanced gastric carcinoma (AGC). Herein, we performed a meta-analysis to comprehensively compare the efficacy and safety of S-1-based chemotherapy versus capecitabine-based chemotherapy as first-line treatment for AGC. METHODS: PubMed/Medline, EmBase, Cochrane library, and China National Knowledge Infrastructure databases were searched for articles comparing S-1-based chemotherapy to capecitabine-based chemotherapy for AGC. Primary outcomes were overall response rate (ORR), time to progression (TTP), overall survival (OS), progression-free probability, and survival probability. Secondary outcomes were toxicities. Fixed-effects model were used and all the results were confirmed by random-effects model. RESULTS: Five randomized controlled trials and five cohort studies with 821 patients were included. We found equivalent ORR (38.3% vs. 39.1%, odds ratio [OR] 0.92, 95% confidence interval [CI] 0.69-1.24, P = 0.59), TTP (harzad ratio [HR] 0.98, 95% CI 0.82-1.16, P = 0.79), OS (HR 0.99, 95% CI 0.87-1.13, P = 0.91), progression-free probability (3-month OR 1.02, 95% CI 0.62 1.68, P = 0.94; 6-month OR 1.34, 95% CI 0.88-2.04, P = 0.18) and survival probability (0.5-year OR 0.90, 95% CI 0.61-1.31, P =0.57; 1-year OR 0.97, 95% CI 0.70- 1.33, P = 0.84; 2-year OR 1.15, 95% CI 0.61-2.17, P = 0.66). Equivalent grade 3 to 4 hematological and non-hematological toxicities were found except hand-foot syndrome was less prominent in S-1-based chemotherapy (0.3% vs. 5.9%, OR 0.19, 95% CI 0.06-0.56, P = 0.003). There're no significant heterogeneity and publication bias. Cumulative analysis found stable time-dependent trend. Consistent results stratified by study design, age, regimen, cycle, country were observed. CONCLUSION: S-1-based chemotherapy was associated with non-inferior antitumor efficacy and better safety profile, compared with capecitabine-based therapy. We recommended S-1 and capecitabine can be used interchangeably for AGC, at least in Asia. PMID- 24349364 TI - Impacts of CA9 gene polymorphisms on urothelial cell carcinoma susceptibility and clinicopathologic characteristics in Taiwan. AB - BACKGROUND: Carbonic anhydrase 9 (CA9) is reportedly overexpressed in several types of carcinomas and is generally considered a marker of malignancy. The current study explored the effect of CA9 gene polymorphisms on the susceptibility of developing urothelial cell carcinoma (UCC) and the clinicopathological status. METHODOLOGY AND PRINCIPAL FINDINGS: A total of 442 participants, including 221 healthy people and 221 patients with UCC, were recruited for this study. Four single-nucleotide polymorphisms (SNPs) of the CA9 gene were assessed by a real time PCR with the TaqMan assay. After adjusting for other co-variants, the individuals carrying at least one A allele at CA9 rs1048638 had a 2.303-fold risk of developing UCC than did wild-type (CC) carriers. Furthermore, UCC patients who carried at least one A allele at rs1048638 had a higher invasive stage risk (p< 0.05) than did patients carrying the wild-type allele. Moreover, among the UCC patients with smoker, people with at least one A allele of CA9 polymorphisms (rs1048638) had a 4.75-fold (95% CI = 1.204-18.746) increased risk of invasive cancer. CONCLUSION: The rs1048638 polymorphic genotypes of CA9 might contribute to the prediction of susceptibility to and pathological development of UCC. This is the first study to provide insight into risk factors associated with CA9 variants in carcinogenesis of UCC in Taiwan. PMID- 24349365 TI - Symptom burden of patients with dry eye disease: a four domain analysis. AB - PURPOSE: To determine which sensory (symptom persistence and intensity) and reactive (activity and affective interference) domains of symptom analysis are essential for assessing symptom burden in dry eye disease (DED) patients. METHODS: A symptom domain tool was developed to investigate all four symptom domains in DED. In a cross-sectional pilot study, we administered the symptom burden tool and the Ocular Surface Disease Index (OSDI) questionnaire to 48 DED patients. Total and domain scores from the symptom burden tool and the OSDI were normalized to achieve comparability. Spearman correlation coefficients were calculated to measure the relationship between domains and subscales. Agreement between the symptom burden tool and OSDI was assessed by Bland-Altman plot. Assigned treatments were compared by symptom burden to determine whether treatment aggressiveness is linked to symptom intensity. RESULTS: There was high agreement between the symptom burden tool and the OSDI. Symptom persistence had a stronger correlation with affective interference (r = 0.62 for the symptom burden tool and r = 0.73 for the OSDI) than activity interference (r = 0.58 for the symptom burden tool and r = 0.60 for the OSDI). Symptom intensity correlated weakly with affective interference (r = 0.38) and activity interference (r = 0.37) in the symptom burden tool (OSDI does not have a subscale for intensity). In patients with equal persistence of symptoms, those having high symptom intensity were receiving more aggressive treatment (66.7%) than those with lower symptom intensity (33.3%). CONCLUSIONS: Persistence of symptoms correlates better with affective interference than activity interference. Intensity of symptoms may be important for treatment decisions. PMID- 24349366 TI - Immediate postmastectomy breast reconstruction showed limited advantage in patient survival after stratifying by family income. AB - BACKGROUND: Postmastectomy breast reconstruction is widely used in breast cancer patients for its aesthetic effect. Although several studies have casted suspicion upon the oncological safety of immediate breast reconstruction after mastectomy, the potential impact of different reconstruction methods on patient survival remains unclear. PATIENTS AND METHODS: We identified 35,126 female patients diagnosed with breast cancer from January 1, 1998 to December 31, 2002 in the Surveillance, Epidemiology, and End Results database. Breast cancer-specific survival (BCSS) and overall survival (OS) were compared among patients who underwent mastectomy with or without immediate breast reconstruction (autologous reconstruction or implant reconstruction) using Cox proportional hazard regression models. RESULTS: In multivariate analysis unadjusted for family income, patients undergoing immediate postmastectomy reconstruction exhibited improved BCSS [POOLED reconstruction (any types of reconstruction): hazard ratio (HR) = 0.87, 95% confidence interval (CI) 0.80-0.95, P = 0.001] and OS (pooled reconstruction: HR = 0.70, 95% CI 0.65-0.75, P<0.001) compared to patients who underwent mastectomy alone. However, after stratifying by family income, patients receiving reconstruction showed limited advantage in BCSS and OS compared with those undergoing mastectomy alone. When comparing between the two reconstruction methods, no significant differences were observed in either BCSS (implant versus autologous reconstruction: HR = 1.11, 95%CI 0.90-1.35, P = 0.330) or OS (implant versus autologous reconstruction: HR = 1.07, 95% 0.90-1.28, P = 0.424). CONCLUSIONS: Compared to mastectomy alone, immediate postmastectomy reconstruction had limited advantage in survival after adjusting for confounding factor of family income. Our findings, if validated in other large databases, may help to illustrate the actual effect of immediate postmastectomy reconstruction on patient survival. PMID- 24349367 TI - Development of a high-throughput three-dimensional invasion assay for anti-cancer drug discovery. AB - The lack of three-dimensional (3-D) high-throughput (HT) screening assays designed to identify anti-cancer invasion drugs is a major hurdle in reducing cancer-related mortality, with the key challenge being assay standardization. Presented is the development of a novel 3-D invasion assay with HT potential that involves surrounding cell-collagen spheres within collagen to create a 3-D environment through which cells can invade. Standardization was achieved by designing a tooled 96-well plate to create a precisely designated location for the cell-collagen spheres and by using dialdehyde dextran to inhibit collagen contraction, maintaining uniform size and shape. This permits automated readout for determination of the effect of inhibitory compounds on cancer cell invasion. Sensitivity was demonstrated by the ability to distinguish varying levels of invasiveness of cancer cell lines, and robustness was determined by calculating the Z-factor. A Z-factor of 0.65 was obtained by comparing the effects of DMSO and anti-beta1-integrin antibody, an inhibitory reagent, on the invasion of Du145 cancer cells, suggesting this novel assay is suitable for large scale drug discovery. As proof of principle, the NCI Diversity Compound Library was screened against human invasive cancer cells. Nine compounds exhibiting high potency and low toxicity were identified, including DX-52-1, a compound previously reported to inhibit cell migration, a critical determinant of cancer invasion. The results indicate that this innovative HT platform is a simple, precise, and easy to replicate 3-D invasion assay for anti-cancer drug discovery. PMID- 24349368 TI - The mechanism of heterogeneous beta-lactam resistance in MRSA: key role of the stringent stress response. AB - All methicillin resistant S. aureus (MRSA) strains carry an acquired genetic determinant--mecA or mecC--which encode for a low affinity penicillin binding protein -PBP2A or PBP2A'--that can continue the catalysis of peptidoglycan transpeptidation in the presence of high concentrations of beta-lactam antibiotics which would inhibit the native PBPs normally involved with the synthesis of staphylococcal cell wall peptidoglycan. In contrast to this common genetic and biochemical mechanism carried by all MRSA strains, the level of beta lactam antibiotic resistance shows a very wide strain to strain variation, the mechanism of which has remained poorly understood. The overwhelming majority of MRSA strains produce a unique--heterogeneous--phenotype in which the great majority of the bacteria exhibit very poor resistance often close to the MIC value of susceptible S. aureus strains. However, cultures of such heterogeneously resistant MRSA strains also contain subpopulations of bacteria with extremely high beta-lactam MIC values and the resistance level and frequency of the highly resistant cells in such strain is a characteristic of the particular MRSA clone. In the study described in this communication, we used a variety of experimental models to understand the mechanism of heterogeneous beta-lactam resistance. Methicillin-susceptible S. aureus (MSSA) that received the mecA determinant in the laboratory either on a plasmid or in the form of a chromosomal SCCmec cassette, generated heterogeneously resistant cultures and the highly resistant subpopulations that emerged in these models had increased levels of PBP2A and were composed of bacteria in which the stringent stress response was induced. Each of the major heterogeneously resistant clones of MRSA clinical isolates could be converted to express high level and homogeneous resistance if the growth medium contained an inducer of the stringent stress response. PMID- 24349369 TI - Effects of remifemin treatment on bone integrity and remodeling in rats with ovariectomy-induced osteoporosis. AB - This study aims to evaluate the effects of Remifemin (isopropanolic extract of Cimicifuga Racemosa) on postmenopausal osteoporosis. 120 female Sprague-Dawley rats were randomly assigned to four groups: sham surgery with vehicle, ovariectomy with vehicle, ovariectomy with estradiol valerate, or ovariectomy with Remifemin. Daily oral administrations of the vehicle, estradiol valerate, or Remifemin began 2 weeks after surgery and lasted to 4, 8, or 12 weeks. Ten rats in each group were sacrificed at each timestep with assessment of bone mineral density, trabecular bone structure, and biomechanical parameters of the femur and lumbar vertebra. Bone turnover markers were evaluated 12 weeks after surgery. Both drugs prevented bone density loss in the distal end of the femur and preserved the trabecular bone structure in both the lumbar vertebra and distal end of the femur following ovariectomy. Both drugs protected bone stiffness at the tested regions and reduced bone reabsorption in ovariectomized rats. The preventive effects of Remifemin against bone-loss can rival those of estradiol valerate if treatment duration is adequately extended. In conclusion, Remifemin may demonstrate equivalent effects to estradiol valerate in terms of preventing postmenopausal osteoporosis. PMID- 24349370 TI - Global analysis of transcriptome responses and gene expression profiles to cold stress of Jatropha curcas L. AB - BACKGROUND: Jatropha curcas L., also called the Physic nut, is an oil-rich shrub with multiple uses, including biodiesel production, and is currently exploited as a renewable energy resource in many countries. Nevertheless, because of its origin from the tropical MidAmerican zone, J. curcas confers an inherent but undesirable characteristic (low cold resistance) that may seriously restrict its large-scale popularization. This adaptive flaw can be genetically improved by elucidating the mechanisms underlying plant tolerance to cold temperatures. The newly developed Illumina HiseqTM 2000 RNA-seq and Digital Gene Expression (DGE) are deep high-throughput approaches for gene expression analysis at the transcriptome level, using which we carefully investigated the gene expression profiles in response to cold stress to gain insight into the molecular mechanisms of cold response in J. curcas. RESULTS: In total, 45,251 unigenes were obtained by assembly of clean data generated by RNA-seq analysis of the J. curcas transcriptome. A total of 33,363 and 912 complete or partial coding sequences (CDSs) were determined by protein database alignments and ESTScan prediction, respectively. Among these unigenes, more than 41.52% were involved in approximately 128 known metabolic or signaling pathways, and 4,185 were possibly associated with cold resistance. DGE analysis was used to assess the changes in gene expression when exposed to cold condition (12 degrees C) for 12, 24, and 48 h. The results showed that 3,178 genes were significantly upregulated and 1,244 were downregulated under cold stress. These genes were then functionally annotated based on the transcriptome data from RNA-seq analysis. CONCLUSIONS: This study provides a global view of transcriptome response and gene expression profiling of J. curcas in response to cold stress. The results can help improve our current understanding of the mechanisms underlying plant cold resistance and favor the screening of crucial genes for genetically enhancing cold resistance in J. curcas. PMID- 24349371 TI - Germ-line recombination activity of the widely used hGFAP-Cre and nestin-Cre transgenes. AB - Herein we demonstrate with PCR, immunodetection and reporter gene approaches that the widely used human Glial Fibrillary Acidic Protein (hGFAP)-Cre transgene exhibits spontaneous germ-line recombination activity in leading to deletion in brain, heart and tail tissue with high frequency. The ectopic activity of hGFAP Cre requires a rigorous control. We likewise observed that a second widely used nestin-Cre transgene shows germ-line deletion. Here we describe procedures to identify mice with germ-line recombination mediated by the hGFAP-Cre and nestin Cre transgenes. Such control is essential to avoid pleiotropic effects due to germ-line deletion of loxP-flanked target genes and to maintain the CNS restricted deletion status in transgenic mouse colonies. PMID- 24349372 TI - Effects of vitamin A on in vitro maturation of pre-pubertal mouse spermatogonial stem cells. AB - Testicular tissue cryopreservation is the only potential option for fertility preservation in pre-pubertal boys exposed to gonadotoxic treatment. Completion of spermatogenesis after in vitro maturation is one of the future uses of harvested testicular tissue. The purpose of the current study was to evaluate the effects of vitamin A on in vitro maturation of fresh and frozen-thawed mouse pre-pubertal spermatogonial stem cells in an organ culture system. Pre-pubertal CD1 mouse fresh testes were cultured for 7 (D7), 9 (D9) and 11 (D11) days using an organ culture system. Basal medium was supplemented with different concentrations of retinol (Re) or retinoic acid (RA) alone or in combination. Seminiferous tubule morphology (tubule diameter, intra-tubular cell type), intra-tubular cell death and proliferation (PCNA antibody) and testosterone level were assessed at D7, D9 and D11. Pre-pubertal mouse testicular tissue were frozen after a soaking temperature performed at -7 degrees C, -8 degrees C or -9 degrees C and after thawing, were cultured for 9 days, using the culture medium preserving the best fresh tissue functionality. Retinoic acid at 10(-6)M and retinol at 3.3.10(-7)M, as well as retinol 10(-6)M are favourable for seminiferous tubule growth, maintenance of intra-tubular cell proliferation and germ cell differentiation of fresh pre-pubertal mouse spermatogonia. Structural and functional integrity of frozen-thawed testicular tissue appeared to be well-preserved after soaking temperature at -8 degrees C, after 9 days of organotypic culture using 10(-6)M retinol. RA and Re can control in vitro germ cell proliferation and differentiation. Re at a concentration of 10(-6)M maintains intra-tubular cell proliferation and the ability of spermatogonia to initiate spermatogenesis in fresh and frozen pre-pubertal mouse testicular tissue using a soaking temperature at -8 degrees C. Our data suggested a possible human application for in vitro maturation of cryopreserved pre-pubertal testicular tissue. PMID- 24349373 TI - Boost protein expression through co-expression of LEA-like peptide in Escherichia coli. AB - The boost protein expression has been done successfully by simple co-expression with a late embryogenesis abundant (LEA)-like peptide in Escherichia coli. Frequently, overexpression of a recombinant protein fails to provide an adequate yield. In the study, we developed a simple and efficient system for overexpressing transgenic proteins in bacteria by co-expression with an LEA-like peptide. The design of this peptide was based on part of the primary structure of an LEA protein that is known hydrophilic protein to suppress aggregation of other protein molecules. In our system, the expression of the target protein was increased remarkably by co-expression with an LEA-like peptide consisting of only 11 amino acid residues. This could provide a practical method for producing recombinant proteins efficiently. PMID- 24349375 TI - Evidence of a high density population of harvested leopards in a montane environment. AB - Populations of large carnivores can persist in mountainous environments following extensive land use change and the conversion of suitable habitat for agriculture and human habitation in lower lying areas of their range. The significance of these populations is poorly understood, however, and little attention has focussed on why certain mountainous areas can hold high densities of large carnivores and what the conservation implications of such populations might be. Here we use the leopard (Panthera pardus) population in the western Soutpansberg Mountains, South Africa, as a model system and show that montane habitats can support high numbers of leopards. Spatially explicit capture-recapture (SECR) analysis recorded the highest density of leopards reported outside of state protected areas in sub-Saharan Africa. This density represents a temporally high local abundance of leopards and we explore the explanations for this alongside some of the potential conservation implications. PMID- 24349374 TI - Mipu1, a novel direct target gene, is involved in hypoxia inducible factor 1 mediated cytoprotection. AB - Mipu1 (myocardial ischemic preconditioning up-regulated protein 1), recently identified in our lab, is a novel zinc-finger transcription factor which is up regulated during ischemic preconditioning. However, it is not clear what transcription factor contributes to its inducible expression. In the present study, we reported that HIF-1 regulates the inducible expression of Mipu1 which is involved in the cytoprotection of HIF-1alpha against oxidative stress by inhibiting Bax expression. Our results showed that the inducible expression of Mipu1 was associated with the expression and activation of transcription factor HIF-1 as indicated by cobalt chloride (CoCl2) treatment, HIF-1alpha overexpression and knockdown assays. EMSA and luciferase reporter gene assays showed that HIF-1alpha bound to the hypoxia response element (HRE) within Mipu1 promoter region and promoted its transcription. Moreover, our results revealed that Mipu1 inhibited the expression of Bax, an important pro-apoptosis protein associated with the intrinsic pathway of apoptosis, elevating the cytoprotection of HIF-1 against hydrogen peroxide (H2O2)-mediated injury in H9C2 cells. Our findings implied that Bax may be a potential target gene of transcription factor Mipu1, and provided a novel insight for understanding the cytoprotection of HIF-1 and new clues for further elucidating the mechanisms by which Mipu1 protects cell against pathological stress. PMID- 24349376 TI - Prognostic value of discs large homolog 7 transcript levels in prostate cancer. AB - Hypoxia has been associated with malignant progression, metastasis and resistance to therapy. Hence, we studied expression of hypoxia-regulated genes in 100 prostate cancer (CaP) bulk tissues and 71 adjacent benign tissues. We found 24 transcripts significantly overexpressed (p <= 0.02). Importantly, higher transcript levels of disc large (drosophila) homolog-associated protein 5 (DLGAP5)/discs large homolog 7 (DLG7)/hepatoma up-regulated protein (HURP), hyaluronan-mediated motility receptor (HMMR) and cyclin B1 (CCNB1) were associated with higher Gleason score and more advanced systemic progression. Since the products of HMMR and CCNB1 have been identified recently as molecular markers of CaP progression, we postulated that DLG7 has prognostic value too. To test this hypothesis, we measured transcript levels for DLG7 in a 150-pair case control cohort. The cases (progression to systemic disease within six years of surgery) and controls (no progression within eight years) were matched for clinical and pathologic prognostic variables, including grade, stage, and preoperative serum levels of PSA. The overall prognostic ability of DLG7, as tested in receiver operating characteristic analysis was of 0.74 (95% CI, 0.68 to 0.8). Overall, our data indicate that expression of DLG7, a hypoxia-controlled gene, holds prognostic potential in high-risk CaP; this also demonstrates that variation of oxygen tension may constitute a tool for identification of novel biomarkers for CaP. PMID- 24349378 TI - How a hat may affect 3-month-olds' recognition of a face: an eye-tracking study. AB - Recent studies have shown that infants' face recognition rests on a robust face representation that is resilient to a variety of facial transformations such as rotations in depth, motion, occlusion or deprivation of inner/outer features. Here, we investigated whether 3-month-old infants' ability to represent the invariant aspects of a face is affected by the presence of an external add-on element, i.e. a hat. Using a visual habituation task, three experiments were carried out in which face recognition was investigated by manipulating the presence/absence of a hat during face encoding (i.e. habituation phase) and face recognition (i.e. test phase). An eye-tracker system was used to record the time infants spent looking at face-relevant information compared to the hat. The results showed that infants' face recognition was not affected by the presence of the external element when the type of the hat did not vary between the habituation and test phases, and when both the novel and the familiar face wore the same hat during the test phase (Experiment 1). Infants' ability to recognize the invariant aspects of a face was preserved also when the hat was absent in the habituation phase and the same hat was shown only during the test phase (Experiment 2). Conversely, when the novel face identity competed with a novel hat, the hat triggered the infants' attention, interfering with the recognition process and preventing the infants' preference for the novel face during the test phase (Experiment 3). Findings from the current study shed light on how faces and objects are processed when they are simultaneously presented in the same visual scene, contributing to an understanding of how infants respond to the multiple and composite information available in their surrounding environment. PMID- 24349377 TI - Generation of human induced pluripotent stem cells using epigenetic regulators reveals a germ cell-like identity in partially reprogrammed colonies. AB - Previous studies have shown that induced pluripotent stem cells (iPSCs) can be derived from fibroblasts by ectopic expression of four transcription factors, OCT4, SOX2, KLF4 and c-MYC using various methods. More recent studies have focused on identifying alternative approaches and factors that can be used to increase reprogramming efficiency of fibroblasts to pluripotency. Here, we use nucleofection, morpholino technologies and novel epigenetic factors, which were chosen based on their expression profile in human embryos, fibroblasts and undifferentiated/differentiated human embryonic stem cells (hESCs) and conventionally generated iPSCs, to reprogram human fibroblasts into iPSCs. By over expressing DNMT3B, AURKB, PRMT5 and/or silencing SETD7 in human fibroblasts with and without NANOG, hTERT and/or SV40 overexpression, we observed the formation of colonies resembling iPSCs that were positive for certain pluripotency markers, but exhibited minimal proliferation. More importantly, we also demonstrate that these partially-reprogrammed colonies express high levels of early to mid germ cell-specific genes regardless of the transfection approach, which suggests conversion to a germ cell-like identity is associated with early reprogramming. These findings may provide an additional means to evaluate human germ cell differentiation in vitro, particularly in the context of pluripotent stem cell-derived germ cell development, and contribute to our understanding of the epigenetic requirements of the reprogramming process. PMID- 24349379 TI - Steps to take to enhance gait stability: the effect of stride frequency, stride length, and walking speed on local dynamic stability and margins of stability. AB - The purpose of the current study was to investigate whether adaptations of stride length, stride frequency, and walking speed, independently influence local dynamic stability and the size of the medio-lateral and backward margins of stability during walking. Nine healthy subjects walked 25 trials on a treadmill at different combinations of stride frequency, stride length, and consequently at different walking speeds. Visual feedback about the required and the actual combination of stride frequency and stride length was given during the trials. Generalized Estimating Equations were used to investigate the independent contribution of stride length, stride frequency, and walking speed on the measures of gait stability. Increasing stride frequency was found to enhance medio-lateral margins of stability. Backward margins of stability became larger as stride length decreased or walking speed increased. For local dynamic stability no significant effects of stride frequency, stride length or walking speed were found. We conclude that adaptations in stride frequency, stride length and/or walking speed can result in an increase of the medio-lateral and backward margins of stability, while these adaptations do not seem to affect local dynamic stability. Gait training focusing on the observed stepping strategies to enhance margins of stability might be a useful contribution to programs aimed at fall prevention. PMID- 24349380 TI - Metabolomics of the tumor microenvironment in pediatric acute lymphoblastic leukemia. AB - The tumor microenvironment is emerging as an important therapeutic target. Most studies, however, are focused on the protein components, and relatively little is known of how the microenvironmental metabolome might influence tumor survival. In this study, we examined the metabolic profiles of paired bone marrow (BM) and peripheral blood (PB) samples from 10 children with acute lymphoblastic leukemia (ALL). BM and PB samples from the same patient were collected at the time of diagnosis and after 29 days of induction therapy, at which point all patients were in remission. We employed two analytical platforms, high-resolution magnetic resonance spectroscopy and gas chromatography-mass spectrometry, to identify and quantify 102 metabolites in the BM and PB. Standard ALL therapy, which includes l asparaginase, completely removed circulating asparagine, but not glutamine. Statistical analyses of metabolite correlations and network reconstructions showed that the untreated BM microenvironment was characterized by a significant network-level signature: a cluster of highly correlated lipids and metabolites involved in lipid metabolism (p<0.006). In contrast, the strongest correlations in the BM upon remission were observed among amino acid metabolites and derivatives (p<9.2 * 10(-10)). This study provides evidence that metabolic characterization of the cancer niche could generate new hypotheses for the development of cancer therapies. PMID- 24349381 TI - Hypoxia regulates the expression of the neuromedin B receptor through a mechanism dependent on hypoxia-inducible factor-1alpha. AB - The neuromedin B receptor (NMB-R), a member of the mammalian bombesin receptor family, is frequently overexpressed in various tumors. In the present study, we found that exposure to hypoxic conditions increases the levels of NMBR mRNA and protein in breast cancer cells, which are tightly regulated by hypoxia-inducible factor-1alpha (HIF-1alpha). We confirmed the effect of HIF-1alpha on NMBR transcription by performing an NMBR promoter-driven reporter assay and then identified a functional hypoxia-responsive element (HRE) in the human NMBR promoter region. Further, the binding of HIF-1alpha to the NMBR promoter was corroborated by electrophoretic mobility shift and chromatin immunoprecipitation assays, which showed that HIF-1alpha specifically and directly bound to the NMBR promoter in response to hypoxia. Immunohistochemical analysis of a xenograft and a human breast cancer tissue array revealed a significant correlation between NMB R and HIF-1alpha expression. Taken together, our findings indicate that hypoxia induces NMB-R expression through a novel mechanism to regulate HIF-1alpha expression in breast cancer cells. PMID- 24349382 TI - Tumor infiltrating PD1-positive lymphocytes and the expression of PD-L1 predict poor prognosis of soft tissue sarcomas. AB - Recently, the possibility of PD1 pathway-targeted therapy has been extensively studied in various human malignant tumors. However, no previous study has investigated their potential application for soft-tissue sarcomas (STS). In this study, we evaluated the clinical impact of intra-tumoral infiltration of PD1 positive lymphocytes and PD-L1 expression in tumor cells in 105 cases of STS. Intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression were seen in 65% and 58% of STS, respectively. Both PD1-positivity and PD-L1 expression were significantly associated with advanced clinicopathological parameters such as higher clinical stage, presence of distant metastasis, higher histological grade, poor differentiation of tumor, and tumor necrosis. Moreover, both PD1-positivity and PD-L1 positivity were independent prognostic indicators of overall survival (OS) and event-free survival (EFS) of STS by multivariate analysis. In addition, the combined pattern of PD1- and PD-L1-positivity was also an independent prognostic indicator for OS and EFS by multivariate analysis. The patents with a PD1(+)/PD-L1(+) pattern had the shortest survival time. In conclusion, this study is the first to demonstrate that the infiltration of PD1 positive lymphocytes and PD-L1 expression in STS cells could be used as novel prognostic indicators for STS. Moreover, the evaluation of PD1- and PD-L1 positivity in STS is also available as possible criteria for selection of patients suitable for PD1-based immunotherapy. PMID- 24349383 TI - Mycobacterium avium infection induces H-ferritin expression in mouse primary macrophages by activating Toll-like receptor 2. AB - Important for both host and pathogen survivals, iron is a key factor in determining the outcome of an infectious process. Iron with-holding, including sequestration inside tissue macrophages, is considered an important strategy to fight infection. However, for intra-macrophagic pathogens, such as Mycobacterium avium, host defence may depend on intracellular iron sequestration mechanisms. Ferritin, the major intracellular iron storage protein, plays a critical role in this process. In the current study, we studied ferritin expression in mouse bone marrow-derived macrophages upon infection with M. avium. We found that H-ferritin is selectively increased in infected macrophages, through an up-regulation of gene transcription. This increase was mediated by the engagement of Toll like receptor-2, and was independent of TNF-alpha or nitric oxide production. The formation of H-rich ferritin proteins and the consequent iron sequestration may be an important part of the panoply of antimicrobial mechanisms of macrophages. PMID- 24349384 TI - Protein transfection study using multicellular tumor spheroids of human hepatoma Huh-7 cells. AB - Several protein transfection reagents are commercially available and are powerful tools for elucidating function of a protein in a cell. Here we described protein transfection studies of the commercially available reagents, Pro-DeliverIN, Xfect, and TuboFect, using Huh-7 multicellular tumor spheroid (MCTS) as a three dimensional in vitro tumor model. A cellular uptake study using specific endocytosis inhibitors revealed that each reagent was internalized into Huh-7 MCTS by different mechanisms, which were the same as monolayer cultured Huh-7 cells. A certain amount of Pro-DeliverIN and Xfect was uptaken by Huh-7 cells through caveolae-mediated endocytosis, which may lead to transcytosis through the surface-first layered cells of MCTS. The results presented here will help in the choice and use of protein transfection reagents for evaluating anti-tumor therapeutic proteins against MCTS models. PMID- 24349385 TI - Eating behaviour among multi-ethnic adolescents in a middle-income country as measured by the self-reported Children's Eating Behaviour Questionnaire. AB - BACKGROUND: Escalating weight gain among the Malaysian paediatric population necessitates identifying modifiable behaviours in the obesity pathway. OBJECTIVES: This study describes the adaptation and validation of the Children's Eating Behaviour Questionnaire (CEBQ) as a self-report for adolescents, investigates gender and ethnic differences in eating behaviour and examines associations between eating behaviour and body mass index (BMI) z-scores among multi-ethnic Malaysian adolescents. METHODOLOGY: This two-phase study involved validation of the Malay self-reported CEBQ in Phase 1 (n = 362). Principal Axis Factoring with Promax rotation, confirmatory factor analysis and reliability tests were performed. In Phase 2, adolescents completed the questionnaire (n = 646). Weight and height were measured. Gender and ethnic differences in eating behaviour were investigated. Associations between eating behaviour and BMI z scores were examined with complex samples general linear model (GLM) analyses, adjusted for gender, ethnicity and maternal educational level. RESULTS: Exploratory factor analysis revealed a 35-item, 9-factor structure with 'food fussiness' scale split into two. In confirmatory factor analysis, a 30-item, 8 factor structure yielded an improved model fit. Reliability estimates of the eight factors were acceptable. Eating behaviours did not differ between genders. Malay adolescents reported higher Food Responsiveness, Enjoyment of Food, Emotional Overeating, Slowness in Eating, Emotional Undereating and Food Fussiness 1 scores (p<0.05) compared to Chinese and Indians. A significant negative association was observed between BMI z-scores and Food Fussiness 1 ('dislike towards food') when adjusted for confounders. CONCLUSION: Although CEBQ is a valuable psychometric instrument, adjustments were required due to age and cultural differences in our sample. With the self-report, our findings present that gender, ethnic and weight status influenced eating behaviours. Obese adolescents were found to display a lack of dislike towards food. Future longitudinal and qualitative studies are warranted to further understand behavioural phenotypes of obesity to guide prevention and intervention strategies. PMID- 24349386 TI - "Candidatus Similichlamydia laticola", a novel Chlamydia-like agent of epitheliocystis in seven consecutive cohorts of farmed Australian barramundi, Lates calcarifer (Bloch). AB - Six consecutively hatched cohorts and one cohort of pre-hatch eggs of farmed barramundi (Lates calcarifer) from south Australia were examined for Chlamydia like organisms associated with epitheliocystis. To identify and characterise the bacteria, 59 gill samples and three pre-hatch egg samples were processed for histology, in situ hybridisation and 16S rRNA amplification, sequencing and comprehensive phylogenetic analysis. Cases of epitheliocystis were observed microscopically and characterised by membrane-enclosed basophilic cysts filled with a granular material that caused hypertrophy of the epithelial cells. In situ hybridisation with a Chlamydiales-specific probe lead to specific labelling of the epitheliocystis inclusions within the gill epithelium. Two distinct but closely related 16S rRNA chlamydial sequences were amplified from gill DNA across the seven cohorts, including from pre-hatch eggs. These genotype sequences were found to be novel, sharing 97.1 - 97.5% similarity to the next closest 16S rRNA sequence, Ca. Similichlamydia latridicola, from Australian striped trumpeter. Comprehensive phylogenetic analysis of these genotype sequences against representative members of the Chlamydiales order and against other epitheliocystis agents revealed these Chlamydia-like organisms to be novel and taxonomically placed them within the recently proposed genus Ca. Similichlamydia. Following Fredricks and Relman's molecular postulates and based on these observations, we propose the epitheliocystis agents of barramundi to be known as "Candidatus Similichlamydia laticola" (sp. nov.). PMID- 24349387 TI - A circle-monitor for computerised assessment of visual neglect in peripersonal space. AB - Current assessment of visual neglect involves paper-and-pencil tests or computer based tasks. Both have been criticised because of their lack of ecological validity as target stimuli can only be presented in a restricted visual range. This study examined the user-friendliness and diagnostic strength of a new "Circle-Monitor" (CM), which enlarges the range of the peripersonal space, in comparison to a standard paper-and-pencil test (Neglect-Test, NET). METHODS: Ten stroke patients with neglect and ten age-matched healthy controls were examined by the NET and the CM test comprising of four subtests (Star Cancellation, Line Bisection, Dice Task, and Puzzle Test). RESULTS: The acceptance of the CM in elderly controls and neglect patients was high. Participants rated the examination by CM as clear, safe and more enjoyable than NET. Healthy controls performed at ceiling on all subtests, without any systematic differences between the visual fields. Both NET and CM revealed significant differences between controls and patients in Line Bisection, Star Cancellation and visuo-constructive tasks (NET: Figure Copying, CM: Puzzle Test). Discriminant analyses revealed cross-validated assignment of patients and controls to groups was more precise when based on the CM (hit rate 90%) as compared to the NET (hit rate 70%). CONCLUSION: The CM proved to be a sensitive novel tool to diagnose visual neglect symptoms quickly and accurately with superior diagnostic validity compared to a standard neglect test while being well accepted by patients. Due to its upgradable functions the system may also be a valuable tool not only to test for non-visual neglect symptoms, but also to provide treatment and assess its outcome. PMID- 24349388 TI - The correlates of body composition with heart rate recovery after step test: an exploratory study of Malaysian adolescents. AB - BACKGROUND: In adults, heart rate recovery is a predictor of mortality, while in adolescents it is associated with cardio-metabolic risk factors. The aim of this study was to examine the relationship between body composition measures and heart rate recovery (HRR) after step test in Malaysian secondary school students. METHODS: In the Malaysian Health and Adolescents Longitudinal Research Team (MyHEART) study, 1071 healthy secondary school students, aged 13 years old, participated in the step test. Parameters for body composition measures were body mass index z-score, body fat percentage, waist circumference, and waist height ratio. The step test was conducted by using a modified Harvard step test. Heart rate recovery of 1 minute (HRR1min) and heart rate recovery of 2 minutes (HRR2min) were calculated by the difference between the peak pulse rate during exercise and the resting pulse rate at 1 and 2 minutes, respectively. Analysis was done separately based on gender. Pearson correlation analysis was used to determine the association between the HRR parameters with body composition measures, while multiple regression analysis was used to determine which body composition measures was the strongest predictor for HRR. RESULTS: For both gender groups, all body composition measures were inversely correlated with HRR1min. In girls, all body composition measures were inversely correlated with HRR2min, while in boys all body composition measures, except BMI z-score, were associated with HRR2min. In multiple regression, only waist circumference was inversely associated with HRR2min (p=0.024) in boys, while in girls it was body fat percentage for HRR2min (p=0.008). CONCLUSION: There was an inverse association between body composition measurements and HRR among apparently healthy adolescents. Therefore, it is important to identify cardio-metabolic risk factors in adolescent as an early prevention of consequent adulthood morbidity. This reiterates the importance of healthy living which should start from young. PMID- 24349389 TI - A randomised placebo-controlled trial to differentiate the acute cognitive and mood effects of chlorogenic acid from decaffeinated coffee. AB - In the current study, sixty healthy older adults aged 50 years or older, and who were light to moderate coffee drinkers, were administered 6g of a decaffeinated green coffee blend (NESCAFE Green Blend coffee; GB) or 540mg pure chlorogenic acids (CGA) or placebo in a double-blind acute cross-over design, with cognitive and mood assessments pre-dose, 40-mins and 120-mins post-dose. The primary outcome measure was accuracy in Rapid Visual Information Processing (RVIP). Secondary cognitive outcome measures included RVIP reaction time as well as Inspection time (IT), Jensen Box decision/reaction times, serial subtraction and N-Back working memory. Secondary mood measures included Bond-Lader and caffeine Research visual analogue scales (VAS). No significant treatment effects were found for the primary outcome measure, although significant effects were found amongst secondary measures. Overall, CGA in isolation was not found to significantly improve cognitive function relative to placebo whereas the GB was found to improve sustained attention as measured by the N-Back task in comparison to placebo overall (t=2.45,p=.05), as well as decision time on a 2-choice reaction time task (Jensen box) in comparison to placebo at 40 minutes post-dose (t=2.45,p=.05). Similarly, GB was found to improve alertness on both the Bond Lader at 120 minutes relative to CGA (t=2.86, p=0.02) and the caffeine Research VAS relative to CGA (t=3.09, p=0.009) and placebo (t=2.75,p=0.02) at 120 minutes post-dose. Both the GB and CGA were also found to significantly improve symptoms of headache at 120 minutes relative to placebo (t=2.51,p=0.03 and t=2.43,p=.04 respectively), whilst there was a trend towards a reduction in jitteriness with GB and CGA in comparison to placebo at 40 minutes post-dose (t=2.24,p=0.06 and t=2.20,p=0.06 respectively). These findings suggest that the improvements in mood observed with GB, but not the improvements in cognitive function, are likely to some extent to be attributable to CGAs. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12611000067976 www.anzctr.org.au. PMID- 24349390 TI - Near-infrared laser adjuvant for influenza vaccine. AB - Safe and effective immunologic adjuvants are often essential for vaccines. However, the choice of adjuvant for licensed vaccines is limited, especially for those that are administered intradermally. We show that non-tissue damaging, near infrared (NIR) laser light given in short exposures to small areas of skin, without the use of additional chemical or biological agents, significantly increases immune responses to intradermal influenza vaccination without augmenting IgE. The NIR laser-adjuvanted vaccine confers increased protection in a murine influenza lethal challenge model as compared to unadjuvanted vaccine. We show that NIR laser treatment induces the expression of specific chemokines in the skin resulting in recruitment and activation of dendritic cells and is safe to use in both mice and humans. The NIR laser adjuvant technology provides a novel, safe, low-cost, simple-to-use, potentially broadly applicable and clinically feasible approach to enhancing vaccine efficacy as an alternative to chemical and biological adjuvants. PMID- 24349391 TI - Pulsed estrogen therapy prevents post-OVX porcine dura mater microvascular network weakening via a PDGF-BB-dependent mechanism. AB - In postmenopausal women, estrogen (E2) deficiencies are frequently associated with higher risk of intracranial hemorrhage, increased incidence of stroke, cerebral aneurysm, and decline in cognitive abilities. In younger postpartum women and those using oral contraceptives, perturbations in E2 are associated with higher risk of cerebral venous thrombosis. A number of serious intracranial pathologic conditions linked to E2 deficiencies, such as dural sinus thrombosis, dural fistulae, non-parenchymal intracranial hemorrhages, migraines, and spontaneous cerebrospinal fluid leaks, involve the vessels not of the brain itself, but of the outer fibrous membrane of the brain, the dura mater (DM). The pathogenesis of these disorders remains mysterious and how estrogen regulates structural and functional integrity of DM vasculature is largely unknown. Here, we demonstrate that post ovariectomy (OVX) DM vascular remodeling is manifested by microvessel destabilization, capillary rarefaction, increased vascular permeability, and aberrant angio-architecture, and is the result of disrupted E2 regulated PDGF-BB signaling within dura microvasculature. These changes, associated with the reduction in systemic PDGF-BB levels, are not corrected by a flat-dose E2 hormone replacement therapy (HRT), but are largely prevented using HRT schedules mimicking physiological E2 fluctuations. We demonstrate that 1) E2 regulates PDGF-BB production by endothelial cells in a dose-dependent manner and 2) optimization of PDGF-BB levels and induction of robust PDGF-mediated endothelial cell-vascular pericyte interactions require high (estrous) E2 concentrations. We conclude that high (estrous) levels of E2 are important in controlling PDGF-mediated crosstalk between endothelial cells and pericytes, a fundamental mechanism governing microvessel stability and essential for preserving intracranial homeostasis. PMID- 24349393 TI - Clinical characteristics with an impact on ADL functions of PD patients with cognitive impairment indicative of dementia. AB - BACKGROUND: Dementia in Parkinson's disease (PD) is defined as cognitive decline severe enough to affect activities of daily living function (ADL). The aim of our exploratory study was to compare two groups of PD patients. Both groups had cognitive deficits severe enough to justify diagnosis of dementia, but they differed according to caregivers' rating on ADL dysfunction. Parameters which differed between the two groups were interpreted to affect the caregivers' perception of ADL dysfunction in PD patients with cognitive impairment indicative of Parkinson's disease dementia. METHODOLOGY/PRINCIPAL FINDINGS: Thirty of 131 Parkinson's disease patients fulfilled the Movement Disorders Society Task Force recommended, cognitive Level-I-criteria for dementia. According to standardized caregiver ratings, volunteers were grouped into 18 patients with (ADL-) and 12 without instrumental activities of daily living dysfunction (ADL+). Caregiver activities of daily living function ratings closely correlated with self estimates of patients and those of physician (p<0.001). ADL- patients performed worse on tests assessing visual-construction (p<0.05) and attention (p=0.03) than ADL+ patients. Moreover, the postural instability and gait disorder subtype was more frequent in ADL- patients (p=0.009). ADL- patients tended to have more communication problems (p=0.05), more anxiety (p=0.05) and showed a tendency to be treated more often with neuroleptics (p=0.049) than ADL+. CONCLUSIONS/SIGNIFICANCE: Results indicate that worse attention, visual construction abilities, the postural instability and gait disorder subtype, communication problems, medication and presence of anxiety are related to activities of daily living dysfunctions in Parkinson's disease patients with cognitive decline indicative of dementia. Our data suggests that not only cognitive factors but also non-cognitive factors seem to be linked to the diagnosis of Parkinson's disease dementia associated with significant impact on instrumental activities of daily living function. Further studies with larger sample sizes are needed to verify our results. PMID- 24349392 TI - An adaptive physical activity intervention for overweight adults: a randomized controlled trial. AB - BACKGROUND: Physical activity (PA) interventions typically include components or doses that are static across participants. Adaptive interventions are dynamic; components or doses change in response to short-term variations in participant's performance. Emerging theory and technologies make adaptive goal setting and feedback interventions feasible. OBJECTIVE: To test an adaptive intervention for PA based on Operant and Behavior Economic principles and a percentile-based algorithm. The adaptive intervention was hypothesized to result in greater increases in steps per day than the static intervention. METHODS: Participants (N = 20) were randomized to one of two 6-month treatments: 1) static intervention (SI) or 2) adaptive intervention (AI). Inactive overweight adults (85% women, M = 36.9 +/- 9.2 years, 35% non-white) in both groups received a pedometer, email and text message communication, brief health information, and biweekly motivational prompts. The AI group received daily step goals that adjusted up and down based on the percentile-rank algorithm and micro-incentives for goal attainment. This algorithm adjusted goals based on a moving window; an approach that responded to each individual's performance and ensured goals were always challenging but within participants' abilities. The SI group received a static 10,000 steps/day goal with incentives linked to uploading the pedometer's data. RESULTS: A random effects repeated-measures model accounted for 180 repeated measures and autocorrelation. After adjusting for covariates, the treatment phase showed greater steps/day relative to the baseline phase (p<.001) and a group by study phase interaction was observed (p .017). The SI group increased by 1,598 steps/day on average between baseline and treatment while the AI group increased by 2,728 steps/day on average between baseline and treatment; a significant between-group difference of 1,130 steps/day (Cohen's d = .74). CONCLUSIONS: The adaptive intervention outperformed the static intervention for increasing PA. The adaptive goal and feedback algorithm is a "behavior change technology" that could be incorporated into mHealth technologies and scaled to reach large populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT01793064. PMID- 24349394 TI - Genetic diversity and population genetic structure analysis of Echinococcus granulosus sensu stricto complex based on mitochondrial DNA signature. AB - The genetic diversity and population genetics of the Echinococcus granulosus sensu stricto complex were investigated based on sequencing of mitochondrial DNA (mtDNA). Total 81 isolates of hydatid cyst collected from ungulate animals from different geographical areas of North India were identified by sequencing of cytochrome c oxidase subunit1 (coxi) gene. Three genotypes belonging to E. granulosus sensu stricto complex were identified (G1, G2 and G3 genotypes). Further the nucleotide sequences (retrieved from GenBank) for the coxi gene from seven populations of E. granulosus sensu stricto complex covering 6 continents, were compared with sequences of isolates analysed in this study. Molecular diversity indices represent overall high mitochondrial DNA diversity for these populations, but low nucleotide diversity between haplotypes. The neutrality tests were used to analyze signatures of historical demographic events. The Tajima's D test and Fu's FS test showed negative value, indicating deviations from neutrality and both suggested recent population expansion for the populations. Pairwise fixation index was significant for pairwise comparison of different populations (except between South America and East Asia, Middle East and Europe, South America and Europe, Africa and Australia), indicating genetic differentiation among populations. Based on the findings of the present study and those from earlier studies, we hypothesize that demographic expansion occurred in E. granulosus after the introduction of founder haplotype particular by anthropogenic movements. PMID- 24349395 TI - In vivo characterization of dynein-driven nanovectors using Drosophila oocytes. AB - Molecular motors transport various cargoes including vesicles, proteins and mRNAs, to distinct intracellular compartments. A significant challenge in the field of nanotechnology is to improve drug nuclear delivery by engineering nanocarriers transported by cytoskeletal motors. However, suitable in vivo models to assay transport and delivery efficiency remain very limited. Here, we develop a fast and genetically tractable assay to test the efficiency and dynamics of fluospheres (FS) using microinjection into Drosophila oocytes coupled with time lapse microscopy. We designed dynein motor driven FS using a collection of dynein light chain 8 (LC8) peptide binding motifs as molecular linkers and characterized in real time the efficiency of the FS movement according to its linker's sequence. Results show that the conserved LC8 binding motif allows fast perinuclear nanoparticle's accumulation in a microtubule and dynein dependent mechanism. These data reveal the Drosophila oocyte as a new valuable tool for the design of motor driven nanovectors. PMID- 24349396 TI - A low serum bicarbonate concentration as a risk factor for mortality in peritoneal dialysis patients. AB - BACKGROUND AND AIM: Metabolic acidosis is common in patients with chronic kidney disease and is associated with increased mortality in hemodialysis patients. However, this relationship has not yet been determined in peritoneal dialysis (PD) patients. METHODS: This prospective observational study included a total of 441 incident patients who started PD between January 2000 and December 2005. Using time-averaged serum bicarbonate (TA-Bic) levels, we aimed to investigate whether a low serum bicarbonate concentration can predict mortality in these patients. RESULTS: Among the baseline parameters, serum bicarbonate level was positively associated with hemoglobin level and residual glomerular filtration rate (GFR), while it was negatively associated with albumin, C-reactive protein (CRP) levels, peritoneal Kt/V urea, and normalized protein catabolic rate (nPCR) in a multivariable linear regression analysis. During a median follow-up of 34.8 months, 149 deaths were recorded. After adjustment for age, diabetes, coronary artery disease, serum albumin, ferritin, CRP, residual GFR, peritoneal Kt/V urea, nPCR, and percentage of lean body mass, TA-Bic level was associated with a significantly decreased risk of mortality (HR per 1 mEq/L increase, 0.83; 95% CI, 0.76-0.91; p < 0.001). In addition, compared to patients with a TA-Bic level of 24-26 mEq/L, those with a TA-Bic level < 22 and between 22-24 mEq/L conferred a 13.10- and 2.13-fold increased risk of death, respectively. CONCLUSIONS: This study showed that a low serum bicarbonate concentration is an independent risk factor for mortality in PD patients. This relationship between low bicarbonate levels and adverse outcome could be related to enhanced inflammation and a more rapid loss of RRF associated with metabolic acidosis. Large randomized clinical trials to correct acidosis are warranted to confirm our findings. PMID- 24349397 TI - Appraisal tools for clinical practice guidelines: a systematic review. AB - INTRODUCTION: Clinical practice guidelines can improve healthcare processes and patient outcomes, but are often of low quality. Guideline appraisal tools aim to help potential guideline users in assessing guideline quality. We conducted a systematic review of publications describing guideline appraisal tools in order to identify and compare existing tools. METHODS: Among others we searched MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews from 1995 to May 2011 for relevant primary and secondary publications. We also handsearched the reference lists of relevant publications. On the basis of the available literature we firstly generated 34 items to be used in the comparison of appraisal tools and grouped them into thirteen quality dimensions. We then extracted formal characteristics as well as questions and statements of the appraisal tools and assigned them to the items. RESULTS: We identified 40 different appraisal tools. They covered between three and thirteen of the thirteen possible quality dimensions and between three and 29 of the possible 34 items. The main focus of the appraisal tools were the quality dimensions "evaluation of evidence" (mentioned in 35 tools; 88%), "presentation of guideline content" (34 tools; 85%), "transferability" (33 tools; 83%), "independence" (32 tools; 80%), "scope" (30 tools; 75%), and "information retrieval" (29 tools; 73%). The quality dimensions "consideration of different perspectives" and "dissemination, implementation and evaluation of the guideline" were covered by only twenty (50%) and eighteen tools (45%) respectively. CONCLUSIONS: Most guideline appraisal tools assess whether the literature search and the evaluation, synthesis and presentation of the evidence in guidelines follow the principles of evidence-based medicine. Although conflicts of interest and norms and values of guideline developers, as well as patient involvement, affect the trustworthiness of guidelines, they are currently insufficiently considered. Greater focus should be placed on these issues in the further development of guideline appraisal tools. PMID- 24349398 TI - Diversification of two lineages of symbiotic Photobacterium. AB - Understanding of processes driving bacterial speciation requires examination of closely related, recently diversified lineages. To gain an insight into diversification of bacteria, we conducted comparative genomic analysis of two lineages of bioluminescent symbionts, Photobacterium leiognathi and 'P. mandapamensis'. The two lineages are evolutionary and ecologically closely related. Based on the methods used in bacterial taxonomy for classification of new species (DNA-DNA hybridization and ANI), genetic relatedness of the two lineages is at a cut-off point for species delineation. In this study, we obtained the whole genome sequence of a representative P. leiognathi strain lrivu.4.1, and compared it to the whole genome sequence of 'P. mandapamensis' svers.1.1. Results of the comparative genomic analysis suggest that P. leiognathi has a more plastic genome and acquired genes horizontally more frequently than 'P. mandapamensis'. We predict that different rates of recombination and gene acquisition contributed to diversification of the two lineages. Analysis of lineage-specific sequences in 25 strains of P. leiognathi and 'P. mandapamensis' found no evidence that bioluminescent symbioses with specific host animals have played a role in diversification of the two lineages. PMID- 24349399 TI - Auditory cortex processes variation in our own speech. AB - As we talk, we unconsciously adjust our speech to ensure it sounds the way we intend it to sound. However, because speech production involves complex motor planning and execution, no two utterances of the same sound will be exactly the same. Here, we show that auditory cortex is sensitive to natural variations in self-produced speech from utterance to utterance. We recorded event-related potentials (ERPs) from ninety-nine subjects while they uttered "ah" and while they listened to those speech sounds played back. Subjects' utterances were sorted based on their formant deviations from the previous utterance. Typically, the N1 ERP component is suppressed during talking compared to listening. By comparing ERPs to the least and most variable utterances, we found that N1 was less suppressed to utterances that differed greatly from their preceding neighbors. In contrast, an utterance's difference from the median formant values did not affect N1. Trial-to-trial pitch (f0) deviation and pitch difference from the median similarly did not affect N1. We discuss mechanisms that may underlie the change in N1 suppression resulting from trial-to-trial formant change. Deviant utterances require additional auditory cortical processing, suggesting that speaking-induced suppression mechanisms are optimally tuned for a specific production. PMID- 24349400 TI - Hydroxyurea could be a good clinically relevant iron chelator. AB - Our previous study showed a reduction in serum ferritin of beta-thalassemia patients on hydroxyurea therapy. Here we aimed to evaluate the efficacy of hydroxyurea alone and in combination with most widely used iron chelators like deferiprone and deferasirox for reducing iron from experimentally iron overloaded mice. 70 BALB/c mice received intraperitonial injections of iron-sucrose. The mice were then divided into 8 groups and were orally given hydroxyurea, deferiprone or deferasirox alone and their combinations for 4 months. CBC, serum ferritin, TBARS, sTfr and hepcidin were evaluated before and after iron overload and subsequently after 4 months of drug therapy. All animals were then killed. Iron staining of the heart and liver tissue was done using Perl's Prussian Blue stain. Dry weight of iron in the heart and liver was determined by atomic absorption spectrometry. Increased serum-ferritin, TBARS, hepcidin and dry weight of iron in the liver and heart showed a significant reduction in groups treated with iron chelators with maximum reduction in the group treated with a combination of deferiprone, deferasirox and hydroxyurea. Thus hydroxyurea proves its role in reducing iron from iron overloaded mice. The iron chelating effect of these drugs can also be increased if given in combination. PMID- 24349401 TI - General anesthetics inhibit LPS-induced IL-1beta expression in glial cells. AB - BACKGROUND: Glial cells, including microglia and astrocytes, are considered the primary source of proinflammatory cytokines in the brain. Immune insults stimulate glial cells to secrete proinflammatory cytokines that modulate the acute systemic response, which includes fever, behavioral changes, and hypothalamic-pituitary-adrenal (HPA) axis activation. We investigated the effect of general anesthetics on proinflammatory cytokine expression in the primary cultured glial cells, the microglial cell line BV-2, the astrocytic cell line A-1 and mouse brain. METHODOLOGY/PRINCIPAL FINDINGS: Primary cultured glial cells were exposed to lipopolysaccharide (LPS) in combination with general anesthetics including isoflurane, pentobarbital, midazolam, ketamine, and propofol. Following this treatment, we examined glial cell expression of the proinflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF alpha). LPS-induced expression of IL-1beta mRNA and protein were significantly reduced by all the anesthetics tested, whereas IL-6 and TNF-alpha mRNA expression was unaffected. The anesthetics suppressed LPS-induced extracellular signal regulated kinase 1/2 (ERK 1/2) phosphorylation, but did not affect nuclear factor kappaB and activator protein-1 activation. The same effect was observed with BV 2, but not with A-1 cells. In the mouse experiments, LPS was injected intraperitoneally, and isoflurane suppressed IL-1beta in the brain and adrenocorticotropic hormone in plasma, but not IL-1beta in plasma. CONCLUSIONS/SIGNIFICANCE: Taken together, our results indicate that general anesthetics inhibit LPS-induced IL-1beta upregulation in glial cells, particularly microglia, and affects HPA axis participation in the stress response. PMID- 24349402 TI - Risk factors for poor treatment outcomes in patients with MDR-TB and XDR-TB in China: retrospective multi-center investigation. AB - BACKGROUND: The treatment of patients with MDR- and XDR-TB is usually more complex, toxic and costly and less effective than treatment of other forms of TB. However, there is little information available on risk factors for poor outcomes in patients with MDR- and XDR-TB in China. METHODOLOGY/PRINCIPAL FINDINGS: We retrospectively analyzed the clinical records of HIV-negative TB Patients with culture-proven MDR- or XDR-TB who were registered from July 2006 to June 2011 at five large-scale Tuberculosis Specialized Hospitals in China. Among 1662 HIV seronegative TB cases which were culture-positive for M. tuberculosis complex and had positive sputum-smear microscopy results, 965 cases (58.1%) were DR-TB, and 586 cases (35.3%) were classified as having MDR-TB, accounting for 60.7% of DR TB. 169 cases (10.2%) were XDR-TB, accounting for 17.5% of DR-TB, 28.8% of MDR TB. The MDR-TB patients were divided into XDR-TB group (n=169) and other MDR-TB group (non-XDR MDR-TB) (n=417). In total, 240 patients (40.95%) had treatment success, and 346 (59.05%) had poor treatment outcomes. The treatment success rate in other MDR-TB group was 52.2%, significantly higher than that in the XDR-TB group (13%, P<0.001). In multivariate logistic regression analysis, poor outcomes were associated with duration of previous anti-TB treatment of more than one year (OR, 0.077; 95% CI, 0.011-0.499, P<0.001), a BMI less than 18.5 kg/m(2) (OR, 2.185; 95% CI, 1.372-3.478, P<0.001), XDR (OR, 13.368; 95% CI, 6.745-26.497, P<0.001), retreatment (OR, 0.171; 95% CI, 0.093-0.314, P<0.001), diabetes (OR, 0.305; 95% CI, 0.140-0.663, P=0.003), tumor (OR, 0.095; 95% CI, 0.011-0.795, P=0.03), decreased albumin (OR, 0.181; 95% CI, 0.118-0.295, P<0.001), cavitation (OR, 0.175; 95% CI, 0.108-0.286, P<0.001). CONCLUSIONS/SIGNIFICANCE: The patients with MDR-TB and XDR-TB have poor treatment outcomes in China.The presence of extensive drug resistance, low BMI, hypoalbuminemia, comorbidity, cavitary disease and previous anti-TB treatment are independent prognostic factors for poor outcome in patients with MDR-TB. PMID- 24349403 TI - Utility of sepsis biomarkers and the infection probability score to discriminate sepsis and systemic inflammatory response syndrome in standard care patients. AB - Physicians are regularly faced with severely ill patients at risk of developing infections. In literature, standard care wards are often neglected, although their patients frequently suffer from a systemic inflammatory response syndrome (SIRS) of unknown origin. Fast identification of patients with infections is vital, as they immediately require appropriate therapy. Further, tools with a high negative predictive value (NPV) to exclude infection or bacteremia are important to increase the cost effectiveness of microbiological examinations and to avoid inappropriate antibiotic treatment. In this prospective cohort study, 2,384 patients with suspected infections were screened for suffering from two or more SIRS criteria on standard care wards. The infection probability score (IPS) and sepsis biomarkers with discriminatory power were assessed regarding their capacity to identify infection or bacteremia. In this cohort finally consisting of 298 SIRS-patients, the infection prevalence was 72%. Bacteremia was found in 25% of cases. For the prediction of infection, the IPS yielded 0.51 ROC-AUC (30.1% sensitivity, 64.6% specificity). Among sepsis biomarkers, lipopolysaccharide binding protein (LBP) was the best parameter with 0.63 ROC-AUC (57.5% sensitivity, 67.1% specificity). For the prediction of bacteremia, the IPS performed slightly better with a ROC-AUC of 0.58 (21.3% sensitivity, 65% specificity). Procalcitonin was the best discriminator with 0.78 ROC-AUC, 86.3% sensitivity, 59.6% specificity and 92.9% NPV. Furthermore, bilirubin and LBP (ROC AUC: 0.65, 0.62) might also be considered as useful parameters. In summary, the IPS and widely used infection parameters, including CRP or WBC, yielded a poor diagnostic performance for the detection of infection or bacteremia. Additional sepsis biomarkers do not aid in discriminating inflammation from infection. For the prediction of bacteremia procalcitonin, and bilirubin were the most promising parameters, which might be used as a rule for when to take blood cultures or using nucleic acid amplification tests for microbiological diagnostics. PMID- 24349404 TI - Association between ischemic stroke and iron-deficiency anemia: a population based study. AB - BACKGROUND: Very little is known about the relationship between non-sickle cell anemia and stroke. The purpose of this study is to evaluate the association of iron-deficiency anemia (IDA) with stroke based on a nationwide coverage database in Taiwan. METHODS: The case-control study subjects were obtained from the Taiwanese Longitudinal Health Insurance Database 2000. We included 51,093 subjects with stroke as cases and randomly selected 153,279 controls (3 controls per case) in this study.Separate conditional logistic regression analyses were used to calculate the odds ratio (OR) for having been previously diagnosed with IDA between cases and controls.We further analyzed the association between stroke and IDA by stroke subtype. RESULTS: Results showed that 3,685 study subjects (1.81%) had been diagnosed with IDA prior to the index date; of those subjects, 1,268 (2.48%) were cases and 2,417 (1.58%) were controls (p<0.001). Conditional logistic regression shows that the OR of having previously received an IDA diagnosis among cases was 1.49 (95% CI: 1.39~1.60; p < 0.01) that of controls after adjusting for monthly income, geographic region, hypertension, diabetes, coronary heart disease, atrial fibrillation, heart failure, hyperlipidemia, tobacco use disorder, and alcohol abuse/alcohol dependency syndrome. Furthermore, the adjusted OR of prior IDA for cases with ischemic stroke was found to be 1.45 (95% CI: 1.34~1.58) compared to controls. However, we did not find any significant relationship between IDA and subarachnoid/intracerebral hemorrhage even adjusting for other confounding factors (OR=1.17, 95% CI=0.97~1.40). CONCLUSION: There is a significant association between prior IDA and ischemic stroke. PMID- 24349405 TI - Catchment-scale conservation units identified for the threatened Yarra pygmy perch (Nannoperca obscura) in highly modified river systems. AB - Habitat fragmentation caused by human activities alters metapopulation dynamics and decreases biological connectivity through reduced migration and gene flow, leading to lowered levels of population genetic diversity and to local extinctions. The threatened Yarra pygmy perch, Nannoperca obscura, is a poor disperser found in small, isolated populations in wetlands and streams of southeastern Australia. Modifications to natural flow regimes in anthropogenically-impacted river systems have recently reduced the amount of habitat for this species and likely further limited its opportunity to disperse. We employed highly resolving microsatellite DNA markers to assess genetic variation, population structure and the spatial scale that dispersal takes place across the distribution of this freshwater fish and used this information to identify conservation units for management. The levels of genetic variation found for N. obscura are amongst the lowest reported for a fish species (mean heterozygosity of 0.318 and mean allelic richness of 1.92). We identified very strong population genetic structure, nil to little evidence of recent migration among demes and a minimum of 11 units for conservation management, hierarchically nested within four major genetic lineages. A combination of spatial analytical methods revealed hierarchical genetic structure corresponding with catchment boundaries and also demonstrated significant isolation by riverine distance. Our findings have implications for the national recovery plan of this species by demonstrating that N. obscura populations should be managed at a catchment level and highlighting the need to restore habitat and avoid further alteration of the natural hydrology. PMID- 24349406 TI - Conversion of exogenous cholesterol into glycoalkaloids in potato shoots, using two methods for sterol solubilisation. AB - Steroidal glycoalkaloids (SGA) are toxic secondary metabolites naturally occurring in the potato, as well as in certain other Solanaceous plant species, such as tomato, eggplant and pepper. To investigate the steroidal origin of SGA biosynthesis, cut potato shoots were fed cholesterol labelled with deuterium (D) in the sterol ring structure (D5- or D6-labelled), or side chain (D7-labelled), and analysed after three or five weeks. The labelled cholesterol and presence of D-labelled SGA were analysed by GC-MS and LC-MS/MS, respectively. When feeding D labelled cholesterol solubilised in Tween-80, labelled cholesterol in free form became present in both leaves and stems, although the major part was recovered as steryl esters. Minor amounts of D-labelled SGA (alpha-solanine and alpha chaconine) were identified in cholesterol-treated shoots, but not in blank controls, or in shoots fed D6-27-hydroxycholesterol. Solubilising the labelled cholesterol in methyl-beta-cyclodextrin instead of Tween-80 increased the levels of labelled SGA up to 100-fold, and about 1 mole% of the labelled cholesterol was recovered as labelled SGA in potato leaves. Both side chain and ring structure D labels were retained in SGA, showing that the entire cholesterol molecule is converted to SGA. However, feeding side chain D7-labelled cholesterol resulted in D5-labelled SGA, indicating that two hydrogen atoms were released during formation of the SGA nitrogen-containing ring system. Feeding with D7-sitosterol did not produce any labelled SGA, indicating that cholesterol is a specific SGA precursor. In conclusion, we have demonstrated a superior performance of methyl beta-cyclodextrin for delivery of cholesterol in plant tissue feeding experiments, and given firm evidence for cholesterol as a specific sterol precursor of SGA in potato. PMID- 24349407 TI - Recall responses to tetanus and diphtheria vaccination are frequently insufficient in elderly persons. AB - Demographic changes and a more active life-style in older age have contributed to an increasing public awareness of the need for lifelong vaccination. Currently many older persons have been vaccinated against selected pathogens during childhood but lack regular booster immunizations. The impact of regular vaccinations when started late in life was analyzed in an open, explorative trial by evaluating the immune response against tetanus and diphtheria in healthy older individuals. 252 persons aged above 60 years received a booster vaccination against tetanus, diphtheria, pertussis and polio and a subcohort (n=87) was recruited to receive a second booster vaccination against tetanus, diphtheria and pertussis 5 years later. The percentage of unprotected individuals at the time of enrollment differed substantially for tetanus (12%) and diphtheria (65%). Despite protective antibody concentrations 4 weeks after the first vaccination in almost all vaccinees, antibodies had again dropped below protective levels in 10% (tetanus) and 45% (diphtheria) of the cohort after 5 years. Protection was restored in almost all vaccinees after the second vaccination. No correlation between tetanus- and diphtheria-specific responses was observed, and antibody concentrations were not associated with age-related changes in the T cell repertoire, inflammatory parameters, or CMV-seropositivity suggesting that there was no general biological "non-responder type." Post-vaccination antibody concentrations depended on pre-existing plasma cells and B cell memory as indicated by a strong positive relationship between post-vaccination antibodies and pre-vaccination antibodies as well as antibody-secreting cells. In contrast, antigen-specific T cell responses were not or only weakly associated with antibody concentrations. In conclusion, our findings demonstrate that single shot vaccinations against tetanus and/or diphtheria do not lead to long-lasting immunity in many elderly persons despite administration at relatively short intervals. Sufficient antigen-specific B cell memory B generated by adequate priming and consecutive booster vaccinations and/or exposure is a prerequisite for long-term protection. TRIAL REGISTRATION: EU Clinical Trials Register (EU CTR); EudraCT number 2009-011742-26; www.clinicaltrialsregister.eu/ctr search/trial/2009-011742-26/AT. PMID- 24349408 TI - Arsenic compromises conducting airway epithelial barrier properties in primary mouse and immortalized human cell cultures. AB - Arsenic is a lung toxicant that can lead to respiratory illness through inhalation and ingestion, although the most common exposure is through contaminated drinking water. Lung effects reported from arsenic exposure include lung cancer and obstructive lung disease, as well as reductions in lung function and immune response. As part of their role in innate immune function, airway epithelial cells provide a barrier that protects underlying tissue from inhaled particulates, pathogens, and toxicants frequently found in inspired air. We evaluated the effects of a five-day exposure to environmentally relevant levels of arsenic {<4MUM [~300 MUg/L (ppb)] as NaAsO2} on airway epithelial barrier function and structure. In a primary mouse tracheal epithelial (MTE) cell model we found that both micromolar (3.9 MUM) and submicromolar (0.8 MUM) arsenic concentrations reduced transepithelial resistance, a measure of barrier function. Immunofluorescent staining of arsenic-treated MTE cells showed altered patterns of localization of the transmembrane tight junction proteins claudin (Cl) Cl-1, Cl-4, Cl-7 and occludin at cell-cell contacts when compared with untreated controls. To better quantify arsenic-induced changes in tight junction transmembrane proteins we conducted arsenic exposure experiments with an immortalized human bronchial epithelial cell line (16HBE14o-). We found that arsenic exposure significantly increased the protein expression of Cl-4 and occludin as well as the mRNA levels of Cl-4 and Cl-7 in these cells. Additionally, arsenic exposure resulted in altered phosphorylation of occludin. In summary, exposure to environmentally relevant levels of arsenic can alter both the function and structure of airway epithelial barrier constituents. These changes likely contribute to the observed arsenic-induced loss in basic innate immune defense and increased infection in the airway. PMID- 24349409 TI - Fibroblast growth factor receptor 1 signaling in adult cardiomyocytes increases contractility and results in a hypertrophic cardiomyopathy. AB - Fibroblast growth factors (FGFs) and their receptors are highly conserved signaling molecules that have been implicated in postnatal cardiac remodeling. However, it is not known whether cardiomyocyte-expressed FGF receptors are necessary or sufficient for ventricular remodeling in the adult heart. To determine whether cardiomyocytes were competent to respond to an activated FGF receptor, and to determine if this signal would result in the development of hypertrophy, we engineered a doxycycline (DOX)-inducible, cardiomyocyte-specific, constitutively active FGF receptor mouse model (alphaMHC-rtTA, TRE-caFgfr1-myc). Echocardiographic and hemodynamic analysis indicated that acute expression of caFGFR1 rapidly and directly increased cardiac contractility, while chronic expression resulted in significant hypertrophy with preservation of systolic function. Subsequent histologic analysis showed increased cardiomyocyte cross sectional area and regions of myocyte disarray and fibrosis, classic features of hypertrophic cardiomyopathy (HCM). Analysis of downstream pathways revealed a lack of clear activation of classical FGF-mediated signaling pathways, but did demonstrate a reduction in Serca2 expression and troponin I phosphorylation. Isolated ventricular myocytes showed enhanced contractility and reduced relaxation, an effect that was partially reversed by inhibition of actin-myosin interactions. We conclude that adult cardiomyocytes are competent to transduce FGF signaling and that FGF signaling is sufficient to promote increased cardiomyocyte contractility in vitro and in vivo through enhanced intrinsic actin myosin interactions. Long-term, FGFR overexpression results in HCM with a dynamic outflow tract obstruction, and may serve as a unique model of HCM. PMID- 24349410 TI - Evaluating the impact of different sequence databases on metaproteome analysis: insights from a lab-assembled microbial mixture. AB - Metaproteomics enables the investigation of the protein repertoire expressed by complex microbial communities. However, to unleash its full potential, refinements in bioinformatic approaches for data analysis are still needed. In this context, sequence databases selection represents a major challenge. This work assessed the impact of different databases in metaproteomic investigations by using a mock microbial mixture including nine diverse bacterial and eukaryotic species, which was subjected to shotgun metaproteomic analysis. Then, both the microbial mixture and the single microorganisms were subjected to next generation sequencing to obtain experimental metagenomic- and genomic-derived databases, which were used along with public databases (namely, NCBI, UniProtKB/SwissProt and UniProtKB/TrEMBL, parsed at different taxonomic levels) to analyze the metaproteomic dataset. First, a quantitative comparison in terms of number and overlap of peptide identifications was carried out among all databases. As a result, only 35% of peptides were common to all database classes; moreover, genus/species-specific databases provided up to 17% more identifications compared to databases with generic taxonomy, while the metagenomic database enabled a slight increment in respect to public databases. Then, database behavior in terms of false discovery rate and peptide degeneracy was critically evaluated. Public databases with generic taxonomy exhibited a markedly different trend compared to the counterparts. Finally, the reliability of taxonomic attribution according to the lowest common ancestor approach (using MEGAN and Unipept software) was assessed. The level of misassignments varied among the different databases, and specific thresholds based on the number of taxon-specific peptides were established to minimize false positives. This study confirms that database selection has a significant impact in metaproteomics, and provides critical indications for improving depth and reliability of metaproteomic results. Specifically, the use of iterative searches and of suitable filters for taxonomic assignments is proposed with the aim of increasing coverage and trustworthiness of metaproteomic data. PMID- 24349411 TI - Comparative analysis of radiosensitizers for K-RAS mutant rectal cancers. AB - Approximately 40% of rectal cancers harbor activating K-RAS mutations, and these mutations are associated with poor clinical response to chemoradiotherapy. We aimed to identify small molecule inhibitors (SMIs) that synergize with ionizing radiation (IR) ("radiosensitizers") that could be incorporated into current treatment strategies for locally advanced rectal cancers (LARCs) expressing mutant K-RAS. We first optimized a high-throughput assay for measuring individual and combined effects of SMIs and IR that produces similar results to the gold standard colony formation assay. Using this screening platform and K-RAS mutant rectal cancer cell lines, we tested SMIs targeting diverse signaling pathways for radiosensitizing activity and then evaluated our top hits in follow-up experiments. The two most potent radiosensitizers were the Chk1/2 inhibitor AZD7762 and the PI3K/mTOR inhibitor BEZ235. The chemotherapeutic agent 5 fluorouracil (5-FU), which is used to treat LARC, synergized with AZD7762 and enhanced radiosensitization by AZD7762. This study is the first to compare different SMIs in combination with IR for the treatment of K-RAS mutant rectal cancer, and our findings suggest that Chk1/2 inhibitors should be evaluated in new clinical trials for LARC. PMID- 24349412 TI - Functional environmental screening of a metagenomic library identifies stlA; a unique salt tolerance locus from the human gut microbiome. AB - Functional environmental screening of metagenomic libraries is a powerful means to identify and assign function to novel genes and their encoded proteins without any prior sequence knowledge. In the current study we describe the identification and subsequent analysis of a salt-tolerant clone from a human gut metagenomic library. Following transposon mutagenesis we identified an unknown gene (stlA, for "salt tolerance locus A") with no current known homologues in the databases. Subsequent cloning and expression in Escherichia coli MKH13 revealed that stlA confers a salt tolerance phenotype in its surrogate host. Furthermore, a detailed in silico analysis was also conducted to gain additional information on the properties of the encoded StlA protein. The stlA gene is rare when searched against human metagenome datasets such as MetaHit and the Human Microbiome Project and represents a novel and unique salt tolerance determinant which appears to be found exclusively in the human gut environment. PMID- 24349413 TI - Correlates of unintended pregnancy in Ethiopia: results from a national survey. AB - BACKGROUND: Unintended pregnancy has been a major reproductive health challenge in resource poor settings including Ethiopia. It has adverse consequences to the mother, child and the health sector's resources. Understanding the extent of unintended pregnancy and the factors associated is crucial to devise evidence based interventions. The analysis was aimed at assessing the unintended pregnancy prevalence rate among pregnant women and the factors predisposing to unintended pregnancy. METHODS: This secondary data analysis was done on women's dataset from the 2011 Ethiopian Demographic and Health Survey (DHS). A total of 1267 pregnant women were included in the analysis. Multiple logistic regression analysis was performed using SPSS software to identify the factors associated with unintended pregnancy. Odds Ratio with 95% confidence interval (95% CI) was computed to assess the association of different factors with unintended pregnancy. RESULTS: The overall prevalence of unintended pregnancy was found to be 24%: those who wanted it at a later time and not at all accounted for 17.1% and 6.9%, respectively. The unintended pregnancy rate ranged from 1.5% in Afar Regional State to 39.8% in Oromiya Regional State. Women who knew the timing of ovulation had a 45% reduced chance of unintended pregnancy (OR (95% CI): 0.55 (0.35, 0.85)). Ever use of family planning, presence of five or more born children, and two or more births in the past five years were associated with unintended pregnancy (OR (95% CI): 1.79 (1.31, 2.45), 2.36 (1.01, 5.49) and 2.00 (1.12, 3.58), respectively). CONCLUSIONS: A significant proportion of the current pregnancies were found to be unintended with significant variations among the different regions. Women already burdened with higher fertility were suffering from unintended pregnancy. Family planning programs need to concentrate on the highly affected regions and target women with higher fertility to reduce the level of unintended pregnancy at national level. PMID- 24349414 TI - Psychoacoustic assessment to improve tinnitus diagnosis. AB - The diagnosis of tinnitus relies on self-report. Psychoacoustic measurements of tinnitus pitch and loudness are essential for assessing claims and discriminating true from false ones. For this reason, the quantification of tinnitus remains a challenging research goal. We aimed to: (1) assess the precision of a new tinnitus likeness rating procedure with a continuous-pitch presentation method, controlling for music training, and (2) test whether tinnitus psychoacoustic measurements have the sensitivity and specificity required to detect people faking tinnitus. Musicians and non-musicians with tinnitus, as well as simulated malingerers without tinnitus, were tested. Most were retested several weeks later. Tinnitus pitch matching was first assessed using the likeness rating method: pure tones from 0.25 to 16 kHz were presented randomly to participants, who had to rate the likeness of each tone to their tinnitus, and to adjust its level from 0 to 100 dB SPL. Tinnitus pitch matching was then assessed with a continuous-pitch method: participants had to match the pitch of their tinnitus to an external tone by moving their finger across a touch-sensitive strip, which generated a continuous pure tone from 0.5 to 20 kHz in 1-Hz steps. The predominant tinnitus pitch was consistent across both methods for both musicians and non-musicians, although musicians displayed better external tone pitch matching abilities. Simulated malingerers rated loudness much higher than did the other groups with a high degree of specificity (94.4%) and were unreliable in loudness (not pitch) matching from one session to the other. Retest data showed similar pitch matching responses for both methods for all participants. In conclusion, tinnitus pitch and loudness reliably correspond to the tinnitus percept, and psychoacoustic loudness matches are sensitive and specific to the presence of tinnitus. PMID- 24349415 TI - Recombinant IL-7/HGFbeta hybrid cytokine enhances T cell recovery in mice following allogeneic bone marrow transplantation. AB - T cell immunodeficiency is a major complication of bone marrow (BM) transplantation (BMT). Therefore, approaches to enhance T cell reconstitution after BMT are required. We have purified a hybrid cytokine, consisting of IL-7 and the beta-chain of hepatocyte growth factor (HGFbeta) (IL-7/HGFbeta), from a unique long-term BM culture system. We have cloned and expressed the IL-7/HGFbeta gene in which the IL-7 and HGFbeta genes are connected by a flexible linker to generate rIL-7/HGFbeta protein. Here, we show that rIL-7/HGFbeta treatment enhances thymopoiesis after allogeneic BMT. Although rIL-7 treatment also enhances the number of thymocytes, rIL-7/HGFbeta hybrid cytokine was more effective than was rIL-7 and the mechanisms by which rIL-7 and rIL-7/HGFbeta increase the numbers of thymocytes are different. rIL-7 enhances the survival of double negative (DN), CD4 and CD8 single positive (SP) thymocytes. In contrast, rIL-7/HGFbeta enhances the proliferation of the DN, SP thymocytes, as well as the survival of CD4 and CD8 double positive (DP) thymocytes. rIL-7/HGFbeta treatment also increases the numbers of early thymocyte progenitors (ETPs) and thymic epithelial cells (TECs). The enhanced thymic reconstitution in the rIL-7/HGFbeta treated allogeneic BMT recipients results in increased number and functional activities of peripheral T cells. Graft-versus-host-disease (GVHD) is not induced in the rIL-7/HGFbeta-treated BMT mice. Therefore, rIL-7/HGFbeta may offer a new tool for the prevention and/or treatment of T cell immunodeficiency following BMT. PMID- 24349416 TI - Stereoacuity with Frisby and revised FD2 stereo tests. AB - We compared near stereoacuity, measured with the Frisby test, and distance stereoacuity, measured with the revised Frisby-Davis (FD2) test, enabling a comparison with the original version of the FD2. In the revised version of the FD2 test, a white background is used instead of a backlit background. We also examined the effect of age, gender and visual problems. We used the Frisby test at distances ranging from 30-80 cm and FD2 at 6 m. The best possible score was 20 seconds of arc (arcsec) on the Frisby and 5 arcsec on the FD2; participants who could not perform a test despite demonstrating understanding of it were classed as stereonegative. We examined both the whole population recruited, and a sub population screened so as to exclude visual problems. We analysed our results in three age-groups: "visually developing" (36 children aged 5-10 years); "visually mature" (300 participants aged 11-49 years) and "older" (29 participants aged 50 82). In the whole population, the median stereoacuity on the Frisby test was 25, 20 and 85 arcsec in the three age-groups. In the sub-population with no visual problems, median Frisby stereoacuity was similar at 20, 20 and 80 arcsec respectively. On the FD2, the medians were 10, 10, 20 arcsec for the whole population and 7.5, 10 and 12.5 for the sub-population. Children were more likely than adults to be stereonegative on the FD2, although none of the children were stereonegative on the Frisby. The two tests showed fair agreement when used to classify people into three categories of stereovision. Poor stereovision was often associated with binocular problems such as tropia, but with many exceptions. In line with previous studies, we found improvements in measured stereoacuity in childhood and declines in late adulthood. The new FD2 test gives comparable values to the original FD2. PMID- 24349417 TI - Identifying vulnerable populations using a social determinants of health framework: analysis of national survey data across six Asia-Pacific countries. AB - BACKGROUND: In order to improve the health of the most vulnerable groups in society, the WHO called for research on the multiple and inter-linking factors shaping the social determinants of health (SDH). This paper analyses four key SDH (social cohesion, social inclusion, social empowerment and socioeconomic security) across six Asia-Pacific countries: Australia, Hong Kong, Japan, South Korea, Taiwan, and Thailand. METHODS: Population surveys were undertaken using a validated instrument in 2009-10, with sample sizes around 1000 in each country. The four SDH were analysed using multivariate binomial logistic regression to identify socio-demographic predictors in each country. RESULTS: Low socio economic security was associated with low income in all six study countries and with poor subjective health in Japan, South Korea and Thailand and with being married or cohabiting in Australia and Hong Kong. Low social cohesion was associated with low income in all countries and with undertaking household duties in South Korea, Thailand and Taiwan. Low social inclusion was associated with low income in Australia, South Korea and Taiwan and with poor subjective health in Australia, Japan and South Korea. Older people had lower social inclusion in Taiwan (50-59 years) and Hong Kong (retired), younger people in Japan and South Korea (20-29 years in both countries) and younger and middle-aged people in Australia. Low social empowerment was associated with low income in Australia, Thailand and Taiwan, with being aged 60 years or over in Australia, Hong Kong and South Korea, and over 50 years in Thailand. CONCLUSIONS: This paper provides baseline measures for identifying where and how policy should be altered to improve the SDH. Furthermore, these data can be used for future policy evaluation to identify whether changes in policy have indeed improved the SDH, particularly for marginalised and vulnerable populations. PMID- 24349418 TI - The disease-specific phenotype in cardiomyocytes derived from induced pluripotent stem cells of two long QT syndrome type 3 patients. AB - Long QT syndromes (LQTS) are heritable diseases characterized by prolongation of the QT interval on an electrocardiogram, which often leads to syncope and sudden cardiac death. Here we report the generation of induced pluripotent stems (iPS) cells from two patients with LQTS type 3 carrying a different point mutation in a sodium channel Nav1.5 (p.V240M and p.R535Q) and functional characterization of cardiomyocytes (CM) derived from them. The iPS cells exhibited all characteristic properties of pluripotent stem cells, maintained the disease-specific mutation and readily differentiated to CM. The duration of action potentials at 50% and 90% repolarization was longer in LQTS-3 CM as compared to control CM but this difference did not reach statistical significance due to high variations among cells. Sodium current recordings demonstrated longer time to peak and longer time to 90% of inactivation of the Na(+) channel in the LQTS-3 CM. This hints at a defective Na(+) channel caused by deficiency in open-state inactivation of the Na(+) channel that is characteristic of LQTS-3. These analyses suggest that the effect of channel mutation in the diseased CM is demonstrated in vitro and that the iPS cell-derived CM can serve as a model system for studying the pathophysiology of LQTS-3, toxicity testing and design of novel therapeutics. However, further improvements in the model are still required to reduce cell-to cell and cell line-to-cell line variability. PMID- 24349420 TI - Elucidating emergence and transmission of multidrug-resistant tuberculosis in treatment experienced patients by whole genome sequencing. AB - BACKGROUND: Understanding the emergence and spread of multidrug-resistant tuberculosis (MDR-TB) is crucial for its control. MDR-TB in previously treated patients is generally attributed to the selection of drug resistant mutants during inadequate therapy rather than transmission of a resistant strain. Traditional genotyping methods are not sufficient to distinguish strains in populations with a high burden of tuberculosis and it has previously been difficult to assess the degree of transmission in these settings. We have used whole genome analysis to investigate M. tuberculosis strains isolated from treatment experienced patients with MDR-TB in Uganda over a period of four years. METHODS AND FINDINGS: We used high throughput genome sequencing technology to investigate small polymorphisms and large deletions in 51 Mycobacterium tuberculosis samples from 41 treatment-experienced TB patients attending a TB referral and treatment clinic in Kampala. This was a convenience sample representing 69% of MDR-TB cases identified over the four year period. Low polymorphism was observed in longitudinal samples from individual patients (2-15 SNPs). Clusters of samples with less than 50 SNPs variation were examined. Three clusters comprising a total of 8 patients were found with almost identical genetic profiles, including mutations predictive for resistance to rifampicin and isoniazid, suggesting transmission of MDR-TB. Two patients with previous drug susceptible disease were found to have acquired MDR strains, one of which shared its genotype with an isolate from another patient in the cohort. CONCLUSIONS: Whole genome sequence analysis identified MDR-TB strains that were shared by more than one patient. The transmission of multidrug-resistant disease in this cohort of retreatment patients emphasises the importance of early detection and need for infection control. Consideration should be given to rapid testing for drug resistance in patients undergoing treatment to monitor the emergence of resistance and permit early intervention to avoid onward transmission. PMID- 24349419 TI - Identification and characterisation of Simiate, a novel protein linked to the fragile X syndrome. AB - A strict regulation of protein expression during developmental stages and in response to environmental signals is essential to every cell and organism. Recent research has shown that the mammalian brain is particularly sensitive to alterations in expression patterns of specific proteins and cognitive deficits as well as autistic behaviours have been linked to dysregulated protein expression. An intellectual disability characterised by changes in the expression of a variety of proteins is the fragile X syndrome. Due to the loss of a single mRNA binding protein, the Fragile X Mental Retardation Protein FMRP, vast misregulation of the mRNA metabolism is taking place in the disease. Here, we present the identification and characterisation of a novel protein named Simiate, whose mRNA contains several FMRP recognition motifs and associates with FMRP upon co-precipitation. Sequence analysis revealed that the protein evolved app. 1.7 billion years ago when eukaryotes developed. Applying antibodies generated against Simiate, the protein is detected in a variety of tissues, including the mammalian brain. On the subcellular level, Simiate localises to somata and nuclear speckles. We show that Simiate and nuclear speckles experience specific alterations in FMR1(-/-) mice. An antibody-based block of endogenous Simiate revealed that the protein is essential for cell survival. These findings suggest not only an important role for Simiate in gene transcription and/or RNA splicing, but also provide evidence for a function of nuclear speckles in the fragile X syndrome. Indeed, transcription and splicing are two fundamental mechanisms to control protein expression, that underlie not only synaptic plasticity and memory formation, but are also affected in several diseases associated with mental disabilities. PMID- 24349421 TI - Gathering and exploring scientific knowledge in pharmacovigilance. AB - Pharmacovigilance plays a key role in the healthcare domain through the assessment, monitoring and discovery of interactions amongst drugs and their effects in the human organism. However, technological advances in this field have been slowing down over the last decade due to miscellaneous legal, ethical and methodological constraints. Pharmaceutical companies started to realize that collaborative and integrative approaches boost current drug research and development processes. Hence, new strategies are required to connect researchers, datasets, biomedical knowledge and analysis algorithms, allowing them to fully exploit the true value behind state-of-the-art pharmacovigilance efforts. This manuscript introduces a new platform directed towards pharmacovigilance knowledge providers. This system, based on a service-oriented architecture, adopts a plugin based approach to solve fundamental pharmacovigilance software challenges. With the wealth of collected clinical and pharmaceutical data, it is now possible to connect knowledge providers' analysis and exploration algorithms with real data. As a result, new strategies allow a faster identification of high-risk interactions between marketed drugs and adverse events, and enable the automated uncovering of scientific evidence behind them. With this architecture, the pharmacovigilance field has a new platform to coordinate large-scale drug evaluation efforts in a unique ecosystem, publicly available at http://bioinformatics.ua.pt/euadr/. PMID- 24349422 TI - HDAC inhibitors repress BARD1 isoform expression in acute myeloid leukemia cells via activation of miR-19a and/or b. AB - Over the past years BARD1 (BRCA1-associated RING domain 1) has been considered as both a BRCA1 (BReast Cancer susceptibility gene 1, early onset) interactor and tumor suppressor gene mutated in breast and ovarian cancers. Despite its role as a stable heterodimer with BRCA1, increasing evidence indicates that BARD1 also has BRCA1-independent oncogenic functions. Here, we investigate BARD1 expression and function in human acute myeloid leukemias and its modulation by epigenetic mechanism(s) and microRNAs. We show that the HDACi (histone deacetylase inhibitor) Vorinostat reduces BARD1 mRNA levels by increasing miR-19a and miR-19b expression levels. Moreover, we identify a specific BARD1 isoform, which might act as tumor diagnostic and prognostic markers. PMID- 24349423 TI - A study of cytological changes in the bone marrow of patients with severe fever with thrombocytopenia syndrome. AB - BACKGROUND: Peripheral blood leucopenia and thrombocytopenia are the main manifestations in severe fever with thrombocytopenia syndrome (SFTS) patients. However, the underlying causes are poorly understood. Therefore, we aimed to investigate cytology of bone marrow samples collected from SFTS patients. METHODS: 10 SFTS patients were identified by typical clinical manifestations, detection of peripheral blood leucopenia and thrombocytopenia, and nucleic acid based detection of the newly identified bunyavirus. SFTS patients, along with 10 participants with acute aplastic anemia and 10 healthy volunteers were enrolled in this study after written informed consent to undergo bone marrow cytological examination. RESULTS: We observed similar bone marrow properties in SFTS patients and healthy volunteers, significantly different from the characteristics observed in acute aplastic anemia patients. CONCLUSION: Similarities between bone marrow samples collected from SFTS patients and healthy volunteers suggest that peripheral blood leucopenia and thrombocytopenia do not result from bone marrow cell plasticity. PMID- 24349424 TI - Genetic mapping of quantitative trait loci underlying flowering time in chrysanthemum (Chrysanthemum morifolium). AB - Flowering time is an important trait in chrysanthemum, but its genetic basis remains poorly understood. An intra-specific mapping population bred from the cross between the autumn-flowering cultivar 'Yuhualuoying' and the summer flowering 'Aoyunhanxiao' was used to determine the number and relative effect of QTL segregating for five measures of flowering time. From flowering time data recorded over two consecutive seasons, 35 additive QTL were detected, each explaining between 5.8% and 22.7% of the overall phenotypic variance. Of these, 13 were detected in both years. Nine genomic regions harboring QTL for at least two of the five traits were identified. Ten pairs of loci epistatically determined the flowering time, but their contribution to the overall phenotypic variance was less than for the additive QTL. The results suggest that flowering time in chrysanthemum is principally governed by main effect QTL but that epistasis also contributes to the genetic architecture of the trait, and the major QTL identified herein are useful in our ongoing efforts to streamline the improvement of chrysanthemum via the use of molecular methodology. PMID- 24349425 TI - Identification and validation of reference genes for qPCR detection of serum microRNAs in colorectal adenocarcinoma patients. AB - Serum microRNAs (miRNAs) have become a highlighted research hotspot, especially for their great potential as a novel promising non-invasive biomarker in cancer diagnosis. The most frequently used approach for serum miRNAs detection is quantitative real time polymerase chain reaction (qPCR). In order to obtain reliable qPCR data of miRNAs expression, the use of reference genes as endogenous control is undoubtly necessary. However, no systematic evaluation and validation of reference genes for normalizing qPCR analysis of serum miRNAs has been reported in colorectal adenocarcinoma. We firstly profiled pooled serum of colorectal adenocarcinoma, colorectal adenoma and healthy controls and selected a list of 13 miRNAs as candidate reference genes. U6 snRNA (U6) and above-mentioned 13 miRNAs were included in further confirmation by qPCR. As a result, 5 miRNAs (miR-151a-3p, miR-4446-3p, miR-221-3p, miR-93-5p and miR-3184-3p) were not detected in all samples and 2 miRNAs (miR-197-3p and miR-26a-5p) were relatively low with median Cq more than 35, and were excluded from further stability analysis. Then variable stability of other 6 miRNAs (miR-103b, miR-484, miR-16 5p, miR-3615, miR-18a-3p and miR-191-5p) and U6 were evaluated using two algorithms: geNorm and NormFinder which both identified miR-191-5p as the most stably expressed reference gene and selected miR-191-5p and U6 as the most stable pair of reference genes. After validating in an independent large cohorts and selecting miR-92a-3p as target miRNA to evaluate the effect of reference gene, we propose that combination of miR-191-5p and U6 could be used as reference genes for serum microRNAs qPCR data in colorectal adenocarcinoma, colorectal adenoma and healthy controls. PMID- 24349426 TI - TheTGFB1 functional polymorphism rs1800469 and susceptibility to atrial fibrillation in two Chinese Han populations. AB - Transforming growth factor-beta1 (TGF-beta1) is related to the degree of atrial fibrosis and plays critical roles in the induction and perpetuation of atrial fibrillation (AF). To investigate the association of the common promoter polymorphism rs1800469 in the TGF-beta1 gene (TGFB1) with the risk of AF in Chinese Han population, we carried out a case-control study of two hospital-based independent populations: Southeast Chinese population (581 patients with AF and 723 controls), and Northeast Chinese population (308 AF patients and 292 controls). Two hundred and seventy-eight cases of AF were lone AF and 334 cases of AF were diagnosed as paroxysmal AF. In both populations, AF patients had larger left atrial diameters than the controls did. The rs1800469 genotypes in the TGFB1 gene were determined by polymerase chain reaction-restriction fragment length polymorphism. The genotype and allele frequencies of rs1800469 were not different between AF patients and controls of the Southeast Chinese population, Northeast Chinese population, and total Study Population. After adjustment for age, sex, hypertension and LAD, there was no association between the rs1800469 polymorphism and the risk of AF under the dominant, recessive and additive genetic models. Similar results were obtained from subanalysis of the lone and paroxymal AF subgroups. Our results do not support the role of the TGFB1 rs1800469 functional gene variant in the development of AF in the Chinese Han population. PMID- 24349427 TI - Mechanical ventilation drives inflammation in severe viral bronchiolitis. AB - INTRODUCTION: Respiratory insufficiency due to severe respiratory syncytial virus (RSV) infection is the most frequent cause of paediatric intensive care unit admission in infants during the winter season. Previous studies have shown increased levels of inflammatory mediators in airways of mechanically ventilated children compared to spontaneous breathing children with viral bronchiolitis. In this prospective observational multi-center study we aimed to investigate whether this increase was related to disease severity or caused by mechanical ventilation. MATERIALS AND METHODS: Nasopharyngeal aspirates were collected <1 hour before intubation and 24 hours later in RSV bronchiolitis patients with respiratory failure (n = 18) and non-ventilated RSV bronchiolitis controls (n = 18). Concentrations of the following cytokines were measured: interleukin (IL) 1alpha, IL-1beta, IL-6, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1alpha. RESULTS: Baseline cytokine levels were comparable between ventilated and non-ventilated infants. After 24 hours of mechanical ventilation mean cytokine levels, except for MIP-1alpha, were elevated compared to non-ventilated infected controls: IL-1alpha (159 versus 4 pg/ml, p<0.01), IL-1beta (1068 versus 99 pg/ml, p<0.01), IL-6 (2343 versus 958 pg/ml, p<0.05) and MCP-1 (174 versus 26 pg/ml, p<0.05). CONCLUSIONS: Using pre- and post intubation observations, this study suggests that endotracheal intubation and subsequent mechanical ventilation cause a robust pulmonary inflammation in infants with RSV bronchiolitis. PMID- 24349428 TI - Characterization of amylolysin, a novel lantibiotic from Bacillus amyloliquefaciens GA1. AB - BACKGROUND: Lantibiotics are heat-stable peptides characterized by the presence of thioether amino acid lanthionine and methyllanthionine. They are capable to inhibit the growth of Gram-positive bacteria, including Listeria monocytogenes, Staphylococcus aureus or Bacillus cereus, the causative agents of food-borne diseases or nosocomial infections. Lantibiotic biosynthetic machinery is encoded by gene cluster composed by a structural gene that codes for a pre-lantibiotic peptide and other genes involved in pre-lantibiotic modifications, regulation, export and immunity. METHODOLOGY/FINDINGS: Bacillus amyloliquefaciens GA1 was found to produce an antimicrobial peptide, named amylolysin, active on an array of Gram-positive bacteria, including methicillin resistant S. aureus. Genome characterization led to the identification of a putative lantibiotic gene cluster that comprises a structural gene (amlA) and genes involved in modification (amlM), transport (amlT), regulation (amlKR) and immunity (amlFE). Disruption of amlA led to loss of biological activity, confirming thus that the identified gene cluster is related to amylolysin synthesis. MALDI-TOF and LC-MS analysis on purified amylolysin demonstrated that this latter corresponds to a novel lantibiotic not described to date. The ability of amylolysin to interact in vitro with the lipid II, the carrier of peptidoglycan monomers across the cytoplasmic membrane and the presence of a unique modification gene suggest that the identified peptide belongs to the group B lantibiotic. Amylolysin immunity seems to be driven by only two AmlF and AmlE proteins, which is uncommon within the Bacillus genus. CONCLUSION/SIGNIFICANCE: Apart from mersacidin produced by Bacillus amyloliquefaciens strains Y2 and HIL Y-85,544728, reports on the synthesis of type B-lantibiotic in this species are scarce. This study reports on a genetic and structural characterization of another representative of the type B lantibiotic in B. amyloliquefaciens. PMID- 24349429 TI - LASIK following small incision lenticule extraction (SMILE) lenticule re implantation: a feasibility study of a novel method for treatment of presbyopia. AB - Presbyopia remains a major visual impairment for patients, who have previously undergone laser refractive correction and enjoyed unaided distance vision prior to the onset of presbyopia. Corneal stromal volume restoration through small incision lenticule extraction (SMILE) lenticule re-implantation presents an opportunity for restoring the patients' non-dominant eye to previous low myopia to achieve a monovision. In this study, we investigated the feasibility of performing LASIK after lenticule re-implantation as a method to create presbyopic monovision. A -6.00D SMILE correction was performed in 9 rabbit eyes. The lenticules were cryopreserved for 14 days and re-implanted. Five weeks later, 3 of these eyes underwent LASIK for -5.00D correction (RL group); 3 underwent LASIK flap creation, which was not lifted (RN); and no further procedures were performed on the remaining 3 eyes. These groups were compared with 3 eyes that underwent standard LASIK for a -5.00D correction (LO); 3 that underwent creation of non-lifted flap (LN); and 3 non-operated eyes. Rabbits were euthanized 1 day post-surgery. Tissue responses were analyzed by immunohistochemistry, slit lamp and in vivo confocal microscopy (IVCM). Intrastromal irregularities and elevated reflectivity levels of the excimer-ablated plane were observed on slit lamp and IVCM, respectively in the RL group. The results were comparable (P = 0.310) to IVCM findings in the LO group. RL and LO groups showed similar fibronectin expression levels, number of CD11b-positive cells (P = 0.304) and apoptotic cells (P = 0.198). There was no difference between the RN and LN groups in reflectivity levels (P = 0.627), fibronectin expression levels, CD11b-positive cells (P = 0.135) and apoptotic cells (P = 0.128). LASIK can be performed following lenticule re-implantation to create presbyopic monovision. The tissue responses elicited after performing LASIK on corneas that have undergone SMILE and subsequent lenticule re-implantation are similar to primary procedure. PMID- 24349430 TI - Natural conditions override differences in emergence rhythm among closely related drosophilids. AB - Previous studies on adult emergence rhythm of Drosophila melanogaster (DM) done under semi-natural conditions have shown that emergence is correlated to daily changes in temperature, humidity and light at dawn. Recently we showed that under laboratory conditions D. ananassae (DA), a closely related species of DM exhibits patterns in its activity/rest rhythm distinct from the latter. Here, we report the results of a study aimed at examining whether this difference in activity/rest rhythm among species extends to other circadian behaviours such as the adult emergence rhythm under a more natural environment with multiple cyclic time cues. We monitored the adult emergence rhythm of recently wild-caught DM and DA populations in parallel with those of a related species D. malerkotliana (DK), both in the laboratory and under semi-natural conditions. We find that although DM, DK and DA showed marked difference from one another under laboratory conditions, such differences were not detectable in the emergence behaviour of these three species under semi-natural conditions, and that they respond very similarly to seasonal changes in the environment. The results suggest that seasonal changes in temperature and humidity contribute largely to the variation in adult emergence waveform in terms of gate width, phase and amplitude of the peak and day-to-day variance in the timing of the emergence peak. In all three species, seasons with cooler and wetter conditions make the rhythm less tightly gated, with low amplitude peak and high day-to-day variation in timing of the peak of emergence. We show that in nature the emergence rhythm of DM, DK and DA is strongly influenced by environmental factors such that in a given season all of them exhibit similar time course and waveform and that with the changing season, they all modify their emergence patterns in a similar manner. PMID- 24349431 TI - The ciliary protein cystin forms a regulatory complex with necdin to modulate Myc expression. AB - Cystin is a novel cilia-associated protein that is disrupted in the cpk mouse, a well-characterized mouse model of autosomal recessive polycystic kidney disease (ARPKD). Interestingly, overexpression of the Myc gene is evident in animal models of ARPKD and is thought to contribute to the renal cystic phenotype. Using a yeast two-hybrid approach, the growth suppressor protein necdin, known to modulate Myc expression, was found as an interacting partner of cystin. Deletion mapping demonstrated that the C-terminus of cystin and both termini of necdin are required for their mutual interaction. Speculating that these two proteins may function to regulate gene expression, we developed a luciferase reporter assay and observed that necdin strongly activated the Myc P1 promoter, and cystin did so more modestly. Interestingly, the necdin effect was significantly abrogated when cystin was co-transfected. Chromatin immunoprecipitation and electrophoretic mobility shift assays revealed a physical interaction with both necdin and cystin and the Myc P1 promoter, as well as between these proteins. The data suggest that these proteins likely function in a regulatory complex. Thus, we speculate that Myc overexpression in the cpk kidney results from the dysregulation of the cystin necdin regulatory complex and c-Myc, in turn, contributes to cystogenesis in the cpk mouse. PMID- 24349432 TI - Proteomic profiling of Burkholderia cenocepacia clonal isolates with different virulence potential retrieved from a cystic fibrosis patient during chronic lung infection. AB - Respiratory infections with Burkholderia cepacia complex (Bcc) bacteria in cystic fibrosis (CF) are associated with a worse prognosis and increased risk of death. In this work, we assessed the virulence potential of three B. cenocepacia clonal isolates obtained from a CF patient between the onset of infection (isolate IST439) and before death with cepacia syndrome 3.5 years later (isolate IST4113 followed by IST4134), based on their ability to invade epithelial cells and compromise epithelial monolayer integrity. The two clonal isolates retrieved during late-stage disease were significantly more virulent than IST439. Proteomic profiling by 2-D DIGE of the last isolate recovered before the patient's death, IST4134, and clonal isolate IST439, was performed and compared with a prior analysis of IST4113 vs. IST439. The cytoplasmic and membrane-associated enriched fractions were examined and 52 proteins were found to be similarly altered in the two last isolates compared with IST439. These proteins are involved in metabolic functions, nucleotide synthesis, translation and protein folding, cell envelope biogenesis and iron homeostasis. Results are suggestive of the important role played by metabolic reprogramming in the virulence potential and persistence of B. cenocepacia, in particular regarding bacterial adaptation to microaerophilic conditions. Also, the content of the virulence determinant AidA was higher in the last 2 isolates. Significant levels of siderophores were found to be secreted by the three clonal isolates in an iron-depleted environment, but the two late isolates were more tolerant to low iron concentrations than IST439, consistent with the relative abundance of proteins involved in iron uptake. PMID- 24349433 TI - A trio of viral proteins tunes aphid-plant interactions in Arabidopsis thaliana. AB - BACKGROUND: Virus-induced deterrence to aphid feeding is believed to promote plant virus transmission by encouraging migration of virus-bearing insects away from infected plants. We investigated the effects of infection by an aphid transmitted virus, cucumber mosaic virus (CMV), on the interaction of Arabidopsis thaliana, one of the natural hosts for CMV, with Myzus persicae (common names: 'peach-potato aphid', 'green peach aphid'). METHODOLOGY/PRINCIPAL FINDINGS: Infection of Arabidopsis (ecotype Col-0) with CMV strain Fny (Fny-CMV) induced biosynthesis of the aphid feeding-deterrent 4-methoxy-indol-3-yl methylglucosinolate (4MI3M). 4MI3M inhibited phloem ingestion by aphids and consequently discouraged aphid settling. The CMV 2b protein is a suppressor of antiviral RNA silencing, which has previously been implicated in altering plant aphid interactions. Its presence in infected hosts enhances the accumulation of CMV and the other four viral proteins. Another viral gene product, the 2a protein (an RNA-dependent RNA polymerase), triggers defensive signaling, leading to increased 4MI3M accumulation. The 2b protein can inhibit ARGONAUTE1 (AGO1), a host factor that both positively-regulates 4MI3M biosynthesis and negatively regulates accumulation of substance(s) toxic to aphids. However, the 1a replicase protein moderated 2b-mediated inhibition of AGO1, ensuring that aphids were deterred from feeding but not poisoned. The LS strain of CMV did not induce feeding deterrence in Arabidopsis ecotype Col-0. CONCLUSIONS/SIGNIFICANCE: Inhibition of AGO1 by the 2b protein could act as a booby trap since this will trigger antibiosis against aphids. However, for Fny-CMV the interplay of three viral proteins (1a, 2a and 2b) appears to balance the need of the virus to inhibit antiviral silencing, while inducing a mild resistance (antixenosis) that is thought to promote transmission. The strain-specific effects of CMV on Arabidopsis-aphid interactions, and differences between the effects of Fny-CMV on this plant and those seen previously in tobacco (inhibition of resistance to aphids) may have important epidemiological consequences. PMID- 24349434 TI - Role of miR-17 family in the negative feedback loop of bone morphogenetic protein signaling in neuron. AB - Bone morphogenetic protein (BMP) signaling is active in many tissues including the central nervous system, in which it regulates cell proliferation, differentiation and maturation. The modulation of BMP pathway is crucial since abnormality of BMP signaling may cause cellular malfunction such as apoptosis. There are evidences indicating that miR-17 family is involved in the BMP signaling. In the present study, we demonstrated that BMP2 stimulation directly increased the transcription of miR-17-92 and miR-106b-25 cluster via Smad activation, which leads to the up-regulation of mature miR-17/20a/93. In addition, we provided evidence that BMP2 activation repressed BMPRII expression through modulating miR-17 family in primary neurons. Furthermore, we proved that such negative regulation protected neurons from apoptosis induced by abnormal BMP signaling. Taken together, these results suggest a regulatory pathway of BMP-miR 17 family-BMPRII, which consist a negative feedback loop that balances BMP signaling and maintains cell homeostasis in neurons. PMID- 24349435 TI - Do strategies to improve quality of maternal and child health care in lower and middle income countries lead to improved outcomes? A review of the evidence. AB - OBJECTIVES: Efforts to scale-up maternal and child health services in lower and middle income countries will fail if services delivered are not of good quality. Although there is evidence of strategies to increase the quality of health services, less is known about the way these strategies affect health system goals and outcomes. We conducted a systematic review of the literature to examine this relationship. METHODS: We undertook a search of MEDLINE, SCOPUS and CINAHL databases, limiting the results to studies including strategies specifically aimed at improving quality that also reported a measure of quality and at least one indicator related to health system outcomes. Variation in study methodologies prevented further quantitative analysis; instead we present a narrative review of the evidence. FINDINGS: Methodologically, the quality of evidence was poor, and dominated by studies of individual facilities. Studies relied heavily on service utilisation as a measure of strategy success, which did not always correspond to improved quality. The majority of studies targeted the competency of staff and adequacy of facilities. No strategies addressed distribution systems, public private partnership or equity. Key themes identified were the conflict between perceptions of patients and clinical measures of quality and the need for holistic approaches to health system interventions. CONCLUSION: Existing evidence linking quality improvement strategies to improved MNCH outcomes is extremely limited. Future research would benefit from the inclusion of more appropriate indicators and additional focus on non-facility determinants of health service quality such as health policy, supply distribution, community acceptability and equity of care. PMID- 24349436 TI - A large novel deletion downstream of PAX6 gene in a Chinese family with ocular coloboma. AB - PURPOSE: The paired box gene 6 (PAX6) is an essential transcription factor for eye formation. Genetic alterations in PAX6 can lead to various ocular malformations including aniridia. The purpose of this study was to identify genetic defects as the underlying cause of familial ocular coloboma in a large Chinese family. METHODS: After linkage analysis was carried out in this family, all exons of PAX6 in the proband were sequenced by the Sanger sequencing technique. Then the genome of the proband was evaluated by a microarray-based comparative genomic hybridization (aCGH). Quantitative real-time PCR was applied to verify the abnormal aCGH findings. RESULTS: All patients presented bilateral partial coloboma of iris, severe congenital nystagmus, hyperpresbyopia and congenital posterior polar cataracts. Two-point linkage analysis in the autosomal dominant family showed loss of heterozygosity at the D11S914 locus. There was no pathogenic mutation in the exons of PAX6. The aCGH analysis revealed a 681 kb heterozygous deletion on chromosome 11p13. Quantitative real-time PCR verified the deletion in the patients and further confirmed this deletion cosegregation with the ocular coloboma phenotype in the family. CONCLUSIONS: The 681 kb large deletion of chromosome 11p13 downstream of PAX6 is the genetic cause of the familial ocular coloboma in this large Chinese family. aCGH should be applied if there is a negative result for the mutation detection of PAX6 in patients with ocular coloboma. PMID- 24349437 TI - Cell-specific cre recombinase expression allows selective ablation of glutamate receptors from mouse horizontal cells. AB - In the mouse retina, horizontal cells form an electrically coupled network and provide feedback signals to photoreceptors and feedforward signals to bipolar cells. Thereby, horizontal cells contribute to gain control at the first visual synapse and to the antagonistic organization of bipolar and ganglion cell receptive fields. However, the nature of horizontal cell output remains a matter of debate, just as the exact contribution of horizontal cells to center-surround antagonism. To facilitate studying horizontal cell function, we developed a knockin mouse line which allows ablating genes exclusively in horizontal cells. This knockin line expresses a Cre recombinase under the promoter of connexin57 (Cx57), a gap junction protein only expressed in horizontal cells. Consistently, in Cx57+/Cre mice, Cre recombinase is expressed in almost all horizontal cells (>99%) and no other retinal neurons. To test Cre activity, we crossbred Cx57+/Cre mice with a mouse line in which exon 11 of the coding sequence for the ionotropic glutamate receptor subunit GluA4 was flanked by two loxP sites (GluA4fl/fl). In GluA4fl/fl:Cx57+/Cre mice, GluA4 immunoreactivity was significantly reduced (~ 50%) in the outer retina where horizontal cells receive photoreceptor inputs, confirming the functionality of the Cre/loxP system. Whole-cell patch-clamp recordings from isolated horizontal cell somata showed a reduction of glutamate induced inward currents by ~ 75%, suggesting that the GluA4 subunit plays a major role in mediating photoreceptor inputs. The persistent current in GluA4-deficient cells is mostly driven by AMPA and to a very small extent by kainate receptors as revealed by application of the AMPA receptor antagonist GYKI52466 and concanavalin A, a potentiator of kainate receptor-mediated currents. In summary, the Cx57+/Cre mouse line provides a versatile tool for studying horizontal cell function. GluA4fl/fl:Cx57+/Cre mice, in which horizontal cells receive less excitatory input, can thus be used to analyze the contribution of horizontal cells to retinal processing. PMID- 24349438 TI - Lin28 induces epithelial-to-mesenchymal transition and stemness via downregulation of let-7a in breast cancer cells. AB - The RNA-binding protein Lin28 is known to promote malignancy by inhibiting the biogenesis of let-7, which functions as a tumor suppressor. However, the role of the Lin28/let-7 axis in the epithelial-to-mesenchymal transition (EMT) and stemness in breast cancer has not been clearly expatiated. In our previous study, we demonstrated that let-7 regulates self-renewal and tumorigenicity of breast cancer stem cells. In the present study, we demonstrated that Lin28 was highly expressed in mesenchymal (M) type cells (MDA-MB-231 and SK-3rd), but it was barely detectable in epithelial (E) type cells (MCF-7 and BT-474). Lin28 remarkably induced the EMT, increased a higher mammosphere formation rate and ALDH activity and subsequently promoted colony formation, as well as adhesion and migration in breast cancer cells. Furthermore, we demonstrated that Lin28 induced EMT in breast cancer cells via downregulation of let-7a. Strikingly, Lin28 overexpression was found in breast cancers that had undergone metastasis and was strongly predictive of poor prognoses in breast cancers. Given that Lin28 induced the EMT via let-7a and promoted breast cancer metastasis, Lin28 may be a therapeutic target for the eradication of breast cancer metastasis. PMID- 24349439 TI - Propranolol restricts the mobility of single EGF-receptors on the cell surface before their internalization. AB - The epidermal growth factor receptor is involved in morphogenesis, proliferation and cell migration. Its up-regulation during tumorigenesis makes this receptor an interesting therapeutic target. In the absence of the ligand, the inhibition of phosphatidic acid phosphohydrolase activity by propranolol treatment leads to internalization of empty/inactive receptors. The molecular events involved in this endocytosis remain unknown. Here, we quantified the effects of propranolol on the mobility of single quantum-dot labelled receptors before the actual internalization took place. The single receptors showed a clear stop-and-go motion; their diffusive tracks were continuously interrupted by sub-second stalling events, presumably caused by transient clustering. In the presence of propranolol we found that: i) the diffusion rate reduced by 22 %, which indicates an increase in drag of the receptor. Atomic force microscopy measurements did not show an increase of the effective membrane tension, such that clustering of the receptor remains the likely mechanism for its reduced mobility. ii) The receptor got frequently stalled for longer periods of multiple seconds, which may signal the first step of the internalization process. PMID- 24349440 TI - Structures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling. AB - Zinc RING finger 3 (ZNRF3) and its homolog RING finger 43 (RNF43) antagonize Wnt signaling in adult stem cells by ubiquitinating Frizzled receptors (FZD), which leads to endocytosis of the Wnt receptor. Conversely, binding of ZNRF3/RNF43 to LGR4-6 - R-spondin blocks Frizzled ubiquitination and enhances Wnt signaling. Here, we present crystal structures of the ZNRF3 ectodomain and its complex with R-spondin 1 (RSPO1). ZNRF3 binds RSPO1 and LGR5-RSPO1 with micromolar affinity via RSPO1 furin-like 1 (Fu1) domain. Anonychia-related mutations in RSPO4 support the importance of the observed interface. The ZNRF3-RSPO1 structure resembles that of LGR5-RSPO1-RNF43, though Fu2 of RSPO1 is variably oriented. The ZNRF3 binding site overlaps with trans-interactions observed in 2:2 LGR5-RSPO1 complexes, thus binding of ZNRF3/RNF43 would disrupt such an arrangement. Sequence conservation suggests a single ligand-binding site on ZNRF3, consistent with the proposed competing binding role of ZNRF3/RNF43 in Wnt signaling. PMID- 24349441 TI - Functional complementation of sir2Delta yeast mutation by the human orthologous gene SIRT1. AB - Sirtuins, class III histone deacetylases, are proteins homologous to the yeast protein Sir2p. Mammalian Sirt1 has been shown to be involved in energy metabolism, brain functions, inflammation and aging through its deacetylase activity, acting on both histone and non-histone substrates. In order to verify whether Sirt1 can replace Sir2p in the yeast cells, we expressed the full-length human Sirt1 protein in S.cerevisiae sir2Delta mutant strain. The structure of chromatin is basically maintained from yeast to human. Thus, yeast chromatin is a favourable environment to evaluate, inhibit or activate an ectopic histone deacetylase activity in an in vivo substrate. Mutant sir2Delta shows a series of different phenotypes, all dependent on the deacetylase activity of Sir2p. We analyzed the three silent loci where normally Sir2p acts: ribosomal DNA, telomeres and the mating type loci. Moreover, we verified extrachromosomal ribosomal DNA circles production and histone hyperacetylation levels, typical marks of sir2Delta strains. By strong SIRT1 overexpression in sir2Delta cells, we found that specific molecular phenotypes of the mutant revert almost to a wild type condition. In particular, transcriptional silencing at rDNA was restored, extrachromosomal rDNA circles formation was repressed and histone acetylation at H3K9 and H4K16 decreased. The complementation at the other studied loci: HM loci, telomere and sub-telomere does not occur. Overall, our observations indicate that: i) SIRT1 gene is able to complement different molecular phenotypes of the sir2Delta mutant at rDNA ii) the in vivo screening of Sirt1 activity is possible in yeast. PMID- 24349442 TI - A trifluoromethyl analogue of celecoxib exerts beneficial effects in neuroinflammation. AB - Celecoxib is a selective cyclooxygenase-2 (COX2) inhibitor. We have previously shown that celecoxib inhibits experimental autoimmune encephalomyelitis (EAE) in COX-2-deficient mice, suggestive for a mode of action involving COX2-independent pathways. In the present study, we tested the effect of a trifluoromethyl analogue of celecoxib (TFM-C) with 205-fold lower COX-2 inhibitory activity in two models of neuroinflammation, i.e. cerebellar organotypic cultures challenged with LPS and the EAE mouse model for multiple sclerosis. TFM-C inhibited secretion of IL-1beta, IL-12 and IL-17, enhanced that of TNF-alpha and RANTES, reduced neuronal axonal damage and protected from oxidative stress in the organotypic model. TFM-C blocked TNF-alpha release in microglial cells through a process involving intracellular retention, but induced TNF-alpha secretion in primary astrocyte cultures. Finally, we demonstrate that TFM-C and celecoxib ameliorated EAE with equal potency. This coincided with reduced secretion of IL 17 and IFN-gamma by MOG-reactive T-cells and of IL-23 and inflammatory cytokines by bone marrow-derived dendritic cells. Our study reveals that non-coxib analogues of celecoxib may have translational value in the treatment of neuro inflammatory conditions. PMID- 24349444 TI - The clinical value of Huangqi injection in the treatment of leucopenia: a meta analysis of clinical controlled trials. AB - BACKGROUND: Huangqi injection is derived from Astragalus membranaceus root. In China, recent reports of Huangqi injection for the treatment of leucopenia have emerged. However, a systematic review of these reports has not been performed. Thus, we conducted a meta-analysis of clinical controlled trials to assess the clinical value of Huangqi injection in the treatment of leucopenia. METHODS: We searched the Chinese Biomedical Literature Database (CBM), Wanfang Database, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Full text Database (VIP), as well as PubMed and EMBASE to collect the data about trials of Huangqi injection for treating leucopenia. A meta-analysis was performed using RevMan 5.2 software. RESULTS: A total of 13 studies involving 841 patients were included in this study. The overall study quality was lower according to the Jadad scale. The meta-analysis showed that experimentally treated patients experienced greater therapeutic efficacy and lower white blood cell counts than control groups treated with Western medicine (P < 0.05). No publication bias was evident, according to Egger's test. CONCLUSIONS: The validity of this meta-analysis was limited by the overall poor quality of the included studies. Huangqi injection may have potential clinical value in the treatment of leucopenia, but confirmation with rigorously well-designed multi center trials is needed. PMID- 24349443 TI - Association of TERC and OBFC1 haplotypes with mean leukocyte telomere length and risk for coronary heart disease. AB - OBJECTIVE: To replicate the associations of leukocyte telomere length (LTL) with variants at four loci and to investigate their associations with coronary heart disease (CHD) and type II diabetes (T2D), in order to examine possible causal effects of telomere maintenance machinery on disease aetiology. METHODS: Four SNPs at three loci BICD1 (rs2630578 GgammaC), 18q12.2 (rs2162440 GgammaT), and OBFC1 (rs10786775 CgammaG, rs11591710 AgammaC) were genotyped in four studies comprised of 2353 subjects out of which 1148 had CHD and 566 T2D. Three SNPs (rs12696304 CgammaG, rs10936601G>T and rs16847897 GgammaC) at the TERC locus were genotyped in these four studies, in addition to an offspring study of 765 healthy students. For all samples, LTL had been measured using a real-time PCR-based method. RESULTS: Only one SNP was associated with a significant effect on LTL, with the minor allele G of OBFC1 rs10786775 SNP being associated with longer LTL (beta=0.029, P=0.04). No SNPs were significantly associated with CHD or T2D. For OBFC1 the haplotype carrying both rare alleles (rs10786775G and rs11591710C, haplotype frequency 0.089) was associated with lower CHD prevalence (OR: 0.77; 95% CI: 0.61-0.97; P= 0.03). The TERC haplotype GTC (rs12696304G, rs10936601T and rs16847897C, haplotype frequency 0.210) was associated with lower risk for both CHD (OR: 0.86; 95% CI: 0.75-0.99; P=0.04) and T2D (OR: 0.74; 95% CI: 0.61-0.91; P= 0.004), with no effect on LTL. Only the last association remained after adjusting for multiple testing. CONCLUSION: Of reported associations, only that between the OBFC1 rs10786775 SNP and LTL was confirmed, although our study has a limited power to detect modest effects. A 2-SNP OBFC1 haplotype was associated with higher risk of CHD, and a 3-SNP TERC haplotype was associated with both higher risk of CHD and T2D. Further work is required to confirm these results and explore the mechanisms of these effects. PMID- 24349445 TI - Secreted hCLCA1 is a signaling molecule that activates airway macrophages. AB - The CLCA gene family produces both secreted and membrane-associated proteins that modulate ion-channel function, drive mucus production and have a poorly understood pleiotropic effect on airway inflammation. The primary up-regulated human CLCA ortholog in airway inflammation is hCLCA1. Here we show that this protein can activate airway macrophages, inducing them to express cytokines and to undertake a pivotal role in airway inflammation. In a U-937 airway macrophage monocyte cell line, conditioned media from HEK 293 cells heterologously expressing hCLCA1 (with or without fetal bovine serum) increased the levels of pro-inflammatory cytokines (IL-1beta, IL-6, TNF-alpha and IL-8). This effect was independent of the metalloprotease domain of hCLCA1. Primary porcine alveolar macrophages were similarly activated, demonstrating the effect was not cell line dependent. Similarly, immuno-purified hCLCA1 at physiologically relevant concentration of ~100 pg/mL was able to activate macrophages and induce pro inflammatory response. This cytokine response increased with higher concentration of immuno-purified hCLCA1. These findings demonstrate the ability of hCLCA1 to function as a signaling molecule and activate macrophages, central regulators of airway inflammation. PMID- 24349446 TI - Molecular characterization and clinical implications of spindle cells in nasopharyngeal carcinoma: a novel molecule-morphology model of tumor progression proposed. AB - Up to now, the precise molecular and morphological changes underlying the invasive and metastatic properties of nasopharyngeal carcinoma (NPC) remain largely unresolved. We speculate that neoplastic spindle cells, which are prominently found in the invasive tumor front and the surrounding stroma, might be responsible for the aggressive patterns. Expression profiling of various biomarkers relevant to cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) was performed by tissue microarray-based immunohistochemistry in NPC samples. The expression of EBER and LMP1 was detected by in situ hybridization and immunohistochemistry, respectively. We found that overexpression of CSCs-related markers (ALDH1, Nanog and ABCG2) and up-regulation of EMT markers (Fibronectin, MMP-2, Periostin, SPARC, Snail and Slug), together with E- to N-cadherin switching, occurred preferentially in tumors containing a large proportion of spindle-shaped malignant cells. Furthermore, CSCs-like properties were highly present in spindle cells compared with non-spindle cells of tumors, and correlated strongly with EMT features. In addition, EBV-related factors EBER and LMP1 were highly expressed and correlated strongly with CSCs and EMT characteristics in neoplastic spindle cells. Importantly, high proportion of spindle cells (>=20%) correlated significantly with various aggressive aspects including lymph node metastasis (P = 0.031) and local recurrence (P = 0.014). Patients with high proportion of spindle cells had poor survival (P = 0.004), though it was not an independent value. In conclusion, we demonstrate that spindle cells could be valuable morphological indicators of tumor progression and unfavorable prognosis of NPC. An integrated molecule-morphology model of NPC firstly constructed may shed significant light on the metastatic cascade and clinical relevance of patients. PMID- 24349447 TI - Age-related decrements in heat dissipation during physical activity occur as early as the age of 40. AB - Older adults typically experience greater levels of thermal strain during physical efforts in the heat compared to young individuals. While this may be related to an age-dependent reduction in whole-body sweating, no study has clearly delineated at what age this occurs. In the present study, we report direct measurements of human heat dissipation during physical activity in the heat in males ranging in age from 20-70 years. Eighty-five males performed four 15-min bouts of cycling separated by 15-min rest periods, in a calorimeter regulated to 35 degrees C and 20% relative humidity. Direct calorimetry was used to measure total heat loss (whole-body evaporative heat loss and dry heat exchange). We also used indirect calorimetry as a continuous measure of metabolic heat production. Body heat storage was calculated as the temporal summation of heat production and total heat loss over the experimental session. Whole-body sweat rate (WBSR) was calculated from measurements of evaporative heat loss. Males were divided into five age categories for the analysis of WBSR and body heat storage: 20-31 years (n = 18), 40-44 years (n = 15), 45-49 years (n = 15), 50-55 years (n = 21) and 56-70 years (n = 16). Relative to young males, WBSR was reduced in males aged 56-70 during each exercise (all P<0.05), in males aged 50 55 during the second (P = 0.031) and third exercises (P = 0.028) and in males aged 45-49 during the final exercise bout (P = 0.046). Although not significantly different, 40-44 years old males also had a lower rate of heat loss compared to younger males. Over the sum of two hours, the change in body heat content was greater in males 40-70 years compared to young males (all P<0.05). Our findings suggest that middle-aged and older adults have impairments in heat dissipation when doing physical activity in the heat, thus possibly increasing their risk of heat-related illness under such conditions. PMID- 24349448 TI - A cross-sectional survey of bacterial species in plaque from client owned dogs with healthy gingiva, gingivitis or mild periodontitis. AB - Periodontal disease is the most widespread oral disease in dogs which if left untreated results in significant pain to the pet and loss of dentition. The objective of this study was to identify bacterial species in canine plaque that are significantly associated with health, gingivitis and mild periodontitis (<25% attachment loss). In this survey subgingival plaque samples were collected from 223 dogs with healthy gingiva, gingivitis and mild periodontitis with 72 to 77 samples per health status. DNA was extracted from the plaque samples and subjected to PCR amplification of the V1-V3 region of the 16S rDNA. Pyrosequencing of the PCR amplicons identified a total of 274 operational taxonomic units after bioinformatic and statistical analysis. Porphyromonas was the most abundant genus in all disease stages, particularly in health along with Moraxella and Bergeyella. Peptostreptococcus, Actinomyces, and Peptostreptococcaceae were the most abundant genera in mild periodontitis. Logistic regression analysis identified species from each of these genera that were significantly associated with health, gingivitis or mild periodontitis. Principal component analysis showed distinct community profiles in health and disease. The species identified show some similarities with health and periodontal disease in humans but also major differences. In contrast to human, healthy canine plaque was found to be dominated by Gram negative bacterial species whereas Gram positive anaerobic species predominate in disease. The scale of this study surpasses previously published research and enhances our understanding of the bacterial species present in canine subgingival plaque and their associations with health and early periodontal disease. PMID- 24349449 TI - Structural propensities of human ubiquitination sites: accessibility, centrality and local conformation. AB - The existence and function of most proteins in the human proteome are regulated by the ubiquitination process. To date, tens of thousands human ubiquitination sites have been identified from high-throughput proteomic studies. However, the mechanism of ubiquitination site selection remains elusive because of the complicated sequence pattern flanking the ubiquitination sites. In this study, we perform a systematic analysis of 1,330 ubiquitination sites in 505 protein structures and quantify the significantly high accessibility and unexpectedly high centrality of human ubiquitination sites. Further analysis suggests that the higher centrality of ubiquitination sites is associated with the multi functionality of ubiquitination sites, among which protein-protein interaction sites are common targets of ubiquitination. Moreover, we demonstrate that ubiquitination sites are flanked by residues with non-random local conformation. Finally, we provide quantitative and unambiguous evidence that most of the structural propensities contain specific information about ubiquitination site selection that is not represented by the sequence pattern. Therefore, the hypothesis about the structural level of the ubiquitination site selection mechanism has been substantially approved. PMID- 24349450 TI - Biotransformation of bisphenol AF to its major glucuronide metabolite reduces estrogenic activity. AB - Bisphenol AF (BPAF), an endocrine disrupting chemical, can induce estrogenic activity through binding to estrogen receptor (ER). However, the metabolism of BPAF in vivo and the estrogenic activity of its metabolites remain unknown. In the present study, we identified four metabolites including BPAF diglucuronide, BPAF glucuronide (BPAF-G), BPAF glucuronide dehydrated and BPAF sulfate in the urine of Sprague-Dawley (SD) rats. BPAF-G was further characterized by nuclear magnetic resonance (NMR). After treatment with a single dose of BPAF, BPAF was metabolized rapidly to BPAF-G, as detected in the plasma of SD rats. Biotransformation of BPAF to BPAF-G was confirmed with human liver microsomes (HLM), and Vmax of glucuronidation for HLM was 11.6 nmol/min/mg. We also found that BPAF glucuronidation could be mediated through several human recombinant UDP glucuronosyltransferases (UGTs) including UGT1A1, UGT1A3, UGT1A8, UGT1A9, UGT2B4, UGT2B7, UGT2B15 and UGT2B17, among which UGT2B7 showed the highest efficiency of glucuronidation. To explain the biological function of BPAF biotransformation, the estrogenic activities of BPAF and BPAF-G were evaluated in ER-positive breast cancer T47D and MCF7 cells. BPAF significantly stimulates ER-regulated gene expression and cell proliferation at the dose of 100 nM and 1 MUM in breast cancer cells. However, BPAF-G did not show any induction of estrogenic activity at the same dosages, implying that formation of BPAF-G is a potential host defense mechanism against BPAF. Based on our study, biotransformation of BPAF to BPAF-G can eliminate BPAF-induced estrogenic activity, which is therefore considered as reducing the potential threat to human beings. PMID- 24349451 TI - A fully automated high-throughput training system for rodents. AB - Addressing the neural mechanisms underlying complex learned behaviors requires training animals in well-controlled tasks, an often time-consuming and labor intensive process that can severely limit the feasibility of such studies. To overcome this constraint, we developed a fully computer-controlled general purpose system for high-throughput training of rodents. By standardizing and automating the implementation of predefined training protocols within the animal's home-cage our system dramatically reduces the efforts involved in animal training while also removing human errors and biases from the process. We deployed this system to train rats in a variety of sensorimotor tasks, achieving learning rates comparable to existing, but more laborious, methods. By incrementally and systematically increasing the difficulty of the task over weeks of training, rats were able to master motor tasks that, in complexity and structure, resemble ones used in primate studies of motor sequence learning. By enabling fully automated training of rodents in a home-cage setting this low-cost and modular system increases the utility of rodents for studying the neural underpinnings of a variety of complex behaviors. PMID- 24349452 TI - Alveolar macrophage innate response to Mycobacterium immunogenum, the etiological agent of hypersensitivity pneumonitis: role of JNK and p38 MAPK pathways. AB - Mycobacterium immunogenum is an emerging pathogen of the immune-mediated lung disease hypersensitivity pneumonitis (HP) reported in machinists occupationally exposed to contaminated metal working fluid (MWF). However, the mechanism of its interaction with the host lung is unclear. Considering that alveolar macrophages play a central role in host defense in the exposed lung, understanding their interaction with the pathogen could provide initial insights into the underlying immunopathogenesis events and mechanisms. In the current study, M. immunogenum 700506, a predominant genotype isolated from HP-linked fluids, was shown to multiply intracellularly, induce proinflammatory mediators (TNF-alpha, IL-1alpha, IL-1beta, IL-6, GM-CSF, NO) and cause cytotoxicity/cell death in the cultured murine alveolar macrophage cell line MH-S in a dose- and time-dependent manner. The responses were detected as early as 3h post-infection. Comparison of this and four additional genotypes of M. immunogenum (MJY-3, MJY-4, MJY-12, MJY-14) using an effective dose-time combination (100 MOI for 24h) showed these macrophage responses in the following order (albeit with some variations for individual response indicators). Inflammatory: MJY-3 >= 700506 > MJY-4 >= MJY-14 >= MJY-12; Cytotoxic: 700506 >= MJY-3 > MJY-4 >= MJY-12 >= MJY-14. In general, 700506 and MJY-3 showed a more aggressive response than other genotypes. Chemical blocking of either p38 or JNK inhibited the induction of proinflammatory mediators (cytokines, NO) by 700506. However, the cellular responses showed a somewhat opposite effect. This is the first report on M. immunogenum interactions with alveolar macrophages and on the identification of JNK- and p38- mediated signaling and its role in mediating the proinflammatory responses during these interactions. PMID- 24349453 TI - Hippocampal hypertrophy and sleep apnea: a role for the ischemic preconditioning? AB - The full impact of multisystem disease such as obstructive sleep apnoea (OSA) on regions of the central nervous system is debated, as the subsequent neurocognitive sequelae are unclear. Several preclinical studies suggest that its purported major culprits, intermittent hypoxia and sleep fragmentation, can differentially affect adult hippocampal neurogenesis. Although the prospective biphasic nature of chronic intermittent hypoxia in animal models of OSA has been acknowledged, so far the evidence for increased 'compensatory' neurogenesis in humans is uncertain. In a cross-sectional study of 32 patients with mixed severity OSA and 32 non-apnoeic matched controls inferential analysis showed bilateral enlargement of hippocampi in the OSA group. Conversely, a trend for smaller thalami in the OSA group was noted. Furthermore, aberrant connectivity between the hippocampus and the cerebellum in the OSA group was also suggested by the correlation analysis. The role for the ischemia/hypoxia preconditioning in the neuropathology of OSA is herein indicated, with possible further reaching clinical implications. PMID- 24349454 TI - Fitness consequences of northward dispersal as possible adaptation to climate change, using experimental translocation of a migratory passerine. AB - Climate change leads to rapid, differential changes in phenology across trophic levels, often resulting in temporal mismatches between predators and their prey. If a species cannot easily adjust its timing, it can adapt by choosing a new breeding location with a later phenology of its prey. In this study, we experimentally investigated whether long-distance dispersal to northern breeding grounds with a later phenology could be a feasible process to restore the match between timing of breeding and peak food abundance and thus improve reproductive success. Here, we report the successful translocation of pied flycatchers (Ficedula hypoleuca) to natural breeding sites 560 km to the Northeast. We expected translocated birds to have a fitness advantage with respect to environmental phenology, but to potentially pay costs through the lack of other locally adapted traits. Translocated individuals started egg laying 11 days earlier than northern control birds, which were translocated only within the northern site. The number of fledglings produced was somewhat lower in translocated birds, compared to northern controls, and fledglings were in lower body condition. Translocated individuals were performing not significantly different to control birds that remained at the original southern site. The lack of advantage of the translocated individuals most likely resulted from the exceptionally cold spring in which the experiment was carried out. Our results, however, suggest that pied flycatchers can successfully introduce their early breeding phenotype after dispersing to more northern areas, and thus that adaptation through dispersal is a viable option for populations that get locally maladapted through climate change. PMID- 24349455 TI - Relative importance of coral cover, habitat complexity and diversity in determining the structure of reef fish communities. AB - The structure of coral reef habitat has a pronounced influence on the diversity, composition and abundance of reef-associated fishes. However, the particular features of the habitat that are most critical are not always known. Coral habitats can vary in many characteristics, notably live coral cover, topographic complexity and coral diversity, but the relative effects of these habitat characteristics are often not distinguished. Here, we investigate the strength of the relationships between these habitat features and local fish diversity, abundance and community structure in the lagoon of Lizard Island, Great Barrier Reef. In a spatial comparison using sixty-six 2m(2) quadrats, fish species richness, total abundance and community structure were examined in relation to a wide range of habitat variables, including topographic complexity, habitat diversity, coral diversity, coral species richness, hard coral cover, branching coral cover and the cover of corymbose corals. Fish species richness and total abundance were strongly associated with coral species richness and cover, but only weakly associated with topographic complexity. Regression tree analysis showed that coral species richness accounted for most of the variation in fish species richness (63.6%), while hard coral cover explained more variation in total fish abundance (17.4%), than any other variable. In contrast, topographic complexity accounted for little spatial variation in reef fish assemblages. In degrading coral reef environments, the potential effects of loss of coral cover and topographic complexity are often emphasized, but these findings suggest that reduced coral biodiversity may ultimately have an equal, or greater, impact on reef-associated fish communities. PMID- 24349456 TI - From PII signaling to metabolite sensing: a novel 2-oxoglutarate sensor that details PII-NAGK complex formation. AB - The widespread PII signal transduction proteins are known for integrating signals of nitrogen and energy supply and regulating cellular behavior by interacting with a multitude of target proteins. The PII protein of the cyanobacterium Synechococcus elongatus forms complexes with the controlling enzyme of arginine synthesis, N-acetyl-L-glutamate kinase (NAGK) in a 2-oxoglutarate- and ATP/ADP dependent manner. Fusing NAGK and PII proteins to either CFP or YFP yielded a FRET sensor that specifically responded to 2-oxoglutarate. The impact of the fluorescent tags on PII and NAGK was evaluated by enzyme assays, surface plasmon resonance spectroscopy and isothermal calorimetric experiments. The developed FRET sensor provides real-time data on PII - NAGK interaction and its modulation by the effector molecules ATP, ADP and 2-oxoglutarate in vitro. Additionally to its utility to monitor 2-oxoglutarate levels, the FRET assay provided novel insights into PII - NAGK complex formation: (i) It revealed the formation of an encounter-complex between PII and NAGK, which holds the proteins in proximity even in the presence of inhibitors of complex formation; (ii) It revealed that the PII T-loop residue Ser49 is neither essential for complex formation with NAGK nor for activation of the enzyme but necessary to form a stable complex and efficiently relieve NAGK from arginine inhibition; (iii) It showed that arginine stabilizes the NAGK hexamer and stimulates PII - NAGK interaction. PMID- 24349457 TI - Lung protective ventilation induces immunotolerance and nitric oxide metabolites in porcine experimental postoperative sepsis. AB - Low tidal volume ventilation is beneficial in patients with severe pulmonary dysfunction and would, in theory, reduce postoperative complications if implemented during routine surgery. The study aimed to investigate whether low tidal volume ventilation and high positive end-expiratory pressure (PEEP) in a large animal model of postoperative sepsis would attenuate the systemic inflammatory response and organ dysfunction. Thirty healthy pigs were randomized to three groups: Group Prot-7h, i.e. protective ventilation for 7 h, was ventilated with a tidal volume of 6 mL x kg(-1) for 7 h; group Prot-5h, i.e. protective ventilation for 5 h, was ventilated with a tidal volume of 10 mL x kg( 1) for 2 h, after which the group was ventilated with a tidal volume of 6 mL x kg(-1); and a control group that was ventilated with a tidal volume of 10 mL x kg(-1) for 7 h. In groups Prot-7h and Prot-5h PEEP was 5 cmH2O for 2 h and 10 cmH2O for 5 h. In the control group PEEP was 5 cmH2O for the entire experiment. After surgery for 2 h, postoperative sepsis was simulated with an endotoxin infusion for 5 h. Low tidal volume ventilation combined with higher PEEP led to lower levels of interleukin 6 and 10 in plasma, higher PaO2/FiO2, better preserved functional residual capacity and lower plasma troponin I as compared with animals ventilated with a medium high tidal volume and lower PEEP. The beneficial effects of protective ventilation were seen despite greater reductions in cardiac index and oxygen delivery index. In the immediate postoperative phase low VT ventilation with higher PEEP was associated with reduced ex vivo plasma capacity to produce TNF-alpha upon endotoxin stimulation and higher nitrite levels in urine. These findings might represent mechanistic explanations for the attenuation of systemic inflammation and inflammatory-induced organ dysfunction. PMID- 24349458 TI - Inflammasome-mediated inhibition of Listeria monocytogenes-stimulated immunity is independent of myelomonocytic function. AB - Activation of the Nlrc4 inflammasome results in the secretion of IL-1beta and IL 18 through caspase-1 and induction of pyroptosis. L. monocytogenes engineered to activate Nlrc4 by expression of Legionella pneumophilia flagellin (L. monocytogenes L.p.FlaA) are less immunogenic for CD8(+) T cell responses than wt L. monocytogenes. It is also known that IL-1beta orchestrates recruitment of myelomonocytic cells (MMC), which have been shown to interfere with T cell dendritic cells (DC) interactions in splenic white pulp (WP), limiting T cell priming and protective immunity. We have further analyzed the role of MMCs in the immunogenicity of L. monocytogenes L.p.FlaA. We confirmed that MMCs infiltrate the WP between 24-48 hours in response to wt L. monocytogenes infection and that depletion of MMCs enhances CD8(+) T cell priming and protective memory. L. monocytogenes L.p.FlaA elicited accelerated recruitment of MMCs into the WP. While MMCs contribute to control of L. monocytogenes L.p.FlaA, MMC depletion did not increase immunogenicity of L.p.FlaA expressing strains. There was a significant decrease in L. monocytogenes L.p.FlaA in CD8alpha(+) DCs independent of MMCs. These findings suggest that limiting inflammasome activation is important for bacterial accumulation in CD8alpha(+) DCs, which are known to be critical for T cell response to L. monocytogenes. PMID- 24349459 TI - Pegylated interferon-alpha2a inhibits proliferation of human liver cancer cells in vitro and in vivo. AB - PURPOSE: We investigated the effects of pegylated interferon-alpha2a (PEG-IFN alpha2a) on the growth of human liver cancer cells. METHODS: The effect of PEG IFN-alpha2a on the proliferation of 13 liver cancer cell lines was investigated in vitro. Cells were cultured with medium containing 0-4,194 ng/mL of PEG-IFN alpha2a, and after 1, 2, 3, or 4 days of culture, morphologic observation and growth assay were performed. After hepatocellular carcinoma (HCC) cells (HAK-1B and KIM-1) were transplanted into nude mice, various doses of PEG-IFN-alpha2a were subcutaneously administered to the mice once a week for 2 weeks, and tumor volume, weight, and histology were examined. RESULTS: PEG-IFN-alpha2a inhibited the growth of 8 and 11 cell lines in a time- and dose-dependent manner, respectively, although the 50% growth inhibitory concentrations of 7 measurable cell lines on Day 4 were relatively high and ranged from 253 ng/mL to 4,431 ng/mL. Various levels of apoptosis induction were confirmed in 8 cell lines. PEG IFN-alpha2a induced a dose-dependent decrease in tumor volume and weight, and a significant increase of apoptotic cells in the tumor. Subcutaneous administration of clinical dose for chronic hepatitis C (3 MUg/kg, 0.06 MUg/mouse) was effective and induced about 30-50% reduction in the tumor volume and weight as compared with the control. CONCLUSIONS: Although in vitro anti-proliferative effects of PEG-IFN-alpha2a were relatively weak, PEG-IFN-alpha2a induced strong anti-tumor effects on HCC cells in vivo. The data suggest potential clinical application of PEG-IFN-alpha2a for the prevention and treatment of HCC. PMID- 24349460 TI - Defense responses in two ecotypes of Lotus japonicus against non-pathogenic Pseudomonas syringae. AB - Lotus japonicus is a model legume broadly used to study many important processes as nitrogen fixing nodule formation and adaptation to salt stress. However, no studies on the defense responses occurring in this species against invading microorganisms have been carried out at the present. Understanding how this model plant protects itself against pathogens will certainly help to develop more tolerant cultivars in economically important Lotus species as well as in other legumes. In order to uncover the most important defense mechanisms activated upon bacterial attack, we explored in this work the main responses occurring in the phenotypically contrasting ecotypes MG-20 and Gifu B-129 of L. japonicus after inoculation with Pseudomonas syringae DC3000 pv. tomato. Our analysis demonstrated that this bacterial strain is unable to cause disease in these accessions, even though the defense mechanisms triggered in these ecotypes might differ. Thus, disease tolerance in MG-20 was characterized by bacterial multiplication, chlorosis and desiccation at the infiltrated tissues. In turn, Gifu B-129 plants did not show any symptom at all and were completely successful in restricting bacterial growth. We performed a microarray based analysis of these responses and determined the regulation of several genes that could play important roles in plant defense. Interestingly, we were also able to identify a set of defense genes with a relative high expression in Gifu B-129 plants under non-stress conditions, what could explain its higher tolerance. The participation of these genes in plant defense is discussed. Our results position the L. japonicus-P. syringae interaction as a interesting model to study defense mechanisms in legume species. PMID- 24349462 TI - Integrating the meaning of person names into discourse context: an event-related potential study. AB - The meaning of person names is determined by their associated information. This study used event related potentials to investigate the time course of integrating the newly constructed meaning of person names into discourse context. The meaning of person names was built by two-sentence descriptions of the names. Then we manipulated the congruence of person names relative to discourse context in a way that the meaning of person names either matched or did not match the previous context. ERPs elicited by the names were compared between the congruent and the incongruent conditions. We found that the incongruent names elicited a larger N400 as well as a larger P600 compared to the congruent names. The results suggest that the meaning of unknown names can be effectively constructed from short linguistic descriptions and that the established meaning can be rapidly retrieved and integrated into contexts. PMID- 24349461 TI - Influence of APOE genotype on whole-brain functional networks in cognitively normal elderly. AB - This study aimed to investigate the influence of apolipoprotein E (APOE) epsilon4 allele on whole-brain functional networks in cognitively normal (CN) elderly by applying graph theoretical analysis to brain glucose metabolism. Eighty-six CN elderly [28 APOE epsilon4 carriers (epsilon4+) and 58 non-carriers (epsilon4-)] underwent clinical evaluation and resting [(18)F] fluorodeoxyglucose positron emission tomography scan. Whole-brain functional networks were constructed from correlations of the 90 regions of interest using the automated anatomical labeling template, and analyzed using graph theoretical approaches. The overall small-world property seen in epsilon4- was preserved in epsilon4+. However, both local clustering and path length were lower in epsilon4+ compared to epsilon4-. In terms of the hubs of functional networks, epsilon4+ showed decreased centrality of the right hippocampus but increased centrality of several brain regions associated with the default mode network compared to epsilon4-. Our results indicate that genetic vulnerability to Alzheimer's disease may alter whole-brain functional networks even before clinical symptoms appear. PMID- 24349463 TI - Elucidation of molecular mechanisms of physiological variations between bovine subcutaneous and visceral fat depots under different nutritional regimes. AB - Adipose tissue plays a critical role in energy homeostasis and metabolism. There is sparse understanding of the molecular regulation at the protein level of bovine adipose tissues, especially within different fat depots under different nutritional regimes. The objective of this study was to analyze the differences in protein expression between bovine subcutaneous and visceral fat depots in steers fed different diets and to identify the potential regulatory molecular mechanisms of protein expression. Subcutaneous and visceral fat tissues were collected from 16 British-continental steers (15.5 month old) fed a high-fat diet (7.1% fat, n=8) or a control diet (2.7% fat, n=8). Protein expression was profiled using label free quantification LC-MS/MS and expression of selected transcripts was evaluated using qRT-PCR. A total of 682 proteins were characterized and quantified with fat depot having more impact on protein expression, altering the level of 51.0% of the detected proteins, whereas diet affected only 5.3%. Functional analysis revealed that energy production and lipid metabolism were among the main functions associated with differentially expressed proteins between fat depots, with visceral fat being more metabolically active than subcutaneous fat as proteins associated with lipid and energy metabolism were upregulated. The expression of several proteins was significantly correlated to subcutaneous fat thickness and adipocyte size, indicating their potential as adiposity markers. A poor correlation (r=0.245) was observed between mRNA and protein levels for 9 genes, indicating that many proteins may be subjected to post-transcriptional regulation. A total of 8 miRNAs were predicted to regulate more than 20% of lipid metabolism proteins differentially expressed between fat depots, suggesting that miRNAs play a role in adipose tissue regulation. Our results show that proteomic changes support the distinct metabolic and physiological characteristics observed between subcutaneous and visceral adipose tissue depots in cattle. PMID- 24349464 TI - ADP protects cardiac mitochondria under severe oxidative stress. AB - ADP is not only a key substrate for ATP generation, but also a potent inhibitor of mitochondrial permeability transition pore (mPTP). In this study, we assessed how oxidative stress affects the potency of ADP as an mPTP inhibitor and whether its reduction of reactive oxygen species (ROS) production might be involved. We determined quantitatively the effects of ADP on mitochondrial Ca(2+) retention capacity (CRC) until the induction of mPTP in normal and stressed isolated cardiac mitochondria. We used two models of chronic oxidative stress (old and diabetic mice) and two models of acute oxidative stress (ischemia reperfusion (IR) and tert-butyl hydroperoxide (t-BH)). In control mitochondria, the CRC was 344 +/- 32 nmol/mg protein. 500 MUmol/L ADP increased CRC to 774 +/- 65 nmol/mg protein. This effect of ADP seemed to relate to its concentration as 50 MUmol/L had a significantly smaller effect. Also, oligomycin, which inhibits the conversion of ADP to ATP by F0F1ATPase, significantly increased the effect of 50 MUmol/L ADP. Chronic oxidative stress did not affect CRC or the effect of 500 MUmol/L ADP. After IR or t-BH exposure, CRC was drastically reduced to 1 +/- 0.2 and 32 +/- 4 nmol/mg protein, respectively. Surprisingly, ADP increased the CRC to 447 +/- 105 and 514 +/- 103 nmol/mg protein in IR and t-BH, respectively. Thus, it increased CRC by the same amount as in control. In control mitochondria, ADP decreased both substrate and Ca(2+)-induced increase of ROS. However, in t-BH mitochondria the effect of ADP on ROS was relatively small. We conclude that ADP potently restores CRC capacity in severely stressed mitochondria. This effect is most likely not related to a reduction in ROS production. As the effect of ADP relates to its concentration, increased ADP as occurs in the pathophysiological situation may protect mitochondrial integrity and function. PMID- 24349465 TI - Identification of putative target genes of the transcription factor RUNX2. AB - Comparisons of the genomes of Neandertals and Denisovans with present-day human genomes have suggested that the gene RUNX2, which encodes a transcription factor, may have been positively selected during early human evolution. Here, we overexpress RUNX2 in ten human cell lines and identify genes that are directly or indirectly affected by RUNX2 expression. We find a number of genes not previously known to be affected by RUNX2 expression, in particular BIRC3, genes encoded on the mitochondrial genome, and several genes involved in bone and tooth formation. These genes are likely to provide inroads into pathways affected by RUNX2 and potentially by the evolutionary changes that affected RUNX2 in modern humans. PMID- 24349467 TI - Worldwide topology of the scientific subject profile: a macro approach in the country level. AB - BACKGROUND: Models for the production of knowledge and systems of innovation and science are key elements for characterizing a country in view of its scientific thematic profile. With regard to scientific output and publication in journals of international visibility, the countries of the world may be classified into three main groups according to their thematic bias. METHODOLOGY/PRINCIPAL FINDINGS: This paper aims to classify the countries of the world in several broad groups, described in terms of behavioural models that attempt to sum up the characteristics of their systems of knowledge and innovation. We perceive three clusters in our analysis: 1) the biomedical cluster, 2) the basic science & engineering cluster, and 3) the agricultural cluster. The countries are conceptually associated with the clusters via Principal Component Analysis (PCA), and a Multidimensional Scaling (MDS) map with all the countries is presented. CONCLUSIONS/SIGNIFICANCE: As we have seen, insofar as scientific output and publication in journals of international visibility is concerned, the countries of the world may be classified into three main groups according to their thematic profile. These groups can be described in terms of behavioral models that attempt to sum up the characteristics of their systems of knowledge and innovation. PMID- 24349466 TI - Dynamics of defense responses and cell fate change during Arabidopsis-Pseudomonas syringae interactions. AB - Plant-pathogen interactions involve sophisticated action and counteraction strategies from both parties. Plants can recognize pathogen derived molecules, such as conserved pathogen associated molecular patterns (PAMPs) and effector proteins, and subsequently activate PAMP-triggered immunity (PTI) and effector triggered immunity (ETI), respectively. However, pathogens can evade such recognitions and suppress host immunity with effectors, causing effector triggered susceptibility (ETS). The differences among PTI, ETS, and ETI have not been completely understood. Toward a better understanding of PTI, ETS, and ETI, we systematically examined various defense-related phenotypes of Arabidopsis infected with different Pseudomonas syringae pv. maculicola ES4326 strains, using the virulence strain DG3 to induce ETS, the avirulence strain DG34 that expresses avrRpm1 (recognized by the resistance protein RPM1) to induce ETI, and HrcC(-) that lacks the type three secretion system to activate PTI. We found that plants infected with different strains displayed dynamic differences in the accumulation of the defense signaling molecule salicylic acid, expression of the defense marker gene PR1, cell death formation, and accumulation/localization of the reactive oxygen species, H2O2. The differences between PTI, ETS, and ETI are dependent on the doses of the strains used. These data support the quantitative nature of PTI, ETS, and ETI and they also reveal qualitative differences between PTI, ETS, and ETI. Interestingly, we observed the induction of large cells in the infected leaves, most obviously with HrcC(-) at later infection stages. The enlarged cells have increased DNA content, suggesting a possible activation of endoreplication. Consistent with strong induction of abnormal cell growth by HrcC(-), we found that the PTI elicitor flg22 also activates abnormal cell growth, depending on a functional flg22-receptor FLS2. Thus, our study has revealed a comprehensive picture of dynamic changes of defense phenotypes and cell fate determination during Arabidopsis-P. syringae interactions, contributing to a better understanding of plant defense mechanisms. PMID- 24349468 TI - Physiological mechanisms for high salt tolerance in wild soybean (Glycine soja) from Yellow River Delta, China: photosynthesis, osmotic regulation, ion flux and antioxidant capacity. AB - Glycine soja (BB52) is a wild soybean cultivar grown in coastal saline land in Yellow River Delta, China. In order to reveal the physiological mechanisms adapting to salinity, we examined photosynthesis, ion flux, antioxidant system and water status in Glycine soja under NaCl treatments, taking a cultivated soybean, ZH13, as control. Upon NaCl exposure, higher relative water content and water potential were maintained in the leaf of BB52 than ZH13, which might depend on the more accumulation of osmotic substances such as glycinebetaine and proline. Compared with ZH13, activities of antioxidant enzymes including superoxide dismutase, catalase, ascorbate peroxidase and contents of ascorbate, glutathione and phenolics were enhanced to a higher level in BB52 leaf under NaCl stress, which could mitigate the salt-induced oxidative damage in BB52. Consistently, lipid peroxidation indicated by malondialdehyde content was lower in BB52 leaf. Photosynthetic rate (Pn) was decreased by NaCl stress in BB52 and ZH13, and the decrease was greater in ZH13. The decreased Pn in BB52 was mainly due to stomatal limitation. The inhibited activation of rubisco enzyme in ZH13 due to the decrease of rubisco activase content became an important limiting factor of Pn, when NaCl concentration increased to 200 mM. Rubisco activase in BB52 was not affected by NaCl stress. Less negative impact in BB52 derived from lower contents of Na(+) and Cl(-) in the tissues, and non-invasive micro-test technique revealed that BB52 roots had higher ability to extrude Na(+) and Cl(-). Wild soybean is a valuable genetic resource, and our study may provide a reference for molecular biologist to improve the salt tolerance of cultivated soybean in face of farmland salinity. PMID- 24349469 TI - B-lymphocytes as key players in chemical-induced asthma. AB - T-lymphocytes and B-lymphocytes are key players in allergic asthma, with B lymphocytes producing antigen-specific immunoglobulins E (IgE). We used a mouse model of chemical-induced asthma and transferred B-lymphocytes from sensitized animals into naive wild type mice, B-lymphocyte knock-out (B-KO) mice or severe combined immunodeficiency (SCID) mice. On days 1 and 8, BALB/c mice were dermally sensitized with 0.3% toluene diisocyanate (TDI) (20 ul/ear). On day 15, mice were euthanized and the auricular lymph nodes isolated. B-lymphocytes (CD19(+)) were separated from the whole cell suspension and 175,000 cells were injected in the tail vein of naive wild type, B-KO or SCID mice. Three days later, the mice received a single oropharyngeal challenge with 0.01% TDI (20 ul) or vehicle (acetone/olive oil (AOO)) (controls). Airway reactivity to methacholine and total and differential cell counts in the bronchoalveolar lavage (BAL) fluid were measured 24 hours after challenge. B-lymphocytes of AOO or TDI-sensitized mice were characterized for the expression of surface markers and production of cytokines. We found that transfer of B-cells obtained from mice dermally sensitized to toluene diisocyanate (TDI) into naive wild type mice, B-KO mice or SCID mice led, within three days, to an acute asthma-like phenotype after an airway challenge with TDI. This response was specific and independent of IgE. These B-lymphocytes showed antigen presenting capacities (CD80/CD86 and CD40) and consisted of B effector (Be)2- (IL-4) and Be1-lymphocytes (IFN-gamma). The transferred B-lymphocytes were visualized near large airways, 24 hours after TDI challenge. Thus, B-lymphocytes can provoke an asthmatic response without the action of T-lymphocytes and without major involvement of IgE. PMID- 24349470 TI - First-in-human phase I study of PRS-050 (Angiocal), an Anticalin targeting and antagonizing VEGF-A, in patients with advanced solid tumors. AB - BACKGROUND: To report the nonrandomized first-in-human phase I trial of PRS-050, a novel, rationally engineered Anticalin based on human tear lipocalin that targets and antagonizes vascular endothelial growth factor A (VEGF-A). METHODS: Patients with advanced solid tumors received PRS-050 at 0.1 mg/kg to 10 mg/kg by IV in successive dosing cohorts according to the 3+3 escalation scheme. The primary end point was safety. RESULTS: Twenty-six patients were enrolled; 25 were evaluable. Two patients experienced dose-limiting toxicity, comprising grade (G) 3 hypertension and G3 pyrexia, respectively. The maximum tolerated dose was not reached. Most commonly reported treatment-emergent adverse events (AEs) included chills (52%; G3, 4%), fatigue (52%; G3, 4%), hypertension (44%; G3, 16%), and nausea (40%, all G1/2). No anti-PRS-050 antibodies following multiple administration of the drug were detected. PRS-050 showed dose-proportional pharmacokinetics (PK), with a terminal half-life of approximately 6 days. Free VEGF-A was detectable at baseline in 9/25 patients, becoming rapidly undetectable after PRS-050 infusion for up to 3 weeks. VEGF-A/PRS-050 complex was detectable for up to 3 weeks at all dose levels, including in patients without detectable baseline-free VEGF-A. We also detected a significant reduction in circulating matrix metalloproteinase 2, suggesting this end point could be a pharmacodynamic (PD) marker of the drug's activity. CONCLUSIONS: PRS-050, a novel Anticalin with high affinity for VEGF-A, was well-tolerated when administered at the highest dose tested, 10 mg/kg. Based on target engagement and PK/PD data, the recommended phase II dose is 5 mg/kg every 2 weeks administered as a 120-minute infusion. TRIAL REGISTRATION: ClinicalTrials.gov NCT01141257 http://clinicaltrials.gov/ct2/show/NCT01141257. PMID- 24349471 TI - Inflammation but not dietary macronutrients insufficiency associated with the malnutrition-inflammation score in hemodialysis population. AB - Malnutrition is associated with increased risk of mortality in hemodialysis patients. And insufficient dietary intake is the common cause for malnutrition. So, in order to survey the dietary intake of hemodialysis patients and study the relationship between the dietary feature and nutritional status, a cross sectional study was performed. 75 hemodialysis patients from South China participated in the dietary intake survey and nutrition assessment. A three-day diet diary record was used to estimate the major dietary macronutrients. Nutritional status was assessed by malnutrition-inflammation score (MIS) in addition to several related anthropometric measurements. Serum albumin, transferrin, and high-sensitivity C-reactive protein (CRP) were measured. Receiver operating characteristic (ROC) curve analysis was used to quantify the assessing value of independent parameters for nutritional status. The results showed that 48% patients were malnourished according to the MIS. The malnourished patients had a lower body mass index (BMI), fat mass (FM), albumin and a higher level of CRP, compared with normal nourished patients (P < 0.05). However, no significant differences of macronutrients (calories, protein, fat, carbohydrates, etc) were found between the two nutrition groups (P > 0.05). The multivariate regression analysis showed that the major macronutrients had no significant association with MIS (P > 0.05). In conclusion, malnutrition is very common in South China hemodialysis population and these data indicated that inflammation but not dietary macronutrients insufficiency might be the candidate cause for malnutrition in hemodialysis population. PMID- 24349472 TI - Cinnamon counteracts the negative effects of a high fat/high fructose diet on behavior, brain insulin signaling and Alzheimer-associated changes. AB - Insulin resistance leads to memory impairment. Cinnamon (CN) improves peripheral insulin resistance but its effects in the brain are not known. Changes in behavior, insulin signaling and Alzheimer-associated mRNA expression in the brain were measured in male Wistar rats fed a high fat/high fructose (HF/HFr) diet to induce insulin resistance, with or without CN, for 12 weeks. There was a decrease in insulin sensitivity associated with the HF/HFr diet that was reversed by CN. The CN fed rats were more active in a Y maze test than rats fed the control and HF/HFr diets. The HF/HFr diet fed rats showed greater anxiety in an elevated plus maze test that was lessened by feeding CN. The HF/HFr diet also led to a down regulation of the mRNA coding for GLUT1 and GLUT3 that was reversed by CN in the hippocampus and cortex. There were increases in Insr, Irs1 and Irs2 mRNA in the hippocampus and cortex due to the HF/HFr diet that were not reversed by CN. Increased peripheral insulin sensitivity was also associated with increased glycogen synthase in both hippocampus and cortex in the control and HF/HFr diet animals fed CN. The HF/HFr diet induced increases in mRNA associated with Alzheimers including PTEN, Tau and amyloid precursor protein (App) were also alleviated by CN. In conclusion, these data suggest that the negative effects of a HF/HFr diet on behavior, brain insulin signaling and Alzheimer-associated changes were alleviated by CN suggesting that neuroprotective effects of CN are associated with improved whole body insulin sensitivity and related changes in the brain. PMID- 24349473 TI - Whole exome sequencing identifies novel recurrently mutated genes in patients with splenic marginal zone lymphoma. AB - The pathogenesis of splenic marginal zone lymphoma (SMZL) remains largely unknown. Recent high-throughput sequencing studies have identified recurrent mutations in key pathways, most notably NOTCH2 mutations in >25% of patients. These studies are based on small, heterogeneous discovery cohorts, and therefore only captured a fraction of the lesions present in the SMZL genome. To identify further novel pathogenic mutations within related biochemical pathways, we applied whole exome sequencing (WES) and copy number (CN) analysis to a biologically and clinically homogeneous cohort of seven SMZL patients with 7q abnormalities and IGHV1-2*04 gene usage. We identified 173 somatic non-silent variants, affecting 160 distinct genes. In additional to providing independent validation of the presence of mutation in several previously reported genes (NOTCH2, TNFAIP3, MAP3K14, MLL2 and SPEN), our study defined eight additional recurrently mutated genes in SMZL; these genes are CREBBP, CBFA2T3, AMOTL1, FAT4, FBXO11, PLA2G4D, TRRAP and USH2A. By integrating our WES and CN data we identified three mutated putative candidate genes targeted by 7q deletions (CUL1, EZH2 and FLNC), with FLNC positioned within the well-characterized 7q minimally deleted region. Taken together, this work expands the reported directory of recurrently mutated cancer genes in this disease, thereby expanding our understanding of SMZL pathogenesis. Ultimately, this work will help to establish a stratified approach to care including the possibility of targeted therapy. PMID- 24349474 TI - LipL41, a hemin binding protein from Leptospira santarosai serovar Shermani. AB - Leptospirosis is one of the most widespread zoonotic diseases in the world. It is caused by the pathogen Leptospira that results in multiple-organ failure, in particular of the kidney. Outer membrane lipoprotein is the suspected virulence factor of Leptospira. In Leptospira spp LipL41 is one major lipoprotein and is highly conserved. Previous study suggests that LipL41 bears hemin-binding ability and might play a possible role in iron regulation and storage. However, the characterization of hemin-binding ability of LipL41 is still unclear. Here the hemin-binding ability of LipL41 was examined, yielding a K d = 0.59 +/- 0.14 MUM. Two possible heme regulatory motifs (HRMs), C[P/S], were found in LipL41 at (140)Cys-Ser and (220)Cys-Pro. The mutation study indicates that Cys140 and Cys220 might be cooperatively involved in hemin binding. A supramolecular assembly of LipL41 was determined by transmission electron microscopy. The LipL41 oligomer consists of 36 molecules and folds as a double-layered particle. At the C-terminus of LipL41, there are two tetratricopeptide repeats (TPRs), which might be involved in the protein-protein interaction of the supramolecular assembly. PMID- 24349475 TI - Genetic variability and population structure of the mushroom Pleurotus eryngii var. tuoliensis. AB - The genetic diversity of 123 wild strains of Pleurotus eryngii var. tuoliensis, which were collected from nine geographical locations in Yumin, Tuoli, and Qinghe counties in the Xinjiang Autonomous Region of China, was analysed using two molecular marker systems (inter-simple sequence repeat and start codon targeted). At the variety level, the percentage of polymorphic loci and Nei's gene diversity index for P. eryngii var. tuoliensis was 96.32% and 0.238, respectively. At the population level, Nei's gene diversity index ranged from 0.149 to 0.218 with an average of 0.186, and Shannon's information index ranged from 0.213 to 0.339 with an average of 0.284. These results revealed the abundant genetic variability in the wild resources of P. eryngii var. tuoliensis. Nei's gene diversity analysis indicated that the genetic variance was mainly found within individual geographical populations, and the analysis of molecular variance revealed low but significant genetic differentiation among local and regional populations. The limited gene flow (Nm = 1.794) was inferred as a major reason for the extent of genetic differentiation of P. eryngii var. tuoliensis. The results of Mantel tests showed that the genetic distance among geographical populations of P. eryngii var. tuoliensis was positively correlated with the geographical distance and the longitudinal distances (rGo = 0.789 and rLn = 0.873, respectively), which indicates that geographical isolation is an important factor for the observed genetic differentiation. Nine geographical populations of P. eryngii var. tuoliensis were divided into three groups according to their geographical origins, which revealed that the genetic diversity was closely related to the geographical distribution of this wild fungus. PMID- 24349476 TI - Histone H4R3 methylation catalyzed by SKB1/PRMT5 is required for maintaining shoot apical meristem. AB - The shoot apical meristem (SAM) is the source of all of the above-ground tissues and organs in post-embryonic development in higher plants. Studies have proven that the expression of genes constituting the WUSCHEL (WUS)-CLAVATA (CLV) feedback loop is critical for the SAM maintenance. Several histone lysine acetylation and methylation markers have been proven to regulate the transcription level of WUS. However, little is known about how histone arginine methylation regulates the expression of WUS and other genes. Here, we report that H4R3 symmetric dimethylation (H4R3sme2) mediated by SKB1/PRMT5 represses the expression of CORYNE (CRN) to maintain normal SAM geometrics. SKB1 lesion results in small SAM size in Arabidopsis, as well as down-regulated expression of WUS and CLV3. Up-regulation of WUS expression enlarges SAM size in skb1 mutant plants. We find that SKB1 and H4R3sme2 associate with the chromatin of the CRN locus to down regulate its transcription. Mutation of CRN rescues the expression of WUS and the small SAM size of skb1. Thus, SKB1 and SKB1-mediated H4R3sme2 are required for the maintenance of SAM in Arabidopsis seedlings. PMID- 24349477 TI - The effect of an adding histidine on biological activity and stability of Pc-pis from Pseudosciaena crocea. AB - Pc-pis is a novel piscidin-like antimicrobial polypeptide that was identified in Pseudosciaena crocea. Although active against most bacteria tested, Pc-pis was inactive against Aeromonas hydrophila and Pseudomonas aeruginosa. The Pc-pis analogue Pc-pis-His was designed by adding a histidine residue at the carboxyl terminal. Pc-pis-His demonstrated a more broad-spectrum and stronger antimicrobial activity against a representative set of microorganisms and more potent antiparasitic activity against Cryptocaryon irritans trophonts than Pc pis. The stability assay revealed that Pc-pis-His was active against Staphylococcus aureus not only in acidic (pH 5.5-7.3) and relatively low concentration monovalent cation (0-160 mM NaCl) environments but also in alkaline (pH 7.5-9.5), divalent cation (1.25-160 mM MgCl2 and 1.25-40 mM CaCl2) and high concentration monovalent cation (320-2560 mM NaCl) environments, which indicates that the added histidine residue conferred better salt-, acid- and alkali tolerance to Pc-pis-His. Pc-pis-His also possessed the desired heat-tolerance, which was reflected by the antimicrobial activity of the peptide after being boiled for 10-60 minutes. Hemolytic activity analysis revealed that Pc-pis-His at concentrations up to 6 uM exhibited no hemolysis against human erythrocytes, with 6 uM being a concentration that is highly active against most of the microorganisms tested, although the hemolytic activity of Pc-pis-His was enhanced compared to Pc-pis. These results provide a unique, reasonable basis for designing novel piscidins with potent, broad-spectrum and stable antimicrobial activity and new insight into the future development of piscidins as potential therapeutic agents against microbial and external protozoan parasite infections. PMID- 24349478 TI - A regression-based method for estimating risks and relative risks in case-base studies. AB - Both the absolute risk and the relative risk (RR) have a crucial role to play in epidemiology. RR is often approximated by odds ratio (OR) under the rare-disease assumption in conventional case-control study; however, such a study design does not provide an estimate for absolute risk. The case-base study is an alternative approach which readily produces RR estimation without resorting to the rare disease assumption. However, previous researchers only considered one single dichotomous exposure and did not elaborate how absolute risks can be estimated in a case-base study. In this paper, the authors propose a logistic model for the case-base study. The model is flexible enough to admit multiple exposures in any measurement scale-binary, categorical or continuous. It can be easily fitted using common statistical packages. With one additional step of simple calculations of the model parameters, one readily obtains relative and absolute risk estimates as well as their confidence intervals. Monte-Carlo simulations show that the proposed method can produce unbiased estimates and adequate coverage confidence intervals, for ORs, RRs and absolute risks. The case-base study with all its desirable properties and its methods of analysis fully developed in this paper may become a mainstay in epidemiology. PMID- 24349479 TI - Pain and disgust: the facial signaling of two aversive bodily experiences. AB - The experience of pain and disgust share many similarities, given that both are aversive experiences resulting from bodily threat and leading to defensive reactions. The aim of the present study was to investigate whether facial expressions are distinct enough to encode the specific quality of pain and disgust or whether they just encode the similar negative valence and arousal level of both states. In sixty participants pain and disgust were induced by heat stimuli and pictures, respectively. Facial responses (Facial Action Coding System) as well as subjective responses were assessed. Our main findings were that nearly the same single facial actions were elicited during pain and disgust experiences. However, these single facial actions were displayed with different strength and were differently combined depending on whether pain or disgust was experienced. Whereas pain was mostly encoded by contraction of the muscles surrounding the eyes (by itself or in combination with contraction of the eyebrows); disgust was mainly accompanied by contraction of the eyebrows and--in contrast to pain--by raising of the upper lip as well as the combination of upper lip raise and eyebrow contraction. Our data clearly suggests that facial expressions seem to be distinct enough to encode not only the general valence and arousal associated with these two bodily aversive experiences, namely pain and disgust, but also the specific origin of the threat to the body. This implies that the differential decoding of these two states by an observer is possible without additional verbal or contextual information, which is of special interest for clinical practice, given that raising awareness in observers about these distinct differences could help to improve the detection of pain in patients who are not able to provide a self-report of pain (e.g., patients with dementia). PMID- 24349480 TI - Novel targets of sulforaphane in primary cardiomyocytes identified by proteomic analysis. AB - Cardiovascular diseases represent the main cause of mortality in the industrialized world and the identification of effective preventive strategies is of fundamental importance. Sulforaphane, an isothiocyanate from cruciferous vegetables, has been shown to up-regulate phase II enzymes in cardiomyocytes and counteract oxidative stress-induced apoptosis. Aim of the present study was the identification and characterization of novel sulforaphane targets in cardiomyocytes applying a proteomic approach. Two-dimensional gel electrophoresis and mass spectrometry were used to generate protein profiles of primary neonatal rat cardiomyocytes treated and untreated with 5 uM sulforaphane for 1-48 h. According to image analysis, 64 protein spots were found as differentially expressed and their functional correlations were investigated using the MetaCore program. We mainly focused on 3 proteins: macrophage migration inhibitory factor (MIF), CLP36 or Elfin, and glyoxalase 1, due to their possible involvement in cardioprotection. Validation of the time-dependent differential expression of these proteins was performed by western blotting. In particular, to gain insight into the cardioprotective role of the modulation of glyoxalase 1 by sulforaphane, further experiments were performed using methylglyoxal to mimic glycative stress. Sulforaphane was able to counteract methylglyoxal-induced apoptosis, ROS production, and glycative stress, likely through glyoxalase 1 up-regulation. In this study, we reported for the first time new molecular targets of sulforaphane, such as MIF, CLP36 and glyoxalase 1. In particular, we gave new insights into the anti-glycative role of sulforaphane in cardiomyocytes, confirming its pleiotropic behavior in counteracting cardiovascular diseases. PMID- 24349481 TI - A phenotypic screen in zebrafish identifies a novel small-molecule inducer of ectopic tail formation suggestive of alterations in non-canonical Wnt/PCP signaling. AB - Zebrafish have recently emerged as an attractive model for the in vivo bioassay guided isolation and characterization of pharmacologically active small molecules of natural origin. We carried out a zebrafish-based phenotypic screen of over 3000 plant-derived secondary metabolite extracts with the goal of identifying novel small-molecule modulators of the BMP and Wnt signaling pathways. One of the bioactive plant extracts identified in this screen - Jasminum gilgianum, an Oleaceae species native to Papua New Guinea - induced ectopic tails during zebrafish embryonic development. As ectopic tail formation occurs when BMP or non canonical Wnt signaling is inhibited during the tail protrusion process, we suspected a constituent of this extract to act as a modulator of these pathways. A bioassay-guided isolation was carried out on the basis of this zebrafish phenotype, identifying para-coumaric acid methyl ester (pCAME) as the active compound. We then performed an in-depth phenotypic analysis of pCAME-treated zebrafish embryos, including a tissue-specific marker analysis of the secondary tails. We found pCAME to synergize with the BMP-inhibitors dorsomorphin and LDN 193189 in inducing ectopic tails, and causing convergence-extension defects in compound-treated embryos. These results indicate that pCAME may interfere with non-canonical Wnt signaling. Inhibition of Jnk, a downstream target of Wnt/PCP signaling (via morpholino antisense knockdown and pharmacological inhibition with the kinase inhibitor SP600125) phenocopied pCAME-treated embryos. However, immunoblotting experiments revealed pCAME to not directly inhibit Jnk-mediated phosphorylation of c-Jun, suggesting additional targets of SP600125, and/or other pathways, as possibly being involved in the ectopic tail formation activity of pCAME. Further investigation of pCAME's mechanism of action will help determine this compound's pharmacological utility. PMID- 24349482 TI - microRNA 126 inhibits the transition of endothelial progenitor cells to mesenchymal cells via the PIK3R2-PI3K/Akt signalling pathway. AB - AIMS: Endothelial progenitor cells (EPCs) are capable of proliferating and differentiating into mature endothelial cells, and they have been considered as potential candidates for coronary heart disease therapy. However, the transition of EPCs to mesenchymal cells is not fully understood. This study aimed to explore the role of microRNA 126 (miR-126) in the endothelial-to-mesenchymal transition (EndMT) induced by transforming growth factor beta 1 (TGFbeta1). METHODS AND RESULTS: EndMT of rat bone marrow-derived EPCs was induced by TGFbeta1 (5 ng/mL) for 7 days. miR-126 expression was depressed in the process of EPC EndMT. The luciferase reporter assay showed that the PI3K regulatory subunit p85 beta (PIK3R2) was a direct target of miR-126 in EPCs. Overexpression of miR-126 by a lentiviral vector (lenti-miR-126) was found to downregulate the mRNA expression of mesenchymal cell markers (alpha-SMA, sm22-a, and myocardin) and to maintain the mRNA expression of progenitor cell markers (CD34, CD133). In the cellular process of EndMT, there was an increase in the protein expression of PIK3R2 and the nuclear transcription factors FoxO3 and Smad4; PI3K and phosphor-Akt expression decreased, a change that was reversed markedly by overexpression of miR-126. Furthermore, knockdown of PIK3R2 gene expression level showed reversed morphological changes of the EPCs treated with TGFbeta1, thereby giving the evidence that PIK3R2 is the target gene of miR-126 during EndMT process. CONCLUSIONS: These results show that miR-126 targets PIK3R2 to inhibit EPC EndMT and that this process involves regulation of the PI3K/Akt signalling pathway. miR 126 has the potential to be used as a biomarker for the early diagnosis of intimal hyperplasia in cardiovascular disease and can even be a therapeutic tool for treating cardiovascular diseases mediated by the EndMT process. PMID- 24349483 TI - Molecular characterization of a new Babesia bovis thrombospondin-related anonymous protein (BbTRAP2). AB - A gene encoding a Babesia bovis protein that shares significant degree of similarity to other apicomplexan thrombospondin-related anonymous proteins (TRAPs) was found in the genomic database and designated as BbTRAP2. Recombinant protein containing a conserved region of BbTRAP2 was produced in E. coli. A high antigenicity of recombinant BbTRAP2 (rBbTRAP2) was observed with field B. bovis infected bovine sera collected from geographically different regions of the world. Moreover, antiserum against rBbTRAP2 specifically reacted with the authentic protein by Western blot analysis and an indirect fluorescent antibody test. Three bands corresponding to 104-, 76-, and 44-kDa proteins were identified in the parasite lysates and two bands of 76- and 44-kDa proteins were detected in the supernatant of cultivated parasites, indicating that BbTRAP2 was proteolytically processed and shed into the culture. Apical and surface localizations of BbTRAP2 were observed in the intracellular and extracellular parasites, respectively, by confocal laser microscopic examination. Moreover, native BbTRAP2 was precipitated by bovine erythrocytes, suggesting its role in the attachment to erythrocytes. Furthermore, the specific antibody to rBbTRAP2 inhibited the growth of B. bovis in a concentration-dependent manner. Consistently, pre-incubation of the free merozoites with the antibody to rBbTRAP2 resulted in an inhibition of the parasite invasion into host erythrocytes. Interestingly, the antibody to rBbTRAP2 was the most inhibitive for the parasite's growth as compared to those of a set of antisera produced against different recombinant proteins, including merozoite surface antigen 2c (BbMSA 2c), rhoptry-associated protein 1 C-terminal (BbRAP-1CT), and spherical body protein 1 (BbSBP-1). These results suggest that BbTRAP2 might be a potential candidate for development of a subunit vaccine against B. bovis infection. PMID- 24349485 TI - Hepatitis C virus infection causes iron deficiency in Huh7.5.1 cells. AB - Patients with chronic hepatitis C virus (HCV) infection frequently develop systemic iron overload, which exacerbates morbidity. Nevertheless, iron inhibits HCV replication in cell culture models and thereby exerts antiviral activity. We hypothesized that the cellular iron status is crucial for the establishment of HCV infection. We show that HCV infection of permissive Huh7.5.1 hepatoma cells promotes an iron deficient phenotype. Thus, HCV leads to increased iron regulatory protein (IRP) activity, accumulation of IRP2 and suppression of transferrin receptor 1 (TfR1) and divalent metal transporter 1 (DMT1) in the host. These data suggest that HCV regulates cellular iron levels to bypass iron mediated inhibition in viral replication. PMID- 24349484 TI - When, where and how osteoporosis-associated fractures occur: an analysis from the Global Longitudinal Study of Osteoporosis in Women (GLOW). AB - OBJECTIVE: To examine when, where and how fractures occur in postmenopausal women. METHODS: We analyzed data from the Global Longitudinal Study of Osteoporosis in Women (GLOW), including women aged >=55 years from the United States of America, Canada, Australia and seven European countries. Women completed questionnaires including fracture data at baseline and years 1, 2 and 3. RESULTS: Among 60,393 postmenopausal women, 4122 incident fractures were reported (86% non-hip, non-vertebral [NHNV], 8% presumably clinical vertebral and 6% hip). Hip fractures were more likely to occur in spring, with little seasonal variation for NHNV or spine fractures. Hip fractures occurred equally inside or outside the home, whereas 65% of NHNV fractures occurred outside and 61% of vertebral fractures occurred inside the home. Falls preceded 68-86% of NHNV and 68-83% of hip fractures among women aged <=64 to >=85 years, increasing with age. About 45% of vertebral fractures were associated with falls in all age groups except those >=85 years, when only 24% occurred after falling. CONCLUSION: In this multi-national cohort, fractures occurred throughout the year, with only hip fracture having a seasonal variation, with a higher proportion in spring. Hip fractures occurred equally within and outside the home, spine fractures more often in the home, and NHNV fractures outside the home. Falls were a proximate cause of most hip and NHNV fractures. Postmenopausal women at risk for fracture need counseling about reducing potentially modifiable fracture risk factors, particularly falls both inside and outside the home and during all seasons of the year. PMID- 24349486 TI - Effects of textured insoles on balance in people with Parkinson's disease. AB - BACKGROUND: Degradation of the somatosensory system has been implicated in postural instability and increased falls risk for older people and Parkinson's disease (PD) patients. Here we demonstrate that textured insoles provide a passive intervention that is an inexpensive and accessible means to enhance the somatosensory input from the plantar surface of the feet. METHODS: 20 healthy older adults (controls) and 20 participants with PD were recruited for the study. We evaluated effects of manipulating somatosensory information from the plantar surface of the feet using textured insoles. Participants performed standing tests, on two different surfaces (firm and foam), under three footwear conditions: 1) barefoot; 2) smooth insoles; and 3) textured insoles. Standing balance was evaluated using a force plate yielding data on the range of anterior posterior and medial-lateral sway, as well as standard deviations for anterior posterior and medial-lateral sway. RESULTS: On the firm surface with eyes open both the smooth and textured insoles reduced medial-lateral sway in the PD group to a similar level as the controls. Only the textured insole decreased medial lateral sway and medial-lateral sway standard deviation in the PD group on both surfaces, with and without visual input. Greatest benefits were observed in the PD group while wearing the textured insoles, and when standing on the foam surface with eyes closed. CONCLUSIONS: Data suggested that textured insoles may provide a low-cost means of improving postural stability in high falls-risk groups, such as people with PD. PMID- 24349487 TI - Is sustained virological response a marker of treatment efficacy in patients with chronic hepatitis C viral infection with no response or relapse to previous antiviral intervention? AB - BACKGROUND: Randomised clinical trials (RCTs) of antiviral interventions in patients with chronic hepatitis C virus (HCV) infection use sustained virological response (SVR) as the main outcome. There is sparse information on long-term mortality from RCTs. METHODS: We created a decision tree model based on a Cochrane systematic review on interferon retreatment for patients who did not respond to initial therapy or who relapsed following SVR. Extrapolating data to 20 years, we modelled the outcome from three scenarios: (1) observed medium-term (5 year) annual mortality rates continue to the long term (20 years); (2) long term annual mortality in retreatment responders falls to that of the general population while retreatment non-responders continue at the medium-term mortality; (3) long-term annual mortality in retreatment non-responders is the same as control group non-responders (i.e., the increased treatment-related medium mortality "wears off"). RESULTS: The mean differences in life expectancy over 20 years with interferon versus control in the first, second, and third scenarios were -0.34 years (95% confidence interval (CI) -0.71 to 0.03), -0.23 years (95% CI -0.69 to 0.24), and -0.01 (95% CI -0.3 to 0.27), respectively. The life expectancy was always lower in the interferon group than in the control group in scenario 1. In scenario 3, the interferon group had a longer life expectancy than the control group only when more than 7% in the interferon group achieved SVR. CONCLUSIONS: SVR may be a good prognostic marker but does not seem to be a valid surrogate marker for assessing HCV treatment efficacy of interferon retreatment. The SVR threshold at which retreatment increases life expectancy may be different for different drugs depending upon the adverse event profile and treatment efficacy. This has to be determined for each drug by RCTs and appropriate modelling before SVR can be accepted as a surrogate marker. PMID- 24349488 TI - PTEN increases autophagy and inhibits the ubiquitin-proteasome pathway in glioma cells independently of its lipid phosphatase activity. AB - Two major mechanisms of intracellular protein degradation, autophagy and the ubiquitin-proteasome pathway, operate in mammalian cells. PTEN, which is frequently mutated in glioblastomas, is a tumor suppressor gene that encodes a dual specificity phosphatase that antagonizes the phosphatidylinositol 3-kinase class I/AKT/mTOR pathway, which is a key regulator of autophagy. Here, we investigated in U87MG human glioma cells the role of PTEN in the regulation of autophagy and the ubiquitin-proteasome pathway, because both are functionally linked and are relevant in cancer progression. Since U87MG glioma cells lack a functional PTEN, we used stable clones that express, under the control of a tetracycline-inducible system (Tet-on), wild-type PTEN and two of its mutants, G129E-PTEN and C124S-PTEN, which, respectively, lack the lipid phosphatase activity only and both the lipid and the protein phosphatase activities of this protein. Expression of PTEN in U87MG glioma cells decreased proteasome activity and also reduced protein ubiquitination. On the contrary, expression of PTEN increased the autophagic flux and the lysosomal mass. Interestingly, and although PTEN negatively regulates the phosphatidylinositol 3-kinase class I/AKT/mTOR signaling pathway by its lipid phosphatase activity, both effects in U87MG cells were independent of this activity. These results suggest a new mTOR-independent signaling pathway by which PTEN can regulate in opposite directions the main mechanisms of intracellular protein degradation. PMID- 24349489 TI - Whole-exome sequencing to identify a novel LMNA gene mutation associated with inherited cardiac conduction disease. AB - BACKGROUND: Inherited cardiac conduction diseases (CCD) are rare but are caused by mutations in a myriad of genes. Recently, whole-exome sequencing has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases. OBJECTIVE: To investigate the genetic background of a family affected by inherited CCD. METHODS AND RESULTS: We used whole-exome sequencing to study a Chinese family with multiple family members affected by CCD. Using the pedigree information, we proposed a heterozygous missense mutation (c.G695T, Gly232Val) in the lamin A/C (LMNA) gene as a candidate mutation for susceptibility to CCD in this family. The mutation is novel and is expected to affect the conformation of the coiled-coil rod domain of LMNA according to a structural model prediction. Its pathogenicity in lamina instability was further verified by expressing the mutation in a cellular model. CONCLUSIONS: Our results suggest that whole-exome sequencing is a feasible approach to identifying the candidate genes underlying inherited conduction diseases. PMID- 24349490 TI - Rab39a interacts with phosphatidylinositol 3-kinase and negatively regulates autophagy induced by lipopolysaccharide stimulation in macrophages. AB - Rab39a has pleiotropic functions in phagosome maturation, inflammatory activation and neuritogenesis. Here, we characterized Rab39a function in membrane trafficking of phagocytosis and autophagy induction in macrophages. Rab39a localized to the periphery of LAMP2-positive vesicles and showed the similar kinetics on the phagosome to that of LAMP1. The depletion of Rab39a did not influence the localization of LAMP2 to the phagosome, but it augments the autophagosome formation and LC3 processing by lipopolysaccharide (LPS) stimulation. The augmentation of autophagosome formation in Rab39a-knockdown macrophages was suppressed by Atg5 depletion or an inhibitor for phosphatidylinostol 3-kinase (PI3K). Immunoprecipitation analysis revealed that Rab39a interacts with PI3K and that the amino acid residues from 34(th) to 41(st) in Rab39a were indispensable for this interaction. These results suggest that Rab39a negatively regulates the LPS-induced autophagy in macrophages. PMID- 24349491 TI - Mitochondrial DNA damage via augmented oxidative stress regulates endoplasmic reticulum stress and autophagy: crosstalk, links and signaling. AB - Saturated free fatty acids (FFAs) have been implicated in the increase of oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, autophagy, and insulin resistance (IR) observed in skeletal muscle. Previously, we have shown that palmitate-induced mitochondrial DNA (mtDNA) damage triggers mitochondrial dysfunction, mitochondrial reactive oxygen species (mtROS) production, apoptosis and IR in L6 myotubes. The present study showed that mitochondrial overexpression of human 8-oxoguanine DNA glycosylase/AP lyase (hOGG1) decreased palmitate-induced carbonylation of proteins in mitochondria. Additionally, we found that protection of mtDNA from palmitate-induced damage significantly diminished markers of both ER stress and autophagy in L6 myotubes. Moreover, we observed that the addition of ROS scavenger, N-acetylcystein (NAC), to palmitate diminished both ER stress and autophagy markers mimicking the effect of mitochondrial overexpression of hOGG1. This is the first study to show that mtDNA damage is upstream of palmitate-induced ER stress and autophagy in skeletal muscle cells. PMID- 24349492 TI - Sleep-related declarative memory consolidation and verbal replay during sleep talking in patients with REM sleep behavior disorder. AB - OBJECTIVE: To determine if sleep talkers with REM sleep behavior disorder (RBD) would utter during REM sleep sentences learned before sleep, and to evaluate their verbal memory consolidation during sleep. METHODS: Eighteen patients with RBD and 10 controls performed two verbal memory tasks (16 words from the Free and Cued Selective Reminding Test and a 220-263 word long modified Story Recall Test) in the evening, followed by nocturnal video-polysomnography and morning recall (night-time consolidation). In 9 patients with RBD, daytime consolidation (morning learning/recall, evening recall) was also evaluated with the modified Story Recall Test in a cross-over order. Two RBD patients with dementia were studied separately. Sleep talking was recorded using video-polysomnography, and the utterances were compared to the studied texts by two external judges. RESULTS: Sleep-related verbal memory consolidation was maintained in patients with RBD (+24+/-36% words) as in controls (+9+/-18%, p=0.3). The two demented patients with RBD also exhibited excellent nighttime consolidation. The post sleep performance was unrelated to the sleep measures (including continuity, stages, fragmentation and apnea-hypopnea index). Daytime consolidation (-9+/-19%) was worse than night-time consolidation (+29+/-45%, p=0.03) in the subgroup of 9 patients with RBD. Eleven patients with RBD spoke during REM sleep and pronounced a median of 20 words, which represented 0.0003% of sleep with spoken language. A single patient uttered a sentence that was judged to be semantically (but not literally) related to the text learned before sleep. CONCLUSION: Verbal declarative memory normally consolidates during sleep in patients with RBD. The incorporation of learned material within REM sleep-associated sleep talking in one patient (unbeknownst to himself) at the semantic level suggests a replay at a highly cognitive creative level. PMID- 24349493 TI - A coregulatory network of NR2F1 and microRNA-140. AB - BACKGROUND: Both nuclear receptor subfamily 2 group F member 1 (NR2F1) and microRNAs (miRNAs) have been shown to play critical roles in the developing and functional inner ear. Based on previous studies suggesting interplay between NR2F1 and miRNAs, we investigated the coregulation between NR2F1 and miRNAs to better understand the regulatory mechanisms of inner ear development and functional maturation. RESULTS: Using a bioinformatic approach, we identified 11 potential miRNAs that might coregulate target genes with NR2F1 and analyzed their targets and potential roles in physiology and disease. We selected 6 miRNAs to analyze using quantitative real-time (qRT) -PCR and found that miR-140 is significantly down-regulated by 4.5-fold (P=0.004) in the inner ear of NR2F1 knockout (Nr2f1(-/-)) mice compared to wild-type littermates but is unchanged in the brain. Based on this, we performed chromatin-immunoprecipitation followed by qRT-PCR and confirmed that NR2F1 directly binds and regulates both miR-140 and Klf9 in vivo. Furthermore, we performed luciferase reporter assay and showed that miR-140 mimic directly regulates KLF9-3'UTR, thereby establishing and validating an example coregulatory network involving NR2F1, miR-140, and Klf9. CONCLUSIONS: We have described and experimentally validated a novel tissue-dependent coregulatory network for NR2F1, miR-140, and Klf9 in the inner ear and we propose the existence of many such coregulatory networks important for both inner ear development and function. PMID- 24349494 TI - Apolipoprotein E gene variants on the risk of end stage renal disease. AB - OBJECTIVE: End-stage renal disease (ESRD) is a severe health concern over the world. Associations between apolipoprotein E (apoE) gene polymorphisms and the risk of ESRD remained inconclusive. This study aimed to investigate the association between apoE gene polymorphisms and ESRD susceptibility. METHODS: Databases including PubMed, Embase, Web of Science and the Cochrane Library were searched to find relevant studies. Meta-analysis method was used synthesize the eligible studies. RESULTS: Sixteen pertinent case-control studies which included 3510 cases and 13924 controls were analyzed. A significant association was found between epsilon2 allele and the ESRD risk (odds ratio (OR) = 1.30, 95% confidence interval (CI) 1.15-1.46, P < 0.0001; I (2) = 18%, P for heterogeneity = 0.24). The epsilon2epsilon3, epsilon2epsilon4, epsilon3epsilon3, epsilon3epsilon4, epsilon4epsilon4, epsilon3 and epsilon4 were not associated with the susceptibility of ESRD. In the subgroup analysis by ethnicity, there was a statistically significant association between epsilon2epsilon3 or epsilon2 allele and ESRD risk in East Asians (OR = 1.66, 95% CI 1.31-2.10, P < 0.0001; OR = 1.62, 95% CI 1.31-2.01, P < 0.0001, respectively), but not in Caucasians. E2 carriers had higher plasma apoE (mean difference = 16.24 mg/L, 95% CI 7.76-24.73, P = 0.0002) than the (epsilon3 + epsilon4) carriers in patients with ESRD. The publication bias was not significant. CONCLUSION: The epsilon2 allele of apoE gene might increase the risk of ESRD. E2 carriers expressed higher level of plasma apoE in patients with ESRD. More well-designed studies are needed to confirm these associations in the future. PMID- 24349495 TI - Expression of Panton-Valentine leukocidin mRNA among Staphylococcus aureus isolates associates with specific clinical presentations. AB - Panton-Valentine leukocidin (PVL; gene designation lukF/S-PV) is likely an important virulence factor for Staphylococcus aureus (S. aureus), as qualitative expression of the protein correlates with severity for specific clinical presentations, including skin and soft tissue infections (SSTIs). Development of genetic approaches for risk-assessment of patients with S. aureus infections may prove clinically useful, and whether lukF/S-PV gene expression correlates with specific clinical presentations for S. aureus has been largely unexplored. In the present study, we quantified lukS-PV mRNA among 96 S. aureus isolates to determine whether expression levels correlated with specific clinical presentations in adults and children. Expression level of lukS-PV mRNA among isolates from skin and soft tissue infections (SSTIs) was significantly greater than among isolates from blood stream infection (BSIs), and expression level of lukS-PV mRNA among BSI isolates from children was significantly greater than for BSI isolates among adults. Moreover, expression level of lukS-PV mRNA among community-acquired (CA) isolates was significantly greater than for hospital acquired (HA) isolates. These data justify additional studies to determine the potential clinical utility for lukS-PV mRNA quantification as a predictive tool for severity of S. aureus infection. PMID- 24349496 TI - Effects of nutritional supplementation during pregnancy on early adult disease risk: follow up of offspring of participants in a randomised controlled trial investigating effects of supplementation on infant birth weight. AB - BACKGROUND: Observational evidence suggests that improving fetal growth may improve adult health. Experimental evidence from nutritional supplementation trials undertaken amongst pregnant women in the less developed world does not show strong or consistent effects on adult disease risk and no trials from the more developed world have previously been reported. OBJECTIVE: To test the hypothesis that nutritional supplementation during pregnancy influences offspring disease risk in adulthood. DESIGN: Clinical assessment of a range of established diseases risk markers in young adult offspring of 283 South Asian mothers who participated in two trials of nutritional supplementation during pregnancy (protein/energy/vitamins; energy/vitamins or vitamins only) at Sorrento Maternity Hospital in Birmingham UK either unselected or selected on the basis of nutritional status. RESULTS: 236 (83%) offspring were traced and 118 (50%) of these were assessed in clinic. Protein/energy/vitamins supplementation amongst undernourished mothers was associated with increased infant birthweight. Nutritional supplementation showed no strong association with any one of a comprehensive range of markers of adult disease risk and no consistent pattern of association with risk across markers in offspring of either unselected or undernourished mothers. CONCLUSIONS: We found no evidence that nutritional supplements given to pregnant women are an important influence on adult disease risk however our study lacked power to estimate small effects. Our findings do not provide support for a policy of nutritional supplementation for pregnant women as an effective means to improve adult health in more developed societies. PMID- 24349498 TI - Seasonal foraging ecology of non-migratory cougars in a system with migrating prey. AB - We tested for seasonal differences in cougar (Puma concolor) foraging behaviors in the Southern Yellowstone Ecosystem, a multi-prey system in which ungulate prey migrate, and cougars do not. We recorded 411 winter prey and 239 summer prey killed by 28 female and 10 male cougars, and an additional 37 prey items by unmarked cougars. Deer composed 42.4% of summer cougar diets but only 7.2% of winter diets. Males and females, however, selected different proportions of different prey; male cougars selected more elk (Cervus elaphus) and moose (Alces alces) than females, while females killed greater proportions of bighorn sheep (Ovis canadensis), pronghorn (Antilocapra americana), mule deer (Odocoileus hemionus) and small prey than males. Kill rates did not vary by season or between males and females. In winter, cougars were more likely to kill prey on the landscape as: 1) elevation decreased, 2) distance to edge habitat decreased, 3) distance to large bodies of water decreased, and 4) steepness increased, whereas in summer, cougars were more likely to kill in areas as: 1) elevation decreased, 2) distance to edge habitat decreased, and 3) distance from large bodies of water increased. Our work highlighted that seasonal prey selection exhibited by stationary carnivores in systems with migratory prey is not only driven by changing prey vulnerability, but also by changing prey abundances. Elk and deer migrations may also be sustaining stationary cougar populations and creating apparent competition scenarios that result in higher predation rates on migratory bighorn sheep in winter and pronghorn in summer. Nevertheless, cougar predation on rare ungulates also appeared to be influenced by individual prey selection. PMID- 24349497 TI - Next generation inactivated polio vaccine manufacturing to support post polio eradication biosafety goals. AB - Worldwide efforts to eradicate polio caused a tipping point in polio vaccination strategies. A switch from the oral polio vaccine, which can cause circulating and virulent vaccine derived polioviruses, to inactivated polio vaccines (IPV) is scheduled. Moreover, a manufacturing process, using attenuated virus strains instead of wild-type polioviruses, is demanded to enhance worldwide production of IPV, especially in low- and middle income countries. Therefore, development of an IPV from attenuated (Sabin) poliovirus strains (sIPV) was pursued. Starting from the current IPV production process based on wild type Salk strains, adaptations, such as lower virus cultivation temperature, were implemented. sIPV was produced at industrial scale followed by formulation of both plain and aluminium adjuvanted sIPV. The final products met the quality criteria, were immunogenic in rats, showed no toxicity in rabbits and could be released for testing in the clinic. Concluding, sIPV was developed to manufacturing scale. The technology can be transferred worldwide to support post polio-eradication biosafety goals. PMID- 24349499 TI - The bZIP transcription factor Fgap1 mediates oxidative stress response and trichothecene biosynthesis but not virulence in Fusarium graminearum. AB - Redox sensing is of primary importance for fungi to cope with oxidant compounds found in their environment. Plant pathogens are particularly subject to the oxidative burst during the primary steps of infection. In the budding yeast Saccharomyces cerevisiae, it is the transcription factor Yap1 that mediates the response to oxidative stress via activation of genes coding for detoxification enzymes. In the cereal pathogen Fusarium graminearum, Fgap1 a homologue of Yap1 was identified and its role was investigated. During infection, this pathogen produces mycotoxins belonging to the trichothecenes family that accumulate in the grains. The global regulation of toxin biosynthesis is not completely understood. However, it is now clearly established that an oxidative stress activates the production of toxins by F. graminearum. The involvement of Fgap1 in this activation was investigated. A deleted mutant and a strain expressing a truncated constitutive form of Fgap1 were constructed. None of the mutants was affected in pathogenicity. The deleted mutant showed higher level of trichothecenes production associated with overexpression of Tri genes. Moreover activation of toxin accumulation in response to oxidative stress was no longer observed. Regarding the mutant with the truncated constitutive form of Fgap1, toxin production was strongly reduced. Expression of oxidative stress response genes was not activated in the deleted mutant and expression of the gene encoding the mitochondrial superoxide dismutase MnSOD1 was up-regulated in the mutant with the truncated constitutive form of Fgap1. Our results demonstrate that Fgap1 plays a key role in the link between oxidative stress response and F. graminearum secondary metabolism. PMID- 24349500 TI - KIR, HLA, and IL28B variant predict response to antiviral therapy in genotype 1 chronic hepatitis C patients in Japan. AB - Natural killer cell responses play a crucial role in virus clearance by the innate immune system. Although the killer immunoglobulin-like receptor (KIR) in combination with its cognate human leukocyte antigen (HLA) ligand, especially KIR2DL3-HLA-C1, is associated with both treatment-induced and spontaneous clearance of hepatitis C virus (HCV) infection in Caucasians, these innate immunity genes have not been fully clarified in Japanese patients. We therefore investigated 16 KIR genotypes along with HLA-B and -C ligands and a genetic variant of interleukin (IL) 28B (rs8099917) in 115 chronic hepatitis C genotype 1 patients who underwent pegylated-interferon-alpha2b (PEG-IFN) and ribavirin therapy. HLA-Bw4 was significantly associated with a sustained virological response (SVR) to treatment (P = 0.017; odds ratio [OR] = 2.50, ), as was the centromeric A/A haplotype of KIR (P = 0.015; OR 3.37). In contrast, SVR rates were significantly decreased in patients with KIR2DL2 or KIR2DS2 (P = 0.015; OR = 0.30, and P = 0.025; OR = 0.32, respectively). Multivariate logistic regression analysis subsequently identified the IL28B TT genotype (P = 0.00009; OR = 6.87, 95% confidence interval [CI] = 2.62 - 18.01), KIR2DL2/HLA-C1 (P = 0.014; OR = 0.24, 95% CI = 0.08 - 0.75), KIR3DL1/HLA-Bw4 (P = 0.008, OR = 3.32, 95% CI = 1.37 - 8.05), and white blood cell count at baseline (P = 0.009; OR = 3.32, 95% CI = 1.35 - 8.16) as independent predictive factors of an SVR. We observed a significant association between the combination of IL28B TT genotype and KIR3DL1 HLA-Bw4 in responders (P = 0.0019), whereas IL28B TT along with KIR2DL2-HLA-C1 was related to a non-response (P = 0.0067). In conclusion, combinations of KIR3DL1/HLA-Bw4, KIR2DL2/HLA-C1, and a genetic variant of the IL28B gene are predictive of the response to PEG-IFN and ribavirin therapy in Japanese patients infected with genotype 1b HCV. PMID- 24349501 TI - Effect of caffeine-containing beverage consumption on serum alanine aminotransferase levels in patients with chronic hepatitis C virus infection: a hospital-based cohort study. AB - INTRODUCTION: To date, there have been no prospective studies examining the effect of coffee consumption on serum alanine aminotransferase (ALT) level among individuals infected with the hepatitis C virus (HCV). We conducted a hospital based cohort study among patients with chronic HCV infection to assess an association between baseline coffee consumption and subsequent ALT levels for 12 months. MATERIALS AND METHODS: From 1 August 2005 to 31 July 2006, total 376 HCV RNA positive patients were recruited. A baseline questionnaire elicited information on the frequency of coffee consumption and other caffeine-containing beverages. ALT level as a study outcome was followed through the patients' medical records during 12 months. The association between baseline beverage consumption and subsequent ALT levels was evaluated separately among patients with baseline ALT levels within normal range (<=45 IU/L) and among those with higher ALT levels (>45 IU/L). RESULTS: Among 229 patients with baseline ALT levels within normal range, 186 (81%) retained normal ALT levels at 12 months after recruitment. Daily drinkers of filtered coffee were three times more likely to preserve a normal ALT level than non-drinkers (OR=2.74; P=0.037). However, decaffeinated coffee drinkers had a somewhat inverse effect for sustained normal ALT levels, with marginal significance (OR=0.26; P=0.076). In addition, among 147 patients with higher baseline ALT levels, 39 patients (27%) had ALT reductions of >=20 IU/L at 12 months after recruitment. Daily drinkers of filtered coffee had a significantly increased OR for ALT reduction (OR=3.79; P=0.034). However, in decaffeinated coffee drinkers, OR could not be calculated because no patients had ALT reduction. CONCLUSION: Among patients with chronic HCV infection, daily consumption of filtered coffee may have a beneficial effect on the stabilization of ALT levels. PMID- 24349502 TI - New rRNA gene-based phylogenies of the Alphaproteobacteria provide perspective on major groups, mitochondrial ancestry and phylogenetic instability. AB - Bacteria in the class Alphaproteobacteria have a wide variety of lifestyles and physiologies. They include pathogens of humans and livestock, agriculturally valuable strains, and several highly abundant marine groups. The ancestor of mitochondria also originated in this clade. Despite significant effort to investigate the phylogeny of the Alphaproteobacteria with a variety of methods, there remains considerable disparity in the placement of several groups. Recent emphasis on phylogenies derived from multiple protein-coding genes remains contentious due to disagreement over appropriate gene selection and the potential influences of systematic error. We revisited previous investigations in this area using concatenated alignments of the small and large subunit (SSU and LSU) rRNA genes, as we show here that these loci have much lower GC bias than whole genomes. This approach has allowed us to update the canonical 16S rRNA gene tree of the Alphaproteobacteria with additional important taxa that were not previously included, and with added resolution provided by concatenating the SSU and LSU genes. We investigated the topological stability of the Alphaproteobacteria by varying alignment methods, rate models, taxon selection and RY-recoding to circumvent GC content bias. We also introduce RYMK-recoding and show that it avoids some of the information loss in RY-recoding. We demonstrate that the topology of the Alphaproteobacteria is sensitive to inclusion of several groups of taxa, but it is less affected by the choice of alignment and rate methods. The majority of topologies and comparative results from Approximately Unbiased tests provide support for positioning the Rickettsiales and the mitochondrial branch within a clade. This composite clade is a sister group to the abundant marine SAR11 clade (Pelagibacterales). Furthermore, we add support for taxonomic assignment of several recently sequenced taxa. Accordingly, we propose three subclasses within the Alphaproteobacteria: the Caulobacteridae, the Rickettsidae, and the Magnetococcidae. PMID- 24349503 TI - Validation and calibration of a computer simulation model of pediatric HIV infection. AB - BACKGROUND: Computer simulation models can project long-term patient outcomes and inform health policy. We internally validated and then calibrated a model of HIV disease in children before initiation of antiretroviral therapy to provide a framework against which to compare the impact of pediatric HIV treatment strategies. METHODS: We developed a patient-level (Monte Carlo) model of HIV progression among untreated children <5 years of age, using the Cost Effectiveness of Preventing AIDS Complications model framework: the CEPAC Pediatric model. We populated the model with data on opportunistic infection and mortality risks from the International Epidemiologic Database to Evaluate AIDS (IeDEA), with mean CD4% at birth (42%) and mean CD4% decline (1.4%/month) from the Women and Infants' Transmission Study (WITS). We internally validated the model by varying WITS-derived CD4% data, comparing the corresponding model generated survival curves to empirical survival curves from IeDEA, and identifying best-fitting parameter sets as those with a root-mean square error (RMSE) <0.01. We then calibrated the model to other African settings by systematically varying immunologic and HIV mortality-related input parameters. Model-generated survival curves for children aged 0-60 months were compared, again using RMSE, to UNAIDS data from >1,300 untreated, HIV-infected African children. RESULTS: In internal validation analyses, model-generated survival curves fit IeDEA data well; modeled and observed survival at 16 months of age were 91.2% and 91.1%, respectively. RMSE varied widely with variations in CD4% parameters; the best fitting parameter set (RMSE = 0.00423) resulted when CD4% was 45% at birth and declined by 6%/month (ages 0-3 months) and 0.3%/month (ages >3 months). In calibration analyses, increases in IeDEA-derived mortality risks were necessary to fit UNAIDS survival data. CONCLUSIONS: The CEPAC-Pediatric model performed well in internal validation analyses. Increases in modeled mortality risks required to match UNAIDS data highlight the importance of pre enrollment mortality in many pediatric cohort studies. PMID- 24349505 TI - Long-term functional dynamics of an aphidophagous coccinellid community remain unchanged despite repeated invasions. AB - Aphidophagous coccinellids (ladybeetles) are important providers of herbivore suppression ecosystem services. In the last 30 years, the invasion of exotic coccinellid species, coupled with observed declines in native species, has led to considerable interest in the community dynamics and ecosystem function of this guild. Here we examined a 24-year dataset of coccinellid communities in nine habitats in southwestern Michigan for changes in community function in response to invasion. Specifically we analyzed their temporal population dynamics and species diversity, and we modeled the community's potential to suppress pests. Abundance of coccinellids varied widely between 1989 and 2012 and became increasingly exotic-dominated. More than 71% of 57,813 adult coccinellids captured over the 24-year study were exotic species. Shannon diversity increased slightly over time, but herbivore suppression potential of the community remained roughly constant over the course of the study. However, both Shannon diversity and herbivore suppression potential due to native species declined over time in all habitats. The relationship between Shannon diversity and herbivore suppression potential varied with habitat type: a positive relationship in forest and perennial habitats, but was uncorrelated in annual habitats. This trend may have been because annual habitats were dominated by a few, highly voracious exotic species. Our results indicated that although the composition of the coccinellid community in southwestern Michigan has changed dramatically in the past several decades, its function has remained relatively unchanged in both agricultural and natural habitats. While this is encouraging from the perspective of pest management, it should be noted that losses of one of the dominant exotic coccinellids could result in a rapid decline in pest suppression services if the remaining community is unable to respond. PMID- 24349504 TI - Dietary BMAA exposure in an amyotrophic lateral sclerosis cluster from southern France. AB - BACKGROUND: Dietary exposure to the cyanotoxin BMAA is suspected to be the cause of amyotrophic lateral sclerosis in the Western Pacific Islands. In Europe and North America, this toxin has been identified in the marine environment of amyotrophic lateral sclerosis clusters but, to date, only few dietary exposures have been described. OBJECTIVES: We aimed at identifying cluster(s) of amyotrophic lateral sclerosis in the Herault district, a coastal district from Southern France, and to search, in the identified area(s), for the existence of a potential dietary source of BMAA. METHODS: A spatio-temporal cluster analysis was performed in the district, considering all incident amyotrophic lateral sclerosis cases identified from 1994 to 2009 by our expert center. We investigated the cluster area with serial collections of oysters and mussels that were subsequently analyzed blind for BMAA concentrations. RESULTS: We found one significant amyotrophic lateral sclerosis cluster (p = 0.0024), surrounding the Thau lagoon, the most important area of shellfish production and consumption along the French Mediterranean coast. BMAA was identified in mussels (1.8 ug/g to 6.0 ug/g) and oysters (0.6 ug/g to 1.6 ug/g). The highest concentrations of BMAA were measured during summer when the highest picocyanobacteria abundances were recorded. CONCLUSIONS: While it is not possible to ascertain a direct link between shellfish consumption and the existence of this ALS cluster, these results add new data to the potential association of BMAA with sporadic amyotrophic lateral sclerosis, one of the most severe neurodegenerative disorder. PMID- 24349506 TI - Aristolochic acid causes albuminuria by promoting mitochondrial DNA damage and dysfunction in podocyte. AB - Aristolochic acid nephropathy, initially found in patients intaking of slimming herbs containing aristolochic acid (AA), was previously considered as a progressive renal interstitial fibrosis and urothelial malignancy. However, the presence of albuminuria in some patients with AAN suggests that AA may also damage the glomerular filtration barrier. In this study, mice AAN model was generated by daily administration of aristolochic acid I sodium salt intraperitoneally at a dose of 6 mg/kg body weight for 3 days. All of the mice developed heavy albuminuria at day 3 and 7 after receiving AA. In the mice received AA, morphologic change of glomeruli was minor under light microscopy but podocyte foot-process effacement was evident under electron microscopy. In mitochondria isolated from kidney, prominent mitochondrial DNA (mtDNA) damage was accompanied with marked decrease of mtDNA copy number and mitochondrial protein expression level. Similar to those in vivo results, AA treatment impaired the filtration barrier function of cultured podocytes. AA promoted mtDNA damage, decreased mtDNA copy number and mitochondrial protein expression in cultured podocytes. In addition, AA treatment also decreased ATP content, oxygen consumption rate and mitochondrial membrane potential as well as increased cellular reactive oxygen species in cultured podocytes. This study highlighted that AA could induce podocyte damage and albuminuria, which may be mediated by promoting mtDNA damage and mitochondrial dysfunction in podocytes. PMID- 24349507 TI - Influence of the angiotensin converting enzyme insertion or deletion genetic variant and coronary restenosis risk: evidence based on 11,193 subjects. AB - The insertion/deletion (I/D) polymorphism of the gene encoding angiotensin converting enzyme is a controversial risk factor for restenosis after percutaneous transluminal coronary angioplasties (PTCA) in patients. Genetic association studies can be problematic to reproduce due to insufficient power, phenotypic heterogeneity, population stratification, small effect of the variant and even publication biases. To derive a more precise estimation of the relationship as well as to quantify the between-study heterogeneity and potential bias, a meta-analysis including 11,193 patients from 33 published cohort studies was performed. In a combined analysis, the summary per-allele odds ratio for restenosis was 1.31 (95% CI: 1.08-1.58, P = 0.006), and 1.22 (95% CI: 0.95-1.56, P = 0.12), for PTCA-stent and PTCA-balloon, respectively. In the subgroup analysis by ethnicity, significantly increased restenosis risks after PTCA-stent were found in Asians for the polymorphism; whereas no significant associations were found among Caucasians. As for restenosis risks after PTCA-balloon, no evidence of any gene-disease association was obtained in the stratified analyses according to ethnicity and study size. In conclusion, this meta-analysis demonstrated that the DD homozygous of ACE I/D polymorphism was significantly associated with elevated restenosis susceptibility after PTCA-stent among Asian populations. PMID- 24349509 TI - Cadmium induces liver cell apoptosis through caspase-3A activation in purse red common carp (Cyprinus carpio). AB - Caspase-3, the essential effector caspase, plays a pivotal role during caspase dependent apoptosis. In this study, we isolated and characterized caspase-3A gene from common carp. The common carp caspase-3A comprising 273 amino acids showed 71.8% sequence similarity and 59.3% sequence identity to human caspase-3. It exhibited an evolutionarily conserved structure of mammalian caspase-3 genes, including a pro-domain, a large subunit, a small subunit and other motifs such as the pentapeptide active-site motif (QACRG) and the putative cleavage sites at the aspartic acids. Phylogenetic analysis demonstrated that common carp caspase-3A formed a clade with cyprinid fish caspase-3. To assess whether caspase-3A is involved in cadmium (Cd)-induced cell apoptosis in common carp, a Cd exposure experiment was performed. TUNEL analysis showed that Cd triggered liver cell apoptosis; caspase-3A activity was markedly increased; its proenzyme level was significantly decreased, and the levels of its cleaved forms were markedly increased. However, real-time quantitative PCR analysis revealed that the mRNA transcript level of caspase-3A was not significantly elevated. Immunoreactivities were observed in the cytoplasm of hepatocytes by immunohistochemical detection. The findings indicates that Cd can trigger liver cell apoptosis through the activation of caspase-3A. Caspase-3A may play an essential role in Cd-induced apoptosis. PMID- 24349510 TI - Sputum microbiota associated with new, recurrent and treatment failure tuberculosis. AB - Microbiota have recently been shown to be associated with many disease conditions. However, the microbiota associated with tuberculosis (TB) infection, recurrence and treatment outcome have not been systematically characterized. Here, we used high throughput 16S RNA sequencing to analyze the sputum microbiota associated with Mycobacterium tuberculosis infection and also to identify the microorganisms associated with different outcomes of TB treatment. We recruited 25 new TB patients, 30 recurrent TB patients and 20 TB patients with treatment failure, as well as 20 healthy controls. Streptococcus, Gramulicatella and Pseudomonas were more abundant in TB patients while Prevotella, Leptotrichia, Treponema, Catonella and Coprococcus were less abundant in TB patients than in the healthy controls. We found reduced frequency and abundance of some genera such as Bulleidia and Atopobium in recurrent TB patients compared with those in new TB patients. In addition, the ratio of Pseudomonas / Mycobacterium in recurrent TB was higher than that in new TB while the ratio of Treponema / Mycobacterium in recurrent TB was lower than that in new TB, indicating that disruption of these bacteria may be a risk factor of TB recurrence. Furthermore, Pseudomonas was more abundant and more frequently present in treatment failure patients than in cured new patients, and the ratio of Pseudomonas / Mycobacterium in treatment failure was higher than that in new TB. Our data suggest that the presence of certain bacteria and the disorder of lung microbiota may be associated with not only onset of TB but also its recurrence and treatment failure. These findings indicate that lung microbiota may play a role in pathogenesis and treatment outcome of TB and may need to be taken into consideration for improved treatment and control of TB in the future. PMID- 24349508 TI - From knock-out phenotype to three-dimensional structure of a promising antibiotic target from Streptococcus pneumoniae. AB - Given the rise in drug-resistant Streptococcus pneumoniae, there is an urgent need to discover new antimicrobials targeting this pathogen and an equally urgent need to characterize new drug targets. A promising antibiotic target is dihydrodipicolinate synthase (DHDPS), which catalyzes the rate-limiting step in lysine biosynthesis. In this study, we firstly show by gene knock out studies that S. pneumoniae (sp) lacking the DHDPS gene is unable to grow unless supplemented with lysine-rich media. We subsequently set out to characterize the structure, function and stability of the enzyme drug target. Our studies show that sp-DHDPS is folded and active with a k(cat) = 22 s(-1), K(M)(PYR) = 2.55 +/- 0.05 mM and K(M)(ASA) = 0.044 +/- 0.003 mM. Thermal denaturation experiments demonstrate sp-DHDPS exhibits an apparent melting temperature (T(M)(app)) of 72 degrees C, which is significantly greater than Escherichia coli DHDPS (Ec-DHDPS) (T(M)(app) = 59 degrees C). Sedimentation studies show that sp-DHDPS exists in a dimer-tetramer equilibrium with a K(D)(4->2) = 1.7 nM, which is considerably tighter than its E. coli ortholog (K(D)(4->2) = 76 nM). To further characterize the structure of the enzyme and probe its enhanced stability, we solved the high resolution (1.9 A) crystal structure of sp-DHDPS (PDB ID 3VFL). The enzyme is tetrameric in the crystal state, consistent with biophysical measurements in solution. Although the sp-DHDPS and Ec-DHDPS active sites are almost identical, the tetramerization interface of the s. pneumoniae enzyme is significantly different in composition and has greater buried surface area (800 A(2)) compared to its E. coli counterpart (500 A(2)). This larger interface area is consistent with our solution studies demonstrating that sp-DHDPS is considerably more thermally and thermodynamically stable than Ec-DHDPS. Our study describe for the first time the knock-out phenotype, solution properties, stability and crystal structure of DHDPS from S. pneumoniae, a promising antimicrobial target. PMID- 24349511 TI - Deletion of C9ORF72 results in motor neuron degeneration and stress sensitivity in C. elegans. AB - An expansion of the hexanucleotide GGGGCC repeat in the first intron of C9ORF72 gene was recently linked to amyotrophic lateral sclerosis. It is not known if the mutation results in a gain of function, a loss of function or if, perhaps both mechanisms are linked to pathogenesis. We generated a genetic model of ALS to explore the biological consequences of a null mutation of the Caenorhabditis elegans C9ORF72 orthologue, F18A1.6, also called alfa-1. alfa-1 mutants displayed age-dependent motility defects leading to paralysis and the specific degeneration of GABAergic motor neurons. alfa-1 mutants showed differential susceptibility to environmental stress where osmotic stress provoked neurodegeneration. Finally, we observed that the motor defects caused by loss of alfa-1 were additive with the toxicity caused by mutant TDP-43 proteins, but not by the mutant FUS proteins. These data suggest that a loss of alfa-1/C9ORF72 expression may contribute to motor neuron degeneration in a pathway associated with other known ALS genes. PMID- 24349512 TI - Involvement of autonomic nervous activity changes in gastroesophageal reflux in neonates during sleep and wakefulness. AB - BACKGROUND: It has been suggested that disturbed activity of the autonomic nervous system is one of the factors involved in gastroesophageal reflux (GER) in adults. We sought to establish whether transient ANS dysfunction (as assessed by heart rate variability) is associated with the occurrence of GER events in neonates during sleep and wakefulness. METHODS: Nineteen neonates with suspected GER underwent simultaneous, synchronized 12-hour polysomnography and esophageal multichannel impedance-pH monitoring. We compared changes in HRV parameters during three types of periods (control and prior to and during reflux) with respect to the vigilance state. RESULTS: The vigilance state influenced the distribution of GER events (P<0.001), with 53.4% observed during wakefulness, 37.6% observed during active sleep and only 9% observed during quiet sleep. A significant increase in the sympathovagal ratio (+32%, P=0.013) was observed in the period immediately prior to reflux (due to a 15% reduction in parasympathetic activity (P=0.017)), relative to the control period. This phenomenon was observed during both wakefulness and active sleep. CONCLUSION: Our results showed that GER events were preceded by a vigilance-state-independent decrease in parasympathetic tone. This suggests that a pre-reflux change in ANS activity is one of the factors contributing to the mechanism of reflux in neonates. PMID- 24349513 TI - Early transcriptional response of soybean contrasting accessions to root dehydration. AB - Drought is a significant constraint to yield increase in soybean. The early perception of water deprivation is critical for recruitment of genes that promote plant tolerance. DeepSuperSAGE libraries, including one control and a bulk of six stress times imposed (from 25 to 150 min of root dehydration) for drought tolerant and sensitive soybean accessions, allowed to identify new molecular targets for drought tolerance. The survey uncovered 120,770 unique transcripts expressed by the contrasting accessions. Of these, 57,610 aligned with known cDNA sequences, allowing the annotation of 32,373 unitags. A total of 1,127 unitags were up-regulated only in the tolerant accession, whereas 1,557 were up-regulated in both as compared to their controls. An expression profile concerning the most representative Gene Ontology (GO) categories for the tolerant accession revealed the expression "protein binding" as the most represented for "Molecular Function", whereas CDPK and CBL were the most up-regulated protein families in this category. Furthermore, particular genes expressed different isoforms according to the accession, showing the potential to operate in the distinction of physiological behaviors. Besides, heat maps comprising GO categories related to abiotic stress response and the unitags regulation observed in the expression contrasts covering tolerant and sensitive accessions, revealed the unitags potential for plant breeding. Candidate genes related to "hormone response" (LOX, ERF1b, XET), "water response" (PUB, BMY), "salt stress response" (WRKY, MYB) and "oxidative stress response" (PER) figured among the most promising molecular targets. Additionally, nine transcripts (HMGR, XET, WRKY20, RAP2-4, EREBP, NAC3, PER, GPX5 and BMY) validated by RT-qPCR (four different time points) confirmed their differential expression and pointed that already after 25 minutes a transcriptional reorganization started in response to the new condition, with important differences between both accessions. PMID- 24349515 TI - Alterations in white matter microstructure as vulnerability factors and acquired signs of traffic accident-induced PTSD. AB - It remains unclear whether white matter (WM) changes found in post-traumatic stress disorder (PTSD) patients are stress-induced or precursors for vulnerability. The current study aimed to identify susceptibility factors relating to the development of PTSD and to examine the ability of these factors to predict the course of longitudinal PTSD. Sixty two victims who had experienced traffic accidents underwent diffusion tensor imaging using a 3.0T MRI system within 2 days after their accidents. Of these, 21 were diagnosed with PTSD at 1 or 6 months using the Clinician-Administered Ptsd Scale (CAPS). Then, 11 trauma exposed victims with PTSD underwent the second MRI scan. Compared with the victims without PTSD, the victims with PTSD showed decreased fractional anisotropy (FA) in WM of the anterior cingulate cortex, ventromedial prefrontal cortex (vmPFC), temporal lobes and midbrain, and increased mean diffusivity (MD) in the vmPFC within 2 days after the traumatic event. Importantly, decreased FA of the vmPFC in the acute phase predicted greater future CAPS scores. In addition, we found decreased FA in the insula in the follow-up scan in the victims with PTSD, which correlated with the decreased FA of the vmPFC in their baseline scan. These results suggested that the WM might have changed within 2 days after the traumatic event in the individuals who would later develop PTSD. Furthermore, decreased FA of the vmPFC could be a possible vulnerability marker predicting future development of PTSD and may provide an outcome prediction of the acquired signs. PMID- 24349516 TI - Autophagy in the human placenta throughout gestation. AB - BACKGROUND: Autophagy has been reported to be essential for pre-implantation development and embryo survival. However, its role in placental development and regulation of autophagy during pregnancy remain unclear. The aims of this study were to (1) study autophagy by characterizing changes in levels of beclin-1, DRAM, and LC3B in human placenta throughout gestation; (2) determine whether autophagy is involved in regulation of trophoblast invasion in JEG-3 cells (a choriocarcinoma cell line); (3) examine the effects of reduced oxygen and glucose on the autophagic changes; and (4) investigate the effect of reoxygenation and supplementation of glucose after oxygen-glucose deprivation (OGD) on the autophagic changes in primary cytotrophoblasts obtained from normal term pregnancy. METHODOLOGY/PRINCIPAL FINDINGS: An analysis of 40 placental samples representing different gestational stages showed (1) no significant differences in beclin-1, DRAM, and LC3B-II levels in placentas between early and mid gestation, and late gestation with vaginal delivery; (2) placentas from late gestation with cesarean section had lower levels of LC3B-II compared to early and mid-gestation, and late gestation with vaginal delivery; levels of DRAM were also lower compared to placentas from early and mid-gestation; and (3) using explant cultures, villous tissues from early and late gestation had similar rates of autophagic flux under physiological oxygen concentrations. Knockdown of BECN1, DRAM, and LC3B had no effects on viability and invasion activity of JEG-3 cells. On the other hand, OGD caused a significant increase in the levels of LC3B-II in primary cytotrophoblasts, while re-supplementation of oxygen and glucose reduced these changes. Furthermore, there were differential changes in levels of beclin 1, DRAM, and LC3B-II in response to changes in oxygen and glucose levels. CONCLUSIONS/SIGNIFICANCE: Our results indicate that autophagy is involved in development of the human placenta and that changes in oxygen and glucose levels participate in regulation of autophagic changes in cytotrophoblast cells. PMID- 24349514 TI - MicroRNA-494, upregulated by tumor necrosis factor-alpha, desensitizes insulin effect in C2C12 muscle cells. AB - Chronic inflammation is fundamental for the induction of insulin resistance in the muscle tissue of vertebrates. Although several miRNAs are thought to be involved in the development of insulin resistance, the role of miRNAs in the association between inflammation and insulin resistance in muscle tissue is poorly understood. Herein, we investigated the aberrant expression of miRNAs by conducting miRNA microarray analysis of TNF-alpha-treated mouse C2C12 myotubes. We identified two miRNAs that were upregulated and six that were downregulated by a >1.5-fold change compared to normal cells. Among the findings, qRT-PCR analysis confirmed that miR-494 is consistently upregulated by TNF-alpha-induced inflammation. Overexpression of miR-494 in CHO(IR/IRS1) and C2C12 myoblasts suppressed insulin action by down-regulating phosphorylations of GSK-3alpha/beta, AS160 and p70S6K, downstream of Akt. Moreover, overexpression of miR-494 did not regulate TNF-alpha-mediated inflammation . Among genes bearing the seed site for miR-494, RT-PCR analysis showed that the expression of Stxbp5, an inhibitor of glucose transport, was downregulated following miR-494 inhibition. In contrast, the expression of PTEN decreased in the cells analyzed, thus showing that both positive and negative regulators of insulin action may be simultaneously controlled by miR-494. To investigate the overall effect of miR-494 on insulin signaling, we performed a PCR array analysis containing 84 genes related to the insulin signaling pathway, and we observed that 25% of genes were downregulated (P<0.05) and 11% were upregulated (P<0.05). These results confirm that miR-494 might contribute to insulin sensitivity by positive and negative regulation of the expression of diverse genes. Of note, PCR array data showed downregulation of Slc2A4, a coding gene for Glut4. Altogether, the present study concludes that the upregulation of miR-494 expression by TNF-alpha-mediated inflammation exacerbates insulin resistance. Therefore, we suggest that miR-494 could prove an important target for the diagnosis and therapy of inflammation-mediated insulin resistance in muscle. PMID- 24349517 TI - Edwardsiella andrillae, a new species of sea anemone from Antarctic ice. AB - Exploration of the lower surface of the Ross Ice Shelf in Antarctica by the Submersible Capable of under-Ice Navigation and Imaging (SCINI) remotely operated vehicle discovered a new species of sea anemone living in this previously undocumented ecosystem. This discovery was a significant outcome of the Coulman High Project's geophysical and environmental fieldwork in 2010-2011 as part of the ANDRILL (ANtarctic geologic DRILLing) program. Edwardsiella andrillae n. sp., lives with most of its column in the ice shelf, with only the tentacle crown extending into the seawater below. In addition to being the only Antarctic representative of the genus, Edwardsiella andrillae is distinguished from all other species of the genus in the number of tentacles and in the size and distribution of cnidae. The anatomy and histology of Edwardsiella andrillae present no features that explain how this animal withstands the challenges of life in such an unusual habitat. PMID- 24349518 TI - Alcohol, hospital discharge, and socioeconomic risk factors for default from multidrug resistant tuberculosis treatment in rural South Africa: a retrospective cohort study. AB - BACKGROUND: Default from multidrug-resistant tuberculosis (MDR-TB) treatment remains a major barrier to cure and epidemic control. We sought to identify patient risk factors for default from MDR-TB treatment and high-risk time periods for default in relation to hospitalization and transition to outpatient care. METHODS: We retrospectively analyzed a cohort of 225 patients who initiated MDR TB treatment between 2007 through 2010 at a rural TB hospital in the Western Cape Province, South Africa. RESULTS: Fifty percent of patients were cured or completed treatment, 27% defaulted, 14% died, 4% failed treatment, and 5% transferred out. Recent alcohol use was common (63% of patients). In multivariable proportional hazards regression, older age (hazard ratio [HR]= 0.97 [95% confidence interval 0.94-0.99] per year of greater age), formal housing (HR=0.38 [0.19-0.78]), and steady employment (HR=0.41 [0.19-0.90]) were associated with decreased risk of default, while recent alcohol use (HR=2.1 [1.1 4.0]), recent drug use (HR=2.0 [1.0-3.6]), and Coloured (mixed ancestry) ethnicity (HR=2.3 [1.1-5.0]) were associated with increased risk of default (P<0.05). Defaults occurred throughout the first 18 months of the two-year treatment course but were especially frequent among alcohol users after discharge from the initial four-to-five-month in-hospital phase of treatment, with the highest default rates occurring among alcohol users within two months of discharge. Default rates during the first two months after discharge were also elevated for patients who received care from mobile clinics. CONCLUSIONS: Among patients who were not cured or did not complete MDR-TB treatment, the majority defaulted from treatment. Younger, economically-unstable patients and alcohol and drug users were particularly at risk. For alcohol users as well as mobile-clinic patients, the early outpatient treatment phase is a high-risk period for default that could be targeted in efforts to increase treatment completion rates. PMID- 24349520 TI - Quantifying the impact of woodpecker predation on population dynamics of the emerald ash borer (Agrilus planipennis). AB - The emerald ash borer (EAB), Agrilus planipennis, is an invasive beetle that has killed millions of ash trees (Fraxinus spp.) since it was accidentally introduced to North America in the 1990s. Understanding how predators such as woodpeckers (Picidae) affect the population dynamics of EAB should enable us to more effectively manage the spread of this beetle, and toward this end we combined two experimental approaches to elucidate the relative importance of woodpecker predation on EAB populations. First, we examined wild populations of EAB in ash trees in New York, with each tree having a section screened to exclude woodpeckers. Second, we established experimental cohorts of EAB in ash trees in Maryland, and the cohorts on half of these trees were caged to exclude woodpeckers. The following spring these trees were debarked and the fates of the EAB larvae were determined. We found that trees from which woodpeckers were excluded consistently had significantly lower levels of predation, and that woodpecker predation comprised a greater source of mortality at sites with a more established wild infestation of EAB. Additionally, there was a considerable difference between New York and Maryland in the effect that woodpecker predation had on EAB population growth, suggesting that predation alone may not be a substantial factor in controlling EAB. In our experimental cohorts we also observed that trees from which woodpeckers were excluded had a significantly higher level of parasitism. The lower level of parasitism on EAB larvae found when exposed to woodpeckers has implications for EAB biological control, suggesting that it might be prudent to exclude woodpeckers from trees when attempting to establish parasitoid populations. Future studies may include utilizing EAB larval cohorts with a range of densities to explore the functional response of woodpeckers. PMID- 24349519 TI - Proteomic analysis and qRT-PCR verification of temperature response to Arthrospira (Spirulina) platensis. AB - Arthrospira (Spirulina) platensis (ASP) is a representative filamentous, non-N2 fixing cyanobacterium that has great potential to enhance the food supply and possesses several valuable physiological features. ASP tolerates high and low temperatures along with highly alkaline and salty environments, and can strongly resist oxidation and irradiation. Based on genomic sequencing of ASP, we compared the protein expression profiles of this organism under different temperature conditions (15 degrees C, 35 degrees Cand 45 degrees C) using 2-DE and peptide mass fingerprinting techniques. A total of 122 proteins having a significant differential expression response to temperature were retrieved. Of the positively expressed proteins, the homologies of 116 ASP proteins were found in Arthrospira (81 proteins in Arthrospira platensis str. Paraca and 35 in Arthrospira maxima CS 328). The other 6 proteins have high homology with other microorganisms. We classified the 122 differentially expressed positive proteins into 14 functions using the COG database, and characterized their respective KEGG metabolism pathways. The results demonstrated that these differentially expressed proteins are mainly involved in post-translational modification (protein turnover, chaperones), energy metabolism (photosynthesis, respiratory electron transport), translation (ribosomal structure and biogenesis) and carbohydrate transport and metabolism. Others proteins were related to amino acid transport and metabolism, cell envelope biogenesis, coenzyme metabolism and signal transduction mechanisms. Results implied that these proteins can perform predictable roles in rendering ASP resistance against low and high temperatures. Subsequently, we determined the transcription level of 38 genes in vivo in response to temperature and identified them by qRT-PCR. We found that the 26 differentially expressed proteins, representing 68.4% of the total target genes, maintained consistency between transcription and translation levels. The remaining 12 genes showed inconsistent protein expression with transcription level and accounted for 31.6% of the total target genes. PMID- 24349521 TI - Population genetic studies revealed local adaptation in a high gene-flow marine fish, the small yellow croaker (Larimichthys polyactis). AB - The genetic differentiation of many marine fish species is low. Yet local adaptation may be common in marine fish species as the vast and changing marine environment provides more chances for natural selection. Here, we used anonymous as well as known protein gene linked microsatellites and mitochondrial DNA to detect the population structure of the small yellow croaker (Larimichthys polyactis) in the Northwest Pacific marginal seas. Among these loci, we detected at least two microsatellites, anonymous H16 and HSP27 to be clearly under diversifying selection in outlier tests. Sequence cloning and analysis revealed that H16 was located in the intron of BAHCC1 gene. Landscape genetic analysis showed that H16 mutations were significantly associated with temperature, which further supported the diversifying selection at this locus. These marker types presented different patterns of population structure: (i) mitochondrial DNA phylogeny showed no evidence of genetic divergence and demonstrated only one glacial linage; (ii) population differentiation using putatively neutral microsatellites presented a pattern of high gene flow in the L. polyactis. In addition, several genetic barriers were identified; (iii) the population differentiation pattern revealed by loci under diversifying selection was rather different from that revealed by putatively neutral loci. The results above suggest local adaptation in the small yellow croaker. In summary, population genetic studies based on different marker types disentangle the effects of demographic history, migration, genetic drift and local adaptation on population structure and also provide valuable new insights for the design of management strategies in L. polyactis. PMID- 24349522 TI - Imaging evidence of diabetic choroidopathy in vivo: angiographic pathoanatomy and choroidal-enhanced depth imaging. AB - PURPOSE: To describe the pathoanatomy of diabetic choroidopathy (DC) in pre diagnosed diabetic retinopathy (DR) cases and to provide angiographic and optical evidence for DC using indocyanine green angiography (ICGA) and enhanced depth imaging spectral-domain optical coherence tomography (EDI SD-OCT). METHODS: A retrospective analysis of 80 eyes from 40 DR patients was conducted. In Group One, choroidal vascular abnormalities were evaluated by comparing angiographic findings from simultaneous ICGA with those from fundus fluorescein angiography (FFA). In Group Two, EDI SD-OCT was used to evaluate the subfoveal choroidal thickness (SFCT) and define the choroid boundary in order to acquire the bilateral and symmetric choroidal area (CA). Data were then analyzed by Image Pro Plus 6.0. RESULTS: In Group One, choroidal abnormalities that were evident using ICGA but not FFA included early hypofluorescent spots in 47 eyes (75.81%), late hyperfluorescent spots in 37 eyes (59.68%), and late choroidal non-perfusion regions in 32 eyes (51.61%). In particular, a significant difference between proliferative DR (PDR) in 17 of 23 eyes (73.91%) and non-PDR in 16 of 39 eyes (41.03%) was observed in late choroidal non-perfusion regions. Eighteen of 31 eyes (58.06%) also exhibited "inverted inflow phenomena." In Group Two, both the SFCT and CA of eyes with diabetic macular edema and serous macular detachment were significantly greater than those in the other eyes. The CA in panretinal photocoagulation (PRP) treated cases was also greater than that in non-PRP treated cases. CONCLUSIONS: Early hypofluorescent spots, late choroidal non perfusion regions, inverted inflow phenomena, higher SFCT, and larger CA are qualitative and quantitative indexes for DC. Moreover, the late choroidal non perfusion region is a risk factor for DC with DR. Our study suggests that the supplemental use of ICGA and EDI SD-OCT with FFA is a better choice for DR patients. PMID- 24349523 TI - Widespread misinterpretable ChIP-seq bias in yeast. AB - Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is widely used to detect genome-wide interactions between a protein of interest and DNA in vivo. Loci showing strong enrichment over adjacent background regions are typically considered to be sites of binding. Insufficient attention has been given to systematic artifacts inherent to the ChIP-seq procedure that might generate a misleading picture of protein binding to certain loci. We show here that unrelated transcription factors appear to consistently bind to the gene bodies of highly transcribed genes in yeast. Strikingly, several types of negative control experiments, including a protein that is not expected to bind chromatin, also showed similar patterns of strong binding within gene bodies. These false positive signals were evident across sequencing platforms and immunoprecipitation protocols, as well as in previously published datasets from other labs. We show that these false positive signals derive from high rates of transcription, and are inherent to the ChIP procedure, although they are exacerbated by sequencing library construction procedures. This expression bias is strong enough that a known transcriptional repressor like Tup1 can erroneously appear to be an activator. Another type of background bias stems from the inherent nucleosomal structure of chromatin, and can potentially make it seem like certain factors bind nucleosomes even when they don't. Our analysis suggests that a mock ChIP sample offers a better normalization control for the expression bias, whereas the ChIP input is more appropriate for the nucleosomal periodicity bias. While these controls alleviate the effect of the biases to some extent, they are unable to eliminate it completely. Caution is therefore warranted regarding the interpretation of data that seemingly show the association of various transcription and chromatin factors with highly transcribed genes in yeast. PMID- 24349524 TI - Inhibition of PI3K/mTOR overcomes nilotinib resistance in BCR-ABL1 positive leukemia cells through translational down-regulation of MDM2. AB - Chronic myeloid leukemia (CML) is a cytogenetic disorder resulting from formation of the Philadelphia chromosome (Ph), that is, the t(9;22) chromosomal translocation and the formation of the BCR-ABL1 fusion protein. Tyrosine kinase inhibitors (TKI), such as imatinib and nilotinib, have emerged as leading compounds with which to treat CML. t(9;22) is not restricted to CML, 20-30% of acute lymphoblastic leukemia (ALL) cases also carry the Ph. However, TKIs are not as effective in the treatment of Ph+ ALL as in CML. In this study, the Ph+ cell lines JURL-MK2 and SUP-B15 were used to investigate TKI resistance mechanisms and the sensitization of Ph+ tumor cells to TKI treatment. The annexin V/PI (propidium iodide) assay revealed that nilotinib induced apoptosis in JURL-MK2 cells, but not in SUP-B15 cells. Since there was no mutation in the tyrosine kinase domain of BCR-ABL1 in cell line SUP-B15, the cells were not generally unresponsive to TKI, as evidenced by dephosphorylation of the BCR-ABL1 downstream targets, Crk-like protein (CrkL) and Grb-associated binder-2 (GAB2). Resistance to apoptosis after nilotinib treatment was accompanied by the constitutive and nilotinib unresponsive activation of the phosphoinositide 3-kinase (PI3K) pathway. Treatment of SUP-B15 cells with the dual PI3K/mammalian target of rapamycin (mTOR) inhibitor BEZ235 alone induced apoptosis in a low percentage of cells, while combining nilotinib and BEZ235 led to a synergistic effect. The main role of PI3K/mTOR inhibitor BEZ235 and the reason for apoptosis in the nilotinib resistant cells was the block of the translational machinery, leading to the rapid downregulation of the anti-apoptotic protein MDM2 (human homolog of the murine double minute-2). These findings highlight MDM2 as a potential therapeutic target to increase TKI-mediated apoptosis and imply that the combination of PI3K/mTOR inhibitor and TKI might form a novel strategy to combat TKI-resistant BCR-ABL1 positive leukemia. PMID- 24349525 TI - Effects of resveratrol on the recovery of muscle mass following disuse in the plantaris muscle of aged rats. AB - Aging is associated with poor skeletal muscle regenerative ability following extended periods of hospitalization and other forms of muscular disuse. Resveratrol (3,5,4'-trihydroxystilbene) is a natural phytoalexin which has been shown in skeletal muscle to improve oxidative stress levels in muscles of aged rats. As muscle disuse and reloading after disuse increases oxidative stress, we hypothesized that resveratrol supplementation would improve muscle regeneration after disuse. A total of thirty-six male Fisher 344 * Brown Norway rats (32 mo.) were treated with either a water vehicle or resveratrol via oral gavage. The animals received hindlimb suspension for 14 days. Thereafter, they were either sacrificed or allowed an additional 14 day period of cage ambulation during reloading. A total of six rats from the vehicle and the resveratrol treated groups were used for the hindlimb suspension and recovery protocols. Furthermore, two groups of 6 vehicle treated animals maintained normal ambulation throughout the experiment, and were used as control animals for the hindlimb suspension and reloading groups. The data show that resveratrol supplementation was unable to attenuate the decreases in plantaris muscle wet weight during hindlimb suspension but it improved muscle mass during reloading after hindlimb suspension. Although resveratrol did not prevent fiber atrophy during the period of disuse, it increased the fiber cross sectional area of type IIA and IIB fibers in response to reloading after hindlimb suspension. There was a modest enhancement of myogenic precursor cell proliferation in resveratrol-treated muscles after reloading, but this failed to reach statistical significance. The resveratrol associated improvement in type II fiber size and muscle mass recovery after disuse may have been due to decreases in the abundance of pro-apoptotic proteins Bax, cleaved caspase 3 and cleaved caspase 9 in reloaded muscles. Resveratrol appears to have modest therapeutic benefits for improving muscle mass after disuse in aging. PMID- 24349527 TI - Calling by domestic piglets during simulated crushing and isolation: a signal of need? AB - This study examined whether piglet distress vocalizations vary with age, body weight and health status, according to the predictions of the honest signalling of need evolutionary model. Vocalizations were recorded during manual squeezing (a simulation of being crushed by mother sow) and during isolation on Days 1 and 7 after birth in piglets from 15 litters. We predicted that during squeezing, younger, lighter and sick piglets would call more intensely because they are in higher risk of dying during crushing and therefore they benefit more from the sow's reaction to intensive vocalization. For isolation, we predicted that lighter and younger piglets would call more because they are more vulnerable to adverse effects of the separation. Calls were analyzed in their time and frequency domain. The rate of calling, call duration, proportion of high-pitched calls and eight acoustic parameters characterizing frequency distribution and tonality were used as indicators of acoustic signalling intensity. Piglets that experienced "squeezing" on Day 1 produced more intense acoustic distress signalling than on Day 7. Lighter piglets called more during squeezing than heavier piglets. Health status did not significantly affect any of the indicators of intensity of vocalization during squeezing. In isolation, none of the parameters of vocalization intensity were affected either by the age or by the weight of the piglets. In summary, the model of honest signalling of need was confirmed in the squeezed situation, but not in the isolation situation. PMID- 24349526 TI - APEX nuclease (multifunctional DNA repair enzyme) 1 gene Asp148Glu polymorphism and cancer risk: a meta-analysis involving 58 articles and 48903 participants. AB - BACKGROUND: Polymorphisms in the APEX nuclease (multifunctional DNA repair enzyme) 1 gene (APEX1) may be involved in the carcinogenesis by affecting DNA repair. We aimed to summarize available data on the association of the APEX1 Asp148Glu (rs1130409) polymorphism with risk of multiple types of cancer via a meta-analysis. METHODS AND RESULTS: In total, 58 qualified articles including 22,398 cancer patients and 26,505 controls were analyzed, and the data were extracted independently by two investigators. Analyses of the full data set indicated a marginally significant association of the APEX1 Asp148Glu polymorphism with cancer risk under allelic (odds ratio (OR)=1.05; 95% confidence interval (95% CI): 0.99-1.11; P=0.071), dominant (OR=1.09; 95% CI: 1.01-1.17; P=0.028), and heterozygous genotypic (OR=1.08; 95% CI: 1.01-1.16; P=0.026) models, with significant heterogeneity and publication bias. In subgroup analyses by cancer type, with a Bonferroni corrected alpha of 0.05/6, significant association was observed for gastric cancer under both dominant (OR=1.74; 95% CI: 1.2-2.51; P=0.003) and heterozygous genotypic (OR=1.66; 95% CI: 1.2-2.31; P=0.002) models. In subgroup analysis by ethnicity, risk estimates were augmented in Caucasians, especially under dominant (OR=1.11; 95% CI: 1.0-1.24; P=0.049) and heterozygous genotypic (OR=1.11; 95% CI: 0.99-1.24; P=0.063) models. By study design, there were no significant differences between population-based and hospital-based studies. In subgroup analysis by sample size, risk estimates were remarkably overestimated in small studies, and no significance was reached in large studies except under the heterozygous genotypic model (OR=1.23; 95% CI: 1.06-1.43; P=0.006, significant at a Bonferroni corrected alpha of 0.05/2). By quality score, the risk estimates, albeit nonsignificant, were higher in low quality studies than in high-quality studies. Further meta-regression analyses failed to identify any contributory confounders for the associated risk estimates. CONCLUSIONS: Our findings suggest that APEX1 Asp148Glu polymorphism might be a genetic risk factor for the development of gastric cancer. Further investigations on large populations are warranted. PMID- 24349528 TI - Evaluation of assembly strategies using RNA-seq data associated with grain development of wheat (Triticum aestivum L.). AB - Wheat (Triticum aestivum L.) is one of the most important crops cultivated worldwide. Identifying the complete transcriptome of wheat grain could serve as foundation for further study of wheat seed development. However, the relatively large size and the polyploid complexity of the genome have been substantial barriers to molecular genetics and transcriptome analysis of wheat. Alternatively, RNA sequencing has provided some useful information about wheat genes. However, because of the large number of short reads generated by RNA sequencing, factors that are crucial to transcriptome assembly, including software, candidate parameters and assembly strategies, need to be optimized and evaluated for wheat data. In the present study, four cDNA libraries associated with wheat grain development were constructed and sequenced. A total of 14.17 Gb of high-quality reads were obtained and used to assess different assembly strategies. The most successful approach was to filter the reads with Q30 prior to de novo assembly using Trinity, merge the assembled contigs with genes available in wheat cDNA reference data sets, and combine the resulting assembly with an assembly from a reference-based strategy. Using this approach, a relatively accurate and nearly complete transcriptome associated with wheat grain development was obtained, suggesting that this is an effective strategy for generation of a high-quality transcriptome from RNA sequencing data. PMID- 24349529 TI - Global transcriptome sequencing using the Illumina platform and the development of EST-SSR markers in autotetraploid alfalfa. AB - BACKGROUND: Alfalfa is the most widely cultivated forage legume and one of the most economically valuable crops in the world. The large size and complexity of the alfalfa genome has delayed the development of genomic resources for alfalfa research. Second-generation Illumina transcriptome sequencing is an efficient method for generating a global transcriptome sequence dataset for gene discovery and molecular marker development in alfalfa. METHODOLOGY/PRINCIPAL FINDINGS: More than 28 million sequencing reads (5.64 Gb of clean nucleotides) were generated by Illumina paired-end sequencing from 15 different alfalfa tissue samples. In total, 40,433 unigenes with an average length of 803 bp were obtained by de novo assembly. Based on a sequence similarity search of known proteins, a total of 36,684 (90.73%) unigenes were annotated. In addition, 1,649 potential EST-SSRs were identified as potential molecular markers from unigenes with lengths exceeding 1 kb. A total of 100 pairs of PCR primers were randomly selected to validate the assembly quality and develop EST-SSR markers from genomic DNA. Of these primer pairs, 82 were able to amplify sequences in initial screening tests, and 27 primer pairs successfully amplified DNA fragments and detected significant amounts of polymorphism among 10 alfalfa accessions. CONCLUSIONS/SIGNIFICANCE: The present study provided global sequence data for autotetraploid alfalfa and demonstrates the Illumina platform is a fast and effective approach to EST-SSR markers development in alfalfa. The use of these transcriptome datasets will serve as a valuable public information platform to accelerate studies of the alfalfa genome. PMID- 24349531 TI - Investigating the prehistory of Tungusic peoples of Siberia and the Amur-Ussuri region with complete mtDNA genome sequences and Y-chromosomal markers. AB - Evenks and Evens, Tungusic-speaking reindeer herders and hunter-gatherers, are spread over a wide area of northern Asia, whereas their linguistic relatives the Udegey, sedentary fishermen and hunter-gatherers, are settled to the south of the lower Amur River. The prehistory and relationships of these Tungusic peoples are as yet poorly investigated, especially with respect to their interactions with neighbouring populations. In this study, we analyse over 500 complete mtDNA genome sequences from nine different Evenk and even subgroups as well as their geographic neighbours from Siberia and their linguistic relatives the Udegey from the Amur-Ussuri region in order to investigate the prehistory of the Tungusic populations. These data are supplemented with analyses of Y-chromosomal haplogroups and STR haplotypes in the Evenks, Evens, and neighbouring Siberian populations. We demonstrate that whereas the North Tungusic Evenks and Evens show evidence of shared ancestry both in the maternal and in the paternal line, this signal has been attenuated by genetic drift and differential gene flow with neighbouring populations, with isolation by distance further shaping the maternal genepool of the Evens. The Udegey, in contrast, appear quite divergent from their linguistic relatives in the maternal line, with a mtDNA haplogroup composition characteristic of populations of the Amur-Ussuri region. Nevertheless, they show affinities with the Evenks, indicating that they might be the result of admixture between local Amur-Ussuri populations and Tungusic populations from the north. PMID- 24349530 TI - Cytosolic phospholipase A2 regulates TNF-induced production of joint destructive effectors in synoviocytes. AB - INTRODUCTION: Rheumatoid arthritis (RA) is an inflammatory disease of the joint characterized by chronic synovitis causing pain, swelling and loss of function due to destruction of cartilage and bone. The complex series of pathological events occurring in RA is largely regulated via excessive production of pro inflammatory cytokines, the most prominent being tumor necrosis factor (TNF). The objective of this work was to elucidate possible involvement of group IVA cytosolic phospholipase A2 (cPLA2alpha) in TNF-induced regulation of synovitis and joint destructive effectors in RA, to evaluate the potential of cPLA2alpha as a future therapeutic target. METHODS: The involvement of cPLA2alpha in tumor necrosis factor (TNF)-induced intracellular signaling cascades in synoviocytes (synovial fibroblast-like cells) was analyzed by arachidonic acid (AA) release assay, synoviocyte enzyme activity assay, gene expression analysis by real-time PCR and ELISA immunoassay for the detection of prostaglandin E2 (PGE2), interleukin 8 (IL8) and stromelysin-1 (MMP3), respectively. RESULTS: Inhibitors of cPLA2alpha enzyme activity (AVX002, ATK) significantly reduced TNF-induced cellular release of AA, PGE2, IL8 and MMP3. This reduction was evident both at transcriptional, protein or metabolite levels. Interestingly, cPLA2alpha inhibition affected several key points of the arachidonyl cascade; AA-release, cyclooxygenase-2 (COX2) expression and PGE2 production. Furthermore, the results suggest that cPLA2alpha is subject to transcriptional auto-regulation as inhibition of cPLA2alpha resulted in reduced PLA2G4A gene expression in TNF stimulated synoviocytes. CONCLUSIONS: cPLA2alpha appears to be an important regulator of central effectors of inflammation and joint destruction, namely MMP3, IL8, COX2, and PGE2. Decreased transcription of the PLA2G4A and COX2 genes in response to cPLA2alpha enzyme inhibition further suggest a self-reinforcing effect of cPLA2alpha inhibition in response to TNF. Collectively, these results support that cPLA2alpha is an attractive therapeutic target candidate as its inhibition reduces the production of multiple key pro-inflammatory factors involved in RA pathogenesis. PMID- 24349532 TI - Impact of interleukin-18 polymorphisms -607A/C and -137G/C on oral cancer occurrence and clinical progression. AB - BACKGROUND: The purpose of this study was to identify gene polymorphisms of interleukin-18 (IL-18) -607A/C and -137G/C specific to patients with oral cancer susceptibility and clinicopathological status. METHODOLOGY AND PRINCIPAL FINDINGS: A total of 1,126 participants, including 559 healthy people and 567 patients with oral cancer, were recruited for this study. Allelic discrimination of -607A/C (rs1946518) and -137G/C (rs187238) polymorphisms of the IL-18 gene was assessed by a real-time PCR with the TaqMan assay. There was no significant association between IL-18 -607A/C polymorphism and oral cancer risk. However, among alcohol consumers, people with A/A homozygotes of IL-18 -607A/C polymorphism had a 2.38-fold (95% CI=1.17-4.86; p=0.01) increased risk of developing oral cancer compared with those with C/C homozygotes. The participants with G/C heterozygotes of IL-18 -137 polymorphism had a 1.64-fold (95% CI: 1.08 2.48; p=0.02) increased risk of developing oral cancer compared with those with G/G wild type homozygotes. Both sets of statistics were determined after adjusting for confounding factors. Among people who had exposure to oral cancer related environmental risk factors such as areca, alcohol, and tobacco consumption, the adjusted odd ratios and 95% confidence intervals were increased to a 2.02-fold (95% CI=1.01-4.04; p=0.04), 4.04 (95% CI=1.65-9.87; p=0.002) and a 1.66-fold (95% CI=1.00-2.84; p=0.05) risk of developing oral cancer. However, patients with G/C alleles of IL-18 -137 were correlated with a lower clinical stage (AOR=0.59; 95% CI=0.39-0.89; p=0.01), smaller tumor size (AOR=0.56; 95% CI=0.35-0.87; p=0.01), and non-lymph node metastasis (AOR=0.51; 95% CI=0.32-0.80; p=0.003). CONCLUSION: IL-18 -137 G/C gene polymorphism may be a factor that increases the susceptibility to oral cancer, as well as a protective factor for oral cancer progression. The interactions of gene to oral cancer-related environmental risk factors have a synergetic effect that can further enhance oral cancer development. PMID- 24349533 TI - Periostin responds to mechanical stress and tension by activating the MTOR signaling pathway. AB - Current knowledge about Periostin biology has expanded from its recognized functions in embryogenesis and bone metabolism to its roles in tissue repair and remodeling and its clinical implications in cancer. Emerging evidence suggests that Periostin plays a critical role in the mechanism of wound healing; however, the paracrine effect of Periostin in epithelial cell biology is still poorly understood. We found that epithelial cells are capable of producing endogenous Periostin that, unlike mesenchymal cell, cannot be secreted. Epithelial cells responded to Periostin paracrine stimuli by enhancing cellular migration and proliferation and by activating the mTOR signaling pathway. Interestingly, biomechanical stimulation of epithelial cells, which simulates tension forces that occur during initial steps of tissue healing, induced Periostin production and mTOR activation. The molecular association of Periostin and mTOR signaling was further dissected by administering rapamycin, a selective pharmacological inhibitor of mTOR, and by disruption of Raptor and Rictor scaffold proteins implicated in the regulation of mTORC1 and mTORC2 complex assembly. Both strategies resulted in ablation of Periostin-induced mitogenic and migratory activity. These results indicate that Periostin-induced epithelial migration and proliferation requires mTOR signaling. Collectively, our findings identify Periostin as a mechanical stress responsive molecule that is primarily secreted by fibroblasts during wound healing and expressed endogenously in epithelial cells resulting in the control of cellular physiology through a mechanism mediated by the mTOR signaling cascade. PMID- 24349534 TI - Functional cooperation between vitamin D receptor and Runx2 in vitamin D-induced vascular calcification. AB - The transdifferentiation of vascular smooth muscle cells (VSMCs) into osteoblast like cells has been implicated in the context of vascular calcification. We investigated the roles of vitamin D receptor (Vdr) and runt-related transcription factor 2 (Runx2) in the osteoblastic differentiation of VSMCs in response to vitamin D3 using in vitro VSMCs cultures and in vivo in Vdr knockout (Vdr(-/-)) and Runx2 carboxy-terminus truncated heterozygous (Runx2(+/DeltaC)) mice. Treatment of VSMCs with active vitamin D3 promoted matrix mineral deposition, and increased the expressions of Vdr, Runx2, and of osteoblastic genes but decreased the expression of smooth muscle myosin heavy chain in primary VSMCs cultures. Immunoprecipitation experiments suggested an interaction between Vdr and Runx2. Furthermore, silencing Vdr or Runx2 attenuated the procalcific effects of vitamin D3. Functional cooperation between Vdr and Runx2 in vascular calcification was also confirmed in in vivo mouse models. Vascular calcification induced by high dose vitamin D3 was completely inhibited in Vdr(-/-) or Runx2(+/DeltaC) mice, despite elevated levels of serum calcium or alkaline phosphatase. Collectively, these findings suggest that functional cooperation between Vdr and Runx2 is necessary for vascular calcification in response to vitamin D3. PMID- 24349535 TI - Improved mitochondrial function underlies the protective effect of pirfenidone against tubulointerstitial fibrosis in 5/6 nephrectomized rats. AB - Dysfunctional mitochondria participate in the progression of chronic kidney disease (CKD). Pirfenidone is a newly identified anti-fibrotic drug. However, its mechanism remains unclear. Mitochondrial dysfunction is an early event that occurs prior to the onset of renal fibrosis. In this context, we investigated the protective effect of pirfenidone on mitochondria and its relevance to apoptosis and oxidative stress in renal proximal tubular cells. A remnant kidney rat model was established. Human renal proximal tubular epithelial cells (HK2) using rotenone, a mitochondrial respiratory chain complex Iota inhibitor were further investigated in vitro to examine the mitochondrial protective effect of pirfenidone. Pirfenidone protected mitochondrial structures and functions by stabilizing the mitochondrial membrane potential, maintaining ATP production and improving the mitochondrial DNA (mtDNA) copy number. Pirfenidone decreased tubular cell apoptosis by inhibiting the mitochondrial apoptotic signaling pathway. Pirfenidone also reduced oxidative stress by enhancing manganese superoxide dismutase (Mn-SOD) and inhibiting intracellular reactive oxygen species (ROS) generation, which suggested that the anti-oxidant effects occurred at least partially via the mitochondrial pathway. Pirfenidone may be effective prior to the onset of renal fibrosis because this drug exerts its anti-fibrotic effect by protection of mitochondria in renal proximal tubular cells. PMID- 24349536 TI - Efficacy and tolerability of the fixed combinations latanoprost/timolol versus dorzolamide/timolol in patients with elevated intraocular pressure: a meta analysis of randomized controlled trials. AB - OBJECTIVE: To evaluate the efficacy and tolerability of the fixed combination of Latanoprost/Timolol versus Dorzolamide/Timolol in the treatment of patients with elevated intraocular pressure (IOP). METHODS: A comprehensive literature meta analysis was performed according to the Cochrane Collaboration methodology to identify randomized clinical trials comparing latanoprost/timolol FC (FCLT) with dorzolamide/timolol (FCDT) in patients with elevated IOP. The efficacy estimates were measured by the weight mean difference (WMD) for the IOP reduction (IOPR) from baseline to end point, including the diurnal mean IOPR, 8 AM IOPR, 12 PM IOPR, and 4 PM IOPR. The tolerability estimates were measured by RR for adverse events. All outcomes were reported with a 95% confidence interval (CI). The data were synthesized by Stata 12.0 SE for Windows. RESULTS: Eight studies involving 841 patients (841 eyes) were included in the meta-analysis. With a WMD of IOPR in the diurnal mean of 0.16 mmHg (95% CI, -0.31 to 0.63), the FCLT was as effective as FCDT in lowering IOP in patients with elevated IOP (P = 0.51). The WMDs of IOPR were 0.58 mmHg (95% CI: -0.002 to 1.17) at 8 AM, -0.07 mmHg (95% CI: -0.50 to 0.36) at 12 PM, and 0.41 mmHg (95% CI: -0.18 to 1.00) at 4 PM, and there were no significant difference between FCLT and FCDT. FCLT was associated with a significantly lower incidence of eye pain, bitter taste, and irritation/stinging than FCDT, with pooled RRs of 0.34 (95% CI: 0.14 to 0.82), 0.06 (95% CI:0.008 to 0.42), and 0.35 (95% CI: 0.14 to 0.85), respectively. CONCLUSION: FCLT was associated with equivalent efficacy in IOP lowering comparing with FCDT. However, FCLT was better tolerated than FCDT. PMID- 24349537 TI - Integrin alpha6beta4 identifies human distal lung epithelial progenitor cells with potential as a cell-based therapy for cystic fibrosis lung disease. AB - To develop stem/progenitor cell-based therapy for cystic fibrosis (CF) lung disease, it is first necessary to identify markers of human lung epithelial progenitor/stem cells and to better understand the potential for differentiation into distinct lineages. Here we investigated integrin alpha6beta4 as an epithelial progenitor cell marker in the human distal lung. We identified a subpopulation of alpha6beta4(+) cells that localized in distal small airways and alveolar walls and were devoid of pro-surfactant protein C expression. The alpha6beta4(+) epithelial cells demonstrated key properties of stem cells ex vivo as compared to alpha6beta4(-) epithelial cells, including higher colony forming efficiency, expression of stem cell-specific transcription factor Nanog, and the potential to differentiate into multiple distinct lineages including basal and Clara cells. Co-culture of alpha6beta4(+) epithelial cells with endothelial cells enhanced proliferation. We identified a subset of adeno-associated virus (AAVs) serotypes, AAV2 and AAV8, capable of transducing alpha6beta4(+) cells. In addition, reconstitution of bronchi epithelial cells from CF patients with only 5% normal alpha6beta4(+) epithelial cells significantly rescued defects in Cl(-) transport. Therefore, targeting the alpha6beta4(+) epithelial population via either gene delivery or progenitor cell-based reconstitution represents a potential new strategy to treat CF lung disease. PMID- 24349538 TI - Cell type-specific subcellular localization of phospho-TBK1 in response to cytoplasmic viral DNA. AB - Cytoplasmic viral RNA and DNA are recognized by RIG-I-like receptors and DNA sensors that include DAI, IFI16, DDX41, and cGAS. The RNA and DNA sensors evoke innate immune responses through the IPS-1 and STING adaptors. IPS-1 and STING activate TBK1 kinase. TBK1 is phosphorylated in its activation loop, leading to IRF3/7 activation and Type I interferon (IFN) production. IPS-1 and STING localize to the mitochondria and endoplasmic reticulum, respectively, whereas it is unclear where phosphorylated TBK1 is localized in response to cytoplasmic viral DNA. Here, we investigated phospho-TBK1 (p-TBK1) subcellular localization using a p-TBK1-specific antibody. Stimulation with vertebrate DNA by transfection increased p-TBK1 levels. Interestingly, stimulation-induced p-TBK1 exhibited mitochondrial localization in HeLa and HepG2 cells and colocalized with mitochondrial IPS-1 and MFN-1. Hepatitis B virus DNA stimulation or herpes simplex virus type-1 infection also induced p-TBK1 mitochondrial localization in HeLa cells, indicating that cytoplasmic viral DNA induces p-TBK1 mitochondrial localization in HeLa cells. In contrast, p-TBK1 did not show mitochondrial localization in RAW264.7, L929, or T-23 cells, and most of p-TBK1 colocalized with STING in response to cytoplasmic DNA in those mammalian cells, indicating cell type-specific localization of p-TBK1 in response to cytoplasmic viral DNA. A previous knockout study showed that mouse IPS-1 was dispensable for Type I IFN production in response to cytoplasmic DNA. However, we found that knockdown of IPS-1 markedly reduced p-TBK1 levels in HeLa cells. Taken together, our data elucidated the cell type-specific subcellular localization of p-TBK1 and a cell type-specific role of IPS-1 in TBK1 activation in response to cytoplasmic viral DNA. PMID- 24349539 TI - Inferring emotions from speech prosody: not so easy at age five. AB - Previous research has suggested that children do not rely on prosody to infer a speaker's emotional state because of biases toward lexical content or situational context. We hypothesized that there are actually no such biases and that young children simply have trouble in using emotional prosody. Sixty children from 5 to 13 years of age had to judge the emotional state of a happy or sad speaker and then to verbally explain their judgment. Lexical content and situational context were devoid of emotional valence. Results showed that prosody alone did not enable the children to infer emotions at age 5, and was still not fully mastered at age 13. Instead, they relied on contextual information despite the fact that this cue had no emotional valence. These results support the hypothesis that prosody is difficult to interpret for young children and that this cue plays only a subordinate role up until adolescence to infer others' emotions. PMID- 24349541 TI - A predictive model for knee joint replacement in older women. AB - Knee replacement (KR) is expensive and invasive. To date no predictive algorithms have been developed to identify individuals at high risk of surgery. This study assessed whether patient self-reported risk factors predict 10-year KR in a population-based study of 1,462 women aged over 70 years recruited for the Calcium Intake Fracture Outcome Study (CAIFOS). Complete hospital records of prevalent (1980-1998) and incident (1998-2008) total knee replacement were available via the Western Australian Data Linkage System. Potential risk factors were assessed for predicative ability using a modeling approach based on a pre planned selection of risk factors prior to model evaluation. There were 129 (8.8%) participants that underwent KR over the 10 year period. Baseline factors including; body mass index, knee pain, previous knee replacement and analgesia use for joint pain were all associated with increased risk, (P < 0.001). These factors in addition to age demonstrated good discrimination with a C-statistic of 0.79 +/- 0.02 as well as calibration determined by the Hosmer-Lemeshow Goodness of-Fit test. For clinical recommendations, three categories of risk for 10-year knee replacement were selected; low < 5%; moderate 5 to < 10% and high >= 10% predicted risk. The actual risk of knee replacement was; low 16 / 741 (2.2%); moderate 32 / 330 (9.7%) and high 81 / 391 (20.7%), P < 0.001. Internal validation of this 5-variable model on 6-year knee replacements yielded a similar C-statistic of 0.81 +/- 0.02, comparable to the WOMAC weighted score; C-statistic 0.75 +/- 0.03, P = 0.064. In conclusion 5 easily obtained patient self-reported risk factors predict 10-year KR risk well in this population. This algorithm should be considered as the basis for a patient-based risk calculator to assist in the development of treatment regimens to reduce the necessity for surgery in high risk groups such as the elderly. PMID- 24349540 TI - An RNAi-based dimorphic genetic screen identified the double bromodomain protein BET-1 as a sumo-dependent attenuator of RAS-mediated signalling. AB - Attenuation of RAS/RAF/MAPK signalling is essential to prevent hyperactivation of this oncogenic pathway. In C. elegans, the sumoylation pathway and a combination of histone tail modifications regulate gene expression to attenuate the LET-60 (RAS) signalling pathway. We hypothesised that a number of chromatin regulators are likely to depend on sumoylation to attenuate the pathway. To reveal these, we designed an RNAi-based dimorphic genetic screen that selects candidates based on their ability to act as enhancers of a sumo mutant phenotype, such interactions would suggest that the candidates may be physically associated with sumoylation. We found 16 enhancers, one of which BET-1, is a conserved double bromodomain containing protein. We further characterised BET-1 and showed that it can physically associate with SMO-1 and UBC-9, and that it can be sumoylated in vitro within the second bromodomain at lysine 252. Previous work has shown that BET-1 can bind acetyl-lysines on histone tails to influence gene expression. In conclusion, our screening approach has identified BET-1 as a Sumo-dependent attenuator of LET-60-mediated signalling and our characterisation suggests that BET-1 can be sumoylated. PMID- 24349542 TI - National and local influenza surveillance through Twitter: an analysis of the 2012-2013 influenza epidemic. AB - Social media have been proposed as a data source for influenza surveillance because they have the potential to offer real-time access to millions of short, geographically localized messages containing information regarding personal well being. However, accuracy of social media surveillance systems declines with media attention because media attention increases "chatter" - messages that are about influenza but that do not pertain to an actual infection - masking signs of true influenza prevalence. This paper summarizes our recently developed influenza infection detection algorithm that automatically distinguishes relevant tweets from other chatter, and we describe our current influenza surveillance system which was actively deployed during the full 2012-2013 influenza season. Our objective was to analyze the performance of this system during the most recent 2012-2013 influenza season and to analyze the performance at multiple levels of geographic granularity, unlike past studies that focused on national or regional surveillance. Our system's influenza prevalence estimates were strongly correlated with surveillance data from the Centers for Disease Control and Prevention for the United States (r = 0.93, p < 0.001) as well as surveillance data from the Department of Health and Mental Hygiene of New York City (r = 0.88, p < 0.001). Our system detected the weekly change in direction (increasing or decreasing) of influenza prevalence with 85% accuracy, a nearly twofold increase over a simpler model, demonstrating the utility of explicitly distinguishing infection tweets from other chatter. PMID- 24349543 TI - Behaviorally activated mRNA expression profiles produce signatures of learning and enhanced inhibition in aged rats with preserved memory. AB - Aging is often associated with cognitive decline, but many elderly individuals maintain a high level of function throughout life. Here we studied outbred rats, which also exhibit individual differences across a spectrum of outcomes that includes both preserved and impaired spatial memory. Previous work in this model identified the CA3 subfield of the hippocampus as a region critically affected by age and integral to differing cognitive outcomes. Earlier microarray profiling revealed distinct gene expression profiles in the CA3 region, under basal conditions, for aged rats with intact memory and those with impairment. Because prominent age-related deficits within the CA3 occur during neural encoding of new information, here we used microarray analysis to gain a broad perspective of the aged CA3 transcriptome under activated conditions. Behaviorally-induced CA3 expression profiles differentiated aged rats with intact memory from those with impaired memory. In the activated profile, we observed substantial numbers of genes (greater than 1000) exhibiting increased expression in aged unimpaired rats relative to aged impaired, including many involved in synaptic plasticity and memory mechanisms. This unimpaired aged profile also overlapped significantly with a learning induced gene profile previously acquired in young adults. Alongside the increased transcripts common to both young learning and aged rats with preserved memory, many transcripts behaviorally-activated in the current study had previously been identified as repressed in the aged unimpaired phenotype in basal expression. A further distinct feature of the activated profile of aged rats with intact memory is the increased expression of an ensemble of genes involved in inhibitory synapse function, which could control the phenotype of neural hyperexcitability found in the CA3 region of aged impaired rats. These data support the conclusion that aged subjects with preserved memory recruit adaptive mechanisms to retain tight control over excitability under both basal and activated conditions. PMID- 24349545 TI - The uremic toxin adsorbent AST-120 abrogates cardiorenal injury following myocardial infarction. AB - An accelerated progressive decline in renal function is a frequent accompaniment of myocardial infarction (MI). Indoxyl sulfate (IS), a uremic toxin that accumulates from the early stages of chronic kidney disease (CKD), is contributory to both renal and cardiac fibrosis. IS levels can be reduced by administration of the oral adsorbent AST-120, which has been shown to ameliorate pathological renal and cardiac fibrosis in moderate to severe CKD. However, the cardiorenal effect of AST-120 on less severe renal dysfunction in the post-MI setting has not previously been well studied. MI-induced Sprague-Dawley rats were randomized to receive either AST-120 (MI+AST-120) or were untreated (MI+Vehicle) for 16 weeks. Serum IS levels were measured at baseline, 8 and 16 weeks. Echocardiography and glomerular filtration rate (GFR) were assessed prior to sacrifice. Renal and cardiac tissues were assessed for pathological changes using histological and immunohistochemical methods, Western blot analysis and real-time PCR. Compared with sham, MI+Vehicle animals had a significant reduction in left ventricular ejection fraction (by 42%, p<0.001) and fractional shortening (by 52%, p<0.001) as well as lower GFR (p<0.05) and increased serum IS levels (p<0.05). A significant increase in interstitial fibrosis in the renal cortex was demonstrated in MI+Vehicle animals (p<0.001). Compared with MI+Vehicle, MI+AST 120 animals had increased GFR (by 13.35%, p<0.05) and reduced serum IS (p<0.001), renal interstitial fibrosis (p<0.05), and renal KIM-1, collagen-IV and TIMP-1 expression (p<0.05). Cardiac function did not change with AST-120 treatment, however gene expression of TGF-beta1 and TNF-alpha as well as collagen-I and TIMP 1 protein expression was decreased in the non-infarcted myocardium (p<0.05). In conclusion, reduction of IS attenuates cardio-renal fibrotic processes in the post-MI kidney. KIM-1 appears to be a sensitive renal injury biomarker in this setting and is correlated with serum IS levels. PMID- 24349544 TI - Isolation and characterisation of a recombinant antibody fragment that binds NCAM1-expressing intervertebral disc cells. AB - Degeneration of the intervertebral discs (IVD) is a leading cause of neck and low back pain. Degeneration begins in the central nucleus pulposus region, leading to loss of IVD osmotic properties. Regeneration approaches include administration of matrix-mimicking scaffolds, cells and/or therapeutic factors. Cell-targeting strategies are likely to improve delivery due to the low cell numbers in the IVD. Single-chain antibody fragments (scFvs) that bind IVD cells were isolated for potential delivery of therapeutics to degenerated IVD. The most cell-distal domain of neural cell adhesion molecule 1 (NCAM1) was cloned and expressed in Escherichia coli. Phage display technology was used to isolate a human scFv against the recombinant domain by panning a scFv library on the immobilised protein. The isolated scFv bound cultured rat astrocytes, as well as bovine nucleus pulposus and annulus fibrosus cells in immunocytochemical studies. The scFv also labelled cells in bovine spinal cord and six-month and two-year old bovine IVD sections by immunohistochemistry. Antibody fragments can provide cell binding moieties at improved cost, time, yield and functionalisation potential over whole antibodies. The described scFv has potential application in delivery of therapeutics to NCAM1-expressing cells in degenerated IVD. PMID- 24349546 TI - Heart rate variability and blood pressure during dynamic and static exercise at similar heart rate levels. AB - Aim was to elucidate autonomic responses to dynamic and static (isometric) exercise of the lower limbs eliciting the same moderate heart rate (HR) response. METHOD: 23 males performed two kinds of voluntary exercise in a supine position at similar heart rates: static exercise (SE) of the lower limbs (static leg press) and dynamic exercise (DE) of the lower limbs (cycling). Subjective effort, systolic (SBP) and diastolic blood pressure (DBP), mean arterial pressure (MAP), rate pressure product (RPP) and the time between consecutive heart beats (RR intervals) were measured. Time-domain (SDNN, RMSSD), frequency-domain (power in the low and high frequency band (LFP, HFP)) and geometric measures (SD1, SD2) as well as non-linear measures of regularity (approximate entropy (ApEn), sample entropy (SampEn) and correlation dimension D2) were calculated. RESULTS: Although HR was similar during both exercise conditions (88+/-10 bpm), subjective effort, SBP, DBP, MAP and RPP were significantly enhanced during SE. HRV indicators representing overall variability (SDNN, SD 2) and vagal modulated variability (RMSSD, HFP, SD 1) were increased. LFP, thought to be modulated by both autonomic branches, tended to be higher during SE. ApEn and SampEn were decreased whereas D2 was enhanced during SE. It can be concluded that autonomic control processes during SE and DE were qualitatively different despite similar heart rate levels. The differences were reflected by blood pressure and HRV indices. HRV-measures indicated a stronger vagal cardiac activity during SE, while blood pressure response indicated a stronger sympathetic efferent activity to the vessels. The elevated vagal cardiac activity during SE might be a response mechanism, compensating a possible co-activation of sympathetic cardiac efferents, as HR and LF/HF was similar and LFP tended to be higher. However, this conclusion must be drawn cautiously as there is no HRV-marker reflecting "pure" sympathetic cardiac activity. PMID- 24349547 TI - Diagnosing developmental dyscalculia on the basis of reliable single case FMRI methods: promises and limitations. AB - FMRI-studies are mostly based on a group study approach, either analyzing one group or comparing multiple groups, or on approaches that correlate brain activation with clinically relevant criteria or behavioral measures. In this study we investigate the potential of fMRI-techniques focusing on individual differences in brain activation within a test-retest reliability context. We employ a single-case analysis approach, which contrasts dyscalculic children with a control group of typically developing children. In a second step, a support vector machine analysis and cluster analysis techniques served to investigate similarities in multivariate brain activation patterns. Children were confronted with a non-symbolic number comparison and a non-symbolic exact calculation task during fMRI acquisition. Conventional second level group comparison analysis only showed small differences around the angular gyrus bilaterally and the left parieto-occipital sulcus. Analyses based on single-case statistical procedures revealed that developmental dyscalculia is characterized by individual differences predominantly in visual processing areas. Dyscalculic children seemed to compensate for relative under-activation in the primary visual cortex through an upregulation in higher visual areas. However, overlap in deviant activation was low for the dyscalculic children, indicating that developmental dyscalculia is a disorder characterized by heterogeneous brain activation differences. Using support vector machine analysis and cluster analysis, we tried to group dyscalculic and typically developing children according to brain activation. Fronto-parietal systems seem to qualify for a distinction between the two groups. However, this was only effective when reliable brain activations of both tasks were employed simultaneously. Results suggest that deficits in number representation in the visual-parietal cortex get compensated for through finger related aspects of number representation in fronto-parietal cortex. We conclude that dyscalculic children show large individual differences in brain activation patterns. Nonetheless, the majority of dyscalculic children can be differentiated from controls employing brain activation patterns when appropriate methods are used. PMID- 24349548 TI - A lower level of forced expiratory volume in 1 second is a risk factor for all cause and cardiovascular mortality in a Japanese population: the Takahata study. AB - Chronic obstructive pulmonary disease is a known risk factor for cardiovascular death in Western countries. Because Japan has a low cardiovascular death rate, the association between a lower level of forced expiratory volume in 1 s (FEV1) and mortality in Japan's general population is unknown. To clarify this, we conducted a community-based longitudinal study. This study included 3253 subjects, who received spirometry from 2004 to 2006 in Takahata, with a 7-year follow-up. The causes of death were assessed on the basis of the death certificate. In 338 subjects, airflow obstruction was observed by spirometry. A total of 127 subjects died. Cardiovascular death was the second highest cause of death in this population. The pulmonary functions of the deceased subjects were significantly lower than those of the subjects who were alive at the end of follow-up. The relative risk of death by all causes, respiratory failure, lung cancer, and cardiovascular disease was significantly increased with airflow obstruction. The Kaplan-Meier analysis showed that all-cause and cardiovascular mortality significantly increased with a worsening severity of airflow obstruction. After adjusting for possible factors that could influence prognosis, a Cox proportional hazard model analysis revealed that a lower level of FEV1 was an independent risk factor for all-cause and cardiovascular mortality (per 10% increase; hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.82-0.98; and HR, 0.72; 95% CI, 0.61-0.86, respectively). In conclusion, airflow obstruction is an independent risk factor for all-cause and cardiovascular death in the Japanese general population. Spirometry might be a useful test to evaluate the risk of cardiovascular death and detect the risk of respiratory death by lung cancer or respiratory failure in healthy Japanese individuals. PMID- 24349549 TI - Does ploidy level directly control cell size? Counterevidence from Arabidopsis genetics. AB - Ploidy level affects cell size in many organisms, and ploidy-dependent cell enlargement has been used to breed many useful organisms. However, how polyploidy affects cell size remains unknown. Previous studies have explored changes in transcriptome data caused by polyploidy, but have not been successful. The most naive theory explaining ploidy-dependent cell enlargement is that increases in gene copy number increase the amount of protein, which in turn increases the cell volume. This hypothesis can be evaluated by examining whether any strains, mutants, or transgenics show the same cell size before and after a tetraploidization event. I performed this experiment by tetraploidizing various mutants and transgenics of Arabidopsis thaliana, which show a wide range in cell size, and found that the ploidy-dependent increase in cell volume is genetically regulated. This result is not in agreement with the theory described above. PMID- 24349550 TI - Skin autofluorescence is associated with the progression of chronic kidney disease: a prospective observational study. AB - BACKGROUND: Advanced glycation end product (AGE) accumulation is thought to be a measure of cumulative metabolic stress that has been reported to independently predict cardiovascular disease in diabetes and renal failure. The aim of this study was to evaluate the association between AGE accumulation, measured as skin autofluorescence, and the progression of renal disease in pre-dialysis patients with chronic kidney disease (CKD). METHODS: Skin autofluorescence was measured noninvasively with an autofluorescence reader at baseline in 449 pre-dialysis patients with CKD. The primary end point was defined as a doubling of serum creatinine and/or need for dialysis. RESULTS: Thirty-three patients were lost to follow-up. Forty six patients reached the primary end point during the follow-up period (Median 39 months). Kaplan-Meier analysis showed a significantly higher risk of development of the primary end points in patients with skin autofluorescence levels above the optimal cut-off level of 2.31 arbitrary units, derived by receiver operator curve analysis. Cox regression analysis revealed that skin autofluorescence was an independent predictor of the primary end point, even after adjustment for age, gender, smoking history, diabetes, estimated glomerular filtration rate and proteinuria (adjusted hazard ratio 2.58, P = 0.004). CONCLUSIONS: Tissue accumulation of AGEs, measured as skin autofluorescence, is a strong and independent predictor of progression of CKD. Skin autofluorescence may be useful for risk stratification in this group of patients; further studies should clarify whether AGE accumulation could be one of the therapeutic targets to improve the prognosis of CKD. PMID- 24349551 TI - The effect of lubricin on the gliding resistance of mouse intrasynovial tendon. AB - The purpose of this study was to investigate the role of lubricin on the gliding resistance of intrasynovial tendons by comparing lubricin knockout, heterozygous, and wild type mice. A total of thirty-six deep digital flexor (DDF) tendons in the third digits of each hind paw from eighteen adult mice were used, including six lubricin knockout mice (Prg4 -/-), six heterozygous mice (Prg4 +/-), and six wild type mice (Prg4 +/+). The tendon gliding resistance was measured using a custom-made device. Tendon structural changes were evaluated by scanning electron and light microscopy. The gliding resistance of intrasynovial tendons from lubricin knockout mice was significantly higher than the gliding resistance of either wild type or heterozygous mice. The surface of the lubricin knockout tendons appeared to be rougher, compared to the wild type and heterozygous tendons. Synovial hyperplasia was found in the lubricin knockout mice. Cartilage like tissue was found in the tendon and pulley of the lubricin knockout mice. Our findings confirm the importance of lubricin in intrasynovial tendon lubrication. This knockout model may be useful in determining the effect of lubricin on tendon healing and the response to injury. PMID- 24349552 TI - Vitamin D receptor gene polymorphisms on the risk of tuberculosis, a meta analysis of 29 case-control studies. AB - The relationship of four potentially functional polymorphisms of the vitamin D receptor (VDR) gene, ApaI, BsmI, FokI and TaqI , with tuberculosis susceptibility were considered. The aim of this meta-analysis was to explore the association between the four polymorphisms and tuberculosis risk in different ethnic backgrounds. Eligible case-control studies that were catalogued before April 1(st) 2013 were enrolled, and the heterogeneity between the studies was evaluated using a chi(2) based Q-test. Fixed and random effect models were built to evaluate the association of the four polymorphisms with the risk of tuberculosis, and the association between the four polymorphisms and tuberculosis was expressed as the odds ratio (OR) and 95% confidence interval (CI). Finally, twenty nine qualified studies were enrolled for this meta-analysis that included 6179 tuberculosis cases and 6585 healthy controls. The variant homozygote genotype of the FokI polymorphism was associated with a significantly increased risk of tuberculosis when compared to the heterozygote and wild type homozygote genotypes in the Chinese population (ff vs. Ff+FF: OR(recessive) =1.97, 95%CI: 1.32-2.93, P(bonferroni) =0.0032; heterogeneity test: chi(2)=0.24, P=0.62). For European subjects, the homozygote and heterozygote genotypes of the BsmI polymorphism were associated with a significantly decreased risk of tuberculosis when compared to the wild type homozygote (bb+Bb vs. BB: OR(dominant) =0.41, 95%CI, 0.22-0.76, P(bonferroni) =0.02; heterogeneity test: chi(2)=2.59, P=0.11). Based on the above results, we conclude that variants of the VDR gene that are homozygous for the FokI polymorphism might be more susceptible to tuberculosis in Chinese. Furthermore, larger sample studies are warranted to confirm the protective effects of BsmI variants on tuberculosis in the Europeans. PMID- 24349553 TI - Greater ethanol-induced locomotor activation in DBA/2J versus C57BL/6J mice is not predicted by presynaptic striatal dopamine dynamics. AB - A large body of research has aimed to determine the neurochemical factors driving differential sensitivity to ethanol between individuals in an attempt to find predictors of ethanol abuse vulnerability. Here we find that the locomotor activating effects of ethanol are markedly greater in DBA/2J compared to C57BL/6J mice, although it is unclear as to what neurochemical differences between strains mediate this behavior. Dopamine elevations in the nucleus accumbens and caudate putamen regulate locomotor behavior for most drugs, including ethanol; thus, we aimed to determine if differences in these regions predict strain differences in ethanol-induced locomotor activity. Previous studies suggest that ethanol interacts with the dopamine transporter, potentially mediating its locomotor activating effects; however, we found that ethanol had no effects on dopamine uptake in either strain. Ex vivo voltammetry allows for the determination of ethanol effects on presynaptic dopamine terminals, independent of drug-induced changes in firing rates of afferent inputs from either dopamine neurons or other neurotransmitter systems. However, differences in striatal dopamine dynamics did not predict the locomotor-activating effects of ethanol, since the inhibitory effects of ethanol on dopamine release were similar between strains. There were differences in presynaptic dopamine function between strains, with faster dopamine clearance in the caudate-putamen of DBA/2J mice; however, it is unclear how this difference relates to locomotor behavior. Because of the role of the dopamine system in reinforcement and reward learning, differences in dopamine signaling between the strains could have implications for addiction-related behaviors that extend beyond ethanol effects in the striatum. PMID- 24349554 TI - Rapid diversification of FoxP2 in teleosts through gene duplication in the teleost-specific whole genome duplication event. AB - As one of the most conserved genes in vertebrates, FoxP2 is widely involved in a number of important physiological and developmental processes. We systematically studied the evolutionary history and functional adaptations of FoxP2 in teleosts. The duplicated FoxP2 genes (FoxP2a and FoxP2b), which were identified in teleosts using synteny and paralogon analysis on genome databases of eight organisms, were probably generated in the teleost-specific whole genome duplication event. A credible classification with FoxP2, FoxP2a and FoxP2b in phylogenetic reconstructions confirmed the teleost-specific FoxP2 duplication. The unavailability of FoxP2b in Danio rerio suggests that the gene was deleted through nonfunctionalization of the redundant copy after the Otocephala Euteleostei split. Heterogeneity in evolutionary rates among clusters consisting of FoxP2 in Sarcopterygii (Cluster 1), FoxP2a in Teleostei (Cluster 2) and FoxP2b in Teleostei (Cluster 3), particularly between Clusters 2 and 3, reveals asymmetric functional divergence after the gene duplication. Hierarchical cluster analyses of hydrophobicity profiles demonstrated significant structural divergence among the three clusters with verification of subsequent stepwise discriminant analysis, in which FoxP2 of Leucoraja erinacea and Lepisosteus oculatus were classified into Cluster 1, whereas FoxP2b of Salmo salar was grouped into Cluster 2 rather than Cluster 3. The simulated thermodynamic stability variations of the forkhead box domain (monomer and homodimer) showed remarkable divergence in FoxP2, FoxP2a and FoxP2b clusters. Relaxed purifying selection and positive Darwinian selection probably were complementary driving forces for the accelerated evolution of FoxP2 in ray-finned fishes, especially for the adaptive evolution of FoxP2a and FoxP2b in teleosts subsequent to the teleost-specific gene duplication. PMID- 24349555 TI - Transfer of learning between hemifields in multiple object tracking: memory reduces constraints of attention. AB - Many tasks involve tracking multiple moving objects, or stimuli. Some require that individuals adapt to changing or unfamiliar conditions to be able to track well. This study explores processes involved in such adaptation through an investigation of the interaction of attention and memory during tracking. Previous research has shown that during tracking, attention operates independently to some degree in the left and right visual hemifields, due to putative anatomical constraints. It has been suggested that the degree of independence is related to the relative dominance of processes of attention versus processes of memory. Here we show that when individuals are trained to track a unique pattern of movement in one hemifield, that learning can be transferred to the opposite hemifield, without any evidence of hemifield independence. However, learning is not influenced by an explicit strategy of memorisation of brief periods of recognisable movement. The findings lend support to a role for implicit memory in overcoming putative anatomical constraints on the dynamic, distributed spatial allocation of attention involved in tracking multiple objects. PMID- 24349556 TI - Terminal N-acetylgalactosamine-specific leguminous lectin from Wisteria japonica as a probe for human lung squamous cell carcinoma. AB - Millettia japonica was recently reclassified into the genus Wisteria japonica based on chloroplast and nuclear DNA sequences. Because the seed of Wisteria floribunda expresses leguminous lectins with unique N-acetylgalactosamine-binding specificity, we purified lectin from Wisteria japonica seeds using ion exchange and gel filtration chromatography. Glycan microarray analysis demonstrated that unlike Wisteria floribunda and Wisteria brachybotrys lectins, which bind to both terminal N-acetylgalactosamine and galactose residues, Wisteria japonica lectin (WJA) specifically bound to both alpha- and beta-linked terminal N acetylgalactosamine, but not galactose residues on oligosaccharides and glycoproteins. Further, frontal affinity chromatography using more than 100 2 aminopyridine-labeled and p-nitrophenyl-derivatized oligosaccharides demonstrated that the ligands with the highest affinity for Wisteria japonica lectin were GalNAcbeta1-3GlcNAc and GalNAcbeta1-4GlcNAc, with K(a) values of 9.5 * 10(4) and 1.4 * 10(5) M(-1), respectively. In addition, when binding was assessed in a variety of cell lines, Wisteria japonica lectin bound specifically to EBC-1 and HEK293 cells while other Wisteria lectins bound equally to all of the cell lines tested. Wisteria japonica lectin binding to EBC-1 and HEK293 cells was dramatically decreased in the presence of N-acetylgalactosamine, but not galactose, mannose, or N-acetylglucosamine, and was completely abrogated by beta hexosaminidase-digestion of these cells. These results clearly demonstrate that Wisteria japonica lectin binds to terminal N-acetylgalactosamine but not galactose. In addition, histochemical analysis of human squamous cell carcinoma tissue sections demonstrated that Wisteria japonica lectin specifically bound to differentiated cancer tissues but not normal tissue. This novel binding characteristic of Wisteria japonica lectin has the potential to become a powerful tool for clinical applications. PMID- 24349557 TI - The ecological associations of surface-dwelling lizards in Qom Province in the Northwest of Central Plateau of Iran. AB - We used pitfall trapping to investigate the effects of elevation, plant density and soil structure on species diversity and the impact of these habitat factors on lizard habitat selectivity in the Qom Province in the Central Plateau of Iran. From a total of 12 1-ha plots, we captured 363 individuals of 15 species of lizards (six species of Lacertidae, five species of Agamidae, two species of Gekkonidae, one species of Varanidae and one species of Scincidae). A generalized linear model (GLM) determined that elevation was the most important factor impacting species diversity. The highest species diversity was at the intermediate elevation (1289 m). Abundance of 6 out of 15 species showed strong relationships with some habitat factors. These relationships were demonstrated by habitat selectivity index (Ivlev's index). Our result supports other surveys that showed that elevation plays an important role in determining lizard species diversity. PMID- 24349558 TI - The histone deacetylase HDAC4 regulates long-term memory in Drosophila. AB - A growing body of research indicates that pharmacological inhibition of histone deacetylases (HDACs) correlates with enhancement of long-term memory and current research is concentrated on determining the roles that individual HDACs play in cognitive function. Here, we investigate the role of HDAC4 in long-term memory formation in Drosophila. We show that overexpression of HDAC4 in the adult mushroom body, an important structure for memory formation, resulted in a specific impairment in long-term courtship memory, but had no affect on short term memory. Overexpression of an HDAC4 catalytic mutant also abolished LTM, suggesting a mode of action independent of catalytic activity. We found that overexpression of HDAC4 resulted in a redistribution of the transcription factor MEF2 from a relatively uniform distribution through the nucleus into punctate nuclear bodies, where it colocalized with HDAC4. As MEF2 has also been implicated in regulation of long-term memory, these data suggest that the repressive effects of HDAC4 on long-term memory may be through interaction with MEF2. In the same genetic background, we also found that RNAi-mediated knockdown of HDAC4 impairs long-term memory, therefore we demonstrate that HDAC4 is not only a repressor of long-term memory, but also modulates normal memory formation. PMID- 24349559 TI - CD86 is an activation receptor for NK cell cytotoxicity against tumor cells. AB - CTLA4Ig has been successfully used in the clinic for suppression of T cell activation. However, patients treated with CTLA4Ig experienced reduced incidence of tumors than predicted, but the underlying mechanism remains unknown. In this paper, we showed that brief administration of CTLA4Ig significantly reduced tumor metastasis and prolonged the survival of host mice bearing B16 melanoma. Depletion of NK cells prior to CTLA4Ig administration eliminated the CTLA4Ig mediated anti-tumor activity. CTLA4Ig enhanced NK cell cytotoxicity to tumor cells via up-regulation of NK cell effecter molecules CD107a and perforin in vivo. In addition, we demonstrated that, upon activation, NK cells could significantly increase the expression of CD86 both in vitro and in vivo, and ligation of CD86 with CTLA4Ig significantly increased the ability of NK cells to kill tumor cells. Furthermore, a human NK cell line that expressed high level of CD86 was directly activated by CTLA4Ig so that killing of tumor targets was enhanced; this enhanced killing could be inhibited by blocking CD86. Our findings uncover a novel function of CTLA4Ig in tumor immunity and suggest that CD86 on NK cells is an activating receptor and closely involved in the CTLA4Ig-mediated anti tumor response. PMID- 24349560 TI - Linkage analysis in familial non-Lynch syndrome colorectal cancer families from Sweden. AB - Family history is a major risk factor for colorectal cancer and many families segregate the disease as a seemingly monogenic trait. A minority of familial colorectal cancer could be explained by known monogenic genes and genetic loci. Familial polyposis and Lynch syndrome are two syndromes where the predisposing genes are known but numerous families have been tested without finding the predisposing gene. We performed a genome wide linkage analysis in 121 colorectal families with an increased risk of colorectal cancer. The families were ascertained from the department of clinical genetics at the Karolinska University Hospital in Stockholm, Sweden and were considered negative for Familial Polyposis and Lynch syndrome. In total 600 subjects were genotyped using single nucleotide polymorphism array chips. Parametric- and non-parametric linkage analyses were computed using MERLIN in all and subsets of families. No statistically significant result was seen, however, there were suggestive positive HLODs above two in parametric linkage analysis. This was observed in a recessive model for high-risk families, at locus 9q31.1 (HLOD=2.2, rs1338121) and for moderate-risk families, at locus Xp22.33 (LOD=2.2 and HLOD=2.5, rs2306737). Using families with early-onset, recessive analysis suggested one locus on 4p16.3 (LOD=2.2, rs920683) and one on 17p13.2 (LOD/HLOD=2.0, rs884250). No NPL score above two was seen for any of the families. Our linkage study provided additional support for the previously suggested region on chromosome 9 and suggested additional loci to be involved in colorectal cancer risk. Sequencing of genes in the regions will be done in future studies. PMID- 24349561 TI - p120 catenin is required for the stress response in Drosophila. AB - p120ctn is a ubiquitously expressed core component of cadherin junctions and essential for vertebrate development. Surprisingly, Drosophila p120ctn (dp120ctn) is dispensable for adherens junctions and development, which has discouraged Drosophila researchers from further pursuing the biological role of dp120ctn. Here we demonstrate that dp120ctn loss results in increased heat shock sensitivity and reduced animal lifespan, which are completely rescued by ectopic expression of a dp120ctn-GFP transgene. Transcriptomic analysis revealed multiple relish/NF-kappaB target genes differentially expressed upon loss of dp120ctn. Importantly, this aberrant gene expression was rescued by overexpression of dp120ctn-GFP or heterozygosity for relish. Our results uncover a novel role for dp120ctn in the regulation of animal stress response and immune signalling. This may represent an ancient role of p120ctn and can influence further studies in Drosophila and mammals. PMID- 24349562 TI - Can force feedback and science learning enhance the effectiveness of neuro rehabilitation? An experimental study on using a low-cost 3D joystick and a virtual visit to a zoo. AB - In this paper, we demonstrate that healthy adults respond differentially to the administration of force feedback and the presentation of scientific content in a virtual environment, where they interact with a low-cost haptic device. Subjects are tasked with controlling the movement of a cursor on a predefined trajectory that is superimposed on a map of New York City's Bronx Zoo. The system is characterized in terms of a suite of objective indices quantifying the subjects' dexterity in planning and generating the multijoint visuomotor tasks. We find that force feedback regulates the smoothness, accuracy, and duration of the subject's movement, whereby converging or diverging force fields influence the range of variations of the hand speed. Finally, our findings provide preliminary evidence that using educational content increases subjects' satisfaction. Improving the level of interest through the inclusion of learning elements can increase the time spent performing rehabilitation tasks and promote learning in a new context. PMID- 24349563 TI - Selection of reliable biomarkers from PCR array analyses using relative distance computational model: methodology and proof-of-concept study. AB - It is increasingly evident about the difficulty to monitor chemical exposure through biomarkers as almost all the biomarkers so far proposed are not specific for any individual chemical. In this proof-of-concept study, adult male zebrafish (Danio rerio) were exposed to 5 or 25 ug/L 17beta-estradiol (E2), 100 ug/L lindane, 5 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 15 mg/L arsenic for 96 h, and the expression profiles of 59 genes involved in 7 pathways plus 2 well characterized biomarker genes, vtg1 (vitellogenin1) and cyp1a1 (cytochrome P450 1A1), were examined. Relative distance (RD) computational model was developed to screen favorable genes and generate appropriate gene sets for the differentiation of chemicals/concentrations selected. Our results demonstrated that the known biomarker genes were not always good candidates for the differentiation of pair of chemicals/concentrations, and other genes had higher potentials in some cases. Furthermore, the differentiation of 5 chemicals/concentrations examined were attainable using expression data of various gene sets, and the best combination was the set consisting of 50 genes; however, as few as two genes (e.g. vtg1 and hspa5 [heat shock protein 5]) were sufficient to differentiate the five chemical/concentration groups in the present test. These observations suggest that multi-parameter arrays should be more reliable for biomonitoring of chemical exposure than traditional biomarkers, and the RD computational model provides an effective tool for the selection of parameters and generation of parameter sets. PMID- 24349564 TI - Early weight development of goats experimentally infected with Mycobacterium avium subsp. paratuberculosis. AB - Johne's disease is an infectious chronic inflammatory bowel disease in ruminants. The key factor for the management of this disease is an early positive diagnosis. Unfortunately, most diagnostics detect animals with Johne's disease in the clinical stage with positive serology and/or positive fecal cultures. However, for effective management of the disease within herds, it is important to detect infected animals as early as possible. This might only be possible with the help of parameters not specific for Johne's disease but that give an early indication for chronic infections such as weight development. Here we report our findings on the development of total body weight and weight gain during the first six months of goats experimentally infected to induce Johne's disease. Twenty dairy goat kids age 2 to 5 days were included in this study. Goats were divided into two groups: a negative control group and a positive infected group. The weight was obtained weekly throughout the study. Goats of the positive group were infected at the age of seven weeks. We detected significant changes in weight gain and total body weight as early as one week after infection. Differences are significant throughout the six month time period. Weight as a non-specific parameter should be used to monitor infection especially in studies on Johne's disease using the goat model. Our study suggests that goats with Johne's disease have a reduced weight gain and reduced weight when compared with healthy goats of the same age. PMID- 24349565 TI - Histopathological analysis of Salmonella chronic carriage in the mouse hepatopancreatobiliary system. AB - Salmonella Typhi asymptomatic chronic carriage represents a challenge for the diagnosis and prevention of typhoid fever in endemic areas. Such carriers are thought to be reservoirs for further spread of the disease. Gallbladder carriage has been demonstrated to be mediated by biofilm formation on gallstones and by intracellular persistence in the gallbladder epithelium of mice. In addition, both gallstones and chronic carriage have been associated with chronic inflammation and the development of gallbladder carcinoma. However, the pathogenic relationship between typhoid carriage and the development of pre malignant and/or malignant lesions in the hepatopancreatobiliary system as well as the host-pathogen interactions occurring during chronic carriage remains unclear. In this study, we monitored the histopathological features of chronic carriage up to 1 year post-infection. Chronic cholecystitis and hepatitis ranging from mild to severe were present in infected mice regardless of the presence of gallstones. Biliary epithelial hyperplasia was observed more commonly in the gallbladder of mice with gallstones (uninfected or infected). However, pre malignant lesions, atypical hyperplasia and metaplasia of the gallbladder and exocrine pancreas, respectively, were only associated with chronic Salmonella carriage. This study has implications regarding the role of Salmonella chronic infection and inflammation in the development of pre-malignant lesions in the epithelium of the gallbladder and pancreas that could lead to oncogenesis. PMID- 24349566 TI - Oral leucine supplementation is sensed by the brain but neither reduces food intake nor induces an anorectic pattern of gene expression in the hypothalamus. AB - Leucine activates the intracellular mammalian target of the rapamycin (mTOR) pathway, and hypothalamic mTOR signaling regulates food intake. Although central infusion of leucine reduces food intake, it is still uncertain whether oral leucine supplementation is able to affect the hypothalamic circuits that control energy balance. We observed increased phosphorylation of p70s6k in the mouse hypothalamus after an acute oral gavage of leucine. We then assessed whether acute oral gavage of leucine induces the activation of neurons in several hypothalamic nuclei and in the brainstem. Leucine did not induce the expression of Fos in hypothalamic nuclei, but it increased the number of Fos-immunoreactive neurons in the area postrema. In addition, oral gavage of leucine acutely increased the 24 h food intake of mice. Nonetheless, chronic leucine supplementation in the drinking water did not change the food intake and the weight gain of ob/ob mice and of wild-type mice consuming a low- or a high-fat diet. We assessed the hypothalamic gene expression and observed that leucine supplementation increased the expression of enzymes (BCAT1, BCAT2 and BCKDK) that metabolize branched-chain amino acids. Despite these effects, leucine supplementation did not induce an anorectic pattern of gene expression in the hypothalamus. In conclusion, our data show that the brain is able to sense oral leucine intake. However, the food intake is not modified by chronic oral leucine supplementation. These results question the possible efficacy of leucine supplementation as an appetite suppressant to treat obesity. PMID- 24349567 TI - Metamodels for transdisciplinary analysis of wildlife population dynamics. AB - Wildlife population models have been criticized for their narrow disciplinary perspective when analyzing complexity in coupled biological - physical - human systems. We describe a "metamodel" approach to species risk assessment when diverse threats act at different spatiotemporal scales, interact in non-linear ways, and are addressed by distinct disciplines. A metamodel links discrete, individual models that depict components of a complex system, governing the flow of information among models and the sequence of simulated events. Each model simulates processes specific to its disciplinary realm while being informed of changes in other metamodel components by accessing common descriptors of the system, populations, and individuals. Interactions among models are revealed as emergent properties of the system. We introduce a new metamodel platform, both to further explain key elements of the metamodel approach and as an example that we hope will facilitate the development of other platforms for implementing metamodels in population biology, species risk assessments, and conservation planning. We present two examples - one exploring the interactions of dispersal in metapopulations and the spread of infectious disease, the other examining predator-prey dynamics - to illustrate how metamodels can reveal complex processes and unexpected patterns when population dynamics are linked to additional extrinsic factors. Metamodels provide a flexible, extensible method for expanding population viability analyses beyond models of isolated population demographics into more complete representations of the external and intrinsic threats that must be understood and managed for species conservation. PMID- 24349568 TI - Mannitol enhances antibiotic sensitivity of persister bacteria in Pseudomonas aeruginosa biofilms. AB - The failure of antibiotic therapies to clear Pseudomonas aeruginosa lung infection, the key mortality factor for cystic fibrosis (CF) patients, is partly attributed to the high tolerance of P. aeruginosa biofilms. Mannitol has previously been found to restore aminoglycoside sensitivity in Escherichia coli by generating a proton-motive force (PMF), suggesting a potential new strategy to improve antibiotic therapy and reduce disease progression in CF. Here, we used the commonly prescribed aminoglycoside tobramycin to select for P. aeruginosa persister cells during biofilm growth. Incubation with mannitol (10-40 mM) increased tobramycin sensitivity of persister cells up to 1,000-fold. Addition of mannitol to pre-grown biofilms was able to revert the persister phenotype and improve the efficacy of tobramycin. This effect was blocked by the addition of a PMF inhibitor or in a P. aeruginosa mutant strain unable to metabolise mannitol. Addition of glucose and NaCl at high osmolarity also improved the efficacy of tobramycin although to a lesser extent compared to mannitol. Therefore, the primary effect of mannitol in reverting biofilm associated persister cells appears to be an active, physiological response, associated with a minor contribution of osmotic stress. Mannitol was tested against clinically relevant strains, showing that biofilms containing a subpopulation of persister cells are better killed in the presence of mannitol, but a clinical strain with a high resistance to tobramycin was not affected by mannitol. Overall, these results suggest that in addition to improvements in lung function by facilitating mucus clearance in CF, mannitol also affects antibiotic sensitivity in biofilms and does so through an active, physiological response. PMID- 24349569 TI - BOLD Granger causality reflects vascular anatomy. AB - A number of studies have tried to exploit subtle phase differences in BOLD time series to resolve the order of sequential activation of brain regions, or more generally the ability of signal in one region to predict subsequent signal in another region. More recently, such lag-based measures have been applied to investigate directed functional connectivity, although this application has been controversial. We attempted to use large publicly available datasets (FCON 1000, ADHD 200, Human Connectome Project) to determine whether consistent spatial patterns of Granger Causality are observed in typical fMRI data. For BOLD datasets from 1,240 typically developing subjects ages 7-40, we measured Granger causality between time series for every pair of 7,266 spherical ROIs covering the gray matter and 264 seed ROIs at hubs of the brain's functional network architecture. Granger causality estimates were strongly reproducible for connections in a test and replication sample (n=620 subjects for each group), as well as in data from a single subject scanned repeatedly, both during resting and passive video viewing. The same effect was even stronger in high temporal resolution fMRI data from the Human Connectome Project, and was observed independently in data collected during performance of 7 task paradigms. The spatial distribution of Granger causality reflected vascular anatomy with a progression from Granger causality sources, in Circle of Willis arterial inflow distributions, to sinks, near large venous vascular structures such as dural venous sinuses and at the periphery of the brain. Attempts to resolve BOLD phase differences with Granger causality should consider the possibility of reproducible vascular confounds, a problem that is independent of the known regional variability of the hemodynamic response. PMID- 24349571 TI - A case study in serendipity: environmental researchers use of traditional and social media for dissemination. AB - In the face of demands for researchers to engage more actively with a wider range of publics and to capture different kinds of research impacts and engagements, we explored the ways a small number of environmental researchers use traditional and social media to disseminate research. A questionnaire was developed to investigate the impact of different media as a tool to broker contact between researchers and a variety of different stakeholders (for example, publics, other researchers, policymakers, journalists) as well as how researchers perceive that their use of these media has changed over the past five years. The questionnaire was sent to 504 researchers whose work had featured in a policy-oriented e-news service. 149 valid responses were received (29%). Coverage in traditional media (newspapers, broadcast) not only brokers contact with other journalists, but is a good source of contact from other researchers (n=47, 62%) and members of the public (n=36, 26%). Although the use of social media was limited amongst our sample, it did broker contact with other researchers (n=17, 47%) and the public (n=10, 28%). Nevertheless, few environmental researchers were actively using social media to disseminate their research findings, with many continuing to rely on academic journals and face-to-face communication to reach both academic and public audiences. PMID- 24349570 TI - Human breast tumor cells are more resistant to cardiac glycoside toxicity than non-tumorigenic breast cells. AB - Cardiotonic steroids (CTS), specific inhibitors of Na,K-ATPase activity, have been widely used for treating cardiac insufficiency. Recent studies suggest that low levels of endogenous CTS do not inhibit Na,K-ATPase activity but play a role in regulating blood pressure, inducing cellular kinase activity, and promoting cell viability. Higher CTS concentrations inhibit Na,K-ATPase activity and can induce reactive oxygen species, growth arrest, and cell death. CTS are being considered as potential novel therapies in cancer treatment, as they have been shown to limit tumor cell growth. However, there is a lack of information on the relative toxicity of tumor cells and comparable non-tumor cells. We have investigated the effects of CTS compounds, ouabain, digitoxin, and bufalin, on cell growth and survival in cell lines exhibiting the full spectrum of non cancerous to malignant phenotypes. We show that CTS inhibit membrane Na,K-ATPase activity equally well in all cell lines tested regardless of metastatic potential. In contrast, the cellular responses to the drugs are different in non tumor and tumor cells. Ouabain causes greater inhibition of proliferation and more extensive apoptosis in non-tumor breast cells compared to malignant or oncogene-transfected cells. In tumor cells, the effects of ouabain are accompanied by activation of anti-apoptotic ERK1/2. However, ERK1/2 or Src inhibition does not sensitize tumor cells to CTS cytotoxicity, suggesting that other mechanisms provide protection to the tumor cells. Reduced CTS-sensitivity in breast tumor cells compared to non-tumor cells indicates that CTS are not good candidates as cancer therapies. PMID- 24349573 TI - High-aluminum-affinity silica is a nanoparticle that seeds secondary aluminosilicate formation. AB - Despite the importance and abundance of aluminosilicates throughout our natural surroundings, their formation at neutral pH is, surprisingly, a matter of considerable debate. From our experiments in dilute aluminum and silica containing solutions (pH ~ 7) we previously identified a silica polymer with an extraordinarily high affinity for aluminium ions (high-aluminum-affinity silica polymer, HSP). Here, further characterization shows that HSP is a colloid of approximately 2.4 nm in diameter with a mean specific surface area of about 1,000 m(2) g(-1) and it competes effectively with transferrin for Al(III) binding. Aluminum binding to HSP strongly inhibited its decomposition whilst the reaction rate constant for the formation of the beta-silicomolybdic acid complex indicated a diameter between 3.6 and 4.1 nm for these aluminum-containing nanoparticles. Similarly, high resolution microscopic analysis of the air dried aluminum containing silica colloid solution revealed 3.9 +/- 1.3 nm sized crystalline Al rich silica nanoparticles (ASP) with an estimated Al:Si ratio of between 2 and 3 which is close to the range of secondary aluminosilicates such as imogolite. Thus the high-aluminum-affinity silica polymer is a nanoparticle that seeds early aluminosilicate formation through highly competitive binding of Al(III) ions. In niche environments, especially in vivo, this may serve as an alternative mechanism to polyhydroxy Al(III) species binding monomeric silica to form early phase, non-toxic aluminosilicates. PMID- 24349572 TI - Double-strand break repair by interchromosomal recombination: an in vivo repair mechanism utilized by multiple somatic tissues in mammals. AB - Homologous recombination (HR) is essential for accurate genome duplication and maintenance of genome stability. In eukaryotes, chromosomal double strand breaks (DSBs) are central to HR during specialized developmental programs of meiosis and antigen receptor gene rearrangements, and form at unusual DNA structures and stalled replication forks. DSBs also result from exposure to ionizing radiation, reactive oxygen species, some anti-cancer agents, or inhibitors of topoisomerase II. Literature predicts that repair of such breaks normally will occur by non homologous end-joining (in G1), intrachromosomal HR (all phases), or sister chromatid HR (in S/G(2)). However, no in vivo model is in place to directly determine the potential for DSB repair in somatic cells of mammals to occur by HR between repeated sequences on heterologs (i.e., interchromosomal HR). To test this, we developed a mouse model with three transgenes-two nonfunctional green fluorescent protein (GFP) transgenes each containing a recognition site for the I SceI endonuclease, and a tetracycline-inducible I-SceI endonuclease transgene. If interchromosomal HR can be utilized for DSB repair in somatic cells, then I-SceI expression and induction of DSBs within the GFP reporters may result in a functional GFP+ gene. Strikingly, GFP+ recombinant cells were observed in multiple organs with highest numbers in thymus, kidney, and lung. Additionally, bone marrow cultures demonstrated interchromosomal HR within multiple hematopoietic subpopulations including multi-lineage colony forming unit granulocyte-erythrocyte-monocyte-megakaryocte (CFU-GEMM) colonies. This is a direct demonstration that somatic cells in vivo search genome-wide for homologous sequences suitable for DSB repair, and this type of repair can occur within early developmental populations capable of multi-lineage differentiation. PMID- 24349574 TI - A new theraphosid spider toxin causes early insect cell death by necrosis when expressed in vitro during recombinant baculovirus infection. AB - Baculoviruses are the most studied insect viruses in the world and are used for biological control of agricultural and forest insect pests. They are also used as versatile vectors for expression of heterologous proteins. One of the major problems of their use as biopesticides is their slow speed to kill insects. Thus, to address this shortcoming, insect-specific neurotoxins from arachnids have been introduced into the baculovirus genome solely aiming to improve its virulence. In this work, an insecticide-like toxin gene was obtained from a cDNA derived from the venom glands of the theraphosid spider Brachypelma albiceps. The mature form of the peptide toxin (called Ba3) has a high content of basic amino acid residues, potential for three possible disulfide bonds, and a predicted three stranded beta-sheetDifferent constructions of the gene were engineered for recombinant baculovirus Autographa californica multiple nuclepolyhedrovirus (AcMNPV) expression. Five different forms of Ba3 were assessed; (1) the full length sequence, (2) the pro-peptide and mature region, (3) only the mature region, and the mature region fused to an (4) insect or a (5) virus-derived signal peptide were inserted separately into the genome of the baculovirus. All the recombinant viruses induced cell death by necrosis earlier in infection relative to a control virus lacking the toxin gene. However, the recombinant virus containing the mature portion of the toxin gene induced a faster cell death than the other recombinants. We found that the toxin construct with the signal peptide and/or pro-peptide regions delayed the necrosis phenotype. When infected cells were subjected to ultrastructural analysis, the cells showed loss of plasma membrane integrity and structural changes in mitochondria before death. Our results suggest this use of baculovirus is a potential tool to help understand or to identify the effect of insect-specific toxic peptides when produced during infection of insect cells. PMID- 24349575 TI - Effect of metal oxide nanoparticles on microbial community structure and function in two different soil types. AB - Increased availability of nanoparticle-based products will, inevitably, expose the environment to these materials. Engineered nanoparticles (ENPs) may thus find their way into the soil environment via wastewater, dumpsters and other anthropogenic sources; metallic oxide nanoparticles comprise one group of ENPs that could potentially be hazardous for the environment. Because the soil bacterial community is a major service provider for the ecosystem and humankind, it is critical to study the effects of ENP exposure on soil bacteria. These effects were evaluated by measuring bacterial community activity, composition and size following exposure to copper oxide (CuO) and magnetite (Fe3O4) nanosized (<50 nm) particles. Two different soil types were examined: a sandy loam (Bet Dagan) and a sandy clay loam (Yatir), under two ENP concentrations (1%, 0.1%). Results indicate that the bacterial community in Bet-Dagan soil was more susceptible to change due to exposure to these ENPs, relative to Yatir soil. More specifically, CuO had a strong effect on bacterial hydrolytic activity, oxidative potential, community composition and size in Bet-Dagan soil. Few effects were noted in the Yatir soil, although 1% CuO exposure did cause a significant decreased oxidative potential and changes to community composition. Fe3O4 changed the hydrolytic activity and bacterial community composition in Bet-Dagan soil but did not affect the Yatir soil bacterial community. Furthermore, in Bet-Dagan soil, abundance of bacteria annotated to OTUs from the Bacilli class decreased after addition of 0.1% CuO but increased with 1% CuO, while in Yatir soil their abundance was reduced with 1% CuO. Other important soil bacterial groups, including Rhizobiales and Sphingobacteriaceae, were negatively affected by CuO addition to soil. These results indicate that both ENPs are potentially harmful to soil environments. Furthermore, it is suggested that the clay fraction and organic matter in different soils interact with the ENPs and reduce their toxicity. PMID- 24349576 TI - The role of historical barriers in the diversification processes in open vegetation formations during the Miocene/Pliocene using an ancient rodent lineage as a model. AB - The Neotropics harbors a high diversity of species and several hypotheses have been proposed to account for this pattern. However, while species of forested domains are frequently studied, less is known of species from open vegetation formations occupying, altogether, a larger area than the Amazon Forest. Here we evaluate the role of historical barriers and the riverine hypothesis in the speciation patterns of small mammals by analyzing an ancient rodent lineage (Thrichomys, Hystricomorpha). Phylogenetic and biogeographic analyses were carried out with mitochondrial and nuclear DNA markers to analyze the evolutionary relationships between Thrichomys lineages occurring in dry domains along both banks of the Rio Sao Francisco. This river is one of the longest of South America whose course and water flow have been modified by inland tectonic activities and climate changes. Molecular data showed a higher number of lineages than previously described. The T. inermis species complex with 2n = 26, FN = 48 was observed in both banks of the river showing a paraphyletic arrangement, suggesting that river crossing had occurred, from east to west. A similar pattern was also observed for the T. apereoides complex. Thrichomys speciation occurred in Late Miocene when the river followed a different course. The current geographic distribution of Thrichomys species and their phylogenetic relationships suggested the existence of frequent past connections between both banks in the middle section of the Rio Sao Francisco. The extensive palaeodune region found in this area has been identified as a centre of endemism of several vertebrate species and is likely to be a center of Thrichomys diversification. PMID- 24349585 TI - Two women presenting worsening cutaneous ulcers during pregnancy: diagnosis, immune response, and follow-up. PMID- 24349587 TI - MDGs and NTDs: reshaping the global health agenda. PMID- 24349586 TI - Laboratory-based prospective surveillance for community outbreaks of Shigella spp. in Argentina. AB - BACKGROUND: To implement effective control measures, timely outbreak detection is essential. Shigella is the most common cause of bacterial diarrhea in Argentina. Highly resistant clones of Shigella have emerged, and outbreaks have been recognized in closed settings and in whole communities. We hereby report our experience with an evolving, integrated, laboratory-based, near real-time surveillance system operating in six contiguous provinces of Argentina during April 2009 to March 2012. METHODOLOGY: To detect localized shigellosis outbreaks timely, we used the prospective space-time permutation scan statistic algorithm of SaTScan, embedded in WHONET software. Twenty three laboratories sent updated Shigella data on a weekly basis to the National Reference Laboratory. Cluster detection analysis was performed at several taxonomic levels: for all Shigella spp., for serotypes within species and for antimicrobial resistance phenotypes within species. Shigella isolates associated with statistically significant signals (clusters in time/space with recurrence interval >=365 days) were subtyped by pulsed field gel electrophoresis (PFGE) using PulseNet protocols. PRINCIPAL FINDINGS: In three years of active surveillance, our system detected 32 statistically significant events, 26 of them identified before hospital staff was aware of any unexpected increase in the number of Shigella isolates. Twenty-six signals were investigated by PFGE, which confirmed a close relationship among the isolates for 22 events (84.6%). Seven events were investigated epidemiologically, which revealed links among the patients. Seventeen events were found at the resistance profile level. The system detected events of public health importance: infrequent resistance profiles, long-lasting and/or re-emergent clusters and events important for their duration or size, which were reported to local public health authorities. CONCLUSIONS/SIGNIFICANCE: The WHONET-SaTScan system may serve as a model for surveillance and can be applied to other pathogens, implemented by other networks, and scaled up to national and international levels for early detection and control of outbreaks. PMID- 24349584 TI - Dengue research funded by the European Commission-scientific strategies of three European dengue research consortia. PMID- 24349588 TI - Venezuelan equine encephalitis viruses (VEEV) in Argentina: serological evidence of human infection. AB - Venezuelan equine encephalitis viruses (VEEV) are responsible for human diseases in the Americas, producing severe or mild illness with symptoms indistinguishable from dengue and other arboviral diseases. For this reason, many cases remain without certain diagnosis. Seroprevalence studies for VEEV subtypes IAB, ID, IF (Mosso das Pedras virus; MDPV), IV (Pixuna virus; PIXV) and VI (Rio Negro virus; RNV) were conducted in persons from Northern provinces of Argentina: Salta, Chaco and Corrientes, using plaque reduction neutralization test (PRNT). RNV was detected in all studied provinces. Chaco presented the highest prevalence of this virus (14.1%). Antibodies against VEEV IAB and -for the first time- against MDPV and PIXV were also detected in Chaco province. In Corrientes, seroprevalence against RNV was 1.3% in the pediatric population, indicating recent infections. In Salta, this was the first investigation of VEEV members, and antibodies against RNV and PIXV were detected. These results provide evidence of circulation of many VEE viruses in Northern Argentina, showing that surveillance of these infectious agents should be intensified. PMID- 24349589 TI - New insights into the molecular epidemiology and population genetics of Schistosoma mansoni in Ugandan pre-school children and mothers. AB - Significant numbers of pre-school children are infected with Schistosoma mansoni in sub-Saharan Africa and are likely to play a role in parasite transmission. However, they are currently excluded from control programmes. Molecular phylogenetic studies have provided insights into the evolutionary origins and transmission dynamics of S. mansoni, but there has been no research into schistosome molecular epidemiology in pre-school children. Here, we investigated the genetic diversity and population structure of S. mansoni in pre-school children and mothers living in lakeshore communities in Uganda and monitored for changes over time after praziquantel treatment. Parasites were sampled from children (<6 years) and mothers enrolled in the longitudinal Schistosomiasis Mothers and Infants Study at baseline and at 6-, 12- and 18-month follow-up surveys. 1347 parasites from 35 mothers and 45 children were genotyped by direct sequencing of the cytochrome c oxidase (cox1) gene. The cox1 region was highly diverse with over 230 unique sequences identified. Parasite populations were genetically differentiated between lakes and non-synonymous mutations were more diverse at Lake Victoria than Lake Albert. Surprisingly, parasite populations sampled from children showed a similar genetic diversity to those sampled from mothers, pointing towards a non-linear relationship between duration of exposure and accumulation of parasite diversity. The genetic diversity six months after praziquantel treatment was similar to pre-treatment diversity. Our results confirm the substantial genetic diversity of S. mansoni in East Africa and provide significant insights into transmission dynamics within young children and mothers, important information for schistosomiasis control programmes. PMID- 24349590 TI - Geographic variation in access to dog-bite care in Pakistan and risk of dog-bite exposure in Karachi: prospective surveillance using a low-cost mobile phone system. AB - BACKGROUND: Dog-bites and rabies are under-reported in developing countries such as Pakistan and there is a poor understanding of the disease burden. We prospectively collected data utilizing mobile phones for dog-bite and rabies surveillance across nine emergency rooms (ER) in Pakistan, recording patient health-seeking behaviors, access to care and analyzed spatial distribution of cases from Karachi. METHODOLOGY AND PRINCIPAL FINDINGS: A total of 6212 dog-bite cases were identified over two years starting in February 2009 with largest number reported from Karachi (59.7%), followed by Peshawar (13.1%) and Hyderabad (11.4%). Severity of dog-bites was assessed using the WHO classification. Forty percent of patients had Category I (least severe) bites, 28.1% had Category II bites and 31.9% had Category III (most severe bites). Patients visiting a large public hospital ER in Karachi were least likely to seek immediate healthcare at non-medical facilities (Odds Ratio = 0.20, 95% CI 0.17-0.23, p-value<0.01), and had shorter mean travel time to emergency rooms, adjusted for age and gender (32.78 min, 95% CI 31.82-33.78, p-value<0.01) than patients visiting hospitals in smaller cities. Spatial analysis of dog-bites in Karachi suggested clustering of cases (Moran's I = 0.02, p value<0.01), and increased risk of exposure in particular around Korangi and Malir that are adjacent to the city's largest abattoir in Landhi. The direct cost of operating the mHealth surveillance system was USD 7.15 per dog-bite case reported, or approximately USD 44,408 over two years. CONCLUSIONS: Our findings suggest significant differences in access to care and health-seeking behaviors in Pakistan following dog-bites. The distribution of cases in Karachi was suggestive of clustering of cases that could guide targeted disease-control efforts in the city. Mobile phone technologies for health (mHealth) allowed for the operation of a national-level disease reporting and surveillance system at a low cost. PMID- 24349591 TI - Polyfunctional T cell responses in children in early stages of chronic Trypanosoma cruzi infection contrast with monofunctional responses of long-term infected adults. AB - BACKGROUND: Adults with chronic Trypanosoma cruzi exhibit a poorly functional T cell compartment, characterized by monofunctional (IFN-gamma-only secreting) parasite-specific T cells and increased levels of terminally differentiated T cells. It is possible that persistent infection and/or sustained exposure to parasites antigens may lead to a progressive loss of function of the immune T cells. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis, the quality and magnitude of T. cruzi-specific T cell responses were evaluated in T. cruzi infected children and compared with long-term T. cruzi-infected adults with no evidence of heart failure. The phenotype of CD4(+) T cells was also assessed in T. cruzi-infected children and uninfected controls. Simultaneous secretion of IFN gamma and IL-2 measured by ELISPOT assays in response to T. cruzi antigens was prevalent among T. cruzi-infected children. Flow cytometric analysis of co expression profiles of CD4(+) T cells with the ability to produce IFN-gamma, TNF alpha, or to express the co-stimulatory molecule CD154 in response to T. cruzi showed polyfunctional T cell responses in most T. cruzi-infected children. Monofunctional T cell responses and an absence of CD4(+)TNF-alpha(+)-secreting T cells were observed in T. cruzi-infected adults. A relatively high degree of activation and differentiation of CD4(+) T cells was evident in T. cruzi-infected children. CONCLUSIONS/SIGNIFICANCE: Our observations are compatible with our initial hypothesis that persistent T. cruzi infection promotes eventual exhaustion of immune system, which might contribute to disease progression in long-term infected subjects. PMID- 24349592 TI - Ecology and geography of transmission of two bat-borne rabies lineages in Chile. AB - Rabies was known to humans as a disease thousands of years ago. In America, insectivorous bats are natural reservoirs of rabies virus. The bat species Tadarida brasiliensis and Lasiurus cinereus, with their respective, host-specific rabies virus variants AgV4 and AgV6, are the principal rabies reservoirs in Chile. However, little is known about the roles of bat species in the ecology and geographic distribution of the virus. This contribution aims to address a series of questions regarding the ecology of rabies transmission in Chile. Analyzing records from 1985-2011 at the Instituto de Salud Publica de Chile (ISP) and using ecological niche modeling, we address these questions to help in understanding rabies-bat ecological dynamics in South America. We found ecological niche identity between both hosts and both viral variants, indicating that niches of all actors in the system are undifferentiated, although the viruses do not necessarily occupy the full geographic distributions of their hosts. Bat species and rabies viruses share similar niches, and our models had significant predictive power even across unsampled regions; results thus suggest that outbreaks may occur under consistent, stable, and predictable circumstances. PMID- 24349593 TI - Community acceptance of tsetse control baits: a qualitative study in Arua District, North West Uganda. AB - BACKGROUND: There is renewed vigour in efforts to eliminate neglected tropical diseases including sleeping sickness (human African trypanosomiasis or HAT), including attempts to develop more cost-effective methods of tsetse control. In the West Nile region of Uganda, newly designed insecticide-treated targets are being deployed over an area of ~500 km(2). The operational area covers villages where tsetse control has not been conducted previously. The effectiveness of the targets will depend, in part, on their acceptance by the local community. METHODOLOGY/PRINCIPAL FINDINGS: We assessed knowledge, perceptions and acceptance of tsetse baits (traps, targets) in villages where they had or had not been used previously. We conducted sixteen focus group discussions with male and female participants in eight villages across Arua District. Discussions were audio recorded, translated and transcribed. We used thematic analysis to compare the views of both groups and identify salient themes. CONCLUSIONS/SIGNIFICANCE: Despite the villages being less than 10 km apart, community members perceived deployed baits very differently. Villagers who had never seen traps before expressed fear, anxiety and panic when they first encountered them. This was related to associations with witchcraft and "ghosts from the river" which are traditionally linked with physical or mental illness, death and misfortune. By contrast, villagers living in areas where traps had been used previously had positive attitudes towards them and were fully aware of their purpose and benefits. The latter group reported that they had similar negative perceptions when tsetse control interventions first started a decade ago. Our results suggest that despite their proximity, acceptance of traps varies markedly between villages and this is related to the duration of experience with tsetse control programs. The success of community-based interventions against tsetse will therefore depend on early engagements with communities and carefully designed sensitization campaigns that reach all communities, especially those living in areas new to such interventions. PMID- 24349594 TI - Cutaneous distribution and circadian rhythm of Onchocerca lupi microfilariae in dogs. AB - BACKGROUND: Among the arthropod-borne nematodes infesting dogs, Onchocerca lupi (Spirurida: Onchocercidae) is of increasing zoonotic concern, with new human cases of infection diagnosed in Turkey, Tunisia, Iran and the USA. Knowledge of the biology of this nematode is meagre. This study aimed at assessing the distribution and periodicity of O. lupi microfilariae from different body regions in naturally infested dogs. METHODOLOGY/PRINCIPAL FINDINGS: Skin samples were collected from six dogs infested with O. lupi but without apparent clinical signs. Two skin samples were collected from 18 anatomical regions of dog 1 at necropsy. In addition, single skin biopsies were performed from the forehead, inter-scapular and lumbar regions of dogs 2-6, in the morning, afternoon, and at night. Two aliquots of the sediment of each sample were microscopically observed, microfilariae counted and morphologically and molecularly identified. Most of the 1,667 microfilariae retrieved from dog 1 were in the right ear (59.6%), nose (26.5%), left ear (6.7%), forehead (3.0%), and inter-scapular (2.9%) regions. In dogs 2-6, the overall mean number of microfilariae was larger on the head (n = 122.8), followed by the inter-scapular (n = 119.0) and lumbar (n = 12.8) regions. The overall mean number of microfilariae was larger in the afternoon (153.4), followed by night (75.4) and morning (25.8). CONCLUSIONS: Onchocerca lupi microfilariae were more common in the head (i.e., ears and nose) than in the remaining part of the dog's body, indicating they tend to aggregate in specific body regions, which are the best sites to collect skin samples for diagnostic purposes. The periodicity pattern of microfilariae of O. lupi and their concentration in specific body regions is most likely a result of the co evolution with their as-yet-unknown vector. The detection of skin microfilariae in asymptomatic animals, suggests the potential role of these animals as carriers and reservoirs of O. lupi. PMID- 24349595 TI - Impact of six rounds of mass drug administration on Brugian filariasis and soil transmitted helminth infections in eastern Indonesia. AB - BACKGROUND: The lymphatic filarial parasite Brugia timori occurs only in eastern Indonesia where it causes high morbidity. The absence of an animal reservoir, the inefficient transmission by Anopheles mosquitoes and the high sensitivity to DEC/albendazole treatment make this species a prime candidate for elimination by mass drug administration (MDA). METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the effect of MDA using DEC and albendazole on B. timori and soil transmitted helminths (STH) in a cross-sectional study of a sentinel village on Alor Island annually over a period of 10 years. Pre-MDA the microfilaria (MF) prevalence was 26% and 80% of the residents had filaria-specific IgG4 antibodies. In 2010, 34 months after the 6(th) round of MDA, MF and antibody rates were only 0.17% and 6.4%, respectively. The MDA campaign had also a beneficial effect on STH. Baseline prevalence rates for Ascaris, hookworm and Trichuris were 34%, 28%, and 11%, respectively; these rates were reduced to 27%, 4%, and 2% one year after the 5(th) round of MDA. Unfortunately, STH rates rebounded 34 months after cessation of MDA and approached pre-MDA rates. However, the intensity of STH infection in 2009 was still reduced, and no heavy infections were detected. CONCLUSIONS/SIGNIFICANCE: MDA with DEC/albendazole has had a major impact on B. timori MF and IgG4 antibody rates, providing a proof of principle that elimination is feasible. We also documented the value of annual DEC/albendazole as a mass de-worming intervention and the importance of continuing some form of STH control after cessation of MDA for filariasis. PMID- 24349596 TI - Temporal patterns of abundance of Aedes aegypti and Aedes albopictus (Diptera: Culicidae) and mitochondrial DNA analysis of Ae. albopictus in the Central African Republic. AB - The invasive Asian tiger mosquito Aedes albopictus (Diptera: Culicidae) was first reported in central Africa in 2000, in Cameroon, with the indigenous mosquito species Ae. aegypti (Diptera: Culicidae). Today, this invasive species is present in almost all countries of the region, including the Central African Republic (CAR), where it was first recorded in 2009. As invasive species of mosquitoes can affect the distribution of native species, resulting in new patterns of vectors and concomitant risk for disease, we undertook a comparative study early and late in the wet season in the capital and the main cities of CAR to document infestation and the ecological preferences of the two species. In addition, we determined the probable geographical origin of invasive populations of Ae. albopictus with two mitochondrial DNA genes, COI and ND5. Analysis revealed that Ae. aegypti was more abundant earlier in the wet season and Ae. albopictus in the late wet season. Used tyres were the most heavily colonized productive larval habitats for both species in both seasons. The invasive species Ae. albopictus predominated over the resident species at all sites in which the two species were sympatric. Mitochondrial DNA analysis revealed broad low genetic diversity, confirming recent introduction of Ae. albopictus in CAR. Phylogeographical analysis based on COI polymorphism indicated that the Ae. albopictus haplotype in the CAR population segregated into two lineages, suggesting multiple sources of Ae. albopictus. These data may have important implications for vector control strategies in central Africa. PMID- 24349598 TI - Corticosteroids for dengue - why don't they work? AB - BACKGROUND: Dysregulated immune responses may contribute to the clinical complications that occur in some patients with dengue. FINDINGS: In Vietnamese pediatric dengue cases randomized to early prednisolone therapy, 81 gene transcripts (0.2% of the 47,231 evaluated) were differentially abundant in whole blood between high-dose (2 mg/kg) prednisolone and placebo-treated patients two days after commencing therapy. Prominent among the 81 transcripts were those associated with T and NK cell cytolytic functions. Additionally, prednisolone therapy was not associated with changes in plasma cytokine levels. CONCLUSION: The inability of prednisolone treatment to markedly attenuate the host immune response is instructive for planning future therapeutic strategies for dengue. PMID- 24349597 TI - Private selective sweeps identified from next-generation pool-sequencing reveal convergent pathways under selection in two inbred Schistosoma mansoni strains. AB - BACKGROUND: The trematode flatworms of the genus Schistosoma, the causative agents of schistosomiasis, are among the most prevalent parasites in humans, affecting more than 200 million people worldwide. In this study, we focused on two well-characterized strains of S. mansoni, to explore signatures of selection. Both strains are highly inbred and exhibit differences in life history traits, in particular in their compatibility with the intermediate host Biomphalaria glabrata. METHODOLOGY/PRINCIPAL FINDINGS: We performed high throughput sequencing of DNA from pools of individuals of each strain using Illumina technology and identified single nucleotide polymorphisms (SNP) and copy number variations (CNV). In total, 708,898 SNPs were identified and roughly 2,000 CNVs. The SNPs revealed low nucleotide diversity (pi = 2 * 10(-4)) within each strain and a high differentiation level (Fst = 0.73) between them. Based on a recently developed in silico approach, we further detected 12 and 19 private (i.e. specific non overlapping) selective sweeps among the 121 and 151 sweeps found in total for each strain. CONCLUSIONS/SIGNIFICANCE: Functional annotation of transcripts lying in the private selective sweeps revealed specific selection for functions related to parasitic interaction (e.g. cell-cell adhesion or redox reactions). Despite high differentiation between strains, we identified evolutionary convergence of genes related to proteolysis, known as a key virulence factor and a potential target of drug and vaccine development. Our data show that pool-sequencing can be used for the detection of selective sweeps in parasite populations and enables one to identify biological functions under selection. PMID- 24349599 TI - Comparative clinical study of different multiplex real time PCR strategies for the simultaneous differential diagnosis between extrapulmonary tuberculosis and focal complications of brucellosis. AB - BACKGROUND: Both brucellosis and tuberculosis are chronic-debilitating systemic granulomatous diseases with a high incidence in many countries in Africa, Central and South America, the Middle East and the Indian subcontinent. Certain focal complications of brucellosis and extrapulmonary tuberculosis are very difficult to differentiate clinically, biologically and radiologically. As the conventional microbiological methods for the diagnosis of the two diseases have many limitations, as well as being time-consuming, multiplex real time PCR (M RT-PCR) could be a promising and practical approach to hasten the differential diagnosis and improve prognosis. METHODOLOGY/PRINCIPAL FINDINGS: We designed a SYBR Green single-tube multiplex real-time PCR protocol targeting bcsp31 and the IS711 sequence detecting all pathogenic species and biovars of Brucella genus, the IS6110 sequence detecting Mycobacterium genus, and the intergenic region senX3 regX3 specifically detecting Mycobacterium tuberculosis complex. The diagnostic yield of the M RT-PCR with the three pairs of resultant amplicons was then analyzed in 91 clinical samples corresponding to 30 patients with focal complications of brucellosis, 24 patients with extrapulmonary tuberculosis, and 36 patients (Control Group) with different infectious, autoimmune or neoplastic diseases. Thirty-five patients had vertebral osteomyelitis, 21 subacute or chronic meningitis or meningoencephalitis, 13 liver or splenic abscess, eight orchiepididymitis, seven subacute or chronic arthritis, and the remaining seven samples were from different locations. Of the three pairs of amplicons (senX3 regX3+ bcsp3, senX3-regX3+ IS711 and IS6110+ IS711) only senX3-regX3+ IS711 was 100% specific for both the Brucella genus and M. tuberculosis complex. For all the clinical samples studied, the overall sensitivity, specificity, and positive and negative predictive values of the M RT-PCR assay were 89.1%, 100%, 85.7% and 100%, respectively, with an accuracy of 93.4%, (95% CI, 88.3-96.5%). CONCLUSIONS/SIGNIFICANCE: In this study, a M RT-PCR strategy with species specific primers based on senX3-regX3+IS711 sequences proved to be a sensitive and specific test, useful for the highly efficient detection of M. tuberculosis and Brucella spp in very different clinical samples. It thus represents an advance in the differential diagnosis between some forms of extrapulmonary tuberculosis and focal complications of brucellosis. PMID- 24349601 TI - Genes, Economics, and Happiness. AB - We explore the influence of genetic variation on subjective well-being by employing a twin design and genetic association study. In a nationally representative twin sample, we first show that about 33% of the variation in life satisfaction is explained by genetic variation. Although previous studies have shown that baseline happiness is significantly heritable, little research has considered molecular genetic associations with subjective well-being. We study the relationship between a functional polymorphism on the serotonin transporter gene (5-HTTLPR) and life satisfaction. We initially find that individuals with the longer, transcriptionally more efficient variant of this genotype report greater life satisfaction (n=2,545, p=0.012). However, our replication attempts on independent samples produce mixed results indicating that more work needs to be done to better understand the relationship between this genotype and subjective well-being. This work has implications for how economists think about the determinants of utility, and the extent to which exogenous shocks might affect individual well-being. PMID- 24349602 TI - Prevention of early-term deliveries: much ado about nothing? PMID- 24349603 TI - Multicystic dysplastic kidney complicated by pyelonephritis. AB - PATIENT: Female, 21 FINAL DIAGNOSIS: Multicystic Dysplastic Kidney Disease complicated by pyelonephritis Symptoms: Left flank pain (CVAT) * dysuria * fever MEDICATION: Levofloxacin Clinical Procedure: Dimercaptosuccinic acid scan * voiding cystouretrogram Specialty: Nephrology. OBJECTIVE: Rare disease. BACKGROUND: Multicystic dysplastic kidney (MCDK) is a renal dysplasia characterized by the presence of multiple cysts that are non-communicating, separated by dysplastic parenchyma that consumes the renal cortex resulting in a nonfunctional kidney. MCDK has an incidence of 1: 4300 of live births and is usually unilateral, most commonly occurring in the left kidney. Simple MCDK is defined as unilateral dysplasia with a normal contralateral kidney but with compensatory hypertrophy of the contralateral kidney, and no associated genitourinary anomalies. CASE REPORT: A 21 year old Hispanic American female, presented with intermittent, sharp, severe left flank pain, fever and dysuria for two days but had gradually worsened within the last 24 hours prior to presentation. Previous history of multicystic dysplastic kidney, diagnosed four years ago. No pertinent physical examination findings except left costovertebral angle tenderness (CVAT). Urinalysis findings were positive for infection and urine culture grew pan sensitive Escherichia coli. A CT scan of abdominal and pelvis without contrast revealed a normal right kidney and left kidney had multiple non-communicating dilated cystic spaces, but no hydronephrosis, left ureteropelvic junction obstruction and finding were consistent with multicystic dysplastic kidney and also noted perinephric stranding. CONCLUSIONS: VUR is the most common renal abnormality in patients with MCDK, occurring in about 25% of contralateral kidney. Infections involving the MCDK are rare. In fact, cases of infections such as pyelonephritis or an infected renal cyst of MCDK are almost non-existent in the current literature. This patient presented with findings consistent with MCDK complicated by pyelonephritis. PMID- 24349604 TI - Solitary paraganglioma of the hypoglossal nerve: A case report with magnetic resonance imaging findings. AB - PATIENT: Female, 58 FINAL DIAGNOSIS: Solitary paraganglioma of the hypoglossal nerve Symptoms: Neck pain Medication: - Clinical Procedure: Surgical resection Specialty: Otolaryngology. OBJECTIVE: Rare disease. BACKGROUND: Paragangliomas are rare neuroendocrine tumors originating in the neural crest. Only a few cases of hypoglossal paraganglioma have been reported in the published literature. The localization of hypoglossal paragangliomas close to the carotid artery precludes determination of tumor origin preoperatively. CASE REPORT: A 58-year-old female patient was admitted due to neck pain. During physical examination, a significant mass could not be palpated in the upper left part of the neck, despite sensitivity during palpation. Atrophy and left deviation of the left half of the tongue was observed. MRI of the neck revealed a lesion located superior to the carotid bifurcation between the left internal carotid artery and external carotid artery. There was atrophy in the left half of the tongue. The neck mass displaced the left internal carotid artery anteriorly and medially. The operation was performed with left lateral cervical access. This lesion, which derived from the hypoglossal nerve, was excised. Following histopathological evaluation, the lesion was diagnosed as paraganglioma. CONCLUSIONS: Hypoglossal paraganglioma is quite rare and there are no established criteria for preoperative diagnosis. Hypoglossal paraganglioma must be considered to determine treatment options if a lateral neck mass and ipsilateral tongue atrophy are present at the level of the 12th cranial nerve tract. PMID- 24349605 TI - Diffuse large B-cell lymphoma: A metabolic disorder? AB - Patient Male, 81 FINAL DIAGNOSIS: Non-Hodgkin lymphoma Symptoms: General weakness * hypoglycemia * metabolic acidosis MEDICATION: - Clinical Procedure: - Specialty: Hematology. OBJECTIVE: Challenging differential diagnosis. BACKGROUND: B cell lymphoma constitutes 80-85% of cases of Non Hodgkin's lymphoma in the Untied States. Metabolic complications may arise from the disease itself or through its end organ involvement. CASE REPORT: We describe a case of a diffuse large B cell lymphoma diagnosed by abdominal computed tomography after it initially presented as hypoglycemia not correctable by dextrose infusion that instead resulted in increased anion gap metabolic acidosis with elevated lactate levels. CONCLUSIONS: The case illustrates how lymphomas can present unusually with hypoglycemia and lactic acidosis, the latter being an ominous sign that can occur without liver involvement. In this regard, the case demonstrates the metabolic sequelae of lymphoma that should raise suspicion for an underlying process. This has implications for diagnosis, treatment, and patient survival. Attention should be paid especially in the primary care setting in order to minimize delays in diagnosis. PMID- 24349606 TI - Esophageal perforation post pneumatic dilatation for achalasia managed by esophageal stenting. AB - PATIENT: Female, 82 FINAL DIAGNOSIS: Achalasia Symptoms: Nocturnal regurgtation * weight loss MEDICATION: - Clinical Procedure: Esophageal stenting Specialty: Gastroenterology * Hepatology Objective: Unusual or unexpected effect of treatment. BACKGROUND: Pneumatic dilatation is one of the most effective methods for treating achalasia. Esophageal perforation is the most serious complication after pneumatic dilatation and has been reported to occur in the range of 1 to 4.3%. The appropriate management of esophageal perforation can range from conservative medical treatment to surgical intervention. CASE REPORT: We report a case of an 82-year-old male who had an 8 month history of dysphagia for solid and liquids, a 10 lb weight loss and nocturnal regurgitation. The diagnosis of achalasia was established by endoscopic; barium and manometric criteria. He underwent a pneumatic dilation with a 30 mm Rigiflex balloon. A confined or limited esophageal perforation projecting into the mediastinum and located 1-2 cm above the diaphragm was confirmed by a gastrografin swallow study performed immediately after the procedure. There was some accompanying epigastric abdominal pain. PATIENT was treated later that day by placing a fully covered metallic esophageal stent in addition to antibiotics, proton pump inhibitor, and fasting. PATIENT was discharged home 3 days later able to eat liquid-soft foods. Follow up endoscopy 2 weeks later and a gastrografin swallow showed a completely healed perforation and the stent was removed. Symptomatically he has done well, with no dysphagia or heartburn at six and twelve months follow up. CONCLUSIONS: Early esophageal stenting for esophageal perforation after pneumatic dilation for achalasia is a treatment option which accelerates healing shortens recovery period, as well as decreasing hospital stay and costs. PMID- 24349607 TI - The role of the actin cortex in maintaining cell shape. AB - Considering that the plasma membrane is host to a variety of mechanical cues in vivo, and the actin cortex is known to support cell shape, it comes as no surprise that the paired membrane-cortex plays a major role in cellular responses to deformation. In a recent study, we applied highly localized forces to HeLa cells in order to examine the deformation response of the membrane and cortex. Direct visualization of the deformation in the loading plane allowed for the characterization of the observed time-dependent strain. Despite large magnitude and long duration loading regimes, the majority of cells recovered their initial pre-deformed morphology within ~2 min. Unexpectedly, perturbed regions above large-volume nuclei were shown to be quite soft and had negligible influence on morphological recovery. The resistance to deformation and ability to recover was found to be largely influenced by the actin network, and dependent upon rho kinase mediated contractility. PMID- 24349608 TI - Study of possible mechanisms involved in the inhibitory effects of coumarin derivatives on neutrophil activity. AB - To specify the site of action of the synthetic coumarin derivatives 7-hydroxy-3 (4'-hydroxyphenyl) coumarin (HHC) and 7-hydroxy-3-(4'-hydroxyphenyl) dihydrocoumarin (HHDC), we evaluated their effects on extra- and intracellular reactive oxygen species (ROS) formation in phorbol-myristate-13-acetate (PMA) stimulated human neutrophils. We studied also the effects of HHC and HHDC on possible molecular mechanisms which participate in the activation of NADPH oxidase, that is, on PKC activity, on phosphorylation of some PKC isoforms (alpha, betaII, and delta), and on phosphorylation of the NADPH oxidase subunit p40(phox). Without affecting cytotoxicity, both coumarines tested were effective inhibitors/scavengers of ROS produced by neutrophils on extracellular level. HHC markedly diminished oxidant production and also, intracellularly, decreased PKC activity and partly phosphorylation of PKCalpha, betaII. On the other hand, we did not observe any effect of coumarin derivatives on phosphorylation of PKC delta and on phosphorylation of the NADPH oxidase subunit p40(phox), which were suggested to be involved in the PMA-dependent intracellular activation process. In agreement with our previous findings, we assume that the different molecular structures of HHC and HHDC with their different physicochemical and free radical scavenging characteristics are responsible for their diverse effects on the parameters tested. PMID- 24349609 TI - Carbon monoxide attenuates dextran sulfate sodium-induced colitis via inhibition of GSK-3beta signaling. AB - Endogenous carbon monoxide (CO) is produced by heme oxygenase-1 (HO)-1 which mediates the degradation of heme into CO, iron, and biliverdin. Also, CO ameliorates the human inflammatory bowel diseases and ulcerative colitis. However, the mechanism for the effect of CO on the inflammatory bowel disease has not yet been known. In this study, we showed that CO significantly increases survival percentage, body weight, colon length as well as histologic parameters in DSS-treated mice. In addition, CO inhalation significantly decreased DSS induced pro-inflammatory cytokines by inhibition of GSK-3beta in mice model. To support the in vivo observation, TNF-alpha, iNOS and IL-10 after CO and LiCl treatment were measured in mesenteric lymph node cells (MLNs) and bone marrow derived macrophages (BMMs) from DSS treated mice. In addition, we determined that CO potentially inhibited GSK-3beta activation and decreased TNF-alpha and iNOS expression by inhibition of NF-kappaB activation in LPS-stimulated U937 and MLN cells pretreated with CO. Together, our findings indicate that CO attenuates DSS induced colitis via inhibition of GSK-3beta signaling in vitro and in vivo. Importantly, this is the first report that investigated the molecular mechanisms mediated the novel effects of CO via inhibition GSK-3beta in DSS-induced colitis model. PMID- 24349610 TI - Accelerated aging in major depression: the role of nitro-oxidative stress. AB - Nitro-oxidative stress (NOS) plays a fundamental role in aging, as well as in the pathogenesis of neurodegenerative disorders, and major depression (MD). The latter is a very frequent psychiatric illness characterized by accelerated aging, neurodegeneration, high comorbidity with age-related disorders, and premature mortality; all of these conditions find an explanation in an altered redox homeostasis. If aging, neurodegeneration, and major depression share a common biological base in their pathophysiology, common therapeutic tools could be investigated for the prevention and treatment of these disorders. As an example, antidepressants have been demonstrated to present neuroprotective and anti inflammatory properties and to stimulate neurogenesis. In parallel, antioxidants that stimulate the antioxidant defense systems and interact with the monoaminergic system show an antidepressant-like activity. Further research on this topic could lead, in the near future, to the expansion of the therapeutic possibilities for the treatment of NOS-related disorders. PMID- 24349611 TI - Is the oxidative DNA damage level of human lymphocyte correlated with the antioxidant capacity of serum or the base excision repair activity of lymphocyte? AB - A random screening of human blood samples from 24 individuals of nonsmoker was conducted to examine the correlation between the oxidative DNA damage level of lymphocytes and the antioxidant capacity of serum or the base excision repair (BER) activity of lymphocytes. The oxidative DNA damage level was measured with comet assay containing Fpg/Endo III cleavage, and the BER activity was estimated with a modified comet assay including nuclear extract of lymphocytes for enzymatic cleavage. Antioxidant capacity was determined with trolox equivalent antioxidant capacity assay. We found that though the endogenous DNA oxidation levels varied among the individuals, each individual level appeared to be steady for at least 1 month. Our results indicate that the oxidative DNA damage level is insignificantly or weakly correlated with antioxidant capacity or BER activity, respectively. However, lymphocytes from carriers of Helicobacter pylori (HP) or Hepatitis B virus (HBV) tend to give higher levels of oxidative DNA damage (P < 0.05). Though sera of this group of individuals show no particular tendency with reduced antioxidant capacity, the respective BER activities of lymphocytes are lower in average (P < 0.05). Thus, reduction of repair activity may be associated with the genotoxic effect of HP or HBV infection. PMID- 24349612 TI - The influence of long term hydrochlorothiazide administration on the relationship between renin-angiotensin-aldosterone system activity and plasma glucose in patients with hypertension. AB - OBJECTIVE: To observe the relationship between changes in renin-angiotensin aldosterone system (RAAS) activity and blood plasma glucose after administration of hydrochlorothiazide (HCTZ) for one year in patients with hypertension. METHODS: 108 hypertensive patients were given 12.5 mg HCTZ per day for one year. RAAS activity, plasma glucose levels, and other biochemical parameters, as well as plasma oxidized low density lipoprotein (oxLDL) levels, were measured and analyzed at baseline, six weeks, and one year after treatment. RESULTS: After one year of treatment, the reduction in plasma glucose observed between the elevated plasma renin activity (PRA) group (-0.26 +/- 0.26 mmol/L) and the nonelevated PRA group (-1.36 +/- 0.23 mmol/L) was statistically significant (P < 0.05). The decrease of plasma glucose in the elevated Ang II group (-0.17 +/- 0.18 mmol/L) compared to the nonelevated Ang II group (-1.07 +/- 0.21 mmol/L) was statistically significant (P < 0.05). The proportion of patients with elevated plasma glucose in the elevated Ang II group (40.5%) was significantly higher than those in the nonelevated Ang II group (16.3%) (P < 0.05). The relative oxLDL level was not affected by the treatment. CONCLUSIONS: Changes in RAAS activity were correlated with changes in plasma glucose levels after one year of HCTZ therapy. PMID- 24349613 TI - Rosmarinic acid-rich extracts of summer savory (Satureja hortensis L.) protect Jurkat T cells against oxidative stress. AB - Summer savory (Satureja hortensis L., Lamiaceae) is used in several regions of the world as a spice and folk medicine. Anti-inflammatory and cytoprotective effects of S. hortensis and of its rosmarinic acid-rich phenolic fraction have been demonstrated in animal trials. However, previous studies of rosmarinic acid in cell models have yielded controversial results. In this study, we investigated the effects of summer savory extracts on H2O2-challenged human lymphoblastoid Jurkat T cells. LC-MS analysis confirmed the presence of rosmarinic acid and flavonoids such as hesperidin and naringin in the phenolic fraction. Adding 25 or 50 uM of H2O2 to the cell culture caused oxidative stress, manifested as generation of superoxide and peroxyl radicals, reduced cell viability, G0/G1 arrest, and enhanced apoptosis. This stress was significantly alleviated by the ethanolic and aqueous extracts of S. hortensis and by the partially purified rosmarinic acid fraction. The application of an aqueous S. hortensis extract doubled the activity of catalase and superoxide dismutase in the cells. The production of IL-2 and IL-10 interleukins was stimulated by H2O2 and was further enhanced by the addition of the S. hortensis extract or rosmarinic acid fraction. The H2O2-challenged Jurkat cells may serve as a model for investigating cellular mechanisms of cytoprotective phytonutrient effects. PMID- 24349614 TI - Tetrahydroxystilbene glucoside attenuates neuroinflammation through the inhibition of microglia activation. AB - Neuroinflammation is closely implicated in the pathogenesis of neurological diseases. The hallmark of neuroinflammation is the microglia activation. Upon activation, microglia are capable of producing various proinflammatory factors and the accumulation of these factors contribute to the neuronal damage. Therefore, inhibition of microglia-mediated neuroinflammation might hold potential therapy for neurological disorders. 2,3,5,4'-Tetrahydroxystilbene-2-O beta-D-glucoside (TSG), an active component extracted from Polygonum multiflorum, is reported to be beneficial for human health with a great number of pharmacological properties including antioxidant, free radical-scavenging, anti inflammation, antilipemia, and cardioprotective effects. Recently, TSG-mediated neuroprotective effects have been well demonstrated. However, the neuroprotective actions of TSG on microglia-induced neuroinflammation are not known. In the present study, microglia BV2 cell lines were applied to investigate the anti neuroinflammatory effects of TSG. Results showed that TSG reduced LPS-induced microglia-derived release of proinflammatory factors such as TNFalpha, IL-1beta, and NO. Moreover, TSG attenuated LPS-induced NADPH oxidase activation and subsequent reactive oxygen species (ROS) production. Further studies indicated that TSG inhibited LPS-induced NF-kappaB signaling pathway activation. Together, TSG exerted neuroprotection against microglia-mediated neuroinflammation, suggesting that TSG might present a promising benefit for neurological disorders treatment. PMID- 24349615 TI - Reversal of myoblast aging by tocotrienol rich fraction posttreatment. AB - Skeletal muscle satellite cells are heavily involved in the regeneration of skeletal muscle in response to the aging-related deterioration of the skeletal muscle mass, strength, and regenerative capacity, termed as sarcopenia. This study focused on the effect of tocotrienol rich fraction (TRF) on regenerative capacity of myoblasts in stress-induced premature senescence (SIPS). The myoblasts was grouped as young control, SIPS-induced, TRF control, TRF pretreatment, and TRF posttreatment. Optimum dose of TRF, morphological observation, activity of senescence-associated beta-galactosidase (SA-beta galactosidase), and cell proliferation were determined. 50 MUg/mL TRF treatment exhibited the highest cell proliferation capacity. SIPS-induced myoblasts exhibit large flattened cells and prominent intermediate filaments (senescent-like morphology). The activity of SA-beta-galactosidase was significantly increased, but the proliferation capacity was significantly reduced as compared to young control. The activity of SA-beta-galactosidase was significantly reduced and cell proliferation was significantly increased in the posttreatment group whereas there was no significant difference in SA-beta-galactosidase activity and proliferation capacity of pretreatment group as compared to SIPS-induced myoblasts. Based on the data, we hypothesized that TRF may reverse the myoblasts aging through replenishing the regenerative capacity of the cells. However, further investigation on the mechanism of TRF in reversing the myoblast aging is needed. PMID- 24349616 TI - Protective role of melatonin in neonatal diseases. AB - Oxidative stress contributes to the severity of several newborn conditions to the extent that Saugstad coined the phrase "oxygen radical diseases of neonatology." In order to counteract free radicals damage many strategies to augment antioxidant status in ill-term and preterm infants have been proposed and several medications have been experimented with mixed results. Several studies have tested the efficacy of melatonin to counteract oxidative damage in diseases of newborns such as chronic lung disease, perinatal brain injury, necrotizing enterocolitis, and retinopathy of prematurity, giving promising results. The peculiar perinatal susceptibility to oxidative stress indicates that prophylactic use of antioxidants as melatonin could help to prevent or at least reduce oxidative stress related diseases in newborns. However, more studies are needed to confirm these beneficial effects. PMID- 24349617 TI - Histone lysine demethylase (KDM) subfamily 4: structures, functions and therapeutic potential. AB - KDM4 histone demethylases catalyze the removal of methyl marks from histone lysine residues to epigenetically regulate chromatin structure and gene expression. KDM4 expression is tightly regulated to insure proper function in diverse biological processes, such as cellular differentiation. Mounting evidence has shown that disrupting KDM4 expression is implicated in the establishment and progression of multiple diseases including cancer. In particular, genomic regions encoding the KDM4A, B and C genes are often amplified, disrupting normal cellular proliferation. Furthermore, KDM4 demethylases are promising druggable targets. In this review, we highlight the latest advances in characterizing the structures and regulatory mechanisms of KDM4 proteins, as well as our current understanding of their alterations and roles in tumorigenesis. We also review the reported KDM4 inhibitors and discuss their potential as therapeutic agents. PMID- 24349618 TI - Psoriasis and cardiovascular risk factors: increased serum myeloperoxidase and corresponding immunocellular overexpression by Cd11b(+) CD68(+) macrophages in skin lesions. AB - BACKGROUND: Recent studies report independent associations between psoriasis, cardiovascular (CV) events and risk factors. Blood Myeloperoxidase (MPO) from activated myeloid cells is associated with CV risk mainly through lipid oxidation, induction of endothelial dysfunction and release of IL-12 from macrophages. OBJECTIVES: To elucidate associations between psoriasis and conventional CV risk factors. METHODS: We performed a cross-sectional study of 100 psoriasis patients and 53 controls, group matched on age, gender and body mass index, to assess levels of MPO in serum, as well as immunohistochemical staining from psoriasis skin lesions, psoriasis uninvolved skin, and normal skin. RESULTS: Although the groups did not differ on waist circumference, glucose, cholesterol, triglycerides, creatinine or personal history of CV events, psoriasis patients had significantly higher waist-to-hip ratios, blood pressures, proportion of current smokers, and lower high density lipoprotein level than controls. Serum MPO level was elevated 2.5 fold (P<0.001) in psoriasis patients, even after adjusting for the CV risk factors on which the groups differed. MPO did correlate with coronary artery calcification, carotid plaque, carotid intima media thickness and flow mediated dilation, but did not correlate with psoriasis severity. However, MPO was highly expressed in lesional psoriatic skin and colocalized predominantly with CD45(+) CD11b(+) leukocytes. CD11b(+) cell density correlated with circulation MPO levels. CONCLUSION: Lesional skin CD11b(+) leukocytes activated to generate MPO may contribute to serum levels of MPO. Lesional CD11b(+) cell activity may be an alternative measure of disease burden to PASI that underlies the MPO biomarker for systemic inflammation related to Cardiovascular Disease. PMID- 24349619 TI - Transcriptomic changes induced by mycophenolic acid in gastric cancer cells. AB - BACKGROUND: Inhibition of inosine monophosphate dehydrogenase (IMPDH) by mycophenolic acid (MPA) can inhibit proliferation and induce apoptosis in cancer cells. This study investigated the underlying molecular mechanisms of MPA's anticancer activity. METHODS: A gastric cancer cell line (AGS) was treated with MPA and gene expression at different time points was analyzed using Illumina whole genome microarrays and selected genes were confirmed by real-time RT-PCR. RESULTS: Transcriptomic profiling identified 1070 genes with >=2 fold changes and 85 genes with >4 fold alterations. The most significantly altered biological processes by MPA treatment include cell cycle, apoptosis, cell proliferation and migration. MPA treatment altered at least ten KEGG pathways, of which eight (p53 signaling, cell cycle, pathways in cancer, PPAR signaling, bladder cancer, protein processing in ER, small cell lung cancer and MAPK signaling) are cancer related. Among the earliest cellular events induced by MPA is cell cycle arrest which may be caused by six molecular pathways: 1) up-regulation of cyclins (CCND1 and CCNE2) and down-regulation of CCNA2 and CCNB1, 2) down-regulation of cyclin dependent kinases (CDK4 and CDK5); 3) inhibition of cell division related genes (CDC20, CDC25B and CDC25C) and other cell cycle related genes (MCM2, CENPE and PSRC1), 4) activation of p53, which activates the cyclin-dependent kinase inhibitors (CDKN1A), 5) impaired spindle checkpoint function and chromosome segregation (BUB1, BUB1B, BOP1, AURKA, AURKB, and FOXM1); and 6) reduction of availability of deoxyribonucleotides and therefore DNA synthesis through down regulation of the RRM1 enzyme. Cell cycle arrest is followed by inhibition of cell proliferation, which is mainly attributable to the inhibition of the PI3K/AKT/mTOR pathway, and caspase-dependent apoptosis due to up-regulation of the p53 and FAS pathways. CONCLUSIONS: These results suggest that MPA has beneficial anticancer activity through diverse molecular pathways and biological processes. PMID- 24349620 TI - Genetic myostatin decrease in the golden retriever muscular dystrophy model does not significantly affect the ubiquitin proteasome system despite enhancing the severity of disease. AB - Recent studies suggest that inhibiting the protein myostatin, a negative regulator of skeletal muscle mass, may improve outcomes in patients with Duchenne muscular dystrophy by enhancing muscle mass. When the dystrophin-deficient golden retriever muscular dystrophy (GRMD) dog was bred with whippets having a heterozygous mutation for the myostatin gene, affected GRMD dogs with decreased myostatin (GRippets) demonstrated an accelerated physical decline compared to related affected GRMD dogs with full myostatin. To examine the role of the ubiquitin proteasome and calpain systems in this accelerated decline, we determined the expression of the muscle ubiquitin ligases MuRF1, Atrogin-1, RNF25, RNF11, and CHIP: the proteasome subunits PSMA6, PSMB4, and PSME1: and calpain 1/2 by real time PCR in the cranial sartorius and vastus lateralis muscles in control, affected GRMD, and GRippet dogs. While individual affected GRMD and GRippet dogs contributed to an increased variability seen in ubiquitin ligase expression, neither group was significantly different from the control group. The affected GRMD dogs demonstrated significant increases in caspase-like and trypsin-like activity in the cranial sartorius; however, all three proteasome activities in the GRippet muscles did not differ from controls. Increased variability in calpain 1 and calpain 2 expression and activity in the affected GRMD and GRippet groups were identified, but no statistical differences from the control group were seen. These studies suggest a role of myostatin in the disease progression of GRMD, which does not significantly involve key components of the ubiquitin proteasome and calpain systems involved in the protein quality control of sarcomere and other structural skeletal muscle proteins. PMID- 24349621 TI - Pravastatin stimulates angiogenesis in a murine hindlimb ischemia model: a positron emission tomography imaging study with (64)Cu-NOTA-TRC105. AB - In this study, (64)Cu-NOTA-TRC105 (TRC105 is an anti-CD105 monoclonal antibody that binds to both human and murine CD105) positron emission tomography (PET) was used to assess the response to pravastatin treatment in a murine model of peripheral artery disease (PAD). Hindlimb ischemia was induced by ligation of the right femoral arteries in BALB/c mice under anesthesia, and the left hindlimb served as an internal control. Mice in the treatment group were given intraperitoneal pravastatin daily until the end of the study, whereas the animals in the control group were injected with 0.9% sodium chloride solution. Laser Doppler imaging showed that blood flow in the ischemic hindlimb plummeted to ~20% of the normal level after surgery, and gradually recovered to near normal level on day 10 in the treatment group and on day 20 in the control group. Angiogenesis was non-invasively monitored and quantified with (64)Cu-NOTA-TRC105 PET on postoperative days 3, 10, 17, and 24. Tracer uptake at 48 h post-injection in the ischemic hindlimb in the treatment group was significantly higher than that of the control group on day 10 (20.5 +/- 1.9 %ID/g vs 11.4 +/- 1.5 %ID/g), suggesting increased CD105 expression and higher level of angiogenesis upon pravastatin treatment, and gradually decreased to background levels in both groups (4.9 +/- 0.8 %ID/g vs 3.4 +/- 1.9 %ID/g on day 24). The in vivo PET data correlated well with ex vivo biodistribution studies performed on day 24. Increased CD105 expression on days 3 and 10 following ischemia was further confirmed by immunofluorescence staining. Taken together, our results indicated that (64)Cu-NOTA-TRC105 PET is a suitable and non-invasive method to monitor the angiogenesis and therapeutic response in PAD, which can also be utilized for non invasive evaluation of other pro-angiogenic/anti-angiogenic drugs in other cardiovascular diseases and cancer. PMID- 24349622 TI - At pharmacologically relevant concentrations intravenous iron preparations cause pancreatic beta cell death. AB - BACK GROUND: Overt and subtle iron overload cause diabetes by lowering insulin production and promoting insulin resistance. Via divalent metal transporters pancreatic beta cells take up non-transferrin-bound iron which by catalyzing Fenton reaction can cause oxidative stress. Due to their strict dependence on mitochondrial glucose metabolism and limited antioxidant capacity, beta cells are exquisitely vulnerable to oxidative stress and hence catalytically active iron. Intravenous (IV) iron preparations are routinely used in the management of anemia in patients with end stage renal disease. This has led to an epidemic of iron overload in this population. This study explored the effect of pharmacologically relevant concentrations of a commonly used IV iron preparation on the beta cells in isolated pancreatic islets. METHODS: Isolated rat pancreatic islets were incubated for 24 hours in culture media containing vehicle or pharmacologically relevant concentration of ferric sucrose and examined for the extent of cell death and oxidative stress. RESULTS: Exposure to iron sucrose resulted in a concentration-dependent oxidative stress and pancreatic islet cell death predominantly affecting beta cells. CONCLUSIONS: At pharmacologically-relevant concentrations a commonly used IV iron preparation causes oxidative stress and beta cell death. These findings suggest that indiscriminate use of IV iron may impair insulin production capacity in ESRD patients the majority of whom have Type-2 diabetes. PMID- 24349623 TI - Serum miR-200c and clinical outcome of patients with advanced esophageal squamous cancer receiving platinum-based chemotherapy. AB - MicroRNA-200c (miR-200c) influences sensitivity to chemotherapy and radiotherapy in vitro. This study was designed to investigate the prognostic potential of serum miR-200c in patients with advanced esophageal squamous cancer (ESCC). The serum levels of miR-200c was assayed by quantitative RT-PCR in 157 healthy subjects and 157 patients with advanced ESCC who were treated with platinum-based chemotherapy. The serum levels of miR-200c in advanced ESCC patients was significantly increased compared with those in controls (P < 0.001). Serum miR 200c expression was significantly associated with TNM stage (P = 0.037) and treatment response (P = 0.021). Patients with high expression of serum miR-200c had a higher risk for death than those with low expression of serum miR-200c (adjusted hazard ratios = 1.665, 95% confidence intervals: 1.135-2.443, P = 0.009). In conclusion, serum miR-200c may serve as predictor of survival for advanced ESCC and provide information for personalized therapy in advanced ESCC. PMID- 24349624 TI - Assessing the optimal dose for Cetrorelix in Chinese women undergoing ovarian stimulation during the course of IVF-ET treatment. AB - We conducted a prospective, randomized, and controlled trial to assess the optimal dose for GnRH antagonist, cetrorelix, for Chinese women during the course of ovarian stimulation. The patients were randomly divided into two groups, in which 48 patients were advised to inject 0.25 mg Cetrorelix daily (the 0.25 mg group), while 39 patients were instructed to receive a daily dose of 0.125 mg cetrorelix (the 0.125 mg group). In general, a daily dose of 0.125 mg cetrorelix could be more optimal for Chinese women as manifested by the lower cancellation rate, higher implantation rate and clinical pregnancy rate. Specifically, daily administration of 0.125 mg cetrorelix for patients under 35 years old is associated with a 3-fold higher implantation rate and a 5-fold higher clinical pregnancy rate as compared with that of those patients >= 35 years old. On the contrary, higher rates for implantation and clinical pregnancy were noted by daily injection of 0.25 mg cetrorelix in elder patients (>= 35 years old) as compared with that of young patients (< 35 years old). Together, our data suggest that a daily dose of 0.125 mg cetrorelix could be more optimal for patients < 35 years old, while 0.25 mg/day of cetrorelix are likely conducive to higher implantation and clinical pregnancy rate for those patients >= 35 years old. These data could be important for preventing LH surge while maintaining optimal LH levels necessary for embryo implantation for Chinese women during the course of IVF-ET treatment. PMID- 24349625 TI - Hormonal replacement treatment improves clinical pregnancy in frozen-thawed embryos transfer cycles: a retrospective cohort study. AB - This study aimed to assess frozen-thawed embryo transfer (FET) outcomes in natural, hormone replacement treatment (HRT) and semi-HRT cycles. This was a retrospective cohort study of 5414 cycles of patients in an academic hospital. Patients were grouped as 2216 natural cycles, 1180 semi-HRT cycles, and 2018 HRT cycles. Primary outcome measures were implantation rate, clinical pregnancy rate and live birth rate. Other parameters, such as peak endometria-thickness, were also analyzed. Patients undergoing FET with HRT obtained higher implantation rate and clinical pregnancy rate than patients with natural or semi-HR cycles (29.3% vs. 21.5% vs. 25.6%, P=0.01, and 48.7% vs. 42.7% vs. 36.1%, P=0.01, respectively). This finding was not changed in patients with thin endometrium (<=8 mm). A Subanalysis in patients with HRT showed that the implantation and clinical pregnancy rate was higher in patients without ovulation than ovulatory patients (29.8% vs. 16.9%, P<0.01, and 49.5% vs. 26.3%, P<0.01, respectively). This study suggests that HRT increases the possibility of pregnancy. Further, our data showed that ovulation in HRT cycle has a detrimental effect on pregnancy. Therefore, we recommend that HRT should be used in FET cycles, and ovulation of patients should be evaluated during the treatment. PMID- 24349626 TI - Cardiovascular autonomic dysfunction in primary ovarian insufficiency: clinical and experimental evidence. AB - OBJECTIVE: Women with primary ovarian insufficiency (POI) present an increased risk for cardiovascular disease. In this study we tested the hypothesis that POI in women under hormone therapy (HT) are associated with vascular vasodilatation attenuation and cardiovascular autonomic dysfunction and these impairments are related to changes in systemic antioxidant enzymes. Furthermore, the possibility that ovarian hormone deprivation can induce such changes and that HT cannot reverse all of those impairments was examined in an experimental model of POI. METHODS: Fifteen control and 17 patients with primary ovarian insufficiency receiving HT were included in the study. To test the systemic and cardiac consequences of ovarian hormone deprivation, ovariectomy was induced in young female rats that were submitted or not to HT. Spectral analysis of RR interval and blood pressure signals were performed and oxidative stress parameters were determined. RESULTS: POI women under HT have increased mean arterial pressure (94+/-10 vs. 86+/-5 mmHg) despite normal endothelial and autonomic modulation of vasculature. Additionally, they presented impaired baroreflex sensitivity (3.9+/ 1.38 vs. 7.15+/-3.62 ms/mmHg) and reduced heart rate variability (2310+/-1173 vs. 3754+/-1921 ms(2)). Similar results obtained in ovariectomized female rats were accompanied by an increased lipoperoxidation (7433+/-1010 vs. 6180+/-289 cps/mg protein) and decreased antioxidant enzymes in cardiac tissue. As it was observed in women, the HT in animals did not restore hemodynamic and autonomic dysfunctions. CONCLUSION: These data provide clinical and experimental evidence that long term HT may not restore all cardiovascular risk factors associated with ovarian hormone deprivation. PMID- 24349627 TI - Erratum: Epigenetic silencing of miR-34a in human prostate cancer cells and tumor tissue specimens can be reversed by BR-DIM treatment. AB - Androgen Receptor (AR) signaling is critically important during the development and progression of prostate cancer (PCa). The AR signaling is also important in the development of castrate resistant prostate cancer (CRPC) where AR is functional even after androgen deprivation therapy (ADT); however, little is known regarding the transcriptional and functional regulation of AR in PCa. Moreover, treatment options for primary PCa for preventing the occurrence of CRPC is limited; therefore, novel strategy for direct inactivation of AR is urgently needed. In this study, we found loss of miR-34a, which targets AR, in PCa tissue specimens, especially in patients with higher Gleason grade tumors, consistent with increased expression of AR. Forced over-expression of miR-34a in PCa cell lines led to decreased expression of AR and prostate specific antigen (PSA) as well as the expression of Notch-1, another important target of miR-34a. Most importantly, BR-DIM intervention in PCa patients prior to radical prostatectomy showed reexpression of miR-34a, which was consistent with decreased expression of AR, PSA and Notch-1 in PCa tissue specimens. Moreover, BR-DIM intervention led to nuclear exclusion both in PCa cell lines and in tumor tissues. PCa cells treated with BR-DIM and 5-aza-dC resulted in the demethylation of miR-34a promoter concomitant with inhibition of AR and PSA expression in LNCaP and C4-2B cells. These results suggest, for the first time, epigenetic silencing of miR-34a in PCa, which could be reversed by BR-DIM treatment and, thus BR-DIM could be useful for the inactivation of AR in the treatment of PCa.[This corrects the article on p. 14 in vol. 4.]. PMID- 24349628 TI - Speech and Language Impairments in Autism: Insights from Behavior and Neuroimaging. AB - A failure to develop language is one of the earliest signs of autism. The ability to identify the neural signature of this deficit in very young children has become increasingly important, given that the presence of speech before five years of age is the strongest predictor for better outcomes in autism. This review consolidates what is known about verbal and preverbal precursors of language development as a framework for examining behavioral and brain anomalies related to speech and language in autism spectrum disorders. Relating the disruptions in the speech network to the social deficits observed will provide promising targets for behavioral and pharmacological interventions in ASD. PMID- 24349629 TI - Monographs editor. PMID- 24349630 TI - JNK Signaling Network and Cancer. PMID- 24349631 TI - Mixed Lineage Kinase-c-Jun N-Terminal Kinase Axis: A Potential Therapeutic Target in Cancer. AB - Mixed lineage kinases (MLKs) are members of the mitogen-activated protein kinase kinase kinase (MAP3K) family and are reported to activate MAP kinase pathways. There have been at least 9 members of the MLK family identified to date, although the physiological functions of all the family members are yet unknown. However, MLKs in general have been implicated in neurodegenerative diseases, including Parkinson and Alzheimer diseases. Recent reports suggest that some of the MLK members could play a role in cancer via modulating cell migration, invasion, cell cycle, and apoptosis. This review article will first describe the biology of MLK members and then discuss the current progress that relates to their functions in cancer. PMID- 24349633 TI - Linking JNK Activity to the DNA Damage Response. AB - The activity of c-Jun N-terminal kinase (JNK) was initially described as ultraviolet- and oncogene-induced kinase activity on c-Jun. Shortly after this initial discovery, JNK activation was reported for a wider variety of DNA damaging agents, including gamma-irradiation and chemotherapeutic compounds. As the DNA damage response mechanisms were progressively uncovered, the mechanisms governing the activation of JNK upon genotoxic stresses became better understood. In particular, a recent set of papers links the physical breakage in DNA, the activation of the transcription factor NF-kappaB, the secretion of TNF-alpha, and an autocrine activation of the JNK pathway. In this review, we will focus on the pathway that is initiated by a physical break in the DNA helix, leading to JNK activation and the resultant cellular consequences. The implications of these findings will be discussed in the context of cancer therapy with DNA-damaging agents. PMID- 24349634 TI - RACK1 Function in Cell Motility and Protein Synthesis. AB - The receptor for activated C kinase 1 (RACK1) serves as an adaptor for a number of proteins along the MAPK, protein kinase C, and Src signaling pathways. The abundance and near ubiquitous expression of RACK1 reflect its role in coordinating signaling molecules for many critical biological processes, from mRNA translation to cell motility to cell survival and death. Complete deficiency of Rack1 is embryonic lethal, but the recent development of genetic Rack1 hypomorphic mice has highlighted the central role that RACK1 plays in cell movement and protein synthesis. This review focuses on the importance of RACK1 in these processes and places the recent work in the larger context of understanding RACK1 function. PMID- 24349632 TI - Role of p38 MAP Kinase Signal Transduction in Solid Tumors. AB - Mitogen-activated protein kinases (MAPKs) mediate a wide variety of cellular behaviors in response to extracellular stimuli. One of the main subgroups, the p38 MAP kinases, has been implicated in a wide range of complex biologic processes, such as cell proliferation, cell differentiation, cell death, cell migration, and invasion. Dysregulation of p38 MAPK levels in patients are associated with advanced stages and short survival in cancer patients (e.g., prostate, breast, bladder, liver, and lung cancer). p38 MAPK plays a dual role as a regulator of cell death, and it can either mediate cell survival or cell death depending not only on the type of stimulus but also in a cell type specific manner. In addition to modulating cell survival, an essential role of p38 MAPK in modulation of cell migration and invasion offers a distinct opportunity to target this pathway with respect to tumor metastasis. The specific function of p38 MAPK appears to depend not only on the cell type but also on the stimuli and/or the isoform that is activated. p38 MAPK signaling pathway is activated in response to diverse stimuli and mediates its function by components downstream of p38. Extrapolation of the knowledge gained from laboratory findings is essential to address the clinical significance of p38 MAPK signaling pathways. The goal of this review is to provide an overview on recent progress made in defining the functions of p38 MAPK pathways with respect to solid tumor biology and generate testable hypothesis with respect to the role of p38 MAPK as an attractive target for intervention of solid tumors. PMID- 24349635 TI - c-Jun N-Terminal Kinases Mediate a Wide Range of Targets in the Metastatic Cascade. AB - Disseminated cancer cells rely on intricate interactions among diverse cell types in the tumor-associated stroma, vasculature, and immune system for survival and growth. Ubiquitous expression of c-Jun N-terminal kinase (jnk) genes in various cell types permits their control of metastasis. In early stages of metastasis, JNKs affect tumor-associated inflammation and angiogenesis as well as tumor cell migration and intravasation. Within the tumor stroma, JNKs are essential for the release of growth factors that promote epithelial-to-mesenchymal transition (EMT) in tumor cells. JNK3, the least ubiquitous isoform, facilitates angiogenesis by increasing endothelial cell migration. Importantly, JNK expression in tumor cells integrates stromal signals to promote tumor cell invasion. However, JNK isoforms differentially regulate migration toward the endothelial barrier. Once tumor cells enter the bloodstream, JNKs increase circulating tumor cell (CTC) survival and homing to tissues. By promoting fibrosis, JNKs improve CTC attachment to the endothelium. Once anchored, JNKs stimulate EMT to facilitate tumor cell extravasation and enhance the secretion of endothelial barrier disrupters. Tumor cells attract barrier-disrupting macrophages by JNK-dependent transcription of macrophage chemoattractant molecules. In the secondary tissue, JNKs are instrumental in the premetastatic niche and stimulate tumor cell proliferation. JNK expression in cancer cells stimulates tissue-remodeling macrophages to improve tumor colonization. However, in T-cells, JNKs alter cytokine production that increases tumor surveillance and inhibits the recruitment of tissue remodeling macrophages. Therapeutically targeting JNKs for metastatic disease is attractive considering their promotion of metastasis; however, specific JNK tools are needed to determine their definitive actions within the context of the entire metastatic cascade. PMID- 24349636 TI - JNK Signaling in the Control of the Tumor-Initiating Capacity Associated with Cancer Stem Cells. AB - Deregulation of c-Jun NH2-terminal kinase (JNK) signaling occurs frequently in a variety of human cancers, yet the exact role(s) of JNK deregulation in cancer cell biology remains to be fully elucidated. Our recent demonstration that the activity of JNK is required not only for self-renewal of glioma stem cells but also for their tumor initiation has, however, identified a new role for JNK in the control of the stemness and tumor-initiating capacity of cancer cells. Significantly, transient JNK inhibition was sufficient to cause sustained loss of the tumor-initiating capacity of glioma stem cells, suggesting that the phenotype of "lost tumor-initiating capacity" may be as stable as the differentiated state and that the tumor-initiating capacity might therefore be under the control of JNK through an epigenetic mechanism that also governs stemness and differentiation. Here, in this article, we review the role and mechanism of JNK in the control of this "stemness-associated tumor-initiating capacity" (STATIC), a new hypothetical concept we introduce in this review article. Since the idea of STATIC is essentially applicable to both cancer types that do and do not follow the cancer stem cell hypothesis, we also give consideration to the possible involvement of JNK-mediated control of STATIC in a wide range of human cancers in which JNK is aberrantly activated. Theoretically, successful targeting of STATIC through JNK could contribute to long-term control of cancer. Issues to be considered before clinical application of therapies targeting this JNK-STATIC axis are also discussed. PMID- 24349637 TI - The 2 Faces of JNK Signaling in Cancer. AB - c-Jun NH2-terminal kinase (JNK) was discovered almost 20 years ago as the protein kinase responsible for phosphorylating c-Jun at Ser-63 and Ser-73. These sites had previously been demonstrated to be essential for the stimulation of c-Jun activity and for cooperation with Ha-ras in oncogenic transformation. This led to the idea that JNK was a positive regulator of cellular transformation. However, the analysis of jnk gene deletion in various mouse models of cancer has produced conflicting findings, with some studies supporting the pro-oncogenic function of JNK and others providing evidence that JNK acts as a tumor suppressor. This review will discuss how these unexpected findings have increased our understanding of the role of JNK signaling in cancer and have provided a source of new working hypotheses. PMID- 24349638 TI - Mitogen-activated protein kinases and their role in radiation response. AB - Ionizing radiation, like a variety of other cellular stress factors, can activate or down-regulate multiple signaling pathways, leading to either increased cell death or increased cell proliferation. Modulation of the signaling process, however, depends on the cell type, radiation dose, and culture conditions. The mitogen-activated protein kinase (MAPK) pathway transduces signals from the cell membrane to the nucleus in response to a variety of different stimuli and participates in various intracellular signaling pathways that control a wide spectrum of cellular processes, including growth, differentiation, and stress responses, and is known to have a key role in cancer progression. Multiple signal transduction pathways stimulated by ionizing radiation are mediated by the MAPK superfamily including the extracellular signal-regulated kinase (ERK), c-Jun N terminal kinase (JNK), and p38 MAPK. The ERK pathway, activated by mitogenic stimuli such as growth factors, cytokines, and phorbol esters, plays a major role in regulating cell growth, survival, and differentiation. In contrast, JNK and p38 MAPK are weakly activated by growth factors but respond strongly to stress signals including tumor necrosis factor (TNF), interleukin-1, ionizing and ultraviolet radiation, hyperosmotic stress, and chemotherapeutic drugs. Activation of JNK and p38 MAPK by stress stimuli is strongly associated with apoptotic cell death. MAPK signaling is also known to potentially influence tumor cell radiosensitivity because of their activity associated with radiation-induced DNA damage response. This review will discuss the MAPK signaling pathways and their roles in cellular radiation responses. PMID- 24349639 TI - Network Motifs in JNK Signaling. AB - Multiple growth factors and extracellular signals can lead to activation of the c Jun amino N-terminal protein kinase (JNK) pathway. Activation of JNK can in turn lead to a multitude of downstream changes in phosphorylation and transcriptional activation within the cell. Mapping the upstream and downstream connectivity within the JNK network reveals an enrichment of bi-fan and feed-forward network motifs formed immediately upstream and downstream of JNK. In addition, negative feedback loops also exist through transcriptional activation of phosphatases that target the JNK pathway. The combinations of these motifs allow flexibility and tunability in signal integration and processing within the JNK network and may confer the wide range of biological responses that can be regulated by JNK activation. In this review, we highlight the pathways and motifs leading to JNK activation and its downstream signaling as well as the complexity in isoforms within this network. PMID- 24349640 TI - The Implementation of a Telephone-Delivered Intervention for Asian American Disordered Gamblers: A Pilot Study. AB - This report will discuss the implementation and preliminary results of a community-based telephone-delivered gambling treatment program specifically designed for Asian Americans. The intervention was implemented by the NICOS Chinese Health Coalition, a nonprofit community organization based in Northern California, overseen by the UCLA (University of California, Los Angeles) Gambling Studies Program and the California Office of Problem Gambling, and launched in December 2010. It consisted of six 1-hr long telephone-delivered sessions conducted by a mental health provider using a translated version of the Freedom from Problem Gambling Self-Help Workbook. In the current study, 6 providers completed a 30-hr training program for gambling related disorders. One-hundred and 40 callers inquired about the intervention within the first 6 months of its launch, 19 clients expressed interest in participating, and 8 enrolled into the program. The results show that the majority of clients who enrolled into the program did not report any gambling behavior after baseline and improved on self reported measures of overall life satisfaction, gambling urges, and self-control. This study suggests that the implementation of this type of intervention is feasible at a small community-based organization and may be effective in treating gambling-related disorders for Asian American populations. The low rate of clientele enrollment is addressed and potential remedies are discussed. PMID- 24349641 TI - Effects of the Arg-Pro and Gly-Gly-Nle Moieties on Melanocortin-1 Receptor Binding Affinities of alpha-MSH Peptides. AB - The purpose of this study was to examine the effects of the -Arg-Pro-(RP) and Gly-Gly-Nle- (GGNle) moieties on the melanoma targeting and clearance properties of 99mTc-peptides. We synthesized four new peptides {Ac-GGNle-CCEHdFRWC-NH2, Ac GGNle-CCEHdFRWCRP-NH2, Ac-CCEHdFRWC-NleGG-NH2 and Ac-CCEHdFRWCRP-NleGG-NH2} and determined their melanocortin-1 (MC1) receptor binding affinities in B16/F1 melanoma cells. Then we further examined the biodistribution properties of 99mTc Ac-GGNle-CCEHdFRWCRP-NH2 and 99mTc-Ac-CCEHdFRWCRP-NleGG-NH2 in B16/F1 melanoma bearing C57 mice. Overall, the Arg-Pro motif was critical for retaining low nanomolar MC1 receptor binding affinity. The deletion of the -RP- moiety dramatically reduced the receptor binding affinities of the peptides. The N terminus was a better position than C-terminus for the -GGNle- moiety in retaining the lower renal and liver uptake. High melanoma uptake coupled with fast urinary clearance of 99mTc-Ac-GGNle-CCEHdFRWCRP-NH2 provided a new insight into the design of new alpha-melanocyte stimulating hormone (alpha-MSH) peptides. PMID- 24349642 TI - Protein-Ligand Interactions: Thermodynamic Effects Associated with Increasing the Length of an Alkyl Chain. AB - Thermodynamic parameters were determined for complex formation between the Grb2 SH2 domain and tripeptides of the general form Ac-pTyr-Xaa-Asn in which the Xaa residue bears a linear alkyl chain varying in length from 1-5 carbon atoms. Binding affinity increases upon adding a methylene group to the Ala derivative, but further chain extension gives no extra enhancement in potency. The thermodynamic signatures of the ethyl and n-propyl derivatives are virtually identical as are those for the n-butyl and n-pentyl analogs. Crystallographic analysis of the complexes reveals a high degree of similarity in the structure of the domain and the bound ligands with the notable exception that there is a gauche interaction in the side chains in the bound conformations of ligands having n-propyl, n-butyl, and n-pentyl groups. However, eliminating this unfavorable interaction by introducing a Z-double bond into the side chain of the n-propyl analog does not result in an increase in affinity. Increases in the amount of nonpolar surface that is buried upon ligand binding correlate with favorable changes in DeltaH degrees , but these are usually offset by corresponding unfavorable changes in -TDeltaS degrees ; there is little correlation of DeltaCp with changes in the amount of buried nonpolar surface. PMID- 24349643 TI - Diagnostic neuroradiology for the interventional neuroradiologist. AB - In order to further improve the impact of the continuously evolving neurointerventional techniques, the interventional neuroradiologist needs to have at his disposal more powerful techniques to image the central nervous system. With the recent development of diagnostics techniques that are computed tomography and magnetic resonance based we are now able to assess not just morphology, but also physiology, physiopathology and function. This review discusses the place of diagnostic techniques in the evaluation that the interventional neuroradiologist hast to make when confronted with patients. We provide an overview of current techniques for the brain and spine. PMID- 24349644 TI - Screening and early diagnosis of osteoporosis through X-ray and ultrasound based techniques. AB - Effective prevention and management of osteoporosis would require suitable methods for population screenings and early diagnosis. Current clinically available diagnostic methods are mainly based on the use of either X-rays or ultrasound (US). All X-ray based methods provide a measure of bone mineral density (BMD), but it has been demonstrated that other structural aspects of the bone are important in determining fracture risk, such as mechanical features and elastic properties, which cannot be assessed using densitometric techniques. Among the most commonly used techniques, dual X-ray absorptiometry (DXA) is considered the current "gold standard" for osteoporosis diagnosis and fracture risk prediction. Unfortunately, as other X-ray based techniques, DXA has specific limitations (e.g., use of ionizing radiation, large size of the equipment, high costs, limited availability) that hinder its application for population screenings and primary care diagnosis. This has resulted in an increasing interest in developing reliable pre-screening tools for osteoporosis such as quantitative ultrasound (QUS) scanners, which do not involve ionizing radiation exposure and represent a cheaper solution exploiting portable and widely available devices. Furthermore, the usefulness of QUS techniques in fracture risk prediction has been proven and, with the last developments, they are also becoming a more and more reliable approach for assessing bone quality. However, the US assessment of osteoporosis is currently used only as a pre-screening tool, requiring a subsequent diagnosis confirmation by means of a DXA evaluation. Here we illustrate the state of art in the early diagnosis of this "silent disease" and show up recent advances for its prevention and improved management through early diagnosis. PMID- 24349645 TI - Magnetically-coated silica nanospheres for dual-mode imaging at low ultrasound frequency. AB - AIM: To experimentally investigate the acoustical behavior of different dual-mode nanosized contrast agents (NPCAs) for echographic medical imaging at low ultrasound (US) frequency. METHODS: We synthesized three different nanosized structures: (1) Pure silica nanospheres (SiNSs); (2) FePt-iron oxide (FePt-IO) coated SiNSs; and (3) IO-coated SiNSs, employing three different diameter of SiNS core (160, 330 and 660 nm). Tissue mimicking phantoms made of agarose gel solution containing 5 mg of different NPCAs in 2 mL-Eppendorf tubes, were insonified by a commercial echographic system at three different low US pulse values (2.5, 3.5 and 4.5 MHz). The raw radiofrequency signal, backscattered from each considered NPCA containing sample, has been processed in order to calculate the US average backscatter intensity and compare the acoustic behavior of the different NPCA types. RESULTS: The highest US contrast was exhibited by pure SiNSs; FePt-IO-coated SiNSs acoustical behavior followed a similar trend of pure SiNSs with a slight difference in terms of brightness values. The acoustic response of the examined NPCAs resulted function of both SiNS diameter and US frequency. Specifically, higher US frequencies determined higher value of the backscatter for a given SiNS diameter. Frequency-dependent enhancement was marked for pure SiNSs and became less remarkable for FePt-IO-coated SiNSs, whereas IO coated SiNSs resulted almost unaffected by such frequency variations. Pure and FePt-IO-coated SiNSs evidenced an image backscatter increasing with the diameter up to 330 nm. Conversely, among the types of NPCA tested, IO-coated SiNSs showed the lowest acoustical response for each synthesized diameter and employed US frequency, although a diameter-dependent raising trend was evidenced. CONCLUSION: The US characterization of magnetically covered SiNS shows that FePt-IO, rather than IO, was the best magnetic coating for realizing NPCAs suitable for dual mode imaging of deep organs, combining US and magnetic resonance imaging. PMID- 24349646 TI - CT dose and image quality in the last three scanner generations. AB - AIM: To compare the computed tomography (CT) dose and image quality with the filtered back projection against the iterative reconstruction and CT with a minimal electronic noise detector. METHODS: A lung phantom (Chest Phantom N1 by Kyoto Kagaku) was scanned with 3 different CT scanners: the Somatom Sensation, the Definition Flash and the Definition Edge (all from Siemens, Erlangen, Germany). The scan parameters were identical to the Siemens presetting for THORAX ROUTINE (scan length 35 cm and FOV 33 cm). Nine different exposition levels were examined (reference mAs/peek voltage): 100/120, 100/100, 100/80, 50/120, 50/100, 50/80, 25/120, 25/100 and 25 mAs/80 kVp. Images from the SOMATOM Sensation were reconstructed using classic filtered back projection. Iterative reconstruction (SAFIRE, level 3) was performed for the two other scanners. A Stellar detector was used with the Somatom Definition Edge. The CT doses were represented by the dose length products (DLPs) (mGycm) provided by the scanners. Signal, contrast, noise and subjective image quality were recorded by two different radiologists with 10 and 3 years of experience in chest CT radiology. To determine the average dose reduction between two scanners, the integral of the dose difference was calculated from the lowest to the highest noise level. RESULTS: When using iterative reconstruction (IR) instead of filtered back projection (FBP), the average dose reduction was 30%, 52% and 80% for bone, soft tissue and air, respectively, for the same image quality (P < 0.0001). The recently introduced Stellar detector (Sd) lowered the radiation dose by an additional 27%, 54% and 70% for bone, soft tissue and air, respectively (P < 0.0001). The benefit of dose reduction was larger at lower dose levels. With the same radiation dose, an average of 34% (22%-37%) and 25% (13%-46%) more contrast to noise was achieved by changing from FBP to IR and from IR to Sd, respectively. For the same contrast to noise level, an average of 59% (46%-71%) and 51% (38%-68%) dose reduction was produced for IR and Sd, respectively. For the same subjective image quality, the dose could be reduced by 25% (2%-42%) and 44% (33%-54%) using IR and Sd, respectively. CONCLUSION: This study showed an average dose reduction between 27% and 70% for the new Stellar detector, which is equivalent to using IR instead of FBP. PMID- 24349647 TI - New generation aspiration catheter: Feasibility in the treatment of pulmonary embolism. AB - AIM: To report our preliminary experience with a new generation aspiration catheter in the treatment of symptomatic pulmonary embolism (PE). METHODS: A retrospective database search for pulmonary artery embolectomy since introduction of the Pronto .035" and XL extraction catheter (Vascular Solutions, Minneapolis, MN) at our institution in 10/2009 was performed. Ten consecutive patients were identified in which the Pronto .035" or XL catheter was used between 01/2010 and 03/2013. All patients were referred for catheter based embolectomy due to contraindications to systemic lysis, or for being in such a critical clinical condition that immediate percutaneous treatment deemed warranted. The computed tomography (CT) right to left heart ratio as predictor for the severity of the PE was retrospectively evaluated on standard axial views. The difference between pre and post-procedure pulmonary pressure measures was taken to assess the procedural effect. RESULTS: Extensive PE was confirmed angiographically in all patients. Measured right- to left ventricle (RV/LV) ratios were elevated beyond one in seven of the eight available CTs. Acute procedural success defined as clinical removal of visible thrombus and improvement in mean pulmonary artery pressure was seen in all recorded patients (n = 8), the mean pulmonary pressures declined from a median (range) of 35.5 (19-46) to 23 (10-37, P = 0.008) mmHg. Neither death nor other complications occurred intra- or immediately periprocedural, yet short term mortality within 30 d was found in 6 out of 9 patients, one patient was lost in follow up. The cause of death within 30 d in the 6 patients was identified as: Circulatory failure in direct connection with the PE (n = 2), stroke, sepsis, or succumbing to malignancy in a hospice setting (n = 2). CONCLUSION: Success in thrombus removal with improved pulmonary hypertension and systemic hypotension suggests this aspiration technique to be effective. Aspiration catheters should be part of further trials. PMID- 24349648 TI - MDCT imaging following nephrectomy for renal cell carcinoma: Protocol optimization and patterns of tumor recurrence. AB - The purpose of this pictorial essay is to review the common and uncommon sites of renal cell carcinoma recurrence throughout the body by examining their appearances on computerized tomography (CT). CT imaging protocols will be discussed. The sites of recurrence have been categorized into 4 groups: chest and mediastinum, abdomen and pelvis, musculoskeletal, and neurological. For each site of recurrence, a representative CT image correlate with discussion is provided. The unique CT appearance of renal cell carcinoma recurrence and how it can be used in lesion detection will be discussed. Renal cell carcinoma recurrences are hypervascular like the primary tumor, which can aid in not only lesion detection but also in some cases, differentiation from other primary tumors. Through CT case review of various sites of recurrence, lesions are shown to be easily seen on arterial phase while sometimes being nearly inconspicuous on venous or delayed phases. Coronal and sagittal reconstructions can also improve diagnostic sensitivity. CT is the most commonly used imaging tool for surveillance of renal cell carcinoma recurrence after nephrectomy. Knowledge of sites of recurrence as well as the utility of arterial phase imaging and multiplanar reconstructions will aid in optimizing detection of disease recurrence. PMID- 24349649 TI - Mesenteric myolipoma. AB - The authors report on a case of benign myolipoma (synonym lipoleiomyoma) which was first described in 1991. The benign soft tissue tumor is composed of smooth muscle and adipose tissue and occurs sporadically in different locations. In the available literature cases were described retroperitoneal, spinal, orbital and subcutaneous and mostly have been discovered in females. Characteristically myolipomas are very large at diagnosis and reach diameters of 7 to 30 cm particularly in peritoneal or retroperitoneal localization. The sometimes enormous size leads to a displacing growth pattern which ultimately leads to the clinical symptoms. The patients often complain of nonspecific, mostly painless abdominal or thoracic pressure. Bordered by an intact capsule the tumors show no signs of malignancy and in the available literature there is no evidence of metastatic seeding. To the best of our knowledge the presented case is the first description of a diffuse mesenteric myolipoma in a male individual. In this article, we present the multidetector computed tomographic image characteristics, macroscopic appearance and histopathological findings. PMID- 24349650 TI - The economic burden of epilepsy in Korea, 2010. AB - OBJECTIVES: The purposes of this study were to evaluate the prevalence of epilepsy and to estimate the cost of epilepsy in Korea, 2010. METHODS: This study used a prevalence based approach to calculate the cost of epilepsy. Claims data from the Korean national health insurance and data from the Korea health panel, the Korea National Statistical Office's records of causes of death, and labor statistics were used to estimate the cost of epilepsy. Patients were defined as those who were hospitalized or visited an outpatient clinic during 2010 with a diagnosis of epilepsy (International Classification of Diseases 10th revision codes G40-G41). Total costs of epilepsy included direct medical costs, direct non medical cost and indirect costs. RESULTS: The annual prevalence of treated epilepsy was 228 per 100 000 population, and higher in men. The age-specific prevalence was highest for teenagers. The total economic burden of epilepsy was 536 billion Korean won (KW). Indirect cost (304 billion KW) was 1.3 times greater than direct cost (232 billion KW). By gender, the male (347 billion KW) were more burdened than the female (189 billion KW). The estimated cost in young age younger than 20 years old was 24.5% of the total burden of epilepsy. CONCLUSIONS: A significant portion of the economic burden of epilepsy is borne by people in young age. To reduce the economic burden of epilepsy, effective prevention and treatment strategies are needed. PMID- 24349651 TI - Determinants of health care expenditures and the contribution of associated factors: 16 cities and provinces in Korea, 2003-2010. AB - OBJECTIVES: The purpose of this study was to classify determinants of cost increases into two categories, negotiable factors and non-negotiable factors, in order to identify the determinants of health care expenditure increases and to clarify the contribution of associated factors selected based on a literature review. METHODS: The data in this analysis was from the statistical yearbooks of National Health Insurance Service, the Economic Index from Statistics Korea and regional statistical yearbooks. The unit of analysis was the annual growth rate of variables of 16 cities and provinces from 2003 to 2010. First, multiple regression was used to identify the determinants of health care expenditures. We then used hierarchical multiple regression to calculate the contribution of associated factors. The changes of coefficients (R(2)) of predictors, which were entered into this analysis step by step based on the empirical evidence of the investigator could explain the contribution of predictors to increased medical cost. RESULTS: Health spending was mainly associated with the proportion of the elderly population, but the Medicare Economic Index (MEI) showed an inverse association. The contribution of predictors was as follows: the proportion of elderly in the population (22.4%), gross domestic product (GDP) per capita (4.5%), MEI (-12%), and other predictors (less than 1%). CONCLUSIONS: As Baby Boomers enter retirement, an increasing proportion of the population aged 65 and over and the GDP will continue to increase, thus accelerating the inflation of health care expenditures and precipitating a crisis in the health insurance system. Policy makers should consider providing comprehensive health services by an accountable care organization to achieve cost savings while ensuring high quality care. PMID- 24349652 TI - Cancer incidence in Korean Vietnam veterans during 1992-2003: the Korean veterans health study. AB - OBJECTIVES: The aim of this study was to investigate the association between Vietnam experience including exposure to military herbicides and cancer incidence in Korean Vietnam War veterans. METHODS: The cancer cases of 185 265 Vietnam veterans from January 1, 1992 to December 31, 2003 were confirmed from the Korea National Cancer Incidence Database. The age-adjusted incidence and standardized incidence ratios (SIRs) were calculated using the male population during 1992 to 2003 as a standard population. RESULTS: The age-adjusted overall cancer incidence per 100 000 person-years was 455.3 in Vietnam veterans. The overall cancer incidence was slightly yet significantly lower in veterans (SIR, 0.97; 95% confidence interval, 0.95 to 0.99) than in the general population. The overall cancer incidence in enlisted soldiers was not lower (SIR, 1.00), whereas that in officers was significantly lower (SIR, 0.87) than in the general population. The incidences of prostate cancer and T-cell lymphoma in all veterans, and lung cancer and bladder cancer in enlisted soldiers, and colon cancer and kidney cancer in non-commissioned officers, and colon cancer, kidney cancer, and prostate cancer in officers, were higher than in the general population. The SIR for overall cancer among Vietnam veterans rose from 0.92 for 1992-1997 to 0.99 for 1998-2003. CONCLUSIONS: The overall cancer incidence in Vietnam veterans was not higher than in the general male population. Vietnam veterans and military rank subcohorts experienced a higher incidence of several cancers, including prostate cancer, T-cell lymphoma, lung cancer, bladder cancer, kidney cancer, and colon cancer than the general population. The SIR for overall cancer increased over time in Vietnam veterans. PMID- 24349654 TI - Relationship between current sleep duration and past suicidal ideation or attempt among Korean adolescents. AB - OBJECTIVES: To comprehensively examine the relationship between current sleep duration and past suicidal idea or attempt among Korean adolescents. METHODS: Data came from the 2009 Korea Youth Risk Behavior Web-based Survey with 75 066 participants (with the participation rate of 97.6%) in 800 middle and high schools. Binary logistic regression was conducted by gender and depressed mood to identify significant factors for suicidal ideation/attempt. The dependent variable was the log odds of suicidal ideation/attempt, while the independent/control variables were sleep duration and other demographic, socio economic and health-related factors. RESULTS: A negative association between sleep duration and suicidal ideation or attempt was weaker for those with depressed mood than for those without such experience in Korea for Year 2009. The odds ratio of suicidal ideation/attempt regarding less than 4 hours of sleep compared to 6 to 7 hours of sleep, was smaller in a group with depressed mood than in a group without such experience, for example, 1.64 (95% confidence interval [CI], 1.29 to 2.08) vs. 2.06 (95% CI, 1.34 to 3.17) for men's suicidal ideation, 2.50 (95% CI, 1.69 to 3.69) vs. 3.89 (95% CI, 1.74 to 8.66) for men's suicidal attempt. A negative association between age (or self-rated health) and suicidal ideation/attempt was also weaker for those with depressed mood than for those without such experience in the nation for the year. CONCLUSIONS: There was a negative association between sleep duration and suicidal ideation/attempt in Korea for Year 2009 and this association was weaker for those with depressed mood than for those without such experience. Based on the findings of this study, adolescents' better mental health and longer, more comfortable sleep might help to prevent their suicidal ideation and attempt in Korea. PMID- 24349653 TI - Cardiovascular health metrics and all-cause and cardiovascular disease mortality among middle-aged men in Korea: the Seoul male cohort study. AB - OBJECTIVES: This study estimated the association of cardiovascular health behaviors with the risk of all-cause and cardiovascular disease (CVD) mortality in middle-aged men in Korea. METHODS: In total, 12 538 men aged 40 to 59 years were enrolled in 1993 and followed up through 2011. Cardiovascular health metrics defined the following lifestyle behaviors proposed by the American Heart Association: smoking, physical activity, body mass index, diet habit score, total cholesterol, blood pressure, and fasting blood glucose. The cardiovascular health metrics score was calculated as a single categorical variable, by assigning 1 point to each ideal healthy behavior. A Cox proportional hazards regression model was used to estimate the hazard ratio of cardiovascular health behavior. Population attributable risks (PARs) were calculated from the significant cardiovascular health metrics. RESULTS: There were 1054 total and 171 CVD deaths over 230 690 person-years of follow-up. The prevalence of meeting all 7 cardiovascular health metrics was 0.67%. Current smoking, elevated blood pressure, and high fasting blood glucose were significantly associated with all cause and CVD mortality. The adjusted PARs for the 3 significant metrics combined were 35.2% (95% confidence interval [CI], 21.7 to 47.4) and 52.8% (95% CI, 22.0 to 74.0) for all-cause and CVD mortality, respectively. The adjusted hazard ratios of the groups with a 6-7 vs. 0-2 cardiovascular health metrics score were 0.42 (95% CI, 0.31 to 0.59) for all-cause mortality and 0.10 (95% CI, 0.03 to 0.29) for CVD mortality. CONCLUSIONS: Among cardiovascular health behaviors, not smoking, normal blood pressure, and recommended fasting blood glucose levels were associated with reduced risks of all-cause and CVD mortality. Meeting a greater number of cardiovascular health metrics was associated with a lower risk of all cause and CVD mortality. PMID- 24349655 TI - Social network characteristics and body mass index in an elderly Korean population. AB - OBJECTIVES: Research has shown that obesity appears to spread through social ties. However, the association between other characteristics of social networks and obesity is unclear. This study aimed to identify the association between social network characteristics and body mass index (BMI, kg/m(2)) in an elderly Korean population. METHODS: This cross-sectional study analyzed data from 657 Koreans (273 men, 384 women) aged 60 years or older who participated in the Korean Social Life, Health, and Aging Project. Network size is a count of the number of friends. Density of communication network is the number of connections in the social network reported as a fraction of the total links possible in the personal (ego-centric) network. Average frequency of communication (or meeting) measures how often network members communicate (or meet) each other. The association of each social network measure with BMI was investigated by multiple linear regression analysis. RESULTS: After adjusting for potential confounders, the men with lower density (<0.71) and higher network size (4-6) had the higher BMI (beta=1.089, p=0.037) compared to the men with higher density (>0.83) and lower size (1-2), but not in the women (p=0.393). The lowest tertile of communication frequency was associated with higher BMI in the women (beta=0.885, p=0.049), but not in the men (p=0.140). CONCLUSIONS: Our study suggests that social network structure (network size and density) and activation (communication frequency and meeting frequency) are associated with obesity among the elderly. There may also be gender differences in this association. PMID- 24349656 TI - Association of selected medical conditions with breast cancer risk in Korea. AB - OBJECTIVES: To estimate the effect of medical conditions in the population of Korea on breast cancer risk in a case-control study. METHODS: The cases were 3242 women with incident, histologically confirmed breast cancer in two major hospitals interviewed between 2001 and 2007. The controls were 1818 women each admitted to either of those two hospitals for a variety of non-neoplastic conditions. Information on each disease was obtained from a standardized questionnaire by trained personnel. Odds ratios (ORs) for each disease were derived from multiple logistic regression adjusted for age, age of menarche, pregnancy, age of first pregnancy, and family history of breast cancer. RESULTS: Among all of the incident breast cancer patients, pre-existing diabetes (OR, 1.33; 95% confidence interval [CI], 0.99 to 1.78), hypertension (OR, 1.46; 95% CI, 1.18 to 1.83), thyroid diseases (OR, 1.26; 95% CI, 1.00 to 1.58), and ovarian diseases (OR, 1.70; 95% CI, 1.23 to 2.35) were associated with an increased risk of breast cancer when other factors were adjusted for. In a stratified analysis by menopausal status, pre-existing hypertension (pre-menopause OR, 0.80; 95% CI, 0.48 to 1.34 vs. post-menopause OR, 1.87; 95% CI, 1.44 to 2.43; p-heterogeneity <0.01) and ovarian disease (pre-menopause OR, 4.20; 95% CI, 1.91 to 9.24 vs. post menopause OR, 1.39; 95% CI, 1.02 to 1.91; p-heterogeneity 0.01) showed significantly different risks of breast cancer. CONCLUSIONS: Our results suggest the possibility that medical conditions such as hypertension affect breast cancer development, and that this can differ by menopausal status. Our study also indicates a possible correlation between ovarian diseases and breast cancer risk. PMID- 24349657 TI - A trend analysis of the prevalence, awareness, treatment, and control of hypertension by age group. AB - OBJECTIVES: We examined the trends in prevalence, awareness, treatment, and control of hypertension in Korea as a basis for improving hypertension control programs. METHODS: 12 598 participants of the Korean National Health and Nutrition Examination Survey were included in this study. Weighted linear regression to test time trends from 2007 to 2011 was performed. RESULTS: The prevalence of hypertension was 20.7% in 2007, 29.4% in 2009, and 26.2% in 2011. Awareness of hypertension was 64.8% in 2007 and 61.1% in 2011. Awareness in those aged 65 and over was greater than in younger groups (age 19 to 44 and 45 to 64; p<0.001). The treatment rates were 58.4% in 2007 and 56.8% in 2011. The treatment rate was greater for those 65 and over than for younger age groups (p<0.001). The percentage of controlled hypertension was 37.6% in 2011. The percentage of controlled hypertension in those 65 and over was higher than in younger age groups (p<0.001). The treatment-control rates were 65.9% in 2007 and 67.7% in 2011. The prevalence of hypertension was higher in the males (p<0.001), while the awareness (p<0.001), treatment (p<0.001), and control (p<0.001) rates were higher in the females. CONCLUSIONS: The prevalence of hypertension was increasing and the hypertension awareness, treatment, and control rates were low in younger age groups and males. PMID- 24349658 TI - Comparison of estimation algorithms in single-molecule localization. AB - Different techniques have been advocated for estimating single molecule locations from microscopy images. The question arises as to which technique produces the most accurate results. Various factors, e.g. the stochastic nature of the photon emission/detection process, extraneous additive noise, pixelation, etc., result in the estimated single molecule location deviating from its true location. Here, we review the results presented by [Abraham et. al, Optics Express, 2009, 23352 23373], where the performance of the maximum likelihood and nonlinear least squares estimators for estimating single molecule locations are compared. Our results show that on average both estimators recover the true single molecule location in all scenarios. Comparing the standard deviations of the estimates, we find that in the absence of noise and modeling inaccuracies, the maximum likelihood estimator is more accurate than the non-linear least squares estimator, and attains the best achievable accuracy for the sets of experimental and imaging conditions tested. In the presence of noise and modeling inaccuracies, the maximum likelihood estimator produces results with consistent accuracy across various model mismatches and misspecifications. At high noise levels, neither estimator has an accuracy advantage over the other. We also present new results regarding the performance of the maximum likelihood estimator with respect to the objective function used to fit data containing both additive Gaussian and Poisson noise. Comparisons were also carried out between two localization accuracy measures derived previously. User-friendly software packages were developed for single molecule location estimation (EstimationTool) and localization accuracy calculations (FandPLimitTool). PMID- 24349660 TI - Full-Field versus Multifocal Electroretinography. PMID- 24349659 TI - Extracellular membrane vesicles from umbilical cord blood-derived MSC protect against ischemic acute kidney injury, a feature that is lost after inflammatory conditioning. AB - BACKGROUND: Mesenchymal stromal cells (MSC) are shown to have a great therapeutic potential in many immunological disorders. Currently the therapeutic effect of MSCs is considered to be mediated via paracrine interactions with immune cells. Umbilical cord blood is an attractive but still less studied source of MSCs. We investigated the production of extracellular membrane vesicles (MVs) from human umbilical cord blood derived MSCs (hUCBMSC) in the presence (MVstim) or absence (MVctrl) of inflammatory stimulus. METHODS: hUCBMSCs were cultured in serum free media with or without IFN-gamma and MVs were collected from conditioned media by ultracentrifugation. The protein content of MVs were analyzed by mass spectrometry. Hypoxia induced acute kidney injury rat model was used to analyze the in vivo therapeutic potential of MVs and T-cell proliferation and induction of regulatory T cells were analyzed by co-culture assays. RESULTS: Both MVstim and MVctrl showed similar T-cell modulation activity in vitro, but only MVctrls were able to protect rat kidneys from reperfusion injury in vivo. To clarify this difference in functionality we made a comparative mass spectrometric analysis of the MV protein contents. The IFN-gamma stimulation induced dramatic changes in the protein content of the MVs. Complement factors (C3, C4A, C5) and lipid binding proteins (i.e apolipoproteins) were only found in the MVctrls, whereas the MVstim contained tetraspanins (CD9, CD63, CD81) and more complete proteasome complex accompanied with MHCI. We further discovered that differently produced MV pools contained specific Rab proteins suggesting that same cells, depending on external signals, produce vesicles originating from different intracellular locations. CONCLUSIONS: We demonstrate by both in vitro and in vivo models accompanied with a detailed analysis of molecular characteristics that inflammatory conditioning of MSCs influence on the protein content and functional properties of MVs revealing the complexity of the MSC paracrine regulation. PMID- 24349661 TI - Multifocal electroretinography after high dose chloroquine therapy for malaria. AB - PURPOSE: To investigate changes in multifocal electroretinography (mfERG) parameters associated with high dose chloroquine therapy for treatment of malaria in the Amazonia region of Brazil. METHODS: Forty-eight subjects who had received chloroquine treatment for single or multiple malaria infections with a cumulative dose ranging from 1,050 to 27,000mg were included. The control group consisted of 37 healthy aged-matched subjects. Data was collected on amplitude and implicit time of the N1, P1 and N2 waves in the central macular hexagon (R1) and in five concentric rings at different retinal eccentricities (R2-R6). RESULTS: No significant difference was observed in any mfERG parameter between chloroquine treated patients and control subjects. A comparison with previous data obtained from patients with rheumatologic disorders in the same region of Brazil who had received larger cumulative doses of chloroquine and had displayed mfERG changes, indicated that retinal toxicity seems to be dependent on cumulative dose. CONCLUSION: Lack of mfERG changes in the current study suggests that intensive high dose chloroquine therapy for treatment of malaria is not associated with retinal toxicity. PMID- 24349662 TI - Pattern electroretinography in glaucoma suspects and early primary open angle glaucoma. AB - PURPOSE: To explore retinal ganglion cell (RGC) dysfunction in glaucoma suspects and patients with early primary open angle glaucoma (POAG) using pattern electroretinography (PERG). METHODS: Twenty glaucoma suspects (glaucomatous optic disc appearance), 15 early POAG (based on abnormal discs and abnormal visual fields) and 16 normal controls were enrolled. Transient PERG was recorded in response to 0.8 degrees and 16 degrees black and white checkerboard stimuli. Amplitude and peak time (latency) of the P50 and N95 components of the PERG response, and the ratio of N95 amplitude in response to 0.8 degrees and 16 degrees checks were measured. RESULTS: N95 peak time (latency) was significantly increased in both early manifest POAG and glaucoma suspects as compared to normal controls (P<0.001). In early POAG, N95 amplitude in response to small (0.8 degrees ) checks and the small/large check ratio were reduced in comparison to normal eyes (P<0.05). However, in glaucoma suspects no significant N95 amplitude reduction was observed. No significant difference was observed among the study groups in terms of P50 amplitude or peak time. CONCLUSION: The N95 PERG response demonstrated uncoupled peak time and amplitude alterations in glaucoma. N95 peak time was significantly increased both in glaucoma suspects and early POAG; N95 amplitude reduction was present only in early POAG. PERG may detect RGC dysfunction (increased latency) before cell death (decreased amplitude) occurs. PMID- 24349663 TI - Impression cytology in eyes with clinical and confocal scan features of acanthamoeba keratitis. AB - PURPOSE: To report impression cytology findings in specimens obtained from eyes with clinical and confocal microscopic features of Acanthamoeba keratitis (AK). METHODS: In this interventional case series, impression cytology was obtained from corneas of patients with clinical and confocal microscopic features indicative of AK. Specimens were stained with Periodic acid-Schiff/Papanicolaou (PAS/PAP) and examined for the presence of PAS-reactive Acanthamoeba cysts and/or hyperchromatic pear-shaped trophozoites. All specimens were then decolorized and re-stained with calcofluor white (CFW) for the presence of chemofluorescent cysts. RESULTS: Fifty-six eyes of 50 patients with mean age of 25.5+/-9.3 (range, 17 to 78) years were evaluated. Forty-one (82%) cases were female and 51 (91.1%) eyes had history of contact lens wear. PAS-reactive Acanthamoeba cysts and/or hyperchromatic pear-shaped trophozoites were identified in 53 eyes (94.6%), 2 of which demonstrated only trophozoite- like structures. CFW staining was able to reveal the presence of chemofluorescent cysts in all 51 specimens (91.1%) in which cysts had been demonstrated with PAS/PAP staining. Trophozoites were not detected with CFW due to background staining of the cellulose acetate strip used for impression cytology. CONCLUSION: Corneal impression cytology, stained with PAS/PAP or with CFW, successfully detects Acanthamoeba and can be employed for early noninvasive diagnosis of AK. PMID- 24349664 TI - Prevalence of keratoconus and subclinical keratoconus in subjects with astigmatism using pentacam derived parameters. AB - PURPOSE: To determine the prevalence of keratoconus (KCN) and subclinical KCN among subjects with two or more diopters (D) of astigmatism, and to compare Pentacam parameters among these subjects. METHODS: One hundred and twenty eight eyes of 64 subjects with astigmatism >=2D were included in the study. All subjects underwent a complete ophthalmic examination which included refraction, visual acuity measurement, slit lamp biomicroscopy, retinoscopy, fundus examination, conventional corneal topography and elevation-based topography with Pentacam. The diagnosis of KCN and subclinical KCN was made by observing clinical findings and topographic features; and confirmed by corneal thickness and elevation maps of Pentacam. Several parameters acquired from Pentacam were analyzed employing the Mann-Whitney U Test. RESULTS: Mean age of the study population was 29.9+/-9.8 (range 15-45) years which included 39 (60.9%) female and 25 (39.1%) male subjects. Maximum corneal power, index of vertical asymmetry, keratoconus index and elevation values were significantly higher and pachymetry was significantly thinner in eyes with clinical or subclinical KCN than normal astigmatic eyes (P< 0.05). CONCLUSION: The current study showed that subjects with 2D or more of astigmatism who present to outpatient clinics should undergo corneal topography screening for early diagnosis of KCN even if visual acuity is not affected. Pentacam may provide more accurate information about anterior and posterior corneal anatomy especially in suspect eyes. PMID- 24349665 TI - Axial length to corneal radius of curvature ratio and refractive errors. AB - PURPOSE: To determine the distribution of axial length (AL) to corneal radius of curvature (CRC) ratio and to evaluate its association with refractive errors in an Iranian population. METHODS: In this cross sectional study, multistage cluster sampling was used to select subjects 40-64 years of age residing in Shahroud, northern Iran. All subjects underwent manifest and cycloplegic refraction, and biometry using the Allegro Biograph (WaveLight AG, Erlangen, Germany). Individuals with a history of intraocular surgery, extensive pterygia and ocular trauma were excluded. RESULTS: Of a total of 6,311 patients, 5190 (82.2%) participated in the study. We excluded 247 patients to adhere with study criteria and 132 patients due to missing data. Mean AL/CRC was 3.034 [95% confidence interval (CI), 3.031-3.037]. AL/CRC was 3.028 and 3.042 in female and male subjects, respectively (P<0.001). The R2 coefficients between spherical equivalent (SE) refractive error and AL/CRC, AL, CRC, lens thickness, and anterior chamber depth were 0.607, 0.351, 0.012, 0.038, and 0.091, respectively. Linear regression showed a 12.1 diopter (D) shift towards myopia with every 1 unit increase in AL/CRC (P<0.001). Mean AL/CRC was 3.472 among myopes with SE less than-5.0D; this value decreased linearly and was as low as 2.690 among hyperopes with SE more than 5.0D. R2 coefficients for AL/CRC with spherical and cylindrical power were 0.560 and 0.071, respectively. CONCLUSIONS: Minimal changes in AL/CRC lead to large changes in refractive error. The correlation between refractive errors was significantly stronger with the AL/CRC ratio than with AL and CRC alone. PMID- 24349666 TI - Prevalence of refractive errors; the yazd eye study. AB - PURPOSE: To determine the prevalence of refractive errors in Yazd, central Iran. METHODS: This population-based study was performed in 2010-2011 and targeted adults aged 40 to 80 years. Multi-stage random cluster sampling was applied to select samples from urban and rural residents of Yazd. Manifest refraction, visual acuity measurement, retinoscopy and funduscopy were performed for all subjects. Myopia, hyperopia, astigmatism and anisometropia were defined as spherical equivalent (SE) <-0.50 diopters (D), SE >+0.50 D, cylindrical error >0.5 D and SE difference >=1 D between fellow eyes, respectively. RESULTS: From a total of 2,320 selected individuals, 2,098 subjects (90.4%) participated out of which 198 subjects were excluded due to previous eye surgery. The prevalence (95% confidence interval) for myopia, hyperopia, astigmatism, anisometropia, -6 D myopia or worse, and 4 D hyperopia or worse was 36.5% (33.6-39.4%), 20.6% (17.9 23.3%), 53.8% (51.3-56.3%), 11.9% (10.4-13.4%), 2.3% (1.6-2.9%) and 1.2% (0.6 1.8%), respectively. The prevalence of hyperopia, astigmatism and anisometropia increased with age. The prevalence of myopia was significantly higher in female subjects. The prevalence of with-the-rule, against-the-rule and oblique astigmatism was 35.7%, 13.4% and 4.6%, respectively. The prevalence of against the-rule astigmatism increased with age (P<0.001); with-the-rule astigmatism was more common in women (P=0.038). CONCLUSION: More than half of the study population had refractive errors; the prevalence of myopia and astigmatism was higher than earlier studies in Iran. Since refractive errors are a major cause of avoidable visual impairment, their high prevalence in this survey is important from a public health perspective. PMID- 24349667 TI - Rate of Post-traumatic Endophthalmitis with or without Injection of Balanced Salt Solution. AB - PURPOSE: In a study complementing a previous multicenter randomized clinical trial on prophylactic injection of intraocular antibiotics during primary repair of penetrating eye injuries (PEIs), we sought to determine whether needle entrance and injection of balanced salt solution (BSS), per se, could increase the rate of acute post-traumatic bacterial endophthalmitis (APBE). METHODS: Patients randomized to the BSS injection arm (n=167) of the Traumatic Endophthalmitis Trial, and eligible patients who had refused enrollment and received no intraocular injections during primary repair (n=111) were compared for the development of APBE. RESULTS: APBE occurred in 8 of 167 (4.8%) eyes in the BSS group and in 5 of 111 (4.5%) eyes in the non-injection group (P=0.91). Retained intraocular foreign bodies were present in 46 eyes including 25 (15%) eyes in the BSS injection group and 21 (18.9%) eyes in the non-injection group (P=0.38). Logistic regression analysis showed no significant difference between BSS injected and non-injected eyes in terms of APBE (P=0.69). However, the presence of intraocular foreign bodies was strongly associated with the risk of endophthalmitis (P<0.001, OR=14.1, 95% CI: 4.1-48.5). CONCLUSION: Needle entrance and intraocular injection of BSS during primary repair of PEIs does not increase the risk of APBE. PMID- 24349668 TI - The ubiquitin-proteasome system and microvascular complications of diabetes. AB - The ubiquitin-proteasome system (UPS) is the mainstay of protein quality control which regulates cell cycle, differentiation and various signal transduction pathways in eukaryotic cells. The timely and selective degradation of surplus and/or aberrant proteins by the UPS is essential for normal cellular physiology. Any disturbance, delay or exaggeration in the process of selection, sequestration, labeling for degradation and degradation of target proteins by the UPS will compromise cellular and tissue homeostasis. High blood glucose or hyperglycemia caused by diabetes disrupts normal vascular function in several target organs including the retina and kidney resulting in the development of diabetic retinopathy (DR) and diabetic nephropathy (DN). We and others have shown that hyperglycemia and oxidative stress modulate UPS activity in the retina and kidney. The majority of studies have focused on the kidney and provided insights into the contribution of dysregulated UPS to microvascular damage in DN. The eye is a unique organ in which a semi-fluid medium, the vitreous humor, separates the neural retina and its anastomosed blood vessels from the semi-solid lens tissue. The complexity of the cellular and molecular components of the eye may require a normal functioning and well tuned UPS for healthy vision. Altered UPS activity may contribute to the development of retinal microvascular complications of diabetes. A better understanding of the molecular nature of the ocular UPS function under normal and diabetic conditions is essential for development of novel strategies targeting its activity. This review will discuss the association of retinal vascular cell UPS activity with microvascular damage in DR with emphasis on alterations of the PA28 subunits of the UPS. PMID- 24349670 TI - Peripheral exudative hemorrhagic chorioretinopathy: a variant of polypoidal choroidal vasculopathy? AB - PURPOSE: To report a case of peripheral exudative hemorrhagic chorioretinopathy (PEHCR) in an elderly patient. CASE REPORT: A 74-year-old Caucasian woman, with a 20-year history of a stable choroidal nevus in her right eye, was referred for evaluation of two small hemorrhagic pigment epithelial detachments (PEDs) affecting the temporal peripheral fundus of the same eye. Nine months later, the lesions became larger and indocyanine green angiography revealed polypoidal choroidal vascular changes corresponding to the location of the ophthalmoscopically visible PEDs. Despite one session of verteporfin photodynamic therapy, the lesions continued to enlarge eventually resulting in the development of a large hemorrhagic PED, which failed to respond to two subsequent injections of intravitreal bevacizumab. The final ophthalmoscopic appearance of the large hemorrhagic PED was typical of PEHCR. CONCLUSION: This case suggests that polypoidal choroidal vascular changes similar to that seen in our patient may underlie the development of PEHCR in some cases. PMID- 24349669 TI - Cerebrospinal fluid pressure and glaucoma. AB - Eyes with normal-pressure glaucoma and those with high-pressure glaucoma can show a similar optic nerve head appearance, while eyes with vascular optic neuropathies show a markedly different optic disc appearance. Factors in addition to intraocular pressure (IOP) may thus play a role in the pathogenesis of glaucomatous optic neuropathy. Clinical and experimental studies showed that (1) physiologic associations between cerebrospinal fluid (CSF) pressure, systemic arterial blood pressure, IOP and body mass index exist; (2) a low CSF pressure was associated with the development of glaucomatous optic nerve damage in cats; (3) patients with normal (intraocular) pressure glaucoma had significantly lower CSF pressure and a higher trans lamina cribrosa pressure difference when compared to normal subjects; and (4) patients with normal- pressure glaucoma as compared with patients with high-pressure glaucoma have a significantly narrower orbital CSF space. A shallow orbital CSF space has been shown to be associated with a low CSF pressure. Due to anatomic reasons, the orbital CSF pressure and the optic nerve tissue pressure (and not the atmospheric pressure) form the retro-laminar counter-pressure against the IOP and are thus part of the trans-lamina cribrosa pressure difference and gradient. Assuming that an elevated trans-lamina cribrosa pressure difference and a steeper trans-lamina cribrosa pressure gradient are important for glaucomatous optic nerve damage, a low orbital CSF pressure would therefore play a role in the pathogenesis of normal-(intraocular) pressure glaucoma. Due to the association between CSF pressure and blood pressure, a low blood pressure could be indirectly involved. PMID- 24349671 TI - Retinitis Pigmentosa Associated with Vasoproliferative Tumors and Coats-like Fundus. AB - PURPOSE: To report two cases of retinitis pigmentosa (RP) associated with vasoproliferative tumors (VPTs) and Coats-like fundus. CASE REPORTS: Two patients with RP presented with recent loss of vision due to combined VPTs and Coats-like retinal vascular alterations. One patient had two VPTs with adjacent capillary nonperfusion, telangiectasia and aneurysmal vascular changes in one eye. The other patient had prominent VPT with Coats-like retinal vascular alterations in both eyes. These lesions received treatment resulting in improved vision in both patients. CONCLUSION: Although rare, VPTs and Coats-like retinal vascular alterations including retinal exudation associated with telangiectatic vessels, aneurysmal changes and capillary nonperfusion may occur in patients with RP. PMID- 24349672 TI - Hypotropic dissociated vertical deviation; a case report. AB - PURPOSE: To report the clinical features of a rare case of hypotropic dissociated vertical deviation (DVD). CASE REPORT: A 25-year-old female was referred with unilateral esotropia, hypotropia and slow variable downward drift in her left eye. She had history of esotropia since she had been 3-4 months of age. Best corrected visual acuity was 20/20 in her right eye and 20/40 in the left one when hyperopia was corrected. She underwent bimedial rectus muscle recession of 5.25mm for 45 prism diopters (PDs) of esotropia. She was orthophoric 3 months after surgery and no further operation was planned for correction of the hypotropic DVD. CONCLUSION: This rare case of hypotropic DVD showed only mild amblyopia in her non-fixating eye. The etiology was most probably acquired considering hyperopia as a sign of early onset accommodative esotropia. PMID- 24349673 TI - A case of primary congenital glaucoma. PMID- 24349674 TI - Optical coherence tomography findings in a patient with myelinated retinal nerve fiber layer. PMID- 24349675 TI - Indications and techniques of endoscope assisted vitrectomy. AB - The popularization of ophthalmic endoscopy has been promoted by recent technological advancements that increase the number of indications for endoscopy. These advancements have improved the endoscope's capabilities in its two fundamental surgical advantages: (1) bypassing anterior segment opacities, and (2) visualizing anteriorly positioned structures such as the ciliary bodies and sub-iris space. In this article, the current state of the ophthalmic endoscope is reviewed alongside its growing number of applications in glaucoma, vitreoretinal, and ocular trauma surgery. We describe the role of endoscopy in endocyclophotocoagulation for glaucoma, cyclitic membrane peeling in hypotony, retinal detachment surgery, intraocular foreign body removal, severe endophthalmitis, and pediatric traumatic vitreoretinal surgery. This review examines both the pearls and limitations of the ophthalmic application of endoscopy. In doing so, we hope to provide guidelines for using the endoscope and also to highlight applications of endoscopy that merit further study. PMID- 24349676 TI - Behcet's Disease: Autoimmune or Autoinflammatory? PMID- 24349677 TI - Financial Distress in Cancer Patients. AB - Novel diagnostic and therapeutic options offer hope to cancer patients with both localized and advanced disease. However, many of these treatments are often costly and even well-insured patients can face high out-of-pocket costs. Families may also be at risk of financial distress due to lost wages and other treatment related expenses. Research is needed to measure and characterize financial distress in cancer patients and understand how it affects their quality of life. In addition, health care providers need to be trained to counsel patients and their families so they can make patient-centered treatment decisions that reflect their preferences and values. PMID- 24349678 TI - Prenatal exposure to phthalates is associated with decreased anogenital distance and penile size in male newborns. AB - Reproductive effects from phthalate exposure have been documented mostly in animal studies. This study explored the association between prenatal exposure to phthalate metabolites, anogenital distance and penile measurements in male newborns in Toluca, State of Mexico. A total of 174 pregnant women provided urine samples for phthalate analysis during their last prenatal visit, and the 73 who gave birth to male infants were included in the study. The 73 male newborns were weighed and measured using standardized methods after delivery. After adjusting for creatinine and supine length at birth, significant inverse associations were observed between an index of prenatal exposure to total phthalate exposure and the distance from the anus to anterior base of the penis (beta = -0.191 mm per 1 MUg/l, P = 0.037), penile width (beta = -0.0414, P = 0.050) and stretched length (beta = -0.2137, P = 0.034); prenatal exposure to mono-2-ethylhexyl phthalate exposure was associated with a reduction in the stretched length of the penis (beta = -0.2604, P = 0.050). Human exposure to phthalates is a public health concern, and the system most vulnerable to its potential effects seems to be the immature male reproductive tract. PMID- 24349679 TI - Post-traumatic stress in Crohn's disease and its association with disease activity. AB - OBJECTIVE: Violence, accidents and natural disasters are known to cause post traumatic stress, which is typically accompanied by fear, suffering and impaired quality of life. Similar to chronic diseases, such events preoccupy the patient over longer periods. We hypothesised that post-traumatic stress could also be caused by Crohn's disease (CD), and that CD specific post-traumatic stress could be associated with an increased risk of disease exacerbation. METHODS: A cohort of CD patients was observed over 18 months in various types of locations providing gastroenterological treatment in Switzerland. The cohort included 597 consecutively recruited adults. At inclusion, CD specific post-traumatic stress was assessed using the Post-traumatic Diagnostic Scale (range 0-51 points). During follow-up, clinical aggravation was assessed by combining important outcome measures. Patients with post-traumatic stress levels suggestive of a post traumatic stress disorder (>= 15 points) were compared with patients with lower post-traumatic stress levels as well as with patients without post-traumatic stress. Also, the continuous relation between post-traumatic stress severity and risk of disease exacerbation was assessed. RESULTS: The 88 (19.1%) patients scoring >=15 points had 4.3 times higher odds of exacerbation (95% CI 2.6 to 7.2) than the 372 (80.9%) patients scoring <15 points, and 13.0 times higher odds (95% CI 3.6 to 46.2) than the 45 (9.8%) patients scoring 0 points. The odds of exacerbation increased by 2.2 (95% CI 1.6 to 2.8) per standard deviation of post traumatic stress. CONCLUSIONS: CD specific post-traumatic stress is frequent and seems to be associated with exacerbation of CD. Thus gastroenterologists may want to ask about symptoms of post-traumatic stress and, where relevant, offer appropriate management according to current knowledge. PMID- 24349680 TI - Synthesis of cyclobutane lignans via an organic single electron oxidant-electron relay system. AB - A direct method to synthesize lignan cyclobutanes and analogs via photoinduced electron transfer is presented. A variety of oxygenated alkenes are employed to furnish terminal or substituted cyclobutane adducts with complete regiocontrol, yielding cycloadducts with trans stereochemistry. Key to minimizing competing cycloreversion is the inclusion of an aromatic electron relay (ER). This method has been adapted to the synthesis of the natural products magnosalin and pellucidin A. PMID- 24349681 TI - An introduction to the special issue on Multisensory Perception. PMID- 24349682 TI - The roles of physical and physiological simultaneity in audiovisual multisensory facilitation. AB - A series of experiments measured the audiovisual stimulus onset asynchrony (SOAAV), yielding facilitative multisensory integration. We evaluated (1) the range of SOAAV over which facilitation occurred when unisensory stimuli were weak; (2) whether the range of SOAAV producing facilitation supported the hypothesis that physiological simultaneity of unisensory activity governs multisensory facilitation; and (3) whether AV multisensory facilitation depended on relative stimulus intensity. We compared response-time distributions to unisensory auditory (A) and visual (V) stimuli with those to AV stimuli over a wide range (300 and 20 ms increments) of SOAAV, across four conditions of varying stimulus intensity. In condition 1, the intensity of unisensory stimuli was adjusted such that d' ~ 2. In condition 2, V stimulus intensity was increased (d' > 4), while A stimulus intensity was as in condition 1. In condition 3, A stimulus intensity was increased (d' > 4) while V stimulus intensity was as in condition 1. In condition 4, both A and V stimulus intensities were increased to clearly suprathreshold levels (d' > 4). Across all conditions of stimulus intensity, significant multisensory facilitation occurred exclusively for simultaneously presented A and V stimuli. In addition, facilitation increased as stimulus intensity increased, in disagreement with inverse effectiveness. These results indicate that the requirements for facilitative multisensory integration include both physical and physiological simultaneity. PMID- 24349683 TI - Effect of visual stimuli on temporal order judgments of a sequence of pure tones. AB - We investigated what effect visual spatial information had on auditory temporal order judgments (TOJs) and examined what effect visual stimuli had on the TOJs of sequences of pure tones in experiment 1. The auditory stimuli were sequences of four distinct pure tones. The visual stimuli consisted of two vertically aligned flashes: one flashed before the first tone and the other flashed after the last tone. Participants judged whether the temporal order of the second and third tones in auditory stimuli occurred with the higher tone being first or the lower tone being first. As a result, the proportion of responses for higher-tone-first increased when the flash of the upper LED preceded that of the lower LED, independent of the actual temporal order. Participants in experiment 2 were asked to make simultaneity judgments instead, which were also affected by visual stimuli. The auditory stimuli in experiment 3 were the same as those in experiment 1, whereas the visual stimuli consisted of two horizontally aligned flashes. Furthermore, the participants made TOJs, which were not affected by the horizontally aligned visual stimuli. We concluded that vertically aligned visual stimuli had an effect on auditory TOJs with some response bias. PMID- 24349684 TI - Early sound symbolism for vowel sounds. AB - Children and adults consistently match some words (e.g., kiki) to jagged shapes and other words (e.g., bouba) to rounded shapes, providing evidence for non arbitrary sound-shape mapping. In this study, we investigated the influence of vowels on sound-shape matching in toddlers, using four contrasting pairs of nonsense words differing in vowel sound (/i/ as in feet vs. /o/ as in boat) and four rounded-jagged shape pairs. Crucially, we used reduplicated syllables (e.g., kiki vs. koko) rather than confounding vowel sound with consonant context and syllable variability (e.g., kiki vs. bouba). Toddlers consistently matched words with /o/ to rounded shapes and words with /i/ to jagged shapes (p < 0.01). The results suggest that there may be naturally biased correspondences between vowel sound and shape. PMID- 24349685 TI - Effects of retinal position on the visuo-motor adaptation of visual stability in a virtual environment. AB - Although the retinal image changes a great deal with the movement of our head or eyes, we perceive a stable world (a phenomenon known as visual stability or position constancy). Visual stability adaptively changes for each new combination of vision and head motion, or to compensate for manipulated visuo-motor gain. This study aims to investigate the effects of retinal positions on visuo-motor adaptation and to discuss the neural mechanisms involved. I found that visuo motor adaptation occurred, and was transferable from right to left visual fields (Experiment 1), between the upper and lower visual fields (Experiment 2), and between the central and peripheral visual fields (Experiment 4), and that for the left visual field (Experiment 1) and the large visual field (Experiment 3) visuo motor adaptations were effective. The dominance of the central vision was found in Experiment 3 but not found in Experiment 4. These results suggest that the visuo-motor adaptation of visual stability was not specific to the retinal location, but is processed by a relatively high level of the perceptual system. PMID- 24349686 TI - Effects of head movement and proprioceptive feedback in training of sound localization. AB - We investigated the effects of listeners' head movements and proprioceptive feedback during sound localization practice on the subsequent accuracy of sound localization performance. The effects were examined under both restricted and unrestricted head movement conditions in the practice stage. In both cases, the participants were divided into two groups: a feedback group performed a sound localization drill with accurate proprioceptive feedback; a control group conducted it without the feedback. Results showed that (1) sound localization practice, while allowing for free head movement, led to improvement in sound localization performance and decreased actual angular errors along the horizontal plane, and that (2) proprioceptive feedback during practice decreased actual angular errors in the vertical plane. Our findings suggest that unrestricted head movement and proprioceptive feedback during sound localization training enhance perceptual motor learning by enabling listeners to use variable auditory cues and proprioceptive information. PMID- 24349688 TI - Useful field of view in simulated driving: Reaction times and eye movements of drivers. AB - To examine the spatial distribution of a useful field of view (UFOV) in driving, reaction times (RTs) and eye movements were measured in simulated driving. In the experiment, a normal or mirror-reversed letter "E" was presented on driving images with different eccentricities and directions from the current gaze position. The results showed significantly slower RTs in the upper and upper left directions than in the other directions. The RTs were significantly slower in the left directions than in the right directions. These results suggest that the UFOV in driving may be asymmetrical among the meridians in the visual field. PMID- 24349689 TI - SFS? Not likely.... AB - SFS (Shape From Shading) theory is based upon the Lambertian paradigm. Our visual demonstrations imply that this paradigm fails to apply to the conventional stimuli used to probe vision. PMID- 24349687 TI - Uni- and multisensory brain areas are synchronised across spectators when watching unedited dance recordings. AB - The superior temporal sulcus (STS) and gyrus (STG) are commonly identified to be functionally relevant for multisensory integration of audiovisual (AV) stimuli. However, most neuroimaging studies on AV integration used stimuli of short duration in explicit evaluative tasks. Importantly though, many of our AV experiences are of a long duration and ambiguous. It is unclear if the enhanced activity in audio, visual, and AV brain areas would also be synchronised over time across subjects when they are exposed to such multisensory stimuli. We used intersubject correlation to investigate which brain areas are synchronised across novices for uni- and multisensory versions of a 6-min 26-s recording of an unfamiliar, unedited Indian dance recording (Bharatanatyam). In Bharatanatyam, music and dance are choreographed together in a highly intermodal-dependent manner. Activity in the middle and posterior STG was significantly correlated between subjects and showed also significant enhancement for AV integration when the functional magnetic resonance signals were contrasted against each other using a general linear model conjunction analysis. These results extend previous studies by showing an intermediate step of synchronisation for novices: while there was a consensus across subjects' brain activity in areas relevant for unisensory processing and AV integration of related audio and visual stimuli, we found no evidence for synchronisation of higher level cognitive processes, suggesting these were idiosyncratic. PMID- 24349690 TI - Adaptation effects to attractiveness of face photographs and art portraits are domain-specific. AB - We studied the neural coding of facial attractiveness by investigating effects of adaptation to attractive and unattractive human faces on the perceived attractiveness of veridical human face pictures (Experiment 1) and art portraits (Experiment 2). Experiment 1 revealed a clear pattern of contrastive aftereffects. Relative to a pre-adaptation baseline, the perceived attractiveness of faces was increased after adaptation to unattractive faces, and was decreased after adaptation to attractive faces. Experiment 2 revealed similar aftereffects when art portraits rather than face photographs were used as adaptors and test stimuli, suggesting that effects of adaptation to attractiveness are not restricted to facial photographs. Additionally, we found similar aftereffects in art portraits for beauty, another aesthetic feature that, unlike attractiveness, relates to the properties of the image (rather than to the face displayed). Importantly, Experiment 3 showed that aftereffects were abolished when adaptors were art portraits and face photographs were test stimuli. These results suggest that adaptation to facial attractiveness elicits aftereffects in the perception of subsequently presented faces, for both face photographs and art portraits, and that these effects do not cross image domains. PMID- 24349691 TI - Perceptual organization in colour perception: Inverting the gamut expansion effect. AB - In the well-known gamut expansion effect, uniformly coloured target patches are perceived as more colourful when they are embedded in a uniform grey surround than when they are embedded in a variegated one. Here, we provide a demonstration showing that this effect can be inverted when the uniformly coloured target patches are replaced by variegated ones. This observation suggests that the gamut expansion effect is due to mechanisms of transparency perception rather than due to contrast adaptation. PMID- 24349692 TI - Displaying optic flow to simulate locomotion: Comparing heading and steering. AB - Optic flow can be used by humans to determine their direction of heading as well as controlling steering. Dot-flow displays have been widely used to investigate these abilities but it is unclear whether photorealistic textures would provide better information for controlling high-speed steering. Here, we examine the accuracy of heading judgements from dot-flow displays of different densities and luminance and then compare to a scene containing a textured ground. We then examine steering behaviour using these same displays to determine whether accurate heading conditions necessarily equate to successful steering. Our findings suggest that the bright dense dot-flow displays led to equivalent performance as the ground texture when judging heading, and this was also true when steering. The intermediate dot-flow conditions (with fewer and faded dots) revealed that some conditions that led to accurate heading judgements were insufficient for accurate steering. It seems, therefore, that heading perception should not be considered synonymous with successful steering control, and displays that support one ability will not necessarily support the other. PMID- 24349693 TI - Helmholtz illusion makes you look fit only when you are already fit, but not for everyone. AB - A square filled with horizontal stripes is perceived as thinner than one with vertical stripes (Helmholtz illusion). This is not consistent with a common belief that horizontally striped clothing makes a person look fatter, and studies on this problem have shown inconsistent results. Here, we demonstrate three factors that could have complicated the issue. First, the Helmholtz effect is stronger for a thin figure than for a fat one, with possible reversal for the latter. Second, we found large variability across participants, suggesting dependence on features to attend. Third, there was strong hysteresis as to the order of testing fat and thin figures, suggesting the effect of surrounding people in daily life. There can be yet other factors, but we should note that this apparently simple case of application of a geometrical illusion in daily perception should be taken as a rather complex phenomenon. PMID- 24349695 TI - The small step toward asymmetry: Aesthetic judgment of broken symmetries. AB - Symmetry and complexity both affect the aesthetic judgment of abstract patterns. However, although beauty tends to be associated with symmetry, there are indications that small asymmetries can also be beautiful. We investigated the influence of small deviations from symmetry on people's aesthetic liking for abstract patterns. Breaking symmetry not only decreased patterns' symmetry but also increased their complexity. While an increase of complexity normally results in a higher liking, we found that even a small decrease of symmetry has a strong effect, such that patterns with slightly broken symmetries were significantly less liked than fully symmetric ones. PMID- 24349694 TI - Spatial location in brief, free-viewing face encoding modulates contextual face recognition. AB - The effect of the spatial location of faces in the visual field during brief, free-viewing encoding in subsequent face recognition is not known. This study addressed this question by tagging three groups of faces with cheating, cooperating or neutral behaviours and presenting them for encoding in two visual hemifields (upper vs. lower or left vs. right). Participants then had to indicate if a centrally presented face had been seen before or not. Head and eye movements were free in all phases. Findings showed that the overall recognition of cooperators was significantly better than cheaters, and it was better for faces encoded in the upper hemifield than in the lower hemifield, both in terms of a higher d' and faster reaction time (RT). The d' for any given behaviour in the left and right hemifields was similar. The RT in the left hemifield did not vary with tagged behaviour, whereas the RT in the right hemifield was longer for cheaters than for cooperators. The results showed that memory biases in contextual face recognition were modulated by the spatial location of briefly encoded faces and are discussed in terms of scanning reading habits, top-left bias in lighting preference and peripersonal space. PMID- 24349696 TI - Fast lemons and sour boulders: Testing crossmodal correspondences using an internet-based testing methodology. AB - According to a popular family of hypotheses, crossmodal matches between distinct features hold because they correspond to the same polarity on several conceptual dimensions (such as active-passive, good-bad, etc.) that can be identified using the semantic differential technique. The main problem here resides in turning this hypothesis into testable empirical predictions. In the present study, we outline a series of plausible consequences of the hypothesis and test a variety of well-established and previously untested crossmodal correspondences by means of a novel internet-based testing methodology. The results highlight that the semantic hypothesis cannot easily explain differences in the prevalence of crossmodal associations built on the same semantic pattern (fast lemons, slow prunes, sour boulders, heavy red); furthermore, the semantic hypothesis only minimally predicts what happens when the semantic dimensions and polarities that are supposed to drive such crossmodal associations are made more salient (e.g., by adding emotional cues that ought to make the good/bad dimension more salient); finally, the semantic hypothesis does not explain why reliable matches are no longer observed once intramodal dimensions with congruent connotations are presented (e.g., visually presented shapes and colour do not appear to correspond). PMID- 24349697 TI - The artist's advantage: Better integration of object information across eye movements. AB - Over their careers, figurative artists spend thousands of hours analyzing objects and scene layout. We examined what impact this extensive training has on the ability to encode complex scenes, comparing participants with a wide range of training and drawing skills on a possible versus impossible objects task. We used a gaze-contingent display to control the amount of information the participants could sample on each fixation either from central or peripheral visual field. Test objects were displayed and participants reported, as quickly as possible, whether the object was structurally possible or not. Our results show that when viewing the image through a small central window, performance improved with the years of training, and to a lesser extent with the level of skill. This suggests that the extensive training itself confers an advantage for integrating object structure into more robust object descriptions. PMID- 24349698 TI - Comparing sensitivity to facial asymmetry and facial identity. AB - Bilateral symmetry is a facial feature that plays an important role in the aesthetic judgments of faces. The extent to which symmetry contributes to the identification of faces is less clear. We investigated the relationship between facial asymmetry and identity using synthetic face stimuli where the geometric identity of the face can be precisely controlled. Thresholds for all observers were 2 times lower for discriminating facial asymmetry than they were for discriminating facial identity. The advantage for discriminating asymmetrical forms was not observed using nonface shape stimuli, suggesting this advantage is face-specific. Moreover, asymmetry thresholds were not affected when faces were either inverted or constructed about a nonmean face. These results, taken together, suggest that facial asymmetry is a characteristic that we are exquisitely sensitive to, and that may not contribute to face identification. This conclusion is consistent with neuroimaging evidence that suggests that face symmetry and face identity are processed by different neural mechanisms. PMID- 24349699 TI - Image regions contributing to perceptual translucency: A psychophysical reverse correlation study. AB - The spatial luminance relationship between shading patterns and specular highlight is suggested to be a cue for perceptual translucency (Motoyoshi, 2010). Although local image features are also important for translucency perception (Fleming & Bulthoff, 2005), they have rarely been investigated. Here, we aimed to extract spatial regions related to translucency perception from computer graphics (CG) images of objects using a psychophysical reverse-correlation method. From many trials in which the observer compared the perceptual translucency of two CG images, we obtained translucency-related patterns showing which image regions were related to perceptual translucency judgments. An analysis of the luminance statistics calculated within these image regions showed that (1) the global rms contrast within an entire CG image was not related to perceptual translucency and (2) the local mean luminance of specific image regions within the CG images correlated well with perceptual translucency. However, the image regions contributing to perceptual translucency differed greatly between observers. These results suggest that perceptual translucency does not rely on global luminance statistics such as global rms contrast, but rather depends on local image features within specific image regions. There may be some "hot spots" effective for perceptual translucency, although which of many hot spots are used in judging translucency may be observer dependent. PMID- 24349700 TI - Shapes displayed with durations in the microsecond range do not obey Bloch's law of temporal summation. AB - Shape patterns were displayed with simultaneous brief flashes from a light emitting diode array. Flash durations in the microsecond range and luminous intensities were adjusted to vary the degree of successful shape recognition. Four experiments were conducted to test whether Bloch's law would apply in this task. Bloch's law holds that for very brief flashes the perceptual threshold is determined by the total number of photons being delivered, i.e., there is reciprocity of intensity and duration. The present results did not find that effectiveness of flashes was based on the total quantity of photons, as predicted by Bloch's law. Additionally, the evidence points to a visual mechanism that has ultra-high temporal precision that either registers the rate of photon flux or the duration of flashes. PMID- 24349701 TI - Depth effect on lightness revisited: The role of articulation, proximity and fields of illumination. AB - The coplanar ratio principle proposes that when the luminance range in an image is larger than the canonical reflectance range of 30:1, the lightness of a target surface depends on the luminance ratio between that target and its adjacent coplanar neighbor (Gilchrist, 1980). This conclusion is based on experiments in which changes in the perceived target depth produced large changes in its perceived lightness without significantly altering the observers' retinal image. Using the same paradigm, we explored how this depth effect on lightness depends on display complexity (articulation), proximity of the target to its highest coplanar luminance and spatial distribution of fields of illumination. Importantly, our experiments allowed us to test differing predictions made by the anchoring theory (Gilchrist et al., 1999), the coplanar ratio principle, as well as other models. We report three main findings, generally consistent with anchoring theory predictions: (1) Articulation can substantially increase the depth effect. (2) Target lightness depends not on the adjacent luminance but on the highest coplanar luminance, irrespective of its position relative to the target. (3) When a plane contains multiple fields of illumination, target lightness depends on the highest luminance in its field of illumination, not on the highest coplanar luminance. PMID- 24349703 TI - Golden perception: Simulating perceptual habits of the past. AB - Medieval times were neither dark nor grey; natural light illuminated colourful scenes depicted in paintings through coloured windows and via artificial beeswax candlelight. When we enter, for example, a church to inspect its historic treasures ranging from mosaics to depictions of saints, we do this under quite unfavourable conditions; particularly as we mainly depend on artificial halogen, LED or fluorescent light for illuminating the desired object. As these light spectrums are different from the natural light conditions under which the old masterpieces were previously developed and perceived, the perceptual effects may dramatically differ, leading to significantly altered affective and cognitive processing. Different qualities of processing might particularly be triggered when perceiving artworks which deal with specific material prone to strong interaction with idiosyncratic light conditions, for instance gold-leafed surfaces that literally start to glow when lit by candles. We tested the perceptual experiences of a figurative piece of art which we created in 3 (foreground) by 3 (background) versions, illuminated under three different light conditions (daylight, coloured light and beeswax candlelight). Results demonstrated very different perceptual experiences with stunning effects for the interaction of the specific painting depicted on a gold-leafed background lit by candlelight. PMID- 24349702 TI - Apparent sharpness of 3D video when one eye's view is more blurry. AB - When the images presented to each eye differ in sharpness, the fused percept remains relatively sharp. Here, we measure this effect by showing stereoscopic videos that have been blurred for one eye, or both eyes, and psychophysically determining when they appear equally sharp. For a range of blur magnitudes, the fused percept always appeared significantly sharper than the blurrier view. From these data, we investigate to what extent discarding high spatial frequencies from just one eye's view reduces the bandwidth necessary to transmit perceptually sharp 3D content. We conclude that relatively high-resolution video transmission has the most potential benefit from this method. PMID- 24349704 TI - Biochemical and biological characterization of Naja kaouthia venom from North East India and its neutralization by polyvalent antivenom. AB - This study describes biochemical and biological properties of Naja kaouthia (Indian monocled cobra) venom of North-East India. The LD50 of the crude venom was found to be 0.148mg/kg and neurotoxicitic symptoms like paralysis of lower limbs and heavy difficulty in breathing at sub-lethal dose in mice was observed. The venom exhibited PLA2, indirect hemolytic and myotoxic activities but showed weak proteolytic and low direct hemolytic activities. It did not exhibit any hemorrhage when injected intradermally to mice. Anticoagulant activity was prominent when recalcification, prothrombin and activated partial thrombinplastin time were tested on platelet poor plasma. Rotem analysis of whole citrated blood in presence of venom showed delay in coagulation time and clot formation time. Fibrinogen of whole citrated blood was depleted by venom when analyzed in Sonoclot. Crude venom at 10ug and after 16hr of incubation was found to degrade alpha chain of fibrinogen. Neutralization study showed that Indian polyvalent antivenom could neutralize some of the biochemical and biological activities as well as its fibrinogenolytic activity. PMID- 24349705 TI - Anti-thrombogenic properties of a nitric oxide-releasing dextran derivative: evaluation of platelet activation and whole blood clotting kinetics. AB - Controlling platelet activation and clotting initiated by cardiovascular interventions remains a major challenge in clinical practice. In this work, the anti-thrombotic properties of a polysaccharide-based nitric oxide (NO)-releasing dextran derivative are presented. Total platelet adhesion, platelet morphology and whole blood clotting kinetics were used as indicators to evaluate the anti clotting properties of this material. With a total NO delivery of 0.203+/-0.003 MUmol, the NO-releasing dextran derivative (Dex-SNO) mixed with blood plasma demonstrated a significantly lower amount of platelet adhesion and activation onto a surface and reduced whole blood clotting kinetics. Nearly 75% reduction in platelet adhesion and a significant retention of platelet morphology were observed with blood plasma treated with Dex-SNO, suggesting this to be a potential anti-platelet therapeutic agent for preventing thrombosis that does not have an adverse effect on circulating platelets. PMID- 24349706 TI - Microfluidic Assembly of Cationic-beta-Cyclodextrin:Hyaluronic Acid-Adamantane Host:Guest pDNA Nanoparticles. AB - Traditionally, transfection complexes are typically formed by bulk mixing, producing particles with high polydispersity and limited control over vector size. Herein, we demonstrate the use of a commercial micro-reactor to assemble pDNA:cationic cyclodextrin:pendant polymer nanoparticles using a layer-by-layer approach. Our studies reveal that the particles formulated via microfluidic assembly have much smaller sizes, lower polydispersity, lower zeta-potentials, and comparable cell viability and transfection profiles in HeLa cells than bulk mixed particles. The complexes also show a flow rate-dependent stability, with particles formed at slower flow rates giving rise to more stable complexes as determined by heparin challenge. Our findings suggest that microfluidic reactors offer an attractive method for assembling reproducible, size-controlled complexes from multi-component transfection complex assemblies. PMID- 24349707 TI - Collagen-Based Substrates with Tunable Strength for Soft Tissue Engineering. AB - Through the use of mechanical reinforcement of collagen matrices, mechanically strong and compliant 3D tissue mimetic scaffolds can be generated that act as scaffolds for soft tissue engineering. Collagen has been widely used for the development of materials for repair, augmentation or replacement of damaged or diseased tissue. Herein we describe a facile method for the layer-by-layer fabrication of robust planar collagen fiber constructs. Collagen gels cast in a phosphate buffer were dried to form dense collagen mats. Subsequent gels were layered and dried atop mats to create multilayer constructs possessing a range of tunable strengths (0.5 - 11 MPa) and stiffness (1 - 115 MPa). Depending on processing conditions and crosslinking of constructs, strain to failure ranged between 9 to 48%. Collagen mats were constructed into hernia patches that prevented hernia recurrence in Wistar rats. PMID- 24349709 TI - Primary hepatic leiomyosarcoma in a 5-month-old female infant. AB - Leiomyosarcoma is a malignant mesenchymal neoplasm deriving from the smooth muscle cells. Primary hepatic leiomyosarcoma is very rare. Its onset is always during middle and old age. Herein, we present a case of primary hepatic leiomyosarcoma in a 5-month-old girl who may be the youngest patient reported in the known published English literature. PMID- 24349708 TI - Orbital phlebography in idiopathic intracranial hypertension and chronic tension type headache. AB - BACKGROUND: Pathologic signs in orbital phlebographies have been reported in various neurological diseases. PURPOSE: To study if pathologic signs in orbital phlebography may be markers of inflammation primarily affecting intracranial capillaries, which would cause intracranial hypertension. MATERIAL AND METHODS: Two groups with different intracranial cerebrospinal fluid pressures (Pcsf) were compared as to inflammatory markers in serum and pathologic signs in orbital phlebographies. Nine consecutive patients with idiopathic intracranial hypertension (IIH) with bilateral papilledema and eight consecutive patients with chronic tension-type headache (CTTH) were investigated prospectively with fibrinogen, orosomucoid, haptoglobin in serum, and invasive orbital phlebograms. The angiograms were evaluated by two skilled neuroradiologists, independent of each other and without knowledge of the diagnoses or aim of the study, as to the following pathologic signs: (i) narrowing of superior ophthalmic veins; (ii) caliber changes of intraorbital veins; (iii) collaterals of intraorbital veins; (iv) flow to cavernous sinus; and (v) asymmetric drainage of cavernous sinus. RESULTS: Mean body mass index was >30 kg/m(2) in both groups. Pcsf was >200 < 250 mm H2O in 50% of the CTTH and >350 mm H2O in all IIH patients. No difference in inflammatory markers in blood was found. The phlebographies of the IIH patients had more pathologic signs and were considered pathologic significantly more often than the ones of the CTTH patients (P < 0.001). CONCLUSION: The difference as to phlebographic pathologic signs between the IIH and the CTTH patients with different Pcsf supports the hypothesis that such phlebographic signs are markers of inflammation primarily affecting intracranial capillaries, which would disturb cerebrospinal fluid regulation causing intracranial hypertension. PMID- 24349710 TI - A case of pneumoperitoneum and retropneumoperitoneum without bowel perforation due to extensive intestinal necrosis as a complication to chemotherapy: CT evaluation. AB - Acute intestinal ischemia continues to be a challenging diagnostic problem with high mortality. We describe a rare case of acute intestinal necrosis, due to vasculitis, related with chemotherapy. A patient was examined in our emergency department, presenting with abdominal pain. Three months before he had undergone an operation for lung carcinoma (lobectomy) and received chemotherapy. CT of the abdomen demonstrated free air in 10 different locations: hepatic part of the portal vein, branches of mesenteric veins, femoral and iliac veins, the bowel wall, peritoneal cavity and retroperitoneal space, abdominal muscles, inguinal canals, meso-sigmoid space, and in the para-rectal space. Moreover, pathological findings revealed that the free air in the peritoneum and retropneumoperitoneum occurred without intestinal perforation, but with transudation through the necrotic bowel wall. This is a rare complication of chemotherapy. This case refers to the unusual CT findings which appeared in this patient. The key to a better outcome is early diagnosis of this condition and the CT examination of the abdomen plays an important role. PMID- 24349711 TI - Wandering spleen with gastric volvulus and intestinal non-rotation in an adult male patient. AB - We report an extremely rare case of wandering spleen (WS) complicated with gastric volvulus and intestinal non-rotation in a male adult. A 22-year-old man who had been previously treated for Wilson disease was admitted with severe abdominal pain. Radiological findings showed WS in the midline of the pelvic area. The stomach was mesenteroaxially twisted and intestinal non-rotation was observed. Radiology results did not show any evidence of splenic or gastrointestinal (GI) infarction. Elective emergency laparoscopy confirmed WS and intestinal non-rotation; however, gastric volvulus was not observed. It was suspected that the stomach had untwisted when gastric and laparoscopic tubes were inserted. Surgery is strongly recommended for WS because of the high risk of serious complications; however, some asymptomatic adult patients are still treated conservatively, such as the patient in this study. The present case is reported with reference to the literature. PMID- 24349712 TI - Computed tomographic findings of radiation-induced acute adrenal injury with associated radiation nephropathy: a case report. AB - Radiation nephropathy was first recognized in 1906. The kidney is a radiosensitive organ with a tolerance dose (5% complications in 5 years) of 20 Gray. The imaging findings of acute and chronic radiation induced renal injury are previously described. Radiation-induced adrenal injury, to our knowledge, has not been described in the literature. Unlike the kidneys and other upper abdominal organs, the adrenal glands are traditionally thought to be radio resistant, protected from radiation-induced injury by proximity to adjacent organs and by the adrenal medulla which reportedly has increased radio resistance. We present the computed tomographic imaging findings of a patient with acute radiation induced adrenal injury which resulted in adrenal insufficiency following radiotherapy of an adjacent thecal metastasis. PMID- 24349713 TI - Caseous calcification of the mitral annulus on MDCT: a rare intracardiac mass. AB - Caseous calcification of the mitral annulus is a rare form of chronic degenerative process in the mitral valve fibrous ring with a mass-like appearance that has to be in the differential of the radiologist and cardiologist. We present the case of an 82-year-old woman in whom a tumor-like calcified mass in the posterior side of the mitral valve annulus was detected at echocardiography, and the diagnosis of caseous calcification was confirmed on multidetector computed tomography (MDCT). The diagnostic features of this rare cardiac mass are described. PMID- 24349714 TI - Transcatheter arterial embolization of anomalous systemic arterial supply to the basal segment of the lung. AB - We describe the case of a 67-year-old woman with an anomalous systemic arterial supply to the basal segment of the lung, which was managed successfully by transcatheter arterial embolization (TAE) with microcoils. Her chest computed tomography (CT) scan showed diffuse ground-glass opacity in the left lower lobe, no bronchial abnormalities, and blood supply from an anomalous artery originating from the descending thoracic aorta, with drainage to the normal pulmonary vein. We successfully performed TAE under balloon occlusion of the anomalous artery, without complications. TAE is a minimally invasive, safe, and valuable method, and could be used as first-line treatment in such cases. PMID- 24349715 TI - Phantom-based quality assurance measurements in B-mode ultrasound. AB - BACKGROUND: Recommended phantom-based quality assurance measurements in B-mode ultrasound (US) may be tedious. For the purpose of cost-effective US quality assurance it is important to evaluate measurements that effectively reflect the quality of US scanner. PURPOSE: To find out which recommended phantom-based quality assurance measurements are effective in detecting dead or weak transducer elements or channels in US scanners when visual image analysis and manual measurements are used. MATERIAL AND METHODS: Altogether 66 transducers from 33 US scanners were measured using a general purpose phantom and a transducer tester. The measurements were divided into two groups. Group I consisted of phantom-based uniformity measurement, imaging the air with a clean transducer (air image) and measuring the transducer with the transducer tester, and group II of phantom based measurements of depth of penetration, beam profile, near field, axial and lateral resolution, and vertical and horizontal distance accuracy. The group II measurements were compared to group I measurements. RESULTS: With group I measurements, the results with 20% of the transducers were found defective. With 35% of the transducers the results were considered defective in group II measurements. Concurrent flaws in both groups were found with 11% of the transducers. CONCLUSION: Phantom-based measurements of depth of penetration, beam profile, near field, axial and lateral resolution, and vertical and horizontal distance accuracy did not consistently detect dead or weak transducer elements or channels in US scanners. PMID- 24349716 TI - Diagnostic value of apparent diffusion coefficient for the accurate assessment and differentiation of intracranial meningiomas. AB - BACKGROUND: Diffusion-weighted imaging (DWI) along with the calculation of apparent diffusion coefficient (ADC), is a novel, non-invasive, and reliable technique of choice for accurate assessment and for the treatment planning of different types of brain tumors. It is more advantageous in the distinction and differentiation of benign from malignant meningiomas on the basis of ADC values. PURPOSE: To investigate the utility of DW magnetic resonance imaging (MRI), and to compare the apparent diffusion coefficient (ADC) obtained at two b-values for an authentic and preoperative characterization of meningiomas. MATERIAL AND METHODS: Twenty-six patients with clinically diagnosed or histologically verified meningioma (18 benign and 8 malignant) underwent imaging including DWI at 1.5 T. DW images were obtained at b = 1000 s/mm(2) and b = 2000 s/mm(2), ADC maps were generated at both the b-values. Signal intensities (SIs) and ADCs for solid tumorous tissues, contralateral normal tissues, and peritumoral edema were calculated and normalized ADC (NADC) ratio were determined for tumorous tissues. SI scores, ADC maps, and ADC values were analyzed visually and quantitatively, and were compared at both the b-values. RESULTS: DW images at b = 2000 s/mm(2) were more conspicuity (either hyperintense or hypointense) with improved contrast. The mean ADC of malignant meningiomas (0.64 +/- 0.05 and 0.42 +/- 0.03) was significantly lower (P < 0.05) as compared with benign meningiomas (1.04 +/- 0.12 and 0.80 +/- 0.07) at both the b-values. Mean NADC ratio in the malignant type was also significantly lower (P < 0.05) than the benign type at both the b values. Mean ADC values for peritumoral edema do not differ between benign and malignant meningiomas. CONCLUSION: 1.5-T DWI using high b-values improved our ability to differentiate benign from malignant meningiomas. DWI may play an important role in the preoperative radiological evaluation and the recognition of these types for proper surgical treatment. PMID- 24349717 TI - Imaging findings for malignancy-mimicking nodular fasciitis of the breast and a review of previous imaging studies. AB - We report a case of nodular fasciitis of the breast mimicking malignant tumor. A 41-year-old female patient with a palpable mass in the upper center of the left breast present for 1 week visited our hospital. A mammogram showed an oval isodense with a partially indistinct margin. Ultrasonography demonstrated a hypoechoic mass, 8 * 11 mm in size. Breast cancer could not be excluded based on mammographic and ultrasonographic (US) findings. A core needle biopsy and excisional biopsy were performed. Histopathologic examination revealed a diagnosis of nodular fasciitis of the breast. The mammographic and US findings of nodular fasciitis in the breast is reviewed. PMID- 24349718 TI - The Decomposed Affiliation Exposure Model: A Network Approach to Segregating Peer Influences from Crowds and Organized Sports. AB - Self-identification with peer crowds (jocks, popular kids, druggies, etc.) has an important influence on adolescent substance use behavior. However, little is known about the impact of the shared nature of crowd identification on different stages of adolescent drinking behavior, or the way crowd identification interacts with participation in school-sponsored sports activities. This study examines drinking influences from (1) peers with shared crowd identities, and (2) peers who jointly participate in organized sports at their school (activity members). This study introduces a new network analytic approach that can disentangle the effects of crowd identification and sports participation on individual behavior. Using survey data from adolescents in five high schools in a predominantly a Hispanic/Latino district (N=1,707), this article examines the association between social influences and each stage of drinking behavior (intention to drink, lifetime, past-month, and binge drinking) by conducting an ordinal regression analysis. The results show that both shared identities and joint participation were associated with all stages of drinking, controlling for friends' influence. Additionally, shared identification overlapped with joint participation was associated with more frequent drinking. Related policy implications are discussed. PMID- 24349719 TI - Hemocompatibility of Chitosan/poly(acrylic acid) Grafted Polyurethane Tubing. AB - The activation and adhesion of platelets or whole blood exposed to chitosan (CH) grafted surfaces is used to evaluate the hemocompatibility of biomaterials. The biomaterial surfaces are polyurethane (PU) tubes grafted with an inner poly(acrylic acid) (PAA) and an outer CH or quaternary ammonium modified CH (CH Q) brush. The CH, CH-Q and PAA grafted layers were characterized by ellipsometry and fluorescence microscopy. Material wear tests demonstrate that CH (CH-Q) is stably grafted onto PU tubes upon exposure to saline solution for 7 days. Using quartz-crystal microbalances with dissipation (QCM-D), in-situ adsorption of blood plasma proteins on CH and CH-Q compared to a silicon oxide control was measured. The QCM-D results showed that the physically adsorbed plasma protein layer on CH-Q and CH surfaces is softer and more viscous than the protein layer on the SiO2 surface. The CH-Q layer thus has the weakest interaction with plasma proteins. Whole blood and platelet adhesion was reduced by ~92% on CH-Q, which showed the weakest interaction with plasma protein but more viscous adsorbed plasma protein layer, compared to SiO2. Last, to examine the biologic response of platelets and neutrophils to biomaterial surfaces, CH (CH-Q)/PAA, PAA and PU tubes were tested using a Chandler Loop apparatus as an ex vivo model and flow cytometry. The blood adhesion and biologic response results showed that CH and CH Q reduced adhesion and activation of platelets and neutrophils and improved hemocompatibility relative to other surfaces (PU and PAA). Our studies demonstrated that the properties of physically adsorbed plasma protein layer on biomaterial surfaces correlates with blood coagulation on biomaterial surfaces. PMID- 24349720 TI - Determinants of inequity in health care services utilization in markazi province of iran. AB - BACKGROUND: National and international statistics from Iran have indicated that progresses and achievements have been made for most health indicators, but there are differences in some indicators in special groups and at the provincial level. OBJECTIVES: Our aim was to assess the main predictors of inequity in seeking Health Care Utilities (HCU) locally. PATIENTS AND METHODS: Data gathered from the HCU survey, which was conducted in the Markazi province of Iran during 2008, was used in the present study. A systematic sampling method, based on the Iranian household framework, was applied in order to choose 758 households as well as 2711 individuals. The household wealth index constructed by Principle Component Analysis (PCA) and robust login link function in Generalized Estimation Equation (GEE) model were used in order to determine the predictors of inequity. RESULTS: 66.4% of those in need sought outpatient health care from which 97.7% received appropriate services. After adjustment for the clustering effect of household as well as confounding effect of the covariates, GEE model showed that there were inequities in HCU for females (OR = 2.44, CI; 1.24- 4.81) and subjects with inpatient need (OR = 2.14, CI: 1.23-3.72). Being in the lowest quintile of household wealth index was associated with the lower use of outpatient health services (OR = 0.45, CI; 0.23- 0.88). CONCLUSIONS: In spite of improvements in the national health indicator, different groups of people use health care services differently, but these inequities in HCU are related to social and individual factors. Also, it is clear that health sector facilities and the accessibility to health services are not the only predictors. PMID- 24349721 TI - Genetic Analysis of cagA and vacA Genes in Helicobacter Pylori Isolates and Their Relationship with Gastroduodenal Diseases in the West of Iran. AB - BACKGROUND: Helicobacter pylori have different virulence factors which are associated with several gastroduodenal diseases; however, this association is variable in different geographical regions. Data of genotypes of Iranian H. pylori isolates are few. OBJECTIVES: The aim of the current study was to investigate the cagA/vacA genotypes of Helicobacter pylori isolates and determine the relationship between these genotypes with respect to different gastric disorders in patients of Chaharmahalo Bakhtiarian. MATERIALS AND METHODS: In this cross-sectional study, gastric biopsies were taken from 200 patients with gastrodoudenal diseases. Histopathological features were recognized by specialist. The samples were subjected to PCR for detection and identification of ureC, cagA and vacA genes. RESULTS: The frequency of the vacA genotypes, sa1/m1, s1a/m1b, s1a/m2, s1b/m1a, s1b/m1b, s1b/m2, s1c/m1a, s1c/m1b, s1c/m2, s2/m1a, s2/m1b and s2/m2 were 27(6.6%), 8(4.3%), 45(28.04%), 7(3.7%), 5(2.5%), 10 (6.1%), 12 (7.4%), 4 (2.5%), 18(11%), 6(3.7%), 0 and 22(13.5%) respectively. The cagA gene was detected in 92% of strains. Based on our findings, it seemed that cagPAI and vacA s1 genotypes were associated with some gastric disorders in patients with H. pylori. In this region, the isolates carrying s1a/m2 were the most prevalent. CONCLUSIONS: We found considerable relationship between s1a/m1a, s1a/m2, s2/m2 and s1c/m1a and some gastric disorders. Further studies about the role of H. pylori virulence factors and gastric disorders were recommended. PMID- 24349722 TI - Detection of sugar chain expression in hydatidiform mole using lectin histochemistry. AB - BACKGROUND: Hydatidiform moles carry a significant risk for developing persistent gestational trophoblastic disease. Lectins are useful tools to identify cellular glycosylation pattern and changes in glycosylation that occur during growth, development, differentiation and also, during disease states. OBJECTIVES: Considering the changes in glycosylation that occur during cell proliferation, differentiation and transformation, the aim of the present study was to evaluate the sugar chain expression in hydatidiform mole by using HRP-conjugated lectins. MATERIALS AND METHODS: Lectin histochemistry with a panel of HRP-conjugated lectins comprising SBA, PNA, VVA, UEA-1, LTA, GS-I (B4) and WGA were performed in 20 molar (partial & complete moles) formalin-fixed, paraffin-embedded tissue samples. RESULTS: The partial and complete moles generally showed similar reactivity with all used lectins. None of lectins reacted with villous cytotrophoblasts, whereas 4 of 7 lectins comprising WGA, LTA, UEA-I and PNA (after pretreatment with neuraminidase) showed a moderate to strong reactivity with villous syncytiotrophoblasts in both partial and complete hydatidiform moles. The villous stroma reacted with all used lectins except VVA. CONCLUSIONS: Our histochemical findings showed a relatively heavy glycosylation of syncytiotrophoblasts of both partial and complete molar tissues, which was prominent in apical portion. This may play a role in their capacity to increase trophoblastic proliferation. PMID- 24349723 TI - Accuracy of endotracheal tube cuff pressure adjustment by fingertip palpation after training of intensive care unit nurses. AB - BACKGROUND: Untrained fingertip palpation has been shown to be unable to adjust endotracheal tube (ET) cuff pressure in most intubated patients. OBJECTIVE: We determined the impact of a training course of ETT cuff adjustment by palpation in attaining a safe cuff inflation pressure. PATIENTS AND METHODS: Twenty-five nurses were asked to adjust the ETT cuff pressure to 25 cmH2O by palpation on three different patients in seven sessions (S1-S7): before training, two hours and two days after first training session, and two hours, two days, one week, and eight months after second training session. RESULTS: Before training, 41.3% of the cuff pressures were adjusted to the safe range of 21-35 cmH2O. The pressures obtained in S2-S7 were lower and less variable than S1 (P = 0.02 to < 0.0001). After the first training session, all the ETT cuff pressures in the high range (36-50 cmH2O) and 87.5% in the very high range (> 50 cmH2O) changed to the safe range. CONCLUSIONS: Using trained fingertip adjustment of the ETT cuff pressure throughout the nursing shift with protocols for the adjustment of out of range pressures at the beginning of each shift by cuff manometer could decrease the rate of ETT cuff over- and under-inflation. PMID- 24349724 TI - Comparison of Knifelight Surgery versus Conventional Open Surgery in the Treatment of Carpal Tunnel Syndrome. AB - BACKGROUND: A variety of surgical treatment methods for carpal tunnel syndrome are introduced recently, including open surgery, endoscopic and the Knifelight. It is hypothesized that Knifelight method could decrease scar tenderness and time before return to daily activities for patients and is accompanied with less disturbance to fine sensory nerves. OBJECTIVES: To compare the Knifelight instrument and open carpal tunnel release with respect to scar length, operation duration, recovery time needed before return to work and amount of pain three weeks after surgery in patients with neurophysiologically confirmed carpal tunnel syndrome. PATIENTS AND METHODS: FIFTY NINE PATIENTS WITH INDICATION FOR CARPAL TUNNEL RELEASE RANDOMLY ASSIGNED INTO TWO GROUPS: open (n=30) or Knifelight (n=29). The patients compared regarding scar length, operation duration, time to return to daily activities and amount of pain at three weeks after operation based on Visual Analog Scale. RESULTS: There was no significant differences regarding age and sex in the two groups. The scar length, operation duration and time before return to daily activities were significantly lower in the Knifelight group. Although the mean visual analogue scale of Knifelight group found to be lower than the other, it was not statistically significant. CONCLUSIONS: The Knifelight technique is accompanied with advantages over the open surgery regarding operation time, scar length and time to return to daily activities. The pain relieve based on Visual Analog Scale was not statistically different from conventional open surgery. PMID- 24349725 TI - The role of diminishing appetite and serum nesfatin-1 level in patients with burn wound infection. AB - BACKGROUND: The burn wound represents a susceptible site for opportunistic colonization by organisms of endogenous and exogenous origin. Diminishing appetite is known to occur in patients with burn infection, yet its underlying reason is not fully understood. We have examined the levels of nesfatin 1, a protein that we consider to be a potential new treatment target for the solution of appetite and nutrition problem in patients with burn infection. OBJECTIVES: The aim of the present study was therefore to examine nesfatin levels in patients with burn infection. MATERIAL AND METHODS: Laboratory values, medication and dietary records, and patient notes with diagnostic information of burn wounds patients who were admitted to the Division of Burn Treatment Center were obtained from the Erzurum Region Education and Research Hospital electronic database. Post burn wound infection was objectively assessed by culturing wound homogenates from skin tissue. The main immediate inflammatory stress response parameters assessed were serum CRP concentrations, WBC counts, and blood nesfatin concentrations. RESULTS: Scalding was the predominant cause of burns in both categories of patients. In 19 (61.3%) burn wound infection patients, the burns were due to a scald. A significant difference was found for the nesfatin, CRP, and WBC levels between the patients and the control group (P = 0.000). A significant difference was also determined between the nesfatin, CRP, and WBC figures at the time of hospitalization and at discharge from the hospital (P = 0.000). The most predominant bacterial isolate was Pseudomonas aeruginosa 16 (51.6%) followed by Methicilline resistant Staphylococcus aureus (MRSA) 7 (22.6%). CONCLUSIONS: We showed that the serum nesfatin 1 level was significantly lower in the patients with burn than in the control group in our study. We considered that the central nesfatin 1 system should be taken into consideration, rather than the peripheric nesfatin 1 system, when considering the regulation of appetite in patients with burns and particularly those accompanied by infection. In other explanation of the observed negative correlation between nesfatin 1 and burn wound infection suggests that nesfatin 1 may indicate the possible contribution of nesfatin 1 to the energy homeostasis. PMID- 24349726 TI - The efficiency and budgeting of public hospitals: case study of iran. AB - BACKGROUND: Hospitals are the most costly and important components of any health care system, so it is important to know their economic values, pay attention to their efficiency and consider factors affecting them. OBJECTIVE: The aim of this study was to assess the technical scale and economic efficiency of hospitals in the West Azerbaijan province of Iran, for which Data Envelopment Analysis (DEA) was used to propose a model for operational budgeting. MATERIALS AND METHODS: This study was a descriptive-analysis that was conducted in 2009 and had three inputs and two outputs. Deap2, 1 software was used for data analysis. Slack and radial movements and surplus of inputs were calculated for selected hospitals. Finally, a model was proposed for performance-based budgeting of hospitals and health sectors using the DEA technique. RESULTS: The average scores of technical efficiency, pure technical efficiency (managerial efficiency) and scale efficiency of hospitals were 0.584, 0.782 and 0.771, respectively. In other words the capacity of efficiency promotion in hospitals without any increase in costs and with the same amount of inputs was about 41.5%. Only four hospitals among all hospitals had the maximum level of technical efficiency. Moreover, surplus production factors were evident in these hospitals. CONCLUSIONS: Reduction of surplus production factors through comprehensive planning based on the results of the Data Envelopment Analysis can play a major role in cost reduction of hospitals and health sectors. In hospitals with a technical efficiency score of less than one, the original and projected values of inputs were different; resulting in a surplus. Hence, these hospitals should reduce their values of inputs to achieve maximum efficiency and optimal performance. The results of this method was applied to hospitals a benchmark for making decisions about resource allocation; linking budgets to performance results; and controlling and improving hospitals performance. PMID- 24349727 TI - The association between melasma and postinflammatory hyperpigmentation in acne patients. AB - BACKGROUND: Although, melasma is most prevalent among Asian young women, and also darkly pigmented individuals are particularly prone to developing post inflammatory hyperpigmentation, to the best of our knowledge, there are rare or no studies about the association of melasma and Post inflammatory hyperpigmentation. OBJECTIVES: The aim of this study was to investigate how likely is a melasma patient to developed post inflammatory hyperpigmentation when compared to patients with inflammatory acne lesions who do not have melasma. PATIENTS AND METHODS: This comparative study was conducted on 400 participants, 200 subjects involved with pigmented lesions of melasma and inflammatory acne lesions and200 involved only with inflammatory Acne lesions without melasma. Melasma, acne and post inflammatory hyper pigmentation, if existed, were assessed by a dermatologist, and pigmentation depth was assessed by wood's lamp. Multivariate logistic regression analysis suitable for study design was used to assess the association between melasma and post-acne pigmentation. RESULTS: We found out that 24.1% of patients without melasma had post-acne pigmentation compared to 66.8% in melasma group (P < 0.001). The likelihood of observing post acne pigmentation was found to be nearly six times more in melasma patients versus those without melasma. Association existed after controlling for possible confounders such as melanin score and time length of self-reported sun exposure, and acne severity score. CONCLUSIONS: Melasma appears to increase the likelihood of post-acne pigmentation. PMID- 24349728 TI - The reliability and validity of the persian version of sinonasal outcome test 22 (snot 22) questionnaires. AB - BACKGROUND: The quality of life (QOL) is an important indicator for disease severity classification and outcome measurement in obtaining treatment sinonasal diseases. The sinonasal outcome test 22 (SNOT 22) questionnaire has been introduced as the best specific sinonasal instrument for QOL measurement. OBJECTIVES: To prepare a valid and reliable Persian language version of SNOT 22 questionnaire. PATIENTS AND METHODS: After forward and backward translation of the original version of SNOT 22 questionnaire from English to Persian, a group of patients with nasal septal deviation who need septal surgery and another group of healthy volunteers answered the Persian version of the questionnaire. The responsiveness rate, validity (Pearson correlations and differential validity) and reliability (internal consistency and test-retest reliability) of the 22 items of the questionnaire was calculated. P value < 0.05 was considered significant. RESULTS: Thirty adults with nasal septal deviation need surgical correction and 30 healthy volunteers were included (mean age 30.4 +/- 7.1 vs. 33 +/- 6.7, P value = 0.148). The questionnaire was introduced to subjects two times with a two-week-period gap. Total responsiveness rate for 22 items was more than 97%. The total Cronbach's Alfa coefficient was 0.898 (ranging 0.890-0.903). The Pearson correlations were 0.85 and 0.96 for patients and healthy volunteers, respectively. The mean total score were 25.6 +/- 13.3 (range 6-52) and 7.6 +/- 9.1 (range 0-45) in patients and healthy volunteers, respectively (P < 0.0001). The subscales scores were also significantly different between two groups. CONCLUSIONS: The Persian version of SNOT 22 questionnaire is a valid and reliable instrument for accessing sinonasal diseases in Persian-speaking people. PMID- 24349729 TI - Hepatitis a virus seropositivity in nurses and paramedical personnel at a university hospital in north iran. AB - BACKGROUND: The status of hepatitis A virus (HAV) among health care workers has not been studied yet in Iran. OBJECTIVES: This study aimed to evaluate the HAV seropositivity among the healthcare personnel in Ayatollah Rohani Hospital, Babol, Iran, according to age, number of working years, and other demographic data. PATIENTS AND METHODS: This cross sectional study was performed on all nurses, nurses' aid, and paramedical technicians at Ayatollah Rohani Hospital, Babol, from March 2011 to March 2012. Blood was obtained from all cases (466) and the sera were separated. All serum samples were tested for anti-HAV antibodies (IgG) by enzyme-linked immunosorbent assay (ELISA). Data were analyzed by logistic regression analysis using SPSS software, version 18. RESULTS: 330 out of 466 (71%) persons were positive for anti-HAV antibodies (IgG) with no significant difference between females (71.5%) and males (70%) (P = 0.89, 95% CI. 0.533 2.083). The lowest sero-prevalence rate was observed in the 20-29 year age group (57.8%). Seropositivity for HAV significantly increased with age (P < 0.000, 95% CI. 1.626-3.262), 77.4% for 30-39 years and 85.3% for more than 40 years. The seropositivity rate also increased significantly in accordance with the number of working years (P = 0.012, 95%CI. 1.098-2.170). 110 out of 353 (31.2%) cases were seronegative among those with less than 5 years of working time. An obvious decrease of seronegative rate of HAV was seen in those with 5-10 years (27%) and more than 10 years (14.3%) of working time. CONCLUSIONS: These findings indicate relatively high prevalence rate of HA infection among nurses and paramedical personnel at this hospital. Nevertheless, 30% of the health workers have been seronegative and are still at risk of HA infection development. Considering that the disease has more severe course as age increases, improvement of standard hygiene and prevention strategies are recommended. Furthermore, vaccination may play a significant role in the occupational health policy to protect the susceptible health care workers population in the future. PMID- 24349730 TI - The effect of systemic arterial-line leukocyte filtration on the outcome of adult patients undergoing cardiac surgery. AB - BACKGROUND: It is known that cardiopulmonary bypass causes an inflammatory reaction with associated morbidity and mortality. Several anti-inflammatory strategies have been implemented to reduce this response, including leukocyte removal from the circulation using specialized filters. OBJECTIVES: The aim of this randomized clinical study was to assess the impact of arterial-line systemic leukocyte filtration on the postoperative outcome of adult patients undergoing elective cardiac surgery. PATIENTS AND METHODS: 114 patients undergoing CABG or valve replacement in Baqiyatallah hospital, Tehran, Iran from May to August 2011 were randomly assigned to two groups: with and without leukocyte filtration and their outcomes were compared. RESULTS: The postoperative intubation time was significantly shorter in patients with leukocyte filters (0.014). There was no significant difference between two groups regarding other outcome relatedvariables. CONCLUSIONS: Systemic arterial leukocyte filtration reduces the intubation time but has no other beneficial effect on the outcome of patients undergoing CABG or valve surgery. PMID- 24349731 TI - Historical cohort study on the factors affecting blood pressure in workers of polyacryl iran corporation using bayesian multilevel modeling with skew T distribution. AB - BACKGROUND: Hypertension is considered as a major public health problem in most countries due to its association with ischemic heart disease which causes cerebrovascular disease and death. OBJECTIVES: The purpose of the present study was to study factors affecting Blood Pressure (BP). PATIENTS AND METHODS: The data were extracted from annual observation of the workers who worked in Polyacryl Iran Corporation (PIC) between 1998 and 2010. In this research, we assessed the effect of Body Mass Index (BMI), age, sex, job status, marital status, job schedule type, and education level on Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) using Bayesian multilevel modeling with skew t distribution using WinBUGS software. RESULTS: Totally 3965 persons participated in this study, 75(1.9%) female and 3890 (98.1%) male. In this study age, sex, BMI, job status, marital status, and education level had statistical association with SBP. The result for DBP was similar to SBP except the education level which had no statistical association. CONCLUSIONS: Treating obesity, increasing physical activity and quality of married life are proposed as practical solutions to reduce BP. PMID- 24349732 TI - Comparing remifentanil versus propofol effect on pain and homodynamic change of patients undergoing phacoemulsification with topical anesthesia. AB - INTRODUCTION: The purpose of this study was to compare remifentanil versus propofol effect on pain and homodynamic in patients undergoing phacoemulsification with topical anesthesia. MATERIALS AND METHODS: A double blind clinical trial was conducted to research following the approval of the ethical committee research of the university. One hundred volunteer subjects were randomly assigned into two equal groups (n = 50). The subjects in the propofol group received 3mg/kg/hr while the patients in the remifentanil drug received 3 ug/kg/hr of this medication. Phaco time, blood pressure and heart rate before and after surgery, respiratory depression (O2 sat < 90%) and vomiting, pain scores, ophthalmologist satisfaction and demographic data were recorded. RESULTS: The results of analysis showed that there were no significant differences between the age, sex, and duration of operation of the two treatment groups. Systolic, diastolic blood pressure and heart rate were significantly lower in the propofol group .The propofol group complained of pain than the remifentanil group (P = 0.001) while the surgeon satisfaction was higher for the remifentanil condition (P = 0.01). No significant differences were found between the two groups with respect to respiratory depression .No patient suffered from nausea and vomiting. CONCLUSIONS: The results of this study indicated that using appropriate dose of remifentanil instead of propofol results in less pain, more stable homodynamic condition, and satisfaction of surgeon without no respiratory depression or perioperative nausea and vomiting. PMID- 24349733 TI - Histologic evaluation of human pulp response to total etch and self etch adhesive systems. AB - BACKGROUND: To investigate pulp response to the application of two types adhesive systems (total-etch and self-etch) in human premolar teeth. MATERIALS AND METHODS: Cavities limited to enamel walls in all margins with 2.5 mm depth were prepared on buccal surfaces of thirty three human premolars. The cavities were treated with the following adhesive. Single Bond (SB) and Prompt L-Pop (PLP). The teeth were extracted after 30 days and prepared due to histological technique. RESULTS: Pulp responses were evaluated in three field including inflammatory cell response, pulp tissue disorganization and restorative dentin formation. There were no differences in histological response of the pulp tissue (P > 0.05). CONCLUSION: Both adhesive systems showed good biological compatibility. PMID- 24349734 TI - Clinical outcome of ream versus unream intramedullary nailing for femoral shaft fractures. AB - BACKGROUND: Stabilization of fractures with an intramedullary nail is a widespread technique in the treatment of femoral shaft fractures in adults; however, to ream or not to ream is still being debated. OBJECTIVES: The primary objective of this study was to determine clinical results following unreamed versus ream intramedullary nailing of femoral fractures. PATIENTS AND METHODS: Between January 2008 and August 2009, 50 patients with femoral shaft fractures were treated with unreamed or reamed femoral nails in our clinic. From this prospective single centre study, 16 patients were excluded due to insufficient follow-up data. According to the AO classification, fractures in this study were either type A or B. Dynamic proximal locking was performed in all cases. The remaining 34 patients were divided into two groups of 17 with ream or unream nailing. During and after the operation, we evaluated some variables in whole series. RESULTS: After statistical analyzes, we found that there were no differences in radiologic union time (P = 1) or full weight bearing time (P = 0.73) between ream and unream nailing. Nail breakage or iatrogenic fractures during nail insertion did not occur and we did not have any fat emboli in both groups but one secondary loss of reduction occurred in the unream group. Superficial infection after the operation was seen in one case which was treated successfully with antibiotics. In the ream group surgical time was about thirty minutes longer and differences were significant (P = 0.000). Patients had to pay more for ream nailing but the difference was not significant. We found no statistical difference between union time with or without reaming; on the other hand, there was significant increased operation length, blood loss and systemic changes in BP or So2 in the ream group versus the unream group. CONCLUSIONS: We advocate that unream nailing in traumatic femoral shaft fractures is a simple, safe and effective procedure with significant advantages, especially in multitrauma patients. PMID- 24349735 TI - Nocardiosis: risk factors, clinical characteristics and outcome. AB - Nocardiosis has been reported increasingly in recent two decades, probably due to improvement in isolation of the organism and increased burden of immune compromised patients. Nocardia occasionally has been reported in healthy people. A case series of definitive Nocardiosis (2002 to 2010), clinical characteristics, underlying diseases, immune status and in-patient outcome were studied in a tertiary referral center. Twenty one patients with definite diagnosis of Nocardiosis were studied. 17 cases (81%) had an underlying disease (diabetes mellitus, corticosteroid therapy, and chronic granulomatous disease and collagen vascular diseases). Four patients (19%) were immune-competent without any predisposing disease. In 17 patients (81%), Nocardiosis was limited to respiratory tract and in 4 cases (19%) it was disseminated with multi organ involvement. Two cases (9.5%) died in hospital. PMID- 24349736 TI - Prediction of milk consumption among Iranian pregnant women: application of the theory of planned behavior. PMID- 24349737 TI - Comparison of the Effects of Powdered and Powder-free Surgical Gloves on Postlaparotomy Peritoneal Adhesions in Rats. PMID- 24349738 TI - Determination and Comparison of Affecting Two Methods of Self-aid and Body-aid Based on the Multimedia Software Packages Method and the Lecturing on the Amount of Knowledge and Operation of Personals of Selected Combat Battalions. PMID- 24349739 TI - Electrocardiologic and echocardiographic findings in patients with scorpion sting. PMID- 24349740 TI - Comparison of the Effect of 8 weeks Aerobic and Yoga Training on Ambulatory Function, Fatigue and Mood Status in MS Patients. AB - BACKGROUND: Multiple Sclerosis (MS) is a disease of the central nervous system that results in many symptoms including mobility limitation and fatigue. PATIENTS AND METHODS: Thirty-one MS patients, all female with mean of age of 36.75 years and Expanded Disability Status Scale scores (EDSS) of 1.0 to 4.0 were recruited. Subjects were randomly assigned to one of the three groups: treadmill training, yoga or control groups. Treadmill training and yoga practice consisted of 8 weeks (24 sessions, thrice weekly). The control group followed their own routine treatment program. Balance, speed and endurance of walking, fatigue, depression and anxiety were measured by Berg Balance scores, time for 10m walk and distance for a two minute walk, Fatigue Severity Scale (FFS), Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI), respectively. RESULTS: Comparison of results have shown that pre- and post-interventions produced significant improvements in the balance score, walking endurance, FFS score, BDI score and BAI score in the treadmill training group and yoga group. However, 10m walk time decreased in the treadmill training group but did not show any clear change in the yoga group. Moreover, the analysis showed significant differences between the treadmill training group and yoga group for BAI score. CONCLUSIONS: These results suggest that treadmill training and yoga practice improved ambulatory function, fatigue and mood status in the individuals with mild to moderate MS. PMID- 24349742 TI - Path analysis of the risk of low birth weight for multipara. AB - BACKGROUND: LBW rate is one of the most important health indices in every society. It reveals mothers and their new-born infants' health. OBJECTIVES: Our aim, in the present paper, was to present a new statistical framework for analysis based on path analysis techniques. PATIENTS AND METHODS: A prospective study was conducted in two maternity wards, (privet & governmental hospital) in Sari, Iran. In this research a check-list containing 25 questions about mother's demographic information and her new-born infant was prepared. Every new born infant who was born weighing less than 2500 g was entered in our study and just next the newborn infant who was normal all of his/her information use to be taken too, (n = 190). Path analysis, an extension of the regression model, was used in this study. RESULTS: Obviously exactly half of the infants were LBW, and the remainder were normal. There were 97 boys and 93 girls. The percentage of IUGR among mothers who had preterm delivery was 19, while this percentage for mothers who had term delivery was 11.5 (P value = 0.167). LBW infants were 36.7% unexpected, while this percent for normal infants was 15.5 (P value < 0.001). Preterm delivery has a significant and direct effect on LBW (p value < 0.001), and its positive sign of path coefficient shows that if it occurs, the probability of LBW will increase, the second important was IUGR, the results showed unexpected pregnancy had direct effect on LBW but this wasn't significant (P value = 0.292). CONCLUSIONS: By preventing unnecessary termination of pregnancy and keeping fit, the chances of LBW can be reduced. PMID- 24349741 TI - The small round blue cell tumors of the sinonasal area: histological and immunohistochemical findings. AB - BACKGROUND: Primary Small round blue cell tumors (SRBCT) in sinonasal comprise histogenetically diverse entities with overlapping morphologic features. Because of the limited initial biopsy tissue materials, differential diagnostic difficulties may arise, and as they have different management, exact diagnosis and classification are very important. OBJECTIVES: In this study, we analyzed the immunohistochemical expression of a panel of markers in the classification and diagnosis of sinonasal SRBCTs. MATERIAL AND METHODS: This cross sectional study was performed on 36 paraffin embedded tissue samples. Histologic and immunohistochemical slides from 36 patients with SRBCT were analyzed retrospectively. The patients were admitted in Khalili hospital, Shiraz from 1383 to 1388. RESULTS: There were 13 women and 23 men with the mean age of 53 +/-12.1. There were 9 malignant melanoma, seven poorly differentiated SCC; six lymphoma (DLBL); 4 SCNEC; three SNUC; two ON; two Ewing/PNET; two embryonal rhabdomyosarcoma, and one plasmacytoma. Pan-cytokeratin was strongly expressed poorly differentiated SCC and all cases of SNUC. Coexpression of desmin and nuclear myoD1 was only detected in rhabdomyosarcoma. HMB45 was only expressed in sinonasal melanoma. CD99 expression was identified only in Ewing/PNET. FLI-1 was detected in 50% of PNET. P63 was expressed in poorly differentiated SCC (2/7) and SNUC (1/3). CONCLUSIONS: The results of our study indicate that the integration of histopathologic findings with application of limited but highly specific markers led to the separation of carcinomas, lymphoma and melanomas from other small cell tumors. Using a panel of keratin, LCA, desmin, and HMB45 is the most practical and economic approach to accurately classify these tumors. PMID- 24349743 TI - Clinical lipid control success rate before and after percutaneous coronary intervention in iran; a single center study. AB - BACKGROUND: High cholesterol levels have long been considered an independent risk factor for cardiovascular disease (CVD). OBJECTIVE: Controlling risk factors such as dyslipidemia in patients with coronary artery disease is necessary. We aimed to evaluate the success rate of lipid control, during 9 months follow-up after percutaneous coronary intervention (PCI). PATIENTS AND METHODS: A total of 195 patients (67.7% men, mean age = 57.8 +/- 9.4 years) who underwent PCI in Tehran Heart Center were included. Serum lipid profiles were measured in all the patients before PCI and at 9-month follow-up. Dyslipidemia was defined as serum levels of LDL-C >= 100 or TG >= 150 or TC >= 200 or HDL-C <= 40 mg/dl in the men and <= 50 mg/dl or less in the women, or non-HDL-C >= 130 mg/dl with or without the consumption of lipid-lowering agents. During follow up, all patients were given atorvastatin 20-40 mg/day. RESULTS: Overall, 26.2% had diabetes mellitus, 42.6% had hypertension, and 34.9% were smokers. Dyslipidemia was more common in the women. At 9-month follow-up, there was no significant changes in terms of the prevalence of high HDL-C or low TG in patients; however, a significant increase was seen in the prevalence low TC in patients (63.6% vs. 80.5%; p value < 0.001), LDL-C (47.2% vs. 65.6%; p value < 0.001), and non-HDL-C (40.0% vs. 63.1%; p value < 0.001). CONCLUSIONS: Although by current treatments, the prevalence of patients with low TC, LDL-C and non-HDL-C has significantly increased; dyslipidemia persisted in a considerable proportion of patients. These results necessitate further investigations into the relationship between high serum lipids and long term outcome of patients after PCI as well as further evaluations of the dyslipidemia treatment strategies. PMID- 24349744 TI - Frequency of all types of colorectal tumors in the patients referred to selected hospitals in tehran. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide which is not extensively researched in Iran. OBJECTIVES: The present study aims to investigate the epidemiologic characteristics of CRC in patients referred to selected hospitals of Tehran University of Medical Sciences. PATIENTS AND METHODS: In this descriptive-analytic study 218 patients with colorectal cancer were investigated. Data were collected via reviewing recorded pathologic results of patients of these hospitals which then were analyzed by univariant methods. RESULTS: Among 218 patients, 140 (64.2%) were male and 78 (35.8%) were female. Of all patients, 132 (60.0%) suffered from tumors in rectum; 38 (17.4%) in sigmoid; 12 (5.5%) in descending colon; 10 (4.6%) in transverse colon and 26 (11.9%) in ascending colon and cecum. Tumors were well differentiated in 134 patients (61.5%), moderately in 62 cases (28.4%) and poorly differentiated in 22 patients (10.1%). There was no significant difference between males and females regarding the location and degree of tumor differentiation. CONCLUSIONS: Regarding high prevalence of colorectal cancer in Iran and potential environmental and genetic factors, surveillance must be considered for this disease. Its risk factors such as diet, life style and low physical activity should be evaluated and screening should start at younger ages. PMID- 24349745 TI - Determining the Latent Tuberculosis Infection by IFN - gamma Elispot Assay in Healthcare Workers From University Hospitals of Shiraz, South West of Iran. AB - BACKGROUND: Classical screening methods are incapable to properly detect LTBI (Latent TB Infection) and HCWs (Healthcare Workers) are at the high risk of exposure. Only few reports estimated the prevalence of LTBI among Iranian HCWs and they mostly used the TST (Tuberculin Skin Test), rather than assessing the response against TB-specific antigens. OBJECTIVES: The current study aimed to determine the frequency of IFN - gamma producing blood cells of microbiology and radiology ward technicians by an in-house IFN - gamma ELISPOT assay in the University hospitals of Shiraz University of Medical Sciences (SUMS) against recombinant ESAT - 6 and PPD antigens. MATERIALS AND METHODS: 89 HCWs from medical laboratory and radiology departments of Shiraz University of Medical Sciences' hospitals, South of Iran, were screened for LTBI. To achieve the goal, an in-house IFN - gamma (Interferon - gamma) ELISPOT (Enzyme Linked ImmunoSpot) assay was used to detect the reactivity against ESAT - 6 (Early Secreted Antigen Target protein - 6) and the PPD (Purified Protein Derivate). RESULTS: Almost 8% of the personnel showed positive TST (over 10 mm) reaction while 29% of them had considerable T - cell reactivity against PPD in ELISPOT assays. However, the ESAT - 6 reactivity was found only in one case of HCWs. No correlation was found between the patterns of the reactions and the age or the duration of the employment or previous vaccination history of the participants. The ELISPOT results were not correlated with the TST results. CONCLUSIONS: Considering the hindrance of TST, the IFN - gamma ESAT - 6 ELISPOT assay, even in forms of in house tests, could replace traditional methods to properly spot the LTBI among the high risk groups from Iran's health system. PMID- 24349746 TI - Comparing the effect of preoperative administration of methylprednisolone and its administration before and during surgery on the clinical outcome in pediatric open heart surgeries. AB - BACKGROUND: Cardiac surgery under Cardiopulmonary bypass causes a systemic inflammatory response with a multifactorial etiology including direct tissue damage, ischemia and stimulation of immune system induced by cardiopulmonary bypass. This study was designed due to the high prevalence and complications of this stimulated immune system in mortality, morbidity, length of ICU stay, and mechanical ventilation. OBJECTIVES: This study was aimed to compare preoperative and intraoperative methylprednisolone (MP) to intraoperative MP alone with respect to postbypass inflammation and clinical outcome. PATIENTS AND METHODS: Sixty pediatric patients (age < 5years) undergoing cardiopulmonary bypass surgery between September 2011-2012 at Imam Reza hospital-Mashhad were randomly assigned to receive preoperative and intraoperative MP (group 1: 30 mg/kg, 4 hours before bypass and in bypass prime, n = 30) or intraoperative MP only (group 2: 30 mg/kg, n = 30). Postoperative temperature (peak temperature and average temperature during the first 24 hours), amount of inotropic, duration of mechanical ventilation, ICU stay, WBC, BUN, creatinine, and CRP were recorded and compared in both groups. Data were analyzed with SPSS version 13 by T-test, Mann-Whitney test if necessary, and Chi-squared distribution. RESULTS: Patient characteristics including age, weight, gender, and duration of bypass were almost similar in both groups (P > 0.05). No significant difference in amount of inotropic medications used for hemodynamic supports, duration of mechanical ventilation, peak and average temperature and length of ICU stay was observed. Among the laboratory tests (WBC, BUN, creatinine, CRP) only WBC counts raised more in group 2 when compared to group 1(P < 0.05). CONCLUSIONS: There was no difference in clinical outcome after cardiac surgery when we administered an additional dose of methylprednisolone compared to a single dose of methylprednisolone. PMID- 24349747 TI - Comparison of vessel sealing systems with conventional. AB - BACKGROUND: Haemorrhoids are cushions of submucosal vascular tissue located in the anal canal starting just distal to the dentate line. Haemorrhoidal disease is a common anorectal disorder which has symptoms of bleeding, prolapse, pain, thrombosis, mucus discharge, and pruritus. Haemorrhoidectomy is one of most frequently performed anorectal operation worldwide. OBJECTIVES: The aim of this study was to compare the effectiveness of the LigaSure tissue sealing device, Harmonic Scalpel and conventional MM open haemorrhoidectomy. MATERIALS AND METHODS: Sixty-nine patients with newly diagnosed symptomatic grade three or grade four haemorrhoidal disease, from July 2011 to December 2011 were recruited for the study. Patients were prospectively randomized to LigaSure, Harmonic Scalpel and conventional haemorrhoidectomy. Patients were evaluated on the basis of the mean operative time, postoperative pain, day of discharge, early and late complications. RESULTS: Each group has twenty-three patients. Ten (14.5 %) were female and fifty-nine (85.5 %) were male. Mean age were 44.5 +/- 10.8 for LigaSure group, 39.5+/-14.4 for Harmonic Scalpel group and 39.8 +/- 13.6 for conventional haemorrhoidectomy group. Mean operative time was 12.6 +/- 2.9 for LigaSure group, 12.6 +/- 2.5 for Harmonic Scalpel group and 22.3 +/- 4.5 for conventional haemorrhoidectomy group. Postoperative pain and required analgesic dose were significantly lower for conventional haemorrhoidectomy. Wound healing was also more rapid in conventional haemorrhoidectomy than both LigaSure and Harmonic Scalpel. CONCLUSIONS: Lateral heat dissipation of energy based cautery such as Harmonel Scalpel and LigaSure is considerably high when compared with conventional methods. More thermal damage which is generated on tissue seems to be the reason for increased degree of postoperative pain and delay in wound healing. PMID- 24349748 TI - Perforated acute appendicitis in a pre-term neonate. AB - Acute appendicitis is a common occurrence in childhood, but this diagnosis is considered rarely in differential diagnosis of acute abdomen in the neonatal period because its occurrence is very rare in neonates. We report a 20-day- old afghan female baby that was admitted to neonatal intensive care unit, because of irritability and abdominal distension. Complete ultrasound of abdomen and pelvis was normal. In plain Radiographs of chest and abdomen with the exception of Air filled stomach and intestine, there was no abnormality. Due to the lack of improvement and severe abdominal distension, she was transmitted to the operating room and Surgical exploration revealed perforated appendix. Appendicitis should be considered in the differential diagnosis for a neonate with abdominal distension and bilious vomiting and needs strong clinical suspicion. PMID- 24349749 TI - Comparison of three interview methods on response pattern to sensitive and non sensitive questions. AB - BACKGROUND: To get more precise responses when gathering information about sensitive topics such as drug use, it is important to use the most optimal method. OBJECTIVES: This study was carried out to address the impact of three interview methods (street-based, household, and telephone interviews) on response pattern to sensitive and non-sensitive questions in terms of participation, disclosure and discontinuing rates. PATIENTS AND METHODS: We selected three culturally diverse major cities of Iran. Then, we randomly selected 300 subjects, 100 for each type of interview, from each major city (899 in total). For street based interviews only pedestrians who were walking alone were recruited, for household interviews only one individual from each house participated (3-4 houses in each alley were selected), and for telephone interviews we selected phone numbers using a random number list. We asked five non-sensitive and five sensitive (related to drug use and sexual contact among their personal network) questions. RESULTS: For telephone and household interviews, relative to street based interviews, participants were less likely to disclose alcohol and drug related behaviors (Adjusted OR = 0.76; 95% CI: 0.60- 0.97) and sexual behaviors among their network (Adjusted OR telephone/street-based = 0.64; 95% CI: 0.39- 1.07 and Adjusted OR household/ street-based = 0.56; 95% CI: 0.33- 0.95). We found that participants who were interviewed via the telephone were more likely (Adjusted OR = 1.24) and those who were interviewed at home were less likely (Adjusted OR = 0.86) to report non-sensitive information compared to participants who were interviewed on the street; however, these findings were not statistically significant. The largest participation rate and the least discontinuation rate were observed for household interviews. CONCLUSIONS: It seems that the methods of interview effect response to both sensitive and non sensitive questions. We believe that for street-based interviews, respondents may disclose more sensitive information than telephone and household interviews. PMID- 24349751 TI - Accuracy of estrogen and progesterone receptor assessment in core needle biopsy specimens of breast cancer. AB - BACKGROUND: Diagnosis of breast cancer is completed through core needle biopsy (CNB) of the tumors but there is controversy on the accuracy of hormone receptor results on CNB specimens. OBJECTIVES: We undertook this study to compare the results of hormone receptor assessment in CNB and surgical samples on our patients. PATIENTS AND METHODS: Hormone receptor status was determined in CNB and surgical samples in breast cancer patients whose CNB and operation had been performed in this institute from 2009 to 2011 and had not undergone neoadjuvant chemotherapy. RESULTS: About 350 patients, 60 cases met all the criteria for entering the study. The mean age was 49.8 years. Considering a confidence interval (CI) of 95%, the sensitivity of ER and PR assessment in CNB was 92.9% and 81%, respectively and the specificity of both was 100%. The Accuracy of CNB was 98% for ER and 93% for PR. CONCLUSIONS: Our results confirm the acceptable accuracy of ER assessment on CNB. The subject needs further investigation in developing countries where omission of the test in surgical samples can be cost and time-saving. PMID- 24349752 TI - Preparedness of hospitals in north of iran to deal with disasters. AB - INTRODUCTION: Preparedness of hospital has a major impact on their optimal and satisfactory performance. This study aimed to investigate the preparedness of the hospitals to deal with disasters. CASE PRESENTATION: This cross-sectional study was carried in 2011 and all of the hospitals which were located in the northern areas of Iran were investigated through the census method. The data collection instruments were self-administered Managers' Awareness Questionnaire (40 items) and a 141-item checklist. The mean percentage score of hospitals in management of the unanticipated disasters program in the hospital was good. The mean score of managers' awareness of the hospital status was moderate. With the increase in managers' awareness, the preparedness of the hospitals significantly increased (r = 0.73, P < 0.001). CONCLUSIONS: The findings showed the moderate preparedness of the hospitals in the Northern provinces to deal with disasters. PMID- 24349750 TI - Path analysis associations between perceived social support, stressful life events and other psychosocial risk factors during pregnancy and preterm delivery. AB - BACKGROUND: Although several socio-medical risk factors have been identified for preterm labor, there is a gap in understanding the underlying etiology of preterm labor. OBJECTIVES: The current study aimed to analyze the relationship pathway of perceived social support, stressful life events, and other psychosocial risk factors during pregnancy with incidence of preterm labor. MATERIALS AND METHODS: In a prospective cohort study in four hospitals in Tehran, 500 pregnant women in their 24th to 28th gestational weeks were studied. They filled out a self-report questionnaire on perceived social support, depression, anxiety, stress and stressful life events. Sociodemographic characteristics were also assessed. The participants were followed up until labor, and the data about mother and the newborn were collected after labor. The data were analyzed by SPSS 16 and Lisrel 8.8 software programs using pathway analysis. RESULTS: The final path model fit well (CFI = 0.96; RMSEA = .064). The results showed that depression, anxiety, and stress (beta = -0.18) directly, and stressful life events indirectly (beta= 0.0396) had the most predict on gestational age at labor. Perceived social support, directly through socioeconomic status (beta=0.25), and indirectly through stress, depression and anxiety (beta= -0.26) affected the gestational age at birth (beta= 0.0468). CONCLUSIONS: The current study showed that supporting pregnant mother moderates psychological problems such as stress, anxiety, and depression, and hence reduces preterm labor. PMID- 24349753 TI - Diastematomyelia Presenting With no Pain in a 53-Year-Old Man: A Case Report. AB - Initial presentation of diastematomyelia is rarely seen in adults. The purpose of this case report is to present a case of clinically silent diastematomyelia unrecognized into adulthood and review of the literature. A 53-year-old Persian man was admitted to our hospital with gait disturbance, weakness of the right lower extremity, sensory loss of the left and right lower extremity of two weeks' duration, with no pain or sphincter dysfunction. The patient underwent radiological examinations, and diastematomyelia was diagnosed. The deteriorating condition of our patient led to the decision to perform a surgery. A laminectomy was performed from L-3 to L-5 with resection of the soft-tissue mass and excision of the bony spur, and the patient was followed for 6 months. Postoperatively, the patient did not show new neurologic deficit and he returned to work 4 months after surgery. Our case was unique because of the absence of any pain, neurologic signs, and precipitating acute event leading to diagnosis, until 53 years of age. Surgical decompression of bony spur provided relative improvement of his symptoms. PMID- 24349754 TI - Lead poisoning-induced hypertensive crisis managed by prazosin: a case report. AB - INTRODUCTION: Chronic lead exposure is known to be a risk factor for hypertension (HTN). No specific medication is recommended for the treatment of lead-induced hypertension (LIHTN). CASE PRESENTATION: Our patient was a male admitted with the chief complaint of chronic abdominal pain. His whole blood lead level was reported to be 1961 ug/L. He also mentioned a previous history of HTN managed by propranolol (10 mg, TDS). He discharged himself by giving written consent and 19 days later, he was re-admitted due to high blood pressure of 220/140 mmHg. His Blood pressure (BP) was decreased to 180/110 mmHg with sublingual captopril; but, in maintenance therapy, higher doses of captopril could not further decrease BP. Amlodipine was tried which was discontinued due to the patient intolerance. Prazosin was then administered in gradual increasing doses up to 1 mg twice a day and captopril was tapered. CONCLUSIONS: We would like to suggest that LIHTN may better be managed by alpha blockers compared with converting enzyme inhibitors. PMID- 24349755 TI - Atypical giant hydatid cyst at the thoracic wall causing bone and soft tissue destruction: report of a case. AB - Hydatid cyst is a zoonotic disease that is common in the Mediterranean region. Thoracic wall, rib or extrapulmonary intrathoracic localization of the cysts is very rare. Giant extrapulmonary intrathoracic hydatid cysts can lead to both diagnostic and treatment difficulties and can be confused with tumor. We present a case of a hydatid cyst with thoracic wall involvement mimicking tumor. We confirmed diagnosis only by surgical exploration and histopathological examination because radiology is not conclusive .Surgical treatment involved the total extirpation of cyst together wide debridement and resection of affected tissue. Primary thoracic wall closures were performed. In thoracic wall localization of cyst, post-operative course of albendazole for 6 weeks associated with surgery can help in sterilizing the cyst and reduce the recurrence rate. In this article, we presented a thoracic wall hydatidosis which is very uncommon asymptomatic presentation of hydatid cyst disease with its surgical management. PMID- 24349756 TI - Clinical learning environment at shiraz medical school in the educators' and residents' viewpoints. PMID- 24349757 TI - Ipsilateral traumatic fractures of the proximal and distal parts of the humerus (floating arm) with fracture of distal clavicle: a case report. PMID- 24349759 TI - Should External Powered Orthoses be Used by Paraplegic Subjects or Not? PMID- 24349758 TI - Genotyping of acanthamoeba isolated from surface and stagnant waters of qazvin, central iran. PMID- 24349760 TI - A method for biomarker directed survival prediction in advanced non-small-cell lung cancer patients treated with Carboplatin-based therapy. AB - Platinum-based chemotherapy is a primary treatment of choice for advanced non small-cell lung cancer (NSCLC). Analytical methods to specifically evaluate biomarkers predictive of therapeutic efficacy have not been developed. Two randomized phase III trials of carboplatin-based chemotherapy in advanced NSCLC were used for learning and validating the predictive value of ERCC1 in situ protein levels, as measured by accurate quantitative analysis (AQUA). A novel Bayesian method was applied to identify the outcome-based threshold in the learning trial only. Overall survival (OS) was assessed by Kaplan-Meier analysis with log rank testing to determine statistical significance in the validating trial. For patients treated with gemcitabine and carboplatin, the median OS was 9.5 months (95% CI 6.7 to 11.8) for the high ERCC1 group compared to 15.6 months (95% CI 11.6 to 24.8) for the low ERCC1 group in the validation trial (log rank p value = 0.007). The hazard ratio for low ERCC1 was 0.598 (95% CI, 0.394 to 0.908; p = 0.016) relative to high ERCC1 adjusted for age, sex, and histology. CONCLUSIONS: Patients with advanced NSCLC could be stratified into high and low ERCC1 expression groups. Patients with low levels benefited from platinum-based chemotherapy, whereas those with high levels did not. PMID- 24349761 TI - Monitoring Therapeutic Treatments against Burkholderia Infections Using Imaging Techniques. AB - Burkholderia mallei, the etiologic agent of glanders, are Category B select agents with biothreat potential, and yet effective therapeutic treatments are lacking. In this study, we showed that CpG administration increased survival, demonstrating protection in the murine glanders model. Bacterial recovery from infected lungs, liver and spleen was significantly reduced in CpG-treated animals as compared with non-treated mice. Reciprocally, lungs of CpG-treated infected animals were infiltrated with higher levels of neutrophils and inflammatory monocytes, as compared to control animals. Employing the B. mallei bioluminescent strain CSM001 and the Neutrophil-Specific Fluorescent Imaging Agent, bacterial dissemination and neutrophil trafficking were monitored in real-time using multimodal in vivo whole body imaging techniques. CpG-treatment increased recruitment of neutrophils to the lungs and reduced bioluminescent bacteria, correlating with decreased bacterial burden and increased protection against acute murine glanders. Our results indicate that protection of CpG-treated animals was associated with recruitment of neutrophils prior to infection and demonstrated, for the first time, simultaneous real time in vivo imaging of neutrophils and bacteria. This study provides experimental evidence supporting the importance of incorporating optimized in vivo imaging methods to monitor disease progression and to evaluate the efficacy of therapeutic treatment during bacterial infections. PMID- 24349762 TI - Effects of Chronic Central Arginine Vasopressin (AVP) on Maternal Behavior in Chronically Stressed Rat Dams. AB - Exposure of mothers to chronic stressors during pregnancy or the postpartum period often leads to the development of depression, anxiety, or other related mood disorders. The adverse effects of mood disorders are often mediated through maternal behavior and recent work has identified arginine vasopressin (AVP) as a key neuropeptide hormone in the expression of maternal behavior in both rats and humans. Using an established rodent model that elicits behavioral and physiological responses similar to human mood disorders, this study tested the effectiveness of chronic AVP infusion as a novel treatment for the adverse effects of exposure to chronic social stress during lactation in rats. During early (day 3) and mid (day 10) lactation, AVP treatment significantly decreased the latency to initiate nursing and time spent retrieving pups, and increased pup grooming and total maternal care (sum of pup grooming and nursing). AVP treatment was also effective in decreasing maternal aggression and the average duration of aggressive bouts on day 3 of lactation. Central AVP may be an effective target for the development of treatments for enhancing maternal behavior in individuals exposed to chronic social stress. PMID- 24349763 TI - Systems Biology Profiling of AMD on the Basis of Gene Expression. AB - Genetic pathways underlying the initiation and progression of age-related macular degeneration (AMD) have not been yet sufficiently revealed, and the correlations of AMD's genotypes, phenotypes, and disease spectrum are still awaiting resolution. We are tackling both problems with systems biology phylogenetic parsimony analysis. Gene expression data (GSE29801: NCBI, Geo) of macular and extramacular specimens of the retinas and retinal pigment epithelium (RPE) choroid complexes representing dry AMD without geographic atrophy (GA), choroidal neovascularization (CNV), GA, as well as pre-AMD and subclinical pre-AMD were polarized against their respective normal specimens and then processed through the parsimony program MIX to produce phylogenetic cladograms. Gene lists from cladograms' nodes were processed in Genomatix GePS to reveal the affected signaling pathway networks. Cladograms exposed a highly heterogeneous transcriptomic profiles within all the conventional phenotypes. Moreover, clades and nodal synapomorphies did not support the classical AMD phenotypes as valid transcriptomal genotypes. Gene lists defined by cladogram nodes showed that the AMD-related deregulations occurring in the neural retina were different from those in RPE-choroidal tissue. Our analysis suggests a more complex transcriptional profile of the phenotypes than expected. Evaluation of the disease in much earlier stages is needed to elucidate the initial events of AMD. PMID- 24349765 TI - Hemodynamic correlates of late systolic flow velocity augmentation in the carotid artery. AB - Background. The contour of the common carotid artery (CCA) blood flow velocity waveform changes with age; CCA flow velocity increases during late systole, and this may contribute to cerebrovascular disease. Late systolic flow velocity augmentation can be quantified using the flow augmentation index (FAIx). We examined hemodynamic correlates of FAIx to gain insight into determinants of CCA flow patterns. Methods. CCA Doppler ultrasound and wave intensity analysis (WIA) were used to assess regional hemodynamics in 18 young healthy men (age 22 +/- 1 years). Forward waves (W 1) and backward waves (negative area, NA) were measured and used to calculate the reflection index (NA/W 1 = RIx). Additional parameters included W 2 which is a forward travelling expansion/decompression wave of myocardial origin that produces suction, CCA single-point pulse wave velocity (PWV) as a measure of arterial stiffness, and CCA pressure augmentation index (AIx). Results. Primary correlates of FAIx included W 2 (r = - 0.52, P < 0.05), logRIx (r = 0.56, P < 0.05), and AIx (r = 0.60, P < 0.05). FAIx was not associated with CCA stiffness (P > 0.05). Conclusions. FAIx is a complex ventricular-vascular coupling parameter that is associated with both increased expansion wave magnitude (increased suction from the left ventricle) and increased pressure from wave reflections. PMID- 24349764 TI - Oligonucleotide-Based Therapy for FTD/ALS Caused by the C9orf72 Repeat Expansion: A Perspective. AB - Amyotrophic lateral sclerosis (ALS) is a progressive and lethal disease of motor neuron degeneration, leading to paralysis of voluntary muscles and death by respiratory failure within five years of onset. Frontotemporal dementia (FTD) is characterised by degeneration of frontal and temporal lobes, leading to changes in personality, behaviour, and language, culminating in death within 5-10 years. Both of these diseases form a clinical, pathological, and genetic continuum of diseases, and this link has become clearer recently with the discovery of a hexanucleotide repeat expansion in the C9orf72 gene that causes the FTD/ALS spectrum, that is, c9FTD/ALS. Two basic mechanisms have been proposed as being potentially responsible for c9FTD/ALS: loss-of-function of the protein encoded by this gene (associated with aberrant DNA methylation) and gain of function through the formation of RNA foci or protein aggregates. These diseases currently lack any cure or effective treatment. Antisense oligonucleotides (ASOs) are modified nucleic acids that are able to silence targeted mRNAs or perform splice modulation, and the fact that they have proved efficient in repeat expansion diseases including myotonic dystrophy type 1 makes them ideal candidates for c9FTD/ALS therapy. Here, we discuss potential mechanisms and challenges for developing oligonucleotide-based therapy for c9FTD/ALS. PMID- 24349767 TI - Intersection of HIV and Reproductive Health. PMID- 24349766 TI - Preliminary blood pressure screening in a representative sample of extremely obese Kuwaiti adolescents. AB - A relationship between blood pressure (BP) and obesity has been found in young adults, but no data are available for adolescents in Kuwait. 257 adolescent (11 19 years) participants were categorized into two groups according to their BMI; 48 nonobese (21 males: 43.7% and 27 females: 56.3%) with mean age of 15.61 +/- 2.40 years and 209 obese (128 males: 61.25% and 81 females: 38.75%) with mean age of 15.02 +/- 2.82 years. The mean BMI was 21.7 +/- 2.23 kg/m(2) for the nonobese group and 34.47 +/- 4.70 kg/m(3) for the obese group. Most BP measures based on a single screening were significantly higher in the obese group. The prevalence of elevated BP was significantly higher in the obese subjects (nonobese: 13%; obese: 63%; P < 0.0001). In the obese group, there was a significant positive correlation between total sample BMI and all BP measures except the pulse pressure. There was a similar rate of elevated blood pressure between males and females (64% versus 60%; P = 0.66). For both isolated systolic elevated BP and isolated diastolic elevated BP, the prevalences were comparable between the males (systolic: 42%; diastolic: 5%) and females (systolic: 34%; diastolic: 14%). Only systolic BP was positively correlated with BMI in obese adolescent males (Spearman r = 0.18; P < 0.05), with a significant correlation between BMI with diastolic (Spearman r = 0.22; P < 0.05) and mean BP (Spearman r = 0.21; P < 0.05) in females. PMID- 24349768 TI - Diagnosis of severe fetal anemia based on perinatal outcomes: a comparative analysis of the current reference values. AB - Objectives. To compare current criteria for severe fetal anemia diagnosis. Methodology. A cohort study analyzed 105 alloimmunized fetuses that underwent cordocentesis due to risk of anemia. Concordance among the diagnostic criteria for severe fetal anemia, hemoglobin deficit >7 g/dL, hemoglobin deficit >=5 g/dL, and hemoglobin concentration <0.55 MoM, was analyzed using Cohen's Kappa index. Perinatal mortality, fetal hydrops, and fetal acidosis were used to discuss discordances. Results. There was fair concordance among the three criteria analyzed: 0.80 (Kappa index, IC 95%: 0.67 to 0.93) when comparing hemoglobin deficit >7.0 g/dL and hemoglobin concentration <0.55 MoM criteria, 0.63 (Kappa index, IC 95%: 0.47 to 0.69) when comparing hemoglobin deficit >=5.0 g/dL and hemoglobin deficit >7.0 g/dL reference, and 0.77 (Kappa index, IC 95%: 0.64 to 0.90) when comparing hemoglobin deficit>=5.0 g/dL and hemoglobin concentration <0.55 MoM standards. Eighteen cases were classified differently depending on the criteria used. The cut-off point of hemoglobin deficit >=5 g/dL was the best criterion to discriminate fetuses with poor perinatal outcome in our study. Conclusions. Relevant discordances in classification of severe fetal anemia were pointed out. Some criteria may underestimate the real gravity of fetal anemia. PMID- 24349769 TI - The effect of short-term aerobic exercise on depression and body image in Iranian women. AB - The purpose of this study was to determine the effect of short-term aerobic exercise on depression symptoms and body image attitudes among Iranian women. In this quasiexperimental study, 82 females were assigned to experimental group (aerobic exercise group, n = 41) or control group (waiting list, n = 41) and evaluated by Beck Depression Inventory-second edition (BDI-II) and Multidimensional Body Self-Relation Questionnaire (MBSRQ), respectively. The experimental group received four-week aerobic exercise program, and control group had been asked to wait for the next four weeks. Results of this study confirmed the significant decrease in depression symptoms at the experimental group compared to control group (P < 0.5). For the body image dependent variables, significant improvement was also found in appearance evaluation, appearance orientation, health orientation, and illness orientation in aerobic exercise group (P < 0.5). PMID- 24349770 TI - Know your client and know your team: a complexity inspired approach to understanding safe transitions in care. AB - Background. Transitions in care are one of the most important and challenging client safety issues in healthcare. This project was undertaken to gain insight into the practice setting realities for nurses and other health care providers as they manage increasingly complex care transitions across multiple settings. Methods. The Appreciative Inquiry approach was used to guide interviews with sixty-six healthcare providers from a variety of practice settings. Data was collected on participants' experience of exceptional care transitions and opportunities for improving care transitions. Results. Nurses and other healthcare providers need to know three things to ensure safe care transitions: (1) know your client; (2) know your team on both sides of the transfer; and (3) know the resources your client needs and how to get them. Three themes describe successful care transitions, including flexible structures; independence and teamwork; and client and provider focus. Conclusion. Nurses often operate at the margins of acceptable performance, and flexibility with regulation and standards is often required in complex sociotechnical work like care transitions. Priority needs to be given to creating conditions where nurses and other healthcare providers are free to creatively engage and respond in ways that will optimize safe care transitions. PMID- 24349771 TI - Participation in decision making as a property of complex adaptive systems: developing and testing a measure. AB - Objectives. To (1) describe participation in decision-making as a systems-level property of complex adaptive systems and (2) present empirical evidence of reliability and validity of a corresponding measure. Method. Study 1 was a mail survey of a single respondent (administrators or directors of nursing) in each of 197 nursing homes. Study 2 was a field study using random, proportionally stratified sampling procedure that included 195 organizations with 3,968 respondents. Analysis. In Study 1, we analyzed the data to reduce the number of scale items and establish initial reliability and validity. In Study 2, we strengthened the psychometric test using a large sample. Results. Results demonstrated validity and reliability of the participation in decision-making instrument (PDMI) while measuring participation of workers in two distinct job categories (RNs and CNAs). We established reliability at the organizational level aggregated items scores. We established validity of the multidimensional properties using convergent and discriminant validity and confirmatory factor analysis. Conclusions. Participation in decision making, when modeled as a systems-level property of organization, has multiple dimensions and is more complex than is being traditionally measured. Managers can use this model to form decision teams that maximize the depth and breadth of expertise needed and to foster connection among them. PMID- 24349772 TI - Self-care and chronic disease. PMID- 24349773 TI - A systematic review of the utility of residual vein obstruction studies in primary and secondary venous thrombosis. AB - Background. Residual vein obstruction (RVO), the persistence of venous thrombosis with time and often after anticoagulation, may indicate a systemic prothrombotic condition. Prior studies have shown varying efficacy in using RVO as a risk factor for future venous thromboembolic (VTE) recurrence. Methods. To assess whether positive RVO imaging predicts recurrent VTE events, we performed a meta analysis on studies in which patients with documented VTEs, anticoagulated for a minimum of 4 weeks, had repeat sonography to assess RVO and were subsequently followed for recurrent events. Results. Thirteen studies met inclusion criteria: 3531 patient VTE events with 3474 evaluable results were analyzed. The presence of RVO was associated with recurrence in all VTE (OR 1.93; 95% CI: 1.29, 2.89) and secondary VTE (OR 2.78; 95% CI: 1.41, 5.5) but not for primary VTE (OR 1.35; 95% CI: 0.87, 2.08). When cancer patients were eliminated from the secondary VTE group, there was no longer a significant association of RVO with VTE recurrence (OR 1.73; 95% CI: 0.81, 3.67) while in the subset of cancer patients, presence of RVO was associated with an increase in VTE recurrence risk (OR 5.14; 95% CI: 1.59, 16.65, P < 0.006). Conclusions. We conclude that the presence of RVO is associated with recurrence in secondary VTE but not in primary VTE and that association may be driven by the subset with cancer. PMID- 24349774 TI - Use of oral anticoagulation therapy in atrial fibrillation after stroke: results from a nationwide registry. AB - Background. The knowledge is still sparse about patient related factors, influencing oral anticoagulation therapy (OAC) rates, in stroke patients with atrial fibrillation (AF). Aims. To assess the use of OAC in ischemic stroke patients diagnosed with AF and to identify patient related factors influencing the initiation of OAC. Methods. In the nationwide Danish Stroke Registry we identified 55,551 patients admitted with acute ischemic stroke from 2003 to 2011. Frequency analysis was used to assess the use of OAC in patients with AF, and logistic regression was used to determine independent predictors of OAC. Results. 17.1% (n = 9,482) of ischemic stroke patients had AF. OAC prescription rates were increasing, and in 2011 46.6% were prescribed OAC, 42.5% had a contraindication, and 3.7% were not prescribed OAC without a stated contraindication. Younger age, less severe stroke, and male gender were positive predictors of OAC, while excessive alcohol consumption, smoking, and institutionalization were negative predictors of OAC (P values < 0.05). Conclusions. Advanced age, severe stroke, female gender, institutionalization, smoking, and excessive alcohol consumption were associated with lower OAC rates. Contraindications were generally present in patients not in therapy, and the assumed underuse of OAC may be overestimated. PMID- 24349775 TI - Early Therapeutic Drug Monitoring for Isoniazid and Rifampin among Diabetics with Newly Diagnosed Tuberculosis in Virginia, USA. AB - Slow responders to tuberculosis (TB) treatment in Virginia have prolonged treatment duration and consume more programmatic resources. Diabetes is an independent risk factor for slow response and low serum anti-TB drug concentrations. Thus, a statewide initiative of early therapeutic drug monitoring (TDM) for isoniazid and rifampin at 2 weeks after TB treatment was piloted for all diabetics with newly diagnosed TB. During the period of early TDM, 12/01/2011 12/31/2012, 21 diabetics had C 2 hr concentrations performed and 16 (76%) had a value below the expected range for isoniazid, rifampin, or both. Fifteen had follow-up concentrations after dose adjustment and 12 (80%) increased to within the expected range (including all for rifampin). Of 16 diabetic patients with pulmonary TB that had early TDM, 14 (88%) converted their sputum culture to negative in <2 months. Early TDM for diabetics was operationally feasible, may speed response to TB therapy, and can be considered for TB programs with high diabetes prevalence. PMID- 24349776 TI - The immediate effects of orthoses on pain in people with lateral epicondylalgia. AB - Objective. Tennis elbow is a common cause of upper limb dysfunction and a primary reason for pain at the lateral aspect of the elbow. The purpose of this study was to investigate the effects of three commonly used orthoses on pain severity. An elbow band, an elbow sleeve, and a wrist splint were assessed for their ability to reduce the level of reported pain. Method. A crossover randomized controlled trial was used. The orthoses were worn in a randomized order, and all participants were required to complete a control trial for which they wore a placebo orthosis. 52 participants with lateral epicondylalgia were recruited, and the level of pain at their elbow was recorded using the visual analogue scale (VAS). Results. The reported pain for all orthoses was lower than that of the placebo (P < 0.05). Pain reduction was significantly greater with a counterforce elbow band or a counterforce elbow sleeve compared to a wrist splint (P < 0.01). There was no significant difference between a counterforce elbow band and a counterforce elbow sleeve (P = 0.23). Conclusion. All the types of orthoses studied showed an immediate improvement on pain severity in people with lateral epicondylalgia. The counterforce elbow orthoses (elbow band and elbow sleeve) presented the greatest improvement, suggesting that either of them can be used as a first treatment choice to alleviate the pain in people with tennis elbow. PMID- 24349777 TI - Is There a Relation between Tension-Type Headache, Temporomandibular Disorders and Sleep? AB - Introduction. Tension-Type Headache (TTH) is the most prevalent headache often associated with impaired function and quality of life. Temporomandibular Disorders (TMD) and TTH frequently coexist; characterized by pericranial tenderness and impact on daily life. We aim to apply a standardized questionnaire for TMD to characterize and analyse an eventual relation between sleep and oral health in TTH in a controlled design. Material and Methods. 58 consecutive TTH patients and 58 healthy controls were included. The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) questionnaire, Oral Health Impact profile (OHIP) and questionnaires for sleep were applied. Results. TTH-patients had significantly higher pain scores (P < 0.001), decreased quality of life (P < 0.001), and higher total sleep scores (P < 0.001) compared to controls. Conclusion. For the first time we have identified a clear relation between TTH and TMD symptoms, depression, anxiety, poor sleep, and impairments of oral function in carefully classified patients. These findings indicate a close, but incomplete, overlap between TTH and TMD. Their underlying pathophysiological mechanisms need further research. PMID- 24349778 TI - Vest Chest Physiotherapy Airway Clearance is Associated with Nitric Oxide Metabolism. AB - Background. Vest chest physiotherapy (VCPT) enhances airway clearance in cystic fibrosis (CF) by an unknown mechanism. Because cilia are sensitive to nitric oxide (NO), we hypothesized that VCPT enhances clearance by changing NO metabolism. Methods. Both normal subjects and stable CF subjects had pre- and post-VCPT airway clearance assessed using nasal saccharin transit time (NSTT) followed by a collection of exhaled breath condensate (EBC) analyzed for NO metabolites (NO x ). Results. VCPT shorted NSTT by 35% in normal and stable CF subjects with no difference observed between the groups. EBC NO x concentrations decreased 68% in control subjects after VCPT (before = 115 +/- 32 MU M versus after = 37 +/- 17 MU M; P < 0.002). CF subjects had a trend toward lower EBC NO x . Conclusion. We found an association between VCPT-stimulated clearance and exhaled NO x levels in human subjects. We speculate that VCPT stimulates clearance via increased NO metabolism. PMID- 24349779 TI - Danish General Practitioners' Use of Prostate-Specific Antigen in Opportunistic Screening for Prostate Cancer: A Survey Comprising 174 GPs. AB - Background. The use of prostate-specific antigen test has markedly increased in Danish general practice in the last decade. Despite the national guidelines advice against PSA screening, opportunistic screening is supposed to be the primary reason for this increased number of PSA tests performed. Aims. Based on the increase in the amount of PSA conducted, we aimed to analyse how GPs in Denmark use the PSA test. Methods. A self-administrated questionnaire concerning symptomatic and asymptomatic patient cases was developed based on the national and international guidelines and the extensive literature review, and an in-depth interview conducted with a GP was performed. Results. None of the GPs would do a PSA measurement for an asymptomatic 76-year-old man. For asymptomatic 55- and 42 year-old men, respectively, 21.9% and 18.6% of GPs would measure PSA. Patient request and concern could be potential reasons for measuring PSA for asymptomatic patients. Almost all GPs stated that a PSA measurement is indicated for symptomatic 49- and 78-year-old men, respectively, 98.9% and 93.8%. Conclusion. Opportunistic PC screening is being performed in general practice to a high degree. Hence, current guidelines are not followed, and intense focus should be on more effective implementation strategies in order to avoid overuse of PSA. PMID- 24349780 TI - Long-Term Use of Probiotic-Containing Yogurts Is a Safe Way to Prevent Helicobacter pylori: Based on a Mongolian Gerbil's Model. AB - Background. The suppression of Helicobacter pylori (H. pylori) decreases H. pylori-related diseases. The probiotics have an inhibitory effect on H. pylori. Aim. We investigated the effects of long-term use of yogurt on H. pylori based on Mongolian gerbils' model. Materials and Methods. Yogurt (containing a supplement of Lactobacillus acidophilus, Bifidobacterium lactis, etc.) was used. Forty-six gerbils were divided into five groups. All groups were inoculated with H. pylori for 5 to 8 weeks. The yogurt was given as follows: Group (Gr.) A: from 1st to 4th week; Gr. B from 5th to 8th week; Gr. C: from 17th week to sacrifice; Gr. D: from 5th week to sacrifice. Gerbils were sacrificed on the 52nd week. Histology was evaluated according to the Sydney system. Results. The positive rates of H. pylori were 60% (Gr. A), 75% (Gr. B), 67% (Gr. C), 44% (Gr. D), and 100% (Gr. E). Gr. D showed lower inflammatory score. Only Gr. E (60%) had intestinal metaplasia. Gr. D showed higher IL-10 and lower TNF- alpha expression than Gr. E. Conclusion. Long-term intake of yogurt could decrease H. pylori infection. The long-term use of yogurt would be an alternative strategy to manage H. pylori infection. PMID- 24349781 TI - Effects of maternal factors on birth weight in Japan. AB - OBJECTIVE: We investigated the possible factors related to the birth weight (BW) using the Japanese perinatal database. METHODS: The live infants born at 37 to 41 weeks of gestation were enrolled in this study. Cases with diabetic pregnancy, preeclampsia, an anomalous fetus, and a fetus with chromosomal abnormalities were excluded. A multiple regression analysis for confounding factors and an analysis of covariance (ANCOVA) for comparing the BW in 2006 and 2010 were used for the statistical analysis. RESULTS: The BW significantly decreased from 2950.8 g in 2006 (n = 27,723) to 2937.5 g in 2010 (n = 38,008) in the overall population, and this decrease was similar for male and female neonates. All confounding factors, except for the mode of delivery, affected the BW. Primiparity, smoking, and a female gender were related to the decrease in BW, whereas maternal age, maternal height, weight gain during pregnancy, BMI, the use of in vitro fertilization, induction of labor, and gestational duration were related to an increased BW. The ANCOVA showed that no significant change of the BW was seen between 2006 and 2010 (the difference was 2.164 g, P = 0.414). CONCLUSION: The gestational duration is the most important factor affecting the BW in singleton term infants. PMID- 24349783 TI - Retracted: the effects of fetal gender on serum human chorionic gonadotropin and testosterone in normotensive and preeclamptic pregnancies. PMID- 24349782 TI - Effect of folic acid supplementation in pregnancy on preeclampsia: the folic acid clinical trial study. AB - Preeclampsia (PE) is hypertension with proteinuria that develops during pregnancy and affects at least 5% of pregnancies. The Effect of Folic Acid Supplementation in Pregnancy on Preeclampsia: the Folic Acid Clinical Trial (FACT) aims to recruit 3,656 high risk women to evaluate a new prevention strategy for PE: supplementation of folic acid throughout pregnancy. Pregnant women with increased risk of developing PE presenting to a trial participating center between 8(0/7) and 16(6/7) weeks of gestation are randomized in a 1 : 1 ratio to folic acid 4.0 mg or placebo after written consent is obtained. Intent-to-treat population will be analyzed. The FACT study was funded by the Canadian Institutes of Health Research in 2009, and regulatory approval from Health Canada was obtained in 2010. A web-based randomization system and electronic data collection system provide the platform for participating centers to randomize their eligible participants and enter data in real time. To date we have twenty participating Canadian centers, of which eighteen are actively recruiting, and seven participating Australian centers, of which two are actively recruiting. Recruitment in Argentina, UK, Netherlands, Brazil, West Indies, and United States is expected to begin by the second or third quarter of 2013. This trial is registered with NCT01355159. PMID- 24349784 TI - The effect of cesarean delivery skin incision approach in morbidly obese women on the rate of classical hysterotomy. AB - OBJECTIVE: To assess the risk of classical hysterotomy and surgical morbidity among women with a body mass index (BMI) greater than 40 kg/m2 who underwent a supraumbilical incision at the time of cesarean delivery. METHODS: We conducted a retrospective cohort study in women having a BMI greater than 40 kg/m2 who underwent a cesarean delivery of a live, singleton pregnancy from 2007 to 2011 at a single tertiary care institution. Intraoperative and postoperative outcomes were compared between patients undergoing supraumbilical vertical (cohort, n = 45) or Pfannenstiel (controls, n = 90) skin incisions. RESULTS: Women undergoing supraumbilical incisions had a higher risk of classical hysterotomy (OR, 24.6; 95% CI, 9.0-66.8), surgical drain placement (OR, 6.5; 95% CI, 2.6-16.2), estimated blood loss greater than 1 liter (OR, 3.4; 95% CI, 1.4-8.4), and longer operative time (97 +/- 38 minutes versus 68 +/- 30 minutes; P < .001) when compared to subjects with Pfannenstiel incisions (controls). There was no difference in the risk of wound complication between women undergoing supraumbilical or Pfannenstiel incisions (OR, 2.7; 95% CI, 0.9-8.0). CONCLUSION: In women with a BMI above 40 kg/m2, supraumbilical incision at the time of cesarean delivery is associated with a greater risk of classical hysterotomy and operative morbidity. PMID- 24349785 TI - The Anatomical Correlation between the Internal Venous Vertebral System and the Cranial Venae Cavae in Rabbit. AB - The aim of this study was to describe the possible variations in the connection between the internal venous vertebral system and the cranial vena cava in rabbit using corrosion technique. The study was carried out on 40 adult New Zealand white rabbits. The venous system was injected by using Batson's corrosion casting kit number 17. We found the connection between the internal venous vertebral system and the cranial vena cava by means of the vertebral veins and the right azygos vein. The vertebral vein was present as independent tributary in 36 cases (90%). In the rest of the cases, it was found as being double, being triple, or forming a common trunk with other veins. The azygos vein was present as independent tributary of the cranial vena cava in 39 cases (97.5%). We found also a common trunk formed by the junction of the deep cervical vein, the right vertebral vein, and the azygos vein in one case (2.5%). The azygos vein received 6, 7, 8, or 9 pairs of dorsal intercostal veins. Documenting the anatomical variations in the rabbit will aid in the planning of future experimental studies and determining the clinical relevance on such studies. PMID- 24349786 TI - What is New and Innovative in Emergency Neurosurgery? Emerging Diagnostic Technologies Provide Better Care and Influence Outcome: A Specialist Review. AB - The development of emergency medical services and especially neurosurgical emergencies during recent decades has necessitated the development of novel tools. Although the gadgets that the neurosurgeon uses today in emergencies give him important help in diagnosis and treatment, we still need new technology, which has rapidly developed. This review presents the latest diagnostic tools, which offer precious help in everyday emergency neurosurgery practice. New ultrasound devices make the diagnosis of haematomas easier. In stroke, the introduction of noninvasive new gadgets aims to provide better treatment to the patient. Finally, the entire development of computed tomography and progress in radiology have resulted in innovative CT scans and angiographic devices that advance the diagnosis, treatment, and outcome of the patent. The pressure on physicians to be quick and effective and to avoid any misjudgement of the patient has been transferred to the technology, with the emphasis on developing new systems that will provide our patients with a better outcome and quality of life. PMID- 24349787 TI - Roles of motorcycle type and protective clothing in motorcycle crash injuries. AB - Background. The aims of this study were to identify subgroups of motorcyclists with a higher accident risk and evaluate the efficiency of protective clothing for preventing injuries. Methods. A 1-year prospective study of motorcycle crashes was conducted beginning in June 2012. Participants were patients involved in motorcycle crashes and admitted to our emergency department. Results. A total of 226 patients were included in the study. In total, 174 patients were involved in crashes with light motorcycles. Patients involved in a motorcycle accident without a helmet had a higher incidence of head and maxillofacial trauma. Motorcycle jackets were not protective for systemic injuries (P > 0.05) or upper extremity fractures (P > 0.05). Motorcycle pants (P > 0.05) and motorcycle shoes (P > 0.05) were not protective against leg and foot fractures. However, motorcycle protective clothes were protective against soft-tissue injuries (P = 0.001). Conclusion. Riders of heavy motorcycles rode more safely than riders of light motorcycles. Light motorcycle riders were the most vulnerable and comprised the largest percentage of motorcyclists. Helmets may be effective for preventing head and facial injuries. Other protective clothes were not effective against fractures or systemic injuries. PMID- 24349788 TI - 3D versus 2D Systematic Transrectal Ultrasound-Guided Prostate Biopsy: Higher Cancer Detection Rate in Clinical Practice. AB - Objectives. To compare prostate cancer detection rates of extended 2D versus 3D biopsies and to further assess the clinical impact of this method in day-to-day practice. Methods. We analyzed the data of a cohort of 220 consecutive patients with no prior history of prostate cancer who underwent an initial prostate biopsy in daily practice due to an abnormal PSA and/or DRE using, respectively, the classical 2D and the new 3D systems. All the biopsies were done by a single experienced operator using the same standardized protocol. Results. There was no significant difference in terms of age, total PSA, or prostate volume between the two groups. However, cancer detection rate was significantly higher using the 3D versus the 2D system, 50% versus 34% (P < 0.05). There was no statistically significant difference while comparing the 2 groups in term of nonsignificant cancer detection. Conclusion. There is reasonable evidence demonstrating the superiority of the 3D-guided biopsies in detecting prostate cancers that would have been missed using the 2D extended protocol. PMID- 24349789 TI - Immunopathogenic Role of Herpes Simplex Virus in Behcet's Disease. AB - The role of viral infections, such as herpes simplex virus (HSV) infection, in the pathogenesis of Behcet's disease (BD) has been investigated for many years. HSV has been detected in peripheral blood leukocytes, saliva, and genital ulcers of patients with BD. Various cell adhesion molecules on cultured endothelial cells have been induced by HSV in a TNF- alpha dependent manner. In addition, a BD-like animal model was developed by inoculating ICR mouse earlobes with HSV, and antiviral treatment was effective in improving BD-like symptoms in this model. Still, there are several incompletely characterized proteins that possess antiviral properties and are being investigated as mediators of viral infection related chronic inflammatory reactions. Although the role of HSV in the pathogenesis of BD remains to be fully established, recent research findings regarding HSV in BD have expanded our understanding of the disease and will hopefully lead to the development of more effective therapeutic agents in the near future. PMID- 24349790 TI - Staging Investigations in Breast Cancer: Collective Opinion of UK Breast Surgeons. AB - Introduction. Certain clinicopathological factors are associated with a higher likelihood of distant metastases in primary breast cancer. However, there remains inconsistency in which patients undergo formal staging for distant metastasis and the most appropriate investigation(s). Aims. To identify UK surgeon preferences and practice with regard to staging investigations for distant metastases. Methods. A survey was disseminated to members of the Association of Breast Surgery by e-mail regarding surgeon/breast unit demographics, use of staging investigations, and local policy on pre/postoperative staging investigations. Several patient scenarios were also presented. Results. 123 of 474 (25.9%) recipients completed the survey. Investigations routinely employed for patients diagnosed with early breast cancer included serological/haematological tests (72% respondents), axillary ultrasound (67%), liver ultrasound (2%), chest radiograph (36%), and computed tomography (CT) (1%). Three areas contributed to decisions to undertake staging by CT scan: tumour size, axillary nodal status, and plan for chemotherapy. There was widespread variation as to criteria for CT staging based on tumour size and nodal status, as well as the choice of staging investigation for the clinical scenarios presented. Conclusions. There remains variation in the use of staging investigations for distant disease in early breastcancer despite available guidelines. PMID- 24349791 TI - Metastatic lesions to the liver. PMID- 24349792 TI - Distal Femur Allograft Prosthetic Composite Reconstruction for Short Proximal Femur Segments following Tumor Resection. AB - Short metaphyseal segments remaining after distal femoral tumor resection pose a unique challenge. Limb sparing options include a short stemmed modular prosthesis, total endoprosthetic replacement, cross-pin fixation to a custom implant, and allograft prosthetic composite reconstruction (APC). A series of patients with APC reconstruction were evaluated to determine functional and radiologic outcome and complication rates. Twelve patients were retrospectively identified who had a distal femoral APC reconstruction between 1994 and 2007 to salvage an extremity with a segment of remaining bone that was less than 20 centimeters in length. Seventeen APC reconstructions were performed in twelve patients. Eight were primary procedures and nine were revision procedures. Average f/u was 89 months. Twelve APC reconstructions (71%) united and five (29%) were persistent nonunions. At most recent followup 10 patients (83%) had a healed APC which allowed WBAT. One pt (8%) had an amputation and one pt (8%) died prior to union. Average time to union was 19 months. Four pts (33%) or five APC reconstructions (29%) required further surgery to obtain a united reconstruction. Although Distal Femoral APC reconstruction has a high complication rate, a stable reconstruction was obtained in 83% of patients. PMID- 24349793 TI - A preliminary evaluation of the physiological mechanisms of action for sleep restriction therapy. AB - Our objective was to investigate the physiological mechanisms involved in the sleep restriction treatment of insomnia. A multiple baseline across subjects design was used. Sleep of five participants suffering from insomnia was assessed throughout the experimentation by sleep diaries and actigraphy. Ten nights of polysomnography were conducted over five occasions. The first two-night assessment served to screen for sleep disorders and to establish a baseline for dependent measures. Three assessments were undertaken across the treatment interval, with the fifth and last one coming at follow-up. Daily cortisol assays were obtained. Sleep restriction therapy was applied in-lab for the first two nights of treatment and was subsequently supervised weekly. Interrupted time series analyses were computed on sleep diary data and showed a significantly decreased wake time, increased sleep efficiency, and decreased total sleep time. Sleepiness at night seems positively related to sleep variables, polysomnography data suggest objective changes mainly for stage 2, and power spectral analysis shows a decrease in beta-1 and -2 powers for the second night of treatment. Cortisol levels seem to be lower during treatment. These preliminary results confirm part of the proposed physiological mechanisms and suggest that sleep restriction contributes to a rapid decrease in hyperarousal insomnia. PMID- 24349794 TI - The cytology, isozyme, HPLC fingerprint, and interspecific hybridization studies of genus epimedium (berberidaceae). AB - 104 samples from 27 accessions belonging to 12 species of genus Epimedium were studied on the basis of cytology observation, POD (i.e., peroxide) isozyme, high performance liquid chromatography (i.e., HPLC) fingerprint, and interspecific hybridization. The cytology observation showed karyotypes of twelve species studied; all are 2A symmetry type of Stebbins standard and similar to each other, and except for karyotype of E. leptorrhizum which is 2n = 2x = 8m (2SAT) + 4sm, the rest are 2n = 2x = 6m (2SAT) + 6sm. Chromosomes C-banding of barrenwort species varies, with 15 to 22 bands, consisting of centromeric bands, intercalary bands, terminal bands, and middle satellite bands. Results of POD isozyme showed that the zymographs vary greatly and sixteen bands were detected in the eleven species, and each species has its own characteristic bands different from the others. Studies on the HPLC fingerprint showed that the HPLC fingerprint of different species has characteristic peaks, divided into two regions (retention time < 10 min and retention time > 10 min). Results of interspecific hybridization showed that crosses of any combination among seven species studied are successful and the rates of grain set vary greatly. Based on these results, the system and phylogeny of this genus were inferred. PMID- 24349796 TI - The Relationship between Personality Type and Acceptable Noise Levels: A Pilot Study. AB - Objectives. This study examined the relationship between acceptable noise level (ANL) and personality. ANL is the difference between a person's most comfortable level for speech and the loudest level of background noise they are willing to accept while listening to speech. Design. Forty young adults with normal hearing participated. ANLs were measured and two personality tests (Big Five Inventory, Myers-Briggs Type Indicator) were administered. Results. The analysis revealed a correlation between ANL and the openness and conscientious personality dimensions from the Big Five Inventory; no correlation emerged between ANL and the Myers Briggs personality types. Conclusions. Lower ANLs are correlated with full-time hearing aid use and the openness personality dimension; higher ANLs are correlated with part-time or hearing aid nonuse and the conscientious personality dimension. Current data suggest that those more open to new experiences may accept more noise and possibly be good hearing aid candidates, while those more conscientious may accept less noise and reject hearing aids, based on their unwillingness to accept background noise. Knowing something about a person's personality type may help audiologists determine if their patients will likely be good candidates for hearing aids. PMID- 24349797 TI - A simple spatial working memory and attention test on paired symbols shows developmental deficits in schizophrenia patients. AB - People with neuropsychiatric disorders such as schizophrenia often display deficits in spatial working memory and attention. Evaluating working memory and attention in schizophrenia patients is usually based on traditional tasks and the interviewer's judgment. We developed a simple Spatial Working Memory and Attention Test on Paired Symbols (SWAPS). It takes only several minutes to complete, comprising 101 trials for each subject. In this study, we tested 72 schizophrenia patients and 188 healthy volunteers in China. In a healthy control group with ages ranging from 12 to 60, the efficiency score (accuracy divided by reaction time) reached a peak in the 20-27 age range and then declined with increasing age. Importantly, schizophrenia patients failed to display this developmental trend in the same age range and adults had significant deficits compared to the control group. Our data suggests that this simple Spatial Working Memory and Attention Test on Paired Symbols can be a useful tool for studies of spatial working memory and attention in neuropsychiatric disorders. PMID- 24349799 TI - Improved method for the quantification of motility in glia and other morphologically complex cells. AB - Cells such as astrocytes and radial glia with many densely ramified, fine processes pose particular challenges for the quantification of structural motility. Here we report the development of a method to calculate a motility index for individual cells with complex, dynamic morphologies. This motility index relies on boxcar averaging of the difference images generated by subtraction of images collected at consecutive time points. An image preprocessing step involving 2D projection, edge detection, and dilation of the raw images is first applied in order to binarize the images. The boxcar averaging of difference images diminishes the impact of artifactual pixel fluctuations while accentuating the group-wise changes in pixel values which are more likely to represent real biological movement. Importantly, this provides a value that correlates with mean process elongation and retraction rates without requiring detailed reconstructions of very complex cells. We also demonstrate that additional increases in the sensitivity of the method can be obtained by denoising images using the temporal frequency power spectra, based on the fact that rapid intensity fluctuations over time are mainly due to imaging artifact. The MATLAB programs implementing these motility analysis methods, complete with user-friendly graphical interfaces, have been made publicly available for download. PMID- 24349798 TI - NMDA reduces Tau phosphorylation in rat hippocampal slices by targeting NR2A receptors, GSK3beta, and PKC activities. AB - The molecular mechanisms that regulate Tau phosphorylation are complex and currently incompletely understood. In the present study, pharmacological inhibitors were deployed to investigate potential processes by which the N-methyl D-aspartate (NMDA) subtype of glutamate receptors modulates Tau phosphorylation in rat hippocampal slices. Our results demonstrated that Tau phosphorylation at Ser199-202 residues was decreased in NMDA-treated hippocampal slices, an effect that was not reproduced at Ser262 and Ser404 epitopes. NMDA-induced reduction of Tau phosphorylation at Ser199-202 was further promoted when NR2A-containing receptors were pharmacologically isolated and were completely abrogated by the NR2A receptor antagonist NVP-AAM077. Compared with nontreated slices, we observed that NMDA receptor activation was reflected in high Ser9 and low Tyr216 phosphorylation of glycogen synthase kinase-3 beta (GSK3beta), suggesting that NMDA receptor activation might diminish Tau phosphorylation via a pathway involving GSK3beta inhibition. Accordingly, we found that GSK3beta inactivation by a protein kinase C- (PKC-) dependent mechanism is involved in the NMDA-induced reduction of Tau phosphorylation at Ser199-202 epitopes. Taken together, these data indicate that NR2A receptor activation may be important in limiting Tau phosphorylation by a PKC/GSK3beta pathway and strengthen the idea that these receptors might act as an important molecular device counteracting neuronal cell death mechanisms in various pathological conditions. PMID- 24349795 TI - VGLUTs in Peripheral Neurons and the Spinal Cord: Time for a Review. AB - Vesicular glutamate transporters (VGLUTs) are key molecules for the incorporation of glutamate in synaptic vesicles across the nervous system, and since their discovery in the early 1990s, research on these transporters has been intense and productive. This review will focus on several aspects of VGLUTs research on neurons in the periphery and the spinal cord. Firstly, it will begin with a historical account on the evolution of the morphological analysis of glutamatergic systems and the pivotal role played by the discovery of VGLUTs. Secondly, and in order to provide an appropriate framework, there will be a synthetic description of the neuroanatomy and neurochemistry of peripheral neurons and the spinal cord. This will be followed by a succinct description of the current knowledge on the expression of VGLUTs in peripheral sensory and autonomic neurons and neurons in the spinal cord. Finally, this review will address the modulation of VGLUTs expression after nerve and tissue insult, their physiological relevance in relation to sensation, pain, and neuroprotection, and their potential pharmacological usefulness. PMID- 24349800 TI - Increased signal complexity improves the breadth of generalization in auditory perceptual learning. AB - Perceptual learning can be specific to a trained stimulus or optimally generalized to novel stimuli with the breadth of generalization being imperative for how we structure perceptual training programs. Adapting an established auditory interval discrimination paradigm to utilise complex signals, we trained human adults on a standard interval for either 2, 4, or 10 days. We then tested the standard, alternate frequency, interval, and stereo input conditions to evaluate the rapidity of specific learning and breadth of generalization over the time course. In comparison with previous research using simple stimuli, the speed of perceptual learning and breadth of generalization were more rapid and greater in magnitude, including novel generalization to an alternate temporal interval within stimulus type. We also investigated the long term maintenance of learning and found that specific and generalized learning was maintained over 3 and 6 months. We discuss these findings regarding stimulus complexity in perceptual learning and how they can inform the development of effective training protocols. PMID- 24349801 TI - Clinical and imaging findings of true hemifacial hyperplasia. AB - Congenital hemifacial hyperplasia is a rare developmental disorder of unknown etiology, characterized by a marked unilateral facial asymmetry. It involves the hard (bones and teeth) and soft tissues of the face. We report an interesting case of true hemifacial hyperplasia in a 25-year-old male highlighting the clinical and computed tomography imaging findings. PMID- 24349802 TI - Rapidly progressing osteomyelitis of the mandible. AB - Acute osteomyelitis exists as a refractory disease even now, which usually exhibits systemic symptoms such as fever or malaise and local redness or swelling. The present paper describes a case of acute osteomyelitis of the mandible that was rapidly progressing without typical symptoms. The patient had liver cirrhosis, which should be one of the systemic factors that affect immune surveillance and metabolism. Actinomycotic druses and filaments were detected from the sequestrum. These were considered to play a role in the rapid progression of osteomyelitis without typical symptoms. There has been no evidence of local recurrence 24 months after surgery. PMID- 24349803 TI - Management of Extramammary Paget's Disease: A Case Report and Review of the Literature. AB - Extramammary Paget's Disease (EMPD) is a rare condition of the skin that often involves the vulva, perianal region, scrotum, penis, and axilla. Although prognosis is generally favorable, it can be associated with neoplasms of the bladder, urethra, prostate, and rectum. This report presents a case of scrotal EMPD that failed treatment with imiquimod 5% cream and discusses benefits and complications of available treatment options. The variation of treatment success emphasizes the importance of further research. PMID- 24349804 TI - Paediatric orbital fractures: the importance of regular thorough eye assessment and appropriate referral. AB - The paediatric orbital fracture should always raise alarm bells to all clinicians working in an emergency department. A delay or failure in diagnosis and appropriate referral can result in rapidly developing and profound complications. We present a boy of childhood age who sustained trauma to his eye during a bicycle injury. Acceptance of the referral was based on no eye signs; however, on examination in our unit the eye had reduction in visual acuity, no pupillary reaction, and ophthalmoplegia. CT scan suggested bone impinging on the globe and the child was rushed to theatre for removal of the bony fragment. Postoperatively no improvement was noted and a diagnosis of traumatic optic neuropathy was made. An overview of factors complicating paediatric orbital injuries, their associated "red flags", and appropriate referral are discussed in this short paper. PMID- 24349805 TI - Biclonal IgD and IgM Plasma Cell Myeloma: A Report of Two Cases and a Literature Review. AB - Biclonal plasma cell myelomas producing two different isotypes of immunoglobulins are extremely rare entities; to date, the combination of IgD and IgM secretion by a biclonal plasma cell myeloma has not been reported. Bone marrow biopsy immunohistochemical studies in two cases revealed neoplastic plasma cells coexpressing IgD and IgM, but serum protein electrophoresis identified only the IgM monoclonal paraprotein in both cases. Biclonal plasma cell myelomas, while currently not well characterized in terms of their clinical behavior, should be distinguished from B-cell lymphoma with plasmacytic differentiation, given the different therapeutic implications. Both cases reported herein demonstrated chemotherapy-resistant clinical courses. PMID- 24349806 TI - The Sinus That Breeds Fungus: Subcutaneous Zygomycosis Caused by Basidiobolus ranarum at the Injection Site. AB - Subcutaneous zygomycosis is caused by Basidiobolus ranarum which is endemic in India. We report a case of a housewife who presented with a persistent discharging sinus from the right gluteal region subsequent to an intramuscular injection which was refractory to empirical antituberculous therapy. She underwent an excision of the sinus tract, the culture of which yielded B. ranarum. The wound improved with oral potassium iodide. PMID- 24349807 TI - A case of placental mesenchymal dysplasia. AB - Placental mesenchymal dysplasia (PMD) rarely complicates with pregnancy. A 30 year-old woman, gravida 3, para 3, presenting with placentomegaly, was referred to our department at 18 weeks of gestation. An ultrasonography revealed a normal fetus with a large multicystic placenta, measuring 125 * 42 * 80 mm. The border between the lesion and normal region was not clear. Color doppler revealed little blood flow in the lesion. Magnetic resonance imaging revealed normal fetus and a large multicystic placenta. Serum human chorionic gonadotropin level was 20124.97 U/L, which was normal at 20 weeks of gestation. Thus, placental mesenchymal dysplasia rather than hydatidiform mole with coexistent fetus was suspected. Then, routine checkup was continued. Because she had the history of Cesarean section, an elective Cesarean section was performed at 37 weeks of gestation, and 2520 g female infant with apgar score 8/9 was delivered. The baby was normal with no evidence of Beckwith-Wiedemann syndrome. Placenta of 20 * 16 * 2 cm, weighing 720 g, was bulky with grape like vesicles involving whole placenta. Microscopic examination revealed dilated villi and vessels with thick wall which was lacking trophoblast proliferation. Large hydropic stem villi with myxomatous struma and cistern formation were seen. PMD was histopathologically confirmed. PMID- 24349808 TI - Spontaneous twin pregnancy in uterus bicornis unicollis. AB - Abnormal fusion of the Mullerian ducts or failure of resorption of the septum causes varying degrees of congenital uterine malformation. They are often associated with reproductive problems such as miscarriage, premature labour, premature rupture of the membranes, or malpresentation. Twin gestation in a case of bicornuate uterus is extremely rare. A 37-year-old multiparous woman conceived a twin dichorionic diamniotic pregnancy spontaneously. Three-dimensional ultrasound revealed bicornuate uterus with one embryo in each cavity. Perinatal course was uneventful. At 35 weeks of pregnancy, spontaneous labour started and twin babies were delivered by bilateral low transvers caesarean section. Because of the rare occurrence of twin gestation in bicornuate uterus, there is no uniform guideline to manage these cases appropriately. Delivery by planned caesarean section could avoid the possible obstetric complications by dystocia. PMID- 24349809 TI - Diagnosing a gastric submucosal tumor using jumbo biopsy "unroofing" technique: a case report and review of the literature. AB - We report a case of a 40-year-old female who presented with dyspeptic symptoms for six months. Upper GI endoscopy revealed a submucosal nodule in gastric antrum. Using "jumbo biopsy unroofing technique" we were able to get adequate tissue for analysis. Histopathology revealed a type III gastric carcinoid. Patient was treated with laparoscopic distal subtotal gastrectomy with Roux-en-Y reconstruction and partial omentectomy. Although there was no evidence of metastasis on initial presentation, eighteen months later, patient was found to have multiple metastatic lesions in her liver. Patient's lesions were treated with intra-arterial (hepatic artery) Yttrium-90. PMID- 24349810 TI - Atypical B12 deficiency with nonresolving paraesthesia. AB - Vitamin B12 deficiency can present with various hematological, gastrointestinal and neurological manifestations. We report a case of elderly female who presented with neuropathy and vitamin B12 deficiency where the final work-up revealed polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS). This case suggests that, although POEMS syndrome is a rare entity, it can present with vitamin-B12 deficiency and thus specific work up for early diagnosis of POEMS should be considered in patients with B12 deficiency unresponsive to therapy. PMID- 24349811 TI - Nonalpine thyroid angiosarcoma in a patient with hashimoto thyroiditis. AB - Thyroid angiosarcoma is an uncommon thyroid carcinoma and its incidence is the highest in the European Alpine regions. Thyroid angiosarcoma is also a very aggressive tumor that can rapidly spread to the cervical lymph nodes, lungs, and brain or can metastasize to the duodenum, small boewl, and large bowel. Although it is histologically well defined, clear-cut separation between the angiosarcoma and anaplastic thyroid carcinoma is difficult. A 49-year-old Caucasian female patient, born and resident in Southern Italy (Calabria), in an iodine-sufficient area, was admitted to the Surgery Department because she presented with a painless mass in the anterior region of neck enlarged rapidly in the last three months. After total thyroidectomy and right cervical lymphadenectomy, postoperative histological examination revealed the presence of a thyroid angiosarcoma with positive staining for CD31 and for both Factor VIII-related antigen and Vimentin and only partially positive for staining pancytokeratin and presence of metastasis in cervical, supraclavicular, mediastinal and paratracheal lymph nodes. The patient started adjuvant chemotherapy and she was treated for 6 cycles with Doxorubicin, Dacarbazine, Ifosfamide, and Mesna (MAID). After 22 months from surgery, the patient is still alive without both local and systemic recurrence of the disease. PMID- 24349812 TI - Removal of a broken cannulated femoral nail: a novel retrograde impaction technique. AB - This report presents a surgical technique to remove a broken cannulated nail from the femur. A Harrington rod was modified for retrograde impaction of the retained fragment. The broken implant was finally removed without complication. This particular procedure was safe, simple, and promising. PMID- 24349813 TI - Amantadine-induced patulous eustachian tubes in Parkinson's disease. AB - Patulous Eustachian tube (PET) is a common condition that produces symptoms of aural fullness and autophony. We describe a Parkinson's disease (PD) patient that experienced a reversible bilateral patulous (hyperpatent) Eustachian tube syndrome induced by treatment with amantadine hydrochloride. The clinical features, relevant anatomy and physiology, and associated risk factors for PET are reviewed. PMID- 24349814 TI - A rare case of congenital rhabdomyosarcoma with review of the literature. AB - We present a rare case of rhabdomyosarcoma of lip in a neonate with multiple lesions within the head and necksub site hitherto unreported in the medical literature. This case report also reviews the scant medical literature on neonatal rhabdomyosarcoma. PMID- 24349815 TI - Dermoid cyst of the pancreas: a report of an unusual case and a review of the literature. AB - Pancreatic dermoid cysts are a rare entity. Preoperative diagnosis is difficult. The diagnosis is generally taking intraoperative. A 20-year-old female presented with epigastric pain without nausea, vomiting, diarrhea, fever, jaundice, and weight loss of one-month duration. Ultrasonography and computed tomography showed a smooth borders, solid, hyperechoic tumor within midline abdomen, without any connection to the stomach or spleen. At surgery, the entire mass was excised off of the head and inferior part of pancreas. Histopathologic evaluation revealed the rare diagnosis of a dermoid cyst. The diagnosis is difficult preoperatively in evaluating cystic pancreatic lesions by imaging. Therefore, we want to summarize the literature on this rare entity knowledge. PMID- 24349816 TI - Rare case of a chondrosarcoma of the mandible in a child. AB - Chondrosarcoma of the mandible is rare, especially in children. The available literature consists mostly of a few case reports which are partly integrated in small studies. Growing this small pool of literature is helpful in solidifying knowledge about this disease and facilitating appropriate treatment for children. Therefore, we present such a case in a 12-year-old boy, exhibit comprehensive and relevant information concerning this entity, and discuss our findings in the context of other publications. PMID- 24349817 TI - Nutcracker syndrome complicated by left renal vein thrombosis. AB - Isolated renal vein thrombosis is a rare entity. We present a patient whose complaint of flank pain led to the diagnosis of a renal vein thrombosis. In this case, abdominal computed tomography angiography was helpful in diagnosing the nutcracker syndrome complicated by the renal vein thrombosis. Anticoagulation was started and three weeks later, CTA showed complete disappearance of the renal vein thrombosis. To treat the Nutcracker syndrome, we proposed left renal vein transposition that the patient consented to. PMID- 24349818 TI - IgG4-Related Autoimmune Prostatitis: Is It an Unusual or Underdiagnosed Manifestation of IgG4-Related Disease? AB - IgG4-related disease (IgG4-RD) encompasses a wide range of extrapancreatic manifestations. Albeit some are relatively well known, others such as autoimmune prostatitis remain poorly described. We present a 61-year-old Latin-American male with autoimmune pancreatitis (AIP) who presented with lower urinary tract symptoms (LUTS), normal prostate specific antigen (PSA) test, and prostate enlargement attributed to benign prostatic hyperplasia (BPH). He underwent a transurethral resection of the prostate (TURP) after which symptoms were resolved. On histopathology, prostatic stroma had a dense inflammatory infiltrate rich in plasma cells and lymphocytes; immunohistochemical morphometric assessment showed >10 IgG4-positive plasma cells/high power field (HPF). The diagnosis of IgG4-related prostatitis was postoperatively. We compared the patient characteristics with those of previous reports on Asian patients. Shared findings included prostate enlargement, LUTS (symptoms that can be confused with BPH), and PSA within normal limits or mild elevations. IgG4-related prostatitis is rarely considered as a preprocedural diagnosis, even in patients with evidence of IgG4 RD. Involved prostate zones include mainly central and transitional zones and less frequently the peripheral. Currently, there is insufficient data about the natural history and outcome. Whether steroids, transurethral resection, or both are the treatment of choice needs to be elucidated. PMID- 24349819 TI - Retroperitoneal lipoma presenting with nutcracker-like phenomenon. AB - Retroperitoneal lipoma presenting with a nutcracker-like phenomenon is extremely rare. I experienced a case of a 65-year-old man presenting with left flank pain and macrohematuria intermittently for 3 years. Computed tomography revealed a lipoma at the left pedicle of the kidney, 30 mm in diameter, causing a curving of the left renal artery and dilatation of the left renal vein. This patient was treated successfully by retroperitoneoscopic resection of the lipoma. There have been no symptoms for 10 years after the operation. PMID- 24349820 TI - Acoustic Emission Signal of Lactococcus lactis before and after Inhibition with NaN 3 and Infection with Bacteriophage c2. AB - The detection of acoustic emission (AE) from Lactococcus lactis, ssp lactis is reported in which emission intensities are used to follow and define metabolic activity during growth in nutrient broths. Optical density (OD) data were also acquired during L. lactis growth at 32 degrees C and provided insight into the timing of the AE signals relative to the lag, logarithmic, and stationary growth phases of the bacteria. The inclusion of a metabolic inhibitor, NaN3, into the nutrient broth eliminated bacteria metabolic activity according to the OD data, the absence of which was confirmed using AE data acquisition. The OD and AE data were also acquired before and after the addition of Bacteriophage c2 in L. lactis containing nutrient broths during the early or middle logarithmic phase; c2 phage m.o.i. (Multiplicity of infection) was varied to help differentiate whether the detected AE was from bacteria cells during lysis or from the c2 phage during genome injection into the cells. It is proposed that AE measurements using piezoelectric sensors are sensitive enough to detect bacteria at the amount near 10(4) cfu/mL, to provide real time data on bacteria metabolic activity and to dynamically monitor phage infection of cells. PMID- 24349821 TI - Vitamin d predicts all-cause and cardiac mortality in females with suspected acute coronary syndrome: a comparison with brain natriuretic Peptide and high sensitivity C-reactive protein. AB - Vitamin D may not only reflect disease but may also serve as a prognostic indicator. Our aim was to assess the gender-specific utility of vitamin D measured as 25-hydroxy-vitamin D [25(OH)D] to predict all-cause and cardiac death in patients with suspected acute coronary syndrome (ACS) and to compare its prognostic utility to brain natriuretic peptide (BNP) and high-sensitivity C reactive protein (hsCRP). Blood samples were harvested on admission in 982 patients. Forty percent were women (65.9 +/- 12.6 years). Mortality was evaluated in quartiles of 25(OH)D, BNP, and hsCRP, respectively, during a 5-year follow-up, applying univariate and multivariate analyses. One hundred and seventy-three patients died; 78 were women. In 92 patients (37 women), death was defined as cardiac. In women, the univariate hazard ratio (HR) for total death of 25(OH)D in Quartile (Q) 2 versus Q1, Q3 versus Q1, and Q4 versus Q1 was 0.55 (95% CI 0.33 0.93), 0.29 (95% CI 0.15-0.55), and 0.13 (95% CI 0.06-0.32), respectively. In females, it was an independent predictor of total and cardiac death, whereas BNP and hsCRP were less gender-specific. No gender differences in 25(OH)D were noted in a reference material. Accordingly, vitamin D independently predicts mortality in females with suspected ACS. PMID- 24349823 TI - Effects of pH, Temperature, Dissolved Oxygen, and Flow Rate on Phosphorus Release Processes at the Sediment and Water Interface in Storm Sewer. AB - The effects of pH, temperature, dissolved oxygen (DO), and flow rate on the phosphorus (P) release processes at the sediment and water interface in rainwater pipes were investigated. The sampling was conducted in a residential storm sewer of North Li Shi Road in Xi Cheng District of Beijing on August 3, 2011. The release rate of P increased with the increase of pH from 8 to 10. High temperature is favorable for the release of P. The concentration of total phosphorus (TP) in the overlying water increased as the concentration of DO decreased. With the increase of flow rate from 0.7 m s(-1) to 1.1 m s(-1), the concentration of TP in the overlying water increased and then tends to be stable. Among all the factors examined in the present study, the flow rate is the primary influence factor on P release. The cumulative amount of P release increased with the process of pipeline runoff in the rainfall events with high intensities and shorter durations. Feasible measures such as best management practices and low impact development can be conducted to control the P release on urban sediments by slowing down the flow rate. PMID- 24349822 TI - Does a history of migraine affect the rate of thrombolysis in young stroke patients? AB - Background. Migraine is prevalent in young patients and a frequent stroke mimic. To distinguish stroke mimics from true stroke can be difficult, and there is a possibility of misdiagnosing a stroke as a migrainous attack in patients with migraine. We aimed to investigate if a history of migraine affects the rate of thrombolytic therapy in young stroke patients. Methods. All patients below 50 years of age admitted in the period 2006-2013 to the Bergen Stroke Centre with acute ischaemic stroke were included. The rate of thrombolytic therapy in patients with migraine was compared to patients with no history of migraine. A multivariate analysis was performed to adjust confounding factors. Results. A total of 170 young stroke patients were enrolled, 49 with migraine and 121 with no migraine. In total, 10.2% of young patients with migraine received thrombolytic therapy, compared with 26.5% of young patients with nomigraine (P = 0.02). Migraine was associated with a low rate of thrombolytic therapy when adjusting for possible confounding factors (OR 0.19 CI: 0.05-0.72, P = 0.02). Conclusion. Migraine is associated with a low rate of thrombolytic therapy in young patients admitted with acute ischaemic stroke. Migraine patients admitted with acute ischaemic stroke are at risk of maltreatment. PMID- 24349824 TI - Optimization of IC Separation Based on Isocratic-to-Gradient Retention Modeling in Combination with Sequential Searching or Evolutionary Algorithm. AB - GRADIENT ION CHROMATOGRAPHY WAS USED FOR THE SEPARATION OF EIGHT SUGARS: arabitol, cellobiose, fructose, fucose, lactulose, melibiose, N-acetyl-D glucosamine, and raffinose. The separation method was optimized using a combination of simplex or genetic algorithm with the isocratic-to-gradient retention modeling. Both the simplex and genetic algorithms provided well separated chromatograms in a similar analysis time. However, the simplex methodology showed severe drawbacks when dealing with local minima. Thus the genetic algorithm methodology proved as a method of choice for gradient optimization in this case. All the calculated/predicted chromatograms were compared with the real sample data, showing more than a satisfactory agreement. PMID- 24349825 TI - The GC/MS Analysis of Volatile Components Extracted by Different Methods from Exocarpium Citri Grandis. AB - Volatile components from Exocarpium Citri Grandis (ECG) were, respectively, extracted by three methods, that is, steam distillation (SD), headspace solid phase microextraction (HS-SPME), and solvent extraction (SE). A total of 81 compounds were identified by gas chromatography-mass spectrometry including 77 (SD), 56 (HS-SPME), and 48 (SE) compounds, respectively. Despite of the extraction method, terpenes (39.98~57.81%) were the main volatile components of ECG, mainly germacrene-D, limonene, 2,6,8,10,14-hexadecapentaene, 2,6,11,15 tetramethyl-, (E,E,E)-, and trans-caryophyllene. Comparison was made among the three methods in terms of extraction profile and property. SD relatively gave an entire profile of volatile in ECG by long-time extraction; SE enabled the analysis of low volatility and high molecular weight compounds but lost some volatiles components; HS-SPME generated satisfactory extraction efficiency and gave similar results to those of SD at analytical level when consuming less sample amount, shorter extraction time, and simpler procedure. Although SD and SE were treated as traditionally preparative extractive techniques for volatiles in both small batches and large scale, HS-SPME coupled with GC/MS could be useful and appropriative for the rapid extraction and qualitative analysis of volatile components from medicinal plants at analytical level. PMID- 24349826 TI - Simultaneous Determination of Volatile Constituents from Acorus tatarinowii Schott in Rat Plasma by Gas Chromatography-Mass Spectrometry with Selective Ion Monitoring and Application in Pharmacokinetic Study. AB - A sensitive and specific gas chromatographic-mass spectrometry with selected ion monitoring (GC-MS/SIM) method has been developed for simultaneous identification and quantification of alpha -asarone, beta-asarone, and methyl eugenol of Acorus tatarinowii Schott in rat plasma. Chromatographic separation was performed on a Restek Rxi-5MS capillary column (30 m * 0.32 mm * 0.25 MUm), using 1-naphthol as internal standard (IS). MS detection of these compounds and IS was performed at m/z 178, 208, 208, and 144. Intra- and interday precisions of all compounds of interest were less than 10%. The recoveries are situated in the range of 92.4 105.2%. Pharmacokinetics of methyl eugenol confirmed to be one-compartment open model, alpha -asarone and beta -asarone was two-compartment open model, respectively. The method will probably be an alternative to simultaneous determination and pharmacokinetic study of volatile ingredients in Acorus tatarinowii Schott. PMID- 24349827 TI - Global progress against cancer-challenges and opportunities. AB - The last ten years have seen remarkable progress in cancer research. However, despite significant breakthroughs in the understanding, prevention, and treatment of cancer, the disease continues to affect millions of people worldwide. Cancer's complexity compounded with financial, policy and regulatory roadblocks has slowed the rate of progress being made against cancer. In this paper, we review a few of the most recent breakthroughs that are fueling medical advances and bringing new hope for patients affected by this devastating disease. We also address the challenges facing us and the opportunities to accelerate future progress against cancer. The efforts of the American Association for Cancer Research (AACR) to address the cancer burden already extend beyond the borders of the United States of America. The AACR is committed to increasing its efforts to stem the tide of cancer worldwide by promoting innovative programs, strategies, and initiatives for cancer researchers and all those engaged in cancer-related biomedical sciences around the world. PMID- 24349828 TI - Asian trends in primary androgen depletion therapy on prostate cancer. AB - There are notable differences in the incidence and mortality rates for prostate cancer between Asia and Western countries. It is also recognized that there are differences in thinking with regard to treatment options. Recently it is also the case that opinions have been reported concerning the differences between Asian and Western patients with regard to their reaction to androgen depletion therapy (ADT). Given that ADT is a method of treatment that focuses on the elimination of testosterone, an inevitable symptom of its administration is testosterone losing syndrome. It is for this reason that in Western countries ADT has only been recommended in cases of advanced or metastatic cancer. On the other hand, in Asia, ADT is used in relatively many cases, including non-metastatic localized cancer and invasive localized cancer. To date, however, there has been little substantive discussion concerning this difference in utilization of ADT. ADT related drugs for prostate cancer and the development of new drugs for castration resistant prostate cancer (CRPC) have been actively tested in recent years. It could be the case that analyzing the differences in concepts about ADT between Asia and the West could contribute to the effective use of ADT-related drugs and also help to build new treatment strategies for prostate cancer. PMID- 24349830 TI - Why bortezomib cannot go with 'green'? AB - Eat more 'green' or eat 'five a day' is one of the most important healthy lifestyle behaviours in the 21 century. Aiming to fight cancer effectively, more than half patients use vitamins or herbs concurrently with conventional anticancer treatment. Flavonoids or polyphenols existing in vegetables, fruits and green tea are common plant pigments with antioxidant properties and considered acting as cancer preventing or anti-cancer agents. Recently it was found that some flavonoids and vitamin C in diet or supplements have antagonistic effect with the anti-cancer drug bortezomib. Bortezomib is a specific inhibitor for proteasome and is currently used for treatment of relapsed and refractory multiple myeloma. Despite its successful rates in treating multiple myeloma and other solid tumors, it is unable to kill leukemic cells in the blood. It was recently revealed that some flavonoids and vitamin C present in green leaves and green teas in the blood can neutralize bortezomib by directly interaction between two chemicals. Here we summarize why dietary flavonoids should be avoided in patients who take bortezomib as chemotherapeutic drug. PMID- 24349829 TI - Therapeutic resistance in cancer: microRNA regulation of EGFR signaling networks. AB - Receptor tyrosine kinases (RTKs) such as the epidermal growth factor receptor (EGFR) regulate cellular homeostatic processes. EGFR activates downstream signaling cascades that promote tumor cell survival, proliferation and migration. Dysregulation of EGFR signaling as a consequence of overexpression, amplification and mutation of the EGFR gene occurs frequently in several types of cancers and many become dependent on EGFR signaling to maintain their malignant phenotypes. Consequently, concerted efforts have been mounted to develop therapeutic agents and strategies to effectively inhibit EGFR. However, limited therapeutic benefits to cancer patients have been derived from EGFR-targeted therapies. A well documented obstacle to improved patient survival is the presence of EGFR inhibitor resistant tumor cell variants within heterogeneous tumor cell masses. Here, we summarize the mechanisms by which tumors resist EGFR-targeted therapies and highlight the emerging role of microRNAs (miRs) as downstream effector molecules utilized by EGFR to promote tumor initiation, progression and that play a role in resistance to EGFR inhibitors. We also examine evidence supporting the utility of miRs as predictors of response to targeted therapies and novel therapeutic agents to circumvent EGFR-inhibitor resistance mechanisms. PMID- 24349832 TI - Effects of HLEC on the secreted proteins of epithelial ovarian cancer cells prone to metastasize to lymph nodes. AB - OBJECTIVE: To study explores the effect of HLEC on the secreted proteins of epithelial ovarian cancer (EOC) cells (SKOV3-PM4) with directional highly lymphatic metastasis. METHODS: Supernatants of four groups of cultured cells, namely, SKOV3 (A), SKOV3+HLEC (B), SKOV3-PM4 (C), SKOV3-PM4+HLEC (D), were collected, and their proteins were detected by antibody arrays and iTRAQ-2D-LC MALDI-TOF/TOF/MS. Significantly differential proteins were further analyzed via bioinformatics and validated in human serums and cell media via ELISA. RESULTS: Results of antibody arrays and mass spectrometry demonstrated that GRN and VEGFA were upregulated in group C (compared with group A), whereas IGFBP7 and SPARC were downregulated in group D (compared with group C). Comprehensive bioinformatics analysis results showed that IGFBP7 and VEGFA were closely linked to each other. Further validation with serums showed statistical significance in VEGFA and IGFBP7 levels among groups of patients with ovarian cancers, benign tumors, and control groups. Two proteins were upegulated in the first group. VEGFA in the control group was downregulated. For IGFBP, upregulation in the control group and down-regulation in the first group were also observed. CONCLUSION: The HLEC microenvironment is closely associated with directional metastasis to lymph nodes and with differential proteins including cell stromal proteins and adhesion factors. The upregulation of VEGFA and GRN and the downregulation of SPARC and IGFBP7 are closely associated with directional metastasis to lymph nodes in EOC cells. PMID- 24349831 TI - Translational genomics in cancer research: converting profiles into personalized cancer medicine. AB - Cancer genomics is a rapidly growing discipline in which the genetic molecular basis of malignancy is studied at the scale of whole genomes. While the discipline has been successful with respect to identifying specific oncogenes and tumor suppressors involved in oncogenesis, it is also challenging our approach to managing patients suffering from this deadly disease. Specifically cancer genomics is driving clinical oncology to take a more molecular approach to diagnosis, prognostication, and treatment selection. We review here recent work undertaken in cancer genomics with an emphasis on translation of genomic findings. Finally, we discuss scientific challenges and research opportunities emerging from findings derived through analysis of tumors with high-depth sequencing. PMID- 24349833 TI - Analysis of 30 patients with persistent or recurrent squamous cell carcinoma of the cervix within one year after concurrent chemoradiotherapy. AB - OBJECTIVE: To investigate the recurrence sites, risk factors, and prognosis of patients with persistent or recurrent squamous cell carcinoma (SCC) of the cervix within one year after undergoing concurrent chemoradiotherapy (CCRT). METHODS: Clinical data of 30 patients with persistent or recurrent SCC of the cervix within one year after CCRT between July 2006 and July 2011 were analyzed retrospectively. These data were compared with those of 35 SCC cases with no signs of recurrence after complete remission. These 35 patients were treated during the same period (between 2006 and 2011) and selected randomly. RESULTS: Among these 30 patients, 25 exhibited distant metastases of which 14 were observed within 6 months after CCRT. Univariate analysis showed higher incidence of pelvic or para-aortic lymphadenectasis and SCC-ag >10 ng/mL in the group with persistent or recurrent disease before treatment (P<0.01). Multivariate analysis by logistic regression revealed that the pre-therapeutic pelvic or para-aortic lymph node enlargement and SCC-ag >10 ng/mL were the independent risk factors. Palliative chemotherapy was the main treatment option for patients with persistent or recurrent disease. The 2-year survival rate was 21.7%, and the median survival time was 17 months. CONCLUSION: Patients with persistent or recurrent SCC of the cervix after CCRT exhibited a high rate of distant metastasis with poor prognosis. The pre-therapeutic pelvic or para-aortic lymph node enlargement and SCC-ag >10 ng/mL were identified as the independent risk factors for persistent or recurrent SCC within 1 year after CCRT. PMID- 24349834 TI - Rare myeloid sarcoma/acute myeloid leukemia with adrenal mass after allogeneic mobilization peripheral blood stem cell transplantation. AB - Myeloid sarcoma (MS) is a rare hematological neoplasm that develops either de novo or concurrently with acute myeloid leukemia (AML). This neoplasm can also be an initial manifestation of relapse in a previously treated AML that is in remission. A 44-year-old male patient was diagnosed with testis MS in a local hospital in August 2010. After one month, bone marrow biopsy and aspiration confirmed the diagnosis of AML. Allogeneic mobilization peripheral blood stem cell transplantation was performed, with the sister of the patient as donor, after complete remission (CR) was achieved by chemotherapy. Five months after treatment, an adrenal mass was detected by positron emission tomography-computed tomography (PET-CT). Radiotherapy was performed for the localized mass after a multidisciplinary team (MDT) discussion. The patient is still alive as of May 2013, with no evidence of recurrent MS or leukemia. PMID- 24349835 TI - Unusual unilateral multiple muscular variations of back of thigh. AB - During routine cadaveric dissection for the undergraduate students in the Department of Anatomy, we noted multiple muscular variations in a middle-aged male cadaver. All the variations were seen at the back of thigh (flexor compartment) of right lower limb. An anomalous muscle of 17 cm length with average width of 1.5 cm. was inserted to the semitendinosus, a third head of biceps femoris of 6.5 cm length with an average width of 3.5 cm was inserted to the semitendinosus and ununited short and long heads of biceps femoris, both heads were inserted to the head of fibula. To the best of our knowledge, such muscular variations have not been reported in the recent medical literature. A comprehensive knowledge of such rare anatomical variations will be important for surgeons and Traumatologists as this might cause compression of the sciatic nerve. PMID- 24349836 TI - Endometrial osseous metaplasia: case report with literature review. AB - Endometrial osseous metaplasia is a rare pathological condition with mature bone in the endometrium and can be a cause for menorrhagia and infertility as bone in the endometrium acts like intrauterine contraceptive device. We report one such case with brief review of literature in a 28-year-old woman presenting with history of menorrhagia. PMID- 24349837 TI - Twin fetuses papyraeci in a spontaneous triplet pregnancy presenting with unexplained preterm contractions. AB - Fetus papyracie in a triplet pregnancy is indeed rare and can pose serious management challenges. These challenges are more pronounced where facilities for monitoring are either inadequate or nonexistent. A 39-year-old, grand multipara multipara was referred to the University of Maiduguri Teaching Hospital at 27 weeks gestation with preterm contractions. Materno fetal monitoring did not reveal the cause of the preterm contractions. She was delivered via caesarean section, at 36 weeks of gestation, on account of decreased fetal movement and the products were a live female fetus weighing 2.3 kg and two male papyraceous fetuses weighing 150 g and 130 g, respectively. PMID- 24349838 TI - A case report of Plasmodium vivax, Plasmodium falciparum and dengue co-infection in a 6 months pregnancy. AB - India being a tropical country, parasitic infections especially with Plasmodium species are very common in this region. The present case report is that of Plasmodium vivax, Plasmodium falciparum and dengue co-infection in a 6 months pregnant lady who was timely diagnosed and appropriately treated followed by a complete recovery along with feto-maternal well-being. PMID- 24349839 TI - Rectal lipoma associated with genital prolapse. AB - Lipomas are the tumors of mature lipocytes with its occurrence most often on the torso, neck, upper thighs, upper arms, and armpits, but they can occur almost anywhere in the body. They are the rare tumors of intestine, more frequently located in large intestine compared to small intestine. We present the case of a 58-year-old post-menopausal lady presenting with rectal bleeding and utero vaginal prolapse. The prolapsing mass was excised, and histopathological examination diagnosed the lesion to be a lipoma. PMID- 24349840 TI - Sternal tuberculosis. AB - Extra-pulmonary tuberculosis constitutes 15-20% of total tuberculosis (TB) case load in immuno-competent patients. Affliction of the skeletal system is rare with still rarer presentation of sternal osteomyelitis even in endemic countries. A patient with primary sternal TB presenting with multiple cutaneous sinuses over the anterior chest wall is being reported. A high element of suspicion is needed more so in resource limited setting for early diagnosis and treatment. PMID- 24349841 TI - Superior mesenteric artery syndrome: an uncommon cause of abdominal pain mimicking gastric outlet obstruction. AB - Upper gastrointestinal symptoms like vomiting, abdominal pain, abdominal distention may be caused by many conditions like complicated peptic/duodenal ulcer, gastritis or hiatal hernia. However, these symptoms are uncommonly produced by superior mesenteric artery (SMA) syndrome. SMA syndrome is triggered when there is narrowing of the mesenteric angle and shortening of the aortomesenteric distance. We report a case of 42-year-old female who presented with features of gastric outlet obstruction which on further investigation was revealed as SMA syndrome. The aetiology, presentation, diagnosis and management of this unusual condition are discussed. PMID- 24349842 TI - Pediatric stroke: neurological sequelae in uncorrected tetralogy of fallot. AB - Pediatric stroke is an uncommon entity. A risk factor is present in almost half of the children at the time of stroke. The most common cause of stroke in children is probably congenital heart disease. Other risk factors include sickle cell disease, infections, and various prothrombotic conditions. We present a case of a 3-year-old male child, who was previously diagnosed with Tetralogy of Fallot and presented with left-sided weakness and one episode of generalized tonic clonic seizures. PMID- 24349843 TI - Familial dermal eccrine cylindromatosis with emphasis on histology and genetic mapping. AB - Familial cylindromatosis (FC) is an autosomal dominant disorder with apparently complete penetrance, but variable expression. There is an increasing evidence that FC is clinically, genetically, and histologically heterogeneous disorder as the simultaneous occurrence of cylindromas and other tumors of skin appendages within the affected individuals and families. The presence of multiple scalp cylindromas is often associated with autosomal dominant Brooke-Spielger syndrome, a condition in which there are co-existent facial trichoepitheliomas and spiradenomas. We present here a case of multiple cylindromatosis in a family affecting many members successively. PMID- 24349844 TI - Burn injury caused by laptop computers. AB - Laptop burn is a real condition and medical reports indicate that using a laptop across the legs can indeed cause it. in very rare cases, the condition can cause damage leading to skin cancer. A 24-year-old man presented with an asymptomatic reddish brown pigmentation on the thighs. After an extensive work-up, burning caused by use of a laptop was observed. Burning was induced in 3 days by using laptop for 4 h daily. Laptop should be used in properly ventilated and air conditioned rooms. The most effective way of preventing erythema is to use the laptop on the table or desk. PMID- 24349845 TI - Cellular schwannoma arising from sigmoid mesocolon presenting as torsion. AB - Schwannomas are a type of peripheral nerve sheath tumors with clinically indolent behavior. Though, they can occur anywhere in body, the incidence in retroperitoneum, mediastinum, and pelvis is exceedingly rare. We present a case of a 58-year-old female with a massive twisted tumor arising from sigmoid mesocolon. The tumor was diagnosed to be a case of cellular schwannoma, an exceedingly rare tumor in this location with rare presentation. PMID- 24349846 TI - Primary neuroendocrine carcinoma of breast: a rare case report. AB - Primary neuroendocrine carcinoma (PNEC) of breast was an unknown pathologic entity till recently due its rare incidence and lack of definitive criteria for diagnosis. We present a case of PNEC of breast in a middle aged lady. A 34 years lady presented with a breast lump since 1 month, who underwent modified radical mastectomy with axillary clearance. Histopathological diagnoses were infiltrating ductal carcinoma-neuroendocrine (NE) type. Immunohistochemistry showed estrogen, progesterone positivity and NE markers positivity in more than 50% of tumor cells for chromogranin, synaptophysin, neuron specific enolase. On further investigation by whole body computed tomography and magnetic resonance imaging revealed no extra mammary primary tumor. Hence the diagnosis of PNEC of breast was confirmed. Patient received chemo and hormonal therapy and doing well after 6 months of follow up. PMID- 24349847 TI - Periapical infection masquerading as a nasal pustule. AB - Periapical infections may give rise to intraoral and extraoral complications. Extraoral manifestation of periapical infection without an accompanying dental symptom may lead to presentation first to Medical doctor. This is a case of pulpal necrosis of right maxillary central incisor (tooth #11) with a discharging sinus, in the floor of the right nostril. Failure to associate the discolored tooth #11 and a discharging sinus in the floor of the right nostril, lead to the initial presentation of the patient to the Otorhinolaryngologist. The recurrent discharge from the sinus continued despite prolonged antibiotics administration. This case report showed that extraoral sinus tract of dental origin in the nostril poses a diagnostic challenge. It is expected to raise awareness of clinicians about the unusual presentations of periapical infection. There is a need for examination of the maxillary incisors in patients presenting with nasal pustule. PMID- 24349848 TI - Typhoid intestinal perforation: 24 perforations in one patient. AB - Intestine perforation is one of the most dreaded and common complication of typhoid fever remarkably so in developing world; it usually leads to diffuse peritonitis, requiring early surgical intervention. Despite various measures such as safe drinking water supply and safe disposal of waste, intestinal perforation from salmonellosis remains the most common emergency surgery performed. The incidence continues to rise, so also the mortality, despite new antibiotics and improvement in surgical technique. More disturbing is that we now see increasing number of ileal perforations and colonic involvement. We hereby present a case report of 35-year-old male with multiple (24) intestinal perforation in the Ileum and Cecum. PMID- 24349849 TI - Progressive supranuclear palsy misdiagnosed as Parkinson's disease: a case report and review of literature. AB - Because of its increasingly recognized clinical diversity, progressive supranuclear palsy (PSP) may be difficult to diagnose, particularly in resource poor settings where the means of getting supportive tests is a huge challenge. This often results in underdiagnosis or misdiagnosis of PSP, most commonly as Parkinson's disease. The author reported a case of how brain magnetic resonance imaging (MRI) was used to arrive at the diagnosis of PSP in a man previously misdiagnosed as Parkinson's disease. Relevant literatures regarding the diagnostic utility of MRI in PSP were also reviewed. PMID- 24349850 TI - Xanthogranulomatous endometritis: an unusual pathological entity mimicking endometrial carcinoma. AB - Xanthogranulomatous endometritis is an unusual pathological entity mimicking endometrial carcinoma. This shows sheets of foamy histiocytes alongwith other inflammatory cells. We, hereby, report a case of 45 year multigravida female with irregular menstrual history, clinically diagnosed as carcinoma and histopathologically turned out as xanthogranulomatous endometritis. So, this condition should always be dealt with caution, and pathologists and clinicians should be aware of it. PMID- 24349851 TI - Acute pancreatitis associated with elevated troponin levels: whether to thrombolyse or not? AB - The presentation of retrosternal chest pain with normal electrocardiogram (ECG) during chest pain followed by initial presentation of acute pancreatitis can lead to a dilemma in managing such a patient, and whether to thrombolyse such a patient is a real controversy. We hereby present a similar case who was diagnosed to be having acute pancreatitis on admission, on clinical grounds, confirmed by laboratory investigations and ultrasonography, who subsequently developed retrosternal chest pain with normal ECG during the chest pain. All further serial ECGs after the onset of chest pain were within normal limits. The troponin-I level of this patient was positive twice (done 16 h apart). The patient was treated as acute coronary syndrome along with the standard management protocol of acute pancreatitis. PMID- 24349852 TI - Silver: russell syndrome with cryptorchidism. PMID- 24349853 TI - Reasons for Non-compliance of Patients to Attend Referral Hospital After Screening for Oral Pre-cancer Lesions through Camp Approach in Rural Population of Indiaa. PMID- 24349854 TI - Schedule H1: Is it a Solution to Curve Antimicrobial Misuse in India? PMID- 24349855 TI - Plagiarism: trespassing the grey zone between searching and researching. PMID- 24349856 TI - Assessing the Usefulness of Salivary Gland Fine Needle Aspiration Cytology as Diagnostic Aid for Salivary gland Malignancy. PMID- 24349857 TI - A comment on assessment of mild cognitive impairment with mini mental state examination among adults in southeast Nigeria. PMID- 24349858 TI - Author's response. PMID- 24349859 TI - Is Mind-Body Relaxation By Yoga is Effective to Combat with Lifestyle Stress? PMID- 24349860 TI - An extensive denture-induced hyperplasia of maxilla. AB - Denture-induced hyperplasia is a reactive lesion arising from excessive and chronic mechanical pressure on the vestibular oral mucosa. It has a female predilection and it is mostly seen in the maxilla. The size of the lesion may be as small as a few millimeters to massive lesion involving the entire vestibule. It is usually asymptomatic but sometimes severe inflammation and ulceration can occur. Elimination of the inflammation and excision of the lesion is the treatment of choice. Denture induced hyperplasia in right maxillary buccal vestibule in a middle age old female patient was presented. Surgical excision was done and new denture was fabricated. PMID- 24349861 TI - Enthesitis is an Extraintestinal Manifestation of Pediatric Inflammatory Bowel Disease. AB - BACKGROUND: Enthesitis is an extra-intestinal manifestation of inflammatory bowel disease (IBD) in adults. However, little has been published about the prevalence or characteristics of enthesitis in pediatric IBD. METHODS: We conducted a cross sectional study of children and young adults ages 4-21 years with IBD. Subjects were recruited among those receiving routine care in a gastroenterology clinic. All subjects underwent a clinical examination of the entheses and joints, and completed a study questionnaire. RESULTS: We enrolled 43 subjects, who had a median age of 16 years and a median time from IBD diagnosis of 2.7 years. 32 subjects (74%) had Crohn disease, 10 subjects (23%) had indeterminate colitis, and 1 subject (2%) had ulcerative colitis. At least one tender enthesis was present in 21% of subjects and 12% had more than 2 tender entheses. The most commonly affected entheses were located at the inferior patella, the femoral greater trochanter, and the proximal humerus. The presence of enthesitis was associated with a higher intensity of recent musculoskeletal pain (p=0.03). CONCLUSIONS: Enthesitis is a prevalent extra-intestinal manifestation of pediatric IBD and is associated with increased musculoskeletal pain. Future studies should evaluate the functional and long-term impact of enthesitis on children with IBD. PMID- 24349862 TI - Adverse Experiences and Suicidal Ideation in Adolescence: Exploring the Link Using the LONGSCAN Samples. AB - OBJECTIVE: Although widely studied in adults, the link between lifetime adversities and suicidal ideation in youth is poorly understood. The purpose of this study was to explore this link in adolescents. METHODS: The analyses used a sample of 740 16-year-old youth in the LONGSCAN sample, and distinguished between childhood (before the age of 12) and adolescent (between age 12 and age 16) adversities. RESULTS: There was a significant link between cumulative lifetime adversities and suicidal ideation. There was no evidence that this link was moderated by gender. Childhood adversities moderated the effects of adolescent adversities on suicidal ideation; effects of adolescent adversities were strongest at low levels of childhood adversities. There was also some evidence supporting a specific cumulative model of the effects of adversities on suicidal ideation; the most predictive model included the sum of the following adversities: childhood physical abuse, childhood neglect, childhood family violence, childhood residential instability, adolescent physical abuse, adolescent sexual abuse, adolescent psychological maltreatment, and adolescent community violence. CONCLUSION: The timing and nature of adversities are important in understanding youth suicidal ideation risk; in particular, adolescent maltreatment and community violence appear to be strong predictors. Preventing and appropriately responding to the abuse of adolescents has the potential to reduce the risk of suicidal ideation. PMID- 24349863 TI - IS IT THE EXCEPTION OR THE RULE? DAILY CO-OCCURRENCE OF PHYSICAL, SEXUAL, AND PSYCHOLOGICAL PARTNER VIOLENCE IN A 90-DAY STUDY OF SUBSTANCE-USING, COMMUNITY WOMEN. AB - OBJECTIVE: This study aims to describe the daily co-occurrence of physical, sexual, and psychological intimate partner violence (IPV) among substance-using, community-based women currently experiencing IPV. METHODS: A micro-longitudinal study design was used to collect data daily from 49 women for 90 days. RESULTS: On the majority of days (62%), no IPV occurred; 27% of days were characterized by psychological IPV alone, followed by the co-occurrence of psychological and physical IPV (6% of IPV days). Results of person-level analyses showed comparable sized correlations between the proportion of days with physical and sexual IPV and the proportion of days with physical and psychological IPV. However, results of day-level analyses revealed that the association between physical and psychological IPV was much stronger than the association between physical and sexual IPV; Physical IPV was 64 times more likely to occur on days when psychological IPV occurred. CONCLUSIONS: Results revealed new information about physical, sexual, and psychological IPV experiences and demonstrate the utility of a micro-longitudinal design among this high risk population. Implications for practice, future research, and the development of preventive interventions are noted, underscoring the importance of psychological IPV and the range of IPV experiences among women. PMID- 24349865 TI - Clinical functional anatomy of the pterygopalatine ganglion, cephalgia and related dysautonomias: A review. AB - The purpose of this article is to explain the anatomy of the pterygopalatine ganglion (PPG), its location in the pterygopalatine fossa (PPF) in the skull, and the relationship it has to the Vidian nerve terminal branches and the fifth cranial nerve. An overview of the neuro-anatomical/clinical correlations, a spectrum of pathologies affecting the seventh cranial nerve and some therapies both medical and surgical are noted. The focus is the pterygopalatine region with discussion of the proximal courses of the seventh and fifth cranial nerves and their pathological processes. The ganglion is used as an example of neuro anatomical model for explaining cluster headaches (CH). Radiological correlation is included to clarify the location of the PPF and its clinical importance. PMID- 24349864 TI - Minimally invasive management of adult craniopharyngiomas: An analysis of our series and review of literature. AB - BACKGROUND: Craniopharyngiomas (CPs) are slow growing tumors with an incidence of between 1.2% and 4.6%, having a bimodal age distribution typically peaking in childhood and in adults between 45 and 60 years. Recurrences occur even after documented gross total resections necessitating a combination of therapeutic strategies. Obtaining a cure of this tumor in adults without producing major side effects continues to remain elusive. METHODS: We describe our results in 11 patients with CP treated in a minimally invasive fashion using a combination of techniques like burr hole aspiration, Ommaya reservoir placement, ventriculo peritoneal (VP) shunting and focal radiation (Gamma Knife stereotactic radiosurgery/Intensity modulated radiotherapy [GKRS/IMRT]). RESULTS: Visual function remained intact in all patients; endocrine status remained stable with two patients developing new postoperative diabetes insipidus. There was no periprocedural morbidity or mortality, with hospital stays for any in-patient procedure being 48 hours or less. CONCLUSIONS: Minimally invasive techniques such as cyst aspiration, insertion of a catheter with Ommaya reservoir, when combined with stereotactic radiosurgery/IMRT is an effective and safe option for management and long-term control of adult CPs. We believe the Ommaya catheter by itself could act as a stent, creating a tract allowing gradual drainage of cyst fluid and stabilization without necessitating any further interventions in selected cases. PMID- 24349866 TI - Stereotactic radiosurgery for the treatment of Glomus Jugulare Tumors. AB - BACKGROUND: The glomus jugulare tumor is a slowly growing benign neoplasm originating from neural crest. There is a high morbidity associated with surgical resection of glomus jugulare. Radiosurgery play a relevant role as a therapeutic option in these tumors and its use has grown in popularity. The authors describe a retrospective series of 15 patients and reviewed the literature about the glomus jugulare tumors. METHODS: We reviewed retrospectively the data of 15 patients treated with stereotactic linear accelerator stereotactic radiosurgery (LINAC) radiosurgery between 2006 and 2011. RESULTS: The average tumor volume was 18.5 cm(3). The radiation dose to the tumor margin ranged between 12 and 20 Gy. The neurological status improved in three patients and remained unchanged in 12 patients. One patient developed a transient 7(th) nerve palsy that improved after clinical treatment. All tumors remained stable in size on follow-up with resonance magnetic images. CONCLUSIONS: The radiosurgery is a safe and effective therapy for patients with glomus jugulare tumor. Despite the short follow-up period and the limited number of patients analyzed, we can infer that radiosurgery produce a tumor growth control with low morbidity, and may be used as a good option to surgical resection in selected cases. PMID- 24349867 TI - Stereotactic radiosurgery boost to the resection cavity for cerebral metastases: Report of overall survival, complications, and corticosteroid protocol. AB - BACKGROUND: This report focuses on the overall survival and complications associated with treatment of cerebral metastases with surgical resection followed by stereotactic radiosurgery (SRS). Management and complications of corticosteroid therapy are underreported in the literature but represent an important source of morbidity for patients. METHODS: Fifty-nine consecutive patients underwent surgical resection of a cerebral metastasis followed by SRS to the cavity. Patient charts were reviewed retrospectively to ascertain overall survival, local control, surgical complications, SRS complications, and corticosteroid complications. RESULTS: Our mean follow-up was 14.4 months (median 12.0 months, range 0.9-62.9 months). Median overall survival in this series was 15.25 months and local control was 98.3%. There was a statistically significant survival benefit conferred by Radiation Therapy Oncology Group recursive partitioning analysis Classes 1 and 2. The surgical complication rate was 6.8% while the SRS complication rate was 2.4%. Corticosteroid complications are reported and dependence at 1 month was 20.3%, at 3 months 6.8%, at 6 months 1.7%, and at 12 months no patients remained on corticosteroid therapy. CONCLUSIONS: Overall survival and local control with this treatment paradigm compare well to the other published literature. Complications associated with this patient population are low. A corticosteroid tapering protocol is proposed and demonstrated lower rates of steroid-related complications and dependence than previously reported. PMID- 24349868 TI - Neuropsychological effects of deep brain stimulation for Parkinson's disease. AB - BACKGROUND: Putative changes of cognition after deep brain stimulation (DBS) in patients with Parkinson's disease (PD) are a matter of debate. The aim of this study was to assess cognitive abilities before and following bilateral subthalamic nucleus (STN) DBS and to review the available literature. METHODS: Twenty patients underwent bilateral DBS of the STN. Cognitive skills were assessed in a standardized fashion before and at least at 12 months after the surgical intervention. RESULTS: There was a significant decline of both semantic and phonematic verbal fluency and a mild trend for a deterioration of verbal memory after DBS. Mood, general cognitive screening, and visospatial abilities remained unchanged. CONCLUSION: STN DBS in the treatment of PD has resulted in a significant reduction of motor symptoms and improved independence and quality of life in appropriately selected patients. However, it may have isolatable effects on verbal fluency and related function. Case series in the literature reported similar findings. Potential candidates for DBS should be counseled about the risk of mild cognitive declines. PMID- 24349869 TI - Image guided surgery in the management of craniocerebral gunshot injuries. AB - BACKGROUND: A craniocerebral trauma caused by firearms is a complex injury with high morbidity and mortality. One of the most intriguing and controversial part in their management in salvageable patients is the decision to remove the bullet/pellet. A bullet is foreign to the brain and, in principle, should be removed. Surgical options for bullet extraction span from conventional craniotomy, through C-arm-guided surgery to minimally invasive frame or frameless stereotaxy. But what is the best surgical option? METHODS: We prospectively followed up a cohort of 28 patients with cranio-cerebral gunshot injury (CCHSI) managed from January to December 2012 in our department of neurosurgery. The missiles were extracted via stereotaxy (frame or frameless), C-arm-guided, or free-hand-based surgery. Cases managed conservatively were excluded. The Glasgow Outcome Score was used to assess the functional outcome on discharge. RESULTS: Five of the eight "stereotactic cases" had an excellent outcome after missile extraction while the initially planned stereotaxy missed locating the missile in three cases and were thus subjected to free hand craniotomy. Excellent outcome was obtained in five of the nine "neuronavigation cases, five of the eight cases for free hand surgery based on the bony landmarks, and five of the six C-arm based surgery. CONCLUSION: Conventional craniotomy isn't indicated in the extraction of isolated, retained, intracranial firearm missiles in civilian injury but could be useful when the missile is incorporated within a surgical lesion. Stereotactic surgery could be useful for bullet extraction, though with limited precision in identifying small pellets because of their small sizes, thus exposing patients to same risk of brain insult when retrieving a missile by conventional surgery. Because of its availability, C-arm-guided surgery continues to be of much benefit, especially in emergency situations. We recommend an extensive long-term study of these treatment modalities for CCGSI. PMID- 24349870 TI - Management of trigeminal neuralgia in sclerosteosis. AB - BACKGROUND: Sclerosteosis is a rare bone disorder characterized by a progressive craniotubular hyperostosis. The diagnosis of sclerosteosis is based on characteristic clinical and radiographic features and a family history consistent with autosomal recessive inheritance. The skull overgrowth may lead to lethal elevation of intracranial pressure, distortion of the face, and entrapment of cranial nerves, resulting in recurrent facial palsy or secondary trigeminal neuralgia. CASES DESCRIPTION: The authors reported cases of two siblings who were diagnosed with familial sclerosteosis and presented with secondary trigeminal neuralgia. The patients were 28 and 40-year-old and presented with pain in the right V2-V3 and V3 distributions, respectively. The facial pain was resistant to medications and was treated with percutaneous techniques. The foramen ovale puncture was complicated initially and the difficulty increased over the years due to stenosis of the foramen. CONCLUSION: The treatment of the trigeminal neuralgia secondary to hyperostosis and resistant to medications presents a dilemma. The narrowing of the foramen oval and difficulty in the identifying and approaching of the foramen makes the percutaneous technique a challenge for the neurosurgeon in patients harboring sclerosteosis. Microvascular decompression should not be considered since the primary cause of the trigeminal neuralgia is the nerve entrapment by the narrowing of neurovascular foramina and not the neurovascular conflict related to essential trigeminal neuralgia. Stereotactic radiosurgery may be a good treatment option, but there is a lack of published data supporting the use of this method in cranial hyperostosis. PMID- 24349871 TI - Dynamic Stress Factor (DySF): A Significant Predictor of Severe Hypoglycemic Events in Children with Type 1 Diabetes. AB - Hemoglobin A1c (HbA1c) is the current standard used in the clinical treatment of patients with diabetes. However, it has been shown that patients with similar HbA1c values may have widely different fluctuations in blood glucose values over the same period of time, including time spent in hyper- and/or hypo-glycemia. Hence, there exists a need for quantitative measures that can supplement HbA1c in managing patients with diabetes. We introduce and compare the Dynamic Stress Factor, DySF, a newly developed metric that quantifies glycemic volatility based on patient-specific glucose transition density profiles with HbA1c and with currently used glucose variability metrics in predicting severe hypoglycemia in children with type 1 diabetes. DySF, the daily weighted number of large monotonic glycemic transitions that occur within one hour, was calculated for 441 total subjects with type 1 diabetes (146 children, aged 8-14 yrs) to assess the magnitude and frequency of glucose transitions per day. Severe hypoglycemic episodes (HE) were quantified for all subjects and evaluated against HbA1c and existing measures of glucose variability, including SD, MAGE, MODD, and CONGA using logistic regression models. DySF was found to be a predictor of severe HE in children (p = 0.018) with the likelihood of a child, aged 8-14 yrs, experiencing severe hypoglycemia increasing by up to 20% with decreasing values of up to 60% of DySF. Patients of any age who had one or multiple severe hypoglycemic episodes had on average a lower DySF when compared to those with no HE. Additionally, when considering mean glucose levels, DySF/mean was a preliminary predictor of severe HE in patients with HbA1c <= 6.5% (p = 0.062). DySF is a dynamic, quantitative, measure of daily glucose "volatility" that separates patients, within the same strata of HbA1c, into visually distinct patient profiles. DySF can be used as a preliminary predictor of clinically severe hypoglycemia in children and "well-controlled" patients with HbA1c <= 6.5%. PMID- 24349872 TI - Critical Factors in Measuring Angiogenesis Using the Aortic Ring Model. AB - Angiogenesis is a feature of numerous pathologies including cancer and inflammatory conditions and as such is key therapeutic target for the treatment of disorders where excessive or insufficient formation of new blood vessels occurs. The study of angiogenesis in vivo provides many challenges, however the growth of new blood vessels in vitro from aortic explants has provided a highly useful model for the study of this process. In this manuscript we examine the critical factors which can affect this assay and demonstrate that aortas from both female rats and mice exhibit a reduced angiogenic response to males. These findings have implications not only for the experimental design of angiogenesis experiments but also in the use of therapies targeting angiogenesis in the treatment of pathologies, such as cancer. PMID- 24349873 TI - Effects of Cyclic vs. Acyclic Hydrophobic Subunits on the Chemical Structure and Biological Properties of Nylon-3 Co-Polymers. AB - Nylon-3 co-polymers containing both hydrophobic and cationic subunits can mimic the activity profile of host-defense peptides, if subunit identity and proportion are carefully selected. These sequence- and stereo-random co-polymers inhibit bacterial growth at relatively low concentrations, apparently via disruption of bacterial membranes, but they are relatively non-disruptive toward eukaryotic cell membranes (low hemolytic activity). In all previous examples, the hydrophobic subunits have contained cycloalkyl groups that incorporate the backbone Calpha-Cbeta bond. Here we have explored the effects of using analogous acyclic hydrophobic subunits. The results indicate that the replacing cyclic with acyclic hydrophobic subunits has a modest influence on biological properties. This influence appears to arise from differences in subunit flexibility. PMID- 24349874 TI - Clinical response of advanced cancer patients to cellular immunotherapy and intensity-modulated radiation therapy. AB - Patients afflicted with advanced cancers were treated with the intratumoral injection of autologous immature dendritic cells (iDCs) followed by activated T cell infusion and intensity-modulated radiation therapy (IMRT). A second round of iDCs and activated T cells was then administered to patients after the last radiation cycle. This complete regimen was repeated for new and recurring lesions after 6 weeks of follow-up. One year post therapy, outcome analyses were performed to evaluate treatment efficacy. Patients were grouped according to both the number and size of tumors and clinical parameters at treatment initiation, including recurrent disease after standard cancer therapy, Stage IV disease, and no prior therapy. Irrespective of prior treatment status, 23/37 patients with <= 5 neoplastic lesions that were <= 3 cm in diameter achieved complete responses (CRs), and 5/37 exhibited partial responses (PRs). Among 130 individuals harboring larger and more numerous lesions, CRs were observed in 7/74 patients that had received prior SCT and in 2/56 previously untreated patients. Some patients manifested immune responses including an increase in CD8+CD56+ lymphocytes among circulating mononuclear cells in the course of treatment. To prospectively explore the therapeutic use of these cells, CD8+ cells were isolated from patients that had been treated with cellular immunotherapy and IMRT, expanded in vitro, and injected into recurrent metastatic sites in 13 individuals who underwent the same immunoradiotherapeutic regimens but failed to respond. CRs were achieved in 34 of 58 of such recurrent lesions while PRs in 17 of 58. These data support the expanded use of immunoradiotherapy in advanced cancer patients exhibiting progressive disease. PMID- 24349875 TI - HLA-DR expression on myeloid cells is a potential prognostic factor in patients with high-risk neuroblastoma. AB - The adaptive immune system has been reported to play a dual role in many cancers, on one hand inhibiting tumor growth and, on the other hand, promoting disease progression, escape from cancer immunosurveillance and relapse. We have previously reported that the suppression of the adaptive immune response associated with high levels of myeloid-derived suppressor cells (MDSC) was evident in patients with low-risk neuroblastoma. Here, we report the results of a pilot study demonstrating that the amounts of HLA-DR-positive or negative myeloid cells in the peripheral blood might predict disease outcome among individuals affected by high-risk neuroblastoma. PMID- 24349876 TI - Antitumor activity of an immunocytokine composed of an anti-GD2 antibody and the IL-15 superagonist RLI. AB - The use of interleukin (IL)-15 or the IL-15 superagonist RLI as immunological adjuvants presents many advantages over that of IL-2, including a reduced toxicity and an improved efficacy. We have generated an immunocytokine that specifically targets RLI to a tumor-associated antigen, namely, disialoganglioside GD2. This agent displayed robust antitumor activity in 2 syngeneic murine models of malignant disease. PMID- 24349878 TI - Cardiac Hegemony of Senescence. AB - Cardiac senescence and age-related disease development have gained general attention and recognition in the past decades due to increased accessibility and quality of health care. The advancement in global civilization is complementary to concerns regarding population aging and development of chronic degenerative diseases. Cardiac degeneration has been rigorously studied. The molecular mechanisms of cardiac senescence are on multiple cellular levels and hold a multilayer complexity level, thereby hampering development of unambiguous treatment protocols. In particular, the synergistic exchange of the senescence phenotype through a senescence secretome between myocytes and stem cells appears complicated and is of great future therapeutic value. The current review article will highlight hallmarks of senescence, cardiac myocyte and stem cell senescence, and the mutual exchange of senescent secretome. Future cardiac cell therapy approaches require a comprehensive understanding of myocardial senescence to improve therapeutic efficiency as well as efficacy. PMID- 24349877 TI - RELATIONSHIP OF GAIT AND COGNITION IN THE ELDERLY. AB - Gait and cognitive impairments in older adults mostly reflect the co-occurrence of two geriatric syndromes linked by common underlying brain substrates and pathologies. Gait control is predominately mediated by frontal subcortical circuits, which overlap with circuits controlling executive control and attention functions. These circuits are vulnerable to multiple age-related pathologies such as ischemia, inflammation, and neurodegeneration, which could ultimately cause cognitive, gait, or combined cognitive and gait impairments. The following review aims to describe various gait and cognitive classifications, gait based phenotypes, common underlying pathological processes, and provide a link between motor and cognitive impairments in an effort to predict the risk of dementia, as well as remediate impairments by applying appropriate interventions. PMID- 24349879 TI - "It takes a village" to raise research productivity: Impact of a Trauma Interdisciplinary Group for Research (TIGR) at an urban, Level 1 trauma center. AB - BACKGROUND: Few interdisciplinary research groups include basic scientists, pharmacists, therapists, nutritionists, lab technicians, as well as trauma patients and families, in addition to clinicians. Increasing interprofessional diversity within scientific teams working to improve trauma care is a goal of national organizations and federal funding agencies like the National Institutes of Health (NIH). This paper describes the design, implementation, and outcomes of a Trauma Interdisciplinary Group for Research (TIGR) at a Level 1 trauma center as it relates to increasing research productivity, with specific examples excerpted from an on-going NIH-funded study. METHODS: We utilized a pre-test/post test design with objectives aimed at measuring increases in research productivity following a targeted intervention. A SWOT (strengths, weaknesses, opportunities, threats) analysis was used to develop the intervention which included research skill-building activities, accomplished by adding multidisciplinary investigators to an existing NIH-funded project. The NIH project aimed to test the hypothesis that accelerated biologic aging from chronic stress increases baseline inflammation and reduces inflammatory response to trauma (projected N=150). Pre/Post-TIGR data related to participant screening, recruitment, consent, and research processes were compared. Research productivity was measured through abstracts, publications, and investigator-initiated projects. RESULTS: Research products increased from N =12 to N=42; (~ 400%). Research proposals for federal funding increased from N=0 to N=3, with success rate of 66%. Participant screenings for the NIH-funded study increased from N=40 to N=313. Consents increased from N=14 to N=70. Lab service fees were reduced from $300/participant to $5/participant. CONCLUSIONS: Adding diversity to our scientific team via TIGR was exponentially successful in 1) improving research productivity, 2) reducing research costs, and 3) increasing research products and mentoring activities that the team prior to TIGR had not entertained. The team is now well-positioned to apply for more federally funded projects and more trauma clinicians are considering research careers than before. PMID- 24349880 TI - Terpinen-4-ol is the Most Active Ingredient of Tea Tree Oil to Kill Demodex Mites. AB - PURPOSE: To determine the active ingredient in tea tree oil (TTO) responsible for its reported killing effect on Demodex mites, the most common ectoparasite found in the human skin extending to the eye. METHODS: Using a reported in vitro killing assay to measure the survival time of adult Demodex folliculorum up to 150 minutes, we have screened serial concentrations of 13 of the 15 known ingredients of TTO (ISO4730:2004) that were soluble in mineral oil and examined their synergistic relationships in killing mites. The most potent ingredient was then tested for its efficacy in killing Demodex in vivo. RESULTS: All ingredients exhibited a dose-dependent killing effect. Besides Terpinen-4-ol, the order of relative potency did not correlate with the order of relative abundance in TTO for the remaining 12 ingredients. Terpinen-4-ol was the most potent ingredient followed by alpha-Terpineol, 1,8-Cineole and Sabinene. Terpinen-4-ol, the most abundant ingredient in TTO, was more potent than TTO at equivalent concentrations and its killing effect was even observable at a mere concentration of 1%. Terpinen-4-ol exhibited a significant synergistic effect with Terpinolene, but an antagonistic effect with alpha-Terpineol in killing mites (both P < 0.05). In vivo, Terpinen-4-ol was shown to eradicate mites. CONCLUSIONS: The above finding suggests that deployment of Terpinen-4-ol alone should enhance its potency in killing Demodex mites by reducing the adverse and antagonistic effects from other ingredients in TTO. TRANSLATIONAL RELEVANCE: Terpinen-4-ol can be adopted in future formulations of acaricides to treat a number of ocular and cutaneous diseases caused by demodicosis. PMID- 24349881 TI - Validity and Repeatability of Saccadic Response Times Across the Visual Field in Eye Movement Perimetry. AB - PURPOSE: To assess the validity and repeatability of saccadic reaction times (SRT) across the visual field up to 30 degrees using eye movement perimetry (EMP). METHODS: Eighteen subjects (36 eyes) were shown a central stimulus on a flat monitor screen. Next, peripheral stimuli were shown using an overlap paradigm. Subjects were instructed to look at detected peripheral stimuli and then refixate the central stimulus again. In three repetitive measurement series, a total of 288 visual stimuli (3 series * 24 locations * 4 contrast levels) were presented. Levene's test for equality of variances was applied to test the effect of stimulus location and measurement series on SRT variance. A Wilcoxon signed ranks test was used to compare SRTs between measurement series. RESULTS: A total of 26 eyes were included in the study (72%). On average, 90.5% of the peripheral stimuli were labeled as 'seen' based on eye movement responses. Between the series, the mean SD of SRT differences was approximately 100 ms. Significantly faster SRTs were only found at contrast level 0.8 in series III compared with series II. In series I, SRT variance was independent in 75% of all locations. Across the three series, SRT variance was independent in 87.5% of all locations. CONCLUSIONS: The present study demonstrates low variability of SRT across the visual field up to 30 degrees eccentricity and across measurement series. TRANSLATIONAL RELEVANCE: SRT as a measure for visual field responsiveness may be a potential marker to detect risk areas in specific parts of the visual field. PMID- 24349882 TI - Proceedings of the First International Optogenetic Therapies for Vision Symposium. AB - Optogenetics is a research field that uses gene therapy to deliver a gene encoding a light-activated protein to cells providing light-regulated control of targeted cell pathways. The technology is a popular tool in many fields of neuroscience, used to transiently switch cells on and off, for example, to map neural circuits. In inherited retinal degenerative diseases, where loss of vision results from the loss of photoreceptors, optogenetics can be applied to either augment the function of surviving photoreceptors or confer light sensitivity to naturally nonlight sensitive retinal cells, such as a bipolar cells. This can be achieved either by the light sensitive protein integrating with native internal signaling pathways, or by using a dual function membrane protein that integrates light signaling with an ion channel or pump activity. Exposing treated cells to light of the correct wavelength activates the protein, resulting in cellular depolarization or hyperpolarization that triggers neurological signaling to the visual cortex. While there is a lot of interest in optogenetics as a pan-disease clinical treatment for end-stage application in the inherited degenerative diseases of the retina, research to date has been limited to nonhuman clinical studies. To address the clinical translational needs of this technology, the Foundation Fighting Blindness and Massachusetts Eye and Ear Infirmary cohosted an International Optogenetic Therapies for Vision Workshop, which was held at Massachusetts Eye and Ear Infirmary, Boston, Massachusetts on June 1, 2012. PMID- 24349883 TI - A Comparison of Methods for Tracking Progression in X-Linked Retinitis Pigmentosa Using Frequency Domain OCT. AB - PURPOSE: To compare the efficacy of frequency domain optical coherence tomography (fdOCT)-derived outer retinal measures in tracking disease progression in x linked (xl) retinitis pigmentosa (RP) patients. METHODS: Macular volume scans and line scans (Spectralis) were obtained from 27 xlRP patients (15.3 +/- 6.4 years) at two visits approximately 2 years apart. Changes in average outer retinal layer thicknesses across the volume scan were compared to changes detected by measures derived from the edge of the inner segment ellipsoid zone (EZ) band, that is, where the EZ band (also known as inner segment/outer segment border) disappears. Repeatability was tested on an independent set of 18 RP patients (43.5 +/- 18.0 years). RESULTS: Average outer segment (OS) and outer nuclear layer (ONL) thickness showed marginally significant annual changes (P < 0.05), while total receptor (TR) thickness showed a greater change (P < 0.01). All measures derived from the edge of the EZ band significantly decreased (P < 0.01). Mean +/- SD for test-retest differences in horizontal widths was 0.01 +/- 0.06 mm. CONCLUSIONS: Measures of the EZ band are more effective in detecting disease progression than are thickness measures. Given the similar effectiveness of line and volume scans, manually marking the EZ band edge on vertical and/or horizontal line scans can be useful in tracking progression. TRANSLATIONAL RELEVANCE: Because disease progression in RP can be relatively slow, annual changes can be difficult to monitor during the course of a clinical trial. Here we suggest a quick, effective, and reliable method for detecting subtle changes. PMID- 24349884 TI - The Biomechanical Effect of Corneal Collagen Cross-Linking (CXL) With Riboflavin and UV-A is Oxygen Dependent. AB - PURPOSE: In an attempt to reduce treatment time in corneal collagen cross-linking (CXL) with riboflavin and ultraviolet-A (UV-A), recent protocol modifications include shorter irradiation times at higher fluence, while maintaining constant total applied energy (Bunsen-Roscoe law of reciprocity). While such parameter changes might produce similar biological results within a certain range, the limits of reciprocity are unknown. Limitations in the corneal oxygen diffusion capacity and its potential impact on the efficacy of CXL, raise concerns regarding the efficiency of high-fluence CXL, and also of transepithelial CXL. METHODS: Porcine corneas were treated with an epithelium-off CXL at a fluence of 9 mW/cm2 under two different atmospheres: one with a regular oxygen content (21%) and another in a helium-supplemented, low-oxygen environment (<0.1%). Untreated corneas served as controls (n = 20 each). Five-millimeter corneal stripes were prepared and biomechanical stiffness was measured using an extensometer. RESULTS: Corneas cross-linked under normal oxygen levels showed a significant increase in biomechanical stability (14.36 MPa +/- 2.69 SD), whereas corneas treated similarly, but in a low-oxygen atmosphere showed a Young's modulus similar to untreated controls (11.72 MPa +/- 2.77 SD). CONCLUSIONS: The biomechanical effect of CXL seems to be oxygen dependent. This dependency will be of particular importance in high-fluence and transepithelial CXL and will most likely require major protocol modifications to maintain the efficiency of the method. TRANSLATIONAL RELEVANCE: The oxygen dependency of CXL shown here raises concerns about the effectiveness of high-fluence and transepithelial CXL. Both methods were introduced to clinical ophthalmology without thorough validation. PMID- 24349886 TI - Patient report: autism spectrum disorder treated with camel milk. AB - This patient report is about my son, who was diagnosed with autism spectrum disorder (ASD) at 3 years of age, and the effects I observed when he began drinking camel milk daily. Beginning at age 9, he drank one half cup of raw camel milk a day and experienced overnight an improvement in his symptoms. His continued regular consumption of camel milk was associated with sustained symptom improvements for 6 consecutive years (2007-2013). This patient report is a road map of my navigations, consultations with experts and autism care providers, and the apparent effect of camel milk on autism spectrum disorder (ASD). PMID- 24349885 TI - My experience learning about autism. AB - I remember the first time I heard the word "autistic." I was 10 years old, and my mom mentioned that someone had a child who was autistic. I was confused because I mistook her description as "artistic." In April 2001, our first child, Isaiah, was born. My wife, Lanier, was concerned that he had autism at about 11 months of age, but I did not recognize his obvious problems, even though he was not responding to his name, was obsessed with spinning objects, and did not play with toys appropriately. He also had no language, did not walk until 18 months, and had significant gastrointestinal (GI) problems including severe reflux requiring medication and chronic diarrhea. At 19 months of age, Isaiah was diagnosed with autistic disorder. PMID- 24349887 TI - Differential Role of Two-Component Regulatory Systems (phoPQ and pmrAB) in Polymyxin B Susceptibility of Pseudomonas aeruginosa. AB - Polymyxins are often considered as a last resort to treat multidrug resistant P. aeruginosa but polymyxin resistance has been increasingly reported worldwide in clinical isolates. Polymyxin resistance in P. aeruginosa is known to be associated with alterations in either PhoQ or PmrB. In this study, mutant strains of P. aeruginosa carrying amino acid substitution, a single and/or dual inactivation of PhoQ and PmrB were constructed to further understand the roles of PhoQ and PmrB in polymyxin susceptibility. Polymyxin B resistance was caused by both inactivation and/or amino acid substitutions in PhoQ but by only amino acid substitutions of PmrB. Alterations of both PhoQ and PmrB resulted in higher levels of polymyxin B resistance than alteration of either PhoQ or PmrB alone. These results were confirmed by time-killing assays suggesting that high-level polymyxin resistance in P. aeruginosa is caused by alterations of both PhoQ and PmrB. PMID- 24349888 TI - Pancreatic anastomosis leak 15 years after simultaneous pancreas-kidney transplantation from late-onset allograft cytomegalovirus duodenal ulcers presenting with gross hematuria. AB - Cytomegalovirus (CMV) infection is one of the most important causes of morbidity and mortality in solid organ transplantation. It can present with hematuria, the most common urological complication in the early post-simultaneous pancreas kidney (SPK) transplant period. In SPK transplantation, CMV infection usually occurs 1 month after transplantation. We report an instance of bladder-drained SPK transplant presenting with recurrent gross hematuria from CMV infected duodenal graft ulcers 15 years after preserved well-functioning grafts. Serum quantitative Polymerase Chain Reaction (qPCR) for CMV was negative. Postmortem duodenal graft staining for CMV was positive, and revealed the cause of the inciting ulcer. To our knowledge, our patient is the first reported case of very late onset invasive CMV disease causing duodenal graft ulcers 15 years after transplantation, as previously reported cases of posttransplant CMV disease occurred only as late as 18 months. In addition, the absence of correlation between CMV viremia and CMV-infected duodenal allograft in SPK transplant has not been reported. Our case demonstrates that CMV viral load is -unreliable to diagnose invasive CMV disease, and tissue biopsy should be obtained to avoid missed diagnosis causing high morbidity and mortality. PMID- 24349889 TI - Factors affecting household adoption of an evacuation plan in American Samoa after the 2009 earthquake and tsunami. AB - American Samoa is still recovering from the debilitating consequences of the September 29, 2009 tsunami. Little is known about current household preparedness in American Samoa for future earthquakes and tsunamis. Thus, this study sought to enumerate the number of households with an earthquake and tsunami evacuation plan and to identify predictors of having a household evacuation plan through a post tsunami survey conducted in July 2011. Members of 300 households were interviewed in twelve villages spread across regions of the principle island of Tutuila. Multiple logistic regression showed that being male, having lived in one's home for < 30 years, and having a friend who suffered damage to his or her home during the 2009 tsunami event increased the likelihood of having a household evacuation plan. The prevalence of tsunami evacuation planning was 35% indicating that survivors might feel that preparation is not necessary given effective adaptive responses during the 2009 event. Results suggest that emergency planners and public health officials should continue with educational outreach to families to spread awareness around the importance of developing plans for future earthquakes and tsunamis to help mitigate human and structural loss from such natural disasters. Additional research is needed to better understand the linkages between pre-event planning and effective evacuation responses as were observed in the 2009 events. PMID- 24349890 TI - Evaluating the impact of a school-based prevention program on self-esteem, body image, and risky dieting attitudes and behaviors among Kaua'i youth. AB - Eating disorders and obesity (EDO) are increasing among youth, having serious long-term physical and psychological consequences. The purpose of this study was to determine if significant differences exist in EDO risk factors following participation of 4-6th grade students in a school-based EDO prevention curriculum. This community-based research project assessed students at baseline and one week following EDO intervention. Primary outcome variables measured self esteem, body dissatisfaction, and high risk eating attitudes and behaviors. Pre and post-test differences were calculated using mixed models, correcting for clustering within schools and teachers. This study found mean changes in all scores in healthy directions, as well as movement of students into lower risk groups post-intervention. This program demonstrated that a classroom curriculum is associated with decreased risks of EDO in boys and girls, supporting prevention programs at an early age for both sexes. Studies to determine long term benefit and guide booster interventions are warranted. PMID- 24349891 TI - Treatment of median arcuate ligament syndrome via traditional and robotic techniques. AB - Median arcuate ligament syndrome (MALS) is a rare entity characterized by extrinsic compression of the celiac artery and symptoms of postprandial epigastric pain, nausea, vomiting, and weight loss mimicking mesenteric ischemia. We present two patients diagnosed with MALS, the first treated with an open laparotomy by a vascular surgeon and the second using a robot assisted laparoscopic approach by a general surgeon with a vascular surgeon on standby. This is the second ever report of this approach. Both patients recovered without complications and experienced resolution of their symptoms. A discussion of the pathophysiology, literature review, and multispecialty treatment approach are presented. PMID- 24349892 TI - Medical school hotline: Homelessness in Hawai'i: challenges, progress, and prospects. PMID- 24349895 TI - Automated analysis of clonal cancer cells by intravital imaging. AB - Longitudinal analyses of single cell lineages over prolonged periods have been challenging particularly in processes characterized by high cell turn-over such as inflammation, proliferation, or cancer. RGB marking has emerged as an elegant approach for enabling such investigations. However, methods for automated image analysis continue to be lacking. Here, to address this, we created a number of different multicolored poly- and monoclonal cancer cell lines for in vitro and in vivo use. To classify these cells in large scale data sets, we subsequently developed and tested an automated algorithm based on hue selection. Our results showed that this method allows accurate analyses at a fraction of the computational time required by more complex color classification methods. Moreover, the methodology should be broadly applicable to both in vitro and in vivo analyses. PMID- 24349893 TI - Insights in public health: taxing sugar sweetened beverages to improve public health: policy action in Hawai'i. Doctoral Health Policy Seminar, Spring 2013. PMID- 24349896 TI - Altering an extended phenotype reduces intraspecific male aggression and can maintain diversity in cichlid fish. AB - Reduced male aggression towards different phenotypes generating negative frequency-dependent intrasexual selection has been suggested as a mechanism to facilitate the invasion and maintenance of novel phenotypes in a population. To date, the best empirical evidence for the phenomenon has been provided by laboratory studies on cichlid fish with different colour polymorphisms. Here we experimentally tested the hypothesis in a natural population of Lake Malawi cichlid fish, in which males build sand-castles (bowers) to attract females during seasonal leks. We predicted that if bower shape plays an important role in male aggressive interactions, aggression among conspecific males should decrease when their bower shape is altered. Accordingly, we allocated randomly chosen bowers in a Nyassachromis cf. microcephalus lek into three treatments: control, manipulated to a different shape, and simulated manipulation. We then measured male behaviours and bower shape before and after these treatments. We found that once bower shape was altered, males were involved in significantly fewer aggressive interactions with conspecific males than before manipulation. Mating success was not affected. Our results support the idea that an extended phenotype, such as bower shape, can be important in maintaining polymorphic populations. Specifically, reduced male conspecific aggression towards males with different extended phenotypes (here, bower shapes) may cause negative frequency dependent selection, allowing the invasion and establishment of a new phenotype (bower builder). This could help our understanding of mechanisms of diversification within populations, and in particular, the overall diversification of bower shapes within Lake Malawi cichlids. PMID- 24349897 TI - A feasibility open trial of internet-delivered cognitive-behavioural therapy (iCBT) among consumers of a non-governmental mental health organisation with anxiety. AB - Background. To date the efficacy and acceptability of internet-delivered cognitive behavioural treatments (iCBT) has been examined in clinical trials and specialist facilities. The present study reports the acceptability, feasibility and preliminary efficacy of an established iCBT treatment course (the Wellbeing Course) administered by a not-for-profit non-governmental organisation, the Mental Health Association (MHA) of New South Wales, to consumers with symptoms of anxiety. Methods. Ten individuals who contacted the MHA's telephone support line or visited the MHA's website and reported at least mild symptoms of anxiety (GAD 7 total scores >=5) were admitted to the study. Participants were provided access to the Wellbeing Course, which comprises five online lessons and homework assignments, and brief weekly support from an MHA staff member via telephone and email. The MHA staff member was an experienced mental health professional and received minimal training in administering the intervention. Results. All 10 participants completed the course within the 8 weeks. Post-treatment and two month follow-up questionnaires were completed by all participants. Mean within group effect sizes (Cohen's d) for the Generalized Anxiety Disorder 7 Item (GAD 7) and Patient Health Questionnaire 9 Item (PHQ-9) were large (i.e., > .80) and consistent with previous controlled research. The Course was also rated as highly acceptable with all 10 participants reporting it was worth their time and they would recommend it to a friend. Conclusions. These results provide support for the potential clinical utility of iCBT interventions and the acceptability and feasibility of employing non-governmental mental health organisations to deliver these treatments. However, further research is needed to examine the clinical efficacy and cost-effectiveness of delivering iCBT via such organisations. PMID- 24349898 TI - Fine motor deficits in reading disability and language impairment: same or different? AB - Several studies have found evidence of motor deficits in poor readers. There is no obvious reason for motor and literacy skills to go together, and it has been suggested that both deficits could be indicative of an underlying problem with cerebellar function and/or procedural learning. However, the picture is complicated by the fact that reading problems often co-occur with oral language impairments, which have also been linked with motor deficits. This raises the question of whether motor deficits characterise poor readers when language impairment has been accounted for - and vice versa. We considered these questions by assessing motor deficits associated with reading disability (RD) and language impairment (LI). A large community sample provided a subset of 9- to 10-year olds, selected to oversample children with reading and/or language difficulties, to give 37 children with comorbid LI + RD, 67 children with RD only, 32 children with LI only, and 117 typically-developing (TD) children with neither type of difficulty. These children were given four motor tasks that taxed speed, sequence, and imitation abilities to differing extents. Different patterns of results were found for the four motor tasks. There was no effect of RD or LI on two speeded fingertip tapping tasks, one of which involved sequencing of movements. LI, but not RD, was associated with problems in imitating hand positions and slowed performance on a speeded peg-moving task that required a precision grip. Fine motor deficits in poor readers may be more a function of language impairment than literacy problems. PMID- 24349899 TI - Diversity and distribution of extra-floral nectaries in the cerrado savanna vegetation of Brazil. AB - Aim. Throughout evolutionary history, plants and animals have evolved alongside one another. This is especially apparent when considering mutualistic relationships such as between plants with extra-floral nectaries (EFNs, glands on leaves or stems that secrete nectar) and the ants that visit them. Ants are attracted by the nectar and then protect the plant against destructive herbivores. The distribution of these plants is of particular interest, because it can provide insights into the evolutionary history of this unique trait and the plants that possess it. In this study, we investigated factors driving the distribution of woody plants with EFNs in the cerrado vegetation of Brazil. Location. Brazil Methods. We used a database detailing the incidence of 849 plant species at 367 cerrado sites throughout Brazil. We determined which species possessed EFNs and mapped their distributions. We tested for correlations between the proportion of EFN species at each site and (i) three environmental variables (mean annual temperature, mean annual precipitation, and the precipitation in the driest quarter of the year), (ii) a broad soil classification, and (iii) the total species diversity of each site. Results. We found a wide range in the proportion of EFN species at any one site (0-57%). However, whilst low diversity sites had wide variation in the number of EFN species, high diversity sites all had few EFN species. The proportion of EFN species was positively correlated with absolute latitude and negatively correlated with longitude. When accounting for total species diversity, the proportion of EFN species per site was negatively correlated with precipitation in the driest quarter of the year and positively correlated with temperature range. Main Conclusions. These results suggest either that herbivore pressure may be lower in drier sites, or that ants are not as dominant in these locations, or that plant lineages at these sites were unable to evolve EFNs. PMID- 24349900 TI - Differential roles of prostaglandin E-type receptors in activation of hypoxia inducible factor 1 by prostaglandin E1 in vascular-derived cells under non hypoxic conditions. AB - Prostaglandin E1 (PGE1), known pharmaceutically as alprostadil, has vasodilatory properties and is used widely in various clinical settings. In addition to acute vasodilatory properties, PGE1 may exert beneficial effects by altering protein expression of vascular cells. PGE1 is reported to be a potent stimulator of angiogenesis via upregulation of VEGF expression, which is under the control of the transcription factor hypoxia-inducible factor 1 (HIF-1). However, the molecular mechanisms behind the phenomenon are largely unknown. In the present study, we investigated the mechanism by which PGE1 induces HIF-1 activation and VEGF gene expression in human aortic smooth muscle cells (HASMCs) and human umbilical vein endothelial cells (HUVECs), both vascular-derived cells. HUVECs and HASMCs were treated with PGE1 at clinically relevant concentrations under 20% O2 conditions and HIF-1 protein expression was investigated. Expression of HIF- 1alpha protein and the HIF-1-downstream genes were low under 20% O2 conditions and increased in response to PGE1 treatment in both HUVECs and HASMCs in a dose- and time-dependent manner under 20% O2 conditions as comparable to exposure to 1% O2 conditions. Studies using EP-receptor-specific agonists and antagonists revealed that EP1 and EP3 are critical to PGE1-induced HIF-1 activation. In vitro vascular permeability assays using HUVECs indicated that PGE1 increased vascular permeability in HUVECs. Thus, we demonstrate that PGE1 induces HIF- 1alpha protein expression and HIF-1 activation under non-hypoxic conditions and also provide evidence that the activity of multiple signal transduction pathways downstream of EP1 and EP3 receptors is required for HIF-1 activation. PMID- 24349901 TI - Biotic, abiotic and management controls on methanol exchange above a temperate mountain grassland. AB - Methanol (CH3OH) fluxes were quantified above a managed temperate mountain grassland in the Stubai Valley (Tyrol, Austria) during the growing seasons 2008 and 2009. Half-hourly methanol fluxes were calculated by means of the virtual disjunct eddy covariance (vDEC) method using 3-dimensional wind data from a sonic anemometer and methanol volume mixing ratios measured with a proton-transfer reaction mass spectrometer (PTR-MS). During (undisturbed) mature and growing phases methanol fluxes exhibited a clear diurnal cycle with close-to-zero fluxes during nighttime and emissions, up to 10 nmol m-2 s-1, which followed the diurnal course of radiation and air temperature. Management events were found to represent the largest perturbations of methanol exchange at the studied grassland ecosystem: Peak emissions of 144.5 nmol m-2 s-1 were found during/after cutting of the meadow reflecting the wounding of the plant material and subsequent depletion of the leaf internal aqueous methanol pools. After the application of organic fertilizer, elevated methanol emissions of up to 26.7 nmol m-2 s-1 were observed, likely reflecting enhanced microbial activity associated with the applied manure. Simple and multiple linear regression analyses revealed air temperature and radiation as the dominant abiotic controls, jointly explaining 47 % and 70 % of the variability in half-hourly and daily methanol fluxes. In contrast to published leaf-level laboratory studies, the surface conductance and the daily change in the amount of green plant area, used as ecosystem-scale proxies for stomatal conductance and growth, respectively, were found to exert only minor biotic controls on methanol exchange. PMID- 24349902 TI - Influence of secondary structure on in-source decay of protein in matrix-assisted laser desorption/ionization mass spectrometry. AB - The susceptibility of the N-Calpha bond of the peptide backbone to specific cleavage by in-source decay (ISD) in matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) was studied from the standpoint of the secondary structure of three proteins. A naphthalene derivative, 5-amino-1-naphtol (5,1 ANL), was used as the matrix. The resulting c'-ions, which originate from the cleavage at N-Calpha bonds in flexible secondary structures such as turn and bend, and are free from intra-molecular hydrogen-bonded alpha-helix structure, gave relatively intense peaks. Furthermore, ISD spectra of the proteins showed that the N-Calpha bonds of specific amino acid residues, namely Gly-Xxx, Xxx-Asp, and Xxx-Asn, were more susceptible to MALDI-ISD than other amino acid residues. This is in agreement with the observation that Gly, Asp and Asn residues usually located in turns, rather than alpha-helix. The results obtained indicate that protein molecules embedded into the matrix crystal in the MALDI experiments maintain their secondary structures as determined by X-ray crystallography, and that MALDI-ISD has the capability for providing information concerning the secondary structure of protein. PMID- 24349903 TI - Matrix effect on in-source decay products of peptides in matrix-assisted laser desorption/ionization. AB - MALDI-ISD of peptides were studied using several salicylic acid derivatives, 2,5 dihydroxybenzoic acid (2,5-DHB), 5-aminosalicylic acid (5-ASA), 5-formylsalicylic acid (5-FSA), and 5-nitrosalicylic acid (5-NSA) as matrices. The difference in the nature of the functional group at the 5-position in the salicylic acid derivatives can dramatically affect the ISD products. The use of 2,5-DHB and 5 ASA leads to "hydrogen-abundant" peptide radicals and subsequent radical-induced N-Calpha bonds cleavage. N-Calpha bond cleavage gave a c'/z (.) fragment pair and radical z (.)-series fragments gain a hydrogen radical or react with a matrix radical. In contrast, the use of 5-NSA resulted in the production of a "hydrogen deficient" peptide radical that contained a radical site on the amide nitrogen in the peptide backbone. Subsequently, the radical site on the amide nitrogen induces Calpha-C bond dissociation, leading to a (.)/x fragment pair. The a (.) series ions undergo further hydrogen abstraction to form a-series ions after Calpha-C bond cleavage. Since the Pro residue does not contain a nitrogen centered radical site, Calpha-C bond cleavage does not occur. Alternatively, the specific cleavage of CO-N bonds leads to a b (.)/y fragment pair at Xxx-Pro which occurs via hydrogen abstraction from the Calpha-H in the Pro residue. The use of 5-FSA generated both a (.)/x- and c'/z (.)-series fragment pairs. An oxidizing matrix provides useful complementary information in MALDI-ISD compared to a reducing matrix for the analysis of amino acid sequencing and site localization in cases of phosphopeptides. MALDI-ISD, when used in conjunction with both reducing and oxidizing matrices is a potentially useful method for de novo peptide sequencing. PMID- 24349904 TI - In Situ Pressure Probe Sampling and UV-MALDI MS for Profiling Metabolites in Living Single Cells. AB - In this work we describe the use of a combination of a cell pressure probe and a UV-matrix-assisted laser desorption/ionization time of flight (UV-MALDI-TOF) mass spectrometer for the in situ picoliter sampling and shotgun metabolite profiling of living single cells of plants. In addition to quantifiable sampling, the pressure probe has some unique features which differentiate it from other single cell analytical tools. Cell wall and plasma membrane properties and water relations of in situ living single cells can be analyzed before sampling the cell sap. In addition, the fully-controlled sampling of cells located at different depths in plant tissues, measurement of the sample volume, and the addition of internal standards are facilitated by the pressure probe. Using a variety of organic compounds and nanoparticles as UV-MALDI matrices, metabolites from neutral carbohydrates to amino acids and other metabolites can be detected through UV-MALDI-TOF mass spectrometry analyses of picoliter-sized, single-cell samples. PMID- 24349906 TI - Hydrogen radical removal causes complex overlapping isotope patterns of aromatic carboxylic acids in negative-ion matrix-assisted laser desorption/ionization mass spectrometry. AB - We studied the ionization process of aromatic carboxylic acids, including ones with or without hydroxy groups in matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), because many natural products, metabolites, and drags contain those structural units. In the actual experimental data, benzoic acid was ionized as only deprotonated molecule [M-H](-). In contrast, both of negative molecular ion M(-) and deprotonated molecule [M-H](-) were generated from 2-naphthoic acid and 2-anthracenecarboxylic acid, and the ratio of negative molecular ion to deprotonated molecule M(-)/[M-H](-) was increased in 2 anthracenecarboxylic acid. In addition, the ratio of 2-anthracenecarboxylic acid was much higher than those of 1- and 9-anthracenecarboxylic acids among the three isomers. Therefore, 2-substitution induced the generation of the negative molecular ion M(-), which can made us prediction of the substituted positions from their overlapping peak isotope patterns. 2,5-Dihydroxybenzoic acid (2,5 DHBA) showed two deprotonated molecules, [M-H](-) and [M-H*-H](-), which was generated from a neutral hydrogen radical (H*) removal from a phenolic hydroxy group. The deprotonated molecule [M-H*-H](-) of 2,5-DHBA was the most abundant among six DHBAs and three hydroxybenzoic acids (hBAs). This observation raises the possibility that such a property of 2,5-DHBA could be a clue to explain its highest efficiency as a MALDI matrix. The order of the hydrogen radical removal from the phenolic hydroxy groups was the 3-<4-?5-positions in the DHBAs, and the 3-<4-positions in hBAs. We can distinguish among six DHBA isomers and three hBA isomers from their spectral pattern around the deprotonated molecules [M-H*-H](-) and [M-H](-). The intra-molecular hydrogen bonding between 1-carboxy and 2 hydroxy groups was an important factor in hydrogen radical removal in the hydroxylbenzoic acids and dihydroxybenzoic acids. PMID- 24349905 TI - Matrix-Assisted Laser Desorption/Ionization (MALDI) Imaging Mass Spectrometry (IMS): A Challenge for Reliable Quantitative Analyses. AB - Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is capable of determining the distribution of hundreds of molecules at once directly from tissue sections. Since tissues are analyzed intact without homogenization, spatial relationships of molecules are preserved. The technology is, therefore, undoubtedly powerful to investigate the molecular complexity of biological processes. However, several technical refinements are essential for full exploitation of MALDI-IMS to dictate dynamics alteration of biomolecules in situ; these include ways to collect tissues, target-specific tissue pretreatment, matrix choice for efficient ionization, and matrix deposition method to improve imaging resolution. Furthermore, for MALDI-IMS to reach its full potential, quantitative property in the IMS should be strengthened. We review the challenges and new approaches for optimal imaging of proteins, lipids and metabolites, highlighting a novel quantitative IMS of energy metabolites in the recent literature. PMID- 24349907 TI - Correlation between Sweet Spots of Glycopeptides and Polymorphism of the Matrix Crystal in MALDI Samples. AB - A standard dried-droplet preparation using 2,5-dihydroxybenzoic acid (2,5-DHBA) as the matrix results in a large variation in signal intensity and poor shot-to shot reproducibility in matrix-assisted laser desorption/ionization (MALDI). We expected that the differences can be attributed to the nature of the crystal structures in the region of the "sweet spot" within the MALDI samples. 2,5-DHBA crystals with and without analytes on a target plate obtained by means of a dried droplet preparation contain two polymorphs, which can be distinguished by Raman spectra. In comparing the Raman image with the MS image, a clear correlation between the signal distribution of glycopeptides and hydrophilic peptides and the specific crystal form of 2,5-DHBA could be made. The ionization of hydrophobic peptides appears to proceed in both types of polymorphic crystals. In addition, the derivatization of glycopeptides with a pyrene group enabled us to detect glycopeptides regardless the crystal form. As the result, the number of sweet spots increased and MS spectra with a high signal intensity were obtained. The results suggest that the introduction of a hydrophobic/aromatic moiety to glycopeptides results in a more successful MALDI analysis due to the effective incorporation of the analyte into matrix crystals. PMID- 24349908 TI - Flexible xxx-asp/asn and gly-xxx residues of equine cytochrome C in matrix assisted laser desorption/ionization in-source decay mass spectrometry. AB - The backbone flexibility of a protein has been studied from the standpoint of the susceptibility of amino acid residues to in-source decay (ISD) in matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS). Residues more susceptible to MALDI-ISD, namely Xxx-Asp/Asn and Gly-Xxx, were identified from the discontinuous intense peak of c'-ions originating from specific cleavage at N Calpha bonds of the backbone of equine cytochrome c. The identity of the residues susceptible to ISD was consistent with the known flexible backbone amides as estimated by hydrogen/deuterium exchange (HDX) experiments. The identity of these flexible amino acid residues (Asp, Asn, and Gly) is consistent with the fact that these residues are preferred in flexible secondary structure free from intramolecular hydrogen-bonded structures such as alpha-helix and beta-sheet. The MALDI-ISD spectrum of equine cytochrome c gave not only intense N-terminal side c'-ions originating from N-Calpha bond cleavage at Xxx-Asp/Asn and Gly-Xxx residues, but also C-terminal side complement z'-ions originating from the same cleavage sites. The present study implies that MALDI-ISD can give information about backbone flexibility of proteins, comparable with the protection factors estimated by HDX. PMID- 24349909 TI - Label-free analysis of o-glycosylation site-occupancy based on the signal intensity of glycopeptide/peptide ions. AB - Mucin-type O-glycosylation is a major posttranslational modification of proteins. The level of O-glycosylation at a site could be useful in terms of evaluating various disease conditions. To address the feasibility of measuring O glycosylation levels based on the glycopeptide ion intensity in a mass spectrum, apolipoprotein CIII (apoC3), a protein that contains a single core-1 O-glycan Gal GalNAc disaccharide was analyzed by matrix-assisted laser desorption ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS). The intensity of protonated ions for an equimolar mixture of desialylated and deglycosylated apoC3s were the same in linear TOF measurements. No substantial in-source decay, including the cleavage of the protein-sugar linkage was observed. The glycopeptide derived from apoC3 and the unglycosylated counterpart, when analyzed by MALDI reflectron TOF MS indicated that post-source decay was minimal. These collective findings demonstrate the feasibility of label-free quantitation of O-glycan occupancy by MS when the glycans are small and neutral. This method provides a tool for use in glycoproteomics as a complement of our previous report (DOI: 10.1021/pr900913k) for calculating the saccharide composition of O-glycans. PMID- 24349910 TI - Construction of a newly designed small-size mass spectrometer for helium isotope analysis: toward the continuous monitoring of (3)he/(4)he ratios in natural fluids. AB - The construction of a small-size, magnetic sector, single focusing mass spectrometer (He-MS) for the continuous, on-site monitoring of He isotope ratios ((3)He/(4)He) is described. The instrument is capable of measuring (4)He/(20)Ne ratios dissolved in several different types of natural fluids of geochemical interest, such as groundwater and gas from hot springs, volcanoes and gas well fields. The ion optics of He-MS was designed using an ion trajectory simulation program "TRIO," which permits the simultaneous measurement of (3)He and (4)He with a double collector system under a mass resolution power (M/DeltaM) of >700. The presently attained specifications of He-MS are; (1) a mass resolving power of ca. 430, sufficient to separate (3)He(+) from interfering ions, HD(+) and H3 (+), (2) ultra-high vacuum conditions down to 3*10(-8) Pa, and (3) a sufficiently high sensitivity to permit amounts of (3)He to be detected at levels as small as 10( 13) cm(3) STP (3*10(6) atoms). Long term stability for (3)He/(4)He analysis was examined by measuring the (3)He/(4)He standard gas (HESJ) and atmospheric He, resulting in ~3% reproducibility and <=5% experimental error for various amounts of atmospheric He from 0.3 to 2.3*10(-6) cm(3) STP introduced into the instrument. A dynamic range of measurable (3)He/(4)He ratios with He-MS is greater than 10(3) which was determined by measuring various types of natural fluid samples from continental gas (with a low (3)He/(4)He ratio down to 2*10( 8)) to volcanic gas (with a high (3)He/(4)He ratio up to 3*10(-5)). The accuracy and precision of (3)He/(4)He and (4)He/(20)Ne ratios were evaluated by comparing the values with those measured using well established noble gas mass spectrometers (modified VG5400/MS-III and -IV) in our laboratory, and were found to be in good agreement within analytical errors. Usefulness of the selective extraction of He from water/gas using a high permeability of He through a silica glass wall at high temperature (700 degrees C) is demonstrated. PMID- 24349911 TI - N (alpha) Selective Acetylation of Peptides. AB - A chemical tag at the peptide N-terminus, in combination with MS, can be useful for quantitative analysis, N-terminal peptide identification, or peptide sequencing. Here we report on the N (alpha) selective acetylation of a peptide using acetic anhydride, a popular reagent for the modification of amino groups, without the need for the blocking of lysine side-chain epsilon-amino groups, which is usually required for N (alpha) selective acetylation. By controlling the amount of acetic anhydride used and running the reaction at 0 degrees C, it is possible to preferentially acetylate the alpha-amino group. As a typical application of the method, a tryptic digest of an N-terminally blocked protein, cytochrome c, was directly acetylated using the present method. When deuterated acetic anhydride was used as the reagent, the N-terminal blocked peptide could be easily identified as a non-labeled ion peak while the N (alpha)-acetyl groups of all the other peptides were deuterated. PMID- 24349912 TI - In-Situ U-Pb Dating of Apatite by Hiroshima-SHRIMP: Contributions to Earth and Planetary Science. AB - The Sensitive High Resolution Ion MicroProbe (SHRIMP) is the first ion microprobe dedicated to geological isotopic analyses, especially in-situ analyses related to the geochronology of zircon. Such a sophisticated ion probe, which can attain a high sensitivity at a high mass resolution, based on a double focusing high mass resolution spectrometer, designed by Matsuda (1974), was constructed at the Australian National University. In 1996, such an instrument was installed at Hiroshima University and was the first SHRIMP to be installed in Japan. Since its installation, our focus has been on the in-situ U-Pb dating of the mineral apatite, as well as zircon, which is a more common U-bearing mineral. This provides the possibility for extending the use of in-situ U-Pb dating from determining the age of formation of volcanic, granitic, sedimentary and metamorphic minerals to the direct determination of the diagenetic age of fossils and/or the crystallization age of various meteorites, which can provide new insights into the thermal history on the Earth and/or the Solar System. In this paper, we review the methodology associated with in-situ apatite dating and our contribution to Earth and Planetary Science over the past 16 years. PMID- 24349913 TI - Correlations between Chemical Compositions and Retention Times of Methacrylate Random Copolymers Using LC-ESI-MS. AB - Correlations between chemical compositions and chromatographic retention times (Rt) of methacrylate random copolymers were studied by liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS). Twenty-six different polymers including homopolymers of poly(methyl methacrylate) (PMMA), poly(tert butyl methacrylate) (PTBMA) and poly(2-hydroxyethyl methacrylate) (PHEMA), and their random copolymers of P(MMA-TBMA) and P(MMA-HEMA) with known chemical compositions were studied. The results indicate that there is close correlations between the chemical compositions of the random copolymers and their Rt of the C8 column in the mass spectral ranges of m/z 1,800-2,000. The LC-ESI-MS analysis showed molecular weights of the copolymers distribute in the mass range of ca. 500-20,000, and the structures of polymer terminals and their monomer units can be identified. PMID- 24349914 TI - Mass Spectrometry Imaging and Structural Analysis of Lipids Directly on Tissue Specimens by Using a Spiral Orbit Type Tandem Time-of-Flight Mass Spectrometer, SpiralTOF-TOF. AB - In this paper, we report the use of mass spectrometry imaging and structural analysis of lipids directly on a tissue specimen, carried out by means of matrix assisted laser desorption/ionization tandem time-of-flight mass spectrometry, using a combination of spiral orbit-type and reflectron-type time-of-flight mass spectrometers. The most intense peak observed in the mass spectrum from a brain tissue specimen was confirmed as phosphatidylcholine (34 : 1) [M+K](+), using tandem mass spectrometry. The charge remote fragmentation channels, which are characteristically observed using high-energy collision-induced dissociation, contributed significantly to this confirmation. Accurate mass analysis was further facilitated by mass correction using the confirmed peak. In mass spectrometry imaging, the high resolving power of our system could separate doublet peak of less than 0.1 u difference, which would otherwise be problematic when using a low-resolution reflectron type time-of-flight mass spectrometer. Two compounds, observed at m/z 848.56 and 848.65, were found to be located in complementary positions on a brain tissue specimen. These results demonstrate the importance of a high-performance tandem time-of-flight mass spectrometer for mass spectrometry imaging and analysis of observed compounds, to allow distinction between biological molecules. PMID- 24349915 TI - Application of High-Resolution MALDI-TOFMS with a Spiral Ion Trajectory for the Structural Characterization of Free Radical Polymerized Methacrylate Ester Copolymers. AB - The structural characterization of copolymers by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) remains a challenging task, since their random comonomer distribution creates very complicated mass spectra. In this study, a high-resolution TOF mass spectrometer with a spiral ion trajectory was applied to the structural and compositional characterization of free radical copolymerized poly(methyl methacrylate-co-tert butyl methacrylate), poly(MMA-co-tBMA)s in ethyl lactate acting as a chain transfer agent. Virtually complete peak assignments of the isobaric components within the poly(MMA-co-tBMA)s served to identify the end-group combinations and copolymer compositions of individual copolymer components, allowing the distributions of comonomer compositions and six types of end-group combinations to be evaluated. PMID- 24349916 TI - Cluster composition distributions of pure ethanol: influence of water and ion molecule reactions revealed by liquid-ionization tandem mass spectrometry. AB - Studies of clusters in condensed phase at atmospheric pressure are very important for understanding the properties and structures of liquids. Liquid-ionization (LPI) mass spectrometry is useful to study hydrogen-bonded clusters at the liquid surface and in a gas phase. An improved ion source connected to a tandem mass spectrometer provides detailed information about clusters. Mass spectra of pure ethanol (99.5%) observed by the first mass analyzer (Q1) showed neat ethanol cluster ions (C2H5OH) m H(+) with m up to 10 and hydrate ions (C2H5OH) m (H2O) n H(+) with m larger than 7 and n=1, such as those with m-n=8-1 and 9-1. When the flow rate of ethanol (liquid) was increased, large ethanol cluster ions with m larger than 25 were observed by the second mass analyzer (Q3). It is interesting to note that neat ethanol cluster ions are more abundant than corresponding (with the same m) hydrate ions (n=1), and major hydrate ions contain only one molecule of water. Results indicate that ion-molecule reactions occur between Q1 and Q3, because such mass spectra have never been observed by Q1. Various results indicate that neat ethanol clusters exist at the liquid surface and are ionized to give cluster ions. PMID- 24349917 TI - The pH Dependence of Product Ion Spectra Obtained from Precursor Ions with the Same Charge Number in ESI of Carbonic Anhydrase 2. AB - The effect of solvent conditions, including pH, on product ion spectra obtained from precursor ions produced by electrospray ionization (ESI) was examined. Bovine carbonic anhydrase 2 was used as a model protein and the product ions generated by collision induced dissociation of the whole protein were measured under several different solvent conditions (pH 5.0, 3.7, and 0.1% HCOOH (pH 2.6)/MeCN (1/1)). The product ion spectra from precursor ions with the same charge number, the observed m/z values and the relative intensities of the product ions were similar. It therefore appears that the solvent conditions used have no effect on the product ion that is generated. On the other hand, different profiles of the product ion were obtained from precursor ions having different charge numbers. This indicates that the charge number of the precursor ion appears to be a major determinant of the product ion species and its relative intensity in product ion spectra of proteins. PMID- 24349918 TI - Editorial. PMID- 24349919 TI - Foreword. PMID- 24349920 TI - Through a glass darkly: glimpses into the future of mass spectrometry. AB - The paper has three parts, (i) a brief overview of the main achievements made using mass spectrometry across all the fields of science, (ii) a survey of some of the topics currently being pursued most activity, including both applications and fundamental studies, and (iii) some hints as to what the future of mass spectrometry might hold with particular emphasis on revolutionary changes in the subject. Emphasis is given to ambient methods of ionization and their use in disease diagnosis and to their use in combination with miniature mass spectrometers for in-situ measurements. Special attention goes to the chemical aspects of mass spectrometry, including its emerging role as a preparative method based on accelerated bimolecular reaction rates in solution and on ion soft landing as a means of surface tailoring. In summary, the paper covers the proud history, vibrant present and expansive future of mass spectrometry. PMID- 24349921 TI - Selected examples of gas-phase ion chemistry studies. AB - Gas-phase ion chemistry is an area in mass spectrometry that has received much research interest since the mid fifties of the last century. Although the focus of mass spectrometric research has shifted the last twenty years largely to life science studies, including proteomics, genomics and metabolomics, there are still several groups in the world active in gas-phase ion chemistry of both positive and negative ions, either unimolecularly and/or bimolecularly. In this tutorial lecture the formation and determination of tautomeric ion structures and intra ionic catalyzed tautomerization in the gas phase will be discussed. In addition, an example of formation of different tautomeric structures in protic and aprotic solvents under electrospray ionization conditions will be given, as established by gas-phase infrared multiphoton dissociation spectroscopy. This will be followed by presenting an example of time-resolved MS/MS which enables to identify the structure of an ion, generated at a particular molecular ion lifetime. At the end of the lecture the power of ion mobility will be shown in elucidating the mechanism of epimerization of bis-Troger bases having chiral nitrogen centers. PMID- 24349922 TI - Renaissance of cation-radicals in mass spectrometry. AB - This brief overview addresses the topic that was presented in the Thomson Medal Award session at the 19th International Mass Spectrometry Conference in Kyoto, Japan. Mass spectrometry of cation-radicals has enjoyed a remarkable renaissance thanks to the development of new methods for electron attachment to multiply charged peptide ions. The charge-reduced ions that are odd-electron species exhibit interesting reactivity that is useful for peptide and protein sequencing. The paper briefly reviews the fundamental aspects of the formation, energetics, and backbone dissociations of peptide cation-radicals. PMID- 24349923 TI - Peptide radical cations: gender determines dissociation chemistry. AB - Peptide radicals play a significant role in biology as well as mass spectrometry. They can be differentiated into two groups: conventional hydrogen-deficient radicals, e.g. M(+*) as in electron ionization, and much more rare hydrogen abundant radicals, e.g. [M+2H](+*), as in electron capture/transfer dissociation. The dissociation chemistries of these two types of radicals are vastly different. Both types tend to lose small molecules or radical groups, but the overlap between the losses from different radical types is minimal. The backbone cleavage for hydrogen-deficient radicals is dominated by Calpha-C cleavage (a (*), x fragments) and for hydrogen-abundant radicals-by N-Calpha cleavage (c, z (*) ions). The latter types of fragmentation produces more sequencing information than the former. Therefore, hydrogen-abundant peptide radicals are more valuable in mass spectrometry. The efficiency of the main method of their production, electron capture/transfer dissociation, is however limited by charge reduction. Alternative methods of generation of hydrogen-abundant radicals are needed to improve the sequencing capabilities of mass spectrometry. PMID- 24349924 TI - Thermochemistry of non-covalent ion-molecule interactions. AB - The thermochemistry of non-covalent ion-molecule complexes has been examined by measuring quantitative bond dissociation energies using threshold collision induced dissociation in guided ion beam tandem mass spectrometers (GIBMS). The methods used are briefly reviewed and several examples of the types of information and insight that can be obtained from such thermodynamic information are discussed. The hydration of metal cations, both singly and doubly charged, is reviewed and the trends elucidated, mainly on the basis of electrostatic contributions. The binding of alkali metal cations to amino acids has been examined for a range of systems, with both the overall polarizability of the amino acid and the local dipole moment of heteroatomic side-chains shown to be important contributors. The gas-phase interactions of the 12-crown-4 (12C4) polyether with alkali metal cations, classic molecular recognition systems in solution, have been newly compared to previous GIBMS work. These results validate the previous hypothesis that excited conformers were present for Rb(+)(12C4) and Cs(+)(12C4) and offer clues as to how and why they are formed. PMID- 24349925 TI - MALDI and Related Methods: A Solved Problem or Still a Mystery? AB - MALDI ionization mechanisms remain a topic of controversy. Some of the major modern models are compared, with emphasis on those of the author. Primary formation, secondary reaction, and loss mechanisms are considered. PMID- 24349926 TI - What Is the Opposite of Pandora's Box? Direct Analysis, Ambient Ionization, and a New Generation of Atmospheric Pressure Ion Sources. AB - The introduction of DART and DESI sources approximately seven years ago led to the development of a new series of atmospheric pressure ion sources referred to as "ambient ionization" sources. These fall into two major categories: spray techniques like DESI or plasma techniques like DART. The selectivity of "direct ionization," meaning analysis without chromatography and with little or no sample preparation, depends on the mass spectrometer selectivity. Although high resolution and tandem mass spectrometry are valuable tools, rapid and simple sample preparation methods can improve the utility of ambient ionization methods. The concept of ambient ionization has led to the realization that there are many more ways to form ions than might be expected. An interesting example is the use of a flint-and-steel spark source to generate ions from compounds such as phenolphthalein and Gramicidin S. PMID- 24349927 TI - Trace level detection of explosives in solution using leidenfrost phenomenon assisted thermal desorption ambient mass spectrometry. AB - The present paper demonstrates the detection of explosives in solution using thermal desorption technique at a temperature higher than Leidenfrost temperature of the solvent in combination with low temperature plasma (LTP) ionization. Leidenfrost temperature of a solvent is the temperature above which the solvent droplet starts levitation instead of splashing when placed on a hot metallic surface. During this desorption process, slow and gentle solvent evaporation takes place, which leads to the pre-concentration of less-volatile explosive molecules in the droplet and the explosive molecules are released at the last moment of droplet evaporation. The limits of detection for explosives studied by using this thermal desorption LTP ionization method varied in a range of 1 to 10 parts per billion (ppb) using a droplet volume of 20 MUL (absolute sample amount 90-630 fmol). As LTP ionization method was applied and ion-molecule reactions took place in ambient atmosphere, various ion-molecule adduct species like [M+NO2](-), [M+NO3](-), [M+HCO3](-), [M+HCO4](-) were generated together with [M H](-) peak. Each peak was unambiguously identified using 'Exactive Orbitrap' mass spectrometer in negative ionization mode within 3 ppm deviation compared to its exact mass. This newly developed technique was successfully applied to detect four explosives contained in the pond water and soil sample with minor sample pre treatment and the explosives were detected with ppb levels. The present method is simple, rapid and can detect trace levels of explosives with high specificity from solutions. PMID- 24349928 TI - Mass resolution and mass accuracy: how much is enough? AB - Accurate mass measurement requires the highest possible mass resolution, to ensure that only a single elemental composition contributes to the mass spectral peak in question. Although mass resolution is conventionally defined as the closest distinguishable separation between two peaks of equal height and width, the required mass resolving power can be ~10* higher for equal width peaks whose peak height ratio is 100 : 1. Ergo, minimum resolving power requires specification of maximum dynamic range, and is thus 10-100* higher than the conventional definition. Mass resolving power also depends on mass-to-charge ratio. Mass accuracy depends on mass spectral signal-to-noise ratio and digital resolution. Finally, the reliability of elemental composition assignment can be improved by resolution of isotopic fine structure. Thus, the answer to the question of "how much is enough mass resolving power" requires that one first specify S/N ratio, dynamic range, digital resolution, mass-to-charge ratio, and (if available) isotopic fine structure. The highest available broadband mass resolving power and mass accuracy is from Fourier transform ion cyclotron resonance mass spectrometry. Over the past five years, FT-ICR MS mass accuracy has improved by about an order of magnitude, based on higher magnetic field strength, conditional averaging of time-domain transients, better mass calibration (spectral segmentation; inclusion of a space charge term); radially dispersed excitation; phase correction to yield absorption-mode display; and new ICR cell segmentation designs. PMID- 24349929 TI - From Supercomputer Modeling to Highest Mass Resolution in FT-ICR. AB - Understanding of behavior of ion ensembles inside FT-ICR cell based on the computer simulation of ion motion gives rise to the new ideas of cell designs. The recently introduced novel FT-ICR cell based on a Penning ion trap with specially shaped excitation and detection electrodes prevents distortion of ion cyclotron motion phases (normally caused by non-ideal electric trapping fields) by averaging the trapping DC electric field during the ion motion in the ICR cell. Detection times of 5 min resulting in resolving power close to 40,000,000 have been reached for reserpine at m/z 609 at a magnetic field of only 7 Tesla. Fine structures of resolved 13Cn isotopic cluster groups could be measured for molecular masses up to 5.7 kDa (insulin) with resolving power of 4,000,000 at 7 Tesla. Based on resolved fine structure patterns atomic compositions can be directly determined using a new developed algorithm for fine structure processing. Mass spectra of proteins and multimers of proteins reaching masses up to 186 kDa (enolase tetramer) could be measured with isotopic resolution. For instance, at 7 Tesla resolving power of 800,000 was achieved for enolase dimer (96 kDa) and 500,000 for molecular masses above 100 kDa. Experimental data indicate that there is practically no limit for the resolving power of this ICR cell except by collisional damping in the ultrahigh vacuum chamber. PMID- 24349930 TI - Pushing the Frontier of High-Definition Ion Mobility Spectrometry Using FAIMS. AB - Differential ion mobility spectrometry (FAIMS) separates ions in gases based on the difference between their mobilities in strong and weak electric fields, captured directly employing a periodic waveform with dissimilar profiles in opposite polarities. As that difference is not tightly correlated with the ion size or mass, FAIMS separations are generally quite orthogonal to both conventional IMS (based on the absolute ion mobility that reflects the physical ion size) and mass spectrometry (based on mass). Until a few years ago, that advantage was largely offset by poor FAIMS resolving power (~10-20), an order of magnitude below that achieved with conventional (drift-tube) IMS. This article summarizes the major recent technical developments that have raised FAIMS resolving power up to ~500. These include use of higher and more stable voltages provided by new waveform generators, novel buffer gas compositions comprising high helium or hydrogen fractions, and extended filtering times up to ~1 s. These advances have enabled previously unthinkable analyses such as broad baseline separations of peptide sequence inversions, localization variants (post translationally modified peptides with differing PTM attachment sites) even for the larger "middle-down" peptides and smallest PTMs, and lipid regioisomers. PMID- 24349931 TI - Cold-spray ionization mass spectrometry: applications in structural coordination chemistry. AB - Electrospray ionization (ESI)-mass spectrometry (MS) is generally used for the characterization of labile supramolecules in which non-covalent bonding interactions are predominant. However, molecular ions are not detected in many cases because of their instability, and even if such ions are detected, thermal decomposition generates fragment ions that also appear in the mass spectrum. Cold spray ionization (CSI) is designed for the MS detection of labile organic species. It is used to analyze the structures of biomolecular complexes and labile organic species in solution. The method, a variant of ESI-MS, operates at low temperature, allowing simple and precise characterization of labile non covalent complexes that are difficult or impossible to observe by conventional MS techniques. The CSI method is particularly suitable for elucidating the structures of labile organometallic compounds in solution as it offers a means to investigate the dynamic behavior of unstable molecules and/or labile clusters in solution. Various labile organic compounds are analyzed by using the CSI method in the field of organic chemistry. CSI-MS is also used to investigate the behavior of aggregated steroid compounds, namely, bisguanidinobenzene-benzoic acid complexes, in solution. This method is a powerful tool for analyzing the equilibria of multiply linked self-assembling catenanes in solution. Its application to unstable and complex supramolecules will be shown. We have developed an effective ionization method that uses metal-complex-based ionization probes containing 2,6-bis(oxazolinyl) pyridine (pybox) ligands. Using this method, we were able to detect multiply charged ions of target molecules. This method was proven to effectively ionize large complex molecules, including biomolecules and various supramolecules, as well as carbon clusters, such as fullerenes. Moreover, isotope-labeled pybox-La complexes were used to clearly detect isotopic labeling shifts. Their applications to multiply charged ionization, including isotope labeling of biomolecules and carbon clusters using CSI-MS, will be shown. PMID- 24349932 TI - Integrating Native Mass Spectrometry and Top-Down MS for Defining Protein Interactions Important in Biology and Medicine. AB - Native protein mass spectrometry (MS), the measurement of proteins and protein complexes from non-denaturing solutions, with electrospray ionization (ESI) has utility in the biological sciences. Protein complexes exceeding 1 MDa have been measured by MS and ion mobility spectrometry (IMS), and the data yields information not only regarding size, but structural details can be revealed also. ESI-IMS allows the relative stability of protein-ligand binding to be measured. Top-down MS, the direct dissociation of the intact gas phase biomolecule, can generate sequence and identity information for monomeric (denatured) proteins, and topology information for noncovalent protein complexes. For protein complexes with small molecule ligands, i.e., drugs, cofactors, metals, etc., top-down MS with electron capture dissociation can be used to elucidate the site(s) of ligand binding. Increasing protein ESI charging, e.g., supercharging, enhances the efficiency for dissociation of protein complexes. PMID- 24349933 TI - Image and Spectral Processing for ToF-SIMS Analysis of Biological Materials. AB - Time-of-flight secondary ion mass spectrometry (ToF-SIMS) instruments can rapidly produce large complex data sets. Within each spectrum, there can be hundreds of peaks. A typical 256*256 pixel image contains 65,536 spectra. If this is extended to a 3D image, the number of spectra in a given data set can reach the millions. The challenge becomes how to process these large data sets while taking into account the changes and differences between all the peaks in the spectra. This is particularly challenging for biological materials that all contain the same types of proteins and lipids, just in varying concentrations and spatial distributions. This data analysis challenge is further complicated by the limitations in the ion yield of higher mass, more chemically specific species, and potentially by the processing power of typical computers. Herein we briefly discuss analysis methodologies including univariate analysis, multivariate analysis (MVA) methods, and some of the limitations of ToF-SIMS analysis of biological materials. PMID- 24349934 TI - Functional group selective derivatization and gas-phase fragmentation reactions of plasmalogen glycerophospholipids. AB - A reaction strategy involving functional group selective modification of the O alkenyl-ether double bond within plasmenyl ether containing lipids using iodine and methanol, in conjunction with functional group selective derivatization of amine-containing lipids using a novel (13)C1-S,S' dimethylthiobutanoylhydroxysuccinimide ester ((13)C1-DMBNHS) reagent, is shown to improve the capabilities of 'shotgun' high resolution/accurate mass spectrometry for comprehensive lipidome analysis. Importantly, the characteristic mass shifts introduced as a result of these derivatization reactions enables the resolution and unambiguous identification of isobaric mass plasmenyl- and plasmanyl-ether containing lipid species from within crude complex lipid extracts, without need for chromatographic fractionation or additional lipid extraction steps prior to analysis. Additionally, the positive ionization mode tandem mass spectrometry fragmentation behavior of the derivatized plasmenyl ether containing glycerophosphocholine and glycerophosphoethanolamine lipids are shown to yield abundant characteristic product ions that directly enable the assignment of their molecular lipid identities. PMID- 24349935 TI - Is high throughput glycomics possible? AB - The role of glycosylation and their biological functions whether as free oligosaccharides or glycoconjugates has been made possible by the recent advancements in the analyses of these compounds. The heterogeneity and the large structural diversity have made oligosaccharide analysis significantly more difficult than other biopolymers. The next stage of development is to achieve high throughput analysis. However, the structural elucidation of oligosaccharides remains an extremely difficult task. Recent reports reveal that the diversity of structures in a given biological system is finite and may not be large. It may be possible to create a database of structures that can be used to determine the identity of known compounds. This capability would therefore make high throughput glycomics possible. Achieving this task depends on the proper selection of chemical characteristics to identify the compound. In this presentation, nanoflow liquid chromatography retention times, accurate mass, and tandem MS is used to determine structure with a high degree of certainty. The method is used to determine the biological function of milk oligosaccharides as well as to discover glycan-based biomarkers for diseases. PMID- 24349936 TI - Correlation between Serum Levels of Protein-Bound Uremic Toxins in Hemodialysis Patients Measured by LC/MS/MS. AB - Uremic toxins are involved in a variety of symptoms in advanced chronic kidney disease. Especially, the accumulation of protein-bound uremic toxins in the blood of dialysis patients might play an important role in the development of cardiovascular disease. Serum concentration of protein-bound uremic toxins such as indoxyl sulfate, indoxyl glucuronide, indoleacetic acid, p-cresyl sulfate, p cresyl glucuronide, phenyl sulfate, phenyl glucuronide, phenylacetic acid, phenylacetylglutamine, hippuric acid, 4-ethylphenyl sulfate, and 3-carboxy-4 methyl-5-propyl-2-furanpropionic acid (CMPF) in hemodialysis patients were simultaneously measured by liquid chromatography/tandem mass spectrometry. Serum levels of these protein-bound uremic toxins were increased in hemodialysis patients. Indoxyl sulfate, p-cresyl sulfate, and CMPF could not be removed efficiently by hemodialysis due to their high protein-binding ratios. Serum level of total indoxyl sulfate did not show any significant correlation with total p cresyl sulfate. However, free indoxyl sulfate correlated with free p-cresyl sulfate, and reduction rate by hemodialysis of indoxyl sulfate correlated with that of p-cresyl sulfate. Serum levels of total and free indoxyl sulfate showed significantly positive correlation with those of indoxyl glucuronide, phenyl sulfate, and phenyl glucuronide. Serum levels of total and free p-cresyl sulfate showed significantly positive correlation with those of p-cresyl glucuronide, phenylacetylglutamine, and phenylacetic acid. Indoxyl sulfate and indoxyl glucuronide are produced from indole which is produced in the intestine from tryptophan by intestinal bacteria. p-Cresyl sulfate and p-cresyl glucuronide are produced from p-cresol which is produced in the intestine from tyrosine by intestinal bacteria. Thus, intestinal bacteria play an important role in the metabolism of protein-bound uremic toxins. PMID- 24349937 TI - Powerful GC-TOF-MS Techniques for Screening, Identification and Quantification of Halogenated Natural Products. AB - Comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry (GC*GC TOFMS) and gas chromatography/high-resolution time-of-flight mass spectrometry (GC-HRT) were used to detect and identify halogenated natural products (HNPs) in tissue homogenate, in this case brominated analytes present in a marine snail. Two classes of brominated anthropogenic compounds, polybrominated diphenyl ethers (PBDEs) and brominated dibenzofurans, were analyzed for comparison. Following conventional preparation, the sample was analyzed using GC*GC-TOF-MS. Isotope ratio scripts were used to compile a list of putatively brominated analytes from amongst the thousands of features resolved in the two dimensional chromatogram. The structured nature of the chromatogram was exploited to propose identifications for several classes of brominated compounds, and include additional candidates that fell marginally outside the script tolerances. The sample was subsequently analyzed by GC-HRT. The high-resolution mass spectral data confirmed many formula assignments, facilitated confident assignment of an alternate formula when an original proposal did not hold, and enabled unknown identification. Identified HNPs include hydroxylated and methoxylated PBDE analogs, polybrominated dibenzo-p-dioxins (PBDDs) and hydroxyl-PBDDs, permitting the environmental occurrence and fate of such compounds to be studied. PMID- 24349938 TI - Chiral chemicals as tracers of atmospheric sources and fate processes in a world of changing climate. AB - Elimination of persistent organic pollutants (POPs) under national and international regulations reduces "primary" emissions, but "secondary" emissions continue from residues deposited in soil, water, ice and vegetation during former years of usage. In a future, secondary source controlled world, POPs will follow the carbon cycle and biogeochemical processes will determine their transport, accumulation and fate. Climate change is likely to affect mobilisation of POPs through e.g., increased temperature, altered precipitation and wind patterns, flooding, loss of ice cover in polar regions, melting glaciers, and changes in soil and water microbiology which affect degradation and transformation. Chiral compounds offer advantages for following transport and fate pathways because of their ability to distinguish racemic (newly released or protected from microbial attack) and nonracemic (microbially degraded) sources. This paper discusses the rationale for this approach and suggests applications where chiral POPs could aid investigation of climate-mediated exchange and degradation processes. Multiyear measurements of two chiral POPs, trans-chlordane and alpha-HCH, at a Canadian Arctic air monitoring station show enantiomer compositions which cycle seasonally, suggesting varying source contributions which may be under climatic control. Large-scale shifts in the enantioselective metabolism of chiral POPs in soil and water might influence the enantiomer composition of atmospheric residues, and it would be advantageous to include enantiospecific analysis in POPs monitoring programs. PMID- 24349939 TI - Advances in isotope ratio mass spectrometry and required isotope reference materials. AB - The article gives a condensed version of the keynote lecture held at the International Mass Spectrometry Conference 2012 in Kyoto. Starting with some examples for isotope research the key requirements for metrologically valid procedures enabling traceable and comparable isotope data are discussed. Of course multi-collector mass spectrometers are required which offer sufficiently high isotope ratio precision for the intended research work. Following this, corrections for mass fractionation/discrimination, validation of the analytical procedure including chemical sample preparation and complete uncertainty budgets are the most important issues for obtaining a metrologically valid procedure for isotope ratio determination. Only the application of such metrologically valid procedures enables the generation of traceable and comparable isotope data. To realize this suitable isotope and/or delta-reference materials are required, which currently are not sufficiently available for most isotope systems. Boron is given as an example, for which the situation regarding isotope and delta reference materials is excellent. Boron may therefore serve as prototype for other isotope systems. PMID- 24349940 TI - Extractive electrospray ionization mass spectrometry for uranium chemistry studies. AB - Uranium chemistry is of sustainable interest. Breakthroughs in uranium studies make serious impacts in many fields including chemistry, physics, energy and biology, because uranium plays fundamentally important roles in these fields. Substantial progress in uranium studies normally requires development of novel analytical tools. Extractive electrospray ionization mass spectrometry (EESI-MS) is a sensitive technique for trace detection of various analytes in complex matrices without sample pretreatment. EESI-MS shows excellent performance for monitoring uranium species in various samples at trace levels since it tolerates extremely complex matrices. Therefore, EESI-MS is an alternative choice for studying uranium chemistry, especially when it combines ion trap mass spectrometry. In this presentation, three examples of EESI-MS for uranium chemistry studies will be given, illustrating the potential applications of EESI MS in synthesis chemistry, physical chemistry, and analytical chemistry of uranium. More specifically, case studies on EESI-MS for synthesis and characterization of novel uranium species, and for rapid detection of uranium and its isotope ratios in various samples will be presented. Novel methods based on EESI-MS for screening uranium ores and radioactive iodine-129 will be presented. PMID- 24349941 TI - MALDI Imaging Mass Spectrometry-A Mini Review of Methods and Recent Developments. AB - As the only imaging method available, Imaging Mass Spectrometry (IMS) can determine both the identity and the distribution of hundreds of molecules on tissue sections, all in one single run. IMS is becoming an established research technology, and due to recent technical and methodological improvements the interest in this technology is increasing steadily and within a wide range of scientific fields. Of the different IMS methods available, matrix-assisted laser desorption/ionization (MALDI) IMS is the most commonly employed. The course at IMSC 2012 in Kyoto covered the fundamental principles and techniques of MALDI IMS, assuming no previous experience in IMS. This mini review summarizes the content of the one-day course and describes some of the most recent work performed within this research field. PMID- 24349943 TI - Pangola grass as forage for ruminant animals: a review. AB - This review focuses on the introduction and investigation of pangola grass as a tropical forage species especially in Thailand. Pangola grass (Digitaria eriantha Steud., synonym D. decumbens) is one of recent examples of grasses that have been successfully introduced to Southeast Asia and is often considered as one of the highest quality tropical grasses popularly grown as pasture. Pangola grass is utilized extensively as grass for animal grazing, hay and silage making. Its crude protein content is commonly in the order of 5 to 14% of dry matter and may exceed 15% of dry matter with young regrowth under high fertilization. It has been documented that the type and number of ruminants receiving pangola grass can determine the success of its use. Results obtained when pangola grass in fresh, hay or silage form was fed to ruminant animals as supplements showed better performances in body weight gain, feed conversion ratio, carcass yield, meat quality, and milk yield and composition. In conclusion, pangola grass is a promising forage and a source of high quality feed for ruminant animals in tropical countries. PMID- 24349944 TI - Evaluation of rhizosphere, rhizoplane and phyllosphere bacteria and fungi isolated from rice in Kenya for plant growth promoters. AB - Rice (Oryza sativa L.) is the most important staple food crop in many developing countries, and is ranked third in Kenya after maize and wheat. Continuous cropping without replenishing soil nutrients is a major problem in Kenya resulting to declining soil fertility. The use of chemical fertilizers to avert the problem of low soil fertility is currently limited due to rising costs and environmental concerns. Many soil micro-organisms are able to solubilize the unavailable phosphorus, increase uptake of nitrogen and also synthesize growth promoting hormones including auxin. The aim of this study was to isolate and characterize phyllosphere, rhizoplane and rhizosphere micro-organisms from Kenyan rice with growth promoting habits. In this study whole plant rice samples were collected from different rice growing regions of Kenya. 76.2%, over 80% and 38.5% of the bacterial isolates were positive for phosphate solubilization, nitrogenase activity and IAA production whereas 17.5% and 5% of the fungal isolates were positive for phosphate solubilization and IAA production respectively. Hence these micro-organisms have potential for utilization as bio-fertilizers in rice production. PMID- 24349942 TI - P2X receptors in neuroglia. AB - Different types of ionotropic P2X purinoceptors are expressed in all major types of neuroglia, where they mediate a variety of physiological and pathological signaling. Cortical astrocytes express specific P2X1/5 heteromeric receptors that are activated by ongoing synaptic transmission and can trigger fast local signaling through elevation in cytoplasmic Ca2+ and Na+ concentrations. Oligodendrocytes express several types of P2X receptors that may control their development and mediate axonal-glial interactions. In microglia, P2X4 and P2X7 receptors regulate numerous events associated with microglial activation, motility, and release of proinflammatory factors. PMID- 24349945 TI - Complementary pharmacokinetic measures to further define the profile of once daily OROS hydromorphone ER during single-dose and steady-state dosing. AB - Conventional measures such as maximum plasma concentration (C max ) and area under the concentration versus time curve (AUC) may be insufficient to fully describe the pharmacokinetic (PK) profile of extended-release (ER) formulations. A complementary measure, the half-value duration (HVD), corresponds to the period of time during a dosing cycle that plasma concentration is at or above half the value of the maximal concentration (i.e. >=50% C max ). The current post-hoc analysis uses data from 2 previously published studies comparing the PK profiles and HVD of OROS hydromorphone ER (16 mg administered once daily) and immediate release (IR) hydromorphone (4 mg administered every 6 hours), calculating single dose and steady-state condition values. Bioequivalence was demonstrated between the 2 formulations. Mean steady-state once-daily OROS hydromorphone ER concentrations were elevated for most of the 24-hour dosing period and for significantly longer than with the dose-equivalent IR hydromorphone regimen. The duration of time spent >=50% C max was, on average, 2.7 times longer at steady state for the ER formulation, which also maintained steady-state hydromorphone plasma concentrations, with 65% lower mean degree of fluctuation versus IR hydromorphone. Both formulations appeared to be well tolerated. PMID- 24349946 TI - Cryptococcus spp. isolation from excreta of pigeons (Columba livia) in and around Monterrey, Mexico. AB - The presence of Cryptococcus spp. has been reported in Mexico's capital city; however, to our knowledge there are no reports of its presence in the state of Nuevo Leon located in northeast Mexico. This is presumed to be because the hot and dry climate in this region does not favor cryptococcal proliferation. This study confirmed the presence of C. neoformans and C. albidus in 20% (10/50) of randomly selected fecal samples of pigeons (Columba livia) in the Monterrey metropolitan area. The presence of this yeast in the state of Nuevo Leon is proof of its adaptation to the typically hot climate of the area and is consistent with recent reviews of cryptococcosis cases in several local hospitals. The two species were identified and characterized through microbiological tests and molecular identification by DNA extraction and PCR amplification of highly conserved 18S ribosomal DNA using ITS1 and ITS2 as target regions. The PCR products were sequenced and compared with those reported in GenBank. PMID- 24349947 TI - Enhanced glycemic control, pancreas protective, antioxidant and hepatoprotective effects by umbelliferon-alpha-D-glucopyranosyl-(2(I) -> 1(II))-alpha-D glucopyranoside in streptozotocin induced diabetic rats. AB - OBJECTIVE: The objective of the present study was to evaluate the effect of umbelliferon-alpha-D-glucopyranosyl-(2I -> 1II)-alpha-D-glucopyranoside (UFD) from Aegle marmelos Corr. on serum glucose, lipid profile and free radical scavenging activity in normal and STZ (streptozotocin) induced diabetic rats. MATERIALS AND METHODS: Diabetes was induced by single interperitoneal injecting of streptozotocin (60 mg/kg, i.p.) in the rats. All the rats were divided into following groups; I - nondiabeteic, II - nondiabetic + UFD (40 mg/kg, p.o.), III diabetic control, IV - UFD (10 mg/kg, p.o.), V - UFD (20 mg/kg, p.o.), VI - UFD (40 mg/kg) and VII - glibenclamide (10 mg/kg, p.o.). Serum glucose level and body weight were determined periodically. Biochemical parameter, antioxidant enzyme and histopathology study were performed on the day 28. Oral glucose tolerance test study was performed to identify the glucose utilization capacity. RESULTS: All the doses of UFD and glibenclamide decrease the level of serum glucose, glycated hemoglobin, glucose-6-phosphatase, fructose-1-6-biphosphate and increased the level of plasma insulin, hexokinase. The UFD doses also showed effects on antioxidant enzymes viz. superoxide dismutase, catalase and glutathione peroxidase which were significantly increased and the level of malonaldehyde was markedly decreased. Histologically study, focal necrosis, deposition of fats, increased the size of the intercalated disc were observed in the diabetic rat liver, kidney, heart and pancreas but was less obvious in treated groups. The mechanism of action of the UFD emerges to be due to increase the activity of antioxidant enzyme and secretion of pancreatic insulin. CONCLUSION: Reduction in the FBG (fasting blood glucose), glycated hemoglobin, glucose-6-phosphatase, fructose-1-6-biphosphate, superoxide dismutase, catalase, glutathione peroxides, cholesterol, triglyceride, LDL, VLDL levels and improvement in the level of the plasma insulin, hexokinase, HDL was observed by the UFD treated rats. The result indicates that UFD has anti-diabetic activity along with anti hyperlipidemic and antioxidant efficacy and provides a scientific rationale to be used as an Anti-diabetic agent. PMID- 24349948 TI - Generation and selection of anti-flagellin monoclonal antibodies useful for serotyping Salmonella enterica. AB - In developing countries, bacterial acute gastroenteritis continues to be an important cause of morbidity and mortality among young children. Salmonellosis constitutes a major cause of infectious enteritis worldwide, most of them associated to the consumption of contaminated food products. Traditionally, Salmonella has been classified in serovars based on varieties of O and H surface antigens. In the present work we generated and characterized a panel of anti flagellin monoclonal antibodies (MAbs) in order to select antibodies useful for detecting the H surface antigen. Four different MAbs were obtained by somatic hybridization of splenocytes. We found two MAbs that recognised regions of flagellin conserved among different Salmonella serovars. Other two MAbs recognised structures restricted to Salmonella enterica sv. Typhimurium, being one of them suitable for agglutination tests. Using a diverse panel of S. enterica serovars with different H antigen varieties we confirmed that this MAb agglutinates specifically S. Typhimurium (antigenic formula: 4,12:i:1,2) or other serovars expressing flagellar factor i. In conclusion, we generated a valuable immunochemical tool to be used in simple assays for serotyping of epidemiologically relevant strains. The capacity to characterize specific strains and determine the primary sources of Salmonella contamination generate valuable information of the epidemiology of this microorganism, contributing to the improvement of public health. PMID- 24349949 TI - The effects of course length on freestyle swimming speed in elite female and male swimmers - a comparison of swimmers at national and international level. AB - Freestyle swimming performance over 50 m, 100 m, 200 m, 400 m, 800 m and 1,500 m was compared on short (25 m) and long (50 m) course for 92,196 national swimmers (i.e. annual high score list Switzerland) and 1,104 international swimmers (i.e. finalists FINA World Championships) from 2000 to 2012. National and international swimmers of both sexes were on average 2.0 +/- 0.6% faster on short than on long course. Sex-related differences in swimming speed were greater on short than on long course for international and national swimmers from 50 m to 800 m. Freestyle swimming performance improved across years for international swimmers in both short- and long-course whereas only male national swimmers were able to improve on short and long course events except for short course events on 800 m and 1,500 m. Performance in national women competing in short and long course events showed only improvements on 50 m, 100 m and 1,500 m across years. The sex-related differences in freestyle swimming performance showed no change for international swimmers. For national swimmers, the sex-related differences in freestyle swimming performance increased over time in long course from 50 m to 800 m, but decreased for 1,500 m. In conclusion, elite female and male freestyle swimmers at national and international level were about 2% faster on 25 m compared to 50 m course. During the 2000-2012 period, international as well as national swimmers (i.e. for national level predominantly men) improved freestyle swimming performance in both long and short course. More vigorous and optimized training programs focused on muscular force production in combination with efficient swimming skills might close the performance gap between elite swimmers at national level and FINA finalists. Further research especially including effects of anthropometric, biomechanical, and physiological factors is required to fully understand the effects of course length on freestyle swimming performance, and to determine whether course length has similar effects on other swim styles. PMID- 24349950 TI - Asian ascendancy: media in the age of globalization. AB - This paper aims to investigate the media industry in Asia, with reference to international standards of media tools, instruments, content, and coverage. We have also explored factors that may further improve Asian media. We have used an empirical approach. Our findings revealed that the media in Asian significantly contribute to expanding cultural knowledge and the exchange of multilateral dialogues. However, they do not look after the interests of minorities or non dominating communities. Although the media should be a virtual ambassador, they often provoke hostilities within regions. Governments own most media outlets in the developing nations in Asia, and so the media rely on government backing and are subject to restrictions. International and national regulations connected to media freedom or constraints should be explored to protect Asian societies. The practical implications of these negative aspects are that the Asian media does not help the plights of minorities or minimize the fear of war in the region. The universal lesson of brotherhood among humanity for all colors and races should be preached by the media. In this paper, we have concentrated on how Asian media influence cultural expansion, the exchange of multilateral dialogues, the interests of minorities, aggression between nations, and generate income for common citizens. PMID- 24349952 TI - One-stage laparoscopic surgery for inspissated bile syndrome: case report and review of surgical techniques. AB - Inspissated bile syndrome in a 6 week old boy was unresponsive to oral ursodesoxycholic acid. Intraoperative cholangiography revealed complete obstruction of the common bile duct. Therefore, the gallbladder fundus was pulled out through a laparoscopy port site and sutured to the fascia. A catheter was positioned into the infundibulum for irrigation with ursodesoxycholic acid. At day 8 complete resolution of the plug and free passage of contrast medium into the duodenum was documented radiologically. The catheter was removed, skin closed spontaneously without a second surgery for closure of the gall bladder. PMID- 24349951 TI - Carbamoylation correlates of cyanate neuropathy and cyanide poisoning: relevance to the biomarkers of cassava cyanogenesis and motor system toxicity. AB - We sought to elucidate the protein carbamoylation patterns associated with cyanate neuropathy relative to cyanide poisoning. We hypothesized that under a diet deficient in sulfur amino acids (SAA), the carbamoylation pattern associated with cyanide poisoning is similar to that of cyanate neuropathy. Male rats (6-8 weeks old) were fed a diet with all amino acids (AAA) or 75%-deficiency in SAA and treated with 2.5 mg/kg/body weight (bw) NaCN, or 50 mg/kg/bw NaOCN, or 1 MUl/g/bw saline, for up to 6 weeks. Albumin and spinal cord proteins were analyzed using liquid chromatography mass spectrometry (LC-MS/MS). Only NaOCN induced motor deficits with significant levels of carbamoylation. At Day 14, we found a diet-treatment interaction effect on albumin carbamoylation (p = 0.07). At Day 28, no effect was attributed to diet (p = 0.71). Mean number of NaCN carbamoylated sites on albumin was 47.4% higher relative to vehicle (95% CI:16.7 86.4%). Only NaOCN carbamoylated spinal cord proteins, prominently, under SAA restricted diet. Proteins targets included myelin basic and proteolipid proteins, neurofilament light and glial fibrillary acidic proteins, and 2', 3' cyclic nucleotide 3'-phosphodiesterase. Under SAA deficiency, chronic but not acute cyanide toxicity may share biomarkers and pathogenetic similarities with cyanate neuropathy. Prevention of carbamoylation may protect against the neuropathic effects of cyanate. PMID- 24349954 TI - Genotypic variation in sorghum [Sorghum bicolor (L.) Moench] exotic germplasm collections for drought and disease tolerance. AB - Sorghum [Sorghum bicolor (L.) Moench] grain yield is severely affected by abiotic and biotic stresses during post-flowering stages, which has been aggravated by climate change. New parental lines having genes for various biotic and abiotic stress tolerances have the potential to mitigate this negative effect. Field studies were conducted under irrigated and dryland conditions with 128 exotic germplasm and 12 adapted lines to evaluate and identify potential sources for post-flowering drought tolerance and stalk and charcoal rot tolerances. The various physiological and disease related traits were recorded under irrigated and dryland conditions. Under dryland conditions, chlorophyll content (SPAD), grain yield and HI were decreased by 9, 44 and 16%, respectively, compared to irrigated conditions. Genotype RTx7000 and PI475432 had higher leaf temperature and grain yield, however, genotype PI570895 had lower leaf temperature and higher grain yield under dryland conditions. Increased grain yield and optimum leaf temperature was observed in PI510898, IS1212 and PI533946 compared to BTx642 (B35). However, IS14290, IS12945 and IS1219 had decreased grain yield and optimum leaf temperature under dryland conditions. Under irrigated conditions, stalk and charcoal rot disease severity was higher than under dryland conditions. Genotypes IS30562 and 1790E R had tolerance to both stalk rot and charcoal rot respectively and IS12706 was the most susceptible to both diseases. PI510898 showed combined tolerance to drought and Fusarium stalk rot under dryland conditions. The genotypes identified in this study are potential sources of drought and disease tolerance and will be used to develop better adaptable parental lines followed by high yielding hybrids. PMID- 24349953 TI - Granular cell tumor of the appendix: a new case and review of the literature. AB - Granular cell tumor (GCT) is a rare and usually benign lesion of neural / schwannian origin, most frequently found in middle-age women. The appendicular involvement is extremely rare: in over half a century only twelve cases have been reported in the literature, the patients living in America and Europe. Hitherto, no cases are documented from Africa, Asia and Oceania and no cases of malignant GCTs of the appendix have been reported. Most patients were diagnosed preoperatively as having acute appendicitis, whereas in three patients the tumor was incidentally detected during major abdominal surgery. The GCTs were equally distributed between mid-appendix and tip, where lymphoid tissue is more abundant and the anatomical nerve supply is progressively reduced. Moreover, the appendix surrounding the GCTs is characterized by the presence of chronic inflammatory cells (histiocytes, plasmocytes, eosinophils, mastocytes) and, therefore, a chronic inflammation of the appendix may be an antecedent condition favouring the appearance of GCTs. The GCT of the appendix appears so to be a lesion that reflects local reactive changes in the neural / schwannian cells, rather than being a genuine neoplasm. We describe the smallest GCT of the appendix ever reported, with a detailed literature review supporting its reactive origin in the lymphatic tissue-rich sites, such as ileo cecal appendix. PMID- 24349955 TI - Can levels of antioxidants in synovial fluid predict the severity of primary knee osteoarthritis: a preliminary study. AB - BACKGROUND: Little is known about differences in amounts of antioxidants or oxidative stress at different stages of knee osteoarthritis. This study investigated the relationship between concentrations of antioxidants, iron and lipid peroxidation in synovial fluid and levels of severity of primary knee osteoarthritis. MATERIALS AND METHODS: From 2011 to 2013, 23 patients (mean age, 66.7 +/- 7.6 years) with primary knee osteoarthritis were recruited. Patients were divided into 2 groups based on pre-treatment knee society scores (KSS): n = 9, severe KSS <=46; and n = 14, mild-moderate KSS >46. Synovial fluid was analyzed to determine levels of antioxidants, iron concentrations and lipid peroxidation (thiobarbituric acid reactive substances [TBARs]). Baseline data, including Kellgren- Lawrence radiographic grade, were collected for all patients. RESULTS: Mean KSS was 49.1 +/- 10.8. Total mean concentrations of antioxidants were 2.29 +/- 1.71 ng/mL vitamin E and 0.47 +/- 0.51 nmol/mL glutathione (GSH). Total mean levels of TBARs and iron were 1.20 +/- 0.37 nmol/mL and 2.13 +/- 0.82 MUg/mL, respectively. The mean concentration of vitamin E was inversely related to severity of knee osteoarthritis (mild-moderate > severe, p = 0.006). There were no significant differences between the two groups in terms of GSH (p = 0.90), TBARs (p = 0.84) or iron levels (p = 0.27). There was a significant positive correlation between KSS and vitamin E concentration (r = 0.43, p = 0.04). No significant correlations were shown between KSS and GSH (r = -0.01, p = 0.97), TBARs (r = -0.06, p = 0.81) or iron level (r = 0.28, p = 0.20). CONCLUSION: Using synovial fluid profiles, vitamin E concentration is an essential prognostic factor in primary knee osteoarthritis and may act as a basis for treatment directions. The concentration of vitamin E decreased as the clinical severity of primary knee osteoarthritis increased. PMID- 24349956 TI - Effect of microtitanium impregnated tape on the recovery of triceps surae musculotendinous function following strenuous running. AB - We previously reported increased running economy and joint range of motion (ROM) during subsequent exercise performed 48-h following strenuous exercise while wearing garments containing micro-titanium particles generated from high-pressure aqueous processing of titanium (AQUA TITAN(TM)). Here we utilised an isolated plantarflexion triceps surae model and AQUA TITAN-treated flexible tape to determine if dermal application of the micro-titanium could account for meaningful changes in functional properties of the musculotendinous unit. In a randomised double-blind crossover, 20 trained men day 1, baseline measures, AQUA TITAN or placebo tape covering the triceps surae, intermittent high-intensity treadmill running; day 2, rest; day 3, post-stress post-treatment outcome measures. Outcomes comprised: plantarflexion ROM via isokinetic dynamometry; short latency reflex from electromyography; Achilles tendon stiffness from isometric dynamometry, ultrasonography (Achilles-medial-gastrocnemius junction), motion analysis, and force-length modelling. High-intensity exercise with placebo tape reduced tendon stiffness (-16.5%; 95% confidence limits +/-8.1%; small effect size), relative to non-taped baseline, but this effect was negligible ( 5.9%; +/-9.2%) with AQUA TITAN (AQUA TITAN-placebo difference -11.3%; +/-11.6%). Change in latency relative to baseline was trivial with placebo (1.6%; +/-3.8%) but large with AQUA TITAN (-11.3%; +/-3.3%). The effects on ROM with AQUA TITAN (1.6%; +/-2.0%) and placebo were trivial (-1.6% +/-1.9%), but the small difference (3.1%; +/-2.7%) possibly greater with AQUA TITAN. AQUA TITAN tape accelerated the reflex response and attenuated reduced Achilles tendon stiffness following fatiguing exercise. Altered neuromuscular control of tendon stiffness via dermal application of micro-titanium treated materials may facilitate restoration of musculotendinous contractile performance following prior strenuous exercise. PMID- 24349958 TI - A novel promising Trichoderma harzianum strain for the production of a cellulolytic complex using sugarcane bagasse in natura. AB - Brazil is a major producer of agro-industrial residues, such as sugarcane bagasse, which could be used as raw material for microbial production of cellulases as an important strategy for the development of sustainable processes of second generation ethanol production. For this purpose, this work aimed at screening for glycosyl hydrolase activities of fungal strains isolated from the Brazilian Cerrado. Among 13 isolates, a Trichoderma harzianum strain (L04) was identified as a promising candidate for cellulase production when cultured on in natura sugarcane bagasse. Strain L04 revealed a well-balanced cellulolytic complex, presenting fast kinetic production of endoglucanases, exoglucanases and beta-glucosidases, achieving 4,022, U.L(-1) (72 h), 1,228 U.L(-1) (120 h) and 1,968 U.L(-1) (48 h) as the highest activities, respectively. About 60% glucose yields were obtained from sugarcane bagasse after 18 hours hydrolysis. This new strain represents a potential candidate for on-site enzyme production using sugarcane bagasse as carbon source. PMID- 24349957 TI - Coconut shells as filling material for anaerobic filters. AB - In rural areas of developing countries, there is a lack of sanitation services and the installation of such infrastructure is hampered by the high investment costs for initial implementation and by the limited availability of qualified personnel. An alternative to traditional sanitation services include an anaerobic filter, but the high cost of appropriate filling material can be an obstacle to its wide-spread implementation. To decrease this construction cost, the objective of this work was to study the use of coconut shells as filling material for anaerobic filters. Anaerobic filters were built and filled with the studied material and operated with up flow and hydraulic retention time of 9 hours. The reactors provided a removal of 79 +/- 16% in BOD terms, indicating that the coconut shell filling had efficiency consistent with the literature data. In addition, the husks were found to retain their tensile strength following use in the reactors. Coconut husks have more empty bed volume than other low cost materials, such as crushed stone, nearing properties of traditional materials. The results of this study indicate that coconut husks may prove to be a low cost alternative to traditional fillers for anaerobic treatment in rural communities. PMID- 24349959 TI - Negative expression of N-acetylglucosaminyltransferase V in oral squamous cell carcinoma correlates with poor prognosis. AB - N-acetylglucosaminyltransferase V (GnT-V), an enzyme with a key role in the branching of asparagine-linked oligosaccharides, is strongly linked to tumor invasion and metastasis of many solid tumors. Here we searched for correlations between the clinical features of patients with oral squamous cell carcinoma (OSCC) and GnT-V expression in the tumor, and we studied the feasibility of using GnT-V as a marker for oral cancer prognosis. Samples from 68 patients with OSCC were examined by immunohistochemistry using antibodies against GnT-V. Correlations between the expression level of GnT-V in the tumor and patient clinical features were statistically analyzed. Positive GnT-V expression was found in 48 cases (70.6%), and negative GnT-V expression was found in 20 cases (29.4%). Negative GnT-V expression was associated with mode of invasion by multiple logistic regression analysis (OR: 3.605; P = 0.048). Biological characteristics of tumors and the Ki-67 labeling index were higher in tumors with negative GnT-V expression than in those with positive GnT-V expression, although the difference was not significant (P = 0.176). Patients with negative GnT-V expression had significantly shorter survival than those with tumors having positive GnT-V expression (5-year survival rate, 58.2% and 86.5%, respectively; P = 0.025). Negative GnT-V expression was a significant unfavorable prognostic factor for OSCC (hazard ratio, 4.246; P = 0.045). The loss of GnT-V expression is a likely indicator of tumors with high potential of tumor invasion and poor prognosis in OSCC patients. PMID- 24349961 TI - Digital image processing techniques for detecting, quantifying and classifying plant diseases. AB - ABSTRACT: This paper presents a survey on methods that use digital image processing techniques to detect, quantify and classify plant diseases from digital images in the visible spectrum. Although disease symptoms can manifest in any part of the plant, only methods that explore visible symptoms in leaves and stems were considered. This was done for two main reasons: to limit the length of the paper and because methods dealing with roots, seeds and fruits have some peculiarities that would warrant a specific survey. The selected proposals are divided into three classes according to their objective: detection, severity quantification, and classification. Each of those classes, in turn, are subdivided according to the main technical solution used in the algorithm. This paper is expected to be useful to researchers working both on vegetable pathology and pattern recognition, providing a comprehensive and accessible overview of this important field of research. PMID- 24349960 TI - Osteoprotegerin (OPG) as a biomarker for diabetic cardiovascular complications. AB - Osteoprotegerin (OPG) is a glycoprotein involved in bone metabolisms and with a regulatory role in immune, skeletal and vascular systems. Recently, circulating OPG levels have emerged as independent biomarkers of cardiovascular disease (CVD) in patients with acute or chronic heart disease, as well as in the healthy population. Furthermore, OPG has been implicated in various inflammations and linked to diabetes and poor glycaemic control. This review focuses on the relations between circulating OPG levels and cardiovascular complications, with special emphasis on diabetic patients. OPG levels were observed to increase concurrently with the severity of diabetic complications, that is, with the highest circulating OPG levels observed in diabetic patients dying from CVD. Although the clinical prognostic use of OPG may seem far away, OPG does look promising as a biomarker in order to help the cardiologist to a better risk stratification of the patients. PMID- 24349962 TI - Does physician continuity within a clinical trial increase retention and compliance among adolescent smokers? AB - BACKGROUND: Retention and compliance are hurdles in many clinical trials designed for adolescents. Factors that may improve these issues in a challenging population may lead to increased data and power in much needed adolescent substance abuse research. METHODS: Within a large-scale smoking cessation study for adolescents, physician continuity (PC) was examined to determine its effect on retention, compliance, and cessation. RESULTS: In an analysis of 98 participants, participants with physician continuity throughout the study were more likely to attend more treatment visits and be medication compliant. It was also found that PC had no effect on participant smoking cessation. CONCLUSIONS: It appears that PC may be one way to increase retention and compliance within an adolescent clinical trial, without interfering with the specific aim of the research study (in this case, smoking cessation). PMID- 24349965 TI - Atopy and the Development of Chronic Rhinosinusitis in Children with Allergic Rhinitis. AB - The role of allergic rhinitis (AR) in the development of chronic rhinosinusitis (CRS) in children remains unknown. This study demonstrates the degree of atopy, as reflected by the number of aeroallergen sensitivities or the presence of atopic comorbidities, is not associated with progression to CRS in the pediatric age group. PMID- 24349964 TI - Pathological Gambling: Neuropsychopharmacology and Treatment. AB - Pathological gambling (PG) affects about 0.2-2% of adults and the impact extends to family members, employers and society as a whole. Recent research has identified similarities in the pathophysiologies of PG and substance use disorders (SUDs). As such, findings regarding SUDs provide a framework for investigating PG. The aims of the manuscript are two-fold. First, we will briefly revivew neural systems implicated in PG. Cortico-limbic circuitry involving the ventral striatum, ventromedial prefrontal cortex, anterior cingulate cortex, and dorsolateral prefrontal cortex are discussed as are the neurotransmitters norepinephrine, serotonin, dopamine, opioids, glutamate, and gamma-aminobutyric acid (GABA). This background will provide a framework for reviewing the psychopharmacological treatments that have been tested for efficacy and safety in treating PG. Of medications, the strongest data suggest the efficacy and tolerability of opioid antagonists in the treatment of PG, and other agents have varying degree of empirical support. As behavioral therapies have also shown efficacy, they will be briefly considered as well. Future research is needed to understand how treatments work in PG and for whom specific treatments might work best. PMID- 24349963 TI - Oxazaphosphorine bioactivation and detoxification The role of xenobiotic receptors. AB - Oxazaphosphorines, with the most representative members including cyclophosphamide, ifosfamide, and trofosfamide, constitute a class of alkylating agents that have a broad spectrum of anticancer activity against many malignant ailments including both solid tumors such as breast cancer and hematological malignancies such as leukemia and lymphoma. Most oxazaphosphorines are prodrugs that require hepatic cytochrome P450 enzymes to generate active alkylating moieties before manifesting their chemotherapeutic effects. Meanwhile, oxazaphosphorines can also be transformed into non-therapeutic byproducts by various drug-metabolizing enzymes. Clinically, oxazaphosphorines are often administered in combination with other chemotherapeutics in adjuvant treatments. As such, the therapeutic efficacy, off-target toxicity, and unintentional drug drug interactions of oxazaphosphorines have been long-lasting clinical concerns and heightened focuses of scientific literatures. Recent evidence suggests that xenobiotic receptors may play important roles in regulating the metabolism and clearance of oxazaphosphorines. Drugs as modulators of xenobiotic receptors can affect the therapeutic efficacy, cytotoxicity, and pharmacokinetics of coadministered oxazaphosphorines, providing a new molecular mechanism of drug drug interactions. Here, we review current advances regarding the influence of xenobiotic receptors, particularly, the constitutive androstane receptor, the pregnane X receptor and the aryl hydrocarbon receptor, on the bioactivation and detoxification of oxazaphosphorines, with a focus on cyclophosphamide and ifosfamide. PMID- 24349966 TI - Effects of Fatty Acids and Glycation on Drug Interactions with Human Serum Albumin. AB - The presence of elevated glucose concentrations in diabetes is a metabolic change that leads to an increase in the amount of non-enzymatic glycation that occurs for serum proteins. One protein that is affected by this process is the main serum protein, human serum albumin (HSA), which is also an important carrier agent for many drugs and fatty acids in the circulatory system. Sulfonylureas drugs, used to treat type 2 diabetes, are known to have significant binding to HSA. This study employed ultrafiltration and high-performance affinity chromatography to examine the effects of HSA glycation on the interactions of several sulfonylurea drugs (i.e., acetohexamide, tolbutamide and gliclazide) with fatty acids, whose concentrations in serum are also affected by diabetes. Similar overall changes in binding were noted for these drugs with normal HSA or glycated HSA and in the presence of the fatty acids. For most of the tested drugs, the addition of physiological levels of the fatty acids to normal HSA and glycated HSA produced weaker binding. At low fatty acid concentrations, many of these systems followed a direct competition model while others involved a mixed-mode interaction. In some cases, there was a change in the interaction mechanism between normal HSA and glycated HSA, as seen with linoleic acid. Systems with only direct competition also gave notable changes in the affinities of fatty acids at their sites of drug competition when comparing normal HSA and glycated HSA. This research demonstrated the importance of considering how changes in the concentrations and types of metabolites (e.g., in this case, glucose and fatty acids) can alter the function of a protein such as HSA and its ability to interact with drugs or other agents. PMID- 24349968 TI - Minimally invasive mitral valve surgery. PMID- 24349967 TI - Dynamics of childhood growth and obesity: development and validation of a quantitative mathematical model. AB - BACKGROUND: Clinicians and policy makers need the ability to predict quantitatively how childhood bodyweight will respond to obesity interventions. METHODS: We developed and validated a mathematical model of childhood energy balance that accounts for healthy growth and development of obesity, and that makes quantitative predictions about weight-management interventions. The model was calibrated to reference body composition data in healthy children and validated by comparing model predictions with data other than those used to build the model. FINDINGS: The model accurately simulated the changes in body composition and energy expenditure reported in reference data during healthy growth, and predicted increases in energy intake from ages 5-18 years of roughly 1200 kcal per day in boys and 900 kcal per day in girls. Development of childhood obesity necessitated a substantially greater excess energy intake than for development of adult obesity. Furthermore, excess energy intake in overweight and obese children calculated by the model greatly exceeded the typical energy balance calculated on the basis of growth charts. At the population level, the excess weight of US children in 2003-06 was associated with a mean increase in energy intake of roughly 200 kcal per day per child compared with similar children in 1971-74 [corrected]. The model also suggests that therapeutic windows when children can outgrow obesity without losing weight might exist, especially during periods of high growth potential in boys who are not severely obese. INTERPRETATION: This model quantifies the energy excess underlying obesity and calculates the necessary intervention magnitude to achieve bodyweight change in children. Policy makers and clinicians now have a quantitative technique for understanding the childhood obesity epidemic and planning interventions to control it. FUNDING: Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. PMID- 24349969 TI - A meta-analysis of MitraClip system versus surgery for treatment of severe mitral regurgitation. AB - BACKGROUND: Mitral regurgitation (MR) is the second most common valvular heart disease after aortic stenosis. Without intervention, prognosis is poor in patients with severe symptomatic MR. While surgical repair is recommended for many patients with severe degenerative MR (DMR), as many as 49% of patients do not qualify as they are at high surgical risk. Furthermore, surgical correction for functional MR (FMR) is controversial with suboptimal outcomes and significant perioperative mortality. The percutaneous MitraClip implantation can be seen as a viable option in high surgical risk patients. The purpose of this meta-analysis is to compare the safety, clinical efficacy, and survival outcomes of MitraClip implantation with surgical correction of severe MR. METHODS: Six electronic databases were searched for original published studies from January 2000 to August 2013. Two reviewers independently appraised studies, using a standard form, and extracted data on methodology, quality criteria, and outcome measures. All data were extracted and tabulated from the relevant articles' texts, tables, and figures and checked by another reviewer. RESULTS: Overall 435 publications were identified. After applying selection criteria and removing serial publications with accumulating number of patients or increased length of follow up, four publications with the most complete dataset were included for quality appraisal and data extraction. There was one randomized controlled trial (RCT) and three prospective observational studies. At baseline, patients in the MitraClip group were significantly older (P=0.01), had significantly lower LVEF (P=0.03) and significantly higher EuroSCORE (P<0.0001). The number of patients with post-procedure residual MR severity >2 was significantly higher in the MitraClip group compared to the surgical group (17.2% vs. 0.4%; P<0.0001). 30-day mortality was not statistically significant (1.7% vs. 3.5%; P=0.54), nor were neurological events (0.85% vs. 1.74%; P=0.43), reoperations for failed MV procedures (2% vs. 1%; P=0.56), NYHA Class III/IV (5.7% vs. 11.3; P=0.42) and mortality at 12 months (7.4% vs. 7.3%; P=0.66). CONCLUSIONS: Despite a higher risk profile in the MitraClip patients compared to surgical intervention, the clinical outcomes were similar although surgery was more effective in reducing MR in the early post procedure period. We conclude the non-inferiority of the MitraClip as a treatment option for severe, symptomatic MR in comparison to conventional valvular surgery. PMID- 24349970 TI - A meta-analysis of minimally invasive versus conventional mitral valve repair for patients with degenerative mitral disease. AB - BACKGROUND: Minimally invasive mitral valve surgery through a mini-thoracotomy approach was developed in the mid-1990s as an alternative to conventional sternotomy, but with reduced trauma and quicker recovery. However, technical demands and a paucity of comparative data have thus far limited the widespread adoption of minimally invasive mitral valve repair (MIMVR). Previous meta analyses have grouped various surgical techniques and underlying valvular disease aetiologies together for comparison. The present study aimed to compare the clinical outcomes of MIMVR versus conventional mitral valve repair in patients with degenerative mitral valve disease. METHODS: A systematic review of the current literature was performed through nine electronic databases from January 1995 to July 2013 to identify all relevant studies with comparative data on MIMVR versus conventional mitral valve surgery. Measured endpoints included mortality, stroke, renal failure, wound infection, reoperation for bleeding, aortic dissection, myocardial infarction, atrial fibrillation, readmission within 30 days, cross clamp time, cardiopulmonary bypass time and durations of intensive care unit (ICU) stay and overall hospitalization. Echocardiographic outcomes were also assessed when possible. RESULTS: Seven relevant studies were identified according to the predefined study selection criteria, including one randomized controlled trial and six retrospective studies. Meta-analysis of clinical outcomes did not identify any statistically significant differences between MIMVR and conventional mitral valve repair. The duration of ICU stay was significantly shorter for patients who underwent MIMVR, but this did not translate to a shorter hospitalization period. Patients who underwent MIMVR required longer cross clamp time as well as cardiopulmonary bypass time. Both surgical techniques appeared to achieve satisfactory echocardiographic outcomes. Pain-related outcomes was assessed in one study and reported significantly less pain for patients who underwent MIMVR. However, this limited data was not suitable for meta-analysis. CONCLUSIONS: The existing literature has limited data on comparative outcomes after MIMVR versus conventional mitral valve repair for patients with degenerative disease. From the available evidence, there are no significant differences between the two surgical techniques in regards to clinical outcomes. Patients who underwent MIMVR required longer cardiopulmonary bypass and cross clamp times, but the duration of stay in the ICU was significantly shorter than conventional mitral valve repair. PMID- 24349971 TI - Systematic review of robotic minimally invasive mitral valve surgery. AB - BACKGROUND: Robotic telemanipulators have evolved to assist the challenges of minimally invasive mitral valve surgery (MVS). A systematic review was performed to provide a synopsis of the literature, focusing on clinical outcomes and cost effectiveness. METHOD: Structured searches of MEDLINE, Embase, and Cochrane databases were performed in August 2013. All original studies except case-reports were included in qualitative review. Studies with >=50 patients were presented quantitatively. RESULTS: After applying inclusion and exclusion criteria to the search results, 27 studies were included in qualitative review, 16 of which had >=50 patients. All studies were observational in nature, and thus the quality of evidence was rated low to medium. Patients generally had good left ventricular performance, were relatively asymptomatic, and mean patient age ranged from 52.6 58.4 years. Rates of intraoperative outcomes ranged from: 0.0-9.1% for conversion to non-robotic surgery, 106+/-22 to 188.5+/-53.8 min for cardiopulmonary bypass (CPB) time and 79+/-16 to 140+/-40 min for cross-clamp (XC) time. Rates of short term postoperative outcomes ranged from: 0.0-3.0% for mortality, 0.0-3.2% for myocardial infarction (MI), 0.0-3.0% for permanent stroke, 1.6-15% for pleural effusion, 0.0-5.0% for reoperations for bleeding, 0.0-0.3% for infection, and 1.1 6% for prolonged ventilation (>48 hours), 1.5-5.4% for early repair failure, 12.3+/-6.7 to 36.6+/-24.7 hours for intensive care length of stay, 3.1+/-0.3 to 6.3+/-3.9 days for hospital length of stay (HLOS) and 81.7-97.6% had no or trivial mitral regurgitation (MR) before discharge. CONCLUSIONS: All subtypes of mitral valve prolapse are repairable with robotic techniques. CPB and XC times are long, and novel techniques such as the Cor-Knot, Nitinol clips or running sutures may reduce the time required. The overall rates of early postoperative mortality and morbidity are low. Improvements in postoperative quality of life (QoL) and expeditious return to work offset the increase in equipment and intraoperative cost. Evidence for long-term outcomes is as yet limited. PMID- 24349973 TI - Keynote Lecture-Transmitral hypertrophic obstructive cardiomyopathy (HOCM) repair. AB - Hypertrophic obstructive cardiomyopathy (HOCM) is a heterogenous disease causing obstruction of the left and/or right ventricular outflow tract (LVOT and/or RVOT, respectively). The main symptoms include dyspnea on exertion and syncope, and in severe cases, subsequent development of heart failure symptoms with end stage heart failure occurs. In a certain number of patients, surgical intervention is required since pharmacological and/or interventional treatment using transcoronary ablation of septal hypertrophy (TASH) does not relieve symptoms. The primary goal of any surgical technique is to relieve LVOT obstruction, avoid the occurrence and/or recurrence of systolic anterior movement (SAM) of the anterior mitral leaflet (AML) and-if present-reduce mitral valve (MV) regurgitation. Depending on the configuration of LVOT obstruction, myectomy with/without MV replacement has been the "gold standard" in surgical treatment of HOCM. However, considering the known disadvantages of artificial valves, MV preserving techniques will improve postoperative outcomes and decrease major adverse events in the long term. We describe the currently available operative strategies for treatment of HOCM. Special consideration is given to minimally invasive access with subaortic LVOT myectomy and complete resuspension of the AML to treat both HOCM and MV regurgitation. PMID- 24349972 TI - Custodiol for myocardial protection and preservation: a systematic review. AB - INTRODUCTION: Custodiol cardioplegia is attractive for minimally invasive cardiac surgery, as a single dose provides a long period of myocardial protection. Despite widespread use in Europe, there is little data confirming its efficacy compared with conventional (blood or crystalloid) cardioplegia. There is similar enthusiasm for its use in organ preservation for transplant, but also a lack of data. This systematic review aimed to assess the evidence for the efficacy of Custodiol in myocardial protection and as a preservation solution in heart transplant. METHODS: Electronic searches were performed of six databases from inception to October 2013. Reviewers independently identified studies that compared Custodiol with conventional cardioplegia (blood or extracellular crystalloid) in adult patients for meta-analysis; large case series that reported results using Custodiol were analyzed. Next, we identified studies that compared Custodiol with other organ preservation solutions for organ preservation in heart transplant. RESULTS: Fourteen studies compared Custodiol with conventional cardioplegia for myocardial protection in adult cardiac surgery. No difference was identified in mortality; there was a trend for increased incidence of ventricular fibrillation in the Custodiol group that did not reach statistical significance. No difference was identified in studies that compared Custodiol with other solutions for heart transplant. CONCLUSIONS: Despite widespread clinical use, the evidence supporting the superiority of Custodiol over other solutions for myocardial protection or organ preservation is limited. Large randomised trials are required. PMID- 24349974 TI - Cross-sectional survey on minimally invasive mitral valve surgery. AB - BACKGROUND: Minimally invasive mitral valve surgery (MIMVS) has become a standard technique to perform mitral valve surgery in many cardiac centers. However, there remains a question regarding when MIMVS should not be performed due to an increased surgical risk. Consequently, expert surgeons were surveyed regarding their opinions on patient factors, mitral valve pathology and surgical skills in MIMVS. METHODS: Surgeons experienced in MIMVS were identified through an electronic search of the literature. A link to an online survey platform was sent to all surgeons, as well as two follow-up reminders. Survey responses were then submitted to a central database and analyzed. RESULTS: The survey was completed by 20 surgeons. Overall results were not uniform with regard to contraindications to performing MIMVS. Some respondents do not consider left atrial enlargement (95% of surgeons), complexity of surgery (75%), age (70%), aortic calcification (70%), EuroSCORE (60%), left ventricular ejection fraction (55%), or obesity (50%) to be contraindication to surgery. Ninety percent of respondents believe more than 20 cases are required to gain familiarity with the procedure, while 85% believe at least one MIMVS case needs to be performed per week to maintain proficiency. Eighty percent recommend establishment of multi-institutional databases and standardized surgical mentoring courses, while 75% believe MIMVS should be incorporated into current training programs for trainees. CONCLUSIONS: These results suggest that MIMVS has been accepted as a treatment option for patients with mitral valve pathologies according the expert panel. Initial training and continuing practice is recommended to maintain proficiency, as well as further research and formalization of training programs. PMID- 24349975 TI - Total percutaneous femoral vessels cannulation for minimally invasive mitral valve surgery. AB - BACKGROUND: Minimally invasive mitral valve surgery (MIMVS) has experienced several technological changes in the last two decades. Our aim was to describe one of the most recent improvements, the utilization of a total percutaneous femoral vessels cannulation technique during MIMVS. METHODS: We performed a retrospective observational analysis of this technique among 300 consecutive MIMVS patients, with particular focus on cannulation aspects of MIMVS, its success rate and potential complications. RESULTS: From October 2008 to December 2012, 300 patients (60% males) were operated on. Mean age was 62.9+/-16.4 years. Indications for operation included mitral valve repair (93%) and mitral valve replacement (7%). Two femoral arterial catheterizations failed and required conversion to sternotomy. The complications on the arterial side were: 5 (1.6%) cases of bleeding during the introduction of Prostar leading to a preoperative surgical hemostasis; 2 (0.6%) retroperitoneal bleeds during cardiopulmonary bypass requiring difficult surgical control but with an uneventful follow-up; 6 (2%) bleeding episodes after removal of the arterial cannula easily controlled by direct surgical revision; 1 (0.3%) arterio-venous fistula requiring a surgical correction on postoperative day 32; 1 (0.3%) patient had a transitory claudication due to a superficial femoral artery thrombosis progressively compensated by the collateral circulation. There were no postoperative bleeding complications. There were no other complications linked to the femoral cannulations or to the groin occurred during the follow-up. The percentage of uneventful arterial cannulations was 80% among the first 50 patients (N=10 out of 50) and 98.8% thereafter (N=3 out of 250). CONCLUSIONS: Total percutaneous femoral vessels cannulation technique is particularly suitable for MIMVS with a high success rate and few complications after a short learning curve. With the advent of the percutaneous approach, the traditional complications of the groin incision have completely disappeared in modern operations with no groin infection, hematoma or lymphocele. PMID- 24349976 TI - Minimally invasive mitral valve surgery: "The Leipzig experience". AB - BACKGROUND: Minimally invasive mitral valve surgery has become a routine procedure at our institution. The present study analyzed the early and long-term outcomes of patients undergoing minimally invasive mitral valve surgery over the last decade, with special focus on mitral valve repairs (MVRp). METHODS: The preoperative variables, intraoperative data and postoperative outcomes of patients undergoing minimally invasive mitral valve surgery were prospectively collected in our database from May 1999 to December 2010. The survival and freedom from reoperation were evaluated with life tables and Kaplan-Meier analyses. RESULTS: A total of 3,438 patients underwent minimally invasive mitral valve surgery, of which 2,829 were MVRps and 609 were mitral valve replacements (MVR). Forty-five patients (1.6%) required MVR due to failure of repair. The mean age was 60.3+/-13 years. More than a third of patients underwent concomitant procedures like tricuspid valve surgery, atrial septal defect (ASD) closure and cryoablation. The rate of conversion to sternotomy was less than 1.4%. The 30-day mortality was 0.8%. The 5- and 10-year survival of all patients (MVR and MVRp) undergoing minimally invasive mitral valve surgery was 85.7+/-0.6% and 71.5+/ 1.2%, respectively. For MVRp, the survival was 87.0+/-0.7% and 74.2+/-1.4% at 5 and 10 years, respectively. Freedom from reoperation was 96.6+/-0.4% and 92.9+/ 0.9% at 5 and 10 years, respectively. CONCLUSIONS: Minimally invasive MVRp can be performed safely and effectively with very few perioperative complications. The early and long-term outcomes in these patients are acceptable. PMID- 24349977 TI - Rate of repair in minimally invasive mitral valve surgery. AB - BACKGROUND: Valve repair has been shown to be the method of choice in the treatment of patients with severe mitral valve regurgitation. Minimally invasive surgery has raised skepticism regarding the rate of repair especially for supposedly complex lesions, when anterior leaflet involvement or bileaflet prolapse is present. We sought to review our experience of all our patients presenting with degenerative mitral valve regurgitation and operated on minimally invasively. METHOD: From September 2006 to December 2012, 842 patients (mean age 56.12+/-11.62 years old) with degenerative mitral valve regurgitation and anterior leaflet (n=82, 9.7%), posterior leaflet (n=688, 81.7%) and bileaflet (n=72, 8.6%) prolapses were operated on using a minimally invasive approach. RESULTS: 836 patients had a valve repair (99.3%) and received a concomitant ring annuloplasty (mean size, 33.7; range, 28-40). Six patients (0.7%) underwent valve replacement. Two patients had a re-repair due to MR progression or infective endocarditis. Thirty-day mortality was 0.2% (two patients). There were 60 major adverse events (MAE) (7.1%). CONCLUSIONS: A minimally invasive approach allows repair of almost all degenerative valves with good short-term outcomes in a tertiary referral center, when using proven and efficient surgical techniques. PMID- 24349978 TI - Concomitant tricuspid valve repair in patients with minimally invasive mitral valve surgery. AB - BACKGROUND: The aim of this study was to investigate the 10-year Leipzig experience with minimally invasive mitral valve (MIMV) surgery in combination with tricuspid valve (TV) surgery. METHODS: Between January 2002 and December 2011, a total of 441 patients with mitral valve (MV) dysfunction and concomitant TV regurgitation (TR) underwent MIMV surgery at the Leipzig Heart Center. The mean age was 68.7+/-10.0 years, mean LVEF was 56.7%+/-13.1% and 184 patients (41.7%) were male. The Average logEuroSCORE was 8.3%+/-7.2%, and patients had an average follow-up of 3.4+/-2.4 years. RESULTS: Pre-discharge echocardiography showed no or mild mitral regurgitation (MR) in 95.1% and no or mild TR in 84.1%. Overall 30-day mortality was 4.3% with nineteen deaths. Five-year survival was 77.2%+/-2.5%. Five-year freedom from TV-related reoperation was 91.0%+/-1.8%. CONCLUSIONS: Our 10-year experience show that MIMV surgery in combination with TV surgery can be performed routinely with good peri- and post-operative results. Our observations support current recommendations to perform concomitant TV repair, particularly if tricuspid annular dilation is present. PMID- 24349979 TI - Minimally invasive mitral valve surgery in octogenarians-a brief report. PMID- 24349980 TI - Barlow's mitral valve disease: results of conventional and minimally invasive repair approaches. AB - Barlow's valve is a clinically important form of degenerative mitral valve (MV) disease that is characterized by unique clinical, echocardiographic and pathological features. Successful and durable repair of Barlow's MV represents a clinical challenge for most cardiac surgeons. An armamentarium of different MV repair techniques may be required, resectional, neochordal or plicational techniques. Although conventional sternotomy remains the mainstay approach for MV surgery in the majority of cardiac surgery centers, minimally invasive surgery (MIS) is becoming increasingly accepted amongst patients, referring physicians and practicing cardiac surgeons. As surgical approaches, instrumentation and operative experience develop, select centers are now performing MIS MV surgery for nearly all MV patients. Although successful Barlow's MV repair is more complex than that for most degenerative pathologies, several centers have published relatively large series of MIS MV repair for Barlow's disease. In this review article, we highlight and compare the early and long-term results of conventional and minimally invasive approaches to Barlow's and bileaflet mitral prolapse disease. Recent studies from various large volume centers around the world have demonstrated equivalent safety and efficacy outcomes of the MIS approach compared to conventional sternotomy surgery. In addition, MIS MV surgery may allow patients to benefit from a cosmetically appealing incision, a faster recovery and a quicker return to normal activities. However, a definite learning curve has been demonstrated for MIS MV surgery. If a patient with Barlow's disease or other complex MV pathology desires to undergo MIS MV surgery, referral to a center and/or surgeon with extensive experience in MIS MV surgery is recommended. PMID- 24349981 TI - How to start a minimal access mitral valve program. AB - The seven pillars of governance established by the National Health Service in the United Kingdom provide a useful framework for the process of introducing new procedures to a hospital. Drawing from local experience, the author present guidance for institutions considering establishing a minimal access mitral valve program. The seven pillars of governance apply to the practice of minimally invasive mitral valve surgery, based on the principle of patient-centred practice. The author delineate the benefits of minimally invasive mitral valve surgery in terms of: "clinical effectiveness", including reduced length of hospital stay, "risk management effectiveness", including conversion to sternotomy and aortic dissection, "patient experience" including improved cosmesis and quicker recovery, and the effectiveness of communication, resources and strategies in the implementation of minimally invasive mitral valve surgery. Finally, the author have identified seven learning curves experienced by surgeons involved in introducing a minimal access mitral valve program. The learning curves are defined as: techniques of mitral valve repair, Transoesophageal Echocardiography-guided cannulation, incisions, instruments, visualization, aortic occlusion and cardiopulmonary bypass strategies. From local experience, the author provide advice on how to reduce the learning curves, such as practising with the specialised instruments and visualization techniques during sternotomy cases. Underpinning the NHS pillars are the principles of systems awareness, teamwork, communication, ownership and leadership, all of which are paramount to performing any surgery but more so with minimal access surgery, as will be highlighted throughout this paper. PMID- 24349982 TI - How do we use imaging to aid considerations for intervention in patients with severe mitral regurgitation? AB - Increasing life expectancy and comorbid conditions, like obesity, especially in industrialized countries, have led to Valvular Heart Disease (VHD) becoming a major epidemic. Mitral valve disease currently accounts for nearly 10% of Valvular Heart Disease in industrialized countries worldwide. It is a known fact that, left untreated, degenerative mitral valve disease not only shortens an individual's life, but is also associated with increased morbidity. Despite current guidelines, there is often marked delay in appropriately sending patients for consideration of surgical intervention-interventions that when performed well can dramatically restore patients to a more normal lifespan. The critical question is really not what the severity of the mitral regurgitation is, but what the effect of the mitral regurgitation is on the heart. Modern day echocardiography utilizing Transthoracic Echo, Stress Echo, and Transesophageal Echo, can provide the clinician and the surgeon with six key factors that when taken together provide clear direction as to the proper timing for consideration for mitral valve repair. Thinking of these in an integrative fashion, the clinician and the surgeon can more appropriately time proper surgical intervention in primary degenerative mitral regurgitation. PMID- 24349983 TI - New concepts for mitral valve imaging. AB - The high complexity of the mitral valve (MV) anatomy and function is not yet fully understood. Studying especially the dynamic movement and interaction of MV components to describe MV physiology during the cardiac cycle remains a challenge. Imaging is the key to assessing details of MV disease and to studying the lesion and dysfunction of MV according to Carpentier. With the advances of computational geometrical and biomechanical MV models, improved quantification and characterization of the MV has been realized. Geometrical models can be divided into rigid and dynamic models. Both models are based on reconstruction techniques of echocardiographic or computed tomographic data sets. They allow detailed analysis of MV morphology and dynamics throughout the cardiac cycle. Biomechanical models aim to simulate the biomechanics of MV to allow for examination and analysis of the MV structure with blood flow. Two categories of biomechanical MV models can be distinguished: structural models and fluid structure interaction (FSI) models. The complex structure and dynamics of MV apparatus throughout the cardiac cycle can be analyzed with different types of computational models. These represent substantial progress in the diagnosis of structural heart disease since MV morphology and dynamics can be studied in unprecedented detail. It is conceivable that MV modeling will contribute significantly to the understanding of the MV. PMID- 24349984 TI - Value of transesophageal echocardiography (TEE) guidance in minimally invasive mitral valve surgery. AB - The role of intraoperative transesophageal echocardiography (TEE) has increased tremendously since its first use in 1979. Today intraoperative TEE is a class I indication for surgical mitral valve reconstruction for evaluation of mitral valve pathology, graduation of mitral regurgitation and detection of potential risk factors as well as post-repair assessment. Real-time three-dimensional TEE offers anatomical visualization of the mitral valve apparatus, fundamental for virtual surgical planning of proper annuloplasty ring size. As minimally invasive and even off-pump techniques for mitral valve repair become more popular, image guidance by intraoperative TEE will play an essential role. PMID- 24349985 TI - Myocardial protection during minimally invasive mitral valve surgery: strategies and cardioplegic solutions. AB - Effective myocardial protection and perfusion strategies during minimally invasive mitral valve surgery (Mini-MV) have evolved over the last decade. Our institutional approach for right-sided Mini-MV has been standardized over the last 15 years in more than 4,500 cases. Cardiopulmonary bypass (CPB) is usually instituted by right-sided femoral arterial and venous cannulation with additional cannulation of the right jugular vein in patients with a body weight greater than 75 kg or when a concomitant tricuspid valve (TV) procedure and/or atrial septal defect closure is performed. A single dosage of crystalloid-based cardioplegia [Custodial- histidine-trypthophan-ketoglutarate (Custodial-HTK)] administered via the aortic root in combination with moderate hypothermia (34-35 degrees C) has become the standard of care for induction and maintenance of myocardial protection at our institution. The present article highlights and discusses the principal techniques of myocardial protection for Mini-MV. PMID- 24349986 TI - Chordae replacement versus leaflet resection in minimally invasive mitral valve repair. AB - For many years, the quadrangular resection technique first proposed by Carpentier has become the gold standard for repair of posterior leaflet prolapse of the mitral valve (MV). Although this "resection" technique and its modifications are safe and very effective, they do not respect the anatomy of the MV and the physiological role of the posterior leaflet. Therefore some new techniques, aiming to preserve MV leaflets to a different extent, have been proposed. With the use of expanded polytetrafluoroethylene (ePTFE), neochordae leaflet preserving techniques for posterior MV prolapse treatment have emerged. The aim of these techniques is to support the free edge of the prolapsing segments and thereby restore the physiologic function of the MV. A simplified modification of this technique using premeasured ePTFE loops ("loop technique") was successfully introduced to ease the implantation of neochordae, especially in the setting of minimally invasive MV surgery. While "resection" techniques are associated with excellent long-term results, there is evolving evidence in favor of "non resection" techniques supporting the concept of a "respect rather than resect" approach. PMID- 24349987 TI - Robotic mitral valve surgery-current status and future directions. AB - Robotic mitral valve surgery is the most common robotic cardiac procedure performed today. Benefits include smaller, less invasive incisions resulting in less pain, shorter length of hospital stay, improved cosmesis, quicker return to preoperative level of functional activity, and decreased blood transfusion requirements. The history and evolution of robotic mitral valve surgery is detailed in this article. Our institution has performed over 800 robotic mitral valve surgeries, and our technique and outcomes are described. Outcomes and operative times are similar to that for sternotomy and minimally invasive approaches to mitral valve surgery. The benefits and limitations of robotic mitral valve surgery are compared with conventional approaches, and future directions are also discussed. PMID- 24349988 TI - Minimally invasive valve sparing mitral valve repair-the loop technique-how we do it. AB - Mitral valve insufficiency is the second most common heart valve disease, with untreated regurgitation leading to enlargement of the left atrium (LA), atrial fibrillation and heart failure. Besides functional regurgitation, the main cause is degenerative valve disease with elongation of the chordae tendineae and prolapsing of the leaflets. Surgical repair is the gold standard therapy for mitral valve insufficiency today. Recently, the implantation of neochordae (the "loop-technique") has been established and is the preferred technique in many centres including ours. Results of surgical mitral valve repair are good with low rates of re-intervention and mortality. With minimally invasive techniques, patient satisfaction is high and hospital stay is short. In conclusion, mitral valve repair should be the preferred strategy in patients with symptomatic mitral valve insufficiency or with asymptomatic mitral valve insufficiency in accordance with the guidelines. Modern repair techniques like neo-chord implantation with the loop-technique combined with minimally invasive access routes result in low mortality and morbidity and short hospital stay as well as high patient satisfaction. PMID- 24349989 TI - Video-atlas on minimally invasive mitral valve surgery-the Mohr technique. PMID- 24349990 TI - Video-atlas on minimally invasive mitral valve surgery-The David Adams technique. AB - Median sternotomy has unquestionably evolved over recent decades. Modern sternotomy involves a 7-8 cm lower midline skin incision, tunneling of the subcutaneous tissues with subsequent creation of myocutaneous flaps, full sternotomy, and standard cardiopulmonary bypass techniques with central cannulation. In experienced centers, modern sternotomy may achieve all the goals of minimally invasive surgery, including excellent cosmesis, excellent postoperative pain control, low rates of bleeding and transfusion (our re exploration rate for bleeding is <1%), and the ability to perform any reconstructive technique that would be used in a standard sternotomy, with very high repair rates (our most recent series documented a repair rate exceeding 99% in an all-comers population of degenerative disease regardless of complexity). PMID- 24349991 TI - Minimally invasive repair of posterior leaflet mitral valve prolapse with the "respect" approach. PMID- 24349992 TI - Central aortic cannulation for minimally invasive mitral valve surgery through right minithoracotomy. PMID- 24349993 TI - Optimizing outcomes of robotic mitral valve repair for all prolapse anatomy: the Suri-Burkhart technique. PMID- 24349994 TI - Video-atlas on robotically assisted mitral valve surgery. PMID- 24349995 TI - Safeguards and pitfalls in minimally invasive mitral valve surgery. AB - Minimally invasive mitral valve surgery has been established in many institutions worldwide. Appropriate indications and patient selection for this procedure must be based on a thorough understanding of its limitations and specific pitfalls. Particular risks can be minimized with careful attention to detail when planning and performing the surgery. The following chapter offers a stepwise description of the procedure; we point out particular advantages, discuss our rationale for certain steps, as well as focus on potential dangers of minimally invasive mitral valve surgery. Several graphics have also been provided to illustrate our approach and demonstrate important structural and anatomical concepts of the mitral valve apparatus. PMID- 24349996 TI - Conversion rate and contraindications for minimally invasive mitral valve surgery. PMID- 24349997 TI - Systematic Review Protocol: surgical ablation for atrial fibrillation during mitral valve surgery. PMID- 24349999 TI - Minimally invasive mitral valve surgery. PMID- 24349998 TI - Systematic review protocol: surgical ablation versus catheter ablation for atrial fibrillation. PMID- 24350000 TI - Retrograde femoral arterial perfusion and stroke risk during minimally invasive mitral valve surgery: is there cause for concern? AB - Recent data have suggested that retrograde arterial perfusion (RAP) during minimally invasive mitral valve surgery (MIMVS) is associated with a higher stroke rate than sternotomy approaches. To assess whether there is genuine cause for concern, we examine the strengths and weaknesses of this data. A multitude of confounding factors obfuscate interpretation of the data including imprecise definitions of MIMVS, the effect of the substantial learning curve, retrospective comparisons of small historic cohorts with baseline differences and differing risk profiles for atherosclerosis, different methods of aortic occlusion and lack of reporting of peripheral vascular disease (PVD)/aortic assessment in patient populations. In patients with severe (grades IV and V) aortic arch/ascending aortic atherosclerosis, RAP has clearly been shown to be associated with an increase in risk of cerebral embolic complications. It would be reasonable to assume that grades IV/V atheroma anywhere along the aorto-iliac axis (from femoral cannulation site to carotid arteries) may also increase the risk of stroke. Hence those at risk of severe atherosclerotic vascular disease should be screened to fully assess the aortoiliac axis. Apart from this patient group, there is no convincing evidence (without confounding variables) that retrograde perfusion per se during minimally invasive mitral surgery increases the risk of stroke. This may be due to the largely differing aetiologies of vascular and mitral degenerative disease. PMID- 24350001 TI - [Not Available]. PMID- 24350002 TI - Progressive cribriform and zosteriform hyperpigmentation: Where are we at present? PMID- 24350003 TI - Nanocarriers and nanoparticles for skin care and dermatological treatments. AB - NANOTECHNOLOGY (NANO: One billionth) is a novel arena with promising applications in the field of medicine, especially pharmaceuticals for safe and targeted drug delivery. The skin is a phenomenal tool for investigation of nanocarriers for drug delivery for topical and dermatological application. The physicochemical characteristics of the nanoparticles, such as rigidity, hydrophobicity, size and charge are crucial to the skin permeation mechanism. Many nanocarriers such as polymeric, inorganic and lipid nanoparticles and nanoemulsions have been developed and some like carbon nanotubes and fullerenes still need further exploration for future use in skin care and dermatological treatments. Risks of nanopollution and cytotoxicity also need to be kept in mind while exploring various nanoparticles for medical use. PMID- 24350004 TI - Interesting and unusual clinical presentations in leprosy at a referral center. AB - BACKGROUND: Leprosy is a disease of declining global endemicity but is still an important health-care problem in India. Pure neural leprosy is an important subset of presentations of leprosy in India. Leprosy is a known disease of the skin and nerves, but cases of pure neural involvement are relatively less. We hereby present 10 cases of pure neural leprosy in which the diagnosis of leprosy was difficult with routine methods. MATERIALS AND METHODS: The study was conducted at the main referral center and satellite clinics of our organization. A retrospective analysis of patient records for the last four years was undertaken to identify patients presenting with predominantly neurological manifestations and uncommon presentations including those without skin lesions. The medical records of the patients were used as source of data. All the patients were subjected to a detailed clinical examination and bacteriological examination with slit-skin smears. Investigations like nerve biopsy, electromyography, and nerve conduction studies were done in patients with diagnostic difficulties. RESULTS: Patients presented with neurological symptoms like paresthesias (60%), diminished sensations (40%), nonhealing ulcers (30%), and blisters (20%). All except one had thickened nerves on clinical examination. Slit-skin smear was negative in all but one patient. Nerve biopsy confirmed the diagnosis of leprosy in seven cases. CONCLUSION: Pure neural leprosy is difficult to diagnose with routine methods. The diagnosis should be considered, especially by neurologists and dermatologists, who are more likely to see such patients with predominant neural manifestations. The diagnosis should be confirmed with nerve biopsy to prevent delay in therapy and associated complications. PMID- 24350005 TI - Study of oxidative stress in peripheral blood of Indian vitiligo patients. AB - BACKGROUND: Vitiligo is an acquired skin disease that involves the interplay of complex genetic, immunological, neural and self-destructive mechanisms in its pathogenesis. According to autocytotoxic hypothesis, oxidative stress has been suggested to be the initial pathogenic event in melanocyte degeneration. OBJECTIVES: The aim of our investigation was to evaluate the role of oxidative stress by studying the role of catalase (CAT) in the destruction of melanocytes in patients with vitiligo and compare the same in healthy normal controls. MATERIALS AND METHODS: We determined the serum catalase enzyme by ELISA method. The catalase activity was studied in two groups, Group I-localized vitiligo: (i) active stage, (ii) static or inactive stage and Group II-generalized vitiligo: (i) active stage, (ii) static or inactive stage patients, and the levels were compared with healthy controls. RESULTS: Group I active stage patients showed significant difference in the catalase levels with a P < 0.044 when compared with healthy controls, whereas Group II static stage patients did not show any significant difference (P < 0.095) although the catalase activity was increased. CONCLUSION: Our study could not explain the cause of melanocyte damage in patients in the active stage of the disease. The increase in the oxidative stress as detected by catalase activity was more significant in Group I active disease than Group II active disease patients although the levels were higher than the healthy normals. This is the first study conducted on active and static stage of vitilgo in India. It is possible that the number of compounds of hydrogen peroxide produced is not balanced by the production of catalase in the body. PMID- 24350006 TI - Androgenetic alopecia and risk of coronary artery disease. AB - BACKGROUND: Androgenetic alopecia (AGA) or male pattern baldness (MPB) has been found to be associated with the risk of coronary artery disease (CAD). The well known risk factors are family history of CAD, hypertension, increased body mass index (BMI), central obesity, hyperglycemia, and dyslipidemia. The newer risk factors are serum lipoprotein-a (SL-a), serum homocysteine (SH), and serum adiponectin (SA). AIM: Identifying individuals at risk of CAD at an early age might help in preventing CAD and save life. Hence, a comparative study of CAD risk factors was planned in 100 males of AGA between the age of 25 and 40 years with equal number of age- and sex-matched controls. MATERIALS AND METHODS: Patients of AGA grade II or more of Hamilton and Norwood (HN) Scale and controls were examined clinically and advised blood test. The reports were available for fasting blood sugar (FBS), serum total serum cholesterol (SC) in 64 cases, 64 controls; lipoproteins (high, low, very low density, HDL, LDL, VLDL), serum triglycerides (ST) in 63 cases, 63 controls; SL-a in 63 cases, 74 controls; SH in 56 cases, 74 controls; and SA in 62 cases, 74 controls. RESULTS: In these cases family history (FH) of AGA and CAD was significantly high. The blood pressure (BP) was also found to be significantly high in the cases. The difference of mean serum HDL, LDL, VLDL, ST, SH, and SL-a in cases and controls were statistically significant and with increasing grade of AGA, the risk factors also increased. CONCLUSION: Patients with AGA appear to be at an increased risk of developing CAD, therefore, clinical evaluation of cases with AGA of grade II and above may be of help in preventing CAD in future. PMID- 24350007 TI - Necrobiosis lipoidica: A clinicopathological study in the Indian scenario. AB - CONTEXT: Necrobiosis lipoidica (NL) is a chronic granulomatous dermatitis that is commonly associated with diabetes mellitus. Most of the current knowledge about this entity is from western literature. AIMS: This study evaluates the clinicohistological features of NL in an Indian scenario. MATERIALS AND METHODS: We retrospectively reviewed clinical features, associated comorbidities, and biopsies of all patients with NL over a period of one year. RESULTS: Five cases of NL were seen during the duration of the study. The preliminary clinical diagnosis ranged from sarcoidosis to tinea incognito. The commonest clinical presentation in the Indian scenario was of asymptomatic erythematous to skin colored plaques and nodules on the shins with or without central atrophy. The most common site of involvement was the shin (3 of 5 patients). NL was associated with Diabetes mellitus in only two cases, both of whom were male patients. On histology, various patterns of inflammation were seen including the palisading, interstitial, and mixed granulomatous infiltrates. One patient had sarcoidal granulomas in association with an interstitial pattern. Features seen consistently in all cases include perivascular lymphoplasmacytic infiltrates, interstitial lymphocytic infiltrates, and fibroplasia. Interstitial mucin deposition was not observed in any of the biopsies. CONCLUSION: The diagnosis of NL was missed in most cases due to the rarity of the disease, absence of concomitant diabetes, and atypical presentations. Histology was a useful tool in clinching the diagnosis. PMID- 24350008 TI - Two cases of giant pyogenic granuloma of scalp. AB - Pyogenic granuloma is a benign vascular tumor of unknown etiology, though multiple factors play a role in its onset, e.g., trauma, chronic irritation, drugs etc., It is commonly seen in children and adolescents. Giant pyogenic granuloma is its atypical variant. We are presenting two cases of giant pyogenic granuloma, one, in a 28-year-old adult, presenting as a giant fluffy swelling of scalp and the other in a 11-year-old child, presenting as a giant ulcerated globular swelling of the scalp. PMID- 24350009 TI - Dystrophic epidermolysis bullosa associated with non-syndromic hypodontia. AB - Epidermolysis bullosa (EB) is a genetic disease associated with fragility and bullous lesions of the skin and mucous membranes. There are various patterns of inheritance and histopathology. The disease is associated with systemic and oral manifestations, among which may be dental decay necessitating oral rehabilitation. The aim of this article is to present the course of the condition in a child with dystrophic EB and also to report an association between EB, hypodontia, and supernumerary teeth which has not been reported earlier in literature. PMID- 24350010 TI - Benign cephalic histiocytosis. AB - A one and a half year old girl born of a non-consanguineous marriage presented with multiple asymptomatic erythematous to hyperpigmented and skin colored papules on both cheeks slowly increasing in number of 1 year duration. On the basis of clinical, histopathological, and immunohistochemistry findings, a diagnosis of benign cephalic histiocytosis was made. PMID- 24350011 TI - A rare case of onychomycosis in all 10 fingers of an immunocompetent patient. AB - Onychomycosis, traditionally referred as a non-dermatophytic infection of the nail, is now used as a general term to denote any fungal nail infection. It is an important public health problem due to its increasing incidence and has significant clinical consequences in addition to serving as a reservoir of infection. We report a case of Onychomycosis in all 10 fingers of an immunocompetent male with no co-morbid conditions caused by a non-dermatophytic fungus, Aspergillus niger. To the best of our knowledge, this is the first case of its kind to be reported. PMID- 24350012 TI - Perplexing purpura in two females: Rare case of autoerythrocyte sensitization syndrome. AB - Autoerythrocyte sensitization syndrome is a psychologically induced painful bruising condition. Two female, 19 and 30-year-old presented with recurrent episodes of painful ecchymotic bruising over accessible areas of body. In the younger female, episodes were since 3 years and were precipitated by stress and trivial trauma. The elder female presented with similar lesions since 3 months which were spontaneous in presentation. There were no obvious psychiatric manifestations in either. Clinically, ecchymotic changes in various stages of development were seen. Routine hemogram and coagulation profile were normal. Histopathology showed extravasated erythrocytes, perivascular neutrophils and fibrinoid deposition. Intradermal injection of autologous whole blood produced a painful ecchymotic reaction after 2 h similar to the presenting lesions. Psychiatric evaluation revealed mild mixed depression - anxiety disorder in the younger female while the latter revealed no abnormalities. The diagnosis of autoerythrocyte sensitization syndrome was made based on clinical history and findings, positive autoerythrocyte sensitization test, psychiatric evaluation and absence of any other clinical or laboratory pathology. PMID- 24350013 TI - Familial myomatosis cutis et uteri, segmental type 2. AB - Reed's syndrome or familial myomatosis cutis et uteri, an autosomal dominant inherited condition with incomplete penetrance, is characterized by multiple cutaneous and uterine leiomyomas.[1] Uterine leiomyomas usually commence earlier compared to that in the general population and cutaneous leiomyomas may precede, follow or occur concurrently. Few patients may have associated renal cell carcinoma. Herein we report a case of a 50-year-old female with multiple, painful cutaneous leiomyomas and who had undergone hysterectomy owing to large uterine fibroids. Her 18-year-old daughter also has uterine fibroids. PMID- 24350014 TI - Bullous scabies in an adult: A case report with review of literature. AB - Scabies is an infestation caused by Sarcoptes scabiei, characterized by polymorphous lesions that may include burrows, papules, nodules, excoriation, and crusts. Vesicular and bullous lesions are rather rare. Bullous scabies is regarded as a distinct subtype of scabies, closely resembling bullous pemphigoid. Here, we report a case of bullous scabies in an adult male and review the literature. PMID- 24350015 TI - Lupus pernio without systemic involvement. AB - Sarcoidosis is a multisystem, granulomatous disease of unknown etiology that can affect the pulmonary, reticulo-endothelial, skin, gastrointestinal, cardiac, musculo - skeletal, endocrine or central nervous system. Exclusive cutaneous involvement is very rare in sarcoidosis. Lupus pernio is a variant of cutaneous sarcoidosis presenting with erythematous to violaceous nodules and plaques located symmetrically over the nose, cheeks, ears and digits. We present a case of lupus pernio which showed rapid improvement with topical steroids and has yet not developed any systemic involvement even after 6 years of regular follow up. PMID- 24350016 TI - Post-steroid panniculitis: A rare case report. AB - Post-steroid panniculitis (PSP) is a rare clinical entity which presents after rapid withdrawal of high doses of systemic corticosteroids. As few as 20 cases have been reported in literature till now. Here, we report a case of post-steroid panniculitis occurring in a 9-year-old boy after rapid tapering and discontinuation of corticosteroids administered for the treatment of nephrotic syndrome. He presented with multiple erythematous painful indurated nodules over the face, arms, forearms, thighs, and legs. Histopathologic examination of the nodule revealed lobular panniculitis with lymphocytes, neutrophils, and multiple multinucleated giant cells. It also showed multiple needle-shaped clefts. Based on history, clinical features, and histopathologic findings, a diagnosis of post steroid panniculitis was made and the patient was restarted on systemic corticosteroids. The lesions resolved in 4 weeks. We report this case to highlight the importance of gradual tapering of corticosteroids. PMID- 24350017 TI - Inflammatory vitiligo versus hypopigmented mycosis fungoides in a 58-year-old Indian female. AB - Vitiligo, particularly the rarer inflammatory variant, may be difficult to distinguish from hypopigmented mycosis fungoides (MF) clinically. Complicating the distinction is that when biopsies are taken from the periphery of early vitiliginous lesions or from lesions with an inflammatory border (inflammatory vitiligo), a dermal lymphocytic infiltrate, exocytosis, interface dermatitis, and mild spongiosis may be seen, all resembling the findings seen in hypopigmented MF. We present a case demonstrating the difficulty in differentiating between these two diseases and examine some characteristic clinical and histopathological features of each. Often, a conclusive diagnosis cannot be made, necessitating close follow-up of the patient and monitoring for progression of their disease over time. PMID- 24350018 TI - Dermatomyositis associated with malignancy: A report of 3 cases. AB - The association between dermatomyositis (DMS) and various types of malignancies has been reported in several studies, with an estimated frequency of 20-25%. DMS may precede, accompany or follow the diagnosis of malignancy. In the present report, we have discussed three cases of dermatomyositis associated with malignancy. In the first case, DMS preceded the diagnosis of gastric adenocarcinoma while in the second and third cases, it followed the diagnosis of ductal carcinoma of the breast and transitional cell carcinoma of the bladder respectively. In all three patients, cutaneous and musculoskeletal features of DMS showed very good response to the treatment, irrespective of the course of malignancy. PMID- 24350019 TI - Follicular mucinosis. AB - Follicular mucinosis is an uncommon inflammatory disorder that characteristically presents as follicular papules and/or indurated plaques. The face, neck, and scalp are the most frequently affected sites, although lesions may occur on any site of the body. Histologically, the disorder is characterized by mucin deposition in the follicular epithelium. The condition is frequently divided into primary and secondary forms, with the latter form frequently associated with mycosis fungoides. In this case report, we describe a child with follicular mucinosis of the back and trunk and discuss the clinical variants, histopathological pattern, and treatment options. PMID- 24350020 TI - Disseminated Mycobacterium chelonae infection: Complicating a case of hidradenitis suppurativa. AB - Mycobacteium chelonae is a rapidly growing atypical mycobacteria known to be pathogenic in humans. We report a case of Hidradenitis Suppurativa (HS) with diabetes complicated by infection of the lesions with Staphylococcus aureus and M. chelonae leading to non-healing and discharging lesions. HS is a rare, insidious and debilitating disease characterized by swollen, painful, inflamed lesions in the axillae, groin, and other parts of the body that contain apocrine glands. Discharge from HS lesions are often found to be sterile, however, polymicrobial bacterial colonization commonly occurs within sinus tracts which can lead to offensive smelling discharge, infection, cellulitis, and superinfection. The incidence of HS is very low and the association with M. chelonae makes it a rare and interesting case. PMID- 24350021 TI - Erythrokeratodermia variabilis: Two case reports. AB - Erythrokeratodermia variabilis (EKV) is a rare heterogeneous skin disorder. The classical EKV first described by Mendes da Costa is characterized by two types of skin lesions: (1) figurate hyperkeratotic plaques, and (2) transient erythematous areas. Herein, we report two patients presenting with erythematous and hyperkeratotic lesions that were histopathologically diagnosed with EKV. PMID- 24350022 TI - Amyloidosis cutis dyschromica. AB - Amyloidosis cutis dyschromica is a very rare form of primary cutaneous amyloidosis characterized by prepubertal onset of hyper and hypopigmented spots and amyloid deposits in the papillary dermis. We report a case of a 26 year old female with amyloidosis cutis dyschromica who presented with dyschromic skin since birth. PMID- 24350024 TI - Unilateral acrosyringeal lichen planus of palm. AB - Lichen planus (LP) is a pruritic, benign, papulosquamous, inflammatory dermatosis of unknown etiology that affects either or all of the skin, mucus membrane, hair and nail. It presents with varied morphology on the palms and soles. Here we present a case of unusual acrosyringeal variant of LP on palm. The diagnosis was confirmed histologically. PMID- 24350023 TI - Progressive symmetric erythrokeratoderma with nephrotic syndrome: Coincidence or new association? AB - Progressive symmetric erythrokeratoderma (PSEK) is a rare genodermatosis with variable inheritance. It is characterized by symmetrical, erythematous, and hyperkeratotic plaques on the extremities. We report a case of a 15-year-old boy with PSEK of autosomal recessive inheritance associated with nephrotic syndrome. PMID- 24350025 TI - Dermpath quiz. PMID- 24350026 TI - Interest in leprosy is alive among young dermatologists: An account of IADVL CME and workshop on leprosy held in Hyderabad, India. PMID- 24350027 TI - Synopsis of Diet in Dermatology: A one day CME conducted by the Department of Dermatology, Kasturba Medical College, Manipal, March 3, 2013. AB - Food is intricately related to mind and body and is one of the elements sustaining life, in disease as well as in health. There are many myths and misgivings regarding partake of food and its medicinal properties. The Department of Dermatology, Kasturba Medical College (KMC), Manipal organized a continuing medical education (CME) on Diet in Dermatology on 3(rd) March 2013 focusing on pertinent issues regarding diet and medicinal use of food. PMID- 24350028 TI - Vismodegib: A smoothened inhibitor for the treatment of advanced basal cell carcinoma. AB - Incidence of basal cell carcinoma (BCC), the most common skin cancer in humans, is rising. Surgery is the mainstay of treatment but there is no standard of care for locally advanced or metastatic disease. Hedgehog signaling proteins are critical for cell growth and differentiation during embryogenesis; Hh pathway is silenced in adults. Dysregulated or aberrant Hh signaling has been implicated in the pathogenesis of BCC. This hyperactive pathway can be inhibited by use of smoothened inhibitors such as vismodegib. Food and drug administration approved this oral, once-daily medication in 2012 to treat adults with metastatic BCC or locally advanced, recurrent BCC after surgery and also for patients with locally advanced BCC who are not candidates for surgery or radiation treatment. Clinical studies have shown it to be highly efficacious and the most common adverse effects include, muscle spasms, alopecia and dysgeusia. Use of targeted biologic modifiers, exemplified by Hh directed therapeutics offer a new hope to patients with high-surgical morbidity or inoperable tumors. PMID- 24350029 TI - Zosteriform herpes simplex and herpes zoster: A clinical clue. PMID- 24350030 TI - A cases series of Piezogenic pedal papules. PMID- 24350031 TI - Chromoblastomycosis: Report of two cases on face from urban industrial area. PMID- 24350032 TI - SkIndia Quiz 11 Pigmented plaque on abdomen. PMID- 24350033 TI - Nevus lipomatosus cutaneous superficialis. PMID- 24350034 TI - Kyrle's disease. PMID- 24350035 TI - Nasal dermoid sinus cyst in a young female. PMID- 24350036 TI - Cavamax W7 composite psoralen ethosomal gel versus cavamax W7 psoralen solid complex gel for topical delivery: A comparative evaluation. AB - AIM: The present research work was aimed to formulate and characterize psoralen encapsulated cavamax W7 composite ethosomal gel and compare its in vitro and ex vivo behavior against psoralen-cavamax W7-complex reference gel. MATERIALS AND METHODS: A total of nine formulations of composite ethosomes were prepared by injection method using 3(2) factorial design and entrapment efficiency was designated as dependent variable. Concomitantly, psoralen was complexed with cavamax W7 (1:1 molar ratio) by kneading method and formation of complex was confirmed by Diffuse reflectance spectroscopy (DRS), scanning electron microscopy (SEM), X-ray diffraction (XRD), and differential scanning calorimetry (DSC). RESULTS: F9 with vesicle size of 183 +/- 2.8 nm, and highest % entrapment efficiency of 98.12 +/- 1.15 was selected as optimized formulation. Transmission electron microscopy (TEM) revealed uniform and spherical shaped vesicles. The optimized formulation F9 was formulated as carbapol gel and compared against ethosomal gel, psoralen gel, and psoralen cavamax W7 complex gel. The gels were evaluated for permeation characteristics and the rank order was composite ethosomal gel > ethosomal gel > psoralen-cavamax W7 complex gel > psoralen gel. The ethosomal gel (G5) with highest in vitro permeation of 82.48 +/- 2.23% was subjected to in vivo Confocal laser scanning microscopy (CLSM) studies using rhodamine B as tracer. The penetration of rhodamine B was uniform, deeper, and two times faster into epidermis than control gel. CONCLUSION: Conclusively, cavamax W7 composite ethosomes present themselves as efficient carrier for superior topical delivery of psoralen and have potential for clinical applications in minimizing side effects associated with photosensitivity of psoralen. PMID- 24350037 TI - Formulation, characterization, in vitro, in vivo, and histopathological evaluation of transdermal drug delivery containing norfloxacin and Curcuma longa. AB - OBJECTIVE: In an attempt for better treatment of bacterial infections and burn wounds, semisolid formulations containing norfloxacin (NF) and natural wound healing agent Curcuma longa were prepared. The rationale behind employing combination of NF and Curcuma longa is to obtain synergistic wound healing effect. The prepared formulations were compared with silver sulfadiazine cream 1%, USP. MATERIALS AND METHODS: Various ointments containing NF and C. longa were prepared using standard procedures. These formulations were evaluated for antimicrobial activity against various strains of aerobic and anaerobic microorganisms. The wound healing property was evaluated by histopathological examination and by measuring the wound contraction. RESULTS: The significant antimicrobial and wound healing effects were demonstrated by formulations which are comparable with silver sulfadiazine 1% cream (P < 0.05). Various morphological changes were observed by histopathology during the study period (days 1, 4, 8, and 12) which also supported the wound healing process. CONCLUSION: Based on the observed antimicrobial and wound healing effects, the formulations containing combination of NF and Curcuma longa could be employed as an alternative to commercial silver sulfadiazine 1% cream. This innovative mode of formulation can be employed for making burn wound healing process more effective. PMID- 24350038 TI - Teucrium polium L. extract adsorbed on zinc oxide nanoparticles as a fortified sunscreen. AB - INTRODUCTION: Zinc oxide nanoparticles (ZnOn) have been used as carriers and sun protecting agents for Teucrium polium L. extract to enhance sun protection. ZnOn was synthesized by hydrolyzing zinc acetate using sodium hydroxide with mean particle diameter less than 500 nm. MATERIALS AND METHODS: Top flowerings of T. polium L. were extracted by percolation method with petroleum ether, chloroform, and 80% methanol consecutively. Methanolic extract was lyophilized and used as a flavonoid-rich fraction. Sunscreen was prepared by the reconstitution of 0.5 g of the lyophilized extract in water and mixing with 0.5 to 2 g zinc-oxide (ZnO). Sun protection factor (SPF) of the aqueous extract of T. polium, the prepared gel, as well as the zinc oxide suspension alone and in combination with each other was determined spectrophotometrically based on a modified Transpore((r)) tape method. RESULTS AND CONCLUSION: Obtained results showed that the T. polium extract has a wide band of ultraviolet radiation (UV) spectrum absorption ranging from 250 nm to 380 nm. SPF of the combination product in the ultraviolet B (UVB) area was greater than 80, revealing a synergistic action between ZnO and T. polium. The adsorption of flavonoids of T. polium on Zinc-oxide nanoparticles (ZnOn) slowed down their release thereby lengthening their persistence on the skin and contributing to further duration of action. PMID- 24350039 TI - Zinc cross-linked hydroxamated alginates for pulsed drug release. AB - INTRODUCTION: Alginates can be tailored chemically to improve solubility, physicochemical, and biological properties and its complexation with metal ion is useful for controlling the drug release. MATERIALS AND METHODS: Synthesized N,O dimethyl, N-methyl, or N-Benzyl hydroxylamine derivatives of sodium alginate were subsequently complexed with zinc to form beads. Hydroxamation of sodium alginate was confirmed by Fourier transform infra-red spectroscopy (FTIR) and differential scanning calorimetry (DSC). RESULTS: The synthesized polymeric material exhibited reduced aqueous, HCl and NaOH solubility. The hydroxamated derivatives demonstrated pulsed release where change in pH of the dissolution medium stimulated the atenolol release. CONCLUSION: Atenolol loaded Zn cross-linked polymeric beads demonstrated the sustained the plasma drug levels with increased half-life. Although the synthesized derivatives greatly altered the aqueous solubility of sodium alginate, no significant differences in in vitro and in vivo atenolol release behavior amongst the N,O-dimethyl, N-methyl, or N-Benzyl hydroxylamine derivatives of sodium alginate were observed. PMID- 24350040 TI - Formulation and evaluation of sustained release enteric-coated pellets of budesonide for intestinal delivery. AB - INTRODUCTION: The aim of present work was to develop intestinal-targeted pellets of Budesonide, a potent glucocorticoid, used for the treatment of ulcerative colitis and Crohn's disease by extrusion and spheronization method. Current available oral formulations of Budesonide have low efficacy because of the premature drug release in the upper part of the gastrointestinal tract. In this study, a pH-controlled intestinal-targeted pellet of budesonide was established using 3(2) full factorial design by giving an enteric coating with Eudragit S100. MATERIALS AND METHODS: Budesonide-sustained release pellets were prepared by extruder and spheronization technique using a combination of water-soluble and permeable polymers by applying 3(2) full factorial design. The pellets were coated by spray coating technique using Eudragit S100 as an enteric polymer. The pellets were characterized for its flowability, sphericity, friability, and in vitro drug release. Release behaviour was studied in different pH media. The release profile was studied for the mechanism of drug release. RESULT: The optimized formulation showed negligible drug release in the stomach followed by release for 12 h in the intestinal pH. Differential scanning calorimetry and Fourier Transform Infrared Spectroscopy studies indicated no interaction between drug and polymer. Scanning Electron Microscopy image of coated pellets suggested a uniform and smooth coat over the surface of pellets. Accelerated stability studies showed a stable nature of drug in the formulation. All evaluation parameter showed that pellets were good in spherocity and flowability. CONCLUSION: Sustained release pellets of Budesonide could be prepared by extrusion and spheronization which released the drug in intestinal pH for an intestine to treat inflammatory bowel disease. A ratio of polymer combination could be decided using a full factorial design. PMID- 24350041 TI - In vitro and in vivo assessment of piroxicam incorporated Aloe vera transgel. AB - BACKGROUND: The aim of the study was to develop piroxicam-Aloe vera gel (PAG) formulation and make a pharmacodynamic evaluation of the formulation. MATERIALS AND METHODS: The gel was prepared by using carbopol 934 as gelling agent and methyl paraben as a preservative in an Aloe vera gel base. The formulated gel was also evaluated for physicochemical parameters like pH, viscosity, drug content, and in vitro diffusion assessment. Pharmacodynamic activity of the formulation was evaluated in Wistar albino rats. The formulated gel was compared with that of similar marketed gel (commercial piroxicam gel (CPG)) against the same parameters. RESULTS: From in vitro studies, an effective drug release from PAG was observed to be 68.17% when compared with that of the CPG (62.71%) at 180 min indicating better drug release from the gel formulated in this study. Percentage inhibition of edema was greater for the preparation of PAG (29.57 mean percent inhibition after 60 min) compared to marketed gel which exhibited 18.3% after 60 min. CONCLUSION: It was concluded from the results that the Aloe vera gel acts as an effective gel base to prepare piroxicam gel with high drug loading capacity and improved anti-inflammatory effect. From the statistical analysis the formulation of PAG showed better release than the CPG at p < 0.05 level of significance. PMID- 24350042 TI - Development and evaluation of 6-mercaptopurine and metoclopramide polypill formulation for oral administration: In-vitro and ex vivo studies. AB - INTRODUCTION: The present investigation was to develop a polypill of 6 mercaptopurine and metoclopramide. A polypill with delayed release granules of an anticancer and immediate release mucoadhesive tablet of antiemetic may result in the reduction of emesis caused by oral chemotherapy. MATERIALS AND METHODS: 6 Mercaptopurine granules were prepared by wet granulation process. Chitosan, hydroxypropyl methylcellulose, and ethylcellulose were used as individually as delayed release polymers. Seven granule formulations (F1-F7) were prepared and evaluated for flow properties and drug content. Immediate release mucoadhesive tablets of metoclopramide were prepared by direct compression technique using pectin and PVPK-40 as mucoadhesive polymers. Three formulations of pectin (L1-L3) and three formulations of PVPK40 (M1-M3) were prepared using lactose, magnesium stearate, and mannitol and talc as diluent and glidant, respectively. Tablets were evaluated for weight variation, hardness, friability, drug content, ex vivo mucoadhesion time, and in vitro dissolution studies. RESULTS: Formulation F2, F4, F5, and F7 showed maximum drug content. Formulation F7 exhibited the drug release up to 2 h and was selected as the best delayed release formulation. All formulations of metoclopramide showed good drug content ranging from 97.6 % to 100.6%. Formulation M2 among tablets prepared with PVP exhibited desired mucoadhesion time of 15.33 min which prolongs the duration of drug release in gastric pouch of the male Wistar rats. Both the selected formulations F7 and M2 were filled into body of capsule size 0 and capsule was evaluated for technological properties. CONCLUSION: It may be concluded that polypill released the metoclopramide immediately prior to 6-mercaptopurine. PMID- 24350044 TI - SPER 3(rd) Annual Conference: 8 March 2014 at Lovely Professional University (LPU), Punjab, India. PMID- 24350043 TI - Evaluation of in vivo efficacy and toxicity of prednisolone-loaded hydrogel-based drug delivery device. AB - Drugs prescribed for the treatment of moderate to severe inflammatory bowel disease (IBD) are associated with number of side effects. Targeted drug delivery is essential for the treatment of inflammatory bowel disease in order to increase efficacy and reduce toxicity. The established delivery system is designed on enzyme and time-based release of poorly soluble prednisolone, a drug of choice for the treatment of moderate to severe inflammatory bowel disease. Their pharmacological evaluation was done in 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced model of colitis in rat. The drug was administered once daily for 3 consecutive days. Visible severity of colitis, tissue to bodyweight ratio, tissue histology along with nitric oxide (NO), malondialdehyde (MDA) and myeloperoxidase (MPO) activity of colonic tissue were studied to estimate the efficacy of the drug-loaded delivery system. The highest efficacy was observed for formulation in which Eudragit RS100 (EU) was used along with guar gum (GG) in a ratio 2:5 for the preparation of delivery device. An effective recovery was observed from the study of tissue histology of animals treated with the drug loaded optimized formulation and the biochemical parameters supported it. The toxicity of prednisolone (PD) was reduced significantly as predicted from thymus to body weight ratio of treated animals. GG and EU RS100 provided a newer bipolymer combination for the colon-targeted delivery of PD which increased its efficacy and reduced the toxic side effects. The in vivo experiments presented effective amelioration from colitis in TNBS-induced animal model of colitis. PMID- 24350045 TI - Evolution of quality control in pharmaceutical technology. PMID- 24350046 TI - GHB acid: A rage or reprive. AB - Gamma-hydroxybutyric acid (GHB) is a naturally occurring analog of gamma aminobutyric acid (GABA) that has been used in research and clinical medicine for many years. GHB was used clinically as an anesthetic in the 1960s but was withdrawn due to side effects that included seizures and coma. GHB has been implicated in a number of crime types; most notably in drug-facilitated sexual assault. GHB is abused by three main groups of users: Body builders who use the substance believing that it stimulated the release of growth hormone; sexual predators who covertly administer the drug for its sedative and amnesic effects and club-goers (rave parties) who take the drug for its euphoric effects. The short-lived hypnotic effects, relative safety and widespread availability of the drug have made it particularly well suited to this role. The drug has an addictive potential if used for long term. The primary effects of GHB use are those of a CNS depressant and therefore range from relaxation, to euphoria, confusion, amnesia, hallucinations, and coma. Despite the increased regulation, GHB remains widely available through the Internet where one can easily purchase the necessary reagents as well as recipes for home production. There are reports of patients being unresponsive to painful stimuli and cases of oral self mutilations linked to the abuse of GHB, though quiet rare. Such cases should remind odontologists that intra-oral lesions may be the result of self-mutilation either due to mental illness or altered states caused by the use of prescription or non-prescription drugs. PMID- 24350047 TI - Interference from ordinarily used solvents in the outcomes of Artemia salina lethality test. AB - Methanol, ethanol, Tween 20 and dimethyl sulfoxide (DMSO) are widely used as dissolving agents in Artemia salina lethality test (aka brine shrimp lethality test [BSLT]) to screen the pharmaceutical properties of natural products. Nevertheless, there is lack of toxicity level of these solvents against brine shrimp. High concentration of these organic solvent might be toxic for this zoology invertebrate and interfere in the experimental outcomes. To avoid this, permissible concentration of the solvents used in BSLT was identified. BSLT was performed to evaluate the toxicity effect of Tween 20, methanol, ethanol and DMSO at 24 h post-treatment time point against A. salina. The suggested maximum working concentration (v/v) for DMSO, methanol, ethanol was found to be 1.25% and that for Tween 20 was 0.16%. LC50 for the solvents were 8.5% (DMSO), 6.4% (methanol), 3.4% (ethanol) and 2.5% (Tween 20). The findings have shown a toxicity level among the solvents in descending order as Tween 20 > ethanol > methanol > DMSO. DMSO is a safer solvent to be used in BSLT compared with other tested solvents, whereas Tween 20 has been shown to be the most stringent solvent among the tested solvents. The findings are resourcefully useful to avoid interference of solvents in the assessment of natural products using BSLT. PMID- 24350048 TI - Extent of poly-pharmacy, occurrence and associated factors of drug-drug interaction and potential adverse drug reactions in Gondar Teaching Referral Hospital, North West Ethiopia. AB - The aim of this study was to assess the extent of poly-pharmacy, occurrence, and associated factors for the occurrence of drug-drug interaction (DDI) and potential adverse drug reaction (ADR) in Gondar University Teaching Referral Hospital. Institutional-based retrospective cross-sectional study. This study was conducted on prescriptions of both in and out-patients for a period of 3 months at Gondar University Hospital. Both bivariate analysis and multivariate logistic regression were used to identify risk factors for the occurrence of DDI and possible ADRs. All the statistical calculations were performed using SPSS((r)) software. A total of 12,334 prescriptions were dispensed during the study period of which, 2,180 prescriptions were containing two or more drugs per prescription. A total of 21,210 drugs were prescribed and the average number of drugs per prescription was 1.72. Occurrences of DDI of all categories (Major, Moderate, and Minor) were analyzed and DDI were detected in 711 (32.6%) prescriptions. Sex was not found to be a risk factor for the occurrence of DDI and ADR, while age and number of medications per prescription were found to be significant risk factors for the occurrence of DDI and ADR. The mean number of drugs per prescription was 1.72 and hence with regard to the WHO limit of drugs per prescription, Gondar hospital was able to maintain the limit and prescriptions containing multiple drugs supposed to be taken systemically. Numbers of drugs per prescription as well as older age were found to be predisposing factors for the occurrence of DDI and potential ADRs while sex was not a risk factor. PMID- 24350049 TI - Efficacy of a classical antiobesity Unani pharmacopial formulation (Safoof-e Muhazzil) in systolic and diastolic blood pressure: A randomized, open-labeled, controlled clinical study. AB - The aim of this study is to evaluate the efficacy of a Unani formulation in hypertension. A total of 90 patients with total cholesterol level of more than 220 mg/dl with associated conditions were included in this study. A total of 30 patients having a mean systolic blood pressure (BP) of 133.86 mmHg comprising Group A received Unani formulation Safoof-e-Muhazzil (SM) in its classical powder form in the dose of 5 g twice a day orally. Group B comprising of 30 patients with a mean systolic BP of 133.13 mmHg received same drug, but in compressed tablet form in the same dosage, whereas, 30 patients comprising Group C with a mean systolic BP of 129.45 mmHg, received Atorvastatin 10 mg as a standard control. Patients were evaluated on each follow-up at 2(nd), 4(th) and 6(th) week. The mean systolic BP in Group A and B before treatment was 133.86 +/- 3.028 mmHg and 133.13 +/- 2.852 mmHg, which significantly decreased to 119.33 +/- 1.922 mmHg (P < 0.001) and 119 +/- 1.760 mmHg (P < 0.001) respectively. In the control Group C before treatment BP was 129.45 +/- 2.499 mmHg and after treatment it significantly decreased to 124.34 +/- 1.794 mmHg (P < 0.01). The percentage change after treatment was 10.85%, 10.61% and 3.94% respectively in each group. Mean diastolic BP in Group A and B before treatment was 85.06 +/- 2.11 mmHg and 84.56 +/- 1.5 mmHg, which significantly decreased to 79.06 +/- 1.56 mmHg (P < 0.001) and 79.96 +/- 1.15 mmHg (P < 0.001) respectively, BP before treatment in Group C was 83.23 +/- 1.588 mmHg, which was decreased to 124.34 +/- 1.794 mmHg (P < 0.01). The study results indicate that the test drug was quite effective in reducing both systolic as well as diastolic BP. PMID- 24350050 TI - Rationalized design, synthesis and pharmacological screening of amino acid linked spiro pyrrolidino oxyindole analogs through environment friendly reaction. AB - INTRODUCTION: The development of newer synthetic approaches toward the synthesis of polynuclear heteroaromatics and their application in the synthesis of some biologically active compounds has been discussed in this study. MATERIALS AND METHODS: The synthesis of novel spiro pyrrolidino oxindoles was performed for the construction of amino acid linked polynuclear heteroaromatics by cycloaddition reaction. This reaction method is one of the most important methods for the construction of spiro pyrrolidino oxindole from the commercially available starting material isatin. Then the synthesized compounds were subjected for evaluation of nitric oxide scavenging and cytotoxic effects against tumor cell lines. RESULTS: All the six synthesized compounds demonstrated promising antioxidant and cytotoxic effects in vitro. CONCLUSION: Form the present study, it can be concluded that the synthesized compounds are fruitful in terms of their chemical purity, structural novelty, marked biological activities (antioxidant and cytotoxic) in vitro and last of all the lucid and picturesque synthetic methodology to synthesize the molecules in a in a non-hazardous and environmental friendly way. PMID- 24350051 TI - In-vitro alpha amylase and glycosidase inhibitory effect of ethanolic extract of antiasthmatic drug - Shirishadi. AB - Asthma and diabetes have strong relationship; both are cause and effect of each other. Oxidative stress due to bronchial asthma may cause insulin resistance whereas lack of proper insulin can cause defective smooth muscle relaxant. There is no single medicine available that can manage both diseases, rather the mainstay treatment of bronchial asthma causes hyperglycemia. Keeping this problem in focus, in this study the hypoglycemic effect of an indigenous antiasthmatic Ayurvedic drug Shirishadi was evaluated. Pancreatic alpha amylase and glucosidase inhibitors offer an effective strategy to lower the level of post prandial hyperglycemia via control of starch breakdown. For evaluation of hypoglycemic activity of drug, in-vitro alpha amylase and alpha glucosidase enzyme inhibition was calculated. Ethanolic extract of compound showed 76.40% + 0.88% reduction in alpha amylase activity and 63.85% + 0.36% in alpha glucosidase activity with IC50 0.68 mg/ml and 2.89 mg/ml, respectively. This study suggests that the ethanolic extract of Shirishadi polyherbal compound effectively acts as alpha amylase and glucosidase inhibitor leading to a reduction in starch hydrolysis and hence acts as antiasthmatic as well as hypoglycemic drug. PMID- 24350052 TI - Effect of formulation factors on in vitro transcorneal permeation of voriconazole from aqueous drops. AB - The purpose of this research was to evaluate the effect the formulation factors on in vitro permeation of voriconazole through freshly isolated goat and sheep corneas. An increase in the pH of the drops from 4.0 to 8.0 resulted in significant (P < 0.05) increase drug permeation. Raising concentration of the drops from 0.05% to 0.2% (w/v) significantly, (P < 0.05) increased drug permeation, but decreased the percent permeation. Corneal transport of voriconazole is both pH and concentration dependent. Eye drops containing disodium edetate (ethylenediaminetetraacetic acid) alone or combination with benzalkonium chloride showed significantly (P < 0.05) higher permeation as compared with control formulation. Addition of beta-cyclodextrin to the formulation enhanced corneal permeation of voriconazole. Compared with control formulation, voriconazole 0.2% (w/v) drop containing viscosity modifier produced significant (P < 0.05) decrease in permeation. Most of the formulations showed higher zone of inhibition against Candida albicans. PMID- 24350053 TI - Management of knee osteoarthritis with cupping therapy. AB - The study aimed to evaluate the effect of cupping therapy at a clinical setting for knee osteoarthritis. A randomized, controlled clinical trial was conducted. Cupping was performed on 0-6(th) day; 9-11(th) day and 14(th) day, i.e., 11 sittings follow-up to determine longer term carryover of treatment effects utilizing both objective and subjective assessment. The assessment was performed before and after treatment spreading over a period of 15 days. The results of this study shows significant and better results in the overall management of knee osteoarthritis, particularly in relieving pain, edema, stiffness and disability. The efficacy of treatment with cupping therapy in relieving signs and symptoms of knee osteoarthritis is comparable to that of acetaminophen 650 mg thrice a day orally, in terms of analgesia, anti-inflammatory and resolution of edema with minimal and temporary side-effects like echymosis and blister formation while as control drug has greater side-effects particularly on upper gastrointestinal tract. It is recommended that further studies are conducted with a larger study samples and of longer duration. PMID- 24350054 TI - Polypharmacy: The past, present and the future. PMID- 24350055 TI - Beyond DNA Repair: Additional Functions of PARP-1 in Cancer. AB - Poly(ADP-ribose) polymerases (PARPs) are DNA-dependent nuclear enzymes that transfer negatively charged ADP-ribose moieties from cellular nicotinamide adenine-dinucleotide (NAD(+)) to a variety of protein substrates, altering protein-protein and protein-DNA interactions. The most studied of these enzymes is poly(ADP-ribose) polymerase-1 (PARP-1), which is an excellent therapeutic target in cancer due to its pivotal role in the DNA damage response. Clinical studies have shown susceptibility to PARP inhibitors in DNA repair defective cancers with only mild adverse side effects. Interestingly, additional studies are emerging which demonstrate a role for this therapy in DNA repair proficient tumors through a variety of mechanisms. In this review, we will discuss additional functions of PARP-1 - including regulation of inflammatory mediators, cellular energetics and death pathways, gene transcription, sex hormone- and ERK mediated signaling, and mitosis - and the role these PARP-1-mediated processes play in oncogenesis, cancer progression, and the development of therapeutic resistance. As PARP-1 can act in both a pro- and anti-tumor manner depending on the context, it is important to consider the global effects of this protein in determining when, and how, to best use PARP inhibitors in anticancer therapy. PMID- 24350056 TI - Unveiling stem cell kinetics: prime time for integrating experimental and computational models. PMID- 24350058 TI - Rationale for stereotactic body radiation therapy in treating patients with oligometastatic hormone-naive prostate cancer. AB - Despite advances in treatment for metastatic prostate cancer, patients eventually progress to castrate-resistant disease and ultimately succumb to their cancer. Androgen deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer and has been shown to improve median time to progression and median survival time. Research suggests that castrate-resistant clones may be present early in the disease process prior to the initiation of ADT. These clones are not susceptible to ADT and may even flourish when androgen-responsive clones are depleted. Stereotactic body radiation therapy (SBRT) is a safe and efficacious method of treating clinically localized prostate cancer and metastases. In patients with a limited number of metastatic sites, SBRT may have a role in eliminating castrate-resistant clones and possibly delaying progression to castrate-resistant disease. PMID- 24350059 TI - Searching for the Achilles Heel of FOXP3. AB - FOXP3 is a multifaceted transcription factor with a major role in the control of immune homeostasis mediated by T regulatory cells (Treg). The immunoregulatory function of FOXP3 may hinder the induction of immune responses against cancer and infectious agents, and thus, development of inhibitors of its functions might give new therapeutic opportunities for these diseases. But also, FOXP3 is an important tumor suppressor factor in some types of cancers, and therefore, understanding the structure and function of FOXP3 is crucial to gaining insights into the development of FOXP3-targeted therapeutic strategies. FOXP3 homodimerize and likely form supramolecular complexes which might include hundreds of proteins which constitute the FOXP3 interactome. Many of the functions of FOXP3 are clearly regulated by the interactions with these cofactors contributing importantly on the establishment of Treg-cell signature. We summarize here the structural/functional information on this FOXP3 complex, to identify potential opportunities for the development of new strategies to modulate FOXP3 activity. PMID- 24350060 TI - Caspase-2 mediates a Brucella abortus RB51-induced hybrid cell death having features of apoptosis and pyroptosis. AB - Programmed cell death (PCD) can play a crucial role in tuning the immune response to microbial infection. Although PCD can occur in different forms, all are mediated by a family of proteases called caspases. Caspase-2 is the most conserved caspase, however, its function in cell death is ill-defined. Previously we demonstrated that live attenuated cattle vaccine strain Brucella abortus RB51 induces caspase-2-mediated and caspase-1-independent PCD of infected macrophages. We also discovered that rough attenuated B. suis strain VTRS1 induces a caspase-2 mediated and caspase-1-independent proinflammatory cell death in infected macrophages, which was tentatively coined "caspase-2-mediated pyroptosis". However, the mechanism of caspase-2-mediated cell death pathway remained unclear. In this study, we found that caspase-2 mediated proinflammatory cell death of RB51-infected macrophages and regulated many genes in different PCD pathways. We show that the activation of proapoptotic caspases-3 and -8 was dependent upon caspase-2. Caspase-2 regulated mitochondrial cytochrome c release and TNFalpha production, both of which are known to activate caspase-3 and caspase-8, respectively. In addition to TNFalpha, RB51-induced caspase-1 and IL-1beta production was also driven by caspase-2-mediated mitochondrial dysfunction. Interestingly, pore formation, a phenomenon commonly associated with caspase-1 mediated pyroptosis, occurred; however, unlike its role in S. typhimurium-induced pyroptosis, pore formation did not contribute to RB51-induced proinflammatory cell death. Our data suggest that caspase-2 acts as an initiator caspase that mediates a novel RB51-induced hybrid cell death that simulates but differs from typical non-proinflammatory apoptosis and caspase-1-mediated proinflammatory pyroptosis. The initiator role of the caspase-2-mediated cell death was also conserved in cellular stress-induced cell death of macrophages treated with etoposide, naphthalene, or anti-Fas. Caspase-2 also regulated caspase-3 and -8 activation, as well as cell death in macrophages treated with each of the three reagents. Taken together, our data has demonstrated that caspase-2 can play an important role in mediating a proinflammatory response and a hybrid cell death that demonstrates features of both apoptosis and pyroptosis. PMID- 24350063 TI - Zinc and copper toxicity in host defense against pathogens: Mycobacterium tuberculosis as a model example of an emerging paradigm. PMID- 24350061 TI - Aerosol-induced brucellosis increases TLR-2 expression and increased complexity in the microanatomy of astroglia in rhesus macaques. AB - Brucella melitensis, a bacterial pathogen and agent of epizootic abortion causes multiple pathologies in humans as well as a number of agriculturally important animal species. Clinical human brucellosis manifests as a non-specific, chronic debilitating disease characterized by undulant fever, arthropathies, cardiomyopathies and neurological sequelae. These symptoms can occur acutely for a few weeks or persist for months to years. Within the brain, endothelial and glial cells can be infected leading to downstream activation events including matrix metalloprotease (MMP) and cytokine secretion and Toll-like receptor (TLR) signaling. These events are likely to lead to tissue remodeling, including morphologic changes in neuronal and glial cells, which are linked to neurological complications including depressive behavior, immune activation and memory loss. Our hypothesis was that B. melitensis infection and neurobrucellosis would lead to activation of astrocytes through upregulation of TLR2 and stimulate concurrent changes in the microanatomy. All six animals were infected via inhalation route. TLR2 expression was approximately doubled in white matter astrocytes of infected rhesus macaques. There was also a 50% increase in the number of astrocytes per unit area in subcortical white matter tracts suggesting increased innate immune activation. This coincided with dramatic increases in the length and complexity of the cell arbor of hypertrophic astrocytes in both cortical gray and white matter. Thus, aerosol-induced brucellosis results in dramatically increased innate immune activation of astrocytes in the absence of widespread neuroinflammation. PMID- 24350062 TI - Listeria monocytogenes, a down-to-earth pathogen. AB - Listeria monocytogenes is the causative agent of the food-borne life threatening disease listeriosis. This pathogenic bacterium received much attention in the endeavor of deciphering the cellular mechanisms that underlie the onset of infection and its ability to adapt to the food processing environment. Although information is available on the presence of L. monocytogenes in many environmental niches including soil, water, plants, foodstuff and animals, understanding the ecology of L. monocytogenes in outdoor environments has received less attention. Soil is an environmental niche of pivotal importance in the transmission of this bacterium to plants and animals. Soil composition, microbial communities and macrofauna are extrinsic edaphic factors that direct the fate of L. monocytogenes in the soil environment. Moreover, farming practices may further affect its incidence. The genome of L. monocytogenes presents an extensive repertoire of genes encoding transport proteins and regulators, a characteristic of the genome of ubiquitous bacteria. Postgenomic analyses bring new insights in the process of soil adaptation. In the present paper focussing on soil, we review these extrinsic and intrinsic factors that drive environmental adaptation of L. monocytogenes. PMID- 24350064 TI - Food and water security issues in Russia III: food- and waterborne diseases in the Russian Arctic, Siberia and the Far East, 2000-2011. AB - BACKGROUND: The food- and waterborne disease situation in Russia requires special attention. Poor quality of centralized water supplies and sewage systems, biological and chemical contamination of drinking water, as well as contamination of food products, promote widespread infectious diseases, significantly exceeding nationwide rates in the population living in the two-thirds of Russian northern territories. OBJECTIVES: The general aim was to assess the levels of food- and waterborne diseases in selected regions of Russian Arctic, Siberia and the Far East (for the period 2000-2011), and to compare disease levels among regions and with national levels in Russia. STUDY DESIGN AND METHODS: This study is the first comparative assessment of the morbidity in these fields of the population of 18 selected regions of Russian Arctic, Siberia and the Far East, using official statistical sources. The incidences of infectious and parasitic food- and waterborne diseases among the general population (including indigenous peoples) have been analyzed in selected regions (per 100,000 of population, averaged for 2000-2011). RESULTS: Among compulsory registered infectious and parasitic diseases, there were high rates and widespread incidences in selected regions of shigellosis, yersiniosis, hepatitis A, tularaemia, giardiasis, enterobiasis, ascariasis, diphyllobothriasis, opistorchiasis, echinococcosis and trichinellosis. CONCLUSION: Incidences of infectious and parasitic food- and waterborne diseases in the general population of selected regions of the Russian Arctic, Siberia and the Far East (2000-2011) are alarmingly high. Parallel solutions must be on the agenda, including improvement of sanitary conditions of cities and settlements in the regions, modernization of the water supply and of the sewage system. Provision and monitoring of the quality of the drinking water, a reform of the general healthcare system and the epidemiological surveillance (including gender-divided statistics), enhancement of laboratory diagnostics and the introduction of preventive actions are urgently needed. PMID- 24350057 TI - Mitochondrial dysfunction in cancer. AB - A mechanistic understanding of how mitochondrial dysfunction contributes to cell growth and tumorigenesis is emerging beyond Warburg as an area of research that is under-explored in terms of its significance for clinical management of cancer. Work discussed in this review focuses less on the Warburg effect and more on mitochondria and how dysfunctional mitochondria modulate cell cycle, gene expression, metabolism, cell viability, and other established aspects of cell growth and stress responses. There is increasing evidence that key oncogenes and tumor suppressors modulate mitochondrial dynamics through important signaling pathways and that mitochondrial mass and function vary between tumors and individuals but the significance of these events for cancer are not fully appreciated. We explore the interplay between key molecules involved in mitochondrial fission and fusion and in apoptosis, as well as in mitophagy, biogenesis, and spatial dynamics of mitochondria and consider how these distinct mechanisms are coordinated in response to physiological stresses such as hypoxia and nutrient deprivation. Importantly, we examine how deregulation of these processes in cancer has knock on effects for cell proliferation and growth. We define major forms of mitochondrial dysfunction and address the extent to which the functional consequences of such dysfunction can be determined and exploited for cancer diagnosis and treatment. PMID- 24350065 TI - Food and water security issues in Russia II: water security in general population of Russian Arctic, Siberia and Far East, 2000-2011. AB - BACKGROUND: Poor state of water supply systems, shortage of water purification facilities and disinfection systems, low quality of drinking water generally in Russia and particularly in the regions of the Russian Arctic, Siberia and Far East have been defined in the literature. However, no standard protocol of water security assessment has been used in the majority of studies. STUDY DESIGN AND METHODS: Uniform water security indicators collected from Russian official statistical sources for the period 2000-2011 were used for comparison for 18 selected regions in the Russian Arctic, Siberia and Far East. The following indicators of water security were analyzed: water consumption, chemical and biological contamination of water reservoirs of Categories I and II of water sources (centralized--underground and surface, and non-centralized) and of drinking water. RESULTS: Water consumption in selected regions fluctuated from 125 to 340 L/person/day. Centralized water sources (both underground and surface sources) are highly contaminated by chemicals (up to 40-80%) and biological agents (up to 55% in some regions), mainly due to surface water sources. Underground water sources show relatively low levels of biological contamination, while chemical contamination is high due to additional water contamination during water treatment and transportation in pipelines. Non-centralized water sources are highly contaminated (both chemically and biologically) in 32-90% of samples analyzed. Very high levels of chemical contamination of drinking water (up to 51%) were detected in many regions, mainly in the north-western part of the Russian Arctic. Biological contamination of drinking water was generally much lower (2.5-12%) everywhere except Evenki AO (27%), and general and thermotolerant coliform bacteria predominated in drinking water samples from all regions (up to 17.5 and 12.5%, correspondingly). The presence of other agents was much lower: Coliphages--0.2-2.7%, Clostridia spores, Giardia cysts, pathogenic bacteria, Rotavirus--up to 0.8%. Of a total of 56 chemical pollutants analyzed in water samples from centralized water supply systems, 32 pollutants were found to be in excess of hygienic limits, with the predominant pollutants being Fe (up to 55%), Cl (up to 57%), Al (up to 43%) and Mn (up to 45%). CONCLUSION: In 18 selected regions of the Russian Arctic, Siberia and Far East Category I and II water reservoirs, water sources (centralized--underground, surface; non-centralized) and drinking water are highly contaminated by chemical and biological agents. Full-scale reform of the Russian water industry and water security system is urgently needed, especially in selected regions. PMID- 24350066 TI - A review of protective factors and causal mechanisms that enhance the mental health of Indigenous Circumpolar youth. AB - OBJECTIVES: To review the protective factors and causal mechanisms which promote and enhance Indigenous youth mental health in the Circumpolar North. STUDY DESIGN: A systematic literature review of peer-reviewed English-language research was conducted to systematically examine the protective factors and causal mechanisms which promote and enhance Indigenous youth mental health in the Circumpolar North. METHODS: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, with elements of a realist review. From 160 records identified in the initial search of 3 databases, 15 met the inclusion criteria and were retained for full review. Data were extracted using a codebook to organize and synthesize relevant information from the articles. RESULTS: More than 40 protective factors at the individual, family, and community levels were identified as enhancing Indigenous youth mental health. These included practicing and holding traditional knowledge and skills, the desire to be useful and to contribute meaningfully to one's community, having positive role models, and believing in one's self. Broadly, protective factors at the family and community levels were identified as positively creating and impacting one's social environment, which interacts with factors at the individual level to enhance resilience. An emphasis on the roles of cultural and land-based activities, history, and language, as well as on the importance of social and family supports, also emerged throughout the literature. More than 40 protective factors at the individual, family, and community levels were identified as enhancing Indigenous youth mental health. These included practicing and holding traditional knowledge and skills, the desire to be useful and to contribute meaningfully to one's community, having positive role models, and believing in one's self. Broadly, protective factors at the family and community levels were identified as positively creating and impacting one's social environment, which interacts with factors at the individual level to enhance resilience. An emphasis on the roles of cultural and land-based activities, history, and language, as well as on the importance of social and family supports, also emerged throughout the literature. CONCLUSIONS: Healthy communities and families foster and support youth who are resilient to mental health challenges and able to adapt and cope with multiple stressors, be they social, economic, or environmental. Creating opportunities and environments where youth can successfully navigate challenges and enhance their resilience can in turn contribute to fostering healthy Circumpolar communities. Looking at the role of new social media in the way youth communicate and interact is one way of understanding how to create such opportunities. Youth perspectives of mental health programmes are crucial to developing appropriate mental health support and meaningful engagement of youth can inform locally appropriate and culturally relevant mental health resources, programmes and community resilience strategies. PMID- 24350067 TI - Malignancy and idiopathic inflammatory myopathies. AB - Association between idiopathic inflammatory myopathies (IIMs) and malignancy is well known and has been extensively reported in the literature. However, in the recent years, several new studies were published allowing us to better understand the clinical characteristics and pathophysiology of cancer-associated IIMs. We conducted a literature review of cancer-associated IIMs focusing on new data that was published in the recent years. PMID- 24350068 TI - Primary prevention of variceal bleeding: pharmacological therapy versus endoscopic banding. AB - Variceal bleeding is one of the most feared complications in patients with liver cirrhosis. It continues to be a leading cause of death among patients with liver cirrhosis. Although its prognosis has improved over the last several decades, it still carries substantial mortality. Preventing variceal bleeding has been extensively studied and evaluated in several studies in the recent years and the comparison between the different modalities available to prevent variceal bleeding has been an area of discussion. Currently the two most widely used modalities to prevent variceal bleeding are pharmacologic (non-selective beta blockers [NSBB]) and endoscopic (variceal band ligation [VBL]) which have replaced sclerotherapy in the recent years. In addition to NSBB and recent carvedilol, different other medications have been evaluated including isosorbide mononitrates, spironolactone and angiotensin blocking agents. Comparing the outcomes and adverse effects of these two modalities has been evaluated in different studies. Some studies have showed superiority of VBL until recently, when carvedilol has been included, however; overall mortality has been similar in most trials. Despite that, NSBB remain the first line treatment, as they are cheaper and relatively effective in preventing both esophageal and gastric bleeding. The following sections discuss the primary prevention of variceal bleeding with a focus on NSBB, carvedilol and VBL. PMID- 24350069 TI - The Effects of beta - Glucan on Fish Immunity. AB - Administration of glucans through immersion, dietary inclusion or injection has been found to enhance many types of immune responses, resistance to bacterial and viral infections and to environmental stress in many fish species. Although the efficacy of the glucan varies with types and administration, glucan used as an immunomodulatory and mostly immunostimulatory additive has been found satisfactory in eliciting immunity in commercial aquaculture. Development of more efficient administration methods will facilitate the routine and prophylactic use of glucans as natural immunostimulants of fish. Using a PubMed search, this review has an extensive literature on glucan in fish immunity. PMID- 24350070 TI - Onset of Orolingual Angioedema After Treatment of Acute Brain Ischemia with Alteplase Depends on the Site of Brain Ischemia: A Meta-analysis. AB - BACKGROUND: Alteplase is used to treat acute ischemic stroke. However, it has several documented adverse effects, including the development of orolingual angioedema (OA). Although, OA is a rare side-effect, it is thought to be life threatening and is difficult to treat. Until date, little is known about this condition and a better understanding of OA may contribute to improve the morbidity and mortality amongst patients that develop this condition. MATERIALS AND METHODS: Using the PubMed and Medknow databases, we searched for peer reviewed published articles on OA after alteplase administration in 1950-2012. We gathered demographic data and investigated the relationship between the location of OA, neurological symptoms and the site of cerebral ischemia. In addition, we studied the effects of hypertensive premedication on OA development. We identified 19 published manuscripts that fulfilled our search criteria. These manuscripts reported 41 cases of OA after alteplase administration. RESULTS: We found that this condition is associated with cerebral ischemia (P < 0.012) and that 65.9% (n = 27) of patients who developed OA had a hypertensive drug as a premedication. CONCLUSIONS: Although OA is a rare side-effect of alteplase, it can occur depending upon the localization of acute cerebral ischemia. PMID- 24350071 TI - Clinical predictors of acute kidney injury following snake bite envenomation. AB - BACKGROUND: Snake bite envenomation is a major public health concern in developing countries. Acute kidney injury (AKI) is as important cause of mortality in patients with vasculotoxic snake bite. AIMS: This study was to evaluate the clinical profile of snake bite patients and to determine the predictors of developing AKI following snake bite. MATERIALS AND METHODS: Two hundred and eighty-one patients with snake envenomation were included. Eighty seven patients developed AKI (Group A) and 194 (Group B) did not. History, examination findings and investigations results were recorded and compared between the two groups. RESULTS: In group A, 61 (70.11%) patients were male and in group B, 117 (60.30%) patients were male. Out of 281 patients, 232 had cellulitis, 113 had bleeding tendencies, 87 had oliguria, 76 had neuroparalysis, and 23 had hypotension at presentation. After multivariate analysis, bite to hospital time (P = 0.016), hypotension (P = 0.000), albuminuria (P = 0.000), bleeding time (P = 0.000), prothrombin time (P = 0.000), hemoglobin (P = 0.000) and total bilirubin (P = 0.010) were significant independent predictors of AKI. CONCLUSIONS: AKI developed in 30.96% of patients with snake bite, leading to mortality in 39.08% patients. Factors associated with AKI are bite to hospital time, hypotension, albuminuria, prolonged bleeding time, prolonged prothrombin time, low hemoglobin and a high total bilirubin. PMID- 24350072 TI - Tropical pyomyositis. AB - BACKGROUND: Tropical pyomyositis is characterized by suppuration within skeletal muscles, manifesting as single or multiple abscesses. Though primarily a disease of tropics, it is increasingly being reported from temperate regions in immunosuppressed patients. However, India has only few sporadic case reports. AIMS: The aim of this study is to evaluate the causative organisms, clinical presentations, diagnostic modalities, treatment protocols and outcome data in tropical pyomyositis patients. SUBJECTS AND METHODS: The study was carried out in Nilratan Sircar Medical College and Hospital, Kolkata over 3 years (July 2010 to June 2013). A total of 12 patients were diagnosed with tropical pyomyositis (confirmed with aspiration and culture of pus from muscle). All the investigation and treatment data were recorded systematically. RESULTS: The presenting feature was high fever and myalgia in all 12 patients. Quadriceps femoris was the most commonly involved muscle (50%); followed by iliopsoas (25%). Culture of the aspirate showed Staphylococcus aureus in nine patients (75%), Klebsiella pneumonia in one patient (8.33%) and no growth in two patients (16.67%) even after tubercular and fungal culture. CONCLUSIONS: Tropical pyomyositis can affect immune-competent individuals. S. aureus is the most commonly cultured organism. Immediate initiation of appropriate antibiotics and surgical debridement are required to avoid complications. The prognosis remains excellent if promptly treated. PMID- 24350073 TI - Ribosomal protein s6-ps240 is expressed in lesional skin from patients with autoimmune skin blistering diseases. AB - BACKGROUND: The in situ signaling transduction within skin biopsies from patients affected by autoimmune skin blistering diseases is not well-characterized. AIM: In autoimmune skin blistering diseases, autoantibodies seem to trigger several intracellular signaling pathways and we investigated the presence of the phosphorylated form of ribosomal protein S6-pS240 within autoimmune skin blistering diseases biopsies. MATERIALS AND METHODS: We utilized immunohistochemistry to evaluate the presence of S6-pS240 in lesional skin biopsies of patients affected by autoimmune skin blistering diseases including patients with an endemic and nonendemic pemphigus foliaceus (non EPF), with bullous pemphigoid (BP), pemphigus vulgaris (PV), dermatitis herpetiformis (DH), and the respective controls. RESULTS: Most autoimmune bullous skin diseases biopsies stained positive for S6-pS240 around lesional blisters, including adjacent areas of the epidermis; and within upper dermal inflammatory infiltrates, and/or mesenchymal-endothelial cell junctions within the dermis. CONCLUSIONS: We document that S6-pS240 is expressed in lesional areas of skin biopsies from patients with autoimmune skin blistering diseases, as well as on eccrine glands and piloerector muscles. Thus, the role of this molecule in autoimmune skin blistering diseases warrants further study. PMID- 24350074 TI - Towards understanding mechanisms of autoimmune bullous skin diseases. PMID- 24350075 TI - Correlation of severity of coronary artery disease with insulin resistance. AB - BACKGROUND: Insulin resistance (IR) has known to be associated with coronary artery disease (CAD), but the assessment of severity of the CAD based on IR in type 2 diabetes mellitus has not been established in detail. AIMS: The aim of our study was to establish the correlation between IR and the severity of CAD in type 2 diabetes mellitus. MATERIALS AND METHODS: In a cross-sectional study design, 61 consecutive patients with type 2 diabetes mellitus who underwent coronary angiogram for the evaluation of CAD were recruited. Fasting blood glucose, fasting insulin levels, systolic blood pressure and total cholesterol/high density lipoprotein-cholesterol ratio were determined. Homeostasis model assessment-IR (HOMA-IR) was correlated with severity of CAD, which was measured by modified Gensini Score. RESULTS: There was a significant correlation between log HOMA-IR and severity of CAD (r = 0.303, P = 0.009) in diabetic patients. Correlation of the Gensini Score with other known risk factors was not significant. CONCLUSIONS: The results of our study indicate that we might able to predict the severity of CAD by measure of IR. PMID- 24350076 TI - Insulin Resistance and Atherosclerosis: Is it Time to Measure HOMA-IR to Predict Coronary Artery Disease? PMID- 24350077 TI - Mycobacterium Tuberculosis Infection within a Warthin Tumor: A Case Report and Literature Review. AB - CONTEXT: The co-existence of tuberculosis and a Warthin tumor in the parotid gland is extremely rare. CASE REPORT: A 46-year-old male presented with a mass in the left parotid region of 6-month duration. The patient's history was only remarkable for a facial swelling, night sweats and a 38.5 C degrees fever. A 2 * 3-cm mobile, non-tender, mass with a smooth surface was palpated on left parotid tail. CT examination showed a well-defined 30 mm in diameter tumor mass in the left superficial lobe of the parotid gland. A superficial parotidectomy was performed. The final pathological diagnosis of the parotidectomy specimen was reported as a Warthin tumor and epitheloid granulomas with caseification necrosis. Purified protein derivative (PPD) was 30 mm in enduration. Two weeks after the antituberculosis treatment fever declined to normal values and night sweats decreased. CONCLUSION: Tuberculosis can also be seen in parotid tumors which can coexist or mimic pleomorphic adenoma, Warthin tumor. PMID- 24350078 TI - Leaking heart: ticking time bomb! AB - CONTEXT: Cardiac rupture is a very important but under-recognized complication of acute myocardial infarction and usually happens within a week of the event. Sometimes it can be subacute and may not be typical of an acute blow out rupture. Hence careful evaluation is needed as a missed or delayed diagnosis can be fatal. An emergent echocardiogram may aid in immediate diagnosis. Surgery is the only treatment option and is mandatory despite the high mortality risk. CASE REPORT: An elderly male presented with dizziness and hypotension. Based on the timeline of his symptomatology, electrocardiographic abnormalities and labs, a subacute cardiac rupture was suspected in the emergency room itself. A high index of suspicion is needed to diagnose cardiac rupture. CONCLUSION: Subacute cases can be missed easily as presentation may not be dramatic. They can rapidly progress to a blowout rupture increasing mortality risk heavily even with surgical treatment. PMID- 24350079 TI - Bilateral putaminal hemorrhages: serious complication of methanol intoxication. AB - CONTEXT: Methanol intoxication is a life-threatening condition. Hallmark of clinical presentations include severe wide anion gap metabolic acidosis with very high serum osmolar gap and visual complication. CASE REPORT: We report a case of severe methanol intoxication with bilateral putaminal hemorrhage, an uncommon serious complication. A 56-year-old man presented with altered mental status. Fundus examination showed optic disc edema. Arterial Blood Gas (ABG) revealed severe anion gap metabolic acidosis with osmolal gap. Head computed tomography (CT) showed hypodense lesions in basal ganglia bilaterally. Hemodialysis and intravenous fomepizole were initiated. Serum methanol level was significantly elevated. Unfortunately, patient was lethargic 2 weeks after discharge. Repeated CT of head demonstrated new putaminal hemorrhages. CONCLUSION: Bilateral putaminal hemorrhage is an uncommon but serious complication in methanol intoxication. Clinicians should have high index of suspicion for putaminal hemorrhage when patients with recent methanol intoxication present with altered mental status. PMID- 24350080 TI - When to start dialysis in elderly patients. PMID- 24350081 TI - Testosterone replacement therapy: should it be performed in erectile dysfunction? AB - The classical etiology of erectile dysfunction (ED) comprises aging and vascular, neurogenic, psychological and hormonal components. Recent studies have shown that ED can be the forerunner of serious cardiovascular disturbances. It has also been reported that peripheral neuropathy and microvascular injuries caused by pathophysiological changes in patients with diabetes and obesity lead to ED in a significant number of such cases. These patients develop clinically significant ED and comprise a significant portion of the patient group which do not respond to PDE-5 inhibitors. Testosterone has been shown to increase the expression of PDE-5. This function of testosterone supports its effect on the regulation of erection and increasing the sexual libido. In view of the complexity of ED, as well as the effect of testosterone on erection, it is concluded that PDE-5 inhibitors in combination with testosterone replacement would be a better therapy alternative in the management of erectile dysfunction in hypogonadal patients. PMID- 24350082 TI - Comparison of vitamin e and L-carnitine, separately or in combination in patients with intradialytic complications. AB - BACKGROUND: The most common complications during dialysis are hypotension and muscle cramps. There are many strategies to prevent and treat these complications. OBJECTIVES: The aim of this study is to evaluate effects of vitamin E and L-carnitine supplementation alone and in combination on intradialytic complications. PATIENTS AND METHODS: In a prospective study, 20 patients with end stage renal disease on chronic hemodialysis that had intradialytic complications such as hypotension, muscle cramp, nausea, vomiting and headache were studied. These patients were studied in four 45 day periods, beginning with no treatment (step 1), receiving vitamin E (200 IU/d) (step 2), receiving L-carnitine (500 mg/d) (step 3) and their combination (step 4). Intradialytic complications were recorded in each step and compared between treatments. RESULTS: All three treatments significantly reduced frequency of muscle cramps in comparison to baseline values. Vitamin E alone and in combination with L-carnitine reduced the frequency of muscle cramps more effectively. Hypotension was significantly lower in combination therapy in comparison to baseline values and vitamin E treatment. CONCLUSIONS: Vitamin E and L-carnitine both have comparative effects on intradialytic complications. As the combination use of vitamin E and L-carnitine could more effectively reduce the intradialytic complications, it is recommended for daily use in hemodialysis patients. PMID- 24350083 TI - Urethral prolapse: contemporary report on a modified ligation over a urethral catheter treatment approach. AB - BACKGROUND: Most contemporary series on urethral prolapse report either on the use of excisional or conservative treatment approaches. OBJECTIVES: To introduce a modified ligation over a Foley catheter treatment method for urethral prolapse that addresses most of the previously reported complications. PATIENTS AND METHODS: Five consecutive patients with urethral prolapse treated between 2003 and 2011, all using the ligation method on an outpatient basis were studied prospectively. Maintaining the inflated balloon of the Foley catheter with timed removal of the catheters among other modifications to the original technique is further described in the article. The main outcome measures were to evaluate for recurrence, post-operative appearance of the urethral orifice and satisfaction of parents. Secondarily the actions of the parents of the patients and those of the receiving physicians were also recorded. RESULTS: The mean age of the patients was 6 years old (ranging from 3 to 8 years). All parents suspected sexual molestation and in two cases, the suspected perpetrators were verbally threatened of dire consequences of their actions if proven. None of the receiving medical personnel were aware of this condition. Maximum length of catheterization was for 4 days. The post treatment urethral openings appeared normal and there were no complications. CONCLUSIONS: The ligation method with attention to the modifications described further in the article is a simple, safe and cost effective option for the management of urethral prolapse. Maintaining the inflated balloon of the Foley catheter with timed catheter removal especially adds predictability to this technique. PMID- 24350084 TI - Role of multidetector computed tomography for evaluation of living kidney donors. AB - BACKGROUND: Kidney transplantation from living donors has been increased recently. Preoperative evaluation of living donor is important to select the appropriate kidney for transplantation and to decrease donor surgical complications. OBJECTIVES: The aim of this study was to compare the accuracy of the use of multidetector computed tomography (MDCT) to evaluate vascular anatomy in living kidney donors with traditional angiography. PATIENTS AND METHODS: A total number of 60 living kidney donors who underwent open surgical approach for transplantation were selected: Kidney anatomy of donors evaluated by CT angiography (group 1) or traditional angiographic examination (group 2). Renal vessels anatomy was compared with surgical findings in both groups. RESULTS: The accuracy for detecting number of main renal arteries were not different in both groups which were 96.7% in CT angiography group and 90% in traditional angiography group (P = 0.15). The accuracy for detection of main renal veins were 100% in group 1 and 96.7% in group 2 (P = 0.31). CONCLUSIONS: MDCT has the same accuracy as traditional angiography to detect renal abnormalities in living kidney donors. PMID- 24350085 TI - The evaluation of ureteroscopy and pneumatic lithotripsy results in pregnant women with urethral calculi. AB - BACKGROUND: Urinary stone incidence in pregnancy has been reported in a wide range, from 1 in 200 to 1 in 2000 cases. OBJECTIVES: The aim of this study was to investigate the efficacy and safety of ureteroscopic treatment and its results and complications for pregnant women with urinary stones. PATIENTS AND METHODS: From 2003 till 2011, 113 pregnant patients with symptomatic urolithiasis were admitted to the urology emergency clinic at Imam Reza hospital. All patients were initially treated conservatively, resulting in spontaneous passage of the calculi in 69 patients. Forty-four patients with symptomatic urolithiasis were included in the study. Post-operative follow ups, including maternal and fetal health was performed by a gynecologist consult fetal heart rate assessment and urine analysis and culture and renal and urethral ultrasonography. RESULTS: The mean age of the patients was 23 years +/- 2 (19-34) and the mean gestational age was 24 +/- 3 weeks. The overall and pneumatic lithotripsy success rate was 100%. All patients from the interventional group delivered at term with no fetal or maternal complications. There was no morbidity during and after the operation. CONCLUSIONS: In conditions, medical management of urinary stones and consequent renal colic in pregnant women cannot improve patients' symptoms, choosing of a surgical method like setting of a DJ catheter or URS and pneumatic lithotripsy can be a safe and effective way for the health of both the mother and fetus. Of course, more research is needed to establish this approach as the standard method in pregnancy urinary stones. PMID- 24350086 TI - Impact of ureteral length on urological complications and patient survival after kidney transplantation. AB - BACKGROUND: Urologic complications are of the most important complications after kidney transplantation which increases mortality and morbidity significantly. OBJECTIVES: We designed this study to evaluate the association between ureteral length and postoperative complications. PATIENTS AND METHODS: We recorded the length of the transplanted ureter during the operation. Ureter-to-bladder anastomosis was performed using modified Lich-Gregoir method on the ureteral stent. Complications like urine leakage and increased creatinine were evaluated. We used both univariate and multivariate analyses and survival analysis according lengths of ureter. It means that the main variable is ureteral length and other variables are studied based on it. RESULT: A total of 395 patients with the mean age of 37 years (range, 18 to 68 years) were enrolled in the study, twenty six graft lost during the follow-up period. The Mean age of recipients was 37 +/- 13 years. Urinary stenosis was seen in 6 patients (1.5%) and urinary leakage in 4 (1%) patients. The complication rate was not significantly different between these groups (P = 0.67). We found that there were no significant difference among complication (P = 0.25), hospitalization (P = 0.31) and survival (P = 0.84) at 5.5 cm length cut off. CONCLUSIONS: The length of transplanted ureter does not affect the postoperative urologic complications (including urinary fistula and ureter-to-bladder anastomosis stricture), and it seems that decreased rate of complication frequency during the recent years is due to technical improvement, surgeon's skillfulness and development in use of immunosuppressant's postoperatively. PMID- 24350087 TI - Effect of oral administration of magnesium on Cisplatin-induced nephrotoxicity in normal and streptozocin-induced diabetic rats. AB - BACKGROUND: Cisplatin (CP) therapy as the most common potent chemotherapeutic process is accompanied by nephrotoxicity. The diabetic state may protect rat kidney against this toxicity, and magnesium (Mg) on the other hand may reduce the glucose level in diabetic animals. OBJECTIVES: Current study was planned to investigate the effect of oral administration of magnesium supplementation on CP induced nephrotoxicity in normal and Streptozocin (STZ)-induced diabetic rats. MATERIALS AND METHODS: Male Wistar rats were divided into seven groups and underwent two experiment protocols. As protocol 1, group 1 was considered as the sham group. Group 2 (CP group) received CP (2 mg/kg/d) for five consecutive days. Group 3 (CP + Mg group) received magnesium sulphate (MgSO4, 10 g/L added to the drinking water) for 10 days and then treated with CP from sixth day. As protocol 2, animals received a single dose of STZ (65 mg/kg i.p.). Three days after diabetes induction, animals were divided into four groups; Groups 4 (D group), 5 (D + CP group), and 7 (D + Mg + CP group) followed the same manner as groups 1 to 3, respectively; and group 6 (D + Mg group) was treated with MgSO4 alone for 10 days. Finally, blood samples were obtained, and all animals were killed for kidney tissue investigation. RESULTS: CP administration in normoglycemic rats significantly elevated the serum levels of blood urea nitrogen (BUN) and creatinine (Cr) (P < 0.05). However, coadministration of CP and Mg statistically increased the serum levels of BUN and Cr in both normoglycemic and diabetic animals when compared to the rats treated with CP alone (P < 0.05), while the serum level of Mg was significantly increased in nondiabetic groups (P < 0.05). No significant changes were observed in serum and kidney levels of nitrite; as well as the testis weight between all normoglycemic groups, whereas Mg decreased kidney levels of nitrite in diabetic groups when accompanied by CP (P < 0.05). The kidney and serum levels of malondialdehyde (MDA) enhanced significantly in nondiabetic rats treated with Mg and CP (P < 0.05). Kidney tissue damage score (KTDS), kidney weight, and body weight loss were significantly different among normoglycemic groups (P < 0.05), and Mg promoted the KTDS in diabetic animals treated with CP. CONCLUSIONS: Oral Mg supplementation did not protect the CP induced nephrotoxicity in diabetic rats. PMID- 24350089 TI - Different aspects of fatigue experienced by patients receiving maintenance dialysis in hemodialysis units. AB - BACKGROUND: Fatigue, a common symptom reported by patients receiving dialysis, is a multidimensional and subjective experience which is readily understood by individuals but difficult to measure. OBJECTIVES: This study was performed to identify the prevalence of differential aspects of fatigue among patients receiving maintenance dialysis. PATIENTS AND METHODS: The cross-sectional study was conducted in two hemodialysis wards in Tehran with a sample of 163 participants. In this study, the multidimensional fatigue inventory was used to determine the level of fatigue. Demographic data were also collected with self report survey. To analyze data with SPSS statistical software, test Chi square, T test, and ANOVA were used. P- Value less than 0.05 was considered significant. RESULTS: All the patients experienced degrees of fatigue and 50 (30.7%) of the participants experienced a high level of fatigue. Fatigue scores arrangement was founded for physical fatigue followed by reduced activity and general fatigue. Lower levels of fatigue were reported for mental fatigue and reduced motivation. There was no diversity in this study in the levels of fatigue in respects of gender and marital status and employment status. Participants with diabetic nephropathy were the most fatigued. CONCLUSIONS: People with chronic kidney disease regardless of their age, gender, state of health, and duration of hemodialysis experience high levels of fatigue; it is particularly important for health providers to understand this level of fatigue which affects the daily life of patients. PMID- 24350088 TI - Coupled Plasma Filtration and Adsorption (CPFA): A Single Center Experience. AB - BACKGROUND: Coupled plasma filtration adsorption (CPFA) is a novel extracorporeal blood purification therapy for sepsis which adsorbs both proinflammatory and anti inflammatory mediators from filtered plasma, thereby achieving early haemodynamic stability and a reduction in inotropic support requirement. OBJECTIVES: The main objective was to review our centers' experience with CPFA in septic patients. PATIENTS AND METHODS: A retrospective chart review of all septic patients who received CPFA was performed. All patients were initially treated according to the 'surviving sepsis care bundle' with fluid resuscitation, antibiotics, and inotropes as required. CPFA was started as soon as possible after a nephrologists' assessment. RESULTS: Twenty five patients with sepsis received CPFA (15 M, 10 F, mean age 49.60 +/- 18.97 years). Comorbidities included hypertension (n = 10, 40%), diabetes mellitus (n = 6, 24%), ischemic heart disease (n = 6, 24%), and an immunosuppressed state (n = 10, 40%). All patients received one cycle of CPFA with median duration of 5 (1-10) hours. CPFA was well tolerated but we encountered technical problems, especially filter clotting as CPFA was performed heparin free. 14 (56%) patients died within 28 days of treatment. CRP correlated with PCT (P = 0.040) and had an inverse trend with albumin (P = 0.066). Serum albumin was a strong predictor of mortality. CONCLUSIONS: The high prevalence of fungaemia and mortality could be attributed to many patients on chronic immunosuppressive therapy. Nonetheless, CPFA albeit expensive, does add to our armamentarium of extracorporeal treatment for severe sepsis. Regional citrate anticoagulation with CPFA may overcome problems with filter clotting. PMID- 24350090 TI - Health-related quality of life in hemodialysis patients: an Iranian multi-center study. AB - BACKGROUND: The effectiveness of health care and health policy developments are often determined by health-related quality of life (HRQOL) assessment. OBJECTIVES: The objective of this study was to explore the potential corresponding factors and traditional biomarkers of HRQOL in a large number of Iranian hemodialysis patients. PATIENTS AND METHODS: A total of 6,930 chronic hemodialysis (HD) patients enrolled. KDCS-SF version 1.3 questionnaire was used to assess the health related quality of life (HRQOL). We pooled PCS, MCS and KDCS scores with random effect model from 19 similar studies performed between 1996 and 2010. RESULTS: The mean age was 54.4 +/- 17.1 years. Mean PCS, MCS and KDCS scores obtained for the study cohort were 40.79 +/- 20.10, 47.79 +/- 18.31 and 57.97 +/- 11.70, respectively; the total score of SF-36 plus KDCS was 51.12 +/- 13.41 as well. The most common primary known disease was hypertension (31.9%) and the second etiology was diabetes (25.5%). In multilevel logistic regression, Kt/V between 1 and 1.2 and PCS, KDCS more than 50 were considered as a significant reduction in the risk of hospitalization. CONCLUSIONS: This study showed that PCS and MCS score were slightly more than overall results while KDCS was slightly less than overall results. In addition, dialysis adequacy with Kt/V between 1 and 1.2 is associated with lower rate of hospitalization. PMID- 24350091 TI - Comparative study of intravenous iron versus intravenous ascorbic Acid for treatment of functional iron deficiency in patients under hemodialysis: a randomized clinical trial. AB - BACKGROUND: Functional iron deficiency (FID) may cause erythropoietin resistance in patients under hemodialysis (HD). Since the role of chronic inflammation or oxidative stress in its pathogenesis is unclear, controversy remains to whether intravenous iron or intravenous ascorbic acid (an antioxidant) can improve this anemia due to decreased iron availability. OBJECTIVES: The current study compared the effect of intravenous iron versus intravenous ascorbic acid in the management of FID in HD patients. PATIENTS AND METHODS: Forty HD patients with hemoglobin (Hb) <= 11 g/dL, serum ferritin >= 500 ng/mL and transferrin saturation (TSAT) <= 25% were randomly divided into two groups. 20 patients received 100 mg of intravenous (IV) iron (group I), and 20 patients received 300 mg of IV ascorbic acid (group II) postdialysis, twice a week for 5 consecutive weeks. Hb and iron metabolism indices were measured before the onset of the study and after 12 weeks following therapy. RESULTS: Twenty one percent of all HD patients, exhibited high serum ferritin, low TSAT and sufficient data for analysis. Both Group I (n = 20) and Group II (n = 20) patients showed a significant increase in Hb, serum iron, and TSAT (P < 0.001). There were no significant differences between both groups in increasing Hb (P = 0.076), serum iron (P = 0.589), serum ferritin (0.725), and TSAT (P = 0.887). CONCLUSIONS: This study showed that both IV iron and IV ascorbic acid can improve FID in HD patients. A larger randomized trial is warranted to determine the optimal management of FID in HD patients. PMID- 24350092 TI - Vacuolization, dilatation, hyaline cast, debris or degeneration: which one is the most correlated item to score the kidney damage pathologically in Cisplatin induced nephrotoxicity model? AB - BACKGROUND: Nephrotoxicity is characterized and scored by many parameters such as vacuolization, dilatation, hyaline cast, debris or degeneration in injured renal tissue. In this short report, we attempt to find, the most correlated parameters with kidney tissue pathology damage score (PDS) in Cisplatin-induced nephrotoxicity. METHOD: A total of 207 normal and toxic rats' kidney tissue (induced by Cisplatin) were evaluated for toxicity intensity by two methods. In the first method, the tissue damage was scored from 0 to 4, and in the second method the percentage of vacuolization, dilatation, hyaline cast, debris or degeneration were determined. The data was analyzed using stepwise discriminant function and regression analysis. RESULTS: The variables having the higher discriminant function coefficient were hyaline cast, dilatation, and degeneration. The linear regression model and the prediction function to determine the kidney tissue PDS were generated as below. [Formula: see text]. CONCLUSION: According to this finding it is suggested that presence of hyaline cast and dilatation, and then degeneration in the sample of toxic renal tissue are the most important item to score the damage intensity. PMID- 24350093 TI - Bilateral rectus sheath hematoma in kidney transplant patient: case study and literature review. AB - Rectus sheath hematoma usually occurs unilateral but rare cases of bilateral hematoma have been reported. Herein we report the first case of spontaneous bilateral Rectus Sheath Hematoma in the kidney transplanted patient. PMID- 24350094 TI - Vesicourethral reflux in pediatrics with hypermobility syndrome. AB - SUBJECTIVES: Prevalence of benign joint hypermobility syndrome (BJHMS) without systemic disease seems to be high in children. Little literature is currently available related to urinary tract diseases in patients with BJHMS. Here, we report an association between the urinary tract disease and BJHMS. METHODS: We conducted a prospective case series study of 62 pediatric patients with musculoskeletal pain to detect urinary tract diseases in Tehran, Iran from October 2009 to October 2010. The Brighton criteria score was used to diagnose BJHMS. The collected data included age, gender, grading of vesicoureteral reflux (VUR), ultrasonography findings, urodynamic results and biochemical tests. Voiding cystourethrography was used for detection and grading of VUR. RESULTS: VUR was observed in 60% of patients with BJHMS. However, sonography was normal in 66.7% of patients. The most common grading of reflux was grade II of VUR (37.5%). Seventy percent of patients with BJHMS and neurogenic bladder had failure to thrive. CONCLUSION: Our findings showed an increased frequency of VUR in patients with BJHMS. We suggest that Infants and children with BJHMS should be screened for VUR. PMID- 24350095 TI - Forgotten stents, unforgettable patients. PMID- 24350096 TI - Mineral and bone disease in black african hemodialysis patients. PMID- 24350097 TI - Mineral and bone disease in hemodialysis patients. PMID- 24350098 TI - Racial differences in secondary hyperparathyroidism. PMID- 24350101 TI - Submental Artery Island Flap in Reconstruction of Hard Palate after wide Surgical Resection of Verruccous Carcinoma, Two Case Reports. AB - INTRODUCTION: Reconstruction of intraoral soft tissue defects is important in restoring function and esthetic. In large defects, there will be demand for regional pedicle flaps or free flaps. Hard palate separates nasal and oral cavities. Due to the small surface area between flap and remaining palate after surgical resections, optimal blood supply of the flaps for hard palate reconstructions are needed. CASE REPORT: This article demonstrates immediate reconstruction of two edentulous hemimaxillectomy patients with submental artery Island flap and brief review of this flap discussed. CONCLUSION: Submental Artery Island flap is an effective and reliable method for intraoral reconstruction of large soft tissue defects of oral cavity. Donor site morbidity is low and remaining scar is inconspicuous. Head and neck surgeons familiar with facial artery and its branching pattern make this flap an appropriate choice for clinical practice. PMID- 24350102 TI - Treatment of trauma victims: consideration of the whole perspective. PMID- 24350100 TI - Overactive bladder syndrome and the potential role of prostaglandins and phosphodiesterases: an introduction. AB - In this paper, a general introduction is given, presenting the overactive bladder syndrome (OAB) and its impact on the quality of life and economical burden in patients affected. Moreover, the anatomy, physiology and histology of the lower urinary tract are discussed, followed by a brief overview on the possible role of prostaglandin (PG) and phosphodiesterase type 5 (PDE5) in the urinary bladder. The current literature on the role and distribution of PGE2 and its receptors in the urinary bladder is discussed. In both animal models and in human studies, high levels of signaling molecules such as PG and cGMP have been implicated, in decreased functional bladder capacity and micturition volume, as well as in increased voiding contraction amplitude. As a consequence, inhibition of prostanoid production, the use of prostanoid receptor antagonists, or PDE inhibitors might be a rational way to treat patients with detrusor overactivity. Similarly, prostanoid receptor agonists, or agents that stimulate their production, might have a function in treating bladder underactivity. PMID- 24350103 TI - Vascular injuries: trends in management. AB - ABSTRACT: Vascular injury presents a great challenge to the emergency resident because these injuries require urgent intervention to prevent loss of life or limb. Sometimes serious vascular injury presents with only subtle or occult signs or symptoms. The patient may present weeks or months after initial injury with symptoms of vascular insufficiency, embolization, pseudoaneurysm, arteriovenous fistula etc. Although the majority of vascular injuries are caused by penetrating trauma from gunshot wounds, stabbing or blast injury, the possibility of vascular injury needs to be considered in patients presenting with displaced long bone fractures, crush injury, prolonged immobilization in a fixed position by tight casts or bandages and various invasive procedures. iatrogenic vascular injuries constitute about 10% of cases in most series; however the incidence is an increasing trend because more endovascular procedures such as angioplasty and cardiac catheterization are being performed routinely. Civilian trauma is more frequently seen in young males. However, it can occur at any age due to road accidents, firearms, bomb blasts and diagnostic procedures. Most of the time, civilian trauma causes less tissue damage. There is an epidemic of vascular injuries in Kashmir valley because of problems in law and order in the past two decades. This review deals with the topic in detail. PMID- 24350104 TI - Efficacy of a rapid response team on reducing the incidence and mortality of unexpected cardiac arrests. AB - BACKGROUND: Rapid Response Teams (RRTs) assess patients during early phases of deterioration to reduce patient morbidity and mortality. OBJECTIVES: This study aimed to evaluate the ability of earlier medical intervention by a RRT prompted by clinical instability in patients to reduce the incidence of and mortality from unexpected cardiac arrest at our hospital. PATIENTS AND METHODS: A nonrandomized, population-based study before 2008 and after 2010 introduction of the Rapid Response Teams in a 300 bed private hospital. All patients were admitted to the hospital in 2008 (n = 25348) and 2010 (n = 28024). RRT (One doctor, one senior intensive care nurse and one staff nurse) attended to clinically unstable patients immediately with resuscitation drugs, fluid, and equipment. Response was activated by the bedside nurse or doctor according to predefined criteria. Main outcome measures were incidence and outcome of unexpected cardiac arrest. RESULTS: The incidence of unexpected cardiac arrest was 17 per 1000 hospital admissions (431 cases) in 2008 (before RRT intervention) and 12.45 per 1000 admissions (349 cases) in 2010 (after intervention), with mortality being 73.23% (274 patients) and 66.15% (231 patients) respectively. After adjustment for case mix the intervention was associated with a 19% reduction in the incidence of unexpected cardiac arrest (odds ratio 0.81, 95% confidence interval 0.65-0.98). CONCLUSIONS: The RRT was able to detect preventable adverse events and reduce the mortality and incidence of unexpected cardiac arrests. PMID- 24350105 TI - Evaluation of dextrose water, black tea and orange juice on histopathologic recovery of surgery-induced intestinal damage in rabbits. AB - BACKGROUND: The increase in intestinal permeability following damage to the intestinal mucosa in any surgical procedure, trauma or fasting is well- known. OBJECTIVES: Our objective was to experimentally evaluate whether antioxidant consumption is associated with decreased intestinal damage in intestinal surgical procedures. MATERIALS AND METHODS: Forty rabbits were used to compare the pathological changes in the intestine after consumption of dextrose water 5% (D5W), black tea and orange juice in fasting and in cases with intestine resection and anastomosis. They were divided in to five groups as shams (GI), NPO (G II), D5W (GIII), black tea (GIV) and orange juice groups (GV). In GII to GV group with median laparotomy, a 2 cm segment of jejunum was resected and ends of the bowel were anastomosed. Postoperatively, animals fasted for five days. Animals in GII were killed after five days of fasting. On day five case groups were given free access to drinking D5w (GIII), black tea solution (G IV) and orange juice (GV) for a further 7 days. On day 8, animals were reoperated and the repaired segment of intestine was removed. Morphologic data were compared in groups. RESULTS: There were 8 rabbits in each group. There was a significant difference in villi lengths in the groups (P = 0.003). GV rabbits had obvious recovery of the villous architecture. CONCLUSIONS: Orange juice as a source of vitamin C may be an appropriate liquid for postoperative recovery following intestinal surgery. PMID- 24350107 TI - Pain and health-related quality of life in war veterans with bilateral lower limb amputations. AB - BACKGROUND: Amputation and pain may have considerable impact on health-related quality of life. OBJECTIVES: The purpose of this study was to assess the impact of pain on health-related quality of life in a population of war related bilateral lower limb amputees. MATERIALS AND METHODS: The Veterans and Martyrs Affairs Foundation (VMAF) database documented 578 patients with bilateral lower limb amputation; 335 consented to the study (response rate = 58%). The majority of participants in the sample were males (96.7%). Types of pain were investigated using a questionnaire. Health-related quality of life (HRQOL) was investigated using the sf-36 questionnaire. RESULTS: About two third of amputees reported phantom pain 66.7% (n = 223) and vertebral column pain 60.9% (n = 204). The most common type of pain was lumbosacral pain 52.8 % (n = 177) followed by neck 18.2 % (n = 61) and thoracic pain 9.6% (n = 32). Back pain affected on vitality, social function, mental health and mental component scale in our cases (P < 0.05). Neck pain affected all components of health-related quality of life (P < 0.05). Thoracic pain affected quality of life significantly (P < 0.05). The results obtained from logistic regression analysis indicated that none of the three spinal column pains including neck, thoracic and lumbosacral pain resulted in poor physical or mental component scales. CONCLUSIONS: This study revealed that bilateral lower limb amputees suffer from different types of pain and poor health related quality of life. Therefore, the assessment and management of all types of pain are necessary to improve quality of life in veterans. PMID- 24350106 TI - Isolated small bowel mesentery injury after steering wheel trauma. AB - BACKGROUND: Isolated small gut mesentery injury after blunt abdominal trauma from the steering wheel in road traffic accidents is rare. These are always challenging to diagnose and pose a diagnostic dilemma. OBJECTIVES: To study the pattern of small gut mesenteric injury by steering wheel blunt abdominal trauma in road traffic accidents in patients who had laparotomy. PATIENTS AND METHODS: A 10-year retrospective study was done to study isolated small gut mesentery injury. RESULTS: All patients who had isolated mesenteric small gut injury were males. Jejunal mesentery was involved in 13 whereas 4 had ileal mesentery injury. Tear were longitudinal or transverse. CONCLUSIONS: Isolated small mesentery injury after blunt abdominal trauma from the steering wheel in road traffic accidents is rare. Tears are either longitudinal or transverse. Suture repair is to be done. Delay in reaching hospital or reaching the diagnosis could lead to morbidity and mortality. Isolated mesenteric injury should be considered in any patient with blunt abdominal trauma from steering wheel injury with no evidence of any solid organ injury in unstable patients. PMID- 24350108 TI - Role of liberal primary fasciotomy in traumatic vascular injury. AB - BACKGROUND: Vascular injury represents less than 1% of all injuries, but deserves special attention because of its severe complications. Amputation or retention of a painful functionless limb is the most untoward result of severe vascular injury or inadequate treatmet. Thus, vascular injury needs a judicious and multidimensional approach. OBJECTIVES: This retrospective study was done to asess the outcome of minor modifications of the methodology of extremity fasciotomy by making it liberal with respect to incision and definition. MATERIALS AND METHODS: Out of 55 patients in 2008, 45 patients (Group A) had either no fasciotomy or limited primary fasciotomy, 10 patients (Group B) had primary liberal fasciotomy. Another group from 2008 onwards had undergone primary liberal fasciotomy in all the 45 patients (Group C). RESULTS: In group A, we had 5 amputations and one death. In group B, there were no amputations or deaths and from group C, we had one amputation and no deaths. CONCLUSIONS: Blunt and distal traumatic vascular injury of the extremities and its repair should always combined with primary liberal fasciotomy, which although increases manageable morbidity, avoids disability (functional as well as anatomical). PMID- 24350109 TI - Thoracoscopic Sympathicotomy vs Sympathectomy in Primary Hyperhidrosis. AB - BACKGROUND: Primary hyperhidrosis (P.H.H.) is characterized by excessive sweating in certain parts of body. It's estimated prevalence is 0%-6.1% in different populations. In Asian population its prevalence is around 3%. In 57% of cases, there is a positive family history. OBJECTIVES: To evaluate and compare the early and late satisfaction, outcomes and complications of thoracoscopic sympathectomy and sympathicotomy in the treatment of primary hyperhidrosis. MATERIALS AND METHODS: From April 2007 to January 2011, we prospectively treated 60 primary hyperhidrosis patients via thoracoscopic surgery. The first 30 patients underwent sympathectomy and the next 30 patients underwent sympathicotomy. We evaluated early and late satisfactions, outcomes and complications on the first visit (5 8days) following surgery and 12 months after surgery, for all patients. RESULTS: The mean operative time was 66.3 minutes in sympathicotomy group and 110.8 minutes in sympathectomy group (P < 0.001). There were no significant differences between the two groups in overall early and late satisfaction, gustatory sweating, pompholyx and post-operative pain. There was comparatively less early and late compensatory sweating (C.S.), and other adverse influences of C.S. in the sympathicotomy group. CONCLUSIONS: Because of shorter operative time, less C.S. and less adverse influence of C.S., sympathicotomy seems a better treatment for primary hyperhidrosis, compared with sympathectomy. PMID- 24350110 TI - Carpal tunnel syndrome: the role of occupational factors among 906 workers. AB - BACKGROUND: Carpal tunnel syndrome (CTS) is common in the industrial setting. However,there is a controversy about the sole role of occupational ergonomic hazards in CTS. OBJECTIVES: This study was conducted among assembling workers of a detergent factory and computer users with the aims of A) determination of CTS prevalence and B) evaluation of personal risk factors and level of exposure to occupational risk factors via Quick Exposure Check (QEC). MATERIALS AND METHODS: In this descriptive cross-sectional study, 906 cases (332 assembling workers and 574 computer workers) were enrolled. CTS was assessed by symptoms on the Katz hand diagram and physical examination. QEC technique was applied to evaluate physical exposure to the risk factors. RESULTS: According to this study, the prevalence of probable CTS was 14% in men and 8.9% in women; the rate of probable CTS was significantly higher in assembly workers than in computer users (P < 0.001). Mean age and work duration in the probable CTS group was statistically higher than in non-CTS group. But both groups were in the same range (fewer than 30, P = 0.024, 0.004); BMI in the probable CTS group was slightly lower than in non CTS group, but BMI in both groups were in the normal range. Wrist ratio > 0.7 correlated with increased risk of probable CTS (P < 0.001) Prevalence of probable CTS was significantly higher in third and fourth levels of QEC (P < 0.001). CONCLUSIONS: Although this article had limitations, our findings suggest that the level of occupational exposure is an indicator of CTS development. PMID- 24350111 TI - Ibn Sina's (Avicenna) Contributions in the Treatment of Traumatic Injuries. AB - Modern medicine owes much to the endeavours and contributions made by the ancients that are unfortunately anonymous or even neglected intentionally today. This study was done to give attention to "the ancient golden times", as the author believes it deserves the nomination, to give credit to the manner our ancient physicians and masters practiced medicine and managed traumas in particular in a way that remains still unrivalled. Undoubtedly such masters as Galen of Pergamon, Hippocrates, Paul of Aegina and Avicenna paved the road for the so-called modern medicine and trauma surgery. Focus of this study is on Ibn Sina or Avicenna as the westerners call him and his methods in handling traumas of any kind and with any severity in the eleventh century based on the teachings handed down to him from the ancients; but he was not a mere imitator. What made him Avicenna was his genius talent in arranging the puzzles in such a way that was not even imagined by the others. PMID- 24350112 TI - Deep femoral artery branch pseudoaneurysm after orthopedic procedure requiring surgical treatment: a case report. AB - Pseudoaneurysms (PSA) of deep femoral artery (DFA) have been reported following penetrating and blunt trauma to the thigh and orthopedic procedures of the proximal femur. We describe a case of pseudoaneurysm of DFA as a late complication of limb trauma which was confirmed by exploration in an urgent surgery. After two operations successful surgical repair was performed. PMID- 24350113 TI - Necrotizing fasciitis of the upper extremity, case report and review of the literature. AB - ABSTRACT: Necrotizing fasciitis is a rare, life-threatening infection most commonly seen in patients with diabetes mellitus, intravenous drug abuse, and immunocompromised conditions. The extremities are the primary sites of involvement in as many as two thirds of the cases. In a significant proportion of patients, the extremities are involved as a result of trauma, needle puncture or extravasation of drugs. The infection is usually polymicrobial. Treatment involves broad-spectrum antibiotics and multiple surgical debridements or amputation. We present a patient with necrotizing fasciitis of the upper limb and present our experience with this often lethal condition. PMID- 24350114 TI - The long and winding road. PMID- 24350115 TI - Degree of Observance of the WHO Surgical Safety Checklist. AB - BACKGROUND: One of the most important goals of health care organizations is measuring and improving the quality of health care and reduction of adverse events. OBJECTIVES: The aim of this study was to evaluate the degree of observance of the WHO surgical safety checklist at two hospitals in Tehran. MATERIALS AND METHODS: During this analytic cross-sectional study the degree of observance and the effects of the checklist on patient outcomes were studied. The checklist was implemented at two teaching hospitals in Tehran, Iran. RESULTS: One hundred patients (40 +/- 15 years, 44 (44%) male and 56 (56%) female) were enrolled in our study. Determination of patients diagnoses, anesthesia safety check before anesthesia, patient connection to pulse oximetry, allergic airway disturbance check and aspiration risk, confirmation of patient identity, location of surgery and surgical method by surgeon and nurse, correct numbering of materials by nurse and correct ticketing by nurse were carried out in more than 90% of cases. CONCLUSIONS: In conclusion, our study demonstrated that surgery team members comply moderately to the WHO surgery safety checklist in Iran. Iranian health care providers need to show more adherence to some items of the checklist compared to their previous routine. PMID- 24350116 TI - Impact of trauma dispatch algorithm software on the rate of missions of emergency medical services. AB - BACKGROUND: Trauma still stands atop of the list of emergencies. Transfer of these patients via Emergency Medical Services (EMS) dispatch is critical with regard to importance of timing. This aspect has achieved greater importance due to population increase and telephone triage. OBJECTIVES: We aimed to decrease unnecessary Emergency Medical Services (EMS) missions via a computer program designed for an algorithmic approach for trauma care by nurses involved in EMS, to help them evaluate the case more accurately. We named our program "Trauma Dispatch Algorithm". MATERIALS AND METHODS: First, the most common chief complaints regarding traumatic events were chosen from searching all the calls in December 2008 recorded in Tehran, Iran's EMS center; and then an algorithm approach was written for them. These algorithms were revised by three traumatologists and emergency medicine specialists, after their approval the algorithms were evaluated by EMS dispatch center for their practicality. Finally all data were turned into computer software. The program was used at the Tehran EMS center; 100 recorded calls assessed with each system were selected randomly. They were evaluated by another traumatologist whether it was necessary to send a team to the site or not. RESULTS: The age average was 26 years in both groups. The "trauma dispatch algorithm" was significantly effective in reducing the unnecessary missions of EMS by 16% (from 42% to 26%) (P = 0.005). CONCLUSIONS: This program was effective in reducing unnecessary missions. We propose the usage of this system in all EMS centers. PMID- 24350117 TI - Effect of Ilioinguinal Neurectomy on Chronic Pain following Herniorrhaphy. AB - BACKGROUND: Inguinal hernia is one of the most common male diseases all over the world with an incidence rate of 18-24% throughout life. Chronic inguinal pain is one of the complications that prolong return to work time. OBJECTIVES: The main aim of this study was to determine the effect of ilioinguinal neurectomy on postoperative chronic pain (PCP) in patients that underwent open inguinal hernia repair via the Lichtenstein method. MATERIALS AND METHODS: IN THIS RANDOMISED CONTROLLED CLINICAL TRIAL, MALE PATIENTS WITH UNILATERAL INGUINAL HERNIA WERE RANDOMIZED INTO TWO GROUPS: 74 cases in the preserved-nerve group and 66 cases in the nerve-excised group. The method of herniorrhaphy was the classic Lichtenstein method. Pain and numbness were evaluated at 1 day, 1 week, 1 month, 6 months and 1 year after surgery via visual analogue scale (VAS) system. We used SPSS ver.16 for analysis. RESULTS: All patients were male with mean age of 39.1 years (with a range of 18 to 68 years). The follow-up rate was 100% after 1 year. Pain severity was significantly lower in nerve-excised patients at 1 day, 1week, 1 month and 6 months after surgery; but it was not significant after one year, although overall pain severity was low. Numbness was significantly higher in excised patients at all endpoints (1 day, 1month, 3 months, 6 months and one year after surgery). CONCLUSIONS: Ilioinguinal nerve excision at the time of inguinal hernia repair decreased post-surgical inguinal pain, and it can be used as a routine method in herniorrhaphy. PMID- 24350118 TI - Time of admission, gender and age: challenging factors in emergency renal colic - a preliminary study. AB - BACKGROUND: Nephrolithiasis is a relatively common problem and a frequent Emergency Department (ED) diagnosis in patients who present with acute flank/abdominal pain. The pain management in these patients is often challenging. OBJECTIVES: To investigate the most effective dose of morphine with the least side effects in emergency renal colic patients. MATERIALS AND METHODS: 150 renal colic patients who experienced a pain level of 4 or greater, based on visual analog scale (VAS) at admission time were included. Pain was scored on a 100 mm VAS (0 = no pain, 100 = the worst pain imagined). When patients arrived at ED, a physician would examine the patients and assessed initial pain score, then filled a questionnaire according to the patient information. Patients were assigned to receive 2.5 mg morphine sulfate intravenously. We monitored patients' visual analog scale (VAS), and adverse events at different time points (every 15 minutes) for 90 minutes. Additional doses of intravenous morphine (2.5 mg) were administered if the patient still had pain. (Max dose: 10 mg). The cumulative dose of morphine, defined as the total amount of morphine prescribed to each patient during the 90 minutes of the study, was recorded. Patients were not permitted to use any nonsteroidal anti-inflammatory drugs as coadjuvant analgesics during the study period. Subjects with inadequate pain relief at 90 minutes received rescue morphine and were excluded from the study. The primary end point in this study was pain relief at 90 minutes, defined as either VAS<40 or decrease of 50% or more as compared to the initial VAS. The secondary objective was to detect the occurrence of adverse effects at any time points in ED. RESULTS: The studied patients consisted of 104 men and 46 women with the mean age of 43 +/-14 years (range, 18 to 75 years). There was no statistically significant difference between the mean age and gender differences in pain response. Rescue analgesia at 30 minutes were given in 54.5% receiving morphine. The average time to painless was 35 minutes. But there were no statistically significant differences between the mean age and gender differences in pain response (P > 0.05). Older patients responded sooner to morphine than the young. Most of the patients had a pain score of 90 -100 (77.3 %) at the beginning that was reduced to 29.4% during the 30 minutes follow up. During the first hour, we found that 94.7% of the patients had no pain or significant pain reduction and only 2.1% of the patients still had pain. CONCLUSIONS: We conclude that there were no significant differences among the gender, time of admission and side - effects in renal colic patients in response to morphine. PMID- 24350119 TI - Early coverage of upper extremity electrical injury wounds. AB - BACKGROUND: An appropriate and well-timed surgery has great impact on a patient's treatment and can prevent further damage to partially injured structures which if untreated will be lost leading to severe disability. In the present study we report our experience with early coverage of electrically injured upper extremity vital structures with encouraging results. OBJECTIVES: The aim of this study was to evaluate the results of early flap coverage (less than two weeks) after electrical injury in the induced wounds of upper extremity. MATERIALS AND METHODS: The records of electrically injured patients referred during a 10- year period to Firuzgar Medical Center were evaluated. After one or two sessions of debridement, the wounds were covered by distant or pedicled flaps and the results were evaluated according to the number of surgeries, complications and return to work time. RESULTS: Thirty patients were registered in this study, mean age at the time of injury was 26.43 (SD = 10.41) years; 40% of patients had right upper extremity injury, 23.3% had left and 36.7% had bilateral injury. 43.4% of patients had no complications, amputation rate was 23.3% and nerve injury was seen in 13.3% of patients. Mean days of return to work was 132.57 (SD = 64.99). In 11 patients distant flaps were used, 9 patients with graft only and 7 patients had a combination of graft and regional flaps.The dominant hand involvement in electrical injury is very high. CONCLUSIONS: We suggest that the routine treatment protocols of serial debridement until all the wound acquires a bed of granulation tissue should be revised, because the vital structures such as tendons and nerves will have undergone dessication necrosis and a young worker will be crippled for life. Early coverage of partially injured vital structures is gaining acceptance and this paper confirms the above mentioned treatment protocol. PMID- 24350120 TI - Oral and maxillofacial injuries in civilian recruits during mandatory combat training at military garrisons: a nationwide survey. AB - BACKGROUND: There is significant prevalence of physical injuries sustained by civilian recruits at military training garrisons. Civilian recruits sustain these injuries mostly during the intensive and rigorous military combat-training period. OBJECTIVES: We sought to determine the prevalence and causes of oral and maxillofacial injuries as the first step in reducing and preventing them in civilian recruits (males aged over18 years) during their 2-year mandatory military service. MATERIALS AND METHODS: In this 2-year study, we referred to 11major military training garrisons in 8 provinces and collected data from available medical records of military clinics at each garrison. Injuries occurring in civilian recruits during the intense 2-month military combat training period were documented. Data regarding the number of civilian trainees, percentage of those injured, site where the injury was sustained, type of injury and its causes, etc. as well as demographic data were collected. RESULTS: The number of civilians called to military service was 153, 886. The ratio of those injured was 4419/153,886. The percentage of maxillofacial injuries was 20.4% (903/4419). The majorities of maxillofacial injuries occurred during the first month (38%) and were due to nonmilitary (86%) rather than military (14%) causes. From among the military causes, bullets (66%) were the most common cause of injury, while falls (73%) were the major cause of nonmilitary injuries. Mountainous terrain was the main cause of falls (51%). The most common military incidents which led to injury were related to artillery fire and explosions (33%). Nasal bone fracture was the most common maxillofacial fracture (49%), and lacerations were the most common soft tissue injury (54%). Among dental injuries, tooth fracture was most common (66%). CONCLUSIONS: The large number of general and maxillofacial injuries in civilian recruits during the 2-month combat training period at military garrisons is disconcerting. This issue warrants further research to implement methods for identifying, decreasing, and preventing injuries in civilians at military-training garrisons. PMID- 24350121 TI - Epidemiology of burn injuries at a newly established burn care center in rasht. AB - BACKGROUND: Advances in the care of burn injuries have resulted from the efforts of regional patient-based specialist teams at burn care centers. OBJECTIVES: We conducted this study to assess the four-year epidemiology of burn injuries in Rasht, Iran. MATERIALS AND METHODS: In this cross-sectional study, medical records of 2274 burn patients, treated at Velayat hospital from January 2007 to December 2010 in Rasht, Iran, were assessed. Age, sex, level of education, occupation, severity and degree of burn, burn surface area, burn cause and outcome of patients were evaluated. RESULTS: In our study the overall mortality rate was 8.7%; 65.7% of patients were men and 34.3% were women. Mean age of patients was 31.47 +/- 22.67 years. Mean Total Burn Surface Area (TBSA) was 15.24 +/- 18.4. Lowest TBSA was 0.5% and highest TBSA was 100%. Significant associations were observed between age (P = 0.0001), place of residence (P = 0.004), level of education (P = 0.0001), unemployment (P = 0.0001), marital status (P = 0.021), causes of burn (P = 0.0001), TBSA (P = 0.0001) and mortality rate. In our study, no significant difference was observed between age and sex (P = 0.071). CONCLUSIONS: Due to high prevalence of burn injuries in Iran, increasing the level of awareness of the society as well as adhering to safety procedures both at home and workplace is recommended via implementing effective national safety policies. PMID- 24350122 TI - Surgically induced digital distal syndactyly for prevention of digital growth deformities around the joints: a new technique. AB - BACKGROUND: Correction of digit deformities at or near the Joints is performed easily ; however, maintaining the result is often difficult either due to noncompliance of the patient to wear the postoperative splints or problems related to unequal growth of bones or normal tissues compared to the scarred or operated side. OBJECTIVES: The aim of this study was to overcome the above mentioned problems for which we propose the "Distal d Digit Syndactyly" technique. MATERIALS AND METHOD: This method is based on the concept of suturing the distal phalanx of the deformed digit to the normal adjoining finger to help prevent the recurrence of the anomaly during the child's growth period or the very important three or four postoperative months of scar maturation in the adult. After the correction of deformity of the finger or toe, "Distal Syndactyly" is created by two flaps on the adjoining digits; one base is dorsally hinged and the other one volar and after elevating the flaps they are sutured together. During the three postoperative weeks care is taken that this attachment is not disrupted and after healing a "distal syndactyly" is created which is very durable and in children it stretches with growth and does not impede the digit's growth. RESULTS: Eleven patients with congenital and traumatic digit anomalies were treated. The recurrence of the problem was prevented in 9 patients; in 2 patients with intact Syndactyly the contracture recurred by stretching the Syndactyly skin. The period of the "Joining" ranged from 6 months to three years and cosmetic appearance was acceptable to the patient and parents. CONCLUSION: This technique by joining a deformed digit to a normally growing adjacent digit prevents the postoperative recurrence of the contracture or growth induced deviation in the digits of noncompliant patients especially children. PMID- 24350124 TI - Delayed surgical treatment of distal biceps tendon rupture - a case report. AB - ABSTRACT: Traumatic rupture of the distal biceps tendon is rare. Conservative treatment can result in reduced flexion and supination power with reduced function. This case report emphasizes the need for prompt surgical treatment and describes the possible complications of delayed surgical intervention. PMID- 24350123 TI - A simple and light weight external fixator for distraction advancement manoplasty. AB - BACKGROUND: With the growing interest in long bone distraction several types of distractors have been introduced; all have the same principle of an outer structure which acts like a scaffold and the distracting mechanism is a separate device which is mounted on this outer structure. OBJECTIVES: We have used a simple and very light weight external fixator we designed and discuss the results of distraction and advantages of this device . MATERIALS AND METHODS: We applied our distractor to treat 14 men and four women, with a mean age of 39 years. There were three thumbs and 23 fingers; 26 digits (18 patients) lengthened by distraction callotasis and second stage bone grafting evaluated accordingly. RESULTS: All patients but one were satisfied with the results and a stable pinch and grip was obtained. After lengthening, all patients maintained sensation of the finger pulp, as assessed by the Semes - Weinstein test. CONCLUSIONS: The superiority of this device for manoplasty lies in its simplicity of construction in addition to being, lightweight and also eases of application. PMID- 24350125 TI - Salient points to observe in panfacial fracture management. PMID- 24350126 TI - The long and winding road (part 2). PMID- 24350127 TI - Comprehensive Management of Maxillofacial Projectile Injuries at the First Operation; "Picking up the Pieces". PMID- 24350128 TI - Deep vein thrombosis following below knee immobilization: the need for chemoprophylaxis. AB - BACKGROUND: There is controversy regarding routine prophylaxis for deep vein thrombosis (DVT) in patients treated via a short leg cast or splint following lower extremity trauma. OBJECTIVES: The main aim of this study is to evaluate the incidence of DVT and need for chemoprophylaxis in these patients. MATERIALS AND METHODS: Patients with ankle sprains or stable foot/ankle fractures were entered in this cross-sectional study. Serum D-dimer levels were measured 2 weeks following fixation. If the D-dimer levels were above 0.2 micrograms/ml the test was considered positive and the patient was referred for Doppler ultrasound examination (DUE) to confirm or rule out the diagnosis of DVT. Finally, the incidence of DVT was calculated and the role of predisposing factors was investigated. RESULTS: There were 95 patients with an average age of 38 +/- 13.7 (77.9% males); 46 patients had at least one risk factor for DVT. The D-dimer test was positive in 21(22.1%) patients. DVT was confirmed by DUE in 3 patients (3.1%). The incidence of DVT significantly increased in the presence of 3 or more risk factors (P = 0.01). CONCLUSIONS: It seems that DVT is not a common complication of below knee fixation and chemoprophylaxis is not necessary when the patient has less than 3 predisposing factors. With 3 or more risk factors chemoprophylaxis and periodic follow-ups must be considered. PMID- 24350129 TI - Application of removable wrist splint in the management of distal forearm torus fractures. AB - BACKGROUND: There is considerable variation in the treatment of distal forearm torus fractures (DFTF), from soft bandaging to cast immobilization. OBJECTIVES: The present study aimed to show the result of removable wrist splint (RWS) in the treatment of these fractures. MATERIALS AND METHODS: One hundred forty two children aged less than 17 years old with DFTF were studied prospectively. These patients were randomly treated either by a short arm cast (SAC) or a RWS for three weeks. Finally the treatment results of the two groups were compared. RESULTS: There were no significant differences regarding degree of pain, compliance or complications between RWS and SAC groups. Resource savings can be made with this approach also patients' and parents' satisfaction can be increased without compromising patients' care. CONCLUSIONS: RWS can be considered as an easy and acceptable treatment modality with very low costs and complications in the management of DFTF. PMID- 24350130 TI - Mental Health Levels and Incidence of Musculoskeletal Complaints among Speed Boat Crew Members. AB - BACKGROUND: The occupational health is an important issue. In some jobs, the working conditions contribute to musculoskeletal complaints and the overall health of the individual is compromised. Musculoskeletal complaints have gained credence in the public as one of the most important problems in the field of occupational diseases. Physical and mental health of crew members with critical jobs and stressful environments must be considered as well. OBJECTIVES: This study performed an assessment on levels of mental health and the correlation with the frequency of accompanying musculoskeletal complaints (such as neck, back and knee pain) of crew members of speed boats. MATERIAL AND METHODS: 149 onboard crew members of speed boats were recruited in a descriptive-correlation study by nonrandom sampling using conducted GHQ12, NMQ and demographic questionnaires. RESULTS: Although 63.8% (95 people) had what is conventionally defined as normal mental health, 36.2% (54 cases) had an inherent mental health condition. Overall, 61.1% (91 cases) suffered from back pain, 60.4% (90 cases) complained of knee pain, and 40.3% (60 patients) complained of neck pain. The combination of knee and back pain (48.3%) were the most common complaints whereas the combination of neck and knee pain (31.5%) were the least frequent; 28.2% complained of pain in all three areas. Interestingly, there was correlation between the presence of musculoskeletal complaints and less than optimum mental health. CONCLUSIONS: Due to the high number of musculoskeletal complaints and the compromised mental health conditions among one-third of the onboard crew members of speed boats, attention for maintaining and improving the health of these members must be considered. PMID- 24350131 TI - Sonographic Detection of Abdominal Free Fluid: Emergency Residents vs Radiology Residents. AB - BACKGROUND: Focused assessment with sonography for trauma (FAST) has become a part of initial examinations in trauma care at emergency departments (ED). OBJECTIVES: The goal of the present study was to evaluate the accuracy of FASTs performed by emergency residents (ER) in detection of abdominal free fluid following blunt trauma. MATERIALS AND METHODS: In this study, the reports of ERs performing FASTs on 286 admitted patients following blunt trauma were compared with those of radiology residents (RR) in relation to presence of abdominal free fluid. In addition, the reports of the two resident groups were compared with the final abdominal outcome, based on the results of abdominal computed tomography (CT) and clinical follow up. RESULTS: The ERs had reported abdominal free fluid in 20 (6.9%) patients while RRs performing FAST had positive results in 22 (7.6%) patients. The reports of FASTs revealed significant correlation between the two resident groups (P < 0.001). ERs performing FASTs had 90% sensitivity and 98.5% specificity in comparison to RRs sonography reports. Furthermore, ER-performed FASTs had 96.5% accuracy in relation to final outcome. CONCLUSIONS: Following training, ED residents can perform FAST with high accuracy and specificity, similar to RR residents, in patients with blunt abdominal trauma. PMID- 24350132 TI - Outcomes of pin and plaster versus locking plate in distal radius intraarticular fractures. AB - BACKGROUND: Distal radius fractures are among the most prevalent fractures predictive of probable occurrence of other osteoporotic fractures. They are treated via a variety of methods, but the best treatment has not been defined yet. OBJECTIVES: This study was performed to compare the results of open reduction and internal fixation with locking plates versus the pin and plaster method. MATERIALS AND METHODS: In this prospective study, 114 patients aged 40 to 60 years with Fernandez type III fracture referring to Imam-Reza and Mehr hospitals of Mashhad from 2009 to 2011, were selected randomly; after obtaining informed consent, they were treated with pin and plaster fixation (n = 57) or internal fixation with the volar locking plate (n = 57). They were compared at the one year follow up. Demographic features and standard radiographic indices were recorded and MAYO, DASH and SF - 36 tests were performed. Data was analyzed by SPSS software version 13, with descriptive indices, Mann-Whitney and Chi square tests. RESULTS: SF-36 test demonstrated a better general health (P < 0.001), mental health (P = 0.006), physical functioning (P < 0.001), social functioning (P < 0.001) and energy/fatigue (P < 0.001) in LCP group. However, pain (P = 0.647) was not significantly different between the groups. Physical limitation (P < 0.001) and emotional limitation (P < 0.001) were greater in the pin and plaster group. Also, in the LCP group mean MAYO score (P < 0.001) was more than pin and plaster group. Mean DASH score was not different between the groups (P = 0.218). The rate of acceptable results of radiographic indices (P < 0.001), grip strength (P < 0.001) and range of motion in supination-pronation (P < 0.001) in LCP method were better than the pin and plaster method. CONCLUSIONS: In treatment of intra-articular distal radius fractures in middle-aged patients internal fixation with locking plates may be prefered to pin and plaster as the treatment of choice. PMID- 24350133 TI - Local erythropoietin injection in tibiofibular fracture healing. AB - BACKGROUND: Erythropoietin (EPO), in addition to its function as an erythropoiesis regulator has a regenerative activity on some nonhematopoietic tissues. Animal studies have suggested a role for erythropoietin in bone healing. OBJECTIVES: The present study aimed to evaluate the effects of local EPO injection in healing of tibiofibular fractures. MATERIALS AND METHODS: In a prospective double blind study, 60 patients with tibiofibular fracture were divided to equal EPO or placebo groups, randomly. Patients received local injection of either EPO or a placebo to the site of fracture two weeks after surgical fixation. Patients were followed by clinical and radiographic examination to determine the union rate. The period of fracture union and incidence of nonunion were compared between the two groups. RESULTS: The demographic data and types of fractures were similar in the both groups. The mean duration of the fracture union was 2.1 weeks shorter in those treated with EPO (P = 0.01). Nonunion was observed in 6 patients of the control group and 2 receiving EPO (P = 0.02). No patient experienced any adverse effect from local EPO injections. CONCLUSIONS: EPO injection into the site of tibiofibular fractures may possibly accelerate healing. PMID- 24350134 TI - Trauma-related Therapeutic Procedures at Shohada Trauma Center in Tabriz. AB - BACKGROUND: To decrease the burden of injuries it is essential to have an overview of trauma patterns and its management at regional trauma centers. OBJECTIVES: The aim of this study was to investigate some patterns of trauma and trauma-related therapeutic interventions at our trauma center. MATERIALS AND METHODS: In a cross-sectional study, 19530 trauma cases admitted to the emergency department and hospital wards of Shohada University Hospital during 2007-2008 were assessed. RESULTS: Of the 19530 trauma cases, 14960(76.7%) were males. Mean (SD) of age was 31(19.9) years. The elderly aged 65 and above, comprised 10% (1953) of the participants; while 44 were infants. Falls and traffic injuries were the most common cause of injuries among trauma patients. Most of the mortalities were men comprising 74% of the 57 deaths. Reduction of fractures and dislocations were the most common types of operations among trauma patients. CONCLUSIONS: Young men form the target group for possible interventions to decrease the burden of trauma following falls and traffic accidents. PMID- 24350135 TI - Autologous blood injection for treatment of tennis elbow. AB - BACKGROUND: Tennis elbow (TE) is a common myotendinosis. It was first described by Runge in 1873; different modes of treatment are used in management of TE. OBJECTIVES: This study aimed to report the results of autologous blood injection (ABI) in the treatment of TE. MATERIALS AND METHODS: A prospective case study was performed to evaluate the results of ABI in the management of TE. The level of pain based on Nirschl phase scale (NPS) and a visual analogue scale (VAS) was calculated before and 1, 3 and 6 months after injection; then satisfaction was assessed. RESULTS: Twenty-nine patients with diagnosed TE were treated by ABI (24% males, 76 % female). The mean age of the patients was 44.1 +/- 5.2 years. The level of pain on VAS decreased from 6.46 +/- 2.08 to 0.54 +/- 0.7 (P=0.001) and on NPS from 6.15 +/- 1.48 to 0.54 +/- 0.76 (P = 0.001) 6 months after treatment. At the end of the study, 84% of patients expressed a high level of satisfaction. CONCLUSIONS: Given the acceptable outcomes, autologous blood injection can be considered a good treatment option for TE when traditional treatment has fails. PMID- 24350136 TI - Open reduction and internal fixation of intraarticular fractures of the humerus: evaluation of 33 cases. AB - BACKGROUND: Standard treatment of type C elbow fractures is open reduction and internal fixation using reconstruction plates and pins. OBJECTIVES: The aim of this study was to evaluate the functional outcome following internal fixation of intraarticular fractures of the distal humerus (AO Type C) with a minimum follow up of three years. A retrospective evaluation was undertaken. PATIENTS AND METHODS: Thirty-three patients (28 males, 5 females; mean age 34.3years) type C elbow fractures were treated and observed over a period of three years. Six fractures were open and 27 closed; causes were falls (7 cases), traffic accidents (22 cases) and altercation (4 cases). All operations were performed using a posterior approach with an olecranon osteotomy. Mean duration of follow-up was 18 months (range 6-36). Mean duration of fracture healing was 2.3 months (range 2 4). Functional outcomes were assessed by Jupiter criteria. RESULTS: Excellent results were found in 69.7% (23 cases), very good reaults and good results were found in the remaining 30.3% (10 cases). Three of 33 patients 9% (3 cases) presented postoperative complications. No patient exhibited symptoms of ulnar nerve injury following surgery. One patient had cubitusvarus deformities and one case had heterotopic ossification. One patient had malunion and one case had deep infection. CONCLUSIONS: Complications were minimal and outcomes were satisfactory in patients with type C distal humerus fractures who underwent bilateral plate fixation via a posterior approach. PMID- 24350137 TI - Tendon transfer in hand trauma: a case report. AB - In this report we describe our encounter of a case of hand trauma referred to our center presenting with incomplete left thumb amputation at metacarpal level with extensor pollicis longus (EPL) and flexor pollicis longus (FPL) tendon avulsion from the tenomuscular junction. After metacarpal bone fixation the ulnar digital artery was anastomosed and the digital nerves were coapted. Transfer of extensor indicis proprius (EIP) to EPL and side-to-side suturing of the FPL to the deep flexor tendon of the index finger were performed. PMID- 24350138 TI - Non-anatomical surgical solutions for difficult non-unions: case series. AB - ABSTRACT: Non-union occurs when bone healing ceases and does not continue without some type of intervention. Classification of non-union is traditionally based on the amount of callus or bone healing at the fracture site. Successful treatment of non-union often depends on appropriate reduction and realignment of the fracture, bone grafting if necessary, and stabilization. This may not be possible in some neglected and complicated non-unions. Under these circumstances, modification of the standard techniques or a limited surgical interference, that might not be anatomical, may succeed in improving function. We present four cases of non-anatomical salvage solutions for difficult long bone non-unions with satisfactory functional outcome. PMID- 24350140 TI - Don'T you just hate peer review? PMID- 24350139 TI - Posterior hip dislocation associated with posterior wall acetabular fracture and ipsilateral intertrochantric fracture: a very rare case report. AB - ABSTRACT: Traumatic hip dislocations are common in high-energy motor vehicle accidents. We present a case of a 43-year old man who sustained posterior hip dislocation with posterior wall acetabular fracture and ipsilateral intertrochantric fracture following a motorcycle accident. Urgent open reduction and internal fixation of the hip fracture-dislocation and fixation of intertrochantric fracture with a dynamic hip screw were done. To our knowledge, such an injury has been rarely reported in the literature. Possible mechanisms of injury and operative procedures are discussed. Radiographic follow-up after eight months showed union. No major complications were observed in our patient. PMID- 24350141 TI - Orthopedic injuries following the East azerbaijan earthquake. AB - BACKGROUND: Evaluating demographic characteristics, distribution and types of orthopedic injuries following major earthquakes may be helpful in future planning for disasters. OBJECTIVES: This study aimed to analyze data from trauma patients with extremity injury resulting from the earthquakes of East Azerbaijan, Iran. PATIENTS AND METHODS: Medical records of 686 patients admitted to Shohada hospital, Trauma Center of Tabriz University of Medical Sciences were reviewed. There were 200 patients with extremity injury assessed. Demographic characteristics and patterns of injuries in these patients were evaluated. RESULTS: In this study, there were 105 females (52.5%) and 95 males (47.5%), out of which, 6 (3%) patients with associated severe head injuries died. The most common sites of injury were lower extremities (81 patients, 41.5% of total victims) while 32 patients (16%) suffered from both upper and lower extremity injuries. Open Fractures were seen in lower extremities of 26 (13%) patients. Compartment syndrome was observed in 3 (1.5%) patients with lower limb fractures. Also, 42 (21%) patients living in Tabriz were injured while they were running away (falling down the stairs and jumping out of windows). CONCLUSIONS: Extremity injuries especially open fractures of lower limbs account for the majority of hospitalized victims. Compartment syndrome is one of the main problems that should be addressed. Our study demonstrates that people still need more education regarding earthquakes and the government should direct more attention to this issue. PMID- 24350142 TI - Long-term follow-up results of delayed fixation of femoral neck fractures in adults. AB - BACKGROUND: Femoral neck fractures are urgent injuries that require precise reduction and stable fixation. In some cases, however, early treatment is not possible. OBJECTIVES: The present study aimed to evaluate long-term results of delayed fixation of femoral neck fractures using cannulated screws. PATIENTS AND METHODS: This retrospective descriptive-analytical study was conducted on 26 patients with femoral neck fractures. The patients were treated through a closed reduction and fixation method using cannulated screws. Patients were followed up for at least five years and the rate of complications was determined. RESULTS: In this study, 26 patients with mean age of 34.3 years were assessed. Average time interval from injury to surgery was 46.4 +/- 12.2 hours; 18 patients (69%) were operated on with more than 36 hours of delay. Incidence of AVN and nonunion was reported in 10 (38.4%) and 3 (11.5%) patients, respectively. CONCLUSIONS: Time plays an important role in treatment results of femoral neck fractures. To treat the fractures, closed reduction and fixation using cannulated screws may still be the best option. PMID- 24350143 TI - Delayed presentation of traumatic diaphragmatic hernia: a diagnosis of suspicion with increased morbidity and mortality. AB - BACKGROUND: Diaphragmatic rupture due to blunt or penetrating injury may be a missed diagnosis in an acute setting and can present with a delayed complication with significantly increased morbidity and mortality. OBJECTIVES: The objective of this study is to better understand why diaphragmatic tears with delayed presentation and diagnosis are so often missed and why traumatic diaphragmatic tears are difficult to diagnose in emergency settings and how they present with grievous complications. PATIENTS AND METHODS: Eleven patients with diaphragmatic hernias with delayed presentation and delayed diagnosis were operated within the last five years. All patients presented with different complications like gut gangrene or respiratory distress. RESULTS: Out of eleven patients who were operated on for diaphragmatic hernia, three patients (27%) died. Three patients required colonic resection, one patient needed gastrectomy and one patient underwent esophagogastrectomy. CONCLUSIONS: A small diaphragmatic tear due to blunt trauma to the abdomen is difficult to diagnosis in acute settings due to ragged margins and possibly no herniated contents and usually present with a delayed complication. Therefore a careful examination of the entire traumatized area is the best approach in treating delayed presentation of traumatic diaphragmatic hernia prior to development of grievous complications. PMID- 24350144 TI - Mandibular Angle Fractures: Comparison of One Miniplate vs. Two Miniplates. AB - BACKGROUND: Monocortical miniplate fixation is an accepted and reliable method for internal fixation of mandibular angle fractures. Although placement of a second miniplate may theoretically provide more stability; however, the clinical importance of this issue remains controversial. OBJECTIVES: The present study assessed the postoperative complications and outcomes associated with the fixation of mandibular angle fractures using 1 and 2 miniplates in patients with favorable mandibular angle fractures. PATIENTS AND METHODS: A prospective study of 87 patients (73 males, 14 females) with favorable mandibular angle fractures was done. In the first group, a 4-hole miniplate was placed at the superior border through an intraoral approach. In group 2, patients were treated with 2 miniplates, one placed at the superior border (similar to group 1) and the other on the lateral aspect of the angle at the inferior border through an intraoral and transcutaneous approach using a trocar. Postoperative complications including malocclusion, malunion and sensory disturbances associated with surgery, additional maxillomandibular fixation (MMF) by means of an arch bar and wires for a longer period (for delayed union) and infection were assessed in patients of both groups up to 12 months postoperatively. The data were analyzed using the chi square test. RESULTS: In the single miniplate group, 25 patients showed lip numbness associated with surgery (55.6%), 22 patients required additional use of MMF (48.9%) and 3 patients developed infections (6.7%). In the double miniplate group 20 patients showed lip numbness associated with surgery (47.6%), 18 patients required additional use of MMF (42.9%) and 1 patient developed infection (2.4%). None of the patients in either group showed malocclusion or malunion. No significant difference was observed between the groups regarding overall complication rate. CONCLUSIONS: In this study, use of one miniplate or two miniplates for treatment of favorable mandibular angle fractures was associated with a similar incidence of complications. Thus, it seems that the use of two miniplates in this setting may not be warranted, nor cost-efficient. PMID- 24350145 TI - Architecture capabilities to improve healthcare environments. AB - BACKGROUND: The physical environment of healthcare buildings has great importance in issues such as patient safety, functional efficiency, user satisfaction, healthcare outcomes, and energy and resources consumption. OBJECTIVES: The present study assesses physical environments of Iranian healthcare buildings. MATERIALS AND METHODS: This study was performed using a descriptive-analytical method. Data collection was carried out via a written questionnaire. RESULTS: Based on the findings of this study, "functional efficiency", "user satisfaction", "environmental issues", "patient safety", "accountability in incidents and disasters", and "flexibility" are regarded as the most issues in the country's hospitals. Also, none of the parameters is "without any problem" and has a "desirable status". CONCLUSIONS: According to the responses, all of the healthcare buildings in this research had flaws in their physical environment, which require attention. Thus, it is necessary to review and pay more attention to the architecture of the country's healthcare buildings. PMID- 24350146 TI - Surgical management of acetabular fractures: a case series. AB - INTRODUCTION: For decades, acetabular fractures were treated conservatively. Judet et al. in 1960s established the operative treatment of these fractures by continuous improvement of pre-operative evaluation and classification of fractures. Several studies demonstrated that accurate fracture reduction decreases the incidence of post-traumatic arthritis and improves functional outcome. CASE SERIES: We report 67 consecutive patients who underwent surgical treatment for acetabular fracture; 44 patients were available for follow-up. In 35 (79.5%) cases, congruent reductions were achieved. The final mean Harris hip score was 81.8 (53-95). Functional outcomes according to Harris score were excellent and good in 31 patients (70.5%). CONCLUSIONS: The results of internal fixation of displaced acetabular fractures in our series were satisfactory. PMID- 24350148 TI - An unusual combination of acetabular and pelvic fracture: is this a new subtype of acetabular fracture? AB - INTRODUCTION: Acetabular fractures are a common problem among young males. An acetabular fracture with disruption of the joint surface, if untreated, will rapidly lead to post-traumatic osteoarthritis. Proper reduction and internal fixation depend on accurate classification and the quality of imaging. CASE PRESENTATION: We present an unusual form of acetabular fracture, which is not included in the conventional classification (Judet and Letournel) ; this occurred in a middle-aged male who was operatively treated without any complications. In this case due to posterior extension of the fracture into the SI joint and concomitant anterior column fracture in the area above the acetabular dome, no portion of the acetabular anterior surface remained connected to the innominate bone. CONCLUSIONS: We recognized this type of fracture and treated it similarly to both column fractures. We recommend that the classification of acetabular fractures be modified to include this type of fracture. PMID- 24350147 TI - Two-stage surgical treatment for non-union of a shortened osteoporotic femur. AB - INTRODUCTION: We report a case of non-union with severe shortening of the femur following diaphysectomy for chronic osteomyelitis. CASE PRESENTATION: A boy, aged 16 years presented with a dangling and excessively short left lower limb. He was using an elbow crutch in his right hand to help him walk. He had a history of diaphysectomy for chronic osteomyelitis at the age of 9. Examination revealed a freely mobile non-union of the left femur. The femur was the seat of an 18 cm shortening and a 4 cm defect at the non-union site; the knee joint was ankylosed in extension. The tibia and fibula were 10 cm short. Considering the extensive shortening in the femur and tibia in addition to osteoporosis, he was treated in two stages. In stage I, the femoral non-union was treated by open reduction, internal fixation and iliac bone grafting. The patient was then allowed to walk with full weight bearing in an extension brace for 7 months. In Stage II, equalization of leg length discrepancy (LLD) was achieved by simultaneous distraction of the femur and tibia by unilateral frames. At the 6 month follow- up, he was fully weight bearing without any walking aid, with a heel lift to compensate the 1.5 cm shortening. Three years later he reported that he was satisfied with the result of treatment and was leading a normal life as a university student. CONCLUSIONS: Two-stage treatment succeeded to restore about 20 cm of the femoral shortening in a severely osteoporotic bone. It has also succeeded in reducing the treatment time of the external fixator. PMID- 24350150 TI - Ruptured aneurysm of the splenic artery: a rare cause of abdominal pain after blunt trauma. AB - INTRODUCTION: Splenic artery aneurysms (SAAs) are rare (0.2-10.4%); however, they are the most common form of visceral artery aneurysms. Splenic artery aneurysms are important to identify, because up to 25% of the cases are complicated by rupture. Post- rupture mortality rate is 25% -70% based on the underlying cause. Herein we present a young patient with abdominal pain after blunt abdominal trauma due to rupture of an SAA. CASE PRESENTATION: A 27-year-old male, without a remarkable medical history, who suffered from abdominal pain for 2 days after falling was admitted to the emergency department with hypovolemic shock. Upon performing emergency laparotomy a ruptured splenic artery aneurysm was found. CONCLUSIONS: It is important to consider rupture of a splenic artery aneurysm in patients with abdominal pain and hypovolemic shock. PMID- 24350149 TI - A Rare Case of Gorham's Disease: Primary Ulnar Involvement with Secondary Spread to the Radius and Elbow. AB - INTRODUCTION: Gorham's disease is a rare musculoskeletal disease which causes progressive osteolysis and is characterized by massive bone destruction due to proliferation of vascular elements along with a great number of osteoclasts. The etiology of the disease is unknown. Gorham's disease is essentially rare in the forearm bones. As far as we know, only 2 cases of Gorham's disease of the forearm have been reported with 1 of them in the radius and the other starting in the radius and spreading to the lower portion of the humerus. CASE PRESENTATION: This case report shows that Gorham's disease may affect the ulna primarily and spread to adjacent bones despite the fact that there are no such reports in the literature. CONCLUSIONS: Gorham's disease has several manifestations as primary bone involvement. As in this rare case the ulna may be affected first and then the disease may spread to adjacent bones. More studies are needed to better recognize the behavior of this rare disease. PMID- 24350151 TI - Minding the Prevention Protocol for Blood-Borne Diseases via EM Residents. AB - BACKGROUND: The emergency department (ED) is one of the high-risk places for blood-borne disease (BBD) transmission. OBJECTIVES: This study aimed to assess the rate of adherence to preventive measures (PM) against the blood-borne diseases via emergency medicine (EM) residents. MATERIALS AND METHODS: In this descriptive cross-sectional study, 80 emergency residents of an educational public hospital were observed with regard to abiding by the preventive measures from March to May 2010. RESULTS: Cleaning blood tainted skin before phlebotomy or IV line preparation and hand washing before donning latex gloves achieved the maximum (88/150) and minimum (0/150) scores. The most observed barriers of PM were frequent attendance of patients (85%), work load (80%), and need to work rapidly (68%). CONCLUSIONS: It seems that, the preventive instructions are not optimally respected by ERs possibly due to the crowded wards, high work load and the need to work rapidly. PMID- 24350152 TI - Employing the Next Generation: Isn't it time to Make the Transition. PMID- 24350153 TI - Mental Trauma Experienced by Caregivers of patients with Diffuse Axonal Injury or Severe Traumatic Brain Injury. AB - CONTEXT: As with care giving and rehabilitation in chronic illnesses, the concern with traumatic brain injury (TBI), particularly with diffuse axonal injury (DAI), is that the caregivers are so overwhelmingly involved in caring and rehabilitation of the victim that in the process they become traumatized themselves. This review intends to shed light on the hidden and silent trauma sustained by the caregivers of severe brain injury survivors. Motor vehicle accident (MVA) is the highest contributor of TBI or DAI. The essence of trauma is the infliction of pain and suffering and having to bear the pain (i.e. by the TBI survivor) and the burden of having to take care and manage and rehabilitate the TBI survivor (i.e. by the TBI caregiver). Moreover many caregivers are not trained for their care giving task, thus compounding the stress of care giving and rehabilitating patients. Most research on TBI including DAI, focus on the survivors and not on the caregivers. TBI injury and its effects and impacts remain the core question of most studies, which are largely based on the quantitative approach. EVIDENCE ACQUISITION: Qualitative research can better assess human sufferings such as in the case of DAI trauma. While quantitative research can measure many psychometric parameters to assess some aspects of trauma conditions, qualitative research is able to fully reveal the meaning, ramification and experience of TBI trauma. Both care giving and rehabilitation are overwhelmingly demanding; hence , they may complicate the caregivers' stress. However, some positive outcomes also exist. RESULTS: Caregivers involved in caring and rehabilitation of TBI victims may become mentally traumatized. Posttraumatic recovery of the TBI survivor can enhance the entire family's closeness and bonding as well as improve the mental status of the caregiver. CONCLUSIONS: A long-term longitudinal study encompassing integrated research is needed to fully understand the traumatic experiences of caregivers. Unless research on TBI or DAI trauma is given its proper attention, the burden of trauma and injury on societies will continue to exacerbate globally. PMID- 24350154 TI - Prehospital management of gunshot patients at major trauma care centers: exploring the gaps in patient care. AB - BACKGROUND: Prehospital management of gunshot-wounded (GW) patients influences injury-induced morbidity and mortality. OBJECTIVES: To evaluate prehospital management to GW patients emphasizing the protocol of patient transfer to appropriate centers. PATIENTS AND METHODS: This prospective study, included all GW patients referred to four major, level-I hospitals in Mashhad, Iran. We evaluated demographic data, triage, transport vehicles of patients, hospitalization time and the outcome. RESULTS: There were 66 GW patients. The most affected body parts were extremities (60.6%, n = 40); 59% of cases (n = 39) were transferred to the hospitals with vehicles other than an ambulance. Furthermore, 77.3% of patients came to the hospitals directly from the site of event, and 22.7% of patients were referred from other medical centers. EMS action intervals from dispatchers to scene departure was not significantly different from established standards; however, arrival to hospital took longer than optimal standards. Additionally, time spent at emergency wards to stabilize vital signs was significantly less in patients who were transported by EMS ambulances (P = 0.01), but not with private ambulances (P = 0.47). However, ambulance pre hospital care was not associated with a shorter hospital stay. Injury Severity was the only determinant of hospital stay duration (beta = 0.36, P = 0.01) in multivariate analysis. CONCLUSIONS: GW was more frequent in extremities and the most patients were directly transferred from the accident site. EMS (but not private) ambulance transport improved patients' emergency care and standard time intervals were achieved by EMS; however more than a half of the cases were transferred by vehicles other than an ambulance. Nevertheless, ambulance transportation (either by EMS or by private ambulance) was not associated with a shorter hospital stay. This showed that upgrade of ambulance equipment and training of private ambulance personnel may be needed. PMID- 24350155 TI - Fixation of Intertrochanteric Fractures: Dynamic Hip Screw versus Locking Compression Plate. AB - BACKGROUND: According to the existing literature, the Dynamic Hip Screw (DHS) is the preferred standard for the treatment of intertrochanteric fractures. However, some surgeons use other devices such as the Locking Compression Plate (LCP). OBJECTIVES: In this study, we compared the outcome of using DHS or LCP in intertrochanteric fractures. MATERIALS AND METHODS: This cross-sectional study was carried out on 104 patients who were referred to Pursina Hospital in Rasht, Iran with intertrochanteric fractures of the femur treated with either the DHS or LCP devices. Demographic features, existence or nonexistence of stability and operating time were obtained from questionnaires. During a 6-month follow-up after surgery, patients were interviewed to record variables such as Harris Hip Scores and complications. The patients were also interviewed on their final visit (between 9 and 31 postoperative months). The collected data was analyzed using SPSS. RESULTS: We discovered that the number of incidences of limb shortening and device failure was higher for patients treated with the LCP device (P = 0.048 and P = 0.014). Patients treated with the DHS device had higher Harris Hip scores for both the 6-month postoperative and the final evaluation visits (P = 0.01 and P = 0.018). CONCLUSIONS: Despite the complications of fixation with the DHS device, it remains the most successful for treatment of intertrochanteric fractures. PMID- 24350156 TI - Effects of taping on pain, grip strength and wrist extension force in patients with tennis elbow. AB - BACKGROUND: Tennis elbow (TE) is a common musculotendinous degenerative disorder of the extensor origin at the lateral humeral epicondyle. Different modes of treatment are used for management of tennis elbow. OBJECTIVES: This study investigated the effect of the taping technique (TT) on pain, grip strength and wrist extension force in treatment of tennis elbow. PATIENTS AND METHODS: Thirty patients (16 men /14 women with a mean age of 32.2 years) with tennis elbow of their dominant arm participated in this study. Outcome measures were assessment of pain at the lateral aspect of the elbow, grip strength and wrist extension force before and five to ten minutes after application of elbow tape on the affected and unaffected arms. A Visual Analog Scale was used to assess pain. A dynamometer and a hand-held dynamometer were used for evaluation of grip strength and wrist extension force, respectively. RESULTS: Among the variables, significant differences were found in wrist extension forces between effected and unaffected arms (P = 0.02). Changes in grip strength showed statically significant improvements in the affected arm compared to the unaffected arm (P = 0.03). Also, in assessment of pain at the lateral epicondyle, the mean change between affected and unaffected arms was significant, with P = 0.001. CONCLUSIONS: The taping technique, as applied in this study demonstrates an impressive effect on wrist extension force and grip strength of patients with TE. Elbow taping also reduces pain at the lateral aspect of the elbow in these patients. PMID- 24350157 TI - Behavior of healthcare workers after injuries from sharp instruments. AB - BACKGROUND: Injuries with sharps are common occupational hazards for healthcare workers. Such injuries predispose the staff to dangerous infections such as hepatitis B, C and HIV. OBJECTIVES: The present study was conducted to investigate the behaviors of healthcare workers in Kashan healthcare centers after needle sticks and injuries with sharps in 2012. MATERIALS AND METHODS: A cross-sectional study was conducted on 298 healthcare workers of medical centers governed by Kashan University of Medical Sciences. A questionnaire was used in this study. The first part included questions about demographic characteristics. The second part of the questionnaire consisted of 16 items related to the sharp instrument injuries. For data analysis, descriptive and analytical statistics (chi-square, ANOVA and Pearson correlation coefficient) SPSS version 16.0 software was used. RESULTS: From a total of 298 healthcare workers, 114 (38.3%) had a history of injury from needles and sharp instruments in the last six months. Most needle stick and sharp instrument injuries had occurred among the operating room nurses and midwifes; 32.5% of injuries from sharp instruments occurred in the morning shift. Needles were responsible for 46.5% of injuries. The most common actions taken after needle stick injuries were compression (27.2%) and washing the area with soap and water (15.8%). Only 44.6% of the injured personnel pursued follow-up measures after a needle stick or sharp instrument injury. CONCLUSIONS: More than a half of the healthcare workers with needle stick or sharp instrument injury had refused follow-up for various reasons. The authorities should implement education programs along with protocols to be implemented after needle stick injuries or sharps. PMID- 24350158 TI - Mortality and morbidity of fireworks-related burns on the annual last wednesday of the year festival (charshanbeh soori) in iran: an 11-year study. AB - BACKGROUND: Management of firework-related injuries is costly for the patient, society, and government. OBJECTIVES: Evaluating effective factors yielding to such injuries may lead to better management of patients and decreased costs and morbidities. PATIENTS AND MATERIALS: This retrospective cross-sectional study was performed on burn patients referred to Shahid Motahari Burns Hospital on Charshanbeh Soori day festival during the period extending from March 2000 to March 2011 (11 days in an 11-year period). Demographic data, causes of burn injury, severity, and affected body parts were recorded. Data were analyzed using SPSS version 16. RESULTS: There were164 patients in the study with a mean age of 18.34 +/- 9.31 years; 87% (145/164) were male. Homemade grenades were the most frequent cause of injury. Hand injury was reported in 56% (92/164) of the cases. Amputation was executed in 7 (4.3%) cases, and 6 (3.7%) patients died due to severe burn injuries and facial damage. CONCLUSIONS: Fireworks- related injuries during Charshanbeh Soori ceremony causes significant morbidities and damage to different body parts (especially upper limbs and face), and some of these injuries will lead to life time disabilities, amputations, and even death. As most of the injured patients are young teenagers and children, special consideration must be taken into account to prevent long term morbidities. PMID- 24350159 TI - Interpretation of Computed Tomography of the Head: Emergency Physicians versus Radiologists. AB - BACKGROUND: Many patients are brought to crowded emergency departments (ED) of hospitals every day for evaluation of head injuries, headaches, neurologic deficits etc. CT scan of the head is the most common diagnostic measure used to search for pathologies. In many EDs the initial interpretation of images are performed by emergency physicians (EP). Since most decisions are made based on the initial interpretation of the images by emergency physicians and not the radiologists, it is necessary to assess the accuracy of interpretations made by the former group. OBJECTIVES: The objective of this study was to compare the findings reported in the interpretation of head CTs by emergency physicians and compare to radiologists (the gold standard). MATERIALS AND METHODS: This was a prospective cross sectional study conducted from March to May 2009 in a teaching hospital in Tehran, Iran. All non-contrast head CTs obtained during the study period were copied on DVDs and sent separately to a radiologist, 6 emergency medicine (EM) attending physicians and 14 senior EM residents for interpretation. Clinical information pertaining to each patient was also sent with each CT. The radiologist's interpretation was considered as the gold standard and reference for comparison. Data from EM physicians and residents were compared with the reference as well as with each other and statistical analysis was performed using SPSS 18.5. RESULTS: Out of 544 CT scans, EM physicians had 35 false negatives and 53 false positives compared with radiologist's interpretations (P < 0.0001). EM residents had 74 false negatives and 12 false positives compared with radiologist's interpretations (P < 0.0001). CONCLUSIONS: Both EPs and ER residents either missed or falsely called a significant number of pathologies in their interpretations. The interpretations of EPs and ER residents were more sensitive and more specific, respectively. These findings revealed the need for increased training time in head CT reading for residents and the necessity of attending continuing medical education workshops for emergency physicians. PMID- 24350160 TI - Simultaneous bilateral fracture dislocation of the talus: a case report. AB - INTRODUCTION: Fracture - dislocations of the talus are typically due to high energy injuries. Displaced fracture - dislocations of the talus have poor outcomes in general and complications are common. Although talar fracture is common and comprises the second most common tarsal fracture, bilateral fracture - dislocations of the talus are rare. Not many reports regarding the subject can be found in the literature. CASE PRESENTATION: We report a patient with bilateral fracture - dislocations of the talus treated by open reduction and internal fixation. This patient was a 25 year-old man who sustained bilateral fracture - dislocation of the talus due to a motor vehicle accident. CONCLUSIONS: Bilateral talar fracture - dislocation is rare. The surgical approach discussed together with the pathomechanics of this injury can yield good short term results. PMID- 24350161 TI - Undetected Aorto-RV Fistula With Aortic Valve Injury and Delayed Cardiac Tamponade following a Chest Stab Wound: A Case Report. AB - INTRODUCTION: Although a few patients will survive after penetrating cardiac injuries, some of them may have unnoticeable intracardiac injuries. The combination of aorto-right ventricular fistula with aortic valve injury is rare. CASE PRESENTATION: A 19 year-old man referred with an aorto-right ventricular fistula accompanied with aortic regurgitation and delayed tamponade following a stab in the chest. The patient was scheduled for fistula repair, aortic valve replacement and pericardectomy two months after trauma. CONCLUSIONS: To prevent missing intracardiac injury and also late cardiac injury complications, in all pericordial stab wounds, serial clinical examinations and serial echocardiography should be performed. In addition, cardiac injuries should be repaired during the same hospital stay. PMID- 24350162 TI - Spontaneous radial nerve palsy subsequent to non-traumatic neuroma. AB - INTRODUCTION: Spontaneous radial palsy is a not rare finding in hand clinics. The anatomy of the radial nerve renders it prone to pressure paralysis as often called "Saturday night palsy". This problem is a transient nerve lesion and an acute one but the case presented here is very unusual in that it seems this entity can also occur as an acute on chronic situation with neuroma formation. CASE PRESENTATION: A 61 year-old man presented with the chief complaint of inability to extend the wrist and the fingers of the left hand which began suddenly the night before admission, following a three-week history of pain, numbness and tingling sensation of the affected extremity. He had no history of trauma to the extremity. Electromyography revealed a severe conductive defect of the left radial nerve with significant axonal loss at the upper arm. Surgical exploration identified a neuroma of the radial nerve measuring 1.5 cm in length as the cause of the paralysis. The neuroma was removed and an end-to-end nerve coaption was performed. CONCLUSIONS: Complete recovery of the hand and finger extension was achieved in nine months. PMID- 24350163 TI - Queries regarding local erythropoietin injection in tibiofibular fracture healing. PMID- 24350164 TI - In Reply to: Queries Regarding Local Erythropoietin Injection in Tibiofibular Fracture Healing. PMID- 24350165 TI - Cardiac surgery: a matter of life or death. PMID- 24350166 TI - Review of sport-induced groin injuries. AB - CONTEXT: Groin injuries are among the most common injuries co-existing with sports. The aim of this review was to outline the epidemiology and identify risk factors, as well as examine preventative and interventional measures for reducing the occurrence of this form of injury among athletes. EVIDENCE ACQUISITION: An electronic, systematic search for relevant keywords, either separately or in combination was sought in the academic scientific databases. RESULTS: Groin injuries, acute or chronic, consist of a high percentage of injuries that manifest with pain. Despite the specific tendency for injury among some sports, such injuries make up 2-5% of sport-induced injuries. There are few available reports on lower limb injuries, especially groin injuries, in Iran. Numerous factors predispose to groin injuries. A lengthy list of preventive/ treatment measures, from preliminary to sophisticated, have been proposed. CONCLUSIONS: Although using a programmed strategy designed to decrease the risk of groin injuries by taking a strategic approach to exercise may alleviate complications, in some cases the chronic nature of the injury may threaten the professional life of the athlete. More research is required to plan suitable programs for reducing the risk of this type of injury in athletes. PMID- 24350167 TI - Assessment of genitourinary trauma in southeastern iran. AB - BACKGROUND: To survey genitourinary (GU) organ injury following general trauma, we performed an epidemiologic study of urogenital injuries in trauma patients referred to our hospital (a teaching hospital affiliated with the Zahedan University of Medical Sciences). OBJECTIVES: We aimed to assess the epidemiology of urogenital system injuries in southeastern Iran. PATIENTS AND METHODS: From April 2009 to November 2011, all patients with GU injuries referred to our hospital were studied. The data including age, sex, type of injury, mechanism of trauma, and prognosis of patients was collected and analyzed. RESULTS: From a total of 3450 patients, 66 (1.91%) had injuries of the urogenital system; 49(74.24%) were male and 17(25.75%) female. The patients' mean age was 23 +/- 12 years (range 2 to 75 years). Of these 66 patients, 61 (94.24%) had blunt trauma, and 5 (7.57%) had penetrating trauma. Motor vehicle accidents were the most common cause of trauma (63.63%). The most common injured organs were kidneys in 41 (62.12%) and the bladder in 9 (13.6%); 47 patients (71.21%) had associated intra-abdominal injuries, and 42 (63.63%) had other accompanying injuries; 23(34.84%) patients required surgical intervention. Three patients (4.54%) died due to the severity of injuries (Injury Severity Score > 12). CONCLUSIONS: In our assessment, blunt trauma including road traffic accidents were the main cause of urogenital injuries. Most patients with urogenital trauma had multiple injuries, and required a multidisciplinary approach for management. PMID- 24350168 TI - Fine needle aspiration: an atraumatic method to diagnose head and neck masses. AB - BACKGROUND: Patients presenting with a mass require tissue biopsy for histological diagnosis and treatment. Fine needle aspiration (FNA) is offered as an atraumatic, well tolerated, and inexpensive method for obtaining a biopsy from these lesions. OBJECTIVES: In this study we evaluated the accuracy of FNA as an atraumatic method among patients with nonthyroidal masses for diagnosis of neoplastic masses compared to open surgery. PATIENTS AND METHODS: In a cross sectional study, 65 patients with a head and neck masses (nonthyroidal) referred to us from 2004 to 2009. Those who had both FNA and open biopsy (the gold standard) were assessed for specificity, sensitivity, positive and negative predictive values of FNA in diagnoses. RESULTS: Sixty-five cases with both definite diagnoses of open biopsy and FNA were assessed. The mean (+/- standard deviation) age of patients was 39.96 +/- 19.69 years (range 10 to 82 years). Twenty-five (40.8%) subjects were categorized as malignant neoplasms, 16 (19.4%) as benign neoplasms, and 24 (39.8%) as non-neoplastic lesions. The sensitivity, specificity, positive and also negative predictive values of FNA in the diagnosis of neoplastic masses were 95%, 85%, 92.68%, and 91.66% respectively, and the diagnostic accuracy was 92.3%. CONCLUSIONS: It seems that FNA is a useful atraumatic diagnostic technique with a high diagnostic accuracy which can provide a highly sensitive diagnosis with low false positive diagnoses in patients with nonthyroidal masses. PMID- 24350169 TI - Validation of the Iranian Version of the University of California at Los Angeles Posttraumatic Stress Disorder Index for DSM-IV-R. AB - BACKGROUND: Natural disasters, both expected and unexpected, usually cause widespread injuries and destruction with a large number of survivors, including children. Several studies have shown that children may develop posttraumatic stress disorder after exposure to disasters such as an earthquake. OBJECTIVES: This study aimed to evaluate the screening abilities of the University of California at Los Angeles Posttraumatic Stress Disorder Index for DSM-IV (Revision 1) (UCLA PTSD for DSM-IV) among Iranian school-aged children. PATIENTS AND METHODS: Twenty months after the Qeshm Island 6.1-magnitude earthquake in 2008, we screened 50 students aged between 7 and 12 years for posttraumatic stress disorder using the UCLA PTSD INDEX for DSM-IV. A Structured Clinical Interview for DSM-IV criteria was used as the gold standard. RESULTS: The internal consistency for all the scales was good and Cronbach's coefficient for the overall items was 0.76. The sensitivity of this questionnaire was high (0.96), while its specificity was moderate (0.50). CONCLUSIONS: The study findings showed that the Iranian version of UCLA PTSD Index for DS-MIV-R was appropriate for screening PTSD in children. PMID- 24350170 TI - Amputation: a ten-year survey. AB - BACKGROUND: Limb loss occurs due to different causes and has been increased in many countries. It has without exception, great economic, psychological and social impacts. OBJECTIVES: This study assesses the demographics of amputees in one city of Iran. PATIENTS AND METHODS: This retrospective study was undertaken on all of the amputees between April 2002 and December 2011. Patients' demographics including age, sex, the amputated limb, etiology of limb loss and level of amputation were recorded. RESULTS: We had 216 patients in the study. The average number of amputations was 21.6 per year and varied from 14 to 32. The mean age of amputation was 39.26+/- 12.6 years. Of the patients, 172 were male (79.62%) and 44 female (20.37%); 119 of the amputations (55.09 %) were major and 97 minor (44.9 %). The most common cause of amputation was trauma and the most common was the toe. In trauma patients the mean age was 38.12+/- 10.25 years and 98 (83.7%) were male. CONCLUSIONS: In contrast to similar studies in developed countries, trauma was found to be the major cause of all types of amputations. Results of this study may be used in prevention planning. PMID- 24350171 TI - Knee Flexion Strength Before and After ACL Reconstruction Using Hamstring Tendon Autografts. AB - BACKGROUND: Anterior cruciate ligament (ACL) injury is the most common sports injury in both athletes and nonathletes; it can cause disability if not treated correctly. In cases with minor injuries, conservative treatments suffice. But, in cases with ACL tear, surgery by different methods and autografts are indicated. The most prevalent method for ACL reconstruction is the use of hamstring tendon autograft; this requires tendon removal and results in subsequent weakness in patient's knee flexion strength which can cause dissatisfaction. OBJECTIVES: In this study we evaluate a common procedure used for treating ACL injuries. PATIENTS AND METHODS: This study was performed at a hospital in Tehran on 30 patients with ACL tears. Patients' knee flexion strengths before and 2, 4, 6, and 12 months after reconstruction were measured separately at 20, 45, 90, and 110 knee flexion angles, and their means were analyzed using paired t-test. RESULTS: In this study, knee flexion strength decreased after ACL reconstruction. The greatest decrease in knee flexion strength was observed at 90 and 110 knee flexion angles. CONCLUSIONS: Some previous studies have confirmed reduced knee flexion strength following ACL reconstruction at high knee flexion angles. However, some others have denied it. The present study confirmed the reduction in knee flexion strength one year after ACL reconstruction at 90 and 110 flexion angles (P = 0.000). Furthermore, the need for physiotherapy, as a process for rehabilitating these patients was also confirmed. PMID- 24350172 TI - Comparison of harrington rod and cotrel-dubousset devices in surgical correction of adolescent idiopathic scoliosis. AB - BACKGROUND: Since the time of Paul Harrington numerous implants have been introduced for correction of scoliosis, but none are ideal. Newer devices are very expensive, and in our country some patients cannot afford them. OBJECTIVES: The aim of this study was to compare the results of the Harrington rod (HR) device and the newer Cotrel-Dubousset (CD) device in treatment of adolescent idiopathic scoliosis (AIS). MATERIALS AND METHODS: A retrospective review assessed patients with AIS admitted for spinal curve correction treated with HR (n = 120) and CD devices (n = 138) between October 1988 to April 2001 at the Shafa Yahyaeian Hospital, Tehran, Iran. We extracted information from the patient's file and radiographs before, after and two years post-operation. RESULTS: The mean age of patients was 16.7 +/- 2.5 years. There was no statistically significant difference between the two groups regarding gender, age, curve before surgery, and percentage of flexibility. The mean curvature was 70 +/- 20.7 in the HR and 64.81 +/- 19.4 in the CD group before surgery (P = 0.09); and the mean curvature was 40 +/- 16.3 and 26.58 +/- 15.37 in HR and CD groups respectively after surgery (P = 0.156). The mean curvature was 47.2 +/- 15.9 in HR and 31.2 +/- 15.4 in CD groups at two years follow-up (P = 0.156). CONCLUSIONS: Results of many studies have shown no significant impairment in long term quality of life and function in patients treated with Harrington rods. According to previously performed studies and the current study, surgical correction with Harrington rods seem to be comparable with the newer more expensive CD device. Although there is no doubt that the preference is to use newer devices in view of some disadvantages of HR, but this does not preclude using it for patients that cannot afford the newer devices. PMID- 24350173 TI - Cholestasis in a three year-old child following abdominal blunt trauma: a case report. AB - INTRODUCTION: Extra-hepatic bile duct injuries in children following blunt abdominal trauma are rare; early diagnosis and treatment are imperative for a good outcome. The purpose of this report is to describe the management of problems encountered in children with bile duct injuries following blunt abdominal trauma. CASE PRESENTATION: A three year-old girl presented with obstructive jaundice and vomiting following blunt abdominal trauma one month prior to referral. The child was sitting in her father's lap when the accident occurred. She was then examined by an emergency physician to assess the cause of vomiting. An abdominal ultrasonography was performed and revealed dilatation of the common bile duct. CONCLUSIONS: To the best of our knowledge, this is the first report of bile duct injury following blunt trauma and its emergency management. PMID- 24350174 TI - Hypokalemia-induced abnormal movements: case report. AB - INTRODUCTION: A sudden loss of consciousness followed by abnormal movements can be ictal or syncopal in origin. Transient response by the brain to sudden decrease of blood flow may cause sudden loss of consciousness followed by abnormal movements that mimic seizure. Dysrhythmia is one of the important and critical reasons of such events that should be differentiated from seizure. CASE PRESENTATION: In this case report we describe a 55 year-old woman admitted to our emergency department first with the impression of seizure. Eventually, it was realized that she had suffered from brain hypo-perfusion secondary to hypokalemia induced arrhythmia. Her arrhythmia was managed by unsynchronized biphasic shock in acute phase and also potassium replacement. She was then admitted to the CCU (Coronary Care Unit) where she received further care for medical management and drug dose adjustment and was discharged 4 days later. CONCLUSIONS: Syncope from arrhythmia most commonly results from ventricular tachycardia, which accounts for 11% of all cases of syncope. Torsades de point is a unique type of ventricular tachycardia, characterized by QRS complexes of changing amplitude proceeded by prolonged QT intervals and almost often followed by loss of consciousness and also seizure like movements. Prolonged QT interval which is an important provocative factor for torsades de point commonly results from interactions between drug therapy, myocardial ischemia, and electrolyte disturbances such as hypokalemia or hypomagnesaemia. Changes in the extracellular potassium level have predominant and profound influences on the function of the cardiovascular system that may provoke fatal demonstrations such as QT prolongation, ventricular arrhythmia and even cardiac arrest. Electrolyte assessment is particularly important in certain patient populations, such as the elderly in whom a variety of pathological states or conditions like dehydration or renal failure are more common. Early identification and correction of these disturbances are necessary to control either seizures or seizure-like movements and prevent permanent brain damage, as anticonvulsants alone are generally ineffective. PMID- 24350175 TI - Child health and human development over the lifespan. PMID- 24350176 TI - Alcohol-related content of animated cartoons: a historical perspective. AB - This study, based on a stratified (by decade of production) random sample of 1,221 animated cartoons and 4,201 characters appearing in those cartoons, seeks to determine the prevalence of alcohol-related content; how, if at all, the prevalence changed between 1930 and 1996 (the years spanned by this research); and the types of messages that animated cartoons convey about beverage alcohol and drinking in terms of the characteristics that are associated with alcohol use, the contexts in which alcohol is used in cartoons, and the reasons why cartoon characters purportedly consume alcohol. Approximately 1 cartoon in 11 was found to contain alcohol-related content, indicating that the average child or adolescent viewer is exposed to approximately 24 alcohol-related messages each week just from the cartoons that he/she watches. Data indicated that the prevalence of alcohol-related content declined significantly over the years. Quite often, alcohol consumption was shown to result in no effects whatsoever for the drinker, and alcohol use often occurred when characters were alone. Overall, mixed, ambivalent messages were provided about drinking and the types of characters that did/not consume alcoholic beverages. PMID- 24350177 TI - Grand challenge: understanding survival paradoxes in epidemiology. PMID- 24350178 TI - Trends in neuropediatric physical therapy. PMID- 24350179 TI - The infectious disease challenges of our time. PMID- 24350180 TI - Public health in a global context. PMID- 24350181 TI - Daily walking and life expectancy of elderly people in the iowa 65+ rural health study. AB - The purpose of this paper is to investigate the hypothesis that outdoor daily walking, as an exercise, has an effect on the rate of mortality among those elderly people in the Iowa 65+ Rural Health Study (RHS). RHS is a prospective longitudinal cohort study of 8 years follow-up from 1981 to 1989. It consists of a random sample of 3,673 individuals (1,420 men and 2,253 women) aged 65 or older living in Washington and Iowa counties of the State of Iowa. Our analysis was conducted only on those non-institutional individuals who could without any help walk across a small room; this reduced the total number of individuals in the study to 2,717. Moreover, a total of 923 individuals died during the period of the study. The life histories of those individuals were obtained and divided into two cohorts; one containing 1,134 who exercise daily by walking and the other containing 1,583 who do not exercise daily by walking. The interviewers asked participants about 17 medical conditions, from which 13 are included in our study. We found that daily walking exercise is related inversely to total mortality before and after adjusting for the other factors in particular for age group and health conditions. We observed that hazard ratio (HR) of death was the highest among those individuals having a history of cancer (HR = 2.971) and history of stroke (HR = 2.127). However, individuals with a history of stroke in the "daily walking group" have HR = 0.856 and their risk of death were reduced by 81% compared to those in no "daily walking group." PMID- 24350182 TI - Challenging behavior and related factors in people with intellectual disability living in residential care centers in Israel. AB - INTRODUCTION: Adults with intellectual disabilities have higher rates of mental ill-health and problem behaviors than the general population. METHOD: In this study, we present data on trends in challenging behavior in residential care centers in Israel from 1998 to 2008 and further data on trends in employment of psychiatrists from 1998 to 2009 and psychotropic medication use from 1998 to 2008. Data was collected from annual questionnaires sent out to all residential care centers in Israel, from the Office of the Medical Director, Division for Intellectual and Developmental Disabilities, Ministry of Social Affairs and Social Services. RESULTS: Rates of challenging behaviors in people with intellectual disabilities living in residential care centers in Israel continues to rise. Alongside this, trends in regular psychotropic medication use also continues to increase. CONCLUSION: Consideration of biological, psychological, social, and environmental factors in the assessment and management of people with intellectual disabilities and challenging behaviors is important. This is best conducted using a multidisciplinary approach, which may include psychiatric assessment. Non-pharmacological interventions should always be considered either alongside, or instead of medication. PMID- 24350183 TI - Randomized controlled trial designs for operations research in low-income countries: reality or delusion? PMID- 24350184 TI - Self-rated health and public health: a critical perspective. PMID- 24350185 TI - Associations of adiponectin and leptin with incident coronary heart disease and ischemic stroke in african americans: the jackson heart study. AB - BACKGROUND: Because the predictive significance of previously reported racial differences in leptin and adiponectin levels remains unclear, we assessed the prospective association of these adipokines with the risk of cardiovascular disease (CVD) events in African Americans, a population with a high prevalence of cardiometabolic risk factors. METHODS: Serum specimens from 4,571 Jackson Heart Study participants without prevalent CVD at baseline examination (2000-2004) were analyzed for adiponectin and leptin levels. Cox proportional hazard regression models were used to estimate the associations of the two adipokines with incident coronary heart disease (CHD) and incident ischemic stroke. RESULTS: During 6.2 years average of follow-up, 98 incident CHD and 87 incident ischemic stroke events were documented. Among study participants (64% women; mean age 54 +/- 13 years), the mean (standard deviation, SD) was 6.04 (4.32) MUg/mL in women and 4.03 (3.14) MUg/mL in men for adiponectin and 37.35 (23.90) ng/mL in women and 11.03 (10.05) ng/mL in men for leptin. After multivariable adjustment that included age, body mass index, high-density lipoprotein cholesterol, triglycerides, C-reactive protein, insulin resistance by homeostasis model assessment for insulin resistance, systolic blood pressure, hypertension medication, smoking, and physical activity, adiponectin was directly associated in women with incident stroke, HR = 1.41 (1.04-1.91) per one SD increase (p = 0.03), but not in men (p = 0.42). It was not associated with incident CHD in women or men. Leptin was not associated with incident CHD or incident stroke. CONCLUSION: In the largest community-based African American cohort, adiponectin was associated among women with a higher risk of incident stroke. Whether adiponectin harbors harmful properties, or it is produced in response to vascular inflammation to counter the atherosclerotic process, or the putative "adiponectin resistance" phenomenon acts, should be further assessed. PMID- 24350186 TI - Early life factors and risk of childhood rhabdomyosarcoma. AB - Although little is known about etiology of childhood rhabdomyosarcoma (RMS), early life factors are suspected in the etiology. We explored this hypothesis using linked data from the California Cancer Registry and the California birth rolls. Incident cases were 359 children <6-year-old (218 embryonal, 81 alveolar, 60 others) diagnosed in 1988-2008. Controls (205, 173), frequency matched on birth year (1986-2007), were randomly selected from the birth rolls. We examined association of birth characteristics such as birth weight, size for gestational age, and timing of prenatal care with all-type RMS, embryonal, and alveolar subtypes. Crude and adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression. In contrast to a previous study, we observed statistically non-significant association for embryonal subtype among high birth weight (4000-5250 g) children for term births [OR (95% CI): 1.28 (0.85, 1.92)] and all births adjusted for gestational age [OR (95% CI): 1.21 (0.81, 1.81)]. On the other hand, statistically significant 1.7-fold increased risk of alveolar subtype (95% CI: 1.02, 2.87) was observed among children with late or no prenatal care and a 1.3-fold increased risk of all RMS subtypes among children of fathers >=35 years old at child birth (95% CI: 1.00, 1.75), independent of all covariates. Our finding of positive association on male sex for all RMS types is consistent with previous studies. While we did not find a convincingly positive association between high birth weight and RMS, our findings on prenatal care supports the hypothesis that prenatal environment modifies risk for childhood RMS. PMID- 24350187 TI - Epidemiology and economic impact of celiac disease in the South vesuvian area of naples: a survey. PMID- 24350189 TI - Educating the public health workforce. PMID- 24350188 TI - Alpha-1 antitrypsin reduces severity of pseudomonas pneumonia in mice and inhibits epithelial barrier disruption and pseudomonas invasion of respiratory epithelial cells. AB - Nosocomial pneumonia (NP) is the third most common hospital-acquired infection and the leading cause of death due to hospital-acquired infection in the US. During pneumonia and non-pneumonia severe illness, respiratory tract secretions become enriched with the serine protease neutrophil elastase (NE). Several NE activities promote onset and severity of NP. NE in the airways causes proteolytic tissue damage, augments inflammation, may promote invasion of respiratory epithelium by bacteria, and disrupts respiratory epithelial barrier function. These NE activities culminate in enhanced bacterial replication, impaired gas exchange, fluid intrusion into the airways, and loss of bacterial containment that can result in bacteremia. Therefore, neutralizing NE activity may reduce the frequency and severity of NP. We evaluated human alpha-1 antitrypsin (AAT), the prototype endogenous NE inhibitor, as a suppressor of bacterial pneumonia and pneumonia-related pathogenesis. In AAT(+/+) transgenic mice that express human AAT in lungs, mortality due to Pseudomonas aeruginosa (P.aer) pneumonia was reduced 90% compared to non-transgenic control animals. Exogenous human AAT given to non-transgenic mice also significantly reduced P.aer pneumonia mortality. P.aer-infected AAT(+/+) mice demonstrated reduced lung tissue damage, decreased bacterial concentrations in lungs and blood, and diminished circulating cytokine concentrations compared to infected non-transgenic mice. In vitro, AAT suppressed P.aer internalization into respiratory epithelial cells and inhibited NE or P.aer induced disruption of epithelial cell barrier function. The beneficial effects of human AAT in murine P.aer pneumonia raise the possibility of AAT use as a prophylactic treatment for NP in humans, and suggest a role for AAT as an innate immune mediator. PMID- 24350190 TI - Development and Assessment of Traditional and Innovative Media to Reduce Individual HIV/AIDS-Related Stigma Attitudes and Beliefs in India. AB - Although stigma is considered a major barrier to effective response to the HIV/AIDS epidemic, there is a lack of evidence on effective interventions. This media intervention took place among key HIV-vulnerable communities in Southern India. Two HIV stigma videos were created using techniques from traditional film production and new media digital storytelling. A series of 16 focus group discussions were held in 4 rural and 4 urban sites in South India, with specific groups for sex workers, men who have sex with men, young married women, and others. Focus groups with viewers of the traditional film (8 focus groups, 80 participants) and viewers of the new media production (8 focus groups, 69 participants) revealed the mechanisms through which storyline, characters, and esthetics influence viewers' attitudes and beliefs about stigma. A comparative pre-/post-survey showed that audiences of both videos significantly improved their stigma scores. We found that a simple illustrated video, produced on a limited budget by amateurs, and a feature film, produced with an ample budget by professionals, elicited similar responses from audiences and similar positive short-term outcomes on stigma. PMID- 24350191 TI - The Integration of the Neurosciences, Child Public Health, and Education Practice: Hemisphere-Specific Remediation Strategies as a Discipline Partnered Rehabilitation Tool in ADD/ADHD. AB - ADD/ADHD is the most common and most studied neurodevelopmental problem. Recent statistics from the U.S. Center for Disease Control state that 11% or approximately one out of every nine children in the US and one in five high school boys are diagnosed with ADD/ADHD. This number is thought to be increasing at around 15-20% per year. The US National Institute of Mental Health's Multi modal Treatment Study has shown that medication has no long-term benefit for those with ADHD. To effectively address ADD/ADHD from within the framework of child public health, an interdisciplinary strategy is necessary that is based on a neuroeducational model that can be readily implemented on a large-scale within the educational system. This study is based on previous findings that ADD/ADHD children possess underactivity between sub-cortical and cortical regions. An imbalance of activity or arousal in one area can result in functional disconnections similar to that seen in split-brain patients. Since ADD/ADHD children exhibit deficient performance on tests developed to measure perceptual laterality, evidence of weak laterality or failure to develop laterality has been found across various modalities (auditory, visual, tactile). This has reportedly resulted in abnormal cerebral organization and ineffective cortical specialization necessary for the development of language and non-language function. This pilot study examines groups of ADD/ADHD and control elementary school children all of whom were administered all of the subtests of the Wechsler Individual Achievement Tests, the Brown Parent Questionnaire, and given objective performance measures on tests of motor and sensory coordinative abilities. Results measured after a 12-week remediation program aimed at increasing the activity of the hypothesized underactive right hemisphere function, yielded significant improvement of greater than 2 years in grade level in all domains except in mathematical reasoning. The treated group also displayed a significant improvement in behavior with a reduction in Brown scale behavioral scores. Non treated control participants did not exhibit significant differences during the same 12 week period in academic measurements. Controls were significantly different from treatment participants in all domains after a 12-week period. The non-treatment group also demonstrated an increase in behavioral scores and increased symptoms of ADD/ADHD over the same time period when compared to the treated group. Results are discussed in the context of the concept of functional disconnectivity in ADD/ADHD children. PMID- 24350192 TI - Beyond misconceptions: assessing pain in children with mild to moderate intellectual disability. AB - To assess and manage pain in children and adolescents with mild to moderate intellectual disability, healthcare providers need access to updated tools and current knowledge. Recent studies show that these children can verbally express pain and use self-assessment tools accurately. Moreover, they know pain coping strategies. Finally, they show mental imaging skills and are able to recall autobiographical memories. These new data suggest that such children and adolescents could be candidates to for hypno-analgesia protocols and behavioral relaxation. PMID- 24350193 TI - Geriatric workforce capacity: a pending crisis for nursing home residents. AB - INTRODUCTION: The nursing home (NH) population in the US has grown to 1.6 million people and is expected to double by 2030. While 88.3% of NH residents are over 65, the elders aged 85 and more have become the principal group. This demographic change has increased the already high rates of chronic diseases and functional disabilities in NH residents. METHODS: This study reviewed the supply of geriatricians in addressing the growing healthcare needs of NH residents. RESULTS: English-written articles between 1989 and 2012 were reviewed. Trend data demonstrate that the geriatrician workforce has decreased from 10,270 in 2000 to 8,502 in 2010. Further, the pipeline analysis of physicians projected to receive board certification in geriatrics (and maintain this certification) indicates a worsening of the already insufficient supply of geriatricians for this vulnerable population. CONCLUSION: Strategies to attract and maintain a geriatrician workforce are imperative to avert a mounting crisis in the geriatric care in NH and, by extension, other living settings. PMID- 24350194 TI - The utility of intravenous acetaminophen in the perioperative period. AB - Intravenous acetaminophen (IVA) has rapid and effective analgesic properties. Recent studies have shown several benefits of using IVA perioperatively. However, due to its relatively high cost and limited clinical data concerning its efficacy compared with other agents, physicians are hesitant to use IVA in the perioperative period. This brief review examines the utility of this medication in the perioperative period and highlights future areas of clinical and epidemiological research regarding its use. PMID- 24350195 TI - Application of situational leadership to the national voluntary public health accreditation process. AB - Successful navigation through the accreditation process developed by the Public Health Accreditation Board (PHAB) requires strong and effective leadership. Situational leadership, a contingency theory of leadership, frequently taught in the public health classroom, has utility for leading a public health agency through this process. As a public health agency pursues accreditation, staff members progress from being uncertain and unfamiliar with the process to being knowledgeable and confident in their ability to fulfill the accreditation requirements. Situational leadership provides a framework that allows leaders to match their leadership styles to the needs of agency personnel. In this paper, the application of situational leadership to accreditation is demonstrated by tracking the process at a progressive Kentucky county public health agency that served as a PHAB beta test site. PMID- 24350196 TI - Promoting health equity: a new challenge for frontiers in public health. PMID- 24350197 TI - Mapping avian influenza transmission risk at the interface of domestic poultry and wild birds. AB - Emergence of avian influenza viruses with high lethality to humans, such as the currently circulating highly pathogenic A(H5N1) (emerged in 1996) and A(H7N9) cause serious concern for the global economic and public health sectors. Understanding the spatial and temporal interface between wild and domestic populations, from which these viruses emerge, is fundamental to taking action. This information, however, is rarely considered in influenza risk models, partly due to a lack of data. We aim to identify areas of high transmission risk between domestic poultry and wild waterfowl in China, the epicenter of both viruses. Two levels of models were developed: one that predicts hotspots of novel virus emergence between domestic and wild birds, and one that incorporates H5N1 risk factors, for which input data exists. Models were produced at 1 and 30 km spatial resolution, and two temporal seasons. Patterns of risk varied between seasons with higher risk in the northeast, central-east, and western regions of China during spring and summer, and in the central and southeastern regions during winter. Monte-Carlo uncertainty analyses indicated varying levels of model confidence, with lowest errors in the densely populated regions of eastern and southern China. Applications and limitations of the models are discussed within. PMID- 24350198 TI - Assessing the Relationship between the Baseline Value of a Continuous Variable and Subsequent Change Over Time. AB - Analyzing the relationship between the baseline value and subsequent change of a continuous variable is a frequent matter of inquiry in cohort studies. These analyses are surprisingly complex, particularly if only two waves of data are available. It is unclear for non-biostatisticians where the complexity of this analysis lies and which statistical method is adequate. With the help of simulated longitudinal data of body mass index in children, we review statistical methods for the analysis of the association between the baseline value and subsequent change, assuming linear growth with time. Key issues in such analyses are mathematical coupling, measurement error, variability of change between individuals, and regression to the mean. Ideally, it is better to rely on multiple repeated measurements at different times and a linear random effects model is a standard approach if more than two waves of data are available. If only two waves of data are available, our simulations show that Blomqvist's method - which consists in adjusting for measurement error variance the estimated regression coefficient of observed change on baseline value - provides accurate estimates. The adequacy of the methods to assess the relationship between the baseline value and subsequent change depends on the number of data waves, the availability of information on measurement error, and the variability of change between individuals. PMID- 24350199 TI - Depression and antidepressants: a nordic perspective. PMID- 24350201 TI - Adolescence, violence, and public health. PMID- 24350203 TI - Unprotected anal Intercourse among Iranian Intra-Venous Drug Users. AB - PURPOSE: To assess the prevalence and associated factors of unprotected anal intercourse among Iranian male heterosexual Intra-Venous Drug Users (IDUs). METHODS: In a cross-sectional study 360 male heterosexual IDUs were sampled from streets of eight different geographical parts of Iran. Variables such as socio demographics, HIV knowledge (10 items), and HIV attitude (16 items) were entered to a logistic regression to determine the predictors of unprotected anal intercourse during the past month. RESULTS: From all, 20.8% reported unprotected anal intercourse during the past month. HIV knowledge was not significantly different among IDUs with and without unprotected anal intercourse. High age [odds ratio (OR) = 0.954, 95% confidence intervals (CI) = 0.916-0.992] was associated with a lower likelihood of unprotected anal intercourse, while being not married (OR = 2.301, 95% CI = 1.151-4.601), and high perceived HIV risk (OR = 1.776, 95% CI = 1.376-2.290) were associated with a higher likelihood of unprotected anal intercourse. CONCLUSION: Although the results might not be generalizable to all Iranian IDUs, this study findings may still be helpful for design and implementation of public health programs in Iran to prevent sexual transmission of HIV through IDUs. PMID- 24350204 TI - Exploring Perception of Indians about Plain Packaging of Tobacco Products: A Mixed Method Research. AB - This study assessed perceptions and support among the Indian populace about plain packaging for all tobacco products. Twelve focus group discussions (n = 124), stakeholder analysis with 24 officials and an opinion poll with 346 participants were conducted between December 2011 and May 2012, Delhi. Plain packages for tobacco products were favored by majority of participants (69%) and key stakeholders (92%). The majority of participants perceived that plain packaging would reduce the appeal and promotional value of the tobacco pack (>80%), prevent initiation of tobacco use among children and youth (>60%), motivate tobacco users to quit (>80%), increase notice ability, and effectiveness of pictorial health warnings on tobacco packs (>90%), reduce tobacco usage (75% of key stakeholders). Majority of participants favored light gray color for plain packaging. This study provides key evidence to advocate with Indian Government and other countries in South Asia region to introduce plain packaging legislation for all tobacco products. PMID- 24350202 TI - Perceived Risk Modifies the Effect of HIV Knowledge on Sexual Risk Behaviors. AB - BACKGROUND: There is a large controversy in the literature about the inter relations between perceived risk, knowledge, and risk behavior in different settings, and people at HIV risk are not an exception. AIM: To assess additive and multiplicative effect of perceived HIV risk and HIV knowledge on sexual risk behavior of Injecting Drug Users (IDUs). METHOD: We enrolled 162 street based IDUs to this analysis. Data came from a national survey of IDUs in Iran, with a cross sectional design. Socio-demographics (employment, education, marital status), HIV knowledge, perceived HIV risk, and four different sexual risk behavior were registered. In the first step, using spearman test, the association of HIV knowledge and risk behavior were tested, then possible moderating effect of perceived HIV risk on this association was determined. RESULTS: Although among IDUs with low perceived HIV risk, HIV knowledge was negatively associated with sexual risk behavior (P < 0.05 for all), this association was not significant among IDUs with high perceived HIV risk (P > 0.05 for all). Thus perceived HIV risk moderated the association between HIV knowledge and sexual risk behavior. CONCLUSION: Perceived risk should be taken into consideration when studying the effect of HIV knowledge on sexual risk behavior of IDUs. Findings may help us better understand negative effects of fear arousing interventions as a part of HIV prevention media campaigns. PMID- 24350205 TI - Telephone Surveys Underestimate Cigarette Smoking among African-Americans. AB - BACKGROUND: This study tested the hypothesis that data from random digit-dial telephone surveys underestimate the prevalence of cigarette smoking among African American adults. METHOD: A novel, community-sampling method was used to obtain a statewide, random sample of N = 2118 California (CA) African-American/Black adults, surveyed door-to-door. This Black community sample was compared to the Blacks in the CA Health Interview Survey (N = 2315), a statewide, random digit dial telephone survey conducted simultaneously. RESULTS: Smoking prevalence was significantly higher among community (33%) than among telephone survey (19%) Blacks, even after controlling for sample differences in demographics. CONCLUSION: Telephone surveys underestimate smoking among African-Americans and probably underestimate other health risk behaviors as well. Alternative methods are needed to obtain accurate data on African-American health behaviors and on the magnitude of racial disparities in them. PMID- 24350200 TI - A review of traditional and novel treatments for seizures in autism spectrum disorder: findings from a systematic review and expert panel. AB - Despite the fact that seizures are commonly associated with autism spectrum disorder (ASD), the effectiveness of treatments for seizures has not been well studied in individuals with ASD. This manuscript reviews both traditional and novel treatments for seizures associated with ASD. Studies were selected by systematically searching major electronic databases and by a panel of experts that treat ASD individuals. Only a few anti-epileptic drugs (AEDs) have undergone carefully controlled trials in ASD, but these trials examined outcomes other than seizures. Several lines of evidence point to valproate, lamotrigine, and levetiracetam as the most effective and tolerable AEDs for individuals with ASD. Limited evidence supports the use of traditional non-AED treatments, such as the ketogenic and modified Atkins diet, multiple subpial transections, immunomodulation, and neurofeedback treatments. Although specific treatments may be more appropriate for specific genetic and metabolic syndromes associated with ASD and seizures, there are few studies which have documented the effectiveness of treatments for seizures for specific syndromes. Limited evidence supports l carnitine, multivitamins, and N-acetyl-l-cysteine in mitochondrial disease and dysfunction, folinic acid in cerebral folate abnormalities and early treatment with vigabatrin in tuberous sclerosis complex. Finally, there is limited evidence for a number of novel treatments, particularly magnesium with pyridoxine, omega-3 fatty acids, the gluten-free casein-free diet, and low-frequency repetitive transcranial magnetic simulation. Zinc and l-carnosine are potential novel treatments supported by basic research but not clinical studies. This review demonstrates the wide variety of treatments used to treat seizures in individuals with ASD as well as the striking lack of clinical trials performed to support the use of these treatments. Additional studies concerning these treatments for controlling seizures in individuals with ASD are warranted. PMID- 24350206 TI - Nutrition training improves health workers' nutrition knowledge and competence to manage child undernutrition: a systematic review. AB - BACKGROUND: Medical and nursing education lack adequate practical nutrition training to fit the clinical reality that health workers face in their practices. Such a deficit creates health workers with poor nutrition knowledge and child undernutrition management practices. In-service nutrition training can help to fill this gap. However, no systematic review has examined its collective effectiveness. We thus conducted this study to examine the effectiveness of in service nutrition training on health workers' nutrition knowledge, counseling skills, and child undernutrition management practices. METHODS: We conducted a literature search on nutrition interventions from PubMed/MEDLINE, CINAHL, EMBASE, ISI Web of Knowledge, and World Health Organization regional databases. The outcome variables were nutrition knowledge, nutrition-counseling skills, and undernutrition management practices of health workers. Due to heterogeneity, we conducted only descriptive analyses. RESULTS: Out of 3910 retrieved articles, 25 were selected as eligible for the final analysis. A total of 18 studies evaluated health workers' nutrition knowledge and showed improvement after training. A total of 12 studies with nutrition counseling as the outcome variable also showed improvement among the trained health workers. Sixteen studies evaluated health workers' child undernutrition management practices. In all such studies, child undernutrition management practices and competence of health workers improved after the nutrition training intervention. CONCLUSION: In-service nutrition training improves quality of health workers by rendering them more knowledge and competence to manage nutrition-related conditions, especially child undernutrition. In-service nutrition training interventions can help to fill the gap created by the lack of adequate nutrition training in the existing medical and nursing education system. In this way, steps can be taken toward improving the overall nutritional status of the child population. PMID- 24350207 TI - Families Enriched for Exceptional Longevity also have Increased Health-Span: Findings from the Long Life Family Study. AB - Hypothesizing that members of families enriched for longevity delay morbidity compared to population controls and approximate the health-span of centenarians, we compared the health-spans of older generation subjects of the Long Life Family Study (LLFS) to controls without family history of longevity and to centenarians of the New England Centenarian Study (NECS) using Bayesian parametric survival analysis. We estimated hazard ratios, the ages at which specific percentiles of subjects had onsets of diseases, and the gain of years of disease-free survival in the different cohorts compared to referent controls. Compared to controls, LLFS subjects had lower hazards for cancer, cardiovascular disease, severe dementia, diabetes, hypertension, osteoporosis, and stroke. The age at which 20% of the LLFS siblings and probands had one or more age-related diseases was approximately 10 years later than NECS controls. While female NECS controls generally delayed the onset of age-related diseases compared with males controls, these gender differences became much less in the older generation of the LLFS and disappeared amongst the centenarians of the NECS. The analyses demonstrate extended health-span in the older subjects of the LLFS and suggest that this aging cohort provides an important resource to discover genetic and environmental factors that promote prolonged health-span in addition to longer life-span. PMID- 24350208 TI - Improved confidence intervals of a small probability from pooled testing with misclassification. AB - This article concerns construction of confidence intervals for the prevalence of a rare disease using Dorfman's pooled testing procedure when the disease status is classified with an imperfect biomarker. Such an interval can be derived by converting a confidence interval for the probability that a group is tested positive. Wald confidence intervals based on a normal approximation are shown to be inefficient in terms of coverage probability, even for relatively large number of pools. A few alternatives are proposed and their performance is investigated in terms of coverage probability and length of intervals. PMID- 24350209 TI - Firesetting in childhood and adolescence. PMID- 24350210 TI - Human sexuality and adolescence. PMID- 24350213 TI - Disaster and emergency medicine - a conceptual introduction. PMID- 24350212 TI - The effects of a pilot intervention for community-dwelling adults with rheumatoid arthritis in wuhan, china. AB - This study examined the effects of a pilot educational intervention program on knowledge, perceived self-efficacy, and health-related quality of life (HRQoL) of community-dwelling adults with rheumatoid arthritis (RA). A convenience sample of 16 participants with RA completed the program in Wuhan, China. Data were collected in face-to-face interviews using questionnaires at baseline, post-test, and 1 month follow-up. Knowledge scores were significantly increased over time. Significant differences were found in pain self-efficacy, symptoms self-efficacy, bodily pain, social functioning, and role emotional functions. Community health providers should provide educational programs to improve HRQoL for adults with RA. PMID- 24350214 TI - A hybrid online intervention for reducing sedentary behavior in obese women. AB - Sedentary behavior (SB) has emerged as an independent risk factor for cardiovascular disease and type 2 diabetes. While exercise is known to reduce these risks, reducing SB through increases in non-structured PA and breaks from sitting may appeal to obese women who have lower self-efficacy for PA. This study examined effects of a combined face-to-face and online intervention to reduce SB in overweight and obese women. A two-group quasi-experimental study was used with measures taken pre and post. Female volunteers (M age = 58.5, SD = 12.5 years) were enrolled in the intervention (n = 40) or waitlisted (n = 24). The intervention, based on the Social Cognitive Theory, combined group sessions with email messages over 6 weeks. Individualized feedback to support mastery and peer models of active behaviors were included in the emails. Participants self monitored PA with a pedometer. Baseline and post measures of PA and SB were assessed by accelerometer and self-report. Standard measures of height, weight, and waist circumference were conducted. Repeated measures ANOVA was used for analyses. Self-reported SB and light PA in the intervention group (I) changed significantly over time [SB, F(1, 2) = 3.81, p = 0.03, light PA, F(1, 2) = 3.39, p = 0.04]. Significant Group * Time interactions were found for light PA, F(1, 63) = 5.22, p = 0.03, moderate PA, F(1, 63) = 3.90, p = 0.05, and for waist circumference, F(1, 63) = 16.0, p = 0.001. The intervention group decreased significantly while the comparison group was unchanged. Hybrid computer interventions to reduce SB may provide a non-exercise alternative for increasing daily PA and potentially reduce waist circumference, a risk factor for type 2 diabetes. Consumer-grade accelerometers may aide improvements to PA and SB and should be tested as part of future interventions. PMID- 24350211 TI - Marijuana: current concepts(?). AB - Marijuana (cannabis) remains a controversial drug in the twenty-first century. This paper considers current research on use of Cannabis sativa and its constituents such as the cannabinoids. Topics reviewed include prevalence of cannabis (pot) use, other drugs consumed with pot, the endocannabinoid system, use of medicinal marijuana, medical adverse effects of cannabis, and psychiatric adverse effects of cannabis use. Treatment of cannabis withdrawal and dependence is difficult and remains mainly based on psychological therapy; current research on pharmacologic management of problems related to cannabis consumption is also considered. The potential role of specific cannabinoids for medical benefit will be revealed as the twenty-first century matures. However, potential dangerous adverse effects from smoking marijuana are well known and should be clearly taught to a public that is often confused by a media-driven, though false message and promise of benign pot consumption. PMID- 24350215 TI - "I am very, very proud of myself": improving youth activity levels using self determination theory in program development. AB - Many adolescents are not meeting recommended levels for physical activity. Increasing physical activity among urban African American youth is both a challenge and a public health priority. Most research in community-based interventions has taken a didactic approach, focusing on skill and knowledge development alone, with inconclusive results. This 10-week progressive activity intervention with adolescents in an urban faith community introduced a self determination theory (SDT) approach with the aim of promoting the adoption of self-management skills necessary for sustaining activity. Components of SDT included relatedness, competence, and autonomy. Together with didactics, aligning activities with participant interests, and using existing social structures for health message delivery, the approach led to high satisfaction ratings for the three components of SDT along with improved skills, knowledge, and outcomes in cardiovascular fitness. Understanding and utilizing approaches that enhance enjoyment, personal choice, confidence, and social affiliation may lead to more lasting healthy activity behaviors and attitudes than didactic approaches alone in this and other adolescent populations. The SDT is reviewed in the context of this youth intervention. PMID- 24350216 TI - Analysis of the literature pertaining to the education of public health professionals. AB - A well-educated workforce is essential to the infrastructure of a public health system (1). At a time when global focus on public health is increasing, a severe shortage of public health professionals is projected (2). A strong educational framework is thus imperative to ensure the capacity and capability of the worldwide public health workforce for the future. The education of those who work in public health is spread across disciplines, subject-specific training programs and types of academic institutions. In the 2011 report on the Health Professionals for a New Century, Frenk and Chen comment that, compared to medicine and nursing, public health has done the least to examine what and how it teaches (3). This does not bode well for meeting the demands of the public health workforce for the future. The purpose of the study reported here is to analyze the state of pedagogy pertaining to the education of the public health workforce as evidenced by published literature. The focus is on "professionals," defined as those who have formal education, are self-governing, and can work independently. PMID- 24350218 TI - Sequential Metastatic Breast Cancer Chemotherapy: Should the Median be the Message? AB - BACKGROUND: Counseling and anticipatory guidance of the expected course of treatment for women newly diagnosed with metastatic breast cancer (MBC) are difficult due to multiple factors influencing survival following MBC therapy. In order to better tailor counseling at the onset and through the duration of MBC we used non-clinical trial data to better characterize real life experience of sequential MBC treatment. We examined the following aims: (1) What demographic and tumor characteristics are predictive of survival in MBC? (2) What is the median duration of each sequential chemotherapy regimen and subsequent survival of women following each sequence of chemotherapy regimen in MBC? METHODS: Retrospective study included 792 women diagnosed from January 1999 through December 2009 at the University of Pittsburgh Cancer Institute Breast Cancer Program. RESULTS: Median duration of sequential chemotherapy regimen and median survival from completion of sequence of chemotherapy regimens were relatively short with a wide range of treatment duration and survival. Characteristics for poor survival included hormone status, human epidermal growth factor receptor-2 (HER 2/neu) status, and increased number and type of metastatic sites. Women who took more than the second sequential chemotherapy regimens had no more than median 3 months of treatment duration and 6 months survival from treatment termination. DISCUSSION: Median clinical response and survival shorten with sequential chemotherapy regimen but with wide ranges. The rare clinical response of the minority should not set the standard for treatment expectations. All cancer clinicians, including oncology nurses, must ensure that patients are receiving tailored counseling regarding their specific risks and benefits for sequential MBC chemotherapy. PMID- 24350219 TI - Dexamethasone Down-Regulates Expression of Triggering Receptor Expressed on Myeloid Cells-1: Evidence for a TNFalpha-Related Effect. AB - OBJECTIVES: To investigate the effect of dexamethasone on triggering receptor expressed on myeloid cells-1 (TREM-1). METHODS: Wild-type and tumor necrosis factor (TNF (-/-)) mice were pre-treated with saline, dexamethasone, or hydrocortisone and exposed to a lethal infection of Pseudomonas aeruginosa. Mortality and TREM-1 on neutrophil membranes was measured after sacrifice. U937 human monocytic cells were stimulated with lipopolysaccharide (LPS) or heat killed P. aeruginosa without or with dexamethasone or hydrocortisone, and cell surface TREM-1 and soluble TREM-1 (sTREM-1) were quantified. Expression of TREM-1 and sTREM-1 was also studied in LPS-stimulated U937 cells incubated in the absence or presence of TNFalpha or anti-TNFalpha antibody. RESULTS: Pre-treatment with dexamethasone, but not hydrocortisone, prolonged animal survival. Mice pre treated with dexamethasone showed decreased expression of TREM-1 on neutrophils. In U937 cells, LPS or heat-killed P. aeruginosa induced the expression of TREM-1 and the release of sTREM-1. U937 TREM-1 and sTREM-1 were decreased upon addition of dexamethasone but not hydrocortisone. The suppressive effect of dexamethasone was enhanced in the presence of exogenous TNFalpha and lost in the presence of anti-TNFalpha antibody. In TNF (-/-) mice, dexamethasone suppression of mortality and TREM-1 neutrophil expression was lost. Gene expression of TREM-1 in U937 monocytes was decreased after treatment with dexamethasone. CONCLUSION: TREM 1/sTREM-1 is a novel site of action of dexamethasone. This action is associated with down-regulation of gene expression and is mediated by TNFalpha. PMID- 24350217 TI - Dietary patterns and cardiovascular disease-related risks in chinese older adults. AB - Studies of Western populations demonstrate a relationship between dietary patterns and cardiovascular-related risk factors. Similar research regarding Chinese populations is limited. This study explored the dietary patterns of Chinese older adults and their association with cardiovascular-related risk factors, including hypertension, obesity, and metabolic syndrome. Data were collected using a 34-item Chinese food frequency questionnaire from 750 randomly selected older adults aged 50-88 who participated in the study in 2012. Factor analysis revealed four dietary patterns: a "traditional food pattern," consisting of vegetable, fruit, rice, pork, and fish; a "fast and processed food pattern" consisting of fast or processed food products, sugar, and confectionery; a "soybean, grain, and flour food pattern"; and a "dairy, animal liver, and other animal food pattern." These patterns explained 17.48, 9.52, 5.51, and 4.80% of the variances in food intake, respectively. This study suggests that specific dietary patterns are evident in Chinese older adults. Moderate intake of "traditional Chinese food" is associated with decreased blood pressure and cholesterol level. A dietary pattern rich in soybeans, grains, potatoes, and flour is associated with reduced metabolic factors including reduced triglycerides, fasting glucose, waist circumference, and waist-hip ratio, and a high level of dairy, animal liver, and other animal intake food pattern is associated with increased level of Body Mass Index. In conclusion, this study revealed identifiable dietary patterns among Chinese older adults that are significantly related to blood pressure and metabolic biomarkers. Further study using prospective cohort or intervention study should be used to confirm the association between dietary patterns and blood pressure and metabolic factors. PMID- 24350220 TI - Short- and long-term mortality in severe sepsis/septic shock in a setting with low antibiotic resistance: a prospective observational study in a Swedish university hospital. AB - BACKGROUND: There is little epidemiologic data on sepsis, particularly in areas of low antibiotic resistance. Here we report a prospective observational study of severe sepsis and septic shock in patients admitted to the Intensive Care Unit (ICU) at Karolinska University Hospital, Sweden. We aimed to evaluate short- and long-term mortality, and risk factors for sepsis-related death. A second aim was to investigate patient care in relation to gender. METHODS: One hundred and one patients with severe sepsis and septic shock, admitted to the ICU between 2005 and 2009, were prospectively enrolled in the study. Defined primary endpoints were day 28, hospital, and 1-year mortality. Risk factors for sepsis-related death was evaluated with a multivariate analysis in a pooled analysis with two previous sepsis cohorts. In the subset of patient admitted to the ICU through the emergency department (ED), time to clinician evaluation and time to antibiotics were assessed in relation to gender. RESULTS: In the septic cohort, the day 28, hospital, and 1-year mortality rates were 19, 29, and 34%, respectively. Ninety three percent of the patients received adequate antibiotics from the beginning. Multi-resistant bacteria were only found in three cases. Among the 43 patients admitted to the ICU through the ED, the median time to antibiotics was 86 min (interquartile range 52-165), and overall 77% received appropriate antibiotics within 2 h. Female patients received antibiotics significantly later compared to male patients (p = 0.047). CONCLUSION: The results demonstrate relatively low mortality rates among ICU patients with severe sepsis/septic shock, as compared to reports from outside Scandinavia. Early adequate antibiotic treatment and the low incidence of resistant isolates may partly explain these findings. Importantly, a gender difference in time to antibiotic therapy was seen. PMID- 24350221 TI - Recycling metchnikoff: probiotics, the intestinal microbiome and the quest for long life. AB - Over a century ago, Elie Metchnikoff theorized that health could be enhanced and senility delayed by manipulating the intestinal microbiome with host-friendly bacteria found in yogurt. His theory flourished for a time, then drifted to the fringe of medical practice before re-emerging in the mid-1990s as a concept worthy of mainstream medical attention. Metchnikoff also predicted the existence of bacterial translocation and anticipated theories linking chronic inflammation with the pathogenesis of atherosclerosis and other disorders of the aged. PMID- 24350222 TI - Clinical trial subjects: "panning gold". PMID- 24350223 TI - Expanded access for a little boy. PMID- 24350224 TI - When a safety signal appears: do the right thing. PMID- 24350226 TI - The moral development of the child: an integrated model. AB - Previous theories of moral development such as those by Piaget and Kohlberg usually focused on the cognitive or rational aspect, and seldom included the affective aspect in their construction. The characteristics of the stages of moral development in the present paper are elaborated with special reference to psychological needs, altruism and human relationships, and justice reasoning. The three stages are: (1) Physical Survival, Selfishness, and Obedience, (2) Love Needs, Reciprocal Altruism, and Instrumental Purpose; and (3) Belongingness Needs, Primary Group Altruism, and Mutual Interpersonal Expectations. At Stage 1, a deep and profound attachment to parents, empathy toward the significant others, and obedience to authorities all contribute to the physical survival of a person at this stage. People at Stage 2 are self-protective, dominant, exploitative, and opportunistic. The need to love and to be loved is gratified on the basis of reciprocal altruism. People at Stage 3 have a strong desire to gratify their belongingness needs to a primary group. They are willing to sacrifice for the benefits of the group at great cost. While the psychological needs and altruism are related to the affective aspect of moral development, the justice reasoning is related to the cognitive aspect. The proposed theoretical model attempts to integrate the affective and cognitive aspects of moral development, and prototypic responses to questions related to hypothetical moral dilemmas are presented to substantiate the proposed stage structures. It is hypothesized that the sequence of these three stages is invariant of person and culture. PMID- 24350225 TI - Electronic cigarettes and vaping: a new challenge in clinical medicine and public health. A literature review. AB - Electronic cigarette (e-cigarette) use, or vaping, in the United States and worldwide is increasing. Their use is highly controversial from scientific, political, financial, psychological, and sociological ideologies. Given the controversial nature of e-cigarettes and vaping, how should medical care providers advise their patients? To effectively face this new challenge, health care professionals need to become more familiar with the existing literature concerning e-cigarettes and vaping, especially the scientific literature. Thus, the aim of this article is to present a review of the scientific evidence-based primary literature concerning electronic cigarettes and vaping. A search of the most current literature using the pubmed database dating back to 2008, and using electronic cigarette(s) or e-cigarette(s) as key words, yielded a total of 66 highly relevant articles. These articles primarily deal with (1) consumer-based surveys regarding personal views on vaping, (2) chemical analysis of e-cigarette cartridges, solutions, and mist, (3) nicotine content, delivery, and pharmacokinetics, and (4) clinical and physiological studies investigating the effects of acute vaping. When compared to the effects of smoking, the scant available literature suggests that vaping could be a "harm reduction" alternative to smoking and a possible means for smoking cessation, at least to the same degree as other Food and Drug Administration-approved nicotine replacement therapies. However, it is unclear if vaping e-cigarettes will reduce or increase nicotine addiction. It is obvious that more rigorous investigations of the acute and long-term health effects of vaping are required to establish the safety and efficacy of these devices; especially parallel experiments comparing the cardiopulmonary effects of vaping to smoking. Only then will the medical community be able to adequately meet the new challenge e-cigarettes and vaping present to clinical medicine and public health. PMID- 24350227 TI - Macau, world capital for gambling: a longitudinal study of a youth program designed to instill positive values. AB - This study investigated the effectiveness of a positive youth development program for Chinese Secondary 3 students in two schools, who had been followed up since their entry to Secondary 1. A mixed research method was carried out using a pre- and post-test pre-experimental design and a focus group for the participants. The subjective outcome evaluations included participants' perceptions of the program, program instructors, benefits of the program and overall satisfaction, and were positive. The longitudinal data from the objective outcome evaluation showed some notable improvements, and the overall effect of the program was also found to be positive for newcomers in the junior secondary years. The focus group interviews revealed mostly positive feedback in terms of the students' general impressions of the program, with the majority of participants perceiving benefits to themselves from the program. The findings offer positive evidence of the effectiveness of the program. PMID- 24350228 TI - Massive open online courses in public health. AB - Massive open online courses (MOOCs) represent a new and potentially transformative model for providing educational opportunities to learners not enrolled in a formal educational program. The authors describe the experience of developing and offering eight MOOCs on a variety of public health topics. Existing institutional infrastructure and experience with both for-credit online education and open educational resources mitigated the institutional risk and resource requirements. Although learners are able to enroll easily and freely and do so in large numbers, there is considerable variety in the level of participation and engagement among enrollees. As a result, comprehensive and accurate assessment of meaningful learning progress remains a major challenge for evaluating the effectiveness of MOOCs for providing public health education. PMID- 24350229 TI - Self-reported juvenile firesetting: results from two national survey datasets. AB - The main purpose of this study was to address gaps in existing research by examining the relationship between academic performance and attention problems with juvenile firesetting. Two datasets from the Achenbach System for Empirically Based Assessment (ASEBA) were used. The Factor Analysis Dataset (N = 975) was utilized and results indicated that adolescents who report lower academic performance are more likely to set fires. Additionally, adolescents who report a poor attitude toward school are even more likely to set fires. Results also indicated that attention problems are predictive of self-reported firesetting. The National Survey Dataset (N = 1158) was analyzed to determine the prevalence of firesetting in a normative sample and also examine whether these children reported higher levels of internalizing and externalizing behavior problems. It was found that 4.5% of adolescents in the generalized sample reported firesetting. Firesetters reported more internalizing, externalizing, and total problems than their non-firesetting peers. In this normative sample, firesetters were found to have lower academic performance and more attention problems. Limitations include the low overall number of firesetters in each dataset (Factor Analysis n = 123 and National Survey n = 53) and the inclusion of children who had been referred for services in the Factor Analysis Dataset. PMID- 24350231 TI - Examining the Claim that 80-90% of Suicide Cases Had Depression. PMID- 24350230 TI - Concurrent and simultaneous polydrug use: latent class analysis of an Australian nationally representative sample of young adults. AB - BACKGROUND: Alcohol use and illicit drug use peak during young adulthood (around 18-29 years of age), but comparatively little is known about polydrug use in nationally representative samples of young adults. Drawing on a nationally representative cross-sectional survey (Australian National Drug Strategy Household Survey), this study examines polydrug use patterns and associated psychosocial risk factors among young adults (n = 3,333; age 19-29). METHOD: The use of a broad range of licit and illicit drugs were examined, including alcohol, tobacco, cannabis, cocaine, hallucinogens, ecstasy, ketamine, GHB, inhalants, steroids, barbiturates, meth/amphetamines, heroin, methadone/buprenorphine, other opiates, painkillers, and tranquilizers/sleeping pills. Latent class analysis was employed to identify patterns of polydrug use. RESULTS: Polydrug use in this sample was best described using a 5-class solution. The majority of young adults predominantly used alcohol only (52.3%), alcohol and tobacco (34.18%). The other classes were cannabis, ecstasy, and licit drug use (9.4%), cannabis, amphetamine derivative, and licit drug use (2.8%), and sedative and alcohol use (1.3%). Young adult males with low education and/or high income were most at risk of polydrug use. CONCLUSION: Almost half of young adults reported polydrug use, highlighting the importance of post-high school screening for key risk factors and polydrug use profiles, and the delivery of early intervention strategies targeting illicit drugs. PMID- 24350232 TI - Multiple hypotheses testing procedures in clinical trials and genomic studies. AB - We review and compare multiple hypothesis testing procedures used in clinical trials and those in genomic studies. Clinical trials often employ global tests, which draw an overall conclusion for all the hypotheses, such as SUM test, Two Step test, Approximate Likelihood Ratio test (ALRT), Intersection-Union Test (IUT), and MAX test. The SUM and Two-Step tests are most powerful under homogeneous treatment effects, while the ALRT and MAX test are robust in cases with non-homogeneous treatment effects. Furthermore, the ALRT is robust to unequal sample sizes in testing different hypotheses. In genomic studies, stepwise procedures are used to draw marker-specific conclusions and control family wise error rate (FWER) or false discovery rate (FDR). FDR refers to the percent of false positives among all significant results and is preferred over FWER in screening high-dimensional genomic markers due to its interpretability. In cases where correlations between test statistics cannot be ignored, Westfall Young resampling method generates the joint distribution of P-values under the null and maintains their correlation structure. Finally, the GWAS data from a clinical trial searching for SNPs associated with nephropathy among Type 1 diabetic patients are used to illustrate various procedures. PMID- 24350233 TI - Local health department epidemiologic capacity: a stratified cross-sectional assessment describing the quantity, education, training, and perceived competencies of epidemiologic staff. AB - INTRODUCTION: Local health departments (LHDs) must have sufficient numbers of staff functioning in an epidemiologic role with proper education, training, and skills to protect the health of communities they serve. This pilot study was designed to describe the composition, training, and competency level of LHD staff and examine the hypothesis that potential disparities exist between LHDs serving different sized populations. MATERIALS AND METHODS: Cross-sectional surveys were conducted with directors and epidemiologic staff from a sample of 100 LHDs serving jurisdictions of varied sizes. Questionnaires included inquiries regarding staff composition, education, training, and measures of competency modeled on previously conducted studies by the Council of State and Territorial Epidemiologists. Number of epidemiologic staff, academic degree distribution, epidemiologic training, and both director and staff confidence in task competencies were calculated for each LHD size strata. RESULTS: Disparities in measurements were observed in LHDs serving different sized populations. LHDs serving small populations reported a smaller average number of epidemiologic staff than those serving larger jurisdictions. As size of population served increased, percentages of staff and directors holding bachelors' and masters' degrees increased, while those holding RN degrees decreased. A higher degree of perceived competency of staff in most task categories was reported in LHDs serving larger populations. DISCUSSION: LHDs serving smaller populations reported fewer epidemiologic staff, therefore might benefit from additional resources. Differences observed in staff education, training, and competencies suggest that enhanced epidemiologic training might be particularly needed in LHDs serving smaller populations. RESULTS can be used as a baseline for future research aimed at identifying areas where training and personnel resources might be particularly needed to increase the capabilities of LHDs. PMID- 24350234 TI - The Association between Trust in Health Care Providers and Medication Adherence among Black Women with Hypertension. AB - BACKGROUND: Black women have the highest prevalence of hypertension in the world. Reasons for this disparity are poorly understood. The historical legacy of medical maltreatment of Blacks in the U.S. provides some insight into distrust in the medical profession, refusal of treatment, and poor adherence to treatment regimens. METHODS: Black women (N = 80) who were prescribed antihypertensive medications were recruited from urban communities in North Carolina. Study participants completed the Trust in Physician and Hill-Bone Compliance to High Blood Pressure Therapy questionnaires. An exact discrete-event model was used to examine the relationship between trust and medication adherence. RESULTS: Mean age of study participants was 48 +/- 9.2 years. The majority of participants (67%) were actively employed and 30% had incomes at or below the federal poverty level. Increasing levels of trust in the health care provider was independently associated with greater medication adherence (P Trend = 0.015). CONCLUSION: Black women with hypertension who trusted their health care providers were more likely to be adherent with their prescribed antihypertensive medications than those who did not trust their health care providers. Findings suggest that trusting relationships between Black women and health care providers are important to decreasing disparate rates of hypertension. PMID- 24350235 TI - Hypertension Awareness and Associated Factors among Older Chinese Adults. AB - Hypertension is one of the most preventable chronic conditions. Improving hypertension awareness is a critical first step to reducing morbidity and mortality from hypertension in the elderly, yet the factors associated with hypertension awareness in China are poorly understood. The objective of this paper is to examine the extent to which older Chinese adults are aware of their hypertension, and factors associated with this awareness. We included 2404 adults aged 60 years or older clinically identified as hypertensive from panel data surveyed in 1997, 2000, 2004, and 2006 as part of the China Health and Nutrition Survey. Comparing this data with respondents' self-reported diagnosis of hypertension enabled us to characterize hypertension awareness. Covariates included socio-demographic, health status, functional disability, and behavioral factors. Generalized estimating equations were used to identify factors for hypertension awareness. We found 22.9% in 1997 and 42.7% in 2006 of study participants were aware of their hypertensive status. Lower awareness was found among those who lived in rural areas [odds ratio (OR) = 0.64, 95% Confidence Interval (CI), 0.47-0.88]. Higher awareness was noted for persons who were aware of their hypertensive status in a previous survey wave (OR = 7.43, 95% CI, 5.45 10.13), had high income (OR = 1.55, 95% CI, 1.05-2.28), had stage two hypertension (OR = 2.28, 95% CI, 1.69-3.06), had acute condition (OR = 2.54, 95% CI, 1.89-3.42), and had greater activities of daily living limitations (OR = 1.24, 95% CI, 1.08-1.43). Studying dynamics of hypertension awareness can help inform both clinical and public health approaches to improve healthcare. PMID- 24350236 TI - What is Normal? The Impact of Psychiatric Classification on Mental Health Practice and Research. PMID- 24350237 TI - Comparing Adult Males and Females in the United States to Examine the Association between Body Mass Index and Frequent Mental Distress: An Analysis of Data from BRFSS 2011. AB - Background. There is conflicting evidence regarding the association of body mass index (BMI) with mental distress. Studies have focused on different dimensions of mental health and used different definitions and many of them have not controlled for confounding factors. The aim of this study was to examine the relationship between frequent mental distress (FMD) and BMI among adults in the United States, with special emphasis on gender differences. Methods. Data from the Behavioral Risk Factor Surveillance System (BRFSS) for the year 2011 were used in logistic regression models to predict FMD, defined as having 14 or more days of poor mental health in the previous month. Sociodemographic factors, tobacco and alcohol use, diet and physical activity, and number of chronic diseases were controlled for. Results. 11.95% (n = 53,715) of the participants with valid responses (n = 496,702) had FMD. The adjusted ORs of having FMD among underweight, overweight, and obese females were 1.13 (95% CI: 1.10, 1.60), 1.10 (95% CI: 1.03, 1.19), and 1.21 (95% CI: 1.13, 1.31), respectively, but they were not statistically significant for males. Conclusions. These findings suggest a relationship between BMI and FMD, independent of other variables. It may be useful to explore longitudinal trend in this association. PMID- 24350238 TI - Differential Expression of Myogenic Regulatory Factor Genes in the Skeletal Muscles of Tambaqui Colossoma macropomum (Cuvier 1818) from Amazonian Black and Clear Water. AB - Hypothesizing that the Amazonian water system differences would affect the expression of muscle growth-related genes in juvenile tambaqui Colossoma macropomum (Cuvier 1818), this study aimed to analyze the morphometric data and expression of myogenic regulatory factors (MRFs) in the white and red muscle from tambaqui obtained from clear and black Amazonian water systems. All of the MRF transcript levels (myod, myf5, myogenin, and mrf4) were significantly lower in the red muscle from black water fish in comparison to clear water fish. However, in white muscle, only the myod transcript level was significantly decreased in the black water tambaqui. The changes in MRFs gene expression in muscle fibers of tambaqui from black water system provide relevant information about the environmental influence as that of water systems on gene expression of muscle growth related genes in the C. macropomum. Our results showed that the physical and chemical water characteristics change the expression of genes that promote muscle growth, and these results may be also widely applicable to future projects that aim to enhance muscle growth in fish that are of substantial interest to the aquaculture. PMID- 24350239 TI - Microarray analysis of transcriptome of medulla identifies potential biomarkers for Parkinson's disease. AB - To complement the molecular pathways contributing to Parkinson's disease (PD) and identify potential biomarkers, gene expression profiles of two regions of the medulla were compared between PD patients and control. GSE19587 containing two groups of gene expression profiles [6 dorsal motor nucleus of the vagus (DMNV) samples from PD patients and 5 from controls, 6 inferior olivary nucleus (ION) samples from PD patients and 5 from controls] was downloaded from Gene Expression Omnibus. As a result, a total of 1569 and 1647 differentially expressed genes (DEGs) were, respectively, screened in DMNV and ION with limma package of R. The functional enrichment analysis by DAVID server (the Database for Annotation, Visualization and Integrated Discovery) indicated that the above DEGs may be involved in the following processes, such as regulation of cell proliferation, positive regulation of macromolecule metabolic process, and regulation of apoptosis. Further analysis showed that there were 365 common DEGs presented in both regions (DMNV and ION), which may be further regulated by eight clusters of microRNAs retrieved with WebGestalt. The genes in the common DEGs-miRNAs regulatory network were enriched in regulation of apoptosis process via DAVID analysis. These findings could not only advance the understandings about the pathogenesis of PD, but also suggest potential biomarkers for this disease. PMID- 24350240 TI - Why is diabetes mellitus a risk factor for contrast-induced nephropathy? AB - Contrast-induced nephropathy (CIN) remains a leading cause of iatrogenic acute kidney injury, as the usage of contrast media for imaging and intravascular intervention keeps expanding. Diabetes is an important predisposing factor for CIN, particularly in patients with renal functional impairment. Renal hypoxia, combined with the generation of reactive oxygen species, plays a central role in the pathogenesis of CIN, and the diabetic kidney is particularly susceptible to intensified hypoxic and oxidative stress following the administration of contrast media. The pathophysiology of this vulnerability is complex and involves various mechanisms, including a priori enhanced tubular transport activity, oxygen consumption, and the generation of reactive oxygen species. The regulation of vascular tone and peritubular blood flow may also be altered, particularly due to defective nitrovasodilation, enhanced endothelin production, and a particular hyperresponsiveness to adenosine-related vasoconstriction. In addition, micro- and macrovascular diseases and chronic tubulointerstitial changes further compromise regional oxygen delivery, and renal antioxidant capacity might be hampered. A better understanding of these mechanisms and their control in the diabetic patient may initiate novel strategies in the prevention of contrast nephropathy in these susceptible patients. PMID- 24350241 TI - Prediction of drugs target groups based on ChEBI ontology. AB - Most drugs have beneficial as well as adverse effects and exert their biological functions by adjusting and altering the functions of their target proteins. Thus, knowledge of drugs target proteins is essential for the improvement of therapeutic effects and mitigation of undesirable side effects. In the study, we proposed a novel prediction method based on drug/compound ontology information extracted from ChEBI to identify drugs target groups from which the kind of functions of a drug may be deduced. By collecting data in KEGG, a benchmark dataset consisting of 876 drugs, categorized into four target groups, was constructed. To evaluate the method more thoroughly, the benchmark dataset was divided into a training dataset and an independent test dataset. It is observed by jackknife test that the overall prediction accuracy on the training dataset was 83.12%, while it was 87.50% on the test dataset-the predictor exhibited an excellent generalization. The good performance of the method indicates that the ontology information of the drugs contains rich information about their target groups, and the study may become an inspiration to solve the problems of this sort and bridge the gap between ChEBI ontology and drugs target groups. PMID- 24350242 TI - New trends in biotechnological processes to increase the environmental protection. PMID- 24350243 TI - Topical promethazine side effects: our experience and review of the literature. AB - Promethazine hydrochloride is a first-generation H1 receptor antagonist, antihistamine, and antiemetic medication that can also have strong sedative effects. The apparent ability of topical H1r/2r antagonists to target epidermal H1/2r was translated into increased efficacy in the treatment of inflammatory dermatoses, likely due to decreased inflammation and enhanced barrier function. PMID- 24350244 TI - Robotic technologies and rehabilitation: new tools for stroke patients' therapy. AB - INTRODUCTION: The role of robotics in poststroke patients' rehabilitation has been investigated intensively. This paper presents the state-of-the-art and the possible future role of robotics in poststroke rehabilitation, for both upper and lower limbs. MATERIALS AND METHODS: We performed a comprehensive search of PubMed, Cochrane, and PeDRO databases using as keywords "robot AND stroke AND rehabilitation." RESULTS AND DISCUSSION: In upper limb robotic rehabilitation, training seems to improve arm function in activities of daily living. In addition, electromechanical gait training after stroke seems to be effective. It is still unclear whether robot-assisted arm training may improve muscle strength, and which electromechanical gait-training device may be the most effective for walking training implementation. CONCLUSIONS: In the field of robotic technologies for stroke patients' rehabilitation we identified currently relevant growing points and areas timely for developing research. Among the growing points there is the development of new easily transportable, wearable devices that could improve rehabilitation also after discharge, in an outpatient or home-based setting. For developing research, efforts are being made to establish the ideal type of treatment, the length and amount of training protocol, and the patient's characteristics to be successfully enrolled to this treatment. PMID- 24350245 TI - Pyrolytic and kinetic analysis of two coastal plant species: Artemisia annua and Chenopodium glaucum. AB - The large amount of coastal plant species available makes them ideal candidates for energy production. In this study, thermogravimetric analysis was used to evaluate the fuel properties of two coastal plant species, and the distributed activation energy model (DAEM) was employed in kinetic analysis. The major mass loss due to devolatilization started at 154 and 162 degrees C at the heating rate of 10 degrees C min(-1) for Artemisia annua and Chenopodium glaucum, respectively. The results showed that the average activation energies of Artemisia annua and Chenopodium glaucum were 169.69 and 170.48 kJ mol(-1), respectively. Furthermore, the activation energy changed while the conversion rate increased, and the frequency factor k 0 decreased greatly while the activation energy decreased. The results also indicated that the devolatilization of the two coastal plant species underwent a set of first-order reactions and could be expressed by the DAEM. Additionally, a simplified mathematical model was proposed to facilitate the prediction of devolatilization curves. PMID- 24350247 TI - Clinical application of vascular regenerative therapy for peripheral artery disease. AB - Prognosis of peripheral artery disease (PAD), especially critical limb ischemia, is very poor despite the development of endovascular therapy and bypass surgery. Many patients result in leg amputation and, therefore, vascular regenerative therapy is expected in this field. Gene therapy using vascular endothelial growth factor is the first step of vascular regenerative therapy, but did not confirm effectiveness in a large-scale randomized comparative study. Based on animal experiments, bone marrow mononuclear cells (MNCs), peripheral blood MNCs were used as the cell source for regenerative therapy. Those cells were confirmed to be effective to decrease rest pain and ulcer size, but its effect was not fully satisfied. Mesenchymal stem cells (MSCs) are expected as an effective cell source for vascular regeneration and clinical studies are ongoing, because the cells are able to differentiate into various cell types and produce a significant amount of vascular growth factors. Of vascular regeneration therapy, peripheral MNCs and bone marrow MNCs were recognized as advanced medical technology but do not attain to the standard therapy. However, clinical use of MSCs have already started, and induced pluripotent stem cells are surely promising tool for vascular regeneration therapy although further basic studies are required for clinical application. PMID- 24350248 TI - Ovarian stimulation affects the population of mouse uterine NK cells at early pregnancy. AB - The aim of this study was to determine the influence of ovarian stimulation on endometrial mouse NK cell population. For superovulation, the female adult NMRI mice were injected i.p. with 10 IU of the pregnant mare serum gonadotropin followed 48 h later by an i.p. injection of 10 IU human chorionic gonadotropin hormone. Ovarian stimulated and nonstimulated mice were mated with fertile male. The presence of vaginal plug proved natural pregnancy, and this day was considered as day one of pregnancy. Tissue samples were prepared from the uterine horn and spleen of both groups of study on 7th day of pregnancy. Serum estradiol 17beta and progesterone were measured at the same time. The tissue cryosections were prepared and double stained for CD 161 and CD3 markers, and NK cells population was analyzed. Relative frequency of NK cells was significantly lower in stroma and myometrium in hyperstimulated mice compared with the control group. However, no difference was seen in percentage of NK cells in spleen. The ovarian stimulation influences the proportion of uterine NK cells and may affect the embryo implantation. PMID- 24350246 TI - Pattern recognition receptors and cytokines in Mycobacterium tuberculosis infection--the double-edged sword? AB - Tuberculosis, an infectious disease caused by Mycobacterium tuberculosis (Mtb), remains a major cause of human death worldwide. Innate immunity provides host defense against Mtb. Phagocytosis, characterized by recognition of Mtb by macrophages and dendritic cells (DCs), is the first step of the innate immune defense mechanism. The recognition of Mtb is mediated by pattern recognition receptors (PRRs), expressed on innate immune cells, including toll-like receptors (TLRs), complement receptors, nucleotide oligomerization domain like receptors, dendritic cell-specific intercellular adhesion molecule grabbing nonintegrin (DC SIGN), mannose receptors, CD14 receptors, scavenger receptors, and FCgamma receptors. Interaction of mycobacterial ligands with PRRs leads macrophages and DCs to secrete selected cytokines, which in turn induce interferon-gamma- (IFNgamma-) dominated immunity. IFNgamma and other cytokines like tumor necrosis factor-alpha (TNFalpha) regulate mycobacterial growth, granuloma formation, and initiation of the adaptive immune response to Mtb and finally provide protection to the host. However, Mtb can evade destruction by antimicrobial defense mechanisms of the innate immune system as some components of the system may promote survival of the bacteria in these cells and facilitate pathogenesis. Thus, although innate immunity components generally play a protective role against Mtb, they may also facilitate Mtb survival. The involvement of selected PRRs and cytokines on these seemingly contradictory roles is discussed. PMID- 24350249 TI - Prostaglandin analogous and antioxidant activity mediated gastroprotective action of Tabernaemontana divaricata (L.) R. Br. flower methanolic extract against chemically induced gastric ulcers in rats. AB - The present study was conducted to evaluate the antiulcerogenic effect and recognize the basic mechanism of action of Tabernaemontana divaricata (L.) R. Br. flowers. T. divaricata flower methanolic extract (TDFME) was screened for antiulcer activity versus aspirin and ethanol induced gastric ulcers at three doses--125, 250, and 500 mg/kg--orally using misoprostol as a standard. Besides histopathological examination, seven parameters, that is, ulcer index, total protein, nonprotein sulphhydryls, mucin, catalase, malondialdehyde, and superoxide dismutase levels, were estimated. In addition to HPLC profiling, GC-MS analysis and electrospray ionization--high resolution mass spectral (ESI-HRMS) analysis of crude TDFME were carried out in an attempt to identify known phytochemicals present in the extract on the basis of m/z value. The results revealed a significant increase in the levels of catalase, superoxide dismutase, mucin, and nonprotein sulphhydryls, while they revealed a reduction in ulcer index, the levels of total protein, and malondialdehyde. Histopathological observations also demonstrated the protective effect. Though all the doses of TDFME exhibited gastroprotective function, higher doses were found to be more effective. Mass spectral analysis gave a few characteristic m/z values suggesting the presence of a few known indole alkaloids, while HPLC profiling highlighted the complexity of the extract. TDFME was found to exhibit its gastroprotective effect through antioxidant mechanism and by enhancing the production of gastric mucous. PMID- 24350250 TI - Extraction and separation of fucoidan from Laminaria japonica with chitosan as extractant. AB - Herein the extraction method of fucoidan from Laminaria japonica is reported. Firstly, chitosan, chitosan-N-2-hydroxypropyl trimethyl ammonium chloride (HACC), and hexadecyltrimethylammonium bromide (CPAB) were used to extract the fucoidan. The results showed that chitosan was the optimal extractant compared with the other two extractants. After extraction, different aqueous solutions, including NaCl, KCl, and HCl (pH2), were used to separate fucoidan from chitosan-fucoidan complex. The results showed that the separation ability of NaCl was slightly higher than that of KCl. Moreover, the price of NaCl is lower than that of KCl. Given the quality-price rate, NaCl solution was chosen as the separation solution. Thirdly, the concentration and ratio of NaCl solution : sediment influence the separation of fucoidan from chitosan-fucoidan complex. The results showed that the optimal separation conditions include 4 mol/L NaCl solution with the ratio of NaCl solution to sediment at 30 : 1. Fucoidan content was found to be affected by different separation time. Fucoidan content increased with the increase of separation time, and the optimal separation time was 6 h. Compared with traditional alkali extraction method, this method not only reduces the usage of alkali and acid and alleviate environment pollution, but also has the comparable extraction yield of fucoidan. It is a potential method for extraction of fucoidan. PMID- 24350251 TI - Modification of a rodent hindlimb model of secondary lymphedema: surgical radicality versus radiotherapeutic ablation. AB - Secondary lymphedema is an intractable disease mainly caused by damage of the lymphatic system during surgery, yet studies are limited by the lack of suitable animal models. The purpose of this study was to create an improved model of secondary lymphedema in the hindlimbs of rodents with sustained effects and able to mimic human lymphedema. This was achieved by combining previously reported surgical methods and radiation to induce chronic lymphedema. Despite more radical surgical destruction of superficial and deep lymphatic vessels, surgery alone was not enough to sustain increased hindlimb volume. Radiotherapy was necessary to prolong these effects, with decreased lymphatic flow on lymphoscintigraphy, but hindlimb necrosis occurred after 4 weeks due to radiation toxicity. The applicability of this model for studies of therapeutic lymphangiogenesis was subsequently tested by injecting muscle-derived stem cells previously cocultured with the supernatant of human lymphatic endothelial cells in vitro. There was a tendency for increased lymphatic flow which significantly increased lymphatic vessel formation after cell injection, but attenuation of hindlimb volume was not observed. These results suggest that further refinement of the rodent hindlimb model is needed by titration of adequate radiation dosage, while stem cell lymphangiogenesis seems to be a promising approach. PMID- 24350252 TI - Translational biomedical informatics and computational systems medicine. PMID- 24350253 TI - Association of genetic variants of BMP4 with type 2 diabetes mellitus and clinical traits in a Chinese Han population. AB - BMP4 is one of the transforming growth factor- beta superfamily, which can participate in adipogenesis. Gene encoding BMP4 is acknowledged as a convincing candidate that may contribute to both glucose and lipid metabolism. In this paper, we aimed to test the impacts of BMP4 variants on type 2 diabetes in a large sample of Chinese population. We genotyped 10 tagging single nucleotide polymorphisms within the BMP4 region in 6822 participants and acquired detailed clinical investigations and biochemistry measurements. We found that BMP4 rs8014363 showed nominal association towards type 2 diabetes, with the T allele conferring a high risk of type 2 diabetes (OR = 1.108, 95%CI 0.999-1.229, P = 0.051 for allele; OR = 1.110, 95%CI 1.000-1.231, P = 0.050 for genotype), but it was no longer statistically significant after adjusting for multiple testing (empirical P = 0.3689 for allele based on 10,000 permutations). Moreover, we observed a significant association of rs8014363 with triglyceride level and a trend towards association with high-density lipoprotein cholesterol after adjusting for age, gender, and BMI (P = 0.035 and 0.068, resp.). Our data suggested that the genetic variants of BMP4 may not play a dominant role in glucose metabolism in Chinese Han population, but a minor effect cannot be ignored. PMID- 24350254 TI - Polymorphism of the transferrin gene in eye diseases: keratoconus and Fuchs endothelial corneal dystrophy. AB - Oxidative stress may play a role in the pathogenesis of keratoconus (KC) and Fuchs endothelial corneal dystrophy (FECD). Iron may promote the stress by the Fenton reaction, so its homeostasis should be strictly controlled. Transferrin is essential for iron homeostasis because it transports iron from plasma into cells. The malfunction of transferrin, which may be caused by variation in its gene (TF) variation, may contribute to oxidative stress and change KC and FECD risk. To verify this hypothesis we investigated the association between three polymorphisms of the TF gene, g.3296G>A (rs8177178), g.3481A>G (rs8177179), and c.-2G>A (rs1130459), and KC and FECD occurrence. Genotyping was performed in blood lymphocytes in 216 patients with KC, 130 patients with FECD and 228 controls by PCR-RFLP. We studied also the influence of other risk factors. The A/A genotype and the A allele of the g.3296G>A polymorphism were associated with KC occurrence, while the G allele was negatively correlated with it. We observed a decrease in KC occurrence associated with the A/G genotype of the g.3481A>G polymorphism. We did not find any association between the c.-2G>A polymorphism and KC. No association was found between all three polymorphisms and FECD occurrence. PMID- 24350255 TI - Grappling the high altitude for safe edible bamboo shoots with rich nutritional attributes and escaping cyanogenic toxicity. AB - Consumption of bamboo species with high level of total cyanogenic content (TCC) in Asia by many ethnic groups is significantly associated with food poisoning and occasionally Konzo (a neurological disorder). Adequate characterization of edible bamboo species with low level of TCC and high nutritious attributes is required for consumer's safety as well as for the conservation of the gene pool. Here, we employed morphological descriptors, atomic absorption spectrophotometer, RAPD, and trnL-F intergenic spacer to characterize 15 indigenous edible bamboo species of north-east India. The study indicates that morphologically and genetically evolved edible bamboo species having large and robust bamboo-shoot texture and growing at low altitude contain high level of TCC, low antioxidant properties, and low levels of beneficial macronutrients and micronutrients. Importantly, Dendrocalamus species are shown to be rich in TCC irrespective of the growing altitude while Bambusa species are found to have moderate level of TCC. The findings clearly demonstrated that Chimonobambusa callosa growing at high altitude represents safe edible bamboo species with nutritious attributes. PMID- 24350256 TI - Role of stenting for intracranial atherosclerosis in the post-SAMMPRIS era. AB - Introduction. The initial promise of endovascular stenting for the treatment of intracranial atherosclerotic disease (ICAD) has been tempered by the results of the SAMMPRIS trial which demonstrated better outcomes with medical management compared to stenting for symptomatic ICAD. We review post-SAMMPRIS ICAD stenting outcomes. Methods. A comprehensive literature search was performed using PubMed to identify all ICAD stenting series published after the SAMMPRIS in September 2011. The type and design of the stent, number of patients and lesions, inclusion criteria, and clinical and angiographic outcomes were noted. Results. From October 2011 to August 2013, 19 ICAD stenting series were identified describing the interventional outcomes for 2,196 patients with 2,314 lesions. Of the 38 different stents used, 87% were balloon-expandable stents (BESs) and 13% were self-expanding stents. The median minimum stenosis was 50%. The median rates of technical success rate, postprocedural ischemic events, and symptomatic in-stent restenosis (ISR) were 98% (range 87-100%), 9.4% (range 0-25%), and 2.7% (range 0 11.1%), respectively. The median follow-up durations were one to 67 months. Conclusions. The management of severe ICAD remains controversial. Future trials are needed to define the optimal patient, lesion, and stent characteristics which will portend the best outcomes with intervention. PMID- 24350258 TI - Changes in maternal serum transforming growth factor beta-1 during pregnancy: a cross-sectional study. AB - Changes in circulating levels of maternal serum transforming growth factor beta-1 (TGF-beta1), collected from 98 women (AGA) at different gestational ages (10-38 weeks) were measured and comparisons were made between levels in pregnant and nonpregnant controls and also between 10 women with small-for-gestational age (SGA) and 7 with appropriate-for-gestational age (AGA) fetuses. Maternal serum TGF-beta1 levels at all stages of pregnancy were higher than those in normal healthy nonpregnant adults. The mean TGF-beta1 levels in SGA pregnancies at 34 week gestation (32.5 + 3.2 ng/mL) were significantly less than those in AGA pregnancies (39.2 + 9.8 ng/mL) while at 38-week gestation, the levels were similar in the two groups (36.04 + 4.3 versus 36.7 + 7.0 ng/mL). This differential change in TGF-beta1 levels is probably an important modulating factor in the aetiopathogenesis of abnormal intrauterine fetal growth. PMID- 24350257 TI - Dual inhibiting senescence and epithelial-to-mesenchymal transition by erythropoietin preserve tubular epithelial cell regeneration and ameliorate renal fibrosis in unilateral ureteral obstruction. AB - This study aims to investigate the renoprotective effect of recombinant human erythropoietin (rhEPO) treatment could preserve tubular epithelial cell regeneration and ameliorate renal fibrosis by dual inhibition of stress-induced senescence and EMT in unilateral ureteric obstruction (UUO) mouse model. UUO or sham-operated mice were randomly assigned to receive rhEPO or vehicle treatment and were sacrificed on days 3, 7, and 14. Kidney specimens were fixed for histopathological and immunohistochemical study. The expression of S100A4, TGF beta1, BMP-7, Smad2/3, Smad1/5/8, and p16(INK4a) was determined by western blot and real-time RT-PCR. Vehicle treated UUO mice had increased tubular atrophy and interstitial fibrosis within 3 to 14 days. An increase in TGF-beta1, Smad2/3, S100A4, and p16(INK4a) expression and a decrease in BMP-7 and Smad1/5/8 expression were observed in the obstructed kidneys. p16(INK4a) was positively correlated with TGF-beta1/Smad2/3 and negatively correlated with BMP-7/Smad1/5/8 in UUO mice. rhEPO treatment significantly suppressed the upregulation of TGF beta, Smad2/3, S100A4, and p16(INK4a) and preserved the downregulation of BMP-7 and Smad1/5/8, resulting in markedly reduced TA/IF compared to the vehicle treated mice. The renoprotective effects of rhEPO could ameliorate renal TA/IF by modulating senescence and EMT which could be a part of therapeutic option in patients with chronic kidney disease. PMID- 24350260 TI - Microbial removal of the pharmaceutical compounds Ibuprofen and diclofenac from wastewater. AB - Studies on the occurrence of pharmaceuticals show that the widely used pharmaceuticals ibuprofen and diclofenac are present in relevant concentrations in the environment. A pilot plant treating hospital wastewater with relevant concentrations of these pharmaceuticals was evaluated for its performance to reduce the concentration of the pharmaceuticals. Ibuprofen was completely removed, whereas diclofenac yielded a residual concentration, showing the necessity of posttreatment to remove diclofenac, for example, activated carbon. Successively, detailed laboratory experiments with activated sludge from the same wastewater treatment plant showed bioremediation potential in the treatment plant. The biological degradation pathway was studied and showed a mineralisation of ibuprofen and degradation of diclofenac. The present microbes were further studied in laboratory experiments, and DGGE analyses showed the enrichment and isolation of highly purified cultures that degraded either ibuprofen or diclofenac. This research illuminates the importance of the involved bacteria for the effectiveness of the removal of pharmaceuticals in a wastewater treatment plant. A complete removal of pharmaceuticals from wastewater will stimulate water reuse, addressing the worldwide increasing demand for clean and safe fresh water. PMID- 24350259 TI - Effects of DL-homocysteine thiolactone on cardiac contractility, coronary flow, and oxidative stress markers in the isolated rat heart: the role of different gasotransmitters. AB - Considering the adverse effects of DL-homocysteine thiolactone hydrochloride (DL Hcy TLHC) on vascular function and the possible role of oxidative stress in these mechanisms, the aim of this study was to assess the influence of DL-Hcy TLHC alone and in combination with specific inhibitors of important gasotransmitters, such as L-NAME, DL-PAG, and PPR IX, on cardiac contractility, coronary flow, and oxidative stress markers in an isolated rat heart. The hearts were retrogradely perfused according to the Langendorff technique at a 70 cm H2O and administered 10 MUM DL-Hcy TLHC alone or in combination with 30 MUM L-NAME, 10 MUM DL-PAG, or 10 MUM PPR IX. The following parameters were measured: dp/dt max, dp/dt min, SLVP, DLVP, MBP, HR, and CF. Oxidative stress markers were measured spectrophotometrically in coronary effluent through TBARS, NO2, O2(-), and H2O2 concentrations. The administration of DL-Hcy TLHC alone decreased dp/dt max, SLVP, and CF but did not change any oxidative stress parameters. DL-Hcy TLHC with L-NAME decreased CF, O2(-), H2O2, and TBARS. The administration of DL-Hcy TLHC with DL-PAG significantly increased dp/dt max but decreased DLVP, CF, and TBARS. Administration of DL-Hcy TLHC with PPR IX caused a decrease in dp/dt max, SLVP, HR, CF, and TBARS. PMID- 24350261 TI - Practical considerations and challenges involved in surfactant enhanced bioremediation of oil. AB - Surfactant enhanced bioremediation (SEB) of oil is an approach adopted to overcome the bioavailability constraints encountered in biotransformation of nonaqueous phase liquid (NAPL) pollutants. Fuel oils contain n-alkanes and other aliphatic hydrocarbons, monoaromatics, and polynuclear aromatic hydrocarbons (PAHs). Although hydrocarbon degrading cultures are abundant in nature, complete biodegradation of oil is rarely achieved even under favorable environmental conditions due to the structural complexity of oil and culture specificities. Moreover, the interaction among cultures in a consortium, substrate interaction effects during the degradation and ability of specific cultures to alter the bioavailability of oil invariably affect the process. Although SEB has the potential to increase the degradation rate of oil and its constituents, there are numerous challenges in the successful application of this technology. Success is dependent on the choice of appropriate surfactant type and dose since the surfactant-hydrocarbon-microorganism interaction may be unique to each scenario. Surfactants not only enhance the uptake of constituents through micellar solubilization and emulsification but can also alter microbial cell surface characteristics. Moreover, hydrocarbons partitioned in micelles may not be readily bioavailable depending on the microorganism-surfactant interactions. Surfactant toxicity and inherent biodegradability of surfactants may pose additional challenges as discussed in this review. PMID- 24350262 TI - Physiotherapists have accurate expectations of their patients' future health related quality of life after first assessment in a subacute rehabilitation setting. AB - BACKGROUND: Expectations held by health professionals and their patients are likely to affect treatment choices in subacute inpatient rehabilitation settings for older adults. There is a scarcity of empirical evidence evaluating whether health professionals expectations of the quality of their patients' future health states are accurate. METHODS: A prospective longitudinal cohort investigation was implemented to examine agreement (kappa coefficients, exact agreement, limits-of agreement, and intraclass-correlation coefficients) between physiotherapists' (n = 23) prediction of patients' discharge health-related quality of life (reported on the EQ-5D-3L) and the actual health-related quality of life self-reported by patients (n = 272) at their discharge assessment (using the EQ-5D-3L). The mini mental state examination was used as an indicator of patients' cognitive ability. RESULTS: Overall, 232 (85%) patients had all assessment data completed and were included in analysis. Kappa coefficients (exact agreement) ranged between 0.37 0.57 (58%-83%) across EQ-5D-3L domains in the lower cognition group and 0.53-0.68 (81%-85%) in the better cognition group. CONCLUSIONS: Physiotherapists in this subacute rehabilitation setting predicted their patients' discharge health related quality of life with substantial accuracy. Physiotherapists are likely able to provide their patients with sound information regarding potential recovery and health-related quality of life on discharge. The prediction accuracy was higher among patients with better cognition than patients with poorer cognition. PMID- 24350263 TI - Speciation in Thaparocleidus (Monogenea: Dactylogyridae) parasitizing Asian Pangasiid catfishes. AB - The phylogeny of monogeneans of the genus Thaparocleidus that parasitize the gills of Pangasiidae in Borneo and Sumatra was inferred from molecular data to investigate parasite speciation. The phylogeny of the Pangasiidae was also reconstructed in order to investigate host-parasite coevolutionary history. The monophyly of Thaparocleidus parasitizing Pangasiidae was confirmed. Low intraspecies molecular variability was observed in three Thaparocleidus species collected from geographically distant localities. However, a high intraspecies molecular variability was observed in two Thaparocleidus species suggesting that these species represent a complex of species highly similar in morphology. Distance-based and tree-based methods revealed a significant global fit between parasite and host phylogenies. Parasite duplication (i.e., intrahost speciation) was recognized as the most common event in Thaparocleidus, while the numbers of cospeciation and host switches were lower and similar to each other. When collapsing nodes correspond to duplication cases, our results suggest host switches in the Thaparocleidus-Pangasiidae system precluding congruence between host and parasite trees. We found that the morphometric variability of the parasite attachment organ is not linked to phylogeny, suggesting that the attachment organ is under adaptive constraint. We showed that haptor morphometry is linked to host specificity, whereby nonspecific parasites display higher morphometric variability than specialists. PMID- 24350264 TI - Regulation of PKC autophosphorylation by calponin in contractile vascular smooth muscle tissue. AB - Protein kinase C (PKC) is a key enzyme involved in agonist-induced smooth muscle contraction. In some cases, regulatory phosphorylation of PKC is required for full activation of the enzyme. However, this issue has largely been ignored with respect to PKC-dependent regulation of contractile vascular smooth muscle (VSM) contractility. The first event in PKC regulation is a transphosphorylation by PDK at a conserved threonine in the activation loop of PKC, followed by the subsequent autophosphorylation at the turn motif and hydrophobic motif sites. In the present study, we determined whether phosphorylation of PKC is a regulated process in VSM and also investigated a potential role of calponin in the regulation of PKC. We found that calponin increases the level of in vitro PKCalpha phosphorylation at the PDK and hydrophobic sites, but not the turn motif site. In vascular tissues, phosphorylation of the PKC hydrophobic site, but not turn motif site, as well as phosphorylation of PDK at S241 increased in response to phenylephrine. Calponin knockdown inhibits autophosphorylation of cellular PKC in response to phenylephrine, confirming results with recombinant PKC. Thus these results show that autophosphorylation of PKC is regulated in dVSM and calponin is necessary for autophosphorylation of PKC in VSM. PMID- 24350265 TI - A biomechanical research of growth control of spine by shape memory alloy staples. AB - Shape memory alloy (SMA) staples in nickel titanium with shape memory effect are effective for spinal growth control. This study was designed to evaluate the biomechanical properties of the staples and observe the stability of the fixed segments spine after the staples were implanted. According to the vertical distance of the vertebrae, SMA staples of 5, 6.5, and 8 mm were designed. The recovery stress of 24 SMA staples in three groups was measured. The pullout strength of SMA staples and stainless steel staples in each functional spinal unit was measured. Each of the six fresh specimens was divided into three conditions: normal, single staple, and double staples. Under each condition, the angle and torque of spinal movements in six directions were tested. Results show that the differences in recovery stress and maximum pullout strength between groups were statistically significant. In left and right bending, flextion, and extention, the stability of spine was decreased in conditions of single staple and double staples. Biomechanical function of SMA staples was superior to stainless steel staple. SMA staples have the function of hemiepiphyseal compression and kyphosis and scoliosis model of thoracic vertebrae in goat could be successfully created by the fusionless technique. PMID- 24350266 TI - What would be the most appropriate alpha/beta ratio in the setting of stereotactic body radiation therapy for early stage non-small cell lung cancer. AB - We hypothesize that the correlation between the radiation dose expressed as the biologically effective dose (BED) and the clinical endpoints will correlate better as the value of the alpha/beta ratio is increased to >10 Gy, which theoretically minimizes the overestimation of the dose potency associated with the linear quadratic (LQ) formula in the setting of stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC). A search was conducted in the PubMed electronic databases in August 2011. In the studies analyzed, increasing the alpha/beta ratio is associated with an increase in the strength of the correlation between isocenter BED and local control, especially in the studies with median followup of >=24 months, for which Spearman's correlation coefficients of 0.74-0.76 were achieved for alpha/beta of 20 Gy, 30 Gy, and 50 Gy (P = 0.007-0.008). A trend toward statistical significance was observed for the correlation of isocenter BED and the 2-year overall survival when an alpha/beta of 20 Gy was used approached statistical significance (P = 0.073). Our results suggest that an alpha/beta > 10 Gy may be more appropriate for the prediction of dose response in the setting of lung SBRT. PMID- 24350268 TI - The continuing debate on deep molluscan phylogeny: evidence for Serialia (Mollusca, Monoplacophora + Polyplacophora). AB - Molluscs are a diverse animal phylum with a formidable fossil record. Although there is little doubt about the monophyly of the eight extant classes, relationships between these groups are controversial. We analysed a comprehensive multilocus molecular data set for molluscs, the first to include multiple species from all classes, including five monoplacophorans in both extant families. Our analyses of five markers resolve two major clades: the first includes gastropods and bivalves sister to Serialia (monoplacophorans and chitons), and the second comprises scaphopods sister to aplacophorans and cephalopods. Traditional groupings such as Testaria, Aculifera, and Conchifera are rejected by our data with significant Approximately Unbiased (AU) test values. A new molecular clock indicates that molluscs had a terminal Precambrian origin with rapid divergence of all eight extant classes in the Cambrian. The recovery of Serialia as a derived, Late Cambrian clade is potentially in line with the stratigraphic chronology of morphologically heterogeneous early mollusc fossils. Serialia is in conflict with traditional molluscan classifications and recent phylogenomic data. Yet our hypothesis, as others from molecular data, implies frequent molluscan shell and body transformations by heterochronic shifts in development and multiple convergent adaptations, leading to the variable shells and body plans in extant lineages. PMID- 24350267 TI - Acoustic droplet vaporization in biology and medicine. AB - This paper reviews the literature regarding the use of acoustic droplet vaporization (ADV) in clinical applications of imaging, embolic therapy, and therapeutic delivery. ADV is a physical process in which the pressure waves of ultrasound induce a phase transition that causes superheated liquid nanodroplets to form gas bubbles. The bubbles provide ultrasonic imaging contrast and other functions. ADV of perfluoropentane was used extensively in imaging for preclinical trials in the 1990s, but its use declined rapidly with the advent of other imaging agents. In the last decade, ADV was proposed and explored for embolic occlusion therapy, drug delivery, aberration correction, and high intensity focused ultrasound (HIFU) sensitization. Vessel occlusion via ADV has been explored in rodents and dogs and may be approaching clinical use. ADV for drug delivery is still in preclinical stages with initial applications to treat tumors in mice. Other techniques are still in preclinical studies but have potential for clinical use in specialty applications. Overall, ADV has a bright future in clinical application because the small size of nanodroplets greatly reduces the rate of clearance compared to larger contrast agent bubbles and yet provides the advantages of ultrasonographic contrast, acoustic cavitation, and nontoxicity of conventional perfluorocarbon contrast agent bubbles. PMID- 24350269 TI - Enhancement of oxygen mass transfer and gas holdup using palm oil in stirred tank bioreactors with xanthan solutions as simulated viscous fermentation broths. AB - Volumetric mass transfer coefficient (kLa) is an important parameter in bioreactors handling viscous fermentations such as xanthan gum production, as it affects the reactor performance and productivity. Published literatures showed that adding an organic phase such as hydrocarbons or vegetable oil could increase the kLa. The present study opted for palm oil as the organic phase as it is plentiful in Malaysia. Experiments were carried out to study the effect of viscosity, gas holdup, and kLa on the xanthan solution with different palm oil fractions by varying the agitation rate and aeration rate in a 5 L bench-top bioreactor fitted with twin Rushton turbines. Results showed that 10% (v/v) of palm oil raised the kLa of xanthan solution by 1.5 to 3 folds with the highest kLa value of 84.44 h(-1). It was also found that palm oil increased the gas holdup and viscosity of the xanthan solution. The kLa values obtained as a function of power input, superficial gas velocity, and palm oil fraction were validated by two different empirical equations. Similarly, the gas holdup obtained as a function of power input and superficial gas velocity was validated by another empirical equation. All correlations were found to fit well with higher determination coefficients. PMID- 24350270 TI - Acid lipase from Candida viswanathii: production, biochemical properties, and potential application. AB - Influences of environmental variables and emulsifiers on lipase production of a Candida viswanathii strain were investigated. The highest lipase activity (101.1 U) was observed at 210 rpm, pH 6.0, and 27.5 degrees C. Other fermentation parameters analyzed showed considerable rates of biomass yield (Y L/S = 1.381 g/g), lipase yield (Y L/S = 6.892 U/g), and biomass productivity (P X = 0.282 g/h). Addition of soybean lecithin increased lipase production in 1.45-fold, presenting lipase yield (Y L/S ) of 10.061 U/g. Crude lipase presented optimal activity at acid pH of 3.5, suggesting a new lipolytic enzyme for this genus and yeast in general. In addition, crude lipase presented high stability in acid conditions and temperature between 40 and 45 degrees C, after 24 h of incubation in these temperatures. Lipase remained active in the presence of organic solvents maintaining above 80% activity in DMSO, methanol, acetonitrile, ethanol, acetone, 1-propanol, isopropanol, and 2-propanol. Effectiveness for the hydrolysis of a wide range of natural triglycerides suggests that this new acid lipase has high potential application in the oleochemical and food industries for hydrolysis and/or modification of triacylglycerols to improve the nutritional properties. PMID- 24350271 TI - The importance and perspective of magnetic resonance imaging in the evaluation of endometriosis. AB - MR imaging is becoming increasingly important in the assessment of patients with endometriosis. Its multiplanar capabilities and superior soft tissue contrast are particularly useful in the detection of deep infiltrating endometriotic implants. Endometriosis, defined as the presence of endometrial glands and stroma outside the endometrium, is among the most common gynaecological disorders affecting women in their reproductive age. The diagnosis and evaluation of the extension of endometriosis are difficult only with physical examination and laparoscopy. According to the authors' personal experience, a special MRI technique and some imaging guidelines regarding different anatomical localizations of endometriosis are discussed. This review is a brief presentation of current evidence on the diagnostic accuracy of MRI in the evaluation of endometriosis concerning other diagnostic methods, the limitations of MRI and its essential usefulness for preoperative diagnosis of deep pelvic endometriosis, and future perspectives in monitoring this disease. PMID- 24350272 TI - An improved biometrics-based remote user authentication scheme with user anonymity. AB - The authors review the biometrics-based user authentication scheme proposed by An in 2012. The authors show that there exist loopholes in the scheme which are detrimental for its security. Therefore the authors propose an improved scheme eradicating the flaws of An's scheme. Then a detailed security analysis of the proposed scheme is presented followed by its efficiency comparison. The proposed scheme not only withstands security problems found in An's scheme but also provides some extra features with mere addition of only two hash operations. The proposed scheme allows user to freely change his password and also provides user anonymity with untraceability. PMID- 24350273 TI - Ligand-specific regulation of the endogenous mu-opioid receptor by chronic treatment with mu-opioid peptide agonists. AB - Since the discovery of the endomorphins (EM), the postulated endogenous peptide agonists of the mu-opioid receptors, several analogues have been synthesized to improve their binding and pharmacological profiles. We have shown previously that a new analogue, cis-1S,2R-aminocyclohexanecarboxylic acid(2)-endomorphin-2 (ACHC EM2), had elevated mu-receptor affinity, selectivity, and proteolytic stability over the parent compound. In the present work, we have studied its antinociceptive effects and receptor regulatory processes. ACHC-EM2 displayed a somewhat higher (60%) acute antinociceptive response than the parent peptide, EM2 (45%), which peaked at 10 min after intracerebroventricular (icv) administration in the rat tail-flick test. Analgesic tolerance developed to the antinociceptive effect of ACHC-EM2 upon its repeated icv injection that was complete by a 10-day treatment. This was accompanied by attenuated coupling of mu-sites to G-proteins in subcellular fractions of rat brain. Also, the density of mu-receptors was upregulated by about 40% in the light membrane fraction, with no detectable changes in surface binding. Distinct receptor regulatory processes were noted in subcellular fractions of rat brains made tolerant by the prototypic full mu agonist peptide, DAMGO, and its chloromethyl ketone derivative, DAMCK. These results are discussed in light of the recently discovered phenomenon, that is, the "so-called biased agonism" or "functional selectivity". PMID- 24350274 TI - Cytotoxicity and genotoxicity evaluation of organochalcogens in human leucocytes: a comparative study between ebselen, diphenyl diselenide, and diphenyl ditelluride. AB - Organochalcogens, particularly ebselen, have been used in experimental and clinical trials with borderline efficacy. (PhSe)2 and (PhTe)2 are the simplest of the diaryl dichalcogenides and share with ebselen pharmacological properties. In view of the concerns with the use of mammals in studies and the great number of new organochalcogens with potential pharmacological properties that have been synthesized, it becomes important to develop screening protocols to select compounds that are worth to be tested in vivo. This study investigated the possible use of isolated human white cells as a preliminary model to test organochalcogen toxicity. Human leucocytes were exposed to 5-50 MUM of ebselen, (PhSe)2, or (PhTe)2. All compounds were cytotoxic (Trypan's Blue exclusion) at the highest concentration tested, and Ebselen was the most toxic. Ebselen and (PhSe)2 were genotoxic (Comet Assay) only at 50 MUM, and (PhTe)2 at 5-50 MUM. Here, the acute cytotoxicity did not correspond with in vivo toxicity of the compounds. But the genotoxicity was in the same order of the in vivo toxicity to mice. These results indicate that in vitro genotoxicity in white blood cells should be considered as an early step in the investigation of potential toxicity of organochalcogens. PMID- 24350275 TI - Ropivacaine-induced contraction is attenuated by both endothelial nitric oxide and voltage-dependent potassium channels in isolated rat aortae. AB - This study investigated endothelium-derived vasodilators and potassium channels involved in the modulation of ropivacaine-induced contraction. In endothelium intact rat aortae, ropivacaine concentration-response curves were generated in the presence or absence of the following inhibitors: the nonspecific nitric oxide synthase (NOS) inhibitor N (omega) -nitro-L-arginine methyl ester (L-NAME), the neuronal NOS inhibitor N (omega) -propyl-L-arginine hydrochloride, the inducible NOS inhibitor 1400W dihydrochloride, the nitric oxide-sensitive guanylyl cyclase (GC) inhibitor ODQ, the NOS and GC inhibitor methylene blue, the phosphoinositide 3 kinase inhibitor wortmannin, the cytochrome p450 epoxygenase inhibitor fluconazole, the voltage-dependent potassium channel inhibitor 4-aminopyridine (4 AP), the calcium-activated potassium channel inhibitor tetraethylammonium (TEA), the inward-rectifying potassium channel inhibitor barium chloride, and the ATP sensitive potassium channel inhibitor glibenclamide. The effect of ropivacaine on endothelial nitric oxide synthase (eNOS) phosphorylation in human umbilical vein endothelial cells was examined by western blotting. Ropivacaine-induced contraction was weaker in endothelium-intact aortae than in endothelium-denuded aortae. L-NAME, ODQ, and methylene blue enhanced ropivacaine-induced contraction, whereas wortmannin, N (omega) -propyl-L-arginine hydrochloride, 1400W dihydrochloride, and fluconazole had no effect. 4-AP and TEA enhanced ropivacaine induced contraction; however, barium chloride and glibenclamide had no effect. eNOS phosphorylation was induced by ropivacaine. These results suggest that ropivacaine-induced contraction is attenuated primarily by both endothelial nitric oxide and voltage-dependent potassium channels. PMID- 24350276 TI - Effects of seawater salinity and temperature on growth and pigment contents in Hypnea cervicornis J. Agardh (Gigartinales, Rhodophyta). AB - This study simulated outdoor environmental living conditions and observed the growth rates and changes of several photosynthetic pigments (Chl a, Car, PE, and PC) in Hypnea cervicornis J. Agardh (Gigartinales, Rhodophyta) by setting up different ranges of salinity (25, 30, 35, 40, 45, and 50) and temperature (15, 20, 25, and 30 degrees C). At conditions of culture, the results are as follows. (1) Changes in salinity and temperature have significant effects on the growth of H. cervicornis. The growth rates first increase then decrease as the temperature increases, while growth tends to decline as salinity increases. The optimum salinity and temperature conditions for growth are 25 and 25 degrees C, respectively. (2) Salinity and temperature have significant or extremely significant effects on photosynthetic pigments (Chl a, Car, PE, and PC) in H. cervicornis. The results of this study are advantageous to ensure propagation and economic development of this species in the southern sea area of China. PMID- 24350277 TI - Purification and characterization of tannin acyl hydrolase produced by mixed solid state fermentation of wheat bran and marigold flower by Penicillium notatum NCIM 923. AB - Tannin acyl hydrolase produced extracellularly by the fungal strain Penicillium notatum NCIM 923 in mixed solid state fermentation of wheat bran and marigold flower in the ratio 4 : 1 was purified from the cell-free extract broth by ammonium sulphate fractionation followed by diethylaminoethyl-cellulose column chromatography. Tannase was purified by 19.89-fold with yield of 11.77%. The specific activity of crude tannase was found to be 1.31 U/mg protein while that of purified tannase was 22.48 U/mg protein. SDS-PAGE analysis indicated that the enzyme is dimeric with one major band of molecular mass 97 kDa and a very light band of molecular mass 43 kDa. Temperature of 35 to 40 degrees C and pH 5 were optimum for tannase activity. The enzyme retained more than 60% of its stability at 60 degrees C and 40% stability at pH 3 and 8, respectively. K m was found to be 0.33 * 10(-2) M and V max = 40 U/mg. Since the enzyme is active over a wide range of pH and temperature, it could find potential use in the food processing industry. PMID- 24350278 TI - Immunohistochemical analysis of P63 expression in odontogenic lesions. AB - P63 may have a role in tumorigenesis and cytodifferentiation of odontogenic lesions. We investigated the immunohistochemical expression of P63 in a total of 30 cases of odontogenic cysts and tumors. The percentage of positive cells was calculated in the lining of odontogenic cysts and islands of ameloblastoma. P63 expression was evident in all types of odontogenic lesions. P63 was expressed throughout the lining epithelium of odontogenic keratocyst except surface parakeratinized layer. In addition, calcifying odontogenic cyst showed P63 expression in all layers. In almost all radicular and dentigerous cysts, the basal and parabasal layers were immunoreactive. Peripheral cells of ameloblastoma expressed P63; however, stellate reticulum had weaker immunostaining. No significant difference in P63 expression was observed between studied lesions (P = 0.86). Expression of P63 in odontogenic lesions suggests that this protein is important in differentiation and proliferation of odontogenic epithelial cells. However, it seems that it could not be a useful marker to differentiate between aggressive and nonaggressive lesions. P63 also represents a progenitor or basal cell marker, and it is not expressed in mature differentiated cells. PMID- 24350279 TI - Association of CILP2 and ACE gene polymorphisms with cardiovascular risk factors in Slovak midlife women. AB - The aim of this study is to assess the association of two polymorphisms, the cartilage intermediate layer protein 2 (CILP2) G/T and angiotensin converting enzyme (ACE) I/D, with blood pressure and anthropometrical and biochemical parameters related to the development of cardiovascular disease. The entire study sample comprised 341 women ranging in age from 39 to 65 years. The CILP2 genotypes were determined by PCR-RFLP and the ACE genotypes by PCR. The Bonferroni pairwise comparisons showed the effect of the CILP2 genotype on high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL C), apolipoprotein B (apoB), apoB-to-apoA1 ratio, the total cholesterol (TC)-to HDL-C ratio, non-HDL-C, and the LDL-C-to-HDL-C ratio (P < 0.05). Here, higher mean levels of HDL-C and lower mean levels of the remaining above mentioned lipid parameters were registered in the GT/TT genotype carriers than in GG carriers. Statistically significant association was identified between the ACE genotype and the following parameters: TC, LDL-C, and non-HDL-C (P < 0.05). The II genotype can lower serum level of TC (B = 0.40), LDL-C (B = 0.37), and non-HDL-C levels. The results of this study suggest that the minor T allele of CILP2 gene and I allele of ACE gene have a protective effect against elevated serum lipid and lipoprotein levels. PMID- 24350280 TI - Expression sensitivity analysis of human disease related genes. AB - Background. Genome-wide association studies (GWAS) have shown its revolutionary power in seeking the influenced loci on complex diseases genetically. Thousands of replicated loci for common traits are helpful in diseases risk assessment. However it is still difficult to elucidate the variations in these loci that directly cause susceptibility to diseases by disrupting the expression or function of a protein currently. Results. We evaluate the expression features of disease related genes and find that different diseases related genes show different expression perturbation sensitivities in various conditions. It is worth noting that the expression of some robust disease-genes doesn't show significant change in their corresponding diseases, these genes might be easily ignored in the expression profile analysis. Conclusion. Gene ontology enrichment analysis indicates that robust disease-genes execute essential function in comparison with sensitive disease-genes. The diseases associated with robust genes seem to be relatively lethal like cancer and aging. On the other hand, the diseases associated with sensitive genes are apparently nonlethal like psych and chemical dependency diseases. PMID- 24350281 TI - Ultraviolet-visible and fluorescence spectroscopy techniques are important diagnostic tools during the progression of atherosclerosis: diet zinc supplementation retarded or delayed atherosclerosis. AB - BACKGROUND: In this study, we examined whether UV-visible and fluorescence spectroscopy techniques detect the progression of atherosclerosis in serum of rabbits fed on high-cholesterol diet (HCD) and HCD supplemented with zinc (HCD + Zn) compared with the control. METHODS: The control rabbits group was fed on 100 g/day of normal diet. The HCD group was fed on Purina Certified Rabbit Chow supplemented with 1.0% cholesterol plus 1.0% olive oil (100 g/day) for the same period. The HCD + Zn group was fed on normal Purina Certified Rabbit Chow plus 1.0% cholesterol and 1.0% olive oil supplemented with 470 ppm Zn for the same feeding period. UV-visible and fluorescence spectroscopy and biochemistry in Rabbit's blood serum and blood hematology were measured in Rabbit's blood. RESULTS: We found that the fluorescent peak of HCD shifted toward UV-visible wavelength compared with the control using fluorescent excitation of serum at 192 nm. In addition, they showed that supplementation of zinc (350 ppm) restored the fluorescent peak closely to the control. By using UV-visible spectroscopy approach, we found that the peak absorbance of HCD (about 280 nm) was higher than that of control and that zinc supplementation seemed to decrease the absorbance. CONCLUSIONS: This study demonstrates that ultraviolet-visible and fluorescence spectroscopy techniques can be applied as noninvasive techniques on a sample blood serum for diagnosing or detecting the progression of atherosclerosis. The Zn supplementation to rabbits fed on HCD delays or retards the progression of atherosclerosis. Inducing anemia in rabbits fed on HCD delays the progression of atherosclerosis. PMID- 24350282 TI - P-glycoprotein-activity measurements in multidrug resistant cell lines: single cell versus single-well population fluorescence methods. AB - BACKGROUND: P-gp expression has been linked to the efflux of chemotherapeutic drugs in human cancers leading to multidrug resistance. Fluorescence techniques have been widely applied to measure the P-gp activity. In this paper, there is a comparison between the advantages of two fluorescence approaches of commonly available and affordable instruments: the microplate reader (MPR) and the flow cytometer to detect the P-gp efflux activity using calcein-AM. RESULTS: The selectivity, sensibility, and reproducibility of the two methods have been defined. Our results showed that the MPR is more powerful for the detection of small inhibition, whereas the flow cytometry method is more reliable at higher concentrations of the inhibitors. We showed that to determine precisely the inhibition efficacy the flow cytometry is better; hence, to get the correct E max and EC50 values, we cannot only rely on the MPR. CONCLUSION: Both techniques can potentially be used extensively in the pharmaceutical industry for high throughput drug screening and in biology laboratories for academic research, monitoring the P-gp efflux in specific assays. PMID- 24350283 TI - Role of intracellular Ca2+ and Na+/Ca2+ exchanger in the pathogenesis of contrast induced acute kidney injury. AB - The precise mechanisms underlying contrast-induced acute kidney injury (CI-AKI) are not well understood. Intracellular Ca(2+) overload is considered to be a key factor in CI-AKI. Voltage-dependent Ca(2+) channel (VDC) and Na(+)/Ca(2+) exchanger (NCX) system are the main pathways of intracellular Ca(2+) overload in pathological conditions. Here, we review the potential underlying mechanisms involved in CI-AKI and discuss the role of NCX-mediated intracellular Ca(2+) overload in the contrast media-induced renal tubular cell injury and renal hemodynamic disorder. PMID- 24350284 TI - Changes of regulatory T and B cells in patients with papillary thyroid carcinoma after 131I radioablation: a preliminary study. AB - Introduction. Lymphocytic infiltration and specific lymphocytes subsets may play important roles in papillary thyroid carcinoma (PTC) progression and prognosis. In this study, we try to understand the influence of (131)I radioablation on the important lymphocytes subtypes of regulatory T and B cells (Tregs and Bregs). Methods. Peripheral blood mononuclear cells from 30 PTC patients before and after (131)I therapy, and 20 healthy donors were collected. The expression of Tregs (CD4(+)CD25(+)CD127(-/low)) and B cell (CD5(+)CD19(+)) and production and secretion of interleukin 10 (IL-10) were analyzed by FACS and ELISA assay, respectively. Results. For Tregs percentage in peripheral blood lymphocytes, there was no difference between pretreatment and control and between posttreatment and control. Compared with pretherapy, increased Tregs infiltration was noted in posttherapy (P < 0.05). Although no difference was between pretreatment and control, compared with these two groups, decreased CD19(+) and CD5(+)CD19(+) B cell percentage in posttreatment was observed (P < 0.05). Among these groups, no significant difference was displayed in intracellular IL-10 production and extracellular IL-10 secretion. Conclusions. (131)I Radioablation increased Tregs and decreased CD19(+) and CD5(+)CD19(+) B cells percentage after treatment. However, it has no effect on IL-10 and lymphocytes in peripheral blood. Therefore, longer follow-up of Tregs and Bregs should be further investigated. PMID- 24350285 TI - Usefulness of traditional serum biomarkers for management of breast cancer patients. AB - The measurement of serum tumor markers levels in breast cancer (BC) patients is an economic and noninvasive diagnostic assay frequently requested by clinical oncologists to get information about the presence or absence of disease as well as its evolution. Despite their wide use in clinical practice, there is still an intense debate between scientific organizations about the real usefulness for patient monitoring during followup as well as response to therapy evaluation in case of advanced BC. In this review, we want to highlight the current recommendations published by scientific organizations about the use of "established" BC serum markers (CEA, TPA, TPS, CIFRA-21, CA15-3, and s-HER2) in clinical oncology practice. Moreover, we will focus on recent papers evidencing the usefulness of tumor markers levels measurement as a guide for the prescription and diagnostic integration of molecular imaging exams such as those performed by hybrid 18-fluorofeoxyglucose-positron emission tomography with integrated computed tomography. This technology is nowadays able to detect early cancer lesions undetectable by conventional morphological imaging investigation and most likely responsible for increasing of serum tumor markers levels. PMID- 24350286 TI - A systems' biology approach to study microRNA-mediated gene regulatory networks. AB - MicroRNAs (miRNAs) are potent effectors in gene regulatory networks where aberrant miRNA expression can contribute to human diseases such as cancer. For a better understanding of the regulatory role of miRNAs in coordinating gene expression, we here present a systems biology approach combining data-driven modeling and model-driven experiments. Such an approach is characterized by an iterative process, including biological data acquisition and integration, network construction, mathematical modeling and experimental validation. To demonstrate the application of this approach, we adopt it to investigate mechanisms of collective repression on p21 by multiple miRNAs. We first construct a p21 regulatory network based on data from the literature and further expand it using algorithms that predict molecular interactions. Based on the network structure, a detailed mechanistic model is established and its parameter values are determined using data. Finally, the calibrated model is used to study the effect of different miRNA expression profiles and cooperative target regulation on p21 expression levels in different biological contexts. PMID- 24350287 TI - Prooxidant mechanisms in iron overload cardiomyopathy. AB - Iron overload cardiomyopathy (IOC), defined as the presence of systolic or diastolic cardiac dysfunction secondary to increased deposition of iron, is emerging as an important cause of heart failure due to the increased incidence of this disorder seen in thalassemic patients and in patients of primary hemochromatosis. At present, although palliative treatment by regular iron chelation was recommended; whereas IOC is still the major cause for mortality in patient with chronic heart failure induced by iron-overloading. Because iron is a prooxidant and the associated mechanism seen in iron-overload heart is still unclear; therefore, we intend to delineate the multiple signaling pathways involved in IOC. These pathways may include organelles such as calcium channels, mitochondria; paracrine effects from both macrophages and fibroblast, and novel mediators such as thromboxane A2 and adiponectin; with increased oxidative stress and inflammation found commonly in these signaling pathways. With further understanding on these complex and inter-related molecular mechanisms, we can propose potential therapeutic strategies to ameliorate the cardiac toxicity induced by iron-overloading. PMID- 24350288 TI - MHC universal cells survive in an allogeneic environment after incompatible transplantation. AB - Cell, tissue, and organ transplants are commonly performed for the treatment of different diseases. However, major histocompatibility complex (MHC) diversity often prevents complete donor-recipient matching, resulting in graft rejection. This study evaluates in a preclinical model the capacity of MHC class I-silenced cells to engraft and grow upon allogeneic transplantation. Short hairpin RNA targeting beta2-microglobulin (RN_shbeta2m) was delivered into fibroblasts derived from LEW/Ztm (RT1(l)) (RT1-A(l)) rats using a lentiviral-based vector. MHC class I (RT1-A-) expressing and -silenced cells were injected subcutaneously in LEW rats (RT1(l)) and MHC-congenic LEW.1W rats (RT1(u)), respectively. Cell engraftment and the status of the immune response were monitored for eight weeks after transplantation. In contrast to RT1-A-expressing cells, RT1-A-silenced fibroblasts became engrafted and were still detectable eight weeks after allogeneic transplantation. Plasma levels of proinflammatory cytokines IL-1 alpha , IL-1 beta , IL-6, TNF- alpha , and IFN- gamma were significantly higher in animals transplanted with RT1-A-expressing cells than in those receiving RT1-A silenced cells. Furthermore, alloantigen-specific T-cell proliferation rates derived from rats receiving RT1-A-expressing cells were higher than those in rats transplanted with RT1-A-silenced cells. These data suggest that silencing MHC class I expression might overcome the histocompatibility barrier, potentially opening up new avenues in the field of cell transplantation and regenerative medicine. PMID- 24350289 TI - Identifying breast cancer subtype related miRNAs from two constructed miRNAs interaction networks in silico method. AB - BACKGROUND: It has been known that microRNAs (miRNAs) regulate the expression of multiple proteins and therefore are likely to emerge as more effective targets of selective therapeutic modalities for breast cancer. Although recent lines of evidence have approved that miRNAs are associated with the most common molecular breast cancer subtypes, the studies to breast cancer subtypes have not been well characterized. OBJECTIVES: In this study, we propose a silico method to identify breast cancer subtype related miRNAs based on two constructed miRNAs interaction networks using miRNA-mRNA dual expression profiling data arising from the same samples. METHODS: Firstly, we used a new mutual information estimation method to construct two miRNAs interaction networks based on miRNA-mRNA dual expression profiling data. Secondly, we compared and analyzed the topological properties of these two networks. Finally, miRNAs showing the outstanding topological properties in both of the two networks were identified. Results. Further functional analysis and literature evidence confirm that the identified potential breast cancer subtype related miRNAs are essential to unraveling their biological function. CONCLUSIONS: This study provides a new silico method to predict candidate miRNAs of breast cancer subtype from a system biology level and can help exploit for functional studies of important breast cancer subtype related miRNAs. PMID- 24350290 TI - Parthenium hysterophorus: a probable source of anticancer, antioxidant and anti HIV agents. AB - The present work reports the anticancer, antioxidant, lipo-protective, and anti HIV activities of phytoconstituents present in P. hysterophorus leaf. Dried leaf samples were sequentially extracted with nonpolar and polar solvents. Ethanol fraction showed noticeable cytotoxic activity (81-85%) in SRB assay against MCF-7 and THP-1 cancer cell lines at 100 MUg/ml concentration, while lower activity was observed with DU-145 cell line. The same extract exhibited 17-98% growth inhibition of HL-60 cancer cell lines in MTT assay, showing concentration dependent response. Ethanol extract caused 12% reduction in mitochondrial membrane potential and 10% increment in sub G1 population of HL-60 cell lines. Several leaf fractions, namely, ethyl acetate, ethanol, and aqueous fractions exhibited considerable reducing capability at higher concentrations. Most of the extracts demonstrated appreciable (>75%) metal ion chelating and hydroxyl radical scavenging activities at 200 ug/ml. All the extracts except aqueous fraction accounted for about 70-80% inhibition of lipid peroxidation in rat liver homogenate indicating protective response against membrane damage. About 40% inhibition of reverse transcriptase (RT) activity was observed in hexane fraction in anti-HIV assay at 6.0 ug/ml concentration. The study showed that phytochemicals present in P. hysterophorus leaf have considerable potential as cytotoxic and antioxidant agents with low to moderate anti-HIV activity. PMID- 24350292 TI - Integration of data from omic studies with the literature-based discovery towards identification of novel treatments for neovascularization in diabetic retinopathy. AB - Diabetic retinopathy (DR) is a secondary complication of diabetes associated with retinal neovascularization and represents the leading cause of blindness in the adult population in the developed world. Despite research efforts, the nature of pathogenetic processes leading to DR is still unknown, making development of novel effective treatments difficult. Advances in omic technologies now offer unprecedented insight into global molecular alterations in DR, but identification of novel treatments based on massive amounts of data generated in omic studies still represents a considerable challenge. For this reason, we attempted to facilitate discovery of novel treatments for DR by complementing the interpretation of omic results using the vast body of information existing in the published literature with the literature-based discovery (LBD) approaches. To achieve this, we collected data from transcriptomic studies performed on retinal tissue from animal models of DR, performed a meta-analysis of these datasets and identified altered genes and pathways. Using the SemBT LBD framework, we have determined which therapies could regulate perturbed pathways or that could stabilize the gene expression alterations in DR. We show that by using this approach, we not only could reidentify drugs currently in use or in clinical trials, but also could indicate novel treatment directions for ameliorating neovascularization processes in DR. PMID- 24350291 TI - Tumor necrosis factor receptor 2: its contribution to acute cellular rejection and clear cell renal carcinoma. AB - Tumor necrosis factor receptor 2 (TNFR2) is a type I transmembrane glycoprotein and one of the two receptors that orchestrate the complex biological functions of tumor necrosis factor (TNF, also designed TNF- alpha ). Accumulating experimental evidence suggests that TNFR2 plays an important role in renal disorders associated with acute cellular rejection and clear cell renal carcinoma but its exact role in these settings is still not completely understood. This papers reviews the factors that may mediate TNFR2 induction in acute cellular rejection and clear cell renal carcinoma and its contribution to these conditions and discusses its therapeutic implications. A greater understanding of the function of TNFR2 may lead to the development of new anti-TNF drugs. PMID- 24350293 TI - Treatment of Chagas cardiomyopathy. AB - Chagas' disease (ChD), caused by the protozoa Trypanosoma cruzi (T. cruzi), was discovered and described by the Brazilian physician Carlos Chagas in 1909. After a century of original description, trypanosomiasis still brings much misery to humanity and is classified as a neglected tropical disease prevalent in underdeveloped countries, particularly in South America. It is an increasing worldwide problem due to the number of cases in endemic areas and the migration of infected subjects to more developed regions, mainly North America and Europe. Despite its importance, chronic chagas cardiomyopathy (CCC) pathophysiology is yet poorly understood, and independently of its social, clinical, and epidemiological importance, the therapeutic approach of CCC is still transposed from the knowledge acquired from other cardiomyopathies. Therefore, the objective of this review is to describe the treatment of Chagas cardiomyopathy with emphasis on its peculiarities. PMID- 24350295 TI - Depletion of luminal pyridine nucleotides in the endoplasmic reticulum activates autophagy with the involvement of mTOR pathway. AB - It has been recently shown that redox imbalance of luminal pyridine nucleotides in the endoplasmic reticulum (ER) together with oxidative stress results in the activation of autophagy. In the present study we demonstrated that decrease of luminal NADPH/NADP(+) ratio alone by metyrapone was sufficient to promote the mechanism of "self-eating" detected by the activation of LC3. Depletion of luminal NADPH had also significant effect on the key proteins of mTOR pathway, which got inactivated by dephosphorylation. These findings were also confirmed by silencing the proteins (glucose-6-phosphate transporter and hexose-6-phosphate dehydrogenase) responsible for NADPH generation in the ER lumen. However, silencing the key components and addition of metyrapone had different effects on downstream substrates 4EBP1 and p70S6K of mTOR. The applied treatments did not compromise the viability of the cells. Our data suggest that ER stress caused by luminal NADPH depletion activates a pro-survival autophagic mechanism firmly coupled to the activation of mTOR pathway. PMID- 24350294 TI - From single nucleotide polymorphisms to constant immunosuppression: mesenchymal stem cell therapy for autoimmune diseases. AB - The regenerative abilities and the immunosuppressive properties of mesenchymal stromal cells (MSCs) make them potentially the ideal cellular product of choice for treatment of autoimmune and other immune mediated disorders. Although the usefulness of MSCs for therapeutic applications is in early phases, their potential clinical use remains of great interest. Current clinical evidence of use of MSCs from both autologous and allogeneic sources to treat autoimmune disorders confers conflicting clinical benefit outcomes. These varied results may possibly be due to MSC use across wide range of autoimmune disorders with clinical heterogeneity or due to variability of the cellular product. In the light of recent genome wide association studies (GWAS), linking predisposition of autoimmune diseases to single nucleotide polymorphisms (SNPs) in the susceptible genetic loci, the clinical relevance of MSCs possessing SNPs in the critical effector molecules of immunosuppression is largely undiscussed. It is of further interest in the allogeneic setting, where SNPs in the target pathway of MSC's intervention may also modulate clinical outcome. In the present review, we have discussed the known critical SNPs predisposing to disease susceptibility in various autoimmune diseases and their significance in the immunomodulatory properties of MSCs. PMID- 24350296 TI - Use of Frankia and actinorhizal plants for degraded lands reclamation. AB - Degraded lands are defined by soils that have lost primary productivity due to abiotic or biotic stresses. Among the abiotic stresses, drought, salinity, and heavy metals are the main threats in tropical areas. These stresses affect plant growth and reduce their productivity. Nitrogen-fixing plants such as actinorhizal species that are able to grow in poor and disturbed soils are widely planted for the reclamation of such degraded lands. It has been reported that association of soil microbes especially the nitrogen-fixing bacteria Frankia with these actinorhizal plants can mitigate the adverse effects of abiotic and biotic stresses. Inoculation of actinorhizal plants with Frankia significantly improves plant growth, biomass, shoot and root N content, and survival rate after transplanting in fields. However, the success of establishment of actinorhizal plantation in degraded sites depends upon the choice of effective strains of Frankia. Studies related to the beneficial role of Frankia on the establishment of actinorhizal plants in degraded soils are scarce. In this review, we describe some examples of the use of Frankia inoculation to improve actinorhizal plant performances in harsh conditions for reclamation of degraded lands. PMID- 24350297 TI - Plasma levels of soluble HLA-E and HLA-F at diagnosis may predict overall survival of neuroblastoma patients. AB - The purpose of this study was to identify the plasma/serum biomarkers that are able to predict overall survival (OS) of neuroblastoma (NB) patients. Concentration of soluble (s) biomarkers was evaluated in plasma (sHLA-E, sHLA-F, chromogranin, and B7H3) or serum (calprotectin) samples from NB patients or healthy children. The levels of biomarkers that were significantly higher in NB patients were then analyzed considering localized or metastatic subsets. Finally, biomarkers that were significantly different in these two subsets were correlated with patient's outcome. With the exception of B7H3, levels of all molecules were significantly higher in NB patients than those in controls. However, only chromogranin, sHLA-E, and sHLA-F levels were different between patients with metastatic and localized tumors. sHLA-E and -F levels correlated with each other but not chromogranin. Chromogranin levels correlated with different event-free survival (EFS), whereas sHLA-E and -F levels also correlated with different OS. Association with OS was also detected considering only patients with metastatic disease. In conclusion, low levels of sHLA-E and -F significantly associated with worse EFS/OS in the whole cohort of NB patients and in patients with metastatic NB. Thus, these molecules deserve to be tested in prospective studies to evaluate their predictive power for high-risk NB patients. PMID- 24350298 TI - Levels of inflammatory cytokines in type 2 diabetes patients with different urinary albumin excretion rates and their correlation with clinical variables. AB - Although the pathogenetic mechanism of DN has not been elucidated, an inflammatory mechanism has been suggested as a potential contributor. This study was designed to explore the relationship between low-grade inflammation and renal microangiopathy in T2DM. A total of 261 diabetic subjects were divided into three groups according to UAE: a normal albuminuria group, a microalbuminuria group, and a macroalbuminuria group. A control group was also chosen. Levels of hs-CRP, TNF-alpha, uMCP-1, SAA, SCr, BUN, serum lipid, blood pressure, and HbA1c were measured in all subjects. Compared with the normal controls, levels of hs-CRP, TNF-alpha, uMCP-1, and SAA in T2DM patients were significantly higher. They were also elevated in the normal albuminuria group, P < 0.05. Compared with the normal albuminuria group, levels of these inflammatory cytokines were significantly higher in the microalbuminuria and macroalbuminuria group, P < 0.01. The macroalbuminuria group also showed higher levels than the microalbuminuria group, P < 0.01. Also they were positively correlated with UAE, SBP, DBP, LDL-C, and TC. We noted no significance correlated with course, TG, or HDL-C. Only TNF-alpha; was positively correlated with HbA1c. This study revealed the importance of these inflammatory cytokines in DN pathogenesis. Further studies are needed to fully establish the potential of these cytokines as additional biomarkers for the development of DN. PMID- 24350299 TI - Evaluation of the association of plasma pentraxin 3 levels with type 2 diabetes and diabetic nephropathy in a Malay population. AB - Recent reports have demonstrated that elevated plasma long pentraxin 3 (PTX3) levels are associated with cardiovascular and chronic kidney diseases. In the current study, we investigated the plasma PTX3 levels in 296 Malay subjects including the subjects with normal glucose tolerance (NGT) and type 2 diabetes (T2DM) patients with or without DN by using an enzyme-linked immune-sorbent assay. Results showed that in males, plasma PTX3 levels in T2DM patients without DN were lower than that in the subjects with NGT (2.78 versus 3.98 ng/mL; P = 0.021). Plasma PTX3 levels in T2DM patients with DN were decreased compared to the patients without DN (1.63 versus 2.78 ng/mL; P = 0.013). In females, however, no significant alteration of plasma PTX3 levels among NGT subjects and T2DM patients with and without DN was detected. Furthermore, an inverse correlation between PTX3 and body mass index was found in male subjects with NGT (P = 0.012; r = -0.390), but not in male T2DM patients, neither in all females. The current study provided the first evidence that decreased plasma PTX3 levels are associated with T2DM and DN in Malay men and also suggested that PTX3 may have different effects in DN and chronic kidney diseases. PMID- 24350300 TI - Relevance of plasma obestatin and early arteriosclerosis in patients with type 2 diabetes mellitus. AB - We investigated the correlation between obestatin and metabolic parameters and carotid intima-media thickness (IMT) in plasma of patients with type 2 diabetes mellitus (T2DM). We collected 103 patients aged from 60 to 83 years (69.26 +/- 5.83 years) form January, 2007 to May, 2009. All patients were divided into normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and T2DM according to the oral glucose tolerance test (OGTT). We found that higher levels of fasting insulin (Fins), fasting blood glucose, 2 h OGTT glucose, homeostasis model assessment of insulin resistance (HOMA-IR), low density lipoprotein cholesterol, glycated haemoglobin, and C-reactive protein (CRP), as well as lower obestatin level and higher intima-media thickness level (IMT), existed in T2DM group compared with NGT group and IGT group (P < 0.01). Also, obestatin level was independently associated with HOMA-IR and CRP, while IMT level was independently associated with HOMA-IR, triglyceride, Fins, and obestatin (P < 0.01), based on stepwise multiple regression analysis. Therefore, we deduced that the low level of plasma obestatin might be related to early arteriosclerosis in patients with T2DM via increasing IMT level, and elevated plasma obestatin levels might protect T2DM patients against carotid atherosclerosis to some extent. PMID- 24350301 TI - Correlation of abdominal fat distribution with different types of diabetes in a Chinese population. AB - To investigate abdominal fat distribution in Chinese subjects with diabetes and its correlation with different types of diabetes. A total of 176 diabetic subjects were enrolled, 92 with type 1 and 84 with type 2, with a mean age of 27.41 and 49.3 yrs. No subject has history of severe diseases. Multi-slice CT was used to measure total abdominal adipose (TA) and visceral adipose (VA) tissues. Subcutaneous adipose (SA) tissue was obtained by subtracting VA from TA. There were differences between subjects with T1DM and T2DM for TA, VA, SA, VA/SA, body mass index (BMI), triglyceride (TG) and high density lipoprotein, but not total Cholesterol or low density lipoprotein. There were positive correlations between TA, VA, SA, VA/SA and T1DM and T2DM (P < 0.05 and r > 0.86). In subjects with T1DM, VA was negatively correlated with HDL, positively with BMI and age, and SA was positively correlated with BMI and sex (P < 0.05 and r > 0.86 for all). In subjects with T2DM, VA was positively correlated to BMI, TG and age, and SA was positively correlated to TG and sex (P < 0.05 and r > 0.86 for all). Abdominal fat content was positively correlated to diabetes in Chinese, which differs in different types of diabetes. PMID- 24350302 TI - Seroprevalence of Brucellosis and Q-Fever in Southeast Ethiopian Pastoral Livestock. AB - To assess seroprevalences of Brucella and C. burnetii in pastoral livestock in southeast Ethiopia, a cross-sectional study was carried out in three livestock species (cattle, camels and goats). The study was conducted from July 2008 to August 2010, and eight pastoral associations (PAs) from the selected districts were included in the study. Sera from a total of 1830 animals, comprising 862 cattle, 458 camels and 510 goats were screened initially with Rose Bengal plate test (RBPT) for Brucella. All RBPT positive and 25% of randomly selected negative sera were further tested by ELISA. These comprise a total of 460 animals (211 cattle, 102 camels and 147 goats). Out of sera from total of 1830 animals, 20% were randomly selected (180 cattle, 90 camels and 98 goats) and tested for C. burnetii using ELISA. The seroprevalences of Brucella was 1.4% (95% confidence interval (CI), 0.8-2.6), 0.9% (95% CI, 0.3-2.7)b and 9.6% (95% CI, 5.2-17.1) in cattle, camels and goats, respectively. Goats and older animals were at higher risk of infection (OR=7.3, 95% CI, 2.8-19.1) and (OR=1.7 95% CI, 0.9-2.9), respectively. Out of 98 RBPT negative camel sera, 12.0% were positive for ELISA. The seroprevalences of C. burnetii were 31.6% (95% CI, 24.7-39.5), 90.0% (95% CI, 81.8-94.7) and 54.2% (95% CI, 46.1-62.1) in cattle, camels and goats, respectively. We found positive animals for C. burnetii test in all tested PAs for all animal species. Being camel and older animal was a risk factor for infection (OR=19.0, 95% CI, 8.9-41.2) and (OR=3.6, 95% CI, 2.0-6.6), respectively. High seropositivity of C. burnetii in all livestock species tested and higher seropositive in goats for Brucella, implies risks of human infection by both diseases. Thus, merit necessity of further study of both diseases in animals and humans in the area. PMID- 24350303 TI - A Novel Perspective on Dopaminergic Processing of Human Addiction. AB - Converging evidence from clinical, animal, and neuroimaging experiments suggests that the addictive behavior is associated with dysregulated dopamine neurotransmission. The precise role of dopamine in establishment and maintenance of addiction however is unclear. In this context animal studies on the brain reward system and the associative memory processing provide a novel insight. It was shown that both processing involve dopamine neurotransmission and both are disrupted in addiction. These findings indicate that dysregulated dopamine neurotransmission alters the brain processing of not only the reward system but also that of the memory of association between an addictive substance and reward. These alterations lead to maladaptive motivational behavior leading to chemical dependency. This concept however is based mostly on the data obtained in laboratory animals because of the paucity of human data. Due to lack of a reliable technique to study neurotransmission in the live human brain, it has been a problem to study the role of dopamine in human volunteers. A recently developed dynamic molecular imaging technique however, provides an opportunity to study these concepts in human volunteers because the technique allows detection, mapping and measurement of dopamine released in the live human brain during task performance. PMID- 24350304 TI - Unachievable Region in Precision-Recall Space and Its Effect on Empirical Evaluation. AB - Precision-recall (PR) curves and the areas under them are widely used to summarize machine learning results, especially for data sets exhibiting class skew. They are often used analogously to ROC curves and the area under ROC curves. It is known that PR curves vary as class skew changes. What was not recognized before this paper is that there is a region of PR space that is completely unachievable, and the size of this region depends only on the skew. This paper precisely characterizes the size of that region and discusses its implications for empirical evaluation methodology in machine learning. PMID- 24350305 TI - Design, expression and characterization of a highly stable tetratricopeptide based protein scaffold for phage display application. AB - Tetratricopeptide repeat (TPR) is a structural motif mediating variety of protein protein interactions. It has a high potential to serve as a small, stable and robust, non-immunoglobulin ligand binding scaffold. In this study, we showed the consensus approach to design the novel protein called designed tetratricopeptide repeat (dTPR), composed of three repeated 34 amino-acid tetratricopeptide motifs. The designed sequence was efficiently overexpressed in E. coli and purified to homogeneity. Recombinant dTPR is monomeric in solution and preserves its secondary structure within the pH range from 2.0 to 11.0. Its denaturation temperature at pH 7.5 is extremely high (104.5 degrees C) as determined by differential scanning calorimetry. At extreme pH values the protein is still very stable: denaturation temperature is 90.1 degrees C at pH 2.0 and 60.4 degrees C at pH 11. Chemical unfolding of the dTPR is a cooperative, two-state process both at pH 7.5 and 2.0. The free energy of denaturation in the absence of denaturant equals to 15.0 kcal/mol and 13.5 kcal/mol at pH 7.5 and 2.0, respectively. Efficient expression and extraordinary biophysical properties make dTPR a promising framework for a biotechnological application, such as generation of specific ligand- binding molecules. PMID- 24350306 TI - Personalization of structural PDB files. AB - PDB format is most commonly applied by various programs to define three dimensional structure of biomolecules. However, the programs often use different versions of the format. Thus far, no comprehensive solution for unifying the PDB formats has been developed. Here we present an open-source, Python-based tool called PDBinout for processing and conversion of various versions of PDB file format for biostructural applications. Moreover, PDBinout allows to create one's own PDB versions. PDBinout is freely available under the LGPL licence at http://pdbinout.ibch.poznan.pl. PMID- 24350307 TI - Evaluation of the activity of thermostable DNA polymerases in the presence of heme, as a key inhibitor in the real time PCR method in diagnostics of sepsis. AB - The study aim was evaluation of the usefulness of several thermostable DNA polymerases in real time PCR conducted in the presence of the heme. Our study had the advantage of testing several different polymerases, one of which proved to be the least sensitive to heme activity. We also found that there is no need of supplementing the reaction mixture with protective substances like BSA. Selection of the appropriate polymerase can increase the efficiency of the PCR reaction which is very important for diagnosis of sepsis and for other analyses performed on DNA template isolated from the blood. PMID- 24350308 TI - Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness. AB - Tetrahydrobiopterin (BH4) has been recently approved as a treatment of patients with phenylketonuria. However, as a confirmation of BH4-responsiveness, it might require a very expensive trial treatment with BH4 or prolonged BH4-loading procedures. The selection of patients eligible for BH4-therapy by means of genotyping of the PAH gene mutations may be recommended as a complementary approach. A population-wide genotyping study was carried out in 1286 Polish phenyloketonuria-patients. The aim was to estimate the BH4 demand and to cover prospectively the treatment by a National Health Fund. A total of 95 types of mutations were identified. Genetic variants corresponding with probable BH4 responsiveness were found in 28.2% of cases. However, patients with mild or classical phenylketonuria who require continuous treatment accounted for 11.4% of the studied population only. Analysis of the published data shows similar percentage of the "BH4-responsive" variants of a PAH gene in patients from other countries of Eastern Europe. Therefore, it can be concluded, that the proportion of phenylketonuria-patients who could benefit from the use of BH4 reaches approximately 10% in the entire region. PMID- 24350309 TI - Medical practice on Tristan da Cunha--the remotest island community in the world. AB - Midway between Africa and South America, on the edge of the 'roaring 40s' (37 degrees S 12 degrees W) is an archipelago of five tiny volcanic islands. Tristan, a British Overseas Territory, is the largest--seven miles across and rising 7,000 feet above sea level. There is no airport, no air access except for an occasional ship's helicopter and no sheltered anchorage. The nearest port is over 1,700 miles away--a week or more by ship and the tiny harbour requires constant repair due to the impact of the relentless South Atlantic. Ship-to-shore travel is hazardous as passengers (and medevacs) are transferred sitting in a box hoisted by crane to a raft or rigid inflatable boat. Tristan has traditionally had a resident 'ships surgeon' or 'island doctor'; although these terms may not have changed, the training and experience to fill these roles have. The island needs a general physician with experience of primary care or a general practitioner with experience of secondary care. Additional training is required in surgical and gynaecological emergencies. The two authors between them had appropriate experience in general medicine, general practice, resuscitation and critical care and to be able to worry together is a better prospect than worrying alone--so a joint appointment for six months seemed sensible and was found to be effective. PMID- 24350310 TI - Improving antimicrobial prescribing: implementation of an antimicrobial i.v.-to oral switch policy. AB - Antimicrobial stewardship programmes reduce the risk of hospital associated infections (HAI) and antimicrobial resistance, and include early intravenous-to oral switch (IVOS) as a key stewardship measure. We audited the number of patients on intravenous antimicrobials suitable for oral switch, assessed whether prescribing guidelines were followed and reviewed prescribing documentation in three clinical areas in the Western General Hospital, Edinburgh, in late 2012. Following this, the first cycle results and local guidelines were presented at a local level and at the hospital grand rounds, posters with recommendations were distributed, joint infection consult and antimicrobial rounds commenced and an alert antimicrobial policy was introduced before re-auditing in early 2013. We demonstrate suboptimal prescribing of intravenous antimicrobials, with 43.9% (43/98) of patients eligible for IVOS at the time of auditing. Only 56.1% (55/98) followed empiric prescribing recommendations. Documentation of antimicrobial prescribing was poor with stop dates recorded in 14.3%, indication on prescription charts in 18.4% and in the notes in 90.8%. The commonest reason for deferring IVOS was deteriorating clinical condition or severe sepsis. Further work to encourage prudent antimicrobial prescribing and earlier consideration of IVOS is required. PMID- 24350311 TI - Assessing frailty in the acute medical admission of elderly patients. AB - BACKGROUND: Managing acute admission of frail older patients is a challenge in hospitals. Length of inpatient stay, inpatient mortality and the 90-day readmission rate are significant in this group of patients. The Comprehensive Geriatric Assessment (CGA), a multidisciplinary diagnostic and treatment process, is the best approach for identifying medical conditions, mental health, functional capacity and social circumstances in acute geriatric care. METHODS: A review of the records of older patients aged 75 and over, acutely admitted to a district general hospital in England from 15 March 2012 to 16 April 2012 was conducted. We developed a frailty assessment tool and applied it to these patients, in order to determine who would be classified as frail. We then established if the patients meeting this criteria were then correctly assessed using the CGA. All patient data were processed and analysed using a statistical package for data analysis. RESULTS: A total of 232 patients with a mean age of 84.25 +/- 5.8 years were included. Out of these, 129 patients (55.6%) fulfilled the frailty criteria as determined with our frailty-assessment tool; 80.6% presented with lack of mobility over 24 hours, 69.8% were admitted with falls, 47.3% had known dementia or delirium and 45% were admitted from care homes. Patients aged over 85 years were more likely to have frailty compared with patients aged 75-85 years old (odds ratio [OR]: 4.78, 95% confidence interval [CI]: 2.6-8.6, p value >0.001). Patients assessed by a front door geriatric team were more likely to be reviewed with the CGA than those not seen by this team (adjusted OR 2.8, 95% CI: 1-7.6, p value=0.04). CONCLUSION: The prevalence of frailty is high in acute admissions of older patients and it is important that they are properly identified and assessed with a CGA in order to ensure effective multidisciplinary care. PMID- 24350312 TI - A case of Berardinelli-Seip syndrome presenting with cirrhosis. AB - Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare autosomal recessive disorder of generalised lipoatrophy, characterised by the absence of functioning adipocytes, with lipid being stored in muscles, the liver and the pancreas. The usual presentation is in adulthood, with manifestations of insulin resistance, hypertriglyceridaemia and liver steatosis. Cirrhosis as the first presentation of BSCL in a young adult is rare. We describe a patient with BSCL presenting with cirrhosis. To the best of our knowledge this is the first case of BSCL reported in a Sri Lankan patient. PMID- 24350313 TI - Granulomatous cheilitis. AB - A 19-year-old labourer presented with progressively worsening swelling of both lips. Clinical assessment and investigations led to the diagnosis of granulomatous cheilitis. PMID- 24350314 TI - Intensive lifestyle intervention has little effect on cardiovascular complications in people with type 2 diabetes. PMID- 24350315 TI - RCPE UK consensus conference on 'Acute medicine: improving quality of care through effective patient flow--it's everyone's business!'. PMID- 24350316 TI - Social media: the way forward or a waste of time for physicians? AB - Social media is everywhere; its use has grown exponentially over recent years. The prevalence of these outlets for communication raises some interesting and potentially risky issues for physicians. On the one hand, some believe that physicians should have a strong social media presence and can benefit greatly from access to a global community of peers and leaders through blogs, online forums, Facebook, Twitter and other communication channels. Dr Anne Marie Cunningham provides a strong case for the advantages of developing networks and figuring out who and what to pay attention to online. On the other hand however, others believe that the use of social media places doctors at a professional and ethical risk and is essentially a waste of time for the already time-pressured physician. Professor DeCamp argues that the risks of social media outweigh their benefits. It makes it more difficult to maintain a distinction between private and professional personas, and as we have seen, one mistyped or inappropriate comment can have potentially negative consequences when taken out of context. With an already time-pressured day, the priority should be patients, not tweets. Whatever your thoughts on the benefits and risks of social media, it is here to stay. Specific guidelines and guidance are needed to ensure that physicians who decide to join an online community reap the benefits of global communication, rather than regret it. PMID- 24350317 TI - Acute kidney injury. AB - Acute kidney injury (AKI) represents a medical emergency associated with poor clinical outcomes. The international guideline group Kidney Disease: Improving Global Outcomes (KDIGO) has defined AKI according to rises in serum creatinine and/or reductions in urine output. Any patient who meets the criteria for AKI should be reviewed to ascertain the cause of AKI and the severity of the injury should be staged. Patients with more severe AKI are at greater risk of progression to chronic kidney disease (CKD). The 2009 National Confidential Enquiry into Patient Outcomes and Death (NCEPOD) reported that only 50% of patients who died with a diagnosis with AKI received good care. The mortality from AKI has remained unchanged for the last four decades and there are currently no specific therapies for the majority of cases of AKI. Patients with rarer forms of AKI need urgent renal referral for specific therapy. At present, serum creatinine and urine output remain the best biomarkers for detecting AKI. However, significant kidney damage has usually occurred by the time changes in these biomarkers are manifest and newer biomarkers are under investigation. Management of AKI is based upon general supportive measures, which includes treatment of the underlying cause and the initiation of renal replacement therapy (RRT) in patients with complications refractory to medical management. The optimal choice of intravenous fluid therapy remains controversial. There is currently renewed interest in more specific therapies for AKI secondary to hypoperfusion and/or sepsis, which have been previously unsuccessful. A number of therapeutic strategies are presently being explored in clinical trials. PMID- 24350318 TI - Current practices in the management of diabetic nephropathy. AB - The social and economic burden of treating patients with diabetes mellitus (DM) is rapidly rising. Current projections estimate the global prevalence of individuals with DM to rise from 6.4% (285 million) in 2010 to 7.7% (439 million) in 2030.1 The main problem with this disease entity is its propensity to incur macro- and micro-vascular complications over time, including diabetic nephropathy (DN). Diabetic nephropathy affects approximately one-third of individuals with diabetes. It is the leading cause of end-stage renal disease (ESRD) worldwide, accounting for 42% of all patients on renal replacement therapy (RRT) in the United States.2 The magnitude of this problem has continued to grow in the face of an inexorable rise in the number of diabetic patients. The search for therapeutic modalities to stem this tide remains the quest of many nephrologists. One of the hallmarks of DN is increased urinary protein excretion, and microalbuminuria has long been proposed as an early manifestation of this disease.3,4 Albuminuria and chronic kidney disease (CKD) are strong determinants of cardiovascular disease and to a large extent, the survival of patients with DN is determined by cardiovascular morbidity. Although there remains no cure at present, treatment options to prevent or slow disease progression are available. In this update, we aim to address the current armamentarium in the management of DN. PMID- 24350319 TI - Psoriasis. AB - Psoriasis is a chronic, immune-mediated inflammatory skin disease affecting 1.3 2.2% of the UK population.1 Most commonly, psoriasis is characterised by well demarcated, red plaques with adherent scale with a predilection for the scalp and extensor surfaces of the limbs. However, the effects of psoriasis go far beyond a patient's skin and may result in a degree of disability and impaired quality of life similar to that of other major medical conditions, such as cancer and heart disease. First-line therapies for most patients are topical treatments such as topical corticosteroids and vitamin D analogues. For those with more severe or treatment-resistant disease, second- or third-line therapies include phototherapy, systemic therapies such as methotrexate and more recently biologic therapies such as tumour necrosis factor (TNF) inhibitors. These therapeutic modalities are proven to be highly effective; however, the potential for long term toxicity needs to be considered. Aside from the visible skin disease, psoriasis is also increasingly recognised to have important systemic manifestations. Psoriatic arthritis has long been established as an associated condition and, more recently, it has emerged that psoriasis is also associated with an increased risk of inflammatory bowel disease, cardiovascular disease and the metabolic syndrome. Both National Institute for Health and Care Excellence (NICE)2 and Scottish Intercollegiate Guidelines Network (SIGN)3 have recently published guidelines for the assessment and management of psoriasis which highlight the need for regular assessment in order to detect the development of arthritis and the presence of other co-morbidities such as obesity, diabetes, dyslipidaemia and hypertension. PMID- 24350320 TI - Predicting and preventing avoidable hospital admissions: a review. AB - The strongest risk factors for avoidable hospital admission are age and deprivation but ethnicity, distance to hospital, rurality, lifestyle and meteorological factors are also important, as well as access to primary care. There is still considerable uncertainty around which admissions are avoidable. In terms of services to reduce admissions there is evidence of effectiveness for education, self-management, exercise and rehabilitation, and telemedicine in certain patient populations, mainly respiratory and cardiovascular. Specialist heart failure services and end-of-life care also reduce these admissions. However, case management, specialist clinics, care pathways and guidelines, medication reviews, vaccine programmes and hospital at home do not appear to reduce avoidable admissions. There is insufficient evidence on the role of combinations or coordinated system-wide care services, emergency department interventions, continuity of care, home visits or pay-by-performance schemes. This highlights the importance of robust evaluation of services as they are introduced into health and social care systems. PMID- 24350321 TI - The 1918-19 influenza pandemic revisited. AB - The worldwide influenza outbreak of 1918-19 was a medical catastrophe, causing the deaths of around 50 million people. There is evidence however that the major wave, in November 1918, was not part of the pandemic that started in the summer of 1918. The virus responsible for the major wave has been isolated but the structural features responsible for its severity remain incompletely understood. In 1918-19 influenza was an infection so little understood that the government was unsure of what action to take. In contrast, during the pandemic starting in 2009, international and national bodies used many means of communication to keep the public fully informed, with beneficial results. In addition, antiviral agents, a vaccine and antibiotics to treat secondary infection were available. Such a response is possible only with appropriate funding and a comprehensive medical infrastructure, making the potential outbreak of severe influenza in a poor part of the world a matter of grave concern. PMID- 24350322 TI - Henry VIII, McLeod syndrome and Jacquetta's curse. AB - The mental decline of King Henry VIII from being a jovial, charismatic and athletic young man into an increasingly paranoid, brutal tyrant in later life, ever more concerned at his lack of one or more male heirs, has attracted many medical diagnostic theories. Previous hypotheses have included diabetes, syphilis and hypothyroidism, among others. However, these inadequately explain Henry's failure to produce a male heir, despite multiple pairings. The latest postulated diagnoses for Henry are the coexistence of both Kell blood group antigenicity (possibly inherited from Jacquetta Woodville, Henry's maternal great grandmother) causing related impaired fertility, and McLeod syndrome, causing psychotic changes. As the mutated McLeod protein of the syndrome significantly reduces the expression, effectively inactivating the Kell antigen, we critically review this theory, examining in detail the pathophysiology of these conditions and assessing the genealogy of Henry VIII and its effect in subsequent generations. PMID- 24350323 TI - James Taylor (1859-1946): favourite disciple of Hughlings Jackson and William Gowers. AB - In neurological circles today the name James Taylor (1859-1946) is probably remembered mainly for his role in editing the Selected Writings of John Hughlings Jackson, the most readily available source of Jackson's contributions to neurological knowledge. Taylors' own neurological achievements are largely or entirely forgotten, but in his day he was an influential figure whose career linked the great figures of the golden era of late nineteenth century British neurology to the neurology of the first half of the twentieth century. Not only was he a junior professional colleague and close friend of both John Hughlings Jackson and William Gowers, he also produced a substantial corpus of neurological writings in his own right, including a textbook of child neurology and the first English language account of subacute combined degeneration of the spinal cord. PMID- 24350324 TI - The eclipse and rehabilitation of JJR Macleod, Scotland's insulin laureate. AB - John JR Macleod (1876-1935,) an Aberdonian Scot who had emigrated to North America, shared the 1923 Nobel Prize with Frederick Banting for their discovery of insulin at the University of Toronto in 1921-22. Macleod finished his career as Regius Professor of Physiology at the University of Aberdeen from 1928 to 1935. Macleod's posthumous reputation was deeply tarnished by the campaigns against him carried out by his fellow laureate, Banting, and by Banting's student assistant during the insulin research, Charles Best. Banting's denigration of Macleod was based on their almost total personality conflict; Best's was based on a hunger for personal recognition. New research indicates how scarred both men were in their obsessions. The rehabilitation of Macleod's reputation, begun in 1982 with my book, The Discovery of Insulin, has continued in both scholarly and popular circles. By 2012, the ninetieth anniversary of the discovery of insulin, it had become complete both at the University of Toronto and in Canada. PMID- 24350325 TI - Peter Lowe's Whole course of chirurgerie... 1597. PMID- 24350326 TI - Diagnosing the dead. PMID- 24350327 TI - Fluorescence sensor for Cu(II) in the serum sample based on click chemistry. AB - Cu(II) can be reduced to Cu(I) by sodium ascorbate (SA) in situ, which in turn induces CuAAC reaction between the weak fluorescent compound (3-azido-7 hydroxycoumarin) and propargyl alcohol to form a strong fluorescent compound. Based on such principle, a simple and sensitive fluorescence sensor for Cu(II) can be developed, which combines the character of high selectivity of click chemistry and high sensitivity of fluorescence detection. The value of fluorescence increase factor shows a good linear relationship with the concentration of Cu(II) in the range of 0.25 MUM-2.5 MUM with a detection limit of 0.08 MUM. In addition, the developed sensor shows high selectivity towards Cu(II) assay even in the presence of other common metal ions and it has been successfully applied to detect Cu(II) in human serum with satisfactory results. PMID- 24350328 TI - ATR-FTIR spectroscopy as a tool to probe surface adsorption on nanoparticles at the liquid-solid interface in environmentally and biologically relevant media. AB - Given the importance of nanoparticle surface composition in nanotoxicology, analytical tools that can probe nanoparticle surfaces in aqueous media are crucial but remain limited. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy is a technique capable of in situ characterization of the liquid-solid interface to probe surface adsorption on nanoparticle surfaces in environmentally and biologically relevant media. Furthermore, given that the interfacial region in these media is dynamic, ATR FTIR spectroscopy facilitates monitoring these dynamics by interrogating a layer of immobilized nanoparticles coated on the ATR element while changing the overlying aqueous phase. The molecular information acquired from this technique allows for the determination of the adsorption mode, including conformational and structural changes of the coordinating ligand, and can directly measure ligand displacement reactions. Furthermore, in some cases, ATR-FTIR spectroscopy can be used as a quantitative surface analytical tool. In this article, we briefly review the fundamentals of the technique and then provide several examples of using ATR-FTIR spectroscopy to probe nanoparticle surfaces in general with respect to: (i) the adsorption of different environmentally and biologically relevant coordinating ligands; (ii) competitive ligand adsorption and; (iii) the determination of kinetic and thermodynamic parameters. We have also investigated surface adsorption of TiO2 nanoparticles in different biological media typically used for toxicity studies and show that the surface composition of TiO2 nanoparticles depends to a large extent on the composition of the medium due to surface adsorption. This result has important implications for the interpretation of toxicity data as well as inter-comparisons between toxicity studies. PMID- 24350329 TI - Negative area compressibility in silver(I) tricyanomethanide. AB - The molecular framework Ag(tcm) (tcm(-) = tricyanomethanide) expands continuously in two orthogonal directions under hydrostatic compression. The first of its kind, this negative area compressibility behaviour arises from the flattening of honeycomb-like layers during rapid pressure-driven collapse of the interlayer separation. PMID- 24350330 TI - Creation of artificial cellulosomes on DNA scaffolds by zinc finger protein guided assembly for efficient cellulose hydrolysis. AB - For the first time, artificial cellulosome structures were created on DNA scaffolds based on zinc finger protein (ZFP)-guided assembly. These resulting two component cellulosome structures exhibited enhancement in cellulose hydrolysis compared to the non-complexed mixture depending on the number of CBMs and cellulases assembled. PMID- 24350331 TI - New porphyrin derivatives for phosphate anion sensing in both organic and aqueous media. AB - New porphyrin-based anion receptors have been prepared from meso tetrakis(pentafluorophenyl)porphyrin () and diamine derivatives. These receptors (compounds ) interact preferentially with phosphate anions both in organic solutions and in basic aqueous media when coated on gold piezoelectric quartz crystals. A single crystal X-ray structure of the bis-HF complex of a imine derivative of was obtained; it serves to highlight the main interactions between the anion and cation receptors in the solid state. PMID- 24350332 TI - High rate sodium ion insertion into core-shell nanoparticles of Prussian blue analogues. AB - We demonstrate that core-shell nanoparticles consisting of two different Prussian blue analogues, one high capacity and the other robust, can provide enhanced rate capability as cathode materials in sodium-ion batteries. PMID- 24350333 TI - Tadpole pupil. PMID- 24350334 TI - Practice patterns for intraoperative neurophysiologic monitoring. PMID- 24350336 TI - Proceedings of the Third Annual RECOMB Satellite Workshop on Massively Parallel Sequencing (RECOMB-seq 2013), April 11-12, 2013, Beijing, China. PMID- 24350335 TI - Coordinating unspecified living kidney donation and transplantation across the blood-type barrier in kidney exchange. AB - BACKGROUND: This article studies multicenter coordination of unspecified living kidney donation and transplantation across the blood-type barrier in kidney exchange. Important questions are whether such coordination should use domino paired donation or non simultaneous extended altruistic donor chains, what the length of the segments in such chains should be, when they should be terminated, and how much time should be allowed between matching rounds. Furthermore, it is controversial whether the different modalities should be coordinated centrally or locally and independently. METHODS: Kidney exchange policies are simulated using actual data from the Dutch national kidney exchange program. Sensitivity analysis is performed on the composition of the population, the time unspecified and bridge donors wait before donating to the wait list, the time between matching rounds, and donor renege rates. RESULTS: Central coordination of unspecified donation and transplantation across the blood-type barrier can increase transplants by 10% (PG0.001). Especially highly sensitized and blood type O patients benefit. Sufficient time between matching rounds is essential: three monthly exchanges result in 31% more transplants than weekly exchanges. Benefits of non simultaneous extended altruistic donor chains are limited in case of low numbers of highly sensitized patients and sufficient unspecified donors. Chains are best terminated when no further segment is part of an optimal exchange within 3 months. CONCLUSIONS: There is clear synergy in the central coordination of both unspecified donation and transplantation across the blood-type barrier in kidney exchange. The best configuration of a national program depends on the composition of the patient Y donor population. PMID- 24350337 TI - Proceedings of the 11th OESO World Conference: Reflux disease, September 1-4, 2012, Como, Italy. PMID- 24350338 TI - Reply to Boslough et al.: Decades of comet research counter their claims. PMID- 24350339 TI - Reply to Subramaniam, van Heel, and Henderson: Validity of the cryo-electron microscopy structures of the HIV-1 envelope glycoprotein complex. PMID- 24350340 TI - Reply to Coyne: Genomic analyses are unthwarted. PMID- 24350342 TI - Proceeding of the Challenges in Environmental Science and Engineering, CESE-2012: September 9-13, 2012, Melbourne, Australia. PMID- 24350341 TI - This issue is dedicated to the memory of Professor Norman B. Hecht. PMID- 24350343 TI - Proceedings of the Chinese-Canada Symposium in Atherosclerosis and Cardiovascular Disease, September 23-25, 2011, Beijing, China. PMID- 24350344 TI - Special issue dedicated to Norman Letvin. PMID- 24350345 TI - Proceedings of the 15th Congress of the ESVCN, 14 - 16 September 2011, Zaragoza, Spain. PMID- 24350347 TI - Proceedings of the 3rd EAO Consensus Conference, 15-18 February 2012, Pfaffikon, Schwyz, Switzerland. PMID- 24350346 TI - Proceedings of the Ninth International Conference on Information Processing in Cells and Tissues (IPCAT), March 31-April 2, 2012, Cambridge, England. PMID- 24350348 TI - FUS: a putative biomarker for essential tremor raised by whole-exome sequencing analyses. PMID- 24350349 TI - Genetic biomarkers of essential tremor: time to think outside of the box. PMID- 24350351 TI - The role of fibroblast growth factor 21 in controlling reproduction during nutritional deprivation. PMID- 24350352 TI - My name is nobody. PMID- 24350353 TI - Computing: Out of the hood. PMID- 24350355 TI - Protecting health-care workers in the firing line. PMID- 24350354 TI - WHO AFRO: looking for a leader. PMID- 24350356 TI - 21st-century oncology: a tangled web. PMID- 24350357 TI - Colorectal-cancer incidence and mortality after screening. PMID- 24350358 TI - Explaining radiation risks to patients. PMID- 24350359 TI - Principles of radiotherapy. PMID- 24350360 TI - Clubbing. PMID- 24350361 TI - Management of acute toxicity associated with radiotherapy. PMID- 24350362 TI - [Therapy refractory compulsive disorders and psychosocial interventions at the psychiatric institute outpatient service of the Leipzig University Clinic]. PMID- 24350363 TI - [Decision for collaborative pathway of care: ergotherapy in dialectical behavioral therapy]. PMID- 24350364 TI - Reply: To PMID 22889743. PMID- 24350365 TI - [Naming and packaging of pharmaceutical products]. PMID- 24350366 TI - Reply: To PMID 22889743. PMID- 24350367 TI - [Interview by Anne-Katrin Dobler]. PMID- 24350368 TI - Developmental biology: Support mothers to secure future public health. PMID- 24350370 TI - Failure of care. PMID- 24350369 TI - Bibliometrics: global gender disparities in science. PMID- 24350371 TI - The patent bargain. PMID- 24350372 TI - Gender progress (?). PMID- 24350373 TI - Author reply: To PMID 23522699. PMID- 24350375 TI - Media highlights. PMID- 24350374 TI - Twin research reports. PMID- 24350376 TI - Retraction note to: Intestinal microbiota, probiotics and human gastrointestinal cancers. PMID- 24350377 TI - In the production of knowledge in Occupational Health it is necessary to be committed. PMID- 24350378 TI - Degloving injuries of the abdominal wall. AB - OBJECTIVE: To stress the local, regional and global impact of degloving injuries of abdominal wall based on which the surgeon can design the management protocol. METHOD: A retrospective series of seven cases who met with high velocity run-over accidents between the year 2002 to 2007. All patients were clinically examined and the findings confirmed radiologically, which guided the management. RESULTS: Out of the seven patients treated, six survived. All patients had open degloving injury of abdominal wall and in different areas of the lower limbs, while three had an additional closed degloving in the back, thighs and gluteal regions. All of them had pelvic fractures of various types. Three patients had peritoneal injury, of whom one had additional diaphragmatic injury. None of them had hollow viscus perforation or injury to solid viscera despite the varied severity of injuries to the abdominal wall, pelvic bone and diaphragm. CONCLUSION: Degloving injuries of the abdominal wall are rarely encountered in our practice. The associated morbidity and mortality are very high. However, the prognosis can be improved by successful revival and rehabilitation of these patients, which is possible by early resuscitation, recognition of all bony and soft tissue injuries, early debridement and coverage. PMID- 24350379 TI - ["Magic" oil to treat lice infestations]. PMID- 24350380 TI - [Not Available]. PMID- 24350381 TI - [Not Available]. PMID- 24350382 TI - No informed consumers without price transparency. PMID- 24350383 TI - New immunotherapies for cancer yield exciting results but high cost. PMID- 24350384 TI - Next-generation cancer biologics shine in studies. PMID- 24350385 TI - United States obesity, overweight rates to soar. PMID- 24350388 TI - [Diagnosis of a giant abdominal nodule triggered by abdominal pain]. PMID- 24350390 TI - An investigation of Salmonella Typhimurium linked to contaminated eggs on the Central Coast of NSW, 2008. PMID- 24350389 TI - Cholinergic efferent synaptic transmission regulates the maturation of auditory hair cell ribbon synapses. AB - Spontaneous electrical activity generated by developing sensory cells and neurons is crucial for the maturation of neural circuits. The full maturation of mammalian auditory inner hair cells (IHCs) depends on patterns of spontaneous action potentials during a 'critical period' of development. The intrinsic spiking activity of IHCs can be modulated by inhibitory input from cholinergic efferent fibres descending from the brainstem, which transiently innervate immature IHCs. However, it remains unknown whether this transient efferent input to developing IHCs is required for their functional maturation. We used a mouse model that lacks the alpha9-nicotinic acetylcholine receptor subunit (alpha9nAChR) in IHCs and another lacking synaptotagmin-2 in the efferent terminals to remove or reduce efferent input to IHCs, respectively. We found that the efferent system is required for the developmental linearization of the Ca(2+) sensitivity of vesicle fusion at IHC ribbon synapses, without affecting their general cell development. This provides the first direct evidence that the efferent system, by modulating IHC electrical activity, is required for the maturation of the IHC synaptic machinery. The central control of sensory cell development is unique among sensory systems. PMID- 24350391 TI - Secondary service connection for diagnosable illnesses associated with traumatic brain injury. Final rule. AB - The Department of Veterans Affairs (VA) amends its adjudication regulations concerning service connection. This final rule acts upon a report of the National Academy of Sciences, Institute of Medicine (IOM), Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury, regarding the association between traumatic brain injury (TBI) and five diagnosable illnesses. This amendment establishes that if a veteran who has a service-connected TBI also has one of these diagnosable illnesses, then that illness will be considered service connected as secondary to the TBI. PMID- 24350392 TI - Patient Protection and Affordable Care Act; maximizing January 1, 2014 coverage opportunities. Interim final rule with comment period. AB - This interim final rule amends the date by which a qualified individual must select a qualified health plan (QHP) through any Exchange for an effective coverage date of January 1, 2014. This rule generally allows consumers to select a QHP until December 23, 2013, which is a change from the previously stated regulatory date of December 15, 2013, but permits State Exchanges to select a different date. It also establishes a related policy regarding the date by which a consumer needs to pay any applicable initial premium to ensure timely effectuation of coverage. This rule pertains to the individual market and Small Business Health Options Program in both the Federally-facilitated Exchanges and State Exchanges. This rule does not change the plan selection or premium payment dates for coverage offered outside of the Exchanges. PMID- 24350393 TI - Nurse-led PICC insertion: is it cost effective? AB - AIMS: Repeated attempts to cannulate small veins can cause considerable distress for patients and expend substantial staff time.For longer term venous access, a peripherally inserted central catheter(PICC) may be used instead of a peripheral cannula. Previous studies indicate that insertion of a PICC costs three times more than a cannula but the lifespan is substantially longer. This study aimed to compare insertion cost, patient satisfaction, and infection rates of PICCs for the two main staff groups (trained nurses and radiologists) inserting these devices in a district general hospital. MATERIALS AND METHODS: The study took place over 4 months in 2012-13.A questionnaire was attached to all identified PICCs in stock at Raigmore Hospital to collect details of the date of insertion, patient involved, time taken, attendant staff grade and experience level,consumables used and insertion success. The lead author's personal observation of PICC insertion by different staff groups allowed estimation of staff time, costs and success rates. Patient experience and satisfaction was assessed before and after insertion using a patient questionnaire. PICC longevity, infection rates and failures were assessed by review of patient notes. RESULTS: The radiologist group had a statistically significant (p< 0.01) increased cost (42%) over the nurse group. Patient satisfaction regarding explanation of treatment before insertion was higher in the nurse group. Insertion success and infection rates were higher in the radiologist group. CONCLUSION: The authors conclude that the majority of PICCs can be safely performed without x-ray screening in a ward-based environment. This is likely to be the most cost-effective solution for large volume services. PMID- 24350395 TI - Use of winged infusion devices in intravenous therapy. AB - This article has been written to highlight the licensed use of winged infusion devices for short-term intravenous (IV) therapy. There is limited published literature on the subject, yet this clinical audit has demonstrated that the use of winged infusion devices has clear advantages for patients and nurses. The audit was conducted in the community setting but could be replicated in any community or hospital environment where short-term intravenous therapy of nonvesicant fluids are administered. For the purpose of this audit, nonvesicant antibiotics were administered. PMID- 24350394 TI - Vascular access: viewing the vein. PMID- 24350396 TI - Patients' experiences of community IV therapy. AB - AIM: To explore patients' experiences of receiving community intravenous therapy (CIVT) compared with traditional inpatient hospital care. METHOD: The study used a qualitative descriptive methodology. Semi-structured interviews were conducted with eight participants, transcribed verbatim and thematically analysed. RESULTS: Five themes were identified: 'finances'; 'travelling'; 'hospital admission';'being at home'; and 'safety'. DISCUSSION: The study revealed that participants felt privileged and valued when they were treated at home.CIVT allowed them the comfort of being in a familiar environment and the convenience of doing what they wanted, when they wanted. CONCLUSION: This study concurs that patients do prefer to be treated at home rather than being admitted to secondary care. The findings from this study suggest that participants appreciated the opportunity to receive CIVT. PMID- 24350397 TI - Needle-free drug delivery. PMID- 24350398 TI - Nuclear cardiology. PMID- 24350399 TI - Physician assistants in dermatology. PMID- 24350400 TI - Deep brain stimulation. PMID- 24350401 TI - Clinical neurophysiology. PMID- 24350402 TI - Physician assistants in orthopedic surgery. PMID- 24350403 TI - Puzzles in practice. Arrhythmogenic right ventricular dysplasia (ARVD). PMID- 24350404 TI - Hyperprolactinemia: a 12-year retrospective study at gynecologic endocrinology unit, Siriraj Hospital. AB - BACKGROUND: Hyperprolactinemia is one of the most common endocrine disorders of the hypothalamic-pituitary axis. To date, no available data about hyperprolactinemia in Thai women has been published OBJECTIVE: To determine clinical and laboratory findings of Thai female patients with different etiology of hyperprolactinemia, as well as the response of treatment, recurrence, and pregnancy after treatment. MATERIAL AND METHOD: Medical records of 139 female patients with the diagnosis of hyperprolactinemia in Gynecologic Endocrinology Unit, Siriraj Hospital between January 1, 1999 and December 30, 2011 were retrospectively reviewed after the study protocol was approved by Siriraj Institutional Review Board. The data was analyzed to determine patient demographic data, presenting symptoms, duration of symptoms, initial serum prolactin levels, causes, imaging studies, treatment, treatment outcomes, and adverse events. RESULTS: Ninety-seven female patients with hyperprolactinemia were included in the study. Mean age at diagnosis was 31.8 +/- 7.7 years. Amenorrhea was the most common presenting symptom (49.5%) followed by galactorrhea (44.3%). Median initial serum prolactin level was 117 ng/mL (25.1 1,624 ng/mL). Pituitary adenoma is the most common cause (40.2%) followed by idiopathic hyperprolactinemia (37.1%). Microadenomas were found in 74.3% of pituitary adenoma. The median size of the tumor was 9 mm. Medical treatment was given to 79 (88.8%) patients. Bromocriptine was given to 66 patients. Mean of maximum dose of bromocriptine was 5.8 mg. Median duration of treatment was 35.8 months. Adverse events were reported in 24.2% of patients, dizziness was the most common adverse event. Median time to normalize serum prolactin level was 3.8 months. In 29 patients who desired pregnancy, eight patients got pregnant. Median time to pregnancy was 25.9 months. Patients with macroadenoma had significantly higher prolactin level than those with microadenoma (p = 0.024). Patients with galactorrhea had the shortest duration of symptom (p = 0. 010). There were no statistically significant difference in symptoms, duration of symptoms, and initial prolactin level between patients with and without pituitary adenoma. Patients with pituitary adenoma needed higher doses (p = 0.009) and longer duration of treatment (p = 0.007) than those without a tumor Normalization of prolactin level and recurrence rate was not different between the two groups (p = 0.056 and 0.374). Log rank test showed that the time to normalize and survival time of recurrence were not significantly different between patients with and without a tumor (p = 0.136 and 0.146, respectively). CONCLUSION: Amenorrhea was the most common presenting symptom in Thai hyperprolactinemic females, who attended Siriraj gynecologic endocrinology unit, followed by galactorrhea. Pituitary adenoma is the most common cause followed by idiopathic hyperprolactinemia. Patients with pituitary adenoma needed higher doses and longer duration of treatment than those without a tumor PMID- 24350405 TI - Efficacy of dietary modification following the National Cholesterol Education Program (NCEP) recommendation on lipid profiles among hyperlipidemia subjects. AB - BACKGROUND: Hyperlipidemia has adverse effects on atherosclerosis, causing it to develop into cardiovascular disease. The prevalence of hyperlipidemia has been increasing among those in the working-age group and may be caused by inappropriate dietary patterns. Dietary modification should form the basis of lipid management. OBJECTIVE: Evaluate the effects of a dietary modification following the NCEP-ATP III recommendation on lipid profiles among hyperlipidemia subjects. MATERIAL AND METHOD: The design was a quasi-experimental study, with a pre-test/post-test two-group design. Each group consisted of 31 hyperlipidemia subjects aged 30 to 59 years old with total cholesterol (TC) greater than or equal to 240 mg/dl or low-density lipoprotein cholesterol (LDL-C) greater than or equal to 130 mg/dl. The present study was conducted between January and June 2009. The research procedure included 6-week nutrition counseling and a 2-week follow-up for 12 weeks. Data were collected by self-reported questionnaire and a 3-day food record. Dietary and biological assessments were compared before and after the experiment. Statistical analysis was performed using means, standard deviations, independent and paired t-tests, Friedman test, Mann-Whitney U test, and Wilcoxon signed-rank test. RESULTS: The intervention group had a significant reduction of TC and LDL-C at the end of the experiment (p < 0.05). Moreover this group had a significantly higher percentage reduction of TC and LDL-C than the control group (8.5% vs. 3.0%, and 10.8% vs. 2.4%, respectively) (p < 0.05). Distributions of monounsaturated fatty acids (MUFAs) in the intervention group were significantly higher than in the control group (p < 0.05). Distribution of saturated fatty acids (SFAs):MUFAs:polyunsaturated fatty acids (PUFAs) were 12.0:13.4:6.3% in the intervention group and 12.3:9.2:5.6% in the control group. Neither group was able to reduce SFAs intake to < 7% as recommended. Neither the recommended one-third of vegetable protein nor two-thirds of complex carbohydrate was achieved Dietary fiber was less than 10 g/1,000 kcal. The cholesterol intake in the intervention group was less than in the control group (155.9 vs. 206.3 mg/d). CONCLUSION: The dietary modification in the present study significantly lowered TC and LDL-C. However compliance with the recommendation of high MUFAs intake was difficult to achieve. The dietary modification might be focused instead on lowering intake of SFAs, replacing animal protein with vegetable protein, and increasing complex carbohydrates, fruits, and vegetables to raise dietary fiber. PMID- 24350406 TI - Electrolytes imbalance in saltwater near-drowning victims in the Gulf of Thailand. AB - BACKGROUND: Near-drowning victims in saltwater are expected to have multiple electrolytes imbalance that affected treatment outcome. There are limited data about these parameters in Thailand to guide the treatment plan. OBJECTIVE: To study the characteristic of electrolytes imbalance in saltwater near-drowning victims in the Gulf of Thailand. MATERIAL AND METHOD: Retrospective analytic study of 39 medical records of near-drowning patients admitted to Burapha University Hospital between 2000 and 2010. Characteristics of the patients and serum electrolytes were analyzed by SPSS version 19 for windows. RESULTS: The study included 23 male, 16 female patients. Average age was 14.46 +/- 11.15 years and 19/39 (48.72%) patients were aged 10 or less. The following electrolytes imbalance were identified, hypokalemia 8/39 (20.51%), hypernatremia 12/39 (30.77%), hyperchloremia 15/39 (38.46%), high anion gap 23/39 (58.97%), and hypobicarbonatemia 28/39 (71.79%). Seven out of eight patients in the hypokalemia group were in the high anion gap group. Mean SpO2 in the patients who had high anion gap was significantly lower than those who had normal anion gap (87.06 +/- 17.68% vs. 95.8 +/- 5.94% p = 0.031) without difference in systolic blood pressure (112.59 +/- 14.63 vs. 105.67 +/- 13.98 p = 0.159). Those who were hypotensive significantly had lower bicarbonate (17.00 +/- 3.51 vs. 20.59 +/- 3.81 p = 0.038) and higher anion gap (19.29 +/- 1.799 vs. 16.25 +/- 6.25 p = 0.025) than normotensive patients. CONCLUSION: Hypobicarbonatemia, high anion gap, hypernatremia, and hypokalemia were common in saltwater near-drowning patients in the Gulf of Thailand. The cause of high anion gap was probably due to hypoxia and hypotension. PMID- 24350407 TI - Outcomes of MDR/XDR-TB patients treated with linezolid: experience in Thailand. AB - BACKGROUND: Multi-drug-resistant/extensively drug-resistant tuberculosis (MDR/XDR TB) becomes an increasing problem in management. Linezolid has been off-label used in treatment of MDR/XDR-TB with major adverse effects. OBJECTIVE: To study outcomes of MDR/XDR-TB patients treated with linezolid in Central Chest Institute of Thailand. MATERIAL AND METHOD: MDR/XDR-TB patients treated with linezolid from 2009-2012 were retrospective analyzed RESULTS: Seventeen from 24 cases had finished treatment. Linezolid, capreomycin, cycloserine, clofazimine, moxifloxacin, ethambutol, kanamycin, ethionamide, and PAS were used in 24, 21, 8, 7, 5, 5, 2, 2, and 2 cases respectively. Long-term injection of capreomycin was used in 14/17cases for an average of 14.7 months. Three point three drugs were used as an average. Average conversion time of smear and culture were 53.5 and 52.1 days respectively Treatment time averaged 19.1 months. Fifteen of 24 cases were cured, seven were still ongoing treatment, all had sputum culture conversion, and two cases failed. There was no relapse in 13 cases after a follow up that averaged 10.6 months. Linezolid was stopped in five cases from peripheral or optic neuropathy. Capreomycin was stopped in four cases from vestibulotoxic and nephrotoxic. CONCLUSION: Linezolid has good efficacy in treatment of MDR/XDR TB with major adverse effect and should be used with caution. If capreomycin is susceptible or likely active, long-term injection should be considered when likely active drugs are not enough to strengthen the regimen. PMID- 24350408 TI - Pharmacodynamics of meropenem in critically ill patients with ventilator associated pneumonia. AB - BACKGROUND: Pharmacokinetic changes have been found in critically ill patients, including ventilator-associated pneumonia (VAP) when compared with healthy volunteers leading to fluctuation of plasma concentrations. OBJECTIVE: To compare the probability of target attainment (PTA) and cumulative fraction of response (CFR) for meropenem between administration by a bolus injection and a 3-hour infusion. MATERIAL AND METHOD: The study was a randomized three-way crossover in nine patients with VAP. Each patient received meropenem in three regimens consecutively: (i) a bolus injection of 1 g every eight hours (q8h) for 24 hours; (ii) a 3-hour infusion of 1 g q8h for 24 hours; and (iii) a 3-hour infusion of 2 g q8h for 24 hours. The pharmacodynamic analysis of meropenem was performed to determine the PTA by using the Monte Carlo simulation and the study used susceptibility patterns obtained from EUCAST and MYSTIC for assessment of CFR. RESULTS: For an MIC of 4 microg/ml, the PTAs achieving 40% T > MIC following a bolus injection of 1 g q8h, a 3-hour infusion of 1 g q8h, and a 3-hour infusion of 2 g q8h were 87.71%, 98.80%, and 99.90%, respectively. Only the 3-hour infusion regimens were predicted to achieve a CFR > or = 90% against E. coli, Klebsiella spp., P. aeruginosa, and Acinetobacter spp. CONCLUSION: A 3-hour infusion of 2 g of meropenem regimen was predicted to have the highest PTA rates. Only the prolonged infusion regimens achieved a high CFR against E. coli, Klebsiella spp., P. aeruginosa, and Acinetobacter spp. PMID- 24350409 TI - Prevalence, clinical manifestations and mortality rate in patients with spontaneous pneumothorax in Thammasat University Hospital. AB - BACKGROUND: Spontaneous pneumothorax (SP) can be a medical emergency requiring early diagnosis and treatment to prevent subsequent respiratory failure and death. SP epidemiologic and clinical data are limited in Thailand OBJECTIVE: To study the prevalence, clinical manifestations, and mortality rate of SP in Thai patients. MATERIAL AND METHOD: A retrospective case study was conducted between July 2004 and December 2010 in patients with a confirmed diagnosis of SP Demographic, etiologic, clinical, radiographic, and outcome data were collected. RESULTS: One hundred patients with SP were identified (66 primary, 34 secondary SP), for a prevalence of 76.3 per 100,000 hospital admissions. Males numbered 83. Male to female ratios were 7.5:1 and 4.1:1 for primary and secondary SP respectively. Mean (+/- standard deviation) age and body mass index were 35.3 +/- 20.3 years and 18.0 +/- 2.2 kilogram/meter2. The common presenting symptoms were dyspnea (73%), chest pain or discomfort (68%), pleuritic pain (46%), cough (20%), and fever (13%). Causes of secondary SP were pulmonary tuberculosis (19/34, 55.9%), chronic obstructive pulmonary disease (14/34, 41.2%), and pneumonia (8/34, 23.5%). There were 12 deaths (12%), 11 with secondary SP CONCLUSION: Spontaneous pneumothorax was relatively common with typical clinicalfeatures. Almost all of mortality cases rate suffered secondary SP Prospective studies are needed to develop evidenced based algorithms, especially for secondary SP patients. PMID- 24350410 TI - Prevalence of coronary artery disease in different ethnic groups at a tertiary care hospital. AB - OBJECTIVE: To compare the prevalence of coronary artery disease (CAD) between Thai Muslim and Thai Buddhist patients. MATERIAL AND METHOD: A hospital based retrospective study was carried out to investigate the prevalence of CAD and cardiovascular risk factors of these two ethnic and religious groups at Nopparat Rajathanee Hospital between June 2012 and December 2012. All Thai Muslim patients aged > or = 35 years who visited the internal medicine outpatient department (OPD) were studied. The compared population was randomly selected and matched by age and sex from the Thai Buddhist patients in the same period RESULTS: Five hundred seventy nine patients with median age of 62 years (interquartile range = 24) were studied. There were 289 Thai Muslims and 290 Thai Buddhists. The prevalence of definite CAD in Muslims (14.20%) was significantly higher than the prevalence in Buddhists (6.2%) (p = 0.002). The prevalence of diabetes mellitus, hypertension, high total cholesterol (> or = 240 mg/dl), and high triglyceride in Muslims were significantly higher For high-density lipoprotein cholesterol (HDL C), only Muslim females showed significantly higher prevalence of low HDL-C than that of Buddhist females. CONCLUSION: Thai Muslims showed significantly higher prevalence of definite CAD than that of Thai Buddhists. The greater prevalence of certain risk factors may contribute to higher prevalence of CAD in Thai Muslim patients. PMID- 24350411 TI - Spontaneous craniocervical arterial dissection: a clinical and vascular neuroimaging study. AB - BACKGROUND: Spontaneous craniocervical arterial dissection (SCAD) is an important cause of stroke in the young and middle-aged population. However clinical data of SCAD is limited in Thailand. This present study aims to describe the clinical profiles of SCAD in a tertiary care center in Thailand. MATERIAL AND METHOD: All SCAD patients admitted to King Chulalongkorn Memorial Hospital between January 1997 and October 2011 were enrolled. All of the patients fulfilled vascular imaging diagnostic criteria for SCAD. Clinical profiles, associated risk factors, vascular neuroimaging patterns, treatments, and outcomes were analyzed by SPSS program version 17. RESULTS: Fifty patients with SCAD were identified (0.5% of total hospitalized ischemic cerebrovascular disease and subarachnoid hemorrhage (SAH) patients). SCAD was found in 1.6% of patients under the age of 45 years. Eighty-six percent of the patients were diagnosed during the last five years of this present study period. Internal carotid artery dissection (ICAD) and vertebral artery dissection (VAD) were detected in 42% and 58% respectively. The mean age was 48.3 +/- 15.3 years. Atherosclerotic risk factors included hypertension (16%), diabetes mellitus (24%), and dyslipidemia (28%). History of previous minor head injury and migraine were encountered in 8% and 4% respectively. Headache was detected in 80% of the cases. Localized headache was observed in 64% of the cases. Diffuse headache due to SAH was detected in 14% of the cases. Neurological syndromes at presentation were ischemic stroke (72%), transient ischemic attack (TIA) (80%), and SAH (16%). Pathognomonic vascular neuroimaging patterns of dissection included wall hematoma (36%), flame-shaped appearance (28%), dissecting pseudoaneurysm (24%), and intimal flap (8%). Other vascular imaging features included dissecting vessel stenosis (58%) and dissecting vessel occlusion (18%). Treatment consisted of anticoagulants (60%), antiplatelets (10%), surgical intervention (22%), and conservative management (8%). Neurological outcomes at discharge with MRS 0-3 were 72%. No recurrent dissection or recurrent cerebrovascular events were observed during the six-month follow-up period In this present study, significant differences between ICAD and VAD in terms of percentage of SAH, severity, and outcomes were observed CONCLUSION: SCAD results in diverse cerebrovascular events such as ischemic stroke, TIA, and SAH in the young and middle-aged population. Advances in vascular neuroimaging play a crucial role in the diagnosis of SCAD. Prompt management is essential for SCAD with a rather favorable outcome. PMID- 24350412 TI - Allergic family history as a protective determinant to helminthic infection. AB - OBJECTIVE: Investigate the resistance to helminths in children with an allergic family history. MATERIAL AND METHOD: The study was undertaken as part of the Prospective Cohort Study of Thai Children (PCTC) that followed all births in the year 2001 from rural districts in Thailand. The family histories of allergic diseases were validated by the physicians'diagnoses and medical record reviews. Fresh stool examinations were carried out at 18 to 36 months of age. RESULTS: Of 1,076 live births in the cohort, 659 children had complete information. A family history of allergy presented in 5.4% of the children. The prevalence of any helminthic infection, Ascaris lumbricoides, Trichuris trichiura, and hookworm were 25.0%, 18.2%, 9.2%, and 5.3%, respectively. The adjusted odds ratio of a family history of allergy for helminthic infection was 0.28 (95% CI, 0.08-0.95). CONCLUSION: A family history of allergic diseases independently increases resistance to helminthic infection. PMID- 24350413 TI - The impact of child's severity on quality-of-life among parents of children with autism spectrum disorder: the mediating role of optimism. AB - OBJECTIVE: Investigate the impact of child severity and optimism on quality-of life in parents of children with Autism Spectrum Disorder (ASD). Additionally, the role of optimism as mediator between child's severity and parental quality-of life was also evaluated MATERIAL AND METHOD: Three hundred three parents of children with ASD were recruited from the local autistic centers and schools in Bangkok, Thailand. A set of demographic information sheet, the Childhood Autism Rating Scale (CARS), the Life Oriented Test-Revised (LOT-R), and the WHOQOL-BREF test were submitted for collecting parental information. RESULTS: Using Pearson Correlation, a significant negative association was found between child's severity and parental quality-of-life while optimism was found to correlate positively with parental outcomes. The finding from path-analysis confirmed that impairment of language and repetitive behavior of an ASD child associated with optimism that, in turn, predicted level of parental quality-of-life in all domains. CONCLUSION: The current findings assured a role of optimism as mediator between child's severity and parental quality-of-life. Implications for the development of intervention focused on enhancing parent's optimism were recommended. PMID- 24350414 TI - Effects of rapid response trauma team in thoracic injuries in northern trauma center level I. AB - BACKGROUND AND OBJECTIVE: Associated thoracic injury is the first priority at the initial assessment and its outcomes are time-dependent. Faculty of Medicine, Chiang Mai University organized a rapid response trauma team (RRTT) at mid-year 2006. The aims of this present paper were to report the effects of RRTT regarding outcomes of thoracic injury. MATERIAL AND METHOD: We performed a retrospective review for admitted thoracic injury patients between January 2004 and September 2009. The interval prior to July 2006 was defined as "before RRTT" and the latter as "after RRTT". The severity-adjusted mortality was calculated. RESULTS: During the 69 months, 951 patients were included (427 in "before RRTT", 524 in "after RRTT"). Although the severity injury score (ISS) was significantly lower before RRTT the severe trauma patients (ISS > 15) had a significantly higher mortality (25.3% vs. 15.3%; p = 0.01). RRTTsignificantly improved the mortality odds ratio in the overall and severe trauma [0.39 (0.22-0.68); p < 0.01 and 0.43 (0.25 0.73); p < 0.01]. Subgroup analysis found to have positive effects with the RRTT in maxillofacial, head, and orthopedics associated injuries. CONCLUSION: RRTT for thoracic injuries in the tertiary level I trauma center could decrease the severity-adjusted mortality, especially in severe trauma patients. PMID- 24350415 TI - Low molecular weight heparin prevents the progression of precollapse osteonecrosis of the hip. AB - BACKGROUND: Hypercoaguable state has been indicated as a major risk factor in predisposing the idiopathic osteonecrosis of the hip. Furthermore, many studies have demonstrated that low molecular weight heparin (LMWH) can reverse the pathophysiology of the osteonecrosis of the hip in thrombophilic patients. OBJECTIVE: Determine whether LMWH can prevent the progression of idiopathic osteonecrosis of the hip. MATERIAL AND METHOD: A retrospective study of 36 patients who had bilateral idiopathic osteonecrosis with at least one hip in the pre-collapsed stage (Ficat & Arlet stage I-II) was conducted. In the study group, 18 patients (26 hips) received 6,000 units of Enoxaparin daily for 12 weeks. In the control group, 18 patients (23 hips) received no Enoxaparin. All patients were given radiographic evaluations every three months for a minimum of24 months. RESULTS: At the last follow-up, 15 hips (57.7%) from the study group and five hips (21.7%) from the control group were observed to remain in the pre-collapse stage (p = 0.042). Coagulation disorder was observed in seven patients (38.9%) of the experimental group and five patients (27.8%) of the control group. One patient from the study group exhibited hematuria with spontaneous resolution after the course ofEnoxaparin injection. CONCLUSION: A progression rate of idiopathic osteonecrosis of the hip from the pre-collapse stage to the collapsed stage was found to be significantly lower in patients who received LMWH. PMID- 24350416 TI - Efficacy of benzydamine hydrochloride dripping at endotracheal tube cuff for prevention of postoperative sore throat. AB - BACKGROUND: Postoperative sore throat (POST) is a frequent consequence following ETT intubation, which may negatively affect the postoperative course and patient satisfaction. Benzydamine hydrochloride is a topically-applied non-steroidal anti inflammatory drug (NSAID). The authors evaluated the analgesic effect of benzydamine hydrochloride dripping on the ETT cuff on POST. MATERIAL AND METHOD: Eighty-six patients participated in this randomized controlled trial. They were assigned into either the benzydamine hydrochloride or the control group. The whole ETT cuff was dripped either with 3 ml (4.5 mg) of benzydamine hydrochloride or nothing five minutes prior to anesthesia induction. The incidence and severity of POST at 0, 2, 4, 6, 12 and 24 hours postoperatively were assessed. The potential adverse effects of benzydamine hydrochloride (throat numbness throat burning sensation, dry mouth, and thirst) were also evaluated. RESULTS: Twenty five patients (58.14%) in each group had POST (p-value = 1). The severity of POST (calculated from affected patients) in both groups at different time points was not significantly different. Patients in the benzydamine hydrochloride group did not have a higher incidence of adverse effects. CONCLUSION: We found that dripping benzydamine hydrochloride on the ETT cuff neither reduced the incidence of POST nor increased the incidence of adverse effects in comparison with no intervention. PMID- 24350417 TI - The improved quality process after implementation of the hemithyroidectomy care map. AB - OBJECTIVE: To report the improved quality process in service care of the patients undergoing hemithyroidectomy and the results of the care map implementation. MATERIAL AND METHOD: Descriptive analysis and retrospective chart reviews were performed in the patients who underwent hemithyroidectomy in the Department of Otorhinolaryngology, Faculty of Medicine Siriraj Hospital before and after the care map implementation between January 2004 and December 2006. RESULTS: Hemithyroidectomy care map has been created with good cooperation of all members of our department in January 2005. Two hundred seventy nine patients, including 246 females (88%) and 33 males (12%) participated in this study. The care map was used in all patients. Hospital stay was reduced from five to eight days to less than four days in 93% of the patients. The estimated expenses of 97% of the patients differed from the true expense at less than 20%. Complications were minimized to the acceptable level by close supervision of the attending staffs. Incidence of vocal cord paralysis was reduced from 8.7% before the care map implementation to 2.4% and 2.3% in the first and second years. Hematoma was observed in three cases within 24 hours postoperatively and could not be prevented by drain insertion. Only minimal content was found in the drain after 48 hours. CONCLUSION: The improved quality process in hemithyroidectomy care received good cooperation from all members in our department. Effective resource utilization was achieved with maximal patients'benefit and satisfaction. Close supervision by attending staffs, meticulous surgical techniques, and adequate bleeding control are the keys of effective clinical care. Hospital stay is possibly reduced to one to two days by good pre-anesthetic care before admission and by avoiding or using drain only in selected cases for six to 48 hours. PMID- 24350418 TI - The factors affecting quality of life in Thai psoriasis patients. AB - OBJECTIVE: To identify the factors that affect quality of life in Thai psoriasis patients. MATERIAL AND METHOD: Data collected from 326 psoriasis patients that visited dermatology clinic at Siriraj Hospital, Bangkok, Thailand between 2001 and 2007 was used. Dermatology Life Quality Index (DLQI) was used to measure quality of life. Severity was evaluated by Psoriasis Area and Severity Index (PASI). RESULTS: Overall, psoriasis had moderate to very large negative effect on the patient's life. There was a tendency that elderly patients had a slightly better quality of life than younger adult and middle-age patients. However other demographic variables (i.e., gender, occupation, and income) had no influence on quality of life. This study also identified a linear trend of increased overall DLQI with greater PASI. CONCLUSION: Only older age and lesser severity of disease had association with few burdens in Thai psoriasis patients. PMID- 24350419 TI - Cost-effectiveness analysis of 18F-FDG PET/CT in detecting suspected recurrence or metastasis in well-differentiated thyroid carcinoma patients with negative diagnostic total body scan in Thailand: a decision analysis. AB - OBJECTIVE: To evaluate cost-effectiveness analysis of 18F-FDG PET/CT to detect tumor recurrence or metastasis in well-differentiated thyroid cancer patients with high Tg but negative TBS in Thailand. MATERIAL AND METHOD: A retrospective literature review of 55 studies published between 1978 and 2010 was done. Decision analysis by TreeAge program showed an evaluation of the most cost effective treatment and 18F-FDG PET/CT scan in thyroid cancer patients with high Tg but negative TBS. The incremental cost and life years gained associated with seven strategies approached were analyzed by the decision tree model. The first strategy was treatment with empirical high dose 131I therapy. The second to the seventh strategies were using imaging investigations by CT scan of neck and chest, 99mTc MIBI scan, and 18F-FDG PET/CT scan to identify recurrent, persistent, and metastatic lesions before the specific treatment via curative surgery, external radiotherapy, and high dose 131I therapy. All strategies were adopted using hospital perspective and direct medical cost was estimated based on the reference price of Siriraj Hospital. Deterministic sensitivity analysis was conducted to investigate the effect of the cost of PET/CT scan. RESULTS: The strategy using 18F-FDG PET/CT scan to detect recurrence or metastasis and possible curative surgery in operable cases and high dose 131I therapy in inoperable cases gave the highest life years gained of 27.08 with cost of 90,227.61 Baht (2,926.24 US dollars) and acceptable incremental cost effectiveness ratio (ICER) of 6,936.88 Baht (224.98 US dollars) per life year gained when compared to the least costly strategy using 99mTc MIBI scan and additional 18F-FDG PET/CT scan in negative MIBI result. Other strategies were dominated by this PET/CT strategy. Deterministic sensitivity analysis (based on the willingness to pay (WTP) 360,000 Baht (11,675.42 US dollars) showed that the cost of PET/CT scan has no impact on the net health benefit. CONCLUSION: Based on the hospital perspective, the cost-effectiveness of 18F-FDG PET/CT scan in detecting suspected recurrence or metastasis in thyroid carcinoma patients with negative diagnostic TBS but high Tg was first done using 18F-FDG PET/CT scan to identify disease, followed by curative surgery or high dose 131I therapy. Moreover cost of PET/CT scan did not influence the net health benefit. This PET/CT benefit is helpfulfor considering the proper PET/CT use for thyroid cancer in Thailand. PMID- 24350420 TI - Diagnostic performance of advanced MRI in differentiating high-grade from low grade gliomas in a setting of routine service. AB - OBJECTIVE: To evaluate the usefulness of advanced MRI techniques in differentiating high-grade (HGG) from low-grade gliomas (LGG). MATERIAL AND METHOD: Sixty-four patients with suspected gliomas were prospectively evaluated by conventional and advanced MRI studies including MR spectroscopy (MRS), diffusion tensor imagining (DTI), and dynamic susceptibility contrast (DSC) MRI. The parametric measurements of metabolic profile, cerebral blood volume, flow (CBV, CBF), apparent diffusion coefficient (ADC), fractional anisotropy, and their ratios by internal normalization were analyzed to differentiate LGG from HGG. Histopathologic findings were used as the gold standard. RESULTS: Forty three cases with pathologically-proven gliomas were included The best discriminating features between HGG and LGG were CBV and CBF of the solid tumoral region (p < 0.05) whereas the minADC/corpus callosum ratio for DTI and the ratio of Cho/Cr for MRS of the solid tumoral region provided the best diagnostic performance (p < 0.05). With a predetermined threshold for each parametric measurement, the combination of all advanced MRI modalities was associated with the best accuracy whereas the combination of DSC MRI and MRS provided the highest specificity. When all parametric measurements were positive, the probability of HGG was 0.889. CONCLUSION: Comprehensive advanced MRI studies provided better diagnostic performance than using conventional MRI alone in the evaluation of gliomas. PMID- 24350421 TI - The specimen handling of GI mucosal biopsy: a simple and effective quality improvement initiative. AB - OBJECTIVE: Histologic diagnostic foci on GI mucosal biopsy may be patchy. Therefore, slides with good orientation of mucosal tissue in a perpendicular plane and demonstrating an entire layer of mucosa will increase the diagnostic yield. Department of Pathology Faculty of Medicine Siriraj Hospital has launched the two steps quality improvement program and a parallel research aiming to demonstrate the importance of tissue orientation of GI biopsy. MATERIAL AND METHOD: Step 1: quality improvement was introduced at the pathology laboratory. Embedding technicians were trained to embed tissue in perpendicular plane. Step 2: quality improvement at endoscopy unit, endoscopic nurses were trained to spread the biopsy tissues on a mesh with upward mucosal surface before fixing them into formalin. Three sets of 50 consecutive cases of GI mucosal biopsy were retrieved from before, after step 1, and after step 2. The number of high quality slides, diagnostic discrepancy, and diagnostic confidence of the pathologists were compared between the three sets. RESULTS: High quality slides were significantly increased from 23 (46%) before quality improvement to 30 (60%) after step 1, and 37 (74%) after step 2 (p-value = 0.017). Diagnostic discrepancy was decreased while diagnostic confidence was increased after quality improvement. CONCLUSION: The quality of GI mucosal biopsy slides were significantly improved after a simple and feasible program indicating that both educating and training of medical personnel for tissue procurement and tissue processing are crucial. Higher quality of slide can lead to more accurate diagnosis and fewer laboratory resources used. PMID- 24350422 TI - Cervical myelopathy from retro-odontoid calcium pyrophosphate dihydrate mass: a case report. AB - Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is one of the most common forms of crystal-associated arthropathy in the elderly. However, cervical spine is rarely affected, especially in upper cervical area. There have been previous reported cases of symptomatic retro-odontoid CPPD deposition disease in English literature but this case is the first reported in Thai patients. This is a case report of a 67-year-old man who presented with neck pain with progressive myelopathy. Neurologic examination demonstrated a cervical myelopathy with muscle weakness and sensory disturbance of both extremities. Imaging studies showed extradural retro-odontoid mass compressing the spinal cord. The patient underwent occiput to C3 fusion with plating, posterior arch of atlas resection, transoral odontoidectomy, and mass removal. Histological examination of the mass revealed fibrocartilage tissue and rhomboid shaped crystals that showed positive biferingent in polarized light microscopy consistent with CPPD crystals. After surgery, no complication was found, and his neurological function had improved. PMID- 24350423 TI - Trials registration: a new era in Thailand. AB - Registration of clinical trials or research can result in many benefits. Patients have access to pertinent information. We have a better and more indicative picture of research status in areas where registration is mandatory. Researchers can use the information to form a common interest group and collaborate their research as well as to avoid unnecessary duplication. Registered information can also enable detection of defective design and can lead to improvements of trial protocol or its implementation. Most importantly, it can help to reduce problems of publication bias and selective reporting. Journals do not like to publish negative or inconclusive results. Pharmaceutical companies are reluctant to report results that may jeopardize their revenue. We need absolute transparency to utilize evidence with trust. PMID- 24350424 TI - Special issue: Sustainable technologies: bioenergy and biofuel from biowaste and biomass. PMID- 24350425 TI - Bacterial synthesis gas (syngas) fermentation. AB - Acetogenic bacteria employing the Wood-Ljungdahl pathway can be used as biocatalysts in syngas fermentation for the production ofbiofuels such as ethanol or butanol as well as biocommodities such as acetate, lactate, butyrate, 2,3 butanediol, and acetone. The potential of such processes can be projected by the global syngas output, which was 70,817 megawatts thermal in 2010 and is expected to increase up to 72% in 2016. To date, different acetogens are used as commercial production strains for industrial syngas fermentations in pilot or demonstration plants (Coskata, INEOS Bio, LanzaTech) and first commercial units are expected to launch operation in the near future (INEOS Bio, LanzaTech). Considerations on potential yields are quite promising for fermentative production. New methods for metabolic engineering were established to construct novel recombinant acetogenic biocatalysts. Synthetic biology will certainly play a major role in constructing strains for commercial operations. This way, a cheap and abundant carbon source most probably replace, processes based on crude oil or sugar in the near future. PMID- 24350426 TI - Trends in biohydrogen production: major challenges and state-of-the-art developments. AB - Hydrogen has shown enormous potential to be an alternative fuel of the future. Hydrogen production technology has gained much attention in the last few decades due to advantages such as its high conversion efficiency, recyclability and non polluting nature. Over the last few decades, biological hydrogen production has shown great promise for generating large scale sustainable energy to meet ever increasing global energy demands. Various microorganisms, namely bacteria, cyanobacteria, and algae which are capable of producing hydrogen from water, solar energy, and a variety of organic substrates, are explored and studied in detail. Current biohydrogen production technologies, however, face two major challenges such as low-yield and high production cost. Advances have been made in recent years in biohydrogen research to improve the hydrogen yield through process modifications, physiological manipulations, through metabolic and genetic engineering. Recently, cell immobilization such as microbes trapping with nanoparticles within the bioreactor has shown an increase in hydrogen production. This review critically evaluated various biological hydrogen production technologies, key challenges, and recent advancements in biohydrogen research and development. PMID- 24350427 TI - Household anaerobic digester for bioenergy production in developing countries: opportunities and challenges. AB - Access to clean and affordable energy is vital for advancing development objectives, particularly in rural areas of developing countries. There are some three billion people in these regions, however, who lack consistent access to energy and rely on traditional solid fuels such as firewood, cattle manure, and crop residues for meeting cooking and heating needs. Excessive use of such highly polluting resources creates serious environmental, social and public health issues. In this context, household digesters (which convert readily available feedstocks such as cattle manure, human excreta, and crop residues into biogas) have the potential to play a significant role in supplying methane as a clean, renewable energy resource for remote geographies. In addition to bioenergy production, the slurry generated from anaerobic digestion is rich in nutrients and can improve the physical, chemical, and biological attributes of soil when applied to agricultural land. This type of approach has the potential to significantly reduce greenhouse gas emissions while simultaneously improving the quality of life. Despite a long history of research and innovation for the development and optimization of household digesters, little is known and has been reported for the application of these systems in decentralized communities. The primary purpose of this paper seeks to review the dearth of literature pertaining to small-scale anaerobic digesters in remote geographies and in regions where much of the world's population reside. PMID- 24350428 TI - Butanol fermentation. AB - This review provides an overview on bacterial butanol production and recent developments concerning strain improvement, newly built butanol production plants, and the importance of alternative substrates, especially lignocellulosic hydrolysates. The butanol fermentation using solventogenic clostridial strains, particularly Clostridium acetobutylicum, is a very old industrial process (acetone-butanol-ethanol-ABE fermentation). The genome of this organism has been sequenced and analysed, leading to important improvements in rational strain construction. As the traditional ABE fermentation process is economically unfavourable, novel butanol production strains are being developed. In this review, some newly engineered solvent-producing Clostridium strains are described and strains of which sequences are available are compared with C. acetobutylicum. Furthermore, the past and present of commercial butanol fermentation are presented, including active plants and companies. Finally, the use of biomass as substrate for butanol production is discussed. Some advances concerning processing of biomass in a biorefinery are highlighted, which would allow lowering the price of the butanol fermentation process at industrial scale. PMID- 24350429 TI - Membrane bioreactors' potential for ethanol and biogas production: a review. AB - Companies developing and producing membranes for different separation purposes, as well as the market for these, have markedly increased in numbers over the last decade. Membrane and separation technology might well contribute to making fuel ethanol and biogas production from lignocellulosic materials more economically viable and productive. Combining biological processes with membrane separation techniques in a membrane bioreactor (MBR) increases cell concentrations extensively in the bioreactor. Such a combination furthermore reduces product inhibition during the biological process, increases product concentration and productivity, and simplifies the separation of product and/or cells. Various MBRs have been studied over the years, where the membrane is either submerged inside the liquid to be filtered, or placed in an external loop outside the bioreactor. All configurations have advantages and drawbacks, as reviewed in this paper. The current review presents an account of the membrane separation technologies, and the research performed on MBRs, focusing on ethanol and biogas production. The advantages and potentials of the technology are elucidated. PMID- 24350430 TI - Sustainability of soil fertility and the use of lignocellulosic crop harvest residues for the production of biofuels: a literature review. AB - Use of lignocellulosic crop harvest residues for liquid or gaseous biofuel production may impact soil quality, long-term soil fertility and the major determinants of the latter, stocks of soil organic carbon and nutrients. When soil organic carbon stocks of mineral cropland soils are to be maintained, there is scope for the removal of lignocellulosic harvest residues in several systems with much reduced tillage or no tillage. The scope for such removal might be increased when suitably treated residues from the conversion of harvest residues into biofuel are returned to cropland soils. For mineral cropland soils under conventional tillage, the scope for the production of liquid biofuels from harvest residues is likely to be less than in the case of no-till systems. When fertility of cropland soils is to be sustainable, nutrients present in suitably treated biofuel production residues have to be returned to these soils. Apparently, the actual return of carbon and nutrients present in residues of biofuel production from crop harvest residues to arable soils currently predominantly concerns the application of digestates of anaerobic digestion. The effects thereof on soil fertility and quality need further clarification. Further clarification about the effects on soil fertility and quality of chars and of co products of lignocellulosic ethanol production is also needed. PMID- 24350431 TI - Supercritical CO2 and ionic liquids for the pretreatment of lignocellulosic biomass in bioethanol production. AB - Owing to high petroleum prices, there has been a major push in recent years to use lignocellulosic biomass as biorefinery feedstocks. Unfortunately, by nature's design, lignocellulosic biomass is notoriously recalcitrant. Cellulose is the most abundant renewable carbon source on the planet and comprises glucan polysaccharides which self-assemble into paracrystalline microfibrils. The extent of cellulose crystallinity largely contributes to biomass recalcitrance. Additionally, cellulose microfibrils are embedded into both hemicellulose and lignin polymeric networks, making cellulose accessibility an additional obstacle. Pretreatment is necessary before enzymatic hydrolysis in order to liberate high yields of glucose and other fermentable sugars from biomass polysaccharides. This work discusses two pretreatment methods, supercritical CO2 and ionic liquids (ILs). Both methods utilize green solvents that do not emit toxic vapours. Mechanisms for destroying or weakening biomass recalcitrance have been explored. Various pretreatment operating parameters such as temperature, pressure, time, dry biomass/solvent ratio, water content, etc. have been investigated for the pretreatment of various biomass types such as corn stover, switchgrass, sugarcane bagasse, soft and hard wood. The two pretreatment methods have their pros and cons. For example, supercritical CO2 explosion pretreatment uses inexpensive CO2, but requires a high pressure. By comparison, while IL pretreatment does not require an elevated pressure, ILs are still too expensive for large-scale uses. Further research and development are needed to make the two green pretreatment methods practical. PMID- 24350432 TI - Membranes for bioelectrochemical systems: challenges and research advances. AB - Increasing energy demand has been a big challenge for current society, as the fossil fuel sources are gradually decreasing. Hence, development of renewable and sustainable energy sources for the future is considered one of the top priorities in national strategic plans. Bioenergy can meet future energy requirements - renewability, sustainability, and even carbon-neutrality. Bioenergy production from wastes and wastewaters is especially attractive because of dual benefits of energy generation and contaminant stabilization. There are several bioenergy technologies using wastes and wastewaters as electron donor, which include anaerobic digestion, dark biohydrogen fermentation, biohydrogen production using photosynthetic microorganisms, and bioelectrochemical systems (BESs). Among them BES seems to be very promising as we can produce a variety of value-added products from wastes and wastewaters, such as electric power, hydrogen gas, hydrogen peroxide, acetate, ethanol etc. Most ofthe traditional BES uses a membrane to separate the anode and cathode chamber, which is essential for improving microbial metabolism on the anode and the recovery of value-added products on the cathode. Performance of BES lacking a membrane can be seriously deteriorated, due to oxygen diffusion or substantial loss of synthesized products. For this reason, usage of a membrane seems essential to facilitate BES performance. However, a membrane can bring several technical challenges to BES application compared to membrane-less BES. These challenges include poor proton permeability, substrate loss, oxygen back diffusion, pH gradient, internal resistance, biofouling, etc. This paper aims to review the major technical barriers associated with membranes and future research directions for their application in BESs. PMID- 24350433 TI - Improving the feasibility of producing biofuels from microalgae using wastewater. AB - Biofuels have received much attention recently owing to energy consumption and environmental concerns. Despite many of the technologies being technically feasible, the processes are often too costly to be commercially viable. The major stumbling block to full-scale production of algal biofuels is the cost of upstream and downstream processes and environmental impacts such as water footprint and indirect greenhouse gas emissions from chemical nutrient production. The technoeconomics of biofuels production from microalgae is currently unfeasible due to the cost of inputs and productivities achieved. The use of a biorefinery approach sees the production costs reduced greatly due to utilization of waste streams for cultivation and the generation of several potential energy sources and value-added products while offering environmental protection. The use of wastewater as a production media, coupled with CO2 sequestration from flue gas greatly reduces the microalgal cultivation costs. Conversion of residual biomass and by-products, such as glycerol, for fuel production using an integrated approach potentially holds the key to near future commercial implementation of biofuels production. PMID- 24350434 TI - An assessment of the economic aspects of CO2 sequestration in a route for biodiesel production from microalgae. AB - Photosynthetic microalgae are unicellular organisms that, during their cultivation, can fix carbon dioxide efficiently from various sources, including the air and exhaust gases from industrial processes. This feature can lead to economic benefits in the production process of biodiesel by way of the clean development mechanism, for which carbon credits for environmental benefits may be granted and which will contribute towards reducing costs in the production process. This study seeks to quantify the contribution of carbon credits in the operating costs of a route for biodiesel production from microalgae, as proposed by Davis et al. [Techno-economic analysis ofautotrophic microalgae for fuel production. Appl Energy. 2011; 88:3524-3531]. The results showed a reduction in annual operating costs by around 5%. This figure may be conservative, since the production process considered can be further improved to reduce operating costs and thus increase the contribution margin of carbon credits, which will reduce costs. On the other hand, the price of carbon may also rise in the future, thereby increasing its contribution towards a reduction in operating costs. PMID- 24350435 TI - Addressing the challenges for sustainable production of algal biofuels: I. Algal strains and nutrient supply. AB - Microalgae hold promise for the production of sustainable replacement of fossil fuels due to their high growth rates, ability to grow on non-arable land and their high content, under the proper conditions, of high energy compounds that can be relatively easily chemically converted to fuels using existing technology. However, projected large-scale algal production raises a number of sustainability concerns concerning land use, net energy return, water use and nutrient supply. The state-of-the-art of algal production of biofuels is presented with emphasis on some possible avenues to provide answers to the sustainability questions that have been raised. Here, issues concerning algal strains and supply of nutrients for large-scale production are discussed. Since sustainability concerns necessitate the use of wastewaters for supply of bulk nutrients, emphasis is placed on the composition and suitability of different wastewater streams. At the same time, algal cultivation has proven useful in waste treatment processes, and thus this aspect is also treated in some detail. PMID- 24350437 TI - Conversion of switchgrass to ethanol using dilute ammonium hydroxide pretreatment: influence of ecotype and harvest maturity. AB - Switchgrass (Panicum virgatum L.) is a perennial C4 grass that is being developed as a bioenergy crop because it has high production yields and suitable agronomic traits. Five switchgrass biomass samples from upland and lowland switchgrass ecotypes harvested at different stages or maturity were used in this study. Switchgrass samples contained 317.0-385.0 g glucans/kg switchgrass dry basis (db) and 579.3-660.2 g total structural carbohydrates/kg switchgrass, db. Carbohydrate contents were greater for the upland ecotype versus lowland ecotype and increased with harvest maturity. Pretreatment of switchgrass with dilute ammonium hydroxide (8% w/w ammonium loading) at 170 degrees C for 20 min was determined to be effective for preparing switchgrass for enzymatic conversion to monosaccharides; glucose recoveries were 66.9-90.5% and xylose recoveries 60.1-84.2% of maximum and decreased with increased maturity at harvest. Subsequently, pretreated switchgrass samples were converted to ethanol by simultaneous saccharification and fermentation using engineered xylose-fermenting Saccharomyces cerevisiae strain YRH400. Ethanol yields were 176.2-202.01/Mg of switchgrass (db) and followed a similar trend as observed for enzymatic sugar yields. PMID- 24350436 TI - Addressing the challenges for sustainable production of algal biofuels: II. Harvesting and conversion to biofuels. AB - In order to ensure the sustainability of algal biofuel production, a number of issues need to be addressed. Previously, we reviewed some of the questions in this area involving algal species and the important challenges of nutrient supply and how these might be met. Here, we take up issues involving harvesting and the conversion ofbiomass to biofuels. Advances in both these areas are required if these third-generation fuels are to have a sufficiently high net energy ratio and a sustainable footprint. A variety of harvesting technologies are under investigation and recent studies in this area are presented and discussed. A number of different energy uses are available for algal biomass, each with their own advantages as well as challenges in terms of efficiencies and yields. Recent advances in these areas are presented and some of the especially promising conversion processes are highlighted. PMID- 24350438 TI - Landfill leachate--a water and nutrient resource for algae-based biofuels. AB - There is a pressing need for sustainable renewable fuels that do not negatively impact food and water resources. Algae have great potential for the production of renewable biofuels but require significant water and fertilizer resources for large-scale production. Municipal solid waste (MSW) landfill leachate (LL) was evaluated as a cultivation medium to reduce both water and elemental fertilizer demands of algae cultivation. Daily growth rate and cell yield of two isolated species of algae (Scenedesmus cf. rubescens and Chlorella cf. ellipsoidea) were cultivated in MSW LL and compared with Bold's Basal Medium (BBM). Results suggest that LL can be used as a nutrient resource and medium for the cultivation of algae biomass. S. cf. rubescens grew well in 100% LL, when pH was regulated, with a mean growth rate and cell yield 91.2% and 92.8% of those observed in BBM, respectively. S. cf. rubescens was more adaptable than C. cf. ellipsoidea to the LL tested. The LL used in this study supported a maximum volumetric productivity of 0.55 g/L/day of S. cf. rubescens biomass. The leachate had sufficient nitrogen to supply 17.8 g/L of algae biomass, but was limited by total phosphorus. Cultivation of algae on LL offsets both water and fertilizer consumption, reducing the environmental footprint and increasing the potential sustainability of algae-based biofuels. PMID- 24350439 TI - The analysis of macroalgae biomass found around Hawaii for bioethanol production. AB - Macroalgae commonly found in the ocean around Hawaii were collected from near shore locations and their potential as biomass feedstock for fermentative ethanol was investigated. A green alga, Ulva reticulata, was selected for further analysis. This species forms large complex structures that grow quickly and has high dry biomass percentage (20%), soluble carbohydrates (18%); and high total carbohydrates along with low quantities of lignin (13%). During acid saccharification, it was determined that 49% of the total mass was observed as sugars in the hydrolysate; however, fermentation was problematic. Enzymatic saccharification using cellulase from Trichoderma reesei was attempted which recovered a measured maximum of 20% glucose based on the initial dry mass. Fermentation successfully converted all the glucose to ethanol. The measured ethanol yield corresponded to approximately 90 L per tonne of dried macroalgae. PMID- 24350440 TI - Photosynthesis-fermentation hybrid system to produce lipid feedstock for algal biofuel. AB - To avoid bacterial contamination due to medium replacement in the expanded application of a photosynthesis-fermentation model, an integrated photosynthesis fermentation hybrid system was set up and evaluated for algal lipid production using Chlorella protothecoides. In this system, the CO2-rich off-gas from the fermentation process was recycled to agitate medium in thephotobioreactor, which could provide initial cells for the heterotrophic fermentation. The cell concentration reached 1.03 +/- 0.07 g/L during photoautotrophic growth and then the concentrated green cells were switched to heterotrophic fermentation after removing over 99.5% ofnitrogen in the medium by a nitrogen removal device. At the end offermentation in the system, the cell concentration could reach as high as 100.51 +/- 2.03 g/L, and 60.05 +/- 1.38% lipid content was achieved simultaneously. The lipid yield (60.36 +/- 2.63 g/L) in the hybrid system was over 700 times higher than that in a photobioreactor and exceeded that by fermentation alone (47.56 +/- 7.31 g/L). The developed photosynthesis fermentation hybrid system in this study was not only a feasible option to enhance microalgal lipid production, but also an environment-friendly approach to produce biofuel feedstock through concurrent utilization of ammonia nitrogen, CO2, and organic carbons. PMID- 24350441 TI - Algal biomass production and wastewater treatment in high rate algal ponds receiving disinfected effluent. AB - Algal biomass production associated with wastewater is usually carried out in high rate algal ponds (HRAPs), which are concomitantly used in the treatment of such effluent. However, most types of wastewater have high levels of bacteria that can inhibit the growth of algal biomass by competing for space and nutrients. The objective of this study was to assess the influence of ultraviolet (UV) pre-disinfection on the performance of HRAPs used for wastewater treatment and algal biomass production. Two HRAPs were tested: one received effluent from an upflow anaerobic sludge blanket (UASB) reactor- HRAP -and the second received UASB effluent pre-disinfected by UV radiation-(UV)HRAP. Physical, chemical and microbiological parameters were monitored, as well as algal biomass productivity and daily pH and dissolved oxygen (DO) variation. The (UV)HRAP presented highest DO and pH values, as well as greater percentage of chlorophyll a in the biomass, which indicates greater algal biomass productivity. The average percentages of chlorophyll a found in the biomass obtained from the HRAP and the (UV)HRAP were 0.95 +/- 0.65% and 1.58 +/- 0.65%, respectively. However, total biomass productivity was greater in the HRAP (11.4 gVSSm(-2) day(-1)) compared with the (UV)HRAP (9.3 gVSSm(-2) day(-1)). Mean pH values were 7.7 +/- 0.7 in the HRAP and 8.1 +/- 1.0 in the (UV)HRAP, and mean values of DO percent saturation were 87 +/- 26% and 112 +/- 31% for the HRAP and the (UV)HRAP, respectively. Despite these differences, removal efficiencies of organic carbon, chemical oxygen demand, ammoniacal nitrogen and soluble phosphorus were statistically equal at the 5% significance level. PMID- 24350442 TI - Effects of calcium, magnesium and sodium chloride in enhancing lipid accumulation in two green microalgae. AB - Biodiesel from microalgae has the potential as a sustainable fuel, since some species show exceptionally high lipid accumulation potential under various stresses. Effects of different concentrations of Ca, Mg and NaCl in the growth medium on biomass yield and lipid accumulation of Chlorella vulgaris and Scenedesmus obliquus grown under batch culture mode were investigated. Starvation of Mg showed a marginal rise in lipid content for a short period of time. Ca starved cultures, however, demonstrated a profound rise in lipid content, i.e. 40% of dry cell wt. (dcw) was recorded against 11.9% control for C. vulgaris and 37% (dcw) against 11.3% for S. obliquus. Under increased concentration of Mg, significant rise in biomass and lipid yield was recorded. Effect of NaCl-induced osmotic stress showed lipid accumulation of approximately 40% (dcw) in both the test algae, whereas the biomass yield was severely affected. The fatty acid profiles under the above stresses were analysed and discussed. PMID- 24350443 TI - Screening for novel bacteria from the bioenergy feedstock switchgrass (Panicum virgatum L.). AB - Switchgrass is considered as a good candidate for biofuel, especially ethanol production due to its huge biomass output and high cellulose content. In a search for novel microorganisms capable of using and degrading switchgrass to produce sugars and ethanol, enrichment experiments were established to screen for microorganisms from soil samples obtained at the University of Tennessee Agricultural Research Station, Jackson, Tennessee. Three enrichments were prepared and incubated at different pH and temperatures: (1) 30 degrees C, pH 5, (2) 30 degrees C, pH 8 and (3) 60 degrees C, pH5. Bulk community DNA was directly extracted from the enrichments. Microbial community structures were determined by phylogenetic analysis of 16S rRNA gene sequences retrieved from the enrichment cultures containing switchgrass as the carbon source. The mesophilic enrichments were dominated by Sarcina, Anaerobacter, and Clostrium, which were not found in the thermophilic enrichment. The thermophilic enrichment selected for two types of bacteria belonging to the class Bacilli (Geobacillus and Saccharococcus). The thermophilic enrichments were dominated by the Geobacillus spp. (Firmicutes, class Bacilli), and Saccharococcus (Firmicutes, class Bacilli); both containing thermophilic microorganisms with some cellulolytic members. Enzymatic assays detected the presence of enzymes involved in cellulose (beta-glucosidase and cellobiohydrolase) and hemicellulose degradations (beta-xylosidase); and the activity tends to be higher in the enrichments incubated at 30 degrees C. PMID- 24350444 TI - A cooperative microbial fuel cell system for waste treatment and energy recovery. AB - A cooperative microbial fuel cell (MFC) system was developed and investigated for its performance in waste treatment and bioenergy production. The system consisted of a conventional MFC and a dual-cathode MFC that was specially designed for nitrogen removal. Three feeding solutions, including a synthetic solution (acetate as an organic source), digested sludge and landfill leachate, were used as substrates. The MFC system removed more than 99% of chemical oxygen demand (COD) from the synthetic solution, and the organic removal mainly occurred in the anodes of the MFCs. Nitrogen, on the other hand, was removed in the cathodes of the MFC system, which achieved more than 98% removal of ammonium and 96% removal of total nitrogen. The MFC system also effectively treated the actual wastes and removed more than 85% of the total COD and 50-70% of the total nitrogen from the digested sludge and landfill leachate. The organic removal rates with the actual wastes were significantly higher than in other MFC systems. In general, the MFC system consumed less than 0.06 kWh/m3 or 0.1 kWh/kg COD, demonstrating that low energy consumption is a major advantage of MFC technology. The MFC system produced 0.1023 kWh/kg COD from the synthetic solution, much higher than the 0.0097 kWh/kg COD and 0.0019 kWh/kg COD from the actual wastes, resulting in a theoretically positive energy balance with the synthetic solution; however, the net energy with the actual wastes was negative. PMID- 24350445 TI - Microbial fuel cells and microbial electrolysis cells for the production of bioelectricity and biomaterials. AB - Today's global energy crisis requires a multifaceted solution. Bioenergy is an important part of the solution. The microbial fuel cell (MFC) technology stands out as an attractive potential technology in bioenergy. MFCs can convert energy stored in organic matter directly into bioelectricity. MFCs can also be operated in the electrolysis mode as microbial electrolysis cells to produce bioproducts such as hydrogen and ethanol. Various wastewaters containing low-grade organic carbons that are otherwise unutilized can be used as feed streams for MFCs. Despite major advances in the past decade, further improvements in MFC power output and cost reduction are needed for MFCs to be practical. This paper analysed MFC operating principles using bioenergetics and bioelectrochemistry. Several major issues were explored to improve the MFC performance. An emphasis was placed on the use of catalytic materials for MFC electrodes. Recent advances in the production of various biomaterials using MFCs were also investigated. PMID- 24350446 TI - Effect of temperature change on power generation of microbial fuel cell. AB - Microbial fuel cell (MFC), which can directly generate electricity from biodegradable materials, has been receiving increasing attention. Effects of temperature change on power density, electrode potential, columbic efficiency, chemical oxygen demand removal and internal resistance in two chambers MFCs were examined in this paper. The maximum power density of 7.89 W/m3 was achieved at 37 degrees C, with 199% higher at 10 degrees C (2.64 W/m3), 24% higher at 30 degrees C (6.34 W/m3) and 21% higher at 43 degrees C, no steady power generation was observed at 55 degrees C. Low temperature to 10 degrees C might have a huge effect on anode potential, especially at higher current, but increasing the temperature to 43 degrees C had a main effect on the cathode performance when the MFCs have been established at 37 degrees C. The internal resistance of MFC was about 29 omega at 37 degrees C, and increased 62% and 303% when MFC switched to 30 degrees C and 10 degrees C. Similarly, internal resistance increased 48% at 43 degrees C. The effect of temperature on MFC performance was expressed by internal resistance, the higher the internal resistance of MFC, the lesser the power density obtained. The Columbic efficiencies were 8.65% at 30 degrees C, 8.53% at 37 degrees C, and 13.24% at 43 degrees C. These results demonstrate that MFCs can effectively be operated over a wide range of temperatures. PMID- 24350447 TI - Integrated conversion of food waste diluted with sewage into volatile fatty acids through fermentation and electricity through a fuel cell. AB - In this study, domestic wastewater was given a second life as dilution medium for concentrated organic waste streams, in particular artificial food waste. A two step continuous process with first volatile fatty acid (VFA)/hydrogen production and second electricity production in microbial fuel cells (MFCs) was employed. For primary treatment, bioreactors were optimized to produce hydrogen and VFAs. Hydrolysis of the solids and formation of fermentation products and hydrogen was monitored. In the second step, MFCs were operated batch-wise using the effluent rich in VFAs specifically acetic acid from the continuous reactor of the first step. The combined system was able to reduce the chemical oxygen demand load by 90%. The concentration of VFAs was also monitored regularly in the MFCs and showed a decreasing trend over time. Further, the anode potential changed from 500 to OmV vs. Ag/AgCl when the VFAs (especially acetate) were depleted in the system. On feeding the system again with the effluent, the anode potential recovered back to -500 mV vs. Ag/AgCl. Thus, the overall aim of converting chemical energy into electrical energy was achieved with a columbic efficiency of 46% generating 65.33 mA/m2 at a specific cell potential of 148 mV. PMID- 24350448 TI - A flat microbial fuel cell for decentralized wastewater valorization: process performance and optimization potential. AB - A very compact flat microbial fuel cell (MFC), with 64 cm2 each for the anode surface and the cathode surface and 1 cm3 each for the anode and cathode chambers, was tested for wastewater treatment with simultaneous electricity production with the ultimate goal of implementing an autonomous service in decentralized wastewater treatment systems. The MFC was operated with municipal wastewater in sequencing batch reactor mode with re-circulation. Current densities up to 407 W/m3 and a carbon removal of 83% were obtained. Interruption in the operation slightly decreased power density, while the re-circulation ratio did not influence power generation. The anode biofilm presented high conductivity, activity and diversity. The denaturing gradient gel electrophoresis band-pattern of the DNA showed the presence of several ribotypes with different species of Shewanellaceae and Geobacteraceae families. PMID- 24350449 TI - Inoculum selection to enhance performance of a microbial fuel cell for electricity generation during wastewater treatment. AB - Experiments were designed to evaluate the influence of various anaerobic inoculums to enhance microbial fuel cell (MFC) performance utilizing tannery wastewater as substrate. Three bacterial electrogenic strains, tolerant to tannery environment, were isolated from soil contaminated with tannery waste and tannery wastewater was inoculated with these monotypes and mixed consortia of three bacterial strains in different MFCs. Comparative analysis was made by treating the tannery wastewater with foreign microbial consortia (activated sludge inoculum) and with only natural habitat microbes already present in plain wastewater. It was observed that inoculum contributes great effect on the MFC performance. Among the studied inoculation strategies, mixed electrogenic strain inocula enabled higher current yield along with concurrent substrate removal efficiency. On the contrary, plain wastewater resulted in relatively low efficiency. PMID- 24350450 TI - Effect of thermal pre-treatment on inoculum sludge to enhance bio-hydrogen production from alkali hydrolysed rice straw in a mesophilic anaerobic baffled reactor. AB - The effect of thermal pre-treatment on inoculum sludge for continuous H2 production from alkali hydrolysed rice straw using anaerobic baffled reactor (ABR) was investigated. Two reactors, ABR1 and ABR2, were inoculated with untreated and thermally pre-treated sludge, respectively. Both reactors were operated in parallel at a constant hydraulic retention time of 20 h and organic loading rate ranged from 0.5 to 2.16 g COD/L d. The results obtained indicated that ABR2 achieved a better hydrogen conversion rate and hydrogen yield as compared with ABR1. The hydrogen conversion rates were 30% and 24%, while the hydrogen yields were 1.19 and 0.97 mol H2/mol glucose for ABR2 and ABR1, respectively. Similar trend was observed for chemical oxygen demand (COD) and carbohydrate removal, where ABR2 provided a removal efficiency of 53 +/- 2.3% for COD and 46 +/- 2% for carbohydrate. The microbial community analysis using 16S rRNA phylogeny revealed the presence of different species of bacteria, namely Clostridium, Prevotella, Paludibacter, Ensifer, and Petrimonas within the reactors. Volatile fatty acids generated from ABR1 and ABR2 were mainly in the form of acetate and butyrate and a relatively low fraction ofpropionate was detected in ABR1. Based on these results, thermal pre-treatment ofinoculum sludge is preferable for hydrogen production from hydrolysed rice straw. PMID- 24350451 TI - Crustacean zooplankton in aerated wastewater treatment lagoons as a potential feedstock for biofuel. AB - Zooplankton biomass productivity was estimated for two 64,000 m3 (1.7 ha) facultative aerated wastewater treatment lagoons to evaluate potential biodiesel production from zooplankton biomass. Lagoons were monitored bi-weekly during summer 2010. Lipid accumulated by crustacean zooplankton was considered the most efficient means by which to collect lipid produced by phytoplankton owing to the greater ease in the collection of these organisms (>0.153mm) compared with unicellular algae (size <0.06 mm). In terms of biomass, the cladoceran Daphnia and the copepod Cyclops were the dominant zooplankton in these hypereutrophic lagoons, while unicellular chlorophytes dominated the phytoplankton community. Secondary productivity of these lagoons (250 g of dry weight m(-2) yr(-1)) is comparable to the secondary productivity of other sewage lagoons. The potential biodiesel production for one lagoon was estimated to be 0.04 +/- 0.02 L m(-2) yr( 1), which results in a total of 1120 +/- 560 L from two lagoons. This study showed that there are organisms present in wastewater lagoons, besides algae, that can serve as a biofuel feedstock. Additionally, this research expands the current knowledge of facultative aerated wastewater lagoon ecology and waste stream-derived biofuel. Future research should include complete life cycle and economic analyses to determine if harvesting zooplankton from wastewater lagoons is a sustainable endeavour. PMID- 24350452 TI - Integrating syngas fermentation with the carboxylate platform and yeast fermentation to reduce medium cost and improve biofuel productivity. AB - To ensure economic implementation of syngas fermentation as a fuel-producing platform, engineers and scientists must both lower operating costs and increase product value. A considerable part of the operating costs is spent to procure chemicals for fermentation medium that can sustain sufficient growth of carboxydotrophic bacteria to convert synthesis gas (syngas: carbon monoxide, hydrogen, and carbon dioxide) into products such as ethanol. Recently, we have observed that wildtype carboxydotrophic bacteria (including Clostridium ljungdahlii) can produce alcohols with a longer carbon chain than ethanol via syngas fermentation when supplied with the corresponding carboxylic acid precursors, resulting in possibilities of increasing product value. Here, we evaluated a proof-of-concept system to couple syngas fermentation with the carboxylate platform to both lower medium costs and increase product value. Our carboxylate platform concept consists of an open culture, anaerobic fermentor that is fed with corn beer from conventional yeast fermentation in the corn kernel-to-ethanol industry. The mixed-culture anaerobic fermentor produces a mixture ofcarboxylic acids at dilute concentrations within the carboxylate platform effluent (CPE). Besides providing carboxylic acid precursors, this effluent may represent an inexpensive growth medium. An elemental analysis demonstrated that the CPE lacked certain essential trace metals, but contained ammonium, phosphate, sodium, chloride, potassium, magnesium, calcium, and sulphate at required concentrations. CPE medium with the addition of a trace metal solution supported growth and alcohol production of C. ljungdahlii at similar or better levels compared with an optimized synthetic medium (modified ATCC 1754 medium). Other expensive supplements, such as yeast extract or macro minerals (ammonium, phosphate), were not required. Finally, n-butyric acid and n caproic acid within the CPE were converted into their corresponding medium-chain alcohols n-butanol and n-hexanol. PMID- 24350453 TI - Isolation and screening of carboxydotrophs isolated from composts and their potential for butanol synthesis. AB - Carboxydotrophs are known for their ability to convert carbon monoxide (CO) to butanol through fermentation. Such a platform offers a promising alternative approach to biofuel production from synthesis gas feedstocks. In this study, carboxydotrophs were isolated from various manure compost. Out of 500 isolates, only 11 carboxydotrophs (7 mesophiles and 4 thermophiles) were found to utilize CO as the sole source of carbon and energy. To assess the biochemical basis for their ability to produce biofuel (butanol), the level of activities of CO dehydrogenase (CODH), hydrogenase and butanol dehydrogenase (BDH) enzymes for these isolates against the known carboxydotroph, Butyribacterium methylotrophicum was assessed. All isolates showed evidence of enzyme activities (0.16-2.20 micromol min(-1)), with the majority exhibiting higher activities compared with the known carboxydotroph, B. methylotrophicum (0.33-0.71 micromol min(-1)). The level of activities for CODH and BDH ranged from 0.163-3.59 micromolmin(-1) and 0.19-2.2 micromolmin(-1), respectively. Three isolates (M7-1, T2-22, and T3-14) demonstrated enzymatic activity three to seven times higher than B. methylotrophicum. Of these, T2-22 exhibited the highest BDH activity and shows great promise in the conversion of toxic CO into butanol more so than other carboxytotrophs known thus far. This study revealed some biochemical basis for butanol production from CO by carboxydotrophs. However, more research is needed to discover a direct biological route for butanol production from CO to strengthen their potential for synthesis gas bioprocessing. Follow-up work will focus on whole-genome sequencing of the promising isolate T2-22 to provide system level insights into how carboxydotrophs utilize and regulate their molecular machineries for butanol production. PMID- 24350454 TI - Comparative assessment of various lipid extraction protocols and optimization of transesterification process for microalgal biodiesel production. AB - Biodiesel, using microalgae as feedstocks, is being explored as the most potent form of alternative diesel fuel for sustainable economic development. A comparative assessment of various protocols for microalgal lipid extraction was carried out using five green algae, six blue-green algae and two diatom species treated with different single and binary solvents both at room temperature and using a soxhlet. Lipid recovery was maximum with chloroform-methanol in the soxhlet extractor. Pretreatments ofbiomass, such as sonication, homogenization, bead-beating, lyophilization, autoclaving, microwave treatment and osmotic shock did not register any significant rise in lipid recovery. As lipid recovery using chloroform-methanol at room temperature demonstrated a marginally lower value than that obtained under the soxhlet extractor, on economical point of view, the former is recommended for microalgal total lipid extraction. Transesterification process enhances the quality of biodiesel. Experiments were designed to determine the effects of catalyst type and quantity, methanol to oil ratio, reaction temperature and time on the transesterification process using response surface methodology. Fatty acid methyl ester yield reached up to 91% with methanol:HCl:oil molar ratio of 82:4:1 at 65 degrees C for 6.4h reaction time. The biodiesel yield relative to the weight of the oil was found to be 69%. PMID- 24350455 TI - Experimental investigation on performance and exhaust emissions of castor oil biodiesel from a diesel engine. AB - Biodiesel, produced from plant and animal oils, is an important alternative to fossil fuels because, apart from dwindling supply, the latter are a major source of air pollution. In this investigation, effects of castor oil biodiesel blends have been examined on diesel engine performance and emissions. After producing castor methyl ester by the transesterification method and measuring its characteristics, the experiments were performed on a four cylinder, turbocharged, direct injection, diesel engine. Engine performance (power, torque, brake specific fuel consumption and thermal efficiency) and exhaust emissions were analysed at various engine speeds. All the tests were done under 75% full load. Furthermore, the volumetric blending ratios of biodiesel with conventional diesel fuel were set at 5, 10, 15, 20 and 30%. The results indicate that lower blends of biodiesel provide acceptable engine performance and even improve it. Meanwhile, exhaust emissions are much decreased. Finally, a 15% blend of castor oil biodiesel was picked as the optimized blend of biodiesel-diesel. It was found that lower blends of castor biodiesel are an acceptable fuel alternative for the engine. PMID- 24350456 TI - Evaluation of the biomethane potential from multiple waste streams for a proposed community scale anaerobic digester. AB - This paper examines the biomethane potential from organic waste for a proposed community scale anaerobic digester in a rural town. The biomethane potential test is used to assess the suitability of waste streams for biomethane production and to examine the variation in biomethane potential between waste sub-streams. A methodology for accurately estimating the biomethane potential from multiple heterogeneous organic waste substrates is sought. Five main waste streams were identified as possible substrates for biogas production, namely Abattoir waste (consisting of paunch and de-watered activated sludge); cheese factory effluent; commercial and domestic food waste; pig slurry and waste water treatment sludge. The biomethane potential of these waste streams ranged from as low as 99 L CH4 kg VS(-1) for pig slurry to as high as 787 L CH4 kg VS(-1) for dissolved air floatation (DAF) sludge from a cheese effluent treatment plant. The kinetic behaviour of the biomethane production in the batch test is also examined. The objective of the paper is to suggest an optimum substrate mix in terms of biomethane yield per unit substrate for the proposed anaerobic digester. This should maximize the yield of biomethane per capital investment. Food waste displayed the highest biomethane yield (128 m(n)(3) t(-1)) followed by cheese waste (38 m(n)(3) t(-1)) and abattoir waste (36 m(n)(3) t(-1)). It was suggested that waste water sludge (16 m(n)(3) t(-1)) and pig slurry (4 m(n)(3) t(-1)) should not be digested. However, the biomethane potential test does not give information on the continuous operation of an anaerobic digester. PMID- 24350457 TI - Selection of microalgae suitable for culturing with digestate from methane fermentation. AB - The effects ofdigestate on the growth rates of Euglena gracilis, Chlorella vulgaris, and Dunaliella tertiolecta were investigated to select suitable microalgae for culturing with digestate from methane fermentation. Microalgae were cultured in an aqueous solution containing digestate at concentrations of 5%, 10%, 13%, 20%, 40%, 50%, and 100%, and Cramer-Myers (CM) solution as a control, at photosynthetic photon flux densities (PPFDs) of 75-150 micromol m(-2) s(-1) with continuous illumination at 30 degrees C. The number of cells was monitored daily, and specific growth rates (mu) were calculated as cellular multiplication rates. The maximum mu values of these species were greater in appropriate concentrations of digestate than in CM medium. The maximum mu values were 0.047 h(-1) in 10% digestate for E. gracilis, 0.065 h(-1) in 20% digestate for C. vulgaris, and 0.052 h(-1) in 50% digestate for D. tertiolecta at a PPFD of 150 micromol m(-2) s(-1). The mu of D. tertiolecta were 2.5 and 1.1 times higher than those of E. gracilis and C. vulgaris, respectively, in 50% digestate. These results demonstrated that these species could be cultured at high growth rates with diluted methane fermentation sludge and that, among these species, Dunaliella sp. was suitable for culturing at higher concentration of digestate under relatively low-level light conditions. PMID- 24350458 TI - Modified batch anaerobic digestion assay for testing efficiencies of trace metal additives to enhance methane production of energy crops. AB - Batch biochemical methane potential (BMP) assays to evaluate the methane yield of biogas substrates such as energy crops are usually carried out with undiluted inoculum. A BMP assay was performed on two energy crops (green cuttings and grass silage). Anaerobic digestion was performed both with and without supplementation of three commercial additives containing trace metals in liquid, solid or adsorbed form (on clay particles). In order to reveal positive effects of trace metal supplementation on the methane yield, besides undiluted inoculum, 3-fold and 10-fold dilutions of the inoculum were applied for substrate digestion. Diluted inoculum variants were supplemented with both mineral nutrients and pH buffering substances to prevent a collapse of the digestion process. As expected, commercial additives had no effect on the digestion process performed with undiluted inoculum, while significant increases of methane production through trace element supplementation could be observed on the diluted variants. The effect of inoculum dilution may be twofold: (1) decrease in trace metal supplementation from the inoculum and (2) reduction in the initial number of bacterial cells. Bacteria require higher growth rates for substrate degradation and hence have higher trace element consumption. According to common knowledge of the biogas process, periods with volatile fatty acids accumulation and decreased pH may have occurred in the course ofanaerobic digestion. These effects may have led to inhibition, not only ofmethanogenes and acetogenes involved in the final phases of methane production, but also offibre-degrading bacterial strains involved in polymer hydrolysis. Further research is required to confirm this hypothesis. PMID- 24350459 TI - Evaluation of the biomethane yield from anaerobic co-digestion of nitrogenous substrates. AB - This paper examines three substrates for anaerobic co-digestion: abattoir waste; cheese waste and food waste. These substrates were assessed in detail for suitability for biomethane production. Biomethane potential (BMP) assays were carried out in mono and co-digestion for the three substrates and two mixes: T1 (40% abattoir waste; 50% cheese waste and 10% food waste on a wet weight basis) and T2 (30% abattoir waste; 40% cheese waste and 30% food waste). The C:N ratio of both mixes was below optimum. Low levels suggest that the production of free ammonia (NH3) in semi-continuous digestion was of primary concern. Both mixes were digested in a semi-continuous process for 25 weeks. The recommended operating condition for T1 was a loading rate of 3 kg VS mn(-3) day(-1) at a retention time of 23 days. The biomethane yield was 305 L CH4 kg(-1) volatile solids (VS) which was 87% of the BMP value and equivalent to 61% biodegradability. For T2 (with the higher C:N ratio) a higher loading rate of 4kg VS mn(-3) day(-1) at a lower retention time of 15 days was recommended. The biomethane yield was 439 L CH4 kg(-1) VS (99% of the BMP value and 84% biodegradibility). At these conditions, levels of total ammonical nitrogen (TAN) were 4109 and 4831 mg L(-1) for T1 and T2, respectively. These values are on the large side according to the literature. The temperature was reduced to 35 degrees C to minimize toxicity associated with TAN. Ratios of volatile acids to bicarbonate were typically in the range of 0.2-0.3 suggesting stable operation. PMID- 24350460 TI - Enhancement of methane yield from wheat straw, miscanthus and willow using aqueous ammonia soaking. AB - The increasing demand for methane production cannot be satisfied by the use of anaerobic digestion only from waste/wastewater treatment. Perennial energy crops, such as miscanthus and willow, as well as agricultural residues can be considered as options for increasing the methane production through biomass digestion, due to their high organic content and biomass yield. These materials present a great potential, which is only limited by the rigid lignocellulosic structure. In this case, it is possible to apply a pretreatment step in order to achieve increased biogas production. In the present study, aqueous ammonia soaking (AAS) has been investigated as a method to disrupt the lignocellulosic structure and increase the methane yield of wheat straw, miscanthus and willow. Among the three biomasses tested, wheat straw and miscanthus were the most promising in terms of methane production, yielding around 200 and 230 ml of methane per gram of total solids. In all three cases, AAS resulted to an increase in methane yield of 37 41%, 25-27% and 94-162% for wheat straw, miscanthus and willow, respectively. A comparison of the methane yields after 20 and 50 days of anaerobic digestion revealed that AAS affected positively the methane production rate as well. AAS also resulted to a low solubilization of sugars, with a 15.4% and 8.9% increase in soluble xylose concentration in miscanthus and willow, respectively, and a 5% solubilization of glucose in AAS-pretreated miscanthus. PMID- 24350461 TI - Biogas production by encased bacteria in synthetic membranes: protective effects in toxic media and high loading rates. AB - A bioreactor including encased digesting bacteria for biogas production was developed, and its performance in toxic media and under high organic loading rates (OLRs) was examined and compared with traditional digestion reactors. The bacteria (3 g) were encased and sealed in 3 x 6 cm2 PVDF (polyvinylidene fluoride) membranes with a pore size of 0.1 microm, and then several sachets were placed in the reactors. They were then examined in toxic medium containing up to 3% limonene as a model inhibitor in batch reactors, and OLRs of up to 20 g COD/L.day in semi-continuous digestions. The free and encased cells with an identical total bacterial concentration of 9 g in a medium containing 2% limonene produced at most 6.56 and 23.06 mL biogas per day, respectively. In addition, the digestion with free cells completely failed at an OLR of 7.5 gCOD/L.day, while the encased cells were still fully active with a loading of 15 g COD/L x day. PMID- 24350462 TI - Management of various organic fractions of municipal solid waste via recourse to VFA and biogas generation. AB - A hybrid anaerobic solid-liquid system was used for anaerobic digestion of organic fraction of municipal solid waste (OFMSW) consisting of mixed food + fruit waste and vegetable waste. Hydrolysis and acidogenesis potential of the above wastes were evaluated with the aim of producing value-added products in the form of volatile fatty acids (VFAs) and biogas recovery. Efficient hydrolysis and acidogenesis of mixed food + fruit waste was observed at a hydraulic retention time (HRT) of 1-3 d with a five-fold increase in soluble chemical oxygen demand (SCOD) followed by VFA production consisting of 50-75% acetic acid. Longer time was required for hydrolysis of vegetable waste with optimum hydrolysis and SCOD generation at 9 d HRT followed by VFA synthesis consisting of 45% acetic acid. Higher inoculum:substrate ratios resulted in improved hydrolysis and acidogenesis rates for vegetable waste in shorter time of 6 d with higher VFA production and increase in acetic acid content to 70%. When acidogenic leachate was fed into methanogenic reactors, detectable biogas production was observed after 25 d with 37-53% SCOD removal from leachate from mixed food + fruit waste and methane production of 0.066-0.1 L g(-1) SCOD removed and methane content of 38%. Though biogas yield from acidogenic leachate from vegetable waste was lower, nearly 94% volatile solids (VS) removal was observed in the reactors thereby providing methane yield of 0.13-0.21 L g(-1) VS consumed. Thus, the study provided a method for generation of value-added products from an otherwise misplaced resource in the form of OFMSW. PMID- 24350463 TI - Recovery of biogas as a source of renewable energy from ice-cream production residues and wastewater. AB - Proper management of waste streams and residues from agro-industry is very important to prevent environmental pollution. In particular, the anaerobic co digestion process can be used as an important tool for safe disposal and energy recovery from agro-industry waste streams and residues. The primary objective of this laboratory-scale study was to determine whether it was possible to recover energy (biogas) from ice-cream production residues and wastewater, through a mesophilic anaerobic co-digestion process. A high methane yield of 0.338 L CH4/gCOD(removed) could be achieved from anaerobic digestion of ice-cream wastewater alone, with almost 70% of methane in biogas, while anaerobic digestion of ice-cream production residue alone did not seem feasible. When wastewater and ice-cream production residue were anaerobically co-digested at a ratio of 9:1 by weight, the highest methane yield of 0.131 L CH4/gCOD(removed) was observed. Buffering capacity seemed to be imperative in energy recovery from these substrates in the anaerobic digestion process. PMID- 24350464 TI - The effect of solids retention time on dissolved methane concentration in anaerobic membrane bioreactors. AB - We assessed the effect of solids retention times (SRT) on dissolved methane concentration in a lab-scale anaerobic membrane bioreactor (AnMBR) operated at SRT 20d and 40d at ambient temperature (23 +/- 1 degrees C). Daily methane production was 196 +/- 17 mL/d and 285 +/- 18 mL/d for SRT 20d and 40d, respectively. In comparison, the average concentration of dissolved methane in AnMBR permeates was 9.9 +/- 2.3 mg/L for SRT 20d (close to thermodynamic equilibrium), which was decreased to 4.3 +/- 0.3 mg/L for SRT 40d. We often found oversaturation of dissolved methane at SRT 20d, which means that mass transfer of dissolved methane from liquid to gas phase is dynamic at this short SRT. However, we never detected oversaturation of dissolved methane at SRT 40d, due to slow endogenous decay kinetics. Higher daily methane production at SRT 40d than that at SRT 20d indicates that methane was supplementarily produced from biomass electrons by endogenous decay. This study shows that operation of AnMBRs under long SRT can keep low dissolved methane concentration in AnMBR permeate, along with high methane yield. PMID- 24350465 TI - Biological pretreatment of non-flocculated sludge augments the biogas production in the anaerobic digestion of the pretreated waste activated sludge. AB - High-efficiency resource recovery from municipal solid waste (MSW) has been a focus of attention. The objective of this research is to develop a bio pretreatment process for application prior to the anaerobic digestion of MSW to improve methane productivity. Bacillus licheniformis was used for pretreating MSW (non-flocculated with 0.07% citric acid), followed by anaerobic digestion. Laboratory-scale experiments were carried out in semi-continuous bioreactors, with a total volume of 5 L and working volume of 3 L. Among the nine organic loading rates (OLRs) investigated, the OLR of 0.84 kg SS m(-3) reactor day(-1) was found to be the most appropriate for economic operation of the reactor. Pretreatment of MSW prior to anaerobic digestion led to 55% and 64% increase of suspended solids (SS) and volatile solids reduction, respectively, with an improvement of 57% in biogas production. The results indicate that the pretreatment of non-flocculated sludge with Bacillus licheniformis which consumes less energy compared to other pretreatment techniques could be a cost-effective and environmentally sound method for producing methane from MSW. PMID- 24350466 TI - Biogas production performance of mesophilic and thermophilic anaerobic co digestion with fat, oil, and grease in semi-continuous flow digesters: effects of temperature, hydraulic retention time, and organic loading rate. AB - Anaerobic co-digestions with fat, oil, and grease (FOG) were investigated in semi continuous flow digesters under various operating conditions. The effects of hydraulic retention times (HRTs) of 12 and 24 days, organic loading rates (OLRs) between 1.19 and 8.97 gTVS/Ld, and digestion temperatures of 37 degrees C and 55 degrees C on biogas production were evaluated. It was proposed that, compared to anaerobic digestion with wastewater treatment plant sludge (primary raw sludge), semi-continuous flow anaerobic co-digestion with FOG could effectively enhance biogas and methane production. Thermophilic (55 degrees C) co-digestions exhibited higher biogas production and degradation of organics than mesophilic co digestions. The best biogas production rate of 17.4 +/- 0.86 L/d and methane content 67.9 +/- 1.46% was obtained with a thermophilic co-digestion at HRT = 24 days and OLR = 2.43 +/- 0.15 g TVS/Ld. These were 32.8% and 7.10% higher than the respective values from the mesophilic co-digestion under similar operating conditions. PMID- 24350467 TI - Continuous anaerobic digestion of food waste and design of digester with lipid removal. AB - Separation of municipal solid waste has been implemented in many cities in China. As a major component of municipal solid waste, food waste can be treated by anaerobic digestion (AD) for energy production. To provide reference data for disposing of food waste through engineering applications, continuous AD was carried out under various organic loading rates (OLRs) at 27 +/- 2 degrees C in the laboratory. The anaerobic reactor was stable with pH 7.0-7.1, total volatile fatty acid (VFA) concentrations of 206-746 mg/L, and NH4+ -N concentrations of 525-1293 mg/L when the OLR was 1.118-5.588 kg volatile solids (VS)/m(3) x d. The maximum volumetric biogas production rate was 4.41 L/L x d when the OLR was increased to 5.588 kg VS/m(3) x d with a hydraulic retention time of 30 d. When the OLR was increased to 6.706 and 8.382 kg VS/m(3) x d, biogas production was seriously inhibited by VFAs, with maximum total VFA and propionate concentrations of 8738 mg/L and 2864 mg/L, respectively. Due to the incomplete degradation of lipids, the specific methane production rate of 353-488 L/kg VS accounted for 55.2-76.3% of the theoretical methane potential calculated based on the component composition. A retrofitted anaerobic digester with lipid removal was designed to improve the efficiency. PMID- 24350468 TI - Characterization of co-digestion of industrial sludges for biogas production by artificial neural network and statistical regression models. AB - The characteristics and impact of industrial sludges of paper, chemical, petrochemical, automobile, and food industries situated in the Ulsan Industrial Complex, Ulsan, Republic of Korea in co-digestion for biogas production were assessed by artificial neural network (ANN) and statistical regression models. The regression model was based on a simplex-centroid mixture design and the ANN was based on a resilient back-propagation algorithm (topology 5-7-1). Using connection weights and bias of the trained ANN model, the impact of each sludge of co-digestion was assessed using Garsons' algorithm. Results suggested that the modelling and predictability of ANN were superior to the regression model with accuracy (A(f)) 1.01, bias (B(f)) 1.00, root mean square error 3.56, and standard error of prediction 2.51%. Sludge from the chemical industry showed the highest impact on specific methane yield (SMY(VS)) with a relative importance of 28.59% followed by sludges from paper (20.07%), food (19.59%), petrochemical (15.92%), and automobile (15.82%) industries. The interactions between diverse industrial sludges were successfully modelled and partitioned into various synergistic and antagonistic effects on SMY(VS). Synergistic interactions between the chemical industry sludge and either petrochemical or food industry sludges on SMY(VS) were detected. However, strong negative interaction between automobile sludge and other sludges was observed. This study indicates that though the ANN model performed better in prediction and impact assessments, the regression model reveals the synergistic and antagonistic interactions among sludges. PMID- 24350469 TI - Application of optimized alkaline pretreatment for enhancing the anaerobic digestion of different sunflower stalks varieties. AB - The use of lignocellulosic residues such as sunflower stalks (SS) for the production of bioenergy such as methane is a promising alternative to fossil fuels. However, their recalcitrant structure justifies the use of pretreatment to enhance the accessibility of holocelluloses and their further conversion into methane. First, different conditions of alkaline pretreatment (i.e. duration and NaOH concentration (g/100 g TS) at a fixed temperature of 55 degrees C) were tested to enhance the methane potential of the stalks of the Serin sunflower (193 mL of methane per gram of volatile solids (VS)). The greatest improvement to the methane potential (262 mL CH4 g(-1) VS) was observed at 55 degrees C, 24 h, 4 g NaOH/100 g TS. Fourier Transform Infrared spectra highlighted an accumulation of lignin in the digestate and the degradation of holocelluloses during the anaerobic process, both for pretreated and untreated SS. In a second stage, this optimum condition for alkaline pretreatment (55 degrees C, 24 h, 4 g NaOH/100 g TS) was applied to the stalks of three other varieties of sunflower. Alkaline pretreatment was effective in the delignification of the stalks of the different sunflower varieties, with lignin reduction varying from 23.3% to 36.3% VS. This reduction of lignin was concomitant with the enhancement of methane potential as compared to that of raw SS, with an increase ranging from 29% to 44% for the different SS. PMID- 24350470 TI - Mesophilic co-digestion of palm oil mill effluent and empty fruit bunches. AB - The palm oil mill industry generates palm oil mill effluent (POME) and empty fruit bunches (EFB) as by-products. This study reports the mesophilic co digestion of POME with EFB. The biochemical methane potential (BMP) of POME and EFB was 0.397 L CH4/g volatile solids (VS) and 0.264 L CH4/g VS, respectively. In a series of batch tests at various EFB to POME ratios, the maximum methane production rate was achieved at an EFB:POME ratio of 0.25-0.31:1. Performance data from lab-scale digesters confirmed the positive synergism by the addition of EFB to POME, which was attributed to the balanced chemical composition, for example the chemical oxygen demand (COD) to total Kjeldahl nitrogen (TKN) ratio. The EFB addition enhanced the acceptable organic loading rate, methane production, COD removal, and microbial activity. The mesophilic co-digestion of POME and EFB promises to be a viable recycling method to alleviate pollution problems and recover renewable energy in the palm oil mill industry. PMID- 24350471 TI - Biocrude production by activated sludge microbial cultures using pulp and paper wastewaters as fermentation substrate. AB - Municipal wastewater activated sludge contains a mixed microbial community, which can be manipulated to produce biocrude, a lipid feedstock for biodiesel production. In this study, the potential of biocrude production by activated sludge microorganisms grown in three different types of pulp and paper mill wastewaters was investigated. A 20% (v/v) activated sludge was inoculated into pulp and paper wastewater, supplemented with glucose (60 g/L) and nutrients (nitrogen and phosphorus) to obtain a high carbon to nitrogen ratio (70:1). The culture was incubated aerobically for seven days. The results showed that the activated sludge microorganisms were able to grow and accumulate lipids when cultivated in amended wastewaters. Microorganisms growing in anaerobic settling pond effluent water showed the highest lipid accumulation of up to 40.6% cell dry weight (CDW) after five days of cultivation compared with pulp wash wastewater (PuWW) (11.7% CDW) and mixed wastewater (MWW) (8.2% CDW) after seven days of cultivation. The lipids mostly contained C16-C18 fatty acids groups with oleic acid and palmitic acid being the dominant fatty acids. The maximum biodiesel yield was about 6-8% CDW for all the wastewaters. The results showed the potential of utilizing pulp and paper mill effluents and other waste streams, such as activated sludge for the sustainable production of lipids for biofuel production. PMID- 24350472 TI - Anaerobic digestion of crude glycerol as sole substrate in mixed reactor. AB - Utilization of crude glycerol (CG) from the biodiesel industry in the production of biogas offers a perspective of further energy generation, which may result into the drop of biodiesel costs on the developing world market. This contribution is focused on anaerobic treatment of CG as a single substrate in mixed laboratory reactors. Experiences from long-term operation of mixed reactors processing either untreated or acidulated CG are discussed. The possibility of cofermentation of washing water (WW) from biodiesel production with CG was also attempted. It was demonstrated that long-term mesophilic anaerobic treatment of CG as the only substrate is possible. Except for nitrogen, and possibly phosphorus, the addition of other nutrients is unnecessary. Processing of both non-acidulated and acidulated CG in laboratory mixed reactors inoculated with suspended sludge resulted in a stable operation with high specific methane production (0.328 L/g chemical oxygen demand (COD) for non-acidulated CG and 0.345 L/g COD for acidulated CG), regarding organic loading rate of up to 4 g COD/(L x d). Due to the considerable content of dissolved inorganic salts in CG it is recommended to dilute this substrate with water to prevent the accumulation of salts and inhibition of the biomass activity. WW was proved to be a problematic substrate for anaerobic cofermentation with CG because its addition to the reactor caused a decrease in the pH value and biogas production. PMID- 24350473 TI - Optimal design of ethanol supply chains considering carbon trading effects and multiple technologies for side-product exploitation. AB - This work proposes a spatially explicit mixed integer linear programming modelling framework representing the dynamic evolution of a bioethanol supply chain (SC) under increasing biofuel demand and greenhouse gas (GHG) emission savings over time. Key features of the proposed framework comprise: (i) the incorporation of available set-aside rural surfaces for energy crop cultivation; (ii) the acknowledgement ofan economic value to the overall GHG emissions through the introduction of an Emission Trading System. Multiple technological options are assessed to exploit the co-product Distiller's Dried Grains with Solubles either as animal fodder (standard usage) or as fuel for heat and power generation or as raw material for biogas production (and hence heat and power). Bioethanol production in Northern Italy is chosen as a demonstrative case study. PMID- 24350474 TI - Hybrid response surface methodology-genetic algorithm optimization of ultrasound assisted transesterification of waste oil catalysed by immobilized lipase on mesoporous silica/iron oxide magnetic core-shell nanoparticles. AB - The production ofbiodiesel by transesterification of waste cooking oil (WCO) to partially substitute petroleum diesel is one of the measures for solving the twin problems of environment pollution and energy demand. An environmentally benign process for the enzymatic transesterification using immobilized lipase has attracted considerable attention for biodiesel production. Here, a superparamagnetic, high surface area substrate for lipase immobilization is evaluated. These immobilization substrates are composed of mesoporous silica/superparamagnetic iron oxide core-shell nanoparticles. The effects of methanol ratio to WCO, lipase concentration, water content and reaction time on the synthesis of biodiesel were analysed by utilizing the response surface methodology (RSM). A quadratic response surface equation for calculating fatty acid methyl ester (FAME) content as the objective function was established based on experimental data obtained in accordance with the central composite design. The RSM-based model was then used as the fitness function for genetic algorithm (GA) to optimize its input space. Hybrid RSM-GA predicted the maximum FAME content (91%) at the optimum level of medium variables: methanol ratio to WCO, 4.34; lipase content, 43.6%; water content, 10.22%; and reaction time, 6h. Moreover, the immobilized lipase could be used for four times without considerable loss of the activity. PMID- 24350475 TI - Development of a simple model for anaerobic digestion based on preliminary measurements of the bacterial sulphur activity in wastewater stabilization ponds. AB - The present study was undertaken to develop a simple and practical model for anaerobic digestion, encompassing sulphate reduction and sulphur oxidation, in a waste stabilization pond. The basic microbiological phases of the model consisted of four processes, namely acidogenesis, methanogenesis, sulphate reduction and sulphur oxidation. It also incorporated multiple reaction stoichiometry and substrate utilization kinetics. The study also aimed to investigate the mutual interaction between sulphate-reducing bacteria (SRB) and photosynthetic sulphur bacteria (PSB) in an anaerobic sludge consortia using batch reactors. The results revealed that for an initial concentration of sulphate ranging between 250 and 2800 mg x l(-1), SRB activity ranged between 20 and 190 mgSO4(2-)(reduced). The gVSS(-1) x d(-1) and PSB activity varied between 60 and 320 mgSO4(2-)(produced). gVSS(-1) x d(-1), and PSB activity was noted to be twice as high as that of SRB. PSB can, therefore, be used effectively in the fight against odors. The most important environmental factors affecting the sulphur cycle in the waste stabilization pond were likely to be the availability of sulphate and light for SRB and PSB, respectively. PMID- 24350476 TI - Fate of heavy metals and major nutrients in a sludge-soil-plant-leachate system during the sludge phyto-treatment process. AB - Land application of sewage sludge usually leads to increased levels of heavy metals in soil, plants and groundwater. Pre-treatment using plants has been proposed to reduce the contents of heavy metals and water in sludge prior to land application. This study quantified the transfer of Zn, Cd, Pb and major nutrients in a sludge-soil-plant-leachate system during the treatment of sewage sludge. To accomplish this, a two year pot experiment was carried out to collect leachate, mono- and co-cropping of Sedum alfredii and feed crops was conducted in sludge with an under-layer soil support. Sludge phyto-treatment increased Zn and Cd concentrations in the under-layer soil, but not Pb. Specifically, 70%, 70% and 80% of the original Zn, Cd and Pb, respectively, remained in the sludge, while about 40%, 70% and 60% of the original N, P and K remained. Only 3% to 5% of Cd and Zn and < 1% of Pb were transferred into the under-layer soils or leachates, while more than 12% of the N and P were transferred. Co-planting S. alfredii and feed crops led to a significant reduction of heavy metals in leachates when compared with sludge without planting. Overall, sludge leachate is more appropriate than whole sludge for recycling in agriculture since it reduces the chance of heavy metal contamination in the agro-ecosystem; therefore, co-cropping phytotreatment of sludge can be coupled with sludge leachate recycling for crop production and re-collection of the sludge residue for landfilling. PMID- 24350477 TI - Advanced oxidation of hypophosphite and phosphite using a UV/H2O2 process. AB - The oxidation of hypophosphite and phosphite in an aqueous solution by an ultraviolet (UV)/H2O2 process was studied in this work. The reactions were performed in a lab-scale batch photoreactor. The effect of different parameters such as H2O2 dosage, H2O2 feeding mode and the initial pH of the solution on the oxidation efficiency of the process was investigated. The results indicated that the UV/H2O2 process could effectively oxidize hypophosphite and phosphite in both synthesized and real wastewater. However, neither H2O2 nor UV alone was able to appreciably oxidize the hypophosphite or phosphite. The best way of feeding H2O2 was found to be 'continuous feeding', which maximized the reaction rate. It was also found that the process presented a wide range of applicable initial pH (5 11). When treating real rinse-wastewater, which was obtained from the electroless nickel plating industry, both hypophosphite and phosphite were completely oxidized within 60 min, and by extending by another 30 min, over 90% of the chemical oxygen demand removal was obtained. Without any additional catalyst, the UV/H2O2 process can oxidize hypophosphite and phosphite to easily removable phosphate. It is really a powerful and environmentally friendly treatment method for the wastewater containing hypophosphite and phosphite. PMID- 24350478 TI - Development of porous ceramsite from construction and demolition waste. AB - The disposal of construction and demolition (C&D) waste has become a serious problem in China due to the rapid increase of Chinese construction industry in recent years. In the present study, typical C&D waste was employed for ceramsite fabrication so as to find a new way for its effective recycling. A novel process was developed for manufacturing high-quality porous ceramsite according to the special chemical composition and properties of C&D waste. Most importantly, a unique bloating agent was developed for the porous structure formation since it was difficult to obtain a suitable porous structure using traditional bloating agents. The effects of processing parameters such as sintering temperature, heating rate and soaking time were investigated, and the bloating mechanism for ceramsite was discussed. The C&D waste ceramsite (CDWC), with high-intensity, low density and homogeneous mechanical properties, was much more suitable for application in the construction field. This study provides a practical process for efficient recycling of the rapidly increasing quantities of C&D waste. PMID- 24350479 TI - Phenol biodegradation by different mixed cultures and the optimization of efficiency of the degradation. AB - In this study, the phenol degradation capacities of four different mixed cultures, namely, Ankara Stream (AS), petroleum-contaminated soil (PS), olive mill wastewater (OMW), and drug mill wastewater (DMW) were investigated with regards to different pH levels, phenol (497.2-1183.0 mg/L) and biomass concentrations (0.5-3.0%(v/v)). The most efficient culture was selected and the optimal conditions required for its highest performance in phenol degradation were studied. We found 100% phenol degradation for DMW at nearly 1000 mg/L initial concentration. The optimum pH was 8 and the mixed culture could tolerate phenol levels up to approximately 1500 mg/L. The selected culture degraded all of the phenol concentrations ranging from 497.2 to 1183.0 mg/L with 100% efficiency after 48 h and 120 h incubation, respectively. Increasing the biomass concentration from 0.5% to 3.0% (v/v) level decreased the incubation time needed for complete degradation. The data indicate that the mixed culture used in this study can be taken as a good candidate for effective treatment of waters contaminated by phenol. PMID- 24350480 TI - Optimization of marine waste based-growth media for microbial lipase production using mixture design methodology. AB - Lipase production by Staphylococcus xylosus and Rhizopus oryzae was investigated using a culture medium based on a mixture of synthetic medium and supernatants generated from tuna by-products and Ulva rigida biomass. The proportion of the three medium components was optimized using the simplex-centroid mixture design method (SCMD). Results indicated that the experimental data were in good agreement with predicted values, indicating that SCMD was a reliable method for determining the optimum mixture proportion of the growth medium. Maximal lipase activities of 12.5 and 23.5 IU/mL were obtained with a 50:50 (v:v) mixture of synthetic medium and tuna by-product supernatant for Staphylococcus xylosus and Rhizopus oryzae, respectively. The predicted responses from these mixture proportions were also validated experimentally. PMID- 24350481 TI - Performance of 14 full-scale sewage treatment plants: comparison between four aerobic technologies regarding effluent quality, sludge production and energy consumption. AB - The performance of 14 Full-Scale Sewage Treatment Plants (STPs) was evaluated. STPs were divided into four aerobic technologies: a) Aerated Lagoon (AL), and three configurations of activated sludge technologies, b) conventional (CAS), c) Extended Aeration (EA), d) Sequencing Batch Reactor (SBR). Comparison between these configurations were made regarding: a) control parameters, organic loading rate (OLR), Mixed Liquor Volatile Suspended Solids (MLVSS) concentrations, Food to Microorganism ratio (F/M), sludge age (theta(c)), Hydraulic Retention Time (HRT) and return sludge ratio (R); b) effluent quality, through 5-day Biological Oxygen Demand (BOD5), Chemical Oxygen Demand (COD), Total Suspended Solids (TSS), Total Kjeldahl Nitrogen (TKN), Total Phosphorus (TP); and c) indicators related to sludge production (on a dry basis) and electrical energy consumption. Also, complementary costs analyses were made. The results show that in terms of effluent quality, for all configurations organic matter (BOD5 and COD) and TKN removal efficiency were up to 90%, while TSS and TP were up to 90% and 50%, respectively. However, CAS, EA, SBR, and AL had stability problems with effluent concentrations. The results of the electrical energy consumption and sludge production analyses show that SBRs reduce these indicators by 40%. Cost analysis showed that CAS, EA, SBR and AL had similar cost structures, with more than 50% of total operating and maintenance cost being related to electrical energy and sludge management. Therefore, SBR could be defined as the configuration with a more stable performance. PMID- 24350482 TI - Green energy from marine algae: biogas production and composition from the anaerobic digestion of Irish seaweed species. AB - Marine algae have emerged as an alternative feedstock for the production of a number of renewable fuels, including biogas. In addition to energy potential, other characteristics make them attractive as an energy source, including their ability to absorb carbon dioxide (CO2), higher productivity rates than land-based crops and the lack of water use or land competition. For Ireland, biofuels from marine algae can play an important role by reducing imports of fossil fuels as well as providing the necessary energy in rural communities. In this study, five potential seaweed species common in Irish waters, Saccorhiza polyschides, Ulva sp., Laminaria digitata, Fucus serratus and Saccharina latissima, were co digested individually with bovine slurry. Batch reactors of 120ml and 1000ml were set up and incubated at 35 degrees C to investigate their suitability for production of biogas. Digesters fed with S. latissima produced the maximum methane yield (335 ml g volatile solids(-1) (g(VS)(-1) followed by S. polyschides with 255 ml g(VS)(-1). L. digitata produced 246ml g(VS)(-1) and the lowest yields were from the green seaweed Ulva sp. 191ml g(VS)(-1). The methane and CO2 percentages ranged between 50-72% and 10-45%, respectively. The results demonstrated that the seaweed species investigated are good feedstocks candidates for the production of biogas and methane as a source of energy. Their use on a large-scale process will require further investigation to increase yields and reduce production costs. PMID- 24350483 TI - Direct removal of aqueous As(III) and As(V) by amorphous titanium dioxide nanotube arrays. AB - Amorphous titanium dioxide nanotube arrays (TiO2 NTs) were prepared by a simple anodization process without subsequent calcination at high temperature, and the effectiveness of amorphous TiO2 NTs as adsorbents in removing arsenite (As(III)) and arsenate (As(V)) was investigated. The TiO2 NTs were not only effective for arsenic removal without a pre-oxidation of As(III) to As(V) and/or adjusting the pH value of water before the adsorption process, but also can be separated and recovered easily from the solution. The adsorption kinetics and adsorption capacity of the amorphous TiO2 NTs for As(III) and As(V) were studied separately by batch experiments. The apparent values for Langmuir monolayer sorption capacities were 28.9 mg/g for As(III) and 24.7 mg/g for As(V) at pH 7. Kinetics studies indicated that the adsorption process on TiO2 NTs followed a pseudo second-order kinetics model. Arsenic adsorption of TiO2 NTs remains stable over a broad pH range. Moreover, the TiO2 NTs have excellent stability and regeneration, and they can be used repeatedly at least five times. PMID- 24350484 TI - Suppression of phosphorus release from sediments using water clarifier sludge as capping material. AB - Water clarifier sludge was assessed as a capping material for preventing release of phosphorus from eutrophic pond sediments. Sediment incubation experiments were carried out over two months using five capping materials (sludge, sludge sintered respectively at 200, 400 and 600 degrees C, and sea sand) to evaluate the effect of sintering temperature. We also examined reduction in the nitrogen eluted from the sludge. Sludge, sludge sintered at 400 and 600 degrees C, and sea sand suppressed phosphorus release from sediments into the overlying water, whereas sludge and sludge sintered at 200 degrees C increased nitrogen release relative to that without capping. Sludge sintered at 600 degrees C was the most effective in reducing total nitrogen (TN) flux. Our experiments revealed that nitrogen and organic substances must be removed completely from sludge in order to avoid their release. The phosphate removal efficiency of sludge (including sintered sludge) was expressed in terms of Freundlich adsorption isotherms. The results showed that sludge sintered at 600 degrees C was suitable for use as a capping material since (1) its organic content (ignition loss) and TN were low (1.1% and 0.014 mg g(-1) dry, respectively), (2) its phosphorus adsorption capacity was 2.2 times higher than that ofunsintered sludge, and (3) it was effective in suppressing the diffusion of phosphorus and NH4+-N from sediments when used as a capping material. PMID- 24350485 TI - Surface modification of porous suspended ceramsite used for water treatment by activated carbon/Fe3O4 magnetic composites. AB - In this study, porous suspended ceramsite with a specific density close to that of water was prepared by high-temperature calcination using fly ash, feldspar, calcite, fired talc and kaolin as the raw materials. The ceramsite was modified by activated carbon/Fe3O4 magnetic composites. The optimum modification conditions determined by methylene blue adsorption experiment were: KOH/glucose ratio of 1.5:1, carbonization temperature of 400 degrees C, activation temperature of 850 degrees C, activation time of 1 h, and Fe3O4/KOH+glucose ratio of 1:10. The results demonstrated that the adsorption capacity of the modified ceramsite for methylene blue was significantly higher than that of the unmodified ones. The presence of the composites did not lead to significant decrease in the mechanical properties of the modified ceramsite. Moreover, the modified ceramsite showed good resistance towards acid and alkali. The modified ceramsite can be used as biocarrier and adsorbent for a wide range of contaminants in water and can subsequently be removed from the medium by a simple magnetic procedure. PMID- 24350486 TI - 4-nitrophenol removal from aqueous solutions by emulsion liquid membranes using type I facilitation. AB - Nitrophenols are common organic pollutants that enter the environment during the manufacture and processing of a variety of industrial products. The removal of 4 nitrophenol (4NP) from aqueous solutions by emulsion liquid membranes using the type I facilitated transport mechanism is investigated in this paper. The liquid membrane consisted of kerosene as the organic diluent, sorbitan monooleate as the emulsifying agent and sodium hydroxide as the stripping agent. The most important operational variables governing the emulsion stability and the 4NP removal process--such as the stripper agent and surfactant concentrations, the volume ratios of membrane phase/internal phase and emulsion phase/feed phase and stirring speed - were studied and the optimal conditions of the removal process were experimentally determined. Apparent initial permeabilities of the transport process in the different operational conditions were also obtained. Ninety-eight per cent of4NP was removed in 10 minutes and an apparent initial permeability of 1.2986 min(-1) was obtained in those optimal conditions. PMID- 24350487 TI - Ammonia removal from landfill leachate by air stripping and absorption. AB - An old landfill leachate was pre-treated in a pilot-scale aerated packed tower operated in batch mode for total ammoniacal nitrogen (TAN) removal. The stripped ammonia was recovered with a 0.4 mol L(-1) H2SO4 solution, deionized water and tap water. Ca(OH)2 (95% purity) or commercial hydrated lime was added to the raw leachate to adjust its pH to 11, causing removal of colour (82%) and heavy metals (70-90% for Zn, Fe and Mn). The 0.4 molL(-1) H2SO4 solution was able to neutralize 80% of the stripped ammonia removed from 12 L of leachate. The effectiveness of the neutralization of ammonia with deionized water was 75%. Treating 100 L of leachate, the air stripping tower removed 88% of TAN after 72 h of aeration, and 87% of the stripped ammonia was recovered in two 31 L pilot scale absorption units filled with 20 L of tap water. PMID- 24350488 TI - Removal efficiency of a constructed wetland combined with ultrasound and UV devices for wastewater reuse in agriculture. AB - This study evaluates the treatment efficiency of a chemical-free water treatment for treating the secondary effluent of a municipal wastewater treatment plant with the aim of reusing the water for agriculture. Urban wastewater was treated by three units run in series: a full-scale horizontal sub-surface flow constructed wetland, a small pond with an ultrasound (US) system and a UV device. The treatment efficiency was evaluated in terms of the Italian wastewater limits for irrigation reuse, water quality improvement (removal percentage) and algae bloom control. The tolerable infection risk, associated with the use of wastewaters for irrigating crops, was also assessed by applying the microbial risk analyses proposed in the WHO guidelines for wastewater reuse. The constructed wetland was efficient in reducing physical-chemical and microbiological concentrations, and its efficiency was very steady over the investigation period. The UV system significantly improved water quality (p<0.05) in terms of pathogen concentration with a further average decrease from 0.35 to 1.23 log units, depending on the microbiological parameter. The US device was able to prevent algae bloom on a free water surface and maintain Chlorophyll-a concentration stable and low 2 months after activation. PMID- 24350489 TI - Treatment of domestic wastewater using conventional and baffled septic tanks. AB - The main theme of the study was a comparative study of domestic wastewater treatment using conventional and baffled septic tanks. The septic tanks were fed continuously with domestic wastewater at three different hydraulic retention times (HRTs). The HRTs chosen were 24, 48 and 72 h with corresponding organic loads of 0.321, 0.436 and 0.885 kg chemical oxygen demand (COD) per m3 per day, respectively. The performance of the septic tanks at the three HRTs gave satisfactory results. For the conventional septic tank, COD removal was 53.4%, 56% and 65.3%, at an HRT of 24, 48 and 72 h, respectively, with residual COD of 412, 380 and 334mg/l, respectively. At HRTs of 72, 48 and 24 h, the following percentages removals were realized for: biochemical oxygen demand (BOD), 68.4%, 57, 53.5%; total suspended solid (TSS), 65.3%, 58.3, 55%; phosphorus, 29.3%, 26.9, 25.6%; total Kjeldahl nitrogen 26.8%, 20.8, 17.7%, respectively. On the contrary, ammonia concentrations increased by 7.1%, 5.2 and 4.2% under the same conditions. Consequently, the results showed that the removal of fecal coliform at all HRTs was less than one log. The two baffled septic tanks exhibited superior results at HRTs of 72, 48 and 24 h. Comparing the treated domestic wastewater quality produced by the two types of septic tanks in terms of physico chemical and biological characteristics, better results were obtained using the two baffles type. PMID- 24350490 TI - Analysis of up-flow aerated biological activated carbon filter technology in drinking water treatment. AB - Problems have been found in the traditional post-positioned down-flow biological activated carbon filter (DBACF), such as microorganism leakage and low biodegradability. A pilot test was carried out to place a BACF between the sediment tank and the sand filter; a new technology of dual media up-flow aerated biological activated carbon filter (UBACF) was developed. Results showed that in terms of the new process, the up-flow mode was better than the down-flow. Compared with the DBACF, the problem of microorganism leakage could be well resolved with the UBACF process by adding disinfectant before the sand filtration, and a similar adsorption effect could be obtained. For the tested raw water, the COD(Mn) and NH3-N removal rate was 54.6% and 85.0%, respectively, similar to the waterworks with the DBACF process. The UBACF greatly enhanced oxygen supply capability and mass transfer rate via aeration, and the NH3-N removal ability was significantly improved from 1.5 mg/L to more than 3 mg/L. Influent to the UBACF with higher turbidity could be coped with through the primary filtration of the ceramisite layer combined with fluid-bed technology, which gave the carbon bed a low-turbidity environment of less than 1.0 NTU. The backwashing parameters and carbon abrasion rate of the two processes were almost the same. PMID- 24350491 TI - Kinetics of chlorite dismutase in a perchlorate degrading reactor sludge. AB - Kinetics of chlorite dismutase (CD), the terminal enzyme involved in the perchlorate (ClO4(-)) reduction pathway, in a ClO4(-)-degrading bioreactor are reported in this study. Enzyme activity was determined from dissolved oxygen released during disproportionation of chlorite (ClO2(-)). CD activity was in the range 29.8-36.4 U/mg dry weight sludge, and kinetic constants Vmax and K(m) of the enzyme were 37.83 U/mg dry weight and 0.28 mM, respectively. Among reactor operational conditions, enzyme activity was observed at pH 4.0-9.0, with an optimum at pH 6.0. Redox potential in the range -50 to +120mV and NaCl up to 3.5 g/L had no significant effect on CD activity. However, co-occurring pollutants such as ammonium at 10 ppm, nitrite at 50 ppm and EDTA at 100 microM reduced CD activity substantially. The present study highlights ideal bioreactor conditions to avoid ClO2(-) toxicity, while indicating the buffering potential of a mixed microbial system against inhibiting factors to maintain stable CD activity in bioreactors. PMID- 24350492 TI - Adsorption of glycerol, monoglycerides and diglycerides present in biodiesel produced from soybean oil. AB - The most common methods currently used for the removal of waste glycerol, monoglycerides and diglycerides remaining after phase separation during biodiesel production involve wet processes. These procedures are not environmentally viable because they require large volumes of water and thus generate significant quantities of effluent. In this study, adsorption was employed to replace this purification step. Some commercial activated carbons were tested along with adsorbents chemically modified with HNO3. A kinetics study was conducted at 30 degrees C and adsorption isotherms were obtained at 20 degrees C, 30 degrees C and 40 degrees C. The results indicated that the adsorption of glycerol increased with the use of chemically-modified activated carbon, showing that pH has a strong influence on glycerol adsorption. The pseudo-first-order kinetic model provided the best fit with the experimental data for the monoglycerides while the pseudo-second-order model showed a better fit for the glycerol and diglycerides. The Freundlich model had the best fit with experimental data on the adsorption equilibrium for all temperatures. The thermodynamic study indicated that the adsorption process is endothermic and thus adsorption is favoured by increasing the temperature. The adsorption process using chemically-modified activated carbon was therefore very effective for the removal of waste glycerol resulting from biodiesel production, which is of considerable significance given the legal limits imposed. PMID- 24350493 TI - Advanced treatment of biologically pretreated coking wastewater by a bipolar three-dimensional electrode reactor. AB - Electrochemical oxidation is a promising technology for the treatment ofbio refractory wastewater. In this research, advanced treatment of coking wastewater which had previously undergone A/O (anaerobic-aerobic biological) treatment was investigated over Ti/RuO2 x IrO2 anode, stainless steel cathode and coke powder particle electrodes which were packed into the electrodes in a bipolar three dimensional electrode reactor (BTDR). The results showed that the removal efficiency of COD and ammonia nitrogen increased with applied current density. The main influencing factors of BTDR were evaluated by an orthogonal test, including reaction time, plate distance, current density, plate amounts and aeration flow rate. With reaction time of 60 min, plate distance of 1.0 cm, current density of 20 mA/cm2 and plate amounts of four pairs, most of the contaminants in coking wastewater can be remediated by BTDR, which can then meet the discharge limit for coking wastewater in China. For organic pollutants, 12 kinds of organic pollutants can be completely removed, and the removal efficiencies of 11 kinds of organic pollutants are between 13.3 and 70.3% by advanced treatment with BTDR. We conclude that there is great potential for BTDR in engineering applications as a final treatment for coking wastewater. PMID- 24350494 TI - Counter-current acid leaching process for the removal of Cu, Pb, Sb and Zn from shooting range soil. AB - This research explores the performance of a counter-current leaching process (CCLP) for Cu, Pb, Sb and Zn extraction in a polluted shooting range soil. The initial metal concentrations in the soil were 1790 mg Cu/kg, 48,300 mg Pb/kg, 840 mg Sb/kg and 368 mg Zn/kg. The leaching process consisted of five one-hour acid leaching steps, which used 1 M H2SO4 + 4 M NaCl (20 degrees C, soil suspension = 100 g/L) followed by two water rinsing steps. Ten counter-current remediation cycles were completed and the average metal removal yields were 98.3 +/- 0.3% of Cu, 99.5 +/- 0.1% of Pb, 75.5 +/- 5.1% of Sb and 29.1 +/- 27.2% of Zn. The quality of metal leaching did not deteriorate throughout the 10 remediation cycles completed for this study. The CCLP reduced acid and salt use by approximately 68% and reduced water consumption by approximately 60%, exceeding reductions achieved by a standard acid leaching process. PMID- 24350495 TI - Persistent organochlorine pollutants and metals residues in sediment and freshwater fish species cultured in a shallow lagoon, Egypt. AB - Six freshwater fish species cultured in Lake Edku fish farm, one of the northern Nile Delta lakes in Egypt that receives input from numerous anthropogenic activities in addition to agriculture wastes through several huge drains, were collected for the detection and evaluation of residues of the persistent organochlorine (OC) pollutants polychlorinated biphenyls (PCBs), 1,1,1 -trichloro 2,2-di(4-chlorophenyl)ethane (DDT), total cyclodienes (TC), hexachlorocyclohexanes (HCHs) and heavy metals (Cu, Cd and Pb) in their edible parts. In all fish and sediment samples, PCBs were found in higher concentrations than pesticides; the edible parts of Mugil capito, Tilapia galilaeus, Tilapia zilli and Clarias lazera had the highest PCBs (3.49, 0.83, 1.06 and 4.29 ng/g wet weight respectively), PCB 28 being most prevalent in Mugilcapito and Clarias lazera with ratios 86 and 62%, respectively, of the total PCBs. PCB 180 was most prevalent in Tilapia zilli (about 56% of the total PCBs). In these four fish species OCs were found in the order: PCBs > DDTs > HCHs > TC. The other two species (Tilapia nilotica and Tilapia aureus) had the highest concentrations of pesticides (7.58 and 1.13 ng/g wet weight, respectively) with HCHs being most prevalent (96% and 74% of the total pesticides, respectively). OCs were found in the order: HCHs >> PCBs > DDTs > TC in the edible Tilapia nilotica, and in the order: PCBs > HCHs > DDTs > TC in the other species. The mean concentrations of PCBs and pesticides in sediments are 539.66 +/- 48.8 and 259.17 +/- 81.2 ng/g dry weight, respectively. Among the studied metals in the edible parts of the fish samples, about 67% of the samples contained marginally higher Pb content in the edible parts, above the European Community's legal limit. About 50% of the samples contained marginally higher Cd content (N.D to 0.88 microg/g) above the permissible level of Cd in fish edible parts; the Cu content ranged from 0.37 2.36 microg/g, with a marginally higher content in the fish but below the maximum permissible limits. As for the concentration of the studied metals in sediments of Edku lagoon, results showed that copper had the highest concentration (2.2 +/- 0.37 microg/g) in the lake sediment. PMID- 24350496 TI - Activated carbon prepared from yerba mate used as a novel adsorbent for removal of tannery dye from aqueous solution. AB - Activated carbon prepared from yerba mate (Ilex paraguariensis) was used as adsorbent for the removal of tannery dye from aqueous solution. The activated carbon was characterized, and it showed a mesoporous texture, with surface area of 537.4 m2 g(-1). The initial dye concentration, contact time and pH influenced the adsorption capacity. The equilibrium data were in good agreement with both Langmuir and Freundlich isotherms. The adsorption kinetics of the tannery dye on activated carbon prepared from yerba mate followed a pseudo-second-order model. The adsorption process was found to be controlled by both external mass-transfer and intraparticle diffusion, but the external diffusion was the dominating process. This work highlights the potential application of activated carbon produced from yerba mate in the field of adsorption. PMID- 24350497 TI - Effect of hydroxyapatite, octacalcium phosphate and calcium phosphate on the auto flocculation of the microalgae in a high-rate algal pond. AB - Recovering microalgae is one of the main technological and economic concerns in a high-rate algal pond (HRAP) because of their small size and their low density. This paper emphasizes the characterization (identification and assessment of potential flocculation) of chemical compounds involved in microalgae auto flocculation in a HRAP. First, thermodynamic simulations were performed, using two models (i.e. Visual Minteq and a simplified thermodynamic model) in order to determine the chemical compounds of interest. Experimental tests were then carried out with these compounds for assessing their flocculation ability. Both models revealed that precipitates of calcium phosphates and their substituted forms were the compounds involved in the auto-flocculation. Moreover, experimental tests showed that the stoichiometric neutralization of algal charges by calcium phosphates (i.e. hydroxyapatite (Ca5(PO4)3OH), octacalcium phosphate (Ca4H(PO4)3) and amorphous calcium phosphate (Ca3(PO4)2)), at a pH within the range 7-10 yields 70-82% recovered algal biomass. The optimum ratio required for algae auto-flocculation was 0.33 Ca5(PO4)3OH/g DM(algae) at pH 10, 0.11 Ca4H(PO4)3/g DM(algae) at pH 7 and 0.23 g Ca3(PO4)2/g DM(algae) at pH 9. Auto flocculation appears as a simple, sustainable and promising method for efficient harvesting of microalgae in a HRAP. PMID- 24350498 TI - Application of fluorescence in situ hybridization for the study and characterization of nitrifying bacteria in nitrifying/denitrifying wastewater treatment plants. AB - The aim of this study was to verify fluorescence in situ hybridization for the detection of nitrifying bacteria in activated sludge and biofilms, and to determine the distribution of nitrifiers in selected wastewater treatment plants (WWTPs). Both Czech and foreign WWTPs with intensification of nitrification (for example, in situ bioaugmentation of nitrification or biofilms) and without intensification were studied. The two-dimensional and three-dimensional analyses of microscopic images were focused on quantifying the parameters and their differences with regard to the arrangement, capacity and sludge age of the WWTPs. This is the first time such a study has been performed in the Czech Republic. PMID- 24350499 TI - Study of nickel and copper biosorption on brown algae Sargassum angustifolium: application of response surface methodology (RSM). AB - This study has been focused on the batch culture removal of Cu2+ and Ni2+ ions from the aqueous solution using marine brown algae Sargassum angustifolium. Influences of parameters like pH, initial metal ions concentration and biosorbent dosage on nickel and copper adsorption were also examined using the Box-Behnken design matrix. For biosorption of Cu2+ the optimum pH value was determined as 5.0, optimum biosorbent concentration to 1.0 g/L and optimum initial concentration 0.15 mmol/L. For the biosorption of Ni2+, the optimal condition was the same but the optimum pH value was determined as 6.0. Desorption experiments indicated that CH3COOH and EDTA were efficient desorbents for recovery from Cu2+ and Ni2+. The Langmuir isotherm model was applied to describe the biosorption of the Cu2+ and Ni2+ into S. angustifolium. The maximum uptake of Cu2+ and Ni2+ ions by the S. angustifolium biomass under the optimal conditions was approximately 0.94 and 0.78 mmol/g dry alga, respectively. Response surface models showed that the data were adequately fitted to a second-order polynomial model. Analysis of variance showed a high coefficient of determination value (R2 = 0.993 for Cu2+ and 0.991 for Ni2+) and a satisfactory second-order regression model was derived. In addition, results reported in this research demonstrated the feasibility of employing S. angustifolium as biosorbent for Ni2+ and Cu2+ removal. PMID- 24350500 TI - Degradation of tetracycline and sulfadiazine during continuous thermophilic composting of pig manure and sawdust. AB - During composting, the thermophilic phase resulted in high degradation of antibiotics in the composting mass; thus temperature is considered as the major factor for degradation of antibiotics. Therefore, to achieve complete removal of antibiotics, the effect of continuous thermophilic composting on the degradation of antibiotics and their effect on antibiotic resistant bacteria in the pig manure were evaluated. Pig manure was mixed with sawdust, spiked with tetracycline (10 and 100 mg/kg) and sulfadiazine (2 and 20mg/kg) on dry weight (DW) basis and composted at 55 degrees C for six weeks. Based on the organic decomposition, the antibiotics did not affect the composting process significantly, but negatively influenced the bacterial population. Tetracycline clearly exhibited a negative but marginal influence on carbon decomposition at 100 mg/kg level. The bacterial population initially decreased steeply approximately 2 logs and slowly increased thereafter. Sulfadiazine and tetracycline resistant bacterial populations were stable/marginally increased after an initial decrease of about 2 or 3-5 logs, respectively. Sulfadiazine was not detectable after three days; whereas, approximately 8% of tetracycline was detected after 42 days of composting with a t(1/2) of approximately 11 days, irrespective of the initial concentration. The presence of tetracycline in the compost after 42 days of thermophilic composting indicates the involvement of a mesophilic microbial-mediated degradation; however, further studies are required to confirm the direct microbial involvement in the degradation of antibiotics. PMID- 24350501 TI - Degradation of antibiotic amoxicillin using 1 x 1 molecular sieve-structured manganese oxide. AB - The kinetics and mechanism ofamoxicillin (AMO) degradation using a 1 x 1 molecular sieve-structured manganese oxide (MnO2) was studied. The presence of the buffer solution (i.e., NaHCO3, NaH2PO4 and KH2PO4) diminished AMO binding to MnO2, thus reducing AMO degradation in the pretest; therefore, all other experiments in this study were conducted without the addition of a buffer. Third order rate constants, second-order on AMO and first-order on MnO2 increased with elevating pH level (2.81-7.23) from 0.54 to 9.17 M(-2) s(-1), and it decreased to 4.27 M(-2) s(-1) at pH 8.53 beyond the pk(a2) of AMO (7.3). The dissolution of the MnO2 suspension with and without AMO exhibited a similar trend; that is, Mn2+ concentration increased with decreasing pH. However, the dissolution of MnO2 with AMO was greater than that without AMO, except for the reaction occurring at pH 8.53, partially indicating that MnO2 acts as an oxidant in AMO degradation. The preliminary chromatogram data display different products with varying pH reaction s, implying that AMO elimination using this 1 x 1 molecular sieve-structured MnO2 is by adsorption as well as oxidative degradation. A complementary experiment indicates that the amount of oxidatively degraded AMO increases substantially from 65.5% at 4 h to 95% at 48 h, whereas the AMO adsorbed onto MnO2 decreases slightly from 4.5% at4 h to 2.4% at 48 h. The oxidative degradation accounted for more AMO removal than adsorption over the whole reaction course, indicating that the oxidative reaction of AMO on MnO2 dominated the AMO removal. PMID- 24350502 TI - An instrument to differentiate between clinical research and quality improvement. PMID- 24350503 TI - Payment to participants in pediatric research: variation in IRB members' attitudes. PMID- 24350504 TI - Barriers to research on research ethics review and conflicts of interest. PMID- 24350505 TI - Diagnosis and treatment of spondylodiscitis in HIV-positive patients. AB - With an incidence between 1:100,000 and 1:250,000, spondylodiscitis is rare, but is increasingly reported due to longer life expectancy, risk factors, and comorbidities, with HIV+ patients being at greater risk. We reviewed the literature on the diagnostic tools, and on the benefits and drawbacks of different treatments of spondylodiscitis in HIV- positive patients. We discuss basic strategies and indications for surgery. Recently, the trend was toward early mobilization of patients after surgical treatment. Modern surgical and antibiotic treatment can prevent a recurrence in these patients. The decision to opt for conservative or surgical treatment should be made depending on the extent of infection and the responsible pathogen, without regard to HIV. However, these patients should be treated in a specialized hospital by an experienced interdisciplinary team of consultants. PMID- 24350507 TI - Complications following kyphoplasty in unstable osteoporotic vertebral body fractures. A guide to correct fracture analysis. AB - The possibilities offered by kyphoplasty in the treatment of osteoporotic vertebral fractures have been widely described. Kyphoplasty is technically not very demanding, it can be easily learned and it is minimally invasive when compared to open surgical fracture treatment. Like many other simple surgical methods, it has spread rapidly and as a consequence of the above factors combined with its good reimbursement in many countries, it has experienced a widening in the indications for which it is being employed. The intial purpose of kyphoplasty was pain relief based on vertebral body stabilisation combined with restoration of vertebral body height. An increasingly uncritical use of the method can be observed and as a consequence, an increase in serious complications. During recent years, spinal surgery departments have received an increasing number of patients with serious complications following kyphoplasty, requiring major reconstructive spinal surgery. On the basis of 12 cases treated over the past 36 months, we aim to provide guidelines for the indications of the kyphoplasty procedure. PMID- 24350506 TI - Orthopaedics and diabetes. AB - With about 12% of orthopaedic patients being diabetic and a large proportion of them being obese as well, orthopaedic surgeons are commonly involved in managing diabetic patients in both outpatient and inpatient setting. This review summarizes current concepts in diabetes management including specific orthopaedic issues and future directions of diabetes management. PMID- 24350508 TI - Valgus instability as a cause for recurrent lateral patellar dislocation: a new mechanism for patellofemoral instability? AB - An association between lateral patellar dislocation (LPD) and medial collateral ligament injury (MCL) has recently been demonstrated on MRI. The same valgus injury that disrupts the femoral MCL insertion can also cause a simultaneous MPFL tear at its femoral insertion, due to the close anatomical relationship of both ligamentous structures. Valgus laxity due to MCL-deficiency increases the Q-angle and further adversely affects patellar stability. A knee diagnosed with a severe MCL tear, should be evaluated for patellofemoral instability, as a temporary patella dislocation could have been caused by the same injury and an acute LPD indicating a tear of the MPFL can be associated with a concomitant injury of the MCL. In case of recurrent symptoms of patellofemoral instability in a MCL deficient knee, both the MPFL and MCL should be managed operatively. An isolated MPFL reconstruction in this knee is likely to fail due to a persistent increase of the Q-angle. PMID- 24350509 TI - Anterolateral acromial approach in locking plate fixation of proximal humerus fractures in elderly patients. AB - We describe our experience with a two-incision anterolateral acromial approach in locking plate fixation of proximal humeral fractures in older adults. Mean time between injury and surgery was 3.08 +/- 1.24 days. A proximal anterolateral transverse incision and a more distal longitudinal incision were used. A locking plate was inserted along the lateral side of the humerus from the proximal incision to the distal fragment of the humerus. Mean operation time was 62.37 +/- 19.05 minutes. There were no instances of axillary nerve paralysis or infection. Postoperative imaging results were satisfactory in all cases. Three obese patients experienced fat liquefaction at the incision site. Mean total Neer score one year after surgery was 88.16 +/- 5.05. We conclude that the two-incision anterolateral acromial approach with use of locking plates appears to be an effective means to treat proximal humeral fractures in older adults. PMID- 24350510 TI - Surgical treatment outcome for open supracondylar humerus fractures in children. AB - Although numerous studies have been conducted on supracondylar humerus fractures in children, there is only a limited number of studies regarding the outcome of open fractures. In this study, the early and late outcome of open supracondylar humerus fractures in children were evaluated. The outcome in 26 children (19 males, 7 females) treated for open supracondylar humerus fractures was evaluated retrospectively. The mean age was 73 years (range: 4 to 14) and the mean follow up period was 43 years (range: 2-8). According to the Gustilo-Anderson classification, 18 patients (69%) had type 1 and 8 patients (31%) type 2 open fractures. Nine patients (34%) presented with a nerve injury. Distal pulses could not be detected in four patients (15%). Functional outcomes were evaluated according to the scoring criteria by Flynn et al. Pin tract infection developed in one patient (3%). Artery repair via an anterior approach was performed in one patient. In nine patients with neurological symptoms, nerve functions were restored within three to six months. The mean union time was six weeks (5-8 weeks). According to the scoring criteria by Flynn et al, an excellent outcome was achieved in 23 patients, and a successful outcome in 3 patients. According to these findings, although vascular and nerve injuries frequently accompany open supracondylar humerus fractures in children, the late radiological and functional outcome was as good as in closed fractures. PMID- 24350511 TI - Outcome of simultaneous surgical treatment of hyperextension of metacarpophalangeal and basal joint osteoarthritis of the thumb. AB - The effect of correction of metacarpophalangeal (MCP) joint hyperextension on the outcome of reconstructive surgery for basal joint osteoarthritis of the thumb was studied. Impairment, pain and satisfaction were similar after a combined surgical treatment of MCP hyperextension and basal thumb osteoarthritis in 33 patients, as in a series of 233 patients at the same institution after osteoarthritis surgery with a normal MCP joint. PMID- 24350512 TI - Addition-subtraction osteotomy without ligamentoplasty for symptomatic trapezial dysplasia with metacarpal instability. AB - Trapeziometacarpal joint pain is often associated with a dynamic adduction deformity of the thumb metacarpal, combined with radial subluxation at the base of the thumb metacarpal, due to trapeziometacarpal dysplasia. Addition subtraction osteotomy is a surgical option to correct the bony deformity when conservative treatment fails. Eight patients who underwent surgery with this technique were prospectively evaluated. All patients were female and mean age was 42 (range 27-59) years. Mean follow-up period was 23 (range 10-42) months postoperatively. Seven patients (87.5%) were very satisfied. Joint mobility and strength of the operated thumb was restored to a degree comparable to the contralateral thumb. Overall function according to the Quick-DASH score improved by 75.5% and pain according to the Visual Analogue Scale decreased by 65%. Radiological evaluation showed a decrease of the trapezial slope. Mean angle between the articular surface of the trapezium and the long axis of the second metacarpal measured 1420 preoperatively 1290 and postoperatively. In the present study results of addition-subtraction osteotomy without ligamentoplasty were promising, especially for function and pain. The technique may be a valuable treatment option for trapeziometacarpal dysplasia with metacarpal instability. PMID- 24350513 TI - A comparison of ultrasonography and radiography in the management of infants with suspected developmental dysplasia of the hip. AB - The aim of this study was to determine the sensitivity and specificity of plain radiography in the detection of developmental dysplasia of the hip, using hip ultrasonography as a reference standard. A retrospective review was made in 44 infants ranging in age from 4 weeks to 50 weeks (mean age: 21.7 weeks). Both radiographic and ultrasonographic images were obtained for 86 hips. Radiography and ultrasonography were found to be significantly correlated in terms of classification of developmental dysplasia of the hip presence or absence (p < 0.0001, Fisher's exact test). With ultrasonography accepted as the standard for the diagnosis of developmental dysplasia of the hip, radiography had a sensitivity of 61% and a specificity of 87%. The results of this study suggest that the two imaging methods give similar overall results, but that low grade dysplasia detected on ultrasonography may go undetected on radiography. PMID- 24350514 TI - Early results of trabecular metal augment for acetabular reconstruction in revision hip arthroplasty. AB - The management of acetabular bone defects presents a challenge in revision total hip arthroplasty (THA). The aim of this study was to assess the early clinical and radiological outcome of revision of acetabular components using trabecular metal cups and augments for acetabular reconstruction. The study included 18 consecutive patients with failed acetabular components after total hip arthroplasty, with acetabular defects that were revised using porous tantalum acetabular components and augments. The mean follow-up was 18 months (range: 12 24). At the most recent follow-up, 6 patients (33%) were graded as having an excellent result, 9 (50%) a good result, 3 (17%) a fair result according to the HHS. The hip centre was restored to its normal position. There were no cases of hip dislocation. One patient had a partial sciatic nerve palsy which had resolved two months postoperatively. Based on these early clinical and radiological results, TM acetabular components and augments for acetabular defects (Paprosky II and III) appear to be a promising solution for this complex situation. We continue to monitor these patients, and a larger series with longer follow-up will be required to determine the long-term outcome of these augments. PMID- 24350515 TI - High flex total knee arthroplasty--a prospective, randomized study with results after 10 years. AB - This prospective randomized study compares the long term results between total knee arthroplasty with a mobile bearing high flex and a fixed bearing posterior stabilized knee (LPS) in 39 patients. The Hospital for Special Surgery score (HSS) was calculated and radiographs in AP and lateral view were analyzed after a minimum follow-up of 10 years. No significant differences between the two groups were found. The mean HSS-score was 90.67 (+/- 5.75) for LPS group patients and 90.83 (+/- 8.57) points for the high flex group patients. Three patients in the high flex group had undergone a reoperation on their knee. One knee was revised for painful mid-flexion instability and the others for symptomatic aseptic loosening of the tibial prosthesis. Based on these and other findings, the use of a high flex knee system may be seriously re-considered. Further studies are required to evaluate possible long-term adverse effects of high flex knee systems. PMID- 24350517 TI - Simultaneous multiple anterior cruciate ligament reconstructions using a single Achilles tendon allograft. AB - This study aimed to evaluate simultaneous multiple anterior cruciate ligament (ACL) reconstructions performed with a single Achilles allograft. After selection of an Achilles allograft with suitable length, the circumference of the isthmus and length of the tendinous portion were measured. The Achilles tendon was divided along its fibers into two or three strips and each strip was looped into a two-strand construct. Fifteen Achilles allografts were used for 31 ACL reconstructions in 30 subjects. The median circumference at the isthmus was 29 mm and the median length of the Achilles tendon 185 mm before and 206 mm after removal of the insertional bone block. The median difference in length before and after removal of the bone block was 19 mm. Achilles allografts with proper length consistently yielded two free tendon grafts suitable for simultaneous multiple ACL reconstruction with good short-term results. PMID- 24350516 TI - The incidence of knee and anterior cruciate ligament injuries over one decade in the Belgian Soccer League. AB - In an epidemiological study we assessed the evolution in the incidence and possible risk factors of knee injuries, especially anterior cruciate ligament (ACL) injuries, in Belgian soccer over one decade. Two soccer seasons (1999-2000 and 2009-2010) were compared and 56,364 injury reports registered by the KBVB URBSFA were retrieved. Knee injuries totaled 9.971 cases, 5.495 in the first season (1999-2000) and 4.476 in the second (2009-2010): a significant decrease in incidence from 1.5 per 100 players in 2000 to 1.2 knee injuries in 2010. Six percent of all knee injuries were ACL injuries. The reported incidence of ACL tears slightly increased from 0.081 to 0.084 per 100 players. Female gender, competition and age over 18 years were prognosticators for ACL injuries. Enhanced prevention programs for ACL injuries, especially in those sports groups are warranted. PMID- 24350518 TI - Long-term outcome of chevron-osteotomy in juvenile hallux valgus. AB - The long-term outcome of juvenile hallux valgus treated by a modified Austin procedure was investigated. The clinical (subjective, AOFA Scores) and radiological outcome (hallux valgus angles, intermetatarsal angles, position of the sesamoid bones and metatarsal index of 15 feet in 12 patients, aged 14 years and 2 months (SD +/- 1 year 10 months) were assessed pre- and postoperatively and after 7 years and 3 months (SD +/- 3 years). A significant improvement of the hallux valgus angle and of the intermetatarsal angle was obtained, persisting until final follow-up. The mean American Orthopaedic Foot and Ankle Society hallux metatarsophalangeal-interphalangeal and AOFA-Midfoot score were 94.5 points and 853 points, respectively. The modified Austin procedure appears to be an effective procedure to correct a juvenile hallux valgus deformity, with long lasting improvement, no growth disturbances and good functional outcome. PMID- 24350519 TI - Calcaneocuboid distraction arthrodesis with allogenic bone grafting for correction of pes planovalgus. AB - Calcaneocuboid distraction arthrodesis is regarded as an excellent and reliable surgical procedure for correction of pes planovalgus. Despite a potentially high complication rate, the use of an autologous iliac crest graft is regarded as the method of choice. In a prospective trial the results in 12 feet after calcaneocuboid distraction arthrodesis for pes planovalgus correction with allogenic bone graft were investigated. The mean age was 64 (52-81) years. An angle-stable plate was generally used for fixation of the arthrodesis. Successful bone healing was diagnosed clinically if local pain was absent during weight bearing, forefoot manipulation and palpation. The AOFAS score improved from 58.9 (+/- 6) points preoperatively to 89.8 (+/- 6.3) points 12 months postoperatively and the Visual Analogue Pain Scale (VAS) from 5.1 (+/- 1.4) to 0.7 (+/- 1) 12 months postoperatively. On radiological analysis, the lateral and dorsoplantar talometatarsal axis, hindfoot axis, the navicular floor distance and talonavicular coverage angle improved considerably. Bone fusion was observed in 11 of 12 cases postoperatively. In conclusion, the use of an allogenic graft for calcaneocuboid distraction arthrodesis did not result in a higher pseudarthrosis rate compared with results reported after use of an autologous iliac crest graft. Fixation with an angle-stable plate is recommended. PMID- 24350520 TI - Effect of shape and severity of vertebral fractures on the outcomes of kyphoplasty. AB - The aim of this retrospective study was to evaluate the effect of shape and severity of osteoporotic vertebral fractures on the clinical and surgical outcomes of kyphoplasty. Ninety-four patients with single level vertebral fractures were enrolled. Fractures were divided into two types according to the shape of the fractured vertebrae: wedge type (n = 54) or biconcave type (n = 40). All fractures were further classified into 3 grades (grade 1-3) according to their severity. The Visual Analog Score for back pain improved significantly in the "wedge" and in the "biconcave" group: there was no significant difference between groups. Wedge type fractures had a significantly greater correction of anterior vertebral height and kyphotic angle than biconcave type fractures (p < 0.01). Biconcave type fractures had a significantly greater correction of the middle vertebral height (p < 0.01), but had a higher risk of intradiscal cement leakage (p = 0.03). Rates of cement leakage in grade 1, grade 2, and grade 3 fractures were 12.8%, 25.8%, and 50.0%, respectively : there was a gradually higher risk of cement leakage as the severity of compression increased (p < 0.01). CONCLUSION: assessing the shape and severity of fractured osteoporotic vertebrae gives an idea of the potential correction of body height and kyphosis, and of the risk of cement leakage. PMID- 24350521 TI - Factors influencing outcome of knee bone marrow oedema: a clinical study. AB - Bone marrow oedema has a long recovery time. Conservative and surgical treatments have been used. This study aimed at identifying a profile of patients who may benefit from nonsurgical management. We compared the results of periodic clinical and radiological examinations of patients who visited our clinic with knee pain and were diagnosed with bone marrow oedema following magnetic resonance imaging (MRI) examinations. Clinically, the patients were evaluated using the Lysholm knee score and a visual analogue scale. The study included 67 patients (31 males, 36 females) who were followed for 6-24 months. Patient age, gender, body mass index, affected area, and concomitant intra-articular pathology were analysed. Of the 67 patients, 63 were treated conservatively, and four underwent decompression. Patients with involvement of both the medial femoral condyle and tibial plateau were found to be more resistant to treatment than those in which only the tibial plateau was affected. Intra-articular pathologies were frequently noted together with bone marrow oedema, causing knee pain to persist after the bone marrow oedema had subsided. PMID- 24350522 TI - Vitamin D insufficiency in osteoporotic hip fracture patients: rapid substitution therapy with high dose oral cholecalciferol (vitamin D3). AB - Assessment and treatment of osteoporosis are recommended following hip fracture. Osteoporosis treatment assumes an adequate calcium intake and a normal vitamin D plasma level. The authors conducted a study in three phases. Phase I: circulating 25-hydroxyvitamin D levels were retrospectively recorded from in the case records of 381 consecutive patients with 387 hip fractures, between March 2010 and September 2011. Only 27 patients had sufficient (> 75 nmol/L) circulating vitamin D, and of these 22 were taking vitamin D supplements. The remainder, 354 patients, had abnormally low vitamin D levels, with a mean value of 26.4 nmol/L. These findings confirmed literature data, and gave rise to the prospective Phase II (October 2011): 14 consecutive patients with a hip fracture received rapid substitution therapy with 50,000 IU cholecalciferol (vitamin D3) daily for 3 days. Patients with corrected calcium level (calcium level based on the serum albumin level) > 2.60 mmol/L were excluded from phase II (and phase III), in order to avoid hypercalcemia. Substitution resulted in an increase in vitamin D plasma levels from +/- 29.6 nmol/L to +/- 81.4 nmol/L (p < 0.0001), after +/- 14 days. However, vitamin D level remained below the desired threshold of 75 nmol/L in 29%. Therefore it was decided to increase the treatment period from 3 days to 7 days in the next 54 patients with a hip fracture in a prospective phase III (October 2011-January 2012). This time rapid substitution resulted in an increase from +/-31.4 nmol/L to +/-131.1 nmol/L (p < 0.0001), after +/- 16 days, and 100% of treated patients achieved plasma levels above the desired threshold of 75 nmol/L. CONCLUSION: virtually all patients with a hip fracture have low vitamin D plasma levels; substitution with 50,000 IU oral cholecalciferol daily for 7 days increases vitamin D plasma levels rapidly, safely and consistently. PMID- 24350523 TI - Vitamin D deficiency in orthopaedic patients: a single center analysis. AB - Vitamin D is essential to bone health and is a major regulator of calcium homeostasis. Many recent reports demonstrated worldwide high rates of vitamin D deficiency, but few studies have been published on the vitamin D status of orthopaedic patients. The present study aimed to investigate the extent of hypovitaminosis D of orthopaedic patients and possible variations in vitamin D status according to the body region which was scheduled to undergo surgery. We measured the vitamin D level of 1119 patients consecutively admitted to an orthopaedic surgery department of a university hospital in Germany in 2011. The prevalence of normal (< or =30 ng/ml), insufficient (20-30 ng/ml) and deficient (< or =20 ng/ml) 25-OH-D levels was determined. Serum Vitamin D levels and rates of insufficiency and deficiency were compared between the different cohorts using two-tailed tests. The level of significance was set at p < or =0.05. The serum 25 OH-D levels for all participants were normally distributed, with a mean of 2057 ng/ml. Overall, we noted an alarmingly high rate of vitamin D insufficiency or deficiency among orthopaedic patients. No significant difference was found related with the various body regions scheduled to undergo surgery. Given the well-known effects of vitamin D on bone metabolism and muscle health, vitamin D insufficiency may negatively affect patients. PMID- 24350524 TI - Minimally invasive correction of phalangeal malunion under local anaesthesia. AB - Posttraumatic malunion of the proximal phalanx of the fingers may cause visible deformities and impair hand function. Severe dysfunction requires surgical correction, most often via open corrective osteotomies. However, such an approach requires longer bone healing time, inevitably results in a scar, and has a higher potential for extensor tendon adhesion. When performed under general anaesthesia it is also difficult to assess dynamic finger position such as rotational malunion. Thus, the authors have devised and applied a technique of minimal invasive corrective osteotomy under local anaesthesia, permitting active flexion and extension, which leads to more accurate reduction, and earlier recovery. PMID- 24350526 TI - An analysis of chronic kidney disease risk factors in a Louisiana nursing home population: a cross-sectional study. AB - BACKGROUND: Chronic Kidney Disease (CKD) and its progression are associated with multiple risk factors. CKD is prevalent in nursing homes residents, but factors related to CKD in this setting have not been defined. METHODS: A cross-sectional study was conducted (n=103). Data was abstracted using standardized forms and analyzed (SAS 9.2). Chi square and t-test statistics were used to compare proportions and means; correlation coefficients were used to describe associations. Logistic models were fit to the data to determine multivariate associations. Modification of Diet in Renal Disease (MDRD) formula was used to estimate GFR. CKD was defined according to established standards. A cutoff point of 60 was chosen for further analysis. RESULTS: Twenty-three percent of subjects had CKD. Mean age for eGFR <60 was 70.8 +/- 13 and for eGFR >60 was 61.7 +/-14. Frequent co-morbidities were hypertension (75%), GERD (40%), obesity (39%), dyslipidemia (35%), depression (34%), anemia (32%), and diabetes (32%). CONCLUSIONS: Our population is unique in terms of its age and reasons for nursing home admission. Factors associated with CKD in our study include age >65 years old, being male, having a positive history of cardiovascular disease (including congestive heart failure and coronary artery disease,) anemia, polypharmacy, and being obese (BMI >30). Further analysis showed that age and anemia are the strongest factors associated with CKD in our population. Management targeted at CKD risk factor reduction may play a vital role in controlling the magnitude of this disease. Prospective studies to investigate the relationship between gender, a BMI greater than 30, cardiovascular disease, and CKD and its complications are warranted. PMID- 24350525 TI - Percutaneous radiologic gastrostomy: results and analysis of factors contributing to complications. AB - INTENT: Assessment of feasibility of percutaneous radiologic gastrostomy (PRG) for long- or short-term nutritional support and analysis of attendant complications and their underlying causes. MATERIALS AND METHODS: A retrospective analysis of outcome, complications, and their underlying causes was carried out in 391 patients who had percutaneous gastrostomies performed in two different university medical centers from January 2005 to April 2010 by interventional radiology. Forty-three were performed under general anesthesia and 348 were under local anesthesia and conscious sedation; in 349, fluoroscopic guidance was used, in 17 ultrasound, and in 22 CT. RESULTS: Three hundred and seventy-six procedures were technically successful (96%). The procedure-related mortality was 2.5%. Fifty-seven gastrostomies were removed after clinical condition of the patients had improved. Only 36 gastrostomies remained functional for a year or longer. Major complications attributable to PRGs occurred in 6.1% (24 of 391) of our patients. On retrospective analysis, faulty technique may have been a major factor in many of these 24 patients. Injuries of abdominal organs and misplaced gastrostomies occasioned by improper localization of T fasteners were the major culprits. Minor complications occurred in 17.6% of patients. DISCUSSION AND CONCLUSION: Meticulous pre-procedural assessment of the topographic anatomy, preferably by CT, is mandatory to avoid or minimize by injury of colon, spleen, liver etc. Precise placement of T fasteners and confirmation of gastric access under cross-table lateral fluoroscopy is necessary for proper placement of the gastrostomy tube. Percutaneous radiologic gastrostomy has proven an excellent technique for short- and long-term nutritional support. PMID- 24350527 TI - Nasal tip infantile hemangioma, a case of mistaken identity. AB - Infantile hemangioma is the most common vascular tumor in the pediatric population, and the majority of cases are diagnosed only on history and physical examination. This report highlights a case in which a 3-year-old girl undergoes surgical removal of what was thought to be an infantile hemangioma. Immunohistochemical staining, however, showed the absence of GLUT-1 marker, which discredited the original diagnosis. The vascular tumor was found to be a unique presentation of a pyogenic granuloma. When the clinical diagnosis is in question, referral for biopsy may prevent unnecessary medical interventions. PMID- 24350528 TI - Educational efforts to improve cost awareness do not reduce average drug cost per case in adult cardiac anesthesia. PMID- 24350529 TI - Updates for responsible sun exposure behavior and photoprotection in the south. AB - In Louisiana, the "Sportsman's Paradise," and throughout the Southern United States (US), outdoor pursuits are among the most popular physical activities, despite well-documented associations between excessive solar ultraviolet (UV) radiation and skin cancer. Although there have been recent advances in broad spectru m sunscreens, photoprotective clothing, and photoprotective sunglasses, few peer-reviewed publications have focused specifically on recommendations for responsible sun behavior and photoprotection for residents of the South. In response, the objectives of this review will be (1) to describe the adverse health effects of excessive UV radiation exposures; (2) to review recent cohort studies of public perceptions regarding sun behavior and photoprotection; (3) to identify special populations at increased risks of UV-associated skin cancers; and (4) to recommend responsible sun behavior and photoprotection strategies. Internet search engines were queried with the key words as search terms to examine the latest references on photoprotection and the epidemiology of UV associated skin cancers and other adverse effects of UV-radiation exposures. Observational studies have demonstrated that the public knows little about proper sunscreen selection and UV protection, and cohort studies have identified populations at increased risks of UV-associated skin cancers. Southerners should avoid intense sunlight, wear photoprotective clothing, wear sunglasses, and select the right sunscreen for their skin type. Physicians should counsel their patients about responsible sun behavior and photoprotection and encourage them to take advantage of recent advances in the development of more effective broad spectrum sunscreens and photoprotective clothing and sunglasses for themselves and their children. PMID- 24350530 TI - Orlistat-induced oxalate nephropathy may be dose-independent and present as a late manifestation. AB - We present the case of a 61-year-old Caucasian male veteran who had been on orlistat (120mg dosing) for four years, and had changed to the over-the-counter (OTC) form, Alli (orlistat 60mg), about three months before presentation. He had been experiencing nausea and vomiting for three weeks prior to evaluation. Laboratory studies revealed a serum creatinine of 6.2 mg/dL--his previous renal function having been normal. An ultrasound-guided renal biopsy was performed, which revealed deposition of calcium oxalate crystals in the renal tubules. Orlistat is a popular weight-loss medication. Orlistat-induced oxalate crystal nephropathy has recently been reported in the literature, resulting from the original, patented version. We report a case with the first such complication from the OTC version, Alli - which is a reduced-dose formulation. Our case report highlights that this complication can occur after several years of use of the medication and is not necessarily dose dependant. PMID- 24350531 TI - Epigastric pain in a 63-year-old woman. Atrial flutter with 2:1 atrioventricular block; acute inferoposterior myocardial infarction. PMID- 24350532 TI - Atypical scaphoid avascular necrosis. Right scaphoid non-union fracture with avascular necrosis of the distal pole. PMID- 24350533 TI - A 31-year-old man with AIDS, fever, and a rash. PMID- 24350534 TI - Bilateral renal artery stenosis. PMID- 24350535 TI - [Relationship between corneal thickness and postmortem interval in rabbit]. AB - OBJECTIVE: To explore the relationship between corneal thickness and postmortem interval (PMI) in rabbit. METHODS: The rabbit model was established by air embolism. The rabbit cornea was sampled at 6-hour-interval from 0 to 72 h postmortem. After routine HE staining, the whole cornea image was collected by the optical microscope. Three markers were observed including corneal epithelial thickness (x1), corneal stromal thickness (x2) and whole corneal thickness (x3) using Motic Images Plus 2.0 image analysis software and the data were statistically analyzed to establish the regression function with PMI (y). RESULTS: Within 72 h postmortem, rabbit corneal stromal thickness and whole corneal thickness increased at 12h postmortem and reached the peak at 54h postmortem. The two markers showed positive correlation with PMI. The regression functions of the two markers were y = -0.070 2 x2(2) +11.398 x2 + 1634 (R2 = 0.712 2, P < 0.05) and y = -0.074 9 x3(2) +12.036 x3 + 1819.4 (R = 0.675 0, P < 0.05), respectively. CONCLUSION: The two markers of corneal stromal thickness and the whole corneal thickness showed the strong linear correlation with PMI. The correlation of the corneal stromal thickness is better than the whole corneal thickness. The two markers can be used to estimate PMI. PMID- 24350536 TI - [Bone development trend in the knee joint of Tibetan teenagers in Aba Prefecture of Sichuan Province]. AB - OBJECTIVE: To discuss bone development trend in the knee joint of Tibetan teenagers in Sichuan province and to effectively update the database for estimating the living age of Tibetan teenagers in terms of bone age of the knee joint. METHODS: Radiographs including epiphysis of distal femur, proximal tibia and proximal fibula were taken from 483 Tibetan male and female teenagers aged from 14 to 19 years old in Aba prefecture of Sichuan province in order to observe epiphyseal growth situation. The descriptive data of the epiphyseal closure ages of these teenagers' knee joints were statistically analyzed by SPSS 16.0 software. RESULTS: The distal femur epiphyseal closure occurred earliest, while the proximal fibula epiphyseal closure occurred latest. The epiphyseal growth of knee joints of females occurred about one year earlier than that of males. CONCLUSION: The forensic information and data related to Tibetan teenagers' bone age identification should be updated regularly. These results provide potential value for the practice of forensic medicine, anthropology and clinical medicine. PMID- 24350537 TI - Mathematical models for teenager's living age evaluation based on CT image of medial clavicular epiphysis. AB - OBJECTIVE: To explore the correlation between volume rendering (VR) statistics of medial clavicular epiphysis and living age, and establish the mathematical models for living age evaluation using the CT image of medial clavicular epiphysis based on the growth rules of osteoepiphysis of medial clavicle. METHODS: The CT images of the medial clavicles from 795 teenagers aged 15-25, 387 males and 408 females, were collected in East and South China. VR 3D images were reconstructed from 0.60 mm-thick slice CT images. The epiphyseal diameter, sternal end diameter, and their respective diameter ratio (the left: X1; the right: x3); epiphyseal area, sternal end area, and their respective area ratio (the left: x2; the right: x4), were measured and calculated. All these observations were analyzed using SPSS 19.0 statistical software. The statistical differences in gender and age were analyzed by Mann-Whitney U test. The mathematical models were established using least square. Sixty trained subjects, 30 males and 30 females, were tested to verify the accuracy of the established mathematical models. RESULTS: In the group of same age, x1 showed significant difference in gender; the same results were observed in x2, x3, and x4, which suggested that the growth rules of osteoepiphysis of medial clavicle were highly correlated with living age. The accuracy of these mathematical models were all above 67.6% (+/- 1.0 year) and 78.5% (+/- 1.5 year). CONCLUSION: The mathematical models with reasonable accuracy could be manageable in practice to confirm the conclusion of the atlas method. The current study can contribute to the single skeletal age evaluation. PMID- 24350538 TI - [Characteristics of computed dynamic posturography of patients with peripheral vertigo]. AB - OBJECTIVE: To quantify the posture control ability of patients with peripheral vertigo by computed dynamic posturography (CDP). METHODS: Ninety-one subjects diagnosed with peripheral vertigo by caloric test were divided into unilateral vestibular dysfunction group (unilateral group) and bilateral vestibular disorder dysfunction group (bilateral group). CDP tests including sensory organization test (SOT) and motor control test (MCT) were performed on all subjects. The CDP results were compared with the normal data by t-test. RESULTS: In unilateral group, there was no statistically significant difference in SOT compared with normal data (P > 0.05). In bilateral group, the composite equilibrium score was lower than the normal data, especially during the moving of the platform and the changes of visual stimulation (P < 0.05). In MCT test, the latencies of both groups showed no statistically significant difference compared with normal data (P > 0.05). CONCLUSION: During the non-acute period of peripheral vertigo, patients could maintain static equilibrium. Compared with normal people, dynamic equilibrium function is normal in patients with unilateral vestibular dysfunction, but declined in patients with bilateral vestibular dysfunction. PMID- 24350539 TI - [Age estimation using content of sjTREC in human peripheral blood]. AB - OBJECTIVE: To determine and verify the correlation formula of age estimation using the content of signal joint T-cell receptor excision DNA circle (sjTREC) in human peripheral blood and to discuss its application value in forensic biological practice. METHODS: The samples of peripheral blood stains were collected from 30 healthy unrelated individuals whose ages were known. The DNAs were extracted from the samples stored at room temperature after 4 weeks. The content of sjTREC was measured by real-time fluorescent quantitative PCR technique, and the TATA box binding protein (TBP) was selected as reference genes. The age of each sample was predicted with the formula which was Age = 7.181 5 Y-42.458 +/- 9.42 (Y = dCtTBP-sjTREC), and the result was compared with the real age of each individual to determine the accuracy of the formula. RESULTS: sjTREC and TBP gene were detectable in all 30 samples of peripheral blood. The contents of sjTREC in human peripheral blood showed a decreasing tendency with aging. The accuracy rate for the age estimation by this method was 76.67%. CONCLUSION: The method for the age estimation with the content of sjTREC was simple, fast, sensitive, and good species specific with important potential application prospect. PMID- 24350540 TI - [Determination of the biological attribute of evidence at the scene using reverse transcription PCR and real-time fluorescent quantitative PCR]. AB - OBJECTIVE: To explore the feasibility of biological method to identify the biological attribute of samples at crime scene. METHODS: Thirty samples of ten blood stains, ten saliva stains and ten semen stains were selected, and all the samples were processed by the routine method and biomolecular method, respectively. Both RNA and DNA were isolated using DNA-RNA co-extraction technology and the mRNA was converted into cDNA using reverse transcription PCR (RT-PCR). Three pairs of specific primers were designed for blood stain, saliva stain and semen stain based on the different target genes in three specific tissues and the primers were amplified using real-time fluorescent quantitative PCR. The differences in these biological samples were evaluated by melting temperature (Tm) values and the size of the amplification fragment. RESULTS: The Tm values of blood stain, saliva stain and semen stain were (84.5 +/- 0.2) degrees C, (76.9 +/- 0.3) degrees C and (88.5 +/- 0.2) degrees C, respectively. The length of PCR fragments of them was 177bp, 134bp and 294bp, respectively. CONCLUSION: Compared with the routine method, RT-PCR with real-time fluorescent quantitative PCR is highly specific, sensitive and reliable to identify the biological attribute of evidence, and can be potentially applied to determine evidence attribute in forensic practice. PMID- 24350541 TI - [Difference between the cognitive and control ability and the responsibility in forensic psychiatry evaluation]. AB - OBJECTIVE: To analyze the difference between the cognitive and control ability and the responsibility in forensic psychiatry evaluation. METHODS: To compare the results of the responsibility evaluation from 2001.1 to 2006.10 (the first period) with that of the cognitive and control ability evaluation from 2006.11 to 2010.10 (the second period). The admissibility opinions on court judgment and evaluation were investigated by return visit. The legal professions' opinions on forensic psychiatric issues from the police office, the procuratorate, the court, and the judiciary were investigated. RESULTS: There was no significant difference of the criminal types between two periods (P > 0.05). There was significant difference of the diagnostic types between two periods (P < 0.05). The proportion of normal range and part loss of the cognitive and control ability in the second period were higher than that in the first period, but the proportion of complete loss of the cognitive and control ability in the second period was lower than that in the first period (P < 0.05). Among the legal professions, 70.5% of them thought that "the evaluation of cognitive and control ability" was different from "the evaluation of criminal responsibility" and 94.9% of them thought that "to confirm the influence of the forensic psychiatric evaluation of mental disorder on the crime behavior" or "to assess of cognitive and control ability" met requirements of normative judicial expertise. CONCLUSION: The evaluation of cognitive and control ability is more aligned with legal requirements and behavioral norms of own subject than the evaluation of responsibility. PMID- 24350542 TI - [Determination of cinobufagin and resibufogenin in liver tissue by HPLC-MS/MS]. AB - OBJECTIVE: To develop a sensitive and accurate assay for detecting cinobufagin and resibufogenin in liver tissue using high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). METHODS: The homogenization of liver tissue with internal standard dexamethasone was extracted with dichloromethane. The extracts with methanol were purified through ProElut C18 solid phase extraction and tested in positive electrospray ionization with multiple reaction monitoring of HPLC-MS/MS. RESULTS: The good linear relationship of cinobufagin and resibufogenin in liver tissue were 1-204 ng/g and 1-206 ng/g, respectively. The minimal detection threshold (S/N > or = 3) of this method was 0.3 ng/g for both cinobufagin and resibufogenin. The matrix effect was 96.5%-126.7%. The extraction recovery coefficient was 70.0%-82.3%. The precision of intra-day and inter-day was less than 10%. CONCLUSION: This method is sensitive and reliable, and can be used in forensic toxicological analysis. PMID- 24350543 TI - [Sudden death caused by aortic dissection: 63 cases of forensic pathological analysis]. AB - OBJECTIVE: To explore the cause of death, clinical manifestations and forensic pathological features of death cases caused by aortic dissection. METHODS: Sixty three cases of aortic dissection were selected from forensic medical center, Sun Yat-sen University from 2001 to 2011 and retrospectively analyzed. RESULTS: The patients were mostly young and middle-aged male, aged from 30 to 49 years old. The DeBakey type II was the most common pathological type and the main cause of death was pericardial tamponade. The most common symptom was abdominal pain. However, the location of aorta dissection did not always correlate with the location of pain. Some cases showed no obvious clinical symptoms. The rupture was usually located in ascending aorta with atherosclerosis and pathological changes of hypertension. CONCLUSION: It is significant for diagnosis and evaluation the cause of death of aortic dissection by knowing the clinical symptoms and forensic pathological features. PMID- 24350544 TI - [Disability appraisal for common peroneal nerve injury in traffic accidents: 8 cases analysis]. AB - OBJECTIVE: To investigate the characteristics of forensic clinical identification on common peroneal nerve injury in traffic accident. METHODS: Eight cases of common peroneal nerve injury in traffic accidents were analyzed, including general condition of the wounded, the way of injury, the imaging results, the EMG results, and the degree of injury, etc. RESULTS: In 8 cases, 2 cases of complete common peroneal nerve injury were determined to grade 9 (disability degree) and 6 cases of partial common peroneal nerve injury were determined to grade 10 (disability degree). CONCLUSION: By comparison, the disability degree of complete common peroneal nerve injury is higher than that of partial common peroneal nerve injury. The forensic clinical identification of common peroneal nerve should be made with synthetical consideration of medical history, symptoms, and auxiliary examinations. PMID- 24350545 TI - [Characteristics of recidivism in patients with mental disorders: 156 cases analysis]. AB - OBJECTIVE: To analyze the characteristics of recidivism in patients with mental disorders, including criminology, clinic and guardianship, in order to provide references for preventing recidivism. METHODS: Using the self-designed questionnaire, 156 psychotic patients who had repeated crimes were appraised by West China Forensic Science Center of Sichuan University from 2007 to 2011 and the data were collected and analyzed. RESULTS: In the majority of these cases, patients were male, 26-45 years old, junior high school or below diploma, unmarried, and farmers or jobless. Each patient broke law 3.26 times on average. The main crimes were intentional injury (34.6%) and murder (15.7%). Within 5 years after diagnosis with mental disorder, 56.4% of the patients committed first crime. Within 1 year after the first time breaking the law, 55.8% of them repeated crimes. The diagnoses of schizophrenia (63.5%) were in the majority. The assessment results were mostly irresponsibility (61.5%). Among the patients, 44.9% of them didn't receive treatment while 34.6% of them were out of supervision. After the first crime, 66.1% of them didn't receive criminal prosecution while only 7.1% of them went through the appraisement of forensic psychiatry. CONCLUSION: Most of the patients had low education and low income. Meanwhile, low outpatient rate and pool supervision occurred in this special crowd. A good system for care and treatment of these mental patients should be built to prevent them from recidivism. PMID- 24350546 TI - [Genetic polymorphisms of 16 STR loci in Tibetan Mastiff]. AB - OBJECTIVE: To explore the genetic polymorphisms of 16 STR loci from 449 Tibetan Mastiffs in order to set up gene polymorphism database of Tibetan Mastiff. METHODS: The PCR amplification was performed using the 16 STR loci fluorescent multiple amplification kit for dog. The amplified products were detected and statistically analyzed. RESULTS: In the 16 STR loci from 449 Tibetan Mastiffs, CDP was 0.999 999 999 999 999 and CEP was 0.999 997 795. Except FH2010 (10 alleles), PEZ21 (12 alleles), and PEZ05 (13 alleles), the other STR loci had more than 15 alleles. In the 16 STR loci, H was > 0.5 and PIC was > 0.7. CONCLUSION: The 16 STR loci have high polymorphism to be suitable for individual identification and paternity testing of Tibetan Mastiff. The data obtained through this study can be used to establish DNA polymorphism database of Tibetan Mastiff. PMID- 24350547 TI - [Multifocal visual electrophysiology in visual function evaluation]. AB - Multifocal visual electrophysiology, consisting of multifocal electroretinography (mfERG) and multifocal visual evoked potential (mfVEP), can objectively evaluate retina function and retina-cortical conduction pathway status by stimulating many local retinal regions and obtaining each local response simultaneously. Having many advantages such as short testing time and high sensitivity, it has been widely used in clinical ophthalmology, especially in the diagnosis of retinal disease and glaucoma. It is a new objective technique in clinical forensic medicine involving visual function evaluation of ocular trauma in particular. This article summarizes the way of stimulation, the position of electrodes, the way of analysis, the visual function evaluation of mfERG and mfVEP, and discussed the value of multifocal visual electrophysiology in forensic medicine. PMID- 24350548 TI - [Reflection of estimating postmortem interval in forensic entomology and the Daubert standard]. AB - Estimating postmortem interval (PMI) is always the emphasis and difficulty in forensic practice. Forensic entomology plays a significant indispensable role. Recently, the theories and technologies of forensic entomology are increasingly rich. But many problems remain in the research and practice. With proposing the Daubert standard, the reliability and accuracy of estimation PMI by forensic entomology need more demands. This review summarizes the application of the Daubert standard in several aspects of ecology, quantitative genetics, population genetics, molecular biology, and microbiology in the practice of forensic entomology. It builds a bridge for basic research and forensic practice to provide higher accuracy for estimating postmortem interval by forensic entomology. PMID- 24350549 TI - Quality control system of judicial expertise in China. PMID- 24350550 TI - Symposium introduction: challenges of intergovernmental management. PMID- 24350551 TI - Comparative federal health care policy: evidence of collaborative federalism in Pakistan and Venezuela. AB - Collaborative federalism has provided an effective analytical foundation for understanding how complex public policies are implemented in federal systems through intergovernmental and intersectoral alignments. This has particularly been the case in issue areas like public health policy where diseases are detected and treated at the local level. While past studies on collaborative federalism and health care policy have focused on federal systems that are largely democratic, little research has been conducted to examine the extent of collaboration in authoritarian structures. This article applies the collaborative federalism approach to the Islamic Republic of Pakistan and the Bolivarian Republic of Venezuela. Evidence suggests that while both nations have exhibited authoritarian governing structures, there have been discernible policy areas where collaborative federalism is embraced to facilitate the implementation process. Further, while not an innate aspect of their federal structures, Pakistan and Venezuela can potentially expand their use of the collaborative approach to successfully implement health care policy and the epidemiological surveillance and intervention functions. Yet, as argued, this would necessitate further development of their structures on a sustained basis to create an environment conducive for collaborative federalism to flourish, and possibly expand to other policy areas as well. PMID- 24350552 TI - Assessment of pandemic preparedness in a socially vulnerable community in south Texas. AB - The purpose of this research was to obtain information about general and pandemic preparedness efforts of residents within San Patricio County in South Texas, as well as to identify the most effective means of communicating the risks posed by pandemic influenza. The population of San Patricio County is socially vulnerable to a variety of disasters, including influenza pandemics due to the unique demographic profile of the county as well as its location on the Gulf Coast. The goals of this study were to help with pandemic planning efforts and to provide recommendations that could serve as a foundation for building more resilient communities within San Patricio County. Clearly the various governmental levels must work together to assist communities prepare for pandemic preparedness but broad, inclusive community participation is also necessary to strengthen community resilience. PMID- 24350553 TI - Decisional inconsistencies in the management of contaminated, sport-caught fish. AB - Persistent toxic pollutants such as polychlorinated biphenyls and mercury accumulate in tissues of fish that are caught and consumed by sport anglers and their families. Unlike commercially-sold fish, the U.S. Food and Drug Administration (FDA) does not regulate sport-caught fish that are contaminated with these and other pollutants. Instead, nearly every state in the U.S. develops and issues consumption advice for contaminated sport-caught fish. We examined fish consumption advice issued by states that border and share waters of the Mississippi River. Our examination identified numerous jurisdictional inconsistencies that threaten the receptivity and credibility of consumption advice and, more important, threaten the health of individuals who consume contaminated sport-caught fish. PMID- 24350554 TI - Faith-based partnerships and foster parent satisfaction. AB - Throughout the last several decades, there has been a chronic shortage of foster and adoptive families in the United States. Recruiting families to begin the licensure process to become foster and adoptive parents is already a difficult undertaking. But research shows that a very large proportion of families drop out of the licensure process early on due to frustration or a lack of support. This paper studies two faith-based partnerships that have arisen to create new capacity in the child welfare system. These programs recruit prospective families from churches and then provide training and ongoing support to those families throughout the licensure process. Using survey data collected from program participants, respondent perceptions of the licensure process are compared to a nationally representative sample of foster parents from the National Foster Care Adoptions Attitude Survey. Statistical results demonstrate that participants with the faith-based programs reported much higher levels of satisfaction with the process than the national sample. These findings provide evidence that these faith-based partnerships may provide an important additional source of capacity for an overburdened child welfare system. PMID- 24350555 TI - Future directions in intergovernmental relations. PMID- 24350556 TI - Strong and anisotropic superexchange in the single-molecule magnet (SMM) [MnIII(6)OsIII]3+: promoting SMM behavior through 3d-5d transition metal substitution. AB - The reaction of the in situ generated trinuclear triplesalen complex [(talent Bu2)MnIII3(solv)n]3+ with (Ph4P)3[OsIII(CN)6] and NaClO4.H2O affords [MnIII6OsIII](ClO4)3 (= [{(talent-Bu2)MnIII3}2{OsIII(CN)6}](ClO4)3) in the presence of the oxidizing agent [(tacn)2NiIII](ClO4)3 (tacn =1,4,7 triazacyclononane), while the reaction of [(talent-Bu2)MnIII3(solv)n]3+ with K4[OsII(CN)6] and NaClO4.H2O yields [MnIII6OsII](ClO4)2 under an argon atmosphere. The molecular structure of [MnIII6OsIII]3+ as determined by single crystal X-ray diffraction is closely related to the already published [MnIII6Mc]3+ complexes (Mc = CrIII, FeIII, CoIII, MnIII). The half-wave potential of the OsIII/OsII couple is E1/2 = 0.07 V vs Fc+/Fc. The FT-IR and electronic absorption spectra of [MnIII6OsII]2+ and [MnIII6OsIII]3+ exhibit distinct features of dicationic and tricationic [MnIII6Mc]n+ complexes, respectively. The dc magnetic data (MUeff vs T, M vs B, and VTVH) of [MnIII6OsII]2+ are successfully simulated by a full-matrix diagonalization of a spin-Hamiltonian including isotropic exchange, zero-field splitting with full consideration of the relative orientation of the D-tensors, and Zeeman interaction, indicating antiferromagnetic MnIII-MnIII interactions within the trinuclear triplesalen subunits (JMn-Mn(1) = -(0.53 +/- 0.01) cm-1, Hex = -2?i=10 cm, presence of lymph node metastasis and main portal vein tumour thrombosis compared to the TACE+RT group. The OS in the TACE+RT group was significantly longer compared to the sorafenib group (14.1 months vs. 3.3 months, P < 0.001). In the propensity score-matched cohort, baseline characteristics did not differ between the two groups. The TACE+RT group showed prolonged OS compared to the sorafenib group (6.7 months vs. 3.1 months, P < 0.001). Multivariate analysis revealed that TACE+RT was the only independent prognostic factor associated with survival in the propensity score-matched cohort (HR = 0.172, P < 0.001). CONCLUSIONS: The OS of TACE+RT was longer compared to sorafenib treatment in locally advanced HCC patients without distant metastasis. Further prospective studies are warranted to confirm these findings. PMID- 24350565 TI - Interaction between RB protein and NuMA is required for proper alignment of spindle microtubules. AB - Retinoblastoma protein (pRB) controls cell cycle progression and cell cycle exit through interactions with cellular proteins. Many pRB-binding proteins, which function in gene transcription or modulation of chromatin structure, harbor LXCXE motifs in their binding domain for pRB. In this study, we found that nuclear mitotic apparatus protein (NuMA), a mitotic spindle organizer, interacts with pRB through LSCEE sequences located in its C-terminal region. siRNA-mediated down regulation of pRB caused aberrant distribution of NuMA and alignment of spindle microtubules in mitotic cells. Abnormal organization of spindle microtubules was also accompanied by misalignment of an over-expressed NuMA mutant (mut-NuMA) with a defect in pRB binding caused by an LSGEK mutation. The mut-NuMA-over-expressing cells showed lower potency for survival than wild-type NuMA (wt-NuMA)-over expressing cells during 2 weeks of culture. Interestingly, knockdown of pRB reduced the population of wt-NuMA-over-expressing cells to the same level as mut NuMA cells after 2 weeks. Taken together, pRB may have a novel function in regulating the mitotic function of NuMA and spindle organization, which are required for proper cell cycle progression. PMID- 24350566 TI - Comparison of collagen membrane and bone substitute as a carrier for rhBMP-2 in lateral onlay graft. AB - OBJECTIVES: To evaluate the bone regenerative effect of bioresorbable collagen membrane (CM) as a carrier for recombinant human bone morphogenetic protein-2 (rhBMP-2) when performing lateral onlay grafts using bovine hydroxyapatite incorporated with collagen matrix (BHC) in combination with CM in dogs. MATERIAL AND METHODS: A guided bone regeneration (GBR) was performed at the buccal aspect of edentulous maxillary alveolar ridges in dogs (n = 5): (1) BHC group, in which rhBMP-2-loaded BHC was covered by a CM, and (2) CM group, in which BHC was covered by an rhBMP-2-loaded CM. A histologic and histometric analysis was performed after 8 weeks of healing. RESULTS: Both the BHC and CM groups exhibited substantial newly formed bone (NB). More NB was found in the CM group than in the BHC group without statistical significance. Most of the NB was in direct contact with the residual bone substitute in the BHC group, whereas the projections and islands of NB were observed in the spaces between the residual bone substitute clusters in the CM group. The bone-to-residual bone substitute contact ratio was significantly lower in the CM group than in the BHC group (P = 0.043). CONCLUSIONS: Within the limitations of this study, it can be concluded that rhBMP 2-loaded CM performed lateral onlay grafts as effectively as rhBMP-2-loaded BHC while showing less bone-residual bone substitute contact ratio in dogs. The loading of CMs with rhBMP-2 might therefore be a recommendable treatment option for facilitating lateral onlay graft combined with rhBMP-2. PMID- 24350568 TI - Mental pain, communication difficulties, and medically serious suicide attempts: a case-control study. AB - Medical severe suicide attempts (MSSA) are epidemiologically very similar to individuals who complete suicide. Thus the investigation of individuals who have made MSSAs may add to our understanding of the risk factors for completed suicide. The aim of this study was to assess the role of mental pain and communication difficulties in MSSA. A total of 336 subjects were divided into 4 groups: 78 meeting criteria for MSSA compared with116 subjects who made a medically non-serious suicide attempt (MNSSA), 47 psychiatric controls with no history of suicidal behavior, and 95 healthy controls. Mental pain variants (e.g., hopelessness), facets of communication difficulties (e.g., self disclosure), as well as socio-demographic and clinical characteristics were assessed. The MSSA had significantly higher communication difficulties than the other 3 groups. Moreover, the interaction between mental pain and communication difficulties explained some of the variance in suicide lethality, above and beyond the contribution of each component alone. This report underlines the importance of mental pain for suicide attempts in general while difficulties in communication abilities play a critical role in differentiating MSSA from MNSSA. The co-existence of unbearable mental pain with difficulties in communication significantly enhances the risk for more lethal forms of suicidal behavior. PMID- 24350567 TI - Controlled multiple growth factor delivery from bone tissue engineering scaffolds via designed affinity. AB - It is known that angiogenesis plays an important role in bone regeneration and that release of angiogenic and osteogenic growth factors can enhance bone formation. Multiple growth factors play key roles in processes that lead to tissue formation/regeneration during natural tissue development and repair. Therefore, treatments aiming to mimic tissue regeneration can benefit from multiple growth factor release, and there remains a need for simple clinically relevant approaches for dual growth factor release. We hypothesized that mineral coatings could be used as a platform for controlled incorporation and release of multiple growth factors. Specifically, mineral-coated scaffolds were "dip coated" in multiple growth factor solutions, and growth factor binding and release were dictated by the growth factor-mineral binding affinity. Beta tricalcium phosphate (beta-TCP) scaffolds were fabricated using indirect solid-free form fabrication techniques and coated with a thin conformal mineral layer. Mineral-coated beta TCP scaffolds were sequentially dipped in recombinant human vascular endothelial growth factor (rhVEGF) and a modular bone morphogenetic peptide, a mineral binding version of bone morphogenetic protein 2 (BMP2), solutions to allow for the incorporation of each growth factor. The dual release profile showed sustained release of both growth factors for over more than 60 days. Scaffolds releasing either rhVEGF alone or the combination of growth factors showed an increase in blood vessel ingrowth in a dose-dependent manner in a sheep intramuscular implantation model. This approach demonstrates a "modular design" approach, in which a controllable biologics carrier is integrated into a structural scaffold as a thin surface coating. PMID- 24350569 TI - Preliminary experience with stenting for management of non-urolith urethral obstruction in eight cats. AB - OBJECTIVE: To (1) describe minimally invasive transurethral antegrade and retrograde techniques for the placement of self-expanding metallic stents (SEMS) to reestablish urethral patency in cats with non-urolith urethral obstructions and (2) to report the procedural complications, incontinence rates, and long-term effectiveness in maintaining a patent urethra. STUDY DESIGN: Case series. ANIMALS: Cats (n = 8). METHODS: Signalment, history, clinical signs, physical examination, severity of stranguria and incontinence, clinicopathologic data, diagnostic procedures performed, diagnosis, interventional technique, type and dimensions of stent placed, complications and final outcome of 8 cats treated with SEMS for the management of urethral strictures or masses are presented. Each cat was followed for >=12 months. Follow-up information was obtained from the medical record or by telephone interview of the owner and/or referring veterinarian. RESULTS: Four cats were continent after stent placement, 2 were moderately incontinent, and 2 were severely incontinent. Long-term follow-up (median, 462 days) was available. At follow-up, 5 cats were alive and 3 had been euthanatized at 88, 233, and 305 days. Long-term outcome, as assessed by the authors, was good (1) to excellent (3) in 4 cats, and fair (2) to poor (2) in 4 cats. Owner reported outcomes were excellent in 3/8, good to excellent in 1/8, good in 2/8, and poor in 2/8. CONCLUSION: Palliative stenting of urethral obstructions is a minimally invasive method to re-establish urethral patency in cats. PMID- 24350570 TI - Attachment insecurities and women's sexual function and satisfaction: the mediating roles of sexual self-esteem, sexual anxiety, and sexual assertiveness. AB - We examined the potential role of three mediators--sexual self-esteem, sexual anxiety, and sexual assertiveness--of the association between romantic attachment insecurities (anxiety and avoidance) and two aspects of women's sexual functioning: sexual function and sexual satisfaction. A sample of 556 women aged 18 to 30 agreed to complete an online series of validated questionnaires assessing attachment insecurities and several aspects of sexual functioning. Lower sexual self-esteem and higher sexual anxiety mediated the associations between attachment anxiety and lower sexual function and satisfaction. Lower sexual self-esteem and higher sexual anxiety also partially mediated the links between attachment-related avoidance and the two sexual functioning variables. Sexual assertiveness, however, did not mediate these associations. A significant interaction between attachment anxiety and avoidance was also found to predict sexual satisfaction, with women high in avoidance and low in anxiety being the least satisfied. Results are discussed in terms of theoretical and clinical implications. PMID- 24350571 TI - Parental depression and child conduct problems: evaluation of parental service use and associated costs after attending the Incredible Years Basic Parenting Programme. AB - BACKGROUND: There is co-morbidity between parental depression and childhood conduct disorder. The Incredible Years (IY) parenting programmes reduce both conduct disorder in children and depression in their parents. Recent U.K. and Ireland trials of the effectiveness and cost-effectiveness of IY parenting programmes have assessed children's health and social care service use, but little is known about the programme's impact on parental service use. This paper explores whether an above clinical cut-off score on the Beck Depression Inventory II (BDI II) is associated with high or low parental health and social care service use in high-risk families receiving the IY Basic Programme. METHODS: This is a secondary analysis of a subsample (N = 119) from the first U.K. community based randomised controlled trial of the 12-week IY Basic Programme (N = 153). Parents with children at risk of developing conduct disorder were randomised to receive the programme or to a waiting-list control group. BDI II total and BDI II clinical depression cut-off scores were compared to frequencies and costs of parents' service use, at baseline, six, twelve and eighteen months post-baseline for the intervention group and at baseline and six months post-baseline for the control group. RESULTS: Intervention group parents who scored above the clinical cut-off on the BDI II at baseline used more health and social care services than those who scored below at baseline, six and eighteen months. Significant reductions in service use frequencies were found for the intervention group only. CONCLUSION: Parents with higher levels or depression used more health and social care service and parenting programmes have been shown to reduce parental depression and also health and social service use. However, further exploration of depressed parents' service use and the cost implications for publically funded health and social care services is needed. PMID- 24350572 TI - Predictability and irreversibility of genetic changes associated with flower color evolution in Penstemon barbatus. AB - Two outstanding questions in evolutionary biology are whether, and how often, the genetic basis of phenotypic evolution is predictable; and whether genetic change constrains evolutionary reversibility. We address these questions by studying the genetic basis of red flower color in Penstemon barbatus. The production of red flowers often involves the inactivation of one or both of two anthocyanin pathway genes, Flavonoid 3',5'-hydroxylase (F3'5'h) and Flavonoid 3'-hydroxylase (F3'h). We used gene expression and enzyme function assays to determine that redundant inactivating mutations to F3'5'h underlie the evolution of red flowers in P. barbatus. Comparison of our results to previously characterized shifts from blue to red flowers suggests that the genetic change associated with the evolution of red flowers is predictable: when it involves elimination of F3'5'H activity, functional inactivation or deletion of this gene tends to occur; however, when it involves elimination of F3'H activity, tissue-specific regulatory substitutions occur and the gene is not functionally inactivated. This pattern is consistent with emerging data from physiological experiments indicating that F3'h may have pleiotropic effects and is thus subject to purifying selection. The multiple, redundant inactivating mutations to F3'5'h suggest that reversal to blue-purple flowers in this group would be unlikely. PMID- 24350573 TI - The bacterial communities in plant phloem-sap-feeding insects. AB - The resident microbiota of animals represents an important contribution to the global microbial diversity, but it is poorly known in many animals. This study investigated the bacterial diversity in plant phloem-sap-feeding whiteflies, aphids and psyllids by pyrosequencing bacterial 16S rRNA gene amplicons. After correction for sequencing error, just 3-7 bacterial operational taxonomic units were recovered from each insect sample sequenced to sufficient depth for saturation of rarefaction curves. Most samples were dominated by primary and secondary symbionts, which are localized to insect cells or the body cavity, indicative of a dearth of bacterial colonists of the gut lumen. Diversity indices of the bacterial communities (Shannon's index: 0.40-1.46, Simpson's index: 0.15 0.74) did not differ significantly between laboratory and field samples of the phloem-feeding insects, but were significantly lower than in drosophilid flies quantified by the same methods. Both the low bacterial content of the phloem sap diet and biological processes in the insect may contribute to the apparently low bacterial diversity in these phloem-feeding insects. PMID- 24350574 TI - Variational attenuation correction in two-view confocal microscopy. AB - BACKGROUND: Absorption and refraction induced signal attenuation can seriously hinder the extraction of quantitative information from confocal microscopic data. This signal attenuation can be estimated and corrected by algorithms that use physical image formation models. Especially in thick heterogeneous samples, current single view based models are unable to solve the underdetermined problem of estimating the attenuation-free intensities. RESULTS: We present a variational approach to estimate both, the real intensities and the spatially variant attenuation from two views of the same sample from opposite sides. Assuming noise free measurements throughout the whole volume and pure absorption, this would in theory allow a perfect reconstruction without further assumptions. To cope with real world data, our approach respects photon noise, estimates apparent bleaching between the two recordings, and constrains the attenuation field to be smooth and sparse to avoid spurious attenuation estimates in regions lacking valid measurements. CONCLUSIONS: We quantify the reconstruction quality on simulated data and compare it to the state-of-the art two-view approach and commonly used one-factor-per-slice approaches like the exponential decay model. Additionally we show its real-world applicability on model organisms from zoology (zebrafish) and botany (Arabidopsis). The results from these experiments show that the proposed approach improves the quantification of confocal microscopic data of thick specimen. PMID- 24350575 TI - Introducing palliative care into entry-level physical therapy education. AB - BACKGROUND AND OBJECTIVE: There is a paucity of information related to teaching palliative care to entry-level physical therapy students. The aim of this study was to evaluate the impact of an undergraduate course in palliative care on the preparedness of entry-level physical therapy students to practice within the palliative care setting. METHODS: Participants were all entry-level undergraduate students enrolled in the third year of a 4-year undergraduate degree. All students enrolled in the course, "Physiotherapy Through Lifestages" took part in the learning modules relating to the care of patients undergoing palliative care. A survey instrument was used in the study, a modified version of an existing unpublished written questionnaire previously used to evaluate palliative care education in other allied health professions. RESULTS AND CONCLUSIONS: Participation in the course resulted in an increase in self-rated knowledge and confidence for working in the palliative care setting for entry-level physical therapy students and is considered to provide a useful ongoing resource for the presentation of this topic material. Although the impact of the delivery of this education module may be considered successful in this regard, it would appear that some of the underlying attitudes and emotional responses to this area of physiotherapy practice were less easily influenced. Further research is required to understand the influences on emotional preparedness of students to undertake this area of study and practice and to determine the optimal stage of study for delivery of this content. PMID- 24350576 TI - Association of microRNA-126 expression with clinicopathological features and the risk of biochemical recurrence in prostate cancer patients undergoing radical prostatectomy. AB - OBJECTIVE: Numerous studies have suggested that microRNA-126 (miR-126) is involved in development of various cancer types as well as in malignant proliferation and invasion. However, its role in human prostate cancer (PCa) is still unclear. The aim of this study was to investigate miR-126 expression in PCa and its prognostic value for PCa patients undergoing radical prostatectomy. METHODS: A series of 128 cases with PCa were evaluated for the expression levels of miR-126 by quantitative reverse-transcription PCR (qRT-PCR). Kaplan-Meier analysis and Cox proportional hazards regression models were used to investigate the correlation between miR-126 expression and prognosis of PCa patients. RESULTS: Compared with non-cancerous prostate tissues, the expression level of miR-126 was significantly decreased in PCa tissues (PCa vs. non-cancerous prostate: 1.05 +/- 0.63 vs. 2.92 +/- 0.98, P < 0.001). Additionally, the loss of miR-126 expression was dramatically associated with aggressive clinical pathological features, including advanced pathological stage (P = 0.001), positive lymph node metastasis (P = 0.006), high preoperative PSA (P = 0.003) and positive angiolymphatic invasion (P = 0.001). Moreover, Kaplan-Meier survival analysis showed that PCa patients with low miR-126 expression have shorter biochemical recurrence (BCR)-free survival than those with high miR-126 expression. Furthermore, multivariate analysis indicated that miR-126 expression was an independent prognostic factor for BCR-free survival after radical prostatectomy. CONCLUSION: These findings suggest for the first time that the loss of miR-126 expression may play a positive role in the malignant progression of PCa. More importantly, the downregulation of miR-126 may serve as an independent predictor of BCR-free survival in patients with PCa. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1740080792113255. PMID- 24350577 TI - The impact of economic factors on migration considerations among Icelandic specialist doctors: a cross-sectional study. AB - BACKGROUND: Globalization has facilitated the employability of doctors almost anywhere in the world. In recent years, the migration of doctors seems to have increased. However, we lack studies on doctors' migration from developed countries. Because the economic recession experienced by many countries might have affected the migration of doctors, research on this topic is important for the retention of doctors. Iceland was hit hard by the economic recession in 2008. Therefore, we want to explore how many specialist doctors in Iceland have considered migrating and whether economic factors at work and in private life, such as extensive cost-containment initiatives at work and worries about personal finances, are related to doctors' migration considerations. METHODS: In 2010, all doctors in Iceland registered with the Icelandic Medical Association were sent an electronic cross-sectional survey by email. The 467 specialists who participated in this study represent 55% of all specialist doctors working in Iceland. Information on doctors' contemplation of migration was available from responses to the question: "Have you considered moving and working abroad?" The predictor variables in our logistic regression model are perceived cost-containment initiatives at work, stress related to personal finances, experience of working abroad during vacations, job dissatisfaction, job position, age, and gender. RESULTS: Sixty-three per cent of Iceland's specialist doctors had considered relocation abroad, 4% were moving in the next year or two, and 33% had not considered relocating. Logistic regression analysis shows that, controlling for age, gender, job position, job satisfaction, and experience of working abroad during vacations, doctors' migration considerations were significantly affected by their experiences of cost-containment initiatives at work (odds ratio (OR) = 2.0, p < 0.01) and being stressed about personal finances (OR = 1.6, p < 0.001). Age, job satisfaction, and working abroad during vacations also had an effect, whereas job position did not. CONCLUSIONS: Economic factors affect whether specialist doctors in Iceland consider migration. More studies on the effect of economic recession on migration by doctors are needed. PMID- 24350578 TI - The eye-tracking computer device for communication in amyotrophic lateral sclerosis. AB - OBJECTIVE: To explore the effectiveness of communication and the variables affecting the eye-tracking computer system (ETCS) utilization in patients with late-stage amyotrophic lateral sclerosis (ALS). METHODS: We performed a telephone survey on 30 patients with advanced non-demented ALS that were provisioned an ECTS device. Median age at interview was 55 years (IQR = 48-62), with a relatively high education (13 years, IQR = 8-13). A one-off interview was made and answers were later provided with the help of the caregiver. The interview included items about demographic and clinical variables affecting the daily ETCS utilization. RESULTS: The median time of ETCS device possession was 15 months (IQR = 9-20). The actual daily utilization was 300 min (IQR = 100-720), mainly for the communication with relatives/caregiver, internet surfing, e-mailing, and social networking. 23.3% of patients with ALS (n = 7) had a low daily ETCS utilization; most reported causes were eye-gaze tiredness and oculomotor dysfunction. CONCLUSIONS: Eye-tracking computer system is a valuable device for AAC in patients with ALS, and it can be operated with a good performance. The development of oculomotor impairment may limit its functional use. PMID- 24350579 TI - Is adjuvant radiotherapy warranted in resected pT1-2 node-positive rectal cancer? AB - BACKGROUND: Stage T1-2 rectal cancers are unlikely to have lymph node metastases and neoadjuvant therapy is not routinely administered. Postoperative management is controversial if lymph node metastases are detected in the resected specimen. We studied the outcomes of patients with pT1-2 node-positive rectal cancer in order to determine whether adjuvant radiotherapy was beneficial. METHODS: We conducted a retrospective analysis of 284 patients with pathological T1-2 node positive rectal cancer from a single institution. Outcomes, including local recurrence (LR), distant metastasis (DM), disease free survival (DFS) and overall survival (OS), were studied in patients with detailed TN staging and different adjuvant treatment modalities. RESULTS: The overall 5-year LR, DM, DFS and OS rates for all patients were 12.5%, 32.9%, 36.4% and 76.8%, respectively. Local control was inferior among patients who received no adjuvant therapy. Patients could be divided into three risk subsets: Low-risk, T1N1; Intermediate-risk, T2N1 and T1N2; and High-risk, T2N2. The 5-year LR rates were 5.3%, 9.8% and 26.4%, respectively (p = 0.005). In High-risk patients, addition of radiotherapy achieved a 5-year LR rate of 9.1%, compared 34.8% without radiotherapy. CONCLUSIONS: In our study, we provide the detailed outcomes and preliminary survival analysis in a relatively infrequent subset of rectal cancer. Three risk subsets could be identified based on local control for pT1-2 node positive rectal cancer. Postoperative treatment needs to be individualized for patients with pT1 2 node-positive rectal cancer. PMID- 24350580 TI - Sequencing error correction without a reference genome. AB - BACKGROUND: Next (second) generation sequencing is an increasingly important tool for many areas of molecular biology, however, care must be taken when interpreting its output. Even a low error rate can cause a large number of errors due to the high number of nucleotides being sequenced. Identifying sequencing errors from true biological variants is a challenging task. For organisms without a reference genome this difficulty is even more challenging. RESULTS: We have developed a method for the correction of sequencing errors in data from the Illumina Solexa sequencing platforms. It does not require a reference genome and is of relevance for microRNA studies, unsequenced genomes, variant detection in ultra-deep sequencing and even for RNA-Seq studies of organisms with sequenced genomes where RNA editing is being considered. CONCLUSIONS: The derived error model is novel in that it allows different error probabilities for each position along the read, in conjunction with different error rates depending on the particular nucleotides involved in the substitution, and does not force these effects to behave in a multiplicative manner. The model provides error rates which capture the complex effects and interactions of the three main known causes of sequencing error associated with the Illumina platforms. PMID- 24350581 TI - Circular permutation of a WW domain: folding still occurs after excising the turn of the folding-nucleating hairpin. AB - A hyperstable Pin1 WW domain has been circularly permuted via excision of the fold-nucleating turn; it still folds to form the native three-strand sheet and hydrophobic core features. Multiprobe folding dynamics studies of the normal and circularly permuted sequences, as well as their constituent hairpin fragments and comparable-length beta-strand-loop-beta-strand models, indicate 2-state folding for all topologies. N-terminal hairpin formation is the fold nucleating event for the wild-type sequence; the slower folding circular permutant has a more distributed folding transition state. PMID- 24350583 TI - Does enhancement of oxidative stress markers mediate health effects of ambient air particles? AB - Evidence indicates that oxidative stress generation may contribute to health effects associated with particulate matter (PM) exposure. We investigated oxidative stress markers in 113 workers exposed to metal-rich PM and 61 nonexposed comparable volunteers. The plasma levels of soluble NOX2-derived peptide (sNOX2-dp) and two oxidative stress markers, urinary 8 hydroxydeoxyguanosine (8-OHdG) and 8-iso-prostaglandinF2alpha (8-iso-PGF2alpha), were analyzed. The plasma levels of the antioxidant alpha-tocopherol were also evaluated. The workers' average exposure to PM with an aerodynamic diameter <10 MUm (PM10) was much higher at the workplace than in the city, where the volunteers lived. Workers had significantly higher urinary 8-iso-PGF2alpha and 8 OHdG and plasma sNOX2-dp levels than nonexposed subjects. Alpha-tocopherol was much lower in workers compared with nonexposed subjects. In multivariable regression models adjusted for age, body mass index, and smoking, 8-iso-PGF2alpha increased in workers in association with PM10 and metal exposure; 8-OHdG and sNOX2-dp were associated only with iron. Alpha-tocopherol was inversely associated with each of the oxidative stress markers. Our observation leads to the hypothesis that the enhancement of oxidative stress markers associated with exposure to high metal-rich PM levels represents a possible step in the pathways leading from particle exposure to systemic (e.g., cardiovascular) effects. PMID- 24350582 TI - Improvement in rheumatic fever and rheumatic heart disease management and prevention using a health centre-based continuous quality improvement approach. AB - BACKGROUND: Rheumatic heart disease (RHD) remains a major health concern for Aboriginal Australians. A key component of RHD control is prevention of recurrent acute rheumatic fever (ARF) using long-term secondary prophylaxis with intramuscular benzathine penicillin (BPG). This is the most important and cost effective step in RHD control. However, there are significant challenges to effective implementation of secondary prophylaxis programs. This project aimed to increase understanding and improve quality of RHD care through development and implementation of a continuous quality improvement (CQI) strategy. METHODS: We used a CQI strategy to promote implementation of national best-practice ARF/RHD management guidelines at primary health care level in Indigenous communities of the Northern Territory (NT), Australia, 2008-2010. Participatory action research methods were employed to identify system barriers to delivery of high quality care. This entailed facilitated discussion with primary care staff aided by a system assessment tool (SAT). Participants were encouraged to develop and implement strategies to overcome identified barriers, including better record keeping, triage systems and strategies for patient follow-up. To assess performance, clinical records were audited at baseline, then annually for two years. Key performance indicators included proportion of people receiving adequate secondary prophylaxis (>=80% of scheduled 4-weekly penicillin injections) and quality of documentation. RESULTS: Six health centres participated, servicing approximately 154 people with ARF/RHD. Improvements occurred in indicators of service delivery including proportion of people receiving >=40% of their scheduled BPG (increasing from 81/116 [70%] at baseline to 84/103 [82%] in year three, p = 0.04), proportion of people reviewed by a doctor within the past two years (112/154 [73%] and 134/156 [86%], p = 0.003), and proportion of people who received influenza vaccination (57/154 [37%] to 86/156 [55%], p = 0.001). However, the proportion receiving >=80% of scheduled BPG did not change. Documentation in medical files improved: ARF episode documentation increased from 31/55 (56%) to 50/62 (81%) (p = 0.004), and RHD risk category documentation from 87/154 (56%) to 103/145 (76%) (p < 0.001). Large differences in performance were noted between health centres, reflected to some extent in SAT scores. CONCLUSIONS: A CQI process using a systems approach and participatory action research methodology can significantly improve delivery of ARF/RHD care. PMID- 24350586 TI - Evaluation of two modified culture media for Leishmania infantum cultivation versus different culture media. AB - The aim of this study is to improve the cultivation of Leishmania promastigotes without the use of common, semisolid culture media such as Evans' modified Tobie's medium (EMTM), liquid RPMI 1640, and Peptone-yeast extract medium (P-Y). Although EMTM medium permits the growth of a high number of parasites, it is technically difficult to prepare as it requires the use of fresh rabbit blood from animals bred on farms, while RPMI 1640 and P-Y show lower growth rates than the EMTM. There is, therefore, a need to develop new blood-free and time-saving culture systems. The aim of this paper is to propose new modified microbiological media, named RPMI-PY and Tobie-PY, to isolate Leishmania and cultivate parasites for research and diagnostic purposes. This study compares classic culture media to the new media, RPMI-PY and Tobie-PY, and demonstrates that the new media have superior performance in terms of time and parasitic load. The growth rate of the parasite was significantly higher at 24, 48, and 72 hr cultivation, based on counts using Burker's chambers, when compared to classic media. This study was carried out at the National References Centre for Leishmaniasis (C.Re.Na.L.) where the isolation procedures are conducted daily from a number of different biological matrices. PMID- 24350587 TI - Streptococcus pneumoniae serotype distribution in children in the Russian Federation before the introduction of pneumococcal conjugate vaccines into the National Immunization Program. AB - WHO recommends the inclusion of PCVs in childhood vaccination programs world wide. Many countries including the Russian Federation are currently planning the inclusion of PCVs in their National Immunization Programs and, therefore, data on the pneumococcal serotype distribution is important to estimate the potential disease impact. Here we review eight recent epidemiological studies on the pneumococcal serotype distribution from Russia. Across all studies, serotypes 6B, 14, 19F and 23F were the most prevalent. Interestingly, serotype 3 was relatively common. Serotype 19A was prevalent among AOM, CAP and nasopharyngeal isolates and among antibiotic resistant isolates in all age groups. The differences in serotype coverage between PCV10 and PCV13 were up to 26%. Based on the current data on serotype distribution, a wide use of PCVs in Russia may lead to a significant reduction of the pneumococcal disease burden. PMID- 24350588 TI - In depth analysis of the quenching of three fluorene-phenylene-based cationic conjugated polyelectrolytes by DNA and DNA bases. AB - The interaction of three cationic poly {9,9-bis[N,N (trimethylammonium)hexyl]fluorene-co-1,4-phenylene} polymers with average chain lengths of ~6, 12, and 100 repeat units (PFP-NR36(I),12(Br),100(Br)) with both double and single stranded, short and long, DNA and DNA bases have been studied by steady state and time-resolved fluorescence techniques. Fluorescence of PFP NR3 polymers is quenched with high efficiency by DNA (both double and single stranded) and DNA bases. The resulting quenching plots are sigmoidal and are not accurately described by using a Stern-Volmer quenching mechanism. Here, the quenching mechanism is well modeled in terms of an equilibrium in which a PFP NR3/DNA aggregate complex is formed which brings polymer chains into close enough proximity to allow interchain excitation energy migration and quenching at aggregate or DNA base traps. Such an analysis gives equilibrium constants of 8.4 * 10(6) (+/-1.2 * 10(6)) M(-1) for short-dsDNA and 8.6 * 10(6) (+/-1.7 * 10(6)) M(-1) for short-ssDNA with PFP-NR36(I). PMID- 24350589 TI - Age at menarche and risky sexual partnerships in adulthood: does a biosocial model explain any associations? AB - BACKGROUND: The purpose of this study was to examine the association between menarcheal age and subsequent sexual partnering in women aged 21-44 years. METHODS: Data from the 2006-2010 National Survey of Family Growth were used (n=7,962). Menarcheal age was defined as <= 11, 12-14, or >= 15 years. Sexual partnering was defined as being concurrent, serially monogamous or monogamous in the previous year. Polytomous logistic regression models evaluated the association between age of menarche and sexual partnering. RESULTS: Nearly 6% reported concurrent partnerships and ~ 4% serial monogamy. Age of menarche was not associated with subsequent concurrent sexual partnering (adjusted odds ratio relative to >= 18 years [aOR <= 11]: 1.09; 95% confidence interval [CI]: 0.57 2.09; aOR12-14: 1.13; 95% CI: 0.64-1.99) or serial monogamy (aOR <= 11: 0.75; 95% CI: 0.41-1.38; aOR12-14: 0.71; 95% CI: 0.39-1.29). CONCLUSIONS: Early menarche is not a risk factor for sexual partnering in adulthood. However, menarche provides an opportunity for education to aid young women to make decisions regarding sexual debut and sexual partnering that are healthy for them. PMID- 24350591 TI - Assessment of sex differences in plaque morphology by coronary computed tomography angiography--are men and women the same? AB - PURPOSE: The objective of this study was to assess whether sex differences exist in plaque burden and plaque subtype as assessed by coronary computed tomography angiography (CCTA). METHODS: The study cohort included 937 consecutive patients who underwent CCTA between 2008 and 2010. Stenosis was quantified using the Society of Cardiovascular Computed Tomography stenosis grading scale and a total stenosis score (TSS) was generated. Plaque morphology (PM) was reported as predominantly calcified (CP), noncalcified (NCP), or mixed (MP) plaque, and CP, NCP, and MP percentages were calculated. RESULTS: On multivariate analysis, men were significantly more likely to have plaque (65.9% of men vs. 44.6% of women, p<0.001), at least one segment with >=50% stenosis (22.7% of men vs. 10.3% of women, p<0.001) and higher TSS (mean score=2.81 for men vs. 1.58 for women, p<0.001). Sex was the strongest predictor in all models (odds ratio [OR]=2.55, 95% confidence interval [CI] 1.78-3.67, p<0.001 for any plaque; OR=2.48, 95% CI 1.48-4.16, p<0.01 for segments with >=50% stenosis; beta=1.46, 95% CI 0.69-2.22, p<0.001 for TSS). Among patients with coronary plaque present, no significant sex differences in PM were found. CONCLUSIONS: Sex was the strongest risk factor for the presence and extent of plaque. Significant sex differences in PM did not exist. PMID- 24350590 TI - Socioeconomic disparities in breast cancer treatment among older women. AB - BACKGROUND: Racial disparities in breast cancer treatment among Medicare beneficiaries have been documented. This study aimed to determine whether racial disparities exist among white and black female Medicare beneficiaries in Alabama, an economically disadvantaged U.S. state. METHODS: From a linked dataset of breast cancer cases from the Alabama Statewide Cancer Registry and fee-for service claims from Medicare, we identified 2,097 white and black females, aged 66 years and older, who were diagnosed with stages 1-3 breast cancer from January 1, 2000, to December 31, 2002. Generalized estimating equation (GEE) models were used to determine whether there were racial differences in initiating and completing National Comprehensive Cancer Network Clinical Practice guideline specific treatment. RESULTS: Sixty-two percent of whites and 64.7% of blacks had mastectomy (p=0.27); 34.6% of whites and 30.2% of blacks had breast conserving surgery (BCS) (p=0.12). Among those who had BCS, 76.8% of whites and 83.3% of blacks started adjuvant radiation therapy (p=0.33) and they equally completed adjuvant radiation therapy (p=0.29). For women with tumors over 1 centimeter, whites and blacks were equally likely to start (16.1% of whites and 18.3% of black; p=0.34) and complete (50.6% of whites and 46.3% of black; p=0.87) adjuvant chemotherapy. There were still no differences after adjusting for confounders using GEE. However, differences were observed by area-level socioeconomic status (SES), with lower SES residents more likely to receive a mastectomy (odds ratio [OR]=1.26; 95% confidence interval [CI]: 1.01-1.57) and initiate radiation after BCS (OR=2.24; 95% CI: 1.28-3.93). CONCLUSIONS: No racial differences were found in guideline-specific breast cancer treatment or treatment completion, but there were differences by SES. Future studies should explore reasons for SES differences and whether similar results hold in other economically disadvantaged U.S. states. PMID- 24350592 TI - Syntheses, crystal structures, and magnetic properties of four new cyano-bridged bimetallic complexes based on the mer-[Fe(III)(qcq)(CN)3]- building block. AB - Four new cyano-bridged bimetallic complexes, [{Mn(III)(salen)}2{Fe(III)(qcq)(CN)3}2]n.3nCH3CN.nH2O (1) [salen = N,N' ethylenebis(salicylideneiminato) dianion; qcq(-) = 8-(2-quinoline-2 carboxamido)quinoline anion], [{Mn(III)(salpn)}2{Fe(III)(qcq)(CN)3}2]n.4nH2O (2) [salpn = N,N'-1,2-propylenebis(salicylideneiminato)dianion], [{Mn(II)(bipy)(CH3OH)}{Fe(III)(qcq)(CN)3}2]2.2H2O.2CH3OH (3) (bipy = 2,2' bipyridine), and [{Mn(II)(phen)2}{Fe(III)(qcq)(CN)3}2].CH3CN.2H2O (4) (phen = 1,10-phenanthroline) have been synthesized and characterized both structurally and magnetically. The structures of 1 and 2 are both unique 1-D linear branch chains with additional structural units of {Mn(III)(salen/salpn)}{Fe(III)(qcq)(CN)3} dangling on the sides. In contrast, 3 and 4 are cyano-bridged bimetallic hexanuclear and trinuclear clusters, respectively. The intermolecular short contacts such as pi-pi interactions and hydrogen bonds extend 1-4 into high dimensional supermolecular networks. Magnetic investigation reveals the dominant intramolecular antiferromagnetic interactions in 1, 3, and 4, while ferromagnetic and antiferromagnetic interactions coexist in 2. Alternating current measurement at low temperature indicates the existence of slow magnetic relaxation in 1 and 2, which should be due to the single ion anisotropy of Mn(III). PMID- 24350593 TI - Suicidal behavior and attitudes in Slovak and Turkish high school students: a cross-cultural investigation. AB - Suicidal behavior and its variation across social contexts are of importance for the science of suicidology. Due to its special character controlled experimental studies on suicide are ruled out for ethical reasons. Cross-cultural studies may throw light on the etiology of both suicidal behavior and its cross-cultural variation. The present study compared suicidal behavior and attitudes in 423 Slovak and 541 Turkish high school students by means of a self-report questionnaire. The two groups reported similar percentages (Slovak = 36.4%; Turkish = 33.8%) of lifetime, past 12-months or current suicidal ideation but significantly more Turkish (12.2%) than Slovak (4.8%) students reported lifetime or past 12-months suicide attempts. Slovak adolescents displayed more liberal and permissive attitudes toward suicide, while those of Turkish adolescents were more rejecting. Turkish students rated themselves to be more religious and hence they believed to a greater extent that suicidal persons would be punished in a life after death than their Slovak peers. However, attitudes of Turkish students toward an imagined suicidal close friend were more accepting than the attitudes of Slovak students. Comparison of suicidal and nonsuicidal students revealed that those reporting suicidal ideation or attempts were more accepting of suicide and viewed suicide as a solution to a greater extent than the nonsuicidal ones. The results from this study suggest that cultural factors play a role in suicidal behavior, attitudes and reactions in a predicted direction. PMID- 24350594 TI - Plasticity of in vitro-generated urothelial cells for functional tissue formation. AB - Tissue-engineering and regenerative medicine strategies for the bladder and urinary tract are dependent on the ability to generate adequate numbers of differentiation-competent uro-epithelial cells. In situ, urothelium is a mitotically quiescent, but highly regenerative epithelium. Although evidence supports a resident, basally located urothelial progenitor population, no specific stem cell has been identified. Our aim was to isolate basal and suprabasal urothelial subpopulations and characterize their regenerative and differentiation potentials in vitro. We showed that the low-affinity nerve growth factor receptor (NGFR) is a cell surface-expressed marker that is restricted to basal cells in normal human and porcine urothelia in situ. We used NGFR immunoseparation and differential adherence to collagen to isolate subpopulations of urothelial cells for culture. Isolated basal-derived porcine NGFR+ urothelial cells initially showed a higher proliferative and clonogenic phenotype than their suprabasal NGFR- counterparts in vitro. However, after a short period of adaptation to culture, both NGFR+ and NGFR- subpopulations became indistinguishable and displayed similar long-term growth and differentiation potentials. Both populations generated hierarchically organized, differentiated tissue equivalents similar to native urothelium, including a fully reconstituted NGFR+ basal cell layer by the NGFR- suprabasal-derived population. Similarly, slow collagen-adherent human urothelial cells initially displayed a longer lag phase than rapid-adherent cultures, but after adaptation, both populations showed similar long-term proliferation, exponential growth rates, and capacity to form a functional barrier urothelium. Our results support a model where urothelial cell phenotype is plastic and determined by the niche or local environment. This has direct implications for tissue-engineering strategies requiring urothelial cell expansion and provides a new perspective toward understanding urothelial regeneration and differentiated tissue hierarchy. PMID- 24350595 TI - Facile synthesis of acridine derivatives by ZnCl2-promoted intramolecular cyclization of o-arylaminophenyl Schiff bases. AB - A concise and efficient method for the synthesis of a wide range of acridine derivatives and polycyclic aza-aromatic compounds from a ZnCl2-promoted cyclization reaction of readily available o-arylaminophenyl Schiff base compounds under convenient conditions was developed. Reaction conditions and scope of the new method were examined in detail. PMID- 24350596 TI - Cascaded assembly of complex multiparticle patterns. AB - A method for the cascaded capillary assembly of different particle populations in a single assembly cycle is presented. The method addresses the increasing need for fast and simple fabrication of multicomponent arrays from colloidal micro- and nanoscale building blocks for constructing nanoelectronic, optical, and sensing devices. It is based on the use of a microfluidic device from which two independent capillary bridges extend. The menisci of the capillary bridges are pulled over a template with trapping sites that receive the colloidal particles. We describe the parameters for simultaneous, high-yield assembly from both menisci and demonstrate the applicability of the process by means of the size selective assembly of particles of different diameters and also by the fabrication of two-component particle clusters with defined shape and composition. This approach allows the fabrication of multifunctional particle clusters having different functionalities at predetermined positions. PMID- 24350597 TI - Changes in peak fat oxidation in response to different doses of endurance training. AB - The effect of different doses of endurance training on the capacity to oxidize fat during exercise in sedentary, overweight men and assessment of variables associated with changes in peak fat oxidation (PFO) were evaluated. Young, sedentary, overweight men were randomized to either the high-dose (HIGH, 600 kcal/day, n = 17) or moderate-dose (MOD, 300 kcal/day, n = 18) endurance training groups or controls (CON, n = 15). PFO and peak oxygen uptake (VO2 peak) were measured using indirect calorimetry, body composition using dual-energy x-ray absorptiometry, and protein levels of mitochondrial enzymes determined by Western blotting. PFO increased in both MOD [1.2 mg/kg fat-free mass (FFM)/min, 95% confidence interval (CI): 0.08:2.3, P = 0.03] and HIGH (1.8 mg/kg FFM/min, CI: 0.6:2.9, P < 0.001) compared with CON. Skeletal muscle expression of citrate synthase, beta-hydroxyacyl-CoA dehydrogenase, and mitochondrial oxphos complexes II-V increased similarly in MOD and HIGH. Stepwise multiple linear regression analysis with backward elimination of individual variables correlated with changes in PFO revealed increases in cycling efficiency, FFM, and VO2 peak as the remaining associated variables. In conclusion, PFO during exercise increased with both moderate- and high-dose endurance training. Increases in PFO were mainly predicted by changes in VO2 peak, FFM, and cycling efficiency, and less with skeletal muscle mitochondrial enzymes. PMID- 24350598 TI - Nonscalable oxidation catalysis of gold clusters. AB - Small, negatively charged gold clusters isolated in vacuum can oxidize CO via electron-transfer-mediated activation of O2. This suggests that Au clusters can act as aerobic oxidation catalysts in the real world when their structure parameters satisfy given required conditions. However, there is a technical challenge for the development of Au cluster oxidation catalysts; the structural parameters of the Au clusters, such as size and composition, must be precisely controlled because the intrinsic chemical properties of the clusters are strongly dependent on these parameters. This Account describes our efforts to achieve precision synthesis of small (diameter <2 nm) Au clusters, stabilized by polymers and immobilized on supports, for a variety of catalytic applications. Since we aim to develop Au cluster catalysts by taking full advantage of their intrinsic, size-specific chemical nature, we chose chemically inert materials for the stabilizers and supports. We began by preparing small Au clusters weakly stabilized by polyvinylpyrrolidone (PVP) to test the hypothesis that small Au clusters in the real world will also show size-specific oxidation catalysis. The size of Au:PVP was controlled using a microfluidic device and monitored by mass spectrometry. We found that only Au clusters smaller than a certain critical size show a variety of aerobic oxidation reactions and proposed that the reactions proceed via catalytic activation of O2 by negatively charged Au clusters. We also developed a method to precisely control the size and composition of supported Au clusters using ligand-protected Au and Au-based bimetallic clusters as precursors. These small Au clusters immobilized on mesoporous silica, hydroxyapatite, and carbon nanotubes acted as oxidation catalysts. We have demonstrated for the first time an optimal Au cluster size for the oxidation of cyclohexane and a remarkable improvement in the oxidation catalysis of Au25 clusters by single-atom Pd doping. The non-scalable catalysis of Au clusters that we reported here points to the possibility that novel catalysis beyond that expected from bulk counterparts can be developed simply by reducing the catalyst size to the sub-2 nm regime. PMID- 24350599 TI - Variation in the coding and 3' untranslated regions of the porcine prolactin receptor short form modifies protein expression and function. AB - The actions of prolactin (PRL) are mediated by both long (LF) and short isoforms (SF) of the PRL receptor (PRLR). Here, we report on a genetic and functional analysis of the porcine PRLR (pPRLR) SF. Three single nucleotide polymorphisms (SNPs) within exon 11 of the pPRLR-SF give rise to four amino acid haplotypes of the intracellular domain. We identified the dimorphic insertion of a short interspersed repetitive DNA element (PRE-1) along with 32 SNPs and four other insertion/deletion sites within the 3' untranslated region (UTR) of pPRLR-SF. The PRE-1 element reduced protein translation in vitro by 75%, whereas the combination of 10 SNPs and one insertion/deletion decreased translation by 50%. Full-length cDNAs for all four haplotypes of pPRLR-SF were cloned behind the elongation factor 1-alpha promoter and functionally analyzed in vitro. None of the haplotypes could initiate transcription from the beta-casein promoter, whereas all four were dominant negatives against PRL-activation of the pPRLR-LF. Two of the haplotypes completely inhibited pPRLR-LF activity at a four-fold excess, whereas the others required a six-fold excess to impart the same effect. The ligand binding affinities of the pPRLR-SF haplotypes did not differ. Expression of the pPRLR-SF increased linearly during gestation in the endometrium and was hormonally regulated in a tissue-specific manner in the mammary glands and uterus. In conclusion, we identified a PRE-1 and other SNPs in the pPRLR-SF 3' UTR that reduce protein expression and four haplotypes of the pPRLR-SF that suppress pPRLR-LF signaling and may differentially impact the phenotypic effects of PRL in vivo. PMID- 24350600 TI - Sexual hookups and adverse health outcomes: a longitudinal study of first-year college women. AB - "Hookups" are sexual encounters between partners who are not in a romantic relationship and do not expect commitment. We examined the associations between sexual hookup behavior and depression, sexual victimization (SV), and sexually transmitted infections (STIs) among first-year college women. In this longitudinal study, 483 women completed 13 monthly surveys assessing oral and vaginal sex with hookup and romantic partners, depression, SV, and self-reported STIs. Participants also provided biological specimens that were tested for STIs. During the study, 50% of participants reported hookup sex and 62% reported romantic sex. Covariates included previous levels of the outcome, alcohol use, impulsivity, sensation seeking, and romantic sex. Autoregressive cross-lagged models showed that, controlling for covariates, hookup behavior during college was correlated with depression, Bs = .21, ps < .05, and SV, Bs = .19, ps < .05. In addition, precollege hookup behavior predicted SV early in college, B = .62, p < .05. Hookup sex, OR 1.32, p < .05, and romantic sex, OR 1.19, p < .05, were associated with STIs. Overall, sexual hookup behavior among college women was positively correlated with experiencing depression, SV, and STIs, but the nature of these associations remains unclear, and hooking up did not predict future depression. PMID- 24350602 TI - Recommendations abstracted from the American Geriatrics Society Consensus Statement on vitamin D for Prevention of Falls and Their Consequences. AB - The goal of this Consensus Statement is to help primary care practitioners achieve adequate vitamin D intake from all sources in their older patients, with the goal of reducing falls and fall-related injuries. The workgroup graded the quality of evidence and assigned an evidence level using established criteria. Based on the evidence for fall and fracture reduction in the clinical trials of older community-dwelling and institutionalized persons and metaanalyses, the workgroup concluded that a serum 25 hydroxyvitamin D (25(OH)D) concentration of 30 ng/mL (75 nmol/L) should be a minimum goal to achieve in older adults, particularly in frail adults, who are at higher risk of falls, injuries, and fractures. The workgroup concluded that the goal--to reduce fall injuries related to low vitamin D status--could be achieved safely and would not require practitioners to measure serum 25(OH)D concentrations in older adults in the absence of underlying conditions that increase the risk of hypercalcemia (e.g., advanced renal disease, certain malignancies, sarcoidosis). PMID- 24350601 TI - Probabilistic grammatical model for helix-helix contact site classification. AB - BACKGROUND: Hidden Markov Models power many state-of-the-art tools in the field of protein bioinformatics. While excelling in their tasks, these methods of protein analysis do not convey directly information on medium- and long-range residue-residue interactions. This requires an expressive power of at least context-free grammars. However, application of more powerful grammar formalisms to protein analysis has been surprisingly limited. RESULTS: In this work, we present a probabilistic grammatical framework for problem-specific protein languages and apply it to classification of transmembrane helix-helix pairs configurations. The core of the model consists of a probabilistic context-free grammar, automatically inferred by a genetic algorithm from only a generic set of expert-based rules and positive training samples. The model was applied to produce sequence based descriptors of four classes of transmembrane helix-helix contact site configurations. The highest performance of the classifiers reached AUCROC of 0.70. The analysis of grammar parse trees revealed the ability of representing structural features of helix-helix contact sites. CONCLUSIONS: We demonstrated that our probabilistic context-free framework for analysis of protein sequences outperforms the state of the art in the task of helix-helix contact site classification. However, this is achieved without necessarily requiring modeling long range dependencies between interacting residues. A significant feature of our approach is that grammar rules and parse trees are human-readable. Thus they could provide biologically meaningful information for molecular biologists. PMID- 24350604 TI - Oases to oblivion: the rapid demise of springs in the South-eastern Great Artesian Basin, Australia. PMID- 24350603 TI - Structural proteins from whelk egg capsule with long range elasticity associated with a solid-state phase transition. AB - The robust, proteinaceous egg capsules of marine prosobranch gastropods (genus Busycotypus ) exhibit unique biomechanical properties such as high elastic strain recovery and elastic energy dissipation capability. Capsule material possesses long-range extensibility that is fully recoverable and is the result of a secondary structure phase transition from alpha-helical coiled-coil to extended beta-sheet rather than of entropic (rubber) elasticity. We report here the characterization of the precursor proteins that make up this material. Three different proteins have been purified and analyzed, and complete protein sequences deduced from messenger ribonucleic acid (mRNA) transcripts. Circular dichroism (CD) and Fourier transform infrared (FTIR) spectroscopy indicate that the proteins are strongly alpha-helical in solution and primary sequence analysis suggests that these proteins have a propensity to form coiled-coils. This is in agreement with previous wide-angle X-ray scattering (WAXS) and solid-state Raman spectroscopic analysis of mature egg capsules. PMID- 24350605 TI - Role of gap junctions modulating hepatic vascular tone in cirrhosis. AB - BACKGROUND & AIMS: Gap junctions are formed by connexins (Cx), a family of proteins that couple endothelial and smooth muscle cells in systemic vessels. In this context, Cx allow the transmission of signals modulating vascular tone. Recently, vascular Cx have been observed in liver cells implicated in liver blood flow regulation. Here, we investigated the role of Cx in the regulation of intrahepatic vascular tone in cirrhosis. METHODS: Livers of Sprague-Dawley control and cirrhotic (common bile duct ligation-CBDL and CCl4 ) rats were perfused, and concentration-effect curves in response to acetylcholine (ACh) precontracted with methoxamine were obtained in the presence of the specific Cx inhibitor 18-alpha-glycyrrhetinic acid or vehicle. Cx expression was assessed by immunofluorescence, western blot and reverse-transcription polymerase chain reaction in liver tissue, hepatic stellate cells, sinusoidal endothelial cells and hepatocytes isolated from control and cirrhotic rat livers. Cx protein expression was also determined in cirrhotic human tissue. RESULTS: Gap junction blockade markedly attenuated relaxation of hepatic vasculature in response to ACh in control (maximal relaxation, -55 +/- 10.5% vs. -95.3 +/- 10% with vehicle; P < 0.01) and CBDL rats (50.9 +/- 18.5% vs. -18.7 +/- 5.5% with vehicle; P = 0.01). Livers from CBDL rats and patients with cirrhosis exhibited Cx overexpression. By contrast, CCl4 -cirrhotic rats did not show attenuated relaxation of hepatic vasculature after blockade and Cx expression was significantly lower than in controls. CONCLUSIONS: Gap junctions may contribute to modulating portal pressure and intrahepatic vascular relaxation. Liver gap junctions may represent a new therapeutic target in cirrhotic portal hypertension. PMID- 24350606 TI - Functional link between Rab GTPase-mediated membrane trafficking and PI4,5P2 signaling. AB - Fission yeast its3(+) encodes an essential phosphatidylinositol-4-phosphate 5 kinase (PI4P5K) that regulates cell integrity and cytokinesis. We performed a genetic screen to identify genes that function in PI4P5K-mediated signaling, and identified gyp10(+) encoding a Rab GTPase-activating protein (GAP), a negative regulator for Rab GTPase signaling. Its3 overproduction caused growth defects and abnormal cytoplasmic accumulation of the Its3 protein, which can be stained by calcofluor. Notably, Its3 overproducing cells displayed abnormal membranous structures, multilamella Golgi and fragmented vacuoles showed by Electron microscopy. Furthermore, the excess cytoplasmic Its3 structure partly colocalized with the fluorescence of FM4-64. Gyp10 rescued both growth defects and abnormal Its3 localization when it was over-expressed. Gyp10 functionally interacted with the Rab GTPases Ypt3 and Ryh1, both of which regulate Golgi membrane trafficking. Consistently, mutation or deletion of Ypt3 and Ryh1 suppressed phenotypes associated with Its3 overproduction. Importantly, the plasma membrane localization of Its3 was also affected by the impairment of the Ypt3/Ryh1 Rab membrane trafficking, thus suggesting that membrane trafficking events regulated by two Rab GTPases functionally interacts with PI4,5P2 signaling. These results suggest a mechanism whereby PI4P5K signaling/localization is affected by Golgi membrane trafficking, thus provide a functional link between the PI4,5P2 signaling and Rab-mediated trafficking. PMID- 24350607 TI - Determinants of regioselective hydroxylation in the fungal polysaccharide monooxygenases. AB - The ubiquitous fungal polysaccharide monooxygenases (PMOs) (also known as GH61 proteins, LPMOs, and AA9 proteins) are structurally related but have significant variation in sequence. A heterologous expression method in Neurospora crassa was developed as a step toward connecting regioselectivity of the chemistry to PMO phylogeny. Activity assays, as well as sequence and phylogenetic analyses, showed that the majority of fungal PMOs fall into three major groups with distinctive active site surface features. PMO1s and PMO2s hydroxylate glycosidic positions C1 and C4, respectively. PMO3s hydroxylate both C1 and C4. A subgroup of PMO3s (PMO3*) hydroxylate C1. Mutagenesis studies showed that an extra subdomain of about 12 amino acids contribute to C4 oxidation in the PMO3 family. PMID- 24350608 TI - Rapid genomic and transcriptomic alterations induced by wide hybridization: Chrysanthemum nankingense * Tanacetum vulgare and C. crassum * Crossostephium chinense (Asteraceae). AB - BACKGROUND: Hybridization is a major driver of evolution in plants. In a number of plant species, the process of hybridization has been revealed to be accompanied by wide-ranging genetic and epigenetic alterations, some of which have consequences on gene transcripts. The Asteraceae family includes a number of polyploid species, and wide crossing is seen as a viable means of genetically improving ornamental species such as Chrysanthemum spp. However, the consequences of hybridization in this taxon have yet to be characterized. RESULTS: Amplified fragment length polymorphism (AFLP), methylation sensitive amplification polymorphism (MSAP) and cDNA-AFLP profiling of the two intergeneric hybrids C. nankingense * Tanacetum vulgare and C. crassum * Crossostephium chinense were employed to characterize, respectively, the genomic, epigenomic and transcriptomic changes induced by the hybridization event. The hybrids' AFLP profiles included both the loss of specific parental fragments and the gain of fragments not present in either parent's profile. About 10% of the paternal fragments were not inherited by the hybrid, while the corresponding rate for the maternal parent fragments was around 4-5%. The novel fragments detected may have arisen either due to heterozygosity in one or other parent, or as a result of a deletion event following the hybridization. Around one half of the cDNA-AFLP fragments were common to both parents, about 30% were specific to the female parent, and somewhat under 20% specific to the male parent; the remainder (2.9 4.7%) of the hybrids' fragments were not present in either parent's profile. The MSAP fingerprinting demonstrated that the hybridization event also reduced the amount of global cytosine methylation, since > 50% of the parental fragments were methylated, while the corresponding frequencies for the two hybrids were 48.5% and 50.4%. CONCLUSIONS: Combining two different Asteraceae genomes via hybridization clearly induced a range of genomic and epigenomic alterations, some of which had an effect on the transcriptome. The rapid genomic and transcriptomic alterations induced by hybridization may accelerate the evolutionary process among progenies. PMID- 24350609 TI - Bacterial profiling of White Plague Disease across corals and oceans indicates a conserved and distinct disease microbiome. AB - Coral diseases are characterized by microbial community shifts in coral mucus and tissue, but causes and consequences of these changes are vaguely understood due to the complexity and dynamics of coral-associated bacteria. We used 16S rRNA gene microarrays to assay differences in bacterial assemblages of healthy and diseased colonies displaying White Plague Disease (WPD) signs from two closely related Caribbean coral species, Orbicella faveolata and Orbicella franksi. Analysis of differentially abundant operational taxonomic units (OTUs) revealed strong differences between healthy and diseased specimens, but not between coral species. A subsequent comparison to data from two Indo-Pacific coral species (Pavona duerdeni and Porites lutea) revealed distinct microbial community patterns associated with ocean basin, coral species and health state. Coral species were clearly separated by site, but also, the relatedness of the underlying bacterial community structures resembled the phylogenetic relationship of the coral hosts. In diseased samples, bacterial richness increased and putatively opportunistic bacteria were consistently more abundant highlighting the role of opportunistic conditions in structuring microbial community patterns during disease. Our comparative analysis shows that it is possible to derive conserved bacterial footprints of diseased coral holobionts that might help in identifying key bacterial species related to the underlying etiopathology. Furthermore, our data demonstrate that similar-appearing disease phenotypes produce microbial community patterns that are consistent over coral species and oceans, irrespective of the putative underlying pathogen. Consequently, profiling coral diseases by microbial community structure over multiple coral species might allow the development of a comparative disease framework that can inform on cause and relatedness of coral diseases. PMID- 24350611 TI - Diffusion of subsidized ACTs in accredited drug shops in Tanzania: determinants of stocking and characteristics of early and late adopters. AB - BACKGROUND: Many households in sub-Saharan Africa utilize the private sector as a primary source of treatment for malaria episodes. Expanding access to effective treatment in private drug shops may help reduce incidence of severe disease and mortality. This research leveraged a longitudinal survey of stocking of subsidized artemisinin combination therapies (ACTs), an effective anti-malarial, in Accredited Drug Dispensing Outlets (ADDOs) in two regions of Tanzania. This provided a unique opportunity to explore shop and market level determinants of product diffusion in a developing country retail market. METHODS: 356 ADDOs in the Rukwa and Mtwara regions of Tanzania were surveyed at seven points between Feb 2011 and May 2012. Shop level audits were used to measure the availability of subsidized ACTs at each shop. Data on market and shop level factors were collected during the survey and also extracted from GIS layers. Regression and network based methodologies were used. Shops classified as early and late adopters, following Rogers' model of product diffusion, were compared. The Bass model of product diffusion was applied to determine whether shops stocked ACTs out of a need to imitate market competitors or a desire to satisfy customer needs. RESULTS: Following the introduction of a subsidy for ACTs, stocking increased from 12% to nearly 80% over the seven survey rounds. Stocking was influenced by higher numbers of proximal shops and clinics, larger customer traffic and the presence of a licensed pharmacist. Early adopters were characterized by a larger percentage of customers seeking care for malaria, a larger catchment and sourcing from specific wholesalers/suppliers. The Bass model of product diffusion indicated that shops were adopting products in response to competitor behavior, rather than customer demand. CONCLUSIONS: Decisions to stock new pharmaceutical products in Tanzanian ADDOs are influenced by a combination of factors related to both market competition and customer demand, but are particularly influenced by the behavior of competing shops. Efforts to expand access to new pharmaceutical products in developing country markets could benefit from initial targeting of high profile shops in competitive markets and wholesale suppliers to encourage faster product diffusion across all drug retailers. PMID- 24350612 TI - Chemoprevention of skin cancer using low HLB surfactant nanoemulsion of 5 fluorouracil: a preliminary study. AB - Oral delivery of 5-fluorouracil (5-FU) is difficult due to its serious adverse effects and extremely low bioavailability. Therefore, the aim of present investigation was to develop and evaluate low HLB surfactant nanoemulsion of 5-FU for topical chemoprevention of skin cancer. Low HLB surfactant nanoemulsions were prepared by oil phase titration method. Thermodynamically stable nanoemulsions were characterized in terms of droplet size distribution, zeta potential, viscosity and refractive index. Selected formulations and control were subjected to in vitro skin permeation studies through rat skin using Franz diffusion cells. Optimized formulation F9 was subjected to stability and in vitro cytotoxic studies on melanoma cell lines. Enhancement ratio was found to be 22.33 in formulation F9 compared with control and other formulations. The values of steady state flux and permeability coefficient for formulation F9 were found to be 206.40 +/- 14.56 ug cm(-2) h(-1) and 2.064 * 10(-2) +/- 0.050 * 10(-2 )cm h(-1), respectively. Optimized formulation F9 was found to be physical stable. In vitro cytotoxicity studies on SK-MEL-5 cancer cells indicated that 5-FU in optimized nanoemulsion is much more efficacious than free 5-FU. From these results, it can be concluded that the developed nanoemulsion might be a promising vehicle for chemoprevention of skin cancer. PMID- 24350613 TI - Robust anger: recognition of deteriorated dynamic bodily emotion expressions. AB - In two studies, the robustness of anger recognition of bodily expressions is tested. In the first study, video recordings of an actor expressing four distinct emotions (anger, despair, fear, and joy) were structurally manipulated as to image impairment and body segmentation. The results show that anger recognition is more robust than other emotions to image impairment and to body segmentation. Moreover, the study showed that arms expressing anger were more robustly recognised than arms expressing other emotions. Study 2 added face blurring as a variable to the bodily expressions and showed that it decreased accurate emotion recognition-but more for recognition of joy and despair than for anger and fear. In sum, the paper indicates the robustness of anger recognition in multileveled deteriorated bodily expressions. PMID- 24350610 TI - Role of reactive oxygen species in neonatal pulmonary vascular disease. AB - SIGNIFICANCE: Abnormal lung development in the perinatal period can result in severe neonatal complications, including persistent pulmonary hypertension (PH) of the newborn and bronchopulmonary dysplasia. Reactive oxygen species (ROS) play a substantive role in the development of PH associated with these diseases. ROS impair the normal pulmonary artery (PA) relaxation in response to vasodilators, and ROS are also implicated in pulmonary arterial remodeling, both of which can increase the severity of PH. RECENT ADVANCES: PA ROS levels are elevated when endogenous ROS-generating enzymes are activated and/or when endogenous ROS scavengers are inactivated. Animal models have provided valuable insights into ROS generators and scavengers that are dysregulated in different forms of neonatal PH, thus identifying potential therapeutic targets. CRITICAL ISSUES: General antioxidant therapy has proved ineffective in reversing PH, suggesting that it is necessary to target specific signaling pathways for successful therapy. FUTURE DIRECTIONS: Development of novel selective pharmacologic inhibitors along with nonantioxidant therapies may improve the treatment outcomes of patients with PH, while further investigation of the underlying mechanisms may enable earlier detection of the disease. PMID- 24350615 TI - Route to benzo- and pyrido-fused 1,2,4-triazinyl radicals via N'-(het)aryl-N'-[2 nitro(het)aryl]hydrazides. AB - A two-step route to 1,3-disubstituted benzo- and pyrido-fused 1,2,4-triazinyl radicals is presented. The route involves the N'-(2-nitroarylation) of easily prepared N'-(het)arylhydrazides via nucleophilic aromatic substitution of 1-halo 2-nitroarenes, which in most cases gives N'-(het)aryl-N'-[2 nitro(het)aryl]hydrazides in good yields. Mild reduction of the nitro group followed by an acid-mediated cyclodehydration gives the fused triazines, which upon alkali treatment afford the desired radicals. Fifteen examples of radicals are presented bearing a range of substituents at N-1, C-3, and C-7, including the pyrid-2-yl and 8-aza analogues. This route to the N'-(het)aryl-N'-[2 nitro(het)aryl]hydrazides, which works well with benzo- and picolinohydrazides, required a modification for aceto- and trifluoroacetohydrazides that involved a multistep synthesis of asymmetrically 1,1-diaryl-substituted hydrazines. PMID- 24350614 TI - Second-generation prophylactic HPV vaccines: successes and challenges. AB - The role of HPV as the causative factor in cervical cancer has led to the development of the HPV vaccines Gardasil and Cervarix. These vaccines effectively protect against two HPV types associated with 70% of cervical cancer cases. Despite this success, researchers continue to develop second-generation HPV vaccines to protect against more HPV types and allow increased uptake in developing countries. While a reformulated vaccine based on the current technology is currently in clinical trials, another strategy consists of targeting highly conserved epitopes in the minor capsid protein of HPV, L2. Vaccines targeting L2 induce broadly neutralizing antibodies, capable of blocking infection by a wide range of HPV types. Several vaccine designs have been developed to optimize the display of L2 epitopes to the immune system and to reduce the cost of manufacture and distribution. L2-based vaccines show considerable promise as a potential next-generation HPV vaccine. PMID- 24350617 TI - Implementation of a multicomponent psychosocial programme for persons with dementia and their families in Norwegian municipalities: experiences from the perspective of healthcare professionals who performed the intervention. AB - BACKGROUND: A randomised controlled intervention study was conducted in 17 Norwegian municipalities to provide home-dwelling people with dementia and their families with knowledge and skills to cope with the emerging problems and stresses of everyday life. It included training health professionals to carry out the intervention. Since little is known about possible benefits for health professionals of participating in such a study in terms of knowledge and change of practice as well as their views on whether the intervention is useful, we carried out this study. AIM: To investigate the outcome of the study from the perspective of the healthcare professionals who participated in the intervention. METHOD: Interviews with 19 health professionals were performed during 2012, using three focus groups and six individual interviews. The sample was purposive and included informants aged 34-61 years from 13 municipalities. RESULTS: Three main categories emerged: challenges, new knowledge and service development. The category challenges details the challenges connected with professionals' participation in the intervention and how they dealt with them and is described in three subcategories. The category new knowledge demonstrates the knowledge the professionals achieved while conducting the intervention and is described through three subcategories. Service development presented how the informants' experiences could contribute to improve the provision of care and details in one subcategory. CONCLUSION: The results revealed a need for more knowledge among health professionals about the situation of home-dwelling persons with dementia and their families. The study indicated that health professionals must be more aware of these persons' abilities to find their own solutions to their problems. Structured individual interventions as well as group-based interventions in the early stages of dementia and throughout the course of the disorder seem beneficial. There is a need for better collaboration between the specialist health services, GPs and health workers in the municipalities. PMID- 24350616 TI - High mobility group box 1 acts as an adjuvant for tuberculosis subunit vaccines. AB - In order to ensure an ample supply of quality candidate tuberculosis (TB) subunit vaccines for clinical trials, it is imperative to develop new immunostimulatory adjuvants. High Mobility Box Group 1 (HMGB1), a member of the alarmin group of immunostimulatory proteins, is released by antigen-presenting cells under various conditions and has been shown to induce T helper type 1 cytokines. We report that HMGB1 is effective as an adjuvant to enhance the protective efficacy and cellular immune response of TB subunit vaccines and that it is not dependent on the interaction between HMGB1 and receptor for advanced glycation end products, a major receptor for HMGB1. In the mouse model of TB, HMGB1 protein, when formulated with dioctadecylammonium bromide and 6000 MW early secretory antigenic target (ESAT-6), was protective as a subunit vaccine but did not protect as molecular adjuvant in an ESAT-6-based DNA formulation. We then evaluated the immunoprophylactic and protective potential of a fusion protein of HMGB1 and ESAT 6. The HMGB1-ESAT-6 fusion protein induced strong antigen-specific T helper type 1 cytokines at 30 days post-immunization. The fusion protein vaccine enhanced activated and effector memory CD4 and CD8 T-cell responses in the lungs and spleens of mice at 80 days post vaccination. Vaccination with the HMGB1-ESAT-6 fusion protein also resulted in elevated numbers of poly-functional CD4 T cells co-expressing interleukin-2, interferon-gamma and tumour necrosis factor-alpha. The potent cell-mediated immune response generated by the fusion protein correlated with protection against subsequent challenge with Mycobacterium tuberculosis in the mouse TB model. PMID- 24350618 TI - Postoperative recurrence pattern and prognosis of patients with hepatocellular carcinoma, with particular reference to the hepatitis viral infection status. AB - BACKGROUND & AIMS: Various modalities have been employed effectively according to the tumour recurrence status in patients with hepatocellular carcinoma (HCC) undergoing hepatectomy. Therefore, their overall prognosis depends largely on the pattern of recurrence/treatment. We investigated the patterns of recurrence and prognosis in HCC patients, especially in relation to the hepatitis virus infection status. METHODS: The study population comprised 244 patients with HCC undergoing hepatectomy. Curative treatments, including repeated hepatectomies, were performed for recurrences, whenever possible. Detailed information on recurrences was collected until the recurrences exceeded Milan criteria. RESULTS: The 5-year disease-free survival, survival within the Milan criteria and overall survival were 38.4%, 56.3% and 74.5% respectively. In the comparison between patients with hepatitis C and B virus-related HCC (HC-HCC: n = 122; and HB-HCC: n = 45 respectively), the former showed lower disease-free (30.2% vs. 40.7% at 5 years, P = 0.061) and overall (65.7% vs. 89.7% at 5 years, P = 0.011) survivals; they also showed a higher incidence of multinodular (>=4) intrahepatic recurrences (19.4% vs. 5.3% at 3 years, P = 0.010). However, the incidences of recurrences exceeding the Milan criteria because of other components were comparable. Patients with HC-HCC showed a higher incidence of intrahepatic recurrences characterized by multiple lesions and the difference became increasingly more pronounced with time. CONCLUSIONS: Patients with HC-HCC were associated with a higher carcinogenesis in the background liver than those with HB-HCC, and this difference was aggravated with time after hepatic resection. PMID- 24350619 TI - "Did you come?" A qualitative exploration of gender differences in beliefs, experiences, and concerns regarding female orgasm occurrence during heterosexual sexual interactions. AB - This study explored gender differences in young adult heterosexual men's and women's experiences, beliefs, and concerns regarding the occurrence or nonoccurrence of orgasm during sexual interactions, with emphasis on the absence of female orgasm during intercourse. Qualitative reports were obtained from five female focus groups (N = 24, M age = 19.08) and five male focus groups (N = 21, M age = 19.29), involving three to five participants per group. Transcripts of the discussions were analyzed for emerging themes across focus group discussions. Results indicated that, for both male and female participants, the most common concern regarding lack of female orgasm in a partnered context focused on the negative impact this might have on the male partner's ego. Male and female participants also agreed that men have the physical responsibility to stimulate their female partner to orgasm, while women have the psychological responsibility of being mentally prepared to experience the orgasm. Men and women tended to maintain different beliefs, however, regarding clitoral stimulation during intercourse, as well as the importance of female orgasm for a woman's sexual satisfaction in a partnered context. Findings suggest foci for sexual education. PMID- 24350620 TI - An inorganic hole conductor for organo-lead halide perovskite solar cells. Improved hole conductivity with copper iodide. AB - Organo-lead halide perovskite solar cells have emerged as one of the most promising candidates for the next generation of solar cells. To date, these perovskite thin film solar cells have exclusively employed organic hole conducting polymers which are often expensive and have low hole mobility. In a quest to explore new inorganic hole conducting materials for these perovskite based thin film photovoltaics, we have identified copper iodide as a possible alternative. Using copper iodide, we have succeeded in achieving a promising power conversion efficiency of 6.0% with excellent photocurrent stability. The open-circuit voltage, compared to the best spiro-OMeTAD devices, remains low and is attributed to higher recombination in CuI devices as determined by impedance spectroscopy. However, impedance spectroscopy revealed that CuI exhibits 2 orders of magnitude higher electrical conductivity than spiro-OMeTAD which allows for significantly higher fill factors. Reducing the recombination in these devices could render CuI as a cost-effective competitor to spiro-OMeTAD in perovskite solar cells. PMID- 24350622 TI - Effect of solvent polarizability on the assembly and ordering of nanoscale polyhedral oligomeric silsesquioxane films. AB - Understanding the factors that affect molecular self-assembly is crucial to building designed nanoscale structures. We have deposited nanoscale films of polyhedral oligomeric silsesquioxane (POSS) onto polished silicon substrates from a range of organic solvents. We studied these films using synchrotron X-ray reflectivity and found that dip-coating from benzene, toluene, or chloroform results in near-substrate ordering only, but when acetone, hexane, or THF is used, self-assembled layers are formed throughout the entire deposited film. We conclude that solvent polarizability is the factor that determines the alignment of the POSS molecules. We have successfully tested this prediction using additional solvents selected on the basis of their calculated polarizabilities. PMID- 24350621 TI - Biased gene expression in early honeybee larval development. AB - BACKGROUND: Female larvae of the honeybee (Apis mellifera) develop into either queens or workers depending on nutrition. This nutritional stimulus triggers different developmental trajectories, resulting in adults that differ from each other in physiology, behaviour and life span. RESULTS: To understand how these trajectories are established we have generated a comprehensive atlas of gene expression throughout larval development. We found substantial differences in gene expression between worker and queen-destined larvae at 6 hours after hatching. Some of these early changes in gene expression are maintained throughout larval development, indicating that caste-specific developmental trajectories are established much earlier than previously thought. Within our gene expression data we identified processes that potentially underlie caste differentiation. Queen-destined larvae have higher expression of genes involved in transcription, translation and protein folding early in development with a later switch to genes involved in energy generation. Using RNA interference, we were able to demonstrate that one of these genes, hexamerin 70b, has a role in caste differentiation. Both queen and worker developmental trajectories are associated with the expression of genes that have alternative splice variants, although only a single variant of a gene tends to be differentially expressed in a given caste. CONCLUSIONS: Our data, based on the biases in gene expression early in development together with published data, supports the idea that caste development in the honeybee consists of two phases; an initial biased phase of development, where larvae can still switch to the other caste by differential feeding, followed by commitment to a particular developmental trajectory. PMID- 24350623 TI - Brain on the stage - spotlight on nervous system development in zebrafish: EMBO practical course, KIT, Sept. 2013. AB - During the EMBO course 'Imaging of Neural Development in Zebrafish', held on September 9-15th 2013, researchers from different backgrounds shared their latest results, ideas and practical expertise on zebrafish as a model to address open questions regarding nervous system development. PMID- 24350624 TI - Effect of pubic bone marrow edema on recovery from endoscopic surgery for athletic pubalgia. AB - Athletic pubalgia (sportsman's hernia) is often repaired by surgery. The presence of pubic bone marrow edema (BME) in magnetic resonance imaging (MRI) may effect on the outcome of surgery. Surgical treatment of 30 patients with athletic pubalgia was performed by placement of totally extraperitoneal endoscopic mesh behind the painful groin area. The presence of pre-operative BME was graded from 0 to 3 using MRI and correlated to post-operative pain scores and recovery to sports activity 2 years after operation. The operated athletes participated in our previous prospective randomized study. The athletes with (n = 21) or without (n = 9) pubic BME had similar patients' characteristics and pain scores before surgery. Periostic and intraosseous edema at symphysis pubis was related to increase of post-operative pain scores only at 3 months after surgery (P = 0.03) but not to long-term recovery. Two years after surgery, three athletes in the BME group and three in the normal MRI group needed occasionally pain medication for chronic groin pain, and 87% were playing at the same level as before surgery. This study indicates that the presence of pubic BME had no remarkable long-term effect on recovery from endoscopic surgical treatment of athletic pubalgia. PMID- 24350625 TI - Exploring transition pathway and free-energy profile of large-scale protein conformational change by combining normal mode analysis and umbrella sampling molecular dynamics. AB - Large-scale conformational changes of proteins are usually associated with the binding of ligands. Because the conformational changes are often related to the biological functions of proteins, understanding the molecular mechanisms of these motions and the effects of ligand binding becomes very necessary. In the present study, we use the combination of normal-mode analysis and umbrella sampling molecular dynamics simulation to delineate the atomically detailed conformational transition pathways and the associated free-energy landscapes for three well known protein systems, viz., adenylate kinase (AdK), calmodulin (CaM), and p38alpha kinase in the absence and presence of respective ligands. For each protein under study, the transient conformations along the conformational transition pathway and thermodynamic observables are in agreement with experimentally and computationally determined ones. The calculated free-energy profiles reveal that AdK and CaM are intrinsically flexible in structures without obvious energy barrier, and their ligand binding shifts the equilibrium from the ligand-free to ligand-bound conformation (population shift mechanism). In contrast, the ligand binding to p38alpha leads to a large change in free-energy barrier (DeltaDeltaG ~ 7 kcal/mol), promoting the transition from DFG-in to DFG out conformation (induced fit mechanism). Moreover, the effect of the protonation of D168 on the conformational change of p38alpha is also studied, which reduces the free-energy difference between the two functional states of p38alpha and thus further facilitates the conformational interconversion. Therefore, the present study suggests that the detailed mechanism of ligand binding and the associated conformational transition is not uniform for all kinds of proteins but correlated to their respective biological functions. PMID- 24350626 TI - Production and characterization of monoclonal antibodies against aflatoxin B1. AB - In this article, we embarked on production of mouse monoclonal antibodies against aflatoxin B1 which is the most commonly occurring fungal toxin in food and feed products. After immunization and fusion with myloma cells, two stable clones (A218 and B319) were selected. Isotyping showed that these monoclonal antibodies (mAbs) were IgG2b with kappa light chains. The affinity of A218 and B319 clons were 5*10(11) M(-1) and 6*10(9) M(-1), respectively. Competitive indirect ELISA results indicated these mAbs had complete (100%) cross-reaction with four major types of aflatoxins: B1, B2, G1, and G2. These mAbs could be used for immunoassay measurement of aflatoxins with high affinity and low detection limits. PMID- 24350627 TI - Risk factors for nontuberculous mycobacterial infections in solid organ transplant recipients: a case-control study. AB - BACKGROUND: The epidemiology of nontuberculous mycobacteria (NTM) disease in solid organ transplant recipients is poorly defined. METHODS: We identified all solid organ transplant recipients with NTM disease at a single center over a 7.5 year period, and collected data on patient demographics, co-morbidities, immunosuppressive medications, and rejection. We conducted a case-control study to identify risk factors for disease, matching 3 control patients to each case patient by date of transplantation. RESULTS: A total of 34 cases of NTM disease occurred during the study period, involving 6 single lung, 13 bilateral lung, 8 heart, 4 liver, 2 kidney, and 1 pancreas-kidney recipients. Cases were predominantly male (24/34), with a median age of 55 years (interquartile range [IQR]: 46-61 years), and developed after a median of 8 months post transplantation (IQR: 2-87 months). Mycobacterium abscessus and Mycobacterium avium complex were the most common pathogens, and the lung (including pleura) was the most common site of disease. In the adjusted case-control analysis, lung transplant recipients had the highest risk of NTM disease. CONCLUSIONS: Additional studies are needed to evaluate the role of targeted surveillance measures for NTM disease in high-risk patients, particularly lung transplant recipients, and to characterize the mechanisms of disease acquisition. PMID- 24350628 TI - Estimation of time-dependent association for bivariate failure times in the presence of a competing risk. AB - This article targets the estimation of a time-dependent association measure for bivariate failure times, the conditional cause-specific hazards ratio (CCSHR), which is a generalization of the conditional hazards ratio (CHR) to accommodate competing risks data. We model the CCSHR as a parametric regression function of time and event causes and leave all other aspects of the joint distribution of the failure times unspecified. We develop a pseudo-likelihood estimation procedure for model fitting and inference and establish the asymptotic properties of the estimators. We assess the finite-sample properties of the proposed estimators against the estimators obtained from a moment-based estimating equation approach. Data from the Cache County study on dementia are used to illustrate the proposed methodology. PMID- 24350629 TI - Evaluation of heme peripheral group interactions in extremely low-dielectric constant media and their contributions to the heme reduction potential. AB - In this study, we measured the contributions of the ionization of the heme propionates to the reduction potentials of heme b and heme a (bis)N methylimidazole complexes in various low-dielectric constant conditions. Additionally, we measured the effects of H-bond to the heme a formyl group on the reduction potential of the heme. The performed electrochemical measurements show that ionization of the heme propionates lead to the largest redox change in dichloromethane with no electrolyte. The measured reduction potential changes for heme b and heme a were -55 and -47 mV (+/-10 mV) per ionized propionate, respectively. For heme a, the study demonstrates how the dielectric constant of the medium is important in the magnification of the DeltapKa upon redox-linked ionization of the heme propionates and their roles in the proton pump of cytochrome c oxidase. PMID- 24350631 TI - An unusual termination of a wide complex tachycardia. PMID- 24350632 TI - Past suicide attempts in depressed inpatients: clinical versus research assessment. AB - The objective of this study was to compare structured clinical assessment versus research measurement of suicidal risk among inpatients with major depression. Fifty depressed inpatients underwent a structured clinical and an independent research assessment of suicidal risk. Agreement between both assessments and its impact upon time to first readmission was tested. A false negative rate of 25% in the clinical screening of past suicide attempts was associated with older age, concealment, and reported lower frequency of suicidal thoughts. Mean times to first readmission (2.5 years follow-up) were 74 weeks (discordant responders) and 118 weeks (concordant responders). A failure to detect 25% of patients with past suicide attempt history in the clinical assessment was associated with older age and concealment of suicidal thoughts. PMID- 24350633 TI - Is asymmetric dimethylarginine associated with being born small and large for gestational age? AB - Low and high birth weights have been linked to increased susceptibility to cardiovascular and metabolic alterations. However, the natural history of cardiometabolic disturbances in children born small (SGA) and large (LGA) for gestational age is still unclear and no reliable biomarker of cardiovascular risk has definitively been identified in these subjects. Interestingly, asymmetric dimethylarginine (ADMA), antagonist of nitric oxide (NO) production, has been recognized as novel cardiovascular marker able to identify subjects at higher risk of health disturbances. Despite the well-described role of ADMA as a predictor of degenerative disease in adults, its potential application in pediatrics, and specifically in SGA and LGA children, has not been explored as only few data in preterm infants and SGA newborns are available. Therefore, we investigated potential alterations in circulating ADMA and NO levels in SGA and LGA children compared with those born appropriate (AGA) for gestational age. Of note, ADMA was significantly higher in SGA and LGA children than AGA peers. Intriguingly, SGA and LGA categories as well as insulin resistance were independently related to ADMA. Our observations lead to the intriguing hypothesis that ADMA could be involved in the development of cardiometabolic alterations in SGA and LGA children already during the prepubertal age. PMID- 24350634 TI - Design and development of novel lipid based gastroretentive delivery system: response surface analysis, in-vivo imaging and pharmacokinetic study. AB - Famotidine HCl has low bioavailability (40-45%) due to its narrow absorption window and low solubility in intestinal pH. Lipids were utilized in the formulation of novel gastroretentive dosage forms to increase the availability of famotidine HCl at its absorption site. Novel non-swellable gastroretentive lipid disks (D) and swellable compression coated tablets with a lipid core (T) were prepared. Formulae were characterized by friability testing, in-vitro buoyancy, in-vitro drug release and scanning electron microscopy (SEM). Factorial designs of 2(2 )* 3(1) and 3(2) were planned for the optimization of disks and tablets, respectively, using Design-Expert(r) software. X-ray imaging was used for the in vivo visualization of the selected formula in human gastrointestinal tract (GIT). Moreover, a bioavailability study was performed in healthy human volunteers using the optimized disk formula (D10). Results showed that formulae D10 (containing stearyl alcohol and polyethylene glycol in a ratio of 9:1 w/w) and T7 (containing polyethylene oxide only) had highest desirability values (0.684 and 0.842, respectively). Lipids achieved instantaneous floating and sustained the release of famotidine HCl over a prolonged period of time with significant bioavailability enhancement. PMID- 24350630 TI - Intrigues and intricacies of the biosynthetic pathways for the enzymatic quinocofactors: PQQ, TTQ, CTQ, TPQ, and LTQ. PMID- 24350636 TI - Searching for emotion or race: task-irrelevant facial cues have asymmetrical effects. AB - Facial cues of threat such as anger and other race membership are detected preferentially in visual search tasks. However, it remains unclear whether these facial cues interact in visual search. If both cues equally facilitate search, a symmetrical interaction would be predicted; anger cues should facilitate detection of other race faces and cues of other race membership should facilitate detection of anger. Past research investigating this race by emotional expression interaction in categorisation tasks revealed an asymmetrical interaction. This suggests that cues of other race membership may facilitate the detection of angry faces but not vice versa. Utilising the same stimuli and procedures across two search tasks, participants were asked to search for targets defined by either race or emotional expression. Contrary to the results revealed in the categorisation paradigm, cues of anger facilitated detection of other race faces whereas differences in race did not differentially influence detection of emotion targets. PMID- 24350637 TI - Active surveillance for adverse events following immunization. AB - Comprehensive surveillance of adverse events following immunization (AEFI) is required to detect potential serious adverse events that may not be identified in prelicensure vaccine trials. Surveillance systems have traditionally been passive, relying upon spontaneous reporting, but increasingly active surveillance and supplemental strategies are being incorporated into vaccine safety programs. These include active screening for targeted conditions of interest (e.g., hospitalization), monitoring of new data sources and real-time methodologies to detect changes in vaccine safety data in these sources. The role of improved causality assessment in AEFI surveillance is discussed, with its important role in determining whether a temporal association may have occurred by chance alone. Strong local vaccine safety networks are required to support national immunization programs, with recent progress in developing a framework for low- and middle-income countries. Global collaboration is increasingly required to address challenges in active AEFI surveillance, particularly for rare serious adverse events. PMID- 24350635 TI - Magnesium sulphate for fetal neuroprotection: a cost-effectiveness analysis. AB - BACKGROUND: The aim of this study was to assess the cost-effectiveness of administering magnesium sulphate to patients in whom preterm birth at < 32+0 weeks gestation is either imminent or threatened for the purpose of fetal neuroprotection. METHODS: Multiple decision tree models and probabilistic sensitivity analyses were used to compare the administration of magnesium sulphate with the alternative of no treatment. Two separate cost perspectives were utilized in this series of analyses: a health system and a societal perspective. In addition, two separate measures of effectiveness were utilized: cases of cerebral palsy (CP) averted and quality-adjusted life years (QALYs). RESULTS: From a health system and a societal perspective, respectively, a savings of $2,242 and $112,602 is obtained for each QALY gained and a savings of $30,942 and $1,554,198 is obtained for each case of CP averted when magnesium sulphate is administered to patients in whom preterm birth is imminent. From a health system perspective and a societal perspective, respectively, a cost of $2,083 is incurred and a savings of $108,277 is obtained for each QALY gained and a cost of $28,755 is incurred and a savings of $1,494,500 is obtained for each case of CP averted when magnesium sulphate is administered to patients in whom preterm birth is threatened. CONCLUSIONS: Administration of magnesium sulphate to patients in whom preterm birth is imminent is a dominant (i.e. cost-effective) strategy, no matter what cost perspective or measure of effectiveness is used. Administration of magnesium sulphate to patients in whom preterm birth is threatened is a dominant strategy from a societal perspective and is very likely to be cost effective from a health system perspective. PMID- 24350638 TI - Digital dissection - using contrast-enhanced computed tomography scanning to elucidate hard- and soft-tissue anatomy in the Common Buzzard Buteo buteo. AB - Gross dissection has a long history as a tool for the study of human or animal soft- and hard-tissue anatomy. However, apart from being a time-consuming and invasive method, dissection is often unsuitable for very small specimens and often cannot capture spatial relationships of the individual soft-tissue structures. The handful of comprehensive studies on avian anatomy using traditional dissection techniques focus nearly exclusively on domestic birds, whereas raptorial birds, and in particular their cranial soft tissues, are essentially absent from the literature. Here, we digitally dissect, identify, and document the soft-tissue anatomy of the Common Buzzard (Buteo buteo) in detail, using the new approach of contrast-enhanced computed tomography using Lugol's iodine. The architecture of different muscle systems (adductor, depressor, ocular, hyoid, neck musculature), neurovascular, and other soft-tissue structures is three-dimensionally visualised and described in unprecedented detail. The three-dimensional model is further presented as an interactive PDF to facilitate the dissemination and accessibility of anatomical data. Due to the digital nature of the data derived from the computed tomography scanning and segmentation processes, these methods hold the potential for further computational analyses beyond descriptive and illustrative proposes. PMID- 24350639 TI - Late onset of clinically apparent central vein stenosis due to previous central venous catheter in a patient with inherited thrombophilia. AB - We describe a case of a patient with a functional kidney transplant who was admitted to our department with clinically evident central vein stenosis (CVS) 7 years after the removal of a central venous catheter (CVC) from the right internal jugular vein. The catheter was used as a hemodialysis access for a 2 month period. In the interval before his last admission, the patient suffered two episodes of deep vein thrombosis. Investigation revealed heterozygosity for factor V Leiden, the most common inherited thrombophilia encountered in 5% of Caucasians, and anticoagulation treatment was started. Magnetic resonance angiography showed stenosis just after the convergence of the right subclavian vein with the internal jugular vein to the innominate vein. Transluminal angioplasty restored venous patency and right upper arm edema resolved. Coexistence of CVS, accompanied by hemodynamic changes and endothelial dysfunction, with thrombophilia fulfill all the elements of the Virchow's triad. Therefore, the patient was at great risk for central vein thrombosis, from which he was possibly protected by the early administration of anticoagulant treatment. This case indicates that CVS can be asymptomatic for several years after CVC removal and also raises the question if thrombophilia workup and investigation for CVS may be beneficial in every patient with CVC placement in order to avoid any harmful outcomes. PMID- 24350640 TI - Noninvasive encapsulated follicular variant of papillary thyroid carcinoma: is lobectomy sufficient for tumours >=1 cm? PMID- 24350641 TI - Porous organic material from discotic tricarboxyamide: side chain-core interactions. AB - The benzene-1,3,5-tricarboxyamide containing three l-methionine (1) self-assemble through 3-fold amide-amide hydrogen bonds and pi-pi stacking to fabricate one dimensional nanorod like structure. However, the tyrosine analogue (2) carrying multiple H-bonding side chains lost the C3 symmetry and 3-fold amide-amide hydrogen bonds and developed a porous structure. The porous material exhibits ten times more N2 sorption (155 cc/g) than the columnar one, indicating that side chain-core interactions have a drastic effect on structure and function. PMID- 24350642 TI - Components of a hyperthermia clinic: recommendations for staffing, equipment, and treatment monitoring. AB - Like other technically sophisticated medical endeavours, a hyperthermia clinic relies on skilled staffing. Physicians, physicists and technologists perform multiple tasks to ensure properly functioning equipment, appropriate patient selection, and to plan and administer this treatment. This paper reviews the competencies and tasks that are used in a hyperthermia clinic. PMID- 24350643 TI - Chemical pyrophosphorylation of functionally diverse peptides. AB - A highly selective and convenient method for the synthesis of pyrophosphopeptides in solution is reported. The remarkable compatibility with functional groups (alcohol, thiol, amine, carboxylic acid) in the peptide substrates suggests that the intrinsic nucleophilicity of the phosphoserine residue is much higher than previously appreciated. Because the methodology operates in polar solvents, including water, a broad range of pyrophosphopeptides can be accessed. We envision these peptides will find widespread applications in the development of mass spectrometry and antibody-based detection methods for pyrophosphoproteins. PMID- 24350645 TI - Tailored Gallium(III) chelator NOPO: synthesis, characterization, bioconjugation, and application in preclinical Ga-68-PET imaging. AB - The bifunctional chelator NOPO (1,4,7-triazacyclononane-1,4 bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2 carboxyethyl)phosphinic acid]) shows remarkably high Ga(III) complexation efficiency and comprises one carboxylic acid moiety which is not involved into metal ion coordination. An improved synthetic protocol affords NOPO with 45% overall yield. Stepwise protonation constants (log Ka), determined by potentiometry, are 11.96, 5.22, 3.77, and 1.54; the stability constant of the Ga(III) complex is log KGaL = 25.0. Within 5 min, (68)Ga(III) incorporation by NOPO is virtually quantitative at room temperature between pH 3 and 4, and at 95 degrees C at pH ranging from 0.5 to 7, at NOPO concentrations of 30 MUM and 10 MUM, respectively. During amide bond formation at the distant carboxylate using the HATU coupling reagent, an intramolecular phosphinic acid ester (phosphilactone) is formed, which is cleaved during (68)Ga complexation or in acidic media, such as trifluoroacetic acid (TFA). Phosphilactone formation can also be suppressed by complexation of Zn(2+) prior to conjugation, the resulting zinc-containing conjugates nevertheless being suitable for direct (68)Ga labeling. In AR42J (rat pancreatic carcinoma) xenografted CD-1 nude mice, (68)Ga labeled NOPO-NaI(3)-octreotide conjugate ((68)Ga-NOPO-NOC) showed high and fully blockable tumor uptake (13.9 +/- 5% ID/g, 120 min p.i., compared to 0.9 +/- 0.4% ID/g with 5 mg/kg of nonlabeled peptide). Uptake in other tissues was generally below 3% ID/g, except appearance of excretion-related activity accumulation in kidneys. NOPO-functionalized compounds tend to be more hydrophilic than the corresponding DOTA- and NODAGA-conjugates, thus promoting fast and extensive renal excretion of (68)Ga-NOPO-radiopharmaceuticals. NOPO-functionalized peptides provide suitable pharmacokinetics in vivo and meet all requirements for efficient (68)Ga-labeling even at room temperature in a kit-like manner. PMID- 24350644 TI - An overview of gene expression dynamics during early ovarian folliculogenesis: specificity of follicular compartments and bi-directional dialog. AB - BACKGROUND: Successful early folliculogenesis is crucial for female reproductive function. It requires appropriate gene specific expression of the different types of ovarian cells at different developmental stages. To date, most gene expression studies on the ovary were conducted in rodents and did not distinguish the type of cell. In mono-ovulating species, few studies have addressed gene expression profiles and mainly concerned human oocytes. RESULTS: We used a laser capture microdissection method combined with RNA-seq technology to explore the transcriptome in oocytes and granulosa cells (GCs) during development of the sheep ovarian follicle. We first documented the expression profile of 15 349 genes, then focused on the 5 129 genes showing differential expression between oocytes and GCs. Enriched functional categories such as oocyte meiotic arrest and GC steroid synthesis reflect two distinct cell fates. We identified the implication of GC signal transduction pathways such as SHH, WNT and RHO GTPase. In addition, signaling pathways (VEGF, NOTCH, IGF1, etc.) and GC transzonal projections suggest the existence of complex cell-cell interactions. Finally, we highlighted several transcription regulators and specifically expressed genes that likely play an important role in early folliculogenesis. CONCLUSIONS: To our knowledge, this is the first comprehensive exploration of transcriptomes derived from in vivo oocytes and GCs at key stages in early follicular development in sheep. Collectively, our data advance our understanding of early folliculogenesis in mono-ovulating species and will be a valuable resource for unraveling human ovarian dysfunction such as premature ovarian failure (POF). PMID- 24350646 TI - Effect of PEGylation on drug entry into lipid bilayer. AB - Poly(ethylene glycol) (PEG) is a polymer commonly used for functionalization of drug molecules to increase their bloodstream lifetime, hence efficacy. However, the interactions between the PEGylated drugs and biomembranes are not clearly understood. In this study, we employed atomic-scale molecular dynamics (MD) simulations to consider the behavior of two drug molecules functionalized with PEG (tetraphenylporphyrin used in cancer phototherapy and biochanin A belonging to the isoflavone family) in the presence of a lipid bilayer. The commonly held view is that functionalization of a drug molecule with a polymer acts as an entropic barrier, inhibiting the penetration of the drug molecule through a cell membrane. Our results indicate that in the bloodstream there is an additional source of electrostatic repulsive interactions between the PEGylated drugs and the lipid bilayer. Both the PEG chain and lipids can bind Na(+) ions, thus effectively becoming positively charged molecules. This leads to an extra repulsive effect resulting from the presence of salt in the bloodstream. Thus, our study sheds further light on the role of PEG in drug delivery. PMID- 24350647 TI - Successful penile reconstruction after multimodal therapy in patients with primitive neuroectodermal tumor originating from the penis. AB - We herein present an extremely rare case of primitive neuroectodermal tumor originating in the penis. A 16-year-old male adolescent presented with painful penile swelling. Pathological, immunohistochemical and cytogenetical examinations of the specimens obtained from total penectomy confirmed the diagnosis of primitive neuroectodermal tumor. After total penectomy, the patient received adjuvant chemotherapy with ifosfamide-based regimen for 48 weeks. As a series of therapies, the patient underwent penile reconstruction surgery after completing adjuvant chemotherapy. The patient has not shown any evidence of recurrence for the 7 years after penile reconstruction surgery, and voiding function is completely normal. A favorable outcome was observed by multimodal therapy including aggressive resection for local control, intensive adjuvant chemotherapy, and penile reconstruction with cosmetic and functional success. Similar therapeutic approaches might be selected for children with primary malignant tumors of the penis. PMID- 24350648 TI - First reported multistate human Q fever outbreak in the United States, 2011. AB - In April, 2011, the Q fever bacterium Coxiella burnetii was identified at a Washington farm where an abortion storm took place among goats. Soon after, Q fever cases were reported among visitors to the farm from Washington and Montana. A cross-sectional investigation was conducted among humans and goats associated with the index farm or with 16 other farms that purchased goats from the index farm or housed goats at the index farm for breeding purposes. Questionnaire data were analyzed, along with human and goat specimens collected for evidence of C. burnetii infection. Twenty-one persons (19%) of the 109-person cohort from Washington and Montana met the outbreak case definition of an epidemiologic link to the index farm and a C. burnetii Phase II immunoglobulin G (IgG) titer >=1:128 by immunofluorescence assay. Seventy-one percent of cases (15 of 21) were symptomatic, compared with approximately 50% during previous Q fever outbreaks. National Q fever surveillance reports increase in frequency with age, but 29% (6 of 21) of cases during this outbreak occurred in children aged <14 years. Goat specific Q fever risk factors included direct contact with a newborn (prevalence ratio [PR] 10.7; confidence interval [CI] 1.5, 77.4), exposure to a newborn that died (PR 5.5; CI 1.7, 18.2), exposure to a weak newborn (PR 4.4; CI 1.7, 11.6), living on a property with goats (PR 4.2; CI 1.3, 13.9), and direct contact with birth/afterbirth products (PR 2.8; CI 1.1, 6.9). Evidence of C. burnetii infection was detected in all 17 goat herds sampled (13 Washington, 3 Montana, 1 Oregon) by PCR and/or enzyme-linked immunosorbent assay. Following this investigation, Washington and Montana implemented a herd management plan to encourage best-management practices among livestock owners, reduce the potential for future outbreaks, and promote continued communication between state public health and agricultural authorities. PMID- 24350649 TI - Simultaneous determination of 36 pesticide residues in spinach and cauliflower by LC-MS/MS using multi-walled carbon nanotubes-based dispersive solid-phase clean up. AB - A multi-residue method based on a modified QuEChERS sample preparation with multi walled carbon nanotubes (MWCNTs) as reversed-dispersive solid-phase extraction (r DSPE) material and LC-MS/MS determination by MRM mode was validated for 36 representative pesticides in spinach and cauliflower. It was demonstrated that MWCNTs can be used as effective r-DSPE materials with the QuEChERS method for the clean-up of extract from different matrices. However, MWCNTs could absorb pyrimethanil, diflubenzuron, and chlorbenzuron in both spinach and cauliflower, which leads to the low recoveries compared with PSA. The LODs and LOQs for 36 pesticides ranged from 0.1 to 5 MUg kg(-1) and from 2 to 30 MUg kg(-1), respectively. Good linearity was found for all pesticides with coefficients better than 0.995 in a range of 0.02-0.5 mg l(-1). The developed method with MWCNTs clean-up was successfully used to determine the 36 pesticides in real samples. PMID- 24350650 TI - Impact of myocardial viability and left ventricular lead location on clinical outcome in cardiac resynchronization therapy recipients with ischemic cardiomyopathy. AB - INTRODUCTION: Cardiac resynchronization therapy (CRT) recipients with ischemic cardiomyopathy (ICM) have scar segments that may limit ventricular resynchronization and clinical response. The impact of myocardial viability at the left ventricular (LV) pacing site on CRT response is poorly elucidated. METHODS AND RESULTS: A retrospective cohort of 160 ICM patients with single photon emission computed tomography-myocardial perfusion imaging before device implantation were included. Coronary venous angiography and chest radiographs helped classify segmental location of LV lead (LVL). The primary outcome was a composite of heart failure (HF) hospitalization and mortality at 3 years, and secondary outcome was change in systolic function at 6 months. The patients were divided into groups based on the myocardial substrate at the site of LVL: LVL on or adjacent to (1) normal myocardium (LVL-N, n = 64), (2) segmental scar (LVL-S, n = 62), and (3) scar and ischemia (LVL-SI, n = 34). Upon follow-up, 75 (47%) patients reached primary endpoint with a higher incidence noted in LVL-S (60%), and LVL-SI (53%), compared to 31% in LVL-N (P = 0.004). Kaplan Meier method demonstrated poor event free survival for primary outcome in LVL-S (P = 0.002), and LVL-SI (P = 0.03). In Cox proportional hazard model, LVL-S (HR: 2.26, P = 0.004), and LVL-SI (1.9, P = 0.047) were independent predictors of primary outcome. CONCLUSION: In CRT recipients with ICM, scar and reversible ischemia in or adjacent to LV pacing site were independent predictors of HF hospitalization and death. PMID- 24350651 TI - An immunohistochemical assay on human tissue using a human primary antibody. AB - Non human antibodies administered to human patients often generate anti-antibody responses, leading in extreme cases to anaphylactic shock. Completely human antibodies are therefore favored over their murine, chimeric and humanized counterparts. However, the accurate evaluation of human antibodies on human tissue samples cannot be achieved using indirect immunohistochemical methods because of endogenous immunoglobulins that are co-detected by the secondary antibodies. Direct detection is often used instead, but this lacks the signal amplification conferred by the secondary antibody and is therefore less sensitive. We developed a simple fluorescence-based indirect immunohistochemical method that allows human primary antibodies bound specifically to their target antigens in human tissue samples to be detected clearly and without interfering background staining. This approach involves a biotinylated human primary antibody (H10(Biotin)) and Cy3-conjugated streptavidin (Strep(Cy3)). We tested the protocol using a human carcinoembryonic antigen (CEA) specific IgG1 (H10). We identified an exposure time threshold that allowed the elimination of low Strep(Cy3) background staining, yet achieved sufficient signal amplification to make our approach four times more sensitive than comparable direct immunohistochemical procedures. The principle of this indirect immunohistochemical assay should be transferable to other species allowing the specific and sensitive detection of any primary antibody on homologous tissues. PMID- 24350653 TI - Conformational polymorphism. PMID- 24350652 TI - Failure of malaria chemoprophylaxis with mefloquine in an oversize traveller to Mozambique. AB - A case of failure of mefloquine prophylaxis in an oversize traveller, who correctly took the drug. This case seems to be attributed to mefloquine resistance, however it is suggested that mefloquine dosage should be modulated by body weight, as is already indicated by some authorities. PMID- 24350654 TI - First manic episode associated with use of human chorionic gonadotropin for obesity: a case report. AB - BACKGROUND: Although highly controversial, the treatment of obesity with exogenous human chorionic gonadotropin (HCG) remains popular in the USA. We report the case of a patient whose first manic episode was associated with the use of HCG for weight loss. CASE REPORT: A 32-year-old female patient was admitted to our psychiatric inpatient unit due to a two-week history of manic symptoms. She had no previous history of manic or hypomanic episodes and had completed a 45-day course of sublingual HCG for weight loss immediately prior to the onset of the manic episode. The patient was treated with lithium carbonate and aripiprazole, and progressed with improvement in the symptoms. CONCLUSION: While it is not possible to definitively link the HCG use to the development of mania, available evidence suggests that HCG may have a contributing role in triggering manic symptomatology. PMID- 24350655 TI - An evaluation of independent component analyses with an application to resting state fMRI. AB - We examine differences between independent component analyses (ICAs) arising from different assumptions, measures of dependence, and starting points of the algorithms. ICA is a popular method with diverse applications including artifact removal in electrophysiology data, feature extraction in microarray data, and identifying brain networks in functional magnetic resonance imaging (fMRI). ICA can be viewed as a generalization of principal component analysis (PCA) that takes into account higher-order cross-correlations. Whereas the PCA solution is unique, there are many ICA methods-whose solutions may differ. Infomax, FastICA, and JADE are commonly applied to fMRI studies, with FastICA being arguably the most popular. Hastie and Tibshirani (2003) demonstrated that ProDenICA outperformed FastICA in simulations with two components. We introduce the application of ProDenICA to simulations with more components and to fMRI data. ProDenICA was more accurate in simulations, and we identified differences between biologically meaningful ICs from ProDenICA versus other methods in the fMRI analysis. ICA methods require nonconvex optimization, yet current practices do not recognize the importance of, nor adequately address sensitivity to, initial values. We found that local optima led to dramatically different estimates in both simulations and group ICA of fMRI, and we provide evidence that the global optimum from ProDenICA is the best estimate. We applied a modification of the Hungarian (Kuhn-Munkres) algorithm to match ICs from multiple estimates, thereby gaining novel insights into how brain networks vary in their sensitivity to initial values and ICA method. PMID- 24350656 TI - Genotype-dependency of butyrate efficacy in children with congenital chloride diarrhea. AB - BACKGROUND: Congenital chloride diarrhea (CLD) is an autosomal recessive disorder characterized by life-long, severe diarrhea with intestinal Cl- malabsorption. It results from a reduced activity of the down regulated in adenoma exchanger (DRA), due to mutations in the solute carrier family 26, member 3 (SLC26A3) gene. Currently available therapies are not able to limit the severity of diarrhea in CLD. Conflicting results have been reported on the therapeutic efficacy of oral butyrate. METHODS: We investigated the effect of oral butyrate (100 mg/kg/day) in seven CLD children with different SLC26A3 genotypes. Nasal epithelial cells were obtained to assess the effect of butyrate on the expression of the two main Cl- transporters: DRA and putative anion transporter-1 (PAT-1). RESULTS: A variable clinical response to butyrate was observed regarding the stool pattern and fecal ion loss. The best response was observed in subjects with missense and deletion mutations. Variable response to butyrate was also observed on SLC26A3 (DRA) and SLC26A6 (PAT1) gene expression in nasal epithelial cells of CLD patients. CONCLUSIONS: We demonstrate a genotype-dependency for butyrate therapeutic efficacy in CLD. The effect of butyrate is related in part on a different modulation of the expression of the two main apical membrane Cl- exchangers of epithelial cells, members of the SLC26 anion family. TRIAL REGISTRATION: Australian New Zealand Clinical trial Registry ACTRN12613000450718. PMID- 24350657 TI - The significance of FM associations for women with FM. AB - PURPOSE: Living with fibromyalgia (FM) means living with a long-term pain syndrome that is invisible to others. Support and understanding from others seem to be important to managing the affected daily life. The aim of this study was to describe the significance of FM associations for women with FM. METHODS: Data collection was carried out through focus group discussions with seventeen women with FM. Data were analyzed through thematic content analysis. RESULTS: The findings show that women experienced associations for people with FM as important as they gave access to contacts with others with similar experiences. Their need of togetherness was fulfilled at the association and they described being strengthened by the support received. Because of the lack of information and knowledge about FM, the association was described as an important venue for getting and mediating information about the illness. CONCLUSIONS: At the association the women seem to be empowered, which increases their ability to manage their daily lives despite the limitations imposed by FM. Healthcare personnel could not satisfy the women's needs and to manage to support women with FM. There is a need for communication based on a shared understanding between the women and healthcare personnel. IMPLICATIONS FOR REHABILITATION: This study highlighted the need for communication based on a shared understanding between people with chronic illness and healthcare personnel to support and strengthen women with FM in their daily lives. The FM associations meet the needs for togetherness, confirmation, and information that the women with FM in this study described and healthcare personnel could not satisfy. Healthcare personnel can learn from FM associations how to empower women with FM in their everyday lives. PMID- 24350658 TI - The influence of foetal prednisone exposure on the cortisol levels in the offspring. AB - OBJECTIVE: Pregnant women suffering from autoimmune disease use glucocorticoids. Glucocorticoids can partly diffuse to the foetus and may influence the development of the foetal hypothalamic-pituitary-adrenal axis, especially in early stage of pregnancy. The objective was to investigate whether prednisone exposure in utero influences the cortisol levels of the prepubertal children. DESIGN: Mothers participated in a prospective cohort study on rheumatoid arthritis (RA) and pregnancy. Children were exposed (n = 44) or nonexposed (n = 65) to prednisone in utero. Salivary cortisol levels were taken from all children during 1 day: at awakening, 30 min after awakening, 1 p.m. and bedtime. Cortisol levels between groups were also analysed using area under the curve (AUC), cortisol awakening response (CAR) and slope. RESULTS: The mean age (SD) of the children was 6.98 (1.23). The difference in mean (SD) cortisol level at '1 p.m.' was 5.42 nm (4.08) in the prednisone-exposed and 3.97 nm (4.00) in the nonexposed (P = 0.03). Prednisone-exposed children had a higher AUC (beta = 13.28; P = 0.02), even after correction for RA disease activity. No differences were found on CAR, slope or blood pressure. The cortisol levels of the nonexposed were more similar to the age-specific references than the prednisone-exposed. CONCLUSION: Prednisone use during pregnancy is associated with a higher daytime cortisol level, in the prepubertal offspring, not yet accompanied with clinical outcomes. This conclusion will have no consequences at this moment, but it does raise questions concerning prednisone exposure in utero and the long-term consequences for the offspring. PMID- 24350659 TI - A 23Na magic angle spinning nuclear magnetic resonance, XANES, and high temperature X-ray diffraction study of NaUO3, Na4UO5, and Na2U2O7. AB - The valence state of uranium has been confirmed for the three sodium uranates NaU(V)O3/[Rn](5f(1)), Na4U(VI)O5/[Rn](5f(0)), and Na2U(VI)2O7/[Rn](5f(0)), using X-ray absorption near-edge structure (XANES) spectroscopy. Solid-state (23)Na magic angle spinning nuclear magnetic resonance (MAS NMR) measurements have been performed for the first time, yielding chemical shifts at -29.1 (NaUO3), 15.1 (Na4UO5), and -14.1 and -19 ppm (Na1 8-fold coordinated and Na2 7-fold coordinated in Na2U2O7), respectively. The [Rn]5f(1) electronic structure of uranium in NaUO3 causes a paramagnetic shift in comparison to Na4UO5 and Na2U2O7, where the electronic structure is [Rn]5f(0). A (23)Na multi quantum magic angle spinning (MQMAS) study on Na2U2O7 has confirmed a monoclinic rather than rhombohedral structure with evidence for two distinct Na sites. DFT calculations of the NMR parameters on the nonmagnetic compounds Na4UO5 and Na2U2O7 have permitted the differentiation between the two Na sites of the Na2U2O7 structure. The linear thermal expansion coefficients of all three compounds have been determined using high-temperature X-ray diffraction: alphaa = 22.7 * 10(-6) K( 1), alphab = 12.9 * 10(-6) K(-1), alphac = 16.2 * 10(-6) K(-1), and alphavol = 52.8 * 10(-6) K(-1) for NaUO3 in the range 298-1273 K; alphaa = 37.1 * 10(-6) K( 1), alphac = 6.2 * 10(-6) K(-1), and alphavol = 81.8 * 10(-6) K(-1) for Na4UO5 in the range 298-1073 K; alphaa = 6.7 * 10(-6) K(-1), alphab = 14.4 * 10(-6) K(-1), alphac = 26.8 * 10(-6) K(-1), alphabeta = -7.8 * 10(-6) K(-1), and alphavol = 217.6 * 10(-6) K(-1) for Na2U2O7 in the range 298-573 K. The alpha to beta phase transition reported for the last compound above about 600 K was not observed in the present studies, either by high-temperature X-ray diffraction or by differential scanning calorimetry. PMID- 24350660 TI - Immediate placement and restoration of dental implants in the esthetic region: clinical case series. AB - AIM: The objective of this study was to assess the hard and soft tissue changes following immediate placement and provisional restoration of single-tooth implants in the aesthetic zone. METHODS: Thirteen patients with immediately placed and restored implants were included in this study. All participating patients underwent the same treatment strategy that involved removal of the failed tooth, flapless surgery, immediate implant placement, and connection of a screw-retained provisional restoration. Three months following implant placement, the temporary crowns were replaced by the definitive restorations. Implant survival rates, and hard and soft tissue changes were measured using periapical X rays and photographs. The range of the observation period was between 12 and 37 months with a mean period of 23.2 +/- 7.6 months. RESULTS: At the time of follow up, all implants were present with no complications. Radiographic evaluation revealed a mean mesial bone gain of 1.20 +/- 1.01 mm and a mean distal bone gain of 0.80 +/- 1.14 mm, which reached statistical significance. The mean mid-buccal recession was 0.20 +/- 0.78 mm, whereas the mesial and distal papillae height loss was 0.50 +/- 1.26 mm and 0.30 +/- 0.82 mm, respectively. The changes in the soft tissues did not reach statistical significance. CONCLUSION: Notwithstanding the limitation of a small sample size, this study shows that immediate implant placement and provisional restoration in the maxillary aesthetic zone can result in favorable treatment outcomes with regards to soft and hard tissues changes over a follow-up period of 23.2 +/- 7.6 months. CLINICAL SIGNIFICANCE: Most clinical trials investigating immediate implant placement and immediate restoration in the maxillary anterior zone have focused on implant survival and implant success, with particular emphasis on radiographically assessed hard tissues changes. However, this study assesses the soft tissue changes associated with this procedure, which is an important area of study given the esthetic demands of implant therapy in the maxillary anterior region. PMID- 24350661 TI - What is and what could have been: experiencing regret and relief across childhood. AB - Counterfactual emotions, such as regret and relief, are considered important in daily-life choice behaviour, learning and emotion regulation. A prominent question is from which age counterfactual emotions develop. In this study, we compared a more "traditional" analysis with a latent-class analysis (LCA) that allows the study of individual differences and a more detailed assessment of counterfactual emotions. Four groups of children (5-6 years, 7-8 years, 9-10 years and 11-13 years) and a group of young adults performed a choice task in which they encountered a Regret situation (chosen option was worse than alternative), a Relief situation (chosen option was better than alternative) and a Baseline situation (chosen option was equal to alternative). Traditional analyses indicated regret and relief to be present from ages 7 to 8. In contrast, the LCA indicated that subgroups experiencing regret and relief were present in all age groups, although regret and relief subgroups increased with age. Moreover, analyses indicated that higher reasoning scores increased the probability to belong to regret and relief subgroups and that the experience of regret dependent on trial order, being more prominent in later trials. We conclude that an individual-difference approach can advance insight into emotional development. PMID- 24350663 TI - Noncovalent interactions in microsolvated networks of trimethylamine N-oxide. AB - The effects of the formation of hydrogen-bonded networks on the important osmolyte trimethylamine N-oxide (TMAO) are explored in a joint Raman spectroscopic and electronic structure theory study. Spectral shifts in the experimental Raman spectra of TMAO and deuterated TMAO microsolvated with water, methanol, ethanol, and ethylene glycol are compared with the results of electronic structure calculations on explicit hydrogen-bonded molecular clusters. Very good agreement between experiment and theory suggests that it is the local hydrogen-bonded geometry at TMAO's oxygen atom that dominates the structure of the extended hydrogen-bonded networks and that TMAO's unique stabilizing abilities are a result of the "indirect effect" model. Natural bonding orbital (NBO) calculations further reveal that hyperconjugation results in vibrational blue shifts in TMAO's C-H stretching region when solvated and a red shift in methanol's C-H stretching region when hydrogen bonding with TMAO. PMID- 24350664 TI - Improving immunization data management: an editorial on the potential of Electronic Health Records. AB - Immunizations are critical for maintaining individual and population health. Yet ensuring that complete immunization histories are available at the point of care is challenging. Currently, immunization information systems (IIS) are used to aggregate data at a regional level, although their value is often limited by incomplete data. The Electronic Health Record (EHR) Incentive Program, which is an unprecedented federal initiative promoting EHR use, is linking financial payments in part to demonstrating ability to transmit EHR data directly to IIS and thus has potential to change immunization data management on a large scale. We believe that EHRs are critical for allowing more complete and timely immunization data capture and will offer many benefits. To achieve these benefits, however, it will be necessary to engage the EHR vendor community in developing EHRs that allow for comprehensive immunization data capture and policy makers to incentivize bidirectional, real-time exchange between IIS and EHRs. PMID- 24350662 TI - Efficacy and safety of once-daily oxybutynin patch versus placebo and propiverine in Japanese patients with overactive bladder: A randomized double-blind trial. AB - OBJECTIVES: To evaluate the efficacy and safety of once-daily oxybutynin patch therapy for overactive bladder. METHODS: A randomized double-blind trial was carried out in patients with overactive bladder syndrome, who received an oxybutynin patch, propiverine (20 mg) or placebo once daily for 12 weeks. The primary efficacy end-point was the change of the mean daily number of micturitions in week 12. RESULTS: A total of 1530 patients were randomized to receive the oxybutynin patch (573), propiverine (576) or placebo (381). The change of the mean daily frequency of micturition from baseline in the full analysis set was -1.89 +/- 2.04 with the oxybutynin patch, which was significantly higher than with placebo (-1.44 +/- 2.23) (P = 0.0015). The difference of the mean change in the mean daily number of micturitions between the oxybutynin patch and propiverine groups showed a 95% confidence interval of 0.28 to 0.21, and the upper limit of this interval was below the predefined non inferiority margin of 0.37, showing non-inferiority of the oxybutynin patch to propiverine. The incidence of dry mouth and constipation was higher with propiverine than with the oxybutynin patch or placebo. Application site dermatitis was more frequent with the oxybutynin patch (31.8%) than with propiverine (5.9%) or placebo (5.2%), but the dermatitis was generally mild. CONCLUSION: This trial shows the efficacy of the new once-daily oxybutynin patch for overactive bladder. Despite a higher rate of dermatitis with the oxybutynin patch, dry mouth and constipation occurs less often than during treatment with propiverine. PMID- 24350665 TI - Lung mesenchymal stromal cells in development and disease: to serve and protect? AB - SIGNIFICANCE: Bronchopulmonary dysplasia (BPD) is a disease of the developing lung that afflicts extreme preterm infants in the neonatal intensive care unit. Follow-up studies into adulthood show that BPD is not merely a problem of the neonatal period, as it also may predispose to early-onset emphysema and poor lung function in later life. RECENT ADVANCES: The increasing promise of bone marrow- or umbilical cord-derived mesenchymal stromal cells (MSCs) to repair neonatal and adult lung diseases may for the first time offer the chance to make substantial strides in improving the outcome of extreme premature infants at risk of developing BPD. As more knowledge has been obtained on MSCs over the past decades, it has become clear that each organ has its own reservoir of endogenous MSCs, including the lung. CRITICAL ISSUES: We have only barely scratched the surface on what resident lung MSCs exactly are and what their role and function in lung development may be. Moreover, what happens to these putative repair cells in BPD when alveolar development goes awry and why do their counterparts from the bone marrow and umbilical cord succeed in restoring normal alveolar development when they themselves do not? FUTURE DIRECTIONS: Much work remains to be carried out to validate lung MSCs, but with the high potential of MSC-based treatment for BPD and other lung diseases, a thorough understanding of the endogenous lung MSC will be pivotal to get to the bottom of these diseases. PMID- 24350666 TI - Enantioselective alkylation by binaphthyl chiral phase-transfer catalysts: a DFT based conformational analysis. AB - A conformational search method based on the density functional theory (DFT) was successfully applied to explore a mechanism for the highly enantioselective alkylation by binaphthyl-modifed chiral phase-transfer catalysts. Key interactions that govern the enantioselectivity were analyzed. The computational results are encouraging for further application of the DFT-based conformational search toward the rational design of next-generation asymmetric phase transfer catalysts. PMID- 24350667 TI - Catalytic reduction of N2 to NH3 by an Fe-N2 complex featuring a C-atom anchor. AB - While recent spectroscopic studies have established the presence of an interstitial carbon atom at the center of the iron-molybdenum cofactor (FeMoco) of MoFe-nitrogenase, its role is unknown. We have pursued Fe-N2 model chemistry to explore a hypothesis whereby this C-atom (previously denoted as a light X atom) may provide a flexible trans interaction with an Fe center to expose an Fe N2 binding site. In this context, we now report on Fe complexes of a new tris(phosphino)alkyl (CP(iPr)3) ligand featuring an axial carbon donor. It is established that the iron center in this scaffold binds dinitrogen trans to the C(alkyl)-atom anchor in three distinct and structurally characterized oxidation states. Fe-C(alkyl) lengthening is observed upon reduction, reflective of significant ionic character in the Fe-C(alkyl) interaction. The anionic (CP(iPr)3)FeN2(-) species can be functionalized by a silyl electrophile to generate (CP(iPr)3)Fe-N2SiR3. (CP(iPr)3)FeN2(-) also functions as a modest catalyst for the reduction of N2 to NH3 when supplied with electrons and protons at -78 degrees C under 1 atm N2 (4.6 equiv NH3/Fe). PMID- 24350668 TI - Estimating nanoparticle optical absorption with magnetic resonance temperature imaging and bioheat transfer simulation. AB - PURPOSE: Optically activated nanoparticle-mediated heating for thermal therapy applications is an area of intense research. The ability to characterise the spatio-temporal heating potential of these particles for use in modelling under various exposure conditions can aid in the exploration of new approaches for therapy as well as more quantitative prospective approaches to treatment planning. The purpose of this research was to investigate an inverse solution to the heat equation using magnetic resonance temperature imaging (MRTI) feedback, for providing optical characterisation of two types of nanoparticles (gold-silica nanoshells and gold nanorods). METHODS: The optical absorption of homogeneous nanoparticle-agar mixtures was measured during exposure to an 808 nm laser using real-time MRTI. A coupled finite element solution of heat transfer was registered with the data and used to solve the inverse problem. The L2 norm of the difference between the temperature increase in the model and MRTI was minimised using a pattern search algorithm by varying the absorption coefficient of the mixture. RESULTS: Absorption fractions were within 10% of literature values for similar nanoparticles. Comparison of temporal and spatial profiles demonstrated good qualitative agreement between the model and the MRTI. The weighted root mean square error was <1.5 sigmaMRTI and the average Dice similarity coefficient for DeltaT = 5 degrees C isotherms was >0.9 over the measured time interval. CONCLUSION: This research demonstrates the feasibility of using an indirect method for making minimally invasive estimates of nanoparticle absorption that might be expanded to analyse a variety of geometries and particles of interest. PMID- 24350670 TI - Plasmodium vivax malaria incidence over time and its association with temperature and rainfall in four counties of Yunnan Province, China. AB - BACKGROUND: Transmission of Plasmodium vivax malaria is dependent on vector availability, biting rates and parasite development. In turn, each of these is influenced by climatic conditions. Correlations have previously been detected between seasonal rainfall, temperature and malaria incidence patterns in various settings. An understanding of seasonal patterns of malaria, and their weather drivers, can provide vital information for control and elimination activities. This research aimed to describe temporal patterns in malaria, rainfall and temperature, and to examine the relationships between these variables within four counties of Yunnan Province, China. METHODS: Plasmodium vivax malaria surveillance data (1991-2006), and average monthly temperature and rainfall were acquired. Seasonal trend decomposition was used to examine secular trends and seasonal patterns in malaria. Distributed lag non-linear models were used to estimate the weather drivers of malaria seasonality, including the lag periods between weather conditions and malaria incidence. RESULTS: There was a declining trend in malaria incidence in all four counties. Increasing temperature resulted in increased malaria risk in all four areas and increasing rainfall resulted in increased malaria risk in one area and decreased malaria risk in one area. The lag times for these associations varied between areas. CONCLUSIONS: The differences detected between the four counties highlight the need for local understanding of seasonal patterns of malaria and its climatic drivers. PMID- 24350671 TI - Stud identity among female-born youth of color: joint conceptualizations of gender variance and same-sex sexuality. AB - Little is known about the experiences of individuals who may fall under the umbrella of "transgender" but do not transition medically and/or socially. The impact of the increasingly widespread use of the term "transgender" itself also remains unclear. The authors present narratives from four female-born youth of color who report a history of identifying as a "stud." Through analysis of their processes of identity signification, the authors demonstrate how stud identity fuses aspects of gender and sexuality while providing an alternate way of making meaning of gender variance. As such, this identity has important implications for research and organizing centered on an LGBT-based identity framework. PMID- 24350669 TI - Loss of IP3 receptor function in neuropeptide secreting neurons leads to obesity in adult Drosophila. AB - BACKGROUND: Intracellular calcium signaling regulates a variety of cellular and physiological processes. The inositol 1,4,5 trisphosphate receptor (IP3R) is a ligand gated calcium channel present on the membranes of endoplasmic reticular stores. In previous work we have shown that Drosophila mutants for the IP3R (itprku) become unnaturally obese as adults with excessive storage of lipids on a normal diet. While the phenotype manifests in cells of the fat body, genetic studies suggest dysregulation of a neurohormonal axis. RESULTS: We show that knockdown of the IP3R, either in all neurons or in peptidergic neurons alone, mimics known itpr mutant phenotypes. The peptidergic neuron domain includes, but is not restricted to, the medial neurosecretory cells as well as the stomatogastric nervous system. Conversely, expression of an itpr+ cDNA in the same set of peptidergic neurons rescues metabolic defects of itprku mutants. Transcript levels of a gene encoding a gastric lipase CG5932 (magro), which is known to regulate triacylglyceride storage, can be regulated by itpr knockdown and over-expression in peptidergic neurons. Thus, the focus of observed itpr mutant phenotypes of starvation resistance, increased body weight, elevated lipid storage and hyperphagia derive primarily from peptidergic neurons. CONCLUSIONS: The present study shows that itpr function in peptidergic neurons is not only necessary but also sufficient for maintaining normal lipid metabolism in Drosophila. Our results suggest that intracellular calcium signaling in peptidergic neurons affects lipid metabolism by both cell autonomous and non autonomous mechanisms. PMID- 24350672 TI - A research agenda for documenting disability status within healthcare organizations to address disparities in care. AB - Individuals with disabilities are at a greater risk of experiencing healthcare disparities. To address these disparities, healthcare organizations (HCOs) need to consistently and accurately document patients' disability status. Unfortunately, the evidence base does not yet exist to guide HCOs in determining what data to collect or the best method to collect the data. The authors propose a research agenda for developing and administering disability status questions. To determine what data to collect, researchers need to addresses the following challenges: disability is a complex concept, a wide range of types of disabilities exists, severity levels of disability can differ and, finally, patients might use assistive devices or aids to mitigate or ameliorate their disability. Additionally, research is needed to determine the frequency with which to administer questions due to the dynamic nature of disability, and to develop protocols for assessing the most appropriate person to answer disability status questions. Targeted research will lead to disability status questions that accurately and consistently identify individuals with disabilities and produce actionable data that HCOs can use to detect and address potential disparities in care. PMID- 24350673 TI - Small bright charged colloidal quantum dots. AB - Using electrochemical charge injection, the fluorescence lifetimes of negatively charged core/shell CdTe/CdSe QDs are measured as a function of core size and shell thickness. It is found that the ensemble negative trion lifetimes reach a maximum (~4.5 ns) for an intermediate shell thickness. This leads to the smallest particles (~4.5 nm) with the brightest trion to date. Single dot measurements show that the negative charge suppresses blinking and that the trion can be as bright as the exciton at room temperature. In contrast, the biexciton lifetimes remain short and exhibit only a monotonous increase with shell thickness, showing no correlation with the negative trion decays. The suppression of the Auger process in small negatively charged CdTe/CdSe quantum dots is unprecedented and a significant departure from prior results with ultrathick CdSe/CdS core/shell or dot-in-rod structures. The proposed reason for the optimum shell thickness is that the electron-hole overlap is restricted to the CdTe core while the electron is tuned to have zero kinetic energy in the core for that optimum shell thickness. The different trend of the biexciton lifetime is not explained but tentatively attributed to shorter-lived positive trions at smaller sizes. These results improve our understanding of multiexciton recombination in colloidal quantum dots and may lead to the design of bright charged QDs for more efficient light-emitting devices. PMID- 24350674 TI - Simultaneous determination of selected biogenic amines in alcoholic beverage samples by isotachophoretic and chromatographic methods. AB - A simple and useful method for the determination of biogenic amines in beverage samples based on isotachophoretic separation is described. The proposed procedure permitted simultaneous analysis of histamine, tyramine, cadaverine, putrescine, tryptamine, 2-phenylethylamine, spermine and spermidine. The data presented demonstrate the utility, simplicity, flexibility, sensitivity and environmentally friendly character of the proposed method. The precision of the method expressed as coefficient of variations varied from 0.1% to 5.9% for beverage samples, whereas recoveries varied from 91% to 101%. The results for the determination of biogenic amines were compared with an HPLC procedure based on a pre-column derivatisation reaction of biogenic amines with dansyl chloride. Furthermore, the derivatisation procedure was optimised by verification of concentration and pH of the buffer, the addition of organic solvents, reaction time and temperature. PMID- 24350675 TI - Resistant bipolar depressive disorder: case analysis of adjunctive transcranial magnetic stimulation efficiency in medical comorbid conditions. PMID- 24350676 TI - Fish oil, contained in eicosapentaenoic acid and docosahexaenoic acid, attenuates testicular and spermatological damage induced by cisplatin in rats. AB - The aim of this study was to investigate the beneficial effects of the fish oil (FO) supplementation on oxidative stress, sperm characteristics and histological alterations in the male reproductive system of rats against cisplatin (CP) toxicity. The rats were divided randomly into 4 equal groups (control, FO, CP and FO + CP). FO was orally administered at the dose of 1 softgel per rat per day for 14 days and CP was intraperitoneally given at the dose of 7 mg kg(-1) with a single injection. In CP + FO group, they were applicated at the same doses and times. The results showed that CP caused a significant oxidative damage via induction of lipid peroxidation and reduction in the antioxidant defence system potency in the testis tissue. In addition, sperm motility and sperm concentration significantly decreased but the abnormal sperm rate and histopathological testicular damage increased with CP treatment. On the other hand, FO treatment prevented oxidative, histopathological and spermatological effects of CP and reversed side effects of CP. In conclusion, FO supplementation had significant beneficial effects against CP toxicity on male reproductive system and toxic effects of CP can be prevented by FO treatment. Therefore, it appears that fish oil may be useful for the prevention and treatment of cisplatin-induced reproductive system toxicity. PMID- 24350677 TI - Bayesian model selection in complex linear systems, as illustrated in genetic association studies. AB - Motivated by examples from genetic association studies, this article considers the model selection problem in a general complex linear model system and in a Bayesian framework. We discuss formulating model selection problems and incorporating context-dependent a priori information through different levels of prior specifications. We also derive analytic Bayes factors and their approximations to facilitate model selection and discuss their theoretical and computational properties. We demonstrate our Bayesian approach based on an implemented Markov Chain Monte Carlo (MCMC) algorithm in simulations and a real data application of mapping tissue-specific eQTLs. Our novel results on Bayes factors provide a general framework to perform efficient model comparisons in complex linear model systems. PMID- 24350678 TI - Detecting cellular reprogramming determinants by differential stability analysis of gene regulatory networks. AB - BACKGROUND: Cellular differentiation and reprogramming are processes that are carefully orchestrated by the activation and repression of specific sets of genes. An increasing amount of experimental results show that despite the large number of genes participating in transcriptional programs of cellular phenotypes, only few key genes, which are coined here as reprogramming determinants, are required to be directly perturbed in order to induce cellular reprogramming. However, identification of reprogramming determinants still remains a combinatorial problem, and the state-of-art methods addressing this issue rests on exhaustive experimentation or prior knowledge to narrow down the list of candidates. RESULTS: Here we present a computational method, without any preliminary selection of candidate genes, to identify reduced subsets of genes, which when perturbed can induce transitions between cellular phenotypes. The method relies on the expression profiles of two stable cellular phenotypes along with a topological analysis stability elements in the gene regulatory network that are necessary to cause this multi-stability. Since stable cellular phenotypes can be considered as attractors of gene regulatory networks, cell fate and cellular reprogramming involves transition between these attractors, and therefore current method searches for combinations of genes that are able to destabilize a specific initial attractor and stabilize the final one in response to the appropriate perturbations. CONCLUSIONS: The method presented here represents a useful framework to assist researchers in the field of cellular reprogramming to design experimental strategies with potential applications in the regenerative medicine and disease modelling. PMID- 24350679 TI - Mechanisms of biotic resistance across complex life cycles. AB - Biotic resistance is the ability of communities to inhibit the establishment, spread or impact of novel species. However, the interactions that underlie biotic resistance depend heavily on the contexts in which species interact. Consequently, studies of biotic resistance that consider single processes, patches, species or life-history stages may provide an incomplete picture of the capacity for communities to resist invasion. Many organisms have multiphasic life cycles, where individuals can occupy distinct niches at different stages of the life history. Generally, studies of biotic resistance focus on interactions within a single life-history stage, and interactions at other life-history stages are overlooked. Here, we demonstrate that different mechanisms of biotic resistance occur across the life history and together limit the invasion success of an introduced marine invertebrate (Ciona intestinalis) in Northern California. We tested the role of interactions (competition and predation) with the resident community in limiting the abundance of Ciona through experiments conducted on fertilization, larval survival, settlement, early postsettlement survival, and the survival of juveniles and adults. Under some circumstances, Ciona became abundant in mid-successional stages and showed more rapid growth rates than a morphologically similar native species, Ascidia ceratodes. However, predators reduced Ciona abundance much more than that of Ascidia at several life stages. Furthermore, Ciona appeared to be a weaker competitor at the adult stage. Early life-history interactions with other sessile species at the fertilization, larval and recruit stages had modest to no effects on Ciona abundance. The presence of biotic resistance mechanisms acting at multiple life stages, and potentially under different conditions, suggests that different components of biotic resistance interact to enhance the resident community's resistance to invasion. PMID- 24350680 TI - Analysis of covalent modifications of proteins by oxidized phospholipids using a novel method of peptide enrichment. AB - Free radical-induced oxidation of phospholipids contributes significantly to pathologies associated with inflammation and oxidative stress. Detection of covalent interaction between oxidized phospholipids (oxPL) and proteins by LC MS/MS could provide valuable information about the molecular mechanisms of oxPL effects. However, such studies are very limited because of significant challenges in detection of the comparatively low levels of oxPL-protein adducts in complex biological systems. Current approaches have several limitations, most important of which is the inability to detect protein modifications by naturally occurring oxPL. We now report, for the first time, an enrichment method that can be applied to the global analysis of protein adducts with various naturally occurring oxPL in relevant biological systems. This method exploits intrinsic properties of peptides modified by oxPL, allowing highly efficient enrichment of oxPL-modified peptides from biological samples. Very low levels of oxPL-protein adducts (<2 ppm) were detected using this enrichment method in combination with LC-MS/MS. We applied the method to several model systems, including oxidation of high density lipoprotein (HDL) and interaction of human platelets with a specific oxPL, and demonstrated its extremely high efficiency and productivity. We report multiple new modifications of apolipoproteins in HDL and proteins in human platelets. PMID- 24350681 TI - Remestemcel-L for acute graft-versus-host disease therapy. AB - INTRODUCTION: Remestemcel-L (Prochymal(r), Osiris) is an off-the-shelf adult mesenchymal stromal cell product that has been applied to acute graft-versus-host disease (aGvHD) for its immunomodulatory properties. AREAS COVERED: This article discusses preclinical and clinical studies supporting the use of remestemcel-L in aGvHD as well as the current regulatory status. This information was based upon a PubMed and Internet search. EXPERT OPINION: Phase II studies suggest remestemcel L may have clinical activity in aGvHD and confirm tolerability. However, these results must be interpreted cautiously with any use of remestemcel-L optimally occurring in the context of a clinical trial. Further clarity will be obtained when the results of a completed Phase III study are published. There is a small market for remestemcel-L in aGvHD. A possible future scenario is that a more prevalent indication is found and remestemcel-L is approved for that indication, but use continues for aGvHD. PMID- 24350682 TI - Consistency of safety profile of new oral anticoagulants in patients with renal failure. AB - BACKGROUND: The use of new oral anticoagulants (NOACs) in patients with impaired renal function has raised major concerns, in particular the possibility of an increased risk of bleeding due to accumulation. The aims of this work were to assess the safety of NOACs in patients with renal failure and describe the relationship between clinical events and drug renal excretion magnitude. METHODS: All phase III trials comparing NOACs with vitamin K antagonists (VKAs) in patients with estimated glomerular filtration (eGFR) rate < 50 mL min(-1) were eligible. The main safety and efficacy outcomes were major bleeding and thrombosis. A meta-regression was performed to estimate the correlation between the treatment effect estimate and the percentage of renal excretion. RESULTS: Nine studies (12 272 patients) were included. A significantly greater relative reduction in major bleeding was seen for NOACs with renal excretion <50% (RR, 0.61; CI, 0.51-0.74) than for those with high renal excretion (RR, 0.96; CI, 0.85 1.07) (interaction test, P < 0.0001). A linear relationship between the relative risk of major bleeding and the magnitude of renal excretion was found by meta regression (R(2) = 0.66, P = 0.03). For thrombosis, a greater treatment effect of NOA vs. INR-adjusted VKA was observed in patients with eGFR < 50 mL min(-1) (RR 0.78, CI 0.67-0.92), but no correlation between treatment effect and renal excretion was found. CONCLUSIONS: New oral anticoagulants were at least as effective as VKAs, with reduced risks of major bleeding and thrombosis in patients with eGFR < 50 mL min(-1) . The renal excretion of these new drugs seemed to modify the safety profile, contrary to the efficacy. PMID- 24350683 TI - Open pentameric calixarene nanocage. AB - A novel open helmetlike coordination cage has been synthesized based on Co4 calixarene shuttlecock-like secondary building units and in situ generated phosphate anions, where the opening of the cage comprises a large 16-membered ring. The above unprecedented Co20 nanocage presents the first pentameric calixarene coordination compound. Sorption behavior and magnetic properties are also investigated. PMID- 24350684 TI - Editorial comment from Dr Karatag et al. to tubeless simultaneous bilateral percutaneous nephrolithotomy: safety, feasibility and efficacy in an Indian setting. PMID- 24350685 TI - Synthesis of uranium-ligand multiple bonds by cleavage of a trityl protecting group. AB - Addition of KSCPh3 to [U(NR2)3] (R = SiMe3) in tetrahydrofuran, followed by addition of 18-crown-6, results in formation of the U(IV) sulfide, [K(18-crown 6)][U(S)(NR2)3] (1) and Gomberg's dimer. Similarly, addition of KOCPh3 to [U(NR2)3] in tetrahydrofuran, followed by addition of 18-crown-6, results in formation of the U(IV) oxide, [K(18-crown-6)][U(O)(NR2)3] (3). Also observed in this transformation are the triphenylmethyl anion, [K(18-crown-6)(THF)2][CPh3] (5), and the U(IV) alkoxide, [U(OCPh3)(NR2)3] (4). PMID- 24350687 TI - Live attenuated vaccine: the first clinically approved dengue vaccine? AB - Dengue virus (DENV) is the most prevalent mosquito-borne viral pathogen in humans. There are 390 million human infections each year, with 96 million infections exhibiting disease symptoms. Currently, there is no clinically approved vaccine and antiviral for DENV. The four serotypes of DENV (DENV-1, -2, 3 and -4) have 25-40% variation at the amino acid level. Such variation has posed challenges for the development of a tetravalent vaccine and therapeutics. PMID- 24350686 TI - Coarse-grained models for aqueous polyethylene glycol solutions. AB - A new coarse-grained force field is developed for polyethylene glycol (PEG) in water. The force field is based on the MARTINI model but with the big multipole water (BMW) model for the solvent. The polymer force field is reparameterized using the MARTINI protocol. The new force field removes the ring-like conformations seen in simulations of short chains with the MARTINI force field; these conformations are not observed in atomistic simulations. We also investigate the effect of using parameters for the end-group that are different from those for the repeat units, with the MARTINI and BMW/MARTINI models. We find that the new BMW/MARTINI force field removes the ring-like conformations seen in the MARTINI models and has more accurate predictions for the density of neat PEG. However, solvent-separated-pairs between chain ends and slow dynamics of the PEG reflect its own artifacts. We also carry out fine-grained simulations of PEG with bundled water clusters and show that the water bundling can lead to ring-like conformations of the polymer molecules. The simulations emphasize the pitfalls of coarse-graining several molecules into one site and suggest that polymer-solvent systems might be a stringent test for coarse-grained force fields. PMID- 24350688 TI - Intrathecal baclofen associated with improvement of consciousness disorders in spasticity patients. AB - OBJECTIVE: Intrathecal baclofen (ITB) pump is a therapeutic option for persistent vegetative state and minimal conscious state patients that have associated spasticity. We investigated whether this treatment modality can affect their level of consciousness. METHOD: In this prospective, open label, observational study, we implanted ITB pumps for the treatment of spasticity in eight patients with disorders of consciousness (vegetative state and minimally conscious state) and we followed them with the Coma Recovery Scale-Revised, the Eastern Cooperative Oncology Group (ECOG) performance scale, and the Modified Ashworth spasticity scale. Baclofen dose and complications also were noted. RESULTS: The offending pathologies were traumatic brain injury in six, anoxia due to cardiac arrest in one, acute obstructive hydrocephalus in one. Two of the patients showed a marked, persistent improvement that fulfilled the criteria of emergence from minimally conscious state. Two of patients had their ITB pumps prematurely removed because of complications. The ECOG score was 4 for all patients and did not change during the study. CONCLUSION: ITB might be associated with a significant improvement in the disorder of consciousness of two patients from a total of six that had a chronic ITB treatment. PMID- 24350689 TI - Genetic variation in scaly hair-fin anchovy Setipinna tenuifilis (Engraulididae) based on the mitochondrial DNA control region. AB - Scaly hair-fin anchovy (Setipinna tenuifilis) is a small, pelagic and economical species and widely distributed in Chinese coastal water. However, resources of S. tenuifilis have been reduced due to overfishing. For better fishery management, it is necessary to understand the pattern of S. tenuifilis's biogeography. Genetic analyses were taken place to detect their population genetic variation. A total of 153 individuals from 7 locations (Dongying, Yantai, Qingdao, Nantong, Wenzhou, Xiamen and Beibu Bay) were sequenced at the 5' end of mtDNA control region. A 39-bp tandem repeated sequence was found at the 5' end of the segment and a polymorphism of tandem repeated sequence was detected among 7 populations. Both mismatch distribution analysis and neutrality tests showed S. tenuifilis had experienced a recent population expansion. The topology of neighbor-joining tree and Bayesian evolutionary tree showed no significant genealogical branches or clusters of samples corresponding to sampling locality. Hierarchical analysis of molecular variance and conventional pairwise population Fst value at group hierarchical level implied that there might have genetic divergence between southern group (population WZ, XM and BB) and northern group (population DY, YT, QD and NT). We concluded that there might have three different fishery management groups of S. tenuifilis and the late Pleistocene glacial event might have a crucial effect on present-day demography of S. tenuifilis in this region. PMID- 24350690 TI - When expectation meets experience: parents' recollections of and experiences with a child diagnosed with hearing loss soon after birth. AB - OBJECTIVE: To examine parents' recollections of and their experiences with bringing up a child diagnosed with hearing loss at a very young age. DESIGN: Based on the analysis of informal parent discussion groups, four open-ended questions were formulated to solicit information about parents' expectations following diagnosis, as well as experiences and challenges when raising a child with a hearing loss. STUDY SAMPLE: Forty parents of children, aged between three to five years, who were diagnosed with hearing loss before the age of three years. RESULTS: Parents' responses revealed strong support for early intervention, high expectations for their child's development, and desire for information tailored to individual needs. Parents also reported anxiety relating to their perceptions of the significance of consistent device usage on their child's development. Further concerns arose from their observations of the difficulties experienced by their child in real-world environments despite consistent device usage, and their perception of their child's language delay despite early intervention. CONCLUSIONS: The findings point to a need to support parents to form realistic expectations based on current knowledge. Implications for clinicians to provide improved management of children with hearing loss are discussed. PMID- 24350691 TI - Longitudinal outcomes of children with hearing impairment (LOCHI). PMID- 24350692 TI - A comparison of NAL and DSL prescriptive methods for paediatric hearing-aid fitting: predicted speech intelligibility and loudness. AB - OBJECTIVE: To examine the impact of prescription on predicted speech intelligibility and loudness for children. DESIGN: A between-group comparison of speech intelligibility index (SII) and loudness, based on hearing aids fitted according to NAL-NL1, DSL v4.1, or DSL m[i/o] prescriptions. A within-group comparison of gains prescribed by DSL m[i/o] and NAL-NL2 for children in terms of SII and loudness. STUDY SAMPLE: Participants were 200 children, who were randomly assigned to first hearing-aid fitting with either NAL-NL1, DSL v4.1, or DSL m[i/o]. Audiometric data and hearing-aid data at 3 years of age were used. RESULTS: On average, SII calculated on the basis of hearing-aid gains were higher for DSL than for NAL-NL1 at low input level, equivalent at medium input level, and higher for NAL-NL1 than DSL at high input level. Greater loudness was associated with DSL than with NAL-NL1, across a range of input levels. Comparing NAL-NL2 and DSL m[i/o] target gains revealed higher SII for the latter at low input level. SII was higher for NAL-NL2 than for DSL m[i/o] at medium- and high input levels despite greater loudness for gains prescribed by DSL m[i/o] than by NAL-NL2. CONCLUSION: The choice of prescription has minimal effects on speech intelligibility predictions but marked effects on loudness predictions. PMID- 24350693 TI - Hearing-aid safety: a comparison of estimated threshold shifts for gains recommended by NAL-NL2 and DSL m[i/o] prescriptions for children. AB - OBJECTIVE: To investigate the predicted threshold shift associated with the use of nonlinear hearing aids fitted to the NAL-NL2 or the DSL m[i/o] prescription for children with the same audiograms. For medium and high input levels, we asked: (1) How does predicted asymptotic threshold shifts (ATS) differ according to the choice of prescription? (2) How does predicted ATS vary with hearing level for gains prescribed by the two prescriptions? DESIGN: A mathematical model consisting of the modified power law combined with equations for predicting temporary threshold shift (Macrae, 1994b) was used to predict ATS. STUDY SAMPLE: Predicted threshold shift were determined for 57 audiograms at medium and high input levels. RESULTS: For the 57 audiograms, DSL m[i/o] gains for high input levels were associated with increased risk relative to NAL-NL2. The variation of ATS with hearing level suggests that NAL-NL2 gains became unsafe when hearing loss > 90 dB HL. The gains prescribed by DSL m[i/o] became unsafe when hearing loss > 80 dB HL at a medium input level, and > 70 dB HL at a high input level. CONCLUSION: There is a risk of damage to hearing for children using nonlinear amplification. Vigilant checking for threshold shift is recommended. PMID- 24350694 TI - Introduction to the longitudinal outcomes of children with hearing impairment (LOCHI) study: background, design, sample characteristics. AB - OBJECTIVE: This article describes the background and the design of the longitudinal outcomes of children with hearing impairment (LOCHI) study, and the characteristics of the study cohort. DESIGN: Children born between 2002 and 2007 who were identified with hearing loss and received audiological intervention by 3 years of age in Australia enrolled in the study. Their demographic characteristics are described. STUDY SAMPLE: Four hundred and fifty-one children in New South Wales, Victoria, and Southern Queensland. RESULTS: Data on age at first hearing-aid fitting for different degrees of hearing loss are reported together with demographic characteristics of the cohort. CONCLUSION: A unique environment in Australia where all children with varied access to universal newborn hearing screening received the same consistent hearing services from a national hearing service provider makes it possible to investigate the effects of access to early auditory intervention on children's outcomes at a population level. PMID- 24350695 TI - A randomized controlled trial of nonlinear frequency compression versus conventional processing in hearing aids: speech and language of children at three years of age. AB - OBJECTIVE: To determine the effect of nonlinear frequency compression (NLFC) on children's development of speech and language at three years of age. DESIGN: A randomized controlled trial was conducted as part of the population-based longitudinal study on outcomes of children with hearing impairment (LOCHI). Participants were randomly assigned to fitting with NLFC (Phonak Naida V SP or UP) or with conventional processing in hearing aids, prescribed by using either the NAL or the DSL formula. Standardized tests of speech production, receptive and expressive language were administered, and parent ratings were collected. All assessments were double-blinded. STUDY SAMPLE: Participants were 44 of the 450 children in the LOCHI cohort. RESULTS: Compared to children using conventional processing, receptive and expressive language was higher but receptive vocabulary and consonant articulation scores were lower for children who use NLFC. There was increased substitution of affricates by fricatives for children using NLFC, compared to children using conventional amplification. After allowing for the effect of multiple demographic variables, the difference in global language scores between groups was not significant (effect: 0.8 [95% confidence interval: 6.7, 8.3]). CONCLUSIONS: There is insufficient evidence to indicate a difference in language ability between children using NLFC and those using conventional amplification. PMID- 24350696 TI - Impact of the presence of auditory neuropathy spectrum disorder (ANSD) on outcomes of children at three years of age. AB - OBJECTIVE: To determine the influence of the presence of auditory neuropathy spectrum disorder (ANSD) on speech, language, and psycho-social development of children at three years of age. DESIGN: A population-based, longitudinal study was performed on outcomes of children with hearing impairment (LOCHI) in Australia. The demographic characteristics of the children were described, and their developmental outcomes were evaluated at three years of age. Performance of children with ANSD was compared with that of children without ANSD in the LOCHI study. STUDY SAMPLE: There were 47 children with ANSD in the study sample. RESULTS: Sixty-four percent of children with ANSD have hearing sensitivity loss ranging from mild to severe degree, and the remaining have profound hearing loss. At three years, 27 children used hearing aids, 19 used cochlear implants, and one child did not use any hearing device. Thirty percent of children have disabilities in addition to hearing loss. On average, there were no significant differences in performance level between children with and without ANSD. Also, the variability of scores was not significantly different between the two groups. CONCLUSIONS: There was no significant difference in performance levels or variability between children with and without ANSD, both for children who use hearing aids, and children who use cochlear implants. PMID- 24350698 TI - Formal carbon insertion of N-tosylhydrazone into B-B and B-Si bonds: gem diborylation and gem-silylborylation of sp3 carbon. AB - A convenient method is developed to synthesize 1,1-diboronates from the corresponding N-tosylhydrazones. This method is also applicable to synthesize 1 silyl-1-boron compounds. Meanwhile, derivatization and consecutive Pd-catalyzed cross-coupling reactions with 1,1-boronates were explored, demonstrating the synthetic potential of 1,1-diboronates. PMID- 24350697 TI - Major findings of the LOCHI study on children at 3 years of age and implications for audiological management. AB - OBJECTIVE: This article describes the major findings of the Longitudinal Outcomes of Children with Hearing Impairment (LOCHI) study. DESIGN: A population-based prospective cohort study; with randomized controlled trials of hearing aid prescription and non-linear frequency compression. SAMPLE: 451 children in New South Wales, Victoria and Southern Queensland. RESULTS: Significant predictors of language outcomes at 3 years of age included severity of hearing loss, gender, presence of additional disabilities, maternal education, and age at cochlear implantation. Although prescription did not have a significant effect on outcomes, its influence on loudness and hearing aid safety has implications for management. After controlling for a range of predictor variables, nonlinear frequency compression did not have a significant effect on outcomes. For the same hearing sensitivity, the presence of auditory neuropathy did not have a significant effect on outcomes. CONCLUSIONS: These findings form the basis for evidence-based guidelines for management of children with hearing loss. PMID- 24350699 TI - Analyses by UPLC Q-TOF MS of products of aflatoxin B(1) after ozone treatment. AB - Analysing the products of ozone-treated aflatoxin B1 (AFB1) is essential in order to study the practical use of ozone treatment. In this paper, the products of AFB1 were investigated using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC Q-TOF MS). The products were well separated using UPLC, and the accurate masses of all the products were determined using Q-TOF MS. Finally, the possible pathways of fragmentation ion generation from the products of AFB1 and the structures of four products were proposed. From the view of the proposed structures of products, the C8-C9 double bond in the terminal furan ring was destroyed. According to the structure-activity relationship, the toxicity of products was significantly reduced compared with that of AFB1. The result indicated that ozone was an effective agent for degrading AFB1, and UPLC Q-TOF MS was a useful analytical tool for proposing and identifying a series of unknown products. PMID- 24350700 TI - Bilirubin is an independent factor inversely associated with glycated hemoglobin level in pediatric patients with type 1 diabetes. AB - OBJECTIVE: Bilirubin is a potent antioxidant, and serum total bilirubin (STB) concentrations correlate negatively with cardiovascular risk. In adult diabetic patients and in healthy adults, a negative correlation between STB and glycated hemoglobin (HbA1c) has been reported. We investigated whether there is such an association in children and adolescents with type 1 diabetes mellitus. METHODS: The study group included 224 patients with type 1 diabetes duration of more than 12 months. Patients with suspected or confirmed hemolytic anemia or liver dysfunction were excluded. RESULTS: A statistically significant negative correlation was found between STB and HbA1c (R = -0.15; p = 0.024), which retained its significance in multivariate analysis (beta = -0.18, p = 0.005). Patients' age and daily insulin dose were positively correlated with HbA1c levels, whereas other variables included in the multivariate analysis [sex, diabetes duration, insulin regimen, C-peptide, hemoglobin, mean corpuscular hemoglobin concentration (MCHC), alanine transaminase (ALT), and aspartate transaminase (AST)] did not correlate with HbA1c. The mean HbA1c level in patients with STB >1.2 mg/dL (>21 umol/L; the threshold for clinical diagnosis of Gilbert's syndrome) was lower than in patients with STB <=1.2 mg/dL (<=21 umol/L), and the mean difference was 0.63% (6.9 mmol/mol; 95% CI: 0.11-1.16%). CONCLUSIONS: These results show that in young patients with type 1 diabetes, STB concentration is an independent factor inversely associated with HbA1c level. Further studies should investigate the background and long-term effects of this association. PMID- 24350701 TI - Biomimetic nitration of conjugated linoleic acid: formation and characterization of naturally occurring conjugated nitrodienes. AB - Nitro-conjugated linoleic acids (NO2-cLA), endogenous nitrodiene lipids which act as inflammatory signaling mediators, were isolated and single isomers purified from the biomimetic acidic nitration products of conjugated linoleic acid (CLA). Structures were elucidated by means of detailed NMR and HPLC-MS/MS spectroscopic analysis and the relative double bond configurations assigned. Additional synthetic methods produced useful quantities and similar isomeric distributions of these unusual and reactive compounds for biological studies and isotopic standards, and the potential conversion of nitro-linoleic to nitro-conjugated linoleic acids was explored via a facile base-catalyzed isomerization. This represents one of the few descriptions of naturally occurring conjugated nitro dienes (in particular, 1-nitro 1,3-diene), an unusual and highly reactive motif with few biological examples extant. PMID- 24350702 TI - New stable QTLs for berry weight do not colocalize with QTLs for seed traits in cultivated grapevine (Vitis vinifera L.). AB - BACKGROUND: In grapevine, as in other fruit crops, fruit size and seed content are key components of yield and quality; however, very few Quantitative Trait Loci (QTLs) for berry weight and seed content (number, weight, and dry matter percentage) have been discovered so far. To identify new stable QTLs for marker assisted selection and candidate gene identification, we performed simultaneous QTL detection in four mapping populations (seeded or seedless) with various genetic backgrounds. RESULTS: For berry weight, we identified five new QTLs, on linkage groups (LGs) 1, 8, 11, 17 and 18, in addition to the known major QTL on LG 18. The QTL with the largest effect explained up to 31% of total variance and was found in two genetically distant populations on LG 17, where it colocalized with a published putative domestication locus. For seed traits, besides the major QTLs on LG 18 previously reported, we found four new QTLs explaining up to 51% of total variance, on LGs 4, 5, 12 and 14. The previously published QTL for seed number on LG 2 was found related in fact to sex. We found colocalizations between seed and berry weight QTLs only for the major QTL on LG 18 in a seedless background, and on LGs 1 and 13 in a seeded background. Candidate genes belonging to the cell number regulator CNR or cytochrome P450 families were found under the berry weight QTLs on LGs 1, 8, and 17. The involvement of these gene families in fruit weight was first described in tomato using a QTL-cloning approach. Several other interesting candidate genes related to cell wall modifications, water import, auxin and ethylene signalling, transcription control, or organ identity were also found under berry weight QTLs. CONCLUSION: We discovered a total of nine new QTLs for berry weight or seed traits in grapevine, thereby increasing more than twofold the number of reliable QTLs for these traits available for marker assisted selection or candidate gene studies. The lack of colocalization between berry and seed QTLs suggests that these traits may be partly dissociated. PMID- 24350704 TI - Breastfeeding infants with phenylketonuria in the United States and Canada. AB - OBJECTIVE: This study described the prevalence and duration of mothers' breastfeeding infants with phenylketonuria (PKU) and explored factors related to duration of breastfeeding as a surrogate for breastfeeding success. SUBJECTS AND METHODS: Descriptive analysis as performed from an international Internet survey of mothers (n=103) who met the inclusion criteria: (1) at least 21 years of age, (2) able to read and write in English, (3) child with PKU, and (4) living in the United States or Canada. RESULTS: Of the 103 mothers, 89 (86%) initiated breastfeeding immediately following delivery, whereas 14 (14%) chose bottle feeding. In comparison to breastfeeding after delivery, significantly fewer mothers breastfed after diagnosis (McNemar's chi(2)=30.33, p<0.001; n=72 vs. n=89). Breastfeeding duration ranged from less than 1 month to 24 months with one modal duration category (n=20, 22%) at less than 1 month. The timing of the addition of commercial infant formula to supplement breastfeeding or expressed mothers' milk was associated with a shorter duration of breastfeeding among infants with PKU: chi(2) (42, n=73)=88.13, p<0.001. CONCLUSIONS: PKU is treated with phenylalanine (Phe) restriction. Breastfeeding infants with PKU is challenging in part because Phe intake is difficult to determine precisely. We studied breastfeeding duration in infants with PKU and factors associated with success. Further research should identify the unique needs of mothers' breastfeeding infants with PKU to guide the development of interventions specific to these mothers to support their efforts to continue breastfeeding after the diagnosis of PKU. PMID- 24350711 TI - Photodamage and the importance of photoprotection in biomolecular-powered device applications. AB - In recent years, an enhanced understanding of the mechanisms underlying photobleaching and photoblinking of fluorescent dyes has led to improved photoprotection strategies, such as reducing and oxidizing systems (ROXS) that reduce blinking and oxygen scavenging systems to reduce bleaching. Excitation of fluorescent dyes can also result in damage to catalytic proteins (e.g., biomolecular motors), affecting the performance of integrated devices. Here, we characterized the motility of microtubules driven by kinesin motor proteins using various photoprotection strategies, including a microfluidic deoxygenation device. Impaired motility of microtubules was observed at high excitation intensities in the absence of photoprotection as well as in the presence of an enzymatic oxygen scavenging system. In contrast, using a polydimethylsiloxane (PDMS) microfluidic deoxygenation device and ROXS, not only were the fluorophores slower to bleach but also moving the velocity and fraction of microtubules over time remained unaffected even at high excitation intensities. Further, we demonstrate the importance of photoprotection by examining the effect of photodamage on the behavior of a switchable mutant of kinesin. Overall, these results demonstrate that improved photoprotection strategies may have a profound impact on functional fluorescently labeled biomolecules in integrated devices. PMID- 24350703 TI - Taste of milk from inflamed breasts of breastfeeding mothers with mastitis evaluated using a taste sensor. AB - BACKGROUND: The refusal of infants to suckle from a breast that is inflamed with mastitis suggests that the taste of the milk has changed. However, the taste of milk from a breast with mastitis has never been empirically determined. The present study compares the taste of milk from breastfeeding mothers with or without mastitis and identifies specific changes in the taste of milk from mothers with mastitis. SUBJECTS AND METHODS: The intensity of four basic tastes (sourness, saltiness, bitterness, and umami) of breastmilk from 24 healthy mothers at 3-5 days and at 2-3, 4-5, and 8-10 weeks postpartum and from 14 mothers with mastitis was determined objectively using a taste sensor. The intensity of each basic taste and the concentrations of main taste substances in milk were compared between the inflamed breasts and the normal breasts of control mothers or the contralateral asymptomatic breast of mothers with unilateral mastitis. RESULTS: The transition from colostrum to mature milk was accompanied by changes in the taste of the milk, such as decreased saltiness and umami and increased bitterness and sourness. Umami and saltiness increased in milk from inflamed breasts. Contents of sodium, glutamate, and guanosine monophosphate increased in milk from inflamed breasts. CONCLUSIONS: Tastes that were specifically associated with inflamed breasts appeared to include an increase in umami and saltiness, which might have resulted from an increased content in factors associated with umami and sodium. PMID- 24350712 TI - Human cytochrome P450 oxidation of 5-hydroxythalidomide and pomalidomide, an amino analogue of thalidomide. AB - The sedative and antiemetic drug thalidomide [alpha-(N-phthalimido)glutarimide] was withdrawn in the early 1960s because of its potent teratogenic effects but was approved for the treatment of lesions associated with leprosy in 1998 and multiple myeloma in 2006. The mechanism of teratogenicity of thalidomide still remains unclear, but it is well-established that metabolism of thalidomide is important for both teratogenicity and cancer treatment outcome. Thalidomide is oxidized by various cytochrome P450 (P450) enzymes, the major one being P450 2C19, to 5-hydroxy-, 5'-hydroxy-, and dihydroxythalidomide. We previously reported that P450 3A4 oxidizes thalidomide to the 5-hydroxy and dihydroxy metabolites, with the second oxidation step involving a reactive intermediate, possibly an arene oxide, that can be trapped by glutathione (GSH) to GSH adducts. We now show that the dihydroxythalidomide metabolite can be further oxidized to a quinone intermediate. Human P450s 2J2, 2C18, and 4A11 were also found to oxidize 5-hydroxythalidomide to dihydroxy products. Unlike P450s 2C19 and 3A4, neither P450 2J2, 2C18, nor 4A11 oxidized thalidomide itself. A recently approved amino analogue of thalidomide, pomalidomide (CC-4047, Actimid), was also oxidized by human liver microsomes and P450s 2C19, 3A4, and 2J2 to the corresponding phthalimide ring-hydroxylated product. PMID- 24350713 TI - The fibrotic microenvironment as a heterogeneity facet of hepatocellular carcinoma. AB - It has long been recognized that hepatocellular carcinoma heterogeneity arises from variation in the microenvironment or from genomic alteration. Only recently it has become clear that non-genetic alterations, such as cytoskeletal rearrangement, protein localization and formation of protein complexes, are also involved in generating phenotype variability. These proteome fluctuations cause genetically identical cells to vary significantly in their responsiveness to microenvironment stimuli. In the cirrhotic liver pre-malignant hepatocytes are continuously exposed to abnormal microenvironments, such as direct contact with activated hepatic stellate cells (HSCs) and extracellular matrix components. These abnormal environments can have pronounced influences on the epigenetic aspects of cells, translating into abnormal phenotypes. Here we discuss non genetic causes of phenotypic heterogeneity of hepatocellular carcinoma, with an emphasis on variability of membrane protein complexes and transferred functions raising important implications for diagnosis and treatment. PMID- 24350716 TI - A new approach for the automatic evaluation of the solidification structure in steel using orientational entropy filtering. AB - We present a new method for the automatic evaluation of the dendritic solidification structure in metallurgical micrographs of solidified steel. The evaluation of the microstructural parameters such as the primary dendrite arm spacing and the primary grain size are of high importance due to their direct relationship with the internal quality and mechanical properties of the cast product. Given the repeated geometric features in the micrographs and the regular pattern in colour intensity, we applied a filter mask to determine the local entropies within the masks in order to detect the centre coordinates of each individual dendrite. The orientation of the dendrites was determined by rotating the filter mask over each pixel to find the orientation which corresponds to the lowest entropy value. The segmentation of the microstructure was then performed via Delaunay tessellation and subsequent transformation of the triangular mesh into a rectangular grid, enabling the determination of the desired microstructural parameters. PMID- 24350717 TI - Fast forward selection for generalized estimating equations with a large number of predictor variables. AB - We propose a new variable selection criterion designed for use with forward selection algorithms; the score information criterion (SIC). The proposed criterion is based on score statistics which incorporate correlated response data. The main advantage of the SIC is that it is much faster to compute than existing model selection criteria when the number of predictor variables added to a model is large, this is because SIC can be computed for all candidate models without actually fitting them. A second advantage is that it incorporates the correlation between variables into its quasi-likelihood, leading to more desirable properties than competing selection criteria. Consistency and prediction properties are shown for the SIC. We conduct simulation studies to evaluate the selection and prediction performances, and compare these, as well as computational times, with some well-known variable selection criteria. We apply the SIC on a real data set collected on arthropods by considering variable selection on a large number of interactions terms consisting of species traits and environmental covariates. PMID- 24350715 TI - Verrucous carcinoma of the head and neck - not a human papillomavirus-related tumour? AB - Association between verrucous carcinoma (VC) of the head and neck and human papillomaviruses (HPV) is highly controversial. Previous prevalence studies focused mostly on alpha-PV, while little is known about other PV genera. Our aim was to investigate the prevalence of a broad spectrum of HPV in VC of the head and neck using sensitive and specific molecular assays. Formalin-fixed, paraffin embedded samples of 30 VC and 30 location-matched normal tissue samples were analysed, by using six different polymerase chain reaction-based methods targeting DNA of at least 87 HPV types from alpha-PV, beta-PV, gamma-PV and MU-PV genera, and immunohistochemistry against p16 protein. alpha-PV, gamma-PV and MU PV were not detected. beta-PV DNA was detected in 5/30 VC (16.7%) and in 18/30 normal tissue samples (60.0%): HPV-19, -24 and -36 were identified in VC, and HPV 5, -9, -12, -23, -24, -38, -47, -49 and -96 in normal tissue, whereas HPV type was not determined in 2/5 cases of VC and in 6/18 normal tissue samples. p16 expression was detected in a subset of samples and was higher in VC than in normal tissue. However, the reaction was predominantly cytoplasmic and only occasionally nuclear, and the extent of staining did not exceed 75%. Our results indicate that alpha-PV, gamma-PV and MU-PV are not associated with aetiopathogenesis of VC of the head and neck. beta-PV DNA in a subset of VC and normal tissue might reflect incidental colonization, but its potential biological significance needs further investigation. PMID- 24350718 TI - Balancing novelty with confined chemical space in modern drug discovery. AB - INTRODUCTION: The concept of chemical space has broad applications in drug discovery. In response to the needs of drug discovery campaigns, different approaches are followed to efficiently populate, mine and select relevant chemical spaces that overlap with biologically relevant chemical spaces. AREAS COVERED: This paper reviews major trends in current drug discovery and their impact on the mining and population of chemical space. We also survey different approaches to develop screening libraries with confined chemical spaces balancing physicochemical properties. In this context, the confinement is guided by criteria that can be divided in two broad categories: i) library design focused on a relevant therapeutic target or disease and ii) library design focused on the chemistry or a desired molecular function. EXPERT OPINION: The design and development of chemical libraries should be associated with the specific purpose of the library and the project goals. The high complexity of drug discovery and the inherent imperfection of individual experimental and computational technologies prompt the integration of complementary library design and screening approaches to expedite the identification of new and better drugs. Library design approaches including diversity-oriented synthesis, biological-oriented synthesis or combinatorial library design, to name a few, and the design of focused libraries driven by target/disease, chemical structure or molecular function are more efficient if they are guided by multi-parameter optimization. In this context, consideration of pharmaceutically relevant properties is essential for balancing novelty with chemical space in drug discovery. PMID- 24350719 TI - Isolation of two different Ni2Zn complexes with an unprecedented cocrystal formed by one of them and a "coordination positional isomer" of the other. AB - A new homometallic trinuclear Ni(II) complex [(NiL)2Ni(NCS)2] (1) and three heterometallic trinuclear Ni(II)-Zn(II)-Ni(II) complexes [(NiL)2Zn(NCS)2] (2), [(NiL)2Zn(NCS)2(CH3OH)2].2CH3OH (3) and {[(NiL)2Zn(NCS)2(CH3OH)2]} {[(NiL)2Zn(NCS)2]} (4) have been synthesized by using the "complex as ligand" approach with the "metalloligand" [NiL] (H2L = N,N'-bis(salicylidene)-1,3 propanediamine) and thiocyanate in different ratios. All the complexes have been structurally and magnetically characterized. In the isomorphous complexes 1 and 2, the two terminal square planar Ni atoms and the central octahedral nickel atom (in 1) or zinc atom (in 2) are arranged in a bent structure where two cis kappaN SCN(-) thiocyanate ions are coordinated to the central atom. The chemical composition of 3 is very similar to that of 2 but, in 3, the central Zn atom is tetrahedral and the kappaN-SCN(-) thiocyanate ions occupy an axial position of each terminal nickel atom (which now are octahedral with the sixth position occupied by a methanol molecule). Complex 4 consists of two closely related trinuclear units 4A and 4B. In 4A, the coordination environments of the metals are identical to those of 3 whereas 4B is a "coordination position isomer" of complex 2 with the central square pyramidal Zn and one of the terminal square pyramidal Ni atoms coordinated by two kappaN-SCN(-) thiocyanate ions. Complex 4 is a unique example of a cocrystal formed by two similar trinuclear units (4A and 4B) where 4A is identical to an existing complex (3) and 4B is a "coordination position isomer" of another existing complex (2). PMID- 24350721 TI - Cancer inflammation and inflammatory biomarkers: can neutrophil, lymphocyte, and platelet counts represent the complexity of the immune system? PMID- 24350714 TI - High protein intake is associated with low prevalence of frailty among old Japanese women: a multicenter cross-sectional study. AB - BACKGROUND: Protein intake has been inversely associated with frailty. However, no study has examined the effect of the difference of protein sources (animal or plant) or the amino acid composing the protein on frailty. Therefore, we examined the association of protein and amino acid intakes with frailty among elderly Japanese women. METHODS: A total of 2108 grandmothers or acquaintances of dietetic students aged 65 years and older participated in this cross-sectional multicenter study, which was conducted in 85 dietetic schools in 35 prefectures of Japan. Intakes of total, animal, and plant protein and eight selected amino acids were estimated from a validated brief-type self-administered diet history questionnaire and amino acid composition database. Frailty was defined as the presence of three or more of the following four components: slowness and weakness (two points), exhaustion, low physical activity, and unintentional weight loss. RESULTS: The number of subjects with frailty was 481 (23%). Adjusted ORs (95% CI) for frailty in the first, second, third, fourth, and fifth quintiles of total protein intake were 1.00 (reference), 1.02 (0.72, 1.45), 0.64 (0.45, 0.93), 0.62 (0.43, 0.90), and 0.66 (0.46, 0.96), respectively (P for trend = 0.001). Subjects categorized to the third, fourth, and fifth quintiles of total protein intake (>69.8 g/d) showed significantly lower ORs than those to the first quintile (all P <0.03). The intakes of animal and plant protein and all selected amino acids were also inversely associated with frailty (P for trend <0.04), with the multivariate adjusted OR in the highest compared to the lowest quintile of 0.73 for animal protein and 0.66 for plant protein, and 0.67-0.74 for amino acids, albeit that the ORs for these dietary variables were less marked than those for total protein. CONCLUSIONS: Total protein intake was significantly inversely associated with frailty in elderly Japanese women. The association of total protein with frailty may be observed regardless of the source of protein and the amino acid composing the protein. PMID- 24350722 TI - The rate of charge tunneling is insensitive to polar terminal groups in self assembled monolayers in Ag(TS)S(CH2)(n)M(CH2)(m)T//Ga2O3/EGaIn junctions. AB - This paper describes a physical-organic study of the effect of uncharged, polar, functional groups on the rate of charge transport by tunneling across self assembled monolayer (SAM)-based large-area junctions of the form Ag(TS)S(CH2)(n)M(CH2)(m)T//Ga2O3/EGaIn. Here Ag(TS) is a template-stripped silver substrate, -M- and -T are "middle" and "terminal" functional groups, and EGaIn is eutectic gallium-indium alloy. Twelve uncharged polar groups (-T = CN, CO2CH3, CF3, OCH3, N(CH3)2, CON(CH3)2, SCH3, SO2CH3, Br, P(O)(OEt)2, NHCOCH3, OSi(OCH3)3), having permanent dipole moments in the range 0.5 < MU < 4.5, were incorporated into the SAM. A comparison of the electrical characteristics of these junctions with those of junctions formed from n-alkanethiolates led to the conclusion that the rates of charge tunneling are insensitive to the replacement of terminal alkyl groups with the terminal polar groups in this set. The current densities measured in this work suggest that the tunneling decay parameter and injection current for SAMs terminated in nonpolar n-alkyl groups, and polar groups selected from common polar organic groups, are statistically indistinguishable. PMID- 24350723 TI - Web-based participatory surveillance of infectious diseases: the Influenzanet participatory surveillance experience. AB - To overcome the limitations of the state-of-the-art influenza surveillance systems in Europe, we established in 2008 a European-wide consortium aimed at introducing an innovative information and communication technology approach for a web-based surveillance system across different European countries, called Influenzanet. The system, based on earlier efforts in The Netherlands and Portugal, works with the participation of the population in each country to collect real-time information on the distribution of influenza-like illness cases through web surveys administered to volunteers reporting their symptoms (or lack of symptoms) every week during the influenza season. Such a large European-wide web-based monitoring infrastructure is intended to rapidly identify public health emergencies, contribute to understanding global trends, inform data-driven forecast models to assess the impact on the population, optimize the allocation of resources, and help in devising mitigation and containment measures. In this article, we describe the scientific and technological issues faced during the development and deployment of a flexible and readily deployable web tool capable of coping with the requirements of different countries for data collection, during either a public health emergency or an ordinary influenza season. Even though the system is based on previous successful experience, the implementation in each new country represented a separate scientific challenge. Only after more than 5 years of development are the existing platforms based on a plug-and-play tool that can be promptly deployed in any country wishing to be part of the Influenzanet network, now composed of The Netherlands, Belgium, Portugal, Italy, the UK, France, Sweden, Spain, Ireland, and Denmark. PMID- 24350725 TI - SLC19A1 80G allele as a biomarker of methotrexate-related gastrointestinal toxicity in Portuguese rheumatoid arthritis patients. AB - AIM: The aim of our study was to characterize the association of clinicopathological variables and the SLC19A1/RFC-1 G80A polymorphism in methotrexate (MTX)-related toxicity in Portuguese patients with rheumatoid arthritis. PATIENTS & METHODS: The study included 233 consecutively recruited patients with rheumatoid arthritis under MTX treatment. The SLC19A1 G80A polymorphism was evaluated by PCR-RFLP. RESULTS: Statistical analysis revealed that SLC19A1 80G carriers had increased risk of gastrointestinal toxicity (odds ratio [OR]: 2.61, p = 0.019) and that regular folic acid supplementation was associated with both overall and gastrointestinal toxicity protection (OR: 0.15, p < 0.001 and OR: 0.19, p < 0.001, respectively). Multivariate analysis confirmed the association of SLC19A1 80G and regular folic acid supplementation to gastrointestinal toxicity (OR: 5.53 and 0.13, respectively). Moreover, a multivariate Cox regression model demonstrated a higher risk of earlier gastrointestinal toxicity in SLC19A1 80G carriers (hazard ratio: 3.63, p = 0.002). CONCLUSION: SLC19A1 G80A genotyping may be a useful tool for clinicians to identify patients at higher risk for developing gastrointestinal toxicity related to MTX treatment. PMID- 24350726 TI - Modulation of bone morphogenic protein signaling in T-cells for cancer immunotherapy. AB - Immunotherapy is becoming an increasingly attractive therapeutic alternative for conventional cancer therapy. In recent years Foxp3(+) regulatory T-cells (T(R)) were identified as the major obstacle to effective cancer immunotherapy. The abundance of these cells in peripheral blood is increased in patients with multiple types of cancer and their prevalence among tumor-infiltrating lymphocytes correlated with poor clinical prognosis. In contrast, removal or inactivation of T(R) cells led to enhanced anti-tumor immune response and better efficacy of cancer vaccines. This study reports that Bone Morphogenic Protein Receptor 1alpha (BMPR1alpha, Alk-3) is expressed by activated effector CD4(+) and T(R) cells and modulates functions of both cell types. Bone Morphogenic Proteins (BMPs) belong to the transforming growth factor (TGF)-beta family of cytokines that also include TGFbeta and activins. BMPs play crucial roles in embryonic development, tissue differentiation and homeostasis, and development of cancer. It was demonstrated that BMPs and activins synergize with TGFbeta to regulate thymic T-cell development, maintain T(R) cells, and control peripheral tolerance. Inactivation of BMPR1alpha in T-cells results in impaired thymic and peripheral generation of T(R) cells. BMPR1alpha-deficient activated T-cells produced a higher level of interferon (IFN)-gamma than BMPR1alpha-sufficient T-cells. Moreover, transplanted B16 melanoma tumors grew smaller in mice lacking expression of BMPR1alpha in T-cells and tumors had few infiltrating TR cells and a higher proportion of CD8(+) T-cells than wild-type mice. PMID- 24350727 TI - Hepatic effects of aminoglutethimide: a model aromatic amine. AB - Primary aromatic amine drugs are structural alerts in drug development because of their association with a high incidence of idiosyncratic drug reactions (IDRs). If biomarkers could be found that predict IDR risk, it would have a major impact on drug development. Previous attempts to do this through screening of hepatic gene expression profiles in rodents treated with aromatic amine drugs found limited changes. Of the drugs studied, aminoglutethimide (AMG) induced the most changes, and this led to a more comprehensive study of its effects on the liver. Brown Norway rats treated with AMG for up to 14 days showed only a transient elevation of glutamate dehydrogenase. Pathway-specific PCR arrays found few AMG induced gene changes associated with an immune response and, of these changes, the majority were involved with innate immunity such as Tlr2, Ticam2, CD14, and C3. AMG treatment also led to significant changes in the apoptosis and mitochondrial panel of genes. It was recently found that AMG does induce significant changes in the bone marrow of rats, and agranulocytosis is a common IDR caused by AMG. In contrast, liver injury is not a common IDR associated with AMG. Therefore, the liver may be able to effectively deal with AMG reactive metabolites, and changes observed in this study may be involved in adaptation. Myeloperoxidase is also known to be able to oxidize aromatic amines to reactive metabolites, and these observations suggest that metabolism outside of the liver may be important for the mechanism of aromatic amine-induced IDRs. PMID- 24350729 TI - Tandem C-2 functionalization-intramolecular azide-alkyne 1,3-dipolar cycloaddition reaction: a convenient route to highly diversified 9H benzo[b]pyrrolo[1,2-g][1,2,3]triazolo[1,5-d][1,4]diazepines. AB - An efficient diversity-oriented synthetic approach to annulated 9H benzo[b]pyrrolo[1,2-g][1,2,3]triazolo[1,5-d][1,4]diazepines has been developed using a Sc(OTf)3-catalyzed two-component tandem C-2 functionalization intramolecular azide-alkyne 1,3-dipolar cycloaddition reaction. The reaction shows high substrate tolerance and provides a library of fused heterocycles that may lead to novel biologically active compounds or drug lead molecules. PMID- 24350728 TI - Study protocol to examine the effects of spaceflight and a spaceflight analog on neurocognitive performance: extent, longevity, and neural bases. AB - BACKGROUND: Long duration spaceflight (i.e., 22 days or longer) has been associated with changes in sensorimotor systems, resulting in difficulties that astronauts experience with posture control, locomotion, and manual control. The microgravity environment is an important causal factor for spaceflight induced sensorimotor changes. Whether spaceflight also affects other central nervous system functions such as cognition is yet largely unknown, but of importance in consideration of the health and performance of crewmembers both in- and post flight. We are therefore conducting a controlled prospective longitudinal study to investigate the effects of spaceflight on the extent, longevity and neural bases of sensorimotor and cognitive performance changes. Here we present the protocol of our study. METHODS/DESIGN: This study includes three groups (astronauts, bed rest subjects, ground-based control subjects) for which each the design is single group with repeated measures. The effects of spaceflight on the brain will be investigated in astronauts who will be assessed at two time points pre-, at three time points during-, and at four time points following a spaceflight mission of six months. To parse out the effect of microgravity from the overall effects of spaceflight, we investigate the effects of seventy days head-down tilted bed rest. Bed rest subjects will be assessed at two time points before-, two time points during-, and three time points post-bed rest. A third group of ground based controls will be measured at four time points to assess reliability of our measures over time. For all participants and at all time points, except in flight, measures of neurocognitive performance, fine motor control, gait, balance, structural MRI (T1, DTI), task fMRI, and functional connectivity MRI will be obtained. In flight, astronauts will complete some of the tasks that they complete pre- and post flight, including tasks measuring spatial working memory, sensorimotor adaptation, and fine motor performance. Potential changes over time and associations between cognition, motor-behavior, and brain structure and function will be analyzed. DISCUSSION: This study explores how spaceflight induced brain changes impact functional performance. This understanding could aid in the design of targeted countermeasures to mitigate the negative effects of long-duration spaceflight. PMID- 24350730 TI - Antioxidant and antiapoptotic effects of 1,1'-(biphenyl-4,4'-diyl)-bis(3 (dimethylamino)-propan-1-one) on protecting PC12 cells from Abeta-induced injury. AB - Abnormal extracellular deposition of beta-amyloid (Abeta) is thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Preventing Abeta induced neurotoxicity has become a potential therapeutic approach to improve the onset and progression of AD. Here we report the synthesis of 1,1'-(biphenyl-4,4' diyl)-bis(3-(dimethylamino)-propan-1-one) (BDBDP) and evaluate whether it protects PC12 cells from Abeta1-42-induced cytotoxicity in PC12 cells. Treating cells with Abeta1-42 significantly reduced cell viability and mitochondrial membrane potential while also significantly increasing apoptosis and production of reactive oxygen species (ROS). Pretreating the cells with BDBDP significantly ameloriated these Abeta1-42-induced effects. Futhermore, BDBDP strongly reduced pro-apoptotic signaling in response to ROS by reducing levels of activated caspase-3 and increasing the ratio of Bcl-2 to Bax. These findings provide evidence that BDBDP protects against Abeta1-42-induced neurotoxicity in PC12 cells by inhibiting oxidative stress and cell apoptosis. PMID- 24350732 TI - Teaming up: feasibility of an online treatment environment for adolescents with type 1 diabetes. AB - OBJECTIVE: To evaluate the feasibility of an online interactive treatment environment for adolescents with type 1 diabetes, called Sugarsquare, to supplement usual care. RESEARCH DESIGN AND METHODS: Sugarsquare provides easily accessible contact with the diabetes team, peer support, and treatment overview. Of 120 eligible patients, 62 adolescents aged 11-21 (M = 15.23, SD = 2.00) were assigned to a usual-care group (n = 31) or a usual-care + intervention group (n = 31). Feasibility was assessed in terms of acceptability, demand, practicability, integration, and efficacy in a 9-month study-period. RESULTS: Assessment of acceptability and demand revealed that 20 adolescents in the intervention group (65%) logged in at least once; 16 adolescents (52%) logged in repeatedly. Usage resulted in 5795 page-views, 3580 chat-messages, 427 forum-messages, and in 40 private interactions between 11 adolescents (35%) and professionals. Assessment of practicability revealed that all 13 professionals (100%) accessed the intervention. Slow processing speed and security procedures formed obstacles for usage. Assessment of integration showed that international standards for diabetes care (International Diabetes Federation/International Society for Pediatric and Adolescent Diabetes/American Diabetes Association) were met. Assessment of efficacy revealed improvement in the intervention group in evaluation of care (Patients' Evaluation of Quality of Diabetes), F(1,30) = 5.35, p < 0.05, and quality of life, communication (PedsQL), F(1,30) = 11.65, p <0.05. The latter was correlated with posted chat-messages (r = 0.42, p < 0.05). No between-group differences were found. CONCLUSIONS: This study shows that Sugarsquare is feasible in adolescents with type 1 diabetes. It meets a demand in adolescents and can support professionals when organizing on-going care according to international standards. Results are promising and next steps are a full-scale randomized controlled trial and subsequent implementation in daily care. PMID- 24350731 TI - The issue of mandatory vaccination for healthcare workers in Europe. AB - Mandatory policies have occasionally been implemented, targeting optimal vaccination uptake among healthcare workers (HCWs). Herein, we analyze the existing recommendations in European countries and discuss the feasibility of implementing mandatory vaccination for HCWs. As reflected by a survey among vaccine experts from 29 European countries, guidelines on HCW vaccination were issued in all countries, though with substantial differences in targeted diseases, HCW groups and type of recommendation. Mandatory policies were only exceptionally implemented. Results from a second survey suggested that such policies would not become easily adopted, and recommendations might work better if focusing on specific HCW groups and appropriate diseases such as hepatitis B, influenza and measles. In conclusion, guidelines for HCW vaccination, but not mandatory policies, are widely adopted in Europe. Recommendations targeting specific HCW groups and diseases might be better accepted and facilitate higher vaccine uptake than policies vaguely targeting all HCW groups. PMID- 24350733 TI - Review of radiation therapy services for neurofibromatosis (NF2) patients in England. AB - OBJECTIVE: It is widely accepted that stereotactic radiosurgery (SRS) is less effective in controlling NF2-related vestibular schwannomas (VS-NF2), than sporadic VS. Concerns persist regarding the risks of malignant transformation and the development of secondary tumours. In recent years there has been an increase in the number of centres offering SRS and fractionated stereotactic radiotherapy (SRT) services for VS. The NF2 National Commissioning Group service framework has recommended limiting radiation therapies for VS-NF2 to SRS (Gamma Knife) provided in Sheffield. The aims of this review were to: 1) Establish the current provision of SRT and SRS services in England. 2) Determine the radiation therapies employed for NF2 patients since 2000. 3) Determine the feasibility of identifying a national cohort of NF2 patients in England who have received radiation therapy since 2000. METHODS: The lead clinicians managing VS patients in the major regional neurosurgical units in England, and those providing SRS services to NF2 patients were contacted and when possible, databases were examined. RESULTS: A total of 18 NHS centres and 2 private centres were included. This included the four NF2 'hub centres' (Cambridge, London, Oxford and Manchester). Their NF2 databases identified 4, 8, 23 and 42 VS-NF2 treatments with SRS or SRT, respectively since 2000. Eleven centres reported that they had referred VS-NF2 patients exclusively to Sheffield. Each estimated that they had referred no more than one patient per year. The survey identified four Gamma Knife Centres and six Linac SRS/SRT centres with the capacity to treat VS and VS-NF2 patients. Of these, four centres confirmed that they had treated VS-NF2 patients. CONCLUSION: Since 2000 fewer than 100 SRS and SRT treatments have been undertaken for VS-NF2 patients. Approximately 60% of these have been performed in Sheffield. There is considerable uncertainty regarding the role of radiation therapy in the management of VS-NF2 and consequently a range of views and practice. PMID- 24350734 TI - Diffuse cerebral vasospasm following resection of a hypoglossal schwannoma in a child. AB - Diffuse cerebral vasospasm is a rare complication following tumour resection. This phenomenon seems to be even rarer in the paediatric population and more so following resections of posterior fossa tumours. Here we report diffuse cerebral vasospasm in a child with hypoglossal nerve Schwannoma eight days following resection of the tumour. PMID- 24350735 TI - Fat necrosis appearing as intraorbital tumour: case report. AB - A 33-year-old male presented with an extremely rare case of intraorbital fat necrosis. A magnetic resonance imaging scan showed a 10-mm mass lesion within the right lateral rectal muscle. Surgical removal was performed. Histological analysis showed diffuse adipose cells surrounded by macrophage cells. Fat necrosis was diagnosed. PMID- 24350736 TI - Microsurgical treatment assisted by intraoperative ultrasound localization: a controlled trial in patients with hypertensive basal ganglia hemorrhage. AB - This study investigated the clinical value of performing microsurgical treatment on hypertensive basal ganglia hemorrhage assisted by intraoperative ultrasound localization (IUL). A total of 107 patients with hypertensive basal ganglia hemorrhage were randomly separated into two groups for this controlled clinical trial. In the IUL group, 51 patients with hypertensive basal ganglia hemorrhage were operated on with the support of ultrasonic imaging; 56 patients underwent conventional microsurgery to evacuate the hemorrhage. The results of the two methods were evaluated according to the rate of hematoma evacuation, re hemorrhage, mortality, complications, and activities of daily living (ADL). A greater quantity of the hemorrhage was removed from patients in the IUL group, with over 90% of masses being eliminated from the brain in 78.43% of these patients (40 out of 51 patients) compared with 60.71% of patients in the control group (34 out of 56 patients). The IUL group experienced a lower rate of re hemorrhage after the operation (7.84%, 4 out of 51 patients) compared with the control group (17.86%, 10 out of 56 patients). A significant difference in the ADL score was recorded between the two groups, with ADL scores of the IUL group exceeding 60 (indicating good recovery) at 6 months after the operative procedure (P < 0.05). In conclusion, the microsurgical treatment of hypertensive basal ganglia hemorrhage assisted by IUL improved the precision of the operation. This procedure removed the hemorrhage and reduced the changes of re-occurrence, as well as elevated the quality of life of patients after the operation. PMID- 24350737 TI - Analysis of antimicrobial resistance genes in Aeromonas spp. isolated from cultured freshwater animals in China. AB - The development of resistance to antimicrobials used in aquatic animals is an increasing concern for aquaculture and public health. To monitor the occurrence of antimicrobial resistance and resistance genes in Aeromonas, a total of 106 isolates were collected from cultured freshwater animals in China from 1995 to 2012. Antimicrobial susceptibilities were determined by the disk diffusion method. The highest resistance percentage occurred with ampicillin, rifampin, streptomycin, and nalidixic acid. Most strains were sensitive to fluoroquinolones, doxycycline, cefotaxime, chloramphenicol, and amikacin. The isolates from turtle samples had the highest levels of resistance to 11 of the 12 tested antimicrobials when compared with those from fish or shrimp. Polymerase chain reaction and DNA sequence results showed that all trimethoprim/sulfamethoxazole-resistant strains contained sul1, and 37.0% were positive for tetA in tetracycline-resistant strains. ant(3")-Ia was identified in 13 (24.5%) streptomycin-resistant strains. Plasmid-borne quinolone resistance genes were detected in five Aeromonas hydrophila (4.7%), two of which carried qnrS2, while the other three strains harbored aac(6')-Ib-cr. Two cefotaxime resistant A. hydrophila were positive for bla(TEM-1) and bla(CTX-M-3). To our knowledge, this is the first report characterizing antimicrobial resistance in Aeromonas isolated from cultured freshwater animals in China, and providing resistance information of pathogen in Chinese aquaculture. PMID- 24350746 TI - A recovery-oriented alternative to hospital emergency departments for persons in emotional distress: "the living room". AB - Persons with severe mental illness experience episodic crises, resulting in frequent visits to hospital emergency departments (EDs). EDs, however, are not the most effective treatment environments for these individuals who might better be served elsewhere in an environment based on recovery-oriented framework. The purpose of this study is to describe the lived experience of guests (persons in emotional distress) and staff (counselors, psychiatric nurses, and peer counselors) of a community, recovery-oriented, alternative crisis intervention environment-The Living Room (TLR). The total sample is comprised of 18 participants. An existential phenomenological approach was used for this qualitative, descriptive, study. Through non-directive in-depth interviews, participants were asked to describe what stands out to them about The Living Room. Interviews were audio-recorded, transcribed verbatim, and systematically analyzed using descriptive phenomenological methods of analysis by an interdisciplinary and community-based participatory research team. Participants' experiences in hospital EDs and inpatient psychiatric units contextualized the phenomenological experience of TLR environment. The final thematic structure of the experience of TLR included the following predominant themes: A Safe Harbor, At Home with Uncomfortable Feelings, and It's a Helping, No Judging Zone. Findings from this qualitative study of a recovery-based alternative to hospital EDs for persons in emotional distress are supported by anecdotal and empirical evidence that suggests that non-clinical care settings are perceived as helpful and positive. PMID- 24350747 TI - Divergent views of placement decision-making: a qualitative case study. AB - The purpose of this qualitative case study is to describe the contrasting perspectives between a family caregiver and the caregiver's professional provider in regards to the placement decision-making experience of the caregiver. A qualitative, descriptive, revelatory case study, using a grounded theory approach for data analysis, was conducted to identify and compare major themes drawn from interviews with the caregiver-professional dyad. The case is described on the basis of three interviews, two caregiver interviews (pre- and post-placement) and one health professional interview. The 77-year-old caregiver in this case was a wife caring for her 88-year-old husband who was diagnosed with Alzheimer's disease. The health professional was a social worker who led the support group the caregiver attended. Separate and private interviews were conducted by the principal investigator with the caregiver and health professional. Analysis revealed 11 major emerging categories that were compared from the caregiver's and professional's perspective. The perspectives of the family caregiver and the health professional had some elements that were congruent and some that were incongruent. Professionals may be unaware that they are not providing the kind of help that the situation requires. In particular, anticipatory guidance is needed before crisis events make placement immediately necessary. Further research is needed to identify what kind of conditions contribute to smoother decision-making processes and long-term care transitions for caregivers of relatives with dementia. PMID- 24350748 TI - Emergence of Yalom's therapeutic factors in a peer-led, asynchronous, online support group for family caregivers. AB - Support groups fill a critical void in the health care system, harnessing the power of shared experiences to provide support to group members. Likewise, family caregivers fill a void in the health care system, providing billions in unpaid care to the chronically ill. Caregiver support groups offer an opportunity for alleviating the psychological burden of caregiving. The power of any group, including a support group, to foster psychological well-being lies in its ability to cultivate Yalom's therapeutic factors. Gaps in the literature remain regarding the ability of non-prototypical groups to promote therapeutic mechanisms of change. The purpose of this study was to determine if and when Yalom's therapeutic group factors emerged in a peer-led support group delivered in an asynchronous, online format. Qualitative content analysis utilizing deductive category application was employed. Participants' responses were coded and frequency counts were conducted. Results revealed that 9 of 11 therapeutic factors emerged over the course of the group, with Group Cohesiveness, Catharsis, Imparting of Information, and Universality occurring most often. Several factors, including Interpersonal Learning, Corrective Recapitulation of the Primary Family Group, Imitative Behavior, and Development of Socializing Techniques were absent or virtually absent, likely due to the peer-led format of the group. Progression of therapeutic factors over the course of the group is presented. Findings demonstrate the presence of a variety of Yalom's therapeutic factors in an asynchronous, peer-led online support group. PMID- 24350749 TI - Mental health nursing in Australia: resilience as a means of sustaining the specialty. AB - As a concept, resilience is continuing to attract considerable attention and its importance across various life domains is increasingly recognised. Few studies, however, have defined or considered the notion of the group or collective resilience of a profession, including the capacity of that profession to withstand adversity and continue to develop positively in the face of change. This article considers the notion of resilience from the perspective of the specialty of mental health nursing, including the ways the specialty has adapted- and continues to develop--to changes experienced since deinstitutionalisation. Insights are drawn from a national Delphi study undertaken in Australia to develop a Scope of Practice for Mental Health Nurses, with responses used as a springboard to consider the impact of the perceived loss of professional identity on the collective resilience of the profession. Recommendations for a way forward for the profession are considered, including the ways in which a collective professional resilience could be developed to sustain and strengthen the professional identity of mental health nursing in Australia and across the globe. PMID- 24350750 TI - Sexual health and dissociative experiences among abused women. AB - Sexually transmitted infections are a significant public health issue impacting women. Intimate partner violence (IPV) is one risk factor for STIs/HIV. Women who are the victims of IPV often experience psychological difficulties, including dissociation. Dissociative symptoms may play a role in women's ability to practice safe sex and negotiate condom use, although this has been underexplored. This mixed methods study examined the dissociative symptoms of 22 women experiencing IPV and examined the ways in which these women described their own sexual health and behaviors as well as how they protected themselves from sexually transmitted infections and HIV. PMID- 24350751 TI - It's the anxiety: facilitators and inhibitors to nursing students' career interests in mental health nursing. AB - Increasing the rate of recruitment of nursing students into mental health nursing (MHN) is vital to long-term sustainability of health care system support for people diagnosed with mental illness. However MHN is not a popular career path; this raises questions about what attitudes and beliefs may divert or attract students to this specialisation. The current research involved a survey of undergraduate nursing students at a regional university in Australia to clarify the nature of relationships between attitudes (e.g., the value of mental health nursing, stereotypes of people with mental illness) and how they may be antecedents to considering MHN as a career path. Through a structural equation model, it was ascertained that anxiety surrounding mental illness leads to less interest in MHN as a future career and suggests that anxiety is (a) partly due to negative stereotypes, and (b) countered by preparedness for a MHN role. Beliefs on how MHN can make a valuable contribution to people's well-being did not affect interest in pursuing MHN. These findings reconfirm the need to reduce anxiety about mental illness by educational approaches that effectively prepare students for MHN, combined with challenging negative stereotypes. PMID- 24350752 TI - Patients' and family members' experiences of a psychoeducational family intervention after a first episode psychosis: a qualitative study. AB - The objective of this study is to explore patients' and family members' experiences of the different elements of a psychoeducational family intervention. A qualitative, explorative study was performed based on digitally recorded in depth interviews with 12 patients and 14 family members. The interview data were transcribed in a slightly modified verbatim mode and analysed using systematic text condensation. Six themes that both patients and family members experienced as important in the family intervention were identified: alliance, support, anxiety and tension, knowledge and learning, time, and structure. A good relationship between the group leaders and participants was essential in preventing dropout. Meeting with other people in the same situation reduced feelings of shame and increased hope for the future. Hearing real life stories was experienced as being more important for gaining new knowledge about psychosis than lectures and workshops. However, many patients experienced anxiety and tension during the meetings. The group format could be demanding for patients immediately after a psychotic episode and for those still struggling with distressing psychotic symptoms. Group leaders need to recognise patients' levels of anxiety before, and during, the intervention, and consider the different needs of patients and family members in regards to when the intervention starts, the group format, and the patients' level of psychotic symptoms. The findings in the present study may help to tailor family work to better meet the needs of both patients and family members. PMID- 24350753 TI - The Nanny State, free will, and public health. PMID- 24350754 TI - Electroconvulsive therapy: issues for mental health nurses to consider. PMID- 24350756 TI - Total and inorganic arsenic in foods of the first Hong Kong total diet study. AB - Arsenic (As) is a metalloid that occurs in different inorganic and organic forms, which are found in the environment from both natural occurrence and anthropogenic activity. The inorganic forms of As (iAs) are more toxic as compared with the organic As, but so far most of the occurrence data in food collected in the framework of official food control are still reported as total As without differentiating the various As species. In this paper, total As and iAs contents of 600 total diet study (TDS) samples, subdivided into 15 different food groups, were quantified by high-resolution inductively coupled plasma mass spectrometry (HR-ICP/MS) and hydride generation (HG) ICP/MS respectively. The method detection limits for both total As and iAs were 3 MUg As kg(-1). As the samples were prepared for TDS, food items were purchased directly from the market or prepared as for normal consumption, i.e. table ready, in the manner most representative of and consistent with cultural habits in Hong Kong as far as practicable. The highest total As and iAs content were found in 'fish, seafood and their products' and 'vegetables and their products' respectively. Besides, this paper also presents the ratios of iAs and total As content in different ready-to-eat food items. The highest ratio of iAs to total As was found in 'vegetables and their products'. It is likely that iAs in vegetables maintained its status even after cooking. PMID- 24350757 TI - Occurrence of alk(en)ylresorcinols in the fruits of two mango (Mangifera indica L.) cultivars during on-tree maturation and postharvest storage. AB - Regarding their relevance for the fungal resistance of mangoes in long supply chains, the alk(en)ylresorcinols (AR) were quantitated in peel and mesocarp throughout storage (27 days, 14 degrees C, ethylene absorption). The 12 'Chok Anan' and 11 'Nam Dokmai #4' lots picked between 83 and 115 days after full bloom (DAFB) had different harvest maturity indices. The development of dry matter and fruit growth indicated physiological maturity ~100 DAFB. During storage, all fruits ripened slowly, mostly until over-ripeness and visible decay. The total AR contents always ranged at 73 +/- 4.5 and 6.4 +/- 0.7 mg hg(-1) of 'Chok Anan' and 'Nam Dokmai #4' peel dry weight, respectively, but only at 6.7 +/- 0.7 and 0.9 +/ 0.1 mg hg(-1) for the corresponding mesocarp (P <= 0.05). These narrow concentration ranges were contradictory to the decreasing fungal resistance. Accordingly, the alk(en)ylresorcinols have not been a deciding factor for the fungal resistance. PMID- 24350758 TI - Semiparametric analysis of linear transformation models with covariate measurement errors. AB - We take a semiparametric approach in fitting a linear transformation model to a right censored data when predictive variables are subject to measurement errors. We construct consistent estimating equations when repeated measurements of a surrogate of the unobserved true predictor are available. The proposed approach applies under minimal assumptions on the distributions of the true covariate or the measurement errors. We derive the asymptotic properties of the estimator and illustrate the characteristics of the estimator in finite sample performance via simulation studies. We apply the method to analyze an AIDS clinical trial data set that motivated the work. PMID- 24350759 TI - Evaluating predictability. PMID- 24350760 TI - Cu(I)-NHC catalyzed asymmetric silyl transfer to unsaturated lactams and amides. AB - The first asymmetric silylation of unsaturated lactams and amides using Cu(I)-NHC catalysts and PhMe2SiBpin has been accomplished. The method has been exploited in an expedient asymmetric synthesis of the (R)-enantiomer of the nootropic drug oxiracetam. PMID- 24350761 TI - Computational insights on the geometrical arrangements of Cu(II) with a mixed donor N3S3 macrobicyclic ligand. AB - The macrobicyclic mixed-donor N3S3 cage ligand AMME-N3S3sar (1-methyl-8-amino 3,13,16-trithia-6,10,19-triazabicyclo[6.6.6]eicosane) can form complexes with Cu(II) in which it acts as hexadentate (N3S3) or tetradentate (N2S2) donor. These two complexes are in equilibrium that is strongly influenced by the presence of halide ions (Br(-) and Cl(-)) and the nature of the solvent (DMSO, MeCN, and H2O). In the absence of halides the hexadentate coordination mode of the ligand is preferred and the encapsulated complex ("Cu-in(2+)") is formed. Addition of halide ions in organic solvents (DMSO or MeCN) leads to the tetradentate complex ("Cu-out(+)") in a polyphasic kinetic process, but no Cu-out(+) complex is formed when the reaction is performed in water. Here we applied density functional theory calculations to study the mechanism of this interconversion as well as to understand the changes in the reactivity associated with the presence of water. Calculations were performed at the B3LYP/(SDD,6-31G**) level, in combination with continuum (MeCN) or discrete-continuum (H2O) solvent models. Our results show that formation of Cu-out(+) in organic media is exergonic and involves sequential halide-catalyzed inversion of the configuration of a N-donor of the macrocycle, rapid halide coordination, and inversion of the configuration of a S-donor. In aqueous solution the solvent is found to have an effect on both the thermodynamics and the kinetics of the reaction. Thermodynamically, the process becomes endergonic mainly due to the preferential solvation of halide ions by water, while the kinetics is influenced by formation of a network of H-bonded water molecules that surrounds the complex. PMID- 24350763 TI - Single centre prospective study of the efficacy of percutaneous cement augmentation in the treatment of vertebral compression fractures. AB - INTRODUCTION: Despite controversial outcomes of recent published trials, percutaneous cement augmentation remains widely used in managing painful vertebral compression fractures. We prospectively assessed patients with such fractures using an eleven-point visual analogue scale for pain and the Qualeffo 41 questionnaire for quality of life. METHODS: Consecutive patients undergoing percutaneous cement augmentation for painful vertebral compression fractures were recruited. Patients were assessed pre-procedure by completing a visual analogue scale for pain, on a scale of 0 to 10. A Qualeffo 41 questionnaire was also completed. Patients were followed up at 1 week and 3 months. RESULTS: Fifty six patients were prospectively recruited (111 vertebroplasty and 5 kyphoplasty). Visual analogue scores dropped from 6.4 +/- 2.3 pre-procedure to 4.0 +/- 2.7 at 1 week (p < 0.0001) and 4.3 +/- 2.7 (p < 0.0001) at 3 months. Three subgroups were identified; osteoporotic patients (n = 28), a second non-osteoporotic group (n = 20) who had acute fracture following fall and a third group with compression fractures secondary to metastatic disease (n = 8). At 3-month follow-up, patients with osteoporotic fractures had reduction in pain score from 6.3 +/- 2.1 to 4.8 +/- 2.7 (p = 0.02). Patients who had traumatic fractures experienced more significant pain relief, 6.4 +/- 2.6 to 3.8 +/- 2.7 (p = 0.0009) but patients with malignant fracture had most benefit, 6.0 +/- 3.0 to 1.8 +/- 0.8 (p = 0.01). Total Qualeffo scores improved from 63 +/- 15 to 49 +/- 22 (p < 0.0001). Within the domains of the Qualeffo questionnaire, most improvement was seen in pain and physical function. Median in-patient stay post procedure was one day. CONCLUSION: In our experience percutaneous cement augmentation is safe and efficacious in the management of painful VCF related to osteoporosis, trauma and cancer, achieving rapid and significant pain reduction and improvement in physical function as measured with a visual analogue scale and the Qualeffo 41 questionnaire. PMID- 24350764 TI - Spinal dural arteriovenous fistulas--presentation, management and outcome in a single neurosurgical institution. AB - OBJECTIVE: To compare the outcome, with respect to treatment modality, of patients treated with spinal dural arteriovenous fistulas (SDAVF). METHOD: Retrospective cohort study of patients with SDAVF assessed at a single tertiary referral centre, between 1999 and 2009. Intervention type, pre-/ post intervention Aminoff-Logue disability score (ALDS) and recurrence rate were obtained from medical records. RESULTS: 26 patients were identified with 23 receiving intervention. All patients initially received super selective angiogram, with 13 undergoing endovascular embolization at this stage, after discussion between the surgeon and interventional radiologist. Six patients who underwent embolization had a recurrence. The remaining 10 patients had fistulas marked during angiography, and were then treated surgically, after discussion. One of these recurred. The difference in recurrence rate between the two intervention types was not statistically significant. Fistulas treated with the embolization material onyx were twice as likely to recur as those treated with the alternative material, histoacryl-lipiodol. There was a statistically significant difference between the modes of intervention in relation to clinical outcome. Surgeries lead to an improvement in neurology, whereas treatment via embolization did not. Neurological improvement was seen in non-recurring cases, however deterioration in neurological function occurred with fistula recurrence. CONCLUSION: Super selective angiography is effective in defining the relevant vascular anatomy and allows for precise fistula localization during any potential subsequent surgery. Onyx was associated with a higher recurrence rate, suggesting it is less suitable as an embolization material for SDAVF treatment. Surgery appeared to correlate to reversal of neurological impairment seen at presentation, possibly due to a lower recurrence rate. The study is limited by small patient numbers, emphasizing the need for further studies of SDAVF patients. PMID- 24350766 TI - Respiratory syncytial virus in critically ill adult patients with community acquired respiratory failure: a prospective observational study. AB - The incidence of respiratory syncytial virus (RSV) and influenza virus infection was determined during three RSV seasons in 158 adult patients consecutively admitted to the intensive care unit with community-acquired respiratory failure. Nasopharyngeal swabs were tested for the presence of RSV and influenza virus by real-time polymerase chain reaction. Six patients (4%) were positive for RSV and all recovered. This finding was in sharp contrast to influenza (23 (15%) patients, 4 (17%) deaths). In conclusion, even in the midst of the RSV season, RSV is an infrequent cause of respiratory failure in adults admitted to the intensive care unit. PMID- 24350767 TI - Transfer from pediatric to adult health care: effects on diabetes outcomes. AB - The transfer from pediatric to adult diabetes health care for emerging adults with type 1 diabetes (T1D) has received increasing attention in the literature. This review analyzes the effect of this health care transfer on the outcomes of diabetes care visit attendance, glycemic control, and acute diabetes-related complications, and assesses the methodological strength of the studies reporting observational and interventional data. Observational studies, often limited by incomplete data, report a decline in diabetes care visits but an improvement or no change in hemoglobin A1c (HbA1c) after transfer to adult care. Results from studies reporting a transition intervention are restricted by lack of appropriate control groups and the collection of data both before and after transfer of care. Very few methodologically strong studies are available to guide clinicians with the transition from pediatric to adult care, and these shortcomings should be addressed in future studies designed to facilitate and improve the care of emerging adults with T1D. PMID- 24350768 TI - A case of pericardial tuberculoma presenting as a left anterior chest wall mass. AB - INTRODUCTION: Tuberculosis (TB) can present both in its pulmonary or extra pulmonary forms. Cardiac tuberculoma previously described only after autopsy is continuously seen with the advent of more advanced imaging modalities. CASE REPORT: A 23-year-old male with a four month history of a progressively increasing left anterior thoracic wall mass of 5 cm in diameter was referred from oncology for clinical re-evaluation and for echocardiography. Systemic examination was essentially normal. Transthoracic and trans-oesophageal echocardiography showed the presence of a pericardial mass around the right atrioventricular junction. Thoracic CT scan showed an anterior mass in left chest wall extending to the pericardium and also the presence of mediastinal lymphadenopathy. Mantoux test was positive and histological examination of tissue biopsy confirmed the presence of TB. However, blood tests and culture of aspirated purulent fluid were unyielding. A diagnosis of pericardial tuberculoma with mediastinal and parietal extension was made and patient was successfully treated with standard anti-TB chemotherapy. DISCUSSION: The possible differential diagnoses for chest wall tumors are varied and a high degree of suspicion is needed to diagnose cardiac tuberculoma especially in endemic regions. Imaging though helpful in morphological description cannot make precise diagnosis. The diagnosis depends on histological and culture studies. There is usually a good evolution with anti-TB treatment. CONCLUSION: In an era of an increasing number of acquired immune-compromised patients, and with increasing number of diagnoses of tuberculosis, a diagnosis of cardiac tuberculoma should be considered in patients presenting with a thoracic wall mass. PMID- 24350769 TI - Phenylpropanoid pathway is potentiated by silicon in the roots of banana plants during the infection process of Fusarium oxysporum f. sp. cubense. AB - Fusarium wilt, caused by Fusarium oxysporum f. sp. cubense, is a disease that causes large reductions in banana yield worldwide. Considering the importance of silicon (Si) to potentiate the resistance of several plant species to pathogen infection, this study aimed to investigate, at the histochemical level, whether this element could enhance the production of phenolics on the roots of banana plants in response to F. oxysporum f. sp. cubense infection. Plants of cultivar Maca, which is susceptible to F. oxysporum f. sp. cubense, were grown in plastic pots amended with 0 (-Si) or 0.39 g of Si (+Si) per kilogram of soil and inoculated with race 1 of F. oxysporum f. sp. cubense. The root Si concentration was increased by 35.6% for +Si plants in comparison to the -Si plants, which contributed to a 27% reduction in the symptoms of Fusarium wilt on roots. There was an absence of fluorescence for the root sections of the -Si plants treated with the Neu and Wilson's reagents. By contrast, for the root sections obtained from the +Si plants treated with Neu's reagent, strong yellow-orange fluorescence was observed in the phloem, and lemon-yellow fluorescence was observed in the sclerenchyma and metaxylem vessels, indicating the presence of flavonoids. For the root sections of the +Si plants treated with Wilson's reagent, orange yellowish autofluorescence was more pronounced around the phloem vessels, and yellow fluorescence was more pronounced around the metaxylem vessels, also indicating the presence of flavonoids. Lignin was more densely deposited in the cortex of the roots of the +Si plants than for the -Si plants. Dopamine was barely detected in the roots of the -Si plants after using the lactic and glyoxylic acid stain, but was strongly suspected to occur on the phloem and metaxylem vessels of the roots of the +Si plants as confirmed by the intense orange-yellow fluorescence. The present study provides new evidence of the pivotal role of the phenylpropanoid pathway in the resistance of banana plants to F. oxysporum f. sp. cubense infection when supplied with Si. PMID- 24350771 TI - Quantitative compositional profiling of conjugated quantum dots with single atomic layer depth resolution via time-of-flight medium-energy ion scattering spectroscopy. AB - We report the quantitative compositional profiling of 3-5 nm CdSe/ZnS quantum dots (QDs) conjugated with a perfluorooctanethiol (PFOT) layer using the newly developed time-of-flight (TOF) medium-energy ion scattering (MEIS) spectroscopy with single atomic layer resolution. The collection efficiency of TOF-MEIS is 3 orders of magnitude higher than that of conventional MEIS, enabling the analysis of nanostructured materials with minimized ion beam damage and without ion neutralization problems. The spectra were analyzed using PowerMEIS ion scattering simulation software to allow a wide acceptance angle. Thus, the composition and core-shell structure of the CdSe cores and ZnS shells were determined with a 3% composition uncertainty and a 0.2-nm depth resolution. The number of conjugated PFOT molecules per QD was also quantified. The size and composition of the QDs were consistent with those obtained from high-resolution transmission electron microscopy and X-ray photoelectron spectroscopy, respectively. We suggest TOF MEIS as a nanoanalysis technique to successfully elucidate the core-shell and conjugated layer structures of QDs, which is critical for the practical application of QDs in various nano- and biotechnologies. PMID- 24350770 TI - MOPED enables discoveries through consistently processed proteomics data. AB - The Model Organism Protein Expression Database (MOPED, http://moped.proteinspire.org) is an expanding proteomics resource to enable biological and biomedical discoveries. MOPED aggregates simple, standardized and consistently processed summaries of protein expression and metadata from proteomics (mass spectrometry) experiments from human and model organisms (mouse, worm, and yeast). The latest version of MOPED adds new estimates of protein abundance and concentration as well as relative (differential) expression data. MOPED provides a new updated query interface that allows users to explore information by organism, tissue, localization, condition, experiment, or keyword. MOPED supports the Human Proteome Project's efforts to generate chromosome- and diseases-specific proteomes by providing links from proteins to chromosome and disease information as well as many complementary resources. MOPED supports a new omics metadata checklist to harmonize data integration, analysis, and use. MOPED's development is driven by the user community, which spans 90 countries and guides future development that will transform MOPED into a multiomics resource. MOPED encourages users to submit data in a simple format. They can use the metadata checklist to generate a data publication for this submission. As a result, MOPED will provide even greater insights into complex biological processes and systems and enable deeper and more comprehensive biological and biomedical discoveries. PMID- 24350772 TI - Activation of cellular immunity and marked inhibition of liver cancer in a mouse model following gene therapy and tumor expression of GM-SCF, IL-21, and Rae-1. AB - BACKGROUND: Cancer is both a systemic and a genetic disease. The pathogenesis of cancer might be related to dampened immunity. Host immunity recognizes nascent malignant cells - a process referred to as immune surveillance. Augmenting immune surveillance and suppressing immune escape are crucial in tumor immunotherapy. METHODS: A recombinant plasmid capable of co-expressing granulocyte-macrophage colony- stimulating factor (GM-SCF), interleukin-21 (IL-21), and retinoic acid early transcription factor-1 (Rae-1) was constructed, and its effects determined in a mouse model of subcutaneous liver cancer. Serum specimens were assayed for IL-2 and INF-gamma by ELISA. Liver cancer specimens were isolated for Rae-1 expression by RT-PCR and Western blot, and splenocytes were analyzed by flow cytometry. RESULTS: The recombinant plasmid inhibited the growth of liver cancer and prolonged survival of tumor-loaded mice. Activation of host immunity might have contributed to this effect by promoting increased numbers and cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL) following expression of GM-SCF, IL-21, and Rae-1. By contrast, the frequency of regulatory T cells was decreased, Consequently, activated CTL and NK cells enhanced their secretion of INF-gamma, which promoted cytotoxicity of NK cells and CTL. Moreover, active CTL showed dramatic secretion of IL-2, which stimulates CTL. The recombinant expression plasmid also augmented Rae-1 expression by liver cancer cells. Rae-1 receptor expressing CTL and NK cells removed liver cancer. CONCLUSIONS: The recombinant expression plasmid inhibited liver cancer by a mechanism that involved activation of cell-mediated immunity and Rae-1 in liver cancer. PMID- 24350774 TI - Lymphatic system: a prospective area for advanced targeting of particulate drug carriers. AB - INTRODUCTION: The lymphatic system has a critical role in the immune system's recognition and response to disease and it is an additional circulatory system throughout the entire body. Extensive multidisciplinary investigations have been carried out in the area of lymphatic delivery, and lymphatic targeting has attracted a lot of attention for providing preferential chemotherapy and improving bioavailability of drugs that undergo hepatic first-pass metabolism. AREAS COVERED: This review focuses on progress in the field of lymphatic therapeutics and diagnosis. Moreover, the anatomy and physiology of the lymphatic system, particulate drug carriers and different physicochemical parameters of both modified and unmodified particulate drug carriers and their effect on lymphatic targeting are addressed. EXPERT OPINION: Particulate drug carriers have encouraged lymphatic targeting, but there are still challenges in targeting drugs and bioactives to specific sites, maintaining desired action and crossing all the physiological barriers. Lymphatic therapy using drug-encapsulated lipid carriers, especially liposomes and solid lipid nanoparticles, emerges as a new technology to provide better penetration into the lymphatics where residual disease exists. Size is the most important criteria when designing nanocarriers for targeting lymphatic vessels as the transportation of these particles into lymphatic vessels is size dependent. By increasing our understanding of lymphatic transport and uptake, and the role of lymphatics in various diseases, we can design new therapeutics for effective disease control. PMID- 24350775 TI - Clinical course and seizure outcome of idiopathic childhood epilepsy: determinants of early and long-term prognosis. AB - BACKGROUND: Idiopathic epilepsies and epileptic syndromes predominate childhood and adolescence epilepsy. The aim of the present study was to investigate the clinical course and outcome of idiopathic childhood epilepsy and identify variables determining both early and long-term prognosis. METHODS: We followed 303 children with newly diagnosed idiopathic epilepsy aged 1-14 years old, both prospectively and retrospectively. Outcome was defined at one, 2 and 4 years of follow-up, as well as at the end of the study period for all patients. Based on the data collected, patients were classified in four patterns of clinical course: "excellent", "improving", "relapsing" and "poor". Variables defined at intake and after the initial year of treatment were analyzed for their prognostic relevance towards the clinical course and outcome of the patients. RESULTS: The mean age at seizure onset was 6.7 years and the mean duration of follow-up was 8.3 years (range 2,0-22,0,SD 4,24). During the initial year of treatment, 70,3% of patients were seizure-free. The course of epilepsy was "excellent" in 53,1% of the subjects, "improving" in 22,8%, "relapsing" in 22,1% whereas only 6 children with idiopathic epilepsy (2%) had a "poor" clinical course exhibiting drug-resistance. After multivariate analysis, variables predictive of a poor initial response to therapy were early seizure onset, multiple seizure types and history of status epilepticus. At the end of follow-up, early response to treatment was of significant positive predictive value, while the presence of multiple seizure types and the history of migraine had a negative impact on prognosis. CONCLUSIONS: In the vast majority of children, the long-term prognosis of idiopathic epilepsy is favorable. More than half of the patients attain seizure freedom immediately and their clinical course is considered "excellent". About one fifth exhibit either an improving or a fluctuating course. Early seizure onset, multiple seizure types and status epilepticus are predictive of an initial poor response to treatment in children with idiopathic epilepsy. Initial non response to treatment, multiple seizure types and history of migraine are determinants of a less favorable final outcome after long-term follow-up. PMID- 24350776 TI - Pyrosequencing as a tool for rapid fish species identification and commercial fraud detection. AB - The increased consumption of fish products, as well as the occurrence of exotic fish species in the Mediterranean Sea and in the fish market, has increased the risk of commercial fraud. Furthermore, the great amount of processed seafood products has greatly limited the application of classic identification systems. DNA-based identification allows a clear and unambiguous detection of polymorphisms between species, permitting differentiation and identification of both commercial fraud and introduction of species with potential toxic effects on humans. In this study, a novel DNA-based approach for differentiation of fish species based on pyrosequencing technology has been developed. Raw and processed fish products were tested, and up to 25 species of fish belonging to Clupeiformes and Pleuronectiformes groups were uniquely and rapidly identified. The proper identification based on short and unique genetic sequence signatures demonstrates that this approach is promising and cost-effective for large-scale surveys. PMID- 24350777 TI - Biogenic nanopalladium based remediation of chlorinated hydrocarbons in marine environments. AB - Biogenic catalysts have been studied over the last 10 years in freshwater and soil environments, but neither their formation nor their application has been explored in marine ecosystems. The objective of this study was to develop a biogenic nanopalladium-based remediation method for reducing chlorinated hydrocarbons from marine environments by employing indigenous marine bacteria. Thirty facultative aerobic marine strains were isolated from two contaminated sites, the Lagoon of Mar Chica, Morocco, and Priolo Gargallo Syracuse, Italy. Eight strains showed concurrent palladium precipitation and biohydrogen production. X-ray diffraction and thin section transmission electron microscopy analysis indicated the presence of metallic Pd nanoparticles of various sizes (5 20 nm) formed either in the cytoplasm, in the periplasmic space, or extracellularly. These biogenic catalysts were used to dechlorinate trichloroethylene in simulated marine environments. Complete dehalogenation of 20 mg L(-1) trichloroethylene was achieved within 1 h using 50 mg L(-1) biogenic nanopalladium. These biogenic nanoparticles are promising developments for future marine bioremediation applications. PMID- 24350778 TI - Faldaprevir (BI 201335) for the treatment of hepatitis C in patients co-infected with HIV. AB - Chronic HCV infection affects 130-170 million individuals worldwide and there are currently 34 million people living with HIV/AIDS. The aim of treatment of HCV is the elimination of the virus (sustained virological response). With development of drugs that specifically target HCV replication, direct-acting agents, sustained virological response rates have dramatically changed for genotype 1 infections. Challenges in the use of direct-acting agents in patients with HIV/HCV co-infection include the potential for drug-drug interactions between HIV and HCV drugs, additional drug toxicities and the need for therapy with IFN alpha. Faldaprevir (FDV), previously known as BI 201335, is a second-wave HCV NS3/4A protease inhibitor with highly potent in vitro activity against HCV GT 1a/1b and improved pharmacokinetics suitable for once-daily dosing. FDV is currently in Phase III development. This article will review the pharmacology and pharmacodynamics of FDV, the efficacy and safety of the drug and explore possible future developments in the management of chronic hepatitis C infection, focusing on HIV/HCV co-infected patients. PMID- 24350779 TI - Endogenous and xenobiotic metabolite profiling of liver extracts from SCID and chimeric humanized mice following repeated oral administration of troglitazone. AB - 1. Metabonomic analysis, via a combination of untargeted and targeted liquid chromatography-mass spectrometry (LC-MS) and untargeted (1)H NMR spectroscopy based metabolite profiling, was performed on aqueous (AQ) and organic liver extracts from control (SCID) and chimeric humanized (PXB) mice dosed with troglitazone at 0, 300 and 600 mg/kg/day for seven days. 2. LC-MS analysis of AQ liver extracts showed a more "human-like" profile for troglitazone metabolites for PXB, compared with SCID, mice. 3. LC-MS detected differences in endogenous metabolites, particularly lipid species in dosed mice, including elevated triacylglycerols and 1-alkyl,2-acylglycerophosphates as well as lowered diacylglycerophosphocholines and 1-alkyl,2-acylglycerophosphocholines for PXB compared with SCID mouse liver extracts. Following drug administration changes in the relative proportions of the ions for various unsaturated fatty acids were observed for both types of mouse, some of which were specific to PXB or SCID mice. 4. (1)H NMR spectroscopy revealed that AQ PXB mouse liver extracts had elevated amounts of inosine, fumarate, creatine, aspartate, trimethylamine N oxide, glycerophosphocholine, phosphocholine, choline, glutamine, glutamate, acetate, alanine and lactate relative to SCID mice and decreased histidine, glycogen, alpha- and beta-glucose, taurine, and glutathione. Increased uracil and tyrosine concentrations were detected for PXB mice on troglitazone administration. 5. Metabonomic profiling thus showed clear differences between humanized and SCID mice, including after administration of troglitazone. PMID- 24350780 TI - The lymphatic system plays a major role in the intravenous and subcutaneous pharmacokinetics of trastuzumab in rats. AB - Therapeutic monoclonal antibodies are currently delivered mainly via the intravenous route, since large volumes are often required to deliver a therapeutic dose. Administration via the subcutaneous route would have several therapeutic advantages; the absorption mechanisms for antibodies dosed subcutaneously are poorly understood. This study was conducted to develop a better understanding of the mechanisms governing the subcutaneous absorption and trafficking of monoclonal antibodies. Specifically, the role of the lymphatic system in the absorption and prolonged plasma exposure of trastuzumab was explored in thoracic lymph duct-cannulated rats after SC and IV dosing. A population pharmacokinetic model was developed in S-ADAPT to simultaneously fit all plasma and lymph concentrations and to predict the pharmacokinetics in nonlymph duct-cannulated animals. The estimated absolute bioavailability of trastuzumab after SC administration in rats was 85.5%. Following SC administration, 53.1% of the trastuzumab dose was absorbed via a first-order process (mean absorption time: 99.6 h) into the peripheral lymph compartment and 32.4% of the dose was absorbed by a Michaelis-Menten process into the central compartment. Recovery in thoracic lymph over 30 h was 26.7% after SC and 44.1% after IV administration. This study highlights for the first time the significant role of the lymphatic system in maintaining the long plasma exposure of trastuzumab, with the model predicting an extensive distribution of this monoclonal antibody into the lymph following SC and IV administration. This extensive direct absorption from the SC injection site into lymph may enable novel therapeutic strategies for the treatment of lymph resident metastatic cancer. PMID- 24350781 TI - Cutaneous collagenous vasculopathy associated with intravascular occlusive fibrin thrombi. AB - Cutaneous collagenous vasculopathy (CCV) is a rare cutaneous microangiopathy that clinically resembles generalized essential telangiectasia with only 12 cases reported to date. The perivascular fibrosis is thought to be due to production of abnormal collagen by veil cells in the outer vessel walls as a result of unknown factors. This report is of an 84-year-old male with progressive telangiectasia. Biopsies showed characteristic features of CCV. In addition, there were multiple intravascular fibrin thrombi, some organizing and associated with endothelial cell hyperplasia with recanalization reminiscent of glomeruloid bodies and simulating reactive angioendotheliomatosis (RAE). Histochemically and ultrastructurally fibrin was noted within the vessel walls integrating into the fibrous tissue around the vessels; however, the patient had no evidence of coagulation disorder, cryoglobulinemia or cold agglutinemia. Immunofluorescence showed fibrinogen within the vessel walls but no immunoglobulins or C3. As well, there were minimal inflammatory cells. This suggests pauci-inflammatory injury to the endothelial cells by unknown angiogenic factors causing local intravascular fibrin thrombi with fibrin leaking and incorporating into the vessel walls, eventually leading to reparative perivascular fibrosis. This case suggests that some cases of CCV are related to a primary local intravascular occlusive thrombotic microangiopathy. However, the primary triggering factor causing the endothelial cell damage has yet to be elucidated. PMID- 24350783 TI - Characterization of a tryptophan 2-monooxygenase gene from Puccinia graminis f. sp. tritici involved in auxin biosynthesis and rust pathogenicity. AB - The plant hormone indole-3-acetic acid (IAA) is best known as a regulator of plant growth and development but its production can also affect plant-microbe interactions. Microorganisms, including numerous plant-associated bacteria and several fungi, are also capable of producing IAA. The stem rust fungus Puccinia graminis f. sp. tritici induced wheat plants to accumulate auxin in infected leaf tissue. A gene (Pgt-IaaM) encoding a putative tryptophan 2-monooxygenase, which makes the auxin precursor indole-3-acetamide (IAM), was identified in the P. graminis f. sp. tritici genome and found to be expressed in haustoria cells in infected plant tissue. Transient silencing of the gene in infected wheat plants indicated that it was required for full pathogenicity. Expression of Pgt-IaaM in Arabidopsis caused a typical auxin expression phenotype and promoted susceptibility to the bacterial pathogen Pseudomonas syringae pv. tomato DC3000. PMID- 24350784 TI - Source localization with MEG data: A beamforming approach based on covariance thresholding. AB - Reconstructing neural activities using non-invasive sensor arrays outside the brain is an ill-posed inverse problem since the observed sensor measurements could result from an infinite number of possible neuronal sources. The sensor covariance-based beamformer mapping represents a popular and simple solution to the above problem. In this article, we propose a family of beamformers by using covariance thresholding. A general theory is developed on how their spatial and temporal dimensions determine their performance. Conditions are provided for the convergence rate of the associated beamformer estimation. The implications of the theory are illustrated by simulations and a real data analysis. PMID- 24350785 TI - Spirochetemia due to Treponema pallidum using polymerase-chain-reaction assays in patients with early syphilis: prevalence, associated factors and treatment response. AB - Between 2009 and 2013, polymerase-chain-reaction assay was used to detect Treponema pallidum in the blood samples collected from 296 patients with early syphilis (241 being HIV infected) and 102 patients (34.5%) had spirochetemia. The presence of spirochetemia was associated with lower CD4 counts (per 10-cell/mm(3) decrease, adjusted odds ratio (AOR), 1.020; 95% CI, 1.006-1.036) and secondary syphilis (AOR, 4.967; 95% CI, 2.016-12.238). Patients with early latent syphilis were less likely to achieve serological response compared with those with primary or secondary syphilis (AOR, 0.317; 95% CI, 0.142-0.708). However, serological response was not affected by presence of spirochetemia or antibiotic regimens. PMID- 24350786 TI - Regression of brain metastases from breast cancer with eribulin: a case report. AB - BACKGROUND: Eribulin is a recently approved new therapeutic option for patients with metastatic breast cancer. According to several reports, eribulin has limited ability to cross the blood brain barrier. Recently, capecitabine and eribulin have been recognized as drugs with similar application for patients with advanced breast cancer. Although there have been several case reports describing the efficacy of capecitabine against brain metastases, no report of eribulin demonstrating efficacy for brain metastases exists today. CASE PRESENTATION: We describe a case of a 57-year-old Japanese woman who was diagnosed with breast cancer stage IV metastasized to multiple organs including liver and lung. After she received 3 regimens, she showed evidence of brain metastases, and whole brain radiation therapy was performed. Lapatinib and capecitabine was then administered as fourth-line chemotherapy, but the patient was hospitalized due to the exacerbation of interstitial pneumonitis and progression of brain and liver metastases. To control the systemic disease, eribulin was commenced as fifth-line chemotherapy. One month later, a significant response of brain metastases had been achieved, and this response has persisted for the last 4 months. We now describe a remarkable antitumor effect of eribulin against brain metastases from breast cancer. This case is the first report which indicates potential treatment of brain metastases using this medication. CONCLUSION: This report suggests that eribulin treatment may be beneficial for breast cancer patients with brain metastases progressing after whole brain radiation therapy. However, further clinical studies are warranted to determine the clinical effect of eribulin in brain metastases. PMID- 24350787 TI - Learning curve assessment of robot-assisted radical prostatectomy compared with open-surgery controls from the premier perspective database. AB - INTRODUCTION: The primary aims of this study were to assess the learning curve effect of robot-assisted radical prostatectomy (RARP) in a large administrative database consisting of multiple U.S. hospitals and surgeons, and to compare the results of RARP with open radical prostatectomy (ORP) from the same settings. MATERIALS AND METHODS: The patient population of study was from the Premier Perspective Database (Premier, Inc., Charlotte, NC) and consisted of 71,312 radical prostatectomies performed at more than 300 U.S. hospitals by up to 3739 surgeons by open or robotic techniques from 2004 to 2010. The key endpoints were surgery time, inpatient length of stay, and overall complications. We compared open versus robotic, results by year of procedures, results by case volume of specific surgeons, and results of open surgery in hospitals with and without a robotic system. RESULTS: The mean surgery time was longer for RARP (4.4 hours, standard deviation [SD] 1.7) compared with ORP (3.4 hours, SD 1.5) in the same hospitals (p<0.0001). Inpatient stay was shorter for RARP (2.2 days, SD 1.9) compared with ORP (3.2 days, SD 2.7) in the same hospitals (p<0.0001). The overall complications were less for RARP (10.6%) compared with ORP (15.8%) in the same hospitals, as were transfusion rates. ORP results in hospitals without a robot were not better than ORP with a robot, and pretreatment co-morbidity profiles were similar in all cohorts. Trending of results by year of procedure showed no differences in the three cohorts, but trending of RARP results by surgeon experience showed improvements in surgery time, hospital stay, conversion rates, and complication rates. CONCLUSIONS: During the initial 7 years of RARP development, outcomes showed decreased hospital stay, complications, and transfusion rates. Learning curve trends for RARP were evident for these endpoints when grouped by surgeon experience, but not by year of surgery. PMID- 24350789 TI - Failure of ESI spectra to represent metal-complex solution composition: a study of lanthanide-carboxylate complexes. AB - Electrospray ionization-mass spectrometry (ESI-MS) shows great promise as a rapid method to identify metal-ligand complexes in solution. However, its application for quantitative determination of the distribution of species present in complicated equilibria is still in its infancy, and a direct correlation between ions observed in the gas phase and species expected in solution must be made with caution. The present work focuses on a seemingly simple system; the complexation of lanthanide cations with the acetate ligand. Using a high resolution quadrupole time-of-flight mass spectrometer, ions created by electrospray of solutions containing trivalent neodymium and acetate were identified. The gas phase distribution of species was compared to the solution phase speciation predicted using thermodynamic complexation constants. Apparent gas phase speciation diagrams were constructed as a function of solution conditions and fragmentation potential. Despite the expected variability of metal-ligand complexes as solution conditions change, the observed gas phase speciation was independent of the metal to ligand ratio but dependent on the operating conditions of the ESI-MS. PMID- 24350788 TI - Metal-free synthesis of ynones from acyl chlorides and potassium alkynyltrifluoroborate salts. AB - A straightforward method for the preparation of ynones from acyl chlorides and potassium alkynyltrifluoroborate salts has been developed. The one-pot reaction proceeds rapidly in the presence of a Lewis acid without exclusion of air and moisture. PMID- 24350790 TI - Chlamydia trachomatis infection during pregnancy: knowledge, test practices, and attitudes of Dutch midwives. AB - BACKGROUND: Chlamydia trachomatis infection in pregnancy may lead to adverse pregnancy outcomes. In the Netherlands, testing for C. trachomatis is based on risk assessment. We assessed midwives' knowledge, test practices, assessment of risk behavior, and attitudes regarding testing for C. trachomatis infection during pregnancy. We evaluated the association between midwives' characteristics and their knowledge of C. trachomatis infection in terms of symptomatology and outcomes. METHODS: This was a cross-sectional study among primary care midwives in the Netherlands. Between September and November 2011, midwives from all Dutch primary care midwifery practices were invited to complete a questionnaire about C. trachomatis infection. RESULTS: Of the 518 midwives invited to participate in this study, 331 (63.9%) responded. The overall median knowledge score for questions about symptomatology and outcomes was 10 out of a maximum score of 15. The median knowledge score was higher among midwives in urban areas. In total, 239 (72.2%) midwives reported testing pregnant women for C. trachomatis. The primary reason for testing was a request by the woman herself (96.2%), followed by symptoms of infection (89.1%), risk behavior (59.3%), and risk factors for infection (7.3%). Almost 25% of midwives showed positive attitudes towards universal screening for C. trachomatis. CONCLUSIONS: Midwives were knowledgeable about symptoms of infection, but less about outcomes. Midwives test pregnant women for C. trachomatis mainly on the women's request. Otherwise, testing is based on symptoms of infection rather than on known risk factors. This may contribute to under-diagnosis and under-treatment, leading to maternal, perinatal, and neonatal morbidity. PMID- 24350793 TI - Comparison of utility weighted DMFT with patient-reported oral well-being. AB - This study investigated a method of measuring oral health, as opposed to measuring disease. The objective was to compare DMF score and whole mouth utility scores to a patient-reported outcome measure (PROM). Disutility values for lost and restored teeth were used to weight the decayed, missing and filled teeths(DMFTs) of 10 adult patients. This gave two whole mouth utility scores (WMU). These scores were then compared with a patient-reported oral health outcome measure recorded by the use of a visual analogue scale (VAS). The anchors for the VAS were 'my mouth could not be worse' and 'my mouth could not be better'. There was a positive correlation (r = 0.6457) between WMU1 and the patient-reported outcome measure (P < 0.05) and a negative correlation (r = 0.8383) between WMU1 and DMFT which was significant at the P < 0.01 level. There was a statistically significant positive correlation of r = 0.7926 between WMU2 and the patient-reported outcome measure (P < 0.01) and a negative correlation (r = -0.9393) between WMU2 and DMFT (P < 0.01). The Pearson's correlation between DMFT and the patient-reported outcome measure was -0.8757, which was significant at the 0.01 level. Patient reports of their perceived level of health correlate well with DMFT scores. Weighting DMFT scores according to the differential values assigned to missing, or missing and filled, teeth does not increase the degree of correlation between the measure and the patients' personal quantification of their oral health. Decayed, missing and filled teeth therefore seems to adequately capture the patient's sense of well-being. PMID- 24350791 TI - Spatial and temporal aspects and the interplay of Grb14 and protein tyrosine phosphatase-1B on the insulin receptor phosphorylation. AB - BACKGROUND: Growth factor receptor-bound protein 14 (Grb14) is an adapter protein implicated in receptor tyrosine kinase signaling. Grb14 knockout studies highlight both the positive and negative roles of Grb14 in receptor tyrosine kinase signaling, in a tissue specific manner. Retinal cells are post-mitotic tissue, and insulin receptor (IR) activation is essential for retinal neuron survival. Retinal cells express protein tyrosine phosphatase-1B (PTP1B), which dephosphorylates IR and Grb14, a pseudosubstrate inhibitor of IR. This project asks the following major question: in retinal neurons, how does the IR overcome inactivation by PTP1B and Grb14? RESULTS: Our previous studies suggest that ablation of Grb14 results in decreased IR activation, due to increased PTP1B activity. Our research propounds that phosphorylation in the BPS region of Grb14 inhibits PTP1B activity, thereby promoting IR activation. We propose a model in which phosphorylation of the BPS region of Grb14 is the key element in promoting IR activation, and failure to undergo phosphorylation on Grb14 leads to both PTP1B and Grb14 exerting their negative roles in IR. Consistent with this hypothesis, we found decreased phosphorylation of Grb14 in diabetic type 1 Ins2Akita mouse retinas. Decreased retinal IR activation has previously been reported in this mouse line. CONCLUSIONS: Our results suggest that phosphorylation status of the BPS region of Grb14 determines the positive or negative role it will play in IR signaling. PMID- 24350794 TI - High birth weights but not excessive weight gain prior to manifestation are related to earlier onset of diabetes in childhood: 'accelerator hypothesis' revisited. AB - AIMS/HYPOTHESIS: Aim of this study was to test Wilkin's 'accelerator hypothesis': whether excessive weight gain accelerates the onset of type 1 diabetes. SUBJECTS AND METHODS: Anthropometric birth data of 1117 children who developed diabetes between 1988 and April 2013 were compared with those of a sex, age, and gestational age matched, contemporary regional control group (n = 54 344). Cases were divided into three manifestation groups (G1:0-4.9 yr, G2:5-9.9 yr, and G3: 10-20 yr). Furthermore, growth data of 540 children with diabetes were compared with controls (n = 134 249) in pre-, peri-, and post-onset intervals (interval: 1 6). Also, correlation of age at onset and body mass index (BMI) standard deviation score (SDS) at this point of time were examined. RESULTS: Cases had significantly higher SDSs for birth weight when compared with controls (boys: p = 0.007, girls: p = 0.002). Children with early manifestation had the highest mean of birth weight SDS (G1>G2>G3), (p = 0.22, adjusted r(2) = 0.001). BMI SDS trend curves of cases are slightly higher compared with those of the healthy controls. This was only significant in years after diagnosis (interval 6, p < 0.000). Cases did not show excessive weight gain in any of the examined intervals before the onset of diagnosis (interval 1-3). One year after diagnosis, we found an inverse correlation between age at diagnosis and BMI SDS at diabetes manifestation. The youngest children at diagnosis (G1) had the lowest BMI SDS at manifestation and vice versa (G1